39	33549120	P53 was divided into normal (IRS score 3-8) and abnormal (IRS 0-2 or 9-12), with both strong, diffuse positivity and complete negativity considered as evidence of a P53 mutation.	('mutation', 'Var', (169, 177))	('P53', 'Gene', (0, 3))	('P53', 'Gene', (165, 168))	('P53', 'Gene', '7157', (0, 3))	('P53', 'Gene', '7157', (165, 168))
132	33549120	Our novel hypothesis that HNF-1ss expression may portend drug resistance needs confirmation and may influence future care standards.	('HNF-1', 'Gene', (26, 31))	('drug resistance', 'MPA', (57, 72))	('HNF-1', 'Gene', '6927', (26, 31))	('expression', 'Var', (34, 44))	('drug resistance', 'biological_process', 'GO:0009315', ('57', '72'))	('drug resistance', 'Phenotype', 'HP:0020174', (57, 72))	('portend', 'Reg', (49, 56))	('drug resistance', 'biological_process', 'GO:0042493', ('57', '72'))	('influence', 'Reg', (100, 109))
159	30953521	Furthermore, EGFL7 is reported to be epigenetic modified in gastric cancer and esophageal squamous cell carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('EGFL7', 'Gene', '51162', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('esophageal squamous cell carcinoma', 'Disease', (79, 113))	('gastric cancer', 'Disease', (60, 74))	('epigenetic modified', 'Var', (37, 56))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))	('EGFL7', 'Gene', (13, 18))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (79, 113))
163	30953521	Mechanistically, histone H3 acetylation of EGFL7 promoter caused by URRCC could increase AKT signaling pathway and suppress P-AKT downstream FOXO3 signaling, enhancing cell proliferation and invasion in vitro and in vivo.	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('suppress', 'NegReg', (115, 123))	('increase', 'PosReg', (80, 88))	('cell proliferation', 'biological_process', 'GO:0008283', ('168', '186'))	('signaling pathway', 'biological_process', 'GO:0007165', ('93', '110'))	('AKT', 'Gene', '207', (89, 92))	('AKT signaling', 'biological_process', 'GO:0043491', ('89', '102'))	('P', 'Chemical', 'MESH:D010758', (124, 125))	('URRCC', 'Gene', (68, 73))	('AKT', 'Gene', (126, 129))	('cell proliferation', 'CPA', (168, 186))	('enhancing', 'PosReg', (158, 167))	('histone', 'Var', (17, 24))	('EGFL7', 'Gene', (43, 48))	('FOXO3', 'Gene', (141, 146))	('URRCC', 'Chemical', '-', (68, 73))	('signaling', 'biological_process', 'GO:0023052', ('147', '156'))	('EGFL7', 'Gene', '51162', (43, 48))	('invasion', 'CPA', (191, 199))	('histone H3 acetylation', 'biological_process', 'GO:0043966', ('17', '39'))	('AKT', 'Gene', '207', (126, 129))	('AKT', 'Gene', (89, 92))	('FOXO3', 'Gene', '2309', (141, 146))
217	30953521	The chromatin was immunoprecipitated using an anti-acetyl-histone H3 or anti-acetyl-histone H4 antibody, or anti-FOXO3 antibody.	('antibody', 'cellular_component', 'GO:0042571', ('95', '103'))	('antibody', 'cellular_component', 'GO:0019815', ('119', '127'))	('antibody', 'cellular_component', 'GO:0042571', ('119', '127'))	('FOXO3', 'Gene', (113, 118))	('antibody', 'cellular_component', 'GO:0019815', ('95', '103'))	('acetyl-histone', 'Chemical', '-', (51, 65))	('FOXO3', 'Gene', '2309', (113, 118))	('chromatin', 'cellular_component', 'GO:0000785', ('4', '13'))	('antibody', 'cellular_component', 'GO:0019814', ('119', '127'))	('antibody', 'molecular_function', 'GO:0003823', ('119', '127'))	('antibody', 'cellular_component', 'GO:0019814', ('95', '103'))	('anti-acetyl-histone', 'Var', (72, 91))	('antibody', 'molecular_function', 'GO:0003823', ('95', '103'))	('acetyl-histone', 'Chemical', '-', (77, 91))
228	30953521	To search for the potential lncRNAs involved in ccRCC progression, we systematically analyzed the dis-regulated lncRNAs expression profiles of ccRCC tissues versus matched normal kidney tissues using two published GEO DataSets (GSE46699 and GSE53757).	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('S', 'Chemical', 'MESH:D013455', (229, 230))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('RCC', 'Disease', (50, 53))	('S', 'Chemical', 'MESH:D013455', (242, 243))	('ccRCC', 'Phenotype', 'HP:0006770', (143, 148))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('S', 'Chemical', 'MESH:D013455', (222, 223))	('GSE46699', 'Var', (228, 236))
230	30953521	We computed the intersection between the result sets of these two datasets through heatmap analysis and focused on 3 potential lncRNAs (AK026225, BX649059 and AK055783) whose expression increased among top 50 lncRNAs that up-regulated in ccRCC tissues compared to paired normal renal tissues (Additional file 3: Figure S1B and C).	('expression', 'MPA', (175, 185))	('ccRCC', 'Phenotype', 'HP:0006770', (238, 243))	('up-regulated', 'PosReg', (222, 234))	('RCC', 'Disease', (240, 243))	('S', 'Chemical', 'MESH:D013455', (319, 320))	('RCC', 'Disease', 'MESH:C538614', (240, 243))	('AK055783', 'Var', (159, 167))	('RCC', 'Phenotype', 'HP:0005584', (240, 243))
231	30953521	The expression of these 3 lncRNAs was validated using qRT-PCR analysis and the outcome showed that only BX649059 expression was dramatically higher in 20 ccRCC tissues compared to paired noncancerous renal tissues (Fig.	('expression', 'MPA', (113, 123))	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('ccRCC', 'Phenotype', 'HP:0006770', (154, 159))	('RCC', 'Disease', (156, 159))	('P', 'Chemical', 'MESH:D010758', (58, 59))	('noncancerous renal tissues', 'Disease', (187, 213))	('higher', 'PosReg', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('BX649059', 'Var', (104, 112))	('noncancerous renal tissues', 'Disease', 'MESH:D007674', (187, 213))
234	30953521	However, the other two lncRNAs (AK026225 and AK055783) seemed to be no differences between ccRCC tissues and paired noncancerous renal tissues (Additional file 3: Figure S1D).	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('noncancerous renal tissues', 'Disease', 'MESH:D007674', (116, 142))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('RCC', 'Disease', (93, 96))	('S', 'Chemical', 'MESH:D013455', (170, 171))	('AK026225', 'Var', (32, 40))	('noncancerous renal tissues', 'Disease', (116, 142))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('AK055783', 'Var', (45, 53))
235	30953521	Moreover, the transcript level of BX649059 was reproducibly upregulated in 96 ccRCC tissues compared to 25 unpaired normal renal tissues (Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('transcript level', 'MPA', (14, 30))	('upregulated', 'PosReg', (60, 71))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('BX649059', 'Var', (34, 42))
236	30953521	Therefore, we named BX649059 as LncRNA-URRCC (up-regulation in clear cell renal cell carcinoma).	('regulation', 'biological_process', 'GO:0065007', ('49', '59'))	('up-regulation', 'PosReg', (46, 59))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (63, 94))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (74, 94))	('URRCC', 'Chemical', '-', (39, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('BX649059', 'Var', (20, 28))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (63, 94))	('clear cell renal cell carcinoma', 'Disease', (63, 94))
246	30953521	In the univariate analysis, high URRCC expression in tumors (hazard ratio, HR = 2.59; 95% confidence interval, CI = 1.46-4.33; p = 0.001), Tumor size (HR = 1.59; 95%CI = 1.44-2.74; p = 0.035), T stage (HR = 1.42; 95%CI = 1.25-2.68; p = 0.038) and metastasis (HR = 1.47; 95%CI = 1.05-1.86; p = 0.026) was remarkably correlated with overall survival (Additional file 6: Table S5).	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('overall', 'MPA', (331, 338))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('URRCC', 'Chemical', '-', (33, 38))	('correlated', 'Reg', (315, 325))	('URRCC', 'Gene', (33, 38))	('Tumor', 'Disease', 'MESH:D009369', (139, 144))	('Tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('high', 'Var', (28, 32))	('S', 'Chemical', 'MESH:D013455', (374, 375))	('Tumor', 'Disease', (139, 144))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('tumors', 'Disease', (53, 59))	('metastasis', 'CPA', (247, 257))
251	30953521	Preliminary experiments showed that knocking down the expression of URRCC could inhibit the proliferation and invasion of 786-O cells (Additional file 7: Figure S2C and D).	('invasion of 786-O cells', 'CPA', (110, 133))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('inhibit', 'NegReg', (80, 87))	('S', 'Chemical', 'MESH:D013455', (161, 162))	('knocking down', 'Var', (36, 49))	('URRCC', 'Chemical', '-', (68, 73))	('URRCC', 'Gene', (68, 73))
252	30953521	Then we established to knock down URRCC with sh-URRCC in human A498 cells.	('knock', 'Var', (23, 28))	('URRCC', 'Gene', (34, 39))	('A498', 'CellLine', 'CVCL:1056', (63, 67))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('URRCC', 'Chemical', '-', (34, 39))	('human', 'Species', '9606', (57, 62))	('URRCC', 'Chemical', '-', (48, 53))
253	30953521	2a and b, knocked-down URRCC dramatically decreased the growth speed of A498 cells, when compared with control cells through MTT assay.	('decreased', 'NegReg', (42, 51))	('URRCC', 'Gene', (23, 28))	('A498', 'CellLine', 'CVCL:1056', (72, 76))	('growth speed of A498 cells', 'CPA', (56, 82))	('URRCC', 'Chemical', '-', (23, 28))	('knocked-down', 'Var', (10, 22))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('MTT', 'Chemical', 'MESH:C070243', (125, 128))
254	30953521	In addition, transwell invasion assay also demonstrated that sh-URRCC attenuated invasive capability of A498 cells than that of control cells (Fig.	('attenuated', 'NegReg', (70, 80))	('invasive capability of A498 cells', 'CPA', (81, 114))	('A498', 'CellLine', 'CVCL:1056', (104, 108))	('sh-URRCC', 'Var', (61, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('URRCC', 'Chemical', '-', (64, 69))
258	30953521	Consistently, overexpressed URRCC also induced invasion of OSRC-2 cells through transwell invasion assay (Fig.	('overexpressed', 'Var', (14, 27))	('OSRC-2', 'CellLine', 'CVCL:1901', (59, 65))	('URRCC', 'Gene', (28, 33))	('transwell invasion assay', 'CPA', (80, 104))	('invasion of OSRC-2 cells', 'CPA', (47, 71))	('induced', 'Reg', (39, 46))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('URRCC', 'Chemical', '-', (28, 33))
263	30953521	3a showed, URRCC knocked-down effectively inhibited tumor proliferation, as revealed by measuring tumor mass.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('URRCC', 'Gene', (11, 16))	('URRCC', 'Chemical', '-', (11, 16))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('knocked-down', 'Var', (17, 29))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('inhibited', 'NegReg', (42, 51))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
266	30953521	A dramatic reduction of metastatic luciferase expression in lungs of A498/sh-URRCC mice was detected by In Vivo Imaging Systems (IVIS) compared with sh-control group (Fig.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('reduction', 'NegReg', (11, 20))	('A498/sh-URRCC', 'Var', (69, 82))	('A498', 'CellLine', 'CVCL:1056', (69, 73))	('S', 'Chemical', 'MESH:D013455', (132, 133))	('mice', 'Species', '10090', (83, 87))	('metastatic luciferase', 'Enzyme', (24, 45))	('URRCC', 'Chemical', '-', (77, 82))	('S', 'Chemical', 'MESH:D013455', (120, 121))	('expression', 'MPA', (46, 56))
267	30953521	HE analysis also showed a decrease of pulmonary metastasis in A498/sh-URRCC group compared with sh-control group (Fig.	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('URRCC', 'Chemical', '-', (70, 75))	('decrease', 'NegReg', (26, 34))	('A498/sh-URRCC', 'Var', (62, 75))	('pulmonary metastasis', 'Disease', (38, 58))	('A498', 'CellLine', 'CVCL:1056', (62, 66))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (38, 58))
269	30953521	In addition, IHC demonstrated the decreased expression of Ki67 from sh-URRCC group compared with sh-control group, while the increased expression of Ki67 from oe-URRCC group compared with the mock group in pulmonary metastasis (Fig.	('expression', 'MPA', (44, 54))	('increased', 'PosReg', (125, 134))	('pulmonary metastasis', 'Disease', (206, 226))	('decreased', 'NegReg', (34, 43))	('URRCC', 'Chemical', '-', (162, 167))	('sh-URRCC', 'Var', (68, 76))	('Ki67', 'Chemical', '-', (58, 62))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (206, 226))	('expression', 'MPA', (135, 145))	('URRCC', 'Chemical', '-', (71, 76))	('Ki67', 'Gene', (58, 62))	('Ki67', 'Var', (149, 153))	('Ki67', 'Chemical', '-', (149, 153))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
274	30953521	Among them, JMY and EGFL7 were markedly decreased by knocking down URRCC at mRNA expression (Fig.	('EGFL7', 'Gene', '51162', (20, 25))	('JMY', 'Gene', '133746', (12, 15))	('URRCC', 'Chemical', '-', (67, 72))	('URRCC', 'Gene', (67, 72))	('JMY', 'Gene', (12, 15))	('knocking down', 'Var', (53, 66))	('EGFL7', 'Gene', (20, 25))	('decreased', 'NegReg', (40, 49))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
276	30953521	qRT-PCR and WB analysis revealed that sh-URRCC dramatically decreased the mRNA and protein levels of EGFL7 in A498 and OSRC-2 cells (Fig.	('URRCC', 'Chemical', '-', (41, 46))	('decreased', 'NegReg', (60, 69))	('EGFL7', 'Gene', (101, 106))	('A498', 'CellLine', 'CVCL:1056', (110, 114))	('P', 'Chemical', 'MESH:D010758', (4, 5))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('EGFL7', 'Gene', '51162', (101, 106))	('OSRC-2', 'CellLine', 'CVCL:1901', (119, 125))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('sh-URRCC', 'Var', (38, 46))
284	30953521	Meanwhile, ChIP assay confirmed that sh-URRCC caused a significant decreased level of histone H3 acetylation, but not histone H4 across EGFL7 promoter region (- 2000 to + 50 bp relative to Transcriptional start site (TSS)) in A498 cells (Fig.	('acetylation', 'MPA', (97, 108))	('EGFL7', 'Gene', '51162', (136, 141))	('histone H3 acetylation', 'biological_process', 'GO:0043966', ('86', '108'))	('sh-URRCC', 'Var', (37, 45))	('P', 'Chemical', 'MESH:D010758', (14, 15))	('URRCC', 'Chemical', '-', (40, 45))	('EGFL7', 'Gene', (136, 141))	('histone H3', 'Protein', (86, 96))	('decreased', 'NegReg', (67, 76))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('A498', 'CellLine', 'CVCL:1056', (226, 230))
286	30953521	Conversely, oe-URRCC increased histone H3 acetylation level across EGFL7 promoter region in OSRC-2 cells (- 2000 to + 50 bp relative to TSS) (Fig.	('histone H3 acetylation level', 'MPA', (31, 59))	('histone H3 acetylation', 'biological_process', 'GO:0043966', ('31', '53'))	('increased', 'PosReg', (21, 30))	('- 2000', 'Var', (106, 112))	('URRCC', 'Chemical', '-', (15, 20))	('OSRC-2', 'CellLine', 'CVCL:1901', (92, 98))	('EGFL7', 'Gene', (67, 72))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('EGFL7', 'Gene', '51162', (67, 72))
288	30953521	Interestingly, aberrant enrichment of the H3K27ac histone mark were found across the promoter region of EGFL7 (Fig.	('EGFL7', 'Gene', '51162', (104, 109))	('EGFL7', 'Gene', (104, 109))	('H3K27ac', 'Var', (42, 49))
292	30953521	Aberrant AKT signaling pathway played an important role in ccRCC and our group constantly concentrated on the studies of AKT signaling pathway.	('AKT', 'Gene', '207', (9, 12))	('signaling pathway', 'biological_process', 'GO:0007165', ('125', '142'))	('signaling pathway', 'biological_process', 'GO:0007165', ('13', '30'))	('Aberrant', 'Var', (0, 8))	('AKT signaling', 'biological_process', 'GO:0043491', ('121', '134'))	('AKT signaling', 'biological_process', 'GO:0043491', ('9', '22'))	('AKT', 'Gene', (121, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('AKT', 'Gene', (9, 12))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('AKT', 'Gene', '207', (121, 124))
296	30953521	Contrarily, oe-URRCC could enhance EGFL7/P-AKT signaling pathway in both cell lines while decrease the FOXO3 expression (Fig.	('expression', 'MPA', (109, 119))	('oe-URRCC', 'Var', (12, 20))	('EGFL7', 'Gene', (35, 40))	('AKT', 'Gene', '207', (43, 46))	('signaling pathway', 'biological_process', 'GO:0007165', ('47', '64'))	('EGFL7', 'Gene', '51162', (35, 40))	('enhance', 'PosReg', (27, 34))	('URRCC', 'Chemical', '-', (15, 20))	('AKT signaling', 'biological_process', 'GO:0043491', ('43', '56'))	('P', 'Chemical', 'MESH:D010758', (41, 42))	('FOXO3', 'Gene', (103, 108))	('AKT', 'Gene', (43, 46))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('decrease', 'NegReg', (90, 98))	('FOXO3', 'Gene', '2309', (103, 108))
300	30953521	Altogether, our data suggested that URRCC could enhance renal cancer cell proliferation and invasion through EGFL7/P-AKT/FOXO3 signaling.	('AKT', 'Gene', '207', (117, 120))	('FOXO3', 'Gene', '2309', (121, 126))	('EGFL7', 'Gene', '51162', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('signaling', 'biological_process', 'GO:0023052', ('127', '136'))	('invasion', 'CPA', (92, 100))	('AKT', 'Gene', (117, 120))	('URRCC', 'Var', (36, 41))	('renal cancer', 'Disease', (56, 68))	('enhance', 'PosReg', (48, 55))	('renal cancer', 'Disease', 'MESH:D007680', (56, 68))	('FOXO3', 'Gene', (121, 126))	('URRCC', 'Chemical', '-', (36, 41))	('P', 'Chemical', 'MESH:D010758', (115, 116))	('EGFL7', 'Gene', (109, 114))	('renal cancer', 'Phenotype', 'HP:0009726', (56, 68))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('cell proliferation', 'biological_process', 'GO:0008283', ('69', '87'))
306	30953521	6d), which was correspond with the Kaplan-Meier survival analysis from TCGA KIRC datasets that ccRCC patients with high FOXO3 expression had longer survival times than patients with low FOXO3 levels (Log-rank test, p < 0.001, Fig.	('high', 'Var', (115, 119))	('RCC', 'Disease', (97, 100))	('FOXO3', 'Gene', '2309', (186, 191))	('patients', 'Species', '9606', (101, 109))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('FOXO3', 'Gene', (120, 125))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('survival times', 'CPA', (148, 162))	('FOXO3', 'Gene', '2309', (120, 125))	('longer', 'PosReg', (141, 147))	('patients', 'Species', '9606', (168, 176))	('low FOXO3 levels', 'Phenotype', 'HP:0031037', (182, 198))	('FOXO3', 'Gene', (186, 191))
308	30953521	In addition, qRT-PCR assays showed there is a negative correlation between URRCC and FOXO3 in mRNA level in cell lines (Additional file 13: Figure S4B) and knockdown of FOXO3 could enhance the mRNA expression of URRCC and EGFL7, while over-expression of FOXO3 could down-regulate the mRNA expression of URRCC and EGFL7 (Additional file 13: Figure S4C-F).	('S', 'Chemical', 'MESH:D013455', (347, 348))	('knockdown', 'Var', (156, 165))	('FOXO3', 'Gene', (254, 259))	('RCC', 'Phenotype', 'HP:0005584', (305, 308))	('mRNA expression', 'MPA', (193, 208))	('EGFL7', 'Gene', (313, 318))	('URRCC', 'Protein', (212, 217))	('enhance', 'PosReg', (181, 188))	('FOXO3', 'Gene', '2309', (169, 174))	('EGFL7', 'Gene', '51162', (313, 318))	('URRCC', 'Chemical', '-', (75, 80))	('FOXO3', 'Gene', '2309', (254, 259))	('S', 'Chemical', 'MESH:D013455', (147, 148))	('down-regulate', 'NegReg', (266, 279))	('FOXO3', 'Gene', (85, 90))	('P', 'Chemical', 'MESH:D010758', (17, 18))	('mRNA expression', 'MPA', (284, 299))	('URRCC', 'Chemical', '-', (303, 308))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('EGFL7', 'Gene', (222, 227))	('RCC', 'Phenotype', 'HP:0005584', (214, 217))	('FOXO3', 'Gene', '2309', (85, 90))	('URRCC', 'Chemical', '-', (212, 217))	('EGFL7', 'Gene', '51162', (222, 227))	('FOXO3', 'Gene', (169, 174))
310	30953521	As figures shown, knocked-down URRCC dramatically induced the apoptosis of A498 cells, while overexpressed URRCC decreased apoptosis of A498 cells (Additional file 13: Figure S4G and S4H).	('URRCC', 'Chemical', '-', (107, 112))	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('URRCC', 'Chemical', '-', (31, 36))	('URRCC', 'Gene', (31, 36))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('apoptosis', 'biological_process', 'GO:0006915', ('123', '132'))	('S', 'Chemical', 'MESH:D013455', (183, 184))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('apoptosis', 'CPA', (62, 71))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('induced', 'PosReg', (50, 57))	('knocked-down', 'Var', (18, 30))	('S', 'Chemical', 'MESH:D013455', (175, 176))	('apoptosis', 'biological_process', 'GO:0097194', ('123', '132'))	('A498', 'CellLine', 'CVCL:1056', (136, 140))	('A498', 'CellLine', 'CVCL:1056', (75, 79))
312	30953521	In this study, we validated a new identified lncRNA-URRCC serving as a tumor-inducer in renal cancer progression through a combined bioinformatics and experimental approach.	('URRCC', 'Chemical', '-', (52, 57))	('renal cancer', 'Disease', 'MESH:D007680', (88, 100))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('lncRNA-URRCC', 'Var', (45, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('renal cancer', 'Disease', (88, 100))	('tumor', 'Disease', (71, 76))	('renal cancer', 'Phenotype', 'HP:0009726', (88, 100))
327	30953521	The differential expression of EGFL7 in several cancers was associated with epigenetic modification, involving malignant pleural mesothelioma, gastric cancer, and esophageal squamous cell carcinoma.	('EGFL7', 'Gene', (31, 36))	('EGFL7', 'Gene', '51162', (31, 36))	('gastric cancer', 'Disease', (143, 157))	('malignant pleural mesothelioma', 'Disease', (111, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (174, 197))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (163, 197))	('gastric cancer', 'Disease', 'MESH:D013274', (143, 157))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancers', 'Disease', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (111, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('associated', 'Reg', (60, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (143, 157))	('epigenetic modification', 'Var', (76, 99))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (121, 141))	('esophageal squamous cell carcinoma', 'Disease', (163, 197))	('cancers', 'Disease', 'MESH:D009369', (48, 55))
328	30953521	Here, we identified that knocked down URRCC potently abrogated EGFL7 expression and blunted cell growth and invasion while overexpressed URRCC markedly elevated EGFL7 expression and enhanced cell growth and invasion.	('EGFL7', 'Gene', '51162', (161, 166))	('blunted', 'NegReg', (84, 91))	('elevated', 'PosReg', (152, 160))	('EGFL7', 'Gene', '51162', (63, 68))	('cell growth', 'biological_process', 'GO:0016049', ('92', '103'))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('knocked down', 'Var', (25, 37))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('enhanced', 'PosReg', (182, 190))	('expression', 'MPA', (69, 79))	('abrogated', 'NegReg', (53, 62))	('cell growth', 'biological_process', 'GO:0016049', ('191', '202'))	('URRCC', 'Chemical', '-', (137, 142))	('EGFL7', 'Gene', (161, 166))	('URRCC', 'Chemical', '-', (38, 43))	('EGFL7', 'Gene', (63, 68))	('expression', 'MPA', (167, 177))	('URRCC', 'Gene', (38, 43))
334	30953521	FOXO3 deregulation plays essential roles in the development of cancer and thus FOXO3 has been classified as a tumor suppressor.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('deregulation', 'Var', (6, 18))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('FOXO3', 'Gene', (0, 5))	('FOXO3', 'Gene', (79, 84))	('FOXO3', 'Gene', '2309', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('FOXO3', 'Gene', '2309', (79, 84))	('tumor suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('cancer', 'Disease', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
335	30953521	Previous studies have demonstrated that FOXO3 could repress lncRNA and be promoted by circular RNA or Foxo3 pseudogene.	('Foxo3', 'Gene', '2309', (102, 107))	('promoted', 'PosReg', (74, 82))	('RNA', 'cellular_component', 'GO:0005562', ('95', '98'))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('FOXO3', 'Gene', (40, 45))	('Foxo3', 'Gene', (102, 107))	('FOXO3', 'Gene', '2309', (40, 45))	('repress', 'NegReg', (52, 59))	('pseudogene', 'Var', (108, 118))	('lncRNA', 'MPA', (60, 66))
340	30953521	In summary, our research reveals that URRCC functions as a tumor-inducer to control the ccRCC progression via modulating URRCC/EGFL7/P-AKT/FOXO3 positive feedback loop and cause cascading effects in ccRCC.	('FOXO3', 'Gene', '2309', (139, 144))	('tumor', 'Disease', (59, 64))	('EGFL7', 'Gene', '51162', (127, 132))	('P', 'Chemical', 'MESH:D010758', (133, 134))	('AKT', 'Gene', (135, 138))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('RCC', 'Disease', (90, 93))	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('RCC', 'Disease', (201, 204))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (199, 204))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('AKT', 'Gene', '207', (135, 138))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('modulating', 'Var', (110, 120))	('URRCC', 'Chemical', '-', (121, 126))	('RCC', 'Disease', (40, 43))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('FOXO3', 'Gene', (139, 144))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('URRCC', 'Chemical', '-', (38, 43))	('EGFL7', 'Gene', (127, 132))
350	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))
352	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'))
360	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))
361	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))	('men', 'Species', '9606', (142, 145))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('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))
362	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))
372	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))	('cell cycle regulation', 'CPA', (382, 403))	('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))	('deletion', 'Var', (73, 81))	('proliferation', 'CPA', (405, 418))
375	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))
376	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))
381	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))
385	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))
389	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'))
391	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))	('Deregulation', 'Var', (0, 12))	('RNF20', 'Gene', (111, 116))	('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))
392	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'))
393	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))	('breast', 'Disease', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('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))	('tumors', 'Disease', (67, 73))	('reported', 'Reg', (47, 55))	('colorectal', 'Disease', (90, 100))
395	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))
415	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'))
417	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))
419	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))
420	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))
424	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))	('K120', 'Chemical', '-', (96, 100))	('H2Bub1', 'Gene', '8349', (86, 92))	('facilitates', 'PosReg', (110, 121))	('H2Bub1', 'Gene', (86, 92))	('K120', 'Var', (96, 100))	('K79', 'Gene', (147, 150))	('transcription', 'biological_process', 'GO:0006351', ('171', '184'))	('K79', 'Gene', '338785', (147, 150))
428	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))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('MCF-7', 'CellLine', 'CVCL:0031', (104, 109))	('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))
433	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))
435	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))
436	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))
437	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))
438	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))
440	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))	('leukemia', 'Disease', 'MESH:D007938', (146, 154))	('MLL', 'Gene', '4297', (28, 31))	('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))
441	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))
444	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))
453	29934362	Interestingly, genes encoding polycomb group protein BMI-1 and EZH2 are found to be amplified in metastatic prostate cancer, with a concomitant increase in levels of H2Aub1 and H3K27me3.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('EZH2', 'Gene', '2146', (63, 67))	('polycomb group protein BMI-1', 'Gene', (30, 58))	('prostate cancer', 'Disease', 'MESH:D011471', (108, 123))	('H3K27me3', 'Var', (177, 185))	('levels', 'MPA', (156, 162))	('prostate cancer', 'Phenotype', 'HP:0012125', (108, 123))	('EZH2', 'Gene', (63, 67))	('H2A', 'Gene', '8337', (166, 169))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('amplified', 'PosReg', (84, 93))	('H2A', 'Gene', (166, 169))	('polycomb group protein BMI-1', 'Gene', '648', (30, 58))	('increase', 'PosReg', (144, 152))	('prostate cancer', 'Disease', (108, 123))
455	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))
458	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))	('H2Bub1', 'Gene', '8349', (107, 113))	('H460', 'CellLine', 'CVCL:0459', (41, 45))	('trimethylation', 'MPA', (192, 206))	('decrease', 'NegReg', (165, 173))	('lung cancer A549', 'Disease', 'MESH:D008175', (12, 28))	('H1299', 'CellLine', 'CVCL:0060', (30, 35))	('suppression', 'NegReg', (92, 103))	('K79', 'Gene', (188, 191))	('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))
459	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))	('invasion', 'CPA', (154, 162))	('cellular signaling pathways', 'Pathway', (87, 114))	('proliferation', 'CPA', (128, 141))	('H2Bub1', 'Gene', (65, 71))	('RNF20', 'Gene', (26, 31))	('migration', 'CPA', (143, 152))	('enhanced', 'PosReg', (119, 127))
461	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))
476	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))	('activate', 'PosReg', (86, 94))	('SREBP', 'Gene', (174, 179))	('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))
483	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))
488	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))	('potentiates', 'PosReg', (26, 37))	('NBS1', 'Gene', (21, 25))	('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'))
492	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'))	('ionizing radiation', 'CPA', (50, 68))	('mitomycin C', 'Chemical', 'MESH:D016685', (137, 148))	('Silencing', 'Var', (0, 9))	('DNA repair', 'biological_process', 'GO:0006281', ('176', '186'))	('neocarzinostatin', 'Chemical', 'MESH:D009353', (115, 131))	('men', 'Species', '9606', (43, 46))	('camptothecin', 'Chemical', 'MESH:D002166', (101, 113))	('si/shRNA', 'Var', (22, 30))	('RNF20', 'Gene', (13, 18))	('augmented', 'PosReg', (40, 49))	('men', 'Species', '9606', (168, 171))
493	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))	('DSB', 'Disease', (164, 167))	('H2B', 'Gene', (35, 38))	('silencing', 'Var', (43, 52))	('H2B', 'Gene', '8349', (157, 160))	('ubiquitinating', 'MPA', (142, 156))	('H2B', 'Gene', '8349', (35, 38))	('RNF20', 'Gene', (123, 128))
494	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'))
504	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))
510	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'))
515	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'))
591	28757600	The 44 ccRCCs were categorized into three groups according to the RTC value, which included groups of RTC <=0.6, 0.6< RTC <1, and RTC >=1.	('RCC', 'Disease', 'MESH:C538614', (9, 12))	('RCC', 'Disease', (9, 12))	('0.6<', 'Var', (113, 117))	('RTC >=1', 'Gene', '8634', (130, 137))	('RTC <1', 'Gene', (118, 124))	('RTC <1', 'Gene', '8634', (118, 124))	('RTC <=0.6', 'Var', (102, 111))	('RTC >=1', 'Gene', (130, 137))
593	28757600	Significant difference was noted in MVD1 in the group of RTC <=0.6 with the other groups (F=7.98, p<0.01), while MVD1 did not differ significantly from the groups of 0.6< RTC <1 and RTC >=1.	('RTC >=1', 'Gene', '8634', (182, 189))	('RTC <1', 'Gene', (171, 177))	('RTC <1', 'Gene', '8634', (171, 177))	('RTC >=1', 'Gene', (182, 189))	('MVD1', 'Gene', '4597', (36, 40))	('MVD1', 'Gene', '4597', (113, 117))	('MVD1', 'Gene', (36, 40))	('RTC <=0.6', 'Var', (57, 66))	('MVD1', 'Gene', (113, 117))
687	30681558	Immunohistochemical analysis revealed positive for AE1/AE3, PAX-8, Vimentin, CA 9, CD 10, EMA, and Ki-67 (Fig.	('PAX-8', 'Gene', (60, 65))	('AE1', 'Gene', '6521', (51, 54))	('AE3', 'Gene', (55, 58))	('CD 10', 'Gene', (83, 88))	('AE1', 'Gene', (51, 54))	('positive', 'Reg', (38, 46))	('Vimentin', 'cellular_component', 'GO:0045098', ('67', '75'))	('CD 10', 'molecular_function', 'GO:0004245', ('83', '88'))	('PAX-8', 'Gene', '7849', (60, 65))	('AE3', 'Gene', '6508', (55, 58))	('CA 9', 'Gene', (77, 81))	('Vimentin', 'Gene', (67, 75))	('Vimentin', 'cellular_component', 'GO:0045099', ('67', '75'))	('CA 9', 'Gene', '768', (77, 81))	('CD 10', 'Gene', '4311', (83, 88))	('Vimentin', 'Gene', '7431', (67, 75))	('Ki-67', 'Var', (99, 104))
703	30681558	Subsequently these changes lead to the development of RCC by angiogenesis.	('changes', 'Var', (19, 26))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('angiogenesis', 'CPA', (61, 73))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('lead to', 'Reg', (27, 34))	('angiogenesis', 'biological_process', 'GO:0001525', ('61', '73'))
792	32737333	indicated that P4HA3 is upregulated in gastric cancer and epigenetically activated by slug.	('slug', 'Gene', (86, 90))	('gastric cancer', 'Disease', (39, 53))	('P4HA3', 'Gene', '283208', (15, 20))	('P4HA3', 'Gene', (15, 20))	('gastric cancer', 'Disease', 'MESH:D013274', (39, 53))	('slug', 'Gene', '6591', (86, 90))	('gastric cancer', 'Phenotype', 'HP:0012126', (39, 53))	('upregulated', 'PosReg', (24, 35))	('epigenetically activated', 'Var', (58, 82))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
840	33217850	The hepatitis virus test showed positivity for hepatitis B surface antigen (HBsAg), but he was negative for HCV.	('hepatitis', 'Phenotype', 'HP:0012115', (4, 13))	('hepatitis B', 'Disease', 'MESH:D006509', (47, 58))	('hepatitis B', 'Disease', (47, 58))	('hepatitis', 'Phenotype', 'HP:0012115', (47, 56))	('positivity', 'Var', (32, 42))
842	33217850	The clinical presumptive diagnoses were RCCC (T1N0M0) and HCC (T2N0M0).	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('HCC', 'Disease', (58, 61))	('RCC', 'Disease', (40, 43))	('T2N0M0', 'Var', (63, 69))
848	33217850	The immunohistochemistry results of the kidney tumor were as follows: CD10 (+), CK7 (-), EMA (+), and vimentin (+).	('kidney tumor', 'Phenotype', 'HP:0009726', (40, 52))	('vimentin', 'cellular_component', 'GO:0045099', ('102', '110'))	('kidney tumor', 'Disease', 'MESH:D007680', (40, 52))	('vimentin', 'Gene', (102, 110))	('CK7', 'Gene', (80, 83))	('CD10', 'molecular_function', 'GO:0004245', ('70', '74'))	('CK7', 'Gene', '3855', (80, 83))	('vimentin', 'Gene', '7431', (102, 110))	('vimentin', 'cellular_component', 'GO:0045098', ('102', '110'))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('kidney tumor', 'Disease', (40, 52))	('CD10 (+', 'Var', (70, 77))
849	33217850	Based on the radiological imaging and pathological results, neither regional lymph node nor distant lymph node metastasis was found, and the TNM (tumor-node-metastasis) classification was T1N0M0 for RCCC and T2aN0M0 for PCCCL.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('PCCCL', 'Chemical', '-', (220, 225))	('T2aN0M0', 'Var', (208, 215))	('tumor', 'Disease', (146, 151))	('RCC', 'Disease', (199, 202))	('T1N0M0', 'Var', (188, 194))	('RCC', 'Disease', 'MESH:C538614', (199, 202))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
859	33217850	The molecular mechanism of MPMN, however, remains unclear, and some putative risk factors have been implicated in its pathogenesis, including older age, exposure to chemotherapy and radiotherapy, genetic mutation, and a history of tobacco and alcohol use, and several shared pathways are likely to contribute to the development of MPMNs.	('tobacco', 'Species', '4097', (231, 238))	('MPMN', 'Disease', (27, 31))	('alcohol', 'Chemical', 'MESH:D000438', (243, 250))	('contribute', 'Reg', (298, 308))	('genetic mutation', 'Var', (196, 212))	('pathogenesis', 'biological_process', 'GO:0009405', ('118', '130'))	('alcohol use', 'Phenotype', 'HP:0030955', (243, 254))	('implicated', 'Reg', (100, 110))
874	33217850	This patient received RFA for adrenal metastasis, and the tumor was completely ablated and devascularized, with the disappearance of tumor enhancement 3 months after RFA (Fig.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('patient', 'Species', '9606', (5, 12))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('disappearance', 'NegReg', (116, 129))	('RFA', 'Var', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', (133, 138))
886	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))
903	31481087	Overexpression of G3BP1 has been implicated in defective signaling pathways seen several types of human tumors including gastric cancer, breast cancer, and RCC.	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('RCC', 'Disease', (156, 159))	('tumors', 'Disease', (104, 110))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('implicated', 'Reg', (33, 43))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('signaling pathways', 'Pathway', (57, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('defective', 'NegReg', (47, 56))	('expression', 'Species', '29278', (4, 14))	('gastric cancer', 'Disease', (121, 135))	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Disease', (137, 150))	('G3BP1', 'Gene', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('human', 'Species', '9606', (98, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))
904	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))
912	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))
915	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))
930	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))
972	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))
973	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))	('metastatic', 'CPA', (84, 94))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('involved', 'Reg', (72, 80))
979	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))
982	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))
983	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))
985	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))
986	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))
988	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'))
991	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', (70, 73))	('p65', 'Gene', '5970', (70, 73))	('p65', 'Gene', '5970', (117, 120))	('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))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('p65', 'Gene', (117, 120))	('YBX1', 'Gene', (4, 8))
994	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))
995	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))
996	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))
1001	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))
1014	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))
1015	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))	('RCC tumor', 'Disease', 'MESH:C538614', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('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'))
1019	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))	('suppressed', 'NegReg', (96, 106))	('tumor', 'Disease', (37, 42))	('G3BP1', 'Gene', (90, 95))	('mice', 'Species', '10090', (131, 135))
1025	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))
1026	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))
1030	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.	('knockdown', 'Var', (35, 44))	('YBX1', 'Gene', (48, 52))	('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))
1033	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))	('migration', 'CPA', (67, 76))	('RCC', 'Disease', (43, 46))	('knockdown', 'Var', (14, 23))	('cell proliferation', 'biological_process', 'GO:0008283', ('47', '65'))	('inhibited', 'NegReg', (33, 42))
1042	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))
1044	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))	('SPP1', 'Gene', (44, 48))	('invasion', 'CPA', (139, 147))	('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))
1049	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'))
1053	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))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('p65', 'Gene', '5970', (129, 132))	('RCC', 'Disease', (151, 154))	('p65', 'Gene', '5970', (82, 85))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('knockdown', 'Var', (24, 33))	('Ser536', 'Chemical', '-', (87, 93))	('Ser', 'cellular_component', 'GO:0005790', ('87', '90'))
1056	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))
1058	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))
1071	29050255	We found that high granulocyte colony-stimulating factor expression was associated with diminished recurrence-free survival (P<0.001).	('granulocyte colony-stimulating factor', 'Gene', (19, 56))	('recurrence-free survival', 'CPA', (99, 123))	('high', 'Var', (14, 18))	('granulocyte colony-stimulating factor', 'Gene', '1440', (19, 56))	('granulocyte colony-stimulating factor', 'molecular_function', 'GO:0005130', ('19', '56'))	('diminished', 'NegReg', (88, 98))
1109	29050255	Notably, T2-T3 patients had a 65.5% RFS rate at the last follow-up, once these patients presented high G-CSF expression, their RFS rate would remarkably dropped to 34.3% (P=0.003).	('patients', 'Species', '9606', (15, 23))	('T2-T3', 'Var', (9, 14))	('RFS', 'MPA', (36, 39))	('G-CSF', 'Gene', '1440', (103, 108))	('G-CSF', 'Gene', (103, 108))	('patients', 'Species', '9606', (79, 87))
1117	29050255	As listed in Table 2, high G-CSF expression was significantly associated with worse RFS in univariate analyses (HR: 7.745, 95%CI: 2.927-20.492, P<0.001).	('G-CSF', 'Gene', (27, 32))	('high', 'Var', (22, 26))	('G-CSF', 'Gene', '1440', (27, 32))	('RFS', 'Disease', (84, 87))
1129	29050255	Furthermore, high expression of G-CSF was also associated with advanced pathologic features and high-risk group in our study.	('high', 'Var', (13, 17))	('G-CSF', 'Gene', (32, 37))	('G-CSF', 'Gene', '1440', (32, 37))	('associated', 'Reg', (47, 57))
1193	31357507	Moderate ROS levels are widely recognized to trigger cancer initiation and progression by inducing mutations and promoting genome instability, eventually activating oncogenic signaling pathways that promote cell survival, proliferation, and stress resistance.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('signaling', 'biological_process', 'GO:0023052', ('175', '184'))	('promote', 'PosReg', (199, 206))	('cell survival', 'CPA', (207, 220))	('mutations', 'Var', (99, 108))	('inducing', 'Reg', (90, 98))	('ROS', 'Chemical', 'MESH:D017382', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('proliferation', 'CPA', (222, 235))	('stress resistance', 'CPA', (241, 258))	('activating', 'Reg', (154, 164))	('promoting', 'PosReg', (113, 122))	('genome instability', 'MPA', (123, 141))	('oncogenic signaling pathways', 'Pathway', (165, 193))
1194	31357507	On the contrary, massive ROS accumulations can also limit cancer growth by causing severe oxidative damage of biomolecules, which finally can lead to cell death.	('cell death', 'CPA', (150, 160))	('oxidative damage of biomolecules', 'MPA', (90, 122))	('ROS', 'Chemical', 'MESH:D017382', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ROS', 'Protein', (25, 28))	('limit', 'NegReg', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('accumulations', 'Var', (29, 42))	('causing', 'Reg', (75, 82))	('cell death', 'biological_process', 'GO:0008219', ('150', '160'))	('cancer', 'Disease', (58, 64))	('lead to', 'Reg', (142, 149))
1209	31357507	About 90% of all ccRCCs carry mutations in the von Hippel-Lindau (VHL) tumor suppressor gene, which was originally identified in a hereditary disease called VHL syndrome.	('VHL syndrome', 'Disease', 'MESH:D006623', (157, 169))	('tumor suppressor', 'biological_process', 'GO:0051726', ('71', '87'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('71', '87'))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('hereditary disease', 'Disease', (131, 149))	('VHL syndrome', 'Disease', (157, 169))	('RCC', 'Disease', (19, 22))	('hereditary disease', 'Disease', 'MESH:D030342', (131, 149))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mutations', 'Var', (30, 39))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (47, 76))
1229	31357507	The frequently activating mutations and amplification of MET in type I pRCC enable the activation of MET/HGF signaling and its above-mentioned downstream pathways to promote cancer cell proliferation, angiogenesis, and malignant transformation.	('angiogenesis', 'CPA', (201, 213))	('signaling', 'biological_process', 'GO:0023052', ('109', '118'))	('HGF', 'Gene', '3082', (105, 108))	('mutations', 'Var', (26, 35))	('angiogenesis', 'biological_process', 'GO:0001525', ('201', '213'))	('activating', 'PosReg', (15, 25))	('HGF', 'Gene', (105, 108))	('MET', 'Gene', (57, 60))	('MET', 'Gene', '4233', (57, 60))	('malignant transformation', 'CPA', (219, 243))	('cancer', 'Disease', (174, 180))	('pRCC', 'Gene', '5546', (71, 75))	('cell proliferation', 'biological_process', 'GO:0008283', ('181', '199'))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('promote', 'PosReg', (166, 173))	('MET', 'Gene', '4233', (101, 104))	('MET', 'Gene', (101, 104))	('activation', 'PosReg', (87, 97))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('pRCC', 'Gene', (71, 75))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('amplification', 'Var', (40, 53))
1230	31357507	Frequent mutations in type II pRCC include CDKN2A silencing, SETD2 mutations, and TFE3 fusions.	('fusions', 'Var', (87, 94))	('CDKN2A', 'Gene', (43, 49))	('silencing', 'NegReg', (50, 59))	('TFE3', 'Gene', (82, 86))	('SETD2', 'Gene', (61, 66))	('pRCC', 'Gene', (30, 34))	('mutations', 'Var', (67, 76))	('CDKN2A', 'Gene', '1029', (43, 49))	('TFE3', 'Gene', '7030', (82, 86))	('pRCC', 'Gene', '5546', (30, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
1233	31357507	Furthermore, fumarate hydratase (FH) mutations are also frequently found in type II pRCC.	('pRCC', 'Gene', (84, 88))	('fumarate hydratase', 'Gene', '2271', (13, 31))	('FH', 'Gene', '2271', (33, 35))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('fumarate hydratase', 'Gene', (13, 31))	('found', 'Reg', (67, 72))	('mutations', 'Var', (37, 46))	('pRCC', 'Gene', '5546', (84, 88))
1234	31357507	The FH gene encodes a TCA cycle enzyme that catalyzes the hydration of fumarate to malate, and its deficiency causes fumarate and succinate accumulation.	('FH', 'Gene', '2271', (4, 6))	('deficiency', 'Var', (99, 109))	('fumarate', 'Chemical', 'MESH:D005650', (71, 79))	('TCA cycle', 'biological_process', 'GO:0006099', ('22', '31'))	('succinate', 'Chemical', 'MESH:D019802', (130, 139))	('causes', 'Reg', (110, 116))	('fumarate', 'Chemical', 'MESH:D005650', (117, 125))	('malate', 'Chemical', 'MESH:C030298', (83, 89))	('TCA', 'Chemical', 'MESH:D014238', (22, 25))
1235	31357507	Accumulated fumarate and succinate are believed to be able to suppress the hydroxylation of the proline residues in the ODD domain of HIFalpha, and thus FH mutations in type II pRCC also cause the stabilization of HIFalpha, similarly to ccRCC.	('pRCC', 'Gene', '5546', (177, 181))	('RCC', 'Disease', (178, 181))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('HIF', 'Gene', (214, 217))	('succinate', 'Chemical', 'MESH:D019802', (25, 34))	('HIF', 'Gene', (134, 137))	('hydroxylation of', 'MPA', (75, 91))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('fumarate', 'Chemical', 'MESH:D005650', (12, 20))	('pRCC', 'Gene', (177, 181))	('HIF', 'Gene', '405', (214, 217))	('HIF', 'Gene', '405', (134, 137))	('stabilization', 'MPA', (197, 210))	('mutations', 'Var', (156, 165))	('proline', 'Chemical', 'MESH:D011392', (96, 103))	('FH', 'Gene', '2271', (153, 155))	('RCC', 'Disease', (239, 242))	('RCC', 'Phenotype', 'HP:0005584', (239, 242))	('cause', 'Reg', (187, 192))	('suppress', 'NegReg', (62, 70))	('RCC', 'Disease', 'MESH:C538614', (239, 242))
1237	31357507	Mutations of the above-mentioned genes and activation of the oncopathways are the main driver mutations in the progression of pRCC.	('pRCC', 'Gene', (126, 130))	('Mutations', 'Var', (0, 9))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('pRCC', 'Gene', '5546', (126, 130))
1238	31357507	How do these genetic alterations in pRCC translate to the protein and metabolite level?	('pRCC', 'Gene', (36, 40))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('pRCC', 'Gene', '5546', (36, 40))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('genetic alterations', 'Var', (13, 32))
1248	31357507	One of the most characteristic genetic features of chRCC is the monosomy of chromosomes 1, 2, 6, 10, 13, 17, and often 21.	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('monosomy', 'Var', (64, 72))
1249	31357507	The most commonly mutated genes in chRCC are TP53 (32%), PTEN (20%), and gene fusions involving the TERT promoter.	('TP53', 'Gene', (45, 49))	('gene fusions', 'Var', (73, 85))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('TERT', 'Gene', (100, 104))	('PTEN', 'Gene', (57, 61))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('PTEN', 'Gene', '5728', (57, 61))	('TERT', 'Gene', '7015', (100, 104))	('TP53', 'Gene', '7157', (45, 49))
1250	31357507	Mutations in these tumor suppressors combined with the deletion of one of their chromosomes leads to a complete loss of function.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('Mutations', 'Var', (0, 9))	('loss', 'NegReg', (112, 116))	('tumor', 'Disease', (19, 24))	('deletion', 'Var', (55, 63))
1266	31357507	Validation by siRNA-mediated silencing of GCLC led to a strong cell number reduction of ccRCC cell lines, which was accompanied by significantly decreased GSH levels.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('GSH levels', 'MPA', (155, 165))	('GSH', 'Chemical', '-', (155, 158))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('silencing', 'Var', (29, 38))	('cell number', 'CPA', (63, 74))	('decreased', 'NegReg', (145, 154))	('reduction', 'NegReg', (75, 84))	('GCLC', 'Gene', (42, 46))	('GCLC', 'Gene', '2729', (42, 46))	('RCC', 'Disease', (90, 93))
1304	31357507	However, in response to a diverse array of stimuli, such as oxidative stress, the cysteine residues within KEAP1, Cys151, Cys273, and Cys288 can be modified, which results in a conformational change along with the dissociation of NRF2 to avoid KEAP1-mediated degradation.	('Cys273', 'Chemical', '-', (122, 128))	('Cys288', 'Var', (134, 140))	('Cys288', 'Chemical', '-', (134, 140))	('degradation', 'MPA', (259, 270))	('Cys273', 'Var', (122, 128))	('NRF2', 'Gene', '4780', (230, 234))	('Cys151', 'Chemical', '-', (114, 120))	('KEAP1', 'Gene', '9817', (244, 249))	('oxidative stress', 'Phenotype', 'HP:0025464', (60, 76))	('KEAP1', 'Gene', (244, 249))	('Cys151', 'Var', (114, 120))	('NRF2', 'Gene', (230, 234))	('KEAP1', 'Gene', '9817', (107, 112))	('dissociation', 'MPA', (214, 226))	('KEAP1', 'Gene', (107, 112))	('degradation', 'biological_process', 'GO:0009056', ('259', '270'))	('cysteine', 'Chemical', 'MESH:D003545', (82, 90))	('results in', 'Reg', (164, 174))	('conformational change', 'MPA', (177, 198))
1309	31357507	Apart from mutations in FH, NRF2, CUL3, or KEAP1 in type II pRCC, several other mechanisms can also lead to increased NRF2 activity in other cancers, including epigenetic silencing, modifications of cysteine residues, metabolic alterations, and oncogene-dependent signaling.	('mutations', 'Var', (11, 20))	('KEAP1', 'Gene', (43, 48))	('FH', 'Gene', '2271', (24, 26))	('pRCC', 'Gene', (60, 64))	('NRF2', 'Gene', (118, 122))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('metabolic alterations', 'CPA', (218, 239))	('cysteine', 'Chemical', 'MESH:D003545', (199, 207))	('NRF2', 'Gene', (28, 32))	('increased', 'PosReg', (108, 117))	('KEAP1', 'Gene', '9817', (43, 48))	('CUL3', 'Gene', (34, 38))	('signaling', 'biological_process', 'GO:0023052', ('264', '273'))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('oncogene-dependent', 'CPA', (245, 263))	('cancers', 'Disease', (141, 148))	('modifications', 'Var', (182, 195))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('pRCC', 'Gene', '5546', (60, 64))	('activity', 'MPA', (123, 131))	('NRF2', 'Gene', '4780', (118, 122))	('CUL3', 'Gene', '8452', (34, 38))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('epigenetic silencing', 'Var', (160, 180))	('NRF2', 'Gene', '4780', (28, 32))
1326	31357507	Pharmacological inhibition of xCT decreases cystine uptake and induces ferroptosis in cancer cells, which makes xCT inhibitors potential treatment agents for cancer.	('xCT', 'Gene', '23657', (30, 33))	('induces', 'Reg', (63, 70))	('xCT', 'Gene', (112, 115))	('cancer', 'Disease', (158, 164))	('ferroptosis in cancer', 'Disease', 'MESH:D009369', (71, 92))	('cystine', 'Chemical', 'MESH:D003553', (44, 51))	('xCT', 'Gene', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('ferroptosis', 'biological_process', 'GO:0097707', ('71', '82'))	('cancer', 'Disease', (86, 92))	('inhibition', 'Var', (16, 26))	('decreases', 'NegReg', (34, 43))	('ferroptosis in cancer', 'Disease', (71, 92))	('cystine uptake', 'MPA', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('uptake', 'biological_process', 'GO:0098657', ('52', '58'))	('decreases cystine', 'Phenotype', 'HP:0500152', (34, 51))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('xCT', 'Gene', '23657', (112, 115))	('uptake', 'biological_process', 'GO:0098739', ('52', '58'))	('cancer', 'Disease', 'MESH:D009369', (86, 92))
1327	31357507	Sorafenib, an FDA-approved kinase inhibitor drug used for almost 15 years for the treatment of RCC, has multiple kinase inhibition activities, including cell surface tyrosine kinases (e.g., vascular endothelial growth factor receptor, VEGFR; platelet-derived growth factor receptor, PDGFR; tyrosine-protein kinase kit, KIT; Fms-like tyrosine kinase 3, FLT3; RET proto-oncogene, RET) and downstream intracellular serine/threonine kinases (e.g., both wild-type and mutant BRAF and CRAF).	('vascular endothelial growth factor', 'Gene', '7422', (190, 224))	('intracellular', 'cellular_component', 'GO:0005622', ('398', '411'))	('Fms-like tyrosine kinase 3', 'Gene', '2322', (324, 350))	('KIT', 'molecular_function', 'GO:0005020', ('319', '322'))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('242', '272'))	('VEGFR', 'Gene', '3791', (235, 240))	('vascular endothelial growth factor', 'Gene', (190, 224))	('VEGFR', 'Gene', (235, 240))	('CRAF', 'Gene', (479, 483))	('cell surface', 'cellular_component', 'GO:0009986', ('153', '165'))	('Fms-like tyrosine kinase 3', 'Gene', (324, 350))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('190', '224'))	('PDGFR', 'Gene', (283, 288))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('PDGFR', 'Gene', '5159', (283, 288))	('RCC', 'Disease', (95, 98))	('FLT3', 'Gene', (352, 356))	('CRAF', 'Gene', '5894', (479, 483))	('Sorafenib', 'Chemical', 'MESH:D000077157', (0, 9))	('Fms', 'molecular_function', 'GO:0005011', ('324', '327'))	('CRAF', 'molecular_function', 'GO:0004709', ('479', '483'))	('FLT3', 'Gene', '2322', (352, 356))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('27', '43'))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('BRAF', 'Gene', '673', (470, 474))	('protein', 'cellular_component', 'GO:0003675', ('299', '306'))	('BRAF', 'Gene', (470, 474))	('mutant', 'Var', (463, 469))
1331	31357507	Erastin is a small molecule that inhibits xCT activity through the mitochondrial voltage-dependent anion channel 2 and 3 (VDAC2 and VDAC3), causing abolition of the antioxidant defenses of the cell, and it furthermore has selectively lethal activity toward oncogenic RAS mutant cell lines.	('VDAC3', 'Gene', (132, 137))	('mutant', 'Var', (271, 277))	('antioxidant defenses', 'MPA', (165, 185))	('xCT', 'Gene', (42, 45))	('lethal activity', 'CPA', (234, 249))	('Erastin', 'Chemical', 'MESH:C477224', (0, 7))	('inhibits', 'NegReg', (33, 41))	('xCT', 'Gene', '23657', (42, 45))	('abolition', 'NegReg', (148, 157))	('VDAC3', 'Gene', '7419', (132, 137))
1332	31357507	A cystine addiction of VHL-deficient RCC cells was identified, and the deprivation thereof or treatment with erastin or sulfasalazine in RCC cells induced cell death.	('VHL-deficient RCC', 'Disease', 'MESH:C538614', (23, 40))	('VHL-deficient RCC', 'Disease', (23, 40))	('cell death', 'biological_process', 'GO:0008219', ('155', '165'))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('cystine', 'Chemical', 'MESH:D003553', (2, 9))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('erastin', 'Chemical', 'MESH:C477224', (109, 116))	('sulfasalazine', 'Chemical', 'MESH:D012460', (120, 133))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('cell death', 'CPA', (155, 165))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))	('deprivation thereof', 'Var', (71, 90))
1343	31357507	found that the abundance of pyruvate carboxylase (PC), which catalyzes the conversion of pyruvate to oxaloacetate to fuel the TCA cycle, strongly correlated with resistance, and knockdown of PC reduced TCA cycle activity and sensitized cells to CB-839 treatment, suggesting that PC expression may be a biomarker of resistance to CB-839.	('CB-839', 'Chemical', 'MESH:C000593334', (329, 335))	('correlated', 'Reg', (146, 156))	('pyruvate carboxylase', 'Gene', '397630', (28, 48))	('CB-839', 'Chemical', 'MESH:C000593334', (245, 251))	('oxaloacetate', 'Chemical', 'MESH:D062907', (101, 113))	('TCA', 'Enzyme', (202, 205))	('TCA', 'Chemical', 'MESH:D014238', (126, 129))	('pyruvate', 'Chemical', 'MESH:D019289', (89, 97))	('TCA', 'Chemical', 'MESH:D014238', (202, 205))	('pyruvate', 'Chemical', 'MESH:D019289', (28, 36))	('TCA cycle', 'biological_process', 'GO:0006099', ('126', '135'))	('pyruvate carboxylase', 'Gene', (28, 48))	('reduced', 'NegReg', (194, 201))	('knockdown', 'Var', (178, 187))	('TCA cycle', 'biological_process', 'GO:0006099', ('202', '211'))	('sensitized', 'Reg', (225, 235))	('resistance', 'MPA', (162, 172))
1345	31357507	In addition, decreases in mTOR signaling were also observed in RCC cell lines that were sensitive to CB-839, indicating that CB-839-induced glutamate deprivation has a direct influence on the mTOR pathway.	('decreases', 'NegReg', (13, 22))	('RCC', 'Disease', (63, 66))	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('deprivation', 'NegReg', (150, 161))	('glutamate', 'Chemical', 'MESH:D018698', (140, 149))	('CB-839', 'Chemical', 'MESH:C000593334', (125, 131))	('influence', 'Reg', (175, 184))	('CB-839-induced', 'Var', (125, 139))	('CB-839', 'Chemical', 'MESH:C000593334', (101, 107))	('glutamate', 'MPA', (140, 149))	('mTOR', 'Gene', (26, 30))	('mTOR', 'Gene', '2475', (26, 30))	('mTOR', 'Gene', (192, 196))	('mTOR', 'Gene', '2475', (192, 196))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
1346	31357507	These observations suggest that receptor tyrosine kinase (RTK) signaling or mTOR inhibitors would have synergistic effects with CB-839 to increase cytotoxicity in RCC cell lines.	('increase', 'PosReg', (138, 146))	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('signaling', 'biological_process', 'GO:0023052', ('63', '72'))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('mTOR', 'Gene', (76, 80))	('RCC', 'Disease', (163, 166))	('inhibitors', 'Var', (81, 91))	('mTOR', 'Gene', '2475', (76, 80))	('RTK', 'Gene', '5979', (58, 61))	('cytotoxicity', 'Disease', (147, 159))	('receptor tyrosine kinase', 'Gene', (32, 56))	('receptor tyrosine kinase', 'Gene', '5979', (32, 56))	('CB-839', 'Chemical', 'MESH:C000593334', (128, 134))	('cytotoxicity', 'Disease', 'MESH:D064420', (147, 159))	('RTK', 'Gene', (58, 61))
1362	31357507	In a pilot study and a phase I clinical trial, BSO in combination with melphalan was well tolerated and had therapeutic activity toward recurrent and refractory high-risk neuroblastoma (NCT00002730, NCT00005835).	('melphalan', 'Chemical', 'MESH:D008558', (71, 80))	('neuroblastoma', 'Disease', 'MESH:D009447', (171, 184))	('BSO', 'Chemical', 'MESH:D019328', (47, 50))	('neuroblastoma', 'Disease', (171, 184))	('NCT00002730', 'Var', (186, 197))	('neuroblastoma', 'Phenotype', 'HP:0003006', (171, 184))
1369	31357507	Individual DUB inhibitors, such as MI-2, PR-619, and EERI, were not effective in inducing cell death alone but led to an induction of proteotoxic stress and cell death in combination with BSO in many different cancer cell lines.	('PR-619', 'Var', (41, 47))	('led to', 'Reg', (111, 117))	('MI-2', 'Var', (35, 39))	('cell death', 'biological_process', 'GO:0008219', ('90', '100'))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('induction', 'Reg', (121, 130))	('BSO', 'Chemical', 'MESH:D019328', (188, 191))	('cell death', 'CPA', (157, 167))	('proteotoxic stress', 'MPA', (134, 152))	('cell death', 'biological_process', 'GO:0008219', ('157', '167'))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))
1370	31357507	The significant decrease in the global ubiquitination pattern in rho0 cells can be explained by the lack of main ROS generators localized within the oxidative phosphorylation system, namely complex I and III, which reduce the oxidative damage of proteins to a minimal level.	('oxidative damage of proteins', 'MPA', (226, 254))	('decrease', 'NegReg', (16, 24))	('global ubiquitination pattern', 'MPA', (32, 61))	('complex I', 'cellular_component', 'GO:0030964', ('190', '199'))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('149', '174'))	('rho0', 'Var', (65, 69))	('ROS', 'Chemical', 'MESH:D017382', (113, 116))
1383	31357507	As glutamine addiction is one of the main features of RCC, glutamine may be a limiting nutrient factor in the tumor microenvironment, and thus a lack of glutamine can induce immunosuppression.	('glutamine', 'Disease', (3, 12))	('glutamine', 'Protein', (153, 162))	('glutamine', 'Chemical', 'MESH:D005973', (153, 162))	('iron', 'Chemical', 'MESH:D007501', (124, 128))	('RCC', 'Disease', (54, 57))	('tumor', 'Disease', (110, 115))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('glutamine', 'Chemical', 'MESH:D005973', (59, 68))	('induce', 'Reg', (167, 173))	('glutamine', 'Chemical', 'MESH:D005973', (3, 12))	('lack', 'Var', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
1385	31357507	Reduced GSH levels in antigen-presenting cells have been shown to influence antigen processing and presentation as well as T-cell differentiation into T-helper 1 or 2 phenotypes.	('GSH levels', 'MPA', (8, 18))	('GSH', 'Chemical', '-', (8, 11))	('T-cell differentiation', 'CPA', (123, 145))	('T-cell differentiation', 'biological_process', 'GO:0030217', ('123', '145'))	('influence', 'Reg', (66, 75))	('Reduced', 'Var', (0, 7))	('antigen processing', 'MPA', (76, 94))	('antigen processing and presentation', 'biological_process', 'GO:0019882', ('76', '111'))	('presentation', 'MPA', (99, 111))
1390	31357507	The dysregulated respiratory chain is the main source of electron leakage, resulting in excessive ROS.	('ROS', 'Chemical', 'MESH:D017382', (98, 101))	('dysregulated', 'Var', (4, 16))	('ROS', 'MPA', (98, 101))	('respiratory chain', 'cellular_component', 'GO:0070469', ('17', '34'))
1439	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))
1440	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))
1451	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))
1454	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))
1482	30999966	Different from the role of CD8+ TILs in breast tumor which is associated with improved clinical outcomes, CD4+ TILs including FOXP3+ Tregs, Th1, and Th17 cells have controversial prognostic roles.	('Th1', 'Gene', (140, 143))	('breast tumor', 'Phenotype', 'HP:0100013', (40, 52))	('CD4+', 'Var', (106, 110))	('clinical', 'Species', '191496', (87, 95))	('Th1', 'Gene', (149, 152))	('breast tumor', 'Disease', 'MESH:D001943', (40, 52))	('CD8', 'Gene', (27, 30))	('FOXP3', 'Gene', '50943', (126, 131))	('CD8', 'Gene', '925', (27, 30))	('Th1', 'Gene', '51497', (140, 143))	('breast tumor', 'Disease', (40, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Th1', 'Gene', '51497', (149, 152))	('FOXP3', 'Gene', (126, 131))
1483	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.	('high levels', 'Var', (43, 54))	('FOXP3', 'Gene', (188, 193))	('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))
1598	30121971	In breast cancers, the formation of fibrosis by remodeling of the ECM was also found to be associated with gene expression patterns related to adverse prognosis and cancer metastasis.	('breast cancers', 'Phenotype', 'HP:0003002', (3, 17))	('cancer metastasis', 'Disease', (165, 182))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancers', 'Disease', 'MESH:D001943', (3, 17))	('breast cancers', 'Disease', (3, 17))	('cancer metastasis', 'Disease', 'MESH:D009362', (165, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('formation', 'biological_process', 'GO:0009058', ('23', '32'))	('remodeling', 'Var', (48, 58))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('gene expression', 'MPA', (107, 122))	('gene expression', 'biological_process', 'GO:0010467', ('107', '122'))	('fibrosis', 'Disease', 'MESH:D005355', (36, 44))	('fibrosis', 'Disease', (36, 44))	('associated', 'Reg', (91, 101))
1629	30459151	In the setting of pathway inhibition, glycolytic flux can be reduced, diverted or unchanged, each of which have broad implications for the future therapeutic effect, whether growth arrest or cell death.	('pathway', 'Pathway', (18, 25))	('inhibition', 'Var', (26, 36))	('growth arrest', 'Disease', 'MESH:D006323', (174, 187))	('growth arrest', 'Disease', (174, 187))	('cell death', 'biological_process', 'GO:0008219', ('191', '201'))	('glycolytic flux', 'MPA', (38, 53))	('reduced', 'NegReg', (61, 68))	('growth arrest', 'Phenotype', 'HP:0001510', (174, 187))
1632	30459151	Multi-region genomics of ccRCC tumor samples from long-term responders to single agent mTORi have been performed, which demonstrated the presence of early convergent evolution of mutation events centering on the core mTORC1 pathway in many of these cases.	('mTORC1', 'Gene', '382056', (217, 223))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('mutation', 'Var', (179, 187))	('mTORC1', 'Gene', (217, 223))	('ccRCC', 'Phenotype', 'HP:0006770', (25, 30))	('mTORC1', 'cellular_component', 'GO:0031931', ('217', '223'))	('RCC', 'Disease', 'MESH:D002292', (27, 30))	('RCC', 'Disease', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('core', 'cellular_component', 'GO:0019013', ('212', '216'))
1653	30459151	Antibodies used for immunoblot analysis are as follows: anti-pSer-473 AKT (no.	('anti-pSer-473', 'Var', (56, 69))	('AKT', 'Gene', '207', (70, 73))	('AKT', 'Gene', (70, 73))
1654	30459151	9271, Cell Signaling Technology), anti-pThr-308 AKT1 (no.	('anti-pThr-308', 'Var', (34, 47))	('AKT1', 'Gene', '207', (48, 52))	('Signaling', 'biological_process', 'GO:0023052', ('11', '20'))	('AKT1', 'Gene', (48, 52))
1658	30459151	9202, Cell Signaling Technology), anti-pSer-65 4EBP1 (no.	('4EBP1', 'Gene', '1978', (47, 52))	('4EBP1', 'Gene', (47, 52))	('anti-pSer-65', 'Var', (34, 46))	('Signaling', 'biological_process', 'GO:0023052', ('11', '20'))
1661	30459151	9107, Cell Signaling Technology), anti-pSer9 GSK-3beta (no.	('anti-pSer9', 'Var', (34, 44))	('GSK-3beta', 'Gene', (45, 54))	('GSK', 'molecular_function', 'GO:0050321', ('45', '48'))	('Signaling', 'biological_process', 'GO:0023052', ('11', '20'))	('GSK-3beta', 'Gene', '2931', (45, 54))
1712	30459151	Interestingly, the ratio of lactate production to glucose consumption decreases from 0.700 +- 0.095 to 0.410+- 0.082 (41.4%) in JHRCC228 cells, while the ratio remains unchanged in JHRCC12 cells (Fig.	('lactate production', 'MPA', (28, 46))	('RCC', 'Disease', 'MESH:D002292', (183, 186))	('RCC', 'Disease', (183, 186))	('decreases', 'NegReg', (70, 79))	('glucose', 'Chemical', 'MESH:D005947', (50, 57))	('RCC', 'Disease', (130, 133))	('0.410+-', 'Var', (103, 110))	('lactate', 'Chemical', 'MESH:D019344', (28, 35))	('RCC', 'Disease', 'MESH:D002292', (130, 133))
1719	30459151	mTORC1 recruits substrates through regulatory-associated protein of mTOR (RAPTOR), which binds a TOR signaling (TOS) motif in substrate proteins such as ribosomal S6 kinase (S6K) and 4E-BP.	('regulatory-associated protein of mTOR', 'Gene', (35, 72))	('TOR signaling', 'biological_process', 'GO:0031929', ('97', '110'))	('mTORC1', 'cellular_component', 'GO:0031931', ('0', '6'))	('S6K', 'Mutation', 'p.S6K', (174, 177))	('mTORC1', 'Gene', '382056', (0, 6))	('regulatory-associated protein of mTOR', 'Gene', '57521', (35, 72))	('RAPTOR', 'Gene', (74, 80))	('4E-BP', 'Var', (183, 188))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('mTORC1', 'Gene', (0, 6))	('RAPTOR', 'Gene', '57521', (74, 80))
1724	30459151	In addition, we found p-AKT (S473), p-AKT (T308) and p-GSK3beta levels moderately increase with rapamycin treatment (Fig.	('GSK3beta', 'Gene', '2931', (55, 63))	('AKT', 'Gene', (24, 27))	('AKT', 'Gene', (38, 41))	('S473', 'Chemical', 'MESH:C015765', (29, 33))	('GSK', 'molecular_function', 'GO:0050321', ('55', '58'))	('AKT', 'Gene', '207', (24, 27))	('T308', 'Var', (43, 47))	('increase', 'PosReg', (82, 90))	('AKT', 'Gene', '207', (38, 41))	('rapamycin', 'Chemical', 'MESH:D020123', (96, 105))	('GSK3beta', 'Gene', (55, 63))
1735	30459151	Recent work has shown that with targeted inhibition of signaling pathways, changes in in vivo HP lactate non-invasively indicate early changes in tumor metabolism, though the relationship between target inhibition and metabolic changes remains unclear.	('changes', 'Reg', (135, 142))	('HP lactate', 'MPA', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('metabolism', 'biological_process', 'GO:0008152', ('152', '162'))	('tumor', 'Disease', (146, 151))	('signaling pathways', 'Pathway', (55, 73))	('signaling', 'biological_process', 'GO:0023052', ('55', '64'))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('targeted inhibition', 'Var', (32, 51))	('HP lactate', 'Chemical', 'MESH:D019344', (94, 104))
1739	30459151	The total lactate was significantly decreased more than 50% (p=0.00031) in treated PIK3CA mutant JHRCC228 tumors with rapamycin treatment, whereas there was no detectable difference in JHRCC12 (Fig.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('RCC', 'Disease', (187, 190))	('lactate', 'MPA', (10, 17))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('mutant', 'Var', (90, 96))	('RCC', 'Disease', 'MESH:D002292', (187, 190))	('rapamycin', 'Chemical', 'MESH:D020123', (118, 127))	('RCC', 'Disease', 'MESH:D002292', (99, 102))	('RCC', 'Disease', (99, 102))	('PIK3CA', 'Gene', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('PIK3CA', 'Gene', '5290', (83, 89))	('lactate', 'Chemical', 'MESH:D019344', (10, 17))	('decreased', 'NegReg', (36, 45))
1746	30459151	More importantly, the imaging results demonstrate a biomarker dependent on the pathway and highlights that a PIK3CA mutant, which requires increased glycolytic metabolism to lactate, is sensitive to pathway inhibition and would benefit from such a therapeutic intervention.	('benefit', 'Reg', (228, 235))	('PIK3CA', 'Gene', (109, 115))	('PIK3CA', 'Gene', '5290', (109, 115))	('increased', 'PosReg', (139, 148))	('lactate', 'Chemical', 'MESH:D019344', (174, 181))	('metabolism', 'biological_process', 'GO:0008152', ('160', '170'))	('mutant', 'Var', (116, 122))	('glycolytic metabolism to lactate', 'MPA', (149, 181))
1749	30459151	In this demonstration, a PDX model of ccRCC harboring a PIK3CA activating mutation shows reduced in vivo flux to HP lactate with inhibition, whereas this is not the case for a wild-type PDX.	('mutation', 'Var', (74, 82))	('HP lactate', 'Chemical', 'MESH:D019344', (113, 123))	('RCC', 'Disease', (40, 43))	('activating', 'PosReg', (63, 73))	('flux to HP lactate', 'MPA', (105, 123))	('PIK3CA', 'Gene', (56, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('RCC', 'Disease', 'MESH:D002292', (40, 43))	('reduced', 'NegReg', (89, 96))	('PIK3CA', 'Gene', '5290', (56, 62))
1760	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))
1762	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))
1766	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))
1767	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))
1773	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))	('SETD2', 'Gene', '29072', (177, 182))	('PBRM1', 'Gene', '55193', (170, 175))	('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))
1774	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))
1778	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))
1789	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))
1791	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))	('demethylating', 'Var', (119, 132))	('JMJD6', 'Var', (23, 28))	('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))
1792	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))
1793	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'))
1795	33634984	33 ,  34  Knockouts of JMJD6 could lead to severe defects in mice, which suggested critical roles of JMJD6 in development.	('lead', 'Reg', (35, 39))	('Knockouts', 'Var', (10, 19))	('mice', 'Species', '10090', (61, 65))	('JMJD6', 'Gene', (23, 28))
1796	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'))
1832	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))
1850	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', 'MESH:C538614', (90, 93))	('suppressed', 'NegReg', (40, 50))	('knockdown', 'Var', (19, 28))	('RCC', 'Disease', (51, 54))	('JMJD6', 'Gene', (13, 18))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (90, 93))
1854	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))
1858	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))
1859	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))
1860	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))
1863	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))	('RCC growth', 'Disease', 'MESH:C538614', (52, 62))	('Caki-1', 'CellLine', 'CVCL:0234', (74, 80))	('JMJD6', 'Gene', (13, 18))
1865	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))
1866	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))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', (184, 189))	('knocking out', 'Var', (109, 121))	('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))
1867	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', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('JMJD6-KO', 'Var', (134, 142))	('Ki-67', 'Gene', '17345', (51, 56))
1868	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))	('enhanced', 'PosReg', (63, 71))	('JMJD6', 'Gene', (57, 62))	('Caki-1', 'CellLine', 'CVCL:0234', (112, 118))	('invasion', 'CPA', (90, 98))
1870	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))
1874	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))
1877	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))
1878	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'))
1883	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))
1886	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))
1894	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))
1895	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))
1899	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'))
1900	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))
1904	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))
1907	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))
1908	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))
1911	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))
1913	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))
1918	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))
1921	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))
1927	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))
1933	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))
1936	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))
1941	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))
1946	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'))
1947	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))
1952	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))
1954	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))
1962	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))
1963	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))
1964	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))
1971	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))	('efficacy', 'MPA', (74, 82))	('JMJD6', 'Var', (102, 107))	('sunitinib', 'Chemical', 'MESH:D000077210', (64, 73))	('sunitinib', 'Chemical', 'MESH:D000077210', (112, 121))	('combination', 'Interaction', (87, 98))
1973	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'))	('inhibit', 'NegReg', (123, 130))	('suppress', 'NegReg', (53, 61))	('SKLB325', 'Var', (25, 32))	('CD34', 'Gene', (150, 154))	('mice', 'Species', '10090', (114, 118))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('CD105', 'Gene', (159, 164))	('CD105', 'Gene', '13805', (159, 164))	('expressions', 'MPA', (135, 146))	('CD34', 'Gene', '12490', (150, 154))
1974	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))
1976	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))
1979	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))
2045	31636361	We isolated NFs from five normal renal cortical tissues (>6 cm apart from renal cancer tissues) named as NF170829, NF170831, NF170923, NF171006, NF171130, respectively.	('NF171006', 'Var', (135, 143))	('renal cancer', 'Disease', 'MESH:D007680', (74, 86))	('NF171130', 'Var', (145, 153))	('NF170829', 'Var', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('renal cancer', 'Phenotype', 'HP:0009726', (74, 86))	('NF170831', 'Var', (115, 123))	('renal cancer', 'Disease', (74, 86))	('NF170923', 'Var', (125, 133))
2049	31636361	NF-CM was collected from RPIM 1640 culturing NFs for 72 h. We first evaluated the effect of different NF-CMs (NF170829, NF170831, NF170923, NF171006, and NF171130) on the growth of ccRCC cells by CCK-8 assay.	('RCC', 'Phenotype', 'HP:0005584', (183, 186))	('NF170831', 'Var', (120, 128))	('RPIM 1640', 'Chemical', '-', (25, 34))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('RCC', 'Disease', (183, 186))	('NF170923', 'Var', (130, 138))	('NF171006', 'Var', (140, 148))	('NF170829', 'Var', (110, 118))	('NF171130', 'Var', (154, 162))
2056	31636361	Taken together, these results demonstrate that NFs can attenuate the proliferation and enhance the migration potential of renal cancer cells with no appreciable effect on EMT programming.	('NFs', 'Var', (47, 50))	('renal cancer', 'Disease', (122, 134))	('proliferation', 'CPA', (69, 82))	('renal cancer', 'Phenotype', 'HP:0009726', (122, 134))	('renal cancer', 'Disease', 'MESH:D007680', (122, 134))	('enhance', 'PosReg', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('attenuate', 'NegReg', (55, 64))	('EMT', 'biological_process', 'GO:0001837', ('171', '174'))
2063	31636361	3b, the phosphorylated STAT3 (p-STAT3) was increased by onefold to fourfold (P < 0.001) in 769-P and ACHN cells with the presence of NF-CM, while total STAT3 level had no changes at all.	('STAT3', 'Gene', '6774', (152, 157))	('presence', 'Var', (121, 129))	('STAT3', 'Gene', '6774', (23, 28))	('STAT3', 'Gene', '6774', (32, 37))	('STAT3', 'Gene', (152, 157))	('STAT3', 'Gene', (23, 28))	('STAT3', 'Gene', (32, 37))	('increased', 'PosReg', (43, 52))	('NF-CM', 'Var', (133, 138))
2088	31636361	We have made two novel findings in this study: (1) NFs largely enhanced ccRCC cell migration through the IL6/STAT3 pathway and (2) GATA3 suppressed such migration by inhibiting IL6-induced activation of STAT3.	('suppressed', 'NegReg', (137, 147))	('IL6', 'Gene', (177, 180))	('IL6', 'Gene', (105, 108))	('enhanced', 'PosReg', (63, 71))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('IL6', 'molecular_function', 'GO:0005138', ('177', '180'))	('STAT3', 'Gene', (109, 114))	('STAT3', 'Gene', (203, 208))	('GATA3', 'Gene', '2625', (131, 136))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('STAT3', 'Gene', '6774', (109, 114))	('STAT3', 'Gene', '6774', (203, 208))	('GATA3', 'Gene', (131, 136))	('cell migration', 'biological_process', 'GO:0016477', ('78', '92'))	('NFs', 'Var', (51, 54))	('IL6', 'Gene', '3569', (177, 180))	('IL6', 'Gene', '3569', (105, 108))	('IL6', 'molecular_function', 'GO:0005138', ('105', '108'))	('inhibiting', 'NegReg', (166, 176))
2095	31636361	Our result showed that NF-CM did not change the expressions of E-cadherin and alpha-SMA, suggesting that EMT might not happen in the process of the NF-CM enhanced metastasis in renal cancer cells.	('E-cadherin', 'Gene', '999', (63, 73))	('alpha-SMA', 'Gene', '58', (78, 87))	('renal cancer', 'Disease', 'MESH:D007680', (177, 189))	('enhanced', 'PosReg', (154, 162))	('metastasis', 'CPA', (163, 173))	('NF-CM', 'Var', (148, 153))	('alpha-SMA', 'Gene', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('EMT', 'biological_process', 'GO:0001837', ('105', '108'))	('E-cadherin', 'Gene', (63, 73))	('renal cancer', 'Disease', (177, 189))	('cadherin', 'molecular_function', 'GO:0008014', ('65', '73'))	('renal cancer', 'Phenotype', 'HP:0009726', (177, 189))
2096	31636361	Tumor metastasis is usually associated with abnormal expression of cytokines, especially CXCL12, VEGF, IL1beta, and IL6, while CAFs can promote tumor growth and invasion via a plethora of active factors.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('promote', 'PosReg', (136, 143))	('IL6', 'Gene', (116, 119))	('IL1beta', 'Gene', '3552', (103, 110))	('Tumor metastasis', 'Disease', (0, 16))	('IL1beta', 'Gene', (103, 110))	('invasion', 'CPA', (161, 169))	('IL6', 'molecular_function', 'GO:0005138', ('116', '119'))	('abnormal', 'Var', (44, 52))	('VEGF', 'Gene', '7422', (97, 101))	('plethora', 'Phenotype', 'HP:0001050', (176, 184))	('tumor', 'Disease', (144, 149))	('associated', 'Reg', (28, 38))	('VEGF', 'Gene', (97, 101))	('CXCL12', 'Gene', '6387', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('CXCL12', 'Gene', (89, 95))	('Tumor metastasis', 'Disease', 'MESH:D009362', (0, 16))	('IL6', 'Gene', '3569', (116, 119))	('IL1', 'molecular_function', 'GO:0005149', ('103', '106'))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
2111	31636361	NFs have a profound impact on ccRCC migration and accelerate the cancer invasion and metastasis, which was mainly through a IL6-induced STAT3 activation.	('accelerate', 'PosReg', (50, 60))	('NFs', 'Var', (0, 3))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('impact', 'Reg', (20, 26))	('IL6', 'Gene', '3569', (124, 127))	('STAT3', 'Gene', '6774', (136, 141))	('IL6', 'Gene', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('IL6', 'molecular_function', 'GO:0005138', ('124', '127'))	('STAT3', 'Gene', (136, 141))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
2124	28543182	High methylation in LEPR was associated with increased risk of recurrence (HR=3.15; 95%CI: 1.23-8.07; p=0.02).	('LEPR', 'Gene', '3953', (20, 24))	('recurrence', 'Disease', (63, 73))	('LEPR', 'Gene', (20, 24))	('High methylation', 'Var', (0, 16))	('methylation', 'biological_process', 'GO:0032259', ('5', '16'))
2125	28543182	Patients with high-methylation in LEPR had shorter recurrence-free survival than low-methylation group (Log-Rank p=2.25E-03).	('LEPR', 'Gene', '3953', (34, 38))	('methylation', 'biological_process', 'GO:0032259', ('85', '96'))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('high-methylation', 'Var', (14, 30))	('LEPR', 'Gene', (34, 38))	('recurrence-free survival', 'CPA', (51, 75))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (43, 50))
2135	28543182	Previous studies have revealed the association of overweight and obesity with increased RCC risk; however, patients with higher BMI had a significantly better RCC prognosis compared with normal weight patients, a phenomenon well known as the "obesity paradox".	('obesity', 'Phenotype', 'HP:0001513', (243, 250))	('patients', 'Species', '9606', (201, 209))	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('obesity', 'Phenotype', 'HP:0001513', (65, 72))	('obesity', 'Disease', 'MESH:D009765', (243, 250))	('overweight', 'Phenotype', 'HP:0025502', (50, 60))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('obesity', 'Disease', (243, 250))	('BMI', 'Var', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('obesity', 'Disease', 'MESH:D009765', (65, 72))	('better', 'PosReg', (152, 158))	('obesity', 'Disease', (65, 72))	('patients', 'Species', '9606', (107, 115))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))
2137	28543182	To date, there are well-established obesity-related genes whose expressions are regulated through epigenetic mechanisms (e.g., DNA methylation, histone modification and miRNAs).	('miRNAs', 'Var', (169, 175))	('expressions', 'MPA', (64, 75))	('obesity', 'Disease', 'MESH:D009765', (36, 43))	('obesity', 'Phenotype', 'HP:0001513', (36, 43))	('histone modification', 'biological_process', 'GO:0016570', ('144', '164'))	('obesity', 'Disease', (36, 43))	('DNA methylation', 'Var', (127, 142))	('histone', 'Protein', (144, 151))	('established obesity', 'Phenotype', 'HP:0012743', (24, 43))	('regulated', 'Reg', (80, 89))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))	('DNA methylation', 'biological_process', 'GO:0006306', ('127', '142'))
2140	28543182	Previous studies have shown that aberrant DNA methylations contribute to RCC tumorigenesis and clinical outcomes.	('DNA', 'Protein', (42, 45))	('RCC tumor', 'Disease', 'MESH:C538614', (73, 82))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('contribute', 'Reg', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('aberrant', 'Var', (33, 41))	('RCC tumor', 'Disease', (73, 82))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
2141	28543182	The methylations of several genes, including DAL-1/4.1B, COL14A1, SFRP1, GREM1, NEURL, LAD1 and NEFH, and DAB2IP, have been shown as independent prognostic factors for RCC.	('DAL-1/4.1B', 'Gene', '23136', (45, 55))	('NEURL', 'Gene', (80, 85))	('LAD1', 'Gene', '3898', (87, 91))	('SFRP1', 'Gene', '6422', (66, 71))	('DAL-1/4.1B', 'Gene', (45, 55))	('NEFH', 'Gene', '4744', (96, 100))	('DAB2IP', 'Gene', (106, 112))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('GREM1', 'Gene', '26585', (73, 78))	('RCC', 'Disease', (168, 171))	('COL14A1', 'Gene', (57, 64))	('GREM1', 'Gene', (73, 78))	('LAD1', 'Gene', (87, 91))	('NEFH', 'Gene', (96, 100))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('NEURL', 'Gene', '9148', (80, 85))	('COL14A1', 'Gene', '7373', (57, 64))	('SFRP1', 'Gene', (66, 71))	('methylations', 'Var', (4, 16))	('DAB2IP', 'Gene', '153090', (106, 112))
2147	28543182	LEP exerts its action through leptin receptor (LEPR), a class I cytokine receptor; disrupted LEP/LEPR signaling has been associated with RCC invasion.	('LEP', 'Gene', (0, 3))	('LEPR', 'Gene', (47, 51))	('LEP', 'Gene', '3952', (47, 50))	('LEP', 'Gene', '3952', (93, 96))	('signaling', 'biological_process', 'GO:0023052', ('102', '111'))	('LEP', 'Gene', (47, 50))	('disrupted', 'Var', (83, 92))	('class I cytokine receptor', 'Gene', '9466', (56, 81))	('LEP', 'Gene', (93, 96))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('RCC', 'Disease', (137, 140))	('LEPR', 'Gene', '3953', (97, 101))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('LEP', 'Gene', '3952', (97, 100))	('LEPR', 'Gene', (97, 101))	('associated', 'Reg', (121, 131))	('LEP', 'Gene', '3952', (0, 3))	('LEP', 'Gene', (97, 100))	('leptin receptor', 'Gene', (30, 45))	('leptin receptor', 'Gene', '3953', (30, 45))	('class I cytokine receptor', 'Gene', (56, 81))	('LEPR', 'Gene', '3953', (47, 51))
2168	28543182	Cox proportional hazard models were used to examine the association between obesity-related gene methylation and recurrence risk.	('obesity', 'Disease', 'MESH:D009765', (76, 83))	('obesity', 'Disease', (76, 83))	('Cox', 'Gene', (0, 3))	('Cox', 'Gene', '1351', (0, 3))	('association', 'Interaction', (56, 67))	('obesity', 'Phenotype', 'HP:0001513', (76, 83))	('methylation', 'biological_process', 'GO:0032259', ('97', '108'))	('methylation', 'Var', (97, 108))
2185	28543182	Multivariate Cox model adjusted by age, gender, pathologic stage, grade, smoking status, BMI, hypertension and histology identified high methylation levels in LEP as predictor of recurrence in RCC patients (HR=5.14; 95% CI: 1.07-24.66; p=0.04) as well as in the ccRCC subset (HR=5.96; 95% CI: 1.02-34.76; p=0.05) (Table 4).	('recurrence', 'Disease', (179, 189))	('RCC', 'Disease', 'MESH:C538614', (264, 267))	('RCC', 'Disease', (264, 267))	('RCC', 'Phenotype', 'HP:0005584', (264, 267))	('high methylation levels', 'Var', (132, 155))	('RCC', 'Disease', (193, 196))	('patients', 'Species', '9606', (197, 205))	('Cox', 'Gene', (13, 16))	('LEP', 'Gene', (159, 162))	('Cox', 'Gene', '1351', (13, 16))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('RCC', 'Phenotype', 'HP:0005584', (193, 196))	('hypertension', 'Phenotype', 'HP:0000822', (94, 106))	('methylation', 'biological_process', 'GO:0032259', ('137', '148'))	('LEP', 'Gene', '3952', (159, 162))	('hypertension', 'Disease', 'MESH:D006973', (94, 106))	('hypertension', 'Disease', (94, 106))
2187	28543182	Kaplan-Meier curves showed a significant association between methylation in LEP and LEPR (low vs. high methylation) and RFS (Log-Rank p=2.65E-03 and p=0.01, respectively) (Figure 1B and 1C).	('LEPR', 'Gene', (84, 88))	('methylation', 'Var', (61, 72))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('LEP', 'Gene', (76, 79))	('LEP', 'Gene', (84, 87))	('LEPR', 'Gene', '3953', (84, 88))	('LEP', 'Gene', '3952', (76, 79))	('methylation', 'biological_process', 'GO:0032259', ('103', '114'))	('LEP', 'Gene', '3952', (84, 87))	('RFS', 'Gene', (120, 123))
2193	28543182	In the multivariate Cox proportional hazards model, patients with high methylation levels in LEPR had an increased risk of recurrence (HR=3.15; 95% CI: 1.23-8.07; p=0.02) as compared with low methylation group in RCC patients as well in the ccRCC subset (HR=6.00; 95% CI: 1.92-18.82; p=2.00E-03) (Table 4).	('high methylation levels', 'Var', (66, 89))	('LEPR', 'Gene', (93, 97))	('Cox', 'Gene', '1351', (20, 23))	('Cox', 'Gene', (20, 23))	('LEPR', 'Gene', '3953', (93, 97))	('methylation', 'biological_process', 'GO:0032259', ('192', '203'))	('RCC', 'Disease', 'MESH:C538614', (243, 246))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('RCC', 'Disease', (243, 246))	('RCC', 'Disease', (213, 216))	('RCC', 'Phenotype', 'HP:0005584', (243, 246))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('patients', 'Species', '9606', (217, 225))	('patients', 'Species', '9606', (52, 60))
2195	28543182	Patients with high LEPR methylation in the tumor tissue had shorter RFS than low LEPR methylation group (p=2.25E-03) (Figure 1F).	('LEPR', 'Gene', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('methylation', 'biological_process', 'GO:0032259', ('86', '97'))	('high', 'Var', (14, 18))	('LEPR', 'Gene', (81, 85))	('Patients', 'Species', '9606', (0, 8))	('LEPR', 'Gene', '3953', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('RFS', 'MPA', (68, 71))	('shorter', 'NegReg', (60, 67))	('tumor', 'Disease', (43, 48))	('LEPR', 'Gene', '3953', (81, 85))
2197	28543182	There was no significant association between NPY and LEP methylation and RFS in RCC patients (Log-Rank p=0.70 and p=0.09, respectively) (Figure 1D and 1E).	('methylation', 'Var', (57, 68))	('LEP', 'Gene', '3952', (53, 56))	('patients', 'Species', '9606', (84, 92))	('RCC', 'Disease', (80, 83))	('NPY', 'Gene', '4852', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('RFS', 'Disease', (73, 76))	('LEP', 'Gene', (53, 56))	('methylation', 'biological_process', 'GO:0032259', ('57', '68'))	('NPY', 'Gene', (45, 48))
2202	28543182	This result suggests that the hypermethylation of the CpG islands in the promoter region of the LEPR may be a mechanism downregulating its expression in RCC tumors.	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('LEPR', 'Gene', '3953', (96, 100))	('RCC tumors', 'Disease', (153, 163))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('LEPR', 'Gene', (96, 100))	('RCC tumors', 'Disease', 'MESH:C538614', (153, 163))	('expression', 'MPA', (139, 149))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('hypermethylation', 'Var', (30, 46))	('downregulating', 'NegReg', (120, 134))
2205	28543182	We found a significant correlation between high LEPR methylation and high pathologic stage (p=1.77E-04) and a borderline significant correlation between LEPR methylation and high Fuhrman grade (p=0.05) (Supplementary Table S3).	('methylation', 'biological_process', 'GO:0032259', ('158', '169'))	('LEPR', 'Gene', (153, 157))	('high', 'Var', (43, 47))	('LEPR', 'Gene', '3953', (48, 52))	('LEPR', 'Gene', '3953', (153, 157))	('high Fuhrman grade', 'CPA', (174, 192))	('high pathologic stage', 'CPA', (69, 90))	('LEPR', 'Gene', (48, 52))	('methylation', 'biological_process', 'GO:0032259', ('53', '64'))
2207	28543182	Our study demonstrates that methylation in NPY, LEP and LEPR promoters is involved in RCC tumorigenesis.	('RCC tumor', 'Disease', (86, 95))	('NPY', 'Gene', (43, 46))	('LEP', 'Gene', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('LEP', 'Gene', (56, 59))	('LEPR', 'Gene', '3953', (56, 60))	('LEP', 'Gene', '3952', (48, 51))	('RCC tumor', 'Disease', 'MESH:C538614', (86, 95))	('NPY', 'Gene', '4852', (43, 46))	('LEP', 'Gene', '3952', (56, 59))	('methylation', 'Var', (28, 39))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('LEPR', 'Gene', (56, 60))	('involved', 'Reg', (74, 82))
2208	28543182	Additionally, the comparison of methylation data between tumor and normal adjacent tissues revealed that hypermethylation in these particular obesity-related genes was specific for renal cell carcinoma tumors; besides NPY, LEP and LEPR showed to be low or unmethylated in normal tissues from the surrounding tissues.	('LEP', 'Gene', (223, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('tumor', 'Disease', (202, 207))	('NPY', 'Gene', (218, 221))	('obesity', 'Phenotype', 'HP:0001513', (142, 149))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('LEPR', 'Gene', '3953', (231, 235))	('LEP', 'Gene', '3952', (231, 234))	('obesity', 'Disease', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('LEPR', 'Gene', (231, 235))	('renal cell carcinoma tumors', 'Disease', 'MESH:C538614', (181, 208))	('LEP', 'Gene', '3952', (223, 226))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('LEP', 'Gene', (231, 234))	('hypermethylation', 'Var', (105, 121))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (181, 201))	('obesity', 'Disease', 'MESH:D009765', (142, 149))	('NPY', 'Gene', '4852', (218, 221))	('renal cell carcinoma tumors', 'Disease', (181, 208))
2210	28543182	Moreover, high methylation in LEPR and the clinicopathologic data indicates that promoter hypermethylation in LEPR methylation might be a late event in kidney tumorigenesis and tumor differentiation.	('methylation', 'Var', (115, 126))	('LEPR', 'Gene', '3953', (30, 34))	('LEPR', 'Gene', '3953', (110, 114))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('LEPR', 'Gene', (30, 34))	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('LEPR', 'Gene', (110, 114))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('methylation', 'biological_process', 'GO:0032259', ('115', '126'))
2211	28543182	Promoter hypermethylation in VHL, p16INK4a, p14ARF, APC, GSTP1, MGMT, RASSF1A, RARbeta2, E-Cadherin and TIMP3 have been evaluated in kidney tumors; Dulaimi et al, demonstrated that aberrant promoter hypermethylation in tumor suppressor and cancer genes may disrupt critical pathways, and thus, play an important role in kidney tumorigenesis.	('kidney tumors', 'Disease', 'MESH:D007674', (133, 146))	('kidney tumors', 'Phenotype', 'HP:0009726', (133, 146))	('tumor', 'Disease', (219, 224))	('play', 'Reg', (294, 298))	('Cadherin', 'molecular_function', 'GO:0008014', ('91', '99'))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('p14ARF', 'Gene', '1029', (44, 50))	('MGMT', 'Gene', '4255', (64, 68))	('cancer', 'Disease', (240, 246))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('p16INK4a', 'Gene', '1029', (34, 42))	('disrupt', 'NegReg', (257, 264))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('tumor', 'Disease', (327, 332))	('E-Cadherin', 'Gene', (89, 99))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('219', '235'))	('GSTP1', 'Gene', '2950', (57, 62))	('aberrant promoter hypermethylation', 'Var', (181, 215))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('APC', 'Gene', '324', (52, 55))	('kidney tumors', 'Disease', (133, 146))	('TIMP3', 'Gene', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (327, 332))	('VHL', 'Disease', 'MESH:D006623', (29, 32))	('GSTP1', 'Gene', (57, 62))	('TIMP3', 'Gene', '7078', (104, 109))	('p14ARF', 'Gene', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor suppressor', 'biological_process', 'GO:0051726', ('219', '235'))	('APC', 'cellular_component', 'GO:0005680', ('52', '55'))	('RASSF1A', 'Gene', '11186', (70, 77))	('MGMT', 'Gene', (64, 68))	('p16INK4a', 'Gene', (34, 42))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('MGMT', 'molecular_function', 'GO:0003908', ('64', '68'))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('RASSF1A', 'Gene', (70, 77))	('APC', 'Gene', (52, 55))	('critical pathways', 'Pathway', (265, 282))	('E-Cadherin', 'Gene', '999', (89, 99))	('VHL', 'Disease', (29, 32))	('tumor', 'Disease', (140, 145))
2212	28543182	Recent high-resolution epigenomic and genomic map of RCC tumors have reported a significantly increased number of hypermethylated loci in RCC tumors compared with controls; the majority of DMRs (differentially methylated regions) in RCC were localized on enhancer regions of the kidney genome.	('RCC', 'Disease', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('RCC tumors', 'Disease', (138, 148))	('DMRs', 'Var', (189, 193))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('RCC tumors', 'Disease', (53, 63))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('RCC tumors', 'Disease', 'MESH:C538614', (138, 148))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('RCC', 'Phenotype', 'HP:0005584', (233, 236))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('RCC', 'Disease', 'MESH:C538614', (233, 236))	('RCC', 'Disease', (233, 236))	('RCC tumors', 'Disease', 'MESH:C538614', (53, 63))
2214	28543182	To our knowledge, this is the first study in RCC using paired tumor and normal tissue to evaluate the role of obesity-related gene methylation in RCC tumorigenesis and to associate high methylation in LEPR with risk of recurrence in RCC patients.	('methylation', 'biological_process', 'GO:0032259', ('131', '142'))	('RCC', 'Disease', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('RCC', 'Phenotype', 'HP:0005584', (233, 236))	('patients', 'Species', '9606', (237, 245))	('RCC', 'Disease', (233, 236))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('obesity', 'Phenotype', 'HP:0001513', (110, 117))	('methylation', 'biological_process', 'GO:0032259', ('186', '197'))	('LEPR', 'Gene', '3953', (201, 205))	('RCC tumor', 'Disease', 'MESH:C538614', (146, 155))	('RCC', 'Disease', 'MESH:C538614', (233, 236))	('LEPR', 'Gene', (201, 205))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('high methylation', 'Var', (181, 197))	('obesity', 'Disease', (110, 117))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))	('obesity', 'Disease', 'MESH:D009765', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('RCC tumor', 'Disease', (146, 155))
2217	28543182	Furthermore, a recent study reported that LEPR displayed distinct expression patterns in different histological subtypes of thyroid carcinoma and positive LEPR expression was associated with longer disease-free survival in anaplastic thyroid carcinoma patients.	('thyroid carcinoma', 'Disease', (124, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('patients', 'Species', '9606', (252, 260))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (124, 141))	('LEPR', 'Gene', '3953', (42, 46))	('LEPR', 'Gene', '3953', (155, 159))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (234, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (234, 251))	('positive', 'Var', (146, 154))	('LEPR', 'Gene', (42, 46))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (223, 251))	('LEPR', 'Gene', (155, 159))	('longer', 'PosReg', (191, 197))	('thyroid carcinoma', 'Disease', (234, 251))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (124, 141))	('disease-free survival', 'CPA', (198, 219))
2219	28543182	Moreover, low LEPR was associated with more aggressive tumors.	('LEPR', 'Gene', '3953', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('aggressive tumors', 'Disease', 'MESH:D001523', (44, 61))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('aggressive tumors', 'Disease', (44, 61))	('LEPR', 'Gene', (14, 18))	('low', 'Var', (10, 13))
2220	28543182	Biologically, methylation in the promoter-associated CpG sites of LEPR presumably down-regulates LEPR expression in RCC tumors, and this assumption is supported indirectly by the information reported in TCGA portal regarding LEPR expression in tissue pairs of RCC tumor and normal-adjacent tissues.	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('RCC tumor', 'Disease', 'MESH:C538614', (116, 125))	('RCC tumor', 'Disease', 'MESH:C538614', (260, 269))	('methylation', 'Var', (14, 25))	('LEPR', 'Gene', '3953', (225, 229))	('LEPR', 'Gene', (225, 229))	('LEPR', 'Gene', '3953', (66, 70))	('LEPR', 'Gene', '3953', (97, 101))	('RCC tumors', 'Disease', (116, 126))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))	('LEPR', 'Gene', (66, 70))	('LEPR', 'Gene', (97, 101))	('RCC tumors', 'Disease', 'MESH:C538614', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('down-regulates', 'NegReg', (82, 96))	('expression', 'MPA', (102, 112))	('RCC', 'Phenotype', 'HP:0005584', (260, 263))	('RCC tumor', 'Disease', (260, 269))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
2221	28543182	Epigenetic regulation of LEPR expression has been previously suggested in thyroid cancer cells.	('LEPR', 'Gene', '3953', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('regulation', 'biological_process', 'GO:0065007', ('11', '21'))	('LEPR', 'Gene', (25, 29))	('Epigenetic regulation', 'Var', (0, 21))	('thyroid cancer', 'Phenotype', 'HP:0002890', (74, 88))	('thyroid cancer', 'Disease', (74, 88))	('thyroid cancer', 'Disease', 'MESH:D013964', (74, 88))
2222	28543182	Nevertheless, direct experimental data showing promoter hypermethylation leading to reduced LEPR expression in RCC cells is warranted to provide biological insights into the role of LEPR methylation in RCC prognosis.	('LEPR', 'Gene', '3953', (182, 186))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('hypermethylation', 'Var', (56, 72))	('LEPR', 'Gene', (92, 96))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('methylation', 'biological_process', 'GO:0032259', ('187', '198'))	('reduced', 'NegReg', (84, 91))	('promoter hypermethylation', 'Var', (47, 72))	('LEPR', 'Gene', '3953', (92, 96))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('LEPR', 'Gene', (182, 186))	('RCC', 'Disease', (202, 205))	('RCC', 'Phenotype', 'HP:0005584', (202, 205))	('expression', 'MPA', (97, 107))
2223	28543182	RCC patients with high methylation in LEPR have a higher risk of recurrence and shorter RFS time.	('LEPR', 'Gene', '3953', (38, 42))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('methylation', 'biological_process', 'GO:0032259', ('23', '34'))	('RFS time', 'CPA', (88, 96))	('shorter', 'NegReg', (80, 87))	('LEPR', 'Gene', (38, 42))	('patients', 'Species', '9606', (4, 12))	('high methylation', 'Var', (18, 34))	('recurrence', 'CPA', (65, 75))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('RCC', 'Disease', (0, 3))
2229	28543182	Even though our findings suggest an association between epigenetic alteration in obesity-related genes and RCC recurrence, the potential clinical relevance and the interaction of LEPR methylation with obesity/BMI are not fully understood due to the complexity of metabolic cancer pathways in particular leptin/leptin receptor signaling.	('metabolic cancer', 'Disease', (263, 279))	('LEPR', 'Gene', '3953', (179, 183))	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('RCC', 'Disease', (107, 110))	('obesity', 'Disease', (201, 208))	('obesity', 'Disease', (81, 88))	('signaling', 'biological_process', 'GO:0023052', ('326', '335'))	('methylation', 'biological_process', 'GO:0032259', ('184', '195'))	('LEPR', 'Gene', (179, 183))	('association', 'Interaction', (36, 47))	('metabolic cancer', 'Disease', 'MESH:D009369', (263, 279))	('leptin receptor', 'Gene', (310, 325))	('obesity', 'Disease', 'MESH:D009765', (201, 208))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('obesity', 'Disease', 'MESH:D009765', (81, 88))	('leptin receptor', 'Gene', '3953', (310, 325))	('leptin', 'Gene', '3952', (310, 316))	('leptin', 'Gene', '3952', (303, 309))	('leptin', 'Gene', (310, 316))	('leptin', 'Gene', (303, 309))	('obesity', 'Phenotype', 'HP:0001513', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('epigenetic alteration', 'Var', (56, 77))	('obesity', 'Phenotype', 'HP:0001513', (81, 88))
2235	28543182	In conclusion, our findings demonstrates that methylation in NPY, LEP and LEPR promoters is involved in RCC tumorigenesis.	('NPY', 'Gene', '4852', (61, 64))	('LEP', 'Gene', '3952', (74, 77))	('involved', 'Reg', (92, 100))	('methylation', 'Var', (46, 57))	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('LEP', 'Gene', (66, 69))	('LEPR', 'Gene', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('LEP', 'Gene', '3952', (66, 69))	('RCC tumor', 'Disease', 'MESH:C538614', (104, 113))	('NPY', 'Gene', (61, 64))	('LEP', 'Gene', (74, 77))	('LEPR', 'Gene', '3953', (74, 78))	('RCC tumor', 'Disease', (104, 113))
2238	28543182	In this study of 240 tumor-normal pairs from renal cell carcinoma (RCC) patients, we found methylation in obesity-related genes was involved in RCC tumorigenesis and prognosis.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('obesity', 'Phenotype', 'HP:0001513', (106, 113))	('tumor', 'Disease', (21, 26))	('RCC', 'Disease', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('obesity', 'Disease', (106, 113))	('RCC tumor', 'Disease', (144, 153))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('methylation', 'Var', (91, 102))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (45, 65))	('obesity', 'Disease', 'MESH:D009765', (106, 113))	('involved', 'Reg', (132, 140))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('RCC tumor', 'Disease', 'MESH:C538614', (144, 153))	('tumor', 'Disease', (148, 153))	('renal cell carcinoma', 'Disease', (45, 65))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (45, 65))	('patients', 'Species', '9606', (72, 80))
2239	28543182	Specifically, high methylation in leptin receptor (LEPR) gene was associated with more advanced tumor features and correlated with short recurrence-free survival.	('LEPR', 'Gene', '3953', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('associated', 'Reg', (66, 76))	('tumor', 'Disease', (96, 101))	('LEPR', 'Gene', (51, 55))	('leptin receptor', 'Gene', (34, 49))	('high methylation', 'Var', (14, 30))	('leptin receptor', 'Gene', '3953', (34, 49))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
2244	33178689	The innate immune, ratio between CD8+T cell versus Treg cell as well as Th17 cell versus Th2 cell were significantly decreased in high methylation risk group.	('CD8', 'Gene', (33, 36))	('CD8', 'Gene', '925', (33, 36))	('innate immune', 'MPA', (4, 17))	('high methylation', 'Var', (130, 146))	('decreased', 'NegReg', (117, 126))	('Th17 cell', 'CPA', (72, 81))	('methylation', 'biological_process', 'GO:0032259', ('135', '146'))
2246	33178689	Patients with higher methylation risk were associated genomic alteration and poor immune microenvironment.	('methylation', 'biological_process', 'GO:0032259', ('21', '32'))	('methylation', 'Var', (21, 32))	('Patients', 'Species', '9606', (0, 8))	('poor immune', 'Phenotype', 'HP:0002721', (77, 88))	('genomic', 'Disease', (54, 61))
2256	33178689	Epigenetic alterations have been demonstrated to serve as key contributors to the regulation of gene expression and involved in various kinds of malignancies as well as the clinicopathology of other medical conditions.	('Epigenetic alterations', 'Var', (0, 22))	('malignancies', 'Disease', (145, 157))	('involved', 'Reg', (116, 124))	('regulation of gene expression', 'MPA', (82, 111))	('malignancies', 'Disease', 'MESH:D009369', (145, 157))	('regulation of gene expression', 'biological_process', 'GO:0010468', ('82', '111'))
2258	33178689	Therefore, aberrant methylation CpG sites could be selected as novel prognostication markers in human cancers including ccRCC.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ccRCC', 'Phenotype', 'HP:0006770', (120, 125))	('human', 'Species', '9606', (96, 101))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('aberrant methylation', 'Var', (11, 31))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('cancers', 'Disease', (102, 109))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))
2259	33178689	In the present study, we identified a combination of 11 methylation sites associated with the survival, genomic alteration, and tumor microenvironment of patients with ccRCC, and suggested that it could be an independent prognostic factor in patients with ccRCC.	('RCC', 'Disease', (258, 261))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('ccRCC', 'Phenotype', 'HP:0006770', (256, 261))	('RCC', 'Disease', (170, 173))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('patients', 'Species', '9606', (154, 162))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('RCC', 'Disease', 'MESH:C538614', (258, 261))	('ccRCC', 'Phenotype', 'HP:0006770', (168, 173))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('tumor', 'Disease', (128, 133))	('methylation', 'Var', (56, 67))	('RCC', 'Phenotype', 'HP:0005584', (258, 261))	('associated', 'Reg', (74, 84))	('patients', 'Species', '9606', (242, 250))
2261	33178689	GSE113501, measured by Illumina HumanMethylation450 BeadChip and included 115 ccRCC patients and the associated methylation profile, were downloaded for Gene Expression Omnibus (GEO)3.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('patients', 'Species', '9606', (84, 92))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('Gene Expression', 'biological_process', 'GO:0010467', ('153', '168'))	('methylation', 'biological_process', 'GO:0032259', ('112', '123'))	('GSE113501', 'Var', (0, 9))	('Human', 'Species', '9606', (32, 37))
2269	33178689	To investigate the mechanisms that the DNA methylation-based panel affected the survival of ccRCC patients, we performed Spearman's rank correlation analysis to characterize the relationship between the methylation risk of ccRCC patients and genomic metrics of ccRCC patients including total numbers of mutations, clonal heterogeneity measured by the mutant-allele tumor heterogeneity (MATH), and somatic copy number alteration (SCNAs).	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('patients', 'Species', '9606', (229, 237))	('tumor', 'Phenotype', 'HP:0002664', (365, 370))	('patients', 'Species', '9606', (267, 275))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('RCC', 'Disease', (225, 228))	('RCC', 'Phenotype', 'HP:0005584', (225, 228))	('ccRCC', 'Phenotype', 'HP:0006770', (223, 228))	('DNA methylation', 'biological_process', 'GO:0006306', ('39', '54'))	('RCC', 'Disease', (263, 266))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('patients', 'Species', '9606', (98, 106))	('RCC', 'Phenotype', 'HP:0005584', (263, 266))	('tumor', 'Disease', (365, 370))	('ccRCC', 'Phenotype', 'HP:0006770', (261, 266))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Disease', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (365, 370))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('mutant-allele', 'Var', (351, 364))	('methylation', 'biological_process', 'GO:0032259', ('203', '214'))	('RCC', 'Disease', 'MESH:C538614', (263, 266))
2296	33178689	identified a 3- CpG site based promoter methylation signature associated with aggressive tumor phenotype and progression free survival in patients with ccRCC after surgical treatment.	('methylation', 'Var', (40, 51))	('aggressive tumor', 'Disease', (78, 94))	('associated with', 'Reg', (62, 77))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('RCC', 'Disease', (154, 157))	('RCC', 'Phenotype', 'HP:0005584', (154, 157))	('ccRCC', 'Phenotype', 'HP:0006770', (152, 157))	('methylation', 'biological_process', 'GO:0032259', ('40', '51'))	('progression free survival', 'CPA', (109, 134))	('aggressive tumor', 'Disease', 'MESH:D001523', (78, 94))	('patients', 'Species', '9606', (138, 146))
2303	33178689	As shown in Figure 6, the methylation risk of ccRCC patients was significantly correlated with total mutation number (R = 0.31, P < 0.0001, Figure 6A), SCNA (R = 0.29, P < 0.0001, Figure 6B), and MATH (R = 0.23, P < 0.0001, Figure 6C).	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('correlated', 'Interaction', (79, 89))	('RCC', 'Disease', (48, 51))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('methylation', 'MPA', (26, 37))	('mutation', 'Var', (101, 109))	('patients', 'Species', '9606', (52, 60))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
2312	33178689	As shown in Supplementary Figure S5, the methylation levels of cg15014975, cg07996594, cg26256263, cg18502142, cg15811515, cg09257635, cg10009968, cg08840441, and cg01977762 was obviously higher in ccRCCs compared with those in normal renal tissues (no significantly differences regarding the methylation levels of the others two CpG sites (cg24463471 and cg18279094) between the two groups), which was in accordance with the result of differentially methylation analysis above.	('ccRCC', 'Phenotype', 'HP:0006770', (198, 203))	('cg01977762', 'Var', (163, 173))	('cg15014975', 'Var', (63, 73))	('methylation', 'MPA', (41, 52))	('RCC', 'Disease', (200, 203))	('cg18502142', 'Var', (99, 109))	('RCC', 'Phenotype', 'HP:0005584', (200, 203))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('cg08840441', 'Var', (147, 157))	('higher', 'PosReg', (188, 194))	('RCC', 'Disease', 'MESH:C538614', (200, 203))	('cg10009968', 'Var', (135, 145))	('cg26256263', 'Var', (87, 97))	('methylation', 'biological_process', 'GO:0032259', ('451', '462'))	('methylation', 'biological_process', 'GO:0032259', ('293', '304'))	('cg07996594', 'Var', (75, 85))	('cg15811515', 'Var', (111, 121))	('cg09257635', 'Var', (123, 133))
2323	33178689	As expected, patients with higher methylation risk were associated with higher total mutation load, which was consistent with previous observations in other tumors.	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('methylation', 'Var', (34, 45))	('patients', 'Species', '9606', (13, 21))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('higher', 'PosReg', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
2327	33178689	As another genomic alteration, MATH, a measure of intratumor heterogeneity, utilized the broadness of the distribution of mutant allele frequencies and had been used to assess the clonal and genetic heterogeneity of tumors.	('tumor', 'Disease', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Disease', (216, 222))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('mutant', 'Var', (122, 128))
2331	33178689	In the present study, we investigated the associations between the methylation risk and the infiltrating immune cells of ccRCC patients.	('methylation', 'biological_process', 'GO:0032259', ('67', '78'))	('RCC', 'Disease', (123, 126))	('patients', 'Species', '9606', (127, 135))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (121, 126))	('methylation', 'Var', (67, 78))
2337	33178689	Meanwhile, we found the ratio between Th17 cells (antitumorigenic) versus Th2 (protumorigenic) cells was significantly decreased in high versus low methylation risk patients.	('decreased', 'NegReg', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('methylation', 'biological_process', 'GO:0032259', ('148', '159'))	('patients', 'Species', '9606', (165, 173))	('tumor', 'Disease', (54, 59))	('high', 'Var', (132, 136))	('tumor', 'Disease', (82, 87))
2343	33178689	The innate immune, and ratios between CD8+T cell versus Treg cell as well as Th17 cell versus Th2 cell were significantly decreased in high methylation risk group.	('decreased', 'NegReg', (122, 131))	('CD8', 'Gene', (38, 41))	('CD8', 'Gene', '925', (38, 41))	('high methylation risk', 'Var', (135, 156))	('methylation', 'biological_process', 'GO:0032259', ('140', '151'))	('innate immune', 'CPA', (4, 17))
2360	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))
2388	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))
2435	32286310	We examined the molecular differences of potential biomarkers reported in these studies for potential mechanisms that alter immunotherapy responsiveness, including TMB, individual gene mutations (PBRM1, BRCA2), GEP, neoantigen load, CYT and protein expression of checkpoint mediators (CTLA-4, PD-L1, PD-L2).	('TMB', 'Chemical', '-', (164, 167))	('PD-L1', 'Gene', (293, 298))	('BRCA2', 'Gene', '675', (203, 208))	('CTLA-4', 'Gene', (285, 291))	('CYT', 'MPA', (233, 236))	('PD-L1', 'Gene', '29126', (293, 298))	('CTLA-4', 'Gene', '1493', (285, 291))	('neoantigen load', 'MPA', (216, 231))	('PBRM1', 'Gene', (196, 201))	('GEP', 'MPA', (211, 214))	('PD-L2', 'Gene', '80380', (300, 305))	('protein', 'cellular_component', 'GO:0003675', ('241', '248'))	('PBRM1', 'Gene', '55193', (196, 201))	('mutations', 'Var', (185, 194))	('PD-L2', 'Gene', (300, 305))	('TMB', 'Gene', (164, 167))	('BRCA2', 'Gene', (203, 208))	('alter', 'Reg', (118, 123))
2444	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))
2475	31416266	Then, within the anti-CD45-Ab negative fractions, cells positive for anti-G250-Ab or anti-EpCAM-Ab are recognized as RCC CTC.	('RCC', 'Disease', 'MESH:D002292', (117, 120))	('RCC', 'Disease', (117, 120))	('CD45', 'Gene', '5788', (22, 26))	('EpCAM', 'Gene', (90, 95))	('anti-G250-Ab', 'Var', (69, 81))	('CD45', 'Gene', (22, 26))	('EpCAM', 'Gene', '4072', (90, 95))
2476	31416266	However, the sensitivity of these two markers for RCC CTC, sensitivity of anti-G250-Ab is much higher than that of anti-EpCAM-Ab.	('anti-G250-Ab', 'Var', (74, 86))	('sensitivity', 'MPA', (59, 70))	('higher', 'PosReg', (95, 101))	('RCC', 'Disease', 'MESH:D002292', (50, 53))	('RCC', 'Disease', (50, 53))	('EpCAM', 'Gene', (120, 125))	('EpCAM', 'Gene', '4072', (120, 125))
2484	31416266	The PBMCs and CTCs were distinguished by triple-staining with anti-D45, anti-G250, and anti-EpCAM antibodies.	('anti-G250', 'Var', (72, 81))	('anti-D45', 'Var', (62, 70))	('EpCAM', 'Gene', (92, 97))	('EpCAM', 'Gene', '4072', (92, 97))
2524	31416266	G250 antigen is expressed by virtually all ccRCC cells, but its expression in normal tissues is restricted.	('G250', 'Var', (0, 4))	('RCC', 'Disease', 'MESH:D002292', (45, 48))	('RCC', 'Disease', (45, 48))
2526	31416266	The mouse monoclonal antibody against human renal cell carcinoma mAb G250 specifically recognizes the ccRCC membrane antigen (G250).	('mouse', 'Species', '10090', (4, 9))	('RCC', 'Disease', 'MESH:D002292', (104, 107))	('human', 'Species', '9606', (38, 43))	('antibody', 'cellular_component', 'GO:0019815', ('21', '29'))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('antibody', 'cellular_component', 'GO:0019814', ('21', '29'))	('antibody', 'molecular_function', 'GO:0003823', ('21', '29'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (44, 64))	('G250', 'Var', (126, 130))	('membrane', 'cellular_component', 'GO:0016020', ('108', '116'))	('antibody', 'cellular_component', 'GO:0042571', ('21', '29'))	('renal cell carcinoma mAb', 'Disease', 'MESH:D002292', (44, 68))	('renal cell carcinoma mAb', 'Disease', (44, 68))	('RCC', 'Disease', (104, 107))
2527	31416266	G250 antigen has been shown to be expressed in 95% and 75% of primary tumors and metastatic lesions in immunohistological research, and its expression is hardly recognized in other normal tissues including the kidney.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('primary tumors', 'Disease', (62, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('G250', 'Var', (0, 4))	('primary tumors', 'Disease', 'MESH:D001932', (62, 76))	('metastatic lesions', 'CPA', (81, 99))
2536	31416266	In this study, we showed, for the first time, the specificity of G250 to RCC.	('G250', 'Var', (65, 69))	('RCC', 'Disease', 'MESH:D002292', (73, 76))	('RCC', 'Disease', (73, 76))
2585	33027921	PI3K and AKT/PKB are likely the most important protein kinases activated by the presence of PIP3.	('AKT', 'Gene', '207', (9, 12))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('PIP3', 'Chemical', '-', (92, 96))	('presence', 'Var', (80, 88))	('PIP3', 'Var', (92, 96))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('PI3K', 'Pathway', (0, 4))	('AKT', 'Gene', (9, 12))
2593	33027921	Interestingly, PDK1 phosphorylates both AKT and PKC, however, while PDK1-catalyzed phosphorylation of PKC represents a maturation step for PKC, phosphorylation of AKT directly activates this kinase.	('PDK1', 'Gene', (15, 19))	('PKC', 'Gene', '112476', (139, 142))	('PDK1', 'Gene', (68, 72))	('PKC', 'molecular_function', 'GO:0004697', ('48', '51'))	('AKT', 'Gene', (163, 166))	('AKT', 'Gene', '207', (40, 43))	('phosphorylation', 'Var', (144, 159))	('PKC', 'Gene', (139, 142))	('PDK1', 'Gene', '5163', (15, 19))	('PKC', 'Gene', '112476', (48, 51))	('PKC', 'molecular_function', 'GO:0004697', ('139', '142'))	('AKT', 'Gene', '207', (163, 166))	('PKC', 'Gene', '112476', (102, 105))	('PDK1', 'Gene', '5163', (68, 72))	('activates', 'PosReg', (176, 185))	('PDK1', 'molecular_function', 'GO:0004740', ('68', '72'))	('phosphorylation', 'biological_process', 'GO:0016310', ('144', '159'))	('PKC', 'Gene', (48, 51))	('phosphorylation', 'biological_process', 'GO:0016310', ('83', '98'))	('PKC', 'molecular_function', 'GO:0004697', ('102', '105'))	('AKT', 'Gene', (40, 43))	('PKC', 'Gene', (102, 105))	('PDK1', 'molecular_function', 'GO:0004740', ('15', '19'))
2612	33027921	Metabolic reprogramming in cancer cells was first reported in 1924 when Otto Warburg and co-workers demonstrated alterations in glucose metabolism resulting in aerobic glycolysis to support the high growth rates of transformed cells.	('glucose metabolism', 'Disease', (128, 146))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('glucose metabolism', 'biological_process', 'GO:0006006', ('128', '146'))	('glucose metabolism', 'Disease', 'MESH:D044882', (128, 146))	('cancer', 'Disease', (27, 33))	('glycolysis', 'biological_process', 'GO:0006096', ('168', '178'))	('alterations', 'Var', (113, 124))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('ob', 'Gene', '16846', (163, 165))
2613	33027921	While aberrant glucose metabolism was mistakenly attributed to defects in the function of mitochondria, it is generally accepted that increased glycolysis, even in the presence of oxygen, provides intermediates for the biosynthesis of nucleosides and amino acids.	('mitochondria', 'cellular_component', 'GO:0005739', ('90', '102'))	('nucleosides', 'Chemical', 'MESH:D009705', (235, 246))	('glucose metabolism', 'Disease', (15, 33))	('aberrant', 'Var', (6, 14))	('glucose metabolism', 'Disease', 'MESH:D044882', (15, 33))	('oxygen', 'Chemical', 'MESH:D010100', (180, 186))	('glycolysis', 'MPA', (144, 154))	('glucose metabolism', 'biological_process', 'GO:0006006', ('15', '33'))	('glycolysis', 'biological_process', 'GO:0006096', ('144', '154'))	('increased', 'PosReg', (134, 143))	('biosynthesis', 'biological_process', 'GO:0009058', ('219', '231'))
2614	33027921	Genomic and transcriptomic data derived from over thousands tumor samples across different types of cancer revealed that mutations on specific driver genes are the main force responsible for the development of cancer cells and drive a selection process which primarily converges on a metabolic network of reactions.	('mutations', 'Var', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('responsible', 'Reg', (175, 186))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('tumor', 'Disease', (60, 65))	('cancer', 'Disease', (210, 216))
2617	33027921	Marked increases in ACLY expression and activity have been found in many types of cancer cells and inhibition of this enzyme has been shown to reduce tumorigenesis in vivo.	('increases', 'PosReg', (7, 16))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ACLY', 'Gene', (20, 24))	('expression', 'MPA', (25, 35))	('inhibition', 'Var', (99, 109))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('cancer', 'Disease', (82, 88))	('reduce', 'NegReg', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('ACLY', 'Gene', '47', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('activity', 'MPA', (40, 48))	('tumor', 'Disease', (150, 155))
2618	33027921	Overexpression of ACC is often reported in advanced breast cancer and pre-neoplastic lesions and associated with increased risk of infiltrating breast cancer and reduced survival of patients.	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('pre', 'molecular_function', 'GO:0003904', ('70', '73'))	('reported', 'Reg', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('reduced', 'NegReg', (162, 169))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('ACC', 'Gene', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('Overexpression', 'Var', (0, 14))	('survival', 'CPA', (170, 178))	('ACC', 'Gene', '31', (18, 21))	('patients', 'Species', '9606', (182, 190))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (74, 92))
2633	33027921	In support of this, inhibition of mTORC2, but not mTORC1, has been shown to reduce the expression of genes regulating de novo lipogenesis and lipid content in hepatocellular carcinoma in vivo.	('de novo lipogenesis', 'MPA', (118, 137))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (159, 183))	('hepatocellular carcinoma', 'Disease', (159, 183))	('inhibition', 'Var', (20, 30))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (159, 183))	('mTORC1', 'Gene', (50, 56))	('lipid', 'Chemical', 'MESH:D008055', (142, 147))	('mTORC2', 'Gene', (34, 40))	('mTORC1', 'cellular_component', 'GO:0031931', ('50', '56'))	('expression', 'MPA', (87, 97))	('mTORC2', 'cellular_component', 'GO:0031932', ('34', '40'))	('mTORC2', 'Gene', '74343', (34, 40))	('reduce', 'NegReg', (76, 82))	('lipogenesis', 'biological_process', 'GO:0008610', ('126', '137'))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('mTORC1', 'Gene', '382056', (50, 56))
2635	33027921	SREBP1a and SREBP1c result from the alternative splicing of the SREBPF1 gene while SREBP2 is encoded by the SREBPF2 gene.	('splicing', 'biological_process', 'GO:0045292', ('48', '56'))	('alternative splicing', 'Var', (36, 56))	('SREBP2', 'Gene', '6721', (83, 89))	('SREBP1a', 'Gene', (0, 7))	('SREBP2', 'Gene', (83, 89))	('SREBP1c', 'Gene', (12, 19))	('SREBP1c', 'Gene', '6720', (12, 19))	('SREBP1a', 'Gene', '6720', (0, 7))	('SREBPF1', 'Gene', (64, 71))
2640	33027921	This is supported by in vivo studies employing EGFRvIII-bearing glioblastoma cells showing the high dependency of the cells on SREBP1 for survival and demonstrating that inhibition of SREBP1 and FASN, respectively, promotes massive tumor cell death in cancer cells bearing activated EGFR signaling.	('tumor cell death', 'Disease', 'MESH:D003643', (232, 248))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cell death', 'biological_process', 'GO:0008219', ('238', '248'))	('SREBP1', 'Gene', (184, 190))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'molecular_function', 'GO:0005006', ('283', '287'))	('inhibition', 'Var', (170, 180))	('FASN', 'Gene', (195, 199))	('tumor cell death', 'Disease', (232, 248))	('EGFR', 'Gene', '1956', (283, 287))	('SREBP1', 'Gene', '6720', (127, 133))	('SREBP1', 'Gene', (127, 133))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('cancer', 'Disease', (252, 258))	('signaling', 'biological_process', 'GO:0023052', ('288', '297'))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('EGFR', 'Gene', (47, 51))	('promotes', 'PosReg', (215, 223))	('glioblastoma', 'Disease', (64, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('FASN', 'Gene', '2194', (195, 199))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('SREBP1', 'Gene', '6720', (184, 190))	('EGFR', 'Gene', (283, 287))
2655	33027921	Although it is a phenomenon resulting from oncogenic mutations, the metabolic switch observed in the majority of cancer types seems to be context-dependent, namely, largely attributable to the microenvironment, rather than specific to the particular type of malignancy.	('malignancy', 'Disease', 'MESH:D009369', (258, 268))	('malignancy', 'Disease', (258, 268))	('ob', 'Gene', '16846', (85, 87))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('mutations', 'Var', (53, 62))	('cancer', 'Disease', (113, 119))	('metabolic', 'MPA', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
2658	33027921	Apart from the fact that metabolic regulation is substantially similar between the tumor and the normal tissue from which the malignancy derived, the analysis of gene expression changes across 13 different types of primary tumors has revealed that oncogenic mutations independently contribute to the deregulation of cell metabolism; however, they all seem to influence a common sub-set of pathways converging to the control of energy nucleotides and lipid metabolism.	('deregulation', 'MPA', (300, 312))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Disease', (223, 229))	('tumor', 'Disease', (83, 88))	('lipid', 'Chemical', 'MESH:D008055', (450, 455))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('malignancy', 'Disease', (126, 136))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (223, 228))	('metabolism', 'biological_process', 'GO:0008152', ('321', '331'))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('gene expression', 'biological_process', 'GO:0010467', ('162', '177'))	('mutations', 'Var', (258, 267))	('lipid metabolism', 'biological_process', 'GO:0006629', ('450', '466'))	('cell metabolism', 'MPA', (316, 331))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('regulation', 'biological_process', 'GO:0065007', ('35', '45'))	('malignancy', 'Disease', 'MESH:D009369', (126, 136))	('influence', 'Reg', (359, 368))	('oncogenic', 'Gene', (248, 257))
2666	33027921	Genetic loss on chromosome 14 is also frequently observed and this is associated with the loss of HIF-1A, which unlike HIF-2A has been predicted to be a ccRCC tumor suppressor gene product at least in certain conditions.	('ccRCC', 'Phenotype', 'HP:0006770', (153, 158))	('HIF-1A', 'Gene', (98, 104))	('tumor suppressor', 'biological_process', 'GO:0051726', ('159', '175'))	('ccRCC tumor', 'Disease', (153, 164))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('loss', 'Var', (90, 94))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('159', '175'))	('Genetic', 'Var', (0, 7))	('HIF-2A', 'Gene', '2034', (119, 125))	('loss', 'NegReg', (8, 12))	('HIF-2A', 'Gene', (119, 125))	('ccRCC tumor', 'Disease', 'MESH:D009369', (153, 164))	('chromosome', 'cellular_component', 'GO:0005694', ('16', '26'))	('HIF-1A', 'Gene', '3091', (98, 104))	('ob', 'Gene', '16846', (49, 51))
2681	33027921	Gene reprogramming in lipid metabolism under hypoxia results in enhanced lipogenesis by modulation of proteins controlling fatty acids synthesis, storage and uptake.	('modulation', 'Reg', (88, 98))	('Gene reprogramming', 'Var', (0, 18))	('lipid', 'Chemical', 'MESH:D008055', (22, 27))	('uptake', 'biological_process', 'GO:0098739', ('158', '164'))	('lipid metabolism', 'biological_process', 'GO:0006629', ('22', '38'))	('lipogenesis', 'MPA', (73, 84))	('synthesis', 'biological_process', 'GO:0009058', ('135', '144'))	('hypoxia', 'Disease', (45, 52))	('hypoxia', 'Disease', 'MESH:D000860', (45, 52))	('storage', 'biological_process', 'GO:0051235', ('146', '153'))	('uptake', 'biological_process', 'GO:0098657', ('158', '164'))	('fatty acids', 'Chemical', 'MESH:D005227', (123, 134))	('proteins', 'Protein', (102, 110))	('lipogenesis', 'biological_process', 'GO:0008610', ('73', '84'))	('enhanced', 'PosReg', (64, 72))
2739	33027921	In recent years, CX-4945 has been employed in Phase I, I/II clinical trials in patients with advanced solid cancers, Castelman'2 disease or multiple myeloma (test IDs: NCT00891280, NCT01199718), cholangiocarcinoma (test ID: NCT02128282), carcinoma, basal cell (test ID: NCT03897036) or pediatric medulloblastoma (test ID: NCT03904862).	('basal cell', 'Disease', (249, 259))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (195, 213))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('multiple myeloma', 'Phenotype', 'HP:0006775', (140, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('carcinoma', 'Disease', (238, 247))	('multiple myeloma', 'Disease', 'MESH:D009101', (140, 156))	("Castelman'2 disease", 'Disease', (117, 136))	("Castelman'2 disease", 'Disease', 'MESH:D004194', (117, 136))	('NCT01199718', 'Var', (181, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('medulloblastoma', 'Disease', 'MESH:D008527', (296, 311))	('medulloblastoma', 'Phenotype', 'HP:0002885', (296, 311))	('carcinoma', 'Disease', (204, 213))	('medulloblastoma', 'Disease', (296, 311))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancers', 'Disease', (108, 115))	('multiple myeloma', 'Disease', (140, 156))	('carcinoma', 'Disease', 'MESH:D009369', (238, 247))	('CX-4945', 'Chemical', 'MESH:C555142', (17, 24))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (195, 213))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('patients', 'Species', '9606', (79, 87))	('carcinoma', 'Disease', 'MESH:D009369', (204, 213))	('cholangiocarcinoma', 'Disease', (195, 213))
2752	33027921	However, the glucose-mediated activation of PII expression is suppressed following the phosphorylation of Sp1 by CK2 resulting in decreased Sp1 DNA binding (Figure 2A).	('phosphorylation', 'Var', (87, 102))	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))	('DNA binding', 'molecular_function', 'GO:0003677', ('144', '155'))	('CK2', 'Gene', (113, 116))	('suppressed', 'NegReg', (62, 72))	('glucose', 'Chemical', 'MESH:D005947', (13, 20))	('CK2', 'Gene', '13000', (113, 116))	('glucose-mediated activation', 'MPA', (13, 40))	('Sp1 DNA binding', 'Interaction', (140, 155))	('decreased', 'NegReg', (130, 139))	('PII', 'Gene', (44, 47))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))
2783	33027921	This is based on the fact that (i) CK2 phosphorylates LPIN1 at two distinct amino acids residues and lack of phosphorylation attenuates LPIN1 binding with 14-3-3beta a regulatory protein that normally facilitates the cytoplasmic localization of LPIN1, (ii) CK2 phosphorylates LXR and this post-translational modification modulates LXR transcriptional activity and restricts the range of LXR-responsive genes, and (iii) pharmacological inhibition of CK2 negatively affects the mTORC1 signaling cascade.	('CK2', 'Gene', '13000', (257, 260))	('CK2', 'Gene', '13000', (35, 38))	('LPIN1', 'Gene', '23175', (54, 59))	('CK2', 'Gene', (449, 452))	('LPIN1', 'Gene', (136, 141))	('CK2', 'Gene', (257, 260))	('CK2', 'Gene', (35, 38))	('LXR transcriptional activity', 'MPA', (331, 359))	('restricts', 'NegReg', (364, 373))	('binding', 'molecular_function', 'GO:0005488', ('142', '149'))	('LPIN1', 'Gene', (245, 250))	('signaling cascade', 'biological_process', 'GO:0007165', ('483', '500'))	('affects', 'Reg', (464, 471))	('lack', 'Var', (101, 105))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('negatively', 'NegReg', (453, 463))	('mTORC1', 'Gene', (476, 482))	('LPIN1', 'Gene', '23175', (136, 141))	('LPIN1', 'Gene', (54, 59))	('range', 'MPA', (378, 383))	('mTORC1', 'Gene', '382056', (476, 482))	('modulates', 'Reg', (321, 330))	('LPIN1', 'Gene', '23175', (245, 250))	('phosphorylation', 'biological_process', 'GO:0016310', ('109', '124'))	('localization', 'biological_process', 'GO:0051179', ('229', '241'))	('attenuates', 'NegReg', (125, 135))	('binding', 'Interaction', (142, 149))	('CK2', 'Gene', '13000', (449, 452))	('post-translational modification', 'biological_process', 'GO:0043687', ('289', '320'))	('mTORC1', 'cellular_component', 'GO:0031931', ('476', '482'))
2784	33027921	Additionally, AMPK represses the expression of SREBP1 target genes and the inhibition of CK2 up-regulates AMPK in vitro and in vivo (Figure 2B and Figure 3A).	('AMPK', 'molecular_function', 'GO:0050405', ('14', '18'))	('AMPK', 'molecular_function', 'GO:0004691', ('106', '110'))	('inhibition', 'Var', (75, 85))	('AMPK', 'Gene', '5562', (106, 110))	('AMPK', 'molecular_function', 'GO:0047322', ('106', '110'))	('AMPK', 'molecular_function', 'GO:0004691', ('14', '18'))	('SREBP1', 'Gene', '6720', (47, 53))	('up-regulates', 'PosReg', (93, 105))	('AMPK', 'molecular_function', 'GO:0047322', ('14', '18'))	('AMPK', 'Gene', (106, 110))	('CK2', 'Gene', (89, 92))	('AMPK', 'Gene', '5562', (14, 18))	('expression', 'MPA', (33, 43))	('AMPK', 'Gene', (14, 18))	('CK2', 'Gene', '13000', (89, 92))	('AMPK', 'molecular_function', 'GO:0050405', ('106', '110'))	('SREBP1', 'Gene', (47, 53))
2819	33027921	identified two CK2 sites targeting Ser-659 and Ser-661 in human cells in vitro and in vivo.	('Ser', 'Chemical', 'MESH:D012694', (47, 50))	('Ser', 'cellular_component', 'GO:0005790', ('35', '38'))	('Ser', 'Chemical', 'MESH:D012694', (35, 38))	('human', 'Species', '9606', (58, 63))	('CK2', 'Gene', (15, 18))	('Ser-661', 'Var', (47, 54))	('CK2', 'Gene', '13000', (15, 18))	('Ser', 'cellular_component', 'GO:0005790', ('47', '50'))	('Ser-659', 'Var', (35, 42))
2823	33027921	Later on, it was shown that the phosphorylation of SIRT1 at Ser-164 inhibited its nuclear localization and affected in part its deacetylase activity.	('deacetylase activity', 'MPA', (128, 148))	('phosphorylation', 'biological_process', 'GO:0016310', ('32', '47'))	('deacetylase activity', 'molecular_function', 'GO:0019213', ('128', '148'))	('localization', 'biological_process', 'GO:0051179', ('90', '102'))	('Ser', 'cellular_component', 'GO:0005790', ('60', '63'))	('inhibited', 'NegReg', (68, 77))	('affected', 'Reg', (107, 115))	('Ser', 'Chemical', 'MESH:D012694', (60, 63))	('phosphorylation', 'MPA', (32, 47))	('nuclear localization', 'MPA', (82, 102))	('Ser-164', 'Var', (60, 67))	('SIRT1', 'Gene', (51, 56))
2824	33027921	Ser-164 is part of a typical CK2 recognition site, i.e., S164SSD.	('Ser', 'Chemical', 'MESH:D012694', (0, 3))	('S164SSD', 'Mutation', 'p.S164SSD', (57, 64))	('S164SSD', 'Var', (57, 64))	('CK2', 'Gene', (29, 32))	('CK2', 'Gene', '13000', (29, 32))	('Ser', 'cellular_component', 'GO:0005790', ('0', '3'))
2832	33027921	Chronic inhibition of CK2 by small-molecule compounds for forty days has been shown to protect mice from diet-induced obesity.	('small-molecule', 'Var', (29, 43))	('obesity', 'Disease', (118, 125))	('mice', 'Species', '10090', (95, 99))	('inhibition', 'NegReg', (8, 18))	('CK2', 'Gene', (22, 25))	('diet-induced obesity', 'Phenotype', 'HP:0012743', (105, 125))	('obesity', 'Phenotype', 'HP:0001513', (118, 125))	('CK2', 'Gene', '13000', (22, 25))	('obesity', 'Disease', 'MESH:D009765', (118, 125))
2833	33027921	Interestingly, CK2 protein and activity levels are greatly up-regulated not only in WAT from ob/ob and db/db mice, but also in obese patients.	('up-regulated', 'PosReg', (59, 71))	('ob', 'Gene', '16846', (93, 95))	('patients', 'Species', '9606', (133, 141))	('activity levels', 'MPA', (31, 46))	('CK2', 'Gene', (15, 18))	('obese', 'Disease', 'MESH:D009765', (127, 132))	('CK2', 'Gene', '13000', (15, 18))	('ob', 'Gene', '16846', (127, 129))	('protein', 'cellular_component', 'GO:0003675', ('19', '26'))	('ob', 'Gene', '16846', (96, 98))	('db/db', 'Var', (103, 108))	('obese', 'Disease', (127, 132))	('mice', 'Species', '10090', (109, 113))
2835	33027921	Therefore, inhibition of CK2 may open a new therapeutic approach to target human obesity.	('CK2', 'Gene', '13000', (25, 28))	('obesity', 'Disease', 'MESH:D009765', (81, 88))	('obesity', 'Disease', (81, 88))	('inhibition', 'Var', (11, 21))	('CK2', 'Gene', (25, 28))	('human', 'Species', '9606', (75, 80))	('obesity', 'Phenotype', 'HP:0001513', (81, 88))
2845	33027921	reported the phosphorylation of Ser-338 in SIRT6, catalyzed by protein kinase CK2.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('protein kinase CK2', 'Gene', (63, 81))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('phosphorylation', 'MPA', (13, 28))	('SIRT6', 'Gene', (43, 48))	('Ser', 'cellular_component', 'GO:0005790', ('32', '35'))	('Ser', 'Chemical', 'MESH:D012694', (32, 35))	('protein kinase CK2', 'Gene', '1457', (63, 81))	('SIRT6', 'Gene', '51548', (43, 48))	('Ser-338', 'Var', (32, 39))
2846	33027921	Overexpression of SIRT6 in breast cancer cells increased proliferation, but mutation at the CK2 Ser-338 phosphorylation site of SIRT6 inhibited the proliferation of breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('SIRT6', 'Gene', '51548', (18, 23))	('CK2', 'Gene', (92, 95))	('mutation', 'Var', (76, 84))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('SIRT6', 'Gene', (128, 133))	('breast cancer', 'Disease', (165, 178))	('proliferation', 'CPA', (148, 161))	('phosphorylation', 'biological_process', 'GO:0016310', ('104', '119'))	('SIRT6', 'Gene', '51548', (128, 133))	('Ser', 'Chemical', 'MESH:D012694', (96, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('Ser', 'cellular_component', 'GO:0005790', ('96', '99'))	('inhibited', 'NegReg', (134, 143))	('breast cancer', 'Disease', (27, 40))	('proliferation', 'CPA', (57, 70))	('SIRT6', 'Gene', (18, 23))	('CK2', 'Gene', '13000', (92, 95))
2859	33027921	Hence, pharmacological inhibition of this enzyme might be an attractive approach to combat obesity and improve the care of obesity-associated diseases.	('obesity', 'Disease', 'MESH:D009765', (91, 98))	('obesity', 'Disease', (91, 98))	('obesity', 'Disease', 'MESH:D009765', (123, 130))	('pharmacological', 'Var', (7, 22))	('obesity', 'Disease', (123, 130))	('obesity', 'Phenotype', 'HP:0001513', (91, 98))	('obesity', 'Phenotype', 'HP:0001513', (123, 130))
2866	29098020	Renin angiotensin system deregulation as renal cancer risk factor For numerous years, the non-cardiovascular role of the renin-angiotensin system (RAS) was underestimated, but recent studies have advanced the understanding of its function in various processes, including carcinogenesis.	('deregulation', 'Var', (25, 37))	('renal cancer', 'Disease', (41, 53))	('Renin', 'Gene', '5972', (0, 5))	('renal cancer', 'Disease', 'MESH:D007680', (41, 53))	('renin', 'Gene', '5972', (121, 126))	('carcinogenesis', 'Disease', 'MESH:D063646', (271, 285))	('renin', 'Gene', (121, 126))	('renal cancer', 'Phenotype', 'HP:0009726', (41, 53))	('Renin', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('carcinogenesis', 'Disease', (271, 285))
2872	29098020	Recent evidence regarding the treatment of hypertension associated with tyrosine kinase inhibitors, one of the most pronounced and common side effects in modern RCC treatment, are also outlined.	('hypertension', 'Disease', 'MESH:D006973', (43, 55))	('hypertension', 'Disease', (43, 55))	('hypertension', 'Phenotype', 'HP:0000822', (43, 55))	('tyrosine', 'Var', (72, 80))	('RCC', 'Disease', (161, 164))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('RCC', 'Disease', 'MESH:C538614', (161, 164))
2879	29098020	The most common alteration include inactivation of Von Hippel-Lindau gene (VHL), mutations in cMET and TP53 genes, upregulation of vascular endothelial growth factor A (VEGFA), and plateled-derived growth factor B (PDGFB).	('TP53', 'Gene', '7157', (103, 107))	('Von Hippel-Lindau', 'Disease', (51, 68))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('131', '165'))	('VHL', 'Gene', (75, 78))	('upregulation', 'PosReg', (115, 127))	('PDGFB', 'Gene', '5155', (215, 220))	('TP53', 'Gene', (103, 107))	('inactivation', 'Var', (35, 47))	('cMET', 'Gene', '4233', (94, 98))	('VHL', 'Gene', '7428', (75, 78))	('VEGFA', 'Gene', (169, 174))	('cMET', 'Gene', (94, 98))	('vascular endothelial growth factor A', 'Gene', '7422', (131, 167))	('vascular endothelial growth factor A', 'Gene', (131, 167))	('PDGFB', 'Gene', (215, 220))	('mutations', 'Var', (81, 90))	('Von Hippel-Lindau', 'Disease', 'MESH:D006623', (51, 68))	('VEGFA', 'Gene', '7422', (169, 174))
2891	29098020	Ang-II can also undergo further modifications by aminopeptidases A and N to produce angiotensin III (Ang-III) and angiotensin IV (Ang-IV), respectively.	('angiotensin II', 'Gene', '183', (84, 98))	('Ang-I', 'Gene', (101, 106))	('angiotensin I', 'Gene', '183', (114, 127))	('angiotensin I', 'Gene', '183', (84, 97))	('Ang-II', 'Gene', '183', (101, 107))	('angiotensin II', 'Gene', (84, 98))	('aminopeptidases A', 'Enzyme', (49, 66))	('Ang-I', 'Gene', '183', (130, 135))	('Ang-I', 'Gene', '183', (0, 5))	('Ang-II', 'Gene', (0, 6))	('Ang-I', 'Gene', (130, 135))	('Ang-I', 'Gene', (0, 5))	('angiotensin I', 'Gene', (114, 127))	('modifications', 'Var', (32, 45))	('Ang-II', 'Gene', '183', (0, 6))	('Ang-I', 'Gene', '183', (101, 106))	('Ang-II', 'Gene', (101, 107))
2898	29098020	Dysregulation or over-activity of the system is associated with cardiovascular diseases, predominantly hypertension.	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (64, 87))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (64, 87))	('Dysregulation', 'Var', (0, 13))	('associated', 'Reg', (48, 58))	('over-activity', 'PosReg', (17, 30))	('hypertension', 'Disease', 'MESH:D006973', (103, 115))	('hypertension', 'Disease', (103, 115))	('hypertension', 'Phenotype', 'HP:0000822', (103, 115))	('cardiovascular diseases', 'Disease', (64, 87))
2924	29098020	ACE2 is a carboxypeptidase that cleaves single amino acids from Ang-I to produce angiotensin- or to degrade Ang-II to Ang 1-7.	('Ang-I', 'Gene', (108, 113))	('Ang-I', 'Gene', '183', (108, 113))	('angiotensin-', 'MPA', (81, 93))	('ACE2', 'Gene', (0, 4))	('produce', 'PosReg', (73, 80))	('Ang 1-7', 'Gene', '284;285;51378;27329', (118, 125))	('Ang-II', 'Gene', (108, 114))	('Ang-I', 'Gene', (64, 69))	('Ang-I', 'Gene', '183', (64, 69))	('ACE2', 'Gene', '59272', (0, 4))	('degrade', 'NegReg', (100, 107))	('cleaves', 'Var', (32, 39))	('Ang-II', 'Gene', '183', (108, 114))	('Ang 1-7', 'Gene', (118, 125))
2943	29098020	It is hypothesized that ACEI influences cancer incidence, and prognosis may be associated with differences in ACE activity in plasma, which is strongly correlated with the insertion/deletion (I/D) polymorphisms of 287 base pairs in intron 16 of the ACE gene (rs4646994).	('polymorphisms', 'Var', (197, 210))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('correlated', 'Reg', (152, 162))	('ACE activity', 'molecular_function', 'GO:0004246', ('110', '122'))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('ACE', 'Gene', (249, 252))	('rs4646994', 'Mutation', 'rs4646994', (259, 268))	('cancer', 'Disease', (40, 46))	('influences', 'Reg', (29, 39))	('rs4646994', 'Var', (259, 268))	('insertion/deletion', 'Var', (172, 190))	('prognosis', 'CPA', (62, 71))	('ACE activity', 'MPA', (110, 122))
2945	29098020	In the large cohort analyzed for a correlation between the rs4646994 polymorphism and cancer incidence among RAS inhibitors users, Van der Knaap et al concluded that using RAS inhibitors is associated with a significant decrease in the risk of four of the most common non-skin cancers (colorectal, lung, breast and prostate) in individuals with the DD genotype, especially among long-term users.	('rs4646994', 'Var', (59, 68))	('non-skin cancers', 'Disease', 'MESH:D012878', (268, 284))	('lung', 'Disease', (298, 302))	('rs4646994', 'Mutation', 'rs4646994', (59, 68))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('RAS', 'Protein', (172, 175))	('decrease', 'NegReg', (220, 228))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('skin cancers', 'Phenotype', 'HP:0008069', (272, 284))	('colorectal', 'Disease', (286, 296))	('colorectal', 'Disease', 'MESH:D015179', (286, 296))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('non-skin cancers', 'Disease', (268, 284))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('breast', 'Disease', (304, 310))	('cancer', 'Disease', (86, 92))
2952	29098020	The rs4646994 polymorphism is linked with RCC development but not progression.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('rs4646994', 'Var', (4, 13))	('rs4646994', 'Mutation', 'rs4646994', (4, 13))	('linked', 'Reg', (30, 36))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))
2954	29098020	Polymorphisms rs4295 and rs4343 are not associated with RCC risk, neither in hypertensive nor in normotensive patients.	('hypertensive', 'Disease', (77, 89))	('rs4295', 'Mutation', 'rs4295', (14, 20))	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('rs4343', 'Var', (25, 31))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('rs4295', 'Var', (14, 20))	('hypertensive', 'Disease', 'MESH:D006973', (77, 89))	('rs4343', 'Mutation', 'rs4343', (25, 31))	('patients', 'Species', '9606', (110, 118))
2955	29098020	Andreotti et al has examined another 11 polymorphisms in the ACE gene but did not discover any associations with RCC risk.	('polymorphisms', 'Var', (40, 53))	('ACE', 'Gene', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))
2956	29098020	Polymorphisms in two other genes encoding RAS proteins-AGT (preangiotensinogen) and AGTR1, were examined by Andreotti et al, and five AGT single nucleotide polymorphisms (SNPs) [rs1326889, rs2493137, rs7539020, rs3889728, rs3789662] are significantly associated with RCC when adjusted for age, gender, country, smoking status, BMI, hypertension, and lead exposure.	('rs2493137', 'Mutation', 'rs2493137', (189, 198))	('rs3889728', 'Mutation', 'rs3889728', (211, 220))	('AGT', 'Gene', '183', (55, 58))	('RCC', 'Disease', (267, 270))	('RCC', 'Phenotype', 'HP:0005584', (267, 270))	('hypertension', 'Phenotype', 'HP:0000822', (332, 344))	('rs1326889', 'Mutation', 'rs1326889', (178, 187))	('rs3889728', 'Var', (211, 220))	('AGT', 'Gene', '183', (134, 137))	('rs2493137', 'Var', (189, 198))	('AGT', 'Gene', (55, 58))	('RCC', 'Disease', 'MESH:C538614', (267, 270))	('rs7539020', 'Mutation', 'rs7539020', (200, 209))	('AGTR1', 'Gene', (84, 89))	('AGT', 'Gene', '183', (84, 87))	('AGTR1', 'Gene', '185', (84, 89))	('AGT', 'Gene', (134, 137))	('rs7539020', 'Var', (200, 209))	('associated', 'Reg', (251, 261))	('angiotensinogen', 'Gene', (63, 78))	('AGT', 'Gene', (84, 87))	('rs3789662]', 'Var', (222, 232))	('rs3789662', 'Mutation', 'rs3789662', (222, 231))	('angiotensinogen', 'Gene', '183', (63, 78))	('hypertension', 'Disease', 'MESH:D006973', (332, 344))	('hypertension', 'Disease', (332, 344))	('[rs1326889', 'Var', (177, 187))
2957	29098020	Rs1326889 has the highest impact on kidney cancer with OR 1.26.	('Rs1326889', 'Var', (0, 9))	('kidney cancer', 'Disease', (36, 49))	('Rs1326889', 'Mutation', 'Rs1326889', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('kidney cancer', 'Disease', 'MESH:D007680', (36, 49))	('kidney cancer', 'Phenotype', 'HP:0009726', (36, 49))
2964	29098020	Specific inhibitors of AT2-R (PD123319, PD123117, CGP42114, saralasin), AT4-R (Divalnal-Ang-IV), and MasR (A-779, D-Pro7-Ang 1-7) receptors have been discovered, but so far they are used only in research and clinical studies.	('AT2', 'Gene', '186', (23, 26))	('PD123117', 'Chemical', '-', (40, 48))	('Ang-I', 'Gene', (88, 93))	('PD123319', 'Chemical', 'MESH:C073402', (30, 38))	('Ang-I', 'Gene', '183', (88, 93))	('Ang 1-7', 'Gene', '284;285;51378;27329', (121, 128))	('CGP42114', 'Gene', (50, 58))	('PD123117', 'Var', (40, 48))	('PD123319', 'Var', (30, 38))	('AT2', 'Gene', (23, 26))	('Ang 1-7', 'Gene', (121, 128))
2972	29098020	Additionally, ACEIs decrease the degradation of bradykinin, which stimulates the production of vasodilatatory factors, such as NO, cGMP, prostaglandin E2, and prostacyclin.	('prostaglandin E2', 'MPA', (137, 153))	('prostacyclin', 'Chemical', 'MESH:D011464', (159, 171))	('degradation', 'biological_process', 'GO:0009056', ('33', '44'))	('bradykinin', 'Gene', '3827', (48, 58))	('bradykinin', 'Gene', (48, 58))	('production of vasodilatatory factors', 'MPA', (81, 117))	('decrease', 'NegReg', (20, 28))	('ACEIs', 'Var', (14, 19))	('prostacyclin', 'MPA', (159, 171))	('cGMP', 'Chemical', 'MESH:D006152', (131, 135))	('stimulates', 'PosReg', (66, 76))	('cGMP', 'MPA', (131, 135))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (137, 153))
3035	29098020	In a multivariate analysis, ASI use was independently associated with improved PFS (HR=0.54).	('ASI', 'Var', (28, 31))	('ASI', 'Chemical', '-', (28, 31))	('improved', 'PosReg', (70, 78))	('PFS', 'Disease', (79, 82))
3037	29098020	OS was significantly longer in ASI users than in non-users (adjusted HR 0.848, 95% CI 0.731-0.960) and individuals receiving no antihypertensive treatment (adjusted HR 0.81, 95% CI 0.707-0.929).	('ASI', 'Chemical', '-', (31, 34))	('hypertensive', 'Disease', (132, 144))	('ASI', 'Var', (31, 34))	('hypertensive', 'Disease', 'MESH:D006973', (132, 144))
3038	29098020	Similarly, PFS was significantly longer in ASI users compared with users of other drugs (HR 0.786, 95% CI 0.707-0.876, median 8.4 vs. 6.70 months).	('PFS', 'MPA', (11, 14))	('longer', 'PosReg', (33, 39))	('ASI', 'Var', (43, 46))	('ASI', 'Chemical', '-', (43, 46))
3042	29098020	Results similar to those of Keizman et al and McKay et al were presented by Izzedine et al, who in a multivariable Cox regression model also showed the significant association between ASI use and PFS and OS, with HR=0.4 (0.24-0.66; P<0.001) and HR=0.55 (0.35-0.86; P=0.009), respectively.	('ASI', 'Var', (184, 187))	('PFS', 'Disease', (196, 199))	('ASI', 'Chemical', '-', (184, 187))
3045	29098020	Recently, a secondary pooled analysis of two Phase III randomized controlled trials of patients with mRCC (NCT00334282 and NCT00720941) was published.	('NCT00720941', 'Var', (123, 134))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('NCT00334282', 'Var', (107, 118))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('patients', 'Species', '9606', (87, 95))
3047	29098020	When individual VEGF-targeted therapies were analyzed separately, there was a marginally significant association between ASI use and improved OS in patients receiving sunitinib (HR 0.73, P=0.03), but not for those receiving pazopanib or a placebo.	('patients', 'Species', '9606', (148, 156))	('VEGF', 'Gene', '7422', (16, 20))	('ASI', 'Chemical', '-', (121, 124))	('pazopanib', 'Chemical', 'MESH:C516667', (224, 233))	('improved OS', 'Disease', (133, 144))	('VEGF', 'Gene', (16, 20))	('sunitinib', 'Chemical', 'MESH:D000077210', (167, 176))	('ASI', 'Gene', (121, 124))	('sunitinib', 'Var', (167, 176))
3055	29098020	Many authors suggest that a blockage of the RAS leads to decreased cell proliferation and changes in the tumor microenvironment.	('blockage', 'Var', (28, 36))	('cell proliferation', 'CPA', (67, 85))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('changes', 'Reg', (90, 97))	('tumor', 'Disease', (105, 110))	('decreased', 'NegReg', (57, 66))	('RAS', 'Protein', (44, 47))
3064	29098020	The median PFS and OS are significantly longer among patients with HTN than among those without, with no difference in whether HTN was defined as SBP or DBP over the normal limit.	('patients', 'Species', '9606', (53, 61))	('longer', 'PosReg', (40, 46))	('DBP', 'Gene', '1628', (153, 156))	('PFS', 'MPA', (11, 14))	('HTN', 'Phenotype', 'HP:0000822', (127, 130))	('HTN', 'Var', (67, 70))	('HTN', 'Phenotype', 'HP:0000822', (67, 70))	('DBP', 'Gene', (153, 156))
3069	29098020	Clinical data were confirmed in a mouse model where plasma renin activity was decreased in rats exposed to TKI cediranib.	('renin', 'Gene', (59, 64))	('rats', 'Species', '10116', (91, 95))	('cediranib', 'Chemical', 'MESH:C500926', (111, 120))	('mouse', 'Species', '10090', (34, 39))	('renin', 'Gene', '5972', (59, 64))	('TKI', 'Var', (107, 110))	('decreased', 'NegReg', (78, 87))	('renin activity', 'molecular_function', 'GO:0004195', ('59', '73'))
3084	29098020	The concomitant use of ACEI captopril with sorafenib can lead to a 30-mmHg decrease in a rise in BP in comparison with sorafenib alone (155 vs. 182 mmHg, P<0.05) and can reduce albuminuria by 50%.	('reduce', 'NegReg', (170, 176))	('albuminuria', 'Disease', (177, 188))	('decrease', 'NegReg', (75, 83))	('albuminuria', 'Phenotype', 'HP:0012592', (177, 188))	('albuminuria', 'Disease', 'MESH:D000419', (177, 188))	('sorafenib', 'Chemical', 'MESH:D000077157', (43, 52))	('ACEI', 'Var', (23, 27))	('captopril', 'Chemical', 'MESH:D002216', (28, 37))	('sorafenib', 'Chemical', 'MESH:D000077157', (119, 128))
3101	29098020	Despite a general decrease in cancer incidence, one study showed an increase in RCC among ACEI recipients.	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('ACEI', 'Var', (90, 94))	('increase', 'PosReg', (68, 76))	('decrease', 'NegReg', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
3104	29098020	Some authors present data suggesting ACEIs decrease survival in a mouse model, while others prove decreases in tumor growth, cell viability, and proliferation when used alone or combined with sunitinib.	('decrease', 'NegReg', (43, 51))	('ACEIs', 'Var', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('sunitinib', 'Chemical', 'MESH:D000077210', (192, 201))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mouse', 'Species', '10090', (66, 71))	('cell viability', 'CPA', (125, 139))	('proliferation', 'CPA', (145, 158))	('tumor', 'Disease', (111, 116))	('survival', 'CPA', (52, 60))	('decreases', 'NegReg', (98, 107))
3107	29098020	ACEI affects the levels of many RAS components: Ang-I, Ang-II, ACE, Ang 1-7, and ACE2, as well as bradykinin, whose cleavage is mediated by ACE (Fig.	('ACEI', 'Var', (0, 4))	('cleavage', 'MPA', (116, 124))	('Ang-I', 'Gene', (55, 60))	('ACE2', 'Gene', (81, 85))	('affects', 'Reg', (5, 12))	('Ang 1-7', 'Gene', (68, 75))	('Ang-II', 'Gene', (55, 61))	('Ang-I', 'Gene', '183', (48, 53))	('ACE2', 'Gene', '59272', (81, 85))	('Ang 1-7', 'Gene', '284;285;51378;27329', (68, 75))	('bradykinin', 'Gene', '3827', (98, 108))	('levels', 'MPA', (17, 23))	('bradykinin', 'Gene', (98, 108))	('Ang-I', 'Gene', (48, 53))	('Ang-II', 'Gene', '183', (55, 61))	('Ang-I', 'Gene', '183', (55, 60))
3120	30975145	Notably, CD103+ CSC exosomes were enriched in tumor cells and in lung as well, highlighting the organotropism conferred by CD103.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('CD103+', 'Var', (9, 15))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
3123	30975145	CD103+ acted to guide CSC exosomes to target cancer cells and organs, conferring the higher metastatic capacity of CCRCC to lungs, suggesting CD103+ exosomes as a potential metastatic diagnostic biomarker.	('CD103+', 'Var', (142, 148))	('metastatic capacity', 'CPA', (92, 111))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('higher', 'PosReg', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('CCRCC', 'Phenotype', 'HP:0006770', (115, 120))	('cancer', 'Disease', (45, 51))
3150	30975145	We proposed based upon the messages presented above that CSC exosomes play an important role in determining the destination or target organ/tissue for distant metastasis of CCRCC by actin of miRNAs for delivery of epigenetic information.	('miR', 'Gene', (191, 194))	('epigenetic', 'Var', (214, 224))	('CCRCC', 'Disease', (173, 178))	('CCRCC', 'Phenotype', 'HP:0006770', (173, 178))	('miR', 'Gene', '220972', (191, 194))
3205	30975145	The lentivirus carrying the antisense inhibitor of miR-19b (anti-miR) was used to knock down endogenous miR-19b-3p and the levels of miR-19b-3p in CSCs exosomes were successfully decreased by lentivirus infection of the CSCs (Fig.	('miR-19b', 'Gene', (51, 58))	('miR', 'Gene', (133, 136))	('miR-19b', 'Gene', '406980', (133, 140))	('miR', 'Gene', '220972', (51, 54))	('miR-19b', 'Gene', (104, 111))	('lentivirus infection of the CSCs', 'Disease', 'MESH:D016180', (192, 224))	('miR-19b', 'Gene', '406980', (51, 58))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (51, 54))	('miR', 'Gene', '220972', (104, 107))	('miR', 'Gene', (65, 68))	('miR-19b', 'Gene', '406980', (104, 111))	('miR-19b', 'Gene', (133, 140))	('miR', 'Gene', (104, 107))	('levels', 'MPA', (123, 129))	('decreased', 'NegReg', (179, 188))	('miR', 'Gene', '220972', (133, 136))	('lentivirus infection of the CSCs', 'Disease', (192, 224))	('knock down', 'Var', (82, 92))
3206	30975145	3d & e, infection of the cells with anti-miR to knock down endogenous miR-19b-3p attenuated the migration- and invasion-promoting effects of S-Exo and M-S-Exo.	('Exo', 'Gene', '24127', (143, 146))	('Exo', 'Gene', (155, 158))	('Exo', 'Gene', '24127', (155, 158))	('miR-19b', 'Gene', '406980', (70, 77))	('miR', 'Gene', '220972', (41, 44))	('miR', 'Gene', (41, 44))	('and', 'Var', (147, 150))	('endogenous', 'Gene', (59, 69))	('to knock', 'Var', (45, 53))	('miR', 'Gene', '220972', (70, 73))	('miR', 'Gene', (70, 73))	('Exo', 'Gene', (143, 146))	('miR-19b', 'Gene', (70, 77))
3209	30975145	The above results indicate that miR-19b-3p might be an initiator of EMT since knockdown of this miRNA resulted in downregulation of N-cadherin, Vimentin and Twist.	('miR', 'Gene', (32, 35))	('N-cadherin', 'Gene', '1000', (132, 142))	('Vimentin', 'Gene', '7431', (144, 152))	('cadherin', 'molecular_function', 'GO:0008014', ('134', '142'))	('knockdown', 'Var', (78, 87))	('EMT', 'biological_process', 'GO:0001837', ('68', '71'))	('Twist', 'CPA', (157, 162))	('miR-19b', 'Gene', (32, 39))	('miR', 'Gene', '220972', (96, 99))	('Vimentin', 'cellular_component', 'GO:0045098', ('144', '152'))	('miR', 'Gene', (96, 99))	('miR', 'Gene', '220972', (32, 35))	('Vimentin', 'cellular_component', 'GO:0045099', ('144', '152'))	('miR-19b', 'Gene', '406980', (32, 39))	('N-cadherin', 'Gene', (132, 142))	('Vimentin', 'Gene', (144, 152))	('downregulation', 'NegReg', (114, 128))
3215	30975145	Aberrant expression of PTEN has been implicated as a key mediator of cell migration which is closely related to EMT.	('Aberrant expression', 'Var', (0, 19))	('cell migration', 'biological_process', 'GO:0016477', ('69', '83'))	('PTEN', 'Gene', (23, 27))	('cell migration', 'CPA', (69, 83))	('PTEN', 'Gene', '5728', (23, 27))	('EMT', 'biological_process', 'GO:0001837', ('112', '115'))
3261	30975145	The larger proportion of CD103+ exosomes over total exosomes in CSCs of metastatic patients seemed to be a crucial factor in directing metastatic sites of exosomes (Additional file 2: Figure S1).	('patients', 'Species', '9606', (83, 91))	('CD103+', 'Var', (25, 31))	('metastatic', 'MPA', (135, 145))
3270	30975145	Such malignant effects of miR-19b-3p could be reversed by its antisense inhibitor to knockdown this miRNA.	('miR', 'Gene', '220972', (26, 29))	('miR', 'Gene', (26, 29))	('miR', 'Gene', '220972', (100, 103))	('miR', 'Gene', (100, 103))	('knockdown', 'Var', (85, 94))	('miR-19b', 'Gene', (26, 33))	('miR-19b', 'Gene', '406980', (26, 33))
3280	30975145	In addition, the pivotal effect of CD103 in guiding organotropism suggest that depleting CD103+ CSC exosomes might represent another novel strategy for the treatment of metastatic CCRCC patients.	('depleting', 'Var', (79, 88))	('CD103+ CSC exosomes', 'MPA', (89, 108))	('metastatic CCRCC', 'Disease', (169, 185))	('CCRCC', 'Phenotype', 'HP:0006770', (180, 185))	('patients', 'Species', '9606', (186, 194))
3285	29457966	Because dysregulation of histone deacetylase and DNA methyltransferases are hallmarks of malignancy, they have become promising therapeutic targets.	('dysregulation', 'Var', (8, 21))	('malignancy', 'Disease', (89, 99))	('DNA methyltransferase', 'Gene', (49, 70))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('histone', 'Protein', (25, 32))	('DNA methyltransferase', 'Gene', '1786', (49, 70))	('malignancy', 'Disease', 'MESH:D009369', (89, 99))
3289	29457966	The combination of VPA and 5-Aza also elicited more apoptosis and produced more cell cycle arrest in the G1 phase for both cell lines.	('VPA', 'Chemical', 'MESH:D014635', (19, 22))	('5-Aza', 'Chemical', 'MESH:D001374', (27, 32))	('5-Aza', 'Var', (27, 32))	('elicited', 'Reg', (38, 46))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (80, 97))	('G1 phase', 'biological_process', 'GO:0051318', ('105', '113'))	('cell cycle arrest in the G1 phase', 'CPA', (80, 113))	('apoptosis', 'CPA', (52, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('52', '61'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('80', '97'))	('apoptosis', 'biological_process', 'GO:0006915', ('52', '61'))
3290	29457966	On the other hand, treatment of RCC cells with VPA, 5-Aza, or a combination of both resulted in slow wound healing and impaired migration.	('slow wound healing', 'Phenotype', 'HP:0001058', (96, 114))	('5-Aza', 'Chemical', 'MESH:D001374', (52, 57))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('VPA', 'Chemical', 'MESH:D014635', (47, 50))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('5-Aza', 'Var', (52, 57))	('migration', 'CPA', (128, 137))	('RCC', 'Disease', (32, 35))	('slow', 'NegReg', (96, 100))	('impaired', 'NegReg', (119, 127))	('wound healing', 'biological_process', 'GO:0042060', ('101', '114'))
3302	29457966	Studies have shown that VPA exhibits anti-tumor effects in various malignancies, including glioblastoma, neuroblastoma, breast and ovarian cancers, colorectal cancer, prostate cancer, thyroid cancer, liver cancer, melanoma, etc.. VPA can inhibit cancer cell proliferation as well as induces cell apoptosis.	('inhibit', 'NegReg', (238, 245))	('neuroblastoma', 'Disease', 'MESH:D009447', (105, 118))	('cell proliferation', 'biological_process', 'GO:0008283', ('253', '271'))	('glioblastoma', 'Disease', 'MESH:D005909', (91, 103))	('malignancies', 'Disease', (67, 79))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('colorectal cancer', 'Phenotype', 'HP:0003003', (148, 165))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (192, 198))	('VPA', 'Var', (230, 233))	('glioblastoma', 'Disease', (91, 103))	('induces', 'Reg', (283, 290))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (120, 146))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('thyroid cancer', 'Disease', (184, 198))	('tumor', 'Disease', (42, 47))	('cancer', 'Disease', (246, 252))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('melanoma', 'Disease', (214, 222))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('liver cancer', 'Disease', 'MESH:D006528', (200, 212))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('prostate cancer', 'Disease', 'MESH:D011471', (167, 182))	('prostate cancer', 'Phenotype', 'HP:0012125', (167, 182))	('colorectal cancer', 'Disease', 'MESH:D015179', (148, 165))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('thyroid cancer', 'Disease', 'MESH:D013964', (184, 198))	('prostate cancer', 'Disease', (167, 182))	('colorectal cancer', 'Disease', (148, 165))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('liver cancer', 'Phenotype', 'HP:0002896', (200, 212))	('malignancies', 'Disease', 'MESH:D009369', (67, 79))	('liver cancer', 'Disease', (200, 212))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('apoptosis', 'biological_process', 'GO:0097194', ('296', '305'))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('apoptosis', 'biological_process', 'GO:0006915', ('296', '305'))	('cancer', 'Disease', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('thyroid cancer', 'Phenotype', 'HP:0002890', (184, 198))	('neuroblastoma', 'Disease', (105, 118))	('cell apoptosis', 'CPA', (291, 305))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('VPA', 'Chemical', 'MESH:D014635', (24, 27))	('VPA', 'Chemical', 'MESH:D014635', (230, 233))	('melanoma', 'Disease', 'MESH:D008545', (214, 222))	('neuroblastoma', 'Phenotype', 'HP:0003006', (105, 118))	('cancer', 'Disease', (176, 182))	('ovarian cancers', 'Phenotype', 'HP:0100615', (131, 146))
3304	29457966	5-Aza-2'-deoxycytidine (5-Aza) is a nucleoside analog that acts as an inhibitor of DNMTs and greatly represses DNMT functions during DNA replication through DNA demethylation or hemi-demethylation.	('5-Aza', 'Chemical', 'MESH:D001374', (0, 5))	('DNMT', 'Gene', (83, 87))	('DNA demethylation', 'biological_process', 'GO:0080111', ('157', '174'))	('nucleoside', 'Chemical', 'MESH:D009705', (36, 46))	('5-Aza', 'Chemical', 'MESH:D001374', (24, 29))	('demethylation', 'biological_process', 'GO:0070988', ('183', '196'))	("5-Aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (0, 22))	('DNA replication', 'biological_process', 'GO:0006260', ('133', '148'))	('DNMT', 'Gene', (111, 115))	('represses', 'NegReg', (101, 110))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('hemi-demethylation', 'Var', (178, 196))	('DNA demethylation', 'Var', (157, 174))	('DNMT', 'Gene', '1786', (83, 87))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('DNMT', 'Gene', '1786', (111, 115))
3341	29457966	When treatment with VPA and 5-Aza was combined, a higher proportion of G1 cells were detected for both 786-O and 769-P cells, although the increase was less than 5% compared to the VPA group (Figure 3).	('5-Aza', 'Chemical', 'MESH:D001374', (28, 33))	('769-P cells', 'Var', (113, 124))	('VPA', 'Chemical', 'MESH:D014635', (20, 23))	('VPA', 'Chemical', 'MESH:D014635', (181, 184))	('G1 cells', 'CPA', (71, 79))	('786-O', 'Var', (103, 108))
3348	29457966	A Transwell assay suggested that the migratory ability of 786-O and 769-P cells was significantly decreased after treatment with VPA or 5-Aza, and the inhibitory effect of the combined treatment was more pronounced compared to the control group (P<0.01, Figure 5B.	('5-Aza', 'Var', (136, 141))	('decreased', 'NegReg', (98, 107))	('VPA', 'Chemical', 'MESH:D014635', (129, 132))	('5-Aza', 'Chemical', 'MESH:D001374', (136, 141))
3354	29457966	Epigenetic changes, as important regulator of gene expression, play important roles in gene transcription and early events in tumorigenesis.	('gene expression', 'biological_process', 'GO:0010467', ('46', '61'))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('transcription', 'biological_process', 'GO:0006351', ('92', '105'))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('Epigenetic changes', 'Var', (0, 18))	('tumor', 'Disease', (126, 131))
3355	29457966	Therefore, disruption of the balance between HATs and HDACs is known to be involved in cancer genesis and progression.	('cancer', 'Disease', (87, 93))	('involved', 'Reg', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('disruption', 'Var', (11, 21))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
3361	29457966	DNA methylation alterations are one of the most consistent epigenetic modifications occurring during carcinogenesis and are widely accepted as a feature of RCC.	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'Gene', (0, 3))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('carcinogenesis', 'Disease', (101, 115))	('RCC', 'Disease', (156, 159))	('alterations', 'Var', (16, 27))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('carcinogenesis', 'Disease', 'MESH:D063646', (101, 115))	('methylation alterations', 'Var', (4, 27))
3362	29457966	As hypermethylation inactivates transcription of CpG dinucleotides in promoter regions of tumor suppressor genes leading to gene silencing, re-expression of epigenetically silenced tumor suppressor genes with DNA methyltransferase (DNMT) inhibitors is a rational strategy for the treatment of human neoplasms.	('tumor suppressor', 'biological_process', 'GO:0051726', ('90', '106'))	('transcription', 'MPA', (32, 45))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('181', '197'))	('neoplasms', 'Disease', 'MESH:D009369', (299, 308))	('tumor', 'Disease', (90, 95))	('DNA methyltransferase', 'Gene', '1786', (209, 230))	('tumor suppressor', 'biological_process', 'GO:0051726', ('181', '197'))	('inactivates', 'NegReg', (20, 31))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('transcription', 'biological_process', 'GO:0006351', ('32', '45'))	('gene', 'MPA', (124, 128))	('neoplasms', 'Disease', (299, 308))	('DNMT', 'Gene', '1786', (232, 236))	('DNMT', 'Gene', (232, 236))	('human', 'Species', '9606', (293, 298))	('hypermethylation', 'Var', (3, 19))	('DNA', 'cellular_component', 'GO:0005574', ('209', '212'))	('tumor', 'Disease', (181, 186))	('DNA methyltransferase', 'Gene', (209, 230))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('90', '106'))	('gene silencing', 'biological_process', 'GO:0016458', ('124', '138'))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('neoplasms', 'Phenotype', 'HP:0002664', (299, 308))
3422	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))	('CK7', 'Var', (49, 52))	('positive', 'Reg', (81, 89))	('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))
3449	27690003	The key molecular abnormalities observed in RCC are frequent mutations of the VHL gene that lead to activation of the HIF1A/ARNT transcription factor pathway.	('transcription factor', 'molecular_function', 'GO:0000981', ('129', '149'))	('HIF1A', 'Gene', '3091', (118, 123))	('VHL', 'Gene', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('mutations', 'Var', (61, 70))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('VHL', 'Gene', '7428', (78, 81))	('ARNT', 'Gene', (124, 128))	('activation', 'PosReg', (100, 110))	('HIF1A', 'Gene', (118, 123))	('transcription', 'biological_process', 'GO:0006351', ('129', '142'))	('ARNT', 'Gene', '405', (124, 128))
3463	27690003	To see if SRSF2 affects spontaneous apoptosis in renal cancer cells, we silenced SRSF2 in the Caki-2 cell line and analysed populations of apoptotic cells using annexin V/propidium iodide (PI) staining.	('apoptosis', 'biological_process', 'GO:0097194', ('36', '45'))	('renal cancer', 'Disease', (49, 61))	('SRSF2', 'Gene', (81, 86))	('Caki-2', 'CellLine', 'CVCL:0235', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('renal cancer', 'Phenotype', 'HP:0009726', (49, 61))	('apoptosis', 'biological_process', 'GO:0006915', ('36', '45'))	('silenced', 'Var', (72, 80))	('renal cancer', 'Disease', 'MESH:D007680', (49, 61))	('propidium iodide', 'Chemical', 'MESH:D011419', (171, 187))	('annexin V', 'Gene', '308', (161, 170))	('annexin V', 'Gene', (161, 170))
3466	27690003	RNA from Caki-2 cells with silenced SRSF2 expression was subjected to the array analysis and the results were independently validated on three additional renal cancer-derived cell lines (UOK171, KIJ-265T, and KIJ-308T) (Figure S3).	('silenced', 'Var', (27, 35))	('additional renal cancer', 'Disease', (143, 166))	('SRSF2', 'Gene', (36, 41))	('renal cancer', 'Phenotype', 'HP:0009726', (154, 166))	('Caki-2', 'CellLine', 'CVCL:0235', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('UOK171', 'CellLine', 'CVCL:B223', (187, 193))	('additional renal cancer', 'Disease', 'MESH:D007680', (143, 166))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))
3467	27690003	Silencing of SRSF2 changed expression of six genes, involved in extrinsic (TNFRSF9, TNFRSF1B, and CRADD) and intrinsic (BCL2L2, BCL2A1) apoptotic pathways, as well as the expression of TP53.	('BCL2L2', 'Gene', (120, 126))	('SRSF2', 'Gene', (13, 18))	('TNFRSF9', 'Gene', (75, 82))	('expression', 'MPA', (27, 37))	('BCL2A1', 'Gene', (128, 134))	('BCL2A1', 'Gene', '597', (128, 134))	('BCL2', 'molecular_function', 'GO:0015283', ('120', '124'))	('TNFRSF1B', 'Gene', '7133', (84, 92))	('changed', 'Reg', (19, 26))	('TNFRSF9', 'Gene', '3604', (75, 82))	('BCL2L2', 'Gene', '599', (120, 126))	('BCL2', 'molecular_function', 'GO:0015283', ('128', '132'))	('Silencing', 'Var', (0, 9))	('CRADD', 'Gene', (98, 103))	('CRADD', 'Gene', '8738', (98, 103))	('TNFRSF1B', 'Gene', (84, 92))
3468	27690003	Specifically, in all four tested cell lines, depletion of SRSF2 resulted in decreased expression of TNFRSF9 and CRADD.	('TNFRSF9', 'Gene', (100, 107))	('TNFRSF9', 'Gene', '3604', (100, 107))	('decreased', 'NegReg', (76, 85))	('expression', 'MPA', (86, 96))	('SRSF2', 'Gene', (58, 63))	('depletion', 'Var', (45, 54))	('CRADD', 'Gene', (112, 117))	('CRADD', 'Gene', '8738', (112, 117))
3469	27690003	In three out of the four tested cell lines silencing of SRSF2 resulted in decreased expression of TNFRSF1B and BCL2L2, as well as increased expression of TP53.	('TNFRSF1B', 'Gene', '7133', (98, 106))	('increased', 'PosReg', (130, 139))	('BCL2L2', 'Gene', '599', (111, 117))	('expression', 'MPA', (140, 150))	('TNFRSF1B', 'Gene', (98, 106))	('BCL2L2', 'Gene', (111, 117))	('silencing', 'Var', (43, 52))	('BCL2', 'molecular_function', 'GO:0015283', ('111', '115'))	('SRSF2', 'Gene', (56, 61))	('decreased', 'NegReg', (74, 83))	('expression', 'MPA', (84, 94))	('TP53', 'MPA', (154, 158))
3472	27690003	Silencing of SRSF2 in the four renal cancer-derived cell lines resulted in concomitant changes of splicing profile of eight out of the 14 analysed genes (Figure 4).	('splicing profile', 'MPA', (98, 114))	('renal cancer', 'Disease', (31, 43))	('SRSF2', 'Gene', (13, 18))	('splicing', 'biological_process', 'GO:0045292', ('98', '106'))	('renal cancer', 'Disease', 'MESH:D007680', (31, 43))	('renal cancer', 'Phenotype', 'HP:0009726', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('changes', 'Reg', (87, 94))	('Silencing', 'Var', (0, 9))
3473	27690003	Specifically, in all four tested cell lines depletion of SRSF2 resulted in decreased expression of proapoptotic: caspase-9a, Smac3 (a splice variant of SMAC/DIABLO that counteracts caspase-9 inhibition), surv-2B (a splice variant of BIRC5/survivin that activates caspase-9), BimS and Bimalpha3, as well as MCL-1S.	('activates', 'PosReg', (253, 262))	('caspase-9', 'Gene', (181, 190))	('SMAC', 'Gene', '56616', (152, 156))	('depletion', 'Var', (44, 53))	('BIRC5', 'Gene', '332', (233, 238))	('BIRC5', 'Gene', (233, 238))	('caspase-9', 'Gene', '842', (263, 272))	('Smac3', 'Gene', (125, 130))	('DIABLO', 'Gene', '56616', (157, 163))	('caspase-9', 'Gene', '842', (113, 122))	('expression', 'MPA', (85, 95))	('SRSF2', 'Gene', (57, 62))	('proapoptotic', 'MPA', (99, 111))	('caspase-9', 'Gene', (263, 272))	('caspase-9', 'Gene', '842', (181, 190))	('MCL-1S', 'Gene', '4170', (306, 312))	('MCL-1S', 'Gene', (306, 312))	('SMAC', 'Gene', (152, 156))	('caspase-9', 'Gene', (113, 122))	('DIABLO', 'Gene', (157, 163))	('decreased', 'NegReg', (75, 84))
3474	27690003	Furthermore, silencing of SRSF2 resulted in increased expression of anti-apoptotic isoforms of caspases: -9b (in all four tested cell lines), and -8L (in three out of the four tested cell lines).	('expression', 'MPA', (54, 64))	('caspase', 'Gene', (95, 102))	('anti-apoptotic isoforms', 'MPA', (68, 91))	('caspase', 'Gene', '835;839;841;842', (95, 102))	('SRSF2', 'Gene', (26, 31))	('increased', 'PosReg', (44, 53))	('silencing', 'Var', (13, 22))
3476	27690003	Finally, in all four tested cell lines, silencing of SRSF2 resulted in a new splice variant of CFLAR with canonical splice sites (GT/AG) confirmed by sequencing.	('SRSF2', 'Gene', (53, 58))	('CFLAR', 'Gene', (95, 100))	('resulted in', 'Reg', (59, 70))	('silencing', 'Var', (40, 49))	('CFLAR', 'Gene', '8837', (95, 100))
3477	27690003	Basic Local Alignment Search Tool analysis revealed that open reading frame (ORF) sequence of the new CFLAR variant resembled the sequence of previously published CFLAR isoform called Usurpine-beta (Gene Bank Acc.	('CFLAR', 'Gene', (102, 107))	('CFLAR', 'Gene', '8837', (163, 168))	('variant', 'Var', (108, 115))	('CFLAR', 'Gene', '8837', (102, 107))	('CFLAR', 'Gene', (163, 168))
3480	27690003	Silencing of SRSF2 resulted in 40% decrease of caspase-9 activation.	('caspase-9', 'Gene', '842', (47, 56))	('SRSF2', 'Gene', (13, 18))	('decrease', 'NegReg', (35, 43))	('caspase-9', 'Gene', (47, 56))	('Silencing', 'Var', (0, 9))	('activation', 'MPA', (57, 67))
3482	27690003	These effects of SRSF2 depletion were accompanied by inhibition of apoptosis and increased viability of renal cancer cells.	('viability', 'CPA', (91, 100))	('apoptosis', 'CPA', (67, 76))	('inhibition', 'NegReg', (53, 63))	('depletion', 'Var', (23, 32))	('inhibition of apoptosis', 'biological_process', 'GO:0043066', ('53', '76'))	('renal cancer', 'Disease', (104, 116))	('SRSF2', 'Gene', (17, 22))	('renal cancer', 'Disease', 'MESH:D007680', (104, 116))	('renal cancer', 'Phenotype', 'HP:0009726', (104, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('increased', 'PosReg', (81, 90))
3484	27690003	In agreement with a previous study, we observed that silencing of SRSF2 resulted in induced expression of antiapoptotic caspase-8L and caspase-9b, with concomitant inhibition of proapoptotic caspase-9a.	('caspase', 'Gene', (135, 142))	('caspase', 'Gene', (191, 198))	('caspase', 'Gene', '835;839;841;842', (191, 198))	('caspase-9', 'Gene', '842', (191, 200))	('caspase', 'Gene', '835;839;841;842', (135, 142))	('antiapoptotic', 'MPA', (106, 119))	('caspase-9', 'Gene', (135, 144))	('caspase-9', 'Gene', (191, 200))	('caspase', 'Gene', '835;839;841;842', (120, 127))	('caspase', 'Gene', (120, 127))	('SRSF2', 'Gene', (66, 71))	('silencing', 'Var', (53, 62))	('caspase-9', 'Gene', '842', (135, 144))	('inhibition', 'NegReg', (164, 174))	('expression', 'MPA', (92, 102))
3485	27690003	Depletion of SRSF2 also resulted in decreased expression of proapoptotic Smac3 (a splice variant of DIABLO that inhibits XIAP (X-linked inhibitor of apoptosis)), Surv-2B (a splice variant of survivin that induces mitochondria-dependent apoptosis), MCL-1S (an inhibitor of antiapoptotic MCL-1L), and BimS (an inhibitor of antiapoptotic BCL2 and activator of proapoptotic BAX).	('apoptosis', 'biological_process', 'GO:0097194', ('236', '245'))	('BCL2', 'molecular_function', 'GO:0015283', ('335', '339'))	('apoptosis', 'biological_process', 'GO:0006915', ('236', '245'))	('DIABLO', 'Gene', (100, 106))	('XIAP', 'Gene', '331', (121, 125))	('Depletion', 'Var', (0, 9))	('MCL-1L', 'Gene', '4170', (286, 292))	('Smac3', 'Gene', (73, 78))	('mitochondria', 'cellular_component', 'GO:0005739', ('213', '225'))	('MCL-1L', 'Gene', (286, 292))	('MCL-1S', 'Gene', '4170', (248, 254))	('SRSF2', 'Gene', (13, 18))	('MCL-1S', 'Gene', (248, 254))	('apoptosis', 'biological_process', 'GO:0097194', ('149', '158'))	('apoptosis', 'biological_process', 'GO:0006915', ('149', '158'))	('X-linked inhibitor of apoptosis', 'Gene', (127, 158))	('X-linked inhibitor of apoptosis', 'Gene', '331', (127, 158))	('BCL2', 'Gene', '596', (335, 339))	('XIAP', 'Gene', (121, 125))	('DIABLO', 'Gene', '56616', (100, 106))	('Surv-2B', 'Gene', (162, 169))	('expression', 'MPA', (46, 56))	('BCL2', 'Gene', (335, 339))	('BAX', 'Gene', (370, 373))	('BAX', 'Gene', '581', (370, 373))	('inhibits', 'NegReg', (112, 120))	('decreased', 'NegReg', (36, 45))
3486	27690003	Furthermore, decreased expression of genes coding for death receptors (TNFRSF1B and TNFRSF9) and CRADD (encoding a protein recruiting caspase-2 to death receptors) are also in line with inhibition of apoptosis induced by SRSF2 silencing.	('decreased', 'NegReg', (13, 22))	('silencing', 'Var', (227, 236))	('inhibition of apoptosis', 'biological_process', 'GO:0043066', ('186', '209'))	('TNFRSF1B', 'Gene', (71, 79))	('TNFRSF9', 'Gene', (84, 91))	('TNFRSF1B', 'Gene', '7133', (71, 79))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('CRADD', 'Gene', (97, 102))	('caspase-2', 'Gene', '835', (134, 143))	('CRADD', 'Gene', '8738', (97, 102))	('caspase-2', 'Gene', (134, 143))	('TNFRSF9', 'Gene', '3604', (84, 91))	('apoptosis', 'CPA', (200, 209))	('expression', 'MPA', (23, 33))
3489	27690003	Furthermore, silencing of SRSF2 resulted in increased expression of a new splice variant of CFLAR with ORF sequence resembling the sequence of CFLAR isoform called Usurpin-beta.	('expression', 'MPA', (54, 64))	('CFLAR', 'Gene', (92, 97))	('CFLAR', 'Gene', '8837', (143, 148))	('SRSF2', 'Gene', (26, 31))	('CFLAR', 'Gene', (143, 148))	('Usurpin-beta', 'Gene', '8837', (164, 176))	('Usurpin-beta', 'Gene', (164, 176))	('increased', 'PosReg', (44, 53))	('CFLAR', 'Gene', '8837', (92, 97))	('silencing', 'Var', (13, 22))
3498	27690003	Furthermore, changes in alternative splicing of apoptotic genes influence sensitivity of cancer cells to chemotherapeutics, e.g., cisplatin or paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (143, 153))	('alternative', 'MPA', (24, 35))	('changes', 'Var', (13, 20))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('influence', 'Reg', (64, 73))	('cancer', 'Disease', (89, 95))	('splicing', 'biological_process', 'GO:0045292', ('36', '44'))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('apoptotic genes', 'Gene', (48, 63))	('sensitivity', 'MPA', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
3502	27690003	The changes introduced by the depletion of SRSF2 consist of up-regulation of apoptotic inhibitors and decreased expression of activators of programmed cell death, and culminate in inhibition of caspase-9 and protection of cell viability (Figure 6).	('regulation', 'biological_process', 'GO:0065007', ('63', '73'))	('SRSF2', 'Gene', (43, 48))	('depletion', 'Var', (30, 39))	('caspase-9', 'Gene', (194, 203))	('up-regulation', 'PosReg', (60, 73))	('programmed cell death', 'biological_process', 'GO:0012501', ('140', '161'))	('cell viability', 'CPA', (222, 236))	('caspase-9', 'Gene', '842', (194, 203))	('expression of activators', 'MPA', (112, 136))	('inhibition', 'NegReg', (180, 190))	('decreased', 'NegReg', (102, 111))	('apoptotic inhibitors', 'Protein', (77, 97))
3522	27690003	The new CFLAR splice variant was amplified using Perpetual OptiTaq DNA Polymerase HOT START (EURx, Gdansk, Poland), and primers (cflip-ex1-F: CTTCCAGGCTTTCGGTTTCTTTGC and cflip-ex12b-R: TTGGTTTCTTATGTGTAGGAGAGG) under the following conditions: 95  C, 10 min (initial denaturation), followed by 35 cycles at: 95  C, 30 s; 57  C, 30 s; 72  C, 1.5 min; final elongation: 61  C, 10 min.	('CFLAR', 'Gene', (8, 13))	('HOT START', 'Phenotype', 'HP:0031217', (82, 91))	('cflip-ex1-F', 'Var', (129, 140))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('CFLAR', 'Gene', '8837', (8, 13))	('cflip-ex12b-R', 'Var', (171, 184))
3618	32616076	Final approval of manuscript: All authors Cancer Center Core Grant P30 CA008748 from the National Cancer Institute.	('P30 CA008748', 'Var', (67, 79))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Cancer', 'Disease', (98, 104))	('Cancer', 'Disease', 'MESH:D009369', (42, 48))	('Cancer', 'Disease', (42, 48))	('Cancer', 'Disease', 'MESH:D009369', (98, 104))	('Cancer', 'Phenotype', 'HP:0002664', (42, 48))
3623	28489074	Clustering copy number alterations shows that most cell lines resemble ccRCC, a few (including some often used as models of ccRCC) resemble pRCC, and none resemble chRCC.	('RCC', 'Disease', (141, 144))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('RCC', 'Disease', (166, 169))	('copy', 'Var', (11, 15))	('RCC', 'Disease', (126, 129))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
3625	28489074	We stratify mutations and copy number alterations for important kidney cancer genes by the consistency between databases, and classify cell lines into established gene expression-based indolent and aggressive subtypes.	('mutations', 'Var', (12, 21))	('gene expression', 'biological_process', 'GO:0010467', ('163', '178'))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('kidney cancer', 'Phenotype', 'HP:0009726', (64, 77))	('kidney cancer', 'Disease', 'MESH:D007680', (64, 77))	('kidney cancer', 'Disease', (64, 77))
3641	28489074	Recurrent copy number alterations (CNAs) of chromosomes 5, 8 and 14 have been identified as additional pathogenic mechanisms of ccRCC.	('CNA', 'Gene', (35, 38))	('CNA', 'Gene', '19055', (35, 38))	('copy number alterations', 'Var', (10, 33))	('RCC', 'Disease', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (130, 133))
3652	28489074	This is in agreement with recent work reporting discrepancies in the detection of missense mutations in cell lines common to CCLE and CCLP (57% conformity).	('CCLE', 'Chemical', '-', (125, 129))	('CCLE', 'Disease', (125, 129))	('missense mutations', 'Var', (82, 100))
3667	28489074	These tumours also display a higher extent of copy number aberrations (mean fraction genome altered: 19% versus 12%), and more frequent mutations in genes such as BAP1 (12.3% versus 5.4%), SETD2 (12.7% versus 8.1%) and MTOR (6% versus 4.7%), which are associated with more aggressive disease (though only BAP1 has a statistically significant difference:P value 0.025, Fisher's exact test).	('BAP1', 'Gene', (305, 309))	('MTOR', 'Gene', '2475', (219, 223))	('aggressive disease', 'Disease', 'MESH:D001523', (273, 291))	('SETD2', 'Gene', '29072', (189, 194))	('BAP1', 'Gene', '8314', (163, 167))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('aggressive disease', 'Disease', (273, 291))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('copy', 'MPA', (46, 50))	('mutations', 'Var', (136, 145))	('BAP1', 'Gene', (163, 167))	('MTOR', 'Gene', (219, 223))	('BAP1', 'Gene', '8314', (305, 309))	('SETD2', 'Gene', (189, 194))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('tumours', 'Disease', (6, 13))
3672	28489074	In the set of 1,508 overlapping genes profiled for mutations by CCLE, CCLP and TCGA, the median number of mutated genes is 40 in CCLE kidney cell lines (minimum: 22, maximum: 92) and 26 in CCLP kidney cell lines (min 5, max 72) compared to 6 (min 0, max 27) in TCGA ccRCC tumours.	('mutations', 'Var', (51, 60))	('ccRCC tumours', 'Disease', (266, 279))	('tumour', 'Phenotype', 'HP:0002664', (272, 278))	('ccRCC tumours', 'Disease', 'MESH:D009369', (266, 279))	('tumours', 'Phenotype', 'HP:0002664', (272, 279))	('CCLE', 'Chemical', '-', (64, 68))	('CCLE', 'Chemical', '-', (129, 133))
3678	28489074	In the 16 important kidney cancer genes covered by CCLE, the CCLE kidney cell lines had a range of 0-3 mutations and a median of 1 mutation, with ACHN, KMRC1, KMRC3, SNU349, SNU1272, RCC10RGB and TUHR4TKB showing no mutations in these key genes.	('CCLE', 'Chemical', '-', (61, 65))	('mutations', 'Var', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('kidney cancer', 'Phenotype', 'HP:0009726', (20, 33))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('RCC', 'Disease', (183, 186))	('CCLE', 'Chemical', '-', (51, 55))	('kidney cancer', 'Disease', (20, 33))	('kidney cancer', 'Disease', 'MESH:D007680', (20, 33))
3679	28489074	None of the CCLP cell lines had a mutation in any of the genes FLCN, ARID1A, MICALCL, SLC1A3, STAG2 or TCEB1; while none of the CCLE cell lines had a mutation in FLCN, ARID1A, FLCN, NF2 or TSC1.	('SLC1A3', 'Gene', '6507', (86, 92))	('FLCN', 'Gene', (63, 67))	('NF2', 'Gene', '4771', (182, 185))	('ARID1A', 'Gene', '8289', (69, 75))	('CCLE', 'Chemical', '-', (128, 132))	('TSC1', 'Gene', '7248', (189, 193))	('NF2', 'Gene', (182, 185))	('STAG2', 'Gene', '10735', (94, 99))	('ARID1A', 'Gene', (168, 174))	('FLCN', 'Gene', '201163', (162, 166))	('MICALCL', 'Gene', '84953', (77, 84))	('STAG2', 'Gene', (94, 99))	('FLCN', 'Gene', (162, 166))	('ARID1A', 'Gene', '8289', (168, 174))	('TCEB1', 'Gene', (103, 108))	('MICALCL', 'Gene', (77, 84))	('SLC1A3', 'Gene', (86, 92))	('FLCN', 'Gene', '201163', (176, 180))	('mutation', 'Var', (150, 158))	('FLCN', 'Gene', '201163', (63, 67))	('TCEB1', 'Gene', '6921', (103, 108))	('FLCN', 'Gene', (176, 180))	('ARID1A', 'Gene', (69, 75))	('TSC1', 'Gene', (189, 193))
3681	28489074	Given that VHL is a notoriously challenging gene to sequence, we additionally culled the existing literature for evidence of VHL mutations in the various RCC cell lines (Supplementary Table 1).	('VHL', 'Gene', (125, 128))	('mutations', 'Var', (129, 138))	('VHL', 'Gene', '7428', (125, 128))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('VHL', 'Gene', (11, 14))	('RCC', 'Disease', (154, 157))	('VHL', 'Gene', '7428', (11, 14))
3682	28489074	Interestingly, several cell lines that cluster with ccRCC and demonstrate the classical copy number characteristics do not harbour VHL mutations.	('VHL', 'Gene', (131, 134))	('mutations', 'Var', (135, 144))	('VHL', 'Gene', '7428', (131, 134))	('RCC', 'Disease', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (54, 57))
3683	28489074	Furthermore, mutations of mTOR pathway genes including MTOR, TSC1, TSC2, PTEN and PIK3CA are detected in nine (41%) of CCLE and 14 (42%) of the CCLP RCC cell lines.	('RCC', 'Disease', (149, 152))	('CCLE', 'Chemical', '-', (119, 123))	('PTEN', 'Gene', (73, 77))	('MTOR', 'Gene', '2475', (55, 59))	('PIK3CA', 'Gene', (82, 88))	('PTEN', 'Gene', '5728', (73, 77))	('CCLE', 'Disease', (119, 123))	('detected', 'Reg', (93, 101))	('TSC1', 'Gene', '7248', (61, 65))	('RCC', 'Disease', 'MESH:C538614', (149, 152))	('TSC1', 'Gene', (61, 65))	('PIK3CA', 'Gene', '5290', (82, 88))	('mTOR', 'Gene', (26, 30))	('TSC2', 'Gene', '7249', (67, 71))	('mTOR', 'Gene', '2475', (26, 30))	('mutations', 'Var', (13, 22))	('TSC2', 'Gene', (67, 71))	('MTOR', 'Gene', (55, 59))
3694	28489074	Taken together, our analysis reveals CAL54 as the only cell line with perfect agreement on mutation and CNAs in key kidney cancer genes, with 769-P and a few other cell lines also showing a high degree of concordance.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mutation', 'Var', (91, 99))	('CNA', 'Gene', '19055', (104, 107))	('kidney cancer', 'Phenotype', 'HP:0009726', (116, 129))	('CNA', 'Gene', (104, 107))	('key kidney cancer', 'Disease', (112, 129))	('key kidney cancer', 'Disease', 'MESH:D007680', (112, 129))
3696	28489074	To quantify 3p loss, we computed the fraction of chromosome 3p where the CNA data supported at least low-level copy number loss (using a log2 ratio).	('CNA', 'Gene', (73, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('49', '59'))	('copy number loss', 'Var', (111, 127))	('CNA', 'Gene', '19055', (73, 76))
3697	28489074	While this characteristic ccRCC genomic feature is observed in the majority of ccRCC cell lines, 3p loss is absent or significantly diminished in several of them, namely VMRCRCW, SLR20, SLR21, and BFTC909 (as well as the immortalized epithelial cell lines HK2 and HEKTE) in CCLE; and U031, KMRC-1, 786-0, VMRC-RCW, SN12C and BFTC-909 in CCLP (Supplementary Table 2).	('loss', 'NegReg', (100, 104))	('BFTC', 'Chemical', '-', (325, 329))	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('absent', 'NegReg', (108, 114))	('BFTC909', 'Var', (197, 204))	('SLR21', 'Var', (186, 191))	('HK2', 'CellLine', 'CVCL:0302', (256, 259))	('RCC', 'Disease', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('CCLE', 'Chemical', '-', (274, 278))	('SLR20', 'Var', (179, 184))	('HK2', 'molecular_function', 'GO:0008256', ('256', '259'))	('CCLE', 'Disease', (274, 278))	('KMRC-1', 'CellLine', 'CVCL:2983', (290, 296))	('BFTC', 'Chemical', '-', (197, 201))	('RCC', 'Disease', (28, 31))	('diminished', 'NegReg', (132, 142))
3698	28489074	Of the cell lines lacking 3p loss, SLR21 and SLR20 in CCLE and SN12C and U031 in CCLP also lack other characteristic features of ccRCC such as chromosomal gains in five and eight or losses in chromosome 14, though SLR21 and U031 do show some gain in 8q.	('U031', 'Var', (73, 77))	('lack', 'NegReg', (91, 95))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (131, 134))	('loss', 'NegReg', (29, 33))	('lacking', 'NegReg', (18, 25))	('gain', 'PosReg', (242, 246))	('losses', 'NegReg', (182, 188))	('chromosome', 'cellular_component', 'GO:0005694', ('192', '202'))	('CCLE', 'Chemical', '-', (54, 58))
3706	28489074	In our cluster analysis, ACHN co-segregates with tumours displaying amplifications in chromosomes 7 and 17, furthering the notion that this appears to derive from papillary origins.	('tumours', 'Disease', (49, 56))	('amplifications in', 'Var', (68, 85))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('ACHN', 'Gene', (25, 29))	('tumours', 'Disease', 'MESH:D009369', (49, 56))
3709	28489074	Our results indicate that 786-0 harbours more alterations than A-498 even though both cluster with ccRCC on a copy number level and harbour VHL mutations (Fig.	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Disease', (101, 104))	('VHL', 'Gene', (140, 143))	('mutations', 'Var', (144, 153))	('VHL', 'Gene', '7428', (140, 143))	('cluster', 'Reg', (86, 93))
3722	28489074	By comparing tumours which cluster with the cell lines based on CNAs with tumours that cluster away from the cell lines, we found that the tumours likely to be best represented by the cell lines carry hallmarks of aggressive disease, such as higher stage, higher grade, greater extent of CNAs, and more frequent mutations in genes such as SETD2, BAP1 and MTOR, which have been associated with more aggressive disease and poorer outcomes.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('tumours', 'Disease', (139, 146))	('SETD2', 'Gene', '29072', (339, 344))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('tumours', 'Disease', (74, 81))	('CNA', 'Gene', (288, 291))	('tumours', 'Phenotype', 'HP:0002664', (139, 146))	('tumours', 'Disease', 'MESH:D009369', (139, 146))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('tumours', 'Disease', 'MESH:D009369', (74, 81))	('CNA', 'Gene', '19055', (288, 291))	('BAP1', 'Gene', '8314', (346, 350))	('hallmarks of aggressive disease', 'Disease', (201, 232))	('aggressive disease', 'Disease', (398, 416))	('CNA', 'Gene', (64, 67))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('aggressive disease', 'Disease', 'MESH:D001523', (398, 416))	('tumours', 'Disease', (13, 20))	('CNA', 'Gene', '19055', (64, 67))	('aggressive disease', 'Disease', 'MESH:D001523', (214, 232))	('BAP1', 'Gene', (346, 350))	('MTOR', 'Gene', (355, 359))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('MTOR', 'Gene', '2475', (355, 359))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('mutations', 'Var', (312, 321))	('SETD2', 'Gene', (339, 344))	('hallmarks of aggressive disease', 'Disease', 'MESH:D001523', (201, 232))
3730	28489074	More specifically, we show that despite clustering with ccRCC, several of these cell lines lack VHL mutations.	('mutations', 'Var', (100, 109))	('lack', 'NegReg', (91, 95))	('VHL', 'Gene', (96, 99))	('RCC', 'Disease', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('VHL', 'Gene', '7428', (96, 99))
3734	28489074	Previous work from our group demonstrated that mTOR pathway activating mutations sensitize patients to rapalogs, hence this new information may now be applied to in vitro work as well.	('activating', 'PosReg', (60, 70))	('patients', 'Species', '9606', (91, 99))	('sensitize', 'Reg', (81, 90))	('mutations', 'Var', (71, 80))	('mTOR', 'Gene', '2475', (47, 51))	('mTOR', 'Gene', (47, 51))
3735	28489074	We address the discrepancy in genomic data from CCLE and CCLP via a detailed comparison of mutations in 15 key kidney cancer genes, and of CNAs in 18 key kidney cancer genes (Fig.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('kidney cancer', 'Phenotype', 'HP:0009726', (111, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('key kidney cancer', 'Disease', 'MESH:D007680', (107, 124))	('CCLE', 'Chemical', '-', (48, 52))	('key kidney cancer', 'Disease', (150, 167))	('mutations', 'Var', (91, 100))	('CNA', 'Gene', (139, 142))	('CNA', 'Gene', '19055', (139, 142))	('kidney cancer', 'Phenotype', 'HP:0009726', (154, 167))	('key kidney cancer', 'Disease', (107, 124))	('key kidney cancer', 'Disease', 'MESH:D007680', (150, 167))
3737	28489074	Thus, CAL-54 has the most reliable mutation and CNA data for key kidney cancer genes in terms of validation via two independent sources, while 769-P is a close second.	('CNA', 'Gene', '19055', (48, 51))	('kidney cancer', 'Phenotype', 'HP:0009726', (65, 78))	('CNA', 'Gene', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('key kidney cancer', 'Disease', (61, 78))	('mutation', 'Var', (35, 43))	('key kidney cancer', 'Disease', 'MESH:D007680', (61, 78))
3765	28489074	For the analysis of mutation in key kidney cancer genes, we chose not to further filter the CCLE data due to the risk of inadvertently removing mutations in key cancer genes.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('key kidney cancer', 'Disease', (32, 49))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', (161, 167))	('mutations', 'Var', (144, 153))	('CCLE', 'Chemical', '-', (92, 96))	('key kidney cancer', 'Disease', 'MESH:D007680', (32, 49))	('kidney cancer', 'Phenotype', 'HP:0009726', (36, 49))
3770	28489074	A log2 (sample intensity/reference intensity) threshold of 0.2 (for amplification, -0.2 for deletion) was used for both the TCGA tumour samples as well as the CCLE cell lines.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('deletion', 'Var', (92, 100))	('tumour', 'Disease', (129, 135))	('CCLE', 'Chemical', '-', (159, 163))
3776	28489074	Tier 1 consists of cases with identical mutations in both CCLE and CCLP.	('mutations', 'Var', (40, 49))	('CCLE', 'Gene', (58, 62))	('CCLP', 'Gene', (67, 71))	('CCLE', 'Chemical', '-', (58, 62))
3777	28489074	Similarly, for CNAs, we defined three tiers using GISTIC scores (+2:high-level amplification, +1:gain, 0:no alteration, -1: shallow loss, -2: deep deletion) for a given gene and CNA.	('deep deletion', 'Var', (142, 155))	('loss', 'NegReg', (132, 136))	('CNA', 'Gene', (15, 18))	('gain', 'PosReg', (97, 101))	('CNA', 'Gene', '19055', (15, 18))	('CNA', 'Gene', (178, 181))	('CNA', 'Gene', '19055', (178, 181))
3808	30867751	Detection of aberrantly expressed miRNAs can distinguish ccRCC from normal tissue and predict the prognosis of patients with ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('miRNAs', 'Protein', (34, 40))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))	('aberrantly expressed', 'Var', (13, 33))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('ccRCC', 'Phenotype', 'HP:0006770', (125, 130))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('patients', 'Species', '9606', (111, 119))
3811	30867751	Reduced expression of miR-218 was associated with advanced tumor stage and lymph node metastasis in ovarian cancer, and restoration of miR-218 expression levels inhibited cell proliferation, migration and invasion in vitro by targeting runt-related transcription factor 2.	('tumor', 'Disease', (59, 64))	('miR-218', 'Gene', (22, 29))	('node metastasis in ovarian cancer', 'Disease', (81, 114))	('miR-218', 'Gene', (135, 142))	('targeting', 'Reg', (226, 235))	('miR-218', 'Gene', '387214', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('miR-218', 'Gene', '387214', (135, 142))	('node metastasis in ovarian cancer', 'Disease', 'MESH:D009362', (81, 114))	('runt-related transcription factor 2', 'Gene', (236, 271))	('inhibited', 'NegReg', (161, 170))	('ovarian cancer', 'Phenotype', 'HP:0100615', (100, 114))	('expression', 'MPA', (8, 18))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('expression', 'MPA', (143, 153))	('cell proliferation', 'biological_process', 'GO:0008283', ('171', '189'))	('runt-related transcription factor 2', 'Gene', '860', (236, 271))	('Reduced', 'NegReg', (0, 7))	('transcription', 'biological_process', 'GO:0006351', ('249', '262'))	('restoration', 'Var', (120, 131))	('cell proliferation', 'CPA', (171, 189))	('transcription factor', 'molecular_function', 'GO:0000981', ('249', '269'))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))
3830	30867751	For the luciferase reporter assay, the wild-type and mutant 3'-UTR of CIP2A was cloned into psiCHECK-2 luciferase reporter vector (Promega Cooperation, Madison, WI, USA) and termed CIP2A WT and CIP2A MUT, respectively.	('CIP2A', 'Gene', (181, 186))	('CIP2A', 'Gene', '57650', (181, 186))	('CIP2A', 'Gene', (70, 75))	('CIP2A', 'Gene', (194, 199))	('CIP2A', 'Gene', '57650', (70, 75))	('mutant', 'Var', (53, 59))	('CIP2A', 'Gene', '57650', (194, 199))
3862	30867751	The results of MTT and wound-healing assays revealed that the knockdown of CIP2A significantly reduced the cell proliferation and migration in the two cell lines (Fig.	('CIP2A', 'Gene', '57650', (75, 80))	('cell proliferation', 'biological_process', 'GO:0008283', ('107', '125'))	('wound-healing', 'biological_process', 'GO:0042060', ('23', '36'))	('reduced', 'NegReg', (95, 102))	('CIP2A', 'Gene', (75, 80))	('MTT', 'Chemical', 'MESH:C070243', (15, 18))	('knockdown', 'Var', (62, 71))
3869	30867751	In addition, it has been hypothesized that an improved understanding of the alterations of miRNA expression in ccRCC may lead to an improved understanding of the mechanisms underlying ccRCC progression, which may provide improvements in the diagnosis and treatment measures for advanced ccRCC.	('RCC', 'Disease', (289, 292))	('improvements', 'Reg', (221, 233))	('alterations', 'Var', (76, 87))	('RCC', 'Phenotype', 'HP:0005584', (289, 292))	('RCC', 'Disease', 'MESH:C538614', (289, 292))	('ccRCC', 'Phenotype', 'HP:0006770', (287, 292))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('RCC', 'Disease', (186, 189))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('miRNA', 'Gene', (91, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('ccRCC', 'Phenotype', 'HP:0006770', (184, 189))
3882	30867751	Further in vitro functional assays revealed that knockdown of CIP2A reduced cell proliferation and migration.	('knockdown', 'Var', (49, 58))	('CIP2A', 'Gene', (62, 67))	('cell proliferation', 'biological_process', 'GO:0008283', ('76', '94'))	('cell proliferation', 'CPA', (76, 94))	('CIP2A', 'Gene', '57650', (62, 67))	('migration', 'CPA', (99, 108))	('reduced', 'NegReg', (68, 75))
3908	33381539	However, many recent studies have confirmed a significant correlation between abnormal fatty acid metabolism and tumor development.	('tumor', 'Disease', (113, 118))	('fatty acid', 'Chemical', 'MESH:D005227', (87, 97))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('87', '108'))	('abnormal fat', 'Phenotype', 'HP:0009124', (78, 90))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('abnormal fatty acid metabolism', 'Phenotype', 'HP:0004359', (78, 108))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('abnormal', 'Var', (78, 86))
3918	33381539	Changes in VHL tumor suppressors that stabilize hypoxia-inducible factors (HIFs) are the most common molecular feature of clear cell tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('VHL tumor', 'Disease', 'MESH:D006623', (11, 20))	('HIFs', 'Disease', 'None', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Changes', 'Var', (0, 7))	('VHL tumor', 'Disease', (11, 20))	('hypoxia', 'Disease', 'MESH:D000860', (48, 55))	('clear cell tumors', 'Disease', 'MESH:C538614', (122, 139))	('clear cell tumors', 'Disease', (122, 139))	('hypoxia', 'Disease', (48, 55))	('HIFs', 'Disease', (75, 79))
3936	33381539	The sequences of CPT1A primers used for PCR were F-5'-CTGGACAATACCTCGGAGCC-3' and R-5'-AACGTCACAAAGAACGCTGC-3'.	("F-5'-CTGGACAATACCTCGGAGCC-3", 'Var', (49, 76))	('TCA', 'Chemical', 'MESH:D014238', (91, 94))	('CPT', 'molecular_function', 'GO:0004142', ('17', '20'))	('CPT', 'molecular_function', 'GO:0004095', ('17', '20'))	('CPT1A', 'Gene', (17, 22))	("R-5'-AACGTCACAAAGAACGCTGC-3", 'Var', (82, 109))	('CPT1A', 'Gene', '1374', (17, 22))
3964	33381539	The wound healing experiment demonstrated that the wound healing rates of the 786-O and ACHN cells overexpressing CPT1A were significantly lower than those of the control group (Figure 4(a)), and a histogram was drawn to show the difference (Figure 4(b)).	('wound healing rates', 'CPA', (51, 70))	('CPT', 'molecular_function', 'GO:0004142', ('114', '117'))	('CPT1A', 'Gene', (114, 119))	('CPT', 'molecular_function', 'GO:0004095', ('114', '117'))	('overexpressing', 'Var', (99, 113))	('wound healing', 'biological_process', 'GO:0042060', ('51', '64'))	('lower', 'NegReg', (139, 144))	('wound healing', 'biological_process', 'GO:0042060', ('4', '17'))	('CPT1A', 'Gene', '1374', (114, 119))
3983	33381539	Survival analysis demonstrated that the prognosis of patients with high expression of CPT1A was significantly worse than that of patients with low expression of CPT1A.	('CPT1A', 'Gene', (161, 166))	('CPT', 'molecular_function', 'GO:0004142', ('86', '89'))	('patients', 'Species', '9606', (53, 61))	('patients', 'Species', '9606', (129, 137))	('CPT1A', 'Gene', '1374', (161, 166))	('CPT', 'molecular_function', 'GO:0004142', ('161', '164'))	('CPT', 'molecular_function', 'GO:0004095', ('86', '89'))	('CPT1A', 'Gene', (86, 91))	('worse', 'NegReg', (110, 115))	('CPT1A', 'Gene', '1374', (86, 91))	('high expression', 'Var', (67, 82))	('CPT', 'molecular_function', 'GO:0004095', ('161', '164'))
3984	33381539	Subsequent studies confirmed that the small molecule inhibitor of CPT1A can reduce fatty acid oxidation in tumor cells of leukemia and exert an anticancer effect by inhibiting cell proliferation and inducing apoptosis.	('leukemia', 'Disease', (122, 130))	('tumor', 'Disease', (107, 112))	('leukemia', 'Disease', 'MESH:D007938', (122, 130))	('inhibiting', 'NegReg', (165, 175))	('cell proliferation', 'CPA', (176, 194))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('inducing', 'Reg', (199, 207))	('fatty acid', 'Chemical', 'MESH:D005227', (83, 93))	('reduce', 'NegReg', (76, 82))	('inhibitor', 'Var', (53, 62))	('CPT', 'molecular_function', 'GO:0004095', ('66', '69'))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('cell proliferation', 'biological_process', 'GO:0008283', ('176', '194'))	('apoptosis', 'biological_process', 'GO:0097194', ('208', '217'))	('CPT1A', 'Gene', '1374', (66, 71))	('cancer', 'Disease', (148, 154))	('apoptosis', 'CPA', (208, 217))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('fatty acid oxidation', 'MPA', (83, 103))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('CPT1A', 'Gene', (66, 71))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('83', '103'))	('CPT', 'molecular_function', 'GO:0004142', ('66', '69'))	('apoptosis', 'biological_process', 'GO:0006915', ('208', '217'))
4041	29092932	Analogous NG-CHMs can be generated for many other types of data including microRNA expression, protein expression, DNA methylation, DNA copy number change, and mutational status.	('protein expression', 'MPA', (95, 113))	('DNA methylation', 'biological_process', 'GO:0006306', ('115', '130'))	('CHM', 'Gene', '43928', (13, 16))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('mutational', 'Var', (160, 170))	('microRNA expression', 'MPA', (74, 93))	('DNA', 'cellular_component', 'GO:0005574', ('115', '118'))	('CHM', 'Gene', (13, 16))	('copy number change', 'Var', (136, 154))
4081	33227984	All examinations were performed by one experienced consultant radiologist (European Federation of Societies for Ultrasound in Medicine and Biology Level 3) using high-end ultrasound systems with CEUS-specific protocols (GE Healthcare LOGIQ E9, Chicago, IL, USA, Philips EPIQ7, Seattle, Washington, USA, Siemens Ultrasound Sequoia S20000, S3000, ACUSON Sequoia, Mountain View, CA, USA).	('men', 'Species', '9606', (306, 309))	('ACUSON Sequoia', 'Disease', (345, 359))	('S3000', 'Var', (338, 343))
4148	31562290	In vitro assay found TIP-B1 knockdown dramatically inhibited KIRC cells proliferation, migration and invasion.	('TIP-B1', 'Gene', '83442', (21, 27))	('TIP-B1', 'Gene', (21, 27))	('knockdown', 'Var', (28, 37))	('inhibited', 'NegReg', (51, 60))	('invasion', 'CPA', (101, 109))	('KIRC cells proliferation', 'CPA', (61, 85))
4149	31562290	In vivo assay found down regulated TIP-B1 could suppress tumor growth and metastasis.	('suppress', 'NegReg', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('TIP-B1', 'Gene', '83442', (35, 41))	('TIP-B1', 'Gene', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('down regulated', 'Var', (20, 34))
4169	31562290	Functionally, TIP-B1 knockdown suppressed KIRC growth and metastasis both in vitro and in vivo.	('TIP-B1', 'Gene', (14, 20))	('KIRC growth', 'CPA', (42, 53))	('TIP-B1', 'Gene', '83442', (14, 20))	('suppressed', 'NegReg', (31, 41))	('knockdown', 'Var', (21, 30))
4188	31562290	Both univariate analysis and multivariate analysis (Figure 1O, Supplementary Table 3) indicated that high TIP-B1 expression level was an independent risk factor for worse overall survival, together with tumor recurrence, grade and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('worse', 'NegReg', (165, 170))	('TIP-B1', 'Gene', '83442', (106, 112))	('TIP-B1', 'Gene', (106, 112))	('overall survival', 'MPA', (171, 187))	('expression level', 'MPA', (113, 129))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('high', 'Var', (101, 105))
4200	31562290	Overall survival analysis indicated that KIRC patients with high expression of TIP-B1 had significantly lower 5-year overall survival rates (Figure 2E), the same results were also confirmed by the Human Protein Atlas website (https://www.proteinatlas.org/) (Supplementary Figure 7).	('Human', 'Species', '9606', (197, 202))	('patients', 'Species', '9606', (46, 54))	('high expression', 'Var', (60, 75))	('overall survival rates', 'CPA', (117, 139))	('TIP-B1', 'Gene', '83442', (79, 85))	('TIP-B1', 'Gene', (79, 85))	('lower', 'NegReg', (104, 109))
4202	31562290	To further study whether the dysregulation of TIP-B1 correlated with the OS rate of KIRC patients, we then performed Kaplan-Meier method and Cox proportional hazard model.	('correlated', 'Reg', (53, 63))	('Cox', 'Gene', '1351', (141, 144))	('patients', 'Species', '9606', (89, 97))	('Cox', 'Gene', (141, 144))	('TIP-B1', 'Gene', (46, 52))	('TIP-B1', 'Gene', '83442', (46, 52))	('dysregulation', 'Var', (29, 42))
4204	31562290	Collectively, from public database to our TMA cohort, from RNA level to protein level, our data indicated that high level of TIP-B1 might play a critical role in KIRC progression and metastasis.	('high level', 'Var', (111, 121))	('TIP-B1', 'Gene', '83442', (125, 131))	('metastasis', 'CPA', (183, 193))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('TIP-B1', 'Gene', (125, 131))	('TMA', 'Disease', 'MESH:D014652', (42, 45))	('TMA', 'Disease', (42, 45))	('RNA', 'cellular_component', 'GO:0005562', ('59', '62'))	('KIRC', 'Disease', (162, 166))	('play', 'Reg', (138, 142))
4207	31562290	Then we knocked down TIP-B1 by shRNA (sh-TIP-B1) in OS-RC-2 (Figure 3C) and 786-O (Figure 3D) cells which have a higher endogenous TIP-B1 expression, and chose the higher efficiency shRNA1 for further investigation.	('knocked', 'Var', (8, 15))	('TIP-B1', 'Gene', '83442', (21, 27))	('TIP-B1', 'Gene', '83442', (41, 47))	('TIP-B1', 'Gene', (21, 27))	('TIP-B1', 'Gene', (41, 47))	('higher', 'PosReg', (113, 119))	('TIP-B1', 'Gene', '83442', (131, 137))	('expression', 'MPA', (138, 148))	('TIP-B1', 'Gene', (131, 137))	('786-O', 'Chemical', 'MESH:C002925', (76, 81))
4210	31562290	Similarly, using the transwell migration and matrigel-coated invasion assay, we found that knocking down TIP-B1 in OS-RC-2 and 786-O cells decreased cell migration (Figure 3I) and invasion (Figure 3J) abilities compared to the vector control (pLKO) group.	('invasion', 'CPA', (180, 188))	('cell migration', 'biological_process', 'GO:0016477', ('149', '163'))	('786-O', 'Chemical', 'MESH:C002925', (127, 132))	('decreased', 'NegReg', (139, 148))	('cell migration', 'CPA', (149, 163))	('TIP-B1', 'Gene', '83442', (105, 111))	('knocking down', 'Var', (91, 104))	('TIP-B1', 'Gene', (105, 111))
4211	31562290	In conclusion, results from in vitro assays demonstrated that TIP-B1 plays key role in regulating KIRC cell proliferation and a high level of TIP-B1 could increase KIRC cell migration and invasion abilities.	('increase', 'PosReg', (155, 163))	('high level', 'Var', (128, 138))	('TIP-B1', 'Gene', '83442', (62, 68))	('TIP-B1', 'Gene', (62, 68))	('KIRC cell migration', 'CPA', (164, 183))	('TIP-B1', 'Gene', '83442', (142, 148))	('TIP-B1', 'Gene', (142, 148))	('cell migration', 'biological_process', 'GO:0016477', ('169', '183'))	('cell proliferation', 'biological_process', 'GO:0008283', ('103', '121'))	('invasion abilities', 'CPA', (188, 206))
4214	31562290	Besides, the linear curve also recorded that knockdown TIP-B1 dramatically inhibited the growth (Figure 4C) and average weight (Figure 4D) of tumors in nude mice.	('nude mice', 'Species', '10090', (152, 161))	('average weight', 'CPA', (112, 126))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('inhibited', 'NegReg', (75, 84))	('TIP-B1', 'Gene', '83442', (55, 61))	('TIP-B1', 'Gene', (55, 61))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('growth', 'CPA', (89, 95))	('knockdown', 'Var', (45, 54))
4221	31562290	Taken together, our data demonstrated that inhibiting TIP-B1 could modulate the aggressive and metastatic abilities of KIRC in vivo.	('TIP-B1', 'Gene', '83442', (54, 60))	('inhibiting', 'Var', (43, 53))	('modulate', 'Reg', (67, 75))	('TIP-B1', 'Gene', (54, 60))
4224	31562290	Interestingly, GSEA analysis revealed that the tight junction function, an important part of the epithelial-mesenchymal transition (EMT) process, was significantly decreased in TIP-B1 high group (Figure 5A).	('decreased', 'NegReg', (164, 173))	('high group', 'Var', (184, 194))	('EMT', 'biological_process', 'GO:0001837', ('132', '135'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('97', '130'))	('TIP-B1', 'Gene', '83442', (177, 183))	('tight junction function', 'MPA', (47, 70))	('TIP-B1', 'Gene', (177, 183))	('tight junction', 'cellular_component', 'GO:0070160', ('47', '61'))
4229	31562290	In order to examine the effects of TIP-B1 on KIRC cell activities through AKT pathway, we treated KIRC cell with MK-2206 (a highly selective inhibitor of pan-AKT) or SC-79 (AKT phosphorylation activator) and divided cells into four groups (DMSO, MK-2206, sh-TIP-B1, sh-TIP-B1+SC-79).	('phosphorylation', 'biological_process', 'GO:0016310', ('177', '192'))	('AKT', 'Gene', '207', (173, 176))	('TIP-B1', 'Gene', (258, 264))	('TIP-B1', 'Gene', '83442', (258, 264))	('AKT', 'Gene', '207', (74, 77))	('AKT', 'Gene', (173, 176))	('TIP-B1', 'Gene', '83442', (35, 41))	('TIP-B1', 'Gene', '83442', (269, 275))	('MK-2206', 'Chemical', 'MESH:C548887', (246, 253))	('TIP-B1', 'Gene', (35, 41))	('TIP-B1', 'Gene', (269, 275))	('AKT', 'Gene', '207', (158, 161))	('DMSO', 'Chemical', 'MESH:D004121', (240, 244))	('MK-2206', 'Var', (113, 120))	('AKT', 'Gene', (74, 77))	('MK-2206', 'Chemical', 'MESH:C548887', (113, 120))	('AKT', 'Gene', (158, 161))
4230	31562290	The CCK-8 assay showed both AKT inhibition and TIP-B1 knockdown could hindered KIRC cells proliferation, whereas AKT activation could attenuate the inhibitory effects of TIP-B1 knockdown on OS-RC-2 (Figure 5I) and 786-O (Figure 5J) cells.	('TIP-B1', 'Gene', (47, 53))	('knockdown', 'Var', (54, 63))	('AKT', 'Gene', (28, 31))	('KIRC cells proliferation', 'CPA', (79, 103))	('inhibition', 'NegReg', (32, 42))	('786-O', 'Chemical', 'MESH:C002925', (214, 219))	('AKT', 'Gene', '207', (113, 116))	('TIP-B1', 'Gene', '83442', (170, 176))	('knockdown', 'Var', (177, 186))	('hindered', 'NegReg', (70, 78))	('AKT', 'Gene', (113, 116))	('TIP-B1', 'Gene', (170, 176))	('attenuate', 'NegReg', (134, 143))	('TIP-B1', 'Gene', '83442', (47, 53))	('AKT', 'Gene', '207', (28, 31))
4231	31562290	Besides, the increase of epithelial gene ZO-1, E-cadherin, and the decrease of mesenchymal gene N-cadherin, vimentin, twist, snail and slug caused by TIP-B1 knockdown could be rescued by AKT activation through WB assays in KIRC cells (Figure 5K).	('slug', 'Gene', (135, 139))	('twist', 'MPA', (118, 123))	('increase', 'PosReg', (13, 21))	('TIP-B1', 'Gene', (150, 156))	('snail', 'Gene', (125, 130))	('vimentin', 'cellular_component', 'GO:0045098', ('108', '116'))	('AKT', 'Gene', (187, 190))	('epithelial', 'MPA', (25, 35))	('decrease', 'NegReg', (67, 75))	('slug', 'Gene', '6591', (135, 139))	('N-cadherin', 'Gene', (96, 106))	('cadherin', 'molecular_function', 'GO:0008014', ('98', '106'))	('mesenchymal', 'MPA', (79, 90))	('N-cadherin', 'Gene', '1000', (96, 106))	('vimentin', 'cellular_component', 'GO:0045099', ('108', '116'))	('TIP-B1', 'Gene', '83442', (150, 156))	('vimentin', 'Gene', '7431', (108, 116))	('AKT', 'Gene', '207', (187, 190))	('vimentin', 'Gene', (108, 116))	('cadherin', 'molecular_function', 'GO:0008014', ('49', '57'))	('E-cadherin', 'Gene', (47, 57))	('E-cadherin', 'Gene', '999', (47, 57))	('knockdown', 'Var', (157, 166))	('snail', 'Gene', '6615', (125, 130))
4232	31562290	The rescue experiments of transwell assay also confirmed AKT inhibition could suppressed KIRC cells migration and invasion capacities, whereas AKT activation could release the inhibitory effects of TIP-B1 knockdown on KIRC cells (Figure 5L-5O, Supplementary Figure 8).	('KIRC cells migration', 'CPA', (89, 109))	('suppressed', 'NegReg', (78, 88))	('inhibition', 'NegReg', (61, 71))	('invasion capacities', 'CPA', (114, 133))	('5O', 'Chemical', 'MESH:D013481', (240, 242))	('knockdown', 'Var', (205, 214))	('AKT', 'Gene', '207', (143, 146))	('AKT', 'Gene', '207', (57, 60))	('TIP-B1', 'Gene', (198, 204))	('TIP-B1', 'Gene', '83442', (198, 204))	('activation', 'PosReg', (147, 157))	('AKT', 'Gene', (143, 146))	('AKT', 'Gene', (57, 60))
4237	31562290	Interesting, knockdown TIP-B1 significantly inhibited AKT activation triggered by EGF stimulation compared to the control group (Figure 6B).	('TIP-B1', 'Gene', (23, 29))	('EGF', 'molecular_function', 'GO:0005154', ('82', '85'))	('inhibited', 'NegReg', (44, 53))	('AKT', 'Gene', '207', (54, 57))	('AKT', 'Gene', (54, 57))	('knockdown', 'Var', (13, 22))	('TIP-B1', 'Gene', '83442', (23, 29))
4238	31562290	More importantly, the phosphorylation levels of the three residues in EGFR (Tyr992, Tyr1068 and Tyr1086) were significantly reduced after downregulation of TIP-B1 (Figure 6C).	('Tyr1068', 'Chemical', 'MESH:C056418', (84, 91))	('reduced', 'NegReg', (124, 131))	('Tyr1086', 'Var', (96, 103))	('phosphorylation levels', 'MPA', (22, 44))	('Tyr992', 'Chemical', 'MESH:C120975', (76, 82))	('EGFR', 'Gene', '1956', (70, 74))	('Tyr1086', 'Chemical', 'MESH:C108687', (96, 103))	('TIP-B1', 'Gene', '83442', (156, 162))	('Tyr1068', 'Var', (84, 91))	('EGFR', 'molecular_function', 'GO:0005006', ('70', '74'))	('EGFR', 'Gene', (70, 74))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('Tyr992', 'Var', (76, 82))	('TIP-B1', 'Gene', (156, 162))	('downregulation', 'NegReg', (138, 152))
4239	31562290	Moreover, under the stimulation of EGFR-specific tyrosine kinase inhibitor (AG1478), the inhibitory effect of knockdown TIP-B1 on EGFR and AKT phosphorylation was furtherly enhanced, demonstrating that TIP-B1 might play a key role in EGFR mediated activation of AKT (Figure 6D).	('knockdown', 'Var', (110, 119))	('TIP-B1', 'Gene', (120, 126))	('EGFR', 'Gene', (234, 238))	('AKT', 'Gene', (262, 265))	('AKT', 'Gene', '207', (139, 142))	('EGFR', 'molecular_function', 'GO:0005006', ('130', '134'))	('phosphorylation', 'biological_process', 'GO:0016310', ('143', '158'))	('EGFR', 'Gene', (130, 134))	('TIP-B1', 'Gene', '83442', (202, 208))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('58', '74'))	('EGFR', 'Gene', (35, 39))	('AG1478', 'Chemical', 'MESH:C101044', (76, 82))	('tyrosine', 'Chemical', 'None', (49, 57))	('AKT', 'Gene', '207', (262, 265))	('EGFR', 'Gene', '1956', (234, 238))	('inhibitory effect', 'MPA', (89, 106))	('TIP-B1', 'Gene', '83442', (120, 126))	('AKT', 'Gene', (139, 142))	('EGFR', 'molecular_function', 'GO:0005006', ('35', '39'))	('enhanced', 'PosReg', (173, 181))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'molecular_function', 'GO:0005006', ('234', '238'))	('TIP-B1', 'Gene', (202, 208))	('EGFR', 'Gene', '1956', (35, 39))
4240	31562290	To further investigate whether TIP-B1 knockdown could affect EGFR protein degradation, we detected the protein level of EGFR under EGF stimulation.	('protein degradation', 'biological_process', 'GO:0030163', ('66', '85'))	('EGFR', 'molecular_function', 'GO:0005006', ('120', '124'))	('detected', 'Reg', (90, 98))	('TIP-B1', 'Gene', (31, 37))	('EGF', 'molecular_function', 'GO:0005154', ('131', '134'))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('protein level', 'MPA', (103, 116))	('TIP-B1', 'Gene', '83442', (31, 37))	('affect', 'Reg', (54, 60))	('EGFR', 'Gene', '1956', (120, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('61', '65'))	('knockdown', 'Var', (38, 47))	('EGFR', 'Gene', '1956', (61, 65))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('EGFR', 'Gene', (61, 65))	('EGFR', 'Gene', (120, 124))
4242	31562290	Our data of WB analysis revealed that TIP-B1 knockdown could dramatically enhanced the degradation of EGFR (Figure 6E).	('TIP-B1', 'Gene', (38, 44))	('degradation', 'MPA', (87, 98))	('TIP-B1', 'Gene', '83442', (38, 44))	('EGFR', 'Gene', (102, 106))	('degradation', 'biological_process', 'GO:0009056', ('87', '98'))	('EGFR', 'molecular_function', 'GO:0005006', ('102', '106'))	('EGFR', 'Gene', '1956', (102, 106))	('enhanced', 'PosReg', (74, 82))	('knockdown', 'Var', (45, 54))
4255	31562290	What's more, both overall survival and disease-free survival analysis showed that KIRC patients with high levels of TIP-B1 had dramatically shorter OS and DFS than those with low levels of TIP-B1.	('shorter', 'NegReg', (140, 147))	('TIP-B1', 'Gene', '83442', (189, 195))	('patients', 'Species', '9606', (87, 95))	('TIP-B1', 'Gene', (189, 195))	('high levels', 'Var', (101, 112))	('DFS', 'MPA', (155, 158))	('TIP-B1', 'Gene', '83442', (116, 122))	('TIP-B1', 'Gene', (116, 122))
4260	31562290	Our functional experiments showed that reducing TIP-B1 could inhibit KIRC tumor cell proliferation, migration and invasion.	('reducing', 'Var', (39, 47))	('TIP-B1', 'Gene', '83442', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('TIP-B1', 'Gene', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('inhibit', 'NegReg', (61, 68))	('cell proliferation', 'biological_process', 'GO:0008283', ('80', '98'))	('tumor', 'Disease', (74, 79))	('invasion', 'CPA', (114, 122))
4262	31562290	Consistently, the WB assay found silent TIP-B1 lead to the alteration of EMT related markers.	('TIP-B1', 'Gene', '83442', (40, 46))	('silent', 'Var', (33, 39))	('EMT', 'biological_process', 'GO:0001837', ('73', '76'))	('TIP-B1', 'Gene', (40, 46))	('alteration', 'Reg', (59, 69))	('EMT related markers', 'CPA', (73, 92))
4266	31562290	In our current study, we found that inhibition of TIP-B1 expression could significantly attenuate the AKT signaling pathway, which was also confirmed by the GSEA and correlation analysis from TCGA database.	('AKT signaling', 'biological_process', 'GO:0043491', ('102', '115'))	('inhibition', 'Var', (36, 46))	('signaling pathway', 'biological_process', 'GO:0007165', ('106', '123'))	('AKT', 'Gene', '207', (102, 105))	('TIP-B1', 'Gene', '83442', (50, 56))	('attenuate', 'NegReg', (88, 97))	('TIP-B1', 'Gene', (50, 56))	('AKT', 'Gene', (102, 105))
4316	30017803	Genetic background is thought to be a pivotal factor in RCC carcinogenesis; for example, approximately two-thirds of patients with clear cell RCC (ccRCC) harbor mutations in the von Hippel Lindau gene, while loss of chromosome 3p is also prevalent in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (253, 256))	('patients', 'Species', '9606', (117, 125))	('chromosome', 'cellular_component', 'GO:0005694', ('216', '226'))	('RCC carcinogenesis', 'Disease', (56, 74))	('RCC carcinogenesis', 'Disease', 'MESH:C538614', (56, 74))	('von Hippel Lindau', 'Disease', (178, 195))	('RCC', 'Disease', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('RCC', 'Disease', (142, 145))	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('RCC', 'Disease', (253, 256))	('RCC', 'Phenotype', 'HP:0005584', (253, 256))	('mutations', 'Var', (161, 170))	('von Hippel Lindau', 'Disease', 'MESH:D006623', (178, 195))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
4373	30017803	As hypothesized, the results of the current study indicated that the association between obesity and RCC risk in women was modified by estrogen status, with a positive association between high BMI/WC and RCC risk in pre-menopausal, but not post-menopausal women.	('men', 'Species', '9606', (258, 261))	('pre', 'molecular_function', 'GO:0003904', ('216', '219'))	('high BMI/WC', 'Var', (188, 199))	('obesity', 'Disease', 'MESH:D009765', (89, 96))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Disease', (204, 207))	('RCC', 'Disease', (101, 104))	('obesity', 'Disease', (89, 96))	('men', 'Species', '9606', (115, 118))	('women', 'Species', '9606', (256, 261))	('RCC', 'Phenotype', 'HP:0005584', (204, 207))	('men', 'Species', '9606', (245, 248))	('obesity', 'Phenotype', 'HP:0001513', (89, 96))	('women', 'Species', '9606', (113, 118))	('men', 'Species', '9606', (220, 223))
4377	30017803	Moreover, our results showing a non-existent or weak association between high BMI/WC and RCC risk in post-menopausal women were also in accordance with the findings of previous studies.	('BMI/WC', 'Gene', (78, 84))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('men', 'Species', '9606', (119, 122))	('high', 'Var', (73, 77))	('women', 'Species', '9606', (117, 122))	('men', 'Species', '9606', (106, 109))
4415	27491085	Loss of vhl in the zebrafish pronephros recapitulates early stages of human clear cell renal cell carcinoma Patients with von Hippel-Lindau (VHL) disease harbor a germline mutation in the VHL gene leading to the development of several tumor types including clear cell renal cell carcinoma (ccRCC).	('von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (122, 153))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('ccRCC', 'Phenotype', 'HP:0006770', (290, 295))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (76, 107))	('VHL', 'Gene', (188, 191))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (82, 107))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (257, 288))	('carcinoma', 'Phenotype', 'HP:0030731', (279, 288))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (263, 288))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (76, 107))	('leading to', 'Reg', (197, 207))	('vhl', 'Gene', '791202', (8, 11))	('human', 'Species', '9606', (70, 75))	('vhl', 'Gene', (8, 11))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (257, 288))	('RCC', 'Disease', (292, 295))	('Patients', 'Species', '9606', (108, 116))	('germline mutation', 'Var', (163, 180))	('clear cell renal cell carcinoma', 'Disease', (76, 107))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (87, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('tumor', 'Disease', (235, 240))	('zebrafish', 'Species', '7955', (19, 28))	('RCC', 'Disease', 'MESH:C538614', (292, 295))	('clear cell renal cell carcinoma', 'Disease', (257, 288))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (268, 288))
4418	27491085	VHL inactivation leads to the stabilization of hypoxia inducible factors 1a and 2a [HIF1a and HIF2a (HIF2a is also known as EPAS1)] with consequent up-regulation of specific target genes involved in cell proliferation, angiogenesis and erythropoiesis.	('inactivation', 'Var', (4, 16))	('up-regulation', 'PosReg', (148, 161))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('stabilization', 'MPA', (30, 43))	('EPAS1', 'Gene', '555192', (124, 129))	('hypoxia', 'Disease', (47, 54))	('angiogenesis', 'biological_process', 'GO:0001525', ('219', '231'))	('cell proliferation', 'biological_process', 'GO:0008283', ('199', '217'))	('VHL', 'Gene', (0, 3))	('regulation', 'biological_process', 'GO:0065007', ('151', '161'))	('EPAS1', 'Gene', (124, 129))	('erythropoiesis', 'biological_process', 'GO:0030218', ('236', '250'))
4421	27491085	Our data show that the vhl-/- zebrafish kidney is characterized by an increased tubule diameter, disorganized cilia, the dramatic formation of cytoplasmic lipid vesicles, glycogen accumulation, aberrant cell proliferation and abnormal apoptosis.	('apoptosis', 'CPA', (235, 244))	('glycogen', 'MPA', (171, 179))	('glycogen', 'Chemical', 'MESH:D006003', (171, 179))	('cell proliferation', 'CPA', (203, 221))	('increased', 'PosReg', (70, 79))	('aberrant cell proliferation', 'Phenotype', 'HP:0031377', (194, 221))	('apoptosis', 'biological_process', 'GO:0097194', ('235', '244'))	('lipid', 'Chemical', 'MESH:D008055', (155, 160))	('apoptosis', 'biological_process', 'GO:0006915', ('235', '244'))	('vhl-/-', 'Var', (23, 29))	('formation of cytoplasmic lipid vesicles', 'MPA', (130, 169))	('zebrafish', 'Species', '7955', (30, 39))	('cell proliferation', 'biological_process', 'GO:0008283', ('203', '221'))	('disorganized cilia', 'CPA', (97, 115))	('formation', 'biological_process', 'GO:0009058', ('130', '139'))	('tubule diameter', 'CPA', (80, 95))
4423	27491085	Treatment of vhl-/- zebrafish embryos with a small-molecule HIF2a inhibitor rescued the pronephric abnormalities, underscoring the value of the zebrafish model in drug discovery for treatment of VHL disease and ccRCC.	('zebrafish', 'Species', '7955', (20, 29))	('VHL disease', 'Disease', (195, 206))	('pronephric abnormalities', 'MPA', (88, 112))	('HIF2a', 'Gene', (60, 65))	('zebrafish', 'Species', '7955', (144, 153))	('ccRCC', 'Phenotype', 'HP:0006770', (211, 216))	('inhibitor', 'Var', (66, 75))	('VHL disease', 'Disease', 'MESH:D006623', (195, 206))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('RCC', 'Disease', (213, 216))	('rescued', 'PosReg', (76, 83))
4424	27491085	Summary: Zebrafish with an inactivating mutation in the vhl gene can be used as a model of early stage clear cell renal cell carcinoma, with applications for genetic studies and drug screens.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (103, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (114, 134))	('inactivating mutation', 'Var', (27, 48))	('vhl', 'Gene', (56, 59))	('Zebrafish', 'Species', '7955', (9, 18))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (103, 134))	('clear cell renal cell carcinoma', 'Disease', (103, 134))
4425	27491085	Patients with a germline mutation in the VHL gene develop clear cell renal cell carcinoma (ccRCC), retinal and central nervous system hemangioblastomas, pheochromocytomas, pancreatic neuroendocrine tumors, cystadenomas of the pancreas and middle ear, and erythrocytosis.	('nervous system hemangioblastomas', 'Phenotype', 'HP:0006880', (119, 151))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (69, 89))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('RCC', 'Disease', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('central nervous system hemangioblastomas', 'Disease', 'MESH:D018325', (111, 151))	('clear cell renal cell carcinoma', 'Disease', (58, 89))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (58, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (153, 170))	('germline mutation', 'Var', (16, 33))	('cystadenomas of the pancreas', 'Phenotype', 'HP:0001737', (206, 234))	('cystadenomas of the pancreas', 'Disease', (206, 234))	('Patients', 'Species', '9606', (0, 8))	('retinal', 'Disease', (99, 106))	('cystadenomas of the pancreas', 'Disease', 'MESH:D003537', (206, 234))	('central nervous system hemangioblastomas', 'Disease', (111, 151))	('retinal', 'Disease', 'MESH:D012173', (99, 106))	('erythrocytosis', 'Phenotype', 'HP:0001901', (255, 269))	('erythrocytosis', 'Disease', (255, 269))	('middle ear', 'Disease', (239, 249))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (172, 204))	('VHL', 'Gene', (41, 44))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (58, 89))	('pancreatic neuroendocrine tumors', 'Disease', (172, 204))	('develop', 'PosReg', (50, 57))	('pheochromocytomas', 'Disease', 'MESH:D010673', (153, 170))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('pheochromocytomas', 'Disease', (153, 170))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (183, 204))
4426	27491085	In addition to hereditary VHL disease, inactivation of the VHL tumor suppressor gene is the earliest molecular lesion identified in more than 90% of sporadic ccRCC.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('63', '79'))	('hereditary VHL disease', 'Disease', (15, 37))	('hereditary VHL disease', 'Disease', 'MESH:D006623', (15, 37))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('ccRCC', 'Phenotype', 'HP:0006770', (158, 163))	('RCC', 'Disease', (160, 163))	('VHL tumor', 'Disease', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('inactivation', 'Var', (39, 51))	('tumor suppressor', 'biological_process', 'GO:0051726', ('63', '79'))	('VHL tumor', 'Disease', 'MESH:D006623', (59, 68))
4433	27491085	Inactivation of HIF2a by the VHL tumor suppressor protein is necessary and sufficient for the tumor suppressor function of VHL in ccRCC.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('94', '110'))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (130, 135))	('RCC', 'Disease', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('VHL tumor', 'Disease', 'MESH:D006623', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (94, 99))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('33', '49'))	('HIF2a', 'Gene', (16, 21))	('tumor', 'Disease', (33, 38))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('33', '49'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('94', '110'))	('Inactivation', 'Var', (0, 12))	('VHL tumor', 'Disease', (29, 38))
4436	27491085	Inactivation of the VHL tumor suppressor gene is the earliest molecular event occurring in the premalignant cystic lesions of VHL patients and in sporadic ccRCC.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor suppressor', 'biological_process', 'GO:0051726', ('24', '40'))	('VHL', 'Disease', (126, 129))	('VHL tumor', 'Disease', (20, 29))	('patients', 'Species', '9606', (130, 138))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('24', '40'))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('VHL tumor', 'Disease', 'MESH:D006623', (20, 29))	('RCC', 'Disease', (157, 160))	('Inactivation', 'Var', (0, 12))	('ccRCC', 'Phenotype', 'HP:0006770', (155, 160))
4437	27491085	Inactivation of Vhl in the mouse kidney epithelium leads to cellular proliferation, lipid accumulation and cortical cyst formation but not to the formation of ccRCC.	('Vhl', 'Gene', (16, 19))	('cortical cyst formation', 'CPA', (107, 130))	('mouse', 'Species', '10090', (27, 32))	('lipid', 'CPA', (84, 89))	('ccRCC', 'Phenotype', 'HP:0006770', (159, 164))	('formation', 'biological_process', 'GO:0009058', ('121', '130'))	('cortical cyst', 'Phenotype', 'HP:0000803', (107, 120))	('cellular proliferation', 'CPA', (60, 82))	('RCC', 'Disease', (161, 164))	('lipid', 'Chemical', 'MESH:D008055', (84, 89))	('formation', 'biological_process', 'GO:0009058', ('146', '155'))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('Inactivation', 'Var', (0, 12))
4438	27491085	Comprehensive genomic analysis of human sporadic ccRCC tumors identified recurrent mutations in the PI3K-mTOR pathway, chromatin remodelers and chromatin modifiers, in addition to inactivation of the VHL gene.	('mutations', 'Var', (83, 92))	('human', 'Species', '9606', (34, 39))	('VHL', 'Gene', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('chromatin', 'cellular_component', 'GO:0000785', ('119', '128'))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('PI3K-mTOR pathway', 'Pathway', (100, 117))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('chromatin', 'cellular_component', 'GO:0000785', ('144', '153'))	('PI3K', 'molecular_function', 'GO:0016303', ('100', '104'))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
4440	27491085	It has been previously reported that vhl-/- larvae develop abnormal vascular proliferative lesions in the brain and retina, resembling human hemangioblastomas, as well as erythrocytosis.	('vascular proliferative lesions', 'CPA', (68, 98))	('vhl-/-', 'Var', (37, 43))	('hemangioblastomas', 'Disease', (141, 158))	('hemangioblastomas', 'Disease', 'MESH:D018325', (141, 158))	('human', 'Species', '9606', (135, 140))	('erythrocytosis', 'Phenotype', 'HP:0001901', (171, 185))	('erythrocytosis', 'MPA', (171, 185))
4447	27491085	Sporadic ccRCC is commonly treated with inhibitors of the vascular endothelial growth factor (VEGF) signaling pathway, which results in a prolongation of disease progression and overall survival by only a few months.	('prolongation of disease', 'Disease', (138, 161))	('VEGF', 'Gene', '30682', (94, 98))	('signaling pathway', 'biological_process', 'GO:0007165', ('100', '117'))	('VEGF', 'Gene', (94, 98))	('vascular endothelial growth factor', 'Gene', (58, 92))	('inhibitors', 'Var', (40, 50))	('prolongation of disease', 'Disease', 'MESH:D011273', (138, 161))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('58', '92'))	('VEGF) signaling', 'biological_process', 'GO:0038084', ('94', '109'))	('vascular endothelial growth factor', 'Gene', '30682', (58, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (9, 14))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))
4453	27491085	The overall histological disorganization of the vhl-/- pronephros, in addition to the presence of cytoplasmic lipid vesicles and glycogen, is reminiscent of 'clear cell' histology, indicating that the vhl-/- mutant zebrafish might serve as a model of early stage ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (263, 268))	('glycogen', 'Chemical', 'MESH:D006003', (129, 137))	('vhl-/- mutant', 'Var', (201, 214))	('lipid', 'Chemical', 'MESH:D008055', (110, 115))	('zebrafish', 'Species', '7955', (215, 224))	('RCC', 'Disease', 'MESH:C538614', (265, 268))	('RCC', 'Disease', (265, 268))
4455	27491085	In order to develop a model of ccRCC in zebrafish, and considering that the first genetic event in the formation of this tumor is loss of VHL, we assayed vhl-/- zebrafish pronephric epithelial cells for features of ccRCC cells.	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('ccRCC', 'Phenotype', 'HP:0006770', (215, 220))	('RCC', 'Disease', (217, 220))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('formation', 'biological_process', 'GO:0009058', ('103', '112'))	('ccRCC', 'Phenotype', 'HP:0006770', (31, 36))	('loss', 'Var', (130, 134))	('zebrafish', 'Species', '7955', (40, 49))	('VHL', 'Gene', (138, 141))	('zebrafish', 'Species', '7955', (161, 170))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
4488	27491085	Compound-76-treated fish had more organized nuclei, fewer lipid vesicles and a significantly larger and more structured lumen (seen in transverse sections) (Fig.	('lipid vesicles', 'MPA', (58, 72))	('more', 'PosReg', (29, 33))	('fewer', 'NegReg', (52, 57))	('lipid', 'Chemical', 'MESH:D008055', (58, 63))	('Compound-76-treated', 'Var', (0, 19))	('more', 'PosReg', (104, 108))
4493	27491085	The mutant proximal pronephric tubules also contain lipid-filled cytoplasmic vesicles, aberrant glycogen accumulation, a distorted lumen and disorderly cilia compared to their wt siblings.	('mutant', 'Var', (4, 10))	('glycogen', 'Chemical', 'MESH:D006003', (96, 104))	('disorderly cilia', 'Disease', 'MESH:C536287', (141, 157))	('lipid', 'Chemical', 'MESH:D008055', (52, 57))	('aberrant glycogen accumulation', 'Phenotype', 'HP:0500030', (87, 117))	('glycogen accumulation', 'MPA', (96, 117))	('disorderly cilia', 'Disease', (141, 157))	('lipid-filled cytoplasmic', 'MPA', (52, 76))
4507	27491085	Neutral lipids have been found to accumulate in Vhl-deficient hepatocytes resulting in the clear cell morphology characteristic of ccRCC.	('clear cell morphology', 'CPA', (91, 112))	('Vhl-deficient', 'Gene', (48, 61))	('Vhl-deficient', 'Var', (48, 61))	('lipids', 'Chemical', 'MESH:D008055', (8, 14))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('accumulate', 'PosReg', (34, 44))
4510	27491085	Further exploration using available BODIPY probes and lipidomic analysis is required to evaluate the effect of pVHL loss in our mutant fish on cholesteryl esters and other lipid types.	('pVHL loss', 'Disease', (111, 120))	('lipid', 'Chemical', 'MESH:D008055', (54, 59))	('lipid', 'Chemical', 'MESH:D008055', (172, 177))	('mutant', 'Var', (128, 134))	('pVHL loss', 'Disease', 'MESH:D015431', (111, 120))	('cholesteryl esters', 'MPA', (143, 161))	('cholesteryl esters', 'Chemical', 'MESH:D002788', (143, 161))
4511	27491085	Compared to their wt siblings, the vhl-/- mutants have significantly more lipids in their proximal pronephros.	('vhl-/-', 'Gene', (35, 41))	('mutants', 'Var', (42, 49))	('lipids in', 'MPA', (74, 83))	('lipids', 'Chemical', 'MESH:D008055', (74, 80))	('more', 'PosReg', (69, 73))
4523	27491085	They found that conditional inactivation of Vhl in these PEPCK-Cre mutants caused the development of both macroscopic and microscopic renal cysts, but not ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (155, 160))	('Vhl', 'Gene', (44, 47))	('PEPCK-Cre', 'Gene', (57, 66))	('renal cysts', 'Phenotype', 'HP:0000107', (134, 145))	('mutants', 'Var', (67, 74))	('caused', 'Reg', (75, 81))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', (157, 160))	('renal cysts', 'Disease', (134, 145))	('renal cysts', 'Disease', 'MESH:D007674', (134, 145))
4532	27491085	Defects in primary cilia have been linked to development of polycystic disease in the kidney, which also occurs in some VHL patients.	('linked', 'Reg', (35, 41))	('Defects', 'Var', (0, 7))	('polycystic disease', 'Disease', (60, 78))	('polycystic disease', 'Disease', 'MESH:D007690', (60, 78))	('patients', 'Species', '9606', (124, 132))	('primary cilia', 'Protein', (11, 24))
4538	27491085	Because HIF2a functions as an oncogene in VHL-associated and sporadic cases of ccRCC, we treated the vhl-/- mutants with a small-molecule HIF2a inhibitor, Compound 76.	('mutants', 'Var', (108, 115))	('vhl-/-', 'Gene', (101, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))
4545	27491085	Taking all these data together, our compound treatment results strongly indicate that the vhl-/- mutant pronephric tubule disorganization is driven, at least in part, by the zebrafish orthologs of human HIF2a.	('vhl-/-', 'Gene', (90, 96))	('zebrafish', 'Species', '7955', (174, 183))	('mutant', 'Var', (97, 103))	('human', 'Species', '9606', (197, 202))	('pronephric tubule disorganization', 'CPA', (104, 137))
4548	27491085	The results of this drug test indicate that small-molecule HIF2a inhibitors show promise in ccRCC treatment and merit further exploration.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Disease', (94, 97))	('HIF2a', 'Gene', (59, 64))	('inhibitors', 'Var', (65, 75))
4549	27491085	Given the conservation of hypoxia, angiogenesis and erythropoiesis pathways between humans and fish, zebrafish vhl mutants provide a uniquely effective model for further studies of VHL-related tumor biology and ccRCC development, as well as a platform for developing innovative new drug treatments.	('hypoxia', 'Disease', (26, 33))	('hypoxia', 'Disease', 'MESH:D000860', (26, 33))	('ccRCC', 'Phenotype', 'HP:0006770', (211, 216))	('humans', 'Species', '9606', (84, 90))	('erythropoiesis', 'biological_process', 'GO:0030218', ('52', '66'))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('zebrafish', 'Species', '7955', (101, 110))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('mutants', 'Var', (115, 122))	('RCC', 'Disease', (213, 216))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('angiogenesis', 'biological_process', 'GO:0001525', ('35', '47'))	('vhl', 'Gene', (111, 114))	('tumor', 'Disease', (193, 198))
4573	27491085	A filtered, 1:20 dilution of Richardson's stock solution [equal parts 1% Methylene Blue (Sigma #M9140-25G) in 1% borax (VWR #RC105016) and 1% azure II (Sigma #861065-25G)] was used to counterstain for 1 min and slides were then rinsed under running water for 5 min.	('Sigma #M9140-25G', 'Var', (89, 105))	('borax', 'Chemical', 'MESH:C018851', (113, 118))	('Methylene Blue', 'Chemical', 'MESH:D008751', (73, 87))	('Sigma #861065-25G)]', 'Var', (152, 171))	('water', 'Chemical', 'MESH:D014867', (249, 254))
4603	29416592	SCD1 overexpression is observed in a multitude of aggressive malignancies, and targeted inhibition of this enzyme has been previously shown to impair tumor cell proliferation, and produce tumor-specific cellular stress and apoptosis in representative tumor models.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', (251, 256))	('impair', 'NegReg', (143, 149))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('inhibition', 'Var', (88, 98))	('overexpression', 'PosReg', (5, 19))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('aggressive malignancies', 'Disease', 'MESH:D009369', (50, 73))	('produce', 'Reg', (180, 187))	('tumor', 'Disease', (150, 155))	('aggressive malignancies', 'Disease', (50, 73))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('apoptosis', 'CPA', (223, 232))	('rat', 'Species', '10116', (168, 171))	('cell proliferation', 'biological_process', 'GO:0008283', ('156', '174'))	('SCD1', 'Gene', (0, 4))	('apoptosis', 'biological_process', 'GO:0097194', ('223', '232'))	('apoptosis', 'biological_process', 'GO:0006915', ('223', '232'))
4605	29416592	On the other hand, discovery of SCD1 inhibitors such as MF-438, MK-8245, and SAR707 required the manipulation of the medicinal scaffold of known SCD1 inhibitors.	('SCD1', 'Gene', (32, 36))	('MF-438', 'Var', (56, 62))	('SAR707', 'Var', (77, 83))	('MK-8245', 'Var', (64, 71))	('SAR707', 'Chemical', 'MESH:C584534', (77, 83))
4612	29416592	The de novo ligands were first decomposed from A939572, MF-238 and SAR707, which had the cores stripped away and only the periphery/"edges" retained (Figure 1).	('SAR707', 'Chemical', 'MESH:C584534', (67, 73))	('A939572', 'Var', (47, 54))	('SAR707', 'Var', (67, 73))
4616	29416592	Top inhibitor shape scores were 0.513, 0.881, 0.803, 0.660, and 0.642, for SSI-1, SSI-2, SSI-3 and SSI-4, respectively (Table 2).	('SSI-1, SSI-2', 'Disease', 'MESH:D003924', (75, 87))	('SSI-3', 'Gene', '9021', (89, 94))	('0.642', 'Var', (64, 69))	('SSI-3', 'Gene', (89, 94))
4620	29416592	In order to illustrate candidate inhibitor docking poses (pink wire frame) throughout the identified binding pocket of SCD1, we overlaid their distribution with all commercial inhibitors (licorice style CPK molecules), which include A939572, GSK993, MF-438, ChemBL375265, and SAR707 (Figure 1b).	('rat', 'Species', '10116', (18, 21))	('CPK', 'Gene', (203, 206))	('GSK993', 'CellLine', 'CVCL:E952', (242, 248))	('SCD1', 'Gene', (119, 123))	('A939572', 'Var', (233, 240))	('CPK', 'Gene', '5286', (203, 206))	('binding', 'molecular_function', 'GO:0005488', ('101', '108'))	('SAR707', 'Chemical', 'MESH:C584534', (276, 282))	('GSK', 'molecular_function', 'GO:0050321', ('242', '245'))
4624	29416592	Within the tunnel-like crevice of the enzyme where each of these inhibitors fit, Met79, Val339, Ile115, Thr231, Leu232, Tyr334, Ala343, Arg347, and Ile348 all approach within 4.5 A of these inhibitors (Figure 2d).	('Ile115', 'Var', (96, 102))	('Met79', 'Var', (81, 86))	('Val339', 'Chemical', '-', (88, 94))	('Tyr334', 'Chemical', '-', (120, 126))	('Ile348', 'Chemical', '-', (148, 154))	('Leu232', 'Var', (112, 118))	('Ile115', 'Chemical', '-', (96, 102))	('Ile348', 'Var', (148, 154))	('Thr231', 'Chemical', '-', (104, 110))	('Ala343', 'Chemical', '-', (128, 134))	('Arg347', 'Chemical', '-', (136, 142))	('Tyr334', 'Var', (120, 126))	('Leu232', 'Chemical', '-', (112, 118))	('Met79', 'Chemical', '-', (81, 86))	('Val339', 'Var', (88, 94))	('approach', 'Reg', (159, 167))	('Thr231', 'Var', (104, 110))	('Arg347', 'Var', (136, 142))	('Ala343', 'Var', (128, 134))
4626	29416592	The outcome of our docking analyses is a set of 286 compounds with docking scores ranging from -12.55 kca/mol to -7 kcal/mol, including our top scoring ligands SSI-1 (-9.92 kcal/mol), SSI-2 (-9.0 kcal/mol), SSI-3 (-10.38 kcal/mol), and SSI-4 (-10.91 kcal/mol) (Supplementary Table 2).	('-10.38', 'Var', (214, 220))	('to -7', 'Species', '1214577', (110, 115))	('SSI-1', 'Gene', (160, 165))	('SSI-2', 'Gene', (184, 189))	('SSI-3', 'Gene', (207, 212))	('SSI-1', 'Gene', '8651', (160, 165))	('SSI-2', 'Gene', '8835', (184, 189))	('SSI-3', 'Gene', '9021', (207, 212))
4647	29416592	SCD1 expression correlates with poor cancer patient outcomes as evidenced by decreased survival in multiple cancers including gastric, lung, ovarian and renal cell carcinoma (Figure 5a-5b, Supplementary Figure 9a-9b).	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('ovarian and renal cell carcinoma', 'Disease', 'MESH:C538614', (141, 173))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('expression', 'Var', (5, 15))	('lung', 'Disease', (135, 139))	('survival', 'MPA', (87, 95))	('cancer', 'Disease', (37, 43))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (153, 173))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('decreased', 'NegReg', (77, 86))	('cancer', 'Disease', (108, 114))	('cancers', 'Disease', (108, 115))	('gastric', 'Disease', (126, 133))	('patient', 'Species', '9606', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('SCD1', 'Gene', (0, 4))
4663	29416592	An increasing trend for the use of computational, structure-based studies for accelerating drug discovery and leapfrogging multiple chemical syntheses, with guided 3D-QSAR, or Field-based QSAR, have improved medicinal chemistry studies for drugs such as MK-8931 or SAR707.	('medicinal chemistry studies', 'MPA', (208, 235))	('improved', 'PosReg', (199, 207))	('rat', 'Species', '10116', (84, 87))	('SAR707', 'Chemical', 'MESH:C584534', (265, 271))	('MK-8931', 'Var', (254, 261))
4665	29416592	Aberrant SCD1 expression is commonly observed in aggressive malignancies, and negatively correlates with patient outcomes, generating a clear prospective for targeted therapy of this enzyme.	('patient', 'Species', '9606', (105, 112))	('Aberrant', 'Var', (0, 8))	('SCD1', 'Gene', (9, 13))	('observed', 'Reg', (37, 45))	('expression', 'MPA', (14, 24))	('rat', 'Species', '10116', (127, 130))	('aggressive malignancies', 'Disease', (49, 72))	('aggressive malignancies', 'Disease', 'MESH:D009369', (49, 72))
4706	29416592	Specifically, SRM was executed for 13C18-stearoyl CoA (m/z 1052   545), 13C18-oleoyl CoA (m/z 1050   543), and heptadecanoyl CoA I.S.	('13C18-stearoyl CoA', 'Chemical', '-', (35, 53))	('m/z 1052   545', 'Var', (55, 69))	('13C18-oleoyl CoA', 'Chemical', '-', (72, 88))	('m/z 1050   543', 'Var', (90, 104))	('heptadecanoyl CoA', 'Chemical', 'MESH:C032420', (111, 128))
4730	33686949	A series of genetic or epigenetic alterations have been demonstrated to play a vital role in the initiation and progression of ccRCC and may serve as potential biomarkers for clinical application.	('epigenetic alterations', 'Var', (23, 45))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('RCC', 'Disease', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('genetic', 'Var', (12, 19))
4737	33686949	In addition, we compared the differences among three subgroups of ccRCC samples, which were divided according to mPS scores, regarding mutations and copy number variations (CNVs), and immune cell infiltrations.	('copy number variations', 'Var', (149, 171))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))
4760	33686949	Based on the Limma R package, a total of 434 genes were identified to differentially express between low- and high-mPS groups, of which 279 genes were up-regulated and 155 genes were down-regulated in high-mPS group compared with low-mPS group.	('age', 'Gene', (25, 28))	('high-mPS', 'Var', (201, 209))	('down-regulated', 'NegReg', (183, 197))	('age', 'Gene', '5973', (25, 28))	('up-regulated', 'PosReg', (151, 163))
4765	33686949	According to the above analysis, the TCGA ccRCC samples can be divided into three groups, namely low-mPS group (mPS<22), median-mPS group (22<=mPS<30), and high-mPS group (mPS>=30), and the number of samples in these three groups were 129, 55, 347, respectively.	('mPS<22', 'Var', (112, 118))	('22<=mPS<30', 'Var', (139, 149))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (42, 47))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('mPS', 'Var', (172, 175))
4769	33686949	In general, a worse outcome may be correlated with more genomic abnormality, revealing that the chromosomal amplification and deletion identified by mPS system can be a patient stratification for immune checkpoint therapy.	('chromosomal amplification', 'Var', (96, 121))	('mPS system', 'Gene', (149, 159))	('deletion', 'Var', (126, 134))	('patient', 'Species', '9606', (169, 176))
4793	33686949	Zinc finger protein 395 (ZNF395), a ccRCC master regulator, was identified as a downstream protein of CCDC50-S, and the interaction initiated oncogenic pathways which were highly associated with the pathogenesis of ccRCC.	('RCC', 'Disease', (38, 41))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('Zinc finger protein 395', 'Gene', (0, 23))	('interaction', 'Var', (120, 131))	('RCC', 'Disease', 'MESH:C538614', (38, 41))	('CCDC50', 'Gene', '152137', (102, 108))	('protein', 'cellular_component', 'GO:0003675', ('12', '19'))	('Zinc finger protein 395', 'Gene', '55893', (0, 23))	('ZNF395', 'Gene', (25, 31))	('RCC', 'Phenotype', 'HP:0005584', (217, 220))	('CCDC50', 'Gene', (102, 108))	('ccRCC', 'Phenotype', 'HP:0006770', (215, 220))	('RCC', 'Disease', (217, 220))	('associated', 'Reg', (179, 189))	('initiated', 'Reg', (132, 141))	('pathogenesis', 'biological_process', 'GO:0009405', ('199', '211'))	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('ZNF395', 'Gene', '55893', (25, 31))	('oncogenic pathways', 'Pathway', (142, 160))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))
4812	33686949	Studies have convinced the roles of DNA repair deregulation in promoting immune recognition and immune destruction of cancer cells.	('cancer', 'Disease', (118, 124))	('promoting', 'PosReg', (63, 72))	('immune recognition', 'CPA', (73, 91))	('DNA repair', 'biological_process', 'GO:0006281', ('36', '46'))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('DNA', 'Gene', (36, 39))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('immune destruction', 'CPA', (96, 114))	('deregulation', 'Var', (47, 59))
4813	33686949	Emerging evidence has identified that defects in DNA repair machinery play an important part in the pathogenesis and progression of human cancer.	('cancer', 'Disease', (138, 144))	('DNA repair', 'biological_process', 'GO:0006281', ('49', '59'))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('human', 'Species', '9606', (132, 137))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('pathogenesis', 'biological_process', 'GO:0009405', ('100', '112'))	('defects', 'Var', (38, 45))
4814	33686949	Moreover, the information gathered so far indicated that E2F is one of the most important transcription factors that regulates various cellular functions related to cell cycle and apoptosis and involves not only in proliferation and tumorigenesis but also in apoptosis and differentiation.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('E2F', 'Var', (57, 60))	('apoptosis', 'biological_process', 'GO:0006915', ('259', '268'))	('tumor', 'Disease', (233, 238))	('apoptosis', 'biological_process', 'GO:0097194', ('180', '189'))	('involves', 'Reg', (194, 202))	('apoptosis', 'biological_process', 'GO:0097194', ('259', '268'))	('cell cycle', 'biological_process', 'GO:0007049', ('165', '175'))	('apoptosis', 'biological_process', 'GO:0006915', ('180', '189'))	('regulates', 'Reg', (117, 126))	('cellular', 'MPA', (135, 143))	('differentiation', 'CPA', (273, 288))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('proliferation', 'CPA', (215, 228))	('apoptosis', 'CPA', (259, 268))	('transcription', 'biological_process', 'GO:0006351', ('90', '103'))
4816	33686949	Mutations and CNVs have been vital forms of epigenetic modifications, which can cause genomic and molecular phenotype heterogeneity, promoting the initiation and progression of complex diseases, including cancer.	('CNVs', 'Var', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (205, 211))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('promoting', 'PosReg', (133, 142))	('cause', 'Reg', (80, 85))
4856	32300145	CREB1 is affected by the microRNAs miR-22-3p, miR-26a-5p, miR-27a-3p, and miR-221-3p and correlates with adverse clinicopathological features in renal cell carcinoma The transcription factor cAMP response element-binding protein (CREB1) has been shown to be involved in diverse biological pathways including the regulation of cell proliferation, apoptosis, cell cycle progression, and metastasis.	('cell cycle progression', 'CPA', (357, 379))	('miR-22-3p', 'Gene', '407008', (35, 44))	('transcription factor', 'molecular_function', 'GO:0000981', ('170', '190'))	('CREB1', 'Gene', '1385', (0, 5))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (145, 165))	('CREB1', 'Gene', '1385', (230, 235))	('cAMP', 'Chemical', 'MESH:D000242', (191, 195))	('cell proliferation', 'CPA', (326, 344))	('miR-22-3p', 'Gene', (35, 44))	('protein', 'cellular_component', 'GO:0003675', ('221', '228'))	('apoptosis', 'biological_process', 'GO:0097194', ('346', '355'))	('apoptosis', 'biological_process', 'GO:0006915', ('346', '355'))	('apoptosis', 'CPA', (346, 355))	('miR-27a-3p', 'Var', (58, 68))	('men', 'Species', '9606', (208, 211))	('transcription', 'biological_process', 'GO:0006351', ('170', '183'))	('cell cycle', 'biological_process', 'GO:0007049', ('357', '367'))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('renal cell carcinoma', 'Disease', (145, 165))	('cAMP response element-binding', 'molecular_function', 'GO:0035497', ('191', '220'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (145, 165))	('miR-221-3p', 'Var', (74, 84))	('regulation of cell proliferation', 'biological_process', 'GO:0042127', ('312', '344'))	('metastasis', 'CPA', (385, 395))	('involved', 'Reg', (258, 266))	('CREB1', 'Gene', (230, 235))	('CREB1', 'Gene', (0, 5))
4857	32300145	In this context, aberrant expression of CREB1 and the functional consequences are well investigated in a number of hematopoietic and solid tumors.	('aberrant', 'Var', (17, 25))	('CREB1', 'Gene', '1385', (40, 45))	('solid tumors', 'Disease', 'MESH:D009369', (133, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('CREB1', 'Gene', (40, 45))	('solid tumors', 'Disease', (133, 145))
4859	32300145	The present study confirmed a deregulation of CREB1 protein in the clear cell type of RCC (ccRCC) and analysis of in-house ccRCC cell lines suggested a post-transcriptional control.	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Disease', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('protein', 'Protein', (52, 59))	('CREB1', 'Gene', (46, 51))	('transcriptional control', 'biological_process', 'GO:0006355', ('157', '180'))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('deregulation', 'Var', (30, 42))	('CREB1', 'Gene', '1385', (46, 51))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
4860	32300145	The combination of miRNA enrichment assay, in silico analysis and molecular biological approaches revealed four novel CREB1-regulating miRNAs, namely miR-22-3p, miR-26a-5p, miR-27a-3p, and miR-221-3p.	('miR-26a', 'Gene', '407015', (161, 168))	('CREB1', 'Gene', '1385', (118, 123))	('men', 'Species', '9606', (31, 34))	('miR-221-3p', 'Var', (189, 199))	('miR-26a', 'Gene', (161, 168))	('miR-22-3p', 'Gene', (150, 159))	('CREB1', 'Gene', (118, 123))	('miR-22-3p', 'Gene', '407008', (150, 159))	('miR-27a-3p', 'Var', (173, 183))
4872	32300145	The deregulation of HIF1A and HIF2A results in the up-regulation of various growth factors like vascular endothelial growth factor (VEGF), platelet-derived growth factor beta (PDGFB), and transforming growth factor alpha (TGFA) responsible for the development of the tumor.	('VEGF', 'Gene', (132, 136))	('up-regulation', 'PosReg', (51, 64))	('HIF1A', 'Gene', '3091', (20, 25))	('PDGFB', 'Gene', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('HIF2A', 'Gene', (30, 35))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('139', '169'))	('vascular endothelial growth factor', 'Gene', (96, 130))	('men', 'Species', '9606', (255, 258))	('TGFA', 'Gene', (222, 226))	('transforming growth factor alpha', 'Gene', (188, 220))	('transforming growth factor alpha', 'molecular_function', 'GO:0005154', ('188', '220'))	('transforming growth factor alpha', 'Gene', '7124', (188, 220))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('96', '130'))	('deregulation', 'Var', (4, 16))	('HIF1A', 'Gene', (20, 25))	('TGFA', 'Gene', '7039', (222, 226))	('PDGFB', 'Gene', '5155', (176, 181))	('regulation', 'biological_process', 'GO:0065007', ('54', '64'))	('VEGF', 'Gene', '7422', (132, 136))	('vascular endothelial growth factor', 'Gene', '7422', (96, 130))	('tumor', 'Disease', (267, 272))	('HIF2A', 'Gene', '2034', (30, 35))
4899	32300145	The ccRCC cell line MZ2733RC and the corresponding normal tissue cell line MZ2733NN showed a divergence in CREB1 protein expression (Fig.	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('CREB1', 'Gene', (107, 112))	('MZ2733RC', 'Var', (20, 28))	('CREB1', 'Gene', '1385', (107, 112))	('MZ2733RC', 'Chemical', '-', (20, 28))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('MZ2733NN', 'Chemical', '-', (75, 83))	('RCC', 'Disease', (6, 9))
4901	32300145	Thus, MZ2733RC was selected for further analysis focusing on the identification of miRNAs as post-transcriptional regulators of CREB1.	('MZ2733RC', 'Var', (6, 14))	('CREB1', 'Gene', (128, 133))	('MZ2733RC', 'Chemical', '-', (6, 14))	('CREB1', 'Gene', '1385', (128, 133))
4902	32300145	To determine whether the known CREB1-specific miRNAs are up-regulated in MZ2733RC and therefore responsible for low CREB1 protein levels, the expression of the seven best validated CREB1-specific miRNAs, namely miR-9, -17, -34, -181a, -181b, -200b, and miR-203a were analyzed in MZ2733RC and MZ2733NN by small RNA-seq and qRT-PCR (Fig.	('miR-203a', 'Gene', '406986', (253, 261))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('CREB1', 'Gene', (181, 186))	('RNA', 'cellular_component', 'GO:0005562', ('310', '313'))	('MZ2733RC', 'Var', (279, 287))	('MZ2733NN', 'Chemical', '-', (292, 300))	('CREB1', 'Gene', '1385', (31, 36))	('CREB1', 'Gene', (31, 36))	('CREB1', 'Gene', '1385', (116, 121))	('MZ2733RC', 'Var', (73, 81))	('MZ2733RC', 'Chemical', '-', (279, 287))	('MZ2733NN', 'Var', (292, 300))	('MZ2733RC', 'Chemical', '-', (73, 81))	('CREB1', 'Gene', '1385', (181, 186))	('up-regulated', 'PosReg', (57, 69))	('miR-9, -17, -34, -181a, -181b, -200b', 'Gene', '406952;407040;406984', (211, 247))	('CREB1', 'Gene', (116, 121))	('miR-203a', 'Gene', (253, 261))
4909	32300145	Using different miRNA prediction algorithms including Targetscan, RNAhybrid, miRanda, and miRWalk2.0 miR-22-3p, miR-26a-5p, miR-27a-3p, miR-30a-5p, and miR-221-3p were identified as novel putative CREB1-specific miRNAs (Table 1).	('miR-26a', 'Gene', (112, 119))	('miR-22-3p', 'Gene', '407008', (101, 110))	('miR-30a-5p', 'Var', (136, 146))	('CREB1', 'Gene', '1385', (197, 202))	('miR-221-3p', 'Var', (152, 162))	('CREB1', 'Gene', (197, 202))	('miR-27a-3p', 'Var', (124, 134))	('miR-26a', 'Gene', '407015', (112, 119))	('miR-30a-5p', 'Chemical', '-', (136, 146))	('miR-22-3p', 'Gene', (101, 110))
4917	32300145	In order to exclude an indirect/secondary effect responsible for the down-regulation of CREB1 protein after overexpression of the respective miRNA as well as to determine the exact miRNA binding site in the 3'-UTR of CREB1, luciferase (luc) reporter gene assays were performed using the wild type (wt) 3'-UTR or a mutated version of the miRNA binding site (Fig.	('CREB1', 'Gene', (217, 222))	('regulation', 'biological_process', 'GO:0065007', ('74', '84'))	('CREB1', 'Gene', '1385', (88, 93))	('mutated', 'Var', (314, 321))	('CREB1', 'Gene', '1385', (217, 222))	('CREB1', 'Gene', (88, 93))	('miRNA binding', 'molecular_function', 'GO:0035198', ('337', '350'))	('miRNA binding', 'molecular_function', 'GO:0035198', ('181', '194'))	('down-regulation', 'NegReg', (69, 84))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))
4918	32300145	The mutation of the expected miRNA binding site in the 3'-UTR of CREB1 abolished this effect indicating a direct interaction of miR-22-3p, miR-26a-5p, miR-27a-3p, and miR-221-3p with the predicted sequence.	('CREB1', 'Gene', (65, 70))	('miR-22-3p', 'Gene', (128, 137))	('miR-22-3p', 'Gene', '407008', (128, 137))	('mutation', 'Var', (4, 12))	('miRNA binding', 'MPA', (29, 42))	('miR-27a-3p', 'Var', (151, 161))	('miR-26a', 'Gene', '407015', (139, 146))	('CREB1', 'Gene', '1385', (65, 70))	('miRNA binding', 'molecular_function', 'GO:0035198', ('29', '42'))	('miR-26a', 'Gene', (139, 146))	('interaction', 'Interaction', (113, 124))
4921	32300145	Altogether, these data suggest that miR-27a-3p is at least partially involved in the post-transcriptional regulation of CREB1 in the tumor cell line MZ2733RC.	('regulation', 'biological_process', 'GO:0065007', ('106', '116'))	('miR-27a-3p', 'Var', (36, 46))	('MZ2733RC', 'Chemical', '-', (149, 157))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('involved', 'Reg', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('CREB1', 'Gene', '1385', (120, 125))	('tumor', 'Disease', (133, 138))	('CREB1', 'Gene', (120, 125))
4929	32300145	Only miR-9-5p was found to be reduced after CREB1 knock-down (Fig.	('knock-down', 'Var', (50, 60))	('CREB1', 'Gene', '1385', (44, 49))	('miR-9-5p', 'Gene', (5, 13))	('miR-9-5p', 'Gene', '407052', (5, 13))	('CREB1', 'Gene', (44, 49))
4932	32300145	Expression levels were significantly reduced for miR-26a, miR-27a-3p, and miR-221-3p, while miR-22-3p showed a non-significant tendency for lower RNA quantity in the CREB1 high samples.	('RNA', 'cellular_component', 'GO:0005562', ('146', '149'))	('lower', 'NegReg', (140, 145))	('miR-26a', 'Gene', '407015', (49, 56))	('CREB1', 'Gene', (166, 171))	('miR-22-3p', 'Gene', (92, 101))	('Expression levels', 'MPA', (0, 17))	('miR-26a', 'Gene', (49, 56))	('miR-27a-3p', 'Var', (58, 68))	('miR-22-3p', 'Gene', '407008', (92, 101))	('CREB1', 'Gene', '1385', (166, 171))	('reduced', 'NegReg', (37, 44))	('miR-221-3p', 'Var', (74, 84))	('RNA quantity', 'MPA', (146, 158))
4950	32300145	In these types of cancer deregulation of CREB1 was shown to be associated with enhanced proliferation, reduced apoptosis and increased angiogenesis.	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('deregulation', 'Var', (25, 37))	('increased', 'PosReg', (125, 134))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('CREB1', 'Gene', (41, 46))	('reduced', 'NegReg', (103, 110))	('enhanced', 'PosReg', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('angiogenesis', 'biological_process', 'GO:0001525', ('135', '147'))	('proliferation', 'CPA', (88, 101))	('CREB1', 'Gene', '1385', (41, 46))	('cancer', 'Disease', (18, 24))	('apoptosis', 'CPA', (111, 120))	('angiogenesis', 'CPA', (135, 147))
4954	32300145	However, underlying mechanisms responsible for aberrant CREB1 expression in general are only poorly understood.	('aberrant', 'Var', (47, 55))	('CREB1', 'Gene', '1385', (56, 61))	('CREB1', 'Gene', (56, 61))
4959	32300145	Using the combination of miTRAP, in silico analysis and molecular biological approaches, we were able to identify four novel CREB1-regulating miRNAs, namely miR-22-3p, miR-26a-5p, miR-27a-3p, and miR-221-3p.	('CREB1', 'Gene', '1385', (125, 130))	('miR-221-3p', 'Var', (196, 206))	('CREB1', 'Gene', (125, 130))	('miR-26a', 'Gene', (168, 175))	('miR-22-3p', 'Gene', (157, 166))	('miR-27a-3p', 'Var', (180, 190))	('miR-22-3p', 'Gene', '407008', (157, 166))	('miR-26a', 'Gene', '407015', (168, 175))
4960	32300145	These new miRNAs complete a list of already known CREB1-specific miRNAs including miR-9, -17-92 cluster, -27b, -34b, -181a/b, -182, -200b, -203, and miR-433.	('miR-9', 'Var', (82, 87))	('miR-433', 'Gene', '574034', (149, 156))	('CREB1', 'Gene', '1385', (50, 55))	('miR-433', 'Gene', (149, 156))	('CREB1', 'Gene', (50, 55))
4964	32300145	Expression analysis in CREB1 negative and CREB1 high RCC samples revealed a significant inverse correlation of CREB1 and miR-26a-5p, miR-27a-3p, and miR-221-3p expression.	('CREB1', 'Gene', '1385', (111, 116))	('CREB1', 'Gene', (42, 47))	('miR-27a-3p', 'Var', (133, 143))	('inverse', 'NegReg', (88, 95))	('CREB1', 'Gene', (111, 116))	('miR-26a', 'Gene', '407015', (121, 128))	('miR-221-3p', 'Var', (149, 159))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('CREB1', 'Gene', '1385', (23, 28))	('RCC', 'Disease', (53, 56))	('CREB1', 'Gene', (23, 28))	('miR-26a', 'Gene', (121, 128))	('CREB1', 'Gene', '1385', (42, 47))
4965	32300145	Therefore, the miRNAs miR-26a-5p, miR-27a-3p, and miR-221-3p may provide a tool for diagnostic purposes identifying CREB1 negative/low and CREB1 high tumors and, thus, potentially important CREB1-regulated targets, such as members of the cyclin family, VEGF, and MMP-2.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('CREB1', 'Gene', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('miR-26a', 'Gene', (22, 29))	('tumors', 'Disease', (150, 156))	('CREB1', 'Gene', '1385', (190, 195))	('miR-26a', 'Gene', '407015', (22, 29))	('CREB1', 'Gene', (116, 121))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('MMP-2', 'molecular_function', 'GO:0004228', ('263', '268'))	('negative/low', 'NegReg', (122, 134))	('MMP-2', 'Gene', '4313', (263, 268))	('CREB1', 'Gene', '1385', (116, 121))	('CREB1', 'Gene', (139, 144))	('miR-221-3p', 'Var', (50, 60))	('VEGF', 'Gene', '7422', (253, 257))	('CREB1', 'Gene', '1385', (139, 144))	('VEGF', 'Gene', (253, 257))	('cyclin', 'molecular_function', 'GO:0016538', ('238', '244'))	('MMP-2', 'Gene', (263, 268))
4975	32300145	The authors showed that CREB1 depletion induces the expression of cell-cycle related genes and accelerates G1/S phase transition which in turn supports oncogenesis.	('CREB1', 'Gene', (24, 29))	('accelerates', 'PosReg', (95, 106))	('depletion', 'Var', (30, 39))	('supports', 'PosReg', (143, 151))	('expression', 'MPA', (52, 62))	('oncogenesis', 'biological_process', 'GO:0007048', ('152', '163'))	('cell-cycle', 'biological_process', 'GO:0007049', ('66', '76'))	('S phase', 'biological_process', 'GO:0051320', ('110', '117'))	('cell-cycle related genes', 'Gene', (66, 90))	('G1/S phase transition', 'CPA', (107, 128))	('induces', 'PosReg', (40, 47))	('CREB1', 'Gene', '1385', (24, 29))	('oncogenesis', 'CPA', (152, 163))
4981	32300145	In-house established ccRCC cell lines MZ2862RC, MZ2733RC, autologous normal kidney cell line MZ2733NN and HEK293T (purchased from the American Type Culture Collection) were maintained in Dulbecco's Modified Eagle Medium (DMEM, Invitrogen) supplemented with 10% (v/v) fetal bovine serum (FCS) (PAA), 0,1 mM non-essential amino acids (Gibco), 2 mM L-glutamine (Lonza), and 1% penicillin/streptomycin (v/v; PAA) and incubated at 37  C, 5% CO2.	('MZ2733NN', 'Var', (93, 101))	('PAA', 'cellular_component', 'GO:1990295', ('293', '296'))	('PAA', 'cellular_component', 'GO:1990295', ('404', '407'))	('MZ2862RC', 'Var', (38, 46))	('MZ2733NN', 'Chemical', '-', (93, 101))	('HEK293T', 'CellLine', 'CVCL:0063', (106, 113))	('MZ2733RC', 'Var', (48, 56))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('men', 'Species', '9606', (245, 248))	('RCC', 'Disease', (23, 26))	('MZ2862RC', 'CellLine', 'CVCL:X422', (38, 46))	('MZ2733RC', 'Chemical', '-', (48, 56))
4983	32300145	30 ng of esiCREB or esiCONTROL (specific for GFP) RNAs were used to transfect MZ2862RC cell line using Lipofectamine RNAi MAX (Invitrogen) according to the manufacturers' protocol.	('Lipofectamine', 'Chemical', 'MESH:C086724', (103, 116))	('esiCREB or esiCONTROL', 'Disease', (9, 30))	('RNAi', 'biological_process', 'GO:0016246', ('117', '121'))	('esiCREB or esiCONTROL', 'Disease', 'None', (9, 30))	('MZ2862RC', 'CellLine', 'CVCL:X422', (78, 86))	('transfect', 'Var', (68, 77))
5001	32300145	Small RNA sequencing of RNA derived from the cell lines MZ2733RC and MZ2733NN was carried out at Novogene (Hong-Kong).	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('MZ2733RC', 'Chemical', '-', (56, 64))	('MZ2733NN', 'Chemical', '-', (69, 77))	('MZ2733RC', 'Var', (56, 64))	('MZ2733NN', 'Var', (69, 77))	('RNA', 'cellular_component', 'GO:0005562', ('24', '27'))
5013	32300145	Mutagenesis of the predicted miRNA binding site was enabled by NEBs Q5  Site-Directed Mutagenesis Kit using the oligonucleotides listed in Supplementary Table 1.	('Kit', 'Gene', '3815', (98, 101))	('NEBs', 'Chemical', '-', (63, 67))	('Mutagenesis', 'biological_process', 'GO:0006280', ('0', '11'))	('men', 'Species', '9606', (145, 148))	('Mutagenesis', 'Var', (0, 11))	('Mutagenesis', 'biological_process', 'GO:0006280', ('86', '97'))	('oligonucleotides', 'Chemical', 'MESH:D009841', (112, 128))	('Kit', 'Gene', (98, 101))	('miRNA binding', 'molecular_function', 'GO:0035198', ('29', '42'))
5035	33495417	In vitro cell results also confirmed that HIPK3 over-expression could inhibit tumor growth and malignant characteristics.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('malignant characteristics', 'CPA', (95, 120))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('HIPK3', 'Gene', '10114', (42, 47))	('HIPK3', 'Gene', (42, 47))	('tumor', 'Disease', (78, 83))	('inhibit', 'NegReg', (70, 77))	('over-expression', 'Var', (48, 63))
5045	33495417	The phosphorylation of extracellular signal regulated kinase (p-ERK) pathway was associated with poor prognosis of ccRCC patients.	('extracellular', 'cellular_component', 'GO:0005576', ('23', '36'))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('ERK', 'Gene', (64, 67))	('ERK', 'Gene', '2048', (64, 67))	('associated', 'Reg', (81, 91))	('phosphorylation', 'Var', (4, 19))	('ERK', 'molecular_function', 'GO:0004707', ('64', '67'))	('patients', 'Species', '9606', (121, 129))
5050	33495417	The expression and function of HIPK3 may be associate with BAP1 mutation or expression of TWIST1, CDH1(E-Cadherin), Vimentin.	('Vimentin', 'Gene', '7431', (116, 124))	('associate', 'Reg', (44, 53))	('mutation', 'Var', (64, 72))	('BAP1', 'Gene', (59, 63))	('HIPK3', 'Gene', (31, 36))	('TWIST1', 'Gene', (90, 96))	('CDH1', 'Gene', '999', (98, 102))	('Vimentin', 'cellular_component', 'GO:0045098', ('116', '124'))	('TWIST1', 'Gene', '7291', (90, 96))	('Cadherin', 'molecular_function', 'GO:0008014', ('105', '113'))	('E-Cadherin', 'Gene', (103, 113))	('Vimentin', 'Gene', (116, 124))	('HIPK3', 'Gene', '10114', (31, 36))	('E-Cadherin', 'Gene', '999', (103, 113))	('CDH1', 'Gene', (98, 102))	('Vimentin', 'cellular_component', 'GO:0045099', ('116', '124'))	('BAP1', 'Gene', '8314', (59, 63))	('function', 'MPA', (19, 27))
5061	33495417	Univariate analysis and multivariate analysis results showed the prognostic indicators of HIPKs with OS and DFS in Figure 3A-3D.	('DFS', 'Var', (108, 111))	('HIPKs', 'Disease', (90, 95))	('HIPKs', 'Disease', 'None', (90, 95))
5071	33495417	The expression of HIPK3 is downregulated with BAP1 mutation (Figure 5A).	('BAP1', 'Gene', '8314', (46, 50))	('expression', 'MPA', (4, 14))	('downregulated', 'NegReg', (27, 40))	('HIPK3', 'Gene', '10114', (18, 23))	('mutation', 'Var', (51, 59))	('HIPK3', 'Gene', (18, 23))	('BAP1', 'Gene', (46, 50))
5072	33495417	High expression of HIPK3 is correlate with good OS and DFS of renal cancer between wild-type and mutation subsets of these genes (Figure 5B, 5C).	('HIPK3', 'Gene', '10114', (19, 24))	('expression', 'MPA', (5, 15))	('HIPK3', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('DFS of renal cancer', 'Disease', (55, 74))	('renal cancer', 'Phenotype', 'HP:0009726', (62, 74))	('DFS of renal cancer', 'Disease', 'MESH:D007680', (55, 74))	('mutation', 'Var', (97, 105))
5075	33495417	In addition, a subgroup ROC curve analysis of clinical characteristics suggests that low expression of HIPK3 may have diagnostic value in ccRCC patients with living vs deceased (AUC = 0.6397, 95% CI: 0.5893-0.6900, p < 0.0001, Figure 6C), recurred vs disease free (AUC = 0.6128, 95% CI: 0.5555-0.6702, p=0.0002, Figure 6D), M1 / M0 stage (AUC = 0.5929, 95% CI: 0.5175-0.6587, p=0.008, Figure 6E), (T3 + T4) / (T1 + T2) (AUC = 0.5750, 95% CI: 0.5244-0.6256 p=0.004, Figure 6F), pathological stage (III + IV)/ (I + II) (AUC = 0.6012, 95% CI: 0.5516-0.6206, p < 0.0001, Figure 6G).	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('low', 'Var', (85, 88))	('T3', 'Var', (398, 400))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('patients', 'Species', '9606', (144, 152))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('HIPK3', 'Gene', '10114', (103, 108))	('RCC', 'Disease', (140, 143))	('HIPK3', 'Gene', (103, 108))
5099	33495417	In our study, HIPK2 did not have a significant difference in renal cancer tissues, but its low expression predicted a poor prognosis, and the univariate analysis and multivariate analysis also indicates that low expression may be an independent prognostic marker for ccRCC.	('low', 'NegReg', (91, 94))	('RCC', 'Disease', (269, 272))	('renal cancer', 'Phenotype', 'HP:0009726', (61, 73))	('renal cancer', 'Disease', 'MESH:D007680', (61, 73))	('HIPK2', 'Gene', '28996', (14, 19))	('HIPK2', 'Gene', (14, 19))	('RCC', 'Phenotype', 'HP:0005584', (269, 272))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('low expression', 'Var', (208, 222))	('ccRCC', 'Phenotype', 'HP:0006770', (267, 272))	('renal cancer', 'Disease', (61, 73))	('expression', 'MPA', (95, 105))	('RCC', 'Disease', 'MESH:C538614', (269, 272))
5103	33495417	Our research results showed HIPK3 had a significantly lower expression in renal cancer tissues, and its low expression predicted a poor prognosis, and univariate analysis and multivariate analysis also indicates that low expression may be a novel independent prognostic marker for ccRCC.	('expression', 'MPA', (60, 70))	('renal cancer', 'Disease', 'MESH:D007680', (74, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (281, 286))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('RCC', 'Disease', (283, 286))	('RCC', 'Phenotype', 'HP:0005584', (283, 286))	('HIPK3', 'Gene', '10114', (28, 33))	('HIPK3', 'Gene', (28, 33))	('RCC', 'Disease', 'MESH:C538614', (283, 286))	('expression', 'MPA', (108, 118))	('low', 'NegReg', (104, 107))	('low', 'Var', (217, 220))	('renal cancer', 'Disease', (74, 86))	('lower', 'NegReg', (54, 59))	('renal cancer', 'Phenotype', 'HP:0009726', (74, 86))
5110	33495417	The expression of HIPK3 decreased when BAP1 mutation.	('decreased', 'NegReg', (24, 33))	('mutation', 'Var', (44, 52))	('expression', 'MPA', (4, 14))	('HIPK3', 'Gene', '10114', (18, 23))	('BAP1', 'Gene', '8314', (39, 43))	('HIPK3', 'Gene', (18, 23))	('BAP1', 'Gene', (39, 43))
5111	33495417	High expression of HIPK3 is correlate with good OS and DFS of renal cancer between wild-type and mutation subsets of TP53, VHL, BAP1, and PBRM1.	('HIPK3', 'Gene', '10114', (19, 24))	('expression', 'MPA', (5, 15))	('HIPK3', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('DFS of renal cancer', 'Disease', (55, 74))	('TP53', 'Gene', '7157', (117, 121))	('BAP1', 'Gene', '8314', (128, 132))	('TP53', 'Gene', (117, 121))	('VHL', 'Gene', (123, 126))	('PBRM1', 'Gene', (138, 143))	('renal cancer', 'Phenotype', 'HP:0009726', (62, 74))	('DFS of renal cancer', 'Disease', 'MESH:D007680', (55, 74))	('BAP1', 'Gene', (128, 132))	('VHL', 'Gene', '7428', (123, 126))	('mutation', 'Var', (97, 105))	('PBRM1', 'Gene', '55193', (138, 143))
5112	33495417	Loss of HIPK1 and HIPK2 leads to upregulation of angiogenic genes.	('HIPK1', 'Gene', '204851', (8, 13))	('HIPK1', 'Gene', (8, 13))	('upregulation', 'PosReg', (33, 45))	('HIPK2', 'Gene', '28996', (18, 23))	('HIPK2', 'Gene', (18, 23))	('angiogenic genes', 'Gene', (49, 65))	('Loss', 'Var', (0, 4))
5142	31155610	Our results indicated that high expressions of BMP1 were poor prognostic factors and gene therapy could be an effective treatment for ccRCC.	('high', 'Var', (27, 31))	('BMP1', 'Gene', (47, 51))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('BMP1', 'molecular_function', 'GO:0017026', ('47', '51'))	('RCC', 'Disease', (136, 139))
5161	31155610	In vitro and in vivo experiments certificated knockdown BMP1 suppressed malignancy of ccRCC.	('suppressed', 'NegReg', (61, 71))	('BMP1', 'Gene', (56, 60))	('knockdown', 'Var', (46, 55))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('malignancy of ccRCC', 'Disease', 'MESH:D009369', (72, 91))	('malignancy of ccRCC', 'Disease', (72, 91))	('BMP1', 'molecular_function', 'GO:0017026', ('56', '60'))
5177	31155610	After transfer to the PVDF membrane, the membrane was blocked in PBS containing 5% skim milk for 1 h and then incubated with antibodies against BMP1 (1:1000; ab205394; Abcam Co., Ltd) and GAPDH (1:2000; BM3876; Wuhan Boster Biological Technology, Ltd, Wuhan, China) at 4  C overnight.	('GAPDH', 'Gene', (188, 193))	('membrane', 'cellular_component', 'GO:0016020', ('41', '49'))	('1:1000;', 'Var', (150, 157))	('BMP1', 'molecular_function', 'GO:0017026', ('144', '148'))	('PBS', 'Chemical', 'MESH:D007854', (65, 68))	('BMP1', 'Gene', (144, 148))	('membrane', 'cellular_component', 'GO:0016020', ('27', '35'))	('PVDF', 'Chemical', 'MESH:C024865', (22, 26))	('GAPDH', 'Gene', '2597', (188, 193))
5191	31155610	KM analysis demonstrated that the patients with high BMP1, BMP7, and BMP8A expression had shorter OS and DFS than those with low expression (Fig.	('DFS', 'MPA', (105, 108))	('BMP8A', 'Gene', '353500', (69, 74))	('BMP7', 'Gene', (59, 63))	('BMP1', 'molecular_function', 'GO:0017026', ('53', '57'))	('shorter', 'NegReg', (90, 97))	('expression', 'Var', (75, 85))	('BMP1', 'Gene', (53, 57))	('patients', 'Species', '9606', (34, 42))	('BMP8A', 'Gene', (69, 74))	('BMP7', 'Gene', '655', (59, 63))	('high', 'Var', (48, 52))
5205	31155610	4a, b), two BMP1 shRNA plasmids were transfected into the A498 and Caki-1 cells, resulting in a consistent BMP1 knockdown (Fig.	('BMP1', 'Gene', (107, 111))	('Caki-1', 'CellLine', 'CVCL:0234', (67, 73))	('BMP1', 'molecular_function', 'GO:0017026', ('107', '111'))	('knockdown', 'Var', (112, 121))	('BMP1', 'molecular_function', 'GO:0017026', ('12', '16'))
5206	31155610	4c, d), CCK-8 and transwell experimental experiments revealed that BMP1 knockdown inhibited the proliferation, cell migration, and invasion in A498 and Caki-1 cells (Fig.	('cell migration', 'biological_process', 'GO:0016477', ('111', '125'))	('BMP1', 'molecular_function', 'GO:0017026', ('67', '71'))	('invasion', 'CPA', (131, 139))	('Caki-1', 'CellLine', 'CVCL:0234', (152, 158))	('inhibited', 'NegReg', (82, 91))	('cell migration', 'CPA', (111, 125))	('BMP1', 'Gene', (67, 71))	('knockdown', 'Var', (72, 81))
5208	31155610	Caki-1 cells stably infected with lentiviral shRNA-BMP1 and implanted into flank of node mice.	('shRNA-BMP1', 'Gene', (45, 55))	('BMP1', 'molecular_function', 'GO:0017026', ('51', '55'))	('infected', 'Disease', 'MESH:D007239', (20, 28))	('mice', 'Species', '10090', (89, 93))	('infected', 'Disease', (20, 28))	('Caki-1', 'CellLine', 'CVCL:0234', (0, 6))	('lentiviral', 'Var', (34, 44))
5210	31155610	We found that BMP1 knockdown in Caki-1 cells significantly reduced tumor volume and tumor weight (Fig.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('reduced', 'NegReg', (59, 66))	('Caki-1', 'CellLine', 'CVCL:0234', (32, 38))	('knockdown', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (84, 89))	('BMP1', 'molecular_function', 'GO:0017026', ('14', '18'))	('tumor', 'Disease', (67, 72))	('BMP1', 'Gene', (14, 18))
5212	31155610	5d, e, IHC staining indicated that knockdown BMP1 decreased Ki67 protein expression.	('knockdown', 'Var', (35, 44))	('Ki67', 'Gene', (60, 64))	('BMP1', 'molecular_function', 'GO:0017026', ('45', '49'))	('decreased', 'NegReg', (50, 59))	('Ki67', 'Gene', '17345', (60, 64))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('BMP1', 'Gene', (45, 49))
5226	31155610	In this study, we investigated the expression of BMPs with clinicopathological features and patient survival in TCGA database, We found that: (I) BMP1 exhibited the most obvious high expression in ccRCC; (II) high BMP1 expression was significantly associated with T stage, N stage, M stage, TNM stages, and grade; (III) the BMP1 expression level was an independent predictor of prognostic of OS and DFS in TCGA-KIRC; (IV) high BMP1 expression was associated with the gene set of EMT, hypoxia pathway, angiogenesis, G2M checkpoint, and KRAS signaling with GSEA; and (V) downregulation of BMP1 suppresses malignancy of ccRCC in vitro and in vivo.	('suppresses', 'NegReg', (592, 602))	('BMP', 'Gene', (587, 590))	('BMP', 'Gene', (324, 327))	('BMP1', 'molecular_function', 'GO:0017026', ('427', '431'))	('RCC', 'Disease', 'MESH:C538614', (619, 622))	('BMP', 'Gene', (427, 430))	('EMT', 'biological_process', 'GO:0001837', ('479', '482'))	('signaling', 'biological_process', 'GO:0023052', ('540', '549'))	('BMP', 'Gene', (214, 217))	('BMP1', 'molecular_function', 'GO:0017026', ('214', '218'))	('TNM', 'Gene', '10178', (291, 294))	('BMP', 'Gene', '649', (146, 149))	('BMP1', 'molecular_function', 'GO:0017026', ('324', '328'))	('malignancy of ccRCC', 'Disease', (603, 622))	('TNM', 'Gene', (291, 294))	('hypoxia', 'Disease', (484, 491))	('BMP', 'Gene', '649', (49, 52))	('BMP1', 'molecular_function', 'GO:0017026', ('146', '150'))	('BMP', 'Gene', (146, 149))	('BMP1', 'molecular_function', 'GO:0017026', ('587', '591'))	('BMP', 'Gene', '649', (587, 590))	('hypoxia', 'Disease', 'MESH:D000860', (484, 491))	('GSEA', 'Chemical', '-', (555, 559))	('RCC', 'Disease', (199, 202))	('BMP', 'Gene', '649', (324, 327))	('RCC', 'Phenotype', 'HP:0005584', (199, 202))	('malignancy of ccRCC', 'Disease', 'MESH:D009369', (603, 622))	('patient', 'Species', '9606', (92, 99))	('BMP', 'Gene', (49, 52))	('BMP', 'Gene', '649', (427, 430))	('downregulation', 'Var', (569, 583))	('BMP', 'Gene', '649', (214, 217))	('RCC', 'Disease', (619, 622))	('RCC', 'Phenotype', 'HP:0005584', (619, 622))	('angiogenesis', 'biological_process', 'GO:0001525', ('501', '513'))	('G2M checkpoint', 'biological_process', 'GO:0000075', ('515', '529'))	('RCC', 'Disease', 'MESH:C538614', (199, 202))
5229	31155610	GSEA demonstrated that high BMP1 expression was associated with the hypoxia signaling pathways in patients with ccRCC, it may be hypothesized that BMP1 could positively regulated by hypoxia signaling, or even upregulated HIF expression in ccRCC, further experiments need to be verified.	('associated', 'Reg', (48, 58))	('hypoxia', 'Disease', 'MESH:D000860', (68, 75))	('BMP1', 'molecular_function', 'GO:0017026', ('147', '151'))	('expression', 'MPA', (33, 43))	('RCC', 'Disease', (241, 244))	('RCC', 'Phenotype', 'HP:0005584', (241, 244))	('regulated', 'Reg', (169, 178))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('high', 'Var', (23, 27))	('upregulated', 'PosReg', (209, 220))	('hypoxia', 'Disease', (182, 189))	('RCC', 'Disease', 'MESH:C538614', (241, 244))	('GSEA', 'Chemical', '-', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('signaling', 'biological_process', 'GO:0023052', ('190', '199'))	('patients', 'Species', '9606', (98, 106))	('hypoxia', 'Disease', 'MESH:D000860', (182, 189))	('BMP1', 'molecular_function', 'GO:0017026', ('28', '32'))	('signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('hypoxia', 'Disease', (68, 75))	('BMP1', 'Gene', (147, 151))	('BMP1', 'Gene', (28, 32))
5235	31155610	We proved that knockdown BMP1 suppressed malignancy of ccRCC in vitro and in vivo.	('knockdown', 'Var', (15, 24))	('BMP1', 'molecular_function', 'GO:0017026', ('25', '29'))	('suppressed', 'NegReg', (30, 40))	('malignancy of ccRCC', 'Disease', 'MESH:D009369', (41, 60))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('BMP1', 'Gene', (25, 29))	('malignancy of ccRCC', 'Disease', (41, 60))
5254	31007253	Non-silent mutation of VHL may be a predictor for the outcome of ccRCC treated with axitinib.	('axitinib', 'Chemical', 'MESH:D000077784', (84, 92))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('VHL', 'Gene', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('VHL', 'Gene', '7428', (23, 26))	('Non-silent mutation', 'Var', (0, 19))
5266	31007253	Cancer patients with high TMB levels have been reported to have better response towards immunotherapy than those with low TMB levels.	('better', 'PosReg', (64, 70))	('TMB', 'Chemical', '-', (122, 125))	('TMB', 'MPA', (26, 29))	('response', 'CPA', (71, 79))	('Cancer', 'Disease', (0, 6))	('high', 'Var', (21, 25))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('TMB', 'Chemical', '-', (26, 29))	('patients', 'Species', '9606', (7, 15))
5300	31007253	Twenty-one out of 44 aberrated genes appeared repeatedly when the data of ccRCC patients in 2 cohorts calculated together.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('patients', 'Species', '9606', (80, 88))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('aberrated genes', 'Var', (21, 36))
5301	31007253	The top 3 most frequent aberrated genes in 2 cohorts were ABCB1, UGT1A1, and VHL, with percentages of 50.00%, 42.86%, and 35.52% respectively.	('VHL', 'Gene', (77, 80))	('UGT1A1', 'Gene', '54658', (65, 71))	('ABCB1', 'Gene', (58, 63))	('ABCB1', 'Gene', '5243', (58, 63))	('VHL', 'Gene', '7428', (77, 80))	('UGT1A1', 'Gene', (65, 71))	('aberrated', 'Var', (24, 33))
5309	31007253	Our present study demonstrated that the top 3 most frequent aberrated genes in Chinese ccRCC patients were ABCB1, UGT1A1 and VHL, with percentages of 50.00%, 42.86%, and 34.52% respectively.	('VHL', 'Gene', (125, 128))	('VHL', 'Gene', '7428', (125, 128))	('UGT1A1', 'Gene', '54658', (114, 120))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('ABCB1', 'Gene', (107, 112))	('ABCB1', 'Gene', '5243', (107, 112))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('UGT1A1', 'Gene', (114, 120))	('patients', 'Species', '9606', (93, 101))	('aberrated', 'Var', (60, 69))
5315	31007253	The frequency of VHL alterations in that study was 67%, which was almost 2 times that found in our study.	('VHL', 'Gene', '7428', (17, 20))	('VHL', 'Gene', (17, 20))	('alterations', 'Var', (21, 32))
5321	31007253	Half of the ccRCC patients in our study possess ABCB1 alterations, which may partially explain the chemoresistance property of this disease.	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('RCC', 'Disease', (14, 17))	('ABCB1', 'Gene', (48, 53))	('ABCB1', 'Gene', '5243', (48, 53))	('patients', 'Species', '9606', (18, 26))	('alterations', 'Var', (54, 65))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
5322	31007253	The polymorphism of UGT1A1 was associated with the plasma level of targeted agents in RCC.	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('UGT1A1', 'Gene', (20, 26))	('plasma level of targeted agents', 'MPA', (51, 82))	('associated', 'Reg', (31, 41))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('UGT1A1', 'Gene', '54658', (20, 26))	('polymorphism', 'Var', (4, 16))
5326	31007253	Those 3 patients had similar performance status and TNM stage, except that patient ID 2 possessed a mutation in VHL which was predicted resulting in the dysfunction of this tumor suppressor gene.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor suppressor', 'biological_process', 'GO:0051726', ('173', '189'))	('VHL', 'Gene', (112, 115))	('TNM', 'Gene', '10178', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('mutation', 'Var', (100, 108))	('tumor', 'Disease', (173, 178))	('VHL', 'Gene', '7428', (112, 115))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('173', '189'))	('dysfunction', 'MPA', (153, 164))	('patient', 'Species', '9606', (8, 15))	('TNM', 'Gene', (52, 55))	('patient', 'Species', '9606', (75, 82))	('patients', 'Species', '9606', (8, 16))
5327	31007253	ccRCC with mutated VHL was highly vascularized, therefore, had a good response towards anti-angiogenetic agents.	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('VHL', 'Gene', (19, 22))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('VHL', 'Gene', '7428', (19, 22))	('mutated', 'Var', (11, 18))
5337	32126023	Using the methylation data, the methylation status of 2 CpG sites (cg07807470 and cg15161854) and 2 CpG sites (cg00953154 and cg16459265) were negatively correlated with SNHG3 and SNHG15 expression, respectively.	('negatively', 'NegReg', (143, 153))	('cg16459265', 'Var', (126, 136))	('cg15161854', 'Var', (82, 92))	('cg07807470', 'Chemical', '-', (67, 77))	('SNHG3', 'Gene', '8420', (170, 175))	('cg07807470', 'Var', (67, 77))	('SNHG3', 'Gene', (170, 175))	('SNHG15', 'Gene', (180, 186))	('cg16459265', 'Chemical', '-', (126, 136))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('methylation', 'MPA', (32, 43))	('cg15161854', 'Chemical', '-', (82, 92))	('expression', 'MPA', (187, 197))	('SNHG15', 'Gene', '285958', (180, 186))	('methylation', 'biological_process', 'GO:0032259', ('10', '21'))	('cg00953154', 'Var', (111, 121))
5343	32126023	Mutations and inactivation of VHL lead to accumulation of HIF-alpha proteins and upregulation of HIF-alpha target genes, which has been considered as a key mechanism to promote the progression of ccRCC.	('HIF-alpha proteins', 'Protein', (58, 76))	('VHL', 'Gene', (30, 33))	('accumulation', 'PosReg', (42, 54))	('inactivation', 'Var', (14, 26))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('RCC', 'Disease', (198, 201))	('Mutations', 'Var', (0, 9))	('upregulation', 'PosReg', (81, 93))	('VHL', 'Gene', '7428', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('promote', 'PosReg', (169, 176))
5350	32126023	snoRNAs have been considered to be one of the best characterized classes of non-coding RNAs (ncRNAs) with a wide variety of cellular functions, such as chemical RNA modifications (such as methylations and pseudouridylations), pre-RNA processing and alternative splicing control.	('RNA', 'cellular_component', 'GO:0005562', ('161', '164'))	('RNA processing', 'biological_process', 'GO:0006396', ('230', '244'))	('methylations', 'Var', (188, 200))	('pre', 'molecular_function', 'GO:0003904', ('226', '229'))	('RNA', 'cellular_component', 'GO:0005562', ('230', '233'))	('snoRNA', 'Gene', (0, 6))	('splicing', 'biological_process', 'GO:0045292', ('261', '269'))	('snoRNA', 'Gene', '85391', (0, 6))
5353	32126023	Thus, the SNHGs, as the host genes of snoRNAs, may have multiple regulatory effects on tumor cell processes and play crucial roles in cancer.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('cancer', 'Disease', (134, 140))	('snoRNA', 'Gene', '85391', (38, 44))	('play', 'Reg', (112, 116))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('snoRNA', 'Gene', (38, 44))	('SNHGs', 'Var', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('roles', 'Reg', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
5363	32126023	Moreover, results of the log-rank test also showed that the high SNHG15 expression group had significantly shorter RFS than its low expression group (Figure 3B).	('high', 'Var', (60, 64))	('RFS', 'MPA', (115, 118))	('SNHG15', 'Gene', (65, 71))	('shorter', 'NegReg', (107, 114))	('SNHG15', 'Gene', '285958', (65, 71))
5374	32126023	The analysis results showed that compared with adjacent normal tissues, 2 sites of SNHG3 DNA, 3 sites of SNHG15 DNA, 6 sites of SNHG12 DNA and 8 sites of SNHG17 DNA were significantly hypomethylated in ccRCC (Figure 5E-5H).	('hypomethylated', 'Var', (184, 198))	('SNHG3', 'Gene', (83, 88))	('SNHG17', 'Gene', '388796', (154, 160))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('SNHG12', 'Gene', (128, 134))	('RCC', 'Disease', (204, 207))	('RCC', 'Phenotype', 'HP:0005584', (204, 207))	('SNHG15', 'Gene', '285958', (105, 111))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('SNHG3', 'Gene', '8420', (83, 88))	('SNHG12', 'Gene', '85028', (128, 134))	('SNHG15', 'Gene', (105, 111))	('SNHG17', 'Gene', (154, 160))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))
5376	32126023	Correlation analysis results showed that the expressions of SNHG3, SNHG15, SNHG12 and SNHG17 were negatively associated with the methylation levels of 2 sites (cg07807470 r=-0.1963, cg15161854 r=-0.2752), 3 sites (cg00953154 r=-0.4113, cg03440944 r=-0.3342, cg16459265 r=-0.4082), 6 sites (cg03542031 r=-0.5038, cg07033395 r=-0.394, cg12640482 r=-0.3214, cg15601452 r=-0.3814, cg19712659 r=-0.5023, cg26328951 r=-0.4231) and 3 sites (cg04560741 r=-0.1919, cg13610455 r=-0.2631, cg24310959 r=-0.2744), respectively (Figure 6A-6D).	('cg13610455 r=-0.2631', 'Var', (456, 476))	('SNHG17', 'Gene', (86, 92))	('cg04560741 r=-0.1919', 'Var', (434, 454))	('cg16459265', 'Chemical', '-', (258, 268))	('negatively', 'NegReg', (98, 108))	('cg00953154 r=-0.4113', 'Var', (214, 234))	('cg16459265 r=-0.4082', 'Var', (258, 278))	('SNHG3', 'Gene', '8420', (60, 65))	('cg03440944 r=-0.3342', 'Var', (236, 256))	('SNHG12', 'Gene', (75, 81))	('SNHG17', 'Gene', '388796', (86, 92))	('cg15161854', 'Chemical', '-', (182, 192))	('methylation levels', 'MPA', (129, 147))	('cg12640482 r=-0.3214', 'Var', (333, 353))	('cg07807470', 'Chemical', '-', (160, 170))	('cg07033395 r=-0.394', 'Var', (312, 331))	('cg24310959 r=-0.2744', 'Var', (478, 498))	('SNHG15', 'Gene', (67, 73))	('cg15161854 r=-0.2752', 'Var', (182, 202))	('SNHG12', 'Gene', '85028', (75, 81))	('cg07807470', 'Var', (160, 170))	('methylation', 'biological_process', 'GO:0032259', ('129', '140'))	('cg15601452 r=-0.3814', 'Var', (355, 375))	('cg26328951 r=-0.4231', 'Var', (399, 419))	('SNHG15', 'Gene', '285958', (67, 73))	('cg19712659 r=-0.5023', 'Var', (377, 397))	('SNHG3', 'Gene', (60, 65))	('cg03542031 r=-0.5038', 'Var', (290, 310))
5377	32126023	Moreover, results of the log-rank test showed that low methylation levels of cg07807470 (SNHG3), cg15161854 (SNHG3), cg00953154 (SNHG15), cg16459265 (SNHG15) and cg07033395 (SNHG12) were significantly associated with the shorter OS of ccRCC patients (Figure 6E-6G).	('RCC', 'Disease', 'MESH:C538614', (237, 240))	('SNHG3', 'Gene', '8420', (109, 114))	('cg07033395', 'Var', (162, 172))	('SNHG15', 'Gene', '285958', (129, 135))	('SNHG3', 'Gene', (89, 94))	('cg15161854', 'Var', (97, 107))	('SNHG15', 'Gene', (150, 156))	('SNHG12', 'Gene', '85028', (174, 180))	('cg15161854', 'Chemical', '-', (97, 107))	('SNHG15', 'Gene', '285958', (150, 156))	('cg16459265', 'Chemical', '-', (138, 148))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))	('SNHG3', 'Gene', '8420', (89, 94))	('OS', 'Chemical', '-', (229, 231))	('SNHG3', 'Gene', (109, 114))	('RCC', 'Disease', (237, 240))	('cg00953154', 'Var', (117, 127))	('RCC', 'Phenotype', 'HP:0005584', (237, 240))	('patients', 'Species', '9606', (241, 249))	('cg07807470', 'Var', (77, 87))	('cg07807470', 'Chemical', '-', (77, 87))	('methylation', 'MPA', (55, 66))	('cg16459265', 'Var', (138, 148))	('low', 'NegReg', (51, 54))	('SNHG12', 'Gene', (174, 180))	('SNHG15', 'Gene', (129, 135))
5378	32126023	Furthermore, low methylation levels of cg07807470 (SNHG3), cg15161854 (SNHG3) and cg16459265 (SNHG15) were also related to the shorter RFS (Figure 6H, 6I).	('shorter', 'NegReg', (127, 134))	('cg15161854', 'Chemical', '-', (59, 69))	('cg16459265', 'Var', (82, 92))	('SNHG3', 'Gene', '8420', (71, 76))	('SNHG15', 'Gene', '285958', (94, 100))	('SNHG3', 'Gene', (51, 56))	('cg07807470', 'Chemical', '-', (39, 49))	('low', 'NegReg', (13, 16))	('methylation levels', 'MPA', (17, 35))	('RFS', 'MPA', (135, 138))	('cg15161854', 'Var', (59, 69))	('cg16459265', 'Chemical', '-', (82, 92))	('SNHG3', 'Gene', (71, 76))	('SNHG15', 'Gene', (94, 100))	('SNHG3', 'Gene', '8420', (51, 56))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('cg07807470', 'Var', (39, 49))
5379	32126023	Taken together, these results indicated that the expressions of SNHG3 and SNHG15 were more likely to be modulated by DNA methylation in ccRCC.	('RCC', 'Disease', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('modulated', 'Reg', (104, 113))	('DNA methylation', 'biological_process', 'GO:0006306', ('117', '132'))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('SNHG15', 'Gene', '285958', (74, 80))	('SNHG3', 'Gene', '8420', (64, 69))	('SNHG3', 'Gene', (64, 69))	('DNA methylation', 'Var', (117, 132))	('SNHG15', 'Gene', (74, 80))	('DNA', 'cellular_component', 'GO:0005574', ('117', '120'))
5384	32126023	In addition, the methylation status of 4 CpG sites (cg07807470, cg15161854, cg00953154 and cg16459265) in 15 paired clinical samples were tested through pyrosequencing.	('cg15161854', 'Var', (64, 74))	('cg16459265', 'Chemical', '-', (91, 101))	('cg07807470', 'Var', (52, 62))	('clinical samples', 'Species', '191496', (116, 132))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('cg16459265', 'Var', (91, 101))	('cg07807470', 'Chemical', '-', (52, 62))	('cg15161854', 'Chemical', '-', (64, 74))	('cg00953154', 'Var', (76, 86))
5385	32126023	The methylation levels of cg07807470, cg15161854, cg00953154 and cg16459265 were significantly lower in ccRCC compared with adjacent normal tissues (Figure 7C).	('cg07807470', 'Var', (26, 36))	('lower', 'NegReg', (95, 100))	('cg07807470', 'Chemical', '-', (26, 36))	('cg15161854', 'Var', (38, 48))	('cg00953154', 'Var', (50, 60))	('methylation levels', 'MPA', (4, 22))	('cg16459265', 'Var', (65, 75))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('cg16459265', 'Chemical', '-', (65, 75))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('cg15161854', 'Chemical', '-', (38, 48))
5386	32126023	Besides, the methylation levels of cg07807470 (r=-0.5662) and cg15161854 (r=-0.6244) were significantly negatively correlated with SNHG3 expression (Figure 7D), while the methylation levels of cg00953154 (r=-0.5461) and cg16459265 (r=-0.6629) were negatively associated with SNHG15 expression (Figure 7E), which were consistent with the results from the TCGA datasets.	('methylation', 'MPA', (13, 24))	('cg15161854', 'Chemical', '-', (62, 72))	('SNHG3', 'Gene', (131, 136))	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('expression', 'MPA', (137, 147))	('cg16459265', 'Var', (220, 230))	('negatively', 'NegReg', (104, 114))	('cg00953154', 'Var', (193, 203))	('correlated', 'Interaction', (115, 125))	('SNHG15', 'Gene', (275, 281))	('cg15161854', 'Var', (62, 72))	('cg07807470', 'Var', (35, 45))	('cg16459265', 'Chemical', '-', (220, 230))	('SNHG3', 'Gene', '8420', (131, 136))	('SNHG15', 'Gene', '285958', (275, 281))	('cg07807470', 'Chemical', '-', (35, 45))	('methylation', 'biological_process', 'GO:0032259', ('171', '182'))
5387	32126023	Furthermore, the methylation levels of cg15161854 with a higher correlation with SNHG3 expression and cg16459265 with a higher correlation with SNHG15 expression in another 36 available ccRCC samples were tested through pyrosequencing for survival analysis.	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('cg16459265', 'Var', (102, 112))	('SNHG3', 'Gene', '8420', (81, 86))	('higher', 'PosReg', (57, 63))	('methylation levels', 'MPA', (17, 35))	('SNHG15', 'Gene', '285958', (144, 150))	('cg15161854', 'Chemical', '-', (39, 49))	('cg16459265', 'Chemical', '-', (102, 112))	('SNHG3', 'Gene', (81, 86))	('expression', 'MPA', (87, 97))	('RCC', 'Disease', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('cg15161854', 'Gene', (39, 49))	('SNHG15', 'Gene', (144, 150))
5388	32126023	Consistent with the survival analysis results of TCGA samples, our results showed that low methylation levels of cg15161854 and cg16459265 were associated with the shorter OS (Figure 7F) and RFS (Figure 7G) of ccRCC patients.	('cg15161854', 'Chemical', '-', (113, 123))	('methylation levels', 'MPA', (91, 109))	('shorter', 'NegReg', (164, 171))	('cg15161854', 'Var', (113, 123))	('OS', 'Chemical', '-', (172, 174))	('RFS', 'MPA', (191, 194))	('patients', 'Species', '9606', (216, 224))	('RCC', 'Phenotype', 'HP:0005584', (212, 215))	('cg16459265', 'Var', (128, 138))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))	('RCC', 'Disease', (212, 215))	('low', 'NegReg', (87, 90))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('cg16459265', 'Chemical', '-', (128, 138))
5392	32126023	Interestingly, the modification of ribosomal biogenesis was associated with the development of cancer, suggesting that the classical function of snoRNA may contribute to the development of cancer.	('modification', 'Var', (19, 31))	('snoRNA', 'cellular_component', 'GO:0005733', ('145', '151'))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Disease', (95, 101))	('snoRNA', 'Gene', '85391', (145, 151))	('ribosomal', 'MPA', (35, 44))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('snoRNA', 'Gene', (145, 151))	('associated', 'Reg', (60, 70))	('cancer', 'Disease', (189, 195))
5393	32126023	In addition to the initial evidence of snoRNA involvement in cancer development, increasing evidence has demonstrated that dysregulated small nucleolar RNA host genes may contribute to multiple cancer progression.	('snoRNA', 'Gene', (39, 45))	('snoRNA', 'Gene', '85391', (39, 45))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('small nucleolar RNA', 'cellular_component', 'GO:0005733', ('136', '155'))	('contribute', 'Reg', (171, 181))	('cancer', 'Disease', (61, 67))	('small nucleolar RNA', 'molecular_function', 'GO:0005569', ('136', '155'))	('small', 'Protein', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('dysregulated', 'Var', (123, 135))	('snoRNA', 'cellular_component', 'GO:0005733', ('39', '45'))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
5394	32126023	For example, SNHG1 was upregulated in human colorectal cancer tissues, and high SNHG1 expression was associated with shorter OS; SNHG1 contributed to sorafenib resistance by activating the Akt pathway in hepatocellular carcinoma cells; SNHG17 was upregulated in non-small-cell lung cancer (NSCLC), and the knockdown of SNHG17 inhibited the proliferation and migration and promoted the apoptosis of NSCLC cells.	('NSCLC', 'Disease', (398, 403))	('colorectal cancer', 'Disease', (44, 61))	('SNHG17', 'Gene', '388796', (319, 325))	('SNHG1', 'Gene', '23642', (236, 241))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (204, 228))	('promoted', 'PosReg', (372, 380))	('SNHG1', 'Gene', '23642', (13, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (398, 403))	('SNHG17', 'Gene', (236, 242))	('SNHG1', 'Gene', (319, 324))	('Akt', 'Gene', (189, 192))	('apoptosis', 'biological_process', 'GO:0097194', ('385', '394'))	('knockdown', 'Var', (306, 315))	('lung cancer', 'Disease', (277, 288))	('apoptosis', 'biological_process', 'GO:0006915', ('385', '394'))	('activating', 'PosReg', (174, 184))	('SNHG1', 'Gene', (80, 85))	('SNHG1', 'Gene', '23642', (129, 134))	('Akt', 'Gene', '207', (189, 192))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (204, 228))	('colorectal cancer', 'Phenotype', 'HP:0003003', (44, 61))	('SNHG17', 'Gene', '388796', (236, 242))	('NSCLC', 'Disease', 'MESH:D002289', (290, 295))	('inhibited', 'NegReg', (326, 335))	('human', 'Species', '9606', (38, 43))	('OS', 'Chemical', '-', (125, 127))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('upregulated', 'PosReg', (247, 258))	('SNHG1', 'Gene', '23642', (319, 324))	('NSCLC', 'Disease', (290, 295))	('hepatocellular carcinoma', 'Disease', (204, 228))	('SNHG1', 'Gene', (236, 241))	('apoptosis', 'CPA', (385, 394))	('lung cancer', 'Disease', 'MESH:D008175', (277, 288))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('SNHG17', 'Gene', (319, 325))	('SNHG1', 'Gene', (13, 18))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (266, 288))	('SNHG1', 'Gene', '23642', (80, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (277, 288))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('NSCLC', 'Disease', 'MESH:D002289', (398, 403))	('NSCLC', 'Phenotype', 'HP:0030358', (290, 295))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (262, 288))	('colorectal cancer', 'Disease', 'MESH:D015179', (44, 61))	('SNHG1', 'Gene', (129, 134))	('sorafenib', 'Chemical', 'MESH:D000077157', (150, 159))
5410	32126023	Moreover, a recent study demonstrated that the higher expression of SNHG3 could predict worse clinical prognosis, and knockdown of SNHG3 could significantly inhibit the proliferation and metastasis of ccRCC in vitro and in vivo.	('expression', 'MPA', (54, 64))	('SNHG3', 'Gene', (131, 136))	('knockdown', 'Var', (118, 127))	('SNHG3', 'Gene', '8420', (68, 73))	('higher', 'PosReg', (47, 53))	('metastasis', 'CPA', (187, 197))	('SNHG3', 'Gene', '8420', (131, 136))	('clinical', 'Species', '191496', (94, 102))	('proliferation', 'CPA', (169, 182))	('inhibit', 'NegReg', (157, 164))	('SNHG3', 'Gene', (68, 73))	('RCC', 'Disease', 'MESH:C538614', (203, 206))	('RCC', 'Disease', (203, 206))	('RCC', 'Phenotype', 'HP:0005584', (203, 206))
5413	32126023	Furthermore, SNHG15 was significantly upregulated in RCC tissues and cell lines compared with its adjacent normal tissues and a proximal tubule epithelial cell line, and SNHG15 knockdown could inhibit RCC proliferation, invasion and migration.	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('SNHG15', 'Gene', '285958', (170, 176))	('RCC', 'Disease', (201, 204))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('inhibit', 'NegReg', (193, 200))	('upregulated', 'PosReg', (38, 49))	('knockdown', 'Var', (177, 186))	('invasion', 'CPA', (220, 228))	('RCC', 'Disease', (53, 56))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('SNHG15', 'Gene', '285958', (13, 19))	('SNHG15', 'Gene', (170, 176))	('migration', 'CPA', (233, 242))	('SNHG15', 'Gene', (13, 19))
5415	32126023	Epigenetic alterations such as DNA methylation, histone modification, and loss of genome imprinting play crucial roles in the formation and progression of cancer.	('DNA methylation', 'Var', (31, 46))	('formation', 'biological_process', 'GO:0009058', ('126', '135'))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('histone modification', 'Var', (48, 68))	('loss', 'NegReg', (74, 78))	('DNA methylation', 'biological_process', 'GO:0006306', ('31', '46'))	('histone modification', 'biological_process', 'GO:0016570', ('48', '68'))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
5417	32126023	For example, hypermethylation of the CpG shore of the Shh gene resulted in Shh loss, and inhibition of DNA methylation increased Shh expression to halt the initiation of bladder cancer at the early stage of progression; DNA methylation at an enhancer of the three prime repair exonuclease 2 gene (TREX2) was linked to decreased TREX2 gene expression and protein expression, which may affect drug-induced DNA damage repair in laryngeal cancer; and Epigenetic Silencing of miRNA-338-5p and miRNA-421 drived SPINK1-Positive Prostate Cancer.	('Prostate Cancer', 'Disease', (521, 536))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('laryngeal cancer', 'Disease', 'MESH:D007822', (425, 441))	('TREX2', 'Gene', '11219', (297, 302))	('decreased', 'NegReg', (318, 327))	('Epigenetic Silencing', 'Var', (447, 467))	('TREX2', 'Gene', '11219', (328, 333))	('Shh loss', 'Disease', (75, 83))	('Shh', 'Gene', '6469', (129, 132))	('laryngeal cancer', 'Disease', (425, 441))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (425, 441))	('initiation of bladder cancer', 'Disease', 'MESH:D001749', (156, 184))	('three prime repair exonuclease 2', 'Gene', (258, 290))	('DNA methylation', 'biological_process', 'GO:0006306', ('220', '235'))	('protein', 'cellular_component', 'GO:0003675', ('354', '361'))	('Shh', 'Gene', (54, 57))	('enhancer', 'PosReg', (242, 250))	('affect', 'Reg', (384, 390))	('initiation of bladder cancer', 'Disease', (156, 184))	('Prostate Cancer', 'Disease', 'MESH:D011471', (521, 536))	('protein', 'Protein', (354, 361))	('Shh', 'Gene', (75, 78))	('DNA', 'cellular_component', 'GO:0005574', ('404', '407'))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('drived', 'Reg', (498, 504))	('Shh', 'Gene', '6469', (75, 78))	('three prime repair exonuclease 2', 'Gene', '11219', (258, 290))	('miRNA-338-5p', 'Var', (471, 483))	('Cancer', 'Phenotype', 'HP:0002664', (530, 536))	('inhibition of DNA methylation', 'biological_process', 'GO:1905642', ('89', '118'))	('Shh', 'Gene', '6469', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (435, 441))	('miRNA-421', 'Gene', (488, 497))	('Prostate Cancer', 'Phenotype', 'HP:0012125', (521, 536))	('expression', 'MPA', (339, 349))	('DNA', 'cellular_component', 'GO:0005574', ('220', '223'))	('SPINK1', 'Gene', (505, 511))	('Shh', 'Gene', (129, 132))	('SPINK1', 'Gene', '6690', (505, 511))	('TREX2', 'Gene', (297, 302))	('TREX2', 'Gene', (328, 333))	('bladder cancer', 'Phenotype', 'HP:0009725', (170, 184))	('methylation', 'Var', (224, 235))	('Shh loss', 'Disease', 'MESH:D015431', (75, 83))	('expression', 'MPA', (362, 372))	('DNA', 'Var', (220, 223))	('gene expression', 'biological_process', 'GO:0010467', ('334', '349'))
5418	32126023	Besides, a recent study reported that downregulation of CLDN7 due to promoter hypermethylation contributed to human ccRCC progression and poor prognosis, indicating DNA methylation may also play vital roles in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('RCC', 'Disease', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('CLDN7', 'Gene', (56, 61))	('DNA methylation', 'biological_process', 'GO:0006306', ('165', '180'))	('downregulation', 'NegReg', (38, 52))	('CLDN7', 'Gene', '1366', (56, 61))	('human', 'Species', '9606', (110, 115))	('RCC', 'Disease', (212, 215))	('RCC', 'Phenotype', 'HP:0005584', (212, 215))	('DNA', 'cellular_component', 'GO:0005574', ('165', '168'))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('promoter hypermethylation', 'Var', (69, 94))
5420	32126023	Results showed that the expression levels of SNHG3 and SNHG15 were more likely to be modulated by methylation in ccRCC.	('SNHG3', 'Gene', (45, 50))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('expression levels', 'MPA', (24, 41))	('methylation', 'biological_process', 'GO:0032259', ('98', '109'))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('SNHG15', 'Gene', (55, 61))	('methylation', 'Var', (98, 109))	('RCC', 'Disease', (115, 118))	('modulated', 'Reg', (85, 94))	('SNHG3', 'Gene', '8420', (45, 50))	('SNHG15', 'Gene', '285958', (55, 61))
5421	32126023	The methylation levels of cg07807470 and cg15161854 were negatively associated with SNHG3 expression, and the methylation levels of cg00953154, cg03440944 and cg16459265 were negatively correlated with SNHG15 expression in ccRCC.	('SNHG3', 'Gene', '8420', (84, 89))	('cg00953154', 'Var', (132, 142))	('expression', 'MPA', (209, 219))	('cg15161854', 'Var', (41, 51))	('cg16459265', 'Var', (159, 169))	('methylation levels', 'MPA', (4, 22))	('expression', 'MPA', (90, 100))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('cg15161854', 'Chemical', '-', (41, 51))	('cg07807470', 'Chemical', '-', (26, 36))	('RCC', 'Disease', (225, 228))	('RCC', 'Phenotype', 'HP:0005584', (225, 228))	('negatively', 'NegReg', (57, 67))	('negatively', 'NegReg', (175, 185))	('cg07807470', 'Var', (26, 36))	('SNHG3', 'Gene', (84, 89))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('cg16459265', 'Chemical', '-', (159, 169))	('methylation', 'biological_process', 'GO:0032259', ('110', '121'))	('SNHG15', 'Gene', (202, 208))	('cg03440944', 'Var', (144, 154))	('methylation', 'MPA', (110, 121))	('SNHG15', 'Gene', '285958', (202, 208))
5422	32126023	Moreover, low methylation levels of cg07807470, cg15161854, cg00953154 and cg16459265 were significantly associated with poor OS of ccRCC patients.	('cg16459265', 'Chemical', '-', (75, 85))	('cg15161854', 'Var', (48, 58))	('cg00953154', 'Var', (60, 70))	('cg07807470', 'Chemical', '-', (36, 46))	('RCC', 'Phenotype', 'HP:0005584', (134, 137))	('RCC', 'Disease', (134, 137))	('poor OS', 'Disease', (121, 128))	('low', 'NegReg', (10, 13))	('OS', 'Chemical', '-', (126, 128))	('methylation levels', 'MPA', (14, 32))	('cg16459265', 'Var', (75, 85))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))	('cg15161854', 'Chemical', '-', (48, 58))	('patients', 'Species', '9606', (138, 146))	('cg07807470', 'Var', (36, 46))
5423	32126023	Low methylation levels of cg07807470, cg15161854 and cg16459265 were also related to the shorter RFS.	('cg07807470', 'Var', (26, 36))	('cg16459265', 'Chemical', '-', (53, 63))	('cg07807470', 'Chemical', '-', (26, 36))	('cg15161854', 'Var', (38, 48))	('methylation levels', 'MPA', (4, 22))	('cg16459265', 'Var', (53, 63))	('Low', 'NegReg', (0, 3))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('cg15161854', 'Chemical', '-', (38, 48))
5425	32126023	Consistent with the survival analysis results of TCGA samples, our results showed that low methylation levels of cg15161854 and cg16459265 were associated with the shorter OS and RFS of ccRCC patients.	('methylation levels', 'MPA', (91, 109))	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('shorter', 'Disease', (164, 171))	('cg15161854', 'Var', (113, 123))	('OS', 'Chemical', '-', (172, 174))	('patients', 'Species', '9606', (192, 200))	('cg16459265', 'Var', (128, 138))	('RCC', 'Disease', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))	('cg15161854', 'Chemical', '-', (113, 123))	('low', 'NegReg', (87, 90))	('RFS', 'CPA', (179, 182))	('cg16459265', 'Chemical', '-', (128, 138))
5426	32126023	Taken together, SNHG3 and SNHG15 expression levels might be substantially modulated by DNA methylation in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('methylation', 'Var', (91, 102))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('modulated', 'Reg', (74, 83))	('SNHG15', 'Gene', '285958', (26, 32))	('SNHG3', 'Gene', (16, 21))	('SNHG15', 'Gene', (26, 32))	('expression', 'MPA', (33, 43))	('DNA methylation', 'biological_process', 'GO:0006306', ('87', '102'))	('SNHG3', 'Gene', '8420', (16, 21))
5497	31040082	The proportion of distant metastases in patients with T1a (<=4 cm) RCCs was significantly associated with increased tumor size.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('patients', 'Species', '9606', (40, 48))	('RCC', 'Disease', (67, 70))	('T1a', 'Var', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('metastases', 'Disease', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('metastases', 'Disease', 'MESH:D009362', (26, 36))
5505	31040082	In a single-institutional study comparing cryoablation, radiofrequency ablation, and partial nephrectomy, local recurrence-free survival (RFS) rates were similar among the three therapies; however, metastases-free survival was significantly better after partial nephrectomy and cryoablation than after radiofrequency ablation.	('cryoablation', 'Var', (278, 290))	('metastases', 'Disease', (198, 208))	('metastases', 'Disease', 'MESH:D009362', (198, 208))	('better', 'PosReg', (241, 247))
5506	31040082	Patients who underwent partial nephrectomy were significantly younger and had higher OS, affirming the selection bias inherent to comparisons of surgery and other treatment modalities such as ablation or AS.	('Patients', 'Species', '9606', (0, 8))	('partial nephrectomy', 'Var', (23, 42))	('higher', 'PosReg', (78, 84))	('men', 'Species', '9606', (168, 171))
5548	31040082	In all, 203 patients were included in the analysis, with 23 (11.3%) patients having either recurrence or death from disease, and mutations in KDM5C were found to be significantly associated with poor outcomes.	('patients', 'Species', '9606', (12, 20))	('associated', 'Reg', (179, 189))	('KDM5C', 'Gene', '8242', (142, 147))	('death', 'Disease', 'MESH:D003643', (105, 110))	('death', 'Disease', (105, 110))	('mutations', 'Var', (129, 138))	('patients', 'Species', '9606', (68, 76))	('KDM5C', 'Gene', (142, 147))
5549	31040082	Additionally, the absence of mutations known to be associated with metastatic disease and poor clinical outcomes including BAP1, SETD2, and TP53 can also aid in the management of SRMs.	('BAP1', 'Gene', (123, 127))	('SETD2', 'Gene', '29072', (129, 134))	('aid', 'Gene', (154, 157))	('TP53', 'Gene', (140, 144))	('SETD2', 'Gene', (129, 134))	('mutations', 'Var', (29, 38))	('SRM', 'Gene', (179, 182))	('aid', 'Gene', '57379', (154, 157))	('SRM', 'Gene', '6723', (179, 182))	('BAP1', 'Gene', '8314', (123, 127))	('men', 'Species', '9606', (171, 174))	('TP53', 'Gene', '7157', (140, 144))
5555	31040082	Many studies have demonstrated that SRMs, particularly in ccRCC, have a similar frequency of alterations in driver mutations, primarily those that are considered truncal events (ie, VHL in ccRCC).	('mutations', 'Var', (115, 124))	('RCC', 'Disease', (191, 194))	('RCC', 'Phenotype', 'HP:0005584', (191, 194))	('alterations', 'Var', (93, 104))	('RCC', 'Disease', 'MESH:C538614', (191, 194))	('RCC', 'Disease', (60, 63))	('VHL', 'Gene', (182, 185))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('SRM', 'Gene', '6723', (36, 39))	('VHL', 'Gene', '7428', (182, 185))	('SRM', 'Gene', (36, 39))
5557	31040082	They looked at five recurrent ccRCC gene mutations; VHL, PBRM1, SETD2, BAP1, and KDM5C, performing three to five separate biopsies of the tumor.	('mutations', 'Var', (41, 50))	('PBRM1', 'Gene', (57, 62))	('VHL', 'Gene', '7428', (52, 55))	('tumor', 'Disease', (138, 143))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('KDM5C', 'Gene', (81, 86))	('PBRM1', 'Gene', '55193', (57, 62))	('RCC', 'Disease', (32, 35))	('SETD2', 'Gene', '29072', (64, 69))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('BAP1', 'Gene', '8314', (71, 75))	('KDM5C', 'Gene', '8242', (81, 86))	('SETD2', 'Gene', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('BAP1', 'Gene', (71, 75))	('VHL', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
5558	31040082	This study demonstrated that mutational heterogeneity existed in SRMs, outside of VHL, with 25-60% of the mutations in PBRM1, SETD2, BAP1, and KDM5C detected in any biopsy of each patient present across all core biopsies of the same patient.	('SETD2', 'Gene', '29072', (126, 131))	('core', 'cellular_component', 'GO:0019013', ('207', '211'))	('patient', 'Species', '9606', (233, 240))	('PBRM1', 'Gene', (119, 124))	('PBRM1', 'Gene', '55193', (119, 124))	('SRM', 'Gene', (65, 68))	('VHL', 'Gene', (82, 85))	('SRM', 'Gene', '6723', (65, 68))	('BAP1', 'Gene', '8314', (133, 137))	('KDM5C', 'Gene', (143, 148))	('SETD2', 'Gene', (126, 131))	('VHL', 'Gene', '7428', (82, 85))	('mutations', 'Var', (106, 115))	('KDM5C', 'Gene', '8242', (143, 148))	('patient', 'Species', '9606', (180, 187))	('BAP1', 'Gene', (133, 137))
5560	31040082	These results are further supported by the recent TracerX studies that identified the first event in ccRCC being chromothripsis with 3p loss, which is frequently followed by a second hit including the loss of the four most commonly mutated ccRCC genes of VHL, PBRM1, BAP1, and SETD2.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (242, 245))	('RCC', 'Phenotype', 'HP:0005584', (242, 245))	('ccRCC being chromothripsis', 'Disease', (101, 127))	('loss', 'NegReg', (201, 205))	('RCC', 'Disease', 'MESH:C538614', (242, 245))	('BAP1', 'Gene', '8314', (267, 271))	('PBRM1', 'Gene', '55193', (260, 265))	('mutated', 'Var', (232, 239))	('SETD2', 'Gene', (277, 282))	('ccRCC being chromothripsis', 'Disease', 'MESH:D000072837', (101, 127))	('VHL', 'Gene', (255, 258))	('loss', 'NegReg', (136, 140))	('BAP1', 'Gene', (267, 271))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('PBRM1', 'Gene', (260, 265))	('SETD2', 'Gene', '29072', (277, 282))	('VHL', 'Gene', '7428', (255, 258))
5562	31040082	This study also provided further evidence that through tumor growth, the overall burden of mutations increased with tumor size.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', (55, 60))	('mutations', 'Var', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
5566	31040082	Their results point toward SRMs having a less diverse but shared subset of mutations seen in larger and more advanced ccRCCs.	('SRM', 'Gene', (27, 30))	('SRM', 'Gene', '6723', (27, 30))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('mutations', 'Var', (75, 84))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))
5569	31040082	Landmark papers from Gerlinger and colleagues demonstrated that >75% of driver alterations in ccRCC were subclonal, meaning not shared in all evolutionary branches.	('RCC', 'Disease', (96, 99))	('alterations', 'Var', (79, 90))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
5577	31040082	In an aforementioned series, Sankin et al identified that three separate biopsies would detect mutations when present in PBRM1, SETD2, BAP1, and KDM5C with 90% certainty.	('KDM5C', 'Gene', '8242', (145, 150))	('SETD2', 'Gene', (128, 133))	('BAP1', 'Gene', '8314', (135, 139))	('men', 'Species', '9606', (11, 14))	('SETD2', 'Gene', '29072', (128, 133))	('detect', 'Reg', (88, 94))	('PBRM1', 'Gene', (121, 126))	('BAP1', 'Gene', (135, 139))	('mutations', 'Var', (95, 104))	('PBRM1', 'Gene', '55193', (121, 126))	('KDM5C', 'Gene', (145, 150))
5585	31040082	The TracerX study demonstrated that increasing chromosomal complexity (which is reduced in SRM) was associated with rapid progression of metastatic disease, information that could be gathered from a tumor biopsy.	('tumor', 'Disease', (199, 204))	('increasing', 'PosReg', (36, 46))	('chromosomal complexity', 'Var', (47, 69))	('metastatic disease', 'Disease', (137, 155))	('SRM', 'Gene', '6723', (91, 94))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('SRM', 'Gene', (91, 94))
5587	31040082	Importantly for SRMs, the VHL Mono-drivers along with multiple clonal drivers required the fewest biopsies for classification.	('VHL', 'Gene', (26, 29))	('VHL', 'Gene', '7428', (26, 29))	('Mono-drivers', 'Var', (30, 42))	('SRM', 'Gene', (16, 19))	('SRM', 'Gene', '6723', (16, 19))
5609	27879367	Alternative splicing of EZH2 pre-mRNA by SF3B3 contributes to the tumorigenic potential of renal cancer Deregulation or mutation of the EZH2 gene causes various tumors, including ccRCC.	('tumors', 'Disease', (161, 167))	('tumorigenic potential', 'MPA', (66, 87))	('renal cancer', 'Disease', (91, 103))	('renal cancer', 'Phenotype', 'HP:0009726', (91, 103))	('EZH2', 'Gene', (136, 140))	('EZH2', 'Gene', '2146', (136, 140))	('EZH2', 'Gene', '2146', (24, 28))	('EZH2', 'Gene', (24, 28))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('SF3B3', 'Gene', (41, 46))	('splicing', 'biological_process', 'GO:0045292', ('12', '20'))	('renal cancer', 'Disease', 'MESH:D007680', (91, 103))	('SF3B3', 'Gene', '23450', (41, 46))	('mutation', 'Var', (120, 128))	('ccRCC', 'Disease', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('causes', 'Reg', (146, 152))	('pre', 'molecular_function', 'GO:0003904', ('29', '32'))
5612	27879367	Proliferation, migration, clonogenicity and tumorigenicity of renal cancer cells either exhibiting knock-down of EZH2 or its splicing factor SF3B3 were assessed by CCK8, Transwell, and murine xenograft experiments.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('splicing factor', 'Gene', (125, 140))	('knock-down', 'Var', (99, 109))	('renal cancer', 'Disease', (62, 74))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('migration', 'CPA', (15, 24))	('renal cancer', 'Phenotype', 'HP:0009726', (62, 74))	('splicing', 'biological_process', 'GO:0045292', ('125', '133'))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('splicing factor', 'Gene', '10569', (125, 140))	('renal cancer', 'Disease', 'MESH:D007680', (62, 74))	('EZH2', 'Gene', (113, 117))	('clonogenicity', 'CPA', (26, 39))	('tumor', 'Disease', (44, 49))	('murine', 'Species', '10090', (185, 191))
5613	27879367	We found that inclusion of alternative EZH2 exon 14 was significantly increased in ccRCC samples and renal cancer cell lines.	('increased', 'PosReg', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('EZH2 exon', 'Gene', (39, 48))	('renal cancer', 'Disease', (101, 113))	('ccRCC', 'Disease', (83, 88))	('inclusion', 'Var', (14, 23))	('renal cancer', 'Phenotype', 'HP:0009726', (101, 113))	('renal cancer', 'Disease', 'MESH:D007680', (101, 113))
5614	27879367	In ccRCC lines, enforced expression of EZH2Delta14 inhibited, and EZH2 promoted, cell growth, migration, proliferation and tumorigenicity in a xenograft model.	('tumor', 'Disease', (123, 128))	('promoted', 'PosReg', (71, 79))	('EZH2Delta14', 'Var', (39, 50))	('cell growth', 'CPA', (81, 92))	('EZH2', 'Gene', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cell growth', 'biological_process', 'GO:0016049', ('81', '92'))	('inhibited', 'NegReg', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
5615	27879367	Coexpression of EZH2Delta14 variant with full-length EZH2 not only abrogated DAB2IP and HOXA9 suppression but also inhibited EZH2-driven tumorigenesis.	('HOXA9', 'Gene', (88, 93))	('tumor', 'Disease', (137, 142))	('DAB2IP', 'Gene', (77, 83))	('abrogated', 'NegReg', (67, 76))	('DAB2IP', 'Gene', '153090', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('HOXA9', 'Gene', '3205', (88, 93))	('inhibited', 'NegReg', (115, 124))	('variant', 'Var', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
5618	27879367	PRC2 catalyses the mono-, di- and trimethylation of lysine 27 of histone H3, which plays an important role in regulation of tumor transformation and progression.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('di-', 'MPA', (26, 29))	('tumor', 'Disease', (124, 129))	('regulation', 'biological_process', 'GO:0065007', ('110', '120'))	('mono-', 'MPA', (19, 24))	('trimethylation', 'Var', (34, 48))	('lysine', 'Chemical', 'MESH:D008239', (52, 58))	('PRC2', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
5620	27879367	Mechanismly, EZH2, and by inference H3K27 methylation, targets many tumor suppressor genes such as DAB2IP and HOXA9.	('tumor', 'Disease', (68, 73))	('tumor suppressor', 'biological_process', 'GO:0051726', ('68', '84'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('68', '84'))	('DAB2IP', 'Gene', (99, 105))	('HOXA9', 'Gene', '3205', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('H3K27', 'Protein', (36, 41))	('DAB2IP', 'Gene', '153090', (99, 105))	('methylation', 'biological_process', 'GO:0032259', ('42', '53'))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('methylation', 'Var', (42, 53))	('HOXA9', 'Gene', (110, 115))
5621	27879367	Besides, EZH2 also has other HMT-independent functions, including DNA methylation, STAT3 methylation, GATA4 methylation, RORalpha methylation, NOTCH1 activation, and androgen receptor activation.	('androgen receptor', 'Gene', (166, 183))	('NOTCH1', 'Gene', (143, 149))	('GATA4', 'Gene', '2626', (102, 107))	('androgen receptor', 'Gene', '367', (166, 183))	('HMT', 'Gene', '56979', (29, 32))	('EZH2', 'Gene', (9, 13))	('activation', 'PosReg', (184, 194))	('NOTCH1', 'Gene', '4851', (143, 149))	('methylation', 'Var', (130, 141))	('STAT3', 'Gene', (83, 88))	('methylation', 'biological_process', 'GO:0032259', ('89', '100'))	('methylation', 'biological_process', 'GO:0032259', ('130', '141'))	('DNA methylation', 'biological_process', 'GO:0006306', ('66', '81'))	('activation', 'PosReg', (150, 160))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('HMT', 'Gene', (29, 32))	('GATA4', 'Gene', (102, 107))	('RORalpha', 'Gene', (121, 129))	('STAT3', 'Gene', '6774', (83, 88))	('methylation', 'biological_process', 'GO:0032259', ('108', '119'))	('DNA methylation', 'MPA', (66, 81))
5625	27879367	Increasing evidence suggests that tumorigenesis often involves large-scale alterations in alternative splicing (reviewed in).	('tumor', 'Disease', (34, 39))	('alterations', 'Var', (75, 86))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('alternative splicing', 'MPA', (90, 110))	('splicing', 'biological_process', 'GO:0045292', ('102', '110'))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
5627	27879367	Thus, the deregulation of alternative RNA splicing plays a critical role in tumor development and progression.	('alternative RNA splicing', 'MPA', (26, 50))	('deregulation', 'Var', (10, 22))	('RNA splicing', 'biological_process', 'GO:0008380', ('38', '50'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('RNA', 'cellular_component', 'GO:0005562', ('38', '41'))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
5629	27879367	In this study, we observe that inclusion of EZH2 exon 14 is significantly increased in renal cancer cell lines and renal cancer samples.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('renal cancer', 'Disease', (87, 99))	('renal cancer', 'Disease', 'MESH:D007680', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('increased', 'PosReg', (74, 83))	('renal cancer', 'Disease', (115, 127))	('renal cancer', 'Phenotype', 'HP:0009726', (87, 99))	('renal cancer', 'Disease', 'MESH:D007680', (87, 99))	('renal cancer', 'Phenotype', 'HP:0009726', (115, 127))	('EZH2', 'Gene', (44, 48))	('inclusion', 'Var', (31, 40))
5630	27879367	EZH2Delta14 inhibits, and EZH2 promotes, renal tumor tumorigenesis.	('renal tumor', 'Phenotype', 'HP:0009726', (41, 52))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('promotes', 'PosReg', (31, 39))	('renal tumor', 'Disease', 'MESH:D007674', (41, 52))	('EZH2', 'Var', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('EZH2Delta14', 'Var', (0, 11))	('renal tumor', 'Disease', (41, 52))	('inhibits', 'NegReg', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (47, 52))
5631	27879367	Mechanistically, EZH2Delta14 competes with EZH2 for other PRC2 components and lncRNA binding, but had little or no histone methyltransferase (HMT) activity, and EZH2Delta14 isoform functions as a dominant-negative inhibitor of full-length EZH2.	('histone methyltransferase', 'Gene', '56979', (115, 140))	('HMT', 'Gene', (142, 145))	('lncRNA', 'Protein', (78, 84))	('HMT', 'Gene', '56979', (142, 145))	('EZH2Delta14', 'Var', (17, 28))	('histone methyltransferase', 'Gene', (115, 140))	('lncRNA binding', 'molecular_function', 'GO:0106222', ('78', '92'))
5654	27879367	Human EZH2 spans ~76 kb and contains 20 exons; exon 14 is subject to alternative splicing regulation, which generates variants dependent on inclusion or skipping of the exon 14 (Fig.	('Human', 'Species', '9606', (0, 5))	('variants', 'Var', (118, 126))	('inclusion', 'Var', (140, 149))	('regulation', 'biological_process', 'GO:0065007', ('90', '100'))	('skipping', 'Var', (153, 161))	('splicing', 'biological_process', 'GO:0045292', ('81', '89'))
5658	27879367	These data suggested that the dysregulation of EZH2 exon 14 alternative splicing may play an important role in renal cancer development.	('EZH2', 'Gene', (47, 51))	('role', 'Reg', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('dysregulation', 'Var', (30, 43))	('renal cancer', 'Disease', (111, 123))	('play', 'Reg', (85, 89))	('renal cancer', 'Phenotype', 'HP:0009726', (111, 123))	('renal cancer', 'Disease', 'MESH:D007680', (111, 123))	('splicing', 'biological_process', 'GO:0045292', ('72', '80'))
5661	27879367	Together, these results demonstrated that EZH2Delta14 retains EZH2's ability to complex with EED and SUZ12 in the nucleus.	('complex', 'Interaction', (80, 87))	('SUZ12', 'Gene', '23512', (101, 106))	('ability', 'MPA', (69, 76))	('EZH2', 'Gene', (62, 66))	('EED', 'Gene', '8726', (93, 96))	('SUZ12', 'Gene', (101, 106))	('nucleus', 'cellular_component', 'GO:0005634', ('114', '121'))	('EED', 'Gene', (93, 96))	('EZH2Delta14', 'Var', (42, 53))
5662	27879367	We next assessed the histone methyltransferase activity of EZH2Delta14 in comparison to EZH2 in their abilities to rescue the depletion of H3K27me3 and to induce EZH2 target genes in EZH2-knockout cells.	('H3K27me3', 'Protein', (139, 147))	('histone methyltransferase activity', 'molecular_function', 'GO:0008469', ('21', '55'))	('histone methyltransferase activity', 'molecular_function', 'GO:0042054', ('21', '55'))	('rescue', 'PosReg', (115, 121))	('histone methyltransferase', 'Gene', '56979', (21, 46))	('EZH2Delta14', 'Var', (59, 70))	('depletion', 'MPA', (126, 135))	('induce', 'PosReg', (155, 161))	('histone methyltransferase', 'Gene', (21, 46))
5670	27879367	S3B), demonstrating that EZH2Delta14 inhibits EMT.	('EMT', 'biological_process', 'GO:0001837', ('46', '49'))	('EMT', 'Gene', (46, 49))	('EMT', 'Gene', '3702', (46, 49))	('EZH2Delta14', 'Var', (25, 36))	('inhibits', 'NegReg', (37, 45))
5672	27879367	These results indicate that EZH2Delta14 inhibits, while EZH2 promotes, tumorigenicity of renal tumor cells in both in vitro and in vivo assays.	('renal tumor', 'Phenotype', 'HP:0009726', (89, 100))	('renal tumor', 'Disease', (89, 100))	('promotes', 'PosReg', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('inhibits', 'NegReg', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('EZH2', 'Gene', (56, 60))	('tumor', 'Disease', (71, 76))	('EZH2Delta14', 'Var', (28, 39))	('tumor', 'Disease', (95, 100))	('renal tumor', 'Disease', 'MESH:D007674', (89, 100))
5673	27879367	As expected, RT-qPCR assays showed that co-expression of EZH2Delta14 along with full-length EZH2 diminished the inhibitory effect of DAB2IP and HOXA9 expression in a dose-dependent manner (Fig.	('diminished', 'NegReg', (97, 107))	('expression', 'MPA', (150, 160))	('EZH2Delta14', 'Var', (57, 68))	('HOXA9', 'Gene', (144, 149))	('DAB2IP', 'Gene', (133, 139))	('inhibitory effect', 'MPA', (112, 129))	('DAB2IP', 'Gene', '153090', (133, 139))	('HOXA9', 'Gene', '3205', (144, 149))
5674	27879367	3A), indicating EZH2Delta14 inhibits full-length EZH2-mediated repression of DAB2IP and HOXA9.	('HOXA9', 'Gene', (88, 93))	('EZH2Delta14', 'Var', (16, 27))	('inhibits', 'NegReg', (28, 36))	('repression', 'MPA', (63, 73))	('DAB2IP', 'Gene', (77, 83))	('DAB2IP', 'Gene', '153090', (77, 83))	('HOXA9', 'Gene', '3205', (88, 93))
5676	27879367	3B, C), suggesting that EZH2Delta14 competes with full-length EZH2 for EED and SUZ12 binding.	('SUZ12', 'Gene', '23512', (79, 84))	('SUZ12', 'Gene', (79, 84))	('EZH2Delta14', 'Var', (24, 35))	('EED', 'Gene', '8726', (71, 74))	('binding', 'molecular_function', 'GO:0005488', ('85', '92'))	('binding', 'Interaction', (85, 92))	('EED', 'Gene', (71, 74))
5677	27879367	Furthermore, EZH2Delta14 also competes with EZH2 for the HOXA9 promoter and HOTAIR lncRNA binding (Fig.	('lncRNA binding', 'molecular_function', 'GO:0106222', ('83', '97'))	('HOTAIR', 'Gene', (76, 82))	('HOXA9', 'Gene', (57, 62))	('HOTAIR', 'Gene', '100124700', (76, 82))	('lncRNA binding', 'MPA', (83, 97))	('EZH2Delta14', 'Var', (13, 24))	('HOXA9', 'Gene', '3205', (57, 62))
5679	27879367	Aberrant splicing can result from mutations in cis-acting splicing elements and changes in the activity of trans-acting splicing factors.	('splicing', 'biological_process', 'GO:0045292', ('58', '66'))	('splicing', 'MPA', (9, 17))	('changes', 'Reg', (80, 87))	('splicing', 'biological_process', 'GO:0045292', ('120', '128'))	('result from', 'Reg', (22, 33))	('Aberrant', 'Var', (0, 8))	('cis-acting splicing elements', 'Protein', (47, 75))	('splicing', 'biological_process', 'GO:0045292', ('9', '17'))	('splicing factor', 'Gene', '10569', (120, 135))	('activity', 'MPA', (95, 103))	('mutations', 'Var', (34, 43))	('splicing factor', 'Gene', (120, 135))
5683	27879367	Based on reproducibility (4 of 4 pilot experiments) and the magnitude of change (>5 fold) in the exon 14+/14- mRNA ratio upon knockdown of indicated factor via shRNAs, SFPQ and SF3B3 were selected for further investigation.	('SFPQ', 'Gene', '6421', (168, 172))	('SFPQ', 'Gene', (168, 172))	('exon 14+/14- mRNA ratio', 'MPA', (97, 120))	('change', 'Reg', (73, 79))	('knockdown', 'Var', (126, 135))
5685	27879367	4A), suggesting that the effect of SFPQ or SF3B3 on EZH2 exon 14 splicing was not cell-type specific.	('SFPQ', 'Gene', '6421', (35, 39))	('SFPQ', 'Gene', (35, 39))	('EZH2', 'Gene', (52, 56))	('splicing', 'biological_process', 'GO:0045292', ('65', '73'))	('SF3B3', 'Var', (43, 48))
5687	27879367	Transient transfection of EZH2 dual luciferase splice reporter into ACHN and 293T cells revealed that relative firefly luciferase activity (F-Luc/R-Luc ratio) was significantly elevated when SFPQ or SF3B3 expression was knocked down (Fig.	('firefly luciferase activity', 'molecular_function', 'GO:0047077', ('111', '138'))	('SFPQ', 'Gene', '6421', (191, 195))	('SFPQ', 'Gene', (191, 195))	('elevated', 'PosReg', (177, 185))	('firefly', 'MPA', (111, 118))	('SF3B3', 'Gene', (199, 204))	('knocked', 'Var', (220, 227))	('293T', 'CellLine', 'CVCL:0063', (77, 81))	('activity', 'MPA', (130, 138))
5688	27879367	To further confirm the effect of SFPQ and SF3B3 on the protein level of EZH2Delta14 isoforms, we established a 293T cell line stably expressing the mini-EZH2 gene constructs by blasticidin selection (Supplementary Fig.	('SFPQ', 'Gene', '6421', (33, 37))	('SFPQ', 'Gene', (33, 37))	('293T', 'CellLine', 'CVCL:0063', (111, 115))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('blasticidin', 'Chemical', 'MESH:C004500', (177, 188))	('mini-EZH2', 'Var', (148, 157))
5689	27879367	The BSD-EGFP level was significantly increased when SFPQ or SF3B3 was knocked down (Supplementary Fig.	('SFPQ', 'Gene', '6421', (52, 56))	('SFPQ', 'Gene', (52, 56))	('SF3B3', 'Gene', (60, 65))	('BSD-EGFP level', 'MPA', (4, 18))	('knocked down', 'Var', (70, 82))	('increased', 'PosReg', (37, 46))
5690	27879367	S6D), suggesting that the relative expression level of EZH2 and EZH2Delta14 protein isoforms could be changed by SFPQ or SF3B3 depletion.	('expression level', 'MPA', (35, 51))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('EZH2Delta14', 'Gene', (64, 75))	('EZH2', 'Gene', (55, 59))	('SFPQ', 'Gene', (113, 117))	('SFPQ', 'Gene', '6421', (113, 117))	('SF3B3 depletion', 'Var', (121, 136))	('changed', 'Reg', (102, 109))
5696	27879367	In addition, SF3B3 knockdown in ACHN and 786-O cells resulted in downregulation of mesenchymal markers expression and upregulation of epithelial marker, demonstrating that SF3B3 knockdown inhibits EMT (Supplementary Fig.	('upregulation', 'PosReg', (118, 130))	('knockdown', 'Var', (19, 28))	('mesenchymal markers', 'CPA', (83, 102))	('EMT', 'Gene', (197, 200))	('SF3B3', 'Gene', (13, 18))	('downregulation', 'NegReg', (65, 79))	('EMT', 'biological_process', 'GO:0001837', ('197', '200'))	('SF3B3', 'Gene', (172, 177))	('EMT', 'Gene', '3702', (197, 200))	('inhibits', 'NegReg', (188, 196))	('epithelial marker', 'MPA', (134, 151))
5697	27879367	Moreover, we also found that knockdown of SF3B3 inhibited in vivo tumor growth in xenograft models with statistical significance (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('knockdown', 'Var', (29, 38))	('tumor', 'Disease', (66, 71))	('inhibited', 'NegReg', (48, 57))	('SF3B3', 'Gene', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
5704	27879367	This study provides the first direct evidence that EZH2 is alternatively spliced at exon 14, and demonstrates that EZH2 exon 14 inclusion is a frequent event in renal cancers.	('renal cancers', 'Disease', (161, 174))	('event', 'Reg', (152, 157))	('renal cancer', 'Phenotype', 'HP:0009726', (161, 173))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('exon 14', 'Var', (120, 127))	('renal cancers', 'Disease', 'MESH:D007680', (161, 174))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('EZH2', 'Gene', (115, 119))
5706	27879367	Splicing dysregulation is one of the molecular hallmarks of cancer.	('Splicing dysregulation', 'Var', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('Splicing', 'biological_process', 'GO:0045292', ('0', '8'))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
5707	27879367	Our finding that SF3B3 regulates EZH2 alternative splicing not only provides a mechanism for the regulation of EZH2 but also suggests that upregulation of SF3B3, a common event in renal cancer, is an important mechanism contributing to the frequently increased expression of exon14-containing EZH2 transcripts in tumors.	('increased', 'PosReg', (251, 260))	('regulation', 'biological_process', 'GO:0065007', ('97', '107'))	('upregulation', 'PosReg', (139, 151))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('splicing', 'biological_process', 'GO:0045292', ('50', '58'))	('expression', 'MPA', (261, 271))	('tumors', 'Disease', (313, 319))	('EZH2', 'Gene', (293, 297))	('renal cancer', 'Disease', (180, 192))	('SF3B3', 'Var', (155, 160))	('tumors', 'Disease', 'MESH:D009369', (313, 319))	('tumors', 'Phenotype', 'HP:0002664', (313, 319))	('renal cancer', 'Phenotype', 'HP:0009726', (180, 192))	('exon14-containing', 'Var', (275, 292))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('renal cancer', 'Disease', 'MESH:D007680', (180, 192))
5708	27879367	Like most of other human genes, the alternative splicing of EZH2 locus can give rise to different EZH2 mRNAs.	('give rise to', 'Reg', (75, 87))	('EZH2', 'Gene', (60, 64))	('EZH2', 'Gene', (98, 102))	('alternative splicing', 'Var', (36, 56))	('splicing', 'biological_process', 'GO:0045292', ('48', '56'))	('human', 'Species', '9606', (19, 24))
5709	27879367	Here we show that the exon14-lacking EZH2Delta14 isoform is downregulated, and exon14-containing EZH2 isoform is upregulated, in renal cancer cell lines and renal cancer tissues, suggesting an important role for the splicing variants of EZH2 in the tumorigenesis of human renal cancer.	('renal cancer', 'Phenotype', 'HP:0009726', (157, 169))	('tumor', 'Disease', (249, 254))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('EZH2Delta14', 'Gene', (37, 48))	('renal cancer', 'Disease', 'MESH:D007680', (157, 169))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('renal cancer', 'Disease', (129, 141))	('renal cancer', 'Phenotype', 'HP:0009726', (129, 141))	('splicing variants', 'Var', (216, 233))	('upregulated', 'PosReg', (113, 124))	('renal cancer', 'Disease', (272, 284))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('renal cancer', 'Phenotype', 'HP:0009726', (272, 284))	('EZH2', 'Gene', (237, 241))	('splicing', 'biological_process', 'GO:0045292', ('216', '224'))	('exon14-lacking', 'Var', (22, 36))	('downregulated', 'NegReg', (60, 73))	('renal cancer', 'Disease', 'MESH:D007680', (129, 141))	('renal cancer', 'Disease', (157, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('renal cancer', 'Disease', 'MESH:D007680', (272, 284))	('human', 'Species', '9606', (266, 271))
5711	27879367	It remains an open question whether dysregulation of alternative splicing of EZH2 is also involved in other cancer types.	('dysregulation', 'Var', (36, 49))	('EZH2', 'Gene', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('involved', 'Reg', (90, 98))	('splicing', 'biological_process', 'GO:0045292', ('65', '73'))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
5714	27879367	This raises the possibility that the differential inclusion of EZH2 exon 14 may be a frequent event in many human cancers, and EZH2 splice variants may be novel cancer markers.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancers', 'Disease', (114, 121))	('EZH2', 'Gene', (63, 67))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('splice variants', 'Var', (132, 147))	('human', 'Species', '9606', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', (114, 120))
5715	27879367	We also provide functional evidence that full length EZH2 promotes, and EZH2Delta14, inhibits, cancer cell growth, migration, and colony formation in vitro and tumorigenesis in vivo.	('inhibits', 'NegReg', (85, 93))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('migration', 'CPA', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('formation', 'biological_process', 'GO:0009058', ('137', '146'))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('cancer', 'Disease', (95, 101))	('promotes', 'PosReg', (58, 66))	('colony formation', 'CPA', (130, 146))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cell growth', 'biological_process', 'GO:0016049', ('102', '113'))	('EZH2Delta14', 'Var', (72, 83))	('tumor', 'Disease', (160, 165))	('EZH2', 'Gene', (53, 57))
5717	27879367	Our study suggests that EZH2Delta14 lacks histone methyltransferase (HMT) activity and has a distinct function in the tumorigenesis of human renal cancer, and this result supports the notion that the CXC domain of EZH2 is required for histone methyl transferase (HMT) activity.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('histone methyl transferase', 'Gene', (235, 261))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('HMT', 'Gene', '56979', (69, 72))	('renal cancer', 'Disease', (141, 153))	('HMT', 'Gene', (263, 266))	('renal cancer', 'Phenotype', 'HP:0009726', (141, 153))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('human', 'Species', '9606', (135, 140))	('renal cancer', 'Disease', 'MESH:D007680', (141, 153))	('HMT', 'Gene', (69, 72))	('histone methyl transferase', 'Gene', '56979', (235, 261))	('histone methyltransferase', 'Gene', (42, 67))	('HMT', 'Gene', '56979', (263, 266))	('lacks', 'NegReg', (36, 41))	('activity', 'MPA', (74, 82))	('tumor', 'Disease', (118, 123))	('EZH2Delta14', 'Var', (24, 35))	('histone methyltransferase', 'Gene', '56979', (42, 67))
5720	27879367	For example, EZH2 depletion accelerates lymphomagenesis in Emu-Myc transgenic mice, which acts as a tumor suppressor for myeloid malignancies.	('EZH2', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('100', '116'))	('lymphomagenesis', 'CPA', (40, 55))	('tumor', 'Disease', (100, 105))	('transgenic mice', 'Species', '10090', (67, 82))	('myeloid malignancies', 'Disease', (121, 141))	('tumor suppressor', 'biological_process', 'GO:0051726', ('100', '116'))	('depletion', 'Var', (18, 27))	('accelerates', 'PosReg', (28, 39))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('myeloid malignancies', 'Disease', 'MESH:D009369', (121, 141))
5723	27879367	This study provides the first evidence that EZH2 is also regulated by alternative splicing, and that such alternative splicing is associated with carcinogenesis.	('alternative splicing', 'Var', (70, 90))	('carcinogenesis', 'Disease', (146, 160))	('splicing', 'biological_process', 'GO:0045292', ('82', '90'))	('regulated', 'Reg', (57, 66))	('carcinogenesis', 'Disease', 'MESH:D063646', (146, 160))	('EZH2', 'Gene', (44, 48))	('splicing', 'biological_process', 'GO:0045292', ('118', '126'))	('associated', 'Reg', (130, 140))
5725	27879367	Specifically, our results suggest that modulating EZH2 splicing may be an effective way to influence EZH2 activity in cancer.	('cancer', 'Disease', (118, 124))	('influence', 'Reg', (91, 100))	('modulating', 'Var', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('splicing', 'biological_process', 'GO:0045292', ('55', '63'))	('activity', 'MPA', (106, 114))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
5728	27879367	Previously, SF3b mutations were identified in multiple cancer types, especially in myelodysplastic syndromes (MDSs).	('MDSs', 'Phenotype', 'HP:0002863', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (83, 108))	('identified', 'Reg', (32, 42))	('myelodysplastic syndromes', 'Disease', (83, 108))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('SF3b', 'Gene', (12, 16))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (83, 108))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', (55, 61))
5729	27879367	These mutations appear to promote use of many cryptic 3' splice site that induces global splicing changes and generates aberrant transcripts; in many cases, inappropriate exon skipping is observed.	('induces', 'Reg', (74, 81))	('cryptic', 'Gene', '55997', (46, 53))	('cryptic', 'Gene', (46, 53))	('global splicing changes', 'MPA', (82, 105))	('splicing', 'biological_process', 'GO:0045292', ('89', '97'))	('transcripts', 'MPA', (129, 140))	('mutations', 'Var', (6, 15))
5730	27879367	Because we found that EZH2 was not sufficient to rescue the growth defects following SF3B3 inhibition, the effects of SF3B3 knockdown on cell growth likely involves a number of other genes.	('inhibition', 'Var', (91, 101))	('growth defects', 'Disease', 'MESH:D006130', (60, 74))	('SF3B3', 'Gene', (85, 90))	('cell growth', 'biological_process', 'GO:0016049', ('137', '148'))	('growth defects', 'Disease', (60, 74))
5736	27879367	We also confirmed that knockdown of SF3B3 can inhibit cancer cell growth, migration and invasion in vitro and tumorigenicity and metastasis in vivo.	('cell growth', 'biological_process', 'GO:0016049', ('61', '72'))	('inhibit', 'NegReg', (46, 53))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('knockdown', 'Var', (23, 32))	('tumor', 'Disease', (110, 115))	('SF3B3', 'Gene', (36, 41))	('cancer', 'Disease', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
5740	27879367	Most importantly, we analyzed the data from 90 Chinese ccRCC patients, and found that the expression level of SF3B3 is clearly correlated with the stage of renal cancer and that SF3B3 overexpression is associated with poor prognosis of ccRCC patients.	('overexpression', 'PosReg', (184, 198))	('patients', 'Species', '9606', (242, 250))	('ccRCC', 'Disease', (236, 241))	('SF3B3', 'Var', (178, 183))	('patients', 'Species', '9606', (61, 69))	('renal cancer', 'Disease', 'MESH:D007680', (156, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('stage', 'Disease', (147, 152))	('renal cancer', 'Disease', (156, 168))	('correlated', 'Reg', (127, 137))	('renal cancer', 'Phenotype', 'HP:0009726', (156, 168))	('SF3B3', 'Gene', (110, 115))	('expression level', 'MPA', (90, 106))
5742	27879367	In summary, our study reveals tumorigenic roles for dysregulated EZH2 exon14 splicing, and identifies SF3B3 as regulator of the splicing of EZH2 pre-mRNA in a manner that contributes to tumorigenesis of renal cancer cells.	('pre', 'molecular_function', 'GO:0003904', ('145', '148'))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('renal cancer', 'Disease', (203, 215))	('contributes', 'Reg', (171, 182))	('dysregulated', 'Var', (52, 64))	('EZH2', 'Gene', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', (186, 191))	('renal cancer', 'Phenotype', 'HP:0009726', (203, 215))	('renal cancer', 'Disease', 'MESH:D007680', (203, 215))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('splicing', 'biological_process', 'GO:0045292', ('128', '136'))	('splicing', 'biological_process', 'GO:0045292', ('77', '85'))	('tumor', 'Disease', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
5744	27879367	Dysregulated expression or mutation of EZH2 is being recognized as a critical event in several genetic disorders and cancer, but the regulation of EZH2 splicing, and the functional and clinical significance of the variants in ccRCC remains unexplored.	('clinical', 'Species', '191496', (185, 193))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('genetic disorders', 'Disease', (95, 112))	('mutation', 'Var', (27, 35))	('ccRCC', 'Disease', (226, 231))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('variants', 'Var', (214, 222))	('regulation', 'biological_process', 'GO:0065007', ('133', '143'))	('cancer', 'Disease', (117, 123))	('genetic disorders', 'Disease', 'MESH:D030342', (95, 112))	('splicing', 'biological_process', 'GO:0045292', ('152', '160'))
5745	31112866	HSP60 silencing promotes Warburg-like phenotypes and switches the mitochondrial function from ATP production to biosynthesis in ccRCC cells HSP60 is a major mitochondrial chaperone for maintaining mitochondrial proteostasis.	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('promotes', 'PosReg', (16, 24))	('silencing', 'Var', (6, 15))	('ATP', 'Chemical', 'MESH:D000255', (94, 97))	('mitochondrial function', 'MPA', (66, 88))	('HSP60', 'Gene', (140, 145))	('HSP60', 'Gene', '3329', (140, 145))	('Warburg-like', 'Disease', (25, 37))	('HSP60', 'Gene', (0, 5))	('HSP60', 'Gene', '3329', (0, 5))	('switches', 'Reg', (53, 61))	('biosynthesis', 'biological_process', 'GO:0009058', ('112', '124'))
5748	31112866	We also stably knocked down or overexpressed HSP60 in ccRCC cells to investigate the effects of HSP60 expression on the transition between oxidative phosphorylation and glycolysis.	('HSP60', 'Gene', (96, 101))	('knocked down', 'Var', (15, 27))	('HSP60', 'Gene', '3329', (96, 101))	('glycolysis', 'biological_process', 'GO:0006096', ('169', '179'))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('139', '164'))	('HSP60', 'Gene', '3329', (45, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('HSP60', 'Gene', (45, 50))
5749	31112866	We confirmed that HSP60 knockdown increased cell proliferation, whereas its overexpression decreased cell growth.	('cell proliferation', 'CPA', (44, 62))	('decreased', 'NegReg', (91, 100))	('cell growth', 'CPA', (101, 112))	('HSP60', 'Gene', (18, 23))	('cell proliferation', 'biological_process', 'GO:0008283', ('44', '62'))	('cell growth', 'biological_process', 'GO:0016049', ('101', '112'))	('increased', 'PosReg', (34, 43))	('knockdown', 'Var', (24, 33))	('HSP60', 'Gene', '3329', (18, 23))	('overexpression', 'PosReg', (76, 90))
5750	31112866	Proteomics and metabolomics revealed that HSP60 knockdown promoted Warburg-like phenotypes with enhanced glycolysis and decreased mitochondrial activity.	('decreased', 'NegReg', (120, 129))	('HSP60', 'Gene', '3329', (42, 47))	('mitochondrial activity', 'MPA', (130, 152))	('enhanced', 'PosReg', (96, 104))	('glycolysis', 'MPA', (105, 115))	('Warburg-like phenotypes', 'Disease', (67, 90))	('promoted', 'PosReg', (58, 66))	('HSP60', 'Gene', (42, 47))	('decreased mitochondrial activity', 'Phenotype', 'HP:0040013', (120, 152))	('glycolysis', 'biological_process', 'GO:0006096', ('105', '115'))	('knockdown', 'Var', (48, 57))
5752	31112866	However, HSP60 silencing enhanced mitochondrial functions in glutamine-directed biosynthesis with increased flow in two parts of the TCA cycle: Gln alphaKG OAA Asp and Gln alphaKG ISO acetyl-CoA, resulting in elevated de novo nucleotide synthesis and lipid synthesis.	('TCA', 'Chemical', 'MESH:D014238', (133, 136))	('enhanced', 'PosReg', (25, 33))	('HSP60', 'Gene', (9, 14))	('lipid', 'Chemical', 'MESH:D008055', (251, 256))	('Gln alphaKG OAA', 'Var', (144, 159))	('silencing', 'Var', (15, 24))	('lipid synthesis', 'MPA', (251, 266))	('mitochondrial functions', 'MPA', (34, 57))	('glutamine-directed biosynthesis', 'MPA', (61, 92))	('TCA cycle', 'biological_process', 'GO:0006099', ('133', '142'))	('elevated', 'PosReg', (209, 217))	('increased', 'PosReg', (98, 107))	('nucleotide synthesis', 'biological_process', 'GO:0009165', ('226', '246'))	('flow', 'MPA', (108, 112))	('HSP60', 'Gene', '3329', (9, 14))	('biosynthesis', 'biological_process', 'GO:0009058', ('80', '92'))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (184, 194))	('Gln alphaKG', 'Var', (168, 179))	('de novo nucleotide synthesis', 'MPA', (218, 246))	('glutamine', 'Chemical', 'MESH:D005973', (61, 70))	('Asp', 'Chemical', 'MESH:D001224', (160, 163))	('lipid synthesis', 'biological_process', 'GO:0008610', ('251', '266'))
5753	31112866	Proteomic analysis indicated that HSP60 silencing activated NRF2-mediated oxidative stress responses, while glutamate generated from glutamine increased glutathione synthesis for quenching excessive reactive oxygen species (ROS) produced upon elevated cell growth.	('increased', 'PosReg', (143, 152))	('ROS', 'Chemical', 'MESH:D017382', (224, 227))	('excessive reactive oxygen species', 'Phenotype', 'HP:0025464', (189, 222))	('glutathione', 'Chemical', 'MESH:D005978', (153, 164))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (199, 222))	('silencing', 'Var', (40, 49))	('NRF2', 'Gene', (60, 64))	('activated', 'PosReg', (50, 59))	('glutathione synthesis', 'MPA', (153, 174))	('HSP60', 'Gene', '3329', (34, 39))	('quenching', 'MPA', (179, 188))	('glutamate', 'Chemical', 'MESH:D018698', (108, 117))	('glutamine', 'Chemical', 'MESH:D005973', (133, 142))	('NRF2', 'Gene', '2551', (60, 64))	('oxidative stress', 'Phenotype', 'HP:0025464', (74, 90))	('glutathione synthesis', 'biological_process', 'GO:0006750', ('153', '174'))	('glutamine increased', 'Phenotype', 'HP:0003217', (133, 152))	('HSP60', 'Gene', (34, 39))	('oxidative stress responses', 'MPA', (74, 100))	('cell growth', 'biological_process', 'GO:0016049', ('252', '263'))
5754	31112866	We further found that HSP60 silencing activated the MEK/ERK/c-Myc axis to promote glutamine addiction, and confirmed that ccRCC cells were susceptible to oxidative stress and glutaminase inhibition.	('glutaminase', 'Gene', '2744', (175, 186))	('ERK', 'Gene', (56, 59))	('promote', 'PosReg', (74, 81))	('oxidative stress', 'Phenotype', 'HP:0025464', (154, 170))	('silencing', 'Var', (28, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (122, 127))	('glutaminase', 'Gene', (175, 186))	('HSP60', 'Gene', (22, 27))	('glutamine', 'Chemical', 'MESH:D005973', (82, 91))	('HSP60', 'Gene', '3329', (22, 27))	('MEK', 'Gene', (52, 55))	('c-Myc', 'Gene', '4609', (60, 65))	('MEK', 'Gene', '5609', (52, 55))	('activated', 'PosReg', (38, 47))	('ERK', 'molecular_function', 'GO:0004707', ('56', '59'))	('glutamine addiction', 'MPA', (82, 101))	('c-Myc', 'Gene', (60, 65))	('ERK', 'Gene', '5594', (56, 59))
5755	31112866	Collectively, our data show that HSP60 knockdown drives metabolic reprogramming in ccRCC to promote tumor progression and enhances mitochondrial-dependent biosynthesis.	('mitochondrial-dependent biosynthesis', 'MPA', (131, 167))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('promote', 'PosReg', (92, 99))	('tumor', 'Disease', (100, 105))	('HSP60', 'Gene', (33, 38))	('knockdown', 'Var', (39, 48))	('HSP60', 'Gene', '3329', (33, 38))	('enhances', 'PosReg', (122, 130))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('ccRCC', 'Disease', (83, 88))	('biosynthesis', 'biological_process', 'GO:0009058', ('155', '167'))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
5757	31112866	HSP60 silencing promotes ccRCC progression via the enhanced Warburg effect.	('promotes', 'PosReg', (16, 24))	('ccRCC', 'Disease', (25, 30))	('enhanced', 'PosReg', (51, 59))	('Warburg effect', 'CPA', (60, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (25, 30))	('HSP60', 'Gene', (0, 5))	('HSP60', 'Gene', '3329', (0, 5))	('silencing', 'Var', (6, 15))
5769	31112866	Tumorigenesis in ccRCC is mainly attributed to mutation in the von Hippel-Lindau (VHL) gene, which leads to stabilization of hypoxia-inducible factors, causing the accumulation of glycogens and fat in tumor cells.	('hypoxia', 'Disease', (125, 132))	('VHL', 'Disease', (82, 85))	('leads to', 'Reg', (99, 107))	('attributed', 'Reg', (33, 43))	('VHL', 'Disease', 'MESH:D006623', (82, 85))	('von Hippel-Lindau', 'Gene', (63, 80))	('Tumorigenesis', 'CPA', (0, 13))	('mutation', 'Var', (47, 55))	('accumulation', 'PosReg', (164, 176))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('ccRCC', 'Phenotype', 'HP:0006770', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('von Hippel-Lindau', 'Gene', '7428', (63, 80))	('ccRCC', 'Disease', (17, 22))	('tumor', 'Disease', (201, 206))	('hypoxia', 'Disease', 'MESH:D000860', (125, 132))	('stabilization', 'MPA', (108, 121))
5770	31112866	In this disease, mutations are also frequently present in chromatin modifiers and genes encoding products involved in the mTOR and PI3K pathways.	('present', 'Reg', (47, 54))	('PI3K', 'molecular_function', 'GO:0016303', ('131', '135'))	('chromatin', 'cellular_component', 'GO:0000785', ('58', '67'))	('mTOR', 'Gene', (122, 126))	('mTOR', 'Gene', '2475', (122, 126))	('mutations', 'Var', (17, 26))
5779	31112866	We carried out proteomics, metabolomics, and isotope tracing to delineate the effects of HSP60 knockdown on metabolic reprogramming in ccRCC.	('knockdown', 'Var', (95, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('HSP60', 'Gene', (89, 94))	('HSP60', 'Gene', '3329', (89, 94))	('ccRCC', 'Disease', (135, 140))
5780	31112866	We revealed that HSP60 silencing induced glutamine addiction in ccRCC to support nucleotide synthesis and to quench ROS generated upon mitochondrial dysfunction, which facilitates cell proliferation in ccRCC.	('silencing', 'Var', (23, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (202, 207))	('nucleotide synthesis', 'biological_process', 'GO:0009165', ('81', '101'))	('HSP60', 'Gene', (17, 22))	('support', 'PosReg', (73, 80))	('glutamine addiction', 'MPA', (41, 60))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (135, 160))	('glutamine', 'Chemical', 'MESH:D005973', (41, 50))	('facilitates', 'PosReg', (168, 179))	('cell proliferation', 'biological_process', 'GO:0008283', ('180', '198'))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (135, 160))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('cell proliferation', 'CPA', (180, 198))	('mitochondrial dysfunction', 'Disease', (135, 160))	('HSP60', 'Gene', '3329', (17, 22))	('nucleotide synthesis', 'MPA', (81, 101))	('ROS', 'Chemical', 'MESH:D017382', (116, 119))	('quench', 'NegReg', (109, 115))	('ccRCC', 'Disease', (202, 207))
5814	31112866	This demonstrates that low HSP60 expression promotes tumor progression.	('promotes', 'PosReg', (44, 52))	('low', 'Var', (23, 26))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('expression', 'MPA', (33, 43))	('tumor', 'Disease', (53, 58))	('HSP60', 'Gene', (27, 32))	('HSP60', 'Gene', '3329', (27, 32))
5820	31112866	Consistent with a previous observation, HSP60 silencing promoted the growth of 786-O and 769-P cells compared with that in the control cells.	('silencing', 'Var', (46, 55))	('growth', 'CPA', (69, 75))	('HSP60', 'Gene', (40, 45))	('HSP60', 'Gene', '3329', (40, 45))	('promoted', 'PosReg', (56, 64))
5821	31112866	In contrast, HSP60 overexpression in 786-O cells inhibited cell proliferation, which demonstrated that low HSP60 expression promoted the growth of ccRCC cells in vitro and in patients.	('HSP60', 'Gene', (107, 112))	('low', 'Var', (103, 106))	('HSP60', 'Gene', '3329', (107, 112))	('growth', 'MPA', (137, 143))	('cell proliferation', 'CPA', (59, 77))	('patients', 'Species', '9606', (175, 183))	('ccRCC', 'Disease', (147, 152))	('promoted', 'PosReg', (124, 132))	('HSP60', 'Gene', (13, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (147, 152))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('inhibited', 'NegReg', (49, 58))	('HSP60', 'Gene', '3329', (13, 18))
5827	31112866	In contrast, HSP60 silencing lowered basal respiration and decreased ATP production in 786-O cells (Fig.	('lowered', 'NegReg', (29, 36))	('decreased', 'NegReg', (59, 68))	('ATP production', 'MPA', (69, 83))	('silencing', 'Var', (19, 28))	('respiration', 'biological_process', 'GO:0045333', ('43', '54'))	('ATP', 'Chemical', 'MESH:D000255', (69, 72))	('basal respiration', 'MPA', (37, 54))	('HSP60', 'Gene', (13, 18))	('respiration', 'biological_process', 'GO:0007585', ('43', '54'))	('HSP60', 'Gene', '3329', (13, 18))
5828	31112866	These results clearly demonstrate that HSP60 knockdown aggravated the Warburg effect by triggering the glycolysis-oxidative phosphorylation switch.	('aggravated', 'PosReg', (55, 65))	('HSP60', 'Gene', (39, 44))	('HSP60', 'Gene', '3329', (39, 44))	('glycolysis-oxidative phosphorylation switch', 'MPA', (103, 146))	('glycolysis', 'biological_process', 'GO:0006096', ('103', '113'))	('Warburg effect', 'Disease', (70, 84))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('114', '139'))	('triggering', 'Reg', (88, 98))	('knockdown', 'Var', (45, 54))
5830	31112866	The inhibition of PDH prevents pyruvate to acetyl-CoA conversion and induces glycolytic metabolism.	('acetyl-CoA', 'Chemical', 'MESH:D000105', (43, 53))	('glycolytic metabolism', 'MPA', (77, 98))	('pyruvate', 'Chemical', 'MESH:D019289', (31, 39))	('prevents', 'NegReg', (22, 30))	('induces', 'Reg', (69, 76))	('inhibition', 'Var', (4, 14))	('PDH', 'molecular_function', 'GO:0004246', ('18', '21'))	('metabolism', 'biological_process', 'GO:0008152', ('88', '98'))	('PDH', 'Gene', (18, 21))	('pyruvate to acetyl-CoA conversion', 'MPA', (31, 64))	('PDH', 'molecular_function', 'GO:0004739', ('18', '21'))	('PDH', 'molecular_function', 'GO:0033718', ('18', '21'))	('PDH', 'Gene', '54704', (18, 21))
5833	31112866	Taking these findings together, it is demonstrated that HSP60 silencing simultaneously enhances glycolysis, and downregulates PDH expression to block pyruvate from entering the TCA cycle for oxidative phosphorylation, and decreases oxidative respiration, leading to aggravated Warburg phenotypes.	('expression', 'MPA', (130, 140))	('TCA cycle', 'biological_process', 'GO:0006099', ('177', '186'))	('aggravated', 'PosReg', (266, 276))	('pyruvate', 'MPA', (150, 158))	('HSP60', 'Gene', (56, 61))	('silencing', 'Var', (62, 71))	('PDH', 'molecular_function', 'GO:0004246', ('126', '129'))	('PDH', 'Gene', (126, 129))	('PDH', 'molecular_function', 'GO:0033718', ('126', '129'))	('oxidative respiration', 'MPA', (232, 253))	('TCA', 'Chemical', 'MESH:D014238', (177, 180))	('enhances', 'PosReg', (87, 95))	('downregulates', 'NegReg', (112, 125))	('PDH', 'molecular_function', 'GO:0004739', ('126', '129'))	('Warburg phenotypes', 'Disease', (277, 295))	('block', 'NegReg', (144, 149))	('pyruvate', 'Chemical', 'MESH:D019289', (150, 158))	('HSP60', 'Gene', '3329', (56, 61))	('glycolysis', 'biological_process', 'GO:0006096', ('96', '106'))	('respiration', 'biological_process', 'GO:0007585', ('242', '253'))	('glycolysis', 'MPA', (96, 106))	('decreases', 'NegReg', (222, 231))	('PDH', 'Gene', '54704', (126, 129))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('191', '216'))	('respiration', 'biological_process', 'GO:0045333', ('242', '253'))
5834	31112866	Analysis of metabolomics data by MetaboAnalyst 4.0 revealed that HSP60 silencing activated pyrimidine metabolism and alanine, aspartate, and glutamate metabolism (Fig.	('pyrimidine', 'Chemical', 'MESH:C030986', (91, 101))	('glutamate metabolism', 'MPA', (141, 161))	('pyrimidine metabolism', 'MPA', (91, 112))	('pyrimidine metabolism', 'biological_process', 'GO:0006213', ('91', '112'))	('alanine', 'Chemical', 'MESH:D000409', (117, 124))	('activated', 'PosReg', (81, 90))	('silencing', 'Var', (71, 80))	('glutamate', 'Chemical', 'MESH:D018698', (141, 150))	('aspartate', 'Chemical', 'MESH:D001224', (126, 135))	('glutamate metabolism', 'biological_process', 'GO:0006536', ('141', '161'))	('pyrimidine metabolism', 'biological_process', 'GO:0006206', ('91', '112'))	('pyrimidine metabolism', 'biological_process', 'GO:0006220', ('91', '112'))	('HSP60', 'Gene', (65, 70))	('HSP60', 'Gene', '3329', (65, 70))	('aspartate', 'MPA', (126, 135))	('alanine', 'MPA', (117, 124))
5842	31112866	These results indicate that HSP60 knockdown promoted glutamine-directed nucleotide synthesis.	('HSP60', 'Gene', '3329', (28, 33))	('promoted', 'PosReg', (44, 52))	('glutamine', 'Chemical', 'MESH:D005973', (53, 62))	('nucleotide synthesis', 'biological_process', 'GO:0009165', ('72', '92'))	('HSP60', 'Gene', (28, 33))	('knockdown', 'Var', (34, 43))	('glutamine-directed nucleotide synthesis', 'MPA', (53, 92))
5846	31112866	Consistent with this, HSP60 silencing decreased glutamine levels in both cells and the medium, whereas intracellular glutamate levels were significantly increased (Fig.	('decreased', 'NegReg', (38, 47))	('decreased glutamine', 'Phenotype', 'HP:0500147', (38, 57))	('increased', 'PosReg', (153, 162))	('glutamate', 'Chemical', 'MESH:D018698', (117, 126))	('intracellular', 'cellular_component', 'GO:0005622', ('103', '116'))	('HSP60', 'Gene', (22, 27))	('intracellular glutamate levels', 'MPA', (103, 133))	('HSP60', 'Gene', '3329', (22, 27))	('silencing', 'Var', (28, 37))	('glutamine levels', 'MPA', (48, 64))	('glutamine', 'Chemical', 'MESH:D005973', (48, 57))
5848	31112866	Using western blotting, we found that HSP60 silencing did not alter KGA, but upregulated GAC, indicating that GAC plays a key role in ccRCC progression (Fig.	('GAC', 'Gene', '2744', (89, 92))	('upregulated', 'PosReg', (77, 88))	('ccRCC', 'Disease', (134, 139))	('KGA', 'Gene', (68, 71))	('GAC', 'Gene', (89, 92))	('GAC', 'Gene', '2744', (110, 113))	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('KGA', 'Gene', '2744', (68, 71))	('silencing', 'Var', (44, 53))	('GAC', 'Gene', (110, 113))	('HSP60', 'Gene', (38, 43))	('HSP60', 'Gene', '3329', (38, 43))
5850	31112866	We further treated cells with the GLS1 inhibitor BPTES and discovered that HSP60 silencing sensitized cells to GLS1 inhibition (Fig.	('GLS1', 'Gene', '2744', (111, 115))	('GLS1', 'Gene', (34, 38))	('HSP60', 'Gene', (75, 80))	('HSP60', 'Gene', '3329', (75, 80))	('silencing', 'Var', (81, 90))	('BPTES', 'Chemical', '-', (49, 54))	('GLS1', 'Gene', (111, 115))	('GLS1', 'Gene', '2744', (34, 38))
5855	31112866	When cells were treated with U0126, an inhibitor of ERK1/2, the cell growth of HSP60-KD cells was significantly suppressed as compared to control cells (Fig.	('U0126', 'Var', (29, 34))	('suppressed', 'NegReg', (112, 122))	('U0126', 'Chemical', 'MESH:C113580', (29, 34))	('cell growth', 'biological_process', 'GO:0016049', ('64', '75'))	('HSP60', 'Gene', (79, 84))	('HSP60', 'Gene', '3329', (79, 84))	('ERK1', 'molecular_function', 'GO:0004707', ('52', '56'))
5862	31112866	S3D), indicating that HSP60 silencing promoted glutamine reductive carboxylation.	('glutamine', 'Chemical', 'MESH:D005973', (47, 56))	('glutamine reductive carboxylation', 'MPA', (47, 80))	('HSP60', 'Gene', (22, 27))	('HSP60', 'Gene', '3329', (22, 27))	('promoted', 'PosReg', (38, 46))	('silencing', 'Var', (28, 37))
5863	31112866	Taken together, these findings provide experimental evidence that HSP60 silencing rewires metabolic pathways in mitochondria to enhance glutamine-directed biosynthesis.	('HSP60', 'Gene', (66, 71))	('HSP60', 'Gene', '3329', (66, 71))	('silencing', 'Var', (72, 81))	('glutamine-directed biosynthesis', 'MPA', (136, 167))	('mitochondria', 'cellular_component', 'GO:0005739', ('112', '124'))	('biosynthesis', 'biological_process', 'GO:0009058', ('155', '167'))	('glutamine', 'Chemical', 'MESH:D005973', (136, 145))	('enhance', 'PosReg', (128, 135))	('metabolic pathways in mitochondria', 'Pathway', (90, 124))	('rewires', 'Reg', (82, 89))
5865	31112866	Indeed, HSP60 silencing significantly increased ROS levels in both 786-O cells and 769-P cells (Fig.	('silencing', 'Var', (14, 23))	('HSP60', 'Gene', (8, 13))	('HSP60', 'Gene', '3329', (8, 13))	('ROS', 'Chemical', 'MESH:D017382', (48, 51))	('increased', 'PosReg', (38, 47))	('ROS levels', 'MPA', (48, 58))
5868	31112866	In contrast, the ROS scavenger NAc and PBN greatly enhanced cell growth, suggesting that the quenching of ROS promotes the growth of ccRCC cells (Fig.	('NAc', 'Chemical', 'MESH:D000111', (31, 34))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('ccRCC', 'Disease', (133, 138))	('ROS', 'Chemical', 'MESH:D017382', (17, 20))	('ROS', 'Chemical', 'MESH:D017382', (106, 109))	('cell growth', 'biological_process', 'GO:0016049', ('60', '71'))	('PBN', 'Chemical', 'MESH:D007854', (39, 42))	('growth', 'MPA', (123, 129))	('enhanced', 'PosReg', (51, 59))	('ROS', 'Gene', (106, 109))	('cell growth', 'CPA', (60, 71))	('promotes', 'PosReg', (110, 118))	('NAc', 'cellular_component', 'GO:0005854', ('31', '34'))	('quenching', 'Var', (93, 102))
5869	31112866	Metabolomics analysis showed that HSP60 silencing did not alter the intracellular GSH levels, whereas it boosted the GSSG level (Fig.	('GSSG', 'Chemical', 'MESH:D019803', (117, 121))	('GSSG level', 'MPA', (117, 127))	('GSH', 'Chemical', '-', (82, 85))	('silencing', 'Var', (40, 49))	('intracellular', 'cellular_component', 'GO:0005622', ('68', '81'))	('HSP60', 'Gene', (34, 39))	('HSP60', 'Gene', '3329', (34, 39))	('boosted', 'PosReg', (105, 112))
5876	31112866	In summary, the present study demonstrated that HSP60 knockdown aggravated classical Warburg phenotypes in ccRCC cells, conferring a poor prognosis on ccRCC patients with low HSP60 expression.	('HSP60', 'Gene', '3329', (48, 53))	('knockdown', 'Var', (54, 63))	('patients', 'Species', '9606', (157, 165))	('aggravated', 'PosReg', (64, 74))	('HSP60', 'Gene', (175, 180))	('ccRCC', 'Disease', (151, 156))	('HSP60', 'Gene', (48, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (151, 156))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('HSP60', 'Gene', '3329', (175, 180))
5877	31112866	HSP60 silencing activated the MEK/ERK/c-Myc pathway to enhance glutamine-directed metabolism, which switched mitochondria from ATP production to biosynthesis to promote tumor progression.	('mitochondria', 'cellular_component', 'GO:0005739', ('109', '121'))	('ERK', 'molecular_function', 'GO:0004707', ('34', '37'))	('metabolism', 'biological_process', 'GO:0008152', ('82', '92'))	('enhance', 'PosReg', (55, 62))	('promote', 'PosReg', (161, 168))	('ERK', 'Gene', '5594', (34, 37))	('glutamine-directed metabolism', 'MPA', (63, 92))	('HSP60', 'Gene', (0, 5))	('MEK', 'Gene', (30, 33))	('silencing', 'Var', (6, 15))	('tumor', 'Disease', (169, 174))	('ERK', 'Gene', (34, 37))	('glutamine', 'Chemical', 'MESH:D005973', (63, 72))	('c-Myc', 'Gene', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('HSP60', 'Gene', '3329', (0, 5))	('c-Myc', 'Gene', '4609', (38, 43))	('ATP', 'Chemical', 'MESH:D000255', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('biosynthesis', 'biological_process', 'GO:0009058', ('145', '157'))	('MEK', 'Gene', '5609', (30, 33))
5878	31112866	HSP60 knockdown also enhanced NRF2-mediated oxidative stress responses to increase GSH production for quenching ROS generated in rapidly proliferating cells.	('GSH production', 'MPA', (83, 97))	('NRF2', 'Gene', (30, 34))	('ROS', 'Chemical', 'MESH:D017382', (112, 115))	('oxidative stress', 'Phenotype', 'HP:0025464', (44, 60))	('enhanced', 'PosReg', (21, 29))	('GSH', 'Chemical', '-', (83, 86))	('increase', 'PosReg', (74, 82))	('HSP60', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))	('HSP60', 'Gene', '3329', (0, 5))	('quenching ROS generated', 'MPA', (102, 125))	('NRF2', 'Gene', '2551', (30, 34))
5907	31821170	In total, 263 DEIRGs were found to be significantly associated with the overall survival (OS) of ccRCC patients (p < 0.05) (Figure 2).	('ccRCC', 'Disease', 'MESH:D002292', (97, 102))	('overall survival', 'MPA', (72, 88))	('DEIRGs', 'Var', (14, 20))	('associated with', 'Reg', (52, 67))	('patients', 'Species', '9606', (103, 111))	('ccRCC', 'Disease', (97, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))
5937	31821170	These results demonstrated that the dysregulation of immune-related risk gene expression is associated with the development of ccRCC.	('dysregulation', 'Var', (36, 49))	('expression', 'MPA', (78, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('ccRCC', 'Disease', (127, 132))	('ccRCC', 'Disease', 'MESH:D002292', (127, 132))	('gene expression', 'biological_process', 'GO:0010467', ('73', '88'))	('associated', 'Reg', (92, 102))
6008	31258756	Autophagic gene polymorphisms are associated with progression-free survival (PFS) of ccRCC patients treated with pazopanib.	('progression-free', 'Disease', (50, 66))	('polymorphisms', 'Var', (16, 29))	('Autophagic gene', 'Gene', (0, 15))	('RCC', 'Disease', (87, 90))	('associated', 'Reg', (34, 44))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('pazopanib', 'Chemical', 'MESH:C516667', (113, 122))	('patients', 'Species', '9606', (91, 99))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
6020	31258756	Overexpression of VMP1 can induce autophagy.	('autophagy', 'CPA', (34, 43))	('autophagy', 'biological_process', 'GO:0016236', ('34', '43'))	('autophagy', 'biological_process', 'GO:0006914', ('34', '43'))	('VMP1', 'Gene', (18, 22))	('induce', 'PosReg', (27, 33))	('Overexpression', 'Var', (0, 14))	('VMP1', 'Gene', '81671', (18, 22))
6030	31258756	Initiation of autophagy is also activated by phosphatidylinositol 3-phosphate (PI3P), a product of the action of type III PI3K and Vps34.	('autophagy', 'CPA', (14, 23))	('autophagy', 'biological_process', 'GO:0006914', ('14', '23'))	('activated', 'PosReg', (32, 41))	('Vps34', 'Gene', (131, 136))	('PI3K', 'molecular_function', 'GO:0016303', ('122', '126'))	('autophagy', 'biological_process', 'GO:0016236', ('14', '23'))	('Vps34', 'Gene', '5289', (131, 136))	('phosphatidylinositol', 'Var', (45, 65))	('phosphatidylinositol 3-phosphate', 'Chemical', 'MESH:C055525', (45, 77))
6035	31258756	Loss of other autophagy-related regulators also tends to promote tumorigenesis: ATG4C-/- mice exhibit high sensitivity to fibrosarcoma induced by chemical carcinogens; The UVRAG-binding protein BIF1 is a positive regulator of autophagy that interacts with BECN1 and its complete deletion results in spontaneous tumorigenesis in mice; ATG5-/- immortalized neonatal mouse kidney cells (iBMK) and BECN1+/- immortalized mouse mammary epithelial cells (iMMECs), which are deficient in autophagy, are more likely to form tumors in nude mice than autophagy-complete cells; Systemic mosaic deletion of ATG5 and liver-specific deletion of ATG7 can lead to hepatic benign adenoma in autophagy-defective hepatocytes.	('tumor', 'Disease', 'MESH:D009369', (515, 520))	('autophagy', 'biological_process', 'GO:0016236', ('673', '682'))	('ATG7', 'Gene', (630, 634))	('autophagy', 'biological_process', 'GO:0006914', ('14', '23'))	('autophagy', 'biological_process', 'GO:0006914', ('226', '235'))	('deletion', 'Var', (582, 590))	('tumors', 'Phenotype', 'HP:0002664', (515, 521))	('hepatic benign adenoma', 'Disease', 'MESH:C564190', (647, 669))	('mice', 'Species', '10090', (530, 534))	('nude mice', 'Species', '10090', (525, 534))	('fibrosarcoma', 'Disease', 'MESH:D005354', (122, 134))	('mouse', 'Species', '10090', (364, 369))	('tumor', 'Disease', (65, 70))	('fibrosarcoma', 'Disease', (122, 134))	('tumor', 'Phenotype', 'HP:0002664', (515, 520))	('autophagy', 'biological_process', 'GO:0006914', ('673', '682'))	('tumors', 'Disease', (515, 521))	('protein', 'cellular_component', 'GO:0003675', ('186', '193'))	('lead to', 'Reg', (639, 646))	('BIF1', 'Gene', (194, 198))	('deletion', 'Var', (618, 626))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (311, 316))	('binding', 'molecular_function', 'GO:0005488', ('178', '185'))	('mice', 'Species', '10090', (328, 332))	('BIF1', 'Gene', '268294', (194, 198))	('ATG4C', 'Gene', (80, 85))	('ATG7', 'Gene', '74244', (630, 634))	('UVRAG', 'Gene', '7405', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('autophagy', 'biological_process', 'GO:0016236', ('480', '489'))	('tumors', 'Disease', 'MESH:D009369', (515, 521))	('autophagy', 'biological_process', 'GO:0016236', ('540', '549'))	('UVRAG', 'Gene', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('autophagy', 'biological_process', 'GO:0016236', ('14', '23'))	('autophagy', 'biological_process', 'GO:0016236', ('226', '235'))	('ATG5', 'Gene', (594, 598))	('mouse', 'Species', '10090', (416, 421))	('mice', 'Species', '10090', (89, 93))	('hepatic benign adenoma', 'Disease', (647, 669))	('tumor', 'Disease', (515, 520))	('ATG4C', 'Gene', '242557', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (122, 134))	('autophagy', 'biological_process', 'GO:0006914', ('480', '489'))	('autophagy', 'biological_process', 'GO:0006914', ('540', '549'))
6037	31258756	Degenhardt et al found that autophagic defects impair the viability of apoptosis-deficient mouse cells in the absence of growth factors and in metabolic stress state.	('viability', 'CPA', (58, 67))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('autophagic', 'CPA', (28, 38))	('defects', 'Var', (39, 46))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('mouse', 'Species', '10090', (91, 96))	('impair', 'NegReg', (47, 53))
6040	31258756	Some researchers believe that autophagy plays an important role in the survival of tumor cells in the treatment of tumor radiotherapy and chemotherapy, and inhibition of autophagy improves the sensitivity of tumors to treatment.	('inhibition', 'Var', (156, 166))	('autophagy', 'biological_process', 'GO:0016236', ('170', '179'))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', (115, 120))	('autophagy', 'biological_process', 'GO:0006914', ('30', '39'))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('improves', 'PosReg', (180, 188))	('autophagy', 'biological_process', 'GO:0006914', ('170', '179'))	('tumor', 'Disease', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('autophagy', 'CPA', (170, 179))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('autophagy', 'biological_process', 'GO:0016236', ('30', '39'))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))
6042	31258756	This bidirectional effect may be related to the following factors: a. tumor stage, such as the initial stage, advanced stage, metastatic stage, or gradual drug resistance stage; b. the tissue type of the tumor; c. genetic changes of the tumor.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('drug resistance', 'biological_process', 'GO:0009315', ('155', '170'))	('drug resistance', 'Phenotype', 'HP:0020174', (155, 170))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (70, 75))	('drug resistance', 'biological_process', 'GO:0042493', ('155', '170'))	('genetic changes', 'Var', (214, 229))	('tumor', 'Disease', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
6047	31258756	Many cases, such as tumor suppressor gene of phosphatase and tensin homolog (PTEN) and tuberous sclerosis complex (TSC) 1 and TSC2 deletions, type I PI3K mutations, AKT overexpression, sustained activation of tyrosine kinase growth factor receptors and so on, will lead to the abnormal activation of this signaling pathway and ultimately inhibit the autophagy process.	('TSC2', 'Gene', '7249', (126, 130))	('autophagy', 'biological_process', 'GO:0006914', ('350', '359'))	('TSC', 'Gene', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('PTEN', 'Gene', (77, 81))	('deletions', 'Var', (131, 140))	('TSC', 'Gene', '7248;7249', (126, 129))	('PI3K', 'molecular_function', 'GO:0016303', ('149', '153'))	('AKT', 'Gene', (165, 168))	('PI3K mutations', 'Var', (149, 163))	('TSC2', 'Gene', (126, 130))	('PTEN', 'Gene', '5728', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TSC', 'Gene', (115, 118))	('overexpression', 'PosReg', (169, 183))	('inhibit', 'NegReg', (338, 345))	('tyrosine', 'Protein', (209, 217))	('activation', 'PosReg', (286, 296))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (87, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('20', '36'))	('TSC', 'Gene', '7248;7249', (115, 118))	('AKT', 'Gene', '207', (165, 168))	('signaling pathway', 'biological_process', 'GO:0007165', ('305', '322'))	('phosphatase', 'molecular_function', 'GO:0016791', ('45', '56'))	('autophagy process', 'CPA', (350, 367))	('tuberous sclerosis', 'Disease', (87, 105))	('autophagy', 'biological_process', 'GO:0016236', ('350', '359'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('20', '36'))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('45', '75'))	('activation', 'PosReg', (195, 205))	('mutations', 'Var', (154, 163))	('tuberous sclerosis complex', 'cellular_component', 'GO:0033596', ('87', '113'))	('tumor', 'Disease', (20, 25))
6049	31258756	Inhibiting the PI3K signaling axis will have an adverse effect on rapidly proliferating tumor cells, thereby inhibiting tumor growth.	('PI3K', 'molecular_function', 'GO:0016303', ('15', '19'))	('inhibiting', 'NegReg', (109, 119))	('Inhibiting', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('PI3K signaling', 'biological_process', 'GO:0014065', ('15', '29'))	('PI3K signaling axis', 'Pathway', (15, 34))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (120, 125))
6050	31258756	Sourbier et al found that the increased phosphorylation of AKT at S473 and T308 increased the expression of AKT in 7 types of renal cancer cell lines (786-O, UOK-126, UOK-128, A498, ACHN, Caki-1, and Caki-2), whereas the expression of AKT was positively correlated with the expression of PI3K and inversely correlated with the expression of PTEN.	('PI3K', 'Disease', (288, 292))	('renal cancer', 'Disease', (126, 138))	('PTEN', 'Gene', '5728', (341, 345))	('renal cancer', 'Phenotype', 'HP:0009726', (126, 138))	('increased', 'PosReg', (30, 39))	('phosphorylation', 'MPA', (40, 55))	('renal cancer', 'Disease', 'MESH:D007680', (126, 138))	('AKT', 'Gene', (108, 111))	('Caki-1', 'CellLine', 'CVCL:0234', (188, 194))	('AKT', 'Gene', (235, 238))	('T308', 'Var', (75, 79))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('AKT', 'Gene', (59, 62))	('expression', 'MPA', (94, 104))	('PI3K', 'molecular_function', 'GO:0016303', ('288', '292'))	('AKT', 'Gene', '207', (108, 111))	('PTEN', 'Gene', (341, 345))	('AKT', 'Gene', '207', (235, 238))	('increased', 'PosReg', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('AKT', 'Gene', '207', (59, 62))	('UOK-126', 'CellLine', 'CVCL:B108', (158, 165))
6051	31258756	To confirm whether the PI3K/AKT pathway is involved in renal tumor cell proliferation, the team treated the 786-O and Caki-1 cell lines with the specific PI3K inhibitor LY294002 and found that the number of cell deaths was significantly increased compared to the control group, and the difference was statistically significant (P<0.05).	('increased', 'PosReg', (237, 246))	('Caki-1', 'CellLine', 'CVCL:0234', (118, 124))	('LY294002', 'Chemical', 'MESH:C085911', (169, 177))	('AKT', 'Gene', (28, 31))	('renal tumor', 'Disease', 'MESH:D007674', (55, 66))	('renal tumor', 'Phenotype', 'HP:0009726', (55, 66))	('PI3K', 'molecular_function', 'GO:0016303', ('154', '158'))	('LY294002', 'Var', (169, 177))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('cell deaths', 'CPA', (207, 218))	('PI3K', 'molecular_function', 'GO:0016303', ('23', '27'))	('renal tumor', 'Disease', (55, 66))	('AKT', 'Gene', '207', (28, 31))
6052	31258756	Seo et al found that co-treatment with PP242 (inhibitor of mTORC1 and mTORC2) and curcumin induced the downregulation of the Rictor (an mTORC2 complex protein) and AKT protein levels, which led to lysosomal damage and induced autophagy in renal carcinoma cells.	('Rictor', 'MPA', (125, 131))	('autophagy in renal carcinoma', 'Disease', (226, 254))	('autophagy', 'biological_process', 'GO:0006914', ('226', '235'))	('induced', 'Reg', (218, 225))	('mTORC2', 'Gene', (136, 142))	('mTORC1', 'cellular_component', 'GO:0031931', ('59', '65'))	('mTORC1', 'Gene', (59, 65))	('AKT', 'Gene', (164, 167))	('mTORC2', 'cellular_component', 'GO:0031932', ('70', '76'))	('mTORC1', 'Gene', '382056', (59, 65))	('led to', 'Reg', (190, 196))	('curcumin', 'Chemical', 'MESH:D003474', (82, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('PP242', 'Chemical', 'MESH:C572919', (39, 44))	('mTORC2', 'Gene', '74343', (136, 142))	('mTORC2', 'Gene', (70, 76))	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('autophagy in renal carcinoma', 'Disease', 'MESH:C538614', (226, 254))	('AKT', 'Gene', '207', (164, 167))	('lysosomal damage', 'CPA', (197, 213))	('mTORC2', 'Gene', '74343', (70, 76))	('autophagy', 'biological_process', 'GO:0016236', ('226', '235'))	('PP242', 'Var', (39, 44))	('mTORC2', 'cellular_component', 'GO:0031932', ('136', '142'))	('renal carcinoma', 'Phenotype', 'HP:0005584', (239, 254))	('downregulation', 'NegReg', (103, 117))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))
6053	31258756	The authors believe that this results reveal that combined PP242 and curcumin treatment could induce autophagy-mediated cell death in renal cancer.	('autophagy', 'biological_process', 'GO:0006914', ('101', '110'))	('renal cancer', 'Disease', 'MESH:D007680', (134, 146))	('renal cancer', 'Phenotype', 'HP:0009726', (134, 146))	('autophagy-mediated cell death', 'CPA', (101, 130))	('induce', 'PosReg', (94, 100))	('cell death', 'biological_process', 'GO:0008219', ('120', '130'))	('PP242', 'Var', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('curcumin', 'Chemical', 'MESH:D003474', (69, 77))	('renal cancer', 'Disease', (134, 146))	('autophagy', 'biological_process', 'GO:0016236', ('101', '110'))	('PP242', 'Chemical', 'MESH:C572919', (59, 64))
6058	31258756	However, some studies have found that removal of p53 in the cytoplasm via gene or drug pathways can induce autophagy, indicating that extranuclear p53 is an effective inhibitor of autophagy.	('autophagy', 'biological_process', 'GO:0016236', ('107', '116'))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('removal', 'Var', (38, 45))	('autophagy', 'CPA', (107, 116))	('autophagy', 'biological_process', 'GO:0006914', ('107', '116'))	('induce', 'Reg', (100, 106))	('p53', 'Gene', '7157', (147, 150))	('autophagy', 'biological_process', 'GO:0016236', ('180', '189'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('60', '69'))	('autophagy', 'biological_process', 'GO:0006914', ('180', '189'))	('p53', 'Gene', (147, 150))
6061	31258756	But a study found that RCC cells can survive and grow by inactivating p53 through TGase-2 mediated autophagy, which supplies recycled amino acids and bases under condition of starvation.	('autophagy', 'biological_process', 'GO:0016236', ('99', '108'))	('p53', 'Gene', (70, 73))	('TGase-2', 'Gene', (82, 89))	('p53', 'Gene', '7157', (70, 73))	('TGase-2', 'Gene', '7052', (82, 89))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('autophagy', 'biological_process', 'GO:0006914', ('99', '108'))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('inactivating', 'Var', (57, 69))	('RCC', 'Disease', (23, 26))	('autophagy', 'CPA', (99, 108))
6062	31258756	It is surprising that p53 levels are suppressed in RCC, although only 2.7% of RCC samples have p53 alterations in cBioPortal database.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('p53', 'Gene', (22, 25))	('RCC', 'Disease', (78, 81))	('alterations', 'Var', (99, 110))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('p53', 'Gene', '7157', (22, 25))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
6070	31258756	They injected LC3B shRNA lentiviral particles into subcutaneous renal cancer cell 786-O tumors in nude mice and found that the tumor volume was significantly smaller at 9 days than in the control group (P=0.0007).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('subcutaneous renal cancer', 'Disease', 'MESH:D007680', (51, 76))	('smaller', 'NegReg', (158, 165))	('renal cancer', 'Phenotype', 'HP:0009726', (64, 76))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', (127, 132))	('LC3B', 'Var', (14, 18))	('nude mice', 'Species', '10090', (98, 107))	('subcutaneous renal cancer', 'Disease', (51, 76))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', (88, 93))
6076	31258756	They also found that a low level of LC3-II was associated with poor prognosis in ccRCC, indicating that autophagy might be suppressed and associated with progression in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('LC3-II', 'Gene', (36, 42))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('autophagy', 'biological_process', 'GO:0016236', ('104', '113'))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('autophagy', 'CPA', (104, 113))	('low', 'Var', (23, 26))	('suppressed', 'NegReg', (123, 133))	('autophagy', 'biological_process', 'GO:0006914', ('104', '113'))	('associated', 'Reg', (138, 148))	('LC3-II', 'Gene', '84557', (36, 42))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('RCC', 'Disease', (171, 174))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))
6078	31258756	Loss of MAP1S leads to autophagy defects, which can cause mitochondrial dysfunction and affect cell growth.	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (58, 83))	('MAP1S', 'Gene', '55201', (8, 13))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (58, 83))	('MAP1S', 'Gene', (8, 13))	('affect', 'Reg', (88, 94))	('mitochondrial dysfunction', 'Disease', (58, 83))	('cell growth', 'biological_process', 'GO:0016049', ('95', '106'))	('cell growth', 'CPA', (95, 106))	('autophagy defects', 'Disease', 'MESH:C564093', (23, 40))	('cause', 'Reg', (52, 57))	('autophagy defects', 'Disease', (23, 40))	('autophagy', 'biological_process', 'GO:0016236', ('23', '32'))	('Loss', 'Var', (0, 4))	('MAP', 'molecular_function', 'GO:0004239', ('8', '11'))	('autophagy', 'biological_process', 'GO:0006914', ('23', '32'))
6085	31258756	The cumulative survival time of patients with high expression of MAP1S was significantly higher than that of patients with low expression (P<0.01) by plotting Kaplan-Meier curves of ccRCC patients.	('MAP', 'molecular_function', 'GO:0004239', ('65', '68'))	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (109, 117))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('RCC', 'Disease', (184, 187))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('MAP1S', 'Gene', '55201', (65, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (182, 187))	('patients', 'Species', '9606', (188, 196))	('higher', 'PosReg', (89, 95))	('MAP1S', 'Gene', (65, 70))	('high expression', 'Var', (46, 61))
6092	31258756	Fabrizio et al found that the expression level of KEAP1 gene was decreased after promoter methylation, which increased the expression of NRF2 and played an important role in ccRCC.	('KEAP1', 'Gene', (50, 55))	('RCC', 'Disease', (176, 179))	('expression', 'MPA', (123, 133))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('decreased', 'NegReg', (65, 74))	('role', 'Reg', (166, 170))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('ccRCC', 'Phenotype', 'HP:0006770', (174, 179))	('methylation', 'biological_process', 'GO:0032259', ('90', '101'))	('NRF2', 'Gene', '4780', (137, 141))	('KEAP1', 'Gene', '9817', (50, 55))	('promoter methylation', 'Var', (81, 101))	('played', 'Reg', (146, 152))	('increased', 'PosReg', (109, 118))	('expression level', 'MPA', (30, 46))	('NRF2', 'Gene', (137, 141))
6111	31258756	Inhibition of AKT by small molecule inhibitors or genetic modifications can reduce rasfonin-dependent autophagic flux and PARP-1 cleavage.	('genetic modifications', 'Var', (50, 71))	('rasfonin-dependent autophagic flux', 'CPA', (83, 117))	('AKT', 'Gene', (14, 17))	('PARP-1', 'Gene', (122, 128))	('PARP-1', 'Gene', '142', (122, 128))	('reduce', 'NegReg', (76, 82))	('AKT', 'Gene', '207', (14, 17))
6124	31258756	Since inhibition of mTOR could induce autophagy, activation of autophagy may be a key mechanism for everolimus resistance.	('autophagy', 'biological_process', 'GO:0006914', ('38', '47'))	('everolimus', 'Chemical', 'MESH:D000068338', (100, 110))	('induce', 'Reg', (31, 37))	('autophagy', 'biological_process', 'GO:0016236', ('63', '72'))	('autophagy', 'biological_process', 'GO:0006914', ('63', '72'))	('inhibition', 'Var', (6, 16))	('autophagy', 'biological_process', 'GO:0016236', ('38', '47'))	('mTOR', 'Gene', '2475', (20, 24))	('autophagy', 'CPA', (38, 47))	('mTOR', 'Gene', (20, 24))
6128	31258756	CQ/HCQ disrupts the degradation of autophagic proteins and prevents the conversion of LC3B-I to LC3B-II and inhibits the formation of autophagosomes.	('formation of autophagosomes', 'CPA', (121, 148))	('CQ', 'Chemical', 'MESH:D002738', (4, 6))	('degradation', 'biological_process', 'GO:0009056', ('20', '31'))	('degradation of autophagic proteins', 'MPA', (20, 54))	('inhibits', 'NegReg', (108, 116))	('disrupts', 'NegReg', (7, 15))	('prevents', 'NegReg', (59, 67))	('HCQ', 'Chemical', 'MESH:D006886', (3, 6))	('LC3B-I', 'Protein', (86, 92))	('formation', 'biological_process', 'GO:0009058', ('121', '130'))	('conversion', 'MPA', (72, 82))	('CQ/HCQ', 'Var', (0, 6))	('CQ', 'Chemical', 'MESH:D002738', (0, 2))
6145	30648791	The Von Hippel-Lindau-deficient cells expressing FTO restores mitochondrial activity, induces oxidative stress and ROS production and shows impaired tumour growth, through increasing expression of PGC-1alpha by reducing m6A levels in its mRNA transcripts.	('oxidative stress', 'MPA', (94, 110))	('restores', 'PosReg', (53, 61))	('impaired tumour growth', 'Disease', (140, 162))	('impaired tumour growth', 'Disease', 'MESH:D006130', (140, 162))	('m6A', 'Gene', '56339', (220, 223))	('induces', 'PosReg', (86, 93))	('PGC-1alpha', 'Gene', '10891', (197, 207))	('increasing', 'PosReg', (172, 182))	('ROS production', 'MPA', (115, 129))	('mitochondrial activity', 'MPA', (62, 84))	('expression', 'MPA', (183, 193))	('FTO', 'Var', (49, 52))	('oxidative stress', 'Phenotype', 'HP:0025464', (94, 110))	('m6A', 'Gene', (220, 223))	('PGC-1alpha', 'Gene', (197, 207))	('Von Hippel-Lindau-deficient', 'Disease', (4, 31))	('reducing', 'NegReg', (211, 219))	('Von Hippel-Lindau-deficient', 'Disease', 'MESH:D006623', (4, 31))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('ROS', 'Chemical', 'MESH:D017382', (115, 118))
6179	30648791	The DNA fragments of PGC-1alpha-3'UTR containing the wild-type m6A motifs as well as mutant motifs (m6A was replaced by C) were directly synthesized from GeneCreate (Wuhan, China).	('m6A', 'Gene', (63, 66))	('m6A', 'Gene', '56339', (100, 103))	('m6A', 'Gene', '56339', (63, 66))	('PGC-1alpha', 'Gene', (21, 31))	('PGC-1alpha', 'Gene', '10891', (21, 31))	('mutant', 'Var', (85, 91))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))	('m6A', 'Gene', (100, 103))
6180	30648791	Wild-type and mutant PGC-1alpha-3'UTR were inserted into downstream of firefly luciferase of pMIR-GLO vector38 (pmirGLO Dual-Luciferase miRNA Target Expression Vector; Promega, Madison, WI, USA).	('mutant', 'Var', (14, 20))	('PGC-1alpha', 'Gene', (21, 31))	('PGC-1alpha', 'Gene', '10891', (21, 31))
6181	30648791	For dual-luciferase reporter assay, 100 ng wild-type or mutant PGC-1alpha-3'UTR, 200 ng pCMV3-FTO (or pCMV3-FTO-Mut or pCMV3-flag) were cotransfected into HEK-293T cells in 24-well plate.	('FTO-Mut', 'Gene', (108, 115))	('mutant', 'Var', (56, 62))	('PGC-1alpha', 'Gene', (63, 73))	('FTO-Mut', 'Gene', '79068', (108, 115))	('PGC-1alpha', 'Gene', '10891', (63, 73))	('HEK-293T cells', 'CellLine', 'CVCL:0063', (155, 169))
6182	30648791	The sequences of PGC-1alpha-3'UTR with wild-type and mutant m6A sites were shown in Table S2.	('m6A', 'Gene', (60, 63))	('PGC-1alpha', 'Gene', (17, 27))	('m6A', 'Gene', '56339', (60, 63))	('mutant', 'Var', (53, 59))	('PGC-1alpha', 'Gene', '10891', (17, 27))
6187	30648791	Membranes were blocked for 1 hour with 5% non-fat milk in TBST (Trisbuffered saline containing 0.1% Tween 20) and incubated overnight at 4 C with anti-FTO antibody (ab124892; Abcam, Shanghai, China), anti-beta-actin (3700S; Cell Signal Technology, Danvers, MA, USA), anti-Vinculin (ab129002, Abcam), anti-PGC-1alpha (ab54481, Abcam).	('PGC-1alpha', 'Gene', (305, 315))	('PGC-1alpha', 'Gene', '10891', (305, 315))	('antibody', 'cellular_component', 'GO:0042571', ('155', '163'))	('Tween 20', 'Chemical', 'MESH:D011136', (100, 108))	('Vinculin', 'Gene', (272, 280))	('Vinculin', 'Gene', '7414', (272, 280))	('ab129002', 'Var', (282, 290))	('antibody', 'cellular_component', 'GO:0019815', ('155', '163'))	('TBST', 'Chemical', '-', (58, 62))	('antibody', 'cellular_component', 'GO:0019814', ('155', '163'))	('saline', 'Chemical', 'MESH:D012965', (77, 83))	('antibody', 'molecular_function', 'GO:0003823', ('155', '163'))
6205	30648791	As shown in Figure 2A-E, wild-type FTO, but not the FTO mutant (two point mutations, H231A and D233A, which lead to disruption of the enzymatic activity of FTO40), reduced cell time-dependent proliferation, anchorage-independent growth and increased apoptosis; conversely, FTO knockdown resulted in an increase in cell proliferation and a reduce in apoptosis.	('FTO40', 'Gene', (156, 161))	('increase', 'PosReg', (302, 310))	('apoptosis', 'CPA', (349, 358))	('cell time-dependent proliferation', 'CPA', (172, 205))	('apoptosis', 'biological_process', 'GO:0097194', ('250', '259'))	('apoptosis', 'biological_process', 'GO:0006915', ('250', '259'))	('reduce', 'NegReg', (339, 345))	('FTO', 'Gene', (273, 276))	('D233A', 'Mutation', 'p.D233A', (95, 100))	('increased', 'PosReg', (240, 249))	('apoptosis', 'CPA', (250, 259))	('apoptosis', 'biological_process', 'GO:0097194', ('349', '358'))	('H231A', 'Mutation', 'p.H231A', (85, 90))	('apoptosis', 'biological_process', 'GO:0006915', ('349', '358'))	('cell proliferation', 'biological_process', 'GO:0008283', ('314', '332'))	('reduced', 'NegReg', (164, 171))	('anchorage-independent growth', 'CPA', (207, 235))	('knockdown', 'Var', (277, 286))	('H231A', 'Var', (85, 90))	('D233A', 'Var', (95, 100))	('cell proliferation', 'CPA', (314, 332))
6219	30648791	As expected, luciferase activity of PGC-1alpha 3'-UTR luciferase reporter was significantly increased upon FTO overexpression, while mutations in the m6A sites rendered resistance to the effect of FTO overexpression (Figure 5C).	('luciferase activity', 'molecular_function', 'GO:0045289', ('13', '32'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('13', '32'))	('luciferase activity', 'MPA', (13, 32))	('luciferase activity', 'molecular_function', 'GO:0050397', ('13', '32'))	('PGC-1alpha', 'Gene', (36, 46))	('PGC-1alpha', 'Gene', '10891', (36, 46))	('luciferase activity', 'molecular_function', 'GO:0050248', ('13', '32'))	('m6A', 'Gene', (150, 153))	('increased', 'PosReg', (92, 101))	('mutations', 'Var', (133, 142))	('luciferase activity', 'molecular_function', 'GO:0047077', ('13', '32'))	('m6A', 'Gene', '56339', (150, 153))
6223	30648791	To further explore the role of the FTO-PGC1alpha regulatory axis in ccRCC, we performed the PGC-1alpha knockdown in FTO stably overexpressing 769-P cells, and observed that FTO regulation of oxidative stress and cell proliferation could be largely reversed by PGC-1alpha knockdown (Figure 5E,F).	('PGC-1alpha', 'Gene', (92, 102))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('PGC-1alpha', 'Gene', (260, 270))	('PGC-1alpha', 'Gene', '10891', (92, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('PGC-1alpha', 'Gene', '10891', (260, 270))	('PGC1alpha', 'Gene', (39, 48))	('cell proliferation', 'biological_process', 'GO:0008283', ('212', '230'))	('regulation', 'biological_process', 'GO:0065007', ('177', '187'))	('oxidative stress', 'Phenotype', 'HP:0025464', (191, 207))	('PGC1alpha', 'Gene', '10891', (39, 48))	('knockdown', 'Var', (271, 280))
6225	30648791	Given our results that ectopic FTO expression increased the expression of PGC-1alpha, induction of oxidative stress and suppression of ccRCC growth, which led to our test whether ectopic expression of PGC-1alpha can inhibit ccRCC growth.	('expression', 'MPA', (60, 70))	('PGC-1alpha', 'Gene', '10891', (201, 211))	('PGC-1alpha', 'Gene', (74, 84))	('ectopic', 'Var', (23, 30))	('increased', 'PosReg', (46, 55))	('PGC-1alpha', 'Gene', '10891', (74, 84))	('inhibit', 'NegReg', (216, 223))	('FTO', 'Gene', (31, 34))	('RCC', 'Disease', 'MESH:C538614', (226, 229))	('RCC', 'Disease', (226, 229))	('RCC', 'Disease', (137, 140))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('suppression', 'NegReg', (120, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (224, 229))	('PGC-1alpha', 'Gene', (201, 211))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('expression', 'Var', (35, 45))	('oxidative stress', 'Phenotype', 'HP:0025464', (99, 115))
6236	30648791	Furthermore, we demonstrate that forced expression of FTO in VHL-deficient ccRCC cell lines facilitates mitochondria function depending on its m6A demethylase activity as mutations in the FTO catalytic domain significantly diminish the function of FTO.	('m6A', 'Gene', '56339', (143, 146))	('diminish', 'NegReg', (223, 231))	('function', 'MPA', (236, 244))	('activity', 'MPA', (159, 167))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('mitochondria', 'cellular_component', 'GO:0005739', ('104', '116'))	('FTO', 'Gene', (54, 57))	('VHL-deficient', 'Disease', 'MESH:D006623', (61, 74))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('mitochondria function', 'MPA', (104, 125))	('VHL-deficient', 'Disease', (61, 74))	('FTO', 'Gene', (188, 191))	('mutations', 'Var', (171, 180))	('FTO', 'MPA', (248, 251))	('m6A', 'Gene', (143, 146))	('facilitates', 'PosReg', (92, 103))	('demethylase activity', 'molecular_function', 'GO:0032451', ('147', '167'))
6237	30648791	Remarkably, the increases in mitochondria biogenesis and oxidative phosphorylation upon expression of FTO are correlated with stimulation of oxidative stress in VHL-deficient ccRCC cell lines.	('oxidative stress', 'MPA', (141, 157))	('expression', 'Var', (88, 98))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('RCC', 'Disease', (177, 180))	('mitochondria', 'cellular_component', 'GO:0005739', ('29', '41'))	('mitochondria biogenesis', 'MPA', (29, 52))	('stimulation', 'PosReg', (126, 137))	('FTO', 'Gene', (102, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (175, 180))	('oxidative phosphorylation', 'MPA', (57, 82))	('VHL-deficient', 'Disease', 'MESH:D006623', (161, 174))	('VHL-deficient', 'Disease', (161, 174))	('increases', 'PosReg', (16, 25))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('57', '82'))	('oxidative stress', 'Phenotype', 'HP:0025464', (141, 157))
6238	30648791	Specific mechanically, we demonstrate that FTO post-transcriptionally demethylates and stabilizes PGC-1alpha mRNA.	('PGC-1alpha', 'Gene', (98, 108))	('PGC-1alpha', 'Gene', '10891', (98, 108))	('stabilizes', 'MPA', (87, 97))	('demethylates', 'Var', (70, 82))	('demethylates', 'Chemical', '-', (70, 82))
6244	30648791	One possibility is that m6A modification is dynamic and tissue-specific process, thus performing distinct genetic programs in variant cancer types.	('m6A', 'Gene', (24, 27))	('m6A', 'Gene', '56339', (24, 27))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('modification', 'Var', (28, 40))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
6252	30277889	Reliable Gene Mutation Prediction in Clear Cell Renal Cell Carcinoma through Multi-classifier Multi-objective Radiogenomics Model Genetic studies have identified associations between gene mutations and clear cell renal cell carcinoma (ccRCC).	('ccRCC', 'Phenotype', 'HP:0006770', (235, 240))	('ccRCC', 'Disease', (235, 240))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (213, 233))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (202, 233))	('ccRCC', 'Disease', 'MESH:D002292', (235, 240))	('associations', 'Interaction', (162, 174))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:D002292', (37, 68))	('Carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (48, 68))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (37, 68))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (202, 233))	('RCC', 'Phenotype', 'HP:0005584', (237, 240))	('mutations', 'Var', (188, 197))	('Clear Cell Renal Cell Carcinoma', 'Disease', (37, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('clear cell renal cell carcinoma', 'Disease', (202, 233))
6254	30277889	Additionally, a new similarity-based multi-objective optimization algorithm (SMO) was developed for training the MCMO to predict ccRCC related gene mutations (VHL, PBRM1 and BAP1) using quantitative CT features.	('ccRCC', 'Phenotype', 'HP:0006770', (129, 134))	('mutations', 'Var', (148, 157))	('ccRCC', 'Disease', (129, 134))	('BAP1', 'Gene', (174, 178))	('PBRM1', 'Gene', (164, 169))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('ccRCC', 'Disease', 'MESH:D002292', (129, 134))	('PBRM1', 'Gene', '55193', (164, 169))	('VHL', 'Gene', (159, 162))	('BAP1', 'Gene', '8314', (174, 178))	('VHL', 'Gene', '7428', (159, 162))
6258	30277889	Most cases of ccRCC present with somatic (or germline) inactivating mutations in the von Hippel-Lindau tumor suppressor (VHL) gene, which are generally absent in other cancers.	('VHL', 'Gene', '7428', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('inactivating mutations', 'Var', (55, 77))	('present', 'Reg', (20, 27))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('ccRCC', 'Phenotype', 'HP:0006770', (14, 19))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('tumor suppressor', 'biological_process', 'GO:0051726', ('103', '119'))	('ccRCC', 'Disease', (14, 19))	('cancers', 'Disease', (168, 175))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('von Hippel-Lindau tumor suppressor', 'Gene', '7428', (85, 119))	('ccRCC', 'Disease', 'MESH:D002292', (14, 19))	('von Hippel-Lindau tumor suppressor', 'Gene', (85, 119))	('VHL', 'Gene', (121, 124))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('103', '119'))
6259	30277889	Several other mutations in genes involved in regulating chromatin states, including those in the BRCA1-associated protein 1 (BAP1), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), and lysine (K)-specific demethylase 5C (KDM5C), were recently identified.	('polybromo 1', 'Gene', '55193', (132, 143))	('lysine (K)-specific demethylase 5C', 'Gene', '8242', (190, 224))	('BAP1', 'Gene', '8314', (125, 129))	('BRCA1-associated protein 1', 'Gene', '8314', (97, 123))	('KDM5C', 'Gene', '8242', (226, 231))	('SETD2', 'Gene', '29072', (178, 183))	('polybromo 1', 'Gene', (132, 143))	('BRCA1-associated protein 1', 'Gene', (97, 123))	('chromatin', 'cellular_component', 'GO:0000785', ('56', '65'))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('BAP1', 'Gene', (125, 129))	('KDM5C', 'Gene', (226, 231))	('SETD2', 'Gene', (178, 183))	('PBRM1', 'Gene', (145, 150))	('PBRM1', 'Gene', '55193', (145, 150))	('mutations', 'Var', (14, 23))
6260	30277889	Mutations in BAP1 and SETD2 were found to be associated with advanced stage and poor outcome.	('BAP1', 'Gene', (13, 17))	('SETD2', 'Gene', '29072', (22, 27))	('SETD2', 'Gene', (22, 27))	('associated', 'Reg', (45, 55))	('advanced stage', 'CPA', (61, 75))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (13, 17))
6269	30277889	used CT image features to predict the mutation status of EGFR in non small cell lung cancer (NSCLC).	('small cell lung cancer', 'Phenotype', 'HP:0030357', (69, 91))	('NSCLC', 'Disease', (93, 98))	('non small cell lung cancer', 'Disease', 'MESH:D002289', (65, 91))	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('EGFR', 'Gene', '1956', (57, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('mutation', 'Var', (38, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('non small cell lung cancer', 'Disease', (65, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('EGFR', 'Gene', (57, 61))	('non small cell lung cancer', 'Phenotype', 'HP:0030358', (65, 91))
6273	30277889	For example, the BAP1 mutation was associated with ill-defined tumor margins and calcification.	('tumor', 'Disease', (63, 68))	('calcification', 'Disease', (81, 94))	('mutation', 'Var', (22, 30))	('associated', 'Reg', (35, 45))	('calcification', 'Disease', 'MESH:D002114', (81, 94))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('BAP1', 'Gene', '8314', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('BAP1', 'Gene', (17, 21))
6276	30277889	To overcome the disadvantages of using a single classifier and a single objective function, we sought to develop a multi-classifier multi-objective (MCMO) radiogenomics model predict most mutations in most commonly mutated genes in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (232, 237))	('ccRCC', 'Disease', (232, 237))	('ccRCC', 'Disease', 'MESH:D002292', (232, 237))	('RCC', 'Phenotype', 'HP:0005584', (234, 237))	('mutations', 'Var', (188, 197))
6281	30277889	All 57 patients fulfilled the following criteria: (a) histopathologic diagnosis of ccRCC and exome sequencing, including information on VHL, PBRM1, and BAP1 gene mutations, considered as frequent mutations in ccRCC; (b) availability of images from a pretreatment contrast-enhanced CT including a corticomedullary phase.	('mutations', 'Var', (162, 171))	('RCC', 'Phenotype', 'HP:0005584', (211, 214))	('BAP1', 'Gene', '8314', (152, 156))	('ccRCC', 'Phenotype', 'HP:0006770', (209, 214))	('ccRCC', 'Disease', (209, 214))	('ccRCC', 'Disease', 'MESH:D002292', (83, 88))	('VHL', 'Gene', '7428', (136, 139))	('VHL', 'Gene', (136, 139))	('ccRCC', 'Disease', 'MESH:D002292', (209, 214))	('ccRCC', 'Disease', (83, 88))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('BAP1', 'Gene', (152, 156))	('PBRM1', 'Gene', (141, 146))	('patients', 'Species', '9606', (7, 15))	('PBRM1', 'Gene', '55193', (141, 146))
6290	30277889	Size_P1 is the maximum 3 dimensional diameter of the tumor, measured as the largest pairwise Euclidean distance between the voxels on the surface of the tumor volume; size_P2 and size_P3 are the tumor size along the directions orthogonal to the direction of maximum size (figure 2(b)).	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (195, 200))	('size_P3', 'Var', (179, 186))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Disease', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('size_P2', 'Var', (167, 174))
6293	30277889	For example, we assume two models that predict the VHL gene mutation with the label vector [1, 0].	('VHL', 'Gene', '7428', (51, 54))	('mutation', 'Var', (60, 68))	('VHL', 'Gene', (51, 54))
6294	30277889	Assume that  represents the probability output of true positives and the corresponding true label vector is The similarity of true positives TPsimis defined as:  In gene mutation prediction, j=1 represents mutation, j=2 represents non-mutation, and is the mutation probability.	('j=2', 'Gene', (216, 219))	('j=1', 'Gene', (191, 194))	('non-mutation', 'MPA', (231, 243))	('j=1', 'Gene', '28950', (191, 194))	('mutation', 'Var', (206, 214))	('j=2', 'Gene', '28949', (216, 219))
6298	30277889	A tumor with smaller Kurtosis is more likely to carry a VHL mutation (figure 5(a) and figure 6).	('VHL', 'Gene', (56, 59))	('mutation', 'Var', (60, 68))	('smaller Kurtosis', 'Disease', 'MESH:C564159', (13, 29))	('VHL', 'Gene', '7428', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('tumor', 'Disease', (2, 7))	('smaller Kurtosis', 'Disease', (13, 29))
6301	30277889	Therefore, larger Variance, and smaller Homogeneity were associated with the likelihood that a tumor carried a BAP1 mutation.	('BAP1', 'Gene', '8314', (111, 115))	('mutation', 'Var', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('BAP1', 'Gene', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
6312	30277889	The study of the association between diagnostic imaging features and mutations is a first critical step in the radiogenomics of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('mutations', 'Var', (69, 78))	('ccRCC', 'Disease', (128, 133))	('ccRCC', 'Disease', 'MESH:D002292', (128, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))
6314	30277889	Two hypothesis-generating studies indicated the potential association between individual CT features and mutations of the VHL gene, and also mutations in the PBRM1, BAP1, SETD2 and, KDM5C genes.	('KDM5C', 'Gene', '8242', (182, 187))	('mutations', 'Var', (141, 150))	('BAP1', 'Gene', (165, 169))	('SETD2', 'Gene', '29072', (171, 176))	('PBRM1', 'Gene', (158, 163))	('SETD2', 'Gene', (171, 176))	('VHL', 'Gene', (122, 125))	('mutations', 'Var', (105, 114))	('PBRM1', 'Gene', '55193', (158, 163))	('VHL', 'Gene', '7428', (122, 125))	('KDM5C', 'Gene', (182, 187))	('BAP1', 'Gene', '8314', (165, 169))
6320	30277889	reported that nodular, heterogeneous enhancement and visibility of intratumoral blood vessels in tumors were more common among ccRCCs with underlying VHL mutations.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('VHL', 'Gene', '7428', (150, 153))	('tumors', 'Disease', (97, 103))	('ccRCC', 'Disease', 'MESH:D002292', (127, 132))	('nodular', 'MPA', (14, 21))	('heterogeneous enhancement', 'MPA', (23, 48))	('tumor', 'Disease', (97, 102))	('ccRCC', 'Disease', (127, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('common', 'Reg', (114, 120))	('tumor', 'Disease', (72, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('VHL', 'Gene', (150, 153))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('mutations', 'Var', (154, 163))
6321	30277889	Also, investigators found an association between a well-defined tumor margin and the VHL mutation, and an association between solid ccRCC and mutations in VHL and PBRM1.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mutations', 'Var', (142, 151))	('VHL', 'Gene', '7428', (155, 158))	('tumor', 'Disease', (64, 69))	('ccRCC', 'Disease', (132, 137))	('association', 'Interaction', (106, 117))	('ccRCC', 'Disease', 'MESH:D002292', (132, 137))	('VHL', 'Gene', (85, 88))	('mutation', 'Var', (89, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('VHL', 'Gene', '7428', (85, 88))	('RCC', 'Phenotype', 'HP:0005584', (134, 137))	('association', 'Interaction', (29, 40))	('PBRM1', 'Gene', (163, 168))	('VHL', 'Gene', (155, 158))	('PBRM1', 'Gene', '55193', (163, 168))
6322	30277889	However, did not observe any imaging characteristics associated with PBRM1 and VHL mutations.	('mutations', 'Var', (83, 92))	('VHL', 'Gene', '7428', (79, 82))	('PBRM1', 'Gene', (69, 74))	('PBRM1', 'Gene', '55193', (69, 74))	('VHL', 'Gene', (79, 82))
6325	30277889	In a study by, the BAP1 mutation was found to be associated with ill-defined tumor margins and calcification.	('associated', 'Reg', (49, 59))	('BAP1', 'Gene', '8314', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('calcification', 'Disease', 'MESH:D002114', (95, 108))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutation', 'Var', (24, 32))	('BAP1', 'Gene', (19, 23))	('tumor', 'Disease', (77, 82))	('calcification', 'Disease', (95, 108))
6331	30277889	Second, recent advances in genetics have led to the identification of several mutations associated with ccRCC, including those involving the VHL, BAP1, PBRM1, SETD2, MUC4 and KDM5C genes.	('PBRM1', 'Gene', '55193', (152, 157))	('ccRCC', 'Disease', 'MESH:D002292', (104, 109))	('VHL', 'Gene', '7428', (141, 144))	('BAP1', 'Gene', '8314', (146, 150))	('MUC4', 'Gene', '4585', (166, 170))	('SETD2', 'Gene', '29072', (159, 164))	('VHL', 'Gene', (141, 144))	('BAP1', 'Gene', (146, 150))	('mutations', 'Var', (78, 87))	('KDM5C', 'Gene', (175, 180))	('MUC4', 'Gene', (166, 170))	('PBRM1', 'Gene', (152, 157))	('KDM5C', 'Gene', '8242', (175, 180))	('associated', 'Reg', (88, 98))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))	('ccRCC', 'Disease', (104, 109))	('SETD2', 'Gene', (159, 164))
6339	30277889	We proposed a multi-classifier multi-objective (MCMO) radiogenomics model that predicts VHL, PBRM1, and BAP1 gene mutations in ccRCC using quantitative CT feature set.	('BAP1', 'Gene', '8314', (104, 108))	('mutations', 'Var', (114, 123))	('VHL', 'Gene', (88, 91))	('BAP1', 'Gene', (104, 108))	('VHL', 'Gene', '7428', (88, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('ccRCC', 'Disease', (127, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('PBRM1', 'Gene', (93, 98))	('ccRCC', 'Disease', 'MESH:D002292', (127, 132))	('PBRM1', 'Gene', '55193', (93, 98))
6346	30334016	The median ages of the patients with positive and negative EPO expression were 56.2 years and 66.6 years.	('positive', 'Var', (37, 45))	('patients', 'Species', '9606', (23, 31))	('EPO', 'Gene', '2056', (59, 62))	('negative', 'NegReg', (50, 58))	('EPO', 'Gene', (59, 62))
6349	30334016	In a multivariate analysis, the absence of EPO expression proved to be a bad prognostic factor and negatively affected the OS (p < 0.001) and DSS (p < 0.001) rates.	('DSS', 'CPA', (142, 145))	('EPO', 'Gene', '2056', (43, 46))	('absence', 'Var', (32, 39))	('DSS', 'Chemical', '-', (142, 145))	('EPO', 'Gene', (43, 46))	('affected', 'Reg', (110, 118))	('negatively', 'NegReg', (99, 109))	('OS', 'Chemical', '-', (123, 125))
6350	30334016	The absence of tumour EPO expression is an independent predictive factor with a negative effect on survival rates.	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('tumour', 'Disease', (15, 21))	('EPO', 'Gene', (22, 25))	('absence', 'Var', (4, 11))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('negative', 'NegReg', (80, 88))	('EPO', 'Gene', '2056', (22, 25))
6410	30334016	In addition to these factors, negativity for EPO expression remained an independent predictor of the risk of death, and negatively affected OS (HR 9.67; 95% CI 3.45-27.10; p < 0.001) and DSS (HR 9.54; 95% CI 3.04-29.92; p < 0.001) (Table 2).	('EPO', 'Gene', (45, 48))	('negativity', 'Var', (30, 40))	('death', 'Disease', 'MESH:D003643', (109, 114))	('death', 'Disease', (109, 114))	('EPO', 'Gene', '2056', (45, 48))	('DSS', 'MPA', (187, 190))	('DSS', 'Chemical', '-', (187, 190))	('OS', 'Chemical', '-', (140, 142))	('negatively', 'NegReg', (120, 130))	('affected', 'Reg', (131, 139))
6413	30334016	In addition to hypoxia, another mechanism that leads to the stabilisation of HIF-1alpha in the cytoplasm, with the subsequent increased production of these angiogenic factors, occurs via VHL gene deletions and methylation.	('hypoxia', 'Disease', (15, 22))	('production of', 'MPA', (136, 149))	('hypoxia', 'Disease', 'MESH:D000860', (15, 22))	('HIF-1alpha', 'Gene', '3091', (77, 87))	('stabilisation', 'MPA', (60, 73))	('cytoplasm', 'cellular_component', 'GO:0005737', ('95', '104'))	('deletions', 'Var', (196, 205))	('VHL', 'Disease', (187, 190))	('methylation', 'Var', (210, 221))	('VHL', 'Disease', 'MESH:D006623', (187, 190))	('HIF-1alpha', 'Gene', (77, 87))	('increased', 'PosReg', (126, 135))	('methylation', 'biological_process', 'GO:0032259', ('210', '221'))
6430	30334016	The proportion of patients who were positive for EPO expression was greater in patients with incidental tumours, in those with a KPS>=80, in those whose tumours were <7.0 cm, in those with a pre-operative haemoglobin level>=12 g/dl and in those not transfused at the time of nephrectomy.	('tumours', 'Disease', 'MESH:D009369', (153, 160))	('pre', 'molecular_function', 'GO:0003904', ('191', '194'))	('EPO', 'Gene', (49, 52))	('tumours', 'Disease', (153, 160))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('EPO', 'Gene', '2056', (49, 52))	('KPS>=80', 'Var', (129, 136))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('patients', 'Species', '9606', (79, 87))	('patients', 'Species', '9606', (18, 26))	('tumours', 'Phenotype', 'HP:0002664', (153, 160))	('tumours', 'Disease', 'MESH:D009369', (104, 111))	('tumours', 'Disease', (104, 111))	('greater', 'PosReg', (68, 75))
6438	30334016	reported that the risk of death in patients positive for EPO expression was approximately twice as high as that for patients who were negative for expression (HR 2.34; 95% CI 1.27-4.3; p = 0.006).	('death', 'Disease', 'MESH:D003643', (26, 31))	('EPO', 'Gene', '2056', (57, 60))	('patients', 'Species', '9606', (116, 124))	('death', 'Disease', (26, 31))	('expression', 'Var', (61, 71))	('EPO', 'Gene', (57, 60))	('patients', 'Species', '9606', (35, 43))
6441	30334016	Moreover, the multivariate analysis indicated that negativity for EPO expression remained an independent predictor of worse DSS and OS rates.	('OS rates', 'CPA', (132, 140))	('OS', 'Chemical', '-', (132, 134))	('DSS', 'Chemical', '-', (124, 127))	('DSS', 'Disease', (124, 127))	('EPO', 'Gene', '2056', (66, 69))	('negativity', 'Var', (51, 61))	('EPO', 'Gene', (66, 69))
6505	28256615	To identify the latent pairwise relationships among the radiomic features, microvascular density and VEGF, we constructed three data set matrices: (1) RF for radiomic features; (2) MVD for microvascular density; (3) VEGFset.	('VEGF', 'Gene', (101, 105))	('VEGF', 'Gene', '7422', (216, 220))	('MVD', 'Var', (181, 184))	('VEGF', 'Gene', '7422', (101, 105))	('VEGF', 'Gene', (216, 220))
6517	28256615	In Figs 3, 4, 5, 6, it can be observed that the effects of DCE, Dixon_F and PET of RF dominate all four pairs of canonical components.	('Dixon_F', 'Gene', (64, 71))	('DCE', 'Var', (59, 62))	('DCE', 'Chemical', '-', (59, 62))
6528	28256615	The effects of VEGF-B on pathological angiogenesis were less pronounced, and the deficiency of VEGF-B in mice does not impair angiogenesis in normal development.	('deficiency', 'Var', (81, 91))	('VEGF-B', 'Gene', (95, 101))	('men', 'Species', '9606', (156, 159))	('angiogenesis', 'biological_process', 'GO:0001525', ('38', '50'))	('mice', 'Species', '10090', (105, 109))	('angiogenesis', 'biological_process', 'GO:0001525', ('126', '138'))
6606	30459061	We performed logistic regression analyses to identify risk factors for diagnosis of RCC at a younger age (<50), and race/ethnicity and obesity were independently associated with an increased odds of diagnosis at younger age (Table 2).	('obesity', 'Disease', 'MESH:D009765', (135, 142))	('obesity', 'Disease', (135, 142))	('race/ethnicity', 'Var', (116, 130))	('associated', 'Reg', (162, 172))	('RCC', 'Disease', 'MESH:D002292', (84, 87))	('RCC', 'Disease', (84, 87))	('obesity', 'Phenotype', 'HP:0001513', (135, 142))
6673	29138263	Previously, it has been reported that SREBPs are associated with aberrant lipid metabolism required for tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('aberrant', 'Var', (65, 73))	('associated', 'Reg', (49, 59))	('tumor', 'Disease', (104, 109))	('SREBPs', 'Disease', (38, 44))	('aberrant lipid metabolism', 'Phenotype', 'HP:0003119', (65, 90))	('lipid', 'Chemical', 'MESH:D008055', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('lipid metabolism', 'biological_process', 'GO:0006629', ('74', '90'))
6683	29138263	To date, it has been established that the primary etiology of ccRCC is resulted from inactivation of von Hippel-Lindau (VHL) tumor suppressor gene and the consequent activation of hypoxia-inducible factor (HIF).	('activation', 'PosReg', (166, 176))	('inactivation', 'Var', (85, 97))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('hypoxia', 'Disease', 'MESH:D000860', (180, 187))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (101, 130))	('tumor suppressor', 'biological_process', 'GO:0051726', ('125', '141'))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('ccRCC', 'Disease', (62, 67))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('125', '141'))	('hypoxia', 'Disease', (180, 187))
6690	29138263	Spontaneous deletion of VHL is the most common cause of hereditary and sporadic forms of ccRCC.	('VHL', 'Gene', '7428', (24, 27))	('cause', 'Reg', (47, 52))	('Spontaneous deletion', 'Var', (0, 20))	('ccRCC', 'Disease', (89, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (89, 94))	('VHL', 'Gene', (24, 27))
6697	29138263	First, they show that low level of RNF20 is significantly associated with poor prognosis in ccRCC patients, regardless of VHL mutation status.	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RNF20', 'Gene', (35, 40))	('associated', 'Reg', (58, 68))	('ccRCC', 'Disease', (92, 97))	('patients', 'Species', '9606', (98, 106))	('VHL', 'Gene', (122, 125))	('VHL', 'Gene', '7428', (122, 125))	('low level', 'Var', (22, 31))
6722	29138263	Recently, it has been demonstrated that epigenetic regulation of certain genes is important during the tumorigenic and metabolic processes.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('regulation', 'biological_process', 'GO:0065007', ('51', '61'))	('tumor', 'Disease', (103, 108))	('metabolic processes', 'CPA', (119, 138))	('important', 'Reg', (82, 91))	('epigenetic regulation', 'Var', (40, 61))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
6764	31375000	The median s-APEX1 concentrations of the HCC, CC, ccRCC, healthy control, and HBV DNA (+) groups were 0.294, 0.710, 0.474, 0.038, and 2.384 ng/mL, respectively (p < 0.001).	('APEX', 'cellular_component', 'GO:0097683', ('13', '17'))	('ccRCC', 'Phenotype', 'HP:0006770', (50, 55))	('0.474', 'Var', (116, 121))	('CC', 'Phenotype', 'HP:0030153', (42, 44))	('HCC', 'Gene', (41, 44))	('CC', 'Phenotype', 'HP:0030153', (53, 55))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('APEX1', 'Gene', '328', (13, 18))	('CC', 'Phenotype', 'HP:0030153', (46, 48))	('HCC', 'Gene', '619501', (41, 44))	('HCC', 'Phenotype', 'HP:0001402', (41, 44))	('0.710', 'Var', (109, 114))	('APEX1', 'Gene', (13, 18))	('0.038', 'Var', (123, 128))
6814	31375000	Multivariate analysis with other clinicopathological values including age, sex, HBV infection, cirrhosis, histologic grading, and pathologic TNM staging showed that cytoplasmic APEX1 expression in HCC and CC cells is also a predictor of a shorter DFS period (p = 0.009 and p = 0.011, respectively) (Table 5 and Table 6).	('APEX1', 'Gene', '328', (177, 182))	('HCC', 'Gene', '619501', (197, 200))	('cirrhosis', 'Phenotype', 'HP:0001394', (95, 104))	('cirrhosis', 'Disease', 'MESH:D005355', (95, 104))	('CC', 'Phenotype', 'HP:0030153', (205, 207))	('HCC', 'Phenotype', 'HP:0001402', (197, 200))	('APEX1', 'Gene', (177, 182))	('DFS period', 'MPA', (247, 257))	('CC', 'Phenotype', 'HP:0030153', (198, 200))	('cytoplasmic', 'Var', (165, 176))	('HBV infection', 'Disease', (80, 93))	('APEX', 'cellular_component', 'GO:0097683', ('177', '181'))	('HCC', 'Gene', (197, 200))	('shorter', 'NegReg', (239, 246))	('cirrhosis', 'Disease', (95, 104))	('HBV infection', 'Disease', 'MESH:D006509', (80, 93))
6817	31375000	The average number of copies of APEX1 in the 50 ng cDNA template in the HCC tissue/non-neoplastic hepatic tissue was 10167.76/8.64.	('CC', 'Phenotype', 'HP:0030153', (73, 75))	('APEX1', 'Gene', '328', (32, 37))	('APEX', 'cellular_component', 'GO:0097683', ('32', '36'))	('HCC', 'Phenotype', 'HP:0001402', (72, 75))	('10167.76/8.64', 'Var', (117, 130))	('APEX1', 'Gene', (32, 37))	('HCC', 'Gene', (72, 75))	('neoplastic hepatic tissue', 'Phenotype', 'HP:0002896', (87, 112))	('HCC', 'Gene', '619501', (72, 75))
6823	31375000	The criteria to distinguish the HCC, CC, and ccRCC groups from the healthy control group were >0.1534 ng/mL (sensitivity: 81.4; specificity: 94.9), >0.202 ng/mL (sensitivity: 73.9; specificity: 97.4), and >0.202 ng/mL (sensitivity: 82.5; specificity: 97.4), respectively (Figure 4A-C).	('>0.202 ng/mL', 'Var', (205, 217))	('HCC', 'Gene', '619501', (32, 35))	('CC', 'Phenotype', 'HP:0030153', (33, 35))	('>0.1534 ng/mL', 'Var', (94, 107))	('HCC', 'Phenotype', 'HP:0001402', (32, 35))	('CC', 'Phenotype', 'HP:0030153', (37, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('HCC', 'Gene', (32, 35))	('CC', 'Phenotype', 'HP:0030153', (48, 50))	('>0.202 ng/mL', 'Var', (148, 160))
6824	31375000	The criteria to distinguish the HBV DNA (+) group from the HCC, CC, and ccRCC groups were >0.5517 ng/mL (sensitivity: 93.7; specificity: 89.8), >1.1376 ng/mL (sensitivity: 75.0; specificity: 76.1), and >1.5859 ng/mL (sensitivity: 62.5; specificity: 100.0), respectively (Figure 4D-F).	('HCC', 'Phenotype', 'HP:0001402', (59, 62))	('>0.5517 ng/mL', 'Var', (90, 103))	('>1.1376 ng/mL', 'Var', (144, 157))	('CC', 'Phenotype', 'HP:0030153', (75, 77))	('HCC', 'Gene', (59, 62))	('CC', 'Phenotype', 'HP:0030153', (60, 62))	('CC', 'Phenotype', 'HP:0030153', (64, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('HCC', 'Gene', '619501', (59, 62))	('>1.5859 ng/mL', 'Var', (202, 215))
6856	31375000	According to the TCGA database, the correlation between mRNA expression level and ccRCC patient survival rate was lower in the low-expression ccRCC patients than in the high-expression patients .	('patients', 'Species', '9606', (148, 156))	('patient', 'Species', '9606', (88, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('ccRCC', 'Disease', (82, 87))	('low-expression', 'Var', (127, 141))	('CC', 'Phenotype', 'HP:0030153', (145, 147))	('patient', 'Species', '9606', (185, 192))	('mRNA expression level', 'MPA', (56, 77))	('CC', 'Phenotype', 'HP:0030153', (85, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('lower', 'NegReg', (114, 119))	('patients', 'Species', '9606', (185, 193))	('patient', 'Species', '9606', (148, 155))	('ccRCC', 'Disease', (142, 147))
6885	30008862	Previous studies have demonstrated that mutations of VHL are significant drivers of ccRCC by regulating various biological processes, and VHL alterations are considered as prognostic markers in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('VHL', 'Gene', '7428', (138, 141))	('VHL', 'Gene', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (196, 199))	('VHL', 'Gene', (53, 56))	('mutations', 'Var', (40, 49))	('VHL', 'Gene', '7428', (53, 56))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('RCC', 'Disease', 'MESH:C538614', (196, 199))	('RCC', 'Disease', (196, 199))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('regulating', 'Reg', (93, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (194, 199))
6887	30008862	VHL alterations alone are insufficient to cause the cancer, as ccRCC is a systemic biological disease.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('insufficient', 'Disease', 'MESH:D000309', (26, 38))	('alterations', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('insufficient', 'Disease', (26, 38))	('cause', 'Reg', (42, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('VHL', 'Gene', (0, 3))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('VHL', 'Gene', '7428', (0, 3))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
6888	30008862	Sequencing studies have identified some other specific molecular genetic alterations of ccRCC, such as mutations of TCEB1, PBRM1 and abnormal expression of miR-92, miR-210.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('TCEB1', 'Gene', '6921', (116, 121))	('mutations', 'Var', (103, 112))	('miR-92', 'Gene', (156, 162))	('TCEB1', 'Gene', (116, 121))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('PBRM1', 'Gene', (123, 128))	('miR-210', 'Gene', (164, 171))	('PBRM1', 'Gene', '55193', (123, 128))	('miR-92', 'Gene', '407047', (156, 162))	('expression', 'MPA', (142, 152))	('miR-210', 'Gene', '406992', (164, 171))	('RCC', 'Disease', (90, 93))
6913	30008862	The results showed that patients in the high mRNA expression group for ENO2 had significantly worse OS than those in the low/medium expression group (P=0.023) (Fig.	('high mRNA expression', 'Var', (40, 60))	('ENO2', 'Gene', (71, 75))	('OS', 'Chemical', '-', (100, 102))	('worse', 'NegReg', (94, 99))	('patients', 'Species', '9606', (24, 32))	('ENO2', 'Gene', '2026', (71, 75))
6914	30008862	While high mRNA expression level of CCND1 was associated with longer OS for ccRCC patients (P=0.000), as well as FLT1 (P=0.004), PLG (P=0.000), and VWF (P=0.008) (Fig.	('OS', 'Chemical', '-', (69, 71))	('patients', 'Species', '9606', (82, 90))	('CCND1', 'Gene', (36, 41))	('PLG', 'Gene', (129, 132))	('mRNA expression level', 'MPA', (11, 32))	('RCC', 'Disease', (78, 81))	('VWF', 'Gene', '7450', (148, 151))	('FLT1', 'Gene', (113, 117))	('high', 'Var', (6, 10))	('PLG', 'Gene', '5340', (129, 132))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('CCND1', 'Gene', '595', (36, 41))	('VWF', 'Gene', (148, 151))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('FLT1', 'Gene', '2321', (113, 117))
6942	30008862	Interestingly, our results showed that high expression of CCND1 was associated with favorable prognosis in ccRCC.	('CCND1', 'Gene', '595', (58, 63))	('high expression', 'Var', (39, 54))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('CCND1', 'Gene', (58, 63))
6946	30008862	The importance of VEGF in RCC progression is well established and several VEGFR inhibitors such as sunitinib and sorafenib have proven to be significantly beneficial for progression-free survival (PFS) and OS in phase 3 trials.	('VEGF', 'Gene', '7422', (74, 78))	('OS', 'Chemical', '-', (206, 208))	('beneficial', 'PosReg', (155, 165))	('VEGFR', 'Gene', (74, 79))	('RCC', 'Disease', (26, 29))	('VEGF', 'Gene', (74, 78))	('VEGF', 'Gene', '7422', (18, 22))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('progression-free survival', 'CPA', (170, 195))	('sorafenib', 'Chemical', 'MESH:D000077157', (113, 122))	('VEGF', 'Gene', (18, 22))	('VEGFR', 'Gene', '3791', (74, 79))	('sunitinib', 'Chemical', 'MESH:D000077210', (99, 108))	('inhibitors', 'Var', (80, 90))
6985	30972853	Mutations or deletions in the tumor suppressor von Hippel-Lindau gene (VHL) have been frequently observed in RCC.	('observed', 'Reg', (97, 105))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (47, 64))	('VHL', 'Gene', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('deletions', 'Var', (13, 22))	('VHL', 'Gene', '7428', (71, 74))	('RCC', 'Disease', (109, 112))	('Mutations', 'Var', (0, 9))	('von Hippel-Lindau', 'Disease', (47, 64))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('tumor', 'Disease', (30, 35))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))
7002	30972853	Human ccRCC cells harboring mutant VHL, OS-RC-2 (RIKEN Cell Bank, Ibaraki, Japan) and human ccRCC cells harboring wild-type VHL, Caki-1 (Cell Resource Center for Biomedical Research, Tohoku University, Miyagi, Japan) were cultured in RPMI-1640 medium (Thermo Fisher Scientific, Waltham, MA, USA) and minimum essential medium (MEM; Thermo Fisher Scientific) containing 10% FBS, 100 U/mL penicillin, and 100 mug/mL streptomycin, respectively.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('Human', 'Species', '9606', (0, 5))	('RCC', 'Disease', (8, 11))	('RCC', 'Disease', (94, 97))	('mutant', 'Var', (28, 34))	('VHL', 'Gene', '7428', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('human', 'Species', '9606', (86, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (6, 11))	('OS-RC-2', 'CellLine', 'CVCL:1626', (40, 47))	('Caki-1', 'CellLine', 'CVCL:0234', (129, 135))	('VHL', 'Gene', (35, 38))	('VHL', 'Gene', '7428', (35, 38))	('VHL', 'Gene', (124, 127))	('mug', 'molecular_function', 'GO:0043739', ('406', '409'))
7014	30972853	Immunoblotting was carried out as previously described.10 Antibodies against c-Ski (#A303-518A; Bethyl Laboratories, Montgomery, TX, USA), Noggin (4C9; Sigma-Aldrich), and HA (3F10; Sigma-Aldrich) were used as primary antibodies.	('Noggin', 'Gene', '9241', (139, 145))	('c-Ski', 'Gene', '6497', (77, 82))	('Noggin', 'Gene', (139, 145))	('#A303-518A;', 'Var', (84, 95))	('c-Ski', 'Gene', (77, 82))	('rat', 'Species', '10116', (107, 110))
7036	30972853	Bioluminescence imaging analyses showed that injection of Caki-1-c-Ski cells also led to the formation of larger tumors than injection of Caki-1-GFP cells (Figure 3D,E).	('Bioluminescence', 'biological_process', 'GO:0008218', ('0', '15'))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('Caki-1-c-Ski', 'CellLine', 'CVCL:0234', (58, 70))	('formation', 'biological_process', 'GO:0009058', ('93', '102'))	('Caki-1', 'CellLine', 'CVCL:0234', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('Caki-1-c-Ski', 'Var', (58, 70))	('Caki-1', 'CellLine', 'CVCL:0234', (138, 144))
7043	30972853	In vivo and ex vivo bioluminescence imaging experiments showed that primary tumor formation caused by OS-RC-2 cells was accelerated by the introduction of dnTbetaRII (Figure 4C,D).	('dnTbetaRII', 'Gene', (155, 165))	('bioluminescence', 'biological_process', 'GO:0008218', ('20', '35'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('introduction', 'Var', (139, 151))	('accelerated', 'PosReg', (120, 131))	('dnTbetaRII', 'Chemical', '-', (155, 165))	('formation', 'biological_process', 'GO:0009058', ('82', '91'))	('OS-RC-2', 'CellLine', 'CVCL:1626', (102, 109))	('rat', 'Species', '10116', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
7044	30972853	Moreover, ex vivo bioluminescence imaging showed that OS-RC-2-dnTbetaRII cells caused metastasis in the lung, which was rarely observed in OS-RC-2-GFP-xenografted mice (Figure 4E).	('bioluminescence', 'biological_process', 'GO:0008218', ('18', '33'))	('caused', 'Reg', (79, 85))	('OS-RC-2', 'CellLine', 'CVCL:1626', (139, 146))	('OS-RC-2', 'CellLine', 'CVCL:1626', (54, 61))	('OS-RC-2-dnTbetaRII cells', 'Var', (54, 78))	('dnTbetaRII', 'Chemical', '-', (62, 72))	('mice', 'Species', '10090', (163, 167))	('metastasis in the lung', 'CPA', (86, 108))
7046	30972853	TGF-beta signal transduction was inhibited by the introduction of dnTbetaRII in Caki-1 cells (Figure 5A,B).	('Caki-1', 'CellLine', 'CVCL:0234', (80, 86))	('signal transduction', 'biological_process', 'GO:0007165', ('9', '28'))	('inhibited', 'NegReg', (33, 42))	('introduction', 'Var', (50, 62))	('TGF-beta', 'Gene', '7040', (0, 8))	('dnTbetaRII', 'Chemical', '-', (66, 76))	('dnTbetaRII', 'Gene', (66, 76))	('TGF-beta', 'Gene', (0, 8))
7047	30972853	Primary tumor formation by Caki-1 cells was enhanced by dnTbetaRII (Figure 5C,D).	('Caki-1', 'CellLine', 'CVCL:0234', (27, 33))	('Primary tumor', 'Disease', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('dnTbetaRII', 'Chemical', '-', (56, 66))	('formation', 'biological_process', 'GO:0009058', ('14', '23'))	('Primary tumor', 'Disease', 'MESH:D009369', (0, 13))	('dnTbetaRII', 'Var', (56, 66))	('enhanced', 'PosReg', (44, 52))
7070	30972853	Many types of abnormalities in TGF-beta signaling components have been identified in cancers.14 In particular, alterations of Smad4 and TbetaRII, frequently observed in cancers, strongly attenuate TGF-beta signaling.	('cancers', 'Disease', (169, 176))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('TbetaRII', 'Gene', '7048', (136, 144))	('TGF-beta', 'Gene', '7040', (31, 39))	('attenuate', 'NegReg', (187, 196))	('Smad4', 'Gene', '4089', (126, 131))	('cancers', 'Disease', 'MESH:D009369', (169, 176))	('TGF-beta', 'Gene', '7040', (197, 205))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('signaling', 'biological_process', 'GO:0023052', ('40', '49'))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('TGF-beta', 'Gene', (31, 39))	('signaling', 'biological_process', 'GO:0023052', ('206', '215'))	('rat', 'Species', '10116', (115, 118))	('alterations', 'Var', (111, 122))	('TGF-beta', 'Gene', (197, 205))	('TbetaRII', 'Gene', (136, 144))	('Smad4', 'Gene', (126, 131))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
7121	32998233	In the precise case of ccRCC (clear cell renal cell carcinoma), up to 95% of the tumor genomes are constitutionally VHL gene muted or deleted, thus leading to constitutive activation of HIF1 and CAIX upregulation, even in normoxic conditions.	('upregulation', 'PosReg', (200, 212))	('muted', 'Gene', '63915', (125, 130))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (30, 61))	('VHL', 'Gene', (116, 119))	('deleted', 'Var', (134, 141))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (41, 61))	('RCC', 'Disease', (25, 28))	('tumor', 'Disease', (81, 86))	('CAIX', 'Gene', (195, 199))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('HIF1', 'Gene', '3091', (186, 190))	('clear cell renal cell carcinoma', 'Disease', (30, 61))	('VHL', 'Gene', '7428', (116, 119))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('HIF1', 'Gene', (186, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('muted', 'Gene', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('activation', 'PosReg', (172, 182))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (30, 61))
7122	32998233	The comparison of cDNA sequences between cancer and normal cells does not reveal any mutations or alternative splicing, and therefore the pathological mutations appear upstream in the signaling pathway.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('signaling pathway', 'Pathway', (184, 201))	('splicing', 'biological_process', 'GO:0045292', ('110', '118'))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('mutations', 'Var', (151, 160))	('signaling pathway', 'biological_process', 'GO:0007165', ('184', '201'))
7128	32998233	proposed a two-step strategy for the use of immunostaining in renal cell carcinoma subtype diagnosis: first with the triple panel described above (CK7, AMACR and CAIX) and then, if necessary, with others markers like c-kit, CD10 or cathepsin-K. Another team proposed to enlarge the panel adding the detection of TFE3 (transcription factor binding to IGHM enhancer 3) in IHC, permitting to detect the Xp11 translocation associated RCC.	('TFE3', 'Gene', (312, 316))	('Xp11 translocation', 'Var', (400, 418))	('CD10', 'molecular_function', 'GO:0004245', ('224', '228'))	('CK7', 'Gene', '3855', (147, 150))	('TFE3', 'Gene', '7030', (312, 316))	('cathepsin-K', 'Gene', (232, 243))	('CD10', 'Gene', '4311', (224, 228))	('c-kit', 'Gene', (217, 222))	('AMACR', 'Gene', (152, 157))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('318', '346'))	('cathepsin-K', 'Gene', '1513', (232, 243))	('RCC', 'Disease', (430, 433))	('CD10', 'Gene', (224, 228))	('IGHM', 'Gene', '3507', (350, 354))	('AMACR', 'Gene', '23600', (152, 157))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (62, 82))	('RCC', 'Disease', 'MESH:C538614', (430, 433))	('transcription', 'biological_process', 'GO:0006351', ('318', '331'))	('c-kit', 'Gene', '3815', (217, 222))	('CK7', 'Gene', (147, 150))	('IGHM', 'Gene', (350, 354))	('renal cell carcinoma', 'Disease', (62, 82))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (62, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
7138	32998233	Moreover, the principal rational is that High CAIX expression could witness the VHL-associated tumorigenesis, and ccRCC presenting an abnormally low CAIX rate could reflect the tumor de-differentiation and aggressiveness.	('RCC', 'Disease', (116, 119))	('VHL', 'Gene', (80, 83))	('aggressiveness', 'Disease', 'MESH:D001523', (206, 220))	('VHL', 'Gene', '7428', (80, 83))	('High', 'Var', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('CAIX', 'Protein', (46, 50))	('aggressiveness', 'Disease', (206, 220))	('expression', 'MPA', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('aggressiveness', 'Phenotype', 'HP:0000718', (206, 220))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', (95, 100))
7139	32998233	realized a retrospective study on 143 extirpated local ccRCC, and tested 6 markers in IHC on the tumor's samples: CAIX, c-MYC, Ki67, p53, vimentin and PTEN.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Ki67', 'Var', (127, 131))	('c-MYC', 'Gene', '4609', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('vimentin', 'cellular_component', 'GO:0045099', ('138', '146'))	('vimentin', 'Gene', (138, 146))	('p53', 'Gene', '7157', (133, 136))	('vimentin', 'cellular_component', 'GO:0045098', ('138', '146'))	('tumor', 'Disease', (97, 102))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('p53', 'Gene', (133, 136))	('tested', 'Reg', (66, 72))	('c-MYC', 'Gene', (120, 125))	('PTEN', 'Gene', (151, 155))	('vimentin', 'Gene', '7431', (138, 146))	('PTEN', 'Gene', '5728', (151, 155))
7140	32998233	The results showed that low CAIX expression (under 30%) and vimentin over-expression (over 50%) were associated with the worst outcomes (overall survival, progression-free survival and disease-free survival).	('under', 'Var', (45, 50))	('CAIX', 'Protein', (28, 32))	('over-expression', 'PosReg', (69, 84))	('vimentin', 'cellular_component', 'GO:0045099', ('60', '68'))	('progression-free survival', 'CPA', (155, 180))	('vimentin', 'Gene', '7431', (60, 68))	('low', 'NegReg', (24, 27))	('vimentin', 'cellular_component', 'GO:0045098', ('60', '68'))	('expression', 'MPA', (33, 43))	('vimentin', 'Gene', (60, 68))
7151	32998233	In other terms, high CAIX expression in ccRCC seemed to be associated with better prognosis, while high CAIX expression in pRCC seemed to be unfavorable.	('RCC', 'Disease', (124, 127))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('high', 'Var', (16, 20))	('pRCC', 'Gene', (123, 127))	('pRCC', 'Gene', '5546', (123, 127))	('RCC', 'Disease', (42, 45))	('CAIX', 'Protein', (21, 25))
7152	32998233	High CAIX expression seemed to be associated with lower tumor stage (pT1T2 vs. pT3T4), lower tumor grade (G1G2 vs. G3G4), absence of nodal involvement (N0 vs. N+) and favorable ECOG score (0 vs. >=1).	('lower', 'NegReg', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('High', 'Var', (0, 4))	('lower', 'NegReg', (87, 92))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (93, 98))	('nodal', 'Gene', (133, 138))	('expression', 'MPA', (10, 20))	('CAIX', 'Protein', (5, 9))	('nodal', 'Gene', '4838', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
7154	32998233	A high CAIX score (>200) was associated with prolonged DFS and OS.	('CAIX', 'Gene', (7, 11))	('DFS', 'Disease', (55, 58))	('>200', 'Var', (19, 23))	('DFS', 'Disease', 'None', (55, 58))
7156	32998233	analyzed the correlation between CAIX high expression in RCC metastatic patients and increased tumor sensitivity to interleukin-2 (IL-2).	('CAIX', 'Gene', (33, 37))	('IL-2', 'molecular_function', 'GO:0005134', ('131', '135'))	('high', 'Var', (38, 42))	('interleukin-2', 'Gene', '3558', (116, 129))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('IL-2', 'Gene', '3558', (131, 135))	('RCC', 'Disease', (57, 60))	('increased', 'PosReg', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('IL-2', 'Gene', (131, 135))	('interleukin-2', 'Gene', (116, 129))	('tumor', 'Disease', (95, 100))	('patients', 'Species', '9606', (72, 80))
7237	32998233	Introduction of a pharmacological CAIX inhibitor, or transfection with shRNA-mediated knockdown of CAIX, in xenografted nude mice with ccRCC (786-O cells) resulted in a better response (in vitro) to irradiation (6Gy), compared with mice receiving either irradiation or pharmacological alone.	('response', 'MPA', (176, 184))	('knockdown', 'Var', (86, 95))	('transfection', 'Var', (53, 65))	('mice', 'Species', '10090', (125, 129))	('nude mice', 'Species', '10090', (120, 129))	('CAIX', 'Gene', (99, 103))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))	('better', 'PosReg', (169, 175))	('mice', 'Species', '10090', (232, 236))
7268	31214494	Recent studies have shown that aberrant miRNA expression is associated with overall patient survival, tumor stage and the development of metastases and recurrences.	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('aberrant', 'Var', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('patient', 'Species', '9606', (84, 91))	('metastases', 'Disease', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('associated', 'Reg', (60, 70))
7323	31214494	Recently, dysregulation of miRNAs has gained attention in RCC as well as other cancers.	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('dysregulation', 'Var', (10, 23))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
7349	31214494	Inhibition of mitochondria-dependent apoptosis might induce tumor aggressiveness.	('apoptosis', 'biological_process', 'GO:0097194', ('37', '46'))	('apoptosis', 'biological_process', 'GO:0006915', ('37', '46'))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (60, 80))	('tumor aggressiveness', 'Disease', (60, 80))	('mitochondria', 'cellular_component', 'GO:0005739', ('14', '26'))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Inhibition', 'Var', (0, 10))	('aggressiveness', 'Phenotype', 'HP:0000718', (66, 80))	('induce', 'PosReg', (53, 59))	('mitochondria-dependent', 'Protein', (14, 36))
7354	31214494	In the present study, dysregulation of miRNA-135a-5p was well correlated with metachronous metastasis, suggesting miRNA-135a-5p may be a potential prognostic biomarker in ccRCC.	('dysregulation', 'Var', (22, 35))	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('RCC', 'Disease', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('ccRCC', 'Phenotype', 'HP:0006770', (171, 176))	('metachronous metastasis', 'CPA', (78, 101))	('miR', 'Gene', '220972', (114, 117))	('miR', 'Gene', (114, 117))	('correlated', 'Reg', (62, 72))
7437	31186719	Postoperatively, patients with a high expression level of TUSC3 exhibited a higher overall survival rate compared with that of patients with a high expression level of TUSC3 (P<0.01; Fig.	('TUSC3', 'Gene', (58, 63))	('overall survival', 'CPA', (83, 99))	('TUSC3', 'Gene', (168, 173))	('patients', 'Species', '9606', (127, 135))	('TUSC3', 'Gene', '7991', (168, 173))	('high expression level', 'Var', (33, 54))	('patients', 'Species', '9606', (17, 25))	('TUSC3', 'Gene', '7991', (58, 63))	('higher', 'PosReg', (76, 82))
7443	31186719	Compared with the control group (HKC8 cells), A498, 786-O, OS-RC-2 and ACHN cells exhibited lower protein expression levels of TUSC3 (P<0.05; Fig.	('ACHN', 'Gene', '55323', (71, 75))	('A498', 'Var', (46, 50))	('TUSC3', 'Gene', (127, 132))	('ACHN', 'Gene', (71, 75))	('protein expression levels', 'MPA', (98, 123))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('TUSC3', 'Gene', '7991', (127, 132))	('OS-RC-2', 'CellLine', 'CVCL:1626', (59, 66))	('lower', 'NegReg', (92, 97))
7458	31186719	TUSC3 was identified as a potential anti-oncogene when it was first identified in the 1990s, and deletion of TUSC3 expression is associated with the malignant transformation of cells.	('associated', 'Reg', (129, 139))	('TUSC3', 'Gene', '7991', (109, 114))	('TUSC3', 'Gene', (0, 5))	('TUSC3', 'Gene', '7991', (0, 5))	('malignant transformation of cells', 'CPA', (149, 182))	('TUSC3', 'Gene', (109, 114))	('deletion', 'Var', (97, 105))
7459	31186719	A large number of studies reported that the carcinogenesis of pancreatic, gastric, ovarian and prostate cancer may be associated with the mutation or deletion of TUSC3.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('TUSC3', 'Gene', (162, 167))	('carcinogenesis of pancreatic, gastric, ovarian and prostate cancer', 'Disease', 'MESH:D013274', (44, 110))	('deletion', 'Var', (150, 158))	('mutation', 'Var', (138, 146))	('associated', 'Reg', (118, 128))	('TUSC3', 'Gene', '7991', (162, 167))	('prostate cancer', 'Phenotype', 'HP:0012125', (95, 110))
7467	31186719	Subsequently, a study explored the molecular mechanism of TUSC3 in ovarian cancer, which revealed that the hypermethylation of the TUSC3 promoter could lead to low expression of TUSC3, and the methylation of promoter is a prognostic indicator of patients with cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (67, 81))	('patients', 'Species', '9606', (246, 254))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('TUSC3', 'Gene', '7991', (178, 183))	('TUSC3', 'Gene', '7991', (58, 63))	('low', 'NegReg', (160, 163))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('ovarian cancer', 'Disease', (67, 81))	('TUSC3', 'Gene', (131, 136))	('ovarian cancer', 'Phenotype', 'HP:0100615', (67, 81))	('TUSC3', 'Gene', (58, 63))	('TUSC3', 'Gene', (178, 183))	('methylation', 'biological_process', 'GO:0032259', ('193', '204'))	('cancer', 'Disease', (260, 266))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('expression', 'MPA', (164, 174))	('cancer', 'Disease', (75, 81))	('hypermethylation', 'Var', (107, 123))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('TUSC3', 'Gene', '7991', (131, 136))
7472	31186719	Dysfunction of TUSC3 may result in improper protein glycosylation, potentially leading to disorders of cellular biological function.	('TUSC3', 'Gene', '7991', (15, 20))	('Dysfunction', 'Var', (0, 11))	('protein glycosylation', 'biological_process', 'GO:0006486', ('44', '65'))	('disorders', 'MPA', (90, 99))	('improper protein glycosylation', 'MPA', (35, 65))	('TUSC3', 'Gene', (15, 20))	('leading to', 'Reg', (79, 89))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('result in', 'Reg', (25, 34))
7473	31186719	The present study revealed that TUSC3 expression may inhibit tumor progression in patients with ccRCC, and TUSC3 may serve as a biomarker to identify tumor progression and the prognosis of patients with ccRCC.	('TUSC3', 'Gene', (107, 112))	('inhibit', 'NegReg', (53, 60))	('RCC', 'Disease', (205, 208))	('TUSC3', 'Gene', '7991', (32, 37))	('patients', 'Species', '9606', (82, 90))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('RCC', 'Disease', (98, 101))	('expression', 'Var', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('TUSC3', 'Gene', (32, 37))	('patients', 'Species', '9606', (189, 197))	('TUSC3', 'Gene', '7991', (107, 112))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', (61, 66))
7501	31978894	Many previous studies illustrated that MTDH can enhance tumor progression and metastasis through activating several classic cancer-promoting signaling pathways, such as epithelial-mesenchymal transition (EMT) and the NF-kappaB and MAPK signaling pathways.	('cancer', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('EMT', 'biological_process', 'GO:0001837', ('204', '207'))	('tumor', 'Disease', (56, 61))	('MAPK signaling pathways', 'Pathway', (231, 254))	('NF-kappaB', 'Gene', '4790', (217, 226))	('epithelial-mesenchymal transition', 'Pathway', (169, 202))	('MTDH', 'Var', (39, 43))	('enhance', 'PosReg', (48, 55))	('NF-kappaB', 'Gene', (217, 226))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('169', '202'))	('MAPK', 'molecular_function', 'GO:0004707', ('231', '235'))	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('activating', 'PosReg', (97, 107))	('MAPK signaling', 'biological_process', 'GO:0000165', ('231', '245'))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
7503	31978894	Previous studies of ccRCC suggested that increased MTDH expression is correlated with higher clinical staging, a more advanced grade and shorter patient survival, and knockdown of MTDH inhibited growth and induced apoptosis.	('apoptosis', 'CPA', (214, 223))	('increased', 'PosReg', (41, 50))	('apoptosis', 'biological_process', 'GO:0097194', ('214', '223'))	('apoptosis', 'biological_process', 'GO:0006915', ('214', '223'))	('MTDH', 'Gene', (180, 184))	('inhibited', 'NegReg', (185, 194))	('ccRCC', 'Disease', (20, 25))	('knockdown', 'Var', (167, 176))	('MTDH', 'Protein', (51, 55))	('expression', 'MPA', (56, 66))	('ccRCC', 'Disease', 'MESH:D002292', (20, 25))	('patient', 'Species', '9606', (145, 152))	('ccRCC', 'Phenotype', 'HP:0006770', (20, 25))	('induced', 'Reg', (206, 213))	('growth', 'CPA', (195, 201))
7518	31978894	In the PKU-KIRC dataset, immunostaining confirmed that ccRCC patients with high MTDH protein expression levels had a shorter OS (Figure 2E, p=0.00214) and CSS (Figure 2F, p<0.0001).	('ccRCC', 'Disease', 'MESH:D002292', (55, 60))	('CSS', 'Chemical', '-', (155, 158))	('high', 'Var', (75, 79))	('patients', 'Species', '9606', (61, 69))	('MTDH', 'Gene', (80, 84))	('PKU', 'Disease', (7, 10))	('shorter', 'NegReg', (117, 124))	('CSS', 'MPA', (155, 158))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))	('ccRCC', 'Disease', (55, 60))	('PKU', 'Disease', 'MESH:D010661', (7, 10))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
7519	31978894	Moreover, ccRCC patients with high MTDH protein expression levels experienced recurrent or metastatic tumors earlier after radical nephrectomy (Figure 2G: PFS, p=0.0001 and Figure 2H: MFS, p<0.0001).	('recurrent', 'CPA', (78, 87))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('patients', 'Species', '9606', (16, 24))	('MTDH', 'Gene', (35, 39))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('high', 'Var', (30, 34))	('ccRCC', 'Phenotype', 'HP:0006770', (10, 15))	('ccRCC', 'Disease', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('experienced', 'Reg', (66, 77))	('ccRCC', 'Disease', 'MESH:D002292', (10, 15))
7521	31978894	Multivariate Cox regression analysis indicated that MTDH is an independent prognostic factor for both CSS and MFS (Tables 2 and 3).	('MTDH', 'Var', (52, 56))	('Cox', 'Gene', (13, 16))	('CSS', 'Disease', (102, 105))	('CSS', 'Chemical', '-', (102, 105))	('MFS', 'Disease', (110, 113))	('Cox', 'Gene', '1351', (13, 16))
7522	31978894	In addition, both univariate and multivariate analyses of the PKU-KIRC dataset showed that ccRCC patients expressing high levels of MTDH had a shorter overall survival (OS) and progression-free survival (PFS) than patients with low MTDH expression (Supplementary Tables 3 and 4).	('overall survival', 'CPA', (151, 167))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('shorter', 'NegReg', (143, 150))	('ccRCC', 'Disease', (91, 96))	('patients', 'Species', '9606', (214, 222))	('high levels', 'Var', (117, 128))	('ccRCC', 'Disease', 'MESH:D002292', (91, 96))	('PKU', 'Disease', (62, 65))	('progression-free survival', 'CPA', (177, 202))	('PKU', 'Disease', 'MESH:D010661', (62, 65))	('patients', 'Species', '9606', (97, 105))
7529	31978894	A significant reduction in tumor metastasis in the MTDH knockdown group compared with the control group was identified (Figure 3M).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('MTDH', 'Gene', (51, 55))	('tumor metastasis', 'Disease', 'MESH:D009362', (27, 43))	('tumor metastasis', 'Disease', (27, 43))	('reduction', 'NegReg', (14, 23))	('knockdown', 'Var', (56, 65))
7536	31978894	Moreover, MTDH also increased the expression of p-NF-kappaB and p-p38, executing its function in promoting cancer (Supplementary Figure 1E).	('increased', 'PosReg', (20, 29))	('expression', 'MPA', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('promoting', 'PosReg', (97, 106))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('p-p38', 'Gene', (64, 69))	('MTDH', 'Var', (10, 14))	('cancer', 'Disease', (107, 113))	('NF-kappaB', 'Gene', '4790', (50, 59))	('NF-kappaB', 'Gene', (50, 59))
7557	31978894	As shown in Supplementary Figure 2D and 2E, the group with high SND1 mRNA expression had a poorer OS and shorter relapse-free survival (RFS) than the group with low SND1 mRNA expression (OS: p = 0.014, RFS: p = 0.0151).	('relapse-free survival', 'CPA', (113, 134))	('SND1', 'Gene', (64, 68))	('Supplementary Figure 2D', 'Disease', (12, 35))	('high', 'Var', (59, 63))	('SND1', 'Gene', '27044', (64, 68))	('SND1', 'Gene', (165, 169))	('Supplementary Figure 2D', 'Disease', 'MESH:D017034', (12, 35))	('shorter', 'NegReg', (105, 112))	('poorer', 'NegReg', (91, 97))	('SND1', 'Gene', '27044', (165, 169))
7560	31978894	In the PKU-KIRC dataset, SND1 protein expression was elevated in ccRCC patients with postsurgical metastasis (Figure 5B), and ccRCC patients with high SND1 protein expression levels had a shorter MFS than those with low SND1 protein expression levels (Figure 5C, p = 0.0061).	('elevated', 'PosReg', (53, 61))	('patients', 'Species', '9606', (71, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('SND1', 'Gene', (25, 29))	('ccRCC', 'Disease', 'MESH:D002292', (126, 131))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('PKU', 'Disease', 'MESH:D010661', (7, 10))	('SND1', 'Gene', '27044', (151, 155))	('patients', 'Species', '9606', (132, 140))	('ccRCC', 'Disease', (126, 131))	('SND1', 'Gene', (151, 155))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('protein', 'Protein', (30, 37))	('SND1', 'Gene', '27044', (220, 224))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('protein', 'cellular_component', 'GO:0003675', ('225', '232'))	('SND1', 'Gene', (220, 224))	('ccRCC', 'Disease', 'MESH:D002292', (65, 70))	('high', 'Var', (146, 150))	('MFS', 'MPA', (196, 199))	('ccRCC', 'Disease', (65, 70))	('PKU', 'Disease', (7, 10))	('SND1', 'Gene', '27044', (25, 29))	('shorter', 'NegReg', (188, 195))
7567	31978894	As shown in Figure 5F, knockdown of SND1 abolished the increased migration and invasion capabilities of ccRCC cells promoted by MTDH overexpression.	('ccRCC', 'Disease', 'MESH:D002292', (104, 109))	('SND1', 'Gene', (36, 40))	('MTDH', 'Gene', (128, 132))	('abolished', 'NegReg', (41, 50))	('increased', 'PosReg', (55, 64))	('knockdown', 'Var', (23, 32))	('SND1', 'Gene', '27044', (36, 40))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))	('ccRCC', 'Disease', (104, 109))
7568	31978894	Silencing SND1 largely abolished the increased expression of the p-ERK1/2 and snail proteins induced by MTDH overexpression (Figure 5G).	('snail', 'Gene', '6615', (78, 83))	('Silencing', 'Var', (0, 9))	('snail', 'Gene', (78, 83))	('ERK1/2', 'Gene', (67, 73))	('ERK1/2', 'Gene', '5595;5594', (67, 73))	('SND1', 'Gene', (10, 14))	('SND1', 'Gene', '27044', (10, 14))	('abolished', 'NegReg', (23, 32))	('ERK1', 'molecular_function', 'GO:0004707', ('67', '71'))	('expression', 'MPA', (47, 57))
7596	31978894	By triggering the PI3K/AKT signaling pathway, MTDH regulates the downstream expression of genes encoding metastasis-associated proteins and apoptosis-associated proteins (Bad, p21 and p27) and contributes to the induction of a malignant cell phenotype.	('induction', 'Reg', (212, 221))	('MTDH', 'Var', (46, 50))	('AKT', 'Gene', '207', (23, 26))	('malignant cell phenotype', 'CPA', (227, 251))	('triggering', 'Reg', (3, 13))	('apoptosis', 'biological_process', 'GO:0097194', ('140', '149'))	('PI3K', 'molecular_function', 'GO:0016303', ('18', '22'))	('p21', 'Gene', (176, 179))	('AKT', 'Gene', (23, 26))	('regulates', 'Reg', (51, 60))	('p21', 'Gene', '644914', (176, 179))	('signaling pathway', 'biological_process', 'GO:0007165', ('27', '44'))	('apoptosis', 'biological_process', 'GO:0006915', ('140', '149'))	('p27', 'Gene', '3429', (184, 187))	('p27', 'Gene', (184, 187))	('contributes', 'Reg', (193, 204))	('AKT signaling', 'biological_process', 'GO:0043491', ('23', '36'))
7600	31978894	All ccRCC gene microarray profiling data with a sample size greater than 20 (GSE781, GSE15641, GSE16449, GSE36895, GSE46699, GSE53000, GSE53757, GSE68417, GSE71963, GSE14994, GSE40435, GSE66272, GSE105288) were included in this study and obtained from the Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/).	('GSE36895', 'Var', (105, 113))	('GSE71963', 'Var', (155, 163))	('GSE105288', 'Var', (195, 204))	('Gene Expression', 'biological_process', 'GO:0010467', ('256', '271'))	('ccRCC', 'Phenotype', 'HP:0006770', (4, 9))	('GSE16449', 'Var', (95, 103))	('GSE15641', 'Var', (85, 93))	('GSE40435', 'Var', (175, 183))	('ccRCC', 'Disease', (4, 9))	('GSE66272', 'Var', (185, 193))	('GSE46699', 'Var', (115, 123))	('GSE781', 'Var', (77, 83))	('GSE14994', 'Var', (165, 173))	('GSE53000', 'Var', (125, 133))	('ccRCC', 'Disease', 'MESH:D002292', (4, 9))	('GSE68417', 'Var', (145, 153))	('GSE53757', 'Var', (135, 143))
7640	30406146	The results of survival analysis and regression analysis indicated that 6 DElncRNAs named COL18A1-AS1, WT1-AS, LINC00443, TCL6, AL356356.1, and SLC25A5-AS1 were significantly correlative with the clinical traits of ccRCC patients and could be served as predictors for ccRCC.	('patients', 'Species', '9606', (221, 229))	('SLC25A5-AS1', 'Var', (144, 155))	('LINC00443', 'Gene', (111, 120))	('AL356356', 'Chemical', '-', (128, 136))	('clinical', 'Species', '191496', (196, 204))	('RCC', 'Phenotype', 'HP:0005584', (217, 220))	('ccRCC', 'Phenotype', 'HP:0006770', (215, 220))	('RCC', 'Disease', (217, 220))	('RCC', 'Phenotype', 'HP:0005584', (270, 273))	('RCC', 'Disease', (270, 273))	('TCL6', 'Gene', (122, 126))	('WT1', 'Gene', (103, 106))	('TCL6', 'Gene', '27004', (122, 126))	('AL356356.1', 'Var', (128, 138))	('ccRCC', 'Phenotype', 'HP:0006770', (268, 273))	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('LINC00443', 'Gene', '100874173', (111, 120))	('RCC', 'Disease', 'MESH:C538614', (270, 273))	('correlative', 'Reg', (175, 186))	('COL18A1-AS1', 'Gene', (90, 101))	('WT1', 'Gene', '7490', (103, 106))
7646	30406146	Although several evidences have documented that somatic genetic mutations were linked with the formation and progress of ccRCC, it is imperative to identify more effective biomarkers that could help us uncover more thorough pathogenesis regarding the biological characteristics of ccRCC.	('linked', 'Reg', (79, 85))	('ccRCC', 'Phenotype', 'HP:0006770', (281, 286))	('RCC', 'Disease', (283, 286))	('RCC', 'Phenotype', 'HP:0005584', (283, 286))	('formation', 'biological_process', 'GO:0009058', ('95', '104'))	('RCC', 'Disease', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (283, 286))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('pathogenesis', 'biological_process', 'GO:0009405', ('224', '236'))	('mutations', 'Var', (64, 73))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (121, 126))
7674	30406146	As indicated in Table 3, 6 out of 34 lncRNAs named COL18A1-AS1, WT1-AS, LINC00443, TCL6, AL356356.1, and SLC25A5-AS1 were served as covariates (P < 0.05) in the training set.	('AL356356.1', 'Var', (89, 99))	('WT1', 'Gene', (64, 67))	('LINC00443', 'Gene', (72, 81))	('TCL6', 'Gene', '27004', (83, 87))	('AL356356', 'Chemical', '-', (89, 97))	('TCL6', 'Gene', (83, 87))	('LINC00443', 'Gene', '100874173', (72, 81))	('WT1', 'Gene', '7490', (64, 67))
7677	30406146	In terms of the above analysis from microarray analysis, these 6 lncRNAs (COL18A1-AS1, WT1-AS, LINC00443, TCL6, AL356356.1, and SLC25A5-AS1) involving ceRNA network were regarded as potential biomarkers linked with ccRCC patients (Table 4).	('AL356356.1', 'Var', (112, 122))	('LINC00443', 'Gene', (95, 104))	('patients', 'Species', '9606', (221, 229))	('RCC', 'Disease', (217, 220))	('AL356356', 'Chemical', '-', (112, 120))	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('ccRCC', 'Phenotype', 'HP:0006770', (215, 220))	('WT1', 'Gene', '7490', (87, 90))	('TCL6', 'Gene', '27004', (106, 110))	('LINC00443', 'Gene', '100874173', (95, 104))	('TCL6', 'Gene', (106, 110))	('WT1', 'Gene', (87, 90))	('RCC', 'Phenotype', 'HP:0005584', (217, 220))
7683	30406146	Nowadays, increasing studies have showed the crucial biological functions of lncRNAs involved in the development and process of human diseases by epigenetic regulation and transcription as well as posttranscription regulation.	('transcription', 'biological_process', 'GO:0006351', ('172', '185'))	('transcription', 'MPA', (172, 185))	('involved', 'Reg', (85, 93))	('human', 'Species', '9606', (128, 133))	('regulation', 'biological_process', 'GO:0065007', ('157', '167'))	('regulation', 'biological_process', 'GO:0065007', ('215', '225'))	('epigenetic regulation', 'Var', (146, 167))
7698	30406146	Moreover, high expression of lncRNA WT1-AS was related to poor prognosis based on KM curve.	('related', 'Reg', (47, 54))	('WT1', 'Gene', '7490', (36, 39))	('WT1', 'Gene', (36, 39))	('high', 'Var', (10, 14))
7700	30406146	In addition, the result of ceRNA network showed that the targeted miRNAs of lncRNA WT1-AS were miR-141 miR-155 and miR-216b, suggesting that it may be acted as a sponge to compete with these three key DEmiRNAs participated in the pathogenesis mechanism of ccRCC carcinogenesis.	('RCC', 'Disease', (258, 261))	('pathogenesis', 'biological_process', 'GO:0009405', ('230', '242'))	('ccRCC', 'Phenotype', 'HP:0006770', (256, 261))	('RCC', 'Phenotype', 'HP:0005584', (258, 261))	('carcinogenesis', 'Disease', 'MESH:D063646', (262, 276))	('lncRNA', 'Gene', (76, 82))	('WT1', 'Gene', '7490', (83, 86))	('miR-216b', 'Gene', '100126319', (115, 123))	('miR-216b', 'Gene', (115, 123))	('WT1', 'Gene', (83, 86))	('carcinogenesis', 'Disease', (262, 276))	('miR-141 miR-155', 'Var', (95, 110))	('RCC', 'Disease', 'MESH:C538614', (258, 261))
7705	30406146	Our results showed that lncRNA TCL6 could be served as a ceRNA to in regulation the expression of targeted genes by sponging miR-210, miR-216b, and miR-122, further reinforcing their conclusion.	('miR-210', 'Gene', (125, 132))	('TCL6', 'Gene', (31, 35))	('TCL6', 'Gene', '27004', (31, 35))	('regulation', 'biological_process', 'GO:0065007', ('69', '79'))	('miR-216b', 'Gene', (134, 142))	('miR-122', 'Gene', '406906', (148, 155))	('miR-122', 'Gene', (148, 155))	('miR-210', 'Gene', '406992', (125, 132))	('sponging', 'Var', (116, 124))	('expression', 'MPA', (84, 94))	('miR-216b', 'Gene', '100126319', (134, 142))
7706	30406146	Furthermore, other lncRNAs (COL18A1-AS1, LINC00443, AL356356.1, and SLC25A5-AS1) were also significantly aberrantly expressed in the ccRCC tumors compared with the normal samples, but there are scarcely reports about them until now.	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('aberrantly', 'Reg', (105, 115))	('LINC00443', 'Gene', (41, 50))	('RCC', 'Disease', (135, 138))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('AL356356.1', 'Var', (52, 62))	('AL356356', 'Chemical', '-', (52, 60))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('LINC00443', 'Gene', '100874173', (41, 50))
7721	33151962	Algorithmic assessment of missense mutation severity in the Von-Hippel Lindau protein Von Hippel-Lindau disease (VHL) is an autosomal dominant rare disease that causes the formation of angiogenic tumors.	('formation', 'biological_process', 'GO:0009058', ('172', '181'))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('VHL', 'Gene', (113, 116))	('tumors', 'Disease', (196, 202))	('Von-Hippel Lindau', 'Disease', (60, 77))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('autosomal dominant rare disease', 'Disease', 'MESH:D035583', (124, 155))	('VHL', 'Gene', '7428', (113, 116))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('Von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (86, 111))	('Von-Hippel Lindau', 'Disease', 'MESH:D006623', (60, 77))	('autosomal dominant rare disease', 'Disease', (124, 155))	('missense mutation', 'Var', (26, 43))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('Von Hippel-Lindau disease', 'Disease', (86, 111))
7723	33151962	Genetic mutations that perturb the structure of pVHL result in dysregulation of HIF, causing a wide array of tumor pathologies including retinal angioma, pheochromocytoma, central nervous system hemangioblastoma, and clear cell renal carcinoma.	('pVHL', 'Gene', '7428', (48, 52))	('renal carcinoma', 'Phenotype', 'HP:0005584', (228, 243))	('pVHL', 'Gene', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('retinal angioma', 'Disease', (137, 152))	('causing', 'Reg', (85, 92))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (217, 243))	('mutations', 'Var', (8, 17))	('dysregulation', 'MPA', (63, 76))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('pheochromocytoma', 'Disease', 'MESH:D010673', (154, 170))	('central nervous system hemangioblastoma', 'Disease', (172, 211))	('clear cell renal carcinoma', 'Disease', (217, 243))	('pheochromocytoma', 'Disease', (154, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (154, 170))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (217, 243))	('central nervous system hemangioblastoma', 'Disease', 'MESH:D018325', (172, 211))	('central nervous system hemangioblastoma', 'Phenotype', 'HP:0006880', (172, 211))	('retinal angioma', 'Disease', 'MESH:D006391', (137, 152))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (195, 211))	('tumor', 'Disease', (109, 114))
7726	33151962	Understanding how these specific mutations correlate with the myriad of observed pathologies for VHL could provide clinicians insight into the potential severity and onset of disease.	('mutations', 'Var', (33, 42))	('VHL', 'Gene', '7428', (97, 100))	('VHL', 'Gene', (97, 100))
7727	33151962	Using a select set of 285 ClinVar mutations in VHL, we developed a multiparametric scoring algorithm to evaluate the overall clinical severity of missense mutations in pVHL.	('missense mutations', 'Var', (146, 164))	('pVHL', 'Gene', '7428', (168, 172))	('VHL', 'Gene', '7428', (169, 172))	('pVHL', 'Gene', (168, 172))	('VHL', 'Gene', (47, 50))	('VHL', 'Gene', '7428', (47, 50))	('VHL', 'Gene', (169, 172))
7728	33151962	Our approach establishes a novel in silico method by which VHL-specific mutations can be assessed for their severity and effect on the biophysical functions of the VHL protein.	('VHL', 'Gene', '7428', (59, 62))	('mutations', 'Var', (72, 81))	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('biophysical', 'MPA', (135, 146))	('VHL', 'Gene', (164, 167))	('VHL', 'Gene', '7428', (164, 167))	('VHL', 'Gene', (59, 62))
7735	33151962	Upon spontaneous inactivation of the second allele, tumor development can initiate, making the loss of heterozygosity (LOH) a crucial step in the development of VHL disease.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('loss of heterozygosity', 'Var', (95, 117))	('VHL disease', 'Disease', (161, 172))	('tumor', 'Disease', (52, 57))	('VHL disease', 'Disease', 'MESH:D006623', (161, 172))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
7738	33151962	This stabilizes EloB, EloC, and pVHL, making them resistant to proteosomal degradation; however, upon mutation of pVHL, contacts with EloB and C become disrupted, making pVHL unstable and a target for degradation.	('contacts', 'Interaction', (120, 128))	('EloB', 'Gene', '6923', (16, 20))	('degradation', 'biological_process', 'GO:0009056', ('75', '86'))	('EloC', 'Gene', '6921', (22, 26))	('mutation', 'Var', (102, 110))	('EloB', 'Gene', (16, 20))	('EloB', 'Gene', '6923', (134, 138))	('pVHL', 'Gene', '7428', (170, 174))	('pVHL', 'Gene', '7428', (32, 36))	('EloC', 'Gene', (22, 26))	('pVHL', 'Gene', (170, 174))	('EloB', 'Gene', (134, 138))	('pVHL', 'Gene', (32, 36))	('pVHL', 'Gene', '7428', (114, 118))	('pVHL', 'Gene', (114, 118))	('disrupted', 'NegReg', (152, 161))	('degradation', 'biological_process', 'GO:0009056', ('201', '212'))
7753	33151962	While loss-of-function mutations cause global disruption of the VHL protein, missense mutations may only affect certain interaction partners and cellular pathways involving pVHL.	('missense mutations', 'Var', (77, 95))	('disruption', 'NegReg', (46, 56))	('VHL', 'Gene', (64, 67))	('loss-of-function', 'NegReg', (6, 22))	('VHL', 'Gene', (174, 177))	('mutations', 'Var', (23, 32))	('VHL', 'Gene', '7428', (64, 67))	('interaction partners', 'Interaction', (120, 140))	('pVHL', 'Gene', '7428', (173, 177))	('VHL', 'Gene', '7428', (174, 177))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('pVHL', 'Gene', (173, 177))	('cellular pathways', 'Pathway', (145, 162))
7754	33151962	A recent study completed by Razafinjatovo et al used an in silico approach to determine the thermodynamic stability of a given pVHL mutation.	('mutation', 'Var', (132, 140))	('pVHL', 'Gene', (127, 131))	('pVHL', 'Gene', '7428', (127, 131))
7755	33151962	It was determined that the most thermodynamically unstable missense mutations resulted in pathogenic disease via global destabilization of pVHL and stabilization of HIF.	('destabilization', 'NegReg', (120, 135))	('resulted in', 'Reg', (78, 89))	('pVHL', 'Gene', '7428', (139, 143))	('pVHL', 'Gene', (139, 143))	('missense mutations', 'Var', (59, 77))	('pathogenic disease', 'Disease', (90, 108))
7756	33151962	This suggests that while some VHL missense mutations might only affect specific functions of the protein, others cause global misfolding and destabilization of the protein.	('destabilization', 'MPA', (141, 156))	('cause', 'Reg', (113, 118))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('functions', 'MPA', (80, 89))	('VHL', 'Gene', (30, 33))	('missense mutations', 'Var', (34, 52))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('VHL', 'Gene', '7428', (30, 33))	('misfolding', 'MPA', (126, 136))	('affect', 'Reg', (64, 70))
7757	33151962	A comprehensive examination of the effects of a given missense mutation for pVHL can provide significant insight into how a given patient mutation can be predictive of disease severity; however, a systematic examination of the role of a given missense mutation (and subsequent amino acid replacement) must take into account multiple factors: secondary structure, thermodynamic stability, binding partners, translation rate, among other biophysical and biochemical properties.	('patient', 'Species', '9606', (130, 137))	('pVHL', 'Gene', '7428', (76, 80))	('pVHL', 'Gene', (76, 80))	('binding', 'molecular_function', 'GO:0005488', ('388', '395'))	('mutation', 'Var', (138, 146))	('translation', 'biological_process', 'GO:0006412', ('406', '417'))
7759	33151962	Currently, some publically available online databases provide investigators with basic information on the pathogenicity of a given mutation in genetic diseases, including VHL.	('VHL', 'Gene', (171, 174))	('VHL', 'Gene', '7428', (171, 174))	('genetic diseases', 'Disease', 'MESH:D030342', (143, 159))	('genetic diseases', 'Disease', (143, 159))	('mutation', 'Var', (131, 139))
7761	33151962	Previously, we developed a computational, multiparameteric approach to evaluate the biophysical consequences of missense mutations on the structure and stability of the Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome) protein (MPSIIIA).	('Mucopolysaccharidosis Type IIIA', 'Gene', '6448', (169, 200))	('Mucopolysaccharidosis Type IIIA', 'Gene', (169, 200))	('missense mutations', 'Var', (112, 130))	('protein', 'cellular_component', 'GO:0003675', ('223', '230'))
7762	33151962	In this study, we created an advanced weighted-score multiparametric approach to validate the use of a computational algorithm to assess the potential disease severity of genetic missense mutations in pVHL.	('pVHL', 'Gene', (201, 205))	('missense mutations', 'Var', (179, 197))	('pVHL', 'Gene', '7428', (201, 205))
7763	33151962	We focused not only on mutations that can affect the overall proteostasis of pVHL, but also noted the specific mutations that would impact VHL-specific functional properties.	('affect', 'Reg', (42, 48))	('mutations', 'Var', (111, 120))	('VHL', 'Gene', (139, 142))	('VHL', 'Gene', '7428', (139, 142))	('VHL', 'Gene', (78, 81))	('proteostasis', 'MPA', (61, 73))	('impact', 'Reg', (132, 138))	('mutations', 'Var', (23, 32))	('VHL', 'Gene', '7428', (78, 81))	('functional', 'MPA', (152, 162))	('pVHL', 'Gene', '7428', (77, 81))	('pVHL', 'Gene', (77, 81))
7764	33151962	Our multiparametric algorithm for VHL included a set of eight biophysical parameters with individually weighted scores that gave an overall assessment of the ability of a given missense mutation in VHL to result in protein impairment: 1. aggregation propensity; 2. protein-protein interactions; 3. secondary structure; 4. conformational flexibility; 5. solvent accessibility; 6. protein stability; 7. post-translational modifications, and 8. translational rate.	('post', 'Gene', '159371', (401, 405))	('solvent accessibility', 'MPA', (353, 374))	('protein-protein interactions', 'MPA', (265, 293))	('protein', 'cellular_component', 'GO:0003675', ('379', '386'))	('translational rate', 'MPA', (442, 460))	('VHL', 'Gene', (198, 201))	('post', 'Gene', (401, 405))	('conformational flexibility', 'MPA', (322, 348))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('VHL', 'Gene', (34, 37))	('protein stability', 'MPA', (379, 396))	('VHL', 'Gene', '7428', (198, 201))	('missense mutation', 'Var', (177, 194))	('protein', 'cellular_component', 'GO:0003675', ('265', '272'))	('VHL', 'Gene', '7428', (34, 37))	('secondary structure', 'MPA', (298, 317))	('protein', 'cellular_component', 'GO:0003675', ('273', '280'))	('aggregation', 'MPA', (238, 249))
7765	33151962	A set of 285 missense mutations in the human VHL gene, arising from a single nucleotide polymorphism (SNP) was acquired from ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) (S2 File).	('VHL', 'Gene', '7428', (45, 48))	('VHL', 'Gene', (45, 48))	('human', 'Species', '9606', (39, 44))	('missense mutations', 'Var', (13, 31))
7766	33151962	An additional set of 1380 mutations was generated to represent all possible theoretical missense mutations (APMM) of VHL from a SNP (S1 File).	('missense mutations', 'Var', (88, 106))	('VHL', 'Gene', '7428', (117, 120))	('VHL', 'Gene', (117, 120))
7769	33151962	The unstructured N-terminus of VHL is missing from published crystal structures; therefore, to assess the effect of mutations in this region for their effects on protein stability, ITASSER (https://zhanglab.ccmb.med.umich.edu/I-TASSER/) was used to generate a putative structure of VHL as input for Parameter 6.	('VHL', 'Gene', '7428', (31, 34))	('VHL', 'Gene', (282, 285))	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('VHL', 'Gene', '7428', (282, 285))	('mutations', 'Var', (116, 125))	('VHL', 'Gene', (31, 34))
7770	33151962	A positive aggregation score was assigned if a given mutation enhanced the hydrophobic character and aggregation propensity of the VHL polypeptide chain.	('hydrophobic character', 'MPA', (75, 96))	('mutation', 'Var', (53, 61))	('VHL', 'Gene', (131, 134))	('aggregation propensity', 'MPA', (101, 123))	('VHL', 'Gene', '7428', (131, 134))	('enhanced', 'PosReg', (62, 70))
7777	33151962	In this analysis, any missense mutation involving changes in proline, glycine, or cysteine residues were scored as positive.	('changes', 'Reg', (50, 57))	('glycine', 'Chemical', 'MESH:D005998', (70, 77))	('proline', 'Chemical', 'MESH:D011392', (61, 68))	('proline', 'MPA', (61, 68))	('cysteine', 'Chemical', 'MESH:D003545', (82, 90))	('cysteine residues', 'MPA', (82, 99))	('glycine', 'MPA', (70, 77))	('missense', 'Var', (22, 30))
7778	33151962	We evaluated the effects of missense mutations on the stability of pVHL as destabilizing mutations could prevent proper folding and function.	('prevent', 'NegReg', (105, 112))	('missense mutations', 'Var', (28, 46))	('pVHL', 'Gene', '7428', (67, 71))	('function', 'MPA', (132, 140))	('pVHL', 'Gene', (67, 71))	('folding', 'MPA', (120, 127))
7779	33151962	To determine if overall protein stability was altered via a missense mutation, pVHL missense mutations were assessed using the CUPSAT (http://cupsat.tu-bs.de/) online prediction server.	('pVHL', 'Gene', '7428', (79, 83))	('pVHL', 'Gene', (79, 83))	('altered', 'Reg', (46, 53))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('missense mutation', 'Var', (60, 77))
7781	33151962	To assess the specific roles of PTMs in our algorithmic assessment of VHL disease, missense mutations that occurred at a position known to be post-translationally modified were positively scored.	('VHL disease', 'Disease', (70, 81))	('missense mutations', 'Var', (83, 101))	('VHL disease', 'Disease', 'MESH:D006623', (70, 81))	('post', 'Gene', '159371', (142, 146))	('post', 'Gene', (142, 146))
7782	33151962	Symphony (http://biosig.unimelb.edu.au/symphony/), an online program to predict the risk of ccRCC in a given VHL mutation, was also used to develop the pathogenicity index by scoring the same 211 ClinVar mutations.	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('mutation', 'Var', (113, 121))	('ccRCC', 'Disease', (92, 97))	('mutations', 'Var', (204, 213))	('VHL', 'Gene', (109, 112))	('ClinVar', 'Gene', (196, 203))	('VHL', 'Gene', '7428', (109, 112))
7783	33151962	Using a set of 285 missense mutations from the ClinVar database and another set of 1380 possible missense mutations (APMM) in pVHL, we began to evaluate the consequences of missense mutations, arising from a SNP.	('pVHL', 'Gene', (126, 130))	('pVHL', 'Gene', '7428', (126, 130))	('missense mutations', 'Var', (173, 191))
7784	33151962	Our multiparametric approach provided a holistic view of the consequences of a mutation on the overall structure and stability of pVHL by evaluating the following parameters: aggregation propensity, protein-protein interactions, secondary structure, conformational flexibility, solvent accessibility, protein stability, post-translational modification, and translational rate.	('protein', 'cellular_component', 'GO:0003675', ('207', '214'))	('pVHL', 'Gene', '7428', (130, 134))	('protein-protein interactions', 'MPA', (199, 227))	('post', 'Gene', '159371', (320, 324))	('solvent accessibility', 'MPA', (278, 299))	('post', 'Gene', (320, 324))	('aggregation propensity', 'MPA', (175, 197))	('protein', 'cellular_component', 'GO:0003675', ('301', '308'))	('mutation', 'Var', (79, 87))	('post-translational modification', 'biological_process', 'GO:0043687', ('320', '351'))	('conformational flexibility', 'MPA', (250, 276))	('secondary structure', 'MPA', (229, 248))	('protein stability', 'MPA', (301, 318))	('pVHL', 'Gene', (130, 134))	('protein', 'cellular_component', 'GO:0003675', ('199', '206'))
7785	33151962	In order to improve our strategy for the algorithmic assessment of missense mutations, a weighting strategy was developed using the pathogenicity indications available on ClinVar and Symphony, an online predictor of ccRCC risk of mutations in VHL.	('ccRCC', 'Phenotype', 'HP:0006770', (216, 221))	('ccRCC', 'Disease', (216, 221))	('VHL', 'Gene', (243, 246))	('mutations', 'Var', (230, 239))	('VHL', 'Gene', '7428', (243, 246))
7787	33151962	Indeed, mean algorithm scores were significantly higher in regions of helix or sheet compared to random coil regions of the VHL protein (Fig 2A).	('VHL', 'Gene', '7428', (124, 127))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('helix', 'Var', (70, 75))	('algorithm scores', 'MPA', (13, 29))	('higher', 'PosReg', (49, 55))	('VHL', 'Gene', (124, 127))
7793	33151962	Due to the importance of each VHL protein interface (A,B,C) in the ubiquitin ligase function of VHL and subsequent HIF regulation by VHL, we expected to observe higher average algorithm scores for mutations occurring within these interfaces.	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('ubiquitin ligase function', 'MPA', (67, 92))	('VHL', 'Gene', (133, 136))	('VHL', 'Gene', (30, 33))	('mutations', 'Var', (197, 206))	('VHL', 'Gene', '7428', (133, 136))	('VHL', 'Gene', '7428', (30, 33))	('VHL', 'Gene', (96, 99))	('higher', 'PosReg', (161, 167))	('ubiquitin', 'molecular_function', 'GO:0031386', ('67', '76'))	('VHL', 'Gene', '7428', (96, 99))	('regulation', 'biological_process', 'GO:0065007', ('119', '129'))
7795	33151962	Recent studies into the distribution of mutations within the VHL structure have observed that amino acid changes occurring on the surface of the pVHL are more deleterious for overall function.	('VHL', 'Gene', (146, 149))	('amino acid', 'MPA', (94, 104))	('deleterious', 'Reg', (159, 170))	('VHL', 'Gene', '7428', (146, 149))	('pVHL', 'Gene', '7428', (145, 149))	('mutations', 'Var', (40, 49))	('VHL', 'Gene', (61, 64))	('pVHL', 'Gene', (145, 149))	('function', 'MPA', (183, 191))	('VHL', 'Gene', '7428', (61, 64))
7797	33151962	Since VHL functions as a scaffold for the assembly of the VCB complex, we would expect that mutations occurring on the surface of the protein, and therefore affecting the binding sites for interaction partners, would result in higher algorithm scores and more severe disease.	('binding', 'molecular_function', 'GO:0005488', ('171', '178'))	('binding', 'Interaction', (171, 178))	('affecting', 'Reg', (157, 166))	('interaction', 'Interaction', (189, 200))	('VCB complex', 'cellular_component', 'GO:0030891', ('58', '69'))	('mutations', 'Var', (92, 101))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('VHL', 'Gene', (6, 9))	('higher', 'PosReg', (227, 233))	('VCB', 'Chemical', '-', (58, 61))	('VHL', 'Gene', '7428', (6, 9))	('algorithm scores', 'MPA', (234, 250))
7798	33151962	The p-value (p = .06) indicated that the algorithm scores for comparing the surface versus core-located mutations approached significance at the .05 alpha-value, suggesting that the observed trend towards a higher algorithm score (mean score = 13.2) in the surface mutations versus mutations occurring deeper in the VHL structure (mean score = 10.4) may have biological importance (Fig 2D).	('core', 'cellular_component', 'GO:0019013', ('91', '95'))	('surface mutations', 'Var', (257, 274))	('algorithm score', 'MPA', (214, 229))	('VHL', 'Gene', (316, 319))	('VHL', 'Gene', '7428', (316, 319))	('higher', 'PosReg', (207, 213))
7799	33151962	We investigated the capacity of our algorithm to identify mutations that have been described as highly destabilizing to VHL.	('mutations', 'Var', (58, 67))	('VHL', 'Gene', (120, 123))	('destabilizing', 'NegReg', (103, 116))	('VHL', 'Gene', '7428', (120, 123))
7800	33151962	Razafinjatovo et al identified W117 and L184 as missense mutation hotspots that can highly destabilize pVHL.	('W117', 'Var', (31, 35))	('pVHL', 'Gene', (103, 107))	('pVHL', 'Gene', '7428', (103, 107))	('L184', 'Var', (40, 44))
7801	33151962	Other VHL mutation hot spots, such as L158 and N78 (scores of 13.0 and 16.3, respectively), also scored highly above the average for pathogenic ClinVar mutations; however, R167, another annotated VHL hotspot, received a below average pathogenic score (9.6) (Table 2).	('R167', 'Var', (172, 176))	('VHL', 'Gene', (6, 9))	('VHL', 'Gene', (196, 199))	('VHL', 'Gene', '7428', (6, 9))	('VHL', 'Gene', '7428', (196, 199))
7802	33151962	In this way, pathogenic mutations such as Y98, with low algorithm scores may not ultimately cause disease phenotypes by destabilizing pVHL protein, but through a more direct local effect that is critical for VHL function and protein interaction.	('VHL', 'Gene', (135, 138))	('VHL', 'Gene', (208, 211))	('Y98', 'Var', (42, 45))	('VHL', 'Gene', '7428', (135, 138))	('VHL', 'Gene', '7428', (208, 211))	('protein', 'cellular_component', 'GO:0003675', ('225', '232'))	('pVHL', 'Gene', '7428', (134, 138))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('pVHL', 'Gene', (134, 138))
7804	33151962	Other studies have found that specific mutations at the Y98 position will cause different VHL cancer phenotypes with Y98H causing type 2B disease and Y98N causing type 2A disease by modulating the efficacy of binding to HIFalpha.	('type 2A disease', 'Disease', (163, 178))	('Y98H', 'Var', (117, 121))	('binding', 'molecular_function', 'GO:0005488', ('209', '216'))	('Y98N', 'SUBSTITUTION', 'None', (150, 154))	('binding', 'Interaction', (209, 216))	('causing', 'Reg', (155, 162))	('VHL', 'Gene', (90, 93))	('cancer', 'Disease', (94, 100))	('HIFalpha', 'Protein', (220, 228))	('modulating', 'Reg', (182, 192))	('Y98H', 'SUBSTITUTION', 'None', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cause', 'Reg', (74, 79))	('Y98N', 'Var', (150, 154))	('VHL', 'Gene', '7428', (90, 93))	('causing', 'Reg', (122, 129))	('efficacy', 'MPA', (197, 205))	('Y98', 'Var', (56, 59))	('type 2B disease', 'Disease', (130, 145))	('HIFalpha', 'Chemical', '-', (220, 228))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
7806	33151962	Next, we assessed if our algorithm would be able to identify missense mutations that are more likely to be associated with an early age of onset of VHL-related pathologies.	('VHL', 'Gene', (148, 151))	('associated', 'Reg', (107, 117))	('missense mutations', 'Var', (61, 79))	('VHL', 'Gene', '7428', (148, 151))
7809	33151962	These data indicate that our algorithm can distinguish more pathogenic mutations from less pathogenic ones that are based on age-related onset of different VHL related cancer types.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('VHL', 'Gene', '7428', (156, 159))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('mutations', 'Var', (71, 80))	('cancer', 'Disease', (168, 174))	('VHL', 'Gene', (156, 159))
7812	33151962	Our analysis provide significant support for the use and refinement of in silico evaluation of VHL mutations and their capacity for large scale protein dysfunction to predict pathogenic outcomes.	('mutations', 'Var', (99, 108))	('VHL', 'Gene', '7428', (95, 98))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('VHL', 'Gene', (95, 98))
7817	33151962	Computational and biophysical approaches aimed at predicting the severity of a mutation and its deleterious consequences on the function of pVHL can contribute additional information on how the disease might progress.	('pVHL', 'Gene', (140, 144))	('pVHL', 'Gene', '7428', (140, 144))	('mutation', 'Var', (79, 87))
7818	33151962	We have provided a multiparameteric algorithmic approach to evaluate the severity of missense mutations in VHL.	('missense mutations', 'Var', (85, 103))	('VHL', 'Gene', '7428', (107, 110))	('VHL', 'Gene', (107, 110))
7820	33151962	Taken together, our multiparameteric algorithm can be used to identify pathogenic from benign mutations in pVHL.	('pVHL', 'Gene', '7428', (107, 111))	('pVHL', 'Gene', (107, 111))	('mutations', 'Var', (94, 103))
7823	33151962	The N-terminus is predicted to exist as an unstructured/random coil region; therefore, we expected lower average algorithm scores for mutations occurring in the coil regions of pVHL (Fig 2A).	('lower', 'NegReg', (99, 104))	('algorithm scores', 'MPA', (113, 129))	('pVHL', 'Gene', (177, 181))	('mutations', 'Var', (134, 143))	('pVHL', 'Gene', '7428', (177, 181))
7828	33151962	Mutations that occur in this region are poised to interrupt the protein interactions crucial for HIF regulation, leading to tumor development.	('interrupt', 'NegReg', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('tumor', 'Disease', (124, 129))	('leading to', 'Reg', (113, 123))	('Mutations', 'Var', (0, 9))	('regulation', 'biological_process', 'GO:0065007', ('101', '111'))	('protein', 'Protein', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
7830	33151962	pVHL functions to complex proteins together; therefore, mutations occurring on the surface of the protein, regardless of interface, should be more deleterious to overall function than mutations occurring towards the interior of the protein.	('deleterious', 'Reg', (147, 158))	('pVHL', 'Gene', '7428', (0, 4))	('mutations', 'Var', (56, 65))	('pVHL', 'Gene', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('232', '239'))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('function', 'MPA', (170, 178))
7832	33151962	Upon spontaneous mutation of the wild-type allele in susceptible tissue types, tumor development begins.	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('mutation', 'Var', (17, 25))	('tumor', 'Disease', (79, 84))
7835	33151962	The approach outlined in this paper can identify mutations that are destabilizing, but this trend was not maintained for all mutations identified as VHL mutation hot spots, such as Y98 (Table 2).	('VHL', 'Gene', '7428', (149, 152))	('VHL', 'Gene', (149, 152))	('mutations', 'Var', (49, 58))
7836	33151962	Our multiparametric scoring algorithm evaluates the consequences of a missense mutation on the overall stability and folding dynamics of pVHL.	('folding', 'MPA', (117, 124))	('stability', 'MPA', (103, 112))	('missense mutation', 'Var', (70, 87))	('pVHL', 'Gene', (137, 141))	('pVHL', 'Gene', '7428', (137, 141))
7837	33151962	Pathogenic mutations with lower algorithm scores, such as Y98, may serve a more direct role in protein-protein interactions or posttranslational modification, may be missed in our algorithm.	('post', 'Gene', '159371', (127, 131))	('Y98', 'Var', (58, 61))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('post', 'Gene', (127, 131))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('posttranslational modification', 'biological_process', 'GO:0043687', ('127', '157'))	('protein-protein interactions', 'MPA', (95, 123))
7839	33151962	For example, some same-sense mutations can cause exon skipping in VHL, like the synonymous c.414A>G, p.Pro138Pro mutation The dysregulation of splicing creates a truncated protein product consisting of exons 1 and 3.	('mutations', 'Var', (29, 38))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('c.414A>G', 'Mutation', 'rs869025648', (91, 99))	('p.Pro138Pro', 'Mutation', 'rs869025648', (101, 112))	('splicing', 'biological_process', 'GO:0045292', ('143', '151'))	('VHL', 'Gene', (66, 69))	('VHL', 'Gene', '7428', (66, 69))
7840	33151962	This deleterious variant of pVHL is unable to regulate HIF expression.	('pVHL', 'Gene', '7428', (28, 32))	('pVHL', 'Gene', (28, 32))	('HIF expression', 'MPA', (55, 69))	('variant', 'Var', (17, 24))	('unable', 'NegReg', (36, 42))
7842	33151962	In exceptional cases as this clinical mutation, a more detailed understanding of the mechanism of exon skipping could inform future algorithmic approaches for the assessment of exon skipping risk in the VHL gene.	('VHL', 'Gene', (203, 206))	('exon skipping', 'Var', (177, 190))	('inform', 'Reg', (118, 124))	('VHL', 'Gene', '7428', (203, 206))
7843	33151962	We have provided the first comprehensive multiparametric assessment of VHL missense mutations on the function of the VHL protein.	('missense mutations', 'Var', (75, 93))	('VHL', 'Gene', '7428', (117, 120))	('VHL', 'Gene', (71, 74))	('VHL', 'Gene', '7428', (71, 74))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('VHL', 'Gene', (117, 120))
7844	33151962	Our platform provides the first steps to understand the phenotypic heterogeneity associated with missense mutations in pVHL.	('pVHL', 'Gene', '7428', (119, 123))	('missense mutations', 'Var', (97, 115))	('pVHL', 'Gene', (119, 123))
7878	33050520	In principle, multi-epitope tumor vaccines limit the risk of immune escape tumor variants, which, under the selective pressure of immunotherapies via genetic or epigenetic modifications, have down-regulated, single-targeted antigens or HLA class I or class II alleles.	('single-targeted', 'Var', (208, 223))	('tumor', 'Disease', (28, 33))	('epigenetic modifications', 'Var', (161, 185))	('down-regulated', 'NegReg', (192, 206))	('antigens', 'Protein', (224, 232))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('variants', 'Var', (81, 89))	('tumor', 'Disease', (75, 80))
7899	33050520	Through this linkage, the AE36 15-mer has a stronger binding affinity with MHC class II molecules, thus prolonging the interaction of the cognate CD4+ T cells with the antigen-presenting cells and, in this way, inducing more potent CD4+ T cell activation.	('interaction', 'Interaction', (119, 130))	('stronger', 'PosReg', (44, 52))	('prolonging', 'PosReg', (104, 114))	('binding', 'molecular_function', 'GO:0005488', ('53', '60'))	('AE36 15-mer', 'Var', (26, 37))	('CD4', 'Gene', (232, 235))	('CD4', 'Gene', (146, 149))	('binding affinity', 'Interaction', (53, 69))	('CD4', 'Gene', '920', (146, 149))	('inducing', 'Reg', (211, 219))	('CD4', 'Gene', '920', (232, 235))	('T cell activation', 'biological_process', 'GO:0042110', ('237', '254'))	('AE36', 'Chemical', '-', (26, 30))
7900	33050520	Moreover, AE36 contains in its sequence HLA-class I binding motifs, thus being capable of activating activate CD8+ T cells specifically (in addition to CD4+ T cells).	('binding', 'molecular_function', 'GO:0005488', ('52', '59'))	('AE36', 'Chemical', '-', (10, 14))	('CD4', 'Gene', (152, 155))	('binding', 'Interaction', (52, 59))	('CD8', 'Gene', (110, 113))	('CD4', 'Gene', '920', (152, 155))	('activating', 'MPA', (90, 100))	('AE36', 'Var', (10, 14))	('CD8', 'Gene', '925', (110, 113))
7903	33050520	High-risk node-negative patients were defined if they had any of following: HER2 overexpressing tumor, >=T2, grade 3, lymphovascular invasion, estrogen or progesterone receptor negative.	('HER2', 'Gene', (76, 80))	('lymphovascular invasion', 'CPA', (118, 141))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('HER2', 'Gene', '2064', (76, 80))	('progesterone receptor', 'Gene', (155, 176))	('progesterone receptor', 'Gene', '5241', (155, 176))	('>=T2', 'Var', (103, 107))	('tumor', 'Disease', (96, 101))	('overexpressing', 'PosReg', (81, 95))	('patients', 'Species', '9606', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
7906	33050520	Patients in the vaccine group (AE37/GM-CSF) developed significant AE37-specific IFNgamma and proliferative responses as well as DTH reactions as compared to the placebo arm (GM-CSF).	('GM-CSF', 'Gene', (36, 42))	('GM-CSF', 'Gene', '1437', (36, 42))	('IFNgamma', 'Gene', (80, 88))	('IFNgamma', 'Gene', '3458', (80, 88))	('GM-CSF', 'Gene', (174, 180))	('GM-CSF', 'Gene', '1437', (174, 180))	('proliferative responses', 'CPA', (93, 116))	('AE37-specific', 'Var', (66, 79))	('Patients', 'Species', '9606', (0, 8))	('DTH', 'Phenotype', 'HP:0002972', (128, 131))	('DTH', 'Disease', (128, 131))
7907	33050520	However, when patients were subgrouped by clinicopathological parameters, AE37 was associated with improved clinical benefits.	('patients', 'Species', '9606', (14, 22))	('clinical benefits', 'CPA', (108, 125))	('improved', 'PosReg', (99, 107))	('AE37', 'Var', (74, 78))
7917	33050520	Another interesting finding from the AE37 phase II trial was that in the subgroups of BCa patients the AE37 vaccine showed clinical efficacy over the placebo (i.e., the Kaplan-Meier survival curves for the two arms separated 12 months following the vaccinations).	('BCa', 'Phenotype', 'HP:0003002', (86, 89))	('patients', 'Species', '9606', (90, 98))	('AE37', 'Var', (103, 107))	('BCa', 'Disease', (86, 89))
7932	33050520	Patients who received cyclophosphamide had significantly reduced numbers of circulating Tregs and, among those, immunological responders to any of the IMA901 peptides had significantly prolonged survival.	('prolonged', 'PosReg', (185, 194))	('survival', 'CPA', (195, 203))	('Tregs', 'Chemical', '-', (88, 93))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (22, 38))	('Patients', 'Species', '9606', (0, 8))	('cyclophosphamide', 'Var', (22, 38))	('reduced', 'NegReg', (57, 64))
7955	33050520	Neuvax is a vaccine consisting of the E75 peptide (the HER2 nonamer: 369-377) and GM-CSF as an adjuvant, and was used to vaccinate in phase I and phase II trials (i.e., stage II or stage III breast cancer patients who expressed HER2 at all levels (immunohistochemical staining 1+, 2+, 3+)).	('III breast cancer', 'Disease', (187, 204))	('vaccinate', 'Chemical', '-', (121, 130))	('patients', 'Species', '9606', (205, 213))	('HER2', 'Gene', (228, 232))	('GM-CSF', 'Gene', (82, 88))	('HER2', 'Gene', '2064', (228, 232))	('GM-CSF', 'Gene', '1437', (82, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))	('E75', 'Var', (38, 41))	('Neuvax', 'Chemical', '-', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('HER2', 'Gene', (55, 59))	('III breast cancer', 'Disease', 'MESH:D001943', (187, 204))	('HER2', 'Gene', '2064', (55, 59))
7999	33050520	Such improvements will advance clinical responses among non-vaccinated patients in the phase III trials, thus prolonging their survival and possibly masking any vaccine effects within the defined time frame of the clinical study.	('prolonging', 'NegReg', (110, 120))	('advance', 'PosReg', (23, 30))	('masking', 'NegReg', (149, 156))	('clinical', 'MPA', (31, 39))	('patients', 'Species', '9606', (71, 79))	('improvements', 'Var', (5, 17))	('men', 'Species', '9606', (12, 15))	('vaccinate', 'Chemical', '-', (60, 69))	('survival', 'MPA', (127, 135))
8001	33050520	For instance, in the IMPACT phase III trial, Sipuleucel-T, the only FDA-approved therapeutic vaccine, prolonged OS in prostate cancer patients who had asymptomatic metastatic castrate-resistant disease (mCRPC), and during vaccinations did not need to concomitantly receive docetaxel.	('prostate cancer', 'Disease', (118, 133))	('prolonged', 'PosReg', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('prostate cancer', 'Disease', 'MESH:D011471', (118, 133))	('patients', 'Species', '9606', (134, 142))	('prostate cancer', 'Phenotype', 'HP:0012125', (118, 133))	('Sipuleucel-T', 'Var', (45, 57))	('docetaxel', 'Chemical', 'MESH:D000077143', (273, 282))
8054	28405930	In contrast, WES and WGS provide greater coverage of the genome and an increased ability to discover mutations; however, as genome coverage increases so does the false positive rate.	('mutations', 'Var', (101, 110))	('rat', 'Species', '10116', (177, 180))	('false positive', 'MPA', (162, 176))	('discover', 'Reg', (92, 100))	('false', 'biological_process', 'GO:0071878', ('162', '167'))	('false', 'biological_process', 'GO:0071877', ('162', '167'))
8057	28405930	Comparing SCS results to bulk tumor sequence can be used to estimate technical errors; however, this approach may decrease the ability to detect variants specific to the single cells.	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('variants', 'Var', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('SCS', 'molecular_function', 'GO:0004776', ('10', '13'))	('decrease', 'NegReg', (114, 122))	('tumor', 'Disease', (30, 35))
8061	28405930	Tissue-specific stem cells may accumulate certain mutations over time that initiate carcinogenesis, causing them to become cancer stem cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('carcinogenesis', 'Disease', (84, 98))	('mutations', 'Var', (50, 59))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('carcinogenesis', 'Disease', 'MESH:D063646', (84, 98))
8062	28405930	Additional mutations in cancer stem cells that alter molecular pathways influencing genome stability, resistance to apoptosis, and normal growth and differentiation, may occur during tumorigenesis, leading to substantial genetic and functional diversity among clonal populations of cells within a primary carcinoma.	('mutations', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('primary carcinoma', 'Disease', (297, 314))	('leading to', 'Reg', (198, 208))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('apoptosis', 'biological_process', 'GO:0097194', ('116', '125'))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('tumor', 'Disease', (183, 188))	('primary carcinoma', 'Disease', 'MESH:D002277', (297, 314))	('apoptosis', 'biological_process', 'GO:0006915', ('116', '125'))
8063	28405930	Although the development of genetic diversity in cancer stem cells has not been well defined, SCS is now being used to study cancer stem cells to identify mutations in key functional pathways promoting tumorigenesis.	('promoting', 'PosReg', (192, 201))	('mutations', 'Var', (155, 164))	('tumor', 'Disease', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('SCS', 'molecular_function', 'GO:0004776', ('94', '97'))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('cancer', 'Disease', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
8081	28405930	Alterations in copy number were widely shared, suggesting they occurred early in carcinogenesis, while point mutations appeared to evolve gradually over a longer period of time.	('rat', 'Species', '10116', (4, 7))	('Alterations', 'Var', (0, 11))	('carcinogenesis', 'Disease', (81, 95))	('carcinogenesis', 'Disease', 'MESH:D063646', (81, 95))
8083	28405930	Similarly, in two patients with estrogen receptor (ER)-positive breast cancer, chromosomal alterations characteristic of ER+ tumors including duplications of 1q and 8q and deletion of 11q were shared across most single cells from both patients, indicating that these events occurred early in the development of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('rat', 'Species', '10116', (95, 98))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (317, 323))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('patients', 'Species', '9606', (235, 243))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', (317, 323))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('estrogen receptor', 'Gene', '2099', (32, 49))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (317, 323))	('patients', 'Species', '9606', (18, 26))	('deletion of 11q', 'Var', (172, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('ER', 'Gene', '2099', (121, 123))	('ER', 'Gene', '2099', (51, 53))	('estrogen receptor', 'Gene', (32, 49))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('duplications', 'Var', (142, 154))	('breast cancer', 'Disease', (64, 77))
8084	28405930	Together, the SCS data suggest that the earliest steps of tumor development involve copy number changes that occur in punctuated bursts, but point mutations evolve gradually, driving clonal expansions and generating extensive clonal diversity within a primary carcinoma.	('driving', 'Reg', (175, 182))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('SCS', 'molecular_function', 'GO:0004776', ('14', '17'))	('primary carcinoma', 'Disease', (252, 269))	('copy number changes', 'Var', (84, 103))	('generating', 'Reg', (205, 215))	('rat', 'Species', '10116', (209, 212))	('point mutations', 'Var', (141, 156))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('primary carcinoma', 'Disease', 'MESH:D002277', (252, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))
8085	28405930	NGS technology is being used extensively to identify genetic variability associated with acquired resistance to chemotherapy, which has become a major barrier to successful cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('acquired resistance', 'Disease', (89, 108))	('cancer', 'Disease', (173, 179))	('associated', 'Reg', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('genetic variability', 'Var', (53, 72))
8086	28405930	Large-scale RNA-seq on single cells from breast cancer cell lines has shown that cells exhibiting high variability in RNA transcripts, which was also evident at the protein level, possess increased metastatic capacity and survival following chemotherapeutic treatment.	('survival', 'CPA', (222, 230))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('RNA', 'Gene', (118, 121))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('RNA', 'cellular_component', 'GO:0005562', ('12', '15'))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('RNA', 'cellular_component', 'GO:0005562', ('118', '121'))	('variability', 'Var', (103, 114))	('increased', 'PosReg', (188, 197))	('metastatic capacity', 'CPA', (198, 217))
8093	28405930	Combining the status of the Kirsten rat sarcoma viral oncogene homolog (KRAS) G12D (35G>A) mutation with the expression profiles of 69 genes associated with clinical prognosis classified the adenocarcinoma cells into four groups with different gene expression patterns.	('35G>A', 'Mutation', 'rs121913529', (84, 89))	('mutation', 'Var', (91, 99))	('KRAS', 'Gene', (72, 76))	('rat', 'Species', '10116', (36, 39))	('adenocarcinoma', 'Disease', 'MESH:D000230', (191, 205))	('gene expression', 'biological_process', 'GO:0010467', ('244', '259'))	('sarcoma', 'Disease', 'MESH:D012509', (40, 47))	('sarcoma', 'Disease', (40, 47))	('G12D', 'Mutation', 'rs121913529', (78, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('adenocarcinoma', 'Disease', (191, 205))
8097	28405930	Focusing on the LC2/ad cell line and a derivative cell line (LC2/ad-R), which has acquired resistance to the multi-tyrosine kinase inhibitor drug vandetanib, showed that average gene expression levels changed more in LC2/ad-R cells than in LC2/ad cells in response to vandetanib treatment, potentially reflecting an acquired plasticity in the ability to respond to vandetanib.	('LC2/ad-R', 'Var', (217, 225))	('changed', 'Reg', (201, 208))	('vandetanib', 'Chemical', 'MESH:C452423', (268, 278))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('124', '140'))	('gene expression levels', 'MPA', (178, 200))	('vandetanib', 'Chemical', 'MESH:C452423', (365, 375))	('vandetanib', 'Chemical', 'MESH:C452423', (146, 156))	('gene expression', 'biological_process', 'GO:0010467', ('178', '193'))
8100	28405930	Extensive cellular and molecular heterogeneity is a common feature of glioblastomas, including multiple alterations in the epidermal growth factor receptor (EGFR) gene that may affect treatment response.	('epidermal growth factor receptor', 'Gene', (123, 155))	('EGFR', 'Gene', (157, 161))	('alterations', 'Var', (104, 115))	('rat', 'Species', '10116', (108, 111))	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('glioblastomas', 'Disease', (70, 83))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('123', '146'))	('epidermal growth factor receptor', 'Gene', '1956', (123, 155))	('EGFR', 'molecular_function', 'GO:0005006', ('157', '161'))	('affect', 'Reg', (177, 183))	('glioblastomas', 'Phenotype', 'HP:0012174', (70, 83))	('EGFR', 'Gene', '1956', (157, 161))	('glioblastomas', 'Disease', 'MESH:D005909', (70, 83))
8102	28405930	conducted single-nucleus WGS on two glioblastomas with focal amplification of EGFR.	('glioblastomas', 'Phenotype', 'HP:0012174', (36, 49))	('glioblastoma', 'Phenotype', 'HP:0012174', (36, 48))	('glioblastomas', 'Disease', 'MESH:D005909', (36, 49))	('focal amplification', 'Var', (55, 74))	('glioblastomas', 'Disease', (36, 49))	('nucleus', 'cellular_component', 'GO:0005634', ('17', '24'))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('EGFR', 'Gene', (78, 82))
8103	28405930	EGFR copy number was observed to be highly variable between single cells due to varying levels of EGFR amplification (5-200 copies), EGFRvII truncation (deletion of exons 14-15), and EGFRvIII deletion (deletion of exons 2-7).	('EGFR', 'Gene', (98, 102))	('deletion', 'Var', (153, 161))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (183, 187))	('EGFR', 'Gene', (183, 187))	('deletion', 'Var', (192, 200))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (133, 137))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (133, 137))
8104	28405930	These data suggest that heterogeneity in the expression of oncogenic EGFR mutations may contribute to therapy resistance and combining multiple EGFR inhibitors that act through different mechanisms may be required in glioblastoma patients who carry multiple EGFR variants.	('EGFR', 'Gene', '1956', (258, 262))	('EGFR', 'Gene', '1956', (69, 73))	('contribute', 'Reg', (88, 98))	('EGFR', 'Gene', (144, 148))	('EGFR', 'molecular_function', 'GO:0005006', ('144', '148'))	('EGFR', 'Gene', (258, 262))	('EGFR', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('258', '262'))	('glioblastoma', 'Disease', (217, 229))	('patients', 'Species', '9606', (230, 238))	('EGFR', 'molecular_function', 'GO:0005006', ('69', '73'))	('glioblastoma', 'Phenotype', 'HP:0012174', (217, 229))	('glioblastoma', 'Disease', 'MESH:D005909', (217, 229))	('EGFR', 'Gene', '1956', (144, 148))
8106	28405930	In agreement with the study described above by Francis et al., several oncogenic variants of EGFR were detected within a single glioblastoma.	('EGFR', 'molecular_function', 'GO:0005006', ('93', '97'))	('EGFR', 'Gene', '1956', (93, 97))	('detected', 'Reg', (103, 111))	('EGFR', 'Gene', (93, 97))	('glioblastoma', 'Disease', (128, 140))	('glioblastoma', 'Disease', 'MESH:D005909', (128, 140))	('variants', 'Var', (81, 89))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))
8110	28405930	Unlike many types of human cancer, linear models of evolution have been developed for colon cancer, with mutations in genes such as adenomatous polyposis coli (APC) and tumor protein p53 (TP53) playing critical roles in tumor progression.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('roles', 'Reg', (211, 216))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Disease', (220, 225))	('p53', 'Gene', '7157', (183, 186))	('mutations', 'Var', (105, 114))	('APC', 'Gene', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('colon cancer', 'Disease', (86, 98))	('p53', 'Gene', (183, 186))	('APC', 'cellular_component', 'GO:0005680', ('160', '163'))	('tumor', 'Disease', (169, 174))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('TP53', 'Gene', '7157', (188, 192))	('protein', 'cellular_component', 'GO:0003675', ('175', '182'))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('cancer', 'Disease', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (132, 158))	('colon cancer', 'Phenotype', 'HP:0003003', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('adenomatous polyposis coli', 'Disease', (132, 158))	('APC', 'Gene', '324', (160, 163))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (132, 153))	('human', 'Species', '9606', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancer', 'Disease', (27, 33))	('colon cancer', 'Disease', 'MESH:D015179', (86, 98))	('TP53', 'Gene', (188, 192))
8112	28405930	The major subgroup of tumor cells was characterized by a high frequency of APC and TP53 mutations while in the minor subgroup, mutations in the cell division cycle 27 (CDC27) and polyadenylate-binding protein, cytoplasmic, 1 (PABPC1) genes were predominant.	('TP53', 'Gene', '7157', (83, 87))	('CDC27', 'Gene', (168, 173))	('APC', 'Gene', '324', (75, 78))	('protein', 'cellular_component', 'GO:0003675', ('201', '208'))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('TP53', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('APC', 'cellular_component', 'GO:0005680', ('75', '78'))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('PABPC1', 'Gene', '26986', (226, 232))	('cell division cycle', 'biological_process', 'GO:0007049', ('144', '163'))	('CDC27', 'Gene', '996', (168, 173))	('tumor', 'Disease', (22, 27))	('polyadenylate-binding protein, cytoplasmic, 1', 'Gene', '26986', (179, 224))	('PABPC1', 'Gene', (226, 232))	('APC', 'Gene', (75, 78))	('polyadenylate-binding', 'molecular_function', 'GO:0008143', ('179', '200'))
8113	28405930	The authors concluded that this tumor was bi-clonal in origin, with each subpopulation deriving from separate ancestors; however, this conclusion has been questioned as not all cells in the major population had mutations in APC and TP53 and mutations in CDC27 and PABPC1 were present in both groups, suggesting possible technical difficulties associated with WGA.	('CDC27', 'Gene', (254, 259))	('PABPC1', 'Gene', '26986', (264, 270))	('PABPC1', 'Gene', (264, 270))	('rat', 'Species', '10116', (105, 108))	('APC', 'Gene', (224, 227))	('APC', 'cellular_component', 'GO:0005680', ('224', '227'))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('mutations', 'Var', (211, 220))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('CDC27', 'Gene', '996', (254, 259))	('APC', 'Gene', '324', (224, 227))	('TP53', 'Gene', '7157', (232, 236))	('TP53', 'Gene', (232, 236))	('tumor', 'Disease', (32, 37))
8114	28405930	In a separate study, RNA-seq data generated on 96 single cells from the HCT116 colon cancer cell line were used to assess patterns of gene expression and detect enrichment of DNA variants in colon cancer-related pathways.	('colon cancer', 'Disease', (79, 91))	('RNA', 'cellular_component', 'GO:0005562', ('21', '24'))	('rat', 'Species', '10116', (9, 12))	('variants', 'Var', (179, 187))	('colon cancer', 'Disease', (191, 203))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('DNA', 'cellular_component', 'GO:0005574', ('175', '178'))	('HCT116', 'CellLine', 'CVCL:0291', (72, 78))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('gene expression', 'biological_process', 'GO:0010467', ('134', '149'))	('rat', 'Species', '10116', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('colon cancer', 'Phenotype', 'HP:0003003', (191, 203))	('colon cancer', 'Disease', 'MESH:D015179', (191, 203))
8115	28405930	This study showed that single-cell RNA-seq of colon cancers may reveal cryptic genetic alterations in cancer-related genes, enrichment of certain functional pathways, and presence of fusion proteins that may play important roles in the development of colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('fusion proteins', 'Protein', (183, 198))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('colon cancer', 'Disease', (251, 263))	('colon cancers', 'Phenotype', 'HP:0003003', (46, 59))	('roles', 'Reg', (223, 228))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('colon cancer', 'Phenotype', 'HP:0003003', (46, 58))	('RNA', 'cellular_component', 'GO:0005562', ('35', '38'))	('rat', 'Species', '10116', (91, 94))	('colon cancer', 'Phenotype', 'HP:0003003', (251, 263))	('cancer', 'Disease', (102, 108))	('colon cancers', 'Disease', 'MESH:D015179', (46, 59))	('cancer', 'Disease', (52, 58))	('colon cancer', 'Disease', 'MESH:D015179', (46, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('colon cancers', 'Disease', (46, 59))	('alterations', 'Var', (87, 98))	('colon cancer', 'Disease', 'MESH:D015179', (251, 263))	('cancer', 'Disease', (257, 263))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
8119	28405930	The authors hypothesized that the bladder cancer cells were subjected to selective pressure and accumulated mutually-exclusive driver mutations within these cell lineages during development.	('bladder cancer', 'Phenotype', 'HP:0009725', (34, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('bladder cancer', 'Disease', 'MESH:D001749', (34, 48))	('mutations', 'Var', (134, 143))	('bladder cancer', 'Disease', (34, 48))
8120	28405930	The projected timing of key mutations during cancer growth suggests that mutations in cancer-associated genes may initiate carcinogenesis and lead to genetically-distinct cell lineages that influence resistance to treatment.	('lead to', 'Reg', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('carcinogenesis', 'Disease', 'MESH:D063646', (123, 137))	('initiate', 'Reg', (114, 122))	('resistance to treatment', 'CPA', (200, 223))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('carcinogenesis', 'Disease', (123, 137))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (45, 51))	('mutations', 'Var', (73, 82))	('influence', 'Reg', (190, 199))	('cancer', 'Disease', (86, 92))
8124	28405930	Because these pathways represent important targets for anti-cancer therapeutics, heterogeneity in expression may affect tumor response to therapy and patient survival.	('heterogeneity', 'Var', (81, 94))	('patient', 'Species', '9606', (150, 157))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('affect', 'Reg', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('patient survival', 'CPA', (150, 166))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', (120, 125))
8129	28405930	Although no significant sub-clonal populations of cells were detected within the tumor, there were many rare mutations, each present in only a few cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('mutations', 'Var', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cancer', 'Disease', (147, 153))	('tumor', 'Disease', (81, 86))
8140	28405930	To delineate the clonal structure and evolutionary history of acute lymphoblastic leukemia (ALL), targeted sequencing of a panel of SNVs, deletions, and immunoglobulin heavy chain sequences was performed on 1479 single cells from six children with pediatric ALL.	('immunoglobulin', 'molecular_function', 'GO:0003823', ('153', '167'))	('ALL', 'Phenotype', 'HP:0006721', (92, 95))	('acute lymphoblastic leukemia', 'Disease', (62, 90))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (62, 90))	('ALL', 'Phenotype', 'HP:0006721', (258, 261))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (68, 90))	('deletions', 'Var', (138, 147))	('children', 'Species', '9606', (234, 242))	('leukemia', 'Phenotype', 'HP:0001909', (82, 90))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (62, 90))
8141	28405930	As seen with other types of cancer, ALL carcinomas were characterized by distinct clonal populations of cells where alterations in copy number preceded the occurrence of SNVs.	('ALL', 'Phenotype', 'HP:0006721', (36, 39))	('copy number', 'Var', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('rat', 'Species', '10116', (120, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('alterations', 'Var', (116, 127))	('carcinomas', 'Disease', 'MESH:D002277', (40, 50))	('cancer', 'Disease', (28, 34))	('carcinomas', 'Disease', (40, 50))
8142	28405930	Phylogenetic analysis revealed that KRAS-associated driver mutations occurred late in tumor development and facilitated the expansion of certain clones, which became dominant but did not completely outcompete all of the other clones in each patient.	('KRAS-associated driver', 'Gene', (36, 58))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('expansion', 'CPA', (124, 133))	('tumor', 'Disease', (86, 91))	('patient', 'Species', '9606', (241, 248))	('mutations', 'Var', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('facilitated', 'PosReg', (108, 119))
8146	28405930	SCS identified subpopulations of cells within each tumor that harbored copy number alterations not detected in whole-tumor analysis.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', (51, 56))	('SCS', 'molecular_function', 'GO:0004776', ('0', '3'))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('copy number alterations', 'Var', (71, 94))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('rat', 'Species', '10116', (87, 90))
8149	28405930	Although more than half of all ET patients carry mutations in the Janus kinase 2 (JAK2) gene, mutations in other genes are known to affect disease phenotype and clinical outcome.	('Janus kinase 2', 'Gene', (66, 80))	('mutations', 'Var', (49, 58))	('affect', 'Reg', (132, 138))	('Janus kinase 2', 'Gene', '3717', (66, 80))	('JAK2', 'Gene', (82, 86))	('patients', 'Species', '9606', (34, 42))	('JAK', 'molecular_function', 'GO:0004713', ('82', '85'))
8153	28405930	At the single-cell level, most primary tumors are polyclonal due to punctuated clonal evolution where copy number alterations serve as founder mutations and additional CNVs and/or point mutations occur later in tumor development.	('copy number alterations', 'Var', (102, 125))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('rat', 'Species', '10116', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', (39, 44))	('point mutations', 'Var', (180, 195))	('tumors', 'Disease', (39, 45))
8154	28405930	These subsequent mutations are restricted to subpopulations of cells where they contribute to clonal fitness and thus influence resistance to treatment and patient survival.	('clonal fitness', 'CPA', (94, 108))	('resistance to treatment', 'CPA', (128, 151))	('patient', 'Species', '9606', (156, 163))	('patient survival', 'CPA', (156, 172))	('mutations', 'Var', (17, 26))	('contribute', 'Reg', (80, 90))	('influence', 'Reg', (118, 127))
8164	28405930	NGS of 68 cancer-associated genes in individual CTCs from patients with stage IV colorectal cancer found that most mutations, particularly those in driver genes, observed in the primary tumor and metastatic deposits were also present in CTCs, suggesting that the mutational spectrum of complex tumor genomes can be inferred from CTCs.	('tumor', 'Disease', (294, 299))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('mutations', 'Var', (115, 124))	('cancer', 'Disease', (92, 98))	('colorectal cancer', 'Disease', (81, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))	('cancer', 'Disease', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))
8166	28405930	In patients with prostate cancer, 70% (51/73) to 86% (197/229) of all mutations observed in individual CTCs were also found in the primary tumor and metastasis.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mutations', 'Var', (70, 79))	('prostate cancer', 'Phenotype', 'HP:0012125', (17, 32))	('found', 'Reg', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('prostate cancer', 'Disease', (17, 32))	('patients', 'Species', '9606', (3, 11))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('prostate cancer', 'Disease', 'MESH:D011471', (17, 32))
8168	28405930	For example, mutational heterogeneity in the TP53 gene, platelet-derived growth factor receptor, alpha (PDGFRA), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), and other genes has been observed among individual CTCs from women with metastatic breast cancer.	('TP53', 'Gene', (45, 49))	('PDGFRA', 'Gene', (104, 110))	('TP53', 'Gene', '7157', (45, 49))	('breast cancer', 'Disease', 'MESH:D001943', (278, 291))	('PDGFRA', 'Gene', '5156', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('women', 'Species', '9606', (256, 261))	('breast cancer', 'Disease', (278, 291))	('breast cancer', 'Phenotype', 'HP:0003002', (278, 291))	('PIK3CA', 'Gene', (186, 192))	('mutational', 'Var', (13, 23))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('56', '86'))	('platelet-derived growth factor receptor, alpha', 'Gene', '5156', (56, 102))	('PIK3CA', 'Gene', '5290', (186, 192))
8169	28405930	Similarly, the mutational status of TP53 has been shown to vary among CTCs in breast cancer patients, with some CTCs carrying the same mutation(s) as the corresponding primary carcinoma, while other CTCs carry different mutations.	('primary carcinoma', 'Disease', 'MESH:D002277', (168, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('vary', 'Reg', (59, 63))	('mutational', 'Var', (15, 25))	('carrying', 'Reg', (117, 125))	('patients', 'Species', '9606', (92, 100))	('TP53', 'Gene', '7157', (36, 40))	('primary carcinoma', 'Disease', (168, 185))	('TP53', 'Gene', (36, 40))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
8176	28405930	Men with prostate cancer may be initially responsive to androgen receptor (AR) inhibitors, but in some patients, single-cell RNA-seq of individual CTCs detected heterogeneity in the expression of AR gene mutations and activation of non-canonical (beta-catenin-independent) Wnt signaling, which may promote invasiveness and malignant progression, thereby contributing to treatment failure.	('androgen receptor', 'Gene', (56, 73))	('beta-catenin', 'Gene', '1499', (247, 259))	('invasiveness', 'CPA', (306, 318))	('activation', 'PosReg', (218, 228))	('RNA', 'cellular_component', 'GO:0005562', ('125', '128'))	('signaling', 'biological_process', 'GO:0023052', ('277', '286'))	('AR', 'Gene', '367', (75, 77))	('androgen receptor', 'Gene', '367', (56, 73))	('treatment failure', 'Disease', (370, 387))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('prostate cancer', 'Disease', 'MESH:D011471', (9, 24))	('prostate cancer', 'Phenotype', 'HP:0012125', (9, 24))	('prostate cancer', 'Disease', (9, 24))	('mutations', 'Var', (204, 213))	('malignant progression', 'CPA', (323, 344))	('treatment failure', 'Disease', 'MESH:D016609', (370, 387))	('promote', 'PosReg', (298, 305))	('AR', 'Gene', '367', (196, 198))	('patients', 'Species', '9606', (103, 111))	('beta-catenin', 'Gene', (247, 259))	('Men', 'Species', '9606', (0, 3))
8181	28405930	The presence of single DTCs in bone marrow has been established as a strong predictor of distant disease-free survival and breast cancer-specific survival in breast cancer patients.	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('distant disease-free survival', 'CPA', (89, 118))	('breast cancer', 'Disease', (158, 171))	('breast cancer', 'Disease', (123, 136))	('DTC', 'Chemical', '-', (23, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('patients', 'Species', '9606', (172, 180))	('presence', 'Var', (4, 12))	('single DTCs', 'Var', (16, 27))
8188	28405930	In patients carrying a mutation in the anaplastic lymphoma kinase (ALK) gene in their primary tumor, single-cell WGA and sequencing detected the same mutation in single DTCs from bone marrow.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('anaplastic lymphoma kinase', 'Gene', (39, 65))	('DTC', 'Chemical', '-', (169, 172))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (39, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (50, 58))	('mutation', 'Var', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('ALK', 'Gene', '238', (67, 70))	('tumor', 'Disease', (94, 99))	('anaplastic lymphoma kinase', 'Gene', '238', (39, 65))	('patients', 'Species', '9606', (3, 11))	('ALK', 'Gene', (67, 70))
8192	28405930	Targeted therapeutics are designed to focus on actionable mutations detected in a biopsy of the primary tumor, but these "actionable" mutations may no longer drive disease progression once tumor cells disseminate from the primary carcinoma and undergo unique genomic changes.	('mutations', 'Var', (58, 67))	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('primary carcinoma', 'Disease', (222, 239))	('tumor', 'Disease', (104, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('primary carcinoma', 'Disease', 'MESH:D002277', (222, 239))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
8195	28405930	Identification of clinically-actionable mutations at an early stage could lead to targeted treatment before tumor heterogeneity and multiple genomically-distinct clones that are resistant to therapy can evolve.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('lead to', 'Reg', (74, 81))	('tumor', 'Disease', (108, 113))	('mutations', 'Var', (40, 49))
8199	28405930	The ability to identify common mutations throughout a carcinoma could permit use of single agents that target the bulk of the tumor, while assaying heterogeneous actionable mutations could lead to implementing combinatorial approaches that target sub-clonal populations of cells.	('mutations', 'Var', (31, 40))	('carcinoma', 'Disease', 'MESH:D002277', (54, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('lead', 'Reg', (189, 193))	('carcinoma', 'Disease', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
8212	28405930	Likewise, the ability to couple genome-wide methylation and/or proteomic analysis with single-cell DNA- and RNA-sequencing from individual cells may reveal mechanisms by which genetic and epigenetic modifications regulate transcriptional heterogeneity in cancer.	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('epigenetic modifications', 'Var', (188, 212))	('transcriptional heterogeneity', 'MPA', (222, 251))	('RNA', 'cellular_component', 'GO:0005562', ('108', '111'))	('regulate', 'Reg', (213, 221))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))	('methylation', 'biological_process', 'GO:0032259', ('44', '55'))
8220	28405930	ALK anaplastic lymphoma kinase ALL acute lymphoblastic leukemia APC adenomatous polyposis coli AR androgen receptor ccRCC clear cell renal cell carcinoma CD45- leukocyte common antigen 45- CDC27 cell division cycle 27 cDNA complimentary DNA CEL-seq cell expression by linear amplification and sequencing CNV copy number variant CTC circulating tumor cell DOP-PCR degenerate oligonucleotide-primed polymerase chain reaction DTC disseminated tumor cell EGFR epidermal growth factor receptor EMT epithelial-to-mesenchymal transition EpCAM+ epithelial cell adhesion molecule ER estrogen receptor ET essential thrombocythemia HER2 human epidermal growth factor receptor 2 JAK2 Janus kinase 2 JAK-STAT Janus kinase/signal transducers and activators of transcription KRAS Kirsten rat sarcoma viral oncogene homolog LCM laser capture microdissection MALBAC multiple annealing and looping based amplification cycles MAPK mitogen-activated protein kinase MDA multiple-displacement amplification mRNA messenger RNA NGS next-generation sequencing PABPC1 polyadenylate-binding protein, cytoplasmic, 1 PDGFRA platelet-derived growth factor receptor, alpha PDX patient-derived xenograft PI3K phosphoinositide 3-kinase PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha RNA-seq RNA sequencing SCS single-cell sequencing SMART-seq switching mechanism at the 5'-end of the RNA transcript SNV single nucleotide variant STRT single-cell tagged reverse transcription TP53 tumor protein p53 UMI unique molecular identifier VEGF vascular endothelial growth factor WES whole-exome sequencing WGA whole-genome amplification WGS whole-genome sequencing WTA whole-transcriptome amplification	('anaplastic lymphoma kinase', 'Gene', '238', (4, 30))	('patient', 'Species', '9606', (1146, 1153))	('thrombocythemia', 'Phenotype', 'HP:0001894', (605, 620))	('PIK3CA', 'Gene', (1203, 1209))	('SCS', 'molecular_function', 'GO:0004776', ('1305', '1308'))	('estrogen receptor', 'Gene', '2099', (574, 591))	('CD45', 'Gene', (154, 158))	('acute lymphoblastic leukemia', 'Disease', (35, 63))	('epidermal growth factor receptor', 'Gene', '1956', (632, 664))	('transcription', 'biological_process', 'GO:0006351', ('746', '759'))	('thrombocythemia', 'Disease', 'MESH:D013922', (605, 620))	('RNA', 'cellular_component', 'GO:0005562', ('1282', '1285'))	('tumor', 'Phenotype', 'HP:0002664', (1479, 1484))	('EpCAM+', 'Gene', '4072', (530, 536))	('rat', 'Species', '10116', (773, 776))	('PABPC1', 'Gene', '26986', (1035, 1041))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('protein', 'cellular_component', 'GO:0003675', ('1064', '1071'))	('adenomatous polyposis coli', 'Disease', (68, 94))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('1534', '1568'))	('MAPK', 'molecular_function', 'GO:0004707', ('907', '911'))	('vascular endothelial growth factor', 'Gene', '7422', (1534, 1568))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('Janus kinase 2', 'Gene', (672, 686))	('CEL', 'Gene', '1056', (241, 244))	('ALK', 'Gene', (0, 3))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (41, 63))	('rat', 'Species', '10116', (1017, 1020))	('APC', 'cellular_component', 'GO:0005680', ('64', '67'))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('493', '529'))	('TP53', 'Gene', (1474, 1478))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (4, 23))	('p53', 'Gene', (1493, 1496))	('cell adhesion', 'biological_process', 'GO:0007155', ('548', '561'))	('CD45', 'Gene', '5788', (154, 158))	('human', 'Species', '9606', (626, 631))	('tumor', 'Disease', (344, 349))	('ER', 'Gene', '2099', (571, 573))	('sarcoma', 'Phenotype', 'HP:0100242', (777, 784))	('polyadenylate-binding', 'molecular_function', 'GO:0008143', ('1042', '1063'))	('CDC27', 'Gene', '996', (189, 194))	('DTC', 'Chemical', '-', (423, 426))	('tumor', 'Disease', 'MESH:D009369', (344, 349))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (35, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('451', '455'))	('epithelial cell adhesion molecule', 'Gene', '4072', (537, 570))	('epidermal growth factor receptor', 'Gene', '1956', (456, 488))	('ER', 'Gene', '2099', (622, 624))	('thrombocythemia', 'Disease', (605, 620))	('CEL', 'Gene', (241, 244))	('APC', 'Gene', '324', (64, 67))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (68, 89))	('clear cell renal cell carcinoma', 'Disease', (122, 153))	('p53', 'Gene', '7157', (1493, 1496))	('sarcoma', 'Disease', 'MESH:D012509', (777, 784))	('PABPC1', 'Gene', (1035, 1041))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('548', '570'))	('sarcoma', 'Disease', (777, 784))	('JAK', 'molecular_function', 'GO:0004713', ('687', '690'))	('leukemia', 'Phenotype', 'HP:0001909', (55, 63))	('epidermal growth factor receptor 2', 'Gene', (632, 666))	('cell division cycle', 'biological_process', 'GO:0007049', ('195', '214'))	('DNA', 'cellular_component', 'GO:0005574', ('237', '240'))	('reverse transcription', 'biological_process', 'GO:0001171', ('1452', '1473'))	('PI3K', 'molecular_function', 'GO:0016303', ('1172', '1176'))	('APC', 'Gene', (64, 67))	('tumor', 'Disease', (1479, 1484))	('RNA', 'cellular_component', 'GO:0005562', ('1383', '1386'))	('tumor', 'Disease', 'MESH:D009369', (1479, 1484))	('polyadenylate-binding protein, cytoplasmic, 1', 'Gene', '26986', (1042, 1087))	('epithelial cell adhesion molecule', 'Gene', (537, 570))	('AR', 'Gene', '367', (1334, 1336))	('AR', 'Gene', '367', (95, 97))	('TP53', 'Gene', '7157', (1474, 1478))	('androgen receptor', 'Gene', (98, 115))	('estrogen receptor', 'Gene', (574, 591))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (122, 153))	('platelet-derived growth factor receptor, alpha', 'Gene', '5156', (1095, 1141))	('PI3', 'Gene', '5266', (1172, 1175))	('PDGFRA', 'Gene', '5156', (1088, 1094))	('PDGFRA', 'Gene', (1088, 1094))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('632', '655'))	('tumor', 'Phenotype', 'HP:0002664', (440, 445))	('rat', 'Species', '10116', (369, 372))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (133, 153))	('VEGF', 'Gene', (1529, 1533))	('protein', 'cellular_component', 'GO:0003675', ('930', '937'))	('PI3', 'Gene', (1172, 1175))	('vascular endothelial growth factor', 'Gene', (1534, 1568))	('RNA', 'cellular_component', 'GO:0005562', ('1000', '1003'))	('EMT', 'biological_process', 'GO:0001837', ('489', '492'))	('EGFR', 'Gene', '1956', (451, 455))	('anaplastic lymphoma kinase', 'Gene', (4, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('Janus kinase 2', 'Gene', '3717', (672, 686))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (122, 153))	('RNA', 'cellular_component', 'GO:0005562', ('1290', '1293'))	('tumor', 'Disease', (440, 445))	('variant', 'Var', (1420, 1427))	('ALL', 'Phenotype', 'HP:0006721', (31, 34))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('1095', '1125'))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (35, 63))	('HER2', 'Gene', (621, 625))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('456', '479'))	('tumor', 'Disease', 'MESH:D009369', (440, 445))	('lymphoma', 'Phenotype', 'HP:0002665', (15, 23))	('JAK', 'molecular_function', 'GO:0004713', ('667', '670'))	('epidermal growth factor receptor', 'Gene', (456, 488))	('EpCAM+', 'Gene', (530, 536))	('EGFR', 'Gene', (451, 455))	('CDC27', 'Gene', (189, 194))	('ALK', 'Gene', '238', (0, 3))	('PIK3CA', 'Gene', '5290', (1203, 1209))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (68, 94))	('androgen receptor', 'Gene', '367', (98, 115))	('protein', 'cellular_component', 'GO:0003675', ('1485', '1492'))	('VEGF', 'Gene', '7422', (1529, 1533))	('epidermal growth factor receptor 2', 'Gene', '2064', (632, 666))	('HER2', 'Gene', '2064', (621, 625))
8226	32226521	Results: Through database analysis, we found that TNFAIP8 was highly expressed in ccRCC patients and was positively correlated with tumor stage and grade, indicating that TNFAIP8 is associated with the development of advanced ccRCC and poor prognosis.	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('RCC', 'Disease', 'MESH:C538614', (228, 231))	('ccRCC', 'Phenotype', 'HP:0006770', (226, 231))	('associated with', 'Reg', (182, 197))	('RCC', 'Disease', (228, 231))	('patients', 'Species', '9606', (88, 96))	('TNFAIP8', 'Gene', (50, 57))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('RCC', 'Phenotype', 'HP:0005584', (228, 231))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('RCC', 'Disease', (84, 87))	('tumor', 'Disease', (132, 137))	('correlated', 'Reg', (116, 126))	('TNFAIP8', 'Var', (171, 178))	('highly', 'PosReg', (62, 68))
8228	32226521	Conclusion: High expression of TNFAIP8 reinforces migration and regulates the EMT in ccRCC, conferring the metastatic potential of ccRCC and suggesting that TNFAIP8 may be a potential therapeutic target for the treatment of advanced ccRCC.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('reinforces', 'PosReg', (39, 49))	('RCC', 'Phenotype', 'HP:0005584', (235, 238))	('ccRCC', 'Phenotype', 'HP:0006770', (233, 238))	('RCC', 'Disease', (235, 238))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('EMT', 'CPA', (78, 81))	('metastatic potential', 'CPA', (107, 127))	('RCC', 'Disease', 'MESH:C538614', (235, 238))	('migration', 'CPA', (50, 59))	('High expression', 'Var', (12, 27))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))	('EMT', 'biological_process', 'GO:0001837', ('78', '81'))	('RCC', 'Disease', (87, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('regulates', 'Reg', (64, 73))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('RCC', 'Disease', (133, 136))	('TNFAIP8', 'Gene', (31, 38))
8251	32226521	Tumors were staged based on the eighth edition of the tumor-node-metastasis (TNM) classification of the American Joint Committee on Cancer (AJCC): T1 = tumor <=7 cm in the largest dimension, limited to the kidney; T2 = tumor >7 cm in the largest dimension, limited to the kidney; T3 = tumor extends into major veins or invades adrenal gland or perinephric tissues but not beyond Gerota's fascia; and T4 = tumor invades beyond Gerota's fascia.	("Gerota's fascia", 'Disease', 'MESH:D010300', (379, 394))	('tumor', 'Disease', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	("Gerota's fascia", 'Disease', 'MESH:D010300', (426, 441))	('tumor-node-metastasis', 'Disease', (54, 75))	('tumor-node-metastasis', 'Disease', 'MESH:D009362', (54, 75))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (152, 157))	('Tumors', 'Disease', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('Cancer', 'Disease', 'MESH:D009369', (132, 138))	('tumor', 'Disease', (405, 410))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (405, 410))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	("Gerota's fascia", 'Disease', (379, 394))	('T2 =', 'Var', (214, 218))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (285, 290))	('T3 =', 'Var', (280, 284))	('tumor', 'Phenotype', 'HP:0002664', (405, 410))	('tumor', 'Disease', (54, 59))	("Gerota's fascia", 'Disease', (426, 441))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
8254	32226521	769-P cells were cultured in RPMI-1640 medium (PM150110, Procell, Wuhan, China), ACHN cells were cultured in minimum essential medium (MEM, PM150410, Procell, Wuhan, China), and 293T cells were cultured in Dulbecco's modified Eagle's medium (DMEM, HyClone, Palo Alto, CA).	('RPMI-1640', 'Chemical', '-', (29, 38))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (206, 240))	('ACHN', 'Gene', '55323', (81, 85))	('PM150110', 'Var', (47, 55))	('essential medium', 'Chemical', '-', (117, 133))	('DMEM', 'Chemical', '-', (242, 246))	('ACHN', 'Gene', (81, 85))
8282	32226521	To investigate the role of TNFAIP8 in human ccRCC, we first analyzed available human datasets of ccRCC patients in the Gene Expression Omnibus (GEO) database, and we randomly collected two data sets (GSE40435 and GSE53757) to draw volcano plots.	('human', 'Species', '9606', (79, 84))	('GSE40435', 'Var', (200, 208))	('human', 'Species', '9606', (38, 43))	('RCC', 'Disease', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('Gene Expression', 'biological_process', 'GO:0010467', ('119', '134'))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('GSE53757', 'Var', (213, 221))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('patients', 'Species', '9606', (103, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))
8304	32226521	Then, we overexpressed TNFAIP8 in 769-P cells and knocked down TNFAIP8 in ACHN cells.	('ACHN', 'Gene', '55323', (74, 78))	('ACHN', 'Gene', (74, 78))	('TNFAIP8', 'Gene', (23, 30))	('TNFAIP8', 'Gene', (63, 70))	('knocked down', 'Var', (50, 62))
8319	32226521	In RCC, the EMT can be induced by a variety of factors, such as TNF-alpha, deletion of VHL, and dysregulation of miRNAs.	('EMT', 'biological_process', 'GO:0001837', ('12', '15'))	('TNF-alpha', 'Gene', (64, 73))	('deletion', 'Var', (75, 83))	('induced', 'Reg', (23, 30))	('EMT', 'CPA', (12, 15))	('RCC', 'Disease', (3, 6))	('VHL', 'Disease', 'MESH:D006623', (87, 90))	('VHL', 'Disease', (87, 90))	('dysregulation', 'Var', (96, 109))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('TNF-alpha', 'Gene', '7124', (64, 73))	('RCC', 'Disease', 'MESH:C538614', (3, 6))
8322	32226521	In addition, TNFAIP8 is also a risk factor for non-Hodgkin's lymphoma; high levels of TNFAIP8 expression are also associated with more aggressive epithelial ovarian cancer and nonsmall cell lung cancer.	('nonsmall cell lung cancer', 'Disease', (176, 201))	("non-Hodgkin's lymphoma", 'Disease', (47, 69))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (51, 69))	('aggressive epithelial ovarian cancer', 'Disease', (135, 171))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (176, 201))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (146, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (47, 69))	('aggressive epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (135, 171))	('lymphoma', 'Phenotype', 'HP:0002665', (61, 69))	('ovarian cancer', 'Phenotype', 'HP:0100615', (157, 171))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (47, 69))	('associated with', 'Reg', (114, 129))	('high levels', 'Var', (71, 82))	('TNFAIP8', 'Gene', (86, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
8360	32133279	Pathological assessment of nodal stage offers valuable prognostic insight as positive nodal status is independently associated with worse survival in both metastatic and non-metastatic RCC.	('RCC', 'Disease', (185, 188))	('positive', 'Var', (77, 85))	('worse', 'NegReg', (132, 137))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('metastatic', 'Disease', (155, 165))	('RCC', 'Disease', 'MESH:D002292', (185, 188))
8413	30466904	The American Urological Association guidelines for management of renal masses contemplate active surveillance (AS) as a valid option for patients with comorbidities and T1a (<=4cm) or T1b (4-7 cm) tumors.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('T1a', 'Gene', '10630', (169, 172))	('T1a', 'Gene', (169, 172))	('patients', 'Species', '9606', (137, 145))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('<=4cm', 'Var', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('renal masses', 'Phenotype', 'HP:0009726', (65, 77))	('tumors', 'Disease', (197, 203))
8465	30466904	Similarly, texture features on T2-weighted images have been shown to be predictive of molecular alterations in other tumors such as glioblastomas .	('molecular alterations', 'Var', (86, 107))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('glioblastomas', 'Disease', (132, 145))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('glioblastomas', 'Phenotype', 'HP:0012174', (132, 145))	('glioblastomas', 'Disease', 'MESH:D005909', (132, 145))
8467	30466904	Mutations/inactivation of VHL in the unregulated expression of hypoxia response elements and ultimately angiogenesis, which has been described to be associated with ccRCC prognosis and ability to metastasize .	('VHL', 'Disease', (26, 29))	('Mutations/inactivation', 'Var', (0, 22))	('angiogenesis', 'biological_process', 'GO:0001525', ('104', '116'))	('hypoxia', 'Disease', (63, 70))	('unregulated expression', 'MPA', (37, 59))	('ccRCC', 'Disease', (165, 170))	('associated', 'Reg', (149, 159))	('hypoxia', 'Disease', 'MESH:D000860', (63, 70))	('ccRCC', 'Disease', 'MESH:D002292', (165, 170))	('ccRCC', 'Phenotype', 'HP:0006770', (165, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('angiogenesis', 'CPA', (104, 116))	('VHL', 'Disease', 'MESH:D006623', (26, 29))
8478	30466904	Studies have also evaluated the use of quantitative and qualitative imaging features on CT to predict genetic mutations in renal cell carcinoma.	('renal cell carcinoma', 'Disease', (123, 143))	('genetic mutations', 'Var', (102, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (123, 143))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (123, 143))
8479	30466904	Qualitative features of ccRCC including ill-defined tumor margins, calcifications, and renal vein invasion have been reported to correlate with mutations in BRCA1-associated protein 1 (BAP-1), which is known to be associated with high-grade ccRCC .	('tumor', 'Disease', (52, 57))	('renal vein invasion', 'Disease', 'MESH:D007674', (87, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (241, 246))	('ccRCC', 'Disease', (24, 29))	('RCC', 'Phenotype', 'HP:0005584', (243, 246))	('associated', 'Reg', (214, 224))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('mutations', 'Var', (144, 153))	('renal vein invasion', 'Disease', (87, 106))	('BAP-1', 'Gene', '8314', (185, 190))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('ccRCC', 'Phenotype', 'HP:0006770', (24, 29))	('BAP-1', 'Gene', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('BRCA1-associated protein 1', 'Gene', '8314', (157, 183))	('ccRCC', 'Disease', 'MESH:D002292', (241, 246))	('ccRCC', 'Disease', 'MESH:D002292', (24, 29))	('ccRCC', 'Disease', (241, 246))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))	('BRCA1-associated protein 1', 'Gene', (157, 183))
8489	30466904	The presence of fibromuscular stroma has been reported in both low-grade tumors (TCEB1 mutated) and high-grade tumors (without TCEB1 mutation)(Figure 9).	('TCEB1', 'Gene', (81, 86))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('mutated', 'Var', (87, 94))	('TCEB1', 'Gene', '6921', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('TCEB1', 'Gene', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('TCEB1', 'Gene', '6921', (81, 86))
8551	30697081	Patients with higher SIRI values (>1.35) had a significantly worse OS (P<0.001) and cancer-specific survival (CSS; P<0.001) than those with lower SIRI values (<=1.35) in the primary cohort before PSM analysis (Figure 1A, B).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('CSS', 'Chemical', '-', (110, 113))	('SIRI', 'Disease', (21, 25))	('>1.35', 'Var', (34, 39))	('cancer', 'Disease', (84, 90))	('SIRI', 'Disease', 'None', (146, 150))	('OS', 'Chemical', '-', (67, 69))	('SIRI', 'Disease', (146, 150))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('worse', 'NegReg', (61, 66))	('SIRI', 'Disease', 'None', (21, 25))
8559	30697081	The prognostic significance of the preoperative SIRI was further elucidated in subgroups of TNM stage (I+II/III+IV) and Fuhrman grade (G1+G2/G3+G4).	('SIRI', 'Disease', 'None', (48, 52))	('TNM', 'Gene', (92, 95))	('G1+G2/G3+G4', 'Var', (135, 146))	('SIRI', 'Disease', (48, 52))	('TNM', 'Gene', '10178', (92, 95))
8594	31036064	Genes involved in oxygen-sensing are clinically relevant and have significant implications for prognosis.	('oxygen', 'Chemical', 'MESH:D010100', (18, 24))	('implications', 'Reg', (78, 90))	('Genes', 'Var', (0, 5))
8599	31036064	Signature 1 (KDM8, KDM6B, P4HTM, ALKBH4, ALKBH7) and signature 2 (KDM3A, P4HA1, ASPH, PLOD1, PLOD2) were associated with good and poor prognosis.	('KDM6B', 'Gene', (19, 24))	('ASPH', 'Gene', '444', (80, 84))	('ALKBH7', 'Gene', (41, 47))	('ALKBH4', 'Gene', '54784', (33, 39))	('KDM6B', 'Gene', '23135', (19, 24))	('P4HTM', 'Gene', (26, 31))	('PLOD2', 'Gene', (93, 98))	('KDM3A', 'Gene', '55818', (66, 71))	('ALKBH7', 'Gene', '84266', (41, 47))	('P4HTM', 'Gene', '54681', (26, 31))	('HA1', 'cellular_component', 'GO:0030121', ('75', '78'))	('ALKBH4', 'Gene', (33, 39))	('KDM8', 'Var', (13, 17))	('ASPH', 'Gene', (80, 84))	('P4HA1', 'Gene', '5033', (73, 78))	('PLOD2', 'Gene', '5352', (93, 98))	('PLOD1', 'Gene', (86, 91))	('KDM3A', 'Gene', (66, 71))	('P4HA1', 'Gene', (73, 78))	('PLOD1', 'Gene', '5351', (86, 91))
8618	31036064	In addition, the epigenetic alterations and inactivating mutations of the Jumonji-C domain-containing lysine demethylase (KDM) family are frequently observed in multiple cancers such as multiple myeloma, esophageal squamous cell carcinoma, renal cell carcinoma, breast cancer, colorectal cancer, and glioblastoma.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('multiple cancers', 'Disease', 'MESH:D009369', (161, 177))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (240, 260))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (204, 238))	('breast cancer', 'Disease', 'MESH:D001943', (262, 275))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (215, 238))	('breast cancer', 'Disease', (262, 275))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('glioblastoma', 'Disease', (300, 312))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('inactivating mutations', 'Var', (44, 66))	('glioblastoma', 'Phenotype', 'HP:0012174', (300, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('multiple myeloma', 'Phenotype', 'HP:0006775', (186, 202))	('colorectal cancer', 'Disease', 'MESH:D015179', (277, 294))	('multiple cancers', 'Disease', (161, 177))	('renal cell carcinoma', 'Disease', (240, 260))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (240, 260))	('colorectal cancer', 'Disease', (277, 294))	('observed', 'Reg', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('multiple myeloma', 'Disease', 'MESH:D009101', (186, 202))	('epigenetic alterations', 'Var', (17, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('esophageal squamous cell carcinoma', 'Disease', (204, 238))	('breast cancer', 'Phenotype', 'HP:0003002', (262, 275))	('multiple myeloma', 'Disease', (186, 202))	('glioblastoma', 'Disease', 'MESH:D005909', (300, 312))	('colorectal cancer', 'Phenotype', 'HP:0003003', (277, 294))	('KDM', 'Gene', (122, 125))
8685	31036064	Mutations in PCDHA1, a cell adhesion gene from the cadherin superfamily, were associated with short survival in bladder urothelial carcinoma (BLCA: HR, 1.649; 95% CI 1.058-2.569; P = 0.027) and gastric adenocarcinoma (STAD: HR, 1.525; 95% CI 1.007-2.307; P = 0.046) but with prolonged survival in uterine corpus endometrial carcinoma (UCEC: HR, 0.516; 95% CI 0.272-0.978; P = 0.042) (Additional file 3).	('cell adhesion', 'biological_process', 'GO:0007155', ('23', '36'))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (312, 333))	('corpus endometrial carcinoma', 'Disease', (305, 333))	('PCDHA1', 'Gene', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('PCDHA1', 'Gene', '56147', (13, 19))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (305, 333))	('Mutations', 'Var', (0, 9))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (194, 216))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (112, 140))	('cadherin', 'molecular_function', 'GO:0008014', ('51', '59'))	('bladder urothelial carcinoma', 'Disease', (112, 140))	('gastric adenocarcinoma', 'Disease', (194, 216))
8686	31036064	Mutations in another gene from the protocadherin alpha cluster, PCDHA2, were also associated with adverse outcomes in gastric adenocarcinoma (STAD: HR, 1.604; 95% CI 1.061-2.427; P = 0.025) (Additional file 3).	('associated', 'Reg', (82, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('PCDHA2', 'Gene', '56146', (64, 70))	('Mutations', 'Var', (0, 9))	('PCDHA2', 'Gene', (64, 70))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (118, 140))	('gastric adenocarcinoma', 'Disease', (118, 140))
8687	31036064	Mutations in TTN and the tumor suppressor TP53 were associated with short survival in bladder urothelial carcinoma (BLCA: HR, 1.610; 95% CI 1.091-2.376; P = 0.016) and uterine corpus endometrial carcinoma (UCEC: HR, 1.780; 95% CI 1.025-3.090; P = 0.041) (Additional file 3).	('TTN', 'Gene', (13, 16))	('corpus endometrial carcinoma', 'Disease', (176, 204))	('TP53', 'Gene', '7157', (42, 46))	('tumor suppressor', 'Gene', '7248', (25, 41))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('25', '41'))	('bladder urothelial carcinoma', 'Disease', (86, 114))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (176, 204))	('TP53', 'Gene', (42, 46))	('TTN', 'Gene', '7273', (13, 16))	('Mutations', 'Var', (0, 9))	('tumor suppressor', 'Gene', (25, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('tumor suppressor', 'biological_process', 'GO:0051726', ('25', '41'))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (183, 204))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (86, 114))
8688	31036064	Interestingly, another tumor suppressor PTEN, when mutated, was linked to better outcomes in uterine corpus endometrial carcinoma (UCEC: HR, 0.427; 95% CI 0.234-0.781; P = 0.006) (Additional file 3).	('better', 'PosReg', (74, 80))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('23', '39'))	('PTEN', 'Gene', (40, 44))	('tumor suppressor', 'Gene', (23, 39))	('corpus endometrial carcinoma', 'Disease', (101, 129))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (101, 129))	('PTEN', 'Gene', '5728', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor suppressor', 'biological_process', 'GO:0051726', ('23', '39'))	('tumor suppressor', 'Gene', '7248', (23, 39))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (108, 129))	('mutated', 'Var', (51, 58))
8690	31036064	Likewise, MUC4 mutations prolonged survival in renal clear cell carcinoma patients (KIRC: HR, 0.570; 95% CI 0.370-0.880; P = 0.012) (Additional file 3), an observation that is consistent with another study.	('MUC4', 'Gene', (10, 14))	('patients', 'Species', '9606', (74, 82))	('mutations', 'Var', (15, 24))	('prolonged', 'PosReg', (25, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (47, 73))	('MUC4', 'Gene', '4585', (10, 14))	('renal clear cell carcinoma', 'Disease', (47, 73))	('survival', 'MPA', (35, 43))
8692	31036064	Signatures 1 or 2 and mutation status were collectively associated with OS (Fig.	('mutation status', 'Var', (22, 37))	('OS', 'Chemical', '-', (72, 74))	('associated with', 'Reg', (56, 71))
8693	31036064	In bladder urothelial carcinoma, high-risk patients (low signature 1 score) harboring mutant alleles of PCDHA1 had ~ 50% increased mortality at 5 years compared to low-risk patients (high signature 1 score) with wild-type PCDHA1 (P = 0.016; Fig.	('PCDHA1', 'Gene', '56147', (222, 228))	('mutant alleles', 'Var', (86, 100))	('patients', 'Species', '9606', (173, 181))	('increased', 'PosReg', (121, 130))	('PCDHA1', 'Gene', (104, 110))	('patients', 'Species', '9606', (43, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('PCDHA1', 'Gene', '56147', (104, 110))	('PCDHA1', 'Gene', (222, 228))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (3, 31))	('bladder urothelial carcinoma', 'Disease', (3, 31))
8695	31036064	In gastric adenocarcinoma, high-risk patients (high signature 2 scores) with mutant PCDHA1 had the worst outcomes (P = 0.002; Fig.	('patients', 'Species', '9606', (37, 45))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (3, 25))	('gastric adenocarcinoma', 'Disease', (3, 25))	('PCDHA1', 'Gene', (84, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('mutant', 'Var', (77, 83))	('PCDHA1', 'Gene', '56147', (84, 90))
8696	31036064	Conversely, PCDHA1 mutation was associated with good prognosis in uterine corpus endometrial carcinoma, hence high-risk patients with wild-type PCDHA1 had the lowest survival rates while survival was prolonged by ~ 20% in low-risk patients with mutant PCDHA1 (P = 0.003; Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('mutation', 'Var', (19, 27))	('patients', 'Species', '9606', (231, 239))	('PCDHA1', 'Gene', '56147', (144, 150))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (81, 102))	('survival rates', 'MPA', (166, 180))	('PCDHA1', 'Gene', (12, 18))	('PCDHA1', 'Gene', (252, 258))	('corpus endometrial carcinoma', 'Disease', (74, 102))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (74, 102))	('patients', 'Species', '9606', (120, 128))	('mutant', 'Var', (245, 251))	('prolonged', 'PosReg', (200, 209))	('PCDHA1', 'Gene', (144, 150))	('lowest', 'NegReg', (159, 165))	('PCDHA1', 'Gene', '56147', (12, 18))	('PCDHA1', 'Gene', '56147', (252, 258))
8697	31036064	PIK3CA (P < 0.001) and PTEN mutations (P = 0.001) were associated with good outcomes in uterine corpus endometrial carcinoma (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('PTEN', 'Gene', (23, 27))	('PIK3CA', 'Gene', (0, 6))	('PTEN', 'Gene', '5728', (23, 27))	('PIK3CA', 'Gene', '5290', (0, 6))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (103, 124))	('corpus endometrial carcinoma', 'Disease', (96, 124))	('mutations', 'Var', (28, 37))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (96, 124))
8698	31036064	Mutations in another cadherin gene PCDHA2 when considered alongside signature 2 were also associated with survival in gastric adenocarcinoma (P < 0.001; Fig.	('PCDHA2', 'Gene', (35, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('associated with', 'Reg', (90, 105))	('Mutations', 'Var', (0, 9))	('cadherin', 'molecular_function', 'GO:0008014', ('21', '29'))	('PCDHA2', 'Gene', '56146', (35, 41))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (118, 140))	('gastric adenocarcinoma', 'Disease', (118, 140))
8699	31036064	Survival rates were reduced by ~ 37% in high-risk patients with mutant PCDHA2 (Fig.	('reduced', 'NegReg', (20, 27))	('patients', 'Species', '9606', (50, 58))	('PCDHA2', 'Gene', (71, 77))	('PCDHA2', 'Gene', '56146', (71, 77))	('Survival rates', 'CPA', (0, 14))	('mutant', 'Var', (64, 70))
8700	31036064	Joint relation between TP53 mutations and signature 1 significantly influenced survival in uterine corpus endometrial carcinoma (P = 0.002; Fig.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (106, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (99, 127))	('corpus endometrial carcinoma', 'Disease', (99, 127))	('influenced', 'Reg', (68, 78))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
8701	31036064	Since MUC4 mutations were associated with good outcomes, survival rates were the lowest in high-risk patients (high signature 2 scores) with wild-type MUC4 (P = 0.003; Fig.	('mutations', 'Var', (11, 20))	('MUC4', 'Gene', (151, 155))	('patients', 'Species', '9606', (101, 109))	('lowest', 'NegReg', (81, 87))	('MUC4', 'Gene', (6, 10))	('survival rates', 'MPA', (57, 71))	('MUC4', 'Gene', '4585', (151, 155))	('MUC4', 'Gene', '4585', (6, 10))
8703	31036064	Patients with high KDM8 levels had a significantly lower risk of death in pancreatic and liver cancer cohorts (Fig.	('liver cancer', 'Phenotype', 'HP:0002896', (89, 101))	('lower', 'NegReg', (51, 56))	('high KDM8 levels', 'Var', (14, 30))	('Patients', 'Species', '9606', (0, 8))	('death in pancreatic and liver cancer', 'Disease', 'MESH:D010190', (65, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
8706	31036064	Moreover, KDM8 expression was negatively correlated with hypoxia score, indicating that patients with low levels of KDM8 had more hypoxic tumors and poorer survival outcomes (Fig.	('low levels', 'Var', (102, 112))	('survival outcomes', 'CPA', (156, 173))	('hypoxia', 'Disease', (57, 64))	('hypoxia', 'Disease', 'MESH:D000860', (57, 64))	('hypoxic tumors', 'Disease', (130, 144))	('patients', 'Species', '9606', (88, 96))	('KDM8', 'Gene', (116, 120))	('hypoxic tumors', 'Disease', 'MESH:D009369', (130, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('poorer', 'NegReg', (149, 155))	('more', 'PosReg', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
8720	31036064	Our results suggest that dysregulated oxygen sensing in diverse cancer types may activate other oncogenic pathways such as the loss of cell polarity and cell cycle regulation, which collectively influenced clinical outcomes in patients.	('activate', 'PosReg', (81, 89))	('oxygen', 'Chemical', 'MESH:D010100', (38, 44))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cell polarity', 'CPA', (135, 148))	('patients', 'Species', '9606', (227, 235))	('influenced', 'Reg', (195, 205))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('153', '174'))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('loss', 'NegReg', (127, 131))	('oncogenic pathways', 'Pathway', (96, 114))	('cell polarity', 'biological_process', 'GO:0007163', ('135', '148'))	('dysregulated', 'Var', (25, 37))	('cell cycle regulation', 'CPA', (153, 174))
8723	31036064	In colorectal cancer, high KDM6B expression predicted good prognosis, and knock-down of KDM6B was associated with augmented cell proliferation and inhibited apoptosis.	('KDM6B', 'Gene', '23135', (27, 32))	('knock-down', 'Var', (74, 84))	('apoptosis', 'CPA', (157, 166))	('inhibited', 'NegReg', (147, 156))	('high', 'Var', (22, 26))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cell proliferation', 'biological_process', 'GO:0008283', ('124', '142'))	('augmented', 'PosReg', (114, 123))	('KDM6B', 'Gene', (27, 32))	('colorectal cancer', 'Disease', (3, 20))	('KDM6B', 'Gene', '23135', (88, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('157', '166'))	('expression', 'MPA', (33, 43))	('cell proliferation', 'CPA', (124, 142))	('apoptosis', 'biological_process', 'GO:0006915', ('157', '166'))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('KDM6B', 'Gene', (88, 93))
8730	31036064	Moreover, 5-year survival rates dropped to ~ 12% in bladder cancer patients with low expression of signature 1 genes (high-risk), which included KDM8 and PCDHA1 mutations.	('expression', 'MPA', (85, 95))	('low', 'NegReg', (81, 84))	('patients', 'Species', '9606', (67, 75))	('PCDHA1', 'Gene', '56147', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('PCDHA1', 'Gene', (154, 160))	('bladder cancer', 'Phenotype', 'HP:0009725', (52, 66))	('mutations', 'Var', (161, 170))	('bladder cancer', 'Disease', 'MESH:D001749', (52, 66))	('bladder cancer', 'Disease', (52, 66))	('dropped', 'NegReg', (32, 39))	('KDM8', 'Gene', (145, 149))
8731	31036064	Additive effects conferred by mutations in this cell-adhesion protein supports the hypothesis that KDM8 is likely a tumor suppressor and down-regulation of this gene may lead to a loss of epithelial phenotype and cell adhesion to promote cancer invasion.	('loss', 'NegReg', (180, 184))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('116', '132'))	('cell adhesion', 'biological_process', 'GO:0007155', ('213', '226'))	('cancer', 'Disease', (238, 244))	('cell adhesion', 'CPA', (213, 226))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('promote', 'PosReg', (230, 237))	('tumor suppressor', 'biological_process', 'GO:0051726', ('116', '132'))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cell-adhesion', 'biological_process', 'GO:0007155', ('48', '61'))	('tumor suppressor', 'Gene', (116, 132))	('mutations', 'Var', (30, 39))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('regulation', 'biological_process', 'GO:0065007', ('142', '152'))	('epithelial phenotype', 'CPA', (188, 208))	('KDM8', 'Gene', (99, 103))	('down-regulation', 'NegReg', (137, 152))	('tumor suppressor', 'Gene', '7248', (116, 132))
8737	31036064	Collectively, imbalance in the Jumonji-C subfamily of lysine demethylases such as KDM8 and KDM6B is likely to result in broad-ranging but cell type-specific biological effects.	('imbalance', 'Phenotype', 'HP:0002172', (14, 23))	('KDM6B', 'Gene', (91, 96))	('KDM8', 'Gene', (82, 86))	('KDM6B', 'Gene', '23135', (91, 96))	('result', 'Reg', (110, 116))	('imbalance', 'Var', (14, 23))
8742	27682877	Tumour suppressor gene (CDKNA2) status on chromosome 9p in resected renal tissue improves prognosis of localised kidney cancer Genetic alterations on chromosome 9p, including inactivation of the tumour suppressor gene, CDKN2A, result in cellular proliferation and growth of tumours.	('tumours', 'Phenotype', 'HP:0002664', (274, 281))	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('tumour', 'Disease', (195, 201))	('CDKN2A', 'Gene', '1029', (219, 225))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('kidney cancer', 'Disease', 'MESH:D007680', (113, 126))	('cellular proliferation', 'CPA', (237, 259))	('result in', 'Reg', (227, 236))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumour', 'Phenotype', 'HP:0002664', (274, 280))	('tumour', 'Disease', 'MESH:D009369', (274, 280))	('tumour', 'Disease', (274, 280))	('growth of tumours', 'Disease', 'MESH:D006130', (264, 281))	('chromosome', 'cellular_component', 'GO:0005694', ('42', '52'))	('kidney cancer', 'Phenotype', 'HP:0009726', (113, 126))	('growth of tumours', 'Disease', (264, 281))	('chromosome', 'cellular_component', 'GO:0005694', ('150', '160'))	('kidney cancer', 'Disease', (113, 126))	('inactivation', 'Var', (175, 187))	('CDKN2A', 'Gene', (219, 225))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
8746	27682877	The LOH in the coding region of CDKN2A, at D9S974 and D9S942, was associated with a higher pT-stage (p = 0.004) and metastasis (p = 0.006, both markers).	('CDKN2A', 'Gene', (32, 38))	('CDKN2A', 'Gene', '1029', (32, 38))	('D9S974', 'Var', (43, 49))	('D9S942', 'Var', (54, 60))	('D9S974', 'CellLine', 'CVCL:U295', (43, 49))	('metastasis', 'CPA', (116, 126))	('higher', 'PosReg', (84, 90))
8747	27682877	The rate of chromosome 9p deletion in ccRCC was 44% (35/80 cases) according to FISH.	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('chromosome 9p deletion', 'Var', (12, 34))	('RCC', 'Disease', (40, 43))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))
8749	27682877	The cases with copy number loss, loss of heterozygosity and copy number neutral (n = 42) were at a higher risk of cancer-specific death when compared to tumours in category D (n = 32) (Log-rank: p = 0.001).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('tumours', 'Disease', 'MESH:D009369', (153, 160))	('tumours', 'Disease', (153, 160))	('death', 'Disease', 'MESH:D003643', (130, 135))	('death', 'Disease', (130, 135))	('copy number loss', 'Var', (15, 31))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumours', 'Phenotype', 'HP:0002664', (153, 160))	('loss of heterozygosity', 'Var', (33, 55))	('copy number neutral', 'Var', (60, 79))	('cancer', 'Disease', (114, 120))
8751	27682877	Multivariate analysis showed that LOH or copy number loss at CDKN2A retained its independent prognostic effect, improving the predictive accuracy of stage and SSIGN score by concordance Index C from 0.823 to 0.878 (p = 0.001).	('LOH', 'Var', (34, 37))	('CDKN2A', 'Gene', (61, 67))	('improving', 'PosReg', (112, 121))	('CDKN2A', 'Gene', '1029', (61, 67))	('copy number loss', 'Var', (41, 57))
8753	27682877	Five microsatellite markers (D9S916, D9S1814, D9S974, D9S942 and D9S171) assessed loss of heterogeneity (LOH) using DNA samples and in the same cohort FISH analysis was accomplished on tissue microarray slides.	('loss', 'MPA', (82, 86))	('D9S1814', 'Var', (37, 44))	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('S916', 'CellLine', 'CVCL:8863', (31, 35))	('D9S974', 'Var', (46, 52))	('D9S942', 'Var', (54, 60))	('D9S974', 'CellLine', 'CVCL:U295', (46, 52))	('D9S171', 'Var', (65, 71))	('D9S916', 'Var', (29, 35))
8759	27682877	In addition, this plays an active role in cellular senescence, p16 through interconnections influences tumor suppressor P53 pathways Any alteration in this region (mutation or hypermethylation) can potentially lead to reduced or no synthesis of these proteins and hence unregulated growth of cells.	('synthesis', 'biological_process', 'GO:0009058', ('232', '241'))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cellular senescence', 'biological_process', 'GO:0090398', ('42', '61'))	('tumor', 'Disease', (103, 108))	('hypermethylation', 'Var', (176, 192))	('synthesis', 'MPA', (232, 241))	('P53', 'Gene', (120, 123))	('p16', 'Gene', (63, 66))	('alteration', 'Var', (137, 147))	('P53', 'Gene', '7157', (120, 123))	('lead to', 'Reg', (210, 217))	('tumor suppressor', 'biological_process', 'GO:0051726', ('103', '119'))	('influences', 'Reg', (92, 102))	('reduced', 'NegReg', (218, 225))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('103', '119'))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('p16', 'Gene', '1029', (63, 66))
8765	27682877	By contrast, studies using microsatellite analysis have demonstrated that LOH on chromosome 9p is associated with adverse histological features and a risk of progression of renal cancer.	('renal cancer', 'Disease', 'MESH:D007680', (173, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('chromosome', 'cellular_component', 'GO:0005694', ('81', '91'))	('LOH on', 'Var', (74, 80))	('renal cancer', 'Disease', (173, 185))	('renal cancer', 'Phenotype', 'HP:0009726', (173, 185))
8766	27682877	Microsatellite analysis, using paired control normal renal tissue and tumour DNA, is a sensitive technique for detecting LOH in tumours.	('tumours', 'Disease', 'MESH:D009369', (128, 135))	('tumour', 'Disease', (128, 134))	('tumours', 'Disease', (128, 135))	('Microsatellite', 'Var', (0, 14))	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('tumour', 'Disease', (70, 76))
8768	27682877	were the first to propose that LOH in the region of 9p21 was associated with progression of RCC and metastasis, but the study lacked long-term follow-up.	('LOH in', 'Var', (31, 37))	('RCC', 'Disease', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('associated', 'Reg', (61, 71))	('metastasis', 'CPA', (100, 110))	('9p21', 'Gene', (52, 56))
8771	27682877	This phenomenon is also known as copy number neutral LOH (CNNLOH) and was previously called uniparental disomy (UPD).	('copy number', 'Var', (33, 44))	('uniparental disomy', 'Disease', 'MESH:D024182', (92, 110))	('UPD', 'Disease', 'MESH:D024182', (112, 115))	('UPD', 'Disease', (112, 115))	('uniparental disomy', 'Disease', (92, 110))
8772	27682877	Studies on oesophageal cancer have shown that copy number neutral LOH is a common phenomenon The literature contains few reports on CNN-LOH in clear cell RCC especially in the region of chromosome 9p21, which harbours CDKN2A/B, one of the main tumour suppressor genes.	('copy', 'Var', (46, 50))	('CDKN2A/B', 'Gene', '1029;1030', (218, 226))	('oesophageal cancer', 'Disease', 'MESH:D009369', (11, 29))	('tumour', 'Phenotype', 'HP:0002664', (244, 250))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('oesophageal cancer', 'Disease', (11, 29))	('RCC', 'Disease', (154, 157))	('chromosome', 'cellular_component', 'GO:0005694', ('186', '196'))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('CDKN2A/B', 'Gene', (218, 226))	('tumour', 'Disease', 'MESH:D009369', (244, 250))	('tumour', 'Disease', (244, 250))
8778	27682877	Four markers (D9S916, D9S974, D9S942 and D9S1814) were within the 9p21 region and 1 marker (D9S171) was within 9p13 region.	('D9S1814', 'Var', (41, 48))	('S916', 'CellLine', 'CVCL:8863', (16, 20))	('D9S974', 'Var', (22, 28))	('D9S942', 'Var', (30, 36))	('D9S974', 'CellLine', 'CVCL:U295', (22, 28))	('D9S916', 'Var', (14, 20))
8782	27682877	In addition to previous publication, LOH at D9S916 was statistically associated with a higher pT stage (p = 0.005), sarcomatoid changes (p = 0.026), and renal sinus invasion (p = 0.014), with only an observed trend for metastasis (p = 0.10).	('LOH at D9S916', 'Var', (37, 50))	('D9S916', 'Var', (44, 50))	('sarcomatoid', 'Disease', 'MESH:C538614', (116, 127))	('sarcomatoid changes', 'Phenotype', 'HP:0100242', (116, 135))	('pT stage', 'CPA', (94, 102))	('S916', 'CellLine', 'CVCL:8863', (46, 50))	('renal sinus invasion', 'Disease', 'MESH:D007674', (153, 173))	('renal sinus invasion', 'Disease', (153, 173))	('sarcomatoid', 'Disease', (116, 127))	('higher', 'PosReg', (87, 93))
8783	27682877	The LOH within the coding region of CDKN2A, at D9S974 and D9S942, was also associated with higher pT stage (p = 0.004 and p = 0.003, respectively and metastasis (p = 0.006, both markers).	('CDKN2A', 'Gene', (36, 42))	('higher', 'PosReg', (91, 97))	('CDKN2A', 'Gene', '1029', (36, 42))	('metastasis', 'CPA', (150, 160))	('pT stage', 'CPA', (98, 106))	('D9S974', 'Var', (47, 53))	('D9S974', 'CellLine', 'CVCL:U295', (47, 53))	('D9S942', 'Var', (58, 64))
8784	27682877	The LOH within D9S974 and D9S942 was also associated with renal sinus invasion (p = 0.015 and p = 0.006, respectively.	('renal sinus invasion', 'Disease', 'MESH:D007674', (58, 78))	('associated', 'Reg', (42, 52))	('renal sinus invasion', 'Disease', (58, 78))	('D9S974', 'Var', (15, 21))	('D9S942', 'Var', (26, 32))	('D9S974', 'CellLine', 'CVCL:U295', (15, 21))
8791	27682877	Based on I-FISH interpretation using pre-set criteria, the rate of chromosome 9p deletion in ccRCC was 44% (35/80 cases).	('pre', 'molecular_function', 'GO:0003904', ('37', '40'))	('chromosome', 'cellular_component', 'GO:0005694', ('67', '77'))	('chromosome 9p deletion', 'Var', (67, 89))	('I-FISH', 'Species', '215395', (9, 15))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('RCC', 'Disease', (95, 98))
8793	27682877	Ninety-six cases (paired tumour and normal tissue) were assessed for microsatellite analysis and included in the concordance analysis for 9p loss using FISH.	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumour', 'Disease', (25, 31))	('microsatellite', 'Var', (69, 83))	('tumour', 'Disease', 'MESH:D009369', (25, 31))
8794	27682877	Of the 68 cases with informative markers within the coding region of CDKN2A (D9S974 and D9S942), LOH was observed in 17 tumours (25.7%), with 7 tumours showing LOH at both microsatellites and 10 tumours showing LOH for one of the two markers.	('CDKN2A', 'Gene', '1029', (69, 75))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('D9S942', 'Var', (88, 94))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('D9S974', 'Var', (77, 83))	('tumours', 'Disease', 'MESH:D009369', (195, 202))	('CDKN2A', 'Gene', (69, 75))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('tumours', 'Disease', (120, 127))	('tumours', 'Disease', 'MESH:D009369', (144, 151))	('tumours', 'Disease', (144, 151))	('tumours', 'Disease', (195, 202))	('D9S974', 'CellLine', 'CVCL:U295', (77, 83))	('LOH', 'Disease', (97, 100))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
8797	27682877	In total, 59 tumours were available for concordance analysis between microsatellites and I-FISH.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('microsatellites', 'Var', (69, 84))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('tumours', 'Disease', (13, 20))	('I-FISH', 'Species', '215395', (89, 95))
8798	27682877	Both techniques agreed on 30 tumours showing no LOH or copy number loss at CDKN2A.	('copy number loss', 'Var', (55, 71))	('tumours', 'Disease', 'MESH:D009369', (29, 36))	('CDKN2A', 'Gene', (75, 81))	('tumours', 'Disease', (29, 36))	('CDKN2A', 'Gene', '1029', (75, 81))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))
8801	27682877	On the other hand, microsatellite analysis showed LOH at CDKN2A in 9 tumours that did not show copy number loss on FISH.	('tumours', 'Disease', (69, 76))	('CDKN2A', 'Gene', (57, 63))	('CDKN2A', 'Gene', '1029', (57, 63))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('LOH', 'Var', (50, 53))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
8806	27682877	Seventeen patients with localised ccRCC developed recurrence; fourteen of these showed either LOH or somatic copy number loss at CDKN2A (Figure 3: Log-rank: p = 0.005).	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('CDKN2A', 'Gene', (129, 135))	('LOH', 'Var', (94, 97))	('CDKN2A', 'Gene', '1029', (129, 135))	('patients', 'Species', '9606', (10, 18))
8807	27682877	Univariate Cox-proportional hazard analysis revealed that cases with LOH or copy number loss at CDKN2A showed a higher hazard ratio when compared to each aberration independently for disease-specific survival (DSS) and recurrence-free survival (RFS) (Table 1).	('CDKN2A', 'Gene', '1029', (96, 102))	('higher', 'PosReg', (112, 118))	('copy number loss', 'Var', (76, 92))	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('DSS', 'Chemical', '-', (210, 213))	('LOH', 'Var', (69, 72))	('CDKN2A', 'Gene', (96, 102))
8808	27682877	All cases were categorised based on LOH status and copy number loss at CDKN2A in relation to validated prognostic nomograms for metastasis or RFS and DSS in ccRCC (Table 2).	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('CDKN2A', 'Gene', (71, 77))	('CDKN2A', 'Gene', '1029', (71, 77))	('copy number loss', 'Var', (51, 67))	('RCC', 'Disease', (159, 162))	('DSS', 'Chemical', '-', (150, 153))
8809	27682877	Multivariate analysis for DSS revealed that LOH or copy number loss at CDKN2A retained its independent prognostic effect with pathological T stage and state of metastasis in model 1 (Table 3).	('LOH', 'Var', (44, 47))	('CDKN2A', 'Gene', (71, 77))	('CDKN2A', 'Gene', '1029', (71, 77))	('copy number loss', 'Var', (51, 67))	('DSS', 'Chemical', '-', (26, 29))
8811	27682877	On the other hand, multivariate analysis for RFS showed that combination of copy number loss or LOH at CDKN2A is an independent prognostic factor for recurrence in ccRCC in addition to the pT stage in model 3 (Table 4).	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('copy number loss', 'Var', (76, 92))	('RCC', 'Disease', (166, 169))	('LOH', 'Var', (96, 99))	('CDKN2A', 'Gene', (103, 109))	('CDKN2A', 'Gene', '1029', (103, 109))
8812	27682877	The integration of copy number loss or LOH at CDKN2A with the Leibovich score enhanced its predictive accuracy expressed by concordance Index C from 0.734 to 0.801 (p = 0.009).	('LOH', 'Var', (39, 42))	('CDKN2A', 'Gene', (46, 52))	('copy number loss', 'Var', (19, 35))	('CDKN2A', 'Gene', '1029', (46, 52))	('predictive accuracy', 'MPA', (91, 110))	('enhanced', 'PosReg', (78, 86))
8813	27682877	This study has confirmed previous findings where the LOH on chromosome 9p in clear cell RCC is associated with adverse histopathological features and worse prognosis, but it also showed enhanced prognostic significance when LOH is combined with FISH analysis.	('LOH on chromosome 9p', 'Var', (53, 73))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))	('enhanced', 'PosReg', (186, 194))
8815	27682877	The LOH within the coding region of CDKN2A was associated with higher tumour grade and a higher risk of metastasis.	('CDKN2A', 'Gene', (36, 42))	('metastasis', 'CPA', (104, 114))	('LOH', 'Var', (4, 7))	('CDKN2A', 'Gene', '1029', (36, 42))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('higher', 'PosReg', (63, 69))	('tumour', 'Disease', (70, 76))
8816	27682877	The frequency of LOH for all 4 markers on 9p21 (D9S916, D9S974, D9S942 and D9S1814) was significantly associated with locally advanced tumours, highlighting our previous observation that LOH could be a biomarker for aggressive renal cell cancer.	('D9S974', 'Var', (56, 62))	('D9S1814', 'Var', (75, 82))	('associated', 'Reg', (102, 112))	('tumours', 'Disease', 'MESH:D009369', (135, 142))	('tumours', 'Disease', (135, 142))	('S916', 'CellLine', 'CVCL:8863', (50, 54))	('aggressive renal cell cancer', 'Disease', 'MESH:C538614', (216, 244))	('D9S974', 'CellLine', 'CVCL:U295', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('renal cell cancer', 'Phenotype', 'HP:0005584', (227, 244))	('D9S916', 'Var', (48, 54))	('D9S942', 'Var', (64, 70))	('aggressive renal cell cancer', 'Disease', (216, 244))	('tumours', 'Phenotype', 'HP:0002664', (135, 142))
8818	27682877	In the group of clinically localised ccRCC, the LOH in the CDKN2A region was associated with a higher risk of recurrence or development of metastatic disease, as determined by univariate analysis (p = 0.023; HR 4.04).	('CDKN2A', 'Gene', (59, 65))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('LOH', 'Var', (48, 51))	('RCC', 'Disease', (39, 42))	('metastatic disease', 'CPA', (139, 157))	('recurrence', 'CPA', (110, 120))	('CDKN2A', 'Gene', '1029', (59, 65))
8819	27682877	These findings confirm again that LOH involving chromosome 9p21, and particularly LOH at the coding region of CDKN2A, portends a worse prognosis in ccRCC in long term follow up and they validated the findings from I-FISH-based analysis of 9p deletion.	('CDKN2A', 'Gene', (110, 116))	('LOH', 'Var', (82, 85))	('LOH', 'Var', (34, 37))	('CDKN2A', 'Gene', '1029', (110, 116))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('RCC', 'Disease', (150, 153))	('I-FISH', 'Species', '215395', (214, 220))	('chromosome', 'cellular_component', 'GO:0005694', ('48', '58'))
8820	27682877	Previous studies have suggested that the LOH on chromosome 9p is associated with adverse histological features and risk of progression of renal cancer.	('LOH on', 'Var', (41, 47))	('renal cancer', 'Disease', (138, 150))	('associated', 'Reg', (65, 75))	('renal cancer', 'Disease', 'MESH:D007680', (138, 150))	('renal cancer', 'Phenotype', 'HP:0009726', (138, 150))	('chromosome', 'cellular_component', 'GO:0005694', ('48', '58'))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
8821	27682877	Our literature search revealed several studies that reported on allelic deletion on chromosome 9p in renal cancer, but only a few studies established correlations between allelic deletion of 9p and survival with sufficient follow-up periods.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('reported', 'Reg', (52, 60))	('renal cancer', 'Disease', (101, 113))	('renal cancer', 'Phenotype', 'HP:0009726', (101, 113))	('allelic deletion', 'Var', (64, 80))	('renal cancer', 'Disease', 'MESH:D007680', (101, 113))
8828	27682877	The incidence of CNNLOH has been studied in detail in oesophageal cancer, and it appeared to play a role in carcinogenesis and was associated with a change in gene expression levels, either by up-regulation or down- regulation.	('oesophageal cancer', 'Disease', (54, 72))	('CNNLOH', 'Var', (17, 23))	('regulation', 'biological_process', 'GO:0065007', ('196', '206'))	('oesophageal cancer', 'Disease', 'MESH:D009369', (54, 72))	('down- regulation', 'NegReg', (210, 226))	('gene expression', 'biological_process', 'GO:0010467', ('159', '174'))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('change', 'Reg', (149, 155))	('up-regulation', 'PosReg', (193, 206))	('regulation', 'biological_process', 'GO:0065007', ('216', '226'))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('gene expression levels', 'MPA', (159, 181))	('role', 'Reg', (100, 104))	('carcinogenesis', 'Disease', (108, 122))
8829	27682877	The authors suggested that CNNLOH was more common than LOH with copy number alteration in oesophageal cancer and represented 70% of all allelic deletions detected by single nucleotide polymorphism (SNP) arrays.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('oesophageal cancer', 'Disease', (90, 108))	('oesophageal cancer', 'Disease', 'MESH:D009369', (90, 108))	('copy number alteration', 'Var', (64, 86))	('CNNLOH', 'Disease', (27, 33))
8830	27682877	reported copy neutral LOH of the p53 locus in p53 mutant oesophageal cancer and suggested that this could be a major mechanism for inactivation of the intact allele in oesophageal squamous cell carcinogenesis associated with a mutation at p53.	('oesophageal cancer', 'Disease', (57, 75))	('oesophageal squamous cell carcinogenesis', 'Disease', 'MESH:D063646', (168, 208))	('p53', 'Gene', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('p53', 'Gene', '7157', (46, 49))	('oesophageal squamous cell carcinogenesis', 'Disease', (168, 208))	('p53', 'Gene', (239, 242))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('mutation', 'Var', (227, 235))	('mutant', 'Var', (50, 56))	('p53', 'Gene', '7157', (239, 242))	('oesophageal cancer', 'Disease', 'MESH:D009369', (57, 75))
8835	27682877	This discordance can be explained by a number of factors; for example, contamination of tumour samples during macro-dissection (viable tumour areas were marked by a specialist pathologist on tumour blocks in this study); intratumour heterogeneity causing contamination of DNA predominantly from a sub clone with no copy number loss; or a high percentage of homozygous loss or DNA sample contamination with normal renal tissue.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('tumour', 'Disease', 'MESH:D009369', (191, 197))	('DNA', 'cellular_component', 'GO:0005574', ('272', '275'))	('tumour', 'Disease', (88, 94))	('tumour', 'Disease', (191, 197))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('DNA', 'cellular_component', 'GO:0005574', ('376', '379'))	('tumour', 'Disease', 'MESH:D009369', (226, 232))	('heterogeneity', 'Var', (233, 246))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('tumour', 'Disease', (226, 232))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('tumour', 'Disease', (135, 141))
8836	27682877	The lack of sensitivity of microsatellite analysis in reference to FISH to detect copy number loss LOH comes down predominantly to the superiority of FISH to cut through tumour complexity at a cellular level, allowing the observer to score regions of tumour in more than one core that has a high concentration of cells with copy number loss.	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('core', 'cellular_component', 'GO:0019013', ('275', '279'))	('tumour', 'Disease', (170, 176))	('tumour', 'Disease', 'MESH:D009369', (251, 257))	('copy number loss', 'Var', (82, 98))	('tumour', 'Disease', (251, 257))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('tumour', 'Disease', 'MESH:D009369', (170, 176))
8842	27682877	The addition of copy number status to allelic deletion measured by LOH analysis at the CDKN2A coding region on chromosome 9p significantly enhances the predictive accuracy of the SSIGN score and Leibovich score for cancer-specific death and development of metastasis in patients undergoing resection for clinically localised renal cell carcinoma.	('CDKN2A', 'Gene', '1029', (87, 93))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('copy', 'Var', (16, 20))	('enhances', 'PosReg', (139, 147))	('renal cell carcinoma', 'Disease', (325, 345))	('patients', 'Species', '9606', (270, 278))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (325, 345))	('development of metastasis', 'CPA', (241, 266))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (325, 345))	('carcinoma', 'Phenotype', 'HP:0030731', (336, 345))	('chromosome', 'cellular_component', 'GO:0005694', ('111', '121'))	('death', 'Disease', 'MESH:D003643', (231, 236))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('death', 'Disease', (231, 236))	('CDKN2A', 'Gene', (87, 93))
8866	27682877	Four markers map to 9p21; D9S916, D9S1814, D9S974 and D9S942.	('S916', 'CellLine', 'CVCL:8863', (28, 32))	('D9S916', 'Var', (26, 32))	('D9S1814', 'Var', (34, 41))	('D9S974', 'Var', (43, 49))	('to 9', 'Species', '1214577', (17, 21))	('D9S942', 'Var', (54, 60))	('D9S974', 'CellLine', 'CVCL:U295', (43, 49))
8868	27682877	D9S916 is telomeric to CDKN2A and CDKN2B, whereas D9S1814 is centromeric to CDKN2B.	('D9S1814', 'Var', (50, 57))	('CDKN2B', 'Gene', '1030', (76, 82))	('CDKN2A', 'Gene', (23, 29))	('CDKN2B', 'Gene', (34, 40))	('S916', 'CellLine', 'CVCL:8863', (2, 6))	('D9S916', 'Var', (0, 6))	('CDKN2A', 'Gene', '1029', (23, 29))	('CDKN2B', 'Gene', '1030', (34, 40))	('CDKN2B', 'Gene', (76, 82))
8869	27682877	D9S171 is at 9p13 (proximal toCDKN2A/B).	('CDKN2A/B', 'Gene', (30, 38))	('D9S171', 'Var', (0, 6))	('CDKN2A/B', 'Gene', '1029;1030', (30, 38))
8892	29378660	A large meta-analysis including 49 studies and 1244 patients with non-ccRCC who were treated with anti-angiogenic and targeted agents approved for treatment of ccRCC, demonstrated that non-ccRCC patients had lower ORR, OS, and PFS compared to patients with ccRCC included in these studies.	('OS', 'Chemical', '-', (219, 221))	('ccRCC', 'Phenotype', 'HP:0006770', (160, 165))	('patients', 'Species', '9606', (243, 251))	('non-ccRCC', 'Var', (185, 194))	('ccRCC', 'Phenotype', 'HP:0006770', (189, 194))	('ccRCC', 'Phenotype', 'HP:0006770', (257, 262))	('patients', 'Species', '9606', (195, 203))	('PFS', 'CPA', (227, 230))	('ccRCC', 'Phenotype', 'HP:0006770', (70, 75))	('lower', 'NegReg', (208, 213))	('ORR', 'CPA', (214, 217))	('patients', 'Species', '9606', (52, 60))
8915	29378660	One patient had Xp11 translocation carcinoma and another patient had mucinous tubular and spindle cell carcinoma (MTSCC).	('carcinoma', 'Disease', 'MESH:D002277', (35, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('spindle cell carcinoma', 'Disease', (90, 112))	('patient', 'Species', '9606', (57, 64))	('carcinoma', 'Disease', (103, 112))	('patient', 'Species', '9606', (4, 11))	('spindle cell carcinoma', 'Disease', 'MESH:D002277', (90, 112))	('carcinoma', 'Disease', (35, 44))	('spindle', 'cellular_component', 'GO:0005819', ('90', '97'))	('carcinoma', 'Disease', 'MESH:D002277', (103, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('Xp11 translocation', 'Var', (16, 34))
8962	29378660	PDL1 positivity of tumor cells was also noted in about 10% of biopsies and PDL1 positivity in both tumor cells and TIMCs was associated with worse clinical outcomes.	('tumor', 'Disease', (99, 104))	('PDL1', 'Gene', '29126', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('PDL1', 'Gene', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('PDL1', 'Gene', (0, 4))	('associated with', 'Reg', (125, 140))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('positivity', 'Var', (80, 90))	('tumor', 'Disease', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('PDL1', 'Gene', '29126', (75, 79))
9009	29299153	As for ccRCC, there are evidences showing that some important genes play key roles in ccRCC tumor like frequent mutation or methylation of the tumor suppressor gene (VHL), frequent mutations of PBRM1, BAP1, SETD2 and KDM5C genes.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('methylation', 'MPA', (124, 135))	('VHL', 'Disease', 'MESH:D006623', (166, 169))	('KDM5C', 'Gene', '8242', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('143', '159'))	('methylation', 'biological_process', 'GO:0032259', ('124', '135'))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mutations', 'Var', (181, 190))	('tumor suppressor', 'biological_process', 'GO:0051726', ('143', '159'))	('mutation', 'Var', (112, 120))	('SETD2', 'Gene', (207, 212))	('BAP1', 'Gene', '8314', (201, 205))	('RCC', 'Disease', (9, 12))	('RCC', 'Phenotype', 'HP:0005584', (9, 12))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (7, 12))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('KDM5C', 'Gene', (217, 222))	('VHL', 'Disease', (166, 169))	('PBRM1', 'Gene', '55193', (194, 199))	('SETD2', 'Gene', '29072', (207, 212))	('tumor', 'Disease', (143, 148))	('RCC', 'Disease', 'MESH:C538614', (9, 12))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('BAP1', 'Gene', (201, 205))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('PBRM1', 'Gene', (194, 199))
9019	29299153	15 genes were selected eventually including LOC150197, SUSD4, HLA-G, C4orf49, LOC338588, CYS1, COL5A1, PLAU, GDNF, OTOA, IGFN1, C2orf40 (also known as MGARP), BARX2, HOXB13, MUC12.	('C4orf49', 'Gene', (69, 76))	('COL5A1', 'Gene', (95, 101))	('C2orf40', 'Gene', (128, 135))	('HOXB13', 'Gene', (166, 172))	('C2orf40', 'Gene', '84417', (128, 135))	('MGARP', 'Gene', '84709', (151, 156))	('LOC150197', 'Var', (44, 53))	('BARX2', 'Gene', (159, 164))	('CYS1', 'Gene', '192668', (89, 93))	('CYS1', 'Gene', (89, 93))	('HLA-G', 'Gene', (62, 67))	('IGFN1', 'Gene', (121, 126))	('MUC12', 'Gene', (174, 179))	('LOC338588', 'Gene', (78, 87))	('COL5A1', 'Gene', '1289', (95, 101))	('OTOA', 'Gene', (115, 119))	('PLAU', 'Gene', '5328', (103, 107))	('MUC12', 'Gene', '10071', (174, 179))	('OTOA', 'Gene', '146183', (115, 119))	('HOXB13', 'Gene', '10481', (166, 172))	('GDNF', 'Gene', '2668', (109, 113))	('SUSD4', 'Gene', '55061', (55, 60))	('C4orf49', 'Gene', '84709', (69, 76))	('MGARP', 'Gene', (151, 156))	('BARX2', 'Gene', '8538', (159, 164))	('HLA-G', 'Gene', '3135', (62, 67))	('GDNF', 'Gene', (109, 113))	('PLAU', 'Gene', (103, 107))	('SUSD4', 'Gene', (55, 60))	('IGFN1', 'Gene', '91156', (121, 126))
9026	29299153	Patients with higher expression levels of the rest 8 genes (COL5A1, HOXB13, IGFN1, LOC150197, LOC338588, MUC12, PLAU and SUSD4) have significantly worse overall survival prognoses than those with lower expression levels of 8 genes (Figure 4B).	('MUC12', 'Gene', (105, 110))	('HOXB13', 'Gene', '10481', (68, 74))	('COL5A1', 'Gene', '1289', (60, 66))	('IGFN1', 'Gene', (76, 81))	('SUSD4', 'Gene', '55061', (121, 126))	('MUC12', 'Gene', '10071', (105, 110))	('Patients', 'Species', '9606', (0, 8))	('HOXB13', 'Gene', (68, 74))	('SUSD4', 'Gene', (121, 126))	('higher', 'PosReg', (14, 20))	('PLAU', 'Gene', '5328', (112, 116))	('COL5A1', 'Gene', (60, 66))	('worse', 'NegReg', (147, 152))	('expression levels', 'MPA', (21, 38))	('LOC338588', 'Var', (94, 103))	('overall survival prognoses', 'CPA', (153, 179))	('IGFN1', 'Gene', '91156', (76, 81))	('PLAU', 'Gene', (112, 116))	('LOC150197', 'Var', (83, 92))
9033	29299153	In addition, HLA-G-regulatory miRNAs like mir-548q and mir-628-5p were identified.	('mir-548q', 'Gene', '100313841', (42, 50))	('HLA-G', 'Gene', (13, 18))	('HLA-G', 'Gene', '3135', (13, 18))	('mir-628-5p', 'Var', (55, 65))	('mir-548q', 'Gene', (42, 50))
9036	29299153	Aberrant promoter hypermethylation is a common mechanism for inactivation of tumor suppressor genes in cancer cells.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('77', '93'))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Aberrant', 'Var', (0, 8))	('tumor suppressor', 'biological_process', 'GO:0051726', ('77', '93'))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('promoter', 'MPA', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Disease', (77, 82))	('inactivation', 'NegReg', (61, 73))
9037	29299153	Gene PLAU, plasminogen activator, urokinase, was showed that cancer cell-specific methylation in RCC cell lines.	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('methylation', 'Var', (82, 93))	('cancer', 'Disease', (61, 67))	('methylation', 'biological_process', 'GO:0032259', ('82', '93'))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('PLAU', 'Gene', (5, 9))	('PLAU', 'Gene', '5328', (5, 9))
9038	29299153	Gene COL5A1, has shown that its deregulated level was caused by mir-25-3p in renal cancer.	('renal cancer', 'Disease', 'MESH:D007680', (77, 89))	('COL5A1', 'Gene', '1289', (5, 11))	('renal cancer', 'Phenotype', 'HP:0009726', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mir-25-3p', 'Var', (64, 73))	('deregulated level', 'MPA', (32, 49))	('caused', 'Reg', (54, 60))	('renal cancer', 'Disease', (77, 89))	('COL5A1', 'Gene', (5, 11))
9042	29299153	Furthermore, HOXB13 methylation correlated positively with tumor grade and microvessel invasion.	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))	('tumor', 'Disease', (59, 64))	('HOXB13', 'Gene', '10481', (13, 19))	('methylation', 'Var', (20, 31))	('microvessel invasion', 'CPA', (75, 95))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('HOXB13', 'Gene', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
9043	29299153	These results suggest that HOXB13 is a novel candidate tumor suppressor gene in RCC and that its inactivation may play an important role in both RCC tumorigenesis and progression.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('play', 'Reg', (114, 118))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor suppressor', 'biological_process', 'GO:0051726', ('55', '71'))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('tumor', 'Disease', (55, 60))	('HOXB13', 'Gene', '10481', (27, 33))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('55', '71'))	('inactivation', 'Var', (97, 109))	('tumor', 'Disease', (149, 154))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('HOXB13', 'Gene', (27, 33))
9088	31825895	Using high-risk patients from ASSURE, those treated with high dose (>= 1246 mg/cycle) sunitinib did not have a better CDFS significantly than these patients treated with low dose (<828 mg/cycle, small differences, d value was <0.3, Supplementary Table 3).	('patients', 'Species', '9606', (148, 156))	('>= 1246 mg/cycle', 'Var', (68, 84))	('CDFS', 'MPA', (118, 122))	('patients', 'Species', '9606', (16, 24))	('sunitinib', 'Chemical', 'MESH:C473478', (86, 95))
9148	31057605	We used Kruskal-Wallis test with Bonferroni adjustment to identify the differential expression of TMED3 in different T stages using appropriate statistical methods (GSE11024 and GSE14762, Welch two sample t-test; GSE12606, paired t-test).	('GSE14762', 'Var', (178, 186))	('GSE12606', 'Var', (213, 221))	('TMED3', 'Gene', '23423', (98, 103))	('GSE11024', 'Var', (165, 173))	('TMED3', 'Gene', (98, 103))
9155	31057605	Additionally, we confirmed TMED3 expression in cancer tissues are higher than normal tissues by using GSE11024, GSE12606, and GSE14762) (Supplementary Figure S2).	('TMED3', 'Gene', '23423', (27, 32))	('GSE14762', 'Var', (126, 134))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('TMED3', 'Gene', (27, 32))	('GSE11024', 'Var', (102, 110))	('higher', 'PosReg', (66, 72))	('expression', 'MPA', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('GSE12606', 'Var', (112, 120))
9157	31057605	The high TMED3 expression group had a significantly shorter survival than the low TMED3 expression group in the TCGA (Figure 2) and ICGC cohorts (Figure 3).	('TMED3', 'Gene', (82, 87))	('TMED3', 'Gene', '23423', (9, 14))	('shorter', 'NegReg', (52, 59))	('survival', 'MPA', (60, 68))	('high', 'Var', (4, 8))	('TMED3', 'Gene', '23423', (82, 87))	('TMED3', 'Gene', (9, 14))
9176	28749461	DNMT1-maintained hypermethylation of Kruppel-like factor 5 involves in the progression of clear cell renal cell carcinoma Clear cell renal cell carcinoma (ccRCC) is the major subtype of renal cell carcinoma (RCC) that is resistant to conventional radiation and chemotherapy.	('clear cell renal cell carcinoma', 'Disease', (90, 121))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (101, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (122, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('Kruppel-like factor 5', 'Gene', '688', (37, 58))	('Kruppel-like factor 5', 'Gene', (37, 58))	('renal cell carcinoma', 'Disease', (186, 206))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (186, 206))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (90, 121))	('DNMT1', 'Gene', '1786', (0, 5))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (133, 153))	('involves', 'Reg', (59, 67))	('RCC', 'Phenotype', 'HP:0005584', (208, 211))	('RCC', 'Disease', (208, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (101, 121))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (122, 153))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (90, 121))	('Clear cell renal cell carcinoma', 'Disease', (122, 153))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (186, 206))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('DNMT1', 'Gene', (0, 5))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (133, 153))	('ccRCC', 'Phenotype', 'HP:0006770', (155, 160))	('RCC', 'Disease', (157, 160))	('hypermethylation', 'Var', (17, 33))
9182	28749461	Ectopic KLF5 expression inhibits ccRCC cell proliferation and migration/invasion in vitro and decreases xenograft growth and metastasis in vivo.	('RCC', 'Disease', (35, 38))	('inhibits', 'NegReg', (24, 32))	('decreases', 'NegReg', (94, 103))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('Ectopic', 'Var', (0, 7))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
9193	28749461	It has been widely investigated that alterations of DNA methylation, especially hypermethylation of tumor suppressor genes, mediate tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('100', '116'))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('DNA methylation', 'biological_process', 'GO:0006306', ('52', '67'))	('hypermethylation', 'Var', (80, 96))	('mediate', 'Reg', (124, 131))	('tumor suppressor', 'biological_process', 'GO:0051726', ('100', '116'))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('tumor', 'Disease', (132, 137))	('alterations', 'Var', (37, 48))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('DNA', 'MPA', (52, 55))
9200	28749461	found that 5-Aza-CdR could suppress Caki-1 (a human metastatic RCC cell line) growth in vivo.	('Caki-1', 'Gene', (36, 42))	('RCC', 'Disease', (63, 66))	('growth', 'MPA', (78, 84))	('human', 'Species', '9606', (46, 51))	('5-Aza-CdR', 'Var', (11, 20))	('suppress', 'NegReg', (27, 35))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
9202	28749461	Hence, epigenetic treatment with 5-Aza-CdR seems to be a promising therapeutic regimen for ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('RCC', 'Disease', (93, 96))	('epigenetic treatment', 'Var', (7, 27))
9208	28749461	In kidney and its collecting system, KLF5 was reported to express in the collecting duct epithelium and mice with specific deletion of KLF5 in the collecting duct exerted enhanced interstitial fibrosis after unilateral ureteral obstruction (UUO).	('collecting system', 'Phenotype', 'HP:0000081', (18, 35))	('enhanced', 'PosReg', (171, 179))	('collecting duct exerted', 'Phenotype', 'HP:0000081', (147, 170))	('ureteral obstruction', 'Phenotype', 'HP:0006000', (219, 239))	('mice', 'Species', '10090', (104, 108))	('deletion', 'Var', (123, 131))	('KLF5', 'Gene', (135, 139))	('UUO', 'Phenotype', 'HP:0006000', (241, 244))	('fibrosis', 'Disease', 'MESH:D005355', (193, 201))	('fibrosis', 'Disease', (193, 201))	('ureteral obstruction', 'Disease', 'MESH:D014517', (219, 239))	('ureteral obstruction', 'Disease', (219, 239))	('interstitial fibrosis', 'Phenotype', 'HP:0005576', (180, 201))
9215	28749461	Overall survival rate of ccRCC patients with high KLF5 expression was significantly higher than patients with low KLF5 expression, especially after about 7 years (2500 days).	('high KLF5 expression', 'Var', (45, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (25, 30))	('patients', 'Species', '9606', (31, 39))	('patients', 'Species', '9606', (96, 104))	('Overall', 'MPA', (0, 7))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('higher', 'PosReg', (84, 90))
9223	28749461	It is well known that inactivation of the tumor suppressor gene Von Hippel-Lindau (VHL), including deletion, mutation and hypermethylation, is an archetypical tumor-initiating event in ccRCC, which leads to constitutive activation HIF-alpha that promotes tumorigenesis.	('RCC', 'Disease', (187, 190))	('promotes', 'PosReg', (246, 254))	('RCC', 'Phenotype', 'HP:0005584', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('ccRCC', 'Phenotype', 'HP:0006770', (185, 190))	('VHL', 'Disease', (83, 86))	('inactivation', 'Var', (22, 34))	('tumor', 'Disease', (42, 47))	('RCC', 'Disease', 'MESH:C538614', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('HIF-alpha', 'Protein', (231, 240))	('Von Hippel-Lindau', 'Gene', '7428', (64, 81))	('tumor', 'Disease', (255, 260))	('Von Hippel-Lindau', 'Gene', (64, 81))	('tumor', 'Disease', (159, 164))	('VHL', 'Disease', 'MESH:D006623', (83, 86))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('42', '58'))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('mutation', 'Var', (109, 117))	('tumor suppressor', 'biological_process', 'GO:0051726', ('42', '58'))	('deletion', 'Var', (99, 107))	('hypermethylation', 'Var', (122, 138))
9236	28749461	The results demonstrated that both mRNA and protein level of KLF5 in these ccRCC cells were significantly and dose-dependently upregulated by 5-Aza-CdR (Figures 2D and E).	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('upregulated', 'PosReg', (127, 138))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('5-Aza-CdR', 'Var', (142, 151))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))
9238	28749461	These results suggested hypermethylation might contribute to the downregulation of KLF5 in ccRCC.	('hypermethylation', 'Var', (24, 40))	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('KLF5', 'Protein', (83, 87))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('RCC', 'Disease', (93, 96))	('downregulation', 'NegReg', (65, 79))
9241	28749461	Compared with control ShRNA (ShCon) expressing 786-O cells, DNMT1 knockdown significantly increased KLF5 expression both in mRNA and protein level, while DNMT3A knockdown had no effect on KLF5 expression and DNMT3B knockdown slightly increased KLF5 expression (Figures 3a and b).	('increased', 'PosReg', (234, 243))	('DNMT3B', 'Gene', (208, 214))	('DNMT3B', 'Gene', '1789', (208, 214))	('KLF5 expression', 'MPA', (244, 259))	('DNMT3A', 'Gene', (154, 160))	('KLF5 expression', 'MPA', (100, 115))	('increased', 'PosReg', (90, 99))	('DNMT3A', 'Gene', '1788', (154, 160))	('knockdown', 'Var', (215, 224))	('DNMT1', 'Gene', (60, 65))	('DNMT1', 'Gene', '1786', (60, 65))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('knockdown', 'Var', (66, 75))
9244	28749461	Compared with ShCon-expressing 786-O cells, knockdown of DNMT1 decreased KLF5 methylation levels in high-methylated area (Figure 3c).	('KLF5 methylation levels in high-methylated area', 'MPA', (73, 120))	('decreased', 'NegReg', (63, 72))	('DNMT1', 'Gene', (57, 62))	('DNMT1', 'Gene', '1786', (57, 62))	('methylation', 'biological_process', 'GO:0032259', ('78', '89'))	('knockdown', 'Var', (44, 53))
9262	28749461	Given that ectopic KLF5 expression inhibited ccRCC cell growth in vitro, whether KLF5 also affected tumor growth in vivo was further investigated.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('cell growth', 'biological_process', 'GO:0016049', ('51', '62'))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('tumor', 'Disease', (100, 105))	('ectopic', 'Var', (11, 18))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('KLF5', 'Gene', (19, 23))	('RCC', 'Disease', (47, 50))	('inhibited', 'NegReg', (35, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
9268	28749461	Together, these findings strongly indicated ectopic expression of KLF5 could significantly inhibited ccRCC growth in vivo.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('KLF5', 'Gene', (66, 70))	('inhibited', 'NegReg', (91, 100))	('ectopic expression', 'Var', (44, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))
9270	28749461	In Figures 4c and d, we showed that ectopic KLF5 expression inhibited ccRCC cell lines migration/invasion in vitro.	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('ectopic', 'Var', (36, 43))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('inhibited', 'NegReg', (60, 69))	('KLF5', 'Protein', (44, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (70, 75))
9275	28749461	Representative hematoxylin-eosin (H&E) staining exhibited KLF5 expression inhibited the formation of metastatic colonies in lungs (Figure 6i).	('eosin', 'Chemical', 'MESH:D004801', (27, 32))	('expression', 'NegReg', (63, 73))	('formation', 'biological_process', 'GO:0009058', ('88', '97'))	('KLF5', 'Var', (58, 62))	('H&E', 'Chemical', '-', (34, 37))	('exhibited', 'Gene', (48, 57))	('the formation of metastatic colonies in', 'CPA', (84, 123))	('hematoxylin', 'Chemical', 'MESH:D006416', (15, 26))
9277	28749461	Since hypermethylation of KLF5 suppressed its expression and ectopic KLF5 could inhibit ccRCC growth both in vitro and in vivo, it is very interesting to evaluate whether upregulating endogenous KLF5 expression by demethylation of KLF5 gene could inhibit cell growth.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('demethylation', 'Var', (214, 227))	('upregulating', 'PosReg', (171, 183))	('hypermethylation', 'Var', (6, 22))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('KLF5', 'Gene', (69, 73))	('inhibit', 'NegReg', (80, 87))	('ectopic', 'Var', (61, 68))	('KLF5', 'Gene', (231, 235))	('cell growth', 'CPA', (255, 266))	('inhibit', 'NegReg', (247, 254))	('cell growth', 'biological_process', 'GO:0016049', ('255', '266'))	('suppressed', 'NegReg', (31, 41))	('KLF5', 'Gene', (26, 30))	('demethylation', 'biological_process', 'GO:0070988', ('214', '227'))	('expression', 'MPA', (46, 56))	('RCC', 'Disease', (90, 93))
9279	28749461	As showed in Figures 7e and f, cells expressing ShKLF5 endowed higher concentration of 5-Aza-CdR treatment than those ShCon-expressing ccRCC cells, which suggested that KLF5 expression contributed to the growth inhibition of 5-Aza-CdR.	('growth', 'MPA', (204, 210))	('concentration', 'MPA', (70, 83))	('5-Aza-CdR treatment', 'MPA', (87, 106))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('ShKLF5', 'Var', (48, 54))	('RCC', 'Disease', (137, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('higher', 'PosReg', (63, 69))
9281	28749461	In this study, our data evidence that KLF5 is a tumor suppressor in ccRCC based on the following facts: first, KLF5 expression is inhibited in ccRCC patients no matter through database analysis or clinical patient samples histochemical staining, and patients with high expression of KLF5 have better prognostic outcome; second, KLF5 expression is suppressed by DNMT1-maintained genomic hypermethylation, and ectopic expression of KLF5 inhibits ccRCC cells proliferation and migration/invasion in vitro and xenograft growth and metastasis in vivo; last but not least, DNMTs' inhibitor 5-Aza-CdR can restore KLF5 expression and suppress ccRCC cell growth, while knockdown KLF5 can decrease drug sensitivity to 5-Aza-CdR and abolish 5-Aza-CdR-induced cell growth inhibition.	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('cell growth', 'biological_process', 'GO:0016049', ('748', '759'))	('DNMT1', 'Gene', '1786', (361, 366))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('abolish', 'NegReg', (722, 729))	('cell growth', 'biological_process', 'GO:0016049', ('641', '652'))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('patients', 'Species', '9606', (149, 157))	('RCC', 'Disease', (145, 148))	('decrease', 'NegReg', (679, 687))	('drug sensitivity to 5-Aza-CdR', 'MPA', (688, 717))	('RCC', 'Disease', (637, 640))	('RCC', 'Phenotype', 'HP:0005584', (637, 640))	('patient', 'Species', '9606', (206, 213))	('ccRCC', 'Phenotype', 'HP:0006770', (635, 640))	('KLF5 expression', 'MPA', (606, 621))	('patient', 'Species', '9606', (149, 156))	('RCC', 'Disease', (446, 449))	('RCC', 'Phenotype', 'HP:0005584', (446, 449))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('48', '64'))	('DNMT1', 'Gene', (361, 366))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('ccRCC', 'Phenotype', 'HP:0006770', (444, 449))	('suppress', 'NegReg', (626, 634))	('tumor', 'Disease', (48, 53))	('drug sensitivity', 'Phenotype', 'HP:0020174', (688, 704))	('patients', 'Species', '9606', (250, 258))	('RCC', 'Disease', 'MESH:C538614', (637, 640))	('ccRCC', 'Phenotype', 'HP:0006770', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor suppressor', 'biological_process', 'GO:0051726', ('48', '64'))	('restore', 'PosReg', (598, 605))	('patient', 'Species', '9606', (250, 257))	('knockdown', 'Var', (660, 669))	('RCC', 'Disease', 'MESH:C538614', (446, 449))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
9283	28749461	Hypermethylation of promoter or enhancer can result in inactivation of important tumor suppressor genes whereas hypomethylation of genomic DNA is associated with chromosomal instability and tumorigenesis.	('inactivation', 'MPA', (55, 67))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor suppressor', 'biological_process', 'GO:0051726', ('81', '97'))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('81', '97'))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', (190, 195))	('result', 'Reg', (45, 51))	('chromosomal instability', 'Phenotype', 'HP:0040012', (162, 185))	('chromosomal', 'Disease', (162, 173))	('associated', 'Reg', (146, 156))	('tumor', 'Disease', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('hypomethylation', 'Var', (112, 127))
9288	28749461	Previous studies have showed hypermethylation of KLF5 in intron 1 that downregulated KLF5 expression might correlated with DNMT3A mutation in AML.	('KLF5', 'Gene', (85, 89))	('correlated', 'Reg', (107, 117))	('downregulated', 'NegReg', (71, 84))	('AML', 'Disease', (142, 145))	('AML', 'Phenotype', 'HP:0004808', (142, 145))	('mutation', 'Var', (130, 138))	('DNMT3A', 'Gene', (123, 129))	('DNMT3A', 'Gene', '1788', (123, 129))	('hypermethylation', 'Var', (29, 45))	('expression', 'MPA', (90, 100))	('AML', 'Disease', 'MESH:D015470', (142, 145))
9289	28749461	In this study, we found that KLF5 expression was also suppressed by hypermethylation, but the methylated loci reported in AML, including that in proximal promoter (-529 to -318 bp from transcription start site (TSS)) and in intron 1 (+1284 to +1571 bp from TSS), could not be found in ccRCC.	('-529 to -318 bp', 'Var', (164, 179))	('transcription', 'biological_process', 'GO:0006351', ('185', '198'))	('RCC', 'Phenotype', 'HP:0005584', (287, 290))	('+1284', 'Var', (234, 239))	('AML', 'Disease', 'MESH:D015470', (122, 125))	('RCC', 'Disease', 'MESH:C538614', (287, 290))	('ccRCC', 'Phenotype', 'HP:0006770', (285, 290))	('RCC', 'Disease', (287, 290))	('AML', 'Phenotype', 'HP:0004808', (122, 125))	('AML', 'Disease', (122, 125))
9292	28749461	When knockdown DNMT3B, KLF5 expression was upregulated weakly.	('upregulated', 'PosReg', (43, 54))	('DNMT3B', 'Gene', '1789', (15, 21))	('knockdown', 'Var', (5, 14))	('DNMT3B', 'Gene', (15, 21))	('KLF5', 'Gene', (23, 27))
9295	28749461	Surprisingly, we first observed that hypermethylated loci of KLF5 located at proximal exon 4 in ccRCC.	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('hypermethylated loci', 'Var', (37, 57))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('KLF5', 'Gene', (61, 65))
9296	28749461	When treated with 5-Aza-CdR or knockdown DNMT1 expression, methylation levels of ccRCC cells at proximal exon 4 area were decreased.	('DNMT1', 'Gene', (41, 46))	('DNMT1', 'Gene', '1786', (41, 46))	('RCC', 'Disease', (83, 86))	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('methylation levels', 'MPA', (59, 77))	('knockdown', 'Var', (31, 40))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('decreased', 'NegReg', (122, 131))
9297	28749461	These findings indicated that hypermethylated loci at proximal exon 4 area, which were far away from KLF5 TSS, could affect KLF5 expression in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('KLF5 expression', 'MPA', (124, 139))	('ccRCC', 'Phenotype', 'HP:0006770', (143, 148))	('hypermethylated loci', 'Var', (30, 50))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('affect', 'Reg', (117, 123))
9301	28749461	It has been found that acetylation of KLF5 influenced its roles in tumor and interruption KLF5 acetylation could reverse its role from a tumor suppressor to a tumor promoter.	('interruption', 'Var', (77, 89))	('tumor', 'Disease', (137, 142))	('influenced', 'Reg', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('acetylation', 'MPA', (95, 106))	('acetylation', 'MPA', (23, 34))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('137', '153'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor suppressor', 'biological_process', 'GO:0051726', ('137', '153'))
9303	28749461	demonstrated that KLF5 deletion in PTEN-null mice upregulated epidermal growth factor (EGF) and its downstream signaling molecules AKT and ERK and initiated luminal-type mouse prostate tumors.	('upregulated', 'PosReg', (50, 61))	('EGF', 'molecular_function', 'GO:0005154', ('87', '90'))	('mice', 'Species', '10090', (45, 49))	('AKT', 'Gene', '11651', (131, 134))	('KLF5', 'Gene', (18, 22))	('deletion', 'Var', (23, 31))	('ERK', 'molecular_function', 'GO:0004707', ('139', '142'))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('initiated', 'PosReg', (147, 156))	('AKT', 'Gene', (131, 134))	('prostate tumors', 'Disease', 'MESH:D011471', (176, 191))	('signaling', 'biological_process', 'GO:0023052', ('111', '120'))	('mouse', 'Species', '10090', (170, 175))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('62', '85'))	('epidermal', 'Protein', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('prostate tumors', 'Disease', (176, 191))	('ERK', 'Pathway', (139, 142))
9304	28749461	It has been reported that tumor suppressor gene PTEN was deleted or mutated during ccRCC carcinogenesis.	('PTEN', 'Gene', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('tumor suppressor', 'biological_process', 'GO:0051726', ('26', '42'))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('RCC', 'Disease', (85, 88))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('26', '42'))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('mutated', 'Var', (68, 75))
9316	28749461	In this study, we demonstrated that KLF5, as a tumor suppressor, was suppressed by DNMT1-maintained hypermethylation in ccRCC.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('47', '63'))	('hypermethylation', 'Var', (100, 116))	('DNMT1', 'Gene', '1786', (83, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (120, 125))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('tumor suppressor', 'biological_process', 'GO:0051726', ('47', '63'))	('KLF5', 'Gene', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('suppressed', 'NegReg', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('DNMT1', 'Gene', (83, 88))	('RCC', 'Disease', (122, 125))	('tumor', 'Disease', (47, 52))
9328	28749461	IHC staining of KLF5 and Ki-67 for 786-O xenograft were performed with anti-KLF5 and anti-Ki-67 (Abcam, Cambridge, MA, USA, ab16667) polyclonal antibody.	('anti-KLF5', 'Var', (71, 80))	('antibody', 'cellular_component', 'GO:0042571', ('144', '152'))	('antibody', 'cellular_component', 'GO:0019815', ('144', '152'))	('antibody', 'cellular_component', 'GO:0019814', ('144', '152'))	('Ki-67', 'Chemical', '-', (25, 30))	('Ki-67', 'Chemical', '-', (90, 95))	('antibody', 'molecular_function', 'GO:0003823', ('144', '152'))	('anti-Ki-67', 'Var', (85, 95))
9354	28749461	To segregate 531 patients according to high- or low-KLF5 expression, the median expression was calculated.	('high-', 'Var', (39, 44))	('patients', 'Species', '9606', (17, 25))	('low-KLF5 expression', 'Var', (48, 67))
9369	32812490	In addition, long noncoding RNA lung cancer-associated transcript 1 was found to promote activation of the transforming growth factor-beta signaling pathway.	('transforming growth factor-beta', 'Gene', (107, 138))	('transforming growth factor-beta', 'Gene', '7124', (107, 138))	('lung cancer-associated transcript 1', 'Gene', (32, 67))	('long noncoding RNA', 'Var', (13, 31))	('activation', 'PosReg', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('transforming growth factor-beta', 'molecular_function', 'GO:0005160', ('107', '138'))	('lung cancer-associated transcript 1', 'Gene', '100505994', (32, 67))	('RNA', 'cellular_component', 'GO:0005562', ('28', '31'))	('signaling pathway', 'biological_process', 'GO:0007165', ('139', '156'))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
9370	32812490	Furthermore, long noncoding RNA lung cancer-associated transcript 1 knockdown restricted the growth of multiple myeloma cells in vivo.	('multiple myeloma', 'Disease', 'MESH:D009101', (103, 119))	('multiple myeloma', 'Phenotype', 'HP:0006775', (103, 119))	('lung cancer-associated transcript 1', 'Gene', (32, 67))	('multiple myeloma', 'Disease', (103, 119))	('knockdown', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('restricted', 'NegReg', (78, 88))	('lung cancer-associated transcript 1', 'Gene', '100505994', (32, 67))	('RNA', 'cellular_component', 'GO:0005562', ('28', '31'))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
9383	32812490	The data from a previous study has suggested that TGF-beta signaling pathway blockade decreased tumor burden and alleviated the tumor microenvironment so as to hamper the myeloma progression.	('TGF-beta', 'Gene', '7039', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('signaling pathway', 'biological_process', 'GO:0007165', ('59', '76'))	('decreased tumor', 'Disease', (86, 101))	('blockade', 'Var', (77, 85))	('myeloma', 'Disease', (171, 178))	('hamper', 'NegReg', (160, 166))	('tumor', 'Disease', (96, 101))	('decreased tumor', 'Disease', 'MESH:D002303', (86, 101))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('TGF-beta', 'Gene', (50, 58))	('alleviated', 'NegReg', (113, 123))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('myeloma', 'Disease', 'MESH:D009101', (171, 178))
9423	32812490	Rabbit anti-human Ki67 (1: 500, ab15580, Abcam) and goat anti-rabbit secondary antibody (1: 1000, ab7090, Abcam) were used in the experiment.	('Ki67', 'Gene', '17345', (18, 22))	('antibody', 'cellular_component', 'GO:0042571', ('79', '87'))	('ab15580', 'Var', (32, 39))	('antibody', 'molecular_function', 'GO:0003823', ('79', '87'))	('antibody', 'cellular_component', 'GO:0019815', ('79', '87'))	('human', 'Species', '9606', (12, 17))	('antibody', 'cellular_component', 'GO:0019814', ('79', '87'))	('Ki67', 'Gene', (18, 22))
9441	32812490	Additionally, downregulated lncRNA LUCAT1 also promoted the cell cycle arrest of H929 and U266 cells in the G0/G1 phase, thereby promoting the apoptosis of H929 and U266 cells (Figure 3D, E).	('LUCAT1', 'Gene', (35, 41))	('G1 phase', 'biological_process', 'GO:0051318', ('111', '119'))	('H929', 'CellLine', 'CVCL:1600', (156, 160))	('promoted', 'PosReg', (47, 55))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (60, 77))	('arrest', 'Disease', 'MESH:D006323', (71, 77))	('U266', 'CellLine', 'CVCL:0566', (165, 169))	('apoptosis', 'CPA', (143, 152))	('promoting', 'PosReg', (129, 138))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('arrest', 'Disease', (71, 77))	('downregulated', 'Var', (14, 27))	('H929', 'CellLine', 'CVCL:1600', (81, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('60', '77'))	('LUCAT1', 'Gene', '100505994', (35, 41))	('U266', 'CellLine', 'CVCL:0566', (90, 94))
9445	32812490	The results indicated that inhibition of LUCAT1 restricted the growth rate and tumor weight of xenografts in vivo (Figure 5A, B).	('LUCAT1', 'Gene', '100505994', (41, 47))	('tumor', 'Disease', (79, 84))	('growth rate', 'CPA', (63, 74))	('inhibition', 'Var', (27, 37))	('restricted', 'NegReg', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('LUCAT1', 'Gene', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
9446	32812490	Moreover, the number of Ki67 positive cells in the tumors was reduced after lncRNA LUCAT1 knockdown (Figure 5C).	('LUCAT1', 'Gene', (83, 89))	('Ki67', 'Gene', '17345', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('knockdown', 'Var', (90, 99))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('Ki67', 'Gene', (24, 28))	('reduced', 'NegReg', (62, 69))	('LUCAT1', 'Gene', '100505994', (83, 89))
9456	32812490	Consistently, the cell proliferation rate and the number of cell clones was remarkably reduced, yet the apoptosis rate was distinctly enhanced in ovarian cancer cells with lncRNA LUCAT1 silencing.	('ovarian cancer', 'Disease', (146, 160))	('apoptosis rate', 'CPA', (104, 118))	('enhanced', 'PosReg', (134, 142))	('apoptosis', 'biological_process', 'GO:0006915', ('104', '113'))	('reduced', 'NegReg', (87, 94))	('silencing', 'Var', (186, 195))	('cell proliferation', 'biological_process', 'GO:0008283', ('18', '36'))	('cell proliferation rate', 'CPA', (18, 41))	('ovarian cancer', 'Phenotype', 'HP:0100615', (146, 160))	('LUCAT1', 'Gene', '100505994', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('apoptosis', 'biological_process', 'GO:0097194', ('104', '113'))	('ovarian cancer', 'Disease', 'MESH:D010051', (146, 160))	('LUCAT1', 'Gene', (179, 185))
9458	32812490	Intriguingly, an article has demonstrated that knockdown of lncRNA LUCAT1 restricted epithelial-mesenchymal transition process of hepatoblastoma cells, implying the stimulative effect of lncRNA LUCAT1 in hepatoblastoma.	('hepatoblastoma', 'Disease', 'MESH:D018197', (204, 218))	('LUCAT1', 'Gene', '100505994', (194, 200))	('LUCAT1', 'Gene', (194, 200))	('LUCAT1', 'Gene', '100505994', (67, 73))	('LUCAT1', 'Gene', (67, 73))	('hepatoblastoma', 'Disease', 'MESH:D018197', (130, 144))	('knockdown', 'Var', (47, 56))	('hepatoblastoma', 'Disease', (204, 218))	('restricted', 'NegReg', (74, 84))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (204, 218))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('85', '118'))	('hepatoblastoma', 'Disease', (130, 144))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (130, 144))
9459	32812490	Evidence has pointed out that lncRNA LUCAT1 expression was enhanced in the tissues and cells of glioma, and depleted lncRNA LUCAT1 hindered growth of glioma cells in vitro.	('LUCAT1', 'Gene', '100505994', (37, 43))	('expression', 'MPA', (44, 54))	('LUCAT1', 'Gene', (37, 43))	('enhanced', 'PosReg', (59, 67))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('depleted', 'Var', (108, 116))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('hindered', 'NegReg', (131, 139))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('glioma', 'Disease', (150, 156))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))	('LUCAT1', 'Gene', '100505994', (124, 130))	('glioma', 'Disease', (96, 102))	('LUCAT1', 'Gene', (124, 130))
9460	32812490	Furthermore, silencing of lncRNA LUCAT1 has also been found to restrict cell progression in vitro, and suppressed tumorigenesis of ccRCC cells in vivo.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('restrict', 'NegReg', (63, 71))	('LUCAT1', 'Gene', '100505994', (33, 39))	('cell progression', 'CPA', (72, 88))	('LUCAT1', 'Gene', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('suppressed', 'NegReg', (103, 113))	('tumor', 'Disease', (114, 119))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('ccRCC', 'Disease', (131, 136))	('silencing', 'Var', (13, 22))
9465	32812490	Moreover, SB431542, a TGF-beta1 inhibitor, diminished cell invasion in MM cells, which was mediated via the TGF-beta1/Smad2/matrix metallopeptidase 3 signaling pathway.	('signaling pathway', 'biological_process', 'GO:0007165', ('150', '167'))	('Smad2', 'Gene', (118, 123))	('TGF-beta1', 'Gene', '7040', (108, 117))	('TGF-beta1', 'Gene', (108, 117))	('SB431542', 'Chemical', 'MESH:C459179', (10, 18))	('TGF-beta1', 'Gene', '7040', (22, 31))	('SB431542', 'Var', (10, 18))	('cell invasion in MM cells', 'CPA', (54, 79))	('TGF-beta1', 'Gene', (22, 31))	('diminished', 'NegReg', (43, 53))	('Smad2', 'Gene', '4087', (118, 123))
9467	32812490	It is reported that knockdown of lncRNA MALAT1 decreased TGF-beta1 secretion and LTBP3 transcription.	('MALAT1', 'Gene', (40, 46))	('secretion', 'MPA', (67, 76))	('transcription', 'MPA', (87, 100))	('LTBP3', 'Gene', '4054', (81, 86))	('secretion', 'biological_process', 'GO:0046903', ('67', '76'))	('TGF-beta1', 'Gene', '7040', (57, 66))	('MALAT1', 'Gene', '378938', (40, 46))	('TGF-beta1', 'Gene', (57, 66))	('knockdown', 'Var', (20, 29))	('LTBP3', 'Gene', (81, 86))	('transcription', 'biological_process', 'GO:0006351', ('87', '100'))	('decreased', 'NegReg', (47, 56))
9473	32812490	Takeuchi et al stated that TGF-beta inhibition may ameliorate tumor growth and improved MM-related clinical features.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('inhibition', 'Var', (36, 46))	('improved', 'PosReg', (79, 87))	('TGF-beta', 'Gene', '7039', (27, 35))	('tumor', 'Disease', (62, 67))	('ameliorate', 'PosReg', (51, 61))	('MM-related clinical features', 'CPA', (88, 116))	('TGF-beta', 'Gene', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
9525	33177244	Hierarchical clustering, pathway enrichment and GSEA analyses demonstrated that PBRM1 mutations promote tumor progression by activating hypoxia inducible factor (HIF)-related signaling pathways and increasing expression of vascular endothelial growth factor family genes.	('increasing', 'PosReg', (198, 208))	('mutations', 'Var', (86, 95))	('PBRM1', 'Gene', '55193', (80, 85))	('expression', 'MPA', (209, 219))	('GSEA', 'Chemical', '-', (48, 52))	('hypoxia', 'Disease', (136, 143))	('hypoxia', 'Disease', 'MESH:D000860', (136, 143))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('signaling', 'biological_process', 'GO:0023052', ('175', '184'))	('vascular endothelial growth factor', 'Gene', (223, 257))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('223', '257'))	('tumor', 'Disease', (104, 109))	('promote', 'PosReg', (96, 103))	('activating', 'PosReg', (125, 135))	('vascular endothelial growth factor', 'Gene', '7422', (223, 257))	('PBRM1', 'Gene', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
9530	33177244	Moreover, high CCL5 expression was associated with poorer survival outcomes in ccRCC patients.	('CCL5', 'Gene', '6352', (15, 19))	('expression', 'MPA', (20, 30))	('poorer', 'NegReg', (51, 57))	('CCL5', 'Gene', (15, 19))	('patients', 'Species', '9606', (85, 93))	('RCC', 'Disease', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('high', 'Var', (10, 14))	('CCL', 'molecular_function', 'GO:0044101', ('15', '18'))
9535	33177244	Functional loss of VHL stabilizes the hypoxia-inducible factor (HIF) and activates the VEGF (vascular endothelial growth factor) and mTOR (mammalian target of rapamycin) signaling pathways.	('mammalian target of rapamycin', 'Gene', '2475', (139, 168))	('mammalian target of rapamycin', 'Gene', (139, 168))	('stabilizes', 'Reg', (23, 33))	('loss', 'Var', (11, 15))	('signaling', 'biological_process', 'GO:0023052', ('170', '179'))	('VHL', 'Gene', (19, 22))	('mTOR', 'Gene', '2475', (133, 137))	('hypoxia', 'Disease', 'MESH:D000860', (38, 45))	('vascular endothelial growth factor', 'Gene', (93, 127))	('VEGF', 'Gene', '7422', (87, 91))	('vascular endothelial growth factor', 'Gene', '7422', (93, 127))	('mTOR', 'Gene', (133, 137))	('hypoxia', 'Disease', (38, 45))	('activates', 'PosReg', (73, 82))	('VEGF', 'Gene', (87, 91))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('93', '127'))
9536	33177244	The standard therapy for ccRCC patients includes tyrosine kinase inhibitors targeting the VEGF signaling pathway, such as sunitinib and pazopanib, and mTOR kinase inhibitors, such as, everolimus and temsiromus.	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('everolimus', 'Chemical', 'MESH:D000068338', (184, 194))	('VEGF', 'Gene', (90, 94))	('pazopanib', 'Chemical', 'MESH:C516667', (136, 145))	('tyrosine', 'Var', (49, 57))	('signaling pathway', 'biological_process', 'GO:0007165', ('95', '112'))	('VEGF', 'Gene', '7422', (90, 94))	('VEGF signaling', 'biological_process', 'GO:0038084', ('90', '104'))	('ccRCC', 'Phenotype', 'HP:0006770', (25, 30))	('patients', 'Species', '9606', (31, 39))	('mTOR', 'Gene', (151, 155))	('mTOR', 'Gene', '2475', (151, 155))	('RCC', 'Disease', (27, 30))	('temsiromus', 'Chemical', '-', (199, 209))	('sunitinib', 'Chemical', 'MESH:D000077210', (122, 131))
9542	33177244	PBRM1 mutations that disrupt the nucleosome remodeling complex have been implicated in RCC, non-small cell lung cancer, and prostate cancer.	('implicated', 'Reg', (73, 83))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('prostate cancer', 'Disease', 'MESH:D011471', (124, 139))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('PBRM1', 'Gene', (0, 5))	('nucleosome remodeling complex', 'cellular_component', 'GO:0016585', ('33', '62'))	('PBRM1', 'Gene', '55193', (0, 5))	('prostate cancer', 'Phenotype', 'HP:0012125', (124, 139))	('lung cancer', 'Disease', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (92, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('prostate cancer', 'Disease', (124, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('mutations', 'Var', (6, 15))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (96, 118))
9546	33177244	report, PBRM1 mutations also did not impact cancer-specific survival.	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('PBRM1', 'Gene', '55193', (8, 13))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('mutations', 'Var', (14, 23))	('PBRM1', 'Gene', (8, 13))
9547	33177244	However, there were opposite reports claiming that loss of PBRM1 is associated with advanced tumor stage, low differentiation grade tumors, and worse patient survival outcomes.	('patient', 'Species', '9606', (150, 157))	('associated', 'Reg', (68, 78))	('loss', 'Var', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('PBRM1', 'Gene', (59, 64))	('tumor', 'Disease', (93, 98))	('PBRM1', 'Gene', '55193', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
9549	33177244	Moving forward, ccRCC tumors with PBRM1 mutations are associated with higher expression of angiogenetic genes.	('ccRCC tumors', 'Disease', (16, 28))	('angiogenetic genes', 'Gene', (91, 109))	('expression', 'MPA', (77, 87))	('PBRM1', 'Gene', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('PBRM1', 'Gene', '55193', (34, 39))	('mutations', 'Var', (40, 49))	('ccRCC tumors', 'Disease', 'MESH:D009369', (16, 28))	('higher', 'PosReg', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('ccRCC', 'Phenotype', 'HP:0006770', (16, 21))
9550	33177244	PBRM1 mutations also correlate with outcomes in ccRCC patients treated with immune checkpoint inhibitors.	('correlate with', 'Reg', (21, 35))	('patients', 'Species', '9606', (54, 62))	('PBRM1', 'Gene', (0, 5))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('PBRM1', 'Gene', '55193', (0, 5))	('RCC', 'Disease', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('mutations', 'Var', (6, 15))
9551	33177244	reported that PBRM1 mutations were associated with poor response to immune clinical response therapy in nearly 700 ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('PBRM1', 'Gene', (14, 19))	('poor response to immune clinical', 'Phenotype', 'HP:0002721', (51, 83))	('PBRM1', 'Gene', '55193', (14, 19))	('patients', 'Species', '9606', (121, 129))	('mutations', 'Var', (20, 29))
9552	33177244	reported that PBRM1 mutations were associated with better immune clinical response therapy in more than 100 ccRCC patients, and also in David et al's.	('RCC', 'Disease', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('immune clinical response therapy', 'CPA', (58, 90))	('PBRM1', 'Gene', (14, 19))	('better', 'PosReg', (51, 57))	('PBRM1', 'Gene', '55193', (14, 19))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('patients', 'Species', '9606', (114, 122))	('mutations', 'Var', (20, 29))
9553	33177244	report, they revealed that PBRM1 mutations were associated with improved response, progression free survival and overall survival with PD-1 blockade in 592 patients with advanced ccRCC cohort.	('patients', 'Species', '9606', (156, 164))	('ccRCC', 'Phenotype', 'HP:0006770', (179, 184))	('progression free survival', 'CPA', (83, 108))	('mutations', 'Var', (33, 42))	('PBRM1', 'Gene', (27, 32))	('RCC', 'Disease', 'MESH:C538614', (181, 184))	('PBRM1', 'Gene', '55193', (27, 32))	('improved', 'PosReg', (64, 72))	('response', 'MPA', (73, 81))	('RCC', 'Disease', (181, 184))
9554	33177244	Immune clinical response was affected by immune tumor microenvironment, but the mechanisms by which mutations in PBRM1 modulate the tumor microenvironment (TME) are still poorly understood, which need further study.	('mutations', 'Var', (100, 109))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('PBRM1', 'Gene', (113, 118))	('PBRM1', 'Gene', '55193', (113, 118))	('modulate', 'Reg', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
9560	33177244	In ccRCC tissues, the status of VHL mutations do not correlate with the expression of immune cells, whereas, PBRM1 mutations are associated with T cell infiltration and immune-related gene expression.	('associated', 'Reg', (129, 139))	('mutations', 'Var', (115, 124))	('PBRM1', 'Gene', (109, 114))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('T cell infiltration', 'CPA', (145, 164))	('RCC', 'Disease', (5, 8))	('PBRM1', 'Gene', '55193', (109, 114))	('gene expression', 'biological_process', 'GO:0010467', ('184', '199'))
9561	33177244	However, the mechanistic details of the crosstalk between PBRM1 mutations in ccRCC cells, the tumor microenvironment, and immune cell infiltration and function is not clear.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('PBRM1', 'Gene', (58, 63))	('PBRM1', 'Gene', '55193', (58, 63))	('mutations', 'Var', (64, 73))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
9563	33177244	We analyzed the gene expression and mutation data of 178 ccRCC patients in the TCGA KIRC database to evaluate the relationship between mutations in VHL, PBRM1, BAP1, and SETD2 genes in the ccRCC tissues and the infiltration of 22 different immune cell types in the TME.	('VHL', 'Gene', (148, 151))	('PBRM1', 'Gene', '55193', (153, 158))	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('SETD2', 'Gene', (170, 175))	('RCC', 'Disease', (191, 194))	('BAP1', 'Gene', '8314', (160, 164))	('mutations', 'Var', (135, 144))	('RCC', 'Disease', 'MESH:C538614', (191, 194))	('ccRCC', 'Phenotype', 'HP:0006770', (189, 194))	('gene expression', 'biological_process', 'GO:0010467', ('16', '31'))	('BAP1', 'Gene', (160, 164))	('patients', 'Species', '9606', (63, 71))	('SETD2', 'Gene', '29072', (170, 175))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('PBRM1', 'Gene', (153, 158))
9564	33177244	We observed that VHL and PBRM1 were mutated in 47% and 40% of ccRCC patients (Supplementary Figure 1A).	('mutated', 'Var', (36, 43))	('patients', 'Species', '9606', (68, 76))	('PBRM1', 'Gene', (25, 30))	('VHL', 'Gene', (17, 20))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('RCC', 'Disease', (64, 67))	('PBRM1', 'Gene', '55193', (25, 30))
9567	33177244	These results show that PBRM1 mutation in the ccRCC cells promotes immune suppression and alters immune cell profiles in the TME.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('mutation', 'Var', (30, 38))	('promotes', 'PosReg', (58, 66))	('immune suppression', 'CPA', (67, 85))	('PBRM1', 'Gene', (24, 29))	('immune cell profiles in the TME', 'CPA', (97, 128))	('PBRM1', 'Gene', '55193', (24, 29))	('alters', 'Reg', (90, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('RCC', 'Disease', (48, 51))
9568	33177244	We next evaluated the effects of mutations in VHL and PBRM1 genes on the infiltration of 22 different immune cell subpopulations in ccRCC tissues.	('PBRM1', 'Gene', (54, 59))	('VHL', 'Gene', (46, 49))	('PBRM1', 'Gene', '55193', (54, 59))	('mutations', 'Var', (33, 42))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('RCC', 'Disease', (134, 137))	('ccRCC', 'Phenotype', 'HP:0006770', (132, 137))
9579	33177244	Analysis of the association between 27 gene cluster modules and 4 mutant genotypes (VHL, PBRM1, SETD2, and BAP1) in ccRCC patients showed strong correlation between six gene modules (dark-orange, white, medium purple3, yellow-green, green, and saddlebrown).	('BAP1', 'Gene', '8314', (107, 111))	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('RCC', 'Disease', (118, 121))	('green', 'Var', (233, 238))	('PBRM1', 'Gene', (89, 94))	('BAP1', 'Gene', (107, 111))	('PBRM1', 'Gene', '55193', (89, 94))	('patients', 'Species', '9606', (122, 130))	('correlation', 'Interaction', (145, 156))	('yellow-green', 'Var', (219, 231))	('dark-orange', 'Var', (183, 194))	('white', 'Var', (196, 201))	('medium purple3', 'Var', (203, 217))	('SETD2', 'Gene', '29072', (96, 101))	('SETD2', 'Gene', (96, 101))
9587	33177244	These results suggest that PBRM1 mutation promotes mast cell infiltration into the TME and activates HIF-related signaling pathways that drive growth and progression of ccRCC.	('signaling', 'biological_process', 'GO:0023052', ('113', '122'))	('mutation', 'Var', (33, 41))	('PBRM1', 'Gene', '55193', (27, 32))	('drive', 'PosReg', (137, 142))	('PBRM1', 'Gene', (27, 32))	('promotes', 'PosReg', (42, 50))	('HIF-related signaling pathways', 'Pathway', (101, 131))	('activates', 'PosReg', (91, 100))	('mast cell infiltration', 'CPA', (51, 73))	('RCC', 'Disease', (171, 174))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))
9602	33177244	This suggests that PBRM1 silencing enhances G1-S transition of ccRCC cells, thereby increasing cell proliferation.	('silencing', 'Var', (25, 34))	('cell proliferation', 'CPA', (95, 113))	('increasing', 'PosReg', (84, 94))	('PBRM1', 'Gene', '55193', (19, 24))	('cell proliferation', 'biological_process', 'GO:0008283', ('95', '113'))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('enhances', 'PosReg', (35, 43))	('G1-S transition', 'CPA', (44, 59))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('PBRM1', 'Gene', (19, 24))	('RCC', 'Disease', (65, 68))
9603	33177244	Overall, these results demonstrate that PBRM1 silencing enhances angiogenesis and ccRCC cell proliferation.	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('angiogenesis', 'biological_process', 'GO:0001525', ('65', '77'))	('PBRM1', 'Gene', (40, 45))	('silencing', 'Var', (46, 55))	('PBRM1', 'Gene', '55193', (40, 45))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('cell proliferation', 'biological_process', 'GO:0008283', ('88', '106'))	('angiogenesis', 'CPA', (65, 77))	('enhances', 'PosReg', (56, 64))
9614	33177244	CCL5 knockdown inhibited the numbers of migratory HMC-1 cells were also verified in PBRM1-silenced Caki-1 cells (Supplementary Figure 4G, 4H).	('CCL5', 'Gene', (0, 4))	('inhibited', 'NegReg', (15, 24))	('PBRM1', 'Gene', '55193', (84, 89))	('knockdown', 'Var', (5, 14))	('Caki-1', 'CellLine', 'CVCL:0234', (99, 105))	('numbers of migratory HMC-1 cells', 'CPA', (29, 61))	('HMC-1', 'CellLine', 'CVCL:0003', (50, 55))	('CCL5', 'Gene', '6352', (0, 4))	('PBRM1', 'Gene', (84, 89))	('CCL', 'molecular_function', 'GO:0044101', ('0', '3'))
9625	33177244	Overall, our results confirm that high CCL5 expression promotes immune suppression and is positively associated with adverse outcomes in ccRCC patients.	('expression', 'MPA', (44, 54))	('CCL5', 'Gene', '6352', (39, 43))	('promotes', 'PosReg', (55, 63))	('patients', 'Species', '9606', (143, 151))	('RCC', 'Disease', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('high', 'Var', (34, 38))	('CCL5', 'Gene', (39, 43))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('associated', 'Reg', (101, 111))	('CCL', 'molecular_function', 'GO:0044101', ('39', '42'))	('immune suppression', 'CPA', (64, 82))
9628	33177244	Drugs that target aberrantly upregulated VEGF and mTOR signaling pathways because of VHL mutations show limited antitumor activity in ccRCC patients.	('upregulated', 'PosReg', (29, 40))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('VEGF', 'Gene', '7422', (41, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('VHL', 'Gene', (85, 88))	('mTOR', 'Gene', (50, 54))	('mTOR', 'Gene', '2475', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('signaling', 'biological_process', 'GO:0023052', ('55', '64'))	('mutations', 'Var', (89, 98))	('patients', 'Species', '9606', (140, 148))	('VEGF', 'Gene', (41, 45))	('tumor', 'Disease', (116, 121))	('RCC', 'Disease', (136, 139))
9632	33177244	We also demonstrate that the infiltration of 22 different types of immune cells into the tumor microenvironment is dependent on the status of PBRM1 mutations (Figure 2B, 2D) and independent of VHL mutations (Figure 2A).	('mutations', 'Var', (148, 157))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('PBRM1', 'Gene', (142, 147))	('PBRM1', 'Gene', '55193', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
9633	33177244	who reported that the expression of immune-related factors such as IFNgamma, CD8alpha, CD47, and IL10 are associated with PBRM1 mutations, but independent of VHL mutation status.	('CD47', 'Gene', '961', (87, 91))	('PBRM1', 'Gene', (122, 127))	('mutations', 'Var', (128, 137))	('associated', 'Reg', (106, 116))	('IFNgamma', 'Gene', '3458', (67, 75))	('CD8alpha', 'Gene', (77, 85))	('IL10', 'Gene', (97, 101))	('IFNgamma', 'Gene', (67, 75))	('CD47', 'Gene', (87, 91))	('PBRM1', 'Gene', '55193', (122, 127))	('IL10', 'Gene', '3586', (97, 101))	('CD8alpha', 'Gene', '925', (77, 85))	('IL10', 'molecular_function', 'GO:0005141', ('97', '101'))	('expression', 'MPA', (22, 32))
9640	33177244	Miao's study was consistent with David's report, which identified that CD8+T cell infiltrated tumors are relatively depleted for PBRM1 mutations, and CD8+T cell infiltration by itself is not associated with response to anti-PD-1.	('CD8', 'Gene', (150, 153))	('PBRM1', 'Gene', (129, 134))	('PBRM1', 'Gene', '55193', (129, 134))	('CD8', 'Gene', '925', (71, 74))	('CD8', 'Gene', '925', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mutations', 'Var', (135, 144))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('CD8', 'Gene', (71, 74))
9641	33177244	Taken together, these contradictory results suggest that further multicenter large cohort studies are required to assess the relationship between PBRM1 mutation status and clinical benefit from immune therapy in ccRCC patients.	('ccRCC', 'Phenotype', 'HP:0006770', (212, 217))	('patients', 'Species', '9606', (218, 226))	('RCC', 'Disease', (214, 217))	('RCC', 'Disease', 'MESH:C538614', (214, 217))	('PBRM1', 'Gene', (146, 151))	('PBRM1', 'Gene', '55193', (146, 151))	('mutation', 'Var', (152, 160))
9644	33177244	However, in David's study, they found PBRM1 alterations were associated with lower IL6-JAK-STAT3 signaling.	('lower', 'NegReg', (77, 82))	('STAT3', 'Gene', '6774', (91, 96))	('PBRM1', 'Gene', (38, 43))	('IL6', 'Gene', '3569', (83, 86))	('alterations', 'Var', (44, 55))	('IL6', 'Gene', (83, 86))	('PBRM1', 'Gene', '55193', (38, 43))	('JAK', 'molecular_function', 'GO:0004713', ('87', '90'))	('signaling', 'biological_process', 'GO:0023052', ('97', '106'))	('STAT3', 'Gene', (91, 96))	('IL6', 'molecular_function', 'GO:0005138', ('83', '86'))
9672	33177244	The wild-type PBRM1 (PBRM1WT) and mutant PBRM1 (PBRM1MUT) patient groups were determined by first removing the low-value genes using heterogeneity analysis followed by normalizing the data sets using the variance stabilizing transformation (VST) method in the DESeq2 package as previously described.	('PBRM1MUT', 'Gene', '55193', (48, 56))	('PBRM1MUT', 'Gene', (48, 56))	('patient', 'Species', '9606', (58, 65))	('PBRM1', 'Gene', (14, 19))	('PBRM1', 'Gene', (48, 53))	('PBRM1', 'Gene', (21, 26))	('PBRM1', 'Gene', '55193', (21, 26))	('PBRM1', 'Gene', '55193', (14, 19))	('PBRM1', 'Gene', '55193', (48, 53))	('PBRM1', 'Gene', (41, 46))	('PBRM1', 'Gene', '55193', (41, 46))	('mutant', 'Var', (34, 40))
9673	33177244	The wild-type VHL (VHLWT) and mutant VHL (VHLMUT) patient groups were established as described above for PBRM1.	('PBRM1', 'Gene', (105, 110))	('PBRM1', 'Gene', '55193', (105, 110))	('VHL', 'Gene', (37, 40))	('mutant', 'Var', (30, 36))	('patient', 'Species', '9606', (50, 57))
9675	33177244	Maftools was used to identify the top 20 gene mutations in the ccRCC dataset of the TCGA KIRC (kidney renal clear cell carcinoma) database.	('mutations', 'Var', (46, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (95, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('kidney renal clear cell carcinoma', 'Disease', (95, 128))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
9677	33177244	Then, we removed outlier samples and calculated the infiltration of the 22 immune cells in 178 samples including those with wild-type and mutant PBRM1 with the CIBERSORT algorithm (https://cibersort.stanford.edu/) using 1000 permutations and the LM22 expression matrix.	('LM22', 'CellLine', 'CVCL:5998', (246, 250))	('PBRM1', 'Gene', (145, 150))	('PBRM1', 'Gene', '55193', (145, 150))	('mutant', 'Var', (138, 144))
9681	33177244	Then we established co-expression networks within these 28 gene cluster modules to determine the correlation between immune cell infiltration and gene mutations (VHL, PBRM1, SETD2, and BAP1).	('VHL', 'Gene', (162, 165))	('BAP1', 'Gene', '8314', (185, 189))	('PBRM1', 'Gene', (167, 172))	('PBRM1', 'Gene', '55193', (167, 172))	('BAP1', 'Gene', (185, 189))	('SETD2', 'Gene', '29072', (174, 179))	('SETD2', 'Gene', (174, 179))	('mutations', 'Var', (151, 160))
9708	33177244	The si-NC- and si-PBRM1-transfected ccRCC cells were washed with phosphate-buffered saline (PBS) and permeabilized with pre-chilled 70% ethanol at -20 C overnight.	('RCC', 'Disease', (38, 41))	('phosphate-buffered saline', 'Chemical', '-', (65, 90))	('si-NC-', 'Var', (4, 10))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('PBRM1', 'Gene', (18, 23))	('ethanol', 'Chemical', 'MESH:D000431', (136, 143))	('PBS', 'Chemical', '-', (92, 95))	('pre', 'molecular_function', 'GO:0003904', ('120', '123'))	('chilled', 'Phenotype', 'HP:0025143', (124, 131))	('PBRM1', 'Gene', '55193', (18, 23))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
9713	33177244	We used the Proteintech human CCL5 ELISA Kit (#KE00093, Proteintech Inc., IL, USA) to measure human CCL5 levels in the conditioned media from control and PBRM1 knockdown ccRCC cells according the manufacturer's instructions.	('Kit', 'Gene', '3815', (41, 44))	('human', 'Species', '9606', (24, 29))	('CCL', 'molecular_function', 'GO:0044101', ('100', '103'))	('knockdown', 'Var', (160, 169))	('PBRM1', 'Gene', (154, 159))	('PBRM1', 'Gene', '55193', (154, 159))	('CCL5', 'Gene', '6352', (30, 34))	('ccRCC', 'Phenotype', 'HP:0006770', (170, 175))	('CCL5', 'Gene', (30, 34))	('CCL5', 'Gene', '6352', (100, 104))	('human', 'Species', '9606', (94, 99))	('CCL', 'molecular_function', 'GO:0044101', ('30', '33'))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('RCC', 'Disease', (172, 175))	('Kit', 'Gene', (41, 44))	('CCL5', 'Gene', (100, 104))
9723	31675502	Aberrant dysregulation of the VHL gene is a nearly universal founding event.	('VHL', 'Gene', '7428', (30, 33))	('VHL', 'Gene', (30, 33))	('Aberrant dysregulation', 'Var', (0, 22))
9724	31675502	Subsequent genomic alterations involving PBRM1, SETD2, KDM5C, or BAP1 are required for disease progression and are associated with aggressive phenotypes.	('associated with', 'Reg', (115, 130))	('KDM5C', 'Gene', '8242', (55, 60))	('BAP1', 'Gene', '8314', (65, 69))	('BAP1', 'Gene', (65, 69))	('alterations', 'Var', (19, 30))	('SETD2', 'Gene', '29072', (48, 53))	('PBRM1', 'Gene', (41, 46))	('PBRM1', 'Gene', '55193', (41, 46))	('SETD2', 'Gene', (48, 53))	('KDM5C', 'Gene', (55, 60))
9741	31675502	Strikingly, we observed fourteen tumors in our cohort displayed extensive CNVs across all chromosomes, indicating a high degree of genomic instability.	('N', 'Chemical', 'MESH:D009584', (75, 76))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('CNVs', 'Var', (74, 78))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Disease', (33, 39))
9744	31675502	A previous report identified chromosome translocation as a mechanism of concurrent 3p loss and 5q gain in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('loss', 'NegReg', (86, 90))	('chromosome', 'cellular_component', 'GO:0005694', ('29', '39'))	('gain', 'PosReg', (98, 102))	('chromosome translocation', 'Var', (29, 53))
9750	31675502	Dysregulation of VHL was the most frequent alteration and was observed in 85% of tumors.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('Dysregulation', 'Var', (0, 13))	('VHL', 'Gene', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('VHL', 'Gene', '7428', (17, 20))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
9753	31675502	Overall, inactivating genomic events resulted in reduced expression of mRNA and protein (Figure 1C), indicating loss-of-function and supporting the classification of these genes as ccRCC tumor suppressors.	('loss-of-function', 'NegReg', (112, 128))	('N', 'Chemical', 'MESH:D009584', (73, 74))	('ccRCC tumor', 'Disease', (181, 192))	('reduced', 'NegReg', (49, 56))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('inactivating', 'Var', (9, 21))	('ccRCC tumor', 'Disease', 'MESH:D009369', (181, 192))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))
9754	31675502	Unique to SETD2 was the relationship of gene inactivation due to t(3:2), with a higher frequency of mutations and reduced protein expression relative to other translocation events involving chromosome 3p (Figures S1E and S1F).	('mutations', 'Var', (100, 109))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('reduced', 'NegReg', (114, 121))	('gene', 'MPA', (40, 44))	('SETD2', 'Gene', '29072', (10, 15))	('chromosome', 'cellular_component', 'GO:0005694', ('190', '200'))	('SETD2', 'Gene', (10, 15))	('protein expression', 'MPA', (122, 140))
9755	31675502	Investigation into the rate of mutation co-occurrence revealed that VHL mutations were associated with the presence of other mutations (PBRM1, BAP1, SETD2, and KDM5C), while PBRM1 mutations were associated with mutation of SETD2 and KDM5C but not BAP1 (Figure S1G).	('BAP1', 'Gene', (247, 251))	('KDM5C', 'Gene', (160, 165))	('PBRM1', 'Gene', '55193', (136, 141))	('KDM5C', 'Gene', '8242', (233, 238))	('BAP1', 'Gene', (143, 147))	('mutations', 'Var', (72, 81))	('PBRM1', 'Gene', (136, 141))	('associated', 'Reg', (87, 97))	('VHL', 'Gene', (68, 71))	('PBRM1', 'Gene', '55193', (174, 179))	('SETD2', 'Gene', (223, 228))	('associated', 'Reg', (195, 205))	('mutations', 'Var', (180, 189))	('PBRM1', 'Gene', (174, 179))	('KDM5C', 'Gene', '8242', (160, 165))	('SETD2', 'Gene', '29072', (223, 228))	('KDM5C', 'Gene', (233, 238))	('VHL', 'Gene', '7428', (68, 71))	('BAP1', 'Gene', '8314', (247, 251))	('SETD2', 'Gene', (149, 154))	('BAP1', 'Gene', '8314', (143, 147))	('SETD2', 'Gene', '29072', (149, 154))
9758	31675502	We identified 36 tumors (34%) with CIMP+ status, which was associated with higher grade (p < 9.0 e-05) and stage (p < 0.001), and higher frequency of genomic instability (p < 0.004) (Figure 1A; Table S2).	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('genomic instability', 'MPA', (150, 169))	('higher', 'PosReg', (75, 81))	('CIMP+', 'Chemical', '-', (35, 40))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('CIMP+ status', 'Var', (35, 47))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
9759	31675502	Genomic alterations can impact mRNA and protein abundance at the same locus (cis-effects), as well as other loci (trans-effects).	('impact', 'Reg', (24, 30))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('Genomic alterations', 'Var', (0, 19))	('N', 'Chemical', 'MESH:D009584', (33, 34))
9767	31675502	Interestingly, unique to IQSEC1, we found that gene methylation was associated with reduced protein and phosphorylation levels, but not mRNA.	('IQSEC1', 'Gene', '9922', (25, 31))	('phosphorylation', 'biological_process', 'GO:0016310', ('104', '119'))	('IQSEC1', 'Gene', (25, 31))	('gene methylation', 'Var', (47, 63))	('reduced', 'NegReg', (84, 91))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('N', 'Chemical', 'MESH:D009584', (138, 139))
9768	31675502	This distinctive feature of methylation affecting protein but not mRNA expression was also observed in several other genes, including BCL9L (11q23.3) and AHDC1 (1p35.3) (Figure S2C; Table S3), and may indicate a post-translational regulatory mechanism.	('BCL9L', 'Gene', '283149', (134, 139))	('protein', 'MPA', (50, 57))	('affecting', 'Reg', (40, 49))	('BCL9L', 'Gene', (134, 139))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('AHDC1', 'Gene', (154, 159))	('N', 'Chemical', 'MESH:D009584', (68, 69))	('p35', 'cellular_component', 'GO:0070745', ('162', '165'))	('methylation', 'Var', (28, 39))	('AHDC1', 'Gene', '27245', (154, 159))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))	('p35', 'cellular_component', 'GO:0043514', ('162', '165'))
9769	31675502	Next, we focused on identifying cellular processes correlated with cis- and trans-effects driven by major CNV or mutation events in ccRCC and identified multiple pathways that were disparate or commonly dysregulated among distinct genomic alterations (Figures 2B and S2D; Table S3).	('mul', 'Gene', (153, 156))	('mutation', 'Var', (113, 121))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('N', 'Chemical', 'MESH:D009584', (107, 108))	('RCC', 'Disease', (134, 137))	('mul', 'Gene', '4591', (153, 156))
9770	31675502	Loss of chromosome 3p was associated with upregulation of hypoxic signaling, cell-cycle regulation and glycolysis, downregulation of oxidative phosphorylation (OXPHOS), fatty acid metabolism, and the TCA cycle.	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('TCA cycle', 'CPA', (200, 209))	('cell-cycle regulation', 'biological_process', 'GO:0051726', ('77', '98'))	('cell-cycle', 'CPA', (77, 87))	('fatty acid', 'Chemical', 'MESH:D005227', (169, 179))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('133', '158'))	('hypoxic signaling', 'MPA', (58, 75))	('downregulation', 'NegReg', (115, 129))	('upregulation', 'PosReg', (42, 54))	('signaling', 'biological_process', 'GO:0023052', ('66', '75'))	('Loss', 'Var', (0, 4))	('TCA', 'Chemical', 'MESH:D014238', (200, 203))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('169', '190'))	('chromosome', 'Gene', (8, 18))	('glycolysis', 'biological_process', 'GO:0006096', ('103', '113'))	('TCA cycle', 'biological_process', 'GO:0006099', ('200', '209'))	('OXPHOS', 'biological_process', 'GO:0002082', ('160', '166'))	('glycolysis', 'MPA', (103, 113))	('fatty acid metabolism', 'MPA', (169, 190))
9773	31675502	Investigation of trans-effects involving chromosome 3p genes revealed that VHL mutations resulted in dysregulation of similar pathways as 3p loss including downregulation of metabolic pathways and upregulation of G1/S cell-cycle transition and interferon-alpha response.	('downregulation', 'NegReg', (156, 170))	('VHL', 'Gene', (75, 78))	('interferon-alpha', 'CPA', (244, 260))	('cell-cycle transition', 'biological_process', 'GO:0044770', ('218', '239'))	('loss', 'NegReg', (141, 145))	('upregulation', 'PosReg', (197, 209))	('VHL', 'Gene', '7428', (75, 78))	('G1/S cell-cycle', 'CPA', (213, 228))	('cell-cycle transition', 'biological_process', 'GO:0044771', ('218', '239'))	('metabolic pathways', 'Pathway', (174, 192))	('chromosome', 'cellular_component', 'GO:0005694', ('41', '51'))	('mutations', 'Var', (79, 88))	('dysregulation', 'MPA', (101, 114))
9774	31675502	PBRM1 mutations drove downregulation of OXPHOS and upregulation of G2/M cell-cycle transition, mitogen-activated protein kinase (MAPK) signaling, and focal adhesion pathways.	('upregulation', 'PosReg', (51, 63))	('downregulation', 'NegReg', (22, 36))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('OXPHOS', 'biological_process', 'GO:0002082', ('40', '46'))	('focal adhesion', 'cellular_component', 'GO:0005925', ('150', '164'))	('cell-cycle transition', 'biological_process', 'GO:0044771', ('72', '93'))	('G2/M', 'MPA', (67, 71))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('mitogen-activated protein', 'MPA', (95, 120))	('MAPK', 'molecular_function', 'GO:0004707', ('129', '133'))	('OXPHOS', 'MPA', (40, 46))	('MAPK) signaling', 'biological_process', 'GO:0000165', ('129', '144'))	('cell-cycle transition', 'biological_process', 'GO:0044770', ('72', '93'))	('mutations', 'Var', (6, 15))	('focal adhesion pathways', 'Pathway', (150, 173))
9775	31675502	BAP1 mutations were associated with upregulation of protein translation pathways and interferon-gamma signaling, with the latter feature also associated with SETD2 mutations (Figure S2D; Table S3).	('interferon-gamma', 'molecular_function', 'GO:0005133', ('85', '101'))	('BAP1', 'Gene', (0, 4))	('interferon-gamma', 'Gene', (85, 101))	('upregulation', 'PosReg', (36, 48))	('mutations', 'Var', (5, 14))	('SETD2', 'Gene', '29072', (158, 163))	('protein translation', 'biological_process', 'GO:0006412', ('52', '71'))	('interferon-gamma', 'Gene', '3458', (85, 101))	('protein translation pathways', 'Pathway', (52, 80))	('associated', 'Reg', (142, 152))	('signaling', 'biological_process', 'GO:0023052', ('102', '111'))	('SETD2', 'Gene', (158, 163))	('BAP1', 'Gene', '8314', (0, 4))	('mutations', 'Var', (164, 173))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
9776	31675502	KD5MC mutations shared a similar trans-effect profile as 3p locus/VHL loss, including downregulation of select metabolic pathways and increased cell-cycle regulation.	('cell-cycle regulation', 'CPA', (144, 165))	('VHL loss', 'Disease', 'MESH:D006623', (66, 74))	('VHL loss', 'Disease', (66, 74))	('select metabolic pathways', 'Pathway', (104, 129))	('cell-cycle regulation', 'biological_process', 'GO:0051726', ('144', '165'))	('downregulation', 'NegReg', (86, 100))	('increased', 'PosReg', (134, 143))	('mutations', 'Var', (6, 15))
9779	31675502	Loss of 14q, involving the potential tumor suppressors NDRG2 (14q11.2) and HIF1A (14q23.2), displayed decreased WNT signaling expression and upregulation of MYC signaling, N-linked glycosylation, and interferon-gamma response.	('interferon-gamma', 'Gene', '3458', (200, 216))	('14q', 'Chemical', '-', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('signaling', 'biological_process', 'GO:0023052', ('161', '170'))	('MYC', 'Gene', '4609', (157, 160))	('N', 'Chemical', 'MESH:D009584', (172, 173))	('14q', 'Chemical', '-', (8, 11))	('HIF1A', 'Gene', '3091', (75, 80))	('14q', 'Chemical', '-', (62, 65))	('NDRG2', 'Gene', (55, 60))	('WNT signaling expression', 'MPA', (112, 136))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('decreased', 'NegReg', (102, 111))	('glycosylation', 'biological_process', 'GO:0070085', ('181', '194'))	('N-linked glycosylation', 'MPA', (172, 194))	('upregulation', 'PosReg', (141, 153))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('Loss', 'Var', (0, 4))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))	('HIF1A', 'Gene', (75, 80))	('MYC', 'Gene', (157, 160))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('200', '216'))	('interferon-gamma', 'Gene', (200, 216))	('tumor', 'Disease', (37, 42))	('N', 'Chemical', 'MESH:D009584', (55, 56))	('NDRG2', 'Gene', '57447', (55, 60))
9780	31675502	We detected a high percentage of CIMP+ tumors with 14q loss (75%) (Figure 1C).	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('CIMP+', 'Disease', (33, 38))	('14q loss', 'Var', (51, 59))	('14q', 'Chemical', '-', (51, 54))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('CIMP+', 'Chemical', '-', (33, 38))	('tumors', 'Disease', (39, 45))
9787	31675502	Adjusting for tumor purity (STAR Methods), we detected a trend of higher sample-wise correlation in tumors associated with clinical features such as higher grade (p = 0.006), chromosome 14 loss (p = 0.0006), and BAP1 mutations (p = 0.00004) (Figure 3B; Table S4).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (14, 19))	('BAP1', 'Gene', '8314', (212, 216))	('BAP1', 'Gene', (212, 216))	('chromosome', 'cellular_component', 'GO:0005694', ('175', '185'))	('tumor', 'Disease', (100, 105))	('STAR', 'Gene', '6770', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('STAR', 'Gene', (28, 32))	('higher', 'PosReg', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('mutations', 'Var', (217, 226))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('loss', 'NegReg', (189, 193))	('chromosome 14', 'Gene', (175, 188))
9804	31675502	The G2/M checkpoint is the final safeguard of genomic fidelity prior to mitosis; our data support a mechanism of G2-stalling that prevents mitotic arrest-induced apoptosis in tumors, evidenced by elevated levels of the inhibitory CDK1-Y15 phosphorylation, especially in more aggressive tumors (p < 0.05) (Figure S5B).	('tumors', 'Disease', (175, 181))	('aggressive tumors', 'Disease', (275, 292))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('S5B', 'Gene', (312, 315))	('tumors', 'Disease', (286, 292))	('aggressive tumors', 'Disease', 'MESH:D001523', (275, 292))	('G2-stalling', 'Var', (113, 124))	('mitotic arrest', 'Disease', 'MESH:D006323', (139, 153))	('phosphorylation', 'biological_process', 'GO:0016310', ('239', '254'))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('mitosis', 'biological_process', 'GO:0000278', ('72', '79'))	('apoptosis', 'biological_process', 'GO:0006915', ('162', '171'))	('tumors', 'Disease', 'MESH:D009369', (286, 292))	('S5B', 'Gene', '5711', (312, 315))	('prevents', 'NegReg', (130, 138))	('CDK1', 'Gene', '983', (230, 234))	('mitotic arrest', 'Disease', (139, 153))	('CDK1', 'Gene', (230, 234))	('G2/M checkpoint', 'biological_process', 'GO:0000075', ('4', '19'))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('elevated', 'PosReg', (196, 204))	('apoptosis', 'biological_process', 'GO:0097194', ('162', '171'))	('CDK', 'molecular_function', 'GO:0004693', ('230', '233'))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
9812	31675502	The cell-cycle module included multiple cell-cycle checkpoint proteins involved in the G1/S-phase transition (CDKN1B, SKP2), S-phase regulatory elements (MCM4, MCM6), and the G2/M phase (CDK1, TK1, CDC20) (Figure S5D), with phosphorylation of CDC20 representing another mechanism of mitotic-arrest.	('SKP2', 'Gene', (118, 122))	('MCM4', 'Gene', '4173', (154, 158))	('CDC20', 'Gene', '991', (243, 248))	('SKP2', 'Gene', '6502', (118, 122))	('CDKN1B', 'Gene', '1027', (110, 116))	('mul', 'Gene', '4591', (31, 34))	('CDK', 'molecular_function', 'GO:0004693', ('187', '190'))	('mul', 'Gene', (31, 34))	('CDC20', 'Gene', (243, 248))	('mitotic-arrest', 'Disease', 'MESH:D006323', (283, 297))	('phosphorylation', 'Var', (224, 239))	('MCM4', 'Gene', (154, 158))	('S-phase', 'biological_process', 'GO:0051320', ('125', '132'))	('CDC20', 'Gene', '991', (198, 203))	('MCM6', 'Gene', '4175', (160, 164))	('phosphorylation', 'biological_process', 'GO:0016310', ('224', '239'))	('S-phase', 'biological_process', 'GO:0051320', ('90', '97'))	('mitotic-arrest', 'Disease', (283, 297))	('MCM6', 'Gene', (160, 164))	('M phase', 'biological_process', 'GO:0000279', ('178', '185'))	('CDC20', 'Gene', (198, 203))	('CDKN1B', 'Gene', (110, 116))	('cell-cycle', 'biological_process', 'GO:0007049', ('4', '14'))	('TK1', 'Gene', (193, 196))	('TK1', 'Gene', '7083', (193, 196))	('cell-cycle checkpoint', 'biological_process', 'GO:0000075', ('40', '61'))	('CDK1', 'Gene', '983', (187, 191))	('CDK1', 'Gene', (187, 191))
9825	31675502	Corresponding to the elevated CD8+ T cell presence was a higher frequency of BAP1 mutations, a feature previously associated with increased immune infiltration in a kidney cancer xenograft model.	('kidney cancer', 'Disease', 'MESH:D007680', (165, 178))	('CD8', 'Gene', (30, 33))	('CD8', 'Gene', '925', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('kidney cancer', 'Disease', (165, 178))	('BAP1', 'Gene', '8314', (77, 81))	('mutations', 'Var', (82, 91))	('CD8+ T cell presence', 'Phenotype', 'HP:0005422', (30, 50))	('BAP1', 'Gene', (77, 81))	('kidney cancer', 'Phenotype', 'HP:0009726', (165, 178))
9831	31675502	Together, these associated pathways are representative of TME-tumor crosstalk, with PDGF signaling driving fibroblast recruitment and activation, and CAFs subsequently inducing an EMT-phenotype in tumors.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('CAFs', 'Var', (150, 154))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('PDGF signaling', 'Gene', (84, 98))	('inducing', 'Reg', (168, 176))	('tumors', 'Disease', (197, 203))	('activation', 'PosReg', (134, 144))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('EMT', 'biological_process', 'GO:0001837', ('180', '183'))	('TME-tumor', 'Disease', (58, 67))	('PDGF', 'molecular_function', 'GO:0005161', ('84', '88'))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('fibroblast recruitment', 'CPA', (107, 129))	('TME-tumor', 'Disease', 'MESH:D009369', (58, 67))
9835	31675502	Interestingly, these tumor subtypes had a higher frequency of chromosome 7 gain and lower frequency of chromosome 14 loss, with the latter feature inversely correlated with endothelial cell presence (Figures 6A and 6C).	('chromosome', 'cellular_component', 'GO:0005694', ('103', '113'))	('loss', 'NegReg', (117, 121))	('chromosome', 'cellular_component', 'GO:0005694', ('62', '72'))	('tumor', 'Disease', (21, 26))	('lower', 'NegReg', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('chromosome', 'Var', (62, 72))	('gain', 'PosReg', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
9850	31675502	The latter result reflects the aggregation of multiple features in the CD8+ Inflamed subtype that are considered as poor prognosticators in ccRCC, including higher frequency of BAP1 mutations (chi-square test adjusted p < 0.05), increased proportion of higher grade tumors, and increased PD-1/PD-L1 expression (t test adjusted p < 0.05).	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('CD8', 'Gene', '925', (71, 74))	('BAP1', 'Gene', (177, 181))	('PD-1', 'Gene', (288, 292))	('higher', 'PosReg', (157, 163))	('mul', 'Gene', '4591', (46, 49))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('increased PD', 'Phenotype', 'HP:0008151', (278, 290))	('mul', 'Gene', (46, 49))	('mutations', 'Var', (182, 191))	('CD8', 'Gene', (71, 74))	('PD-L1', 'Gene', (293, 298))	('PD-L1', 'Gene', '29126', (293, 298))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumors', 'Disease', (266, 272))	('RCC', 'Disease', (142, 145))	('increased', 'PosReg', (278, 287))	('PD-1', 'Gene', '9825', (288, 292))	('BAP1', 'Gene', '8314', (177, 181))	('expression', 'MPA', (299, 309))	('tumors', 'Disease', 'MESH:D009369', (266, 272))
9865	31675502	Tumors in ccRCC3 displayed a higher frequency of PBRM1 mutations (p < 0.05), whereas those in ccRCC1 had a higher frequency of BAP1 mutations (p < 0.0001), CIMP+ status (p < 0.007), and genomic instability (p < 0.0001) (Figure 7B).	('RCC', 'Disease', (96, 99))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('BAP1', 'Gene', (127, 131))	('BAP1', 'Gene', '8314', (127, 131))	('mutations', 'Var', (55, 64))	('CIMP+ status', 'Var', (156, 168))	('mutations', 'Var', (132, 141))	('RCC', 'Disease', (12, 15))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('genomic instability', 'CPA', (186, 205))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('PBRM1', 'Gene', (49, 54))	('PBRM1', 'Gene', '55193', (49, 54))	('CIMP+', 'Chemical', '-', (156, 161))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
9987	31675502	CNVEX uses whole-genome aligned reads to estimate coverage within fixed genomic intervals and whole-genome and whole-exome variant calls to compute B-allele frequencies (BAFs) at variable positions (we used VarDict germline calls).	('variant', 'Var', (123, 130))	('BAF', 'Gene', '8815', (170, 173))	('BAF', 'Gene', (170, 173))	('N', 'Chemical', 'MESH:D009584', (1, 2))
10001	31675502	Clonal loss or LOH of 3p is very likely in ccRCC, whereas near-haploid and very high ploidy solutions are unlikely.	('LOH of', 'Var', (15, 21))	('Clonal loss', 'Disease', (0, 11))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('Clonal loss', 'Disease', 'MESH:C580365', (0, 11))
10007	31675502	Cysteine carbamidomethylation (+57.0215) and lysine TMT labeling (+229.1629) were specified as fixed modifications, and methionine oxidation (+15.9949), N-terminal protein acetylation (+42.0106), and TMT labeling of peptide N terminus and serine residues were specified as variable modifications.	('N', 'Chemical', 'MESH:D009584', (153, 154))	('protein acetylation', 'biological_process', 'GO:0006473', ('164', '183'))	('+229.1629', 'Var', (66, 75))	('methionine', 'Chemical', 'MESH:D008715', (120, 130))	('+42.0106', 'Var', (185, 193))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('methionine oxidation', 'MPA', (120, 140))	('Cysteine', 'Chemical', 'MESH:D003545', (0, 8))	('+15.9949', 'Var', (142, 150))	('+57.0215', 'Var', (31, 39))	('N', 'Chemical', 'MESH:D009584', (224, 225))	('lysine', 'Chemical', 'MESH:D008239', (45, 51))	('TMT', 'molecular_function', 'GO:0018708', ('52', '55'))	('Cysteine carbamidomethylation', 'MPA', (0, 29))	('TMT', 'molecular_function', 'GO:0018708', ('200', '203'))	('serine', 'Chemical', 'MESH:D012694', (239, 245))
10009	31675502	For the analysis of phosphopeptide enriched data, the set of variable modifications also included phosphorylation (+79.9663) of serine, threonine, and tyrosine residues.	('+79.9663', 'Var', (115, 123))	('threonine', 'Chemical', 'MESH:D013912', (136, 145))	('phosphorylation', 'biological_process', 'GO:0016310', ('98', '113'))	('phosphorylation', 'MPA', (98, 113))	('tyrosine residues', 'MPA', (151, 168))	('serine', 'Chemical', 'MESH:D012694', (128, 134))	('serine', 'MPA', (128, 134))	('threonine', 'MPA', (136, 145))	('tyrosine', 'Chemical', 'MESH:D014443', (151, 159))	('phosphopeptide', 'Chemical', 'MESH:D010748', (20, 34))
10034	31675502	netMHCpan was then used to predict HLA peptide binding affinity for somatic mutation-derived variant peptides with a length between 8-11 amino acids.	('netMHCpan', 'Chemical', '-', (0, 9))	('peptide binding', 'molecular_function', 'GO:0042277', ('39', '54'))	('HLA peptide', 'Protein', (35, 46))	('peptides', 'Chemical', 'MESH:D010455', (101, 109))	('variant', 'Var', (93, 100))
10041	31675502	One additional missed cleavage was retained for peptides containing KP and RP amino acids.	('ret', 'Gene', (35, 38))	('ret', 'Gene', '5979', (35, 38))	('peptides', 'Chemical', 'MESH:D010455', (48, 56))	('RP amino acids', 'Var', (75, 89))
10088	31675502	Samples C3N-00492 and C3N-00175 showed one copy loss of chromosomes 1, 2, 6, 10, 13 and 17 along with TP53 mutations and contained high expression of several biomarkers (such as FOXI1, RHCG) that are characteristic of chromophobe RCC (chRCC).	('TP53', 'Gene', (102, 106))	('chromophobe RCC', 'Disease', (218, 233))	('expression', 'MPA', (136, 146))	('mutations', 'Var', (107, 116))	('C3N-00492', 'Var', (8, 17))	('FOXI1', 'Gene', '2299', (178, 183))	('C3N-00175', 'Var', (22, 31))	('N', 'Chemical', 'MESH:D009584', (10, 11))	('RHCG', 'Gene', (185, 189))	('RHCG', 'Gene', '51458', (185, 189))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('chromophobe RCC', 'Disease', 'MESH:C538614', (218, 233))	('RCC', 'Disease', (237, 240))	('RCC', 'Disease', 'MESH:C538614', (230, 233))	('TP53', 'Gene', '7157', (102, 106))	('RCC', 'Disease', (230, 233))	('RCC', 'Disease', 'MESH:C538614', (237, 240))	('FOXI1', 'Gene', (178, 183))
10089	31675502	In addition, samples C3N-00832 and C3N-00313 contained PTEN mutations, and the latter also showed outlier expression of the papillary RCC biomarker VSTM2A, along with gain of chr7, and PIK3R1 mutation and were thus categorized as likely papillary RCCs.	('VSTM2A', 'Gene', (148, 154))	('PTEN', 'Gene', '5728', (55, 59))	('N', 'Chemical', 'MESH:D009584', (37, 38))	('N', 'Chemical', 'MESH:D009584', (23, 24))	('PIK3R1', 'Gene', '5295', (185, 191))	('C3N-00832', 'Var', (21, 30))	('PIK3R1', 'Gene', (185, 191))	('RCC', 'Disease', 'MESH:C538614', (247, 250))	('VSTM2A', 'Gene', '222008', (148, 154))	('RCC', 'Disease', (134, 137))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('contained', 'Reg', (45, 54))	('C3N-00313', 'Var', (35, 44))	('mutations', 'Var', (60, 69))	('RCC', 'Disease', (247, 250))	('PTEN', 'Gene', (55, 59))
10090	31675502	Sample C3L-00359 contained bi-allelic loss of TSC1 along with histologic features of eosinophilic solid cystic RCC (ESC-RCC), while C3N-01180 had a SFPQ-TFE3 gene fusion, a hallmark of translocation RCC.	('TFE3', 'Gene', (153, 157))	('RCC', 'Disease', 'MESH:C538614', (199, 202))	('TSC1', 'Gene', (46, 50))	('SFPQ', 'Gene', (148, 152))	('SFPQ', 'Gene', '6421', (148, 152))	('RCC', 'Disease', (111, 114))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('TFE3', 'Gene', '7030', (153, 157))	('eosinophilic solid cystic RCC', 'Disease', 'MESH:C538614', (85, 114))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Disease', (199, 202))	('eosinophilic solid cystic RCC', 'Disease', (85, 114))	('loss', 'NegReg', (38, 42))	('C3N-01180', 'Var', (132, 141))	('TSC1', 'Gene', '7248', (46, 50))
10091	31675502	Finally, C3N-00435 contained 3p loss with a PIK3CA hotspot mutation.	('PIK3CA', 'Gene', (44, 50))	('loss', 'NegReg', (32, 36))	('PIK3CA', 'Gene', '5290', (44, 50))	('mutation', 'Var', (59, 67))	('N', 'Chemical', 'MESH:D009584', (11, 12))	('C3N-00435', 'Var', (9, 18))
10096	31675502	The underlying data consist of quantitative information on copy number alteration, mutation, methylation, RNA-seq gene expression, protein expression, and phosphosite expression for 22,867 genes across 110 samples.	('copy number alteration', 'Var', (59, 81))	('phosphosite', 'Chemical', '-', (155, 166))	('methylation', 'biological_process', 'GO:0032259', ('93', '104'))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('RNA', 'cellular_component', 'GO:0005562', ('106', '109'))	('N', 'Chemical', 'MESH:D009584', (107, 108))	('RNA-seq', 'Gene', (106, 113))	('gene expression', 'biological_process', 'GO:0010467', ('114', '129'))
10097	31675502	Data tracks for each gene are labeled as: "Mut"-mutation data ("Yes" is any types of mutation, "No" is no mutation), "Methy"-beta value of CpG island in the promoter region of the gene (standardized), "CNV (lr)"-the log ratio of copy number variation, "CNV (baf)"-the b-allele frequency of the copy number variation (standardized), "mRNA"-gene expression levels (standardized), "Protein"-gene-level protein abundance (standardized), and "Phospho"-gene-level phosphoprotein abundance (standardized).	('baf', 'Gene', '8815', (258, 261))	('Protein"-gene-level protein abundance', 'MPA', (379, 416))	('mRNA"-gene expression levels', 'MPA', (333, 361))	('Phospho"-gene-level phosphoprotein abundance', 'MPA', (438, 482))	('mutation', 'Var', (85, 93))	('N', 'Chemical', 'MESH:D009584', (335, 336))	('N', 'Chemical', 'MESH:D009584', (203, 204))	('N', 'Chemical', 'MESH:D009584', (254, 255))	('N', 'Chemical', 'MESH:D009584', (96, 97))	('baf', 'Gene', (258, 261))
10099	31675502	Bottom-placed tracks visualize CNV data for chromosomes 5q, 7p, 9p, and 14q, t(3;2) and t(3;5) chromosome translocations, CIMP status, and genomic instability status, as well as grade, stage, and gender information.	('CIMP status', 'Var', (122, 133))	('N', 'Chemical', 'MESH:D009584', (32, 33))	('chromosome', 'cellular_component', 'GO:0005694', ('95', '105'))	('CIMP', 'Chemical', '-', (122, 126))	('14q', 'Chemical', '-', (72, 75))	('genomic', 'MPA', (139, 146))
10102	31675502	Specifically, three types of translocation categories, Chr3-Chr2, Chr3-Chr5, and Chr3-other, were simultaneously considered in the regression models, and an ANOVA test was applied to assess whether any translocation was associated with the protein abundances in the tumors.	('protein abundances', 'MPA', (240, 258))	('mul', 'Gene', '4591', (100, 103))	('associated', 'Reg', (220, 230))	('translocation', 'Var', (202, 215))	('mul', 'Gene', (100, 103))	('protein', 'cellular_component', 'GO:0003675', ('240', '247'))	('N', 'Chemical', 'MESH:D009584', (158, 159))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('tumors', 'Disease', (266, 272))
10105	31675502	Post-ANOVA assessment of each event indicated that Chr3-Chr2 translocation was significantly associated with decreased abundance in SETD protein abundance (Figure S1F), which is consistent with the high mutation rate observed in Chr3-Chr2 group (Figure S1E).	('translocation', 'Var', (61, 74))	('decreased', 'NegReg', (109, 118))	('Chr3-Chr2', 'Gene', (51, 60))	('SETD protein abundance', 'MPA', (132, 154))	('N', 'Chemical', 'MESH:D009584', (6, 7))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('abundance', 'MPA', (119, 128))
10106	31675502	The integrative analysis tool, iProFun, was used to identify functional molecular quantitative traits perturbed by DNA-level variations (https://github.com/WangLab-MSSM/iProFun).	('N', 'Chemical', 'MESH:D009584', (116, 117))	('iProFun', 'Chemical', '-', (169, 176))	('variations', 'Var', (125, 135))	('perturbed', 'Reg', (102, 111))	('DNA', 'cellular_component', 'GO:0005574', ('115', '118'))	('iProFun', 'Chemical', '-', (31, 38))
10108	31675502	Specifically, we considered three functional molecular quantitative traits (mRNA expression levels, global protein abundances, and phosphopeptide abundances) for their associations with four DNA-level variations (copy number alterations measured by log ratios, copy number alterations measured by b-allele frequency, DNA methylations and somatic mutations).	('copy number alterations', 'Var', (213, 236))	('N', 'Chemical', 'MESH:D009584', (318, 319))	('associations', 'Interaction', (168, 180))	('DNA', 'cellular_component', 'GO:0005574', ('191', '194'))	('phosphopeptide', 'Chemical', 'MESH:D010748', (131, 145))	('N', 'Chemical', 'MESH:D009584', (78, 79))	('copy number alterations', 'Var', (261, 284))	('DNA', 'cellular_component', 'GO:0005574', ('317', '320'))	('DNA methylations', 'Var', (317, 333))	('N', 'Chemical', 'MESH:D009584', (192, 193))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
10270	31936065	in this study, we provide a comprehensive review of multiple reported and ongoing clinical trials evaluating the combination of PD-1/PD-L1 inhibitors with either ipilimumab (a cytotoxic T-lymphocyte-associated protein 4, CTLA-4 inhibitor) or with anti-VEGF targeted therapy.	('inhibitors', 'Var', (139, 149))	('CTLA-4', 'Gene', '1493', (221, 227))	('protein', 'cellular_component', 'GO:0003675', ('210', '217'))	('PD-L1', 'Gene', (133, 138))	('ipilimumab', 'Chemical', 'MESH:D000074324', (162, 172))	('CTLA-4', 'Gene', (221, 227))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (176, 219))	('VEGF', 'Gene', (252, 256))	('PD-L1', 'Gene', '29126', (133, 138))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', (176, 219))	('VEGF', 'Gene', '7422', (252, 256))
10287	31936065	VEFG inhibition can restore antitumor immunity by normalizing the vasculature and endothelial cell activation.	('endothelial cell activation', 'CPA', (82, 109))	('inhibition', 'Var', (5, 15))	('VEFG', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('restore', 'PosReg', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('vasculature', 'MPA', (66, 77))	('endothelial cell activation', 'biological_process', 'GO:0042118', ('82', '109'))	('tumor', 'Disease', (32, 37))
10288	31936065	Additionally, PD-1 blockage also promotes cytotoxic T-cell infiltration into the tumor and significantly enhances antitumor immunity.	('promotes', 'PosReg', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('enhances', 'PosReg', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('PD-1', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', (118, 123))	('blockage', 'Var', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
10294	31936065	Additionally, the high Teff gene signature expression, a maker of a high preexisting anti-tumor immune response, was associated with improved PFS with atezolizumab  +  bevacizumab when compared to sunitinib monotherapy.	('PFS', 'Disease', (142, 145))	('immune response', 'biological_process', 'GO:0006955', ('96', '111'))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('atezolizumab', 'Chemical', 'MESH:C000594389', (151, 163))	('bevacizumab', 'Chemical', 'MESH:D000068258', (168, 179))	('high', 'Var', (18, 22))	('sunitinib', 'Chemical', 'MESH:D000077210', (197, 206))	('improved', 'PosReg', (133, 141))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
10299	31936065	In this review, we summarize the clinical trials evaluating the combination of PD1/PDL1 inhibitors with either ipilimumab (a cytotoxic T-lymphocyte-associated protein 4, CTLA-4 inhibitor) or angiogenesis inhibitors.	('PD1', 'Gene', (79, 82))	('PD1', 'Gene', '5133', (79, 82))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('ipilimumab', 'Chemical', 'MESH:D000074324', (111, 121))	('PDL1', 'Gene', '29126', (83, 87))	('CTLA-4', 'Gene', (170, 176))	('PDL1', 'Gene', (83, 87))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (125, 168))	('angiogenesis', 'biological_process', 'GO:0001525', ('191', '203'))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', (125, 168))	('inhibitors', 'Var', (88, 98))	('CTLA-4', 'Gene', '1493', (170, 176))
10321	31936065	The ORRs were better with the combination therapy when compared to sunitinib and were 59.3% vs. 35.7%, respectively.	('better', 'PosReg', (14, 20))	('sunitinib', 'Chemical', 'MESH:D000077210', (67, 76))	('combination', 'Var', (30, 41))	('ORRs', 'MPA', (4, 8))
10340	31936065	In this study, Albiges and colleagues found that 34.5% of the patients that received avelumab and axitinib had >=30% shrinkage in renal lesions in comparison to 9.6% who received sunitinib, indicating future areas of research in neoadjuvant therapy with immunotherapy and tyrosine kinase inhibitor.	('sunitinib', 'Chemical', 'MESH:D000077210', (179, 188))	('avelumab', 'Chemical', 'MESH:C000609138', (85, 93))	('axitinib', 'Chemical', 'MESH:D000077784', (98, 106))	('shrinkage', 'NegReg', (117, 126))	('avelumab', 'Var', (85, 93))	('renal lesions', 'Disease', (130, 143))	('to 9', 'Species', '1214577', (158, 162))	('renal lesions', 'Disease', 'MESH:D007674', (130, 143))	('patients', 'Species', '9606', (62, 70))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('281', '297'))
10440	31746384	Furthermore, a previous study demonstrated that knockdown of circRNA_0001451 significantly enhanced tumor proliferation in vitro; the levels of circRNA_0001451 were associated with the differentiation grade of patients with CCRCC.	('CCRCC', 'Disease', 'MESH:D002292', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('associated', 'Reg', (165, 175))	('CCRCC', 'Disease', (224, 229))	('RCC', 'Phenotype', 'HP:0005584', (226, 229))	('circRNA_0001451', 'Var', (61, 76))	('circRNA_0001451', 'Var', (144, 159))	('patients', 'Species', '9606', (210, 218))	('CCRCC', 'Phenotype', 'HP:0006770', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('enhanced', 'PosReg', (91, 99))	('knockdown', 'Var', (48, 57))
10441	31746384	In addition, circRNA ZNF609 has been reported to serve as a ceRNA in modulating the expression of Forkhead box P4 via sponging miR-138-5p in renal cancer; high circ-ZNF609 expression was determined to enhance the growth and invasive characteristics of renal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('renal cancer', 'Disease', (141, 153))	('ZNF609', 'Gene', (165, 171))	('ZNF609', 'Gene', (21, 27))	('ZNF609', 'Gene', '23060', (21, 27))	('ZNF609', 'Gene', '23060', (165, 171))	('renal cancer', 'Phenotype', 'HP:0009726', (141, 153))	('renal cancer', 'Disease', (252, 264))	('renal cancer', 'Phenotype', 'HP:0009726', (252, 264))	('Forkhead box P4', 'Gene', (98, 113))	('invasive characteristics of', 'CPA', (224, 251))	('Forkhead box P4', 'Gene', '116113', (98, 113))	('renal cancer', 'Disease', 'MESH:D007680', (141, 153))	('growth', 'CPA', (213, 219))	('renal cancer', 'Disease', 'MESH:D007680', (252, 264))	('miR', 'Gene', '220972', (127, 130))	('enhance', 'PosReg', (201, 208))	('high', 'Var', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('miR', 'Gene', (127, 130))
10463	31746384	KEGG pathway analysis suggested that DEGs were associated with 'ascorbate and aldarate metabolism', 'pentose and glucuronate interconversions', 'steroid hormone biosynthesis' and 'retinol metabolism'.	('retinol metabolism', 'biological_process', 'GO:0042572', ('180', '198'))	('retinol', 'Chemical', 'MESH:D014801', (180, 187))	('metabolism', 'biological_process', 'GO:0008152', ('87', '97'))	('glucuronate', 'Chemical', 'MESH:D005965', (113, 124))	('steroid', 'Chemical', 'MESH:D013256', (145, 152))	('pentose', 'Chemical', 'MESH:D010429', (101, 108))	('DEGs', 'Var', (37, 41))	("'steroid hormone biosynthesis'", 'MPA', (144, 174))	('hormone biosynthesis', 'biological_process', 'GO:0042446', ('153', '173'))	('ascorbate', 'Chemical', 'MESH:D001205', (64, 73))
10495	31746384	In a study investigating the role of gene copy number variation in relation to the clinical parameters of metastatic CCRCC, the loss of PLG was associated with advanced tumor stage and Fuhrman grade.	('Fuhrman', 'Disease', (185, 192))	('associated', 'Reg', (144, 154))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('loss', 'Var', (128, 132))	('CCRCC', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('CCRCC', 'Phenotype', 'HP:0006770', (117, 122))	('PLG', 'Gene', '5340', (136, 139))	('tumor', 'Disease', (169, 174))	('CCRCC', 'Disease', 'MESH:D002292', (117, 122))	('PLG', 'Gene', (136, 139))
10505	33767130	Overexpression of Runx2 promoted malignant proliferation and migration of ccRCC cells, and inversely, interfering Runx2 with siRNA attenuates its oncogenic ability.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('Runx2', 'Gene', '860', (18, 23))	('malignant proliferation', 'CPA', (33, 56))	('Runx2', 'Gene', (18, 23))	('interfering', 'Var', (102, 113))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('attenuates', 'NegReg', (131, 141))	('Runx2', 'Gene', '860', (114, 119))	('Runx2', 'Gene', (114, 119))	('migration', 'CPA', (61, 70))	('promoted', 'PosReg', (24, 32))	('oncogenic ability', 'CPA', (146, 163))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))
10508	33767130	Kaplan-Meier survival analyses indicated that ccRCC patients with high Zic2/Runx2 and low NOLC1 had the worst outcome.	('Zic2', 'Gene', '7546', (71, 75))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('Runx2', 'Gene', '860', (76, 81))	('Runx2', 'Gene', (76, 81))	('Zic2', 'Gene', (71, 75))	('patients', 'Species', '9606', (52, 60))	('high', 'Var', (66, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('low', 'Var', (86, 89))	('NOLC1', 'Gene', (90, 95))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
10526	33767130	For instance, high expression of Runx2 was significantly correlated with larger tumor size, lymph node metastasis, and shorter postoperative survival time of patients with non-small cell lung cancer.	('shorter', 'NegReg', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (176, 198))	('lung cancer', 'Disease', 'MESH:D008175', (187, 198))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (172, 198))	('lymph node metastasis', 'CPA', (92, 113))	('tumor', 'Disease', (80, 85))	('high expression', 'Var', (14, 29))	('Runx2', 'Gene', (33, 38))	('Runx2', 'Gene', '860', (33, 38))	('patients', 'Species', '9606', (158, 166))	('lung cancer', 'Disease', (187, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
10529	33767130	Therefore, dysregulation of Runx2 modulates tumor cell proliferation and metastasis, and revealing the underlying mechanism is urgent in the future development of individual treatments against different types of cancer.	('Runx2', 'Gene', '860', (28, 33))	('Runx2', 'Gene', (28, 33))	('modulates', 'Reg', (34, 43))	('metastasis', 'CPA', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('cancer', 'Disease', (212, 218))	('dysregulation', 'Var', (11, 24))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
10531	33767130	In the present study, we clearly characterized the expression and prognosis prediction of Runx2 in ccRCC, and found that aberrant overexpression of Runx2 was significantly associated with poor survival of ccRCC patients.	('ccRCC', 'Phenotype', 'HP:0006770', (205, 210))	('patients', 'Species', '9606', (211, 219))	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('poor', 'NegReg', (188, 192))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('Runx2', 'Gene', (148, 153))	('overexpression', 'PosReg', (130, 144))	('associated', 'Reg', (172, 182))	('Runx2', 'Gene', (90, 95))	('RCC', 'Disease', (101, 104))	('RCC', 'Disease', (207, 210))	('aberrant', 'Var', (121, 129))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('Runx2', 'Gene', '860', (148, 153))	('Runx2', 'Gene', '860', (90, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))
10533	33767130	Therefore, our findings clearly demonstrate that dysregulation of Zic2/Runx2/NOLC1 signaling promotes ccRCC progression.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('Zic2', 'Gene', (66, 70))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('Zic2', 'Gene', '7546', (66, 70))	('Runx2', 'Gene', '860', (71, 76))	('dysregulation', 'Var', (49, 62))	('promotes', 'PosReg', (93, 101))	('Runx2', 'Gene', (71, 76))	('RCC', 'Disease', (104, 107))
10567	33767130	For tumor formation in vivo, 1 x 106 ACHN and 786-O cells after knockdown of Runx2 were resuspended with 100 mul of PBS and subcutaneously injected into the back of nude mice, respectively (4 mice/group).	('tumor', 'Disease', (4, 9))	('mice', 'Species', '10090', (192, 196))	('formation', 'biological_process', 'GO:0009058', ('10', '19'))	('PBS', 'Chemical', 'MESH:D007854', (116, 119))	('knockdown', 'Var', (64, 73))	('nude mice', 'Species', '10090', (165, 174))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('mice', 'Species', '10090', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('Runx2', 'Gene', '860', (77, 82))	('Runx2', 'Gene', (77, 82))
10570	33767130	For the lung metastasis in nude mice, 5 x 105 786-O cells with or without Runx2 knockdown were suspended in 100 mul of PBS and injected into the tail vein of nude mice (six mice for each group).	('lung metastasis', 'CPA', (8, 23))	('knockdown', 'Var', (80, 89))	('PBS', 'Chemical', 'MESH:D007854', (119, 122))	('mice', 'Species', '10090', (163, 167))	('Runx2', 'Gene', (74, 79))	('Runx2', 'Gene', '860', (74, 79))	('nude mice', 'Species', '10090', (158, 167))	('mice', 'Species', '10090', (32, 36))	('nude mice', 'Species', '10090', (27, 36))	('mice', 'Species', '10090', (173, 177))
10576	33767130	Next, correlations analyses of Runx2 level and clinicopathological characteristics based on TCGA dataset suggested that high expression of Runx2 was associated with poorly differentiated grade and advanced stage of ccRCC (Fig.	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('ccRCC', 'Phenotype', 'HP:0006770', (215, 220))	('RCC', 'Disease', (217, 220))	('Runx2', 'Gene', '860', (31, 36))	('Runx2', 'Gene', (31, 36))	('high', 'Var', (120, 124))	('Runx2', 'Gene', '860', (139, 144))	('Runx2', 'Gene', (139, 144))	('associated', 'Reg', (149, 159))	('RCC', 'Phenotype', 'HP:0005584', (217, 220))	('poorly differentiated grade', 'CPA', (165, 192))
10577	33767130	Survival analysis using TCGA clinical data showed that ccRCC patients with high expression of Runx2 had shorter overall survival and disease-free survival than patients with low level of Runx2 (P < 0.001, Figs.	('high expression', 'Var', (75, 90))	('disease-free survival', 'CPA', (133, 154))	('patients', 'Species', '9606', (160, 168))	('shorter', 'NegReg', (104, 111))	('patients', 'Species', '9606', (61, 69))	('Runx2', 'Gene', '860', (94, 99))	('Runx2', 'Gene', (94, 99))	('Runx2', 'Gene', '860', (187, 192))	('Runx2', 'Gene', (187, 192))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))	('overall survival', 'CPA', (112, 128))
10581	33767130	Kaplan-Meier survival analysis showed that high expression of Runx2 was correlated with adverse overall survival for ccRCC patients (P = 0.031, Fig.	('high expression', 'Var', (43, 58))	('Runx2', 'Gene', (62, 67))	('Runx2', 'Gene', '860', (62, 67))	('patients', 'Species', '9606', (123, 131))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('adverse', 'NegReg', (88, 95))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('RCC', 'Disease', (119, 122))	('overall survival', 'MPA', (96, 112))
10591	33767130	Next, the in vitro and in vivo functional studies were performed to analyze the effect of Runx2 knockdown on ccRCC cell growth and metastasis.	('knockdown', 'Var', (96, 105))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('Runx2', 'Gene', '860', (90, 95))	('Runx2', 'Gene', (90, 95))	('cell growth', 'biological_process', 'GO:0016049', ('115', '126'))
10593	33767130	ACHN and 786-O cells with knockdown of Runx2 were subcutaneously injected into nude mice, and the tumor volume was measured every week.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('knockdown', 'Var', (26, 35))	('nude mice', 'Species', '10090', (79, 88))	('Runx2', 'Gene', '860', (39, 44))	('Runx2', 'Gene', (39, 44))	('tumor', 'Disease', (98, 103))
10594	33767130	Results showed that tumors derived from ACHN and 786-O cells with knockdown of Runx2 were growing slowly, compared to tumors originated from the control cells (Fig.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('Runx2', 'Gene', '860', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('slowly', 'NegReg', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumors', 'Disease', (118, 124))	('knockdown', 'Var', (66, 75))	('Runx2', 'Gene', (79, 84))
10597	33767130	Results indicated that knockdown of Runx2 inhibited ccRCC cell metastasis (Fig.	('knockdown', 'Var', (23, 32))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('inhibited', 'NegReg', (42, 51))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('Runx2', 'Gene', '860', (36, 41))	('Runx2', 'Gene', (36, 41))
10600	33767130	qRT-PCR and western blot analyses confirmed that NOLC1 was significantly upregulated after knockdown of Runx2 in ACHN and 786-O cells (Fig.	('Runx2', 'Gene', '860', (104, 109))	('Runx2', 'Gene', (104, 109))	('knockdown', 'Var', (91, 100))	('upregulated', 'PosReg', (73, 84))	('NOLC1', 'Gene', (49, 54))
10608	33767130	Recent study reported that NOLC1 expression was decreased in HCC tissue, and ectopic expression of NOLC1 inhibited tumor growth in mouse by repressing the proliferation of HCC cells, which suggests the tumor suppressive role of NOLC1.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (202, 207))	('HCC cells', 'CPA', (172, 181))	('inhibited', 'NegReg', (105, 114))	('proliferation', 'CPA', (155, 168))	('ectopic expression', 'Var', (77, 95))	('tumor', 'Disease', (115, 120))	('mouse', 'Species', '10090', (131, 136))	('decreased', 'NegReg', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('HCC', 'Phenotype', 'HP:0001402', (61, 64))	('NOLC1', 'Gene', (99, 104))	('expression', 'MPA', (33, 43))	('HCC', 'Phenotype', 'HP:0001402', (172, 175))	('repressing', 'NegReg', (140, 150))	('NOLC1', 'Gene', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
10611	33767130	Moreover, survival analyses using TCGA data indicated that ccRCC patients with low level of NOLC1 had short overall and disease-free survival than whose with high expression of NOLC1 (Fig.	('short', 'NegReg', (102, 107))	('disease-free survival', 'CPA', (120, 141))	('NOLC1', 'Gene', (92, 97))	('low level', 'Var', (79, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('patients', 'Species', '9606', (65, 73))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))
10612	33767130	Importantly, in vitro functional analyses showed that silencing of NOLC1 could rescue the inhibition of cell growth and migration induced by Runx2 knockdown in 786-O and ACHN cells (Fig.	('NOLC1', 'Gene', (67, 72))	('silencing', 'Var', (54, 63))	('Runx2', 'Gene', '860', (141, 146))	('Runx2', 'Gene', (141, 146))	('inhibition of cell growth', 'biological_process', 'GO:0030308', ('90', '115'))	('knockdown', 'Var', (147, 156))
10614	33767130	The above data have demonstrated that high expression of Runx2 aggravated ccRCC progression, but the regulation of Runx2 expression in ccRCC was unclear.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('regulation', 'biological_process', 'GO:0065007', ('101', '111'))	('Runx2', 'Gene', '860', (115, 120))	('Runx2', 'Gene', (115, 120))	('high expression', 'Var', (38, 53))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('RCC', 'Disease', (137, 140))	('Runx2', 'Gene', '860', (57, 62))	('Runx2', 'Gene', (57, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))	('aggravated', 'PosReg', (63, 73))
10618	33767130	Silencing Zic2 with siRNA in 786-O and ACHN cells reduced the expression of Runx2 at mRNA and protein levels (Figs.	('Silencing', 'Var', (0, 9))	('expression', 'MPA', (62, 72))	('Runx2', 'Gene', (76, 81))	('Runx2', 'Gene', '860', (76, 81))	('Zic2', 'Gene', '7546', (10, 14))	('reduced', 'NegReg', (50, 57))	('Zic2', 'Gene', (10, 14))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))
10623	33767130	High expression of Zic2 was related to the worse overall survival of patients with ccRCC.	('High', 'Var', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('Zic2', 'Gene', (19, 23))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('RCC', 'Disease', (85, 88))	('patients', 'Species', '9606', (69, 77))	('Zic2', 'Gene', '7546', (19, 23))
10625	33767130	Survival analysis suggested that high expression of Zic2 was associated with the worse outcome of patients with ccRCC (P < 0.0001, Fig.	('Zic2', 'Gene', (52, 56))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('high', 'Var', (33, 37))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('patients', 'Species', '9606', (98, 106))	('Zic2', 'Gene', '7546', (52, 56))
10627	33767130	We confirmed the downregulation of 45S pre-rRNA in 786-O cells after knockdown of Zic2 and Runx2 by qRT-PCR (Fig.	('45S pre-rRNA', 'MPA', (35, 47))	('pre', 'molecular_function', 'GO:0003904', ('39', '42'))	('Zic2', 'Gene', '7546', (82, 86))	('downregulation', 'NegReg', (17, 31))	('Zic2', 'Gene', (82, 86))	('Runx2', 'Gene', '860', (91, 96))	('Runx2', 'Gene', (91, 96))	('knockdown', 'Var', (69, 78))
10629	33767130	In conclusion, dysregulation of Zic2/Runx2/NOLC1 signaling enhanced ccRCC progression by promoting cell growth and metastasis.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('cell growth', 'biological_process', 'GO:0016049', ('99', '110'))	('Zic2', 'Gene', (32, 36))	('enhanced', 'PosReg', (59, 67))	('Runx2', 'Gene', '860', (37, 42))	('Runx2', 'Gene', (37, 42))	('Zic2', 'Gene', '7546', (32, 36))	('dysregulation', 'Var', (15, 28))	('promoting', 'PosReg', (89, 98))
10632	33767130	Results of Kaplan-Meier survival analyses showed that co-overexpression of Zic2 and Runx2 in ccRCC tissues predicated the worse prognosis of ccRCC patients, compared to other groups (P < 0.001, Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (141, 146))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('Zic2', 'Gene', '7546', (75, 79))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('Runx2', 'Gene', '860', (84, 89))	('RCC', 'Disease', (95, 98))	('Runx2', 'Gene', (84, 89))	('patients', 'Species', '9606', (147, 155))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('co-overexpression', 'Var', (54, 71))	('Zic2', 'Gene', (75, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('RCC', 'Disease', (143, 146))
10633	33767130	Finally, multi-survival curves showed that ccRCC patients with high Zic2/Runx2 and low NOLC1 had the worst overall survival (P < 0.001, Fig.	('low', 'Var', (83, 86))	('Zic2', 'Gene', '7546', (68, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('worst', 'NegReg', (101, 106))	('Runx2', 'Gene', '860', (73, 78))	('Runx2', 'Gene', (73, 78))	('Zic2', 'Gene', (68, 72))	('high', 'Var', (63, 67))	('NOLC1', 'Gene', (87, 92))	('patients', 'Species', '9606', (49, 57))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
10648	33767130	RNA sequencing was used to analyze the target genes of Runx2 in ccRCC cells, and we found that gene NOLC1 expression was significantly downregulated after silencing of Runx2.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('silencing', 'Var', (155, 164))	('Runx2', 'Gene', '860', (168, 173))	('Runx2', 'Gene', (168, 173))	('Runx2', 'Gene', (55, 60))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('expression', 'MPA', (106, 116))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('Runx2', 'Gene', '860', (55, 60))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('NOLC1', 'Gene', (100, 105))	('RCC', 'Disease', (66, 69))	('downregulated', 'NegReg', (135, 148))
10652	33767130	In addition, cell proliferation and migration assays also confirmed that regression of NOLC1 was responsible for the oncogenic function of Runx2 in ccRCC cells.	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('RCC', 'Disease', (150, 153))	('Runx2', 'Gene', (139, 144))	('Runx2', 'Gene', '860', (139, 144))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('ccRCC', 'Phenotype', 'HP:0006770', (148, 153))	('NOLC1', 'Gene', (87, 92))	('oncogenic function', 'MPA', (117, 135))	('regression', 'Var', (73, 83))	('cell proliferation', 'biological_process', 'GO:0008283', ('13', '31'))
10658	33767130	Moreover, knockdown of NOLC1 with siRNA could increase the proliferation and migration abilities of ccRCC cells in vitro.	('proliferation', 'CPA', (59, 72))	('NOLC1', 'Gene', (23, 28))	('increase', 'PosReg', (46, 54))	('migration abilities', 'CPA', (77, 96))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('knockdown', 'Var', (10, 19))
10660	33767130	Recently, dysregulation of Runx2 expression has been confirmed in various cancers, such as colorectal, thyroid cancer and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('colorectal, thyroid cancer', 'Disease', 'MESH:D015179', (91, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('Runx2', 'Gene', '860', (27, 32))	('Runx2', 'Gene', (27, 32))	('thyroid cancer', 'Phenotype', 'HP:0002890', (103, 117))	('dysregulation', 'Var', (10, 23))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancers', 'Disease', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
10674	30428628	Among all modifications occurring in RNA molecules, N6-methyladenosine (m6A) is the most frequent, especially among mRNAs.	('m6A', 'Gene', (72, 75))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (52, 70))	('m6A', 'Gene', '56339', (72, 75))	('RNA', 'cellular_component', 'GO:0005562', ('37', '40'))	('N6-methyladenosine', 'Var', (52, 70))
10684	30428628	Importantly, contrarily to DNA modifications that primarily regulate gene transcription, RNA modifications regulate the many aspects of RNAs fate, including localization, splicing, nuclear export, targeting for destruction, stability, secondary structure and efficiency of translation, ultimately allowing the formation of a functional RNA molecule.	('splicing', 'MPA', (171, 179))	('targeting for', 'MPA', (197, 210))	('translation', 'biological_process', 'GO:0006412', ('273', '284'))	('localization', 'MPA', (157, 169))	('stability', 'MPA', (224, 233))	('translation', 'MPA', (273, 284))	('transcription', 'biological_process', 'GO:0006351', ('74', '87'))	('localization', 'biological_process', 'GO:0051179', ('157', '169'))	('formation', 'MPA', (310, 319))	('regulate', 'Reg', (107, 115))	('secondary structure', 'MPA', (235, 254))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))	('D', 'Chemical', 'MESH:D003903', (27, 28))	('modifications', 'Var', (93, 106))	('allowing', 'Reg', (297, 305))	('RNA', 'cellular_component', 'GO:0005562', ('336', '339'))	('nuclear export', 'MPA', (181, 195))	('RNAs', 'Protein', (136, 140))	('nuclear export', 'biological_process', 'GO:0051168', ('181', '195'))	('RNA', 'cellular_component', 'GO:0005562', ('89', '92'))	('RNA', 'Gene', (89, 92))	('splicing', 'biological_process', 'GO:0045292', ('171', '179'))	('formation', 'biological_process', 'GO:0009058', ('310', '319'))
10691	30428628	The epitranscriptome of cancer cells has been demonstrated to be disrupted, and associations with dysregulation of expression of m6A-related proteins (i.e., their writer, readers and erasers) have been increasingly found in many neoplasms.	('dysregulation', 'Var', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('neoplasms', 'Phenotype', 'HP:0002664', (229, 238))	('found', 'Reg', (215, 220))	('associations', 'Interaction', (80, 92))	('cancer', 'Disease', (24, 30))	('m6A', 'Gene', (129, 132))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('expression', 'MPA', (115, 125))	('neoplasms', 'Disease', 'MESH:D009369', (229, 238))	('neoplasm', 'Phenotype', 'HP:0002664', (229, 237))	('neoplasms', 'Disease', (229, 238))	('epitranscriptome', 'MPA', (4, 20))	('m6A', 'Gene', '56339', (129, 132))
10694	30428628	Modifications in m6A levels and/or m6A-related proteins expression have been found in a broad spectrum of cancer types.	('m6A', 'Gene', (35, 38))	('m6A', 'Gene', '56339', (35, 38))	('found', 'Reg', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('expression', 'MPA', (56, 66))	('cancer', 'Disease', (106, 112))	('m6A', 'Gene', (17, 20))	('Modifications', 'Var', (0, 13))	('m6A', 'Gene', '56339', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
10697	30428628	Polymorphisms in intron 1 of FTO have been associated with a higher risk for development of many neoplasms; however, a metanalysis concluded that, except for pancreatic cancer, the risk was mainly due to body mass index (BMI).	('pancreatic cancer', 'Disease', (158, 175))	('pancreatic cancer', 'Disease', 'MESH:D010190', (158, 175))	('FTO', 'Gene', (29, 32))	('Polymorphisms', 'Var', (0, 13))	('neoplasms', 'Disease', 'MESH:D009369', (97, 106))	('neoplasms', 'Disease', (97, 106))	('neoplasm', 'Phenotype', 'HP:0002664', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('men', 'Species', '9606', (84, 87))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (158, 175))	('FTO', 'Gene', '79068', (29, 32))	('associated', 'Reg', (43, 53))	('neoplasms', 'Phenotype', 'HP:0002664', (97, 106))
10698	30428628	However, a single-nucleotide polymorphism (SNP) in FTO intron 8 was found to be associated with a higher risk for melanoma, and, as for breast cancer (BCa), another SNP in FTO intron 1 was identified as a susceptibility locus for estrogen-negative BCa, both not explained by BMI.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('single-nucleotide polymorphism', 'Var', (11, 41))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('FTO', 'Gene', '79068', (172, 175))	('FTO', 'Gene', '79068', (51, 54))	('breast cancer', 'Disease', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('associated', 'Reg', (80, 90))	('FTO', 'Gene', (172, 175))	('BCa', 'Phenotype', 'HP:0003002', (151, 154))	('FTO', 'Gene', (51, 54))	('estrogen-negative BCa', 'Disease', (230, 251))	('BCa', 'Phenotype', 'HP:0003002', (248, 251))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))
10700	30428628	Also in BCa, a link between hypoxia, tumor invasiveness/metastasis and m6A has been proposed, with hypoxia-inducible factors (HIFs) leading to increased mRNA expression of the pluripotency factor homeobox transcription factor Nanog (NANOG) (and subsequent BCa stem cells specification) by means of m6A demethylation by the eraser ALKBH5.	('increased', 'PosReg', (143, 152))	('hypoxia', 'Disease', 'MESH:D000860', (99, 106))	('m6A', 'Gene', (71, 74))	('BCa', 'Phenotype', 'HP:0003002', (256, 259))	('hypoxia', 'Disease', 'MESH:D000860', (28, 35))	('demethylation', 'Var', (302, 315))	('mRNA expression', 'MPA', (153, 168))	('demethylation', 'biological_process', 'GO:0070988', ('302', '315'))	('BCa', 'Phenotype', 'HP:0003002', (8, 11))	('transcription', 'biological_process', 'GO:0006351', ('205', '218'))	('NANOG', 'Gene', '79923', (233, 238))	('NANOG', 'Gene', (233, 238))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor invasiveness/metastasis', 'Disease', 'MESH:D009362', (37, 66))	('transcription factor', 'molecular_function', 'GO:0000981', ('205', '225'))	('m6A', 'Gene', '56339', (298, 301))	('BCa', 'Disease', (8, 11))	('m6A', 'Gene', (298, 301))	('homeobox transcription factor Nanog', 'Gene', '79923', (196, 231))	('ALKBH5', 'Gene', (330, 336))	('hypoxia', 'Disease', (99, 106))	('homeobox transcription factor Nanog', 'Gene', (196, 231))	('hypoxia', 'Disease', (28, 35))	('tumor invasiveness/metastasis', 'Disease', (37, 66))	('m6A', 'Gene', '56339', (71, 74))	('ALKBH5', 'Gene', '54890', (330, 336))
10703	30428628	In this tumor model, METTL3-mediated m6A modification targets suppressor of cytokine signaling 2 (SOCS2), promoting its degradation, in a process dependent of YTHDF2 reader.	('degradation', 'biological_process', 'GO:0009056', ('120', '131'))	('SOCS2', 'Gene', '8835', (98, 103))	('METTL3', 'Gene', '56339', (21, 27))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('METTL3', 'Gene', (21, 27))	('suppressor of cytokine signaling 2', 'Gene', (62, 96))	('suppressor of cytokine signaling 2', 'Gene', '8835', (62, 96))	('m6A', 'Gene', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('YTHDF2', 'Gene', '51441', (159, 165))	('modification', 'Var', (41, 53))	('SOCS2', 'Gene', (98, 103))	('tumor', 'Disease', (8, 13))	('promoting', 'PosReg', (106, 115))	('degradation', 'MPA', (120, 131))	('YTHDF2', 'Gene', (159, 165))	('m6A', 'Gene', '56339', (37, 40))
10705	30428628	In addition, m6A and related proteins are implicated in treatment resistance, as shown in pancreatic cancer cells, in which knockdown of the writer METTL3 improved sensitivity to both chemo- and radiation therapy, clearly demonstrating the rationale for using treatments targeting m6A modulators.	('knockdown', 'Var', (124, 133))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('men', 'Species', '9606', (265, 268))	('improved', 'PosReg', (155, 163))	('pancreatic cancer', 'Disease', (90, 107))	('METTL3', 'Gene', '56339', (148, 154))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('m6A', 'Gene', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('m6A', 'Gene', (281, 284))	('men', 'Species', '9606', (61, 64))	('METTL3', 'Gene', (148, 154))	('implicated', 'Reg', (42, 52))	('sensitivity to', 'MPA', (164, 178))	('m6A', 'Gene', '56339', (13, 16))	('m6A', 'Gene', '56339', (281, 284))
10708	30428628	Again, the knockdown of YTHDF3 sensitized cancer cells to chemotherapy and, additionally, oncogene c-Myc was found to drive YTHDF1 expression.	('YTHDF3', 'Gene', (24, 30))	('YTHDF1', 'Gene', (124, 130))	('drive', 'PosReg', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('sensitized', 'Reg', (31, 41))	('expression', 'MPA', (131, 141))	('YTHDF3', 'Gene', '253943', (24, 30))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('c-Myc', 'Gene', '4609', (99, 104))	('c-Myc', 'Gene', (99, 104))	('knockdown', 'Var', (11, 20))	('YTHDF1', 'Gene', '54915', (124, 130))
10712	30428628	More recently, it was demonstrated that the eraser FTO is also upregulated in cervical cancer and leads to chemo- and radiation therapy resistance by demethylating the mRNA transcripts of its target, beta-catenin.	('mRNA transcripts', 'MPA', (168, 184))	('FTO', 'Gene', '79068', (51, 54))	('demethylating', 'Var', (150, 163))	('cervical cancer', 'Disease', 'MESH:D002583', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('beta-catenin', 'Gene', (200, 212))	('cervical cancer', 'Disease', (78, 93))	('upregulated', 'PosReg', (63, 74))	('beta-catenin', 'Gene', '1499', (200, 212))	('FTO', 'Gene', (51, 54))	('chemo- and', 'MPA', (107, 117))	('leads to', 'Reg', (98, 106))
10713	30428628	In addition, a recent study in endometrial cancer has elegantly shown that decreased m6A caused by a mutation in METTL14 or downregulation of METTL3 ultimately leads to increased proliferation by activating the AKT signaling pathway.	('signaling pathway', 'biological_process', 'GO:0007165', ('215', '232'))	('endometrial cancer', 'Phenotype', 'HP:0012114', (31, 49))	('METTL3', 'Gene', (142, 148))	('m6A', 'Gene', '56339', (85, 88))	('METTL14', 'Gene', (113, 120))	('endometrial cancer', 'Disease', (31, 49))	('METTL3', 'Gene', '56339', (142, 148))	('AKT', 'Gene', (211, 214))	('m6A', 'Gene', (85, 88))	('endometrial cancer', 'Disease', 'MESH:D016889', (31, 49))	('downregulation', 'NegReg', (124, 138))	('proliferation', 'CPA', (179, 192))	('AKT signaling', 'biological_process', 'GO:0043491', ('211', '224'))	('increased', 'PosReg', (169, 178))	('activating', 'PosReg', (196, 206))	('AKT', 'Gene', '207', (211, 214))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('mutation', 'Var', (101, 109))	('METTL14', 'Gene', '57721', (113, 120))	('decreased', 'NegReg', (75, 84))
10715	30428628	In addition, high levels of the eraser ALKBH5 associated with poor prognostic features and METTL3 associated with radiation therapy resistance.	('associated with', 'Reg', (98, 113))	('METTL3', 'Gene', (91, 97))	('high', 'Var', (13, 17))	('ALKBH5', 'Gene', '54890', (39, 45))	('radiation therapy resistance', 'CPA', (114, 142))	('ALKBH5', 'Gene', (39, 45))	('associated', 'Reg', (46, 56))	('METTL3', 'Gene', '56339', (91, 97))	('poor prognostic features', 'CPA', (62, 86))
10719	30428628	It was shown that mutations in m6A-related proteins confer poor prognosis in acute myeloid leukemia (AML).	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (77, 99))	('AML', 'Disease', 'MESH:D015470', (101, 104))	('m6A', 'Gene', '56339', (31, 34))	('AML', 'Phenotype', 'HP:0004808', (101, 104))	('acute myeloid leukemia', 'Disease', (77, 99))	('AML', 'Disease', (101, 104))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (83, 99))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (77, 99))	('leukemia', 'Phenotype', 'HP:0001909', (91, 99))	('m6A', 'Gene', (31, 34))	('mutations', 'Var', (18, 27))
10720	30428628	Mutations in writers (METTL3, METTL14, WTAP, RBM15) promote and maintain leukemogenesis in AML, whereas overexpression of the eraser FTO in AML cell lines also promoted proliferation and decreased apoptosis.	('WTAP', 'Gene', (39, 43))	('promoted', 'PosReg', (160, 168))	('RBM15', 'Gene', '64783', (45, 50))	('METTL3', 'Gene', (22, 28))	('apoptosis', 'biological_process', 'GO:0097194', ('197', '206'))	('apoptosis', 'CPA', (197, 206))	('apoptosis', 'biological_process', 'GO:0006915', ('197', '206'))	('leukemogenesis', 'Disease', (73, 87))	('AML', 'Phenotype', 'HP:0004808', (140, 143))	('Mutations', 'Var', (0, 9))	('METTL3', 'Gene', '56339', (22, 28))	('METTL14', 'Gene', '57721', (30, 37))	('WTAP', 'Gene', '9589', (39, 43))	('METTL14', 'Gene', (30, 37))	('FTO', 'Gene', '79068', (133, 136))	('RBM15', 'Gene', (45, 50))	('AML', 'Disease', 'MESH:D015470', (91, 94))	('FTO', 'Gene', (133, 136))	('AML', 'Disease', (91, 94))	('AML', 'Disease', 'MESH:D015470', (140, 143))	('AML', 'Phenotype', 'HP:0004808', (91, 94))	('AML', 'Disease', (140, 143))	('decreased', 'NegReg', (187, 196))	('promote', 'PosReg', (52, 59))
10721	30428628	Moreover, FTO plays a role in response to all-trans-retinoic acid (ATRA) and, interestingly, D-2-hydroxyglutarate (D2-HG) (the metabolite accumulated in isocitrate dehydrogenase 1 and 2 (IDH1/2)-mutant leukemias (20% of AMLs)) functions as an inhibitor of FTO demethylase, meaning that FTO expression is context-dependent and has to be interpreted according to IDH mutational status.	('ATRA', 'Chemical', 'MESH:D014212', (67, 71))	('D', 'Chemical', 'MESH:D003903', (93, 94))	('IDH', 'Gene', '3417', (361, 364))	('FTO', 'Gene', '79068', (256, 259))	('D', 'Chemical', 'MESH:D003903', (188, 189))	('FTO', 'Gene', '79068', (10, 13))	('FTO', 'Gene', (256, 259))	('D', 'Chemical', 'MESH:D003903', (115, 116))	('D', 'Chemical', 'MESH:D003903', (362, 363))	('IDH1/2', 'Gene', '3417;3418', (187, 193))	('FTO', 'Gene', (10, 13))	('all-trans-retinoic acid', 'Chemical', 'MESH:D014212', (42, 65))	('IDH1/2', 'Gene', (187, 193))	('-mutant', 'Var', (194, 201))	('IDH', 'Gene', (187, 190))	('leukemias', 'Disease', 'MESH:D007938', (202, 211))	('leukemia', 'Phenotype', 'HP:0001909', (202, 210))	('FTO', 'Gene', '79068', (286, 289))	('AML', 'Disease', 'MESH:D015470', (220, 223))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (95, 113))	('AML', 'Phenotype', 'HP:0004808', (220, 223))	('leukemias', 'Phenotype', 'HP:0001909', (202, 211))	('AML', 'Disease', (220, 223))	('FTO', 'Gene', (286, 289))	('IDH', 'Gene', (361, 364))	('IDH', 'Gene', '3417', (187, 190))	('leukemias', 'Disease', (202, 211))
10723	30428628	One of our main research goals is to uncover and characterize new epigenetic modifiers in urological malignancies, to be applied in diagnosis, prognosis and disease monitoring.	('malignancies', 'Disease', (101, 113))	('epigenetic', 'Var', (66, 76))	('malignancies', 'Disease', 'MESH:D009369', (101, 113))
10739	30428628	In addition, no mutations are described for YTHDF3 and YTHDC2 that may explain the deregulation, and only three samples disclosed a missense mutation in VIRMA.	('YTHDF3', 'Gene', '253943', (44, 50))	('YTHDC2', 'Gene', '64848', (55, 61))	('missense mutation', 'Var', (132, 149))	('YTHDC2', 'Gene', (55, 61))	('YTHDF3', 'Gene', (44, 50))
10745	30428628	Although still largely unexplored, there is already a study (using both cell lines and human tissues from 35 patients) reporting m6A alterations in PCa.	('patients', 'Species', '9606', (109, 117))	('human', 'Species', '9606', (87, 92))	('PCa', 'Disease', (148, 151))	('m6A', 'Gene', (129, 132))	('alterations', 'Var', (133, 144))	('m6A', 'Gene', '56339', (129, 132))
10754	30428628	In addition, the manipulation of these Epi-markers might provide ways of uncovering therapies with improved antitumor activity, less toxicity and that may overcome cisplatin resistance.	('toxicity', 'Disease', 'MESH:D064420', (133, 141))	('toxicity', 'Disease', (133, 141))	('improved', 'PosReg', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('cisplatin resistance', 'MPA', (164, 184))	('overcome', 'NegReg', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('manipulation', 'Var', (17, 29))	('tumor', 'Disease', (112, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (164, 173))
10759	30428628	Paralleling our analysis on PCa, deregulation of VIRMA and the reader YTHDF3 is particularly interesting in TGCTs as well, being the two most commonly altered genes in the pathway (52% and 48% of samples, respectively).	('YTHDF3', 'Gene', '253943', (70, 76))	('altered', 'Reg', (151, 158))	('YTHDF3', 'Gene', (70, 76))	('deregulation', 'Var', (33, 45))
10773	30428628	Regarding survival analysis, the only genes with impact on survival were METTL4 (cases with alterations showing worse DFS, p = 0.0249), WTAP (cases with alterations showing worse DFS, p = 0.0402) and YTHDF1 (cases with alterations showing worse OS, p = 0.0440).	('D', 'Chemical', 'MESH:D003903', (203, 204))	('WTAP', 'Gene', '9589', (136, 140))	('YTHDF1', 'Gene', (200, 206))	('D', 'Chemical', 'MESH:D003903', (179, 180))	('METTL4', 'Gene', '64863', (73, 79))	('D', 'Chemical', 'MESH:D003903', (118, 119))	('alterations', 'Var', (92, 103))	('YTHDF1', 'Gene', '54915', (200, 206))	('METTL4', 'Gene', (73, 79))	('WTAP', 'Gene', (136, 140))
10804	30428628	The rate of somatic mutations in these genes was only 0.5%, 0.5% and 0.7% for YTHDF1, METTL4, and YTHDF3, respectively; VIRMA and RBM15 mutations were found in 9 (2.2%) and 12 (2.9%) cases.	('RBM15', 'Gene', '64783', (130, 135))	('YTHDF3', 'Gene', (98, 104))	('METTL4', 'Gene', '64863', (86, 92))	('YTHDF3', 'Gene', '253943', (98, 104))	('RBM15', 'Gene', (130, 135))	('YTHDF1', 'Gene', '54915', (78, 84))	('YTHDF1', 'Gene', (78, 84))	('mutations', 'Var', (136, 145))	('METTL4', 'Gene', (86, 92))	('found', 'Reg', (151, 156))
10831	30428628	Nevertheless, it emphasizes the relevance of epitranscriptomics, and of m6A alteration in particular, in the genesis and progression of urological cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('m6A', 'Gene', (72, 75))	('urological cancers', 'Disease', 'MESH:D014571', (136, 154))	('m6A', 'Gene', '56339', (72, 75))	('urological cancers', 'Disease', (136, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('alteration', 'Var', (76, 86))
10867	30383629	The samples with mRNA expression contained 510 patients with primary tumor and 70 patients with solid tissue normal.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('patients', 'Species', '9606', (82, 90))	('tumor', 'Disease', (69, 74))	('patients', 'Species', '9606', (47, 55))	('mRNA', 'Var', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
10868	30383629	The samples with microRNA expression contained 254 patients with primary tumor and 71 patients with solid tissue normal.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('microRNA', 'Var', (17, 25))	('tumor', 'Disease', (73, 78))	('patients', 'Species', '9606', (51, 59))	('patients', 'Species', '9606', (86, 94))
10935	29176561	Alterations in the VHL tumor suppressor stabilizing the hypoxia-inducible factors (HIFs) are the most prevalent molecular features of clear cell tumors.	('VHL tumor', 'Disease', (19, 28))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('23', '39'))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('Alterations', 'Var', (0, 11))	('VHL tumor', 'Disease', 'MESH:D006623', (19, 28))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('prevalent', 'Reg', (102, 111))	('hypoxia', 'Disease', 'MESH:D000860', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('clear cell tumors', 'Disease', (134, 151))	('clear cell tumors', 'Disease', 'MESH:D008649', (134, 151))	('tumor suppressor', 'biological_process', 'GO:0051726', ('23', '39'))	('rat', 'Species', '10116', (4, 7))	('hypoxia', 'Disease', (56, 63))
10948	29176561	The canonical molecular alteration in ccRCC is inactivation of the von Hippel-Lindau tumor suppressor (VHL) located on chromosome 3p.	('inactivation', 'Var', (47, 59))	('chromosome', 'cellular_component', 'GO:0005694', ('119', '129'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('85', '101'))	('VHL', 'Gene', '7428', (103, 106))	('von Hippel-Lindau tumor', 'Disease', 'MESH:D006623', (67, 90))	('von Hippel-Lindau tumor', 'Disease', (67, 90))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('85', '101'))	('ccRCC', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('rat', 'Species', '10116', (28, 31))	('VHL', 'Gene', (103, 106))
10949	29176561	Whether due to genetic predisposition, as in the case of von Hippel-Lindau disease, or due to somatic mutations or methylation, VHL alterations have been estimated to occur in near 90% of all clear cell tumors.	('methylation', 'Var', (115, 126))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('VHL', 'Gene', '7428', (128, 131))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('alterations', 'Var', (132, 143))	('clear cell tumors', 'Disease', 'MESH:D008649', (192, 209))	('von Hippel-Lindau disease', 'Disease', (57, 82))	('clear cell tumors', 'Disease', (192, 209))	('mutations', 'Var', (102, 111))	('rat', 'Species', '10116', (136, 139))	('methylation', 'biological_process', 'GO:0032259', ('115', '126'))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (57, 82))	('VHL', 'Gene', (128, 131))
10951	29176561	As an E3 ubiquitin ligase, VHL inactivation leads to constitutive activation of HIF1 and HIF2 through the stabilization of oxygen labile HIFalpha subunits.	('HIF1', 'Gene', (80, 84))	('VHL', 'Gene', '7428', (27, 30))	('HIFalpha', 'Gene', (137, 145))	('inactivation', 'Var', (31, 43))	('oxygen', 'Chemical', 'MESH:D010100', (123, 129))	('stabilization', 'MPA', (106, 119))	('E3 ubiquitin ligase', 'Gene', '79594', (6, 25))	('HIF2', 'Gene', (89, 93))	('HIF1', 'Gene', '3091', (80, 84))	('VHL', 'Gene', (27, 30))	('HIFalpha', 'Gene', '3091;2034', (137, 145))	('ubiquitin', 'molecular_function', 'GO:0031386', ('9', '18'))	('E3 ubiquitin ligase', 'Gene', (6, 25))	('activation', 'PosReg', (66, 76))
10983	29176561	LA/OA treatement has long been known to induce lipid droplets in adipocytes, but not kidney epithelial cells.	('treatement', 'Var', (6, 16))	('induce', 'Reg', (40, 46))	('lipid', 'Chemical', 'MESH:D008055', (47, 52))	('lipid droplets', 'MPA', (47, 61))
11004	29176561	To specifically rule out CD36, an hypoxia-inducible scavenger receptor for oxidized low-density lipoprotein and long-chain fatty acids, as a mediator of lipid uptake, we performed shRNA knockdown of CD36 in RCC4 cells (Fig.	('knockdown', 'Var', (186, 195))	('long-chain fatty acids', 'Chemical', '-', (112, 134))	('low-density lipoprotein', 'molecular_function', 'GO:0005322', ('84', '107'))	('CD36', 'Species', '42374', (25, 29))	('lipid uptake', 'biological_process', 'GO:0140354', ('153', '165'))	('CD36', 'Species', '42374', (199, 203))	('lipid', 'Chemical', 'MESH:D008055', (153, 158))	('RCC4', 'Gene', '84925', (207, 211))	('hypoxia', 'Disease', (34, 41))	('RCC4', 'Gene', (207, 211))	('hypoxia', 'Disease', 'MESH:D000860', (34, 41))	('CD36', 'Gene', (199, 203))
11005	29176561	3d) and found that almost complete knockdown had non-significant effects on lipid droplet formation (Fig.	('knockdown', 'Var', (35, 44))	('lipid droplet formation', 'biological_process', 'GO:0140042', ('76', '99'))	('lipid droplet formation', 'MPA', (76, 99))	('lipid droplet', 'cellular_component', 'GO:0005811', ('76', '89'))	('lipid', 'Chemical', 'MESH:D008055', (76, 81))
11010	29176561	Knockdown of either HIF isoform resulted in a statistically significant decrease in droplet formation compared to the shGFP control cells, ranging from 23% for the HIF1alpha knockdown to 42% for the HIF2alpha knockdown (Fig.	('formation', 'biological_process', 'GO:0009058', ('92', '101'))	('HIF1alpha', 'Gene', (164, 173))	('HIF2alpha', 'Gene', '2034', (199, 208))	('HIF1alpha', 'Gene', '3091', (164, 173))	('droplet formation', 'MPA', (84, 101))	('knockdown', 'Var', (174, 183))	('HIF2alpha', 'Gene', (199, 208))	('decrease', 'NegReg', (72, 80))
11011	29176561	The most dramatic decrease resulted from the double knockdown of HIF1alpha and HIF2alpha (p < 0.0001, Student's t test), demonstrating the HIF dependence of lipid storage in RCC cells.	('lipid storage', 'biological_process', 'GO:0019915', ('157', '170'))	('lipid', 'Chemical', 'MESH:D008055', (157, 162))	('HIF2alpha', 'Gene', (79, 88))	('HIF2alpha', 'Gene', '2034', (79, 88))	('HIF1alpha', 'Gene', (65, 74))	('HIF1alpha', 'Gene', '3091', (65, 74))	('double knockdown', 'Var', (45, 61))	('decrease', 'NegReg', (18, 26))	('rat', 'Species', '10116', (128, 131))
11017	29176561	4a), in agreement with a model of increased HIF in response to VHL inactivation leading to decreased CPT1A and subsequently increased lipid storage.	('lipid', 'Chemical', 'MESH:D008055', (134, 139))	('inactivation', 'Var', (67, 79))	('CPT', 'molecular_function', 'GO:0004095', ('101', '104'))	('increased', 'PosReg', (124, 133))	('lipid storage', 'MPA', (134, 147))	('CPT1A', 'Gene', (101, 106))	('VHL', 'Gene', (63, 66))	('CPT', 'molecular_function', 'GO:0004142', ('101', '104'))	('increased lipid', 'Phenotype', 'HP:0003077', (124, 139))	('lipid storage', 'biological_process', 'GO:0019915', ('134', '147'))	('VHL', 'Gene', '7428', (63, 66))	('decreased', 'NegReg', (91, 100))
11020	29176561	4f, all three knockdown constructs dramatically increased lipid deposition compared to the control RCC4 VHL shGFP cells, in the range of three-fourfold (Fig.	('increased', 'PosReg', (48, 57))	('VHL', 'Gene', '7428', (104, 107))	('RCC4', 'Gene', (99, 103))	('lipid deposition', 'MPA', (58, 74))	('lipid', 'Chemical', 'MESH:D008055', (58, 63))	('knockdown', 'Var', (14, 23))	('VHL', 'Gene', (104, 107))	('increased lipid', 'Phenotype', 'HP:0003077', (48, 63))	('RCC4', 'Gene', '84925', (99, 103))
11029	29176561	Unexpectedly, however, knockdown of neither Snail (Fig.	('Snail', 'Gene', '6615', (44, 49))	('knockdown', 'Var', (23, 32))	('Snail', 'Gene', (44, 49))
11032	29176561	Conversely, knockdown of CPT1A did lead to a reduction in PGC1alpha expression suggesting some overlap of the pathways (Fig.	('CPT', 'molecular_function', 'GO:0004142', ('25', '28'))	('expression', 'MPA', (68, 78))	('CPT1A', 'Gene', (25, 30))	('PGC1alpha', 'Gene', '10891', (58, 67))	('CPT', 'molecular_function', 'GO:0004095', ('25', '28'))	('knockdown', 'Var', (12, 21))	('reduction', 'NegReg', (45, 54))	('PGC1alpha', 'Gene', (58, 67))
11048	29176561	In accordance with increased lipid oxidation, elevation of CPT1A increased oxygen consumption (Fig.	('oxygen', 'Chemical', 'MESH:D010100', (75, 81))	('increased', 'PosReg', (65, 74))	('CPT1A', 'Gene', (59, 64))	('lipid oxidation', 'biological_process', 'GO:0034440', ('29', '44'))	('oxygen consumption', 'MPA', (75, 93))	('increased lipid', 'Phenotype', 'HP:0003077', (19, 34))	('CPT', 'molecular_function', 'GO:0004142', ('59', '62'))	('CPT', 'molecular_function', 'GO:0004095', ('59', '62'))	('increased', 'PosReg', (19, 28))	('lipid oxidation', 'MPA', (29, 44))	('lipid', 'Chemical', 'MESH:D008055', (29, 34))	('elevation', 'Var', (46, 55))
11053	29176561	CPT1A restoration led to significant decreases in tumor growth, as assessed by two-way ANOVA (p = 0.0034) (Fig.	('CPT1A', 'Gene', (0, 5))	('restoration', 'Var', (6, 17))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('rat', 'Species', '10116', (11, 14))	('CPT', 'molecular_function', 'GO:0004142', ('0', '3'))	('decreases', 'NegReg', (37, 46))	('CPT', 'molecular_function', 'GO:0004095', ('0', '3'))	('tumor', 'Disease', (50, 55))
11070	29176561	In seven samples, we found an average decrease in activity of 81% in validated VHL mutant tumors compared to their normal tissues, and found that CPT1A was repressed in all cases (Fig.	('CPT', 'molecular_function', 'GO:0004095', ('146', '149'))	('VHL', 'Gene', '7428', (79, 82))	('mutant', 'Var', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('decrease', 'NegReg', (38, 46))	('tumors', 'Disease', (90, 96))	('activity', 'MPA', (50, 58))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('CPT', 'molecular_function', 'GO:0004142', ('146', '149'))	('VHL', 'Gene', (79, 82))
11074	29176561	We identify the rate-limiting enzyme in fatty acid entry into the mitochondria (CPT1A) as a direct target of transcriptional repression by the HIF1alpha and HIF2alpha subunits through promoter silencing.	('HIF2alpha', 'Gene', '2034', (157, 166))	('promoter silencing', 'Var', (184, 202))	('rat', 'Species', '10116', (16, 19))	('HIF1alpha', 'Gene', (143, 152))	('HIF2alpha', 'Gene', (157, 166))	('fatty acid', 'Chemical', 'MESH:D005227', (40, 50))	('HIF1alpha', 'Gene', '3091', (143, 152))	('CPT', 'molecular_function', 'GO:0004142', ('80', '83'))	('CPT', 'molecular_function', 'GO:0004095', ('80', '83'))	('mitochondria', 'cellular_component', 'GO:0005739', ('66', '78'))
11076	29176561	Accordingly, depletion of CPT1A in VHL reconstituted cell lines restores the lipid deposition phenotype.	('lipid deposition phenotype', 'MPA', (77, 103))	('restores', 'PosReg', (64, 72))	('depletion', 'Var', (13, 22))	('CPT', 'molecular_function', 'GO:0004142', ('26', '29'))	('VHL', 'Gene', (35, 38))	('CPT', 'molecular_function', 'GO:0004095', ('26', '29'))	('VHL', 'Gene', '7428', (35, 38))	('lipid', 'Chemical', 'MESH:D008055', (77, 82))	('CPT1A', 'Gene', (26, 31))
11085	29176561	Importantly, interruption of the pathway decreased lipid droplets and the tumorigenic capacity of xenografts in mice while increasing cellular reactive oxygen species (ROS), leading the authors to conclude that hypoxia-driven lipid accumulation serves as a protective barrier against oxidative stress-induced toxicity.	('interruption', 'Var', (13, 25))	('lipid', 'Chemical', 'MESH:D008055', (226, 231))	('ROS', 'Chemical', 'MESH:D017382', (168, 171))	('oxidative stress', 'Phenotype', 'HP:0025464', (284, 300))	('lipid droplets', 'MPA', (51, 65))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('toxicity', 'Disease', 'MESH:D064420', (309, 317))	('decreased', 'NegReg', (41, 50))	('hypoxia', 'Disease', 'MESH:D000860', (211, 218))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('increasing', 'PosReg', (123, 133))	('lipid', 'Chemical', 'MESH:D008055', (51, 56))	('toxicity', 'Disease', (309, 317))	('tumor', 'Disease', (74, 79))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (143, 166))	('cellular reactive oxygen species', 'MPA', (134, 166))	('mice', 'Species', '10090', (112, 116))	('hypoxia', 'Disease', (211, 218))
11114	29176561	Restoring fatty acid metabolism with C75, a compound that induces CPT1 activity, led to reduction or prevention of the fibrotic phenotype.	('CPT', 'molecular_function', 'GO:0004095', ('66', '69'))	('CPT1', 'Gene', (66, 70))	('Restoring fatty acid metabolism', 'MPA', (0, 31))	('fatty acid', 'Chemical', 'MESH:D005227', (10, 20))	('CPT', 'molecular_function', 'GO:0004142', ('66', '69'))	('CPT1', 'Gene', '1374', (66, 70))	('C75', 'Var', (37, 40))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('10', '31'))
11146	29176561	Lentiviral transduction of shRNA was performed with pLKO.1 plasmids from Sigma: HIF1alpha (TRCN0000003809), HIF2alpha (TRCN0000003803), CPT1A (TRCN000036279, TRCN000036282, TRCN000036283), Snail (TRCN000063819), and DEC1 (TRCN0000013249 and TRCN0000013251).	('TRCN0000013249 and TRCN0000013251', 'Disease', 'None', (222, 255))	('transduction', 'biological_process', 'GO:0009293', ('11', '23'))	('HIF2alpha', 'Gene', (108, 117))	('CPT', 'molecular_function', 'GO:0004142', ('136', '139'))	('Snail', 'Gene', '6615', (189, 194))	('TRCN000036279', 'Var', (143, 156))	('Snail', 'Gene', (189, 194))	('DEC1', 'Gene', (216, 220))	('CPT', 'molecular_function', 'GO:0004095', ('136', '139'))	('DEC1', 'Gene', '50514', (216, 220))	('HIF2alpha', 'Gene', '2034', (108, 117))	('TRCN0000003803', 'Var', (119, 133))	('TRCN000063819', 'Var', (196, 209))	('HIF1alpha', 'Gene', (80, 89))	('TRCN0000003809', 'Var', (91, 105))	('HIF1alpha', 'Gene', '3091', (80, 89))
11186	28052770	Cubilin (CUBN) was identified and validated as a marker with the potential to classify RCC patients into low- and high-risk groups, as loss of CUBN expression was significantly and independently associated with less favorable patient outcome.	('associated', 'Reg', (195, 205))	('CUBN', 'Gene', (143, 147))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('less', 'NegReg', (211, 215))	('RCC', 'Disease', (87, 90))	('patients', 'Species', '9606', (91, 99))	('patient', 'Species', '9606', (226, 233))	('Cubilin', 'Gene', '8029', (0, 7))	('loss', 'Var', (135, 139))	('CUBN', 'Gene', (9, 13))	('Cubilin', 'Gene', (0, 7))	('CUBN', 'Gene', '8029', (9, 13))	('expression', 'MPA', (148, 158))	('patient', 'Species', '9606', (91, 98))	('CUBN', 'Gene', '8029', (143, 147))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
11207	28052770	Two antibodies targeting CUBN were tested (HPA043854 and HPA004133, Atlas Antibodies AB, Stockholm, Sweden).	('CUBN', 'Gene', '8029', (25, 29))	('HPA043854', 'Var', (43, 52))	('CUBN', 'Gene', (25, 29))	('Atlas Antibodies AB', 'Disease', (68, 87))	('Atlas Antibodies AB', 'Disease', 'MESH:D049290', (68, 87))	('HPA004133', 'Var', (57, 66))
11242	28052770	In cohort 3, positive CUBN staining was significantly associated with localized disease (Table 2, P = 0.009).	('positive', 'Var', (13, 21))	('localized disease', 'Disease', (70, 87))	('CUBN', 'Gene', '8029', (22, 26))	('associated', 'Reg', (54, 64))	('CUBN', 'Gene', (22, 26))
11245	28052770	A significant correlation was observed between positive CUBN expression and lower Fuhrman grade (P = 0.006) and negative nodal status (P = 0.006).	('positive', 'Var', (47, 55))	('CUBN', 'Gene', (56, 60))	('Fuhrman grade', 'CPA', (82, 95))	('CUBN', 'Gene', '8029', (56, 60))	('lower', 'NegReg', (76, 81))	('expression', 'MPA', (61, 71))
11281	29435132	Finally, we discovered a correlation between VHL inactivation and reduced HR gene expression in a large panel of human renal carcinoma samples.	('renal carcinoma', 'Disease', 'MESH:C538614', (119, 134))	('reduced', 'NegReg', (66, 73))	('VHL', 'Gene', '7428', (45, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('gene expression', 'biological_process', 'GO:0010467', ('77', '92'))	('inactivation', 'Var', (49, 61))	('renal carcinoma', 'Disease', (119, 134))	('renal carcinoma', 'Phenotype', 'HP:0005584', (119, 134))	('VHL', 'Gene', (45, 48))	('HR gene', 'Gene', (74, 81))	('human', 'Species', '9606', (113, 118))
11289	29435132	Analogously, inactivation of pVHL results in constitutive HIF alpha-subunit stabilization.	('inactivation', 'Var', (13, 25))	('constitutive', 'MPA', (45, 57))	('pVHL', 'Gene', '7428', (29, 33))	('pVHL', 'Gene', (29, 33))	('HIF alpha-subunit stabilization', 'MPA', (58, 89))
11298	29435132	Instead, hypoxic stress facilitates the down-regulation of cellular DNA repair pathways through transcriptional, translational, and epigenetic mechanisms (reviewed in).	('epigenetic', 'Var', (132, 142))	('hypoxic stress', 'Disease', 'MESH:D004194', (9, 23))	('hypoxic stress', 'Disease', (9, 23))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('DNA repair', 'biological_process', 'GO:0006281', ('68', '78'))	('regulation', 'biological_process', 'GO:0065007', ('45', '55'))	('down-regulation', 'NegReg', (40, 55))	('cellular DNA repair pathways', 'Pathway', (59, 87))
11306	29435132	Given the similar downstream effects of VHL mutations and physiologic hypoxia, we hypothesized that VHL-deficient RCC may have reduced DNA repair capacity that could be exploited for therapeutic gain.	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('DNA repair', 'biological_process', 'GO:0006281', ('135', '145'))	('VHL', 'Gene', (40, 43))	('VHL', 'Gene', '7428', (40, 43))	('hypoxia', 'Disease', 'MESH:D000860', (70, 77))	('VHL-deficient RCC', 'Disease', 'MESH:C538614', (100, 117))	('VHL-deficient RCC', 'Disease', (100, 117))	('mutations', 'Var', (44, 53))	('DNA repair capacity', 'MPA', (135, 154))	('hypoxia', 'Disease', (70, 77))	('VHL', 'Gene', (100, 103))	('reduced', 'NegReg', (127, 134))	('VHL', 'Gene', '7428', (100, 103))
11309	29435132	Loss of pVHL thus leads to reduced p53 activation, impaired cell cycle checkpoint activation, and in some cases, reduced apoptosis in response to DNA damage.	('reduced', 'NegReg', (27, 34))	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('cell cycle checkpoint activation', 'CPA', (60, 92))	('activation', 'PosReg', (39, 49))	('response to DNA damage', 'MPA', (134, 156))	('apoptosis', 'CPA', (121, 130))	('DNA', 'cellular_component', 'GO:0005574', ('146', '149'))	('pVHL', 'Gene', '7428', (8, 12))	('reduced', 'NegReg', (113, 120))	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('60', '81'))	('pVHL', 'Gene', (8, 12))	('apoptosis', 'biological_process', 'GO:0097194', ('121', '130'))	('impaired', 'NegReg', (51, 59))	('Loss', 'Var', (0, 4))	('apoptosis', 'biological_process', 'GO:0006915', ('121', '130'))
11314	29435132	In this study, we have investigated the possibility that VHL mutations, through induction of hypoxia-like signaling pathways, may lead to down-regulation of DNA repair pathways and sensitivity to DNA damage.	('down-regulation', 'NegReg', (138, 153))	('sensitivity to DNA damage', 'MPA', (181, 206))	('mutations', 'Var', (61, 70))	('VHL', 'Gene', (57, 60))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('DNA', 'cellular_component', 'GO:0005574', ('196', '199'))	('DNA repair pathways', 'Pathway', (157, 176))	('hypoxia', 'Disease', 'MESH:D000860', (93, 100))	('VHL', 'Gene', '7428', (57, 60))	('down-regulation of DNA repair', 'biological_process', 'GO:0045738', ('138', '167'))	('hypoxia', 'Disease', (93, 100))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))
11333	29435132	Previous studies have found that loss of pVHL can lead to altered cell cycle progression.	('lead', 'Reg', (50, 54))	('pVHL', 'Gene', (41, 45))	('cell cycle progression', 'CPA', (66, 88))	('cell cycle', 'biological_process', 'GO:0007049', ('66', '76'))	('loss', 'Var', (33, 37))	('pVHL', 'Gene', '7428', (41, 45))	('altered', 'Reg', (58, 65))
11349	29435132	VHL deficiency in renal carcinomas can occur via inactivating mutations or allelic loss.	('VHL deficiency in renal carcinomas', 'Disease', (0, 34))	('renal carcinoma', 'Phenotype', 'HP:0005584', (18, 33))	('allelic loss', 'Var', (75, 87))	('inactivating mutations', 'Var', (49, 71))	('renal carcinomas', 'Phenotype', 'HP:0005584', (18, 34))	('VHL deficiency in renal carcinomas', 'Disease', 'MESH:D006623', (0, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('occur', 'Reg', (39, 44))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))
11350	29435132	We therefore sorted the tumor samples into groups with and without VHL point mutations and groups with copy number alterations of 0/1, -1, or -2.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('VHL', 'Gene', '7428', (67, 70))	('tumor', 'Disease', (24, 29))	('VHL', 'Gene', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('point mutations', 'Var', (71, 86))
11351	29435132	In addition, we determined the putative VHL genotype of each tumor sample based on the combination of point mutations and copy number alterations and sorted the samples into homozygous WT (+/+), heterozygous (+/-), and homozygous mutant (-/-) groups (Figure 5A).	('tumor', 'Disease', (61, 66))	('point mutations', 'Var', (102, 117))	('mutant', 'Var', (230, 236))	('VHL', 'Gene', (40, 43))	('VHL', 'Gene', '7428', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('alterations', 'Var', (134, 145))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('copy number alterations', 'Var', (122, 145))
11352	29435132	We first analyzed VHL mRNA levels and found reduced expression in the samples with copy number loss, but not with point mutations, as expected (Figure 5B).	('VHL', 'Gene', '7428', (18, 21))	('expression', 'MPA', (52, 62))	('VHL', 'Gene', (18, 21))	('reduced', 'NegReg', (44, 51))	('copy number loss', 'Var', (83, 99))
11353	29435132	We then analyzed the mRNA expression of the HR and MMR genes that we found to be reduced in the VHL-deficient cell lines, FANCD2, BRCA1, RAD51, and MLH1, and found an association between VHL inactivation and reduced mRNA expression of these four genes in each grouping method (Figure 5C-5F).	('MMR', 'biological_process', 'GO:0006298', ('51', '54'))	('FANCD2', 'Gene', (122, 128))	('BRCA1', 'Gene', '672', (130, 135))	('MLH1', 'Gene', (148, 152))	('reduced', 'NegReg', (81, 88))	('VHL-deficient', 'Disease', 'MESH:D006623', (96, 109))	('RAD51', 'Gene', (137, 142))	('VHL', 'Gene', (187, 190))	('BRCA1', 'Gene', (130, 135))	('RAD51', 'Gene', '5888', (137, 142))	('FANCD2', 'Gene', '2177', (122, 128))	('reduced', 'NegReg', (208, 215))	('mRNA expression', 'MPA', (216, 231))	('MLH1', 'Gene', '4292', (148, 152))	('VHL', 'Gene', '7428', (187, 190))	('VHL', 'Gene', (96, 99))	('inactivation', 'Var', (191, 203))	('VHL-deficient', 'Disease', (96, 109))	('RAD', 'biological_process', 'GO:1990116', ('137', '140'))	('MMR genes', 'Gene', (51, 60))	('VHL', 'Gene', '7428', (96, 99))
11355	29435132	In this study we have discovered a novel DNA repair deficiency in VHL-deficient clear cell renal carcinoma.	('VHL-deficient clear cell renal carcinoma', 'Disease', 'MESH:C538614', (66, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('renal carcinoma', 'Phenotype', 'HP:0005584', (91, 106))	('deficiency', 'Var', (52, 62))	('DNA repair', 'biological_process', 'GO:0006281', ('41', '51'))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('VHL-deficient clear cell renal carcinoma', 'Disease', (66, 106))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (80, 106))
11362	29435132	Hypoxia regulates DNA repair through many different mechanisms, and it is likely that many of the same processes occur upon loss of VHL due to the constitutive activation of hypoxia-induced signaling pathways.	('VHL', 'Gene', (132, 135))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('signaling', 'biological_process', 'GO:0023052', ('190', '199'))	('loss', 'Var', (124, 128))	('Hypoxia', 'Disease', (0, 7))	('VHL', 'Gene', '7428', (132, 135))	('hypoxia', 'Disease', (174, 181))	('activation', 'PosReg', (160, 170))	('hypoxia', 'Disease', 'MESH:D000860', (174, 181))	('DNA repair', 'biological_process', 'GO:0006281', ('18', '28'))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))	('DNA repair', 'MPA', (18, 28))
11378	29435132	The term "BRCAness" has been coined to describe tumors with a defect in DNA double-strand break repair by homologous recombination in the absence of BRCA1 or BRCA2 mutations.	('homologous recombination', 'biological_process', 'GO:0035825', ('104', '128'))	('BRCA', 'Gene', '672', (158, 162))	('tumors', 'Disease', (48, 54))	('BRCA', 'Gene', '672', (149, 153))	('BRCA', 'Gene', (158, 162))	('DNA double-strand break repair', 'MPA', (72, 102))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('BRCA', 'Gene', (149, 153))	('BRCA2', 'Gene', (158, 163))	('BRCA', 'Gene', '672', (10, 14))	('defect', 'NegReg', (62, 68))	('double-strand break repair', 'biological_process', 'GO:0006302', ('74', '100'))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('mutations', 'Var', (164, 173))	('BRCA2', 'Gene', '675', (158, 163))	('BRCA', 'Gene', (10, 14))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('BRCA1', 'Gene', '672', (149, 154))	('BRCA1', 'Gene', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
11379	29435132	BRCAness can arise from defects in other individual genes involved in HR or its regulation, epigenetic silencing of HR genes, or other non-genetic changes that lead to reduced HR such as hypoxia.	('arise from', 'Reg', (13, 23))	('hypoxia', 'Disease', (187, 194))	('BRCA', 'Gene', (0, 4))	('regulation', 'biological_process', 'GO:0065007', ('80', '90'))	('defects', 'Disease', 'MESH:D005128', (24, 31))	('HR genes', 'Gene', (116, 124))	('BRCA', 'Gene', '672', (0, 4))	('defects', 'Disease', (24, 31))	('hypoxia', 'Disease', 'MESH:D000860', (187, 194))	('epigenetic silencing', 'Var', (92, 112))	('reduced', 'NegReg', (168, 175))
11392	29435132	This treatment strategy is growing increasingly promising as a clinical trial of combination therapy with the VEGF inhibitor Cediranib and the PARP inhibitor Olaparib showed efficacy in a cohort of breast cancer patients, both with and without BRCA mutations.	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('BRCA', 'Gene', '672', (244, 248))	('PARP', 'Gene', (143, 147))	('BRCA', 'Gene', (244, 248))	('mutations', 'Var', (249, 258))	('VEGF', 'Gene', '7422', (110, 114))	('patients', 'Species', '9606', (212, 220))	('Cediranib', 'Chemical', 'MESH:C500926', (125, 134))	('PARP', 'Gene', '142', (143, 147))	('Olaparib', 'Chemical', 'MESH:C531550', (158, 166))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('breast cancer', 'Disease', 'MESH:D001943', (198, 211))	('VEGF', 'Gene', (110, 114))	('breast cancer', 'Disease', (198, 211))
11414	29435132	VHL mutation and copy number alteration data, and VHL, FANCD2, BRCA1, RAD51, MLH1, VEGFA and CA9 mRNA expression Z-scores (RNA Seq V2 RSEM) for 446 complete tumor samples in the TCGA Provisional Kidney Renal Clear Cell Carcinoma dataset generated by the TCGA Research Network (http://cancergenome.nih.gov) were downloaded via cBioPortal.	('FANCD2', 'Gene', '2177', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('mutation', 'Var', (4, 12))	('VEGFA', 'Gene', '7422', (83, 88))	('VHL', 'Gene', '7428', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('MLH1', 'Gene', (77, 81))	('Kidney Renal Clear Cell Carcinoma', 'Disease', 'MESH:C538614', (195, 228))	('Carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('Kidney Renal Clear Cell Carcinoma', 'Disease', (195, 228))	('BRCA1', 'Gene', '672', (63, 68))	('RAD51', 'Gene', (70, 75))	('VHL', 'Gene', (50, 53))	('MLH1', 'Gene', '4292', (77, 81))	('BRCA1', 'Gene', (63, 68))	('cancer', 'Disease', (284, 290))	('RAD51', 'Gene', '5888', (70, 75))	('CA9', 'Gene', (93, 96))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('tumor', 'Disease', (157, 162))	('VEGFA', 'Gene', (83, 88))	('FANCD2', 'Gene', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('VHL', 'Gene', '7428', (50, 53))	('CA9', 'Gene', '768', (93, 96))	('VHL', 'Gene', (0, 3))	('RNA', 'cellular_component', 'GO:0005562', ('123', '126'))	('RAD', 'biological_process', 'GO:1990116', ('70', '73'))
11422	31627290	In this study, the exposure of 786-O human renal cancer cells to MnTnHex-2-PyP5+ (MnP), a very promising SODm, led to a concentration and time-dependent decrease in cell viability and in the cell proliferation indices, as well as to an increase in apoptosis.	('MnP', 'Chemical', 'MESH:C583825', (82, 85))	('MnTnHex-2-PyP5+', 'Chemical', 'MESH:C583825', (65, 80))	('SOD', 'Gene', (105, 108))	('SOD', 'Gene', '6647', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cell proliferation indices', 'CPA', (191, 217))	('increase', 'PosReg', (236, 244))	('apoptosis', 'biological_process', 'GO:0097194', ('248', '257'))	('apoptosis', 'biological_process', 'GO:0006915', ('248', '257'))	('pen', 'Gene', (145, 148))	('renal cancer', 'Disease', (43, 55))	('renal cancer', 'Phenotype', 'HP:0009726', (43, 55))	('human', 'Species', '9606', (37, 42))	('apoptosis', 'CPA', (248, 257))	('MnTnHex-2-PyP5+', 'Var', (65, 80))	('decrease', 'NegReg', (153, 161))	('renal cancer', 'Disease', 'MESH:D007680', (43, 55))	('cell viability', 'CPA', (165, 179))	('pen', 'Gene', '27344', (145, 148))	('cell proliferation', 'biological_process', 'GO:0008283', ('191', '209'))
11425	31627290	Overall, these results suggest that MnP has a beneficial impact on reducing renal cancer cell viability and migration and warrant further studies regarding SODm-based therapeutic strategies against human renal cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('migration', 'CPA', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('SOD', 'Gene', (156, 159))	('renal cancer', 'Disease', (204, 216))	('renal cancer', 'Disease', (76, 88))	('human', 'Species', '9606', (198, 203))	('MnP', 'Chemical', 'MESH:C583825', (36, 39))	('renal cancer', 'Phenotype', 'HP:0009726', (76, 88))	('renal cancer', 'Phenotype', 'HP:0009726', (204, 216))	('reducing', 'NegReg', (67, 75))	('SOD', 'Gene', '6647', (156, 159))	('renal cancer', 'Disease', 'MESH:D007680', (204, 216))	('renal cancer', 'Disease', 'MESH:D007680', (76, 88))	('MnP', 'Var', (36, 39))
11431	31627290	The majority of sporadic ccRCC is associated with defects in von Hippel-Lindau (VHL) tumor suppressor gene.	('associated', 'Reg', (34, 44))	('tumor suppressor', 'biological_process', 'GO:0051726', ('85', '101'))	('defects', 'Var', (50, 57))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('85', '101'))	('ccRCC', 'Phenotype', 'HP:0006770', (25, 30))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (61, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('ccRCC', 'Disease', (25, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('ccRCC', 'Disease', 'MESH:D002292', (25, 30))
11439	31627290	The MnSOD polymorphism (Ala16Ala), which results in a lower activity of SOD, has been associated with an increased susceptibility to develop renal cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('SOD', 'Gene', (72, 75))	('renal cancer', 'Disease', (141, 153))	('associated', 'Reg', (86, 96))	('Ala16Ala', 'Chemical', 'MESH:C026593', (24, 32))	('SOD', 'Gene', '6647', (6, 9))	('SOD', 'molecular_function', 'GO:0004784', ('72', '75'))	('lower', 'NegReg', (54, 59))	('MnSOD', 'Gene', '6648', (4, 9))	('renal cancer', 'Disease', 'MESH:D007680', (141, 153))	('renal cancer', 'Phenotype', 'HP:0009726', (141, 153))	('SOD', 'Gene', '6647', (72, 75))	('Ala16Ala', 'Var', (24, 32))	('MnSOD', 'Gene', (4, 9))	('SOD', 'Gene', (6, 9))
11494	31627290	Exposure to MnP (0.1-25 muM) induced a decrease in cell viability as assessed by the crystal violet (CV) staining assay (Figure 1A,B) at different exposure times (16 and 24 h).	('MnP', 'Var', (12, 15))	('decrease', 'NegReg', (39, 47))	('muM', 'Gene', '56925', (24, 27))	('cell viability', 'CPA', (51, 65))	('muM', 'Gene', (24, 27))	('MnP', 'Chemical', 'MESH:C583825', (12, 15))
11497	31627290	However, when 786-O cells were exposed to a higher concentration of MnP (5 muM), a time-dependent cytotoxic effect was observed.	('MnP', 'Chemical', 'MESH:C583825', (68, 71))	('cytotoxic effect', 'CPA', (98, 114))	('pen', 'Gene', (90, 93))	('MnP', 'Var', (68, 71))	('pen', 'Gene', '27344', (90, 93))	('muM', 'Gene', '56925', (75, 78))	('muM', 'Gene', (75, 78))
11507	31627290	Exposure to MnP (5 muM, 24 h) showed an increase in apoptotic cells of ~20% (p < 0.001 vs non-treated control cells, Figure 3E) which is consistent with the observed increase of the sub-G1 population.	('MnP', 'Var', (12, 15))	('muM', 'Gene', (19, 22))	('apoptotic cells', 'CPA', (52, 67))	('MnP', 'Chemical', 'MESH:C583825', (12, 15))	('muM', 'Gene', '56925', (19, 22))
11515	31627290	The exposure to MnP at the highest concentration (5 muM) led to a reduction in the frequency of binucleated (BN) cells of approximately 18% (Figure 5A).	('muM', 'Gene', '56925', (52, 55))	('muM', 'Gene', (52, 55))	('MnP', 'Chemical', 'MESH:C583825', (16, 19))	('MnP', 'Var', (16, 19))	('reduction', 'NegReg', (66, 75))
11518	31627290	Importantly, the frequency of micronucleated binucleated cells (MNBN) and the total number of MN cells did not show significant differences in the presence of MnP, when compared with non-exposed control cells (Figure 5C,D).	('MnP', 'Var', (159, 162))	('micronucleated binucleated cells', 'CPA', (30, 62))	('MnP', 'Chemical', 'MESH:C583825', (159, 162))
11523	31627290	Although many data have been published regarding the beneficial effects of MnPs in different pathologies, including cancer treatment, its influence in renal cancer has not previously been addressed.	('MnPs', 'Var', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('MnPs', 'Chemical', 'MESH:C027155', (75, 79))	('renal cancer', 'Disease', (151, 163))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('men', 'Species', '9606', (128, 131))	('renal cancer', 'Phenotype', 'HP:0009726', (151, 163))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('beneficial', 'PosReg', (53, 63))	('renal cancer', 'Disease', 'MESH:D007680', (151, 163))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
11524	31627290	MnSOD and MnPs were shown to reduce the cell viability or induce cell death in different in vitro cancer models, including in breast cancer, skin cancer, prostate carcinoma or colorectal cancer.	('cancer', 'Disease', (146, 152))	('colorectal cancer', 'Disease', 'MESH:D015179', (176, 193))	('induce', 'Reg', (58, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('MnPs', 'Var', (10, 14))	('MnSOD', 'Gene', '6648', (0, 5))	('colorectal cancer', 'Disease', (176, 193))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('skin cancer', 'Disease', 'MESH:D012878', (141, 152))	('reduce', 'NegReg', (29, 35))	('prostate carcinoma', 'Disease', 'MESH:D011471', (154, 172))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('MnSOD', 'Gene', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Disease', (126, 139))	('cell death', 'CPA', (65, 75))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (154, 172))	('cell viability', 'CPA', (40, 54))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('colorectal cancer', 'Phenotype', 'HP:0003003', (176, 193))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cell death', 'biological_process', 'GO:0008219', ('65', '75'))	('skin cancer', 'Disease', (141, 152))	('cancer', 'Disease', (133, 139))	('prostate carcinoma', 'Disease', (154, 172))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Disease', (187, 193))	('MnPs', 'Chemical', 'MESH:C027155', (10, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('skin cancer', 'Phenotype', 'HP:0008069', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
11528	31627290	The selection of 786-O cells in this study was therefore based on the clinical and epidemiological data of RCC as well as in their specific cellular and genetic characteristics, including the inherent invasiveness and the defective VHL expression.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('VHL', 'Gene', (232, 235))	('RCC', 'Disease', 'MESH:D002292', (107, 110))	('RCC', 'Disease', (107, 110))	('VHL', 'Gene', '7428', (232, 235))	('defective', 'Var', (222, 231))
11533	31627290	In the present work, a concentration- and time-dependent cytotoxic effect of the MnP in 786-O cells was clearly observed.	('pen', 'Gene', '27344', (49, 52))	('cytotoxic effect', 'CPA', (57, 73))	('MnP', 'Var', (81, 84))	('MnP', 'Chemical', 'MESH:C583825', (81, 84))	('pen', 'Gene', (49, 52))
11542	31627290	While disproportionating superoxide anion, SODm generates H2O2 and it is known that in peroxidase-containing cells, H2O2 oxidizes DHR.	('superoxide', 'Chemical', 'MESH:D013481', (25, 35))	('DHR', 'MPA', (130, 133))	('SOD', 'Gene', '6647', (43, 46))	('H2O2', 'Chemical', 'MESH:D014867', (116, 120))	('H2O2', 'Chemical', 'MESH:D014867', (58, 62))	('SOD', 'Gene', (43, 46))	('DHR', 'Chemical', 'MESH:C492712', (130, 133))	('H2O2', 'MPA', (58, 62))	('H2O2', 'Var', (116, 120))
11546	31627290	The MnPs have shown to be associated with a low in vitro toxicity potential demonstrated in studies performed with non-tumor cell lines as well as in in vivo studies.	('toxicity', 'Disease', (57, 65))	('tumor', 'Disease', (119, 124))	('MnPs', 'Var', (4, 8))	('MnPs', 'Chemical', 'MESH:C027155', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('toxicity', 'Disease', 'MESH:D064420', (57, 65))
11552	31627290	On the other hand, with the concentration of 5 microM of MnP the threshold of toxicity may be reached, and this mechanism may contribute to the differential cytotoxic effects observed.	('MnP', 'Chemical', 'MESH:C583825', (57, 60))	('toxicity', 'Disease', 'MESH:D064420', (78, 86))	('toxicity', 'Disease', (78, 86))	('MnP', 'Var', (57, 60))	('contribute', 'Reg', (126, 136))
11564	31627290	In our study, the MnP did not lead to a reduction in collective cell motility, but it significantly decreased the chemotactic migration.	('MnP', 'Chemical', 'MESH:C583825', (18, 21))	('chemotactic migration', 'CPA', (114, 135))	('decreased', 'NegReg', (100, 109))	('MnP', 'Var', (18, 21))	('cell motility', 'biological_process', 'GO:0048870', ('64', '77'))	('collective cell motility', 'CPA', (53, 77))
11566	31627290	The effect of the MnP in cell migration could be also related to the modulation of the nuclear transcription factor kappa B (NF-kappaB), hypoxia-inducible factors (HIF) and mTOR pathways, which have been reported to influence cell migration.	('NF-kappaB', 'Gene', (125, 134))	('cell migration', 'biological_process', 'GO:0016477', ('25', '39'))	('hypoxia', 'Disease', 'MESH:D000860', (137, 144))	('cell migration', 'CPA', (25, 39))	('nuclear transcription factor kappa B', 'Gene', (87, 123))	('transcription', 'biological_process', 'GO:0006351', ('95', '108'))	('influence', 'Reg', (216, 225))	('mTOR', 'Gene', '2475', (173, 177))	('hypoxia', 'Disease', (137, 144))	('nuclear transcription factor kappa B', 'Gene', '4790', (87, 123))	('MnP', 'Chemical', 'MESH:C583825', (18, 21))	('mTOR', 'Gene', (173, 177))	('NF-kappaB', 'Gene', '4790', (125, 134))	('transcription factor', 'molecular_function', 'GO:0000981', ('95', '115'))	('MnP', 'Var', (18, 21))	('cell migration', 'biological_process', 'GO:0016477', ('226', '240'))	('modulation', 'Reg', (69, 79))	('cell migration', 'CPA', (226, 240))
11569	31627290	Furthermore, at 5 microM, MnP is clearly cytotoxic, increases the % of apoptosis and decreases cell division/proliferation indices.	('decreases', 'NegReg', (85, 94))	('MnP', 'Var', (26, 29))	('increases', 'PosReg', (52, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('cell division/proliferation indices', 'CPA', (95, 130))	('cell division', 'biological_process', 'GO:0051301', ('95', '108'))	('MnP', 'Chemical', 'MESH:C583825', (26, 29))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))
11571	31627290	Taken together, these observations suggest that MnP may have a beneficial impact on reducing the viability and migration of renal cancer cells.	('MnP', 'Chemical', 'MESH:C583825', (48, 51))	('renal cancer', 'Disease', (124, 136))	('viability', 'CPA', (97, 106))	('renal cancer', 'Disease', 'MESH:D007680', (124, 136))	('renal cancer', 'Phenotype', 'HP:0009726', (124, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('MnP', 'Var', (48, 51))	('reducing', 'NegReg', (84, 92))
11587	31131513	For instance, several important tumor-associated signaling pathways have been identified as frequently genetically altered in cancers, such as the cell cycle, Hippo and Myc pathways 6, 7.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cell cycle', 'CPA', (147, 157))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('cell cycle', 'biological_process', 'GO:0007049', ('147', '157'))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('altered', 'Reg', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('Myc', 'Gene', '4609', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancers', 'Disease', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('genetically', 'Var', (103, 114))	('tumor', 'Disease', (32, 37))	('Myc', 'Gene', (169, 172))
11589	31131513	It has now been well established that cancers and aging share similar characteristics such as genomic instability, mutations and intercellular signal exchanges 8.	('aging', 'biological_process', 'GO:0007568', ('50', '55'))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('mutations', 'Var', (115, 124))	('intercellular', 'MPA', (129, 142))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('cancers', 'Disease', (38, 45))
11592	31131513	For instance, research into mutant NOTCH1 clones colonizing the human esophagus with age suggested a complex relationship between aging and cancers 11.	('human', 'Species', '9606', (64, 69))	('mutant', 'Var', (28, 34))	('aging', 'biological_process', 'GO:0007568', ('130', '135'))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('NOTCH1', 'Gene', '4851', (35, 41))	('NOTCH1', 'Gene', (35, 41))
11608	31131513	Further, SLC9A7 (P-value = 3.44 x 10-10 and FDR = 2.98 x 10-6) is involved in enhancing cell growth of certain tumors 23 and is associated with multiple neurological syndromes 24.	('enhancing', 'PosReg', (78, 87))	('SLC9A7', 'Gene', '84679', (9, 15))	('SLC9A7', 'Gene', (9, 15))	('multiple neurological syndromes', 'Disease', (144, 175))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cell growth', 'biological_process', 'GO:0016049', ('88', '99'))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('cell growth', 'CPA', (88, 99))	('associated', 'Reg', (128, 138))	('FDR =', 'Var', (44, 49))
11619	31131513	To gain a deeper understanding of the biological functions of mutation-related differential expression modules, the eQTL method was used to identify differential expression modules that were affected by aging acceleration-associated mutations, and the hypergeometric test was performed to identify enriched genes in KEGG pathways and GO BP terms (Materials and methods).	('KEGG pathways', 'Pathway', (316, 329))	('aging', 'biological_process', 'GO:0007568', ('203', '208'))	('mutations', 'Var', (233, 242))	('GO BP', 'Chemical', '-', (334, 339))	('affected', 'Reg', (191, 199))
11631	31131513	At present, studies have shown that abnormal thyroid function affects the level of reproductive hormones, thus affecting women's ovulation cycle 33.	('women', 'CPA', (121, 126))	('thyroid', 'Disease', (45, 52))	('abnormal thyroid function', 'Phenotype', 'HP:0002926', (36, 61))	('abnormal thyroid', 'Phenotype', 'HP:0000820', (36, 52))	('abnormal', 'Var', (36, 44))	('affects', 'Reg', (62, 69))	('level of reproductive hormones', 'MPA', (74, 104))	('ovulation cycle 33', 'CPA', (129, 147))	('affecting', 'Reg', (111, 120))	('ovulation cycle', 'biological_process', 'GO:0042698', ('129', '144'))	('women', 'Species', '9606', (121, 126))
11645	31131513	Studies have shown that dysfunction of the thyroid led to imbalance of sex hormone levels 43, 44, resulting in cancer of organs regulated by sex hormones such as the breast and the prostate.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('dysfunction', 'Var', (24, 35))	('breast', 'Disease', (166, 172))	('prostate', 'Disease', (181, 189))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('imbalance of sex hormone levels 43', 'MPA', (58, 92))	('imbalance', 'Phenotype', 'HP:0002172', (58, 67))
11653	31131513	The paired DNA methylation profiles (333 x 25 978), expression profiles (333 x 14 530), mutation profiles (333 x 15 713) and corresponding clinical data (333 x 1) of both adjacent normal tissues and cancers were downloaded from The Cancer Genome Atlas public access portal (through the xena platform https://xenabrowser.net/hub/).	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('Cancer', 'Phenotype', 'HP:0002664', (232, 238))	('Cancer Genome Atlas public access', 'Disease', (232, 265))	('Cancer Genome Atlas public access', 'Disease', 'MESH:D009369', (232, 265))	('DNA methylation', 'biological_process', 'GO:0006306', ('11', '26'))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('333', 'Var', (107, 110))	('cancers', 'Disease', (199, 206))
11671	31131513	First, differential expression genes were selected as candidate genes, which complied with the following criteria: the sign-test was applied to the expression of cancers and adjacent normal tissues and FDR adjustment performed; the threshold was P-value < 0.05 and FDR < 0.2; the fold-change was greater than 2.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('cancers', 'Disease', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('P-value <', 'Var', (246, 255))
11689	32817070	In this cohort, an integrated genomic and transcriptomic analysis with immune phenotyping by CD8 immunofluorescence was performed showing that CD8+ T-cell infiltrated tumours are relatively depleted for PBRM1 mutations, which is associated with response to CPI, while are enriched for chromosomal losses of 9p21.3 associated with resistance to PD-1 blockade in infiltrated tumours.	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('tumour', 'Phenotype', 'HP:0002664', (373, 379))	('PD-1 blockade in infiltrated tumours', 'Disease', (344, 380))	('tumours', 'Phenotype', 'HP:0002664', (167, 174))	('tumours', 'Phenotype', 'HP:0002664', (373, 380))	('PD-1 blockade in infiltrated tumours', 'Disease', 'MESH:D010300', (344, 380))	('CD8', 'Gene', (143, 146))	('tumours', 'Disease', 'MESH:D009369', (167, 174))	('CD8', 'Gene', '925', (143, 146))	('PBRM1', 'Gene', (203, 208))	('tumours', 'Disease', 'MESH:D009369', (373, 380))	('PBRM1', 'Gene', '55193', (203, 208))	('tumours', 'Disease', (167, 174))	('tumours', 'Disease', (373, 380))	('mutations', 'Var', (209, 218))	('CD8', 'Gene', (93, 96))	('CPI', 'Chemical', 'MESH:C110747', (257, 260))	('CD8', 'Gene', '925', (93, 96))
11690	32817070	Overall, although infiltrated tumours are considered immunogenically 'hot', they are relatively depleted of PBRM1 mutations, which correlate with improved survival with anti-PD-1 therapy and are enriched for 9p21.3 deletions, which are associated with worse outcomes after PD-1 blockade.	('PBRM1', 'Gene', '55193', (108, 113))	('PD-1', 'Gene', (273, 277))	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('deletions', 'Var', (215, 224))	('mutations', 'Var', (114, 123))	('PD-1', 'Gene', (174, 178))	('PD-1', 'Gene', '9825', (273, 277))	('tumours', 'Disease', 'MESH:D009369', (30, 37))	('tumours', 'Disease', (30, 37))	('improved', 'PosReg', (146, 154))	('PD-1', 'Gene', '9825', (174, 178))	('PBRM1', 'Gene', (108, 113))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
11692	32817070	As commented by the authors, due to the limited number of samples for which immunofluorescence and whole exome sequencing data were available, this potential interplay between CD8+ T-cell infiltration and del9p21.3 will need to be confirmed in future studies of ICI monotherapy in ccRCC.	('CD8', 'Gene', '925', (176, 179))	('ccRCC', 'Phenotype', 'HP:0006770', (281, 286))	('ccRCC', 'Disease', (281, 286))	('CD8', 'Gene', (176, 179))	('del9p21.3', 'Var', (205, 214))
11700	32817070	They identified eight specific categories of alterations that were enriched in the resistant tumours: biallelic disruption of RB1, activating mutations and/or amplification of AKT1, activating mutations in KRAS/HRAS/NRAS, activating mutations and/or amplification of FGFR2, activating mutations in ERBB2, amplifications of CCNE2, amplification of AURKA and loss of ER (assessed by immunohistochemistry).	('HRAS', 'Gene', '3265', (211, 215))	('ERBB2', 'Gene', '2064', (298, 303))	('mutations', 'Var', (193, 202))	('NRAS', 'Gene', (216, 220))	('FGFR2', 'Gene', '2263', (267, 272))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('HRAS', 'Gene', (211, 215))	('activating', 'PosReg', (222, 232))	('RB1', 'Gene', (126, 129))	('resistant tumours', 'Disease', (83, 100))	('amplification', 'Var', (330, 343))	('activating', 'PosReg', (182, 192))	('resistant tumours', 'Disease', 'MESH:D009369', (83, 100))	('amplification', 'Var', (250, 263))	('mutations', 'Var', (285, 294))	('KRAS', 'Gene', '3845', (206, 210))	('RB1', 'Gene', '5925', (126, 129))	('FGFR', 'molecular_function', 'GO:0005007', ('267', '271'))	('AKT1', 'Gene', '207', (176, 180))	('activating', 'PosReg', (131, 141))	('loss', 'NegReg', (357, 361))	('NRAS', 'Gene', '4893', (216, 220))	('KRAS', 'Gene', (206, 210))	('amplifications', 'Var', (305, 319))	('activating', 'PosReg', (274, 284))	('AURKA', 'Gene', '6790', (347, 352))	('CCNE2', 'Gene', '9134', (323, 328))	('AURKA', 'Gene', (347, 352))	('ERBB2', 'Gene', (298, 303))	('FGFR2', 'Gene', (267, 272))	('AKT1', 'Gene', (176, 180))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('CCNE2', 'Gene', (323, 328))
11701	32817070	Interestingly, they showed additional alterations that they were not implicated in resistance mechanism of CDK4/6i: TP53 mutations were enriched in resistant specimens, but they were not sufficient to drive resistance; PIK3CA mutations and copy number gains in FGFR1 occurred in both sensitive and resistant samples and ESR1 mutations were related with endocrine resistance.	('FGFR1', 'Gene', '2260', (261, 266))	('TP53', 'Gene', (116, 120))	('ESR1', 'Gene', '2099', (320, 324))	('PIK3CA', 'Gene', (219, 225))	('CDK4/6i', 'Gene', (107, 114))	('endocrine', 'MPA', (353, 362))	('FGFR', 'molecular_function', 'GO:0005007', ('261', '265'))	('copy number gains', 'Var', (240, 257))	('ESR1', 'Gene', (320, 324))	('related', 'Reg', (340, 347))	('PIK3CA', 'Gene', '5290', (219, 225))	('mutations', 'Var', (325, 334))	('TP53', 'Gene', '7157', (116, 120))	('mutations', 'Var', (226, 235))	('FGFR1', 'Gene', (261, 266))	('CDK4/6i', 'Gene', '1019', (107, 114))	('CDK', 'molecular_function', 'GO:0004693', ('107', '110'))
11702	32817070	To confirm, whether these alterations confer resistance to CDK4/6i, they studied two luminal breast cancer cell lines.	('CDK', 'molecular_function', 'GO:0004693', ('59', '62'))	('CDK4/6i', 'Gene', '1019', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('alterations', 'Var', (26, 37))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('CDK4/6i', 'Gene', (59, 66))	('luminal', 'Chemical', 'MESH:D010634', (85, 92))
11704	32817070	As expected, similar results were obtained at in vitro level, showing that all alterations were sufficient to cause resistance to CDK4/6i.	('CDK4/6i', 'Gene', '1019', (130, 137))	('alterations', 'Var', (79, 90))	('CDK', 'molecular_function', 'GO:0004693', ('130', '133'))	('resistance', 'MPA', (116, 126))	('CDK4/6i', 'Gene', (130, 137))	('cause', 'Reg', (110, 115))
11707	32817070	The majority of alterations identified as mechanisms of resistance to CDK4/6 are druggable biomarkers.	('alterations', 'Var', (16, 27))	('CDK4/6', 'Gene', (70, 76))	('CDK', 'molecular_function', 'GO:0004693', ('70', '73'))	('CDK4/6', 'Gene', '1019;1021', (70, 76))
11726	29021138	Upon glutaminase inhibition with CB-839 or BPTES, the RCC cell lines SN12PM-6-1 (SN12) and 786-O exhibited decreased survival and pronounced apoptosis associated with a decreased GSH/GSSG ratio, augmented nuclear factor erythroid related factor 2 (NRF2), and increased 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a marker of DNA damage.	('increased', 'PosReg', (259, 268))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('decreased', 'NegReg', (169, 178))	('CB-839', 'Chemical', 'MESH:C000593334', (33, 39))	('apoptosis', 'CPA', (141, 150))	('BPTES', 'Chemical', 'MESH:C523193', (43, 48))	('apoptosis', 'biological_process', 'GO:0097194', ('141', '150'))	('nuclear factor erythroid related factor 2', 'Gene', (205, 246))	('apoptosis', 'biological_process', 'GO:0006915', ('141', '150'))	('SN12PM-6-1', 'Var', (69, 79))	("8-oxo-7,8-dihydro-2'-deoxyguanosine", 'Chemical', 'MESH:C067134', (269, 304))	('8-oxodG', 'Chemical', 'MESH:C067134', (306, 313))	('GSH', 'Chemical', '-', (179, 182))	('NRF2', 'Gene', (248, 252))	('GSSG', 'Chemical', 'MESH:D019803', (183, 187))	('GSH/GSSG ratio', 'MPA', (179, 193))	('augmented', 'PosReg', (195, 204))	('DNA', 'cellular_component', 'GO:0005574', ('328', '331'))	('nuclear factor erythroid related factor 2', 'Gene', '18024', (205, 246))	('RCC', 'Disease', (54, 57))	('decreased', 'NegReg', (107, 116))	('SN12PM-6-1', 'CellLine', 'CVCL:9549', (69, 79))
11753	29021138	The GLS inhibitor BPTES (bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide) and all other reagents were purchased from Sigma (St. Louis, MO) 786-O cells were purchased from American Type Culture Collection (Rockville, MD, USA) in January 2014 and authenticated originally by the source using short tandem repeat (STR).	('bis', 'molecular_function', 'GO:0033815', ('25', '28'))	('BPTES', 'Chemical', 'MESH:C523193', (18, 23))	('short tandem repeat', 'Var', (303, 322))	('bis-2', 'Gene', (25, 30))	('bis-2', 'Gene', '107521', (25, 30))
11839	29021138	Furthermore, GSH, which has glutamate as a precursor, was decreased by CB-839 treatment, and GSSG was relatively increased (also reflected by a decreased GSH/GSSG ratio), demonstrating increased levels of oxidative stress within the cells in the presence of GLS inhibition (Fig.	('treatment', 'Var', (78, 87))	('GSH', 'MPA', (13, 16))	('decreased', 'NegReg', (144, 153))	('GSSG', 'Chemical', 'MESH:D019803', (158, 162))	('glutamate', 'Chemical', 'MESH:D018698', (28, 37))	('decreased', 'NegReg', (58, 67))	('GSSG', 'Chemical', 'MESH:D019803', (93, 97))	('CB-839', 'Gene', (71, 77))	('GSH', 'Chemical', '-', (154, 157))	('increased', 'PosReg', (113, 122))	('CB-839', 'Chemical', 'MESH:C000593334', (71, 77))	('levels', 'MPA', (195, 201))	('GSH', 'Chemical', '-', (13, 16))	('increased', 'PosReg', (185, 194))	('oxidative stress', 'Phenotype', 'HP:0025464', (205, 221))
11841	29021138	The tumors from mice treated with CB-839 also showed a decreased trend in GSH/GSSG (p=0.139) compared to tumors from mice treated with vehicle (Fig.2B, far right panel) indicative of increased oxidative stress as a result of GLS inhibition and consistent with the in vitro data.	('tumors', 'Disease', (105, 111))	('CB-839', 'Chemical', 'MESH:C000593334', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('mice', 'Species', '10090', (117, 121))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('oxidative stress', 'MPA', (193, 209))	('inhibition', 'NegReg', (229, 239))	('GLS', 'Protein', (225, 228))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CB-839', 'Var', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('decreased', 'NegReg', (55, 64))	('GSH', 'Chemical', '-', (74, 77))	('oxidative stress', 'Phenotype', 'HP:0025464', (193, 209))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (183, 209))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('increased', 'PosReg', (183, 192))	('tumors', 'Disease', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('GSSG', 'Chemical', 'MESH:D019803', (78, 82))	('mice', 'Species', '10090', (16, 20))
11852	29021138	To further support the role of the GSH pathway in neutralizing ROS, we incubated SN12 cells with CB-839 for 20 h and then induced oxidative stress by adding H2O2 for 4 h. Under these conditions, CB-839 dose-dependently sensitized RCC cells to H2O2, as evidenced by an increased percentage of apoptotic and dead cells demonstrated both by flow cytometry using annexin V and 7-AAD staining (Fig.	('sensitized', 'Reg', (219, 229))	('GSH', 'Chemical', '-', (35, 38))	('CB-839', 'Chemical', 'MESH:C000593334', (195, 201))	('oxidative stress', 'Phenotype', 'HP:0025464', (130, 146))	('annexin V', 'Gene', '11747', (359, 368))	('ROS', 'Chemical', 'MESH:D017382', (63, 66))	('7-AAD', 'Chemical', 'MESH:C025942', (373, 378))	('annexin V', 'Gene', (359, 368))	('H2O2', 'Chemical', 'MESH:D006861', (243, 247))	('CB-839', 'Chemical', 'MESH:C000593334', (97, 103))	('CB-839', 'Var', (195, 201))	('H2O2', 'Chemical', 'MESH:D006861', (157, 161))	('RCC', 'Disease', 'MESH:C538614', (230, 233))	('RCC', 'Disease', (230, 233))
11857	29021138	A significant increase of 8-oxodG was also detected in tumors from mice treated with CB-839 (Fig.4A, right panel) demonstrating that CB-839 is increasing oxidative stress at the DNA level.	('8-oxodG', 'Chemical', 'MESH:C067134', (26, 33))	('CB-839', 'Chemical', 'MESH:C000593334', (133, 139))	('8-oxodG', 'MPA', (26, 33))	('DNA', 'cellular_component', 'GO:0005574', ('178', '181'))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('oxidative stress', 'Phenotype', 'HP:0025464', (154, 170))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('increasing', 'PosReg', (143, 153))	('CB-839', 'Gene', (85, 91))	('CB-839', 'Var', (133, 139))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('oxidative stress', 'MPA', (154, 170))	('mice', 'Species', '10090', (67, 71))	('increase', 'PosReg', (14, 22))	('CB-839', 'Chemical', 'MESH:C000593334', (85, 91))
11860	29021138	Subcellular localization of NRF2 in SN12 cells after incubation with CB-839 and H2O2 and showed an increase in nuclear NRF2 in CB-839 treated cells, which was more pronounced upon H2O2 treatment (Fig.	('localization', 'biological_process', 'GO:0051179', ('12', '24'))	('H2O2', 'Chemical', 'MESH:D006861', (180, 184))	('H2O2', 'Var', (180, 184))	('CB-839', 'Chemical', 'MESH:C000593334', (127, 133))	('H2O2', 'Chemical', 'MESH:D006861', (80, 84))	('NRF2', 'Gene', (28, 32))	('CB-839', 'Chemical', 'MESH:C000593334', (69, 75))	('increase', 'PosReg', (99, 107))	('nuclear', 'MPA', (111, 118))	('NRF2', 'Gene', (119, 123))
11878	29021138	Indeed, there are several recent reports which demonstrate that, contrary to lay press reports of antioxidants being beneficial dietary supplements, these compounds can in fact accelerate lung cancer progression in mice and promote distant metastases in human melanoma cells; similar findings have most recently been shown in pancreatic cancer by deletion of malic enzyme 2.	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('promote', 'PosReg', (224, 231))	('melanoma', 'Disease', 'MESH:D008545', (260, 268))	('lung cancer', 'Disease', (188, 199))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (326, 343))	('metastases', 'Disease', 'MESH:D009362', (240, 250))	('human', 'Species', '9606', (254, 259))	('malic enzyme', 'molecular_function', 'GO:0004473', ('359', '371'))	('deletion', 'Var', (347, 355))	('metastases', 'Disease', (240, 250))	('malic enzyme 2', 'Gene', (359, 373))	('melanoma', 'Phenotype', 'HP:0002861', (260, 268))	('melanoma', 'Disease', (260, 268))	('lung cancer', 'Disease', 'MESH:D008175', (188, 199))	('mice', 'Species', '10090', (215, 219))	('pancreatic cancer', 'Disease', 'MESH:D010190', (326, 343))	('lung cancer', 'Phenotype', 'HP:0100526', (188, 199))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('malic enzyme 2', 'Gene', '4200', (359, 373))	('pancreatic cancer', 'Disease', (326, 343))	('malic enzyme', 'molecular_function', 'GO:0004471', ('359', '371'))	('accelerate', 'PosReg', (177, 187))
11917	31750330	With the wider use of immune check-point inhibitors and tyrosine kinase inhibitors in metastatic CCRCC, surgery may eventually be reserved only for palliative purposes.	('tyrosine', 'Var', (56, 64))	('CCRCC', 'Disease', (97, 102))	('CCRCC', 'Phenotype', 'HP:0006770', (97, 102))	('tyrosine', 'Chemical', 'None', (56, 64))	('CCRCC', 'Disease', 'MESH:D002292', (97, 102))
12011	31750330	With the wider use of immune check-point and tyrosine kinase inhibitors in metastatic CCRCC, surgery may eventually be reserved only for palliative purposes.	('tyrosine', 'Var', (45, 53))	('CCRCC', 'Disease', (86, 91))	('CCRCC', 'Phenotype', 'HP:0006770', (86, 91))	('tyrosine', 'Chemical', 'None', (45, 53))	('CCRCC', 'Disease', 'MESH:D002292', (86, 91))
12012	33628845	Identification of a New Prognostic Risk Signature of Clear Cell Renal Cell Carcinoma Based on N6-Methyladenosine RNA Methylation Regulators As the most prevalent internal eukaryotic modification, N6-methyladenosine (m6A) is installed by methyltransferases, removed by demethylases, and recognized by readers.	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (53, 84))	('m6A', 'Gene', '56339', (216, 219))	('Carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('RNA Methylation', 'biological_process', 'GO:0001510', ('113', '128'))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (196, 214))	('N6-methyladenosine', 'Var', (196, 214))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (53, 84))	('RNA', 'cellular_component', 'GO:0005562', ('113', '116'))	('m6A', 'Gene', (216, 219))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (64, 84))	('Clear Cell Renal Cell Carcinoma', 'Disease', (53, 84))
12026	33628845	N6-Methyladenosine (m6A) is a modified adenosine residue, methylated at position N6.	('N6-Methyladenosine', 'Var', (0, 18))	('N6-Methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('m6A', 'Gene', '56339', (20, 23))	('adenosine', 'Chemical', 'MESH:D000241', (9, 18))	('adenosine', 'Chemical', 'MESH:D000241', (39, 48))	('m6A', 'Gene', (20, 23))
12029	33628845	There have been many recent studies on m6A, and results indicate that m6A methylation contributes to the pathogenesis and progression of tumors and even those cancer responses to treatments are related to m6A.	('cancer', 'Disease', (159, 165))	('methylation', 'Var', (74, 85))	('m6A', 'Gene', (70, 73))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('pathogenesis', 'biological_process', 'GO:0009405', ('105', '117'))	('m6A', 'Gene', '56339', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('m6A', 'Gene', (205, 208))	('m6A', 'Gene', (39, 42))	('contributes', 'Reg', (86, 97))	('m6A', 'Gene', '56339', (205, 208))	('m6A', 'Gene', '56339', (39, 42))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('methylation', 'biological_process', 'GO:0032259', ('74', '85'))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
12030	33628845	The dynamic process of m6A modification is orchestrated by writers (methyltransferase complexes), erasers (demethylases), and readers (Figure 1(a)).	('m6A', 'Gene', (23, 26))	('m6A', 'Gene', '56339', (23, 26))	('modification', 'Var', (27, 39))
12094	33628845	We found that they can play roles in DNA repair, RNA splicing, and other physiological processes such as apoptosis, cell cycle, and epithelial mesenchymal transformation (EMT), and even inhibit or activate cell signaling pathways, including the PI3K/Akt pathway.	('DNA repair', 'biological_process', 'GO:0006281', ('37', '47'))	('cell signaling pathways', 'Pathway', (206, 229))	('PI3K', 'molecular_function', 'GO:0016303', ('245', '249'))	('epithelial mesenchymal transformation', 'CPA', (132, 169))	('apoptosis', 'biological_process', 'GO:0097194', ('105', '114'))	('Akt', 'Gene', (250, 253))	('RNA splicing', 'Var', (49, 61))	('apoptosis', 'biological_process', 'GO:0006915', ('105', '114'))	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('Akt', 'Gene', '207', (250, 253))	('cell cycle', 'biological_process', 'GO:0007049', ('116', '126'))	('EMT', 'biological_process', 'GO:0001837', ('171', '174'))	('cell cycle', 'CPA', (116, 126))	('RNA', 'cellular_component', 'GO:0005562', ('49', '52'))	('apoptosis', 'CPA', (105, 114))	('inhibit', 'NegReg', (186, 193))	('DNA', 'Disease', (37, 40))	('signaling', 'biological_process', 'GO:0023052', ('211', '220'))	('activate', 'PosReg', (197, 205))	('RNA splicing', 'biological_process', 'GO:0008380', ('49', '61'))
12107	33628845	In addition, in patients with acute myelocytic leukemia, the overexpression of IGF2BP2 indicates poor survival, and IGF2BP2 expression is associated with mutations in FLT3-ITD and IDH1, which are also indicators of poor prognosis.	('acute myelocytic leukemia', 'Disease', 'MESH:D015470', (30, 55))	('overexpression', 'PosReg', (61, 75))	('patients', 'Species', '9606', (16, 24))	('acute myelocytic leukemia', 'Phenotype', 'HP:0004808', (30, 55))	('leukemia', 'Phenotype', 'HP:0001909', (47, 55))	('acute myelocytic leukemia', 'Disease', (30, 55))	('IGF2BP2', 'Gene', (116, 123))	('IGF2BP2', 'Gene', '10644', (79, 86))	('poor', 'NegReg', (97, 101))	('IDH1', 'Gene', (180, 184))	('FLT3', 'Gene', (167, 171))	('IGF2BP2', 'Gene', '10644', (116, 123))	('FLT3', 'Gene', '2322', (167, 171))	('IDH1', 'Gene', '3417', (180, 184))	('associated', 'Reg', (138, 148))	('expression', 'MPA', (124, 134))	('mutations', 'Var', (154, 163))	('myelocytic leukemia', 'Phenotype', 'HP:0012324', (36, 55))	('IGF2BP2', 'Gene', (79, 86))
12113	33628845	Here, we found that the expression of HNRNPA2B1 in the high-risk group was also significantly increased, and that the prognosis of the group with high levels of this regulator is worse than that of the group with low levels.	('HNRNPA2B1', 'Gene', '3181', (38, 47))	('expression', 'MPA', (24, 34))	('increased', 'PosReg', (94, 103))	('high levels', 'Var', (146, 157))	('HNRNPA2B1', 'Gene', (38, 47))
12121	33628845	These data are consistent with our results that suggest that a high expression of METTL14 can inhibit tumor growth or other harmful physiological processes.	('METTL14', 'Gene', '57721', (82, 89))	('METTL14', 'Gene', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('high expression', 'Var', (63, 78))	('harmful physiological processes', 'CPA', (124, 155))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('inhibit', 'NegReg', (94, 101))
12156	32529862	There is also a relationship between polygene mutation and RCC.	('relationship', 'Reg', (16, 28))	('polygene mutation', 'Var', (37, 54))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
12157	32529862	Mutations in the tumor suppressor gene von Hippel-Lindau (VHL) can be found in more than 80% of clear-cell renal carcinoma (ccRCC) subtypes.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('17', '33'))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('clear-cell renal carcinoma', 'Phenotype', 'HP:0006770', (96, 122))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('tumor suppressor', 'biological_process', 'GO:0051726', ('17', '33'))	('von Hippel-Lindau', 'Gene', '7428', (39, 56))	('VHL', 'Gene', (58, 61))	('Mutations', 'Var', (0, 9))	('renal carcinoma', 'Phenotype', 'HP:0005584', (107, 122))	('tumor', 'Disease', (17, 22))	('clear-cell renal carcinoma', 'Disease', 'MESH:C538614', (96, 122))	('clear-cell renal carcinoma', 'Disease', (96, 122))	('RCC', 'Disease', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('VHL', 'Gene', '7428', (58, 61))	('found', 'Reg', (70, 75))	('von Hippel-Lindau', 'Gene', (39, 56))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('ccRCC', 'Phenotype', 'HP:0006770', (124, 129))
12217	32529862	In a phase III clinical trial, the pazopanil group significantly prolonged progression-free survival (9.2 months vs. 4.2 months, HR: 0.46, 95% CI: 0.34-0.62, P < 0.0001) and the overall response rate (30% vs. 3%, P < 0.001) compared with the placebo group.	('pazopanil', 'Var', (35, 44))	('pazopanil', 'Chemical', '-', (35, 44))	('prolonged', 'PosReg', (65, 74))	('progression-free survival', 'CPA', (75, 100))
12249	32529862	The two groups were similar in terms of adverse reactions, but the axitinib group more commonly reported hypertension, fatigue, language disorders, and hypothyroidism than the sorafenib group.	('fatigue', 'Phenotype', 'HP:0012378', (119, 126))	('axitinib', 'Chemical', 'MESH:D000077784', (67, 75))	('language disorders', 'Disease', (128, 146))	('hypertension', 'Disease', (105, 117))	('sorafenib', 'Chemical', 'MESH:D000077157', (176, 185))	('reported', 'Reg', (96, 104))	('hypertension', 'Phenotype', 'HP:0000822', (105, 117))	('hypothyroidism', 'Disease', 'MESH:D007037', (152, 166))	('language disorders', 'Phenotype', 'HP:0002463', (128, 146))	('hypothyroidism', 'Phenotype', 'HP:0000821', (152, 166))	('hypothyroidism', 'Disease', (152, 166))	('axitinib', 'Var', (67, 75))	('fatigue', 'Disease', 'MESH:D005221', (119, 126))	('hypertension', 'Disease', 'MESH:D006973', (105, 117))	('language disorders', 'Disease', 'MESH:D007806', (128, 146))	('fatigue', 'Disease', (119, 126))
12256	32529862	Targeted therapy is currently the standard treatment for mRCC and can greatly reduce tumor load in the body and improve progression-free and overall survival.	('tumor', 'Disease', (85, 90))	('improve', 'PosReg', (112, 119))	('reduce', 'NegReg', (78, 84))	('overall survival', 'CPA', (141, 157))	('Targeted', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
12262	30909494	Mutations of the von Hippel-Lindau (VHL) tumor-suppressor gene and the resultant overexpression of hypoxia-inducible factor (HIF)-1alpha protein are considered hallmarks of ccRCC.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('ccRCC', 'Phenotype', 'HP:0006770', (173, 178))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('41', '57'))	('tumor-suppressor', 'Gene', '7248', (41, 57))	('hypoxia-inducible factor (HIF)-1alpha', 'Gene', '3091', (99, 136))	('overexpression', 'PosReg', (81, 95))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('41', '57'))	('Mutations', 'Var', (0, 9))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('RCC', 'Disease', (175, 178))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (17, 46))	('RCC', 'Disease', 'MESH:C538614', (175, 178))	('tumor-suppressor', 'Gene', (41, 57))
12276	30909494	Mutation of the von Hippel-Lindau (VHL) tumor suppressor gene and the resultant overexpression of hypoxia-inducible factor (HIF)-1alpha protein are considered hallmarks of ccRCC.	('overexpression', 'PosReg', (80, 94))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('Mutation', 'Var', (0, 8))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('ccRCC', 'Phenotype', 'HP:0006770', (172, 177))	('RCC', 'Disease', (174, 177))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (16, 45))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('hypoxia-inducible factor (HIF)-1alpha', 'Gene', '3091', (98, 135))	('tumor suppressor', 'biological_process', 'GO:0051726', ('40', '56'))
12278	30909494	Several cell lines have been used to model ccRCC in research with some expressing wild-type VHL, and others characterized by a loss-of-function mutation in VHL.	('loss-of-function', 'NegReg', (127, 143))	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('VHL', 'Gene', (92, 95))	('VHL', 'Gene', '7428', (156, 159))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))	('mutation', 'Var', (144, 152))	('VHL', 'Gene', '7428', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('VHL', 'Gene', (156, 159))
12283	30909494	Specifically, metformin acts through inhibiting gluconeogenesis (glucose production) in the liver via activation of AMPK signaling in hepatocytes.	('signaling', 'biological_process', 'GO:0023052', ('121', '130'))	('AMPK signaling', 'MPA', (116, 130))	('AMPK', 'molecular_function', 'GO:0050405', ('116', '120'))	('metformin', 'Var', (14, 23))	('glucose', 'Chemical', 'MESH:D005947', (65, 72))	('AMPK', 'molecular_function', 'GO:0004691', ('116', '120'))	('activation', 'PosReg', (102, 112))	('inhibiting gluconeogenesis', 'Phenotype', 'HP:0005959', (37, 63))	('metformin', 'Chemical', 'MESH:D008687', (14, 23))	('AMPK', 'molecular_function', 'GO:0047322', ('116', '120'))	('gluconeogenesis', 'biological_process', 'GO:0006094', ('48', '63'))	('gluconeogenesis', 'MPA', (48, 63))	('inhibiting', 'NegReg', (37, 47))
12284	30909494	In addition, metformin also inhibits pyruvate dehydrogenase activity and mitochondrial respiration, which in turn increases the theoretical risk of lactic acidosis in cells.	('acidosis', 'Phenotype', 'HP:0001941', (155, 163))	('lactic acidosis', 'Disease', 'MESH:D000140', (148, 163))	('pyruvate dehydrogenase activity', 'molecular_function', 'GO:0004738', ('37', '68'))	('inhibits', 'NegReg', (28, 36))	('metformin', 'Var', (13, 22))	('pyruvate dehydrogenase', 'Enzyme', (37, 59))	('mitochondrial respiration', 'MPA', (73, 98))	('respiration', 'biological_process', 'GO:0007585', ('87', '98'))	('rat', 'Species', '10116', (92, 95))	('increases', 'PosReg', (114, 123))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('respiration', 'biological_process', 'GO:0045333', ('87', '98'))	('lactic acidosis', 'Phenotype', 'HP:0003128', (148, 163))	('activity', 'MPA', (60, 68))	('lactic acidosis', 'Disease', (148, 163))	('pyruvate dehydrogenase activity', 'molecular_function', 'GO:0052737', ('37', '68'))
12291	30909494	demonstrated contrasting properties of HIF-1alpha and HIF-2alpha in VHL-defective ccRCC cells, with HIF-1alpha inhibiting and HIF-2alpha promoting cell growth.	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('HIF-1alpha', 'Var', (100, 110))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('HIF-2alpha', 'Gene', (126, 136))	('HIF-2alpha', 'Gene', (54, 64))	('rat', 'Species', '10116', (7, 10))	('cell growth', 'biological_process', 'GO:0016049', ('147', '158'))	('inhibiting', 'NegReg', (111, 121))	('HIF-1alpha and HIF-2alpha in VHL-defective', 'Disease', 'MESH:D006623', (39, 81))	('cell growth', 'CPA', (147, 158))	('promoting', 'PosReg', (137, 146))	('HIF-2alpha', 'Gene', '2034', (126, 136))	('HIF-2alpha', 'Gene', '2034', (54, 64))
12295	30909494	The VHL gene is often mutated in ccRCC cell lines (e.g., 786-O and UM-RC-2) with subsequent activation of the HIF pathway that regulates the expression of various target proteins involved in ccRCC progression; however, the status of VHL alone cannot predict the differential sensitivity of ccRCC to cancer treatments.	('ccRCC', 'Phenotype', 'HP:0006770', (290, 295))	('mutated', 'Var', (22, 29))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('RCC', 'Disease', (35, 38))	('RCC', 'Disease', (193, 196))	('RCC', 'Phenotype', 'HP:0005584', (193, 196))	('HIF pathway', 'Pathway', (110, 121))	('VHL', 'Gene', (233, 236))	('VHL', 'Gene', (4, 7))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (191, 196))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('expression', 'MPA', (141, 151))	('VHL', 'Gene', '7428', (233, 236))	('VHL', 'Gene', '7428', (4, 7))	('cancer', 'Disease', (299, 305))	('RCC', 'Disease', (292, 295))	('RCC', 'Phenotype', 'HP:0005584', (292, 295))	('activation', 'PosReg', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('regulates', 'Reg', (127, 136))	('RCC', 'Disease', 'MESH:C538614', (292, 295))
12341	30909494	It is well-documented that oncogenic mutations can disrupt apoptosis and deregulate apoptotic signaling pathways, thereby enabling cancer cells to evade programmed cell death and subsequently leading to uncontrolled cell growth and migration.	('cancer', 'Disease', (131, 137))	('apoptosis', 'biological_process', 'GO:0097194', ('59', '68'))	('apoptotic signaling pathways', 'Pathway', (84, 112))	('apoptosis', 'biological_process', 'GO:0006915', ('59', '68'))	('evade', 'NegReg', (147, 152))	('uncontrolled', 'MPA', (203, 215))	('cell growth', 'biological_process', 'GO:0016049', ('216', '227'))	('disrupt', 'NegReg', (51, 58))	('signaling', 'biological_process', 'GO:0023052', ('94', '103'))	('rat', 'Species', '10116', (235, 238))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mutations', 'Var', (37, 46))	('apoptosis', 'CPA', (59, 68))	('leading to', 'Reg', (192, 202))	('programmed cell death', 'biological_process', 'GO:0012501', ('153', '174'))	('deregulate', 'Reg', (73, 83))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
12349	30909494	We found that metformin treatment noticeably inhibited the capacity of wound healing in both Caki-1 (Figure 4A,C) and Caki-2 cells (Figure 4B,D), suggesting that metformin could effectively inhibit cell migration and invasion in both cell types whereas untreated Caki-1 and Caki-2 cells (controls) demonstrated a higher capacity to migrate and invade (gap closed within 24 h).	('inhibit', 'NegReg', (190, 197))	('migrate', 'CPA', (332, 339))	('rat', 'Species', '10116', (305, 308))	('wound healing', 'biological_process', 'GO:0042060', ('71', '84'))	('cell migration', 'biological_process', 'GO:0016477', ('198', '212'))	('Caki-2', 'CellLine', 'CVCL:0235', (118, 124))	('metformin', 'Var', (162, 171))	('rat', 'Species', '10116', (335, 338))	('Caki-2', 'CellLine', 'CVCL:0235', (274, 280))	('invasion', 'CPA', (217, 225))	('rat', 'Species', '10116', (206, 209))	('invade', 'CPA', (344, 350))	('cell migration', 'CPA', (198, 212))	('inhibited', 'NegReg', (45, 54))	('metformin', 'Chemical', 'MESH:D008687', (14, 23))	('metformin', 'Chemical', 'MESH:D008687', (162, 171))
12356	30909494	The overexpression of HIF-1alpha protein has been shown to be involved in the development and progression of ccRCC due to mutations in the VHL gene.	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('VHL', 'Gene', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('VHL', 'Gene', '7428', (139, 142))	('involved', 'Reg', (62, 70))	('mutations', 'Var', (122, 131))	('overexpression', 'PosReg', (4, 18))
12366	30909494	On the other hand, as depicted in Figure 6C,D, our results also revealed a dose-dependent reduction of Akt phosphorylation in both cell lines in the presence of metformin, with the most prominent effect observed at the concentration of 10 mM of metformin.	('metformin', 'Chemical', 'MESH:D008687', (245, 254))	('metformin', 'Var', (161, 170))	('reduction', 'NegReg', (90, 99))	('Akt', 'Gene', (103, 106))	('Akt', 'Gene', '207', (103, 106))	('metformin', 'Chemical', 'MESH:D008687', (161, 170))	('phosphorylation', 'biological_process', 'GO:0016310', ('107', '122'))	('rat', 'Species', '10116', (226, 229))
12376	30909494	The canonical Wnt/beta-catenin signaling pathway plays a critical role in various cellular and developmental processes, and its aberrant activation has been linked with some cancers including ccRCC.	('linked', 'Reg', (157, 163))	('beta-catenin', 'Gene', (18, 30))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('beta-catenin', 'Gene', '1499', (18, 30))	('RCC', 'Disease', 'MESH:C538614', (194, 197))	('ccRCC', 'Phenotype', 'HP:0006770', (192, 197))	('aberrant', 'Var', (128, 136))	('cancers', 'Disease', (174, 181))	('RCC', 'Disease', (194, 197))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('RCC', 'Phenotype', 'HP:0005584', (194, 197))	('signaling pathway', 'biological_process', 'GO:0007165', ('31', '48'))	('activation', 'PosReg', (137, 147))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
12385	30909494	There is an increasing body of evidence that metformin can inhibit cell proliferation and differentiation in various types of cancers such as cancers of the lung, prostate, liver, and pancreas.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('metformin', 'Var', (45, 54))	('metformin', 'Chemical', 'MESH:D008687', (45, 54))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('rat', 'Species', '10116', (79, 82))	('liver', 'Disease', (173, 178))	('cancers of the lung', 'Disease', (142, 161))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancers', 'Disease', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('cancers', 'Disease', (126, 133))	('inhibit', 'NegReg', (59, 66))	('cancers of the lung', 'Disease', 'MESH:D008175', (142, 161))	('pancreas', 'Disease', (184, 192))	('prostate', 'Disease', (163, 171))	('cell proliferation', 'CPA', (67, 85))
12386	30909494	Consistent with these previous studies, our findings demonstrated that metformin was capable of blunting cell growth in both Caki-1 and Caki-2 cells.	('metformin', 'Var', (71, 80))	('metformin', 'Chemical', 'MESH:D008687', (71, 80))	('cell growth', 'biological_process', 'GO:0016049', ('105', '116'))	('cell growth', 'CPA', (105, 116))	('rat', 'Species', '10116', (60, 63))	('Caki-2', 'CellLine', 'CVCL:0235', (136, 142))	('blunting', 'NegReg', (96, 104))
12397	30909494	revealed that metformin induces cell death in 786-O renal cancer cells under conditions of low nutritional status, which taken together with our results indicate a differential sensitivity of ccRCC cells to metformin, adding to the heterogeneity of this cancer.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cell death', 'CPA', (32, 42))	('metformin', 'Chemical', 'MESH:D008687', (207, 216))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('metformin', 'Var', (14, 23))	('RCC', 'Disease', 'MESH:C538614', (194, 197))	('renal cancer', 'Disease', (52, 64))	('RCC', 'Disease', (194, 197))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('RCC', 'Phenotype', 'HP:0005584', (194, 197))	('ccRCC', 'Phenotype', 'HP:0006770', (192, 197))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('renal cancer', 'Phenotype', 'HP:0009726', (52, 64))	('cancer', 'Disease', (254, 260))	('metformin', 'Chemical', 'MESH:D008687', (14, 23))	('cell death', 'biological_process', 'GO:0008219', ('32', '42'))	('cancer', 'Disease', (58, 64))	('renal cancer', 'Disease', 'MESH:D007680', (52, 64))
12402	30909494	It is well-documented that the mutation of the VHL tumor suppressor gene promotes the constitutive activation of HIF-1alpha and HIF-2alpha subunits in RCC.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('VHL tumor', 'Disease', (47, 56))	('mutation', 'Var', (31, 39))	('constitutive activation', 'MPA', (86, 109))	('promotes', 'PosReg', (73, 81))	('VHL tumor', 'Disease', 'MESH:D006623', (47, 56))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (113, 138))	('RCC', 'Disease', (151, 154))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('tumor suppressor', 'biological_process', 'GO:0051726', ('51', '67'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('51', '67'))
12410	30909494	In the present study, as expected, metformin upregulated the phosphorylation of AMPK in both Caki-1 and Caki-2 cells.	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))	('phosphorylation', 'MPA', (61, 76))	('Caki-2', 'CellLine', 'CVCL:0235', (104, 110))	('AMPK', 'molecular_function', 'GO:0050405', ('80', '84'))	('metformin', 'Var', (35, 44))	('upregulated', 'PosReg', (45, 56))	('AMPK', 'molecular_function', 'GO:0004691', ('80', '84'))	('AMPK', 'molecular_function', 'GO:0047322', ('80', '84'))	('metformin', 'Chemical', 'MESH:D008687', (35, 44))	('AMPK', 'Protein', (80, 84))
12417	30909494	Although many previous studies have demonstrated the significance of mTOR as an essential negative regulator of autophagy induction, to our surprise, our results were contrasting in both Caki-1 and Caki-2 cells as metformin caused a significant inhibition of autophagy (measured using LC3-II levels) compared to a control.	('autophagy', 'biological_process', 'GO:0016236', ('259', '268'))	('inhibition', 'NegReg', (245, 255))	('metformin', 'Chemical', 'MESH:D008687', (214, 223))	('LC3', 'Gene', '84557', (285, 288))	('rat', 'Species', '10116', (43, 46))	('LC3', 'Gene', (285, 288))	('autophagy', 'CPA', (259, 268))	('Caki-2', 'CellLine', 'CVCL:0235', (198, 204))	('autophagy', 'biological_process', 'GO:0006914', ('259', '268'))	('autophagy', 'biological_process', 'GO:0016236', ('112', '121'))	('autophagy', 'biological_process', 'GO:0006914', ('112', '121'))	('metformin', 'Var', (214, 223))
12423	30909494	Thus, inhibition of autophagy is regarded as an effective strategy to suppress tumor progression in certain cancers.	('autophagy', 'CPA', (20, 29))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('suppress', 'NegReg', (70, 78))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('autophagy', 'biological_process', 'GO:0006914', ('20', '29'))	('rat', 'Species', '10116', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('inhibition', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('autophagy', 'biological_process', 'GO:0016236', ('20', '29'))	('cancers', 'Disease', (108, 115))
12425	30909494	Besides VHL mutation with subsequent overactivation of HIF-1alpha and mTOR signaling pathways, other signaling pathways may also play a vital role in the development and progression of ccRCC.	('overactivation', 'PosReg', (37, 51))	('RCC', 'Disease', (187, 190))	('VHL', 'Gene', '7428', (8, 11))	('RCC', 'Phenotype', 'HP:0005584', (187, 190))	('play', 'Reg', (129, 133))	('VHL', 'Gene', (8, 11))	('RCC', 'Disease', 'MESH:C538614', (187, 190))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('ccRCC', 'Phenotype', 'HP:0006770', (185, 190))	('mTOR signaling pathways', 'Pathway', (70, 93))	('mutation', 'Var', (12, 20))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))	('HIF-1alpha', 'Protein', (55, 65))
12426	30909494	Of particular interest, Wnt/beta-catenin pathway and its dysregulation with subsequent overactivation of beta-catenin have been implicated in ccRCC pathogenesis.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('beta-catenin', 'Gene', (28, 40))	('dysregulation', 'Var', (57, 70))	('beta-catenin', 'Gene', '1499', (28, 40))	('overactivation', 'PosReg', (87, 101))	('beta-catenin', 'Gene', (105, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('pathogenesis', 'biological_process', 'GO:0009405', ('148', '160'))	('beta-catenin', 'Gene', '1499', (105, 117))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('implicated', 'Reg', (128, 138))
12432	30909494	Furthermore, we highlighted here that antineoplastic effects of metformin against ccRCC are, at least partly, based on its ability to activate AMPK and the subsequent inhibition of Akt/mTOR axis in addition to a focal effect on the inhibition of the Wnt/beta-catenin pathway.	('AMPK', 'molecular_function', 'GO:0004691', ('143', '147'))	('metformin', 'Var', (64, 73))	('beta-catenin', 'Gene', (254, 266))	('activate', 'PosReg', (134, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('AMPK', 'molecular_function', 'GO:0047322', ('143', '147'))	('beta-catenin', 'Gene', '1499', (254, 266))	('inhibition', 'NegReg', (167, 177))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('metformin', 'Chemical', 'MESH:D008687', (64, 73))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('Akt', 'Gene', '207', (181, 184))	('AMPK', 'MPA', (143, 147))	('antineoplastic effects', 'MPA', (38, 60))	('AMPK', 'molecular_function', 'GO:0050405', ('143', '147'))	('Akt', 'Gene', (181, 184))
12434	30909494	and A.A. conceptualized and designed the study, acquired funding, supervised the experiments, curated the data, wrote the discussion section, and edited the manuscript; M.P., S.K.S., and R.F.	('M.P.', 'Var', (169, 173))	('rat', 'Species', '10116', (96, 99))	('S.K.S.', 'Var', (175, 181))
12442	29559707	Experimentally, we show that knockout of ARRB2 decreases rate of RCC cell proliferation and migration in vitro and xenograft tumor growth in animals.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('knockout', 'Var', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('migration', 'CPA', (92, 101))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('ARRB2', 'Gene', (41, 46))	('decreases', 'NegReg', (47, 56))	('ARRB2', 'Gene', '409', (41, 46))	('cell proliferation', 'biological_process', 'GO:0008283', ('69', '87'))	('RCC', 'Disease', (65, 68))
12457	29559707	Likewise, betaArr2 mediates the initiation and progression of myeloid leukemia through the activation of Wnt signaling, forms complex with c-Src that promotes epidermal growth factor receptor (EGFR) transactivation, and induces tumor cell proliferation and metastasis.	('c-Src', 'Gene', (139, 144))	('signaling', 'biological_process', 'GO:0023052', ('109', '118'))	('promotes', 'PosReg', (150, 158))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('activation', 'PosReg', (91, 101))	('myeloid leukemia', 'Disease', (62, 78))	('EGFR', 'molecular_function', 'GO:0005006', ('193', '197'))	('transactivation', 'biological_process', 'GO:2000144', ('199', '214'))	('EGFR', 'Gene', (193, 197))	('transactivation', 'MPA', (199, 214))	('c-Src', 'Gene', '6714', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('myeloid leukemia', 'Disease', 'MESH:D007951', (62, 78))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (62, 78))	('induces', 'PosReg', (220, 227))	('EGFR', 'Gene', '1956', (193, 197))	('betaArr2', 'Var', (10, 18))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('159', '182'))	('cell proliferation', 'biological_process', 'GO:0008283', ('234', '252'))	('metastasis', 'CPA', (257, 267))	('epidermal growth factor receptor', 'Gene', (159, 191))	('tumor', 'Disease', (228, 233))	('epidermal growth factor receptor', 'Gene', '1956', (159, 191))	('Wnt signaling', 'Pathway', (105, 118))
12468	29559707	1E), and survival data showed that patients (diagnosed with ccRCC) with high ARRB2 expression levels had significantly lower survival outcomes compared to patients with low ARRB2 expression (Fig.	('ARRB2', 'Gene', (173, 178))	('ARRB2', 'Gene', '409', (173, 178))	('ARRB2', 'Gene', (77, 82))	('lower', 'NegReg', (119, 124))	('survival outcomes', 'CPA', (125, 142))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('ARRB2', 'Gene', '409', (77, 82))	('expression', 'MPA', (83, 93))	('patients', 'Species', '9606', (155, 163))	('RCC', 'Disease', (62, 65))	('patients', 'Species', '9606', (35, 43))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('high', 'Var', (72, 76))
12485	29559707	We observed that outer cells in control colonies displayed spike-like extensions whereas colonies originating from cells with betaArr2ko had smooth edges, like those of the non-tumorigenic HK2 cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('HK2', 'Gene', (189, 192))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('HK2', 'Gene', '3099', (189, 192))	('tumor', 'Disease', (177, 182))	('HK2', 'molecular_function', 'GO:0008256', ('189', '192'))	('betaArr2ko', 'Var', (126, 136))
12487	29559707	We also tested impact of betaArr2 on the cell invasion of matrigel and could show that the knockdown of betaArr2 inhibited ACHN cell invasion by 60% compared to control cells (Supplemental Fig.	('tested', 'Reg', (8, 14))	('inhibited', 'NegReg', (113, 122))	('ACHN', 'Gene', '55323', (123, 127))	('knockdown', 'Var', (91, 100))	('ACHN', 'Gene', (123, 127))	('betaArr2', 'Gene', (104, 112))
12494	29559707	3D-F) growth, the results showed that tumors from betaArr2ko clones grew significantly less, in comparison to tumors originating from control cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('grew', 'CPA', (68, 72))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('betaArr2ko', 'Var', (50, 60))	('less', 'NegReg', (87, 91))
12495	29559707	Macroscopic analysis of the sacrificed animals evidenced presence of metastatic growth throughout the viscera of mice harboring control SN12C tumors, but not in animals implanted with betaArr2ko SN12C cells (Supplemental Fig.	('metastatic growth', 'CPA', (69, 86))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('SN12C', 'Var', (136, 141))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('mice', 'Species', '10090', (113, 117))
12496	29559707	Concordantly, staining of kidney tissue sections with a human LDHA antibody revealed that tumors from betaArr2ko SN12C cells failed to invade through the cortex of the kidney, in contrast to control tumors where majority of the kidney cortex was infiltrated by the SN12C cells (Fig.	('antibody', 'cellular_component', 'GO:0042571', ('67', '75'))	('betaArr2ko', 'Var', (102, 112))	('antibody', 'cellular_component', 'GO:0019815', ('67', '75'))	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('antibody', 'cellular_component', 'GO:0019814', ('67', '75'))	('LDHA', 'Gene', (62, 66))	('LDHA', 'Gene', '3939', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('antibody', 'molecular_function', 'GO:0003823', ('67', '75'))	('human', 'Species', '9606', (56, 61))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('failed', 'NegReg', (125, 131))
12505	29559707	betaArr2ko caused fundamental changes in RCC cells, including the decreased rate of cell and tumor growth (Figs.	('betaArr2ko', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('decreased', 'NegReg', (66, 75))	('tumor', 'Disease', (93, 98))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
12509	29559707	To support the idea that betaArr2 impacts the cell cycle, control and betaArr2ko cells were stained with DAPI, that reflects DNA content, and analyzed 48 hr after seeding.	('cell cycle, control', 'biological_process', 'GO:1901987', ('46', '65'))	('betaArr2ko', 'Var', (70, 80))	('cell cycle', 'CPA', (46, 56))	('impacts', 'Reg', (34, 41))	('DNA', 'cellular_component', 'GO:0005574', ('125', '128'))	('DAPI', 'Chemical', 'MESH:C007293', (105, 109))
12512	29559707	Western blot analysis revealed that Cyclin A expression was reduced in betaArr2ko cells compared to the control cells (Fig.	('Cyclin A', 'Gene', (36, 44))	('expression', 'MPA', (45, 55))	('reduced', 'NegReg', (60, 67))	('Cyclin', 'molecular_function', 'GO:0016538', ('36', '42'))	('Cyclin A', 'Gene', '890', (36, 44))	('betaArr2ko', 'Var', (71, 81))
12514	29559707	These observations are consistent with our results showing that the cell cycle arrest observed in betaArr2ko cells is at the S/G2 check point (Fig.	('S/G2', 'Var', (125, 129))	('S/G2', 'SUBSTITUTION', 'None', (125, 129))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (68, 85))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('68', '85'))	('betaArr2ko', 'Var', (98, 108))	('cell cycle arrest', 'CPA', (68, 85))
12517	29559707	Indeed, we found that the knockout of betaArr2 blunts the activation, but not expression, of c-Src as evidenced by the decreased c-Src phosphorylation on Y416 (Fig.	('c-Src', 'Gene', (93, 98))	('blunts', 'NegReg', (47, 53))	('activation', 'MPA', (58, 68))	('decreased', 'NegReg', (119, 128))	('phosphorylation', 'biological_process', 'GO:0016310', ('135', '150'))	('c-Src', 'Gene', (129, 134))	('c-Src', 'Gene', '6714', (129, 134))	('knockout', 'Var', (26, 34))	('betaArr2', 'Gene', (38, 46))	('c-Src', 'Gene', '6714', (93, 98))
12524	29559707	Herein, we show that inhibition of betaArr2 attenuates c-Src activation, Cyclin A expression, and the ensuing cell cycle progression that controls the cell growth (Fig.	('activation', 'MPA', (61, 71))	('c-Src', 'Gene', (55, 60))	('Cyclin', 'molecular_function', 'GO:0016538', ('73', '79'))	('c-Src', 'Gene', '6714', (55, 60))	('expression', 'MPA', (82, 92))	('Cyclin A', 'Gene', '890', (73, 81))	('cell cycle progression', 'CPA', (110, 132))	('inhibition', 'Var', (21, 31))	('cell growth', 'biological_process', 'GO:0016049', ('151', '162'))	('betaArr2', 'Gene', (35, 43))	('cell cycle', 'biological_process', 'GO:0007049', ('110', '120'))	('Cyclin A', 'Gene', (73, 81))	('attenuates', 'NegReg', (44, 54))
12525	29559707	The knockout of betaArr2 inhibited the cell cycle progression and cell proliferation in vitro, and xenograft tumor formation in animals.	('cell cycle', 'biological_process', 'GO:0007049', ('39', '49'))	('cell proliferation', 'CPA', (66, 84))	('betaArr2', 'Gene', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('knockout', 'Var', (4, 12))	('cell cycle progression', 'CPA', (39, 61))	('formation', 'biological_process', 'GO:0009058', ('115', '124'))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('inhibited', 'NegReg', (25, 34))	('tumor', 'Disease', (109, 114))
12529	29559707	In addition to the regulation of c-Src activation that is critical for cell proliferation, the knockout of betaArr2 inhibited Cyclin A expression and cell cycle progression.	('cell proliferation', 'biological_process', 'GO:0008283', ('71', '89'))	('Cyclin', 'molecular_function', 'GO:0016538', ('126', '132'))	('cell cycle', 'biological_process', 'GO:0007049', ('150', '160'))	('Cyclin A', 'Gene', '890', (126, 134))	('knockout', 'Var', (95, 103))	('c-Src', 'Gene', (33, 38))	('inhibited', 'NegReg', (116, 125))	('regulation', 'biological_process', 'GO:0065007', ('19', '29'))	('c-Src', 'Gene', '6714', (33, 38))	('Cyclin A', 'Gene', (126, 134))	('cell cycle progression', 'CPA', (150, 172))	('betaArr2', 'Gene', (107, 115))
12534	29559707	However, VHL inactivation alone may not be sufficient to drive tumor formation as evidenced in genetically engineered Vhl-/- animal models.	('tumor', 'Disease', (63, 68))	('formation', 'biological_process', 'GO:0009058', ('69', '78'))	('inactivation', 'Var', (13, 25))	('VHL', 'Gene', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
12535	29559707	In addition to VHL inactivation, recent studies in mice have identified mutations in other genes, including cell cycle regulating genes, in the development of ccRCC.	('mutations', 'Var', (72, 81))	('mice', 'Species', '10090', (51, 55))	('RCC', 'Disease', (161, 164))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('cell cycle', 'biological_process', 'GO:0007049', ('108', '118'))
12536	29559707	Our study showed that knockout of betaArr2 inhibits the cell cycle programs and RCC xenograft tumor growth in mice, suggesting deregulated expression of betaArr2 may collaborate with disease-driving genetic mutations in the development of RCC.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('RCC', 'Disease', (80, 83))	('deregulated', 'Var', (127, 138))	('RCC xenograft tumor', 'Disease', (80, 99))	('betaArr2', 'Gene', (153, 161))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('mice', 'Species', '10090', (110, 114))	('knockout', 'Var', (22, 30))	('RCC', 'Disease', (239, 242))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (239, 242))	('cell cycle', 'biological_process', 'GO:0007049', ('56', '66'))	('RCC', 'Disease', 'MESH:C538614', (239, 242))	('RCC xenograft tumor', 'Disease', 'MESH:C538614', (80, 99))	('betaArr2', 'Gene', (34, 42))	('inhibits', 'NegReg', (43, 51))	('cell cycle programs', 'CPA', (56, 75))
12537	29559707	In a recent study, it was reported that ccRCC can develop in mice with deletion of Vhl, Trp53 and Rb1 genes, but inactivation of Trp53 and Rb1 is rare in human ccRCC.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('human', 'Species', '9606', (154, 159))	('RCC', 'Disease', (162, 165))	('Trp53', 'Gene', '22059', (88, 93))	('mice', 'Species', '10090', (61, 65))	('Trp53', 'Gene', '22059', (129, 134))	('RCC', 'Phenotype', 'HP:0005584', (162, 165))	('Rb1', 'Gene', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('deletion', 'Var', (71, 79))	('Rb1', 'Gene', (98, 101))	('Rb1', 'Gene', '19645', (98, 101))	('Rb1', 'Gene', '19645', (139, 142))	('Trp53', 'Gene', (129, 134))	('Trp53', 'Gene', (88, 93))	('Vhl', 'Gene', (83, 86))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))
12538	29559707	It is worth mentioning that tumor tissues from the Vhl/Trp53/Rb1 mouse expressed recurrent mutations in other genes, including Kif3a, and betaArr2 appears to regulate Kif3a function and cilium formation.	('Kif3a', 'Gene', '16568', (167, 172))	('tumor', 'Disease', (28, 33))	('cilium formation', 'CPA', (186, 202))	('mouse', 'Species', '10090', (65, 70))	('Trp53', 'Gene', (55, 60))	('cilium', 'cellular_component', 'GO:0005929', ('186', '192'))	('Kif3a', 'Gene', '16568', (127, 132))	('cilium formation', 'biological_process', 'GO:0060271', ('186', '202'))	('Rb1', 'Gene', '19645', (61, 64))	('Kif3a', 'Gene', (167, 172))	('mutations', 'Var', (91, 100))	('regulate', 'Reg', (158, 166))	('Rb1', 'Gene', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('Trp53', 'Gene', '22059', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('Kif3a', 'Gene', (127, 132))	('function', 'MPA', (173, 181))
12540	29559707	Our bioinformatics analyses revealed an association between increased expression of betaArr2, and not betaArr1, in RCC, implying functional specificity among the two related proteins.	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('increased', 'PosReg', (60, 69))	('expression', 'MPA', (70, 80))	('betaArr2', 'Var', (84, 92))
12544	29559707	Inhibition of betaArr2 expression reduced localized and metastatic RCC tumor growth.	('reduced', 'NegReg', (34, 41))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC tumor', 'Disease', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Inhibition', 'Var', (0, 10))	('RCC tumor', 'Disease', 'MESH:C538614', (67, 76))	('betaArr2', 'Gene', (14, 22))
12546	29559707	Antibodies were obtained as follows: anti-betaArr1/2 (D24H9), anti-betaArr2 (C16D9), anti-human LDHA (3582), anti-phospho-Src (Y416) (D49G4), anti-Src (36D10), anti-Cyclin D1 (92G2), anti-GAPDH (2118S), and Signal Stain Boost IHC detection reagent from Cell Signaling; anti-human Ki67 (ab92742); anti-Actin (ab3280) from Abcam; anti-HSP90 (610419) from Fischer; anti-Cyclin A (H-432) from Santa Cruz Biotechnology; anti-Flag M2 (F3165) from Sigma; and HRP-coupled anti-rabbit (711-035-152) or anti-mouse (715-035-150) from Jackson Immuno Research Laboratories.	('GAPDH', 'Gene', (188, 193))	('LDHA', 'Gene', (96, 100))	('Src', 'Gene', '6714', (122, 125))	('human', 'Species', '9606', (90, 95))	('Cyclin', 'molecular_function', 'GO:0016538', ('165', '171'))	('Cyclin A', 'Gene', (367, 375))	('HSP90', 'Gene', (333, 338))	('mouse', 'Species', '10090', (498, 503))	('Cyclin D1', 'Gene', '595', (165, 174))	('betaArr1/2', 'Gene', (42, 52))	('Cyclin', 'molecular_function', 'GO:0016538', ('367', '373'))	('Cyclin D1', 'Gene', (165, 174))	('Cyclin A', 'Gene', '890', (367, 375))	('HSP90', 'Gene', '3320', (333, 338))	('Src', 'Gene', (147, 150))	('LDHA', 'Gene', '3939', (96, 100))	('rabbit', 'Species', '9986', (469, 475))	('Signaling', 'biological_process', 'GO:0023052', ('258', '267'))	('GAPDH', 'Gene', '2597', (188, 193))	('betaArr1/2', 'Gene', '409', (42, 52))	('Src', 'Gene', (122, 125))	('Src', 'Gene', '6714', (147, 150))	('610419', 'Var', (340, 346))	('human', 'Species', '9606', (274, 279))
12554	29559707	The primers used for gene amplification of human 18S (QT00199367), ARRB1 (QT00071197) and ARRB2 (QT00058051) were obtained from Qiagen.	('QT00199367', 'Var', (54, 64))	('ARRB1', 'Gene', (67, 72))	('ARRB1', 'Gene', '408', (67, 72))	('QT00071197', 'Var', (74, 84))	('QT00058051', 'Var', (97, 107))	('ARRB2', 'Gene', '409', (90, 95))	('ARRB2', 'Gene', (90, 95))	('human', 'Species', '9606', (43, 48))
12574	33380840	The deletion of HCP5 inhibited the proliferation, migration and invasion of RCC in vitro and the metastasis of RCC in vivo.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('HCP5', 'Gene', '10866', (16, 20))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('metastasis of', 'CPA', (97, 110))	('proliferation', 'CPA', (35, 48))	('HCP5', 'Gene', (16, 20))	('migration', 'CPA', (50, 59))	('invasion', 'CPA', (64, 72))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('deletion', 'Var', (4, 12))	('inhibited', 'NegReg', (21, 30))
12592	33380840	We predicted the latent specific binding of HCP5 to miR to further explore the mechanism of HCP5 and found that miR-214-3p had specific binding with HCP5.	('HCP5', 'Gene', (149, 153))	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('HCP5', 'Gene', '10866', (44, 48))	('HCP5', 'Gene', '10866', (92, 96))	('HCP5', 'Gene', (44, 48))	('HCP5', 'Gene', (92, 96))	('miR-214-3p', 'Chemical', '-', (112, 122))	('binding', 'molecular_function', 'GO:0005488', ('136', '143'))	('miR-214-3p', 'Var', (112, 122))	('HCP5', 'Gene', '10866', (149, 153))	('binding', 'Interaction', (136, 143))
12593	33380840	Previous studies have revealed that miR-214-3p acts in neoplasm invasion, so we speculate that there might be a regulatory relationship between HCP5 and miR-214-3p.	('neoplasm invasion', 'Disease', 'MESH:D009361', (55, 72))	('neoplasm', 'Phenotype', 'HP:0002664', (55, 63))	('miR-214-3p', 'Chemical', '-', (153, 163))	('miR-214-3p', 'Chemical', '-', (36, 46))	('HCP5', 'Gene', '10866', (144, 148))	('HCP5', 'Gene', (144, 148))	('neoplasm invasion', 'Disease', (55, 72))	('miR-214-3p', 'Var', (36, 46))
12642	33380840	We predicted the latent miR of HCP5, and found that there was a targeting relationship of miR-214-3p with HCP5 (Figure 3A), and miR-214-3p was enhanced in transfected cells by qRT-PCR (Figure 3B).	('HCP5', 'Gene', (31, 35))	('qRT-PCR', 'Var', (176, 183))	('miR-214-3p', 'Chemical', '-', (128, 138))	('enhanced', 'PosReg', (143, 151))	('miR-214-3p', 'Chemical', '-', (90, 100))	('miR-214-3p', 'Var', (90, 100))	('miR-214-3p', 'Var', (128, 138))	('HCP5', 'Gene', '10866', (106, 110))	('HCP5', 'Gene', (106, 110))	('HCP5', 'Gene', '10866', (31, 35))
12643	33380840	Furthermore, the targeting correlation of HCP5 with miR-214-3p was verified by double luciferase and RIP experiments (Figure 3C-D).	('HCP5', 'Gene', (42, 46))	('miR-214-3p', 'Chemical', '-', (52, 62))	('HCP5', 'Gene', '10866', (42, 46))	('miR-214-3p', 'Var', (52, 62))
12644	33380840	Furthermore, we found that miR-214-3p was low expressed in neoplasm tissues of patients with ccRCC by qRT-PCR (Figure 3E) and was negatively correlated with HCP5 (Figure 3F).	('correlated', 'Reg', (141, 151))	('neoplasm', 'Disease', (59, 67))	('neoplasm', 'Phenotype', 'HP:0002664', (59, 67))	('miR-214-3p', 'Var', (27, 37))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('neoplasm', 'Disease', 'MESH:D009369', (59, 67))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('RCC', 'Disease', (95, 98))	('HCP5', 'Gene', '10866', (157, 161))	('HCP5', 'Gene', (157, 161))	('negatively', 'NegReg', (130, 140))	('low', 'NegReg', (42, 45))	('patients', 'Species', '9606', (79, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('miR-214-3p', 'Chemical', '-', (27, 37))
12646	33380840	MAPK1 is predicted to be a latent target of miR-214-3p through TargetScan, starbase, Tarbase and miRDB websites.	('MAPK1', 'Gene', (0, 5))	('MAPK', 'molecular_function', 'GO:0004707', ('0', '4'))	('miR-214-3p', 'Chemical', '-', (44, 54))	('MAPK1', 'Gene', '5594', (0, 5))	('miR-214-3p', 'Var', (44, 54))
12647	33380840	In order to verify the targeting relationship between them (Figure 4A), it was proved by double luciferase report experiment that miR-214-3p-mimics could inhibit the fluorescence activity of MAPK1-wt (Figure 4B).	('MAPK', 'molecular_function', 'GO:0004707', ('191', '195'))	('miR-214-3p-mimics', 'Var', (130, 147))	('inhibit', 'NegReg', (154, 161))	('MAPK1', 'Gene', '5594', (191, 196))	('miR-214-3p', 'Chemical', '-', (130, 140))	('fluorescence activity', 'MPA', (166, 187))	('MAPK1', 'Gene', (191, 196))
12651	33380840	Therefore, HCP5 can mediate miR-214-3p to affect MAPK1.	('affect', 'Reg', (42, 48))	('MAPK', 'molecular_function', 'GO:0004707', ('49', '53'))	('miR-214-3p', 'Var', (28, 38))	('MAPK1', 'Gene', '5594', (49, 54))	('MAPK1', 'Gene', (49, 54))	('miR-214-3p', 'Chemical', '-', (28, 38))	('HCP5', 'Gene', '10866', (11, 15))	('HCP5', 'Gene', (11, 15))
12653	33380840	The experiment found that pcDNA-3.1-HCP5 inhibited the proliferation and invasion of RCC cells by miR-214-3p-mimics (Figure 5A-B), and reduced apoptosis (Figure 5C).	('miR-214-3p-mimics', 'Var', (98, 115))	('HCP5', 'Gene', '10866', (36, 40))	('HCP5', 'Gene', (36, 40))	('proliferation', 'CPA', (55, 68))	('miR-214-3p', 'Chemical', '-', (98, 108))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('reduced', 'NegReg', (135, 142))	('RCC', 'Disease', (85, 88))	('apoptosis', 'CPA', (143, 152))	('inhibited', 'NegReg', (41, 50))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))
12654	33380840	While si-HCP5#1 inhibited miR-214-3p-inhibit from promoting proliferation and invasion, and promoted apoptosis.	('miR-214-3p-inhibit', 'Var', (26, 44))	('inhibited', 'NegReg', (16, 25))	('HCP5', 'Gene', '10866', (9, 13))	('HCP5', 'Gene', (9, 13))	('invasion', 'CPA', (78, 86))	('promoted', 'PosReg', (92, 100))	('apoptosis', 'biological_process', 'GO:0097194', ('101', '110'))	('promoting', 'PosReg', (50, 59))	('miR-214-3p', 'Chemical', '-', (26, 36))	('apoptosis', 'biological_process', 'GO:0006915', ('101', '110'))	('apoptosis', 'CPA', (101, 110))
12655	33380840	These experiments can prove that HCP5 can regulate MAPK1 to change the progression and metastasis of RCC through miR-214-3p.	('HCP5', 'Gene', '10866', (33, 37))	('change', 'Reg', (60, 66))	('MAPK1', 'Gene', '5594', (51, 56))	('metastasis', 'CPA', (87, 97))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('HCP5', 'Gene', (33, 37))	('RCC', 'Disease', (101, 104))	('MAPK', 'molecular_function', 'GO:0004707', ('51', '55'))	('MAPK1', 'Gene', (51, 56))	('miR-214-3p', 'Chemical', '-', (113, 123))	('progression', 'CPA', (71, 82))	('miR-214-3p', 'Var', (113, 123))
12663	33380840	Later, we found that HCP5 can hinder the progression of RCC in vitro, and FACS detection also found that the apoptosis rate increased after knocking down HCP5.	('knocking down', 'Var', (140, 153))	('hinder', 'NegReg', (30, 36))	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('increased', 'PosReg', (124, 133))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('apoptosis rate', 'CPA', (109, 123))	('HCP5', 'Gene', '10866', (154, 158))	('progression', 'CPA', (41, 52))	('HCP5', 'Gene', '10866', (21, 25))	('HCP5', 'Gene', (154, 158))	('HCP5', 'Gene', (21, 25))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))
12667	33380840	In this research, it was revealed that miR-214-3p and HCP5 have targeted binding sites by analyzing the binding of HCP5 to miR.	('HCP5', 'Gene', '10866', (54, 58))	('HCP5', 'Gene', (54, 58))	('HCP5', 'Gene', (115, 119))	('miR-214-3p', 'Chemical', '-', (39, 49))	('binding', 'Interaction', (73, 80))	('binding', 'Interaction', (104, 111))	('binding', 'molecular_function', 'GO:0005488', ('104', '111'))	('miR-214-3p', 'Var', (39, 49))	('HCP5', 'Gene', '10866', (115, 119))	('binding', 'molecular_function', 'GO:0005488', ('73', '80'))
12668	33380840	miR-214-3p is a short-chain non-coding RNA discovered in the early stage, which has low expression in various neoplasms such as lung carcinoma and colon carcinoma, and is a neoplasm suppressor gene.	('neoplasms', 'Phenotype', 'HP:0002664', (110, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('neoplasm', 'Phenotype', 'HP:0002664', (173, 181))	('colon carcinoma', 'Disease', 'MESH:D003110', (147, 162))	('expression', 'MPA', (88, 98))	('lung carcinoma', 'Disease', 'MESH:D008175', (128, 142))	('neoplasm', 'Disease', 'MESH:D009369', (110, 118))	('neoplasms', 'Disease', 'MESH:D009369', (110, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('neoplasm', 'Disease', (110, 118))	('miR-214-3p', 'Var', (0, 10))	('neoplasms', 'Disease', (110, 119))	('neoplasm', 'Disease', 'MESH:D009369', (173, 181))	('miR-214-3p', 'Chemical', '-', (0, 10))	('lung carcinoma', 'Disease', (128, 142))	('colon carcinoma', 'Disease', (147, 162))	('neoplasm', 'Phenotype', 'HP:0002664', (110, 118))	('neoplasm', 'Disease', (173, 181))	('RNA', 'cellular_component', 'GO:0005562', ('39', '42'))
12670	33380840	We also found that miR-214-3p was reduced in ccRCC neoplasms, which verified each other.	('reduced', 'NegReg', (34, 41))	('neoplasm', 'Phenotype', 'HP:0002664', (51, 59))	('ccRCC neoplasms', 'Disease', (45, 60))	('miR-214-3p', 'Chemical', '-', (19, 29))	('neoplasms', 'Phenotype', 'HP:0002664', (51, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('ccRCC neoplasms', 'Disease', 'MESH:D009369', (45, 60))	('miR-214-3p', 'Var', (19, 29))
12671	33380840	In addition, there was a correlation of miR-214-3p with HCP5 in ccRCC by correlation analysis.	('HCP5', 'Gene', (56, 60))	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('correlation', 'Interaction', (25, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('miR-214-3p', 'Chemical', '-', (40, 50))	('miR-214-3p', 'Var', (40, 50))	('RCC', 'Disease', (66, 69))	('HCP5', 'Gene', '10866', (56, 60))
12673	33380840	In order to further determine the in-depth mechanism of HCP5, we predicted the target gene of miR-214-3p, and found that there was targeted binding of MAPK1 with miR-214-3p.	('HCP5', 'Gene', (56, 60))	('miR-214-3p', 'Chemical', '-', (162, 172))	('MAPK1', 'Gene', '5594', (151, 156))	('miR-214-3p', 'Chemical', '-', (94, 104))	('binding', 'molecular_function', 'GO:0005488', ('140', '147'))	('binding', 'Interaction', (140, 147))	('miR-214-3p', 'Var', (162, 172))	('miR-214-3p', 'Var', (94, 104))	('MAPK1', 'Gene', (151, 156))	('MAPK', 'molecular_function', 'GO:0004707', ('151', '155'))	('HCP5', 'Gene', '10866', (56, 60))
12676	33380840	miR-214-3p-mimics/inhibit can inhibit or promote the fluorescence activity of MAPK1-wt, indicating that miR-214-3p can regulate MAPK1 in a targeted way.	('MAPK1', 'Gene', (78, 83))	('miR-214-3p', 'Chemical', '-', (0, 10))	('MAPK', 'molecular_function', 'GO:0004707', ('128', '132'))	('regulate', 'Reg', (119, 127))	('inhibit', 'NegReg', (30, 37))	('miR-214-3p', 'Chemical', '-', (104, 114))	('MAPK1', 'Gene', '5594', (128, 133))	('MAPK', 'molecular_function', 'GO:0004707', ('78', '82'))	('promote', 'PosReg', (41, 48))	('MAPK1', 'Gene', '5594', (78, 83))	('miR-214-3p-mimics/inhibit', 'NegReg', (0, 25))	('miR-214-3p-mimics/inhibit', 'Var', (0, 25))	('MAPK1', 'Gene', (128, 133))	('fluorescence activity', 'MPA', (53, 74))
12677	33380840	After co-transfection, we found that miR-214-3p-mimics inhibited MAPK1 mRNA and protein in RCC cells, while transfection of si-HCP5#1 inhibited the promotion of miR-214-3p-inhibit on MAPK1 mRNA and protein in RCC cells.	('miR-214-3p-mimics', 'Var', (37, 54))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('HCP5', 'Gene', '10866', (127, 131))	('RCC', 'Disease', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (209, 212))	('protein', 'cellular_component', 'GO:0003675', ('198', '205'))	('RCC', 'Disease', (209, 212))	('MAPK1', 'Gene', '5594', (183, 188))	('MAPK1', 'Gene', (65, 70))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', 'MESH:C538614', (209, 212))	('MAPK', 'molecular_function', 'GO:0004707', ('183', '187'))	('miR-214-3p', 'Chemical', '-', (161, 171))	('HCP5', 'Gene', (127, 131))	('MAPK1', 'Gene', (183, 188))	('inhibited', 'NegReg', (134, 143))	('miR-214-3p', 'Chemical', '-', (37, 47))	('MAPK', 'molecular_function', 'GO:0004707', ('65', '69'))	('inhibited', 'NegReg', (55, 64))	('MAPK1', 'Gene', '5594', (65, 70))
12679	33380840	Therefore, HCP5 could regulate MAPK1 to change the growth of RCC through miR-214-3p.	('change', 'Reg', (40, 46))	('MAPK1', 'Gene', '5594', (31, 36))	('miR-214-3p', 'Chemical', '-', (73, 83))	('MAPK', 'molecular_function', 'GO:0004707', ('31', '35'))	('miR-214-3p', 'Var', (73, 83))	('MAPK1', 'Gene', (31, 36))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('growth', 'MPA', (51, 57))	('HCP5', 'Gene', '10866', (11, 15))	('HCP5', 'Gene', (11, 15))
12683	32547941	Analysis of Genetic Alteration Signatures and Prognostic Values of m6A Regulatory Genes in Head and Neck Squamous Cell Carcinoma Genetic alteration involving N6-methyladenosine (m6A) regulatory genes is a frequent characteristic of multiple tumors.	('Genetic alteration', 'Var', (129, 147))	('m6A', 'Gene', (67, 70))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (158, 176))	('Carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('tumors', 'Disease', (241, 247))	('Neck Squamous Cell Carcinoma', 'Disease', (100, 128))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('alteration', 'Var', (137, 147))	('Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (100, 128))	('m6A', 'Gene', '56339', (67, 70))	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (91, 128))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('m6A', 'Gene', (178, 181))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('m6A', 'Gene', '56339', (178, 181))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
12687	32547941	The results suggest that alteration of m6A regulatory genes was correlated with clinical staging.	('m6A', 'Gene', '56339', (39, 42))	('alteration', 'Var', (25, 35))	('m6A', 'Gene', (39, 42))	('correlated', 'Reg', (64, 74))
12688	32547941	Patients with high expression of ALKBH5, FTO, METTL14, WTAP, YTHDC1, YTHDF1, and YTHDF2 had poor overall survival (OS) than those with low expression.	('YTHDF2', 'Gene', '51441', (81, 87))	('YTHDC1', 'Gene', '91746', (61, 67))	('YTHDF1', 'Gene', (69, 75))	('FTO', 'Gene', '79068', (41, 44))	('ALKBH5', 'Gene', '54890', (33, 39))	('overall survival', 'MPA', (97, 113))	('WTAP', 'Gene', '9589', (55, 59))	('YTHDF2', 'Gene', (81, 87))	('WTAP', 'Gene', (55, 59))	('poor', 'NegReg', (92, 96))	('ALKBH5', 'Gene', (33, 39))	('Patients', 'Species', '9606', (0, 8))	('FTO', 'Gene', (41, 44))	('high expression', 'Var', (14, 29))	('METTL14', 'Gene', (46, 53))	('YTHDC1', 'Gene', (61, 67))	('YTHDF1', 'Gene', '54915', (69, 75))	('METTL14', 'Gene', '57721', (46, 53))
12690	32547941	However, patients with high YTHDC2 expression had better OS.	('patients', 'Species', '9606', (9, 17))	('better', 'PosReg', (50, 56))	('high YTHDC2 expression', 'Var', (23, 45))
12692	32547941	Here, we identified alterations to m6A regulatory genes in HNSCC for the first time and found that seven m6A regulators were associated with poor prognosis, especially ALKBH5, whereas YTHDC2 was associated with better prognosis.	('m6A', 'Gene', (35, 38))	('alterations', 'Var', (20, 31))	('m6A', 'Gene', '56339', (35, 38))	('m6A', 'Gene', (105, 108))	('associated', 'Reg', (125, 135))	('m6A', 'Gene', '56339', (105, 108))	('ALKBH5', 'Gene', '54890', (168, 174))	('HNSCC', 'Phenotype', 'HP:0012288', (59, 64))	('ALKBH5', 'Gene', (168, 174))	('HNSCC', 'Disease', (59, 64))
12708	32547941	Emerging evidence shows that m6A modification is related to tumor proliferation, differentiation, occurrence, invasion, and metastasis and plays the role of oncogene or antioncogenes in malignant tumors.	('modification', 'Var', (33, 45))	('malignant tumors', 'Disease', (186, 202))	('malignant tumors', 'Disease', 'MESH:D009369', (186, 202))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', (196, 201))	('metastasis', 'CPA', (124, 134))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('m6A', 'Gene', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('related', 'Reg', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('invasion', 'CPA', (110, 118))	('tumor', 'Disease', (60, 65))	('m6A', 'Gene', '56339', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
12712	32547941	The deletion of m6A methyltransferase METTL3 leads to selective splicing and gene expression alteration of >20 genes involved in the TP53 signaling pathway in hepatocellular carcinoma (HCC).	('gene expression', 'MPA', (77, 92))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (159, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('gene expression', 'biological_process', 'GO:0010467', ('77', '92'))	('alteration', 'Reg', (93, 103))	('m6A', 'Gene', (16, 19))	('METTL3', 'Gene', (38, 44))	('splicing', 'MPA', (64, 72))	('hepatocellular carcinoma', 'Disease', (159, 183))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (159, 183))	('METTL3', 'Gene', '56339', (38, 44))	('splicing', 'biological_process', 'GO:0045292', ('64', '72'))	('TP53 signaling pathway', 'biological_process', 'GO:0030330', ('133', '155'))	('m6A', 'Gene', '56339', (16, 19))	('deletion', 'Var', (4, 12))	('TP53', 'Gene', '7157', (133, 137))	('HCC', 'Phenotype', 'HP:0001402', (185, 188))	('TP53', 'Gene', (133, 137))
12717	32547941	SNP analysis was based on VarScan2 variant aggregation and masking data in TCGA, in particular for mutation analysis of 10 m6A regulatory genes.	('m6A', 'Gene', (123, 126))	('variant', 'Var', (35, 42))	('TCGA', 'Gene', (75, 79))	('m6A', 'Gene', '56339', (123, 126))
12729	32547941	Briefly, paraffin sections were dewaxed, and endogenous peroxidase activity was blocked with 0.3% hydrogen peroxide for 10 min at 37 C. Following antigen retrieval, the tissue sections were incubated with primary antibody YTHDC2 (1:500; EPR21820-49, AB220160; Abcam, Inc., Cambridge, MA, USA) or ALKBH5 (1:2000; EPR18958, ab195377, Abcam, Inc.) at 4 C overnight and then with a secondary antibody at room temperature (25 C) overnight.	('ALKBH5', 'Gene', (296, 302))	('antibody', 'cellular_component', 'GO:0019814', ('213', '221'))	('antibody', 'cellular_component', 'GO:0042571', ('388', '396'))	('antibody', 'molecular_function', 'GO:0003823', ('213', '221'))	('1:2000; EPR18958', 'Var', (304, 320))	('antibody', 'cellular_component', 'GO:0019814', ('388', '396'))	('antibody', 'cellular_component', 'GO:0019815', ('388', '396'))	('peroxidase activity', 'molecular_function', 'GO:0004601', ('56', '75'))	('paraffin', 'Chemical', 'MESH:D010232', (9, 17))	('antibody', 'cellular_component', 'GO:0042571', ('213', '221'))	('antibody', 'molecular_function', 'GO:0003823', ('388', '396'))	('ALKBH5', 'Gene', '54890', (296, 302))	('antibody', 'cellular_component', 'GO:0019815', ('213', '221'))
12731	32547941	Of the 506 patients with sequencing data used for SNP mutation analysis, only 41 (8.1%) of the samples had mutation events in any of the 10 m6A regulatory genes as shown in Figure 1.	('patients', 'Species', '9606', (11, 19))	('mutation', 'Var', (107, 115))	('m6A', 'Gene', '56339', (140, 143))	('m6A', 'Gene', (140, 143))
12742	32547941	Additionally, SNP analysis revealed that the most frequent variant classification of m6A regulatory gene mutation was missense mutation, and the largest number of variant types was SNP (Figure S1).	('m6A', 'Gene', '56339', (85, 88))	('m6A', 'Gene', (85, 88))	('mutation', 'Var', (105, 113))	('missense mutation', 'Var', (118, 135))
12743	32547941	The most obvious mutations involved TP53 as mentioned before (66%) and TTN (35%).	('TTN', 'Gene', '7273', (71, 74))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (36, 40))	('TTN', 'Gene', (71, 74))	('mutations', 'Var', (17, 26))
12744	32547941	We then evaluated the relationship between CNV alterations in 10 m6A regulatory genes and clinicopathological features of HNSCC patients.	('m6A', 'Gene', '56339', (65, 68))	('HNSCC', 'Phenotype', 'HP:0012288', (122, 127))	('HNSCC', 'Disease', (122, 127))	('alterations', 'Var', (47, 58))	('patients', 'Species', '9606', (128, 136))	('m6A', 'Gene', (65, 68))
12746	32547941	The results showed that alterations to m6A regulatory genes were significantly related to age, gender, and clinical stage (P < 0.05) (Table 1).	('related', 'Reg', (79, 86))	('m6A', 'Gene', '56339', (39, 42))	('alterations', 'Var', (24, 35))	('m6A', 'Gene', (39, 42))
12749	32547941	With CNV events from deletion to amplification, gene expression of the 10 m6A regulatory genes also showed an upward trend; that is, gene expression increased with increased CNV amplification and decreased with CNV deletion.	('gene expression', 'biological_process', 'GO:0010467', ('48', '63'))	('CNV amplification', 'Var', (174, 191))	('decreased', 'NegReg', (196, 205))	('increased', 'PosReg', (149, 158))	('gene expression', 'MPA', (133, 148))	('m6A', 'Gene', (74, 77))	('deletion', 'Var', (21, 29))	('m6A', 'Gene', '56339', (74, 77))	('gene expression', 'biological_process', 'GO:0010467', ('133', '148'))
12758	32547941	Combined with the results of the previous analysis (Figure 2A), among the 10 genes, the incidence of CNV events involving YTHDC2 was second only to YTHDF3, and YTHDC2 gene expression and survival prognosis results were also significant.	('YTHDC2', 'Var', (122, 128))	('YTHDF3', 'Gene', (148, 154))	('gene expression', 'biological_process', 'GO:0010467', ('167', '182'))	('YTHDF3', 'Gene', '253943', (148, 154))
12763	32547941	GSEA analysis implied that high expression of YTHDC2 is associated with certain key pathways, such as apoptosis, ubiquitin-mediated proteolysis, long-term potentiation, and rig-i-like receptor signaling pathways, revealing the underlying mechanisms involved in HNSCC pathogenesis (Figure 9).	('pathogenesis', 'biological_process', 'GO:0009405', ('267', '279'))	('long-term potentiation', 'biological_process', 'GO:0060291', ('145', '167'))	('HNSCC', 'Disease', (261, 266))	('ubiquitin', 'molecular_function', 'GO:0031386', ('113', '122'))	('HNSCC', 'Phenotype', 'HP:0012288', (261, 266))	('key pathways', 'Pathway', (80, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('102', '111'))	('apoptosis', 'MPA', (102, 111))	('rig-i-like receptor signaling pathways', 'Pathway', (173, 211))	('apoptosis', 'biological_process', 'GO:0006915', ('102', '111'))	('associated', 'Reg', (56, 66))	('proteolysis', 'biological_process', 'GO:0006508', ('132', '143'))	('long-term potentiation', 'MPA', (145, 167))	('high expression', 'Var', (27, 42))	('signaling', 'biological_process', 'GO:0023052', ('193', '202'))	('ubiquitin-mediated proteolysis', 'MPA', (113, 143))	('GSEA', 'Chemical', '-', (0, 4))	('YTHDC2', 'Gene', (46, 52))
12777	32547941	In the ccRCC cohort, m6A regulatory gene alterations were significantly related to higher Fuhrman nuclear grading.	('m6A', 'Gene', '56339', (21, 24))	('ccRCC', 'Phenotype', 'HP:0006770', (7, 12))	('higher Fuhrman nuclear grading', 'CPA', (83, 113))	('related', 'Reg', (72, 79))	('m6A', 'Gene', (21, 24))	('alterations', 'Var', (41, 52))
12779	32547941	In our HNSCC samples, the alterations to m6A regulatory genes were significantly correlated with age, sex, and clinical stage.	('m6A', 'Gene', '56339', (41, 44))	('HNSCC', 'Phenotype', 'HP:0012288', (7, 12))	('alterations', 'Var', (26, 37))	('correlated', 'Reg', (81, 91))	('m6A', 'Gene', (41, 44))
12780	32547941	This indicated that alterations in m6A CNV may show different clinical characteristics in different tumors.	('m6A', 'Gene', (35, 38))	('alterations', 'Var', (20, 31))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('m6A', 'Gene', '56339', (35, 38))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))
12787	32547941	In HNSCC cases, we observed longer OS with diploid or copy number gain, which is different from the situation in AML but similar to that of ccRCC.	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('copy number', 'Var', (54, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('gain', 'PosReg', (66, 70))	('AML', 'Disease', 'MESH:D015470', (113, 116))	('AML', 'Phenotype', 'HP:0004808', (113, 116))	('AML', 'Disease', (113, 116))	('diploid', 'Var', (43, 50))	('HNSCC', 'Disease', (3, 8))
12797	32547941	The translation efficiency of Smc3 (target YTHDC2 in spermatogenesis) is significantly decreased in YTHDC2-/- mice compared to YTHDC2 +/+ animals.	('Smc3', 'Gene', '13006', (30, 34))	('spermatogenesis', 'biological_process', 'GO:0007283', ('53', '68'))	('decreased', 'NegReg', (87, 96))	('Smc', 'cellular_component', 'GO:0016029', ('30', '33'))	('mice', 'Species', '10090', (110, 114))	('Smc3', 'Gene', (30, 34))	('YTHDC2-/-', 'Var', (100, 109))	('translation', 'MPA', (4, 15))	('translation', 'biological_process', 'GO:0006412', ('4', '15'))
12798	32547941	In addition, the testes and epididymis from adult YTHDC2-/- mice are smaller in size than wild type (YTHDC2 +/+).	('smaller', 'NegReg', (69, 76))	('mice', 'Species', '10090', (60, 64))	('YTHDC2-/-', 'Var', (50, 59))
12809	32547941	The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2020.00718/full#supplementary-material m6A N6-methyladenosine HNSCC head and neck squamous cell carcinoma CNV copy number variation TCGA The Cancer Genome Atlas GEO Gene Expression Omnibus ccRCC clear cell renal cell carcinoma AML acute myeloid leukemia OS overall survival GSEA gene set enrichment analysis IHC immunohistochemistry.	('AML', 'Disease', 'MESH:D015470', (345, 348))	('clear cell renal cell carcinoma', 'Disease', (313, 344))	('GSEA', 'Chemical', '-', (392, 396))	('AML', 'Disease', (345, 348))	('AML', 'Phenotype', 'HP:0004808', (345, 348))	('acute myeloid leukemia', 'Disease', (349, 371))	('carcinoma', 'Phenotype', 'HP:0030731', (335, 344))	('leukemia', 'Phenotype', 'HP:0001909', (363, 371))	('Cancer', 'Disease', 'MESH:D009369', (259, 265))	('m6A', 'Gene', '56339', (157, 160))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (186, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (313, 344))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (355, 371))	('m6A', 'Gene', (157, 160))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (349, 371))	('Gene Expression', 'biological_process', 'GO:0010467', ('283', '298'))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (349, 371))	('Cancer', 'Phenotype', 'HP:0002664', (259, 265))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (324, 344))	('neck squamous cell carcinoma', 'Disease', (195, 223))	('copy number variation', 'Var', (228, 249))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (313, 344))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (200, 223))	('HNSCC', 'Phenotype', 'HP:0012288', (180, 185))	('neck', 'cellular_component', 'GO:0044326', ('195', '199'))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (195, 223))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (161, 179))	('Cancer', 'Disease', (259, 265))	('ccRCC', 'Phenotype', 'HP:0006770', (307, 312))
12812	33552650	The data, presented during the Plenary Program of the ASCO20 Virtual Scientific Program, indicated the survival benefit among all patients enrolled in the trial, in patients who were PD-L1 positive, and in all prespecified subgroups.	('PD-L1', 'Gene', (183, 188))	('survival benefit', 'CPA', (103, 119))	('positive', 'Var', (189, 197))	('patients', 'Species', '9606', (130, 138))	('patients', 'Species', '9606', (165, 173))
12845	33552650	In an international trial, treatment with MK-6482, a small-molecule inhibitor of hypoxia-inducible factor (HIF)-2a, was well tolerated and resulted in clinical responses for patients with von Hippel-Lindau disease-associated renal cell carcinoma (RCC).	('MK-6482', 'Chemical', '-', (42, 49))	('von Hippel-Lindau disease-associated renal cell carcinoma', 'Disease', 'MESH:D006623', (188, 245))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (225, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('patients', 'Species', '9606', (174, 182))	('RCC', 'Phenotype', 'HP:0005584', (247, 250))	('hypoxia-inducible factor (HIF)-2a', 'Gene', '2034', (81, 114))	('MK-6482', 'Var', (42, 49))	('RCC', 'Disease', 'MESH:C538614', (247, 250))	('RCC', 'Disease', (247, 250))
12849	33552650	The VHL mutation causes cells to lose their ability to respond to oxygen levels properly and leads to a buildup of HIF proteins inside the tumor cell.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('HIF proteins', 'Disease', 'MESH:D018455', (115, 127))	('VHL', 'Gene', '7428', (4, 7))	('ability', 'MPA', (44, 51))	('lose', 'NegReg', (33, 37))	('HIF proteins', 'Disease', (115, 127))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('leads to', 'Reg', (93, 101))	('oxygen', 'Chemical', 'MESH:D010100', (66, 72))	('VHL', 'Gene', (4, 7))	('mutation', 'Var', (8, 16))	('buildup of', 'MPA', (104, 114))	('respond to oxygen levels', 'MPA', (55, 79))
12851	33552650	The inactivation of the VHL tumor-suppressor protein is also observed in more than 90% of sporadic RCC tumors.	('VHL tumor', 'Disease', 'MESH:D006623', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('inactivation', 'Var', (4, 16))	('sporadic RCC tumors', 'Disease', 'MESH:C538614', (90, 109))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('28', '44'))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('VHL tumor', 'Disease', (24, 33))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('28', '44'))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('sporadic RCC tumors', 'Disease', (90, 109))
12852	33552650	MK-6482 directly targets HIF-2a, hindering cancer cell growth, spread, and abnormal blood vessel development.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('MK-6482', 'Chemical', '-', (0, 7))	('blood vessel development', 'biological_process', 'GO:0001568', ('84', '108'))	('HIF-2a', 'Gene', (25, 31))	('cancer', 'Disease', (43, 49))	('spread', 'CPA', (63, 69))	('MK-6482', 'Var', (0, 7))	('hindering', 'NegReg', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cell growth', 'biological_process', 'GO:0016049', ('50', '61'))	('HIF-2a', 'Gene', '2034', (25, 31))
12858	33552650	Patients received MK-6482 orally once daily until disease progression, unacceptable toxicity, or investigator's or patient's decision to withdraw.	('MK-6482', 'Chemical', '-', (18, 25))	('Patients', 'Species', '9606', (0, 8))	('patient', 'Species', '9606', (115, 122))	('MK-6482', 'Var', (18, 25))	('toxicity', 'Disease', 'MESH:D064420', (84, 92))	('toxicity', 'Disease', (84, 92))
12871	33552650	Future studies to be considered include testing whether MK-6482 can prevent the development of new lesions in patients with von Hippel-Lindau disease.	('prevent', 'NegReg', (68, 75))	('von Hippel-Lindau disease', 'Disease', (124, 149))	('MK-6482', 'Chemical', '-', (56, 63))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (124, 149))	('patients', 'Species', '9606', (110, 118))	('MK-6482', 'Var', (56, 63))
12878	33552650	In this phase II trial, 61 adults with germline VHL variations with measurable, nonmetastatic RCC received MK-6482 at 120 mg daily.	('VHL', 'Gene', '7428', (48, 51))	('MK-6482', 'Var', (107, 114))	('RCC', 'Disease', (94, 97))	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('variations', 'Var', (52, 62))	('MK-6482', 'Chemical', '-', (107, 114))	('VHL', 'Gene', (48, 51))
12886	33552650	Immune checkpoint inhibitors included anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-programmed cell death protein 1 (PD-1), and anti-programmed cell death ligand 1 (PD-L1) therapies.	('programmed cell death', 'biological_process', 'GO:0012501', ('151', '172'))	('anti-programmed', 'Var', (146, 161))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', (43, 86))	('death', 'Disease', 'MESH:D003643', (167, 172))	('death', 'Disease', (167, 172))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', '397286', (43, 86))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('programmed cell death protein 1', 'Gene', (102, 133))	('programmed cell death protein 1', 'Gene', '100533201', (102, 133))	('ligand', 'molecular_function', 'GO:0005488', ('173', '179'))	('death', 'Disease', 'MESH:D003643', (118, 123))	('death', 'Disease', (118, 123))	('programmed cell death', 'biological_process', 'GO:0012501', ('102', '123'))
12895	33552650	Among six evaluable patients receiving combined PD-1 and CTLA-4 inhibition as second-line therapy, response was observed in one patient (17%) who had received single-agent PD-L1 inhibition as first-line therapy.	('inhibition', 'Var', (64, 74))	('CTLA-4', 'Gene', (57, 63))	('PD-1', 'Gene', (48, 52))	('patient', 'Species', '9606', (20, 27))	('patients', 'Species', '9606', (20, 28))	('patient', 'Species', '9606', (128, 135))
12922	31443471	Cellular damage causes cell division arrest, so the cell can repair itself, and cell death is induced if repair is not possible to avoid the development of a malignant cell line.	('cell death', 'biological_process', 'GO:0008219', ('80', '90'))	('Cellular damage', 'Var', (0, 15))	('division arrest', 'Disease', 'MESH:D006323', (28, 43))	('division arrest', 'Disease', (28, 43))	('cell division', 'biological_process', 'GO:0051301', ('23', '36'))
12970	31443471	Interim analysis has confirmed the combination of monoclonal antibodies prolonged progression-free survival in the PD-L1 positive patients (HR = 0.74; 95% CI 0.57-0.96; p = 0 02), but not in the overall population.	('prolonged', 'PosReg', (72, 81))	('patients', 'Species', '9606', (130, 138))	('positive', 'Var', (121, 129))	('progression-free survival', 'CPA', (82, 107))	('PD-L1', 'Gene', (115, 120))
12991	31443471	Grade 3-4 AEs occurred in 39% of the cabozantinib group and 40% of patients treated with everolimus.	('patients', 'Species', '9606', (67, 75))	('Grade 3-4 AEs', 'Disease', (0, 13))	('cabozantinib', 'Var', (37, 49))	('everolimus', 'Chemical', 'MESH:C107135', (89, 99))	('cabozantinib', 'Chemical', 'MESH:C558660', (37, 49))
12997	31443471	The overall survival was higher with cabozantinib (30.3 vs. 21.8 months), but the difference did not reach statistical significance (HR 0.80; 95% CI 0.50-1.26).	('overall survival', 'MPA', (4, 20))	('cabozantinib', 'Var', (37, 49))	('cabozantinib', 'Chemical', 'MESH:C558660', (37, 49))	('higher', 'PosReg', (25, 31))
13032	31443471	Response rates are better in PD-L1 positive tumors, but there is also a significant response in PD-L1 negative ones.	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumors', 'Disease', (44, 50))	('better', 'PosReg', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('PD-L1 positive', 'Var', (29, 43))
13080	31348324	The survival risk score was calculated as follows: survival risk score = (0.34745) x ERG + (0.76291) x RRM2 + (0.33446) x EGF.	('RRM2', 'Gene', (103, 107))	('RRM2', 'Gene', '6241', (103, 107))	('0.33446', 'Var', (111, 118))	('EGF', 'molecular_function', 'GO:0005154', ('122', '125'))	('EGF', 'Gene', (122, 125))	('EGF', 'Gene', '1950', (122, 125))	('ERG', 'Gene', '2078', (85, 88))	('ERG', 'Gene', (85, 88))
13086	31348324	5 of 11 DEmiRNAs were associated with OS, including hsa-mir-145, hsa-mir-211, hsa-mir-214, hsa-mir-216a, hsa-mir-217 (Fig.	('mir-145', 'Gene', '406937', (56, 63))	('mir-214', 'Gene', '406996', (82, 89))	('mir-217', 'Gene', (109, 116))	('mir-217', 'Gene', '406999', (109, 116))	('hsa-mir-216a', 'Var', (91, 103))	('mir-211', 'Gene', (69, 76))	('mir-211', 'Gene', '406993', (69, 76))	('mir-145', 'Gene', (56, 63))	('associated', 'Reg', (22, 32))	('mir-214', 'Gene', (82, 89))
13101	31348324	Due to the gene fusion with the promoter region of the androgen-induced TMPRRSS2 gene, ERG has become highly correlated with prostate cancer development.	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('gene fusion', 'Var', (11, 22))	('prostate cancer', 'Disease', 'MESH:D011471', (125, 140))	('ERG', 'Gene', '2078', (87, 90))	('ERG', 'Gene', (87, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (125, 140))	('prostate cancer', 'Disease', (125, 140))	('androgen', 'Chemical', 'MESH:D000728', (55, 63))	('TMPRRSS2', 'Gene', (72, 80))	('correlated with', 'Reg', (109, 124))
13103	31348324	Overexpression of RRM2 has been showed to be associated with aggressiveness and prognosis of bladder cancer, head and neck cancer, adrenocortical cancer, breast cancer, and pancreas adenocarcinoma.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('RRM2', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('head and neck cancer', 'Disease', 'MESH:D006258', (109, 129))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('pancreas adenocarcinoma', 'Disease', 'MESH:D000230', (173, 196))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (131, 152))	('pancreas adenocarcinoma', 'Phenotype', 'HP:0006725', (173, 196))	('pancreas adenocarcinoma', 'Disease', (173, 196))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('associated', 'Reg', (45, 55))	('bladder cancer', 'Disease', 'MESH:D001749', (93, 107))	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('aggressiveness', 'Disease', (61, 75))	('adrenocortical cancer', 'Disease', (131, 152))	('breast cancer', 'Disease', (154, 167))	('bladder cancer', 'Disease', (93, 107))	('RRM2', 'Gene', '6241', (18, 22))	('aggressiveness', 'Phenotype', 'HP:0000718', (61, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('bladder cancer', 'Phenotype', 'HP:0009725', (93, 107))	('head and neck cancer', 'Phenotype', 'HP:0012288', (109, 129))	('aggressiveness', 'Disease', 'MESH:D001523', (61, 75))	('neck', 'cellular_component', 'GO:0044326', ('118', '122'))
13105	31348324	Dysregulation of EGF has been recognized as an essential molecular event in carcinogenesis.	('Dysregulation', 'Var', (0, 13))	('EGF', 'Gene', (17, 20))	('EGF', 'molecular_function', 'GO:0005154', ('17', '20'))	('carcinogenesis', 'Disease', 'MESH:D063646', (76, 90))	('EGF', 'Gene', '1950', (17, 20))	('carcinogenesis', 'Disease', (76, 90))
13119	31348324	However, there are still a deficiency of reports on correlations between AP000525.1, GDNF-AS1, GPC5-AS1, LINC00327, and cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('AS1', 'Gene', '5729', (90, 93))	('AP000525.1', 'Var', (73, 83))	('GPC5', 'Gene', (95, 99))	('GDNF-AS1', 'Gene', '100861519', (85, 93))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('LINC00327', 'Gene', (105, 114))	('LINC00327', 'Gene', '100506697', (105, 114))	('AS1', 'Gene', '5729', (100, 103))	('AS1', 'Gene', (100, 103))	('AS1', 'Gene', (90, 93))	('GPC5', 'Gene', '2262', (95, 99))	('GDNF-AS1', 'Gene', (85, 93))
13139	29793450	We have found that silencing of cystathionine-beta-synthase and cystathionine gamma-lyase prevented induction of apoptosis.	('cystathionine gamma-lyase', 'Gene', '1491', (64, 89))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('100', '122'))	('apoptosis', 'CPA', (113, 122))	('silencing', 'Var', (19, 28))	('cystathionine gamma-lyase', 'Gene', (64, 89))	('cystathionine-beta-synthase', 'Gene', '875', (32, 59))	('prevented', 'NegReg', (90, 99))	('cystathionine-beta-synthase', 'Gene', (32, 59))
13166	29793450	The ccRCC frequently carries von Hippel-Lindau tumor-suppressor gene mutations or loss, which causes uncontrolled hypoxia-inducible factor activation.	('mutations', 'Var', (69, 78))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('47', '63'))	('von Hippel-Lindau tumor', 'Disease', 'MESH:D006623', (29, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (4, 9))	('von Hippel-Lindau tumor', 'Disease', (29, 52))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('47', '63'))	('loss', 'NegReg', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('hypoxia', 'Disease', (114, 121))	('hypoxia', 'Disease', 'MESH:D000860', (114, 121))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))
13184	29793450	Subsequently labeling reaction was performed using Cy3-dCTP (unaffected tissue samples) and Cy5-dCTP (tumor samples) to obtained cRNA.	('Cy3-dCTP', 'Chemical', '-', (51, 59))	('Cy5-dCTP', 'Var', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('Cy5-dCTP', 'Chemical', 'MESH:C544355', (92, 100))
13220	29793450	Effectivity of silencing of CBS was ~ 60%, CSE ~ 70% and MPST ~ 50%, as determined by gene expression.	('gene expression', 'biological_process', 'GO:0010467', ('86', '101'))	('CSE', 'Gene', (43, 46))	('silencing', 'Var', (15, 24))	('CBS', 'Gene', '875', (28, 31))	('MPST', 'Gene', (57, 61))	('CBS', 'Gene', (28, 31))	('MPST', 'Gene', '4357', (57, 61))	('CSE', 'Gene', '1491', (43, 46))
13241	29793450	Inhibition of either CSE or CBS in pathological states severely worsens renal damage.	('renal damage', 'Disease', (72, 84))	('CSE', 'Gene', '1491', (21, 24))	('worsens', 'NegReg', (64, 71))	('CSE', 'Gene', (21, 24))	('CBS', 'Gene', '875', (28, 31))	('Inhibition', 'Var', (0, 10))	('CBS', 'Gene', (28, 31))	('renal damage', 'Disease', 'MESH:D007674', (72, 84))
13283	31881506	For example, tumors with mismatch repair (MMR) deficiency have high response rates and the FDA-approved use of the anti-PD-1 agent pembrolizumab in patients with refractory tumor microsatellite instability or mismatch repair deficiency (MMRd) solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('tumors', 'Disease', (13, 19))	('pembrolizumab', 'Chemical', 'MESH:C582435', (131, 144))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('mismatch repair', 'biological_process', 'GO:0006298', ('25', '40'))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('response', 'MPA', (68, 76))	('refractory tumor microsatellite instability or mismatch repair deficiency (MMRd) solid tumors', 'Disease', 'MESH:C536928', (162, 255))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('mismatch repair', 'biological_process', 'GO:0006298', ('209', '224'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('MMR', 'biological_process', 'GO:0006298', ('42', '45'))	('tumors', 'Disease', (249, 255))	('deficiency', 'Var', (47, 57))
13284	31881506	The mechanistic hypothesis is that tumor antigenicity generated by mutations promotes T-cell expansion, which enhances the anti-PD-1 response.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('promotes', 'PosReg', (77, 85))	('cell expansion', 'biological_process', 'GO:0016049', ('88', '102'))	('tumor', 'Disease', (35, 40))	('mutations', 'Var', (67, 76))	('enhances', 'PosReg', (110, 118))	('anti-PD-1 response', 'MPA', (123, 141))	('T-cell expansion', 'CPA', (86, 102))
13296	31881506	For immunohistochemical staining of tissue, microarray slides or formalin fixed and paraffin-embedded tumor tissue antibodies directed against CD3 (IR503, Dako, Glostrup, Denmark), CD8 (C8/144B, Dako), CD20 (IR604, Dako), CD56 (123C3, Dako), CD68 (PG-M1, Dako), CD138 (MI15, Dako), FoxP3 (236A/E7, Abcam, Cambridge, United Kingdom), myeloperoxidase (MPO) (IR511, Dako), PD-1 (NAT105, Abcam), and PD-L1 (EPR19759, Abcam) were used.	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('IR511', 'Var', (356, 361))	('MPO', 'molecular_function', 'GO:0004601', ('350', '353'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
13309	31881506	CD20 was used as a marker for B-cells, CD56 for natural killer cells (NK cells), CD68 for tumor-associated macrophages (TAMs), CD138 for plasma cells, and MPO for granulocytes.	('MPO', 'molecular_function', 'GO:0004601', ('155', '158'))	('TAMs', 'Chemical', '-', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('CD68', 'Var', (81, 85))	('CD138', 'Var', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
13331	31881506	Further analyses on the influence of PD-L1 status on CSS after dichotomization of the patient collective regarding synchronous distant metastasis (negative vs. positive), tumor size (pT1/2 vs. pT3/4), or grading (G1/2 vs. G3) were performed: Strikingly, patients with synchronous distant metastases and high PD-L1 expression of tumor cells showed a significantly worse CSS in comparison to synchronously metastasized patients with low PD-L1 expression (Figure 4B).	('CSS', 'MPA', (369, 372))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('metastases', 'Disease', (288, 298))	('CSS', 'Chemical', '-', (369, 372))	('CSS', 'Chemical', '-', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('high', 'Var', (303, 307))	('worse', 'NegReg', (363, 368))	('metastases', 'Disease', 'MESH:D009362', (288, 298))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', (328, 333))
13333	31881506	In multivariate analysis after adjustment for all other examined parameters and immune cells, high PD-L1 expression of tumor cells (HR 6.92; CI 2.29-20.9; p < 0.001) stayed significantly associated with poor prognosis, thus being an independent prognostic factor in ccRCC (Figure 2B).	('tumor', 'Disease', (119, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (266, 271))	('ccRCC', 'Disease', (266, 271))	('PD-L1', 'Gene', (99, 104))	('ccRCC', 'Disease', 'MESH:D002292', (266, 271))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('associated', 'Reg', (187, 197))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('expression', 'MPA', (105, 115))	('high', 'Var', (94, 98))
13346	31881506	While PD-L1 expression of tumor cells seems not to be of prognostic value in non-ccRCC, a high PD-L1 expression in ccRCC provides a strong negative prognostic value regarding patients' survival.	('ccRCC', 'Disease', 'MESH:D002292', (115, 120))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('ccRCC', 'Disease', (81, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('high', 'Var', (90, 94))	('PD-L1', 'Gene', (95, 100))	('ccRCC', 'Disease', 'MESH:D002292', (81, 86))	('expression', 'MPA', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('negative', 'NegReg', (139, 147))	('ccRCC', 'Disease', (115, 120))
13349	31881506	A high expression of PD-L1 of tumor cells was associated with a more aggressive tumor phenotype and proved to be an independent prognostic factor for poor CSS.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('more', 'PosReg', (64, 68))	('CSS', 'Chemical', '-', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('high', 'Var', (2, 6))	('aggressive tumor', 'Disease', 'MESH:D001523', (69, 85))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('PD-L1', 'Gene', (21, 26))	('aggressive tumor', 'Disease', (69, 85))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('associated with', 'Reg', (46, 61))	('poor CSS', 'Disease', (150, 158))	('tumor', 'Disease', (30, 35))
13375	31881506	Our analyses show that a high amount of TAM in ccRCC is associated with poor prognosis compared with patients with a low amount.	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('ccRCC', 'Disease', (47, 52))	('TAM', 'Chemical', '-', (40, 43))	('ccRCC', 'Disease', 'MESH:D002292', (47, 52))	('high amount', 'Var', (25, 36))
13381	31881506	Also, any presence of TAN in localized RCC was an independent prognostic marker for shorter recurrence-free survival, CSS, and overall survival.	('recurrence-free survival', 'CPA', (92, 116))	('CSS', 'Chemical', '-', (118, 121))	('RCC', 'Disease', 'MESH:D002292', (39, 42))	('RCC', 'Disease', (39, 42))	('shorter', 'NegReg', (84, 91))	('presence', 'Var', (10, 18))	('overall survival', 'CPA', (127, 143))	('CSS', 'Disease', (118, 121))
13395	31956367	Kaplan-Meier curves revealed that high 5hmC expression had a good prognostic impact on RCC patients.	('patients', 'Species', '9606', (91, 99))	('RCC', 'Disease', (87, 90))	('RCC', 'Disease', 'MESH:D002292', (87, 90))	('5hmC', 'Chemical', 'MESH:C011865', (39, 43))	('5hmC', 'Protein', (39, 43))	('high', 'Var', (34, 38))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
13411	31956367	There are exact evidences that the Von Hippel-Lindau (VHL) tumor suppressor gene is mutated or inactivated in more than 80% of ccRCC patients.	('Von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (35, 64))	('patients', 'Species', '9606', (133, 141))	('mutated', 'Var', (84, 91))	('RCC', 'Disease', (129, 132))	('RCC', 'Disease', 'MESH:D002292', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('tumor suppressor', 'biological_process', 'GO:0051726', ('59', '75'))	('inactivated', 'NegReg', (95, 106))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('59', '75'))
13412	31956367	However, in mouse (Mus musculus) experiments, it was found that the deletion of this gene did not cause the formation of clear cell carcinoma, which indicates that there are other tumorigenic mechanisms.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('Mus musculus', 'Species', '10090', (19, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('deletion', 'Var', (68, 76))	('formation', 'biological_process', 'GO:0009058', ('108', '117'))	('mouse', 'Species', '10090', (12, 17))	('clear cell carcinoma', 'Disease', (121, 141))	('clear cell carcinoma', 'Disease', 'MESH:D002292', (121, 141))
13413	31956367	Previous studies have also found that mutations associated with renal carcinogenesis and prognosis occur mainly in genes encoding epiregulatory factors, such as the BAP1 gene that regulates histone H2A ubiquitination, the histone methyltransferase gene SETD2, and the TET2 gene which catalyzes the conversion of DNA methylation of cytosine (5mC) to 5hmC.	('histone H2A ubiquitination', 'biological_process', 'GO:0033522', ('190', '216'))	('renal carcinogenesis', 'Disease', (64, 84))	('SETD2', 'Gene', (253, 258))	('cytosine', 'Chemical', 'MESH:D003596', (331, 339))	('BAP1', 'Gene', (165, 169))	('TET2', 'Gene', (268, 272))	('associated', 'Reg', (48, 58))	('histone methyltransferase', 'Gene', '56979', (222, 247))	('renal carcinogenesis', 'Disease', 'MESH:D063646', (64, 84))	('5hmC', 'Chemical', 'MESH:C011865', (349, 353))	('TET2', 'Gene', '54790', (268, 272))	('DNA', 'cellular_component', 'GO:0005574', ('312', '315'))	('DNA methylation', 'biological_process', 'GO:0006306', ('312', '327'))	('histone methyltransferase', 'Gene', (222, 247))	('mutations', 'Var', (38, 47))	('BAP1', 'Gene', '8314', (165, 169))	('SETD2', 'Gene', '29072', (253, 258))
13414	31956367	As one of the most widely studied epigenetic modifications, 5mC of the CpG dinucleotide in gene promoter is usually related to the transcriptional silencing of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('transcriptional', 'MPA', (131, 146))	('cancer', 'Disease', (160, 166))	('related', 'Reg', (116, 123))	('CpG dinucleotide', 'Var', (71, 87))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('5mC', 'Var', (60, 63))	('silencing', 'NegReg', (147, 156))
13461	31956367	Two-sample t test and standard nonparametric Mann-Whitney U-test showed ccRCC patients in 5hmC low group with a higher clinical stage, higher T stage, lower Furhman grade, compared with 5hmC high group RCC patients (p<0.05, Table 1).	('5hmC', 'Chemical', 'MESH:C011865', (90, 94))	('patients', 'Species', '9606', (78, 86))	('RCC', 'Disease', (202, 205))	('RCC', 'Phenotype', 'HP:0005584', (202, 205))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('RCC', 'Disease', 'MESH:D002292', (202, 205))	('clinical stage', 'CPA', (119, 133))	('low', 'Var', (95, 98))	('RCC', 'Disease', 'MESH:D002292', (74, 77))	('5hmC low', 'Var', (90, 98))	('5hmC', 'Chemical', 'MESH:C011865', (186, 190))	('higher', 'PosReg', (112, 118))	('Furhman grade', 'CPA', (157, 170))	('lower', 'NegReg', (151, 156))	('patients', 'Species', '9606', (206, 214))	('T stage', 'CPA', (142, 149))	('higher', 'PosReg', (135, 141))
13469	31956367	This finding indicated that high 5hmC expression led to a good prognostic impact for RCC patients.	('5hmC', 'Chemical', 'MESH:C011865', (33, 37))	('5hmC', 'Protein', (33, 37))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('patients', 'Species', '9606', (89, 97))	('RCC', 'Disease', (85, 88))	('RCC', 'Disease', 'MESH:D002292', (85, 88))	('high', 'Var', (28, 32))
13486	31956367	Kaplan-Meier curves revealed that high 5hmC level led to good prognostic impact for RCC patients.	('5hmC level', 'MPA', (39, 49))	('patients', 'Species', '9606', (88, 96))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('5hmC', 'Chemical', 'MESH:C011865', (39, 43))	('RCC', 'Disease', 'MESH:D002292', (84, 87))	('RCC', 'Disease', (84, 87))	('high', 'Var', (34, 38))
13489	31956367	Numerous studies have shown that the loss of 5hmC is associated with the cancer aggressiveness.	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer aggressiveness', 'Disease', (73, 94))	('5hmC', 'Chemical', 'MESH:C011865', (45, 49))	('5hmC', 'Protein', (45, 49))	('associated', 'Reg', (53, 63))	('loss', 'Var', (37, 41))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (73, 94))	('aggressiveness', 'Phenotype', 'HP:0000718', (80, 94))
13494	31956367	Furthermore, Kaplan-Meier curves revealed that the high 5hmC expression had a good prognostic impact in RCC patients.	('5hmC', 'Chemical', 'MESH:C011865', (56, 60))	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:D002292', (104, 107))	('high', 'Var', (51, 55))	('5hmC expression', 'Protein', (56, 71))	('patients', 'Species', '9606', (108, 116))	('RCC', 'Disease', (104, 107))
13587	30431594	Tumor markers such as CEA, CA125, and CA19-9 may rise slightly in few cases, but there is no specificity.	('CA19-9', 'Chemical', 'MESH:C086528', (38, 44))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CEA', 'Gene', (22, 25))	('CA125', 'Gene', '94025', (27, 32))	('CEA', 'Gene', '1084', (22, 25))	('CA19-9', 'Var', (38, 44))	('CA125', 'Gene', (27, 32))
13628	28367246	Through analyzing published data in The Cancer Genome Atlas (TCGA), our pilot study indicated that G6PD mRNA expression was significantly higher in advanced Fuhrman grade in clear cell renal cell carcinoma (ccRCC).	('ccRCC', 'Phenotype', 'HP:0006770', (207, 212))	('Cancer Genome Atlas', 'Disease', (40, 59))	('Cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (40, 59))	('G6PD', 'Var', (99, 103))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (185, 205))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (174, 205))	('RCC', 'Phenotype', 'HP:0005584', (209, 212))	('RCC', 'Disease', 'MESH:C538614', (209, 212))	('RCC', 'Disease', (209, 212))	('clear cell renal cell carcinoma', 'Disease', (174, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('higher', 'PosReg', (138, 144))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (174, 205))
13629	28367246	These clues promoted us to further evaluate the expression profile of G6PD and its prognostic impact in patients with ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('G6PD', 'Var', (70, 74))	('patients', 'Species', '9606', (104, 112))
13631	28367246	The results showed that compared with that in the normal renal samples, G6PD was found highly expressed in 51.0% of ccRCC (p<0.05).	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('RCC', 'Disease', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('G6PD', 'Var', (72, 76))
13632	28367246	High expression of G6PD was significantly correlated to tumor extent, lymph node metastasis, Fuhrman grade, and TNM stage of ccRCC (all p<0.05).	('lymph node metastasis', 'CPA', (70, 91))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('TNM', 'Gene', '10178', (112, 115))	('tumor', 'Disease', (56, 61))	('TNM', 'Gene', (112, 115))	('Fuhrman', 'Disease', (93, 100))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('correlated', 'Reg', (42, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (125, 130))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('G6PD', 'Var', (19, 23))
13633	28367246	Moreover, positive G6PD expression was associated with poorer overall survival in ccRCC (p<0.001).	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('poorer', 'NegReg', (55, 61))	('RCC', 'Disease', (84, 87))	('positive G6PD expression', 'Var', (10, 34))	('overall survival', 'MPA', (62, 78))
13634	28367246	In Cox regression analyses, high expression of G6PD also could be an independent prognostic factor for overall survival in ccRCC (p=0.007).	('G6PD', 'Var', (47, 51))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))
13635	28367246	This study suggests that overexpression of G6PD is associated with advanced disease status and therefore may become an important prognosticator for poor outcomes in ccRCC, as well as a potential therapeutic target for developing effective treatment modalities.	('G6PD', 'Var', (43, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (165, 170))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('overexpression', 'PosReg', (25, 39))
13642	28367246	Recent studies demonstrated that G6PD was involved in the cell growth regulation and tumorigenesis.	('tumor', 'Disease', (85, 90))	('regulation', 'biological_process', 'GO:0065007', ('70', '80'))	('cell growth', 'biological_process', 'GO:0016049', ('58', '69'))	('involved', 'Reg', (42, 50))	('cell growth regulation', 'CPA', (58, 80))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('G6PD', 'Var', (33, 37))
13643	28367246	Wei-ying et al reported that overexpression of G6PD in NIH 3T3 could not only alter cell morphology and contact inhibition feature, but also gave rise to rapid growth and large fibrosarcomas in nude mice.	('NIH 3T3', 'CellLine', 'CVCL:0594', (55, 62))	('alter', 'Reg', (78, 83))	('overexpression', 'PosReg', (29, 43))	('G6PD', 'Var', (47, 51))	('nude mice', 'Species', '10090', (194, 203))	('fibrosarcomas', 'Disease', 'MESH:D005354', (177, 190))	('gave rise to', 'Reg', (141, 153))	('fibrosarcomas', 'Disease', (177, 190))	('NIH 3T3', 'Gene', (55, 62))	('contact inhibition', 'CPA', (104, 122))	('cell morphology', 'CPA', (84, 99))	('contact inhibition', 'biological_process', 'GO:0060242', ('104', '122'))
13644	28367246	These results imply that G6PD can act as a tumor driver gene.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('G6PD', 'Var', (25, 29))
13646	28367246	Moreover, G6PD overexpression is closely related to the progression of gastric cancer and breast carcinoma, and also might be regarded as an independent predictor of poor prognosis for these cancers.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('overexpression', 'PosReg', (15, 29))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('gastric cancer', 'Disease', (71, 85))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancers', 'Disease', (191, 198))	('gastric cancer', 'Disease', 'MESH:D013274', (71, 85))	('G6PD', 'Var', (10, 14))	('breast carcinoma', 'Disease', (90, 106))	('breast carcinoma', 'Disease', 'MESH:D001943', (90, 106))	('gastric cancer', 'Phenotype', 'HP:0012126', (71, 85))	('related', 'Reg', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('breast carcinoma', 'Phenotype', 'HP:0003002', (90, 106))
13647	28367246	Additionally, our previous reports also demonstrated that silencing G6PD expression decreased melanoma cell proliferation and enhanced apoptosis.	('apoptosis', 'CPA', (135, 144))	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('enhanced', 'PosReg', (126, 134))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('G6PD', 'Protein', (68, 72))	('melanoma', 'Disease', (94, 102))	('cell proliferation', 'biological_process', 'GO:0008283', ('103', '121'))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))	('decreased', 'NegReg', (84, 93))	('silencing', 'Var', (58, 67))
13648	28367246	However, there are still no reports that published regarding the expression profile of G6PD in human ccRCC, and what its clinical significance are, to date, unknown.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('human', 'Species', '9606', (95, 100))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('G6PD', 'Var', (87, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))
13650	28367246	Hence, in the present study, we extracted the data from "The Cancer Gene Atlas (TCGA)" to gain insight into the role of G6PD in ccRCC and additionally verified the clinicopathological significance of G6PD in ccRCC by immunohistochemical analysis.	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Cancer', 'Disease', (61, 67))	('G6PD', 'Var', (120, 124))	('Cancer', 'Disease', 'MESH:D009369', (61, 67))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (210, 213))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('RCC', 'Disease', (210, 213))	('RCC', 'Phenotype', 'HP:0005584', (210, 213))	('G6PD', 'Var', (200, 204))	('ccRCC', 'Phenotype', 'HP:0006770', (208, 213))
13664	28367246	The Kaplan-Meier method was applied to assess the effect of G6PD overexpression on the ccRCC patient survival and the significance was evaluated by the log-rank test.	('G6PD', 'Var', (60, 64))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('patient', 'Species', '9606', (93, 100))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))
13668	28367246	Moreover, G6PD showed a stepwise increment from G1 to G4 in ccRCC (Figure 1B).	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('G6PD', 'Var', (10, 14))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))
13669	28367246	These findings prompted us to justify whether the G6PD expression was of significance in this current cohort of ccRCCs.	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('G6PD', 'Var', (50, 54))
13671	28367246	These results showed that ccRCC patients who owned higher expression levels of G6PD but with a shorter survival rate (p<0.0001, log-rank test, Figure 1C), indicating that G6PD mRNA overexpression were correlated with poor outcomes in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('patients', 'Species', '9606', (32, 40))	('RCC', 'Disease', (236, 239))	('expression', 'MPA', (58, 68))	('G6PD', 'Var', (171, 175))	('RCC', 'Phenotype', 'HP:0005584', (236, 239))	('ccRCC', 'Phenotype', 'HP:0006770', (26, 31))	('RCC', 'Disease', 'MESH:C538614', (236, 239))	('overexpression', 'PosReg', (181, 195))	('ccRCC', 'Phenotype', 'HP:0006770', (234, 239))	('RCC', 'Disease', (28, 31))	('RCC', 'Phenotype', 'HP:0005584', (28, 31))
13673	28367246	Moreover, weak, moderate and strong positive expression of G6PD was detected in 49.0% (73/149), 28.2% (42/149) and 22.8% (34/149) of the ccRCC tissues (Figure 2B-D top panel), 62.4% (93/149), 30.2% (45/149) and 7.4% (11/149) of the noncancerous renal tissues (Figure 2B-D bottom panel).	('noncancerous renal tissues', 'Disease', 'MESH:D007674', (232, 258))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('G6PD', 'Var', (59, 63))	('noncancerous renal tissues', 'Disease', (232, 258))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
13675	28367246	High expression of G6PD was detected in 51.0% (76/149) of the ccRCC specimens and 37.6% (56/149) of the adjacent samples (Figure 3A), and the score of G6PD expression in ccRCC and adjacent tissues was significantly different (p<0.05, chi2 test, Figure 3B).	('detected', 'Reg', (28, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (170, 175))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('RCC', 'Disease', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('RCC', 'Disease', (172, 175))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))	('G6PD', 'Var', (19, 23))
13676	28367246	In addition, high expression levels of G6PD were also found in various ccRCC cell lines when compared with that in HK2 cell (a normal human renal tubular epithelial cell line) (Data not shown).	('human', 'Species', '9606', (134, 139))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('RCC', 'Disease', (73, 76))	('G6PD', 'Var', (39, 43))	('expression levels', 'MPA', (18, 35))	('HK2', 'Gene', (115, 118))	('HK2', 'Gene', '3099', (115, 118))	('HK2', 'molecular_function', 'GO:0008256', ('115', '118'))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
13677	28367246	These above results demonstrate that G6PD expression is significantly higher in ccRCC and might be associated with renal tumorigenesis.	('G6PD', 'Var', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('renal tumor', 'Disease', 'MESH:D007674', (115, 126))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('renal tumor', 'Phenotype', 'HP:0009726', (115, 126))	('higher', 'PosReg', (70, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('renal tumor', 'Disease', (115, 126))	('associated', 'Reg', (99, 109))
13679	28367246	The results showed that the expression of G6PD was significantly associated with the tumor extent, lymph node metastasis, Fuhrman tumor grade, and TNM stage (p=0.031, p<0.001, p=0.001, and p=0.004, respectively; chi2 test, Table 2), but not significantly related to other clinicopathological features such as gender, age at surgery, or tumor max diameter (p>0.05, chi2 test, Table 2).	('tumor', 'Disease', (85, 90))	('TNM', 'Gene', '10178', (147, 150))	('Fuhrman tumor', 'Disease', 'MESH:D009369', (122, 135))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('TNM', 'Gene', (147, 150))	('tumor', 'Disease', (336, 341))	('associated', 'Reg', (65, 75))	('G6PD', 'Var', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Fuhrman tumor', 'Disease', (122, 135))	('lymph node metastasis', 'CPA', (99, 120))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('tumor', 'Disease', (130, 135))
13681	28367246	Likewise, the rate and score of G6PD expression in progressively advanced regional lymph node metastasis (p<0.001, chi2 test, Figure 4B), Fuhrman tumor grade 3 and 4 (G3/4) (p<0.01, chi2 test, Figure 4E), and TNM stage III and IV (III/IV) (p<0.01, chi2 test, Figure 4F) was also significantly different when compared with that in each control.	('Fuhrman tumor', 'Disease', (138, 151))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('TNM', 'Gene', (209, 212))	('regional lymph node metastasis', 'CPA', (74, 104))	('advanced', 'PosReg', (65, 73))	('Fuhrman tumor', 'Disease', 'MESH:D009369', (138, 151))	('G6PD', 'Var', (32, 36))	('TNM', 'Gene', '10178', (209, 212))
13686	28367246	Similarly, both in stage I/II ccRCC and stage III/IV ccRCC, patients with higher G6PD expression had worse overall survival (p=0.013 and p=0.034, respectively; log-rank test, Figure 5B and Figure 5C).	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('RCC', 'Disease', (55, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('overall survival', 'MPA', (107, 123))	('higher', 'PosReg', (74, 80))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('patients', 'Species', '9606', (60, 68))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('worse', 'NegReg', (101, 106))	('G6PD expression', 'Var', (81, 96))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
13689	28367246	When the G6PD level and other joined five factors were analyzed again using multivariate Cox hazard regression, the results showed that G6PD expression (p=0.007, Table 3), as well as Fuhrman grade (p<0.001, Table 3) and TNM stage (p=0.019, Table 3) were independent prognostic factors for ccRCC survival.	('TNM', 'Gene', '10178', (220, 223))	('TNM', 'Gene', (220, 223))	('RCC', 'Disease', (291, 294))	('RCC', 'Phenotype', 'HP:0005584', (291, 294))	('G6PD expression', 'Var', (136, 151))	('RCC', 'Disease', 'MESH:C538614', (291, 294))	('ccRCC', 'Phenotype', 'HP:0006770', (289, 294))
13690	28367246	In conclusion, these results demonstrate that higher expression of G6PD might be served as an independent prognostic factor of poor survival of ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('G6PD', 'Var', (67, 71))	('higher', 'PosReg', (46, 52))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('patients', 'Species', '9606', (150, 158))	('expression', 'MPA', (53, 63))
13697	28367246	The pentose phosphate pathway which is controlled by G6PD and always get disordered in cancers has been recognized to generate reducing agents and ribose 5-phosphate for maintenance of cancer cells' redox homeostasis and nucleotides biosynthesis.	('disordered in cancers', 'Disease', 'MESH:D009369', (73, 94))	('cancer', 'Disease', (87, 93))	('biosynthesis', 'biological_process', 'GO:0009058', ('233', '245'))	('pentose phosphate', 'Chemical', 'MESH:D010428', (4, 21))	('G6PD', 'Var', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('ribose 5-phosphate', 'Chemical', 'MESH:C031626', (147, 165))	('pentose phosphate pathway', 'Pathway', (4, 29))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('4', '29'))	('disordered in cancers', 'Disease', (73, 94))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('homeostasis', 'biological_process', 'GO:0042592', ('205', '216'))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Disease', (185, 191))
13699	28367246	In this study, to examine the role of G6PD in the pathogenesis of ccRCC, we downloaded transcriptomic and survival data from TCGA to analyze the expression levels of G6PD in ccRCC and normal renal tissues and then evaluate its correlation to the overall survival of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (268, 271))	('RCC', 'Disease', (176, 179))	('RCC', 'Disease', (268, 271))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('RCC', 'Phenotype', 'HP:0005584', (268, 271))	('ccRCC', 'Phenotype', 'HP:0006770', (266, 271))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('pathogenesis', 'biological_process', 'GO:0009405', ('50', '62'))	('ccRCC', 'Phenotype', 'HP:0006770', (174, 179))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('G6PD', 'Var', (166, 170))
13703	28367246	More importantly, the results also revealed that higher expression of G6PD was associated with poor overall survival in patients with ccRCC.	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('overall survival', 'MPA', (100, 116))	('poor', 'NegReg', (95, 99))	('expression', 'MPA', (56, 66))	('patients', 'Species', '9606', (120, 128))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('G6PD', 'Var', (70, 74))	('higher', 'PosReg', (49, 55))	('RCC', 'Disease', (136, 139))
13704	28367246	Our findings support that G6PD overexpression might be exploited to increase the incidence or progression of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('G6PD', 'Var', (26, 30))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('progression', 'CPA', (94, 105))	('increase', 'PosReg', (68, 76))
13705	28367246	To further confirm whether G6PD has the potential to become a new biomarkers for improving the diagnosis and to predict the prognosis of ccRCC patients, protein expression levels of G6PD in 149 primary ccRCC specimens (117 with follow-up data) and corresponding adjacent normal tissue samples were examined by using immunohistochemical analysis.	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('RCC', 'Disease', (204, 207))	('RCC', 'Phenotype', 'HP:0005584', (204, 207))	('protein', 'cellular_component', 'GO:0003675', ('153', '160'))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('patients', 'Species', '9606', (143, 151))	('RCC', 'Disease', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (202, 207))	('G6PD', 'Var', (182, 186))
13706	28367246	We found that G6PD protein was expressed at higher levels in ccRCC tissues, and aberrant expression of G6PD was significantly correlated to tumor extent, lymph node metastasis, Fuhrman grade, and TNM stage of ccRCC.	('RCC', 'Disease', (63, 66))	('TNM', 'Gene', '10178', (196, 199))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('RCC', 'Disease', (211, 214))	('RCC', 'Phenotype', 'HP:0005584', (211, 214))	('RCC', 'Disease', 'MESH:C538614', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (211, 214))	('ccRCC', 'Phenotype', 'HP:0006770', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('G6PD', 'Var', (103, 107))	('aberrant expression', 'Var', (80, 99))	('TNM', 'Gene', (196, 199))	('lymph node metastasis', 'CPA', (154, 175))	('correlated', 'Reg', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('protein', 'cellular_component', 'GO:0003675', ('19', '26'))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('tumor', 'Disease', (140, 145))
13707	28367246	Positive G6PD expression was associated with shorter overall survival and it is prognostically independent for G6PD overexpression with worse overall survival in ccRCC.	('G6PD', 'Var', (9, 13))	('shorter', 'NegReg', (45, 52))	('overall survival', 'MPA', (53, 69))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('ccRCC', 'Phenotype', 'HP:0006770', (162, 167))	('RCC', 'Disease', (164, 167))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))
13708	28367246	These results demonstrate that G6PD may be served as a prognostic biomarker to predict the prognosis of patients with ccRCC and become a potent therapeutic target for RCC treatment.	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (167, 170))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('G6PD', 'Var', (31, 35))	('patients', 'Species', '9606', (104, 112))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))
13709	28367246	Our above immunohistochemical results found that G6PD was aberrantly high expressed in ccRCC than that of their normal counterparts which was similar to other study conclusions which used different cohorts and with distinct analytical approaches.	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('G6PD', 'Var', (49, 53))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('high', 'PosReg', (69, 73))
13710	28367246	Moreover, we also found that G6PD expression in ccRCC was a prognostic molecular and high expression of G6PD predicted worse overall survival in ccRCC patients.	('worse', 'NegReg', (119, 124))	('overall survival', 'MPA', (125, 141))	('G6PD', 'Var', (29, 33))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('patients', 'Species', '9606', (151, 159))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (145, 150))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('RCC', 'Disease', (147, 150))	('G6PD', 'Var', (104, 108))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('RCC', 'Disease', 'MESH:C538614', (147, 150))
13714	28367246	Besides the ethnic differences of RCC patients, different experimental methods for analyzing the association between G6PD and ccRCC features may also be the reasons for different findings.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('patients', 'Species', '9606', (38, 46))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('G6PD', 'Var', (117, 121))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('RCC', 'Disease', (34, 37))
13720	28367246	In our pioneer study, we found that overexpression of G6PD in ACHN, a commonly used cell line for ccRCC study, could increase NOX4 expression and promote cell proliferation and migration (unpublished data).	('cell proliferation', 'CPA', (154, 172))	('G6PD', 'Var', (54, 58))	('NOX4', 'Gene', (126, 130))	('increase', 'PosReg', (117, 125))	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('overexpression', 'PosReg', (36, 50))	('cell proliferation', 'biological_process', 'GO:0008283', ('154', '172'))	('expression', 'MPA', (131, 141))	('NOX4', 'Gene', '50507', (126, 130))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('promote', 'PosReg', (146, 153))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('ACHN', 'Gene', (62, 66))
13721	28367246	Although the molecular mechanism underlying G6PD overexpression is still not well defined in ccRCC, we have confidence that G6PD must possess multi-functions in facilitating ccRCC oncogenesis and further investigations are waiting to be carried out for testifying this hypothesis.	('RCC', 'Disease', (176, 179))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('oncogenesis', 'biological_process', 'GO:0007048', ('180', '191'))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (174, 179))	('RCC', 'Disease', (95, 98))	('G6PD', 'Var', (124, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('oncogenesis', 'CPA', (180, 191))
13722	28367246	Collectively, by data mining the publicly-available datasets and immunohistochemical analysis, we demonstrated that G6PD was overexpressed in ccRCC and significantly correlated to advanced Fuhrman grade and TNM stage.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('advanced Fuhrman grade', 'CPA', (180, 202))	('correlated', 'Reg', (166, 176))	('G6PD', 'Var', (116, 120))	('overexpressed', 'PosReg', (125, 138))	('TNM', 'Gene', '10178', (207, 210))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('TNM', 'Gene', (207, 210))
13723	28367246	Furthermore, G6PD expression was associated with ccRCC worse outcomes and high levels of G6PD expression could act as an independent unfavorable prognostic biomarker for ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('ccRCC', 'Phenotype', 'HP:0006770', (170, 175))	('high levels of G6PD', 'Phenotype', 'HP:0410186', (74, 93))	('associated', 'Reg', (33, 43))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('G6PD expression', 'Var', (13, 28))	('RCC', 'Disease', (172, 175))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
13724	28367246	Hence, our results indicate that G6PD may be regarded as a specific diagnostic biomarker and served as an independent predictor of poor prognosis to ccRCC patients and that the G6PD suppression represents a potential target for ccRCC treatment.	('G6PD', 'Var', (177, 181))	('RCC', 'Disease', 'MESH:C538614', (230, 233))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('patients', 'Species', '9606', (155, 163))	('RCC', 'Disease', (151, 154))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('RCC', 'Disease', (230, 233))	('RCC', 'Phenotype', 'HP:0005584', (230, 233))	('ccRCC', 'Phenotype', 'HP:0006770', (149, 154))	('G6PD', 'Var', (33, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (228, 233))
13725	28367246	Furthermore, the exact molecular mechanisms by which G6PD regulate the progression of ccRCC needs to be further elucidated.	('G6PD', 'Var', (53, 57))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('regulate', 'Reg', (58, 66))
13729	32541093	High hsa_circ_0085576 expression was significantly correlated with tumor size, clinical stage, and metastasis status and poorer survival.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('High hsa_circ_0085576 expression', 'Var', (0, 32))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('metastasis status', 'CPA', (99, 116))	('correlated', 'Reg', (51, 61))
13730	32541093	Moreover, hsa_circ_0085576 silencing significantly suppressed tumor growth and metastasis, whereas overexpression of hsa_circ_0085576 had the opposite effects, in vivo, Our results further showed that hsa_circ_0085576 acted as a competitive endogenous RNAs to interact with microRNA-498, to attenuate its repressive effect on target gene Yes-associated protein 1 (YAP1).	('YAP1', 'Gene', (364, 368))	('silencing', 'Var', (27, 36))	('Yes-associated protein 1', 'Gene', (338, 362))	('YAP1', 'Gene', '10413', (364, 368))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('suppressed', 'NegReg', (51, 61))	('repressive effect', 'MPA', (305, 322))	('microRNA-498', 'Gene', (274, 286))	('microRNA-498', 'Gene', '574460', (274, 286))	('protein', 'cellular_component', 'GO:0003675', ('353', '360'))	('Yes-associated protein 1', 'Gene', '10413', (338, 362))	('metastasis', 'CPA', (79, 89))	('hsa_circ_0085576', 'Var', (201, 217))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('attenuate', 'NegReg', (291, 300))
13732	32541093	Based on these findings, hsa_circ_0085576 may represent a valuable prognostic biomarker and a potential therapeutic target to curb the tumorigenesis and metastasis of ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (167, 172))	('ccRCC', 'Disease', (167, 172))	('metastasis', 'CPA', (153, 163))	('tumor', 'Disease', (135, 140))	('hsa_circ_0085576', 'Var', (25, 41))	('curb', 'NegReg', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
13739	32541093	Besides, abnormal circRNAs expression could lead to alteration of gene products that contributing to tumor biology including cell proliferation, apoptosis, and metastasis.	('lead to alteration', 'Reg', (44, 62))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('metastasis', 'CPA', (160, 170))	('abnormal', 'Var', (9, 17))	('cell proliferation', 'CPA', (125, 143))	('apoptosis', 'biological_process', 'GO:0097194', ('145', '154'))	('apoptosis', 'biological_process', 'GO:0006915', ('145', '154'))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('cell proliferation', 'biological_process', 'GO:0008283', ('125', '143'))	('apoptosis', 'CPA', (145, 154))	('gene products', 'MPA', (66, 79))
13743	32541093	Hsa_circ_0085576 may serve as an oncogene to promote ccRCC metastasis and be applied to a novel therapeutic target.	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('ccRCC metastasis', 'Disease', (53, 69))	('ccRCC metastasis', 'Disease', 'MESH:D009362', (53, 69))	('Hsa_circ_0085576', 'Var', (0, 16))	('promote', 'PosReg', (45, 52))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
13744	32541093	GSE100186 consists of 3 normal, 3 RCC samples and GSE137836 consists of 3 primary tumor tissues and 3 humans metastatic RCC samples.	('GSE100186', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('humans', 'Species', '9606', (102, 108))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('tumor', 'Disease', (82, 87))	('GSE137836', 'Var', (50, 59))
13746	32541093	For the KEGG pathway, the most enriched KEGG pathway corresponding to the circRNAs up-regulated in the GSE100186 and GSE137836 dataset was the YAP1 signaling pathway (Supplementary Figure 1H).	('YAP1', 'Gene', '10413', (143, 147))	('up-regulated', 'PosReg', (83, 95))	('KEGG pathway', 'Pathway', (40, 52))	('GSE100186', 'Var', (103, 112))	('signaling pathway', 'biological_process', 'GO:0007165', ('148', '165'))	('YAP1', 'Gene', (143, 147))	('KEGG pathway', 'Pathway', (8, 20))
13748	32541093	We then applied RNase R, a processive 3' to 5' exoribonuclease, to digest total RNAs and found that compared with linear ASAP1, hsa_circ_0085576 was significantly resistant to RNase R, implying that hsa_circ_0085576 is circular (Figure 1C, 1D).	('ASAP1', 'Gene', '50807', (121, 126))	('resistant', 'MPA', (163, 172))	('ASAP1', 'Gene', (121, 126))	('RNase', 'Enzyme', (176, 181))	('hsa_circ_0085576', 'Var', (128, 144))
13749	32541093	Afterward, RT-qPCR analysis found that hsa_circ_0085576 was significantly upregulated in the ccRCC tissues when compared with adjacent normal tissues (Figure 1E), and further upregulated in the invasive ccRCC tissues when compared with those in the non-invasive tumor tissues (Figure 1F).	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('upregulated', 'PosReg', (74, 85))	('invasive tumor', 'Disease', 'MESH:D009361', (253, 267))	('hsa_circ_0085576', 'Var', (39, 55))	('RCC', 'Phenotype', 'HP:0005584', (205, 208))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('upregulated', 'PosReg', (175, 186))	('ccRCC', 'Phenotype', 'HP:0006770', (203, 208))	('invasive tumor', 'Disease', (253, 267))	('ccRCC', 'Disease', (93, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))
13752	32541093	Primarily, we found that that hsa_circ_0085576 was significantly higher in patients with advanced stage, large tumor size, or lymph node metastasis (Figure 2B).	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('patients', 'Species', '9606', (75, 83))	('hsa_circ_0085576', 'Var', (30, 46))	('tumor', 'Disease', (111, 116))	('lymph node metastasis', 'CPA', (126, 147))	('higher', 'PosReg', (65, 71))
13754	32541093	hsa_circ_0085576 was positively correlated with the clinical stage, tumor stage and distant metastasis.	('tumor', 'Disease', (68, 73))	('distant metastasis', 'CPA', (84, 102))	('clinical stage', 'CPA', (52, 66))	('correlated', 'Reg', (32, 42))	('hsa_circ_0085576', 'Var', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
13755	32541093	Additionally, multivariate cox regression analysis revealed that clinical stage, tumor stage, distant metastasis and high hsa_circ_0085576 expression are independent predictors of OS in patients with ccRCC (Table 2).	('ccRCC', 'Disease', (200, 205))	('distant metastasis', 'CPA', (94, 112))	('patients', 'Species', '9606', (186, 194))	('hsa_circ_0085576', 'Gene', (122, 138))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('high', 'Var', (117, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (200, 205))	('RCC', 'Phenotype', 'HP:0005584', (202, 205))	('tumor', 'Disease', (81, 86))
13756	32541093	Kaplan-Meier survival analysis then showed poorer overall survival (OS) and disease-free survival (DFS) of ccRCC patients with high hsa_circ_0085576 levels (Figure 2D, 2E).	('high hsa_circ_0085576 levels', 'Var', (127, 155))	('patients', 'Species', '9606', (113, 121))	('overall survival', 'CPA', (50, 66))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('ccRCC', 'Disease', (107, 112))	('disease-free survival', 'CPA', (76, 97))	('poorer', 'NegReg', (43, 49))
13760	32541093	For the analysis of cell apoptosis, inhibition of hsa_circ_0085576 promoted apoptosis of A498 cells (Figure 3F), whereas enhanced GINS4 expression inhibited apoptosis of 786O cells (Figure 3G).	('hsa_circ_0085576', 'Var', (50, 66))	('expression', 'MPA', (136, 146))	('promoted', 'PosReg', (67, 75))	('apoptosis', 'biological_process', 'GO:0097194', ('76', '85'))	('apoptosis', 'biological_process', 'GO:0006915', ('157', '166'))	('GINS4', 'Gene', (130, 135))	('GINS4', 'Gene', '84296', (130, 135))	('enhanced', 'PosReg', (121, 129))	('apoptosis', 'biological_process', 'GO:0006915', ('25', '34'))	('apoptosis', 'biological_process', 'GO:0097194', ('25', '34'))	('apoptosis', 'biological_process', 'GO:0097194', ('157', '166'))	('inhibited', 'NegReg', (147, 156))	('apoptosis', 'CPA', (76, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('76', '85'))
13761	32541093	The tumor growth model showed that hsa_circ_0085576 knockdown notably inhibited tumor growth whereas overexpression of hsa_circ_0085576 facilitated tumor growth (Figure 4A, 4D).	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (148, 153))	('facilitated', 'PosReg', (136, 147))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('inhibited', 'NegReg', (70, 79))	('knockdown', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
13762	32541093	Meanwhile, the sizes and weights of tumors in hsa_circ_0085576 knockdown group were markedly lower than those in the control group (Figure 4B, 4C), and the tumors in the hsa_circ_0085576 overexpressing group tumors were larger than its corresponding control group (Figure 4E, 4F).	('tumors', 'Disease', (156, 162))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('lower', 'NegReg', (93, 98))	('tumors', 'Disease', (208, 214))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('sizes', 'CPA', (15, 20))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('tumors', 'Disease', (36, 42))	('larger', 'PosReg', (220, 226))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('hsa_circ_0085576', 'Var', (46, 62))
13763	32541093	The KEGG pathway analysis revealed that hsa_circ_0085576 affected many signaling pathways, including the Hippo, MAPK, and Jak-STAT signaling pathways (Figure 5B).	('signaling', 'biological_process', 'GO:0023052', ('71', '80'))	('affected', 'Reg', (57, 65))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('hsa_circ_0085576', 'Var', (40, 56))	('Hippo', 'Pathway', (105, 110))	('Jak', 'molecular_function', 'GO:0004713', ('122', '125'))	('STAT', 'Gene', '6774', (126, 130))	('MAPK', 'Pathway', (112, 116))	('STAT', 'Gene', (126, 130))	('signaling pathways', 'Pathway', (71, 89))	('MAPK', 'molecular_function', 'GO:0004707', ('112', '116'))
13766	32541093	Subsequent western blot analysis confirmed that overexpression of hsa_circ_0085576 activated YAP1 signaling pathway, as evidenced by increased YAP1, LATS1, LATS2, TEAD2 and TEAD3 (Figure 5E).	('LATS1', 'Gene', (149, 154))	('LATS2', 'Gene', (156, 161))	('YAP1', 'Gene', '10413', (143, 147))	('TEAD2', 'Gene', '8463', (163, 168))	('TEAD2', 'Gene', (163, 168))	('LATS2', 'Gene', '26524', (156, 161))	('TEAD3', 'Gene', '7005', (173, 178))	('LATS1', 'Gene', '9113', (149, 154))	('YAP1', 'Gene', (93, 97))	('YAP1', 'Gene', '10413', (93, 97))	('signaling pathway', 'biological_process', 'GO:0007165', ('98', '115'))	('overexpression', 'PosReg', (48, 62))	('increased', 'PosReg', (133, 142))	('hsa_circ_0085576', 'Var', (66, 82))	('YAP1', 'Gene', (143, 147))	('activated', 'PosReg', (83, 92))	('TEAD3', 'Gene', (173, 178))
13772	32541093	RIP assay showed the enrichment of hsa_circ_0085576 and miR-498 could be combined with Ago2 protein in 786O cells (Figure 6G).	('miR-498', 'Gene', '574460', (56, 63))	('miR-498', 'Gene', (56, 63))	('Ago2', 'Gene', (87, 91))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('hsa_circ_0085576', 'Var', (35, 51))	('Ago2', 'Gene', '27161', (87, 91))
13773	32541093	subsequent correlation analysis found circ0085576 was negatively correlated with miR-498 expression in ccRCC tissues (Figure 6H).	('expression', 'MPA', (89, 99))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('miR-498', 'Gene', '574460', (81, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('ccRCC', 'Disease', (103, 108))	('negatively', 'NegReg', (54, 64))	('circ0085576', 'Var', (38, 49))	('miR-498', 'Gene', (81, 88))
13775	32541093	Conversely, we found knockdown of hsa_circ_0085576 in A498 and 786O cells notably increased miR-498 expression (Figure 6K).	('hsa_circ_0085576', 'Gene', (34, 50))	('miR-498', 'Gene', '574460', (92, 99))	('expression', 'MPA', (100, 110))	('increased', 'PosReg', (82, 91))	('knockdown', 'Var', (21, 30))	('miR-498', 'Gene', (92, 99))
13783	32541093	Meanwhile, miR-498 inhibitors enhanced luciferase activity of wild type reporter for YAP1, but not for mutant one (Figure 7G).	('YAP1', 'Gene', (85, 89))	('enhanced', 'PosReg', (30, 38))	('luciferase', 'Enzyme', (39, 49))	('YAP1', 'Gene', '10413', (85, 89))	('miR-498', 'Gene', (11, 18))	('luciferase activity', 'molecular_function', 'GO:0047077', ('39', '58'))	('inhibitors', 'Var', (19, 29))	('luciferase activity', 'molecular_function', 'GO:0045289', ('39', '58'))	('activity', 'MPA', (50, 58))	('luciferase activity', 'molecular_function', 'GO:0047712', ('39', '58'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('39', '58'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('39', '58'))	('miR-498', 'Gene', '574460', (11, 18))
13784	32541093	Subsequently, western blot analysis demonstrated that overexpression of miR-498 markedly suppressed YAP1 signaling pathway, whereas knockdown of miR-498 activated YAP1 signaling, as evidenced by the changes of YAP1, LATS1, LATS2, TEAD2 and TEAD3 protein expression (Figure 7H).	('miR-498', 'Gene', (72, 79))	('suppressed', 'NegReg', (89, 99))	('LATS1', 'Gene', (216, 221))	('LATS2', 'Gene', (223, 228))	('LATS2', 'Gene', '26524', (223, 228))	('LATS1', 'Gene', '9113', (216, 221))	('TEAD3', 'Gene', (240, 245))	('changes', 'Reg', (199, 206))	('TEAD3', 'Gene', '7005', (240, 245))	('signaling', 'biological_process', 'GO:0023052', ('168', '177'))	('YAP1', 'Gene', '10413', (100, 104))	('knockdown', 'Var', (132, 141))	('miR-498', 'Gene', '574460', (145, 152))	('YAP1', 'Gene', (100, 104))	('activated', 'PosReg', (153, 162))	('YAP1', 'Gene', '10413', (210, 214))	('YAP1', 'Gene', '10413', (163, 167))	('miR-498', 'Gene', '574460', (72, 79))	('protein', 'cellular_component', 'GO:0003675', ('246', '253'))	('TEAD2', 'Gene', (230, 235))	('YAP1', 'Gene', (210, 214))	('signaling pathway', 'biological_process', 'GO:0007165', ('105', '122'))	('miR-498', 'Gene', (145, 152))	('TEAD2', 'Gene', '8463', (230, 235))	('YAP1', 'Gene', (163, 167))
13789	32541093	Similarly, the enhanced cell apoptosis of both cell lines induced by LV-sh-circ0085567 was partly abolished by co-transfection with miR-498 inhibitors or YAP1 overexpression plasmids (Figure 8F).	('YAP1', 'Gene', (154, 158))	('YAP1', 'Gene', '10413', (154, 158))	('miR-498', 'Gene', '574460', (132, 139))	('apoptosis', 'biological_process', 'GO:0006915', ('29', '38'))	('LV-sh-circ0085567', 'Var', (69, 86))	('cell apoptosis', 'CPA', (24, 38))	('miR-498', 'Gene', (132, 139))	('apoptosis', 'biological_process', 'GO:0097194', ('29', '38'))	('abolished', 'NegReg', (98, 107))	('enhanced', 'PosReg', (15, 23))
13793	32541093	Hsa_circ_0085576 was found to be significantly associated with tumor size, clinical stage and metastasis in our study.	('tumor', 'Disease', (63, 68))	('metastasis', 'CPA', (94, 104))	('Hsa_circ_0085576', 'Var', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('clinical stage', 'CPA', (75, 89))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('associated', 'Reg', (47, 57))
13796	32541093	Luciferase assays and RIP showed that hsa_circ_0085576 interacted with miR-498, which provided evidence that hsa_circ_0085576 competes with miR-498 in ccRCC cells.	('hsa_circ_0085576', 'Var', (109, 125))	('miR-498', 'Gene', (140, 147))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('miR-498', 'Gene', '574460', (71, 78))	('miR-498', 'Gene', '574460', (140, 147))	('ccRCC', 'Disease', (151, 156))	('miR-498', 'Gene', (71, 78))	('ccRCC', 'Phenotype', 'HP:0006770', (151, 156))
13803	32541093	Therefore, hsa_circ_0085576 may exert its physiological functions via sponging miR-498.	('miR-498', 'Gene', (79, 86))	('hsa_circ_0085576', 'Var', (11, 27))	('miR-498', 'Gene', '574460', (79, 86))
13807	32541093	A recent study demonstrated that circ-104075 stimulated YAP1 expression via absorbing miR-582-3p, therefore to stimulate hepatocellular carcinoma tumorigenesis.	('circ-104075', 'Var', (33, 44))	('hepatocellular carcinoma tumorigenesis', 'Disease', (121, 159))	('hepatocellular carcinoma tumorigenesis', 'Disease', 'MESH:D006528', (121, 159))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('expression', 'MPA', (61, 71))	('YAP1', 'Gene', (56, 60))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (121, 145))	('stimulate', 'PosReg', (111, 120))	('YAP1', 'Gene', '10413', (56, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('miR-582-3p', 'MPA', (86, 96))	('stimulated', 'PosReg', (45, 55))
13808	32541093	In the present study, we found that YAP1 was upregulated and positively associated with hsa_circ_0085576 expression.	('hsa_circ_0085576 expression', 'Var', (88, 115))	('positively', 'PosReg', (61, 71))	('upregulated', 'PosReg', (45, 56))	('YAP1', 'Gene', (36, 40))	('YAP1', 'Gene', '10413', (36, 40))	('associated', 'Interaction', (72, 82))
13816	32541093	In summary, hsa_circ_0085576 could serve as a predictor for clinical outcomes in patients with ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('patients', 'Species', '9606', (81, 89))	('ccRCC', 'Disease', (95, 100))	('hsa_circ_0085576', 'Var', (12, 28))
13844	32541093	A498 and 786O cells (1x104 cells/well) were cultured in 24-well plates and co-transfected with wild-type (WT) or mutant (Mut) hsa_circ_0085576 and miR-NC or miR-498 using Lipofectamine 2000 (Invitrogen).	('miR-NC', 'Gene', (147, 153))	('miR-498', 'Gene', (157, 164))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (171, 189))	('hsa_circ_0085576', 'Gene', (126, 142))	('miR-498', 'Gene', '574460', (157, 164))	('mutant', 'Var', (113, 119))
13846	32541093	Protein was separated by electrophoresis in 12% SDS-PAGE and transferred to PVDF membranes, blocked with 5% milk in Tris-buffered saline with Tween 20, and probed with the primary antibodies against YAP1 (ab52771), LATS1 (ab70562), LATS2 (ab110780), TEAD2 (ab92279), TEAD3 (ab75192) and beta-actin antibody (MAB8929, 1:1000; R&D systems).	('Tris-buffered saline', 'Chemical', '-', (116, 136))	('LATS2', 'Gene', (232, 237))	('LATS2', 'Gene', '26524', (232, 237))	('YAP1', 'Gene', '10413', (199, 203))	('antibody', 'molecular_function', 'GO:0003823', ('298', '306'))	('PVDF', 'Chemical', 'MESH:C024865', (76, 80))	('antibody', 'cellular_component', 'GO:0042571', ('298', '306'))	('ab70562', 'Var', (222, 229))	('YAP1', 'Gene', (199, 203))	('TEAD2', 'Gene', (250, 255))	('LATS1', 'Gene', (215, 220))	('antibody', 'cellular_component', 'GO:0019815', ('298', '306'))	('LATS1', 'Gene', '9113', (215, 220))	('TEAD2', 'Gene', '8463', (250, 255))	('ab110780', 'Var', (239, 247))	('ab75192', 'Var', (274, 281))	('SDS', 'Chemical', 'MESH:D012967', (48, 51))	('ab52771', 'Var', (205, 212))	('TEAD3', 'Gene', (267, 272))	('TEAD3', 'Gene', '7005', (267, 272))	('antibody', 'cellular_component', 'GO:0019814', ('298', '306'))	('Tween 20', 'Chemical', 'MESH:D011136', (142, 150))
13854	30271486	Although Hsa_circ_0001451 has been investigated in colorectal cancer, it remains unclear about the relationship between Hsa_circ_0001451 and clear cell renal cell carcinoma (ccRCC).	('colorectal cancer', 'Disease', 'MESH:D015179', (51, 68))	('RCC', 'Disease', (176, 179))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Hsa_circ_0001451', 'Var', (120, 136))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('colorectal cancer', 'Phenotype', 'HP:0003003', (51, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (152, 172))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (141, 172))	('ccRCC', 'Phenotype', 'HP:0006770', (174, 179))	('colorectal cancer', 'Disease', (51, 68))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (141, 172))	('clear cell renal cell carcinoma', 'Disease', (141, 172))
13859	30271486	Bioinformatics results also displayed that Hsa_circ_0001451 might be involved in the regulation of tumor progression.	('regulation', 'biological_process', 'GO:0065007', ('85', '95'))	('tumor', 'Disease', (99, 104))	('Hsa_circ_0001451', 'Var', (43, 59))	('involved', 'Reg', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
13860	30271486	Conclusion: Taken together, our finding showed that Hsa_circ_0001451 might become a novel potential biomarker in the diagnosis of ccRCC and a potential novel target for the treatment of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (130, 135))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('RCC', 'Disease', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('ccRCC', 'Phenotype', 'HP:0006770', (186, 191))	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('Hsa_circ_0001451', 'Var', (52, 68))
13864	30271486	Recently, mutations in PBRM1, BAP1 and SETD2 are identified to be the molecular biomarkers for the prognosis of RCC.	('PBRM1', 'Gene', (23, 28))	('PBRM1', 'Gene', '55193', (23, 28))	('BAP1', 'Gene', (30, 34))	('SETD2', 'Gene', (39, 44))	('BAP1', 'Gene', '8314', (30, 34))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('mutations', 'Var', (10, 19))	('SETD2', 'Gene', '29072', (39, 44))
13868	30271486	In this study, we found that Hsa_circ_0001451 was downregulated both in renal cell carcinoma tissues and cells, and functioned as an anti-oncogene in renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (72, 92))	('renal cell carcinoma', 'Disease', (150, 170))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (150, 170))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (72, 92))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (150, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('downregulated', 'NegReg', (50, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('Hsa_circ_0001451', 'Var', (29, 45))	('renal cell carcinoma', 'Disease', (72, 92))
13885	30271486	After transfection, cells were induced apoptosis using H2O2(100 microM for 2h),then cells were fixed 10min with the fixed solution, then washed it with PBS for 2 times, 3min each time and drained the liquid, Finally added 0.5ml Hoechst staining solution (Wanlei biological science and technology, Shenyang, China) to dye 5min.	('H2O2', 'Chemical', 'MESH:D006861', (55, 59))	('H2O2', 'Var', (55, 59))	('Hoechst', 'Chemical', '-', (228, 235))	('apoptosis', 'biological_process', 'GO:0097194', ('39', '48'))	('transfection', 'Var', (6, 18))	('2h', 'Chemical', 'MESH:D003903', (75, 77))	('apoptosis', 'biological_process', 'GO:0006915', ('39', '48'))	('PBS', 'Chemical', 'MESH:D007854', (152, 155))
13891	30271486	Figure 1A shows the normal kidney tissue (HE, x50; HE, x200), and Figure 1B shows the clear cell renal cell carcinoma tissue (HE, x50; HE, x200).	('clear cell renal cell carcinoma', 'Disease', (86, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (97, 117))	('HE', 'Chemical', 'MESH:D006371', (51, 53))	('HE', 'Var', (42, 44))	('HE', 'Chemical', 'MESH:D006371', (135, 137))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (86, 117))	('HE, x50; HE, x200', 'Var', (126, 143))	('HE', 'Chemical', 'MESH:D006371', (126, 128))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (86, 117))	('HE', 'Chemical', 'MESH:D006371', (42, 44))
13893	30271486	As shown in Fig 2A, the expression level of Hsa_circ_0001451 was significantly downregulated in ccRCC tissues compared with the matched normal tissues (p < 0.001).	('expression level', 'MPA', (24, 40))	('Hsa_circ_0001451', 'Var', (44, 60))	('downregulated', 'NegReg', (79, 92))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))
13894	30271486	These data implied that Hsa_circ_0001451 might be associated with the progression of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('Hsa_circ_0001451', 'Var', (24, 40))	('associated', 'Reg', (50, 60))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
13895	30271486	Next, we analyzed the correlation between the expression of Hsa_circ_0001451 with the clinicopathological parameters of 52 patients definitely diagnosed with ccRCC.	('Hsa_circ_0001451', 'Var', (60, 76))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('ccRCC', 'Phenotype', 'HP:0006770', (158, 163))	('RCC', 'Disease', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('patients', 'Species', '9606', (123, 131))
13898	30271486	Kaplan-Meier survival analysis disclosed that low level of Hsa_circ_0001451 was negatively correlated with overall survival of patients with ccRCC (Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (141, 146))	('overall survival', 'MPA', (107, 123))	('negatively', 'NegReg', (80, 90))	('Hsa_circ_0001451', 'Var', (59, 75))	('patients', 'Species', '9606', (127, 135))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', (143, 146))
13899	30271486	Then we included the variable including age, gender, clinical stage, tumor stage, lymph node, metastasis, and Hsa_circ_0001451 mRNA level into a multivariate Cox regression model and found that the mRNA level of Hsa_circ_0001451 was an independent predictor for overall status of ccRCC patients (HR=0.375, 95%CI 0.142-0.987, p=0.047, Table 2).	('Cox', 'Gene', '1351', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('RCC', 'Disease', 'MESH:C538614', (282, 285))	('ccRCC', 'Phenotype', 'HP:0006770', (280, 285))	('RCC', 'Disease', (282, 285))	('RCC', 'Phenotype', 'HP:0005584', (282, 285))	('Cox', 'Gene', (158, 161))	('tumor', 'Disease', (69, 74))	('mRNA', 'MPA', (198, 202))	('Hsa_circ_0001451', 'Var', (212, 228))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('patients', 'Species', '9606', (286, 294))
13904	30271486	To further investigate the function of Hsa_circ_0001451, we firstly detected its expression level in the renal cell carcinoma cell lines (OS-RC-2,786-O, OS-RC-1, ACHN, Caki1) and the normal cell line (HK-2, 293-T), respectively.	('OS-RC-2', 'CellLine', 'CVCL:1626', (138, 145))	('ACHN', 'Gene', (162, 166))	('OS-RC-1', 'CellLine', 'CVCL:1626', (153, 160))	('HK-2', 'CellLine', 'CVCL:0302', (201, 205))	('Hsa_circ_0001451', 'Var', (39, 55))	('renal cell carcinoma', 'Disease', (105, 125))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (105, 125))	('HK-2', 'molecular_function', 'GO:0008256', ('201', '205'))	('293-T', 'CellLine', 'CVCL:0063', (207, 212))	('ACHN', 'Gene', '55323', (162, 166))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (105, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))
13908	30271486	The findings above indicated that knockdown of hsa_circ_000145 could enhance the proliferation of ccRCC cells.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('hsa_circ_000145', 'Gene', (47, 62))	('enhance', 'PosReg', (69, 76))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('knockdown', 'Var', (34, 43))	('proliferation', 'CPA', (81, 94))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
13909	30271486	We then performed flow cytometric analyses to further evaluate whether Hsa_circ_0001451 affected proliferation of OS-RC-2 and 786-O cells by altering apoptosis.	('affected', 'Reg', (88, 96))	('Hsa_circ_0001451', 'Var', (71, 87))	('OS-RC-2', 'CellLine', 'CVCL:1626', (114, 121))	('apoptosis', 'CPA', (150, 159))	('apoptosis', 'biological_process', 'GO:0097194', ('150', '159'))	('altering', 'Reg', (141, 149))	('apoptosis', 'biological_process', 'GO:0006915', ('150', '159'))
13910	30271486	OS-RC-2 and 786-O cells transfected with si-Hsa_circ_0001451 obviously inhibited cell apoptosis (Fig.	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('inhibited', 'NegReg', (71, 80))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('cell apoptosis', 'CPA', (81, 95))	('OS-RC-2', 'CellLine', 'CVCL:1626', (0, 7))	('si-Hsa_circ_0001451', 'Var', (41, 60))
13911	30271486	In order to verify the cause of cell apoptosis change, the Bax and Bcl-2 protein levels were assessed in OS-RC-2 and 786-O by western blot after si-Hsa_circ_0001451 or si-NC transfection (Fig.	('Bax', 'Gene', '581', (59, 62))	('Bcl-2', 'molecular_function', 'GO:0015283', ('67', '72'))	('apoptosis', 'biological_process', 'GO:0097194', ('37', '46'))	('apoptosis', 'biological_process', 'GO:0006915', ('37', '46'))	('si-NC', 'Var', (168, 173))	('OS-RC-2', 'CellLine', 'CVCL:1626', (105, 112))	('Bcl-2', 'Gene', (67, 72))	('Bcl-2', 'Gene', '596', (67, 72))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('Bax', 'Gene', (59, 62))	('si-Hsa_circ_0001451', 'Var', (145, 164))
13913	30271486	Our results suggested that inhibition of Hsa_circ_0001451 promoted the proliferation of OS-RC-2 and 786-O cells and affected cell apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('affected', 'Reg', (116, 124))	('Hsa_circ_0001451', 'Gene', (41, 57))	('OS-RC-2', 'CellLine', 'CVCL:1626', (88, 95))	('inhibition', 'Var', (27, 37))	('promoted', 'PosReg', (58, 66))	('proliferation', 'CPA', (71, 84))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))
13915	30271486	In research of ccRCC, many studies have focused on the epigenetic regulation of its pathogenesis and potential targets for therapy, including microRNAs and long noncoding RNAs (lncRNAs).	('regulation', 'biological_process', 'GO:0065007', ('66', '76'))	('epigenetic', 'Var', (55, 65))	('pathogenesis', 'biological_process', 'GO:0009405', ('84', '96'))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (15, 20))
13918	30271486	In the process of research, we identified that Hsa_circ_0001451 is aberrantly expressed in ccRCC compared with normal kidney tissue.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('RCC', 'Disease', (93, 96))	('Hsa_circ_0001451', 'Var', (47, 63))
13919	30271486	Through loss of function, we found that Hsa_circ_0001451 is important in the process of the development of clear cell renal cell carcinoma.	('Hsa_circ_0001451', 'Var', (40, 56))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (107, 138))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (118, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('loss of function', 'NegReg', (8, 24))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (107, 138))	('clear cell renal cell carcinoma', 'Disease', (107, 138))
13921	30271486	Through the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we identified that 6 pathways were significantly enriched, including Hsa05200: Pathways in cancer, Hsa05212: Pancreatic cancer, Hsa0210: Colorectal cancer, Hsa04060: Cytokine-cytokine receptor interaction, Hsa04010: MAPK signal pathway, Hsa04350: TGF-beta signaling pathway, but only the enrichments of Hsa05200: Pathways in cancer were significant after FDR correction (Figure 5B, Supplementary material, Table S4).	('MAPK signal pathway', 'Pathway', (293, 312))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (225, 231))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (214, 231))	('MAPK', 'molecular_function', 'GO:0004707', ('293', '297'))	('Pancreatic cancer', 'Disease', (186, 203))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (402, 408))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('Hsa0210', 'Var', (205, 212))	('Colorectal cancer', 'Disease', 'MESH:D015179', (214, 231))	('TGF-beta signaling pathway', 'Pathway', (324, 350))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('Colorectal cancer', 'Disease', (214, 231))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (186, 203))	('cancer', 'Disease', (402, 408))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (402, 408))	('signaling pathway', 'biological_process', 'GO:0007165', ('333', '350'))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (186, 203))
13923	30271486	There is no doubt that in the future research, except needing more samples, it's necessary to explore more function of molecular mechanisms of Hsa_circ_0001451 in the progression of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('RCC', 'Disease', (184, 187))	('Hsa_circ_0001451', 'Var', (143, 159))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('ccRCC', 'Phenotype', 'HP:0006770', (182, 187))
13924	30271486	In conclusion, Hsa_circ_0001451 could be detected as a circRNA in human renal cell carcinoma (RCC) tissues and adjacent tissues.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('Hsa_circ_0001451', 'Var', (15, 31))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (72, 92))	('human', 'Species', '9606', (66, 71))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (72, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('renal cell carcinoma', 'Disease', (72, 92))
13927	27595393	On-Target Efficacy of a HIF2alpha Antagonist in Preclinical Kidney Cancer Models Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is usually linked to inactivation of the pVHL tumor suppressor protein and consequent accumulation of the HIF2alpha transcription factor .	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Clear cell renal cell carcinoma', 'Disease', (81, 112))	('HIF2alpha', 'Gene', '2034', (24, 33))	('HIF2alpha', 'Gene', (267, 276))	('kidney cancer', 'Phenotype', 'HP:0009726', (146, 159))	('tumor suppressor', 'biological_process', 'GO:0051726', ('207', '223'))	('Kidney Cancer', 'Disease', 'MESH:D007680', (60, 73))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (92, 112))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('transcription', 'biological_process', 'GO:0006351', ('277', '290'))	('kidney cancer', 'Disease', (146, 159))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('transcription factor', 'molecular_function', 'GO:0000981', ('277', '297'))	('accumulation', 'PosReg', (247, 259))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (81, 112))	('pVHL', 'Gene', '7428', (202, 206))	('HIF2alpha', 'Gene', '2034', (267, 276))	('pVHL', 'Gene', (202, 206))	('protein', 'cellular_component', 'GO:0003675', ('224', '231'))	('HIF2alpha', 'Gene', (24, 33))	('tumor', 'Disease', (207, 212))	('Kidney Cancer', 'Disease', (60, 73))	('inactivation', 'Var', (182, 194))	('Kidney Cancer', 'Phenotype', 'HP:0009726', (60, 73))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('kidney cancer', 'Disease', 'MESH:D007680', (146, 159))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (81, 112))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('207', '223'))
13934	27595393	PT2399 minimally affected a panel of 68 receptors, ion channels, and enzymes (Supplementary Table 1).	('PT2399', 'Chemical', 'MESH:C000614278', (0, 6))	('affected', 'Reg', (17, 25))	('enzymes', 'Enzyme', (69, 76))	('ion channels', 'molecular_function', 'GO:0022831', ('51', '63'))	('PT2399', 'Var', (0, 6))
13935	27595393	Treating 786-O VHL-/- ccRCC cells with PT2399 repressed various HIF target genes in mRNA microarray (Fig.	('VHL', 'Gene', (15, 18))	('PT2399', 'Var', (39, 45))	('PT2399', 'Chemical', 'MESH:C000614278', (39, 45))	('VHL', 'Gene', '7428', (15, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (22, 27))
13936	27595393	PT2399 did not suppress HIF1alpha-specific targets such as BNIP3 (Fig.	('PT2399', 'Chemical', 'MESH:C000614278', (0, 6))	('BNIP3', 'Gene', (59, 64))	('HIF1alpha', 'Gene', (24, 33))	('HIF1alpha', 'Gene', '3091', (24, 33))	('BNIP3', 'Gene', '664', (59, 64))	('PT2399', 'Var', (0, 6))
13937	27595393	PT2399 destabilized HIF2alpha, which might enhance its effects on HIF2alpha DNA-binding activity (Fig.	('PT2399', 'Chemical', 'MESH:C000614278', (0, 6))	('HIF2alpha', 'Gene', '2034', (20, 29))	('HIF2alpha', 'Gene', (66, 75))	('HIF2alpha', 'Gene', '2034', (66, 75))	('effects', 'MPA', (55, 62))	('DNA-binding', 'molecular_function', 'GO:0003677', ('76', '87'))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('PT2399', 'Var', (0, 6))	('destabilized', 'NegReg', (7, 19))	('HIF2alpha', 'Gene', (20, 29))	('DNA-binding', 'Interaction', (76, 87))	('enhance', 'PosReg', (43, 50))
13941	27595393	We then lentivirally reintroduced wild-type HIF2alpha, or a HIF2alpha missense mutant (S304M) with an occluded PT2399-binding pocket , into these cells (Fig.	('PT2399', 'Chemical', 'MESH:C000614278', (111, 117))	('HIF2alpha', 'Gene', '2034', (60, 69))	('HIF2alpha', 'Gene', '2034', (44, 53))	('HIF2alpha', 'Gene', (44, 53))	('HIF2alpha', 'Gene', (60, 69))	('S304M', 'Mutation', 'p.S304M', (87, 92))	('S304M', 'Var', (87, 92))	('binding', 'molecular_function', 'GO:0005488', ('118', '125'))
13943	27595393	1c, d) or producing HIF2alpha S304M (Fig.	('S304M', 'Var', (30, 35))	('S304M', 'Mutation', 'p.S304M', (30, 35))	('HIF2alpha', 'Gene', (20, 29))	('HIF2alpha', 'Gene', '2034', (20, 29))
13945	27595393	20 muM PT2399 caused off-target toxicity because it inhibited the proliferation of HIF2alpha -/- 786-O cells (Extended Data Fig.	('muM', 'Gene', '56925', (3, 6))	('muM', 'Gene', (3, 6))	('proliferation', 'CPA', (66, 79))	('HIF2alpha', 'Gene', '2034', (83, 92))	('inhibited', 'NegReg', (52, 61))	('toxicity', 'Disease', 'MESH:D064420', (32, 40))	('toxicity', 'Disease', (32, 40))	('PT2399', 'Var', (7, 13))	('PT2399', 'Chemical', 'MESH:C000614278', (7, 13))	('HIF2alpha', 'Gene', (83, 92))
13947	27595393	PT2399 did, however, inhibit 786-O cell soft agar growth at 0.2-2 muM (Fig.	('PT2399', 'Chemical', 'MESH:C000614278', (0, 6))	('muM', 'Gene', '56925', (66, 69))	('agar', 'Chemical', 'MESH:D000362', (45, 49))	('muM', 'Gene', (66, 69))	('inhibit', 'NegReg', (21, 28))	('PT2399', 'Var', (0, 6))
13948	27595393	This effect was specific because it was reversed by HIF2alpha S304M (Fig.	('S304M', 'Mutation', 'p.S304M', (62, 67))	('S304M', 'Var', (62, 67))	('HIF2alpha', 'Gene', '2034', (52, 61))	('HIF2alpha', 'Gene', (52, 61))
13951	27595393	Therefore, PT2399 decreases HIF-dependent transcription and soft agar growth in an on-target manner.	('PT2399', 'Chemical', 'MESH:C000614278', (11, 17))	('decreases', 'NegReg', (18, 27))	('PT2399', 'Var', (11, 17))	('transcription', 'biological_process', 'GO:0006351', ('42', '55'))	('agar', 'Chemical', 'MESH:D000362', (65, 69))	('HIF-dependent transcription', 'MPA', (28, 55))	('soft agar growth', 'CPA', (60, 76))
13953	27595393	As expected, PT2399 inhibited Luc activity in the VHL-/- cells, but not in their pVHL-proficient counterparts (Fig.	('VHL', 'Gene', (50, 53))	('Luc activity', 'MPA', (30, 42))	('VHL', 'Gene', '7428', (50, 53))	('VHL', 'Gene', (82, 85))	('inhibited', 'NegReg', (20, 29))	('VHL', 'Gene', '7428', (82, 85))	('PT2399', 'Var', (13, 19))	('PT2399', 'Chemical', 'MESH:C000614278', (13, 19))	('pVHL', 'Gene', '7428', (81, 85))	('pVHL', 'Gene', (81, 85))
13955	27595393	As expected, PT2399 did not affect Luc driven by constitutive promoters, such as the CMV promoter (Fig.	('PT2399', 'Chemical', 'MESH:C000614278', (13, 19))	('Luc', 'MPA', (35, 38))	('PT2399', 'Var', (13, 19))
13958	27595393	Two days of PT2399 decreased the 3XHRE-Luc signal by more than 60%, similar to its effects in vitro (Fig.	('decreased', 'NegReg', (19, 28))	('PT2399', 'Chemical', 'MESH:C000614278', (12, 18))	('3XHRE-Luc signal', 'MPA', (33, 49))	('PT2399', 'Var', (12, 18))
13963	27595393	In contrast, PT2399 caused tumor stasis or regression (Fig.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor stasis', 'Disease', 'MESH:D014647', (27, 39))	('PT2399', 'Var', (13, 19))	('PT2399', 'Chemical', 'MESH:C000614278', (13, 19))	('tumor stasis', 'Disease', (27, 39))
13965	27595393	In this model PT2399 still caused marked tumor regressions and prolonged survival (Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('prolonged', 'PosReg', (63, 72))	('PT2399', 'Chemical', 'MESH:C000614278', (14, 20))	('survival', 'CPA', (73, 81))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('PT2399', 'Var', (14, 20))
13967	27595393	Introducing HIF2alpha S304M into M2A cells (Fig.	('HIF2alpha', 'Gene', (12, 21))	('S304M', 'Var', (22, 27))	('HIF2alpha', 'Gene', '2034', (12, 21))	('S304M', 'Mutation', 'p.S304M', (22, 27))
13970	27595393	PT2399 also inhibited A498 VHL-/- ccRCC cells in soft agar and orthotopic tumor assays (Extended Data Fig.	('inhibited', 'NegReg', (12, 21))	('PT2399', 'Chemical', 'MESH:C000614278', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (34, 39))	('tumor', 'Disease', (74, 79))	('VHL', 'Gene', (27, 30))	('PT2399', 'Var', (0, 6))	('agar', 'Chemical', 'MESH:D000362', (54, 58))	('VHL', 'Gene', '7428', (27, 30))	('A498', 'CellLine', 'CVCL:1056', (22, 26))
13972	27595393	In contrast, PT2399 did not suppress orthotopic tumors formed by VHL-/- UMRC-2 cells or VHL-/- 769-P cells (Fig.	('VHL', 'Gene', '7428', (65, 68))	('VHL', 'Gene', (88, 91))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('VHL', 'Gene', '7428', (88, 91))	('UMRC-2', 'CellLine', 'CVCL:2739', (72, 78))	('PT2399', 'Var', (13, 19))	('PT2399', 'Chemical', 'MESH:C000614278', (13, 19))	('VHL', 'Gene', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
13974	27595393	To study this differential sensitivity further we measured HIF2alpha abundance and the response of selected HIF target genes to PT2399 and to pVHL across a VHL-/- ccRCC cell line panel.	('VHL', 'Gene', '7428', (143, 146))	('PT2399', 'Var', (128, 134))	('pVHL', 'Gene', '7428', (142, 146))	('PT2399', 'Chemical', 'MESH:C000614278', (128, 134))	('HIF2alpha', 'Gene', '2034', (59, 68))	('pVHL', 'Gene', (142, 146))	('VHL', 'Gene', '7428', (156, 159))	('HIF2alpha', 'Gene', (59, 68))	('VHL', 'Gene', (143, 146))	('response', 'MPA', (87, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (163, 168))	('VHL', 'Gene', (156, 159))
13975	27595393	The PT2399-sensitive 786-O and A498 cells had higher HIF2alpha levels than the insensitive UMRC-2 and 769-P cells (Fig.	('HIF2alpha', 'Gene', '2034', (53, 62))	('UMRC-2', 'CellLine', 'CVCL:2739', (91, 97))	('PT2399', 'Chemical', 'MESH:C000614278', (4, 10))	('higher', 'PosReg', (46, 52))	('A498', 'CellLine', 'CVCL:1056', (31, 35))	('HIF2alpha', 'Gene', (53, 62))	('PT2399-sensitive', 'Var', (4, 20))
13978	27595393	The latter further supported that this differential sensitivity to PT2399 reflects differences in HIF2alpha dependence rather than differences in intracellular drug accumulation.	('HIF2alpha', 'Gene', '2034', (98, 107))	('PT2399', 'Var', (67, 73))	('HIF2alpha', 'Gene', (98, 107))	('PT2399', 'Chemical', 'MESH:C000614278', (67, 73))	('intracellular', 'cellular_component', 'GO:0005622', ('146', '159'))
13979	27595393	Indeed, soft agar growth by UMRC-2 cells and 769-P cells was, in contrast to 786-O and A-498 cells, insensitive to Cas9-mediated inactivation of HIF2alpha and to PT2399 (Fig.	('agar', 'Chemical', 'MESH:D000362', (13, 17))	('HIF2alpha', 'Gene', (145, 154))	('UMRC-2', 'CellLine', 'CVCL:2739', (28, 34))	('PT2399', 'Chemical', 'MESH:C000614278', (162, 168))	('A-498', 'CellLine', 'CVCL:1056', (87, 92))	('soft agar growth', 'CPA', (8, 24))	('HIF2alpha', 'Gene', '2034', (145, 154))	('inactivation', 'Var', (129, 141))	('Cas9', 'Chemical', '-', (115, 119))	('Cas', 'cellular_component', 'GO:0005650', ('115', '118'))
13980	27595393	Similarly, soft agar growth by SKRC-20 and UMRC-6 VHL-/- ccRCC cells was unaffected by genetic disruption of HIF2alpha and to PT2399 (Extended Data Fig.	('HIF2alpha', 'Gene', '2034', (109, 118))	('UMRC-6', 'CellLine', 'CVCL:2741', (43, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('VHL', 'Gene', (50, 53))	('VHL', 'Gene', '7428', (50, 53))	('soft agar growth', 'CPA', (11, 27))	('HIF2alpha', 'Gene', (109, 118))	('PT2399', 'Chemical', 'MESH:C000614278', (126, 132))	('agar', 'Chemical', 'MESH:D000362', (16, 20))	('genetic disruption', 'Var', (87, 105))
13983	27595393	Finally, we confirmed that genetic disruption of HIF2alpha, like PT2399, did not affect orthotopic tumor growth by UMRC-2 cells (Extended Data Fig.	('tumor', 'Disease', (99, 104))	('PT2399', 'Chemical', 'MESH:C000614278', (65, 71))	('HIF2alpha', 'Gene', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('UMRC-2', 'CellLine', 'CVCL:2739', (115, 121))	('HIF2alpha', 'Gene', '2034', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('genetic disruption', 'Var', (27, 45))
13985	27595393	Moreover, Cas9-mediated ablation of HIF1alpha in UMRC-2 cells did not render them HIF2alpha-dependent in soft agar assays (Extended Data Fig.	('HIF1alpha', 'Gene', (36, 45))	('Cas', 'cellular_component', 'GO:0005650', ('10', '13'))	('HIF1alpha', 'Gene', '3091', (36, 45))	('HIF2alpha', 'Gene', (82, 91))	('agar', 'Chemical', 'MESH:D000362', (110, 114))	('Cas9', 'Chemical', '-', (10, 14))	('UMRC-2', 'CellLine', 'CVCL:2739', (49, 55))	('ablation', 'Var', (24, 32))	('HIF2alpha', 'Gene', '2034', (82, 91))
13993	27595393	p53 was not induced by DNA damage in the HIF2-independent lines UMRC-2 and 769-P, suggesting they also have p53 pathway mutations, but was induced in the HIF2-independent lines UMRC-6 and Caki-2 (Extended Data Fig.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (108, 111))	('UMRC-2', 'CellLine', 'CVCL:2739', (64, 70))	('p53', 'Gene', '7157', (108, 111))	('mutations', 'Var', (120, 129))	('Caki-2', 'CellLine', 'CVCL:0235', (188, 194))	('UMRC-6', 'CellLine', 'CVCL:2741', (177, 183))	('DNA', 'cellular_component', 'GO:0005574', ('23', '26'))
13994	27595393	Of note, p53 was modestly induced by PT2399 and Cas9-mediated loss of HIF2alpha in p53+/+ 786-O cells (Extended Data Fig.	('loss', 'NegReg', (62, 66))	('HIF2alpha', 'Gene', (70, 79))	('Cas', 'cellular_component', 'GO:0005650', ('48', '51'))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('PT2399', 'Var', (37, 43))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('PT2399', 'Chemical', 'MESH:C000614278', (37, 43))	('HIF2alpha', 'Gene', '2034', (70, 79))	('Cas9', 'Chemical', '-', (48, 52))
13998	27595393	The current view that p53 mutations are uncommon in ccRCC is based mainly on studies of primary tumors removed at nephrectomy.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('p53', 'Gene', (22, 25))	('mutations', 'Var', (26, 35))	('p53', 'Gene', '7157', (22, 25))	('primary tumors', 'Disease', (88, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('ccRCC', 'Disease', (52, 57))	('primary tumors', 'Disease', 'MESH:D009369', (88, 102))
13999	27595393	p53 pathway mutations might be more common in metastatic ccRCC, from which most ccRCC lines are derived, or might arise after ccRCC therapies .	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('metastatic ccRCC', 'Disease', (46, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('mutations', 'Var', (12, 21))	('common', 'Reg', (36, 42))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))
14000	27595393	Alternatively, some p53 mutations in ccRCC lines might have arisen ex vivo.	('mutations', 'Var', (24, 33))	('p53', 'Gene', '7157', (20, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('p53', 'Gene', (20, 23))
14005	29066084	P-M pairs with SETD2 mutations demonstrated higher discordance than pairs with wild-type SETD2.	('SETD2', 'Gene', '29072', (15, 20))	('SETD2', 'Gene', (15, 20))	('SETD2', 'Gene', '29072', (89, 94))	('SETD2', 'Gene', (89, 94))	('discordance', 'MPA', (51, 62))	('mutations', 'Var', (21, 30))
14006	29066084	We observed that patients who received therapy before sampling of the P or M tissue had higher concordance of mutations for P-M pairs than patients who did not (Mann-Whitney p = 0.088).	('patients', 'Species', '9606', (17, 25))	('P-M pairs', 'Gene', (124, 133))	('mutations', 'Var', (110, 119))	('patients', 'Species', '9606', (139, 147))
14010	29066084	Forty-seven patients carried nonidentical cancer gene mutations within their matched primary-metastatic pair.	('patients', 'Species', '9606', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('mutations', 'Var', (54, 63))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
14018	29066084	ccRCC is characterized by nearly ubiquitous biallelic loss of the tumor suppressor gene VHL, frequent concomitant loss or mutation of several other tumor suppressors on chromosome 3p, including PBRM1, BAP1, and SETD2, and clustered mutations of the oncogene MTOR.	('MTOR', 'Gene', '2475', (258, 262))	('SETD2', 'Gene', (211, 216))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('66', '82'))	('PBRM1', 'Gene', (194, 199))	('ccRCC', 'Disease', (0, 5))	('VHL', 'Gene', '7428', (88, 91))	('chromosome', 'cellular_component', 'GO:0005694', ('169', '179'))	('SETD2', 'Gene', '29072', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor suppressor', 'biological_process', 'GO:0051726', ('66', '82'))	('tumor', 'Disease', (66, 71))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('mutation', 'Var', (122, 130))	('mutations', 'Reg', (232, 241))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('BAP1', 'Gene', '8314', (201, 205))	('loss', 'NegReg', (114, 118))	('PBRM1', 'Gene', '55193', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('VHL', 'Gene', (88, 91))	('tumor', 'Disease', (148, 153))	('loss', 'NegReg', (54, 58))	('MTOR', 'Gene', (258, 262))	('ccRCC', 'Disease', 'MESH:D002292', (0, 5))	('BAP1', 'Gene', (201, 205))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
14022	29066084	In spite of limitations in sample size, Gerlinger and colleagues provided a seminal description of parallel, convergent evolution involving loss-of-function mutations to SETD2, KDM5C, and PTEN within the same tumor.	('tumor', 'Disease', (209, 214))	('SETD2', 'Gene', (170, 175))	('loss-of-function', 'NegReg', (140, 156))	('KDM5C', 'Gene', (177, 182))	('KDM5C', 'Gene', '8242', (177, 182))	('PTEN', 'Gene', (188, 192))	('mutations', 'Var', (157, 166))	('PTEN', 'Gene', '5728', (188, 192))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('SETD2', 'Gene', '29072', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
14023	29066084	In a distinct but equally important study, Gerlinger and colleagues described the stark prevalence of subclonal driver mutations in RCC tumors, emphasizing the importance of comprehensive multiregion sequencing of these cancers.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('RCC', 'Disease', 'MESH:D002292', (132, 135))	('RCC', 'Disease', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('cancers', 'Disease', (220, 227))	('mutations', 'Var', (119, 128))	('cancers', 'Disease', 'MESH:D009369', (220, 227))
14040	29066084	A measure of concordance/discordance was determined for each tumor pair by first counting the number of shared (S) and private (Pr) mutations, and the concordance score was calculated as (S - Pr)/(S + Pr).	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mutations', 'Var', (132, 141))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (61, 66))
14043	29066084	Enrichment of Pr/S mutations was calculated separately for ccRCC and nccRCC samples, as well as for the whole cohort.	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('mutations', 'Var', (19, 28))	('ccRCC', 'Disease', (59, 64))	('Pr/S', 'Gene', (14, 18))	('ccRCC', 'Disease', (70, 75))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('ccRCC', 'Disease', 'MESH:D002292', (59, 64))	('ccRCC', 'Disease', 'MESH:D002292', (70, 75))
14045	29066084	For a null model, we parametrized a binomial model with the probability of success equal to PPr, the number of trials equal to the total number of mutations in a gene (counting each shared mutation once), and the number of successes equal to the number of Pr mutations.	('PPr', 'Gene', '100528023', (92, 95))	('mutations', 'Var', (147, 156))	('PPr', 'Gene', (92, 95))
14046	29066084	For each patient, we identified a list of mutation events and labeled them as either Pr or S, so that each S mutation was counted once (because it occurs in the ancestral tumor cell) and each Pr mutation was also counted once.	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('patient', 'Species', '9606', (9, 16))	('tumor', 'Disease', (171, 176))	('mutation', 'Var', (109, 117))
14053	29066084	In ccRCC samples only, 132/312 (42%) mutations were Pr, whereas in nccRCC samples, 14/40 (35%) mutations were Pr.	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('mutations', 'Var', (37, 46))	('ccRCC', 'Disease', (68, 73))	('ccRCC', 'Disease', 'MESH:D002292', (68, 73))	('ccRCC', 'Disease', (3, 8))	('ccRCC', 'Disease', 'MESH:D002292', (3, 8))
14054	29066084	In other disease settings it has been found that specific genes are mutated at higher rates in metastatic compared to primary samples (eg, androgen receptor mutations in metastatic prostate cancers).	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('prostate cancers', 'Disease', 'MESH:D011471', (181, 197))	('prostate cancer', 'Phenotype', 'HP:0012125', (181, 196))	('androgen receptor', 'Gene', (139, 156))	('metastatic', 'Disease', (95, 105))	('mutations', 'Var', (157, 166))	('prostate cancers', 'Phenotype', 'HP:0012125', (181, 197))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('prostate cancers', 'Disease', (181, 197))	('androgen receptor', 'Gene', '367', (139, 156))
14057	29066084	Nevertheless, ATM (2 mutations in primary samples, 5 in metastatic samples) and PTEN (3 mutations in primary samples, 7 mutations in metastatic samples) mutations were enriched more than twofold in metastatic samples.	('PTEN', 'Gene', (80, 84))	('mutations', 'Var', (153, 162))	('PTEN', 'Gene', '5728', (80, 84))	('ATM', 'Gene', (14, 17))	('mutations', 'Var', (21, 30))
14059	29066084	In brief, for the binomial model we empirically determined the probability of a Pr mutation in our data set (PPr = 0.41), and used this to parameterize a null model.	('mutation', 'Var', (83, 91))	('PPr', 'Gene', '100528023', (109, 112))	('PPr', 'Gene', (109, 112))
14061	29066084	Consistent with its role as a truncal, founding mutation in ccRCC, we found that nearly all VHL mutations were shared between primary and metastatic samples (44/46 mutations shared, binomial q < 10-8, permutation q < 10-3).	('ccRCC', 'Disease', (60, 65))	('VHL', 'Gene', (92, 95))	('ccRCC', 'Disease', 'MESH:D002292', (60, 65))	('VHL', 'Gene', '7428', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('mutations', 'Var', (164, 173))	('mutations', 'Var', (96, 105))
14062	29066084	By contrast, SETD2 mutations were enriched for Pr mutations under the binomial model, but not the permutation model (16/25 mutations private, binomial q = 0.077, permutation p = 0.25; Fig.	('mutations', 'Var', (50, 59))	('mutations', 'Var', (19, 28))	('SETD2', 'Gene', (13, 18))	('SETD2', 'Gene', '29072', (13, 18))
14064	29066084	In particular, all six PTEN mutations in ccRCC samples were Pr (1 in a primary tumor and 5 in metastatic tumors).	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('ccRCC', 'Disease', 'MESH:D002292', (41, 46))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('PTEN', 'Gene', (23, 27))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('PTEN', 'Gene', '5728', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('ccRCC', 'Disease', (41, 46))	('tumor', 'Disease', (105, 110))	('mutations', 'Var', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
14065	29066084	By contrast, PTEN mutations in nccRCC samples were S mutations.	('ccRCC', 'Disease', (32, 37))	('ccRCC', 'Disease', 'MESH:D002292', (32, 37))	('PTEN', 'Gene', (13, 17))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('PTEN', 'Gene', '5728', (13, 17))	('mutations', 'Var', (18, 27))
14066	29066084	We found that tumors with either SETD2 or KDM5C mutations demonstrated higher discordance between primary and metastatic tumors than tumors with wild-type SETD2 (q = 0.068) or KDM5C (q = 0.078).	('higher', 'PosReg', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('SETD2', 'Gene', '29072', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (48, 57))	('KDM5C', 'Gene', '8242', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('SETD2', 'Gene', (33, 38))	('KDM5C', 'Gene', '8242', (176, 181))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('SETD2', 'Gene', '29072', (33, 38))	('tumors', 'Disease', (133, 139))	('discordance', 'MPA', (78, 89))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', (14, 20))	('KDM5C', 'Gene', (42, 47))	('KDM5C', 'Gene', (176, 181))	('tumors than tumors', 'Disease', 'MESH:D009369', (121, 139))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Disease', (121, 127))	('metastatic', 'CPA', (110, 120))	('primary', 'Disease', (98, 105))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('SETD2', 'Gene', (155, 160))	('tumors than tumors', 'Disease', (121, 139))
14067	29066084	When restricting the analysis to either ccRCC or nccRCC histology, the findings became marginally stronger for enrichment of SETD2 (q = 0.048) and KDM5C (q = 0.062) mutations in discordant samples.	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('ccRCC', 'Disease', (50, 55))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('ccRCC', 'Disease', (40, 45))	('ccRCC', 'Disease', 'MESH:D002292', (40, 45))	('ccRCC', 'Disease', 'MESH:D002292', (50, 55))	('SETD2', 'Gene', '29072', (125, 130))	('KDM5C', 'Gene', (147, 152))	('mutations', 'Var', (165, 174))	('KDM5C', 'Gene', '8242', (147, 152))	('SETD2', 'Gene', (125, 130))
14068	29066084	These findings for SETD2 mutations are consistent with prior studies demonstrating that spatially separated regions of RCC tumors tend to harbor distinct SETD2 mutations and promote ccRCC progression.	('tumors', 'Disease', (123, 129))	('SETD2', 'Gene', (19, 24))	('mutations', 'Var', (160, 169))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('SETD2', 'Gene', '29072', (154, 159))	('promote', 'PosReg', (174, 181))	('RCC', 'Disease', 'MESH:D002292', (184, 187))	('RCC', 'Disease', (184, 187))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('SETD2', 'Gene', (154, 159))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('RCC', 'Disease', 'MESH:D002292', (119, 122))	('RCC', 'Disease', (119, 122))	('ccRCC', 'Disease', (182, 187))	('ccRCC', 'Disease', 'MESH:D002292', (182, 187))	('SETD2', 'Gene', '29072', (19, 24))
14069	29066084	Two of these samples (P-0007981 and P-0005409) showed no common mutations between the primary and metastasis samples, suggesting that metastasis arose from a primary tumor clone that was not captured by our sequencing.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('P-0005409', 'Chemical', 'MESH:D010695', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('P-0005409', 'Var', (36, 45))	('tumor', 'Disease', (166, 171))	('metastasis', 'CPA', (134, 144))
14070	29066084	To evaluate whether the method of tissue acquisition (surgical excision vs core needle biopsy) affected P-M mutational differences, we tested whether levels of discordance varied between patients who did and did not have tissue acquired via core needle biopsy.	('core', 'cellular_component', 'GO:0019013', ('241', '245'))	('patients', 'Species', '9606', (187, 195))	('mutational', 'Var', (108, 118))	('core', 'cellular_component', 'GO:0019013', ('75', '79'))	('P-M', 'Gene', (104, 107))	('tested', 'Reg', (135, 141))	('affected', 'Reg', (95, 103))
14071	29066084	Of the remaining samples, we found 14 pairs (24%) with Pr mutations restricted to the primary tumor, and 12 (20%) with Pr mutations restricted to the metastatic site.	('mutations', 'Var', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', (94, 99))
14074	29066084	Interestingly, tumor size was positively correlated with concordance (Spearman correlation 0.31, p = 0.02), indicating that larger metastases were likely to have a larger proportion of shared mutations in comparison to smaller metastases.	('metastases', 'Disease', (131, 141))	('metastases', 'Disease', 'MESH:D009362', (227, 237))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('metastases', 'Disease', 'MESH:D009362', (131, 141))	('tumor', 'Disease', (15, 20))	('metastases', 'Disease', (227, 237))	('mutations', 'Var', (192, 201))
14083	29066084	Nevertheless, the observation that of higher mutation concordance for specimens from patients who received treatment before sequencing suggests that systemic therapy may induce a contraction of the mutational landscape in a patient.	('patient', 'Species', '9606', (85, 92))	('mutational landscape', 'MPA', (198, 218))	('patient', 'Species', '9606', (224, 231))	('patients', 'Species', '9606', (85, 93))	('mutation', 'Var', (45, 53))	('higher', 'PosReg', (38, 44))	('contraction', 'NegReg', (179, 190))
14087	29066084	Nine pairs carried the same mutation of an individual gene, yet six had additional Pr mutations of the same gene in the primary tumor (typical cases of convergent evolution on key tumor genes seen on multiregion sequencing) and three had additional Pr mutations of the same gene in the metastatic tumor, implying subclone reseeding.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('tumor', 'Disease', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('mutation', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', (297, 302))
14088	29066084	Of note, these cases were highly enriched for mutations in SETD2 (n = 4) and PBRM1 (n = 4), all in ccRCC.	('PBRM1', 'Gene', (77, 82))	('mutations', 'Var', (46, 55))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('ccRCC', 'Disease', (99, 104))	('PBRM1', 'Gene', '55193', (77, 82))	('SETD2', 'Gene', '29072', (59, 64))	('SETD2', 'Gene', (59, 64))	('ccRCC', 'Disease', 'MESH:D002292', (99, 104))
14106	29066084	Overall, 41% of the mutations we identified in our cohort were Pr mutations in the primary or metastatic tumor.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', (105, 110))	('mutations', 'Var', (20, 29))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
14108	29066084	In some cases, we were able to identify evolutionary convergence in the form of parallel acquisition of distinct, independent mutations to genes in the primary and metastatic samples (eg, PBRM1 and SETD2) in various spatiotemporally divergent patterns.	('SETD2', 'Gene', (198, 203))	('PBRM1', 'Gene', (188, 193))	('PBRM1', 'Gene', '55193', (188, 193))	('mutations', 'Var', (126, 135))	('SETD2', 'Gene', '29072', (198, 203))
14109	29066084	Furthermore, we found evidence of an association between SETD2 mutations and higher P-M mutation discordance.	('mutations', 'Var', (63, 72))	('SETD2', 'Gene', '29072', (57, 62))	('SETD2', 'Gene', (57, 62))
14111	29066084	Such sequencing could reveal the presence of targetable mutations that would influence therapeutic decisions for a subset of patients.	('patients', 'Species', '9606', (125, 133))	('mutations', 'Var', (56, 65))	('influence', 'Reg', (77, 86))
14112	29066084	In fact, two patients in our cohort harbored mutations in TSC1 or TSC2 that were evident in the primary but not the matched metastatic sample, suggesting that treatment with everolimus might not have been effective in the metastatic setting.	('mutations', 'Var', (45, 54))	('TSC2', 'Gene', '7249', (66, 70))	('patients', 'Species', '9606', (13, 21))	('TSC2', 'Gene', (66, 70))	('TSC1', 'Gene', '7248', (58, 62))	('everolimus', 'Chemical', 'MESH:C107135', (174, 184))	('TSC1', 'Gene', (58, 62))
14113	29066084	Furthermore, the primary tumor from patient P-0001232 (labeled with asterisk in Fig.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('P-0001232', 'Chemical', 'MESH:D010695', (44, 53))	('P-0001232', 'Var', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('patient', 'Species', '9606', (36, 43))
14114	29066084	1) harbored mutations in both PBRM1 and BAP1, which predict poor clinical outcome; nevertheless, this patient had a relatively indolent clinical course and responded to targeted therapies.	('PBRM1', 'Gene', (30, 35))	('patient', 'Species', '9606', (102, 109))	('mutations', 'Var', (12, 21))	('PBRM1', 'Gene', '55193', (30, 35))	('BAP1', 'Gene', '8314', (40, 44))	('BAP1', 'Gene', (40, 44))
14115	29066084	Sequencing of the metastatic tumor from patient P-0001232 revealed that it carried only the PBRM1 mutation.	('patient', 'Species', '9606', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mutation', 'Var', (98, 106))	('P-0001232', 'Var', (48, 57))	('PBRM1', 'Gene', '55193', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('carried', 'Reg', (75, 82))	('P-0001232', 'Chemical', 'MESH:D010695', (48, 57))	('tumor', 'Disease', (29, 34))	('PBRM1', 'Gene', (92, 97))
14121	29066084	Using next-generation sequencing, we determined mutation discordance for cancer genes between matched primary and metastatic tumor samples from patients with renal cell carcinoma.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (158, 178))	('tumor', 'Disease', (125, 130))	('patients', 'Species', '9606', (144, 152))	('renal cell carcinoma', 'Disease', (158, 178))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (158, 178))	('mutation discordance', 'Var', (48, 68))
14122	29066084	As most precision cancer medicine administers targeted agents on the basis of mutations detected in primary tumors, further investigation into the genomic discordance between primary and metastatic tumor pairs is warranted.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('primary tumors', 'Disease', (100, 114))	('tumor', 'Disease', (108, 113))	('mutations', 'Var', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('primary tumors', 'Disease', 'MESH:D001932', (100, 114))	('tumor', 'Disease', (198, 203))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
14128	33177176	Samples were categorized as CD73negative (CS=0), CD73low or CD73high (< and >=median CS, respectively).	('CS', 'Chemical', '-', (85, 87))	('CD73high', 'Var', (60, 68))	('CS', 'Chemical', '-', (42, 44))	('CD73negative', 'Var', (28, 40))	('CD73low', 'Var', (49, 56))
14134	33177176	In the TCGA analysis, high NT5E expression was associated with significantly worse 5-year OS (p=0.008).	('5-year OS', 'CPA', (83, 92))	('high', 'Var', (22, 26))	('NT5E', 'Gene', '4907', (27, 31))	('worse', 'NegReg', (77, 82))	('expression', 'MPA', (32, 42))	('NT5E', 'Gene', (27, 31))
14138	33177176	Recent studies combining PD-1/L1 inhibitors with either the vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor axitinib or the anti-CTLA-4 antibody ipilimumab have demonstrated improved objective response rates (ORRs), progression-free survival (PFS) and overall survival (OS) compared with sunitinib.	('sunitinib', 'Chemical', 'MESH:D000077210', (317, 326))	('objective response rates', 'CPA', (212, 236))	('antibody', 'molecular_function', 'GO:0003823', ('165', '173'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('120', '136'))	('antibody', 'cellular_component', 'GO:0042571', ('165', '173'))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('60', '94'))	('VEGF', 'Gene', '7422', (96, 100))	('antibody', 'cellular_component', 'GO:0019815', ('165', '173'))	('VEGF', 'Gene', (96, 100))	('ipilimumab', 'Chemical', 'MESH:D000074324', (174, 184))	('axitinib', 'Chemical', 'MESH:D000077784', (137, 145))	('CTLA-4', 'Gene', '1493', (158, 164))	('CTLA-4', 'Gene', (158, 164))	('overall survival', 'CPA', (281, 297))	('antibody', 'cellular_component', 'GO:0019814', ('165', '173'))	('improved', 'PosReg', (203, 211))	('PD-1/L1', 'Gene', (25, 32))	('progression-free survival', 'CPA', (245, 270))	('inhibitors', 'Var', (33, 43))
14144	33177176	Adenosine generated by CD73 and CD39 binds to and activates G protein-coupled A1, A2A, A2B, and A3 receptors.	('Adenosine', 'Chemical', 'MESH:D000241', (0, 9))	('A2B', 'Protein', (87, 90))	('activates', 'PosReg', (50, 59))	('A2A', 'Protein', (82, 85))	('CD39', 'Gene', '953', (32, 36))	('binds', 'Interaction', (37, 42))	('A3 receptors', 'Protein', (96, 108))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))	('CD73', 'Var', (23, 27))	('CD39', 'Gene', (32, 36))	('G protein-coupled A1', 'Protein', (60, 80))
14150	33177176	Using gene expression data from The Cancer Genome Atlas (TCGA) Kidney Renal Clear Cell Carcinoma (KIRC) dataset, we also evaluated the correlation of mRNA expression of CD73 (NT5E), CD39 (ENTPD1) and A2AR (ADORA2A) with gene expression signatures reflecting angiogenesis, myeloid inflammation and effector T-cell response (Teff) and infiltrating immune cell subsets.	('Kidney Renal Clear Cell Carcinoma', 'Disease', (63, 96))	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('myeloid inflammation', 'Disease', 'MESH:D007249', (272, 292))	('NT5E', 'Gene', '4907', (175, 179))	('CD73', 'Var', (169, 173))	('A2AR', 'Gene', (200, 204))	('myeloid inflammation', 'Disease', (272, 292))	('Cancer', 'Disease', (36, 42))	('ADORA2A', 'Gene', '135', (206, 213))	('angiogenesis', 'biological_process', 'GO:0001525', ('258', '270'))	('ENTPD1', 'Gene', '953', (188, 194))	('gene expression', 'biological_process', 'GO:0010467', ('220', '235'))	('CD39', 'Gene', (182, 186))	('NT5E', 'Gene', (175, 179))	('CD39', 'Gene', '953', (182, 186))	('Cancer', 'Disease', 'MESH:D009369', (36, 42))	('gene expression', 'biological_process', 'GO:0010467', ('6', '21'))	('A2AR', 'Gene', '135', (200, 204))	('ENTPD1', 'Gene', (188, 194))	('inflammation', 'biological_process', 'GO:0006954', ('280', '292'))	('ADORA2A', 'Gene', (206, 213))	('Kidney Renal Clear Cell Carcinoma', 'Disease', 'MESH:C538614', (63, 96))	('Carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
14161	33177176	Patients with CD73 positivity were categorized into CD73low and CD73high subgroups.	('Patients', 'Species', '9606', (0, 8))	('positivity', 'Var', (19, 29))	('CD73high', 'Var', (64, 72))	('CD73', 'Gene', (14, 18))
14171	33177176	The distribution of CD73 expression in the primary tumor (CD73negative vs CD73low or CD73high) by baseline clinical and pathologic characteristics was compared using the Cochran-Armitage Trend test (for variables with two categories) and Jonckheere-Terpstra test (for variables three or more ordered categories).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('CD73low', 'Var', (74, 81))	('tumor', 'Disease', (51, 56))	('CD73', 'Gene', (20, 24))	('CD73negative', 'Var', (58, 70))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('CD73high', 'Var', (85, 93))
14192	33177176	Similarly, high CD73 expression was more frequent in grade four tumors (27%) compared with grade 3 (13%) or grade 1-2 (15%, ptrend=0.035, figure 2), pathologic stage >=T3 (22%) compared with T2 (19%) and T1 (12%; ptrend=0.004) and locally advanced disease stage (AJCC stage, IV: 29% vs III: 12% vs II: 21% vs I: 9%; ptrend <0.0001).	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('CD73', 'Protein', (16, 20))	('expression', 'MPA', (21, 31))	('high', 'Var', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
14194	33177176	In contrast, in tumors without sarcomatoid features, only 24% (n=30) demonstrated any CD73 expression and only 12% (n=15) were CD73high (p<0.001).	('expression', 'MPA', (91, 101))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('sarcomatoid', 'Disease', 'MESH:C538614', (31, 42))	('CD73high', 'Var', (127, 135))	('tumors', 'Disease', (16, 22))	('CD73', 'Protein', (86, 90))	('sarcomatoid', 'Disease', (31, 42))
14196	33177176	DFS at 5 years for patients in the CD73negative, CD73low and CD73high groups was 75%, 50% and 42%, respectively (figure 3A).	('CD73negative', 'Var', (35, 47))	('CD73high', 'Var', (61, 69))	('patients', 'Species', '9606', (19, 27))	('CD73low', 'Var', (49, 56))
14197	33177176	In an exploratory analysis evaluating OS in patients with de novo mRCC (n=31), there was no statistically significant difference in 2-year OS between patients in the CD73negative (43%), CD73low (50%) and CD73high groups (52%, online supplemental figure 2; p=0.52).	('CD73low', 'Var', (186, 193))	('patients', 'Species', '9606', (44, 52))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('CD73high', 'Var', (204, 212))	('patients', 'Species', '9606', (150, 158))	('CD73negative', 'Var', (166, 178))
14198	33177176	In the complementary analysis using TCGA RNA-seq data, high NT5E expression was associated with significantly lower 5-year OS compared with intermediate or low NT5E expression (figure 4A) in AJCC stage IV tumors.	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('NT5E', 'Gene', '4907', (60, 64))	('NT5E', 'Gene', '4907', (160, 164))	('RNA', 'cellular_component', 'GO:0005562', ('41', '44'))	('NT5E', 'Gene', (160, 164))	('NT5E', 'Gene', (60, 64))	('lower', 'NegReg', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('high', 'Var', (55, 59))	('5-year', 'CPA', (116, 122))	('tumors', 'Disease', (205, 211))	('expression', 'Var', (65, 75))
14204	33177176	Teff, myeloid inflammation, and other immune cell signatures (eg, CD8+ T cells, B cells, neutrophils, and macrophages) were not significantly different between the low intermediate and high NT5E, ENTPD1 or ADORA2A expression groups.	('ENTPD1', 'Gene', (196, 202))	('myeloid inflammation', 'Disease', 'MESH:D007249', (6, 26))	('ADORA2A', 'Gene', '135', (206, 213))	('NT5E', 'Gene', (190, 194))	('inflammation', 'biological_process', 'GO:0006954', ('14', '26'))	('ENTPD1', 'Gene', '953', (196, 202))	('ADORA2A', 'Gene', (206, 213))	('CD8', 'Gene', (66, 69))	('CD8', 'Gene', '925', (66, 69))	('myeloid inflammation', 'Disease', (6, 26))	('low intermediate', 'Var', (164, 180))	('NT5E', 'Gene', '4907', (190, 194))
14207	33177176	In a complementary analysis using the TCGA gene expression dataset, high NT5E (CD73) gene expression was associated with significantly worse OS in AJCC stage IV tumors.	('gene expression', 'biological_process', 'GO:0010467', ('85', '100'))	('gene expression', 'biological_process', 'GO:0010467', ('43', '58'))	('high', 'Var', (68, 72))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('CD73', 'Gene', (79, 83))	('worse', 'NegReg', (135, 140))	('NT5E', 'Gene', '4907', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('NT5E', 'Gene', (73, 77))
14217	33177176	Similarly, in the TCGA dataset, high NT5E expression was associated with worse outcomes in patients with AJCC stage IV RCC.	('high', 'Var', (32, 36))	('patients', 'Species', '9606', (91, 99))	('NT5E', 'Gene', '4907', (37, 41))	('expression', 'MPA', (42, 52))	('NT5E', 'Gene', (37, 41))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))
14224	33177176	We observed CD73 positivity in 39% of our non-ccRCC samples with 24% demonstrating high CD73 expression.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('CD73', 'Gene', (12, 16))	('positivity', 'Var', (17, 27))	('expression', 'MPA', (93, 103))	('RCC', 'Disease', (48, 51))	('CD73', 'Gene', (88, 92))
14236	33177176	Further, there was no significant difference in MDSC signature between low and high NT5E expression groups (p=3.50E-01).	('MDSC signature', 'MPA', (48, 62))	('NT5E', 'Gene', '4907', (84, 88))	('E-01', 'CellLine', 'CVCL:9726', (114, 118))	('NT5E', 'Gene', (84, 88))	('high', 'Var', (79, 83))
14238	33177176	Preclinical evidence also suggests that CD73-adenosine signaling may promote angiogenesis through vasodilation, release of proangiogenic factors such as VEGF, and recruitment of endothelial progenitor cells.	('adenosine', 'Chemical', 'MESH:D000241', (45, 54))	('CD73-adenosine', 'Var', (40, 54))	('VEGF', 'Gene', (153, 157))	('release', 'MPA', (112, 119))	('angiogenesis', 'CPA', (77, 89))	('signaling', 'biological_process', 'GO:0023052', ('55', '64'))	('recruitment', 'CPA', (163, 174))	('VEGF', 'Gene', '7422', (153, 157))	('promote', 'PosReg', (69, 76))	('vasodilation', 'CPA', (98, 110))	('angiogenesis', 'biological_process', 'GO:0001525', ('77', '89'))	('vasodilation', 'biological_process', 'GO:0042311', ('98', '110'))
14240	33177176	Dysregulation of the proangiogenic HIF pathway is a critical oncogenic driver in RCC, and A2AR has been identified as a downstream proangiogenic target unique to HIF-2alpha.	('Dysregulation', 'Var', (0, 13))	('HIF-2alpha', 'Gene', '2034', (162, 172))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('A2AR', 'Gene', '135', (90, 94))	('A2AR', 'Gene', (90, 94))	('HIF-2alpha', 'Gene', (162, 172))
14245	33177176	Among patients with treatment-refractory mRCC, ciforadenant demonstrated encouraging efficacy, and disease control lasting at least 6 months was seen in 39% of patients treated with the combination.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('patients', 'Species', '9606', (160, 168))	('ciforadenant', 'Var', (47, 59))	('patients', 'Species', '9606', (6, 14))	('RCC', 'Disease', (42, 45))
14246	33177176	Multiple ongoing trials are investigating adenosine pathway blockade via inhibition of CD73, A2AR, and CD39 as monotherapy and combinations (eg, NCT04148937, NCT03549000, NCT03454451, NCT03835949, NCT03884556, NCT03381274, and NCT04336098).	('NCT03835949', 'Var', (184, 195))	('NCT03884556', 'Var', (197, 208))	('adenosine', 'Chemical', 'MESH:D000241', (42, 51))	('NCT03381274', 'Var', (210, 221))	('CD73', 'Gene', (87, 91))	('CD39', 'Gene', (103, 107))	('NCT04148937', 'Var', (145, 156))	('adenosine pathway', 'Pathway', (42, 59))	('CD39', 'Gene', '953', (103, 107))	('A2AR', 'Gene', '135', (93, 97))	('NCT04336098', 'Var', (227, 238))	('A2AR', 'Gene', (93, 97))	('NCT03454451', 'Var', (171, 182))	('NCT03549000', 'Var', (158, 169))
14254	33177176	In addition, gene expression of CD73, CD39 and A2AR was associated with increased immunosuppressive cell markers and while A2AR expression correlated with the angiogenesis signature in the TCGA cohort.	('A2AR', 'Gene', '135', (123, 127))	('A2AR', 'Gene', (47, 51))	('immunosuppressive cell markers', 'MPA', (82, 112))	('increased', 'PosReg', (72, 81))	('A2AR', 'Gene', (123, 127))	('gene expression', 'biological_process', 'GO:0010467', ('13', '28'))	('correlated', 'Reg', (139, 149))	('CD39', 'Gene', (38, 42))	('CD73', 'Var', (32, 36))	('CD39', 'Gene', '953', (38, 42))	('angiogenesis', 'CPA', (159, 171))	('expression', 'MPA', (128, 138))	('angiogenesis', 'biological_process', 'GO:0001525', ('159', '171'))	('A2AR', 'Gene', '135', (47, 51))
14256	32260198	A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2 In a recent report, no significance of transglutaminase 2 (TGase 2) was noted in the analyses of expression differences between normal and clear cell renal cell carcinoma (ccRCC), although we found that knock down of TGase 2 induced significant p53-mediated cell death in ccRCC.	('Carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('TGase 2', 'Gene', (299, 306))	('p53', 'Gene', '7157', (327, 330))	('RCC', 'Disease', 'MESH:C538614', (356, 359))	('transglutaminase 2', 'Gene', (121, 139))	('transglutaminase 2', 'Gene', '7052', (121, 139))	('knock down', 'Var', (285, 295))	('p53', 'Gene', (327, 330))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (221, 252))	('ccRCC', 'Phenotype', 'HP:0006770', (254, 259))	('RCC', 'Disease', (256, 259))	('RCC', 'Phenotype', 'HP:0005584', (256, 259))	('cell death', 'biological_process', 'GO:0008219', ('340', '350'))	('Renal Cell Carcinoma', 'Disease', (29, 49))	('clear cell renal cell carcinoma', 'Disease', (221, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('RCC', 'Disease', 'MESH:C538614', (256, 259))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (232, 252))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (29, 49))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (221, 252))	('RCC', 'Phenotype', 'HP:0005584', (356, 359))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (29, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (354, 359))	('RCC', 'Disease', (356, 359))
14260	32260198	Therefore, most of ccRCC presents high level expression of TGase 2 because over 90% of ccRCC showed VHL inactivity through mutation and methylation.	('methylation', 'Var', (136, 147))	('mutation', 'Var', (123, 131))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('VHL', 'Gene', (100, 103))	('methylation', 'biological_process', 'GO:0032259', ('136', '147'))	('RCC', 'Disease', (21, 24))	('inactivity', 'NegReg', (104, 114))	('VHL', 'Gene', '7428', (100, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (19, 24))
14266	32260198	To date, germline mutations of genes have been associated with an increased risk of kidney cancer and have provided the foundation for mapping the genetic pathways altered in RCC.	('kidney cancer', 'Disease', (84, 97))	('RCC', 'Disease', 'MESH:C538614', (175, 178))	('kidney cancer', 'Phenotype', 'HP:0009726', (84, 97))	('kidney cancer', 'Disease', 'MESH:D007680', (84, 97))	('RCC', 'Disease', (175, 178))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('associated', 'Reg', (47, 57))	('germline mutations', 'Var', (9, 27))
14267	32260198	Mutation of these genes such as von Hippel-Lindau (VHL) tumor suppressor gene can activate the hypoxia-inducible factor (HIF) pathway and upregulate the phosphoinositide 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) pathway.	('tumor suppressor', 'biological_process', 'GO:0051726', ('56', '72'))	('activate', 'PosReg', (82, 90))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('56', '72'))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('PI3K', 'molecular_function', 'GO:0016303', ('180', '184'))	('hypoxia', 'Disease', (95, 102))	('hypoxia', 'Disease', 'MESH:D000860', (95, 102))	('mammalian target of rapamycin', 'Gene', '2475', (187, 216))	('Mutation', 'Var', (0, 8))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (32, 61))	('mTOR', 'Gene', '2475', (218, 222))	('mTOR', 'Gene', (218, 222))	('phosphoinositide 3-kinase', 'Gene', '5295', (153, 178))	('phosphoinositide 3-kinase', 'Gene', (153, 178))	('mammalian target of rapamycin', 'Gene', (187, 216))	('upregulate', 'PosReg', (138, 148))
14268	32260198	Inactivation of pVHL through protein modification also induces signaling of HIF-1alpha and NF-kappaB.	('signaling', 'biological_process', 'GO:0023052', ('63', '72'))	('NF-kappaB', 'Gene', '4790', (91, 100))	('pVHL', 'Gene', '7428', (16, 20))	('HIF-1alpha', 'Gene', (76, 86))	('NF-kappaB', 'Gene', (91, 100))	('signaling', 'MPA', (63, 72))	('induces', 'Reg', (55, 62))	('protein modification', 'biological_process', 'GO:0036211', ('29', '49'))	('protein', 'Protein', (29, 36))	('HIF-1alpha', 'Gene', '3091', (76, 86))	('Inactivation', 'Var', (0, 12))	('pVHL', 'Gene', (16, 20))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))
14296	32260198	Drosophila larvae with TGase knock out showed increased mortality after septic injury.	('mortality', 'Disease', (56, 65))	('septic injury', 'Disease', 'MESH:D001170', (72, 85))	('increased', 'PosReg', (46, 55))	('mortality', 'Disease', 'MESH:D003643', (56, 65))	('TGase', 'Gene', (23, 28))	('Drosophila', 'Species', '7227', (0, 10))	('septic injury', 'Disease', (72, 85))	('knock out', 'Var', (29, 38))
14304	32260198	Therefore, TGase 2 knock down reduced the cell attachment, migration and invasion in cancer, showing the same effect produced by knock down of fibronectin.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('TGase 2', 'Gene', (11, 18))	('fibronectin', 'Gene', '2335', (143, 154))	('cancer', 'Disease', (85, 91))	('knock down', 'Var', (19, 29))	('reduced', 'NegReg', (30, 37))	('invasion', 'CPA', (73, 81))	('cell attachment', 'CPA', (42, 57))	('migration', 'CPA', (59, 68))	('fibronectin', 'Gene', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
14309	32260198	Later, we were surprised by the opposite regulation, in that TGase 2 was also able to activate NF-kappaB through I-kappaBalpha depletion via polymerization in immortalized glial cells and breast cancer cells.	('NF-kappaB', 'Gene', '4790', (95, 104))	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('polymerization', 'Var', (141, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('I-kappaBalpha', 'Gene', (113, 126))	('breast cancer', 'Disease', (188, 201))	('depletion', 'NegReg', (127, 136))	('NF-kappaB', 'Gene', (95, 104))	('activate', 'PosReg', (86, 94))	('regulation', 'biological_process', 'GO:0065007', ('41', '51'))	('I-kappaBalpha', 'Gene', '4792', (113, 126))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
14311	32260198	VHL mutation is often observed in cancer, which results in an increase of the HIF-1alpha protein level and IGF-1R transcription level.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('transcription', 'biological_process', 'GO:0006351', ('114', '127'))	('IGF-1R', 'Gene', '3480', (107, 113))	('HIF-1alpha', 'Gene', '3091', (78, 88))	('mutation', 'Var', (4, 12))	('observed', 'Reg', (22, 30))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))	('VHL', 'Gene', (0, 3))	('cancer', 'Disease', (34, 40))	('VHL', 'Gene', '7428', (0, 3))	('HIF-1alpha', 'Gene', (78, 88))	('IGF-1R', 'Gene', (107, 113))	('increase', 'PosReg', (62, 70))
14320	32260198	For example, when two TGase 2 substrates such as histamine (KM: 0.38 mM) and ornithine (KM: 1.35 mM) are present in the same concentration, TGase 2 will bind and react preferentially with histamine.	('histamine', 'Chemical', 'MESH:D006632', (188, 197))	('bind', 'Interaction', (153, 157))	('ornithine', 'Chemical', 'MESH:D009952', (77, 86))	('react', 'Interaction', (162, 167))	('KM:', 'Var', (88, 91))	('KM:', 'Var', (60, 63))	('histamine', 'Protein', (188, 197))	('histamine', 'Chemical', 'MESH:D006632', (49, 58))	('preferentially', 'PosReg', (168, 182))
14331	32260198	It has been shown that TGase 2 knock down induced p53-mediated cell death and that inhibition of TGase 2 by a single treatment of 0.2 mg/kg of streptonigrin showed almost a complete response of therapeutic effect in ccRCC xenograft models.	('TGase 2', 'Gene', (23, 30))	('knock down', 'Var', (31, 41))	('streptonigrin', 'Chemical', 'MESH:D013308', (143, 156))	('ccRCC', 'Phenotype', 'HP:0006770', (216, 221))	('therapeutic effect', 'CPA', (194, 212))	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('RCC', 'Disease', (218, 221))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))	('RCC', 'Phenotype', 'HP:0005584', (218, 221))	('TGase 2', 'Gene', (97, 104))	('inhibition', 'Var', (83, 93))	('cell death', 'biological_process', 'GO:0008219', ('63', '73'))
14332	32260198	A series of reports showed that in ccRCC cell lines, cell death was induced by TGase 2 knock down using siRNA of TGase 2, while TGase 2 knock down did not lead to any cell death effect in the normal immortalized cell HEK293.	('cell death', 'biological_process', 'GO:0008219', ('167', '177'))	('knock down', 'Var', (87, 97))	('HEK293', 'CellLine', 'CVCL:0045', (217, 223))	('induced', 'Reg', (68, 75))	('TGase 2', 'Gene', (79, 86))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('cell death', 'biological_process', 'GO:0008219', ('53', '63'))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('ccRCC', 'Phenotype', 'HP:0006770', (35, 40))	('cell death', 'CPA', (53, 63))
14335	32260198	Additionally, p53 inactivation in cancer is associated with aggressive growth and poor prognosis.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('p53', 'Gene', '7157', (14, 17))	('p53', 'Gene', (14, 17))	('inactivation', 'Var', (18, 30))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('aggressive growth', 'CPA', (60, 77))	('cancer', 'Disease', (34, 40))
14336	32260198	Many cancer types have a high level of p53 mutation that abrogates p53's tumor suppressive role.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('mutation', 'Var', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Disease', (5, 11))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('abrogates', 'NegReg', (57, 66))	('tumor', 'Disease', (73, 78))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
14337	32260198	However, less than 5% of ccRCCs show p53 mutations, even though p53 levels are down-regulated.	('mutations', 'Var', (41, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (25, 30))	('p53', 'Gene', '7157', (37, 40))	('p53', 'Gene', (37, 40))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('p53', 'Gene', (64, 67))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('p53', 'Gene', '7157', (64, 67))
14339	32260198	TGase 2 targets the DNA-binding domain (residue 102-292 of p53).	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('residue 102-292', 'Var', (40, 55))	('DNA-binding', 'molecular_function', 'GO:0003677', ('20', '31'))	('DNA', 'cellular_component', 'GO:0005574', ('20', '23'))
14340	32260198	Upon deletion of this region, p53 completely loses its capacity to bind to TGase 2. p53-TGase 2-p62 complexes are specifically transported to the autophagosome and are degraded by the autophagic process.	('deletion', 'Var', (5, 13))	('p62', 'Gene', '23636', (96, 99))	('degraded', 'NegReg', (168, 176))	('p62', 'Gene', (96, 99))	('autophagic process', 'CPA', (184, 202))	('autophagosome', 'cellular_component', 'GO:0005776', ('146', '159'))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))
14358	32260198	Somatic mutation or inactivation via gene modification of both VHL tumor suppressor alleles is commonly observed in ccRCC.	('VHL tumor', 'Disease', 'MESH:D006623', (63, 72))	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('RCC', 'Disease', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('inactivation', 'Var', (20, 32))	('tumor suppressor', 'biological_process', 'GO:0051726', ('67', '83'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('gene modification', 'Var', (37, 54))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('67', '83'))	('VHL tumor', 'Disease', (63, 72))	('observed', 'Reg', (104, 112))
14366	32260198	Therefore, the high level of VHL inactivation in ccRCC was primarily responsible for the induction of TGase 2 expression (Figure 1).	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('TGase 2', 'Gene', (102, 109))	('induction', 'PosReg', (89, 98))	('VHL', 'Gene', (29, 32))	('VHL', 'Gene', '7428', (29, 32))	('expression', 'MPA', (110, 120))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('inactivation', 'Var', (33, 45))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
14372	32260198	TGase 2 expression was down regulated 4-8 fold by miR-1285 transfection in RCC (Figure 1).	('TGase 2', 'Gene', (0, 7))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('miR-1285 transfection', 'Var', (50, 71))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('transfection', 'Var', (59, 71))	('expression', 'MPA', (8, 18))	('down regulated', 'NegReg', (23, 37))	('miR-1285', 'Chemical', '-', (50, 58))
14373	32260198	Furthermore, this report showed that TGase 2 knock down significantly reduced cell proliferation and invasion in RCC cells, which corroborates other reports that TGase 2 knock down induced cell death.	('TGase 2', 'Gene', (37, 44))	('knock down', 'Var', (45, 55))	('cell proliferation', 'biological_process', 'GO:0008283', ('78', '96'))	('reduced', 'NegReg', (70, 77))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('cell death', 'biological_process', 'GO:0008219', ('189', '199'))	('RCC', 'Disease', (113, 116))	('cell proliferation', 'CPA', (78, 96))
14380	32260198	Although this report did not show the mechanism by which TGase 2 was induced by mTOR inhibition, it showed that combined inhibition of TGase 2 and mTOR reversed mTOR resistance in cancer cell.	('cancer', 'Disease', (180, 186))	('mTOR', 'Gene', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('mTOR', 'Gene', '2475', (80, 84))	('mTOR', 'Gene', '2475', (147, 151))	('inhibition', 'Var', (121, 131))	('mTOR', 'Gene', (161, 165))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('mTOR', 'Gene', '2475', (161, 165))	('TGase 2', 'Gene', (135, 142))	('mTOR', 'Gene', (147, 151))
14382	32260198	However, it is also known that mTOR inhibition induces drug resistance through autophagy induction in cancer cells.	('autophagy induction', 'CPA', (79, 98))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('induces', 'Reg', (47, 54))	('mTOR', 'Gene', (31, 35))	('inhibition', 'Var', (36, 46))	('mTOR', 'Gene', '2475', (31, 35))	('drug resistance', 'CPA', (55, 70))	('drug resistance', 'Phenotype', 'HP:0020174', (55, 70))	('drug resistance', 'biological_process', 'GO:0042493', ('55', '70'))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('autophagy', 'biological_process', 'GO:0016236', ('79', '88'))	('autophagy', 'biological_process', 'GO:0006914', ('79', '88'))	('drug resistance', 'biological_process', 'GO:0009315', ('55', '70'))
14387	32260198	Loss of TGase 2 expression causes great damage in sepsis but conversely, it helps with evading inflammation in an allergic reaction.	('allergic reaction', 'Disease', 'MESH:D004342', (114, 131))	('sepsis', 'Disease', 'MESH:D018805', (50, 56))	('inflammation', 'Disease', 'MESH:D007249', (95, 107))	('allergic reaction', 'Disease', (114, 131))	('helps', 'Reg', (76, 81))	('allergic reaction', 'Phenotype', 'HP:0012393', (114, 131))	('inflammation', 'Disease', (95, 107))	('inflammation', 'biological_process', 'GO:0006954', ('95', '107'))	('TGase 2', 'Gene', (8, 15))	('Loss', 'Var', (0, 4))	('sepsis', 'Phenotype', 'HP:0100806', (50, 56))	('sepsis', 'Disease', (50, 56))
14388	32260198	In cancer, TGase 2 knock down causes down regulation of cancer progression because the roles of TGase 2 in cancer converge, promoting cancer progression by way of adhesion, proliferation, and EMT (reviewed in).	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (56, 62))	('promoting', 'PosReg', (124, 133))	('TGase 2', 'Gene', (11, 18))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('proliferation', 'CPA', (173, 186))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('TGase 2', 'Gene', (96, 103))	('adhesion', 'CPA', (163, 171))	('EMT', 'CPA', (192, 195))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Disease', (107, 113))	('EMT', 'biological_process', 'GO:0001837', ('192', '195'))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('knock down', 'Var', (19, 29))	('cancer', 'Disease', (3, 9))	('regulation', 'biological_process', 'GO:0065007', ('42', '52'))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
14389	32260198	TGase 2 knock down or inhibition by single targeting specifically induces an anti-cancer effect in ccRCC through stabilization of p53, because p53 binds directly to TGase 2 and is thus chaperoned to the autophagosome for degradation.	('binds', 'Interaction', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TGase 2', 'Gene', (0, 7))	('p53', 'Gene', '7157', (143, 146))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('degradation', 'biological_process', 'GO:0009056', ('221', '232'))	('autophagosome', 'cellular_component', 'GO:0005776', ('203', '216'))	('induces', 'Reg', (66, 73))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('knock down', 'Var', (8, 18))	('RCC', 'Disease', (101, 104))	('stabilization', 'MPA', (113, 126))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('p53', 'Gene', (130, 133))	('p53', 'Gene', (143, 146))	('p53', 'Gene', '7157', (130, 133))
14396	30519310	Comprehensive analysis including survival, transcriptome and methylation between BAP1 mutated and wild-type cases was performed using bioinformatics tools in silico.	('BAP1', 'Gene', '8314', (81, 85))	('mutated', 'Var', (86, 93))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('BAP1', 'Gene', (81, 85))
14397	30519310	Pathways and molecules related to BAP1 mutation were analyzed using Database for Annotation, Visualization and Integrated Discovery (DAVID) and protein-protein interaction (PPI) network.	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('mutation', 'Var', (39, 47))	('BAP1', 'Gene', (34, 38))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('PPI', 'biological_process', 'GO:0060134', ('173', '176'))	('BAP1', 'Gene', '8314', (34, 38))
14398	30519310	Results: BAP1 mutated ccRCC patients had a worse overall survival (OS) and disease free survival (DFS) than BAP1 wild-type patients.	('RCC', 'Disease', (24, 27))	('overall survival', 'CPA', (49, 65))	('mutated', 'Var', (14, 21))	('BAP1', 'Gene', '8314', (108, 112))	('RCC', 'Disease', 'MESH:C538614', (24, 27))	('ccRCC', 'Phenotype', 'HP:0006770', (22, 27))	('patients', 'Species', '9606', (123, 131))	('BAP1', 'Gene', '8314', (9, 13))	('BAP1', 'Gene', (108, 112))	('disease free survival', 'CPA', (75, 96))	('BAP1', 'Gene', (9, 13))	('RCC', 'Phenotype', 'HP:0005584', (24, 27))	('patients', 'Species', '9606', (28, 36))	('worse', 'NegReg', (43, 48))
14402	30519310	Finally, BAP1 mutation had a strong correlation with CpG island methylator phenotype (CIMP).	('CIMP', 'Chemical', '-', (86, 90))	('BAP1', 'Gene', '8314', (9, 13))	('mutation', 'Var', (14, 22))	('correlation', 'Interaction', (36, 47))	('BAP1', 'Gene', (9, 13))
14416	30519310	In addition, a comprehensive understanding of pathway changes caused by BAP1 mutations may also be useful in filtering potential therapeutic targets.	('BAP1', 'Gene', (72, 76))	('mutations', 'Var', (77, 86))	('BAP1', 'Gene', '8314', (72, 76))
14417	30519310	Previous studies revealed that in ccRCC patients, BAP1 has a high mutation rate in somatic cells and BAP1 germline mutations will lead to a hereditary renal carcinoma syndrome.	('hereditary renal carcinoma syndrome', 'Disease', (140, 175))	('germline', 'Var', (106, 114))	('lead to', 'Reg', (130, 137))	('RCC', 'Disease', (36, 39))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('BAP1', 'Gene', '8314', (101, 105))	('patients', 'Species', '9606', (40, 48))	('BAP1', 'Gene', '8314', (50, 54))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (34, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('BAP1', 'Gene', (101, 105))	('hereditary renal carcinoma syndrome', 'Disease', 'MESH:D007680', (140, 175))	('BAP1', 'Gene', (50, 54))	('renal carcinoma', 'Phenotype', 'HP:0005584', (151, 166))	('mutation', 'MPA', (66, 74))
14421	30519310	In this study, we analyzed 445 ccRCC cases using the complete gene expression data and somatic BAP1 mutation data retrieved from The Cancer Genome Atlas (TCGA) database.	('gene expression', 'biological_process', 'GO:0010467', ('62', '77'))	('Cancer Genome Atlas', 'Disease', (133, 152))	('BAP1', 'Gene', (95, 99))	('Cancer', 'Phenotype', 'HP:0002664', (133, 139))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (133, 152))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('mutation', 'Var', (100, 108))	('BAP1', 'Gene', '8314', (95, 99))	('ccRCC', 'Phenotype', 'HP:0006770', (31, 36))
14422	30519310	We performed a comprehensive analysis including survival, transcriptome, and methylation between BAP1-mutated and wild-type cases, and highlighted pathways and molecules related to BAP1 mutations.	('methylation', 'biological_process', 'GO:0032259', ('77', '88'))	('BAP1', 'Gene', (181, 185))	('BAP1', 'Gene', '8314', (97, 101))	('mutations', 'Var', (186, 195))	('BAP1', 'Gene', (97, 101))	('BAP1', 'Gene', '8314', (181, 185))
14428	30519310	We also excluded one ccRCC case with a BAP1 mutation that was not in the UCH domain or NLS.	('mutation', 'Var', (44, 52))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (21, 26))	('RCC', 'Disease', (23, 26))	('BAP1', 'Gene', '8314', (39, 43))	('BAP1', 'Gene', (39, 43))
14429	30519310	Finally, 445 ccRCC cases were entered in our analysis, including 39 cases with BAP1 mutations and 406 cases with wild-type BAP1.	('BAP1', 'Gene', (123, 127))	('BAP1', 'Gene', '8314', (79, 83))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('RCC', 'Disease', (15, 18))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('BAP1', 'Gene', (79, 83))	('mutations', 'Var', (84, 93))	('BAP1', 'Gene', '8314', (123, 127))
14431	30519310	To test overall survival (OS) and disease-free survival (DFS) differences between cases with or without BAP1 mutations, the Kaplan-Meier method was used to compare survival curves for these two groups.	('BAP1', 'Gene', '8314', (104, 108))	('BAP1', 'Gene', (104, 108))	('mutations', 'Var', (109, 118))
14438	30519310	Overall, 445 ccRCC cases were divided into two cohorts (39 patients with BAP1 mutations and 406 patients without BAP1 mutations).	('BAP1', 'Gene', '8314', (73, 77))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('RCC', 'Disease', (15, 18))	('BAP1', 'Gene', (73, 77))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('mutations', 'Var', (78, 87))	('BAP1', 'Gene', '8314', (113, 117))	('patients', 'Species', '9606', (59, 67))	('patients', 'Species', '9606', (96, 104))	('BAP1', 'Gene', (113, 117))
14441	30519310	BAP1 mutations in these patients are shown in Table 2, and the total mutation frequency was 8.76% (39/445).	('BAP1', 'Gene', '8314', (0, 4))	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (24, 32))
14442	30519310	Among 538 ccRCC cases in TCGA, 40 patients carried a somatic BAP1 mutation.	('BAP1', 'Gene', (61, 65))	('RCC', 'Phenotype', 'HP:0005584', (12, 15))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('RCC', 'Disease', (12, 15))	('ccRCC', 'Phenotype', 'HP:0006770', (10, 15))	('patients', 'Species', '9606', (34, 42))	('mutation', 'Var', (66, 74))	('carried', 'Reg', (43, 50))	('BAP1', 'Gene', '8314', (61, 65))
14443	30519310	Most of the BAP1 mutations altered the UCH domain or NLS (39/40), and only 1 out of 40 mutation sites did not involve these two regions, which suggested that mutations in the UCH domain or NLS may play a role in tumorigenesis.	('altered', 'Reg', (27, 34))	('NLS', 'MPA', (53, 56))	('UCH domain', 'MPA', (39, 49))	('play', 'Reg', (197, 201))	('role', 'Reg', (204, 208))	('BAP1', 'Gene', '8314', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('mutations', 'Var', (158, 167))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('BAP1', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))	('tumor', 'Disease', (212, 217))
14445	30519310	Kaplan-Meier curves of 5-year OS and DFS between mutated and wild-type groups indicated that ccRCC patients with somatic BAP1 functional mutations had a significantly shorter OS (P=0.035) and DFS (P=0.036).	('shorter', 'NegReg', (167, 174))	('BAP1', 'Gene', '8314', (121, 125))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('DFS', 'MPA', (192, 195))	('BAP1', 'Gene', (121, 125))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('mutations', 'Var', (137, 146))	('RCC', 'Disease', (95, 98))	('patients', 'Species', '9606', (99, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))
14450	30519310	Gene methylation data of 260 ccRCC tumor tissues (23 with BAP1 mutations) were clustered and cases were divided into a CIMP cluster and non-CIMP cluster based on the clustering results (Figure 4).	('mutations', 'Var', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('BAP1', 'Gene', (58, 62))	('tumor', 'Disease', (35, 40))	('CIMP', 'Chemical', '-', (119, 123))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))	('CIMP', 'Chemical', '-', (140, 144))	('methylation', 'biological_process', 'GO:0032259', ('5', '16'))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))	('BAP1', 'Gene', '8314', (58, 62))
14457	30519310	Mutations in TP53 drives carcinogenesis in various cancers.	('TP53', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Mutations', 'Var', (0, 9))	('carcinogenesis', 'Disease', 'MESH:D063646', (25, 39))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('TP53', 'Gene', '7157', (13, 17))	('carcinogenesis', 'Disease', (25, 39))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('drives', 'Reg', (18, 24))
14473	30519310	TSPO-binding drugs have also been demonstrated to cause death of several cancer cells, and TSPO has already been viewed as a novel target for cancer chemotherapy.	('cause', 'Reg', (50, 55))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('TSPO', 'Gene', '706', (91, 95))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('drugs', 'Var', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('TSPO', 'Gene', '706', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('binding', 'molecular_function', 'GO:0005488', ('5', '12'))	('TSPO', 'Gene', (91, 95))	('death', 'Disease', 'MESH:D003643', (56, 61))	('death', 'Disease', (56, 61))	('TSPO', 'Gene', (0, 4))	('cancer', 'Disease', (142, 148))
14483	30519310	Recently, BAP1 was reported to be mutated in up to 14% of sporadic ccRCCs and was associated with more aggressive tumors and poorer patient outcomes.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('RCC', 'Disease', (69, 72))	('associated with', 'Reg', (82, 97))	('aggressive tumors', 'Disease', (103, 120))	('more', 'PosReg', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('BAP1', 'Gene', (10, 14))	('BAP1', 'Gene', '8314', (10, 14))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('aggressive tumors', 'Disease', 'MESH:D001523', (103, 120))	('patient', 'Species', '9606', (132, 139))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('mutated', 'Var', (34, 41))
14484	30519310	In addition, ccRCC with a pathogenic germline BAP1 mutation has already been defined as a tumor predisposition syndrome.	('germline', 'Var', (37, 45))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('BAP1', 'Gene', '8314', (46, 50))	('RCC', 'Disease', (15, 18))	('tumor', 'Disease', (90, 95))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('pathogenic', 'Reg', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('BAP1', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
14486	30519310	More clinical trials of new therapies like PARP inhibitors and immunotherapy, for patients with BAP1 mutations, will appear in the future.	('mutations', 'Var', (101, 110))	('PARP', 'Gene', (43, 47))	('BAP1', 'Gene', (96, 100))	('patients', 'Species', '9606', (82, 90))	('PARP', 'Gene', '1302', (43, 47))	('BAP1', 'Gene', '8314', (96, 100))
14495	30013825	Through the Gene Expression Omnibus (GEO) database, the Cancer Genome Atlas (TCGA) database and immunohistochemical (IHC) staining, we observed that compared with adjacent normal renal tissues, in ccRCC tissues the mRNA and protein levels of MMP9 were enhanced, and the mRNA levels of GTP-binding protein smg p21B(RAP1B), B rapidly accelerated fibrosarcoma (RAF), methyl ethyl ketone2 (MEK2), extracellular regulated protein kinases1 (ERK1), ERK2, v-ets avian erythroblastosis virus E26 oncogene homolog1 (ETS1) and ETS2 also increased.	('ERK2', 'molecular_function', 'GO:0004707', ('442', '446'))	('extracellular', 'cellular_component', 'GO:0005576', ('393', '406'))	('Gene Expression', 'biological_process', 'GO:0010467', ('12', '27'))	('RAP1B', 'Gene', (314, 319))	('fibrosarcoma', 'Disease', (344, 356))	('protein', 'cellular_component', 'GO:0003675', ('297', '304'))	('ethyl ketone', 'Chemical', 'MESH:C027452', (371, 383))	('GTP-binding', 'molecular_function', 'GO:0005525', ('285', '296'))	('ETS1', 'Gene', (506, 510))	('MMP9', 'molecular_function', 'GO:0004229', ('242', '246'))	('RAP1B', 'Gene', '5908', (314, 319))	('ERK2', 'Gene', (442, 446))	('MEK', 'Gene', '5609', (386, 389))	('smg p21B', 'Var', (305, 313))	('sarcoma', 'Phenotype', 'HP:0100242', (349, 356))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (56, 75))	('methyl ethyl ketone2', 'MPA', (364, 384))	('mRNA', 'MPA', (270, 274))	('ERK1', 'Gene', (435, 439))	('ETS2', 'Gene', '2114', (516, 520))	('ERK1', 'molecular_function', 'GO:0004707', ('435', '439'))	('MEK', 'Gene', (386, 389))	('accelerated', 'PosReg', (332, 343))	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Cancer Genome Atlas', 'Disease', (56, 75))	('rat', 'Species', '10116', (338, 341))	('ERK1', 'Gene', '5595', (435, 439))	('increased', 'PosReg', (526, 535))	('protein', 'cellular_component', 'GO:0003675', ('224', '231'))	('extracellular regulated protein kinases1', 'MPA', (393, 433))	('MMP9', 'Gene', '4318', (242, 246))	('MMP9', 'Gene', (242, 246))	('MEK2', 'molecular_function', 'GO:0004708', ('386', '390'))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (344, 356))	('enhanced', 'PosReg', (252, 260))	('v-ets avian erythroblastosis virus E26 oncogene homolog1', 'Gene', '2113', (448, 504))	('ETS2', 'Gene', (516, 520))	('ccRCC', 'Phenotype', 'HP:0006770', (197, 202))	('ERK2', 'Gene', '5594', (442, 446))	('protein', 'cellular_component', 'GO:0003675', ('417', '424'))	('ETS1', 'Gene', '2113', (506, 510))	('mRNA and', 'MPA', (215, 223))	('fibrosarcoma', 'Disease', 'MESH:D005354', (344, 356))
14496	30013825	The Kaplan-Meier survival analysis suggested that high MMP9 expression was an unfavorable prognostic biomarker for ccRCC patients.	('expression', 'MPA', (60, 70))	('MMP9', 'Gene', (55, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('MMP9', 'Gene', '4318', (55, 59))	('MMP9', 'molecular_function', 'GO:0004229', ('55', '59'))	('ccRCC', 'Disease', (115, 120))	('high', 'Var', (50, 54))	('patients', 'Species', '9606', (121, 129))
14507	30013825	GTP-binding protein smg p21B (RAP1B), a RAS family member, can activate B-Raf and subsequently activate MEK via Raf-mediated phosphorylation.	('smg p21B', 'Var', (20, 28))	('protein', 'cellular_component', 'GO:0003675', ('12', '19'))	('B-Raf', 'Gene', '673', (72, 77))	('RAP1B', 'Gene', '5908', (30, 35))	('activate', 'PosReg', (63, 71))	('activate', 'PosReg', (95, 103))	('GTP-binding', 'molecular_function', 'GO:0005525', ('0', '11'))	('MEK', 'Gene', (104, 107))	('MEK', 'Gene', '5609', (104, 107))	('phosphorylation', 'biological_process', 'GO:0016310', ('125', '140'))	('B-Raf', 'Gene', (72, 77))	('RAP1B', 'Gene', (30, 35))
14536	30013825	4) In the TCGA ccRCC cohort, we observed that patients with advanced stage and high expression level of MMP9 were at significantly increased risk of death.	('patients', 'Species', '9606', (46, 54))	('MMP9', 'Gene', (104, 108))	('high expression level', 'Var', (79, 100))	('MMP9', 'Gene', '4318', (104, 108))	('MMP9', 'molecular_function', 'GO:0004229', ('104', '108'))	('ccRCC', 'Phenotype', 'HP:0006770', (15, 20))	('death', 'Disease', 'MESH:D003643', (149, 154))	('death', 'Disease', (149, 154))
14555	30013825	Moreover, high expression of MMP9 in ccRCC was associated with the poor prognosis (Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('ccRCC', 'Disease', (37, 42))	('MMP9', 'Gene', (29, 33))	('MMP9', 'molecular_function', 'GO:0004229', ('29', '33'))	('high', 'Var', (10, 14))	('MMP9', 'Gene', '4318', (29, 33))	('associated', 'Reg', (47, 57))
14557	32690542	Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer Among more than 200 BAP1-mutant families affected by the "BAP1 cancer syndrome," nearly all individuals inheriting a BAP1 mutant allele developed one or more malignancies during their lifetime, mostly uveal and cutaneous melanoma, mesothelioma, and clear-cell renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (353, 362))	('cancer syndrome', 'Disease', (145, 160))	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('malignancies', 'Disease', 'MESH:D009369', (240, 252))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('mesothelioma', 'Disease', (313, 325))	('malignancies', 'Disease', (240, 252))	('BAP1', 'Gene', '8314', (102, 106))	('mesothelioma', 'Disease', 'MESH:D008654', (313, 325))	('Cancer', 'Disease', (75, 81))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (331, 362))	('BAP1', 'Gene', (199, 203))	('cutaneous melanoma', 'Disease', (293, 311))	('Human', 'Species', '9606', (69, 74))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (293, 311))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (293, 311))	('Mutations', 'Var', (56, 65))	('BAP1', 'Gene', '8314', (51, 55))	('BAP1', 'Gene', '8314', (140, 144))	('developed', 'Reg', (218, 227))	('BAP1', 'Gene', (102, 106))	('clear-cell renal cell carcinoma', 'Disease', (331, 362))	('Cancer', 'Disease', 'MESH:D009369', (75, 81))	('mutant', 'Var', (204, 210))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (342, 362))	('cancer syndrome', 'Disease', 'MESH:D009369', (145, 160))	('BAP1', 'Gene', (51, 55))	('BAP1', 'Gene', (140, 144))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (331, 362))	('melanoma', 'Phenotype', 'HP:0002861', (303, 311))	('BAP1', 'Gene', '8314', (199, 203))
14558	32690542	These cancer types are also those that, when they occur sporadically, are more likely to carry somatic biallelic BAP1 mutations.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutations', 'Var', (118, 127))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('biallelic', 'Var', (103, 112))	('cancer', 'Disease', (6, 12))	('BAP1', 'Gene', (113, 117))
14561	32690542	BAP1 has emerged as a critical tumor suppressor across multiple cancer types, predisposing to tumor development when mutated in the germline as well as somatically.	('tumor suppressor', 'biological_process', 'GO:0051726', ('31', '47'))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mutated', 'Var', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('BAP1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (31, 36))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('31', '47'))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
14567	32690542	Because of the powerful tumor suppressor activity of BAP1 and of its role in modulating "gene-environment" (GxE) interactions in cancer, an increasing number of researchers are investigating the biological mechanisms and medical implications of inherited and acquired BAP1 mutations.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumor suppressor', 'biological_process', 'GO:0051726', ('24', '40'))	('tumor', 'Disease', (24, 29))	('BAP1', 'Gene', (268, 272))	('cancer', 'Disease', (129, 135))	('mutations', 'Var', (273, 282))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('24', '40'))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('BAP1', 'Gene', (53, 57))
14569	32690542	It is an important component of the pathologic diagnosis of mesothelioma and early-detection clinical trials have been established at the NCI and elsewhere for carriers of germline BAP1 mutations (NCT03830229), including trials targeting BAP1 (NCT03207347, NCT03531840).	('NCT03830229', 'Var', (197, 208))	('BAP1', 'Gene', (181, 185))	('mesothelioma', 'Disease', 'MESH:D008654', (60, 72))	('mutations (NCT03830229', 'Var', (186, 208))	('NCT03207347', 'Var', (244, 255))	('NCT03531840', 'Var', (257, 268))	('mesothelioma', 'Disease', (60, 72))
14570	32690542	Here we review current understanding of how BAP1 suppresses tumorigenesis and how BAP1 status can inform diagnosis, prognosis, targeted therapy, and cancer prevention in patients with cancer with hereditary and acquired BAP1 mutations.	('cancer', 'Disease', (184, 190))	('patients', 'Species', '9606', (170, 178))	('cancer', 'Disease', (149, 155))	('mutations', 'Var', (225, 234))	('BAP1', 'Gene', (220, 224))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('suppresses', 'NegReg', (49, 59))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('BAP1', 'Gene', (44, 48))
14571	32690542	Moreover, we discuss some puzzling questions, such as why germline BAP1 mutations are associated with mesothelioma of low aggressiveness, but very aggressive uveal melanoma.	('mutations', 'Var', (72, 81))	('mesothelioma of low aggressiveness', 'Disease', 'MESH:D008654', (102, 136))	('aggressiveness', 'Phenotype', 'HP:0000718', (122, 136))	('associated', 'Reg', (86, 96))	('aggressive uveal melanoma', 'Disease', (147, 172))	('mesothelioma of low aggressiveness', 'Disease', (102, 136))	('uveal melanoma', 'Phenotype', 'HP:0007716', (158, 172))	('aggressive uveal melanoma', 'Disease', 'MESH:C536494', (147, 172))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('BAP1', 'Gene', (67, 71))
14575	32690542	The investigators proposed that GxE interactions caused the mesothelioma epidemic among genetically predisposed families, challenging the dogma that mesothelioma was an example of a malignancy caused exclusively by exposure to carcinogenic fibers.	('malignancy', 'Disease', 'MESH:D009369', (182, 192))	('interactions', 'Var', (36, 48))	('mesothelioma', 'Disease', 'MESH:D008654', (149, 161))	('malignancy', 'Disease', (182, 192))	('caused', 'Reg', (49, 55))	('mesothelioma', 'Disease', 'MESH:D008654', (60, 72))	('carcinogenic fibers', 'Disease', (227, 246))	('carcinogenic fibers', 'Disease', 'MESH:D000071075', (227, 246))	('mesothelioma', 'Disease', (149, 161))	('mesothelioma', 'Disease', (60, 72))
14581	32690542	Both tumors have a high frequency of 3p deletions, and, by sequencing 3p, Carbone and colleagues discovered that the individuals affected by mesothelioma, uveal melanoma, or breast cancer in both families carried truncating BAP1 mutations, a condition they named the "BAP1 cancer syndrome".	('uveal melanoma', 'Disease', 'MESH:C536494', (155, 169))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('uveal melanoma', 'Disease', (155, 169))	('BAP1', 'Gene', (224, 228))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('cancer syndrome', 'Disease', (273, 288))	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('uveal melanoma', 'Phenotype', 'HP:0007716', (155, 169))	('breast cancer', 'Disease', (174, 187))	('mutations', 'Var', (229, 238))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('truncating', 'Var', (213, 223))	('carried', 'Reg', (205, 212))	('tumors', 'Disease', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer syndrome', 'Disease', 'MESH:D009369', (273, 288))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('mesothelioma', 'Disease', (141, 153))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))
14582	32690542	A parallel study by Weisner and colleagues reported that BAP1 germline mutations were causally linked to benign melanocytic tumors developing at a young age, which were initially identified as atypical Spitz tumors.	('Spitz tumors', 'Disease', 'MESH:D018332', (202, 214))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('germline', 'Var', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('Spitz tumors', 'Disease', (202, 214))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('linked to', 'Reg', (95, 104))	('BAP1', 'Gene', (57, 61))	('benign melanocytic tumors', 'Disease', 'MESH:D009369', (105, 130))	('benign melanocytic tumors', 'Disease', (105, 130))
14600	32690542	Studying primary fibroblast cell cultures derived from skin-punch biopsies of individuals from two separate families carrying heterozygous BAP1 mutations (BAP1+/-), and wild-type BAP1 (BAP1+/+) control fibroblasts (matched for sex and age from individuals from the same families), it was found that BAP1 localizes to the endoplasmic reticulum (ER), where it deubiquitylates and thus stabilizes the type 3 inositol-1,4,5-trisphosphate receptor (IP3R3; ref.).	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('321', '342'))	('IP3R3', 'Gene', '3710', (444, 449))	('IP3R3', 'Gene', (444, 449))	('deubiquitylates', 'MPA', (358, 373))	('BAP1', 'Gene', (299, 303))	('stabilizes', 'MPA', (383, 393))	('BAP1', 'Gene', (139, 143))	('mutations', 'Var', (144, 153))
14612	32690542	The transcriptional repression of ATF3 and CHOP is dependent upon the deubiquitinylation of H2A (at K119) by BAP1.	('transcriptional', 'MPA', (4, 19))	('H2A', 'Protein', (92, 95))	('CHOP', 'Gene', (43, 47))	('at K119', 'Var', (97, 104))	('K119', 'Chemical', 'MESH:C118156', (100, 104))	('deubiquitinylation', 'MPA', (70, 88))	('ATF3', 'Gene', '467', (34, 38))	('dependent', 'Reg', (51, 60))	('BAP1', 'Gene', (109, 113))	('ATF3', 'Gene', (34, 38))	('CHOP', 'Gene', '1649', (43, 47))
14613	32690542	By engineering a knock-in mouse model expressing the catalytically inactive C91A Bap1 mutant, He and colleagues showed that the loss of function of BAP1 has a proapoptotic effect in mouse embryonic stem cells, fibroblasts, liver, and pancreas, but not in melanocytes and mesothelial cells, the cells that give rise to the cancer types most commonly associated with BAP1 mutations in humans.	('proapoptotic effect', 'MPA', (159, 178))	('Bap1', 'Gene', (81, 85))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('humans', 'Species', '9606', (383, 389))	('mouse', 'Species', '10090', (182, 187))	('C91A', 'Var', (76, 80))	('loss', 'Var', (128, 132))	('cancer', 'Disease', (322, 328))	('mutant', 'Var', (86, 92))	('BAP1', 'Gene', (148, 152))	('C91A', 'SUBSTITUTION', 'None', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('BAP1', 'Gene', (365, 369))	('mouse', 'Species', '10090', (26, 31))	('mutations', 'Var', (370, 379))	('Bap1', 'Gene', '104416', (81, 85))
14620	32690542	Moreover, using a genetically engineered inducible Bap1 knockout murine model, it has been demonstrated that the deletion of Bap1 altered several metabolic pathways.	('Bap1', 'Gene', '104416', (125, 129))	('deletion', 'Var', (113, 121))	('Bap1', 'Gene', (51, 55))	('Bap1', 'Gene', (125, 129))	('metabolic pathways', 'Pathway', (146, 164))	('altered', 'Reg', (130, 137))	('murine', 'Species', '10090', (65, 71))	('Bap1', 'Gene', '104416', (51, 55))
14624	32690542	In 2010, Harbour and colleagues reported that 26 of 31 metastasizing uveal melanomas carried inactivating somatic BAP1 mutations, and one of the patients also carried a germline BAP1 mutation.	('patients', 'Species', '9606', (145, 153))	('inactivating', 'MPA', (93, 105))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('metastasizing uveal melanomas', 'Disease', 'MESH:D009362', (55, 84))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('uveal melanomas', 'Phenotype', 'HP:0007716', (69, 84))	('metastasizing uveal melanomas', 'Disease', (55, 84))	('BAP1', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))
14625	32690542	In 2011, Carbone's team reported that germline BAP1 mutations predisposed to mesothelioma and uveal melanoma, the BAP1 cancer syndrome.	('mutations', 'Var', (52, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('predisposed', 'Reg', (62, 73))	('mesothelioma', 'Disease', (77, 89))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('uveal melanoma', 'Disease', (94, 108))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('germline', 'Var', (38, 46))	('cancer syndrome', 'Disease', 'MESH:D009369', (119, 134))	('cancer syndrome', 'Disease', (119, 134))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('BAP1', 'Gene', (47, 51))
14626	32690542	In 2012, Brugarolas and colleagues reported that 15% of ccRCCs carried somatic BAP1 mutations, and subsequently found that some patients also had inactivating germline mutations.	('carried', 'Reg', (63, 70))	('BAP1', 'Gene', (79, 83))	('mutations', 'Var', (84, 93))	('RCC', 'Disease', (58, 61))	('patients', 'Species', '9606', (128, 136))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
14628	32690542	Numerous studies have now confirmed and expanded on the direct link of BAP1 germline mutations to a cancer syndrome characterized by a predisposition to mesothelioma, uveal melanoma, and less frequently cutaneous melanoma, as well as ccRCC, which are the core cancer types in the BAP1 cancer syndrome.	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('RCC', 'Disease', 'MESH:C538614', (236, 239))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer syndrome', 'Disease', 'MESH:D009369', (285, 300))	('uveal melanoma', 'Disease', 'MESH:C536494', (167, 181))	('uveal melanoma', 'Disease', (167, 181))	('mesothelioma', 'Disease', (153, 165))	('cancer syndrome', 'Disease', 'MESH:D009369', (100, 115))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('BAP1', 'Gene', (71, 75))	('cancer', 'Disease', (285, 291))	('cutaneous melanoma', 'Disease', (203, 221))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (203, 221))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (203, 221))	('cancer syndrome', 'Disease', (285, 300))	('mesothelioma', 'Disease', 'MESH:D008654', (153, 165))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Disease', (260, 266))	('uveal melanoma', 'Phenotype', 'HP:0007716', (167, 181))	('mutations', 'Var', (85, 94))	('link', 'Reg', (63, 67))	('cancer', 'Disease', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cancer syndrome', 'Disease', (100, 115))	('RCC', 'Disease', (236, 239))	('core', 'cellular_component', 'GO:0019013', ('255', '259'))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
14629	32690542	Although the term "mutations" has been widely used to encompass different types of genetic damage, most BAP1-mutant families carry truncating BAP1 mutations.	('mutations', 'Var', (147, 156))	('BAP1-mutant', 'Gene', (104, 115))	('truncating', 'MPA', (131, 141))	('BAP1', 'Gene', (142, 146))	('genetic damage', 'Disease', 'MESH:D030342', (83, 97))	('genetic damage', 'Disease', (83, 97))
14636	32690542	Recently, Badhai and colleagues reported that the combined deletion in the mesothelial cell lineage of Bap1, Nf2, and Cdkn2ab caused mesothelioma in 100% of mice.	('Bap1', 'Gene', '104416', (103, 107))	('Nf2', 'Gene', (109, 112))	('mice', 'Species', '10090', (157, 161))	('mesothelioma', 'Disease', 'MESH:D008654', (133, 145))	('Nf2', 'Gene', '18016', (109, 112))	('Cdkn2ab', 'Gene', (118, 125))	('Bap1', 'Gene', (103, 107))	('deletion', 'Var', (59, 67))	('mesothelioma', 'Disease', (133, 145))	('caused', 'Reg', (126, 132))
14637	32690542	Bap1 deletion alone caused mesothelioma in 5% of unexposed mice, and combined Nf2 and Cdkn2ab deletion alone did not.	('mesothelioma', 'Disease', (27, 39))	('Bap1', 'Gene', '104416', (0, 4))	('deletion', 'Var', (5, 13))	('mice', 'Species', '10090', (59, 63))	('Bap1', 'Gene', (0, 4))	('Nf2', 'Gene', (78, 81))	('mesothelioma', 'Disease', 'MESH:D008654', (27, 39))	('Nf2', 'Gene', '18016', (78, 81))	('caused', 'Reg', (20, 26))
14638	32690542	In summary, inherited BAP1 mutations cause cancer in mice and in humans, and cancer incidence increases upon exposure to asbestos or other carcinogenic fibers and when other mutations are present.	('mutations', 'Var', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('carcinogenic fibers', 'Disease', (139, 158))	('asbestos', 'Chemical', 'MESH:D001194', (121, 129))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('carcinogenic fibers', 'Disease', 'MESH:D000071075', (139, 158))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('humans', 'Species', '9606', (65, 71))	('cause', 'Reg', (37, 42))	('mice', 'Species', '10090', (53, 57))	('BAP1', 'Gene', (22, 26))
14639	32690542	However, the spontaneous development of mesotheliomas in Bap1+/- mice not exposed to asbestos, and the development of multiple cancer types in carriers of BAP1 mutations (Fig.	('Bap1', 'Gene', (57, 61))	('asbestos', 'Chemical', 'MESH:D001194', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mutations', 'Var', (160, 169))	('mice', 'Species', '10090', (65, 69))	('BAP1', 'Gene', (155, 159))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('carriers', 'Reg', (143, 151))	('cancer', 'Disease', (127, 133))	('Bap1', 'Gene', '104416', (57, 61))	('mesotheliomas', 'Disease', 'MESH:D008654', (40, 53))	('mesotheliomas', 'Disease', (40, 53))
14640	32690542	2B), including tumor types that have not been associated with known carcinogens, suggests that BAP1 mutations also drive tumor growth independently of genotoxic stress, perhaps by favoring the accumulation of age-related DNA damage.	('mutations', 'Var', (100, 109))	('genotoxic stress', 'Disease', 'MESH:D000079225', (151, 167))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('genotoxic stress', 'Disease', (151, 167))	('BAP1', 'Gene', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('favoring', 'PosReg', (180, 188))	('DNA damage', 'MPA', (221, 231))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (15, 20))	('DNA', 'cellular_component', 'GO:0005574', ('221', '224'))	('accumulation', 'MPA', (193, 205))	('drive', 'PosReg', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
14642	32690542	However, patients with uveal melanoma with germline BAP1 mutations always have an initiating mutation in the G-alpha-q (Gq) pathway, suggesting that additional genetic variants play a critical role in the development of uveal melanoma.	('patients', 'Species', '9606', (9, 17))	('uveal melanoma', 'Phenotype', 'HP:0007716', (220, 234))	('initiating', 'Reg', (82, 92))	('uveal melanoma', 'Disease', (220, 234))	('uveal melanoma', 'Disease', 'MESH:C536494', (220, 234))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('uveal melanoma', 'Phenotype', 'HP:0007716', (23, 37))	('uveal melanoma', 'Disease', 'MESH:C536494', (23, 37))	('G-alpha-q', 'Gene', (109, 118))	('BAP1', 'Gene', (52, 56))	('mutations', 'Var', (57, 66))	('uveal melanoma', 'Disease', (23, 37))	('Gq', 'Chemical', '-', (120, 122))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('mutation', 'Var', (93, 101))	('G-alpha-q', 'Gene', '2776', (109, 118))
14645	32690542	Carriers of germline BAP1 mutations often develop multiple cancers during their lifetime.	('BAP1', 'Gene', (21, 25))	('multiple cancers', 'Disease', (50, 66))	('develop', 'Reg', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mutations', 'Var', (26, 35))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('multiple cancers', 'Disease', 'MESH:D009369', (50, 66))
14647	32690542	The fact that most BAP1-associated cancers arise in middle-age and older individuals, and that the penetrance for any particular cancer type is less than 100%, suggests that genomic aberrations in addition to BAP1 loss are required for cancer formation, for example, mutations in the Gq signaling pathway.	('BAP1', 'Gene', (209, 213))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Disease', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Gq', 'Chemical', '-', (284, 286))	('cancer', 'Disease', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Gq signaling pathway', 'Pathway', (284, 304))	('signaling pathway', 'biological_process', 'GO:0007165', ('287', '304'))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('formation', 'biological_process', 'GO:0009058', ('243', '252'))	('cancer', 'Disease', (236, 242))	('mutations', 'Var', (267, 276))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('BAP1-associated', 'Gene', (19, 34))	('loss', 'NegReg', (214, 218))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))
14648	32690542	The first cancer in which somatic (i.e., acquired) BAP1 mutations were found to be common was uveal melanoma, where these mutations are present in approximately 45% of primary tumors and are highly correlated with the poor prognosis class 2 transcriptional signature and metastatic phenotype (ref.	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('mutations', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('BAP1', 'Gene', (51, 55))	('uveal melanoma', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('correlated', 'Reg', (198, 208))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
14650	32690542	Other cancers in which acquired somatic BAP1 mutations are common include mesothelioma (60%-70% of them; ref.)	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('BAP1', 'Gene', (40, 44))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('mesothelioma', 'Disease', (74, 86))
14653	32690542	The parallel between the tumor types developing most frequently in carriers of germline BAP1 mutations and the tumor types that most frequently contain somatic BAP1 mutations underscores the increased susceptibility of uveal, mesothelial, and kidney cells to BAP1 loss.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mutations', 'Var', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (25, 30))	('germline', 'Var', (79, 87))	('tumor', 'Disease', (111, 116))	('BAP1', 'Gene', (160, 164))	('mutations', 'Var', (165, 174))	('BAP1', 'Gene', (88, 92))
14654	32690542	Somatic BAP1 mutations are also present in other malignancies, although at lower rates: thymic carcinoma (13%), cholangiocarcinoma (7%), cutaneous melanoma (5%), basal cell carcinoma (4%), and others (ref.	('carcinoma', 'Disease', 'MESH:D009369', (173, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (137, 155))	('malignancies', 'Disease', 'MESH:D009369', (49, 61))	('carcinoma', 'Disease', (121, 130))	('malignancies', 'Disease', (49, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (112, 130))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (162, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('carcinoma', 'Disease', 'MESH:D009369', (121, 130))	('BAP1', 'Gene', (8, 12))	('cholangiocarcinoma', 'Disease', (112, 130))	('carcinoma', 'Disease', (95, 104))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (112, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (162, 182))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('mutations', 'Var', (13, 22))	('carcinoma', 'Disease', (173, 182))	('basal cell carcinoma', 'Disease', (162, 182))	('carcinoma', 'Disease', 'MESH:D009369', (95, 104))	('cutaneous melanoma', 'Disease', (137, 155))
14656	32690542	The role of BAP1 as a two-hit tumor suppressor gene is underscored by the fact that in humans they are accompanied by monoallelic loss of 3p, or by biallelic deletions of the BAP1 locus (LOH), including broad deletions of 3p21, narrow deletions of several exons, or loss of the entire BAP1 allele.	('humans', 'Species', '9606', (87, 93))	('BAP1', 'Gene', (175, 179))	('3p21', 'Protein', (222, 226))	('narrow deletions', 'Var', (228, 244))	('loss', 'NegReg', (266, 270))	('BAP1', 'Gene', (285, 289))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('loss', 'NegReg', (130, 134))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('tumor', 'Disease', (30, 35))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))
14657	32690542	Initial studies underestimated the frequency of BAP1 mutations in mesothelioma as 22% to 23%.	('mesothelioma', 'Disease', 'MESH:D008654', (66, 78))	('BAP1', 'Gene', (48, 52))	('mesothelioma', 'Disease', (66, 78))	('mutations', 'Var', (53, 62))
14658	32690542	A subsequent study using a comprehensive integrated genomic approach that included Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), copy-number analysis, and cDNA sequencing, combined with IHC and DNA methylation analyses in mesothelioma biopsies, found that >60% carried biallelic somatic BAP1 mutations.	('mesothelioma', 'Disease', (252, 264))	('DNA methylation', 'biological_process', 'GO:0006306', ('224', '239'))	('mutations', 'Var', (322, 331))	('mesothelioma', 'Disease', 'MESH:D008654', (252, 264))	('DNA', 'cellular_component', 'GO:0005574', ('224', '227'))	('BAP1', 'Gene', (317, 321))
14659	32690542	This is because of the frequent occurrence of minute BAP1 deletions in the range of 250 to 3,000 kb, which are not reliably detected by targeted NGS (tNGS), by whole-exome sequencing (WES), or by Sanger sequencing, but are instead detected by MLPA.	('deletions', 'Var', (58, 67))	('tNGS', 'Chemical', '-', (150, 154))	('BAP1', 'Gene', (53, 57))
14660	32690542	These findings were supported by a study in which high-density aCGH to detect deletions larger than 250 bp, and tNGS to detect nucleotide level mutations, resulted in a much higher prevalence of BAP1 mutations in human mesothelioma biopsies than either technique alone (~50%).	('human', 'Species', '9606', (213, 218))	('BAP1', 'Gene', (195, 199))	('mutations', 'Var', (200, 209))	('mesothelioma', 'Disease', (219, 231))	('tNGS', 'Chemical', '-', (112, 116))	('mesothelioma', 'Disease', 'MESH:D008654', (219, 231))
14662	32690542	Additional studies confirmed that BAP1 is the most frequently mutated gene in mesothelioma; however, studies that relied only on tNGS or WES invariably underestimated the true incidence of BAP1 mutations.	('tNGS', 'Chemical', '-', (129, 133))	('mesothelioma', 'Disease', 'MESH:D008654', (78, 90))	('BAP1', 'Gene', (189, 193))	('mutations', 'Var', (194, 203))	('mesothelioma', 'Disease', (78, 90))
14663	32690542	Similarly, Harbour and colleagues used an integrated DNA/RNA-sequencing approach and a customized bioinformatics pipeline to improve the detection of BAP1 mutations in uveal melanoma, identifying BAP1 mutations in approximately 45% of uveal melanomas, twice the rate detected by previous NGS approaches.	('BAP1', 'Gene', (196, 200))	('uveal melanoma', 'Disease', 'MESH:C536494', (168, 182))	('mutations', 'Var', (201, 210))	('BAP1', 'Gene', (150, 154))	('uveal melanomas', 'Disease', (235, 250))	('uveal melanomas', 'Phenotype', 'HP:0007716', (235, 250))	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('uveal melanomas', 'Disease', 'MESH:C536494', (235, 250))	('RNA', 'cellular_component', 'GO:0005562', ('57', '60'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (235, 249))	('uveal melanoma', 'Disease', 'MESH:C536494', (235, 249))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanomas', 'Phenotype', 'HP:0002861', (241, 250))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (168, 182))	('uveal melanoma', 'Disease', (168, 182))
14665	32690542	A detailed analysis of 3p deletions in sporadic mesotheliomas revealed that deletions are not contiguous but rather preferentially occur in BAP1 and in some nearby genes (SETD2, PBRM1, and SMARCC1), alternating with segments showing oscillating copy-number changes along the 3p21 chromosome, findings suggestive of chromothripsis.	('SMARCC1', 'Gene', (189, 196))	('chromothripsis', 'Disease', 'MESH:D000072837', (315, 329))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (39, 61))	('deletions', 'Var', (26, 35))	('BAP1', 'Gene', (140, 144))	('SETD2', 'Gene', '29072', (171, 176))	('sporadic mesotheliomas', 'Disease', (39, 61))	('PBRM1', 'Gene', (178, 183))	('SETD2', 'Gene', (171, 176))	('occur', 'Reg', (131, 136))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (39, 60))	('chromosome', 'cellular_component', 'GO:0005694', ('280', '290'))	('chromothripsis', 'Disease', (315, 329))	('deletions', 'Var', (76, 85))	('SMARCC1', 'Gene', '6599', (189, 196))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (39, 61))
14666	32690542	The occurrence of chromothripsis in mesothelioma may be favored by BAP1 inactivation, and it has been confirmed by mate-pair sequencing (MPseq) analyses and by WES.	('favored', 'PosReg', (56, 63))	('chromothripsis in mesothelioma', 'Disease', (18, 48))	('inactivation', 'Var', (72, 84))	('chromothripsis in mesothelioma', 'Disease', 'MESH:D000072837', (18, 48))	('BAP1', 'Gene', (67, 71))
14675	32690542	Negative BAP1 nuclear staining by IHC, regardless of cytoplasmic staining, is found in about 60% to 70% of mesotheliomas and is a reliable, rapid, and economical approach to identify biallelic BAP1 inactivating mutations.	('biallelic', 'Var', (183, 192))	('mesotheliomas', 'Disease', 'MESH:D008654', (107, 120))	('mesotheliomas', 'Disease', (107, 120))	('Negative', 'NegReg', (0, 8))	('inactivating mutations', 'Var', (198, 220))	('BAP1', 'Gene', (193, 197))
14676	32690542	In most tumor cells showing no nuclear staining (e.g., mutated BAP1), there is also no staining in the cytoplasm (Fig.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('mutated', 'Var', (55, 62))	('BAP1', 'Gene', (63, 67))	('cytoplasm', 'cellular_component', 'GO:0005737', ('103', '112'))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))
14683	32690542	The two discordant samples had missense mutations in the catalytic domain (p.Gly13Val and p.Phe170Leu).	('p.Phe170Leu', 'SUBSTITUTION', 'None', (90, 101))	('p.Phe170Leu', 'Var', (90, 101))	('p.Gly13Val', 'SUBSTITUTION', 'None', (75, 85))	('p.Gly13Val', 'Var', (75, 85))
14684	32690542	In addition, Western blot analyses of an IHC-negative sample with wild-type BAP1 failed to reveal detectable BAP1 protein, suggesting that BAP1 may have been inactivated through mutations eluding detection by conventional Sanger sequencing, as described in mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (257, 269))	('mutations', 'Var', (178, 187))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('mesothelioma', 'Disease', (257, 269))
14687	32690542	Baumann and colleagues reported that the presence of germ line BAP1 mutations strikingly increased the 5-year survival rate of patients with mesothelioma by 7-fold [47% (95% confidence interval [CI], 24-67) vs. 6.7% (95% CI, 6.2-7.3)], indicating that mesothelioma is less aggressive when it occurs in the context of the BAP1 cancer syndrome.	('mesothelioma', 'Disease', (252, 264))	('BAP1', 'Gene', (63, 67))	('mesothelioma', 'Disease', 'MESH:D008654', (252, 264))	('patients', 'Species', '9606', (127, 135))	('cancer syndrome', 'Disease', 'MESH:D009369', (326, 341))	('cancer syndrome', 'Disease', (326, 341))	('mesothelioma', 'Disease', (141, 153))	('mutations', 'Var', (68, 77))	('increased', 'PosReg', (89, 98))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
14688	32690542	In these individuals, normal cells contain 50% of the BAP1 protein, whereas tumor cells show biallelic BAP1 mutations and thus do not contain a biologically functional BAP1 protein.	('mutations', 'Var', (108, 117))	('protein', 'Protein', (59, 66))	('BAP1', 'Gene', (103, 107))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('protein', 'cellular_component', 'GO:0003675', ('173', '180'))	('BAP1 protein', 'Protein', (54, 66))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
14692	32690542	Most subjects (43/79) carried germline BAP1 mutations; 12 of 79 carried germline mutations in other tumor suppressors; and 5 of 79 carried mutations in BAP1 and also in other cancer-related genes.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('mutations', 'Reg', (139, 148))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('mutations', 'Var', (44, 53))	('BAP1', 'Gene', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('BAP1', 'Gene', (39, 43))
14694	32690542	An analysis conducted at the University of Chicago on the germline DNA of 198 patients with mesothelioma using targeted capture and NGS of 85 cancer susceptibility genes revealed that 12% of patients within this cohort carried pathogenic germline mutations; BAP1 was the most commonly mutated gene.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('patients', 'Species', '9606', (191, 199))	('mesothelioma', 'Disease', 'MESH:D008654', (92, 104))	('germline mutations', 'Var', (238, 256))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('patients', 'Species', '9606', (78, 86))	('BAP1', 'Gene', (258, 262))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('pathogenic', 'Reg', (227, 237))	('mesothelioma', 'Disease', (92, 104))	('cancer', 'Disease', (142, 148))
14695	32690542	A similar survey conducted at the NCI on a cohort of 385 patients using a panel of 73 genes involved in DNA repair and tumor suppression demonstrated that 12% of them carried germline mutations (mostly germline BAP1 mutations).	('tumor', 'Disease', (119, 124))	('patients', 'Species', '9606', (57, 65))	('germline BAP1 mutations', 'Var', (202, 225))	('germline mutations', 'Var', (175, 193))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('carried', 'Reg', (167, 174))	('DNA repair', 'biological_process', 'GO:0006281', ('104', '114'))
14696	32690542	The presence of inherited mutations significantly increased median overall survival compared with patients without these mutations (7.9 years vs. 2.4 years, P = 0.001; ref.).	('mutations', 'Var', (26, 35))	('overall survival', 'MPA', (67, 83))	('increased', 'PosReg', (50, 59))	('patients', 'Species', '9606', (98, 106))
14697	32690542	Together, these studies validate the prognostic significance of germline mutations that confer a significantly improved survival to patients with mesothelioma (Fig.	('improved', 'PosReg', (111, 119))	('germline mutations', 'Var', (64, 82))	('mesothelioma', 'Disease', (146, 158))	('mesothelioma', 'Disease', 'MESH:D008654', (146, 158))	('survival', 'MPA', (120, 128))	('patients', 'Species', '9606', (132, 140))
14698	32690542	The improved survival was also observed among patients who, in addition to mesothelioma, developed other aggressive malignancies, which, rather than an exception, is the norm among those carrying germline BAP1 mutations.	('improved', 'PosReg', (4, 12))	('aggressive malignancies', 'Disease', (105, 128))	('mutations', 'Var', (210, 219))	('patients', 'Species', '9606', (46, 54))	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('aggressive malignancies', 'Disease', 'MESH:D009369', (105, 128))	('mesothelioma', 'Disease', (75, 87))
14700	32690542	Because almost all BAP1-mutated cancers contain biallelic BAP1 mutations, regardless of whether they are sporadic or occur in carriers of germline mutations, the markedly improved prognosis of mesotheliomas occurring in carriers of germline BAP1 mutations does not seem to be related only to the mutation in the tumor cells.	('mutations', 'Var', (63, 72))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('cancers', 'Disease', (32, 39))	('BAP1', 'Gene', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('BAP1', 'Gene', (241, 245))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('mutations', 'Var', (246, 255))	('mesotheliomas', 'Disease', 'MESH:D008654', (193, 206))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Disease', (312, 317))	('mesotheliomas', 'Disease', (193, 206))	('biallelic', 'Var', (48, 57))	('improved', 'PosReg', (171, 179))	('BAP1-mutated', 'Gene', (19, 31))
14701	32690542	Therefore, the improved prognosis of mesothelioma and other cancer types in carriers of germline BAP1 mutations may be influenced by the microenvironment and/or the immune system.	('mesothelioma', 'Disease', 'MESH:D008654', (37, 49))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('influenced', 'Reg', (119, 129))	('cancer', 'Disease', (60, 66))	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('improved', 'PosReg', (15, 23))	('mesothelioma', 'Disease', (37, 49))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
14703	32690542	In contrast to mesothelioma, a study of 8 patients with uveal melanoma with germline BAP1 mutations found an increased risk of metastasis (p.003) compared with uveal melanoma patients with wild-type BAP1 in their germline, confirming that BAP1 mutations induce a metastatic phenotype.	('mutations', 'Var', (90, 99))	('p.0', 'SUBSTITUTION', 'None', (139, 142))	('metastasis', 'CPA', (127, 137))	('induce', 'Reg', (254, 260))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('mutations', 'Var', (244, 253))	('uveal melanoma', 'Disease', 'MESH:C536494', (56, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('uveal melanoma', 'Disease', (56, 70))	('uveal melanoma', 'Disease', 'MESH:C536494', (160, 174))	('p.0', 'Var', (139, 142))	('uveal melanoma', 'Disease', (160, 174))	('mesothelioma', 'Disease', (15, 27))	('patients', 'Species', '9606', (42, 50))	('BAP1', 'Gene', (85, 89))	('uveal melanoma', 'Phenotype', 'HP:0007716', (56, 70))	('mesothelioma', 'Disease', 'MESH:D008654', (15, 27))	('patients', 'Species', '9606', (175, 183))	('uveal melanoma', 'Phenotype', 'HP:0007716', (160, 174))
14705	32690542	Somatic BAP1 mutations in the tumor biopsy are the strongest known risk factor for uveal melanoma metastatic death.	('uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('uveal melanoma metastatic death', 'Disease', (83, 114))	('uveal melanoma metastatic death', 'Disease', 'MESH:C536494', (83, 114))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('BAP1', 'Gene', (8, 12))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('mutations', 'Var', (13, 22))	('tumor', 'Disease', (30, 35))
14706	32690542	These phenotypic differences among cancer types associated with BAP1 mutations suggest that there are cell type- and context-dependent differences in the role of BAP1 in biology and cancer.	('mutations', 'Var', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))	('BAP1', 'Gene', (64, 68))
14707	32690542	It is not yet clear whether germline BAP1 mutations are associated with improved survival in RCC.	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Disease', (93, 96))	('improved', 'PosReg', (72, 80))	('germline', 'Var', (28, 36))	('BAP1', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))
14708	32690542	Mesotheliomas with acquired BAP1 mutations are mostly of the epithelial type and may have a slightly improved prognosis of a few months compared with mesotheliomas of similar histologic type with wild-type BAP1; however, some studies did not support this finding.	('mesotheliomas', 'Disease', (150, 163))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('improved', 'PosReg', (101, 109))	('Mesotheliomas', 'Disease', 'MESH:D008654', (0, 13))	('Mesotheliomas', 'Disease', (0, 13))	('mesotheliomas', 'Disease', 'MESH:D008654', (150, 163))
14709	32690542	Intriguingly, the opposite correlation with survival was observed in uveal melanoma, ccRCC, and cholangiocarcinoma, where somatic biallelic BAP1 mutations were associated with a metastatic phenotype and poor prognosis.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('BAP1', 'Gene', (140, 144))	('uveal melanoma', 'Disease', (69, 83))	('mutations', 'Var', (145, 154))	('biallelic', 'Var', (130, 139))	('uveal melanoma', 'Disease', 'MESH:C536494', (69, 83))	('cholangiocarcinoma', 'Disease', (96, 114))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (96, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (96, 114))	('metastatic', 'CPA', (178, 188))	('associated', 'Reg', (160, 170))
14710	32690542	In uveal melanoma, detection of BAP1 mutations directly by sequencing, or indirectly via the class 2 transcriptional signature or other methods, is now a routine part of patient care, with high-risk patients stratified for increased surveillance and clinical trial entry.	('uveal melanoma', 'Disease', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('patient', 'Species', '9606', (199, 206))	('mutations', 'Var', (37, 46))	('BAP1', 'Gene', (32, 36))	('patients', 'Species', '9606', (199, 207))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('patient', 'Species', '9606', (170, 177))
14712	32690542	Brugarolas and colleagues found that ccRCCs with somatic BAP1 mutations were associated with high-grade tumors.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('BAP1', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))	('associated', 'Reg', (77, 87))
14715	32690542	To determine whether BAP1 and PBRM1 directly affect tumor grade, mice were generated with targeted inactivation of Bap1 or Pbrm1 in the kidney using the same Cre driver.	('affect', 'Reg', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('mice', 'Species', '10090', (65, 69))	('Bap1', 'Gene', '104416', (115, 119))	('Pbrm1', 'Gene', (123, 128))	('Pbrm1', 'Gene', '66923', (123, 128))	('Bap1', 'Gene', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('inactivation', 'Var', (99, 111))
14716	32690542	Inactivation of Bap1 or Pbrm1, along with Vhl, which is uniformly inactivated in ccRCC, led to the development of ccRCC.	('RCC', 'Disease', (116, 119))	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('Vhl', 'Gene', (42, 45))	('led to', 'Reg', (88, 94))	('Pbrm1', 'Gene', (24, 29))	('Pbrm1', 'Gene', '66923', (24, 29))	('Bap1', 'Gene', '104416', (16, 20))	('Vhl', 'Gene', '7428', (42, 45))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('Bap1', 'Gene', (16, 20))	('Inactivation', 'Var', (0, 12))
14722	32690542	Following VHL inactivation, which is the signature and initiating event in ccRCC, a mutation of the second copy of BAP1 or PBRM1 likely leads to tumors of different grade and prognosis.	('leads to', 'Reg', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('PBRM1', 'Gene', (123, 128))	('RCC', 'Disease', (77, 80))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('BAP1', 'Gene', (115, 119))	('VHL', 'Gene', (10, 13))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('VHL', 'Gene', '7428', (10, 13))	('mutation', 'Var', (84, 92))
14723	32690542	A fourth tumor suppressor gene in the same 3p region, SETD2, is also mutated in ccRCC and is associated with poor prognosis.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('9', '25'))	('SETD2', 'Gene', '29072', (54, 59))	('mutated', 'Var', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('SETD2', 'Gene', (54, 59))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('tumor', 'Disease', (9, 14))	('RCC', 'Disease', (82, 85))	('tumor suppressor', 'biological_process', 'GO:0051726', ('9', '25'))
14724	32690542	Whereas mutations in BAP1 and PBRM1 tend to be mutually exclusive, mutations in PBRM1 and SETD2 appear to cooperate and are found at higher-than-expected frequencies.	('SETD2', 'Gene', (90, 95))	('PBRM1', 'Gene', (30, 35))	('BAP1', 'Gene', (21, 25))	('mutations', 'Var', (8, 17))	('mutations', 'Var', (67, 76))	('PBRM1', 'Gene', (80, 85))	('SETD2', 'Gene', '29072', (90, 95))
14729	32690542	The incorporation of the active metabolite of gemcitabine into DNA causes replication arrest and apoptosis, making this drug one of the most used chemotherapeutic agents against several cancers, including mesothelioma, for which it is approved as second-line treatment.	('incorporation', 'Var', (4, 17))	('mesothelioma', 'Disease', 'MESH:D008654', (205, 217))	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('97', '106'))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('arrest', 'Disease', (86, 92))	('apoptosis', 'biological_process', 'GO:0006915', ('97', '106'))	('mesothelioma', 'Disease', (205, 217))	('gemcitabine', 'Chemical', 'MESH:C056507', (46, 57))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('apoptosis', 'CPA', (97, 106))
14731	32690542	Upon treatment with this agent or with hydroxyurea, the viability of mesothelioma spheroids expressing nonfunctional C91A BAP1 was significantly higher compared with wild-type BAP1 counterparts.	('BAP1', 'Gene', (122, 126))	('C91A', 'Var', (117, 121))	('viability', 'CPA', (56, 65))	('hydroxyurea', 'Chemical', 'MESH:D006918', (39, 50))	('mesothelioma spheroids', 'Disease', 'MESH:D008654', (69, 91))	('C91A', 'SUBSTITUTION', 'None', (117, 121))	('mesothelioma spheroids', 'Phenotype', 'HP:0025014', (69, 91))	('mesothelioma spheroids', 'Disease', (69, 91))	('higher', 'PosReg', (145, 151))
14737	32690542	This combined therapy is the standard of care for BRAFV600E-mutant human melanoma.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('BRAFV600E-mutant', 'Var', (50, 66))	('human', 'Species', '9606', (67, 72))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
14739	32690542	In addition, a large study in more than 100 cases of metastatic RCC demonstrated that BAP1 mutational status did not correlate with clinical benefit upon rapalog therapy, despite the significantly higher aggressiveness of RCC in carriers of BAP1 mutations.	('aggressiveness of RCC', 'Disease', (204, 225))	('aggressiveness', 'Phenotype', 'HP:0000718', (204, 218))	('aggressiveness of RCC', 'Disease', 'MESH:C538614', (204, 225))	('higher', 'PosReg', (197, 203))	('rapalog', 'Chemical', '-', (154, 161))	('BAP1', 'Gene', (241, 245))	('BAP1', 'Gene', (86, 90))	('mutations', 'Var', (246, 255))	('RCC', 'Disease', 'MESH:C538614', (222, 225))	('RCC', 'Disease', (222, 225))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))
14745	32690542	The BAP1-deficient developmental phenotype could be rescued using SAHA or specific depletion of HDAC4.	('BAP1-deficient developmental', 'Disease', 'MESH:D007805', (4, 32))	('depletion', 'Var', (83, 92))	('HDAC4', 'Gene', '9759', (96, 101))	('BAP1-deficient developmental', 'Disease', (4, 32))	('HDAC4', 'Gene', (96, 101))
14748	32690542	In the context of mutations in BRCA1 or BRCA2 genes in patients with breast, ovary, prostate, or pancreatic cancers, PARP inhibitors have shown antitumor activity, and three agents are currently in the clinic.	('PARP', 'Gene', '142', (117, 121))	('pancreatic cancers', 'Disease', (97, 115))	('PARP', 'Gene', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('pancreatic cancers', 'Disease', 'MESH:D010190', (97, 115))	('breast', 'Disease', (69, 75))	('BRCA2', 'Gene', (40, 45))	('prostate', 'Disease', (84, 92))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('ovary', 'Disease', (77, 82))	('BRCA2', 'Gene', '675', (40, 45))	('BRCA1', 'Gene', '672', (31, 36))	('tumor', 'Disease', (148, 153))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (97, 115))	('BRCA1', 'Gene', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('mutations', 'Var', (18, 27))
14753	32690542	A BAP1 mutant by alternative splicing resulting in a 54-bp deletion increased sensitivity to the PARP inhibitor olaparib.	('PARP', 'Gene', '142', (97, 101))	('olaparib', 'Chemical', 'MESH:C531550', (112, 120))	('mutant', 'Var', (7, 13))	('splicing', 'biological_process', 'GO:0045292', ('29', '37'))	('PARP', 'Gene', (97, 101))	('deletion', 'Var', (59, 67))	('increased', 'PosReg', (68, 77))	('BAP1', 'Gene', (2, 6))
14754	32690542	A recent study on HR defects in a cohort of patients with mesothelioma showed both in vitro and by digital gene-expression analysis that loss of BAP1 increased sensitivity to PARP inhibitors.	('patients', 'Species', '9606', (44, 52))	('gene-expression', 'biological_process', 'GO:0010467', ('107', '122'))	('PARP', 'Gene', (175, 179))	('mesothelioma', 'Disease', (58, 70))	('HR defects', 'Disease', 'MESH:D000014', (18, 28))	('PARP', 'Gene', '142', (175, 179))	('mesothelioma', 'Disease', 'MESH:D008654', (58, 70))	('loss', 'Var', (137, 141))	('increased', 'PosReg', (150, 159))	('BAP1', 'Gene', (145, 149))	('HR defects', 'Disease', (18, 28))
14755	32690542	Presently, two ongoing clinical trials are testing the hypothesis that BAP1 mutations increase sensitivity to PARP inhibitors in mesothelioma (NCT03207347, NCT03531840).	('increase', 'PosReg', (86, 94))	('mutations', 'Var', (76, 85))	('mesothelioma', 'Disease', 'MESH:D008654', (129, 141))	('PARP', 'Gene', (110, 114))	('mesothelioma', 'Disease', (129, 141))	('BAP1', 'Gene', (71, 75))	('PARP', 'Gene', '142', (110, 114))
14757	32690542	We propose that these results may indicate that the increased resistance to cell death caused by BAP1 mutations in tumor cells over-come whatever increased DNA damage may be induced by PARP inhibitors in these same cells, making them resistant to this therapy.	('increased', 'PosReg', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('DNA', 'cellular_component', 'GO:0005574', ('156', '159'))	('DNA damage', 'MPA', (156, 166))	('PARP', 'Gene', (185, 189))	('tumor', 'Disease', (115, 120))	('cell death', 'biological_process', 'GO:0008219', ('76', '86'))	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('resistance', 'MPA', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('PARP', 'Gene', '142', (185, 189))
14771	32690542	Moreover, based on the structural rearrangements induced by chromothripsis, which may be favored by BAP1 mutations, Mansfield and colleagues predicted and validated in vitro the expression of altered peptides that may act as neoantigens and thus potentially increase mesothelioma immunogenicity and responsiveness to immunotherapy.	('chromothripsis', 'Disease', 'MESH:D000072837', (60, 74))	('BAP1', 'Gene', (100, 104))	('increase mesothelioma immunogenicity', 'Disease', (258, 294))	('mutations', 'Var', (105, 114))	('chromothripsis', 'Disease', (60, 74))	('increase mesothelioma immunogenicity', 'Disease', 'MESH:D008654', (258, 294))	('peptides', 'Protein', (200, 208))	('altered', 'Var', (192, 199))
14775	32690542	In addition, depletion or pharmacologic inhibition of EZH2 in BAP1-deficient Xenopus embryos did not rescue a neural crest developmental phenotype.	('EZH2', 'Gene', (54, 58))	('BAP1-deficient Xenopus embryos', 'Disease', (62, 92))	('neural crest developmental phenotype', 'CPA', (110, 146))	('depletion', 'Var', (13, 22))	('BAP1-deficient Xenopus embryos', 'Disease', 'MESH:D020964', (62, 92))
14777	32690542	Although the BAP1 cancer syndrome and the driving role of acquired BAP1 mutations in human cancer were discovered less than a decade ago, much progress has been made to elucidate critical mechanisms of BAP1 activities (Fig.	('mutations', 'Var', (72, 81))	('cancer syndrome', 'Disease', (18, 33))	('cancer syndrome', 'Disease', 'MESH:D009369', (18, 33))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('human', 'Species', '9606', (85, 90))	('BAP1', 'Gene', (67, 71))
14779	32690542	Therefore, reduced levels of BAP1, as observed in carriers of heterozygous BAP1 mutations, increase the amount of genetic damage that occurs spontaneously as cells divide, or that occurs in response to exposure to environmental carcinogens.	('BAP1', 'Gene', (75, 79))	('genetic damage', 'Disease', (114, 128))	('mutations', 'Var', (80, 89))	('increase', 'PosReg', (91, 99))	('genetic damage', 'Disease', 'MESH:D030342', (114, 128))
14780	32690542	Moreover, BAP1 loss favors tumor growth by inducing a Warburg effect (i.e., aerobic glycolysis) that provides the metabolic building blocks to support cell division and at the same time helps cancer cells to grow in a hypoxic environment.	('grow', 'CPA', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cell division', 'biological_process', 'GO:0051301', ('151', '164'))	('tumor', 'Disease', (27, 32))	('BAP1', 'Gene', (10, 14))	('Warburg', 'MPA', (54, 61))	('loss', 'Var', (15, 19))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('favors', 'PosReg', (20, 26))	('helps', 'PosReg', (186, 191))	('inducing', 'Reg', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('glycolysis', 'biological_process', 'GO:0006096', ('84', '94'))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
14782	32690542	Therefore, the combined nuclear and cytoplasmic BAP1 activities account for the very high incidence of cancer in carriers of germline BAP1 mutations (Fig.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('BAP1', 'Gene', (134, 138))	('mutations', 'Var', (139, 148))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
14785	32690542	All published data support the notion that BAP1 is a potent tumor suppressor, as almost all carriers of pathogenic germline BAP1 mutations developed one or more cancers during their lifetime.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('60', '76'))	('mutations', 'Var', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('BAP1', 'Gene', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('developed', 'Reg', (139, 148))	('cancers', 'Disease', (161, 168))	('tumor', 'Disease', (60, 65))	('tumor suppressor', 'biological_process', 'GO:0051726', ('60', '76'))
14786	32690542	LOH for BAP1 is observed in 100% of human tumors developing in carriers of germline BAP1 mutations, as well as in sporadic mesotheliomas with somatic BAP1 mutations, underscoring the potent tumor suppressor activity of BAP1.	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (114, 136))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('mutations', 'Var', (89, 98))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('190', '206'))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (114, 135))	('sporadic mesotheliomas', 'Disease', (114, 136))	('tumor', 'Disease', (42, 47))	('tumor suppressor', 'biological_process', 'GO:0051726', ('190', '206'))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('BAP1', 'Gene', (150, 154))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Disease', (190, 195))	('BAP1', 'Gene', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('mutations', 'Var', (155, 164))	('tumors', 'Disease', (42, 48))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (114, 136))	('human', 'Species', '9606', (36, 41))
14787	32690542	Intriguingly, LOH for BAP1 is not always observed in tumors developing in mice carrying germline Bap1 mutations.	('Bap1', 'Gene', '104416', (97, 101))	('Bap1', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutations', 'Var', (102, 111))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('mice', 'Species', '10090', (74, 78))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
14788	32690542	This critical question shall be addressed in the coming years to understand why germline BAP1 mutations cause or are present as somatic mutations more frequently in mesothelioma, uveal melanoma, and ccRCC, rather than in other cancer types.	('uveal melanoma', 'Disease', 'MESH:C536494', (179, 193))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('BAP1', 'Gene', (89, 93))	('mesothelioma', 'Disease', (165, 177))	('mutations', 'Var', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('uveal melanoma', 'Phenotype', 'HP:0007716', (179, 193))	('mesothelioma', 'Disease', 'MESH:D008654', (165, 177))	('cancer', 'Disease', (227, 233))	('cause', 'Reg', (104, 109))	('uveal melanoma', 'Disease', (179, 193))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))
14789	32690542	This information will help to design more effective preventive and therapeutic strategies for patients carrying germline BAP1 mutations or cancers with somatic BAP1 mutations.	('germline', 'Var', (112, 120))	('patients', 'Species', '9606', (94, 102))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('BAP1', 'Gene', (121, 125))	('BAP1', 'Gene', (160, 164))	('mutations', 'Var', (126, 135))	('mutations', 'Var', (165, 174))
14790	32690542	An additional question that will be addressed in coming years is why BAP1 mutations have phenotypic and prognostic implications that are cell type- and context-dependent: Germline mutations confer a better prognosis in mesothelioma, whereas somatic mutations induce a worse prognosis in uveal melanoma and ccRCC.	('better', 'PosReg', (199, 205))	('mesothelioma', 'Disease', (219, 231))	('BAP1', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (287, 301))	('uveal melanoma', 'Disease', (287, 301))	('uveal melanoma', 'Disease', 'MESH:C536494', (287, 301))	('RCC', 'Disease', 'MESH:C538614', (308, 311))	('RCC', 'Disease', (308, 311))	('mesothelioma', 'Disease', 'MESH:D008654', (219, 231))	('melanoma', 'Phenotype', 'HP:0002861', (293, 301))
14791	32690542	The difference in survival is quite significant, with median survival of 5 to 7 years for mesothelioma developing in carriers of heterozygous BAP1 mutations compared with 1-year median survival in sporadic mesotheliomas, cancers characteristically resistant to therapy.	('mutations', 'Var', (147, 156))	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('mesothelioma', 'Disease', (206, 218))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (197, 218))	('cancers', 'Disease', (221, 228))	('sporadic mesotheliomas', 'Disease', (197, 219))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (197, 219))	('mesothelioma', 'Disease', 'MESH:D008654', (206, 218))	('BAP1', 'Gene', (142, 146))	('mesothelioma', 'Disease', (90, 102))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (197, 219))	('mesothelioma', 'Disease', 'MESH:D008654', (90, 102))
14794	32690542	Adding to this puzzle, in sporadic mesotheliomas acquired biallelic BAP1 mutations are frequent, yet these mesotheliomas are not associated with significantly improved survival.	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (26, 47))	('mesotheliomas', 'Disease', 'MESH:D008654', (107, 120))	('mesotheliomas', 'Disease', 'MESH:D008654', (35, 48))	('mesotheliomas', 'Disease', (107, 120))	('mesotheliomas', 'Disease', (35, 48))	('sporadic mesotheliomas', 'Disease', (26, 48))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (26, 48))	('biallelic', 'Var', (58, 67))	('BAP1', 'Gene', (68, 72))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (26, 48))	('mutations', 'Var', (73, 82))
14795	32690542	These findings in the same tumor type suggest that the improved survival in carriers of germline BAP1 mutations may be linked to the microenvironment, the immune system, and maybe in part to early diagnosis, as family members are being enrolled in early-detection screening programs.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('improved', 'PosReg', (55, 63))	('tumor', 'Disease', (27, 32))	('survival', 'MPA', (64, 72))	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
14797	32690542	What if germline BAP1 mutations render the host capable to fight mesothelioma growth by affecting the tumor microenvironment?	('affecting', 'Reg', (88, 97))	('mesothelioma', 'Disease', (65, 77))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('mutations', 'Var', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('fight', 'CPA', (59, 64))	('BAP1', 'Gene', (17, 21))
14798	32690542	BAP1 mutations may influence the response to immunotherapy by increasing the propensity to chromothripsis, by deregulating the expression of genes that modulate immune checkpoints, and by promoting a proinflammatory tumor microenvironment.	('tumor', 'Disease', (216, 221))	('influence', 'Reg', (19, 28))	('BAP1', 'Gene', (0, 4))	('expression of', 'MPA', (127, 140))	('deregulating', 'Reg', (110, 122))	('mutations', 'Var', (5, 14))	('chromothripsis', 'Disease', (91, 105))	('increasing', 'PosReg', (62, 72))	('proinflammatory', 'MPA', (200, 215))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('response to immunotherapy', 'MPA', (33, 58))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('promoting', 'PosReg', (188, 197))	('chromothripsis', 'Disease', 'MESH:D000072837', (91, 105))
14799	32690542	By studying patients and mice with germline BAP1 mutations, we may learn how to treat mesotheliomas and maybe other cancers more effectively.	('patients', 'Species', '9606', (12, 20))	('mice', 'Species', '10090', (25, 29))	('mutations', 'Var', (49, 58))	('mesotheliomas', 'Disease', 'MESH:D008654', (86, 99))	('mesotheliomas', 'Disease', (86, 99))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('BAP1', 'Gene', (44, 48))
14800	32690542	For example, the role of metformin, a drug that reprograms cell metabolism by restraining aerobic glycolysis and promoting mitochondrial respiration, could be explored in the existing mouse models carrying heterozygous Bap1 mutations and in xenografts of BAP1-mutated tumors.	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('Bap1', 'Gene', (219, 223))	('respiration', 'biological_process', 'GO:0045333', ('137', '148'))	('restraining', 'NegReg', (78, 89))	('tumors', 'Disease', (268, 274))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('mouse', 'Species', '10090', (184, 189))	('respiration', 'biological_process', 'GO:0007585', ('137', '148'))	('metabolism', 'biological_process', 'GO:0008152', ('64', '74'))	('tumors', 'Disease', 'MESH:D009369', (268, 274))	('mutations', 'Var', (224, 233))	('metformin', 'Chemical', 'MESH:D008687', (25, 34))	('aerobic glycolysis', 'MPA', (90, 108))	('promoting', 'PosReg', (113, 122))	('mitochondrial respiration', 'MPA', (123, 148))	('glycolysis', 'biological_process', 'GO:0006096', ('98', '108'))	('Bap1', 'Gene', '104416', (219, 223))
14802	32690542	Family members of carriers of germline BAP1 mutations should be tested for BAP1 mutations, and those found to carry mutations should be enrolled in early-detection clinical trials (NCT03830229) that can help identify malignancies at an early stage, when they can be cured by surgery (uveal melanoma, RCC, cutaneous melanoma, etc.	('BAP1', 'Gene', (75, 79))	('RCC', 'Disease', 'MESH:C538614', (300, 303))	('RCC', 'Disease', (300, 303))	('melanoma', 'Phenotype', 'HP:0002861', (290, 298))	('malignancies', 'Disease', 'MESH:D009369', (217, 229))	('uveal melanoma', 'Phenotype', 'HP:0007716', (284, 298))	('uveal melanoma', 'Disease', 'MESH:C536494', (284, 298))	('melanoma', 'Phenotype', 'HP:0002861', (315, 323))	('mutations', 'Var', (44, 53))	('cutaneous melanoma', 'Disease', (305, 323))	('uveal melanoma', 'Disease', (284, 298))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (305, 323))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (305, 323))	('malignancies', 'Disease', (217, 229))	('BAP1', 'Gene', (39, 43))
14804	32690542	Moreover, BAP1 mutant carriers should limit exposure to diagnostic and therapeutic ionizing radiation that in these individuals may carry a higher cancer risk than in the population at large.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('BAP1', 'Gene', (10, 14))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('mutant', 'Var', (15, 21))
14841	33564363	The genes with CNV amplifications exhibited a significantly higher expression in cancer tissues than in normal controls (e.g., HK3 and ENO2), while the genes with CNV deletions exhibited significantly lower expression (e.g., ALDOB and PSAT1) (Figure 2(b)).	('ALDOB', 'Gene', (225, 230))	('ENO2', 'Gene', (135, 139))	('deletions', 'Var', (167, 176))	('HK3', 'Gene', (127, 130))	('higher', 'PosReg', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('PSAT1', 'Gene', (235, 240))	('PSAT1', 'Gene', '29968', (235, 240))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('HK3', 'molecular_function', 'GO:0008257', ('127', '130'))	('cancer', 'Disease', (81, 87))	('HK3', 'Gene', '3101', (127, 130))	('ALDOB', 'Gene', '229', (225, 230))	('expression', 'MPA', (67, 77))	('ENO2', 'Gene', '2026', (135, 139))	('expression', 'MPA', (207, 217))	('lower', 'NegReg', (201, 206))
14915	33564363	High expression of FBP1 inhibits the growth, metastasis, and glycolysis of breast cancer.	('glycolysis of breast cancer', 'Disease', (61, 88))	('metastasis', 'CPA', (45, 55))	('glycolysis of breast cancer', 'Disease', 'MESH:D001943', (61, 88))	('High expression', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('FBP1', 'Gene', (19, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('glycolysis', 'biological_process', 'GO:0006096', ('61', '71'))	('inhibits', 'NegReg', (24, 32))	('growth', 'CPA', (37, 43))	('FBP1', 'Gene', '2203', (19, 23))
14934	30945310	We downloaded genomic profiles of GSE781, GSE6244, GSE53757, and GSE66271 from the Gene Expression Omnibus (GEO) database.	('Gene Expression', 'biological_process', 'GO:0010467', ('83', '98'))	('Ge', 'Chemical', 'MESH:D005857', (83, 85))	('GSE66271', 'Var', (65, 73))	('GSE53757', 'Var', (51, 59))	('GSE6244', 'Var', (42, 49))
14945	30945310	(2009) found no relationship between VHL mutations/deletions and prognosis in ccRCC patients.	('VHL', 'Disease', (37, 40))	('patients', 'Species', '9606', (84, 92))	('ccRCC', 'Disease', (78, 83))	('ccRCC', 'Disease', 'MESH:D002292', (78, 83))	('mutations/deletions', 'Var', (41, 60))	('VHL', 'Disease', 'MESH:D006623', (37, 40))
14975	30945310	Cell proliferation in GNG7 knockdown was carried out as previously described (Xu et al., 2016).	('knockdown', 'Var', (27, 36))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('GNG7', 'Gene', '2788', (22, 26))	('GNG7', 'Gene', (22, 26))
14999	30945310	We found that the distribution curves tended to be "bumpy" in phenotype in GNG7 expression high-group enrichment when compared to the enrichment plot of GNG7 low expression group (Figure S3).	('men', 'Species', '9606', (140, 143))	('GNG7', 'Gene', (153, 157))	('men', 'Species', '9606', (108, 111))	('GNG7', 'Gene', (75, 79))	('GNG7', 'Gene', '2788', (153, 157))	('high-group', 'Var', (91, 101))	('GNG7', 'Gene', '2788', (75, 79))
15002	30945310	These results reveal that repressed GNG7 was associated with increased cell proliferation and viability in ccRCC progression.	('GNG7', 'Gene', (36, 40))	('cell proliferation', 'biological_process', 'GO:0008283', ('71', '89'))	('repressed', 'Var', (26, 35))	('increased', 'PosReg', (61, 70))	('viability', 'CPA', (94, 103))	('ccRCC', 'Disease', (107, 112))	('GNG7', 'Gene', '2788', (36, 40))	('ccRCC', 'Disease', 'MESH:D002292', (107, 112))	('cell proliferation', 'CPA', (71, 89))
15008	30945310	To determine the mechanism of cell growth inhibition in by GNG7, cell-cycle assay was performed in A498 and 786-O cells after knocking down GNG7 for 48 hr (Figure 7e).	('knocking down', 'Var', (126, 139))	('cell growth', 'biological_process', 'GO:0016049', ('30', '41'))	('cell-cycle', 'biological_process', 'GO:0007049', ('65', '75'))	('GNG7', 'Gene', '2788', (59, 63))	('GNG7', 'Gene', '2788', (140, 144))	('GNG7', 'Gene', (140, 144))	('GNG7', 'Gene', (59, 63))
15019	30945310	These findings are consistent with the previous reports showing that loss of GNG7 was related to large tumor and tumor invasion and aggressiveness in squamous cell carcinoma of head and neck and esophageal cancer (S. Wu, F. Wu, & Jiang, 2017; Ohta et al., 2008), respectively.	('GNG7', 'Gene', '2788', (77, 81))	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('aggressiveness', 'Phenotype', 'HP:0000718', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('loss', 'Var', (69, 73))	('tumor', 'Disease', (103, 108))	('GNG7', 'Gene', (77, 81))	('carcinoma of head and neck', 'Phenotype', 'HP:0012288', (164, 190))	('neck', 'cellular_component', 'GO:0044326', ('186', '190'))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('related', 'Reg', (86, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor invasion and aggressiveness in squamous cell carcinoma of head and neck and esophageal cancer', 'Disease', 'MESH:C535575', (113, 212))
15022	30945310	Moreover, GNG7 gene mutation was found in almost all ccRCC patients in this study, further validating the TCGA data set (Figure 3a).	('ccRCC', 'Disease', (53, 58))	('found', 'Reg', (33, 38))	('GNG7', 'Gene', '2788', (10, 14))	('ccRCC', 'Disease', 'MESH:D002292', (53, 58))	('mutation', 'Var', (20, 28))	('GNG7', 'Gene', (10, 14))	('patients', 'Species', '9606', (59, 67))
15023	30945310	This result indicates that GNG7 gene methylation and high CG sit may be responsible for GNG7 gene inactivation in ccRCC progression.	('ccRCC', 'Disease', (114, 119))	('GNG7', 'Gene', '2788', (27, 31))	('ccRCC', 'Disease', 'MESH:D002292', (114, 119))	('GNG7', 'Gene', (88, 92))	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('methylation', 'Var', (37, 48))	('CG sit', 'CPA', (58, 64))	('GNG7', 'Gene', (27, 31))	('GNG7', 'Gene', '2788', (88, 92))	('inactivation', 'NegReg', (98, 110))
15035	30945310	GNG7 gene was strongly suppressed in ccRCC tumor tissues as a result of promoter methylation and frequent gene mutation.	('ccRCC', 'Disease', (37, 42))	('suppressed', 'NegReg', (23, 33))	('GNG7', 'Gene', '2788', (0, 4))	('ccRCC', 'Disease', 'MESH:D002292', (37, 42))	('methylation', 'biological_process', 'GO:0032259', ('81', '92'))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('GNG7', 'Gene', (0, 4))	('mutation', 'Var', (111, 119))	('tumor', 'Disease', (43, 48))
15040	29285300	Renal oncocytoma characterized by the defective complex I of the respiratory chain boosts the synthesis of the ROS scavenger glutathione Renal oncocytomas are rare benign tumors of the kidney and characterized by a deficient complex I (CI) enzyme activity of the oxidative phosphorylation (OXPHOS) system caused by mitochondrial DNA (mtDNA) mutations.	('OXPHOS', 'biological_process', 'GO:0002082', ('290', '296'))	('Renal oncocytoma', 'Disease', 'MESH:C537750', (137, 153))	('defective', 'Var', (38, 47))	('Renal oncocytomas', 'Phenotype', 'HP:0011798', (137, 154))	('tumors of the kidney', 'Disease', (171, 191))	('Renal oncocytomas', 'Disease', (137, 154))	('deficient complex I', 'Phenotype', 'HP:0011923', (215, 234))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('Renal oncocytoma', 'Disease', 'MESH:C537750', (0, 16))	('mutations', 'Var', (341, 350))	('tumors of the kidney', 'Disease', 'MESH:D007674', (171, 191))	('synthesis', 'MPA', (94, 103))	('synthesis', 'biological_process', 'GO:0009058', ('94', '103'))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('315', '332'))	('ROS', 'Chemical', 'MESH:D017382', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('mitochondrial DNA', 'Disease', (315, 332))	('benign tumor', 'Disease', 'MESH:D009369', (164, 176))	('tumors of the kidney', 'Phenotype', 'HP:0009726', (171, 191))	('defective complex I', 'Phenotype', 'HP:0011923', (38, 57))	('Renal oncocytoma', 'Disease', (0, 16))	('Renal oncocytoma', 'Phenotype', 'HP:0011798', (137, 153))	('enzyme activity', 'molecular_function', 'GO:0003824', ('240', '255'))	('respiratory chain', 'cellular_component', 'GO:0070469', ('65', '82'))	('complex I', 'cellular_component', 'GO:0030964', ('225', '234'))	('benign tumor', 'Disease', (164, 176))	('deficient', 'NegReg', (215, 224))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('263', '288'))	('Renal oncocytoma', 'Phenotype', 'HP:0011798', (0, 16))	('glutathione', 'Chemical', 'MESH:D005978', (125, 136))	('mtDNA', 'cellular_component', 'GO:0000262', ('334', '339'))	('complex I', 'cellular_component', 'GO:0030964', ('48', '57'))	('boosts', 'PosReg', (83, 89))	('Renal oncocytomas', 'Disease', 'MESH:C537750', (137, 154))	('activity', 'MPA', (247, 255))
15049	29285300	CI deficiency is mainly due to mutations in mitochondrial DNA (mtDNA), particularly, but not exclusively, in CI genes.	('mutations', 'Var', (31, 40))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('44', '61'))	('mtDNA', 'cellular_component', 'GO:0000262', ('63', '68'))	('CI deficiency', 'Disease', (0, 13))	('due', 'Reg', (24, 27))	('mitochondrial DNA', 'Gene', (44, 61))	('CI deficiency', 'Disease', 'MESH:D007153', (0, 13))
15050	29285300	Most mtDNA mutations detected in renal oncocytomas are well above the threshold for a pathogenic phenotype.	('mutations', 'Var', (11, 20))	('mtDNA', 'Gene', (5, 10))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (33, 49))	('mtDNA', 'cellular_component', 'GO:0000262', ('5', '10'))	('renal oncocytomas', 'Disease', (33, 50))	('renal oncocytomas', 'Disease', 'MESH:C537750', (33, 50))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (33, 50))
15051	29285300	Nonetheless, why and how mutated mtDNA specifically accumulates in oncocytomas still remains unclear.	('accumulates', 'PosReg', (52, 63))	('oncocytomas', 'Disease', 'MESH:D018249', (67, 78))	('mtDNA', 'Gene', (33, 38))	('mtDNA', 'cellular_component', 'GO:0000262', ('33', '38'))	('oncocytomas', 'Disease', (67, 78))	('mutated', 'Var', (25, 32))
15052	29285300	Most mtDNA mutations in renal oncocytomas occur in homopolymeric G-C and A-T stretches, and defects in mtDNA replication (or lack of an efficient repair system) may induce randomly such genetic lesions during cancer progression.	('genetic lesions', 'Disease', (186, 201))	('mutations', 'Var', (11, 20))	('renal oncocytomas', 'Disease', (24, 41))	('mtDNA', 'cellular_component', 'GO:0000262', ('103', '108'))	('induce', 'Reg', (165, 171))	('occur', 'Reg', (42, 47))	('renal oncocytomas', 'Disease', 'MESH:C537750', (24, 41))	('mtDNA', 'Gene', (5, 10))	('mtDNA', 'cellular_component', 'GO:0000262', ('5', '10'))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (24, 41))	('cancer', 'Disease', (209, 215))	('defects', 'Var', (92, 99))	('genetic lesions', 'Disease', 'MESH:D020022', (186, 201))	('mtDNA replication', 'biological_process', 'GO:0006264', ('103', '120'))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (24, 40))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
15053	29285300	Low-heteroplasmy mutations may confer a selection advantage due to an increase in reactive oxygen species (ROS) levels, but when shifted to homoplasmy, mtDNA mutations appear to reduce tumor growth due to their effect on respiratory complex assembly.	('tumor', 'Disease', (185, 190))	('Low-heteroplasmy', 'Disease', (0, 16))	('mtDNA', 'Gene', (152, 157))	('respiratory complex assembly', 'MPA', (221, 249))	('increase', 'PosReg', (70, 78))	('mtDNA', 'cellular_component', 'GO:0000262', ('152', '157'))	('reduce', 'NegReg', (178, 184))	('ROS', 'Chemical', 'MESH:D017382', (107, 110))	('effect', 'Reg', (211, 217))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (82, 105))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('mutations', 'Var', (158, 167))	('mutations', 'Var', (17, 26))	('Low-heteroplasmy', 'Disease', 'MESH:D009800', (0, 16))
15058	29285300	Since mtDNA mutations in CI that cause deficient CI enzyme activity and increased mitochondrial mass are characteristics of renal oncocytomas.	('deficient CI enzyme', 'Disease', (39, 58))	('activity', 'MPA', (59, 67))	('renal oncocytomas', 'Disease', (124, 141))	('mtDNA', 'cellular_component', 'GO:0000262', ('6', '11'))	('increased mitochondrial mass', 'Phenotype', 'HP:0040014', (72, 100))	('increased', 'PosReg', (72, 81))	('enzyme activity', 'molecular_function', 'GO:0003824', ('52', '67'))	('mutations', 'Var', (12, 21))	('renal oncocytomas', 'Disease', 'MESH:C537750', (124, 141))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (124, 141))	('mtDNA', 'Gene', (6, 11))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (124, 140))	('mitochondrial mass', 'MPA', (82, 100))	('deficient CI enzyme', 'Disease', 'MESH:D008661', (39, 58))
15059	29285300	The latter serve as an ideal tool to study the relationship between mtDNA mutations of the oxidative phosphorylation (OXPHOS) system and an indolent cancer phenotype.	('cancer', 'Disease', (149, 155))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('91', '116'))	('mtDNA', 'cellular_component', 'GO:0000262', ('68', '73'))	('mutations', 'Var', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('OXPHOS', 'biological_process', 'GO:0002082', ('118', '124'))	('mtDNA', 'Gene', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
15062	29285300	Whole exome sequencing (WES) led to the identification of cancer-specific mtDNA mutations that affect protein function.	('mtDNA', 'cellular_component', 'GO:0000262', ('74', '79'))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutations', 'Var', (80, 89))	('protein function', 'MPA', (102, 118))	('mtDNA', 'Gene', (74, 79))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('affect', 'Reg', (95, 101))	('cancer', 'Disease', (58, 64))
15069	29285300	The number of tumor-specific nuclear mutations (except silent ones) in oncocytomas were in the range of 65 to 329 (median of 78) per renal oncocytoma (Supplementary Table 2).	('tumor', 'Disease', (14, 19))	('renal oncocytoma', 'Disease', 'MESH:C537750', (133, 149))	('mutations', 'Var', (37, 46))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (133, 149))	('renal oncocytoma', 'Disease', (133, 149))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('oncocytomas', 'Disease', (71, 82))	('oncocytomas', 'Disease', 'MESH:D018249', (71, 82))
15070	29285300	With respect to previous observation, the frequency of transition in our European patient cohort with renal oncocytomas tested was 2-fold higher than that of transversions, whereas C>T (p = 1.03 x 10-6) and T>C (p = 2.02 x 10-2) were significantly enriched in oncocytomas (Supplementary Figure 1, Supplementary Table 3).	('renal oncocytomas', 'Disease', 'MESH:C537750', (102, 119))	('oncocytomas', 'Disease', (260, 271))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (102, 119))	('patient', 'Species', '9606', (82, 89))	('C>T', 'Var', (181, 184))	('oncocytomas', 'Disease', 'MESH:D018249', (260, 271))	('T>C', 'Var', (207, 210))	('renal oncocytomas', 'Disease', (102, 119))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (102, 118))	('oncocytomas', 'Disease', (108, 119))	('oncocytomas', 'Disease', 'MESH:D018249', (108, 119))
15071	29285300	While the "mutational signature" C>T has been found in all cancer types and is the resultant of an endogenous mutational process initiated by spontaneous deamination of 5-methylcytosine, the correlation of C>T transitions with age is indicative of a slow growth of renal oncocytoma.	('renal oncocytoma', 'Phenotype', 'HP:0011798', (265, 281))	('C>T', 'Var', (206, 209))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (169, 185))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('renal oncocytoma', 'Disease', 'MESH:C537750', (265, 281))	('slow growth', 'Phenotype', 'HP:0001510', (250, 261))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('C>T', 'Var', (33, 36))	('renal oncocytoma', 'Disease', (265, 281))
15075	29285300	Insertions in the gene CRIPAK (c.76_77insCA p.S26fs; c.323_324insCA p.L108fs) and single nucleotide variation (SNV) mutations in the gene DRD5 (p.T297P) were identified in both European and American cohorts.	('DRD5', 'Gene', (138, 142))	('p.L108fs', 'Mutation', 'p.L108fsX', (68, 76))	('p.S26fs', 'Mutation', 'p.S26fsX', (44, 51))	('DRD5', 'Gene', '1816', (138, 142))	('c.323_324insCA', 'Mutation', 'rs540461234', (53, 67))	('p.T297P', 'Mutation', 'rs2227851', (144, 151))	('CRIPAK', 'Gene', '285464', (23, 29))	('p.T297P', 'Var', (144, 151))	('mutations', 'Var', (116, 125))	('c.76_77insCA', 'Mutation', 'rs533172496', (31, 43))	('c.76_77insCA', 'Var', (31, 43))	('CRIPAK', 'Gene', (23, 29))	('c.323_324insCA', 'Var', (53, 67))	('single nucleotide variation', 'Var', (82, 109))
15076	29285300	As a negative regulator of PAK1 (p21-activated protein kinase 1), CRIPAK is hormone sensitive and was shown to have deleterious mutations in squamous cell- and adenocarcinoma and was further confirmed in other cancer types (COSMIC: COSG57208).	('CRIPAK', 'Gene', '285464', (66, 72))	('CRIPAK', 'Gene', (66, 72))	('mutations', 'Var', (128, 137))	('adenocarcinoma', 'Disease', 'MESH:D000230', (160, 174))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('PAK1', 'Gene', '5058', (27, 31))	('p21-activated protein kinase 1', 'Gene', (33, 63))	('adenocarcinoma', 'Disease', (160, 174))	('p21-activated protein kinase 1', 'Gene', '5058', (33, 63))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('PAK1', 'Gene', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('cancer', 'Disease', (210, 216))
15079	29285300	In total, we were able to identify 227 renal oncocytoma-associated mutations in 78 distinct human protein complexes, encompassing 182 genes encoding for mitochondrial, and 840 non-mitochondrial proteins.	('renal oncocytoma', 'Disease', 'MESH:C537750', (39, 55))	('mutations', 'Var', (67, 76))	('renal oncocytoma', 'Disease', (39, 55))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (39, 55))	('human', 'Species', '9606', (92, 97))
15080	29285300	Among the putative complexes compiled, 37 complex subunits with mutations relevant to renal oncocytomas were currently functionally unannotated in CORUM (a manually curated repository of experimentally characterized human protein complexes), whereas the remaining macromolecular assemblies includes, for example, those implicated in cellular metabolism (e.g.	('renal oncocytoma', 'Phenotype', 'HP:0011798', (86, 102))	('renal oncocytomas', 'Disease', (86, 103))	('human', 'Species', '9606', (216, 221))	('renal oncocytomas', 'Disease', 'MESH:C537750', (86, 103))	('cellular metabolism', 'biological_process', 'GO:0044237', ('333', '352'))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (86, 103))	('mutations', 'Var', (64, 73))	('protein', 'cellular_component', 'GO:0003675', ('222', '229'))
15082	29285300	missense mutations in DCLRE1C and frame shift mutations in PRKAB1).	('frame shift mutations', 'Var', (34, 55))	('DCLRE1C', 'Gene', (22, 29))	('missense mutations', 'Var', (0, 18))	('PRKAB1', 'Gene', '5564', (59, 65))	('PRKAB1', 'Gene', (59, 65))	('DCLRE1C', 'Gene', '64421', (22, 29))
15083	29285300	The gene artemis (DCLRE1C) is one of the subunits of Artemis/DNA-dependent protein kinase complex, whose mutations have been shown to cause hypersensitivity to DNA double-strand breaks, and interacts with protein kinase AMP-activated non-catalytic subunit Delta1 PRKAB1.	('DNA-dependent protein kinase complex', 'cellular_component', 'GO:0070418', ('61', '97'))	('protein', 'cellular_component', 'GO:0003675', ('205', '212'))	('interacts', 'Reg', (190, 199))	('artemis', 'Gene', (9, 16))	('cause', 'Reg', (134, 139))	('DCLRE1C', 'Gene', '64421', (18, 25))	('hypersensitivity', 'biological_process', 'GO:0002524', ('140', '156'))	('DNA', 'cellular_component', 'GO:0005574', ('160', '163'))	('mutations', 'Var', (105, 114))	('hypersensitivity', 'Disease', 'MESH:D004342', (140, 156))	('DCLRE1C', 'Gene', (18, 25))	('PRKAB1', 'Gene', '5564', (263, 269))	('PRKAB1', 'Gene', (263, 269))	('AMP', 'Chemical', 'MESH:D000249', (220, 223))	('hypersensitivity', 'Disease', (140, 156))
15084	29285300	We have identified missense mutations in DCLRE1C and frame shift mutations in PRKAB1 from renal oncocytoma patient samples.	('renal oncocytoma', 'Disease', (90, 106))	('PRKAB1', 'Gene', '5564', (78, 84))	('PRKAB1', 'Gene', (78, 84))	('DCLRE1C', 'Gene', '64421', (41, 48))	('DCLRE1C', 'Gene', (41, 48))	('frame shift mutations', 'Var', (53, 74))	('renal oncocytoma', 'Disease', 'MESH:C537750', (90, 106))	('patient', 'Species', '9606', (107, 114))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (90, 106))	('missense mutations', 'Var', (19, 37))
15085	29285300	Consistent with the previous studies, AMP-activated protein kinase (AMPK) plays crucial roles in oncocytoma genesis, and this complex along with the mutation in its non-catalytic subunit PRKAB1 could be involved in the progression of renal oncocytoma, as it governs the catabolic state upon stress by switching off many ATP-consuming processes.	('AMPK', 'molecular_function', 'GO:0047322', ('68', '72'))	('AMP', 'Chemical', 'MESH:D000249', (38, 41))	('oncocytoma genesis', 'Disease', (97, 115))	('oncocytoma genesis', 'Disease', 'MESH:D018249', (97, 115))	('ATP-consuming processes', 'MPA', (320, 343))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))	('involved', 'Reg', (203, 211))	('ATP', 'Chemical', 'MESH:D000255', (320, 323))	('AMP', 'Chemical', 'MESH:D000249', (68, 71))	('renal oncocytoma', 'Disease', 'MESH:C537750', (234, 250))	('AMPK', 'molecular_function', 'GO:0004691', ('68', '72'))	('AMPK', 'molecular_function', 'GO:0050405', ('68', '72'))	('PRKAB1', 'Gene', (187, 193))	('mutation', 'Var', (149, 157))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (234, 250))	('renal oncocytoma', 'Disease', (234, 250))	('PRKAB1', 'Gene', '5564', (187, 193))
15086	29285300	Since oncocytomas with mtDNA mutations feature respiratory defects, we examined the assembly of mitochondrial WES reads and found adequate coverage and quality for a reliable mtDNA reconstruction and variant calling (Supplementary Table 6).	('mtDNA', 'cellular_component', 'GO:0000262', ('175', '180'))	('mutations', 'Var', (29, 38))	('mtDNA', 'cellular_component', 'GO:0000262', ('23', '28'))	('oncocytomas', 'Disease', (6, 17))	('mtDNA', 'Gene', (23, 28))	('oncocytomas', 'Disease', 'MESH:D018249', (6, 17))
15088	29285300	Comparison of healthy kidney tissues and matched renal oncocytomas also identified potentially inherited and tumor-specific mtDNA mutations.	('renal oncocytomas', 'Disease', (49, 66))	('renal oncocytomas', 'Disease', 'MESH:C537750', (49, 66))	('mtDNA', 'Gene', (124, 129))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (49, 66))	('mtDNA', 'cellular_component', 'GO:0000262', ('124', '129'))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (49, 65))	('mutations', 'Var', (130, 139))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
15090	29285300	The Heteroplasmic Fractions (HFs) of germline mtDNA mutations were concordant between tumor and normal tissues, suggesting these events did not undergo changes during tumor development, following cell transformation.	('mutations', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('mtDNA', 'Gene', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('mtDNA', 'cellular_component', 'GO:0000262', ('46', '51'))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (167, 172))
15091	29285300	However, when considering the disease score and nucleotide variability thresholds, only 1 (7874A>G/MT-CO2) out of 6 non-synonymous variants were potentially pathogenic (Supplementary Table 6, GM_NonSyn sheet).	('MT-CO2', 'Gene', (99, 105))	('7874A>G', 'SUBSTITUTION', 'None', (91, 98))	('7874A>G', 'Var', (91, 98))	('MT-CO2', 'Gene', '4513', (99, 105))	('pathogenic', 'Reg', (157, 167))
15093	29285300	In this case, the variant m.5628T>C had a RNA prediction score equal to 0.65, greater than the fixed pathogenicity threshold 0.35.	('m.5628T>C', 'Var', (26, 35))	('RNA prediction', 'MPA', (42, 56))	('RNA', 'cellular_component', 'GO:0005562', ('42', '45'))	('m.5628T>C', 'Mutation', 'm.5628T>C', (26, 35))
15094	29285300	Additional examination of renal oncocytomas detected a total of 195 tumor-specific mutations (Supplementary Table 6, Somatic mutations) based on the three mitochondrial reference sets used (indicated above) and did not contribute to define haplogroups.	('tumor', 'Disease', (68, 73))	('mutations', 'Var', (83, 92))	('renal oncocytomas', 'Disease', 'MESH:C537750', (26, 43))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (26, 43))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (26, 42))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('renal oncocytomas', 'Disease', (26, 43))
15095	29285300	Notably, among these, only one mutation was homoplasmic, namely the m.14568C>A/MT-ND6 (Supplementary Table 6, SM_NonSyn highlighted in green).	('MT-ND6', 'Gene', '4541', (79, 85))	('MT-ND6', 'Gene', (79, 85))	('m.14568C>A', 'Var', (68, 78))	('m.14568C>A', 'SUBSTITUTION', 'None', (68, 78))
15096	29285300	Concerning the stop/gain mutations, 8 occurred in CI subunit encoding genes (one in MT-ND2 and 7 in MT-ND5), 8 in the cytochrome B (MT-CYB), 2 in cytochrome c oxidase subunits (one in MT-CO1 and one in MT-CO3) and one in complex V (MT-ATP6) (Supplementary Table 6, SM_stopgain).	('MT-ND2', 'Gene', (84, 90))	('MT-CO1', 'Gene', '4512', (184, 190))	('CI subunit encoding', 'Gene', (50, 69))	('cytochrome c', 'molecular_function', 'GO:0045155', ('146', '158'))	('mutations', 'Var', (25, 34))	('cytochrome B', 'molecular_function', 'GO:0005489', ('118', '130'))	('MT-ND5', 'Gene', '4540', (100, 106))	('MT-CO1', 'Gene', (184, 190))	('cytochrome B', 'Gene', '4519', (118, 130))	('MT-ND5', 'Gene', (100, 106))	('cytochrome B', 'Gene', (118, 130))	('MT-CO3', 'Gene', (202, 208))	('cytochrome B', 'molecular_function', 'GO:0009460', ('118', '130'))	('cytochrome c', 'molecular_function', 'GO:0009461', ('146', '158'))	('MT-CO3', 'Gene', '4514', (202, 208))	('stop/gain', 'Gene', (15, 24))	('ATP6', 'Gene', (235, 239))	('ATP6', 'Gene', '4508', (235, 239))	('MT-ND2', 'Gene', '4536', (84, 90))
15097	29285300	Furthermore, nearly half of the non-protein coding alterations (78 of 195; 40%) were found in renal oncocytomas, of which two-thirds (52 out of 78) mapped within the regulatory MT-DLOOP region.	('alterations', 'Var', (51, 62))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (94, 110))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('renal oncocytomas', 'Disease', (94, 111))	('non-protein coding alterations', 'Var', (32, 62))	('found', 'Reg', (85, 90))	('renal oncocytomas', 'Disease', 'MESH:C537750', (94, 111))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (94, 111))
15098	29285300	Moreover, three subjects harbored a mutation in tRNA genes, namely the m.4428G>A/MT-TM, m.1611G>A/MT-TV and the m.15991C>T/MT-TP, showing null nucleotide variability.	('m.15991C>T', 'Var', (112, 122))	('MT-TV', 'Gene', (98, 103))	('MT-TM', 'Gene', '4569', (81, 86))	('MT-TM', 'Gene', (81, 86))	('MT-TV', 'Gene', '4577', (98, 103))	('tRNA', 'molecular_function', 'GO:0030533', ('48', '52'))	('m.1611G>A', 'Var', (88, 97))	('m.15991C>T', 'SUBSTITUTION', 'None', (112, 122))	('m.4428G>A', 'Var', (71, 80))	('m.4428G>A', 'SUBSTITUTION', 'None', (71, 80))	('tRNA', 'Gene', (48, 52))	('m.1611G>A', 'SUBSTITUTION', 'None', (88, 97))
15099	29285300	Noteworthy, the mutation m.15991C>T in tRNA-Pro (MT-TP) in the anticodon region of the secondary structure of the tRNA displayed a significant HF of 0.57 (Supplementary Table 6, SM_noncodingproteins).	('MT-TP', 'Gene', (49, 54))	('m.15991C>T', 'Mutation', 'm.15991C>T', (25, 35))	('tRNA-Pro', 'Gene', (39, 47))	('m.15991C>T', 'Var', (25, 35))	('tRNA', 'molecular_function', 'GO:0030533', ('39', '43'))	('tRNA', 'molecular_function', 'GO:0030533', ('114', '118'))
15101	29285300	While no homoplasmic tumor specific mtDNA frame shift mutations in protein coding genes were observed, as reported previously, a number of distinct pathogenic low level heteroplasmic mutations with cumulative effect was identified, leading to disassembled CI.	('mtDNA', 'cellular_component', 'GO:0000262', ('36', '41'))	('mutations', 'Var', (183, 192))	('tumor', 'Disease', (21, 26))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
15185	29285300	The main characteristics of renal oncocytomas are mutations within the respiratory chain, especially in CI.	('mutations', 'Var', (50, 59))	('renal oncocytomas', 'Disease', 'MESH:C537750', (28, 45))	('respiratory chain', 'Enzyme', (71, 88))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (28, 45))	('respiratory chain', 'cellular_component', 'GO:0070469', ('71', '88'))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (28, 44))	('renal oncocytomas', 'Disease', (28, 45))
15188	29285300	As well, multiple low level pathogenic heteroplasmic mtDNA mutations resulted in a dramatic decrease of CI protein abundancies, leading to incorrectly assembled or non-functional complex, which may become highly unstable and degrade fast, as previously shown in oncocytic cells bearing ND1 mutations.	('ND1', 'Gene', '4535', (286, 289))	('decrease', 'NegReg', (92, 100))	('mtDNA', 'cellular_component', 'GO:0000262', ('53', '58'))	('incorrectly assembled or non-functional complex', 'MPA', (139, 186))	('unstable', 'MPA', (212, 220))	('mtDNA', 'Gene', (53, 58))	('ND1', 'Gene', (286, 289))	('mutations', 'Var', (59, 68))	('degrade', 'NegReg', (225, 232))	('CI protein abundancies', 'MPA', (104, 126))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
15198	29285300	An impairment of the respiratory chain due to mtDNA mutations was recently shown to alter the cytoskeleton structure, accompanied by mis-orientation of the Golgi body.	('mutations', 'Var', (52, 61))	('respiratory chain', 'cellular_component', 'GO:0070469', ('21', '38'))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('94', '106'))	('mtDNA', 'Gene', (46, 51))	('impairment of the respiratory', 'Disease', (3, 32))	('impairment of the respiratory', 'Disease', 'MESH:D012131', (3, 32))	('cytoskeleton structure', 'MPA', (94, 116))	('mtDNA', 'cellular_component', 'GO:0000262', ('46', '51'))	('Golgi', 'cellular_component', 'GO:0005794', ('156', '161'))	('alter', 'Reg', (84, 89))
15218	29285300	But it still remains a chicken or egg causality dilemma, if mtDNA mutations were the cause or the consequence of high ROS levels.	('mutations', 'Var', (66, 75))	('ROS', 'MPA', (118, 121))	('high ROS levels', 'Phenotype', 'HP:0025464', (113, 128))	('mtDNA', 'cellular_component', 'GO:0000262', ('60', '65'))	('ROS', 'Chemical', 'MESH:D017382', (118, 121))	('mtDNA', 'Gene', (60, 65))	('chicken', 'Species', '9031', (23, 30))
15219	29285300	It was shown previously in cybride cells that only specific mtDNA mutations, such as LOHN mutations increase ROS, thus there is a direct link between mtDNA mutations and ROS levels.	('mutations', 'Var', (66, 75))	('LOHN', 'Disease', (85, 89))	('mtDNA', 'cellular_component', 'GO:0000262', ('150', '155'))	('ROS', 'MPA', (109, 112))	('mtDNA', 'cellular_component', 'GO:0000262', ('60', '65'))	('mtDNA', 'Gene', (60, 65))	('ROS', 'Chemical', 'MESH:D017382', (170, 173))	('ROS', 'Chemical', 'MESH:D017382', (109, 112))	('increase', 'PosReg', (100, 108))
15265	29285300	(2016) are intended to easily target the mitochondrial DNA variants of clinical interest, by prioritizing those variants recognized against the mitochondrial reference sequences (rCRS, RSRS and MHCS), which occurred in non haplogroup-defining sites, featuring nucleotide variability lower than nucleotide variability cutoff (0.0026) and having a disease score above the disease score threshold (0.43, 0.35 and 0.60 for non synonimous coding for proteins, tRNA and rRNA variants respectively).	('RSRS', 'Disease', (185, 189))	('rRNA', 'MPA', (464, 468))	('proteins', 'Protein', (445, 453))	('RSRS', 'Disease', 'None', (185, 189))	('tRNA', 'molecular_function', 'GO:0030533', ('455', '459'))	('tRNA', 'MPA', (455, 459))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('41', '58'))	('variants', 'Var', (112, 120))
15289	29285300	In summary, cancer-specific pathogenic mtDNA mutations lead to a decreased CI abundance and defective respiratory chain in renal oncocytomas.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('mutations', 'Var', (45, 54))	('defective', 'NegReg', (92, 101))	('mtDNA', 'cellular_component', 'GO:0000262', ('39', '44'))	('cancer', 'Disease', (12, 18))	('decreased', 'NegReg', (65, 74))	('mtDNA', 'Gene', (39, 44))	('renal oncocytomas', 'Disease', 'MESH:C537750', (123, 140))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (123, 140))	('respiratory chain', 'cellular_component', 'GO:0070469', ('102', '119'))	('CI abundance', 'MPA', (75, 87))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('respiratory', 'MPA', (102, 113))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (123, 139))	('renal oncocytomas', 'Disease', (123, 140))
15316	32429554	The hallmark molecular alterations of ccRCC include chromosome 3p loss and inactivation of the Von-Hippel Lindau (VHL) gene, which lies at the 3p25 locus.	('inactivation', 'Var', (75, 87))	('chromosome', 'cellular_component', 'GO:0005694', ('52', '62'))	('loss', 'NegReg', (66, 70))	('VHL', 'Gene', '7428', (114, 117))	('RCC', 'Disease', (40, 43))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('Von-Hippel Lindau', 'Disease', (95, 112))	('Von-Hippel Lindau', 'Disease', 'MESH:D006623', (95, 112))	('VHL', 'Gene', (114, 117))
15318	32429554	Inactivation of VHL has been reported in up to 90% of sporadic ccRCC cases.	('VHL', 'Gene', (16, 19))	('VHL', 'Gene', '7428', (16, 19))	('Inactivation', 'Var', (0, 12))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
15319	32429554	Germline inactivations of VHL are associated with Von-Hippel Lindau syndrome, which predisposes individuals to bilateral renal masses, as well as hemangioblastomas and retinal angiomas.	('associated', 'Reg', (34, 44))	('hemangioblastomas', 'Disease', 'MESH:D018325', (146, 163))	('hemangioblastomas', 'Disease', (146, 163))	('retinal angiomas', 'Disease', (168, 184))	('VHL', 'Gene', (26, 29))	('VHL', 'Gene', '7428', (26, 29))	('Von-Hippel Lindau syndrome', 'Disease', 'MESH:D006623', (50, 76))	('bilateral renal masses', 'Disease', (111, 133))	('retinal angiomas', 'Disease', 'MESH:D006391', (168, 184))	('Von-Hippel Lindau syndrome', 'Disease', (50, 76))	('renal masses', 'Phenotype', 'HP:0009726', (121, 133))	('Germline inactivations', 'Var', (0, 22))
15320	32429554	Other mutations associated with ccRCC are PBRM1, SETD2, and BAP1, all of which also lie on chromosome 3p.	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('PBRM1', 'Gene', (42, 47))	('BAP1', 'Gene', '8314', (60, 64))	('SETD2', 'Gene', (49, 54))	('chromosome', 'cellular_component', 'GO:0005694', ('91', '101'))	('PBRM1', 'Gene', '55193', (42, 47))	('SETD2', 'Gene', '29072', (49, 54))	('associated', 'Reg', (16, 26))	('BAP1', 'Gene', (60, 64))	('mutations', 'Var', (6, 15))	('RCC', 'Disease', (34, 37))
15354	32429554	The initial MSKCC risk score included five prognostic factors: low Karnofsky performance status, high serum lactate dehydrogenase, low hemoglobin, high serum calcium, and absence of prior nephrectomy.	('Karnofsky performance status', 'CPA', (67, 95))	('low hemoglobin', 'Phenotype', 'HP:0001903', (131, 145))	('high', 'PosReg', (97, 101))	('high serum calcium', 'Phenotype', 'HP:0003072', (147, 165))	('high serum lactate', 'Phenotype', 'HP:0002151', (97, 115))	('high', 'Var', (147, 151))	('calcium', 'Chemical', 'MESH:D002118', (158, 165))	('low', 'NegReg', (63, 66))	('high serum lactate dehydrogenase', 'Phenotype', 'HP:0025435', (97, 129))	('low', 'NegReg', (131, 134))	('MSKCC', 'Gene', (12, 17))
15357	32429554	In 2018, the MSKCC risk model was updated to incorporate genomic characteristics, specifically the mutational status of BAP1, PBRM1, and TP53 in the stratification algorithm.	('PBRM1', 'Gene', (126, 131))	('PBRM1', 'Gene', '55193', (126, 131))	('BAP1', 'Gene', '8314', (120, 124))	('TP53', 'Gene', '7157', (137, 141))	('TP53', 'Gene', (137, 141))	('mutational status', 'Var', (99, 116))	('BAP1', 'Gene', (120, 124))
15361	32429554	The IMDC model incorporates six prognostic variables: less than one year from the time of diagnosis to onset of systemic therapy, low Karnofsky performance status, low hemoglobin, high calcium, high neutrophil, and high platelet levels.	('high calcium', 'MPA', (180, 192))	('high neutrophil', 'MPA', (194, 209))	('low', 'NegReg', (130, 133))	('low hemoglobin', 'Phenotype', 'HP:0001903', (164, 178))	('high platelet levels', 'MPA', (215, 235))	('low', 'Var', (164, 167))	('high platelet levels', 'Phenotype', 'HP:0001894', (215, 235))	('calcium', 'Chemical', 'MESH:D002118', (185, 192))
15364	32429554	The first shift in the therapeutic approach to mRCC occurred with the advent of small-molecule inhibitors that bind to and inhibit the activity of membranous receptors and intracellular proteins.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('bind', 'Interaction', (111, 115))	('membranous receptors', 'Protein', (147, 167))	('activity', 'MPA', (135, 143))	('inhibit', 'NegReg', (123, 130))	('intracellular', 'cellular_component', 'GO:0005622', ('172', '185'))	('small-molecule', 'Var', (80, 94))	('RCC', 'Disease', (48, 51))
15366	32429554	Mechanistically, VHL mutations lead to decreased ubiquitinylation of hypoxia-inducible factor (HIF) and upregulation of the circulating VEGF molecule which then binds the VEGF receptor, promoting angiogenesis.	('upregulation', 'PosReg', (104, 116))	('VEGF', 'Gene', '7422', (136, 140))	('ubiquitinylation', 'MPA', (49, 65))	('VEGF', 'Gene', '7422', (171, 175))	('hypoxia', 'Disease', (69, 76))	('hypoxia', 'Disease', 'MESH:D000860', (69, 76))	('promoting', 'PosReg', (186, 195))	('angiogenesis', 'biological_process', 'GO:0001525', ('196', '208'))	('angiogenesis', 'CPA', (196, 208))	('VHL', 'Gene', (17, 20))	('VEGF', 'Gene', (136, 140))	('VEGF', 'Gene', (171, 175))	('decreased', 'NegReg', (39, 48))	('binds', 'Interaction', (161, 166))	('VHL', 'Gene', '7428', (17, 20))	('mutations', 'Var', (21, 30))
15369	32429554	Sunitinib was demonstrated to prolong progression-free survival (PFS) compared to IFN-alpha (11 versus 4 months) and was associated with a higher objective response rate (ORR) (31% vs. 6%).	('progression-free survival', 'CPA', (38, 63))	('IFN-alpha', 'Gene', '3439', (82, 91))	('IFN-alpha', 'Gene', (82, 91))	('prolong', 'PosReg', (30, 37))	('Sunitinib', 'Chemical', 'MESH:D000077210', (0, 9))	('Sunitinib', 'Var', (0, 9))	('objective response', 'MPA', (146, 164))
15384	32429554	Dysregulation of this pathway is a metabolic feature of many RCC tumors, making the components of its signaling cascade viable targets for pharmacologic inhibition.	('Dysregulation', 'Var', (0, 13))	('RCC tumors', 'Disease', (61, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('RCC tumors', 'Disease', 'MESH:C538614', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('signaling cascade', 'biological_process', 'GO:0007165', ('102', '119'))
15410	32429554	Likewise, irrespective of PD-L1 status, axitinib + avelumab was again associated with improved PFS (13.8 versus 8.4 months).	('axitinib', 'Chemical', 'MESH:D000077784', (40, 48))	('improved', 'PosReg', (86, 94))	('PFS', 'MPA', (95, 98))	('axitinib', 'Var', (40, 48))
15434	32429554	Mutation of VHL (largely sporadic, but possibly hereditary) leads to decreased ubiquitinylation of HIF.	('ubiquitinylation', 'MPA', (79, 95))	('VHL', 'Gene', (12, 15))	('VHL', 'Gene', '7428', (12, 15))	('decreased', 'NegReg', (69, 78))	('Mutation', 'Var', (0, 8))
15445	32429554	Notably, DNA level data suggested that TERT promoter alterations were a negative predictor of immunotherapy response, with RNA level data from the study identifying multiple TERT-associated pathways that could play a role in immunotherapy resistance.	('TERT', 'Gene', (39, 43))	('TERT', 'Gene', (174, 178))	('TERT', 'Gene', '7015', (39, 43))	('alterations', 'Var', (53, 64))	('immunotherapy response', 'CPA', (94, 116))	('TERT', 'Gene', '7015', (174, 178))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('negative', 'NegReg', (72, 80))	('RNA', 'cellular_component', 'GO:0005562', ('123', '126'))
15446	32429554	Our pooled data indicate, for instance, a preponderance of mutations in VHL, PBRM1, SETD2, and other mutations in the mammalian target of rapamycin (mTOR) pathway.	('PBRM1', 'Gene', (77, 82))	('mammalian target of rapamycin', 'Gene', (118, 147))	('VHL', 'Gene', '7428', (72, 75))	('SETD2', 'Gene', (84, 89))	('mammalian target of rapamycin', 'Gene', '2475', (118, 147))	('mTOR', 'Gene', '2475', (149, 153))	('PBRM1', 'Gene', '55193', (77, 82))	('mTOR', 'Gene', (149, 153))	('mutations', 'Var', (59, 68))	('VHL', 'Gene', (72, 75))	('SETD2', 'Gene', '29072', (84, 89))
15448	32429554	Many phase I and II trials in development focus specifically on these mutations but do so in a tumor agnostic fashion.	('mutations', 'Var', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('men', 'Species', '9606', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
15462	32429554	This is true in mRCC space as well:as one example, COSMIC-021 (NCT03170960) is an international study chaired by investigators at our site.	('NCT03170960', 'Var', (63, 74))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))
15523	29720944	Besides, "sva" (Leek and Storey,) R package was used to remove batch effects between dataset GSE53757 and GSE36895.	('GSE36895', 'Var', (106, 114))	('GSE53757', 'Var', (93, 101))	('Leek', 'Species', '4681', (16, 20))
15526	29720944	The two datasets GSE36895 and GSE40355 used for preservation analysis contained gene expression profiles of 29 and 16 ccRCC samples, respectively.	('gene expression profiles', 'MPA', (80, 104))	('GSE36895', 'Var', (17, 25))	('gene expression', 'biological_process', 'GO:0010467', ('80', '95'))	('GSE40355', 'Var', (30, 38))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))
15539	29720944	The expression matrices for 196 samples containing 101 ccRCC samples and 95 normal kidney samples in datasets GSE53757 and GSE36895 were obtained after data preprocessing.	('GSE36895', 'Var', (123, 131))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('GSE53757', 'Var', (110, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))
15570	29720944	Cell cycle and cell division are the basic process of cell proliferation, the abnormal mediation of which will lead to the tumor progression.	('cell division', 'CPA', (15, 28))	('tumor', 'Disease', (123, 128))	('Cell cycle', 'CPA', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('cell proliferation', 'biological_process', 'GO:0008283', ('54', '72'))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cell division', 'biological_process', 'GO:0051301', ('15', '28'))	('lead to', 'Reg', (111, 118))	('abnormal', 'Var', (78, 86))
15588	28404888	As few as 100 CD73high cells were capable of forming xenograft tumors in non obese diabetic/severe combined immunodeficiency disease mice, whereas 1 x 105 CD73low cells did not initiate tumor formation.	('mice', 'Species', '10090', (133, 137))	('xenograft tumors', 'Disease', (53, 69))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('non obese diabetic', 'Phenotype', 'HP:0005978', (73, 91))	('tumor', 'Disease', (186, 191))	('immunodeficiency disease', 'Disease', (108, 132))	('xenograft tumors', 'Disease', 'MESH:D009369', (53, 69))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('immunodeficiency', 'Phenotype', 'HP:0002721', (108, 124))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (99, 124))	('formation', 'biological_process', 'GO:0009058', ('192', '201'))	('tumor', 'Disease', (63, 68))	('CD73high', 'Var', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('obese diabetic', 'Disease', (77, 91))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('immunodeficiency disease', 'Disease', 'MESH:D007153', (108, 132))	('obese diabetic', 'Disease', 'MESH:D009765', (77, 91))	('diabetic/severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (83, 124))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
15589	28404888	Furthermore, the CD73high cells were more resistant to radiation and DNA-damaging agents than the CD73low cells, and expressed a panel of 'stemness' genes at a higher level than the CD73low cells.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('more', 'PosReg', (37, 41))	('higher', 'PosReg', (160, 166))	("'stemness'", 'Disease', (138, 148))	("'stemness'", 'Disease', 'MESH:D020295', (138, 148))	('CD73high', 'Var', (17, 25))	('expressed', 'MPA', (117, 126))
15626	28404888	A proportion of 21.5 +- 5.9% (n = 6) double positive for Rho123 and CD73-PE existed in specimens of ccRCC.	('CD73-PE', 'Var', (68, 75))	('PE', 'Chemical', '-', (73, 75))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('Rho123', 'Var', (57, 63))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))
15634	28404888	The same number of CD73high and CD73low cells were injected into the right and left inguens of NOD/SCID mice, respectively.	('CD73low', 'Var', (32, 39))	('NOD', 'Gene', '1822', (95, 98))	('mice', 'Species', '10090', (104, 108))	('SCID', 'Gene', '19090', (99, 103))	('CD73high', 'Var', (19, 27))	('SCID', 'Gene', (99, 103))	('NOD', 'Gene', (95, 98))
15637	28404888	The CD73high cells exhibited higher expression of Oct3/4, beta-catenin, and Nanog than the CD73low cells (Figure 4D).	('higher', 'PosReg', (29, 35))	('beta-catenin', 'Gene', (58, 70))	('Nanog', 'Protein', (76, 81))	('Oct3/4', 'Gene', '5460', (50, 56))	('beta-catenin', 'Gene', '1499', (58, 70))	('Oct3/4', 'Gene', (50, 56))	('expression', 'MPA', (36, 46))	('CD73high', 'Var', (4, 12))
15638	28404888	The CD73high subpopulation also exhibited significant resistance to X-ray irradiation (Figure 4E) and MMC (Figure 4F) in comparison to CD73low cells.	('resistance', 'CPA', (54, 64))	('MMC', 'Chemical', 'MESH:D016685', (102, 105))	('CD73high', 'Var', (4, 12))
15639	28404888	Taken together, these results show that the CD73high cells possess the characteristics of CSCs, and CD73 can be considered as a specific cell surface biomarker of ccRCC CSCs.	('cell surface', 'cellular_component', 'GO:0009986', ('137', '149'))	('CSCs', 'Disease', (90, 94))	('CD73', 'Var', (100, 104))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('RCC', 'Disease', (165, 168))
15644	28404888	Among 44 cases of ccRCC examined, the expression levels of CD73 was proportional to the tumor grade of ccRCC and CD73 was more intensively expressed in high-grade G3 and G2 tumors than in low grade G1 tumors (Figure 5B).	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('RCC', 'Disease', (20, 23))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', (173, 179))	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', (88, 93))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (201, 207))	('CD73', 'Var', (113, 117))	('intensively', 'PosReg', (127, 138))
15646	28404888	As shown in Supplementary Figure 3C and Table 1D, when the same amount of cells with control shRNA or CD73 shRNA planted to the right or left inguen of the same mouse, respectively, the amount of tumors formed by RCC cells with CD73 shRNA was less than those with control shRNA, and the maximal tumor size was smaller correspondingly, indicating that tumor formation of cells with reduced CD73 expression was notably suppressed.	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', (351, 356))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('tumor', 'Disease', (295, 300))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumors', 'Disease', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('RCC', 'Disease', (213, 216))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	('suppressed', 'NegReg', (417, 427))	('mouse', 'Species', '10090', (161, 166))	('CD73 shRNA', 'Var', (228, 238))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('less', 'NegReg', (243, 247))	('formation', 'biological_process', 'GO:0009058', ('357', '366'))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))
15651	28404888	identified CSCs basing on ALDH activity in pancreatic neuroendocrine tumor (pNET) clinical specimens and cell lines, and found that CD73 was overexpressed in ALDHhigh cells, and inhibition of CD73 significantly attenuated in vitro sphere formation and cell motility, as well as in vivo tumor growth for ALDHhigh cells.	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (43, 74))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('inhibition', 'Var', (178, 188))	('ALDH', 'Gene', '216', (26, 30))	('ALDH', 'Gene', (303, 307))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cell motility', 'CPA', (252, 265))	('ALDH', 'Gene', (26, 30))	('ALDH', 'Gene', '216', (158, 162))	('formation', 'biological_process', 'GO:0009058', ('238', '247'))	('tumor', 'Disease', (286, 291))	('ALDH', 'Gene', (158, 162))	('pancreatic neuroendocrine tumor', 'Disease', 'MESH:D018358', (43, 74))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('CD73', 'Gene', (192, 196))	('tumor', 'Disease', (69, 74))	('pNET', 'Phenotype', 'HP:0030405', (76, 80))	('ALDH', 'molecular_function', 'GO:0004030', ('26', '30'))	('cell motility', 'biological_process', 'GO:0048870', ('252', '265'))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (54, 74))	('pancreatic neuroendocrine tumor', 'Disease', (43, 74))	('attenuated', 'NegReg', (211, 221))	('ALDH', 'Gene', '216', (303, 307))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
15677	28404888	Furthermore, we found that the Rhohigh and CD73high RCC cells displayed lower expression of P-gp than their counterpart (Supplementary Figure 5B).	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('Rhohigh', 'Var', (31, 38))	('expression', 'MPA', (78, 88))	('P-gp', 'Gene', (92, 96))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('lower', 'NegReg', (72, 77))	('P-gp', 'Gene', '5243', (92, 96))	('CD73high', 'Var', (43, 51))
15715	28404888	To compare the tumor forming capacity of cells with or without CD73 knockdown, 5 x 104, 5 x 103, and 5 x 102 of cells stably expressing CD73 shRNA or control shRNA cells were suspended in serum-free medium, mixed with the same volume of Matrigel and injected into nude mice.	('CD73', 'Var', (136, 140))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('nude mice', 'Species', '10090', (264, 273))
15722	28404888	Antibodies used in this study were anti-beta-actin (Santa Cruz Biotechnology, Santa Cruz, CA),, anti-GADPH (Santa Cruz Biotechnology), anti-P-glycoprotein (Abcam, Cambridge, MA), and anti-human CD73 (Abcam).	('P-glycoprotein', 'Gene', (140, 154))	('anti-GADPH', 'Var', (96, 106))	('P-glycoprotein', 'molecular_function', 'GO:0008559', ('140', '154'))	('human', 'Species', '9606', (188, 193))	('beta-actin', 'Gene', '728378', (40, 50))	('beta-actin', 'Gene', (40, 50))	('P-glycoprotein', 'Gene', '5243', (140, 154))	('anti-human', 'Var', (183, 193))
15740	29156724	Plasmacytoma variant translocation 1 (PVT1), an lncRNA, was shown to be upregulated in clear cell renal cell carcinoma (ccRCC) in our study, while Kaplan-Meier curve and Cox regression analysis showed that high expression of PVT1 was associated with poor overall survival (OS) and disease free survival (DFS) in ccRCC patients.	('ccRCC', 'Phenotype', 'HP:0006770', (312, 317))	('Plasmacytoma variant translocation 1', 'Gene', '5820', (0, 36))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (87, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (120, 125))	('RCC', 'Disease', (314, 317))	('RCC', 'Phenotype', 'HP:0005584', (314, 317))	('poor', 'NegReg', (250, 254))	('PVT1', 'Gene', (38, 42))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (98, 118))	('Cox', 'Gene', '1351', (170, 173))	('PVT1', 'Gene', '5820', (38, 42))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('disease free survival', 'CPA', (281, 302))	('RCC', 'Disease', (122, 125))	('clear cell renal cell carcinoma', 'Disease', (87, 118))	('RCC', 'Disease', 'MESH:C538614', (314, 317))	('high expression', 'Var', (206, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('upregulated', 'PosReg', (72, 83))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('PVT1', 'Gene', (225, 229))	('Cox', 'Gene', (170, 173))	('overall survival', 'CPA', (255, 271))	('Plasmacytoma variant translocation 1', 'Gene', (0, 36))	('PVT1', 'Gene', '5820', (225, 229))	('patients', 'Species', '9606', (318, 326))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (87, 118))	('OS', 'Chemical', '-', (273, 275))	('Plasmacytoma', 'Phenotype', 'HP:0011857', (0, 12))
15761	29156724	After overexpression or silencing of PVT1, a series of in vitro and in vivo experiments were conducted to explore the impacts of PVT1 on proliferation, migration, invasion, and tumorigenicity of ccRCC cells.	('migration', 'CPA', (152, 161))	('PVT1', 'Gene', (37, 41))	('PVT1', 'Gene', '5820', (129, 133))	('RCC', 'Phenotype', 'HP:0005584', (197, 200))	('RCC', 'Disease', 'MESH:C538614', (197, 200))	('PVT1', 'Gene', '5820', (37, 41))	('RCC', 'Disease', (197, 200))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('ccRCC', 'Phenotype', 'HP:0006770', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))	('PVT1', 'Gene', (129, 133))	('silencing', 'Var', (24, 33))	('invasion', 'CPA', (163, 171))
15779	29156724	The results showed that patients with high expression of PVT1 had reduced OS and DFS compared to those with low PVT1 expression (Figure 1G, 1H).	('reduced', 'NegReg', (66, 73))	('PVT1', 'Gene', (112, 116))	('PVT1', 'Gene', (57, 61))	('high expression', 'Var', (38, 53))	('PVT1', 'Gene', '5820', (112, 116))	('PVT1', 'Gene', '5820', (57, 61))	('DFS', 'CPA', (81, 84))	('patients', 'Species', '9606', (24, 32))	('OS', 'Chemical', '-', (74, 76))
15786	29156724	MTS assay (Figure 2A, 2B, 2C, 2D) and colony formation assay (Figure 2E, 2F) showed that knockdown of PVT1 inhibited cell proliferation in 786-O and ACHN, while PVT1 overexpression promoted cell proliferation.	('PVT1', 'Gene', (102, 106))	('PVT1', 'Gene', (161, 165))	('cell proliferation in 786-O', 'CPA', (117, 144))	('PVT1', 'Gene', '5820', (102, 106))	('PVT1', 'Gene', '5820', (161, 165))	('cell proliferation', 'biological_process', 'GO:0008283', ('190', '208'))	('cell proliferation', 'biological_process', 'GO:0008283', ('117', '135'))	('knockdown', 'Var', (89, 98))	('formation', 'biological_process', 'GO:0009058', ('45', '54'))	('inhibited', 'NegReg', (107, 116))
15787	29156724	Flow cytometric analysis showed that PVT1 knockdown increased the number of cells in the G0/G1 phase and reduced the number of cells in the S phase (Figure 2G).	('PVT1', 'Gene', (37, 41))	('increased', 'PosReg', (52, 61))	('G1 phase', 'biological_process', 'GO:0051318', ('92', '100'))	('S phase', 'biological_process', 'GO:0051320', ('140', '147'))	('PVT1', 'Gene', '5820', (37, 41))	('reduced', 'NegReg', (105, 112))	('knockdown', 'Var', (42, 51))
15792	29156724	Wound healing assay (Supplementary Figure 1D, 1E) and Transwell assay showed a higher migratory ability in both cell lines with PVT1 overexpression, while PVT1 knockdown reduced this ability significantly.	('overexpression', 'Var', (133, 147))	('PVT1', 'Gene', '5820', (155, 159))	('Wound healing', 'biological_process', 'GO:0042060', ('0', '13'))	('PVT1', 'Gene', (155, 159))	('PVT1', 'Gene', (128, 132))	('migratory ability', 'CPA', (86, 103))	('higher', 'PosReg', (79, 85))	('PVT1', 'Gene', '5820', (128, 132))
15793	29156724	Western blot showed that PVT1 silencing lead to the upregulation of epithelial markers E-cadherin but downregulation of mesenchymal markers N-cadherin and vimentin, while ectopic expression of PVT1 turned out to decrease E-cadherin and increase the mesenchymal markers (Figure 3C).	('N-cadherin', 'Gene', (140, 150))	('E-cadherin', 'Gene', (87, 97))	('E-cadherin', 'Gene', '999', (87, 97))	('decrease', 'NegReg', (212, 220))	('downregulation', 'NegReg', (102, 116))	('E-cadherin', 'Gene', (221, 231))	('E-cadherin', 'Gene', '999', (221, 231))	('N-cadherin', 'Gene', '1000', (140, 150))	('vimentin', 'cellular_component', 'GO:0045098', ('155', '163'))	('cadherin', 'molecular_function', 'GO:0008014', ('142', '150'))	('mesenchymal', 'CPA', (120, 131))	('increase', 'PosReg', (236, 244))	('silencing', 'Var', (30, 39))	('vimentin', 'cellular_component', 'GO:0045099', ('155', '163'))	('cadherin', 'molecular_function', 'GO:0008014', ('223', '231'))	('PVT1', 'Gene', (193, 197))	('mesenchymal markers', 'CPA', (249, 268))	('vimentin', 'Gene', '7431', (155, 163))	('PVT1', 'Gene', '5820', (193, 197))	('upregulation', 'PosReg', (52, 64))	('vimentin', 'Gene', (155, 163))	('PVT1', 'Gene', (25, 29))	('cadherin', 'molecular_function', 'GO:0008014', ('89', '97'))	('PVT1', 'Gene', '5820', (25, 29))
15825	29156724	All these results suggest a novel PVT1 splicing variant can also regulate BMI1, ZEB1 and ZEB2 by competitively binding miR-200s to exert oncogenic functions, although the splicing mechanisms need further exploration.	('ZEB1', 'Gene', '6935', (80, 84))	('splicing', 'biological_process', 'GO:0045292', ('39', '47'))	('BMI1', 'Gene', (74, 78))	('miR', 'Gene', '220972', (119, 122))	('ZEB1', 'Gene', (80, 84))	('miR', 'Gene', (119, 122))	('PVT1', 'Gene', (34, 38))	('ZEB2', 'Gene', '9839', (89, 93))	('splicing', 'biological_process', 'GO:0045292', ('171', '179'))	('regulate', 'Reg', (65, 73))	('binding', 'Interaction', (111, 118))	('oncogenic functions', 'CPA', (137, 156))	('binding', 'molecular_function', 'GO:0005488', ('111', '118'))	('ZEB2', 'Gene', (89, 93))	('PVT1', 'Gene', '5820', (34, 38))	('variant', 'Var', (48, 55))
15851	29156724	Despite the deletion defect on the fourth exon, it does not affect its binding with miR-200s and the regulatory capability residing in full-length transcript still remains in PVT1DeltaE4.	('miR', 'Gene', '220972', (84, 87))	('miR', 'Gene', (84, 87))	('deletion defect', 'Var', (12, 27))	('PVT1DeltaE4', 'Gene', (175, 186))	('PVT1DeltaE4', 'Gene', '5820', (175, 186))	('binding', 'Interaction', (71, 78))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))
15853	29156724	However, our results also showed that knockdown of oncogenic splicing factor SRSF1 reduced the relative expression of PVT1DeltaE4 and increased the full-length one accordingly, so there might also be certain differences between these two transcripts.	('splicing', 'biological_process', 'GO:0045292', ('61', '69'))	('PVT1DeltaE4', 'Gene', '5820', (118, 129))	('reduced', 'NegReg', (83, 90))	('SRSF1', 'Gene', (77, 82))	('SRSF1', 'Gene', '6426', (77, 82))	('full-length', 'MPA', (148, 159))	('PVT1DeltaE4', 'Gene', (118, 129))	('increased', 'PosReg', (134, 143))	('knockdown', 'Var', (38, 47))
15855	29156724	Considering that aberrant alternative splicing of pre-mRNA is one of the molecular hallmarks of cancer and the emerging functions of lncRNA, the alternative splicing of pre-lncRNA may also have the potential to affect certain cellular processes.	('aberrant', 'Var', (17, 25))	('cellular processes', 'CPA', (226, 244))	('alternative splicing', 'Var', (145, 165))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('pre', 'molecular_function', 'GO:0003904', ('50', '53'))	('splicing', 'biological_process', 'GO:0045292', ('157', '165'))	('splicing', 'biological_process', 'GO:0045292', ('38', '46'))	('affect', 'Reg', (211, 217))	('pre', 'molecular_function', 'GO:0003904', ('169', '172'))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
15882	30849979	Genome-wide identification of cancer-specific alternative splicing in circRNA Circular RNA (circRNA) is a group of RNA families generated by RNA circularization, which was discovered ubiquitously across different cancers.	('splicing', 'biological_process', 'GO:0045292', ('58', '66'))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('alternative splicing', 'Var', (46, 66))	('circ', 'Chemical', '-', (92, 96))	('RNA', 'cellular_component', 'GO:0005562', ('87', '90'))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('RNA', 'cellular_component', 'GO:0005562', ('141', '144'))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancers', 'Disease', 'MESH:D009369', (213, 220))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('RNA', 'cellular_component', 'GO:0005562', ('115', '118'))	('cancers', 'Disease', (213, 220))	('cancer', 'Disease', (213, 219))	('circ', 'Chemical', '-', (70, 74))	('circRNA Circular RNA', 'Disease', (70, 90))	('circ', 'Chemical', '-', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
15920	30849979	There were longer A5SS intron (5472 bp) than A3SS intron (4199 bp) in cancer-specific circ-AS, which was reverse in normal-specific results (Fig.	('A5SS', 'Chemical', '-', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('A5SS', 'Var', (18, 22))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('circ', 'Chemical', '-', (86, 90))
15930	30849979	Overall in ccRCC, we identified 63 oncogenes that had cancer-specific circ-AS, including 44 SE, 20 A3SS and 6 A5SS (Fig.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('SE', 'Disease', 'None', (92, 94))	('ccRCC', 'Disease', (11, 16))	('A5SS', 'Var', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('A3SS', 'Var', (99, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (11, 16))	('circ', 'Chemical', '-', (70, 74))	('A5SS', 'Chemical', '-', (110, 114))
15931	30849979	We also identified 75 TSGs that had cancer-specific circ-AS, including 50 SE, 24 A3SS and 11 A5SS (Fig.	('A5SS', 'Chemical', '-', (93, 97))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('TSG', 'Gene', (22, 25))	('cancer', 'Disease', (36, 42))	('SE', 'Disease', 'None', (74, 76))	('A3SS', 'Var', (81, 85))	('circ', 'Chemical', '-', (52, 56))	('TSG', 'Gene', '57045', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('A5SS', 'Var', (93, 97))
15932	30849979	In bladder cancer, we also identified 22 oncogenes that had cancer-specific circ-AS, including 16 SE, 6 A3SS and 3 A5SS (Fig.	('A5SS', 'Var', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('A5SS', 'Chemical', '-', (115, 119))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('SE', 'Disease', 'None', (98, 100))	('circ', 'Chemical', '-', (76, 80))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('cancer', 'Disease', (11, 17))	('A3SS', 'Var', (104, 108))
15933	30849979	2c), as well as 37 TSGs that had cancer-specific circ-AS, including 19 SE, 16 A3SS, 7 A5SS and 2 RI (Fig.	('A5SS', 'Chemical', '-', (86, 90))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('SE', 'Disease', 'None', (71, 73))	('A3SS', 'Var', (78, 82))	('TSG', 'Gene', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('circ', 'Chemical', '-', (49, 53))	('TSG', 'Gene', '57045', (19, 22))
15949	30849979	In summary, we developed a more efficient and stringent tool for detecting circular RNA alternative splicing between cancer and normal conditions and conducted the first comprehensive analysis for distributions and patterns of cancer-specific circRNA alternative splicing, which is important to the function and regulation research of circRNA in cancers.	('cancer', 'Disease', 'MESH:D009369', (346, 352))	('circ', 'Chemical', '-', (335, 339))	('circular RNA', 'Var', (75, 87))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('splicing', 'biological_process', 'GO:0045292', ('100', '108'))	('cancers', 'Disease', 'MESH:D009369', (346, 353))	('regulation', 'biological_process', 'GO:0065007', ('312', '322'))	('cancer', 'Disease', (117, 123))	('circ', 'Chemical', '-', (243, 247))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (346, 352))	('cancer', 'Disease', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('splicing', 'biological_process', 'GO:0045292', ('263', '271'))	('circ', 'Chemical', '-', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancers', 'Phenotype', 'HP:0002664', (346, 353))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancers', 'Disease', (346, 353))	('RNA', 'cellular_component', 'GO:0005562', ('84', '87'))
15994	29725424	Two-step incubations with a secondary antibody were performed using biotin-labeled goat anti-rabbit IgG and horseradish peroxidase-labeled avidin (A0277 and A0303; Beyotime Institute of Biotechnology, Haimen, China).	('A0277', 'Var', (147, 152))	('horseradish', 'Species', '3704', (108, 119))	('antibody', 'cellular_component', 'GO:0019815', ('38', '46'))	('biotin', 'Chemical', 'MESH:D001710', (68, 74))	('A0303', 'Var', (157, 162))	('rabbit', 'Species', '9986', (93, 99))	('antibody', 'cellular_component', 'GO:0019814', ('38', '46'))	('goat', 'Species', '9925', (83, 87))	('men', 'Species', '9606', (204, 207))	('antibody', 'molecular_function', 'GO:0003823', ('38', '46'))	('antibody', 'cellular_component', 'GO:0042571', ('38', '46'))
16016	29725424	The tumor Fuhrman grades ranged from I to IV, and the TNM stages ranged from T1N0M0 to T3bN0M0.	('tumor', 'Disease', (4, 9))	('TNM', 'Gene', (54, 57))	('T3bN0M0', 'Var', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('TNM', 'Gene', '10178', (54, 57))
16039	29725424	5, that RCC knocked down with ACLY promotes apoptosis as compared with transfected HK-2 or non-transfected RCC.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('HK-2', 'Gene', '3099', (83, 87))	('RCC', 'Disease', (8, 11))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('RCC', 'Disease', (107, 110))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('HK-2', 'molecular_function', 'GO:0008256', ('83', '87'))	('apoptosis', 'CPA', (44, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('HK-2', 'Gene', (83, 87))	('promotes', 'PosReg', (35, 43))	('ACLY', 'Gene', '47', (30, 34))	('knocked down', 'Var', (12, 24))	('ACLY', 'Gene', (30, 34))
16056	29725424	Because ACLY is a key enzyme in the de novo lipogenesis, by catalyzing the conversion of cytosolic citrate into acetyl CoA and oxaloacetate, high molecular and protein ACLY expression in RCC might be closely linked with high tumor cell lipid content.	('RCC', 'Disease', (187, 190))	('RCC', 'Phenotype', 'HP:0005584', (187, 190))	('lipogenesis', 'biological_process', 'GO:0008610', ('44', '55'))	('linked', 'Reg', (208, 214))	('protein', 'Protein', (160, 167))	('high tumor', 'Disease', (220, 230))	('ACLY', 'Gene', '47', (168, 172))	('ACLY', 'Gene', (168, 172))	('high tumor', 'Disease', 'MESH:D009369', (220, 230))	('RCC', 'Disease', 'MESH:C538614', (187, 190))	('ACLY', 'Gene', '47', (8, 12))	('acetyl CoA', 'Chemical', 'MESH:D000105', (112, 122))	('ACLY', 'Gene', (8, 12))	('citrate', 'Chemical', 'MESH:D019343', (99, 106))	('oxaloacetate', 'Chemical', 'MESH:D062907', (127, 139))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('protein', 'cellular_component', 'GO:0003675', ('160', '167'))	('high molecular', 'Var', (141, 155))	('lipid', 'Chemical', 'MESH:D008055', (236, 241))
16059	29725424	Additionally, the possible mechanism for anti-apoptosis effect of ACLY in RCC may be related with promotion of lipogenesis in mitochondria, because inhibition of ACLY would impair lipogenesis, involving activation of AMPK and blocking of its downstream protein ACC1, further mitochondrial function would be impaired.	('inhibition', 'Var', (148, 158))	('ACLY', 'Gene', '47', (66, 70))	('ACLY', 'Gene', (66, 70))	('AMPK', 'molecular_function', 'GO:0047322', ('217', '221'))	('lipogenesis', 'biological_process', 'GO:0008610', ('180', '191'))	('impair', 'NegReg', (173, 179))	('mitochondria', 'cellular_component', 'GO:0005739', ('126', '138'))	('ACC1', 'Gene', '31', (261, 265))	('AMPK', 'MPA', (217, 221))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('lipogenesis', 'MPA', (111, 122))	('protein', 'cellular_component', 'GO:0003675', ('253', '260'))	('anti-apoptosis', 'biological_process', 'GO:0043066', ('41', '55'))	('AMPK', 'molecular_function', 'GO:0050405', ('217', '221'))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('lipogenesis', 'MPA', (180, 191))	('lipogenesis', 'biological_process', 'GO:0008610', ('111', '122'))	('AMPK', 'molecular_function', 'GO:0004691', ('217', '221'))	('ACLY', 'Gene', '47', (162, 166))	('ACLY', 'Gene', (162, 166))	('ACC1', 'Gene', (261, 265))	('activation', 'PosReg', (203, 213))	('blocking', 'NegReg', (226, 234))
16087	28056882	Within this study, we verify the existence of CD105+ and CD133+ populations in selected papillary subtype RCC (pRCC) cell lines.	('pRCC', 'Gene', '5546', (111, 115))	('papillary subtype RCC', 'Disease', 'MESH:C538614', (88, 109))	('papillary subtype RCC', 'Disease', (88, 109))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('CD105', 'Gene', (46, 51))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('CD105', 'Gene', '13805', (46, 51))	('pRCC', 'Gene', (111, 115))	('CD133+', 'Var', (57, 63))
16133	28056882	Cells were stained with (i) CD105-PE (BD Pharmingen, San Diego, CA, USA, clone 266) plus CD133/1-APC (Miltenyi Biotec, Bergisch Gladbach, Germany, clone AC133); or (ii) CD105-FITC (Biolegend, San Diego, CA, USA, clone 43A3) plus CD133/2-APC (Miltenyi Biotec, Bergisch Gladbach, Germany, clone 293C3) according to the manufacturers' protocols with the appropriate isotype controls.	('CD105', 'Gene', '13805', (169, 174))	('APC', 'cellular_component', 'GO:0005680', ('97', '100'))	('293C3', 'CellLine', 'CVCL:0045', (293, 298))	('CD133/1-APC', 'Var', (89, 100))	('CD105', 'Gene', (28, 33))	('APC', 'cellular_component', 'GO:0005680', ('237', '240'))	('CD105', 'Gene', '13805', (28, 33))	('CD105', 'Gene', (169, 174))
16189	28056882	However, oct4 and sox2 expression increased in low O2.	('sox2', 'Gene', '6657', (18, 22))	('sox2', 'Gene', (18, 22))	('O2', 'Chemical', 'MESH:D010100', (51, 53))	('low O2', 'Var', (47, 53))	('oct4', 'Gene', (9, 13))	('oct4', 'Gene', '5460', (9, 13))	('increased', 'PosReg', (34, 43))	('expression', 'MPA', (23, 33))
16345	33658305	The four scores related to T-cell/inflammation status ('CD3TCR', 'TIS', 'T-effector', and 'JAVELIN') had similar predictive accuracy, with AUCs around 70%.	('inflammation', 'Disease', (34, 46))	('TCR', 'cellular_component', 'GO:0042101', ('59', '62'))	('inflammation', 'biological_process', 'GO:0006954', ('34', '46'))	("'CD3TCR", 'Var', (55, 62))	('TCR', 'biological_process', 'GO:0006283', ('59', '62'))	('inflammation', 'Disease', 'MESH:D007249', (34, 46))
16346	33658305	The strength of association with Response, as measured by the OR, was estimated for each gene set score, for the ccrcc4-like subtype, and for PBRM1 mutation status (figure 7D and online supplemental table S13).	('mutation', 'Var', (148, 156))	('PBRM1', 'Gene', (142, 147))	('PBRM1', 'Gene', '55193', (142, 147))
16347	33658305	The previously reported association of PBRM1 mutation status with response was recapitulated in this independent analysis of the CheckMate 009 dataset (50% Response rate in mutants, p=0.011; online supplemental figure S13A).	('PBRM1', 'Gene', '55193', (39, 44))	('mutants', 'Var', (173, 180))	('S13A', 'Var', (218, 222))	('mutation', 'Var', (45, 53))	('S13A', 'SUBSTITUTION', 'None', (218, 222))	('PBRM1', 'Gene', (39, 44))
16348	33658305	The ccrcc4-like subtype and PBRM1 mutation status had ORs of similar magnitude.	('ccrcc4-like subtype', 'Disease', (4, 23))	('PBRM1', 'Gene', (28, 33))	('PBRM1', 'Gene', '55193', (28, 33))	('mutation', 'Var', (34, 42))
16349	33658305	However, PBRM1 status was not associated with ccrcc-like subtype in the 33 patients where both were evaluable (p=0.91, online supplemental figure S13B).	('patients', 'Species', '9606', (75, 83))	('S13B', 'Var', (146, 150))	('S13B', 'SUBSTITUTION', 'None', (146, 150))	('PBRM1', 'Gene', (9, 14))	('PBRM1', 'Gene', '55193', (9, 14))	('ccrcc-like subtype', 'Disease', (46, 64))
16369	33658305	Inhibitors of this enzyme profoundly affect the Th1/Th2 axis and have been clinically tested due to their ability to enhance cellular immune responses and reduce solid tumor growth in mice.	('cellular immune responses', 'CPA', (125, 150))	('Th1/Th2 axis', 'Pathway', (48, 60))	('tumor', 'Disease', (168, 173))	('Inhibitors', 'Var', (0, 10))	('affect', 'Reg', (37, 43))	('enhance', 'PosReg', (117, 124))	('mice', 'Species', '10090', (184, 188))	('reduce', 'NegReg', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
16371	33658305	As with TIGIT, antagonism of PVRIG increases CD8+ T-cell cytokine production and cytotoxic activity, and inhibitors are in clinical development.	('increases', 'PosReg', (35, 44))	('cytotoxic activity', 'CPA', (81, 99))	('PVRIG', 'Gene', '79037', (29, 34))	('CD8', 'Gene', (45, 48))	('CD8', 'Gene', '925', (45, 48))	('PVRIG', 'Gene', (29, 34))	('T-cell cytokine production', 'biological_process', 'GO:0002369', ('50', '76'))	('antagonism', 'Var', (15, 25))
16373	33658305	The TBL1XR1 protein plays a role in Wnt signaling via interaction with N-CoR and beta-catenin, and we found that transcripts for several other Wnt pathway components were associated with lack of response and/or low T-cell abundance at baseline.	('protein', 'cellular_component', 'GO:0003675', ('12', '19'))	('low', 'NegReg', (211, 214))	('beta-catenin', 'Gene', '1499', (81, 93))	('TBL1XR1', 'Gene', '79718', (4, 11))	('N-CoR', 'Gene', (71, 76))	('transcripts', 'Var', (113, 124))	('T-cell', 'CPA', (215, 221))	('N-CoR', 'Gene', '9611', (71, 76))	('lack', 'NegReg', (187, 191))	('signaling', 'biological_process', 'GO:0023052', ('40', '49'))	('TBL1XR1', 'Gene', (4, 11))	('response', 'MPA', (195, 203))	('beta-catenin', 'Gene', (81, 93))	('interaction', 'Interaction', (54, 65))	('Wnt signaling', 'MPA', (36, 49))
16377	33658305	Recently completed trials with girentuximab, a monoclonal antibody against CAIX, showed a non-significant disease-free survival benefit in patients with RCC with high CAIX scores, while CCL28 has also been proposed as an oncology target based on its role in promoting tolerance and angiogenesis.	('antibody', 'molecular_function', 'GO:0003823', ('58', '66'))	('patients', 'Species', '9606', (139, 147))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('CAIX', 'Gene', (167, 171))	('RCC', 'Disease', (153, 156))	('girentuximab', 'Chemical', 'MESH:C106533', (31, 43))	('antibody', 'cellular_component', 'GO:0042571', ('58', '66'))	('CCL', 'molecular_function', 'GO:0044101', ('186', '189'))	('antibody', 'cellular_component', 'GO:0019815', ('58', '66'))	('angiogenesis', 'biological_process', 'GO:0001525', ('282', '294'))	('high', 'Var', (162, 166))	('oncology', 'Phenotype', 'HP:0002664', (221, 229))	('antibody', 'cellular_component', 'GO:0019814', ('58', '66'))
16383	33658305	High RIG-I transcriptional activity has recently been reported as a predictor of response to ipilimumab, implicating these patients as a favorable target group.	('transcriptional activity', 'MPA', (11, 35))	('RIG-I', 'Gene', '23586', (5, 10))	('High', 'Var', (0, 4))	('ipilimumab', 'Chemical', 'MESH:D000074324', (93, 103))	('RIG-I', 'Gene', (5, 10))	('patients', 'Species', '9606', (123, 131))
16421	31333794	County-level median household income was included to represent patients' socioeconomic status and stratified into quintiles for analysis: Quartile 1 (<US $48700), Quartile 2 (US $48701-56200), Quartile 3 (US $56201-66931), and Quartile 4 (>US $66931).	('>US $66931', 'Var', (239, 249))	('US $56201-66931', 'Var', (205, 220))	('US $48701-56200', 'Var', (175, 190))	('patients', 'Species', '9606', (63, 71))	('<US $48700', 'Var', (150, 160))
16460	31333794	Interestingly, studies have suggested that the socioeconomic status is associated with better prognosis in several cancers.	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('socioeconomic status', 'Var', (47, 67))	('better', 'PosReg', (87, 93))
16488	28701475	HIF Activation Causes Synthetic Lethality Between the VHL Tumor Suppressor and the EZH1 Histone Methyltransferase Inactivation of the von Hippel Lindau tumor suppressor protein (pVHL) is the signature lesion in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC).	('VHL Tumor', 'Disease', (54, 63))	('Inactivation', 'Var', (114, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('152', '168'))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (250, 281))	('von Hippel Lindau tumor', 'Disease', (134, 157))	('Synthetic Lethality', 'MPA', (22, 41))	('von Hippel Lindau tumor', 'Disease', 'MESH:D006623', (134, 157))	('tumor suppressor', 'biological_process', 'GO:0051726', ('152', '168'))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('Tumor Suppressor', 'molecular_function', 'GO:0008181', ('58', '74'))	('VHL Tumor', 'Disease', 'MESH:D006623', (54, 63))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (250, 281))	('EZH1', 'Gene', (83, 87))	('Tumor Suppressor', 'biological_process', 'GO:0051726', ('58', '74'))	('kidney cancer', 'Disease', (235, 248))	('kidney cancer', 'Disease', 'MESH:D007680', (235, 248))	('EZH1', 'Gene', '2145', (83, 87))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (261, 281))	('ccRCC', 'Phenotype', 'HP:0006770', (283, 288))	('pVHL', 'Gene', (178, 182))	('pVHL', 'Gene', '7428', (178, 182))	('Tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('clear cell renal cell carcinoma', 'Disease', (250, 281))	('kidney cancer', 'Phenotype', 'HP:0009726', (235, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))
16493	28701475	The most common form of kidney cancer is clear cell renal carcinoma (ccRCC), which is often linked to mutational inactivation or hypermethylation of the VHL tumor suppressor gene.	('kidney cancer', 'Phenotype', 'HP:0009726', (24, 37))	('kidney cancer', 'Disease', 'MESH:D007680', (24, 37))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (41, 67))	('renal carcinoma', 'Phenotype', 'HP:0005584', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('VHL tumor', 'Disease', 'MESH:D006623', (153, 162))	('kidney cancer', 'Disease', (24, 37))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor suppressor', 'biological_process', 'GO:0051726', ('157', '173'))	('linked', 'Reg', (92, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (69, 74))	('clear cell renal carcinoma', 'Disease', (41, 67))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('157', '173'))	('mutational', 'Var', (102, 112))	('hypermethylation', 'Var', (129, 145))	('VHL tumor', 'Disease', (153, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (41, 67))
16498	28701475	Deregulation of HIFalpha, and particularly HIF2alpha, drives the development of pVHL-defective ccRCC.	('Deregulation', 'Var', (0, 12))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('pVHL', 'Gene', '7428', (80, 84))	('ccRCC', 'Disease', (95, 100))	('HIF2alpha', 'Gene', (43, 52))	('pVHL', 'Gene', (80, 84))	('HIF2alpha', 'Gene', '2034', (43, 52))
16499	28701475	VHL inactivation is an early "gatekeeper" event in ccRCC, but is not sufficient to cause ccRCC.	('inactivation', 'Var', (4, 16))	('ccRCC', 'Phenotype', 'HP:0006770', (89, 94))	('gatekeeper', 'Species', '111938', (30, 40))	('VHL', 'Gene', (0, 3))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))	('ccRCC', 'Disease', (51, 56))
16500	28701475	Additional genetic changes that cooperate with VHL loss to promote tumorigenesis include loss of chromosome 14q and gain of chromosome 5q, as well as intragenic mutations that frequently affect chromatin regulators such as BAF180, BAF250, BRG1, BAP1, KDM6A, KDM5C, SETD2, and MLL3.	('VHL loss', 'Disease', (47, 55))	('BAP1', 'Gene', '8314', (245, 249))	('tumor', 'Disease', (67, 72))	('chromatin', 'cellular_component', 'GO:0000785', ('194', '203'))	('MLL3', 'Gene', (276, 280))	('VHL loss', 'Disease', 'MESH:D006623', (47, 55))	('SETD2', 'Gene', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('BAF250', 'Gene', '8289', (231, 237))	('affect', 'Reg', (187, 193))	('BAF250', 'Gene', (231, 237))	('BRG1', 'Gene', '6597', (239, 243))	('KDM5C', 'Gene', (258, 263))	('KDM6A', 'Gene', '7403', (251, 256))	('BAP1', 'Gene', (245, 249))	('SETD2', 'Gene', '29072', (265, 270))	('chromosome', 'cellular_component', 'GO:0005694', ('124', '134'))	('BRG1', 'Gene', (239, 243))	('chromosome', 'cellular_component', 'GO:0005694', ('97', '107'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('BAF180', 'Gene', '55193', (223, 229))	('loss', 'NegReg', (89, 93))	('KDM6A', 'Gene', (251, 256))	('MLL3', 'Gene', '58508', (276, 280))	('promote', 'PosReg', (59, 66))	('mutations', 'Var', (161, 170))	('BAF180', 'Gene', (223, 229))	('KDM5C', 'Gene', '8242', (258, 263))	('gain', 'PosReg', (116, 120))
16511	28701475	Some pRCCs have high HIF expression due to mutations affecting genes other than VHL.	('pRCC', 'Gene', (5, 9))	('VHL', 'Gene', (80, 83))	('pRCC', 'Gene', '5546', (5, 9))	('mutations', 'Var', (43, 52))	('pRCCs', 'Phenotype', 'HP:0006766', (5, 10))	('HIF expression', 'MPA', (21, 35))
16522	28701475	The two EZH1 shRNAs that most effectively downregulated EZH1 (10708 and 734) also selectively inhibited VHL-/- ccRCC cells, whereas the relatively ineffective EZH1 shRNAs had minimal effect (Fig.	('EZH1', 'Gene', '2145', (56, 60))	('10708', 'Var', (62, 67))	('EZH1', 'Gene', '2145', (8, 12))	('downregulated', 'NegReg', (42, 55))	('VHL-/- ccRCC', 'Disease', (104, 116))	('EZH1', 'Gene', (159, 163))	('EZH1', 'Gene', (56, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('EZH1', 'Gene', (8, 12))	('inhibited', 'NegReg', (94, 103))	('EZH1', 'Gene', '2145', (159, 163))
16530	28701475	We also showed that inactivating EZH1 using CRISPR/Cas9 with two different sgRNAs preferentially inhibited VHL-/- cells (Fig.	('EZH1', 'Gene', '2145', (33, 37))	('Cas', 'cellular_component', 'GO:0005650', ('51', '54'))	('inactivating', 'Var', (20, 32))	('inhibited', 'NegReg', (97, 106))	('EZH1', 'Gene', (33, 37))	('VHL-/- cells', 'CPA', (107, 119))
16536	28701475	3B) and is cytotoxic to EZH2 mutant lymphoma cells (fig.	('lymphoma', 'Phenotype', 'HP:0002665', (36, 44))	('EZH2', 'Gene', '2146', (24, 28))	('mutant', 'Var', (29, 35))	('EZH2', 'Gene', (24, 28))	('lymphoma', 'Disease', (36, 44))	('lymphoma', 'Disease', 'MESH:D008223', (36, 44))
16537	28701475	We confirmed that JQ-EZ-05 reversibly and specifically inhibited H3K27me3 in VHL-/- ccRCC cells, as determined by immunoblot analysis (Fig.	('JQ-EZ-05', 'Var', (18, 26))	('JQ-EZ-05', 'Chemical', '-', (18, 26))	('H3K27me3', 'Protein', (65, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('inhibited', 'NegReg', (55, 64))
16538	28701475	Consistent with our genetic studies, JQ-EZ-05 preferentially inhibited the growth and viability of VHL-/- ccRCC cells compared to their pVHL-proficient counterparts in monolayer assays (Fig.	('inhibited', 'NegReg', (61, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('JQ-EZ-05', 'Chemical', '-', (37, 45))	('preferentially', 'PosReg', (46, 60))	('JQ-EZ-05', 'Var', (37, 45))	('pVHL', 'Gene', '7428', (136, 140))	('pVHL', 'Gene', (136, 140))
16540	28701475	4A), which is consistent with the knowledge that the latter is controlled primarily by EZH2 and that the biochemical Ki of JQ-EZ-05 for EZH1 is 10 fold-higher than its Ki for EZH2 (Fig.	('EZH1', 'Gene', (136, 140))	('EZH2', 'Gene', '2146', (175, 179))	('EZH2', 'Gene', (175, 179))	('EZH2', 'Gene', '2146', (87, 91))	('EZH1', 'Gene', '2145', (136, 140))	('EZH2', 'Gene', (87, 91))	('fold-higher', 'PosReg', (147, 158))	('JQ-EZ-05', 'Chemical', '-', (123, 131))	('JQ-EZ-05', 'Var', (123, 131))
16541	28701475	Notably, differential suppression of VHL-/- ccRCC cells relative to pVHL-proficient ccRCC cells by JQ-EZ-05 and GSK-126 might be attenuated because, in addition to EZH1, they both inhibit EZH2 and perhaps other targets.	('EZH2', 'Gene', (188, 192))	('JQ-EZ-05', 'Chemical', '-', (99, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('EZH1', 'Gene', (164, 168))	('inhibit', 'NegReg', (180, 187))	('EZH1', 'Gene', '2145', (164, 168))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('pVHL', 'Gene', '7428', (68, 72))	('GSK', 'molecular_function', 'GO:0050321', ('112', '115'))	('EZH2', 'Gene', '2146', (188, 192))	('pVHL', 'Gene', (68, 72))	('GSK-126', 'Gene', (112, 119))	('JQ-EZ-05', 'Var', (99, 107))
16543	28701475	Finally, JQ-EZ-05 impeded VHL-/- ccRCC cells in orthotopic tumor assays in vivo (Fig.	('tumor', 'Disease', (59, 64))	('JQ-EZ-05', 'Chemical', '-', (9, 17))	('JQ-EZ-05', 'Var', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('impeded', 'NegReg', (18, 25))	('VHL-/- ccRCC cells', 'CPA', (26, 44))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))
16547	28701475	To more formally address whether the antiproliferative effects of JQ-EZ-05 on VHL-/- ccRCC cells were on-target, we asked whether they could be reversed by JQ-EZ-05-resistant EZH1 variants, identified using two different approaches.	('JQ-EZ-05', 'Chemical', '-', (66, 74))	('JQ-EZ-05', 'Chemical', '-', (156, 164))	('EZH1', 'Gene', (175, 179))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('EZH1', 'Gene', '2145', (175, 179))	('variants', 'Var', (180, 188))
16551	28701475	Introduction of this EZH1 variant (DeltaPSET) into VHL-/- ccRCC cells also blunted the antiproliferative effects of JQ-EZ-05 (Fig.	('blunted', 'NegReg', (75, 82))	('EZH1', 'Gene', (21, 25))	('variant', 'Var', (26, 33))	('antiproliferative effects', 'MPA', (87, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('EZH1', 'Gene', '2145', (21, 25))	('JQ-EZ-05', 'Chemical', '-', (116, 124))
16552	28701475	We also randomly mutagenized a lentiviral EZH1 expression plasmid by propagating it in error-prone E. coli (XL1-Red).	('E. coli', 'Species', '562', (99, 106))	('mutagenized', 'Var', (17, 28))	('EZH1', 'Gene', '2145', (42, 46))	('EZH1', 'Gene', (42, 46))
16555	28701475	Moreover, JQ-EZ-05's effect on H3K27me3 after 3 weeks was slightly attenuated in the polyclonal cells that received the mutagenized EZH1 relative to newly infected cells that were infected to produce wild-type EZH1 or GFP (Fig.	('mutagenized', 'Var', (120, 131))	('EZH1', 'Gene', (210, 214))	('H3K27me3', 'Protein', (31, 39))	('attenuated', 'NegReg', (67, 77))	('EZH1', 'Gene', (132, 136))	('EZH1', 'Gene', '2145', (210, 214))	('EZH1', 'Gene', '2145', (132, 136))	('JQ-EZ-05', 'Chemical', '-', (10, 18))
16556	28701475	5E), suggesting that some of the EZH1 random variants could, like the DeltaPSET variant, assume EZH2-like properties.	('EZH1', 'Gene', '2145', (33, 37))	('EZH2', 'Gene', '2146', (96, 100))	('variants', 'Var', (45, 53))	('EZH2', 'Gene', (96, 100))	('EZH1', 'Gene', (33, 37))
16557	28701475	We pooled the resistant cells and used next-gen sequencing to identify the enriched EZH1 variants, which were then individually cloned and studied in secondary assays.	('variants', 'Var', (89, 97))	('EZH1', 'Gene', (84, 88))	('EZH1', 'Gene', '2145', (84, 88))
16558	28701475	We confirmed that two such variants, Y727F and D745N, conferred partial resistance to JQ-EZ-05 in cell viability assays (Fig.	('JQ-EZ-05', 'Chemical', '-', (86, 94))	('Y727F', 'Mutation', 'p.Y727F', (37, 42))	('D745N', 'Mutation', 'rs138757221', (47, 52))	('Y727F', 'Var', (37, 42))	('resistance', 'MPA', (72, 82))	('D745N', 'Var', (47, 52))
16559	28701475	In biochemical and cell-based assays, we confirmed decreased binding of JQ-EZ-05 to the D745N and DeltaPSET EZH1 variants (fig.	('variants', 'Var', (113, 121))	('D745N', 'Mutation', 'rs138757221', (88, 93))	('JQ-EZ-05', 'Chemical', '-', (72, 80))	('EZH1', 'Gene', (108, 112))	('decreased', 'NegReg', (51, 60))	('JQ-EZ-05', 'Gene', (72, 80))	('D745N', 'Var', (88, 93))	('binding', 'molecular_function', 'GO:0005488', ('61', '68'))	('EZH1', 'Gene', '2145', (108, 112))	('binding', 'Interaction', (61, 68))
16560	28701475	S9, E and F), which argues that these variants confer resistance by restoring EZH1 catalytic activity in the presence of JQ-EZ-05 rather than by drug sequestration.	('JQ-EZ-05', 'Chemical', '-', (121, 129))	('catalytic activity', 'molecular_function', 'GO:0003824', ('83', '101'))	('variants', 'Var', (38, 46))	('EZH1', 'Gene', '2145', (78, 82))	('catalytic activity', 'MPA', (83, 101))	('restoring', 'PosReg', (68, 77))	('EZH1', 'Gene', (78, 82))
16561	28701475	In contrast, despite the modeled proximity of Y727 to the putative JQ-EZ-05 binding site within EZH1 (Fig.	('Y727', 'Var', (46, 50))	('EZH1', 'Gene', (96, 100))	('binding', 'molecular_function', 'GO:0005488', ('76', '83'))	('JQ-EZ-05', 'Chemical', '-', (67, 75))	('EZH1', 'Gene', '2145', (96, 100))	('binding', 'Interaction', (76, 83))
16563	28701475	One possibility, among many, is that the Y727F mutation attenuates JQ-EZ-05's effect on EZH1 catalytic activity in vivo, perhaps by increasing EZH1's affinity for S-Adenosyl Methionine (SAM) or EZH1's kcat.	('kcat', 'MPA', (201, 205))	('increasing', 'PosReg', (132, 142))	('EZH1', 'Gene', (88, 92))	('EZH1', 'Gene', (143, 147))	('Y727F', 'Mutation', 'p.Y727F', (41, 46))	('EZH1', 'Gene', '2145', (194, 198))	('Methionine', 'Chemical', 'MESH:D008715', (174, 184))	('catalytic activity', 'molecular_function', 'GO:0003824', ('93', '111'))	('EZH1', 'Gene', '2145', (88, 92))	('Y727F', 'Var', (41, 46))	('attenuates', 'NegReg', (56, 66))	('EZH1', 'Gene', '2145', (143, 147))	('affinity', 'Interaction', (150, 158))	('JQ-EZ-05', 'Chemical', '-', (67, 75))	('EZH1', 'Gene', (194, 198))	('catalytic activity', 'MPA', (93, 111))	('JQ-EZ-05', 'Gene', (67, 75))
16564	28701475	The D745N and Y727F EZH1 variants, unlike the DeltaPSET EZH1 mutant, had little (D745N) or no (Y727F) discernable effect on the loss of bulk H3K27me3 caused by JQ-EZ-05 (Fig.	('EZH1', 'Gene', '2145', (56, 60))	('loss', 'NegReg', (128, 132))	('D745N', 'Var', (4, 9))	('Y727F', 'Var', (14, 19))	('EZH1', 'Gene', (20, 24))	('D745N', 'Mutation', 'rs138757221', (81, 86))	('JQ-EZ-05', 'Var', (160, 168))	('D745N', 'Mutation', 'rs138757221', (4, 9))	('JQ-EZ-05', 'Chemical', '-', (160, 168))	('EZH1', 'Gene', '2145', (20, 24))	('bulk', 'MPA', (136, 140))	('EZH1', 'Gene', (56, 60))	('H3K27me3', 'Protein', (141, 149))	('Y727F', 'Mutation', 'p.Y727F', (95, 100))	('Y727F', 'Mutation', 'p.Y727F', (14, 19))
16566	28701475	The fact that all three EZH1 variants, including the Y727F variant, rescued VHL-/- ccRCC cell viability in the face of a dual EZH1/2 inhibitor suggests that EZH1 has genomic locus-specific effects that are not reflected in bulk H3K27me3 measurements.	('EZH1', 'Gene', (157, 161))	('rescued', 'PosReg', (68, 75))	('EZH1', 'Gene', (126, 130))	('EZH1', 'Gene', (24, 28))	('EZH1', 'Gene', '2145', (157, 161))	('EZH1/2', 'Gene', (126, 132))	('variants', 'Var', (29, 37))	('Y727F', 'Mutation', 'p.Y727F', (53, 58))	('Y727F', 'Var', (53, 58))	('VHL-/- ccRCC', 'Disease', (76, 88))	('EZH1', 'Gene', '2145', (126, 130))	('EZH1', 'Gene', '2145', (24, 28))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('EZH1/2', 'Gene', '2145;2146', (126, 132))
16570	28701475	Similarly, downregulating ARNT using two highly effective shRNAs or with C RISPR/Cas9 conferred resistance to JQ-EZ-05 (Fig 6, E to H, and fig.	('Cas', 'cellular_component', 'GO:0005650', ('81', '84'))	('JQ-EZ-05', 'Chemical', '-', (110, 118))	('downregulating', 'NegReg', (11, 25))	('JQ-EZ-05', 'Var', (110, 118))	('ARNT', 'Gene', (26, 30))	('ARNT', 'Gene', '405', (26, 30))	('resistance', 'MPA', (96, 106))
16574	28701475	Moreover, we consistently noted that compared to their VHL-/- counterparts, the pharmacodynamic effects of JQ-EZ-05 on H3K27me3 were blunted in lentivirally-reconstituted (Fig 4A and fig.	('pharmacodynamic effects', 'MPA', (80, 103))	('JQ-EZ-05', 'Chemical', '-', (107, 115))	('H3K27me3', 'Protein', (119, 127))	('JQ-EZ-05', 'Var', (107, 115))	('blunted', 'NegReg', (133, 140))
16576	28701475	S11C), and restoration of pVHL function in VHL-deficient cells increased H3K27me3 (fig.	('increased', 'PosReg', (63, 72))	('VHL-deficient', 'Disease', 'MESH:D006623', (43, 56))	('S11C', 'SUBSTITUTION', 'None', (0, 4))	('VHL-deficient', 'Disease', (43, 56))	('H3K27me3', 'Protein', (73, 81))	('pVHL', 'Gene', '7428', (26, 30))	('pVHL', 'Gene', (26, 30))	('S11C', 'Var', (0, 4))
16577	28701475	S11D), suggesting that VHL-/- ccRCC cells either have increased H3K27 demethylase activity or decreased H3K27 methyltransferase activity.	('activity', 'MPA', (128, 136))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('demethylase activity', 'molecular_function', 'GO:0032451', ('70', '90'))	('methyltransferase activity', 'molecular_function', 'GO:0008168', ('110', '136'))	('S11D', 'Var', (0, 4))	('increased', 'PosReg', (54, 63))	('S11D', 'SUBSTITUTION', 'None', (0, 4))	('decreased', 'NegReg', (94, 103))	('H3K27 methyltransferase', 'Enzyme', (104, 127))	('activity', 'MPA', (82, 90))	('H3K27', 'Protein', (64, 69))
16578	28701475	In support of the former, we observed that extracts from VHL-deficient cells demethylate H3K27, but not H3K9, on calf thymus core histones more rapidly than extracts from pVHL-proficient cells (Fig.	('pVHL', 'Gene', (171, 175))	('VHL-deficient', 'Disease', 'MESH:D006623', (57, 70))	('VHL-deficient', 'Disease', (57, 70))	('H3K27', 'Protein', (89, 94))	('core', 'cellular_component', 'GO:0019013', ('125', '129'))	('demethylate', 'Var', (77, 88))	('pVHL', 'Gene', '7428', (171, 175))	('calf', 'Species', '9913', (113, 117))
16583	28701475	Although KDM6B can be regulated by HIF1alpha, KDM6B levels were decreased by ARNT sh/sgRNAs in 786-O cells, which contain HIF2alpha and not HIF1alpha, suggesting that KDM6B can be regulated by HIF2alpha (fig S12B).	('HIF1alpha', 'Gene', (140, 149))	('KDM6B', 'Gene', (9, 14))	('HIF1alpha', 'Gene', '3091', (35, 44))	('KDM6B', 'Gene', (167, 172))	('KDM6B', 'Gene', '23135', (9, 14))	('HIF1alpha', 'Gene', (35, 44))	('HIF2alpha', 'Gene', (122, 131))	('ARNT', 'Gene', '405', (77, 81))	('KDM6B', 'Gene', '23135', (167, 172))	('KDM6B', 'Gene', (46, 51))	('S12B', 'SUBSTITUTION', 'None', (208, 212))	('decreased', 'NegReg', (64, 73))	('ARNT', 'Gene', (77, 81))	('KDM6B', 'Gene', '23135', (46, 51))	('HIF2alpha', 'Gene', (193, 202))	('HIF2alpha', 'Gene', '2034', (122, 131))	('HIF1alpha', 'Gene', '3091', (140, 149))	('S12B', 'Var', (208, 212))	('HIF2alpha', 'Gene', '2034', (193, 202))
16584	28701475	Consistent with this notion, eliminating HIF2alpha with CRISPR/Cas9 in UMRC-2 cells, which contain both HIF1alpha and HIF2alpha, downregulated KDM6B (Fig.	('downregulated', 'NegReg', (129, 142))	('eliminating', 'Var', (29, 40))	('HIF2alpha', 'Gene', (118, 127))	('Cas', 'cellular_component', 'GO:0005650', ('63', '66'))	('KDM6B', 'Gene', (143, 148))	('HIF2alpha', 'Gene', '2034', (41, 50))	('UMRC-2', 'CellLine', 'CVCL:2739', (71, 77))	('HIF1alpha', 'Gene', (104, 113))	('HIF1alpha', 'Gene', '3091', (104, 113))	('HIF2alpha', 'Gene', '2034', (118, 127))	('HIF2alpha', 'Gene', (41, 50))	('KDM6B', 'Gene', '23135', (143, 148))
16587	28701475	Therefore, deregulation of HIF-responsive demethylases, and particularly KDM6B, increases the dependence of VHL-/- ccRCCs on EZH1 activity.	('dependence', 'MPA', (94, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('demethylases', 'Enzyme', (42, 54))	('deregulation', 'Var', (11, 23))	('KDM6B', 'Gene', '23135', (73, 78))	('increases', 'PosReg', (80, 89))	('EZH1', 'Gene', (125, 129))	('KDM6B', 'Gene', (73, 78))	('EZH1', 'Gene', '2145', (125, 129))
16590	28701475	S13A), suggesting a non-redundant role for these enzymes in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('ccRCC', 'Disease', (60, 65))	('S13A', 'Var', (0, 4))	('S13A', 'SUBSTITUTION', 'None', (0, 4))
16595	28701475	8B) inactivation of EZH1 and performed GSEA.	('EZH1', 'Gene', (20, 24))	('inactivation', 'Var', (4, 16))	('EZH1', 'Gene', '2145', (20, 24))	('GSEA', 'Chemical', '-', (39, 43))
16596	28701475	Because JQ-EZ-05 inhibits both EZH1 and EZH2, we treated cells expressing wild-type EZH1 and cells expressing the EZH1 Y727F JQ-EZ-05-resistant variant (Fig.	('inhibits', 'NegReg', (17, 25))	('Y727F', 'Mutation', 'p.Y727F', (119, 124))	('EZH1', 'Gene', '2145', (114, 118))	('JQ-EZ-05', 'Chemical', '-', (125, 133))	('EZH1', 'Gene', '2145', (84, 88))	('JQ-EZ-05', 'Chemical', '-', (8, 16))	('EZH1', 'Gene', (31, 35))	('EZH1', 'Gene', '2145', (31, 35))	('EZH2', 'Gene', (40, 44))	('EZH2', 'Gene', '2146', (40, 44))	('EZH1', 'Gene', (114, 118))	('EZH1', 'Gene', (84, 88))	('Y727F', 'Var', (119, 124))
16598	28701475	We focused specifically on gene sets that are induced upon EZH1 loss because H3K27me3 is usually a repressive mark.	('EZH1', 'Gene', (59, 63))	('loss', 'NegReg', (64, 68))	('H3K27me3', 'Var', (77, 85))	('EZH1', 'Gene', '2145', (59, 63))
16600	28701475	A potential link between EZH1 and sterol biosynthesis is noteworthy because dysregulated fatty acid metabolism is believed to cause the 'clear cell' phenotype of VHL-deficient ccRCC.	('VHL-deficient', 'Disease', 'MESH:D006623', (162, 175))	('VHL-deficient', 'Disease', (162, 175))	('EZH1', 'Gene', (25, 29))	('cause', 'Reg', (126, 131))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('89', '110'))	('sterol biosynthesis', 'biological_process', 'GO:0016126', ('34', '53'))	("'clear", 'PosReg', (136, 142))	('fatty acid metabolism', 'MPA', (89, 110))	('dysregulated', 'Var', (76, 88))	('sterol', 'Chemical', 'MESH:D013261', (34, 40))	('EZH1', 'Gene', '2145', (25, 29))	('ccRCC', 'Phenotype', 'HP:0006770', (176, 181))	('fatty acid', 'Chemical', 'MESH:D005227', (89, 99))	('ccRCC', 'Disease', (176, 181))
16601	28701475	We confirmed that multiple SREBP-responsive mRNAs, including the HMGCS1 and SQLE mRNAs, are far more highly induced after EZH1 inactivation in VHL-/- ccRCC cells than in their pVHL-proficient counterparts (Fig.	('EZH1', 'Gene', (122, 126))	('SQLE', 'Gene', (76, 80))	('HMGCS1', 'Gene', '3157', (65, 71))	('inactivation', 'Var', (127, 139))	('ccRCC', 'Phenotype', 'HP:0006770', (150, 155))	('HMGCS1', 'Gene', (65, 71))	('pVHL', 'Gene', '7428', (176, 180))	('EZH1', 'Gene', '2145', (122, 126))	('pVHL', 'Gene', (176, 180))	('SQLE', 'Gene', '6713', (76, 80))	('highly induced', 'PosReg', (101, 115))
16607	28701475	This still did not explain why only loss of KDM6B, but not KDM6A, reversed the dependence on EZH1.	('KDM6A', 'Gene', (59, 64))	('KDM6B', 'Gene', (44, 49))	('loss', 'Var', (36, 40))	('KDM6A', 'Gene', '7403', (59, 64))	('EZH1', 'Gene', (93, 97))	('dependence', 'MPA', (79, 89))	('KDM6B', 'Gene', '23135', (44, 49))	('EZH1', 'Gene', '2145', (93, 97))
16610	28701475	These analyses reveal that the VHL-/- ccRCC cell lines that are hypersensitive to loss of EZH1 H3K27 methyltransferase activity have a gene expression signature consistent with H3K27 hypomethylation and probably depend primarily on KDM6B for H3K27 homeostasis due to decreased KDM6A.	('EZH1', 'Gene', '2145', (90, 94))	('methyltransferase activity', 'molecular_function', 'GO:0008168', ('101', '127'))	('H3K27 methyltransferase', 'Enzyme', (95, 118))	('KDM6A', 'Gene', '7403', (277, 282))	('homeostasis', 'biological_process', 'GO:0042592', ('248', '259'))	('gene expression', 'biological_process', 'GO:0010467', ('135', '150'))	('EZH1', 'Gene', (90, 94))	('H3K27', 'Protein', (177, 182))	('KDM6B', 'Gene', '23135', (232, 237))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('activity', 'MPA', (119, 127))	('hypomethylation', 'Var', (183, 198))	('loss', 'NegReg', (82, 86))	('hypersensitive', 'Disease', (64, 78))	('hypersensitive', 'Disease', 'MESH:D004342', (64, 78))	('KDM6B', 'Gene', (232, 237))	('KDM6A', 'Gene', (277, 282))
16614	28701475	Specifically, the chromatin-associated mutations in ccRCC might arise to mitigate or amplify the effects of HIF-responsive chromatin modifiers that would otherwise suppress or enhance, respectively, tumor growth.	('tumor', 'Disease', (199, 204))	('ccRCC', 'Gene', (52, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('enhance', 'PosReg', (176, 183))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('chromatin', 'cellular_component', 'GO:0000785', ('123', '132'))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('chromatin', 'cellular_component', 'GO:0000785', ('18', '27'))	('suppress', 'NegReg', (164, 172))
16620	28701475	We ensured that the antiproliferative effects of EZH1 shRNAs in VHL-/- ccRCC cells were rescued by restoring the expression of EZH1 with an shRNA-resistant mRNA, and we corroborated our shRNA results with two orthogonal approaches: elimination of EZH1 with CRISPR/Cas9 and pharmacological inhibition of EZH1 methyltransferase activity, again with controls to ensure that the effects we observed were on-target.	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('pharmacological', 'Var', (273, 288))	('EZH1', 'Gene', (49, 53))	('EZH1', 'Gene', (303, 307))	('EZH1', 'Gene', '2145', (247, 251))	('EZH1', 'Gene', '2145', (127, 131))	('methyltransferase activity', 'molecular_function', 'GO:0008168', ('308', '334'))	('EZH1', 'Gene', '2145', (49, 53))	('EZH1', 'Gene', '2145', (303, 307))	('EZH1', 'Gene', (127, 131))	('Cas', 'cellular_component', 'GO:0005650', ('264', '267'))	('EZH1', 'Gene', (247, 251))
16639	28701475	For example, the H3K36 demethylase KDM4A (JMJD2A), which can act as an oncogene, also scored as synthetic lethal with VHL in our screen.	('H3K36', 'Var', (17, 22))	('KDM4A', 'Gene', '9682', (35, 40))	('JMJD2A', 'Gene', '9682', (42, 48))	('JMJD2A', 'Gene', (42, 48))	('KDM4A', 'Gene', (35, 40))
16643	28701475	Moreover, the antitumor effects of JQ-EZ-05 for VHL-/- ccRCCs in vivo were markedly reduced in mice with high tumor burdens.	('JQ-EZ-05', 'Var', (35, 43))	('mice', 'Species', '10090', (95, 99))	('tumor', 'Disease', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('reduced', 'NegReg', (84, 91))	('high tumor', 'Disease', (105, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))	('high tumor', 'Disease', 'MESH:D009369', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('JQ-EZ-05', 'Chemical', '-', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
16644	28701475	On the other hand, JQ-EZ-05 more potently inhibits EZH2 than EZH1 in biochemical assays in vitro, and has not been optimized for in vivo bioavailability.	('EZH1', 'Gene', (61, 65))	('inhibits', 'NegReg', (42, 50))	('EZH2', 'Gene', '2146', (51, 55))	('EZH2', 'Gene', (51, 55))	('JQ-EZ-05', 'Var', (19, 27))	('EZH1', 'Gene', '2145', (61, 65))	('JQ-EZ-05', 'Chemical', '-', (19, 27))	('biochemical assays', 'MPA', (69, 87))
16659	31637882	This study analyzed data for 215 patients with information on 23171 DNA methylation sites and identified a two-DNA methylation signature (cg18034859, cg24199834) with the help of a step-wise multivariable Cox regression model.	('cg18034859', 'Var', (138, 148))	('cg24199834', 'Var', (150, 160))	('patients', 'Species', '9606', (33, 41))	('DNA methylation', 'biological_process', 'GO:0006306', ('68', '83'))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('Cox', 'Gene', '9377', (205, 208))	('DNA methylation', 'biological_process', 'GO:0006306', ('111', '126'))	('Cox', 'Gene', (205, 208))
16666	31637882	Important targets in cancer research, cancer initiation and proliferation are regulated by epigenetic modifications.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('regulated', 'Reg', (78, 87))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('epigenetic modifications', 'Var', (91, 115))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', (38, 44))	('cancer initiation', 'Disease', 'MESH:D009369', (38, 55))	('cancer initiation', 'Disease', (38, 55))
16667	31637882	Abnormal DNA methylation was reported to show a significant relationship with the occurrence and prognosis of various cancers.	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('relationship', 'Reg', (60, 72))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('DNA', 'Protein', (9, 12))	('Abnormal', 'Var', (0, 8))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
16668	31637882	demonstrated that neurofilament heavy (NEFH)-specific hypermethylation in RCC is relevant to overall survival rates among patients undergoing targeted therapy.	('NEFH', 'Gene', '4744', (39, 43))	('NEFH', 'Gene', (39, 43))	('neurofilament', 'cellular_component', 'GO:0005883', ('18', '31'))	('neurofilament heavy', 'Gene', '4744', (18, 37))	('neurofilament heavy', 'Gene', (18, 37))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('hypermethylation', 'Var', (54, 70))	('patients', 'Species', '9606', (122, 130))	('RCC', 'Disease', 'MESH:D002292', (74, 77))
16671	31637882	Furthermore, DNA methylation of specific genes has already been used as biomarkers in early diagnosis and prognosis, such as aldehyde dehydrogenase 1 family member A3 (ALDH1A3) promoter hypermethylation in glioma CpG island methylator phenotype-primary glioblastoma and hypomethylation of cyclin dependent kinase inhibitor 2A (CDKN2A) in colon cancer.	('glioblastoma', 'Disease', (253, 265))	('glioblastoma', 'Phenotype', 'HP:0012174', (253, 265))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('ALDH1A3', 'Gene', (168, 175))	('ALDH', 'molecular_function', 'GO:0004030', ('168', '172'))	('colon cancer', 'Disease', (338, 350))	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('cyclin dependent kinase inhibitor 2A', 'Gene', (289, 325))	('DNA methylation', 'biological_process', 'GO:0006306', ('13', '28'))	('CDKN2A', 'Gene', (327, 333))	('cyclin dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('289', '322'))	('ALDH1A3', 'Gene', '220', (168, 175))	('colon cancer', 'Phenotype', 'HP:0003003', (338, 350))	('glioma', 'Disease', (206, 212))	('aldehyde dehydrogenase 1 family member A3', 'Gene', '220', (125, 166))	('aldehyde dehydrogenase 1 family member A3', 'Gene', (125, 166))	('hypomethylation', 'Var', (270, 285))	('glioblastoma', 'Disease', 'MESH:D005909', (253, 265))	('cyclin dependent kinase inhibitor 2A', 'Gene', '1029', (289, 325))	('CDKN2A', 'Gene', '1029', (327, 333))	('glioma', 'Disease', 'MESH:D005910', (206, 212))	('hypermethylation', 'Var', (186, 202))	('colon cancer', 'Disease', 'MESH:D015179', (338, 350))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('306', '322'))
16673	31637882	It was reported that ccRCC typically shows features of epigenetic alterations and methylated CpGs accompanying progress of disease, although a specific prognostic model has not been proposed.	('epigenetic alterations', 'Var', (55, 77))	('methylated', 'Var', (82, 92))	('CpGs', 'Chemical', 'MESH:C024660', (93, 97))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (21, 26))	('CpGs', 'Gene', (93, 97))	('ccRCC', 'Disease', (21, 26))	('ccRCC', 'Disease', 'MESH:D002292', (21, 26))
16678	31637882	First, methylation markers (p<0.05) found to be closely related to patient survival were defined as candidate markers through univariate Cox proportional hazard analysis.	('Cox', 'Gene', (137, 140))	('methylation', 'Var', (7, 18))	('Cox', 'Gene', '9377', (137, 140))	('patient', 'Species', '9606', (67, 74))	('methylation', 'biological_process', 'GO:0032259', ('7', '18'))
16687	31637882	Finally, two methylation sites (cg18034859, cg24199834) in the hazard ratio (HR) model were identified; their risk coefficients are listed in Table 2. cg24199834 was indicated as a risk factor with a HR of 1.03, while the methylation level of cg24199834 was inversely proportional to the risk of death, with an HR of 0.78, indicating that cg18034859 was a protective factor.	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('methylation', 'biological_process', 'GO:0032259', ('222', '233'))	('death', 'Disease', 'MESH:D003643', (296, 301))	('death', 'Disease', (296, 301))	('cg18034859', 'Var', (339, 349))
16707	31637882	Exploring another database (http://genome.ucsc.edu/), we found cg18034859 and cg2419834 are located in the promoter regions of myosin light chain kinase 2 (MYLK2) and POU class 4 homeobox 2 (POU4F2) genes, respectively, indicating the potential influence of its methylation on gene expression.	('MYLK2', 'Gene', '85366', (156, 161))	('MYLK2', 'Gene', (156, 161))	('cg18034859', 'Var', (63, 73))	('gene expression', 'biological_process', 'GO:0010467', ('277', '292'))	('myosin light chain kinase 2', 'Gene', (127, 154))	('methylation', 'biological_process', 'GO:0032259', ('262', '273'))	('cg2419834', 'Var', (78, 87))	('myosin light chain kinase 2', 'Gene', '85366', (127, 154))	('POU4F2', 'Gene', (191, 197))	('myosin light chain kinase', 'molecular_function', 'GO:0004687', ('127', '152'))	('POU4F2', 'Gene', '5458', (191, 197))
16711	31637882	Moreover, urinary levels of POU4F2 hypermethylation were considered to be having a bearing on non-muscle invasive bladder cancer recurrence, which is in good association with our results for a high DNA methylation level of cg2419834 at POU4F2.	('hypermethylation', 'Var', (35, 51))	('invasive bladder', 'Phenotype', 'HP:0100645', (105, 121))	('DNA methylation', 'biological_process', 'GO:0006306', ('198', '213'))	('POU4F2', 'Gene', (28, 34))	('invasive bladder cancer', 'Disease', (105, 128))	('POU4F2', 'Gene', '5458', (236, 242))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (105, 128))	('DNA', 'cellular_component', 'GO:0005574', ('198', '201'))	('POU4F2', 'Gene', '5458', (28, 34))	('POU4F2', 'Gene', (236, 242))	('bladder cancer', 'Phenotype', 'HP:0009725', (114, 128))	('bearing', 'Reg', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cg2419834', 'Var', (223, 232))
16717	31637882	Kaplan-Meier survival analysis methods exhibited a difference in survival time between high-expression and low-expression groups: the survival time of patients in the high-expression group was significantly shorter (p=0.028) (Supplementary Fig.	('shorter', 'NegReg', (207, 214))	('survival', 'MPA', (134, 142))	('patients', 'Species', '9606', (151, 159))	('high-expression', 'Var', (167, 182))
16721	31637882	In the future, research may want to focus on a functional mechanism for the two-DNA methylation marker and its potential association in carcinogenesis.	('two-DNA', 'Gene', (76, 83))	('carcinogenesis', 'Disease', 'MESH:D063646', (136, 150))	('methylation', 'Var', (84, 95))	('association', 'Interaction', (121, 132))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('carcinogenesis', 'Disease', (136, 150))	('DNA methylation', 'biological_process', 'GO:0006306', ('80', '95'))
16732	30723706	Among them, FAM83H is characterized by its essential roles in dental enamel formation, and mutation of FAM83H was causative in autosomal dominant hypocalcified amelogenesis imperfecta.	('dental enamel', 'Phenotype', 'HP:0009722', (62, 75))	('mutation', 'Var', (91, 99))	('amelogenesis', 'biological_process', 'GO:0097186', ('160', '172'))	('FAM83H', 'Gene', (103, 109))	('enamel formation', 'biological_process', 'GO:0070166', ('69', '85'))	('FAM83H', 'Gene', '286077', (103, 109))	('autosomal dominant hypocalcified amelogenesis imperfecta', 'Disease', 'MESH:D000567', (127, 183))	('FAM83H', 'Gene', (12, 18))	('causative', 'Reg', (114, 123))	('FAM83H', 'Gene', '286077', (12, 18))	('amelogenesis imperfecta', 'Phenotype', 'HP:0000705', (160, 183))
16788	30723706	With these cut-off values, Nu-FAM83H (P < 0.001), Cy-FAM83H (P < 0.001), Nu-PANX2 (P < 0.001), and Cy-PANX2 (P = 0.002) was significantly associated with death of patients from CCRCC (Figure 1B).	('patients', 'Species', '9606', (163, 171))	('FAM83H', 'Gene', '286077', (30, 36))	('death', 'Disease', 'MESH:D003643', (154, 159))	('Cy-PANX2', 'Gene', (99, 107))	('death', 'Disease', (154, 159))	('Cy-PANX2', 'Gene', '56666', (99, 107))	('Nu-PANX2', 'Var', (73, 81))	('associated with', 'Reg', (138, 153))	('FAM83H', 'Gene', (53, 59))	('Cy-FAM83H', 'Gene', '286077', (50, 59))	('FAM83H', 'Gene', (30, 36))	('FAM83H', 'Gene', '286077', (53, 59))	('CCRCC', 'Disease', (177, 182))	('CCRCC', 'Phenotype', 'HP:0006770', (177, 182))	('Cy-FAM83H', 'Gene', (50, 59))
16789	30723706	Nu-FAM83H positivity was significantly associated with larger tumor size (P < 0.001) and higher tumor stage (P = 0.001) (Table 2).	('FAM83H', 'Gene', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('FAM83H', 'Gene', '286077', (3, 9))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (96, 101))	('positivity', 'Var', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
16790	30723706	Cy-FAM83H positivity was significantly associated with older age of patients (P = 0.004), larger tumor size (P < 0.001), higher tumor stage (P < 0.001), and higher histologic grade (P = 0.037) (Table 2).	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Cy-FAM83H', 'Gene', '286077', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Cy-FAM83H', 'Gene', (0, 9))	('positivity', 'Var', (10, 20))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (97, 102))	('patients', 'Species', '9606', (68, 76))	('tumor', 'Disease', (128, 133))
16798	30723706	Nu-PANX2 positivity showed a 4.283-fold (95% CI; 1.984-9.248) greater risk of death and a 3.131-fold (95% CI; 1.627-6.026) greater risk of relapse or death of CCRCC patients.	('death', 'Disease', 'MESH:D003643', (78, 83))	('death', 'Disease', (78, 83))	('death', 'Disease', 'MESH:D003643', (150, 155))	('death', 'Disease', (150, 155))	('Nu-PANX2', 'Gene', (0, 8))	('positivity', 'Var', (9, 19))	('CCRCC', 'Disease', (159, 164))	('CCRCC', 'Phenotype', 'HP:0006770', (159, 164))	('patients', 'Species', '9606', (165, 173))
16799	30723706	Cy-PANX2 positivity showed a 3.713-fold (95% CI; 1.717-8.033) greater risk of death and a 3.432-fold (95% CI; 1.774-6.640) greater risk of relapse or death of CCRCC patients (Table 3).	('death', 'Disease', 'MESH:D003643', (78, 83))	('death', 'Disease', (78, 83))	('death', 'Disease', 'MESH:D003643', (150, 155))	('Cy-PANX2', 'Gene', '56666', (0, 8))	('death', 'Disease', (150, 155))	('Cy-PANX2', 'Gene', (0, 8))	('CCRCC', 'Disease', (159, 164))	('positivity', 'Var', (9, 19))	('CCRCC', 'Phenotype', 'HP:0006770', (159, 164))	('patients', 'Species', '9606', (165, 173))
16807	30723706	As we have shown in Table 2, there was a significant association between Nu-FAM83H, Cy-FAM83H, Nu-PANX2, and Cy-PANX2 positivity.	('Cy-FAM83H', 'Gene', (84, 93))	('FAM83H', 'Gene', (76, 82))	('FAM83H', 'Gene', (87, 93))	('positivity', 'Var', (118, 128))	('FAM83H', 'Gene', '286077', (76, 82))	('FAM83H', 'Gene', '286077', (87, 93))	('Cy-PANX2', 'Gene', (109, 117))	('Cy-PANX2', 'Gene', '56666', (109, 117))	('Cy-FAM83H', 'Gene', '286077', (84, 93))
16808	30723706	In addition, Nu-FAM83H and Nu-PANX2 positivity were more predictive for estimating survival of CCRCC patients compared with Cy-FAM83H and Cy-PANX2 positivity.	('patients', 'Species', '9606', (101, 109))	('FAM83H', 'Gene', (127, 133))	('CCRCC', 'Phenotype', 'HP:0006770', (95, 100))	('FAM83H', 'Gene', '286077', (127, 133))	('FAM83H', 'Gene', '286077', (16, 22))	('Cy-PANX2', 'Gene', (138, 146))	('Nu-PANX2', 'Gene', (27, 35))	('FAM83H', 'Gene', (16, 22))	('Cy-FAM83H', 'Gene', '286077', (124, 133))	('Cy-PANX2', 'Gene', '56666', (138, 146))	('positivity', 'Var', (36, 46))	('Cy-FAM83H', 'Gene', (124, 133))	('CCRCC', 'Disease', (95, 100))	('survival', 'MPA', (83, 91))
16823	30723706	Therefore, we evaluated PANX2 expression after inducing knock-down or overexpression of FAM83H in human CCRCC cells.	('evaluated', 'Reg', (14, 23))	('FAM83H', 'Gene', '286077', (88, 94))	('knock-down', 'Var', (56, 66))	('FAM83H', 'Gene', (88, 94))	('CCRCC', 'Phenotype', 'HP:0006770', (104, 109))	('PANX2', 'Gene', (24, 29))	('human', 'Species', '9606', (98, 103))	('overexpression', 'PosReg', (70, 84))
16827	30723706	Moreover, knock-down of FAM83H inhibited proliferation of CCRCC cells, and overexpression of FAM83H increased proliferation of RCC cells (Figure 4C).	('FAM83H', 'Gene', '286077', (24, 30))	('increased', 'PosReg', (100, 109))	('overexpression', 'PosReg', (75, 89))	('CCRCC', 'Phenotype', 'HP:0006770', (58, 63))	('FAM83H', 'Gene', (93, 99))	('proliferation', 'CPA', (110, 123))	('knock-down', 'Var', (10, 20))	('FAM83H', 'Gene', '286077', (93, 99))	('inhibited', 'NegReg', (31, 40))	('FAM83H', 'Gene', (24, 30))	('proliferation', 'CPA', (41, 54))
16843	30723706	FAM84H mediated proliferation of CCRCC cells was associated with the expression of cyclin D1, cyclin E1, and P27.	('P27', 'Gene', '10671', (109, 112))	('cyclin', 'molecular_function', 'GO:0016538', ('83', '89'))	('FAM84H', 'Chemical', '-', (0, 6))	('P27', 'Gene', (109, 112))	('cyclin E1', 'Gene', (94, 103))	('FAM84H', 'Var', (0, 6))	('cyclin D1', 'Gene', '595', (83, 92))	('cyclin E1', 'Gene', '898', (94, 103))	('proliferation', 'CPA', (16, 29))	('cyclin', 'molecular_function', 'GO:0016538', ('94', '100'))	('cyclin D1', 'Gene', (83, 92))	('CCRCC', 'Phenotype', 'HP:0006770', (33, 38))
16844	30723706	In line with our results, in a previous study knock-down of FAM83H inhibited the colony forming ability of LNCaP prostate cancer cells.	('FAM83H', 'Gene', '286077', (60, 66))	('inhibited', 'NegReg', (67, 76))	('prostate cancer', 'Disease', (113, 128))	('FAM83H', 'Gene', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('LNCaP', 'CellLine', 'CVCL:0395', (107, 112))	('prostate cancer', 'Disease', 'MESH:D011471', (113, 128))	('knock-down', 'Var', (46, 56))	('prostate cancer', 'Phenotype', 'HP:0012125', (113, 128))
16845	30723706	In colorectal cancer cells, knock-down of FAM83H inhibited migration by disrupting keratin cytoskeleton organization.	('FAM83H', 'Gene', (42, 48))	('cytoskeleton organization', 'biological_process', 'GO:0007010', ('91', '116'))	('keratin cytoskeleton', 'MPA', (83, 103))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('knock-down', 'Var', (28, 38))	('FAM83H', 'Gene', '286077', (42, 48))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('91', '103'))	('colorectal cancer', 'Disease', (3, 20))	('disrupting', 'NegReg', (72, 82))	('migration', 'CPA', (59, 68))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('inhibited', 'NegReg', (49, 58))
16861	30723706	Moreover, mutant FAM83H expression in the nuclei increased nuclear localization of beta-catenin in LS8 ameloblast cells.	('FAM83H', 'Gene', (17, 23))	('mutant', 'Var', (10, 16))	('FAM83H', 'Gene', '286077', (17, 23))	('beta-catenin', 'Gene', (83, 95))	('increased', 'PosReg', (49, 58))	('localization', 'biological_process', 'GO:0051179', ('67', '79'))	('nuclear localization of', 'MPA', (59, 82))	('beta-catenin', 'Gene', '1499', (83, 95))	('LS8', 'CellLine', 'CVCL:2105', (99, 102))
16862	30723706	Therefore, nuclear localization of mutant FAM83H plays a role in the inhibition of mineralization of LS8 ameloblast cells via nuclear localization of beta-catenin.	('FAM83H', 'Gene', (42, 48))	('beta-catenin', 'Gene', '1499', (150, 162))	('mutant', 'Var', (35, 41))	('FAM83H', 'Gene', '286077', (42, 48))	('LS8', 'CellLine', 'CVCL:2105', (101, 104))	('localization', 'biological_process', 'GO:0051179', ('19', '31'))	('mineralization of', 'CPA', (83, 100))	('localization', 'biological_process', 'GO:0051179', ('134', '146'))	('mineralization', 'biological_process', 'GO:0110148', ('83', '97'))	('beta-catenin', 'Gene', (150, 162))	('nuclear localization', 'MPA', (126, 146))	('inhibition', 'NegReg', (69, 79))	('nuclear localization', 'MPA', (11, 31))
16863	30723706	However, when considering the role of beta-catenin in tumor progression, especially when it is localized in nuclei, mutant FAM83H-mediated nuclear localization of beta-catenin supports the hypothesis that mutant FAM83H is involved in tumorigenesis.	('beta-catenin', 'Gene', (38, 50))	('involved', 'Reg', (222, 230))	('FAM83H', 'Gene', (212, 218))	('tumor', 'Disease', (234, 239))	('beta-catenin', 'Gene', (163, 175))	('FAM83H', 'Gene', '286077', (212, 218))	('FAM83H', 'Gene', '286077', (123, 129))	('localization', 'biological_process', 'GO:0051179', ('147', '159'))	('FAM83H', 'Gene', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('beta-catenin', 'Gene', '1499', (38, 50))	('nuclear localization', 'MPA', (139, 159))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('beta-catenin', 'Gene', '1499', (163, 175))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Disease', (54, 59))	('mutant', 'Var', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
16864	30723706	However, mutation of FAM83H itself could not explain all for the nuclear localization of FAM83H.	('mutation', 'Var', (9, 17))	('FAM83H', 'Gene', (89, 95))	('FAM83H', 'Gene', (21, 27))	('FAM83H', 'Gene', '286077', (89, 95))	('FAM83H', 'Gene', '286077', (21, 27))	('localization', 'biological_process', 'GO:0051179', ('73', '85'))
16873	30723706	Therefore, when we performed multivariate analysis without including Nu-FAM83H and Cy-FAM83H expressions, Nu-PANX2 positivity was an independent indicator of shorter OS (P = 0.004) and RFS (P = 0.015).	('shorter', 'Disease', (158, 165))	('FAM83H', 'Gene', (86, 92))	('FAM83H', 'Gene', (72, 78))	('Nu-PANX2', 'Gene', (106, 114))	('Cy-FAM83H', 'Gene', '286077', (83, 92))	('positivity', 'Var', (115, 125))	('FAM83H', 'Gene', '286077', (72, 78))	('FAM83H', 'Gene', '286077', (86, 92))	('OS', 'Chemical', '-', (166, 168))	('Cy-FAM83H', 'Gene', (83, 92))	('RFS', 'CPA', (185, 188))
16874	30723706	The patients with Nu-PANX2-positive CCRCC had a 3.186-fold (95% CI; 1.450-7.002) greater risk of cancer-related death and a 2.302-fold (95% CI; 1.180-4.492) greater risk of relapse or cancer-related death compared with the patients with Nu-PANX2-negative CCRCC.	('cancer', 'Disease', (184, 190))	('death', 'Disease', 'MESH:D003643', (112, 117))	('death', 'Disease', (112, 117))	('relapse', 'CPA', (173, 180))	('cancer', 'Disease', (97, 103))	('CCRCC', 'Phenotype', 'HP:0006770', (36, 41))	('Nu-PANX2-positive', 'Var', (18, 35))	('death', 'Disease', 'MESH:D003643', (199, 204))	('death', 'Disease', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('CCRCC', 'Phenotype', 'HP:0006770', (255, 260))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (223, 231))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('CCRCC', 'Disease', (36, 41))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
16877	30723706	CCRCC patients with high PANX2 RNA levels had a 2.571-fold (95% CI; 1.902-3.475, P < 0.001) greater risk of death compared to CCRCC patients with low expression of PANX2 RNA.	('CCRCC', 'Disease', (0, 5))	('CCRCC', 'Phenotype', 'HP:0006770', (0, 5))	('CCRCC', 'Phenotype', 'HP:0006770', (126, 131))	('RNA', 'cellular_component', 'GO:0005562', ('31', '34'))	('PANX2 RNA', 'MPA', (25, 34))	('high', 'Var', (20, 24))	('RNA', 'cellular_component', 'GO:0005562', ('170', '173'))	('patients', 'Species', '9606', (6, 14))	('death', 'Disease', 'MESH:D003643', (108, 113))	('death', 'Disease', (108, 113))	('patients', 'Species', '9606', (132, 140))
16881	30723706	In addition, Nu-PANX2- and Cy-PANX2-positivity was significantly associated with advanced clinicopathological factors and shorter survival of CCRCCs in the univariate analysis.	('shorter', 'NegReg', (122, 129))	('CCRCCs', 'Disease', (142, 148))	('Cy-PANX2', 'Gene', (27, 35))	('Cy-PANX2', 'Gene', '56666', (27, 35))	('Nu-PANX2-', 'Var', (13, 22))	('CCRCC', 'Phenotype', 'HP:0006770', (142, 147))	('survival', 'MPA', (130, 138))	('CCRCCs', 'Phenotype', 'HP:0006770', (142, 148))
16889	30723706	Moreover, in Caki-1 and Caki-2 CCRCC cells, knock-down of FAM83H decreased mRNA and protein levels of PANX2 and overexpression of FAM83H increased mRNA and protein levels of PANX2 (Figure 4).	('FAM83H', 'Gene', (58, 64))	('decreased', 'NegReg', (65, 74))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('FAM83H', 'Gene', '286077', (58, 64))	('Caki-1', 'CellLine', 'CVCL:0234', (13, 19))	('increased', 'PosReg', (137, 146))	('CCRCC', 'Phenotype', 'HP:0006770', (31, 36))	('FAM83H', 'Gene', (130, 136))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('Caki-2', 'CellLine', 'CVCL:0235', (24, 30))	('FAM83H', 'Gene', '286077', (130, 136))	('knock-down', 'Var', (44, 54))
16916	28029648	using both The Cancer Genome Atlas (TCGA) data set and a validation set, it was found that VHL mutations occurred at a lower frequency in black patients and also that vascular endothelial growth factors (VEGF) and hypoxia-inducible factor (HIF) pathways were up-regulated less in black patients.	('Cancer Genome Atlas', 'Disease', (15, 34))	('Cancer', 'Phenotype', 'HP:0002664', (15, 21))	('hypoxia', 'Disease', (214, 221))	('lower', 'NegReg', (119, 124))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (15, 34))	('hypoxia', 'Disease', 'MESH:D000860', (214, 221))	('VEGF', 'Gene', (204, 208))	('patients', 'Species', '9606', (286, 294))	('up-regulated', 'PosReg', (259, 271))	('patients', 'Species', '9606', (144, 152))	('mutations', 'Var', (95, 104))	('VEGF', 'Gene', '7422', (204, 208))	('VHL', 'Disease', 'MESH:D006623', (91, 94))	('VHL', 'Disease', (91, 94))
16921	28029648	pRCC vs. ccRCC is specifically characterized by MET mutations and gains of chromosomes 7,12,16 and 17 as possible drivers whereas losses of heterozygosity of chromosome 3p and inactivating mutations of the VHL gene characterize ccRCC.	('chromosome', 'cellular_component', 'GO:0005694', ('158', '168'))	('VHL', 'Disease', 'MESH:D006623', (206, 209))	('RCC', 'Disease', 'MESH:C538614', (1, 4))	('inactivating mutations', 'Var', (176, 198))	('losses', 'NegReg', (130, 136))	('VHL', 'Disease', (206, 209))	('RCC', 'Disease', (1, 4))	('pRCC', 'Gene', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (1, 4))	('RCC', 'Phenotype', 'HP:0005584', (230, 233))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (230, 233))	('RCC', 'Disease', (230, 233))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('pRCC', 'Gene', '5546', (0, 4))	('RCC', 'Disease', (11, 14))
16954	28029648	However, pRCC is a genetically distinct form of RCC driven by MET mutations and gains of chromosomes 7,12,16 and 17 as possible drivers; and in the present study, enrichment of VEGF pathway conversely suggests increased responsiveness of VEGFR tartgeted therapies among black patients with pRCC.	('patients', 'Species', '9606', (276, 284))	('pRCC', 'Gene', (290, 294))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('VEGFR', 'Gene', (238, 243))	('pRCC', 'Gene', '5546', (9, 13))	('RCC', 'Disease', (291, 294))	('RCC', 'Phenotype', 'HP:0005584', (291, 294))	('RCC', 'Disease', 'MESH:C538614', (291, 294))	('RCC', 'Disease', (10, 13))	('RCC', 'Phenotype', 'HP:0005584', (10, 13))	('pRCC', 'Gene', (9, 13))	('VEGF', 'Gene', '7422', (177, 181))	('increased', 'PosReg', (210, 219))	('responsiveness', 'MPA', (220, 234))	('VEGF', 'Gene', (177, 181))	('MET mutations', 'Var', (62, 75))	('pRCC', 'Gene', '5546', (290, 294))	('VEGF', 'Gene', '7422', (238, 242))	('RCC', 'Disease', (48, 51))	('RCC', 'Disease', 'MESH:C538614', (10, 13))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('VEGF', 'Gene', (238, 242))	('VEGFR', 'Gene', '3791', (238, 243))
16979	28029648	Specifically distinct subclones with distinct mutation and expression within the same tumor may have provided us with different outcomes depending on the sample of the tumor sequenced.	('provided', 'Reg', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('mutation', 'Var', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
16988	28029648	The present retrospective study relied on the University of California Santa Cruz Genome (UCSC) Browser to download publicly available gene-level non-silent somatic mutation data (nonsense, missense, frame-shift indels, splice site mutations, stop codon read-throught, change of start codon, inframe indels) relied on Firewbrowse to download RNASeq gene expression and clinical pRCC TCGA data.	('pRCC', 'Gene', '5546', (378, 382))	('RCC', 'Phenotype', 'HP:0005584', (379, 382))	('gene expression', 'biological_process', 'GO:0010467', ('349', '364'))	('California Santa Cruz Genome', 'Disease', 'MESH:D004670', (60, 88))	('pRCC', 'Gene', (378, 382))	('missense', 'Var', (190, 198))	('frame-shift', 'Var', (200, 211))	('California Santa Cruz Genome', 'Disease', (60, 88))
16994	28029648	In a subset of propensity matched pRCC patients with gene-level mutation and paired clinical data available (n=71), rates of non-silent somatic gene-level mutations were compared between 41 (57.7%) black and 30 (42.3%) white patients.	('patients', 'Species', '9606', (225, 233))	('mutation', 'Var', (64, 72))	('patients', 'Species', '9606', (39, 47))	('pRCC', 'Gene', (34, 38))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('pRCC', 'Gene', '5546', (34, 38))
17004	27528422	Vhl deletion in renal epithelia causes HIF-1alpha-dependent, HIF-2alpha-independent angiogenesis and constitutive diuresis One of the earliest requirements for the formation of a solid tumor is the establishment of an adequate blood supply.	('renal epithelia', 'Disease', 'MESH:D007674', (16, 31))	('HIF-2alpha', 'Gene', (61, 71))	('causes', 'Reg', (32, 38))	('diuresis', 'biological_process', 'GO:0035810', ('114', '122'))	('tumor', 'Disease', (185, 190))	('constitutive diuresis', 'MPA', (101, 122))	('Vhl', 'Gene', '22346', (0, 3))	('renal epithelia', 'Disease', (16, 31))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('formation', 'biological_process', 'GO:0009058', ('164', '173'))	('diuresis', 'biological_process', 'GO:0030146', ('114', '122'))	('HIF-1alpha', 'Gene', '15251', (39, 49))	('deletion', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('angiogenesis', 'CPA', (84, 96))	('HIF-2alpha', 'Gene', '13819', (61, 71))	('HIF-1alpha', 'Gene', (39, 49))	('Vhl', 'Gene', (0, 3))	('angiogenesis', 'biological_process', 'GO:0001525', ('84', '96'))
17005	27528422	Clear cell renal cell carcinomas (ccRCC) are highly vascularized tumors in which the earliest genetic event is most commonly the biallelic inactivation of the VHL tumor suppressor gene, leading to constitutive activation of the HIF-1alpha and HIF-2alpha transcription factors, which are known angiogenic factors.	('tumor suppressor', 'biological_process', 'GO:0051726', ('163', '179'))	('ccRCC', 'Phenotype', 'HP:0006770', (34, 39))	('tumors', 'Disease', (65, 71))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (228, 253))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('biallelic inactivation', 'Var', (129, 151))	('VHL tumor', 'Disease', (159, 168))	('activation', 'PosReg', (210, 220))	('Clear cell renal cell carcinomas', 'Disease', (0, 32))	('VHL tumor', 'Disease', 'MESH:D006623', (159, 168))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('transcription', 'biological_process', 'GO:0006351', ('254', '267'))	('Clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (0, 32))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (11, 32))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('Clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (0, 32))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('163', '179'))
17007	27528422	We show that renal epithelium-specific deletion of Vhl in mice causes increased medullary vascularization and that this phenotype is completely rescued by Hif1a co-deletion, but not by co-deletion of Hif2a.	('co-deletion', 'Var', (161, 172))	('increased', 'PosReg', (70, 79))	('Hif1a', 'Gene', (155, 160))	('medullary vascularization', 'CPA', (80, 105))	('deletion', 'Var', (39, 47))	('mice', 'Species', '10090', (58, 62))	('Vhl', 'Gene', (51, 54))	('Hif2a', 'Gene', '13819', (200, 205))	('Hif1a', 'Gene', '15251', (155, 160))	('Hif2a', 'Gene', (200, 205))
17010	27528422	Co-deletion of Hif1a, but not Hif2a, with Vhl, fully restored kidney morphology and function, correlating with the rescue of the vasculature.	('Hif2a', 'Gene', '13819', (30, 35))	('kidney morphology', 'MPA', (62, 79))	('Hif1a', 'Gene', '15251', (15, 20))	('Co-deletion', 'Var', (0, 11))	('Hif2a', 'Gene', (30, 35))	('Hif1a', 'Gene', (15, 20))	('restored', 'PosReg', (53, 61))
17017	27528422	While numerous mouse models have shown that neither genetic deletion of Vhl, nor stabilization of HIF-1alpha and HIF-2alpha alone or together in renal epithelial cells are sufficient to cause tumor formation in mouse kidneys (reviewed in), we have recently shown that both HIF-1alpha and HIF-2alpha are necessary for the initiation of renal cysts and tumors in Vhl/Trp53 mutant mice.	('Vhl', 'Gene', (72, 75))	('renal epithelia', 'Disease', (145, 160))	('Trp53', 'Gene', (365, 370))	('mouse', 'Species', '10090', (15, 20))	('mice', 'Species', '10090', (378, 382))	('tumor', 'Disease', (351, 356))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (273, 298))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (98, 123))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('tumor', 'Disease', (192, 197))	('tumors', 'Phenotype', 'HP:0002664', (351, 357))	('initiation of renal cysts and tumors', 'Disease', 'MESH:D007674', (321, 357))	('renal cysts', 'Phenotype', 'HP:0000107', (335, 346))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('mouse', 'Species', '10090', (211, 216))	('renal epithelia', 'Disease', 'MESH:D007674', (145, 160))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('mutant', 'Var', (371, 377))	('formation', 'biological_process', 'GO:0009058', ('198', '207'))	('Trp53', 'Gene', '22059', (365, 370))
17022	27528422	Increased blood vessel formation can already be observed surrounding microscopic VHL mutant ccRCC precursor lesions in kidneys of VHL patients, showing that the induction of neoangiogenesis occurs at the earliest stage of tumor development.	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('VHL', 'Gene', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('patients', 'Species', '9606', (134, 142))	('ccRCC', 'Gene', (92, 97))	('formation', 'biological_process', 'GO:0009058', ('23', '32'))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('mutant', 'Var', (85, 91))
17023	27528422	Guided by our analyses of a series of physiological phenotypes in Vhl-deficient mice, in this study we have investigated the consequences of tubular epithelial cell-specific stabilization of HIF-1alpha and HIF-2alpha in causing alterations to the vascular network surrounding Vhl mutant epithelial cells.	('Vhl', 'Gene', (276, 279))	('alterations', 'Reg', (228, 239))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (191, 216))	('mutant', 'Var', (280, 286))	('mice', 'Species', '10090', (80, 84))	('vascular network', 'MPA', (247, 263))
17024	27528422	The starting point for this study was our previous demonstration that renal epithelium-specific deletion of Vhl causes hydronephrosis in mice through an uncharacterized mechanism.	('hydronephrosis', 'Disease', 'MESH:D006869', (119, 133))	('hydronephrosis', 'Disease', (119, 133))	('hydronephrosis', 'Phenotype', 'HP:0000126', (119, 133))	('deletion', 'Var', (96, 104))	('Vhl', 'Gene', (108, 111))	('mice', 'Species', '10090', (137, 141))
17031	27528422	For instance, mutation of Aqp2, a mouse model of nephrogenic diabetes insipidus (NDI), causes polyuria, hydronephrosis and kidney insufficiency.	('hydronephrosis', 'Phenotype', 'HP:0000126', (104, 118))	('diabetes insipidus', 'Phenotype', 'HP:0000873', (61, 79))	('Aqp2', 'Gene', '11827', (26, 30))	('kidney insufficiency', 'Disease', (123, 143))	('NDI', 'Disease', 'MESH:D018500', (81, 84))	('hydronephrosis', 'Disease', (104, 118))	('polyuria', 'Disease', 'MESH:D011141', (94, 102))	('causes', 'Reg', (87, 93))	('NDI', 'Disease', (81, 84))	('nephrogenic diabetes insipidus', 'Disease', 'MESH:D018500', (49, 79))	('polyuria', 'Phenotype', 'HP:0000103', (94, 102))	('polyuria', 'Disease', (94, 102))	('kidney insufficiency', 'Disease', 'MESH:D051437', (123, 143))	('NDI', 'Phenotype', 'HP:0009806', (81, 84))	('nephrogenic diabetes insipidus', 'Phenotype', 'HP:0009806', (49, 79))	('mouse', 'Species', '10090', (34, 39))	('Aqp2', 'Gene', (26, 30))	('kidney insufficiency', 'Phenotype', 'HP:0000083', (123, 143))	('nephrogenic diabetes insipidus', 'Disease', (49, 79))	('hydronephrosis', 'Disease', 'MESH:D006869', (104, 118))	('mutation', 'Var', (14, 22))
17032	27528422	Similar phenotypes have been observed in mice harbouring deletions of the genes encoding Na-K-2Cl-Cotransporter (NKCC2) or the renal outer medullary potassium channel (ROMK), two models for Bartter's syndrome.	('deletions', 'Var', (57, 66))	("Bartter's syndrome", 'Disease', (190, 208))	('NKCC2', 'Gene', (113, 118))	('mice', 'Species', '10090', (41, 45))	('NKCC2', 'Gene', '20495', (113, 118))	("Bartter's syndrome", 'Disease', 'MESH:D001477', (190, 208))	('ROMK', 'Gene', '56379', (168, 172))	('ROMK', 'Gene', (168, 172))	('potassium', 'Chemical', 'MESH:D011188', (149, 158))
17034	27528422	Given these observations, coupled with the fact that the structure of the renal vasculature is important for ensuring correct urinary concentration, we further investigated the effects of loss of Vhl on urinary concentration and other renal functions that could be the cause of the hydronephrosis phenotype.	('urinary concentration', 'MPA', (203, 224))	('hydronephrosis', 'Disease', (282, 296))	('hydronephrosis', 'Disease', 'MESH:D006869', (282, 296))	('Vhl', 'Gene', (196, 199))	('loss', 'Var', (188, 192))	('hydronephrosis', 'Phenotype', 'HP:0000126', (282, 296))
17035	27528422	We demonstrate that these mice exhibit HIF-1alpha-dependent defects in urinary concentration related to increased medullary vascularization, revealing HIF-1alpha as the angiogenic transcription factor that induces crosstalk between Vhl-mutant renal epithelial cells and vascular endothelia.	('transcription', 'biological_process', 'GO:0006351', ('180', '193'))	('defects in urinary concentration', 'Phenotype', 'HP:0004727', (60, 92))	('increased', 'PosReg', (104, 113))	('medullary vascularization', 'MPA', (114, 139))	('induces', 'Reg', (206, 213))	('HIF-1alpha-dependent defects', 'Disease', 'MESH:D019966', (39, 67))	('renal epithelia', 'Disease', 'MESH:D007674', (243, 258))	('renal epithelia', 'Disease', (243, 258))	('crosstalk', 'MPA', (214, 223))	('HIF-1alpha-dependent defects', 'Disease', (39, 67))	('Vhl-mutant', 'Var', (232, 242))	('Vhl-mutant', 'Gene', (232, 242))	('urinary concentration', 'MPA', (71, 92))	('transcription factor', 'molecular_function', 'GO:0000981', ('180', '200'))	('mice', 'Species', '10090', (26, 30))
17036	27528422	Using the Ksp1.3-Cre driver to induce gene deletion in renal epithelial cells in all segments of the nephron we recently generated renal epithelium-specific conditional knockout mice for Vhl, Hif1a, Hif2a, Vhl/Hif1a or Vhl/Hif2a, hereafter referred to as VhlDelta/Delta, Hif1aDelta/Delta, Hif2aDelta/Delta, VhlDelta/DeltaHif1aDelta/Delta and VhlDelta/DeltaHif2aDelta/Delta, respectively.	('Hif1a', 'Gene', (210, 215))	('Hif1a', 'Gene', (321, 326))	('Hif1a', 'Gene', '15251', (321, 326))	('Hif2a', 'Gene', '13819', (199, 204))	('Hif2a', 'Gene', '13819', (223, 228))	('Hif1a', 'Gene', '15251', (210, 215))	('Hif1a', 'Gene', (192, 197))	('Hif2a', 'Gene', (289, 294))	('renal epithelia', 'Disease', 'MESH:D007674', (55, 70))	('Hif1a', 'Gene', (271, 276))	('Hif2a', 'Gene', '13819', (356, 361))	('Hif2a', 'Gene', (199, 204))	('Hif1a', 'Gene', '15251', (192, 197))	('Hif2a', 'Gene', (223, 228))	('Vhl', 'Var', (187, 190))	('Hif1a', 'Gene', '15251', (271, 276))	('renal epithelia', 'Disease', (55, 70))	('mice', 'Species', '10090', (178, 182))	('Hif2a', 'Gene', (356, 361))	('Hif2a', 'Gene', '13819', (289, 294))
17037	27528422	Vhl deletion caused a morphological hydronephrosis phenotype (Figure 1A).	('hydronephrosis', 'Phenotype', 'HP:0000126', (36, 50))	('morphological hydronephrosis', 'Disease', 'MESH:D006869', (22, 50))	('morphological hydronephrosis', 'Disease', (22, 50))	('deletion', 'Var', (4, 12))	('Vhl', 'Gene', (0, 3))	('caused', 'Reg', (13, 19))
17038	27528422	The co-deletion of Hif1a, but not of Hif2a, completely rescued this phenotype (Figure 1B).	('Hif2a', 'Gene', (37, 42))	('Hif1a', 'Gene', '15251', (19, 24))	('Hif2a', 'Gene', '13819', (37, 42))	('co-deletion', 'Var', (4, 15))	('Hif1a', 'Gene', (19, 24))	('rescued', 'PosReg', (55, 62))
17039	27528422	This genetic rescue prompted further investigation of the cause of hydronephrosis following Vhl deletion.	('hydronephrosis', 'Phenotype', 'HP:0000126', (67, 81))	('Vhl', 'Gene', (92, 95))	('deletion', 'Var', (96, 104))	('hydronephrosis', 'Disease', 'MESH:D006869', (67, 81))	('hydronephrosis', 'Disease', (67, 81))
17041	27528422	VhlDelta/Delta kidneys displayed altered structures of the medulla and papilla and the cortex typically displayed a weaker signal from the contrast agent when compared to the cortex of wild type kidneys, suggestive of changes in urine flow, concentration or renal filtration (Figure 1D).	('papilla', 'Disease', (71, 78))	('weaker', 'NegReg', (116, 122))	('changes', 'Reg', (218, 225))	('renal filtration', 'biological_process', 'GO:0097205', ('258', '274'))	('renal filtration', 'MPA', (258, 274))	('concentration', 'MPA', (241, 254))	('papilla', 'Disease', 'MESH:D010211', (71, 78))	('structures', 'MPA', (41, 51))	('altered', 'Reg', (33, 40))	('VhlDelta/Delta', 'Var', (0, 14))	('signal from the', 'MPA', (123, 138))	('urine flow', 'MPA', (229, 239))
17045	27528422	These strong polydipsia and polyuria phenotypes are suggestive of constitutive diuresis, a conclusion supported by the finding that urine from VhlDelta/Delta mice was hypo-osmolar and was more alkaline than that of control mice.	('polyuria', 'Disease', (28, 36))	('polydipsia', 'Phenotype', 'HP:0001959', (13, 23))	('polydipsia', 'Disease', (13, 23))	('hypo-osmolar', 'Disease', 'MESH:D052456', (167, 179))	('mice', 'Species', '10090', (158, 162))	('constitutive', 'MPA', (66, 78))	('mice', 'Species', '10090', (223, 227))	('polyuria', 'Disease', 'MESH:D011141', (28, 36))	('diuresis', 'biological_process', 'GO:0035810', ('79', '87'))	('alkaline', 'MPA', (193, 201))	('polydipsia', 'Disease', 'MESH:D059606', (13, 23))	('polyuria', 'Phenotype', 'HP:0000103', (28, 36))	('hypo-osmolar', 'Disease', (167, 179))	('diuresis', 'biological_process', 'GO:0030146', ('79', '87'))	('VhlDelta/Delta', 'Var', (143, 157))
17047	27528422	Renal epithelium-specific deletion of Hif1a or Hif2a alone did not affect diuresis.	('Hif1a', 'Gene', (38, 43))	('Hif2a', 'Gene', (47, 52))	('Hif2a', 'Gene', '13819', (47, 52))	('diuresis', 'biological_process', 'GO:0035810', ('74', '82'))	('deletion', 'Var', (26, 34))	('diuresis', 'MPA', (74, 82))	('Hif1a', 'Gene', '15251', (38, 43))	('diuresis', 'biological_process', 'GO:0030146', ('74', '82'))
17053	27528422	We next investigated in whole kidney mRNA preparations of wild type and VhlDelta/Delta kidneys the mRNA expression levels of a range of solute and water transporters, as alterations in their expression could conceivably account for the polyuria phenotype.	('polyuria', 'Phenotype', 'HP:0000103', (236, 244))	('alterations', 'Var', (170, 181))	('investigated', 'Reg', (8, 20))	('polyuria', 'Disease', (236, 244))	('water', 'Chemical', 'MESH:D014867', (147, 152))	('account', 'Reg', (220, 227))	('expression', 'MPA', (191, 201))	('polyuria', 'Disease', 'MESH:D011141', (236, 244))
17057	27528422	It is highly unlikely that reduced Pendrin expression is the primary cause of polyuria in Vhl-deficient mice as it has been shown that knockout of Pendrin in the mouse kidney can be compensated by NCC activity and mRNA and protein expression of NCC in VhlDelta/Delta kidneys is unaltered (Figure 2B and 2C).	('NCC', 'Gene', '20497', (197, 200))	('NCC', 'Gene', '20497', (245, 248))	('knockout', 'Var', (135, 143))	('Pendrin', 'Gene', '23985', (35, 42))	('protein', 'cellular_component', 'GO:0003675', ('223', '230'))	('mRNA', 'MPA', (214, 218))	('mice', 'Species', '10090', (104, 108))	('NCC', 'Gene', (245, 248))	('mouse', 'Species', '10090', (162, 167))	('polyuria', 'Phenotype', 'HP:0000103', (78, 86))	('Pendrin', 'Gene', (147, 154))	('NCC', 'Gene', (197, 200))	('polyuria', 'Disease', (78, 86))	('Pendrin', 'Gene', '23985', (147, 154))	('Pendrin', 'Gene', (35, 42))	('polyuria', 'Disease', 'MESH:D011141', (78, 86))
17059	27528422	Since the expression of several proximal tubule-specific genes is decreased in adult Vhl-deficient mice, but the Ksp1.3-Cre transgene drives gene deletion in only a small percentage of proximal tubular cells, it is likely that this observation reflects progressive kidney damage and nephron loss due to persistent hydronephrosis rather than representing the primary cause of the phenotype.	('mice', 'Species', '10090', (99, 103))	('deletion', 'Var', (146, 154))	('hydronephrosis', 'Phenotype', 'HP:0000126', (314, 328))	('nephron loss', 'Disease', 'MESH:D007683', (283, 295))	('small percentage of proximal tubular cells', 'Phenotype', 'HP:0000114', (165, 207))	('kidney damage', 'Disease', 'MESH:D007674', (265, 278))	('decreased', 'NegReg', (66, 75))	('expression', 'MPA', (10, 20))	('progressive kidney damage', 'Phenotype', 'HP:0012622', (253, 278))	('hydronephrosis', 'Disease', (314, 328))	('nephron loss', 'Disease', (283, 295))	('hydronephrosis', 'Disease', 'MESH:D006869', (314, 328))	('kidney damage', 'Disease', (265, 278))	('kidney damage', 'Phenotype', 'HP:0000112', (265, 278))
17060	27528422	Since genetic loss of Vhl has previously been shown to cause senescence or reduce proliferation of various mouse cells we further investigated whether Vhl deletion in highly proliferating epithelial cells may cause subtle cellular proliferative phenotypes that affect the formation of the nephron.	('Vhl', 'Gene', (22, 25))	('reduce', 'NegReg', (75, 81))	('cause', 'Reg', (209, 214))	('mouse', 'Species', '10090', (107, 112))	('senescence', 'biological_process', 'GO:0010149', ('61', '71'))	('formation', 'biological_process', 'GO:0009058', ('272', '281'))	('Vhl', 'Gene', (151, 154))	('deletion', 'Var', (155, 163))	('formation of the nephron', 'CPA', (272, 296))	('proliferation', 'CPA', (82, 95))	('senescence', 'MPA', (61, 71))	('affect', 'Reg', (261, 267))
17064	27528422	We next asked whether the increased urinary output in VhlDelta/Delta mice is associated with renal insufficiency or a salt wasting phenotype.	('urinary output', 'MPA', (36, 50))	('renal insufficiency', 'Phenotype', 'HP:0000083', (93, 112))	('increased urinary output', 'Phenotype', 'HP:0000103', (26, 50))	('mice', 'Species', '10090', (69, 73))	('salt wasting', 'Phenotype', 'HP:0000127', (118, 130))	('renal insufficiency', 'Disease', (93, 112))	('salt', 'Chemical', 'MESH:D012492', (118, 122))	('increased', 'PosReg', (26, 35))	('VhlDelta/Delta', 'Var', (54, 68))	('renal insufficiency', 'Disease', 'MESH:D051437', (93, 112))	('associated', 'Reg', (77, 87))
17066	27528422	Plasma of Hif1aDelta/Delta mice displayed a slightly increased concentration of K+ whereas deletion of Hif2a caused slightly lower levels of phosphorus (Figure 4B), suggesting that basal renal HIF-alpha levels are necessary for the proper regulation of potassium and phosphate homeostasis.	('Hif1a', 'Gene', (10, 15))	('deletion', 'Var', (91, 99))	('regulation', 'biological_process', 'GO:0065007', ('239', '249'))	('potassium', 'Chemical', 'MESH:D011188', (253, 262))	('mice', 'Species', '10090', (27, 31))	('phosphate', 'Chemical', 'MESH:D010710', (267, 276))	('increased', 'PosReg', (53, 62))	('concentration of K+', 'MPA', (63, 82))	('lower', 'NegReg', (125, 130))	('phosphorus', 'Chemical', 'MESH:D010758', (141, 151))	('Hif2a', 'Gene', '13819', (103, 108))	('levels of phosphorus', 'MPA', (131, 151))	('Hif2a', 'Gene', (103, 108))	('Hif1a', 'Gene', '15251', (10, 15))	('homeostasis', 'biological_process', 'GO:0042592', ('277', '288'))
17067	27528422	None of the other parameters were altered in any mice, indicating that overall renal function is not significantly impaired under normal conditions, even in VhlDelta/Delta and VhlDelta/DeltaHif2aDelta/Delta mice that display constitutive diuresis.	('Hif2a', 'Gene', (190, 195))	('diuresis', 'biological_process', 'GO:0030146', ('238', '246'))	('mice', 'Species', '10090', (49, 53))	('diuresis', 'biological_process', 'GO:0035810', ('238', '246'))	('mice', 'Species', '10090', (207, 211))	('Hif2a', 'Gene', '13819', (190, 195))	('VhlDelta/Delta', 'Var', (157, 171))
17069	27528422	Since other mouse models with constitutive diuresis display increased haematocrit levels as a consequence of dehydration, we conclude that VhlDelta/Delta and VhlDelta/DeltaHif2aDelta/Delta mice are not dehydrated and can adequately compensate increased urinary output with increased water intake.	('water', 'Chemical', 'MESH:D014867', (283, 288))	('urinary output', 'MPA', (253, 267))	('dehydration', 'Disease', 'MESH:D003681', (109, 120))	('dehydration', 'Phenotype', 'HP:0001944', (109, 120))	('diuresis', 'biological_process', 'GO:0030146', ('43', '51'))	('mice', 'Species', '10090', (189, 193))	('VhlDelta/Delta', 'Var', (139, 153))	('dehydration', 'Disease', (109, 120))	('haematocrit levels', 'MPA', (70, 88))	('increased urinary output', 'Phenotype', 'HP:0000103', (243, 267))	('mouse', 'Species', '10090', (12, 17))	('Hif2a', 'Gene', '13819', (172, 177))	('Hif2a', 'Gene', (172, 177))	('increased haematocrit', 'Phenotype', 'HP:0001899', (60, 81))	('diuresis', 'biological_process', 'GO:0035810', ('43', '51'))	('increased', 'PosReg', (60, 69))
17070	27528422	The slightly decreased haematocrit in VhlDelta/Delta and VhlDelta/DeltaHif2aDelta/Delta mice is consistent with our demonstration of reduced renal epithelial mitochondrial content and O2 consumption and with a recent study linking renal epithelial O2 consumption and O2 sensing by Epo-producing interstitial cells.	('VhlDelta/Delta', 'Var', (38, 52))	('renal epithelia', 'Disease', (141, 156))	('decreased', 'NegReg', (13, 22))	('Hif2a', 'Gene', '13819', (71, 76))	('O2', 'Chemical', 'MESH:D010100', (184, 186))	('Hif2a', 'Gene', (71, 76))	('O2 consumption', 'MPA', (184, 198))	('O2', 'Chemical', 'MESH:D010100', (248, 250))	('O2', 'Chemical', 'MESH:D010100', (267, 269))	('renal epithelia', 'Disease', 'MESH:D007674', (231, 246))	('Epo', 'Gene', (281, 284))	('renal epithelia', 'Disease', (231, 246))	('Epo', 'Gene', '13856', (281, 284))	('decreased haematocrit', 'Phenotype', 'HP:0031851', (13, 34))	('mice', 'Species', '10090', (88, 92))	('reduced', 'NegReg', (133, 140))	('haematocrit', 'MPA', (23, 34))	('renal epithelia', 'Disease', 'MESH:D007674', (141, 156))
17075	27528422	Polyuria with severely low urine osmolality could result either from an impairment in arginine vasopressin (AVP) function or a dysregulation of aquaporin 2 (AQP2) or/and thick-limb Na-K-2Cl cotransporter (NKCC2).	('low urine osmolality', 'Phenotype', 'HP:0003158', (23, 43))	('function', 'MPA', (113, 121))	('low', 'NegReg', (23, 26))	('NKCC2', 'Gene', '20495', (205, 210))	('impairment', 'NegReg', (72, 82))	('Polyuria', 'Disease', 'MESH:D011141', (0, 8))	('aquaporin', 'molecular_function', 'GO:0015250', ('144', '153'))	('Polyuria', 'Disease', (0, 8))	('aquaporin 2', 'Gene', (144, 155))	('urine osmolality', 'MPA', (27, 43))	('dysregulation', 'Var', (127, 140))	('Polyuria', 'Phenotype', 'HP:0000103', (0, 8))	('AQP2', 'Gene', (157, 161))	('aquaporin 2', 'Gene', '11827', (144, 155))	('NKCC2', 'Gene', (205, 210))	('AQP2', 'Gene', '11827', (157, 161))	('result', 'Reg', (50, 56))
17082	27528422	Both antibodies revealed a striking increase in the number and density of blood vessels in the inner medulla and papilla, but not cortex, of VhlDelta/Delta kidneys (Figure 5A-5B).	('increase', 'PosReg', (36, 44))	('papilla', 'Disease', 'MESH:D010211', (113, 120))	('VhlDelta/Delta', 'Var', (141, 155))	('papilla', 'Disease', (113, 120))
17083	27528422	Staining for Ki67 to mark actively cycling cells revealed that epithelial and interstitial cells were labelled in the cortex and outer medulla in wild type and VhlDelta/Delta kidneys, whereas Ki67 almost exclusively labelled interstitial cells in the inner medulla and papilla in VhlDelta/Delta kidneys but not in wild type kidneys (Figure 5C), suggestive of increased proliferation of endothelial cells in the renal medulla.	('papilla', 'Disease', 'MESH:D010211', (269, 276))	('Ki67', 'Gene', (13, 17))	('Ki67', 'Gene', (192, 196))	('VhlDelta/Delta kidneys', 'Var', (280, 302))	('papilla', 'Disease', (269, 276))	('Ki67', 'Gene', '17345', (13, 17))	('Ki67', 'Gene', '17345', (192, 196))
17086	27528422	Consistent with these findings, VhlDelta/Delta kidneys and VhlDelta/DeltaHif2aDelta/Delta kidneys, but not VhlDelta/DeltaHif1aDelta/Delta kidneys, displayed higher mRNA expression of the angiogenic growth factor Vegfa (Figure 5G).	('Hif2a', 'Gene', (73, 78))	('Hif1a', 'Gene', (121, 126))	('Vegfa', 'Gene', (212, 217))	('mRNA expression', 'MPA', (164, 179))	('VhlDelta/Delta', 'Var', (32, 46))	('higher', 'PosReg', (157, 163))	('Hif1a', 'Gene', '15251', (121, 126))	('Hif2a', 'Gene', '13819', (73, 78))	('Vegfa', 'Gene', '22339', (212, 217))
17088	27528422	Taken together, these data support the hypothesis that HIF-1alpha-dependent changes in the development of the medullary vasculature may disrupt the osmotic gradient in Vhl-deficient mice, washing out salt from the renal interstitium und thereby preventing urine concentration.	('osmotic gradient', 'MPA', (148, 164))	('Vhl-deficient', 'Gene', (168, 181))	('preventing', 'NegReg', (245, 255))	('changes', 'Var', (76, 83))	('out salt', 'Phenotype', 'HP:0030083', (196, 204))	('mice', 'Species', '10090', (182, 186))	('washing out', 'NegReg', (188, 199))	('salt', 'Chemical', 'MESH:D012492', (200, 204))	('urine concentration', 'MPA', (256, 275))	('disrupt', 'NegReg', (136, 143))	('salt', 'MPA', (200, 204))
17090	27528422	We identified that hydronephrosis arises between postnatal day 11 and 14. muCT-based visualization of the urogenital tract in adult mice revealed no obvious delay in renal clearance of the contrast agent and an intact morphology of the ureter and the bladder, indicating that, in contrast to several other animal models for hydronephrosis, Vhl deficient mice do not exhibit malformation or obstructions of the urogenital tract.	('hydronephrosis', 'Phenotype', 'HP:0000126', (324, 338))	('hydronephrosis', 'Phenotype', 'HP:0000126', (19, 33))	('morphology of the ureter', 'Phenotype', 'HP:0000069', (218, 242))	('hydronephrosis', 'Disease', 'MESH:D006869', (324, 338))	('hydronephrosis', 'Disease', (324, 338))	('mice', 'Species', '10090', (354, 358))	('hydronephrosis', 'Disease', (19, 33))	('mice', 'Species', '10090', (132, 136))	('malformation or obstructions of the urogenital tract', 'Phenotype', 'HP:0000119', (374, 426))	('hydronephrosis', 'Disease', 'MESH:D006869', (19, 33))	('Vhl', 'Gene', (340, 343))	('delay in renal clearance', 'Phenotype', 'HP:0012213', (157, 181))	('deficient', 'Var', (344, 353))
17091	27528422	Rather, urine production by VhlDelta/Delta mice is increased by a factor of 10 when compared to non-transgenic littermates, accompanied by a massively reduced urine osmolality, indicative of a diabetes insipidus phenotype.	('mice', 'Species', '10090', (43, 47))	('reduced urine', 'Phenotype', 'HP:0011037', (151, 164))	('urine production', 'MPA', (8, 24))	('VhlDelta/Delta', 'Var', (28, 42))	('reduced', 'NegReg', (151, 158))	('increased', 'PosReg', (51, 60))	('reduced urine osmolality', 'Phenotype', 'HP:0003158', (151, 175))	('urine osmolality', 'MPA', (159, 175))	('a diabetes insipidus', 'Disease', (191, 211))	('a diabetes insipidus', 'Disease', 'MESH:D003919', (191, 211))	('diabetes insipidus', 'Phenotype', 'HP:0000873', (193, 211))
17093	27528422	We propose that excess urine production in Vhl-deficient mice exceeds the ability of the ureter to remove the urine, subsequently building up pressure on the kidney, which causes expansion of the renal pelvis and the collecting system.	('mice', 'Species', '10090', (57, 61))	('collecting system', 'Phenotype', 'HP:0000081', (217, 234))	('excess urine production', 'Phenotype', 'HP:0000103', (16, 39))	('urine', 'MPA', (23, 28))	('causes', 'Reg', (172, 178))	('expansion of the renal pelvis', 'Phenotype', 'HP:0010946', (179, 208))	('renal pelvis', 'Phenotype', 'HP:0000125', (196, 208))	('Vhl-deficient', 'Gene', (43, 56))	('expansion', 'PosReg', (179, 188))	('building', 'Reg', (130, 138))	('Vhl-deficient', 'Var', (43, 56))	('pressure', 'MPA', (142, 150))
17094	27528422	The hydronephrosis, polyuria and polydipsia phenotypes were completely rescued by co-deletion of Hif1a but not Hif2a, demonstrating that constitutive stabilization of HIF-1alpha in renal tubular cells is the cause of these phenotypes.	('polyuria', 'Disease', 'MESH:D011141', (20, 28))	('hydronephrosis', 'Disease', (4, 18))	('Hif1a', 'Gene', (97, 102))	('polydipsia', 'Disease', 'MESH:D059606', (33, 43))	('hydronephrosis', 'Disease', 'MESH:D006869', (4, 18))	('polydipsia', 'Phenotype', 'HP:0001959', (33, 43))	('polyuria', 'Phenotype', 'HP:0000103', (20, 28))	('polydipsia', 'Disease', (33, 43))	('Hif2a', 'Gene', (111, 116))	('Hif2a', 'Gene', '13819', (111, 116))	('hydronephrosis', 'Phenotype', 'HP:0000126', (4, 18))	('Hif1a', 'Gene', '15251', (97, 102))	('polyuria', 'Disease', (20, 28))	('co-deletion', 'Var', (82, 93))
17098	27528422	Mouse models for Bartter syndrome, a group of genetic disorders caused by mutations in renal ion transporters, display an even more severe phenotype as they exhibit an imbalance in electrolytes in addition to the other symptoms.	('Bartter syndrome', 'Disease', (17, 33))	('imbalance', 'Phenotype', 'HP:0002172', (168, 177))	('genetic disorders', 'Disease', (46, 63))	('mutations', 'Var', (74, 83))	('imbalance in electrolytes', 'Phenotype', 'HP:0003111', (168, 193))	('caused by', 'Reg', (64, 73))	('genetic disorders', 'Disease', 'MESH:D030342', (46, 63))	('imbalance in electrolytes', 'MPA', (168, 193))	('Mouse', 'Species', '10090', (0, 5))	('Bartter syndrome', 'Disease', 'MESH:D001477', (17, 33))
17099	27528422	Loss of Vhl in the renal epithelium provides a new and unique model of diabetes insipidus in adult mice.	('mice', 'Species', '10090', (99, 103))	('Vhl', 'Gene', (8, 11))	('diabetes insipidus', 'Disease', (71, 89))	('diabetes insipidus', 'Disease', 'MESH:D003919', (71, 89))	('Loss', 'Var', (0, 4))	('diabetes insipidus', 'Phenotype', 'HP:0000873', (71, 89))
17100	27528422	Staining for two independent endothelial cell markers demonstrated an increased vascularization of the renal medulla in VhlDelta/Delta kidneys in both young and adult mice.	('mice', 'Species', '10090', (167, 171))	('vascularization of the renal medulla', 'CPA', (80, 116))	('VhlDelta/Delta', 'Var', (120, 134))	('increased', 'PosReg', (70, 79))
17103	27528422	We propose that the increased renal medullary vascularization in VhlDelta/Delta mice leads to increased absorption of salts from the renal interstitium by the blood, thereby disrupting the osmotic gradient and preventing efficient urine concentration (Figure 6).	('absorption of salts', 'MPA', (104, 123))	('increased', 'PosReg', (20, 29))	('preventing', 'NegReg', (210, 220))	('VhlDelta/Delta', 'Var', (65, 79))	('increased', 'PosReg', (94, 103))	('disrupting', 'NegReg', (174, 184))	('the osmotic gradient', 'MPA', (185, 205))	('renal medullary vascularization', 'CPA', (30, 61))	('salt', 'Chemical', 'MESH:D012492', (118, 122))	('mice', 'Species', '10090', (80, 84))	('renal medullary vascularization', 'Phenotype', 'HP:0008659', (30, 61))	('efficient urine concentration', 'MPA', (221, 250))
17111	27528422	Finally, our findings have important implications for understanding the development of human ccRCC as they demonstrate that HIF-1alpha but not HIF-2alpha stabilization in Vhl mutant "normal" mouse renal epithelial cells induces the formation of surrounding blood vessels.	('mutant', 'Var', (175, 181))	('human', 'Species', '9606', (87, 92))	('induces', 'Reg', (220, 227))	('renal epithelia', 'Disease', 'MESH:D007674', (197, 212))	('renal epithelia', 'Disease', (197, 212))	('Vhl', 'Gene', (171, 174))	('formation', 'biological_process', 'GO:0009058', ('230', '239'))	('mouse', 'Species', '10090', (191, 196))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('formation of surrounding blood vessels', 'CPA', (232, 270))
17112	27528422	HIF-1alpha is therefore the likely factor that induces neoangiogenesis as a very early consequence of VHL gene mutation in human renal tubular cells, ensuring that pre-tumourigenic VHL mutant cells will have an adequate blood supply that will presumably support them during the earliest stages of tumour development.	('tumour', 'Disease', 'MESH:D009369', (297, 303))	('mutation', 'Var', (111, 119))	('induces', 'Reg', (47, 54))	('mutant', 'Var', (185, 191))	('VHL gene', 'Gene', (102, 110))	('tumour', 'Disease', (297, 303))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('human', 'Species', '9606', (123, 128))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('pre', 'molecular_function', 'GO:0003904', ('164', '167'))	('tumour', 'Phenotype', 'HP:0002664', (297, 303))	('tumour', 'Disease', (168, 174))
17113	27528422	While it is likely that HIF-1alpha regulates many cellular processes that are important for tumour initiation and development, our previous observation that deletion of Hif1a prevents the formation of cysts and tumours in Vhl/Trp53 mutant mice provides at least correlative evidence that is consistent with the notion that this early vascularization is important for the initiation of ccRCCs.	('Trp53', 'Gene', (226, 231))	('Hif1a', 'Gene', '15251', (169, 174))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('Trp53', 'Gene', '22059', (226, 231))	('cysts and tumours', 'Disease', 'MESH:D009369', (201, 218))	('formation', 'biological_process', 'GO:0009058', ('188', '197'))	('deletion', 'Var', (157, 165))	('Hif1a', 'Gene', (169, 174))	('prevents', 'NegReg', (175, 183))	('tumour initiation', 'Disease', 'MESH:D009369', (92, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (385, 390))	('mutant', 'Var', (232, 238))	('tumours', 'Phenotype', 'HP:0002664', (211, 218))	('tumour initiation', 'Disease', (92, 109))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))	('mice', 'Species', '10090', (239, 243))
17130	33455080	In conclusion, dysregulation of Sirt5/IDH2 partially contributes to Sun resistance in RCC cells by affecting antioxidant capacity.	('Sun resistance', 'Disease', (68, 82))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('antioxidant capacity', 'MPA', (109, 129))	('IDH2', 'Chemical', '-', (38, 42))	('affecting', 'Reg', (99, 108))	('Sun', 'Chemical', 'MESH:D000077210', (68, 71))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('contributes', 'Reg', (53, 64))	('RCC', 'Disease', (86, 89))	('dysregulation', 'Var', (15, 28))	('Sirt5/IDH2', 'Gene', (32, 42))
17133	33455080	Dysregulation of Sirt5/IDH2 partially contributes to Sun resistance by disturbing mitochondrial functions and affecting antioxidant capacity of renal cell carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (144, 164))	('contributes', 'Reg', (38, 49))	('mitochondrial functions', 'MPA', (82, 105))	('Sun', 'Chemical', 'MESH:D000077210', (53, 56))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (144, 164))	('Dysregulation', 'Var', (0, 13))	('Sirt5/IDH2', 'Gene', (17, 27))	('antioxidant capacity', 'MPA', (120, 140))	('disturbing', 'Reg', (71, 81))	('renal cell carcinoma', 'Disease', (144, 164))	('affecting', 'Reg', (110, 119))	('IDH2', 'Chemical', '-', (23, 27))	('Sun resistance', 'Disease', (53, 67))
17142	33455080	Cancer cells exhibited mitochondrial metabolism alterations that support cancer cell proliferation, survival and/or progression and include up-regulation of oxidative metabolism and use of alternative substrates, oncometabolites, increased superoxide production, mutated mitochondrial DNA and altered mitochondrial morphology and dynamics [12].	('alterations', 'Reg', (48, 59))	('superoxide', 'Chemical', 'MESH:D013481', (240, 250))	('metabolism', 'biological_process', 'GO:0008152', ('37', '47'))	('mitochondrial metabolism alterations', 'Phenotype', 'HP:0003287', (23, 59))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('271', '288'))	('superoxide production', 'MPA', (240, 261))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', (73, 79))	('altered', 'Reg', (293, 300))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('survival', 'CPA', (100, 108))	('use', 'MPA', (182, 185))	('mitochondrial morphology', 'MPA', (301, 325))	('increased superoxide production', 'Phenotype', 'HP:0025464', (230, 261))	('dynamics', 'MPA', (330, 338))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cell proliferation', 'biological_process', 'GO:0008283', ('80', '98'))	('increased', 'PosReg', (230, 239))	('up-regulation', 'PosReg', (140, 153))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('mitochondrial', 'Protein', (271, 284))	('oxidative metabolism', 'MPA', (157, 177))	('up-regulation of oxidative metabolism', 'biological_process', 'GO:1901857', ('140', '177'))	('Cancer', 'Disease', (0, 6))	('mitochondrial metabolism', 'MPA', (23, 47))	('mutated', 'Var', (263, 270))
17149	33455080	Meanwhile, Sun-R cells had a lower apoptotic ratio when treated with sunitinib, compared with normal cells (Fig.	('sunitinib', 'Chemical', 'MESH:D000077210', (69, 78))	('sunitinib', 'Var', (69, 78))	('Sun', 'Chemical', 'MESH:D000077210', (11, 14))	('apoptotic ratio', 'CPA', (35, 50))	('lower', 'NegReg', (29, 34))
17160	33455080	Meanwhile, it was demonstrated that Sirt5 knockdown could partially decrease the cell viability and increase the apoptosis rates, compared with the si-Negative control (siNC) group, upon treatment with sunitinib (Fig.	('siNC', 'Disease', 'None', (169, 173))	('sunitinib', 'Chemical', 'MESH:D000077210', (202, 211))	('apoptosis', 'biological_process', 'GO:0006915', ('113', '122'))	('decrease', 'NegReg', (68, 76))	('Sirt5', 'Gene', (36, 41))	('siNC', 'Disease', (169, 173))	('apoptosis', 'biological_process', 'GO:0097194', ('113', '122'))	('apoptosis rates', 'CPA', (113, 128))	('increase', 'PosReg', (100, 108))	('knockdown', 'Var', (42, 51))	('cell viability', 'CPA', (81, 95))
17162	33455080	Figure 3A showed that siSirt5 significantly decreased complex IOXPHOS, complex I+IIOXPHOS and complex I+IIETS in both ACHN and 786-O Sun-R cells compared with siNC.	('complex I+IIETS', 'MPA', (94, 109))	('IOXPHOS', 'Chemical', '-', (62, 69))	('Sun', 'Chemical', 'MESH:D000077210', (133, 136))	('I+IIOXPHOS', 'Chemical', '-', (79, 89))	('siNC', 'Disease', 'None', (159, 163))	('ACHN', 'Chemical', 'MESH:C084683', (118, 122))	('complex I', 'cellular_component', 'GO:0030964', ('71', '80'))	('siSirt5', 'Var', (22, 29))	('complex IOXPHOS', 'MPA', (54, 69))	('complex I+IIOXPHOS', 'MPA', (71, 89))	('siNC', 'Disease', (159, 163))	('complex I', 'cellular_component', 'GO:0030964', ('94', '103'))	('IOXPHOS', 'Chemical', '-', (82, 89))	('decreased', 'NegReg', (44, 53))
17163	33455080	Meanwhile, the lactate secretions and ECAR rates were also detected upon Sirt5 knockdown, elucidating that Sun-R cells exhibit decreased glycolysis with decreased ECAR rates and lactate secretions, whereas Sirt5 knockdown partially increased these values (Fig.	('decreased', 'NegReg', (127, 136))	('lactate', 'Chemical', 'MESH:D019344', (15, 22))	('glycolysis', 'biological_process', 'GO:0006096', ('137', '147'))	('ECAR rates', 'MPA', (163, 173))	('lactate secretions', 'MPA', (178, 196))	('lactate', 'Chemical', 'MESH:D019344', (178, 185))	('knockdown', 'Var', (212, 221))	('decreased', 'NegReg', (153, 162))	('Sun', 'Chemical', 'MESH:D000077210', (107, 110))	('decreased glycolysis', 'Phenotype', 'HP:0012270', (127, 147))	('glycolysis', 'MPA', (137, 147))
17164	33455080	Also, Sirt5 knockdown could also increase the levels of both cellular ROS and mitochondrial-specific ROS in both ACHN and 786-O cells (Fig.	('ACHN', 'Chemical', 'MESH:C084683', (113, 117))	('knockdown', 'Var', (12, 21))	('cellular ROS', 'MPA', (61, 73))	('levels', 'MPA', (46, 52))	('increase', 'PosReg', (33, 41))	('Sirt5', 'Gene', (6, 11))	('ROS', 'Chemical', 'MESH:D017382', (70, 73))	('ROS', 'Chemical', 'MESH:D017382', (101, 104))	('mitochondrial-specific ROS', 'MPA', (78, 104))
17165	33455080	Furthermore, the NADPH/NADP+ ratio and the glutathione (GSH)/oxidized glutathione (GSSG) ratio were all increased in Sun-R cells, with Sirt5 knockdown decreasing the levels of these ratios, showing that modulation of Sirt5 levels significantly influenced the antioxidant capacity of RCC cells (Fig.	('knockdown', 'Var', (141, 150))	('antioxidant capacity', 'MPA', (259, 279))	('influenced', 'Reg', (244, 254))	('glutathione', 'Chemical', 'MESH:D005978', (43, 54))	('increased', 'PosReg', (104, 113))	('NADPH', 'Gene', (17, 22))	('GSH', 'Chemical', '-', (56, 59))	('GSSG', 'Chemical', 'MESH:D019803', (83, 87))	('RCC', 'Disease', (283, 286))	('glutathione', 'Chemical', 'MESH:D005978', (70, 81))	('RCC', 'Phenotype', 'HP:0005584', (283, 286))	('NADPH', 'Gene', '1666', (17, 22))	('RCC', 'Disease', 'MESH:C538614', (283, 286))	('decreasing', 'NegReg', (151, 161))	('Sun', 'Chemical', 'MESH:D000077210', (117, 120))	('NADP+', 'Chemical', 'MESH:D009249', (23, 28))	('Sirt5', 'Gene', (135, 140))
17166	33455080	It was demonstrated that the expression levels of hexokinase II, pyruvate dehydrogenase E1alpha subunit (PDHE1alpha), succinate dehydrogenase (SDH) and cytochrome c oxidase IV (COX-IV) did not change significantly, while Sun-R cells exhibited up-regulated isocitrate dehydrogenase 2 (IDH2) levels, which could be attenuated by Sirt5 knockdown (Fig.	('DHE', 'Chemical', 'MESH:C067883', (106, 109))	('SDH', 'Gene', '6390', (143, 146))	('COX-IV', 'Gene', (177, 183))	('cytochrome c', 'molecular_function', 'GO:0009461', ('152', '164'))	('SDH', 'Gene', (143, 146))	('PDH', 'Gene', '54704', (105, 108))	('IDH2', 'Chemical', '-', (284, 288))	('COX-IV', 'Gene', '1327', (177, 183))	('succinate dehydrogenase', 'Gene', '6390', (118, 141))	('knockdown', 'Var', (333, 342))	('PDH', 'Gene', (105, 108))	('cytochrome c', 'molecular_function', 'GO:0045155', ('152', '164'))	('up-regulated', 'PosReg', (243, 255))	('succinate dehydrogenase', 'Gene', (118, 141))	('Sun', 'Chemical', 'MESH:D000077210', (221, 224))	('isocitrate', 'Chemical', 'MESH:C034219', (256, 266))	('Sirt5', 'Gene', (327, 332))
17169	33455080	It was shown that Sirt5 knockdown did not affect the IDH2 mRNA level in both ACHN and 786-O cells (Fig.	('mRNA level', 'MPA', (58, 68))	('IDH2', 'Gene', (53, 57))	('ACHN', 'Chemical', 'MESH:C084683', (77, 81))	('IDH2', 'Chemical', '-', (53, 57))	('knockdown', 'Var', (24, 33))
17170	33455080	For protein levels, it was shown that Sirt5 knockdown significantly decreased the IDH2 levels in both ACHN and 786-O cells (Fig.	('decreased', 'NegReg', (68, 77))	('IDH2 levels', 'MPA', (82, 93))	('ACHN', 'Chemical', 'MESH:C084683', (102, 106))	('Sirt5', 'Gene', (38, 43))	('knockdown', 'Var', (44, 53))	('IDH2', 'Chemical', '-', (82, 86))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
17171	33455080	Moreover, Sirt5 knockdown significantly inhibited the IDH2 activities (Fig.	('inhibited', 'NegReg', (40, 49))	('knockdown', 'Var', (16, 25))	('Sirt5', 'Gene', (10, 15))	('IDH2', 'Chemical', '-', (54, 58))	('IDH2 activities', 'CPA', (54, 69))
17172	33455080	Using cell viability assay, it was shown that IDH2 knockdown by specific siRNA significantly inhibited the viable cells upon sunitinib treatment compared with siNC (Fig.	('siNC', 'Disease', 'None', (159, 163))	('IDH2', 'Gene', (46, 50))	('viable cells', 'CPA', (107, 119))	('sunitinib', 'Chemical', 'MESH:D000077210', (125, 134))	('IDH2', 'Chemical', '-', (46, 50))	('siNC', 'Disease', (159, 163))	('inhibited', 'NegReg', (93, 102))	('knockdown', 'Var', (51, 60))
17177	33455080	It has previously been reported that succinyl-CoA can lead to nonenzymatic succinylation of lysine residues in proteins [20].	('succinyl-CoA', 'Chemical', 'MESH:C012046', (37, 49))	('lead to', 'Reg', (54, 61))	('lysine', 'Chemical', 'MESH:D008239', (92, 98))	('succinyl-CoA', 'Var', (37, 49))	('nonenzymatic succinylation of lysine residues in', 'MPA', (62, 110))
17181	33455080	Among these lysine residues, several sites seem to be highly targeted by SIRT5, including K80, K155, K263, K360 and K413.	('K413', 'Var', (116, 120))	('K80', 'Var', (90, 93))	('K413', 'Chemical', '-', (116, 120))	('K155', 'Var', (95, 99))	('lysine', 'Chemical', 'MESH:D008239', (12, 18))	('SIRT5', 'Gene', (73, 78))	('K360', 'Chemical', '-', (107, 111))	('K360', 'Var', (107, 111))	('SIRT5', 'Gene', '23408', (73, 78))	('K263', 'Var', (101, 105))
17182	33455080	Based on the crystal structure [22], two lysine sites, K360 and K413, which are adjacent to the substrate binding site, imply that succinylation of these two residues might compromise the binding pocket for isocitrate and inhibit IDH2 activity.	('compromise', 'NegReg', (173, 183))	('binding', 'Interaction', (188, 195))	('IDH2', 'Chemical', '-', (230, 234))	('binding', 'molecular_function', 'GO:0005488', ('188', '195'))	('IDH2', 'Enzyme', (230, 234))	('K413', 'Chemical', '-', (64, 68))	('succinylation', 'MPA', (131, 144))	('K360', 'Chemical', '-', (55, 59))	('binding', 'molecular_function', 'GO:0005488', ('106', '113'))	('K360', 'Var', (55, 59))	('inhibit', 'NegReg', (222, 229))	('activity', 'MPA', (235, 243))	('isocitrate', 'Chemical', 'MESH:C034219', (207, 217))	('lysine', 'Chemical', 'MESH:D008239', (41, 47))	('K413', 'Var', (64, 68))
17183	33455080	5E,F, we have further investigated the role of succinylations in K360 and K413 residues using a mutation of each of these two putative succinylation sites to arginine (R) (K360R and K413R).	('K413', 'Chemical', '-', (74, 78))	('K360', 'Chemical', '-', (65, 69))	('K360', 'Chemical', '-', (172, 176))	('K413R', 'Var', (182, 187))	('K360R', 'Mutation', 'rs1217762974', (172, 177))	('arginine', 'Chemical', 'MESH:D001120', (158, 166))	('K413R', 'Mutation', 'p.K413R', (182, 187))	('K413', 'Chemical', '-', (182, 186))	('K360R', 'Var', (172, 177))
17184	33455080	It was shown that the K413 mutation did not significantly affect the IDH2 activity and GSH/GSSG ratio upon Sirt5 knockdown.	('IDH2', 'Chemical', '-', (69, 73))	('GSH', 'Chemical', '-', (87, 90))	('GSH/GSSG ratio', 'CPA', (87, 101))	('K413', 'Chemical', '-', (22, 26))	('activity', 'MPA', (74, 82))	('K413', 'Var', (22, 26))	('GSSG', 'Chemical', 'MESH:D019803', (91, 95))
17185	33455080	More importantly, the K413R mutation could significantly sensitize RCC cells to sunitinib treatment using CCK-8 assay (Fig.	('K413R', 'Mutation', 'p.K413R', (22, 27))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('sensitize', 'Reg', (57, 66))	('sunitinib', 'Chemical', 'MESH:D000077210', (80, 89))	('CCK', 'Gene', (106, 109))	('CCK', 'Gene', '885', (106, 109))	('K413R', 'Var', (22, 27))
17191	33455080	Furthermore, we showed that chronic sunitinib treatment up-regulated Sirt5/IDH2 expression levels, whereas knockdown of Sirt5/IDH2 partially attenuated sunitinib resistance.	('knockdown', 'Var', (107, 116))	('IDH2', 'Chemical', '-', (126, 130))	('attenuated', 'NegReg', (141, 151))	('up-regulated', 'PosReg', (56, 68))	('sunitinib', 'Chemical', 'MESH:D000077210', (152, 161))	('expression levels', 'MPA', (80, 97))	('Sirt5/IDH2', 'Gene', (69, 79))	('sunitinib', 'Chemical', 'MESH:D000077210', (36, 45))	('sunitinib resistance', 'MPA', (152, 172))	('IDH2', 'Chemical', '-', (75, 79))
17193	33455080	RCC is now characterized by a reprogramming of energetic metabolism, and mutations in target genes were involved in metabolic pathways.	('involved', 'Reg', (104, 112))	('metabolic pathways', 'Pathway', (116, 134))	('mutations', 'Var', (73, 82))	('metabolism', 'biological_process', 'GO:0008152', ('57', '67'))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('RCC', 'Disease', (0, 3))
17198	33455080	Meanwhile, imbalance of oxidative stress also contributed to chemoresistance in renal cancer [35].	('imbalance', 'Phenotype', 'HP:0002172', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('oxidative stress', 'Phenotype', 'HP:0025464', (24, 40))	('contributed', 'Reg', (46, 57))	('chemoresistance', 'CPA', (61, 76))	('renal cancer', 'Disease', (80, 92))	('renal cancer', 'Disease', 'MESH:D007680', (80, 92))	('renal cancer', 'Phenotype', 'HP:0009726', (80, 92))	('imbalance', 'Var', (11, 20))
17205	33455080	Sirt5 has been elucidated to promote the glycolysis by demalonylating glyceraldehyde-3 phosphate dehydrogenase and other enzymes in the glycolytic cascade in mouse liver, enhancing the glycolytic flux [19].	('promote', 'PosReg', (29, 36))	('mouse', 'Species', '10090', (158, 163))	('enhancing', 'PosReg', (171, 180))	('glycolysis', 'biological_process', 'GO:0006096', ('41', '51'))	('demalonylating', 'Var', (55, 69))	('Sirt5', 'Gene', (0, 5))	('glycolytic flux', 'MPA', (185, 200))	('glycolysis', 'MPA', (41, 51))
17213	33455080	In this study, we demonstrated that the IDH2 expression levels positively correlated with the Sirt5 expressions in Sun-R RCC cells, while Sirt5 promoted the protein stability of IDH2 by promoting desuccinylation.	('Sirt5', 'Gene', (94, 99))	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('IDH2', 'Chemical', '-', (178, 182))	('RCC', 'Disease', (121, 124))	('promoting', 'PosReg', (186, 195))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('promoted', 'PosReg', (144, 152))	('expression', 'MPA', (45, 55))	('IDH2', 'Chemical', '-', (40, 44))	('Sirt5', 'Var', (138, 143))	('protein stability', 'MPA', (157, 174))	('desuccinylation', 'MPA', (196, 211))	('Sun', 'Chemical', 'MESH:D000077210', (115, 118))
17214	33455080	Also, knockdown of the Sirt5/IDH2 pathway could become a new strategy in alleviating sunitinib resistance.	('alleviating sunitinib resistance', 'MPA', (73, 105))	('Sirt5/IDH2 pathway', 'Pathway', (23, 41))	('IDH2', 'Chemical', '-', (29, 33))	('knockdown', 'Var', (6, 15))	('sunitinib', 'Chemical', 'MESH:D000077210', (85, 94))
17228	33455080	For the measurements of IDH2 activities, Flag-tagged IDH2 were overexpressed in HEK293T cells, immunoprecipitated and eluted by 250 mg mL-1 Flag peptide (Gilson Biochemical, Madison, WI, USA); then the changes of NADPH fluorescence were measured.	('IDH2', 'Chemical', '-', (24, 28))	('Flag-tagged', 'Var', (41, 52))	('NADPH', 'Gene', (213, 218))	('mL-1', 'Gene', (135, 139))	('NADPH', 'Gene', '1666', (213, 218))	('mL-1', 'Gene', '23961', (135, 139))	('IDH2', 'Chemical', '-', (53, 57))	('HEK293T', 'CellLine', 'CVCL:0063', (80, 87))
17230	33455080	The primary antibodies used are as follows: anti-Sirt3 (#5490; Cell Signaling Technology, Boston, MA, USA), anti-Sirt4 (ab124521; Abcam, Cambridge, MA), anti-Sirt5 (#8782; Cell Signaling Technology), anti-alpha-tubulin (Beyotime, Shanghai, China), anti-hexokinase II (ab104836; Abcam), anti-PDHE1alpha (ab168379; Abcam), anti-SDH (ab14714; Abcam), anti-COX-IV (ab33985; Abcam), pan-succinyl-lysine (PTM-401), pan-malonyl-lysine (PTM-901), pan-glutaryl-lysine (PTM-1151), pan-acetyl-lysine (#9441; Cell Signaling Technology) and Flag (4110-20; Shanghai Genomics, Shanghai, China).	('PTM', 'biological_process', 'GO:0043687', ('429', '432'))	('#9441;', 'Var', (490, 496))	('PTM', 'biological_process', 'GO:0043687', ('460', '463'))	('lysine', 'Chemical', 'MESH:D008239', (482, 488))	('SDH', 'Gene', '6390', (326, 329))	('PDH', 'Gene', '54704', (291, 294))	('Sirt3', 'Gene', (49, 54))	('Sirt4', 'Gene', '23409', (113, 118))	('alpha-tubulin', 'Gene', (205, 218))	('Signaling', 'biological_process', 'GO:0023052', ('177', '186'))	('Signaling', 'biological_process', 'GO:0023052', ('502', '511'))	('SDH', 'Gene', (326, 329))	('PDH', 'Gene', (291, 294))	('COX-IV', 'Gene', (353, 359))	('Sirt4', 'Gene', (113, 118))	('Sirt3', 'Gene', '23410', (49, 54))	('COX-IV', 'Gene', '1327', (353, 359))	('lysine', 'Chemical', 'MESH:D008239', (391, 397))	('PTM', 'biological_process', 'GO:0043687', ('399', '402'))	('DHE', 'Chemical', 'MESH:C067883', (292, 295))	('Signaling', 'biological_process', 'GO:0023052', ('68', '77'))	('lysine', 'Chemical', 'MESH:D008239', (421, 427))	('lysine', 'Chemical', 'MESH:D008239', (452, 458))	('PTM-901', 'Var', (429, 436))	('alpha-tubulin', 'Gene', '10376', (205, 218))	('PTM-1151', 'Var', (460, 468))
17239	29616089	The diagnosis in all 3 cases was confirmed by genetic testing, where VHL mutations were detected in all patients.	('VHL', 'Disease', 'MESH:D006623', (69, 72))	('detected', 'Reg', (88, 96))	('VHL', 'Disease', (69, 72))	('patients', 'Species', '9606', (104, 112))	('mutations', 'Var', (73, 82))
17240	29616089	Following surgery, pedigree and genetic analysis was performed in all 3 pedigrees and VHL mutations were identified in 7 family members.	('VHL', 'Disease', (86, 89))	('mutations', 'Var', (90, 99))	('VHL', 'Disease', 'MESH:D006623', (86, 89))
17252	29616089	Mutation, deletion or methylation of the VHL gene may lead to abnormal protein synthesis.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('lead to', 'Reg', (54, 61))	('VHL', 'Disease', 'MESH:D006623', (41, 44))	('VHL', 'Disease', (41, 44))	('protein synthesis', 'MPA', (71, 88))	('methylation', 'biological_process', 'GO:0032259', ('22', '33'))	('deletion', 'Var', (10, 18))	('protein synthesis', 'biological_process', 'GO:0006412', ('71', '88'))	('methylation', 'Var', (22, 33))
17298	29616089	Genetic analysis revealed a mutation in the VHL gene of the patient, c.227_229delTCT (p.Phe76del), which resulted in the deletion of phenylalanine at position 76 of the encoded protein.	('patient', 'Species', '9606', (60, 67))	('VHL', 'Disease', 'MESH:D006623', (44, 47))	('c.227_229delTCT', 'Var', (69, 84))	('resulted in', 'Reg', (105, 116))	('p.Phe76del', 'Mutation', 'rs5030648', (86, 96))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('phenylalanine', 'Protein', (133, 146))	('phenylalanine', 'Chemical', 'MESH:D010649', (133, 146))	('deletion', 'Var', (121, 129))	('c.227_229delTCT', 'Mutation', 'rs5030648', (69, 84))	('VHL', 'Disease', (44, 47))
17317	29616089	The same missense mutation, c.499C>T (p.Arg167Trp), in the VHL gene was found in two family members (II-2 and II-3) and the patient, which led to the substitution of arginine with tryptophan at position 167 of the encoded protein.	('p.Arg167Trp', 'Mutation', 'rs5030820', (38, 49))	('led to', 'Reg', (139, 145))	('VHL', 'Disease', 'MESH:D006623', (59, 62))	('VHL', 'Disease', (59, 62))	('substitution', 'Var', (150, 162))	('arginine', 'Protein', (166, 174))	('arginine with tryptophan at position 167', 'Mutation', 'rs5030820', (166, 206))	('patient', 'Species', '9606', (124, 131))	('protein', 'cellular_component', 'GO:0003675', ('222', '229'))	('c.499C>T', 'Mutation', 'rs5030820', (28, 36))	('c.499C>T', 'Var', (28, 36))
17321	29616089	Another sister of the patient (II-2) carried the mutated VHL gene.	('mutated', 'Var', (49, 56))	('VHL', 'Disease', (57, 60))	('patient', 'Species', '9606', (22, 29))	('VHL', 'Disease', 'MESH:D006623', (57, 60))
17352	29616089	The tests revealed that the same missense mutation in the VHL gene [c.500G>A (p.Arg167Gln)] was found in the patient and his two sons, which led to a substitution of arginine with glutamine at position 167 of the VHL-encoded protein, and this was confirmed by Sanger sequencing (Fig.	('led to', 'Reg', (141, 147))	('VHL', 'Disease', (213, 216))	('VHL', 'Disease', (58, 61))	('patient', 'Species', '9606', (109, 116))	('VHL', 'Disease', 'MESH:D006623', (213, 216))	('VHL', 'Disease', 'MESH:D006623', (58, 61))	('p.Arg167Gln', 'Mutation', 'rs5030821', (78, 89))	('substitution', 'Var', (150, 162))	('protein', 'cellular_component', 'GO:0003675', ('225', '232'))	('arginine with glutamine at position 167', 'Mutation', 'rs5030821', (166, 205))	('[c.500G>A', 'Var', (67, 76))	('c.500G>A', 'Mutation', 'rs5030821', (68, 76))
17364	29616089	Mutations and deletions in the VHL gene are the fundamental causes of VHL syndrome.	('VHL syndrome', 'Disease', (70, 82))	('causes', 'Reg', (60, 66))	('VHL', 'Disease', (31, 34))	('VHL', 'Disease', 'MESH:D006623', (31, 34))	('Mutations', 'Var', (0, 9))	('deletions', 'Var', (14, 23))	('VHL', 'Disease', (70, 73))	('VHL syndrome', 'Disease', 'MESH:D006623', (70, 82))	('VHL', 'Disease', 'MESH:D006623', (70, 73))
17416	29616089	The proband (II-6) carried a deletion in the VHL gene [c.227_229delTCT (p.Phe76del)] that led to the deletion of phenylalanine at position 76 of the VHL-encoded protein.	('deletion', 'Var', (29, 37))	('deletion', 'Var', (101, 109))	('phenylalanine', 'MPA', (113, 126))	('p.Phe76del', 'Mutation', 'rs5030648', (72, 82))	('VHL', 'Disease', (45, 48))	('VHL', 'Disease', (149, 152))	('VHL', 'Disease', 'MESH:D006623', (45, 48))	('VHL', 'Disease', 'MESH:D006623', (149, 152))	('phenylalanine', 'Chemical', 'MESH:D010649', (113, 126))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))	('c.227_229delTCT', 'Mutation', 'rs5030648', (55, 70))
17417	29616089	p.Phe76del blocked the binding of the VHL protein with hypoxia-induced factor-alpha (HIF-alpha), and this affected the stability of HIF-alpha and induced VHL syndrome.	('VHL', 'Disease', (154, 157))	('stability', 'MPA', (119, 128))	('p.Phe76del', 'Mutation', 'rs5030648', (0, 10))	('VHL syndrome', 'Disease', 'MESH:D006623', (154, 166))	('affected', 'Reg', (106, 114))	('VHL', 'Disease', 'MESH:D006623', (38, 41))	('hypoxia', 'Disease', 'MESH:D000860', (55, 62))	('p.Phe76del', 'Var', (0, 10))	('binding', 'molecular_function', 'GO:0005488', ('23', '30'))	('VHL', 'Disease', (38, 41))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('VHL syndrome', 'Disease', (154, 166))	('blocked', 'NegReg', (11, 18))	('hypoxia', 'Disease', (55, 62))	('binding', 'Interaction', (23, 30))	('VHL', 'Disease', 'MESH:D006623', (154, 157))	('induced', 'Reg', (146, 153))
17418	29616089	The p.Phe76del mutation has been reported to be associated with type I VHL syndrome.	('type I VHL syndrome', 'Disease', (64, 83))	('p.Phe76del', 'Mutation', 'rs5030648', (4, 14))	('associated', 'Reg', (48, 58))	('p.Phe76del', 'Var', (4, 14))	('type I VHL syndrome', 'Disease', 'MESH:D006623', (64, 83))
17419	29616089	The remaining family members, including the father of the patient (I-1), did not carry mutations in the VHL gene.	('patient', 'Species', '9606', (58, 65))	('VHL', 'Disease', 'MESH:D006623', (104, 107))	('mutations', 'Var', (87, 96))	('VHL', 'Disease', (104, 107))
17423	29616089	Sequencing of the VHL gene of the 7 family members revealed the same missense mutation in the VHL gene [c.499C>T (p.Arg167Trp)] in the proband (II-4), his sister (II-2) and brother (II-3).	('[c.499C>T', 'Var', (103, 112))	('VHL', 'Disease', (18, 21))	('VHL', 'Disease', (94, 97))	('VHL', 'Disease', 'MESH:D006623', (18, 21))	('VHL', 'Disease', 'MESH:D006623', (94, 97))	('p.Arg167Trp', 'Mutation', 'rs5030820', (114, 125))	('c.499C>T', 'Mutation', 'rs5030820', (104, 112))
17424	29616089	The mutation resulted in the substitution of arginine at position 167 with tryptophan.	('arginine at position 167 with tryptophan', 'Mutation', 'rs5030820', (45, 85))	('resulted in', 'Reg', (13, 24))	('substitution', 'Var', (29, 41))
17425	29616089	Crossey et al and Brauch et al reported that the p.Arg167Trp mutation was closely associated with VHL syndrome.	('associated', 'Reg', (82, 92))	('p.Arg167Trp', 'Mutation', 'rs5030820', (49, 60))	('VHL syndrome', 'Disease', (98, 110))	('p.Arg167Trp', 'Var', (49, 60))	('VHL syndrome', 'Disease', 'MESH:D006623', (98, 110))
17426	29616089	Mutation of the amino acid at position 167 has been reported to increase the risk of pheochromocytoma.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (85, 101))	('pheochromocytoma', 'Disease', (85, 101))	('Mutation', 'Var', (0, 8))	('pheochromocytoma', 'Disease', 'MESH:D010673', (85, 101))
17427	29616089	In a study with 469 pedigrees with VHL syndrome across North America, Europe and Japan, Zbar et al observed that p.Arg167Trp mutation was a hotspot, and the detection rate of this mutation was high in VHL syndrome families with pheochromocytoma.	('VHL syndrome', 'Disease', (201, 213))	('p.Arg167Trp', 'Var', (113, 124))	('VHL syndrome', 'Disease', 'MESH:D006623', (35, 47))	('pheochromocytoma', 'Disease', (228, 244))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (228, 244))	('VHL syndrome', 'Disease', 'MESH:D006623', (201, 213))	('pheochromocytoma', 'Disease', 'MESH:D010673', (228, 244))	('VHL syndrome', 'Disease', (35, 47))	('p.Arg167Trp', 'Mutation', 'rs5030820', (113, 124))
17428	29616089	A total of 21 patients with pheochromocytoma in 33 families carrying the p.Arg167Trp mutation were reported.	('pheochromocytoma', 'Disease', 'MESH:D010673', (28, 44))	('p.Arg167Trp', 'Mutation', 'rs5030820', (73, 84))	('p.Arg167Trp', 'Var', (73, 84))	('pheochromocytoma', 'Disease', (28, 44))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (28, 44))	('patients', 'Species', '9606', (14, 22))
17429	29616089	Siu et al performed genetic screening of 9 Chinese pedigrees with VHL syndrome and detected the p.Arg167Trp mutation in a patient with pheochromocytoma.	('pheochromocytoma', 'Disease', (135, 151))	('patient', 'Species', '9606', (122, 129))	('pheochromocytoma', 'Disease', 'MESH:D010673', (135, 151))	('p.Arg167Trp', 'Mutation', 'rs5030820', (96, 107))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (135, 151))	('VHL syndrome', 'Disease', 'MESH:D006623', (66, 78))	('p.Arg167Trp', 'Var', (96, 107))	('VHL syndrome', 'Disease', (66, 78))
17431	29616089	In case 3, a total of 7 members of the family volunteered for the genetic test, and the same missense mutation [c.500G>A (p.Arg167Gln)] in the VHL gene was detected in the proband (II-4) and his two sons (III-6 and III-7).	('VHL', 'Disease', 'MESH:D006623', (143, 146))	('VHL', 'Disease', (143, 146))	('[c.500G>A', 'Var', (111, 120))	('p.Arg167Gln', 'Mutation', 'rs5030821', (122, 133))	('c.500G>A', 'Mutation', 'rs5030821', (112, 120))
17432	29616089	This mutation led to the substitution of arginine at position 167 with glutamine.	('arginine at position 167 with glutamine', 'Mutation', 'rs5030821', (41, 80))	('led to', 'Reg', (14, 20))	('arginine', 'Protein', (41, 49))	('substitution', 'Var', (25, 37))
17433	29616089	Hes et al reported that the p.Arg167Gln mutation was detected in 11 members from 3 typical VHL syndrome pedigrees.	('p.Arg167Gln', 'Mutation', 'rs5030821', (28, 39))	('p.Arg167Gln', 'Var', (28, 39))	('VHL syndrome', 'Disease', (91, 103))	('VHL syndrome', 'Disease', 'MESH:D006623', (91, 103))
17435	29616089	Additionally, Ciotti et al found in a controlled study of 43 VHL syndrome patients and 42 healthy controls that the p.Arg167Gln mutation was detected in 2 VHL syndrome patients, where one patient exhibited bilateral renal carcinoma and the other had renal carcinoma, pancreatic cysts and ovarian cysts.	('patient', 'Species', '9606', (74, 81))	('detected', 'Reg', (141, 149))	('VHL syndrome', 'Disease', (61, 73))	('patient', 'Species', '9606', (168, 175))	('p.Arg167Gln', 'Mutation', 'rs5030821', (116, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('renal carcinoma', 'Disease', 'MESH:C538614', (250, 265))	('pancreatic cysts and ovarian cysts', 'Disease', 'MESH:D010181', (267, 301))	('VHL syndrome', 'Disease', 'MESH:D006623', (155, 167))	('renal carcinoma', 'Disease', (250, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('renal carcinoma', 'Phenotype', 'HP:0005584', (250, 265))	('bilateral renal carcinoma', 'Disease', 'MESH:D007680', (206, 231))	('VHL syndrome', 'Disease', 'MESH:D006623', (61, 73))	('patient', 'Species', '9606', (188, 195))	('patients', 'Species', '9606', (74, 82))	('ovarian cysts', 'Phenotype', 'HP:0000138', (288, 301))	('renal carcinoma', 'Disease', 'MESH:C538614', (216, 231))	('bilateral renal carcinoma', 'Disease', (206, 231))	('p.Arg167Gln', 'Var', (116, 127))	('renal carcinoma', 'Phenotype', 'HP:0005584', (216, 231))	('pancreatic cysts', 'Phenotype', 'HP:0001737', (267, 283))	('patients', 'Species', '9606', (168, 176))	('VHL syndrome', 'Disease', (155, 167))
17437	29616089	Therefore, the authors of the present report hypothesize that the p.Arg167Gln mutation may be associated with cyst formation in visceral organs.	('p.Arg167Gln', 'Var', (66, 77))	('cyst formation in visceral organs', 'Disease', (110, 143))	('p.Arg167Gln', 'Mutation', 'rs5030821', (66, 77))	('formation', 'biological_process', 'GO:0009058', ('115', '124'))	('associated', 'Reg', (94, 104))
17438	29616089	In the present report, all members from the three pedigrees who remain alive are under follow-up, particularly those carrying the VHL mutations.	('VHL', 'Disease', 'MESH:D006623', (130, 133))	('VHL', 'Disease', (130, 133))	('mutations', 'Var', (134, 143))
17440	29616089	DNA analysis of VHL genetic mutations is the primary method used to confirm the diagnosis of the disease.	('VHL', 'Disease', (16, 19))	('VHL', 'Disease', 'MESH:D006623', (16, 19))	('mutations', 'Var', (28, 37))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))
17446	31727677	While considered undruggable, structural analyses at UT Southwestern Medical Center (UTSW) identified a vulnerability in the alpha subunit, which heterodimerizes with HIF-1beta, ultimately leading to the development of PT2385, a first-in-class inhibitor.	('PT2385', 'Chemical', 'MESH:C000614279', (219, 225))	('leading to', 'Reg', (189, 199))	('PT2385', 'Var', (219, 225))
17450	31727677	PT2385 inhibited HIF-2 in non-tumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations.	('non-tumor', 'Disease', 'MESH:D009369', (26, 35))	('HIF-2', 'Gene', (17, 22))	('erythropoietin', 'Gene', (77, 91))	('PT2385', 'Var', (0, 6))	('patient', 'Species', '9606', (142, 149))	('PT2385', 'Chemical', 'MESH:C000614279', (0, 6))	('erythropoietin', 'molecular_function', 'GO:0005128', ('77', '91'))	('reduction', 'NegReg', (64, 73))	('inhibited', 'NegReg', (7, 16))	('erythropoietin', 'Gene', '2056', (77, 91))	('non-tumor', 'Disease', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
17451	31727677	PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression.	('PT2385', 'Var', (0, 6))	('PT2385', 'Chemical', 'MESH:C000614279', (0, 6))	('ccRCC metastases', 'Disease', (38, 54))	('inhibited', 'NegReg', (60, 69))	('HIF-2', 'Gene', (19, 24))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('gene expression', 'biological_process', 'GO:0010467', ('83', '98'))	('ccRCC metastases', 'Disease', 'MESH:D009362', (38, 54))
17453	31727677	Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E), which interferes with drug binding and precluded HIF-2 complex dissociation.	('acquisition', 'MPA', (43, 54))	('drug binding', 'Interaction', (141, 153))	('interferes', 'NegReg', (125, 135))	('precluded', 'NegReg', (158, 167))	('PT2385', 'Chemical', 'MESH:C000614279', (10, 16))	('G323E', 'SUBSTITUTION', 'None', (111, 116))	('resulted', 'Reg', (27, 35))	('drug binding', 'molecular_function', 'GO:0008144', ('141', '153'))	('G323E', 'Var', (111, 116))	('resistance', 'MPA', (58, 68))	('gatekeeper', 'Species', '111938', (90, 100))
17454	31727677	In addition, we identified an acquired TP53 mutation elsewhere suggesting a possible alternate mechanism of resistance.	('mutation', 'Var', (44, 52))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))
17456	31727677	Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the tumor suppressor gene, von Hippel-Lindau (VHL), which occurs in the majority of tumors.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('tumors', 'Disease', (160, 166))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))	('von Hippel-Lindau', 'Gene', '7428', (103, 120))	('inactivation', 'Var', (60, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('RCC', 'Disease', (35, 38))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('tumor', 'Disease', (80, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('VHL', 'Gene', (122, 125))	('tumor', 'Disease', (160, 165))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('von Hippel-Lindau', 'Gene', (103, 120))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('VHL', 'Gene', '7428', (122, 125))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))
17461	31727677	ccRCC is characterized by high levels of VEGF, and multiple inhibitors of VEGF/VEGFR2 are approved for the treatment of advanced ccRCC.	('VEGF', 'Gene', '7422', (74, 78))	('ccRCC', 'Phenotype', 'HP:0006770', (129, 134))	('VEGF', 'Gene', '7422', (41, 45))	('RCC', 'Disease', (2, 5))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('inhibitors', 'Var', (60, 70))	('RCC', 'Disease', (131, 134))	('VEGF', 'Gene', (74, 78))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('VEGF', 'Gene', '7422', (79, 83))	('VEGFR2', 'Gene', '3791', (79, 85))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('VEGFR2', 'Gene', (79, 85))	('VEGF', 'Gene', (41, 45))	('VEGF', 'Gene', (79, 83))
17466	31727677	However, whether PT2385 effectively inhibits HIF-2 in ccRCC in patients, how specific the effect is, and the overall importance of HIF-2 in ccRCC progression is poorly understood.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('PT2385', 'Var', (17, 23))	('RCC', 'Disease', (142, 145))	('RCC', 'Disease', (56, 59))	('HIF-2', 'Gene', (45, 50))	('PT2385', 'Chemical', 'MESH:C000614279', (17, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('inhibits', 'NegReg', (36, 44))	('patients', 'Species', '9606', (63, 71))
17493	31727677	DUO82047, Sigma-Aldrich), a ligation solution containing ligase at a 1:40 was added, and slides were incubated in a pre-heated humidity chamber for 30 min at 37 C. After washing in buffer A with gentle agitation, amplification solution containing the polymerase was added at a 1:80 dilution, and slides were then incubated in a pre-heated humidity chamber for 100 min at 37 C. After washing in buffer B (Cat.	('gentle agitation', 'Disease', (195, 211))	('pre', 'molecular_function', 'GO:0003904', ('116', '119'))	('DUO82047', 'Var', (0, 8))	('gentle agitation', 'Disease', 'MESH:D011595', (195, 211))	('Cat', 'molecular_function', 'GO:0004096', ('404', '407'))	('agitation', 'Phenotype', 'HP:0000713', (202, 211))	('pre', 'molecular_function', 'GO:0003904', ('328', '331'))
17497	31727677	All SNPs and indels were combined and only kept if there were at least 7 total reads in the normal sample (wild-type and variant) and at least 3 variant reads in the tumor sample.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('variant', 'Var', (145, 152))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))
17504	31727677	Median and 95% CI were used to report the response to PT2385 in terms of (i) RECIST 1.1, (ii) 10% reduction in sum of the longest one-dimensional diameters (SLD), (iii) change in Ktrans, and (iv) ADC.	('PT2385', 'Chemical', 'MESH:C000614279', (54, 60))	('sum of the longest one-dimensional diameters', 'MPA', (111, 155))	('reduction', 'NegReg', (98, 107))	('Ktrans', 'MPA', (179, 185))	('PT2385', 'Var', (54, 60))	('change', 'Reg', (169, 175))	('RECIST 1.1', 'MPA', (77, 87))
17514	31727677	VHL was mutated in tumors from 5 out of 9 patients for whom samples were available and VHL mutations were enriched among patients with stable disease.	('VHL', 'Gene', '7428', (87, 90))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('mutated', 'Var', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('VHL', 'Gene', (0, 3))	('mutations', 'Var', (91, 100))	('VHL', 'Gene', '7428', (0, 3))	('patients', 'Species', '9606', (42, 50))	('VHL', 'Gene', (87, 90))	('patients', 'Species', '9606', (121, 129))
17515	31727677	However, a VHL mutation was also found in a patient with progressive disease (Table 1).	('mutation', 'Var', (15, 23))	('patient', 'Species', '9606', (44, 51))	('VHL', 'Gene', '7428', (11, 14))	('found', 'Reg', (33, 38))	('VHL', 'Gene', (11, 14))	('progressive disease', 'Disease', (57, 76))
17536	31727677	Pre-treatment and on-treatment samples that were adequate were available for 3 patients (Pt27, Pt35, and Pt45).	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('Pt35', 'Var', (95, 99))	('Pt27', 'Chemical', '-', (89, 93))	('Pt45', 'Var', (105, 109))	('patients', 'Species', '9606', (79, 87))
17543	31727677	These data show that PT2385 dissociates HIF-2 complexes in patient metastases and that the effect is specific for HIF-2.	('PT2385', 'Var', (21, 27))	('PT2385', 'Chemical', 'MESH:C000614279', (21, 27))	('metastases', 'Disease', (67, 77))	('patient', 'Species', '9606', (59, 66))	('dissociates', 'NegReg', (28, 39))	('complexes', 'Protein', (46, 55))	('metastases', 'Disease', 'MESH:D009362', (67, 77))	('HIF-2', 'Gene', (40, 45))
17547	31727677	We observed a significant decrease in HIF-2 target genes in tumors from Pt27 and Pt45, but not Pt35 (Fig.	('Pt27', 'Chemical', '-', (72, 76))	('decrease', 'NegReg', (26, 34))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('Pt27', 'Var', (72, 76))	('Pt45', 'Var', (81, 85))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
17549	31727677	Whereas Pt27 and Pt45 derived prolonged benefit from PT2385 and remained on treatment for 32 and 32.9 weeks, respectively, Pt35 progressed after only 5 weeks (Table 1 and Fig.	('Pt27', 'Chemical', '-', (8, 12))	('PT2385', 'Var', (53, 59))	('benefit', 'PosReg', (40, 47))	('PT2385', 'Chemical', 'MESH:C000614279', (53, 59))
17556	31727677	We performed whole exome sequencing (WES) and evaluated the mutations identified in M4 compared to other metastases from the same patient (for a list of samples available from Pt11, see Supplementary Table S5).	('metastases', 'Disease', 'MESH:D009362', (105, 115))	('mutations', 'Var', (60, 69))	('patient', 'Species', '9606', (130, 137))	('metastases', 'Disease', (105, 115))
17559	31727677	Mutations in both VHL and PBRM1, which were found in Pt11, are truncal mutations in ccRCC.	('VHL', 'Gene', '7428', (18, 21))	('PBRM1', 'Gene', (26, 31))	('PBRM1', 'Gene', '55193', (26, 31))	('VHL', 'Gene', (18, 21))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('Mutations', 'Var', (0, 9))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))
17560	31727677	The same VHL and PBRM1 mutations found in M4 were found in previously collected M0 (abdominal wall), M1 (small bowel) and M2 (retroperitoneum) metastases, which showed that all these metastases (collected over a span of 6 years) arose from the same primary tumor (Supplementary Table S6).	('metastases', 'Disease', 'MESH:D009362', (143, 153))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', (257, 262))	('metastases', 'Disease', (183, 193))	('VHL', 'Gene', (9, 12))	('PBRM1', 'Gene', (17, 22))	('VHL', 'Gene', '7428', (9, 12))	('found', 'Reg', (50, 55))	('mutations', 'Var', (23, 32))	('metastases', 'Disease', 'MESH:D009362', (183, 193))	('PBRM1', 'Gene', '55193', (17, 22))	('metastases', 'Disease', (143, 153))	('tumor', 'Disease', 'MESH:D009369', (257, 262))
17561	31727677	WES analyses of M4 identified a c.968G>A substitution in HIF2A (also called EPAS1).	('HIF2A', 'Gene', (57, 62))	('EPAS1', 'Gene', '2034', (76, 81))	('EPAS1', 'Gene', (76, 81))	('c.968G>A', 'Var', (32, 40))	('HIF2A', 'Gene', '2034', (57, 62))	('c.968G>A', 'Mutation', 'rs1221715868', (32, 40))
17564	31727677	Interestingly, this was the same mutation we had previously identified when we modeled resistance to HIF-2 inhibitors using the close analog PT2399 in tumorgraft models (c.968G>A).	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('PT2399', 'Chemical', 'MESH:C000614278', (141, 147))	('tumor', 'Disease', (151, 156))	('c.968G>A', 'Mutation', 'rs1221715868', (170, 178))	('c.968G>A', 'Var', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
17565	31727677	For these experiments, tumorgraft-bearing mice (from a different patient) were treated with PT2399 for over 6 months, until they developed resistance, and the tumors were then sequenced.	('resistance', 'MPA', (139, 149))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('mice', 'Species', '10090', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('PT2399', 'Var', (92, 98))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('patient', 'Species', '9606', (65, 72))	('PT2399', 'Chemical', 'MESH:C000614278', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
17566	31727677	Interestingly, the HIF2A c.968G>A mutation translates to a p.Gly323Glu, and Gly323 lies in the pocket bound by PT2385 and would be expected to interfere with drug binding .	('Gly323', 'Var', (76, 82))	('interfere', 'Reg', (143, 152))	('HIF2A', 'Gene', (19, 24))	('Gly323', 'Chemical', '-', (61, 67))	('c.968G>A', 'Mutation', 'rs1221715868', (25, 33))	('p.Gly323Glu', 'Mutation', 'rs1221715868', (59, 70))	('drug binding', 'molecular_function', 'GO:0008144', ('158', '170'))	('c.968G>A', 'Var', (25, 33))	('PT2385', 'Chemical', 'MESH:C000614279', (111, 117))	('Gly323', 'Chemical', '-', (76, 82))	('drug binding', 'Interaction', (158, 170))	('HIF2A', 'Gene', '2034', (19, 24))
17567	31727677	We hypothesized that if the HIF-2alpha G323E mutation functioned as a gatekeeper, HIF-2 complexes should be preserved in the resistant kidney metastases, and performed proximity ligation assays.	('G323E', 'Var', (39, 44))	('metastases', 'Disease', (142, 152))	('metastases', 'Disease', 'MESH:D009362', (142, 152))	('G323E', 'SUBSTITUTION', 'None', (39, 44))	('gatekeeper', 'Species', '111938', (70, 80))	('HIF-2alpha', 'Gene', (28, 38))
17569	31727677	Thus, we conclude that the G323E substitution prevented HIF-2 dissociation by PT2385 in the renal metastasis.	('HIF-2 dissociation', 'MPA', (56, 74))	('G323E', 'SUBSTITUTION', 'None', (27, 32))	('prevented', 'NegReg', (46, 55))	('G323E', 'Var', (27, 32))	('PT2385', 'Chemical', 'MESH:C000614279', (78, 84))
17570	31727677	These results are in keeping with previous results in cells in culture showing that ectopic expression of HIF-2alpha G323E is sufficient to prevent drug-induced dissociation of HIF-2 complexes .	('drug-induced dissociation', 'MPA', (148, 173))	('G323E', 'SUBSTITUTION', 'None', (117, 122))	('prevent', 'NegReg', (140, 147))	('G323E', 'Var', (117, 122))	('HIF-2alpha', 'Gene', (106, 116))
17571	31727677	Overall, these data show for the first time in humans that resistance to PT2385 treatment arises from the development of a gatekeeper mutation in HIF-2alpha.	('HIF-2alpha', 'Gene', (146, 156))	('humans', 'Species', '9606', (47, 53))	('mutation', 'Var', (134, 142))	('gatekeeper', 'Species', '111938', (123, 133))	('PT2385', 'Chemical', 'MESH:C000614279', (73, 79))
17578	31727677	We then evaluated the 116 genes in the M4 metastasis with the HIF-2alpha G323E mutation.	('G323E', 'SUBSTITUTION', 'None', (73, 78))	('G323E', 'Var', (73, 78))	('HIF-2alpha', 'Gene', (62, 72))
17581	31727677	Overall, these data show that the HIF-2alpha G323E mutation interferes with PT2385-mediated inhibition of HIF-2 target genes in the resistant metastases.	('metastases', 'Disease', (142, 152))	('PT2385', 'Chemical', 'MESH:C000614279', (76, 82))	('metastases', 'Disease', 'MESH:D009362', (142, 152))	('G323E', 'SUBSTITUTION', 'None', (45, 50))	('HIF-2alpha', 'Gene', (34, 44))	('interferes', 'NegReg', (60, 70))	('G323E', 'Var', (45, 50))
17582	31727677	Notably, we identified the same HIF2A mutation (c.968G>A; p.G323E) in a second patient, Pt35 (Supplementary Table S8).	('c.968G>A; p.G323E', 'Var', (48, 65))	('HIF2A', 'Gene', (32, 37))	('c.968G>A', 'Mutation', 'rs1221715868', (48, 56))	('p.G323E', 'Mutation', 'rs1221715868', (58, 65))	('patient', 'Species', '9606', (79, 86))	('HIF2A', 'Gene', '2034', (32, 37))	('p.G323E', 'Var', (58, 65))
17583	31727677	As for Pt11, Pt35 had adequate circulating drug levels and HIF-2 inhibition in non-tumor tissues (Fig.	('inhibition', 'NegReg', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('non-tumor', 'Disease', (79, 88))	('Pt35', 'Var', (13, 17))	('circulating drug levels', 'MPA', (31, 54))	('non-tumor', 'Disease', 'MESH:D009369', (79, 88))	('HIF-2', 'Gene', (59, 64))
17584	31727677	However, the finding of a HIF2A mutation in Pt35 was unexpected.	('HIF2A', 'Gene', (26, 31))	('mutation', 'Var', (32, 40))	('HIF2A', 'Gene', '2034', (26, 31))	('Pt35', 'Gene', (44, 48))
17586	31727677	Manual review of the BAM files showed the PBRM1 mutation in both pretreatment and progression samples (Supplementary Fig.	('mutation', 'Var', (48, 56))	('PBRM1', 'Gene', (42, 47))	('PBRM1', 'Gene', '55193', (42, 47))
17593	31727677	WES analyses of a site of progression failed to identify mutations in HIF2A (or HIF1B, which we previously also linked to resistance in tumorgraft models).	('HIF1B', 'Gene', (80, 85))	('HIF2A', 'Gene', '2034', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('mutations', 'Var', (57, 66))	('HIF1B', 'Gene', '405', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('HIF2A', 'Gene', (70, 75))	('tumor', 'Disease', (136, 141))
17594	31727677	Tantalizingly, we identified a TP53 mutation (c.818G>A; p.R273H) (Supplementary Fig.	('c.818G>A; p.R273H', 'Var', (46, 63))	('p.R273H', 'Mutation', 'rs28934576', (56, 63))	('p.R273H', 'Var', (56, 63))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('c.818G>A', 'Mutation', 'rs28934576', (46, 54))
17595	31727677	The p53 R273H mutation is a well-validated tumor-promoting mutation extensively reported as somatically acquired in tumors (https://cancer.sanger.ac.uk/cosmic).	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', (132, 138))	('p53', 'Gene', '7157', (4, 7))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('R273H', 'Var', (8, 13))	('R273H', 'Mutation', 'rs28934576', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (116, 121))	('p53', 'Gene', (4, 7))
17596	31727677	S4B), the interpretation was confounded by the fact that pre-treatment and on-treatment biopsies had scant tumor cells (as determined also by the evaluation of VHL and PBRM1 mutations; see Supplementary Table S9 and Fig.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('VHL', 'Gene', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('PBRM1', 'Gene', (168, 173))	('VHL', 'Gene', '7428', (160, 163))	('PBRM1', 'Gene', '55193', (168, 173))	('pre', 'molecular_function', 'GO:0003904', ('57', '60'))	('mutations', 'Var', (174, 183))
17597	31727677	TP53 mutations are often associated with protein stabilization, which can be scored by IHC.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('associated', 'Reg', (25, 35))	('protein stabilization', 'MPA', (41, 62))	('mutations', 'Var', (5, 14))	('protein stabilization', 'biological_process', 'GO:0050821', ('41', '62'))
17599	31727677	Overall, these data are consistent with the notion that the TP53 mutation was acquired coincidentally with the development of resistance, and raise the possibility that p53, as previously postulated based on cell line analyses in tissue culture, may also be implicated in resistance to HIF-2 inhibitors.	('p53', 'Gene', (169, 172))	('p53', 'Gene', '7157', (169, 172))	('TP53', 'Gene', '7157', (60, 64))	('mutation', 'Var', (65, 73))	('implicated', 'Reg', (258, 268))	('TP53', 'Gene', (60, 64))
17600	31727677	However, further studies will be required to demonstrate definitively the potential role of p53 mutation in acquisition of HIF-2 inhibitor resistance.	('p53', 'Gene', '7157', (92, 95))	('p53', 'Gene', (92, 95))	('mutation', 'Var', (96, 104))
17602	31727677	Using a combination of approaches, we show for the first time in humans that PT2385 inhibited HIF-2 not only in normal tissues, but also in metastases, leading to the dissociation of HIF-2 heterodimers and the inhibition of HIF-2 target genes.	('PT2385', 'Chemical', 'MESH:C000614279', (77, 83))	('inhibition', 'MPA', (210, 220))	('HIF-2', 'Gene', (94, 99))	('HIF-2 heterodimers', 'Protein', (183, 201))	('metastases', 'Disease', (140, 150))	('heterodimers', 'Protein', (189, 201))	('dissociation', 'MPA', (167, 179))	('PT2385', 'Var', (77, 83))	('humans', 'Species', '9606', (65, 71))	('metastases', 'Disease', 'MESH:D009362', (140, 150))	('inhibited', 'NegReg', (84, 93))
17603	31727677	Furthermore, the identification of an acquired mutation in HIF-2alpha not only validates HIF-2 as the drug target, but unveils a core dependency in RCC tumorigenesis in humans.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('RCC', 'Disease', (148, 151))	('humans', 'Species', '9606', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('mutation', 'Var', (47, 55))	('tumor', 'Disease', (152, 157))	('core', 'cellular_component', 'GO:0019013', ('129', '133'))	('HIF-2alpha', 'Gene', (59, 69))
17604	31727677	We report that prolonged treatment with PT2385 resulted in the acquisition of a gatekeeper mutation preventing HIF-2 dissociation and preserving HIF-2 gene expression despite drug treatment.	('dissociation', 'MPA', (117, 129))	('PT2385', 'Chemical', 'MESH:C000614279', (40, 46))	('gatekeeper', 'Species', '111938', (80, 90))	('mutation', 'Var', (91, 99))	('gene expression', 'biological_process', 'GO:0010467', ('151', '166'))	('expression', 'MPA', (156, 166))	('HIF-2', 'Gene', (111, 116))	('HIF-2', 'Gene', (145, 150))	('PT2385', 'Var', (40, 46))	('preventing', 'NegReg', (100, 110))
17605	31727677	The identification of an acquired resistance mutation validates HIF-2 as the drug target in patients.	('mutation', 'Var', (45, 53))	('acquired resistance', 'MPA', (25, 44))	('patients', 'Species', '9606', (92, 100))
17609	31727677	The situation is akin to EGFR mutations in lung cancer, where the acquisition of resistance mutations reveals a persistent dependency on EGFR activity, which can be targeted with subsequent generation inhibitors.	('EGFR', 'Gene', (137, 141))	('lung cancer', 'Disease', (43, 54))	('EGFR', 'Gene', (25, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('mutations', 'Var', (92, 101))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('EGFR', 'Gene', '1956', (137, 141))	('EGFR', 'molecular_function', 'GO:0005006', ('137', '141'))	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))
17610	31727677	The HIF-2 dependency/therapeutic vulnerability is likely to be similarly acquired early during tumor development, which is believed to start with inactivation of the VHL gene.	('VHL', 'Gene', (166, 169))	('VHL', 'Gene', '7428', (166, 169))	('inactivation', 'Var', (146, 158))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
17613	31727677	The finding of the HIF-2alpha p.G323E mutation in a progressing metastasis after 6 weeks of treatment in Pt35 raises the strong suspicion that the mutation pre-existed (even if it could not be detected) prior to the initiation of PT2385.	('progressing metastasis', 'CPA', (52, 74))	('p.G323E', 'Mutation', 'rs1221715868', (30, 37))	('pre', 'molecular_function', 'GO:0003904', ('156', '159'))	('Pt35', 'Gene', (105, 109))	('PT2385', 'Chemical', 'MESH:C000614279', (230, 236))	('HIF-2alpha', 'Gene', (19, 29))	('p.G323E', 'Var', (30, 37))
17614	31727677	However, a search of the cosmic database for the HIF-2alpha p.G323E mutation fails to reveal other mutations besides the one we previously reported in tumorgrafts, which makes this possibility less likely.	('HIF-2alpha', 'Gene', (49, 59))	('p.G323E', 'Mutation', 'rs1221715868', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('p.G323E', 'Var', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
17615	31727677	That the same resistance mutation (HIF-2alpha, p.G323E) had been previously identified in a preclinical tumorgraft model of acquired resistance from a different patient is in keeping with the notion that tumorgrafts are valid models to study acquired resistance in humans.	('humans', 'Species', '9606', (265, 271))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('patient', 'Species', '9606', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('p.G323E', 'Mutation', 'rs1221715868', (47, 54))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', (204, 209))	('p.G323E', 'Var', (47, 54))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
17616	31727677	Accordingly, we speculate that a second resistance mutation we identified in tumorgrafts, a mutation in HIF-1beta (p.F446L), which increases the binding affinity for HIF-2alpha, may eventually also be found in humans.	('p.F446L', 'Var', (115, 122))	('p.F446L', 'Mutation', 'p.F446L', (115, 122))	('binding', 'molecular_function', 'GO:0005488', ('145', '152'))	('increases', 'PosReg', (131, 140))	('binding', 'Interaction', (145, 152))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('HIF-1beta', 'Gene', (104, 113))	('HIF-2alpha', 'Protein', (166, 176))	('tumor', 'Disease', (77, 82))	('humans', 'Species', '9606', (210, 216))
17617	31727677	The finding of a canonical TP53 mutation in a progression sample suggests that p53 may also be involved in resistance.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('mutation', 'Var', (32, 40))	('involved', 'Reg', (95, 103))
17618	31727677	Interestingly, experiments in RCC cell lines in culture suggested that TP53 mutations may confer resistance to HIF-2 inhibitors.	('mutations', 'Var', (76, 85))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('resistance to', 'MPA', (97, 110))	('RCC', 'Disease', (30, 33))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))
17619	31727677	However, the extent to which TP53 mutations result in resistance remains to be determined, and our previous studies in tumorgrafts showed that p53 mutant tumors (i.e.	('mutant', 'Var', (147, 153))	('tumor', 'Disease', (119, 124))	('tumors', 'Disease', (154, 160))	('p53', 'Gene', '7157', (143, 146))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('p53', 'Gene', (143, 146))	('tumor', 'Disease', (154, 159))
17623	31727677	Overall, these data show that PT2385 inhibits HIF-2 in ccRCC in humans, revealing a core tumor dependency that could be further exploited.	('tumor dependency', 'Disease', (89, 105))	('PT2385', 'Chemical', 'MESH:C000614279', (30, 36))	('core', 'cellular_component', 'GO:0019013', ('84', '88'))	('humans', 'Species', '9606', (64, 70))	('HIF-2', 'Gene', (46, 51))	('tumor dependency', 'Disease', 'MESH:D009376', (89, 105))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))	('PT2385', 'Var', (30, 36))	('inhibits', 'NegReg', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
17636	29963157	Furthermore, the expression of LDHD influenced the serum LDH level (P=0.0126).	('influenced', 'Reg', (36, 46))	('LDHD', 'Gene', (31, 35))	('expression', 'Var', (17, 27))	('LDHD', 'Gene', '197257', (31, 35))	('serum LDH level', 'MPA', (51, 66))
17648	29963157	Previous studies have revealed that pre-treatment serum LDH is a statistically significant prognostic factor in breast, renal, lung and gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('gastric cancer', 'Disease', (136, 150))	('pre', 'molecular_function', 'GO:0003904', ('36', '39'))	('gastric cancer', 'Disease', 'MESH:D013274', (136, 150))	('serum', 'Var', (50, 55))	('LDH', 'Protein', (56, 59))	('breast', 'Disease', (112, 118))	('lung', 'Disease', (127, 131))	('gastric cancer', 'Phenotype', 'HP:0012126', (136, 150))	('renal', 'Disease', (120, 125))
17760	32386122	Our previous studies revealed that PHGDH gene amplification was associated with poor overall survival in clear cell renal cell carcinoma (ccRCC) and that metabolic reprogramming of serine synthesis through PHGDH recruitment allowed ccRCC cells to survive in unfavorable environments.	('ccRCC', 'Phenotype', 'HP:0006770', (232, 237))	('poor', 'NegReg', (80, 84))	('amplification', 'Var', (46, 59))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (105, 136))	('clear cell renal cell carcinoma', 'Disease', (105, 136))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (105, 136))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (116, 136))	('synthesis', 'biological_process', 'GO:0009058', ('188', '197'))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (116, 136))	('PHGDH', 'Gene', (35, 40))
17771	32386122	We previously reported that metabolic reprogramming of serine synthesis thorough PHGDH recruitment was observed when hypoxia-inducible factor 2a was knocked out in sunitinib-resistant renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('knocked out', 'Var', (149, 160))	('PHGDH', 'Gene', (81, 86))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (184, 204))	('hypoxia', 'Disease', 'MESH:D000860', (117, 124))	('hypoxia-inducible factor 2a', 'Gene', (117, 144))	('synthesis', 'biological_process', 'GO:0009058', ('62', '71'))	('hypoxia', 'Disease', (117, 124))	('hypoxia-inducible factor 2a', 'Gene', '2034', (117, 144))	('sunitinib', 'Chemical', 'MESH:D000077210', (164, 173))
17799	32386122	Several reports have shown that DNA amplification of PHGDH underlies the high expression of PHGDH in various types of cancers (melanoma, breast cancer, and clear cell renal cell carcinoma) (Locasale et al., 2011; Possemato et al., 2011).	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('expression', 'MPA', (78, 88))	('PHGDH', 'Gene', (53, 58))	('PHGDH', 'Gene', (92, 97))	('DNA', 'Var', (32, 35))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('melanoma, breast cancer', 'Disease', 'MESH:D001943', (127, 150))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (167, 187))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (156, 187))	('DNA amplification', 'biological_process', 'GO:0006277', ('32', '49'))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
17834	28991563	A recent meta-analysis also suggested that high cadmium exposure was associated with an increased risk for renal cancer as well .	('high cadmium', 'Var', (43, 55))	('renal cancer', 'Disease', (107, 119))	('cadmium', 'Chemical', 'MESH:D002104', (48, 55))	('renal cancer', 'Phenotype', 'HP:0009726', (107, 119))	('renal cancer', 'Disease', 'MESH:D007680', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
17837	28991563	Although a complete discussion of the various syndromes is beyond the scope of this review, the reader should be aware that each of these syndromes tend to be associated with specific histologic subtypes of RCC due to their underlying genetic alterations and that those neoplasms are associated to variable levels of aggressiveness.	('aggressiveness', 'Disease', 'MESH:D001523', (317, 331))	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('neoplasms', 'Phenotype', 'HP:0002664', (270, 279))	('RCC', 'Disease', (207, 210))	('associated', 'Reg', (159, 169))	('aggressiveness', 'Disease', (317, 331))	('genetic alterations', 'Var', (235, 254))	('neoplasm', 'Phenotype', 'HP:0002664', (270, 278))	('neoplasms', 'Disease', 'MESH:D009369', (270, 279))	('aggressiveness', 'Phenotype', 'HP:0000718', (317, 331))	('neoplasms', 'Disease', (270, 279))
17914	28991563	Irregularity or interruption of the tumor pseudocapsule, a rim of normal renal parenchyma surrounding the tumor, suggests locally advanced disease and a high nuclear grade .	('advanced disease', 'Disease', (130, 146))	('advanced disease', 'Disease', 'MESH:D020178', (130, 146))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('Irregularity', 'Var', (0, 12))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', (106, 111))
17932	28991563	For SRMs, partial and radical nephrectomies show similar risks for progression and renal cancer-related deaths, with the former's risks estimated to be 4.5% and 3%, respectively .	('renal cancer', 'Disease', (83, 95))	('progression', 'Disease', (67, 78))	('partial', 'Var', (10, 17))	('renal cancer', 'Disease', 'MESH:D007680', (83, 95))	('renal cancer', 'Phenotype', 'HP:0009726', (83, 95))	('death', 'Disease', 'MESH:D003643', (104, 109))	('death', 'Disease', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
17995	33141518	But, for patients less than 45 years old and patients with metastatic RCC, the survival outcome of pRCC is worse contrarily.	('patients', 'Species', '9606', (9, 17))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('pRCC', 'Gene', (99, 103))	('metastatic', 'Var', (59, 69))	('patients', 'Species', '9606', (45, 53))	('pRCC', 'Gene', '5546', (99, 103))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))
18006	33141518	11  Patients with either ccRCC (International Classification of Disease for Oncology [ICD-O-3] code 8310/3) or pRCC (code 8260/3) from 2004 to 2017 were included in the present study.	('pRCC', 'Gene', '5546', (111, 115))	('RCC', 'Disease', (112, 115))	('Patients', 'Species', '9606', (4, 12))	('RCC', 'Disease', (27, 30))	('code 8260/3', 'Var', (117, 128))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('pRCC', 'Gene', (111, 115))	('Oncology', 'Phenotype', 'HP:0002664', (76, 84))
18149	32397685	A recent sex-specific genome-wide association analysis on a dataset of 13,230 patients (8193 men, 5087 women) with RCC underlined a gender-related association for four single-nucleotide polymorphisms (SNPs) on genes DPF3, EPAS1, SAMD5, and BTBD11.	('EPAS1', 'Gene', (222, 227))	('SAMD5', 'Gene', (229, 234))	('BTBD11', 'Gene', '121551', (240, 246))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('SAMD5', 'Gene', '389432', (229, 234))	('men', 'Species', '9606', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('DPF3', 'Gene', (216, 220))	('RCC', 'Disease', (115, 118))	('DPF3', 'Gene', '8110', (216, 220))	('men', 'Species', '9606', (105, 108))	('patients', 'Species', '9606', (78, 86))	('single-nucleotide polymorphisms', 'Var', (168, 199))	('EPAS1', 'Gene', '2034', (222, 227))	('women', 'Species', '9606', (103, 108))	('BTBD11', 'Gene', (240, 246))
18154	32397685	performed an analysis of three large ccRCC mutation sequencing datasets, and found, in both sexes, mutations of KDM5C, histone demethylase, or BAP1, and the gene coding for a deubiquitinase (both being X-chromosome encoded genes).	('BAP1', 'Gene', (143, 147))	('X-chromosome', 'cellular_component', 'GO:0000805', ('202', '214'))	('KDM5C', 'Gene', (112, 117))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('mutations', 'Var', (99, 108))	('KDM5C', 'Gene', '8242', (112, 117))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('175', '189'))	('BAP1', 'Gene', '8314', (143, 147))
18155	32397685	Mutation of BAP1 was associated with a poorer overall survival (p = 0.0039) in all, and in females (p = 0.0021), but not in males.	('Mutation', 'Var', (0, 8))	('overall survival', 'MPA', (46, 62))	('BAP1', 'Gene', '8314', (12, 16))	('poorer', 'NegReg', (39, 45))	('BAP1', 'Gene', (12, 16))
18156	32397685	Mutation in KDM5C did not reduce patients' survival in total or by gender.	('reduce', 'NegReg', (26, 32))	('patients', 'Species', '9606', (33, 41))	('KDM5C', 'Gene', (12, 17))	('KDM5C', 'Gene', '8242', (12, 17))	('Mutation', 'Var', (0, 8))
18175	32397685	In this regard, there is no significant gender difference in recurrence rate in patients with N0M0 ccRCC after nephrectomy, even if the prognosis is more favorable in women, after recurrence.	('patients', 'Species', '9606', (80, 88))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Disease', (101, 104))	('women', 'Species', '9606', (167, 172))	('N0M0', 'Var', (94, 98))
18183	32397685	The complexity of nephron-sparing surgery (NSS) for RCC could be predicted, in a presurgical setting, by nephrometry scores: the higher the score, the more complex the NSS.	('RCC', 'Disease', (52, 55))	('score', 'Var', (140, 145))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('RCC', 'Disease', 'MESH:C538614', (52, 55))
18185	32397685	on 111 RCCs cT1aN0M0 showed that males had a higher retroperitoneal fat tissue thickness (determined by computed tomography scan) than females, and that, as a consequence, the operative time during retroperitoneal laparoscopic NSS was significantly longer in male patients than in female patients (181.8 +- 34.9 min in males, 150.7 +- 24.7 min in females; p < 0.001).	('retroperitoneal fat tissue thickness', 'MPA', (52, 88))	('longer', 'PosReg', (249, 255))	('patients', 'Species', '9606', (288, 296))	('RCC', 'Disease', 'MESH:C538614', (7, 10))	('patients', 'Species', '9606', (264, 272))	('cT1aN0M0', 'Var', (12, 20))	('higher', 'PosReg', (45, 51))	('RCC', 'Disease', (7, 10))	('RCC', 'Phenotype', 'HP:0005584', (7, 10))
18190	32397685	A recent study on the Surveillance Epidemiology and End Results (SEER) database reported that male gender predicted higher risk for nonsurgical treatment (OR: 1.23, CI 1.13-1.33; p < 0.001) in a population-based study on T1-2N0M0 RCC.	('nonsurgical treatment', 'Disease', (132, 153))	('T1-2N0M0', 'Var', (221, 229))	('men', 'Species', '9606', (149, 152))	('RCC', 'Disease', 'MESH:C538614', (230, 233))	('RCC', 'Disease', (230, 233))	('RCC', 'Phenotype', 'HP:0005584', (230, 233))
18215	32397685	In a subgroup analysis of OS, males had a clear survival advantage with nivolumab (HR: 0.73; 95% CI: 0.58-0.92), while in females there was a survival advantage, but it was not as significant (HR: 0.84; 95% CI: 0.57-1.24).	('nivolumab', 'Chemical', 'MESH:D000077594', (72, 81))	('nivolumab', 'Var', (72, 81))	('advantage', 'PosReg', (57, 66))
18235	32397685	RCC renal cell carcinoma  BMI body mass index  OS overall survival  CSS cancer-specific survival  OR odds ratio  HR hazard ratio  CI confidence interval  NSS nephron sparing surgery  RN radical nephrectomy  ECOG scale Eastern Cooperative Oncology Group scale  AR androgen receptor  RFS recurrence-free survival  ERbeta oestrogen receptor-beta  RR relative risk  SNPs single-nucleotide polymorphisms  CSM cancer-specific mortality  VEGF vascular endothelial growth factor  TKI tyrosine kinase inhibitor  mTOR mammalian target of rapamycin  PD-1 programmed cell death protein-1  CTLA-4 cytotoxic T-lymphocyte-associated protein 4  PFS progression-free survival	('CTLA-4', 'Gene', (577, 583))	('cancer', 'Disease', 'MESH:D009369', (404, 410))	('ERbeta', 'Gene', '2099', (312, 318))	('mTOR', 'Gene', (503, 507))	('mortality', 'Disease', 'MESH:D003643', (420, 429))	('mammalian target of rapamycin', 'Gene', (508, 537))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (4, 24))	('programmed cell death', 'biological_process', 'GO:0012501', ('544', '565'))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('436', '470'))	('cancer', 'Disease', (72, 78))	('RCC renal cell carcinoma  BMI body', 'Disease', (0, 34))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (584, 627))	('RCC renal cell carcinoma  BMI body', 'Disease', 'MESH:C538614', (0, 34))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('androgen receptor', 'Gene', '367', (263, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('mTOR', 'Gene', '2475', (503, 507))	('programmed cell death protein-1', 'Gene', '5133', (544, 575))	('VEGF', 'Gene', '7422', (431, 435))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', (584, 627))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('485', '501'))	('protein', 'cellular_component', 'GO:0003675', ('566', '573'))	('cancer', 'Disease', (404, 410))	('VEGF', 'Gene', (431, 435))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('single-nucleotide polymorphisms', 'Var', (367, 398))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (404, 410))	('mortality', 'Disease', (420, 429))	('PD-1', 'Gene', (539, 543))	('PD-1', 'Gene', '5133', (539, 543))	('androgen receptor', 'Gene', (263, 280))	('programmed cell death protein-1', 'Gene', (544, 575))	('NSS nephron', 'Disease', 'MESH:D007683', (154, 165))	('AR', 'Gene', '367', (260, 262))	('CTLA-4', 'Gene', '1493', (577, 583))	('mammalian target of rapamycin', 'Gene', '2475', (508, 537))	('Oncology', 'Phenotype', 'HP:0002664', (238, 246))	('protein', 'cellular_component', 'GO:0003675', ('618', '625'))	('ERbeta', 'Gene', (312, 318))	('NSS nephron', 'Disease', (154, 165))
18236	28061437	Keap1/Nrf2 pathway in kidney cancer: frequent methylation of KEAP1 gene promoter in clear renal cell carcinoma The Keap1/Nrf2 pathway is a master regulator of the cellular redox state through the induction of several antioxidant defence genes implicated in chemotherapeutic drugs resistance of tumor cells.	('Keap1', 'Gene', (0, 5))	('kidney cancer', 'Disease', (22, 35))	('clear renal cell carcinoma', 'Phenotype', 'HP:0006770', (84, 110))	('clear renal cell carcinoma', 'Disease', (84, 110))	('Nrf2', 'Gene', '4780', (121, 125))	('drugs resistance', 'Phenotype', 'HP:0020174', (274, 290))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (90, 110))	('methylation', 'Var', (46, 57))	('Keap1', 'Gene', '9817', (115, 120))	('Nrf2', 'Gene', (121, 125))	('Nrf2', 'Gene', '4780', (6, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('clear renal cell carcinoma', 'Disease', 'MESH:C538614', (84, 110))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Keap1', 'Gene', (115, 120))	('KEAP1', 'Gene', '9817', (61, 66))	('kidney cancer', 'Disease', 'MESH:D007680', (22, 35))	('Keap1', 'Gene', '9817', (0, 5))	('KEAP1', 'Gene', (61, 66))	('tumor', 'Disease', (294, 299))	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('Nrf2', 'Gene', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('kidney cancer', 'Phenotype', 'HP:0009726', (22, 35))
18241	28061437	Our molecular results show for the the first time the epigenetic silencing of KEAP1 promoter as the leading mechanism for modulation of KEAP1 expression in ccRCCs and corroborate the driver role of Keap1/Nrf2 axis deregulation with potential new function as independent epigenetic prognostic marker in renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('KEAP1', 'Gene', (78, 83))	('renal cell carcinoma', 'Disease', (302, 322))	('KEAP1', 'Gene', (136, 141))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (302, 322))	('deregulation', 'Var', (214, 226))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (302, 322))	('modulation', 'Reg', (122, 132))	('KEAP1', 'Gene', '9817', (136, 141))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('Nrf2', 'Gene', '4780', (204, 208))	('RCC', 'Disease', (158, 161))	('KEAP1', 'Gene', '9817', (78, 83))	('expression', 'MPA', (142, 152))	('epigenetic silencing', 'Var', (54, 74))	('Keap1', 'Gene', '9817', (198, 203))	('Keap1', 'Gene', (198, 203))	('Nrf2', 'Gene', (204, 208))
18243	28061437	Various histotypes of RCC have come to be defined on the basis of their histologic appearance, the presence of distinct driver mutations, varying clinical course, and different responses to therapy.	('RCC', 'Disease', (22, 25))	('mutations', 'Var', (127, 136))	('RCC', 'Disease', 'MESH:C538614', (22, 25))
18254	28061437	Genetic alterations of Keap1/Nrf2 axis were described with a variable incidence in RCC, more frequently in PRCC2.	('Nrf2', 'Gene', (29, 33))	('Genetic alterations', 'Var', (0, 19))	('RCC', 'Disease', (108, 111))	('RCC', 'Disease', (83, 86))	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('PRCC', 'Gene', '5546', (107, 111))	('PRCC', 'Gene', (107, 111))	('Keap1', 'Gene', '9817', (23, 28))	('Keap1', 'Gene', (23, 28))	('Nrf2', 'Gene', '4780', (29, 33))
18255	28061437	Genetic alterations of the Keap1/Nrf2 pathway were reported in a very small fraction of ccRCC patients.	('Genetic alterations', 'Var', (0, 19))	('Nrf2', 'Gene', (33, 37))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('patients', 'Species', '9606', (94, 102))	('Keap1', 'Gene', '9817', (27, 32))	('Keap1', 'Gene', (27, 32))	('Nrf2', 'Gene', '4780', (33, 37))	('RCC', 'Disease', (90, 93))
18256	28061437	However, several studies demonstrated a general high impact of Nrf2 dysfunction in renal cell carcinoma, suggesting that the deregulation of the Keap1 may play a role in carcinogenesis process histotypes beside the presence of genomic alterations.	('Nrf2 dysfunction in renal cell carcinoma', 'Disease', (63, 103))	('carcinogenesis', 'Disease', (170, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('role', 'Reg', (162, 166))	('Keap1', 'Gene', '9817', (145, 150))	('Keap1', 'Gene', (145, 150))	('Nrf2 dysfunction in renal cell carcinoma', 'Disease', 'MESH:C538614', (63, 103))	('deregulation', 'Var', (125, 137))	('carcinogenesis', 'Disease', 'MESH:D063646', (170, 184))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (83, 103))	('play', 'Reg', (155, 159))
18257	28061437	We have previously reported that epigenetic modification by promoter methylation is a main mechanism of regulation of KEAP1 gene expression in Non Small Cell Lung Cancer, malignant gliomas, breast cancer and that it was associated with worst progression free survival.	('Lung Cancer', 'Phenotype', 'HP:0100526', (158, 169))	('regulation', 'biological_process', 'GO:0065007', ('104', '114'))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('epigenetic modification', 'Var', (33, 56))	('Non Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (143, 169))	('promoter', 'MPA', (60, 68))	('gliomas', 'Phenotype', 'HP:0009733', (181, 188))	('malignant gliomas', 'Disease', 'MESH:D005910', (171, 188))	('KEAP1', 'Gene', '9817', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('gene expression', 'biological_process', 'GO:0010467', ('124', '139'))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (147, 169))	('malignant gliomas', 'Disease', (171, 188))	('KEAP1', 'Gene', (118, 123))	('Non Small Cell Lung Cancer', 'Disease', (143, 169))	('Non Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (143, 169))	('methylation', 'biological_process', 'GO:0032259', ('69', '80'))	('Cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))
18258	28061437	Since the role of DNA methylation and genes epigenetically altered in RCC have been an active area of research over the past decade, the main purpose of this study is to investigate the contribution of epigenetic deregulation of the KEAP1 gene in different histotypes of renal cell carcinomas.	('KEAP1', 'Gene', '9817', (233, 238))	('renal cell carcinomas', 'Disease', (271, 292))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (282, 292))	('KEAP1', 'Gene', (233, 238))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (271, 292))	('DNA methylation', 'biological_process', 'GO:0006306', ('18', '33'))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (271, 292))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (271, 291))	('epigenetic', 'Var', (202, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))
18263	28061437	Since the histologic appearance is considered the primary determinant in the classification of Renal Cancer, the discovery of specific variations in methylation profiles could further help to stratify the clear cell renal carcinoma subtype from others.	('clear cell renal carcinoma', 'Disease', (205, 231))	('methylation', 'biological_process', 'GO:0032259', ('149', '160'))	('Renal Cancer', 'Phenotype', 'HP:0009726', (95, 107))	('Renal Cancer', 'Disease', 'MESH:D007680', (95, 107))	('Renal Cancer', 'Disease', (95, 107))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (205, 231))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (205, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('variations', 'Var', (135, 145))	('renal carcinoma', 'Phenotype', 'HP:0005584', (216, 231))	('help', 'Reg', (184, 188))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))
18264	28061437	Moreover, our findings of KEAP1 hypermethylation provide the first indication that this epigenetic mechanism is important also in the regulation of KEAP1 expression in an aggressive renal cancer histotype and could represents an additional and attractive diagnostic and prognostic biomarker.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('KEAP1', 'Gene', (26, 31))	('aggressive renal cancer', 'Disease', 'MESH:D007680', (171, 194))	('KEAP1', 'Gene', '9817', (148, 153))	('renal cancer', 'Phenotype', 'HP:0009726', (182, 194))	('regulation', 'biological_process', 'GO:0065007', ('134', '144'))	('hypermethylation', 'Var', (32, 48))	('KEAP1', 'Gene', (148, 153))	('important', 'Reg', (112, 121))	('KEAP1', 'Gene', '9817', (26, 31))	('aggressive renal cancer', 'Disease', (171, 194))
18278	28061437	In ccRCC methylation was detected in 18 out of 37 cases (48.6%), (Supplementary Figure 4).	('methylation', 'Var', (9, 20))	('men', 'Species', '9606', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('RCC', 'Disease', (5, 8))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('detected', 'Reg', (25, 33))
18283	28061437	A highly significant inverse correlation of aberrant KEAP1 promoter methylation and KEAP1 mRNA expression was found in both ccRCC and PRCC samples showing a methylation value > 0,10 (Figure 2B).	('PRCC', 'Gene', '5546', (134, 138))	('methylation', 'biological_process', 'GO:0032259', ('157', '168'))	('PRCC', 'Gene', (134, 138))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))	('KEAP1', 'Gene', '9817', (53, 58))	('inverse', 'NegReg', (21, 28))	('KEAP1', 'Gene', (53, 58))	('KEAP1', 'Gene', '9817', (84, 89))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('RCC', 'Disease', (126, 129))	('aberrant', 'Var', (44, 52))	('KEAP1', 'Gene', (84, 89))	('RCC', 'Disease', 'MESH:C538614', (126, 129))
18284	28061437	However, a methylation value > 0,10 was observed only in 3% (7 out of 265) of PRCCs, thus confirming results obtained on our small cohort of an inconsistent contribution of the KEAP1 promoter epigenetic silencing in this histology, (Supplementary Figure 5).	('epigenetic silencing', 'Var', (192, 212))	('PRCC', 'Gene', (78, 82))	('methylation', 'biological_process', 'GO:0032259', ('11', '22'))	('KEAP1', 'Gene', '9817', (177, 182))	('PRCC', 'Gene', '5546', (78, 82))	('men', 'Species', '9606', (239, 242))	('KEAP1', 'Gene', (177, 182))
18287	28061437	Moreover, there was no significant association between KEAP1 methylation and disease free survival, local recurrence or overall survival.	('methylation', 'Var', (61, 72))	('KEAP1', 'Gene', '9817', (55, 60))	('local recurrence', 'CPA', (100, 116))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('KEAP1', 'Gene', (55, 60))	('disease free survival', 'CPA', (77, 98))
18290	28061437	Relevant results were summarized in Table 2: CpG methylation at exon 1 and intron 1 revealed significant association with Overall Survival (OS), grading, staging and tumor dimension.	('staging', 'CPA', (154, 161))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('CpG methylation', 'Var', (45, 60))	('Overall Survival', 'MPA', (122, 138))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('grading', 'CPA', (145, 152))	('methylation', 'biological_process', 'GO:0032259', ('49', '60'))	('OS', 'Chemical', '-', (140, 142))	('men', 'Species', '9606', (174, 177))	('association', 'Interaction', (105, 116))
18305	28061437	A growing amount of evidence suggest that an increased activity of Nrf2 due to NFE2L2 or KEAP1 mutations may play a pivotal role in the pathogenesis of many solid tumors and recently emerged as one of the main pathways implicated in Renal Carcinoma.	('solid tumors', 'Disease', (157, 169))	('NFE2L2', 'Gene', (79, 85))	('Renal Carcinoma', 'Phenotype', 'HP:0005584', (233, 248))	('KEAP1', 'Gene', '9817', (89, 94))	('Nrf2', 'Gene', (67, 71))	('activity', 'MPA', (55, 63))	('increased', 'PosReg', (45, 54))	('play', 'Reg', (109, 113))	('KEAP1', 'Gene', (89, 94))	('solid tumors', 'Disease', 'MESH:D009369', (157, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('mutations', 'Var', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('Renal Carcinoma', 'Disease', (233, 248))	('Carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('pathogenesis', 'biological_process', 'GO:0009405', ('136', '148'))	('NFE2L2', 'Gene', '4780', (79, 85))	('Renal Carcinoma', 'Disease', 'MESH:C538614', (233, 248))	('Nrf2', 'Gene', '4780', (67, 71))
18310	28061437	KEAP1 promoter epigenetic silencing as just reported in cancers as well as in the other diseases with a clear association with tumors having a low incidence of somatic mutations.	('cancers', 'Disease', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('tumors', 'Disease', (127, 133))	('KEAP1', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('epigenetic silencing', 'Var', (15, 35))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('KEAP1', 'Gene', '9817', (0, 5))
18312	28061437	As main result, an aberrant promoter KEAP1 methylation was identified in the ccRCC subset with a frequency of 49%.	('methylation', 'biological_process', 'GO:0032259', ('43', '54'))	('KEAP1', 'Gene', '9817', (37, 42))	('aberrant', 'Var', (19, 27))	('KEAP1', 'Gene', (37, 42))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
18317	28061437	Moreover, ccRCCs are heterogeneous/multifocal tumours and intra-tumoral heterogeneity could involve epigenetic changes similar to genetic and genomic events.	('intra-tumoral', 'Disease', (58, 71))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('RCC', 'Disease', (12, 15))	('multifocal tumours', 'Disease', (35, 53))	('involve', 'Reg', (92, 99))	('multifocal tumours', 'Disease', 'None', (35, 53))	('epigenetic changes', 'Var', (100, 118))	('intra-tumoral', 'Disease', 'MESH:D009369', (58, 71))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))
18318	28061437	QMSP is a highly sensitive methodology and methylation signals may be obtained even if cells that carry KEAP1 promoter methylation represent a small proportion among the majority of cells with unmethylated promoter.	('methylation', 'biological_process', 'GO:0032259', ('43', '54'))	('methylation', 'Var', (119, 130))	('KEAP1', 'Gene', '9817', (104, 109))	('KEAP1', 'Gene', (104, 109))	('methylation', 'biological_process', 'GO:0032259', ('119', '130'))
18323	28061437	In papillary RCCs, 8 out of 183 non-synonymous NFE2L2 mutations are described (4%),.	('NFE2L2', 'Gene', (47, 53))	('mutations', 'Var', (54, 63))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', (13, 16))	('NFE2L2', 'Gene', '4780', (47, 53))
18324	28061437	This result partially confirms the previous available published data that reported a low rate of inactivating mutations of CUL3 or activating mutations of NFE2L2 in sporadic PRCC2.	('PRCC', 'Gene', '5546', (174, 178))	('CUL3', 'Gene', '8452', (123, 127))	('CUL3', 'Gene', (123, 127))	('inactivating mutations', 'Var', (97, 119))	('PRCC', 'Gene', (174, 178))	('NFE2L2', 'Gene', '4780', (155, 161))	('activating', 'PosReg', (131, 141))	('NFE2L2', 'Gene', (155, 161))
18331	28061437	A clear association was observed between the hypermethylation of CpGs located in the KEAP1 promoter and an increased ccRCC tumor grading and staging, further supporting their biological relevance.	('KEAP1', 'Gene', (85, 90))	('tumor', 'Disease', (123, 128))	('hypermethylation', 'Var', (45, 61))	('CpGs', 'Protein', (65, 69))	('increased', 'PosReg', (107, 116))	('staging', 'CPA', (141, 148))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('KEAP1', 'Gene', '9817', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
18333	28061437	An increased methylation level of 5/7 CpGs was strongly associated with worse OS in ccRCCs.	('increased', 'PosReg', (3, 12))	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('methylation level', 'MPA', (13, 30))	('worse OS', 'Disease', (72, 80))	('OS', 'Chemical', '-', (78, 80))	('CpGs', 'Var', (38, 42))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))
18334	28061437	Our study reports for the first time the epigenetic modulation of KEAP1 by CpGs promoter hypermethylation as the leading mechanism of KEAP1 deregulation in ccRCC and together with recently published data on PRCC2, corroborate the hypothesis of a driver role of the Keap1/Nrf2 pathway in the ccRCCs subtypes with a specific epigenetic deregulation mechanism.	('Nrf2', 'Gene', '4780', (271, 275))	('RCC', 'Disease', 'MESH:C538614', (293, 296))	('RCC', 'Disease', (293, 296))	('KEAP1', 'Gene', '9817', (66, 71))	('KEAP1', 'Gene', (134, 139))	('Nrf2', 'Gene', (271, 275))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('Keap1', 'Gene', (265, 270))	('RCC', 'Disease', (208, 211))	('PRCC', 'Gene', '5546', (207, 211))	('Keap1', 'Gene', '9817', (265, 270))	('KEAP1', 'Gene', (66, 71))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))	('KEAP1', 'Gene', '9817', (134, 139))	('PRCC', 'Gene', (207, 211))	('epigenetic modulation', 'Var', (41, 62))
18335	28061437	In line with data from previous molecular studies, this epigenetic finding represents a new disease molecular marker for a specific subtype of RCC.	('RCC', 'Disease', (143, 146))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('epigenetic finding', 'Var', (56, 74))
18388	28061437	Proportional hazard Cox regression analysis was performed to assess the association between KEAP1 methylation and overall survival.	('KEAP1', 'Gene', (92, 97))	('Cox', 'Gene', '1351', (20, 23))	('Cox', 'Gene', (20, 23))	('association', 'Interaction', (72, 83))	('methylation', 'biological_process', 'GO:0032259', ('98', '109'))	('methylation', 'Var', (98, 109))	('KEAP1', 'Gene', '9817', (92, 97))
18390	31139560	Significance of PTEN Mutation in Cellular Process, Prognosis, and Drug Selection in Clear Cell Renal Cell Carcinoma It is well established that the PTEN (Phosphatase and Tensin Homolog) mutant is a frequently mutated gene found in clear cell renal cell carcinoma (ccRCC), making it a potential biomarker for individualized treatment opinions.	('PTEN', 'Gene', (148, 152))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (242, 262))	('RCC', 'Disease', (266, 269))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (231, 262))	('RCC', 'Phenotype', 'HP:0005584', (266, 269))	('ccRCC', 'Phenotype', 'HP:0006770', (264, 269))	('PTEN', 'Gene', '5728', (16, 20))	('Clear Cell Renal Cell Carcinoma', 'Disease', (84, 115))	('Cellular Process', 'biological_process', 'GO:0009987', ('33', '49'))	('PTEN', 'Gene', '5728', (148, 152))	('RCC', 'Disease', 'MESH:C538614', (266, 269))	('clear cell renal cell carcinoma', 'Disease', (231, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (84, 115))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (95, 115))	('Carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('Cellular Process', 'cellular_component', 'GO:0042995', ('33', '49'))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (231, 262))	('mutant', 'Var', (186, 192))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (84, 115))	('PTEN', 'Gene', (16, 20))	('Phosphatase', 'molecular_function', 'GO:0016791', ('154', '165'))	('Phosphatase and Tensin Homolog', 'cellular_component', 'GO:1990455', ('154', '184'))
18391	31139560	Here, in the present study, we designed a method to evaluate the significance of the PTEN mutation in the prognosis and drug selection of ccRCC, determine the potential changing pathways and genes associated with the mechanisms.	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('PTEN', 'Gene', '5728', (85, 89))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('PTEN', 'Gene', (85, 89))	('RCC', 'Disease', (140, 143))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('mutation', 'Var', (90, 98))
18392	31139560	The most recent TCGA data shows that the PTEN mutation is found in 5% of ccRCC patients.	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('patients', 'Species', '9606', (79, 87))	('PTEN', 'Gene', (41, 45))	('mutation', 'Var', (46, 54))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))	('PTEN', 'Gene', '5728', (41, 45))
18393	31139560	What is more, patients with the PTEN mutation were associated with a worsened prognosis of ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('RCC', 'Disease', (93, 96))	('mutation', 'Var', (37, 45))	('PTEN', 'Gene', (32, 36))	('PTEN', 'Gene', '5728', (32, 36))	('patients', 'Species', '9606', (14, 22))
18394	31139560	Data from the GDSC database indicated that the selective AKT inhibitor, GSK690693, is a selective inhibitor for ccRCC with the PTEN mutation.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('RCC', 'Disease', (114, 117))	('GSK690693', 'Chemical', 'MESH:C528328', (72, 81))	('PTEN', 'Gene', '5728', (127, 131))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('GSK', 'molecular_function', 'GO:0050321', ('72', '75'))	('AKT', 'Gene', '207', (57, 60))	('PTEN', 'Gene', (127, 131))	('mutation', 'Var', (132, 140))	('AKT', 'Gene', (57, 60))
18395	31139560	Our findings have indicated that multiple genes and pathways may play a crucial role in PTEN mutation ccRCC, offering candidate targets and strategies for PTEN mutation ccRCC individualized treatment.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('PTEN', 'Gene', (155, 159))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('PTEN', 'Gene', '5728', (155, 159))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('PTEN', 'Gene', (88, 92))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('PTEN', 'Gene', '5728', (88, 92))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('RCC', 'Disease', (171, 174))	('mutation', 'Var', (93, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))	('RCC', 'Disease', (104, 107))
18398	31139560	Recent next-generation sequencing results revealed major frequent mutations including VHL, PBRM1, SETD2, BAP1, and KDM5C, thus dividing patients with different mutation types into different prognostic subtypes of ccRCC.	('mutations', 'Var', (66, 75))	('KDM5C', 'Gene', (115, 120))	('PBRM1', 'Gene', (91, 96))	('PBRM1', 'Gene', '55193', (91, 96))	('SETD2', 'Gene', '29072', (98, 103))	('KDM5C', 'Gene', '8242', (115, 120))	('RCC', 'Disease', 'MESH:C538614', (215, 218))	('ccRCC', 'Phenotype', 'HP:0006770', (213, 218))	('RCC', 'Disease', (215, 218))	('BAP1', 'Gene', '8314', (105, 109))	('SETD2', 'Gene', (98, 103))	('RCC', 'Phenotype', 'HP:0005584', (215, 218))	('patients', 'Species', '9606', (136, 144))	('VHL', 'Gene', (86, 89))	('BAP1', 'Gene', (105, 109))	('VHL', 'Gene', '7428', (86, 89))
18402	31139560	PTEN (Phosphatase And Tensin Homolog), which contains a tensin like domain as well as a catalytic domain, similar to that of the dual specificity protein tyrosine phosphatases, serves as a multi-functional tumor suppressor that is mutated in a large number of cancers at high frequency, including ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (299, 302))	('ccRCC', 'Phenotype', 'HP:0006770', (297, 302))	('cancers', 'Disease', 'MESH:D009369', (260, 267))	('tumor suppressor', 'biological_process', 'GO:0051726', ('206', '222'))	('multi-functional tumor', 'Disease', 'MESH:D015140', (189, 211))	('Phosphatase', 'molecular_function', 'GO:0016791', ('6', '17'))	('RCC', 'Disease', 'MESH:C538614', (299, 302))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('Phosphatase And Tensin Homolog', 'cellular_component', 'GO:1990455', ('6', '36'))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('cancers', 'Phenotype', 'HP:0002664', (260, 267))	('cancers', 'Disease', (260, 267))	('PTEN', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('multi-functional tumor', 'Disease', (189, 211))	('mutated', 'Var', (231, 238))	('RCC', 'Disease', (299, 302))	('PTEN', 'Gene', '5728', (0, 4))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('206', '222'))
18403	31139560	Alterations in PTEN expression may predispose RCC formation, which has potential prognostic and clinical significance.	('formation', 'biological_process', 'GO:0009058', ('50', '59'))	('RCC', 'Disease', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('predispose', 'Reg', (35, 45))	('Alterations', 'Var', (0, 11))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('PTEN', 'Gene', (15, 19))	('PTEN', 'Gene', '5728', (15, 19))
18406	31139560	Various signaling pathways and cell metabolic progressions might change in patients with the PTEN mutation compared to PTEN-wild type patients.	('PTEN', 'Gene', (93, 97))	('mutation', 'Var', (98, 106))	('PTEN', 'Gene', '5728', (93, 97))	('cell metabolic progressions', 'CPA', (31, 58))	('patients', 'Species', '9606', (75, 83))	('patients', 'Species', '9606', (134, 142))	('change', 'Reg', (65, 71))	('signaling', 'biological_process', 'GO:0023052', ('8', '17'))	('PTEN', 'Gene', (119, 123))	('PTEN', 'Gene', '5728', (119, 123))	('signaling pathways', 'Pathway', (8, 26))
18408	31139560	Therefore, exploring the changes in various signaling pathways in patients with the PTEN mutation, and evaluating the significance in disease progression, will help us further understand the pathogenesis of the disease, providing more evidence for individualized treatment of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (278, 281))	('RCC', 'Disease', (278, 281))	('mutation', 'Var', (89, 97))	('PTEN', 'Gene', (84, 88))	('pathogenesis', 'biological_process', 'GO:0009405', ('191', '203'))	('signaling', 'biological_process', 'GO:0023052', ('44', '53'))	('PTEN', 'Gene', '5728', (84, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (276, 281))	('RCC', 'Phenotype', 'HP:0005584', (278, 281))	('patients', 'Species', '9606', (66, 74))
18409	31139560	In this study, we analyzed an RNA sequencing (RNA-Seq) dataset of ccRCC and the GDSC database to identify the key pathways and genes associated with the PTEN mutation using bioinformatics analysis approaches, and evaluated the significance in drug selection, expecting to uncover the potential role of the PTEN mutation in serving as a prediction factor for prognosis and individualized treatment options.	('PTEN', 'Gene', (306, 310))	('PTEN', 'Gene', '5728', (306, 310))	('PTEN', 'Gene', (153, 157))	('mutation', 'Var', (158, 166))	('PTEN', 'Gene', '5728', (153, 157))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('RNA', 'cellular_component', 'GO:0005562', ('46', '49'))	('RNA', 'cellular_component', 'GO:0005562', ('30', '33'))
18411	31139560	The corresponding information related to patients with the PTEN mutation was obtained from the cBioPortal for Cancer Genomics website (http://www.cbioportal.org/index.do).	('Cancer', 'Disease', 'MESH:D009369', (110, 116))	('mutation', 'Var', (64, 72))	('patients', 'Species', '9606', (41, 49))	('Cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Cancer', 'Disease', (110, 116))	('PTEN', 'Gene', (59, 63))	('PTEN', 'Gene', '5728', (59, 63))
18415	31139560	We analyzed GSEA v3.0 (http://software.broadinstitute.org/gsea/downloads.jsp) to dig out the differences in gene mRNA expression levels of biological functional annotation and pathways between PTEN mutation and wild-type patients, which helped us understand the effects of the PTEN mutation on various biological function gene sets, in renal clear cell carcinoma patients.	('renal clear cell carcinoma', 'Disease', (336, 362))	('gsea', 'Chemical', '-', (58, 62))	('patients', 'Species', '9606', (221, 229))	('patients', 'Species', '9606', (363, 371))	('PTEN', 'Gene', (193, 197))	('PTEN', 'Gene', '5728', (193, 197))	('PTEN', 'Gene', (277, 281))	('GSEA', 'Chemical', '-', (12, 16))	('PTEN', 'Gene', '5728', (277, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (353, 362))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (336, 362))	('mutation', 'Var', (198, 206))
18416	31139560	The EdgeR, an R package for examining differential expression of RNA-Seq count data, was used according to the user's guide for screening differential expression of genes at gene levels between the PTEN mutation and wild-type renal clear cell carcinoma patients.	('RNA', 'cellular_component', 'GO:0005562', ('65', '68'))	('-type renal clear cell carcinoma', 'Phenotype', 'HP:0006770', (220, 252))	('renal clear cell carcinoma', 'Disease', (226, 252))	('patients', 'Species', '9606', (253, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('PTEN', 'Gene', (198, 202))	('mutation', 'Var', (203, 211))	('PTEN', 'Gene', '5728', (198, 202))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (226, 252))
18417	31139560	The Student's t-test was used to compare the PTEN mRNA expression level between the PTEN mutation and wild-type renal clear cell carcinoma tissue.	('mutation', 'Var', (89, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('PTEN', 'Gene', (84, 88))	('PTEN', 'Gene', '5728', (84, 88))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (112, 138))	('PTEN', 'Gene', (45, 49))	('-type renal clear cell carcinoma', 'Phenotype', 'HP:0006770', (106, 138))	('PTEN', 'Gene', '5728', (45, 49))	('renal clear cell carcinoma', 'Disease', (112, 138))
18421	31139560	There were 23 renal clear cell carcinoma patients (5%) with the PTEN mutation and the rest had the PTEN wild type (Figure 1A).	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (14, 40))	('PTEN', 'Gene', '5728', (64, 68))	('renal clear cell carcinoma', 'Disease', (14, 40))	('mutation', 'Var', (69, 77))	('patients', 'Species', '9606', (41, 49))	('PTEN', 'Gene', (64, 68))	('PTEN', 'Gene', (99, 103))	('PTEN', 'Gene', '5728', (99, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
18425	31139560	We first determined the PTEN mRNA expression level in the wild type and mutated group.	('PTEN', 'Gene', '5728', (24, 28))	('mutated', 'Var', (72, 79))	('PTEN', 'Gene', (24, 28))
18426	31139560	Results showed that PTEN downregulated in mutated ccRCC patients' tumor tissue (Figure 2A).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('patients', 'Species', '9606', (56, 64))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('mutated', 'Var', (42, 49))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (50, 55))	('tumor', 'Disease', (66, 71))	('RCC', 'Disease', (52, 55))	('downregulated', 'NegReg', (25, 38))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('PTEN', 'Gene', (20, 24))	('PTEN', 'Gene', '5728', (20, 24))
18427	31139560	Analysis of the relationship between the PTEN status and disease prognosis showed that patients with the PTEN mutation had poorer prognosis on survival (Figure 2B) and disease recurrence (Figure 2C), which indicated that the PTEN mutation may contribute to ccRCC disease progression.	('poorer', 'NegReg', (123, 129))	('RCC', 'Phenotype', 'HP:0005584', (259, 262))	('PTEN', 'Gene', (105, 109))	('PTEN', 'Gene', (225, 229))	('contribute', 'Reg', (243, 253))	('PTEN', 'Gene', '5728', (225, 229))	('RCC', 'Disease', (259, 262))	('RCC', 'Disease', 'MESH:C538614', (259, 262))	('PTEN', 'Gene', '5728', (105, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (257, 262))	('mutation', 'Var', (110, 118))	('PTEN', 'Gene', (41, 45))	('patients', 'Species', '9606', (87, 95))	('PTEN', 'Gene', '5728', (41, 45))
18428	31139560	Early intervention may be beneficial to patients with the PTEN mutation.	('patients', 'Species', '9606', (40, 48))	('PTEN', 'Gene', '5728', (58, 62))	('PTEN', 'Gene', (58, 62))	('mutation', 'Var', (63, 71))
18431	31139560	With the scope of exploiting potent tumor inhibitors to help ccRCC individualized treatment, we studied the GDSC database to find whether PTEN mutated patients have potential selective compounds.	('RCC', 'Disease', (63, 66))	('PTEN', 'Gene', (138, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('PTEN', 'Gene', '5728', (138, 142))	('patients', 'Species', '9606', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mutated', 'Var', (143, 150))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('tumor', 'Disease', (36, 41))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
18432	31139560	Results showed that GSK690693 was a significant selectivity for the PTEN mutation in various cancer types (Figure 2D), making it a potential compound for patients with the PTEN mutation.	('cancer', 'Disease', (93, 99))	('PTEN', 'Gene', '5728', (172, 176))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('patients', 'Species', '9606', (154, 162))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('PTEN', 'Gene', (68, 72))	('PTEN', 'Gene', '5728', (68, 72))	('GSK', 'molecular_function', 'GO:0050321', ('20', '23'))	('GSK690693', 'Chemical', 'MESH:C528328', (20, 29))	('mutation', 'Var', (73, 81))	('GSK690693', 'Var', (20, 29))	('PTEN', 'Gene', (172, 176))
18433	31139560	We then studied the tissue specificity of GSK690693 and found that it exhibited sensitivity for renal cell carcinoma harboring the PTEN mutation in the GDSC database (Figures 2E,F).	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (96, 116))	('PTEN', 'Gene', (131, 135))	('mutation', 'Var', (136, 144))	('PTEN', 'Gene', '5728', (131, 135))	('renal cell carcinoma', 'Disease', (96, 116))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (96, 116))	('GSK', 'molecular_function', 'GO:0050321', ('42', '45'))	('GSK690693', 'Chemical', 'MESH:C528328', (42, 51))
18434	31139560	Altogether, we showed that GSK690693, a pan-Akt inhibitor targeting Akt1/2/3, conferred selective inhibition in ccRCC cells with the PTEN mutation, which made it a potential individualized compound for such ccRCC patients.	('RCC', 'Phenotype', 'HP:0005584', (209, 212))	('mutation', 'Var', (138, 146))	('PTEN', 'Gene', '5728', (133, 137))	('RCC', 'Disease', (209, 212))	('patients', 'Species', '9606', (213, 221))	('Akt1/2/3', 'Gene', '207;208;10000', (68, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('Akt', 'Gene', (44, 47))	('RCC', 'Disease', 'MESH:C538614', (209, 212))	('Akt', 'Gene', (68, 71))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (207, 212))	('Akt', 'Gene', '207', (44, 47))	('Akt', 'Gene', '207', (68, 71))	('inhibition', 'NegReg', (98, 108))	('GSK', 'molecular_function', 'GO:0050321', ('27', '30'))	('GSK690693', 'Chemical', 'MESH:C528328', (27, 36))	('Akt1/2/3', 'Gene', (68, 76))	('PTEN', 'Gene', (133, 137))	('GSK690693', 'Var', (27, 36))
18435	31139560	All results above shows that the PTEN mutation plays a critical role in ccRCC progression, prognosis and drug selection.	('PTEN', 'Gene', (33, 37))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('PTEN', 'Gene', '5728', (33, 37))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('mutation', 'Var', (38, 46))
18436	31139560	To investigate the mechanism and to obtain some evidence, we first analyzed the effects of the PTEN mutation on cellular processes.	('mutation', 'Var', (100, 108))	('PTEN', 'Gene', (95, 99))	('PTEN', 'Gene', '5728', (95, 99))
18439	31139560	These suggest that the PTEN mutation may promote ccRCC progression by influencing multiple pathways in cancer, migration, DNA repair and metabolism.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('DNA repair', 'biological_process', 'GO:0006281', ('122', '132'))	('influencing', 'Reg', (70, 81))	('PTEN', 'Gene', (23, 27))	('promote', 'PosReg', (41, 48))	('metabolism', 'biological_process', 'GO:0008152', ('137', '147'))	('mutation', 'Var', (28, 36))	('PTEN', 'Gene', '5728', (23, 27))	('DNA', 'cellular_component', 'GO:0005574', ('122', '125'))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('metabolism', 'CPA', (137, 147))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
18449	31139560	PTEN deletions and/or mutations are associated with a variety of human cancers, including renal cell carcinoma.	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (90, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('cancers', 'Disease', (71, 78))	('PTEN', 'Gene', '5728', (0, 4))	('PTEN', 'Gene', (0, 4))	('mutations', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('associated', 'Reg', (36, 46))	('renal cell carcinoma', 'Disease', (90, 110))	('deletions', 'Var', (5, 14))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (90, 110))
18450	31139560	In this study, we intended to evaluate the clinical significance of the PTEN mutation in ccRCC progression, prognosis, and drug selection to promote individualized treatment.	('PTEN', 'Gene', (72, 76))	('mutation', 'Var', (77, 85))	('PTEN', 'Gene', '5728', (72, 76))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (89, 94))	('RCC', 'Disease', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))
18451	31139560	We found that about 5% of patients carried the PTEN mutation among 538 cases, including amplification, truncating, deep deletion, inframe mutation, and missense mutations spanning across the entire gene.	('missense mutations', 'Var', (152, 170))	('deep deletion', 'Var', (115, 128))	('patients', 'Species', '9606', (26, 34))	('PTEN', 'Gene', (47, 51))	('mutation', 'Var', (52, 60))	('PTEN', 'Gene', '5728', (47, 51))	('truncating', 'MPA', (103, 113))
18452	31139560	Clinical analysis showed that ccRCC patients with the PTEN mutation have a significantly poorer prognosis in survival and disease recurrence.	('poorer', 'NegReg', (89, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('patients', 'Species', '9606', (36, 44))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('PTEN', 'Gene', (54, 58))	('mutation', 'Var', (59, 67))	('PTEN', 'Gene', '5728', (54, 58))	('survival', 'CPA', (109, 117))
18453	31139560	All these results indicate the significance of the clinical practice of the PTEN mutation in ccRCC patients, consistent with some recent research.	('PTEN', 'Gene', (76, 80))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('PTEN', 'Gene', '5728', (76, 80))	('mutation', 'Var', (81, 89))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('patients', 'Species', '9606', (99, 107))	('RCC', 'Disease', (95, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))
18454	31139560	The detection of tumor gene mutations has been applied to the clinic, which can help clinicians judge the prognosis of patients and effectively select better individualized treatment strategies.	('tumor', 'Disease', (17, 22))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('mutations', 'Var', (28, 37))
18455	31139560	Our results provide evidence that ccRCC patients with the PTEN mutation are more prone to distant metastasis and that the prognosis of the disease is poorer, indicating that early intervention is required for such patients to obtain a longer survival period.	('distant metastasis', 'CPA', (90, 108))	('PTEN', 'Gene', '5728', (58, 62))	('patients', 'Species', '9606', (214, 222))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('patients', 'Species', '9606', (40, 48))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (34, 39))	('prone', 'Reg', (81, 86))	('mutation', 'Var', (63, 71))	('PTEN', 'Gene', (58, 62))
18456	31139560	CcRCC patients with the PTEN mutation may require more frequent follow-ups and more comprehensive examinations to detect early metastatic tumor tissues, or an earlier application of targeted drugs to cope with poor disease prognosis.	('mutation', 'Var', (29, 37))	('PTEN', 'Gene', '5728', (24, 28))	('tumor', 'Disease', (138, 143))	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('patients', 'Species', '9606', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('PTEN', 'Gene', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
18457	31139560	What is more, data from the GDSC showed preliminary evidence that GSK690693 exhibited sensitivity for renal cell carcinoma harboring the PTEN mutation, which provides more evidence for the application of specific anti-tumor drugs to such patients and provides a basis for further research.	('GSK690693', 'Chemical', 'MESH:C528328', (66, 75))	('GSK', 'molecular_function', 'GO:0050321', ('66', '69'))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('renal cell carcinoma', 'Disease', (102, 122))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('PTEN', 'Gene', '5728', (137, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('PTEN', 'Gene', (137, 141))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (102, 122))	('mutation', 'Var', (142, 150))	('tumor', 'Disease', (218, 223))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (102, 122))	('patients', 'Species', '9606', (238, 246))	('GSK690693', 'Var', (66, 75))
18458	31139560	Maybe in the future, this compound could be used in targeted drugs for ccRCC patients with the PTEN mutation for individualized treatment.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('RCC', 'Disease', (73, 76))	('mutation', 'Var', (100, 108))	('patients', 'Species', '9606', (77, 85))	('PTEN', 'Gene', (95, 99))	('PTEN', 'Gene', '5728', (95, 99))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
18459	31139560	As for the mechanisms, we analyzed the RNA-Seq dataset of ccRCC downloaded from TCGA to identify the key pathways and genes associated with the PTEN mutation, using bioinformatics analysis approaches.	('PTEN', 'Gene', '5728', (144, 148))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('PTEN', 'Gene', (144, 148))	('RNA', 'cellular_component', 'GO:0005562', ('39', '42'))	('mutation', 'Var', (149, 157))
18460	31139560	GSEA analysis in the present study suggests that the PTEN mutation is significantly associated with multiple cancer related pathways, epithelial mesenchymal transition (EMT), DNA repair, and metabolism, such as glycolysis, hypoxia, mTORC1 signaling, MYC targets v2, E2F targets, DNA repair, and interferon alpha response.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('DNA', 'cellular_component', 'GO:0005574', ('279', '282'))	('PTEN', 'Gene', (53, 57))	('epithelial mesenchymal transition', 'CPA', (134, 167))	('DNA repair', 'MPA', (175, 185))	('DNA repair', 'biological_process', 'GO:0006281', ('175', '185'))	('mTORC1', 'Gene', (232, 238))	('MYC', 'Gene', '4609', (250, 253))	('metabolism', 'biological_process', 'GO:0008152', ('191', '201'))	('mutation', 'Var', (58, 66))	('associated', 'Reg', (84, 94))	('PTEN', 'Gene', '5728', (53, 57))	('mTORC1', 'Gene', '382056', (232, 238))	('DNA repair', 'biological_process', 'GO:0006281', ('279', '289'))	('hypoxia', 'Disease', (223, 230))	('GSEA', 'Chemical', '-', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('175', '178'))	('glycolysis', 'MPA', (211, 221))	('glycolysis', 'biological_process', 'GO:0006096', ('211', '221'))	('cancer', 'Disease', (109, 115))	('metabolism', 'MPA', (191, 201))	('epithelial mesenchymal transition', 'biological_process', 'GO:0001837', ('134', '167'))	('hypoxia', 'Disease', 'MESH:D000860', (223, 230))	('signaling', 'biological_process', 'GO:0023052', ('239', '248'))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('EMT', 'biological_process', 'GO:0001837', ('169', '172'))	('mTORC1', 'cellular_component', 'GO:0031931', ('232', '238'))	('MYC', 'Gene', (250, 253))
18462	31139560	Our results indicated that the tumors of patients with the PTEN mutation may be more prone to distant metastasis, supporting its value in clinical applications.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mutation', 'Var', (64, 72))	('distant metastasis', 'CPA', (94, 112))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('patients', 'Species', '9606', (41, 49))	('prone', 'Reg', (85, 90))	('PTEN', 'Gene', (59, 63))	('PTEN', 'Gene', '5728', (59, 63))
18463	31139560	As PTEN is one of the key inhibitors of the PI3K-AKT signaling pathway, the PTEN mutation definitely affects the activity of the mTORC1 signaling pathway.	('PTEN', 'Gene', (3, 7))	('PI3K', 'molecular_function', 'GO:0016303', ('44', '48'))	('AKT', 'Gene', (49, 52))	('PTEN', 'Gene', '5728', (3, 7))	('signaling pathway', 'biological_process', 'GO:0007165', ('53', '70'))	('PTEN', 'Gene', (76, 80))	('mTORC1', 'cellular_component', 'GO:0031931', ('129', '135'))	('mutation', 'Var', (81, 89))	('PTEN', 'Gene', '5728', (76, 80))	('mTORC1', 'Gene', (129, 135))	('AKT signaling', 'biological_process', 'GO:0043491', ('49', '62'))	('signaling pathway', 'biological_process', 'GO:0007165', ('136', '153'))	('activity', 'MPA', (113, 121))	('AKT', 'Gene', '207', (49, 52))	('mTORC1', 'Gene', '382056', (129, 135))	('affects', 'Reg', (101, 108))
18465	31139560	An enrichment analysis indicated that DEGs in the PTEN mutation ccRCC patients were related to biological processes of muscle contraction, G-protein coupled receptor signaling pathway, metabolism, DNA replication, and nucleosome assembly, which implies that patients with the PTEN mutation might have more vigorous cell energy metabolism and cell growth.	('metabolism', 'biological_process', 'GO:0008152', ('327', '337'))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('PTEN', 'Gene', '5728', (276, 280))	('cell energy metabolism', 'CPA', (315, 337))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('patients', 'Species', '9606', (70, 78))	('DNA', 'cellular_component', 'GO:0005574', ('197', '200'))	('mutation', 'Var', (281, 289))	('cell growth', 'biological_process', 'GO:0016049', ('342', '353'))	('PTEN', 'Gene', (50, 54))	('cell growth', 'CPA', (342, 353))	('patients', 'Species', '9606', (258, 266))	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('more', 'PosReg', (301, 305))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('metabolism', 'biological_process', 'GO:0008152', ('185', '195'))	('PTEN', 'Gene', '5728', (50, 54))	('nucleosome', 'cellular_component', 'GO:0000786', ('218', '228'))	('mutation', 'Var', (55, 63))	('G-protein coupled receptor signaling pathway', 'biological_process', 'GO:0007186', ('139', '183'))	('PTEN', 'Gene', (276, 280))	('nucleosome assembly', 'biological_process', 'GO:0006334', ('218', '237'))	('muscle contraction', 'biological_process', 'GO:0006936', ('119', '137'))	('DNA replication', 'biological_process', 'GO:0006260', ('197', '212'))
18468	31139560	Therefore, the analysis above suggests the function of the PTEN mutation in cellular progression and provides insight into the promising therapeutic target in patients with the PTEN mutation for individualized treatment opinions.	('cellular progression', 'CPA', (76, 96))	('mutation', 'Var', (64, 72))	('PTEN', 'Gene', (177, 181))	('PTEN', 'Gene', '5728', (177, 181))	('patients', 'Species', '9606', (159, 167))	('PTEN', 'Gene', (59, 63))	('PTEN', 'Gene', '5728', (59, 63))
18471	31139560	The KEGG and GO analysis of the top three significant modules in the PPI network showed enrichment in DNA replication, nucleosome assembly, G protein- coupled receptors (GPCR) signaling pathway and telomere metabolism, indicating that tumors with the PTEN mutation tend to be more active in cell division and cell signaling transport.	('more active', 'PosReg', (276, 287))	('PTEN', 'Gene', '5728', (251, 255))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('signaling', 'biological_process', 'GO:0023052', ('314', '323'))	('nucleosome', 'cellular_component', 'GO:0000786', ('119', '129'))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('nucleosome assembly', 'biological_process', 'GO:0006334', ('119', '138'))	('cell signaling transport', 'CPA', (309, 333))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('cell division', 'biological_process', 'GO:0051301', ('291', '304'))	('metabolism', 'biological_process', 'GO:0008152', ('207', '217'))	('mutation', 'Var', (256, 264))	('transport', 'biological_process', 'GO:0006810', ('324', '333'))	('DNA replication', 'biological_process', 'GO:0006260', ('102', '117'))	('PPI', 'biological_process', 'GO:0060134', ('69', '72'))	('tumors', 'Disease', (235, 241))	('cell division', 'CPA', (291, 304))	('telomere', 'cellular_component', 'GO:0000781', ('198', '206'))	('GPCR) signaling pathway', 'biological_process', 'GO:0007186', ('170', '193'))	('telomere', 'cellular_component', 'GO:0005696', ('198', '206'))	('PTEN', 'Gene', (251, 255))	('tumors', 'Disease', 'MESH:D009369', (235, 241))
18473	31139560	The mechanism and validation of the PTEN mutation in ccRCC still needs to be further researched in clinical and molecular biology experiments.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('RCC', 'Disease', (55, 58))	('PTEN', 'Gene', (36, 40))	('mutation', 'Var', (41, 49))	('PTEN', 'Gene', '5728', (36, 40))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
18474	31139560	In conclusion, this study determined the main pathways and genes associated with the PTEN mutation in ccRCC, which may facilitate the development of the PTEN mutation to improve ccRCC risk prediction through the development of therapeutic strategies against such special subtypes of ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Phenotype', 'HP:0005584', (285, 288))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('ccRCC', 'Phenotype', 'HP:0006770', (283, 288))	('RCC', 'Disease', (180, 183))	('RCC', 'Phenotype', 'HP:0005584', (180, 183))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (178, 183))	('PTEN', 'Gene', (153, 157))	('PTEN', 'Gene', '5728', (153, 157))	('RCC', 'Disease', (285, 288))	('PTEN', 'Gene', (85, 89))	('PTEN', 'Gene', '5728', (85, 89))	('mutation', 'Var', (90, 98))	('RCC', 'Disease', 'MESH:C538614', (285, 288))	('RCC', 'Disease', (104, 107))
18485	33066813	High SHMT2 expression is associated with poor overall survival in patients with kidney cancer.	('SHMT2', 'Gene', '6472', (5, 10))	('expression', 'Species', '29278', (11, 21))	('High', 'Var', (0, 4))	('kidney cancer', 'Disease', 'MESH:D007680', (80, 93))	('expression', 'MPA', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('kidney cancer', 'Phenotype', 'HP:0009726', (80, 93))	('overall', 'MPA', (46, 53))	('kidney cancer', 'Disease', (80, 93))	('SHMT2', 'Gene', (5, 10))	('patients', 'Species', '9606', (66, 74))
18487	33066813	SHMT2 overexpression led to the increased expression of NDUFA4L2 at both mRNA and protein levels.	('expression', 'Species', '29278', (42, 52))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('SHMT2', 'Gene', '6472', (0, 5))	('overexpression', 'Var', (6, 20))	('NDUFA4L2', 'Gene', (56, 64))	('expression', 'MPA', (42, 52))	('expression', 'Species', '29278', (10, 20))	('increased', 'PosReg', (32, 41))	('NDUFA4L2', 'Gene', '56901', (56, 64))	('SHMT2', 'Gene', (0, 5))
18530	33066813	Our results indicated that SHMT2 was overexpressed in age (41-60 years) and (61-80 years) group compared to age (21-40 years) group (P < 0.05).	('SHMT2', 'Gene', '6472', (27, 32))	('SHMT2', 'Gene', (27, 32))	('overexpressed', 'PosReg', (37, 50))	('61-80 years', 'Var', (77, 88))
18535	33066813	3b, we found that overexpressed SHMT2 is associated with worse overall survival (OS) patients with renal clear cell carcinoma, with P = 0.033 and HR = 1.41 (1.03-1.94).	('renal clear cell carcinoma', 'Disease', (99, 125))	('overall survival', 'MPA', (63, 79))	('overexpressed', 'Var', (18, 31))	('SHMT2', 'Gene', '6472', (32, 37))	('patients', 'Species', '9606', (85, 93))	('SHMT2', 'Gene', (32, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (99, 125))	('worse', 'NegReg', (57, 62))
18536	33066813	For patients with renal papillary cell carcinoma, we found that high expressedSHMT2 are also correlated with poor overall survival compared to those with low expression, with P = 0.0024, HR = 2.45 (1.35-4.44), using the median as the cutoff value (Fig.	('SHMT2', 'Gene', '6472', (78, 83))	('overall survival', 'MPA', (114, 130))	('high', 'Var', (64, 68))	('expression', 'Species', '29278', (158, 168))	('renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (18, 48))	('poor', 'NegReg', (109, 113))	('renal papillary cell carcinoma', 'Disease', (18, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('patients', 'Species', '9606', (4, 12))	('SHMT2', 'Gene', (78, 83))
18571	33066813	Their studies showed that deacetylation of SHMT2 by SIRT3 could enhance colorectal carcinogenesis and was correlated with poorer postoperative overall survival.	('colorectal carcinogenesis', 'Disease', (72, 97))	('enhance', 'PosReg', (64, 71))	('colorectal carcinogenesis', 'Disease', 'MESH:D015179', (72, 97))	('SHMT2', 'Gene', '6472', (43, 48))	('SIRT3', 'Gene', (52, 57))	('SHMT2', 'Gene', (43, 48))	('poorer', 'NegReg', (122, 128))	('deacetylation', 'Var', (26, 39))
18603	30984181	When exploring the impact of nRCT on the phenotype of rectal cancer-infiltrating pDCs and slanMo, we observed that nRCT markedly enhances the percentage of inducible nitric oxide synthase (iNOS)- or tumor necrosis factor (TNF) alpha-producing slanMo.	('necrosis', 'biological_process', 'GO:0070265', ('205', '213'))	('inducible nitric oxide synthase', 'Gene', '4843', (156, 187))	('necrosis', 'biological_process', 'GO:0008219', ('205', '213'))	('rectal cancer', 'Phenotype', 'HP:0100743', (54, 67))	('enhances', 'PosReg', (129, 137))	('necrosis', 'biological_process', 'GO:0019835', ('205', '213'))	('necrosis', 'biological_process', 'GO:0001906', ('205', '213'))	('necrosis', 'biological_process', 'GO:0008220', ('205', '213'))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('rectal cancer', 'Disease', 'MESH:D012004', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('199', '220'))	('tumor necrosis factor (TNF) alpha', 'Gene', '7124', (199, 232))	('inducible nitric oxide synthase', 'Gene', (156, 187))	('nRCT', 'Var', (115, 119))	('rectal cancer', 'Disease', (54, 67))
18610	30984181	However, patients with high expression of Th17 genes had a poor prognosis.	('high', 'Var', (23, 27))	('patients', 'Species', '9606', (9, 17))	('Th1', 'Gene', '51497', (42, 45))	('Th1', 'Gene', (42, 45))
18624	30984181	In addition, pDCs can efficiently enhance the antitumoral capabilities of natural killer (NK) cells and T lymphocytes.	('T lymphocytes', 'CPA', (104, 117))	('enhance', 'PosReg', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('pDCs', 'Var', (13, 17))	('tumor', 'Disease', (50, 55))
18629	30984181	Previous studies have shown that pDCs infiltrate a variety of human cancers including head and neck, breast and ovarian cancer, and that a higher density is associated with poor clinical outcome.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('human', 'Species', '9606', (62, 67))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (101, 126))	('cancers', 'Disease', (68, 75))	('pDCs', 'Var', (33, 37))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('infiltrate', 'Reg', (38, 48))	('ovarian cancer', 'Phenotype', 'HP:0100615', (112, 126))	('neck', 'cellular_component', 'GO:0044326', ('95', '99'))
18695	30984181	In contrast, nRCT significantly increased the frequency of total CD8+ T cells in the nRCT-treated cohort (429.9 +- 284.2 CD8+ T cells/mm2) compared to the untreated cohort (286.8 +- 162.6 CD8+ T cells/mm2) as depicted in Figure 4B.	('CD8', 'Gene', (188, 191))	('CD8', 'Gene', '925', (188, 191))	('CD8', 'Gene', (65, 68))	('CD8', 'Gene', '925', (65, 68))	('increased', 'PosReg', (32, 41))	('CD8', 'Gene', (121, 124))	('CD8', 'Gene', '925', (121, 124))	('429.9', 'Var', (106, 111))
18705	30984181	In contrast, iNOS+ slanMo were only found in 2 out of 10 pre-nRCT rectal cancer tissues, while TNF-alpha+ slanMo were absent in these tissues (Figures 6C,D).	('TNF-alpha', 'Gene', (95, 104))	('iNOS+ slanMo', 'Var', (13, 25))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('rectal cancer', 'Disease', 'MESH:D012004', (66, 79))	('rectal cancer', 'Disease', (66, 79))	('TNF-alpha', 'Gene', '7124', (95, 104))	('pre', 'molecular_function', 'GO:0003904', ('57', '60'))	('rectal cancer', 'Phenotype', 'HP:0100743', (66, 79))
18706	30984181	As depicted in Figure 6E, the proportion of iNOS+ slanMo was significantly higher in post-nRCT tumor tissues (26 +- 24% iNOS+ slanMo) compared to pre-nRCT tumor specimen (1 +- 2% iNOS+ slanMo).	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('higher', 'PosReg', (75, 81))	('tumor', 'Disease', (155, 160))	('pre', 'molecular_function', 'GO:0003904', ('146', '149'))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('iNOS+ slanMo', 'Var', (44, 56))	('tumor', 'Disease', (95, 100))
18740	30984181	When exploring the influence of nRCT on the number of infiltrating pDCs and slanMo in rectal cancer, we found a significantly higher number of pDCs in nRCT-treated tissue specimens, whereas the frequency of slanMo remained stable after nRCT.	('higher', 'PosReg', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('rectal cancer', 'Disease', 'MESH:D012004', (86, 99))	('rectal cancer', 'Disease', (86, 99))	('pDCs', 'Var', (143, 147))	('rectal cancer', 'Phenotype', 'HP:0100743', (86, 99))
18780	30984181	Moreover, we demonstrated for the first time that nRCT results in an accumulation of pDCs as well as an increased proportion of CD83- and IFN-alpha-expressing pDCs in rectal cancer.	('rectal cancer', 'Disease', 'MESH:D012004', (167, 180))	('pDCs', 'Protein', (85, 89))	('rectal cancer', 'Disease', (167, 180))	('CD83', 'Gene', (128, 132))	('increased', 'PosReg', (104, 113))	('rectal cancer', 'Phenotype', 'HP:0100743', (167, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('CD83', 'Gene', '9308', (128, 132))	('accumulation', 'PosReg', (69, 81))	('IFN-alpha', 'Gene', '3439', (138, 147))	('IFN-alpha', 'Gene', (138, 147))	('nRCT', 'Var', (50, 54))
18825	33912466	found that patients with high APJ expression had significant poorer response rate to combined therapy than patients with low APJ expression in the CRT plus endostar group.	('APJ', 'Gene', (30, 33))	('CRT plus endostar', 'Disease', (147, 164))	('CRT plus endostar', 'Disease', 'MESH:D007625', (147, 164))	('response', 'MPA', (68, 76))	('high', 'Var', (25, 29))	('APJ', 'Gene', '187', (125, 128))	('APJ', 'Gene', '187', (30, 33))	('APJ', 'Gene', (125, 128))	('patients', 'Species', '9606', (11, 19))	('patients', 'Species', '9606', (107, 115))	('poorer', 'NegReg', (61, 67))
18826	33912466	Patients with high APJ expression had significant low overall OS compared with those with low APJ expression.	('low', 'NegReg', (50, 53))	('APJ', 'Gene', (19, 22))	('APJ', 'Gene', '187', (94, 97))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('APJ', 'Gene', '187', (19, 22))	('APJ', 'Gene', (94, 97))
18846	33912466	found that inhibition of apelin could lead to the modulating of tumor microenvironment, inhibition of tumor angiogenesis and tumor growth decreasing.	('apelin', 'Protein', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (125, 130))	('inhibition', 'Var', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('angiogenesis', 'biological_process', 'GO:0001525', ('108', '120'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('decreasing', 'NegReg', (138, 148))
18859	33912466	In a study by Podgorska et al., four apelin peptides, including [Pyr1] apelin-13, apelin-13, apelin-17, and apelin-36, could promote colon cancer cells migration and invasion.	('invasion', 'CPA', (166, 174))	('[Pyr1] apelin-13', 'Var', (64, 80))	('colon cancer', 'Disease', 'MESH:D015179', (133, 145))	('colon cancer', 'Phenotype', 'HP:0003003', (133, 145))	('apelin-17', 'Gene', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('colon cancer', 'Disease', (133, 145))	('apelin-36', 'Gene', (108, 117))	('apelin-13', 'Gene', (82, 91))	('promote', 'PosReg', (125, 132))
18877	33912466	discovered that compared to controls, knockdown or knockout of APLN in orthotopic models of proneural or classical glioblastoma subtypes contributed to a significant reduction in glioblastoma vascularization.	('APLN', 'Gene', (63, 67))	('glioblastoma', 'Phenotype', 'HP:0012174', (115, 127))	('reduction', 'NegReg', (166, 175))	('glioblastoma', 'Disease', (179, 191))	('glioblastoma', 'Disease', 'MESH:D005909', (179, 191))	('glioblastoma', 'Phenotype', 'HP:0012174', (179, 191))	('APLN', 'Gene', '8862', (63, 67))	('knockout', 'Var', (51, 59))	('glioblastoma', 'Disease', (115, 127))	('glioblastoma', 'Disease', 'MESH:D005909', (115, 127))
18880	33912466	Besides, the authors also discovered that apelin-F13A could bind to APJ, leading to the inhibition of glioblastoma cell invasion and tumor angiogenesis.	('F13A', 'Var', (49, 53))	('APJ', 'Gene', (68, 71))	('inhibition', 'NegReg', (88, 98))	('glioblastoma', 'Disease', (102, 114))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('glioblastoma', 'Disease', 'MESH:D005909', (102, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (102, 114))	('bind', 'Interaction', (60, 64))	('F13A', 'SUBSTITUTION', 'None', (49, 53))	('tumor', 'Disease', (133, 138))	('APJ', 'Gene', '187', (68, 71))	('angiogenesis', 'biological_process', 'GO:0001525', ('139', '151'))
18910	33912466	High apelin levels were found to be associated with an increased risk of endometrial cancer.	('High', 'Var', (0, 4))	('endometrial cancer', 'Disease', (73, 91))	('endometrial cancer', 'Phenotype', 'HP:0012114', (73, 91))	('apelin', 'Protein', (5, 11))	('endometrial cancer', 'Disease', 'MESH:D016889', (73, 91))	('associated', 'Reg', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
18917	33912466	demonstrated that expression of apelin was significantly associated with tumor recurrence and disease-free survival in oral squamous cell carcinoma (OSCC).	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (119, 147))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('oral squamous cell carcinoma', 'Disease', (119, 147))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('apelin', 'Protein', (32, 38))	('tumor', 'Disease', (73, 78))	('disease-free survival', 'CPA', (94, 115))	('SCC', 'Phenotype', 'HP:0002860', (150, 153))	('expression', 'Var', (18, 28))	('associated', 'Reg', (57, 67))
18970	31959887	The quantitation of particular combinations of ATG1, ATG16L1, ATG5, LC3B and p62, all of which measure the basal level of autophagy, were able to discriminate among normal tissue, crRCC and ccRCC, suggesting that the basal level of autophagy would be a potentially useful parameter for RCC discrimination.	('RCC', 'Disease', 'MESH:D002292', (286, 289))	('LC3B', 'Gene', '81631', (68, 72))	('ATG16L1', 'Gene', '55054', (53, 60))	('ATG1', 'Gene', '8408', (53, 57))	('p62', 'Gene', '8878', (77, 80))	('ATG16L1', 'Gene', (53, 60))	('autophagy', 'biological_process', 'GO:0016236', ('232', '241'))	('p62', 'Gene', (77, 80))	('discriminate', 'Reg', (146, 158))	('ATG1', 'Gene', (47, 51))	('RCC', 'Disease', 'MESH:D002292', (182, 185))	('RCC', 'Disease', (192, 195))	('autophagy', 'biological_process', 'GO:0006914', ('232', '241'))	('ATG5', 'Gene', '9474', (62, 66))	('ATG1', 'Gene', (53, 57))	('autophagy', 'biological_process', 'GO:0016236', ('122', '131'))	('RCC', 'Disease', 'MESH:D002292', (192, 195))	('RCC', 'Disease', (182, 185))	('crRCC', 'Disease', (180, 185))	('RCC', 'Disease', (286, 289))	('combinations', 'Var', (31, 43))	('ATG5', 'Gene', (62, 66))	('ATG1', 'Gene', '8408', (47, 51))	('autophagy', 'biological_process', 'GO:0006914', ('122', '131'))	('crRCC', 'Disease', 'MESH:D002292', (180, 185))	('LC3B', 'Gene', (68, 72))
18982	31959887	In RCC with characteristic cytoplasmic inclusions composed of protein aggregates and peroxisomes, somatic mutations or high frequencies of genetic variations in ATG7, ATG5 and ATG10 were found to be associated with the formation of these inclusions, suggesting a possible defect in autophagy in these patients.	('ATG5', 'Gene', (167, 171))	('associated', 'Reg', (199, 209))	('ATG7', 'Gene', (161, 165))	('ATG10', 'Gene', '83734', (176, 181))	('ATG7', 'Gene', '10533', (161, 165))	('patients', 'Species', '9606', (301, 309))	('ATG5', 'Gene', '9474', (167, 171))	('autophagy', 'biological_process', 'GO:0016236', ('282', '291'))	('autophagy', 'biological_process', 'GO:0006914', ('282', '291'))	('mutations', 'Var', (106, 115))	('RCC', 'Disease', (3, 6))	('formation', 'biological_process', 'GO:0009058', ('219', '228'))	('RCC', 'Disease', 'MESH:D002292', (3, 6))	('genetic variations', 'Disease', (139, 157))	('genetic variations', 'Disease', 'MESH:D030342', (139, 157))	('ATG10', 'Gene', (176, 181))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
19182	29658093	The simplest explanation for the absence of NAAG in renal cancer may be denervation of the tumor, something that is commonly observed and has been reported to enhance cancer metastasis.	('denervation', 'Var', (72, 83))	('cancer metastasis', 'Disease', 'MESH:D009362', (167, 184))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('NAAG', 'Chemical', '-', (44, 48))	('renal cancer', 'Disease', (52, 64))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('enhance', 'PosReg', (159, 166))	('renal cancer', 'Disease', 'MESH:D007680', (52, 64))	('renal cancer', 'Phenotype', 'HP:0009726', (52, 64))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('NAAG', 'Gene', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer metastasis', 'Disease', (167, 184))	('tumor', 'Disease', (91, 96))
19272	33437754	The newly obtained prediction accuracies caused by a gene were compared to the original prediction accuracy from the model for the cancer type labeled by TCGA data.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('gene', 'Var', (53, 57))
19290	33437754	The GCNN model with the PPI+singleton graph included all the 7,091 genes and demonstrated a >5% increase in prediction accuracy compared with the PPI graph with a smaller accuracy variation as shown in Table 2, suggesting that the additional 2,647 genes could be important in determining cancer type.	('PPI', 'biological_process', 'GO:0060134', ('146', '149'))	('GCNN', 'Chemical', '-', (4, 8))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancer', 'Disease', (288, 294))	('prediction', 'MPA', (108, 118))	('PPI+singleton', 'Var', (24, 37))	('increase', 'PosReg', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('PPI', 'biological_process', 'GO:0060134', ('24', '27'))
19297	33437754	A total of 68%, 16%, 95.2%, and 72.9%, out of 166 READ samples were classified into COAD cancer type by the co-expression, co-expression+singleton, PPI, and PPI+singleton GCNN model respectively (confusion matrices in Figure 7 and, Figure 8, and further illustrated in Supplement 2, 3, 4, and 5).	('PPI', 'biological_process', 'GO:0060134', ('148', '151'))	('GCNN', 'Chemical', '-', (171, 175))	('D', 'Chemical', 'MESH:D003903', (87, 88))	('PPI', 'biological_process', 'GO:0060134', ('157', '160'))	('PPI+singleton', 'Var', (157, 170))	('COAD cancer', 'Disease', 'MESH:D029424', (84, 95))	('confusion', 'Phenotype', 'HP:0001289', (196, 205))	('D', 'Chemical', 'MESH:D003903', (53, 54))	('COAD cancer', 'Disease', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
19305	33437754	UCS classification performed poorly (misclassification rate of 25%, 25%, 58.9%, and 21.4% for co-expression, co-expression+singleton, PPI model, and PPI+singleton GCNN model, respectively), and most of these misclassified samples were in UCEC as expected.	('PPI+singleton', 'Var', (149, 162))	('co-expression+singleton', 'Var', (109, 132))	('UCEC', 'Disease', (238, 242))	('GCNN', 'Chemical', '-', (163, 167))	('PPI', 'biological_process', 'GO:0060134', ('149', '152'))	('PPI', 'biological_process', 'GO:0060134', ('134', '137'))	('co-expression', 'Var', (94, 107))	('UCS', 'Phenotype', 'HP:0002891', (0, 3))
19357	31155004	We present a patient with poor-risk metastatic ccRCC with sarcomatoid features and high PD-L1 expression whose disease progressed rapidly despite high-dose interleukin 2 (HD-IL2) and pazopanib, and who had a sustained partial response (PR) on nivolumab, as well as corresponding molecular imaging analysis of PD-L1 using immuno-PET in tumorgraft models.	('PET', 'Gene', '22095', (328, 331))	('PD-L1', 'Gene', (88, 93))	('IL2', 'molecular_function', 'GO:0005134', ('174', '177'))	('HD', 'Disease', 'MESH:D006816', (171, 173))	('PET', 'Gene', (328, 331))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('sarcomatoid', 'Disease', (58, 69))	('tumor', 'Disease', (335, 340))	('RCC', 'Disease', (49, 52))	('patient', 'Species', '9606', (13, 20))	('nivolumab', 'Chemical', 'MESH:D000077594', (243, 252))	('IL2', 'Gene', '3558', (174, 177))	('interleukin 2', 'Gene', (156, 169))	('tumor', 'Disease', 'MESH:D009369', (335, 340))	('interleukin 2', 'Gene', '3558', (156, 169))	('high', 'Var', (83, 87))	('pazopanib', 'Chemical', 'MESH:C516667', (183, 192))	('RCC', 'Disease', 'MESH:C538614', (49, 52))	('sarcomatoid', 'Disease', 'MESH:C538614', (58, 69))	('IL2', 'Gene', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))
19358	31155004	Sarcomatoid differentiation as well as high PD-L1 expression are both associated with aggressive disease.	('high', 'Var', (39, 43))	('Sarcomatoid', 'Disease', (0, 11))	('associated', 'Reg', (70, 80))	('PD-L1', 'Gene', (44, 49))	('aggressive disease', 'Disease', 'MESH:D001523', (86, 104))	('expression', 'MPA', (50, 60))	('aggressive disease', 'Disease', (86, 104))
19362	31155004	While it seems intuitive that tumors with PD-L1 expression may be engaging this checkpoint pathway, the landmark CheckMate-025 trial found that PD-L1 expression (assessed by immunohistochemistry with a threshold of > 1% of tumor cells) was not predictive of overall survival in patients treated with nivolumab.	('tumors', 'Disease', (30, 36))	('nivolumab', 'Chemical', 'MESH:D000077594', (300, 309))	('engaging', 'Reg', (66, 74))	('tumor', 'Disease', (223, 228))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('checkpoint pathway', 'Pathway', (80, 98))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('PD-L1', 'Gene', (144, 149))	('expression', 'Var', (48, 58))	('PD-L1', 'Gene', (42, 47))	('patients', 'Species', '9606', (278, 286))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Disease', (30, 35))
19420	31155004	Accordingly, tumors devoid of PD-L1 expression are unlikely to respond to anti-PD-L1 antibodies (or antibodies to the corresponding receptor, PD-1).	('anti-PD-L1', 'Gene', (74, 84))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('PD-1', 'Gene', (142, 146))	('anti-PD-L1', 'Var', (74, 84))	('PD-1', 'Gene', '5133', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
19457	29096676	Circular RNAs (circRNAs) are a class of RNA molecules that lack 5'-3' ends and poly A tail and covalently form closed loops.	('cir', 'Gene', '3762', (15, 18))	('cir', 'Gene', (15, 18))	('lack', 'NegReg', (59, 63))	("5'-3' ends", 'MPA', (64, 74))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('poly', 'Var', (79, 83))	('Cir', 'Gene', (0, 3))	('Cir', 'Gene', '3762', (0, 3))	('form', 'Reg', (106, 110))
19470	29096676	In addition, all the four types of alternative splicing (namely cassette exon, intron retention, alternative donor site and alternative acceptor site) that have been identified in linear mRNA are found in circRNAs, which adds more complexity to the biogenesis of circRNAs.	('cir', 'Gene', '3762', (205, 208))	('cassette exon', 'Var', (64, 77))	('cir', 'Gene', (205, 208))	('cir', 'Gene', '3762', (263, 266))	('cir', 'Gene', (263, 266))	('donor', 'Species', '9606', (109, 114))	('retention', 'biological_process', 'GO:0051235', ('86', '95'))	('splicing', 'biological_process', 'GO:0045292', ('47', '55'))
19490	29096676	However, circular RNA can be cleaved by endonucleases; therefore, RNA interference can be used to knock down circRNA expression.	('cir', 'Gene', '3762', (9, 12))	('RNA', 'cellular_component', 'GO:0005562', ('66', '69'))	('RNA', 'MPA', (66, 69))	('cir', 'Gene', (9, 12))	('cir', 'Gene', '3762', (109, 112))	('cir', 'Gene', (109, 112))	('knock', 'Var', (98, 103))	('RNA', 'cellular_component', 'GO:0005562', ('18', '21'))	('RNA interference', 'biological_process', 'GO:0016246', ('66', '82'))
19503	29096676	In addtion, when the efficiency of linear splicing increases, circRNA abundance decreases, which suggests that there is a genome-wide competition between canonical splicing and circRNA generation.	('splicing', 'biological_process', 'GO:0045292', ('42', '50'))	('increases', 'PosReg', (51, 60))	('linear splicing', 'Var', (35, 50))	('decreases', 'NegReg', (80, 89))	('cir', 'Gene', (62, 65))	('cir', 'Gene', '3762', (62, 65))	('splicing', 'biological_process', 'GO:0045292', ('164', '172'))	('cir', 'Gene', '3762', (177, 180))	('cir', 'Gene', (177, 180))
19555	29096676	These findings suggest that the deregulated expression of circRNAs is closely associated with the development and progression of ESCC.	('associated', 'Reg', (78, 88))	('deregulated', 'Var', (32, 43))	('expression', 'MPA', (44, 54))	('ESCC', 'Disease', (129, 133))	('cir', 'Gene', '3762', (58, 61))	('cir', 'Gene', (58, 61))
19572	29096676	These results indicate that the abnormal expression of circRNAs may be novel and non-invasive biomarkers for the diagnosis and prognosis of gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('expression', 'MPA', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('gastric cancer', 'Disease', (140, 154))	('abnormal', 'Var', (32, 40))	('gastric cancer', 'Disease', 'MESH:D013274', (140, 154))	('cir', 'Gene', '3762', (55, 58))	('cir', 'Gene', (55, 58))
19585	29096676	The knockdown of circ-BANP could significantly attenuate the proliferation of colorectal cancer cells.	('BANP', 'Gene', '54971', (22, 26))	('cir', 'Gene', (17, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('BANP', 'Gene', (22, 26))	('cir', 'Gene', '3762', (17, 20))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('proliferation', 'CPA', (61, 74))	('knockdown', 'Var', (4, 13))	('attenuate', 'NegReg', (47, 56))	('colorectal cancer', 'Disease', (78, 95))
19595	29096676	CDR1as knockdown suppressed colorectal cancer cell proliferation and invasion via inhibiting the activities of miR-7 targets including EGFR and IGF-1R.	('CDR1as', 'Gene', '103611090', (0, 6))	('miR-7', 'Gene', (111, 116))	('EGFR', 'Gene', '1956', (135, 139))	('IGF-1R', 'Gene', '3480', (144, 150))	('suppressed', 'NegReg', (17, 27))	('IGF-1R', 'Gene', (144, 150))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('miR-7', 'Gene', '10859', (111, 116))	('inhibiting', 'NegReg', (82, 92))	('activities', 'MPA', (97, 107))	('EGFR', 'Gene', (135, 139))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))	('EGFR', 'molecular_function', 'GO:0005006', ('135', '139'))	('colorectal cancer', 'Disease', (28, 45))	('invasion', 'CPA', (69, 77))	('knockdown', 'Var', (7, 16))	('CDR1as', 'Gene', (0, 6))
19614	29096676	CDR1as interacts with miR-7 to derepress the expression of CCNE1 and PIK3CD genes, thereby promoting the proliferation and invasiveness of liver cancer cells.	('CDR1as', 'Gene', '103611090', (0, 6))	('derepress', 'Var', (31, 40))	('invasiveness of liver cancer', 'Disease', 'MESH:D006528', (123, 151))	('CDR1as', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('CCNE1', 'Gene', '898', (59, 64))	('CCNE1', 'Gene', (59, 64))	('miR-7', 'Gene', (22, 27))	('proliferation', 'CPA', (105, 118))	('expression', 'MPA', (45, 55))	('liver cancer', 'Phenotype', 'HP:0002896', (139, 151))	('PIK3CD', 'Gene', '5293', (69, 75))	('miR-7', 'Gene', '10859', (22, 27))	('PIK3CD', 'Gene', (69, 75))	('promoting', 'PosReg', (91, 100))	('invasiveness of liver cancer', 'Disease', (123, 151))
19645	29096676	found that cZNF292 was also expressed in glioma cells and that the silencing of cZNF292 expression could inhibit glioma cell proliferation.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('inhibit', 'NegReg', (105, 112))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('cZNF292', 'Gene', (80, 87))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('glioma', 'Disease', (113, 119))	('silencing', 'Var', (67, 76))	('cell proliferation', 'biological_process', 'GO:0008283', ('120', '138'))	('glioma', 'Disease', (41, 47))	('expression', 'MPA', (88, 98))
19670	29096676	For functional study, the researchers generally use gene over-expression and knockdown strategies to manipulate circRNA expression.	('manipulate', 'Reg', (101, 111))	('cir', 'Gene', '3762', (112, 115))	('knockdown', 'Var', (77, 86))	('cir', 'Gene', (112, 115))
19672	29096676	To study the protein-coding potential of a circRNA, the researchers could predict N6-methyladenosin, internal ribozyme entry site (IRES), and open reading frame in circRNA by bioinformatic analyses.	('cir', 'Gene', '3762', (43, 46))	('cir', 'Gene', (43, 46))	('cir', 'Gene', '3762', (164, 167))	('cir', 'Gene', (164, 167))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('N6-methyladenosin', 'Var', (82, 99))	('N6-methyladenosin', 'Chemical', '-', (82, 99))	('ribozyme', 'cellular_component', 'GO:0005559', ('110', '118'))
19702	33787057	In the present study, we discovered that SNHG12 is up-regulated in ccRCC and that overexpression of SNHG12 predicted poor clinical outcome of ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('patients', 'Species', '9606', (148, 156))	('RCC', 'Disease', (69, 72))	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('up-regulated', 'PosReg', (51, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('RCC', 'Disease', (144, 147))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('SNHG12', 'Var', (100, 106))	('SNHG12', 'Gene', (41, 47))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
19703	33787057	SNHG12 knockdown notably inhibited proliferation and migration of RCC cells.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('inhibited', 'NegReg', (25, 34))	('knockdown', 'Var', (7, 16))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('SNHG12', 'Gene', (0, 6))
19704	33787057	Furthermore, we discovered that miR-30a-3p, a putative ccRCC inhibitor, was competitively sponged by SNHG12.	('miR-30a-3p', 'Chemical', '-', (32, 42))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('miR-30a-3p', 'Var', (32, 42))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))
19705	33787057	Via the crosstalk network, SNHG12 was capable of up-regulating multiple target genes of miR-30a-3p, namely, RUNX2, WNT2 and IGF-1R, which have been identified to facilitate tumorigenesis of ccRCC.	('IGF-1R', 'Gene', '3480', (124, 130))	('tumorigenesis', 'CPA', (173, 186))	('IGF-1R', 'Gene', (124, 130))	('RCC', 'Phenotype', 'HP:0005584', (192, 195))	('RUNX2', 'Gene', '860', (108, 113))	('miR-30a-3p', 'Chemical', '-', (88, 98))	('facilitate', 'PosReg', (162, 172))	('WNT2', 'Gene', (115, 119))	('WNT2', 'Gene', '7472', (115, 119))	('RUNX2', 'Gene', (108, 113))	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('SNHG12', 'Var', (27, 33))	('RCC', 'Disease', (192, 195))	('miR-30a-3p', 'Gene', (88, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (190, 195))	('up-regulating', 'PosReg', (49, 62))
19713	33787057	1   Accumulating evidence have demonstrated that long non-coding RNAs (lncRNAs) can function in a wide variety of biological processes and can play crucial roles in driving tumorigenesis or inhibiting tumour progression.	('tumorigenesis', 'CPA', (173, 186))	('tumour', 'Disease', (201, 207))	('driving', 'PosReg', (165, 172))	('function', 'Reg', (84, 92))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('inhibiting', 'NegReg', (190, 200))	('tumour', 'Disease', 'MESH:D009369', (201, 207))	('long non-coding RNAs', 'Var', (49, 69))
19717	33787057	15 ,  16  The major mechanism of miRNAs facilitating cancer progression is through down-regulating protein expression by binding to seed sequences present in the target genes and influence their biological functions.	('down-regulating', 'NegReg', (83, 98))	('miRNAs', 'Var', (33, 39))	('cancer', 'Disease', (53, 59))	('biological functions', 'MPA', (195, 215))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('influence', 'Reg', (179, 188))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('binding', 'Interaction', (121, 128))	('binding', 'molecular_function', 'GO:0005488', ('121', '128'))	('protein', 'Protein', (99, 106))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))
19718	33787057	16  Studies profiling miRNAs have noted the dysregulation of many miRNAs in ccRCC, for example, miR-215, 17  miR-200, 18  miR-708, 19  miR-199a 20  and miR-30a, which have been reported to regulate growth, invasion and migration of ccRCC cells.	('regulate', 'Reg', (189, 197))	('miR-199a 20', 'Var', (135, 146))	('dysregulation', 'MPA', (44, 57))	('miR-215', 'Gene', (96, 103))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (234, 237))	('miR-200', 'Var', (109, 116))	('RCC', 'Disease', (234, 237))	('miR-708', 'Gene', (122, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (232, 237))	('miR-30a', 'Gene', '407029', (152, 159))	('growth', 'CPA', (198, 204))	('RCC', 'Disease', 'MESH:C538614', (234, 237))	('migration', 'CPA', (219, 228))	('invasion', 'CPA', (206, 214))	('miR-708', 'Gene', '100126333', (122, 129))	('miR-30a', 'Gene', (152, 159))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('miR-215', 'Gene', '406997', (96, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))
19723	33787057	SNHG12 functions as a competing endogenous RNA and interacts with miR-30a-5p, therefore releases the expression of a series of target oncogenes and further promotes the aggressive of ccRCC cells.	('RCC', 'Disease', (185, 188))	('ccRCC', 'Phenotype', 'HP:0006770', (183, 188))	('RNA', 'cellular_component', 'GO:0005562', ('43', '46'))	('miR-30a', 'Gene', (66, 73))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('aggressive', 'CPA', (169, 179))	('SNHG12', 'Var', (0, 6))	('expression', 'MPA', (101, 111))	('miR-30a', 'Gene', '407029', (66, 73))	('releases', 'PosReg', (88, 96))	('promotes', 'PosReg', (156, 164))	('RCC', 'Disease', 'MESH:C538614', (185, 188))
19725	33787057	This study has provided a new explanation of the mechanism through which SNHG12 functions as a oncogene and promotes the carcinogenesis of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (139, 144))	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('promotes', 'PosReg', (108, 116))	('SNHG12', 'Var', (73, 79))	('carcinogenesis', 'CPA', (121, 135))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
19738	33787057	Antibodies to RUNX2 (1:1000, #12556, CST), WNT2 (1:1000, ab109222, Abcam), IGF-1R (1:1000, #3027, CST) and GAPDH (1:1000, #5174, CST) were used according to the manufacturers' protocols.	('CST', 'Gene', (98, 101))	('CST', 'Gene', (129, 132))	('IGF-1R', 'Gene', '3480', (75, 81))	('1:1000', 'Var', (83, 89))	('RUNX2', 'Gene', (14, 19))	('IGF-1R', 'Gene', (75, 81))	('CST', 'Gene', '106478911', (37, 40))	('RUNX2', 'Gene', '860', (14, 19))	('WNT2', 'Gene', (43, 47))	('CST', 'Gene', '106478911', (98, 101))	('CST', 'Gene', '106478911', (129, 132))	('WNT2', 'Gene', '7472', (43, 47))	('CST', 'Gene', (37, 40))
19753	33787057	1 mug of each RNA sample was incubated without/with empty probe or with 5 mug of biotin-labelled MREs mutated SNHG12 anti-sense probe or biotin-labelled SNHG12 anti-sense probe overnight at 4 C, and the complexes were isolated with streptavidin agarose beads (Invitrogen).	('agarose', 'Chemical', 'MESH:D012685', (245, 252))	('biotin', 'Chemical', 'MESH:D001710', (137, 143))	('SNHG12', 'Gene', (110, 116))	('mug', 'molecular_function', 'GO:0043739', ('2', '5'))	('RNA', 'cellular_component', 'GO:0005562', ('14', '17'))	('mug', 'molecular_function', 'GO:0043739', ('74', '77'))	('mutated', 'Var', (102, 109))	('biotin', 'Chemical', 'MESH:D001710', (81, 87))
19761	33787057	Moreover, high expression of SNHG12 is significantly correlated with poor overall survival of ccRCC patients (Figure 1C).	('RCC', 'Disease', (96, 99))	('poor', 'NegReg', (69, 73))	('SNHG12', 'Gene', (29, 35))	('patients', 'Species', '9606', (100, 108))	('high', 'Var', (10, 14))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('overall', 'MPA', (74, 81))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
19762	33787057	Taken together, above data suggested that expression of SNHG12 is significantly elevated in ccRCC tumour tissues, and high expression of SNHG12 is positively correlated with poor survival of ccRCC patients.	('ccRCC tumour', 'Disease', 'MESH:D009369', (92, 104))	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('SNHG12', 'Gene', (56, 62))	('elevated', 'PosReg', (80, 88))	('RCC', 'Disease', (193, 196))	('patients', 'Species', '9606', (197, 205))	('RCC', 'Phenotype', 'HP:0005584', (193, 196))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('SNHG12', 'Var', (137, 143))	('expression', 'MPA', (42, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (191, 196))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('correlated', 'Reg', (158, 168))	('ccRCC tumour', 'Disease', (92, 104))
19772	33787057	With the help of ENCORI software, we noticed that miR-30a-3p is very likely to be targeted by SNHG12 (Figure 3A).	('miR-30a-3p', 'Var', (50, 60))	('SNHG12', 'Gene', (94, 100))	('miR-30a-3p', 'Chemical', '-', (50, 60))
19775	33787057	25  We detected the expression of miR-30a-3p in the same cohort of ccRCC tumour tissue and adjacent normal renal tissue samples using qRT-PCR, and the result demonstrated that miR-30a-3p was significantly down-regulated in ccRCC tissue samples (Figure 3B).	('ccRCC tumour', 'Disease', 'MESH:D009369', (67, 79))	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('RCC', 'Disease', (225, 228))	('RCC', 'Phenotype', 'HP:0005584', (225, 228))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('miR-30a-3p', 'Var', (176, 186))	('miR-30a-3p', 'Chemical', '-', (34, 44))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (223, 228))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('down-regulated', 'NegReg', (205, 219))	('ccRCC tumour', 'Disease', (67, 79))	('miR-30a-3p', 'Chemical', '-', (176, 186))
19778	33787057	Next, the reporter plasmids containing wild-type SNHG12 or mutant-type SNHG12 were, respectively, co-transfected with miR-30a-3p mimics into two ccRCC cell lines, OSRC-2 and 769-p. Dual luciferase reporter assay was performed to measure the transcriptional level of the reporter genes (Figure 3F).	('OSRC-2', 'CellLine', 'CVCL:1901', (163, 169))	('miR-30a-3p', 'Chemical', '-', (118, 128))	('SNHG12', 'Gene', (71, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (145, 150))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('SNHG12', 'Var', (49, 55))	('mutant-type', 'Var', (59, 70))
19779	33787057	Our result revealed that con-transfection of miR-30a-3p significantly decreased the transcription of reporter plasmids harbouring wild-type SNHG12, however, had no effect on that harbouring mutant-type SNHG12.	('SNHG12', 'Var', (140, 146))	('decreased', 'NegReg', (70, 79))	('miR-30a-3p', 'Var', (45, 55))	('transcription', 'MPA', (84, 97))	('transcription', 'biological_process', 'GO:0006351', ('84', '97'))	('miR-30a-3p', 'Chemical', '-', (45, 55))
19784	33787057	Using bioinformatic software, 29  we located that runt-related transcription factor 2 (RUNX2) could be a downstream effector and regulated by miR-30a-3p mediated ceRNA network (Figure 4A).	('miR-30a-3p', 'Chemical', '-', (142, 152))	('regulated', 'Reg', (129, 138))	('runt-related transcription factor 2', 'Gene', '860', (50, 85))	('transcription factor', 'molecular_function', 'GO:0000981', ('63', '83'))	('RUNX2', 'Gene', (87, 92))	('miR-30a-3p', 'Var', (142, 152))	('transcription', 'biological_process', 'GO:0006351', ('63', '76'))	('RUNX2', 'Gene', '860', (87, 92))	('runt-related transcription factor 2', 'Gene', (50, 85))
19788	33787057	Result suggested that RUNX2 expression was significantly reduced in response to SNHG12 knockdown (Figure 4B-D).	('SNHG12', 'Gene', (80, 86))	('expression', 'MPA', (28, 38))	('RUNX2', 'Gene', '860', (22, 27))	('RUNX2', 'Gene', (22, 27))	('reduced', 'NegReg', (57, 64))	('knockdown', 'Var', (87, 96))
19791	33787057	Result suggested that miR-30a-3p significantly reduced the transcription of reported genes contained wild-type RUNX2 when compared with those carried mutant-type RUNX2 (4f).	('RUNX2', 'Gene', '860', (162, 167))	('transcription', 'biological_process', 'GO:0006351', ('59', '72'))	('RUNX2', 'Gene', '860', (111, 116))	('miR-30a-3p', 'Chemical', '-', (22, 32))	('transcription', 'MPA', (59, 72))	('RUNX2', 'Gene', (111, 116))	('RUNX2', 'Gene', (162, 167))	('miR-30a-3p', 'Var', (22, 32))	('reduced', 'NegReg', (47, 54))
19793	33787057	In response to miR-30a-3p overexpression, RUNX2 expression was significantly repressed (Figure 4G).	('miR-30a-3p', 'Chemical', '-', (15, 25))	('overexpression', 'PosReg', (26, 40))	('expression', 'MPA', (48, 58))	('RUNX2', 'Gene', (42, 47))	('repressed', 'NegReg', (77, 86))	('miR-30a-3p', 'Var', (15, 25))	('RUNX2', 'Gene', '860', (42, 47))
19794	33787057	These results demonstrated that RUNX2 could be a downstream target of miR-30a-3p.	('RUNX2', 'Gene', '860', (32, 37))	('RUNX2', 'Gene', (32, 37))	('miR-30a-3p', 'Var', (70, 80))	('miR-30a-3p', 'Chemical', '-', (70, 80))
19798	33787057	Our data confirmed that, expressions of RUNX2, IGF-1R and WNT2 were remarkably down-regulated in response to SNHG12 knockdown, but could be rescued by miR-30a-3p silencing (Figure 4H).	('WNT2', 'Gene', (58, 62))	('RUNX2', 'Gene', (40, 45))	('WNT2', 'Gene', '7472', (58, 62))	('IGF-1R', 'Gene', '3480', (47, 53))	('expressions', 'MPA', (25, 36))	('down-regulated', 'NegReg', (79, 93))	('knockdown', 'Var', (116, 125))	('IGF-1R', 'Gene', (47, 53))	('SNHG12', 'Gene', (109, 115))	('RUNX2', 'Gene', '860', (40, 45))	('miR-30a-3p', 'Chemical', '-', (151, 161))
19799	33787057	The above results suggested that, via the miR-30a-3p mediated ceRNA network, SNHG12 could regulate the expressions of multiple downstream genes and stimulated the tumorigenesis of ccRCC.	('stimulated', 'PosReg', (148, 158))	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('miR-30a-3p', 'Var', (42, 52))	('SNHG12', 'Var', (77, 83))	('miR-30a-3p', 'Chemical', '-', (42, 52))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('expressions of multiple', 'MPA', (103, 126))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('regulate', 'Reg', (90, 98))	('RCC', 'Disease', (182, 185))	('tumorigenesis', 'CPA', (163, 176))
19800	33787057	To demonstrate that SNHG12 promotes the malignancy phenotypes of ccRCC cells, we then performed rescue experiments.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('SNHG12', 'Var', (20, 26))	('promotes', 'PosReg', (27, 35))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('malignancy', 'Disease', 'MESH:D009369', (40, 50))	('malignancy', 'Disease', (40, 50))
19811	33787057	Immunochemistry staining assay showed that SNHG12 knockdown effectively suppressed positive-rate of ki67 in xenograft tumour, whereas miR-30a silencing partially reversed Ki67 positive-rate which was significantly suppressed by SNHG12 knockdown (Figure 6C,D).	('silencing', 'Var', (142, 151))	('Ki67', 'Gene', '17345', (171, 175))	('miR-30a', 'Gene', (134, 141))	('tumour', 'Disease', (118, 124))	('knockdown', 'Var', (50, 59))	('SNHG12', 'Gene', (43, 49))	('ki67', 'Gene', (100, 104))	('Ki67', 'Gene', (171, 175))	('miR-30a', 'Gene', '407029', (134, 141))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('suppressed', 'NegReg', (72, 82))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('ki67', 'Gene', '17345', (100, 104))	('positive-rate', 'MPA', (83, 96))
19815	33787057	14  Interestingly, SNHG12 has been reported to accelerate the progression of renal cell cancer, and high expression of SNHG12 positively correlates with poor clinical outcome of patients with ccRCC.	('accelerate', 'PosReg', (47, 57))	('renal cell cancer', 'Phenotype', 'HP:0005584', (77, 94))	('SNHG12', 'Var', (19, 25))	('RCC', 'Disease', 'MESH:C538614', (194, 197))	('patients', 'Species', '9606', (178, 186))	('RCC', 'Disease', (194, 197))	('RCC', 'Phenotype', 'HP:0005584', (194, 197))	('ccRCC', 'Phenotype', 'HP:0006770', (192, 197))	('SNHG12', 'Gene', (119, 125))	('renal cell cancer', 'Disease', 'MESH:C538614', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('renal cell cancer', 'Disease', (77, 94))
19817	33787057	Silencing of SNHG12 significantly inhibits the proliferation and migration of ccRCC cell lines in vitro and in vivo.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('migration', 'CPA', (65, 74))	('inhibits', 'NegReg', (34, 42))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('proliferation', 'CPA', (47, 60))	('Silencing', 'Var', (0, 9))	('SNHG12', 'Gene', (13, 19))
19823	33787057	In hepatocellular carcinoma (HCC), SNHG12 interacts with miR-199a-5p and consequently up-regulates the expression of mitogen-activated protein kinase 3 (MLK3) as well as the phosphorylation of IkB-alpha and NF-kB.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('up-regulates', 'PosReg', (86, 98))	('mitogen-activated protein kinase 3', 'Gene', (117, 151))	('interacts', 'Interaction', (42, 51))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('MLK3', 'Gene', '4296', (153, 157))	('phosphorylation', 'MPA', (174, 189))	('expression', 'MPA', (103, 113))	('NF-kB', 'Protein', (207, 212))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('mitogen-activated protein kinase 3', 'Gene', '5595', (117, 151))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('IkB-alpha', 'Gene', (193, 202))	('HCC', 'Phenotype', 'HP:0001402', (29, 32))	('phosphorylation', 'biological_process', 'GO:0016310', ('174', '189'))	('IkB-alpha', 'Gene', '4792', (193, 202))	('SNHG12', 'Var', (35, 41))	('hepatocellular carcinoma', 'Disease', (3, 27))	('MLK3', 'Gene', (153, 157))
19827	33787057	Noteworthily, via sponging miR-30a-3p, SNHG12 increases the expression of RUNX2, IGF-1R and WNT2 and promotes the proliferative and migrative capacities of ccRCC cells.	('expression', 'MPA', (60, 70))	('SNHG12', 'Var', (39, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (156, 161))	('IGF-1R', 'Gene', '3480', (81, 87))	('RUNX2', 'Gene', '860', (74, 79))	('increases', 'PosReg', (46, 55))	('WNT2', 'Gene', (92, 96))	('IGF-1R', 'Gene', (81, 87))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('WNT2', 'Gene', '7472', (92, 96))	('RCC', 'Disease', (158, 161))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('promotes', 'PosReg', (101, 109))	('miR-30a-3p', 'Chemical', '-', (27, 37))	('RUNX2', 'Gene', (74, 79))
19835	33787057	25  Data from our study also confirmed that miR-30a-3p suppresses proliferation and migration of RCC cells by inhibiting several target genes, RUNX2, IGF-1R and WNT2.	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('RUNX2', 'Gene', (143, 148))	('RUNX2', 'Gene', '860', (143, 148))	('proliferation', 'CPA', (66, 79))	('IGF-1R', 'Gene', '3480', (150, 156))	('miR-30a-3p', 'Chemical', '-', (44, 54))	('inhibiting', 'NegReg', (110, 120))	('WNT2', 'Gene', (161, 165))	('IGF-1R', 'Gene', (150, 156))	('suppresses', 'NegReg', (55, 65))	('WNT2', 'Gene', '7472', (161, 165))	('miR-30a-3p', 'Var', (44, 54))
19836	33787057	In conclusion, our present study revealed the tumorigenic role of SNHG12 in ccRCC, and we also uncovered a novel mechanism that SNHG12 competitively binds with miR-30a-3p and up-regulates the expression of downstream oncogenes, RUNX2, IGF-1R and WNT2.	('up-regulates', 'PosReg', (175, 187))	('expression', 'MPA', (192, 202))	('IGF-1R', 'Gene', '3480', (235, 241))	('miR-30a-3p', 'Chemical', '-', (160, 170))	('RUNX2', 'Gene', '860', (228, 233))	('RCC', 'Disease', (78, 81))	('WNT2', 'Gene', (246, 250))	('binds', 'Interaction', (149, 154))	('IGF-1R', 'Gene', (235, 241))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('miR-30a-3p', 'Protein', (160, 170))	('WNT2', 'Gene', '7472', (246, 250))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('SNHG12', 'Var', (128, 134))	('RUNX2', 'Gene', (228, 233))
19837	33787057	In vivo experiments also showed that knockdown of SNHG12 significantly inhibited xenograft tumour growth, and co-silencing of SNHG12 and miR-30a-3p partially compromised the tumour growth.	('compromised', 'NegReg', (158, 169))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumour growth', 'Disease', (174, 187))	('tumour growth', 'Disease', 'MESH:D006130', (91, 104))	('inhibited', 'NegReg', (71, 80))	('co-silencing', 'Var', (110, 122))	('tumour growth', 'Disease', 'MESH:D006130', (174, 187))	('knockdown', 'Var', (37, 46))	('SNHG12', 'Gene', (50, 56))	('miR-30a-3p', 'Chemical', '-', (137, 147))	('SNHG12', 'Gene', (126, 132))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('tumour growth', 'Disease', (91, 104))
19868	30911462	According to this evidence, inhibition of the mTOR pathway has been confirmed as an effective strategy to break the vicious cycle of bone metastasis from breast cancer in a preclinical in vitro model.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('bone metastasis', 'CPA', (133, 148))	('breast cancer', 'Disease', (154, 167))	('mTOR', 'Gene', '2475', (46, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('inhibition', 'Var', (28, 38))	('mTOR', 'Gene', (46, 50))
19935	30911462	We showed that mTOR inhibition is able to block the Nf-KB pathway, as suggested by the increase of the unphosphorylated form of Ik-B, inhibitor of the transcription factor Nf-kB (Fig.	('increase', 'PosReg', (87, 95))	('inhibition', 'Var', (20, 30))	('transcription factor', 'molecular_function', 'GO:0000981', ('151', '171'))	('mTOR', 'Gene', (15, 19))	('Nf-KB pathway', 'Pathway', (52, 65))	('mTOR', 'Gene', '2475', (15, 19))	('transcription', 'biological_process', 'GO:0006351', ('151', '164'))	('Ik-B', 'Gene', (128, 132))
19968	30911462	In another study, pre-specified subgroup analysis based on the presence of baseline bone metastasis in advanced ccRCC patients revealed that Cabozantinib was superior to Eve in terms of improving clinical- and bone-related outcomes.	('bone metastasis', 'CPA', (84, 99))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('improving', 'PosReg', (186, 195))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('pre', 'molecular_function', 'GO:0003904', ('18', '21'))	('Cabozantinib', 'Var', (141, 153))	('Cabozantinib', 'Chemical', 'MESH:C558660', (141, 153))	('patients', 'Species', '9606', (118, 126))
19999	30858363	Biallelic inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene is a hallmark event in ccRCC pathogenesis, contributing to ~90% of sporadic cases as well as to hereditary ccRCC in von-Hippel-Lindau syndrome patients.	('contributing', 'Reg', (120, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (184, 189))	('von-Hippel-Lindau syndrome', 'Disease', (193, 219))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('von Hippel-Lindau (VHL) tumour', 'Disease', 'MESH:D006623', (30, 60))	('RCC', 'Disease', (186, 189))	('Biallelic inactivation', 'Var', (0, 22))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('patients', 'Species', '9606', (220, 228))	('RCC', 'Disease', (102, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('von-Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (193, 219))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('pathogenesis', 'biological_process', 'GO:0009405', ('106', '118'))
20000	30858363	The VHL protein mediates proteasomal degradation of the hypoxia-inducible factor (HIF) alpha subunits under normoxic conditions, and genetic VHL inactivation in ccRCC leads to constitutive HIF alpha accumulation and consequent upregulation of hypoxia-associated genes.	('HIF alpha', 'Protein', (189, 198))	('ccRCC', 'Phenotype', 'HP:0006770', (161, 166))	('RCC', 'Disease', (163, 166))	('hypoxia', 'Disease', 'MESH:D000860', (243, 250))	('VHL', 'Gene', '7428', (141, 144))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('degradation', 'biological_process', 'GO:0009056', ('37', '48'))	('VHL', 'Gene', (4, 7))	('hypoxia', 'Disease', (56, 63))	('proteasomal', 'MPA', (25, 36))	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('accumulation', 'PosReg', (199, 211))	('inactivation', 'Var', (145, 157))	('VHL', 'Gene', '7428', (4, 7))	('hypoxia', 'Disease', 'MESH:D000860', (56, 63))	('upregulation', 'PosReg', (227, 239))	('hypoxia', 'Disease', (243, 250))	('constitutive', 'MPA', (176, 188))	('VHL', 'Gene', (141, 144))
20008	30858363	Genetic analysis of ccRCC has identified mutations in components of the PI3K-AKT-mTOR signalling cascade.	('mutations', 'Var', (41, 50))	('AKT', 'Gene', (77, 80))	('AKT', 'Gene', '207', (77, 80))	('RCC', 'Disease', (22, 25))	('signalling cascade', 'biological_process', 'GO:0007165', ('86', '104'))	('RCC', 'Disease', 'MESH:C538614', (22, 25))	('ccRCC', 'Phenotype', 'HP:0006770', (20, 25))	('PI3K', 'molecular_function', 'GO:0016303', ('72', '76'))	('mTOR', 'Gene', (81, 85))	('mTOR', 'Gene', '2475', (81, 85))
20009	30858363	For example, PIK3CA and PTEN are mutated in 2-5% of ccRCCs and some mutations have also been observed in TSC1, a negative regulator of mTOR.	('TSC1', 'Gene', '7248', (105, 109))	('PTEN', 'Gene', '5728', (24, 28))	('PIK3CA', 'Gene', (13, 19))	('TSC1', 'Gene', (105, 109))	('mTOR', 'Gene', '2475', (135, 139))	('RCC', 'Disease', (54, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('mTOR', 'Gene', (135, 139))	('mutated', 'Var', (33, 40))	('PIK3CA', 'Gene', '5290', (13, 19))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('mutations', 'Var', (68, 77))	('PTEN', 'Gene', (24, 28))
20010	30858363	Furthermore, mutations in MTOR are found in approximately 6% of ccRCCs.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('MTOR', 'Gene', (26, 30))	('MTOR', 'Gene', '2475', (26, 30))	('mutations', 'Var', (13, 22))	('RCC', 'Disease', (66, 69))	('found', 'Reg', (35, 40))
20011	30858363	Genetic alterations are thus likely to contribute to mTOR activation in ccRCC, although upstream activating signals still seem to be required in most cases.	('Genetic alterations', 'Var', (0, 19))	('RCC', 'Disease', (74, 77))	('mTOR', 'Gene', (53, 57))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('mTOR', 'Gene', '2475', (53, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('activation', 'PosReg', (58, 68))
20012	30858363	The recent generation of double knockout Vhl-/-;Pbrm1-/- and Vhl-/-;Bap1-/- mouse models have also identified mTORC1 hyper-activation as a potential driver of ccRCC.	('Bap1', 'Gene', (68, 72))	('mTORC1', 'cellular_component', 'GO:0031931', ('110', '116'))	('mTORC1', 'Gene', (110, 116))	('Vhl', 'Gene', '22346', (61, 64))	('Vhl', 'Gene', '22346', (41, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (159, 164))	('mouse', 'Species', '10090', (76, 81))	('Vhl', 'Gene', (61, 64))	('hyper-activation', 'Var', (117, 133))	('Pbrm1', 'Gene', (48, 53))	('mTORC1', 'Gene', '382056', (110, 116))	('Vhl', 'Gene', (41, 44))	('RCC', 'Disease', (161, 164))	('Pbrm1', 'Gene', '66923', (48, 53))	('Bap1', 'Gene', '104416', (68, 72))	('RCC', 'Disease', 'MESH:C538614', (161, 164))
20016	30858363	Apart from large chromosome 3p deletions and inactivation of the second allele of VHL, usually by point mutation, most predicted ccRCC driver mutations are subclonal.	('mutations', 'Var', (142, 151))	('ccRCC', 'Phenotype', 'HP:0006770', (129, 134))	('chromosome', 'cellular_component', 'GO:0005694', ('17', '27'))	('inactivation', 'Var', (45, 57))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (131, 134))	('VHL', 'Gene', (82, 85))	('VHL', 'Gene', '7428', (82, 85))	('point mutation', 'Var', (98, 112))
20017	30858363	This suggests that the opportunities for mutation-based therapeutic approaches in ccRCC are limited to dependencies resulting from inactivation of the VHL pathway.	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('inactivation', 'Var', (131, 143))	('VHL', 'Gene', (151, 154))	('VHL', 'Gene', '7428', (151, 154))
20021	30858363	KLF6 inhibition impairs ccRCC fitness and leads to a profound inhibition of lipid biosynthetic pathways.	('inhibition', 'Var', (5, 15))	('RCC', 'Disease', (26, 29))	('lipid biosynthetic pathways', 'Pathway', (76, 103))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('ccRCC', 'Phenotype', 'HP:0006770', (24, 29))	('lipid', 'Chemical', 'MESH:D008055', (76, 81))	('KLF6', 'Protein', (0, 4))	('inhibition', 'NegReg', (62, 72))	('impairs', 'NegReg', (16, 23))
20023	30858363	Moreover, by supporting the expression of PDGFB, an agonist of the mTOR pathway, KLF6 further promotes lipid metabolism by enhancing the activation of the key lipid metabolic regulators SREBF1 and SREBF2.	('PDGFB', 'Gene', (42, 47))	('SREBF2', 'Gene', '6721', (197, 203))	('SREBF1', 'Gene', (186, 192))	('enhancing', 'PosReg', (123, 132))	('lipid metabolism', 'biological_process', 'GO:0006629', ('103', '119'))	('KLF6', 'Var', (81, 85))	('lipid', 'Chemical', 'MESH:D008055', (103, 108))	('mTOR', 'Gene', (67, 71))	('mTOR', 'Gene', '2475', (67, 71))	('SREBF1', 'Gene', '6720', (186, 192))	('activation', 'PosReg', (137, 147))	('PDGFB', 'Gene', '5155', (42, 47))	('lipid', 'Chemical', 'MESH:D008055', (159, 164))	('SREBF2', 'Gene', (197, 203))	('lipid metabolism', 'MPA', (103, 119))	('promotes', 'PosReg', (94, 102))
20029	30858363	In order to identify transcriptional networks that support ccRCC progression, we analysed H3K27ac chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) data from several VHL mutant ccRCC cell lines and looked for transcription factor-associated super enhancers.	('VHL', 'Gene', (197, 200))	('VHL', 'Gene', '7428', (197, 200))	('transcription factor', 'molecular_function', 'GO:0000981', ('240', '260'))	('chromatin', 'cellular_component', 'GO:0000785', ('98', '107'))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('mutant', 'Var', (201, 207))	('transcription', 'biological_process', 'GO:0006351', ('240', '253'))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('RCC', 'Disease', (210, 213))	('ccRCC', 'Phenotype', 'HP:0006770', (208, 213))	('RCC', 'Disease', 'MESH:C538614', (210, 213))	('H3K27ac', 'Protein', (90, 97))
20036	30858363	We analysed RNA-seq data from several ccRCC cell lines to determine the expression level of the full-length KLF6 as well as the reported three KLF6 variants.	('RNA', 'cellular_component', 'GO:0005562', ('12', '15'))	('RCC', 'Disease', (40, 43))	('variants', 'Var', (148, 156))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))
20037	30858363	To test the biological relevance of KLF6, we inactivated KLF6 using lentivirally delivered CRISPR-Cas9 in VHL mutant ccRCC cell lines.	('Cas', 'cellular_component', 'GO:0005650', ('98', '101'))	('mutant', 'Var', (110, 116))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('KLF6', 'Gene', (57, 61))	('VHL', 'Gene', (106, 109))	('RCC', 'Disease', (119, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('VHL', 'Gene', '7428', (106, 109))
20038	30858363	We used cell lines derived from human tumours (UOK101 and RCC-MF) but also experimentally derived highly metastatic subclones of human ccRCC cell lines (786-M1A and OS-LM1), which recapitulate several important features of human ccRCC at both phenotypic and molecular levels, including high metastatic potential and relevant histology in xenograft assays, in vivo response to drug treatment, mutational landscape, and activation of genes that correlate with poor patient outcome in clinical ccRCC data sets.	('mutational', 'Var', (392, 402))	('response to drug', 'biological_process', 'GO:0042493', ('364', '380'))	('RCC', 'Disease', (58, 61))	('UOK101', 'CellLine', 'CVCL:B076', (47, 53))	('OS-LM1', 'CellLine', 'CVCL:9563', (165, 171))	('human', 'Species', '9606', (223, 228))	('genes', 'Gene', (432, 437))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('human', 'Species', '9606', (32, 37))	('RCC', 'Disease', (137, 140))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (229, 234))	('RCC', 'Disease', (231, 234))	('RCC', 'Disease', (493, 496))	('ccRCC', 'Phenotype', 'HP:0006770', (491, 496))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('clinical', 'Species', '191496', (482, 490))	('tumours', 'Disease', (38, 45))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('patient', 'Species', '9606', (463, 470))	('RCC', 'Disease', 'MESH:C538614', (231, 234))	('RCC', 'Disease', 'MESH:C538614', (493, 496))	('tumours', 'Phenotype', 'HP:0002664', (38, 45))	('activation', 'PosReg', (418, 428))	('human', 'Species', '9606', (129, 134))	('tumours', 'Disease', 'MESH:D009369', (38, 45))
20051	30858363	However, simultaneous inactivation of several constituent enhancers, as well as a large deletion of the super enhancer, resulted in significant KLF6 downregulation, supporting the idea that this large enhancer cluster functions in a modular manner to drive KLF6 expression in ccRCC.	('inactivation', 'Var', (22, 34))	('RCC', 'Disease', 'MESH:C538614', (278, 281))	('RCC', 'Disease', (278, 281))	('deletion', 'Var', (88, 96))	('drive', 'PosReg', (251, 256))	('KLF6', 'MPA', (144, 148))	('ccRCC', 'Phenotype', 'HP:0006770', (276, 281))	('downregulation', 'NegReg', (149, 163))
20063	30858363	In agreement with the finding that KLF6 operated at least partially downstream of the HIF2A pathway, gene set enrichment analysis on the differentially expressed genes revealed a highly significant association between KLF6-depletion and downregulation of the canonical hypoxia-response gene set (Supplementary Fig.	('KLF6-depletion', 'Var', (218, 232))	('HIF2A', 'Gene', '2034', (86, 91))	('downregulation', 'NegReg', (237, 251))	('hypoxia', 'Disease', (269, 276))	('HIF2A', 'Gene', (86, 91))	('hypoxia', 'Disease', 'MESH:D000860', (269, 276))
20076	30858363	Pathways related to lipid homeostasis such as cholesterol and triacylglycerol biosynthesis were among the topmost significantly altered pathways with several key genes being downregulated in the KLF6 knockdown cells (Fig.	('knockdown', 'Var', (200, 209))	('cholesterol', 'Chemical', 'MESH:D002784', (46, 57))	('lipid', 'Chemical', 'MESH:D008055', (20, 25))	('downregulated', 'NegReg', (174, 187))	('lipid homeostasis', 'biological_process', 'GO:0055088', ('20', '37'))	('altered', 'Reg', (128, 135))	('triacylglycerol', 'Chemical', 'MESH:D014280', (62, 77))	('KLF6', 'Gene', (195, 199))	('triacylglycerol biosynthesis', 'biological_process', 'GO:0019432', ('62', '90'))
20077	30858363	Gene set enrichment analysis also revealed a significant association between genes downregulated upon KLF6 inhibition and those involved in cholesterol homeostasis (Fig.	('cholesterol homeostasis', 'biological_process', 'GO:0042632', ('140', '163'))	('cholesterol', 'Chemical', 'MESH:D002784', (140, 151))	('downregulated', 'NegReg', (83, 96))	('KLF6', 'Gene', (102, 106))	('inhibition', 'Var', (107, 117))
20078	30858363	A targeted analysis of the key genes that participate in each step of triacylglycerol and cholesterol biosynthesis pathways revealed that many of these genes were downregulated in the KLF6 knockdown cells (Supplementary Fig.	('cholesterol biosynthesis', 'biological_process', 'GO:0006695', ('90', '114'))	('downregulated', 'NegReg', (163, 176))	('cholesterol', 'Chemical', 'MESH:D002784', (90, 101))	('triacylglycerol', 'Chemical', 'MESH:D014280', (70, 85))	('knockdown', 'Var', (189, 198))
20079	30858363	In addition, two critical transcription factors, SREBF1 and SREBF2, that support the expression of lipid homeostasis genes, were also downregulated by KLF6 inhibition.	('expression', 'MPA', (85, 95))	('inhibition', 'Var', (156, 166))	('lipid', 'Chemical', 'MESH:D008055', (99, 104))	('downregulated', 'NegReg', (134, 147))	('SREBF1', 'Gene', (49, 55))	('SREBF2', 'Gene', '6721', (60, 66))	('lipid homeostasis', 'biological_process', 'GO:0055088', ('99', '116'))	('SREBF1', 'Gene', '6720', (49, 55))	('transcription', 'biological_process', 'GO:0006351', ('26', '39'))	('SREBF2', 'Gene', (60, 66))	('lipid homeostasis', 'MPA', (99, 116))
20101	30858363	To test the role of KLF6 as a direct regulator of lipid metabolism genes, we then performed ChIP-seq on flag-tagged KLF6 that was introduced into KLF6-depleted cells.	('lipid', 'Chemical', 'MESH:D008055', (50, 55))	('lipid metabolism', 'biological_process', 'GO:0006629', ('50', '66'))	('KLF6', 'Gene', (116, 120))	('flag-tagged', 'Var', (104, 115))
20120	30858363	Knocking down PDGFB inhibited mTORC1 activity (Fig.	('PDGFB', 'Gene', (14, 19))	('mTORC1', 'Gene', '382056', (30, 36))	('mTORC1', 'Gene', (30, 36))	('inhibited', 'NegReg', (20, 29))	('PDGFB', 'Gene', '5155', (14, 19))	('mTORC1', 'cellular_component', 'GO:0031931', ('30', '36'))	('Knocking', 'Var', (0, 8))
20125	30858363	The high prevalence of VHL mutations and consequent HIF2A stabilization could thus explain the relatively high KLF6 mRNA levels observed in human ccRCCs.	('mutations', 'Var', (27, 36))	('human', 'Species', '9606', (140, 145))	('RCC', 'Disease', (148, 151))	('VHL', 'Gene', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('HIF2A', 'Gene', '2034', (52, 57))	('KLF6 mRNA levels', 'MPA', (111, 127))	('VHL', 'Gene', '7428', (23, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('HIF2A', 'Gene', (52, 57))
20131	30858363	We characterized one of the strongest super enhancer loci in ccRCC cells by targeted inhibition of several of its constituent enhancers using CRISPRi and by deleting a large 113 kb segment of the super enhancer using CRISPR-Cas9 gene editing.	('Cas', 'cellular_component', 'GO:0005650', ('224', '227'))	('RCC', 'Disease', (63, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('deleting', 'Var', (157, 165))	('inhibition', 'NegReg', (85, 95))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
20133	30858363	Finally, even in the cells with a large deletion that covered several individual enhancers, KLF6 mRNA level was reduced by only ~65%.	('deletion', 'Var', (40, 48))	('KLF6 mRNA level', 'MPA', (92, 107))	('reduced', 'Chemical', '-', (112, 119))	('reduced', 'NegReg', (112, 119))
20134	30858363	It is interesting to note, however, that VHL restoration and the consequent inactivation of HIF2A was able to reduce KLF6 expression by ~50%.	('VHL', 'Gene', '7428', (41, 44))	('HIF2A', 'Gene', (92, 97))	('KLF6 expression', 'MPA', (117, 132))	('inactivation', 'Var', (76, 88))	('VHL', 'Gene', (41, 44))	('HIF2A', 'Gene', '2034', (92, 97))	('reduce', 'NegReg', (110, 116))
20138	30858363	In ccRCC specifically, the large TCGA cohort of 448 cases reports no point mutations and only one tumour with a deep deletion of KLF6.	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('tumour', 'Disease', (98, 104))	('RCC', 'Disease', (5, 8))	('KLF6', 'Gene', (129, 133))	('point mutations', 'Var', (69, 84))
20141	30858363	Mechanistically, we demonstrate that KLF6 regulates the expression of lipid homeostasis genes directly, but it also enhances the activation of SREBF1 and SREBF2 by supporting the expression of PDGFB, a prominent activator of the mTOR pathway.	('expression', 'MPA', (179, 189))	('KLF6', 'Var', (37, 41))	('SREBF2', 'Gene', '6721', (154, 160))	('PDGFB', 'Gene', '5155', (193, 198))	('SREBF1', 'Gene', '6720', (143, 149))	('lipid homeostasis genes', 'Gene', (70, 93))	('mTOR', 'Gene', (229, 233))	('enhances', 'PosReg', (116, 124))	('PDGFB', 'Gene', (193, 198))	('activation', 'PosReg', (129, 139))	('mTOR', 'Gene', '2475', (229, 233))	('expression', 'MPA', (56, 66))	('lipid', 'Chemical', 'MESH:D008055', (70, 75))	('supporting', 'PosReg', (164, 174))	('regulates', 'Reg', (42, 51))	('lipid homeostasis', 'biological_process', 'GO:0055088', ('70', '87'))	('SREBF2', 'Gene', (154, 160))	('SREBF1', 'Gene', (143, 149))
20142	30858363	Genetic and pharmacological inhibition of SREBF1 and SREBF2 activity also reduced ccRCC proliferation, suggesting that effects on lipid metabolism explain at least partially the phenotypic consequences of KLF6 depletion, although our results do not exclude the possibility that KLF6 promotes ccRCC growth through other mechanisms as well.	('reduced', 'Chemical', '-', (74, 81))	('SREBF2', 'Gene', '6721', (53, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('lipid', 'Chemical', 'MESH:D008055', (130, 135))	('lipid metabolism', 'biological_process', 'GO:0006629', ('130', '146'))	('inhibition', 'Var', (28, 38))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('SREBF1', 'Gene', '6720', (42, 48))	('RCC', 'Disease', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (294, 297))	('SREBF2', 'Gene', (53, 59))	('RCC', 'Disease', (294, 297))	('ccRCC', 'Phenotype', 'HP:0006770', (292, 297))	('reduced', 'NegReg', (74, 81))	('SREBF1', 'Gene', (42, 48))
20150	30858363	However, as VHL reintroduction increases CPT1A expression but decreases KLF6 expression, and KLF6 supports CPT1A expression (Supplementary Fig.	('VHL', 'Gene', (12, 15))	('expression', 'MPA', (113, 123))	('decreases', 'NegReg', (62, 71))	('CPT', 'molecular_function', 'GO:0004095', ('41', '44'))	('VHL', 'Gene', '7428', (12, 15))	('KLF6 expression', 'MPA', (72, 87))	('reintroduction', 'Var', (16, 30))	('CPT1A', 'Gene', (107, 112))	('increases', 'PosReg', (31, 40))	('CPT1A', 'Gene', (41, 46))	('CPT', 'molecular_function', 'GO:0004142', ('107', '110'))	('CPT', 'molecular_function', 'GO:0004095', ('107', '110'))	('CPT1A', 'Gene', '1374', (107, 112))	('CPT1A', 'Gene', '1374', (41, 46))	('expression', 'MPA', (47, 57))	('CPT', 'molecular_function', 'GO:0004142', ('41', '44'))
20156	30858363	In a phase II randomised trial of everolimus and lenvatinib (an inhibitor of both PDGFRA and PDGFRB) in combination versus the drugs as monotherapy for patients with metastatic renal cell carcinoma who have progressed after one previous VEGF-targeted therapy, lenvatinib plus everolimus were found to act synergistically to provide a progression-free survival (PFS) benefit over either drug alone, although a significant difference was seen only over everolimus (median PFS 14 6 months vs 5 5 months).	('VEGF', 'Gene', (237, 241))	('lenvatinib', 'Var', (260, 270))	('benefit', 'PosReg', (366, 373))	('everolimus', 'Chemical', 'MESH:D000068338', (34, 44))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (177, 197))	('PDGFRB', 'Gene', '5159', (93, 99))	('PDGFRB', 'Gene', (93, 99))	('lenvatinib', 'Chemical', 'MESH:C531958', (49, 59))	('progression-free survival', 'CPA', (334, 359))	('metastatic renal cell carcinoma', 'Disease', (166, 197))	('metastatic renal cell carcinoma', 'Disease', 'MESH:C538445', (166, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('patients', 'Species', '9606', (152, 160))	('PDGFRA', 'Gene', '5156', (82, 88))	('PDGFRA', 'Gene', (82, 88))	('everolimus', 'Chemical', 'MESH:D000068338', (276, 286))	('lenvatinib', 'Chemical', 'MESH:C531958', (260, 270))	('everolimus', 'Chemical', 'MESH:D000068338', (451, 461))	('VEGF', 'Gene', '7422', (237, 241))
20174	30858363	Fatostatin (F8932), simvastatin (S6196), propylene glycol (W294004) and Tween-80 (P4780) were purchased from Sigma-Aldrich.	('S6196', 'Var', (33, 38))	('Fatostatin', 'Chemical', 'MESH:C545733', (0, 10))	('F8932', 'Var', (12, 17))	('propylene glycol', 'Chemical', 'MESH:D019946', (41, 57))	('simvastatin', 'Chemical', 'MESH:D019821', (20, 31))	('Tween-80', 'Chemical', 'MESH:D011136', (72, 80))	('P4780', 'Var', (82, 87))	('W294004', 'Var', (59, 66))
20189	30858363	Publicly available SREBF1/2 ChIP-seq data sets were collected from NCBI GEO and SRA databases (SRP007993, SRP028819, SRP097662, SRP012412).	('SREBF1', 'Gene', '6720', (19, 25))	('SRP', 'cellular_component', 'GO:0005786', ('117', '120'))	('SRP', 'cellular_component', 'GO:0005786', ('106', '109'))	('SRP', 'cellular_component', 'GO:0005786', ('128', '131'))	('SRP097662', 'Var', (117, 126))	('SRP', 'cellular_component', 'GO:0005786', ('95', '98'))	('SREBF1', 'Gene', (19, 25))	('SRP007993', 'Var', (95, 104))	('SRP012412', 'Var', (128, 137))	('SRP028819', 'Var', (106, 115))
20201	30858363	For CRISPR-Cas9 mutagenesis competitive proliferation assay, control and targeted cells which carried different fluorescent markers (BFP+ or mCherry+) were mixed at a 1:1 ratio and plated onto 6-wells plates.	('Cas', 'cellular_component', 'GO:0005650', ('11', '14'))	('BFP', 'Gene', '7732', (133, 136))	('mutagenesis', 'Var', (16, 27))	('mutagenesis', 'biological_process', 'GO:0006280', ('16', '27'))	('BFP', 'Gene', (133, 136))
20204	30858363	The following TaqMan probes were used: KLF6 (Hs00810569_m1), EPAS1 (Hs01026149_m1), PDGFB (Hs00966522_m1), CXCR4 (Hs00607978_s1), CCND1 (Hs00765663_m1), VEGFA (Hs00900055_m1), BHLHE40 (Hs01041212_m1), SREBF1 (Hs01088679_g1), SREBF2 (Hs01081784_m1), SCD (Hs01682761_m1), LSS (Hs01552331_m1), E2F1 (Hs00153451_m1), CPT1A (Hs00912671_m1) and TBP (Hs00427620_m1).	('Hs01041212_m1', 'Var', (185, 198))	('EPAS1', 'Gene', (61, 66))	('SREBF2', 'Gene', '6721', (225, 231))	('Hs00765663_m1', 'Var', (137, 150))	('Hs00427620_m1', 'Var', (344, 357))	('VEGFA', 'Gene', (153, 158))	('CCND1', 'Gene', (130, 135))	('LSS', 'Gene', (270, 273))	('BHLHE40', 'Gene', '8553', (176, 183))	('SCD', 'Gene', (249, 252))	('Hs01682761_m1', 'Var', (254, 267))	('SREBF1', 'Gene', '6720', (201, 207))	('CXCR4', 'molecular_function', 'GO:0038147', ('107', '112'))	('TBP', 'Gene', (339, 342))	('SCD', 'Gene', '6319', (249, 252))	('PDGFB', 'Gene', '5155', (84, 89))	('SREBF1', 'Gene', (201, 207))	('CXCR4', 'Gene', '7852', (107, 112))	('CPT1A', 'Gene', '1374', (313, 318))	('Hs00900055_m1', 'Var', (160, 173))	('CPT', 'molecular_function', 'GO:0004142', ('313', '316'))	('Hs00966522_m1', 'Var', (91, 104))	('Hs00153451_m1', 'Var', (297, 310))	('CXCR4', 'Gene', (107, 112))	('VEGFA', 'Gene', '7422', (153, 158))	('EPAS1', 'Gene', '2034', (61, 66))	('TBP', 'Gene', '6908', (339, 342))	('Hs00912671_m1', 'Var', (320, 333))	('CPT1A', 'Gene', (313, 318))	('LSS', 'Gene', '4047', (270, 273))	('PDGFB', 'Gene', (84, 89))	('E2F1', 'Gene', (291, 295))	('Hs01081784_m1', 'Var', (233, 246))	('Hs01552331_m1', 'Var', (275, 288))	('Hs01088679_g1', 'Var', (209, 222))	('SREBF2', 'Gene', (225, 231))	('E2F1', 'Gene', '1869', (291, 295))	('BHLHE40', 'Gene', (176, 183))	('CCND1', 'Gene', '595', (130, 135))	('CPT', 'molecular_function', 'GO:0004095', ('313', '316'))
20225	31551755	Within these genes, high Tau/MAPT expression shows the strongest correlation with several indicators of prolonged survival on glioma patients.	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('Tau/MAPT', 'Protein', (25, 33))	('expression', 'MPA', (34, 44))	('patients', 'Species', '9606', (133, 141))	('high', 'Var', (20, 24))	('glioma', 'Disease', (126, 132))
20264	31551755	The following primary antibodies (anti-Tau, Dako A0024; anti-Ki67, Dako M7240 and anti-GFAP, M 0761) were incubated O/N at 4 C. The second day, section was washed with PBS three times prior to incubation with the appropriate fluorescent secondary antibody (anti-mouse and anti rabbit Jackson immunoresearch) for 2 h at room temperature.	('antibody', 'cellular_component', 'GO:0019815', ('247', '255'))	('antibody', 'molecular_function', 'GO:0003823', ('247', '255'))	('GFAP', 'Gene', '2670', (87, 91))	('GFAP', 'cellular_component', 'GO:0045101', ('87', '91'))	('anti-Ki67', 'Var', (56, 65))	('mouse', 'Species', '10090', (262, 267))	('rabbit', 'Species', '9986', (277, 283))	('antibody', 'cellular_component', 'GO:0042571', ('247', '255'))	('GFAP', 'Gene', (87, 91))	('antibody', 'cellular_component', 'GO:0019814', ('247', '255'))
20270	31551755	To begin to address if there is a molecular correlation between gliomas and neurodegenerative diseases we analyzed the TCGA merge dataset for LGG and GBM looking for the presence of mutations and copy number alterations in genes associated with AD, PD, and ALS.	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (76, 101))	('PD', 'Disease', 'MESH:D010300', (249, 251))	('ALS', 'Phenotype', 'HP:0007354', (257, 260))	('neurodegenerative diseases', 'Disease', (76, 102))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('AD', 'Disease', (245, 247))	('ALS', 'Disease', (257, 260))	('AD', 'Phenotype', 'HP:0002511', (245, 247))	('ALS', 'Disease', 'MESH:D000690', (257, 260))	('GBM', 'Disease', (150, 153))	('GBM', 'Disease', 'MESH:D005909', (150, 153))	('AD', 'Disease', 'MESH:D000544', (245, 247))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (76, 102))	('gliomas', 'Disease', (64, 71))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (76, 102))	('GBM', 'Phenotype', 'HP:0012174', (150, 153))	('copy number alterations', 'Var', (196, 219))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))
20274	31551755	Figure 1A shows that there is a very low frequency of somatic mutations or copy number variations (CNV) in glioma samples for all the genes included in the study.	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('copy number variations', 'Var', (75, 97))	('glioma', 'Disease', (107, 113))	('glioma', 'Disease', 'MESH:D005910', (107, 113))
20275	31551755	The higher percentage of genetic alterations was found in the C9orf7 gene (3%), mainly associated with deep deletions that, in any case, are not frequently found in ALS patients.	('C9orf7', 'Gene', '11094', (62, 68))	('C9orf7', 'Gene', (62, 68))	('patients', 'Species', '9606', (169, 177))	('ALS', 'Phenotype', 'HP:0007354', (165, 168))	('ALS', 'Disease', (165, 168))	('associated', 'Reg', (87, 97))	('ALS', 'Disease', 'MESH:D000690', (165, 168))	('deep deletions', 'Var', (103, 117))	('genetic alterations', 'Var', (25, 44))
20276	31551755	Overall, these results suggest that genetic alterations in genes associated with neurodegeneration are not common drivers of gliomas.	('gliomas', 'Disease', (125, 132))	('gliomas', 'Disease', 'MESH:D005910', (125, 132))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('neurodegeneration', 'Phenotype', 'HP:0002180', (81, 98))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('genetic alterations', 'Var', (36, 55))
20294	31551755	To gain further insight into the relevance of Tau in cancer we analyzed the TCGA cohorts for different cancers and we used the median of Tau/MAPT expression to classify tumors into High or Low-Tau.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (53, 59))	('High', 'Var', (181, 185))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancer', 'Disease', (103, 109))	('tumors', 'Disease', (169, 175))	('cancers', 'Disease', (103, 110))
20295	31551755	In accordance with our previous data (Table 1), gliomas with high levels of Tau/MAPT have a much better prognosis (Table 2).	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('Tau/MAPT', 'Protein', (76, 84))	('high levels', 'Var', (61, 72))	('gliomas', 'Disease', (48, 55))
20296	31551755	However, the expression of this gene also correlates with an increase in the overall survival of patients with breast cancer, kidney clear cell carcinoma, lung adenocarcinoma and pheochromocytoma/paraganglioma (Table 2).	('glioma', 'Phenotype', 'HP:0009733', (203, 209))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (179, 195))	('paraganglioma', 'Phenotype', 'HP:0002668', (196, 209))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('expression', 'Var', (13, 23))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('kidney clear cell carcinoma, lung adenocarcinoma and pheochromocytoma/paraganglioma', 'Disease', 'MESH:D018262', (126, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('increase', 'PosReg', (61, 69))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (155, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('breast cancer', 'Disease', (111, 124))	('patients', 'Species', '9606', (97, 105))
20327	31551755	It is worth mentioning that there have been previous reports of deregulations (mutations and copy number losses) observed in PARK2 in GBM, which argue in favor of a possible tumor suppressor function of this gene in such tumors.	('tumor suppressor', 'biological_process', 'GO:0051726', ('174', '190'))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('GBM', 'Phenotype', 'HP:0012174', (134, 137))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('mutations', 'Var', (79, 88))	('tumors', 'Disease', (221, 227))	('deregulations', 'MPA', (64, 77))	('PARK2', 'Gene', '5071', (125, 130))	('tumor', 'Disease', (221, 226))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumor', 'Disease', (174, 179))	('GBM', 'Disease', (134, 137))	('GBM', 'Disease', 'MESH:D005909', (134, 137))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('174', '190'))	('PARK2', 'Gene', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('copy number losses', 'Var', (93, 111))
20328	31551755	Still, our meta-analysis indicates a lower frequency of PARK2 deletions in the joint cohort of gliomas.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('PARK2', 'Gene', '5071', (56, 61))	('PARK2', 'Gene', (56, 61))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('gliomas', 'Disease', (95, 102))	('deletions', 'Var', (62, 71))
20329	31551755	However, we only accounted for those CNV that appear in homozygosity, which could explain why we found a reduced percentage of gliomas with these deletions.	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('deletions', 'Var', (146, 155))	('gliomas', 'Disease', (127, 134))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))
20332	31551755	However, our analysis has found a very small percentage of gliomas (0.3%) with Tau alterations (amplifications and deletions).	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('Tau', 'Protein', (79, 82))	('gliomas', 'Disease', (59, 66))	('deletions', 'Var', (115, 124))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))	('alterations', 'Reg', (83, 94))
20336	31551755	In AD and other tauopathies, it has been postulated that changes in the expression of the different Tau/MAPT splicing isoforms might facilitate the neurodegeneration.	('tauopathies', 'Disease', 'MESH:D024801', (16, 27))	('neurodegeneration', 'CPA', (148, 165))	('tauopathies', 'Disease', (16, 27))	('changes', 'Var', (57, 64))	('splicing', 'biological_process', 'GO:0045292', ('109', '117'))	('expression', 'MPA', (72, 82))	('AD', 'Phenotype', 'HP:0002511', (3, 5))	('AD', 'Disease', 'MESH:D000544', (3, 5))	('AD', 'Disease', (3, 5))	('facilitate', 'PosReg', (133, 143))	('neurodegeneration', 'Phenotype', 'HP:0002180', (148, 165))
20347	31551755	Therefore, we could speculate that changes in Tau expression could affect at the same time the EMT and the invasion capacity of the glioma cells.	('glioma', 'Disease', (132, 138))	('affect', 'Reg', (67, 73))	('EMT', 'biological_process', 'GO:0001837', ('95', '98'))	('EMT', 'CPA', (95, 98))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('Tau', 'Protein', (46, 49))	('changes', 'Var', (35, 42))	('expression', 'MPA', (50, 60))
20353	31551755	More recently, Tau deletion has been linked to defects in the insulin signaling pathway in the brain.	('signaling pathway', 'biological_process', 'GO:0007165', ('70', '87'))	('deletion', 'Var', (19, 27))	('defects', 'NegReg', (47, 54))	('insulin', 'molecular_function', 'GO:0016088', ('62', '69'))	('insulin', 'Gene', (62, 69))	('Tau', 'Gene', (15, 18))	('insulin', 'Gene', '3630', (62, 69))
20363	31551755	Cabazitaxel has been evaluated with a limited success in a phase II study for temozolomide refractory gliomas (NCT01740570 and NCT01866449) and now is being investigated clinically in combination with cisplatin.	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (201, 210))	('Cabazitaxel', 'Chemical', 'MESH:C552428', (0, 11))	('NCT01866449', 'Var', (127, 138))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('temozolomide refractory gliomas', 'Phenotype', 'HP:0012174', (78, 109))	('temozolomide refractory gliomas', 'Disease', (78, 109))	('NCT01740570', 'Var', (111, 122))	('temozolomide refractory gliomas', 'Disease', 'MESH:D005910', (78, 109))
20368	31551755	By contrast, low Tau expression identifies a subset of ER-positive breast cancers that have poor prognosis when treated with tamoxifen alone, although they may benefit from chemotherapy with taxanes.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('Tau', 'Protein', (17, 20))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('ER', 'Gene', '2099', (55, 57))	('low', 'Var', (13, 16))	('taxanes', 'Chemical', 'MESH:C080625', (191, 198))	('breast cancers', 'Phenotype', 'HP:0003002', (67, 81))	('tamoxifen', 'Chemical', 'MESH:D013629', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancers', 'Disease', 'MESH:D001943', (67, 81))	('breast cancers', 'Disease', (67, 81))
20386	29963273	In vitro experiments using ovarian cancer cells with cytoplasmic expression of MCM2 demonstrated that transfection of MCM2-DeltaN enhanced DNA damage-induced apoptosis.	('ovarian cancer', 'Disease', (27, 41))	('DNA', 'CPA', (139, 142))	('enhanced', 'PosReg', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('ovarian cancer', 'Phenotype', 'HP:0100615', (27, 41))	('ovarian cancer', 'Disease', 'MESH:D010051', (27, 41))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('apoptosis', 'biological_process', 'GO:0097194', ('158', '167'))	('apoptosis', 'biological_process', 'GO:0006915', ('158', '167'))	('MCM2-DeltaN', 'Var', (118, 129))
20390	29963273	It was first defined as a histological subtype in 1973 by the World Health Organization (WHO) and found to be distinct from other epithelial ovarian carcinomas with frequent mutations of ARID1A and PIK3CA.	('PIK3CA', 'Gene', '5290', (198, 204))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (141, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('epithelial ovarian carcinomas', 'Disease', 'MESH:D000077216', (130, 159))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (141, 159))	('ARID1A', 'Gene', '8289', (187, 193))	('PIK3CA', 'Gene', (198, 204))	('mutations', 'Var', (174, 183))	('ARID1A', 'Gene', (187, 193))	('epithelial ovarian carcinomas', 'Disease', (130, 159))
20397	29963273	High expression MCM2 level in malignant tumors, including ovarian cancer, is associated with several clinico-pathological parameters such as advanced tumor grade, advanced stage, and poor prognosis.	('ovarian cancer', 'Phenotype', 'HP:0100615', (58, 72))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('ovarian cancer', 'Disease', 'MESH:D010051', (58, 72))	('malignant tumors', 'Disease', (30, 46))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('malignant tumors', 'Disease', 'MESH:D018198', (30, 46))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('ovarian cancer', 'Disease', (58, 72))	('MCM2', 'MPA', (16, 20))	('tumor', 'Disease', (150, 155))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
20399	29963273	The increased apoptosis rate was almost exclusively observed in C3H mice expressing high levels of MCM2 in hematopoietic cells.	('mice', 'Species', '10090', (68, 72))	('MCM2', 'Var', (99, 103))	('apoptosis', 'biological_process', 'GO:0097194', ('14', '23'))	('apoptosis', 'biological_process', 'GO:0006915', ('14', '23'))	('apoptosis rate', 'CPA', (14, 28))
20400	29963273	We also demonstrated that the FLV-derived envelope protein gp70 enhanced cellular apoptotic signaling specifically in cells that overexpressed MCM2.	('gp70', 'Gene', (59, 63))	('MCM2', 'Var', (143, 147))	('signaling', 'biological_process', 'GO:0023052', ('92', '101'))	('gp70', 'Gene', '133418', (59, 63))	('envelope', 'cellular_component', 'GO:0031975', ('42', '50'))	('envelope', 'cellular_component', 'GO:0009274', ('42', '50'))	('cellular apoptotic signaling', 'MPA', (73, 101))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))	('enhanced', 'PosReg', (64, 72))
20432	29963273	However, after treatment with cisplatin, both cell types revealed significant induction of apoptosis with MCM2-FL transfection (Figure 5C, 5D).	('apoptosis', 'CPA', (91, 100))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('78', '100'))	('MCM2-FL transfection', 'Var', (106, 126))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))
20444	29963273	Overexpression of glypican-3 may be related to low-level proliferation of tumor cells and is associated with resistance to chemotherapy and poor prognosis of clear cell carcinoma.	('clear cell carcinoma', 'Disease', (158, 178))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (158, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('low-level proliferation', 'CPA', (47, 70))	('glypican-3', 'Gene', '2719', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('associated', 'Reg', (93, 103))	('tumor', 'Disease', (74, 79))	('Overexpression', 'Var', (0, 14))	('glypican', 'molecular_function', 'GO:0015017', ('18', '26'))	('glypican-3', 'Gene', (18, 28))
20448	29963273	Similarly, the labeling indices of MCM2 and MCM5 proteins of ovarian adenocarcinomas were associated with adverse patient outcomes in univariate and multivariate analyses.	('ovarian adenocarcinomas', 'Disease', 'MESH:D010051', (61, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('associated', 'Reg', (90, 100))	('MCM5', 'Gene', '4174', (44, 48))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (61, 83))	('MCM2', 'Var', (35, 39))	('patient', 'Species', '9606', (114, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('MCM5', 'Gene', (44, 48))	('ovarian adenocarcinomas', 'Disease', (61, 84))
20449	29963273	Therefore, MCM2 and MCM5 proteins are promising prognostic markers in patients with ovarian adenocarcinoma.	('patients', 'Species', '9606', (70, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('MCM5', 'Gene', (20, 24))	('ovarian adenocarcinoma', 'Disease', 'MESH:D010051', (84, 106))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (84, 106))	('MCM2', 'Var', (11, 15))	('ovarian adenocarcinoma', 'Disease', (84, 106))	('MCM5', 'Gene', '4174', (20, 24))
20468	29963273	sc-9839, 1:250 (Santa Cruz Biotechnology, Inc., Dallas, TX, USA); anti-Ki-67 (MIB-1), mouse monoclonal, clone no.	('MIB-1', 'Gene', '57534', (78, 83))	('anti-Ki-67', 'Var', (66, 76))	('mouse', 'Species', '10090', (86, 91))	('MIB-1', 'Gene', (78, 83))
20484	29963273	The protein levels of 3xFLAG-MCM2-FL and 3xFLAG-MCM2-DeltaN were confirmed by western blotting as previously described.	('3xFLAG-MCM2-FL', 'Var', (22, 36))	('3xFLAG-MCM2-DeltaN', 'Gene', '4171', (41, 59))	('3xFLAG-MCM2-DeltaN', 'Gene', (41, 59))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
20486	29963273	Ten thousand OVTOKO and OVISE cells, which overexpressed FLAG-MCM2-FL and 3xFLAG-MCM2-DeltaN, were cultured on Falcon  4 Well Culture Slides (BD Falcon NJ, USA).	('FLAG-MCM2-FL', 'Var', (57, 69))	('overexpressed', 'PosReg', (43, 56))	('3xFLAG-MCM2-DeltaN', 'Gene', (74, 92))	('3xFLAG-MCM2-DeltaN', 'Gene', '4171', (74, 92))
20500	29552295	Meanwhile, silencing of LOC653786 suppressed RCC cell growth and cell cycle progression, which was alleviated by overexpression of FOXM1.	('silencing', 'Var', (11, 20))	('expression', 'Species', '29278', (117, 127))	('cell cycle progression', 'CPA', (65, 87))	('LOC653786', 'Gene', '653786', (24, 33))	('suppressed', 'NegReg', (34, 44))	('cell growth', 'biological_process', 'GO:0016049', ('49', '60'))	('LOC653786', 'Gene', (24, 33))	('cell cycle', 'biological_process', 'GO:0007049', ('65', '75'))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
20522	29552295	As shown in Figure 2, CCK-8 and colony formation assays showed that knockdown of LOC653786 by siRNA significantly suppressed the survival and colony formation of RCC cells, while overexpression of LOC653786 dramatically increased RCC cell viability and colony formation.	('increased', 'PosReg', (220, 229))	('colony formation', 'CPA', (253, 269))	('LOC653786', 'Gene', (197, 206))	('RCC', 'Disease', (162, 165))	('RCC', 'Phenotype', 'HP:0005584', (162, 165))	('knockdown', 'Var', (68, 77))	('formation', 'biological_process', 'GO:0009058', ('149', '158'))	('LOC653786', 'Gene', '653786', (81, 90))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('formation', 'biological_process', 'GO:0009058', ('39', '48'))	('RCC', 'Disease', (230, 233))	('RCC', 'Phenotype', 'HP:0005584', (230, 233))	('formation', 'biological_process', 'GO:0009058', ('260', '269'))	('survival', 'CPA', (129, 137))	('LOC653786', 'Gene', (81, 90))	('expression', 'Species', '29278', (183, 193))	('suppressed', 'NegReg', (114, 124))	('RCC', 'Disease', 'MESH:C538614', (230, 233))	('LOC653786', 'Gene', '653786', (197, 206))	('colony formation', 'CPA', (142, 158))
20532	29552295	As shown in Figure 5, silencing of LOC653786 in RCC cells suppressed the expression of cyclin B1 and cyclin D1, decreased the cell viability and colony formation, and led to a cell cycle arrest at G1 phase.	('G1 phase', 'biological_process', 'GO:0051318', ('197', '205'))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('cell cycle arrest at G1 phase', 'CPA', (176, 205))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('176', '193'))	('formation', 'biological_process', 'GO:0009058', ('152', '161'))	('led to', 'Reg', (167, 173))	('cyclin D1', 'Protein', (101, 110))	('cyclin', 'molecular_function', 'GO:0016538', ('87', '93'))	('decreased', 'NegReg', (112, 121))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (176, 193))	('LOC653786', 'Gene', '653786', (35, 44))	('expression', 'MPA', (73, 83))	('silencing', 'Var', (22, 31))	('cyclin', 'molecular_function', 'GO:0016538', ('101', '107'))	('cyclin B1', 'Protein', (87, 96))	('LOC653786', 'Gene', (35, 44))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('expression', 'Species', '29278', (73, 83))	('suppressed', 'NegReg', (58, 68))
20535	29552295	All the LOC653786 overexpression-induced effects above were markedly alleviated by silencing of FOXM1.	('FOXM1', 'Gene', (96, 101))	('alleviated', 'NegReg', (69, 79))	('overexpression-induced', 'PosReg', (18, 40))	('LOC653786', 'Gene', '653786', (8, 17))	('expression', 'Species', '29278', (22, 32))	('LOC653786', 'Gene', (8, 17))	('silencing', 'Var', (83, 92))
20536	29552295	Additionally, qPCR assays clarified that both the overexpression of FOXM1 in 786-O cells (Supplementery Figure 2A) and the silencing of FOXM1 in ACHN cells (Supplementery Figure 2B) were efficient.	('overexpression', 'PosReg', (50, 64))	('FOXM1', 'Gene', (68, 73))	('FOXM1', 'Gene', (136, 141))	('expression', 'Species', '29278', (54, 64))	('silencing', 'Var', (123, 132))
20543	29552295	ccRCC patients can show different clinical manifestation and treatment response because of the tumor heterogeneity in histology, oncogenicity and molecular alterations in tumor suppressor genes.	('RCC', 'Disease', (2, 5))	('tumor', 'Disease', (95, 100))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('patients', 'Species', '9606', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor suppressor', 'biological_process', 'GO:0051726', ('171', '187'))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('171', '187'))	('molecular alterations', 'Var', (146, 167))
20544	29552295	Furthermore, previous reports have shown that the mutations on Von Hippel-Lindau (VHL), Polybromo-1 (PBRM1) and BRCA1 associated protein-1 (BAP1) are the most common somatic mutations in ccRCC which induces the occurrence and development of ccRCC.	('VHL', 'Disease', (82, 85))	('VHL', 'Disease', 'MESH:D006623', (82, 85))	('BAP1', 'Gene', (140, 144))	('mutations', 'Var', (50, 59))	('induces', 'Reg', (199, 206))	('RCC', 'Disease', 'MESH:C538614', (243, 246))	('Von Hippel-Lindau', 'Disease', 'MESH:D006623', (63, 80))	('RCC', 'Disease', (243, 246))	('RCC', 'Phenotype', 'HP:0005584', (243, 246))	('ccRCC', 'Phenotype', 'HP:0006770', (241, 246))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('ccRCC', 'Phenotype', 'HP:0006770', (187, 192))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('PBRM1', 'Gene', (101, 106))	('RCC', 'Disease', (189, 192))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))	('Von Hippel-Lindau', 'Disease', (63, 80))
20545	29552295	In this study, we found that LOC653786 was upregulated in ccRCC tissues compared to normal tissues by analyzing TCGA data, but it is unclear whether the higher level of LOC653786 in ccRCC tissues was associated with the mutations of VHL, BAP1 and PBRM1.	('VHL', 'Disease', 'MESH:D006623', (233, 236))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('RCC', 'Disease', (184, 187))	('VHL', 'Disease', (233, 236))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (182, 187))	('PBRM1', 'Gene', (247, 252))	('LOC653786', 'Gene', '653786', (29, 38))	('associated', 'Reg', (200, 210))	('LOC653786', 'Gene', '653786', (169, 178))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('LOC653786', 'Gene', (169, 178))	('BAP1', 'Gene', (238, 242))	('mutations', 'Var', (220, 229))	('LOC653786', 'Gene', (29, 38))
20575	29552295	The promoter region of FOXM1 gene (-1975 to +21) was chemically synthesized (Sangon) and inserted into pGL3-Basic vector (Promega, Madison, WI, USA), and the resulting recombinant plasmid was named as pGL3-FOXM1.	('pGL', 'molecular_function', 'GO:0004598', ('103', '106'))	('pGL3', 'Gene', (201, 205))	('-1975', 'Var', (35, 40))	('FOXM1', 'Gene', (23, 28))	('pGL3', 'Gene', '6391', (103, 107))	('pGL', 'molecular_function', 'GO:0004598', ('201', '204'))	('pGL3', 'Gene', '6391', (201, 205))	('pGL3', 'Gene', (103, 107))
20615	33391344	ccRCC is not sensitive to radiotherapy and chemotherapy and exhibits an inherited predisposition to infiltrate and metastasize.. Molecular targeted therapy for advanced or metastatic ccRCC has notable curative effectiveness.	('RCC', 'Disease', (185, 188))	('ccRCC', 'Phenotype', 'HP:0006770', (183, 188))	('RCC', 'Disease', (2, 5))	('Molecular targeted therapy', 'Var', (129, 155))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('RCC', 'Disease', 'MESH:C538614', (185, 188))
20620	33391344	Inhibition of glycolysis has the effect of inhibiting proliferation and killing tumor cells.	('inhibiting', 'NegReg', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Inhibition of glycolysis', 'biological_process', 'GO:0045820', ('0', '24'))	('tumor', 'Disease', (80, 85))	('Inhibition', 'Var', (0, 10))	('proliferation', 'CPA', (54, 67))	('glycolysis', 'MPA', (14, 24))
20670	33391344	Although aerobic glycolysis was more detrimental to ATP production than oxidative phosphorylation, aerobic glycolysis increased NADPH synthesis to meet the needs of tumor growth and survival.	('glycolysis', 'biological_process', 'GO:0006096', ('107', '117'))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('72', '97'))	('increased', 'PosReg', (118, 127))	('glycolysis', 'biological_process', 'GO:0006096', ('17', '27'))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('NADPH', 'Gene', (128, 133))	('ATP', 'Chemical', 'MESH:D000255', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('aerobic', 'Var', (99, 106))	('synthesis', 'biological_process', 'GO:0009058', ('134', '143'))	('NADPH', 'Gene', '1666', (128, 133))	('tumor', 'Disease', (165, 170))
20683	33391344	Abnormal expression of B3GAT3 pushed the speed up process of glycolysis, which contributed to the accelerated proliferation of ccRCC cells and worsen the prognosis of ccRCC patients.	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('patients', 'Species', '9606', (173, 181))	('RCC', 'Disease', (169, 172))	('ccRCC', 'Phenotype', 'HP:0006770', (167, 172))	('glycolysis', 'biological_process', 'GO:0006096', ('61', '71'))	('glycolysis', 'MPA', (61, 71))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('RCC', 'Disease', (129, 132))	('accelerated', 'PosReg', (98, 109))	('worsen', 'NegReg', (143, 149))	('Abnormal', 'Var', (0, 8))	('pushed', 'PosReg', (30, 36))	('B3GAT3', 'Gene', '26229', (23, 29))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('B3GAT3', 'Gene', (23, 29))	('speed up process', 'MPA', (41, 57))
20684	33391344	Therefore, inhibiting the expression of B3GAT3 could block the glycolysis pathway of tumor cells, which could effectively decrease the proliferation of tumor cells and even kill tumor cells.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', (178, 183))	('inhibiting', 'Var', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('glycolysis pathway', 'Pathway', (63, 81))	('decrease', 'NegReg', (122, 130))	('tumor', 'Disease', (152, 157))	('B3GAT3', 'Gene', '26229', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('block', 'NegReg', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('kill', 'NegReg', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('glycolysis', 'biological_process', 'GO:0006096', ('63', '73'))	('B3GAT3', 'Gene', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
20688	33391344	In our study, high expression of CENPA was closely related to the survival of patients with ccRCC.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('patients', 'Species', '9606', (78, 86))	('CENPA', 'Gene', (33, 38))	('high', 'Var', (14, 18))	('CENPA', 'Gene', '1058', (33, 38))	('related', 'Reg', (51, 58))
20690	33391344	Inactivation of AGL participated in the pathogenesis of glycogen storage disease.	('storage', 'biological_process', 'GO:0051235', ('65', '72'))	('AGL', 'Gene', '178', (16, 19))	('participated', 'Reg', (20, 32))	('storage disease', 'Disease', (65, 80))	('glycogen', 'Chemical', 'MESH:D006003', (56, 64))	('storage disease', 'Disease', 'MESH:D016464', (65, 80))	('pathogenesis', 'biological_process', 'GO:0009405', ('40', '52'))	('AGL', 'Gene', (16, 19))	('Inactivation', 'Var', (0, 12))
20692	33391344	Darby Oldenburg had further identified that the loss of AGL promoted rapid cancer cell proliferation dependent on extracellular glucose.	('glucose', 'Chemical', 'MESH:D005947', (128, 135))	('AGL', 'Gene', '178', (56, 59))	('loss', 'Var', (48, 52))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cell proliferation', 'biological_process', 'GO:0008283', ('82', '100'))	('promoted', 'PosReg', (60, 68))	('extracellular', 'cellular_component', 'GO:0005576', ('114', '127'))	('cancer', 'Disease', (75, 81))	('AGL', 'Gene', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
20695	33391344	The abnormal expression of ALDH3A2 had a significant impact on the prognosis of patients with ccRCC.	('impact', 'Reg', (53, 59))	('RCC', 'Disease', (96, 99))	('patients', 'Species', '9606', (80, 88))	('abnormal', 'Var', (4, 12))	('ALDH', 'molecular_function', 'GO:0004030', ('27', '31'))	('expression', 'MPA', (13, 23))	('ALDH3A2', 'Gene', '224', (27, 34))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('ALDH3A2', 'Gene', (27, 34))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
20727	29760223	In these tumors, approximately 75% of driver alterations (copy number and mutations) were found to be subclonal, i.e.	('alterations', 'Var', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutations', 'Var', (74, 83))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
20750	29760223	An increase in 9p21.3 (10 [45.5%] vs 2 [9.1%], p=0.007), 8p11 (13 [59.1%] vs 5 [22.7%], p=0.014), 2q37 (5 [22.7%] vs 0 [0%], p=0.048) losses and 3q26 (6 [27.3%] vs 0 [0%], p=0.021) gain were observed in large tumors, however there were not statistically significant after multiple hypothesis testing.	('2q37', 'Var', (98, 102))	('tumors', 'Disease', (209, 215))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('losses', 'NegReg', (134, 140))	('3q26', 'Var', (145, 149))	('8p11', 'Var', (57, 61))	('9p21.3', 'Var', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('gain', 'PosReg', (181, 185))
20753	29760223	We noted subclonal CNVs were more frequent in large tumors (median [range], 4 [0-10] vs 0 [0-8], p<0.001) (Figure 2c).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('subclonal', 'Var', (9, 18))
20766	29760223	Despite the recognition of various CNVs and somatic mutations associated with worse outcome in ccRCC, genomic characterization has not made its way into established clinical guidelines.	('mutations', 'Var', (52, 61))	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('associated', 'Reg', (62, 72))
20799	29760223	A total of 23 small (<4cm) and 24 large (>7cm) ccRCC had 3 regions sampled for evaluation of copy number, clear-cell A/clear-cell B (ccA/ccB) classification, and cell cycle progression (CCP) score.	('RCC', 'Disease', (49, 52))	('copy number', 'Var', (93, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('cell cycle', 'CPA', (162, 172))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('cell cycle', 'biological_process', 'GO:0007049', ('162', '172'))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
20811	30044793	Functionally, B7-H4 can inhibit CD4 and CD8 T cell proliferation and cytokine production through unidentified B7-H4 receptors on T cells.	('CD8', 'Gene', '925', (40, 43))	('B7-H4', 'Var', (14, 19))	('CD4', 'Gene', (32, 35))	('cytokine production', 'MPA', (69, 88))	('cytokine production', 'biological_process', 'GO:0001816', ('69', '88'))	('T cell proliferation', 'biological_process', 'GO:0042098', ('44', '64'))	('CD4', 'Gene', '12504', (32, 35))	('inhibit', 'NegReg', (24, 31))	('CD8', 'Gene', (40, 43))
20812	30044793	In this study, we investigated the association between serum soluble B7-H4 and the peripheral blood neutrophil count, as well as whether the presence of soluble B7-H4 was associated with poor a prognosis in non-metastatic clear cell renal cell carcinoma patients.	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('patients', 'Species', '9606', (254, 262))	('soluble B7-H4', 'Var', (153, 166))	('presence', 'Var', (141, 149))	('soluble', 'cellular_component', 'GO:0005625', ('153', '160'))	('blood neutrophil count', 'Phenotype', 'HP:0011897', (94, 116))	('renal cell carcinoma', 'Disease', (233, 253))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (233, 253))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (222, 253))	('soluble', 'cellular_component', 'GO:0005625', ('61', '68'))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (233, 253))	('associated', 'Reg', (171, 181))
20827	30044793	The levels of soluble B7-H4 were also significantly higher in renal cancer patients than in the HDs; the mean concentration of soluble B7-H4 in renal cancer patients (167.1 ng/mL in all renal cancer patients and 295.1 ng/ml in positive renal cancer patients with a range of 0.11 to 1021 ng/mL) was significantly higher than in the HDs (0.9 ng/mL in all HDs and 8.5 ng/ml in positive HDs with a range of 0 to 21 ng/mL).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('renal cancer', 'Disease', (62, 74))	('renal cancer', 'Disease', 'MESH:D007680', (144, 156))	('patients', 'Species', '9606', (157, 165))	('renal cancer', 'Phenotype', 'HP:0009726', (62, 74))	('soluble', 'cellular_component', 'GO:0005625', ('127', '134'))	('renal cancer', 'Disease', (236, 248))	('soluble', 'cellular_component', 'GO:0005625', ('14', '21'))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('renal cancer', 'Phenotype', 'HP:0009726', (236, 248))	('renal cancer', 'Disease', (186, 198))	('renal cancer', 'Disease', 'MESH:D007680', (62, 74))	('renal cancer', 'Phenotype', 'HP:0009726', (186, 198))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('renal cancer', 'Disease', 'MESH:D007680', (236, 248))	('patients', 'Species', '9606', (249, 257))	('patients', 'Species', '9606', (75, 83))	('renal cancer', 'Disease', 'MESH:D007680', (186, 198))	('renal cancer', 'Disease', (144, 156))	('renal cancer', 'Phenotype', 'HP:0009726', (144, 156))	('higher', 'PosReg', (312, 318))	('167.1', 'Var', (167, 172))	('patients', 'Species', '9606', (199, 207))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
20830	30044793	Univariate Cox regression showed that the serum soluble B7-H4-positive group was significantly associated with a poor clinical outcome (Tables 2 and 3).	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('serum', 'Var', (42, 47))	('soluble', 'cellular_component', 'GO:0005625', ('48', '55'))
20831	30044793	The multivariate Cox proportional hazards regression model including age, gender, pathological T stage, grade, preoperative peripheral neutrophil count, and serum soluble B7-H4 revealed that the presence of serum soluble B7-H4 was an independent predictive marker of PFS and OS (Tables 2 and 3).	('Cox', 'Gene', '1351', (17, 20))	('soluble', 'cellular_component', 'GO:0005625', ('163', '170'))	('Cox', 'Gene', (17, 20))	('soluble', 'cellular_component', 'GO:0005625', ('213', '220'))	('PFS', 'Disease', (267, 270))	('serum soluble B7-H4', 'Var', (207, 226))	('presence', 'Var', (195, 203))
20841	30044793	found that cell-surface B7-H4 is able to inhibit protumor MDSCs.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cell-surface', 'cellular_component', 'GO:0009986', ('11', '23'))	('tumor', 'Disease', (52, 57))	('B7-H4', 'Var', (24, 29))	('inhibit', 'NegReg', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
20846	30044793	To our knowledge, this is the first report of an association between serum soluble B7-H4 and peripheral blood neutrophil count in patients with renal cancer.	('serum', 'Var', (69, 74))	('renal cancer', 'Disease', (144, 156))	('renal cancer', 'Disease', 'MESH:D007680', (144, 156))	('renal cancer', 'Phenotype', 'HP:0009726', (144, 156))	('soluble', 'cellular_component', 'GO:0005625', ('75', '82'))	('association', 'Interaction', (49, 60))	('patients', 'Species', '9606', (130, 138))	('blood neutrophil count', 'Phenotype', 'HP:0011897', (104, 126))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
20848	33202724	Patient outcomes have improved with these innovations, however, controversy persists regarding optimal sequence and patient selection amongst the available combinations.	('patient', 'Species', '9606', (116, 123))	('improved', 'PosReg', (22, 30))	('Patient', 'Species', '9606', (0, 7))	('innovations', 'Var', (42, 53))
20865	33202724	Similarly, a prospective trial comparing ipilimumab/nivolumab (ipi/nivo) combination vs. sunitinib in untreated advanced ccRCC showed that patients who were at intermediate or poor risk and treated with ipi/nivo had superior 18-month OS, progression free survival (PFS), overall response rate (ORR), and complete response (CR) rates as compared to patients treated with sunitinib alone.	('complete response', 'CPA', (304, 321))	('patients', 'Species', '9606', (348, 356))	('ipi', 'Chemical', '-', (63, 66))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('nivo', 'Chemical', 'MESH:D000077594', (52, 56))	('progression free survival', 'CPA', (238, 263))	('ipilimumab', 'Chemical', 'MESH:D000074324', (41, 51))	('nivo', 'Chemical', 'MESH:D000077594', (67, 71))	('superior', 'PosReg', (216, 224))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('nivo', 'Chemical', 'MESH:D000077594', (207, 211))	('sunitinib', 'Chemical', 'MESH:D000077210', (370, 379))	('patients', 'Species', '9606', (139, 147))	('ipi', 'Chemical', '-', (203, 206))	('nivolumab', 'Chemical', 'MESH:D000077594', (52, 61))	('ipi/nivo', 'Var', (203, 211))	('ipi', 'Chemical', '-', (41, 44))	('poor', 'Var', (176, 180))	('overall response', 'CPA', (271, 287))	('sunitinib', 'Chemical', 'MESH:D000077210', (89, 98))
20867	33202724	In fact, the 18-month OS trended higher for sunitinib, and the ORR was lower and mPFS shorter for the ipi/nivo group in a statistically significant manner, although there was no OS advantage for sunitinib.	('ipi', 'Chemical', '-', (102, 105))	('higher', 'PosReg', (33, 39))	('shorter', 'NegReg', (86, 93))	('nivo', 'Chemical', 'MESH:D000077594', (106, 110))	('ORR', 'MPA', (63, 66))	('mPFS', 'CPA', (81, 85))	('sunitinib', 'Chemical', 'MESH:D000077210', (195, 204))	('sunitinib', 'Var', (44, 53))	('sunitinib', 'Chemical', 'MESH:D000077210', (44, 53))	('lower', 'NegReg', (71, 76))
20870	33202724	Earlier studies on biomarkers focused on driver mutations, epigenetic modifications, or chromosomal aberrations associated with ccRCC to evaluate their potential in clinical prognostication.	('chromosomal aberrations', 'Var', (88, 111))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (88, 111))	('epigenetic modifications', 'Var', (59, 83))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (130, 133))
20871	33202724	An obvious candidate was the von Hippel-Lindau (VHL) gene, which is inactivated in RCC via a point mutation or through epigenetic silencing.	('VHL', 'Gene', '7428', (48, 51))	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('epigenetic silencing', 'Var', (119, 139))	('von Hippel-Lindau', 'Gene', '7428', (29, 46))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('point mutation', 'Var', (93, 107))	('von Hippel-Lindau', 'Gene', (29, 46))	('VHL', 'Gene', (48, 51))
20873	33202724	Inactivation of the protein product of VHL leads to abnormal stabilization of hypoxia-inducible factor (HIF), which drives oncogene transcription.	('transcription', 'biological_process', 'GO:0006351', ('132', '145'))	('hypoxia', 'Disease', (78, 85))	('hypoxia', 'Disease', 'MESH:D000860', (78, 85))	('stabilization', 'MPA', (61, 74))	('VHL', 'Gene', (39, 42))	('VHL', 'Gene', '7428', (39, 42))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('Inactivation', 'Var', (0, 12))
20875	33202724	A meta-analysis from 2017 revealed that VHL was not a predictive marker in patients treated with anti-VEGF-targeted agents, as abnormal VHL failed to show a relationship with ORR, PFS, or OS.	('VEGF', 'Gene', '7422', (102, 106))	('abnormal', 'Var', (127, 135))	('PFS', 'Disease', (180, 183))	('VHL', 'Gene', (40, 43))	('patients', 'Species', '9606', (75, 83))	('VHL', 'Gene', '7428', (40, 43))	('VHL', 'Gene', (136, 139))	('VEGF', 'Gene', (102, 106))	('ORR', 'Disease', (175, 178))	('VHL', 'Gene', '7428', (136, 139))
20878	33202724	However, a study published in 2016 showed that among 31 metastatic ccRCC patients, the vast majority of whom received anti-VEGF therapy, those who were maintained for longer durations of therapy were more likely to harbor a PBRM1 mutation.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('VEGF', 'Gene', '7422', (123, 127))	('harbor', 'Reg', (215, 221))	('mutation', 'Var', (230, 238))	('VEGF', 'Gene', (123, 127))	('PBRM1', 'Gene', (224, 229))	('patients', 'Species', '9606', (73, 81))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('PBRM1', 'Gene', '55193', (224, 229))
20879	33202724	A separate study found that a group of so-called "extreme responders," defined as partial response (PR) or complete response (CR) for >=3 years in mRCC on either first-line sunitinib or pazopanib, was enriched for PBRM1 mutations.	('RCC', 'Disease', (148, 151))	('complete', 'MPA', (107, 115))	('partial', 'Disease', (82, 89))	('PBRM1', 'Gene', '55193', (214, 219))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('sunitinib', 'Chemical', 'MESH:D000077210', (173, 182))	('pazopanib', 'Chemical', 'MESH:C516667', (186, 195))	('mutations', 'Var', (220, 229))	('PBRM1', 'Gene', (214, 219))
20898	33202724	Although the angiogenesis gene signature tended to have upregulation of VHL and PBRM1 mutants, VHL status itself was not associated with differences in PFS.	('PBRM1', 'Gene', '55193', (80, 85))	('mutants', 'Var', (86, 93))	('angiogenesis gene', 'Gene', (13, 30))	('VHL', 'Gene', '7428', (72, 75))	('upregulation', 'PosReg', (56, 68))	('VHL', 'Gene', (95, 98))	('VHL', 'Gene', '7428', (95, 98))	('PBRM1', 'Gene', (80, 85))	('angiogenesis', 'biological_process', 'GO:0001525', ('13', '25'))	('VHL', 'Gene', (72, 75))
20902	33202724	However, this benefit appeared to be abrogated in the group of patients that was enriched for TP53 and BAP1 mutations.	('BAP1', 'Gene', '8314', (103, 107))	('mutations', 'Var', (108, 117))	('BAP1', 'Gene', (103, 107))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('abrogated', 'NegReg', (37, 46))	('patients', 'Species', '9606', (63, 71))
20903	33202724	The group of patients with higher frequency of TP53 and BAP1 mutations tended to have high immune infiltration and higher PD-L1 expression.	('BAP1', 'Gene', '8314', (56, 60))	('patients', 'Species', '9606', (13, 21))	('mutations', 'Var', (61, 70))	('BAP1', 'Gene', (56, 60))	('TP53', 'Gene', '7157', (47, 51))	('expression', 'MPA', (128, 138))	('PD-L1', 'Protein', (122, 127))	('higher', 'PosReg', (115, 121))	('TP53', 'Gene', (47, 51))
20904	33202724	As was the case in IMmotion150 study, in the COMPARZ trial, mRCC tumors with PBRM1 mutations were noted to have upregulated angiogenesis gene expression in contrast to tumors harboring BAP1 mutations, which were associated with decreased expression of angiogenesis-related genes.	('BAP1', 'Gene', (185, 189))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', (65, 71))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('angiogenesis gene', 'Gene', (124, 141))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('angiogenesis', 'biological_process', 'GO:0001525', ('124', '136'))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('gene expression', 'biological_process', 'GO:0010467', ('137', '152'))	('mRCC tumors', 'Disease', (60, 71))	('PBRM1', 'Gene', '55193', (77, 82))	('expression', 'MPA', (142, 152))	('BAP1', 'Gene', '8314', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('angiogenesis', 'biological_process', 'GO:0001525', ('252', '264'))	('mutations', 'Var', (83, 92))	('PBRM1', 'Gene', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('upregulated', 'PosReg', (112, 123))	('mRCC tumors', 'Disease', 'MESH:D009369', (60, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
20905	33202724	There was no association between the angiogenesis gene signature expression level and SETD2 mutation.	('mutation', 'Var', (92, 100))	('angiogenesis gene signature expression level', 'MPA', (37, 81))	('SETD2', 'Gene', '29072', (86, 91))	('angiogenesis', 'biological_process', 'GO:0001525', ('37', '49'))	('SETD2', 'Gene', (86, 91))
20916	33202724	However, when patients were divided into two categories of PFS (<9 months vs. >20 months), the median Ang-2 protein level on treatment was lower in the PFS > 20 month group as compared to PFS < 9 months.	('Ang-2', 'Gene', '285', (102, 107))	('Ang-2', 'Gene', (102, 107))	('PFS > 20 month', 'Var', (152, 166))	('lower', 'NegReg', (139, 144))	('patients', 'Species', '9606', (14, 22))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
20933	33202724	The observation that PD-L1 positivity is linked to poor prognosis was again reported more recently in a post-hoc analysis of the COMPARZ trial (pazopinib vs. sunitinib) which showed that patients who were PD-L1 positive had significantly worse OS and PFS compared to the PD-L1 negative population.	('patients', 'Species', '9606', (187, 195))	('pazopinib', 'Chemical', '-', (144, 153))	('PD-L1', 'Gene', (205, 210))	('PFS', 'CPA', (251, 254))	('worse', 'NegReg', (238, 243))	('sunitinib', 'Chemical', 'MESH:D000077210', (158, 167))	('positive', 'Var', (211, 219))
20934	33202724	This is also supported by an analysis of CHECKMATE-214 study (nivolumab+ipilumimab vs. sunitinib) which demonstrated that PD-L1 positivity was more common in patients with intermediate and poor risk disease as defined by IMDC criteria compared to those with favorable risk disease.	('sunitinib', 'Chemical', 'MESH:D000077210', (87, 96))	('common', 'Reg', (148, 154))	('PD-L1', 'Gene', (122, 127))	('positivity', 'Var', (128, 138))	('ipilumimab', 'Chemical', '-', (72, 82))	('nivolumab', 'Chemical', 'MESH:D000077594', (62, 71))	('intermediate', 'Disease', (172, 184))	('patients', 'Species', '9606', (158, 166))
20935	33202724	It is possible that the prognostic implications of PD-L1 positivity in mRCC also have a negative impact on its usefulness as a predictive biomarker.	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('positivity', 'Var', (57, 67))	('PD-L1', 'Gene', (51, 56))
20936	33202724	Differences in the genomic landscape of RCC have also been the subject of much study in the search for clinical biomarkers for ICB treatment PBRM1 and PBAF complex mutations have drawn much attention in this regard and, as discussed above, have also been investigated as both a prognostic and predictive markers for VEGF TKIs.	('VEGF', 'Gene', (316, 320))	('RCC', 'Disease', (40, 43))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('VEGF', 'Gene', '7422', (316, 320))	('PBAF complex', 'cellular_component', 'GO:0016586', ('151', '163'))	('PBRM1', 'Gene', (141, 146))	('PBAF complex', 'Gene', (151, 163))	('mutations', 'Var', (164, 173))	('PBRM1', 'Gene', '55193', (141, 146))
20940	33202724	This finding was then validated in a separate 63 patient cohort treated with PD-1 or PD-L1 inhibitions alone or in combination with anti-CTLA-4 therapies and replicated findings of association with clinical benefit.	('PD-L1', 'Gene', (85, 90))	('patient', 'Species', '9606', (49, 56))	('CTLA-4', 'Gene', '1493', (137, 143))	('inhibitions', 'Var', (91, 102))	('CTLA-4', 'Gene', (137, 143))	('PD-1', 'Gene', (77, 81))
20942	33202724	of a first-line clinical trial of atezolizumab alone or in combination with bevacizumab vs. sunitinib failed to demonstrate an association with clinical benefit in patients with PBRM1 mutations in the atezolizumab monotherapy arm but instead favored benefit in the sunitinib arm.	('bevacizumab', 'Chemical', 'MESH:D000068258', (76, 87))	('sunitinib', 'Chemical', 'MESH:D000077210', (265, 274))	('mutations', 'Var', (184, 193))	('PBRM1', 'Gene', (178, 183))	('atezolizumab', 'Chemical', 'MESH:C000594389', (34, 46))	('sunitinib', 'Chemical', 'MESH:D000077210', (92, 101))	('patients', 'Species', '9606', (164, 172))	('PBRM1', 'Gene', '55193', (178, 183))	('atezolizumab', 'Chemical', 'MESH:C000594389', (201, 213))
20943	33202724	A subsequent analysis from the Checkmate-025 study of patients with mRCC treated in the second-line or beyond and randomized to nivolumab or everolimus showed that there was enrichment of clinical benefit in the PBRM1 mutant group in nivolumab-treated patients, though this trial did not include a VEGF-targeted therapy.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('everolimus', 'Chemical', 'MESH:D000068338', (141, 151))	('RCC', 'Disease', (69, 72))	('VEGF', 'Gene', '7422', (298, 302))	('PBRM1', 'Gene', (212, 217))	('patients', 'Species', '9606', (54, 62))	('patients', 'Species', '9606', (252, 260))	('nivolumab', 'Chemical', 'MESH:D000077594', (234, 243))	('PBRM1', 'Gene', '55193', (212, 217))	('benefit', 'PosReg', (197, 204))	('VEGF', 'Gene', (298, 302))	('mutant', 'Var', (218, 224))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('nivolumab', 'Chemical', 'MESH:D000077594', (128, 137))
20944	33202724	The effect of PBRM1 mutations on response and survival in this study was modest, with median PFS 5.6 vs. 2.9 months (HR, 0.67; 95% CI, 0.47-0.96; p = 0.03) and median OS 27.9 vs. 20.9 months (HR, 0.65; 95% CI, 0.44-0.96; p = 0.03).	('PBRM1', 'Gene', '55193', (14, 19))	('PBRM1', 'Gene', (14, 19))	('mutations', 'Var', (20, 29))
20945	33202724	Finally, a large retrospective analysis (n = 2936) explored the interaction between PBRM1 mutations and immunotherapy across cancer types and failed to show a statistically significant association with OS (HR 0.9, p = 0.7).	('PBRM1', 'Gene', '55193', (84, 89))	('mutations', 'Var', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', (125, 131))	('PBRM1', 'Gene', (84, 89))
20947	33202724	that PBRM1 mutations increased interferon-gamma (IFNgamma) gene expression and thereby modulated the immune response.	('immune response', 'CPA', (101, 116))	('mutations', 'Var', (11, 20))	('increased', 'PosReg', (21, 30))	('PBRM1', 'Gene', '55193', (5, 10))	('increased interferon-gamma', 'Phenotype', 'HP:0030356', (21, 47))	('increased interferon-', 'Phenotype', 'HP:0009709', (21, 42))	('gene expression', 'biological_process', 'GO:0010467', ('59', '74'))	('immune response', 'biological_process', 'GO:0006955', ('101', '116'))	('IFNgamma', 'Gene', (49, 57))	('interferon-gamma', 'Gene', '3458', (31, 47))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('31', '47'))	('IFNgamma', 'Gene', '3458', (49, 57))	('modulated', 'Reg', (87, 96))	('PBRM1', 'Gene', (5, 10))	('interferon-gamma', 'Gene', (31, 47))
20949	33202724	and a cohort from the previously mentioned COMPARZ trial and showed unchanged or decreased IFNgamma signaling in PBRM1 mutants compared to the wild-type, which conflicted with the hypothesized mechanism of action.	('decreased', 'NegReg', (81, 90))	('IFNgamma', 'Gene', '3458', (91, 99))	('PBRM1', 'Gene', (113, 118))	('IFNgamma', 'Gene', (91, 99))	('PBRM1', 'Gene', '55193', (113, 118))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('mutants', 'Var', (119, 126))
20952	33202724	For example, in non-small cell lung cancer mutations in STK11 have been identified as predictors of poor responses to ICBs.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('mutations', 'Var', (43, 52))	('STK11', 'Gene', (56, 61))	('STK11', 'molecular_function', 'GO:0033868', ('56', '61'))	('ICBs', 'Chemical', '-', (118, 122))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (20, 42))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (16, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('STK11', 'Gene', '6794', (56, 61))
20955	33202724	The authors found that mutations in the TERT promoter were specifically associated with a lack of benefit from ICB.	('TERT', 'Gene', '7015', (40, 44))	('mutations', 'Var', (23, 32))	('TERT', 'Gene', (40, 44))
20961	33202724	The TeffHigh gene signature was also associated with improved ORR and PFS when compared to the TeffLow group within the atezolizumab/bevacizumab arm.	('atezolizumab', 'Chemical', 'MESH:C000594389', (120, 132))	('ORR', 'MPA', (62, 65))	('bevacizumab', 'Chemical', 'MESH:D000068258', (133, 144))	('PFS', 'CPA', (70, 73))	('TeffHigh gene', 'Var', (4, 17))	('improved', 'PosReg', (53, 61))
20962	33202724	They also showed that TeffHigh was associated with improved PFS when compared across groups to the sunitinib arm.	('TeffHigh', 'Var', (22, 30))	('improved', 'PosReg', (51, 59))	('PFS', 'Disease', (60, 63))	('sunitinib', 'Chemical', 'MESH:D000077210', (99, 108))
20971	33202724	Although less common in some other tumor types, RCC can harbor alterations in DNA damage repair (DDR) pathways, including defects in DNA mismatch repair (dMMR).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('alterations', 'Reg', (63, 74))	('tumor', 'Disease', (35, 40))	('mismatch repair', 'biological_process', 'GO:0006298', ('137', '152'))	('DNA mismatch repair', 'MPA', (133, 152))	('defects', 'Var', (122, 129))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
20972	33202724	Loss of function of certain genes related to dMMR defects can lead to lead to high levels of microsatellite instability (MSI), which has been established as a biomarker for response to immunotherapy irrespective of tumor type.	('microsatellite instability', 'MPA', (93, 119))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('defects', 'Var', (50, 57))	('dMMR', 'Gene', (45, 49))	('Loss of function', 'NegReg', (0, 16))	('genes', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (215, 220))
20975	33202724	Looking more broadly, mutations in genes involved in the various DDR pathways, which do not necessarily result in MSI, are relatively prevalent in RCC.	('prevalent', 'Reg', (134, 143))	('RCC', 'Disease', (147, 150))	('mutations', 'Var', (22, 31))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('RCC', 'Disease', 'MESH:C538614', (147, 150))
20976	33202724	In one cohort published by Ged et al., about 19% of patients (43/229) with mRCC harbor DDR mutations, with CHEK2 and ATM being the most frequently mutated.	('CHEK2', 'Gene', '11200', (107, 112))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('ATM', 'Gene', '472', (117, 120))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('CHEK2', 'Gene', (107, 112))	('DDR', 'Gene', (87, 90))	('mutations', 'Var', (91, 100))	('patients', 'Species', '9606', (52, 60))	('ATM', 'Gene', (117, 120))
20977	33202724	In this cohort, they were able to demonstrate a correlation between DDR mutation status and superior OS (HR 0.41; 95% CI: 0.14-1.14; p = 0.09) in patients treated with ICB.	('mutation status', 'Var', (72, 87))	('DDR', 'Gene', (68, 71))	('correlation', 'Interaction', (48, 59))	('superior OS', 'Disease', (92, 103))	('patients', 'Species', '9606', (146, 154))
20978	33202724	who showed that patients with DDR mutant tumors had improved disease control (defined as CR, PR, or SD) with ICB.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('improved', 'PosReg', (52, 60))	('patients', 'Species', '9606', (16, 24))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('DDR', 'Gene', (30, 33))	('disease control', 'CPA', (61, 76))	('mutant', 'Var', (34, 40))
20988	33202724	Paradoxically, it also has been shown that high-TMB is actually associated with inhibition of immune cell infiltrates in RCC tumors, which supports and possibly explains these unexpected clinical observations on a cellular level.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('inhibition', 'NegReg', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('TMB', 'Chemical', '-', (48, 51))	('RCC tumors', 'Disease', 'MESH:C538614', (121, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('high-TMB', 'Var', (43, 51))	('immune cell infiltrates', 'CPA', (94, 117))	('RCC tumors', 'Disease', (121, 131))
20989	33202724	Another interesting observation that may help explain why RCC is such an immunogenic tumor but has a characteristically low TMB is the distribution of mutations that comprise its TMB.	('TMB', 'MPA', (124, 127))	('immunogenic tumor', 'Disease', 'MESH:D009369', (73, 90))	('TMB', 'Chemical', '-', (179, 182))	('TMB', 'Chemical', '-', (124, 127))	('low', 'NegReg', (120, 123))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('immunogenic tumor', 'Disease', (73, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('mutations', 'Var', (151, 160))
20990	33202724	TMB high tumors traditionally have a predominance of many single nucleotide variants (SNVs) making up the majority of mutations, while RCC on the other hand has a uniquely high proportion of insertions and deletions (indels) relative to other tumors.	('tumors', 'Disease', (243, 249))	('TMB high tumors', 'Disease', (0, 15))	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('TMB high tumors', 'Disease', 'MESH:D009369', (0, 15))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutations', 'Var', (118, 127))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('deletions', 'Var', (206, 215))	('single nucleotide variants', 'Var', (58, 84))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('insertions', 'Var', (191, 201))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
20991	33202724	This phenomenon was identified as part of an analysis of the Cancer Genome Atlas study of 5777 solid tumors which identified RCC tumors as having more than double the median proportion of indels to SNVs.	('RCC tumors', 'Disease', (125, 135))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Cancer', 'Disease', (61, 67))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('Cancer', 'Disease', 'MESH:D009369', (61, 67))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('RCC tumors', 'Disease', 'MESH:C538614', (125, 135))	('indels', 'Var', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))
20994	33202724	HLA correction is a computational method by which incorporation of loss of heterozygosity of HLA alleles is thought to improve upon TMB by predicting the proportion of functional neoantigens present.	('improve', 'PosReg', (119, 126))	('TMB', 'MPA', (132, 135))	('predicting', 'Reg', (139, 149))	('TMB', 'Chemical', '-', (132, 135))	('loss of heterozygosity', 'Var', (67, 89))	('HLA', 'Gene', (93, 96))
21014	33202724	Interestingly, they noted that highly infiltrated tumors were less likely to carry PBRM1 mutations, which may help explain the association between PBRM1 mutations and favorable prognosis in RCC.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Disease', (190, 193))	('RCC', 'Phenotype', 'HP:0005584', (190, 193))	('PBRM1', 'Gene', (83, 88))	('PBRM1', 'Gene', (147, 152))	('PBRM1', 'Gene', '55193', (83, 88))	('PBRM1', 'Gene', '55193', (147, 152))	('mutations', 'Var', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
21029	32906592	Therapeutically Significant MicroRNAs in Primary and Metastatic Brain Malignancies The overall survival of brain cancer patients remains grim, with conventional therapies such as chemotherapy and radiotherapy only providing marginal benefits to patient survival.	('brain cancer', 'Disease', (107, 119))	('MicroRNAs', 'Var', (28, 37))	('Brain Malignancies', 'Phenotype', 'HP:0030692', (64, 82))	('patient', 'Species', '9606', (120, 127))	('brain cancer', 'Disease', 'MESH:D001932', (107, 119))	('Primary and Metastatic Brain Malignancies', 'Disease', 'MESH:D001932', (41, 82))	('patients', 'Species', '9606', (120, 128))	('brain cancer', 'Phenotype', 'HP:0030692', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('patient', 'Species', '9606', (245, 252))
21043	32906592	This review focuses on the differential expression of ten miRNAs (miR-145, miR-31, miR-451, miR-19a, miR-143, miR-125b, miR-328, miR-210, miR-146a, and miR-126) in glioblastoma and brain metastasis.	('miR-125b', 'Chemical', '-', (110, 118))	('miR-31', 'Gene', '407035', (75, 81))	('miR-143', 'Var', (101, 108))	('glioblastoma', 'Disease', 'MESH:D005909', (164, 176))	('miR-125b', 'Var', (110, 118))	('miR-19a', 'Gene', (92, 99))	('miR-328', 'Gene', '442901', (120, 127))	('miR-19a', 'Gene', '406979', (92, 99))	('glioblastoma', 'Disease', (164, 176))	('miR-210', 'Gene', '406992', (129, 136))	('glioblastoma', 'Phenotype', 'HP:0012174', (164, 176))	('miR-451', 'Gene', '574411', (83, 90))	('miR-145', 'Gene', '406937', (66, 73))	('miR-210', 'Gene', (129, 136))	('miR-145', 'Gene', (66, 73))	('miR-31', 'Gene', (75, 81))	('miR-451', 'Gene', (83, 90))	('miR-146a', 'Var', (138, 146))	('miR-328', 'Gene', (120, 127))
21087	32906592	Deadenylation promotes subsequent mRNA decapping by the enzymes DCP1 and DCP2, which facilitates 5' to 3' degradation by the exoribonuclease Xrn1p.	('degradation', 'biological_process', 'GO:0009056', ('106', '117'))	('Xrn1p', 'Gene', (141, 146))	('DCP', 'molecular_function', 'GO:0004246', ('64', '67'))	('DCP1', 'Gene', (64, 68))	('Deadenylation', 'Var', (0, 13))	('DCP2', 'Gene', (73, 77))	('DCP2', 'Gene', '167227', (73, 77))	('Xrn1p', 'Gene', '54464', (141, 146))	("5' to 3' degradation", 'MPA', (97, 117))	('DCP', 'molecular_function', 'GO:0004246', ('73', '76'))	('facilitates', 'PosReg', (85, 96))	('DCP1', 'Gene', '196513', (64, 68))	('mRNA decapping', 'MPA', (34, 48))
21088	32906592	In slicer-independent silencing, multiple complementary sites with imperfect base-pairing create bulges in the RNA duplex, inhibiting the slicer activity of Ago2.	('RNA', 'cellular_component', 'GO:0005562', ('111', '114'))	('Ago2', 'Gene', (157, 161))	('inhibiting', 'NegReg', (123, 133))	('base-pairing', 'molecular_function', 'GO:0003676', ('77', '89'))	('slicer activity', 'MPA', (138, 153))	('silencing', 'Var', (22, 31))	('Ago2', 'Gene', '27161', (157, 161))
21096	32906592	Dysregulation of miRNA expression profiles has been associated in most, if not all tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Dysregulation', 'Var', (0, 13))	('associated', 'Reg', (52, 62))	('miRNA expression profiles', 'MPA', (17, 42))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
21101	32906592	Conversely, miRNAs which are often downregulated in cancers, can inhibit tumor progression and are termed tumor suppressor miRs.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('miRNAs', 'Var', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('106', '122'))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (73, 78))	('tumor suppressor', 'biological_process', 'GO:0051726', ('106', '122'))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('inhibit', 'NegReg', (65, 72))	('tumor', 'Disease', (106, 111))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
21103	32906592	miRNA signatures have not only been shown to be dysregulated in cancers; interestingly, restoration of these dysregulated miRNAs have also been shown to abrogate and even reverse the malignant phenotype of cancers.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('abrogate', 'NegReg', (153, 161))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('reverse', 'Reg', (171, 178))	('cancers', 'Disease', (64, 71))	('restoration', 'Var', (88, 99))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Disease', (206, 213))	('malignant phenotype', 'CPA', (183, 202))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('rat', 'Species', '10116', (93, 96))
21106	32906592	In line with recently published reports, the most important miRNAs implicated in the pathology of GBM and BrM are found to be miR-145, miR-31, miR-451, miR-19a, miR-143, miR-125b, miR-328, miR-210, miR-146a, and miR-126.	('miR-19a', 'Gene', '406979', (152, 159))	('miR-125b', 'Chemical', '-', (170, 178))	('miR-328', 'Gene', (180, 187))	('miR-145', 'Gene', '406937', (126, 133))	('miR-451', 'Gene', '574411', (143, 150))	('miR-210', 'Gene', '406992', (189, 196))	('GBM', 'Phenotype', 'HP:0012174', (98, 101))	('miR-31', 'Gene', (135, 141))	('miR-126', 'Var', (212, 219))	('miR-145', 'Gene', (126, 133))	('miR-19a', 'Gene', (152, 159))	('miR-146a', 'Var', (198, 206))	('miR-125b', 'Var', (170, 178))	('miR-143', 'Var', (161, 168))	('miR-210', 'Gene', (189, 196))	('miR-451', 'Gene', (143, 150))	('miR-31', 'Gene', '407035', (135, 141))	('miR-328', 'Gene', '442901', (180, 187))
21107	32906592	Modulated expression of these miRNAs has a significant effect on patient survival.	('Modulated', 'Var', (0, 9))	('patient survival', 'CPA', (65, 81))	('patient', 'Species', '9606', (65, 72))	('expression', 'MPA', (10, 20))
21109	32906592	Both increased and decreased expression of miRNAs such as miR-145, miR-31, miR-125b, and miR-146a were reported to contribute to poor survival of GBM patients.	('miR-31', 'Gene', '407035', (67, 73))	('miR-146a', 'Var', (89, 97))	('miR-125b', 'Var', (75, 83))	('poor', 'NegReg', (129, 133))	('survival', 'CPA', (134, 142))	('GBM', 'Disease', (146, 149))	('miR-125b', 'Chemical', '-', (75, 83))	('miR-31', 'Gene', (67, 73))	('patients', 'Species', '9606', (150, 158))	('miR-145', 'Gene', (58, 65))	('decreased', 'NegReg', (19, 28))	('miR-145', 'Gene', '406937', (58, 65))	('expression', 'MPA', (29, 39))	('GBM', 'Phenotype', 'HP:0012174', (146, 149))
21110	32906592	In addition, low levels of miR-31, miR-126, and high levels of miR-328 shortened survival of BrM patients.	('miR-328', 'Gene', (63, 70))	('survival', 'CPA', (81, 89))	('miR-31', 'Gene', (27, 33))	('miR-328', 'Gene', '442901', (63, 70))	('miR-126', 'Var', (35, 42))	('BrM', 'Disease', (93, 96))	('miR-31', 'Gene', '407035', (27, 33))	('shortened', 'NegReg', (71, 80))	('patients', 'Species', '9606', (97, 105))
21172	32906592	By silencing FOXD2-AS1, cell cycle arrest and CDK1 downregulation were achieved in glioma cells.	('CDK1', 'Gene', (46, 50))	('glioma', 'Disease', (83, 89))	('silencing', 'Var', (3, 12))	('arrest', 'Disease', 'MESH:D006323', (35, 41))	('CDK1', 'Gene', '983', (46, 50))	('CDK', 'molecular_function', 'GO:0004693', ('46', '49'))	('AS1', 'Gene', '5729', (19, 22))	('AS1', 'Gene', (19, 22))	('FOXD2', 'Gene', (13, 18))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('24', '41'))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('arrest', 'Disease', (35, 41))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (24, 41))	('downregulation', 'NegReg', (51, 65))	('FOXD2', 'Gene', '2306', (13, 18))
21176	32906592	Silencing of LINC01116 reduced VEGFA expression and inhibited invasion, migration, angiogenesis, and induced cell cycle arrest of glioma cells both in vitro and in vivo.	('LINC01116', 'Gene', (13, 22))	('migration', 'CPA', (72, 81))	('LINC01116', 'Gene', '375295', (13, 22))	('angiogenesis', 'biological_process', 'GO:0001525', ('83', '95'))	('inhibited', 'NegReg', (52, 61))	('Silencing', 'Var', (0, 9))	('arrest of glioma', 'Disease', (120, 136))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('109', '126'))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('VEGFA', 'Gene', (31, 36))	('rat', 'Species', '10116', (75, 78))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (109, 126))	('arrest of glioma', 'Disease', 'MESH:D006323', (120, 136))	('reduced', 'NegReg', (23, 30))	('expression', 'MPA', (37, 47))	('induced', 'Reg', (101, 108))	('invasion', 'CPA', (62, 70))	('angiogenesis', 'CPA', (83, 95))	('VEGFA', 'Gene', '7422', (31, 36))
21193	32906592	Another study revealed that increasing the expression of miR-451 using 2 -O-methyl (2 -OMe)-modified miR-451 mimics led to apoptosis, reduced viability, and invasion of GBM cells.	('GBM', 'Phenotype', 'HP:0012174', (169, 172))	('mimics', 'Var', (109, 115))	('miR-451', 'Gene', (101, 108))	('miR-451', 'Gene', '574411', (57, 64))	('viability', 'CPA', (142, 151))	('apoptosis', 'CPA', (123, 132))	('increasing', 'PosReg', (28, 38))	('apoptosis', 'biological_process', 'GO:0097194', ('123', '132'))	('miR-451', 'Gene', (57, 64))	('reduced', 'NegReg', (134, 141))	('expression', 'MPA', (43, 53))	('miR-451', 'Gene', '574411', (101, 108))	('apoptosis', 'biological_process', 'GO:0006915', ('123', '132'))	('invasion of GBM cells', 'CPA', (157, 178))	('2 -O-methyl (2 -OMe', 'Chemical', '-', (71, 90))
21209	32906592	This revealed that miR-19a is upregulated in glioma progression and inhibition of miR-19a reduced glioma cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('105', '123'))	('rat', 'Species', '10116', (117, 120))	('reduced', 'NegReg', (90, 97))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('upregulated', 'PosReg', (30, 41))	('miR-19a', 'Gene', '406979', (19, 26))	('inhibition', 'Var', (68, 78))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('miR-19a', 'Gene', '406979', (82, 89))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('glioma', 'Disease', (98, 104))	('miR-19a', 'Gene', (19, 26))	('glioma', 'Disease', (45, 51))	('miR-19a', 'Gene', (82, 89))
21213	32906592	Additionally, miR-19a/b inhibition leads to reduced expression of cyclin-D1, c-MYC, AKT1, and VEGF.	('cyclin', 'molecular_function', 'GO:0016538', ('66', '72'))	('c-MYC', 'Gene', '4609', (77, 82))	('VEGF', 'Gene', (94, 98))	('miR-19a/b', 'Gene', (14, 23))	('expression', 'MPA', (52, 62))	('cyclin-D1', 'Gene', '595', (66, 75))	('inhibition', 'Var', (24, 34))	('VEGF', 'Gene', '7422', (94, 98))	('reduced', 'NegReg', (44, 51))	('AKT1', 'Gene', '207', (84, 88))	('c-MYC', 'Gene', (77, 82))	('cyclin-D1', 'Gene', (66, 75))	('miR-19a/b', 'Gene', '406979', (14, 23))	('AKT1', 'Gene', (84, 88))
21236	32906592	Another study showed that overexpression of miR-143 reduced N-RAS expression, leading to inhibition of PI3K/AKT, extracellular signal-regulated kinase (ERK1/2) phosphorylation, and P65 accumulation in the nucleus.	('AKT', 'Gene', '207', (108, 111))	('reduced', 'NegReg', (52, 59))	('accumulation', 'PosReg', (185, 197))	('ERK1', 'molecular_function', 'GO:0004707', ('152', '156'))	('extracellular', 'cellular_component', 'GO:0005576', ('113', '126'))	('miR-143', 'Var', (44, 51))	('AKT', 'Gene', (108, 111))	('P65', 'Gene', '5970', (181, 184))	('nucleus', 'cellular_component', 'GO:0005634', ('205', '212'))	('P65', 'Gene', (181, 184))	('ERK1/2', 'Gene', (152, 158))	('N-RAS', 'Gene', (60, 65))	('inhibition', 'NegReg', (89, 99))	('expression', 'MPA', (66, 76))	('N-RAS', 'Gene', '4893', (60, 65))	('ERK1/2', 'Gene', '5595;5594', (152, 158))	('phosphorylation', 'biological_process', 'GO:0016310', ('160', '175'))	('PI3K', 'molecular_function', 'GO:0016303', ('103', '107'))
21254	32906592	miR-125b directly binds and negatively regulates the Bcl-2 modifying factor (Bmf), thereby sensitizing these cells to apoptosis.	('Bcl-2 modifying factor', 'Gene', (53, 75))	('apoptosis', 'CPA', (118, 127))	('regulates', 'Reg', (39, 48))	('Bcl-2 modifying factor', 'Gene', '90427', (53, 75))	('Bcl-2', 'molecular_function', 'GO:0015283', ('53', '58'))	('binds', 'Interaction', (18, 23))	('miR-125b', 'Var', (0, 8))	('Bmf', 'Gene', '90427', (77, 80))	('Bmf', 'Gene', (77, 80))	('sensitizing', 'Reg', (91, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('118', '127'))	('apoptosis', 'biological_process', 'GO:0006915', ('118', '127'))	('miR-125b', 'Chemical', '-', (0, 8))	('negatively', 'NegReg', (28, 38))
21258	32906592	In addition, combinatorial use of inhibitors for both miR-125b and PI3K resulted in inactivation of Wnt/beta-catenin signaling, by downregulation of Connexin43 (CX43).	('miR-125b', 'Var', (54, 62))	('PI3K', 'molecular_function', 'GO:0016303', ('67', '71'))	('CX43', 'Gene', (161, 165))	('beta-catenin', 'Gene', (104, 116))	('Connexin', 'molecular_function', 'GO:0005243', ('149', '157'))	('beta-catenin', 'Gene', '1499', (104, 116))	('Connexin43', 'Gene', '2697', (149, 159))	('miR-125b', 'Chemical', '-', (54, 62))	('Connexin43', 'Gene', (149, 159))	('CX43', 'Gene', '2697', (161, 165))	('inactivation', 'NegReg', (84, 96))	('downregulation', 'NegReg', (131, 145))	('PI3K', 'Var', (67, 71))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))
21262	32906592	reported that miR-125b mediated NF-kappaB activity by downregulating tumor necrosis factor alpha-induced protein 3 (TNFAIP3) and NF-kappaB inhibitor interacting RAS-like 2 (NKIRAS2), resulting in TMZ resistance in GBM cells.	('GBM', 'Phenotype', 'HP:0012174', (214, 217))	('NKIRAS2', 'Gene', (173, 180))	('TMZ resistance', 'MPA', (196, 210))	('NF-kappaB inhibitor interacting RAS-like 2', 'Gene', '28511', (129, 171))	('resulting in', 'Reg', (183, 195))	('downregulating', 'NegReg', (54, 68))	('tumor necrosis factor alpha-induced protein 3', 'Gene', (69, 114))	('NKIRAS2', 'Gene', '28511', (173, 180))	('miR-125b', 'Chemical', '-', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('NF-kappaB', 'Gene', (32, 41))	('miR-125b', 'Var', (14, 22))	('necrosis', 'biological_process', 'GO:0008219', ('75', '83'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('69', '90'))	('NF-kappaB inhibitor interacting RAS-like 2', 'Gene', (129, 171))	('TMZ', 'Chemical', 'MESH:D000077204', (196, 199))	('NF-kappaB', 'Gene', '4790', (32, 41))	('tumor necrosis factor alpha-induced protein 3', 'Gene', '7128', (69, 114))	('necrosis', 'biological_process', 'GO:0008220', ('75', '83'))	('NF-kappaB inhibitor', 'biological_process', 'GO:0032088', ('129', '148'))	('NF-kappaB', 'Gene', (129, 138))	('necrosis', 'biological_process', 'GO:0070265', ('75', '83'))	('TNFAIP3', 'Gene', '7128', (116, 123))	('NF-kappaB', 'Gene', '4790', (129, 138))	('necrosis', 'biological_process', 'GO:0019835', ('75', '83'))	('necrosis', 'biological_process', 'GO:0001906', ('75', '83'))	('TNFAIP3', 'Gene', (116, 123))
21264	32906592	reported that miR-125b correlates positively with the migration of CD133+ve GSCs, and miR-125b regulates the expression of matrix metalloproteins (MMP-2, MMP-9) and its inhibitors (RECK and TIMP3), modulating the invasiveness of CD133+ve GSCs.	('migration of CD133+ve GSCs', 'CPA', (54, 80))	('rat', 'Species', '10116', (57, 60))	('RECK', 'Gene', '8434', (181, 185))	('MMP-9', 'molecular_function', 'GO:0004229', ('154', '159'))	('miR-125b', 'Chemical', '-', (14, 22))	('miR-125b', 'Chemical', '-', (86, 94))	('GSCs', 'Chemical', '-', (76, 80))	('miR-125b', 'Var', (86, 94))	('invasiveness of CD133+ve GSCs', 'CPA', (213, 242))	('MMP-9', 'Gene', '4318', (154, 159))	('MMP-2', 'Gene', '4313', (147, 152))	('modulating', 'Reg', (198, 208))	('MMP-9', 'Gene', (154, 159))	('TIMP3', 'Gene', '7078', (190, 195))	('TIMP3', 'Gene', (190, 195))	('expression', 'MPA', (109, 119))	('regulates', 'Reg', (95, 104))	('MMP-2', 'Gene', (147, 152))	('RECK', 'Gene', (181, 185))	('MMP-2', 'molecular_function', 'GO:0004228', ('147', '152'))	('GSCs', 'Chemical', '-', (238, 242))
21265	32906592	stated that increased levels of MMP2, MMP9, and Ki-67 accompanied by increased expression of miR-125b in SU3 cells increased its invasiveness both in vitro and in vivo.	('miR-125b', 'Chemical', '-', (93, 101))	('MMP2', 'Gene', '4313', (32, 36))	('MMP9', 'Gene', '4318', (38, 42))	('increased', 'PosReg', (69, 78))	('expression', 'MPA', (79, 89))	('increased', 'PosReg', (115, 124))	('Ki-67', 'Var', (48, 53))	('invasiveness', 'CPA', (129, 141))	('MMP9', 'molecular_function', 'GO:0004229', ('38', '42'))	('MMP2', 'Gene', (32, 36))	('miR-125b', 'Gene', (93, 101))	('MMP2', 'molecular_function', 'GO:0004228', ('32', '36'))	('MMP9', 'Gene', (38, 42))
21277	32906592	In MGMT unmethylated GBM, miR-125b is reported to be associated with poor prognosis.	('MGMT', 'Gene', (3, 7))	('MGMT', 'Gene', '4255', (3, 7))	('miR-125b', 'Var', (26, 34))	('MGMT', 'molecular_function', 'GO:0003908', ('3', '7'))	('GBM', 'Phenotype', 'HP:0012174', (21, 24))	('miR-125b', 'Chemical', '-', (26, 34))
21290	32906592	Microarray analysis of BrM and non-BrM NSCLCpatient samples revealed that miR-328 and miR-330-3p could potentially discriminate BrM and non-BrM NSCLC.	('NSCLC', 'Disease', (144, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('miR-328', 'Gene', '442901', (74, 81))	('miR-330-3p', 'Chemical', '-', (86, 96))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('miR-328', 'Gene', (74, 81))	('discriminate', 'Reg', (115, 127))	('BrM', 'Disease', (128, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))	('NSCLC', 'Disease', (39, 44))	('miR-330-3p', 'Var', (86, 96))
21302	32906592	In GBM, inhibition of miR-210 led to decreased proliferation, invasion, and increased apoptosis, possibly through targeting ROD1 and SIN3A.	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('proliferation', 'CPA', (47, 60))	('miR-210', 'Gene', (22, 29))	('increased', 'PosReg', (76, 85))	('SIN3A', 'Gene', (133, 138))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('rat', 'Species', '10116', (54, 57))	('GBM', 'Phenotype', 'HP:0012174', (3, 6))	('ROD1', 'Gene', '9991', (124, 128))	('SIN', 'biological_process', 'GO:0031028', ('133', '136'))	('miR-210', 'Gene', '406992', (22, 29))	('SIN3A', 'Gene', '25942', (133, 138))	('invasion', 'CPA', (62, 70))	('inhibition', 'Var', (8, 18))	('ROD1', 'Gene', (124, 128))	('decreased', 'NegReg', (37, 46))	('apoptosis', 'CPA', (86, 95))
21304	32906592	Inhibitors of miR-210 substantially increased ROD1 expression, resulting in apoptosis and cell proliferation inhibition.	('ROD1', 'Gene', (46, 50))	('apoptosis', 'biological_process', 'GO:0097194', ('76', '85'))	('ROD1', 'Gene', '9991', (46, 50))	('Inhibitors', 'Var', (0, 10))	('cell proliferation', 'CPA', (90, 108))	('increased', 'PosReg', (36, 45))	('expression', 'MPA', (51, 61))	('rat', 'Species', '10116', (102, 105))	('cell proliferation', 'biological_process', 'GO:0008283', ('90', '108'))	('apoptosis', 'CPA', (76, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('76', '85'))	('miR-210', 'Gene', (14, 21))	('miR-210', 'Gene', '406992', (14, 21))
21322	32906592	showed that rs2910164 polymorphism in precursor miR-146a resulted in reduced levels of mature miR-146a.	('levels of mature miR-146a', 'MPA', (77, 102))	('rs2910164', 'Var', (12, 21))	('reduced', 'NegReg', (69, 76))	('miR-146a', 'Gene', (48, 56))	('rs2910164', 'DBSNP_MENTION', 'None', (12, 21))
21324	32906592	Specifically, rs2910164 CC/GC genotypes were reported to be associated with increased risk of glioma in elderly people and the C allele with decreased survival of GBM patients.	('rs2910164', 'DBSNP_MENTION', 'None', (14, 23))	('glioma', 'Disease', (94, 100))	('patients', 'Species', '9606', (167, 175))	('decreased', 'NegReg', (141, 150))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('people', 'Species', '9606', (112, 118))	('GBM', 'Phenotype', 'HP:0012174', (163, 166))	('rs2910164', 'Var', (14, 23))
21325	32906592	reported that rs2910164 CC genotype is linked to decreased survival of high-grade glioma patients with a gradual decrease in mature miR-146a expression.	('mature miR-146a expression', 'MPA', (125, 151))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('decrease', 'NegReg', (113, 121))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('rs2910164', 'DBSNP_MENTION', 'None', (14, 23))	('decreased', 'NegReg', (49, 58))	('patients', 'Species', '9606', (89, 97))	('glioma', 'Disease', (82, 88))	('rs2910164', 'Var', (14, 23))	('survival', 'MPA', (59, 67))
21328	32906592	Loss of miR-146a due to the rs2910164 polymorphism altered the Notch1/Notch2 ratio, leading to malignant transformation of GBM cells.	('altered', 'Reg', (51, 58))	('rs2910164', 'DBSNP_MENTION', 'None', (28, 37))	('leading to', 'Reg', (84, 94))	('rat', 'Species', '10116', (77, 80))	('GBM', 'Phenotype', 'HP:0012174', (123, 126))	('Notch1', 'Gene', (63, 69))	('malignant transformation of GBM cells', 'CPA', (95, 132))	('Notch1', 'Gene', '4851', (63, 69))	('Loss', 'NegReg', (0, 4))	('miR-146a', 'Gene', (8, 16))	('Notch2', 'Gene', (70, 76))	('rs2910164', 'Var', (28, 37))	('Notch2', 'Gene', '4853', (70, 76))
21337	32906592	Additionally, miR-146a inhibits metastatic activity of BrM melanoma cells by upregulating beta-catenin and downregulating hnRNPC.	('BrM melanoma', 'Disease', (55, 67))	('upregulating', 'PosReg', (77, 89))	('miR-146a', 'Var', (14, 22))	('downregulating', 'NegReg', (107, 121))	('hnRNPC', 'Gene', (122, 128))	('beta-catenin', 'Gene', (90, 102))	('metastatic activity', 'CPA', (32, 51))	('hnRNPC', 'Gene', '3183', (122, 128))	('beta-catenin', 'Gene', '1499', (90, 102))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('BrM melanoma', 'Disease', 'MESH:D008545', (55, 67))	('inhibits', 'NegReg', (23, 31))
21346	32906592	IRS-1 is regulated by miR-126 through the PI3K/AKT signaling pathway.	('AKT', 'Gene', (47, 50))	('miR-126', 'Var', (22, 29))	('regulated', 'Reg', (9, 18))	('IRS-1', 'Gene', '25467', (0, 5))	('AKT', 'Gene', '207', (47, 50))	('signaling pathway', 'biological_process', 'GO:0007165', ('51', '68'))	('AKT signaling', 'biological_process', 'GO:0043491', ('47', '60'))	('PI3K', 'molecular_function', 'GO:0016303', ('42', '46'))	('IRS-1', 'Gene', (0, 5))
21354	32906592	revealed that miR-126 could potentially induce TMZ sensitivity and overcome resistance in GBM cells, by downregulating the expression of SOX2 (oncoprotein and associated with drug resistance in cancer) and Wnt/beta catenin signaling.	('signaling', 'biological_process', 'GO:0023052', ('223', '232'))	('expression', 'MPA', (123, 133))	('overcome', 'MPA', (67, 75))	('beta catenin', 'Gene', (210, 222))	('SOX2', 'Gene', '6657', (137, 141))	('beta catenin', 'Gene', '1499', (210, 222))	('SOX2', 'Gene', (137, 141))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('GBM', 'Phenotype', 'HP:0012174', (90, 93))	('TMZ', 'Chemical', 'MESH:D000077204', (47, 50))	('induce', 'PosReg', (40, 46))	('cancer', 'Disease', (194, 200))	('drug resistance', 'Phenotype', 'HP:0020174', (175, 190))	('TMZ sensitivity', 'MPA', (47, 62))	('drug resistance', 'biological_process', 'GO:0009315', ('175', '190'))	('downregulating', 'NegReg', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('drug resistance', 'biological_process', 'GO:0042493', ('175', '190'))	('miR-126', 'Var', (14, 21))
21357	32906592	This revealed that loss of miR-126 is associated with breast cancer relapse and metastasis.	('breast cancer', 'Disease', (54, 67))	('metastasis', 'CPA', (80, 90))	('associated', 'Reg', (38, 48))	('miR-126', 'Gene', (27, 34))	('loss', 'Var', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
21370	32906592	Among the ten miRNAs discussed here, some of them are predominantly reported to be tumor suppressors (miR-145, miR-31, miR-451, miR-143, miR-146a, miR-126) and oncomiRs (miR-19a, miR-125b, miR-210).	('miR-145', 'Gene', '406937', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('miR-451', 'Gene', '574411', (119, 126))	('miR-19a', 'Gene', '406979', (170, 177))	('miR-210', 'Gene', '406992', (189, 196))	('tumor', 'Disease', (83, 88))	('miR-31', 'Gene', (111, 117))	('miR-125b', 'Var', (179, 187))	('miR-126', 'Var', (147, 154))	('miR-19a', 'Gene', (170, 177))	('miR-145', 'Gene', (102, 109))	('miR-146a', 'Var', (137, 145))	('miR-451', 'Gene', (119, 126))	('miR-31', 'Gene', '407035', (111, 117))	('miR-125b', 'Chemical', '-', (179, 187))	('miR-210', 'Gene', (189, 196))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('miR-143', 'Var', (128, 135))
21371	32906592	Mimics of tumor suppressor miRNAs including miR-145, miR-31, miR-451, miR-143, miR-146a, and miR-126 could serve as potential therapeutic molecules for tackling primary and metastatic brain cancers.	('brain cancers', 'Disease', (184, 197))	('miR-146a', 'Var', (79, 87))	('miR-451', 'Gene', '574411', (61, 68))	('tumor', 'Disease', (10, 15))	('brain cancers', 'Disease', 'MESH:D001932', (184, 197))	('miR-145', 'Gene', '406937', (44, 51))	('miR-31', 'Gene', (53, 59))	('tackling', 'NegReg', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('10', '26'))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('brain cancer', 'Phenotype', 'HP:0030692', (184, 196))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('miR-145', 'Gene', (44, 51))	('tumor suppressor', 'biological_process', 'GO:0051726', ('10', '26'))	('miR-451', 'Gene', (61, 68))	('miR-143', 'Var', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('miR-31', 'Gene', '407035', (53, 59))	('primary', 'Disease', (161, 168))	('miR-126', 'Var', (93, 100))
21372	32906592	In addition, antimiRs (or antagomiRs) of miR-19a, miR-125b, and miR-210 could be used to suppress glioblastoma progression and metastasis.	('glioblastoma', 'Disease', (98, 110))	('miR-19a', 'Gene', (41, 48))	('antimiRs', 'Var', (13, 21))	('glioblastoma', 'Disease', 'MESH:D005909', (98, 110))	('miR-125b', 'Chemical', '-', (50, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('miR-210', 'Gene', (64, 71))	('miR-210', 'Gene', '406992', (64, 71))	('miR-19a', 'Gene', '406979', (41, 48))	('suppress', 'NegReg', (89, 97))	('miR-125b', 'Var', (50, 58))	('metastasis', 'CPA', (127, 137))
21374	32906592	miRNAs such as miR-145, miR-31, miR-125b, and miR-126 could be considered as prognostic markers in GBM progression.	('miR-126', 'Var', (46, 53))	('miR-31', 'Gene', (24, 30))	('GBM', 'Phenotype', 'HP:0012174', (99, 102))	('miR-125b', 'Chemical', '-', (32, 40))	('miR-145', 'Gene', (15, 22))	('miR-145', 'Gene', '406937', (15, 22))	('miR-31', 'Gene', '407035', (24, 30))	('GBM', 'Disease', (99, 102))	('miR-125b', 'Var', (32, 40))
21378	32906592	Due to the complexity and number of miRNA interactions, and dysregulation of multiple pathways within cancers, it is unlikely that modulating the expression of a single miRNA will have a sustained effect on the overall phenotype.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('interactions', 'Interaction', (42, 54))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('dysregulation', 'Var', (60, 73))
21379	32906592	; writing:original draft preparation, A.A.B., L.M.L., S.C.; writing:review and editing, A.A.B., L.M.L., S.C., R.N.V.	('L.M.L.', 'Var', (96, 102))	('S.C.', 'Var', (104, 108))	('A.A.B.', 'Var', (88, 94))	('rat', 'Species', '10116', (30, 33))
21416	30334003	The International mRCC Database Consortium (IMDC) prognostic model was examined in metastatic chrRCC by categorizing metastatic chrRCC patients into IMDC risk groups using the following prognostic factors: hemoglobin below the lower limit of normal, corrected calcium greater than the upper limit of normal (ULN), neutrophils above ULN, platelets above ULN, Karnofsky performance status (KPS) below 80%, and time from diagnosis to treatment of less than one year.	('hemoglobin', 'MPA', (206, 216))	('RCC', 'Disease', (97, 100))	('patients', 'Species', '9606', (135, 143))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('calcium', 'Chemical', 'MESH:D002118', (260, 267))	('RCC', 'Disease', (131, 134))	('below', 'NegReg', (217, 222))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('RCC', 'Disease', (19, 22))	('below', 'NegReg', (393, 398))	('corrected calcium', 'MPA', (250, 267))	('neutrophils', 'Var', (314, 325))	('Karnofsky performance status', 'CPA', (358, 386))
21442	30334003	This is postulated to be improved in everolimus, as chrRCC has activating mutations in PTEN-PI3K-mTOR pathway, which would result in an appropriate target for an mTOR inhibitor.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('PTEN', 'Gene', (87, 91))	('RCC', 'Disease', (55, 58))	('mTOR', 'Gene', (162, 166))	('mTOR', 'Gene', '2475', (97, 101))	('mTOR', 'Gene', '2475', (162, 166))	('PTEN', 'Gene', '5728', (87, 91))	('mTOR', 'Gene', (97, 101))	('mutations', 'Var', (74, 83))	('everolimus', 'Chemical', 'MESH:D000068338', (37, 47))	('activating', 'PosReg', (63, 73))	('PI3K', 'molecular_function', 'GO:0016303', ('92', '96'))
21466	32337221	Based on our previous study and the verification reported in this article, we propose that demethylation-induced overexpression of LRG1 is likely to accelerate ccRCC progression via the TGF-beta pathway.	('ccRCC', 'Phenotype', 'HP:0006770', (160, 165))	('demethylation-induced', 'Var', (91, 112))	('RCC', 'Disease', (162, 165))	('RCC', 'Phenotype', 'HP:0005584', (162, 165))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('TGF-beta', 'Gene', (186, 194))	('overexpression', 'PosReg', (113, 127))	('demethylation', 'biological_process', 'GO:0070988', ('91', '104'))	('accelerate', 'PosReg', (149, 159))	('LRG1', 'Gene', (131, 135))	('TGF-beta', 'Gene', '7039', (186, 194))
21485	32337221	The First Strand cDNA Synthesis Kit (New England Biolabs, E6560S) was used for cDNA synthesis with a standard protocol.	('synthesis', 'biological_process', 'GO:0009058', ('84', '93'))	('Kit', 'Gene', (32, 35))	('E6560S', 'SUBSTITUTION', 'None', (58, 64))	('Kit', 'Gene', '3815', (32, 35))	('E6560S', 'Var', (58, 64))
21528	32337221	This indicates that a low methylation level upregulates the transcription of LRG1, thus accelerating the progression of ccRCC.	('accelerating', 'PosReg', (88, 100))	('transcription', 'biological_process', 'GO:0006351', ('60', '73'))	('low', 'Var', (22, 25))	('ccRCC', 'Phenotype', 'HP:0006770', (120, 125))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('upregulates', 'PosReg', (44, 55))	('LRG1', 'Gene', (77, 81))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('methylation', 'MPA', (26, 37))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('transcription', 'MPA', (60, 73))	('RCC', 'Disease', (122, 125))
21545	32337221	Methylation is closely associated with immunoproliferative diseases such as cancer, rheumatoid arthritis, and proliferative diabetic retinopathy and even development and senescence.	('retinopathy', 'Phenotype', 'HP:0000488', (133, 144))	('development', 'CPA', (154, 165))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (84, 104))	('Methylation', 'Var', (0, 11))	('senescence', 'CPA', (170, 180))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('immunoproliferative diseases', 'Disease', 'MESH:D007160', (39, 67))	('senescence', 'biological_process', 'GO:0010149', ('170', '180'))	('immunoproliferative diseases', 'Disease', (39, 67))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (84, 104))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('diabetic retinopathy', 'Disease', (124, 144))	('rheumatoid arthritis', 'Disease', (84, 104))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('associated', 'Reg', (23, 33))	('diabetic retinopathy', 'Disease', 'MESH:D003920', (124, 144))	('arthritis', 'Phenotype', 'HP:0001369', (95, 104))
21554	32337221	In conclusion, we suggest that demethylation-induced overexpression of LRG1 accelerates ccRCC progression via the TGF-beta pathway.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('overexpression', 'PosReg', (53, 67))	('TGF-beta', 'Gene', (114, 122))	('demethylation', 'biological_process', 'GO:0070988', ('31', '44'))	('TGF-beta', 'Gene', '7039', (114, 122))	('LRG1', 'Gene', (71, 75))	('accelerates', 'PosReg', (76, 87))	('demethylation-induced', 'Var', (31, 52))	('RCC', 'Disease', (90, 93))
21614	31956465	examined 49 ChRCC tumors and found TP53, PTEN, FAAH2, PDHB, PDXDC1, and ZNF765 to be significantly mutated relative to normal tissue; this is in contrast to ccRCC, which is characterized by mutations in VHL, TCEB1, PTEN, PBRM1, SETD2, BAP1, KDM5C, MTOR, PIK3CA, and TP53 relative to normal tissue.	('FAAH2', 'Gene', '158584', (47, 52))	('ChRCC', 'Disease', (12, 17))	('SETD2', 'Gene', '29072', (228, 233))	('VHL', 'Disease', (203, 206))	('ccRCC', 'Disease', 'MESH:D002292', (157, 162))	('TP53', 'Gene', '7157', (35, 39))	('PIK3CA', 'Gene', '5290', (254, 260))	('tumors', 'Disease', (18, 24))	('TP53', 'Gene', (266, 270))	('PDHB', 'Gene', (54, 58))	('KDM5C', 'Gene', '8242', (241, 246))	('PDXDC1', 'Gene', (60, 66))	('FAAH2', 'Gene', (47, 52))	('PBRM1', 'Gene', '55193', (221, 226))	('MTOR', 'Gene', (248, 252))	('MTOR', 'Gene', '2475', (248, 252))	('ccRCC', 'Disease', (157, 162))	('mutations', 'Var', (190, 199))	('ChRCC', 'Disease', 'MESH:D002292', (12, 17))	('BAP1', 'Gene', '8314', (235, 239))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('ZNF765', 'Gene', (72, 78))	('PTEN', 'Gene', (41, 45))	('PDHB', 'Gene', '5162', (54, 58))	('PBRM1', 'Gene', (221, 226))	('TCEB1', 'Gene', (208, 213))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))	('ccRCC', 'Phenotype', 'HP:0006770', (157, 162))	('PIK3CA', 'Gene', (254, 260))	('TP53', 'Gene', '7157', (266, 270))	('TP53', 'Gene', (35, 39))	('PTEN', 'Gene', (215, 219))	('VHL', 'Disease', 'MESH:D006623', (203, 206))	('KDM5C', 'Gene', (241, 246))	('BAP1', 'Gene', (235, 239))	('TCEB1', 'Gene', '6921', (208, 213))	('PTEN', 'Gene', '5728', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('ZNF765', 'Gene', '91661', (72, 78))	('PDXDC1', 'Gene', '23042', (60, 66))	('SETD2', 'Gene', (228, 233))	('PTEN', 'Gene', '5728', (215, 219))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
21624	31956465	examined genomic features specific to 35 metastatic ChRCC tumors and found that mutations to TP53 and PTEN, and imbalanced chromosome duplication in >=3 chromosomes, were associated with inferior clinical outcomes.	('imbalanced chromosome duplication', 'Var', (112, 145))	('ChRCC', 'Disease', 'MESH:D002292', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('chromosome', 'cellular_component', 'GO:0005694', ('123', '133'))	('tumors', 'Disease', (58, 64))	('mutations', 'Var', (80, 89))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('PTEN', 'Gene', (102, 106))	('ChRCC', 'Disease', (52, 57))	('PTEN', 'Gene', '5728', (102, 106))
21668	31422942	The occurrence and progression of ccRCC are the comprehensive results activation of various oncogenes and inactivation of various tumor suppressor genes.	('tumor', 'Disease', (130, 135))	('inactivation', 'Var', (106, 118))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('130', '146'))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (34, 39))	('ccRCC', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor suppressor', 'biological_process', 'GO:0051726', ('130', '146'))	('activation', 'PosReg', (70, 80))
21690	31422942	Studies have found that high expression of TOP2A promoted the progression of breast cancer.	('breast cancer', 'Disease', (77, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('progression', 'CPA', (62, 73))	('high expression', 'Var', (24, 39))	('TOP2A', 'Gene', '7153', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('promoted', 'PosReg', (49, 57))	('TOP2A', 'Gene', (43, 48))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
21698	31422942	In the regulation of the cell cycle, abnormalities of various molecules may cause tumorigenesis and progression.	('molecules', 'Protein', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('abnormalities', 'Var', (37, 50))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('progression', 'CPA', (100, 111))	('cell cycle', 'biological_process', 'GO:0007049', ('25', '35'))	('cause', 'Reg', (76, 81))	('tumor', 'Disease', (82, 87))	('regulation', 'biological_process', 'GO:0065007', ('7', '17'))
21702	31422942	Trifluoperazine is a typical antipsychotic, but recently some researchers found that trifluoperazine could inhibit the proliferation of multiple cancer cells, such as glioblastoma, Hepatocellular Carcinoma and lung cancer.	('inhibit', 'NegReg', (107, 114))	('cancer', 'Disease', (145, 151))	('Hepatocellular Carcinoma', 'Phenotype', 'HP:0001402', (181, 205))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('glioblastoma', 'Disease', (167, 179))	('glioblastoma', 'Disease', 'MESH:D005909', (167, 179))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('trifluoperazine', 'Var', (85, 100))	('Carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('lung cancer', 'Phenotype', 'HP:0100526', (210, 221))	('glioblastoma', 'Phenotype', 'HP:0012174', (167, 179))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('Trifluoperazine', 'Chemical', 'MESH:D014268', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('Hepatocellular Carcinoma and lung cancer', 'Disease', 'MESH:D006528', (181, 221))	('proliferation', 'CPA', (119, 132))	('trifluoperazine', 'Chemical', 'MESH:D014268', (85, 100))
21727	31207938	Each tumor subtype displays a specific and complex spectrum of gene mutations and molecular altered pathways resulting in a heterogeneous mixture of malignancies associated with different morphologies, immune-histochemical features, clinical behaviors and prognoses.	('malignancies', 'Disease', (149, 161))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('heterogeneous mixture of', 'MPA', (124, 148))	('tumor', 'Disease', (5, 10))	('malignancies', 'Disease', 'MESH:D009369', (149, 161))	('mutations', 'Var', (68, 77))	('resulting in', 'Reg', (109, 121))
21729	31207938	This is mainly (but not only) due to alterations of the Von Hipple Lindau (VHL) gene which occur in about 90% of ccRCC cases.	('Von Hipple Lindau', 'Gene', (56, 73))	('VHL', 'Gene', (75, 78))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('VHL', 'Gene', '7428', (75, 78))	('RCC', 'Disease', (115, 118))	('alterations', 'Var', (37, 48))	('Von Hipple Lindau', 'Gene', '7428', (56, 73))
21755	31207938	If genomic heterogeneity in RCC is commonly observed and leads to an extraordinary number of possible mutations, ultimately resulting in several different genomic profiles, some shared genomic alterations which have been observed in each tumor subtype act as driver mutations, providing the bases for eventual tailored approaches.	('leads', 'Reg', (57, 62))	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('resulting in', 'Reg', (124, 136))	('tumor', 'Disease', (238, 243))	('mutations', 'Var', (102, 111))	('RCC', 'Disease', (28, 31))	('RCC', 'Phenotype', 'HP:0005584', (28, 31))
21756	31207938	What has been suggested in RCC is that the tumor heterogeneity and genomic profile of each disease strictly depend on specific mutations occurring in different phases of disease development, with additional possible different spatial location.	('men', 'Species', '9606', (185, 188))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutations', 'Var', (127, 136))	('tumor', 'Disease', (43, 48))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))
21757	31207938	These mutations are often truncal-type events (e.g., chromosomal 3 losses in ccRCC) which, once they have occurred, lead to a wide spectrum of mutations.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('losses', 'NegReg', (67, 73))	('lead', 'Reg', (116, 120))	('mutations', 'MPA', (143, 152))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('mutations', 'Var', (6, 15))	('RCC', 'Disease', (79, 82))
21759	31207938	In a study of four patients, VHL mutation and 3p loss of heterozygosity were found in all regions of the tumor samples (trunk), while other common mutations recognized as driver mutations (SETD2, PBRM1, MTOR, SETD2, BAP1, KDM5C, TSC1.)	('BAP1', 'Gene', (216, 220))	('MTOR', 'Gene', '2475', (203, 207))	('KDM5C', 'Gene', (222, 227))	('SETD2', 'Gene', (209, 214))	('VHL', 'Gene', (29, 32))	('SETD2', 'Gene', '29072', (209, 214))	('trunk', 'cellular_component', 'GO:0043198', ('120', '125'))	('tumor', 'Disease', (105, 110))	('mutation', 'Var', (33, 41))	('patients', 'Species', '9606', (19, 27))	('loss of heterozygosity', 'NegReg', (49, 71))	('VHL', 'Gene', '7428', (29, 32))	('KDM5C', 'Gene', '8242', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('PBRM1', 'Gene', '55193', (196, 201))	('SETD2', 'Gene', (189, 194))	('BAP1', 'Gene', '8314', (216, 220))	('SETD2', 'Gene', '29072', (189, 194))	('TSC1', 'Gene', (229, 233))	('PBRM1', 'Gene', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('MTOR', 'Gene', (203, 207))	('TSC1', 'Gene', '7248', (229, 233))
21773	31207938	Alterations of this gene have been found only in a very low percentage of RCC specimens.	('Alterations', 'Var', (0, 11))	('men', 'Species', '9606', (83, 86))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (74, 77))
21776	31207938	In particular, the hyper-expression of IL-8 leads to VEGF mRNA transcription and autocrine VEGFR-2 activation.	('VEGF', 'Gene', '7422', (91, 95))	('VEGFR-2', 'Gene', (91, 98))	('IL-8', 'Gene', '3576', (39, 43))	('IL-8', 'Gene', (39, 43))	('mRNA transcription', 'biological_process', 'GO:0009299', ('58', '76'))	('VEGF', 'Gene', (53, 57))	('activation', 'PosReg', (99, 109))	('VEGF', 'Gene', (91, 95))	('VEGFR-2', 'Gene', '3791', (91, 98))	('hyper-expression', 'Var', (19, 35))	('VEGF', 'Gene', '7422', (53, 57))	('IL-8', 'molecular_function', 'GO:0005153', ('39', '43'))
21778	31207938	High levels of both IL-6 and IL-8 have been associated with poor prognoses in RCC; the inhibition of the IL-6 receptor may restore angiogenesis inhibitor efficacy.	('IL-8', 'Gene', (29, 33))	('IL-8', 'molecular_function', 'GO:0005153', ('29', '33'))	('IL-6', 'molecular_function', 'GO:0005138', ('105', '109'))	('restore', 'PosReg', (123, 130))	('IL-6', 'Gene', (105, 109))	('IL-6', 'molecular_function', 'GO:0005138', ('20', '24'))	('angiogenesis', 'biological_process', 'GO:0001525', ('131', '143'))	('IL-6', 'Gene', '3569', (105, 109))	('IL-8', 'Gene', '3576', (29, 33))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('IL-6', 'Gene', (20, 24))	('angiogenesis inhibitor efficacy', 'MPA', (131, 162))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('inhibition', 'Var', (87, 97))	('IL-6', 'Gene', '3569', (20, 24))
21815	31207938	Due to continuous INFgamma exposure, cancers cells may develop down-regulation and/or mutations interfering with INFgamma stimulation.	('mutations', 'Var', (86, 95))	('interfering', 'NegReg', (96, 107))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('regulation', 'biological_process', 'GO:0065007', ('68', '78'))	('cancers', 'Disease', (37, 44))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('down-regulation', 'NegReg', (63, 78))
21816	31207938	For example, mutations occurring in the INFgamma receptor chains (Janus kinases: JAK1/JAK2) or in other points of the intracellular cascade (such as the signal transducer and activators of transcription STATs) may make tumor cells refractory to CTLA-4 inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('JAK', 'molecular_function', 'GO:0004713', ('86', '89'))	('JAK', 'molecular_function', 'GO:0004713', ('81', '84'))	('CTLA-4', 'Gene', '1493', (245, 251))	('tumor', 'Disease', (219, 224))	('make', 'Reg', (214, 218))	('transcription', 'biological_process', 'GO:0006351', ('189', '202'))	('JAK1', 'Gene', (81, 85))	('CTLA-4', 'Gene', (245, 251))	('JAK1', 'Gene', '3716', (81, 85))	('intracellular', 'cellular_component', 'GO:0005622', ('118', '131'))	('STATs', 'Gene', (203, 208))	('STATs', 'Gene', '6774', (203, 208))	('JAK2', 'Gene', '3717', (86, 90))	('mutations', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('INFgamma receptor', 'Protein', (40, 57))	('JAK2', 'Gene', (86, 90))
21821	31207938	Other intracellular mechanisms related to primary resistance to immune-checkpoint inhibitors depend upon the activation of AKT and the reduction of neo-antigens production (also mediated by epigenetic modification).	('reduction', 'NegReg', (135, 144))	('neo-antigens production', 'MPA', (148, 171))	('activation', 'PosReg', (109, 119))	('AKT', 'Gene', '207', (123, 126))	('intracellular', 'cellular_component', 'GO:0005622', ('6', '19'))	('AKT', 'Gene', (123, 126))	('epigenetic modification', 'Var', (190, 213))
21826	31207938	CTLA-4 inhibitors may promote a reduction of Tregs enhancing activity and the function of lymphocyte T effector (Teffs) cells, resulting in immune-response activation.	('CTLA-4', 'Gene', (0, 6))	('immune-response', 'biological_process', 'GO:0006955', ('140', '155'))	('inhibitors', 'Var', (7, 17))	('reduction', 'NegReg', (32, 41))	('CTLA-4', 'Gene', '1493', (0, 6))	('immune-response', 'CPA', (140, 155))	('function', 'MPA', (78, 86))	('Tregs enhancing activity', 'CPA', (45, 69))
21830	31207938	Indeed, after a variable time of response, tumor cells could develop down-regulation or mutations in downstream cascades related to INFgamma.	('regulation', 'biological_process', 'GO:0065007', ('74', '84'))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('mutations', 'Var', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('down-regulation', 'NegReg', (69, 84))
21892	33461173	Furthermore, dysregulation of RBPs has been found in various human cancers, suggesting that RBPs may be reliable early molecular markers and therapeutic targets.	('RBP', 'Gene', '57794', (30, 33))	('RBP', 'Gene', '57794', (92, 95))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('dysregulation', 'Var', (13, 26))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('human', 'Species', '9606', (61, 66))	('RBP', 'Gene', (30, 33))	('RBP', 'Gene', (92, 95))
21941	33461173	Furthermore, the KEGG enrichment analysis demonstrated that the abnormally expressed RBPs participate in the progression of ccRCC by regulating ribosomes, RNA transport, spliceosomes, ribosome biogenesis in eukaryotes, RNA degradation, and polymerases.	('RBP', 'Gene', (85, 88))	('RNA transport', 'biological_process', 'GO:0050658', ('155', '168'))	('polymerases', 'Enzyme', (240, 251))	('RNA', 'cellular_component', 'GO:0005562', ('155', '158'))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('participate', 'Reg', (90, 101))	('regulating', 'Reg', (133, 143))	('ribosomes', 'MPA', (144, 153))	('spliceosomes', 'MPA', (170, 182))	('RNA degradation', 'MPA', (219, 234))	('RNA degradation', 'biological_process', 'GO:0006401', ('219', '234'))	('ribosome', 'cellular_component', 'GO:0005840', ('184', '192'))	('RBP', 'Gene', '57794', (85, 88))	('RNA', 'cellular_component', 'GO:0005562', ('219', '222'))	('abnormally', 'Var', (64, 74))	('RNA transport', 'MPA', (155, 168))	('ribosome biogenesis', 'biological_process', 'GO:0042254', ('184', '203'))	('ribosome biogenesis', 'MPA', (184, 203))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (124, 129))
22002	32106629	Recently, the expression of TfR1 was associated with progression and mortality in clear cell RCC (ccRCC), identifying TfR1 as a novel RCC biomarker and potential therapeutic target.	('expression', 'Var', (14, 24))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Disease', (93, 96))	('TfR1', 'Gene', (28, 32))	('TfR1', 'Gene', '7037', (28, 32))	('mortality', 'Disease', 'MESH:D003643', (69, 78))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('associated', 'Reg', (37, 47))	('RCC', 'Disease', (134, 137))	('TfR1', 'Gene', '7037', (118, 122))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('mortality', 'Disease', (69, 78))	('TfR1', 'Gene', (118, 122))
22018	32106629	Accordingly, TAMs were shown to positively associate with tumor progression and worse patient prognosis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('TAMs', 'Var', (13, 17))	('associate', 'Reg', (43, 52))	('TAMs', 'Chemical', 'MESH:D013629', (13, 17))	('patient', 'Species', '9606', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
22027	32106629	We next analyzed the mRNA expression of iron-dependent genes in relation to tumor grade (G1-G2 vs. G3-G4) and tumor pT-stage (pT1 pT2 vs. pT3-pT4).	('G1-G2', 'Var', (89, 94))	('pT1', 'Gene', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('pT3', 'Gene', '7694', (138, 141))	('pT3', 'Gene', (138, 141))	('iron', 'Chemical', 'MESH:D007501', (40, 44))	('pT1', 'Gene', '58492', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
22061	32106629	In particular, the tridentate chelating unit of EC1 includes a thiosemicarbazone moiety that is common to many anti-proliferative iron chelators; however, the incorporation of a negatively charged sulfonate group significantly limits the ability of EC1 to cross cellular membranes.	('thiosemicarbazone', 'Chemical', 'MESH:D013882', (63, 80))	('limits', 'NegReg', (227, 233))	('iron', 'Chemical', 'MESH:D007501', (130, 134))	('EC1', 'Gene', (48, 51))	('EC1', 'Gene', '4819', (48, 51))	('incorporation', 'Var', (159, 172))	('EC1', 'Gene', (249, 252))	('EC1', 'Gene', '4819', (249, 252))	('sulfonate', 'Chemical', 'MESH:D000476', (197, 206))	('ability', 'MPA', (238, 245))
22099	32106629	Nonetheless, modulating the iron-retaining tumor phenotype reduced growth and progression of both human and mouse carcinomas.	('reduced', 'NegReg', (59, 66))	('modulating', 'Var', (13, 23))	('carcinomas', 'Disease', 'MESH:D009369', (114, 124))	('iron', 'Chemical', 'MESH:D007501', (28, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('carcinomas', 'Disease', (114, 124))	('mouse', 'Species', '10090', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('human', 'Species', '9606', (98, 103))
22177	32106629	HRMS-ESI (m/z): [M - Na]- calcd for [C14H12-N3O4S2]-, 350.02747; found, 350.02741; [M + H]+ calcd for [C14H13-N3NaO4S2]+, 374.02397; found, 374.02401.	('H12-N3', 'Species', '546801', (40, 46))	('4H', 'Chemical', '-', (105, 107))	('[C14H13-N3NaO4S2]+', 'Var', (102, 120))	('[C14H12-N3O4S2]-', 'Var', (36, 52))	('H13-N3', 'Species', '222773', (106, 112))	('4H', 'Chemical', '-', (39, 41))
22179	32106629	13C NMR (125 MHz, DMSO-d6) delta 176.21, 157.17, 145.37, 140.65, 139.76, 131.86, 127.55, 125.85, 125.12, 120.69, 119.70, 116.53.	('131.86', 'Var', (73, 79))	('DMSO-d6', 'Chemical', '-', (18, 25))	('145.37', 'Var', (49, 55))	('13C', 'Chemical', 'MESH:C000615229', (0, 3))
22203	31871500	Silencing of LncRNA APOC1P1 also led to decreased cell migration and invasion (P < 0.05).	('APOC1P1', 'Gene', (20, 27))	('APOC1P1', 'Gene', '342', (20, 27))	('cell migration', 'biological_process', 'GO:0016477', ('50', '64'))	('invasion', 'CPA', (69, 77))	('cell migration', 'CPA', (50, 64))	('Silencing', 'Var', (0, 9))	('decreased', 'NegReg', (40, 49))
22245	31871500	When the cutoff value = -0.442, the diagnostic sensitivity (73.3%) and specificity (93.3%) reached their peak value, indicating that LncRNA APOC1P1 has clinical significance for the diagnosis of ccRCC.	('APOC1P1', 'Gene', (140, 147))	('RCC', 'Phenotype', 'HP:0005584', (197, 200))	('RCC', 'Disease', 'MESH:C538614', (197, 200))	('RCC', 'Disease', (197, 200))	('LncRNA', 'Var', (133, 139))	('APOC1P1', 'Gene', '342', (140, 147))
22253	31871500	Transfection with LncRNA APOC1P1 siRNAs was performed to downregulate the expression of LncRNA APOC1P1, and transfection with siRNA2 and siRNA3 successfully decreased LncRNA APOC1P1 levels in A498 cells compared with the positive control group (P < 0.05, Figure 3(b)).	('APOC1P1', 'Gene', (174, 181))	('expression', 'MPA', (74, 84))	('APOC1P1', 'Gene', '342', (174, 181))	('APOC1P1', 'Gene', (25, 32))	('APOC1P1', 'Gene', '342', (25, 32))	('downregulate', 'NegReg', (57, 69))	('LncRNA', 'Gene', (88, 94))	('transfection', 'Var', (108, 120))	('APOC1P1', 'Gene', (95, 102))	('APOC1P1', 'Gene', '342', (95, 102))	('decreased', 'NegReg', (157, 166))
22256	31871500	The results indicated that si-LncRNA transfection led to cell growth arrest in A498 cells compared with the si-NC group (P < 0.05, Figure 3(c)).	('growth arrest', 'Phenotype', 'HP:0001510', (62, 75))	('si-LncRNA transfection', 'Var', (27, 49))	('cell growth', 'biological_process', 'GO:0016049', ('57', '68'))	('growth arrest', 'Disease', 'MESH:D006323', (62, 75))	('growth arrest', 'Disease', (62, 75))	('transfection', 'Var', (37, 49))
22258	31871500	In the cell cycle analyses, the proportion of cells in the G1-phase was significantly increased after transfection, while the proportion of cells in the S-phase was notably lower than that in the control group, suggesting that LncRNA APOC1P1 knockdown induced G1/S arrest (P < 0.05; Figure 3(e)).	('S arrest', 'Disease', (263, 271))	('G1-phase', 'biological_process', 'GO:0051318', ('59', '67'))	('S arrest', 'Disease', 'MESH:D006323', (263, 271))	('APOC1P1', 'Gene', '342', (234, 241))	('increased', 'PosReg', (86, 95))	('induced', 'Reg', (252, 259))	('knockdown', 'Var', (242, 251))	('APOC1P1', 'Gene', (234, 241))	('cell cycle', 'biological_process', 'GO:0007049', ('7', '17'))	('S-phase', 'biological_process', 'GO:0051320', ('153', '160'))	('LncRNA', 'Var', (227, 233))
22260	31871500	Compared with the si-NC group, cell migration was significantly inhibited after si-LncRNA APOC1P1 transfection, and cell invasive capacity was also markedly reduced (P < 0.05, Figures 3(f) and 3(g)).	('transfection', 'Var', (98, 110))	('cell migration', 'biological_process', 'GO:0016477', ('31', '45'))	('cell migration', 'CPA', (31, 45))	('APOC1P1', 'Gene', (90, 97))	('cell invasive capacity', 'CPA', (116, 138))	('inhibited', 'NegReg', (64, 73))	('APOC1P1', 'Gene', '342', (90, 97))	('si-LncRNA', 'Var', (80, 89))	('reduced', 'NegReg', (157, 164))
22261	31871500	Cell migration was also significantly inhibited after si-LncRNA APOC1P1 transfection (P < 0.05, Figure 3(g)).	('Cell migration', 'biological_process', 'GO:0016477', ('0', '14'))	('Cell migration', 'CPA', (0, 14))	('inhibited', 'NegReg', (38, 47))	('transfection', 'Var', (72, 84))	('si-LncRNA', 'Var', (54, 63))	('APOC1P1', 'Gene', (64, 71))	('APOC1P1', 'Gene', '342', (64, 71))
22269	31871500	Generally, the antisense transcripts produced from pseudogenes can hybridize to corresponding mRNAs, forming dsRNAs cleaved by Dicer to endogenous siRNAs.	('Dicer', 'Gene', (127, 132))	('Dicer', 'Gene', '23405', (127, 132))	('pseudogenes', 'Var', (51, 62))
22280	31871500	Silencing of LncRNA APOC1P1 also led to decreased cell migration and invasion.	('APOC1P1', 'Gene', (20, 27))	('APOC1P1', 'Gene', '342', (20, 27))	('cell migration', 'biological_process', 'GO:0016477', ('50', '64'))	('invasion', 'CPA', (69, 77))	('cell migration', 'CPA', (50, 64))	('Silencing', 'Var', (0, 9))	('decreased', 'NegReg', (40, 49))
22281	31871500	These findings suggest that LncRNA APOC1P1 may impact the clinicopathological features of ccRCC by affecting cell proliferation and invasiveness.	('cell proliferation', 'CPA', (109, 127))	('invasiveness', 'CPA', (132, 144))	('impact', 'Reg', (47, 53))	('APOC1P1', 'Gene', (35, 42))	('affecting', 'Reg', (99, 108))	('APOC1P1', 'Gene', '342', (35, 42))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('cell proliferation', 'biological_process', 'GO:0008283', ('109', '127'))	('LncRNA', 'Var', (28, 34))
22292	32131507	First, we confirmed VEGFR2/KDR as a target gene of miR-221-3p in PCa cells by applying Luciferase reporter assays and Western blotting experiments.	('KDR', 'Gene', (27, 30))	('miR-221-3p', 'Var', (51, 61))	('VEGFR2', 'Gene', (20, 26))	('KDR', 'Gene', '3791', (27, 30))	('miR-221-3p', 'Chemical', '-', (51, 61))	('PCa', 'Phenotype', 'HP:0012125', (65, 68))	('VEGFR2', 'Gene', '3791', (20, 26))
22294	32131507	In vitro miR-221-3p acted as an escape mechanism from TKI in PC3 cells, as displayed by proliferation and apoptosis assays.	('PC3', 'Gene', (61, 64))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('miR-221-3p', 'Var', (9, 19))	('miR-221-3p', 'Chemical', '-', (9, 19))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('PC3', 'Gene', '3853', (61, 64))
22297	32131507	Apart from this therapeutic niche, we identified a partially oncogenic function of miR-221-3p as an escape mechanism from VEGFR2 inhibition.	('VEGFR2', 'Gene', (122, 128))	('oncogenic', 'Reg', (61, 70))	('miR-221-3p', 'Var', (83, 93))	('miR-221-3p', 'Chemical', '-', (83, 93))	('VEGFR2', 'Gene', '3791', (122, 128))
22302	32131507	For clear-cell renal cell carcinoma (ccRCC), the tissue expression of miR-221-3p and miR-222-3p, which are two small, non-coding RNA strands originating from the same cluster, significantly predicted the response towards antiangiogenic therapies in two independent studies.	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (4, 35))	('miR-222', 'Gene', '407007', (85, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('RNA', 'cellular_component', 'GO:0005562', ('129', '132'))	('response towards antiangiogenic therapies', 'MPA', (204, 245))	('miR-221-3p', 'Var', (70, 80))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (15, 35))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('miR-222', 'Gene', (85, 92))	('RCC', 'Disease', (39, 42))	('predicted', 'Reg', (190, 199))	('miR-221-3p', 'Chemical', '-', (70, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (4, 35))	('clear-cell renal cell carcinoma', 'Disease', (4, 35))
22304	32131507	In case of PCa, miR-221-3p and miR-222-3p are significantly downregulated in malignant tissue when compared to benign tissue, as confirmed by previous studies including a recent meta-analysis.	('PCa', 'Disease', (11, 14))	('miR-222', 'Gene', '407007', (31, 38))	('PCa', 'Phenotype', 'HP:0012125', (11, 14))	('miR-221-3p', 'Var', (16, 26))	('miR-222', 'Gene', (31, 38))	('miR-221-3p', 'Chemical', '-', (16, 26))	('downregulated', 'NegReg', (60, 73))
22306	32131507	On a molecular basis, there are conflicting data regarding miR-221-3p function in PCa cells.	('PCa', 'Disease', (82, 85))	('miR-221-3p', 'Var', (59, 69))	('miR-221-3p', 'Chemical', '-', (59, 69))	('PCa', 'Phenotype', 'HP:0012125', (82, 85))
22307	32131507	While our group could show that restoration of miR-221-3p expression had a tumour suppressive role in castration-resistant DU145 and PC3 cells, other researchers demonstrated that miR-221-3p also acted as an oncogene in LNCaP and PC3 cells by supporting progress to a castration-resistant state.	('PC3', 'Gene', '3853', (230, 233))	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('miR-221-3p', 'Chemical', '-', (47, 57))	('PC3', 'Gene', (133, 136))	('tumour', 'Disease', (75, 81))	('miR-221-3p', 'Var', (180, 190))	('supporting', 'PosReg', (243, 253))	('progress', 'CPA', (254, 262))	('miR-221-3p', 'Chemical', '-', (180, 190))	('PC3', 'Gene', (230, 233))	('DU145', 'CellLine', 'CVCL:0105', (123, 128))	('LNCaP', 'CellLine', 'CVCL:0395', (220, 225))	('PC3', 'Gene', '3853', (133, 136))	('miR-221-3p', 'Var', (47, 57))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
22321	32131507	In addition, we introduced a mutation into the miR-221 binding site of the VEGFR2/KDR fragment using the Site-Directed Mutagenesis Kit (QuickChange, Agilent Technologies) and introduced the mutant fragment into the Luciferase reporter plasmid.	('mutation', 'Var', (29, 37))	('VEGFR2', 'Gene', (75, 81))	('KDR', 'Gene', (82, 85))	('KDR', 'Gene', '3791', (82, 85))	('miR-221', 'Gene', '407006', (47, 54))	('Kit', 'Gene', (131, 134))	('Mutagenesis', 'biological_process', 'GO:0006280', ('119', '130'))	('Kit', 'Gene', '3815', (131, 134))	('VEGFR2', 'Gene', '3791', (75, 81))	('binding', 'molecular_function', 'GO:0005488', ('55', '62'))	('miR-221', 'Gene', (47, 54))
22343	32131507	Other solid tumor entities with significantly aberrant VEGFR2 expression within the TCGA database were collected using the UALCAN web tool.	('VEGFR2', 'Gene', '3791', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('VEGFR2', 'Gene', (55, 61))	('aberrant', 'Var', (46, 54))	('tumor', 'Disease', (12, 17))
22347	32131507	Moreover, analyzing the expression levels of miR-221-3p and miR-222-3p within the PCa cohort of the TCGA database (Figure 1B) revealed a Pearson correlation coefficient of r = 0.92 (p < 0.01).	('miR-221-3p', 'Var', (45, 55))	('PCa', 'Phenotype', 'HP:0012125', (82, 85))	('miR-222', 'Gene', (60, 67))	('miR-221-3p', 'Chemical', '-', (45, 55))	('miR-222', 'Gene', '407007', (60, 67))
22348	32131507	Based on this result, we concluded that the expression levels of miR-221-3p and miR-222-3p are tightly linked in PCa tissue.	('PCa', 'Disease', (113, 116))	('expression', 'MPA', (44, 54))	('linked', 'Reg', (103, 109))	('PCa', 'Phenotype', 'HP:0012125', (113, 116))	('miR-222', 'Gene', (80, 87))	('miR-221-3p', 'Var', (65, 75))	('miR-221-3p', 'Chemical', '-', (65, 75))	('miR-222', 'Gene', '407007', (80, 87))
22351	32131507	As shown in Figure 1C, pre-miR-221 co-transfections resulted in a highly significant reduction of relative Luciferase activity (39.97 +- 4.88 RLU, p = 0.0059) compared to control co-transfections (81.35 +- 13.8 RLU).	('Luciferase activity', 'molecular_function', 'GO:0047712', ('107', '126'))	('Luciferase activity', 'molecular_function', 'GO:0047077', ('107', '126'))	('Luciferase activity', 'molecular_function', 'GO:0050248', ('107', '126'))	('miR-221', 'Gene', (27, 34))	('co-transfections', 'Var', (35, 51))	('activity', 'MPA', (118, 126))	('miR-221', 'Gene', '407006', (27, 34))	('reduction', 'NegReg', (85, 94))	('Luciferase activity', 'molecular_function', 'GO:0045289', ('107', '126'))	('Luciferase activity', 'molecular_function', 'GO:0050397', ('107', '126'))	('pre', 'molecular_function', 'GO:0003904', ('23', '26'))	('Luciferase', 'Enzyme', (107, 117))
22352	32131507	Furthermore, co-transfection of miR-221 with a plasmid carrying a mutated VEGFR2/KDR binding site nearly restored the initial relative Luciferase activity and did not show significant changes in Luciferase activity compared to control co-transfections (64.83 +- 12.74 RLU, p = 0.09).	('Luciferase activity', 'molecular_function', 'GO:0050397', ('135', '154'))	('miR-221', 'Gene', (32, 39))	('KDR binding', 'molecular_function', 'GO:0043184', ('81', '92'))	('Luciferase activity', 'molecular_function', 'GO:0047077', ('195', '214'))	('activity', 'MPA', (206, 214))	('VEGFR2', 'Gene', (74, 80))	('miR-221', 'Gene', '407006', (32, 39))	('Luciferase activity', 'molecular_function', 'GO:0047077', ('135', '154'))	('VEGFR2', 'Gene', '3791', (74, 80))	('KDR', 'Gene', (81, 84))	('Luciferase activity', 'molecular_function', 'GO:0047712', ('195', '214'))	('mutated', 'Var', (66, 73))	('Luciferase', 'Enzyme', (135, 145))	('Luciferase activity', 'molecular_function', 'GO:0047712', ('135', '154'))	('Luciferase activity', 'molecular_function', 'GO:0045289', ('195', '214'))	('Luciferase activity', 'molecular_function', 'GO:0045289', ('135', '154'))	('KDR', 'Gene', '3791', (81, 84))	('activity', 'MPA', (146, 154))	('Luciferase activity', 'molecular_function', 'GO:0050248', ('195', '214'))	('Luciferase activity', 'molecular_function', 'GO:0050248', ('135', '154'))	('Luciferase', 'Enzyme', (195, 205))	('restored', 'PosReg', (105, 113))	('Luciferase activity', 'molecular_function', 'GO:0050397', ('195', '214'))
22368	32131507	For PSA progress, the following Kaplan Meier analyses (Figure 2E) revealed a shorter PSA-free survival for PCa patients with high VEGFR2 levels.	('PSA', 'Gene', '354', (4, 7))	('VEGFR2', 'Gene', (130, 136))	('PSA', 'Gene', (4, 7))	('PCa', 'Disease', (107, 110))	('PSA', 'Gene', (85, 88))	('VEGFR2', 'Gene', '3791', (130, 136))	('PCa', 'Phenotype', 'HP:0012125', (107, 110))	('shorter', 'NegReg', (77, 84))	('PSA', 'Gene', '354', (85, 88))	('high', 'Var', (125, 129))	('patients', 'Species', '9606', (111, 119))
22373	32131507	Given that this de-sensitizing effect could also be mediated by other Sunitinib target genes like KIT and Platelet-derived growth factor receptor (PDGFR), we also employed Ki8751 (10 microM), which is a specific inhibitor of VEGFR2 (Figure 3B).	('Sunitinib', 'Chemical', 'MESH:D000077210', (70, 79))	('VEGFR2', 'Gene', (225, 231))	('Platelet-derived growth factor receptor', 'Gene', '5159', (106, 145))	('Platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('106', '136'))	('Ki8751', 'Var', (172, 178))	('KIT', 'Gene', '3815', (98, 101))	('VEGFR2', 'Gene', '3791', (225, 231))	('KIT', 'molecular_function', 'GO:0005020', ('98', '101'))	('KIT', 'Gene', (98, 101))	('Platelet-derived growth factor receptor', 'Gene', (106, 145))	('PDGFR', 'Gene', (147, 152))	('Ki8751', 'Chemical', 'MESH:C499138', (172, 178))	('PDGFR', 'Gene', '5159', (147, 152))
22377	32131507	While pre-miR-221 transfection:in contrast to PC3 cells:led to a hyperproliferation when compared to the control (124.6 +- 9.93% viable cells), Sunitinib treatment together with control transfections resulted in 71.33 +- 15.68% cell viability (Figure 3C).	('PC3', 'Gene', (46, 49))	('miR-221', 'Gene', (10, 17))	('pre', 'molecular_function', 'GO:0003904', ('6', '9'))	('PC3', 'Gene', '3853', (46, 49))	('transfection', 'Var', (18, 30))	('miR-221', 'Gene', '407006', (10, 17))	('cell viability', 'CPA', (228, 242))	('Sunitinib', 'Chemical', 'MESH:D000077210', (144, 153))
22379	32131507	In line with these findings, a response toward Ki8751 was not significantly altered by miR-221 levels, either from 31.63 +- 11.7% in the control transfected to 32.53 +- 11.38% (p = 0.93, Figure 3D).	('Ki8751', 'Chemical', 'MESH:C499138', (47, 53))	('miR-221', 'Gene', '407006', (87, 94))	('Ki8751', 'Var', (47, 53))	('miR-221', 'Gene', (87, 94))
22424	32131507	In contrast to PTEN-null PC3 cells, LNCaP cells show a PTEN mutation.	('mutation', 'Var', (60, 68))	('PTEN', 'Gene', '5728', (55, 59))	('PC3', 'Gene', '3853', (25, 28))	('LNCaP', 'CellLine', 'CVCL:0395', (36, 41))	('PTEN', 'Gene', (15, 19))	('PC3', 'Gene', (25, 28))	('PTEN', 'Gene', '5728', (15, 19))	('PTEN', 'Gene', (55, 59))
22437	28160561	In order to determine the functions of DNA methyltransferase in kidney tumorigenesis on the molecular level, we examined the mRNA expression levels of DNMT1, DNMT3A, DNMT3B, and DNMT3B variants in renal cell carcinoma tissue.	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('DNA methyltransferase', 'Gene', (39, 60))	('DNMT1', 'Gene', (151, 156))	('variants', 'Var', (185, 193))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('DNMT3A', 'Gene', '1788', (158, 164))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (197, 217))	('DNMT3B', 'Gene', (178, 184))	('examined', 'Reg', (112, 120))	('DNMT3B', 'Gene', (166, 172))	('DNMT3B', 'Gene', '1789', (166, 172))	('tumor', 'Disease', (71, 76))	('DNA methyltransferase', 'Gene', '1786', (39, 60))	('renal cell carcinoma', 'Disease', (197, 217))	('DNMT1', 'Gene', '1786', (151, 156))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (197, 217))	('DNMT3A', 'Gene', (158, 164))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('DNMT3B', 'Gene', '1789', (178, 184))
22439	28160561	Additionally, Alu elements and long interspersed nuclear elements (LINE-1) were hypomethylated in renal cell carcinoma tissue.	('Alu', 'Chemical', '-', (14, 17))	('hypomethylated', 'Var', (80, 94))	('renal cell carcinoma', 'Disease', (98, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (98, 118))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (98, 118))
22447	28160561	Thus, genomic and epigenomic changes that disrupt important biological functions and determine intra-tumor heterogeneity may provide a molecular basis for different RCC phenotypes, as well as a better understanding of the complex pathology of ccRCC.	('changes', 'Var', (29, 36))	('intra-tumor', 'Disease', 'MESH:D009369', (95, 106))	('RCC', 'Disease', (245, 248))	('RCC', 'Phenotype', 'HP:0005584', (245, 248))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('RCC', 'Disease', 'MESH:C538614', (245, 248))	('intra-tumor', 'Disease', (95, 106))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('RCC', 'Disease', (165, 168))
22448	28160561	Aberrant epigenetic alterations of DNA methylation in somatic cells are recognized as a hallmark of human carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('carcinomas', 'Disease', (106, 116))	('carcinomas', 'Disease', 'MESH:D002277', (106, 116))	('Aberrant epigenetic alterations', 'Var', (0, 31))	('DNA methylation', 'biological_process', 'GO:0006306', ('35', '50'))	('DNA', 'Gene', (35, 38))	('human', 'Species', '9606', (100, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))
22449	28160561	Epigenetic DNA methylation is catalyzed by DNA methyltransferase (DNMT) and occurs at the 5-C position of cytosine nucleotides in CpG dinucleotides throughout genomic DNA.	('DNMT', 'Gene', (66, 70))	('DNA methyltransferase', 'Gene', (43, 64))	('DNA methylation', 'biological_process', 'GO:0006306', ('11', '26'))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('DNA methyltransferase', 'Gene', '1786', (43, 64))	('DNA', 'cellular_component', 'GO:0005574', ('167', '170'))	('Epigenetic', 'Var', (0, 10))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('CpG dinucleotide', 'Chemical', 'MESH:C015772', (130, 146))	('DNMT', 'Gene', '1786', (66, 70))	('cytosine nucleotides', 'Chemical', 'MESH:D003597', (106, 126))
22450	28160561	While hypermethylation of CpG dinucleotides near the promoter regions of some tumor suppressor genes induces transcriptional silencing of these genes, hypomethylation of CpG dinucleotides in other genomic regions have been associated with increased chromosomal instability.	('hypermethylation', 'Var', (6, 22))	('hypomethylation', 'Var', (151, 166))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('chromosomal instability', 'MPA', (249, 272))	('increased chromosomal instability', 'Phenotype', 'HP:0040012', (239, 272))	('CpG dinucleotide', 'Chemical', 'MESH:C015772', (170, 186))	('tumor suppressor', 'biological_process', 'GO:0051726', ('78', '94'))	('CpG dinucleotide', 'Chemical', 'MESH:C015772', (26, 42))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('transcriptional', 'MPA', (109, 124))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('78', '94'))	('tumor', 'Disease', (78, 83))	('chromosomal instability', 'Phenotype', 'HP:0040012', (249, 272))
22456	28160561	Some reports have indicated that in RCC, multiple tumor suppressor genes are simultaneously inactivated by promoter methylation.	('promoter methylation', 'Var', (107, 127))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor suppressor', 'biological_process', 'GO:0051726', ('50', '66'))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('50', '66'))	('methylation', 'biological_process', 'GO:0032259', ('116', '127'))	('inactivated', 'NegReg', (92, 103))	('tumor', 'Disease', (50, 55))
22463	28160561	We compared mRNA levels of DNMT1, DNMT3A, total DNMT3B, and DNMT3B variants in cancer tissue with those in matched adjacent normal tissue.	('DNMT1', 'Gene', '1786', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('DNMT3B', 'Gene', (60, 66))	('DNMT3A', 'Gene', (34, 40))	('DNMT3A', 'Gene', '1788', (34, 40))	('DNMT3B', 'Gene', '1789', (48, 54))	('DNMT3B', 'Gene', '1789', (60, 66))	('DNMT1', 'Gene', (27, 32))	('DNMT3B', 'Gene', (48, 54))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('variants', 'Var', (67, 75))
22474	28160561	The relative methylation of Alu elements in ccRCC tissue and adjacent normal tissue, as detected by Mbo1 digestion, were 0.106 +- 0.04 and 0.115 +- 0.03, respectively (Figure 3B and 3C).	('methylation', 'MPA', (13, 24))	('Alu', 'Chemical', '-', (28, 31))	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('digestion', 'biological_process', 'GO:0007586', ('105', '114'))	('RCC', 'Disease', (46, 49))	('0.106 +- 0.04', 'Var', (121, 134))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('0.115 +- 0.03', 'Var', (139, 152))
22475	28160561	The relative methylation of LINE-1 sequences in ccRCC tissue and adjacent normal tissue, as detected by Taq1 digestion, were 0.305 +- 0.102 and 0.367+-0.132, respectively (Figure 3D and 3E).	('methylation', 'MPA', (13, 24))	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('0.367+-0.132', 'Var', (144, 156))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('digestion', 'biological_process', 'GO:0007586', ('109', '118'))	('0.305 +- 0.102', 'Var', (125, 139))
22476	28160561	Finally, the relative unmethylation of LINE-1 sequences in ccRCC tissue and adjacent normal tissue, as detected by TSP509 I digestion, were 0.665 +- 0.123 and 0.513 +- 0.159, respectively (Figure 3E and 3F).	('digestion', 'biological_process', 'GO:0007586', ('124', '133'))	('unmethylation', 'MPA', (22, 35))	('0.513 +- 0.159', 'Var', (159, 173))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('0.665 +- 0.123', 'Var', (140, 154))
22485	28160561	Aberrant hypermethylation of DNA may occur near the promoter regions of tumor suppressor genes and inhibit the transcription and activation of these genes in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (158, 163))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('Aberrant hypermethylation', 'Var', (0, 25))	('tumor suppressor', 'biological_process', 'GO:0051726', ('72', '88'))	('tumor', 'Disease', (72, 77))	('inhibit', 'NegReg', (99, 106))	('activation', 'PosReg', (129, 139))	('transcription', 'MPA', (111, 124))	('hypermethylation', 'Var', (9, 25))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('72', '88'))	('transcription', 'biological_process', 'GO:0006351', ('111', '124'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('DNA', 'Gene', (29, 32))
22487	28160561	A report displayed the evidence of epigenetic silenced at least 5% of 289 genes in ccRCC using DNA methylation arrays.	('DNA methylation', 'biological_process', 'GO:0006306', ('95', '110'))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', (85, 88))	('epigenetic silenced', 'Var', (35, 54))
22488	28160561	Higher levels of LINE-1 methylation in blood DNA have also been associated with increased risk of developing RCC in populations.	('associated', 'Reg', (64, 74))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('methylation', 'Var', (24, 35))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('LINE-1', 'Gene', (17, 23))
22495	28160561	However, it should be noted that it is DNMT3B, but not DNMT1 or DNMT3A, that has been implicated in aberrant DNA methylation in tumorigenesis for several types of cancer.	('DNMT1', 'Gene', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('DNMT3B', 'Gene', '1789', (39, 45))	('DNMT3A', 'Gene', (64, 70))	('aberrant', 'Var', (100, 108))	('DNMT1', 'Gene', '1786', (55, 60))	('DNMT3A', 'Gene', '1788', (64, 70))	('DNMT3B', 'Gene', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('DNA methylation', 'biological_process', 'GO:0006306', ('109', '124'))	('tumor', 'Disease', (128, 133))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('implicated', 'Reg', (86, 96))
22497	28160561	Indeed, this is also consistent with our results demonstrating that ccRCC tissue exhibited significantly greater mRNA and protein levels of DMNT3B4, but not DNMT1, or DNMT3A, than normal tissue.	('DMNT3B4', 'Var', (140, 147))	('DNMT3A', 'Gene', '1788', (167, 173))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('DNMT3A', 'Gene', (167, 173))	('DNMT1', 'Gene', (157, 162))	('DNMT1', 'Gene', '1786', (157, 162))	('greater', 'PosReg', (105, 112))
22504	28160561	DNMT3B splice variants can be divided into two groups that are defined by whether or not these variants exhibit DNA methyltransferase activity.	('DNA methyltransferase', 'Gene', (112, 133))	('DNMT3B', 'Gene', '1789', (0, 6))	('DNA methyltransferase', 'Gene', '1786', (112, 133))	('DNA methyltransferase activity', 'molecular_function', 'GO:0009008', ('112', '142'))	('variants', 'Var', (95, 103))	('DNMT3B', 'Gene', (0, 6))	('activity', 'MPA', (134, 142))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))
22509	28160561	In RCC, hypermethylation of the promoter region of the tumor suppressor gene Ras association domain family 1A (RASSF1A) results in inactivation of this gene.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('hypermethylation', 'Var', (8, 24))	('Ras association domain family 1A', 'Gene', '11186', (77, 109))	('tumor suppressor', 'biological_process', 'GO:0051726', ('55', '71'))	('tumor', 'Disease', (55, 60))	('inactivation', 'NegReg', (131, 143))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('55', '71'))	('RASSF1A', 'Gene', (111, 118))	('RCC', 'Disease', (3, 6))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('RCC', 'Disease', 'MESH:C538614', (3, 6))	('RASSF1A', 'Gene', '11186', (111, 118))	('Ras association domain family 1A', 'Gene', (77, 109))
22617	32820162	A pan-cancer analysis of PBAF complex mutations and their association with immunotherapy response There is conflicting data regarding the role of PBAF complex mutations and response to immune checkpoint blockade (ICB) therapy in clear cell renal cell carcinoma (ccRCC) and other solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('PBAF complex', 'Gene', (25, 37))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('PBAF complex', 'cellular_component', 'GO:0016586', ('25', '37'))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (229, 260))	('ccRCC', 'Phenotype', 'HP:0006770', (262, 267))	('mutations', 'Var', (38, 47))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (240, 260))	('PBAF complex', 'cellular_component', 'GO:0016586', ('146', '158'))	('solid tumors', 'Disease', (279, 291))	('clear cell renal cell carcinoma', 'Disease', (229, 260))	('ICB', 'Chemical', '-', (213, 216))	('cancer', 'Disease', (6, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (229, 260))	('solid tumors', 'Disease', 'MESH:D009369', (279, 291))	('PBAF', 'Gene', (146, 150))
22618	32820162	We assess the prevalence of PBAF complex mutations from two large cohorts including the pan-cancer TCGA project (n = 10,359) and the MSK-IMPACT pan-cancer immunotherapy cohort (n = 3700).	('cancer', 'Disease', (148, 154))	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('PBAF complex', 'Gene', (28, 40))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('PBAF complex', 'cellular_component', 'GO:0016586', ('28', '40'))
22619	32820162	In multivariate models of ccRCC patients treated with ICB (n = 189), loss-of-function (LOF) mutations in PBRM1 are not associated with overall survival (OS) (HR = 1.24, p = 0.47) or time to treatment failure (HR = 0.85, p = 0.44).	('PBRM1', 'Gene', (105, 110))	('patients', 'Species', '9606', (32, 40))	('ccRCC', 'Phenotype', 'HP:0006770', (26, 31))	('ccRCC', 'Disease', (26, 31))	('ICB', 'Chemical', '-', (54, 57))	('mutations', 'Var', (92, 101))	('loss-of-function', 'NegReg', (69, 85))	('overall', 'MPA', (135, 142))
22620	32820162	In a series of 11 solid tumors (n = 2936), LOF mutations are not associated with improved OS in a stratified multivariate model (HR = 0.9, p = 0.7).	('solid tumors', 'Disease', 'MESH:D009369', (18, 30))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('mutations', 'Var', (47, 56))	('LOF', 'NegReg', (43, 46))	('solid tumors', 'Disease', (18, 30))
22621	32820162	In a current series of solid tumors treated with ICB, we are unable to demonstrate favorable response to ICB in patients with PBAF complex mutations.	('ICB', 'Chemical', '-', (49, 52))	('mutations', 'Var', (139, 148))	('solid tumors', 'Disease', 'MESH:D009369', (23, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('patients', 'Species', '9606', (112, 120))	('ICB', 'Chemical', '-', (105, 108))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('PBAF', 'Gene', (126, 130))	('PBAF complex', 'cellular_component', 'GO:0016586', ('126', '138'))	('solid tumors', 'Disease', (23, 35))
22623	32820162	Here the authors show that PBAF complex mutations are not associated with favourable response in pan-cancer cohorts of patients treated with immune-checkpoint blockade.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('patients', 'Species', '9606', (119, 127))	('mutations', 'Var', (40, 49))	('PBAF complex', 'cellular_component', 'GO:0016586', ('27', '39'))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('PBAF complex', 'Gene', (27, 39))
22625	32820162	We and others have reported on the association of ICB response with tumor mutation burden (TMB), neoantigen load and clonality, copy number alterations (CNA), microsatellite instability, and human leukocyte antigen zygosity across a variety of cancer types.	('tumor', 'Disease', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('ICB', 'Chemical', '-', (50, 53))	('ICB', 'Gene', (50, 53))	('microsatellite instability', 'MPA', (159, 185))	('association', 'Interaction', (35, 46))	('copy number alterations', 'Var', (128, 151))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('human', 'Species', '9606', (191, 196))	('TMB', 'Chemical', '-', (91, 94))	('neoantigen load', 'MPA', (97, 112))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
22629	32820162	Recent work from several groups pointed to the association of ICB response and mutations in the SWI/SNF chromatin remodeling complex, more specifically the polybromo and BRG-1 associated factors (PBAF) complex which includes the genes ARID2, PBRM1, and BRD7 (refs.	('SWI/SNF', 'Gene', (96, 103))	('ARID2', 'Gene', '196528', (235, 240))	('association', 'Interaction', (47, 58))	('mutations', 'Var', (79, 88))	('BRD7', 'Gene', (253, 257))	('BRD7', 'Gene', '29117', (253, 257))	('PBAF) complex', 'cellular_component', 'GO:0016586', ('196', '209'))	('ARID2', 'Gene', (235, 240))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('104', '124'))	('ICB', 'Chemical', '-', (62, 65))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('104', '132'))	('PBRM1', 'Gene', (242, 247))
22630	32820162	Inactivation of the gene encoded by the PBAF complex was recently found to sensitize melanoma cells to T cell-specific killing.	('PBAF complex', 'cellular_component', 'GO:0016586', ('40', '52'))	('T cell-specific killing', 'CPA', (103, 126))	('PBAF', 'Gene', (40, 44))	('sensitize', 'Reg', (75, 84))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('Inactivation', 'Var', (0, 12))
22631	32820162	demonstrated that in a series of nearly 100 metastatic clear cell renal cell carcinoma (ccRCC) patients, those harboring loss-of-function (LOF) mutations in PBRM1 had clinical benefit from ICB.	('clear cell renal cell carcinoma', 'Disease', (55, 86))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (66, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('patients', 'Species', '9606', (95, 103))	('PBRM1', 'Gene', (157, 162))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (55, 86))	('benefit', 'PosReg', (176, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('loss-of-function', 'NegReg', (121, 137))	('mutations', 'Var', (144, 153))	('ICB', 'Chemical', '-', (189, 192))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (55, 86))
22633	32820162	Similarly, a recent report validated the association between PBRM1 alterations and ICB response in CheckMate 025, a randomized phase 3 trial of nivolumab versus everolimus which demonstrated a survival benefit for nivolumab in the second- and third-line setting.	('ICB', 'Chemical', '-', (83, 86))	('PBRM1', 'Gene', (61, 66))	('nivolumab', 'Chemical', 'MESH:D000077594', (214, 223))	('alterations', 'Var', (67, 78))	('nivolumab', 'Chemical', 'MESH:D000077594', (144, 153))	('everolimus', 'Chemical', 'MESH:D000068338', (161, 171))
22635	32820162	However, in a recent randomized phase II study of metastatic ccRCC, no association was seen between presence of PBRM1 mutations and treatment response to the PD-L1-directed atezolizumab, nor to the combination of atezolizumab plus bevacizumab (n = 136); there was a favorable effect on treatment response in patients receiving sunitinib (anti-VEGF) on the control arm of the same study (n = 72).	('PBRM1', 'Gene', (112, 117))	('PD-L1', 'Gene', '29126', (158, 163))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('atezolizumab', 'Chemical', 'MESH:C000594389', (213, 225))	('sunitinib', 'Chemical', 'MESH:D000077210', (327, 336))	('patients', 'Species', '9606', (308, 316))	('mutations', 'Var', (118, 127))	('VEGF', 'Gene', (343, 347))	('atezolizumab plus bevacizumab', 'Disease', 'MESH:D007625', (213, 242))	('PD-L1', 'Gene', (158, 163))	('atezolizumab plus bevacizumab', 'Disease', (213, 242))	('VEGF', 'Gene', '7422', (343, 347))	('atezolizumab', 'Chemical', 'MESH:C000594389', (173, 185))
22637	32820162	We utilize two large pan-cancer cohorts to determine the frequency of PBAF mutations, and we explore the prognostic significance of PBAF mutations across various solid-tumor malignancies in our Memorial Sloan Kettering Cancer Center (MSKCC) ICB cohort.	('PBAF', 'Gene', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('Cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('mutations', 'Var', (137, 146))	('tumor malignancies', 'Disease', 'MESH:D009369', (168, 186))	('PBAF', 'Gene', (132, 136))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('mutations', 'Var', (75, 84))	('cancer', 'Disease', (25, 31))	('ICB', 'Chemical', '-', (241, 244))	('Memorial Sloan Kettering Cancer', 'Disease', 'MESH:D009369', (194, 225))	('Memorial Sloan Kettering Cancer', 'Disease', (194, 225))	('tumor malignancies', 'Disease', (168, 186))
22638	32820162	Finally, we assess the impact of PBRM1 LOF mutations on TME expression programs using a cohort of 594 ccRCC patients with transcriptomic data.	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('ccRCC', 'Disease', (102, 107))	('LOF', 'NegReg', (39, 42))	('mutations', 'Var', (43, 52))	('patients', 'Species', '9606', (108, 116))	('PBRM1', 'Gene', (33, 38))
22639	32820162	We are ultimately unable to demonstrate a favorable response to ICB in patients with PBAF complex mutations and further, gene-expression analysis of PBRM1 mutated metastatic ccRCC patients demonstrate consistent upregulation in hypoxia inducible factor (HIF) signaling and angiogenesis, but inconsistent interferon gamma signaling and other immune response pathways.	('signaling', 'biological_process', 'GO:0023052', ('259', '268'))	('patients', 'Species', '9606', (71, 79))	('angiogenesis', 'CPA', (273, 285))	('angiogenesis', 'biological_process', 'GO:0001525', ('273', '285'))	('metastatic ccRCC', 'Disease', (163, 179))	('interferon gamma', 'Gene', (304, 320))	('patients', 'Species', '9606', (180, 188))	('mutated', 'Var', (155, 162))	('upregulation', 'PosReg', (212, 224))	('hypoxia', 'Disease', (228, 235))	('interferon gamma', 'Gene', '3458', (304, 320))	('ccRCC', 'Phenotype', 'HP:0006770', (174, 179))	('ICB', 'Chemical', '-', (64, 67))	('PBRM1', 'Gene', (149, 154))	('immune response', 'biological_process', 'GO:0006955', ('341', '356'))	('hypoxia', 'Disease', 'MESH:D000860', (228, 235))	('interferon gamma', 'molecular_function', 'GO:0005133', ('304', '320'))	('gene-expression', 'biological_process', 'GO:0010467', ('121', '136'))	('signaling', 'biological_process', 'GO:0023052', ('321', '330'))	('PBAF complex', 'cellular_component', 'GO:0016586', ('85', '97'))	('mutations', 'Var', (98, 107))
22641	32820162	Overall, 7.7% of all tumors possessed any PBAF complex mutation; incidence among malignancies included in the pan-cancer TCGA cohort was highest in ccRCC (KIRC) particularly for PBRM1 mutations, followed by melanoma (SKCM), cholangiocarcinoma (CHOL), stomach (STAD), uterine (UCEC), and bladder (BLCA) cancers (Fig.	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('melanoma', 'Disease', (207, 215))	('mutations', 'Var', (184, 193))	('PBRM1', 'Gene', (178, 183))	('bladder (BLCA) cancers', 'Disease', 'MESH:D001749', (287, 309))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancers', 'Phenotype', 'HP:0002664', (302, 309))	('cancer', 'Disease', (302, 308))	('malignancies', 'Disease', 'MESH:D009369', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('highest', 'Reg', (137, 144))	('CHOL', 'Disease', 'None', (244, 248))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('malignancies', 'Disease', (81, 93))	('uterine', 'Disease', (267, 274))	('PBAF complex', 'cellular_component', 'GO:0016586', ('42', '54'))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (224, 242))	('ccRCC', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('melanoma', 'Disease', 'MESH:D008545', (207, 215))	('tumors', 'Disease', (21, 27))	('cholangiocarcinoma', 'Disease', (224, 242))	('CHOL', 'Disease', (244, 248))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (224, 242))	('ccRCC', 'Phenotype', 'HP:0006770', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('CHOL', 'Phenotype', 'HP:0030153', (244, 248))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('stomach', 'Disease', (251, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('cancer', 'Disease', (114, 120))
22642	32820162	Additionally, highly mutated tumors were more likely to possess PBAF complex mutations (Fig.	('PBAF complex', 'cellular_component', 'GO:0016586', ('64', '76'))	('tumors', 'Disease', (29, 35))	('PBAF complex', 'Gene', (64, 76))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('highly mutated', 'Var', (14, 28))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))
22643	32820162	Mutations in PBRM1, ARID2, and BRD7 each represented about 3.8% (52.7% LOF), 3.6% (39% LOF), and 1.1% (34.4% LOF), respectively (Supplementary Fig.	('BRD7', 'Gene', (31, 35))	('BRD7', 'Gene', '29117', (31, 35))	('PBRM1', 'Gene', (13, 18))	('ARID2', 'Gene', '196528', (20, 25))	('Mutations', 'Var', (0, 9))	('ARID2', 'Gene', (20, 25))
22644	32820162	We first assessed the incidence of PBRM1 and ARID2 mutations (BRD7 not included in IMPACT) among all patients treated with ICB (n = 3700).	('BRD7', 'Gene', '29117', (62, 66))	('patients', 'Species', '9606', (101, 109))	('mutations', 'Var', (51, 60))	('ARID2', 'Gene', (45, 50))	('ICB', 'Chemical', '-', (123, 126))	('PBRM1', 'Gene', (35, 40))	('BRD7', 'Gene', (62, 66))	('ARID2', 'Gene', '196528', (45, 50))
22645	32820162	For the MSK-IMPACT cohort, we restricted our analysis to 189 ccRCC patients and 2936 patients treated with immunotherapy comprising 11 other cancer types that had a minimum of 50 patients and 5 PBRM1 or ARID2 mutants.	('ARID2', 'Gene', (203, 208))	('patients', 'Species', '9606', (67, 75))	('ccRCC', 'Disease', (61, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('PBRM1', 'Gene', (194, 199))	('patients', 'Species', '9606', (85, 93))	('patients', 'Species', '9606', (179, 187))	('mutants', 'Var', (209, 216))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('ARID2', 'Gene', '196528', (203, 208))	('cancer', 'Disease', (141, 147))
22647	32820162	Available PBAF complex mutations included PBRM1 and ARID2, present at 7.4% and 6.5%, respectively, across the pan-cancer cohort; LOF frequencies are 3.9% and 2.3%, respectively.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('PBAF complex', 'cellular_component', 'GO:0016586', ('10', '22'))	('ARID2', 'Gene', (52, 57))	('PBRM1', 'Gene', (42, 47))	('mutations', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('ARID2', 'Gene', '196528', (52, 57))	('PBAF complex', 'Gene', (10, 22))	('cancer', 'Disease', (114, 120))
22648	32820162	Consistent with the TCGA analysis, PBRM1 mutations were most common in ccRCC patients (46.6%), followed by non-melanoma skin cancer (9%) and melanoma (8%), while ARID2 was most common in melanoma (13%), followed by non-melanoma skin cancer and colorectal cancer (11%) (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('colorectal cancer', 'Phenotype', 'HP:0003003', (244, 261))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('ARID2', 'Gene', (162, 167))	('common', 'Reg', (61, 67))	('PBRM1', 'Gene', (35, 40))	('melanoma', 'Disease', 'MESH:D008545', (219, 227))	('mutations', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('ccRCC', 'Disease', (71, 76))	('melanoma', 'Disease', (111, 119))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (107, 131))	('patients', 'Species', '9606', (77, 85))	('colorectal cancer', 'Disease', 'MESH:D015179', (244, 261))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('common', 'Reg', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colorectal cancer', 'Disease', (244, 261))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (215, 239))	('non-melanoma skin cancer', 'Disease', (107, 131))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('melanoma', 'Disease', (219, 227))	('ARID2', 'Gene', '196528', (162, 167))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('skin cancer', 'Phenotype', 'HP:0008069', (120, 131))	('skin cancer', 'Phenotype', 'HP:0008069', (228, 239))	('non-melanoma skin cancer', 'Disease', (215, 239))
22649	32820162	With the exception of ccRCC, several of the tumors harboring PBAF complex mutations were highly mutated cancer types (Fig.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('ccRCC', 'Disease', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mutations', 'Var', (74, 83))	('PBAF complex', 'Gene', (61, 73))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('PBAF complex', 'cellular_component', 'GO:0016586', ('61', '73'))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (22, 27))
22650	32820162	with respect to PBRM1 LOF mutations and response to ICB in RCC, we analyzed our cohort of ICB-treated metastatic ccRCC patients (n = 189) with more detailed clinical annotations including International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic score (n = 180; Table 2), treatment details and outcomes with therapy, including time-to-treatment failure (TTF).	('ICB', 'Chemical', '-', (90, 93))	('ICB', 'Chemical', '-', (52, 55))	('Metastatic Renal Cell Carcinoma', 'Disease', (202, 233))	('Metastatic Renal Cell Carcinoma', 'Disease', 'MESH:C538445', (202, 233))	('LOF', 'NegReg', (22, 25))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (213, 233))	('patients', 'Species', '9606', (119, 127))	('ccRCC', 'Phenotype', 'HP:0006770', (113, 118))	('Carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('mutations', 'Var', (26, 35))	('PBRM1', 'Gene', (16, 21))
22651	32820162	PBRM1 LOF mutations were present in 61 of these 189 patients (32%), and non-LOF mutations were found in 27 patients (14%).	('PBRM1', 'Gene', (0, 5))	('mutations', 'Var', (10, 19))	('LOF', 'NegReg', (6, 9))	('patients', 'Species', '9606', (107, 115))	('patients', 'Species', '9606', (52, 60))
22652	32820162	Since ARID2 mutations were only present in six patients (4 of them LOF) and might have a distinct effect on outcome, we further analyzed only PBRM1 mutations.	('mutations', 'Var', (12, 21))	('ARID2', 'Gene', (6, 11))	('patients', 'Species', '9606', (47, 55))	('ARID2', 'Gene', '196528', (6, 11))	('PBRM1', 'Gene', (142, 147))	('effect', 'Reg', (98, 104))
22654	32820162	PBRM1 mutation rate was not significantly different in patients who received first line (n = 97, 30% LOF mutations) or second or higher line (n = 92, 35%) ICB or ICB/VEGF combinations.	('ICB', 'Chemical', '-', (155, 158))	('ICB', 'Chemical', '-', (162, 165))	('VEGF', 'Gene', (166, 170))	('LOF', 'NegReg', (101, 104))	('PBRM1', 'Gene', (0, 5))	('mutations', 'Var', (105, 114))	('VEGF', 'Gene', '7422', (166, 170))	('patients', 'Species', '9606', (55, 63))
22655	32820162	When comparing outcomes with first-line ICB therapy in patients with PBRM1 LOF mutations vs. wild type, no significant differences were seen for TTF (HR = 0.6, p = 0.075) or OS (HR = 1.7, p = 0.29); similarly, no differences were seen for those receiving ICB in the second line or higher (TTF HR = 0.87, p = 0.61; OS HR = 1.71.3, p = 0.44) (Fig.	('LOF', 'NegReg', (75, 78))	('ICB', 'Chemical', '-', (40, 43))	('PBRM1', 'Gene', (69, 74))	('patients', 'Species', '9606', (55, 63))	('ICB', 'Chemical', '-', (255, 258))	('mutations', 'Var', (79, 88))
22657	32820162	To assess the impact of PBAF complex mutations in non-RCC cohorts treated with ICB profiled with MSK-IMPACT, we restricted our analysis to 11 tumor types with at least 50 patients and at least 5 patients with PBRM1 or ARID2 mutations (n = 2936).	('ICB', 'Chemical', '-', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('ARID2', 'Gene', '196528', (218, 223))	('PBRM1', 'Gene', (209, 214))	('ARID2', 'Gene', (218, 223))	('patients', 'Species', '9606', (171, 179))	('patients', 'Species', '9606', (195, 203))	('PBAF complex', 'cellular_component', 'GO:0016586', ('24', '36'))	('mutations', 'Var', (224, 233))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
22660	32820162	PBRM1 mutations were not significantly associated with OS in a cohort of 11 cancer types in a Cox model stratified by cancer type (LOF HR = 0.9, 95% CI 0.6,1.4, p = 0.7; non-LOF HR 1.03, 95% CI 0.73,1.5, p = 0.86), and remained insignificant after adjusting for TMB and total CNA (LOF HR = 1.2, 95% CI 0.8,1.81, p = 0.37; non-LOF HR = 1.32, 95% CI 0.92,1.9, p = 0.13) (Supplementary Table 1).	('cancer', 'Disease', (118, 124))	('TMB', 'Chemical', '-', (262, 265))	('PBRM1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('associated', 'Reg', (39, 49))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mutations', 'Var', (6, 15))
22662	32820162	Given the higher frequency of ARID2 mutations in the non-RCC cohorts, we combined PBRM1 and ARID2 LOF and non-LOF mutations for individual subtype analysis, which was significant in non-small-cell lung cancers (Fig.	('PBRM1', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('lung cancers', 'Phenotype', 'HP:0100526', (197, 209))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (182, 208))	('mutations', 'Var', (114, 123))	('ARID2', 'Gene', '196528', (92, 97))	('non-small-cell lung cancer', 'Disease', (182, 208))	('LOF', 'NegReg', (98, 101))	('mutations', 'Var', (36, 45))	('ARID2', 'Gene', '196528', (30, 35))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('lung cancers', 'Disease', (197, 209))	('ARID2', 'Gene', (92, 97))	('ARID2', 'Gene', (30, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (197, 208))	('lung cancers', 'Disease', 'MESH:D008175', (197, 209))
22663	32820162	When univariately examining LOF mutations in PBRM1 and ARID2 as well as LOF in PBRM1 alone, they remained significantly associated with adverse OS in non-small-cell lung cancer (Fig.	('non-small-cell lung cancer', 'Disease', (150, 176))	('ARID2', 'Gene', '196528', (55, 60))	('associated', 'Reg', (120, 130))	('ARID2', 'Gene', (55, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('mutations', 'Var', (32, 41))	('PBRM1', 'Gene', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('LOF', 'NegReg', (28, 31))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (150, 176))
22665	32820162	A significant correlation with adverse OS was also seen in bladder cancer (n = 245; HR 11.85, p < 0.001); however, only three PBRM1 mutants comprised this group.	('PBRM1', 'Gene', (126, 131))	('mutants', 'Var', (132, 139))	('bladder cancer', 'Phenotype', 'HP:0009725', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('bladder cancer', 'Disease', 'MESH:D001749', (59, 73))	('bladder cancer', 'Disease', (59, 73))
22667	32820162	This was further bolstered by the association with improved response of PBRM1 mutated tumors to VEGF blockade therapies.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('improved', 'PosReg', (51, 59))	('response', 'MPA', (60, 68))	('VEGF', 'Gene', '7422', (96, 100))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('PBRM1', 'Gene', (72, 77))	('mutated', 'Var', (78, 85))	('VEGF', 'Gene', (96, 100))
22669	32820162	All three cohorts demonstrated higher hypoxia pathway enrichment in PBRM1 mutated samples with GSEA p value as 0.002, 0.008, and 0.002, respectively.	('PBRM1', 'Gene', (68, 73))	('hypoxia', 'Disease', 'MESH:D000860', (38, 45))	('mutated', 'Var', (74, 81))	('GSEA', 'Chemical', '-', (95, 99))	('hypoxia', 'Disease', (38, 45))	('higher', 'PosReg', (31, 37))
22672	32820162	We consistently observed significantly higher angiogenic gene expression in PBRM1 mutated tumors in the COMPARZ and McDermott et al.	('higher', 'PosReg', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('mutated', 'Var', (82, 89))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('gene expression', 'biological_process', 'GO:0010467', ('57', '72'))	('PBRM1', 'Gene', (76, 81))	('angiogenic gene expression', 'MPA', (46, 72))
22673	32820162	Further, immunohistochemical (IHC) staining from the COMPARZ and McDermott cohort demonstrates significantly higher CD31-positive staining in PBRM1 mutated tumors, implying higher degrees of tumor angiogenesis in PBRM1 mutated tumors (Fig.	('tumor', 'Disease', (227, 232))	('angiogenesis', 'biological_process', 'GO:0001525', ('197', '209'))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('higher', 'PosReg', (173, 179))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('mutated', 'Var', (148, 155))	('higher', 'PosReg', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('PBRM1', 'Gene', (142, 147))	('CD31', 'Gene', '5175', (116, 120))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumors', 'Disease', (227, 233))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (191, 196))	('tumors', 'Disease', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('staining', 'MPA', (130, 138))	('CD31', 'Gene', (116, 120))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
22674	32820162	IHC studies from the two cohorts also reveal higher PD-L1-negative and lower PD-L1-positive staining tumors in PBRM1 mutated tumors compared to wild type (Fig.	('mutated', 'Var', (117, 124))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('PD-L1', 'Gene', '29126', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Disease', (125, 131))	('PD-L1', 'Gene', (77, 82))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('PD-L1', 'Gene', '29126', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('PBRM1', 'Gene', (111, 116))	('higher', 'PosReg', (45, 51))	('PD-L1', 'Gene', (52, 57))	('tumors', 'Disease', (101, 107))	('lower', 'NegReg', (71, 76))
22675	32820162	7b) and no difference in CD8 positivity between PBRM1 mutant and wild-type tumors (Supplementary Fig.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('CD8', 'Gene', (25, 28))	('PBRM1', 'Gene', (48, 53))	('CD8', 'Gene', '925', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mutant', 'Var', (54, 60))	('tumors', 'Disease', (75, 81))
22677	32820162	While several studies seem to validate tumor mutation and neoangtigen burden, along with mismatch repair mutations, numerous other studies have relied on single gene mutations with relatively small cohorts and often not correcting for potential confounding factors such as TMB or microsatellite instability/mismatch repair status.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('mismatch repair', 'biological_process', 'GO:0006298', ('307', '322'))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('mutations', 'Var', (105, 114))	('tumor', 'Disease', (39, 44))	('TMB', 'Chemical', '-', (273, 276))	('mismatch repair', 'biological_process', 'GO:0006298', ('89', '104'))
22679	32820162	Specifically, we found PBAF complex mutations to be most common in ccRCC tumors which were dominated by PBRM1 mutations; interrogation of this cohort of ICB-treated ccRCC patients failed to reveal an association between PBRM1/ARID2 mutations and overall survival or time-to-treat failure.	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('ccRCC tumors', 'Disease', (67, 79))	('ICB', 'Chemical', '-', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('overall survival', 'CPA', (246, 262))	('patients', 'Species', '9606', (171, 179))	('ARID2', 'Gene', '196528', (226, 231))	('mutations', 'Var', (232, 241))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (165, 170))	('PBAF complex', 'cellular_component', 'GO:0016586', ('23', '35'))	('ARID2', 'Gene', (226, 231))	('ccRCC tumors', 'Disease', 'MESH:D009369', (67, 79))
22680	32820162	and our recently analyzed COMPARZ cohort showed unchanged or lower IFNgamma signaling in the PBRM1 mutants.	('lower', 'NegReg', (61, 66))	('signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('IFNgamma', 'Gene', '3458', (67, 75))	('IFNgamma', 'Gene', (67, 75))	('PBRM1', 'Gene', (93, 98))	('mutants', 'Var', (99, 106))
22681	32820162	3p loss (which encompasses four commonly mutated genes: VHL, PBRM1, SETD2, BAP1) is a ubiquitous, pathognomonic event in ccRCC, occurring in upwards of 90% of tumors.	('VHL', 'Gene', (56, 59))	('PBRM1', 'Gene', (61, 66))	('BAP1', 'Gene', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('SETD2', 'Gene', '29072', (68, 73))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('SETD2', 'Gene', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('ccRCC', 'Phenotype', 'HP:0006770', (121, 126))	('BAP1', 'Gene', '8314', (75, 79))	('ccRCC', 'Disease', (121, 126))	('3p loss', 'Var', (0, 7))
22682	32820162	Preclinical data support the notion that VHL (the most commonly mutated gene in clear cell RCC) and PBRM1 co-occur; although VHL is the initial driver event in the pathogenesis of clear cell RCC, genetic deletion of VHL in mice is insufficient to initiate kidney tumors.	('deletion', 'Var', (204, 212))	('kidney tumors', 'Phenotype', 'HP:0009726', (256, 269))	('pathogenesis', 'biological_process', 'GO:0009405', ('164', '176'))	('mice', 'Species', '10090', (223, 227))	('kidney tumors', 'Disease', 'MESH:D007680', (256, 269))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('VHL', 'Gene', (216, 219))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('kidney tumors', 'Disease', (256, 269))
22683	32820162	After loss of VHL, loss of additional 3p21 tumor suppressor genes (PBRM1) further activates HIF1/STAT3 signaling in mouse kidney and positions mTORC1 activation as the third preferred driver event.	('loss', 'NegReg', (6, 10))	('mTORC1', 'cellular_component', 'GO:0031931', ('143', '149'))	('mTORC1', 'Gene', '382056', (143, 149))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('activates', 'PosReg', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('signaling', 'biological_process', 'GO:0023052', ('103', '112'))	('loss', 'Var', (19, 23))	('HIF1/STAT3 signaling', 'MPA', (92, 112))	('mTORC1', 'Gene', (143, 149))	('tumor suppressor', 'biological_process', 'GO:0051726', ('43', '59'))	('VHL', 'Gene', (14, 17))	('tumor', 'Disease', (43, 48))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('43', '59'))	('mouse', 'Species', '10090', (116, 121))	('PBRM1', 'Gene', (67, 72))
22685	32820162	Mutation of PBRM1 leads to the integration of an altered BAF180 subunit and thereby alters the normal activity of the PBAF complex.	('PBRM1', 'Gene', (12, 17))	('BAF180', 'Gene', (57, 63))	('leads to', 'Reg', (18, 26))	('Mutation', 'Var', (0, 8))	('BAF180', 'Gene', '55193', (57, 63))	('normal activity', 'MPA', (95, 110))	('alters', 'Reg', (84, 90))	('PBAF complex', 'cellular_component', 'GO:0016586', ('118', '130'))	('integration', 'MPA', (31, 42))
22693	32820162	showed that PBRM1 knockdown enhanced proliferation and migration of kidney cancer cell lines.	('migration of kidney cancer', 'Disease', 'MESH:D007680', (55, 81))	('knockdown', 'Var', (18, 27))	('PBRM1', 'Gene', (12, 17))	('kidney cancer', 'Phenotype', 'HP:0009726', (68, 81))	('migration of kidney cancer', 'Disease', (55, 81))	('enhanced', 'PosReg', (28, 36))	('proliferation', 'CPA', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
22695	32820162	Moreover, the authors showed that cells deficient in PBRM1 secreted larger amounts of chemokines necessary for the recruitment of effector T cells compared to controls following IFNgamma stimulation and that mRNA levels of PBRM1 negatively correlated with expression of granzyme B and Perforin 1, as well as with the granzyme B/CD8A ratio; all this suggests that a lower expression of PBRM1 correlated to higher cytotoxic T cell activity and that PBRM1 status may be relevant for immune activation and infiltration, perhaps due to STAT3 ISGs.	('granzyme B', 'Gene', '3002', (317, 327))	('expression', 'MPA', (371, 381))	('IFNgamma', 'Gene', '3458', (178, 186))	('cytotoxic T', 'Disease', 'MESH:D064420', (412, 423))	('deficient', 'Var', (40, 49))	('Perforin 1', 'Gene', '5551', (285, 295))	('higher', 'PosReg', (405, 411))	('Perforin 1', 'Gene', (285, 295))	('granzyme B', 'Gene', '3002', (270, 280))	('IFNgamma', 'Gene', (178, 186))	('granzyme B', 'Gene', (317, 327))	('PBRM1', 'Gene', (385, 390))	('cytotoxic T', 'Disease', (412, 423))	('lower', 'NegReg', (365, 370))	('CD8A', 'Gene', '925', (328, 332))	('granzyme B', 'Gene', (270, 280))	('CD8A', 'Gene', (328, 332))	('PBRM1', 'Gene', (53, 58))
22698	32820162	Given the tight counterbalance between the PBAF complex and ISGs it is highly conceivable that additional alteration can shift the balance away from ISG signaling and can explain the lack of efficacy to ICB seen in an array of PBAF complex mutated cancers.	('PBAF', 'Gene', (227, 231))	('cancers', 'Disease', (248, 255))	('balance', 'MPA', (131, 138))	('cancers', 'Disease', 'MESH:D009369', (248, 255))	('signaling', 'biological_process', 'GO:0023052', ('153', '162'))	('mutated', 'Var', (240, 247))	('PBAF complex', 'cellular_component', 'GO:0016586', ('43', '55'))	('PBAF complex', 'cellular_component', 'GO:0016586', ('227', '239'))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('shift', 'Reg', (121, 126))	('tight counterbalance', 'Phenotype', 'HP:0002172', (10, 30))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('ICB', 'Chemical', '-', (203, 206))	('ISG signaling', 'MPA', (149, 162))
22706	32820162	However, when PBRM1 is also lost through mutation, the intrinsic HIF1alpha-STAT3 propagation goes unchecked.	('PBRM1', 'Gene', (14, 19))	('lost', 'NegReg', (28, 32))	('HIF1alpha', 'Gene', (65, 74))	('mutation', 'Var', (41, 49))	('HIF1alpha', 'Gene', '3091', (65, 74))
22708	32820162	Consistently, we found higher angiogenic expression in PBRM1 mutated tumors.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('higher', 'PosReg', (23, 29))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('angiogenic expression', 'MPA', (30, 51))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('mutated', 'Var', (61, 68))	('PBRM1', 'Gene', (55, 60))
22709	32820162	Clinically, this is supported by the fact that PBRM1 mutated tumors respond better to antiangiogenic therapy.	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumors', 'Disease', (61, 67))	('PBRM1', 'Gene', (47, 52))	('mutated', 'Var', (53, 60))	('better', 'PosReg', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
22710	32820162	demonstrated in 105 patients with metastatic ccRCC who had received systemic therapy, TTF with VEGF-targeted therapy differed significantly by PBRM1 mutation status, where PBRM1 mutants associated with more favorable TTF (p = 0.01, median 12.0 months for PBRM1 mutants versus 6.9 months for wild-type tumors).	('mutants', 'Var', (261, 268))	('VEGF', 'Gene', '7422', (95, 99))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))	('tumors', 'Disease', 'MESH:D009369', (301, 307))	('TTF', 'MPA', (217, 220))	('mutants', 'Var', (178, 185))	('PBRM1', 'Gene', (143, 148))	('more', 'PosReg', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('PBRM1', 'Gene', (172, 177))	('patients', 'Species', '9606', (20, 28))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('PBRM1', 'Gene', (255, 260))	('VEGF', 'Gene', (95, 99))	('tumors', 'Disease', (301, 307))
22711	32820162	Finally, we have shown in the COMPARZ cohort that PBRM1 mutations are associated with both higher angiogenesis expression and response to anti-VEGF therapy.	('mutations', 'Var', (56, 65))	('PBRM1', 'Gene', (50, 55))	('VEGF', 'Gene', '7422', (143, 147))	('higher', 'PosReg', (91, 97))	('angiogenesis', 'CPA', (98, 110))	('angiogenesis', 'biological_process', 'GO:0001525', ('98', '110'))	('VEGF', 'Gene', (143, 147))
22713	32820162	cohort, wherein sunitinib efficacy was enriched in highly angiogenic tumors and coincided with PBRM1 mutant tumors, demonstrating improved progression free survival and objective response rates in tumors with high angiogenic gene signature.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('PBRM1', 'Gene', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('mutant', 'Var', (101, 107))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('progression free survival', 'CPA', (139, 164))	('tumors', 'Disease', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('sunitinib', 'Chemical', 'MESH:D000077210', (16, 25))	('improved', 'PosReg', (130, 138))
22714	32820162	recently reported on the association between PBRM1 alterations and ICB response in CheckMate 025, a large randomized phase 3 trial of nivolumab versus everolimus in advanced renal cell carcinoma.	('alterations', 'Var', (51, 62))	('nivolumab', 'Chemical', 'MESH:D000077594', (134, 143))	('ICB', 'Chemical', '-', (67, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('renal cell carcinoma', 'Disease', (174, 194))	('reported', 'Reg', (9, 17))	('PBRM1', 'Gene', (45, 50))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (174, 194))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (174, 194))	('everolimus', 'Chemical', 'MESH:D000068338', (151, 161))
22716	32820162	Intriguingly, this effect was observed in patients who received prior antiangiogenic therapy; previous studies of PBRM1 mutations in the first-line setting had negative results, and PBRM1 alterations have also been associated with benefit from antiangiogenic therapies.	('PBRM1', 'Gene', (182, 187))	('alterations', 'Var', (188, 199))	('mutations', 'Var', (120, 129))	('PBRM1', 'Gene', (114, 119))	('patients', 'Species', '9606', (42, 50))	('benefit', 'PosReg', (231, 238))
22717	32820162	It is noteworthy to mention that among nivolumab-treated patients, a higher proportion of responders (15 of 38) harbored truncating PBRM1 mutations, which was statistically significant but numerically similar to the non-responders (16 of 74).	('nivolumab', 'Chemical', 'MESH:D000077594', (39, 48))	('patients', 'Species', '9606', (57, 65))	('truncating', 'MPA', (121, 131))	('PBRM1', 'Gene', (132, 137))	('mutations', 'Var', (138, 147))
22718	32820162	This lack of effect in the first-line setting may explain the lack of response of the atezolizumab arm in the PBRM1 LOF mutations in the McDermott et al.	('LOF', 'NegReg', (116, 119))	('PBRM1', 'Gene', (110, 115))	('mutations', 'Var', (120, 129))	('atezolizumab', 'Chemical', 'MESH:C000594389', (86, 98))
22721	32820162	TCGA: Pan-cancer TCGA cohort (n = 10,359 from 31 cancer subtypes) data, including ARID2, BRD7, and PBRM1 mutations, mutation count as well as FGA (which is an estimate proportion of the tumor genome affected by copy number gains and losses), were queried and downloaded from MSKCC cBioPortal (cbioportal.mskcc.org).	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('cancer', 'Disease', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('PBRM1', 'Gene', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ARID2', 'Gene', '196528', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Disease', (186, 191))	('mutations', 'Var', (105, 114))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('ARID2', 'Gene', (82, 87))	('BRD7', 'Gene', (89, 93))	('BRD7', 'Gene', '29117', (89, 93))	('cancer', 'Disease', (10, 16))
22725	32820162	After limiting non-renal cell carcinoma patients to 11 cancer types with at least 50 patients and 5 PBRM1 or ARID2 mutations, the pan-cancer cohort was comprised of 2936 patients.	('patients', 'Species', '9606', (170, 178))	('mutations', 'Var', (115, 124))	('patients', 'Species', '9606', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('renal cell carcinoma', 'Disease', (19, 39))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (19, 39))	('ARID2', 'Gene', '196528', (109, 114))	('PBRM1', 'Gene', (100, 105))	('patients', 'Species', '9606', (85, 93))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (19, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('ARID2', 'Gene', (109, 114))	('cancer', 'Disease', (55, 61))
22749	32066735	Large scale sequencing has pointed to loss of the short arm of chromosome 3 and mutations of the Von Hippel Lindau (VHL) gene as the main drivers of ccRCC.	('short arm', 'Phenotype', 'HP:0009824', (50, 59))	('VHL', 'Disease', 'MESH:D006623', (116, 119))	('mutations', 'Var', (80, 89))	('Von Hippel Lindau', 'Gene', (97, 114))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('VHL', 'Disease', (116, 119))	('Von Hippel Lindau', 'Gene', '7428', (97, 114))	('RCC', 'Disease', 'MESH:D002292', (151, 154))	('RCC', 'Disease', (151, 154))	('ccRCC', 'Phenotype', 'HP:0006770', (149, 154))
22750	32066735	Mutations of PBRM1, SETD2, BAP1 are found at lower rates.	('PBRM1', 'Gene', (13, 18))	('BAP1', 'Gene', (27, 31))	('SETD2', 'Gene', '29072', (20, 25))	('Mutations', 'Var', (0, 9))	('SETD2', 'Gene', (20, 25))	('PBRM1', 'Gene', '55193', (13, 18))	('BAP1', 'Gene', '8314', (27, 31))
22752	32066735	Significant improvements in post-surgical treatment have been made in the last two decades: inhibitors of multiple tyrosine kinases, of mTOR or monoclonal antibodies against VEGF.	('VEGF', 'Gene', '7422', (174, 178))	('inhibitors', 'Var', (92, 102))	('mTOR', 'Gene', '2475', (136, 140))	('mTOR', 'Gene', (136, 140))	('VEGF', 'Gene', (174, 178))
22770	32066735	CD24, CD29, CD133), cancer stem cell markers in other malignancies (CD24, CD29, Epcam, CD44, MET, CD90, ALDH1A1 activity), and in the kidney (CD133, CD24, CD105, CXCR4).	('ALDH1A1', 'Gene', (104, 111))	('CD29', 'Gene', '3688', (6, 10))	('CD10', 'Gene', '4311', (155, 159))	('ALDH', 'molecular_function', 'GO:0004030', ('104', '108'))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('activity', 'MPA', (112, 120))	('CD24', 'Gene', (149, 153))	('CD10', 'Gene', (155, 159))	('CD133', 'Gene', (142, 147))	('CD133', 'Gene', '8842', (142, 147))	('CD24', 'Gene', (68, 72))	('CD24', 'Gene', '100133941', (0, 4))	('ALDH1A1', 'Gene', '216', (104, 111))	('CD44', 'Gene', '960', (87, 91))	('malignancies', 'Disease', 'MESH:D009369', (54, 66))	('CD29', 'Gene', '3688', (74, 78))	('CD29', 'Gene', (6, 10))	('Epcam', 'Gene', '4072', (80, 85))	('CD90', 'Gene', (98, 102))	('CD44', 'Gene', (87, 91))	('malignancies', 'Disease', (54, 66))	('CD90', 'Gene', '7070', (98, 102))	('cancer', 'Disease', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('CD24', 'Gene', '100133941', (149, 153))	('CD29', 'Gene', (74, 78))	('MET', 'Var', (93, 96))	('Epcam', 'Gene', (80, 85))	('CD24', 'Gene', '100133941', (68, 72))	('CXCR4', 'molecular_function', 'GO:0038147', ('162', '167'))	('CD133', 'Gene', (12, 17))	('CD24', 'Gene', (0, 4))	('CD133', 'Gene', '8842', (12, 17))
22830	32066735	A knockdown of CTNNB1 (beta-catenin) and NOTCH1 by siRNA treatment strongly reduced the numbers of spheres in the cultures (Fig.	('CTNNB1', 'Gene', (15, 21))	('knockdown', 'Var', (2, 11))	('CTNNB1', 'Gene', '1499', (15, 21))	('beta-catenin', 'Gene', (23, 35))	('reduced', 'NegReg', (76, 83))	('numbers of spheres in the cultures', 'CPA', (88, 122))	('NOTCH1', 'Gene', (41, 47))	('NOTCH1', 'Gene', '4851', (41, 47))	('beta-catenin', 'Gene', '1499', (23, 35))
22834	32066735	In contrast, MAML, NICD, or NOTCH1 siRNA transfections had no significant effects on WNT signaling (Supplementary Fig.	('NICD', 'Disease', 'None', (19, 23))	('transfections', 'Var', (41, 54))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('NOTCH1', 'Gene', '4851', (28, 34))	('NICD', 'Disease', (19, 23))	('NOTCH1', 'Gene', (28, 34))	('WNT signaling', 'MPA', (85, 98))
22862	32066735	Cultures from a majority of patients responded to ICG-001, while DAPT inhibited cultures from three other patients, both in concentration-dependent manners and within one week (Fig.	('ICG-001', 'Chemical', 'MESH:C492448', (50, 57))	('ICG-001', 'Var', (50, 57))	('DAPT', 'Chemical', '-', (65, 69))	('responded', 'MPA', (37, 46))	('patients', 'Species', '9606', (106, 114))	('inhibited', 'NegReg', (70, 79))	('patients', 'Species', '9606', (28, 36))	('ICG', 'cellular_component', 'GO:0035061', ('50', '53'))
22863	32066735	Sphere cultures with ICG-001 IC50 < 20 microM or DAPT IC50 < 30 microM were considered as responders.	('DAPT', 'Gene', (49, 53))	('ICG-001', 'Gene', (21, 28))	('ICG', 'cellular_component', 'GO:0035061', ('21', '24'))	('ICG-001', 'Chemical', 'MESH:C492448', (21, 28))	('DAPT', 'Chemical', '-', (49, 53))	('IC50', 'Var', (54, 58))	('IC50 < 20', 'Var', (29, 38))
22866	32066735	Combinations had a strong effect on ICG-001/DAPT double responders, but were less effective in non-responders indicating that double responders might also benefit from the combined treatment with both inhibitors (Fig.	('DAPT', 'Chemical', '-', (44, 48))	('ICG', 'cellular_component', 'GO:0035061', ('36', '39'))	('ICG-001', 'Chemical', 'MESH:C492448', (36, 43))	('ICG-001/DAPT', 'Gene', (36, 48))	('Combinations', 'Var', (0, 12))
22877	32066735	ICG-001 also produced no significant toxicity in sphere cultures, but led to a reduction of organoid growth (Supplementary Fig.	('toxicity', 'Disease', (37, 45))	('ICG', 'cellular_component', 'GO:0035061', ('0', '3'))	('ICG-001', 'Var', (0, 7))	('ICG-001', 'Chemical', 'MESH:C492448', (0, 7))	('organoid growth', 'CPA', (92, 107))	('reduction', 'NegReg', (79, 88))	('toxicity', 'Disease', 'MESH:D064420', (37, 45))
22878	32066735	To exclude that the effects of ICG-001 were due to unspecific events, we tested additional WNT inhibitors in specimens that responded to ICG-001: the TANKYRASE inhibitor XAV939, the beta-CATENIN inhibitor LF3, and the Porcupine inhibitor C59.	('tested', 'Reg', (73, 79))	('C59', 'Chemical', '-', (238, 241))	('beta-CATENIN', 'Gene', (182, 194))	('ICG', 'cellular_component', 'GO:0035061', ('31', '34'))	('ICG', 'cellular_component', 'GO:0035061', ('137', '140'))	('ICG-001', 'Chemical', 'MESH:C492448', (137, 144))	('TANKYRASE', 'Gene', '8658', (150, 159))	('TANKYRASE', 'Gene', (150, 159))	('LF3', 'Chemical', '-', (205, 208))	('ICG-001', 'Var', (137, 144))	('beta-CATENIN', 'Gene', '1499', (182, 194))	('ICG-001', 'Chemical', 'MESH:C492448', (31, 38))	('XAV939', 'Chemical', 'MESH:C544261', (170, 176))
22923	32066735	Beyond the WNT and NOTCH responders, we identified smaller subgroups of CSCs that were inhibited by targeting other CSC-relevant molecules: CXCR4 with AMD3100 and MET with Crizotinib.	('NOTCH', 'Gene', '31293', (19, 24))	('Crizotinib', 'Chemical', 'MESH:D000077547', (172, 182))	('CSCs', 'Disease', (72, 76))	('AMD3100', 'Var', (151, 158))	('AMD3100', 'Chemical', 'MESH:C088327', (151, 158))	('CXCR4', 'MPA', (140, 145))	('NOTCH', 'Gene', (19, 24))	('CXCR4', 'molecular_function', 'GO:0038147', ('140', '145'))
22941	32066735	For instance, the loss of VHL stabilizes beta-CATENIN via JADE1.	('JADE1', 'Gene', (58, 63))	('VHL', 'Disease', (26, 29))	('loss', 'Var', (18, 22))	('JADE1', 'Gene', '79960', (58, 63))	('beta-CATENIN', 'Gene', (41, 53))	('beta-CATENIN', 'Gene', '1499', (41, 53))	('VHL', 'Disease', 'MESH:D006623', (26, 29))
22943	32066735	WNT signaling can also be promoted by hyper-activated MET observed in ccRCC.	('WNT signaling', 'MPA', (0, 13))	('RCC', 'Disease', 'MESH:D002292', (72, 75))	('RCC', 'Disease', (72, 75))	('hyper-activated', 'Var', (38, 53))	('promoted', 'PosReg', (26, 34))	('ccRCC', 'Phenotype', 'HP:0006770', (70, 75))	('signaling', 'biological_process', 'GO:0023052', ('4', '13'))
22960	32066735	HumanHT-12 v4 bead chip data were normalized and log-transformed in Partek Genomics Suite (Partek) and analyzed using the limma package in R. We identified a stem cell signature that included all genes that were upregulated in either spheres and CXCR4+MET+CD44+ with FC > 1.5 or <-1.5 and p-value < 0.05.	('FC > 1.5', 'Var', (267, 275))	('CD44', 'Gene', '960', (256, 260))	('CXCR4', 'molecular_function', 'GO:0038147', ('246', '251'))	('CD44', 'Gene', (256, 260))	('upregulated', 'PosReg', (212, 223))
22961	32066735	The gene expression analyses of 28 fresh frozen ccRCC specimens has been performed previously at the Charite-University hospital and only the data were used for this study (GEO Accession Code: GSE66270 and GSE66271, for patient information see Supplementary Table 2).	('GSE66271', 'Var', (206, 214))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('RCC', 'Disease', 'MESH:D002292', (50, 53))	('RCC', 'Disease', (50, 53))	('patient', 'Species', '9606', (220, 227))	('gene expression', 'biological_process', 'GO:0010467', ('4', '19'))
22988	32066735	Sections were incubated overnight at 4  C with Ki-67 (1:200, Thermo Fisher), NOTCH1 (1:200, Rockland Inc.), beta-Catenin (1:500, Cell Signaling Technology), Calbindin (1:3000, Sigma Aldrich) primary antibodies and horseradish peroxidase-conjugated secondary antibody.	('antibody', 'cellular_component', 'GO:0042571', ('258', '266'))	('NOTCH1', 'Gene', '4851', (77, 83))	('NOTCH1', 'Gene', (77, 83))	('Ki-67', 'Gene', '17345', (47, 52))	('antibody', 'cellular_component', 'GO:0019815', ('258', '266'))	('horseradish', 'Species', '3704', (214, 225))	('1:200', 'Var', (85, 90))	('antibody', 'cellular_component', 'GO:0019814', ('258', '266'))	('antibody', 'molecular_function', 'GO:0003823', ('258', '266'))	('Ki-67', 'Gene', (47, 52))	('beta-Catenin', 'Gene', (108, 120))	('beta-Catenin', 'Gene', '1499', (108, 120))	('Signaling', 'biological_process', 'GO:0023052', ('134', '143'))
23012	28928896	We found that high-level eIF3b expression in tumors was not only associated with an aggressive tumor phenotype, but was also independently prognostic for patients with ccRCC.	('prognostic', 'Reg', (139, 149))	('aggressive tumor', 'Disease', (84, 100))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('RCC', 'Disease', (170, 173))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('patients', 'Species', '9606', (154, 162))	('associated with', 'Reg', (65, 80))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('high-level', 'Var', (14, 24))	('ccRCC', 'Phenotype', 'HP:0006770', (168, 173))	('aggressive tumor', 'Disease', 'MESH:D001523', (84, 100))	('eIF3b', 'Gene', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('eIF3', 'cellular_component', 'GO:0005852', ('25', '29'))
23014	28928896	Additionally, eIF3b knockdown significantly inhibited the growth of subcutaneous xenografts in mice.	('mice', 'Species', '10090', (95, 99))	('eIF3', 'cellular_component', 'GO:0005852', ('14', '18'))	('inhibited', 'NegReg', (44, 53))	('eIF3b', 'Gene', (14, 19))	('knockdown', 'Var', (20, 29))	('growth of subcutaneous xenografts in mice', 'CPA', (58, 99))
23025	28928896	Furthermore, eIF3b interacts with eIF4G, resulting in formation of the 48S pre-initiation complex, which recognizes the AUG start codon.	('eIF4G', 'Gene', '1981', (34, 39))	('eIF4G', 'Gene', (34, 39))	('pre', 'molecular_function', 'GO:0003904', ('75', '78'))	('eIF3', 'cellular_component', 'GO:0005852', ('13', '17'))	('resulting in', 'Reg', (41, 53))	('eIF3b', 'Var', (13, 18))	('eIF4', 'cellular_component', 'GO:0008304', ('34', '38'))	('formation', 'biological_process', 'GO:0009058', ('54', '63'))	('formation', 'MPA', (54, 63))
23072	28928896	Additionally, eIF3b was expressed at a significantly higher level in metastatic than in non-metastatic tumors (p = 0.0262), indicating that eIF3b contributes to tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('eIF3', 'cellular_component', 'GO:0005852', ('14', '18'))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('eIF3', 'cellular_component', 'GO:0005852', ('140', '144'))	('tumor', 'Disease', (103, 108))	('eIF3b', 'Var', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('contributes', 'Reg', (146, 157))	('tumor', 'Disease', (161, 166))
23073	28928896	Patients with tumors positive for eIF3b (+, ++, +++) (p = 0.002; Table 3, Figure 2B), high TNM grades (p = 0.001; Table 3, Figure 2C), advanced Fuhrman nuclear grades (p = 0.036; Table 3, Figure 2D), and low-level eIF3b expression in ANK tissue (p = 0.047; Table 3, Figure 2E) had significantly poorer prognoses.	('TNM', 'Gene', (91, 94))	('eIF3', 'cellular_component', 'GO:0005852', ('34', '38'))	('eIF3b', 'Gene', (214, 219))	('expression', 'MPA', (220, 230))	('low-level', 'Var', (204, 213))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('eIF3b', 'Gene', (34, 39))	('eIF3', 'cellular_component', 'GO:0005852', ('214', '218'))	('TNM', 'Gene', '10178', (91, 94))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
23077	28928896	Kaplan-Meier analysis indicated that patients with tumor eIF3b (+) and ANK (+ or ++) experienced worse OS compared to the other three groups.	('eIF3', 'cellular_component', 'GO:0005852', ('57', '61'))	('OS', 'Chemical', '-', (103, 105))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('patients', 'Species', '9606', (37, 45))	('tumor', 'Disease', (51, 56))	('ANK', 'Var', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
23079	28928896	Cell proliferation was significantly inhibited after eIF3b knockdown (Figure 3A and 3B; Supplementary Figure 1B).	('Supplementary Figure 1B', 'Disease', (88, 111))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('eIF3b', 'Gene', (53, 58))	('inhibited', 'NegReg', (37, 46))	('eIF3', 'cellular_component', 'GO:0005852', ('53', '57'))	('Supplementary Figure 1B', 'Disease', 'MESH:D017034', (88, 111))	('knockdown', 'Var', (59, 68))	('Cell proliferation', 'CPA', (0, 18))
23083	28928896	We found that the levels of both cyclins D and E decreased after eIF3b knockdown.	('cyclin', 'Gene', '5111', (33, 39))	('cyclin', 'Gene', (33, 39))	('knockdown', 'Var', (71, 80))	('decreased', 'NegReg', (49, 58))	('eIF3', 'cellular_component', 'GO:0005852', ('65', '69'))	('levels of', 'MPA', (18, 27))	('eIF3b', 'Gene', (65, 70))
23084	28928896	Cyclins D and E, Rb, and the inactivated form of Rb (p-Rb) were downregulated after eIF3b knockdown.	('knockdown', 'Var', (90, 99))	('Rb', 'Gene', '5925', (55, 57))	('Cyclin', 'Gene', '5111', (0, 6))	('p-Rb', 'Gene', (53, 57))	('Rb', 'Gene', '5925', (17, 19))	('eIF3', 'cellular_component', 'GO:0005852', ('84', '88'))	('p-Rb', 'Gene', '5925', (53, 57))	('Cyclin', 'Gene', (0, 6))	('eIF3b knockdown', 'Var', (84, 99))	('Rb', 'Gene', '5925', (49, 51))	('downregulated', 'NegReg', (64, 77))
23085	28928896	In addition, the levels of p27 Kip1 and p21 Cip1, inhibitors of the cyclin/CDK complexes, significantly increased after eIF3b knockdown.	('knockdown', 'Var', (126, 135))	('p21 Cip1', 'Gene', (40, 48))	('p21 Cip1', 'Gene', '1026', (40, 48))	('CDK', 'molecular_function', 'GO:0004693', ('75', '78'))	('increased', 'PosReg', (104, 113))	('cyclin', 'molecular_function', 'GO:0016538', ('68', '74'))	('eIF3b', 'Gene', (120, 125))	('cyclin', 'Gene', '5111', (68, 74))	('cyclin', 'Gene', (68, 74))	('levels', 'MPA', (17, 23))	('p27 Kip1', 'Gene', (27, 35))	('eIF3', 'cellular_component', 'GO:0005852', ('120', '124'))	('p27 Kip1', 'Gene', '1027', (27, 35))
23086	28928896	Cyclin A, which accumulates steadily during the G2 phase and is abruptly destroyed at mitosis, was upregulated after eIF3b depletion.	('upregulated', 'PosReg', (99, 110))	('Cyclin A', 'Gene', '890', (0, 8))	('G2 phase', 'biological_process', 'GO:0051319', ('48', '56'))	('depletion', 'Var', (123, 132))	('Cyclin', 'molecular_function', 'GO:0016538', ('0', '6'))	('Cyclin A', 'Gene', (0, 8))	('mitosis', 'biological_process', 'GO:0000278', ('86', '93'))	('eIF3b', 'Gene', (117, 122))	('mitosis', 'Disease', (86, 93))	('mitosis', 'Disease', 'None', (86, 93))	('eIF3', 'cellular_component', 'GO:0005852', ('117', '121'))
23089	28928896	Further analysis (Figure 4E) showed that, after eIF3b knockdown, the pro-apoptotic factors Bax, caspase-3, and the activated form thereof (cleaved caspase-3) were all upregulated and the pro-survival factor Bcl-2 was downregulated.	('caspase-3', 'Gene', (96, 105))	('eIF3', 'cellular_component', 'GO:0005852', ('48', '52'))	('knockdown', 'Var', (54, 63))	('caspase-3', 'Gene', '836', (147, 156))	('upregulated', 'PosReg', (167, 178))	('Bax', 'Gene', (91, 94))	('caspase-3', 'Gene', '836', (96, 105))	('Bcl-2', 'molecular_function', 'GO:0015283', ('207', '212'))	('Bcl-2', 'Gene', (207, 212))	('Bcl-2', 'Gene', '596', (207, 212))	('eIF3b', 'Gene', (48, 53))	('pro-survival', 'biological_process', 'GO:0043066', ('187', '199'))	('Bax', 'Gene', '581', (91, 94))	('caspase-3', 'Gene', (147, 156))
23092	28928896	We found that the epithelial marker E-cadherin was upregulated and the levels of repressors thereof (Slug and Snail) were downregulated after eIF3b depletion.	('levels of repressors thereof', 'MPA', (71, 99))	('downregulated', 'NegReg', (122, 135))	('upregulated', 'PosReg', (51, 62))	('eIF3', 'cellular_component', 'GO:0005852', ('142', '146'))	('E-cadherin', 'Gene', (36, 46))	('E-cadherin', 'Gene', '999', (36, 46))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('Slug', 'Gene', '6591', (101, 105))	('Slug', 'Gene', (101, 105))	('Snail', 'Gene', (110, 115))	('eIF3b', 'Gene', (142, 147))	('depletion', 'Var', (148, 157))	('Snail', 'Gene', '6615', (110, 115))
23095	28928896	We found that beta-catenin expression was significantly downregulated after eIF3b depletion (Figure 5A).	('beta-catenin', 'Gene', (14, 26))	('depletion', 'Var', (82, 91))	('beta-catenin', 'Gene', '1499', (14, 26))	('eIF3', 'cellular_component', 'GO:0005852', ('76', '80'))	('downregulated', 'NegReg', (56, 69))	('eIF3b', 'Gene', (76, 81))
23096	28928896	The level of cyclin D1 (Figure 4B), a target of beta-catenin, was also downregulated after eIF3b depletion.	('downregulated', 'NegReg', (71, 84))	('beta-catenin', 'Gene', (48, 60))	('eIF3', 'cellular_component', 'GO:0005852', ('91', '95'))	('eIF3b', 'Gene', (91, 96))	('cyclin', 'molecular_function', 'GO:0016538', ('13', '19'))	('beta-catenin', 'Gene', '1499', (48, 60))	('cyclin D1', 'Gene', '595', (13, 22))	('cyclin D1', 'Gene', (13, 22))	('depletion', 'Var', (97, 106))
23097	28928896	Together, our data showed that eIF3b depletion inactivated the beta-catenin pathway and inhibited the EMT of ccRCC.	('beta-catenin', 'Gene', (63, 75))	('inactivated', 'NegReg', (47, 58))	('inhibited', 'NegReg', (88, 97))	('EMT', 'biological_process', 'GO:0001837', ('102', '105'))	('depletion', 'Var', (37, 46))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('eIF3', 'cellular_component', 'GO:0005852', ('31', '35'))	('beta-catenin', 'Gene', '1499', (63, 75))	('EMT of', 'CPA', (102, 108))	('eIF3b', 'Gene', (31, 36))
23099	28928896	We found that eIF3b depletion was not associated with any significant change in Akt levels; however, the level of the activated form, p-Akt, fell in parallel with the extent of eIF3b depletion, indicating that the Akt signaling pathway was involved in such depletion.	('eIF3b', 'Var', (177, 182))	('Akt', 'Gene', '207', (80, 83))	('eIF3', 'cellular_component', 'GO:0005852', ('14', '18'))	('Akt', 'Gene', '207', (214, 217))	('signaling pathway', 'biological_process', 'GO:0007165', ('218', '235'))	('Akt', 'Gene', (80, 83))	('Akt', 'Gene', '207', (136, 139))	('fell', 'NegReg', (141, 145))	('Akt', 'Gene', (214, 217))	('Akt signaling', 'biological_process', 'GO:0043491', ('214', '227'))	('Akt', 'Gene', (136, 139))	('level', 'MPA', (105, 110))	('eIF3', 'cellular_component', 'GO:0005852', ('177', '181'))
23100	28928896	After eIF3b knockdown, the levels of integrins alpha2 and alpha5 fell significantly, as did the level of the upstream phosphorylated Focal adhesion kinase (p-FAK) protein, suggesting that integrin/FAK/Akt signaling was inhibited (Figure 5B).	('eIF3', 'cellular_component', 'GO:0005852', ('6', '10'))	('FAK', 'Gene', (197, 200))	('FAK', 'Gene', '5747', (197, 200))	('FAK', 'molecular_function', 'GO:0004717', ('158', '161'))	('Focal adhesion', 'cellular_component', 'GO:0005925', ('133', '147'))	('FAK', 'molecular_function', 'GO:0004717', ('197', '200'))	('Akt', 'Gene', (201, 204))	('FAK', 'Gene', '5747', (158, 161))	('eIF3b', 'Gene', (6, 11))	('knockdown', 'Var', (12, 21))	('Akt signaling', 'biological_process', 'GO:0043491', ('201', '214'))	('protein', 'cellular_component', 'GO:0003675', ('163', '170'))	('inhibited', 'NegReg', (219, 228))	('FAK', 'Gene', (158, 161))	('fell', 'NegReg', (65, 69))	('Akt', 'Gene', '207', (201, 204))	('levels', 'MPA', (27, 33))
23102	28928896	We found that p-mTOR was downregulated after eIF3b knockdown, indicating that the Akt/mTOR pathway was impaired (Figure 5B).	('mTOR', 'Gene', '2475', (86, 90))	('Akt', 'Gene', '207', (82, 85))	('mTOR', 'Gene', (86, 90))	('Akt', 'Gene', (82, 85))	('mTOR', 'Gene', '2475', (16, 20))	('downregulated', 'NegReg', (25, 38))	('mTOR', 'Gene', (16, 20))	('eIF3b', 'Gene', (45, 50))	('eIF3', 'cellular_component', 'GO:0005852', ('45', '49'))	('impaired', 'NegReg', (103, 111))	('knockdown', 'Var', (51, 60))
23103	28928896	Furthermore, the observed downregulation of HIF-1alpha, HIF-2alpha, and p-NF-kappaB after eIF3b depletion may indicate that the Akt/mTOR/HIF and Akt/mTOR/NF-kappaB pathways were also downregulated (Figure 5B), compromising cell proliferation and inducing apoptosis.	('mTOR', 'Gene', '2475', (132, 136))	('NF-kappaB', 'Gene', '4790', (154, 163))	('mTOR', 'Gene', '2475', (149, 153))	('eIF3b', 'Gene', (90, 95))	('eIF3', 'cellular_component', 'GO:0005852', ('90', '94'))	('cell proliferation', 'CPA', (223, 241))	('cell proliferation', 'biological_process', 'GO:0008283', ('223', '241'))	('downregulated', 'NegReg', (183, 196))	('apoptosis', 'biological_process', 'GO:0097194', ('255', '264'))	('Akt', 'Gene', (145, 148))	('apoptosis', 'biological_process', 'GO:0006915', ('255', '264'))	('HIF-1alpha, HIF-2alpha', 'Disease', 'None', (44, 66))	('depletion', 'Var', (96, 105))	('compromising', 'NegReg', (210, 222))	('Akt', 'Gene', '207', (145, 148))	('downregulation', 'NegReg', (26, 40))	('mTOR', 'Gene', (132, 136))	('NF-kappaB', 'Gene', (74, 83))	('Akt', 'Gene', (128, 131))	('NF-kappaB', 'Gene', (154, 163))	('mTOR', 'Gene', (149, 153))	('apoptosis', 'CPA', (255, 264))	('Akt', 'Gene', '207', (128, 131))	('inducing', 'NegReg', (246, 254))	('NF-kappaB', 'Gene', '4790', (74, 83))
23111	28928896	Therefore, eIF3b knockdown inhibited the growth of subcutaneous xenografts in mice.	('eIF3', 'cellular_component', 'GO:0005852', ('11', '15'))	('eIF3b', 'Gene', (11, 16))	('growth of subcutaneous xenografts in mice', 'CPA', (41, 82))	('inhibited', 'NegReg', (27, 36))	('knockdown', 'Var', (17, 26))	('mice', 'Species', '10090', (78, 82))
23116	28928896	This carcinogenic role of eIF3b was confirmed by in vitro experiment that eIF3b knockdown inhibited tumor cell proliferation, migration, and invasion.	('invasion', 'CPA', (141, 149))	('eIF3b', 'Gene', (74, 79))	('knockdown', 'Var', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('eIF3', 'cellular_component', 'GO:0005852', ('74', '78'))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('eIF3', 'cellular_component', 'GO:0005852', ('26', '30'))	('inhibited', 'NegReg', (90, 99))	('migration', 'CPA', (126, 135))	('cell proliferation', 'biological_process', 'GO:0008283', ('106', '124'))
23118	28928896	found that reduction in overall protein synthesis by eIF3b depletion lead to the smaller size of cells which cannot pass the major size regulatory "R or restriction point" checkpoint, which is also a G1/S arrest reason.	('smaller', 'NegReg', (81, 88))	('reduction', 'NegReg', (11, 20))	('eIF3b', 'Gene', (53, 58))	('S arrest', 'Disease', (203, 211))	('protein synthesis', 'MPA', (32, 49))	('eIF3', 'cellular_component', 'GO:0005852', ('53', '57'))	('depletion', 'Var', (59, 68))	('S arrest', 'Disease', 'MESH:D006323', (203, 211))	('protein synthesis', 'biological_process', 'GO:0006412', ('32', '49'))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))
23120	28928896	However, the overall effect of eIF3b depletion was pro-apoptotic in ccRCC.	('eIF3b', 'Protein', (31, 36))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('depletion', 'Var', (37, 46))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('pro-apoptotic', 'PosReg', (51, 64))	('eIF3', 'cellular_component', 'GO:0005852', ('31', '35'))
23122	28928896	We found that the EMT was impaired after eIF3b knockdown, which was characterized by upregulation of E-cadherin and downregulation of N-cadherin, vimentin, and repressors of E-cadherin.	('vimentin', 'Gene', '7431', (146, 154))	('vimentin', 'Gene', (146, 154))	('vimentin', 'cellular_component', 'GO:0045099', ('146', '154'))	('E-cadherin', 'Gene', (101, 111))	('cadherin', 'molecular_function', 'GO:0008014', ('136', '144'))	('downregulation', 'NegReg', (116, 130))	('E-cadherin', 'Gene', '999', (101, 111))	('eIF3', 'cellular_component', 'GO:0005852', ('41', '45'))	('eIF3b', 'Gene', (41, 46))	('cadherin', 'molecular_function', 'GO:0008014', ('103', '111'))	('impaired', 'NegReg', (26, 34))	('EMT', 'biological_process', 'GO:0001837', ('18', '21'))	('upregulation', 'PosReg', (85, 97))	('N-cadherin', 'Gene', (134, 144))	('EMT', 'CPA', (18, 21))	('vimentin', 'cellular_component', 'GO:0045098', ('146', '154'))	('N-cadherin', 'Gene', '1000', (134, 144))	('knockdown', 'Var', (47, 56))	('E-cadherin', 'Gene', (174, 184))	('E-cadherin', 'Gene', '999', (174, 184))	('cadherin', 'molecular_function', 'GO:0008014', ('176', '184'))
23123	28928896	We also found that inhibition of the beta-catenin pathway contributed to the EMT impairment after eIF3b depletion.	('EMT impairment', 'Disease', (77, 91))	('eIF3b', 'Gene', (98, 103))	('EMT', 'biological_process', 'GO:0001837', ('77', '80'))	('beta-catenin', 'Gene', (37, 49))	('inhibition', 'NegReg', (19, 29))	('eIF3', 'cellular_component', 'GO:0005852', ('98', '102'))	('depletion', 'Var', (104, 113))	('EMT impairment', 'Disease', 'MESH:D009422', (77, 91))	('beta-catenin', 'Gene', '1499', (37, 49))
23124	28928896	eIF3b knockdown inhibited many activities of the Akt pathway network in RCC cells, including the integrin/FAK/Akt, Akt/mTOR/HIF/VEGF, Akt/mTOR/NF-kappaB, Akt/Bcl-2/Bax, and Akt/GSK-3beta pathways.	('mTOR', 'Gene', (138, 142))	('Akt', 'Gene', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('Akt', 'Gene', (173, 176))	('GSK', 'molecular_function', 'GO:0050321', ('177', '180'))	('eIF3', 'cellular_component', 'GO:0005852', ('0', '4'))	('Akt', 'Gene', '207', (110, 113))	('Akt', 'Gene', (134, 137))	('Akt', 'Gene', '207', (173, 176))	('Bcl-2', 'Gene', '596', (158, 163))	('FAK', 'molecular_function', 'GO:0004717', ('106', '109'))	('mTOR', 'Gene', '2475', (138, 142))	('eIF3b', 'Gene', (0, 5))	('Akt', 'Gene', '207', (134, 137))	('Bcl-2', 'molecular_function', 'GO:0015283', ('158', '163'))	('VEGF', 'Gene', '7422', (128, 132))	('Akt', 'Gene', (154, 157))	('GSK-3beta', 'Gene', '2932', (177, 186))	('FAK', 'Gene', (106, 109))	('NF-kappaB', 'Gene', (143, 152))	('mTOR', 'Gene', (119, 123))	('VEGF', 'Gene', (128, 132))	('Akt', 'Gene', '207', (154, 157))	('NF-kappaB', 'Gene', '4790', (143, 152))	('Akt', 'Gene', (115, 118))	('GSK-3beta', 'Gene', (177, 186))	('Bax', 'Gene', (164, 167))	('FAK', 'Gene', '5747', (106, 109))	('mTOR', 'Gene', '2475', (119, 123))	('Bax', 'Gene', '581', (164, 167))	('Akt', 'Gene', (49, 52))	('Akt', 'Gene', '207', (115, 118))	('inhibited', 'NegReg', (16, 25))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('activities', 'MPA', (31, 41))	('RCC', 'Disease', (72, 75))	('Akt', 'Gene', '207', (49, 52))	('knockdown', 'Var', (6, 15))	('Bcl-2', 'Gene', (158, 163))
23125	28928896	Inhibition of the integrin/FAK/Akt pathway changed the cellular morphology and impaired adhesion.	('Akt', 'Gene', (31, 34))	('impaired', 'NegReg', (79, 87))	('cellular morphology', 'CPA', (55, 74))	('FAK', 'Gene', (27, 30))	('FAK', 'Gene', '5747', (27, 30))	('adhesion', 'CPA', (88, 96))	('Akt', 'Gene', '207', (31, 34))	('FAK', 'molecular_function', 'GO:0004717', ('27', '30'))	('Inhibition', 'Var', (0, 10))	('changed', 'Reg', (43, 50))
23129	28928896	Therefore, after eIF3b depletion, the translation of oncogenic proteins in the EMT and Akt signaling pathways is significantly inhibited.	('Akt signaling', 'biological_process', 'GO:0043491', ('87', '100'))	('EMT', 'biological_process', 'GO:0001837', ('79', '82'))	('EMT', 'CPA', (79, 82))	('Akt', 'Gene', (87, 90))	('eIF3', 'cellular_component', 'GO:0005852', ('17', '21'))	('depletion', 'Var', (23, 32))	('inhibited', 'NegReg', (127, 136))	('translation', 'MPA', (38, 49))	('eIF3b', 'Gene', (17, 22))	('translation', 'biological_process', 'GO:0006412', ('38', '49'))	('Akt', 'Gene', '207', (87, 90))
23137	28928896	We suggest that eIF3b may, like TGF-beta, play different roles in kidney cancer.	('eIF3b', 'Var', (16, 21))	('TGF-beta', 'Gene', '7040', (32, 40))	('kidney cancer', 'Disease', 'MESH:D007680', (66, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('kidney cancer', 'Phenotype', 'HP:0009726', (66, 79))	('TGF-beta', 'Gene', (32, 40))	('eIF3', 'cellular_component', 'GO:0005852', ('16', '20'))	('kidney cancer', 'Disease', (66, 79))	('play', 'Reg', (42, 46))
23138	28928896	In tumor cells, eIF3b contributes to tumor progression but in non-tumor cells, it plays a protective role in patients with ccRCC.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('eIF3b', 'Var', (16, 21))	('tumor', 'Disease', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('tumor', 'Disease', (66, 71))	('RCC', 'Disease', (125, 128))	('patients', 'Species', '9606', (109, 117))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('eIF3', 'cellular_component', 'GO:0005852', ('16', '20'))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
23140	28928896	eIF3b knockdown inhibited the growth of subcutaneous tumors in mice, confirming eIF3b as a potential therapeutic target for patients with ccRCC.	('inhibited', 'NegReg', (16, 25))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (40, 59))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (40, 59))	('eIF3b', 'Gene', (0, 5))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('eIF3', 'cellular_component', 'GO:0005852', ('0', '4'))	('mice', 'Species', '10090', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('eIF3', 'cellular_component', 'GO:0005852', ('80', '84'))	('knockdown', 'Var', (6, 15))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('subcutaneous tumors', 'Disease', (40, 59))	('patients', 'Species', '9606', (124, 132))
23141	28928896	Nowadays, RNA-based therapeutics, such as small-interfering (siRNA), microRNAs, antisense oligonucleotides (ASOs), CRISPR-Cas9, have great potential to target a large part of the currently undruggable genes to treat cancers.	('RNA', 'cellular_component', 'GO:0005562', ('10', '13'))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('Cas', 'cellular_component', 'GO:0005650', ('122', '125'))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('oligonucleotides', 'Chemical', 'MESH:D009841', (90, 106))	('small-interfering', 'Var', (42, 59))	('cancers', 'Disease', (216, 223))	('cancers', 'Disease', 'MESH:D009369', (216, 223))
23149	28928896	Furthermore, in vitro eIF3b knockdown effectively impaired the Akt pathway, inhibiting cell proliferation by disrupting the cell cycle, and triggering apoptosis.	('eIF3', 'cellular_component', 'GO:0005852', ('22', '26'))	('eIF3b', 'Gene', (22, 27))	('cell cycle', 'biological_process', 'GO:0007049', ('124', '134'))	('disrupting', 'NegReg', (109, 119))	('cell proliferation', 'biological_process', 'GO:0008283', ('87', '105'))	('triggering', 'Reg', (140, 150))	('apoptosis', 'biological_process', 'GO:0097194', ('151', '160'))	('impaired', 'NegReg', (50, 58))	('apoptosis', 'biological_process', 'GO:0006915', ('151', '160'))	('cell proliferation', 'CPA', (87, 105))	('cell cycle', 'CPA', (124, 134))	('inhibiting', 'NegReg', (76, 86))	('Akt', 'Gene', '207', (63, 66))	('knockdown', 'Var', (28, 37))	('apoptosis', 'CPA', (151, 160))	('Akt', 'Gene', (63, 66))
23151	28928896	More work is needed to understand what role eIF3b plays in non-tumor kidney cell and how eIF3b interacts with other eIFs in terms of cancer development.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('eIF3b', 'Var', (89, 94))	('eIF3', 'cellular_component', 'GO:0005852', ('89', '93'))	('eIF3', 'cellular_component', 'GO:0005852', ('44', '48'))	('interacts', 'Reg', (95, 104))	('cancer', 'Disease', (133, 139))	('tumor kidney', 'Phenotype', 'HP:0009726', (63, 75))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('non-tumor kidney', 'Disease', 'MESH:D007674', (59, 75))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('non-tumor kidney', 'Disease', (59, 75))
23170	34040677	HOTAIRM1 can promote glioblastoma progression, but in ccRCC, it is downregulated, serving as a suppressor of HIF1-dependent angiogenic pathways.	('glioblastoma', 'Disease', (21, 33))	('HIF1', 'Gene', (109, 113))	('ccRCC', 'Disease', (54, 59))	('glioblastoma', 'Disease', 'MESH:D005909', (21, 33))	('promote', 'PosReg', (13, 20))	('HOTAIRM1', 'Var', (0, 8))	('glioblastoma', 'Phenotype', 'HP:0012174', (21, 33))	('HIF1', 'Gene', '3091', (109, 113))
23182	31043790	miR-19 was identified as a novel suppressor of FRK in renal cancer cells and it promoted the proliferation of ccRCC by inhibiting the FRK-PTEN axis.	('renal cancer', 'Disease', 'MESH:D007680', (54, 66))	('promoted', 'PosReg', (80, 88))	('PTEN', 'Gene', (138, 142))	('miR-19', 'Var', (0, 6))	('proliferation', 'CPA', (93, 106))	('PTEN', 'Gene', '5728', (138, 142))	('miR-19', 'Chemical', '-', (0, 6))	('FRK', 'Gene', (47, 50))	('FRK', 'Gene', (134, 137))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))	('FRK', 'Gene', '2444', (47, 50))	('FRK', 'Gene', '2444', (134, 137))	('inhibiting', 'NegReg', (119, 129))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('renal cancer', 'Disease', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('renal cancer', 'Phenotype', 'HP:0009726', (54, 66))
23209	31043790	Antibodies used in this study were obtained as follows: anti-FRK (abs133481; Absin, Shanghai, China), anti-PTEN (ab32199; Abcam, Cambridge, MA, USA), anti-GAPDH (5174; Cell Signaling, Danvers, MA, USA).	('PTEN', 'Gene', (107, 111))	('FRK', 'Gene', '2444', (61, 64))	('abs133481;', 'Var', (66, 76))	('GAPDH', 'Gene', '2597', (155, 160))	('PTEN', 'Gene', '5728', (107, 111))	('Signaling', 'biological_process', 'GO:0023052', ('173', '182'))	('FRK', 'Gene', (61, 64))	('GAPDH', 'Gene', (155, 160))
23240	31043790	The CCK-8 results revealed that FRK knockdown promoted the growth of ACNH, CAIK-1, and 786-O cells, whereas FRK overexpression markedly reduced the growth of renal cancer cells compared with control cells (Figure 2A-C).	('promoted', 'PosReg', (46, 54))	('FRK', 'Gene', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('renal cancer', 'Disease', (158, 170))	('renal cancer', 'Disease', 'MESH:D007680', (158, 170))	('renal cancer', 'Phenotype', 'HP:0009726', (158, 170))	('knockdown', 'Var', (36, 45))	('FRK', 'Gene', '2444', (108, 111))	('reduced', 'NegReg', (136, 143))	('FRK', 'Gene', (108, 111))	('growth', 'MPA', (59, 65))	('FRK', 'Gene', '2444', (32, 35))	('growth', 'MPA', (148, 154))
23241	31043790	In the colony formation assay, FRK knockdown in 786-O cells increased the number of 786-O cell colonies, while FRK overexpression led to a lower number of cell colonies (Figure 2D).	('knockdown', 'Var', (35, 44))	('FRK', 'Gene', '2444', (31, 34))	('increased', 'PosReg', (60, 69))	('FRK', 'Gene', (31, 34))	('FRK', 'Gene', '2444', (111, 114))	('formation', 'biological_process', 'GO:0009058', ('14', '23'))	('FRK', 'Gene', (111, 114))
23251	31043790	FRK downregulation could also be a result of dysregulated miRNAs in ccRCC.	('dysregulated', 'Var', (45, 57))	('miRNAs', 'MPA', (58, 64))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('FRK', 'Gene', '2444', (0, 3))	('FRK', 'Gene', (0, 3))	('downregulation', 'NegReg', (4, 18))
23266	31043790	However, cotransfection of miR-19a/b-3p mimics and plasmids with a mutation in the predicted binding site did not result in a reduction of luciferase activity.	('miR-19a', 'Gene', (27, 34))	('mutation', 'Var', (67, 75))	('luciferase', 'Enzyme', (139, 149))	('binding', 'molecular_function', 'GO:0005488', ('93', '100'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('139', '158'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('139', '158'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('139', '158'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('139', '158'))	('b-3p', 'Gene', '28908', (35, 39))	('b-3p', 'Gene', (35, 39))	('reduction', 'NegReg', (126, 135))	('miR-19a', 'Gene', '406979', (27, 34))	('luciferase activity', 'molecular_function', 'GO:0050248', ('139', '158'))	('activity', 'MPA', (150, 158))
23284	31043790	The miR-17~92 cluster, which includes six mature miRNAs (miR-17, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92a), is believed to be the first miRNA cluster with oncogenic potentials.	('miR-20a', 'Gene', (92, 99))	('miR-17', 'Gene', (4, 10))	('miR-19b', 'Gene', (83, 90))	('miR-20a', 'Gene', '406982', (92, 99))	('miR-18a', 'Gene', (65, 72))	('miR-19a', 'Gene', '406979', (74, 81))	('miR-17', 'Gene', '406952', (4, 10))	('miR-17', 'Gene', (57, 63))	('miR-92a', 'Var', (105, 112))	('miR-17~92', 'Gene', '407975', (4, 13))	('miR-17~92', 'Gene', (4, 13))	('miR-18a', 'Gene', '406953', (65, 72))	('miR-19b', 'Gene', '406980', (83, 90))	('miR-17', 'Gene', '406952', (57, 63))	('miR-19a', 'Gene', (74, 81))
23292	31043790	The diagnostic and prognostic values of miR-19 should also be explored in the future since the prognostic data from the TCGA KIRC indicate that high miR-19 expression is associated with poor survival for ccRCC patients.	('poor', 'NegReg', (186, 190))	('miR-19', 'Chemical', '-', (149, 155))	('high', 'Var', (144, 148))	('miR-19', 'Gene', (149, 155))	('patients', 'Species', '9606', (210, 218))	('expression', 'MPA', (156, 166))	('miR-19', 'Chemical', '-', (40, 46))	('RCC', 'Phenotype', 'HP:0005584', (206, 209))	('RCC', 'Disease', 'MESH:C538614', (206, 209))	('RCC', 'Disease', (206, 209))	('ccRCC', 'Phenotype', 'HP:0006770', (204, 209))
23379	30799948	Moreover, the colony formation assays demonstrated that KCNJ15 overexpression prevented the formation of colonies in both Caki-2 and OS-RC-2 cell lines (P<0.05) (Figure 4B, C, E, and F).	('prevented', 'NegReg', (78, 87))	('formation', 'biological_process', 'GO:0009058', ('92', '101'))	('formation of colonies', 'CPA', (92, 113))	('overexpression', 'Var', (63, 77))	('KCNJ15', 'Gene', '3772', (56, 62))	('KCNJ15', 'Gene', (56, 62))	('formation', 'biological_process', 'GO:0009058', ('21', '30'))	('OS-RC-2', 'CellLine', 'CVCL:1626', (133, 140))	('rat', 'Species', '10116', (45, 48))
23384	30799948	As expected, more KCNJ15 overexpression cells were in the G0/G1 phase and fewer were in the S phase when compared with the NC cells (Figure 6), suggesting that KCNJ15 overexpression suppressed cell proliferation by inducing cell cycle arrest at the G1 phase.	('cell cycle arrest at the G1 phase', 'CPA', (224, 257))	('rat', 'Species', '10116', (205, 208))	('cell proliferation', 'CPA', (193, 211))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('224', '241'))	('suppressed', 'NegReg', (182, 192))	('inducing', 'PosReg', (215, 223))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (224, 241))	('G1 phase', 'biological_process', 'GO:0051318', ('61', '69'))	('KCNJ15', 'Gene', (18, 24))	('cell proliferation', 'biological_process', 'GO:0008283', ('193', '211'))	('KCNJ15', 'Gene', '3772', (160, 166))	('G1 phase', 'biological_process', 'GO:0051318', ('249', '257'))	('KCNJ15', 'Gene', '3772', (18, 24))	('S phase', 'biological_process', 'GO:0051320', ('92', '99'))	('overexpression', 'Var', (167, 181))	('KCNJ15', 'Gene', (160, 166))
23386	30799948	Quantitative analysis of apoptosis revealed that KCNJ15 overexpression increased the cell apoptosis rates by ~11.8% in the Caki-2 cell line (P<0.01; Figure 7A and B) and 10% in the OS-RC-2 cell line (P<0.01; Figure 7C and D) relative to the apoptosis rates in the NC groups.	('overexpression', 'Var', (56, 70))	('apoptosis', 'biological_process', 'GO:0097194', ('241', '250'))	('apoptosis', 'biological_process', 'GO:0006915', ('90', '99'))	('apoptosis', 'biological_process', 'GO:0097194', ('90', '99'))	('cell apoptosis rates', 'CPA', (85, 105))	('apoptosis', 'biological_process', 'GO:0006915', ('25', '34'))	('apoptosis', 'biological_process', 'GO:0097194', ('25', '34'))	('KCNJ15', 'Gene', (49, 55))	('KCNJ15', 'Gene', '3772', (49, 55))	('apoptosis', 'biological_process', 'GO:0006915', ('241', '250'))	('increased', 'PosReg', (71, 80))	('rat', 'Species', '10116', (251, 254))	('OS-RC-2', 'CellLine', 'CVCL:1626', (181, 188))	('rat', 'Species', '10116', (100, 103))
23388	30799948	As shown in Figure 8, KCNJ15 overexpression upregulated p21 expression and downregulated N-cadherin, vimentin, and matrix metalloproteinase (MMP)-7 expression but had no impact on the expression of mechanistic target of rapamycin (mTOR), phosphorylated (P-) mTOR, glycogen synthase kinase (GSK)-3beta, P-GSK-3beta, or phosphoinositide 3-kinase (PI3K) in both cell lines (Caki-2 and OS-RC-2).	('expression', 'MPA', (60, 70))	('mTOR', 'Gene', (258, 262))	('mechanistic target of rapamycin', 'Gene', '2475', (198, 229))	('matrix metalloproteinase (MMP)-7', 'Gene', '4316', (115, 147))	('downregulated', 'NegReg', (75, 88))	('KCNJ15', 'Gene', '3772', (22, 28))	('P-GSK-3beta', 'Disease', (302, 313))	('GSK', 'molecular_function', 'GO:0050321', ('304', '307'))	('KCNJ15', 'Gene', (22, 28))	('cadherin', 'molecular_function', 'GO:0008014', ('91', '99'))	('P-GSK-3beta', 'Disease', 'MESH:C579862', (302, 313))	('mTOR', 'Gene', '2475', (258, 262))	('upregulated', 'PosReg', (44, 55))	('p21', 'Gene', (56, 59))	('GSK', 'molecular_function', 'GO:0050321', ('290', '293'))	('mTOR', 'Gene', (231, 235))	('vimentin', 'cellular_component', 'GO:0045098', ('101', '109'))	('N-cadherin', 'Gene', (89, 99))	('PI3K', 'molecular_function', 'GO:0016303', ('345', '349'))	('OS-RC-2', 'CellLine', 'CVCL:1626', (382, 389))	('MMP)-7', 'molecular_function', 'GO:0004235', ('141', '147'))	('mTOR', 'Gene', '2475', (231, 235))	('N-cadherin', 'Gene', '1000', (89, 99))	('phosphoinositide 3-kinase', 'MPA', (318, 343))	('p21', 'Gene', '1026', (56, 59))	('vimentin', 'Gene', '7431', (101, 109))	('vimentin', 'Gene', (101, 109))	('vimentin', 'cellular_component', 'GO:0045099', ('101', '109'))	('overexpression', 'Var', (29, 43))	('expression', 'MPA', (148, 158))	('mechanistic target of rapamycin', 'Gene', (198, 229))
23392	30799948	Furthermore, we examined cell proliferation, migration, cell cycle, and apoptosis in the RCC cell lines after increasing KCNJ15 expression levels and revealed that KCNJ15 overexpression inhibited cell proliferation and migration, suppressed G0/G1-phase entry, and induced cell apoptosis in vitro.	('KCNJ15', 'Gene', '3772', (164, 170))	('rat', 'Species', '10116', (208, 211))	('apoptosis', 'biological_process', 'GO:0006915', ('277', '286'))	('cell proliferation', 'biological_process', 'GO:0008283', ('25', '43'))	('cell cycle', 'biological_process', 'GO:0007049', ('56', '66'))	('cell apoptosis', 'CPA', (272, 286))	('induced', 'Reg', (264, 271))	('inhibited', 'NegReg', (186, 195))	('rat', 'Species', '10116', (48, 51))	('G1-phase', 'biological_process', 'GO:0051318', ('244', '252'))	('cell proliferation', 'biological_process', 'GO:0008283', ('196', '214'))	('KCNJ15', 'Gene', (164, 170))	('suppressed', 'NegReg', (230, 240))	('rat', 'Species', '10116', (222, 225))	('RCC', 'Disease', (89, 92))	('KCNJ15', 'Gene', '3772', (121, 127))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('72', '81'))	('apoptosis', 'biological_process', 'GO:0006915', ('72', '81'))	('rat', 'Species', '10116', (37, 40))	('KCNJ15', 'Gene', (121, 127))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('cell proliferation', 'CPA', (196, 214))	('G0/G1-phase entry', 'CPA', (241, 258))	('overexpression', 'Var', (171, 185))	('apoptosis', 'biological_process', 'GO:0097194', ('277', '286'))
23413	28977844	High fucosyltransferase-III expression was associated with a greater risk of recurrence (p = 0.002) and shortened overall survival (p < 0.001).	('High', 'Var', (0, 4))	('recurrence', 'CPA', (77, 87))	('fucosyltransferase-III', 'Gene', '2525', (5, 27))	('overall', 'MPA', (114, 121))	('fucosyltransferase-III', 'Gene', (5, 27))	('shortened', 'NegReg', (104, 113))
23427	28977844	It has been elucidated that the deactivation of the von Hippel-Lindau gene, a tumor-suppressor gene, can trigger the formation of ccRCC.	('deactivation', 'Var', (32, 44))	('von Hippel-Lindau', 'Disease', (52, 69))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('trigger', 'Reg', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('78', '94'))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (52, 69))	('formation', 'biological_process', 'GO:0009058', ('117', '126'))	('tumor', 'Disease', (78, 83))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('78', '94'))
23447	28977844	Our findings demonstrated the high expression of FUT3 could predict a poor prognosis in patients with ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('FUT3', 'Gene', (49, 53))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('patients', 'Species', '9606', (88, 96))	('high', 'Var', (30, 34))	('FUT3', 'Gene', '2525', (49, 53))	('RCC', 'Disease', (104, 107))
23465	28977844	As presented above, high FUT3 expression correlated with reduced survival and high probability in patients with ccRCC.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('expression', 'MPA', (30, 40))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('FUT3', 'Gene', '2525', (25, 29))	('patients', 'Species', '9606', (98, 106))	('high', 'Var', (20, 24))	('reduced', 'NegReg', (57, 64))	('survival', 'MPA', (65, 73))	('FUT3', 'Gene', (25, 29))
23480	28977844	A recent study illustrated the proliferation and other malignant properties such as migration and invasion capability of gastric carcinoma cell line can be inhibited by FUT3 gene silencing.	('malignant properties', 'CPA', (55, 75))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (121, 138))	('gene silencing', 'biological_process', 'GO:0016458', ('174', '188'))	('proliferation', 'CPA', (31, 44))	('gene silencing', 'Var', (174, 188))	('migration', 'CPA', (84, 93))	('FUT3', 'Gene', (169, 173))	('gastric carcinoma', 'Disease', 'MESH:D013274', (121, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('invasion capability', 'CPA', (98, 117))	('gastric carcinoma', 'Disease', (121, 138))	('FUT3', 'Gene', '2525', (169, 173))	('inhibited', 'NegReg', (156, 165))
23490	28977844	On the other hand, the extrinsic apoptosis pathway is mediated by fucosylation in the TNF-related apoptosis-inducing ligand (TRAIL).	('extrinsic apoptosis pathway', 'Pathway', (23, 50))	('fucosylation', 'biological_process', 'GO:0036065', ('66', '78'))	('TRAIL', 'Gene', '8743', (125, 130))	('mediated by', 'Reg', (54, 65))	('ligand', 'molecular_function', 'GO:0005488', ('117', '123'))	('extrinsic apoptosis', 'biological_process', 'GO:0097191', ('23', '42'))	('TNF-related apoptosis-inducing ligand', 'Gene', '8743', (86, 123))	('TRAIL', 'Gene', (125, 130))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))	('fucosylation', 'Var', (66, 78))	('TNF-related apoptosis-inducing ligand', 'Gene', (86, 123))
23496	28977844	Inhibitor of FUT3 might be a potential therapeutic method for ccRCC.	('FUT3', 'Gene', '2525', (13, 17))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('Inhibitor', 'Var', (0, 9))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))	('FUT3', 'Gene', (13, 17))
23518	30131446	Mechanistically, ESRRG loss occurs via DNA methylation and histone repressive silencing mediated by the polycomb repressor complex 2 (PRC2).	('ESRRG', 'Gene', (17, 22))	('DNA methylation', 'biological_process', 'GO:0006306', ('39', '54'))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('silencing', 'NegReg', (78, 87))	('DNA', 'Var', (39, 42))	('histone', 'Protein', (59, 66))	('loss', 'NegReg', (23, 27))	('ESRRG', 'Gene', '2104', (17, 22))
23519	30131446	Restoration of ESRRG in RCC lines suppresses migratory and invasive phenotypes independently of its canonical role in mitochondrial metabolism.	('RCC', 'Disease', (24, 27))	('ESRRG', 'Gene', '2104', (15, 20))	('metabolism', 'biological_process', 'GO:0008152', ('132', '142'))	('Restoration', 'Var', (0, 11))	('suppresses', 'NegReg', (34, 44))	('ESRRG', 'Gene', (15, 20))	('RCC', 'Phenotype', 'HP:0005584', (24, 27))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
23521	30131446	These data have confirmed the high prevalence of tumor initiating events such as alterations in the VHL tumor suppressor gene which lead to stabilization of hypoxia inducible factors (HIF-1alpha and HIF-2alpha).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor suppressor', 'biological_process', 'GO:0051726', ('104', '120'))	('HIF-2alpha', 'Gene', '2034', (199, 209))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('104', '120'))	('VHL tumor', 'Disease', 'MESH:D006623', (100, 109))	('hypoxia', 'Disease', 'MESH:D000860', (157, 164))	('tumor', 'Disease', (104, 109))	('HIF-1alpha', 'Gene', (184, 194))	('stabilization', 'MPA', (140, 153))	('tumor', 'Disease', (49, 54))	('hypoxia', 'Disease', (157, 164))	('alterations', 'Var', (81, 92))	('HIF-2alpha', 'Gene', (199, 209))	('VHL tumor', 'Disease', (100, 109))	('HIF-1alpha', 'Gene', '3091', (184, 194))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
23522	30131446	Analyses of these datasets have also indicated the importance of epigenetics to RCC malignancy, including the alteration of PBRM1, which encodes a component of the SWI/SNF chromatin remodeling complex as well as BAP1, a gene encoding a known histone deubiquitinase.	('RCC malignancy', 'Disease', (80, 94))	('BAP1', 'Gene', (212, 216))	('PBRM1', 'Gene', '55193', (124, 129))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('172', '200'))	('RCC malignancy', 'Disease', 'MESH:C538614', (80, 94))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('250', '264'))	('PBRM1', 'Gene', (124, 129))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('172', '192'))	('BAP1', 'Gene', '8314', (212, 216))	('alteration', 'Var', (110, 120))
23559	30131446	The following probes were used: ALDOA (Hs00605108_g1), ALDOB (Hs01551887_m1), ALDOC(Hs00902799_g1), ESRRA (Hs01067166_g1), ESRRB (Hs01584024_m1),ESRRG (Hs00976243_m1), ACO2(Hs00426616_g1), OGDH (Hs01081865_m1), SUCLG1 (Hs00388749_m1), MDH2 (Hs00938918_m1), TBP (Hs00427620_m1), RPLP0 (Hs99999902_m1).	('RPLP0', 'Gene', (278, 283))	('Hs01584024_m1', 'Var', (130, 143))	('MDH', 'molecular_function', 'GO:0018468', ('235', '238'))	('MDH2', 'Gene', (235, 239))	('ESRRA', 'Gene', '2101', (100, 105))	('Hs01551887_m1', 'Var', (62, 75))	('Hs00427620_m1', 'Var', (262, 275))	('ACO2', 'Gene', '50', (168, 172))	('Hs01081865_m1', 'Var', (195, 208))	('ALDOB', 'Gene', '229', (55, 60))	('MDH', 'molecular_function', 'GO:0030060', ('235', '238'))	('OGDH', 'Gene', (189, 193))	('ESRRA', 'Gene', (100, 105))	('ESRRG', 'Gene', '2104', (145, 150))	('Hs00388749_m1', 'Var', (219, 232))	('RPLP0', 'Gene', '6175', (278, 283))	('ALDOB', 'Gene', (55, 60))	('MDH', 'molecular_function', 'GO:0033720', ('235', '238'))	('TBP', 'Gene', (257, 260))	('ALDOC', 'Gene', '230', (78, 83))	('ESRRG', 'Gene', (145, 150))	('ALDOA', 'Gene', (32, 37))	('Hs01067166_g1', 'Var', (107, 120))	('SUCLG1', 'Gene', '8802', (211, 217))	('Hs00938918_m1', 'Var', (241, 254))	('MDH2', 'Gene', '4191', (235, 239))	('ALDOA', 'Gene', '226', (32, 37))	('SUCLG1', 'Gene', (211, 217))	('ESRRB', 'Gene', (123, 128))	('ALDOC', 'Gene', (78, 83))	('Hs00605108_g1', 'Var', (39, 52))	('TBP', 'Gene', '6908', (257, 260))	('Hs99999902_m1', 'Var', (285, 298))	('ESRRB', 'Gene', '2103', (123, 128))	('ACO2', 'Gene', (168, 172))	('Hs00976243_m1', 'Var', (152, 165))	('OGDH', 'Gene', '4967', (189, 193))
23574	30131446	These analyses identified 35 RCC specific genes changes demonstrating a statistically significant inverse correlation between mRNA expression status and DNA promoter methylation status (Figure 2A).	('DNA', 'cellular_component', 'GO:0005574', ('153', '156'))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('methylation', 'biological_process', 'GO:0032259', ('166', '177'))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('changes', 'Var', (48, 55))	('DNA promoter methylation', 'MPA', (153, 177))
23609	30131446	As previously noted, low ESRRG expression was associated with worsened overall survival in the TCGA data.	('low ESRRG', 'Phenotype', 'HP:0025022', (21, 30))	('ESRRG', 'Gene', (25, 30))	('low', 'Var', (21, 24))	('expression', 'MPA', (31, 41))	('overall survival', 'MPA', (71, 87))	('worsened', 'NegReg', (62, 70))	('ESRRG', 'Gene', '2104', (25, 30))
23611	30131446	We sought further insight into the silencing of ESRRG in renal cancer given that its expression had prognostic significance.	('ESRRG', 'Gene', (48, 53))	('silencing', 'Var', (35, 44))	('renal cancer', 'Disease', 'MESH:D007680', (57, 69))	('renal cancer', 'Phenotype', 'HP:0009726', (57, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('ESRRG', 'Gene', '2104', (48, 53))	('renal cancer', 'Disease', (57, 69))
23619	30131446	We confirmed EZH2 knockdown via stable transduction with shRNA (Figure 5E).	('knockdown', 'Var', (18, 27))	('EZH2', 'Gene', (13, 17))	('EZH2', 'Gene', '2146', (13, 17))	('transduction', 'biological_process', 'GO:0009293', ('39', '51'))
23622	30131446	GSK126 reduced H3K27me3 levels consistent with EZH2/PRC2 inhibition (Figure 5G).	('reduced', 'NegReg', (7, 14))	('EZH2', 'Gene', (47, 51))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('GSK126', 'Chemical', 'MESH:C577920', (0, 6))	('GSK126', 'Var', (0, 6))	('H3K27me3', 'Protein', (15, 23))	('EZH2', 'Gene', '2146', (47, 51))
23633	30131446	RCC cell migration as determined by a transwell assay was significantly reduced by the expression of ERR-gamma (Figure 6E and 6F).	('cell migration', 'biological_process', 'GO:0016477', ('4', '18'))	('reduced', 'NegReg', (72, 79))	('expression', 'Var', (87, 97))	('ERR-gamma', 'Gene', (101, 110))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('RCC', 'Disease', (0, 3))	('ERR-gamma', 'Gene', '2104', (101, 110))
23649	30131446	However, several other HIF responsive genes were identified as hypomethylated in RCC, including ADM, TNFAIP6, and SLC16A3.	('ADM', 'Gene', '133', (96, 99))	('hypomethylated', 'Var', (63, 77))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('TNFAIP6', 'Gene', '7130', (101, 108))	('TNFAIP6', 'Gene', (101, 108))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('SLC16A3', 'Gene', (114, 121))	('SLC16A3', 'Gene', '9123', (114, 121))	('ADM', 'Gene', (96, 99))
23650	30131446	HIF signaling is activated in the setting of VHL alterations, the most common tumor initiating event in ccRCC.	('VHL', 'Gene', '7428', (45, 48))	('alterations', 'Var', (49, 60))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('activated', 'PosReg', (17, 26))	('HIF signaling', 'MPA', (0, 13))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('VHL', 'Gene', (45, 48))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('signaling', 'biological_process', 'GO:0023052', ('4', '13'))
23652	30131446	However, further increases within metastatic tumor deposits with corresponding promoter hypomethylation indicate an epigenetic basis for the amplification of HIF signaling with tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('signaling', 'biological_process', 'GO:0023052', ('162', '171'))	('increases', 'PosReg', (17, 26))	('promoter hypomethylation', 'Var', (79, 103))	('tumor deposits', 'Disease', 'MESH:D000079822', (45, 59))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor deposits', 'Disease', (45, 59))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
23655	30131446	demonstrate that inactivation of PBRM1, a gene commonly mutated in ccRCC, promotes HIF signaling in VHL null ccRCC.	('promotes', 'PosReg', (74, 82))	('inactivation', 'Var', (17, 29))	('RCC', 'Disease', (69, 72))	('PBRM1', 'Gene', '55193', (33, 38))	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('signaling', 'biological_process', 'GO:0023052', ('87', '96'))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('VHL', 'Gene', '7428', (100, 103))	('VHL', 'Gene', (100, 103))	('HIF signaling', 'MPA', (83, 96))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('PBRM1', 'Gene', (33, 38))
23659	30131446	PBRM1 mutation) may reveal those HIF target genes critical to tumor development and/or progression.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('mutation', 'Var', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
23669	30131446	Loss of ESRRG has previously been implicated in other malignancies including prostate cancer where it impacts proliferation.	('malignancies', 'Disease', (54, 66))	('ESRRG', 'Gene', '2104', (8, 13))	('prostate cancer', 'Disease', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('impacts', 'Reg', (102, 109))	('proliferation', 'CPA', (110, 123))	('implicated', 'Reg', (34, 44))	('ESRRG', 'Gene', (8, 13))	('malignancies', 'Disease', 'MESH:D009369', (54, 66))	('prostate cancer', 'Disease', 'MESH:D011471', (77, 92))	('prostate cancer', 'Phenotype', 'HP:0012125', (77, 92))	('Loss', 'Var', (0, 4))
23671	30131446	For example, high ESRRG expression is associated with a better prognosis in breast cancer patients.	('high ESRRG', 'Phenotype', 'HP:0003565', (13, 23))	('ESRRG', 'Gene', (18, 23))	('high', 'Var', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('ESRRG', 'Gene', '2104', (18, 23))	('patients', 'Species', '9606', (90, 98))
23677	30131446	Our data demonstrating that ERR-gamma re-expression in RCC cells suppresses invasive phenotypes is consistent with a role for this transcription factor in mesenchymal to epithelial transition as previously reported.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('ERR-gamma', 'Gene', (28, 37))	('RCC', 'Disease', (55, 58))	('transcription factor', 'molecular_function', 'GO:0000981', ('131', '151'))	('transcription', 'biological_process', 'GO:0006351', ('131', '144'))	('mesenchymal to epithelial transition', 'CPA', (155, 191))	('mesenchymal to epithelial transition', 'biological_process', 'GO:0060231', ('155', '191'))	('ERR-gamma', 'Gene', '2104', (28, 37))	('re-expression', 'Var', (38, 51))	('invasive phenotypes', 'CPA', (76, 95))	('suppresses', 'NegReg', (65, 75))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
23681	30131446	In addition, we identified several other genes that were hypermethylated and repressed that have been shown to suppress in vitro tumor phenotypes in RCC cells including PLXNB1, ATP1A, and KCNJ1.	('RCC', 'Disease', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('PLXNB1', 'Gene', (169, 175))	('KCNJ1', 'Gene', (188, 193))	('suppress', 'NegReg', (111, 119))	('hypermethylated', 'Var', (57, 72))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('KCNJ1', 'Gene', '3758', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('PLXNB1', 'Gene', '5364', (169, 175))	('tumor', 'Disease', (129, 134))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
23701	30131446	Collectively, these data provide significant insight into the biology of aggressive RCC and demonstrate a novel role for DNA methylation in the promotion of HIF signaling and invasive phenotypes in renal cancer.	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('aggressive RCC', 'Disease', 'MESH:C538614', (73, 87))	('renal cancer', 'Disease', 'MESH:D007680', (198, 210))	('aggressive RCC', 'Disease', (73, 87))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('HIF signaling', 'MPA', (157, 170))	('signaling', 'biological_process', 'GO:0023052', ('161', '170'))	('DNA methylation', 'biological_process', 'GO:0006306', ('121', '136'))	('renal cancer', 'Disease', (198, 210))	('promotion', 'PosReg', (144, 153))	('renal cancer', 'Phenotype', 'HP:0009726', (198, 210))	('methylation', 'Var', (125, 136))
23726	28793246	Comparative analysis of CD105 expression in the whole cell population at the protein (Figure 1A1 and 1A2) level revealed the highest level of expression in SN12-PM6 and lowest in 786-O.	('SN12-PM6', 'Var', (156, 164))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('CD105', 'Gene', '13805', (24, 29))	('CD105', 'Gene', (24, 29))	('expression', 'MPA', (142, 152))
23766	28793246	Interestingly, stemness genes CXCR-4, NANOG, DLK1, SOX-2, OCT-4, KLF4, and C-MYC were decreased concomitantly upon silencing of CD105 (Figure 5A3).	('CXCR-4', 'molecular_function', 'GO:0038147', ('30', '36'))	('SOX-2', 'Gene', '6657', (51, 56))	('CXCR-4', 'Gene', (30, 36))	('C-MYC', 'Gene', '4609', (75, 80))	('SOX-2', 'Gene', (51, 56))	('C-MYC', 'Gene', (75, 80))	('KLF4', 'Gene', '9314', (65, 69))	('OCT-4', 'Gene', '5460', (58, 63))	('CXCR-4', 'Gene', '7852', (30, 36))	('CD105', 'Gene', '13805', (128, 133))	('silencing', 'Var', (115, 124))	('stemness genes', 'Gene', (15, 29))	('decreased', 'NegReg', (86, 95))	('OCT-4', 'Gene', (58, 63))	('DLK1', 'Gene', '8788', (45, 49))	('NANOG', 'Gene', '79923', (38, 43))	('DLK1', 'Gene', (45, 49))	('KLF4', 'Gene', (65, 69))	('NANOG', 'Gene', (38, 43))	('CD105', 'Gene', (128, 133))
23767	28793246	CD105 knockdown also disables the self-renewal capability of CD105+ cells as assessed by the sphere-formation assay, shown in Figure 5B1 and 5B2.	('CD105', 'Gene', '13805', (61, 66))	('CD105', 'Gene', (61, 66))	('CD105', 'Gene', (0, 5))	('self-renewal capability', 'CPA', (34, 57))	('CD105', 'Gene', '13805', (0, 5))	('disables', 'NegReg', (21, 29))	('formation', 'biological_process', 'GO:0009058', ('100', '109'))	('knockdown', 'Var', (6, 15))	('sphere-formation assay', 'CPA', (93, 115))
23773	28793246	An increase in cell senescence brought on by CD105 silencing likely contributed to the reduced tumor-formation ability of these CD105+-shENG cells (Figures 6B and S4A).	('silencing', 'Var', (51, 60))	('increase', 'PosReg', (3, 11))	('CD105', 'Gene', (128, 133))	('reduced', 'NegReg', (87, 94))	('cell senescence', 'CPA', (15, 30))	('senescence', 'biological_process', 'GO:0010149', ('20', '30'))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('CD105', 'Gene', (45, 50))	('formation', 'biological_process', 'GO:0009058', ('101', '110'))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('CD105', 'Gene', '13805', (45, 50))	('ENG', 'Gene', '2022', (137, 140))	('ENG', 'Gene', (137, 140))	('CD105', 'Gene', '13805', (128, 133))	('tumor', 'Disease', (95, 100))
23775	28793246	As shown in Figure 7A, silencing CD105 increased the sensitivity of these cells to gemcitabine, which was correlated with the downregulation of a set of chemoresistance genes (ABCB1, ABCC1, ABCC2, and ATM) together with deaminases (CDA and AICDA) (Figure 7B).	('downregulation', 'NegReg', (126, 140))	('gemcitabine', 'Chemical', 'MESH:C056507', (83, 94))	('silencing', 'Var', (23, 32))	('CDA', 'Gene', (232, 235))	('ABCB1', 'Gene', (176, 181))	('ABCB1', 'Gene', '5243', (176, 181))	('CDA', 'Gene', '978', (232, 235))	('CD105', 'Gene', '13805', (33, 38))	('ABCC1', 'Gene', '4363', (183, 188))	('AICDA', 'Gene', '57379', (240, 245))	('ABCC2', 'Gene', '1244', (190, 195))	('AICDA', 'Gene', (240, 245))	('ATM', 'Gene', '472', (201, 204))	('sensitivity', 'MPA', (53, 64))	('ABCC2', 'Gene', (190, 195))	('ABCC1', 'Gene', (183, 188))	('CD105', 'Gene', (33, 38))	('CDA', 'Gene', (242, 245))	('increased', 'PosReg', (39, 48))	('CDA', 'Gene', '978', (242, 245))	('ATM', 'Gene', (201, 204))
23796	28793246	CD105 has been found to play a critical role in angiogenesis, as congenital mutation of CD105 leads to hereditary hemorrhagic telangiectasia type I, a syndrome of arteriovenous malformation and telangiectasia.	('CD105', 'Gene', '13805', (88, 93))	('CD105', 'Gene', (88, 93))	('telangiectasia', 'Disease', (194, 208))	('CD105', 'Gene', (0, 5))	('arteriovenous malformation', 'Phenotype', 'HP:0100026', (163, 189))	('hereditary hemorrhagic telangiectasia type I', 'Disease', (103, 147))	('CD105', 'Gene', '13805', (0, 5))	('telangiectasia', 'Phenotype', 'HP:0001009', (194, 208))	('telangiectasia', 'Disease', (126, 140))	('telangiectasia', 'Disease', 'MESH:D013684', (194, 208))	('arteriovenous malformation', 'Disease', 'MESH:D001165', (163, 189))	('arteriovenous malformation', 'Disease', (163, 189))	('telangiectasia', 'Disease', 'MESH:D013684', (126, 140))	('leads to', 'Reg', (94, 102))	('telangiectasia', 'Phenotype', 'HP:0001009', (126, 140))	('angiogenesis', 'biological_process', 'GO:0001525', ('48', '60'))	('mutation', 'Var', (76, 84))	('hereditary hemorrhagic telangiectasia type I', 'Disease', 'MESH:C537140', (103, 147))
23809	28793246	Our findings suggest that overexpressing CDA, C-MYC, or NANOG independently can overcome the loss of CSC functions that resulted from the knockdown or knockout of CD105 (Figure S5).	('CDA', 'Gene', (41, 44))	('knockdown', 'Var', (138, 147))	('C-MYC', 'Gene', '4609', (46, 51))	('CDA', 'Gene', '978', (41, 44))	('CSC functions', 'MPA', (101, 114))	('knockout', 'Var', (151, 159))	('NANOG', 'Gene', '79923', (56, 61))	('C-MYC', 'Gene', (46, 51))	('NANOG', 'Gene', (56, 61))	('CD105', 'Gene', '13805', (163, 168))	('CD105', 'Gene', (163, 168))
23812	28793246	In line with our finding in kidney cancer cell xenografts, shRNA-mediated knockdown of CD105 can also decrease the self-renewal capability of CD105+ cells sorted from ccRCC patient primary tumors (Figure S6).	('kidney cancer', 'Phenotype', 'HP:0009726', (28, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('decrease', 'NegReg', (102, 110))	('kidney cancer', 'Disease', (28, 41))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('ccRCC', 'Phenotype', 'HP:0006770', (167, 172))	('RCC', 'Disease', (169, 172))	('knockdown', 'Var', (74, 83))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('CD105', 'Gene', '13805', (87, 92))	('CD105', 'Gene', '13805', (142, 147))	('patient', 'Species', '9606', (173, 180))	('self-renewal capability', 'CPA', (115, 138))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('tumors', 'Disease', (189, 195))	('kidney cancer', 'Disease', 'MESH:D007680', (28, 41))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('CD105', 'Gene', (142, 147))	('CD105', 'Gene', (87, 92))
23814	28793246	According to the phase I mCRPC trial, TRC105 was found to have a potential effect on the decrease of prostate-specific antigen velocity, which indicates a potential therapeutic role in mCRPC patients.	('TRC105', 'Chemical', 'MESH:C579557', (38, 44))	('patients', 'Species', '9606', (191, 199))	('decrease', 'NegReg', (89, 97))	('TRC105', 'Var', (38, 44))	('decrease of prostate', 'Phenotype', 'HP:0008687', (89, 109))	('prostate-specific antigen velocity', 'MPA', (101, 135))
23816	28793246	Even though the anti-CD105 agent TRC105 was developed as an anti-angiogenic drug, it is promising that it can also serve as an agent targeting the tumor-initiating cells in ccRCC.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('TRC105', 'Var', (33, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (173, 178))	('CD105', 'Gene', (21, 26))	('TRC105', 'Chemical', 'MESH:C579557', (33, 39))	('CD105', 'Gene', '13805', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('RCC', 'Disease', (175, 178))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('RCC', 'Disease', 'MESH:C538614', (175, 178))
23821	28793246	The depleted sites can be subsequently replaced by an unmethylated cytidine in a base excision repair process, thereby demethylating the cytosine in the CpG island.	('base excision repair', 'biological_process', 'GO:0006284', ('81', '101'))	('demethylating', 'Var', (119, 132))	('cytosine', 'Chemical', 'MESH:D003596', (137, 145))	('cytosine', 'MPA', (137, 145))	('cytidine', 'Chemical', 'MESH:D003562', (67, 75))
23837	28793246	Data presented were from knockdown with shEGN1, which is consistent with the results from shENG2 (Figure S3).	('knockdown', 'Var', (25, 34))	('ENG', 'Gene', '2022', (92, 95))	('ENG', 'Gene', (92, 95))	('shEGN1', 'Gene', (40, 46))
23852	28793246	NOD/SCID mice were injected with serial dilutions of cells: 1.0 x 102, 1.0 x 104, and 1.0 x 106, respectively, with five male NOD/SCID mice per dilution.	('NOD', 'Gene', (126, 129))	('NOD', 'Gene', (0, 3))	('SCID', 'Disease', 'MESH:D053632', (130, 134))	('SCID', 'Disease', (130, 134))	('SCID', 'Disease', 'MESH:D053632', (4, 8))	('NOD', 'Gene', '1822', (0, 3))	('1.0 x 104', 'Var', (71, 80))	('SCID', 'Disease', (4, 8))	('1.0 x 106', 'Var', (86, 95))	('NOD', 'Gene', '1822', (126, 129))	('mice', 'Species', '10090', (9, 13))	('mice', 'Species', '10090', (135, 139))
23861	28793246	When the tumor reached 0.5 cm in diameter, one group of mice was administered gemcitabine, 0.015 mg/g/day, via intraperitoneal injection on the first, third, sixth, and ninth day while control mice received intraperitoneal injection with saline.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('0.015 mg/g/day', 'Var', (91, 105))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mice', 'Species', '10090', (56, 60))	('tumor', 'Disease', (9, 14))	('mice', 'Species', '10090', (193, 197))	('saline', 'Chemical', 'MESH:D012965', (238, 244))	('gemcitabine', 'Chemical', 'MESH:C056507', (78, 89))
23877	32316597	Gene set enrichment analysis (GSEA) identified tyrosine metabolism, metabolic pathways, peroxisome, and fatty acid degradation as differentially enriched with the high LRRC19 expression in KIRC cases, which are involved in selenium therapy of clear cell renal cell carcinoma.	('fatty acid degradation', 'biological_process', 'GO:0009062', ('104', '126'))	('LRRC19', 'Gene', '64922', (168, 174))	('tyrosine', 'Chemical', 'MESH:D014443', (47, 55))	('metabolic', 'MPA', (68, 77))	('selenium', 'Chemical', 'MESH:D012643', (223, 231))	('LRRC19', 'Gene', (168, 174))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (243, 274))	('expression', 'MPA', (175, 185))	('peroxisome', 'MPA', (88, 98))	('peroxisome', 'cellular_component', 'GO:0005777', ('88', '98'))	('fatty acid', 'Chemical', 'MESH:D005227', (104, 114))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (243, 274))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (254, 274))	('high', 'Var', (163, 167))	('tyrosine metabolism', 'biological_process', 'GO:0006570', ('47', '66'))	('tyrosine metabolism', 'MPA', (47, 66))	('fatty acid degradation', 'MPA', (104, 126))	('clear cell renal cell carcinoma', 'Disease', (243, 274))	('GSEA', 'Chemical', '-', (30, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (265, 274))
23934	32316597	The transcription levels of GPX3 and DIO1 were significantly lower in KIRC patients than normal control cases in subgroup analysis based on gender, age, tumor grade, and nodal metastasis status (Figure 2d).	('lower', 'NegReg', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('KIRC', 'Var', (70, 74))	('GPX3', 'Gene', '2878', (28, 32))	('patients', 'Species', '9606', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('GPX3', 'Gene', (28, 32))	('DIO1', 'Gene', (37, 41))	('DIO1', 'Gene', '1733', (37, 41))	('transcription levels', 'MPA', (4, 24))	('transcription', 'biological_process', 'GO:0006351', ('4', '17'))
23949	32316597	High expression of GPX3 indicated good prognosis in Pancreatic Adenocarcinoma (PAAD), as well as higher risk in Rectum Adenocarcinoma (READ) and Uterine Corpus Endometrial Carcinoma (UCEC).	('High expression', 'Var', (0, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('Corpus Endometrial Carcinoma', 'Disease', 'MESH:D016889', (153, 181))	('Pancreatic Adenocarcinoma', 'Disease', (52, 77))	('Pancreatic Adenocarcinoma', 'Disease', 'MESH:D000230', (52, 77))	('Rectum Adenocarcinoma', 'Disease', (112, 133))	('Carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (160, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('PAAD', 'Phenotype', 'HP:0006725', (79, 83))	('Rectum Adenocarcinoma', 'Disease', 'MESH:D012004', (112, 133))	('GPX3', 'Gene', (19, 23))	('Corpus Endometrial Carcinoma', 'Disease', (153, 181))	('GPX3', 'Gene', '2878', (19, 23))	('Pancreatic Adenocarcinoma', 'Phenotype', 'HP:0006725', (52, 77))
23956	32316597	Then, we drew Venn diagram to explore intersections among the three datasets, GPX3 association genes, DIO1 association genes, and KIRC most common survival genes (Figure 4b).	('genes', 'Var', (95, 100))	('DIO1', 'Gene', '1733', (102, 106))	('DIO1', 'Gene', (102, 106))	('GPX3', 'Gene', (78, 82))	('GPX3', 'Gene', '2878', (78, 82))
23962	32316597	Our analysis assumes that KIRC patients were generally in a low selenium state, and the gene expression of LRRC19 in KIRCs and adjacent tissues might both be affected by selenium deficiency to some extent.	('LRRC19', 'Gene', (107, 113))	('selenium', 'Chemical', 'MESH:D012643', (170, 178))	('gene expression', 'biological_process', 'GO:0010467', ('88', '103'))	('gene expression', 'MPA', (88, 103))	('deficiency', 'Var', (179, 189))	('selenium', 'Chemical', 'MESH:D012643', (64, 72))	('affected', 'Reg', (158, 166))	('patients', 'Species', '9606', (31, 39))	('LRRC19', 'Gene', '64922', (107, 113))	('selenium', 'MPA', (170, 178))
23981	32316597	We chose hsa04146 Peroxisome and hsa00071 Fatty acid degradation for their highest normalized enrichment score (NES) and FDR value.	('Fatty acid degradation', 'biological_process', 'GO:0009062', ('42', '64'))	('Peroxisome', 'cellular_component', 'GO:0005777', ('18', '28'))	('hsa04146', 'Var', (9, 17))	('Fatty acid degradation', 'MPA', (42, 64))	('Fatty acid', 'Chemical', 'MESH:D005227', (42, 52))	('hsa00071', 'Var', (33, 41))
23985	32316597	In the results of the enrichment analysis, hsa00035 Tyrosine metabolism and hsa01100 Metabolic pathways had high NES scores, which were 1.7930 and 1.7351, respectively.	('hsa00035', 'Var', (43, 51))	('Metabolic', 'Enzyme', (85, 94))	('hsa01100', 'Gene', (76, 84))	('Tyrosine metabolism', 'Enzyme', (52, 71))	('Tyrosine metabolism', 'biological_process', 'GO:0006570', ('52', '71'))	('Tyrosine', 'Chemical', 'MESH:D014443', (52, 60))
23986	32316597	Among them, Module 00043 Thyroid hormone biosynthesis was the intersection of these two pathways, which represents the transformation process of tyrosine to triiodothyronine (T3)/thyroxine (T4).	('triiodothyronine', 'Chemical', 'MESH:D014284', (157, 173))	('Module 00043', 'Var', (12, 24))	('tyrosine', 'Chemical', 'MESH:D014443', (145, 153))	('Thyroid', 'MPA', (25, 32))	('T3', 'Chemical', 'MESH:D014284', (175, 177))	('thyroxine', 'Chemical', 'MESH:D013974', (179, 188))	('hormone biosynthesis', 'biological_process', 'GO:0042446', ('33', '53'))
23999	32316597	In these studies, selenium has a sufficient geographic scientific basis as an adjuvant treatment of cancer, reducing the toxicity of chemotherapeutic drugs, increasing the subject's tolerance to chemotherapeutic drugs, etc.	('selenium', 'Var', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('increasing', 'PosReg', (157, 167))	('toxicity', 'Disease', 'MESH:D064420', (121, 129))	('reducing', 'NegReg', (108, 116))	('toxicity', 'Disease', (121, 129))	('tolerance', 'MPA', (182, 191))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('selenium', 'Chemical', 'MESH:D012643', (18, 26))
24003	32316597	For a cancer patient, mutations of the selenoprotein gene and regulation of selenoprotein gene expression may affect the effects on selenium adjuvant chemoradiotherapy.	('gene expression', 'biological_process', 'GO:0010467', ('90', '105'))	('selenium', 'Chemical', 'MESH:D012643', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('selenoprotein gene', 'Gene', (76, 94))	('patient', 'Species', '9606', (13, 20))	('affect', 'Reg', (110, 116))	('selenoprotein gene', 'Gene', (39, 57))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', (6, 12))	('regulation', 'biological_process', 'GO:0065007', ('62', '72'))
24006	32316597	In gastric cancer, decreased expression of GPX3 was reported as s a poor prognosticator, and GPX3 expression is mediated by genetic and epigenetic alterations caused by promoter hypermethylation.	('GPX3', 'Gene', '2878', (43, 47))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('promoter hypermethylation', 'Var', (169, 194))	('GPX3', 'Gene', (93, 97))	('mediated by', 'Reg', (112, 123))	('GPX3', 'Gene', '2878', (93, 97))	('gastric cancer', 'Disease', (3, 17))	('decreased', 'NegReg', (19, 28))	('GPX3', 'Gene', (43, 47))	('expression', 'MPA', (29, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('expression', 'MPA', (98, 108))
24018	32316597	The loss of chromosomal region 9p24.1-p13.3 is implicated in metastatic clear cell renal cell carcinoma, and LRRC19 was significantly more downregulated in primary tumors with gene copy number loss than in those without it.	('clear cell renal cell carcinoma', 'Disease', (72, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (83, 103))	('LRRC19', 'Gene', '64922', (109, 115))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (72, 103))	('LRRC19', 'Gene', (109, 115))	('gene copy number loss', 'Var', (176, 197))	('chromosomal region', 'cellular_component', 'GO:0098687', ('12', '30'))	('downregulated', 'NegReg', (139, 152))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (72, 103))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
24032	32316597	In the results of the enrichment analysis, Module 00043 Thyroid hormone biosynthesis was the intersection of these two DIO1 related pathways, which represents the transformation process of tyrosine to triiodothyronine (T3)/thyroxine (T4).	('thyroxine', 'Chemical', 'MESH:D013974', (223, 232))	('T3', 'Chemical', 'MESH:D014284', (219, 221))	('DIO1', 'Gene', '1733', (119, 123))	('triiodothyronine', 'Chemical', 'MESH:D014284', (201, 217))	('DIO1', 'Gene', (119, 123))	('Module 00043', 'Var', (43, 55))	('hormone biosynthesis', 'biological_process', 'GO:0042446', ('64', '84'))	('tyrosine', 'Chemical', 'MESH:D014443', (189, 197))
24051	30680959	This work identified multiple predicted protein-damaging variants relevant to the pattern of inherited cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('variants', 'Var', (57, 65))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
24052	30680959	Among these, the proband and an affected brother each had a heterozygous Ala45Thr variant in SDHA, a component of the succinate dehydrogenase (SDH) complex.	('SDHA', 'Gene', '6389', (93, 97))	('SDH', 'Gene', '6390', (93, 96))	('SDH', 'Gene', (143, 146))	('SDHA', 'Gene', (93, 97))	('Ala45Thr', 'SUBSTITUTION', 'None', (73, 81))	('succinate dehydrogenase', 'Gene', '6390', (118, 141))	('succinate dehydrogenase', 'Gene', (118, 141))	('SDH', 'Gene', (93, 96))	('SDH', 'Gene', '6390', (143, 146))	('Ala45Thr', 'Var', (73, 81))
24054	30680959	Integrated analysis of public databases and structural predictions indicated that the two affected individuals also had additional variants in genes including TGFB2, TRAP1, PARP1, and EGF, each potentially relevant to cancer risk alone or in conjunction with the SDHA variant.	('TRAP1', 'Gene', (166, 171))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', (218, 224))	('SDHA', 'Gene', '6389', (263, 267))	('PARP1', 'Gene', '142', (173, 178))	('EGF', 'Gene', '1950', (184, 187))	('PARP1', 'Gene', (173, 178))	('variants', 'Var', (131, 139))	('TGFB2', 'Gene', '7042', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('TGFB2', 'Gene', (159, 164))	('EGF', 'molecular_function', 'GO:0005154', ('184', '187'))	('SDHA', 'Gene', (263, 267))	('EGF', 'Gene', (184, 187))
24055	30680959	In addition, allelic imbalances of PARP1 and TGFB2 were detected in the tumor of the proband.	('PARP1', 'Gene', '142', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('PARP1', 'Gene', (35, 40))	('detected', 'Reg', (56, 64))	('tumor', 'Disease', (72, 77))	('imbalances', 'Phenotype', 'HP:0002172', (21, 31))	('TGFB2', 'Gene', '7042', (45, 50))	('TGFB2', 'Gene', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('allelic imbalances', 'Var', (13, 31))	('imbalance', 'Phenotype', 'HP:0002172', (21, 30))
24061	30680959	This work generally supports the idea that an Ala45Thr substitution in the SDHA (OMIM: 600857) gene is a risk factor, and implicates other potential predisposing factors for a family with a high incidence of renal cancers.	('SDHA', 'Gene', (75, 79))	('renal cancer', 'Phenotype', 'HP:0009726', (208, 220))	('Ala45Thr', 'Var', (46, 54))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('renal cancers', 'Disease', 'MESH:D007680', (208, 221))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('renal cancers', 'Disease', (208, 221))	('SDHA', 'Gene', '6389', (75, 79))	('Ala45Thr', 'SUBSTITUTION', 'None', (46, 54))
24074	30680959	(b) Variants were also required to be predicted to impact the protein sequence derived from any RefSeq transcript, or to be previously reported as pathogenic or likely pathogenic by at least one of the variant effect prediction tools (SIFT, POLYPHEN2, LRT, MutationTaster, MutationAssessor, or CADD) or need to be located in the splicing site (2 bp from exon/intron boundary).	('protein', 'Protein', (62, 69))	('CADD', 'Disease', (294, 298))	('Variants', 'Var', (4, 12))	('splicing', 'biological_process', 'GO:0045292', ('329', '337'))	('SIFT', 'Disease', (235, 239))	('CADD', 'Disease', 'None', (294, 298))	('SIFT', 'Disease', 'None', (235, 239))	('impact', 'Reg', (51, 57))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
24082	30680959	The sequences to test the tumor DNA for SDHA LOH by deletion were CAGTTTGCAAGGGGAAATTACT and AGCATGAACTTACGGAATCTGA.	('SDHA', 'Gene', '6389', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('SDHA', 'Gene', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('deletion', 'Var', (52, 60))
24083	30680959	The sequences of the primers used to check for allelic imbalance in chromosome 1q in the tumor were ATTCACCATTGAGGGCATAGG and ACATAAGCACAGCTCAGAAGG for ADAMTS4 rs41270041, TAGAGGTGACATAGGGACACA and CATACGTCTCATTTGCTGCTTC for ATF6 rs2070151, AGTAGAGTCCAGAGAGGTTACG and GAGCTGAGAATCTTCTGATGGG for PARP1 rs3219143, CATCCATCTGCCTCTCATCTTC and GCCTTTGTTTCCTCTCTGTCT for DISC1 rs821616, GAGGAATCGTTGGCATCCTT and CTAACCGTGCTGGCCTATG for OPN3 rs2273712.	('OPN3', 'Gene', (430, 434))	('rs2273712', 'Mutation', 'rs2273712', (435, 444))	('rs3219143', 'Mutation', 'rs3219143', (301, 310))	('DISC1', 'Gene', '27185', (365, 370))	('DISC1', 'Gene', (365, 370))	('ADAMTS4', 'Gene', '9507', (152, 159))	('ATF6', 'Gene', '22926', (225, 229))	('rs41270041', 'Mutation', 'rs41270041', (160, 170))	('rs41270041', 'Var', (160, 170))	('rs821616', 'Mutation', 'rs821616', (371, 379))	('PARP1', 'Gene', (295, 300))	('tumor', 'Disease', (89, 94))	('OPN3', 'Gene', '23596', (430, 434))	('rs821616', 'Var', (371, 379))	('imbalance', 'Phenotype', 'HP:0002172', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('rs2070151', 'Mutation', 'rs2070151', (230, 239))	('ADAMTS4', 'Gene', (152, 159))	('DISC', 'cellular_component', 'GO:0031264', ('365', '369'))	('chromosome', 'cellular_component', 'GO:0005694', ('68', '78'))	('ATF6', 'Gene', (225, 229))	('PARP1', 'Gene', '142', (295, 300))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
24084	30680959	CBioPortal (Cerami, et al., 2012, http://www.cbioportal.org) was used to access data from the most recent TCGA studies based on frequency of somatic alterations (amplification, mutation, deletion) in SDHx genes (data downloaded on 11/22/2017).	('deletion', 'Var', (187, 195))	('mutation', 'Var', (177, 185))	('SDHx', 'Chemical', '-', (200, 204))	('SDHx', 'Gene', (200, 204))
24087	30680959	The somatic missense variants reported in the relevant TCGA studies were analyzed using Annovar prediction tools, including SIFT, PolyPhen 2.0, MutationAssessor (Wang, et al., 2010; see Supporting Information Data S5).	('SIFT', 'Disease', 'None', (124, 128))	('missense variants', 'Var', (12, 29))	('SIFT', 'Disease', (124, 128))
24102	30680959	This revealed no defined pathogenic variant, but two variants of uncertain significance (VUS): c.133G>A (p. Ala45Thr) in SDHA, which encodes a subunit of the succinate dehydrogenase complex, and c.308C>T (p. Pro103Leu) in RECQL4 (OMIM: 603780), which encodes a RecQ family helicase, were identified.	('succinate dehydrogenase', 'Gene', '6390', (158, 181))	('Pro103Leu', 'SUBSTITUTION', 'None', (208, 217))	('VUS', 'Chemical', '-', (89, 92))	('succinate dehydrogenase complex', 'cellular_component', 'GO:0045281', ('158', '189'))	('succinate dehydrogenase', 'Gene', (158, 181))	('c.308C>T', 'Var', (195, 203))	('succinate dehydrogenase complex', 'cellular_component', 'GO:0045282', ('158', '189'))	('SDHA', 'Gene', (121, 125))	('c.308C>T', 'Mutation', 'rs199543866', (195, 203))	('RECQL4', 'Gene', (222, 228))	('Pro103Leu', 'Var', (208, 217))	('Ala45Thr', 'SUBSTITUTION', 'None', (108, 116))	('c.133G>A', 'Var', (95, 103))	('RECQL4', 'Gene', '9401', (222, 228))	('SDHA', 'Gene', '6389', (121, 125))	('c.133G>A', 'Mutation', 'rs140736646', (95, 103))	('Ala45Thr', 'Var', (108, 116))
24103	30680959	Genetic test results of the patient's brother revealed the same variants in SDHA and RECQL4, and an additional VUS predicted to affect protein sequence: c.1098A>T (p. Glu366Asp) in MEN1 (OMIM: 131100), encoding the menin tumor suppressor associated with multiple endocrine neoplasia.	('SDHA', 'Gene', '6389', (76, 80))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('221', '237'))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('c.1098A>T', 'Mutation', 'rs149383809', (153, 162))	('neoplasia', 'Phenotype', 'HP:0002664', (273, 282))	('MEN1', 'Gene', '4221', (181, 185))	('tumor suppressor', 'biological_process', 'GO:0051726', ('221', '237'))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('VUS', 'Chemical', '-', (111, 114))	('multiple endocrine neoplasia', 'Disease', 'MESH:D009377', (254, 282))	('MEN1', 'Gene', (181, 185))	('RECQL4', 'Gene', '9401', (85, 91))	('Glu366Asp', 'SUBSTITUTION', 'None', (167, 176))	('c.1098A>T', 'Var', (153, 162))	('tumor', 'Disease', (221, 226))	('multiple endocrine neoplasia', 'Disease', (254, 282))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (263, 282))	('RECQL4', 'Gene', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('affect', 'Reg', (128, 134))	('Glu366Asp', 'Var', (167, 176))	('SDHA', 'Gene', (76, 80))	('patient', 'Species', '9606', (28, 35))
24105	30680959	To analyze this data, we integrated several filtering approaches (detailed in Methods) to select variants of interest, in the context of their frequency in the general population, and prior knowledge associating specific genes or variants with hereditary cancers or sporadic RCC (e.g., genes with roles in DNA repair, or functionally related to known oncogenes).	('hereditary cancers', 'Disease', (244, 262))	('RCC', 'Disease', 'MESH:C538614', (275, 278))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('DNA', 'cellular_component', 'GO:0005574', ('306', '309'))	('variants', 'Var', (230, 238))	('DNA repair', 'biological_process', 'GO:0006281', ('306', '316'))	('hereditary cancers', 'Disease', 'MESH:D009369', (244, 262))	('variants', 'Var', (97, 105))	('cancers', 'Phenotype', 'HP:0002664', (255, 262))	('RCC', 'Disease', (275, 278))	('RCC', 'Phenotype', 'HP:0005584', (275, 278))
24106	30680959	Upon analysis of distribution in family members for whom sequence information was available, the variant in RECQL4 identified by initial panel analysis was noted only as potentially damaging (and was identified in two unaffected siblings), and the EGF (OMIM: 131550), variant was only identified as damaging by one prediction program; both were inherited through the father.	('variant', 'Var', (97, 104))	('EGF', 'molecular_function', 'GO:0005154', ('248', '251'))	('RECQL4', 'Gene', (108, 114))	('damaging', 'NegReg', (182, 190))	('RECQL4', 'Gene', '9401', (108, 114))	('EGF', 'Gene', (248, 251))	('EGF', 'Gene', '1950', (248, 251))
24107	30680959	The MEN1 variant, also inherited through the father, was predicted to be damaging, but was not found in the proband, and was found in the two unaffected siblings, suggesting less relevance.	('MEN1', 'Gene', (4, 8))	('variant', 'Var', (9, 16))	('MEN1', 'Gene', '4221', (4, 8))
24108	30680959	The other variants identified in the affected individuals, including missense variants in SDHA, TRAP1, (OMIM: 606219), PARP1 (OMIM: 173870), EGF, and TRIB3 (OMIM: 607898), were predicted to be potentially or likely function damaging.	('SDHA', 'Gene', '6389', (90, 94))	('EGF', 'Gene', '1950', (141, 144))	('EGF', 'molecular_function', 'GO:0005154', ('141', '144'))	('TRIB3', 'Gene', (150, 155))	('SDHA', 'Gene', (90, 94))	('missense variants', 'Var', (69, 86))	('EGF', 'Gene', (141, 144))	('PARP1', 'Gene', '142', (119, 124))	('PARP1', 'Gene', (119, 124))	('TRIB3', 'Gene', '57761', (150, 155))	('TRAP1', 'Gene', (96, 101))
24109	30680959	In addition, a compound heterozygosity was found in TGFB2.	('compound heterozygosity', 'Var', (15, 38))	('TGFB2', 'Gene', (52, 57))	('TGFB2', 'Gene', '7042', (52, 57))
24110	30680959	Based on family segregation analysis, the interaction between the SDHA, TRAP1, TGFB2, and potentially EGF variants was considered of interest (Table 1).	('TRAP1', 'Gene', (72, 77))	('variants', 'Var', (106, 114))	('TGFB2', 'Gene', '7042', (79, 84))	('interaction', 'Interaction', (42, 53))	('EGF', 'Gene', (102, 105))	('TGFB2', 'Gene', (79, 84))	('SDHA', 'Gene', (66, 70))	('EGF', 'Gene', '1950', (102, 105))	('EGF', 'molecular_function', 'GO:0005154', ('102', '105'))	('SDHA', 'Gene', '6389', (66, 70))
24111	30680959	Among the variants, the greatest interest was placed in SDHA, given studies implicating this gene in renal cancer pathogenesis.	('SDHA', 'Gene', '6389', (56, 60))	('variants', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('pathogenesis', 'biological_process', 'GO:0009405', ('114', '126'))	('SDHA', 'Gene', (56, 60))	('renal cancer', 'Disease', (101, 113))	('renal cancer', 'Phenotype', 'HP:0009726', (101, 113))	('renal cancer', 'Disease', 'MESH:D007680', (101, 113))
24114	30680959	Two recent studies have identified the variant SDHA p.Arg31stop, previously defined as the most prevalent mutation observed in SDH-deficient (GISTs) (Miettinen & Lasota, 2014), in renal cancer patients (Carlo, et al., 2018; McEvoy, et al., 2018).	('SDHA', 'Gene', (47, 51))	('patients', 'Species', '9606', (193, 201))	('SDH-deficient', 'Disease', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('SDHA', 'Gene', '6389', (47, 51))	('p.Arg31stop', 'Var', (52, 63))	('GISTs', 'Phenotype', 'HP:0100723', (142, 147))	('renal cancer', 'Disease', (180, 192))	('SDH-deficient', 'Disease', 'MESH:D007153', (127, 140))	('GIST', 'Phenotype', 'HP:0100723', (142, 146))	('p.Arg31stop', 'Mutation', 'rs142441643', (52, 63))	('renal cancer', 'Phenotype', 'HP:0009726', (180, 192))	('renal cancer', 'Disease', 'MESH:D007680', (180, 192))
24115	30680959	Association of SDHx germline variants with thyroid cancer risk has also been described (Neumann, et al., 2004; Ni, et al., 2012), of particular relevance to the proband in this study.	('SDHx', 'Chemical', '-', (15, 19))	('SDHx', 'Gene', (15, 19))	('thyroid cancer', 'Disease', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('variants', 'Var', (29, 37))	('thyroid cancer', 'Phenotype', 'HP:0002890', (43, 57))	('thyroid cancer', 'Disease', 'MESH:D013964', (43, 57))	('Association', 'Interaction', (0, 11))
24116	30680959	The SDHA Ala45Thr (rs140736646) variant is most prevalent in Europeans, with the GnomAD database (Lek, et al., 2016) indicating presence in one in 651 individuals.	('Ala45Thr', 'SUBSTITUTION', 'None', (9, 17))	('SDHA', 'Gene', (4, 8))	('Ala45Thr', 'Var', (9, 17))	('rs140736646', 'Mutation', 'rs140736646', (19, 30))	('rs140736646', 'Var', (19, 30))	('SDHA', 'Gene', '6389', (4, 8))
24123	30680959	SDHA immunochemistry on FFPE sections has been validated for the identification of patients with pathogenic germline variants in SDHA (Korpershoek, et al., 2011).	('SDHA', 'Gene', (0, 4))	('SDHA', 'Gene', '6389', (129, 133))	('variants', 'Var', (117, 125))	('SDHA', 'Gene', '6389', (0, 4))	('patients', 'Species', '9606', (83, 91))	('SDHA', 'Gene', (129, 133))
24125	30680959	To evaluate whether the Ala45Thr variant was associated with changes in expression of these proteins, we used immunohistochemistry (IHC) to assess SDHA and SDHB protein levels in normal renal and RCC tumor tissue from the female proband.	('SDHB', 'Gene', '6390', (156, 160))	('SDHA', 'Gene', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('RCC tumor', 'Disease', 'MESH:C538614', (196, 205))	('SDHB', 'Gene', (156, 160))	('expression', 'MPA', (72, 82))	('Ala45Thr', 'SUBSTITUTION', 'None', (24, 32))	('SDHA', 'Gene', '6389', (147, 151))	('Ala45Thr', 'Var', (24, 32))	('RCC tumor', 'Disease', (196, 205))	('RCC', 'Phenotype', 'HP:0005584', (196, 199))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))
24126	30680959	An SDHB-negative gastrointestinal stromal tumor (GIST) from a patient with a heretozygous germline SDHA 3-base deletion that spans the IVS4/exon 5 junction (c.457-2_c457delAGC) (Belinsky, et al., 2013) and two RCC tumors with clear cell features from a patient with wild-type SDHA and SDHB were used as controls.	('SDHA', 'Gene', (99, 103))	('RCC tumors', 'Disease', 'MESH:C538614', (210, 220))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('SDHA', 'Gene', '6389', (99, 103))	('RCC', 'Phenotype', 'HP:0005584', (210, 213))	('deletion', 'Var', (111, 119))	('SDHB', 'Gene', (285, 289))	('patient', 'Species', '9606', (62, 69))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (17, 47))	('SDHA', 'Gene', (276, 280))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (17, 47))	('patient', 'Species', '9606', (253, 260))	('SDHA', 'Gene', '6389', (276, 280))	('GIST', 'Phenotype', 'HP:0100723', (49, 53))	('SDHB', 'Gene', '6390', (3, 7))	('gastrointestinal stromal tumor', 'Disease', (17, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('c.457-2_c457delAGC', 'Mutation', 'c.457-2_C457delAGC', (157, 175))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('SDHB', 'Gene', '6390', (285, 289))	('SDHB', 'Gene', (3, 7))	('RCC tumors', 'Disease', (210, 220))
24132	30680959	Interestingly, while the loss of SDHB protein expression detected by IHC is associated with pathogenic SDHA variants, the tumor from the proband had the characteristics of a clear cell carcinoma without additional features typically associated with SDH-deficient RCC, such as eosinophilic cytoplasm with intracytoplasmic vacuolations and inclusions (Gill, et al., 2014, 2011; Udager & Mehra, 2016).	('carcinoma', 'Disease', (185, 194))	('SDH-deficient RCC', 'Disease', (249, 266))	('eosinophilic', 'Disease', (276, 288))	('SDHB', 'Gene', (33, 37))	('eosinophilic', 'Disease', 'MESH:D004802', (276, 288))	('tumor', 'Disease', (122, 127))	('SDHA', 'Gene', (103, 107))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('carcinoma', 'Disease', 'MESH:D002277', (185, 194))	('cytoplasm', 'cellular_component', 'GO:0005737', ('289', '298'))	('loss', 'NegReg', (25, 29))	('SDHA', 'Gene', '6389', (103, 107))	('protein', 'Protein', (38, 45))	('RCC', 'Phenotype', 'HP:0005584', (263, 266))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('expression', 'MPA', (46, 56))	('SDHB', 'Gene', '6390', (33, 37))	('SDH-deficient RCC', 'Disease', 'MESH:C538614', (249, 266))	('variants', 'Var', (108, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
24134	30680959	Sequence analysis of an amplicon encompassing the mutated amino acid (Ala45/Ala3) in the germline and tumor DNA from the proband revealed no loss of heterozygosity (LOH) by deletion of the wild-type allele in the tumor (see Supporting Information Data S4).	('tumor', 'Disease', (213, 218))	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('deletion', 'Var', (173, 181))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Ala45', 'Chemical', '-', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('Ala3', 'Chemical', '-', (76, 80))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
24136	30680959	We further explored in TCGA the profile of SDHA alterations (Figure 4a) in the various forms of RCC (clear cell [KIRC], papillary [KIRP], and chromophobe [KICH]), and in other cancers observed in the proband family (including pancreatic adenocarcinoma [PAAD], glioblastoma [GBM], and thyroid cancer [THCA]; note, basal cell carcinoma [BCC] is not represented in TCGA).	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('glioblastoma', 'Disease', 'MESH:D005909', (260, 272))	('SDHA', 'Gene', '6389', (43, 47))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('thyroid cancer', 'Disease', 'MESH:D013964', (284, 298))	('cancers', 'Disease', (176, 183))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (313, 333))	('glioblastoma', 'Disease', (260, 272))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (226, 251))	('glioblastoma', 'Phenotype', 'HP:0012174', (260, 272))	('thyroid cancer', 'Phenotype', 'HP:0002890', (284, 298))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RCC', 'Disease', (96, 99))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (313, 333))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (226, 251))	('pancreatic adenocarcinoma', 'Disease', (226, 251))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('basal cell carcinoma', 'Disease', (313, 333))	('alterations', 'Var', (48, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('thyroid cancer', 'Disease', (284, 298))	('SDHA', 'Gene', (43, 47))
24137	30680959	In KICH, mutations in SDHA were observed in five of 66 cases.	('SDHA', 'Gene', (22, 26))	('mutations', 'Var', (9, 18))	('SDHA', 'Gene', '6389', (22, 26))	('observed', 'Reg', (32, 40))
24138	30680959	Low frequencies of SDHA alterations were also observed GBM, PAAD, and THCA (Figure 4a).	('alterations', 'Var', (24, 35))	('GBM', 'Disease', (55, 58))	('SDHA', 'Gene', '6389', (19, 23))	('PAAD', 'Disease', (60, 64))	('SDHA', 'Gene', (19, 23))	('THCA', 'Disease', (70, 74))
24140	30680959	Although mutations in SDHA were observed in KICH, no mutations were reported in the other three SDHx genes, although some SDHD amplifications were detected.	('SDHA', 'Gene', (22, 26))	('mutations', 'Var', (9, 18))	('SDHA', 'Gene', '6389', (22, 26))	('SDHD', 'Gene', (122, 126))	('SDHD', 'Gene', '6392', (122, 126))	('SDHx', 'Chemical', '-', (96, 100))
24141	30680959	In contrast, mutations and/or copy number variations were present at low levels in both KIRC and KIRP, for all SDHx genes.	('SDHx', 'Gene', (111, 115))	('copy number variations', 'Var', (30, 52))	('SDHx', 'Chemical', '-', (111, 115))
24142	30680959	A schematic distribution of SDHA missense variants in cbioportal.org (Figure 4c) indicates most are located close to or within either the FAD-binding domain or the C-terminal fumarate reductase domain.	('missense variants', 'Var', (33, 50))	('SDHA', 'Gene', (28, 32))	('FAD', 'Gene', (138, 141))	('FAD-binding', 'molecular_function', 'GO:0071949', ('138', '149'))	('FAD', 'Gene', '675', (138, 141))	('SDHA', 'Gene', '6389', (28, 32))
24143	30680959	Analysis of the missense mutations in TCGA using Annovar predicted 15 of the 16 somatic mutations was damaging through the consensus of multiple prediction programs (also see Supporting Information Data S5; cancer types relevant to the proband's personal and family history were included in the analysis).	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('missense mutations', 'Var', (16, 34))	('cancer', 'Disease', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('TCGA', 'Gene', (38, 42))
24147	30680959	The sum of this analysis suggests that the Ala45Thr variant is plausibly pathogenic, however, further evaluation is needed to support pathogenicity.	('pathogenic', 'Reg', (73, 83))	('Ala45Thr', 'Var', (43, 51))	('Ala45Thr', 'SUBSTITUTION', 'None', (43, 51))
24148	30680959	Variants in TGFB2 and PARP1 were found in the proband and her affected brother, but not in the two unaffected siblings.	('Variants', 'Var', (0, 8))	('found', 'Reg', (33, 38))	('PARP1', 'Gene', '142', (22, 27))	('PARP1', 'Gene', (22, 27))	('TGFB2', 'Gene', '7042', (12, 17))	('TGFB2', 'Gene', (12, 17))
24152	30680959	Polymorphisms in TGFB2 have been associated with end-stage renal disease (Ki, et al., 2015).	('end-stage renal disease', 'Phenotype', 'HP:0003774', (49, 72))	('Polymorphisms', 'Var', (0, 13))	('TGFB2', 'Gene', '7042', (17, 22))	('TGFB2', 'Gene', (17, 22))	('associated', 'Reg', (33, 43))	('end-stage renal disease', 'Disease', (49, 72))	('end-stage renal disease', 'Disease', 'MESH:D007676', (49, 72))	('renal disease', 'Phenotype', 'HP:0000112', (59, 72))
24154	30680959	The PARP1 variant Thr124Ala was inherited from the father (diagnosed with basal cell cancer at 78, and whose mother had brain cancer at 74).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Thr124Ala', 'Var', (18, 27))	('brain cancer', 'Disease', 'MESH:D001932', (120, 132))	('basal cell cancer', 'Disease', (74, 91))	('brain cancer', 'Phenotype', 'HP:0030692', (120, 132))	('basal cell cancer', 'Disease', 'MESH:D002280', (74, 91))	('basal cell cancer', 'Phenotype', 'HP:0002671', (74, 91))	('brain cancer', 'Disease', (120, 132))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('PARP1', 'Gene', '142', (4, 9))	('Thr124Ala', 'SUBSTITUTION', 'None', (18, 27))	('PARP1', 'Gene', (4, 9))
24157	30680959	T124 is located in the C125C128H159C162 zinc finger ZnF2 which strongly interacts with nicked or gapped DNA during the activation by genotoxic stress that results in cleavage of the ADP-ribose moiety from NAD+ to generate poly(ADP-ribosyl)ation of specific nuclear acceptor proteins, including histones, DNA polymerases, and PARP1 itself (Bossak, et al., 2015; Eustermann, et al., 2011).	('T124', 'Var', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('304', '307'))	('ADP', 'Chemical', 'MESH:D000244', (227, 230))	('generate', 'PosReg', (213, 221))	('histones', 'Protein', (294, 302))	('ZnF2', 'Gene', '7549', (52, 56))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('PARP1', 'Gene', '142', (325, 330))	('ADP', 'Chemical', 'MESH:D000244', (182, 185))	('ZnF2', 'Gene', (52, 56))	('cleavage', 'MPA', (166, 174))	('NAD+', 'Chemical', 'MESH:D009243', (205, 209))	('PARP1', 'Gene', (325, 330))	('ribose', 'Chemical', 'MESH:D012266', (186, 192))	('C125C128H159C162', 'Var', (23, 39))	('interacts', 'Interaction', (72, 81))
24158	30680959	Interestingly, comparative Sanger analysis of the DNA from blood and tumor DNA at the positions of rs7587470101 in TGFB2, and rs139924814 and rs3219143 in PARP1, revealed an over-representation of the paternally inherited allele in the tumor (Figure 5).	('PARP1', 'Gene', (155, 160))	('rs139924814', 'Var', (126, 137))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('over-representation', 'PosReg', (174, 193))	('TGFB2', 'Gene', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('rs3219143', 'Var', (142, 151))	('PARP1', 'Gene', '142', (155, 160))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('rs7587470101', 'DBSNP_MENTION', 'None', (99, 111))	('tumor', 'Disease', (69, 74))	('rs7587470101', 'Var', (99, 111))	('TGFB2', 'Gene', '7042', (115, 120))	('rs139924814', 'Mutation', 'rs139924814', (126, 137))	('rs3219143', 'Mutation', 'rs3219143', (142, 151))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (236, 241))
24162	30680959	The proband and her unaffected sister each carried an epidermal growth factor (EGF) variant, Ser16Thr, classified as PP2 (supporting pathogenic) for missense in a gene that has a low rate in benign missense variation, and in which missense variants are a common mechanism of disease in InterVar (Supporting Information Data S1).	('epidermal growth factor', 'Gene', '1950', (54, 77))	('EGF', 'Gene', '1950', (79, 82))	('missense variants', 'Var', (231, 248))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('54', '77'))	('EGF', 'molecular_function', 'GO:0005154', ('79', '82'))	('missense', 'Var', (149, 157))	('PP2', 'Gene', (117, 120))	('EGF', 'Gene', (79, 82))	('PP2', 'Gene', '4888', (117, 120))	('Ser16Thr', 'Var', (93, 101))	('Ser16Thr', 'SUBSTITUTION', 'None', (93, 101))	('epidermal growth factor', 'Gene', (54, 77))	('Ser', 'cellular_component', 'GO:0005790', ('93', '96'))
24164	30680959	For both predictions, an amino acid change at residue 16 plausibly affects insertion of the pro-EGF precursor into the ER, and hence levels of secretion, which could cause multiple biological consequences, especially in the kidney that expresses high levels of EGF mRNA (Fisher, Salido, & Barajas, 1989).	('EGF', 'molecular_function', 'GO:0005154', ('261', '264'))	('affects', 'Reg', (67, 74))	('amino acid change', 'Var', (25, 42))	('high levels of EGF', 'Phenotype', 'HP:0003496', (246, 264))	('levels of secretion', 'MPA', (133, 152))	('EGF', 'molecular_function', 'GO:0005154', ('96', '99'))	('insertion', 'MPA', (75, 84))	('EGF', 'Gene', (96, 99))	('EGF', 'Gene', (261, 264))	('cause', 'Reg', (166, 171))	('secretion', 'biological_process', 'GO:0046903', ('143', '152'))	('EGF', 'Gene', '1950', (96, 99))	('EGF', 'Gene', '1950', (261, 264))
24166	30680959	The two affected siblings and the unaffected brother inherited a maternal TRAP1 variant, Thr535Ser, with a PM1 classification.	('TRAP1', 'Gene', (74, 79))	('Ser', 'cellular_component', 'GO:0005790', ('95', '98'))	('PM1', 'Gene', (107, 110))	('PM1', 'Gene', '8834', (107, 110))	('Thr535Ser', 'SUBSTITUTION', 'None', (89, 98))	('Thr535Ser', 'Var', (89, 98))
24167	30680959	Consistent with the African descent of the mother noted in the SDHA variant analysis (see Supporting Information Appendix S1), this variant was overrepresented in African populations (Table 1).	('SDHA', 'Gene', '6389', (63, 67))	('SDHA', 'Gene', (63, 67))	('variant', 'Var', (132, 139))
24169	30680959	The Thr535Ser variant was recently described in a patient with Parkinson's disease and characterized as damaging by functionality prediction and destabilizing by structural assessment (Fitzgerald, et al., 2017).	("Parkinson's disease", 'Disease', 'MESH:D010300', (63, 82))	('Ser', 'cellular_component', 'GO:0005790', ('10', '13'))	("Parkinson's disease", 'Disease', (63, 82))	('Thr535Ser', 'SUBSTITUTION', 'None', (4, 13))	('Thr535Ser', 'Var', (4, 13))	('patient', 'Species', '9606', (50, 57))
24170	30680959	Importantly, an examination of the X-ray crystallographic structure of human TRAP1 indicates that the Thr535Ser substitution would disrupt hydrophobic interactions with the side chains of Arg449, Ile452, Val453, and Leu468 that stabilize the middle domain of the protein (Figure 6a).	('Leu468', 'Var', (216, 222))	('Ile452', 'Chemical', '-', (196, 202))	('protein', 'cellular_component', 'GO:0003675', ('263', '270'))	('Leu468', 'Chemical', '-', (216, 222))	('Arg449', 'Chemical', '-', (188, 194))	('Arg449', 'Var', (188, 194))	('TRAP1', 'Gene', (77, 82))	('Ile452', 'Var', (196, 202))	('disrupt', 'NegReg', (131, 138))	('Val453', 'Var', (204, 210))	('Thr535Ser', 'SUBSTITUTION', 'None', (102, 111))	('Thr535Ser', 'Var', (102, 111))	('hydrophobic interactions', 'MPA', (139, 163))	('Ser', 'cellular_component', 'GO:0005790', ('108', '111'))	('Val453', 'Chemical', '-', (204, 210))	('human', 'Species', '9606', (71, 76))
24171	30680959	Further, Leu468 is particularly notable as a variant at an adjacent residue, Arg469His, has been identified as European founder mutation in CAKUT (Congenital Abnormalities of the Kidney and Urinary Tract) which accounts for approximately half of children with chronic kidney disease and is the most frequent cause of end-stage renal disease in children in the US (Saisawat, et al., 2014).	('renal disease', 'Phenotype', 'HP:0000112', (327, 340))	('end-stage renal disease', 'Phenotype', 'HP:0003774', (317, 340))	('Arg469His', 'SUBSTITUTION', 'None', (77, 86))	('children', 'Species', '9606', (344, 352))	('end-stage renal disease', 'Disease', 'MESH:D007676', (317, 340))	('Leu468', 'Var', (9, 15))	('Arg469His', 'Var', (77, 86))	('chronic kidney disease', 'Disease', (260, 282))	('Abnormalities of the Kidney', 'Phenotype', 'HP:0000077', (158, 185))	('children', 'Species', '9606', (246, 254))	('Congenital Abnormalities of the Kidney', 'Disease', (147, 185))	('Leu468', 'Chemical', '-', (9, 15))	('kidney disease', 'Phenotype', 'HP:0000112', (268, 282))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (260, 282))	('Congenital Abnormalities of the Kidney', 'Disease', 'MESH:D007674', (147, 185))	('end-stage renal disease', 'Disease', (317, 340))	('cause', 'Reg', (308, 313))	('chronic kidney disease', 'Disease', 'MESH:D051436', (260, 282))
24175	30680959	Thr535 is closer to the bound client in the model than Arg469, associated with CAKUT.	('Thr535', 'Chemical', '-', (0, 6))	('CAKUT', 'Disease', (79, 84))	('Arg469', 'Chemical', '-', (55, 61))	('Arg469', 'Var', (55, 61))	('Thr535', 'Var', (0, 6))
24176	30680959	In addition to the variants reported above, the affected brother inherited from his mother an TRIB3 R36stop variant, also overrepresented in African population (Table 1).	('R36stop', 'SUBSTITUTION', 'None', (100, 107))	('TRIB3', 'Gene', (94, 99))	('TRIB3', 'Gene', '57761', (94, 99))	('R36stop', 'Var', (100, 107))
24179	30680959	The variant Q84R has been linked to metabolic disease and predisposition to diabetes and atherosclerosis (Prudente & Trischitta, 2015).	('metabolic disease', 'Disease', (36, 53))	('atherosclerosis', 'Phenotype', 'HP:0002621', (89, 104))	('Q84R', 'Var', (12, 16))	('metabolic disease', 'Disease', 'MESH:D008659', (36, 53))	('linked', 'Reg', (26, 32))	('Q84R', 'Mutation', 'rs2295490', (12, 16))	('diabetes and atherosclerosis', 'Disease', 'MESH:D050197', (76, 104))
24180	30680959	In this study of a female proband affected with thyroid and renal cancers, with a pedigree enriched for incidence of kidney and other cancers, we have identified several gene variants that are plausibly linked to kidney cancer risk.	('kidney cancer', 'Disease', 'MESH:D007680', (213, 226))	('variants', 'Var', (175, 183))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('thyroid and renal cancers', 'Disease', 'MESH:D007680', (48, 73))	('kidney cancer', 'Phenotype', 'HP:0009726', (213, 226))	('cancers', 'Disease', (134, 141))	('kidney cancer', 'Disease', (213, 226))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('linked', 'Reg', (203, 209))	('renal cancer', 'Phenotype', 'HP:0009726', (60, 72))
24181	30680959	Among these, several categories of data support the potential significance of a rare, germline SDHA Ala45Thr variant in the DNA of the proband and her affected brother.	('SDHA', 'Gene', (95, 99))	('variant', 'Var', (109, 116))	('DNA', 'cellular_component', 'GO:0005574', ('124', '127'))	('Ala45Thr', 'SUBSTITUTION', 'None', (100, 108))	('SDHA', 'Gene', '6389', (95, 99))	('Ala45Thr', 'Var', (100, 108))
24183	30680959	However, further evidence is required to assign a confident classification of pathogenicity to the SDHA Ala45Thr variant.	('SDHA', 'Gene', (99, 103))	('variant', 'Var', (113, 120))	('SDHA', 'Gene', '6389', (99, 103))	('Ala45Thr', 'SUBSTITUTION', 'None', (104, 112))	('Ala45Thr', 'Var', (104, 112))
24184	30680959	Pathogencity could be supported by evaluations that include assessment of functional impact, and variant segregation with disease (renal cancer or other) in the descendents of the studied proband or other families carrying the variant.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('renal cancer', 'Disease', (131, 143))	('renal cancer', 'Phenotype', 'HP:0009726', (131, 143))	('variant segregation', 'Var', (97, 116))	('renal cancer', 'Disease', 'MESH:D007680', (131, 143))	('variant', 'Var', (227, 234))
24185	30680959	In the proband and affected brother, the Thr124Ala variant in PARP1 and the Thr535Ser variant in TRAP1 are of particular interest because like SDHA, these proteins impact mitochondrial function, and defects in PARP1 and TRAP1 have been associated with cancer risk or CAKUT.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('Thr535Ser', 'SUBSTITUTION', 'None', (76, 85))	('Thr535Ser', 'Var', (76, 85))	('SDHA', 'Gene', (143, 147))	('PARP1', 'Gene', '142', (62, 67))	('PARP1', 'Gene', (210, 215))	('SDHA', 'Gene', '6389', (143, 147))	('associated', 'Reg', (236, 246))	('TRAP1', 'Gene', (220, 225))	('defects', 'Var', (199, 206))	('Ser', 'cellular_component', 'GO:0005790', ('82', '85'))	('cancer', 'Disease', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('Thr124Ala', 'SUBSTITUTION', 'None', (41, 50))	('TRAP1', 'Gene', (97, 102))	('PARP1', 'Gene', (62, 67))	('Thr124Ala', 'Var', (41, 50))	('PARP1', 'Gene', '142', (210, 215))	('mitochondrial function', 'MPA', (171, 193))	('impact', 'Reg', (164, 170))
24186	30680959	Finally, other variants that may serve as primary or modifying factors for kidney cancer risk were identified in the proband, the brother, or both.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('kidney cancer', 'Disease', (75, 88))	('kidney cancer', 'Disease', 'MESH:D007680', (75, 88))	('variants', 'Var', (15, 23))	('kidney cancer', 'Phenotype', 'HP:0009726', (75, 88))
24188	30680959	Comprehensive reviews of SDHA variants over a large disease spectrum in various databases have been published (Bannon, et al., 2017; Casey, et al., 2017; Evenepoel, et al., 2015).	('variants', 'Var', (30, 38))	('SDHA', 'Gene', '6389', (25, 29))	('SDHA', 'Gene', (25, 29))
24189	30680959	To date, there have been few reports of SDHA mutations in sporadic renal cancer: for example, a 17 kbp homozygous deletion leading to the loss of 9 exons of SDHA (Yakirevich, et al., 2015), a heterozygous germline mutation in the initiation codon (Jiang, et al., 2015), a splice site deletion (Ozluk, et al., 2015), and a combined germline/somatic biallelic loss (McEvoy, et al., 2018).	('loss', 'NegReg', (138, 142))	('mutations', 'Var', (45, 54))	('SDHA', 'Gene', (157, 161))	('loss', 'NegReg', (358, 362))	('sporadic renal cancer', 'Disease', 'MESH:D007680', (58, 79))	('renal cancer', 'Phenotype', 'HP:0009726', (67, 79))	('SDHA', 'Gene', '6389', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('sporadic renal cancer', 'Disease', (58, 79))	('SDHA', 'Gene', (40, 44))	('SDHA', 'Gene', '6389', (157, 161))
24190	30680959	The SDHA Ala45Thr variant was previously reported in a case of thoracic paraganglioma (Casey, et al., 2017) but was largely uncharacterized.	('Ala45Thr', 'SUBSTITUTION', 'None', (9, 17))	('reported', 'Reg', (41, 49))	('SDHA', 'Gene', (4, 8))	('Ala45Thr', 'Var', (9, 17))	('paraganglioma', 'Phenotype', 'HP:0002668', (72, 85))	('thoracic paraganglioma', 'Disease', 'MESH:D010235', (63, 85))	('thoracic paraganglioma', 'Disease', (63, 85))	('SDHA', 'Gene', '6389', (4, 8))	('variant', 'Var', (18, 25))
24191	30680959	Another rare variant, at the adjacent position in the primary structure (Lys46Glu), has been reported in a case of abdominal paraganglioma (Casey, et al., 2017).	('Lys46Glu', 'SUBSTITUTION', 'None', (73, 81))	('abdominal paraganglioma', 'Disease', 'MESH:D010235', (115, 138))	('Lys46Glu', 'Var', (73, 81))	('abdominal paraganglioma', 'Disease', (115, 138))	('paraganglioma', 'Phenotype', 'HP:0002668', (125, 138))
24192	30680959	The presence of the SDHA variant in healthy individuals (mother, unaffected brother) suggested that this variant may be considered as incompletely penetrant, rather than strongly predisposing.	('SDHA', 'Gene', (20, 24))	('SDHA', 'Gene', '6389', (20, 24))	('variant', 'Var', (25, 32))
24193	30680959	Low penetrance of SDHA variants with carriers escaping the development of clinical symptoms has been suggested (Casey, et al., 2017; Korpershoek, et al., 2011).	('variants', 'Var', (23, 31))	('SDHA', 'Gene', (18, 22))	('SDHA', 'Gene', '6389', (18, 22))
24195	30680959	In a study of SDHx, in 85 tumors of various types with information on the nature of the second hit, inactivation of the wild-type allele by loss of heterozygosity and somatic mutations occurred with frequency of 73% and 14%, respectively (Evenepoel, et al., 2015).	('inactivation', 'NegReg', (100, 112))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('SDHx', 'Chemical', '-', (14, 18))	('mutations', 'Var', (175, 184))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('loss', 'NegReg', (140, 144))	('tumors', 'Disease', (26, 32))
24196	30680959	In the case of SDH-deficient renal carcinomas, a damaging variant in a SDHx gene seems to most commonly be the cause of lost expression of SDHB (Gill, et al., 2014), enforcing the conclusion that Ala45Thr is a plausible risk factor.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('lost', 'NegReg', (120, 124))	('SDHB', 'Gene', '6390', (139, 143))	('SDHx', 'Chemical', '-', (71, 75))	('Ala45Thr', 'SUBSTITUTION', 'None', (196, 204))	('SDHB', 'Gene', (139, 143))	('SDHx', 'Gene', (71, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (35, 45))	('Ala45Thr', 'Var', (196, 204))	('expression', 'MPA', (125, 135))	('renal carcinomas', 'Phenotype', 'HP:0005584', (29, 45))	('variant', 'Var', (58, 65))	('SDH-deficient renal carcinomas', 'Disease', 'MESH:C538614', (15, 45))	('SDH-deficient renal carcinomas', 'Disease', (15, 45))
24198	30680959	In this context, the TRAP1 and PARP1 variants are of particular interest.	('variants', 'Var', (37, 45))	('TRAP1', 'Gene', (21, 26))	('PARP1', 'Gene', (31, 36))	('PARP1', 'Gene', '142', (31, 36))
24200	30680959	TRAP1 can decrease SDH enzymatic activity, thus resulting in high concentration of succinate, and contributing to tumor cell survival in the stress conditions of neoplastic growth (Masgras, et al., 2017).	('high concentration of succinate', 'MPA', (61, 92))	('SDH', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('TRAP1', 'Var', (0, 5))	('resulting in', 'Reg', (48, 60))	('decrease', 'NegReg', (10, 18))	('tumor', 'Disease', (114, 119))	('high concentration of succinate', 'Phenotype', 'HP:0020149', (61, 92))	('SDH', 'Gene', '6390', (19, 22))	('contributing', 'Reg', (98, 110))	('succinate', 'Chemical', 'MESH:D019802', (83, 92))
24201	30680959	Our structural characterization of the TRAP1 variant Thr535Ser suggests that it potentially affects the chaperone activity of TRAP1, involved in quality control of matrix proteins.	('TRAP1', 'Gene', (39, 44))	('affects', 'Reg', (92, 99))	('chaperone activity', 'biological_process', 'GO:0006457', ('104', '122'))	('chaperone activity', 'biological_process', 'GO:0051131', ('104', '122'))	('chaperone activity', 'biological_process', 'GO:0065003', ('104', '122'))	('chaperone activity', 'molecular_function', 'GO:0044183', ('104', '122'))	('chaperone activity', 'molecular_function', 'GO:0051082', ('104', '122'))	('chaperone activity', 'MPA', (104, 122))	('TRAP1', 'Gene', (126, 131))	('Thr535Ser', 'Var', (53, 62))	('Thr535Ser', 'SUBSTITUTION', 'None', (53, 62))	('chaperone activity', 'molecular_function', 'GO:0003754', ('104', '122'))	('Ser', 'cellular_component', 'GO:0005790', ('59', '62'))
24202	30680959	Interestingly, the undetectable activity of SDHB in the renal tumor-derived cell line UOK269, carrying the SDHB Arg46Gln variant, has been linked to the disrupted binding to another co-chaperone, HSC20 (Saxena, et al., 2016).	('HSC20', 'Gene', (196, 201))	('disrupted', 'NegReg', (153, 162))	('SDHB', 'Gene', '6390', (44, 48))	('SDHB', 'Gene', (107, 111))	('undetectable', 'NegReg', (19, 31))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('binding', 'molecular_function', 'GO:0005488', ('163', '170'))	('SDHB', 'Gene', (44, 48))	('binding', 'Interaction', (163, 170))	('Arg46Gln', 'SUBSTITUTION', 'None', (112, 120))	('Arg46Gln', 'Var', (112, 120))	('UOK269', 'CellLine', 'CVCL:B686', (86, 92))	('renal tumor', 'Disease', 'MESH:D007674', (56, 67))	('SDHB', 'Gene', '6390', (107, 111))	('HSC20', 'Gene', '150274', (196, 201))	('renal tumor', 'Phenotype', 'HP:0009726', (56, 67))	('HSC', 'cellular_component', 'GO:0035301', ('196', '199'))	('renal tumor', 'Disease', (56, 67))
24203	30680959	Of further interest, the paternally inherited PARP1 Thr124Ala was shared by the two affected siblings.	('PARP1', 'Gene', (46, 51))	('Thr124Ala', 'SUBSTITUTION', 'None', (52, 61))	('Thr124Ala', 'Var', (52, 61))	('PARP1', 'Gene', '142', (46, 51))
24205	30680959	In its repair function, PARP1 becomes activated after binding to single- and double-stranded breaks through the zinc fingers ZnF1 and ZnF2, where Thr124 is located.	('PARP1', 'Gene', (24, 29))	('single-', 'Var', (65, 72))	('binding', 'molecular_function', 'GO:0005488', ('54', '61'))	('Thr124', 'Chemical', '-', (146, 152))	('ZnF2', 'Gene', (134, 138))	('ZnF2', 'Gene', '7549', (134, 138))	('activated', 'PosReg', (38, 47))	('PARP1', 'Gene', '142', (24, 29))	('binding', 'Interaction', (54, 61))	('ZnF1', 'Gene', (125, 129))
24208	30680959	Response to ROS-associated DNA damage may be greater in the affected siblings who inherited the paternal Thr124Ala PARP1 variant than in the unaffected mother.	('PARP1', 'Gene', '142', (115, 120))	('Response to ROS', 'biological_process', 'GO:0000302', ('0', '15'))	('greater', 'PosReg', (45, 52))	('PARP1', 'Gene', (115, 120))	('Response', 'MPA', (0, 8))	('Thr124Ala', 'SUBSTITUTION', 'None', (105, 114))	('ROS', 'Chemical', '-', (12, 15))	('Thr124Ala', 'Var', (105, 114))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))
24209	30680959	The tumor of the proband presented an allelic imbalance with over-representation of the Thr124Ala allele.	('tumor', 'Disease', (4, 9))	('Thr124Ala', 'SUBSTITUTION', 'None', (88, 97))	('imbalance', 'Phenotype', 'HP:0002172', (46, 55))	('over-representation', 'PosReg', (61, 80))	('Thr124Ala', 'Var', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
24211	30680959	Interestingly, mutations and allelic imbalance were found to be two mechanisms targeting PARP1 in diffuse large B cell lymphomas (de Miranda, et al., 2013), which may be relevant for the proband and her affected brother.	('B cell lymphomas', 'Disease', (112, 128))	('lymphomas', 'Phenotype', 'HP:0002665', (119, 128))	('mutations', 'Var', (15, 24))	('imbalance', 'Phenotype', 'HP:0002172', (37, 46))	('large B cell', 'Phenotype', 'HP:0005404', (106, 118))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (112, 128))	('targeting', 'Reg', (79, 88))	('B cell lymphomas', 'Disease', 'MESH:D016393', (112, 128))	('PARP1', 'Gene', '142', (89, 94))	('PARP1', 'Gene', (89, 94))
24212	30680959	TRIB3 has been proposed to act as guardian of the genome by protection of nuclear DNA from cytidine deamination by APOBEC3A (Aynaud, et al., 2012), Speculatively, considering this proposed role, response to succinate accumulation may be even further altered in the brother carrying the early truncating variant TRIB3 R36stop, in addition to SDHA and PARP1 variants, possibly explaining the onset at age 35.	('APOBEC3A', 'Gene', (115, 123))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('succinate', 'Chemical', 'MESH:D019802', (207, 216))	('SDHA', 'Gene', (341, 345))	('APOBEC3A', 'Gene', '200315', (115, 123))	('PARP1', 'Gene', (350, 355))	('TRIB3', 'Gene', '57761', (311, 316))	('TRIB3', 'Gene', '57761', (0, 5))	('SDHA', 'Gene', '6389', (341, 345))	('TRIB3', 'Gene', (311, 316))	('altered', 'Reg', (250, 257))	('TRIB3', 'Gene', (0, 5))	('R36stop', 'SUBSTITUTION', 'None', (317, 324))	('cytidine', 'Chemical', 'MESH:D003562', (91, 99))	('cytidine deamination', 'biological_process', 'GO:0009972', ('91', '111'))	('APOBEC', 'cellular_component', 'GO:0030895', ('115', '121'))	('response', 'MPA', (195, 203))	('PARP1', 'Gene', '142', (350, 355))	('R36stop', 'Var', (317, 324))
24213	30680959	The variants in EGF and TGFB2 are more challenging to interpret at this point.	('EGF', 'molecular_function', 'GO:0005154', ('16', '19'))	('variants', 'Var', (4, 12))	('TGFB2', 'Gene', '7042', (24, 29))	('EGF', 'Gene', '1950', (16, 19))	('TGFB2', 'Gene', (24, 29))	('EGF', 'Gene', (16, 19))
24232	27422173	Biallelic loss or inactivation of the von Hippel Lindau (VHL) gene via mutation, deletion or promoter methylation occurs in up to 91 % of sporadic ccRCC and drives a strong pro-survival and angiogenic program due to downstream hypoxia-inducible factor (HIF) accumulation.	('RCC', 'Disease', (149, 152))	('hypoxia', 'Disease', 'MESH:D000860', (227, 234))	('methylation', 'biological_process', 'GO:0032259', ('102', '113'))	('VHL', 'Disease', (57, 60))	('von Hippel Lindau', 'Gene', '7428', (38, 55))	('VHL', 'Disease', 'MESH:D006623', (57, 60))	('inactivation', 'NegReg', (18, 30))	('promoter methylation', 'Var', (93, 113))	('mutation', 'Var', (71, 79))	('accumulation', 'PosReg', (258, 270))	('angiogenic program', 'CPA', (190, 208))	('drives', 'PosReg', (157, 163))	('deletion', 'Var', (81, 89))	('von Hippel Lindau', 'Gene', (38, 55))	('hypoxia', 'Disease', (227, 234))	('loss', 'NegReg', (10, 14))	('pro-survival', 'biological_process', 'GO:0043066', ('173', '185'))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
24273	27422173	Sequencing of VHL in primary tumors and cultures verified a patient tumor-matching VHL mutation in RCC22 cells grown in FBS (Additional file 10: Figure S1B), while the remaining lines did not recapitulate the patients' tumor VHL mutations.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', (219, 224))	('primary tumors', 'Disease', 'MESH:D009369', (21, 35))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('VHL', 'Disease', (83, 86))	('RCC', 'Disease', (99, 102))	('VHL', 'Disease', (225, 228))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Disease', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('VHL', 'Disease', 'MESH:D006623', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('patients', 'Species', '9606', (209, 217))	('VHL', 'Disease', 'MESH:D006623', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('VHL', 'Disease', 'MESH:D006623', (225, 228))	('mutation', 'Var', (87, 95))	('patient', 'Species', '9606', (60, 67))	('primary tumors', 'Disease', (21, 35))	('patient', 'Species', '9606', (209, 216))	('tumor', 'Disease', (29, 34))	('VHL', 'Disease', (14, 17))
24289	27422173	Re-sequencing at later passages (up to 20) verified that the VHL status of both mutant and wild-type cultures was maintained.	('VHL', 'Disease', 'MESH:D006623', (61, 64))	('VHL', 'Disease', (61, 64))	('mutant', 'Var', (80, 86))
24326	27422173	The purification of ccRCC cells expressing CA9 increased both culture accuracy and efficiency substantially for samples bearing VHL mutations.	('CA9', 'Gene', '768', (43, 46))	('RCC', 'Disease', (22, 25))	('efficiency', 'MPA', (83, 93))	('mutations', 'Var', (132, 141))	('RCC', 'Disease', 'MESH:C538614', (22, 25))	('increased', 'PosReg', (47, 56))	('VHL', 'Disease', (128, 131))	('VHL', 'Disease', 'MESH:D006623', (128, 131))	('culture', 'MPA', (62, 69))	('CA9', 'Gene', (43, 46))
24328	27422173	While not all ccRCC tumors have a detectable VHL mutation, VHL loss due to biallelic deletion or epigenetic silencing occurs in many of these patients.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('VHL loss', 'Disease', 'MESH:D006623', (59, 67))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('RCC', 'Disease', (16, 19))	('VHL', 'Disease', 'MESH:D006623', (59, 62))	('epigenetic silencing', 'Var', (97, 117))	('VHL loss', 'Disease', (59, 67))	('VHL', 'Disease', (45, 48))	('VHL', 'Disease', (59, 62))	('VHL', 'Disease', 'MESH:D006623', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('biallelic deletion', 'Var', (75, 93))	('patients', 'Species', '9606', (142, 150))
24355	27422173	We also noted a network of epigenetics-related nodes, concordant with recent findings that widespread deregulation of chromatin status occurs in ccRCC due to activation of hypoxia-related pathways, as well as mutations in epigenetic regulatory genes.	('hypoxia', 'Disease', 'MESH:D000860', (172, 179))	('chromatin', 'cellular_component', 'GO:0000785', ('118', '127'))	('activation', 'PosReg', (158, 168))	('hypoxia', 'Disease', (172, 179))	('deregulation', 'MPA', (102, 114))	('RCC', 'Disease', (147, 150))	('mutations', 'Var', (209, 218))	('epigenetic regulatory genes', 'Gene', (222, 249))	('chromatin status', 'MPA', (118, 134))	('RCC', 'Disease', 'MESH:C538614', (147, 150))
24361	27422173	Likewise, a higher expression of mitochondrial respiration-associated genes in the tumor tissue likely also reflects the presence of stromal cells within the tumor tissue that do not have VHL mutations and thus maintain normal levels of mitochondrial metabolism.	('rat', 'Species', '10116', (52, 55))	('tumor', 'Disease', (158, 163))	('expression', 'MPA', (19, 29))	('VHL', 'Disease', (188, 191))	('VHL', 'Disease', 'MESH:D006623', (188, 191))	('higher', 'PosReg', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('respiration', 'biological_process', 'GO:0007585', ('47', '58'))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('metabolism', 'biological_process', 'GO:0008152', ('251', '261'))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('respiration', 'biological_process', 'GO:0045333', ('47', '58'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mutations', 'Var', (192, 201))	('levels', 'MPA', (227, 233))	('mitochondrial metabolism', 'MPA', (237, 261))	('mitochondrial respiration-associated genes', 'Gene', (33, 75))
24370	28052007	VHL missense mutations in the p53 binding domain show different effects on p53 signaling and HIFalpha degradation in clear cell renal cell carcinoma Clear cell Renal Cell Carcinoma (ccRCC) formation is connected to functional loss of the von Hippel-Lindau (VHL) gene.	('degradation', 'biological_process', 'GO:0009056', ('102', '113'))	('formation', 'biological_process', 'GO:0009058', ('189', '198'))	('VHL', 'Gene', '7428', (0, 3))	('loss', 'NegReg', (226, 230))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (117, 148))	('effects', 'Reg', (64, 71))	('Clear cell Renal Cell Carcinoma', 'Disease', (149, 180))	('von Hippel-Lindau', 'Gene', '7428', (238, 255))	('p53 binding', 'molecular_function', 'GO:0002039', ('30', '41'))	('p53', 'Gene', '7157', (30, 33))	('VHL', 'Gene', (257, 260))	('clear cell renal cell carcinoma', 'Disease', (117, 148))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (128, 148))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('missense mutations', 'Var', (4, 22))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (75, 78))	('HIFalpha degradation', 'MPA', (93, 113))	('VHL', 'Gene', '7428', (257, 260))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (117, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('VHL', 'Gene', (0, 3))	('p53', 'Gene', (75, 78))	('Clear cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (149, 180))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('von Hippel-Lindau', 'Gene', (238, 255))
24373	28052007	We showed that low and absent p53 expression correlated with the severity of VHL mutations in 262 analyzed ccRCC tissues.	('expression', 'MPA', (34, 44))	('VHL', 'Gene', (77, 80))	('VHL', 'Gene', '7428', (77, 80))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('mutations', 'Var', (81, 90))	('ccRCC', 'Disease', (107, 112))	('absent', 'NegReg', (23, 29))
24374	28052007	In contrast to nonsense and frameshift mutations which abrogate virtually all pVHL functions, missense mutations may rather influence one or few functions.	('pVHL', 'Gene', (78, 82))	('influence', 'Reg', (124, 133))	('pVHL', 'Gene', '7428', (78, 82))	('missense mutations', 'Var', (94, 112))
24375	28052007	Therefore, we focused on four VHL missense mutations, which affect the overlapping pVHL binding sites of p53 and Elongin C, by investigating their impact on HIFalpha degradation, p53 expression and signaling, as well as on cellular behavior using ccRCC cell lines and tissues.	('p53', 'Gene', (179, 182))	('signaling', 'biological_process', 'GO:0023052', ('198', '207'))	('Elongin C', 'Gene', (113, 122))	('VHL', 'Gene', (30, 33))	('p53', 'Gene', (105, 108))	('impact', 'Reg', (147, 153))	('degradation', 'biological_process', 'GO:0009056', ('166', '177'))	('VHL', 'Gene', (84, 87))	('binding', 'molecular_function', 'GO:0005488', ('88', '95'))	('RCC', 'Phenotype', 'HP:0005584', (249, 252))	('VHL', 'Gene', '7428', (30, 33))	('Elongin C', 'Gene', '6921', (113, 122))	('HIFalpha degradation', 'MPA', (157, 177))	('pVHL', 'Gene', '7428', (83, 87))	('pVHL', 'Gene', (83, 87))	('VHL', 'Gene', '7428', (84, 87))	('p53', 'Gene', '7157', (179, 182))	('missense mutations', 'Var', (34, 52))	('p53', 'Gene', '7157', (105, 108))
24376	28052007	TP53 mRNA and its effector targets p21, Bax and Noxa, were altered both in engineered cell lines and in tumor tissues which carried the same missense mutations.	('altered', 'Reg', (59, 66))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('p21', 'Gene', (35, 38))	('Bax', 'Gene', (40, 43))	('mRNA', 'MPA', (5, 9))	('tumor', 'Disease', (104, 109))	('Noxa', 'Gene', '5366', (48, 52))	('missense mutations', 'Var', (141, 159))	('Noxa', 'Gene', (48, 52))	('p21', 'Gene', '1026', (35, 38))	('Bax', 'Gene', '581', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
24377	28052007	Two of these mutations were not able to degrade HIFalpha whereas the remaining two mutations led to HIFalpha downregulation, suggesting the latter are p53 binding site-specific.	('p53 binding', 'molecular_function', 'GO:0002039', ('151', '162'))	('downregulation', 'NegReg', (109, 123))	('HIFalpha', 'Gene', (100, 108))	('p53', 'Gene', (151, 154))	('mutations', 'Var', (13, 22))	('p53', 'Gene', '7157', (151, 154))
24378	28052007	The selected VHL missense mutations further enhanced tumor cell survival, but had no effects on cell proliferation.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('missense mutations', 'Var', (17, 35))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('VHL', 'Gene', (13, 16))	('VHL', 'Gene', '7428', (13, 16))	('tumor', 'Disease', (53, 58))	('cell proliferation', 'biological_process', 'GO:0008283', ('96', '114'))	('enhanced', 'PosReg', (44, 52))
24382	28052007	In ccRCC the von Hippel-Lindau tumor suppressor gene (VHL) is frequently altered by deletion of one allele (90%) and promoter methylation (up to 20%) or mutations (70-80%) of the other.	('tumor suppressor', 'biological_process', 'GO:0051726', ('31', '47'))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('methylation', 'biological_process', 'GO:0032259', ('126', '137'))	('deletion', 'Var', (84, 92))	('VHL', 'Gene', (54, 57))	('promoter methylation', 'MPA', (117, 137))	('altered', 'Reg', (73, 80))	('mutations', 'Var', (153, 162))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('31', '47'))	('VHL', 'Gene', '7428', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('ccRCC', 'Disease', (3, 8))	('von Hippel-Lindau tumor suppressor', 'Gene', (13, 47))	('von Hippel-Lindau tumor suppressor', 'Gene', '7428', (13, 47))
24383	28052007	VHL inactivation is considered as a critical part of tumor initiation.	('inactivation', 'Var', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('VHL', 'Gene', (0, 3))	('tumor initiation', 'Disease', 'MESH:D009369', (53, 69))	('VHL', 'Gene', '7428', (0, 3))	('tumor initiation', 'Disease', (53, 69))
24385	28052007	Given different types of VHL mutations, a deeper insight in the biological effects of VHL mutations may allow a better prediction of ccRCC prognosis.	('VHL', 'Gene', '7428', (25, 28))	('ccRCC', 'Disease', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('mutations', 'Var', (29, 38))	('VHL', 'Gene', (25, 28))	('VHL', 'Gene', (86, 89))	('VHL', 'Gene', '7428', (86, 89))
24386	28052007	In particular, VHL loss-of-function mutations (LOF) (frameshift, nonsense and splice site mutations) highly likely abrogate pVHL function, whereas the consequences of missense mutations on pVHL stability and target binding ability are rather unclear.	('pVHL', 'Gene', (189, 193))	('abrogate', 'NegReg', (115, 123))	('VHL loss-of-function', 'Disease', (15, 35))	('VHL loss-of-function', 'Disease', 'MESH:D006623', (15, 35))	('pVHL', 'Gene', '7428', (124, 128))	('binding', 'molecular_function', 'GO:0005488', ('215', '222'))	('mutations', 'Var', (36, 45))	('pVHL', 'Gene', (124, 128))	('nonsense and splice site mutations', 'Var', (65, 99))	('pVHL', 'Gene', '7428', (189, 193))
24387	28052007	Missense mutations may provoke diverse effects on pVHL interactions with binding partners, thus exerting different impact on pathways normally regulated by pVHL.	('exerting', 'Reg', (96, 104))	('interactions', 'Interaction', (55, 67))	('pVHL', 'Gene', '7428', (50, 54))	('pVHL', 'Gene', '7428', (156, 160))	('pVHL', 'Gene', (50, 54))	('pVHL', 'Gene', (156, 160))	('effects', 'Reg', (39, 46))	('pathways', 'Pathway', (125, 133))	('impact', 'Reg', (115, 121))	('binding', 'molecular_function', 'GO:0005488', ('73', '80'))	('Missense mutations', 'Var', (0, 18))
24388	28052007	This was shown for HIF1alpha and HIF2alpha degradation as well as for other pVHL binding partners, including Jade1, RPB1, VDU1, EEF1A1 and CCT-zeta-2, for which loss of binding capability upon missense mutations was demonstrated.	('missense mutations', 'Var', (193, 211))	('binding', 'molecular_function', 'GO:0005488', ('81', '88'))	('VDU1', 'Gene', '23032', (122, 126))	('HIF1alpha', 'Gene', '3091', (19, 28))	('degradation', 'biological_process', 'GO:0009056', ('43', '54'))	('Jade1', 'Gene', '79960', (109, 114))	('VDU1', 'Gene', (122, 126))	('RPB1', 'Gene', '5430', (116, 120))	('HIF1alpha', 'Gene', (19, 28))	('Jade1', 'Gene', (109, 114))	('binding', 'Interaction', (169, 176))	('binding', 'molecular_function', 'GO:0005488', ('169', '176'))	('RPB1', 'Gene', (116, 120))	('EEF1A1', 'Gene', '1915', (128, 134))	('pVHL', 'Gene', '7428', (76, 80))	('HIF2alpha', 'Gene', (33, 42))	('pVHL', 'Gene', (76, 80))	('EEF1A1', 'Gene', (128, 134))	('CCT-zeta-2', 'Gene', '10693', (139, 149))	('CCT-zeta-2', 'Gene', (139, 149))	('HIF2alpha', 'Gene', '2034', (33, 42))
24393	28052007	In addition, pVHL inactivation in RCC cells lead to decreased apoptosis, which may be explained by the lack of phosphorylation of pVHL by checkpoint-kinase 2, impairing the recruitment of p53 coactivators (such as p300 and Tip60).	('recruitment', 'MPA', (173, 184))	('apoptosis', 'CPA', (62, 71))	('pVHL', 'Gene', '7428', (13, 17))	('checkpoint-kinase 2', 'Gene', (138, 157))	('pVHL', 'Gene', (13, 17))	('Tip60', 'Gene', (223, 228))	('impairing', 'NegReg', (159, 168))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('p300', 'Gene', (214, 218))	('p53', 'Gene', '7157', (188, 191))	('phosphorylation', 'biological_process', 'GO:0016310', ('111', '126'))	('lack', 'NegReg', (103, 107))	('inactivation', 'Var', (18, 30))	('p300', 'Gene', '2033', (214, 218))	('p53', 'Gene', (188, 191))	('pVHL', 'Gene', '7428', (130, 134))	('pVHL', 'Gene', (130, 134))	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('Tip60', 'Gene', '10524', (223, 228))	('checkpoint-kinase 2', 'Gene', '11200', (138, 157))	('decreased', 'NegReg', (52, 61))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))
24394	28052007	Tumors with p53 mutations are known to be associated with chemoresistance.	('associated', 'Reg', (42, 52))	('mutations', 'Var', (16, 25))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('chemoresistance', 'CPA', (58, 73))
24396	28052007	suggested that p53 signaling is repressed by mechanisms independent of p53 mutations.	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('p53', 'Gene', '7157', (15, 18))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('p53', 'Gene', (15, 18))	('mutations', 'Var', (75, 84))
24397	28052007	ccRCC is currently treated with anti-angiogenic drugs, such as the Tyrosine-Kinase-Inhibitors (TKI) Sorafenib and Sunitinib, to counter the effects of the HIF1/2alpha accumulation occurring upon pVHL inactivation.	('pVHL', 'Gene', '7428', (195, 199))	('pVHL', 'Gene', (195, 199))	('Sunitinib', 'Chemical', 'MESH:D000077210', (114, 123))	('Sorafenib', 'Chemical', 'MESH:D000077157', (100, 109))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('ccRCC', 'Disease', (0, 5))	('inactivation', 'Var', (200, 212))
24398	28052007	As shown for colorectal cancer where p53 negative cells were less responsive to anti-angiogenic treatment than wild-type p53 cells, alteration of p53 signaling may also be an explanation for the low response rate in ccRCC.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('p53', 'Gene', (121, 124))	('p53', 'Gene', (146, 149))	('colorectal cancer', 'Disease', (13, 30))	('ccRCC', 'Disease', (216, 221))	('p53', 'Gene', '7157', (146, 149))	('p53', 'Gene', '7157', (121, 124))	('less', 'NegReg', (61, 65))	('RCC', 'Phenotype', 'HP:0005584', (218, 221))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (13, 30))	('signaling', 'biological_process', 'GO:0023052', ('150', '159'))	('alteration', 'Var', (132, 142))	('colorectal cancer', 'Phenotype', 'HP:0003003', (13, 30))
24399	28052007	We hypothesized that VHL missense mutations occurring in the p53 binding domain of pVHL lead to deficient p53 transactivation and/or promote HIF1alpha and HIF2alpha accumulation, thus impacting tumor behavior and response to treatment.	('p53', 'Gene', '7157', (106, 109))	('transactivation', 'biological_process', 'GO:2000144', ('110', '125'))	('missense mutations', 'Var', (25, 43))	('tumor', 'Disease', (194, 199))	('VHL', 'Gene', (21, 24))	('p53', 'Gene', (106, 109))	('HIF2alpha', 'Gene', (155, 164))	('VHL', 'Gene', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('transactivation', 'MPA', (110, 125))	('p53 binding', 'molecular_function', 'GO:0002039', ('61', '72'))	('VHL', 'Gene', '7428', (21, 24))	('pVHL', 'Gene', '7428', (83, 87))	('promote', 'PosReg', (133, 140))	('pVHL', 'Gene', (83, 87))	('VHL', 'Gene', '7428', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('HIF2alpha', 'Gene', '2034', (155, 164))	('deficient', 'NegReg', (96, 105))	('p53', 'Gene', '7157', (61, 64))	('HIF1alpha', 'Gene', '3091', (141, 150))	('accumulation', 'PosReg', (165, 177))	('response to treatment', 'CPA', (213, 234))	('HIF1alpha', 'Gene', (141, 150))	('p53', 'Gene', (61, 64))	('impacting', 'Reg', (184, 193))
24400	28052007	In this study, we investigated four different missense mutations located in the p53 binding site (codons 154-163), which is overlapping with the ElonginC binding domain (codons 157-171).	('missense mutations', 'Var', (46, 64))	('p53', 'Gene', (80, 83))	('p53', 'Gene', '7157', (80, 83))	('binding', 'molecular_function', 'GO:0005488', ('154', '161'))	('ElonginC', 'Gene', (145, 153))	('p53 binding', 'molecular_function', 'GO:0002039', ('80', '91'))	('ElonginC', 'Gene', '6921', (145, 153))
24401	28052007	Due to this overlap, the missense mutations investigated could have an impact on p53 signaling and/or on HIF1/2alpha degradation through an altered binding to ElonginC.	('altered', 'Reg', (140, 147))	('impact', 'Reg', (71, 77))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('binding', 'molecular_function', 'GO:0005488', ('148', '155'))	('HIF1/2alpha degradation', 'MPA', (105, 128))	('missense mutations', 'Var', (25, 43))	('ElonginC', 'Gene', (159, 167))	('binding', 'Interaction', (148, 155))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('ElonginC', 'Gene', '6921', (159, 167))	('degradation', 'biological_process', 'GO:0009056', ('117', '128'))
24402	28052007	Our goal was to evaluate the selected missense mutations effectiveness in HIF1/2alpha degradation, p53 transactivation, and their response to chemotherapy and TKI.	('HIF1/2alpha', 'Enzyme', (74, 85))	('transactivation', 'MPA', (103, 118))	('missense mutations', 'Var', (38, 56))	('transactivation', 'biological_process', 'GO:2000144', ('103', '118'))	('degradation', 'biological_process', 'GO:0009056', ('86', '97'))	('p53', 'Gene', '7157', (99, 102))	('p53', 'Gene', (99, 102))	('degradation', 'MPA', (86, 97))
24407	28052007	By separating the 262 ccRCC in VHL wild-type and VHL mutated tumors, we observed that p53 expression was less frequent in tumors with VHL alterations (p=0.0212) (Figure 1B).	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('less', 'NegReg', (105, 109))	('expression', 'MPA', (90, 100))	('VHL', 'Gene', (134, 137))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('VHL', 'Gene', '7428', (31, 34))	('p53', 'Gene', '7157', (86, 89))	('alterations', 'Var', (138, 149))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('VHL', 'Gene', '7428', (134, 137))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('p53', 'Gene', (86, 89))	('tumors', 'Disease', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('VHL', 'Gene', (49, 52))	('RCC', 'Phenotype', 'HP:0005584', (24, 27))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('VHL', 'Gene', (31, 34))	('VHL', 'Gene', '7428', (49, 52))
24408	28052007	Notably, the p53 expression frequency decreased with the predicted impact of mutations on the function of pVHL (Figure 1C).	('decreased', 'NegReg', (38, 47))	('mutations', 'Var', (77, 86))	('pVHL', 'Gene', '7428', (106, 110))	('function', 'MPA', (94, 102))	('p53', 'Gene', (13, 16))	('expression frequency', 'MPA', (17, 37))	('p53', 'Gene', '7157', (13, 16))	('pVHL', 'Gene', (106, 110))
24410	28052007	Among 254 VHL mutations found in 360 ccRCC tissue specimen (70.6%), 25 (9.8%) resided in these binding domains.	('mutations', 'Var', (14, 23))	('resided', 'Reg', (78, 85))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))	('VHL', 'Gene', (10, 13))	('VHL', 'Gene', '7428', (10, 13))
24411	28052007	Eight missense mutations were predicted to destabilize pVHL and three missense mutations had no or little impact on pVHL stability.	('pVHL', 'Gene', '7428', (55, 59))	('pVHL', 'Gene', (55, 59))	('destabilize', 'NegReg', (43, 54))	('missense mutations', 'Var', (6, 24))	('pVHL', 'Gene', '7428', (116, 120))	('pVHL', 'Gene', (116, 120))
24412	28052007	For this study, we selected four out of 11 missense mutations occurring in the p53/EloC binding domain for further analysis.	('missense mutations', 'Var', (43, 61))	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('binding', 'molecular_function', 'GO:0005488', ('88', '95'))	('EloC', 'Gene', '6921', (83, 87))	('EloC', 'Gene', (83, 87))
24413	28052007	Three were predicted to have mild impact on pVHL (Leu158Val, Arg161Gln, and Cys162Arg) and one was predicted to highly destabilize pVHL (Arg161Pro).	('Cys162Arg', 'Var', (76, 85))	('Cys162Arg', 'SUBSTITUTION', 'None', (76, 85))	('Arg161Pro', 'Var', (137, 146))	('destabilize', 'NegReg', (119, 130))	('pVHL', 'Gene', '7428', (131, 135))	('pVHL', 'Gene', (131, 135))	('pVHL', 'Gene', '7428', (44, 48))	('Leu158Val', 'Chemical', '-', (50, 59))	('Leu158Val', 'Var', (50, 59))	('Arg161Gln', 'Var', (61, 70))	('pVHL', 'Gene', (44, 48))	('Arg161Gln', 'SUBSTITUTION', 'None', (61, 70))	('Arg161Pro', 'SUBSTITUTION', 'None', (137, 146))
24414	28052007	Two other missense mutations occurring in the HIF1/2alpha binding domain (Tyr98His, Tyr98Asn), as well as one nonsense mutation located in the p53/EloC binding domain (Arg161X) were predicted to differently impair HIF1/2alpha degradation pathway and were used as controls for the cell line experiments (summarized in Table 1).	('HIF1/2alpha degradation pathway', 'Pathway', (214, 245))	('Tyr98His', 'SUBSTITUTION', 'None', (74, 82))	('p53', 'Gene', '7157', (143, 146))	('Tyr98His', 'Var', (74, 82))	('EloC', 'Gene', '6921', (147, 151))	('binding', 'molecular_function', 'GO:0005488', ('152', '159'))	('binding', 'molecular_function', 'GO:0005488', ('58', '65'))	('missense mutations', 'Var', (10, 28))	('Tyr98Asn', 'Var', (84, 92))	('Arg161X', 'SUBSTITUTION', 'None', (168, 175))	('Arg161X', 'Var', (168, 175))	('Tyr98Asn', 'SUBSTITUTION', 'None', (84, 92))	('EloC', 'Gene', (147, 151))	('impair', 'NegReg', (207, 213))	('p53', 'Gene', (143, 146))	('degradation', 'biological_process', 'GO:0009056', ('226', '237'))
24415	28052007	The established stable cell lines were investigated by Western Blot for the effects of the VHL missense mutations on HIF1/2alpha degradation and the two HIF1/2alpha targets CAIX and Glut1 (Figure 2).	('HIF1/2alpha', 'MPA', (117, 128))	('Glut1', 'Gene', (182, 187))	('missense mutations', 'Var', (95, 113))	('CAIX', 'Gene', (173, 177))	('VHL', 'Gene', (91, 94))	('Glut1', 'Gene', '6513', (182, 187))	('VHL', 'Gene', '7428', (91, 94))	('CAIX', 'Gene', '768', (173, 177))	('degradation', 'biological_process', 'GO:0009056', ('129', '140'))
24416	28052007	As expected, pVHL was undetectable in RCC4 Babe and RCC4 Arg161X.	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('RCC4', 'Gene', '84925', (38, 42))	('RCC4', 'Gene', (38, 42))	('RCC4', 'Gene', (52, 56))	('Arg161X', 'SUBSTITUTION', 'None', (57, 64))	('Arg161X', 'Var', (57, 64))	('RCC4', 'Gene', '84925', (52, 56))	('pVHL', 'Gene', '7428', (13, 17))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('pVHL', 'Gene', (13, 17))
24417	28052007	HIF1alpha and 2alpha were stabilized in RCC4 Babe, Arg161Pro, Arg161X, and also in RCC4 Cys162Arg.	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('RCC4', 'Gene', '84925', (83, 87))	('Arg161Pro', 'SUBSTITUTION', 'None', (51, 60))	('Cys162Arg', 'Var', (88, 97))	('RCC4', 'Gene', (83, 87))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('Cys162Arg', 'SUBSTITUTION', 'None', (88, 97))	('Arg161X', 'SUBSTITUTION', 'None', (62, 69))	('Arg161X', 'Var', (62, 69))	('RCC4', 'Gene', (40, 44))	('RCC4', 'Gene', '84925', (40, 44))	('HIF1alpha and 2alpha', 'Gene', '3091;2034', (0, 20))	('Arg161Pro', 'Var', (51, 60))
24418	28052007	RCC4 Arg161Gln, Tyr98His and Tyr98Asn showed partial HIF1alpha and 2alpha degradation.	('Tyr98His', 'SUBSTITUTION', 'None', (16, 24))	('RCC4', 'Gene', (0, 4))	('RCC4', 'Gene', '84925', (0, 4))	('Tyr98His', 'Var', (16, 24))	('Tyr98Asn', 'Var', (29, 37))	('HIF1alpha and 2alpha', 'Gene', '3091;2034', (53, 73))	('Arg161Gln', 'SUBSTITUTION', 'None', (5, 14))	('Arg161Gln', 'Var', (5, 14))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('Tyr98Asn', 'SUBSTITUTION', 'None', (29, 37))	('degradation', 'biological_process', 'GO:0009056', ('74', '85'))
24419	28052007	HIF1/2alpha strong degradation was seen in Leu158Val which was similar to RCC4 VHL30 (wild-type).	('VHL', 'Gene', '7428', (79, 82))	('Leu158Val', 'Chemical', '-', (43, 52))	('degradation', 'biological_process', 'GO:0009056', ('19', '30'))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('degradation', 'MPA', (19, 30))	('RCC4', 'Gene', '84925', (74, 78))	('Leu158Val', 'Var', (43, 52))	('VHL', 'Gene', (79, 82))	('RCC4', 'Gene', (74, 78))
24422	28052007	Previous studies showed that pVHL enhances p53 transcriptional activity which was reduced by Ser111Arg or Ser111Cys missense mutations.	('Ser111Arg', 'SUBSTITUTION', 'None', (93, 102))	('Ser111Arg', 'Var', (93, 102))	('Ser111Cys', 'Var', (106, 115))	('Ser111Cys', 'SUBSTITUTION', 'None', (106, 115))	('pVHL', 'Gene', '7428', (29, 33))	('enhances', 'PosReg', (34, 42))	('pVHL', 'Gene', (29, 33))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('Ser', 'cellular_component', 'GO:0005790', ('106', '109'))	('Ser', 'cellular_component', 'GO:0005790', ('93', '96'))
24423	28052007	Here we studied the effects of our selected VHL mutations on the RNA level of TP53 and its effectors p21, Bax and Noxa.	('Noxa', 'Gene', '5366', (114, 118))	('Noxa', 'Gene', (114, 118))	('RNA', 'cellular_component', 'GO:0005562', ('65', '68'))	('p21', 'Gene', '1026', (101, 104))	('VHL', 'Gene', (44, 47))	('VHL', 'Gene', '7428', (44, 47))	('p21', 'Gene', (101, 104))	('Bax', 'Gene', (106, 109))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))	('mutations', 'Var', (48, 57))	('Bax', 'Gene', '581', (106, 109))
24424	28052007	The transcription levels of TP53, p21 and Noxa in cells expressing the different mutant forms were generally lower compared to the wild-type form of pVHL (Figure 3).	('TP53', 'Gene', '7157', (28, 32))	('lower', 'NegReg', (109, 114))	('p21', 'Gene', (34, 37))	('TP53', 'Gene', (28, 32))	('pVHL', 'Gene', '7428', (149, 153))	('Noxa', 'Gene', '5366', (42, 46))	('Noxa', 'Gene', (42, 46))	('pVHL', 'Gene', (149, 153))	('mutant', 'Var', (81, 87))	('transcription levels', 'MPA', (4, 24))	('transcription', 'biological_process', 'GO:0006351', ('4', '17'))	('p21', 'Gene', '1026', (34, 37))
24425	28052007	Transcription levels of p21 and Noxa were significantly reduced in most VHL mutants compared to RCC4 expressing VHL wild-type.	('RCC4', 'Gene', '84925', (96, 100))	('VHL', 'Gene', '7428', (72, 75))	('Noxa', 'Gene', (32, 36))	('p21', 'Gene', (24, 27))	('RCC4', 'Gene', (96, 100))	('reduced', 'NegReg', (56, 63))	('VHL', 'Gene', (112, 115))	('p21', 'Gene', '1026', (24, 27))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('mutants', 'Var', (76, 83))	('VHL', 'Gene', '7428', (112, 115))	('Noxa', 'Gene', '5366', (32, 36))	('VHL', 'Gene', (72, 75))	('Transcription levels', 'MPA', (0, 20))
24426	28052007	Bax RNA levels were lower only in RCC4 Leu158Val and Arg161Gln.	('RCC4', 'Gene', '84925', (34, 38))	('lower', 'NegReg', (20, 25))	('Bax', 'Gene', '581', (0, 3))	('RCC4', 'Gene', (34, 38))	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('Bax', 'Gene', (0, 3))	('Arg161Gln', 'SUBSTITUTION', 'None', (53, 62))	('Arg161Gln', 'Var', (53, 62))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('Leu158Val', 'Chemical', '-', (39, 48))
24427	28052007	Among the missense mutations in the p53 binding domain, no significant difference in RNA levels was seen between the three non-destabilizing/slightly destabilizing mutants and the one with destabilizing effects on pVHL.	('RNA levels', 'MPA', (85, 95))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('missense mutations', 'Var', (10, 28))	('RNA', 'cellular_component', 'GO:0005562', ('85', '88'))	('pVHL', 'Gene', '7428', (214, 218))	('p53 binding', 'molecular_function', 'GO:0002039', ('36', '47'))	('pVHL', 'Gene', (214, 218))
24428	28052007	Nine ccRCC tissues (one VHL wild-type, two with mutation Leu158Val (#1, #2), one with Arg161Gln, one with Cys162Arg, one with Arg161Pro, one with Tyr98Asn and two with Arg161X (#1, #2)) and three normal kidney tissues were investigated for RNA expression of VHL, TP53 and its downstream targets.	('Tyr98Asn', 'Var', (146, 154))	('Arg161Gln', 'Var', (86, 95))	('TP53', 'Gene', '7157', (263, 267))	('VHL', 'Gene', '7428', (24, 27))	('RNA', 'cellular_component', 'GO:0005562', ('240', '243'))	('Cys162Arg', 'SUBSTITUTION', 'None', (106, 115))	('VHL', 'Gene', (258, 261))	('Arg161Pro', 'SUBSTITUTION', 'None', (126, 135))	('Cys162Arg', 'Var', (106, 115))	('Arg161Pro', 'Var', (126, 135))	('Tyr98Asn', 'SUBSTITUTION', 'None', (146, 154))	('TP53', 'Gene', (263, 267))	('RCC', 'Phenotype', 'HP:0005584', (7, 10))	('VHL', 'Gene', '7428', (258, 261))	('Arg161Gln', 'SUBSTITUTION', 'None', (86, 95))	('Arg161X', 'SUBSTITUTION', 'None', (168, 175))	('Arg161X', 'Var', (168, 175))	('VHL', 'Gene', (24, 27))	('Leu158Val', 'Var', (57, 66))	('Leu158Val', 'Chemical', '-', (57, 66))
24431	28052007	The RNA levels of TP53 and its downstream targets relative to VHL transcription levels were assessed in ccRCC samples expressing the mutant forms of VHL (Figure 5).	('VHL', 'Gene', '7428', (149, 152))	('TP53', 'Gene', '7157', (18, 22))	('transcription', 'biological_process', 'GO:0006351', ('66', '79'))	('TP53', 'Gene', (18, 22))	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('VHL', 'Gene', (62, 65))	('mutant forms', 'Var', (133, 145))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('VHL', 'Gene', '7428', (62, 65))	('VHL', 'Gene', (149, 152))
24433	28052007	All eight mutant samples showed a decrease of p21, Bax and Noxa RNA levels compared to VHL wild-type except for Noxa in the Cys162Arg mutated tumor.	('VHL', 'Gene', '7428', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('Noxa', 'Gene', '5366', (112, 116))	('Bax', 'Gene', '581', (51, 54))	('Cys162Arg', 'SUBSTITUTION', 'None', (124, 133))	('Noxa', 'Gene', (112, 116))	('tumor', 'Disease', (142, 147))	('p21', 'Gene', '1026', (46, 49))	('Noxa', 'Gene', '5366', (59, 63))	('decrease', 'NegReg', (34, 42))	('RNA', 'cellular_component', 'GO:0005562', ('64', '67'))	('Noxa', 'Gene', (59, 63))	('p21', 'Gene', (46, 49))	('Cys162Arg', 'Var', (124, 133))	('VHL', 'Gene', (87, 90))	('Bax', 'Gene', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
24434	28052007	VHL missense mutations located in the p53 binding domain and VHL mutations in the HIF1/2alpha binding domain were similarly affected in p53 signaling.	('p53 binding', 'molecular_function', 'GO:0002039', ('38', '49'))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('binding', 'molecular_function', 'GO:0005488', ('94', '101'))	('p53', 'Gene', '7157', (136, 139))	('missense mutations', 'Var', (4, 22))	('VHL', 'Gene', (61, 64))	('VHL', 'Gene', (0, 3))	('affected', 'Reg', (124, 132))	('VHL', 'Gene', '7428', (61, 64))	('VHL', 'Gene', '7428', (0, 3))	('signaling', 'biological_process', 'GO:0023052', ('140', '149'))	('mutations', 'Var', (65, 74))	('p53', 'Gene', (136, 139))
24435	28052007	Notably, no significant differences in the RNA levels were observed between the mutation Arg161Pro which highly destabilize pVHL and the other mutations which are predicted to have a lower impact on pVHL stability.	('RNA levels', 'MPA', (43, 53))	('pVHL', 'Gene', '7428', (199, 203))	('pVHL', 'Gene', (199, 203))	('destabilize', 'NegReg', (112, 123))	('pVHL', 'Gene', '7428', (124, 128))	('RNA', 'cellular_component', 'GO:0005562', ('43', '46'))	('pVHL', 'Gene', (124, 128))	('Arg161Pro', 'Var', (89, 98))	('Arg161Pro', 'SUBSTITUTION', 'None', (89, 98))
24436	28052007	Since it is known that HIF1alpha can negatively regulate p53 activity, we next asked whether impaired p53 signaling was directly linked to VHL mutation status or was a consequence of the deregulated pVHL/HIF1alpha axis.	('impaired', 'NegReg', (93, 101))	('pVHL', 'Gene', '7428', (199, 203))	('pVHL', 'Gene', (199, 203))	('VHL', 'Gene', '7428', (200, 203))	('p53', 'Gene', '7157', (57, 60))	('p53', 'Gene', (57, 60))	('p53', 'Gene', '7157', (102, 105))	('VHL', 'Gene', (139, 142))	('HIF1alpha', 'Gene', '3091', (23, 32))	('mutation', 'Var', (143, 151))	('p53', 'Gene', (102, 105))	('activity', 'MPA', (61, 69))	('HIF1alpha', 'Gene', (23, 32))	('HIF1alpha', 'Gene', '3091', (204, 213))	('VHL', 'Gene', (200, 203))	('VHL', 'Gene', '7428', (139, 142))	('negatively', 'NegReg', (37, 47))	('HIF1alpha', 'Gene', (204, 213))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))
24438	28052007	HIF1alpha knockdown led to upregulation of TP53, p21, Bax and Noxa transcription in VHL wild-type and VHL deficient cell lines.	('p21', 'Gene', (49, 52))	('VHL', 'Gene', (102, 105))	('Noxa', 'Gene', '5366', (62, 66))	('VHL', 'Gene', (84, 87))	('VHL deficient', 'Disease', 'MESH:D006623', (102, 115))	('VHL deficient', 'Disease', (102, 115))	('HIF1alpha', 'Gene', '3091', (0, 9))	('Noxa', 'Gene', (62, 66))	('VHL', 'Gene', '7428', (102, 105))	('TP53', 'Gene', (43, 47))	('knockdown', 'Var', (10, 19))	('p21', 'Gene', '1026', (49, 52))	('Bax', 'Gene', (54, 57))	('HIF1alpha', 'Gene', (0, 9))	('VHL', 'Gene', '7428', (84, 87))	('transcription', 'biological_process', 'GO:0006351', ('67', '80'))	('Bax', 'Gene', '581', (54, 57))	('upregulation', 'PosReg', (27, 39))	('TP53', 'Gene', '7157', (43, 47))
24443	28052007	ccRCC with LOF mutations expressed less p21 than VHL wild-type tumors (not significant) and missense mutated tumors (p<0.05) (Figure 7A).	('less', 'NegReg', (35, 39))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('VHL wild-type tumors', 'Disease', (49, 69))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (15, 24))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('VHL wild-type tumors', 'Disease', 'MESH:D006623', (49, 69))	('ccRCC', 'Disease', (0, 5))	('p21', 'Gene', '1026', (40, 43))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('p21', 'Gene', (40, 43))	('tumors', 'Disease', (109, 115))
24447	28052007	The apoptotic behavior of cells expressing different VHL missense mutations was evaluated by Caspase 3/7 assay.	('missense mutations', 'Var', (57, 75))	('Caspase 3', 'Gene', '836', (93, 102))	('VHL', 'Gene', (53, 56))	('VHL', 'Gene', '7428', (53, 56))	('Caspase 3', 'Gene', (93, 102))
24448	28052007	All pVHL mutants were deficient in apoptosis compared to VHL wild- type (Figure 8A).	('pVHL', 'Gene', (4, 8))	('deficient', 'NegReg', (22, 31))	('pVHL', 'Gene', '7428', (4, 8))	('apoptosis', 'biological_process', 'GO:0006915', ('35', '44'))	('VHL', 'Gene', (5, 8))	('VHL', 'Gene', (57, 60))	('mutants', 'Var', (9, 16))	('VHL', 'Gene', '7428', (5, 8))	('VHL', 'Gene', '7428', (57, 60))	('apoptosis', 'CPA', (35, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('35', '44'))
24449	28052007	Cells with p53 binding site-specific VHL mutations showed significantly lower apoptotic activity than those with mutations that affected the HIF1/2alpha binding domain (p=0.0088) (Figure 8B).	('p53', 'Gene', (11, 14))	('mutations', 'Var', (41, 50))	('p53', 'Gene', '7157', (11, 14))	('VHL', 'Gene', (37, 40))	('p53 binding', 'molecular_function', 'GO:0002039', ('11', '22'))	('VHL', 'Gene', '7428', (37, 40))	('lower', 'NegReg', (72, 77))	('binding', 'molecular_function', 'GO:0005488', ('153', '160'))	('apoptotic activity', 'CPA', (78, 96))
24450	28052007	In contrast, cell proliferation was not influenced by the different binding site-specific VHL mutants (Figure 8C-8D).	('VHL', 'Gene', '7428', (90, 93))	('mutants', 'Var', (94, 101))	('binding', 'molecular_function', 'GO:0005488', ('68', '75'))	('VHL', 'Gene', (90, 93))	('cell proliferation', 'biological_process', 'GO:0008283', ('13', '31'))
24454	28052007	Cells with Arg161Gln, Arg161Pro and Tyr98Asn showed the highest response to Camptothecin alone.	('Camptothecin', 'Chemical', 'MESH:D002166', (76, 88))	('Arg161Gln', 'SUBSTITUTION', 'None', (11, 20))	('Arg161Pro', 'Var', (22, 31))	('Arg161Gln', 'Var', (11, 20))	('Tyr98Asn', 'Var', (36, 44))	('response to Camptothecin', 'biological_process', 'GO:1901563', ('64', '88'))	('response', 'MPA', (64, 72))	('Camptothecin alone', 'MPA', (76, 94))	('Tyr98Asn', 'SUBSTITUTION', 'None', (36, 44))	('Arg161Pro', 'SUBSTITUTION', 'None', (22, 31))
24455	28052007	Apoptosis was even increased with combined treatment in Arg161Gln and Tyr98Asn cells (Figure 9A).	('Tyr98Asn', 'Var', (70, 78))	('Arg161Gln', 'SUBSTITUTION', 'None', (56, 65))	('Arg161Gln', 'Var', (56, 65))	('Tyr98Asn', 'SUBSTITUTION', 'None', (70, 78))	('increased', 'PosReg', (19, 28))	('Apoptosis', 'CPA', (0, 9))
24456	28052007	With the exception of Arg161X, cell proliferation was decreased between 30-75% (Figure 9B).	('Arg161X', 'SUBSTITUTION', 'None', (22, 29))	('Arg161X', 'Var', (22, 29))	('cell proliferation', 'CPA', (31, 49))	('decreased', 'NegReg', (54, 63))	('cell proliferation', 'biological_process', 'GO:0008283', ('31', '49'))
24457	28052007	The response to the different treatments was similar for cell lines with missense mutation in the p53 binding domain and in the HIF1/2alpha binding domain.	('binding', 'Interaction', (102, 109))	('binding', 'molecular_function', 'GO:0005488', ('140', '147'))	('missense mutation', 'Var', (73, 90))	('p53 binding', 'molecular_function', 'GO:0002039', ('98', '109'))	('p53', 'Gene', (98, 101))	('p53', 'Gene', '7157', (98, 101))
24458	28052007	By investigating p53 expression in 262 ccRCC, we saw a relationship between p53 expression and the severity of VHL mutations.	('ccRCC', 'Disease', (39, 44))	('mutations', 'Var', (115, 124))	('VHL', 'Gene', (111, 114))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('VHL', 'Gene', '7428', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('relationship', 'Reg', (55, 67))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))
24460	28052007	The correlation between severe VHL mutations and negative or low p53 expression suggests a close relationship between loss of function of pVHL and disturbed p53 signaling in ccRCC.	('VHL', 'Gene', '7428', (31, 34))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (157, 160))	('p53', 'Gene', '7157', (65, 68))	('VHL', 'Gene', (139, 142))	('pVHL', 'Gene', '7428', (138, 142))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('pVHL', 'Gene', (138, 142))	('low', 'NegReg', (61, 64))	('VHL', 'Gene', '7428', (139, 142))	('expression', 'MPA', (69, 79))	('ccRCC', 'Disease', (174, 179))	('signaling', 'biological_process', 'GO:0023052', ('161', '170'))	('loss of function', 'NegReg', (118, 134))	('VHL', 'Gene', (31, 34))	('p53', 'Gene', (157, 160))	('mutations', 'Var', (35, 44))
24461	28052007	As the location of a VHL missense mutation may specifically affect one of the many binding sites of pVHL, we focused on those missense mutations that alter the p53 binding site.	('VHL', 'Gene', (101, 104))	('pVHL', 'Gene', (100, 104))	('missense mutation', 'Var', (25, 42))	('VHL', 'Gene', '7428', (101, 104))	('binding', 'Interaction', (83, 90))	('p53 binding', 'molecular_function', 'GO:0002039', ('160', '171'))	('p53', 'Gene', (160, 163))	('pVHL', 'Gene', '7428', (100, 104))	('p53', 'Gene', '7157', (160, 163))	('binding', 'molecular_function', 'GO:0005488', ('83', '90'))	('VHL', 'Gene', (21, 24))	('affect', 'Reg', (60, 66))	('VHL', 'Gene', '7428', (21, 24))	('binding', 'Interaction', (164, 171))
24463	28052007	The missense mutations were predicted to have different effects on pVHL stability, from highly destabilizing to neutral.. As the p53 binding domain overlaps the ElonginC binding domain, the missense mutations in this region should affect pVHL interactions with p53 and/or HIF1/2alpha.	('interactions', 'Interaction', (243, 255))	('p53', 'Gene', (261, 264))	('p53', 'Gene', '7157', (261, 264))	('ElonginC', 'Gene', (161, 169))	('p53 binding', 'molecular_function', 'GO:0002039', ('129', '140'))	('pVHL', 'Gene', '7428', (238, 242))	('binding', 'molecular_function', 'GO:0005488', ('170', '177'))	('ElonginC', 'Gene', '6921', (161, 169))	('affect', 'Reg', (231, 237))	('pVHL', 'Gene', '7428', (67, 71))	('HIF1/2alpha', 'Protein', (272, 283))	('pVHL', 'Gene', (238, 242))	('p53', 'Gene', (129, 132))	('p53', 'Gene', '7157', (129, 132))	('pVHL', 'Gene', (67, 71))	('missense mutations', 'Var', (190, 208))	('binding', 'Interaction', (133, 140))
24464	28052007	The VHL mutations Cys162Arg, Arg161Pro and Arg161X were unable to downregulate HIF1/2alpha at the protein level.	('Cys162Arg', 'SUBSTITUTION', 'None', (18, 27))	('Arg161Pro', 'Var', (29, 38))	('VHL', 'Gene', '7428', (4, 7))	('Arg161X', 'SUBSTITUTION', 'None', (43, 50))	('Arg161X', 'Var', (43, 50))	('Arg161Pro', 'SUBSTITUTION', 'None', (29, 38))	('HIF1/2alpha', 'Protein', (79, 90))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('Cys162Arg', 'Var', (18, 27))	('VHL', 'Gene', (4, 7))	('downregulate', 'NegReg', (66, 78))
24465	28052007	This result was expected for the nonsense mutation Arg161X and for Arg161Pro due to its predicted destabilizing effect on pVHL stability but not for Cys162Arg which is predicted to be neutral.	('Cys162Arg', 'Var', (149, 158))	('Arg161Pro', 'SUBSTITUTION', 'None', (67, 76))	('Cys162Arg', 'SUBSTITUTION', 'None', (149, 158))	('Arg161Pro', 'Var', (67, 76))	('destabilizing', 'PosReg', (98, 111))	('Arg161X', 'SUBSTITUTION', 'None', (51, 58))	('Arg161X', 'Var', (51, 58))	('pVHL', 'Gene', (122, 126))	('pVHL', 'Gene', '7428', (122, 126))
24466	28052007	As it was demonstrated for the missense mutations Cys162Phe and Cys162Ala, Cys162Arg also seems to impair ElonginC binding, thus leading to HIF1/2alpha accumulation.	('impair', 'NegReg', (99, 105))	('Cys162Arg', 'Var', (75, 84))	('ElonginC', 'Gene', (106, 114))	('leading to', 'Reg', (129, 139))	('Cys162Ala', 'Var', (64, 73))	('Cys162Phe', 'Var', (50, 59))	('Cys162Ala', 'SUBSTITUTION', 'None', (64, 73))	('ElonginC', 'Gene', '6921', (106, 114))	('Cys162Arg', 'SUBSTITUTION', 'None', (75, 84))	('HIF1/2alpha', 'MPA', (140, 151))	('accumulation', 'PosReg', (152, 164))	('Cys162Phe', 'SUBSTITUTION', 'None', (50, 59))	('binding', 'molecular_function', 'GO:0005488', ('115', '122'))
24467	28052007	Mutant Arg161Gln remained only partly functional for HIF1/2alpha degradation but like VHL30 (wild-type), Leu158Val was able to fully downregulate HIF1/2alpha.	('Arg161Gln', 'SUBSTITUTION', 'None', (7, 16))	('Arg161Gln', 'Var', (7, 16))	('downregulate', 'NegReg', (133, 145))	('HIF1/2alpha', 'MPA', (146, 157))	('Leu158Val', 'Chemical', '-', (105, 114))	('HIF1/2alpha degradation', 'MPA', (53, 76))	('degradation', 'biological_process', 'GO:0009056', ('65', '76'))	('VHL', 'Gene', (86, 89))	('Leu158Val', 'Var', (105, 114))	('VHL', 'Gene', '7428', (86, 89))
24468	28052007	Notably, Arg161Gln had a milder effect on HIF1alpha degradation than on HIF2alpha.	('Arg161Gln', 'SUBSTITUTION', 'None', (9, 18))	('HIF1alpha', 'Gene', (42, 51))	('Arg161Gln', 'Var', (9, 18))	('HIF1alpha', 'Gene', '3091', (42, 51))	('HIF2alpha', 'Gene', '2034', (72, 81))	('degradation', 'biological_process', 'GO:0009056', ('52', '63'))	('HIF2alpha', 'Gene', (72, 81))
24469	28052007	In contrast to HIF1/2alpha, p53 expression was hardly affected by the VHL mutations.	('p53', 'Gene', (28, 31))	('VHL', 'Gene', (70, 73))	('VHL', 'Gene', '7428', (70, 73))	('p53', 'Gene', '7157', (28, 31))	('mutations', 'Var', (74, 83))
24471	28052007	We hypothesized that VHL mutations could affect p53 activity rather than stability in our stable cell lines.	('p53', 'Gene', (48, 51))	('mutations', 'Var', (25, 34))	('p53', 'Gene', '7157', (48, 51))	('activity', 'MPA', (52, 60))	('VHL', 'Gene', (21, 24))	('VHL', 'Gene', '7428', (21, 24))	('affect', 'Reg', (41, 47))
24473	28052007	The RNA levels of TP53, p21 and Noxa were lower in all VHL mutant cell lines compared to those in RCC4 VHL30.	('RCC4', 'Gene', (98, 102))	('Noxa', 'Gene', (32, 36))	('VHL', 'Gene', '7428', (103, 106))	('TP53', 'Gene', '7157', (18, 22))	('p21', 'Gene', (24, 27))	('lower', 'NegReg', (42, 47))	('mutant', 'Var', (59, 65))	('TP53', 'Gene', (18, 22))	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('VHL', 'Gene', (55, 58))	('Noxa', 'Gene', '5366', (32, 36))	('RCC4', 'Gene', '84925', (98, 102))	('VHL', 'Gene', '7428', (55, 58))	('p21', 'Gene', '1026', (24, 27))	('VHL', 'Gene', (103, 106))
24476	28052007	In VHL mutated tumors RNA levels of TP53, p21, Bax and Noxa were significantly lower than in tumors with VHL wild-type, which confirmed the results obtained from the cell lines.	('p21', 'Gene', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('TP53', 'Gene', (36, 40))	('Noxa', 'Gene', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('RNA', 'cellular_component', 'GO:0005562', ('22', '25'))	('RNA levels', 'MPA', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('VHL', 'Gene', (3, 6))	('tumors', 'Disease', (15, 21))	('p21', 'Gene', '1026', (42, 45))	('VHL', 'Gene', (105, 108))	('lower', 'NegReg', (79, 84))	('TP53', 'Gene', '7157', (36, 40))	('Bax', 'Gene', (47, 50))	('tumors', 'Disease', (93, 99))	('VHL', 'Gene', '7428', (3, 6))	('Bax', 'Gene', '581', (47, 50))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('Noxa', 'Gene', '5366', (55, 59))	('VHL', 'Gene', '7428', (105, 108))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('mutated', 'Var', (7, 14))
24479	28052007	Our results demonstrated that HIF1alpha knockdown led to an upregulation of TP53 and its downstream targets in both pVHL re-expressing and pVHL deficient RCC4.	('RCC4', 'Gene', '84925', (154, 158))	('HIF1alpha', 'Gene', (30, 39))	('RCC4', 'Gene', (154, 158))	('TP53', 'Gene', '7157', (76, 80))	('HIF1alpha', 'Gene', '3091', (30, 39))	('knockdown', 'Var', (40, 49))	('VHL deficient', 'Disease', (140, 153))	('upregulation', 'PosReg', (60, 72))	('VHL deficient', 'Disease', 'MESH:D006623', (140, 153))	('pVHL', 'Gene', '7428', (139, 143))	('pVHL', 'Gene', (139, 143))	('TP53', 'Gene', (76, 80))	('RCC', 'Phenotype', 'HP:0005584', (154, 157))	('pVHL', 'Gene', '7428', (116, 120))	('pVHL', 'Gene', (116, 120))
24482	28052007	To further prove the association of VHL mutation status with p53 signaling on the protein level in ccRCC tissue, we investigated the expression of the p53 downstream target p21 by immunohistochemistry on the same TMA that was stained for p53.	('mutation', 'Var', (40, 48))	('VHL', 'Gene', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('TMA', 'Disease', (213, 216))	('p53', 'Gene', '7157', (151, 154))	('p53', 'Gene', (238, 241))	('p53', 'Gene', '7157', (238, 241))	('ccRCC', 'Disease', (99, 104))	('VHL', 'Gene', '7428', (36, 39))	('p21', 'Gene', '1026', (173, 176))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('p21', 'Gene', (173, 176))	('TMA', 'Disease', 'MESH:D000783', (213, 216))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('p53', 'Gene', (151, 154))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))
24484	28052007	Similarly to p53, p21 expression was significantly lower in VHL LOF mutants compared to wild-type, thus supporting a potential role of pVHL's integrity in sustaining functional p53 signaling.	('p21', 'Gene', '1026', (18, 21))	('p21', 'Gene', (18, 21))	('VHL', 'Gene', (60, 63))	('p53', 'Gene', (177, 180))	('p53', 'Gene', '7157', (13, 16))	('p53', 'Gene', '7157', (177, 180))	('signaling', 'biological_process', 'GO:0023052', ('181', '190'))	('VHL', 'Gene', '7428', (60, 63))	('pVHL', 'Gene', '7428', (135, 139))	('lower', 'NegReg', (51, 56))	('VHL', 'Gene', (136, 139))	('VHL', 'Gene', '7428', (136, 139))	('LOF', 'NegReg', (64, 67))	('pVHL', 'Gene', (135, 139))	('p53', 'Gene', (13, 16))	('mutants', 'Var', (68, 75))	('expression', 'MPA', (22, 32))
24489	28052007	All our selected VHL mutations led to an attenuated apoptosis compared to VHL wild-type, but no significant change in cell proliferation was seen.	('attenuated', 'NegReg', (41, 51))	('VHL', 'Gene', (74, 77))	('VHL', 'Gene', '7428', (74, 77))	('VHL', 'Gene', (17, 20))	('cell proliferation', 'biological_process', 'GO:0008283', ('118', '136'))	('apoptosis', 'CPA', (52, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('52', '61'))	('VHL', 'Gene', '7428', (17, 20))	('apoptosis', 'biological_process', 'GO:0006915', ('52', '61'))	('mutations', 'Var', (21, 30))
24490	28052007	Given their apoptosis deficiency, VHL mutant cells seem to have a survival advantage compared to VHL wild-type cells.	('mutant', 'Var', (38, 44))	('VHL', 'Gene', '7428', (97, 100))	('survival advantage', 'CPA', (66, 84))	('apoptosis deficiency', 'Disease', 'MESH:D065703', (12, 32))	('VHL', 'Gene', (34, 37))	('apoptosis deficiency', 'Disease', (12, 32))	('VHL', 'Gene', '7428', (34, 37))	('apoptosis', 'biological_process', 'GO:0006915', ('12', '21'))	('apoptosis', 'biological_process', 'GO:0097194', ('12', '21'))	('VHL', 'Gene', (97, 100))
24491	28052007	However, cells with a missense mutation in the p53 binding domain were less apoptotic than cells with missense mutations affecting the HIF1/2alpha binding domain.	('p53 binding', 'molecular_function', 'GO:0002039', ('47', '58'))	('apoptotic', 'CPA', (76, 85))	('less', 'NegReg', (71, 75))	('missense mutation', 'Var', (22, 39))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))	('binding', 'molecular_function', 'GO:0005488', ('147', '154'))
24492	28052007	Since VHL mutant cells affected apoptosis rather than cell proliferation, we treated the cells both with Camptothecin, a chemotherapeutic drug that stabilizes and activates p53 by inducing DNA damage and decreases cell proliferation and Sunitinib, a TKI which negatively influences cell proliferation and is used to treat ccRCC.	('apoptosis', 'biological_process', 'GO:0097194', ('32', '41'))	('apoptosis', 'biological_process', 'GO:0006915', ('32', '41'))	('decreases', 'NegReg', (204, 213))	('VHL', 'Gene', (6, 9))	('mutant', 'Var', (10, 16))	('affected', 'Reg', (23, 31))	('p53', 'Gene', '7157', (173, 176))	('cell proliferation', 'biological_process', 'GO:0008283', ('214', '232'))	('cell proliferation', 'CPA', (214, 232))	('VHL', 'Gene', '7428', (6, 9))	('Sunitinib', 'Chemical', 'MESH:D000077210', (237, 246))	('activates', 'PosReg', (163, 172))	('ccRCC', 'Disease', (322, 327))	('p53', 'Gene', (173, 176))	('cell proliferation', 'biological_process', 'GO:0008283', ('282', '300'))	('RCC', 'Phenotype', 'HP:0005584', (324, 327))	('Camptothecin', 'Chemical', 'MESH:D002166', (105, 117))	('inducing', 'PosReg', (180, 188))	('cell proliferation', 'CPA', (282, 300))	('DNA', 'cellular_component', 'GO:0005574', ('189', '192'))	('cell proliferation', 'biological_process', 'GO:0008283', ('54', '72'))	('DNA damage', 'MPA', (189, 199))
24494	28052007	In a previous study, the VHL mutants S111R and S111C, which are located in the HIF1/2alpha binding domain showed a decrease in apoptosis compared to VHL wild-type via impairment of recruitment of coactivators p300 and Tip60.	('S111C', 'Var', (47, 52))	('decrease', 'NegReg', (115, 123))	('p300', 'Gene', (209, 213))	('VHL', 'Gene', '7428', (149, 152))	('Tip60', 'Gene', (218, 223))	('apoptosis', 'CPA', (127, 136))	('binding', 'molecular_function', 'GO:0005488', ('91', '98'))	('p300', 'Gene', '2033', (209, 213))	('VHL', 'Gene', (25, 28))	('Tip60', 'Gene', '10524', (218, 223))	('apoptosis', 'biological_process', 'GO:0006915', ('127', '136'))	('impairment', 'NegReg', (167, 177))	('S111C', 'Mutation', 'p.S111C', (47, 52))	('VHL', 'Gene', '7428', (25, 28))	('S111R', 'Mutation', 'rs765978945', (37, 42))	('recruitment', 'MPA', (181, 192))	('VHL', 'Gene', (149, 152))	('apoptosis', 'biological_process', 'GO:0097194', ('127', '136'))
24495	28052007	The loss of ability to recruit coactivators of p53 may explain the low apoptotic activity of our cell lines with VHL missense mutations located in the HIF1/2alpha binding domain.	('VHL', 'Gene', (113, 116))	('apoptotic activity', 'CPA', (71, 89))	('binding', 'molecular_function', 'GO:0005488', ('163', '170'))	('VHL', 'Gene', '7428', (113, 116))	('missense mutations', 'Var', (117, 135))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))	('low', 'NegReg', (67, 70))
24496	28052007	In summary, we found an association of the VHL mutation type and p53 signaling, which was reflected by apoptotic deficiency.	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('VHL', 'Gene', (43, 46))	('association', 'Interaction', (24, 35))	('mutation', 'Var', (47, 55))	('signaling', 'biological_process', 'GO:0023052', ('69', '78'))	('VHL', 'Gene', '7428', (43, 46))
24497	28052007	We also showed that pVHL integrity had a dominant effect over HIF1alpha downregulation in enhancing p53 transactivation suggesting disturbed p53 signaling is provoked by mutant pVHL rather than altered pVHL/HIFalpha axis.	('transactivation', 'biological_process', 'GO:2000144', ('104', '119'))	('pVHL', 'Gene', '7428', (20, 24))	('pVHL', 'Gene', (202, 206))	('pVHL', 'Gene', '7428', (177, 181))	('p53', 'Gene', (141, 144))	('p53', 'Gene', '7157', (141, 144))	('pVHL', 'Gene', (20, 24))	('provoked by', 'Reg', (158, 169))	('HIF1alpha', 'Gene', (62, 71))	('p53', 'Gene', '7157', (100, 103))	('HIF1alpha', 'Gene', '3091', (62, 71))	('pVHL', 'Gene', (177, 181))	('mutant', 'Var', (170, 176))	('enhancing', 'PosReg', (90, 99))	('downregulation', 'NegReg', (72, 86))	('signaling', 'biological_process', 'GO:0023052', ('145', '154'))	('pVHL', 'Gene', '7428', (202, 206))	('p53', 'Gene', (100, 103))
24498	28052007	Notably, two VHL missense mutations in the p53 binding domain, Leu158Val and Arg161Gln, altered p53 signaling but retained HIF1/2alpha degradation function, thus confirming our hypothesis of differing effects of missense mutations on pVHL functions (summarized in figure 10) Our results may scrutinize the rationale of the systematic use of anti-angiogenic drugs, particularly for those metastatic ccRCC with VHL missense mutations that specifically affect non HIF1/2alpha binding sites.	('p53', 'Gene', '7157', (96, 99))	('Leu158Val', 'Chemical', '-', (63, 72))	('Leu158Val', 'Var', (63, 72))	('metastatic ccRCC', 'Disease', (387, 403))	('VHL', 'Gene', (13, 16))	('p53', 'Gene', (43, 46))	('altered', 'Reg', (88, 95))	('Arg161Gln', 'Var', (77, 86))	('p53', 'Gene', (96, 99))	('VHL', 'Gene', (235, 238))	('RCC', 'Phenotype', 'HP:0005584', (400, 403))	('VHL', 'Gene', '7428', (13, 16))	('VHL', 'Gene', (409, 412))	('pVHL', 'Gene', '7428', (234, 238))	('degradation', 'biological_process', 'GO:0009056', ('135', '146'))	('pVHL', 'Gene', (234, 238))	('VHL', 'Gene', '7428', (235, 238))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('VHL', 'Gene', '7428', (409, 412))	('p53 binding', 'molecular_function', 'GO:0002039', ('43', '54'))	('binding', 'molecular_function', 'GO:0005488', ('473', '480'))	('p53', 'Gene', '7157', (43, 46))	('Arg161Gln', 'SUBSTITUTION', 'None', (77, 86))
24499	28052007	A systematic characterization of VHL mutations may help optimizing targeted therapy approaches for patients with metastatic ccRCC.	('metastatic ccRCC', 'Disease', (113, 129))	('VHL', 'Gene', (33, 36))	('patients', 'Species', '9606', (99, 107))	('mutations', 'Var', (37, 46))	('VHL', 'Gene', '7428', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))
24503	28052007	We used the Site Directed Mutator in silico tool to characterize VHL missense mutations in 360 FFPE ccRCC samples which were re-reviewed by two pathologists (H.M., E.D.)	('VHL', 'Gene', '7428', (65, 68))	('VHL', 'Gene', (65, 68))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('missense mutations', 'Var', (69, 87))
24504	28052007	The program calculates the thermodynamic change (ddG) occurring after modification of one amino acid according to the main chain conformation, solvent accessibility and hydrogen bonding class.	('thermodynamic change', 'MPA', (27, 47))	('hydrogen', 'Chemical', 'MESH:D006859', (169, 177))	('modification', 'Var', (70, 82))
24505	28052007	The missense mutations were then classified as follows: - ddg < -2.0 or >2.0: highly destabilizing or stabilizing referred as "high impact" - -2.0 <= ddg < 2.0: (slightly) destabilizing, neutral, (slightly) stabilizing referred as "mild impact" The binding domains of HIF1/2alpha (amino acid 67-117), p53 (aa 154-163) and Elongin C (aa 157-171) were assessed as described by Leonardi et al.. We selected four mutations that were located in the overlap of p53 and EloC binding domains of pVHL (aa 157-163): three were predicted to have no or little impact on the protein stability (Leu158Val, Arg161Gln, Cys162Arg, mild impact) and one was predicted to highly destabilize pVHL (Arg161Pro, high impact).	('Cys162Arg', 'Var', (603, 612))	('p53', 'Gene', (455, 458))	('Arg161Gln', 'SUBSTITUTION', 'None', (592, 601))	('p53', 'Gene', '7157', (301, 304))	('Arg161Pro', 'Var', (677, 686))	('pVHL', 'Gene', '7428', (671, 675))	('p53', 'Gene', (301, 304))	('EloC', 'Gene', '6921', (463, 467))	('pVHL', 'Gene', (671, 675))	('Arg161Gln', 'Var', (592, 601))	('protein stability', 'MPA', (562, 579))	('Elongin C', 'Gene', (322, 331))	('EloC', 'Gene', (463, 467))	('pVHL', 'Gene', '7428', (487, 491))	('pVHL', 'Gene', (487, 491))	('Leu158Val', 'Chemical', '-', (581, 590))	('Leu158Val', 'Var', (581, 590))	('Cys162Arg', 'SUBSTITUTION', 'None', (603, 612))	('p53', 'Gene', '7157', (455, 458))	('destabilize', 'NegReg', (659, 670))	('Elongin C', 'Gene', '6921', (322, 331))	('Arg161Pro', 'SUBSTITUTION', 'None', (677, 686))
24506	28052007	Controls located in the HIF1/2alpha binding domain (Tyr98His, Tyr98Asn) and one nonsense mutation (Arg161X) were also included.	('Arg161X', 'SUBSTITUTION', 'None', (99, 106))	('Arg161X', 'Var', (99, 106))	('binding', 'molecular_function', 'GO:0005488', ('36', '43'))	('Tyr98Asn', 'SUBSTITUTION', 'None', (62, 70))	('Tyr98His', 'SUBSTITUTION', 'None', (52, 60))	('Tyr98His', 'Var', (52, 60))	('Tyr98Asn', 'Var', (62, 70))
24507	28052007	The pVHL deficient cell line RCC4 (expressing VHL Ser65Trp, highly destabilizing mutation) was kindly provided by W. Krek (ETH Zurich, Switzerland) and grown under conditions recommended by ATCC.	('pVHL', 'Gene', (4, 8))	('VHL', 'Gene', (46, 49))	('pVHL', 'Gene', '7428', (4, 8))	('VHL deficient', 'Disease', (5, 18))	('VHL', 'Gene', '7428', (46, 49))	('VHL', 'Gene', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('VHL', 'Gene', '7428', (5, 8))	('RCC4', 'Gene', (29, 33))	('RCC4', 'Gene', '84925', (29, 33))	('Ser', 'cellular_component', 'GO:0005790', ('50', '53'))	('Ser65Trp', 'SUBSTITUTION', 'None', (50, 58))	('VHL deficient', 'Disease', 'MESH:D006623', (5, 18))	('Ser65Trp', 'Var', (50, 58))
24509	28052007	A pcDNA3.1 vector encoding VHL wild-type was used to generate the selected mutants with the Quick Change Lightning site-directed mutagenesis kit (Agilent technologies, United States).	('mutagenesis', 'biological_process', 'GO:0006280', ('129', '140'))	('VHL', 'Gene', '7428', (27, 30))	('VHL', 'Gene', (27, 30))	('mutants', 'Var', (75, 82))
24511	28052007	pBabe empty vector and vectors containing the VHL wild-type or the mutant VHL sequences were transfected into Platinum-A Retroviral Packaging Cell Line (Cell Biolabs, United States) for viral pseudo-particles production according to the X-tremeGENE 9 DNA Transfection Reagent 3:1 protocol (Roche Diagnostics, Switzerland).	('VHL', 'Gene', (46, 49))	('VHL', 'Gene', '7428', (46, 49))	('VHL', 'Gene', (74, 77))	('Platinum', 'Chemical', 'MESH:D010984', (110, 118))	('VHL', 'Gene', '7428', (74, 77))	('mutant', 'Var', (67, 73))	('DNA', 'cellular_component', 'GO:0005574', ('251', '254'))
24513	28052007	Polyclonal batches of the transduced RCC4 were then selected with constant concentration of 4mug/mL puromycin for four weeks and then maintained at 2mug/mL for cell culture.	('transduced', 'Var', (26, 36))	('puromycin', 'Chemical', 'MESH:D011691', (100, 109))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('mug', 'molecular_function', 'GO:0043739', ('149', '152'))	('mug', 'molecular_function', 'GO:0043739', ('93', '96'))	('RCC4', 'Gene', (37, 41))	('RCC4', 'Gene', '84925', (37, 41))
24515	28052007	The probes used were Hs00184451 (VHL), Hs00153340 (TP53), Hs00355782 (p21), Hs00180269 (Bax), Hs00736699 (Noxa), Hs00936377 (HIF1alpha) and Hs01026146 (HIF2alpha).	('p21', 'Gene', '1026', (70, 73))	('Hs01026146', 'Var', (140, 150))	('VHL', 'Gene', '7428', (33, 36))	('Hs00355782', 'Var', (58, 68))	('Hs00736699', 'Var', (94, 104))	('TP53', 'Gene', (51, 55))	('Bax', 'Gene', (88, 91))	('Hs00180269', 'Var', (76, 86))	('Bax', 'Gene', '581', (88, 91))	('Hs00936377', 'Var', (113, 123))	('HIF2alpha', 'Gene', (152, 161))	('Noxa', 'Gene', '5366', (106, 110))	('p21', 'Gene', (70, 73))	('HIF1alpha', 'Gene', '3091', (125, 134))	('TP53', 'Gene', '7157', (51, 55))	('Hs00184451', 'Var', (21, 31))	('VHL', 'Gene', (33, 36))	('Noxa', 'Gene', (106, 110))	('HIF2alpha', 'Gene', '2034', (152, 161))	('HIF1alpha', 'Gene', (125, 134))	('Hs00153340', 'Var', (39, 49))
24523	30066941	To investigate the potential genetic mechanism for CLEC3B downregulation in ccRCC, copy number analysis was performed by profiling the copy number variation data from the TCGA project and it was revealed that the copy number loss of CLEC3B was prevalent in up to 88.1% of patients with ccRCC.	('CLEC3B', 'Gene', (233, 239))	('CLEC3B', 'Gene', '7123', (233, 239))	('RCC', 'Disease', (288, 291))	('CLEC3B', 'Gene', (51, 57))	('RCC', 'Disease', (78, 81))	('downregulation', 'NegReg', (58, 72))	('RCC', 'Disease', 'MESH:C538614', (288, 291))	('CLEC3B', 'Gene', '7123', (51, 57))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('patients', 'Species', '9606', (272, 280))	('copy number loss', 'Var', (213, 229))	('prevalent', 'Reg', (244, 253))
24535	30066941	Genetic loss of the tumor suppressor gene VHL, which was originally identified in von Hippel-Lindau disease, is the best recognized gene associated with the development of ccRCC.	('associated', 'Reg', (137, 147))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (82, 107))	('tumor suppressor', 'biological_process', 'GO:0051726', ('20', '36'))	('Genetic', 'Var', (0, 7))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('20', '36'))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('loss', 'NegReg', (8, 12))	('RCC', 'Disease', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('von Hippel-Lindau disease', 'Disease', (82, 107))	('VHL', 'Gene', (42, 45))	('tumor', 'Disease', (20, 25))	('VHL', 'Gene', '7428', (42, 45))
24536	30066941	Loss of VHL, which is located at chromosome 3p25 and encodes phosphorylated (p-)VHL, is the characteristic genetic alteration of ccRCC and is believed to occur at a very early step in renal carcinogenesis.	('renal carcinogenesis', 'Disease', 'MESH:D007674', (184, 204))	('chromosome', 'cellular_component', 'GO:0005694', ('33', '43'))	('VHL', 'Gene', (80, 83))	('VHL', 'Gene', '7428', (8, 11))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (131, 134))	('VHL', 'Gene', '7428', (80, 83))	('Loss', 'Var', (0, 4))	('renal carcinogenesis', 'Disease', (184, 204))	('VHL', 'Gene', (8, 11))
24537	30066941	VHL inactivation increases the risk of developing ccRCC, whereas the restoration of VHL function in VHL-/- ccRCC cells is sufficient to inhibit tumorigenesis in vivo.	('tumor', 'Disease', (144, 149))	('inactivation', 'Var', (4, 16))	('VHL', 'Gene', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('inhibit', 'NegReg', (136, 143))	('VHL', 'Gene', '7428', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('VHL', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('VHL', 'Gene', (100, 103))	('VHL', 'Gene', '7428', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('function', 'MPA', (88, 96))	('VHL', 'Gene', '7428', (100, 103))
24597	30066941	The results demonstrated that the copy number loss of CLEC3B was detected in up to 88.1% of patients with ccRCC, including 10.6% homozygous deletions (deep deletion) and 77.5% hemizygous deletions.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('CLEC3B', 'Gene', '7123', (54, 60))	('RCC', 'Disease', (108, 111))	('patients', 'Species', '9606', (92, 100))	('copy number loss', 'Var', (34, 50))	('CLEC3B', 'Gene', (54, 60))
24599	30066941	Previous studies revealed that ~90% of ccRCC were associated with the bi-allelic somatic mutation in the VHL tumor suppressor gene.	('tumor suppressor', 'biological_process', 'GO:0051726', ('109', '125'))	('VHL tumor', 'Disease', (105, 114))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('109', '125'))	('VHL tumor', 'Disease', 'MESH:D006623', (105, 114))	('bi-allelic somatic mutation', 'Var', (70, 97))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('associated', 'Reg', (50, 60))	('RCC', 'Disease', (41, 44))
24602	30066941	Together, these data indicate that the copy number loss events of CLEC3B and VHL are potentially coupled during ccRCC tumorigenesis.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('VHL', 'Gene', (77, 80))	('CLEC3B', 'Gene', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('coupled', 'Reg', (97, 104))	('CLEC3B', 'Gene', '7123', (66, 72))	('VHL', 'Gene', '7428', (77, 80))	('copy number loss', 'Var', (39, 55))	('tumor', 'Disease', (118, 123))
24603	30066941	It was additionally observed that the copy number loss of the CLEC3B gene appeared to be specific to ccRCC, as the deep deletion frequency was substantially higher in ccRCC compared with all other cancer types in the TCGA project (Fig.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('CLEC3B', 'Gene', (62, 68))	('RCC', 'Disease', (169, 172))	('deep deletion', 'Var', (115, 128))	('cancer', 'Disease', (197, 203))	('CLEC3B', 'Gene', '7123', (62, 68))	('higher', 'PosReg', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))
24607	30066941	These results indicate that the copy number loss is a ccRCC-specific oncogenic driving event during tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('RCC', 'Disease', (56, 59))	('copy number loss', 'Var', (32, 48))	('tumor', 'Disease', (100, 105))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
24614	30066941	It was revealed that the 786-O,769-P and Caki-1 cell lines produced substantially lower levels of endogenous CLEC3B expression compared with the ACHN cell line, and 786-O and 769-P were selected for a transient overexpression study.	('levels', 'MPA', (88, 94))	('786-O', 'Var', (165, 170))	('CLEC3B', 'Gene', (109, 115))	('CLEC3B', 'Gene', '7123', (109, 115))	('lower', 'NegReg', (82, 87))
24617	30066941	Repression of proliferation was also indicated by the significantly decreased level of the proliferative cellular marker Ki-67 in 786-O cells transfected with CLEC3B compared with the negative control (P<0.01; Fig.	('decreased', 'NegReg', (68, 77))	('CLEC3B', 'Gene', (159, 165))	('level of the proliferative cellular marker Ki-67', 'MPA', (78, 126))	('transfected', 'Var', (142, 153))	('CLEC3B', 'Gene', '7123', (159, 165))	('Repression', 'NegReg', (0, 10))
24634	30066941	Genetic alterations, including CNVs, serve an essential role in the dysregulation of cancer genes.	('Genetic alterations', 'Var', (0, 19))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('dysregulation', 'MPA', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
24636	30066941	The present study revealed that the copy number loss of CLEC3B is high in ccRCC, but is not notable in other cancer types, suggesting that CLEC3B loss is a ccRCC-specific event.	('loss', 'NegReg', (146, 150))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('copy number', 'Var', (36, 47))	('RCC', 'Disease', (76, 79))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('CLEC3B', 'Gene', (56, 62))	('CLEC3B', 'Gene', '7123', (56, 62))	('CLEC3B', 'Gene', (139, 145))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))	('CLEC3B', 'Gene', '7123', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
24637	30066941	The chromosomal loss in the VHL gene locus is the characteristic genetic alteration of ccRCC and is believed to increase the risk of developing ccRCC.	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('chromosomal loss', 'Var', (4, 20))	('RCC', 'Disease', (89, 92))	('increase', 'PosReg', (112, 120))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('VHL', 'Gene', (28, 31))	('VHL', 'Gene', '7428', (28, 31))
24646	30066941	CLEC3B C-Type Lectin Domain Family 3 Member B CNV copy number variation TCGA the Cancer Genome Atlas KIRC kidney renal clear cell carcinoma GEO Gene Expression Omnibus ccRCC clear cell renal cell carcinoma VHL von Hippel-Lindau Tumor Suppressor pRCC papillary renal cell carcinoma OS overall survival DFS disease-free survival HR hazard ratio CI confidence interval RTCA real-time cell analyzer system	('Gene Expression', 'biological_process', 'GO:0010467', ('144', '159'))	('Cancer Genome Atlas', 'Disease', (81, 100))	('CLEC3B', 'Gene', '7123', (0, 6))	('variation', 'Var', (62, 71))	('Tumor Suppressor', 'molecular_function', 'GO:0008181', ('228', '244'))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (174, 205))	('OS', 'Chemical', '-', (281, 283))	('kidney renal clear cell carcinoma', 'Disease', (106, 139))	('VHL', 'Gene', '7428', (206, 209))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (250, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))	('Cancer', 'Phenotype', 'HP:0002664', (81, 87))	('CLEC3B', 'Gene', (0, 6))	('Tumor Suppressor', 'biological_process', 'GO:0051726', ('228', '244'))	('RCC', 'Disease', (170, 173))	('pRCC', 'Gene', '5546', (245, 249))	('von Hippel-Lindau Tumor', 'Disease', (210, 233))	('Tumor', 'Phenotype', 'HP:0002664', (228, 233))	('clear cell renal cell carcinoma', 'Disease', (174, 205))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (185, 205))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (250, 280))	('RCC', 'Disease', (246, 249))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('C-Type Lectin Domain Family 3 Member B', 'Gene', (7, 45))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (174, 205))	('pRCC', 'Gene', (245, 249))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (81, 100))	('papillary renal cell carcinoma', 'Disease', (250, 280))	('RCC', 'Disease', 'MESH:C538614', (246, 249))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (260, 280))	('Lectin', 'molecular_function', 'GO:0005530', ('14', '20'))	('VHL', 'Gene', (206, 209))	('von Hippel-Lindau Tumor', 'Disease', 'MESH:D006623', (210, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('C-Type Lectin Domain Family 3 Member B', 'Gene', '7123', (7, 45))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (106, 139))
24650	32406866	The prognostic value of TGFBI was validated by performing OS, CSS, and PFS analyses based on GSE29609 and E-MTAB-3267.	('GSE29609', 'Var', (93, 101))	('E-MTAB', 'Chemical', '-', (106, 112))	('MTAB', 'molecular_function', 'GO:0047152', ('108', '112'))	('TGFBI', 'Gene', '7045', (24, 29))	('TGFBI', 'Gene', (24, 29))
24652	32406866	Further analysis demonstrated that CNVs of TGFBI was associated with OS of patients with ccRCC.	('TGFBI', 'Gene', '7045', (43, 48))	('CNVs', 'Var', (35, 39))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('patients', 'Species', '9606', (75, 83))	('RCC', 'Disease', (91, 94))	('TGFBI', 'Gene', (43, 48))	('associated', 'Reg', (53, 63))
24672	32406866	As for the neoplasm histologic grade, patients with Gx, G1, G2, G3, G4 grade accounted for 0.9% (n = 5), 2.7% (n = 14), 43.1% (n = 227), 39.1% (n = 206), 14.2% (n = 75), respectively.	('G4 grade', 'Var', (68, 76))	('neoplasm', 'Disease', (11, 19))	('neoplasm', 'Phenotype', 'HP:0002664', (11, 19))	('neoplasm', 'Disease', 'MESH:D009369', (11, 19))	('patients', 'Species', '9606', (38, 46))
24676	32406866	After calculating immune score and stromal score of each ccRCC from TCGA-KIRC, immune scores ranged from -1109.36 to 2920.81 meanwhile stromal scores ranged from -1530.11 to 1955.39 as the result suggested (Supplementary Table 1).	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('2920.81', 'Var', (117, 124))
24680	32406866	The result suggested that ccRCC patients with high immune score had worse OS compared with these with low immune score (P = 0.0024, Figure 2B).	('high immune score', 'Var', (46, 63))	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('patients', 'Species', '9606', (32, 40))	('low immune score', 'Phenotype', 'HP:0002721', (102, 118))	('RCC', 'Disease', (28, 31))
24682	32406866	Moreover, DEGs were significantly correlated with four KEGG pathways including complement and coagulation cascades, cytokine-cytokine receptor interaction, staphylococcus aureus infection, and viral protein interaction with cytokine and cytokine receptor suggested by Figure 4D.	('aureus infection', 'Disease', (171, 187))	('cytokine-cytokine receptor interaction', 'MPA', (116, 154))	('staphylococcus aureus infection', 'Phenotype', 'HP:0002726', (156, 187))	('coagulation', 'biological_process', 'GO:0050817', ('94', '105'))	('viral protein', 'Protein', (193, 206))	('KEGG pathways', 'Pathway', (55, 68))	('aureus infection', 'Disease', 'MESH:D013203', (171, 187))	('DEGs', 'Var', (10, 14))	('correlated', 'Reg', (34, 44))	('protein', 'cellular_component', 'GO:0003675', ('199', '206'))
24694	32406866	To validate the prognostic value of TGFBI, we performed three different survival analyses (OS, CSS, PFS) for all the candidate hub genes based on GSE29609.	('GSE29609', 'Var', (146, 154))	('TGFBI', 'Gene', '7045', (36, 41))	('hub', 'Gene', '1993', (127, 130))	('TGFBI', 'Gene', (36, 41))	('hub', 'Gene', (127, 130))
24695	32406866	As shown in Figure 8D, high expressions of TGFBI (P = 0.030) were associated with worse OS.	('TGFBI', 'Gene', (43, 48))	('high expressions', 'Var', (23, 39))	('worse OS', 'Disease', (82, 90))	('TGFBI', 'Gene', '7045', (43, 48))
24696	32406866	Meanwhile, there was a trend that patients with high expression of TGFBI had worse CSS (P = 0.066, Figure 8E) and PFS (P = 0.062 suggested by E-MTAB-3267 (Figure 8C), P = 0.054 suggested by GSE29609 (Figure 8F)).	('TGFBI', 'Gene', '7045', (67, 72))	('MTAB', 'molecular_function', 'GO:0047152', ('144', '148'))	('E-MTAB', 'Chemical', '-', (142, 148))	('CSS', 'CPA', (83, 86))	('TGFBI', 'Gene', (67, 72))	('patients', 'Species', '9606', (34, 42))	('high expression', 'Var', (48, 63))	('PFS', 'CPA', (114, 117))	('worse', 'NegReg', (77, 82))
24709	32406866	When talking about the association between CNVs of TGFBI and survival of patients with ccRCC, there was a trend that amplification of TGFBI caused better OS (Figure 11D) and DFS (Figure 11E) of patients with ccRCC.	('TGFBI', 'Gene', (51, 56))	('patients', 'Species', '9606', (194, 202))	('better', 'PosReg', (147, 153))	('DFS', 'MPA', (174, 177))	('TGFBI', 'Gene', '7045', (134, 139))	('TGFBI', 'Gene', (134, 139))	('RCC', 'Disease', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('TGFBI', 'Gene', '7045', (51, 56))	('RCC', 'Disease', (210, 213))	('patients', 'Species', '9606', (73, 81))	('amplification', 'Var', (117, 130))	('RCC', 'Disease', 'MESH:C538614', (210, 213))
24730	32406866	The result of TGFBI genetical alteration demonstrated that hub gene altered in 75 of 533 ccRCC patients, and the main type was amplification.	('alteration', 'Var', (30, 40))	('patients', 'Species', '9606', (95, 103))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('hub', 'Gene', '1993', (59, 62))	('RCC', 'Disease', (91, 94))	('TGFBI', 'Gene', '7045', (14, 19))	('hub', 'Gene', (59, 62))	('TGFBI', 'Gene', (14, 19))	('altered', 'Reg', (68, 75))
24742	32406866	found that TGFBI expression in esophageal squamous cell carcinoma was associated with poor prognosis and hematogenous metastasis recurrence.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (31, 65))	('associated', 'Reg', (70, 80))	('esophageal squamous cell carcinoma', 'Disease', (31, 65))	('expression', 'Var', (17, 27))	('TGFBI', 'Gene', '7045', (11, 16))	('TGFBI', 'Gene', (11, 16))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
24747	32406866	Secondly, CSS and PFS analyses of hub genes not showed significant results based on GSE29609 as we expected.	('hub', 'Gene', (34, 37))	('GSE29609', 'Var', (84, 92))	('hub', 'Gene', '1993', (34, 37))
24765	32406866	DEGs with P value < 0.05 in both the two survival analyses were thought as candidate hub genes.	('hub', 'Gene', (85, 88))	('DEGs', 'Var', (0, 4))	('hub', 'Gene', '1993', (85, 88))
24771	32406866	Based on E-MTAB-3267 and GSE29609, three different survival analyses including OS, cancer specific survival (CSS), and progression free survival (PFS) were performed to validate the prognostic value of hub genes.	('hub', 'Gene', '1993', (202, 205))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('E-MTAB', 'Chemical', '-', (9, 15))	('MTAB', 'molecular_function', 'GO:0047152', ('11', '15'))	('hub', 'Gene', (202, 205))	('GSE29609', 'Var', (25, 33))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
24796	30670025	In this study, we found that the expression of the lncRNA OTUD6B-AS1 was downregulated in ccRCC tissue samples and that patients with low OTUD6B-AS1 expression had shorter overall survival than patients with high OTUD6B-AS1 expression, which showed that the different expression level of OTUD6B-AS1 indirectly correlated with survival of patients.	('shorter', 'NegReg', (164, 171))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('downregulated', 'NegReg', (73, 86))	('expression', 'MPA', (33, 43))	('patients', 'Species', '9606', (338, 346))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('OTUD6B-AS1', 'Gene', '100506365', (58, 68))	('OTUD6B-AS1', 'Gene', '100506365', (138, 148))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('OTUD6B-AS1', 'Gene', (58, 68))	('OTUD6B-AS1', 'Gene', '100506365', (288, 298))	('patients', 'Species', '9606', (194, 202))	('OTUD6B-AS1', 'Gene', (138, 148))	('OTUD6B-AS1', 'Gene', (288, 298))	('overall survival', 'MPA', (172, 188))	('OTUD6B-AS1', 'Gene', '100506365', (213, 223))	('patients', 'Species', '9606', (120, 128))	('low', 'Var', (134, 137))	('OTUD6B-AS1', 'Gene', (213, 223))
24811	30670025	For instance, the lncRNA HOTAIR is highly expressed in a variety of cancer cells and regulates the methylation level of histone H3K27 by recruiting PRC2 to specific locus, leading to the formation of repressor chromatin complexes and the epigenetic silencing of tumor suppressor genes, which thus promotes the occurrence and progression of multiple malignancies, including colorectal cancer, cervical cancer, and RCC.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('cancer', 'Disease', 'MESH:D009369', (401, 407))	('colorectal cancer', 'Disease', 'MESH:D015179', (373, 390))	('multiple malignancies', 'Disease', (340, 361))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('262', '278'))	('formation', 'biological_process', 'GO:0009058', ('187', '196'))	('HOTAIR', 'Gene', '100124700', (25, 31))	('colorectal cancer', 'Disease', (373, 390))	('PRC2', 'Gene', (148, 152))	('cancer', 'Disease', 'MESH:D009369', (384, 390))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('tumor suppressor', 'biological_process', 'GO:0051726', ('262', '278'))	('HOTAIR', 'Gene', (25, 31))	('promotes', 'PosReg', (297, 305))	('RCC', 'Disease', (413, 416))	('RCC', 'Phenotype', 'HP:0005584', (413, 416))	('tumor', 'Disease', (262, 267))	('cancer', 'Disease', (401, 407))	('cancer', 'Phenotype', 'HP:0002664', (401, 407))	('leading to', 'Reg', (172, 182))	('colorectal cancer', 'Phenotype', 'HP:0003003', (373, 390))	('cervical cancer', 'Disease', 'MESH:D002583', (392, 407))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('cervical cancer', 'Disease', (392, 407))	('RCC', 'Disease', 'MESH:C538614', (413, 416))	('methylation', 'biological_process', 'GO:0032259', ('99', '110'))	('cancer', 'Disease', (384, 390))	('epigenetic silencing', 'Var', (238, 258))	('cancer', 'Disease', (68, 74))	('multiple malignancies', 'Disease', 'MESH:D009369', (340, 361))	('chromatin', 'cellular_component', 'GO:0000785', ('210', '219'))	('cancer', 'Phenotype', 'HP:0002664', (384, 390))
24814	30670025	In addition, a number of studies have confirmed that abnormal expression or functional changes in lncRNA expression are closely related to the formation, local progression, and distant metastasis of urinary tract tumors, such as prostate cancer, bladder cancer and kidney cancer.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('distant metastasis', 'CPA', (177, 195))	('kidney cancer', 'Disease', 'MESH:D007680', (265, 278))	('urinary tract tumors', 'Disease', (199, 219))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('urinary tract tumors', 'Phenotype', 'HP:0010786', (199, 219))	('kidney cancer', 'Phenotype', 'HP:0009726', (265, 278))	('bladder cancer', 'Disease', 'MESH:D001749', (246, 260))	('bladder cancer', 'Disease', (246, 260))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('abnormal', 'Var', (53, 61))	('formation', 'biological_process', 'GO:0009058', ('143', '152'))	('kidney cancer', 'Disease', (265, 278))	('bladder cancer', 'Phenotype', 'HP:0009725', (246, 260))	('expression', 'MPA', (62, 72))	('prostate cancer', 'Disease', 'MESH:D011471', (229, 244))	('urinary tract tumors', 'Disease', 'MESH:D014571', (199, 219))	('prostate cancer', 'Phenotype', 'HP:0012125', (229, 244))	('related', 'Reg', (128, 135))	('prostate cancer', 'Disease', (229, 244))	('lncRNA', 'Protein', (98, 104))	('functional', 'MPA', (76, 86))
24881	30670025	Following the treatment of ACHN and OS-RC-2 cells with 5-Aza-CdR, the expression level of OTUD6B-AS1 was significantly higher in the 5-Aza-CdR-treated cells than in the control cells (Fig.	('OTUD6B-AS1', 'Gene', (90, 100))	('expression level', 'MPA', (70, 86))	('ACHN', 'Gene', '55323', (27, 31))	('OS-RC-2', 'CellLine', 'CVCL:1626', (36, 43))	('higher', 'PosReg', (119, 125))	('OTUD6B-AS1', 'Gene', '100506365', (90, 100))	('5-Aza-CdR', 'Var', (55, 64))	('ACHN', 'Gene', (27, 31))
24929	30670025	In normal mature cells, the Wnt signaling pathway is inactive, but there is abnormal activation of the Wnt signaling pathway in a variety of tumors, and the inhibition of the Wnt/beta-catenin signaling pathway can reduce invasion, metastasis and the occurrence of drug resistance.	('drug resistance', 'CPA', (264, 279))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('metastasis', 'CPA', (231, 241))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('drug resistance', 'biological_process', 'GO:0009315', ('264', '279'))	('drug resistance', 'biological_process', 'GO:0042493', ('264', '279'))	('drug resistance', 'Phenotype', 'HP:0020174', (264, 279))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('103', '124'))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('28', '49'))	('beta-catenin', 'Gene', (179, 191))	('invasion', 'CPA', (221, 229))	('beta-catenin', 'Gene', '1499', (179, 191))	('inhibition', 'Var', (157, 167))	('activation', 'PosReg', (85, 95))	('Wnt signaling pathway', 'Pathway', (103, 124))	('signaling pathway', 'biological_process', 'GO:0007165', ('192', '209'))	('reduce', 'NegReg', (214, 220))
24972	31249809	Mutations in this region such as copy number aberrations and single nucleotide polymorphisms (SNPs) have been implicated in the susceptibility to and progression of cancer.	('implicated', 'Reg', (110, 120))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('copy number aberrations', 'Var', (33, 56))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('single nucleotide polymorphisms', 'Var', (61, 92))
24991	31249809	For instance, in osteosarcoma and colorectal cancer, high PVT1 expression correlated with lymph node metastasis, but this correlation was not observed in ccRCC.	('osteosarcoma', 'Disease', (17, 29))	('lymph node metastasis', 'CPA', (90, 111))	('high', 'Var', (53, 57))	('colorectal cancer', 'Phenotype', 'HP:0003003', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('RCC', 'Disease', (156, 159))	('osteosarcoma', 'Disease', 'MESH:D012516', (17, 29))	('colorectal cancer', 'Disease', (34, 51))	('expression', 'MPA', (63, 73))	('PVT1', 'Gene', (58, 62))	('colorectal cancer', 'Disease', 'MESH:D015179', (34, 51))	('osteosarcoma', 'Phenotype', 'HP:0002669', (17, 29))
25001	31249809	The role of PVT1 in the cell cycle is demonstrated in studies showing that knockdown of PVT1 expression in gastric cancer cells, melanoma cells, and ccRCC significantly induced G0/1 arrest and reduction in S phase.	('S phase', 'CPA', (206, 213))	('arrest', 'Disease', 'MESH:D006323', (182, 188))	('arrest', 'Disease', (182, 188))	('reduction', 'NegReg', (193, 202))	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('knockdown', 'Var', (75, 84))	('cell cycle', 'biological_process', 'GO:0007049', ('24', '34'))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('S phase', 'biological_process', 'GO:0051320', ('206', '213'))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (151, 154))	('gastric cancer', 'Disease', (107, 121))	('induced', 'Reg', (169, 176))	('gastric cancer', 'Disease', 'MESH:D013274', (107, 121))	('PVT1', 'Gene', (88, 92))
25002	31249809	Since the loss of PVT1 expression consistently induced apoptosis and inhibits DNA replication, it is likely that PVT1 regulates the survival, growth, and division of cancer cells.	('loss', 'Var', (10, 14))	('DNA replication', 'CPA', (78, 93))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('DNA replication', 'biological_process', 'GO:0006260', ('78', '93'))	('inhibits', 'NegReg', (69, 77))	('growth', 'CPA', (142, 148))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))	('induced', 'Reg', (47, 54))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('PVT1', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('apoptosis', 'CPA', (55, 64))
25003	31249809	Similarly, knocking down circPVT1 expression in gastric cancer cells decreased cell viability and reduced colony formation.	('circPVT1', 'Gene', (25, 33))	('knocking down', 'Var', (11, 24))	('gastric cancer', 'Phenotype', 'HP:0012126', (48, 62))	('cell viability', 'CPA', (79, 93))	('decreased', 'NegReg', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('colony formation', 'CPA', (106, 122))	('reduced', 'NegReg', (98, 105))	('gastric cancer', 'Disease', (48, 62))	('formation', 'biological_process', 'GO:0009058', ('113', '122'))	('gastric cancer', 'Disease', 'MESH:D013274', (48, 62))
25008	31249809	Mice injected with clear cell renal cell carcinoma, colorectal cancer, or glioma cells overexpressing PVT1 displayed significantly larger tumor volume than control cells, while those injected with cells with knockdown of PVT1 displayed significantly smaller tumor volume.	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', (258, 263))	('clear cell renal cell carcinoma', 'Disease', (19, 50))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('PVT1', 'Var', (102, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('glioma', 'Disease', (74, 80))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (19, 50))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('larger', 'PosReg', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (19, 50))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (30, 50))	('colorectal cancer', 'Disease', (52, 69))
25009	31249809	Knocking down PVT1 significantly reduced tumor volume in bladder, prostate, breast, and lung cancer, as well as hepatocellular carcinoma and glioma.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('lung cancer', 'Disease', (88, 99))	('glioma', 'Phenotype', 'HP:0009733', (141, 147))	('hepatocellular carcinoma', 'Disease', (112, 136))	('breast', 'Disease', (76, 82))	('PVT1', 'Gene', (14, 18))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('reduced', 'NegReg', (33, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))	('tumor', 'Disease', (41, 46))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (112, 136))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('glioma', 'Disease', (141, 147))	('Knocking down', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('glioma', 'Disease', 'MESH:D005910', (141, 147))	('bladder', 'Disease', (57, 64))	('prostate', 'Disease', (66, 74))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (112, 136))
25010	31249809	Overall, mouse xenograft studies confirmed that PVT1 overexpression increased tumor volume and decreased overall survival while knocking down PVT1 had the opposite effect.	('decreased', 'NegReg', (95, 104))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('knocking', 'Var', (128, 136))	('mouse', 'Species', '10090', (9, 14))	('overall survival', 'CPA', (105, 121))	('PVT1', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('overexpression', 'Var', (53, 67))	('tumor', 'Disease', (78, 83))	('increased', 'PosReg', (68, 77))
25012	31249809	Patients who exhibit drug resistance experience poorer prognosis and lower overall survival.	('drug resistance', 'Phenotype', 'HP:0020174', (21, 36))	('lower', 'NegReg', (69, 74))	('Patients', 'Species', '9606', (0, 8))	('drug resistance', 'biological_process', 'GO:0009315', ('21', '36'))	('drug resistance', 'Var', (21, 36))	('overall survival', 'MPA', (75, 91))	('drug resistance', 'biological_process', 'GO:0042493', ('21', '36'))
25017	31249809	Knocking down PVT1 in gastric cancer and osteosarcoma significantly increased cisplatin sensitivity and reversed drug resistance to doxorubicin and cisplatin in resistant cell lines.	('cisplatin sensitivity', 'MPA', (78, 99))	('Knocking down', 'Var', (0, 13))	('osteosarcoma', 'Disease', (41, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('gastric cancer', 'Disease', (22, 36))	('osteosarcoma', 'Phenotype', 'HP:0002669', (41, 53))	('gastric cancer', 'Disease', 'MESH:D013274', (22, 36))	('osteosarcoma', 'Disease', 'MESH:D012516', (41, 53))	('PVT1', 'Gene', (14, 18))	('gastric cancer', 'Phenotype', 'HP:0012126', (22, 36))	('drug resistance', 'Phenotype', 'HP:0020174', (113, 128))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('drug resistance', 'biological_process', 'GO:0042493', ('113', '128'))	('drug resistance', 'biological_process', 'GO:0009315', ('113', '128'))	('reversed', 'NegReg', (104, 112))	('increased', 'PosReg', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('doxorubicin', 'Chemical', 'MESH:D004317', (132, 143))
25022	31249809	Both molecules were analyzed in colorectal and gastric cancers to see how they change with PVT1 knockdown and overexpression.	('knockdown', 'Var', (96, 105))	('PVT1', 'Gene', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('gastric cancers', 'Phenotype', 'HP:0012126', (47, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (47, 61))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('colorectal and gastric cancers', 'Disease', 'MESH:D013274', (32, 62))
25023	31249809	Interestingly, mRNA levels of these molecules decrease with PVT1 knockdown and increase with PVT1 overexpression PVT1 is implicated in DR and MDR in many cancer types, but further study is required to fully understand the pathways that mediate this PVT1-related cancer drug-resistance.	('increase', 'PosReg', (79, 87))	('cancer', 'Disease', (262, 268))	('DR', 'Phenotype', 'HP:0020174', (135, 137))	('drug-resistance', 'Phenotype', 'HP:0020174', (269, 284))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('mRNA levels', 'MPA', (15, 26))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('MDR', 'molecular_function', 'GO:0004745', ('142', '145'))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('DR', 'Phenotype', 'HP:0020174', (143, 145))	('drug-resistance', 'biological_process', 'GO:0042493', ('269', '284'))	('knockdown', 'Var', (65, 74))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('decrease', 'NegReg', (46, 54))	('drug-resistance', 'biological_process', 'GO:0009315', ('269', '284'))	('PVT1', 'Gene', (60, 64))
25033	31249809	In clear cell renal cell carcinoma as well as breast cancer, PVT1 was found to competitively bind miRNAs from the miR-200 family.The miR-200 family has been shown to prevent tumorigenesis and malignancy miR-200 family expression significantly reduces epithelial-mesenchymal transition in mutant p53 expressing cells when exposed to a carcinogen.	('malignancy', 'Disease', (192, 202))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('p53', 'Gene', '7157', (295, 298))	('mutant', 'Var', (288, 294))	('prevent', 'NegReg', (166, 173))	('breast cancer', 'Disease', (46, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (3, 34))	('p53', 'Gene', (295, 298))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 34))	('malignancy', 'Disease', 'MESH:D009369', (192, 202))	('tumor', 'Disease', (174, 179))	('epithelial-mesenchymal transition', 'CPA', (251, 284))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('251', '284'))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('clear cell renal cell carcinoma', 'Disease', (3, 34))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (14, 34))	('reduces', 'NegReg', (243, 250))
25034	31249809	This suggests a link between the competitive binding of miR-200s by PVT1 with the loss of the protective effect of miR-200 expression on mutant p53 expressing cells.	('p53', 'Gene', '7157', (144, 147))	('binding', 'Interaction', (45, 52))	('protective effect', 'CPA', (94, 111))	('binding', 'molecular_function', 'GO:0005488', ('45', '52'))	('loss', 'NegReg', (82, 86))	('mutant', 'Var', (137, 143))	('p53', 'Gene', (144, 147))
25036	31249809	Both miR-190a-5p and miR-488-3p directly target the downstream MEF2C gene, keeping it from binding the JAGGED1 promoter, which has been implicated as a driver of glioma malignancy.	('MEF2C', 'Gene', (63, 68))	('glioma malignancy', 'Disease', 'MESH:D005910', (162, 179))	('glioma malignancy', 'Disease', (162, 179))	('MEF2C', 'Gene', '17260', (63, 68))	('binding', 'molecular_function', 'GO:0005488', ('91', '98'))	('miR-488-3p', 'Var', (21, 31))	('binding', 'Interaction', (91, 98))	('miR-190a-5p', 'Var', (5, 16))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))
25038	31249809	In osteosarcoma, the induction of the PI3K/AKT pathway was found to be induced by PVT1 expression.	('expression', 'Var', (87, 97))	('PI3K/AKT pathway', 'Pathway', (38, 54))	('PVT1', 'Gene', (82, 86))	('osteosarcoma', 'Disease', (3, 15))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('PI3K', 'molecular_function', 'GO:0016303', ('38', '42'))
25040	31249809	In pancreatic cancer, miR-1207-5p/3p inhibition, correlated with PVT1 overexpression, was associated with gemcitabine resistance.	('gemcitabine resistance', 'MPA', (106, 128))	('pancreatic cancer', 'Disease', (3, 20))	('gemcitabine', 'Chemical', 'MESH:C056507', (106, 117))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('associated', 'Reg', (90, 100))	('miR-1207-5p/3p inhibition', 'Var', (22, 47))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))
25044	31249809	Conversely, when PVT1 is knocked down, tumor cell viability decreases, and apoptosis increases.	('decreases', 'NegReg', (60, 69))	('apoptosis', 'biological_process', 'GO:0006915', ('75', '84'))	('PVT1', 'Gene', (17, 21))	('apoptosis', 'CPA', (75, 84))	('knocked down', 'Var', (25, 37))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('increases', 'PosReg', (85, 94))	('apoptosis', 'biological_process', 'GO:0097194', ('75', '84'))
25049	31249809	However, it is well established that high circPVT1 expression correlates with better overall survival in some tumors.	('better', 'PosReg', (78, 84))	('high', 'Var', (37, 41))	('circPVT1', 'Gene', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('expression', 'MPA', (51, 61))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('overall', 'MPA', (85, 92))
25072	33137104	The pVHL-prefoldin interaction was confirmed in human cells and prefoldin knock-down reduced pVHL expression levels.	('pVHL', 'Gene', (4, 8))	('pVHL', 'Gene', '7428', (4, 8))	('knock-down', 'Var', (74, 84))	('human', 'Species', '9606', (48, 53))	('pVHL', 'Gene', '7428', (93, 97))	('pVHL', 'Gene', (93, 97))	('reduced', 'NegReg', (85, 92))
25073	33137104	Furthermore, when pVHL was expressed in Schizosaccharomyces pombe, all prefoldin mutants promoted its aggregation.	('pVHL', 'Gene', '7428', (18, 22))	('pVHL', 'Gene', (18, 22))	('prefoldin', 'Gene', (71, 80))	('aggregation', 'MPA', (102, 113))	('promoted', 'PosReg', (89, 97))	('Schizosaccharomyces pombe', 'Species', '4896', (40, 65))	('mutants', 'Var', (81, 88))
25075	33137104	Low levels of the PFDN3 prefoldin subunit were associated with poor survival in ccRCC patients harboring VHL mutations.	('ccRCC', 'Disease', (80, 85))	('VHL', 'Gene', (105, 108))	('PFDN3', 'Gene', (18, 23))	('mutations', 'Var', (109, 118))	('poor', 'NegReg', (63, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('PFDN3', 'Gene', '7411', (18, 23))	('patients', 'Species', '9606', (86, 94))
25077	33137104	The von Hippel Lindau (VHL) tumor suppressor gene, when mutated, is responsible for the VHL disease, a genetic syndrome predisposing to cancer, and plays a critical early role in the development of sporadic kidney cancers.	('sporadic kidney cancers', 'Disease', (198, 221))	('mutated', 'Var', (56, 63))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('genetic syndrome', 'Disease', (103, 119))	('von Hippel Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (4, 33))	('cancer', 'Disease', (214, 220))	('kidney cancer', 'Phenotype', 'HP:0009726', (207, 220))	('responsible', 'Reg', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('28', '44'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('sporadic kidney cancers', 'Disease', 'MESH:D007680', (198, 221))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('genetic syndrome', 'Disease', 'MESH:D030342', (103, 119))	('tumor suppressor', 'biological_process', 'GO:0051726', ('28', '44'))	('kidney cancers', 'Phenotype', 'HP:0009726', (207, 221))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('VHL disease', 'Disease', 'MESH:D006623', (88, 99))	('VHL disease', 'Disease', (88, 99))
25080	33137104	Furthermore, the expression levels of prefoldin subunit PFDN3 are critical in kidney cancer patients harboring VHL mutations.	('PFDN3', 'Gene', '7411', (56, 61))	('mutations', 'Var', (115, 124))	('VHL', 'Gene', (111, 114))	('PFDN3', 'Gene', (56, 61))	('patients', 'Species', '9606', (92, 100))	('kidney cancer', 'Phenotype', 'HP:0009726', (78, 91))	('kidney cancer', 'Disease', 'MESH:D007680', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('kidney cancer', 'Disease', (78, 91))
25082	33137104	Mutations in the von Hippel Lindau (VHL) gene are responsible for the VHL disease, an autosomal dominant cancer syndrome that predisposes to various benign and malignant tumors, including clear cell Renal Cell Carcinoma (ccRCC), hemangioblastoma or pheochromocytoma.	('VHL disease', 'Disease', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('hemangioblastoma', 'Disease', 'MESH:D018325', (229, 245))	('von Hippel Lindau', 'Disease', 'MESH:D006623', (17, 34))	('VHL', 'Gene', (36, 39))	('pheochromocytoma', 'Disease', 'MESH:D010673', (249, 265))	('Mutations', 'Var', (0, 9))	('ccRCC', 'Phenotype', 'HP:0006770', (221, 226))	('responsible', 'Reg', (50, 61))	('pheochromocytoma', 'Disease', (249, 265))	('autosomal dominant cancer syndrome', 'Disease', 'MESH:D009369', (86, 120))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (199, 219))	('hemangioblastoma', 'Disease', (229, 245))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (229, 245))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (249, 265))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('Carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('malignant tumors', 'Disease', (160, 176))	('malignant tumors', 'Disease', 'MESH:D009369', (160, 176))	('cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (194, 219))	('clear cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (188, 219))	('VHL disease', 'Disease', 'MESH:D006623', (70, 81))	('von Hippel Lindau', 'Disease', (17, 34))	('cell Renal Cell Carcinoma', 'Disease', (194, 219))	('autosomal dominant cancer syndrome', 'Disease', (86, 120))
25083	33137104	Importantly, the VHL gene is also mutated or deleted in 80% of sporadic ccRCC, the most common subtype of kidney cancer.	('kidney cancer', 'Disease', (106, 119))	('VHL gene', 'Gene', (17, 25))	('deleted', 'Var', (45, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('kidney cancer', 'Disease', 'MESH:D007680', (106, 119))	('ccRCC', 'Disease', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('kidney cancer', 'Phenotype', 'HP:0009726', (106, 119))
25090	33137104	Although mutations in pVHL interfering with either HIFalpha and ElonginBC interactions have been characterized, many missense VHL mutations lie outside of known functional pVHL domains raising the possibility that some of these mutations influence pVHL folding and stability by promoting misfolded pVHL degradation.	('promoting', 'PosReg', (278, 287))	('pVHL', 'Gene', (298, 302))	('pVHL', 'Gene', '7428', (172, 176))	('pVHL', 'Gene', '7428', (248, 252))	('missense VHL', 'Gene', (117, 129))	('pVHL', 'Gene', (172, 176))	('mutations', 'Var', (9, 18))	('pVHL', 'Gene', (248, 252))	('stability', 'MPA', (265, 274))	('mutations', 'Var', (228, 237))	('folding', 'MPA', (253, 260))	('mutations', 'Var', (130, 139))	('VHL', 'Gene', (126, 129))	('pVHL', 'Gene', '7428', (22, 26))	('pVHL', 'Gene', '7428', (298, 302))	('degradation', 'biological_process', 'GO:0009056', ('303', '314'))	('pVHL', 'Gene', (22, 26))	('influence', 'Reg', (238, 247))
25102	33137104	Another study of the Drosophila merry-go-round mgr mutant, corresponding to the PFDN3 homologue gene, suggested a cooperation between fruit fly VHL and PFDN3 homologues in tubulin biogenesis and folding.	('fruit fly', 'Species', '7227', (134, 143))	('tubulin', 'Gene', '33501', (172, 179))	('PFDN3', 'Gene', '7411', (80, 85))	('mgr', 'Gene', (47, 50))	('mutant', 'Var', (51, 57))	('mgr', 'Gene', '41365', (47, 50))	('tubulin', 'Gene', (172, 179))	('PFDN3', 'Gene', (80, 85))	('PFDN3', 'Gene', (152, 157))	('Drosophila', 'Species', '7227', (21, 31))	('cooperation', 'Interaction', (114, 125))	('PFDN3', 'Gene', '7411', (152, 157))	('folding', 'MPA', (195, 202))
25106	33137104	Expression of the full-length human PFDN3 subunit, but not a chaperone-deficient mutant, restores pVHL solubility in a yeast pfd3Delta mutant.	('pVHL', 'Gene', (98, 102))	('human', 'Species', '9606', (30, 35))	('mutant', 'Var', (135, 141))	('PFDN3', 'Gene', '7411', (36, 41))	('yeast', 'Species', '4932', (119, 124))	('pfd3', 'Gene', (125, 129))	('restores', 'PosReg', (89, 97))	('pfd3', 'Gene', '7411', (125, 129))	('pVHL', 'Gene', '7428', (98, 102))	('PFDN3', 'Gene', (36, 41))
25107	33137104	In human cells, down-regulation of the whole prefoldin complex through PFDN3 silencing reduces wild-type pVHL expression levels.	('human', 'Species', '9606', (3, 8))	('reduces', 'NegReg', (87, 94))	('down-regulation', 'NegReg', (16, 31))	('regulation', 'biological_process', 'GO:0065007', ('21', '31'))	('PFDN3', 'Gene', '7411', (71, 76))	('silencing', 'Var', (77, 86))	('pVHL', 'Gene', '7428', (105, 109))	('prefoldin complex', 'cellular_component', 'GO:0016272', ('45', '62'))	('pVHL', 'Gene', (105, 109))	('PFDN3', 'Gene', (71, 76))
25108	33137104	In ccRCC TCGA database, a low PFDN3 expression level is correlated with poor survival in patients harboring missense mutated VHL.	('missense mutated', 'Var', (108, 124))	('VHL', 'Gene', (125, 128))	('low', 'NegReg', (26, 29))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('GA', 'Chemical', 'MESH:C001277', (11, 13))	('PFDN3', 'Gene', '7411', (30, 35))	('patients', 'Species', '9606', (89, 97))	('PFDN3', 'Gene', (30, 35))	('poor', 'NegReg', (72, 76))
25110	33137104	Thus, prefoldin function may have an impact on pVHL proteostasis and this should influence VHL-related disease progression.	('prefoldin', 'Protein', (6, 15))	('impact', 'Reg', (37, 43))	('influence', 'Reg', (81, 90))	('pVHL proteostasis', 'Disease', (47, 64))	('VHL-related disease', 'Disease', (91, 110))	('function', 'Var', (16, 24))	('pVHL proteostasis', 'Disease', 'MESH:D057165', (47, 64))
25135	33137104	To confirm this result, we mutated the aa144-156 region of the pVHL ORF by replacing the hydrophobic stretch (GQPIFANITLPVY) by a more neutral stretch of amino acids (GQPSTSNSTSPVY, S3A Fig).	('pVHL', 'Gene', (63, 67))	('mutated', 'Var', (27, 34))	('pVHL', 'Gene', '7428', (63, 67))	('hydrophobic stretch', 'MPA', (89, 108))
25136	33137104	The produced VHL213mut version was fused to BirA, expressed in HEK293 cells and used in a BioID experiment to measure its prefoldin binding capacity.	('VHL213mut', 'Var', (13, 22))	('binding', 'molecular_function', 'GO:0005488', ('132', '139'))	('BirA', 'Chemical', '-', (44, 48))	('HEK293', 'CellLine', 'CVCL:0045', (63, 69))	('binding', 'Interaction', (132, 139))
25137	33137104	As shown on S3B and S3C Fig, the VHL213mut-BirA fusion protein showed a strong reduction in its capacity to biotinylate PFDN1, PFDN3 and PFDN5 that was quite similar to what was observed with the exon-2 deleted VHL172 variant.	('PFDN1', 'Gene', (120, 125))	('VHL172', 'Gene', (211, 217))	('PFDN3', 'Gene', (127, 132))	('PFDN5', 'Gene', '5204', (137, 142))	('VHL213mut-BirA', 'Var', (33, 47))	('PFDN5', 'Gene', (137, 142))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('PFDN1', 'Gene', '5201', (120, 125))	('biotin', 'Chemical', 'MESH:D001710', (108, 114))	('PFDN3', 'Gene', '7411', (127, 132))	('BirA', 'Chemical', '-', (43, 47))	('reduction', 'NegReg', (79, 88))
25139	33137104	Our results also show that alteration of the aa144-156 region of pVHL213 ORF reduced the CUL2 interaction which is essential for the E3 ligase VBC complex function.	('CUL2', 'Gene', '8453', (89, 93))	('VBC complex', 'cellular_component', 'GO:0031462', ('143', '154'))	('pVHL', 'Gene', '7428', (65, 69))	('pVHL', 'Gene', (65, 69))	('alteration', 'Var', (27, 37))	('reduced', 'NegReg', (77, 84))	('VBC', 'Chemical', '-', (143, 146))	('CUL2', 'Gene', (89, 93))	('aa144-156', 'Var', (45, 54))
25147	33137104	All the proteins co-eluted with GFP or GFP-pVHL213 are listed in S1 Table.	('pVHL', 'Gene', (43, 47))	('GFP', 'Var', (32, 35))	('pVHL', 'Gene', '7428', (43, 47))
25151	33137104	We thus decided to study the fate of the pVHL213 protein when expressed in the context of fission yeast prefoldin deletion mutants.	('pVHL', 'Gene', (41, 45))	('fission yeast', 'Species', '4896', (90, 103))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('pVHL', 'Gene', '7428', (41, 45))	('deletion', 'Var', (114, 122))
25152	33137104	As we have identified all PFDN subunits as potential pVHL partners in human cells, we investigated the aggregation propensity of pVHL in the different fission yeast PFDN mutants.	('PFDN', 'Gene', (165, 169))	('fission yeast', 'Species', '4896', (151, 164))	('human', 'Species', '9606', (70, 75))	('mutants', 'Var', (170, 177))	('pVHL', 'Gene', '7428', (53, 57))	('pVHL', 'Gene', '7428', (129, 133))	('pVHL', 'Gene', (53, 57))	('pVHL', 'Gene', (129, 133))
25153	33137104	To date, only two prefoldin subunits have been identified as contributing to protein stability through studies of their deletion mutants in fission yeast.	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('deletion mutants', 'Var', (120, 136))	('contributing', 'Reg', (61, 73))	('fission yeast', 'Species', '4896', (140, 153))	('protein stability', 'MPA', (77, 94))
25158	33137104	To address the role of all prefoldin subunits in pVHL proteostasis in the S. pombe system, pfd1Delta to pfd6Delta deletion mutants were either obtained from other laboratories or prepared in our lab (pfd1Delta, see Materials and Methods).	('pfd1', 'Gene', '5201', (200, 204))	('pVHL proteostasis', 'Disease', (49, 66))	('pfd1', 'Gene', (200, 204))	('pVHL proteostasis', 'Disease', 'MESH:D057165', (49, 66))	('pfd1', 'Gene', '5201', (91, 95))	('pfd1', 'Gene', (91, 95))	('pfd6Delta', 'Gene', (104, 113))	('S. pombe', 'Species', '4896', (74, 82))	('deletion', 'Var', (114, 122))
25162	33137104	Thus, we postulated that other prefoldin mutants should exhibit MT-deficient phenotypes in fission yeast.	('mutants', 'Var', (41, 48))	('prefoldin', 'Protein', (31, 40))	('fission yeast', 'Species', '4896', (91, 104))
25163	33137104	Consistent with this hypothesis, all pfd mutants exhibited hypersensitivity to TBZ, especially alpha-subunit encoding mutants pfd3Delta and pfd5Delta, and cold sensitivity, a phenotype commonly observed for MT-deficient mutants (S6A Fig).	('pfd5Delta', 'Var', (140, 149))	('mutants', 'Var', (41, 48))	('pfd3', 'Gene', (126, 130))	('exhibited', 'Reg', (49, 58))	('pfd3', 'Gene', '7411', (126, 130))	('TBZ', 'Chemical', 'MESH:D013827', (79, 82))	('hypersensitivity', 'Disease', 'MESH:D004342', (59, 75))	('hypersensitivity', 'biological_process', 'GO:0002524', ('59', '75'))	('hypersensitivity', 'Disease', (59, 75))
25164	33137104	In pfd mutants, we observed twice more frequently mitotic defects such as archery-bow like DNA structures and unequal chromosome partition in mitosis (S6D Fig).	('mutants', 'Var', (7, 14))	('mitosis', 'biological_process', 'GO:0000278', ('142', '149'))	('pfd', 'Gene', (3, 6))	('archery-bow like DNA structures', 'CPA', (74, 105))	('mitosis', 'Disease', 'None', (142, 149))	('unequal chromosome partition', 'CPA', (110, 138))	('chromosome', 'cellular_component', 'GO:0005694', ('118', '128'))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('mitotic defects', 'CPA', (50, 65))	('mitosis', 'Disease', (142, 149))
25168	33137104	We conclude that all prefoldin fission yeast mutants show altered MT phenotypes.	('mutants', 'Var', (45, 52))	('fission yeast', 'Species', '4896', (31, 44))	('altered', 'Reg', (58, 65))
25176	33137104	To validate this hypothesis, we out-crossed the strains expressing either GFP or GFP-pVHL213 to the proteasome-deficient mutant nas6Delta.	('pVHL', 'Gene', (85, 89))	('proteasome', 'molecular_function', 'GO:0004299', ('100', '110'))	('proteasome', 'cellular_component', 'GO:0000502', ('100', '110'))	('GFP', 'Var', (74, 77))	('pVHL', 'Gene', '7428', (85, 89))
25177	33137104	We also observed an increase of pVHL213 levels in the insoluble fraction of leu1::VHL213 nas6Delta cell extracts (Fig 3C).	('insoluble fraction', 'cellular_component', 'GO:0005626', ('54', '72'))	('leu1', 'Var', (76, 80))	('pVHL', 'Gene', '7428', (32, 36))	(':VHL213', 'Gene', (81, 88))	('pVHL', 'Gene', (32, 36))	('nas6Delta', 'Var', (89, 98))	('increase', 'PosReg', (20, 28))
25183	33137104	We observed aggregation stimulation in GA-treated leu1::VHL213 but not in leu1::GFP cells (Fig 3D and 3E).	('aggregation', 'MPA', (12, 23))	('leu1::VHL213', 'Var', (50, 62))	('stimulation', 'PosReg', (24, 35))	(':VHL213', 'Var', (55, 62))	('GA', 'Chemical', 'MESH:C001277', (39, 41))
25185	33137104	To address the role of prefoldin interaction with pVHL, we analyzed pVHL aggregation phenotype in all six prefoldin deletion mutants.	('pVHL', 'Gene', '7428', (50, 54))	('deletion mutants', 'Var', (116, 132))	('prefoldin', 'Gene', (106, 115))	('pVHL', 'Gene', (50, 54))	('pVHL', 'Gene', '7428', (68, 72))	('pVHL', 'Gene', (68, 72))
25186	33137104	We microscopically observed that all leu1::VHL213 pfd mutant strains showed a significantly higher proportion of large aggregate-containing cells (up to 10.3% in pfd3Delta mutant) compared to 0.1% in wild-type background (Fig 4A and 4B).	('higher', 'PosReg', (92, 98))	('pfd3', 'Gene', '7411', (162, 166))	('pfd3', 'Gene', (162, 166))	('leu1', 'Gene', (37, 41))	('mutant', 'Var', (54, 60))	('large', 'CPA', (113, 118))	(':VHL213', 'Gene', (42, 49))	('pfd', 'PosReg', (50, 53))
25187	33137104	Therefore, the absence of any single prefoldin subunit stimulated pVHL aggregation.	('stimulated', 'PosReg', (55, 65))	('pVHL', 'Gene', '7428', (66, 70))	('pVHL', 'Gene', (66, 70))	('absence', 'Var', (15, 22))	('prefoldin', 'Protein', (37, 46))
25191	33137104	A similar aggregation stimulation was observed in GA-treated cells showing 27% to 61% of large aggregate containing cells in pfd mutants, contrasting with the 6.9% seen in wild-type cells (Fig 4A and 4B).	('mutants', 'Var', (129, 136))	('pfd', 'Gene', (125, 128))	('GA', 'Chemical', 'MESH:C001277', (50, 52))
25195	33137104	Since we observed that fission yeast pfd mutant cells were cold sensitive (S6 Fig), we assayed wild type and pfd mutant growth on solid medium while cells were overexpressing pVHL213 at both 30 C and 20 C. Interestingly, overexpression of GFP-VHL decreased growth in pfd mutants but not in WT cells.	('decreased', 'NegReg', (247, 256))	('pVHL', 'Gene', (175, 179))	('mutants', 'Var', (271, 278))	('mutant', 'Var', (41, 47))	('GFP-VHL', 'Var', (239, 246))	('growth', 'MPA', (257, 263))	('fission yeast', 'Species', '4896', (23, 36))	('decreased growth', 'Phenotype', 'HP:0001510', (247, 263))	('mutant', 'Var', (113, 119))	('pVHL', 'Gene', '7428', (175, 179))
25196	33137104	This phenotype was exacerbated at 20 C (Fig 4D), even in the OFF condition for some mutants when the expression levels of pVHL213 is repressed.	('mutants', 'Var', (84, 91))	('exacerbated', 'PosReg', (19, 30))	('pVHL', 'Gene', (122, 126))	('pVHL', 'Gene', '7428', (122, 126))
25197	33137104	Thus, overexpression of pVHL213 is toxic in pfd mutant backgrounds whereas it is not in wild type cells.	('pVHL', 'Gene', '7428', (24, 28))	('pVHL', 'Gene', (24, 28))	('mutant', 'Var', (48, 54))	('overexpression', 'PosReg', (6, 20))
25198	33137104	A possible explanation for increased pVHL213 aggregation would be that pfd mutants were subjected to a general proteotoxic stress.	('increased', 'PosReg', (27, 36))	('subjected', 'Reg', (88, 97))	('proteotoxic stress', 'Disease', 'MESH:D000079225', (111, 129))	('mutants', 'Var', (75, 82))	('increased pVHL', 'Phenotype', 'HP:0008151', (27, 41))	('pVHL', 'Gene', '7428', (37, 41))	('aggregation', 'MPA', (45, 56))	('pVHL', 'Gene', (37, 41))	('proteotoxic stress', 'Disease', (111, 129))
25199	33137104	To address this question, we first quantified the Hsp70 steady state levels in prefoldin mutants at 30 C (S7A Fig).	('prefoldin', 'Gene', (79, 88))	('Hsp70', 'Gene', (50, 55))	('Hsp70', 'Gene', '3308', (50, 55))	('mutants', 'Var', (89, 96))
25201	33137104	Altogether, these results suggest that pfd mutants exhibit a wild type response to heat regarding Hsp70 protein levels.	('pfd', 'Gene', (39, 42))	('Hsp70', 'Gene', '3308', (98, 103))	('response to heat', 'biological_process', 'GO:0009408', ('71', '87'))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('Hsp70', 'Gene', (98, 103))	('mutants', 'Var', (43, 50))
25203	33137104	This result suggests that pfd mutants show a similar Hsf1-dependent response to heat shock as wild type cells.	('Hsf1', 'Gene', '3297', (53, 57))	('Hsf1', 'Gene', (53, 57))	('response to heat shock', 'biological_process', 'GO:0033638', ('68', '90'))	('response to heat shock', 'biological_process', 'GO:0009408', ('68', '90'))	('shock', 'Phenotype', 'HP:0031273', (85, 90))	('mutants', 'Var', (30, 37))	('pfd', 'Gene', (26, 29))
25205	33137104	We concluded that prefoldin mutants are unlikely subjected to a permanent proteotoxic stress but rather specifically promote the aggregation of pVHL213.	('prefoldin', 'Protein', (18, 27))	('pVHL', 'Gene', (144, 148))	('mutants', 'Var', (28, 35))	('aggregation', 'MPA', (129, 140))	('proteotoxic stress', 'Disease', (74, 92))	('promote', 'PosReg', (117, 124))	('proteotoxic stress', 'Disease', 'MESH:D000079225', (74, 92))	('pVHL', 'Gene', '7428', (144, 148))
25207	33137104	There was no growth difference between wild type and pfd mutant strains compared to the AZC-sensitive ppr1Delta strain.	('mutant', 'Var', (57, 63))	('AZC', 'Chemical', '-', (88, 91))	('pfd mutant', 'Var', (53, 63))
25210	33137104	No significant difference was observed between pfd1Delta or pfd3Delta mutants and the wild type strain, suggesting a similar content of ubiquitinated proteins in wild type and pfd mutant strains.	('pfd3', 'Gene', '7411', (60, 64))	('pfd1', 'Gene', '5201', (47, 51))	('ubiquitin', 'Gene', '850620', (136, 145))	('pfd1', 'Gene', (47, 51))	('mutant', 'Var', (180, 186))	('ubiquitin', 'Gene', (136, 145))	('pfd3', 'Gene', (60, 64))	('content', 'MPA', (125, 132))
25215	33137104	In wild-type or prefoldin mutant backgrounds, pVHL172 expressing cells never exhibited aggregates.	('mutant', 'Var', (26, 32))	('pVHL', 'Gene', '7428', (46, 50))	('pVHL', 'Gene', (46, 50))
25216	33137104	However, in the presence of BZ, a similar pattern of pVHL172 aggregation was observed in both wild-type and prefoldin mutant strains.	('aggregation', 'MPA', (61, 72))	('mutant', 'Var', (118, 124))	('pVHL', 'Gene', '7428', (53, 57))	('BZ', 'Chemical', 'MESH:D000069286', (28, 30))	('pVHL', 'Gene', (53, 57))
25222	33137104	To confirm this result, we also monitored pVHL213 aggregation in the kinesin microtubule motor-encoding gene deletion mutant tea2Delta which has been reported to exhibit a highly penetrant abnormal MT cytoskeleton phenotype.	('pVHL', 'Gene', '7428', (42, 46))	('deletion mutant', 'Var', (109, 124))	('pVHL', 'Gene', (42, 46))	('microtubule', 'cellular_component', 'GO:0005874', ('77', '88'))	('mutant', 'Var', (118, 124))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('201', '213'))	('tea2Delta', 'Gene', (125, 134))	('kinesin', 'molecular_function', 'GO:0003777', ('69', '76'))
25223	33137104	In leu1::VHL213 tea2Delta cells, no significant alteration of aggregation pattern of pVHL213 was observed compared to control cells (S8B and S8C Fig).	(':VHL213 tea2Delta', 'Var', (8, 25))	('pVHL', 'Gene', (85, 89))	('pVHL', 'Gene', '7428', (85, 89))
25225	33137104	Consecutively, human PFDN3 expression suppressed aggregation and reduced growth as well (Fig 4F and 4G).	('growth', 'MPA', (73, 79))	('reduced', 'NegReg', (65, 72))	('PFDN3', 'Gene', (21, 26))	('aggregation', 'CPA', (49, 60))	('suppressed', 'NegReg', (38, 48))	('PFDN3', 'Gene', '7411', (21, 26))	('human', 'Species', '9606', (15, 20))	('expression', 'Var', (27, 37))
25227	33137104	To support the idea that the chaperone function of the prefoldin complex is involved in pVHL213 aggregation and toxicity in yeast, we expressed PFDN3 DeltaNC, a truncated version of human PFDN3, which alters the prefoldin chaperone function.	('PFDN3', 'Gene', (188, 193))	('PFDN3', 'Gene', (144, 149))	('prefoldin complex', 'cellular_component', 'GO:0016272', ('55', '72'))	('prefoldin chaperone function', 'MPA', (212, 240))	('toxicity', 'Disease', (112, 120))	('human', 'Species', '9606', (182, 187))	('DeltaNC', 'Var', (150, 157))	('pVHL', 'Gene', '7428', (88, 92))	('pVHL', 'Gene', (88, 92))	('PFDN3', 'Gene', '7411', (188, 193))	('involved', 'Reg', (76, 84))	('PFDN3', 'Gene', '7411', (144, 149))	('alters', 'Reg', (201, 207))	('toxicity', 'Disease', 'MESH:D064420', (112, 120))	('yeast', 'Species', '4932', (124, 129))
25230	33137104	The PFDN3 DeltaNC version was unable to suppress pVHL213 aggregation as efficiently as the full-length protein (lower panel, Fig 4F).	('PFDN3', 'Gene', (4, 9))	('DeltaNC', 'Var', (10, 17))	('pVHL', 'Gene', '7428', (49, 53))	('pVHL', 'Gene', (49, 53))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('PFDN3', 'Gene', '7411', (4, 9))	('aggregation', 'MPA', (57, 68))
25233	33137104	Consistent with this, expression of the PFDN3 DeltaNC mutant was still able to rescue the growth defect of pfd3Delta cells overexpressing VHL213 (ON, Fig 4G).	('DeltaNC mutant', 'Var', (46, 60))	('growth defect', 'MPA', (90, 103))	('VHL213', 'Gene', (138, 144))	('pfd3', 'Gene', '7411', (107, 111))	('PFDN3', 'Gene', '7411', (40, 45))	('pfd3', 'Gene', (107, 111))	('mutant', 'Var', (54, 60))	('PFDN3', 'Gene', (40, 45))
25236	33137104	PFDN3 silencing revealed that other PFDN subunits were also down-regulated (PFDN1, PFDN2, PFDN4 and PFDN5; Fig 5A and 5B).	('PFDN4', 'Gene', '5203', (90, 95))	('PFDN1', 'Gene', '5201', (76, 81))	('PFDN2', 'Gene', (83, 88))	('down-regulated', 'NegReg', (60, 74))	('PFDN4', 'Gene', (90, 95))	('PFDN1', 'Gene', (76, 81))	('PFDN5', 'Gene', '5204', (100, 105))	('PFDN3', 'Gene', '7411', (0, 5))	('PFDN2', 'Gene', '5202', (83, 88))	('PFDN5', 'Gene', (100, 105))	('silencing', 'Var', (6, 15))	('PFDN3', 'Gene', (0, 5))
25247	33137104	We observed that neither the PFDN1 nor the PFDN3 knock-down significantly altered pVHL172 levels.	('PFDN1', 'Gene', '5201', (29, 34))	('pVHL', 'Gene', (82, 86))	('PFDN3', 'Gene', '7411', (43, 48))	('knock-down', 'Var', (49, 59))	('pVHL', 'Gene', '7428', (82, 86))	('altered', 'Reg', (74, 81))	('PFDN3', 'Gene', (43, 48))	('PFDN1', 'Gene', (29, 34))
25250	33137104	As PFDN silencing might promote an indirect transcriptional down-regulation of the VHL gene, the effect of the silencing of PFDN1, PFDN3 or PFDN1+PFDN3 on VHL expression in HeLa cells was assessed by RT-qPCR analysis.	('PFDN3', 'Gene', '7411', (131, 136))	('PFDN1', 'Gene', (140, 145))	('PFDN1', 'Gene', '5201', (124, 129))	('PFDN', 'Gene', (3, 7))	('silencing', 'Var', (8, 17))	('HeLa', 'CellLine', 'CVCL:0030', (173, 177))	('PFDN3', 'Gene', (146, 151))	('down-regulation', 'NegReg', (60, 75))	('PFDN1', 'Gene', (124, 129))	('PFDN3', 'Gene', (131, 136))	('VHL gene', 'Gene', (83, 91))	('regulation', 'biological_process', 'GO:0065007', ('65', '75'))	('PFDN1', 'Gene', '5201', (140, 145))	('PFDN3', 'Gene', '7411', (146, 151))
25251	33137104	The experiment showed that none of PFDN siRNA conditions reduced the expression of either the full length (VHL213) or the exon2-deleted (VHL172) VHL variants whereas, as expected, PFDN1 and PFDN3 transcripts were greatly reduced 48 hours after PFDN1 and PFDN3 siRNA transfection, respectively (S11 Fig).	('PFDN1', 'Gene', '5201', (180, 185))	('PFDN1', 'Gene', (244, 249))	('PFDN3', 'Gene', (254, 259))	('PFDN3', 'Gene', '7411', (190, 195))	('PFDN1', 'Gene', (180, 185))	('expression', 'MPA', (69, 79))	('reduced', 'NegReg', (221, 228))	('PFDN3', 'Gene', (190, 195))	('variants', 'Var', (149, 157))	('VHL', 'Gene', (145, 148))	('PFDN1', 'Gene', '5201', (244, 249))	('PFDN3', 'Gene', '7411', (254, 259))
25255	33137104	We observed no difference in PFDN1 and PFDN3 expression levels in pVHL213- expressing cells whereas expression levels of the known HIF2alpha VBC E3 ligase target was greatly diminished (S12A and S12B Fig).	('HIF2alpha', 'Gene', (131, 140))	('S12A', 'SUBSTITUTION', 'None', (186, 190))	('S12A', 'Var', (186, 190))	('pVHL', 'Gene', '7428', (66, 70))	('VBC', 'Chemical', '-', (141, 144))	('PFDN3', 'Gene', '7411', (39, 44))	('expression levels', 'MPA', (100, 117))	('pVHL', 'Gene', (66, 70))	('diminished', 'NegReg', (174, 184))	('PFDN1', 'Gene', '5201', (29, 34))	('S12B', 'SUBSTITUTION', 'None', (195, 199))	('expression', 'MPA', (45, 55))	('HIF2alpha', 'Gene', '2034', (131, 140))	('S12B', 'Var', (195, 199))	('PFDN3', 'Gene', (39, 44))	('PFDN1', 'Gene', (29, 34))
25261	33137104	As shown in S12C Fig, the expression levels of PFDN1 and PFDN3 were not altered in cells expressing either wild type VHL213 (VHL213 wt), a mutated VHL213 deficient for prefoldin binding (S3 Fig, VHL213 mut) or VHL172.	('S12C', 'Mutation', 'p.S12C', (12, 16))	('VHL213', 'Gene', (147, 153))	('PFDN1', 'Gene', '5201', (47, 52))	('mutated', 'Var', (139, 146))	('PFDN3', 'Gene', '7411', (57, 62))	('binding', 'molecular_function', 'GO:0005488', ('178', '185'))	('PFDN1', 'Gene', (47, 52))	('PFDN3', 'Gene', (57, 62))
25266	33137104	We pulled-down total ubiquitin proteins using the GST-TUBE approach (S13A Fig).	('GST', 'Gene', '373156', (50, 53))	('S13A', 'SUBSTITUTION', 'None', (69, 73))	('ubiquitin', 'Gene', '850620', (21, 30))	('GST', 'Gene', (50, 53))	('ubiquitin', 'molecular_function', 'GO:0031386', ('21', '30'))	('S13A', 'Var', (69, 73))	('ubiquitin', 'Gene', (21, 30))
25267	33137104	We verified that the HIF2alpha and the p21CIP1 proteins, known to be ubiquitinated, were recovered in the GST-TUBE fractions as multiple bands (S13B and S13G Fig).	('S13B', 'Var', (144, 148))	('S13G', 'Var', (153, 157))	('p21CIP1', 'Gene', (39, 46))	('GST', 'Gene', '373156', (106, 109))	('HIF2alpha', 'Gene', '2034', (21, 30))	('p21CIP1', 'Gene', '1026', (39, 46))	('S13B', 'SUBSTITUTION', 'None', (144, 148))	('S13G', 'Mutation', 'p.S13G', (153, 157))	('ubiquitin', 'Gene', '850620', (69, 78))	('GST', 'Gene', (106, 109))	('HIF2alpha', 'Gene', (21, 30))	('ubiquitin', 'Gene', (69, 78))
25268	33137104	The HIF2alpha transcription factor is targeted in part by pVHL213 dependent VBC E3 ligase complex and consistently less HIF2alpha was recovered in 786-O-pVHL213 cells (S13B Fig).	('HIF2alpha', 'Gene', '2034', (120, 129))	('less', 'NegReg', (115, 119))	('pVHL', 'Gene', '7428', (58, 62))	('S13B', 'Var', (168, 172))	('HIF2alpha', 'Gene', '2034', (4, 13))	('pVHL', 'Gene', (58, 62))	('VBC', 'Chemical', '-', (76, 79))	('pVHL', 'Gene', '7428', (153, 157))	('transcription', 'biological_process', 'GO:0006351', ('14', '27'))	('pVHL', 'Gene', (153, 157))	('S13B', 'SUBSTITUTION', 'None', (168, 172))	('HIF2alpha', 'Gene', (120, 129))	('HIF2alpha', 'Gene', (4, 13))	('transcription factor', 'molecular_function', 'GO:0000981', ('14', '34'))
25272	33137104	Indeed, in S3 Fig, we demonstrated that aa144-156 are critical for prefoldin-pVHL213 binding.	('aa144-156', 'Var', (40, 49))	('pVHL', 'Gene', (77, 81))	('pVHL', 'Gene', '7428', (77, 81))	('binding', 'molecular_function', 'GO:0005488', ('85', '92'))	('binding', 'Interaction', (85, 92))
25276	33137104	In TCGA database (https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga), we selected patients harboring either wild-type (n = 223) or mutated (n = 197) VHL.	('GA', 'Chemical', 'MESH:C001277', (5, 7))	('patients', 'Species', '9606', (116, 124))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('VHL', 'Gene', (183, 186))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('mutated', 'Var', (165, 172))
25278	33137104	Therefore, we focused on n = 197 ccRCC patients with mutated VHL (mutVHL) and found that the 46 patients with the lowest expression levels of PFDN3 had the worst survival (p = 0.001, Fig 6B).	('ccRCC', 'Disease', (33, 38))	('PFDN3', 'Gene', '7411', (142, 147))	('expression levels', 'MPA', (121, 138))	('patients', 'Species', '9606', (39, 47))	('PFDN3', 'Gene', (142, 147))	('mutated', 'Var', (53, 60))	('VHL', 'Gene', (61, 64))	('patients', 'Species', '9606', (96, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))
25279	33137104	Next, we considered patients for which the putative prefoldin binding site (aa144-156 region) was unaffected (mutVHL aa144-156+, n = 114) and those with mutant VHL which had lost this region due to premature upstream STOP codon, frameshift or splicing mutations (mutVHL aa144-156-, n = 74).	('frameshift or splicing mutations', 'Var', (229, 261))	('VHL', 'Gene', (160, 163))	('splicing', 'biological_process', 'GO:0045292', ('243', '251'))	('mutant', 'Var', (153, 159))	('patients', 'Species', '9606', (20, 28))	('binding', 'molecular_function', 'GO:0005488', ('62', '69'))
25280	33137104	In this context, we found that the expression levels of PFDN3 was still relevant for patients' survival harboring the aa144-156 region (mutVHL aa144-156+).	('patients', 'Species', '9606', (85, 93))	('PFDN3', 'Gene', '7411', (56, 61))	('aa144-156 region', 'Var', (118, 134))	('PFDN3', 'Gene', (56, 61))
25282	33137104	In contrast, for mutVHL aa144-156- patients, the low (n = 24) versus high (n = 50) PFDN3 expression levels did not show a significant difference regarding patients' survival (p = 0.048, Fig 6D).	('PFDN3', 'Gene', (83, 88))	('mutVHL aa144-156-', 'Var', (17, 34))	('patients', 'Species', '9606', (155, 163))	('PFDN3', 'Gene', '7411', (83, 88))	('patients', 'Species', '9606', (35, 43))	('aa144-156-', 'Var', (24, 34))
25283	33137104	Mutant pVHL that could no longer bind to the prefoldin complex are expected to be misfolded because they could not be loaded by the prefoldin complex onto TRiC/CCT chaperone complex.	('chaperone complex', 'cellular_component', 'GO:0101031', ('164', '181'))	('pVHL', 'Gene', '7428', (7, 11))	('pVHL', 'Gene', (7, 11))	('prefoldin complex', 'cellular_component', 'GO:0016272', ('132', '149'))	('prefoldin complex', 'cellular_component', 'GO:0016272', ('45', '62'))	('TRiC', 'cellular_component', 'GO:0005832', ('155', '159'))	('TRiC', 'Gene', '153562', (155, 159))	('Mutant', 'Var', (0, 6))	('TRiC', 'Gene', (155, 159))
25284	33137104	These results suggest that low PFDN3 expression in ccRCC has a strong negative prognostic impact in patients harboring VHL mutation with intact aa144-156 region.	('PFDN3', 'Gene', '7411', (31, 36))	('mutation', 'Var', (123, 131))	('VHL', 'Gene', (119, 122))	('PFDN3', 'Gene', (31, 36))	('low', 'NegReg', (27, 30))	('negative', 'NegReg', (70, 78))	('patients', 'Species', '9606', (100, 108))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))	('expression', 'MPA', (37, 47))	('ccRCC', 'Disease', (51, 56))
25293	33137104	Analysis of PFDN3 expression profile in ccRCC patients, limited to missense VHL mutants, showed that a low expression level correlates with poor survival (Fig 6).	('VHL', 'Gene', (76, 79))	('patients', 'Species', '9606', (46, 54))	('expression level', 'MPA', (107, 123))	('PFDN3', 'Gene', '7411', (12, 17))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('ccRCC', 'Disease', (40, 45))	('mutants', 'Var', (80, 87))	('poor', 'NegReg', (140, 144))	('low', 'NegReg', (103, 106))	('PFDN3', 'Gene', (12, 17))	('missense', 'Var', (67, 75))
25295	33137104	reported that PFDN3 overexpression and shRNA knockdown increased or diminished pVHL expression levels, respectively.	('pVHL', 'Gene', '7428', (79, 83))	('PFDN3', 'Gene', (14, 19))	('pVHL', 'Gene', (79, 83))	('diminished', 'NegReg', (68, 78))	('shRNA', 'Gene', (39, 44))	('PFDN3', 'Gene', '7411', (14, 19))	('knockdown', 'Var', (45, 54))
25304	33137104	A similar protective role of the whole prefoldin complex against aggregation and degradation of several misfolded model proteins has been recently demonstrated for all budding yeast GIM mutants.	('degradation', 'biological_process', 'GO:0009056', ('81', '92'))	('mutants', 'Var', (186, 193))	('prefoldin complex', 'cellular_component', 'GO:0016272', ('39', '56'))	('degradation', 'MPA', (81, 92))	('yeast', 'Species', '4932', (176, 181))	('aggregation', 'MPA', (65, 76))	('budding', 'biological_process', 'GO:0007114', ('168', '175'))
25307	33137104	The fact that human PFDN3 fully restores VHL-dependent growth reduction and VHL solubility of the fission yeast pfd3Delta mutant emphasizes the conservation of this folding function in eukaryotes.	('pfd3', 'Gene', '7411', (112, 116))	('restores', 'PosReg', (32, 40))	('fission yeast', 'Species', '4896', (98, 111))	('human', 'Species', '9606', (14, 19))	('VHL solubility', 'MPA', (76, 90))	('PFDN3', 'Gene', '7411', (20, 25))	('pfd3', 'Gene', (112, 116))	('mutant', 'Var', (122, 128))	('VHL-dependent growth reduction', 'MPA', (41, 71))	('PFDN3', 'Gene', (20, 25))
25310	33137104	Our data in Fig 6 suggest that, for patients with mutated VHL, a higher amount of PFDN3 may reduce the severity of ccRCC, possibly by increasing the steady state levels of the whole prefoldin complex and thereby improving pVHL folding efficiency or stability.	('folding', 'MPA', (227, 234))	('increasing', 'PosReg', (134, 144))	('reduce', 'NegReg', (92, 98))	('patients', 'Species', '9606', (36, 44))	('PFDN3', 'Gene', '7411', (82, 87))	('prefoldin complex', 'cellular_component', 'GO:0016272', ('182', '199'))	('severity', 'MPA', (103, 111))	('VHL', 'Gene', (58, 61))	('pVHL', 'Gene', (222, 226))	('improving', 'PosReg', (212, 221))	('stability', 'MPA', (249, 258))	('mutated', 'Var', (50, 57))	('pVHL', 'Gene', '7428', (222, 226))	('PFDN3', 'Gene', (82, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('ccRCC', 'Disease', (115, 120))
25312	33137104	reported that knock-down of any prefoldin subunit in the H1299 non-small cell lung carcinoma cell line decreased the protein levels of all other subunits, suggesting a protective role of prefoldin complex formation against degradation.	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (67, 92))	('formation', 'biological_process', 'GO:0009058', ('205', '214'))	('decreased', 'NegReg', (103, 112))	('degradation', 'biological_process', 'GO:0009056', ('223', '234'))	('prefoldin complex', 'cellular_component', 'GO:0016272', ('187', '204'))	('H1299', 'CellLine', 'CVCL:0060', (57, 62))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('lung carcinoma', 'Disease', (78, 92))	('knock-down', 'Var', (14, 24))	('lung carcinoma', 'Disease', 'MESH:D008175', (78, 92))	('protein levels of all other subunits', 'MPA', (117, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (63, 92))
25319	33137104	is that the two hybrid COOH terminal pVHL fusion protein preserved the second peak in the exon 3 (after aa156) but not the peak of exon 2 (before aa156).	('exon 3', 'MPA', (90, 96))	('aa156', 'Var', (104, 109))	('second peak in', 'MPA', (71, 85))	('pVHL', 'Gene', '7428', (37, 41))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('pVHL', 'Gene', (37, 41))
25320	33137104	When considering a total of 2,154 VHL missense single mutations reported in VHL diseases, this region is mutated in 128 cases.	('missense single mutations', 'Var', (38, 63))	('VHL diseases', 'Disease', (76, 88))	('VHL', 'Gene', (34, 37))	('VHL diseases', 'Disease', 'MESH:D006623', (76, 88))
25321	33137104	Three out of four major mutations, accounting for 56 of the 128 cases (43.7%) found in this region (A149S, I151S and I151T), are changes from hydrophobic to non-hydrophobic amino acids.	('changes', 'Reg', (129, 136))	('I151T', 'Mutation', 'rs869025655', (117, 122))	('A149S', 'Mutation', 'rs587780077', (100, 105))	('A149S', 'Var', (100, 105))	('I151T', 'Var', (117, 122))	('I151S', 'Var', (107, 112))	('I151S', 'Mutation', 'rs869025655', (107, 112))
25322	33137104	We speculate that the hydrophobic to non-hydrophobic mutations in the aa144-156 may alter the binding of the prefoldin complex and subsequently of the TRiC/CCT complex on pVHL, stimulating degradation of misfolded pVHL.	('pVHL', 'Gene', (171, 175))	('prefoldin complex', 'cellular_component', 'GO:0016272', ('109', '126'))	('alter', 'Reg', (84, 89))	('TRiC', 'Gene', '153562', (151, 155))	('aa144-156', 'Gene', (70, 79))	('binding', 'molecular_function', 'GO:0005488', ('94', '101'))	('degradation', 'biological_process', 'GO:0009056', ('189', '200'))	('TRiC', 'cellular_component', 'GO:0005832', ('151', '155'))	('binding', 'Interaction', (94, 101))	('TRiC', 'Gene', (151, 155))	('pVHL', 'Gene', '7428', (214, 218))	('hydrophobic', 'Var', (22, 33))	('pVHL', 'Gene', (214, 218))	('pVHL', 'Gene', '7428', (171, 175))	('stimulating', 'PosReg', (177, 188))	('degradation', 'MPA', (189, 200))
25323	33137104	Therefore, these VHL mutations might impact VHL disease severity at least in part by preventing an efficient folding process that normally occurs through binding to prefoldin and/or CCT chaperones.	('impact', 'Reg', (37, 43))	('binding', 'Interaction', (154, 161))	('VHL disease', 'Disease', 'MESH:D006623', (44, 55))	('efficient folding process', 'MPA', (99, 124))	('severity', 'MPA', (56, 64))	('VHL', 'Gene', (17, 20))	('VHL disease', 'Disease', (44, 55))	('binding', 'molecular_function', 'GO:0005488', ('154', '161'))	('preventing', 'NegReg', (85, 95))	('mutations', 'Var', (21, 30))
25324	33137104	reported that one mutation, A149S, promoted pVHL instability.	('A149S', 'Mutation', 'rs587780077', (28, 33))	('A149S', 'Var', (28, 33))	('pVHL', 'Gene', '7428', (44, 48))	('promoted', 'PosReg', (35, 43))	('pVHL', 'Gene', (44, 48))
25325	33137104	were able to show that intervening on pVHL A149S stabilization increased pVHL functionality and yet tumor suppression.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('pVHL', 'Gene', (38, 42))	('increased', 'PosReg', (63, 72))	('A149S stabilization', 'Var', (43, 62))	('pVHL', 'Gene', '7428', (73, 77))	('tumor', 'Disease', (100, 105))	('pVHL', 'Gene', (73, 77))	('increased pVHL', 'Phenotype', 'HP:0008151', (63, 77))	('A149S', 'Mutation', 'rs587780077', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('stabilization', 'Var', (49, 62))	('pVHL', 'Gene', '7428', (38, 42))
25326	33137104	A similar stabilization-mediated pVHL functional rescue was also reported for another mutant VHL R167Q, suggesting that this approach can be more broadly extended.	('R167Q', 'Mutation', 'rs5030821', (97, 102))	('R167Q', 'Var', (97, 102))	('pVHL', 'Gene', '7428', (33, 37))	('pVHL', 'Gene', (33, 37))	('VHL', 'Gene', (93, 96))
25329	33137104	We revealed a defect in MT-organization and function for both alpha and beta subunit prefoldin mutants and we confirmed the TBZ sensitivity of all other mutants in addition to pfd5Delta.	('MT-organization', 'CPA', (24, 39))	('alpha', 'Protein', (62, 67))	('defect', 'NegReg', (14, 20))	('TBZ', 'Chemical', 'MESH:D013827', (124, 127))	('prefoldin', 'Protein', (85, 94))	('mutants', 'Var', (95, 102))	('function', 'MPA', (44, 52))
25332	33137104	Interestingly, we and others showed that cold or TBZ sensitive phenotypes of yeast prefoldin mutants can be rescued by expression of their human counterparts, supporting a highly conserved function in tubulin regulation.	('yeast', 'Species', '4932', (77, 82))	('regulation', 'biological_process', 'GO:0065007', ('209', '219'))	('TBZ', 'Chemical', 'MESH:D013827', (49, 52))	('tubulin', 'Gene', '33501', (201, 208))	('mutants', 'Var', (93, 100))	('yeast', 'Gene', (77, 82))	('human', 'Species', '9606', (139, 144))	('tubulin', 'Gene', (201, 208))
25333	33137104	However, our work also showed that a truncated version of PFDN3 also rescued growth at 20 C, suggesting that single subunit truncation that did not prevent prefoldin complex formation may not be sufficient to substantially reduce this function.	('truncation', 'Var', (124, 134))	('growth at 20 C', 'MPA', (77, 91))	('PFDN3', 'Gene', (58, 63))	('formation', 'biological_process', 'GO:0009058', ('174', '183'))	('prefoldin complex', 'cellular_component', 'GO:0016272', ('156', '173'))	('rescued', 'PosReg', (69, 76))	('truncated', 'Var', (37, 46))	('PFDN3', 'Gene', '7411', (58, 63))
25360	33137104	In addition, point mutations within the aa144-156 (GQPIFANITLPVY) sequence of pVHL213 were introduced to convert it into a less hydrophobic domain (GQPSTSNSTSPVY).	('pVHL', 'Gene', (78, 82))	('pVHL', 'Gene', '7428', (78, 82))	('point mutations', 'Var', (13, 28))	('convert', 'Reg', (105, 112))
25362	33137104	The resulting cDNA encoding the full-length VHL cDNA with the desired mutations was cloned into the BamHI-linearized pcDNA3.1 MCS-BirA(R118G)-HA vector using in-fusion cloning.	('mutations', 'Var', (70, 79))	('MCS-BirA', 'Disease', (126, 134))	('R118G', 'Mutation', 'p.R118G', (135, 140))	('MCS-BirA', 'Disease', 'MESH:C536703', (126, 134))	('MCS', 'cellular_component', 'GO:0044232', ('126', '129'))
25363	33137104	To delete pfd1 gene, the whole open reading frame was replaced with the KanMX6 gene by PCR-based gene targeting as described previously.	('delete', 'Var', (3, 9))	('pfd1', 'Gene', '5201', (10, 14))	('pfd1', 'Gene', (10, 14))
25369	33137104	Besides, truncated version of human PFDN3 (AA63-165; i.e.	('human', 'Species', '9606', (30, 35))	('PFDN3', 'Gene', '7411', (36, 41))	('AA63-165', 'Var', (43, 51))	('PFDN3', 'Gene', (36, 41))
25379	33137104	Cells were treated with 40 nM siRNA duplexes against human Pfd1 and/or Pfd3 (sc-40869 and sc-40873, respectively; Santa Cruz Biotechnology), or a MISSION siRNA Universal Negative Control duplex (Sic001; Sigma) for 48 hr.	('Pfd3', 'Gene', '7411', (71, 75))	('sc-40873', 'Var', (90, 98))	('Pfd3', 'Gene', (71, 75))	('human', 'Species', '9606', (53, 58))	('Pfd1', 'Gene', (59, 63))	('Pfd1', 'Gene', '5201', (59, 63))
25402	33137104	Spectral files generated on the Q Exactive OrbiTrap and timsTOF Pro mass spectrometers were searched using Byonic version 3.3.9 (Protein Metrics, USA) against the Schizosaccharomyces pombe reference proteome (Uniprot, 5141 protein entries) with a static modification of carbamidomethyl (+57.0215 Da on Cys) and the following variable modifications: oxidation of methionine (+15.9949 Da), deamidation of glutamine and asparagine (+0.9840 Da) and the formation of pyro-Glu from N-terminal glutamate and glutamine residues (-18.0105 Da for N-Term Glu and -17.0265 Da for N-term Gln).	('formation', 'MPA', (449, 458))	('+0.9840 Da', 'Var', (429, 439))	('deamidation', 'MPA', (388, 399))	('protein', 'cellular_component', 'GO:0003675', ('223', '230'))	('-18.0105 Da', 'Var', (521, 532))	('Schizosaccharomyces pombe', 'Species', '4896', (163, 188))	('N-terminal glutamate', 'Protein', (476, 496))	('+15.9949', 'Var', (374, 382))	('formation', 'biological_process', 'GO:0009058', ('449', '458'))	('oxidation', 'MPA', (349, 358))
25458	32583730	We further used the SCAN module in the TIMER platform to analyze the relationship between infiltration level and DAB2IP mutations in RCC.	('DAB2IP', 'Gene', (113, 119))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('mutations', 'Var', (120, 129))	('rat', 'Species', '10116', (96, 99))
25478	32583730	To analyze the relationship between gene mutations and immune infiltration, we compared the distribution of the abundance of tumor-infiltrating immune cells under different mutation states of the DAB2IP (Figure 5).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('rat', 'Species', '10116', (137, 140))	('DAB2IP', 'Gene', (196, 202))	('rat', 'Species', '10116', (68, 71))	('mutation', 'Var', (173, 181))
25505	32583730	Thirdly, our study found an association between DAB2IP mutations and immune infiltration cells, for example, the arm-level gain or deletion of DAB2IP might be the most statistically significant mutations in immune infiltration cells.	('mutations', 'Var', (55, 64))	('DAB2IP', 'Gene', (143, 149))	('rat', 'Species', '10116', (82, 85))	('rat', 'Species', '10116', (220, 223))	('DAB2IP', 'Gene', (48, 54))	('gain', 'PosReg', (123, 127))	('deletion', 'Var', (131, 139))
25506	32583730	A study found loss of DAB2IP in RCC cells enhances their sensitivities to growth factor stimulation and resistances to SMI (such as mammalian target of rapamycin [mTOR] inhibitors).	('sensitivities to growth factor stimulation', 'MPA', (57, 99))	('loss', 'Var', (14, 18))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('DAB2IP', 'Gene', (22, 28))	('mTOR', 'Gene', '2475', (163, 167))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('mTOR', 'Gene', (163, 167))	('mammalian target of rapamycin', 'Gene', '2475', (132, 161))	('enhances', 'PosReg', (42, 50))	('resistances to SMI', 'MPA', (104, 122))	('mammalian target of rapamycin', 'Gene', (132, 161))
25517	32583730	Moreover, the expression of DAB2IP is related to the immune infiltrating cells and affects the survival of RCC, which worth further study.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('expression', 'Var', (14, 24))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('RCC', 'Disease', (107, 110))	('related', 'Reg', (38, 45))	('DAB2IP', 'Gene', (28, 34))	('rat', 'Species', '10116', (66, 69))	('affects', 'Reg', (83, 90))
25530	28445125	Losses of SMARCA4 or SMARCA2 significantly improved prognosis for overall survival (OS).	('overall survival', 'MPA', (66, 82))	('SMARCA4', 'Gene', (10, 17))	('SMARCA2', 'Gene', (21, 28))	('SMARCA2', 'Gene', '6595', (21, 28))	('SMARCA4', 'Gene', '6597', (10, 17))	('improved', 'PosReg', (43, 51))	('Losses', 'Var', (0, 6))
25533	28445125	One or a few cancerous cells with a few founding mutation(s) are the origins of tumors, then during tumor development additional mutations occurred to aid progression.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancerous', 'Disease', 'MESH:D009369', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (100, 105))	('mutations', 'Var', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', (80, 85))	('progression', 'CPA', (155, 166))	('aid', 'PosReg', (151, 154))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('cancerous', 'Disease', (13, 22))
25540	28445125	In recent years, large-scale sequencing studies identified additional mutated tumor suppressors.	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mutated', 'Var', (70, 77))	('tumor', 'Disease', (78, 83))
25541	28445125	Around 40% of ccRCC tumors were found to harbor mutations in polybromo-1 (PBRM1), a component of a SWI/SNF chromatin-remodeling complex.	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('PBRM1', 'Gene', '55193', (74, 79))	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('107', '127'))	('ccRCC tumors', 'Disease', 'MESH:D009369', (14, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (14, 19))	('chromatin-remodeling complex', 'cellular_component', 'GO:0016585', ('107', '135'))	('polybromo-1', 'Gene', '55193', (61, 72))	('ccRCC tumors', 'Disease', (14, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('polybromo-1', 'Gene', (61, 72))	('PBRM1', 'Gene', (74, 79))	('mutations', 'Var', (48, 57))
25542	28445125	In addition, 10-15% of ccRCC tumors have inactivating mutations in either BRCA1-associated protein 1 (BAP1) or SET domain containing 2 (SETD2), a histone deubiquitinase and a histone methyltransferase respectively.	('inactivating mutations', 'Var', (41, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (23, 28))	('BAP1', 'Gene', (102, 106))	('ccRCC tumors', 'Disease', (23, 35))	('SETD2', 'Gene', '29072', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('SETD2', 'Gene', (136, 141))	('BRCA1-associated protein 1', 'Gene', '8314', (74, 100))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('BRCA1-associated protein 1', 'Gene', (74, 100))	('ccRCC tumors', 'Disease', 'MESH:D009369', (23, 35))	('BAP1', 'Gene', '8314', (102, 106))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('154', '168'))
25543	28445125	In the same tumor, distinct mutations at different parts of the tumor could inactivate the same tumor suppressor genes such as SETD2, Phosphatase And Tensin Homolog (PTEN), and Lysine Demthylase 5C (KDM5C/JARID1C).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('PTEN', 'Gene', '5728', (166, 170))	('tumor', 'Disease', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('inactivate', 'NegReg', (76, 86))	('JARID1C', 'Gene', '8242', (205, 212))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('KDM5C', 'Gene', '8242', (199, 204))	('Phosphatase', 'molecular_function', 'GO:0016791', ('134', '145'))	('Phosphatase And Tensin Homolog', 'cellular_component', 'GO:1990455', ('134', '164'))	('tumor', 'Disease', (96, 101))	('JARID1C', 'Gene', (205, 212))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('SETD2', 'Gene', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('mutations', 'Var', (28, 37))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('96', '112'))	('tumor', 'Disease', (64, 69))	('PTEN', 'Gene', (166, 170))	('SETD2', 'Gene', '29072', (127, 132))	('KDM5C', 'Gene', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor suppressor', 'biological_process', 'GO:0051726', ('96', '112'))
25545	28445125	In tumors with PBRM1 mutations, half of them were truncal.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('PBRM1', 'Gene', '55193', (15, 20))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('PBRM1', 'Gene', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('mutations', 'Var', (21, 30))
25574	28445125	It was found that losses of SMARCA4.Truncal or SMARCA2.Total were associated with significantly better prognosis for patients (hazard ratio of 2.55 and 3.59 respectively), while losses of ARID1A.Total, PBRM1.Truncal, or SETD2.Total were associated with worse prognosis (hazard ratio of 0.23, 0.42, and 0.3 respectively).	('ARID1A', 'Gene', '8289', (188, 194))	('ARID1A', 'Gene', (188, 194))	('losses', 'Var', (18, 24))	('SMARCA2', 'Gene', (47, 54))	('SMARCA4', 'Gene', (28, 35))	('better', 'PosReg', (96, 102))	('SMARCA2', 'Gene', '6595', (47, 54))	('PBRM1', 'Gene', (202, 207))	('SETD2', 'Gene', '29072', (220, 225))	('SMARCA4', 'Gene', '6597', (28, 35))	('PBRM1', 'Gene', '55193', (202, 207))	('SETD2', 'Gene', (220, 225))	('patients', 'Species', '9606', (117, 125))
25583	28445125	A major trend in cancer therapies, precision medicine, based upon the notion that the tumors in each person need a few major driving DNA mutations for tumorigenesis and tumor maintenance, and the drugs that hit the vulnerabilities conferred by such mutations will lead to clinical efficacy.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', (151, 156))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('mutations', 'Var', (137, 146))	('person', 'Species', '9606', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
25584	28445125	This was proven true in many cases: Gleevec for chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST), Gefitinib for non-small cell lung cancer carrying hyperactive and mutated EGFR, and Vemurafenib for melanoma.	('CML', 'Disease', (74, 77))	('Gefitinib', 'Chemical', 'MESH:D000077156', (123, 132))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (137, 163))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (48, 72))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (48, 72))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (56, 72))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))	('melanoma', 'Disease', (223, 231))	('mutated', 'Var', (189, 196))	('GIST', 'Phenotype', 'HP:0100723', (116, 120))	('gastrointestinal stromal tumors', 'Disease', (83, 114))	('EGFR', 'Gene', '1956', (197, 201))	('non-small cell lung cancer', 'Disease', (137, 163))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('EGFR', 'molecular_function', 'GO:0005006', ('197', '201'))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('CML', 'Disease', 'MESH:D015464', (74, 77))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (207, 218))	('CML', 'Phenotype', 'HP:0005506', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('chronic myeloid leukemia', 'Disease', (48, 72))	('EGFR', 'Gene', (197, 201))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('melanoma', 'Disease', 'MESH:D008545', (223, 231))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (141, 163))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (137, 163))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (83, 114))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (83, 114))	('hyperactive', 'Disease', (173, 184))	('leukemia', 'Phenotype', 'HP:0001909', (64, 72))	('hyperactive', 'Disease', 'MESH:D006948', (173, 184))
25586	28445125	In a certain tumor, ITH could mean that a small percentage of the cancer cells do not carry the driving mutations, so over time they would grow up after treatment.	('tumor', 'Disease', (13, 18))	('mutations', 'Var', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('cancer', 'Disease', (66, 72))
25587	28445125	Alternatively, some cancer cells might also harbor other mutations or epigenetic changes that render them drug resistant.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('drug resistant', 'MPA', (106, 120))	('mutations', 'Var', (57, 66))	('cancer', 'Disease', (20, 26))	('epigenetic changes', 'Var', (70, 88))
25590	28445125	However, it is highly likely that many tumor-derived mutations in the cancer genes, especially the point mutations, do not lead to protein expression loss, so mutational analysis will improve the sensitivity of analysis.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('mutations', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('tumor', 'Disease', (39, 44))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
25591	28445125	Only SETD2.Total showed a statistical meaningful association with RFS, and the loss of SETD2 led to shorter RFS (Table 3 and Figure 3).	('SETD2', 'Gene', (5, 10))	('loss', 'Var', (79, 83))	('RFS', 'MPA', (108, 111))	('shorter', 'NegReg', (100, 107))	('RFS', 'Disease', (66, 69))	('association', 'Interaction', (49, 60))	('SETD2', 'Gene', '29072', (87, 92))	('SETD2', 'Gene', (87, 92))	('SETD2', 'Gene', '29072', (5, 10))
25599	28445125	Even though a very low percentage of ccRCC tumors harbor mutations in ARID1A, the high rate of ARID1A expression loss clearly indicates that it plays a critical role in cancer biology in ccRCC, and a clever way to take advantage of its loss to treat ccRCC is worth serious efforts to pursue.	('ccRCC tumors', 'Disease', (37, 49))	('cancer', 'Disease', (169, 175))	('ccRCC', 'Phenotype', 'HP:0006770', (250, 255))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('mutations', 'Var', (57, 66))	('ccRCC tumors', 'Disease', 'MESH:D009369', (37, 49))	('loss', 'NegReg', (113, 117))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('ARID1A', 'Gene', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('ARID1A', 'Gene', (70, 76))	('ARID1A', 'Gene', '8289', (95, 101))	('ccRCC', 'Disease', (187, 192))	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('ccRCC', 'Disease', (250, 255))	('expression', 'MPA', (102, 112))	('ARID1A', 'Gene', '8289', (70, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (187, 192))
25602	28445125	The contribution of PBRM1 mutations to the clinical outcome of ccRCC patients has been somewhat controversial.	('PBRM1', 'Gene', (20, 25))	('PBRM1', 'Gene', '55193', (20, 25))	('mutations', 'Var', (26, 35))	('ccRCC', 'Disease', (63, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('patients', 'Species', '9606', (69, 77))
25657	32838750	Purines are involved in many biological processes, including immune responses and host-tumor interaction, and their metabolism changes continuously in response to cell demands; thus, it is a consequence that the alteration of the enzymes involved in this pathway, organized in dynamic multienzyme complexes called "purinosome", occurs in severe diseases.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Purines', 'Chemical', 'MESH:D011687', (0, 7))	('host-tumor', 'Disease', (82, 92))	('host-tumor', 'Disease', 'MESH:D006086', (82, 92))	('alteration', 'Var', (212, 222))	('metabolism', 'biological_process', 'GO:0008152', ('116', '126'))
25683	33371886	We hypothesized that the alterations of common upstream regulators as well as subtype-specific upstream regulators work together to affect the downstream pathway perturbations and drive cancer initialization and prognosis.	('alterations', 'Var', (25, 36))	('affect', 'Reg', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('drive', 'Reg', (180, 185))	('downstream pathway', 'Pathway', (143, 161))	('prognosis', 'CPA', (212, 221))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
25690	33371886	Genomic alterations lead to differential expression of genes and subsequently induce dysregulation of biological functions to promote tumorigenesis and development.	('induce', 'Reg', (78, 84))	('development', 'CPA', (152, 163))	('dysregulation of biological functions', 'MPA', (85, 122))	('alterations', 'Var', (8, 19))	('promote', 'PosReg', (126, 133))	('expression of genes', 'MPA', (41, 60))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('lead to differential', 'Reg', (20, 40))	('tumor', 'Disease', (134, 139))
25704	33371886	In summary, our work explored the relationships among pathway alterations, upstream regulators as well as clinical outcome for different subtypes of RCC.	('RCC', 'Disease', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('alterations', 'Var', (62, 73))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
25779	33371886	Thus, we hypothesize that the alteration of upstream regulators induced the downregulation of such kind of prognostic pathways, thus contributing to the tumorigenesis and progression of ccRCC.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('alteration', 'Var', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('progression', 'CPA', (171, 182))	('tumor', 'Disease', (153, 158))	('RCC', 'Disease', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('ccRCC', 'Phenotype', 'HP:0006770', (186, 191))	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('contributing', 'Reg', (133, 145))	('downregulation', 'NegReg', (76, 90))
25788	33371886	We hypothesized that the dysregulation of recurrent upstream regulators as well as subtype-specific upstream regulators work together to affect pathway perturbations and further influence cancer prognosis among various RCC subtypes.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('influence', 'Reg', (178, 187))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('pathway perturbations', 'Pathway', (144, 165))	('dysregulation', 'Var', (25, 38))	('cancer', 'Disease', (188, 194))	('RCC', 'Disease', (219, 222))	('RCC', 'Phenotype', 'HP:0005584', (219, 222))	('affect', 'Reg', (137, 143))	('RCC', 'Disease', 'MESH:C538614', (219, 222))
25831	33886004	Authors also showed that high expressions of FAP are associated with development of early metastases and worse cancer-specific survival.	('of', 'Gene', '6688', (81, 83))	('metastases', 'Disease', (90, 100))	('of', 'Gene', '6688', (42, 44))	('FAP', 'Gene', '2191', (45, 48))	('metastases', 'Disease', 'MESH:D009362', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('men', 'Species', '9606', (76, 79))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('high', 'Var', (25, 29))	('associated', 'Reg', (53, 63))	('FAP', 'Gene', (45, 48))	('cancer', 'Disease', (111, 117))	('worse', 'NegReg', (105, 110))
25846	33886004	Authors showed that aberrant expression of ubiquitin-specific protease 2 mRNA acted as independent prognosticator for ccRCC (AUC: 0.89, p < 0.001).	('ubiquitin-specific', 'Protein', (43, 61))	('aberrant expression', 'Var', (20, 39))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('ubiquitin', 'molecular_function', 'GO:0031386', ('43', '52'))	('of', 'Gene', '6688', (40, 42))
25893	33886004	In particular, non-coding RNAs (ncRNAs), which included also microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have been studied as possible biomarkers in several tumors.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('non-coding', 'Var', (15, 25))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('art', 'Gene', '9048', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('art', 'Gene', (4, 7))
25940	29560117	Mutation of VHL gene is frequent in these tumors leading to simulation of hypoxic conditions.	('VHL', 'Gene', (12, 15))	('hypoxic conditions', 'Disease', 'MESH:D009135', (74, 92))	('VHL', 'Gene', '7428', (12, 15))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('Mutation', 'Var', (0, 8))	('frequent', 'Reg', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('hypoxic conditions', 'Disease', (74, 92))
25954	29560117	LCMV causes a persistent infection in common house mice (Mus musculus) and also pet rodents (hamsters, guinea pigs).	('pet', 'Gene', (80, 83))	('mice', 'Species', '10090', (51, 55))	('LCMV', 'Var', (0, 4))	('Mus musculus', 'Species', '10090', (57, 69))	('LCMV', 'Species', '11623', (0, 4))	('infection', 'Disease', (25, 34))	('infection', 'Disease', 'MESH:D007239', (25, 34))	('pet', 'Gene', '22095', (80, 83))	('guinea pigs', 'Species', '10141', (103, 114))	('persistent infection', 'Phenotype', 'HP:0031035', (14, 34))
25972	29560117	Somatic mutations or epigenetic alternations of VHL are observed in >80% of ccRCC.	('VHL', 'Gene', '7428', (48, 51))	('observed', 'Reg', (56, 64))	('RCC', 'Disease', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('epigenetic alternations', 'Var', (21, 44))	('VHL', 'Gene', (48, 51))
25973	29560117	A modest proportion (2-4%) of RCC is associated with VHL syndrome caused by germline mutations in VHL.	('VHL', 'Gene', (53, 56))	('VHL', 'Gene', (98, 101))	('VHL syndrome', 'Disease', (53, 65))	('RCC', 'Disease', (30, 33))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('VHL', 'Gene', '7428', (53, 56))	('VHL', 'Gene', '7428', (98, 101))	('associated', 'Reg', (37, 47))	('VHL syndrome', 'Disease', 'MESH:D006623', (53, 65))	('caused by', 'Reg', (66, 75))	('germline mutations', 'Var', (76, 94))
25974	29560117	All renal tumors bearing VHL mutations have a defective ubiquitination of HIF-1alpha.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('renal tumors', 'Phenotype', 'HP:0009726', (4, 16))	('defective', 'NegReg', (46, 55))	('mutations', 'Var', (29, 38))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('ubiquitination of HIF-1alpha', 'Disease', (56, 84))	('VHL', 'Gene', (25, 28))	('renal tumors', 'Disease', 'MESH:D007674', (4, 16))	('ubiquitination of HIF-1alpha', 'Disease', 'MESH:C563003', (56, 84))	('renal tumors', 'Disease', (4, 16))	('VHL', 'Gene', '7428', (25, 28))
25988	29560117	Also, the chimeric G250 monoclonal antibody has the highest reported uptake in solid renal tumors.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('renal tumors', 'Phenotype', 'HP:0009726', (85, 97))	('antibody', 'cellular_component', 'GO:0042571', ('35', '43'))	('antibody', 'cellular_component', 'GO:0019815', ('35', '43'))	('chimeric G250', 'Var', (10, 23))	('solid renal tumors', 'Disease', 'MESH:D007674', (79, 97))	('antibody', 'cellular_component', 'GO:0019814', ('35', '43'))	('uptake', 'biological_process', 'GO:0098657', ('69', '75'))	('G250', 'Chemical', '-', (19, 23))	('uptake', 'biological_process', 'GO:0098739', ('69', '75'))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('solid renal tumors', 'Disease', (79, 97))	('antibody', 'molecular_function', 'GO:0003823', ('35', '43'))	('uptake', 'MPA', (69, 75))
25990	29560117	G250 can induce receptor-mediated internalization with prolonged intracellular persistence.	('receptor-mediated internalization', 'MPA', (16, 49))	('induce', 'Reg', (9, 15))	('G250', 'Var', (0, 4))	('intracellular', 'cellular_component', 'GO:0005622', ('65', '78'))	('G250', 'Chemical', '-', (0, 4))
25992	29560117	Also, recycling and exposure of G250 with intact Fc fragment on cell surface can prolong ADCC response, which represents its principal anticancer mode of action.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('G250', 'Var', (32, 36))	('cell surface', 'cellular_component', 'GO:0009986', ('64', '76'))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('ADCC response', 'CPA', (89, 102))	('G250', 'Chemical', '-', (32, 36))	('ADCC', 'biological_process', 'GO:0001788', ('89', '93'))	('prolong', 'PosReg', (81, 88))	('cancer', 'Disease', (139, 145))
25997	29560117	In our study, we have described the influence of LCMV on ccRCC cells, which exhibit a permanent pseudohypoxic state due to the VHL mutation.	('hypoxic', 'Disease', (102, 109))	('hypoxic', 'Disease', 'MESH:D000860', (102, 109))	('LCMV', 'Species', '11623', (49, 53))	('VHL', 'Gene', (127, 130))	('VHL', 'Gene', '7428', (127, 130))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('mutation', 'Var', (131, 139))
26004	29560117	VHL mutation is characteristic for renal clear cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (35, 61))	('renal clear cell carcinoma', 'Disease', (35, 61))	('mutation', 'Var', (4, 12))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))
26016	29560117	The doubling time for the uninfected cells was approximately 17 h, while for the infected cells only 14 h. VHL mutation present in the RCC4 cell line leads to activation and stabilization of HIF-1alpha subunit in normoxic conditions.	('HIF-1alpha', 'Gene', '3091', (191, 201))	('VHL', 'Gene', '7428', (107, 110))	('stabilization', 'MPA', (174, 187))	('HIF-1alpha', 'Gene', (191, 201))	('RCC4', 'Gene', '84925', (135, 139))	('activation', 'MPA', (159, 169))	('RCC4', 'Gene', (135, 139))	('mutation', 'Var', (111, 119))	('VHL', 'Gene', (107, 110))
26032	29560117	Loss or mutation of E-cadherin or signal transduction-related destabilization of E-cadherin-catenin interactions all result in reduced cell adhesion which is associated with metastasis and invasion.	('destabilization', 'NegReg', (62, 77))	('cell adhesion', 'biological_process', 'GO:0007155', ('135', '148'))	('E-cadherin', 'Gene', (81, 91))	('interactions', 'Interaction', (100, 112))	('E-cadherin', 'Gene', (20, 30))	('Loss', 'NegReg', (0, 4))	('E-cadherin', 'Gene', '999', (20, 30))	('E-cadherin', 'Gene', '999', (81, 91))	('cell adhesion', 'CPA', (135, 148))	('signal transduction', 'biological_process', 'GO:0007165', ('34', '53'))	('mutation', 'Var', (8, 16))	('reduced', 'NegReg', (127, 134))	('cadherin', 'molecular_function', 'GO:0008014', ('22', '30'))	('cadherin', 'molecular_function', 'GO:0008014', ('83', '91'))
26045	29560117	A unique feature of LCMV strain MX is its reactivation from persistent infection during lower oxygen concentrations.	('LCMV', 'Species', '11623', (20, 24))	('LCMV strain', 'Var', (20, 31))	('oxygen', 'Chemical', 'MESH:D010100', (94, 100))	('infection', 'Disease', (71, 80))	('infection', 'Disease', 'MESH:D007239', (71, 80))	('reactivation', 'MPA', (42, 54))	('persistent infection', 'Phenotype', 'HP:0031035', (60, 80))
26051	29560117	As renal cell carcinoma belongs to the most frequent cancers in the human population and simulates permanent hypoxic conditions due to VHL mutation, we were interested in the effect of LCMV strain MX infection on RCC4 cells.	('VHL', 'Gene', (135, 138))	('RCC4', 'Gene', '84925', (213, 217))	('human', 'Species', '9606', (68, 73))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('renal cell carcinoma', 'Disease', (3, 23))	('infection', 'Disease', (200, 209))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (3, 23))	('infection', 'Disease', 'MESH:D007239', (200, 209))	('mutation', 'Var', (139, 147))	('VHL', 'Gene', '7428', (135, 138))	('LCMV', 'Species', '11623', (185, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('hypoxic conditions', 'Disease', 'MESH:D009135', (109, 127))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 23))	('RCC4', 'Gene', (213, 217))	('hypoxic conditions', 'Disease', (109, 127))
26060	29560117	Presence of HIF-2alpha in preneoplastic lesions correlates with upcoming malignancy.	('malignancy', 'Disease', 'MESH:D009369', (73, 83))	('HIF-2alpha', 'Gene', (12, 22))	('malignancy', 'Disease', (73, 83))	('HIF-2alpha', 'Gene', '2034', (12, 22))	('Presence', 'Var', (0, 8))
26061	29560117	However, HIF-2alpha, but not HIF-1alpha, can overcome VHL's tumor suppressor activity and eliminating HIF-2alpha is sufficient to suppress tumor formation.	('HIF-2alpha', 'Gene', '2034', (9, 19))	('HIF-1alpha', 'Gene', (29, 39))	('tumor', 'Disease', (139, 144))	('HIF-2alpha', 'Gene', (102, 112))	('suppress', 'NegReg', (130, 138))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('60', '76'))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('formation', 'biological_process', 'GO:0009058', ('145', '154'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('60', '76'))	('HIF-2alpha', 'Gene', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('eliminating', 'Var', (90, 101))	("VHL's tumor", 'Disease', 'MESH:D006623', (54, 65))	('HIF-1alpha', 'Gene', '3091', (29, 39))	('HIF-2alpha', 'Gene', '2034', (102, 112))	("VHL's tumor", 'Disease', (54, 65))
26064	29560117	Both proteins can also reciprocally regulate each other's protein levels where loss of HIF-1alpha leads to induction of HIF-2alpha and vice-versa.	('loss', 'Var', (79, 83))	('HIF-1alpha', 'Gene', (87, 97))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('HIF-2alpha', 'Gene', (120, 130))	('induction', 'PosReg', (107, 116))	('HIF-2alpha', 'Gene', '2034', (120, 130))	('HIF-1alpha', 'Gene', '3091', (87, 97))
26066	29560117	It was also reported that renal tumors with high HIF-1alpha but with low HIF-2alpha expression levels had worse overall survival compared to tumors expressing low levels of both, HIF-1alpha and HIF-2alpha.	('renal tumors', 'Phenotype', 'HP:0009726', (26, 38))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('HIF-1alpha', 'Gene', (179, 189))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (179, 204))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('HIF-2alpha', 'Gene', (194, 204))	('tumors', 'Disease', (141, 147))	('HIF-2alpha', 'Gene', '2034', (73, 83))	('HIF-1alpha', 'Gene', '3091', (49, 59))	('overall', 'MPA', (112, 119))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('worse', 'NegReg', (106, 111))	('high', 'Var', (44, 48))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('renal tumors', 'Disease', (26, 38))	('HIF-1alpha', 'Gene', (49, 59))	('HIF-2alpha', 'Gene', (73, 83))	('HIF-1alpha', 'Gene', '3091', (179, 189))	('renal tumors', 'Disease', 'MESH:D007674', (26, 38))	('HIF-2alpha', 'Gene', '2034', (194, 204))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))
26067	29560117	Additionally It was proven that targeted knockdown of HIF-2alpha by siRNA enhanced HIF-1alpha protein levels.	('HIF-1alpha', 'Gene', (83, 93))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))	('HIF-2alpha', 'Gene', (54, 64))	('HIF-1alpha', 'Gene', '3091', (83, 93))	('knockdown', 'Var', (41, 50))	('enhanced', 'PosReg', (74, 82))	('HIF-2alpha', 'Gene', '2034', (54, 64))
26069	29560117	We observed significant changes in the expression of CA IX after infection by LCMV strain MX, but further we were intrigued how the infection affected its pH-regulatory functions.	('LCMV strain', 'Var', (78, 89))	('CA IX', 'Gene', (53, 58))	('infection', 'Disease', (65, 74))	('infection', 'Disease', 'MESH:D007239', (65, 74))	('changes', 'Reg', (24, 31))	('CA IX', 'Gene', '768', (53, 58))	('expression', 'MPA', (39, 49))	('infection', 'Disease', (132, 141))	('LCMV', 'Species', '11623', (78, 82))	('infection', 'Disease', 'MESH:D007239', (132, 141))
26084	29560117	Also, antibody VII/20 was shown to overcome different drawbacks of the tumor microenvironment, such as high cellular density or low pH.	('antibody', 'cellular_component', 'GO:0042571', ('6', '14'))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('antibody', 'cellular_component', 'GO:0019814', ('6', '14'))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('antibody', 'cellular_component', 'GO:0019815', ('6', '14'))	('antibody', 'Var', (6, 14))	('tumor', 'Disease', (71, 76))	('antibody', 'molecular_function', 'GO:0003823', ('6', '14'))	('iron', 'Chemical', 'MESH:D007501', (85, 89))
26086	29560117	In this study we prove that the tumor-associated antigen CA IX is differentially expressed in cells infected with LCMV strain MX.	('CA IX', 'Gene', '768', (57, 62))	('CA IX', 'Gene', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('LCMV strain', 'Var', (114, 125))	('LCMV', 'Species', '11623', (114, 118))	('tumor', 'Disease', (32, 37))
26151	31672157	Further, circ-AKT3/miR-296-3p/E-cadherin axis was shown responsible for circ-AKT3 inhibiting ccRCC metastasis.	('ccRCC metastasis', 'Disease', 'MESH:D002292', (93, 109))	('inhibiting', 'NegReg', (82, 92))	('miR-296', 'Gene', '407022', (19, 26))	('circ-AKT3', 'Var', (72, 81))	('miR-296', 'Gene', (19, 26))	('ccRCC metastasis', 'Disease', (93, 109))	('cadherin', 'molecular_function', 'GO:0008014', ('32', '40'))
26170	31672157	On the other hand, restoration of E-cadherin suppressed cancer progression including metastasis in various in vitro and in vivo tumor models.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('suppressed', 'NegReg', (45, 55))	('restoration', 'Var', (19, 30))	('metastasis', 'CPA', (85, 95))	('tumor', 'Disease', (128, 133))	('E-cadherin', 'Protein', (34, 44))	('cadherin', 'molecular_function', 'GO:0008014', ('36', '44'))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
26211	31672157	On the other hand, we also analyzed the correlation of circ-AKT3 expression with clinicopathologic features of ccRCC patients and found that the expression level of circ-AKT3 significantly correlated with ccRCC Fuhrman grade which is generally used to predict ccRCC metastasis (Additional file 1: Table S3).	('circ-AKT3', 'Var', (165, 174))	('correlated', 'Reg', (189, 199))	('ccRCC', 'Disease', 'MESH:D002292', (111, 116))	('ccRCC', 'Disease', (205, 210))	('ccRCC metastasis', 'Disease', (260, 276))	('ccRCC', 'Disease', 'MESH:D002292', (205, 210))	('expression level', 'MPA', (145, 161))	('ccRCC', 'Disease', (260, 265))	('ccRCC', 'Disease', 'MESH:D002292', (260, 265))	('ccRCC metastasis', 'Disease', 'MESH:D002292', (260, 276))	('patients', 'Species', '9606', (117, 125))	('ccRCC', 'Disease', (111, 116))
26216	31672157	However, after knockdown of circ-AKT3, OSRC-2 cells exhibited enhanced migratory capacity as demonstrated by the Wound healing assay, and vice versa (Fig.	('OSRC', 'Gene', '5925', (39, 43))	('OSRC', 'Gene', (39, 43))	('migratory capacity', 'CPA', (71, 89))	('knockdown', 'Var', (15, 24))	('circ-AKT3', 'Gene', (28, 37))	('enhanced', 'PosReg', (62, 70))	('Wound healing', 'biological_process', 'GO:0042060', ('113', '126'))
26217	31672157	Consistently, the Transwell assay further demonstrated that the silencing of circ-AKT3 significantly promoted the migration and invasion of OSRC-2 cells, which contain relatively high endogenous circ-AKT3 (Fig.	('promoted', 'PosReg', (101, 109))	('circ-AKT3', 'Gene', (77, 86))	('OSRC', 'Gene', '5925', (140, 144))	('OSRC', 'Gene', (140, 144))	('migration', 'CPA', (114, 123))	('silencing', 'Var', (64, 73))
26225	31672157	Online bioinformatics databases (TargetScan and miRanda) were used to find potential miRNAs targeting E-cadherin mRNA and sponged by circ-AKT3, and 4 miRNAs were predicted (miR-330-3p, miR-296-3p, miR-382-5p, and miR-326) (Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('104', '112'))	('miR-326', 'Gene', '442900', (213, 220))	('miR-330-3p', 'Var', (173, 183))	('miR-296', 'Gene', (185, 192))	('miR-382', 'Gene', '494331', (197, 204))	('miRanda', 'Disease', (48, 55))	('miR-296', 'Gene', '407022', (185, 192))	('miRanda', 'Disease', 'MESH:C537402', (48, 55))	('E-cadherin', 'Protein', (102, 112))	('miR-326', 'Gene', (213, 220))	('miR-382', 'Gene', (197, 204))
26246	31672157	To determine whether the predicted miR-296-3p binding site in circ-AKT3 sequence was essential for their interaction, the wild-type and mutated sequences of circ-AKT3 (in the predicted binding site) (Fig.	('miR-296', 'Gene', (35, 42))	('binding', 'molecular_function', 'GO:0005488', ('46', '53'))	('binding', 'molecular_function', 'GO:0005488', ('185', '192'))	('mutated', 'Var', (136, 143))	('miR-296', 'Gene', '407022', (35, 42))
26277	31672157	In summary, our findings suggest a protective role of circ-AKT3 in the metastasis of ccRCC by sponging miR-296-3p and up-regulating E-cadherin expression.	('up-regulating', 'PosReg', (118, 131))	('expression', 'MPA', (143, 153))	('miR-296', 'Gene', (103, 110))	('cadherin', 'molecular_function', 'GO:0008014', ('134', '142'))	('ccRCC', 'Disease', (85, 90))	('E-cadherin', 'Protein', (132, 142))	('metastasis', 'CPA', (71, 81))	('sponging', 'Var', (94, 102))	('ccRCC', 'Disease', 'MESH:D002292', (85, 90))	('circ-AKT3', 'Gene', (54, 63))	('miR-296', 'Gene', '407022', (103, 110))
26282	31672157	This work was supported by National Natural Science Foundation of China (Grant Numbers: 81672520, 81773789, 81870484, 81702508, use for procurement of materials and labor cost); Zhejiang Provincial Natural Science Foundation of China (grant numbers: LY17H160020, LY17H050003, used to pay for the microarray array); Zhejiang science and technology project (grant numbers: 2016C37105, used to pay for the data analysis); Zhejiang Medical and Health Plan Project (Grant number: 2019ZD007, used to pay for materials).	('LY17H050003', 'Var', (263, 274))	('LY17H160020, LY17H050003', 'Chemical', 'MESH:D006859', (250, 274))	('labor cost', 'Disease', 'MESH:D048949', (165, 175))	('LY17H160020', 'Var', (250, 261))	('labor cost', 'Disease', (165, 175))
26285	30886153	The evolution patterns of ccRCC have great inter-patient heterogeneities, with del(3p) being regarded as the common earliest event followed by three early departure points: VHL and PBRM1 mutations, del(14q) and other somatic copy number alterations (SCNAs) including amp(7), del(1p) and del(6q).	('VHL', 'Gene', (173, 176))	('VHL', 'Gene', '7428', (173, 176))	('amp', 'Chemical', 'MESH:D000249', (267, 270))	('ccRCC', 'Phenotype', 'HP:0006770', (26, 31))	('ccRCC', 'Disease', (26, 31))	('del(1p', 'Gene', '10085', (275, 281))	('PBRM1', 'Gene', (181, 186))	('PBRM1', 'Gene', '55193', (181, 186))	('patient', 'Species', '9606', (49, 56))	('mutations', 'Var', (187, 196))	('del(1', 'Gene', '10085', (275, 280))	('amp(7', 'Var', (267, 272))	('del(6q', 'Var', (287, 293))	('del(1', 'Gene', '10085', (198, 203))
26286	30886153	We identify three prognostic subtypes of ccRCC with distinct clonal architectures and immune infiltrates: long-lived patients, enriched with VHL but depleted of BAP1 mutations, have high levels of Th17 and CD8+ T cells while short-lived patients with high burden of SCNAs have high levels of Tregs and Th2 cells, highlighting the importance of evaluating evolution patterns in the clinical management of ccRCC.	('VHL', 'Gene', '7428', (141, 144))	('BAP1', 'Gene', (161, 165))	('mutations', 'Var', (166, 175))	('BAP1', 'Gene', '8314', (161, 165))	('CD8', 'Gene', (206, 209))	('CD8', 'Gene', '925', (206, 209))	('ccRCC', 'Phenotype', 'HP:0006770', (404, 409))	('Th17', 'MPA', (197, 201))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('patients', 'Species', '9606', (117, 125))	('patients', 'Species', '9606', (237, 245))	('VHL', 'Gene', (141, 144))
26290	30886153	To understand the etiology of ccRCC, genetic alterations in ccRCC had been screened in large cohorts of patients previously.	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('ccRCC', 'Disease', (30, 35))	('genetic alterations', 'Var', (37, 56))	('patients', 'Species', '9606', (104, 112))
26291	30886153	Arm-level SCNAs including del(3p), amp(5q), amp(7q), del(9p), amp(12p) and del(14q) were found to affect 45-85% of ccRCC patients and several driver genes including VHL, PBRM1, SETD2 and BAP1 were observed to be mutated in 10-50% of patients.	('amp', 'Chemical', 'MESH:D000249', (44, 47))	('VHL', 'Gene', (165, 168))	('amp', 'Chemical', 'MESH:D000249', (35, 38))	('del(9p', 'Gene', '100240748', (53, 59))	('BAP1', 'Gene', '8314', (187, 191))	('SETD2', 'Gene', (177, 182))	('del(3p', 'Var', (26, 32))	('VHL', 'Gene', '7428', (165, 168))	('amp(12p', 'Var', (62, 69))	('amp(5q', 'Var', (35, 41))	('SETD2', 'Gene', '29072', (177, 182))	('amp', 'Chemical', 'MESH:D000249', (62, 65))	('BAP1', 'Gene', (187, 191))	('patients', 'Species', '9606', (233, 241))	('affect', 'Reg', (98, 104))	('del(1', 'Gene', '10085', (75, 80))	('ccRCC', 'Disease', (115, 120))	('patients', 'Species', '9606', (121, 129))	('PBRM1', 'Gene', '55193', (170, 175))	('amp(7q', 'Var', (44, 50))	('PBRM1', 'Gene', (170, 175))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))
26292	30886153	For instance, BAP1 mutations, mutually exclusive with PBRM1 mutations, can predict poor clinical outcome in ccRCCs independently.	('PBRM1', 'Gene', (54, 59))	('BAP1', 'Gene', '8314', (14, 18))	('PBRM1', 'Gene', '55193', (54, 59))	('ccRCCs', 'Disease', (108, 114))	('BAP1', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('predict', 'Reg', (75, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))
26293	30886153	The development of human cancers is driven by the stepwise accumulation of somatic alterations and mutations acquired at different stages of tumor evolution are likely to be associated with different clinical outcomes.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('associated', 'Reg', (174, 184))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('mutations', 'Var', (99, 108))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('cancers', 'Disease', (25, 32))	('human', 'Species', '9606', (19, 24))	('cancers', 'Disease', 'MESH:D009369', (25, 32))
26296	30886153	These studies found that del(3p) and inactivation of VHL were trunk events while most of the other driver aberrations were subclonal.	('trunk', 'cellular_component', 'GO:0043198', ('62', '67'))	('VHL', 'Gene', (53, 56))	('VHL', 'Gene', '7428', (53, 56))	('inactivation', 'Var', (37, 49))	('del(3p', 'Var', (25, 31))
26299	30886153	Previous studies had demonstrated the possibility of reconstructing the clonal architecture of single tumor biopsy by estimating the fraction of tumor cells carrying either SCNAs or single-nucleotide variants (SNVs).	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (145, 150))	('single-nucleotide variants', 'Var', (182, 208))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
26309	30886153	1a), characterized by C>T transitions at CpG dinucleotides, was observed in different tumor types and was likely to result from 5-methlcytosine deamination.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (41, 58))	('5-methlcytosine', 'MPA', (128, 143))	('result from', 'Reg', (116, 127))	('tumor', 'Disease', (86, 91))	('C>T transitions', 'Var', (22, 37))	('5-methlcytosine', 'Chemical', '-', (128, 143))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
26311	30886153	1a), characterized by a broad spectrum of base changes, was also present in different tumor types and was suggested to be associated with ERCC2 mutations in bladder cancer.	('associated', 'Reg', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('tumor', 'Disease', (86, 91))	('bladder cancer', 'Disease', (157, 171))	('ERCC2', 'Gene', (138, 143))	('bladder cancer', 'Disease', 'MESH:D001749', (157, 171))	('mutations', 'Var', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('ERCC2', 'Gene', '2068', (138, 143))
26319	30886153	2), including del(3p), amp(5q), amp(7) and del(14q).	('del(1', 'Gene', '10085', (43, 48))	('del(3p', 'Var', (14, 20))	('amp', 'Chemical', 'MESH:D000249', (32, 35))	('amp', 'Chemical', 'MESH:D000249', (23, 26))	('amp(5q', 'Var', (23, 29))	('amp(7', 'Var', (32, 37))
26323	30886153	These findings were generally consistent with previous multi-region sequencing of 10 ccRCCs showing that mutations in VHL and PBRM1 tended to be trunk events.	('VHL', 'Gene', (118, 121))	('PBRM1', 'Gene', (126, 131))	('VHL', 'Gene', '7428', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('PBRM1', 'Gene', '55193', (126, 131))	('mutations', 'Var', (105, 114))	('trunk', 'cellular_component', 'GO:0043198', ('145', '150'))
26324	30886153	For instance, mutations in LRP2 (P = 0.037, FDR = 0.1) showed a tendency to be clonal while mutations in MUC16 (P < 0.0001, FDR < 0.0001), PCLO (P = 0.0003, FDR = 0.009) and ABCA13 (P = 0.001, FDR = 0.02) tended to be subclonal, highlighting their potential roles in either the genesis or progression of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (304, 309))	('ABCA13', 'Gene', (174, 180))	('ccRCC', 'Disease', (304, 309))	('PCLO', 'Gene', '27445', (139, 143))	('mutations', 'Var', (92, 101))	('MUC16', 'Gene', (105, 110))	('PCLO', 'Gene', (139, 143))	('LRP2', 'Gene', (27, 31))	('LRP2', 'Gene', '4036', (27, 31))	('ABCA13', 'Gene', '154664', (174, 180))	('MUC16', 'Gene', '94025', (105, 110))	('mutations', 'Var', (14, 23))
26325	30886153	The median CCF of del(3p) was the highest among all the somatic events and several other arm-level SCNAs including del(1), amp(5q) and del(14q) also had slightly higher medians of CCFs than the well-known renal cancer driver VHL mutations, suggesting that the acquirement of certain arm-level SCNAs may play initialing roles in the early stage of ccRCC evolution.	('CCFs', 'MPA', (180, 184))	('VHL', 'Gene', (225, 228))	('higher', 'PosReg', (162, 168))	('renal cancer', 'Disease', 'MESH:D007680', (205, 217))	('del(3p', 'Var', (18, 24))	('VHL', 'Gene', '7428', (225, 228))	('amp', 'Chemical', 'MESH:D000249', (123, 126))	('amp(5q', 'Var', (123, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (347, 352))	('del(1', 'Gene', '10085', (115, 120))	('renal cancer', 'Disease', (205, 217))	('del(1', 'Gene', '10085', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('ccRCC', 'Disease', (347, 352))	('renal cancer', 'Phenotype', 'HP:0009726', (205, 217))
26328	30886153	3b), the earliest event del(3p) was followed by three groups of departure points: (i) somatic mutations involving VHL and PBRM1, (ii) del(14q), and (iii) arm-level SCNAs including amp(7), del(1p) and del(6q).	('amp', 'Chemical', 'MESH:D000249', (180, 183))	('del(1p', 'Gene', '10085', (188, 194))	('PBRM1', 'Gene', (122, 127))	('VHL', 'Gene', '7428', (114, 117))	('del(1', 'Gene', '10085', (134, 139))	('del(1', 'Gene', '10085', (188, 193))	('amp(7', 'Var', (180, 185))	('PBRM1', 'Gene', '55193', (122, 127))	('del(6q', 'Var', (200, 206))	('VHL', 'Gene', (114, 117))
26329	30886153	These divergent routes of tumor evolution finally converged toward the late group of SCNA events such as deletions of chromosomes 10, 18, and 17q and amplifications of 12, 16p, and others (Fig.	('amplifications', 'Var', (150, 164))	('amp', 'Chemical', 'MESH:D000249', (150, 153))	('deletions', 'Var', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
26330	30886153	To evaluate the prognostic values of the frequently mutated genes or SCNAs, we performed Kaplan-Meier analysis of the somatic alterations and identified 18 somatic events (including del(9), amp(12), del(14q), del(1p), del(4), del(13q), amp(3q), del(11q), del(22q), del(15q), del(2q), and mutations in genes VHL and BAP1) as potential factors relevant to the prognosis of ccRCC (Supplementary Data 3).	('del(9', 'Gene', '100240748', (182, 187))	('del(1', 'Gene', '10085', (199, 204))	('amp(12', 'Var', (190, 196))	('del(1', 'Gene', '10085', (245, 250))	('VHL', 'Gene', (307, 310))	('amp(3q', 'Var', (236, 242))	('BAP1', 'Gene', '8314', (315, 319))	('del(1p', 'Gene', '10085', (209, 215))	('del(1', 'Gene', '10085', (226, 231))	('VHL', 'Gene', '7428', (307, 310))	('ccRCC', 'Disease', (371, 376))	('del(2q', 'Var', (275, 281))	('amp', 'Chemical', 'MESH:D000249', (236, 239))	('del(1', 'Gene', '10085', (209, 214))	('amp', 'Chemical', 'MESH:D000249', (190, 193))	('BAP1', 'Gene', (315, 319))	('del(4', 'Var', (218, 223))	('ccRCC', 'Phenotype', 'HP:0006770', (371, 376))	('del(22q', 'Var', (255, 262))	('del(1', 'Gene', '10085', (265, 270))
26331	30886153	Of these genomic alterations, only mutations of VHL indicated good clinical outcome.	('VHL', 'Gene', '7428', (48, 51))	('VHL', 'Gene', (48, 51))	('mutations', 'Var', (35, 44))
26333	30886153	Both clonal and subclonal alterations involving chromosomes 14q, 15q, and BAP1 gene were associated with shortened survival time in ccRCC patients (Supplementary Data 3).	('ccRCC', 'Disease', (132, 137))	('shortened', 'NegReg', (105, 114))	('chromosomes 14q', 'Var', (48, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (132, 137))	('BAP1', 'Gene', '8314', (74, 78))	('survival time', 'CPA', (115, 128))	('BAP1', 'Gene', (74, 78))	('patients', 'Species', '9606', (138, 146))
26335	30886153	Under the univariate analysis model, patients with clonal del(9), del(13q), del(22q), and HMCN1 mutations or with subclonal amp(12), del(1p), del(4q), and amp(3q) were significantly associated with shortened survival.	('del(9', 'Gene', '100240748', (58, 63))	('amp(3q', 'Var', (155, 161))	('patients', 'Species', '9606', (37, 45))	('amp', 'Chemical', 'MESH:D000249', (155, 158))	('shortened', 'NegReg', (198, 207))	('HMCN1', 'Gene', '83872', (90, 95))	('del(1', 'Gene', '10085', (66, 71))	('del(4q', 'Var', (142, 148))	('HMCN1', 'Gene', (90, 95))	('amp', 'Chemical', 'MESH:D000249', (124, 127))	('del(22q', 'Var', (76, 83))	('del(1', 'Gene', '10085', (133, 138))	('del(1p', 'Gene', '10085', (133, 139))	('mutations', 'Var', (96, 105))
26336	30886153	In addition, subclonal mutations in USH2A, a new target shown to be mutated frequently in relapsed leukemia, were significantly associated with dismal clinical outcome in univariate analysis.	('leukemia', 'Phenotype', 'HP:0001909', (99, 107))	('leukemia', 'Disease', 'MESH:D007938', (99, 107))	('leukemia', 'Disease', (99, 107))	('USH2A', 'Gene', (36, 41))	('associated', 'Reg', (128, 138))	('subclonal mutations', 'Var', (13, 32))	('USH2A', 'Gene', '7399', (36, 41))
26337	30886153	Under the multivariate model, only clonal HMCN1 mutations and subclonal amp(12) were significantly associated with dismal clinical outcome (Supplementary Fig.	('amp', 'Chemical', 'MESH:D000249', (72, 75))	('associated with', 'Reg', (99, 114))	('HMCN1', 'Gene', '83872', (42, 47))	('dismal clinical outcome', 'MPA', (115, 138))	('HMCN1', 'Gene', (42, 47))	('mutations', 'Var', (48, 57))
26339	30886153	Comparing with tumors staged as T1 or T2, subclonal del(9), del(4), del(15q), del(1p) and amp(3q) tended to occur more frequently in tumors staged as T3 or T4 (all P < 0.05).	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('amp(3q', 'Var', (90, 96))	('tumors', 'Disease', (133, 139))	('del(1', 'Gene', '10085', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('del(9', 'Gene', '100240748', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('del(4', 'Var', (60, 65))	('occur', 'Reg', (108, 113))	('amp', 'Chemical', 'MESH:D000249', (90, 93))	('del(1p', 'Gene', '10085', (78, 84))	('del(1', 'Gene', '10085', (78, 83))	('tumors', 'Disease', (15, 21))
26344	30886153	Almost all tumors in cluster B harbored VHL mutations but were devoid of BAP1 mutations while tumors in clusters A and C were predominantly enriched with del(14q) and multiple other cluster-specific arm-level SCNAs.	('BAP1', 'Gene', '8314', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('del(1', 'Gene', '10085', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('VHL', 'Gene', (40, 43))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('harbored', 'Reg', (31, 39))	('BAP1', 'Gene', (73, 77))	('VHL', 'Gene', '7428', (40, 43))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (94, 100))	('mutations', 'Var', (44, 53))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
26345	30886153	For instance, three SCNAs including amp(12), amp(3q) and del(9) and seven events including del(1p), del(4), del(13q), del(11q), del(22q), del(15q) and del(2q) were predominantly enriched in clusters A and C, respectively (Supplementary Data 4).	('del(1', 'Gene', '10085', (91, 96))	('del(4', 'Var', (100, 105))	('amp', 'Chemical', 'MESH:D000249', (36, 39))	('del(1', 'Gene', '10085', (138, 143))	('del(9', 'Gene', '100240748', (57, 62))	('del(2q', 'Var', (151, 157))	('amp', 'Chemical', 'MESH:D000249', (45, 48))	('del(22q', 'Var', (128, 135))	('del(1', 'Gene', '10085', (118, 123))	('del(1', 'Gene', '10085', (108, 113))	('del(1p', 'Gene', '10085', (91, 97))
26362	30886153	We ranked the frequent somatic events according to their medians of CCFs and found that most of the top ranked events, including del(1p), del(6q), amp(7), del(14q), and VHL mutations, showed disparities in their evolution patterns and comprised the early departure points during ccRCC evolution (Fig.	('amp(7', 'Var', (147, 152))	('VHL', 'Gene', '7428', (169, 172))	('del(6q', 'Var', (138, 144))	('del(1', 'Gene', '10085', (155, 160))	('amp', 'Chemical', 'MESH:D000249', (147, 150))	('ccRCC', 'Phenotype', 'HP:0006770', (279, 284))	('del(1p', 'Gene', '10085', (129, 135))	('VHL', 'Gene', (169, 172))	('del(1', 'Gene', '10085', (129, 134))
26366	30886153	Almost all patients in cluster B harbored VHL mutations and few of them had BAP1 mutations.	('mutations', 'Var', (46, 55))	('BAP1', 'Gene', '8314', (76, 80))	('BAP1', 'Gene', (76, 80))	('patients', 'Species', '9606', (11, 19))	('VHL', 'Gene', (42, 45))	('harbored', 'Reg', (33, 41))	('VHL', 'Gene', '7428', (42, 45))
26367	30886153	VHL and BAP1 mutations had been shown to be indicators of good and poor clinical outcomes, respectively.	('BAP1', 'Gene', '8314', (8, 12))	('VHL', 'Gene', (0, 3))	('BAP1', 'Gene', (8, 12))	('VHL', 'Gene', '7428', (0, 3))	('mutations', 'Var', (13, 22))
26396	31653509	Evaluation of clear cell subtypes of ovarian and uterine malignancies with anti-PD-L1 and anti-PD1 immunohistochemical expression and their association with stage and survival Clear cell carcinoma (CCC) of ovarian and uterine cancer is associated with unique clinical behavior.	('association', 'Interaction', (140, 151))	('PD-L1', 'Gene', (80, 85))	('uterine malignancies', 'Phenotype', 'HP:0010784', (49, 69))	('ovarian', 'Disease', 'MESH:D010049', (206, 213))	('ovarian', 'Disease', (206, 213))	('malignancies', 'Disease', (57, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('PD-L1', 'Gene', '29126', (80, 85))	('uterine cancer', 'Phenotype', 'HP:0010784', (218, 232))	('CCC', 'cellular_component', 'GO:0030896', ('198', '201'))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('ovarian', 'Disease', 'MESH:D010049', (37, 44))	('anti-PD1', 'Var', (90, 98))	('ovarian', 'Disease', (37, 44))	('malignancies', 'Disease', 'MESH:D009369', (57, 69))	('Clear cell carcinoma (CCC) of ovarian', 'Disease', 'MESH:D008649', (176, 213))
26406	31653509	Both histology and standard IHC expression, including absence of WT1, p53 and ER as well as presence of Napsin A, CK7, and HNF1B, were used to confirm clear cell phenotype.	('HNF1B', 'Gene', (123, 128))	('CK7', 'Gene', (114, 117))	('p53', 'Gene', (70, 73))	('CK7', 'Gene', '3855', (114, 117))	('p53', 'Gene', '7157', (70, 73))	('Napsin A', 'Gene', '9476', (104, 112))	('WT1', 'Gene', '7490', (65, 68))	('ER', 'Gene', '2069', (78, 80))	('WT1', 'Gene', (65, 68))	('HNF1B', 'Gene', '6928', (123, 128))	('presence', 'Var', (92, 100))	('Napsin A', 'Gene', (104, 112))
26431	31653509	Univariate and multivariable Cox proportional hazards model was used in the ovarian cancer cohort to estimate hazard ratios for positive versus negative PD-L1 CPS.	('CPS', 'Chemical', '-', (159, 162))	('PD-L1', 'Gene', (153, 158))	('ovarian cancer', 'Disease', (76, 90))	('ovarian cancer', 'Phenotype', 'HP:0100615', (76, 90))	('positive', 'Var', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('ovarian cancer', 'Disease', 'MESH:D010051', (76, 90))
26457	31653509	Clinical trials are upcoming or underway for recurrent ovarian cancers which include clear cell subtypes, utilizing combination regimens which include checkpoint inhibitors such as pembrolizumab and epicadostat (NCT03602586, NRG-GY016), nivolumab and ipilimumab (NCT03355976), tremelimumab and olaparib (NCT04034927, NRG-GY021), pegylated liposomal doxorubicin with atezolizumab and bevacizumab (NCT02839707, NRG-GY009), durvalumab (NCT03405454), and pembrolizumab with bevacizumab and cyclophosphamide (NCT02853318).	('ipilimumab', 'Chemical', 'MESH:D000074324', (251, 261))	('ovarian cancers', 'Disease', 'MESH:D010051', (55, 70))	('NCT03405454', 'Var', (433, 444))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('NCT04034927', 'Var', (304, 315))	('pembrolizumab', 'Chemical', 'MESH:C582435', (451, 464))	('NCT03355976', 'Var', (263, 274))	('ovarian cancer', 'Phenotype', 'HP:0100615', (55, 69))	('nivolumab', 'Chemical', 'MESH:D000077594', (237, 246))	('NCT02839707', 'Var', (396, 407))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('ovarian cancers', 'Phenotype', 'HP:0100615', (55, 70))	('pembrolizumab', 'Chemical', 'MESH:C582435', (181, 194))	('ovarian cancers', 'Disease', (55, 70))	('NCT03602586', 'Var', (212, 223))
26458	31653509	In recurrent uterine clear cell cancers, there is a single study evaluating the addition of pembrolizumab to standard chemotherapy (NCT03914612, NRG-GY018).	('cell cancers', 'Disease', (27, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('NCT03914612', 'Var', (132, 143))	('GY018', 'Chemical', '-', (149, 154))	('pembrolizumab', 'Chemical', 'MESH:C582435', (92, 105))	('cell cancers', 'Disease', 'MESH:D009369', (27, 39))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
26464	31653509	Our study suggests greater frequency of PD-L1 percent positivity in uterine cancers at 90%, and novel uterine cancer data including a positive PD-L1 CPS in 60%.	('uterine cancers', 'Phenotype', 'HP:0010784', (68, 83))	('cancer', 'Disease', (110, 116))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('CPS', 'Chemical', '-', (149, 152))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('PD-L1', 'Gene', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('PD-L1', 'Gene', (143, 148))	('uterine cancer', 'Phenotype', 'HP:0010784', (102, 116))	('uterine cancer', 'Phenotype', 'HP:0010784', (68, 82))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('positivity', 'Var', (54, 64))
26465	31653509	Similarly, there was greater PD-L1 positivity in our ovarian cohort, at 57.6% as compared to 46% in the data by Hertzog et al, and novel ovarian cancer data including a positive PD-L1 CPS in 34.3%.	('ovarian', 'Disease', (137, 144))	('PD-L1', 'Gene', (29, 34))	('ovarian cancer', 'Phenotype', 'HP:0100615', (137, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('positivity', 'Var', (35, 45))	('CPS', 'Chemical', '-', (184, 187))	('ovarian', 'Disease', 'MESH:D010049', (53, 60))	('ovarian', 'Disease', (53, 60))	('novel ovarian cancer', 'Disease', 'MESH:C000657245', (131, 151))	('PD-L1', 'Gene', (178, 183))	('novel ovarian cancer', 'Disease', (131, 151))	('ovarian', 'Disease', 'MESH:D010049', (137, 144))
26488	31963294	Alternatively, multigene assays may provide prognostic information beyond what is possible with traditional approaches and are now included in standard treatment guidelines for some tumors.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Disease', (182, 188))	('multigene assays', 'Var', (15, 31))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
26491	31963294	More than 90% of ccRCC cases show inactivation of the gene encoding the von Hippel-Lindau tumor suppressor on chromosome 3p.	('von Hippel-Lindau tumor', 'Disease', 'MESH:D006623', (72, 95))	('tumor suppressor', 'biological_process', 'GO:0051726', ('90', '106'))	('von Hippel-Lindau tumor', 'Disease', (72, 95))	('inactivation', 'Var', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('90', '106'))	('chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('ccRCC', 'Disease', (17, 22))	('ccRCC', 'Disease', 'MESH:D002292', (17, 22))
26492	31963294	Additionally, mutations in other tumor suppressor genes are associated with ccRCC tumorigenesis, including polybromo 1 (PBRM1), BRCA1-associated 1 (BAP1), and SET domain-containing 2 (SETD2).	('polybromo 1', 'Gene', '55193', (107, 118))	('PBRM1', 'Gene', '55193', (120, 125))	('tumor', 'Disease', (82, 87))	('SETD2', 'Gene', (184, 189))	('PBRM1', 'Gene', (120, 125))	('BAP1', 'Gene', '8314', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('polybromo 1', 'Gene', (107, 118))	('tumor', 'Disease', (33, 38))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('33', '49'))	('SETD2', 'Gene', '29072', (184, 189))	('mutations', 'Var', (14, 23))	('ccRCC', 'Disease', 'MESH:D002292', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('SET domain-containing 2', 'Gene', '29072', (159, 182))	('tumor suppressor', 'biological_process', 'GO:0051726', ('33', '49'))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BAP1', 'Gene', (148, 152))	('ccRCC', 'Disease', (76, 81))	('associated', 'Reg', (60, 70))	('SET domain-containing 2', 'Gene', (159, 182))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))
26493	31963294	PBRM1 and BAP1 mutations are largely mutually exclusive, and BAP1 mutations are significantly associated with high-grade, high-stage tumors that result in low survival.	('mutations', 'Var', (66, 75))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('BAP1', 'Gene', (61, 65))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('BAP1', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('PBRM1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('PBRM1', 'Gene', '55193', (0, 5))	('associated', 'Reg', (94, 104))	('low', 'NegReg', (155, 158))	('BAP1', 'Gene', '8314', (61, 65))	('high-grade', 'Disease', (110, 120))	('BAP1', 'Gene', '8314', (10, 14))
26494	31963294	Although mutations in lysine-specific demethylase 5C (KDM5C) occur at a lower frequency, they are also associated with poor oncological outcomes.	('lysine-specific demethylase 5C', 'Gene', (22, 52))	('associated', 'Reg', (103, 113))	('mutations', 'Var', (9, 18))	('KDM5C', 'Gene', (54, 59))	('oncological outcomes', 'CPA', (124, 144))	('KDM5C', 'Gene', '8242', (54, 59))	('lysine-specific demethylase 5C', 'Gene', '8242', (22, 52))
26495	31963294	Forkhead box protein C2 (FOXC2) and cytoskeleton-associated protein-glycine (CAP-Gly) rich domain-containing linker protein family member 4 (CLIP4) mutations were associated with early-stage ccRCC and synchronous metastasis.	('Gly', 'Chemical', 'MESH:D005998', (81, 84))	('CLIP4', 'Gene', '79745', (141, 146))	('synchronous metastasis', 'CPA', (201, 223))	('mutations', 'Var', (148, 157))	('Forkhead box protein C2', 'Gene', '2303', (0, 23))	('ccRCC', 'Disease', (191, 196))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('CLIP4', 'Gene', (141, 146))	('CAP', 'Chemical', '-', (77, 80))	('ccRCC', 'Disease', 'MESH:D002292', (191, 196))	('FOXC2', 'Gene', (25, 30))	('FOXC2', 'Gene', '2303', (25, 30))	('Forkhead box protein C2', 'Gene', (0, 23))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('36', '48'))	('associated with', 'Reg', (163, 178))	('glycine', 'Chemical', 'MESH:D005998', (68, 75))
26516	31963294	Mutations were found in the six candidate genes (PBRM1 (11/24, 45.8%), BAP1 (6/24, 25.0%), SETD2 (24/24, 100.0%), KDM5C (9/24, 37.5%), FOXC2 (6/24, 25.0%), and CLIP4 (8/24, 33.3%)) in more than 25% of the patients from our cohort; Figure 3 provides a visual depiction of the frequency of target gene mutations in our cohort.	('SETD2', 'Gene', '29072', (91, 96))	('patients', 'Species', '9606', (205, 213))	('SETD2', 'Gene', (91, 96))	('KDM5C', 'Gene', '8242', (114, 119))	('CLIP4', 'Gene', '79745', (160, 165))	('BAP1', 'Gene', '8314', (71, 75))	('Mutations', 'Var', (0, 9))	('FOXC2', 'Gene', '2303', (135, 140))	('CLIP4', 'Gene', (160, 165))	('FOXC2', 'Gene', (135, 140))	('PBRM1', 'Gene', (49, 54))	('PBRM1', 'Gene', '55193', (49, 54))	('BAP1', 'Gene', (71, 75))	('KDM5C', 'Gene', (114, 119))
26517	31963294	There were no significant differences in the frequencies of the six candidate aggressiveness-associated mutations in patients with aggressive ccRCC and those without aggressive ccRCC (Table S3); however, for the patients with aggressive ccRCC, BAP1, KDM5C, and FOXC2 mutations were enriched by two-fold, and CLIP4 mutations were enriched by three-fold, compared to that in patients without aggressive ccRCC.	('ccRCC', 'Disease', (177, 182))	('patients', 'Species', '9606', (212, 220))	('KDM5C', 'Gene', '8242', (250, 255))	('ccRCC', 'Disease', 'MESH:D002292', (237, 242))	('patients', 'Species', '9606', (117, 125))	('ccRCC', 'Disease', (142, 147))	('BAP1', 'Gene', '8314', (244, 248))	('CLIP4', 'Gene', '79745', (308, 313))	('CLIP4', 'Gene', (308, 313))	('FOXC2', 'Gene', (261, 266))	('ccRCC', 'Disease', 'MESH:D002292', (401, 406))	('FOXC2', 'Gene', '2303', (261, 266))	('ccRCC', 'Disease', (237, 242))	('ccRCC', 'Disease', (401, 406))	('KDM5C', 'Gene', (250, 255))	('BAP1', 'Gene', (244, 248))	('mutations', 'Var', (267, 276))	('mutations', 'Var', (314, 323))	('aggressiveness', 'Phenotype', 'HP:0000718', (78, 92))	('ccRCC', 'Disease', 'MESH:D002292', (177, 182))	('patients', 'Species', '9606', (373, 381))	('ccRCC', 'Disease', 'MESH:D002292', (142, 147))
26528	31963294	The differences in CSS corresponded to a hazard ratio (HR) of 16.057 (95% CI 1.866-138.169, p = 0.011; Figure 4).	('CSS', 'Chemical', '-', (19, 22))	('CSS', 'MPA', (19, 22))	('differences', 'Var', (4, 15))
26536	31963294	Our results showed that DDX11 expression and tumor size were significantly greater in patients with high Fuhrman grade (3 and 4), both in the univariate and multivariate analyses (Table S5).	('expression', 'MPA', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('high', 'Var', (100, 104))	('greater', 'PosReg', (75, 82))	('DDX11', 'Gene', (24, 29))	('DDX11', 'Gene', '1663', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('patients', 'Species', '9606', (86, 94))
26538	31963294	Among the potential target candidate genes, BAP1, KDM5C, FOXC2, and CLIP4 mutations were enriched in patients with aggressive ccRCC.	('patients', 'Species', '9606', (101, 109))	('KDM5C', 'Gene', (50, 55))	('mutations', 'Var', (74, 83))	('ccRCC', 'Disease', (126, 131))	('KDM5C', 'Gene', '8242', (50, 55))	('BAP1', 'Gene', '8314', (44, 48))	('ccRCC', 'Disease', 'MESH:D002292', (126, 131))	('CLIP4', 'Gene', '79745', (68, 73))	('CLIP4', 'Gene', (68, 73))	('FOXC2', 'Gene', (57, 62))	('BAP1', 'Gene', (44, 48))	('FOXC2', 'Gene', '2303', (57, 62))
26542	31963294	As in other large NGS studies, PBRM1 mutation was identified in 45.8% patients.	('patients', 'Species', '9606', (70, 78))	('PBRM1', 'Gene', (31, 36))	('PBRM1', 'Gene', '55193', (31, 36))	('mutation', 'Var', (37, 45))
26543	31963294	However, BAP1 mutation was observed in 25% of patients, which is slightly higher than the value obtained in other studies, perhaps because our cohort comprised patients with more aggressive ccRCC; we intentionally collected aggressive ccRCC to pair with non-aggressive ccRCC.	('ccRCC', 'Disease', 'MESH:D002292', (269, 274))	('ccRCC', 'Disease', (190, 195))	('ccRCC', 'Disease', (235, 240))	('patients', 'Species', '9606', (46, 54))	('ccRCC', 'Disease', 'MESH:D002292', (190, 195))	('ccRCC', 'Disease', 'MESH:D002292', (235, 240))	('patients', 'Species', '9606', (160, 168))	('BAP1', 'Gene', '8314', (9, 13))	('mutation', 'Var', (14, 22))	('observed', 'Reg', (27, 35))	('BAP1', 'Gene', (9, 13))	('ccRCC', 'Disease', (269, 274))
26544	31963294	BAP1, a critical gatekeeper for disease progression, has a mutually exclusive interaction with PBRM1, whereas the BAP1 mutation is associated with worse prognosis and a higher Fuhrman grade than the PBRM1 mutation.	('higher', 'PosReg', (169, 175))	('mutation', 'Var', (119, 127))	('BAP1', 'Gene', (0, 4))	('PBRM1', 'Gene', (95, 100))	('PBRM1', 'Gene', (199, 204))	('BAP1', 'Gene', '8314', (114, 118))	('PBRM1', 'Gene', '55193', (95, 100))	('PBRM1', 'Gene', '55193', (199, 204))	('gatekeeper', 'Species', '111938', (17, 27))	('BAP1', 'Gene', (114, 118))	('BAP1', 'Gene', '8314', (0, 4))	('Fuhrman grade', 'CPA', (176, 189))
26545	31963294	This finding was further supported by the MSKCC cohort study where BAP1 mutations were associated with poor prognostic factors (higher T stage, higher nuclear grade, large size, more necrosis), and the presence of metastatic disease at presentation).	('necrosis', 'biological_process', 'GO:0001906', ('183', '191'))	('mutations', 'Var', (72, 81))	('T stage', 'CPA', (135, 142))	('nuclear', 'MPA', (151, 158))	('necrosis', 'Disease', (183, 191))	('necrosis', 'biological_process', 'GO:0070265', ('183', '191'))	('BAP1', 'Gene', '8314', (67, 71))	('necrosis', 'Disease', 'MESH:D009336', (183, 191))	('necrosis', 'biological_process', 'GO:0008219', ('183', '191'))	('necrosis', 'biological_process', 'GO:0019835', ('183', '191'))	('necrosis', 'biological_process', 'GO:0008220', ('183', '191'))	('metastatic disease', 'CPA', (214, 232))	('BAP1', 'Gene', (67, 71))
26546	31963294	SETD2 mutation was observed in all cases of ccRCC in our study, which diverges from other NGS studies in which the frequency of SETD2 mutation was substantially lower (approximately 11%).	('SETD2', 'Gene', (128, 133))	('observed', 'Reg', (19, 27))	('SETD2', 'Gene', '29072', (0, 5))	('mutation', 'Var', (6, 14))	('ccRCC', 'Disease', (44, 49))	('ccRCC', 'Disease', 'MESH:D002292', (44, 49))	('SETD2', 'Gene', (0, 5))	('SETD2', 'Gene', '29072', (128, 133))
26548	31963294	KDM5C mutations were found in less than 40% of the study population, compared to 3.8-6.8% reported in other NGS studies.	('KDM5C', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('KDM5C', 'Gene', '8242', (0, 5))
26552	31963294	The frequency of PBRM1 mutation was not different in ccRCC with and without aggressive characteristics.	('ccRCC', 'Disease', (53, 58))	('mutation', 'Var', (23, 31))	('ccRCC', 'Disease', 'MESH:D002292', (53, 58))	('PBRM1', 'Gene', (17, 22))	('PBRM1', 'Gene', '55193', (17, 22))
26553	31963294	BAP1, KDM5C, FOXC2, and CLIP4 mutations were enriched in aggressive ccRCC, which was not statistically significant because of small sample sizes.	('FOXC2', 'Gene', (13, 18))	('BAP1', 'Gene', (0, 4))	('FOXC2', 'Gene', '2303', (13, 18))	('ccRCC', 'Disease', (68, 73))	('KDM5C', 'Gene', (6, 11))	('mutations', 'Var', (30, 39))	('ccRCC', 'Disease', 'MESH:D002292', (68, 73))	('CLIP4', 'Gene', '79745', (24, 29))	('KDM5C', 'Gene', '8242', (6, 11))	('BAP1', 'Gene', '8314', (0, 4))	('CLIP4', 'Gene', (24, 29))
26554	31963294	This finding is similar to the results of other studies that have reported an association between BAP1 and KDM5C mutations and aggressiveness of tumors.	('BAP1', 'Gene', (98, 102))	('KDM5C', 'Gene', '8242', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('aggressiveness', 'Phenotype', 'HP:0000718', (127, 141))	('mutations', 'Var', (113, 122))	('BAP1', 'Gene', '8314', (98, 102))	('aggressiveness of tumors', 'Disease', (127, 151))	('KDM5C', 'Gene', (107, 112))	('aggressiveness of tumors', 'Disease', 'MESH:D001523', (127, 151))
26556	31963294	The frequency of PBRM1 mutation was similar between patients with aggressive and non-aggressive ccRCC, perhaps because it is an early, essential event in tumorigenesis that does not impact clinical outcome, but instead plays a principal role in tumor initiation.	('ccRCC', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mutation', 'Var', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('PBRM1', 'Gene', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('PBRM1', 'Gene', '55193', (17, 22))	('tumor', 'Disease', (245, 250))	('ccRCC', 'Disease', 'MESH:D002292', (96, 101))	('patients', 'Species', '9606', (52, 60))	('tumor', 'Disease', (154, 159))
26565	31963294	demonstrated that inhibiting DDX11 in melanoma cells decreased proliferation and rapidly increased apoptosis.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('proliferation', 'CPA', (63, 76))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('DDX11', 'Gene', (29, 34))	('increased', 'PosReg', (89, 98))	('DDX11', 'Gene', '1663', (29, 34))	('apoptosis', 'CPA', (99, 108))	('inhibiting', 'Var', (18, 28))	('decreased', 'NegReg', (53, 62))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('melanoma', 'Disease', (38, 46))
26571	31963294	TRACERx Renal classified tumors into seven distinct evolutionary subtypes, and primary tumors with low ITH, in addition to a low fraction of the tumor genome affected by somatic copy-number alterations (SCNAs), had an overall low metastatic potential.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('primary tumors', 'Disease', (79, 93))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('tumor', 'Disease', (145, 150))	('tumors', 'Disease', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('metastatic potential', 'CPA', (230, 250))	('copy-number alterations', 'Var', (178, 201))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('low', 'NegReg', (226, 229))	('primary tumors', 'Disease', 'MESH:D001932', (79, 93))
26632	33321829	Thus, HIF1alpha and HIF2alpha have contrasting properties in human clear cell renal cell carcinoma (ccRCC), which is characterized by the loss of VHL and the ensuing constitutive stabilization of HIF in normoxic conditions.	('loss', 'NegReg', (138, 142))	('VHL', 'Protein', (146, 149))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (67, 98))	('clear cell renal cell carcinoma', 'Disease', (67, 98))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (78, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (67, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('human', 'Species', '9606', (61, 66))	('HIF2alpha', 'Var', (20, 29))
26633	33321829	In this context HIF1alpha can repress tumor cell proliferation in different biological settings, including that of ccRCC, while HIF2alpha favors the proliferation of VHL-deficient RCCs and tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('HIF1alpha', 'Var', (16, 25))	('tumor', 'Disease', (189, 194))	('favors', 'PosReg', (138, 144))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('HIF2alpha', 'Var', (128, 137))	('RCC', 'Phenotype', 'HP:0005584', (180, 183))	('formation', 'biological_process', 'GO:0009058', ('195', '204'))	('cell proliferation', 'biological_process', 'GO:0008283', ('44', '62'))	('proliferation', 'CPA', (149, 162))	('VHL-deficient RCCs and tumor', 'Disease', 'MESH:D006623', (166, 194))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('repress', 'NegReg', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('ccRCC', 'Disease', (115, 120))
26635	33321829	Unlike, some other genes involved in renal cancer proliferation, such as cyclin D1 (CCND1), transforming growth factor alpha (TGFA) and the amino acid carrier SLC7A5 are preferentially induced by HIF2alpha.	('cyclin D1', 'Gene', (73, 82))	('transforming growth factor alpha', 'Gene', (92, 124))	('renal cancer', 'Disease', 'MESH:D007680', (37, 49))	('induced', 'PosReg', (185, 192))	('transforming growth factor alpha', 'molecular_function', 'GO:0005154', ('92', '124'))	('TGFA', 'Gene', (126, 130))	('CCND1', 'Gene', (84, 89))	('carrier', 'molecular_function', 'GO:0005215', ('151', '158'))	('cyclin', 'molecular_function', 'GO:0016538', ('73', '79'))	('cyclin D1', 'Gene', '12443', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('renal cancer', 'Disease', (37, 49))	('transforming growth factor alpha', 'Gene', '21802', (92, 124))	('HIF2alpha', 'Var', (196, 205))	('renal cancer', 'Phenotype', 'HP:0009726', (37, 49))
26647	33321829	The VHL-deficient ccRCC cells represent a model in which genes preferentially induced by HIF1alpha and HIF2alpha have been identified, and where both HIF isoforms are constitutively active in normoxic conditions.	('HIF2alpha', 'Var', (103, 112))	('VHL-deficient ccRCC', 'Disease', (4, 23))	('HIF1alpha', 'Var', (89, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (18, 23))	('VHL-deficient ccRCC', 'Disease', 'MESH:D006623', (4, 23))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))
26648	33321829	To study the distinct transcriptional responses provoked by HIF1alpha or HIF2alpha in renal cell carcinoma (RCC), we used WT8 cells that were generated by restoration of VHL expression into the 786-O VHL deficient RCC cell line.	('VHL deficient RCC', 'Disease', 'MESH:C538614', (200, 217))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (86, 106))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('VHL', 'Gene', (170, 173))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (86, 106))	('RCC', 'Phenotype', 'HP:0005584', (214, 217))	('renal cell carcinoma', 'Disease', (86, 106))	('HIF2alpha', 'Var', (73, 82))	('VHL deficient RCC', 'Disease', (200, 217))
26650	33321829	As such, the expression of CAIX, BNIP3 and phosphoglycerate mutase-1 (PGM1) was elevated exclusively in HIF1alpha(P-A)2 WT8 cells but not in HIF2alpha(P-A)2 WT8 cells relative to the control cells (Figure 2A), in line with previous studies showing that these genes are induced by HIF1alpha in ccRCC cells.	('BNIP3', 'Gene', (33, 38))	('elevated', 'PosReg', (80, 88))	('PGM1', 'Gene', (70, 74))	('expression', 'MPA', (13, 23))	('phosphoglycerate mutase-1', 'Gene', (43, 68))	('PGM', 'molecular_function', 'GO:0004619', ('70', '73'))	('CAIX', 'Gene', (27, 31))	('RCC', 'Phenotype', 'HP:0005584', (295, 298))	('HIF1alpha(P-A)2 WT8', 'Var', (104, 123))	('phosphoglycerate mutase-1', 'Gene', '24642', (43, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (293, 298))
26651	33321829	By contrast, the expression of other HIF-dependent genes like PHD3, CCND1, solute carrier family 2 member 1 (SLC2A1 or GLUT-1), TGFA, POU domain class 5 transcription factor 1 (POU5F1 or OCT-4) and N-myc downstream regulated gene 1 (NDRG1) was preferentially elevated in HIF2alpha(P-A)2 WT8 cells (Figure 2B), again in line with previous studies showing the participation of HIF2alpha in the gene expression of these genes.	('POU domain class 5 transcription factor 1', 'Gene', '294562', (134, 175))	('N-myc downstream regulated gene 1', 'Gene', '299923', (198, 231))	('N-myc downstream regulated gene 1', 'Gene', (198, 231))	('elevated', 'PosReg', (259, 267))	('SLC2A1', 'Gene', '24778', (109, 115))	('CCND1', 'Gene', (68, 73))	('transcription', 'biological_process', 'GO:0006351', ('153', '166'))	('solute carrier family 2 member 1', 'Gene', '24778', (75, 107))	('POU5F1', 'Gene', (177, 183))	('expression', 'MPA', (17, 27))	('transcription factor', 'molecular_function', 'GO:0000981', ('153', '173'))	('carrier', 'molecular_function', 'GO:0005215', ('82', '89'))	('SLC2A1', 'Gene', (109, 115))	('NDRG1', 'Gene', (233, 238))	('solute carrier family 2 member 1', 'Gene', (75, 107))	('POU5F1', 'Gene', '294562', (177, 183))	('OCT-4', 'Gene', (187, 192))	('gene expression', 'biological_process', 'GO:0010467', ('392', '407'))	('PHD', 'molecular_function', 'GO:0050175', ('62', '65'))	('OCT-4', 'Gene', '18999', (187, 192))	('HIF2alpha', 'Var', (271, 280))	('TGFA', 'Gene', (128, 132))	('POU domain class 5 transcription factor 1', 'Gene', (134, 175))	('PHD3', 'Gene', (62, 66))
26663	33321829	Collectively these data suggest that selective HIF1-dependent induction of CAIX, BNIP3 and PGM1 in WT8 cells requires the presence of both the bHLH-PAS and transactivation NTAD/CTAD regions of HIF1alpha, while the transactivation NTAD/CTAD region of HIF2alpha seem to be more relevant than the bHLH-PAS region to explain the preferential induction of PHD3, CCND1, GLUT-1, TGFA, OCT-4 and NDRG1 by HIF2alpha.	('bHLH', 'Gene', '25334', (143, 147))	('transactivation', 'biological_process', 'GO:2000144', ('156', '171'))	('transactivation', 'biological_process', 'GO:2000144', ('214', '229'))	('TGFA', 'Gene', (372, 376))	('PGM1', 'Gene', (91, 95))	('HIF1', 'Gene', '3091', (47, 51))	('PAS', 'cellular_component', 'GO:0000407', ('148', '151'))	('HIF1', 'Gene', (47, 51))	('PGM', 'molecular_function', 'GO:0004619', ('91', '94'))	('PHD', 'molecular_function', 'GO:0050175', ('351', '354'))	('OCT-4', 'Gene', (378, 383))	('PHD3', 'Gene', (351, 355))	('bHLH', 'Gene', (294, 298))	('bHLH', 'Gene', (143, 147))	('GLUT-1', 'Gene', (364, 370))	('OCT-4', 'Gene', '18999', (378, 383))	('BNIP3', 'Gene', (81, 86))	('HIF1', 'Gene', '3091', (193, 197))	('CCND1', 'Gene', (357, 362))	('PAS', 'cellular_component', 'GO:0000407', ('299', '302'))	('HIF1', 'Gene', (193, 197))	('HIF2alpha', 'Var', (397, 406))	('CAIX', 'Gene', (75, 79))	('NDRG1', 'Gene', (388, 393))	('bHLH', 'Gene', '25334', (294, 298))
26668	33321829	Therefore, the NTAD/CTAD HIF2alpha region appeared to be more relevant to explain the preferential SLC7A5 expression driven by the HIF2alpha isoform, which is similar to the data obtained for the CCND1, GLUT-1, TGFA, OCT-4 and NDRG1 genes (Figure 2B).	('HIF2alpha', 'Var', (131, 140))	('preferential', 'PosReg', (86, 98))	('OCT-4', 'Gene', '18999', (217, 222))	('expression', 'MPA', (106, 116))	('TGFA', 'Gene', (211, 215))	('OCT-4', 'Gene', (217, 222))	('GLUT-1', 'Gene', (203, 209))	('SLC7A5', 'Gene', (99, 105))	('CCND1', 'Gene', (196, 201))	('NDRG1', 'Gene', (227, 232))
26674	33321829	In line with previous studies Epo and mRNA levels are markedly induced in Vhl-/- liver (Figure 3) and kidney (Figure 4) through HIF2alpha isoform.	('HIF2alpha', 'Var', (128, 137))	('Epo', 'Gene', '13856', (30, 33))	('Epo', 'Gene', (30, 33))	('induced', 'PosReg', (63, 70))	('mRNA levels', 'MPA', (38, 49))
26691	33321829	In this line Tgfa and Ndrg1 expression is induced by HIF2alpha in renal cell carcinoma WT8 cells while is not induced in Vhl-/- kidneys.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (66, 86))	('expression', 'MPA', (28, 38))	('HIF2alpha', 'Var', (53, 62))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (66, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('Tgfa', 'Gene', (13, 17))	('induced', 'Reg', (42, 49))	('Ndrg1', 'Gene', (22, 27))	('renal cell carcinoma', 'Disease', (66, 86))
26694	33321829	In this line, it might be considered that these tumors are characterized by a specific ccRCC immune microenvironment and that Vhl gene inactivation by itself is not enough to initiate the generation of a renal cell carcinoma, which might explain the differences between these two models regarding Tgfa expression.	('renal cell carcinoma', 'Disease', (204, 224))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (204, 224))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (204, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('ccRCC', 'Disease', (87, 92))	('inactivation', 'Var', (135, 147))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('Vhl gene', 'Gene', (126, 134))
26696	33321829	However, our data also show that elevated Glut1 and Pgm1 expression in the Vhl-deficient mouse tissues analyzed is not significantly reduced upon Hif1a or Hif2a inactivation, which suggest that both isoforms might be competent to induce Glut1 and Pgm1 in both tissues.	('Glut1', 'Gene', (42, 47))	('expression', 'MPA', (57, 67))	('inactivation', 'Var', (161, 173))	('elevated', 'PosReg', (33, 41))	('Hif1a', 'Gene', (146, 151))	('Pgm', 'molecular_function', 'GO:0004619', ('52', '55'))	('Pgm1', 'Gene', (52, 56))	('Pgm', 'molecular_function', 'GO:0004619', ('247', '250'))	('Hif2a', 'Gene', '13819', (155, 160))	('Hif1a', 'Gene', '15251', (146, 151))	('reduced', 'NegReg', (133, 140))	('Hif2a', 'Gene', (155, 160))	('mouse', 'Species', '10090', (89, 94))
26714	33321829	Previous studies have shown that HIF chimeras that include the HIF1 bHLH-PAS and the HIF2 NTAD/CTAD region induce HIF2alpha targets genes like PHD3, PAI-1 or adrenomedulin (ADM).	('bHLH', 'Gene', (68, 72))	('PHD', 'molecular_function', 'GO:0050175', ('143', '146'))	('HIF2alpha', 'Gene', (114, 123))	('induce', 'PosReg', (107, 113))	('HIF1', 'Gene', '3091', (63, 67))	('PHD3', 'Gene', (143, 147))	('PAI-1', 'Gene', '18787', (149, 154))	('PAS', 'cellular_component', 'GO:0000407', ('73', '76'))	('bHLH', 'Gene', '25334', (68, 72))	('chimeras', 'Var', (37, 45))	('HIF1', 'Gene', (63, 67))	('PAI-1', 'Gene', (149, 154))
26716	33321829	We first found that the expression of these HIF2alpha target genes is not induced or minimally affected by a chimeric HIF construct that contains the HIF2alpha bHLH-PAS half and the HIF1alpha NTAD/CTAD half of the protein.	('HIF2alpha', 'Var', (150, 159))	('bHLH', 'Gene', (160, 164))	('protein', 'cellular_component', 'GO:0003675', ('214', '221'))	('bHLH', 'Gene', '25334', (160, 164))	('PAS', 'cellular_component', 'GO:0000407', ('165', '168'))
26717	33321829	By contrast, a HIF chimera that contains the HIF1alpha bHLH-PAS half and the HIF2alpha NTAD/CTAD half is sufficient to induce in a different extent all the HIF2alpha target genes analyzed, including the amino acid carrier SLC7A5, a HIF2alpha target gene previously identified in different biological settings.	('carrier', 'molecular_function', 'GO:0005215', ('214', '221'))	('induce', 'PosReg', (119, 125))	('bHLH', 'Gene', '25334', (55, 59))	('bHLH', 'Gene', (55, 59))	('HIF1alpha', 'Var', (45, 54))	('PAS', 'cellular_component', 'GO:0000407', ('60', '63'))
26730	33321829	To generate chimeric HIFalpha versions, a novel XbaI restriction site was introduced on aa 411 of HA-HIF1alpha-P402A/P564A and in aa414 of HA-HIF2alpha-P405A/P531A.	('P564A', 'SUBSTITUTION', 'None', (117, 122))	('P402A', 'SUBSTITUTION', 'None', (111, 116))	('P531A', 'Var', (158, 163))	('P531A', 'SUBSTITUTION', 'None', (158, 163))	('P405A', 'SUBSTITUTION', 'None', (152, 157))	('P564A', 'Var', (117, 122))	('P405A', 'Var', (152, 157))	('P402A', 'Var', (111, 116))
26731	33321829	For this purpose the N-terminal half of pBabe-puro HA-HIF1alpha-P402A/P564A (1 to 411) was amplified using a forward primer including an ApaI site (forward, 5'-TTCTCTAgggccc(ApaI)GGCCGGAT-3') and a reverse primer including an XbaI site (reverse, 5'-TCGTTGCTGCCAAAAtctaga(XbaI)GATATGATTGTGTCTCC-3').	('P564A', 'SUBSTITUTION', 'None', (70, 75))	('CA', 'Gene', '12310', (259, 261))	('P402A', 'Var', (64, 69))	('P402A', 'SUBSTITUTION', 'None', (64, 69))	('P564A', 'Var', (70, 75))
26732	33321829	The C-terminal half of pBabe-puro HA-HIF1alpha-P402A/P564A (412 to 826) was amplified using a forward primer including an XbaI site (forward, 5'-GGAGACACAATCATATCtctaga(XbaI)TTTTGGCAGCAACGA-3') and a reverse primer including an XbaI site (reverse, 5'-TAACTGACACACATtctaga(XbaI)GGGTCGACCACTGT-3').	('CA', 'Gene', '12310', (258, 260))	('P402A', 'Var', (47, 52))	('P402A', 'SUBSTITUTION', 'None', (47, 52))	('P564A', 'Var', (53, 58))	('CA', 'Gene', '12310', (285, 287))	('CA', 'Gene', '12310', (180, 182))	('CA', 'Gene', '12310', (183, 185))	('CA', 'Gene', '12310', (262, 264))	('P564A', 'SUBSTITUTION', 'None', (53, 58))	('CA', 'Gene', '12310', (152, 154))	('CA', 'Gene', '12310', (150, 152))	('CA', 'Gene', '12310', (156, 158))	('CA', 'Gene', '12310', (260, 262))
26733	33321829	The N-terminal half of pBabe-puro HA-HIF2alpha-P405A/P531A (1 to 414) was amplified using a forward primer including an ApaI site (forward, 5'-TTCTCTAgggccc(ApaI)GGCCGGAT-3') and a reverse primer including an XbaI site (reverse, 5'-GTTCTGATTCCCGAAAtctaga(XbaI)GAGATGATGGCG-3').	('P531A', 'SUBSTITUTION', 'None', (53, 58))	('P531A', 'Var', (53, 58))	('P405A', 'Var', (47, 52))	('P405A', 'SUBSTITUTION', 'None', (47, 52))
26734	33321829	The C-terminal half of pBabe-puro HA-HIF2alpha-P405A/P531A (415 to 870) was amplified using a forward primer including an XbaI site (forward, 5'-CGCCATCATCTCtctaga(XbaI)TTTCGGGAATCAGAAC-3') and a reverse primer including an XbaI site (reverse, 5'- TAACTGACACACATtctaga(XbaI)GGGTCGACCACTGT-3').	('P531A', 'Var', (53, 58))	('CA', 'Gene', '12310', (151, 153))	('CA', 'Gene', '12310', (179, 181))	('CA', 'Gene', '12310', (255, 257))	('CA', 'Gene', '12310', (282, 284))	('P531A', 'SUBSTITUTION', 'None', (53, 58))	('CA', 'Gene', '12310', (257, 259))	('P405A', 'Var', (47, 52))	('CA', 'Gene', '12310', (259, 261))	('CA', 'Gene', '12310', (148, 150))	('P405A', 'SUBSTITUTION', 'None', (47, 52))
26736	33321829	Then the N-terminal regions of HA-HIF1alpha-P402A/P564A and HA-HIF2alpha-P405A/P531A were excised with ApaI-XbaI to be cloned in pLVX-Puro lentiviral expression vector.	('P405A', 'Var', (73, 78))	('P402A', 'Var', (44, 49))	('P564A', 'Var', (50, 55))	('P402A', 'SUBSTITUTION', 'None', (44, 49))	('P531A', 'Var', (79, 84))	('P564A', 'SUBSTITUTION', 'None', (50, 55))	('P531A', 'SUBSTITUTION', 'None', (79, 84))	('P405A', 'SUBSTITUTION', 'None', (73, 78))
26737	33321829	Finally, the C-terminal region of HA-HIF1alpha-P402A/P564A was excised with XbaI-XbaI to be cloned in the pLVX lentiviral expression vector harboring the N-terminal region of HA-HIF2alpha-P405A/P531A.	('P531A', 'Var', (194, 199))	('P531A', 'SUBSTITUTION', 'None', (194, 199))	('P402A', 'Var', (47, 52))	('P405A', 'SUBSTITUTION', 'None', (188, 193))	('P564A', 'Var', (53, 58))	('P402A', 'SUBSTITUTION', 'None', (47, 52))	('P564A', 'SUBSTITUTION', 'None', (53, 58))	('P405A', 'Var', (188, 193))
26738	33321829	Similarly, the C-terminal region of HA-HIF2alpha-P405A/P531A was excised with XbaI-XbaI to be cloned in the pLVX-Puro lentiviral expression vector harboring the N-terminal region of HA-HIF1alpha-P402A/P564A.	('P531A', 'SUBSTITUTION', 'None', (55, 60))	('P564A', 'Var', (201, 206))	('P402A', 'Var', (195, 200))	('P405A', 'SUBSTITUTION', 'None', (49, 54))	('P402A', 'SUBSTITUTION', 'None', (195, 200))	('P564A', 'SUBSTITUTION', 'None', (201, 206))	('P531A', 'Var', (55, 60))	('P405A', 'Var', (49, 54))
26750	33321829	UBC-Cre-ERT2 VhlLoxP/LoxP mice were generated through the appropriate crosses, along with the corresponding control mice.	('mice', 'Species', '10090', (116, 120))	('ERT2', 'Gene', '26417', (8, 12))	('ERT2', 'Gene', (8, 12))	('UBC', 'Gene', '22190', (0, 3))	('crosses', 'Var', (70, 77))	('UBC', 'Gene', (0, 3))	('mice', 'Species', '10090', (26, 30))
26754	33321829	The UBC-Cre-ERT2 VhlLoxP/LoxPHif2aLoxP/LoxP mice were generated through the appropriate crosses using Epas1tm1Mcs/J mice (Jackson Laboratories, stock no.	('ERT2', 'Gene', '26417', (12, 16))	('mice', 'Species', '10090', (116, 120))	('Hif2a', 'Gene', (29, 34))	('Epas1', 'Gene', '13819', (102, 107))	('crosses', 'Var', (88, 95))	('UBC', 'Gene', '22190', (4, 7))	('ERT2', 'Gene', (12, 16))	('Epas1', 'Gene', (102, 107))	('Mcs', 'cellular_component', 'GO:0044232', ('110', '113'))	('mice', 'Species', '10090', (44, 48))	('Hif2a', 'Gene', '13819', (29, 34))	('UBC', 'Gene', (4, 7))
26761	27894094	High MET expression and MET copy number gains were associated with an aggressive phenotype and an unfavorable patient outcome.	('MET', 'CPA', (24, 27))	('associated', 'Reg', (51, 61))	('patient', 'Species', '9606', (110, 117))	('High MET expression', 'Var', (0, 19))
26762	27894094	Our data reveal that clear-cell RCC with MET upregulation show an aggressive behavior and MET copy number increase is evident in a substantial percentage of patients with high-grade carcinomas and metastatic disease.	('carcinomas', 'Disease', (182, 192))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('patients', 'Species', '9606', (157, 165))	('aggressive behavior', 'CPA', (66, 85))	('upregulation', 'PosReg', (45, 57))	('metastatic', 'CPA', (197, 207))	('aggressive behavior', 'biological_process', 'GO:0002118', ('66', '85'))	('increase', 'PosReg', (106, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('aggressive behavior', 'Phenotype', 'HP:0000718', (66, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (182, 192))	('MET', 'Var', (41, 44))	('carcinomas', 'Disease', 'MESH:D002277', (182, 192))
26770	27894094	The ligand for HGFR is hepatocyte growth factor/scatter factor (HGF/SF) and binding induces recruitment of several signaling effectors.	('HGF/SF', 'Gene', (64, 70))	('HGFR', 'Gene', (15, 19))	('binding', 'Var', (76, 83))	('HGF/SF', 'Gene', '3082', (64, 70))	('ligand', 'molecular_function', 'GO:0005488', ('4', '10'))	('binding', 'molecular_function', 'GO:0005488', ('76', '83'))	('signaling', 'biological_process', 'GO:0023052', ('115', '124'))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('23', '47'))	('recruitment', 'MPA', (92, 103))	('HGFR', 'Gene', '4233', (15, 19))	('induces', 'Reg', (84, 91))
26772	27894094	Activating germline MET mutations have been observed in patients with hereditary papillary RCCs (papRCC) and in 13% of sporadic papillary RCC.	('patients', 'Species', '9606', (56, 64))	('Activating', 'PosReg', (0, 10))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('hereditary papillary RCCs', 'Disease', 'MESH:D002291', (70, 95))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('hereditary papillary RCCs', 'Disease', (70, 95))	('mutations', 'Var', (24, 33))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
26775	27894094	High HGFR protein expression is frequently observed in carcinomas with aggressive phenotype and associated with poor prognosis in non-small cell lung, ovarian and colorectal cancer.	('HGFR', 'Gene', (5, 9))	('carcinomas', 'Phenotype', 'HP:0030731', (55, 65))	('protein', 'Protein', (10, 17))	('High', 'Var', (0, 4))	('carcinomas', 'Disease', 'MESH:D002277', (55, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('non-small cell lung', 'Disease', (130, 149))	('observed', 'Reg', (43, 51))	('carcinomas', 'Disease', (55, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('HGFR', 'Gene', '4233', (5, 9))	('ovarian and colorectal cancer', 'Disease', 'MESH:D015179', (151, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
26777	27894094	Therefore, we systematically assessed the molecular status of MET in ccRCC in correlation with clinical features in a large, hospital-based series with long-term follow-up information and show that elevated HGFR expression and MET amplifications are evident in a substantial percentage of metastatic and/or aggressive ccRCCs and emerge de novo in RCC metastasis.	('RCC', 'Phenotype', 'HP:0005584', (347, 350))	('elevated', 'PosReg', (198, 206))	('MET amplifications', 'Var', (227, 245))	('expression', 'MPA', (212, 222))	('RCC metastasis', 'Disease', 'MESH:C538614', (347, 361))	('aggressive', 'CPA', (307, 317))	('metastatic', 'CPA', (289, 299))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('RCC metastasis', 'Disease', (347, 361))	('HGFR', 'Gene', '4233', (207, 211))	('HGFR', 'Gene', (207, 211))	('RCC', 'Phenotype', 'HP:0005584', (320, 323))
26783	27894094	MET copy number gains could be detected in 310 cases, 47% (272/572) tumors exhibited >2-4 MET copies per nucleus and another 7% (38/572) tumors more than 4 copies per nucleus, the remaining 46% (262/572) cases showed 2 copies per nucleus.	('nucleus', 'cellular_component', 'GO:0005634', ('230', '237'))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('nucleus', 'cellular_component', 'GO:0005634', ('105', '112'))	('nucleus', 'cellular_component', 'GO:0005634', ('167', '174'))	('copy number', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
26786	27894094	However, the protein levels of HGFR and MET copy number showed a weak positive correlation (Spearman's rank correlation rho=0.377; p < 0.001, Supplementary Figure S1C).	('HGFR', 'Gene', '4233', (31, 35))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('HGFR', 'Gene', (31, 35))	('MET', 'Var', (40, 43))	('protein levels', 'MPA', (13, 27))
26792	27894094	As increased HGFR protein levels were observed in the absence of MET copy number gains, HGFR overexpression has to be based on other mechanisms than amplification.	('increased', 'PosReg', (3, 12))	('HGFR', 'Gene', '4233', (13, 17))	('HGFR', 'Gene', (88, 92))	('HGFR', 'Gene', (13, 17))	('MET copy number gains', 'Var', (65, 86))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))	('HGFR', 'Gene', '4233', (88, 92))
26793	27894094	As mutations that inactivate the Cbl binding site lead to constitutive HGFR expression, we checked for MET mutations by targeted next-generation sequencing in 9 tumors with high HGFR protein levels and 2 MET copies/nucleus and 2 tumors with high HGFR protein levels and gains of MET copy numbers.	('HGFR', 'Gene', (246, 250))	('HGFR', 'Gene', (71, 75))	('tumors', 'Disease', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('HGFR', 'Gene', '4233', (178, 182))	('Cbl', 'Gene', '867', (33, 36))	('protein', 'cellular_component', 'GO:0003675', ('251', '258'))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('binding', 'molecular_function', 'GO:0005488', ('37', '44'))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('HGFR', 'Gene', '4233', (246, 250))	('HGFR', 'Gene', '4233', (71, 75))	('tumors', 'Disease', (229, 235))	('lead to', 'Reg', (50, 57))	('HGFR', 'Gene', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('mutations', 'Var', (107, 116))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('constitutive', 'MPA', (58, 70))	('expression', 'MPA', (76, 86))	('nucleus', 'cellular_component', 'GO:0005634', ('215', '222'))	('Cbl', 'Gene', (33, 36))	('mutations', 'Var', (3, 12))
26795	27894094	Besides VHL mutations, we did not identify other recurrent mutations in the examined genes.	('mutations', 'Var', (12, 21))	('VHL', 'Gene', '7428', (8, 11))	('VHL', 'Gene', (8, 11))
26797	27894094	For example, percentage of tumors with high HGFR expression was 17% in G1 compared to 46% in G3 carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('high', 'Var', (39, 43))	('carcinomas', 'Disease', 'MESH:D002277', (96, 106))	('HGFR', 'Gene', (44, 48))	('carcinomas', 'Disease', (96, 106))	('tumors', 'Disease', (27, 33))	('expression', 'MPA', (49, 59))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('HGFR', 'Gene', '4233', (44, 48))
26799	27894094	MET copy number gains were accompanied by dedifferentiation (P < 0.001), higher tumor extent (P < 0.001), positive lymphnode status (P = 0.006), and occurrence of distant metastasis (P = 0.02) (Figure 3).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('distant metastasis', 'CPA', (163, 181))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('dedifferentiation', 'biological_process', 'GO:0043696', ('42', '59'))	('tumor', 'Disease', (80, 85))	('dedifferentiation', 'CPA', (42, 59))	('MET copy number gains', 'Var', (0, 21))	('positive lymphnode status', 'CPA', (106, 131))	('higher', 'PosReg', (73, 79))
26804	27894094	When tumors were grouped according to HGFR expression, univariate survival analysis revealed a decrease in cancer-specific survival (P = 0.008) in patients affected by tumors with high HGFR expression compared to tumors with low/no HGFR expression.	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('HGFR', 'Gene', '4233', (185, 189))	('tumors', 'Disease', (168, 174))	('HGFR', 'Gene', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('HGFR', 'Gene', '4233', (232, 236))	('tumors', 'Disease', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('patients', 'Species', '9606', (147, 155))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('high', 'Var', (180, 184))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('HGFR', 'Gene', '4233', (38, 42))	('HGFR', 'Gene', (185, 189))	('cancer', 'Disease', (107, 113))	('decrease', 'NegReg', (95, 103))	('tumors', 'Disease', (5, 11))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('HGFR', 'Gene', (232, 236))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
26816	27894094	reported that ALK/ROS/MET inhibitor Crizotinib induced long lasting disease control in metastatic papillary renal cell carcinoma type 1 with MET mutation and long term stable disease in a case with MET amplification.	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (98, 128))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (108, 128))	('ALK', 'Gene', '238', (14, 17))	('ROS', 'Chemical', '-', (18, 21))	('papillary renal cell carcinoma type', 'Disease', (98, 133))	('ALK', 'Gene', (14, 17))	('papillary renal cell carcinoma type 1', 'Phenotype', 'HP:0011797', (98, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('MET mutation', 'Var', (141, 153))	('papillary renal cell carcinoma type', 'Disease', 'MESH:C538614', (98, 133))	('Crizotinib', 'Chemical', 'MESH:D000077547', (36, 46))
26833	27894094	Association with clinical and pathological features in primary tumor, MET copy number gains in the context of metastatic spread and initial in-vitro data indicating that MET-signaling acts as mediator of antiangiogenic therapy, suggest a biologic relevance of MET signaling in ccRCCs.	('gains', 'PosReg', (86, 91))	('MET copy number', 'Var', (70, 85))	('signaling', 'biological_process', 'GO:0023052', ('174', '183'))	('primary tumor', 'Disease', (55, 68))	('primary tumor', 'Disease', 'MESH:D009369', (55, 68))	('signaling', 'biological_process', 'GO:0023052', ('264', '273'))	('ccRCCs', 'Disease', (277, 283))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('RCC', 'Phenotype', 'HP:0005584', (279, 282))
26850	27894094	Staining was performed using an automated staining system BenchMark ULTRA (Ventana Medical Systems) in accordance with the manufacturer's instructions, the following solutions were used: OptiView DAB IHC Detection Kit (760-700), Hematoxylin I (790-2208), Bluing Reagent (760-2037).	('DAB', 'Chemical', 'MESH:C000469', (196, 199))	('760-700', 'Var', (219, 226))	('790-2208', 'Var', (244, 252))	('Hematoxylin', 'Chemical', 'MESH:D006416', (229, 240))
26860	31752777	Nrf2 gene mutation and single nucleotide polymorphism rs6721961 of the Nrf2 promoter region in renal cell cancer Nuclear factor erythroid 2-related factor 2 (Nrf2) is involved in cell proliferation by promotion of metabolic activity.	('cell proliferation', 'CPA', (179, 197))	('rs6721961', 'Var', (54, 63))	('Nrf2', 'Gene', '4780', (158, 162))	('renal cell cancer', 'Disease', 'MESH:D002292', (95, 112))	('Nrf2', 'Gene', '4780', (0, 4))	('Nrf2', 'Gene', (71, 75))	('renal cell cancer', 'Phenotype', 'HP:0005584', (95, 112))	('promotion', 'PosReg', (201, 210))	('rs6721961', 'Mutation', 'rs6721961', (54, 63))	('Nrf2', 'Gene', (158, 162))	('Nuclear factor erythroid 2-related factor 2', 'Gene', '4780', (113, 156))	('Nrf2', 'Gene', (0, 4))	('metabolic activity', 'CPA', (214, 232))	('renal cell cancer', 'Disease', (95, 112))	('cell proliferation', 'biological_process', 'GO:0008283', ('179', '197'))	('Nuclear factor erythroid 2-related factor 2', 'Gene', (113, 156))	('Nrf2', 'Gene', '4780', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
26863	31752777	In 50 patients who had metastatic RCC and received cytoreductive nephrectomy, we performed Nrf2 gene mutation analysis using targeted next-generation sequencing, as well as investigating a specific single nucleotide polymorphism (SNP; rs6721961) in the Nrf2 promoter region and Nrf2 protein expression.	('expression', 'MPA', (291, 301))	('Nrf2', 'Gene', (253, 257))	('Nrf2', 'Gene', (91, 95))	('RCC', 'Disease', 'MESH:D002292', (34, 37))	('Nrf2', 'Gene', '4780', (278, 282))	('protein', 'cellular_component', 'GO:0003675', ('283', '290'))	('rs6721961', 'Mutation', 'rs6721961', (235, 244))	('patients', 'Species', '9606', (6, 14))	('Nrf2', 'Gene', (278, 282))	('Nrf2', 'Gene', '4780', (253, 257))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('mutation', 'Var', (101, 109))	('Nrf2', 'Gene', '4780', (91, 95))	('single nucleotide polymorphism', 'Var', (198, 228))	('RCC', 'Disease', (34, 37))
26864	31752777	Targeted next-generation sequencing revealed that five tumors had SNPs of Nrf2 associated with amino acid sequence variation, while 11 tumors had SNPs of Kelch-like ECH-associated protein 1 gene, 35 had SNPs of von Hippel-Lindau gene, and none had SNPs of fumarate hydratase gene.	('fumarate hydratase', 'Gene', '2271', (256, 274))	('associated', 'Reg', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('von Hippel-Lindau', 'Gene', (211, 228))	('tumors', 'Disease', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Nrf2', 'Gene', (74, 78))	('ECH', 'molecular_function', 'GO:0004300', ('165', '168'))	('Kelch-like ECH-associated protein 1', 'Gene', '9817', (154, 189))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Disease', (55, 61))	('von Hippel-Lindau', 'Gene', '7428', (211, 228))	('fumarate hydratase', 'Gene', (256, 274))	('Kelch-like ECH-associated protein 1', 'Gene', (154, 189))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('SNPs', 'Var', (66, 70))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('Nrf2', 'Gene', '4780', (74, 78))	('amino acid sequence variation', 'Var', (95, 124))	('protein', 'cellular_component', 'GO:0003675', ('180', '187'))
26865	31752777	The three genotypes of rs6721961 showed the following frequencies: 60% for C/C, 34% for C/A, and 6% for A/A.	('C/C', 'Disease', (75, 78))	('rs6721961', 'Mutation', 'rs6721961', (23, 32))	('rs6721961', 'Var', (23, 32))	('C/A, and 6%', 'Gene', '729', (88, 99))
26866	31752777	Nrf2 mutation and the C/A or A/A genotypes were significantly associated with increased Nrf2 protein expression (p = 0.0184 and p = 0.0005, respectively).	('Nrf2', 'Gene', (88, 92))	('Nrf2', 'Gene', '4780', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('protein', 'Protein', (93, 100))	('Nrf2', 'Gene', (0, 4))	('increased', 'PosReg', (78, 87))	('Nrf2', 'Gene', '4780', (88, 92))	('expression', 'MPA', (101, 111))	('mutation', 'Var', (5, 13))
26867	31752777	When the primary tumor showed Nrf2 gene mutation, the C/A or A/A genotype, or elevated Nrf2 protein expression, the response of metastases to vascular endothelial growth factor-targeting therapy was significantly worse (p = 0.0142, p = 0.0018, and p <  0.0001, respectively), and overall survival was significantly reduced (p = 0.0343, p = 0.0421, and p <  0.0001, respectively).	('worse', 'NegReg', (213, 218))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('142', '176'))	('Nrf2', 'Gene', (30, 34))	('vascular endothelial growth factor', 'Gene', (142, 176))	('Nrf2', 'Gene', '4780', (87, 91))	('metastases', 'Disease', 'MESH:D009362', (128, 138))	('mutation', 'Var', (40, 48))	('metastases', 'Disease', (128, 138))	('tumor', 'Disease', (17, 22))	('overall survival', 'CPA', (280, 296))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('Nrf2', 'Gene', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('reduced', 'NegReg', (315, 322))	('protein', 'Protein', (92, 99))	('Nrf2', 'Gene', '4780', (30, 34))	('C/A', 'Var', (54, 57))	('elevated', 'PosReg', (78, 86))	('expression', 'MPA', (100, 110))	('response', 'MPA', (116, 124))	('vascular endothelial growth factor', 'Gene', '7422', (142, 176))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
26874	31752777	Somatic mutations of Nrf2 have been reported in many human cancers, with tumorigenic mutations typically leading to activation of Nrf2 targets.	('Nrf2', 'Gene', '4780', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Nrf2', 'Gene', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Nrf2', 'Gene', (21, 25))	('mutations', 'Var', (8, 17))	('reported', 'Reg', (36, 44))	('mutations', 'Var', (85, 94))	('tumor', 'Disease', (73, 78))	('activation', 'PosReg', (116, 126))	('human', 'Species', '9606', (53, 58))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))	('Nrf2', 'Gene', '4780', (130, 134))
26875	31752777	Nrf2 gene mutations have been reported to lead to modification of certain residues in Nrf2 protein.	('Nrf2', 'Gene', (86, 90))	('Nrf2', 'Gene', '4780', (0, 4))	('Nrf2', 'Gene', (0, 4))	('protein', 'Protein', (91, 98))	('Nrf2', 'Gene', '4780', (86, 90))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('residues', 'MPA', (74, 82))	('lead to', 'Reg', (42, 49))	('mutations', 'Var', (10, 19))	('modification', 'MPA', (50, 62))
26876	31752777	In addition, Nrf2 promoter alterations like single nucleotide polymorphisms (SNPs) were reported to cause marked repression of both Nrf2 transcription and activity.	('activity', 'MPA', (155, 163))	('Nrf2', 'Gene', (13, 17))	('repression', 'NegReg', (113, 123))	('Nrf2', 'Gene', '4780', (132, 136))	('transcription', 'biological_process', 'GO:0006351', ('137', '150'))	('single nucleotide polymorphisms', 'Var', (44, 75))	('Nrf2', 'Gene', (132, 136))	('Nrf2', 'Gene', '4780', (13, 17))	('transcription', 'MPA', (137, 150))
26879	31752777	reported the association of a SNP (rs35652124) with cardiovascular mortality in hemodialysis patients.	('association', 'Interaction', (13, 24))	('hemodialysis', 'Disease', (80, 92))	('hemodialysis', 'Disease', 'None', (80, 92))	('rs35652124', 'Var', (35, 45))	('rs35652124', 'Mutation', 'rs35652124', (35, 45))	('patients', 'Species', '9606', (93, 101))	('cardiovascular', 'Disease', (52, 66))
26880	31752777	In addition, a SNP (rs6721961) in the promoter region of Nrf2 (Nrf2 regulatory SNP-617) was reported to be involved in carcinogenesis, and is associated with a significantly higher risk of developing non-small cell lung cancer.	('carcinogenesis', 'Disease', 'MESH:D063646', (119, 133))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('non-small cell lung cancer', 'Disease', (200, 226))	('Nrf2', 'Gene', (57, 61))	('Nrf2', 'Gene', '4780', (63, 67))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (204, 226))	('rs6721961', 'Var', (20, 29))	('involved', 'Reg', (107, 115))	('carcinogenesis', 'Disease', (119, 133))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (200, 226))	('associated', 'Reg', (142, 152))	('Nrf2', 'Gene', (63, 67))	('Nrf2', 'Gene', '4780', (57, 61))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (200, 226))	('lung cancer', 'Phenotype', 'HP:0100526', (215, 226))	('rs6721961', 'Mutation', 'rs6721961', (20, 29))
26881	31752777	It has also been reported that this SNP (rs6721961) is associated with a higher risk of several cardiovascular diseases, including venous thromboembolism, reduced vital capacity, and an impaired forearm vasodilator response.	('impaired', 'NegReg', (186, 194))	('reduced vital capacity', 'Phenotype', 'HP:0002792', (155, 177))	('reduced', 'NegReg', (155, 162))	('cardiovascular diseases', 'Disease', (96, 119))	('rs6721961', 'Mutation', 'rs6721961', (41, 50))	('venous thromboembolism', 'Disease', 'MESH:D054556', (131, 153))	('thromboembolism', 'Phenotype', 'HP:0001907', (138, 153))	('vital capacity', 'MPA', (163, 177))	('forearm vasodilator response', 'MPA', (195, 223))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (96, 119))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (96, 119))	('rs6721961', 'Var', (41, 50))	('venous thromboembolism', 'Disease', (131, 153))
26882	31752777	Thus, SNP (rs6721961) in the promoter region of Nrf2 (Nrf2 regulatory SNP (rSNP)-617) seems to influence Nrf2 expression.	('SNP', 'Var', (6, 9))	('Nrf2', 'Gene', (105, 109))	('rs6721961', 'Mutation', 'rs6721961', (11, 20))	('Nrf2', 'Gene', (54, 58))	('influence', 'Reg', (95, 104))	('Nrf2', 'Gene', '4780', (48, 52))	('Nrf2', 'Gene', (48, 52))	('expression', 'MPA', (110, 120))	('Nrf2', 'Gene', '4780', (54, 58))	('Nrf2', 'Gene', '4780', (105, 109))	('rs6721961', 'Var', (11, 20))
26885	31752777	In order to shed more light on the influence of Nrf2 signaling in human ccRCC, we assessed Nrf2 gene mutations, the rs6721961 SNP, and Nrf2 protein expression in patients with metastatic ccRCC, as well as associations with the response to adjuvant vascular endothelial growth factor (VEGF)-targeting therapy and survival.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('human', 'Species', '9606', (66, 71))	('ccRCC', 'Disease', (72, 77))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('248', '282'))	('Nrf2', 'Gene', (91, 95))	('Nrf2', 'Gene', '4780', (48, 52))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('Nrf2', 'Gene', '4780', (135, 139))	('patients', 'Species', '9606', (162, 170))	('mutations', 'Var', (101, 110))	('ccRCC', 'Disease', 'MESH:D002292', (187, 192))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('rs6721961', 'Mutation', 'rs6721961', (116, 125))	('vascular endothelial growth factor', 'Gene', '7422', (248, 282))	('Nrf2', 'Gene', (48, 52))	('VEGF', 'Gene', '7422', (284, 288))	('Nrf2', 'Gene', (135, 139))	('ccRCC', 'Disease', (187, 192))	('ccRCC', 'Disease', 'MESH:D002292', (72, 77))	('vascular endothelial growth factor', 'Gene', (248, 282))	('VEGF', 'Gene', (284, 288))	('Nrf2', 'Gene', '4780', (91, 95))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))
26896	31752777	Tumor tissue samples of the 50 patients were used to investigate mutations of the Nrf2, Keap1, von Hippel-Lindau (VHL), and fumarate hydratase (FH) genes.	('Tumor', 'Disease', 'MESH:D009369', (0, 5))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Nrf2', 'Gene', (82, 86))	('von Hippel-Lindau', 'Gene', '7428', (95, 112))	('Tumor', 'Disease', (0, 5))	('Nrf2', 'Gene', '4780', (82, 86))	('FH', 'Gene', '2271', (144, 146))	('VHL', 'Disease', (114, 117))	('patients', 'Species', '9606', (31, 39))	('VHL', 'Disease', 'MESH:D006623', (114, 117))	('Keap1', 'Gene', '9817', (88, 93))	('Keap1', 'Gene', (88, 93))	('fumarate hydratase', 'Gene', '2271', (124, 142))	('fumarate hydratase', 'Gene', (124, 142))	('mutations', 'Var', (65, 74))	('von Hippel-Lindau', 'Gene', (95, 112))
26897	31752777	Genotyping of the rs6721961 SNP in the Nrf2 promoter region was performed by the real-time polymerase chain reaction with confronting two-pair primers (PCR-CTPP).	('Nrf2', 'Gene', (39, 43))	('CTPP', 'Gene', '10306', (156, 160))	('rs6721961', 'Mutation', 'rs6721961', (18, 27))	('Nrf2', 'Gene', '4780', (39, 43))	('CTPP', 'Gene', (156, 160))	('rs6721961 SNP', 'Var', (18, 31))
26900	31752777	Pearson's chi2 test for contingency tables was employed to assess the association between Nrf2 polymorphism and Nrf2 protein expression, as well as the relation between the response to VEGF-targeting therapy and Nrf2 polymorphism or Nrf2 protein expression.	('Nrf2', 'Gene', '4780', (233, 237))	('Nrf2', 'Gene', (212, 216))	('Nrf2', 'Gene', (112, 116))	('association', 'Interaction', (70, 81))	('protein', 'Protein', (117, 124))	('Nrf2', 'Gene', '4780', (212, 216))	('expression', 'MPA', (125, 135))	('Nrf2', 'Gene', '4780', (90, 94))	('VEGF', 'Gene', '7422', (185, 189))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('Nrf2', 'Gene', (233, 237))	('polymorphism', 'Var', (95, 107))	('Nrf2', 'Gene', '4780', (112, 116))	('Nrf2', 'Gene', (90, 94))	('protein', 'cellular_component', 'GO:0003675', ('238', '245'))	('VEGF', 'Gene', (185, 189))
26902	31752777	According to targeted next-generation sequencing of primary tumor tissue samples, 5 out of 50 patients had SNPs of the Nrf2 gene associated with amino acid sequence variants.	('associated', 'Reg', (129, 139))	('SNPs', 'Disease', (107, 111))	('patients', 'Species', '9606', (94, 102))	('Nrf2', 'Gene', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('amino acid sequence variants', 'Var', (145, 173))	('tumor', 'Disease', (60, 65))	('Nrf2', 'Gene', '4780', (119, 123))
26903	31752777	In addition, there were SNPs of Keap1 in 11 patients and SNPs of VHL in 35 patients, but no SNPs of FH were detected.	('patients', 'Species', '9606', (44, 52))	('SNPs', 'Var', (57, 61))	('FH', 'Gene', '2271', (100, 102))	('patients', 'Species', '9606', (75, 83))	('VHL', 'Disease', (65, 68))	('VHL', 'Disease', 'MESH:D006623', (65, 68))	('SNPs', 'Var', (24, 28))	('Keap1', 'Gene', '9817', (32, 37))	('Keap1', 'Gene', (32, 37))
26904	31752777	There was no relationship between Nrf2 or Keap1 mutations and the histological grade, pT stage, or pN stage (Table 1).	('Nrf2', 'Gene', '4780', (34, 38))	('Keap1', 'Gene', (42, 47))	('Keap1', 'Gene', '9817', (42, 47))	('histological grade', 'CPA', (66, 84))	('Nrf2', 'Gene', (34, 38))	('mutations', 'Var', (48, 57))
26905	31752777	PCR-CTPP was performed to examine the rs6721961 SNP in the Nrf2 promoter region (Fig.	('rs6721961', 'Mutation', 'rs6721961', (38, 47))	('Nrf2', 'Gene', '4780', (59, 63))	('CTPP', 'Gene', (4, 8))	('rs6721961', 'Var', (38, 47))	('Nrf2', 'Gene', (59, 63))	('CTPP', 'Gene', '10306', (4, 8))
26906	31752777	When all 50 tumor samples were investigated, the three genotypes of this SNP showed the following frequencies: 60% (30 patients) for C/C, 34% (17 patients) for C/A, and 6% (3 patients) for A/A.	('C/A, and 6%', 'Gene', '729', (160, 171))	('C/C', 'Var', (133, 136))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('patients', 'Species', '9606', (175, 183))	('tumor', 'Disease', (12, 17))	('patients', 'Species', '9606', (146, 154))
26909	31752777	Tumors with Nrf2 gene mutations showed increased expression of Nrf2 protein, and the C/A and A/A genotypes of rs6721961 were significantly associated with elevated Nrf2 protein expression (p <  0.0001, Table 2).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Nrf2', 'Gene', (164, 168))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Nrf2', 'Gene', (12, 16))	('Nrf2', 'Gene', '4780', (63, 67))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('expression', 'MPA', (49, 59))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (22, 31))	('Nrf2', 'Gene', (63, 67))	('protein', 'Protein', (68, 75))	('Nrf2', 'Gene', '4780', (164, 168))	('protein', 'Protein', (169, 176))	('rs6721961', 'Mutation', 'rs6721961', (110, 119))	('increased', 'PosReg', (39, 48))	('Nrf2', 'Gene', '4780', (12, 16))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('elevated', 'PosReg', (155, 163))	('rs6721961', 'Var', (110, 119))
26911	31752777	In addition, we found no association of Keap1 gene mutation with the level of Nrf2 expression after dividing the patients into a group with the C/C genotype of rs6721961 and a group with the C/A or A/A genotypes.	('Nrf2', 'Gene', (78, 82))	('Keap1', 'Gene', (40, 45))	('patients', 'Species', '9606', (113, 121))	('association', 'Interaction', (25, 36))	('rs6721961', 'Mutation', 'rs6721961', (160, 169))	('level', 'MPA', (69, 74))	('mutation', 'Var', (51, 59))	('expression', 'MPA', (83, 93))	('Nrf2', 'Gene', '4780', (78, 82))	('Keap1', 'Gene', '9817', (40, 45))	('rs6721961', 'Var', (160, 169))
26913	31752777	When the primary tumor possessed Nrf2 gene mutations, the C/A or A/A genotypes of rs6721961, or elevated Nrf2 protein expression, metastatic lesions demonstrated a worse response to VEGF-targeting therapy (p = 0.0142, p = 0.0018, and p < 0.0001, respectively) (Table 3).	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('Nrf2', 'Gene', (105, 109))	('Nrf2', 'Gene', (33, 37))	('rs6721961', 'Var', (82, 91))	('tumor', 'Disease', (17, 22))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('protein', 'Protein', (110, 117))	('VEGF', 'Gene', '7422', (182, 186))	('mutations', 'Var', (43, 52))	('rs6721961', 'Mutation', 'rs6721961', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('elevated', 'PosReg', (96, 104))	('Nrf2', 'Gene', '4780', (105, 109))	('metastatic lesions', 'CPA', (130, 148))	('Nrf2', 'Gene', '4780', (33, 37))	('VEGF', 'Gene', (182, 186))
26914	31752777	When primary tumors had Nrf2 gene mutations and the C/A or A/A genotypes of rs6721961, Kaplan-Meier analysis showed that survival was shorter than if tumors had the C/C genotype (p = 0.0343 and p = 0.0421, respectively, Fig.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('survival', 'MPA', (121, 129))	('Nrf2', 'Gene', '4780', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('rs6721961', 'Mutation', 'rs6721961', (76, 85))	('Nrf2', 'Gene', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('mutations', 'Var', (34, 43))	('rs6721961', 'Var', (76, 85))	('shorter', 'NegReg', (134, 141))	('C/A', 'Var', (52, 55))
26916	31752777	Keap1 gene mutations were also associated with shorter overall survival, but this association did not reach statistical significance (p = 0.1966, Fig.	('Keap1', 'Gene', (0, 5))	('mutations', 'Var', (11, 20))	('shorter', 'NegReg', (47, 54))	('overall survival', 'MPA', (55, 71))	('Keap1', 'Gene', '9817', (0, 5))
26918	31752777	Although Nrf2 gene mutations were only detected in patients with the C/A or A/A genotypes of rs6721961, there were no differences of Nrf2 expression, the response to VEGF-targeting therapy, and overall survival between Nrf2 mutation (+) patients and Nrf2 mutation (-) patients with the C/A or A/A genotypes of RS 6721961.	('VEGF', 'Gene', (166, 170))	('rs6721961', 'Mutation', 'rs6721961', (93, 102))	('Nrf2', 'Gene', (133, 137))	('Nrf2', 'Gene', (250, 254))	('Nrf2', 'Gene', '4780', (219, 223))	('Nrf2', 'Gene', '4780', (250, 254))	('mutation', 'Var', (224, 232))	('Nrf2', 'Gene', '4780', (9, 13))	('VEGF', 'Gene', '7422', (166, 170))	('Nrf2', 'Gene', (219, 223))	('patients', 'Species', '9606', (51, 59))	('patients', 'Species', '9606', (237, 245))	('patients', 'Species', '9606', (268, 276))	('rs6721961', 'Var', (93, 102))	('Nrf2', 'Gene', '4780', (133, 137))	('Nrf2', 'Gene', (9, 13))
26919	31752777	According to univariate Cox proportional hazards analysis, Nrf2 gene mutations, the rs6721961 SNP, Nrf2 protein expression, histological grade, pT stage, and pN stage were all factors with a significant influence on overall survival, while Keap1 mutation was not (Table 4).	('mutations', 'Var', (69, 78))	('Nrf2', 'Gene', '4780', (99, 103))	('Nrf2', 'Gene', '4780', (59, 63))	('Keap1', 'Gene', '9817', (240, 245))	('Keap1', 'Gene', (240, 245))	('rs6721961 SNP', 'Var', (84, 97))	('Cox', 'Gene', '1351', (24, 27))	('Nrf2', 'Gene', (99, 103))	('influence', 'Reg', (203, 212))	('Nrf2', 'Gene', (59, 63))	('rs6721961', 'Mutation', 'rs6721961', (84, 93))	('Cox', 'Gene', (24, 27))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('overall survival', 'CPA', (216, 232))
26924	31752777	It was reported that Nrf2 gene mutations leading to modification of the Nrf2 protein residues that interact with Keap1 cause activation of the cap'n'collar (CNC) - basic leucine zipper protein (bZIP) transcription factor.	('activation', 'PosReg', (125, 135))	('transcription', 'biological_process', 'GO:0006351', ('200', '213'))	('Nrf2', 'Gene', '4780', (21, 25))	('mutations', 'Var', (31, 40))	('bZIP', 'Gene', '10488', (194, 198))	('Keap1', 'Gene', '9817', (113, 118))	('transcription factor', 'molecular_function', 'GO:0000981', ('200', '220'))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('Nrf2', 'Gene', (21, 25))	('bZIP', 'Gene', (194, 198))	('Nrf2', 'Gene', '4780', (72, 76))	('Keap1', 'Gene', (113, 118))	('basic leucine zipper protein', 'Gene', '10488', (164, 192))	('CNC', 'Gene', '5573', (157, 160))	('basic leucine zipper protein', 'Gene', (164, 192))	('Nrf2', 'Gene', (72, 76))	('CNC', 'Gene', (157, 160))
26925	31752777	Functional Keap1 mutations have been detected in various cancers, and these mutations lead to upregulation of Nrf2 / ARE gene transcription.	('mutations', 'Var', (76, 85))	('Keap1', 'Gene', '9817', (11, 16))	('transcription', 'MPA', (126, 139))	('Keap1', 'Gene', (11, 16))	('Nrf2', 'Gene', '4780', (110, 114))	('upregulation', 'PosReg', (94, 106))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('transcription', 'biological_process', 'GO:0006351', ('126', '139'))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('Nrf2', 'Gene', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (17, 26))
26926	31752777	In the present study, we used targeted next-generation sequencing for mutation analysis of primary tumor tissues from 50 patients metastatic RCC, and we detected Nrf2 gene mutation in 5 patients, Keap1 gene mutation in 11 patients, and VHL gene mutation in 35 patients.	('RCC', 'Disease', 'MESH:D002292', (141, 144))	('tumor', 'Disease', (99, 104))	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('Keap1', 'Gene', '9817', (196, 201))	('Keap1', 'Gene', (196, 201))	('patients', 'Species', '9606', (222, 230))	('Nrf2', 'Gene', '4780', (162, 166))	('Nrf2', 'Gene', (162, 166))	('patients', 'Species', '9606', (260, 268))	('mutation', 'Var', (172, 180))	('detected', 'Reg', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('VHL', 'Disease', (236, 239))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('VHL', 'Disease', 'MESH:D006623', (236, 239))	('patients', 'Species', '9606', (121, 129))	('patients', 'Species', '9606', (186, 194))
26927	31752777	Abnormal VHL-mediated proteolysis is frequent in ccRCC, mainly due to biallelic inactivation of VHL resulting from allelic deletion or loss of heterozygosity together with gene mutation or promoter hypermethylation.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('ccRCC', 'Disease', 'MESH:D002292', (49, 54))	('VHL', 'Disease', 'MESH:D006623', (96, 99))	('proteolysis', 'biological_process', 'GO:0006508', ('22', '33'))	('VHL', 'Disease', (96, 99))	('VHL', 'Disease', 'MESH:D006623', (9, 12))	('loss of heterozygosity', 'Var', (135, 157))	('ccRCC', 'Disease', (49, 54))	('VHL', 'Disease', (9, 12))
26928	31752777	In the present study, we identified somatic VHL gene mutation in 35 of 50 tumors (70%).	('VHL', 'Disease', 'MESH:D006623', (44, 47))	('mutation', 'Var', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('VHL', 'Disease', (44, 47))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
26929	31752777	recently investigated copy numbers and/or methylation in over 100 ccRCC patients, using whole-genome and/or whole-exome sequencing, RNA sequencing, and microarray analysis, and they identified a new Keap1-Nrf2 pathway mutation along with VHL mutation.	('Keap1', 'Gene', '9817', (199, 204))	('Keap1', 'Gene', (199, 204))	('mutation', 'Var', (218, 226))	('Nrf2', 'Gene', '4780', (205, 209))	('RNA', 'cellular_component', 'GO:0005562', ('132', '135'))	('VHL', 'Disease', 'MESH:D006623', (238, 241))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('VHL', 'Disease', (238, 241))	('methylation', 'biological_process', 'GO:0032259', ('42', '53'))	('ccRCC', 'Disease', (66, 71))	('Nrf2', 'Gene', (205, 209))	('ccRCC', 'Disease', 'MESH:D002292', (66, 71))	('patients', 'Species', '9606', (72, 80))
26930	31752777	They confirmed mutual exclusivity of Keap1 and Nrf2 mutation in 6.6% of their patients.	('Nrf2', 'Gene', (47, 51))	('patients', 'Species', '9606', (78, 86))	('Keap1', 'Gene', '9817', (37, 42))	('Keap1', 'Gene', (37, 42))	('mutation', 'Var', (52, 60))	('Nrf2', 'Gene', '4780', (47, 51))
26931	31752777	In this study, we identified Nrf2 mutations (n = 3), Keap1 mutations (n = 9), and mutations of both genes (n = 2) in the primary tumors of 14/50 patients with metastatic ccRCC (28%).	('Nrf2', 'Gene', (29, 33))	('patients', 'Species', '9606', (145, 153))	('ccRCC', 'Disease', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('ccRCC', 'Disease', 'MESH:D002292', (170, 175))	('tumors of 14', 'Disease', (129, 141))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('mutations', 'Var', (82, 91))	('tumors of 14', 'Disease', 'MESH:C535488', (129, 141))	('Nrf2', 'Gene', '4780', (29, 33))	('mutations', 'Var', (59, 68))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))	('Keap1', 'Gene', '9817', (53, 58))	('Keap1', 'Gene', (53, 58))	('mutations', 'Var', (34, 43))
26934	31752777	However, it is possible that Keap1 and/or Nrf2 mutations might have a more important role in RCC than has been recognized up to now, particularly in patients with biologically aggressive tumors.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('patients', 'Species', '9606', (149, 157))	('aggressive tumors', 'Disease', (176, 193))	('RCC', 'Disease', 'MESH:D002292', (93, 96))	('RCC', 'Disease', (93, 96))	('Nrf2', 'Gene', '4780', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('mutations', 'Var', (47, 56))	('Keap1', 'Gene', '9817', (29, 34))	('Keap1', 'Gene', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('Nrf2', 'Gene', (42, 46))	('aggressive tumors', 'Disease', 'MESH:D001523', (176, 193))	('role', 'Reg', (85, 89))
26936	31752777	It was reported that Nrf2 mutation results in a sustained activation of Nrf2in sporadic papillary RCC (pRCC).	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('Nrf2', 'Gene', '4780', (21, 25))	('pRCC', 'Gene', '5546', (103, 107))	('mutation', 'Var', (26, 34))	('Nrf2', 'Gene', (21, 25))	('Nrf2', 'Gene', '4780', (72, 76))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('pRCC', 'Gene', (103, 107))	('papillary RCC', 'Disease', 'MESH:D002292', (88, 101))	('activation', 'PosReg', (58, 68))	('papillary RCC', 'Disease', (88, 101))	('Nrf2', 'Gene', (72, 76))
26937	31752777	Keap1 is an adaptor protein that facilitates ubiquitination and subsequent degradation of Nrf2, which means that Keap1 mutation can lead to sustained Nrf2 activation.	('Keap1', 'Gene', (0, 5))	('mutation', 'Var', (119, 127))	('Keap1', 'Gene', '9817', (113, 118))	('Nrf2', 'Gene', '4780', (150, 154))	('degradation', 'biological_process', 'GO:0009056', ('75', '86'))	('Nrf2', 'Gene', '4780', (90, 94))	('ubiquitination', 'MPA', (45, 59))	('Nrf2', 'Gene', (150, 154))	('degradation', 'MPA', (75, 86))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('Nrf2', 'Gene', (90, 94))	('facilitates', 'PosReg', (33, 44))	('Keap1', 'Gene', (113, 118))	('activation', 'PosReg', (155, 165))	('Keap1', 'Gene', '9817', (0, 5))
26938	31752777	In the present study, we found that Nrf2 gene mutation was associated with elevated Nrf2 protein expression, while Keap1 mutation was not.	('Nrf2', 'Gene', (84, 88))	('elevated', 'PosReg', (75, 83))	('mutation', 'Var', (46, 54))	('Keap1', 'Gene', (115, 120))	('Keap1', 'Gene', '9817', (115, 120))	('Nrf2', 'Gene', '4780', (36, 40))	('Nrf2', 'Gene', '4780', (84, 88))	('protein', 'Protein', (89, 96))	('Nrf2', 'Gene', (36, 40))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
26941	31752777	Therefore, although the mechanism underlying the association of the Nrf2 gene mutations with progression of ccRCC is unclear, it seems likely that mutations of both genes stabilize Nrf2 by disrupting its binding to Keap1 and that sustained activation of Nrf2 could be a prominent feature of ccRCC.	('mutations', 'Var', (147, 156))	('Nrf2', 'Gene', (68, 72))	('binding', 'molecular_function', 'GO:0005488', ('204', '211'))	('binding', 'Interaction', (204, 211))	('Keap1', 'Gene', (215, 220))	('Nrf2', 'Gene', '4780', (254, 258))	('ccRCC', 'Disease', 'MESH:D002292', (291, 296))	('mutations', 'Var', (78, 87))	('activation', 'PosReg', (240, 250))	('Nrf2', 'Gene', '4780', (181, 185))	('ccRCC', 'Disease', 'MESH:D002292', (108, 113))	('ccRCC', 'Disease', (291, 296))	('Nrf2', 'Gene', (254, 258))	('disrupting', 'NegReg', (189, 199))	('Nrf2', 'Gene', '4780', (68, 72))	('ccRCC', 'Disease', (108, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (293, 296))	('Nrf2', 'Gene', (181, 185))	('stabilize', 'PosReg', (171, 180))	('Keap1', 'Gene', '9817', (215, 220))
26942	31752777	On the other hand, inactivating mutation of FH (an enzyme involved in the mitochondrial tricarboxylic acid cycle) causes Nrf2-dependent activation of antioxidant pathways in patients with inherited type 2 pRCC (pRCC2) or hereditary leiomyomatosis and renal cell carcinoma (HLRCC).	('pRCC', 'Gene', (211, 215))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (88, 106))	('Nrf2', 'Gene', '4780', (121, 125))	('hereditary leiomyomatosis and renal cell carcinoma', 'Disease', 'MESH:C535516', (221, 271))	('pRCC2', 'Gene', '5546', (211, 216))	('pRCC2', 'Gene', (211, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('pRCC', 'Gene', '5546', (205, 209))	('activation', 'PosReg', (136, 146))	('FH', 'Gene', '2271', (44, 46))	('Nrf2', 'Gene', (121, 125))	('pRCC', 'Gene', '5546', (211, 215))	('RCC', 'Phenotype', 'HP:0005584', (206, 209))	('pRCC', 'Gene', (205, 209))	('tricarboxylic acid cycle', 'biological_process', 'GO:0006099', ('88', '112'))	('inactivating mutation', 'Var', (19, 40))	('HLRCC', 'Disease', (273, 278))	('HLRCC', 'Disease', 'MESH:C535516', (273, 278))	('patients', 'Species', '9606', (174, 182))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (251, 271))	('RCC', 'Phenotype', 'HP:0005584', (212, 215))	('antioxidant pathways', 'Pathway', (150, 170))	('RCC', 'Phenotype', 'HP:0005584', (275, 278))
26946	31752777	recently reported that the rs6721961 SNP in the ARE-like sequence of the human Nrf2 promoter was associated with an elevated risk of lung cancer, especially among smokers.	('lung cancer', 'Disease', (133, 144))	('Nrf2', 'Gene', '4780', (79, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('rs6721961', 'Mutation', 'rs6721961', (27, 36))	('human', 'Species', '9606', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Nrf2', 'Gene', (79, 83))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))	('associated', 'Reg', (97, 107))	('rs6721961 SNP', 'Var', (27, 40))
26947	31752777	They demonstrated significant reduction of the Nrf2 mRNA level by approximately 40% in A/A homozygotes for the rs6721961 SNP compared with C/A heterozygotes or C/C homozygotes, and the risk of lung cancer was only increased for A/A homozygotes.	('rs6721961 SNP', 'Var', (111, 124))	('lung cancer', 'Disease', 'MESH:D008175', (193, 204))	('Nrf2', 'Gene', (47, 51))	('rs6721961', 'Mutation', 'rs6721961', (111, 120))	('reduction', 'NegReg', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('lung cancer', 'Disease', (193, 204))	('Nrf2', 'Gene', '4780', (47, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (193, 204))
26948	31752777	Based on these results, homozygous substitution of A for C at rs6721961 significantly decreases Nrf2 mRNA expression, and Nrf2 normally protects against carcinogenesis in humans.	('carcinogenesis', 'Disease', (153, 167))	('rs6721961', 'Mutation', 'rs6721961', (62, 71))	('Nrf2', 'Gene', '4780', (96, 100))	('Nrf2', 'Gene', (122, 126))	('decreases', 'NegReg', (86, 95))	('humans', 'Species', '9606', (171, 177))	('rs6721961', 'Var', (62, 71))	('Nrf2', 'Gene', (96, 100))	('carcinogenesis', 'Disease', 'MESH:D063646', (153, 167))	('Nrf2', 'Gene', '4780', (122, 126))	('mRNA expression', 'MPA', (101, 116))
26949	31752777	In contrast to Suzuki et al., we studied primary ccRCC and we found that the genotype frequencies of the rs6721961 SNP were 60% for C/C, 34% for C/A, and 6% for A/A.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('ccRCC', 'Disease', 'MESH:D002292', (49, 54))	('rs6721961', 'Var', (105, 114))	('C/A, and 6%', 'Gene', '729', (145, 156))	('C/C', 'Disease', (132, 135))	('ccRCC', 'Disease', (49, 54))	('rs6721961', 'Mutation', 'rs6721961', (105, 114))
26950	31752777	The C/A and A/A genotypes were both significantly associated with increased Nrf2 protein expression (p < 0.0001), and metastases showed a worse response to VEGF-targeting therapy with shorter overall survival if the primary tumor possessed the C/A or A/A genotype or showed elevation of Nrf2 protein expression.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('VEGF', 'Gene', (156, 160))	('C/A', 'Var', (4, 7))	('Nrf2', 'Gene', '4780', (287, 291))	('Nrf2', 'Gene', (76, 80))	('expression', 'MPA', (89, 99))	('protein', 'Protein', (292, 299))	('elevation', 'PosReg', (274, 283))	('protein', 'cellular_component', 'GO:0003675', ('292', '299'))	('A/A', 'Var', (251, 254))	('increased', 'PosReg', (66, 75))	('Nrf2', 'Gene', (287, 291))	('tumor', 'Disease', (224, 229))	('expression', 'MPA', (300, 310))	('metastases', 'Disease', 'MESH:D009362', (118, 128))	('A/A', 'Var', (12, 15))	('shorter', 'NegReg', (184, 191))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('metastases', 'Disease', (118, 128))	('Nrf2', 'Gene', '4780', (76, 80))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('overall survival', 'MPA', (192, 208))	('VEGF', 'Gene', '7422', (156, 160))	('C/A', 'Var', (244, 247))	('protein', 'Protein', (81, 88))
26951	31752777	Although we did not examine Nrf2 mRNA expression in the ccRCC specimens, these observations suggest that tumor-specific and/or organ-specific variation of Nrf2 transcription and expression mediated via rs6721961 or other SNPs could have a role in various human diseases.	('expression', 'MPA', (178, 188))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('Nrf2', 'Gene', (28, 32))	('Nrf2', 'Gene', (155, 159))	('ccRCC', 'Disease', (56, 61))	('rs6721961', 'Mutation', 'rs6721961', (202, 211))	('human', 'Species', '9606', (255, 260))	('rs6721961', 'Var', (202, 211))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('transcription', 'biological_process', 'GO:0006351', ('160', '173'))	('men', 'Species', '9606', (67, 70))	('Nrf2', 'Gene', '4780', (28, 32))	('Nrf2', 'Gene', '4780', (155, 159))	('role', 'Reg', (239, 243))	('variation', 'Var', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('transcription', 'MPA', (160, 173))	('ccRCC', 'Disease', 'MESH:D002292', (56, 61))
26954	31752777	We previously found increased Nrf2 expression and aerobic glycolysis in HLRCC tumor cells with FH mutation.	('increased', 'PosReg', (20, 29))	('mutation', 'Var', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('aerobic glycolysis', 'MPA', (50, 68))	('expression', 'MPA', (35, 45))	('HLRCC', 'Disease', (72, 77))	('Nrf2', 'Gene', (30, 34))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('glycolysis', 'biological_process', 'GO:0006096', ('58', '68'))	('Nrf2', 'Gene', '4780', (30, 34))	('tumor', 'Disease', (78, 83))	('FH', 'Gene', '2271', (95, 97))	('HLRCC', 'Disease', 'MESH:C535516', (72, 77))
26959	31752777	Also, we studied Nrf2 gene mutations, the rs6721961 SNP, and Nrf2 protein expression in the surgically resected primary tumors of patients with metastatic ccRCC.	('ccRCC', 'Disease', 'MESH:D002292', (155, 160))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('rs6721961', 'Mutation', 'rs6721961', (42, 51))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('Nrf2', 'Gene', (61, 65))	('Nrf2', 'Gene', (17, 21))	('patients', 'Species', '9606', (130, 138))	('rs6721961', 'Var', (42, 51))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('ccRCC', 'Disease', (155, 160))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('Nrf2', 'Gene', '4780', (61, 65))	('Nrf2', 'Gene', '4780', (17, 21))
26961	31752777	Therefore, we should not only study Nrf2 gene mutations, the rs6721961 SNP, and Nrf2 protein expression in early ccRCC, but we should also examine metastatic lesions in order to elucidate the role of Nrf2 in tumor progression.	('Nrf2', 'Gene', (200, 204))	('mutations', 'Var', (46, 55))	('rs6721961', 'Var', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('ccRCC', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('Nrf2', 'Gene', '4780', (200, 204))	('Nrf2', 'Gene', '4780', (36, 40))	('Nrf2', 'Gene', '4780', (80, 84))	('tumor', 'Disease', (208, 213))	('ccRCC', 'Disease', 'MESH:D002292', (113, 118))	('rs6721961', 'Mutation', 'rs6721961', (61, 70))	('Nrf2', 'Gene', (80, 84))	('Nrf2', 'Gene', (36, 40))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
26964	31752777	Although we only tested 5 tumor samples in the present study, we found that the rs6721961 SNP was identical between germline and somatic DNA in all 5 patients.	('rs6721961', 'Mutation', 'rs6721961', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('patients', 'Species', '9606', (150, 158))	('DNA', 'cellular_component', 'GO:0005574', ('137', '140'))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('rs6721961', 'Var', (80, 89))
26968	31752777	When primary RCC displayed Nrf2 gene mutation and the C/A or A/A genotype of rs6721961 at the Nrf2 promoter region, expression of Nrf2 was elevated and metastases showed a worse response to sequential vascular endothelial growth factor-targeting therapy, resulting in unfavorable survival.	('rs6721961', 'Var', (77, 86))	('mutation', 'Var', (37, 45))	('Nrf2', 'Gene', (27, 31))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('201', '235'))	('RCC', 'Disease', 'MESH:D002292', (13, 16))	('elevated', 'PosReg', (139, 147))	('Nrf2', 'Gene', (130, 134))	('metastases', 'Disease', 'MESH:D009362', (152, 162))	('vascular endothelial growth factor', 'Gene', '7422', (201, 235))	('metastases', 'Disease', (152, 162))	('Nrf2', 'Gene', '4780', (94, 98))	('vascular endothelial growth factor', 'Gene', (201, 235))	('expression', 'MPA', (116, 126))	('Nrf2', 'Gene', '4780', (27, 31))	('Nrf2', 'Gene', (94, 98))	('RCC', 'Disease', (13, 16))	('rs6721961', 'Mutation', 'rs6721961', (77, 86))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('Nrf2', 'Gene', '4780', (130, 134))
26971	31752777	Standard deviation SNPs Single nucleotide polymorphisms TNM The TNM classification of Malignant Tumors (T: tumor, N: lymph node, M: metastasis) VEGF Vascular endothelial growth factor VHL Von Hippel-Lindau YY and TK* initiated the study, participated in its concept, design and coordination, carried out the study, performed the statistical analysis, and drafted the manuscript.	('tumor', 'Disease', (107, 112))	('Tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('VHL', 'Disease', (184, 187))	('Malignant Tumors', 'Disease', 'MESH:D009369', (86, 102))	('Malignant Tumors', 'Disease', (86, 102))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('VEGF', 'Gene', '7422', (144, 148))	('Von Hippel-Lindau', 'Disease', (188, 205))	('VEGF', 'Gene', (144, 148))	('TNM', 'Gene', '10178', (64, 67))	('Single nucleotide polymorphisms', 'Var', (24, 55))	('TNM', 'Gene', (64, 67))	('Von Hippel-Lindau', 'Disease', 'MESH:D006623', (188, 205))	('TNM', 'Gene', '10178', (56, 59))	('Tumors', 'Phenotype', 'HP:0002664', (96, 102))	('Vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('149', '183'))	('VHL', 'Disease', 'MESH:D006623', (184, 187))	('TNM', 'Gene', (56, 59))
26988	30596034	Recently, the International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia recognized ccpRCC as a distinct epithelial tumor that could be distinguished from ccRCC and pRCC by genetic differences in the von Hippel-Lindau (VHL)tumor suppressor gene mutation and 3p loss status and the extreme rarity of gains in chromosomes 7 and 17 or the loss of chromosome Y, despite significant morphological, immunohistochemical, and genetic similarities among the three tumors.	('loss', 'NegReg', (299, 303))	('mutation', 'Var', (283, 291))	('pRCC', 'Phenotype', 'HP:0006766', (203, 207))	('RCC', 'Disease', (125, 128))	('RCC', 'Disease', (204, 207))	('tumors', 'Disease', 'MESH:D009369', (493, 499))	('RCC', 'Disease', (195, 198))	('ccRCC', 'Phenotype', 'HP:0006770', (193, 198))	('Neoplasia', 'Phenotype', 'HP:0002664', (101, 110))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('ccpRCC', 'Phenotype', 'HP:0006770', (122, 128))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('261', '277'))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('gains', 'PosReg', (337, 342))	('epithelial tumor', 'Disease', (143, 159))	('tumor suppressor', 'biological_process', 'GO:0051726', ('261', '277'))	('epithelial tumor', 'Disease', 'MESH:D002277', (143, 159))	('epithelial tumor', 'Phenotype', 'HP:0031492', (143, 159))	('tumors', 'Phenotype', 'HP:0002664', (493, 499))	('Classification of Renal Neoplasia', 'Disease', 'MESH:D007674', (77, 110))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('chromosome', 'cellular_component', 'GO:0005694', ('382', '392'))	('loss', 'NegReg', (374, 378))	('pRCC', 'Phenotype', 'HP:0006766', (124, 128))	('chromosome', 'Gene', (382, 392))	('Renal Neoplasia', 'Phenotype', 'HP:0009726', (95, 110))	('von Hippel-Lindau (VHL)tumor', 'Disease', 'MESH:D006623', (238, 266))	('tumor', 'Phenotype', 'HP:0002664', (493, 498))	('Classification of Renal Neoplasia', 'Disease', (77, 110))	('tumors', 'Disease', (493, 499))
26995	30596034	Subsequent pathology revealed a tumor measuring 1.7 cm x 1.4 cm x 1.0 cm with a capsule abutting, leading to a diagnosis of a grade 2 ccpRCC without necrosis and a final pathologic stage of T1aN x M0 (Figure 2).	('pRCC', 'Phenotype', 'HP:0006766', (136, 140))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('necrosis', 'biological_process', 'GO:0070265', ('149', '157'))	('necrosis', 'biological_process', 'GO:0008219', ('149', '157'))	('necrosis', 'Disease', (149, 157))	('necrosis', 'biological_process', 'GO:0019835', ('149', '157'))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('necrosis', 'biological_process', 'GO:0001906', ('149', '157'))	('necrosis', 'biological_process', 'GO:0008220', ('149', '157'))	('capsule', 'cellular_component', 'GO:0042603', ('80', '87'))	('ccpRCC', 'Phenotype', 'HP:0006770', (134, 140))	('T1aN x M0', 'Var', (190, 199))	('necrosis', 'Disease', 'MESH:D009336', (149, 157))	('tumor', 'Disease', (32, 37))
27010	30596034	Although VHL mutation is a hallmark of ccRCC, mutations in this gene have been described in 15%-30% of ccpRCC cases.	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('ccpRCC', 'Phenotype', 'HP:0006770', (103, 109))	('mutations', 'Var', (46, 55))	('mutation', 'Var', (13, 21))	('pRCC', 'Phenotype', 'HP:0006766', (105, 109))	('VHL', 'Disease', 'MESH:D006623', (9, 12))	('RCC', 'Disease', (106, 109))	('VHL', 'Disease', (9, 12))	('RCC', 'Disease', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('described', 'Reg', (79, 88))
27011	30596034	Rather than VHL alterations, pRCC is known to harbor trisomies of chromosomes 7 and 17 and losses of Y, whereas ccpRCC does not exhibit these changes.	('trisomies', 'Var', (53, 62))	('losses', 'NegReg', (91, 97))	('pRCC', 'Phenotype', 'HP:0006766', (114, 118))	('ccpRCC', 'Phenotype', 'HP:0006770', (112, 118))	('pRCC', 'Phenotype', 'HP:0006766', (29, 33))	('pRCC', 'Disease', (29, 33))	('VHL', 'Disease', 'MESH:D006623', (12, 15))	('VHL', 'Disease', (12, 15))
27023	30327690	Nesfatin-1/Nucleobindin-2 Is a Potent Prognostic Marker and Enhances Cell Proliferation, Migration, and Invasion in Bladder Cancer In recent researches, high expression of nesfatin-1/nucleobindin-2 (NUCB2) is linked to poor prognosis in prostate and colon cancer due to the enhancement in proliferation, migration, and invasion.	('nesfatin-1', 'Gene', (172, 182))	('colon cancer', 'Disease', 'MESH:D015179', (250, 262))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (116, 130))	('nucleobindin-2', 'Gene', '4925', (183, 197))	('nucleobindin-2', 'Gene', (183, 197))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('Cancer', 'Disease', (124, 130))	('Nesfatin-1', 'Gene', (0, 10))	('colon cancer', 'Disease', (250, 262))	('Nesfatin-1', 'Gene', '4925', (0, 10))	('prostate', 'Disease', (237, 245))	('Nucleobindin-2', 'Gene', (11, 25))	('Cancer', 'Disease', 'MESH:D009369', (124, 130))	('NUCB2', 'Gene', (199, 204))	('migration', 'CPA', (304, 313))	('invasion', 'CPA', (319, 327))	('enhancement', 'PosReg', (274, 285))	('colon cancer', 'Phenotype', 'HP:0003003', (250, 262))	('proliferation', 'CPA', (289, 302))	('Cell Proliferation', 'biological_process', 'GO:0008283', ('69', '87'))	('Nucleobindin-2', 'Gene', '4925', (11, 25))	('Cancer', 'Phenotype', 'HP:0002664', (124, 130))	('nesfatin-1', 'Gene', '4925', (172, 182))	('high', 'Var', (153, 157))
27040	30327690	High expression level of NUCB2 represents an independent negative prognostic factor in clear cell renal cell carcinoma (ccRCC).	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (87, 118))	('clear cell renal cell carcinoma', 'Disease', (87, 118))	('High', 'Var', (0, 4))	('ccRCC', 'Phenotype', 'HP:0006770', (120, 125))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (87, 118))	('NUCB2', 'Gene', (25, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (98, 118))	('negative', 'NegReg', (57, 65))
27041	30327690	In prostate cancer, gastric cancer, colon cancer, breast carcinoma, and endometrial carcinoma, high expression of NUCB2 was linked to poor prognosis due to the enhancement in cell proliferation and migration.	('breast carcinoma', 'Disease', 'MESH:D001943', (50, 66))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (72, 93))	('colon cancer', 'Disease', 'MESH:D015179', (36, 48))	('migration', 'CPA', (198, 207))	('enhancement', 'PosReg', (160, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('prostate cancer', 'Disease', (3, 18))	('cell proliferation', 'biological_process', 'GO:0008283', ('175', '193'))	('cell proliferation', 'CPA', (175, 193))	('breast carcinoma', 'Phenotype', 'HP:0003002', (50, 66))	('colon cancer', 'Disease', (36, 48))	('gastric cancer', 'Disease', (20, 34))	('NUCB2', 'Gene', (114, 119))	('breast carcinoma', 'Disease', (50, 66))	('high expression', 'Var', (95, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('endometrial carcinoma', 'Disease', (72, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (20, 34))	('colon cancer', 'Phenotype', 'HP:0003003', (36, 48))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (72, 93))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))	('gastric cancer', 'Phenotype', 'HP:0012126', (20, 34))
27043	30327690	In this research, we observed that high expression of NUCB2 was associated with poor prognosis by analyzing immunohistochemistry and information of patients with bladder cancer.	('patients', 'Species', '9606', (148, 156))	('NUCB2', 'Gene', (54, 59))	('bladder cancer', 'Phenotype', 'HP:0009725', (162, 176))	('high expression', 'Var', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('bladder cancer', 'Disease', 'MESH:D001749', (162, 176))	('bladder cancer', 'Disease', (162, 176))
27044	30327690	Then, knocking down NUCB2 decreased proliferation, migration, and invasion in T24 and 5637 cells which are derived from human bladder cancer cells.	('bladder cancer', 'Phenotype', 'HP:0009725', (126, 140))	('human', 'Species', '9606', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('NUCB2', 'Gene', (20, 25))	('migration', 'CPA', (51, 60))	('bladder cancer', 'Disease', 'MESH:D001749', (126, 140))	('bladder cancer', 'Disease', (126, 140))	('proliferation', 'CPA', (36, 49))	('invasion', 'CPA', (66, 74))	('decreased', 'NegReg', (26, 35))	('knocking down', 'Var', (6, 19))
27047	30327690	As shown in Figures 1(b) and 1(c), patients with high expression of NUCB2 had a low overall survival rate (OS) and progression-free survival rate (PFS) and high metastasis and vascular invasion.	('low', 'NegReg', (80, 83))	('vascular invasion', 'CPA', (176, 193))	('progression-free survival rate', 'CPA', (115, 145))	('NUCB2', 'Gene', (68, 73))	('high expression', 'Var', (49, 64))	('patients', 'Species', '9606', (35, 43))	('overall survival rate', 'MPA', (84, 105))
27049	30327690	Firstly, in order to observe functions of NUCB2 in bladder cancer, T24 and 5637 cells were transfected with specific shRNA to knockdown NUCB2.	('bladder cancer', 'Disease', (51, 65))	('NUCB2', 'Gene', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('bladder cancer', 'Phenotype', 'HP:0009725', (51, 65))	('knockdown', 'Var', (126, 135))	('bladder cancer', 'Disease', 'MESH:D001749', (51, 65))
27094	30327690	Firstly, we indicated that expression of NUCB2 was different in bladder cancer patients and high expression of NUCB2 was associated with poor prognosis.	('high', 'Var', (92, 96))	('bladder cancer', 'Phenotype', 'HP:0009725', (64, 78))	('associated', 'Reg', (121, 131))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('bladder cancer', 'Disease', 'MESH:D001749', (64, 78))	('bladder cancer', 'Disease', (64, 78))	('NUCB2', 'Gene', (111, 116))	('patients', 'Species', '9606', (79, 87))
27099	30327690	analyzed a Chinese cohort (training set: 182 patients and validation set: 434 patients) with ccRCC patients and observed through multivariate Cox proportional hazard models that high expression level of NUCB2 was an independent poor prognostic factor for OS and CSS (cancer-specific survival).	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('NUCB2', 'Gene', (203, 208))	('patients', 'Species', '9606', (78, 86))	('patients', 'Species', '9606', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('patients', 'Species', '9606', (45, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('high', 'Var', (178, 182))	('CSS', 'Disease', (262, 265))
27111	30327690	The transwell assay, MTT assay, and expression level of MMP2 and MMP9 revealed that knockdown of NUCB2 with special shRNA inhibits invasion and proliferation in bladder cancer cells which were similar to other reports in breast, colon, and prostate cancer and in clear cell renal cell (ccRCC) carcinoma.	('MMP2', 'Gene', '4313', (56, 60))	('knockdown', 'Var', (84, 93))	('carcinoma', 'Disease', 'MESH:D002277', (293, 302))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast', 'Disease', (221, 227))	('MMP9', 'molecular_function', 'GO:0004229', ('65', '69'))	('bladder cancer', 'Disease', 'MESH:D001749', (161, 175))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('bladder cancer', 'Disease', (161, 175))	('invasion', 'CPA', (131, 139))	('prostate cancer', 'Disease', 'MESH:D011471', (240, 255))	('prostate cancer', 'Phenotype', 'HP:0012125', (240, 255))	('bladder cancer', 'Phenotype', 'HP:0009725', (161, 175))	('NUCB2', 'Gene', (97, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (286, 291))	('prostate cancer', 'Disease', (240, 255))	('clear cell renal cell', 'Disease', (263, 284))	('MTT', 'Chemical', 'MESH:C070243', (21, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (293, 302))	('MMP2', 'Gene', (56, 60))	('carcinoma', 'Disease', (293, 302))	('colon', 'Disease', (229, 234))	('MMP9', 'Gene', (65, 69))	('inhibits', 'NegReg', (122, 130))	('MMP9', 'Gene', '4318', (65, 69))	('MMP2', 'molecular_function', 'GO:0004228', ('56', '60'))
27159	32012885	Mutations in chromatin modifiers are found to be mutated in urothelial carcinoma in a frequency higher than any other cancer, which, again, argues in favor of targeted therapies against these epigenetic modifiers.	('mutated', 'Var', (49, 56))	('cancer', 'Disease', (118, 124))	('chromatin modifiers', 'Gene', (13, 32))	('urothelial carcinoma', 'Disease', (60, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Mutations', 'Var', (0, 9))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (60, 80))	('chromatin', 'cellular_component', 'GO:0000785', ('13', '22'))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
27171	32012885	Among many examples, inhibitors of the methyltransferase EHMT2 were shown to induce apoptosis of BlCa cells; natural compounds such as Honokiol (derived from Magnolia officinalis) inhibited BlCa growth by suppressing EZH2/miR143; and various histone deacetylase (HDAC) inhibitors were shown to be effective in reducing BlCa growth, showing synergy with other classically used therapies such as mitomycin C and additionally increasing sensitivity to chemo- and radiotherapy.	('EHMT2', 'Gene', (57, 62))	('BlCa', 'Disease', (190, 194))	('BlCa', 'Disease', 'MESH:D001749', (190, 194))	('mitomycin C', 'Chemical', 'MESH:D016685', (394, 405))	('HDAC', 'Gene', '9734', (263, 267))	('apoptosis', 'CPA', (84, 93))	('EZH2/miR143', 'MPA', (217, 228))	('HDAC', 'Gene', (263, 267))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('reducing', 'NegReg', (310, 318))	('histone deacetylase', 'Gene', '9734', (242, 261))	('Honokiol', 'Chemical', 'MESH:C005499', (135, 143))	('Magnolia officinalis', 'Species', '85864', (158, 178))	('inhibitors', 'Var', (21, 31))	('BlCa', 'Disease', (97, 101))	('induce', 'Reg', (77, 83))	('histone deacetylase', 'Gene', (242, 261))	('BlCa', 'Disease', 'MESH:D001749', (97, 101))	('BlCa', 'Disease', (319, 323))	('BlCa', 'Disease', 'MESH:D001749', (319, 323))	('suppressing', 'NegReg', (205, 216))	('inhibited', 'NegReg', (180, 189))
27172	32012885	A summary of most recent studies addressing combination strategies between epigenetics and immune environment in BlCa is presented in Table 1.	('BlCa', 'Disease', (113, 117))	('BlCa', 'Disease', 'MESH:D001749', (113, 117))	('epigenetics', 'Var', (75, 86))	('men', 'Species', '9606', (105, 108))
27175	32012885	Two studies pursued a screening of several gene promoters known to be frequently involved in tumor biology, and found that hypermethylation of genes such as CDKN2B (involved in cell cycle regulation), MUS81a and MSH6 (involved in DNA repair) and THBS1 (involved in cell adhesion), associated with better response to BCG-therapy, and both studies acknowledge that the exact mechanisms for explaining these findings deserve investigation in the future.	('MUS81a', 'Gene', (201, 207))	('associated', 'Reg', (281, 291))	('response', 'CPA', (304, 312))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('177', '198'))	('DNA repair', 'biological_process', 'GO:0006281', ('230', '240'))	('cell adhesion', 'biological_process', 'GO:0007155', ('265', '278'))	('tumor', 'Disease', (93, 98))	('hypermethylation', 'Var', (123, 139))	('THBS1', 'Gene', (246, 251))	('MSH6', 'Gene', (212, 216))	('CDKN2B', 'Gene', (157, 163))	('better', 'PosReg', (297, 303))	('BCG', 'Species', '33892', (316, 319))	('DNA', 'cellular_component', 'GO:0005574', ('230', '233'))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
27177	32012885	In a similar setting, another work uncovered that demethylated PMF1 was associated with disease recurrence and poor outcome in these patients, being a biomarker of failure to respond to BCG therapy.	('PMF1', 'Gene', '11243', (63, 67))	('BCG', 'Species', '33892', (186, 189))	('patients', 'Species', '9606', (133, 141))	('associated with', 'Reg', (72, 87))	('disease recurrence', 'CPA', (88, 106))	('demethylated', 'Var', (50, 62))	('PMF1', 'Gene', (63, 67))
27179	32012885	Interestingly, it was demonstrated that high polyamine levels led to apoptosis of macrophages populating pneumocystis pneumonia.	('high', 'Var', (40, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('69', '78'))	('pneumonia', 'Phenotype', 'HP:0002090', (118, 127))	('polyamine levels', 'MPA', (45, 61))	('pneumocystis pneumonia', 'Disease', (105, 127))	('apoptosis', 'biological_process', 'GO:0006915', ('69', '78'))	('pneumocystis pneumonia', 'Disease', 'MESH:D011020', (105, 127))	('polyamine', 'Chemical', 'MESH:D011073', (45, 54))	('apoptosis', 'CPA', (69, 78))	('pneumocystis pneumonia', 'Phenotype', 'HP:0020102', (105, 127))
27180	32012885	This finding seems to wonderfully fit with the BCG therapy, since higher PMF1 expression mediated by demethylation of its promoter would increase polyamine levels and hence trigger apoptosis of macrophages, which would become less available to be activated by the BCG stimulus and result in treatment failure.	('men', 'Species', '9606', (296, 299))	('apoptosis', 'biological_process', 'GO:0097194', ('181', '190'))	('expression', 'MPA', (78, 88))	('apoptosis', 'biological_process', 'GO:0006915', ('181', '190'))	('PMF1', 'Gene', '11243', (73, 77))	('polyamine levels', 'MPA', (146, 162))	('apoptosis', 'CPA', (181, 190))	('increase', 'PosReg', (137, 145))	('BCG', 'Species', '33892', (47, 50))	('polyamine', 'Chemical', 'MESH:D011073', (146, 155))	('higher', 'PosReg', (66, 72))	('trigger', 'Reg', (173, 180))	('demethylation', 'biological_process', 'GO:0070988', ('101', '114'))	('PMF1', 'Gene', (73, 77))	('BCG', 'Species', '33892', (264, 267))	('demethylation', 'Var', (101, 114))
27186	32012885	showed that an assessment of CD4+-cell lineage commitment by looking at specific CpGs methylation status could predict the outcome of BlCa patients, with demethylation of those sites (which include FOXP3, IFNG, IL13, and IL17A) associating with lower stage and, importantly, better response to neoadjuvant chemotherapy.	('IFNG', 'Gene', (205, 209))	('FOXP3', 'Gene', '50943', (198, 203))	('IL13', 'molecular_function', 'GO:0005144', ('211', '215'))	('IL17A', 'Gene', (221, 226))	('BlCa', 'Disease', (134, 138))	('BlCa', 'Disease', 'MESH:D001749', (134, 138))	('IL17A', 'Gene', '3605', (221, 226))	('IL13', 'Gene', (211, 215))	('IFNG', 'Gene', '3458', (205, 209))	('patients', 'Species', '9606', (139, 147))	('IL17', 'molecular_function', 'GO:0030367', ('221', '225'))	('FOXP3', 'Gene', (198, 203))	('men', 'Species', '9606', (21, 24))	('demethylation', 'biological_process', 'GO:0070988', ('154', '167'))	('predict', 'Reg', (111, 118))	('methylation', 'biological_process', 'GO:0032259', ('86', '97'))	('demethylation', 'Var', (154, 167))	('men', 'Species', '9606', (53, 56))	('IL13', 'Gene', '3596', (211, 215))
27189	32012885	The epigenetic modifiers KDM6A and SWI/SNF family are very frequently mutated in BlCa; they inhibit another epigenetic player, EZH2, a histone methyltransferase, hence loss-of-function mutations ultimately lead to EZH2 overexpression and poor prognosis.	('BlCa', 'Disease', (81, 85))	('KDM6A', 'Gene', (25, 30))	('loss-of-function', 'NegReg', (168, 184))	('inhibit', 'NegReg', (92, 99))	('overexpression', 'PosReg', (219, 233))	('BlCa', 'Disease', 'MESH:D001749', (81, 85))	('KDM6A', 'Gene', '7403', (25, 30))	('mutations', 'Var', (185, 194))	('EZH2', 'Gene', (214, 218))
27190	32012885	Indeed, when exposing BlCa cells with loss-of-function mutations of KDM6A and SWI/SNF to the EZH2 inhibitor EPZ011989, this resulted in stimulation of NK cells signaling and in tumor cells death.	('KDM6A', 'Gene', (68, 73))	('NK cells signaling', 'MPA', (151, 169))	('stimulation', 'PosReg', (136, 147))	('BlCa', 'Disease', (22, 26))	('mutations', 'Var', (55, 64))	('loss-of-function', 'NegReg', (38, 54))	('KDM6A', 'Gene', '7403', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('BlCa', 'Disease', 'MESH:D001749', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('signaling', 'biological_process', 'GO:0023052', ('160', '169'))	('tumor', 'Disease', (177, 182))	('SWI/SNF', 'Gene', (78, 85))
27191	32012885	All these strategies bring together epigenetic mechanisms regulating several subtypes of immune cells, that can be therapeutically misused to induce antitumor effects.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('epigenetic', 'Var', (36, 46))	('bring together', 'Reg', (21, 35))
27192	32012885	Non-coding RNAs are also among the epigenetic mechanisms regulating tumor progression in BlCa.	('tumor', 'Disease', (68, 73))	('BlCa', 'Disease', (89, 93))	('Non-coding RNAs', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('BlCa', 'Disease', 'MESH:D001749', (89, 93))
27194	32012885	Moreover, its knockdown attenuated malignant features of BlCa both in vitro and in vivo and, importantly, concomitant knockdown of PD-1 resulted in synergistic antitumor effect mediated by a shift in immune microenvironment, which led to increased interferon (IFN) signaling and reduced immunosuppressive pathways, as well as also enhancement of dendritic cells (DCs) maturation.	('men', 'Species', '9606', (219, 222))	('tumor', 'Disease', (164, 169))	('knockdown', 'Var', (118, 127))	('malignant features', 'CPA', (35, 53))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('PD-1', 'Gene', (131, 135))	('attenuated', 'NegReg', (24, 34))	('reduced', 'NegReg', (279, 286))	('interferon', 'Gene', (248, 258))	('interferon', 'Gene', '3439', (248, 258))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('IFN', 'Gene', '3439', (260, 263))	('immunosuppressive pathways', 'Pathway', (287, 313))	('enhancement', 'PosReg', (331, 342))	('BlCa', 'Disease', (57, 61))	('men', 'Species', '9606', (338, 341))	('IFN', 'Gene', (260, 263))	('increased', 'PosReg', (238, 247))	('BlCa', 'Disease', 'MESH:D001749', (57, 61))	('knockdown', 'Var', (14, 23))	('signaling', 'biological_process', 'GO:0023052', ('265', '274'))
27218	32012885	Despite the relevance of genomic alterations and genomic instability, most recent data demonstrate that the immunogenicity of ccRCC is not explained by mutational load; targeting DNA/histone epigenetic modifications may help increase the efficacy of immune targeted therapies.	('RCC', 'Disease', 'MESH:D002292', (128, 131))	('RCC', 'Disease', (128, 131))	('increase', 'PosReg', (225, 233))	('DNA/histone', 'Var', (179, 190))	('DNA', 'cellular_component', 'GO:0005574', ('179', '182'))
27220	32012885	Indeed, before 2005, the cytokines interferon-alpha and interleukin-2 (IL-2) were the routinely used and available treatments for these patients, demonstrating that subverting the immune environment in KCa was an effective way of fighting this disease.	('KCa', 'Disease', 'MESH:D007680', (202, 205))	('IL-2', 'molecular_function', 'GO:0005134', ('71', '75'))	('interferon', 'Gene', (35, 45))	('interleukin-2', 'Gene', '3558', (56, 69))	('interferon', 'Gene', '3439', (35, 45))	('interleukin-2', 'Gene', (56, 69))	('men', 'Species', '9606', (194, 197))	('subverting', 'Var', (165, 175))	('patients', 'Species', '9606', (136, 144))	('KCa', 'Disease', (202, 205))	('men', 'Species', '9606', (120, 123))
27228	32012885	For example, mutations in the methyltransferase SETD2 are typical of ccRCC, but not in the other RCC subtypes.	('RCC', 'Disease', (97, 100))	('RCC', 'Disease', 'MESH:D002292', (97, 100))	('RCC', 'Disease', 'MESH:D002292', (71, 74))	('RCC', 'Disease', (71, 74))	('SETD2', 'Gene', '29072', (48, 53))	('mutations', 'Var', (13, 22))	('SETD2', 'Gene', (48, 53))
27229	32012885	Indeed, inactivation of this histone-modifying enzyme results in increased tumor progression and aggressiveness, and poorer patient outcome.	('increased', 'PosReg', (65, 74))	('aggressiveness', 'Phenotype', 'HP:0000718', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('aggressiveness', 'Disease', 'MESH:D001523', (97, 111))	('inactivation', 'Var', (8, 20))	('patient', 'Species', '9606', (124, 131))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('aggressiveness', 'Disease', (97, 111))
27232	32012885	Agents targeting specific epigenetic aberrations have also shown anti-neoplastic activity in RCC, including the EZH2 inhibitor GSK126, which suppressed migration and invasion, and various HDAC inhibitors, alone or in combination with routinely used agents.	('GSK', 'molecular_function', 'GO:0050321', ('127', '130'))	('anti-neoplastic activity', 'CPA', (65, 89))	('RCC', 'Disease', (93, 96))	('RCC', 'Disease', 'MESH:D002292', (93, 96))	('GSK126', 'Chemical', 'MESH:C577920', (127, 133))	('epigenetic aberrations', 'Var', (26, 48))	('suppressed', 'NegReg', (141, 151))	('HDAC', 'Gene', (188, 192))	('HDAC', 'Gene', '9734', (188, 192))
27235	32012885	Since IL-2 has been used as a form of immunotherapy for KCa for more than one decade, several studies have explored its combination with epigenetic drugs, including methylation- and acetylation-targeting drugs.	('methylation-', 'Var', (165, 177))	('methylation', 'biological_process', 'GO:0032259', ('165', '176'))	('KCa', 'Disease', (56, 59))	('KCa', 'Disease', 'MESH:D007680', (56, 59))	('IL-2', 'molecular_function', 'GO:0005134', ('6', '10'))
27239	32012885	Indeed, the combination led to an enrichment in CD4- and CD25-positive T cells and in decreasing of FoxP3-positive T regulatory cells (Tregs), and impeded the development of lung metastases in the mouse model, prolonging survival of the animal.	('prolonging', 'PosReg', (210, 220))	('CD4-', 'Var', (48, 52))	('impeded', 'NegReg', (147, 154))	('men', 'Species', '9606', (166, 169))	('FoxP3', 'Gene', (100, 105))	('survival of the animal', 'CPA', (221, 243))	('men', 'Species', '9606', (40, 43))	('mouse', 'Species', '10090', (197, 202))	('FoxP3', 'Gene', '20371', (100, 105))	('lung metastases', 'Disease', (174, 189))	('CD25-positive', 'Var', (57, 70))	('decreasing', 'NegReg', (86, 96))	('lung metastases', 'Disease', 'MESH:D009362', (174, 189))
27240	32012885	Interestingly, the authors hypothesized about the synergism observed between these two agents based on opposite (but complementary) mechanisms: IL-2 enhances activation of effector T cells (which are reduced by MS-275), while MS-275 causes depletion of Tregs (which are potentiated by IL-2):resulting in the end of a net antitumor effect mediated by increased effector cells and decreased Tregs.	('MS-275', 'Var', (226, 232))	('MS-275', 'Chemical', 'MESH:C118739', (211, 217))	('tumor', 'Disease', (325, 330))	('IL-2', 'molecular_function', 'GO:0005134', ('285', '289'))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('IL-2', 'molecular_function', 'GO:0005134', ('144', '148'))	('decreased', 'NegReg', (379, 388))	('Tregs', 'CPA', (389, 394))	('MS-275', 'Chemical', 'MESH:C118739', (226, 232))	('increased', 'PosReg', (350, 359))	('men', 'Species', '9606', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('depletion', 'MPA', (240, 249))
27260	32012885	Also, the comonly observed deletion or mutation of PTEN contributes to the "immune desert" of PCa, since the latter activates IFN1-related pathways.	('mutation', 'Var', (39, 47))	('IFN1', 'Gene', (126, 130))	('deletion', 'Var', (27, 35))	('PCa', 'Disease', (94, 97))	('activates', 'PosReg', (116, 125))	('PCa', 'Disease', 'MESH:D011471', (94, 97))	('IFN1', 'Gene', '3438', (126, 130))	('contributes', 'Reg', (56, 67))	('PTEN', 'Gene', (51, 55))	('PTEN', 'Gene', '5728', (51, 55))
27264	32012885	The study pointed out, however, that among the 26% of the tumors without obvious molecular aberration there was evidence of DNA hypermethylation and mutations in epigenetic enzymes KDM6A and KMT2D.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('124', '144'))	('mutations', 'Var', (149, 158))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('hypermethylation', 'Var', (128, 144))	('KMT2D', 'Gene', (191, 196))	('KMT2D', 'Gene', '8085', (191, 196))	('DNA', 'cellular_component', 'GO:0005574', ('124', '127'))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('KDM6A', 'Gene', '7403', (181, 186))	('KDM6A', 'Gene', (181, 186))
27274	32012885	Several gene promoters are consistently found to be hypermethylated in PCa, including for instance GSTP1, which can be detected in several bodily fluids, including plasma or urine.	('hypermethylated', 'Var', (52, 67))	('GSTP1', 'Gene', (99, 104))	('GSTP1', 'Gene', '2950', (99, 104))	('PCa', 'Disease', (71, 74))	('PCa', 'Disease', 'MESH:D011471', (71, 74))
27276	32012885	From a therapeutic point of view, LSD1 (a lysine histone demethylase) has proved to be an interesting target, since its inhibitors were effective in preventing CRPC tumor growth in vitro and in vivo.	('LSD1', 'Gene', '23028', (34, 38))	('preventing', 'NegReg', (149, 159))	('CRPC', 'Disease', (160, 164))	('inhibitors', 'Var', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('LSD1', 'Gene', (34, 38))	('tumor', 'Disease', (165, 170))
27278	32012885	Moreover, both demethylating agents such as azacitidine, HDAC inhibitors such as vorinostat and even novel agents such as the pan-bromodomain inhibitor JQ1 have shown antitumor effect in prostate cancer models, including CRPC.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('CRPC', 'Disease', (221, 225))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('prostate cancer', 'Disease', 'MESH:D011471', (187, 202))	('inhibitors', 'Var', (62, 72))	('HDAC', 'Gene', (57, 61))	('azacitidine', 'Chemical', 'MESH:D001374', (44, 55))	('prostate cancer', 'Phenotype', 'HP:0012125', (187, 202))	('tumor', 'Disease', (171, 176))	('HDAC', 'Gene', '9734', (57, 61))	('vorinostat', 'Chemical', 'MESH:D000077337', (81, 91))	('prostate cancer', 'Disease', (187, 202))
27279	32012885	A summary of most recent studies addressing combination strategies between epigenetics and immune environment in PCa is depicted in Table 3.	('PCa', 'Disease', (113, 116))	('epigenetics', 'Var', (75, 86))	('PCa', 'Disease', 'MESH:D011471', (113, 116))	('men', 'Species', '9606', (105, 108))
27282	32012885	further elaborated on this; they showed that the same epigenetic modifiers partially restored IFN signaling but, very relevantly, they also showed that this attenuated, but did not completely block viral infection in PCa cells.	('attenuated', 'NegReg', (157, 167))	('restored', 'PosReg', (85, 93))	('IFN', 'Gene', '3439', (94, 97))	('epigenetic modifiers', 'Var', (54, 74))	('PCa', 'Disease', (217, 220))	('PCa', 'Disease', 'MESH:D011471', (217, 220))	('viral infection', 'biological_process', 'GO:0016032', ('198', '213'))	('block viral infection', 'Disease', 'MESH:D014777', (192, 213))	('block viral infection', 'Disease', (192, 213))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('IFN', 'Gene', (94, 97))
27288	32012885	Epigenetic drugs might then result in making PCa cells more immunogenic and amenable to targeting by immune therapies.	('PCa', 'Disease', (45, 48))	('PCa', 'Disease', 'MESH:D011471', (45, 48))	('result', 'Reg', (28, 34))	('men', 'Species', '9606', (77, 80))	('more', 'PosReg', (55, 59))	('Epigenetic drugs', 'Var', (0, 16))
27297	32012885	has recently demonstrated that JQ1, an inhibitor of bromodomain and extra-terminal (BET) bromodomain family, impacts on the immune response players, including PD-L1 downregulation, MHC1 upregulation, additive effect to anti-CTLA-4 agents and inducing an increase in the CD8/Treg ratio, leading to immunogenicity.	('CD8', 'Gene', '925', (270, 273))	('additive', 'Interaction', (200, 208))	('BET', 'Gene', (84, 87))	('PD-L1', 'Gene', (159, 164))	('JQ1', 'Var', (31, 34))	('leading to', 'Reg', (286, 296))	('PD-L1', 'Gene', '29126', (159, 164))	('downregulation', 'NegReg', (165, 179))	('CTLA-4', 'Gene', '1493', (224, 230))	('CTLA-4', 'Gene', (224, 230))	('CD8', 'Gene', (270, 273))	('BET', 'Gene', '92737', (84, 87))	('inducing', 'Reg', (242, 250))	('immune response', 'biological_process', 'GO:0006955', ('124', '139'))	('immunogenicity', 'MPA', (297, 311))	('MHC1', 'Gene', (181, 185))	('upregulation', 'PosReg', (186, 198))	('impacts', 'Reg', (109, 116))	('increase', 'PosReg', (254, 262))
27324	32012885	Given their supranumerical X-chromosome content, the expression of XIST, triggered by demethylation of its promoter, is maintained in these tumors, contrarily to somatic cancers, which may be used as a liquid biopsy marker of the disease.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('XIST', 'Gene', '7503', (67, 71))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('cancers', 'Disease', (170, 177))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('XIST', 'Gene', (67, 71))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('demethylation', 'biological_process', 'GO:0070988', ('86', '99'))	('X-chromosome', 'cellular_component', 'GO:0000805', ('27', '39'))	('expression', 'MPA', (53, 63))	('demethylation', 'Var', (86, 99))
27330	32012885	We have reviewed recent literature that provided evidence for interactions between epigenetic regulation and the immune microenvironment, and that explored the combination of immune therapies with epigenetic therapies, showing promising (synergistic) results in vitro and in vivo.	('epigenetic regulation', 'Var', (83, 104))	('regulation', 'biological_process', 'GO:0065007', ('94', '104'))	('interactions', 'Interaction', (62, 74))	('men', 'Species', '9606', (132, 135))
27341	31344778	We have previously shown that dysregulation in glycolytic and tricarboxylic acid cycle intermediates can distinguish benign lesions from RCC in a stage-specific manner.	('dysregulation', 'Var', (30, 43))	('tricarboxylic acid cycle', 'biological_process', 'GO:0006099', ('62', '86'))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('glycolytic', 'Chemical', '-', (47, 57))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (62, 80))	('RCC', 'Disease', (137, 140))	('benign lesions', 'Disease', (117, 131))
27354	31344778	Heterogeneity in RCC stems from genetic alterations, the most common RCC subtype, clear cell renal cell carcinoma (ccRCC), is characterized by alterations in the Von Hippel Lindau (VHL) gene which subsequently impacts downstream metabolic processes such as cellular glucose transport.	('RCC', 'Disease', (69, 72))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (93, 113))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('clear cell renal cell carcinoma', 'Disease', (82, 113))	('VHL', 'Gene', (181, 184))	('impacts', 'Reg', (210, 217))	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('glucose', 'Chemical', 'MESH:D005947', (266, 273))	('RCC', 'Disease', (17, 20))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('VHL', 'Gene', '7428', (181, 184))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (82, 113))	('Von Hippel Lindau', 'Gene', '7428', (162, 179))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('alterations', 'Var', (143, 154))	('cellular glucose transport', 'MPA', (257, 283))	('Von Hippel Lindau', 'Gene', (162, 179))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (82, 113))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('glucose transport', 'biological_process', 'GO:1904659', ('266', '283'))
27355	31344778	The papillary RCC (PRCC) subtype is associated with mutations in the fumarase hydratase gene, where the function of the resultant and defective tricarboxylic acid (TCA) cycle enzyme fumarase is inhibited.	('RCC', 'Disease', (14, 17))	('papillary RCC', 'Disease', 'MESH:C538614', (4, 17))	('papillary RCC', 'Disease', (4, 17))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (144, 162))	('function', 'MPA', (104, 112))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('RCC', 'Disease', (20, 23))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('inhibited', 'NegReg', (194, 203))	('TCA) cycle', 'biological_process', 'GO:0006099', ('164', '174'))	('fumarase', 'Gene', '2271', (182, 190))	('fumarase', 'Gene', '2271', (69, 77))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('associated', 'Reg', (36, 46))	('mutations', 'Var', (52, 61))	('TCA', 'Chemical', 'MESH:D014233', (164, 167))	('fumarase', 'Gene', (182, 190))	('fumarase', 'Gene', (69, 77))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
27356	31344778	Alterations in genes (SDHB) encoding yet another TCA cycle enzyme, succinate dehydrogenase, have been reported in patients with hereditary paragangliomatosis with phaeochromocytomas and in some ccRCC cases.	('Alterations', 'Var', (0, 11))	('SDHB', 'Gene', '6390', (22, 26))	('succinate', 'Chemical', 'MESH:D019802', (67, 76))	('TCA', 'Chemical', 'MESH:D014233', (49, 52))	('SDHB', 'Gene', (22, 26))	('TCA cycle', 'biological_process', 'GO:0006099', ('49', '58'))	('hereditary paragangliomatosis with phaeochromocytomas', 'Disease', 'MESH:D009386', (128, 181))	('RCC', 'Disease', 'MESH:C538614', (196, 199))	('RCC', 'Disease', (196, 199))	('RCC', 'Phenotype', 'HP:0005584', (196, 199))	('reported', 'Reg', (102, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (194, 199))	('patients', 'Species', '9606', (114, 122))
27359	31344778	Taken together, genetic mutations in RCC result in characteristic metabolic alterations which may be exploited for crucial diagnostic benefits.	('genetic mutations', 'Var', (16, 33))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('metabolic alterations', 'MPA', (66, 87))
27391	31344778	The model comparing oncocytomas to chromophobes (Figure 3a) showed distinct group separation which was attributed to reduced citrate and increased carnitine, trans-aconitate, succinate and pi-methylhistidine in chromophobe RCC, while lower levels of citrate, 1-methylnicotinamide, glycine, 2-hydroxyisobutyrate and higher carnitine, tartrate, trans-aconitate and histamine in ccRCC relative to oncocytoma were observed (Table 3).	('chromophobe RCC', 'Disease', (211, 226))	('RCC', 'Disease', 'MESH:C538614', (223, 226))	('1-methylnicotinamide', 'Chemical', 'MESH:C024058', (259, 279))	('trans-aconitate', 'MPA', (343, 358))	('carnitine', 'MPA', (322, 331))	('succinate', 'Chemical', 'MESH:D019802', (175, 184))	('RCC', 'Disease', (378, 381))	('RCC', 'Phenotype', 'HP:0005584', (378, 381))	('increased carnitine', 'Phenotype', 'HP:0003234', (137, 156))	('2-hydroxyisobutyrate', 'Chemical', 'MESH:C008039', (290, 310))	('carnitine', 'Chemical', 'MESH:D002331', (147, 156))	('glycine', 'Chemical', 'MESH:D005998', (281, 288))	('lower levels of citrate', 'Phenotype', 'HP:0012405', (234, 257))	('succinate', 'MPA', (175, 184))	('higher', 'PosReg', (315, 321))	('trans-aconitate', 'Chemical', '-', (343, 358))	('citrate', 'Chemical', 'MESH:D019343', (125, 132))	('citrate', 'Chemical', 'MESH:D019343', (250, 257))	('increased', 'PosReg', (137, 146))	('trans-aconitate', 'MPA', (158, 173))	('tartrate', 'MPA', (333, 341))	('oncocytoma', 'Disease', (394, 404))	('oncocytoma', 'Disease', (20, 30))	('pi-methylhistidine', 'Var', (189, 207))	('RCC', 'Disease', 'MESH:C538614', (378, 381))	('carnitine', 'MPA', (147, 156))	('histamine', 'MPA', (363, 372))	('trans-aconitate', 'Chemical', '-', (158, 173))	('chromophobe RCC', 'Disease', 'MESH:C538614', (211, 226))	('oncocytomas to chromophobes', 'Disease', (20, 47))	('RCC', 'Phenotype', 'HP:0005584', (223, 226))	('histamine', 'Chemical', 'MESH:D006632', (363, 372))	('tartrate', 'Chemical', 'MESH:C029768', (333, 341))	('RCC', 'Disease', (223, 226))	('pi-methylhistidine', 'Chemical', 'MESH:C028120', (189, 207))	('reduced', 'NegReg', (117, 124))	('carnitine', 'Chemical', 'MESH:D002331', (322, 331))	('oncocytomas to chromophobes', 'Disease', 'MESH:D018249', (20, 47))	('citrate', 'MPA', (125, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (376, 381))	('oncocytoma', 'Disease', 'MESH:D018249', (20, 30))	('oncocytoma', 'Disease', 'MESH:D018249', (394, 404))
27454	31081053	Genetic mutations are an important risk factor for the development of RCC, which can be detected at early stages.	('Genetic mutations', 'Var', (0, 17))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))
27532	31081053	Additionally, EdU staining revealed that, compared with the vector groups (786-O, 27.53+-2.27%; 769-P, 34.24+-1.28%), the proliferation of HOXA6-overexpressing cells (786-O, 18.44+-2.26%, P=0.0079; 769-P, 15.52+-2.07%, P=0.0015) was significantly inhibited.	('786-O', 'Var', (167, 172))	('inhibited', 'NegReg', (247, 256))	('proliferation', 'CPA', (122, 135))	('HOXA6', 'Gene', '3203', (139, 144))	('HOXA6', 'Gene', (139, 144))
27540	31081053	The TUNEL assay also indicated that the apoptotic rates of the HOXA6 overexpression groups (786-O, 30.80+-1.34%; 769-P; 26.72+-1.28%) were significantly increased compared with the vector groups (786-O, 25.31+-2.41%, P=0.0384; 769-P, 23.69+-0.86%, P=0.0332).	('overexpression', 'PosReg', (69, 83))	('786-O', 'Var', (92, 97))	('HOXA6', 'Gene', '3203', (63, 68))	('increased', 'PosReg', (153, 162))	('HOXA6', 'Gene', (63, 68))	('apoptotic rates', 'CPA', (40, 55))
27552	31081053	It has been reported that HOXA6 is upregulated in certain types of cancer and exhibits a role as an oncogene; however, studies have demonstrated that the CpG islands of HOXA6 are hypermethylated in malignant tumors.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('HOXA6', 'Gene', '3203', (26, 31))	('malignant tumors', 'Disease', (198, 214))	('HOXA6', 'Gene', '3203', (169, 174))	('cancer', 'Disease', (67, 73))	('HOXA6', 'Gene', (26, 31))	('malignant tumors', 'Disease', 'MESH:D018198', (198, 214))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('hypermethylated', 'Var', (179, 194))	('HOXA6', 'Gene', (169, 174))
27619	28562332	Patients with high IRF5 expression had significantly poorer OS (p = 0.001) and RFS (p = 0.002) (Figure 2A, 2B) than those with low IRF5 expression.	('RFS', 'CPA', (79, 82))	('IRF5', 'Gene', (131, 135))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('IRF5', 'Gene', '3663', (131, 135))	('IRF5', 'Gene', '3663', (19, 23))	('IRF5', 'Gene', (19, 23))	('RFS', 'Chemical', '-', (79, 82))	('poorer', 'NegReg', (53, 59))	('OS', 'Chemical', '-', (60, 62))
27637	28562332	The results presented here provide for the first time that high IRF5 expression correlated with ccRCC development and progression.	('expression', 'MPA', (69, 79))	('RCC', 'Disease', (98, 101))	('high', 'Var', (59, 63))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('IRF5', 'Gene', (64, 68))	('correlated with', 'Reg', (80, 95))	('IRF5', 'Gene', '3663', (64, 68))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('progression', 'CPA', (118, 129))
27648	28562332	It is reported that in hepatocellular carcinoma and gastric cancer, IRF5 expression is down-regulated due to gene promoter hyper-methylation.	('gastric cancer', 'Phenotype', 'HP:0012126', (52, 66))	('down-regulated', 'NegReg', (87, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (23, 47))	('expression', 'MPA', (73, 83))	('IRF5', 'Gene', '3663', (68, 72))	('hepatocellular carcinoma', 'Disease', (23, 47))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (23, 47))	('IRF5', 'Gene', (68, 72))	('hyper-methylation', 'Var', (123, 140))	('gastric cancer', 'Disease', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('methylation', 'biological_process', 'GO:0032259', ('129', '140'))	('gastric cancer', 'Disease', 'MESH:D013274', (52, 66))
27656	28562332	And in our previous study, we found polarized TAMs were novel independent prognosticator in patients with ccRCC.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('patients', 'Species', '9606', (92, 100))	('TAMs', 'Chemical', '-', (46, 50))	('polarized', 'Var', (36, 45))
27675	28562332	X-Tile software (Yale University School of Medicine, New Haven, CT, USA) was used to determine the cutoff point of high/low expression through minimum p value method based on patients' OS information, and 180 was selected as the cutoff point.	('patients', 'Species', '9606', (175, 183))	('high/low', 'Var', (115, 123))	('expression', 'MPA', (124, 134))	('OS', 'Chemical', '-', (185, 187))
27683	33468235	Kaplan-Meier survival analysis showed that high expression of PHYH had a better prognosis than low expression (p = 9e-05).	('PHYH', 'Gene', (62, 66))	('PHYH', 'Gene', '5264', (62, 66))	('high expression', 'Var', (43, 58))
27727	33468235	As the results show, grade (G2, G3, and G4) and stage (I, II, and IV) are significantly associated with low survivability.	('age', 'Gene', (50, 53))	('survivability', 'CPA', (108, 121))	('age', 'Gene', '5973', (50, 53))	('G2', 'Var', (28, 30))	('low', 'NegReg', (104, 107))	('G4', 'Var', (40, 42))
27734	33468235	To identify signalling pathways that are differentially activated in ccRCC, we conducted Gene Set Enrichment Analysis (GSEA) between low and high TFAP2B expression data sets.	('TFAP2B', 'Gene', (146, 152))	('signalling', 'biological_process', 'GO:0023052', ('12', '22'))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('TFAP2B', 'Gene', '7021', (146, 152))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (69, 74))	('GSEA', 'Chemical', '-', (119, 123))	('high', 'Var', (141, 145))
27759	33468235	Autosomal recessive loss of function mutations in the PEX genes can result in peroxisome biogenesis disorders in the brain bone kidney and liver.	('peroxisome biogenesis disorders', 'Disease', (78, 109))	('Autosomal recessive loss', 'Disease', 'MESH:D030342', (0, 24))	('peroxisome', 'cellular_component', 'GO:0005777', ('78', '88'))	('mutations', 'Var', (37, 46))	('result in', 'Reg', (68, 77))	('peroxisome biogenesis disorders', 'Disease', 'MESH:C536664', (78, 109))	('brain bone kidney', 'Disease', 'MESH:C536326', (117, 134))	('PEX', 'Gene', (54, 57))	('Autosomal recessive loss', 'Disease', (0, 24))	('brain bone kidney', 'Disease', (117, 134))
27767	33468235	The abnormal expression of PHYH in our tumor cells activates the immune checkpoint.	('PHYH', 'Gene', (27, 31))	('activates', 'PosReg', (51, 60))	('abnormal', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('immune checkpoint', 'CPA', (65, 82))	('tumor', 'Disease', (39, 44))	('PHYH', 'Gene', '5264', (27, 31))
27769	33468235	Results from the network analysis also revealed that alteration of PHYH expression in ccRCC phenotype implicates the alpha-oxidation pathway.	('alpha-oxidation pathway', 'Pathway', (117, 140))	('alteration', 'Var', (53, 63))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('implicates', 'Reg', (102, 112))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('PHYH', 'Gene', '5264', (67, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('PHYH', 'Gene', (67, 71))
27779	33468235	In addition, RAS deregulation was demonstrated as a renal cancer risk factor.	('RAS', 'Protein', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('renal cancer', 'Disease', (52, 64))	('renal cancer', 'Phenotype', 'HP:0009726', (52, 64))	('renal cancer', 'Disease', 'MESH:D007680', (52, 64))	('deregulation', 'Var', (17, 29))
27791	30774762	Clear cell RCC (ccRCC)-derived SETD2 knockout 786-0 and SETD2 mutant A498 cells treated with TGX221 (PI3Kbeta-specific) and AZD8186 (PI3Kbeta- and delta-specific) inhibitors displayed decreased cell viability, cell growth, and migration compared to SETD2 proficient 786-0 cells.	('SETD2', 'Gene', (56, 61))	('RCC', 'Disease', (18, 21))	('TGX221', 'Chemical', 'MESH:C504718', (93, 99))	('migration', 'CPA', (227, 236))	('mutant', 'Var', (62, 68))	('A498', 'CellLine', 'CVCL:1056', (69, 73))	('cell growth', 'CPA', (210, 221))	('decreased', 'NegReg', (184, 193))	('cell growth', 'biological_process', 'GO:0016049', ('210', '221'))	('cell viability', 'CPA', (194, 208))	('AZD8186', 'Chemical', 'MESH:C000595972', (124, 131))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (18, 21))
27793	30774762	In vivo, treatment of SETD2 mutant A498 cells, but not SETD2 proficient 786-0 cells, with AZD8186 significantly decreased tumor growth.	('mutant', 'Var', (28, 34))	('SETD2', 'Gene', (22, 27))	('A498', 'CellLine', 'CVCL:1056', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('AZD8186', 'Chemical', 'MESH:C000595972', (90, 97))	('decreased', 'NegReg', (112, 121))	('tumor growth', 'Disease', (122, 134))	('tumor growth', 'Disease', 'MESH:D006130', (122, 134))
27798	30774762	ccRCC tumors are known to be unresponsive to traditional chemotherapies and lack the genetic hallmarks of other solid tumors, such as KRAS and TP53 mutations.	('TP53', 'Gene', (143, 147))	('solid tumors', 'Disease', (112, 124))	('KRAS', 'Gene', '3845', (134, 138))	('mutations', 'Var', (148, 157))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('RCC tumors', 'Disease', (2, 12))	('solid tumors', 'Disease', 'MESH:D009369', (112, 124))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('TP53', 'Gene', '7157', (143, 147))	('RCC tumors', 'Disease', 'MESH:C538614', (2, 12))	('KRAS', 'Gene', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
27802	30774762	Its complete inactivation by either mutation or methylation is observed in more than 80% of ccRCCs and represents the earliest truncal oncogenic event in these tumors.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('inactivation', 'NegReg', (13, 25))	('RCC', 'Disease', (94, 97))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('methylation', 'Var', (48, 59))	('mutation', 'Var', (36, 44))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
27803	30774762	In recent years, large-scale cancer genomic projects have revealed numerous additional mutations in other tumor suppressors genes encoding chromatin remodelers, including protein polybromo 1 (PBRM1/BAF180), BRCA associated protein 1 (BAP1), and Set domain containing 2 (SETD2).	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('BAF180', 'Gene', (198, 204))	('protein polybromo 1', 'Gene', '55193', (171, 190))	('protein', 'cellular_component', 'GO:0003675', ('223', '230'))	('PBRM1', 'Gene', '55193', (192, 197))	('mutations', 'Var', (87, 96))	('tumor', 'Disease', (106, 111))	('PBRM1', 'Gene', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('BAP1', 'Gene', '8314', (234, 238))	('cancer', 'Disease', (29, 35))	('BRCA associated protein 1', 'Gene', '8314', (207, 232))	('SETD2', 'Gene', (270, 275))	('protein polybromo 1', 'Gene', (171, 190))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('BRCA associated protein 1', 'Gene', (207, 232))	('BAP1', 'Gene', (234, 238))	('BAF180', 'Gene', '55193', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('chromatin', 'cellular_component', 'GO:0000785', ('139', '148'))
27804	30774762	As opposed to VHL inactivation, a known founding event of ccRCC, mutations in genes involved in disease progression such as PBRM1, BAP1, and SETD2 are associated with aggressive clinical features.	('VHL', 'Gene', (14, 17))	('aggressive clinical features', 'CPA', (167, 195))	('associated with', 'Reg', (151, 166))	('PBRM1', 'Gene', '55193', (124, 129))	('RCC', 'Disease', (60, 63))	('BAP1', 'Gene', '8314', (131, 135))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('PBRM1', 'Gene', (124, 129))	('BAP1', 'Gene', (131, 135))	('SETD2', 'Gene', (141, 146))	('mutations', 'Var', (65, 74))	('VHL', 'Gene', '7428', (14, 17))
27807	30774762	By methylating such diverse targets, SETD2 contributes to the maintenance of a wide spectrum of biological processes ranging from chromatin accessibility, mRNA splicing and processing, DNA double-strand break repair, genomic stability, and cellular defense against viral infection.	('cellular defense', 'CPA', (240, 256))	('mRNA splicing', 'biological_process', 'GO:0000398', ('155', '168'))	('DNA', 'cellular_component', 'GO:0005574', ('185', '188'))	('viral infection', 'biological_process', 'GO:0016032', ('265', '280'))	('chromatin', 'cellular_component', 'GO:0000785', ('130', '139'))	('mRNA splicing', 'biological_process', 'GO:0006371', ('155', '168'))	('chromatin accessibility', 'MPA', (130, 153))	('methylating', 'Var', (3, 14))	('contributes', 'Reg', (43, 54))	('mRNA splicing', 'biological_process', 'GO:0000394', ('155', '168'))	('mRNA splicing', 'biological_process', 'GO:0000374', ('155', '168'))	('genomic', 'MPA', (217, 224))	('viral infection', 'Disease', (265, 280))	('mRNA splicing', 'MPA', (155, 168))	('mRNA splicing', 'biological_process', 'GO:0000373', ('155', '168'))	('processing', 'MPA', (173, 183))	('mRNA splicing', 'biological_process', 'GO:0000372', ('155', '168'))	('double-strand break repair', 'biological_process', 'GO:0006302', ('189', '215'))	('SETD2', 'Gene', (37, 42))	('viral infection', 'Disease', 'MESH:D001102', (265, 280))	('DNA double-strand break repair', 'MPA', (185, 215))
27811	30774762	A recent study utilizing the Genomics of Drug Sensitivity in Cancer (GDSC) database identified that RCC cells with mutated VHL or SETD2 were sensitive to the small molecule PIK3beta inhibitor TGX221.	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (41, 57))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mutated', 'Var', (115, 122))	('VHL', 'Gene', (123, 126))	('sensitive', 'Reg', (141, 150))	('SETD2', 'Gene', (130, 135))	('TGX221', 'Chemical', 'MESH:C504718', (192, 198))	('VHL', 'Gene', '7428', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))
27812	30774762	TGX221 was also shown to target cancer cells with CDKN2A and PTEN mutations, suggesting nonspecific inhibition at the molar concentration (5 muM) used in the study.	('mutations', 'Var', (66, 75))	('CDKN2A', 'Gene', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('CDKN2A', 'Gene', '1029', (50, 56))	('muM', 'Gene', '56925', (141, 144))	('PTEN', 'Gene', (61, 65))	('muM', 'Gene', (141, 144))	('PTEN', 'Gene', '5728', (61, 65))	('nonspecific inhibition', 'MPA', (88, 110))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('TGX221', 'Chemical', 'MESH:C504718', (0, 6))
27816	30774762	Lastly, SETD2 deficient cell lines treated with MK2206 (AKT-specific inhibitor) recapitulated the effects observed in AZD8186-treated SETD2 deficient cells, implicating canonical PI3K signaling via AKT as a key mechanism of viability.	('AKT', 'Gene', '207', (56, 59))	('MK2206', 'Chemical', 'MESH:C548887', (48, 54))	('PI3K signaling', 'biological_process', 'GO:0014065', ('179', '193'))	('AKT', 'Gene', (56, 59))	('AKT', 'Gene', '207', (198, 201))	('PI3K', 'molecular_function', 'GO:0016303', ('179', '183'))	('MK2206', 'Var', (48, 54))	('AZD8186', 'Chemical', 'MESH:C000595972', (118, 125))	('AKT', 'Gene', (198, 201))
27818	30774762	Notably, SETD2 knockout (KO) ccRCC-derived 786-0 cells, previously generated and described in more detail, showed a significantly higher proliferation rate than their SETD2 proficient (+/+) counterparts (Supplementary Figure 1).	('SETD2', 'Gene', (9, 14))	('knockout', 'Var', (15, 23))	('higher', 'PosReg', (130, 136))	('proliferation rate', 'CPA', (137, 155))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))
27820	30774762	In addition to 786-0 SETD2 proficient (+/+) and SETD2 knockout (KO) cells, we used SETD2 deficient A498 cells, which have lost one SETD2 allele due to loss of the short arm of chromosome 3 (3p) and carry a two-base pair c.6098_6099 deletion (delTG) that causes a frameshift in the carboxyl terminus that inactivates the second allele.	('second allele', 'MPA', (320, 333))	('A498', 'CellLine', 'CVCL:1056', (99, 103))	('frameshift', 'Var', (263, 273))	('inactivates', 'NegReg', (304, 315))	('c.6098_6099 deletion (delTG)', 'Mutation', 'c.6098_6099 deletion (delTG)', (220, 248))	('chromosome', 'cellular_component', 'GO:0005694', ('176', '186'))	('loss', 'NegReg', (151, 155))	('c.6098_6099', 'Var', (220, 231))	('short arm', 'Phenotype', 'HP:0009824', (163, 172))
27824	30774762	The two SETD2 deficient cell lines showed a significant increase in sensitivity to all three PI3Kbeta (AZD8186>TGX221>GSK2636) inhibitors, as evidenced by their decreased relative cell viability.	('SETD2', 'Gene', (8, 13))	('increase', 'PosReg', (56, 64))	('decreased', 'NegReg', (161, 170))	('AZD8186', 'Var', (103, 110))	('deficient', 'NegReg', (14, 23))	('GSK2636', 'Chemical', '-', (118, 125))	('PI3Kbeta', 'Enzyme', (93, 101))	('relative cell viability', 'CPA', (171, 194))	('AZD8186', 'Chemical', 'MESH:C000595972', (103, 110))	('TGX221', 'Chemical', 'MESH:C504718', (111, 117))	('GSK', 'molecular_function', 'GO:0050321', ('118', '121'))	('sensitivity', 'MPA', (68, 79))
27826	30774762	As AZD8186 is known to inhibit both PI3K beta and delta isoforms in a cell-free assay (IC50 = 4 nM and 12 nM, respectively), we also treated cells with the PI3Kdelta-specific inhibitor Idelalisib to see if this PI3K isoform also contributed to synthetic lethality with SETD2 loss.	('PI3K', 'molecular_function', 'GO:0016303', ('36', '40'))	('AZD8186', 'Var', (3, 10))	('SETD2', 'Gene', (269, 274))	('inhibit', 'NegReg', (23, 30))	('PI3K beta', 'Gene', (36, 45))	('PI3Kdelta', 'Gene', (156, 165))	('PI3K beta', 'Gene', '5291', (36, 45))	('AZD8186', 'Chemical', 'MESH:C000595972', (3, 10))	('PI3Kdelta', 'Gene', '5293', (156, 165))	('Idelalisib', 'Chemical', 'MESH:C552946', (185, 195))	('loss', 'NegReg', (275, 279))	('PI3K', 'molecular_function', 'GO:0016303', ('211', '215'))
27828	30774762	When SETD2 deficient cells (KO 786-0 and (-/-) A498) were treated with the Pan-PI3K inhibitor BKM120, they displayed a significant increase in sensitivity that resembled the effects observed with PI3Kbeta-specific inhibitors (Figure 1A and Supplementary Figure 2B).	('sensitivity', 'MPA', (143, 154))	('SETD2', 'Gene', (5, 10))	('BKM120', 'Var', (94, 100))	('increase', 'PosReg', (131, 139))	('BKM120', 'Chemical', 'MESH:C571178', (94, 100))	('PI3K', 'molecular_function', 'GO:0016303', ('79', '83'))	('A498', 'CellLine', 'CVCL:1056', (47, 51))
27829	30774762	To further examine whether the observed sensitivity of SETD2 deficient cells was specifically determined by PI3Kbeta isoform inhibition, we conducted a dose-response assay using AZD8186, as it displayed the most pronounced response among the three PI3Kbeta-specific inhibitors (Figure 1A), along with BYL719 (PI3Kalpha-specific), Idelalisib (PI3Kdelta-specific), and BKM120 (Pan-PI3K) inhibitors and calculated their respective half maximal inhibitory concentrations (IC50s).	('PI3Kdelta', 'Gene', '5293', (342, 351))	('PI3K', 'molecular_function', 'GO:0016303', ('379', '383'))	('PI3Kalpha', 'Gene', '5290', (309, 318))	('PI3Kalpha', 'Gene', (309, 318))	('50s', 'Species', '1214577', (470, 473))	('BKM120', 'Chemical', 'MESH:C571178', (367, 373))	('AZD8186', 'Chemical', 'MESH:C000595972', (178, 185))	('AZD8186', 'Var', (178, 185))	('PI3Kdelta', 'Gene', (342, 351))	('Idelalisib', 'Chemical', 'MESH:C552946', (330, 340))
27830	30774762	Dose-response curves showed that SETD2 deficient 786-0 and A498 cells were highly sensitive to AZD8186 when compared to SETD2 proficient 786-0 cells (IC50 = 0.29 muM, 0.01 muM, and 21 muM respectively) (Figure 1B).	('SETD2', 'Gene', (33, 38))	('muM', 'Gene', '56925', (172, 175))	('A498', 'CellLine', 'CVCL:1056', (59, 63))	('AZD8186', 'Chemical', 'MESH:C000595972', (95, 102))	('sensitive', 'MPA', (82, 91))	('muM', 'Gene', '56925', (162, 165))	('muM', 'Gene', (172, 175))	('muM', 'Gene', '56925', (184, 187))	('AZD8186', 'Var', (95, 102))	('muM', 'Gene', (162, 165))	('muM', 'Gene', (184, 187))
27831	30774762	Idelalisib dose-response curves showed that SETD2 deficient 786-0 and A498 cells were more sensitive to the PI3Kdelta-specific inhibitor than SETD2 proficient 786-0 cells.	('deficient', 'Var', (50, 59))	('sensitive', 'MPA', (91, 100))	('PI3Kdelta', 'Gene', (108, 117))	('SETD2', 'Gene', (44, 49))	('A498', 'CellLine', 'CVCL:1056', (70, 74))	('PI3Kdelta', 'Gene', '5293', (108, 117))	('Idelalisib', 'Chemical', 'MESH:C552946', (0, 10))
27835	30774762	SETD2 deficient cells showed a significantly decreased proliferation rate when treated with TGX221 and consistently more so with AZD8186, while BYL719 showed a mild or no decrease in all tested cell lines (Supplementary Figure 2C).	('AZD8186', 'Chemical', 'MESH:C000595972', (129, 136))	('TGX221', 'Chemical', 'MESH:C504718', (92, 98))	('deficient', 'NegReg', (6, 15))	('proliferation rate', 'CPA', (55, 73))	('decreased', 'NegReg', (45, 54))	('TGX221', 'Gene', (92, 98))	('SETD2', 'Gene', (0, 5))	('AZD8186', 'Var', (129, 136))
27836	30774762	Notably, 786-0 SETD2 KO cells rescued with functional truncated SETD2 (tSETD2) abrogated sensitivity to PI3Kbeta inhibition, whereas a catalytically inactivating mutation in the SET domain (R1625C) still retained increased sensitivity to PI3Kbeta inhibition (Supplementary Figure 2D).	('sensitivity to PI3Kbeta inhibition', 'MPA', (89, 123))	('SETD2', 'Gene', (64, 69))	('R1625C', 'Mutation', 'p.R1625C', (190, 196))	('R1625C', 'Var', (190, 196))	('abrogated', 'NegReg', (79, 88))
27840	30774762	These results show that SETD2 deficient ccRCC-derived cells are significantly less proliferative when treated with PI3Kbeta inhibitors and strongly suggest inhibition of downstream effectors in the PI3K pathway (pAKT-S473 and pS6) may play a role in this synthetic lethal interaction.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('pS6', 'Gene', (226, 229))	('inhibition', 'NegReg', (156, 166))	('RCC', 'Disease', (42, 45))	('less', 'NegReg', (78, 82))	('deficient', 'Var', (30, 39))	('pS6', 'Gene', '338413', (226, 229))	('PI3K pathway', 'Pathway', (198, 210))	('AKT', 'Gene', '207', (213, 216))	('PI3K', 'molecular_function', 'GO:0016303', ('198', '202'))	('SETD2', 'Gene', (24, 29))	('AKT', 'Gene', (213, 216))	('proliferative', 'CPA', (83, 96))
27841	30774762	We predicted that siRNA targeting PI3Kbeta would closely replicate the effect on relative cell viability observed in SETD2 deficient ccRCC-derived cells when treated with PI3Kbeta-specific inhibitors.	('deficient', 'NegReg', (123, 132))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))	('SETD2', 'Gene', (117, 122))	('PI3Kbeta', 'Var', (34, 42))
27844	30774762	Phosphorylation levels of a PI3K downstream effector, pAKT-S473, were assessed by immunoblot analysis to corroborate the efficiency of PI3K isoform knockdowns.	('knockdowns', 'Var', (148, 158))	('PI3K', 'molecular_function', 'GO:0016303', ('28', '32'))	('AKT', 'Gene', (55, 58))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('PI3K', 'molecular_function', 'GO:0016303', ('135', '139'))	('AKT', 'Gene', '207', (55, 58))
27846	30774762	These results strongly suggest that the decrease in pAKT-S473 phosphorylation levels observed when PI3Kbeta is chemically inhibited (TGX221 and more consistently AZD8186) (Figure 1C) was due to the specific inhibition of PI3Kbeta's enzymatic activity, revealing pAKT-S473 as a critical reporter, and perhaps mediator, of the SETD2-dependency on the PI3Kbeta signaling network.	('decrease', 'NegReg', (40, 48))	('inhibition', 'NegReg', (207, 217))	('inhibited', 'NegReg', (122, 131))	('AKT', 'Gene', '207', (263, 266))	('AKT', 'Gene', '207', (53, 56))	('AZD8186', 'Var', (162, 169))	('TGX221', 'Chemical', 'MESH:C504718', (133, 139))	('AKT', 'Gene', (263, 266))	('phosphorylation levels', 'MPA', (62, 84))	('AKT', 'Gene', (53, 56))	('signaling', 'biological_process', 'GO:0023052', ('358', '367'))	('AZD8186', 'Chemical', 'MESH:C000595972', (162, 169))	('phosphorylation', 'biological_process', 'GO:0016310', ('62', '77'))
27849	30774762	Conversely, both SETD2 deficient cell lines showed a less structured spheroid morphology and a significant decrease in their number when treated with PI3Kbeta-specific, but not PI3Kalpha-specific, inhibitors when compared to SETD2 proficient cells (Figure 3A and 3C).	('PI3Kbeta-specific', 'Var', (150, 167))	('less', 'NegReg', (53, 57))	('PI3Kalpha', 'Gene', '5290', (177, 186))	('PI3Kalpha', 'Gene', (177, 186))	('decrease', 'NegReg', (107, 115))	('SETD2', 'Gene', (17, 22))	('number', 'CPA', (125, 131))	('deficient', 'NegReg', (23, 32))
27850	30774762	Interestingly, both Idelalisib (PI3Kdelta-specific) and BKM120 (Pan-PI3K) inhibitors showed significant cell growth decrease in SETD2 deficient cell lines, but more prominently with the latter inhibitor, recapitulating the effects observed with PI3Kbeta-specific inhibitors (Figure 3C).	('Idelalisib', 'Gene', (20, 30))	('SETD2', 'Gene', (128, 133))	('PI3K', 'molecular_function', 'GO:0016303', ('68', '72'))	('inhibitors', 'Var', (74, 84))	('decrease', 'NegReg', (116, 124))	('BKM120', 'Chemical', 'MESH:C571178', (56, 62))	('BKM120', 'Gene', (56, 62))	('cell growth', 'biological_process', 'GO:0016049', ('104', '115'))	('Idelalisib', 'Chemical', 'MESH:C552946', (20, 30))	('PI3Kdelta', 'Gene', (32, 41))	('growth decrease', 'Phenotype', 'HP:0001510', (109, 124))	('cell growth', 'CPA', (104, 115))	('PI3Kdelta', 'Gene', '5293', (32, 41))
27852	30774762	We observed that SETD2 deficient cells were significantly less migratory than their SETD2 proficient counterparts when treated with PI3Kbeta-specific inhibitors, a phenomenon closely resembled by the treatment with the Pan-PI3K inhibitor, BKM120 (Figure 3B and 3D).	('deficient', 'Var', (23, 32))	('BKM120', 'Chemical', 'MESH:C571178', (239, 245))	('PI3K', 'molecular_function', 'GO:0016303', ('223', '227'))	('SETD2', 'Gene', (17, 22))	('migratory', 'CPA', (63, 72))	('less', 'NegReg', (58, 62))
27856	30774762	NOD scid gamma mice were injected subcutaneously with SETD2 mutant ccRCC-derived A498 cells and approximately a month later, mice bearing tumors measuring >=150 mm3 were randomized to treatment with vehicle (control) or AZD8186.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('mice', 'Species', '10090', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('AZD8186', 'Chemical', 'MESH:C000595972', (220, 227))	('mice', 'Species', '10090', (15, 19))	('SETD2 mutant', 'Var', (54, 66))	('A498', 'CellLine', 'CVCL:1056', (81, 85))
27857	30774762	Animals treated with the PI3Kbeta-specific inhibitor AZD8186 showed a significant decrease in tumor growth and final tumor weight compared to control mice (Figure 4A-4C).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mice', 'Species', '10090', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('AZD8186', 'Chemical', 'MESH:C000595972', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('decrease', 'NegReg', (82, 90))	('tumor', 'Disease', (117, 122))	('tumor growth', 'Disease', (94, 106))	('tumor', 'Disease', (94, 99))	('tumor growth', 'Disease', 'MESH:D006130', (94, 106))	('AZD8186', 'Var', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
27859	30774762	Thus, AZD8186 can effectively reduce growth of SETD2 mutant tumors but not SETD2 wild-type tumors, underscoring the importance of the molecular connection between the PI3Kbeta signaling network and SETD2 loss as a promising therapeutic target for ccRCC.	('tumors', 'Disease', (91, 97))	('growth', 'MPA', (37, 43))	('AZD8186', 'Var', (6, 13))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('SETD2', 'Gene', (47, 52))	('reduce', 'NegReg', (30, 36))	('signaling', 'biological_process', 'GO:0023052', ('176', '185'))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('AZD8186', 'Chemical', 'MESH:C000595972', (6, 13))	('RCC', 'Disease', 'MESH:C538614', (249, 252))	('RCC', 'Disease', (249, 252))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mutant', 'Var', (53, 59))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('reduce growth', 'Phenotype', 'HP:0001510', (30, 43))	('tumors', 'Disease', (60, 66))
27860	30774762	Our previous data demonstrating that PI3Kbeta-specific inhibitors decrease phosphorylation levels of key downstream effectors in the PI3K-AKT pathway (pAKT-S473 and pS6-S235/236) in SETD2 deficient ccRCC-derived cells prompted us to further explore the molecular mechanism connecting SETD2 to PI3Kbeta.	('pS6', 'Gene', (165, 168))	('AKT', 'Gene', '207', (152, 155))	('RCC', 'Disease', (200, 203))	('phosphorylation levels', 'MPA', (75, 97))	('AKT', 'Gene', (138, 141))	('RCC', 'Disease', 'MESH:C538614', (200, 203))	('pS6', 'Gene', '338413', (165, 168))	('AKT', 'Gene', (152, 155))	('PI3K', 'molecular_function', 'GO:0016303', ('133', '137'))	('decrease', 'NegReg', (66, 74))	('inhibitors', 'Var', (55, 65))	('phosphorylation', 'biological_process', 'GO:0016310', ('75', '90'))	('SETD2', 'Gene', (182, 187))	('AKT', 'Gene', '207', (138, 141))
27862	30774762	Similar to the treatment with PI3Kbeta-specific inhibitors, we observed that SETD2 deficient cells were more sensitive to MK2206, as evidenced by a significant decrease in their cell viability (Figure 5A and 5B).	('decrease', 'NegReg', (160, 168))	('cell viability', 'CPA', (178, 192))	('SETD2', 'Gene', (77, 82))	('MK2206', 'Var', (122, 128))	('deficient', 'NegReg', (83, 92))	('MK2206', 'Chemical', 'MESH:C548887', (122, 128))
27863	30774762	Immunoblotting of whole-cell lysates from a drug-target engagement assay using 1 muM of MK2206 showed that MK2206 effectively reduces phosphorylation levels of pAKT-S473.	('reduces', 'NegReg', (126, 133))	('MK2206', 'Chemical', 'MESH:C548887', (107, 113))	('phosphorylation levels', 'MPA', (134, 156))	('AKT', 'Gene', '207', (161, 164))	('muM', 'Gene', '56925', (81, 84))	('MK2206', 'Chemical', 'MESH:C548887', (88, 94))	('phosphorylation', 'biological_process', 'GO:0016310', ('134', '149'))	('MK2206', 'Var', (107, 113))	('muM', 'Gene', (81, 84))	('AKT', 'Gene', (161, 164))
27869	30774762	Here, we report a synthetic lethal interaction between targeted PI3Kbeta-AKT axis and loss of SETD2 both in vitro (ccRCC-derived cells) and in vivo (ccRCC cell line-derived xenografts).	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('SETD2', 'Gene', (94, 99))	('loss', 'Var', (86, 90))	('AKT', 'Gene', (73, 76))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (151, 154))	('AKT', 'Gene', '207', (73, 76))
27871	30774762	SETD2 bi-allelic loss occurs in at least 20% of primary human RCC tumors, which is associated with more advanced disease and the lethal metastatic phenotype.	('bi-allelic loss', 'Var', (6, 21))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('RCC tumors', 'Disease', 'MESH:C538614', (62, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('human', 'Species', '9606', (56, 61))	('SETD2', 'Gene', (0, 5))	('RCC tumors', 'Disease', (62, 72))
27872	30774762	Further, bi-allelic loss of SETD2, or mutations rendering the protein catalytically inactive, result in loss of H3K36me3 in ccRCC-derived cells and tumors.	('loss', 'NegReg', (104, 108))	('SETD2', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('H3K36me3', 'Protein', (112, 120))	('mutations', 'Var', (38, 47))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('RCC', 'Disease', (126, 129))	('loss', 'NegReg', (20, 24))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
27873	30774762	Interestingly, a study of ccRCC intratumoral heterogeneity identified distinct SETD2 mutations across subsections of an individual tumor, suggesting a selection bias for SETD2 mutation in the course of ccRCC development.	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('RCC', 'Disease', (204, 207))	('tumor', 'Disease', (131, 136))	('mutations', 'Var', (85, 94))	('tumor', 'Disease', (37, 42))	('SETD2', 'Gene', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('mutation', 'Var', (176, 184))	('RCC', 'Disease', (28, 31))
27877	30774762	Of note, mainly class IA PI3Ks have been implicated in cancer.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('implicated', 'Reg', (41, 51))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('PI3Ks', 'Var', (25, 30))	('cancer', 'Disease', (55, 61))
27878	30774762	Further, the PI3K-AKT axis is known to be activated by gene mutations and copy number alterations (CNAs) than any other altered molecular pathway in cancer.	('copy number alterations', 'Var', (74, 97))	('cancer', 'Disease', (149, 155))	('gene mutations', 'Var', (55, 69))	('AKT', 'Gene', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('PI3K', 'molecular_function', 'GO:0016303', ('13', '17'))	('activated', 'PosReg', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('AKT', 'Gene', '207', (18, 21))
27880	30774762	Supporting the critical role of the PI3K-AKT pathway in ccRCC and the emerging notion as a promising druggable target, a recent study demonstrated a connection between targeted PI3Kbeta inhibition with the small-molecule inhibitor TGX221 and loss of SETD2.	('PI3Kbeta', 'Pathway', (177, 185))	('inhibition', 'NegReg', (186, 196))	('SETD2', 'Gene', (250, 255))	('TGX221', 'Chemical', 'MESH:C504718', (231, 237))	('TGX221', 'Gene', (231, 237))	('AKT', 'Gene', '207', (41, 44))	('RCC', 'Disease', (58, 61))	('loss', 'Var', (242, 246))	('PI3K', 'molecular_function', 'GO:0016303', ('36', '40'))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('AKT', 'Gene', (41, 44))
27881	30774762	In this study, ccRCC-derived cells deficient for both VHL and SETD2 are significantly more sensitive to TGX221 than those deficient for VHL alone.	('deficient', 'Var', (35, 44))	('TGX221', 'Gene', (104, 110))	('VHL', 'Gene', (54, 57))	('sensitive', 'MPA', (91, 100))	('VHL', 'Gene', '7428', (54, 57))	('VHL', 'Gene', '7428', (136, 139))	('VHL', 'Gene', (136, 139))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))	('SETD2', 'Gene', (62, 67))	('TGX221', 'Chemical', 'MESH:C504718', (104, 110))
27884	30774762	Our combined data demonstrating that SETD2 deficient ccRCC-derived cells are significantly sensitive, less migratory, and less capable of forming spheroids and that tumor formation of SETD2 mutant xenografts is abrogated, further underscore the biological relevance of this molecular connection between SETD2 and PI3Kbeta.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('tumor', 'Disease', (165, 170))	('RCC', 'Disease', (55, 58))	('formation', 'biological_process', 'GO:0009058', ('171', '180'))	('SETD2', 'Gene', (37, 42))	('abrogated', 'NegReg', (211, 220))	('less', 'NegReg', (102, 106))	('mutant', 'Var', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('SETD2', 'Gene', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('migratory', 'CPA', (107, 116))	('deficient', 'NegReg', (43, 52))
27885	30774762	We also reveal the critical role that a functional AKT plays in supporting growth and migration specifically in SETD2 mutant ccRCC-derived cells.	('AKT', 'Gene', (51, 54))	('SETD2', 'Gene', (112, 117))	('mutant', 'Var', (118, 124))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('supporting growth', 'CPA', (64, 81))	('RCC', 'Disease', (127, 130))	('AKT', 'Gene', '207', (51, 54))
27886	30774762	Based on our findings, we propose that in ccRCC, which typically harbors inactivating SETD2 mutations, the PI3Kbeta-AKT axis is essential for growth and migration and that when targeted, is inhibitory to cells with SETD2 loss, therefore revealing tantalizing therapeutic applications.	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('RCC', 'Disease', (44, 47))	('AKT', 'Gene', (116, 119))	('mutations', 'Var', (92, 101))	('AKT', 'Gene', '207', (116, 119))	('inactivating', 'Reg', (73, 85))	('SETD2', 'Gene', (86, 91))
27893	30774762	1000 cells per well were plated in quadruplicate for each cell line (SETD2 proficient and KO 786-0 and SETD2 mutant A498 cells) and allowed to attach to bottom of plates overnight.	('SETD2', 'Gene', (103, 108))	('A498', 'CellLine', 'CVCL:1056', (116, 120))	('mutant', 'Var', (109, 115))
27896	30774762	3000 cells per well were plated in quadruplicate for each cell line (SETD2 proficient and KO 786-0 and SETD2 mutant A498 cells) and then allowed to grow for 7 days.	('SETD2', 'Gene', (103, 108))	('A498', 'CellLine', 'CVCL:1056', (116, 120))	('mutant', 'Var', (109, 115))
27900	30774762	3000 cells per well were plated in quadruplicate for each cell line (SETD2 proficient and KO 786-0 and SETD2 mutant A498 cells) and then allowed to grow for 7-10 days in the presence of 1 muM inhibitor.	('muM', 'Gene', (188, 191))	('mutant', 'Var', (109, 115))	('SETD2', 'Gene', (103, 108))	('A498', 'CellLine', 'CVCL:1056', (116, 120))	('muM', 'Gene', '56925', (188, 191))
27904	30774762	For each drug condition, cell mixture (400 mL of cell mixture containing 5000/cells and 500 nM of TGX221, AZD8186, BYL719, BKM120, Idelalisib, MK2206, or DMSO) was plated in triplicate wells of a 48-well plate containing solidified Matrigel.	('AZD8186', 'Var', (106, 113))	('Idelalisib', 'Chemical', 'MESH:C552946', (131, 141))	('MK2206', 'Chemical', 'MESH:C548887', (143, 149))	('BKM120', 'Chemical', 'MESH:C571178', (123, 129))	('drug condition', 'Phenotype', 'HP:0020172', (9, 23))	('AZD8186', 'Chemical', 'MESH:C000595972', (106, 113))	('DMSO', 'Chemical', 'MESH:D004121', (154, 158))	('TGX221', 'Chemical', 'MESH:C504718', (98, 104))	('TGX221', 'Gene', (98, 104))	('BKM120', 'Var', (123, 129))
27907	30774762	Cells were seeded in triplicate in 24-well plates such that, after 24 h of growth, cells would be ~70-80% confluent as a monolayer (25,000 cells/well for SETD2 proficient and KO 786-0 cells; 50,000 cells/well for SETD2 mutant A498).	('mutant A498', 'Var', (219, 230))	('SETD2', 'Gene', (213, 218))	('A498', 'CellLine', 'CVCL:1056', (226, 230))
27915	30774762	Antibodies and dilutions: phospho-AKT-S473 (Cell Signaling 9271, 1:500), AKT (Cell Signaling 9272, 1:1500), phospho-PRAS40 (Cell Signaling 2997, 1:500), phospho-S6-S235/236 (Cell Signaling 4858, 1:500), S6 (Cell Signaling 2217, 1:1500), beta-Actin (Cell Signaling 4970, 1:5000), SETD2 (Sigma HPA042451, 1:500), Histone H3K36me3 (Active Motif 61101, 1:500), Histone H3 (Abcam ab10799, 1:500), p110alpha (Cell Signaling 4249, 1:500), p110beta (Cell Signaling 3011, 1:500), p110delta (Cell Signaling 34050, 1:500).	('Histone H3K36me3', 'Protein', (311, 327))	('Abcam', 'Var', (369, 374))	('AKT', 'Gene', '207', (34, 37))	('Signaling', 'biological_process', 'GO:0023052', ('212', '221'))	('Signaling', 'biological_process', 'GO:0023052', ('447', '456'))	('AKT', 'Gene', '207', (73, 76))	('p110beta', 'Gene', (432, 440))	('Signaling', 'biological_process', 'GO:0023052', ('408', '417'))	('Signaling', 'biological_process', 'GO:0023052', ('129', '138'))	('PRAS40', 'Gene', (116, 122))	('p110beta', 'Gene', '5291', (432, 440))	('Histone H3', 'Protein', (357, 367))	('Signaling', 'biological_process', 'GO:0023052', ('254', '263'))	('Histone H3K36me', 'biological_process', 'GO:0010452', ('311', '326'))	('p110alpha', 'Gene', (392, 401))	('p110alpha', 'Gene', '5290', (392, 401))	('Signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('Signaling', 'biological_process', 'GO:0023052', ('179', '188'))	('p110delta', 'Gene', (471, 480))	('Signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('beta-Actin', 'Gene', (237, 247))	('AKT', 'Gene', (34, 37))	('beta-Actin', 'Gene', '728378', (237, 247))	('PRAS40', 'Gene', '84335', (116, 122))	('AKT', 'Gene', (73, 76))	('p110delta', 'Gene', '5293', (471, 480))	('Signaling', 'biological_process', 'GO:0023052', ('487', '496'))
28019	32164618	USP44 knockdown enhanced the proliferation and migration of 786-O cells and Caki-1 cells.	('USP44', 'Gene', (0, 5))	('proliferation', 'CPA', (29, 42))	('migration', 'CPA', (47, 56))	('knockdown', 'Var', (6, 15))	('USP', 'molecular_function', 'GO:0051748', ('0', '3'))	('enhanced', 'PosReg', (16, 24))	('Caki-1', 'CellLine', 'CVCL:0234', (76, 82))
28032	32164618	By inhibiting USP44 expression in mice, the proportion of aneuploid cells and chromosomal instability can be increased significantly, making them more prone to malignant transformation.	('chromosomal instability', 'Phenotype', 'HP:0040012', (78, 101))	('aneuploid', 'Var', (58, 67))	('prone', 'Reg', (151, 156))	('expression', 'MPA', (20, 30))	('mice', 'Species', '10090', (34, 38))	('inhibiting', 'NegReg', (3, 13))	('chromosomal instability', 'CPA', (78, 101))	('USP', 'molecular_function', 'GO:0051748', ('14', '17'))	('malignant transformation', 'CPA', (160, 184))	('USP44', 'Gene', (14, 19))	('more', 'PosReg', (146, 150))
28038	32164618	The JNK inhibitor JNK-IN-8 (HY-13319, MCE, USA) was dissolved in dimethyl sulfoxide (DMSO) and diluted into a 0.5-muM working solution with complete culture medium, and the same amount of DMSO was set as the control.	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (65, 83))	('JNK', 'molecular_function', 'GO:0004705', ('18', '21'))	('DMSO', 'Chemical', 'MESH:D004121', (188, 192))	('JNK', 'Gene', '5599', (18, 21))	('JNK', 'molecular_function', 'GO:0004705', ('4', '7'))	('DMSO', 'Chemical', 'MESH:D004121', (85, 89))	('HY-13319', 'Var', (28, 36))	('JNK', 'Gene', (4, 7))	('JNK', 'Gene', (18, 21))	('JNK-IN-8', 'Chemical', '-', (18, 26))	('JNK', 'Gene', '5599', (4, 7))
28043	32164618	Kaplan-Meier survival curves were used to show the differences in overall survival between patients with high expression of USP44 and cases with low expression of USP44.	('USP', 'molecular_function', 'GO:0051748', ('124', '127'))	('patients', 'Species', '9606', (91, 99))	('USP', 'molecular_function', 'GO:0051748', ('163', '166'))	('USP44', 'Gene', (124, 129))	('high expression', 'Var', (105, 120))
28075	32164618	To explore further the direct influence of USP44 on ccRCC proliferation, we labeled proliferating cells with BrdU in cells showing overexpression of USP44 and control cells.	('USP', 'molecular_function', 'GO:0051748', ('43', '46'))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('USP', 'molecular_function', 'GO:0051748', ('149', '152'))	('USP44', 'Var', (149, 154))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('ccRCC', 'Disease', (52, 57))	('overexpression', 'PosReg', (131, 145))	('ccRCC', 'Disease', 'MESH:D002292', (52, 57))
28077	32164618	2g, h), which demonstrated that USP44 can inhibit ccRCC proliferation.	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (50, 55))	('ccRCC', 'Disease', (50, 55))	('ccRCC', 'Disease', 'MESH:D002292', (50, 55))	('inhibit', 'NegReg', (42, 49))	('USP44', 'Var', (32, 37))	('USP', 'molecular_function', 'GO:0051748', ('32', '35'))
28082	32164618	Taken together, these results demonstrated that USP44 inhibited proliferation of 786-O cells and Caki-1 cells.	('USP', 'molecular_function', 'GO:0051748', ('48', '51'))	('inhibited', 'NegReg', (54, 63))	('Caki-1', 'CellLine', 'CVCL:0234', (97, 103))	('USP44', 'Var', (48, 53))	('Caki-1 cells', 'CPA', (97, 109))	('proliferation', 'CPA', (64, 77))
28085	32164618	Because the two types of tumor cells we used have different migration abilities, USP44 overexpression slowed down the migration ability of 786-O cells at the early stage (2 h, 3 h), and slowed down the migration ability of Caki-1 cells at the late stage (10 h, 24 h).	('migration ability', 'CPA', (118, 135))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('overexpression', 'Var', (87, 101))	('slowed down', 'NegReg', (102, 113))	('USP', 'molecular_function', 'GO:0051748', ('81', '84'))	('USP44', 'Gene', (81, 86))	('tumor', 'Disease', (25, 30))	('migration ability', 'CPA', (202, 219))	('Caki-1', 'CellLine', 'CVCL:0234', (223, 229))	('slowed down', 'NegReg', (186, 197))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
28091	32164618	Collectively, these results demonstrated that USP44 inhibited the migration of 786-O cells and Caki-1 cells.	('Caki-1', 'CellLine', 'CVCL:0234', (95, 101))	('migration of 786-O cells', 'CPA', (66, 90))	('USP44', 'Var', (46, 51))	('USP', 'molecular_function', 'GO:0051748', ('46', '49'))	('inhibited', 'NegReg', (52, 61))
28094	32164618	USP44 knockdown inhibited P21 expression and upregulated expression of cyclin D1 (Fig.	('expression', 'MPA', (57, 67))	('inhibited', 'NegReg', (16, 25))	('expression', 'MPA', (30, 40))	('P21', 'Gene', '644914', (26, 29))	('cyclin D1', 'Gene', '595', (71, 80))	('USP44', 'Gene', (0, 5))	('cyclin D1', 'Gene', (71, 80))	('upregulated', 'PosReg', (45, 56))	('cyclin', 'molecular_function', 'GO:0016538', ('71', '77'))	('P21', 'Gene', (26, 29))	('knockdown', 'Var', (6, 15))	('USP', 'molecular_function', 'GO:0051748', ('0', '3'))
28095	32164618	The cell-migration assay showed that USP44 deficiency promoted the migration of Caki-1 cells (Fig.	('promoted', 'PosReg', (54, 62))	('Caki-1', 'CellLine', 'CVCL:0234', (80, 86))	('USP44', 'Gene', (37, 42))	('cell-migration', 'biological_process', 'GO:0016477', ('4', '18'))	('migration', 'CPA', (67, 76))	('USP', 'molecular_function', 'GO:0051748', ('37', '40'))	('deficiency', 'Var', (43, 53))
28097	32164618	These results confirmed that USP44 knockdown enhanced the proliferation and migration of Caki-1 cells.	('knockdown', 'Var', (35, 44))	('USP44', 'Gene', (29, 34))	('proliferation', 'CPA', (58, 71))	('migration', 'CPA', (76, 85))	('enhanced', 'PosReg', (45, 53))	('Caki-1', 'CellLine', 'CVCL:0234', (89, 95))	('USP', 'molecular_function', 'GO:0051748', ('29', '32'))
28100	32164618	USP44 overexpression decreased the level of JNK, but not that of AKT, p38 or ERK, compared with control cells in both cell lines (Fig.	('p38', 'Gene', (70, 73))	('AKT', 'Gene', (65, 68))	('overexpression', 'Var', (6, 20))	('JNK', 'Gene', (44, 47))	('decreased', 'NegReg', (21, 30))	('USP44', 'Gene', (0, 5))	('ERK', 'Gene', '5594', (77, 80))	('JNK', 'molecular_function', 'GO:0004705', ('44', '47'))	('ERK', 'Gene', (77, 80))	('ERK', 'molecular_function', 'GO:0004707', ('77', '80'))	('JNK', 'Gene', '5599', (44, 47))	('AKT', 'Gene', '207', (65, 68))	('p38', 'Gene', '1432', (70, 73))	('USP', 'molecular_function', 'GO:0051748', ('0', '3'))
28101	32164618	JNK expression was promoted if USP44 expression was knocked down, but no effect was observed on expression of AKT, p38 or ERK (Fig.	('promoted', 'PosReg', (19, 27))	('JNK', 'Gene', '5599', (0, 3))	('JNK', 'Gene', (0, 3))	('p38', 'Gene', (115, 118))	('AKT', 'Gene', (110, 113))	('ERK', 'molecular_function', 'GO:0004707', ('122', '125'))	('JNK', 'molecular_function', 'GO:0004705', ('0', '3'))	('USP', 'molecular_function', 'GO:0051748', ('31', '34'))	('knocked down', 'Var', (52, 64))	('ERK', 'Gene', '5594', (122, 125))	('ERK', 'Gene', (122, 125))	('expression', 'MPA', (37, 47))	('USP44', 'Gene', (31, 36))	('p38', 'Gene', '1432', (115, 118))	('AKT', 'Gene', '207', (110, 113))
28104	32164618	Results showed that the ability of USP44 knockdown to promote the proliferation and migration of 786-O cells and Caki-1 cells was reduced significantly after treatment with a JNK inhibitor.	('promote', 'PosReg', (54, 61))	('USP', 'molecular_function', 'GO:0051748', ('35', '38'))	('JNK', 'Gene', '5599', (175, 178))	('proliferation', 'CPA', (66, 79))	('JNK', 'molecular_function', 'GO:0004705', ('175', '178'))	('migration', 'CPA', (84, 93))	('JNK', 'Gene', (175, 178))	('Caki-1', 'CellLine', 'CVCL:0234', (113, 119))	('reduced', 'NegReg', (130, 137))	('knockdown', 'Var', (41, 50))	('USP44', 'Gene', (35, 40))
28112	32164618	Patients with high USP44 expression showed good survival benefits.	('USP44', 'Gene', (19, 24))	('benefits', 'PosReg', (57, 65))	('survival', 'CPA', (48, 56))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('USP', 'molecular_function', 'GO:0051748', ('19', '22'))
28114	32164618	Some studies have suggested that USP44 overexpression promotes tumor development, whereas other studies have indicated that USP44 inhibits proliferation of tumor cells.	('USP', 'molecular_function', 'GO:0051748', ('124', '127'))	('tumor', 'Disease', (63, 68))	('USP44', 'Gene', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('USP', 'molecular_function', 'GO:0051748', ('33', '36'))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('USP44', 'Var', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('overexpression promotes', 'PosReg', (39, 62))	('inhibits', 'NegReg', (130, 138))
28124	32164618	Based on the results from Caki-1 cells with USP44 silencing by shRNAs, we demonstrated that USP44 inhibits ccRCC progression in reverse.	('silencing', 'NegReg', (50, 59))	('Caki-1', 'CellLine', 'CVCL:0234', (26, 32))	('USP44', 'Gene', (44, 49))	('USP', 'molecular_function', 'GO:0051748', ('44', '47'))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('ccRCC', 'Disease', (107, 112))	('inhibits', 'NegReg', (98, 106))	('USP44', 'Var', (92, 97))	('USP', 'molecular_function', 'GO:0051748', ('92', '95'))	('ccRCC', 'Disease', 'MESH:D002292', (107, 112))
28131	32164618	If cells are stimulated by extracellular signals, PI3K activates AKT, and the latter further activates its downstream factor mTOR.	('activates', 'PosReg', (93, 102))	('mTOR', 'Gene', '2475', (125, 129))	('activates', 'PosReg', (55, 64))	('AKT', 'Gene', (65, 68))	('mTOR', 'Gene', (125, 129))	('PI3K', 'molecular_function', 'GO:0016303', ('50', '54'))	('extracellular', 'cellular_component', 'GO:0005576', ('27', '40'))	('PI3K', 'Var', (50, 54))	('AKT', 'Gene', '207', (65, 68))
28136	32164618	We found that USP44 inhibited the JNK pathway but not the AKT, ERK or p38 pathways.	('p38', 'Gene', '1432', (70, 73))	('JNK', 'molecular_function', 'GO:0004705', ('34', '37'))	('JNK', 'Gene', '5599', (34, 37))	('USP44', 'Var', (14, 19))	('p38', 'Gene', (70, 73))	('ERK', 'molecular_function', 'GO:0004707', ('63', '66'))	('USP', 'molecular_function', 'GO:0051748', ('14', '17'))	('inhibited', 'NegReg', (20, 29))	('AKT', 'Gene', '207', (58, 61))	('JNK', 'Gene', (34, 37))	('ERK', 'Gene', '5594', (63, 66))	('ERK', 'Gene', (63, 66))	('AKT', 'Gene', (58, 61))
28137	32164618	Rescue experiments showed that silencing USP44 expression to promote the proliferation and migration of tumor cells could be blocked by a JNK inhibitor.	('silencing', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('USP', 'molecular_function', 'GO:0051748', ('41', '44'))	('JNK', 'Gene', '5599', (138, 141))	('proliferation', 'CPA', (73, 86))	('promote', 'PosReg', (61, 68))	('tumor', 'Disease', (104, 109))	('USP44', 'Gene', (41, 46))	('JNK', 'molecular_function', 'GO:0004705', ('138', '141'))	('JNK', 'Gene', (138, 141))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
28138	32164618	JNK activation in USP44 knockdown could have been a result of stress-response activation due to chromosome mis-segregation, as reported by Kumar and colleagues.	('JNK', 'Gene', '5599', (0, 3))	('USP', 'molecular_function', 'GO:0051748', ('18', '21'))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('USP44', 'Gene', (18, 23))	('JNK', 'molecular_function', 'GO:0004705', ('0', '3'))	('JNK', 'Gene', (0, 3))	('knockdown', 'Var', (24, 33))	('activation', 'PosReg', (4, 14))
28141	32164618	USP44 can induce the genesis of prostate cancer cells partly by stabilizing EZH2.	('prostate cancer', 'Disease', (32, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('USP44', 'Var', (0, 5))	('induce', 'PosReg', (10, 16))	('EZH2', 'Gene', '2146', (76, 80))	('genesis', 'CPA', (21, 28))	('prostate cancer', 'Disease', 'MESH:D011471', (32, 47))	('prostate cancer', 'Phenotype', 'HP:0012125', (32, 47))	('EZH2', 'Gene', (76, 80))	('USP', 'molecular_function', 'GO:0051748', ('0', '3'))
28248	33236143	Compared with normal tissue, CapG expression was significantly increased in ccRCC tissue, and high CapG expression was associated with advanced tumor stage, histological grade, lymph node metastasis, and poor overall survival.	('tumor', 'Disease', (144, 149))	('increased', 'PosReg', (63, 72))	('expression', 'MPA', (34, 44))	('CapG', 'Gene', '822', (99, 103))	('CapG', 'Gene', (99, 103))	('lymph node metastasis', 'CPA', (177, 198))	('CapG', 'Gene', '822', (29, 33))	('RCC', 'Disease', (78, 81))	('expression', 'MPA', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('CapG', 'Gene', (29, 33))	('high', 'Var', (94, 98))	('overall survival', 'CPA', (209, 225))	('associated', 'Reg', (119, 129))
28250	33236143	Lentivirus-mediated CapG knockdown significantly inhibited 786-O cell proliferation, migration, and invasion, induced cell cycle arrest at the G2/M phase, and increased apoptosis in vitro.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('118', '135'))	('arrest', 'Disease', (129, 135))	('apoptosis', 'CPA', (169, 178))	('apoptosis', 'biological_process', 'GO:0097194', ('169', '178'))	('CapG', 'Gene', '822', (20, 24))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (118, 135))	('apoptosis', 'biological_process', 'GO:0006915', ('169', '178'))	('CapG', 'Gene', (20, 24))	('increased', 'PosReg', (159, 168))	('arrest', 'Disease', 'MESH:D006323', (129, 135))	('cell proliferation', 'biological_process', 'GO:0008283', ('65', '83'))	('invasion', 'CPA', (100, 108))	('migration', 'CPA', (85, 94))	('M phase', 'biological_process', 'GO:0000279', ('146', '153'))	('induced', 'Reg', (110, 117))	('inhibited', 'NegReg', (49, 58))	('knockdown', 'Var', (25, 34))
28251	33236143	Microarray analysis indicated that RAC, CDC42 and ERK/MAPK signaling were disrupted by CapG knockdown in 786-O cells.	('MAPK', 'molecular_function', 'GO:0004707', ('54', '58'))	('disrupted', 'NegReg', (74, 83))	('CDC42', 'Gene', (40, 45))	('knockdown', 'Var', (92, 101))	('ERK', 'Gene', '5594', (50, 53))	('ERK', 'Gene', (50, 53))	('MAPK signaling', 'biological_process', 'GO:0000165', ('54', '68'))	('CapG', 'Gene', '822', (87, 91))	('RAC', 'MPA', (35, 38))	('CapG', 'Gene', (87, 91))	('ERK', 'molecular_function', 'GO:0004707', ('50', '53'))	('CDC42', 'Gene', '998', (40, 45))
28304	33236143	P4170; Sigma-Aldrich; Merck KGaA) buffer containing 40X PI stock solution (2 mg/ml), 100X RNase stock solution (10 mg/ml), and 1X PBS at a ratio of 25:10:1,000.	('P4170', 'Var', (0, 5))	('PBS', 'Chemical', 'MESH:D007854', (130, 133))	('Aldrich', 'Disease', (13, 20))	('Aldrich', 'Disease', 'MESH:D014923', (13, 20))
28333	33236143	Patients with high CapG expression had a 2.12-time higher risk than those with low expression (HR, 2.121; 95% CI, 1.288-3.493; P=0.003) (Table II).	('high', 'Var', (14, 18))	('CapG', 'Gene', '822', (19, 23))	('CapG', 'Gene', (19, 23))	('Patients', 'Species', '9606', (0, 8))
28335	33236143	The effect of CapG knockdown on 786-O cell proliferation was determined using a CCK-8 cell proliferation assay.	('knockdown', 'Var', (19, 28))	('CapG', 'Gene', (14, 18))	('CCK-8', 'Chemical', '-', (80, 85))	('CapG', 'Gene', '822', (14, 18))	('cell proliferation', 'biological_process', 'GO:0008283', ('86', '104'))	('cell proliferation', 'biological_process', 'GO:0008283', ('38', '56'))
28337	33236143	Thus, CapG knockdown suppresses the proliferation of human ccRCC cells in vitro.	('CapG', 'Gene', '822', (6, 10))	('CapG', 'Gene', (6, 10))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('suppresses', 'NegReg', (21, 31))	('RCC', 'Disease', (61, 64))	('human', 'Species', '9606', (53, 58))	('knockdown', 'Var', (11, 20))
28340	33236143	These findings indicate that CapG silencing induces cell cycle arrest at the G2/M phase and that CapG affects cell cycle distribution.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (52, 69))	('cell cycle distribution', 'CPA', (110, 133))	('arrest', 'Disease', 'MESH:D006323', (63, 69))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('52', '69'))	('cell cycle', 'biological_process', 'GO:0007049', ('110', '120'))	('affects', 'Reg', (102, 109))	('arrest', 'Disease', (63, 69))	('CapG', 'Gene', '822', (97, 101))	('CapG', 'Gene', (97, 101))	('silencing', 'Var', (34, 43))	('M phase', 'biological_process', 'GO:0000279', ('80', '87'))	('induces', 'Reg', (44, 51))	('CapG', 'Gene', '822', (29, 33))	('CapG', 'Gene', (29, 33))
28345	33236143	4A), indicating the migration ability of 786-O cells was significantly inhibited by CapG silencing.	('CapG', 'Gene', (84, 88))	('migration ability of 786-O cells', 'CPA', (20, 52))	('inhibited', 'NegReg', (71, 80))	('silencing', 'Var', (89, 98))	('CapG', 'Gene', '822', (84, 88))
28361	33236143	Consistent with our findings, CapG is upregulated in patients with stage-III serous ovarian adenocarcinoma, and high expression of CapG is correlated with shorter survival.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('patients', 'Species', '9606', (53, 61))	('CapG', 'Gene', '822', (30, 34))	('high expression', 'Var', (112, 127))	('stage-III serous ovarian adenocarcinoma', 'Disease', 'MESH:D000230', (67, 106))	('CapG', 'Gene', (30, 34))	('upregulated', 'PosReg', (38, 49))	('shorter', 'NegReg', (155, 162))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (84, 106))	('stage-III serous ovarian adenocarcinoma', 'Disease', (67, 106))	('CapG', 'Gene', (131, 135))	('CapG', 'Gene', '822', (131, 135))
28362	33236143	Furthermore, high CapG expression has been found to be a unfavorable prognostic factor in prostate cancer and glioma.	('glioma', 'Disease', (110, 116))	('prostate cancer', 'Disease', 'MESH:D011471', (90, 105))	('high', 'Var', (13, 17))	('prostate cancer', 'Phenotype', 'HP:0012125', (90, 105))	('CapG', 'Gene', (18, 22))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('CapG', 'Gene', '822', (18, 22))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('prostate cancer', 'Disease', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('expression', 'MPA', (23, 33))
28364	33236143	In the present study, CapG knockdown significantly inhibited ccRCC cell proliferation in vitro and induced G2/M arrest.	('RCC', 'Disease', (63, 66))	('knockdown', 'Var', (27, 36))	('CapG', 'Gene', '822', (22, 26))	('M arrest', 'Disease', (110, 118))	('CapG', 'Gene', (22, 26))	('induced', 'Reg', (99, 106))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('inhibited', 'NegReg', (51, 60))	('M arrest', 'Disease', 'MESH:D006323', (110, 118))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
28366	33236143	It was also observed that CapG knockdown attenuated the migration and invasion of ccRCC cells.	('attenuated', 'NegReg', (41, 51))	('CapG', 'Gene', '822', (26, 30))	('CapG', 'Gene', (26, 30))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('knockdown', 'Var', (31, 40))
28367	33236143	Consistent with the present study, CapG knockdown is known to inhibit the migration of invasive breast cancer cells, the invasion of gastric cancer cells, and the migration and invasion of glioma cells.	('glioma', 'Disease', (189, 195))	('CapG', 'Gene', '822', (35, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (133, 147))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('invasive breast cancer', 'Disease', (87, 109))	('invasion', 'CPA', (177, 185))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('knockdown', 'Var', (40, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (133, 147))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('migration', 'CPA', (74, 83))	('glioma', 'Disease', 'MESH:D005910', (189, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('gastric cancer', 'Disease', (133, 147))	('CapG', 'Gene', (35, 39))	('invasive breast cancer', 'Disease', 'MESH:D001943', (87, 109))	('invasion', 'CPA', (121, 129))	('inhibit', 'NegReg', (62, 69))
28385	33236143	CapG silencing also inhibits renal carcinoma cell proliferation, migration, and invasion.	('invasion', 'CPA', (80, 88))	('migration', 'CPA', (65, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('renal carcinoma', 'Disease', (29, 44))	('inhibits', 'NegReg', (20, 28))	('CapG', 'Gene', '822', (0, 4))	('silencing', 'Var', (5, 14))	('CapG', 'Gene', (0, 4))	('renal carcinoma', 'Phenotype', 'HP:0005584', (29, 44))	('cell proliferation', 'biological_process', 'GO:0008283', ('45', '63'))	('renal carcinoma', 'Disease', 'MESH:C538614', (29, 44))
28396	32047543	In ectopic-implantation nude mice model, QKI depletion significantly increased tumor sizes and initiation rates.	('increased', 'PosReg', (69, 78))	('tumor', 'Disease', (79, 84))	('QKI', 'Gene', (41, 44))	('initiation rates', 'CPA', (95, 111))	('nude mice', 'Species', '10090', (24, 33))	('depletion', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
28412	32047543	Although it has recently been proven that QKI-5 inhibits ccRCC proliferation through the RAS-MAPK signal pathway, we have differentiated the mechanism by which QKI inhibits ccRCC from its roles in metabolism and angiogenesis.	('ccRCC', 'Phenotype', 'HP:0006770', (173, 178))	('ccRCC', 'Disease', (173, 178))	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('inhibits', 'NegReg', (164, 172))	('ccRCC', 'Disease', 'MESH:D002292', (173, 178))	('inhibits', 'NegReg', (48, 56))	('ccRCC', 'Disease', (57, 62))	('ccRCC', 'Disease', 'MESH:D002292', (57, 62))	('RAS-MAPK signal pathway', 'Pathway', (89, 112))	('metabolism', 'biological_process', 'GO:0008152', ('197', '207'))	('QKI-5', 'Var', (42, 47))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('QKI', 'Var', (160, 163))	('angiogenesis', 'biological_process', 'GO:0001525', ('212', '224'))	('MAPK', 'molecular_function', 'GO:0004707', ('93', '97'))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
28414	32047543	We tested the relationship between renal cell carcinoma and expression of QKI in the following aspects: (1) The expression of QKI in renal cell carcinoma and adjacent normal tissue; (2) The correlation of QKI with the degree of differentiation, degree of invasion, TNM grading, age, tumor size and survival rates of patients with renal cell carcinoma; and (3) How the expression of QKI influences the biological behavior of the cells and tumors both in vitro and in vivo.	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('tumors', 'Disease', 'MESH:D009369', (438, 444))	('patients', 'Species', '9606', (316, 324))	('renal cell carcinoma', 'Disease', (35, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (341, 350))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (35, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('TNM', 'Gene', '10178', (265, 268))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('tumor', 'Disease', (438, 443))	('TNM', 'Gene', (265, 268))	('QKI', 'Gene', (382, 385))	('expression', 'Var', (368, 378))	('tumor', 'Disease', 'MESH:D009369', (438, 443))	('tested', 'Reg', (3, 9))	('biological behavior of the cells', 'CPA', (401, 433))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (133, 153))	('tumors', 'Phenotype', 'HP:0002664', (438, 444))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (330, 350))	('influences', 'Reg', (386, 396))	('renal cell carcinoma', 'Disease', (133, 153))	('tumor', 'Phenotype', 'HP:0002664', (438, 443))	('tumor', 'Disease', (283, 288))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (133, 153))	('renal cell carcinoma', 'Disease', (330, 350))	('tumors', 'Disease', (438, 444))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (330, 350))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (35, 55))
28423	32047543	For immunohistochemical processing, the endogenous peroxidases were blocked using 0.75% H2O2 in phosphate-buffered saline (PBS) for 50 min, followed by incubation in 5 % bovine serum albumin blocking buffer.	('endogenous peroxidases', 'Enzyme', (40, 62))	('phosphate', 'Chemical', 'MESH:D010710', (96, 105))	('H2O2', 'Chemical', 'MESH:D014867', (88, 92))	('H2O2', 'Var', (88, 92))
28466	32047543	In order to investigate the effects of QKI on the biological behavior of cancer cells, we overexpressed and knocked down QKI in the 786-0 and caki-1 cell lines, and verified the efficiency of the expression manipulation in the 786-0 cell line (Fig.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('QKI', 'Gene', (121, 124))	('knocked', 'Var', (108, 115))
28473	32047543	By contrast, in the 786-0 and caki-1 cells with QKI knockdown, the HIF-1alpha expression level was upregulated, and similar to the tendency mentioned above, the HIF-1alpha expression level was even higher under hypoxic than under normoxic conditions (Fig.	('HIF-1alpha', 'Gene', (161, 171))	('HIF-1alpha', 'Gene', '3091', (67, 77))	('upregulated', 'PosReg', (99, 110))	('HIF-1alpha', 'Gene', (67, 77))	('HIF-1alpha', 'Gene', '3091', (161, 171))	('expression level', 'MPA', (78, 94))	('QKI', 'Gene', (48, 51))	('knockdown', 'Var', (52, 61))	('higher', 'PosReg', (198, 204))
28482	32047543	We conducted HE-staining and immunofluorescence staining for CD31 in the tumor mass, which showed a significant increase of vascularization in the QKI knockdown group (Fig.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('vascularization', 'CPA', (124, 139))	('CD31', 'Gene', (61, 65))	('tumor', 'Disease', (73, 78))	('increase', 'PosReg', (112, 120))	('CD31', 'Gene', '5175', (61, 65))	('knockdown', 'Var', (151, 160))
28489	32047543	As shown in Figure 6B and 6C, the tumors that grew in the LV-Scramble group were smaller than those in the LV-QKI group.	('smaller', 'NegReg', (81, 88))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('LV-Scramble', 'Var', (58, 69))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
28490	32047543	In conclusion, LV-QKI 786-0 cells were more tumorigenic than the LV-Scramble 786-0 cells.	('more', 'PosReg', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('LV-QKI', 'Var', (15, 21))
28495	32047543	In the group showing non-decreasing QKI expression, the median survival time of clear cell renal cell carcinoma patients was undefined.	('clear cell renal cell carcinoma', 'Disease', (80, 111))	('patients', 'Species', '9606', (112, 120))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (91, 111))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (80, 111))	('QKI', 'Var', (36, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (80, 111))
28516	32047543	In vivo, the knockdown of QKI promoted tumor growth and upregulated the expression of HIF-1alpha.	('QKI', 'Gene', (26, 29))	('HIF-1alpha', 'Gene', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('promoted', 'PosReg', (30, 38))	('expression', 'MPA', (72, 82))	('HIF-1alpha', 'Gene', '3091', (86, 96))	('tumor', 'Disease', (39, 44))	('knockdown', 'Var', (13, 22))	('upregulated', 'PosReg', (56, 67))
28520	32047543	Conversely, knockdown of QKI can promote the expression of HIF-1alpha and its downstream targets in these cells.	('promote', 'PosReg', (33, 40))	('HIF-1alpha', 'Gene', (59, 69))	('knockdown', 'Var', (12, 21))	('QKI', 'Gene', (25, 28))	('expression', 'MPA', (45, 55))	('HIF-1alpha', 'Gene', '3091', (59, 69))
28523	32047543	Clear cell renal cell carcinoma is associated with loss-of-function mutations in the VHL(von Hippel- Lindau) tumor suppressor gene.	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('tumor suppressor', 'biological_process', 'GO:0051726', ('109', '125'))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (0, 31))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('109', '125'))	('VHL', 'Gene', (85, 88))	('loss-of-function', 'NegReg', (51, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('VHL', 'Gene', '7428', (85, 88))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('mutations', 'Var', (68, 77))	('von Hippel- Lindau) tumor suppressor', 'Gene', '7428', (89, 125))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))
28526	32047543	Conversely, QKI knockdown can promote VEGF expression in these cells.	('promote', 'PosReg', (30, 37))	('VEGF', 'Gene', '7422', (38, 42))	('knockdown', 'Var', (16, 25))	('VEGF', 'Gene', (38, 42))	('QKI knockdown', 'Var', (12, 25))
28651	31123336	The patients with high TB had significantly shorter PFS and OS, compared to those with low TB - 4.36 vs. 8.19 months of PFS and 9.6 vs. 23.5 months of OS respectively.	('TB', 'Chemical', 'MESH:D013725', (91, 93))	('OS', 'Chemical', '-', (151, 153))	('TB', 'Chemical', 'MESH:D013725', (23, 25))	('patients', 'Species', '9606', (4, 12))	('high TB', 'Var', (18, 25))	('shorter', 'NegReg', (44, 51))	('PFS', 'CPA', (52, 55))	('OS', 'Chemical', '-', (60, 62))
28660	31123336	This correlation was supplemented with a complementary hypothesis that greater general overall tumor control with TKIs enables metastases development in organ sites like bone or brain, that would otherwise not have been observed due to shorter survival without treatment.	('metastases development', 'Disease', 'MESH:D009362', (127, 149))	('metastases development', 'Disease', (127, 149))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('TKIs', 'Var', (114, 118))	('tumor', 'Disease', (95, 100))
28690	31123336	Understanding the physiological link between the deregulation of specific genes and homing of certain metastases may impact treatment of RCC patients in the future.	('deregulation', 'Var', (49, 61))	('metastases', 'Disease', (102, 112))	('impact', 'Reg', (117, 123))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))	('patients', 'Species', '9606', (141, 149))	('metastases', 'Disease', 'MESH:D009362', (102, 112))
28694	28785398	It will also explain why, unlike 1 and 2, mutations in isoform 3 in tumor are not likely to be driver ones.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('mutations', 'Var', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
28695	28785398	A model explaining two important features of isocitrate dehydrogenases 1 and 2 mutations, their dominant negative effect and their mutual exclusivity, will be provided.	('isocitrate', 'Chemical', 'MESH:C034219', (45, 55))	('negative', 'NegReg', (105, 113))	('mutations', 'Var', (79, 88))
28696	28785398	The importance of targeting these mutations and the possibility of augmenting such therapy by targeting other cancer-related pathways will also be discussed.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('mutations', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))
28702	28785398	The carcinogenic effect of neomorphic IDH1 and 2 alleles can be attributed to the increased intracellular production of this oncometabolite and its detrimental effect on several key enzymes important in cellular growth and differentiation.	('intracellular', 'cellular_component', 'GO:0005622', ('92', '105'))	('IDH1 and 2', 'Gene', '3417;3418', (38, 48))	('alleles', 'Var', (49, 56))	('carcinogenic', 'Disease', 'MESH:D063646', (4, 16))	('cellular growth', 'biological_process', 'GO:0016049', ('203', '218'))	('carcinogenic', 'Disease', (4, 16))	('increased', 'PosReg', (82, 91))	('intracellular production', 'MPA', (92, 116))	('detrimental', 'NegReg', (148, 159))
28703	28785398	This article will discuss why, unlike IDH1 and 2, mutations in IDH3 in tumor are not likely to be driver ones.	('IDH1 and 2', 'Gene', '3417;3418', (38, 48))	('mutations', 'Var', (50, 59))	('IDH3', 'Chemical', '-', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('IDH3', 'Gene', (63, 67))
28706	28785398	It will also explain why it is likely that, in certain tumors, mutations producing these neomorphic alleles are early events, emphasizing the importance of targeting these driver mutations.	('mutations', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))
28752	28785398	In other words, cancerous cell that has neomorphic IDH2, would still need the wild type IDH1 isoform to catalyze the forward oxidative decarboxylation reaction to produce NADPH.	('NADPH', 'Gene', '1666', (171, 176))	('IDH1', 'Gene', (88, 92))	('cancerous', 'Disease', (16, 25))	('IDH1', 'Gene', '3417', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancerous', 'Disease', 'MESH:D009369', (16, 25))	('neomorphic IDH2', 'Var', (40, 55))	('NADPH', 'Gene', (171, 176))
28755	28785398	As will be elaborated on in a later section of this article; in certain tumors, monoallelic activating mutations in IDH1 and/or 2 (i.e.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (72, 78))	('IDH1', 'Gene', (116, 120))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('monoallelic', 'Var', (80, 91))	('IDH1', 'Gene', '3417', (116, 120))	('activating', 'PosReg', (92, 102))
28756	28785398	On the other hand; although several mutations in each of the three IDH3 subunits have been recovered from different types of tumor samples, none of these mutations were found to be as recurrent as IDH1 and 2 activating mutations.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('mutations', 'Var', (36, 45))	('tumor', 'Disease', (125, 130))	('IDH3', 'Gene', (67, 71))	('IDH1 and 2', 'Gene', '3417;3418', (197, 207))	('IDH3', 'Chemical', '-', (67, 71))
28757	28785398	Moreover, neither the significance of these IDH3 mutations nor their carcinogenic roles have been proven.	('mutations', 'Var', (49, 58))	('IDH3', 'Gene', (44, 48))	('carcinogenic', 'Disease', 'MESH:D063646', (69, 81))	('carcinogenic', 'Disease', (69, 81))	('IDH3', 'Chemical', '-', (44, 48))
28758	28785398	The reason behind that has been speculated to be due the fact that the occurrence of monoallelic IDH1 and IDH2 mutations is more frequent by chance than the biallelic mutations expected for IDH3.	('mutations', 'Var', (111, 120))	('IDH1', 'Gene', (97, 101))	('IDH1', 'Gene', '3417', (97, 101))	('IDH2', 'Gene', (106, 110))	('IDH3', 'Chemical', '-', (190, 194))
28759	28785398	In my opinion; IDH3 mutations, whether mono- or biallelic, are unlikely to be carcinogenic.	('carcinogenic', 'Disease', 'MESH:D063646', (78, 90))	('carcinogenic', 'Disease', (78, 90))	('IDH3', 'Gene', (15, 19))	('IDH3', 'Chemical', '-', (15, 19))	('mutations', 'Var', (20, 29))
28761	28785398	Like IDH1 and 2 mutations (including activating ones as will be explained later), a biallelic mutation in any of the IDH3 subunits is expected to inhibit this reaction (monoallelic inactivating mutation will be harmless and will not inactivate this enzyme due to the enough residual activity contributed by the other normal allele).	('inhibit', 'NegReg', (146, 153))	('IDH1 and 2', 'Gene', '3417;3418', (5, 15))	('biallelic mutation', 'Var', (84, 102))	('IDH3', 'Gene', (117, 121))	('IDH3', 'Chemical', '-', (117, 121))
28763	28785398	Therefore, inactivating IDH3 enzyme by biallelic mutations will inhibit the whole TCA cycle and mitochondrial ATP production, since there would be no mitochondrial production of reduced electron carrier to undergo oxidative phosphorylation by ETC to produce ATP.	('inactivating', 'Var', (11, 23))	('TCA cycle', 'biological_process', 'GO:0006099', ('82', '91'))	('mitochondrial ATP production', 'MPA', (96, 124))	('TCA', 'Enzyme', (82, 85))	('electron carrier', 'molecular_function', 'GO:0009055', ('186', '202'))	('IDH3', 'Chemical', '-', (24, 28))	('biallelic mutations', 'Var', (39, 58))	('ATP', 'Chemical', 'MESH:D000255', (258, 261))	('inhibit', 'NegReg', (64, 71))	('ATP', 'Chemical', 'MESH:D000255', (110, 113))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('214', '239'))	('IDH3', 'Gene', (24, 28))
28764	28785398	Taken together; IDH3 biallelic mutations will have detrimental effect on cellular growth causing the cell to apoptose rather than to overgrow and become cancerous, while monoallelic ones will be tolerated by the cell and will have no carcinogenic role.	('cancerous', 'Disease', (153, 162))	('biallelic mutations', 'Var', (21, 40))	('carcinogenic', 'Disease', 'MESH:D063646', (234, 246))	('IDH3', 'Gene', (16, 20))	('carcinogenic', 'Disease', (234, 246))	('apoptose', 'CPA', (109, 117))	('cancerous', 'Disease', 'MESH:D009369', (153, 162))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('detrimental', 'NegReg', (51, 62))	('cellular growth', 'CPA', (73, 88))	('IDH3', 'Chemical', '-', (16, 20))	('cellular growth', 'biological_process', 'GO:0016049', ('73', '88'))
28766	28785398	Interestingly; unlike IDH3, inactivation of other TCA enzymes like succinate dehydrogenase (SDH) and fumarate hydratase (FH) have been reported in cancer, including paraganglioma and renal cell carcinomas.	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (183, 204))	('SDH', 'Gene', (92, 95))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('paraganglioma and renal cell carcinomas', 'Disease', 'MESH:C538614', (165, 204))	('IDH3', 'Chemical', '-', (22, 26))	('fumarate hydratase', 'Gene', (101, 119))	('paraganglioma', 'Phenotype', 'HP:0002668', (165, 178))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('inactivation', 'Var', (28, 40))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('succinate dehydrogenase', 'Gene', '6390', (67, 90))	('FH', 'Gene', '2271', (121, 123))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (183, 203))	('reported', 'Reg', (135, 143))	('SDH', 'Gene', '6390', (92, 95))	('fumarate hydratase', 'Gene', '2271', (101, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('carcinomas', 'Phenotype', 'HP:0030731', (194, 204))	('cancer', 'Disease', (147, 153))	('succinate dehydrogenase', 'Gene', (67, 90))
28769	28785398	Mutations in subunits B, C, and D have been associated with tumor more frequently compared to those in subunit A.	('associated', 'Reg', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (60, 65))
28773	28785398	One of them is the fact that succinate level will increase due to inactivating mutation in any of the four SDH subunits; however, unlike the other SDH subunits (i.e.	('SDH', 'Gene', '6390', (107, 110))	('SDH', 'Gene', (147, 150))	('succinate', 'Chemical', 'MESH:D019802', (29, 38))	('succinate level', 'MPA', (29, 44))	('increase', 'PosReg', (50, 58))	('inactivating mutation', 'Var', (66, 87))	('SDH', 'Gene', (107, 110))	('SDH', 'Gene', '6390', (147, 150))
28774	28785398	B, C, and D), inactivating mutations of subunit A has only been reported in a few tumor cases.	('tumor', 'Disease', (82, 87))	('inactivating mutations', 'Var', (14, 36))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))
28777	28785398	Another hypothesized mechanism linking SDH deficiency to tumor, is the increased ROS production from inactivating mutations in subunits B, C, and D, but not A.	('ROS production', 'MPA', (81, 95))	('inactivating mutations', 'Var', (101, 123))	('increased ROS production', 'Phenotype', 'HP:0025464', (71, 95))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('SDH deficiency to tumor', 'Disease', (39, 62))	('increased', 'PosReg', (71, 80))	('SDH deficiency to tumor', 'Disease', 'MESH:D009369', (39, 62))	('ROS', 'Chemical', 'MESH:D017382', (81, 84))
28782	28785398	It is thought that if subunit A is normal, and there are defects in the subunit B, C or D, then the oxidation of succinate proceeds but the shuttling of electrons within the whole SDH complex to ubiquinone is impaired.	('ubiquinone', 'Chemical', 'MESH:D014451', (195, 205))	('SDH', 'Gene', '6390', (180, 183))	('shuttling of electrons', 'MPA', (140, 162))	('oxidation of succinate', 'MPA', (100, 122))	('impaired', 'NegReg', (209, 217))	('succinate', 'Chemical', 'MESH:D019802', (113, 122))	('defects', 'Var', (57, 64))	('SDH', 'Gene', (180, 183))
28784	28785398	ROS are thought to elevate intracellular Hif1alpha by inhibiting the metalloenzyme, PHD, probably by oxidizing its Fe2+ that is critical to its function.	('oxidizing', 'MPA', (101, 110))	('ROS', 'Var', (0, 3))	('Fe2+', 'Chemical', 'MESH:C038178', (115, 119))	('PHD', 'Disease', (84, 87))	('Hif1alpha', 'Gene', (41, 50))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('PHD', 'Disease', 'MESH:D011547', (84, 87))	('PHD', 'molecular_function', 'GO:0050175', ('84', '87'))	('intracellular', 'cellular_component', 'GO:0005622', ('27', '40'))	('Fe2+', 'MPA', (115, 119))	('Hif1alpha', 'Gene', '3091', (41, 50))	('elevate', 'PosReg', (19, 26))	('inhibiting', 'NegReg', (54, 64))
28786	28785398	If the later hypothesis were true, only missense mutations producing malfunctioning proteins will be linked to tumor, which is not the case.	('missense mutations', 'Var', (40, 58))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('linked', 'Reg', (101, 107))
28787	28785398	However, IDH3 inactivating mutations on the other hand are not expected to produce ROS and therefore might not have carcinogenic effect.	('inactivating mutations', 'Var', (14, 36))	('ROS', 'MPA', (83, 86))	('carcinogenic', 'Disease', 'MESH:D063646', (116, 128))	('carcinogenic', 'Disease', (116, 128))	('IDH3', 'Gene', (9, 13))	('ROS', 'Chemical', 'MESH:D017382', (83, 86))	('IDH3', 'Chemical', '-', (9, 13))
28790	28785398	Just like SDH subunit A, inactivating mutations in IDH3 subunit alpha might not generate ROS, since no electrons will be captured from its substrate, ICT.	('ROS', 'Chemical', 'MESH:D017382', (89, 92))	('SDH', 'Gene', '6390', (10, 13))	('inactivating mutations', 'Var', (25, 47))	('IDH3', 'Chemical', '-', (51, 55))	('SDH', 'Gene', (10, 13))	('ICT', 'Chemical', 'MESH:C034219', (150, 153))	('IDH3', 'Gene', (51, 55))
28791	28785398	Unlike SDH, the other IDH3 subunits are regulatory ones and do not contain electron carriers through which the NADH electrons would pass and therefore their mutations are not likely to trap those electrons where they would potentially participate in ROS formation.	('SDH', 'Gene', (7, 10))	('NADH', 'Gene', (111, 115))	('ROS formation', 'biological_process', 'GO:1903409', ('250', '263'))	('mutations', 'Var', (157, 166))	('NADH', 'Chemical', 'MESH:D009243', (111, 115))	('ROS', 'Chemical', 'MESH:D017382', (250, 253))	('SDH', 'Gene', '6390', (7, 10))	('IDH3', 'Chemical', '-', (22, 26))
28792	28785398	The other TCA enzyme where inactivating mutations of which are linked to cancer is FH.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('linked', 'Reg', (63, 69))	('inactivating mutations', 'Var', (27, 49))	('FH', 'Gene', '2271', (83, 85))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))
28793	28785398	Individuals with germline inactivating mutations in the gene coding for this enzyme, FH, are predisposed to hereditary leiomyomatosis and renal clear cell cancer (HLRCC).	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('germline inactivating mutations', 'Var', (17, 48))	('predisposed', 'Reg', (93, 104))	('clear cell cancer', 'Phenotype', 'HP:0006770', (144, 161))	('FH', 'Gene', '2271', (85, 87))	('hereditary leiomyomatosis and renal clear cell cancer', 'Disease', 'MESH:C535516', (108, 161))
28802	28785398	From what has been mentioned so far, it is safe to say that neither biallelic nor monoallelic IDH3 mutations would be cancerous.	('cancerous', 'Disease', (118, 127))	('IDH3', 'Gene', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('IDH3', 'Chemical', '-', (94, 98))	('mutations', 'Var', (99, 108))	('cancerous', 'Disease', 'MESH:D009369', (118, 127))
28803	28785398	However, because of the known aberrant tumor DNA replication and repair, IDH3 mutations are found in tumor as "passenger" ones.	('IDH3', 'Gene', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('IDH3', 'Chemical', '-', (73, 77))	('mutations', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('DNA replication', 'biological_process', 'GO:0006260', ('45', '60'))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
28805	28785398	Unlike SDH and FH loss-of-function mutations of which have been identified in various cancers, R132 and R172 mutations in IDH1 and 2 (the neomorphic allele producing mutations); respectively, do not follow Knudson's two-hit model of tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('IDH1 and 2', 'Gene', '3417;3418', (122, 132))	('tumor', 'Disease', (233, 238))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor suppressor', 'biological_process', 'GO:0051726', ('233', '249'))	('SDH', 'Gene', (7, 10))	('R172 mutations', 'Var', (104, 118))	('loss-of-function', 'NegReg', (18, 34))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('233', '249'))	('R132', 'Var', (95, 99))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('FH', 'Gene', '2271', (15, 17))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('SDH', 'Gene', '6390', (7, 10))	('mutations', 'Var', (35, 44))
28806	28785398	Almost all reported cases of these mutations have been heterozygous, and inactivating alterations such as frameshifts, deletions, and nonsense mutations have not been observed in IDH1 or 2 in cancer.	('deletions', 'Var', (119, 128))	('cancer', 'Disease', (192, 198))	('IDH1', 'Gene', (179, 183))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('IDH1', 'Gene', '3417', (179, 183))	('frameshifts', 'Var', (106, 117))	('nonsense mutations', 'Var', (134, 152))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
28809	28785398	Because of these observations, one can conclude that IDH1 R132 and IDH2 R172 mutations lead to gain of function rather than loss of tumor suppressor one.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('132', '148'))	('IDH2', 'Gene', (67, 71))	('gain of function', 'PosReg', (95, 111))	('R172 mutations', 'Var', (72, 86))	('IDH1', 'Gene', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('IDH1', 'Gene', '3417', (53, 57))	('mutations', 'Var', (77, 86))	('tumor', 'Disease', (132, 137))	('tumor suppressor', 'biological_process', 'GO:0051726', ('132', '148'))	('R132', 'Var', (58, 62))
28812	28785398	This hypothesis is not plausible, since even in cells harboring IDH1 R132 or IDH2 R172 mutations, 2KG will still be produced by other pathways including glutamate transamination and dehydrogenation (Fig.	('IDH2 R172', 'Gene', (77, 86))	('dehydrogenation', 'MPA', (182, 197))	('IDH1', 'Gene', (64, 68))	('glutamate transamination', 'MPA', (153, 177))	('IDH1', 'Gene', '3417', (64, 68))	('glutamate', 'Chemical', 'MESH:D018698', (153, 162))	('mutations', 'Var', (87, 96))
28813	28785398	In fact, the mean level of 2KG was not altered in the IDH1 or 2 mutant acute myeloid leukemia (AML) or glioma cells, suggesting that the mutation does not decrease the concentration of this metabolite, a finding that does not support the tumor suppressor role of IDH1 or 2.	('acute myeloid leukemia', 'Disease', (71, 93))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('IDH1', 'Gene', (263, 267))	('IDH1', 'Gene', (54, 58))	('AML', 'Disease', 'MESH:D015470', (95, 98))	('AML', 'Disease', (95, 98))	('IDH1', 'Gene', '3417', (263, 267))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (71, 93))	('glioma', 'Disease', (103, 109))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (71, 93))	('mutant', 'Var', (64, 70))	('leukemia', 'Phenotype', 'HP:0001909', (85, 93))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (77, 93))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('238', '254'))	('tumor', 'Disease', (238, 243))	('IDH1', 'Gene', '3417', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor suppressor', 'biological_process', 'GO:0051726', ('238', '254'))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))
28816	28785398	From what has been mentioned so far, it is very likely that the carcinogenic effect of IDH1 R132 and IDH172 is mediated through the elevated cellular (D)-2HG levels originating from cytoplasm by IDH1 R132 or from mitochondria by IDH2 R172 (where it exits the mitochondria and enters the cytoplasm).	('IDH1', 'Gene', (101, 105))	('carcinogenic', 'Disease', 'MESH:D063646', (64, 76))	('elevated', 'PosReg', (132, 140))	('carcinogenic', 'Disease', (64, 76))	('mitochondria', 'cellular_component', 'GO:0005739', ('213', '225'))	('IDH1', 'Gene', '3417', (101, 105))	('IDH1', 'Gene', '3417', (87, 91))	('mitochondria', 'cellular_component', 'GO:0005739', ('259', '271'))	('IDH1', 'Gene', (195, 199))	('cytoplasm', 'cellular_component', 'GO:0005737', ('182', '191'))	('IDH1', 'Gene', (87, 91))	('IDH2 R172', 'Var', (229, 238))	('cytoplasm', 'cellular_component', 'GO:0005737', ('287', '296'))	('IDH1', 'Gene', '3417', (195, 199))
28817	28785398	Recently, the effects of IDH1 R132 and IDH2 R172 mutations on hematopoietic cell lines were replicated using exogenously applied (D)-2HG, not to mention that IDH inhibitors were found to reduce (D)-2HG production and inhibit the growth of leukemia or glioma cells in a mutant-specific manner, proving that this metabolite mediate IDH1 R132 and IDH2 R172 mutated alleles oncogenicity.	('IDH', 'Gene', (25, 28))	('glioma', 'Disease', 'MESH:D005910', (251, 257))	('IDH', 'Gene', '3417', (344, 347))	('IDH', 'Gene', (158, 161))	('IDH1', 'Gene', '3417', (25, 29))	('leukemia', 'Disease', (239, 247))	('leukemia', 'Disease', 'MESH:D007938', (239, 247))	('IDH', 'Gene', '3417', (25, 28))	('mutations', 'Var', (49, 58))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('IDH', 'Gene', (39, 42))	('IDH1', 'Gene', (330, 334))	('reduce', 'NegReg', (187, 193))	('IDH', 'Gene', '3417', (158, 161))	('IDH', 'Gene', (330, 333))	('inhibit', 'NegReg', (217, 224))	('growth', 'CPA', (229, 235))	('IDH', 'Gene', '3417', (39, 42))	('IDH1', 'Gene', '3417', (330, 334))	('IDH', 'Gene', (344, 347))	('IDH', 'Gene', '3417', (330, 333))	('IDH1', 'Gene', (25, 29))	('glioma', 'Disease', (251, 257))	('leukemia', 'Phenotype', 'HP:0001909', (239, 247))
28824	28785398	It has also been shown that neomorphic IDH1 and 2, as well as loss of function mutations in TET2 establish a hypermethylation phenotype in leukemia.	('leukemia', 'Disease', (139, 147))	('TET2', 'Gene', '54790', (92, 96))	('hypermethylation', 'MPA', (109, 125))	('TET2', 'Gene', (92, 96))	('loss of function', 'NegReg', (62, 78))	('leukemia', 'Phenotype', 'HP:0001909', (139, 147))	('leukemia', 'Disease', 'MESH:D007938', (139, 147))	('IDH1 and 2', 'Gene', '3417;3418', (39, 49))	('mutations', 'Var', (79, 88))
28830	28785398	Phosphoglycerate dehydrogenase (PHGDH), an enzyme involved in the de novo synthesis of serine, has recently been shown to catalyze the NADH-dependent reduction of 2KG to (D)-2HG.	('PHGDH', 'Gene', (32, 37))	('PHGDH', 'Gene', '26227', (32, 37))	('Phosphoglycerate dehydrogenase', 'Gene', '26227', (0, 30))	('synthesis', 'biological_process', 'GO:0009058', ('74', '83'))	('serine', 'Chemical', 'MESH:D012694', (87, 93))	('NADH', 'Chemical', 'MESH:D009243', (135, 139))	('2KG', 'Var', (163, 166))	('Phosphoglycerate dehydrogenase', 'Gene', (0, 30))
28831	28785398	Amplification of PHGDH (located on chromosome 1p12) occurs in about 16% of all human cancers, including 6% of breast cancers and 40% of melanomas.	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('breast cancers', 'Phenotype', 'HP:0003002', (110, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('human', 'Species', '9606', (79, 84))	('chromosome', 'cellular_component', 'GO:0005694', ('35', '45'))	('melanomas', 'Disease', 'MESH:D008545', (136, 145))	('melanomas', 'Disease', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('occurs', 'Reg', (52, 58))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancers', 'Disease', (117, 124))	('Amplification', 'Var', (0, 13))	('PHGDH', 'Gene', '26227', (17, 22))	('melanomas', 'Phenotype', 'HP:0002861', (136, 145))	('PHGDH', 'Gene', (17, 22))	('breast cancers', 'Disease', 'MESH:D001943', (110, 124))	('breast cancers', 'Disease', (110, 124))
28832	28785398	Over expression of PHGDH in breast epithelial cells enhances the acquisition of malignant properties, whereas silencing of PHGDH inhibits growth of PHGDH-amplified cells, which is why PHGDH is now considered as a potential therapeutic target in tumors.	('PHGDH', 'Gene', (184, 189))	('inhibits', 'NegReg', (129, 137))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('PHGDH', 'Gene', (19, 24))	('PHGDH', 'Gene', '26227', (123, 128))	('silencing', 'Var', (110, 119))	('growth', 'CPA', (138, 144))	('acquisition', 'CPA', (65, 76))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('PHGDH', 'Gene', '26227', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('PHGDH', 'Gene', (123, 128))	('PHGDH', 'Gene', '26227', (184, 189))	('PHGDH', 'Gene', '26227', (19, 24))	('PHGDH', 'Gene', (148, 153))	('enhances', 'PosReg', (52, 60))	('tumors', 'Disease', (245, 251))
28841	28785398	It is worth mentioning here that patients with type I d-hydroxyglutaric aciduria, a recessive disorder caused by germline homozygous or compound heterozygous inactivating mutations in D2HGD, have not been found to have increased rate of malignancies.	('hydroxyglutaric aciduria', 'Chemical', '-', (56, 80))	('recessive disorder', 'Disease', 'MESH:D030342', (84, 102))	('HGD', 'molecular_function', 'GO:0043718', ('186', '189'))	('compound heterozygous inactivating mutations', 'Var', (136, 180))	('patients', 'Species', '9606', (33, 41))	('caused', 'Reg', (103, 109))	('aciduria', 'Phenotype', 'HP:0012072', (72, 80))	('D2HGD', 'Gene', '728294', (184, 189))	('malignancies', 'Disease', 'MESH:D009369', (237, 249))	('recessive disorder', 'Disease', (84, 102))	('malignancies', 'Disease', (237, 249))	('d-hydroxyglutaric aciduria', 'MPA', (54, 80))	('D2HGD', 'Gene', (184, 189))	('type', 'MPA', (47, 51))
28847	28785398	an autosomal recessive disorder caused by homozygous or compound heterozygous inactivating mutations in L2HGD) cohorts from distinct geographical regions.	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (3, 31))	('HGD', 'molecular_function', 'GO:0043718', ('106', '109'))	('compound heterozygous inactivating mutations', 'Var', (56, 100))	('L2HGD', 'Gene', (104, 109))	('autosomal recessive disorder', 'Disease', (3, 31))	('caused', 'Reg', (32, 38))
28848	28785398	That is probably because the inhibitory effect of (L)-2HG on 2KG-dependent dioxygenases is stronger than that of (D)-2HG and therefore the carcinogenic effect of the former enantiomer is more than that of the later.	('L)-2HG', 'Var', (51, 57))	('stronger', 'PosReg', (91, 99))	('inhibitory effect', 'MPA', (29, 46))	('oxygen', 'Chemical', 'MESH:D010100', (77, 83))	('carcinogenic', 'Disease', 'MESH:D063646', (139, 151))	('carcinogenic', 'Disease', (139, 151))
28849	28785398	It is also possible that patients with (L)-2HG aciduria live long enough to allow the establishment of the correlation between this disease and the risk of cancer.	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('patients', 'Species', '9606', (25, 33))	('aciduria', 'Phenotype', 'HP:0012072', (47, 55))	('L)-2HG aciduria', 'Var', (40, 55))
28855	28785398	This could be, as proposed by some researchers, due to a neomorphic function the enzyme gained due to the substitution of its critical arginine.	('substitution', 'Var', (106, 118))	('arginine', 'Chemical', 'MESH:D001120', (135, 143))	('gained', 'PosReg', (88, 94))
28857	28785398	It is known that in tumor, the recurrent arginine mutation is only found in heterozygous state.	('arginine', 'Chemical', 'MESH:D001120', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('arginine mutation', 'Var', (41, 58))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
28858	28785398	The existence of wild type-mutant (Wt-Mut) and mutant-mutant (Mut-Mut) dimers in addition to wild type-wild type (Wt-Wt) dimer in a cell heterozygous for IDH mutation has been proven (Fig.	('IDH', 'Gene', (154, 157))	('mutant-mutant', 'Var', (47, 60))	('mutation', 'Var', (158, 166))	('IDH', 'Gene', '3417', (154, 157))
28859	28785398	An illustration of the three dimer types formed in a cell harboring one mutant IDH1 allele is provided in Fig.	('mutant', 'Var', (72, 78))	('IDH1', 'Gene', '3417', (79, 83))	('IDH1', 'Gene', (79, 83))
28863	28785398	Zhao et al., conducted an in vitro study where they showed that the enzymatic activities of three tumor-derived IDH1 mutants, R132H, R132C and R132S, had a greater than 80% reduction in activity as compared with the wild-type.	('R132S', 'Var', (143, 148))	('reduction', 'NegReg', (173, 182))	('activity', 'MPA', (186, 194))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('IDH1', 'Gene', (112, 116))	('enzymatic activities', 'MPA', (68, 88))	('R132S', 'Mutation', 'rs121913499', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('R132H', 'Var', (126, 131))	('tumor', 'Disease', (98, 103))	('IDH1', 'Gene', '3417', (112, 116))	('R132C', 'Var', (133, 138))	('R132C', 'Mutation', 'rs121913499', (133, 138))	('R132H', 'Mutation', 'rs121913500', (126, 131))
28864	28785398	Similarly, mutation of the arginine residue in pig mitochondrial IDH2 equivalent to R132 in human IDH1 caused a dramatic decrease in ICT oxidative decarboxylation.	('pig', 'Species', '9823', (47, 50))	('mitochondrial IDH2', 'Gene', (51, 69))	('arginine', 'Chemical', 'MESH:D001120', (27, 35))	('ICT oxidative decarboxylation', 'MPA', (133, 162))	('ICT', 'Chemical', 'MESH:C034219', (133, 136))	('IDH1', 'Gene', (98, 102))	('decrease', 'NegReg', (121, 129))	('IDH2', 'Gene', (65, 69))	('mutation', 'Var', (11, 19))	('IDH1', 'Gene', '3417', (98, 102))	('human', 'Species', '9606', (92, 97))	('arginine', 'Var', (27, 35))
28867	28785398	2a, b): substitution of two arginine residues on both monomers inactivates both forward oxidative decarboxylation and reverse reductive carboxylation reactions while the presence of one arginine fully inhibits the forward oxidative decarboxylation reaction but changes the product of the reverse reductive carboxylation reaction to be (D)-2HG instead of ICT.	('ICT', 'Chemical', 'MESH:C034219', (354, 357))	('forward oxidative decarboxylation reaction', 'MPA', (214, 256))	('inhibits', 'NegReg', (201, 209))	('forward oxidative decarboxylation', 'MPA', (80, 113))	('arginine', 'Chemical', 'MESH:D001120', (186, 194))	('arginine', 'Chemical', 'MESH:D001120', (28, 36))	('changes', 'Reg', (261, 268))	('reverse reductive carboxylation reactions', 'MPA', (118, 159))	('substitution', 'Var', (8, 20))	('inactivates', 'NegReg', (63, 74))
28869	28785398	because of its structural similarity to 2KG), it is possible that it also inhibits the Wt-Wt dimer form of the respective IDH isoform and that might explain the dominant negative effect of heterozygous arginine substitution (Fig.	('IDH', 'Gene', (122, 125))	('IDH', 'Gene', '3417', (122, 125))	('arginine substitution', 'Var', (202, 223))	('arginine', 'Chemical', 'MESH:D001120', (202, 210))	('inhibits', 'NegReg', (74, 82))	('Wt-Wt dimer form', 'MPA', (87, 103))
28870	28785398	This model also explains why IDH1 R132 or IDH2 R140 only exists in heterozygous state.	('R140', 'Var', (47, 51))	('IDH1', 'Gene', '3417', (29, 33))	('IDH1', 'Gene', (29, 33))
28871	28785398	According to this model; when the cancerous cell that harbors heterozygous IDH1 R132 harbors another R132 mutation on the wild-type allele, the only IDH1 dimer in that cell would be Mut-Mut (Fig.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancerous', 'Disease', 'MESH:D009369', (34, 43))	('R132', 'Var', (80, 84))	('IDH1', 'Gene', (149, 153))	('IDH1', 'Gene', '3417', (75, 79))	('IDH1', 'Gene', '3417', (149, 153))	('IDH1', 'Gene', (75, 79))	('cancerous', 'Disease', (34, 43))
28872	28785398	Interestingly, this model also explains the mutual exclusivity of IDH1 R132 and IDH2 R172 mutations documented in some studies.	('IDH1', 'Gene', '3417', (66, 70))	('R172', 'Var', (85, 89))	('R132', 'Var', (71, 75))	('IDH1', 'Gene', (66, 70))	('IDH2', 'Gene', (80, 84))
28877	28785398	wild type IDH2 in a tumor cell harboring neomorphic f IDH1) and utilize it to survive and divide.	('IDH1', 'Gene', (54, 58))	('neomorphic', 'Var', (41, 51))	('IDH2', 'Gene', (10, 14))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('IDH1', 'Gene', '3417', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
28878	28785398	It is worth mentioning here that rare cases of double neomorphic IDH1/IDH2 allele AML cases have been reported.	('IDH1', 'Gene', '3417', (65, 69))	('double neomorphic', 'Var', (47, 64))	('AML', 'Disease', 'MESH:D015470', (82, 85))	('AML', 'Disease', (82, 85))	('IDH1', 'Gene', (65, 69))
28879	28785398	IDH1 R132 activating mutations were found by several sequencing studies to be very common in specific types of adult brain tumors, occurring in >70% of adult grade II and grade III gliomas and >80% of adult secondary glioblastoma multiforme (GBM).	('brain tumors', 'Disease', (117, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('IDH1', 'Gene', '3417', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('activating', 'PosReg', (10, 20))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('glioblastoma multiforme', 'Disease', (217, 240))	('glioblastoma', 'Phenotype', 'HP:0012174', (217, 229))	('brain tumors', 'Disease', 'MESH:D001932', (117, 129))	('brain tumors', 'Phenotype', 'HP:0030692', (117, 129))	('gliomas', 'Disease', (181, 188))	('IDH1', 'Gene', (0, 4))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (217, 240))	('gliomas', 'Disease', 'MESH:D005910', (181, 188))	('gliomas', 'Phenotype', 'HP:0009733', (181, 188))	('mutations', 'Var', (21, 30))
28880	28785398	It was also found that many of the grade II/III gliomas and secondary GBMs that are IDH1 wild type had mutations at IDH2 R172.	('mutations', 'Var', (103, 112))	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('IDH2', 'Gene', (116, 120))	('IDH1', 'Gene', (84, 88))	('IDH1', 'Gene', '3417', (84, 88))	('gliomas', 'Disease', (48, 55))
28881	28785398	Altogether, 80-90% of adult grade II/III gliomas and secondary GBMs harbor mutations at either R132 of IDH1 or R172 of IDH2.	('IDH1', 'Gene', '3417', (103, 107))	('adult', 'Disease', (22, 27))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('IDH2', 'Gene', (119, 123))	('secondary GBMs', 'CPA', (53, 67))	('R172', 'Var', (111, 115))	('gliomas', 'Disease', 'MESH:D005910', (41, 48))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('gliomas', 'Disease', (41, 48))	('IDH1', 'Gene', (103, 107))
28882	28785398	However, IDH activating mutations are present in <10% of primary GBMs and pediatric GBMs.	('IDH', 'Gene', '3417', (9, 12))	('mutations', 'Var', (24, 33))	('primary GBMs', 'Disease', (57, 69))	('IDH', 'Gene', (9, 12))
28883	28785398	Sequencing studies also confirmed that IDH activating mutations are frequent in clonal myeloid disorders and present in 5-20% of de novo normal karyotype acute myeloid leukemia (NK-AML) cases and in 10-20% of cases of secondary AML resulting from leukemic transformation of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN).	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (154, 176))	('clonal myeloid disorders', 'Disease', 'MESH:C580365', (80, 104))	('MDS', 'Disease', (300, 303))	('leukemia', 'Phenotype', 'HP:0001909', (168, 176))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (274, 298))	('clonal myeloid disorders', 'Disease', (80, 104))	('NK-AML', 'Disease', (178, 184))	('mutations', 'Var', (54, 63))	('IDH', 'Gene', (39, 42))	('neoplasm', 'Phenotype', 'HP:0002664', (328, 336))	('AML', 'Disease', 'MESH:D015470', (228, 231))	('myeloproliferative neoplasm', 'Phenotype', 'HP:0005547', (309, 336))	('AML', 'Disease', (228, 231))	('acute myeloid leukemia', 'Disease', (154, 176))	('AML', 'Disease', 'MESH:D015470', (181, 184))	('IDH', 'Gene', '3417', (39, 42))	('AML', 'Disease', (181, 184))	('myeloproliferative neoplasm', 'Disease', (309, 336))	('MDS', 'Disease', 'MESH:D009190', (300, 303))	('myeloproliferative neoplasm', 'Disease', 'MESH:D009196', (309, 336))	('leukemic transformation of myelodysplastic syndrome', 'Disease', 'MESH:D009190', (247, 298))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (154, 176))	('NK-AML', 'Disease', 'MESH:D015470', (178, 184))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (160, 176))
28884	28785398	At lower frequency (5-10%), these IDH activating mutations are also present in chronic-phase MDS and MPN but are rare in translocation-positive AML.	('AML', 'Disease', (144, 147))	('IDH', 'Gene', '3417', (34, 37))	('IDH', 'Gene', (34, 37))	('MDS', 'Disease', (93, 96))	('mutations', 'Var', (49, 58))	('MDS', 'Disease', 'MESH:D009190', (93, 96))	('AML', 'Disease', 'MESH:D015470', (144, 147))
28885	28785398	In 10-40% of angioimmunoblastic T-cell lymphoma (AITL) were found to harbor IDH2 activating mutations, however these mutations were uncommon in other T- or B-cell lymphoid malignancies.	('cell lymphoma', 'Phenotype', 'HP:0012191', (34, 47))	('lymphoid malignancies', 'Disease', 'MESH:D008223', (163, 184))	('lymphoid malignancies', 'Disease', (163, 184))	('angioimmunoblastic T-cell lymphoma', 'Disease', (13, 47))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (32, 47))	('lymphoma', 'Phenotype', 'HP:0002665', (39, 47))	('lymphoid malignancies', 'Phenotype', 'HP:0002665', (163, 184))	('mutations', 'Var', (92, 101))	('angioimmunoblastic T-cell lymphoma', 'Disease', 'MESH:D016399', (13, 47))	('IDH2', 'Gene', (76, 80))	('activating', 'PosReg', (81, 91))
28886	28785398	Besides glioma, IDH activating mutations have been found in a number of other solid tumors.	('solid tumors', 'Disease', (78, 90))	('mutations', 'Var', (31, 40))	('glioma', 'Disease', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('IDH', 'Gene', (16, 19))	('solid tumors', 'Disease', 'MESH:D009369', (78, 90))	('IDH', 'Gene', '3417', (16, 19))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('glioma', 'Disease', 'MESH:D005910', (8, 14))	('glioma', 'Phenotype', 'HP:0009733', (8, 14))	('found', 'Reg', (51, 56))
28887	28785398	Over 50% of chondrosarcomas harbor IDH activating mutations, and IDH activating mutations have been linked to the pathogenesis of the enchondromatosis syndromes Ollier disease and Maffucci syndrome.	('enchondromatosis syndromes Ollier disease', 'Disease', (134, 175))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (12, 26))	('Maffucci syndrome', 'Disease', (180, 197))	('IDH', 'Gene', (65, 68))	('IDH', 'Gene', (35, 38))	('mutations', 'Var', (80, 89))	('Maffucci syndrome', 'Disease', 'MESH:D004687', (180, 197))	('linked', 'Reg', (100, 106))	('IDH', 'Gene', '3417', (65, 68))	('pathogenesis', 'biological_process', 'GO:0009405', ('114', '126'))	('IDH', 'Gene', '3417', (35, 38))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (12, 27))	('Ollier disease', 'Phenotype', 'HP:0500045', (161, 175))	('chondrosarcomas', 'Disease', 'MESH:D002813', (12, 27))	('enchondromatosis syndromes Ollier disease', 'Disease', 'MESH:D004687', (134, 175))	('chondrosarcomas', 'Disease', (12, 27))
28890	28785398	Interestingly, 40-90% of the tumors in these patients harbor mutations at R132 of IDH1 or R172 of IDH2 while having wild type IDH1 and IDH2 in their normal tissues, suggesting that these IDH activating mutations occurred as a postzygotic event and present in these patients as somatic mosaicism.	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('patients', 'Species', '9606', (45, 53))	('IDH1', 'Gene', '3417', (82, 86))	('IDH', 'Gene', '3417', (98, 101))	('IDH', 'Gene', '3417', (82, 85))	('mutations at R132', 'Var', (61, 78))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('IDH1', 'Gene', (126, 130))	('IDH', 'Gene', (135, 138))	('patients', 'Species', '9606', (265, 273))	('tumors', 'Disease', (29, 35))	('IDH', 'Gene', (126, 129))	('IDH', 'Gene', (187, 190))	('IDH', 'Gene', '3417', (135, 138))	('R172', 'Var', (90, 94))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('IDH1', 'Gene', '3417', (126, 130))	('IDH', 'Gene', '3417', (126, 129))	('IDH1', 'Gene', (82, 86))	('IDH', 'Gene', '3417', (187, 190))	('IDH', 'Gene', (98, 101))	('IDH', 'Gene', (82, 85))
28893	28785398	Few cases of paraganglioma, colon cancer, prostate cancer, and lung cancer have also been found to harbor IDH activating mutations.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('prostate cancer', 'Phenotype', 'HP:0012125', (42, 57))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutations', 'Var', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('paraganglioma', 'Disease', (13, 26))	('lung cancer', 'Disease', (63, 74))	('prostate cancer', 'Disease', (42, 57))	('colon cancer', 'Disease', 'MESH:D015179', (28, 40))	('paraganglioma', 'Disease', 'MESH:D010235', (13, 26))	('glioma', 'Phenotype', 'HP:0009733', (20, 26))	('IDH', 'Gene', '3417', (106, 109))	('colon cancer', 'Disease', (28, 40))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('paraganglioma', 'Phenotype', 'HP:0002668', (13, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('colon cancer', 'Phenotype', 'HP:0003003', (28, 40))	('IDH', 'Gene', (106, 109))	('prostate cancer', 'Disease', 'MESH:D011471', (42, 57))
28894	28785398	It is clear from these cumulative data that these IDH activating mutations are driver ones, which again emphasizes the importance of targeting them in these types of tumor.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('IDH', 'Gene', (50, 53))	('IDH', 'Gene', '3417', (50, 53))	('mutations', 'Var', (65, 74))
28896	28785398	My elaboration on that is as follows: mutations can occur by chance in dividing cells due to replication errors or none dividing ones by several mechanisms including the exposure of cellular DNA to ROS, for instance.	('DNA', 'cellular_component', 'GO:0005574', ('191', '194'))	('replication errors', 'Var', (93, 111))	('due', 'Reg', (86, 89))	('mutations', 'Var', (38, 47))	('ROS', 'Chemical', 'MESH:D017382', (198, 201))
28897	28785398	Notably, most common IDH1 and 2 activating mutations are caused by G>A or C>T transitions [e.g.	('G>A', 'Var', (67, 70))	('IDH1 and 2', 'Gene', '3417;3418', (21, 31))	('C>T transitions', 'Var', (74, 89))	('mutations', 'Var', (43, 52))	('activating', 'PosReg', (32, 42))
28898	28785398	R132H (CGT>CAT), R132C (CGT>TGT), and R172K (AGG>AAG)].	('R132H', 'Mutation', 'rs121913500', (0, 5))	('CGT', 'Gene', '7368', (7, 10))	('R132C', 'Var', (17, 22))	('CGT', 'Gene', (7, 10))	('R132C', 'Mutation', 'rs121913499', (17, 22))	('CGT', 'Gene', '7368', (24, 27))	('R172K', 'Mutation', 'rs121913503', (38, 43))	('CGT', 'molecular_function', 'GO:0047801', ('24', '27'))	('CAT', 'molecular_function', 'GO:0004096', ('11', '14'))	('TGT', 'Gene', (28, 31))	('CGT', 'Gene', (24, 27))	('R172K', 'Var', (38, 43))	('CGT', 'molecular_function', 'GO:0047801', ('7', '10'))	('R132H', 'Var', (0, 5))	('TGT', 'Gene', '9097', (28, 31))
28899	28785398	So, my hypothesis is that it is possible that these IDH activating mutations can occur by chance as early DNA variants in different cell types with different carcinogenic potential.	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('carcinogenic', 'Disease', 'MESH:D063646', (158, 170))	('IDH', 'Gene', '3417', (52, 55))	('IDH', 'Gene', (52, 55))	('carcinogenic', 'Disease', (158, 170))	('mutations', 'Var', (67, 76))
28900	28785398	In other words, it is possible that these substitutions have the highest carcinogenic effect (and might require only few cooperating mutations, if ever) when they occur by chance as an early event in a cell type that significantly relies on the reductive carboxylation activity of these two enzymes in its metabolism.	('carcinogenic', 'Disease', (73, 85))	('metabolism', 'biological_process', 'GO:0008152', ('306', '316'))	('carcinogenic', 'Disease', 'MESH:D063646', (73, 85))	('substitutions', 'Var', (42, 55))
28902	28785398	In these cells the presence of IDH activating mutation alone (without the presence of initiating or other cooperating mutations) would be enough to produce the oncometabolite (D)-2HG and therefore transform the cell into cancerous one.	('IDH', 'Gene', (31, 34))	('produce', 'Reg', (148, 155))	('cancerous', 'Disease', (221, 230))	('transform', 'Reg', (197, 206))	('IDH', 'Gene', '3417', (31, 34))	('activating', 'PosReg', (35, 45))	('cancerous', 'Disease', 'MESH:D009369', (221, 230))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('mutation', 'Var', (46, 54))
28903	28785398	These IDH activating mutations in these tissues are early occurring ones (i.e.	('IDH', 'Gene', '3417', (6, 9))	('IDH', 'Gene', (6, 9))	('mutations', 'Var', (21, 30))
28904	28785398	that is normally not active in citrate synthesis) the same activating mutation alone might not be carcinogenic and must be preceded by cancer initiating mutations causing this cell to start being active in citrate synthesis for cellular growth and division (see the previous section, "Their role in physiology and cancer").	('citrate', 'Chemical', 'MESH:D019343', (206, 213))	('carcinogenic', 'Disease', 'MESH:D063646', (98, 110))	('cancer', 'Disease', (135, 141))	('citrate', 'Chemical', 'MESH:D019343', (31, 38))	('cancer', 'Disease', (314, 320))	('carcinogenic', 'Disease', (98, 110))	('synthesis', 'biological_process', 'GO:0009058', ('39', '48'))	('mutations', 'Var', (153, 162))	('synthesis', 'biological_process', 'GO:0009058', ('214', '223'))	('cellular growth', 'biological_process', 'GO:0016049', ('228', '243'))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('citrate synthesis', 'MPA', (206, 223))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (314, 320))
28905	28785398	Here, these IDH activating mutations are late-occurring ones, but still considered driver ones sine their presence "drove" the cell further towards being cancerous by e.g.	('mutations', 'Var', (27, 36))	('cancerous', 'Disease', 'MESH:D009369', (154, 163))	('IDH', 'Gene', (12, 15))	('IDH', 'Gene', '3417', (12, 15))	('cancerous', 'Disease', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
28910	28785398	Since these non-glial tissues are not active in citrate synthesis, the presence of IDH activating mutations alone might not have carcinogenic effect on that type of cell.	('carcinogenic', 'Disease', 'MESH:D063646', (129, 141))	('carcinogenic', 'Disease', (129, 141))	('IDH', 'Gene', (83, 86))	('citrate', 'Chemical', 'MESH:D019343', (48, 55))	('synthesis', 'biological_process', 'GO:0009058', ('56', '65'))	('IDH', 'Gene', '3417', (83, 86))	('mutations', 'Var', (98, 107))
28912	28785398	Notably, prostate is also known to synthesize citrate in high amount and R132 substitution has been found in prostatic cancer.	('prostatic cancer', 'Disease', 'MESH:D011471', (109, 125))	('R132 substitution', 'Var', (73, 90))	('prostatic cancer', 'Phenotype', 'HP:0012125', (109, 125))	('citrate', 'Chemical', 'MESH:D019343', (46, 53))	('found', 'Reg', (100, 105))	('prostatic cancer', 'Disease', (109, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
28916	28785398	The fact that 50% of chondrosarcomas harbor IDH1or 2 activating mutations, points to the high possibility that chondrocytes are active in citrate synthesis as a source of acetyl CoA and according to my hypothesis, IDH activating mutations are very likely to be early ones in this type of tumor.	('tumor', 'Disease', (288, 293))	('citrate', 'Chemical', 'MESH:D019343', (138, 145))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('synthesis', 'biological_process', 'GO:0009058', ('146', '155'))	('IDH1', 'Gene', (44, 48))	('chondrosarcomas', 'Disease', 'MESH:D002813', (21, 36))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (21, 36))	('IDH', 'Gene', '3417', (214, 217))	('IDH1', 'Gene', '3417', (44, 48))	('chondrosarcomas', 'Disease', (21, 36))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (21, 35))	('mutations', 'Var', (64, 73))	('IDH', 'Gene', (214, 217))	('activating', 'PosReg', (53, 63))	('IDH', 'Gene', (44, 47))	('acetyl CoA', 'Chemical', 'MESH:D000105', (171, 181))	('IDH', 'Gene', '3417', (44, 47))
28918	28785398	So, it is possible that in chondrocytes, citrate synthesis is active and neomorphic IDH enzyme produces (D)-2HG (i.e.	('citrate', 'Enzyme', (41, 48))	('D)-2HG', 'Var', (105, 111))	('synthesis', 'biological_process', 'GO:0009058', ('49', '58'))	('IDH', 'Gene', (84, 87))	('IDH', 'Gene', '3417', (84, 87))	('citrate', 'Chemical', 'MESH:D019343', (41, 48))
28922	28785398	From what has been mentioned so far, it is clear that IDH1 R132 and IDH2 R172 mutations in these types of tumor, whether they occur as early or late ones, are driver mutations and that stresses on the importance of targeting them as a candidate anticancer therapy.	('IDH2 R172', 'Gene', (68, 77))	('IDH1', 'Gene', (54, 58))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('cancer', 'Disease', (249, 255))	('mutations', 'Var', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('IDH1', 'Gene', '3417', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('tumor', 'Disease', (106, 111))
28923	28785398	Based on my hypothesis, that targeted therapy will have beneficial effect on tumors harboring these mutations; especially those e.g.	('tumors', 'Disease', (77, 83))	('mutations', 'Var', (100, 109))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('beneficial', 'PosReg', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))
28932	28785398	Notably, in vitro studies have proven the antitumor efficacy of glutaminase inhibitor on IDH mutant cells.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('glutaminase inhibitor', 'Protein', (64, 85))	('tumor', 'Disease', (46, 51))	('mutant', 'Var', (93, 99))	('IDH', 'Gene', (89, 92))	('IDH', 'Gene', '3417', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
28933	28785398	It would be interesting to conduct a study where mutant IDH targeted therapy is combined with this drug (or any of the aforementioned drugs) to study their combined effect on IDH mutant tumors.	('IDH', 'Gene', '3417', (175, 178))	('mutant', 'Var', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('IDH', 'Gene', (56, 59))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('IDH', 'Gene', '3417', (56, 59))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('IDH', 'Gene', (175, 178))
28936	28785398	However, it is a matter of which is more sensitive to 2KG depletion, the physiological function of the 2KG dependent dioxygenases or the oncometabolite production by mutant IDH (i.e.	('oxygen', 'Chemical', 'MESH:D010100', (119, 125))	('IDH', 'Gene', (173, 176))	('IDH', 'Gene', '3417', (173, 176))	('oncometabolite production', 'MPA', (137, 162))	('mutant', 'Var', (166, 172))
28938	28785398	Based on the in vitro studies on IDH mutant cells that have proven the antitumor efficacy of glutaminase inhibitor, it is very likely that the beneficial effect of 2KG depletion on mutant IDH enzymes outweighs its unwanted effect on 2KG dependent dioxygenases.	('IDH', 'Gene', '3417', (188, 191))	('mutant', 'Var', (181, 187))	('oxygen', 'Chemical', 'MESH:D010100', (249, 255))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('IDH', 'Gene', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('IDH', 'Gene', (188, 191))	('IDH', 'Gene', '3417', (33, 36))	('tumor', 'Disease', (75, 80))	('beneficial', 'PosReg', (143, 153))
28939	28785398	Arguably, 2KG depletion might also have the unwanted generalized inhibitory effect on these dioxygenases present in normal cells.	('dioxygenases', 'Enzyme', (92, 104))	('oxygen', 'Chemical', 'MESH:D010100', (94, 100))	('inhibitory effect', 'MPA', (65, 82))	('2KG depletion', 'Var', (10, 23))
28947	28785398	Theoretically, silencing the wild type allele due to oligonucleotides off target effect would be of limited effect on tissues expressing both genes i.e.	('oligonucleotides off', 'Var', (53, 73))	('silencing', 'NegReg', (15, 24))	('oligonucleotides', 'Chemical', 'MESH:D009841', (53, 69))
28951	28785398	Lastly, some studies have confirmed that IDH1 mutated cancer cells have significantly low intracellular level of coenzyme NAD+.	('NAD+', 'Chemical', 'MESH:D009243', (122, 126))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('mutated', 'Var', (46, 53))	('cancer', 'Disease', (54, 60))	('intracellular', 'cellular_component', 'GO:0005622', ('90', '103'))	('low', 'NegReg', (86, 89))	('IDH1', 'Gene', (41, 45))	('IDH1', 'Gene', '3417', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('intracellular level of coenzyme NAD+', 'MPA', (90, 126))
28953	28785398	This metabolic vulnerability has been exploited as therapeutic modality where depletion of NAD+ using small molecule inhibitors targeting the salvage NAD+ synthesis enzyme nicotinamide phosphoribosyl transferase resulted in strikingly selective cytotoxicity in IDH1 mutant cancer cells.	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('NAD+', 'Chemical', 'MESH:D009243', (91, 95))	('NAD+', 'Chemical', 'MESH:D009243', (150, 154))	('IDH1', 'Gene', '3417', (261, 265))	('cytotoxicity', 'Disease', 'MESH:D064420', (245, 257))	('mutant', 'Var', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('NAD+ synthesis', 'biological_process', 'GO:0009435', ('150', '164'))	('IDH1', 'Gene', (261, 265))	('cytotoxicity', 'Disease', (245, 257))
28960	28785398	It could also explain why in most tumor types neomorphic IDH1 alleles are more common than those of IDH2, except in AITL where neomorphic IDH1 alleles has not been reported and AML where neomorphic IDH1 and IDH2 alleles have similar frequencies.	('neomorphic', 'Var', (46, 56))	('common', 'Reg', (79, 85))	('tumor', 'Disease', (34, 39))	('AML', 'Disease', (177, 180))	('IDH1', 'Gene', '3417', (138, 142))	('IDH1', 'Gene', (198, 202))	('IDH1', 'Gene', (57, 61))	('IDH1', 'Gene', '3417', (198, 202))	('IDH1', 'Gene', '3417', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('IDH1', 'Gene', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('AML', 'Disease', 'MESH:D015470', (177, 180))
28962	28785398	According to my hypothesis, in these cells, the early occurrence of R172 (or less frequently IDH2 R140) mutations even, as lone one, will be enough to produce significantly high level of intracellular (D)-2HG and cause the cancerous transformation of that type of cell.	('mutations', 'Var', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancerous', 'Disease', 'MESH:D009369', (223, 232))	('high', 'PosReg', (173, 177))	('R172', 'Gene', (68, 72))	('cause', 'Reg', (213, 218))	('intracellular', 'cellular_component', 'GO:0005622', ('187', '200'))	('IDH2', 'Gene', (93, 97))	('cancerous', 'Disease', (223, 232))
28963	28785398	Stated differently and based on the same hypothesis, it is likely that the lone occurrence of IDH1 R132 mutation in T cells would not make them transform into AITL.	('IDH1', 'Gene', '3417', (94, 98))	('IDH1', 'Gene', (94, 98))	('mutation', 'Var', (104, 112))
28966	28785398	In the case of AML, it is possible that in myeloid cells both IDH1 and IDH2 are equally active where the occurrence of IDH1 R132 or IDH2 R172 will produce the oncometabolite (D)-2HG in a cellular concentration that is high enough to cause them to transform into AML.	('occurrence', 'Var', (105, 115))	('R132', 'Var', (124, 128))	('AML', 'Disease', 'MESH:D015470', (15, 18))	('AML', 'Disease', (262, 265))	('IDH1', 'Gene', '3417', (62, 66))	('transform', 'MPA', (247, 256))	('AML', 'Disease', (15, 18))	('IDH1', 'Gene', (119, 123))	('produce', 'Reg', (147, 154))	('IDH1', 'Gene', '3417', (119, 123))	('IDH1', 'Gene', (62, 66))	('IDH2 R172', 'Var', (132, 141))	('AML', 'Disease', 'MESH:D015470', (262, 265))
28969	28785398	Unless that mutation is too frequent to occur by simple coincidence in that type of tumor, labeling IDH1 R132 or IDH2 R172 mutations as driver ones in a tumor not frequently seen to harbor them and without proving the high content of (D)-2HG in that tumor, should be advised against.	('IDH2 R172', 'Gene', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('IDH1', 'Gene', '3417', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('IDH1', 'Gene', (100, 104))	('tumor', 'Disease', (250, 255))	('mutations', 'Var', (123, 132))
28970	28785398	That is because it is possible that in that particular tumor the driver mutation was in another gene and IDH2 R172, for instance, was simply a passenger mutation in a gene (i.e.	('particular tumor', 'Disease', 'MESH:D009369', (44, 60))	('particular tumor', 'Disease', (44, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('mutation', 'Var', (72, 80))
28972	28785398	Due to the structure of IDH3 and the unidirectional feature of its action, mutations in its coding genes would be of inactivating type that would have no cancer transforming potential.	('IDH3', 'Chemical', '-', (24, 28))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('mutations', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('IDH3', 'Gene', (24, 28))
28973	28785398	On the contrary, heterozygous mutations resulting in substitution of the key active site arginine cause IDH1 R132 and IDH2 R172 to gain a new function.	('IDH1', 'Gene', '3417', (104, 108))	('R172', 'Var', (123, 127))	('IDH2', 'Gene', (118, 122))	('substitution', 'Var', (53, 65))	('arginine', 'Chemical', 'MESH:D001120', (89, 97))	('R132', 'Var', (109, 113))	('function', 'MPA', (142, 150))	('gain', 'PosReg', (131, 135))	('IDH1', 'Gene', (104, 108))
28974	28785398	These mutant enzymes lose the ability to catalyze the interconversion between ICT and 2KG.	('mutant', 'Var', (6, 12))	('ability', 'MPA', (30, 37))	('catalyze', 'MPA', (41, 49))	('ICT', 'Chemical', 'MESH:C034219', (78, 81))	('lose', 'NegReg', (21, 25))	('interconversion', 'MPA', (54, 69))
28976	28785398	A model based on the ability of this metabolite to inhibit the Wt allele, explains the dominant negative effect and the mutual exclusivity known for IDH1 R132 and IDH2 R172 mutant alleles.	('IDH1', 'Gene', (149, 153))	('R172 mutant', 'Var', (168, 179))	('negative', 'NegReg', (96, 104))	('IDH1', 'Gene', '3417', (149, 153))	('mutant', 'Var', (173, 179))	('R132', 'Var', (154, 158))	('IDH2', 'Gene', (163, 167))
28978	28785398	It is possible that the more active the cell in converting 2KG to ICT, the more likely IDH1 R132 or IDH2 R172 (depending on the preferential IDH gene expression) mutations are early and driver ones.	('IDH', 'Gene', (100, 103))	('mutations', 'Var', (162, 171))	('IDH', 'Gene', (141, 144))	('IDH1', 'Gene', '3417', (87, 91))	('IDH', 'Gene', '3417', (100, 103))	('IDH', 'Gene', (87, 90))	('gene expression', 'biological_process', 'GO:0010467', ('145', '160'))	('IDH', 'Gene', '3417', (141, 144))	('IDH', 'Gene', '3417', (87, 90))	('IDH1', 'Gene', (87, 91))	('ICT', 'Chemical', 'MESH:C034219', (66, 69))
28979	28785398	Based on that; in certain tumors, IDH1 R132 and IDH2 R172 mutations are considered as driver ones, emphasizing the importance of targeting them as a cancer treatment therapy in those tumors.	('IDH1', 'Gene', '3417', (34, 38))	('mutations', 'Var', (58, 67))	('cancer', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('IDH2 R172', 'Gene', (48, 57))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('IDH1', 'Gene', (34, 38))	('tumors', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Disease', (26, 32))
28981	28785398	Preclinical trials have proven the efficacy of mutant IDH1 R132 and IDH2 R172 targeting therapy and combining them with 2KG lowering agents sounds like a feasible subject for future studies.	('IDH1', 'Gene', (54, 58))	('IDH2', 'Gene', (68, 72))	('R172', 'Var', (73, 77))	('agents sounds', 'Phenotype', 'HP:0008765', (133, 146))	('IDH1', 'Gene', '3417', (54, 58))	('R132', 'Var', (59, 63))	('mutant', 'Var', (47, 53))
28982	28785398	AITL angioimmunoblastic T cell lymphoma AML acute myeloid leukemia ccRCC clear-cell renal cell carcinoma (D)-2HG (d)-2-hydroxyglutarate D2HGA2 type II d-hydroxyglutaric aciduria D2HGD (d)-2-hydroxyglutarate dehydrogenase enzyme ETC electron transport chain FAs fatty acids FH fumarate hydratase GBM glioblastoma multiforme Hif1alpha hypoxia induced factor 1 alfa HLRCC hereditary leiomyomatosis and renal clear cell cancer ICT isocitrate IDH isocitrate dehydrogenase (L)-2HG (l)-2-hydroxyglutarate L2HGD (l)-2-hydroxyglutarate dehydrogenase enzyme NK-AML normal karyotype acute myeloid leukemia PARP poly (ADP-ribose) polymerase PHD prolyl hydroxylase PHGDH phosphoglycerate dehydrogenase enzyme SDH succinate dehydrogenase TCA tricarboxylic acid cycle TET2 ten-eleven-translocation 2 VHL Von Hippel-Lindau syndrome MDS myelodysplastic syndrome MPN myeloproliferative neoplasm Mut mutant Wt wild type 2KG 2-ketoglutarate	('AML', 'Disease', (551, 554))	('myelodysplastic syndrome', 'Disease', (820, 844))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (44, 66))	('D2HGD', 'Gene', (178, 183))	('VHL', 'Gene', '7428', (785, 788))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (572, 594))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (578, 594))	('HGD', 'molecular_function', 'GO:0043718', ('500', '503'))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (572, 594))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('lymphoma', 'Phenotype', 'HP:0002665', (31, 39))	('(l)-2-hydroxyglutarate', 'Chemical', '-', (504, 526))	('fumarate hydratase', 'Gene', '2271', (276, 294))	('poly (ADP-ribose) polymerase', 'Gene', (600, 628))	('myeloproliferative neoplasm', 'Disease', (849, 876))	('isocitrate', 'Chemical', 'MESH:C034219', (427, 437))	('SDH', 'Gene', (696, 699))	('cell lymphoma', 'Phenotype', 'HP:0012191', (26, 39))	('NK-AML', 'Disease', (548, 554))	('PARP', 'Gene', '142', (595, 599))	('FAs', 'Chemical', 'MESH:D005227', (257, 260))	('PHGDH', 'Gene', '26227', (652, 657))	('TET2', 'Gene', (753, 757))	('PARP', 'Gene', (595, 599))	('PHD', 'molecular_function', 'GO:0050175', ('629', '632'))	('HGD', 'molecular_function', 'GO:0043718', ('180', '183'))	('hydroxyglutaric aciduria', 'Chemical', '-', (153, 177))	('electron transport chain', 'biological_process', 'GO:0022900', ('232', '256'))	('mutant', 'Var', (881, 887))	('succinate dehydrogenase', 'Gene', (700, 723))	('angioimmunoblastic T cell lymphoma', 'Disease', (5, 39))	('AML', 'Disease', (40, 43))	('NK-AML', 'Disease', 'MESH:D015470', (548, 554))	('acute myeloid leukemia', 'Disease', (44, 66))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (84, 104))	('MDS', 'Disease', 'MESH:D009190', (816, 819))	('ICT', 'Chemical', 'MESH:C034219', (423, 426))	('angioimmunoblastic T cell lymphoma', 'Disease', 'MESH:D016399', (5, 39))	('phosphoglycerate dehydrogenase', 'Gene', '26227', (658, 688))	('aciduria', 'Phenotype', 'HP:0012072', (169, 177))	('clear cell cancer', 'Phenotype', 'HP:0006770', (405, 422))	('AML', 'Disease', 'MESH:D015470', (551, 554))	('MDS', 'Disease', (816, 819))	('(l)-2-hydroxyglutarate', 'Chemical', '-', (475, 497))	('fumarate hydratase', 'Gene', (276, 294))	('cancer', 'Phenotype', 'HP:0002664', (416, 422))	('IDH', 'Gene', (438, 441))	('D2HGA2', 'Gene', '3418', (136, 142))	('TET2', 'Gene', '54790', (753, 757))	('neoplasm', 'Phenotype', 'HP:0002664', (868, 876))	('D2HGA2', 'Gene', (136, 142))	('AML', 'Disease', 'MESH:D015470', (40, 43))	('hypoxia', 'Disease', (333, 340))	('FH', 'Gene', '2271', (273, 275))	('poly (ADP-ribose) polymerase', 'Gene', '142', (600, 628))	('2-ketoglutarate', 'Chemical', 'MESH:D007656', (905, 920))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (299, 322))	('hereditary leiomyomatosis and renal clear cell cancer', 'Disease', 'MESH:C535516', (369, 422))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (820, 844))	('hypoxia', 'Disease', 'MESH:D000860', (333, 340))	('isocitrate', 'Chemical', 'MESH:C034219', (442, 452))	('acute myeloid leukemia', 'Disease', (572, 594))	('leukemia', 'Phenotype', 'HP:0001909', (58, 66))	('PHGDH', 'Gene', (652, 657))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (44, 66))	('Von Hippel-Lindau syndrome', 'Disease', (789, 815))	('renal cell carcinoma', 'Disease', (84, 104))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (84, 104))	('phosphoglycerate dehydrogenase', 'Gene', (658, 688))	('(d)-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (184, 206))	('Hif1alpha', 'Gene', '3091', (323, 332))	('glioblastoma', 'Phenotype', 'HP:0012174', (299, 311))	('D2HGD', 'Gene', '728294', (178, 183))	('leukemia', 'Phenotype', 'HP:0001909', (586, 594))	('(d)-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (113, 135))	('myeloproliferative neoplasm', 'Phenotype', 'HP:0005547', (849, 876))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (24, 39))	('PHD', 'Disease', (629, 632))	('SDH', 'Gene', '6390', (696, 699))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (728, 746))	('IDH', 'Gene', '3417', (438, 441))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (820, 844))	('glioblastoma multiforme', 'Disease', (299, 322))	('Von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (789, 815))	('fatty acids', 'Chemical', 'MESH:D005227', (261, 272))	('Hif1alpha', 'Gene', (323, 332))	('PHD', 'Disease', 'MESH:D011547', (629, 632))	('myeloproliferative neoplasm', 'Disease', 'MESH:D009196', (849, 876))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (50, 66))	('VHL', 'Gene', (785, 788))	('succinate dehydrogenase', 'Gene', '6390', (700, 723))	('tricarboxylic acid cycle', 'biological_process', 'GO:0006099', ('728', '752'))
28983	27556922	An integrative genomics approach for identifying novel functional consequences of PBRM1 truncated mutations in clear cell renal cell carcinoma (ccRCC) Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer.	('PBRM1', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('kidney cancer', 'Phenotype', 'HP:0009726', (218, 231))	('ccRCC', 'Phenotype', 'HP:0006770', (184, 189))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (162, 182))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (151, 182))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('RCC', 'Disease', (186, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('Clear cell renal cell carcinoma', 'Disease', (151, 182))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (122, 142))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (111, 142))	('type of kidney cancer', 'Disease', (210, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (157, 182))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (151, 182))	('PBRM1', 'Gene', '55193', (82, 87))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (117, 142))	('type of kidney cancer', 'Disease', 'MESH:D007680', (210, 231))	('mutations', 'Var', (98, 107))	('cell renal cell carcinoma', 'Disease', (117, 142))
28986	27556922	In this study, we proposed an integrative genomics approach to explore the functional consequences of PBRM1 truncated mutations in ccRCC by incorporating somatic mutations, mRNA expression, DNA methylation, and microRNA (miRNA) expression profiles from The Cancer Genome Atlas (TCGA).	('PBRM1', 'Gene', (102, 107))	('mutations', 'Var', (118, 127))	('PBRM1', 'Gene', '55193', (102, 107))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('Cancer', 'Phenotype', 'HP:0002664', (257, 263))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('Cancer Genome Atlas', 'Disease', (257, 276))	('DNA', 'cellular_component', 'GO:0005574', ('190', '193'))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (257, 276))	('DNA methylation', 'biological_process', 'GO:0006306', ('190', '205'))
28989	27556922	We identified 613 differentially expressed genes (128 up-regulated and 485 down-regulated genes using cutoff  log2FC  < 1 and p < 0.05) in PBRM1 mutated group versus "pan-negative" group.	('PBRM1', 'Gene', '55193', (139, 144))	('mutated', 'Var', (145, 152))	('up-regulated', 'PosReg', (54, 66))	('differentially expressed', 'MPA', (18, 42))	('down-regulated', 'NegReg', (75, 89))	('PBRM1', 'Gene', (139, 144))
28991	27556922	Surprisingly, 26 transcriptional factors (TFs) genes including HOXB9, PAX6 and FOXC1 were found to be significantly differentially expressed (23 over expressed TFs and three lower expressed TFs) in PBRM1 mutated group compared with "pan-negative" group.	('PBRM1', 'Gene', (198, 203))	('PBRM1', 'Gene', '55193', (198, 203))	('mutated', 'Var', (204, 211))	('FOXC1', 'Gene', '2296', (79, 84))	('PAX6', 'Gene', (70, 74))	('PAX6', 'Gene', '5080', (70, 74))	('FOXC1', 'Gene', (79, 84))	('HOXB9', 'Gene', '3219', (63, 68))	('over expressed', 'PosReg', (145, 159))	('HOXB9', 'Gene', (63, 68))
28992	27556922	In addition, we identified 1405 differentially methylated CpG sites (targeting 1308 genes,  log2FC  < 1, p < 0.01) and 185 significantly altered microRNAs ( log2FC  < 1, p < 0.05) associated with truncated PBRM1 mutations.	('truncated', 'Var', (196, 205))	('associated', 'Reg', (180, 190))	('PBRM1', 'Gene', (206, 211))	('PBRM1', 'Gene', '55193', (206, 211))	('mutations', 'Var', (212, 221))	('altered', 'Reg', (137, 144))	('microRNAs', 'MPA', (145, 154))
28993	27556922	Our integrative analysis suggested that methylation and miRNA alterations were likely the downstream events associated with PBRM1 truncation mutations.	('miRNA alterations', 'MPA', (56, 73))	('PBRM1', 'Gene', (124, 129))	('methylation', 'biological_process', 'GO:0032259', ('40', '51'))	('truncation mutations', 'Var', (130, 150))	('methylation', 'MPA', (40, 51))	('PBRM1', 'Gene', '55193', (124, 129))
28994	27556922	In summary, this study provided some important insights into the understanding of tumorigenesis driven by PBRM1 truncated mutations in ccRCC.	('PBRM1', 'Gene', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('PBRM1', 'Gene', '55193', (106, 111))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('RCC', 'Disease', (137, 140))	('tumor', 'Disease', (82, 87))	('truncated mutations', 'Var', (112, 131))
29000	27556922	Unlike other cancer types that are found to have recurrent mutations in oncogenes, ccRCC tumors are mainly associated with somatic mutations in tumor suppressor genes such as VHL, PBRM1, BAP1 and SETD2.	('tumors', 'Disease', (89, 95))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('144', '160'))	('VHL', 'Disease', 'MESH:D006623', (175, 178))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('SETD2', 'Gene', '29072', (196, 201))	('tumor suppressor', 'biological_process', 'GO:0051726', ('144', '160'))	('BAP1', 'Gene', '8314', (187, 191))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('PBRM1', 'Gene', '55193', (180, 185))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', (144, 149))	('VHL', 'Disease', (175, 178))	('associated', 'Reg', (107, 117))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cancer', 'Disease', (13, 19))	('BAP1', 'Gene', (187, 191))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('PBRM1', 'Gene', (180, 185))	('mutations', 'Var', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('RCC', 'Disease', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('SETD2', 'Gene', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
29005	27556922	PBRM1 mutations in ccRCC samples may lead to a dysregulation of several critical cell signaling pathways including actin-based motility by rho, tight junction signaling, axonal guidance signaling and germ cell-sertoli cell junction signaling.	('PBRM1', 'Gene', '55193', (0, 5))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('critical cell signaling pathways', 'Pathway', (72, 104))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('lead to', 'Reg', (37, 44))	('PBRM1', 'Gene', (0, 5))	('tight junction signaling', 'MPA', (144, 168))	('sertoli cell', 'Phenotype', 'HP:0100619', (210, 222))	('signaling', 'biological_process', 'GO:0023052', ('159', '168'))	('actin-based motility', 'CPA', (115, 135))	('mutations', 'Var', (6, 15))	('axonal', 'CPA', (170, 176))	('cell junction', 'cellular_component', 'GO:0030054', ('218', '231'))	('dysregulation', 'MPA', (47, 60))	('signaling', 'biological_process', 'GO:0023052', ('232', '241'))	('tight junction', 'cellular_component', 'GO:0070160', ('144', '158'))	('germ cell-sertoli cell', 'Pathway', (200, 222))	('signaling', 'biological_process', 'GO:0023052', ('186', '195'))	('RCC', 'Disease', (21, 24))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('ccRCC', 'Phenotype', 'HP:0006770', (19, 24))
29006	27556922	Furthermore, mutations in PBRM1 are identified as the root of tumor evolution in a subgroup of ccRCC.	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('PBRM1', 'Gene', (26, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('PBRM1', 'Gene', '55193', (26, 31))	('tumor', 'Disease', (62, 67))	('mutations', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
29008	27556922	Such an analysis is important because tumor suppressor genes play function largely through truncated mutations.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('38', '54'))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('truncated mutations', 'Var', (91, 110))	('tumor suppressor', 'biological_process', 'GO:0051726', ('38', '54'))
29009	27556922	Here, we performed an integrative genomics analysis to investigate the biological consequences of truncated PBRM1 mutations in ccRCC.	('PBRM1', 'Gene', '55193', (108, 113))	('mutations', 'Var', (114, 123))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('RCC', 'Disease', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('PBRM1', 'Gene', (108, 113))
29011	27556922	We systemically compared molecular features in a total of 11 mutated PBRM1 samples with those in 33 "pan-negative" samples; and those samples were all exclusive of any of the five known ccRCC driver genes (VHL, BAP1, SETD2, PTEN and KDM5C).	('PTEN', 'Gene', '5728', (224, 228))	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('VHL', 'Disease', 'MESH:D006623', (206, 209))	('BAP1', 'Gene', '8314', (211, 215))	('VHL', 'Disease', (206, 209))	('PBRM1', 'Gene', (69, 74))	('SETD2', 'Gene', '29072', (217, 222))	('RCC', 'Disease', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('KDM5C', 'Gene', (233, 238))	('mutated', 'Var', (61, 68))	('BAP1', 'Gene', (211, 215))	('SETD2', 'Gene', (217, 222))	('ccRCC', 'Phenotype', 'HP:0006770', (186, 191))	('PBRM1', 'Gene', '55193', (69, 74))	('KDM5C', 'Gene', '8242', (233, 238))	('PTEN', 'Gene', (224, 228))
29012	27556922	We identified a substantial proportion of molecular alterations including changes in gene expression, DNA methylation, and dysregulation of microRNAs (miRNAs) that were significantly associated with truncated PBRM1 mutations, as well as the follow up pathway, co-expression network, and hypothesized mechanism analysis.	('gene expression', 'biological_process', 'GO:0010467', ('85', '100'))	('truncated', 'Var', (199, 208))	('changes', 'Reg', (74, 81))	('gene expression', 'MPA', (85, 100))	('DNA methylation', 'MPA', (102, 117))	('PBRM1', 'Gene', (209, 214))	('PBRM1', 'Gene', '55193', (209, 214))	('mutations', 'Var', (215, 224))	('dysregulation', 'MPA', (123, 136))	('associated', 'Reg', (183, 193))	('DNA methylation', 'biological_process', 'GO:0006306', ('102', '117'))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))
29014	27556922	After examining PBRM1 mutations, we separated samples into two groups including 177 mutated PBRM1 samples and 371 non-mutated PBRM1 samples, respectively (Additional file 1).	('PBRM1', 'Gene', '55193', (16, 21))	('PBRM1', 'Gene', (126, 131))	('PBRM1', 'Gene', '55193', (92, 97))	('PBRM1', 'Gene', '55193', (126, 131))	('mutated', 'Var', (84, 91))	('mutations', 'Var', (22, 31))	('PBRM1', 'Gene', (16, 21))	('PBRM1', 'Gene', (92, 97))
29016	27556922	This process resulted in 31 PBRM1 mutated samples and 109 "pan-negative" samples, respectively (Fig.	('PBRM1', 'Gene', (28, 33))	('PBRM1', 'Gene', '55193', (28, 33))	('mutated', 'Var', (34, 41))
29017	27556922	In the next step, we identified the samples with matched RNA-Seq, DNA methylation, and microRNA-Seq data; this resulted in a total of 11 mutated PBRM1 samples and 33 "pan-negative" samples.	('DNA methylation', 'biological_process', 'GO:0006306', ('66', '81'))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('RNA', 'cellular_component', 'GO:0005562', ('57', '60'))	('mutated', 'Var', (137, 144))	('PBRM1', 'Gene', (145, 150))	('PBRM1', 'Gene', '55193', (145, 150))	('resulted in', 'Reg', (111, 122))
29018	27556922	Importantly, those 11 samples carried "loss of function" mutations in PBRM1 gene, including five nonsense mutations, three splice sites mutations and three frame shift deletions (Fig.	('mutations', 'Var', (57, 66))	('PBRM1', 'Gene', (70, 75))	('frame', 'Var', (156, 161))	('PBRM1', 'Gene', '55193', (70, 75))
29019	27556922	We performed a comparative analysis on gene expression profiles to identify the differential expressed genes (DEGs) between the PBRM1 mutated group and "pan-negative" group using edgeR.	('mutated', 'Var', (134, 141))	('PBRM1', 'Gene', '55193', (128, 133))	('gene expression', 'biological_process', 'GO:0010467', ('39', '54'))	('PBRM1', 'Gene', (128, 133))
29020	27556922	At a significance threshold of absolute log2 transferred fold change ( log2FC ) > 1 and p < 0.05, a total of 613 DEGs were identified including 128 genes having over expression and 485 genes showing lower expression in PBRM1 mutated samples compared with the "pan-negative" group (Fig.	('lower', 'NegReg', (199, 204))	('over expression', 'PosReg', (161, 176))	('mutated', 'Var', (225, 232))	('PBRM1', 'Gene', (219, 224))	('PBRM1', 'Gene', '55193', (219, 224))	('expression', 'MPA', (205, 215))
29021	27556922	Interestingly, four Antp homeobox family and two forkhead family transcriptional factors (HOXA1, HOXB5, HOXB8, HOXB9, FOXP1, and FOXC1) that are involved in cell development and proliferation were found to be down-regulated in the PBRM1 mutated group versus "pan-negative" group.	('FOXC1', 'Gene', '2296', (129, 134))	('PBRM1', 'Gene', '55193', (231, 236))	('HOXA1', 'Gene', (90, 95))	('men', 'Species', '9606', (169, 172))	('HOXB8', 'Gene', (104, 109))	('Antp', 'Protein', (20, 24))	('PBRM1', 'Gene', (231, 236))	('HOXB9', 'Gene', (111, 116))	('FOXP1', 'Gene', '27086', (118, 123))	('cell development', 'biological_process', 'GO:0048468', ('157', '173'))	('HOXB5', 'Gene', (97, 102))	('HOXA1', 'Gene', '3198', (90, 95))	('FOXC1', 'Gene', (129, 134))	('HOXB8', 'Gene', '3218', (104, 109))	('down-regulated', 'NegReg', (209, 223))	('FOXP1', 'Gene', (118, 123))	('HOXB9', 'Gene', '3219', (111, 116))	('proliferation', 'CPA', (178, 191))	('HOXB5', 'Gene', '3215', (97, 102))	('mutated', 'Var', (237, 244))
29022	27556922	Additionally, GATA3, a transcription factor that was observed to be down-regulated in PBRM1 mutated group in our study, was previously found to be an important early event and potential regulator that associated with loss of TGFbeta receptor expression in ccRCC (Fig.	('RCC', 'Disease', (258, 261))	('transcription', 'biological_process', 'GO:0006351', ('23', '36'))	('down-regulated', 'NegReg', (68, 82))	('GATA3', 'Gene', '2625', (14, 19))	('ccRCC', 'Phenotype', 'HP:0006770', (256, 261))	('transcription factor', 'molecular_function', 'GO:0000981', ('23', '43'))	('PBRM1', 'Gene', (86, 91))	('TGFbeta receptor', 'Gene', (225, 241))	('mutated', 'Var', (92, 99))	('PBRM1', 'Gene', '55193', (86, 91))	('RCC', 'Phenotype', 'HP:0005584', (258, 261))	('GATA3', 'Gene', (14, 19))	('loss', 'NegReg', (217, 221))	('RCC', 'Disease', 'MESH:C538614', (258, 261))
29025	27556922	We analyzed genome-scale DNA methylation profiles by comparing beta-value changes (measured as beta-differences) between mutated PBRM1 group and "pan-negative" group (see Methods).	('PBRM1', 'Gene', (129, 134))	('PBRM1', 'Gene', '55193', (129, 134))	('mutated', 'Var', (121, 128))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))	('beta-value', 'MPA', (63, 73))	('DNA methylation', 'biological_process', 'GO:0006306', ('25', '40'))
29026	27556922	Among those genes, 1229 hyper-methylated (94 %) and 79 hypo-methylated genes (6 %) were observed in PBRM1 mutated samples compared to the "pan-negative" samples, suggesting that an global gene inactivation may be associated with PBRM1 truncated mutations (Additional file 2: Table S4, Additional file 4: Figure S2).	('PBRM1', 'Gene', '55193', (229, 234))	('global', 'MPA', (181, 187))	('PBRM1', 'Gene', (100, 105))	('inactivation', 'NegReg', (193, 205))	('PBRM1', 'Gene', '55193', (100, 105))	('PBRM1', 'Gene', (229, 234))	('truncated mutations', 'Var', (235, 254))	('mutated', 'Var', (106, 113))
29027	27556922	This observation is consistent with the differential gene expression results above (more down-regulated genes than up-regulated genes in PBRM1 group); however, these genes may not be immediately regulated by PBRM1 because truncated mutations in a tumor suppressor gene are expected to result in up-regulation of its immediately regulated gene according to the "loss of function" model.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('gene expression', 'biological_process', 'GO:0010467', ('53', '68'))	('PBRM1', 'Gene', '55193', (208, 213))	('immediately regulated gene', 'MPA', (316, 342))	('tumor', 'Disease', (247, 252))	('PBRM1', 'Gene', (137, 142))	('PBRM1', 'Gene', '55193', (137, 142))	('up-regulation', 'PosReg', (295, 308))	('tumor suppressor', 'biological_process', 'GO:0051726', ('247', '263'))	('truncated mutations', 'Var', (222, 241))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('247', '263'))	('PBRM1', 'Gene', (208, 213))	('regulation', 'biological_process', 'GO:0065007', ('298', '308'))
29028	27556922	Functional enrichment analyses indicated that those hyper-methylated genes were significantly enriched in multiple processes including generation of neurons (q = 1.20 x 10-5), cell differentiation (q = 1.22 x 10-5), and regulation of catabolic process (q = 4.02 x 10-5), while glomerulus development was observed to be most significant in hypo-methylated genes (q = 3.21 x 10-3) (Additional file 2: Tables S5 and S6, Additional file 4: Figure S2).	('generation of neurons', 'biological_process', 'GO:0048699', ('135', '156'))	('cell differentiation', 'CPA', (176, 196))	('regulation of catabolic process', 'biological_process', 'GO:0009894', ('220', '251'))	('men', 'Species', '9606', (295, 298))	('glomerulus development', 'biological_process', 'GO:0032835', ('277', '299'))	('hyper-methylated', 'Var', (52, 68))	('cell differentiation', 'biological_process', 'GO:0030154', ('176', '196'))	('men', 'Species', '9606', (17, 20))
29029	27556922	A total of 185 differentially expressed miRNAs were identified to be associated with PBRM1 truncation mutations using the cutoffs: absolute log2 transferred fold change ( log2FC ) > 1 and p < 0.05.	('PBRM1', 'Gene', (85, 90))	('truncation mutations', 'Var', (91, 111))	('PBRM1', 'Gene', '55193', (85, 90))	('associated', 'Reg', (69, 79))
29030	27556922	Among them, 87 miRNAs exhibited up-regulation pattern in PBRM1 mutated samples while the remaining 98 miRNAs exhibited down-regulation pattern (Fig.	('mutated', 'Var', (63, 70))	('PBRM1', 'Gene', (57, 62))	('regulation', 'biological_process', 'GO:0065007', ('35', '45'))	('PBRM1', 'Gene', '55193', (57, 62))	('down-regulation', 'NegReg', (119, 134))	('up-regulation', 'PosReg', (32, 45))	('regulation', 'biological_process', 'GO:0065007', ('124', '134'))
29031	27556922	Interestingly, three identified miRNAs (miR-221, miR-222 and miR-16) exhibiting down-regulation patterns in PBRM1 mutated group were consistent with the previous reports by experimental studies.	('PBRM1', 'Gene', '55193', (108, 113))	('miR-221', 'Gene', '407006', (40, 47))	('men', 'Species', '9606', (179, 182))	('regulation', 'biological_process', 'GO:0065007', ('85', '95'))	('down-regulation', 'NegReg', (80, 95))	('miR-222', 'Gene', '407007', (49, 56))	('miR-16', 'Gene', '51573', (61, 67))	('mutated', 'Var', (114, 121))	('miR-221', 'Gene', (40, 47))	('PBRM1', 'Gene', (108, 113))	('miR-222', 'Gene', (49, 56))	('miR-16', 'Gene', (61, 67))
29032	27556922	Comparisons between miRNA targets and DEGs revealed that 14 miRNA target genes were up-regulated while 129 were down-regulated, in which nine miRNA target genes were hyper-methylated and also down-regulated in PBRM1 mutated group (Fig.	('down-regulated', 'NegReg', (192, 206))	('up-regulated', 'PosReg', (84, 96))	('PBRM1', 'Gene', (210, 215))	('hyper-methylated', 'PosReg', (166, 182))	('mutated', 'Var', (216, 223))	('PBRM1', 'Gene', '55193', (210, 215))
29035	27556922	Six miRNAs (miR-17-5p, miR-9-5p, miR-16-5p, miR-615-3p, miR-124-3p, and miR-93-5p) were observed in both up-regulated and down-regulated co-expression networks, in which different possible targets were involved.	('miR-124-3p', 'Gene', '406909', (56, 66))	('down-regulated', 'NegReg', (122, 136))	('miR-124-3p', 'Gene', (56, 66))	('miR-93', 'Gene', '407051', (72, 78))	('up-regulated', 'PosReg', (105, 117))	('miR-93', 'Gene', (72, 78))	('co-expression networks', 'Pathway', (137, 159))	('miR-17-5p', 'Gene', '406952', (12, 21))	('miR-615-3p', 'Var', (44, 54))	('miR-16', 'Gene', (33, 39))	('miR-17-5p', 'Gene', (12, 21))	('miR-9-5p', 'Gene', (23, 31))	('miR-9-5p', 'Gene', '407052', (23, 31))	('miR-16', 'Gene', '51573', (33, 39))
29038	27556922	Similarly, SDCBP2 and PAX6 were found to be positively co-expressed with many genes in the down-regulated co-expression network (Additional file 1), which further verified the association of compound metabolisms and development with PBRM1 truncation mutations.	('SDCBP2', 'Gene', (11, 17))	('PAX6', 'Gene', (22, 26))	('PAX6', 'Gene', '5080', (22, 26))	('men', 'Species', '9606', (223, 226))	('development', 'CPA', (216, 227))	('PBRM1', 'Gene', (233, 238))	('PBRM1', 'Gene', '55193', (233, 238))	('association', 'Interaction', (176, 187))	('truncation mutations', 'Var', (239, 259))	('SDCBP2', 'Gene', '27111', (11, 17))
29039	27556922	Collectively, PBRM1 truncated mutations may lead to the pre-transcriptional deregulation at DNA methylation level and the post-transcriptional deregulation at the miRNA expression level.	('lead to', 'Reg', (44, 51))	('DNA methylation', 'biological_process', 'GO:0006306', ('92', '107'))	('pre', 'molecular_function', 'GO:0003904', ('56', '59'))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('post-transcriptional deregulation', 'MPA', (122, 155))	('PBRM1', 'Gene', (14, 19))	('mutations', 'Var', (30, 39))	('PBRM1', 'Gene', '55193', (14, 19))
29041	27556922	Based on our integrative genomic analysis results, we proposed the possible regulations linked to the PBRM1 truncated mutations in the tumorigenesis of ccRCC (Fig.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('PBRM1', 'Gene', (102, 107))	('mutations', 'Var', (118, 127))	('PBRM1', 'Gene', '55193', (102, 107))	('tumor', 'Disease', (135, 140))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('RCC', 'Disease', (154, 157))	('RCC', 'Phenotype', 'HP:0005584', (154, 157))	('ccRCC', 'Phenotype', 'HP:0006770', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
29043	27556922	This study highlights the association between PBRM1 truncated mutations and decreased extracellular matrix organization, cell adhesion, ion transport and tissue development.	('cell adhesion', 'biological_process', 'GO:0007155', ('121', '134'))	('tissue development', 'biological_process', 'GO:0009888', ('154', '172'))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('86', '106'))	('extracellular matrix organization', 'CPA', (86, 119))	('cell adhesion', 'CPA', (121, 134))	('decreased', 'NegReg', (76, 85))	('truncated mutations', 'Var', (52, 71))	('ion transport', 'biological_process', 'GO:0006811', ('136', '149'))	('PBRM1', 'Gene', (46, 51))	('extracellular matrix organization', 'biological_process', 'GO:0030198', ('86', '119'))	('tissue development', 'CPA', (154, 172))	('ion transport', 'CPA', (136, 149))	('PBRM1', 'Gene', '55193', (46, 51))	('men', 'Species', '9606', (168, 171))
29045	27556922	In this study, there are more differentially methylated genes (1308 genes) than differential expressed genes (613 genes) in PBRM1 mutated group, suggesting a complicated pre-transcriptional level regulation with DNA methylation involved in PBRM1 mutations.	('regulation', 'biological_process', 'GO:0065007', ('196', '206'))	('DNA', 'cellular_component', 'GO:0005574', ('212', '215'))	('PBRM1', 'Gene', (240, 245))	('mutations', 'Var', (246, 255))	('PBRM1', 'Gene', (124, 129))	('mutated', 'Var', (130, 137))	('PBRM1', 'Gene', '55193', (240, 245))	('DNA methylation', 'biological_process', 'GO:0006306', ('212', '227'))	('pre', 'molecular_function', 'GO:0003904', ('170', '173'))	('PBRM1', 'Gene', '55193', (124, 129))
29046	27556922	Studying the downstream events of a driver gene has become important now because the scientific community has witnessed large amount of genomic data allowing the sample stratification by driver mutation and also because a driver gene may lead to many critical biological events linking to tumorigenesis or drug treatment.	('lead to', 'Reg', (238, 245))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('men', 'Species', '9606', (316, 319))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('tumor', 'Disease', (289, 294))	('gene', 'Var', (229, 233))
29049	27556922	Observations in this study are based on 11 PBRM1 mutated and 33 "pan-negative" ccRCC samples, which may have some bias because of the small sample size.	('mutated', 'Var', (49, 56))	('PBRM1', 'Gene', (43, 48))	('PBRM1', 'Gene', '55193', (43, 48))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))
29051	27556922	This is especially important in cancer genomics studies because driver mutations may affect the same or similar signaling pathways (e.g., Ras pathway).	('signaling pathways', 'Pathway', (112, 130))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('signaling', 'biological_process', 'GO:0023052', ('112', '121'))	('mutations', 'Var', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('affect', 'Reg', (85, 91))	('Ras pathway', 'Pathway', (138, 149))
29052	27556922	Our results suggest that PBRM1 mutations are an important event in the early stage of ccRCC tumor genetics, which paves the way for further PBRM1-related research in ccRCC.	('mutations', 'Var', (31, 40))	('PBRM1', 'Gene', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (166, 171))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('PBRM1', 'Gene', '55193', (140, 145))	('PBRM1', 'Gene', (25, 30))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('tumor', 'Disease', (92, 97))	('RCC', 'Disease', (168, 171))	('PBRM1', 'Gene', '55193', (25, 30))
29053	27556922	To excluded the influences of other driver genes and highlight the effects of PBRM1 in ccRCC, we defined the "pan-negative" ccRCC sample set by excluding samples that contained somatic mutations in any of the five well-known driver genes in ccRCC.	('PBRM1', 'Gene', '55193', (78, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (241, 246))	('RCC', 'Disease', (126, 129))	('RCC', 'Disease', (89, 92))	('RCC', 'Disease', (243, 246))	('RCC', 'Disease', 'MESH:C538614', (243, 246))	('RCC', 'Phenotype', 'HP:0005584', (243, 246))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('mutations', 'Var', (185, 194))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (124, 129))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('PBRM1', 'Gene', (78, 83))
29054	27556922	Our integrative analysis using methylation, gene expression, and miRNA expression is the first to study the PBRM1 truncation mutation specific dysfunction in co-expressed networks.	('PBRM1', 'Gene', '55193', (108, 113))	('gene expression', 'biological_process', 'GO:0010467', ('44', '59'))	('truncation mutation', 'Var', (114, 133))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('PBRM1', 'Gene', (108, 113))
29055	27556922	All mutations in 11 PBRM1 mutated samples are truncation mutations, which signify dysfunction state of PBRM1 as a tumor suppressor gene in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (139, 144))	('RCC', 'Disease', (141, 144))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('tumor suppressor', 'biological_process', 'GO:0051726', ('114', '130'))	('PBRM1', 'Gene', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('truncation', 'Var', (46, 56))	('PBRM1', 'Gene', '55193', (20, 25))	('tumor', 'Disease', (114, 119))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('114', '130'))	('PBRM1', 'Gene', (103, 108))	('PBRM1', 'Gene', '55193', (103, 108))	('mutations', 'Var', (4, 13))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
29056	27556922	First, how our results are related to the influence of PBRM1 on tumor prognosis needs further investigation because previous studies suggest the association between PBRM1 mutations and prognosis of ccRCC is still unclear.	('ccRCC', 'Phenotype', 'HP:0006770', (198, 203))	('tumor', 'Disease', (64, 69))	('RCC', 'Disease', (200, 203))	('RCC', 'Phenotype', 'HP:0005584', (200, 203))	('RCC', 'Disease', 'MESH:C538614', (200, 203))	('PBRM1', 'Gene', (165, 170))	('PBRM1', 'Gene', '55193', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('PBRM1', 'Gene', (55, 60))	('mutations', 'Var', (171, 180))	('PBRM1', 'Gene', '55193', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
29060	27556922	Our analysis focuses on the gene level changes that associated with PBRM1 truncated mutation, in which protein level changes were not considered because of the complicated regulation from gene expression level to protein level.	('PBRM1', 'Gene', (68, 73))	('regulation', 'biological_process', 'GO:0065007', ('172', '182'))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('protein', 'cellular_component', 'GO:0003675', ('213', '220'))	('PBRM1', 'Gene', '55193', (68, 73))	('gene expression', 'biological_process', 'GO:0010467', ('188', '203'))	('truncated mutation', 'Var', (74, 92))
29062	27556922	It is most frequently mutated in ccRCC.	('RCC', 'Disease', (35, 38))	('mutated', 'Var', (22, 29))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))
29063	27556922	Loss of function and expression of PBRM1 was less common in non-ccRCC than in ccRCC, suggesting a specific regulatory role of PBRM1 truncation mutations in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('PBRM1', 'Gene', (126, 131))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('truncation mutations', 'Var', (132, 152))	('ccRCC', 'Phenotype', 'HP:0006770', (156, 161))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('PBRM1', 'Gene', '55193', (126, 131))	('Loss of function', 'NegReg', (0, 16))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))	('PBRM1', 'Gene', (35, 40))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('PBRM1', 'Gene', '55193', (35, 40))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))
29066	27556922	Future studies to dissect the role of PBRM1 in different cancer types would be helpful to better understand the mechanisms of PBRM1 truncation mutations and tumorigenesis.	('tumor', 'Disease', (157, 162))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('PBRM1', 'Gene', (126, 131))	('cancer', 'Disease', (57, 63))	('truncation mutations', 'Var', (132, 152))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('PBRM1', 'Gene', (38, 43))	('PBRM1', 'Gene', '55193', (126, 131))	('PBRM1', 'Gene', '55193', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
29068	27556922	Our study investigated molecular alterations including gene expression, methylation, and miRNA expression that associated with PBRM1 truncation mutations in clear cell renal cell carcinoma.	('gene expression', 'biological_process', 'GO:0010467', ('55', '70'))	('methylation', 'biological_process', 'GO:0032259', ('72', '83'))	('PBRM1', 'Gene', (127, 132))	('truncation mutations', 'Var', (133, 153))	('PBRM1', 'Gene', '55193', (127, 132))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (157, 188))	('miRNA expression', 'MPA', (89, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('clear cell renal cell carcinoma', 'Disease', (157, 188))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (157, 188))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (168, 188))
29069	27556922	Our analysis results identified 613 differentially expressed genes, 1308 differentially methylated genes and 185 differentially expressed miRNAs between PBRM1 mutated group and "pan-negative" group.	('PBRM1', 'Gene', '55193', (153, 158))	('mutated', 'Var', (159, 166))	('PBRM1', 'Gene', (153, 158))
29070	27556922	Hypothesized mechanisms of PBRM1 mutations in ccRCC were explored based on the integrative analysis results.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('mutations', 'Var', (33, 42))	('PBRM1', 'Gene', (27, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('PBRM1', 'Gene', '55193', (27, 32))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
29073	27556922	177 of 548 ccRCC samples (32.3 %) were identified to have PBRM1 mutations and 371 samples (67.7 %) were identified as PBRM1 non-mutated or control samples.	('PBRM1', 'Gene', '55193', (118, 123))	('PBRM1', 'Gene', (58, 63))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('PBRM1', 'Gene', '55193', (58, 63))	('RCC', 'Disease', (13, 16))	('mutations', 'Var', (64, 73))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('ccRCC', 'Phenotype', 'HP:0006770', (11, 16))	('PBRM1', 'Gene', (118, 123))
29075	27556922	Samples with somatic mutations of those five genes were excluded from both mutated and non-mutated PBRM1 samples, resulting in 31 PBRM1 mutated samples and 109 "pan-negative" samples (Fig.	('PBRM1', 'Gene', (130, 135))	('PBRM1', 'Gene', (99, 104))	('PBRM1', 'Gene', '55193', (99, 104))	('PBRM1', 'Gene', '55193', (130, 135))	('mutated', 'Var', (136, 143))
29076	27556922	Finally, 11 PBRM1 mutated samples and 33 "pan-negative" samples that had DNA methylation, gene expression, and miRNA expression data were utilized for all the analyses in this study.	('PBRM1', 'Gene', (12, 17))	('DNA methylation', 'biological_process', 'GO:0006306', ('71', '86'))	('gene expression', 'biological_process', 'GO:0010467', ('88', '103'))	('PBRM1', 'Gene', '55193', (12, 17))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('mutated', 'Var', (18, 25))
29077	27556922	beta-difference value (differences between beta-values) was used to characterize different methylation levels between PBRM1 mutated group and non-mutated "pan-negative" group.	('methylation levels', 'MPA', (91, 109))	('PBRM1', 'Gene', '55193', (118, 123))	('mutated', 'Var', (124, 131))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))	('PBRM1', 'Gene', (118, 123))
29084	27556922	485 down-regulated genes and miRNAs with targets in down-regulated genes were mapped into the reference network, resulting in a PBRM1 mutation specific, down-regulated co-expression network.	('PBRM1', 'Gene', '55193', (128, 133))	('co-expression network', 'MPA', (168, 189))	('mutation', 'Var', (134, 142))	('down-regulated', 'NegReg', (4, 18))	('down-regulated', 'NegReg', (153, 167))	('PBRM1', 'Gene', (128, 133))
29094	32280241	We further confirmed that knockdown of KIF4A suppressed cell proliferation in HTB-47 and CRL-1932 cells.	('KIF4A', 'Gene', (39, 44))	('suppressed', 'NegReg', (45, 55))	('knockdown', 'Var', (26, 35))	('cell proliferation', 'CPA', (56, 74))	('HTB-47', 'CellLine', 'CVCL:L675', (78, 84))	('KIF4A', 'Gene', '24137', (39, 44))	('cell proliferation', 'biological_process', 'GO:0008283', ('56', '74'))	('CRL-1932', 'CellLine', 'None', (89, 97))
29103	32280241	VHL was reportedly considered a potential molecular target for ccRCC, but more mutations were subsequently discovered, such as these mutations in ccRCC leading to further identification of their possible therapeutic role in this cancer.	('RCC', 'Disease', (148, 151))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('VHL', 'Gene', (0, 3))	('mutations', 'Var', (133, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('VHL', 'Gene', '7428', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
29112	32280241	KIF4A ablation also leads to inhibition of lung cancer cell proliferation.	('lung cancer', 'Disease', (43, 54))	('KIF4A', 'Gene', '24137', (0, 5))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('inhibition', 'NegReg', (29, 39))	('cell proliferation', 'biological_process', 'GO:0008283', ('55', '73'))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('ablation', 'Var', (6, 14))	('KIF4A', 'Gene', (0, 5))
29116	32280241	Furthermore, our results indicated that KIF4A depletion dramatically inhibited ccRCC cell proliferation and inhibited tumor growth in mice.	('depletion', 'Var', (46, 55))	('KIF4A', 'Gene', '24137', (40, 45))	('mice', 'Species', '10090', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('cell proliferation', 'biological_process', 'GO:0008283', ('85', '103'))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('tumor', 'Disease', (118, 123))	('KIF4A', 'Gene', (40, 45))	('inhibited', 'NegReg', (69, 78))	('inhibited', 'NegReg', (108, 117))
29119	32280241	Anti-KIF4A (for IHC assays, 1:400 dilution, for immunoblot assays, 1:1000 dilution, ab12227, Abcam, Cambridge, UK), Anti-beta-actin (1:1000 dilution, ab8226, Abcam), Anti-Ki67 (1:1000 dilution, ab16667, Abcam), Anti-proliferating cell nuclear antigen (PCNA) (1:500 dilution, ab92552, Abcam).	('Ki67', 'Gene', '17345', (171, 175))	('proliferating cell nuclear antigen', 'molecular_function', 'GO:0003892', ('216', '250'))	('PCNA', 'Gene', (252, 256))	('PCNA', 'molecular_function', 'GO:0003892', ('252', '256'))	('Ki67', 'Gene', (171, 175))	('Anti-proliferating cell nuclear antigen', 'Gene', '5111', (211, 250))	('1:1000', 'Var', (177, 183))	('Anti-proliferating cell nuclear antigen', 'Gene', (211, 250))	('PCNA', 'Gene', '5111', (252, 256))	('KIF4A', 'Gene', (5, 10))	('beta-actin', 'Gene', '728378', (121, 131))	('beta-actin', 'Gene', (121, 131))	('KIF4A', 'Gene', '24137', (5, 10))
29139	32280241	KIF4A shRNA plasmids were transfected into HTB-47 and CRL-1932 cells were conducted using lipofectamine 2000 (11668019, Invitrogen, Carlsbad, CA, USA).	('KIF4A', 'Gene', '24137', (0, 5))	('CRL-1932', 'CellLine', 'None', (54, 62))	('lipofectamine 2000', 'Chemical', 'MESH:C086724', (90, 108))	('HTB-47', 'CellLine', 'CVCL:L675', (43, 49))	('11668019', 'Var', (110, 118))	('KIF4A', 'Gene', (0, 5))
29141	32280241	Total RNA from human ccRCC cells were extracted via Trizol reagent (15596026, Invitrogen, Carlsbad, CA, USA).	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('Trizol', 'Chemical', 'MESH:C411644', (52, 58))	('15596026', 'Var', (68, 76))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (21, 26))	('RCC', 'Disease', (23, 26))	('human', 'Species', '9606', (15, 20))
29162	32280241	We noticed patients with high KIF4A expression had poor overall survival (OS) and disease-free survival (DFS).	('disease-free survival', 'CPA', (82, 103))	('KIF4A', 'Gene', '24137', (30, 35))	('overall survival', 'CPA', (56, 72))	('high', 'Var', (25, 29))	('poor', 'NegReg', (51, 55))	('patients', 'Species', '9606', (11, 19))	('KIF4A', 'Gene', (30, 35))	('expression', 'MPA', (36, 46))
29173	32280241	To explore the potential function of KIF4A in ccRCC, the KIF4A shRNA plasmids were transfected into t HTB-47 and CRL-1932 cells, to knockdown KIF4A expression.	('KIF4A', 'Gene', '24137', (57, 62))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('knockdown', 'Var', (132, 141))	('KIF4A', 'Gene', (142, 147))	('HTB-47', 'CellLine', 'CVCL:L675', (102, 108))	('KIF4A', 'Gene', (37, 42))	('KIF4A', 'Gene', '24137', (142, 147))	('CRL-1932', 'CellLine', 'None', (113, 121))	('KIF4A', 'Gene', (57, 62))	('expression', 'MPA', (148, 158))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('KIF4A', 'Gene', '24137', (37, 42))	('RCC', 'Disease', (48, 51))
29177	32280241	The knockdown of KIF4A dramatically inhibited the proliferation of ccRCC cells, assessed by the significant reduction in colony numbers (Figure 4A).	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('KIF4A', 'Gene', (17, 22))	('RCC', 'Disease', (69, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('inhibited', 'NegReg', (36, 45))	('proliferation', 'CPA', (50, 63))	('KIF4A', 'Gene', '24137', (17, 22))	('colony numbers', 'CPA', (121, 135))	('knockdown', 'Var', (4, 13))	('reduction', 'NegReg', (108, 117))
29178	32280241	Similarly, through MTT assays, we observed an obvious decreased absorbance value in both HTB-47 and CRL-1932 cells with KIF4A ablation (Figure 4B).	('HTB-47', 'CellLine', 'CVCL:L675', (89, 95))	('KIF4A', 'Gene', '24137', (120, 125))	('MTT', 'Chemical', 'MESH:C070243', (19, 22))	('ablation', 'Var', (126, 134))	('decreased', 'NegReg', (54, 63))	('absorbance value', 'MPA', (64, 80))	('KIF4A', 'Gene', (120, 125))	('CRL-1932', 'CellLine', 'None', (100, 108))
29180	32280241	Consistently, KIF4A ablation resulted in an obvious reduction in Ki67 and PpCNA expression levels in HTB-47 and CRL-1932 cells (Figure 4C and D).	('KIF4A', 'Gene', (14, 19))	('Ki67', 'Gene', '17345', (65, 69))	('KIF4A', 'Gene', '24137', (14, 19))	('PpCNA', 'Gene', (74, 79))	('expression levels', 'MPA', (80, 97))	('HTB-47', 'CellLine', 'CVCL:L675', (101, 107))	('CRL-1932', 'CellLine', 'None', (112, 120))	('ablation', 'Var', (20, 28))	('Ki67', 'Gene', (65, 69))	('reduction', 'NegReg', (52, 61))
29182	32280241	Similar to our previous results, KIF4A ablation led to the inhibition of ccRCC cell proliferation in vitro, and then we speculated that KIF4A stimulated the development of ccRCC in mice.	('inhibition', 'NegReg', (59, 69))	('mice', 'Species', '10090', (181, 185))	('KIF4A', 'Gene', '24137', (136, 141))	('ablation', 'Var', (39, 47))	('KIF4A', 'Gene', (33, 38))	('cell proliferation', 'biological_process', 'GO:0008283', ('79', '97'))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('ccRCC', 'Phenotype', 'HP:0006770', (172, 177))	('RCC', 'Disease', (174, 177))	('KIF4A', 'Gene', '24137', (33, 38))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('KIF4A', 'Gene', (136, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))
29188	32280241	Additionally, silencing of KIF4A was confirmed by IHC assays (Figure 5B).	('silencing', 'Var', (14, 23))	('KIF4A', 'Gene', (27, 32))	('KIF4A', 'Gene', '24137', (27, 32))
29189	32280241	We also examined the expression level of Ki67 in control and KIF4A knockdown groups by IHC assays.	('Ki67', 'Gene', '17345', (41, 45))	('knockdown', 'Var', (67, 76))	('KIF4A', 'Gene', (61, 66))	('Ki67', 'Gene', (41, 45))	('KIF4A', 'Gene', '24137', (61, 66))
29190	32280241	As expected, Ki67 reduction was observed in tumors in the KIF4A knockdown groups, which indicates that KIF4A knockdown impaired proliferation capacity (Figure 5C).	('KIF4A', 'Gene', (103, 108))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('KIF4A', 'Gene', '24137', (58, 63))	('KIF4A', 'Gene', '24137', (103, 108))	('impaired', 'NegReg', (119, 127))	('knockdown', 'Var', (109, 118))	('Ki67', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('proliferation capacity', 'CPA', (128, 150))	('Ki67', 'Gene', '17345', (13, 17))	('KIF4A', 'Gene', (58, 63))
29198	32280241	Similarly, another study indicated that high expression of KIF4A is correlated with lymph node metastasis in patients with colorectal cancer.	('high', 'Var', (40, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (123, 140))	('KIF4A', 'Gene', '24137', (59, 64))	('lymph node metastasis', 'CPA', (84, 105))	('patients', 'Species', '9606', (109, 117))	('colorectal cancer', 'Disease', (123, 140))	('expression', 'MPA', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('correlated', 'Reg', (68, 78))	('KIF4A', 'Gene', (59, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (123, 140))
29208	32280241	Additionally, KIF4A promotes the proliferation of colorectal cancer by the regulation of p21-mediated cell cycle progression, and they found KIF4A knockdown obviously decreased the expression level of pAKT, and the expression level of MEK and ERK was comparable, suggesting that KIF4A promotes CRC proliferation through PI3K/AKT signaling pathway.	('KIF4A', 'Gene', (14, 19))	('p21', 'Gene', '644914', (89, 92))	('KIF4A', 'Gene', (141, 146))	('ERK', 'Gene', (243, 246))	('cell cycle', 'biological_process', 'GO:0007049', ('102', '112'))	('decreased', 'NegReg', (167, 176))	('MEK', 'Gene', '5609', (235, 238))	('AKT', 'Gene', '207', (325, 328))	('AKT', 'Gene', (325, 328))	('promotes', 'PosReg', (20, 28))	('KIF4A', 'Gene', '24137', (279, 284))	('colorectal cancer', 'Phenotype', 'HP:0003003', (50, 67))	('knockdown', 'Var', (147, 156))	('expression level', 'MPA', (181, 197))	('MEK', 'Gene', (235, 238))	('PI3K', 'molecular_function', 'GO:0016303', ('320', '324'))	('AKT', 'Gene', (202, 205))	('KIF4A', 'Gene', '24137', (14, 19))	('AKT signaling', 'biological_process', 'GO:0043491', ('325', '338'))	('KIF4A', 'Gene', '24137', (141, 146))	('regulation', 'biological_process', 'GO:0065007', ('75', '85'))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('CRC proliferation', 'CPA', (294, 311))	('ERK', 'molecular_function', 'GO:0004707', ('243', '246'))	('colorectal cancer', 'Disease', 'MESH:D015179', (50, 67))	('KIF4A', 'Gene', (279, 284))	('ERK', 'Gene', '5594', (243, 246))	('proliferation', 'CPA', (33, 46))	('promotes', 'PosReg', (285, 293))	('signaling pathway', 'biological_process', 'GO:0007165', ('329', '346'))	('AKT', 'Gene', '207', (202, 205))	('p21', 'Gene', (89, 92))	('colorectal cancer', 'Disease', (50, 67))
29212	32280241	Previous studies have indicated KIF4A could be phosphorylated by CDK1 at S1186, triggered chromosome compaction.	('triggered', 'PosReg', (80, 89))	('chromosome compaction', 'CPA', (90, 111))	('at S1186', 'Var', (70, 78))	('KIF4A', 'Gene', (32, 37))	('CDK', 'molecular_function', 'GO:0004693', ('65', '68'))	('chromosome', 'cellular_component', 'GO:0005694', ('90', '100'))	('CDK1', 'Gene', '983', (65, 69))	('CDK1', 'Gene', (65, 69))	('KIF4A', 'Gene', '24137', (32, 37))
29229	28912897	For the remaining tumor types, compared with TIMT II (low PD-L1 and CD8A/CYT), TIMT I (high PD-L1 and CD8A/CYT) had a significantly higher number of mutations or neoantigens in bladder urothelial carcinoma, breast and cervical cancer, colorectal, stomach and lung adenocarcinoma, and melanoma.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (177, 205))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (259, 278))	('CD8A', 'Gene', '925', (102, 106))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (259, 278))	('colorectal', 'Disease', 'MESH:D015179', (235, 245))	('tumor', 'Disease', (18, 23))	('melanoma', 'Phenotype', 'HP:0002861', (284, 292))	('melanoma', 'Disease', (284, 292))	('CD8A', 'Gene', '925', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('CD8A', 'Gene', (102, 106))	('stomach', 'Disease', (247, 254))	('higher', 'PosReg', (132, 138))	('mutations', 'Var', (149, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('neoantigens', 'Var', (162, 173))	('CD8A', 'Gene', (68, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('breast and cervical cancer', 'Disease', 'MESH:D001943', (207, 233))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('lung adenocarcinoma', 'Disease', (259, 278))	('melanoma', 'Disease', 'MESH:D008545', (284, 292))	('bladder urothelial carcinoma', 'Disease', (177, 205))	('colorectal', 'Disease', (235, 245))
29230	28912897	In contrast, TMIT I of kidney clear cell, liver hepatocellular, and thyroid carcinoma were negatively correlated with mutation burden or neoantigen numbers.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (68, 85))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (68, 85))	('liver hepatocellular', 'Disease', 'MESH:D056486', (42, 62))	('mutation burden', 'Var', (118, 133))	('negatively', 'NegReg', (91, 101))	('TMIT', 'Chemical', '-', (13, 17))	('thyroid carcinoma', 'Disease', (68, 85))	('liver hepatocellular', 'Disease', (42, 62))
29233	28912897	Inhibition of immune checkpoint proteins, primarily CTLA-4 or PD-1/PD-L1 may reduce the ability of the tumor microenvironment to suppress host antitumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('CTLA-4', 'Gene', (52, 58))	('reduce', 'NegReg', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('PD-1/PD-L1', 'Gene', (62, 72))	('tumor', 'Disease', (103, 108))	('suppress', 'NegReg', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('Inhibition', 'Var', (0, 10))	('CTLA-4', 'Gene', '1493', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
29256	28912897	As per the study by Teng and colleagues, we classified TCGA samples of each cancer type into four TMITs by merging the mRNA expression levels of PD-L1 and CD8A, or PD-L1 and CYT as follows: type I, PD-L1 high expression and CD8A/CYT high expression; type II, PD-L1 low expression and CD8A/CYT low expression; type III, PD-L1 high expression and CD8A/CYT low expression; and type IV, PD-L1 low expression and CD8A/CYT high expression.	('CD8A', 'Gene', (408, 412))	('CD8A', 'Gene', (224, 228))	('CD8A', 'Gene', '925', (408, 412))	('CD8A', 'Gene', '925', (155, 159))	('CD8A', 'Gene', (155, 159))	('CD8A', 'Gene', '925', (345, 349))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('CD8A', 'Gene', (345, 349))	('CD8A', 'Gene', '925', (284, 288))	('low', 'NegReg', (389, 392))	('PD-L1', 'Var', (319, 324))	('CD8A', 'Gene', (284, 288))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('CD8A', 'Gene', '925', (224, 228))	('cancer', 'Disease', (76, 82))	('TMIT', 'Chemical', '-', (98, 102))
29262	28912897	TMIT was classified only for those tumor types with significant differences in mutation and/or neoantigen number in both PD-L1 and CD8A/CYT RPART subgroups.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('TMIT', 'Chemical', '-', (0, 4))	('neoantigen', 'MPA', (95, 105))	('differences', 'Reg', (64, 75))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('CD8A', 'Gene', '925', (131, 135))	('tumor', 'Disease', (35, 40))	('CD8A', 'Gene', (131, 135))	('mutation', 'Var', (79, 87))
29267	28912897	The number of mutations and neoantigens were significantly positively correlated, with a strong or very strong correlation for almost all tumors (R2 > 0.6), except for the LIHC and PRAD (relatively strong), and THCA (moderate; Supplementary Figure S1).	('almost all tumors', 'Disease', (127, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('mutations', 'Var', (14, 23))	('almost all tumors', 'Disease', 'MESH:D009369', (127, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
29273	28912897	Besides, RPART also better distinguished the different mutation number in the PD-L1 subgroups for BLCA, BRCA, CESC, LIHC, and SKCM; in the CD8A subgroups for BLCA, KIRC, and LIHC; and in CYT subgroups for BRCA, CESC, LUAD, SKCM, and STAD (Figure 2).	('BRCA', 'Gene', '672', (104, 108))	('BLCA', 'Chemical', '-', (158, 162))	('BRCA', 'Gene', (104, 108))	('BRCA', 'Gene', '672', (205, 209))	('PD-L1', 'Gene', (78, 83))	('CD8A', 'Gene', '925', (139, 143))	('BRCA', 'Gene', (205, 209))	('CD8A', 'Gene', (139, 143))	('mutation', 'Var', (55, 63))	('CESC', 'Disease', (110, 114))	('BLCA', 'Chemical', '-', (98, 102))
29274	28912897	In summary, for both mutation and neoantigen number, KIRC differs significantly in the PD-L1 and CD8A subgroups; BLCA, BRCA, SKCM, and STAD differ significantly in the PD-L1 and CYT subgroups; and CESC and LUAD differ significantly in the PD-L1, CD8A, and CYT subgroups.	('CD8A', 'Gene', '925', (97, 101))	('CD8A', 'Gene', (97, 101))	('mutation', 'Var', (21, 29))	('PD-L1', 'Disease', (87, 92))	('CD8A', 'Gene', '925', (246, 250))	('BLCA', 'Chemical', '-', (113, 117))	('BRCA', 'Gene', '672', (119, 123))	('CD8A', 'Gene', (246, 250))	('BRCA', 'Gene', (119, 123))
29278	28912897	Based on the abovementioned results, certain tumor samples were divided into four groups of tumor microenvironments according to the RPART cut-off values of PD-L1 and CD8A/CYT expression: PD-L1+CD8A for KIRC and LIHC; PD-L1+CYT for BLCA, BRCA, SKCM, STAD, and THCA; and PD-L1+CD8A/CYT for CESC, COAD, and LUAD.	('COAD', 'Disease', (295, 299))	('PD-L1+CYT', 'Var', (218, 227))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (92, 97))	('CD8A', 'Gene', '925', (276, 280))	('CD8A', 'Gene', '925', (194, 198))	('CD8A', 'Gene', '925', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('CD8A', 'Gene', (276, 280))	('COAD', 'Disease', 'MESH:D029424', (295, 299))	('BRCA', 'Gene', (238, 242))	('CD8A', 'Gene', (194, 198))	('CD8A', 'Gene', (167, 171))	('BRCA', 'Gene', '672', (238, 242))	('BLCA', 'Chemical', '-', (232, 236))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
29283	28912897	Tumor samples with a higher mutation or neoantigen numbers than the median value also tended to have a higher proportion of TMIT I (Figures 4C-N).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TMIT I', 'Disease', (124, 130))	('TMIT', 'Chemical', '-', (124, 128))	('mutation', 'Var', (28, 36))	('neoantigen numbers', 'Var', (40, 58))
29308	28912897	The objective response rate was also higher in patients with PD-L1 positive status than those with negative status (53% vs. 33%).	('objective response', 'CPA', (4, 22))	('higher', 'PosReg', (37, 43))	('PD-L1', 'Gene', (61, 66))	('patients', 'Species', '9606', (47, 55))	('positive status', 'Var', (67, 82))
29312	28912897	Overall, our results are generally consistent with those observed in clinical trials evaluating checkpoint inhibitor treatment, highlighting that the combination of PD-L1 and CD8A/CYT expression may help better identify subsets of patients who will benefit from anti-PD-1/PD-L1 therapy and avoid any potential toxicities and costs.	('toxicities', 'Disease', (310, 320))	('patients', 'Species', '9606', (231, 239))	('anti-PD-1/PD-L1', 'Var', (262, 277))	('PD-L1', 'Gene', (165, 170))	('toxicities', 'Disease', 'MESH:D064420', (310, 320))	('benefit', 'PosReg', (249, 256))	('CD8A', 'Gene', '925', (175, 179))	('CD8A', 'Gene', (175, 179))
29322	31313716	Expression of pro-angiogenic genes, single nucleotide polymorphisms involving genes of the vascular-endothelial growth factor (VEGF) pathway and somatic mutations of chromatin remodeling genes were associated with response to VEGF-targeted therapy.	('VEGF', 'Gene', '7422', (127, 131))	('associated with', 'Reg', (198, 213))	('VEGF', 'Gene', '7422', (226, 230))	('vascular-endothelial growth factor', 'Gene', (91, 125))	('vascular-endothelial growth factor', 'Gene', '7422', (91, 125))	('chromatin', 'cellular_component', 'GO:0000785', ('166', '175'))	('mutations', 'Var', (153, 162))	('Expression', 'MPA', (0, 10))	('VEGF', 'Gene', (127, 131))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('166', '186'))	('VEGF', 'Gene', (226, 230))	('vascular-endothelial growth factor', 'molecular_function', 'GO:0005172', ('91', '125'))	('single nucleotide polymorphisms', 'Var', (36, 67))
29323	31313716	Outcomes following treatment with mTOR inhibitors were initially associated with mTOR/TSC1/TSC2 mutations; however, subsequent studies did not validate these findings but rather found an association between loss of PTEN expression and PBRM1 mutations and improved outcomes.	('TSC1', 'Gene', (86, 90))	('improved', 'PosReg', (255, 263))	('associated', 'Reg', (65, 75))	('TSC1', 'Gene', '7248', (86, 90))	('mutations', 'Var', (96, 105))	('mTOR', 'Gene', (34, 38))	('TSC2', 'Gene', '7249', (91, 95))	('mTOR', 'Gene', (81, 85))	('mTOR', 'Gene', '2475', (34, 38))	('PBRM1', 'Gene', '55193', (235, 240))	('loss', 'NegReg', (207, 211))	('PTEN', 'Gene', (215, 219))	('mTOR', 'Gene', '2475', (81, 85))	('TSC2', 'Gene', (91, 95))	('PBRM1', 'Gene', (235, 240))	('expression', 'MPA', (220, 230))	('outcomes', 'MPA', (264, 272))	('PTEN', 'Gene', '5728', (215, 219))	('mutations', 'Var', (241, 250))
29324	31313716	Loss of PBRM1 was initially linked to response to immunotherapy however larger studies question this association and showed high expression of T-effector gene signature predicted improved outcome.	('improved', 'PosReg', (179, 187))	('linked', 'Reg', (28, 34))	('PBRM1', 'Gene', '55193', (8, 13))	('Loss', 'Var', (0, 4))	('PBRM1', 'Gene', (8, 13))
29326	31313716	Genetic alterations may help select patients for CN and optimize timing of treatment.	('Genetic alterations', 'Var', (0, 19))	('help', 'Reg', (24, 28))	('patients', 'Species', '9606', (36, 44))
29338	31313716	Loss of chromosome 3p and VHL mutations are the foundational events in this disease occurring in upwards of 90% of patients.	('patients', 'Species', '9606', (115, 123))	('Loss of', 'Var', (0, 7))	('VHL', 'Gene', (26, 29))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('VHL', 'Gene', '7428', (26, 29))	('mutations', 'Var', (30, 39))
29339	31313716	Additional mutations involve PBRM1 (33-41%), SETD2 (11-12%) and BAP1 (10%) all of which are chromatin modifier genes.	('SETD2', 'Gene', (45, 50))	('chromatin', 'cellular_component', 'GO:0000785', ('92', '101'))	('mutations', 'Var', (11, 20))	('PBRM1', 'Gene', '55193', (29, 34))	('BAP1', 'Gene', '8314', (64, 68))	('SETD2', 'Gene', '29072', (45, 50))	('PBRM1', 'Gene', (29, 34))	('BAP1', 'Gene', (64, 68))
29345	31313716	While TP53 mutations were more prevalent in metastatic disease (15% vs. 9%), this was not significant when controlling for multiple testing.	('prevalent', 'Reg', (31, 40))	('mutations', 'Var', (11, 20))	('TP53', 'Gene', '7157', (6, 10))	('TP53', 'Gene', (6, 10))	('metastatic disease', 'Disease', (44, 62))
29346	31313716	In this study 47/60 patients carried nonidentical cancer gene mutations within their matched primary-metastatic pair.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutations', 'Var', (62, 71))
29347	31313716	The study concludes that mutation profiles of the primary tumor alone could compromise precision in selecting effective targeted therapies.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mutation', 'Var', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('compromise', 'NegReg', (76, 86))
29348	31313716	When combining mutational data from these two publications, a higher rate of KDM5C and PBRM1 mutation were found among metastases (p=0.028 and 0.033, respectively, Figure 1).	('KDM5C', 'Gene', (77, 82))	('KDM5C', 'Gene', '8242', (77, 82))	('metastases', 'Disease', (119, 129))	('PBRM1', 'Gene', (87, 92))	('PBRM1', 'Gene', '55193', (87, 92))	('mutation', 'Var', (93, 101))	('metastases', 'Disease', 'MESH:D009362', (119, 129))
29351	31313716	Initial NGS studies have shown an association between PBRM1, BAP1 and SETD2 mutations in the primary tumor and pathological and clinical outcomes.	('PBRM1', 'Gene', (54, 59))	('mutations', 'Var', (76, 85))	('BAP1', 'Gene', (61, 65))	('PBRM1', 'Gene', '55193', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('SETD2', 'Gene', '29072', (70, 75))	('SETD2', 'Gene', (70, 75))	('BAP1', 'Gene', '8314', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
29353	31313716	The most common mutation in ccRCC involves VHL whose loss of function results in constitutive activation of HIF-alpha, which stimulates production of VEGF and increases activity of VEGFR, resulting in increased angiogenesis and metastatic potential.	('VEGFR', 'Gene', '3791', (181, 186))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('activity', 'MPA', (169, 177))	('VEGFR', 'Gene', (181, 186))	('metastatic potential', 'CPA', (228, 248))	('HIF-alpha', 'Protein', (108, 117))	('increased', 'PosReg', (201, 210))	('VHL', 'Gene', (43, 46))	('increases', 'PosReg', (159, 168))	('stimulates', 'PosReg', (125, 135))	('angiogenesis', 'biological_process', 'GO:0001525', ('211', '223'))	('activation', 'PosReg', (94, 104))	('angiogenesis', 'CPA', (211, 223))	('mutation', 'Var', (16, 24))	('VEGF', 'Gene', '7422', (150, 154))	('VEGF', 'Gene', '7422', (181, 185))	('ccRCC', 'Phenotype', 'HP:0006770', (28, 33))	('VHL', 'Gene', '7428', (43, 46))	('RCC', 'Disease', (30, 33))	('VEGF', 'Gene', (181, 185))	('VEGF', 'Gene', (150, 154))	('loss of function', 'NegReg', (53, 69))
29354	31313716	VEGF inhibitors prevent the pro-angiogenic expression of tumors, therefore, it can be posited that patients with genetic mutations resulting in upregulation of these receptors would be more likely respond to VEGF inhibition.	('upregulation', 'PosReg', (144, 156))	('mutations', 'Var', (121, 130))	('VEGF', 'Gene', '7422', (0, 4))	('VEGF', 'Gene', (208, 212))	('patients', 'Species', '9606', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('pro-angiogenic expression', 'MPA', (28, 53))	('VEGF', 'Gene', '7422', (208, 212))	('VEGF', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
29355	31313716	Meta-analyses have shown that VHL and VEGFR1 genetic alterations are not associated with pathologic and oncologic outcomes in patients with ccRCC.	('VEGFR1', 'Gene', '2321', (38, 44))	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('VEGFR1', 'Gene', (38, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('VHL', 'Gene', (30, 33))	('VHL', 'Gene', '7428', (30, 33))	('patients', 'Species', '9606', (126, 134))	('genetic alterations', 'Var', (45, 64))
29357	31313716	Another study found that two SNPs in VHL were associated with decreased overall survival when controlling for clinicopathological characteristics in patients undergoing first-line treatment with TKIs.	('patients', 'Species', '9606', (149, 157))	('VHL', 'Gene', (37, 40))	('decreased', 'NegReg', (62, 71))	('overall survival', 'MPA', (72, 88))	('VHL', 'Gene', '7428', (37, 40))	('two SNPs', 'Var', (25, 33))
29360	31313716	Mutations in genes other than those directly involved in the VEGF pathway have also been implicated in differing outcomes with VEGF inhibitors.	('VEGF', 'Gene', '7422', (127, 131))	('VEGF', 'Gene', '7422', (61, 65))	('Mutations', 'Var', (0, 9))	('implicated', 'Reg', (89, 99))	('VEGF', 'Gene', (127, 131))	('VEGF', 'Gene', (61, 65))
29361	31313716	Genotyping of primary renal tumors in patients treated with first-line sunitinib in the RECORD-3 trial revealed that BAP1 mutations were associated with reduced PFS, whereas patients with KDM5C mutations had longer PFS.	('BAP1', 'Gene', '8314', (117, 121))	('PFS', 'MPA', (161, 164))	('reduced', 'NegReg', (153, 160))	('renal tumors', 'Disease', 'MESH:D007674', (22, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('patients', 'Species', '9606', (174, 182))	('BAP1', 'Gene', (117, 121))	('mutations', 'Var', (122, 131))	('renal tumors', 'Disease', (22, 34))	('KDM5C', 'Gene', (188, 193))	('patients', 'Species', '9606', (38, 46))	('sunitinib', 'Chemical', 'MESH:D000077210', (71, 80))	('KDM5C', 'Gene', '8242', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('renal tumors', 'Phenotype', 'HP:0009726', (22, 34))
29364	31313716	Indeed, the minor allele of SNP rs5275 located in the untranslated region of PTSG2 was found to affect mi-RNA binding resulting in increased expression of the gene and decreased PFS and cancer-specific survival.	('affect', 'Reg', (96, 102))	('increased', 'PosReg', (131, 140))	('decreased', 'NegReg', (168, 177))	('PTSG2', 'Gene', (77, 82))	('PFS', 'CPA', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('RNA binding', 'molecular_function', 'GO:0003723', ('106', '117'))	('SNP rs5275', 'Var', (28, 38))	('expression', 'MPA', (141, 151))	('RNA', 'cellular_component', 'GO:0005562', ('106', '109'))	('mi-RNA', 'Protein', (103, 109))	('rs5275', 'Mutation', 'rs5275', (32, 38))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
29369	31313716	As a result, patients with activating mutations in mTOR or loss of function mutations in TSC1/TSC2 would be expected to best respond to mTOR inhibitors.	('mTOR', 'Gene', (51, 55))	('mutations', 'Var', (76, 85))	('activating', 'PosReg', (27, 37))	('patients', 'Species', '9606', (13, 21))	('TSC2', 'Gene', '7249', (94, 98))	('loss of function', 'NegReg', (59, 75))	('TSC1', 'Gene', '7248', (89, 93))	('TSC2', 'Gene', (94, 98))	('mTOR', 'Gene', (136, 140))	('TSC1', 'Gene', (89, 93))	('mTOR', 'Gene', '2475', (136, 140))	('mTOR', 'Gene', '2475', (51, 55))
29370	31313716	reported that mutations in mTOR, TSC1, or TSC2 were more common in responders (12/43, 28%) than non-responders, (4/36, 11%), (p=0.06).	('TSC1', 'Gene', '7248', (33, 37))	('responders', 'Disease', (67, 77))	('TSC2', 'Gene', '7249', (42, 46))	('TSC1', 'Gene', (33, 37))	('TSC2', 'Gene', (42, 46))	('mTOR', 'Gene', (27, 31))	('mutations', 'Var', (14, 23))	('mTOR', 'Gene', '2475', (27, 31))
29371	31313716	Contrary to this finding, other studies reported no association between PFS and mTOR/TSC1/TSC2 mutations in patients treated with everolimus.	('TSC2', 'Gene', '7249', (90, 94))	('mTOR', 'Gene', (80, 84))	('mTOR', 'Gene', '2475', (80, 84))	('TSC1', 'Gene', '7248', (85, 89))	('TSC2', 'Gene', (90, 94))	('TSC1', 'Gene', (85, 89))	('everolimus', 'Chemical', 'MESH:D000068338', (130, 140))	('mutations', 'Var', (95, 104))	('patients', 'Species', '9606', (108, 116))	('PFS', 'Gene', (72, 75))
29373	31313716	PBRM1 mutations were also associated with increased PFS while BAP1 mutations were associated with a decreased PFS in patients treated with first-line everolimus.	('increased', 'PosReg', (42, 51))	('BAP1', 'Gene', '8314', (62, 66))	('PFS', 'Disease', (52, 55))	('PBRM1', 'Gene', (0, 5))	('BAP1', 'Gene', (62, 66))	('PBRM1', 'Gene', '55193', (0, 5))	('mutations', 'Var', (67, 76))	('everolimus', 'Chemical', 'MESH:D000068338', (150, 160))	('patients', 'Species', '9606', (117, 125))	('mutations', 'Var', (6, 15))
29374	31313716	Thus, patients with loss of function mutations in PTEN and PBRM1 may represent a subset who better respond to everolimus.	('everolimus', 'Chemical', 'MESH:D000068338', (110, 120))	('loss of function', 'NegReg', (20, 36))	('PTEN', 'Gene', (50, 54))	('PBRM1', 'Gene', (59, 64))	('PBRM1', 'Gene', '55193', (59, 64))	('mutations', 'Var', (37, 46))	('PTEN', 'Gene', '5728', (50, 54))	('patients', 'Species', '9606', (6, 14))	('better', 'PosReg', (92, 98))
29377	31313716	Similarly, tumors which are microsatellite instability high and those with deficiencies in mismatch repair genes are more sensitive to checkpoint inhibitors due to a buildup of somatic mutations in tumor cells, a high tumor mutation burden and increased expression of neoantigens.	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (218, 223))	('microsatellite instability', 'Var', (28, 54))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('expression', 'MPA', (254, 264))	('mismatch repair', 'biological_process', 'GO:0006298', ('91', '106'))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (198, 203))	('more', 'PosReg', (117, 121))	('deficiencies', 'Var', (75, 87))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('mismatch repair genes', 'Gene', (91, 112))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('sensitive', 'MPA', (122, 131))	('tumors', 'Disease', (11, 17))	('neoantigens', 'Protein', (268, 279))	('mutations', 'Var', (185, 194))	('increased', 'PosReg', (244, 253))
29378	31313716	When evaluated specifically in ccRCC, an additional marker of positive response to immunotherapy is high endogenous retroviral load, which was associated with increased immune infiltration, checkpoint pathway upregulation, higher CD8+ T cell fraction in infiltrating leukocytes and BAP1 mutation.	('BAP1', 'Gene', '8314', (282, 286))	('immune infiltration', 'CPA', (169, 188))	('mutation', 'Var', (287, 295))	('CD8', 'Gene', (230, 233))	('increased', 'PosReg', (159, 168))	('BAP1', 'Gene', (282, 286))	('RCC', 'Disease', (33, 36))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('CD8', 'Gene', '925', (230, 233))	('ccRCC', 'Phenotype', 'HP:0006770', (31, 36))	('checkpoint pathway', 'Pathway', (190, 208))	('upregulation', 'PosReg', (209, 221))	('higher', 'PosReg', (223, 229))	('cell fraction', 'cellular_component', 'GO:0000267', ('237', '250'))
29379	31313716	Conversely, transcription elongation mutations were associated with poor response to immunotherapy in mRCC and metastatic melanoma patients.	('patients', 'Species', '9606', (131, 139))	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('transcription', 'biological_process', 'GO:0006351', ('12', '25'))	('melanoma', 'Disease', (122, 130))	('mutations', 'Var', (37, 46))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('transcription elongation', 'Gene', (12, 36))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))
29385	31313716	When evaluating alteration at the gene level, no association was found between VHL mutations status and PFS in any group while PBRM1 mutations were associated with improved PFS in the sunitinib group and was not associates with outcome in the atezolizumab monotherapy group.	('atezolizumab', 'Chemical', 'MESH:C000594389', (243, 255))	('mutations', 'Var', (83, 92))	('VHL', 'Gene', '7428', (79, 82))	('improved', 'PosReg', (164, 172))	('PFS', 'Disease', (104, 107))	('sunitinib', 'Chemical', 'MESH:D000077210', (184, 193))	('PBRM1', 'Gene', (127, 132))	('PBRM1', 'Gene', '55193', (127, 132))	('mutations', 'Var', (133, 142))	('PFS', 'MPA', (173, 176))	('VHL', 'Gene', (79, 82))
29386	31313716	who found that loss of function mutations in PBRM1 was associated with clinical benefit in 35 patients who received anti-PD1 monotherapy (p=0.012).	('patients', 'Species', '9606', (94, 102))	('mutations', 'Var', (32, 41))	('PBRM1', 'Gene', (45, 50))	('clinical benefit', 'CPA', (71, 87))	('loss of function', 'NegReg', (15, 31))	('PBRM1', 'Gene', '55193', (45, 50))
29388	31313716	Current studies are underway to better define the role of PBRM1 mutation status in predicting the outcome to immunotherapy.	('PBRM1', 'Gene', (58, 63))	('PBRM1', 'Gene', '55193', (58, 63))	('mutation', 'Var', (64, 72))
29395	31313716	The association between VHL, PBRM1, BAP1, SETD2 AND KDM5C mutation status and overall survival was evaluated in 167 patients with metastatic ccRCC who underwent genomic sequencing of their primary tumor.	('tumor', 'Disease', (197, 202))	('KDM5C', 'Gene', '8242', (52, 57))	('VHL', 'Gene', '7428', (24, 27))	('PBRM1', 'Gene', '55193', (29, 34))	('ccRCC', 'Phenotype', 'HP:0006770', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('patients', 'Species', '9606', (116, 124))	('BAP1', 'Gene', '8314', (36, 40))	('mutation', 'Var', (58, 66))	('SETD2', 'Gene', '29072', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('VHL', 'Gene', (24, 27))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('BAP1', 'Gene', (36, 40))	('RCC', 'Disease', (143, 146))	('PBRM1', 'Gene', (29, 34))	('KDM5C', 'Gene', (52, 57))	('SETD2', 'Gene', (42, 47))
29396	31313716	Mutations in SETD2 (HR=0.58, 95% CI 0.35-0.94, p=0.027) and KDM5C (HR=0.43, 95% CI 0.22-0.85, p=0.019) were associated with a reduced risk of death while BAP1 mutations were associated with an increased risk of death (HR=1.81, 95% CI 1.16-2.83, p=0.008).	('BAP1', 'Gene', (154, 158))	('death', 'Disease', (211, 216))	('mutations', 'Var', (159, 168))	('KDM5C', 'Gene', (60, 65))	('SETD2', 'Gene', '29072', (13, 18))	('Mutations', 'Var', (0, 9))	('death', 'Disease', 'MESH:D003643', (142, 147))	('KDM5C', 'Gene', '8242', (60, 65))	('death', 'Disease', (142, 147))	('SETD2', 'Gene', (13, 18))	('BAP1', 'Gene', '8314', (154, 158))	('reduced', 'NegReg', (126, 133))	('death', 'Disease', 'MESH:D003643', (211, 216))
29404	31313716	Highly sensitivity detection methods and prior knowledge of mutations are required to successfully identify genetic alterations in ctDNA in RCC.	('RCC', 'Disease', (140, 143))	('genetic alterations', 'Var', (108, 127))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('ctDNA', 'Gene', (131, 136))
29411	31313716	For instance, BAP1 mutations are associated with poorer clinical outcomes in patients taking everolimus and sunitinib, but in fact may just be a marker of more aggressive disease.	('aggressive disease', 'Disease', 'MESH:D001523', (160, 178))	('BAP1', 'Gene', '8314', (14, 18))	('everolimus', 'Chemical', 'MESH:D000068338', (93, 103))	('aggressive disease', 'Disease', (160, 178))	('sunitinib', 'Chemical', 'MESH:D000077210', (108, 117))	('BAP1', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('patients', 'Species', '9606', (77, 85))
29416	31313716	Genetic alterations were associated with outcome in patients undergoing cytoreductive nephrectomy followed by systemic treatment.	('Genetic alterations', 'Var', (0, 19))	('patients', 'Species', '9606', (52, 60))	('associated with', 'Reg', (25, 40))
29486	28647866	In fully-adjusted models, ORs for ccRCC risk associated with caffeinated coffee and decaffeinated coffee consumption were 0.77 (95% CI = 0.58-1.02) and 1.40 (95% CI = 0.90-2.17), respectively, compared with no coffee consumption.	('decaffeinated coffee', 'Var', (84, 104))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('caffeinated coffee', 'Chemical', '-', (86, 104))	('RCC', 'Disease', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('caffeinated coffee', 'Chemical', '-', (61, 79))	('decaffeinated coffee', 'Chemical', '-', (84, 104))
29489	28647866	In contrast, decaffeinated coffee consumption was associated with higher risk of the moderate or high aggressive forms of ccRCC (OR = 1.80, 95% CI = 1.01-3.22), and no association was observed with caffeinated coffee consumption.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('decaffeinated coffee', 'Chemical', '-', (13, 33))	('moderate', 'Disease', (85, 93))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('caffeinated coffee', 'Chemical', '-', (15, 33))	('decaffeinated coffee', 'Var', (13, 33))	('caffeinated coffee', 'Chemical', '-', (198, 216))
29527	27581364	Restoration of VHL in RCC4 cells attenuated the growth inhibitory effect of physapubescin.	('growth inhibitory effect', 'MPA', (48, 72))	('VHL', 'Gene', (15, 18))	('Restoration', 'Var', (0, 11))	('RCC', 'Phenotype', 'HP:0005584', (22, 25))	('VHL', 'Gene', '7428', (15, 18))	('attenuated', 'NegReg', (33, 43))	('RCC4', 'Gene', '84925', (22, 26))	('physapubescin', 'Chemical', 'MESH:C586239', (76, 89))	('RCC4', 'Gene', (22, 26))
29545	27581364	The loss of VHL through somatic mutation or hypermethylation occurs in over 80% of clear cell Renal Cell Carcinoma (ccRCC) and is the main driver for cancer growth and metastasis.	('VHL', 'Gene', (12, 15))	('Carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('somatic mutation', 'Var', (24, 40))	('VHL', 'Gene', '7428', (12, 15))	('clear cell Renal Cell Carcinoma', 'Disease', (83, 114))	('clear cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (83, 114))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (94, 114))	('cancer', 'Disease', (150, 156))	('hypermethylation', 'Var', (44, 60))	('loss', 'NegReg', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('clear cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (83, 114))
29546	27581364	VHL inactivation leads to HIF-alpha stabilization and nuclear translocation.	('inactivation', 'Var', (4, 16))	('nuclear translocation', 'CPA', (54, 75))	('stabilization', 'MPA', (36, 49))	('HIF-alpha', 'Protein', (26, 35))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))
29551	27581364	Therefore, inhibition of HIF-2alpha expression and/or function would be an important approach for developing novel agents in treatment of ccRCC with loss of VHL.	('expression', 'MPA', (36, 46))	('HIF-2alpha', 'Gene', '2034', (25, 35))	('loss', 'NegReg', (149, 153))	('VHL', 'Gene', (157, 160))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('inhibition', 'Var', (11, 21))	('VHL', 'Gene', '7428', (157, 160))	('ccRCC', 'Disease', (138, 143))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('function', 'MPA', (54, 62))	('HIF-2alpha', 'Gene', (25, 35))
29552	27581364	Here, we have shown that physapubescin, at concentrations of 2.5 muM and 5 muM, selectively induces apoptosis in 786-O, RCC4 and A498 VHL-null RCC cell lines, but it has a minimal apoptotic effect on the wild-type Caki-2 RCC cell line.	('RCC4', 'Gene', (120, 124))	('muM', 'Gene', (75, 78))	('RCC4', 'Gene', '84925', (120, 124))	('induces', 'Reg', (92, 99))	('RCC', 'Phenotype', 'HP:0005584', (221, 224))	('muM', 'Gene', '56925', (65, 68))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('Caki-2 RCC', 'CellLine', 'CVCL:0235', (214, 224))	('muM', 'Gene', '56925', (75, 78))	('muM', 'Gene', (65, 68))	('physapubescin', 'Var', (25, 38))	('VHL', 'Gene', (134, 137))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('VHL', 'Gene', '7428', (134, 137))	('physapubescin', 'Chemical', 'MESH:C586239', (25, 38))	('apoptosis', 'CPA', (100, 109))
29561	27581364	Both 786-O and A-498 cells harbor a VHL deletion mutation and express high levels of HIF-2alpha protein, but no HIF-1alpha protein.	('deletion mutation', 'Var', (40, 57))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('HIF-1alpha', 'Gene', '3091', (112, 122))	('VHL', 'Gene', (36, 39))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('VHL', 'Gene', '7428', (36, 39))	('HIF-1alpha', 'Gene', (112, 122))	('HIF-2alpha', 'Gene', (85, 95))	('HIF-2alpha', 'Gene', '2034', (85, 95))
29564	27581364	This result suggests that re-expression of wild-type VHL attenuates the growth inhibitory effect of physapubescin.	('VHL', 'Gene', (53, 56))	('re-expression', 'Var', (26, 39))	('VHL', 'Gene', '7428', (53, 56))	('physapubescin', 'Chemical', 'MESH:C586239', (100, 113))	('attenuates', 'NegReg', (57, 67))	('growth inhibitory effect of physapubescin', 'MPA', (72, 113))
29565	27581364	Figure 2C demonstrates that physapubescin, at concentrations of 1.25 muM and 2.5 muM, significantly reduces the colony formation of 786-O cells in soft agar by ~25 and ~50%, respectively, compared to vehicle control treatment [0.05% dimethyl sulfoxide (DMSO)] (Ps < 0.05).	('formation', 'biological_process', 'GO:0009058', ('119', '128'))	('muM', 'Gene', '56925', (69, 72))	('reduces', 'NegReg', (100, 107))	('DMSO', 'Chemical', 'MESH:D004121', (253, 257))	('colony formation of 786-O cells in soft agar', 'CPA', (112, 156))	('muM', 'Gene', (69, 72))	('muM', 'Gene', '56925', (81, 84))	('physapubescin', 'Var', (28, 41))	('physapubescin', 'Chemical', 'MESH:C586239', (28, 41))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (233, 251))	('agar', 'Chemical', 'MESH:D000362', (152, 156))	('muM', 'Gene', (81, 84))
29572	27581364	Flowcytometry analysis of Annexin V and Propidium iodide (PI) stained cells confirmed that physapubescin treatment of VHL-null 786-O cells at concentrations of 2.5 muM and 5 muM resulted in a significant increase in both early (Annexin V staining only, right-lower panels) and late apoptosis (Annexin V and PI staining, right-upper panels) populations as compared to control treatment (Fig.	('Annexin V', 'Gene', (26, 35))	('VHL', 'Gene', (118, 121))	('muM', 'Gene', (174, 177))	('VHL', 'Gene', '7428', (118, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('282', '291'))	('muM', 'Gene', (164, 167))	('physapubescin', 'Var', (91, 104))	('increase', 'PosReg', (204, 212))	('physapubescin', 'Chemical', 'MESH:C586239', (91, 104))	('apoptosis', 'biological_process', 'GO:0006915', ('282', '291'))	('Annexin V', 'Gene', '308', (228, 237))	('Annexin V', 'Gene', '308', (293, 302))	('late apoptosis', 'CPA', (277, 291))	('Annexin V', 'Gene', (293, 302))	('muM', 'Gene', '56925', (174, 177))	('Annexin V', 'Gene', (228, 237))	('Annexin V', 'Gene', '308', (26, 35))	('muM', 'Gene', '56925', (164, 167))
29575	27581364	To see whether the apoptotic effect of physapubescin is involved in activation of a cascade of caspases, the cleavage of caspase-8, caspase-3, and PARP were detected by Western blotting and the activities of caspase-8 and -3 were measured by ELISA.	('caspases', 'Gene', (95, 103))	('cleavage', 'MPA', (109, 117))	('caspases', 'Gene', '841', (95, 103))	('caspase-3', 'Gene', (132, 141))	('PARP', 'Gene', (147, 151))	('physapubescin', 'Var', (39, 52))	('physapubescin', 'Chemical', 'MESH:C586239', (39, 52))	('caspase-8', 'Gene', (121, 130))	('caspase-8 and -3', 'Gene', '841;836', (208, 224))	('caspase-8', 'Gene', '841', (121, 130))	('caspase-8', 'Gene', (208, 217))	('caspase-3', 'Gene', '836', (132, 141))	('caspase-8', 'Gene', '841', (208, 217))	('PARP', 'Gene', '142', (147, 151))
29584	27581364	The mRNA levels of DR5 were also significantly up-regulated by physapubescin (Fig.	('DR5', 'Gene', (19, 22))	('physapubescin', 'Var', (63, 76))	('DR5', 'Gene', '8795', (19, 22))	('physapubescin', 'Chemical', 'MESH:C586239', (63, 76))	('up-regulated', 'PosReg', (47, 59))
29595	27581364	These results indicate that physapubescin induces more apoptosis under hypoxia conditions by down-regulating HIF1/2alpha expression and upregulating DR5 expression.	('upregulating', 'PosReg', (136, 148))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('down-regulating', 'NegReg', (93, 108))	('DR5', 'Gene', (149, 152))	('DR5', 'Gene', '8795', (149, 152))	('HIF1/2alpha', 'Gene', (109, 120))	('expression', 'MPA', (121, 131))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('hypoxia conditions', 'Disease', (71, 89))	('HIF1/2alpha', 'Gene', '3091;2034', (109, 120))	('physapubescin', 'Var', (28, 41))	('physapubescin', 'Chemical', 'MESH:C586239', (28, 41))	('hypoxia conditions', 'Disease', 'MESH:D000860', (71, 89))
29601	27581364	In contrast, treatment of RCC4 cells stably overexpressing VHL with physapubescin did not affected VEGF secretion under normoxia condition, but it did significantly decreased VEGF secretion under hypoxia conditions (Fig.	('VHL', 'Gene', '7428', (59, 62))	('decreased', 'NegReg', (165, 174))	('RCC4', 'Gene', (26, 30))	('hypoxia conditions', 'Disease', 'MESH:D000860', (196, 214))	('VEGF', 'Gene', '7422', (99, 103))	('VEGF', 'Gene', '7422', (175, 179))	('secretion', 'biological_process', 'GO:0046903', ('180', '189'))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('physapubescin', 'Var', (68, 81))	('physapubescin', 'Chemical', 'MESH:C586239', (68, 81))	('VEGF', 'Gene', (175, 179))	('VEGF', 'Gene', (99, 103))	('VHL', 'Gene', (59, 62))	('hypoxia conditions', 'Disease', (196, 214))	('RCC4', 'Gene', '84925', (26, 30))	('secretion', 'biological_process', 'GO:0046903', ('104', '113'))
29609	27581364	Immunohistochemical analysis of tumor tissues further revealed that physapubescin significantly reduced mean vessel density as measured by CD31 staining by about 56%.	('CD31', 'Gene', (139, 143))	('CD31', 'Gene', '5175', (139, 143))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('physapubescin', 'Var', (68, 81))	('mean vessel density', 'CPA', (104, 123))	('physapubescin', 'Chemical', 'MESH:C586239', (68, 81))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('reduced', 'NegReg', (96, 103))
29612	27581364	A new, intellectually appealing strategy for the development of next-generation cancer killing agents would be to exploit vulnerabilities that are associated with the genetic and epigenetic alterations in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('epigenetic alterations', 'Var', (179, 201))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
29613	27581364	ccRCC is uniquely suited for this exploitation since the majority (more than 80%) of ccRCC harbor VHL mutation, which conveys distinct characteristics on tumor cells and drives tumor development via HIF (either HIF-1alpha or HIF-2alpha) stabilization.	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('HIF-1alpha or HIF-2alpha', 'Disease', 'None', (211, 235))	('drives', 'Reg', (170, 176))	('mutation', 'Var', (102, 110))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('VHL', 'Gene', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('VHL', 'Gene', '7428', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('HIF-1alpha or HIF-2alpha', 'Disease', (211, 235))	('ccRCC', 'Gene', (85, 90))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', (154, 159))
29616	27581364	Here we are the first to report that physapubescin, a major withanolide from hairy ground-cherry, selectively induces apoptosis in VHL-null RCC cell lines via down-regulation of HIF -1/2alpha expression and up-regulation of CHOP and DR5.	('down-regulation', 'NegReg', (159, 174))	('withanolide', 'Chemical', 'MESH:D054358', (60, 71))	('up-regulation', 'PosReg', (207, 220))	('ground-cherry', 'Species', '161495', (83, 96))	('regulation', 'biological_process', 'GO:0065007', ('164', '174'))	('apoptosis', 'biological_process', 'GO:0097194', ('118', '127'))	('apoptosis', 'biological_process', 'GO:0006915', ('118', '127'))	('CHOP', 'Gene', (224, 228))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('apoptosis', 'CPA', (118, 127))	('HIF -1/2alpha', 'Protein', (178, 191))	('induces', 'PosReg', (110, 117))	('expression', 'MPA', (192, 202))	('VHL', 'Gene', (131, 134))	('DR5', 'Gene', '8795', (233, 236))	('physapubescin', 'Var', (37, 50))	('physapubescin', 'Chemical', 'MESH:C586239', (37, 50))	('VHL', 'Gene', '7428', (131, 134))	('CHOP', 'Gene', '1649', (224, 228))	('regulation', 'biological_process', 'GO:0065007', ('210', '220'))	('DR5', 'Gene', (233, 236))
29622	27581364	Physapubescin increases both mRNA and protein expression of DR5 and activates caspase-8 and -3, leading to PARP cleavage and apoptotic morphology, such as cell rounding, nuclear fragmentation and condensation.	('Physapubescin', 'Chemical', 'MESH:C586239', (0, 13))	('increases', 'PosReg', (14, 23))	('nuclear fragmentation', 'CPA', (170, 191))	('PARP', 'Gene', '142', (107, 111))	('cell rounding', 'CPA', (155, 168))	('caspase-8 and -3', 'Gene', '841;836', (78, 94))	('apoptotic morphology', 'CPA', (125, 145))	('condensation', 'CPA', (196, 208))	('DR5', 'Gene', (60, 63))	('DR5', 'Gene', '8795', (60, 63))	('Physapubescin', 'Var', (0, 13))	('PARP', 'Gene', (107, 111))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('leading to', 'Reg', (96, 106))	('activates', 'PosReg', (68, 77))
29623	27581364	These results indicate activation of the death receptor mediated apoptotic pathway by physapubescin.	('death receptor mediated apoptotic pathway', 'Pathway', (41, 82))	('physapubescin', 'Var', (86, 99))	('physapubescin', 'Chemical', 'MESH:C586239', (86, 99))	('activation', 'PosReg', (23, 33))
29641	27581364	We also demonstrated that physapubescin significantly decreased vessel density as measured by CD31 staining in tumor tissues.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('CD31', 'Gene', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('physapubescin', 'Var', (26, 39))	('CD31', 'Gene', '5175', (94, 98))	('physapubescin', 'Chemical', 'MESH:C586239', (26, 39))	('tumor', 'Disease', (111, 116))	('vessel density', 'CPA', (64, 78))	('decreased', 'NegReg', (54, 63))
29752	31360564	It is postulated that retrograde venous flow via the ovarian vein facilitates seeding of the vaginal mucosa from the kidneys, making left sided RCC more likely to result in vaginal metastasis due to aberrant flow between the left ovarian vein and the left renal vein.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('vaginal metastasis', 'Disease', 'MESH:D009362', (173, 191))	('result in', 'Reg', (163, 172))	('ovarian vein', 'Disease', 'MESH:D010051', (230, 242))	('ovarian vein', 'Disease', (230, 242))	('vaginal metastasis', 'Disease', (173, 191))	('aberrant', 'Var', (199, 207))	('flow', 'MPA', (208, 212))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('ovarian vein', 'Disease', 'MESH:D010051', (53, 65))	('ovarian vein', 'Disease', (53, 65))
29814	30728073	In fact, the number of low-grade Fuhrman tumors is very large, while the number of high-grade tumors is relatively small, and the number of cases between groups is easily imbalanced.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('low-grade', 'Var', (23, 32))	('easily imbalanced', 'Phenotype', 'HP:0002172', (164, 181))
29816	30728073	This results of this study show that LoG filtering can reduce image noise while highlighting the degree of unevenness inside a tumor, which is a very effective image pre-processing method.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('LoG filtering', 'Var', (37, 50))	('image noise', 'MPA', (62, 73))	('reduce', 'NegReg', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('pre', 'molecular_function', 'GO:0003904', ('166', '169'))
29839	30723697	Previous studies demonstrated that PI3K/AKT/mTOR signaling pathway is one of the most frequently altered pathways in human cancer and dysregulation of this pathway contributes to cancer initiation and progression, including breast cancer, lung cancer, and renal carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung cancer', 'Disease', (239, 250))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('mTOR', 'Gene', '2475', (44, 48))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('AKT', 'Gene', '207', (40, 43))	('cancer', 'Disease', (231, 237))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('lung cancer', 'Disease', 'MESH:D008175', (239, 250))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancer initiation', 'Disease', (179, 196))	('renal carcinoma', 'Disease', 'MESH:C538614', (256, 271))	('PI3K', 'molecular_function', 'GO:0016303', ('35', '39'))	('human', 'Species', '9606', (117, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (239, 250))	('renal carcinoma', 'Disease', (256, 271))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('renal carcinoma', 'Phenotype', 'HP:0005584', (256, 271))	('cancer initiation', 'Disease', 'MESH:D009369', (179, 196))	('cancer', 'Disease', (244, 250))	('signaling pathway', 'biological_process', 'GO:0007165', ('49', '66'))	('contributes', 'Reg', (164, 175))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('dysregulation', 'Var', (134, 147))	('breast cancer', 'Disease', 'MESH:D001943', (224, 237))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('breast cancer', 'Disease', (224, 237))	('mTOR', 'Gene', (44, 48))	('cancer', 'Disease', (123, 129))	('AKT', 'Gene', (40, 43))	('cancer', 'Disease', (179, 185))
29922	30723697	Inhibition of CXCL13 or CXCR5 can impair the migratory and tumorigenic properties of prostate cancer cells.	('tumor', 'Disease', (59, 64))	('impair', 'NegReg', (34, 40))	('CXCL13', 'Gene', (14, 20))	('CXCR5', 'Gene', '643', (24, 29))	('prostate cancer', 'Disease', (85, 100))	('CXCR5', 'Gene', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('CXCL13', 'Gene', '10563', (14, 20))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('prostate cancer', 'Disease', 'MESH:D011471', (85, 100))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('prostate cancer', 'Phenotype', 'HP:0012125', (85, 100))
29936	33482824	Potential diagnostic and prognostic value and regulatory relationship of long noncoding RNA CCAT1 and miR-130a-3p in clear cell renal cell carcinoma MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) could interact with each other to play a vital role in the pathogenesis of cancers.	('cancers', 'Disease', 'MESH:D009369', (278, 285))	('miR', 'Gene', (102, 105))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (117, 148))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('long noncoding', 'Var', (73, 87))	('cancers', 'Phenotype', 'HP:0002664', (278, 285))	('play', 'Reg', (237, 241))	('clear cell renal cell carcinoma', 'Disease', (117, 148))	('RNA', 'cellular_component', 'GO:0005562', ('88', '91'))	('miR', 'Gene', '220972', (160, 163))	('cancers', 'Disease', (278, 285))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (128, 148))	('CCAT1', 'Gene', '100507056', (92, 97))	('CCAT1', 'Gene', (92, 97))	('miR', 'Gene', (160, 163))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (117, 148))	('pathogenesis', 'biological_process', 'GO:0009405', ('262', '274'))	('miR', 'Gene', '220972', (102, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('interact', 'Reg', (209, 217))
29937	33482824	We aimed to examine the expression profile, clinical significance and regulatory relationship of miR-130a-3p and its predicted interactive lncRNA in clear cell renal cell carcinoma (ccRCC).	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (149, 180))	('clear cell renal cell carcinoma', 'Disease', (149, 180))	('miR-130a-3p', 'Var', (97, 108))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (149, 180))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (160, 180))	('ccRCC', 'Phenotype', 'HP:0006770', (182, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('miR-130a-3p', 'Chemical', '-', (97, 108))
29944	33482824	High CCAT1 level suggested a poor survival prognosis.	('CCAT1', 'Gene', '100507056', (5, 10))	('CCAT1', 'Gene', (5, 10))	('High', 'Var', (0, 4))
29945	33482824	There was a negative association between CCAT1 and miR-130a-3p expression (r = - 0.373, P = 0.010).	('CCAT1', 'Gene', (41, 46))	('miR-130a-3p expression', 'Var', (51, 73))	('miR-130a-3p', 'Chemical', '-', (51, 62))	('negative', 'NegReg', (12, 20))	('CCAT1', 'Gene', '100507056', (41, 46))
29946	33482824	MiR-130a-3p mimic and si-CCAT1 inhibited ccRCC cell proliferation and invasion, and induced apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('92', '101'))	('apoptosis', 'biological_process', 'GO:0006915', ('92', '101'))	('induced', 'Reg', (84, 91))	('apoptosis', 'CPA', (92, 101))	('MiR-130a-3p', 'Chemical', '-', (0, 11))	('CCAT1', 'Gene', (25, 30))	('MiR-130a-3p mimic', 'Var', (0, 17))	('inhibited', 'NegReg', (31, 40))	('cell proliferation', 'biological_process', 'GO:0008283', ('47', '65'))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('ccRCC', 'Disease', (41, 46))	('invasion', 'CPA', (70, 78))	('CCAT1', 'Gene', '100507056', (25, 30))
29959	33482824	The dysregulation of miRNA was involved in mediating cell biological processes, which have been linked with the initiation and progression of ccRCC.	('involved', 'Reg', (31, 39))	('dysregulation', 'Var', (4, 17))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('cell biological processes', 'CPA', (53, 78))	('ccRCC', 'Disease', (142, 147))
29961	33482824	MiR-130a-3p is a vertebrate-specific miRNA.	('MiR-130a-3p', 'Chemical', '-', (0, 11))	('miR', 'Gene', '220972', (37, 40))	('miR', 'Gene', (37, 40))	('MiR-130a-3p', 'Var', (0, 11))
29962	33482824	A number of published researches have explored the regulatory function of miR-130a-3p in cancer cells.	('miR-130a-3p', 'Chemical', '-', (74, 85))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('miR-130a-3p', 'Var', (74, 85))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
29963	33482824	The expression level of miR-130a-3p was demonstrated to be decreased in ovarian cancer cells, prostate cancer cells, esophageal cancer cells and hepatocellular carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('cancer', 'Disease', (103, 109))	('miR-130a-3p', 'Var', (24, 35))	('cancer', 'Disease', (80, 86))	('cancer', 'Disease', (128, 134))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (145, 169))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('decreased in ovarian cancer', 'Disease', 'MESH:D002303', (59, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('prostate cancer', 'Disease', 'MESH:D011471', (94, 109))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (145, 169))	('prostate cancer', 'Phenotype', 'HP:0012125', (94, 109))	('decreased in ovarian cancer', 'Disease', (59, 86))	('miR-130a-3p', 'Chemical', '-', (24, 35))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('prostate cancer', 'Disease', (94, 109))	('expression level', 'MPA', (4, 20))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('hepatocellular carcinoma', 'Disease', (145, 169))	('ovarian cancer', 'Phenotype', 'HP:0100615', (72, 86))
29964	33482824	On the contrary, up-regulated expression of miR-130a-3p was observed in human cervical cancer.	('cancer', 'Disease', (87, 93))	('miR-130a-3p', 'Chemical', '-', (44, 55))	('expression', 'MPA', (30, 40))	('miR-130a-3p', 'Var', (44, 55))	('human', 'Species', '9606', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('up-regulated', 'PosReg', (17, 29))
29967	33482824	However, the role of miR-130a-3p in ccRCC remains unclear, especially its signaling pathway, crosstalk with some lncRNAs in the tumorigenesis.	('signaling pathway', 'biological_process', 'GO:0007165', ('74', '91'))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', (128, 133))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('ccRCC', 'Disease', (36, 41))	('miR-130a-3p', 'Chemical', '-', (21, 32))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('miR-130a-3p', 'Var', (21, 32))
29970	33482824	In vivo, we detected the expression of interactive lncRNA and miR-130a-3p in ccRCC tissues, and analyzed their associations with the clinicopathological parameters of ccRCC patients.	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (167, 172))	('ccRCC', 'Disease', (167, 172))	('patients', 'Species', '9606', (173, 181))	('ccRCC', 'Disease', (77, 82))	('miR-130a-3p', 'Chemical', '-', (62, 73))	('associations', 'Interaction', (111, 123))	('miR-130a-3p', 'Var', (62, 73))	('interactive lncRNA', 'Protein', (39, 57))
29991	33482824	According to the binding sites predicted by online bioinformatics tool StarBase, the wild type (WT) and the mutant type (MUT) of CCAT1 were separately amplified by PCR and then cloned into double luciferase reporter vector (pmirGLO Vector).	('CCAT1', 'Gene', (129, 134))	('binding', 'molecular_function', 'GO:0005488', ('17', '24'))	('mutant', 'Var', (108, 114))	('CCAT1', 'Gene', '100507056', (129, 134))
29993	33482824	Using dual-luciferase reporter assay system, we detected the luciferase activity of different groups and confirmed the association between lncRNA CCAT1 and miR-130a-3p.	('CCAT1', 'Gene', '100507056', (146, 151))	('association', 'Interaction', (119, 130))	('detected', 'Reg', (48, 56))	('miR-130a-3p', 'Var', (156, 167))	('activity', 'MPA', (72, 80))	('luciferase', 'Enzyme', (61, 71))	('CCAT1', 'Gene', (146, 151))	('luciferase activity', 'molecular_function', 'GO:0047712', ('61', '80'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('61', '80'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('61', '80'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('61', '80'))	('miR-130a-3p', 'Chemical', '-', (156, 167))	('luciferase activity', 'molecular_function', 'GO:0047077', ('61', '80'))
30002	33482824	CCAT1 was further verified in another online database DIANA-LncBase v2, which also confirmed the interaction between miR-130a-3p and CCAT1.	('CCAT1', 'Gene', '100507056', (133, 138))	('miR-130a-3p', 'Chemical', '-', (117, 128))	('CCAT1', 'Gene', '100507056', (0, 5))	('CCAT1', 'Gene', (133, 138))	('interaction', 'Interaction', (97, 108))	('miR-130a-3p', 'Var', (117, 128))	('CCAT1', 'Gene', (0, 5))
30003	33482824	According to previous research findings, miR-130a-3p may be downregulated and have a tumor-suppressing role in renal carcinoma cells.	('tumor', 'Disease', (85, 90))	('renal carcinoma', 'Disease', (111, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('renal carcinoma', 'Phenotype', 'HP:0005584', (111, 126))	('miR-130a-3p', 'Chemical', '-', (41, 52))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('renal carcinoma', 'Disease', 'MESH:C538614', (111, 126))	('miR-130a-3p', 'Var', (41, 52))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('downregulated', 'NegReg', (60, 73))
30007	33482824	Meanwhile, when compared with HK-2 cells, the expression of miR-130a-3p decreased in 786-O cells (P < 0.05, Fold change = 0.44) (Fig.	('miR-130a-3p', 'Chemical', '-', (60, 71))	('decreased', 'NegReg', (72, 81))	('miR-130a-3p', 'Var', (60, 71))	('HK-2', 'molecular_function', 'GO:0008256', ('30', '34'))	('HK-2', 'CellLine', 'CVCL:0302', (30, 34))	('expression', 'MPA', (46, 56))
30010	33482824	Then, we investigated the relationship of CCAT1 and miR-130a-3p expression with the clinicopathological features of ccRCC patients.	('CCAT1', 'Gene', (42, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('ccRCC', 'Disease', (116, 121))	('investigated', 'Reg', (9, 21))	('patients', 'Species', '9606', (122, 130))	('miR-130a-3p', 'Chemical', '-', (52, 63))	('CCAT1', 'Gene', '100507056', (42, 47))	('miR-130a-3p', 'Var', (52, 63))
30011	33482824	According to the mean value of CCAT1 and miR-130a-3p expression, ccRCC patients were dichotomized into high and low expression groups.	('CCAT1', 'Gene', '100507056', (31, 36))	('CCAT1', 'Gene', (31, 36))	('patients', 'Species', '9606', (71, 79))	('miR-130a-3p', 'Chemical', '-', (41, 52))	('ccRCC', 'Disease', (65, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('miR-130a-3p', 'Var', (41, 52))
30012	33482824	As shown in Table 1, high CCAT1 and low miR-130a-3p expressions were significantly related to bigger tumor size and advanced Tumor Node Metastasis (TNM) stage in ccRCC patients (all P < 0.05).	('miR-130a-3p', 'Chemical', '-', (40, 51))	('low', 'NegReg', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('high', 'Var', (21, 25))	('CCAT1', 'Gene', '100507056', (26, 31))	('CCAT1', 'Gene', (26, 31))	('Tumor', 'Phenotype', 'HP:0002664', (125, 130))	('ccRCC', 'Phenotype', 'HP:0006770', (162, 167))	('patients', 'Species', '9606', (168, 176))	('miR-130a-3p', 'Gene', (40, 51))	('related', 'Reg', (83, 90))	('ccRCC', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
30014	33482824	The results indicated that the ccRCC patients with high CCAT1 level had a worse survival (P = 0.001, Fig.	('CCAT1', 'Gene', '100507056', (56, 61))	('patients', 'Species', '9606', (37, 45))	('CCAT1', 'Gene', (56, 61))	('high', 'Var', (51, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (31, 36))	('ccRCC', 'Disease', (31, 36))
30027	33482824	The results of flow cytometry showed that the apoptotic percentage of 786-O cells in control group, si-NC group and si-CCAT1 mimic group were 7.29 +- 1.53%, 6.83 +- 0.84% and 24.03 +- 2.56% respectively, which suggested that cell apoptosis rate was markedly increased in miR-130a-3p mimic group (P < 0.05) (Fig.	('cell apoptosis rate', 'CPA', (225, 244))	('increased', 'PosReg', (258, 267))	('miR-130a-3p', 'Chemical', '-', (271, 282))	('apoptosis', 'biological_process', 'GO:0097194', ('230', '239'))	('apoptosis', 'biological_process', 'GO:0006915', ('230', '239'))	('CCAT1', 'Gene', '100507056', (119, 124))	('miR-130a-3p mimic', 'Var', (271, 288))	('CCAT1', 'Gene', (119, 124))
30030	33482824	Furthermore, the regulatory effect of CCAT1 on miR-130a-3p in 786-O cells was measured by qRT-PCR.	('miR-130a-3p', 'Chemical', '-', (47, 58))	('miR-130a-3p', 'Var', (47, 58))	('CCAT1', 'Gene', '100507056', (38, 43))	('CCAT1', 'Gene', (38, 43))
30032	33482824	In addition, CCAT1 level was reduced in 786-O cells transfected with miR-130a-3p mimics (P < 0.05) (Fig.	('reduced', 'NegReg', (29, 36))	('miR-130a-3p', 'Chemical', '-', (69, 80))	('CCAT1', 'Gene', '100507056', (13, 18))	('miR-130a-3p', 'Var', (69, 80))	('CCAT1', 'Gene', (13, 18))
30035	33482824	MiR-130a-3p and knockdown of CCAT1 inhibited the ability of proliferation and invasion and induced the apoptosis of ccRCC cells.	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('induced', 'Reg', (91, 98))	('CCAT1', 'Gene', '100507056', (29, 34))	('invasion', 'CPA', (78, 86))	('MiR-130a-3p', 'Chemical', '-', (0, 11))	('ability of proliferation', 'CPA', (49, 73))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('knockdown', 'Var', (16, 25))	('CCAT1', 'Gene', (29, 34))	('inhibited', 'NegReg', (35, 44))	('apoptosis', 'CPA', (103, 112))	('MiR-130a-3p', 'Var', (0, 11))
30038	33482824	Moreover, high CCAT1 level was associated with a poor survival prognosis.	('CCAT1', 'Gene', '100507056', (15, 20))	('CCAT1', 'Gene', (15, 20))	('high', 'Var', (10, 14))
30041	33482824	Similarly, in our study, miR-130a-3p also functioned as a tumor suppressor in ccRCC by suppressing cell proliferation and promoting apoptosis.	('apoptosis', 'CPA', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cell proliferation', 'CPA', (99, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('apoptosis', 'biological_process', 'GO:0097194', ('132', '141'))	('ccRCC', 'Disease', (78, 83))	('apoptosis', 'biological_process', 'GO:0006915', ('132', '141'))	('promoting', 'PosReg', (122, 131))	('miR-130a-3p', 'Chemical', '-', (25, 36))	('cell proliferation', 'biological_process', 'GO:0008283', ('99', '117'))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('suppressing', 'NegReg', (87, 98))	('tumor suppressor', 'biological_process', 'GO:0051726', ('58', '74'))	('miR-130a-3p', 'Var', (25, 36))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('58', '74'))
30042	33482824	The similar tumor suppressing effect of miR-130a-3p has also been observed in ovarian cancer cells, prostate cancer cells, etc.	('miR-130a-3p', 'Chemical', '-', (40, 51))	('prostate cancer', 'Disease', 'MESH:D011471', (100, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian cancer', 'Disease', 'MESH:D010051', (78, 92))	('prostate cancer', 'Phenotype', 'HP:0012125', (100, 115))	('miR-130a-3p', 'Var', (40, 51))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('ovarian cancer', 'Disease', (78, 92))	('prostate cancer', 'Disease', (100, 115))	('tumor', 'Disease', (12, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))
30043	33482824	However, some reports showed that miR-130a-3p may serve as an oncogene such as in cervical cancer.	('miR-130a-3p', 'Chemical', '-', (34, 45))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('miR-130a-3p', 'Var', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
30046	33482824	Therefore, we supposed that miR-130a-3p may have different roles in different circumstances or tissues, and functions differently by targeting different genes in multiple cancers.	('miR-130a-3p', 'Var', (28, 39))	('targeting', 'Reg', (133, 142))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cancers', 'Disease', (171, 178))	('miR-130a-3p', 'Chemical', '-', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
30047	33482824	The potential mechanisms of miR-130a-3p role in different cancers would be an interesting topic.	('miR-130a-3p', 'Var', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('miR-130a-3p', 'Chemical', '-', (28, 39))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))
30056	33482824	In our study, knockdown of CCAT1 inhibited the proliferation and invasion and induced the apoptosis of ccRCC cells, which suggested the tumor-promoting function of CCAT1 in ccRCC.	('CCAT1', 'Gene', (164, 169))	('ccRCC', 'Disease', (173, 178))	('ccRCC', 'Phenotype', 'HP:0006770', (173, 178))	('CCAT1', 'Gene', '100507056', (27, 32))	('proliferation', 'CPA', (47, 60))	('CCAT1', 'Gene', (27, 32))	('induced', 'Reg', (78, 85))	('apoptosis', 'biological_process', 'GO:0097194', ('90', '99'))	('apoptosis', 'biological_process', 'GO:0006915', ('90', '99'))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('knockdown', 'Var', (14, 23))	('invasion', 'CPA', (65, 73))	('apoptosis', 'CPA', (90, 99))	('tumor', 'Disease', (136, 141))	('inhibited', 'NegReg', (33, 42))	('CCAT1', 'Gene', '100507056', (164, 169))
30057	33482824	However, it is still unknown about the regulatory relationship between CCAT1 and miR-130a-3p in ccRCC.	('miR-130a-3p', 'Chemical', '-', (81, 92))	('miR-130a-3p', 'Var', (81, 92))	('CCAT1', 'Gene', '100507056', (71, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('ccRCC', 'Disease', (96, 101))	('CCAT1', 'Gene', (71, 76))
30060	33482824	In detail, CCAT1 silencing significantly increased miR-130a-3p expression, while miR-130a-3p mimics remarkably suppressed CCAT1 expression.	('CCAT1', 'Gene', (11, 16))	('silencing', 'Var', (17, 26))	('increased', 'PosReg', (41, 50))	('miR-130a-3p', 'Chemical', '-', (81, 92))	('miR-130a-3p expression', 'MPA', (51, 73))	('CCAT1', 'Gene', '100507056', (122, 127))	('miR-130a-3p', 'Chemical', '-', (51, 62))	('suppressed', 'NegReg', (111, 121))	('expression', 'MPA', (128, 138))	('CCAT1', 'Gene', '100507056', (11, 16))	('CCAT1', 'Gene', (122, 127))
30061	33482824	The biological roles of miR-130a-3p and CCAT1 in regulating ccRCC progression were also investigated in vitro in our experiments, which suggested that miR-130a-3p and knockdown of CCAT1 inhibited ccRCC cell proliferation and invasion, and induced apoptosis.	('invasion', 'CPA', (225, 233))	('CCAT1', 'Gene', '100507056', (180, 185))	('CCAT1', 'Gene', (180, 185))	('apoptosis', 'biological_process', 'GO:0097194', ('247', '256'))	('induced', 'Reg', (239, 246))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('miR-130a-3p', 'Chemical', '-', (151, 162))	('apoptosis', 'CPA', (247, 256))	('CCAT1', 'Gene', '100507056', (40, 45))	('knockdown', 'Var', (167, 176))	('miR-130a-3p', 'Chemical', '-', (24, 35))	('ccRCC', 'Phenotype', 'HP:0006770', (196, 201))	('cell proliferation', 'biological_process', 'GO:0008283', ('202', '220'))	('apoptosis', 'biological_process', 'GO:0006915', ('247', '256'))	('miR-130a-3p', 'Var', (151, 162))	('CCAT1', 'Gene', (40, 45))	('ccRCC', 'Disease', (196, 201))	('inhibited', 'NegReg', (186, 195))
30070	33482824	The down-regulation of miR-130a-3p was reported in human nasopharyngeal carcinoma and breast cancer tissues, and low expression of miR-130a-3p was closely associated with lymph node metastasis and TNM stage of breast cancer.	('low', 'NegReg', (113, 116))	('human', 'Species', '9606', (51, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('miR-130a-3p', 'Gene', (23, 34))	('miR-130a-3p', 'Chemical', '-', (131, 142))	('regulation', 'biological_process', 'GO:0065007', ('9', '19'))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('TNM stage', 'CPA', (197, 206))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Disease', (86, 99))	('expression', 'MPA', (117, 127))	('associated', 'Reg', (155, 165))	('lymph node metastasis', 'CPA', (171, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (210, 223))	('down-regulation', 'NegReg', (4, 19))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (57, 81))	('miR-130a-3p', 'Chemical', '-', (23, 34))	('miR-130a-3p', 'Var', (131, 142))	('breast cancer', 'Disease', 'MESH:D001943', (210, 223))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('carcinoma and breast cancer', 'Disease', 'MESH:D001943', (72, 99))	('breast cancer', 'Disease', (210, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
30071	33482824	Further, we conducted a comprehensive investigation on the clinical relevance of CCAT1 and miR-130a-3p in ccRCC patients.	('miR-130a-3p', 'Chemical', '-', (91, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('miR-130a-3p', 'Var', (91, 102))	('CCAT1', 'Gene', '100507056', (81, 86))	('patients', 'Species', '9606', (112, 120))	('ccRCC', 'Disease', (106, 111))	('CCAT1', 'Gene', (81, 86))
30072	33482824	The results showed that CCAT1 level was increased in ccRCC tissues, which was consistent with a previous study, while miR-130a-3p expression was aberrantly decreased in ccRCC specimens relative to paracancer tissues.	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('ccRCC', 'Disease', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('miR-130a-3p', 'Var', (118, 129))	('cancer', 'Disease', (201, 207))	('decreased', 'NegReg', (156, 165))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('increased', 'PosReg', (40, 49))	('CCAT1', 'Gene', '100507056', (24, 29))	('CCAT1', 'Gene', (24, 29))	('miR-130a-3p', 'Chemical', '-', (118, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))	('ccRCC', 'Disease', (169, 174))
30079	33482824	The only research about the role of miR-130a-3p in predicting cancer prognosis observed that the overexpressed miR-130a-3p was correlated with a worse outcome of cardiac cancer patients, and appeared to alter the radio- and chemo-sensitivities of cardiac cancer.	('cancer', 'Disease', (170, 176))	('cardiac cancer', 'Disease', (162, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Disease', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('miR-130a-3p', 'Var', (111, 122))	('overexpressed', 'PosReg', (97, 110))	('cardiac cancer', 'Phenotype', 'HP:0100544', (247, 261))	('cancer', 'Disease', (62, 68))	('cardiac cancer', 'Disease', 'MESH:D006338', (162, 176))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cardiac cancer', 'Disease', (247, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('miR-130a-3p', 'Chemical', '-', (111, 122))	('patients', 'Species', '9606', (177, 185))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('alter', 'Reg', (203, 208))	('cardiac cancer', 'Phenotype', 'HP:0100544', (162, 176))	('cardiac cancer', 'Disease', 'MESH:D006338', (247, 261))	('miR-130a-3p', 'Chemical', '-', (36, 47))
30080	33482824	However, to date, it is unclear about the prognostic significance of CCAT1 and miR-130a-3p in ccRCC.	('ccRCC', 'Disease', (94, 99))	('CCAT1', 'Gene', (69, 74))	('miR-130a-3p', 'Chemical', '-', (79, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('miR-130a-3p', 'Var', (79, 90))	('CCAT1', 'Gene', '100507056', (69, 74))
30081	33482824	In this study, we obtained survival data from TCGA to further investigate the prognostic role of CCAT1 and miR-130a-3p in ccRCC.	('miR-130a-3p', 'Var', (107, 118))	('CCAT1', 'Gene', '100507056', (97, 102))	('CCAT1', 'Gene', (97, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (122, 127))	('ccRCC', 'Disease', (122, 127))	('miR-130a-3p', 'Chemical', '-', (107, 118))
30082	33482824	Kaplan-Meier analysis showed that high expression of CCAT1 had a significant impact on a poor survival prognosis, indicating that CCAT1 may act as a prognostic biomarker for ccRCC.	('high expression', 'Var', (34, 49))	('impact', 'Reg', (77, 83))	('CCAT1', 'Gene', '100507056', (53, 58))	('CCAT1', 'Gene', '100507056', (130, 135))	('ccRCC', 'Disease', (174, 179))	('ccRCC', 'Phenotype', 'HP:0006770', (174, 179))	('CCAT1', 'Gene', (53, 58))	('poor survival prognosis', 'CPA', (89, 112))	('CCAT1', 'Gene', (130, 135))
30083	33482824	However, our results failed to demonstrate an association between miR-130a-3p and ccRCC prognosis.	('miR-130a-3p', 'Var', (66, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('ccRCC', 'Disease', (82, 87))	('miR-130a-3p', 'Chemical', '-', (66, 77))
30084	33482824	MiR-130a-3p may have different roles in different circumstances or stages of cancer.	('MiR-130a-3p', 'Chemical', '-', (0, 11))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('MiR-130a-3p', 'Var', (0, 11))
30088	33482824	Taken together, bioinformatics analysis along with biological experiments indicated that CCAT1 might function as a molecular sponge of miR-130a-3p to participate in the pathogenesis of ccRCC.	('miR-130a-3p', 'Chemical', '-', (135, 146))	('miR-130a-3p', 'Var', (135, 146))	('participate', 'Reg', (150, 161))	('pathogenesis', 'biological_process', 'GO:0009405', ('169', '181'))	('ccRCC', 'Phenotype', 'HP:0006770', (185, 190))	('ccRCC', 'Disease', (185, 190))	('CCAT1', 'Gene', '100507056', (89, 94))	('CCAT1', 'Gene', (89, 94))
30089	33482824	MiR-130a-3p and knockdown of CCAT1 inhibited ccRCC cell proliferation and invasion, and induced apoptosis.	('cell proliferation', 'biological_process', 'GO:0008283', ('51', '69'))	('invasion', 'CPA', (74, 82))	('induced', 'Reg', (88, 95))	('CCAT1', 'Gene', '100507056', (29, 34))	('MiR-130a-3p', 'Chemical', '-', (0, 11))	('knockdown', 'Var', (16, 25))	('CCAT1', 'Gene', (29, 34))	('apoptosis', 'CPA', (96, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('inhibited', 'NegReg', (35, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))	('ccRCC', 'Disease', (45, 50))	('MiR-130a-3p', 'Var', (0, 11))
30100	31737127	Numerous immunochemical markers have been reported, including CK7, CD117 (KIT), parvalbumin, DOG1 cyclin D1, vimentin, EMA, S1001A, kidney-specific cadherin (Ksp-cad), Claudin-7, and Claudin-8.	('vimentin', 'cellular_component', 'GO:0045098', ('109', '117'))	('KIT', 'molecular_function', 'GO:0005020', ('74', '77'))	('S1001A', 'Var', (124, 130))	('cadherin', 'molecular_function', 'GO:0008014', ('148', '156'))	('cyclin', 'molecular_function', 'GO:0016538', ('98', '104'))	('EMA', 'Chemical', 'MESH:C519317', (119, 122))	('Claudin-7', 'Gene', (168, 177))	('Claudin-8', 'Gene', (183, 192))	('vimentin', 'Protein', (109, 117))	('S1001A', 'Mutation', 'p.S1001A', (124, 130))	('vimentin', 'cellular_component', 'GO:0045099', ('109', '117'))	('CK7', 'Var', (62, 65))	('CD117', 'Gene', (67, 72))
30102	31737127	Panels of immunostaining markers have been proposed to make a differential diagnosis: DOG1/cyclin D1/CK7/CD117/vimentin, CK7/CD117/PAX2, CK7/parvalbumin, CK7/vimentin/S100A1/CD117, S1001A/CD117, HNF1beta/S100A1, etc.. We have 10 years of experience with the combined immunohistochemistry for the "three 7" markers, that is, CK7, CD117, and Claudin-7, to diagnose chromophobe renal cell carcinoma and exclude the mimics.	('vimentin', 'cellular_component', 'GO:0045098', ('111', '119'))	('S1001A', 'SUBSTITUTION', 'None', (181, 187))	('cyclin', 'molecular_function', 'GO:0016538', ('91', '97'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (375, 395))	('carcinoma', 'Phenotype', 'HP:0030731', (386, 395))	('chromophobe renal cell carcinoma', 'Disease', (363, 395))	('vimentin', 'cellular_component', 'GO:0045099', ('158', '166'))	('vimentin', 'cellular_component', 'GO:0045099', ('111', '119'))	('S1001A', 'Var', (181, 187))	('vimentin', 'cellular_component', 'GO:0045098', ('158', '166'))
30218	33194717	Consequently, the inactivation of the second copy of the VHL gene heralds the development of clinically aggressive ccRCC.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('inactivation', 'Var', (18, 30))	('VHL', 'Gene', (57, 60))	('VHL', 'Gene', '7428', (57, 60))	('heralds', 'Reg', (66, 73))
30220	33194717	Recurrent somatic mutations found in ccRCCs occur in the epigenetic regulators PBRM1, SETD2 and BAP1, all of which are also located on chromosome 3p and are therefore prone to inactivation similar to VHL.	('occur', 'Reg', (44, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('VHL', 'Gene', (200, 203))	('BAP1', 'Gene', (96, 100))	('VHL', 'Gene', '7428', (200, 203))	('PBRM1', 'Gene', (79, 84))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('PBRM1', 'Gene', '55193', (79, 84))	('chromosome', 'cellular_component', 'GO:0005694', ('135', '145'))	('SETD2', 'Gene', '29072', (86, 91))	('BAP1', 'Gene', '8314', (96, 100))	('SETD2', 'Gene', (86, 91))	('mutations', 'Var', (18, 27))
30221	33194717	These specific genetic changes are reflected at the RNA and protein levels, for instance, by activation of the HIF-pathway and a corresponding increase in expression of angiogenesis-related mRNA signatures and hypoxic signaling, which are direct consequences of VHL inactivation.	('activation', 'PosReg', (93, 103))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('RNA', 'cellular_component', 'GO:0005562', ('52', '55'))	('angiogenesis-related mRNA signatures', 'MPA', (169, 205))	('expression', 'MPA', (155, 165))	('signaling', 'biological_process', 'GO:0023052', ('218', '227'))	('angiogenesis', 'biological_process', 'GO:0001525', ('169', '181'))	('inactivation', 'Var', (266, 278))	('hypoxic signaling', 'MPA', (210, 227))	('VHL', 'Gene', (262, 265))	('increase', 'PosReg', (143, 151))	('HIF-pathway', 'Pathway', (111, 122))	('VHL', 'Gene', '7428', (262, 265))
30222	33194717	Extensive metabolic reprogramming is another result of the genetic changes that occur during ccRCC initiation and progression and this is increasingly recognized to correlate with aggressive disease.	('changes', 'Var', (67, 74))	('aggressive disease', 'Disease', (180, 198))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('RCC', 'Disease', (95, 98))	('aggressive disease', 'Disease', 'MESH:D001523', (180, 198))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))
30223	33194717	This is exemplified by the inactivation of the pyruvate dehydrogenase complex (PDC) which in turn impairs the Krebs cycle and oxidative phosphorylation resulting in a metabolic shift toward glycolysis.	('glycolysis', 'biological_process', 'GO:0006096', ('190', '200'))	('inactivation', 'Var', (27, 39))	('impairs', 'NegReg', (98, 105))	('pyruvate dehydrogenase complex', 'cellular_component', 'GO:0045254', ('47', '77'))	('Krebs cycle', 'biological_process', 'GO:0006099', ('110', '121'))	('metabolic shift toward glycolysis', 'MPA', (167, 200))	('Krebs cycle', 'MPA', (110, 121))	('Krebs', 'Chemical', '-', (110, 115))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('126', '151'))	('oxidative phosphorylation', 'MPA', (126, 151))
30224	33194717	Importantly, metabolic rewiring in ccRCC has been shown to induce HIF-signaling independent of VHL through signaling pathways that involve for example mTOR and MET.	('signaling', 'biological_process', 'GO:0023052', ('70', '79'))	('signaling', 'biological_process', 'GO:0023052', ('107', '116'))	('VHL', 'Gene', (95, 98))	('metabolic rewiring', 'Var', (13, 31))	('HIF-signaling', 'MPA', (66, 79))	('VHL', 'Gene', '7428', (95, 98))	('induce', 'Reg', (59, 65))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('ccRCC', 'Phenotype', 'HP:0006770', (35, 40))	('MET', 'Gene', '79811', (160, 163))	('mTOR', 'Gene', (151, 155))	('mTOR', 'Gene', '2475', (151, 155))	('MET', 'Gene', (160, 163))
30225	33194717	This metabolic distortion could influence epigenetic changes and chromatin dysregulation, contributing to the aggressiveness of the tumor.	('influence', 'Reg', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('distortion', 'Var', (15, 25))	('contributing', 'Reg', (90, 102))	('aggressiveness of the tumor', 'Disease', (110, 137))	('aggressiveness of the tumor', 'Disease', 'MESH:D001523', (110, 137))	('epigenetic changes', 'MPA', (42, 60))	('metabolic distortion', 'Var', (5, 25))	('chromatin', 'cellular_component', 'GO:0000785', ('65', '74'))	('chromatin dysregulation', 'MPA', (65, 88))	('aggressiveness', 'Phenotype', 'HP:0000718', (110, 124))
30227	33194717	Conserved trajectories have been identified to lead to metastasis, with PBRM1 mutations often predicating dissemination.	('predicating', 'Reg', (94, 105))	('metastasis', 'CPA', (55, 65))	('lead to', 'Reg', (47, 54))	('mutations', 'Var', (78, 87))	('PBRM1', 'Gene', (72, 77))	('PBRM1', 'Gene', '55193', (72, 77))
30269	33194717	Another important finding from this study is that plasma ctDNA represented 90% of the disparate mutations found in multiple biopsy regions from individual tumors of two well characterized ccRCC patients and thus indicated that ctDNA could be used to circumvent tumor sampling bias that might be present in conventional tissue biopsies.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('patients', 'Species', '9606', (194, 202))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('ccRCC', 'Phenotype', 'HP:0006770', (188, 193))	('RCC', 'Disease', (190, 193))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (155, 160))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('mutations', 'Var', (96, 105))
30282	33194717	Acknowledging the involvement of VHL mutations in ccRCC tumorigenesis, proteins downstream of the hypoxia-pathway represent a class of interesting soluble markers.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (50, 55))	('hypoxia', 'Disease', (98, 105))	('hypoxia', 'Disease', 'MESH:D000860', (98, 105))	('VHL', 'Gene', (33, 36))	('ccRCC tumor', 'Disease', (50, 61))	('mutations', 'Var', (37, 46))	('VHL', 'Gene', '7428', (33, 36))	('soluble', 'cellular_component', 'GO:0005625', ('147', '154'))	('involvement', 'Reg', (18, 29))	('ccRCC tumor', 'Disease', 'MESH:D009369', (50, 61))
30338	33194717	Among the main challenges is the concomitant presence of mutant fragments from non-RCC somatic clones stemming, for example, from CHIP which was identified as a main cause for the discordance between plasma and tissue RCC samples.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('mutant', 'Var', (57, 63))	('RCC', 'Disease', (218, 221))
30344	33194717	Thus, circulating cell-free nucleosomes could become interesting targets for observing mRCC-specific changes in expression programs that are often imposed by alteration in SETD2, PBRM1, or BAP1.	('BAP1', 'Gene', '8314', (189, 193))	('PBRM1', 'Gene', (179, 184))	('BAP1', 'Gene', (189, 193))	('alteration', 'Var', (158, 168))	('RCC', 'Disease', (88, 91))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('SETD2', 'Gene', '29072', (172, 177))	('PBRM1', 'Gene', '55193', (179, 184))	('SETD2', 'Gene', (172, 177))	('expression programs', 'MPA', (112, 131))	('changes', 'Reg', (101, 108))
30393	29343969	The primers used for GAPDH were 5'-AACGTGTCAGTGGTGGACCTG-3' (forward) and 5'-AGTGGGTGTCGCTGTTGAAGT-3' (reverse).	('GAPDH', 'Gene', (21, 26))	("5'-AACGTGTCAGTGGTGGACCTG-3", 'Var', (32, 58))	("5'-AGTGGGTGTCGCTGTTGAAGT-3", 'Var', (74, 100))	('GAPDH', 'Gene', '2597', (21, 26))
30435	29343969	Given the fact that ROCK1 is involved in the regulation of many key cellular functions associated with malignancy, we asked whether restoration of miR-199a may suppress proliferation and invasion in ccRCC cells.	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('malignancy', 'Disease', 'MESH:D009369', (103, 113))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('malignancy', 'Disease', (103, 113))	('suppress', 'NegReg', (160, 168))	('ccRCC', 'Phenotype', 'HP:0006770', (199, 204))	('restoration', 'Var', (132, 143))	('miR', 'Gene', '220972', (147, 150))	('ROCK1', 'Gene', (20, 25))	('miR', 'Gene', (147, 150))	('ROCK1', 'Gene', '6093', (20, 25))	('proliferation', 'CPA', (169, 182))	('199a', 'Chemical', '-', (151, 155))	('regulation', 'biological_process', 'GO:0065007', ('45', '55'))	('invasion', 'CPA', (187, 195))
30466	29343969	Deregulation of miRNAs is associated with several diseases including cancer.	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('miR', 'Gene', '220972', (16, 19))	('miR', 'Gene', (16, 19))	('associated', 'Reg', (26, 36))	('cancer', 'Disease', (69, 75))
30469	29343969	Consistent with the above findings, we found that restoration of miR-199a could suppress proliferation and invasion, but induce apoptosis in ccRCC cells.	('proliferation', 'CPA', (89, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (141, 146))	('induce', 'Reg', (121, 127))	('suppress', 'NegReg', (80, 88))	('restoration', 'Var', (50, 61))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('199a', 'Chemical', '-', (69, 73))	('apoptosis', 'biological_process', 'GO:0097194', ('128', '137'))	('apoptosis', 'biological_process', 'GO:0006915', ('128', '137'))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('invasion', 'CPA', (107, 115))	('RCC', 'Disease', (143, 146))	('apoptosis', 'CPA', (128, 137))
30488	33072592	Comparison of T2N0M0 and T3aN0M0 in Predicting the Prognosis of Patients With Renal Cell Carcinoma Background: To investigate the prognostic role of tumor size in patients with pathological T2N0M0 and T3aN0M0 renal cell carcinoma (RCC) treated by radical surgery.	('patients', 'Species', '9606', (163, 171))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (209, 229))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (78, 98))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('Carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (78, 98))	('RCC', 'Disease', (231, 234))	('RCC', 'Phenotype', 'HP:0005584', (231, 234))	('Renal Cell Carcinoma', 'Disease', (78, 98))	('Patients', 'Species', '9606', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('RCC', 'Disease', 'MESH:C538614', (231, 234))	('T2N0M0', 'Var', (190, 196))	('tumor', 'Disease', (149, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('T3aN0M0', 'Var', (201, 208))	('renal cell carcinoma', 'Disease', (209, 229))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (209, 229))
30490	33072592	Results: In the low-risk T3aN0M0 (perinephric fatty infiltration or sinus fatty infiltration only) group, patients with tumor size <= 7 cm were associated with a better OS (P = 0.009) and CSS (P < 0.001) than those with tumor size >7 cm.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('T3aN0M0', 'Var', (25, 32))	('tumor', 'Disease', (220, 225))	('perinephric fatty infiltration', 'Phenotype', 'HP:0031226', (34, 64))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('patients', 'Species', '9606', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('better', 'PosReg', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Disease', (120, 125))	('CSS', 'CPA', (188, 191))
30491	33072592	However, there was no difference in OS (P = 0.129) and CSS (P = 0.539) between T2bN0M0 patients and low-risk T3aN0M0 patients with tumor size <= 7 cm.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('T2bN0M0', 'Var', (79, 86))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('patients', 'Species', '9606', (117, 125))	('patients', 'Species', '9606', (87, 95))
30492	33072592	A new T classification grouping patients with both T2bN0M0 and T3aN0M0 with tumor diameter <= 7 cm into the same staging category (pT2aN0M0, pT2bN0M0+low-risk pT3aN0M0 [tumor diameter <= 7cm], low-risk pT3aN0M0 [tumor diameter >7 cm], high-risk pT3aN0M0) was proposed and it was found as an independent predictive variable for OS and CSS.	('patients', 'Species', '9606', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('CSS', 'Disease', (334, 337))	('pT2bN0M0+low-risk', 'Var', (141, 158))	('tumor', 'Disease', (212, 217))
30493	33072592	Conclusions: Findings from the present study suggest that the reclassification of pT2N0M0 and pT3aN0M0 RCC can lead to better prediction of OS and CSS.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('pT3aN0M0', 'Var', (94, 102))	('CSS', 'Disease', (147, 150))	('pT2N0M0', 'Var', (82, 89))
30501	33072592	In addition, we have reported the outcomes of 1,869 patients receiving radical nephrectomy from the Surveillance, Epidemiology and End Results (SEER) database, and we have demonstrated that different invasion locations can help distinguish T3aN0M0 clear cell RCC patients with increased risk of cancer-related mortality.	('mortality', 'Disease', (310, 319))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('patients', 'Species', '9606', (263, 271))	('RCC', 'Phenotype', 'HP:0005584', (259, 262))	('cancer', 'Disease', (295, 301))	('RCC', 'Disease', 'MESH:C538614', (259, 262))	('RCC', 'Disease', (259, 262))	('T3aN0M0', 'Var', (240, 247))	('mortality', 'Disease', 'MESH:D003643', (310, 319))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('patients', 'Species', '9606', (52, 60))
30504	33072592	Therefore, there are questionable differences in the prognostic significance of pT2N0M0 and pT3aN0M0 with only PFI or SFI in RCC patients.	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('patients', 'Species', '9606', (129, 137))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('pT2N0M0', 'Var', (80, 87))	('PFI', 'molecular_function', 'GO:0034016', ('111', '114'))	('pT3aN0M0', 'Var', (92, 100))
30505	33072592	To examine such hypothesis, we conducted the difference in prognosis between pT2N0M0 and pT3aN0M0 RCC patients who underwent radical surgery and to compute a model for stratifying their outcome based on the SEER dataset.	('pT3aN0M0', 'Var', (89, 97))	('patients', 'Species', '9606', (102, 110))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('pT2N0M0', 'Var', (77, 84))	('RCC', 'Disease', 'MESH:C538614', (98, 101))
30510	33072592	Based on previous studies, we defined the low-risk T3aN0M0 as one pattern of extrarenal extension (PFI or SFI) and the high-risk T3aN0M0 as multiple pattern of extrarenal extension (PFI+SFI, PFI+ renal vein infiltration [RVI], SFI+RVI, PFI+SFI+RVI).	('RVI', 'Disease', (231, 234))	('PFI', 'molecular_function', 'GO:0034016', ('182', '185'))	('RVI', 'Disease', 'None', (244, 247))	('T3aN0M0', 'Var', (51, 58))	('PFI', 'molecular_function', 'GO:0034016', ('236', '239'))	('RVI', 'Disease', 'None', (221, 224))	('RVI', 'Disease', (244, 247))	('PFI', 'molecular_function', 'GO:0034016', ('191', '194'))	('RVI', 'Disease', 'None', (231, 234))	('SFI+RVI, PFI+SFI+RVI', 'Disease', 'None', (227, 247))	('RVI', 'Disease', (221, 224))	('PFI', 'molecular_function', 'GO:0034016', ('99', '102'))
30523	33072592	Univariate analysis was performed in low-risk pT3aN0M0 RCC patients, and the tumor size was significantly correlated with OS (HR: 1.005, 95%CI: 1.002-1.007, P = 0.003) and CSS (HR: 1.011, 95%CI: 1.007-1.015, P < 0.001), indicating that for every 1 mm increase in tumor size lead to a higher risk of death of OS and CSS.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('CSS', 'Disease', (315, 318))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('death', 'Disease', 'MESH:D003643', (299, 304))	('death', 'Disease', (299, 304))	('pT3aN0M0', 'Var', (46, 54))	('tumor', 'Disease', (263, 268))	('CSS', 'Disease', (172, 175))	('patients', 'Species', '9606', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
30526	33072592	Based on the results of Kaplan-Meier curves, for OS, there was no significance between the patients with T2bN0M0 and Low-risk T3aN0M0 (tumor size <= 7 cm) in the ccRCC (P = 0.649) and non-clear cell RCC (P=0.126) subgroup (Supplementary Figures 4A,B).	('patients', 'Species', '9606', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))	('T3aN0M0', 'Var', (126, 133))	('tumor', 'Disease', (135, 140))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('RCC', 'Disease', (164, 167))	('T2bN0M0', 'Var', (105, 112))	('RCC', 'Disease', (199, 202))	('RCC', 'Phenotype', 'HP:0005584', (199, 202))	('RCC', 'Disease', 'MESH:C538614', (199, 202))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
30529	33072592	According to the Kaplan-Meier plot and log-rank test, we found that there was no difference in terms of OS and CSS between pT2bN0M0 patients and low-risk pT3aN0M0 patients with tumor size <= 7 cm (OS, P = 0.129; CSS, P = 0.539; Figure 2).	('patients', 'Species', '9606', (163, 171))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('pT2bN0M0', 'Var', (123, 131))	('tumor', 'Disease', (177, 182))	('patients', 'Species', '9606', (132, 140))
30530	33072592	Afterwards, we combined pT2bN0M0 and low-risk pT3aN0M0 patients with tumor size <= 7 cm into one group, our results showed that low-risk pT3aN0M0 patients with tumor size >7 cm experienced significantly worse OS and CSS compared with the remaining two groups (pT2aN0M0, or pT2bN0M0+low-risk pT3aN0M0 with tumor size <= 7 cm) (OS, P < 0.001; CSS, P < 0.001; Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('worse', 'PosReg', (203, 208))	('CSS', 'CPA', (216, 219))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('pT3aN0M0', 'Var', (137, 145))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Disease', (305, 310))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('patients', 'Species', '9606', (146, 154))	('tumor', 'Disease', (160, 165))
30531	33072592	However, For CSS, there was no statistical significance between the high-risk pT3aN0M0 and the low-risk pT3aN0M0 patients with tumor size >7 cm (P = 0.122; Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('patients', 'Species', '9606', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('pT3aN0M0', 'Var', (78, 86))
30538	33072592	The proposed cut-off value of 7 cm for the low-risk pT3aN0M0 RCC patients receiving radical surgery could avoid adding unnecessary complexity to the TNM system as it has been widely used for RCC TNM staging system.	('RCC', 'Disease', (191, 194))	('RCC', 'Phenotype', 'HP:0005584', (191, 194))	('RCC', 'Disease', 'MESH:C538614', (191, 194))	('pT3aN0M0', 'Var', (52, 60))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('patients', 'Species', '9606', (65, 73))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))
30539	33072592	Third, the prognosis of pT2bN0M0 RCC patients receiving radical resection was very similar to that of low-risk pT3aN0M0 patients with tumor size <= 7 cm, which might be merged into one staging category.	('pT2bN0M0', 'Var', (24, 32))	('patients', 'Species', '9606', (37, 45))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('patients', 'Species', '9606', (120, 128))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
30540	33072592	Fourth, our results showed significant distinctions among the patients with pT2 and pT3a tumors regarding OS and CSS according to new T classification method, namely, pT2a vs. pT2b+low-risk pT3a with tumor size <= 7 cm vs. low-risk pT3a with tumor size >7 cm vs. high-risk pT3a.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('CSS', 'Disease', (113, 116))	('pT2a', 'Var', (167, 171))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('pT3a', 'Gene', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Disease', (242, 247))	('patients', 'Species', '9606', (62, 70))	('pT2', 'Gene', (76, 79))	('tumor', 'Disease', (89, 94))
30548	33072592	have demonstrated that the tumor size significantly affects the survival outcomes of pT3aN0M0 RCC patients undergoing radical nephrectomy, and a cut-off size of 7 cm can help enhance the prognostic discrimination.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('tumor', 'Disease', (27, 32))	('survival', 'MPA', (64, 72))	('patients', 'Species', '9606', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('affects', 'Reg', (52, 59))	('pT3aN0M0', 'Var', (85, 93))
30552	33072592	We found that there was no significance between the patients with T2b and low-risk T3a (tumor size <= 7 cm) in the ccRCC and non-clear cell RCC subgroups for OS and CSS.	('T2b', 'Var', (66, 69))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('CSS', 'Disease', (165, 168))	('RCC', 'Disease', (140, 143))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('tumor', 'Disease', (88, 93))	('patients', 'Species', '9606', (52, 60))	('T3a', 'Gene', (83, 86))
30559	33072592	Despite these limitations, as far as we know, this was the first study that compared the prognosis between pT2N0M0 and pT3aN0M0 patients with RCC who underwent radical surgery.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('pT2N0M0', 'Var', (107, 114))	('patients', 'Species', '9606', (128, 136))	('pT3aN0M0', 'Var', (119, 127))
30561	33072592	The prognosis of low-risk pT3aN0M0 RCC patients with tumor size <= 7 cm might be similar to that of patients with pT2bN0M0 tumors, while low-risk pT3aN0M0 patients with tumor size > 7 cm may have a worse prognosis than patients with pT2N0M0 in RCC.	('RCC', 'Disease', (244, 247))	('RCC', 'Phenotype', 'HP:0005584', (244, 247))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('patients', 'Species', '9606', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('patients', 'Species', '9606', (100, 108))	('patients', 'Species', '9606', (155, 163))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('RCC', 'Disease', 'MESH:C538614', (244, 247))	('RCC', 'Disease', (35, 38))	('tumor', 'Disease', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (169, 174))	('patients', 'Species', '9606', (219, 227))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('pT3aN0M0', 'Var', (26, 34))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumors', 'Disease', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (53, 58))
30601	32092671	Recently, the first syngeneic mouse model of metastatic RCC deficient in the von Hippel-Lindau (VHL) gene was established by CRISPR-mediated knockout of VHL with the use of lentiviral transduction.	('VHL', 'Disease', (153, 156))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('metastatic RCC deficient in the von Hippel-Lindau', 'Disease', 'MESH:D006623', (45, 94))	('transduction', 'biological_process', 'GO:0009293', ('184', '196'))	('VHL', 'Disease', 'MESH:D006623', (96, 99))	('metastatic RCC deficient in the von Hippel-Lindau', 'Disease', (45, 94))	('VHL', 'Disease', (96, 99))	('VHL', 'Disease', 'MESH:D006623', (153, 156))	('knockout', 'Var', (141, 149))
30604	32092671	Renal tumors appear in heterozygotes and in accordance with the Knudson "two-hit" hypothesis, a tumor occurs when a wild type allele is inactivated by loss of heterozygosity or somatic mutation.	('Renal tumor', 'Disease', 'MESH:D007680', (0, 11))	('Renal tumor', 'Phenotype', 'HP:0009726', (0, 11))	('Renal tumors', 'Disease', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('loss of heterozygosity', 'Var', (151, 173))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('Renal tumors', 'Phenotype', 'HP:0009726', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('Renal tumors', 'Disease', 'MESH:D007680', (0, 12))
30610	32092671	Although the frequency of mutations in p53 is not fully determined, many studies in human renal cancer derived tissues indicate that mutations in p53 occur rarely, as in Eker rats.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('p53', 'Gene', '7157', (39, 42))	('p53', 'Gene', (39, 42))	('mutations', 'Var', (133, 142))	('renal cancer', 'Phenotype', 'HP:0009726', (90, 102))
30611	32092671	In humans, alterations in TSC genes (humans possess two TSC1 or TSC2 genes) are connected with tuberous sclerosis.	('alterations', 'Var', (11, 22))	('TSC', 'Gene', (26, 29))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (95, 113))	('TSC1', 'Gene', (56, 60))	('TSC', 'Gene', (64, 67))	('TSC', 'Gene', '7248;7249;479883;22084;24855', (56, 59))	('TSC', 'Gene', '7248;7249;479883;22084;24855', (26, 29))	('TSC', 'Gene', '7248;7249;479883;22084;24855', (64, 67))	('TSC2', 'Gene', '7249', (64, 68))	('tuberous sclerosis', 'Disease', (95, 113))	('TSC1', 'Gene', '7248', (56, 60))	('TSC', 'Gene', (56, 59))	('TSC2', 'Gene', (64, 68))	('connected', 'Reg', (80, 89))
30620	32092671	Genetically engineered mouse (GEM) models are developed by the introduction of constitutively or conditionally expressed genetic alterations, associated with a particular disease/cancer.	('genetic alterations', 'Var', (121, 140))	('particular disease', 'Disease', 'MESH:D030342', (160, 178))	('particular disease', 'Disease', (160, 178))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))
30627	32092671	For example, kidney epithelium specific co-deletion of Vhl and Pten  or Kif3a (Kinesin Family Member 3A) in mice led to formation of simple, atypical cystic lesions that mimic precursor lesions observed in some ccRCC, however, no cancer cells were found.	('cystic lesions', 'Disease', 'MESH:D052177', (150, 164))	('Kif3a', 'Gene', (72, 77))	('ccRCC', 'Disease', (211, 216))	('Pten', 'Gene', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('Kinesin', 'molecular_function', 'GO:0003777', ('79', '86'))	('Kinesin Family Member 3A', 'Gene', '16568', (79, 103))	('Kinesin Family Member 3A', 'Gene', (79, 103))	('co-deletion', 'Var', (40, 51))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	('formation', 'biological_process', 'GO:0009058', ('120', '129'))	('Kif3a', 'Gene', '16568', (72, 77))	('cystic lesions', 'Disease', (150, 164))	('Vhl', 'Gene', (55, 58))	('Pten', 'Gene', '19211', (63, 67))
30628	32092671	More promising are models with genetic modifications in Vhl, Trp53 and Rb1 , Vhl and Pbrm1 , Vhl and Bap1 , Hif1alpha , Myc , Tfeb , Bhd  or NICD1  that are described below in more detail.	('Hif1alpha', 'Gene', (108, 117))	('Vhl', 'Gene', (77, 80))	('Rb1', 'Gene', (71, 74))	('Pbrm1', 'Gene', (85, 90))	('Bap1', 'Gene', (101, 105))	('genetic modifications', 'Var', (31, 52))	('Trp53', 'Gene', (61, 66))	('Vhl', 'Gene', (56, 59))	('Hif1alpha', 'Gene', '3091', (108, 117))	('Vhl', 'Gene', (93, 96))
30632	32092671	All of VhlDelta/DeltaPbrm1Delta/Delta mice by 20 months of age exhibited a spectrum of premalignant cysts and developed multifocal renal tumors arising within macroscopically normal parenchyma and they were confirmed to originate from proximal renal tubules.	('multifocal renal tumors', 'Disease', (120, 143))	('exhibited', 'Reg', (63, 72))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('developed', 'PosReg', (110, 119))	('renal tumors', 'Phenotype', 'HP:0009726', (131, 143))	('renal tumor', 'Phenotype', 'HP:0009726', (131, 142))	('multifocal renal tumors', 'Disease', 'None', (120, 143))	('VhlDelta/DeltaPbrm1Delta/Delta', 'Var', (7, 37))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
30636	32092671	An additional knock-out of one copy of the mTORC1 negative regulator, Tsc1 gene, in the kidneys along with Vhl and Pbrm1 led to development of tumors with similar appearance to those observed in kidneys with intact Tsc1, but of higher grade and with increased mTORC1 activation.	('Tsc1', 'Gene', (215, 219))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('mTORC1', 'Gene', (43, 49))	('mTORC1', 'Gene', (260, 266))	('mTORC1', 'cellular_component', 'GO:0031931', ('43', '49'))	('mTORC1', 'cellular_component', 'GO:0031931', ('260', '266'))	('Tsc1', 'Gene', '7248', (70, 74))	('tumors', 'CPA', (143, 149))	('Tsc1', 'Gene', (70, 74))	('mTORC1', 'Gene', '382056', (43, 49))	('knock-out', 'Var', (14, 23))	('Tsc1', 'Gene', '7248', (215, 219))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('mTORC1', 'Gene', '382056', (260, 266))
30641	32092671	described the role of Vhl and Brca1 associated protein-1 (Bap1) deletion in mice.	('Brca1 associated protein-1', 'Gene', '104416', (30, 56))	('deletion', 'Var', (64, 72))	('Bap1', 'Gene', (58, 62))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('Brca1 associated protein-1', 'Gene', (30, 56))
30642	32092671	Homozygous deletion of Vhl and Bap1 in the mouse (Six2-Cre; VhlDelta/DeltaBap1Delta/Delta) kidney resulted in early mortality before 1 month.	('Six2', 'Gene', '20472', (50, 54))	('Vhl', 'Gene', (23, 26))	('resulted in', 'Reg', (98, 109))	('Bap1', 'Gene', (31, 35))	('Six2', 'Gene', (50, 54))	('deletion', 'Var', (11, 19))
30646	32092671	Importantly, mutations in Pbrm1, Bap1 and Setd2 were not found in the examined animal tumors, providing evidence that this model may reflect approximately 50% of human ccRCC that do not harbor mutations in those tumor-suppressor genes.	('Setd2', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Pbrm1', 'Gene', (26, 31))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('212', '228'))	('ccRCC', 'Disease', (168, 173))	('Setd2', 'Gene', '29072', (42, 47))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('212', '228'))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('mutations', 'Var', (13, 22))	('Bap1', 'Gene', (33, 37))
30649	32092671	developed a conditional mouse model based on the ectopic expression of a constitutively active intracellular domain of Notch 1 (NICD1) and the disruption of the Vhl gene in renal proximal tubular epithelial cells.	('Notch', 'Gene', (119, 124))	('Notch 1', 'Gene', '18128', (119, 126))	('Notch', 'Gene', '31293', (119, 124))	('disruption', 'Var', (143, 153))	('Notch 1', 'Gene', (119, 126))	('intracellular', 'cellular_component', 'GO:0005622', ('95', '108'))	('NICD1', 'Gene', (128, 133))	('Vhl gene', 'Gene', (161, 169))
30654	32092671	FLCN homozygous deletion usually results in embryonic lethality.	('FLCN', 'Gene', (0, 4))	('embryonic lethality', 'Disease', (44, 63))	('results in', 'Reg', (33, 43))	('deletion', 'Var', (16, 24))	('embryonic lethality', 'Disease', 'MESH:D020964', (44, 63))
30668	32092671	They created a triple mutant (P402A, P564A, N803A) human HIF-1alpha construct using the kidney proximal tubule specific type 1 gamma-glutamyl transpeptidase (GGT) promoter to drive its expression in the proximal tubule cells.	('N803A', 'Var', (44, 49))	('P564A', 'Mutation', 'p.P564A', (37, 42))	('P402A', 'Var', (30, 35))	('P564A', 'Var', (37, 42))	('N803A', 'Mutation', 'p.N803A', (44, 49))	('P402A', 'Mutation', 'p.P402A', (30, 35))
30669	32092671	Transgenic mice developed normally and passed the transgene to offspring following a Mendelian inheritance pattern.	('developed', 'CPA', (16, 25))	('transgene', 'Var', (50, 59))	('Transgenic mice', 'Species', '10090', (0, 15))
30685	32092671	The model (Cdh16Cre::Tfebfs) was obtained by crossing the Tfeb conditional overexpressing mouse line carrying Tfeb-3xFlagfs/fs under the control of the chicken beta-actin promoter with the Cdh16Cre mouse strain, in which Cre recombinase is specifically expressed in renal tubular epithelial cells starting from the embryonic stage.	('Tfeb-3xFlagfs/fs', 'Var', (110, 126))	('Cdh16', 'Gene', (189, 194))	('chicken', 'Species', '9031', (152, 159))	('Cdh16', 'Gene', '12556', (189, 194))	('Cdh16Cre', 'Chemical', '-', (189, 197))	('Cdh16', 'Gene', '12556', (11, 16))	('Cdh16', 'Gene', (11, 16))	('Cdh16Cre', 'Chemical', '-', (11, 19))
30688	32092671	Additionally, the WNT inhibitor PKF118-310 was tested in vivo in this model, resulting in reduction of kidney mass, and the number of cystic and neoplastic lesions.	('PKF118-310', 'Var', (32, 42))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (145, 163))	('reduction of kidney mass', 'Disease', 'MESH:C536030', (90, 114))	('reduction of kidney mass', 'Disease', (90, 114))
30692	32092671	20% of tumors harbor inactivating mutations of the WT1 gene.	('inactivating mutations', 'Var', (21, 43))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('WT1', 'Gene', '7490', (51, 54))	('WT1', 'Gene', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
30697	32092671	Moreover, Wt1 ablation and Igf2 upregulation in tumors results in up-regulation of glucose utilization during initial stages of tumor development, followed by a gradual decrease in tumor glycolytic activity, consistent with the development of large areas of hemorrhagic necrosis.	('upregulation', 'PosReg', (32, 44))	('up-regulation', 'PosReg', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('necrosis', 'biological_process', 'GO:0070265', ('270', '278'))	('necrosis', 'biological_process', 'GO:0019835', ('270', '278'))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('necrosis', 'biological_process', 'GO:0001906', ('270', '278'))	('regulation', 'biological_process', 'GO:0065007', ('69', '79'))	('glucose utilization', 'MPA', (83, 102))	('hemorrhagic necrosis', 'Disease', 'MESH:D006470', (258, 278))	('tumor glycolytic activity', 'MPA', (181, 206))	('hemorrhagic necrosis', 'Disease', (258, 278))	('necrosis', 'biological_process', 'GO:0008219', ('270', '278'))	('decrease', 'NegReg', (169, 177))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('Igf2', 'Gene', (27, 31))	('Igf2', 'Gene', '3481', (27, 31))	('hemorrhagic necrosis', 'Phenotype', 'HP:0010885', (258, 278))	('necrosis', 'biological_process', 'GO:0008220', ('270', '278'))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('ablation', 'Var', (14, 22))
30698	32092671	The same authors have tried to develop this model further by additional stabilizing Ctnnb1 mutation under both the Cited1-Cre and the Six2-Cre recombinase that target nephron progenitors.	('mutation', 'Var', (91, 99))	('Cited1', 'Gene', '4435', (115, 121))	('Ctnnb1', 'Gene', (84, 90))	('Ctnnb1', 'Gene', '1499', (84, 90))	('Cited1', 'Gene', (115, 121))
30721	32092671	Moreover, CyA impairs the production of interleukin-2 and thus suppresses the generation of T-cells, what can promote tumor growth by silencing the immune response of the host animal.	('interleukin-2', 'Gene', (40, 53))	('immune response', 'biological_process', 'GO:0006955', ('148', '163'))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('impairs', 'NegReg', (14, 21))	('interleukin-2', 'Gene', '3558', (40, 53))	('promote', 'PosReg', (110, 117))	('CyA', 'Var', (10, 13))	('tumor growth', 'CPA', (118, 130))	('suppresses', 'NegReg', (63, 73))	('generation of T-cells', 'MPA', (78, 99))
30725	32092671	2-Acetylaminofluorene (2-AAF) has been proposed as another carcinogen useful in establishing a chemically-induced RCC model, however, only 108 of 25916 (0.42 %) Balb/c female mice treated with several dose levels of 2-AAF developed renal tumors, with 27% of them diagnosed as carcinomas and 63% as adenomas.	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('2-AAF', 'Var', (216, 221))	('renal tumor', 'Phenotype', 'HP:0009726', (232, 243))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('2-AAF', 'Chemical', 'MESH:D015073', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('carcinomas', 'Phenotype', 'HP:0030731', (276, 286))	('2-AAF', 'Chemical', 'MESH:D015073', (216, 221))	('developed', 'PosReg', (222, 231))	('renal', 'Disease', (232, 237))	('renal tumors', 'Phenotype', 'HP:0009726', (232, 244))	('2-Acetylaminofluorene', 'Chemical', 'MESH:D015073', (0, 21))
30750	32092671	Fe-NTA is an iron chelate that was found to cause oxidative modification in the kidney, including DNA base modifications such as 8-oxoguanine, thymine-tyrosine cross-links, thiobarbituric acid-reactive substances, saturated and unsaturated mutagenic aldehydes such as 4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA), and HNE- or MDA-modified proteins.	('cause', 'Reg', (44, 49))	('thymine-tyrosine', 'MPA', (143, 159))	('DNA base', 'MPA', (98, 106))	('oxidative modification', 'MPA', (50, 72))	('malondialdehyde', 'Chemical', 'MESH:D008315', (298, 313))	('aldehydes', 'Chemical', 'MESH:D000447', (250, 259))	('thymine', 'Chemical', 'MESH:D013941', (143, 150))	('DNA', 'cellular_component', 'GO:0005574', ('98', '101'))	('Fe-NTA', 'Var', (0, 6))	('4-hydroxy-2-nonenal', 'Chemical', 'MESH:C027576', (268, 287))	('thiobarbituric acid', 'Chemical', 'MESH:C029684', (173, 192))	('proteins', 'Protein', (346, 354))	('tyrosine', 'Chemical', 'MESH:D014443', (151, 159))	('malondialdehyde', 'MPA', (298, 313))	('4-hydroxy-2-nonenal', 'MPA', (268, 287))	('thiobarbituric acid-reactive substances', 'MPA', (173, 212))	('8-oxoguanine', 'Chemical', 'MESH:C024829', (129, 141))
30757	32092671	This observation was confirmed by aCGH where deletions in the Cdkn2a/2b locus, containing p15, p16 and p19 genes, were frequently observed.	('p19', 'Gene', (103, 106))	('p19', 'Gene', '1029', (103, 106))	('deletions', 'Var', (45, 54))	('observed', 'Reg', (130, 138))	('Cdkn2a/2b', 'Gene', (62, 71))	('p19', 'cellular_component', 'GO:0070743', ('103', '106'))
30758	32092671	In this renal carcinogenesis model, preferred alterations were Cdkn2A/2B deletion and Met amplification.	('deletion', 'Var', (73, 81))	('Cdkn2A', 'Gene', (63, 69))	('Met amplification', 'Var', (86, 103))	('Cdkn2A', 'Gene', '1029', (63, 69))
30761	32092671	Despite the well-known potential to induce experimental sarcomas by 20-methylcholanthrene, it has not been successful in creation of renal sarcoma models, mostly due to lack of specificity and possible development of renal carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (223, 233))	('20-methylcholanthrene', 'Var', (68, 89))	('renal carcinomas', 'Phenotype', 'HP:0005584', (217, 233))	('creation of renal sarcoma', 'Disease', 'MESH:D007674', (121, 146))	('creation of renal sarcoma', 'Disease', (121, 146))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('renal carcinoma', 'Phenotype', 'HP:0005584', (217, 232))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('renal sarcoma', 'Phenotype', 'HP:0008663', (133, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))
30765	32092671	Athymic nude mice are hairless, which is an effect of a Forkhead box protein N1 mutation (Foxn1nu).	('Foxn1nu', 'Gene', (90, 97))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('Foxn1nu', 'Gene', '15218', (90, 97))	('mutation', 'Var', (80, 88))
30766	32092671	SCID mice have a single nucleotide polymorphism in the DNA-dependent protein kinase of catalytic polypeptide Prkdc gene (Prkdcscid).	('single nucleotide polymorphism', 'Var', (17, 47))	('scid', 'Gene', (126, 130))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('scid', 'Gene', '19090', (126, 130))
30782	32092671	Because stem cells were c-MET positive, c-MET inhibitor JNJ-38877605 was tested with this model resulting in a complete blockade of bone metastasis development.	('c-MET', 'Gene', '4233', (40, 45))	('blockade', 'NegReg', (120, 128))	('c-MET', 'Gene', '4233', (24, 29))	('c-MET', 'Gene', (40, 45))	('JNJ-38877605', 'Var', (56, 68))	('bone metastasis development', 'CPA', (132, 159))	('c-MET', 'Gene', (24, 29))	('JNJ-38877605', 'Chemical', 'MESH:C000599304', (56, 68))
30810	32092671	Human RCC patients with tumor PD-L1 also show significant increase in tumor progression and high mortality suggesting that PD-L1 is associated with poor prognosis in patients with tumors.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('Human', 'Species', '9606', (0, 5))	('increase', 'PosReg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('tumor progression', 'CPA', (70, 87))	('PD-L1', 'Var', (30, 35))	('tumor PD-L1', 'Var', (24, 35))	('RCC', 'Phenotype', 'HP:0005584', (6, 9))
30813	32092671	Mutations in the Flcn gene in humans are connected with the BHD syndrome, which predisposes to a wide spectrum of renal tumors (hybrid oncocytic tumors, chromophobe and clear cell carcinomas, renal oncocytosis).	('renal oncocytosis', 'Disease', (192, 209))	('renal oncocytosis', 'Disease', 'MESH:D007674', (192, 209))	('renal tumors', 'Disease', (114, 126))	('oncocytic tumors', 'Disease', (135, 151))	('clear cell carcinomas', 'Disease', (169, 190))	('BHD syndrome', 'Disease', (60, 72))	('oncocytic tumors', 'Disease', 'MESH:C535584', (135, 151))	('Mutations', 'Var', (0, 9))	('BHD syndrome', 'Disease', 'MESH:D058249', (60, 72))	('clear cell carcinomas', 'Disease', 'MESH:D002292', (169, 190))	('Flcn', 'Gene', (17, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('renal tumors', 'Phenotype', 'HP:0009726', (114, 126))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('connected', 'Reg', (41, 50))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('renal tumor', 'Phenotype', 'HP:0009726', (114, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
30820	32092671	Choline (also referred to as total choline, tCho, peak at 3.20 ppm) is in fact a sum of signals from trimethylamine groups in glycerylphosphocholine (GPC), phosphocholine (PC) and free choline (Cho).	('glycerylphosphocholine', 'MPA', (126, 148))	('GPC', 'Chemical', 'MESH:D005997', (150, 153))	('trimethylamine', 'Chemical', 'MESH:C023336', (101, 115))	('choline', 'Chemical', 'MESH:D002794', (185, 192))	('choline', 'Chemical', 'MESH:D002794', (35, 42))	('choline', 'Chemical', 'MESH:D002794', (163, 170))	('choline', 'Chemical', 'MESH:D002794', (141, 148))	('phosphocholine', 'Chemical', 'MESH:D010767', (156, 170))	('phosphocholine', 'Chemical', 'MESH:D010767', (134, 148))	('Choline', 'Chemical', 'MESH:D002794', (0, 7))	('Cho', 'molecular_function', 'GO:0043848', ('194', '197'))	('tCho', 'Chemical', '-', (44, 48))	('glycerylphosphocholine', 'Chemical', 'MESH:D005997', (126, 148))	('trimethylamine', 'Var', (101, 115))
30846	32092671	Moreover, discovery of dysregulation of the mammalian target of rapamycin (mTOR) signaling pathway and development of mTOR inhibitors was another step towards effective treatment of RCC.	('mammalian target of rapamycin', 'Gene', (44, 73))	('signaling pathway', 'biological_process', 'GO:0007165', ('81', '98'))	('dysregulation', 'Var', (23, 36))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('RCC', 'Disease', (182, 185))	('mammalian target of rapamycin', 'Gene', '2475', (44, 73))
30914	32567187	In addition, G6PC, a hub gene in PPI network of MPMs, shows significantly prognostic value in 718 ccRCC patients from multiply cohorts.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('PPI', 'biological_process', 'GO:0060134', ('33', '36'))	('G6PC', 'Var', (13, 17))	('hub', 'Gene', '1993', (21, 24))	('ccRCC', 'Disease', (98, 103))	('prognostic', 'Reg', (74, 84))	('hub', 'Gene', (21, 24))	('patients', 'Species', '9606', (104, 112))
30961	32567187	G6PC, a hub gene in PPI network of MPMs, shows significant prognostic value in 699 ccRCC patients from TCGA, CPTAC and ICGC cohorts.	('hub', 'Gene', (8, 11))	('G6PC', 'Var', (0, 4))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('patients', 'Species', '9606', (89, 97))	('ccRCC', 'Disease', (83, 88))	('PPI', 'biological_process', 'GO:0060134', ('20', '23'))	('hub', 'Gene', '1993', (8, 11))
30963	32567187	In transcriptional levels, transcription factor regulation, related LncRNA, targeted miRNA, activation and inhibition of G6PC networks were constructed in Figure S2B G6PC mRNA expression showed a negatively relationship with tumour environment purity (r 2 = -0.1012, P < 0.0001) and immune purity (r 2 = -0.1205, P < 0.0001) in ccRCC (Figure 5B and C).	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('negatively', 'NegReg', (196, 206))	('transcription factor', 'molecular_function', 'GO:0000981', ('27', '47'))	('ccRCC', 'Phenotype', 'HP:0006770', (328, 333))	('ccRCC', 'Disease', (328, 333))	('tumour', 'Disease', (225, 231))	('transcription', 'biological_process', 'GO:0006351', ('27', '40'))	('regulation', 'biological_process', 'GO:0065007', ('48', '58'))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('G6PC', 'Var', (166, 170))
30964	32567187	Differential mRNA expression of G6PC in ccRCC and adjacent normal tissues was displayed based on TCGA, CPTAC and RECA-EU cohorts (Figure 5D-F).	('RECA', 'Gene', '5888', (113, 117))	('RECA', 'Gene', (113, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('ccRCC', 'Disease', (40, 45))	('G6PC', 'Var', (32, 36))
30965	32567187	Low G6PC mRNA expression level was significantly associated with poor prognosis in CPTAC (P = 0.0035, HR = 0.218) and RECA-EU (P = 0.0443, HR = 0.446) cohorts (Figure 5I and J).	('G6PC mRNA expression level', 'MPA', (4, 30))	('CPTAC', 'Disease', (83, 88))	('RECA', 'Gene', (118, 122))	('Low', 'Var', (0, 3))	('RECA', 'Gene', '5888', (118, 122))
30973	32567187	Promoter methylation levels of G6PC were significantly higher in ccRCC samples with nodal metastasis compared with pN0 patients (Figure 7F, P < 0.05).	('nodal metastasis', 'Var', (84, 100))	('Promoter methylation levels', 'MPA', (0, 27))	('patients', 'Species', '9606', (119, 127))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('ccRCC', 'Disease', (65, 70))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('G6PC', 'Protein', (31, 35))	('higher', 'PosReg', (55, 61))
30975	32567187	G6PC expression is significantly higher in normal tissue compared with renal cell carcinomas, while significantly lower in normal samples compared with hepatocellular carcinoma and cholangiocarcinoma (Figure 8A).	('higher', 'PosReg', (33, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (71, 92))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (152, 176))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (71, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (181, 199))	('G6PC', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (71, 91))	('renal cell carcinomas', 'Disease', (71, 92))	('lower', 'NegReg', (114, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('hepatocellular carcinoma and cholangiocarcinoma', 'Disease', 'MESH:D006528', (152, 199))
30976	32567187	Elevated arm-level deletion of G6PC leads to inferior B cell, CD8+ cells, CD4+ cells, macrophage, neutrophil, dendritic cells infiltration compared with normal samples (P < 0.05).	('CD8', 'Gene', (62, 65))	('deletion', 'Var', (19, 27))	('CD8', 'Gene', '925', (62, 65))	('Elevated arm', 'Phenotype', 'HP:0006488', (0, 12))	('CD4', 'Gene', (74, 77))	('inferior B cell', 'CPA', (45, 60))	('G6PC', 'Gene', (31, 35))	('CD4', 'Gene', '920', (74, 77))
30977	32567187	In addition, G6PC significantly participates in abnormal immune infiltration of ccRCC cells and microenvironment, showing significantly negative association with check-point immune signatures, dendritic cells, Th1 cells, MHC class I, cytolytic activity, inflammation promotion, HLA, APC co-inhibition and co-stimulation activities (cor.< -0.7, Figure 8C).	('inflammation', 'biological_process', 'GO:0006954', ('254', '266'))	('inflammation', 'Disease', (254, 266))	('inflammation', 'Disease', 'MESH:D007249', (254, 266))	('G6PC', 'Var', (13, 17))	('participates', 'Reg', (32, 44))	('negative', 'NegReg', (136, 144))	('APC', 'Gene', '324', (283, 286))	('HLA', 'Gene', '3119', (278, 281))	('cytolytic activity', 'CPA', (234, 252))	('association', 'Interaction', (145, 156))	('APC', 'cellular_component', 'GO:0005680', ('283', '286'))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('HLA', 'Gene', (278, 281))	('APC', 'Gene', (283, 286))
30978	32567187	Moreover, GSEA indicated that G6PC significantly involved in several signal pathways, including bile acid metabolism, fatty acid metabolism, epithelial mesenchymal transition and E2F targets in ccRCC (Figure 8D-G).	('GSEA', 'Chemical', '-', (10, 14))	('bile acid', 'Chemical', 'MESH:D001647', (96, 105))	('fatty acid metabolism', 'MPA', (118, 139))	('epithelial mesenchymal transition', 'biological_process', 'GO:0001837', ('141', '174'))	('bile acid metabolism', 'biological_process', 'GO:0008206', ('96', '116'))	('bile acid metabolism', 'MPA', (96, 116))	('G6PC', 'Var', (30, 34))	('epithelial', 'CPA', (141, 151))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('118', '139'))	('fatty acid', 'Chemical', 'MESH:D005227', (118, 128))	('signal pathways', 'Pathway', (69, 84))	('involved in', 'Reg', (49, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (194, 199))	('ccRCC', 'Disease', (194, 199))
30984	32567187	22 ,  23  Metabolic changes promote the proliferation of tumours microenvironment and also help us better understand the alterations of characteristics phenotypes and immune microenvironment of cancers.	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('cancers', 'Disease', (194, 201))	('tumours', 'Disease', (57, 64))	('promote', 'PosReg', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('changes', 'Var', (20, 27))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('proliferation', 'CPA', (40, 53))
30987	32567187	1 ,  28  Metabolic reprogramming in ccRCC is most often associated with mutations in VHL, which occur in about 90% of cases.	('mutations', 'Var', (72, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('ccRCC', 'Disease', (36, 41))	('VHL', 'Gene', (85, 88))	('associated', 'Reg', (56, 66))	('VHL', 'Gene', '7428', (85, 88))
30988	32567187	29  In VHL mutant diseases, activation of metabolic pathways mediated by HIF leads to the activation of pathways contrary to the effects of hypoxia in normoxic environments.	('metabolic pathways', 'Pathway', (42, 60))	('activation', 'PosReg', (90, 100))	('mutant', 'Var', (11, 17))	('hypoxia', 'Disease', (140, 147))	('hypoxia', 'Disease', 'MESH:D000860', (140, 147))	('pathways', 'Pathway', (104, 112))	('activation', 'PosReg', (28, 38))	('VHL', 'Gene', (7, 10))	('VHL', 'Gene', '7428', (7, 10))
30995	32567187	38  Gross, D. N et al claimed that G6PC was related to FoxO1 signalling pathway 39  and G6PC plays a key role in Hexose transport.	('FoxO1', 'Gene', (55, 60))	('FoxO1', 'Gene', '2308', (55, 60))	('G6PC', 'Disease', (35, 39))	('Hexose transport', 'MPA', (113, 129))	('Hexose transport', 'biological_process', 'GO:0008645', ('113', '129'))	('signalling pathway', 'biological_process', 'GO:0007165', ('61', '79'))	('Hexose', 'Chemical', 'MESH:D006601', (113, 119))	('G6PC', 'Var', (88, 92))
30996	32567187	And survival analyses indicated that expression level of G6PC was positively correlated with patients' outcome, suggesting that G6PC may have tumour suppressive properties in ccRCC.	('tumour', 'Disease', (142, 148))	('patients', 'Species', '9606', (93, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (175, 180))	('ccRCC', 'Disease', (175, 180))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('G6PC', 'Var', (128, 132))	('tumour', 'Disease', 'MESH:D009369', (142, 148))
30997	32567187	Ting Guo et al  41  found that G6PC plays a dual role in both glucose metabolism and cell cycle regulation in ovarian cancer, which makes it a promising therapeutic target.	('cell cycle', 'CPA', (85, 95))	('ovarian cancer', 'Disease', (110, 124))	('glucose metabolism', 'Disease', 'MESH:D044882', (62, 80))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('85', '106'))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ovarian cancer', 'Phenotype', 'HP:0100615', (110, 124))	('glucose metabolism', 'biological_process', 'GO:0006006', ('62', '80'))	('glucose metabolism', 'Disease', (62, 80))	('G6PC', 'Var', (31, 35))	('ovarian cancer', 'Disease', 'MESH:D010051', (110, 124))
31000	32567187	Cho Jun-Ho et al  43  also claimed that G6PC could inhibit the occurrence of hepatic carcinoma, which is compatible with our hypothesis.	('hepatic carcinoma', 'Disease', (77, 94))	('hepatic carcinoma', 'Phenotype', 'HP:0001402', (77, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('hepatic carcinoma', 'Disease', 'MESH:D056486', (77, 94))	('Cho', 'molecular_function', 'GO:0043848', ('0', '3'))	('inhibit', 'NegReg', (51, 58))	('G6PC', 'Var', (40, 44))
31001	32567187	In view of the possible inhibitory effect on tumour cells of G6PC, it may shed light on the management of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('G6PC', 'Var', (61, 65))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('ccRCC', 'Disease', (106, 111))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('tumour', 'Disease', (45, 51))
31022	30985497	The mechanism by which the genetic aberration of ccRCC (functional loss of VHL) results in the up regulation of the antigen-presenting machinery and the role played by these genes in the regulation of the immune infiltrate remain to be defined.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('antigen-presenting machinery', 'MPA', (116, 144))	('VHL', 'Gene', (75, 78))	('VHL', 'Gene', '7428', (75, 78))	('regulation', 'biological_process', 'GO:0065007', ('187', '197'))	('regulation', 'biological_process', 'GO:0065007', ('98', '108'))	('loss', 'NegReg', (67, 71))	('up regulation', 'PosReg', (95, 108))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('genetic aberration', 'Var', (27, 45))	('RCC', 'Disease', (51, 54))
31039	30985497	In the murine RCC model Renca, the administration of antibodies against IL-1beta or CXCR2 (the receptor for IL-8 and other pro-angiogenic chemokines) was shown to reduce MDSC accumulation, augment tumor infiltration by CD4+ and CD8+ T cells, and to retard tumor growth, suggesting that tumor cell production of various inflammatory cytokines is an important mechanism by which RCC orchestrate the tumor microenvironment.	('CXCR2', 'Gene', (84, 89))	('RCC', 'Disease', (14, 17))	('IL-8', 'molecular_function', 'GO:0005153', ('108', '112'))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumor', 'Phenotype', 'HP:0002664', (397, 402))	('retard tumor', 'Disease', 'MESH:D009369', (249, 261))	('murine', 'Species', '10090', (7, 13))	('RCC', 'Disease', (377, 380))	('RCC', 'Phenotype', 'HP:0005584', (377, 380))	('CD8', 'Gene', '925', (228, 231))	('IL-1', 'molecular_function', 'GO:0005149', ('72', '76'))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('MDSC accumulation', 'MPA', (170, 187))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('RCC', 'Disease', 'MESH:C538614', (377, 380))	('CXCR2', 'Gene', '12765', (84, 89))	('tumor', 'Disease', (256, 261))	('reduce', 'NegReg', (163, 169))	('tumor', 'Disease', (286, 291))	('augment', 'PosReg', (189, 196))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Disease', (397, 402))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('CD8', 'Gene', (228, 231))	('retard tumor', 'Disease', (249, 261))	('antibodies', 'Var', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (397, 402))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Disease', (197, 202))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))	('IL-1beta', 'Gene', (72, 80))
31055	30985497	The loss of VHL through mutation, deletion, or epigenetic silencing ensures that the two HIFs are allowed to accumulate in tumor cells regardless of the availability of oxygen.	('VHL', 'Gene', (12, 15))	('epigenetic silencing', 'Var', (47, 67))	('tumor', 'Disease', (123, 128))	('VHL', 'Gene', '7428', (12, 15))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('HIFs', 'Disease', 'None', (89, 93))	('deletion', 'Var', (34, 42))	('mutation', 'Var', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('oxygen', 'Chemical', 'MESH:D010100', (169, 175))	('loss', 'NegReg', (4, 8))	('HIFs', 'Disease', (89, 93))
31057	30985497	Mathew et al have shown that RCC have low levels of the microRNAs miR-30-2-3p and miR-30a-3p compared to the normal renal parenchyma.	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('miR-30a-3p', 'Var', (82, 92))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))
31062	30985497	The absence of FBP1 therefore not only promotes glycolysis (the Warburg effect) but ensures the function of HIF-1 and -2 in RCC cells.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('HIF-1 and -2', 'Gene', '3091', (108, 120))	('promotes', 'PosReg', (39, 47))	('FBP1', 'Gene', (15, 19))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('function', 'MPA', (96, 104))	('glycolysis', 'biological_process', 'GO:0006096', ('48', '58'))	('ensures', 'PosReg', (84, 91))	('FBP1', 'Gene', '2203', (15, 19))	('glycolysis', 'MPA', (48, 58))	('absence', 'Var', (4, 11))
31070	30985497	The undifferentiated vessels are particularly abundant in high grade RCC and their presence is associated with short patient survival.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('undifferentiated vessels', 'CPA', (4, 28))	('RCC', 'Disease', (69, 72))	('high grade', 'Var', (58, 68))	('patient', 'Species', '9606', (117, 124))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
31085	30985497	Although inhibitors of the enzyme glutaminase such as CB-839 have multiple effects on tumor cell metabolism, oxidative stress, and DNA methylation that might contribute to their antitumor activity, their ability to increase glutamine levels in the MEV and reverse some aspects of immune dysfunction may be an important component of their overall antitumor effect.	('CB-839', 'Gene', (54, 60))	('metabolism', 'biological_process', 'GO:0008152', ('97', '107'))	('glutamine', 'Chemical', 'MESH:D005973', (224, 233))	('DNA', 'cellular_component', 'GO:0005574', ('131', '134'))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('inhibitors', 'Var', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('oxidative stress', 'Phenotype', 'HP:0025464', (109, 125))	('tumor', 'Disease', (350, 355))	('DNA methylation', 'biological_process', 'GO:0006306', ('131', '146'))	('immune dysfunction', 'Disease', 'MESH:D007154', (280, 298))	('increase glutamine', 'Phenotype', 'HP:0003217', (215, 233))	('tumor', 'Disease', 'MESH:D009369', (350, 355))	('glutamine levels', 'MPA', (224, 240))	('CB-839', 'Chemical', 'MESH:C000593334', (54, 60))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', (86, 91))	('increase', 'PosReg', (215, 223))	('tumor', 'Phenotype', 'HP:0002664', (350, 355))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('oxidative', 'MPA', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('immune dysfunction', 'Disease', (280, 298))	('DNA', 'MPA', (131, 134))
31103	30985497	Finally, it is worth mentioning the various VEGF- or VEGFR-targeted drugs that have recently been shown to augment the efficacy of anti-PD1 or -PDL1 antibodies in the treatment of RCC.	('VEGFR', 'Gene', (53, 58))	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('PDL1', 'Gene', '29126', (144, 148))	('RCC', 'Disease', (180, 183))	('RCC', 'Phenotype', 'HP:0005584', (180, 183))	('efficacy', 'MPA', (119, 127))	('VEGF', 'Gene', (44, 48))	('VEGF', 'Gene', (53, 57))	('PDL1', 'Gene', (144, 148))	('augment', 'PosReg', (107, 114))	('VEGF', 'Gene', '7422', (44, 48))	('VEGFR', 'Gene', '3791', (53, 58))	('VEGF', 'Gene', '7422', (53, 57))	('anti-PD1', 'Var', (131, 139))
31107	30985497	It is therefore conceivable that the ability of these agents to enhance the efficacy of immune checkpoint inhibitors is at least partly mediated through an immunological mechanism involving MDSC within the RCC MEV independent of their anti-angiogenic effects.	('enhance', 'PosReg', (64, 71))	('efficacy', 'MPA', (76, 84))	('immune checkpoint', 'Gene', (88, 105))	('MDSC', 'Var', (190, 194))	('RCC', 'Phenotype', 'HP:0005584', (206, 209))	('RCC', 'Disease', 'MESH:C538614', (206, 209))	('RCC', 'Disease', (206, 209))
31240	33178494	Patients with high levels of sPD-L1 (>0.66 ng/ml) have a median PFS of 19 months compared to 9 months for patients with low levels of sPD-L1 (p value <.0001) (Figure 3(b)), and patients with high levels of sBTN3A1 (>6.84 ng/ml) have a median PFS of 17.5 months compared to 8.4 months for patients with low levels of BTN3A1 (p value = .002) (Figure 3(c)).	('BTN3A1', 'Gene', (316, 322))	('BTN3A1', 'Gene', (207, 213))	('sPD-L1', 'Gene', (134, 140))	('patients', 'Species', '9606', (288, 296))	('patients', 'Species', '9606', (177, 185))	('BTN3A1', 'Gene', '11119', (316, 322))	('Patients', 'Species', '9606', (0, 8))	('sPD-L1', 'Gene', '54908', (29, 35))	('patients', 'Species', '9606', (106, 114))	('BTN3A1', 'Gene', '11119', (207, 213))	('>0.66 ng/ml', 'Var', (37, 48))	('sPD-L1', 'Gene', (29, 35))	('sPD-L1', 'Gene', '54908', (134, 140))
31269	33178494	Patients with high blood sPD-L1 levels seem to have a poorer prognosis and reduced survival than those with low levels in melanoma and nonsmall-cell lung cancer (NSCLC).	('nonsmall-cell lung cancer', 'Disease', 'MESH:D002289', (135, 160))	('sPD-L1', 'Gene', '54908', (25, 31))	('NSCLC', 'Disease', (162, 167))	('survival', 'CPA', (83, 91))	('reduced', 'NegReg', (75, 82))	('nonsmall-cell lung cancer', 'Disease', (135, 160))	('high', 'Var', (14, 18))	('sPD-L1', 'Gene', (25, 31))	('Patients', 'Species', '9606', (0, 8))	('NSCLC', 'Disease', 'MESH:D002289', (162, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))
31270	33178494	Conversely, in gastric cancer, high levels were associated with a favorable prognosis.	('gastric cancer', 'Disease', (15, 29))	('gastric cancer', 'Disease', 'MESH:D013274', (15, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (15, 29))	('high', 'Var', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
31315	33658847	In summary, available data suggest that radiotherapy can lead to immunogenic cell death and stimulate systemic antitumor immune response.	('immunogenic cell death', 'CPA', (65, 87))	('stimulate', 'PosReg', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('radiotherapy', 'Var', (40, 52))	('tumor', 'Disease', (115, 120))	('immune response', 'biological_process', 'GO:0006955', ('121', '136'))	('cell death', 'biological_process', 'GO:0008219', ('77', '87'))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
31320	33658847	Despite the belief that radiotherapy is immunosuppressive, radiotherapy has been shown to promote antitumor immune response, although how radiation interacts with the immune system is unclear.	('immune response', 'biological_process', 'GO:0006955', ('108', '123'))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('promote', 'PosReg', (90, 97))	('radiotherapy', 'Var', (59, 71))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
31334	33658847	In addition to the immune-stimulating effects, radiotherapy can also inhibit the immune response of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('radiotherapy', 'Var', (47, 59))	('immune response', 'biological_process', 'GO:0006955', ('81', '96'))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('inhibit', 'NegReg', (69, 76))
31349	33658847	Lee et al found that 20-25Gy was effective at tumor control in melanoma mice, while it does not work in mice with CD8 T-cells depletion.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('mice', 'Species', '10090', (104, 108))	('tumor', 'Disease', (46, 51))	('20-25Gy', 'Var', (21, 28))	('CD8', 'Gene', (114, 117))	('mice', 'Species', '10090', (72, 76))	('CD8', 'Gene', '925', (114, 117))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
31360	33658847	Several trials (NCT02662062, NCT03419130, NCT02621151, NCT02560636, NCT03287050) investigating the safety, tolerability, and effectiveness of pembrolizumab combined with radiotherapy in muscle-invasive bladder cancer.	('pembrolizumab', 'Chemical', 'MESH:C582435', (142, 155))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('bladder cancer', 'Phenotype', 'HP:0009725', (202, 216))	('NCT02560636', 'Var', (55, 66))	('invasive bladder', 'Phenotype', 'HP:0100645', (193, 209))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (186, 216))	('muscle-invasive bladder cancer', 'Disease', (186, 216))
31361	33658847	The study by Twyman-Saint Victor and his colleagues exploring radiotherapy with dual checkpoint blockage (anti-CTLA-4 and anti-PD-L1 antibodies) in nonurological cancer showed encouraging results.	('nonurological cancer', 'Phenotype', 'HP:0004375', (148, 168))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('CTLA-4', 'Gene', (111, 117))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('anti-PD-L1', 'Var', (122, 132))	('CTLA-4', 'Gene', '1493', (111, 117))
31376	33658847	Under the aforementioned mechanism of radiotherapy to activate immunity, CTLA-4 inhibitors could proliferate T cells, and PD-1 inhibitors could reverse suppressed T cells.	('CTLA-4', 'Gene', '1493', (73, 79))	('T cells', 'CPA', (163, 170))	('proliferate', 'PosReg', (97, 108))	('CTLA-4', 'Gene', (73, 79))	('activate', 'PosReg', (54, 62))	('inhibitors', 'Var', (80, 90))
31387	33658847	Consistent with this, John-Aryankalayil et al showed that genes regulating immune and stress response, cell cycle, and apoptosis were significantly up-regulated by multi-fractionated radiation (2 Gyx5) compared to single dose (10 Gyx1) in human prostate cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('prostate cancer', 'Disease', (245, 260))	('stress', 'Disease', 'MESH:D000079225', (86, 92))	('2 Gyx5', 'Var', (194, 200))	('up-regulated', 'PosReg', (148, 160))	('cell cycle', 'biological_process', 'GO:0007049', ('103', '113'))	('stress', 'Disease', (86, 92))	('cell cycle', 'CPA', (103, 113))	('apoptosis', 'biological_process', 'GO:0097194', ('119', '128'))	('apoptosis', 'CPA', (119, 128))	('genes', 'Gene', (58, 63))	('prostate cancer', 'Disease', 'MESH:D011471', (245, 260))	('apoptosis', 'biological_process', 'GO:0006915', ('119', '128'))	('human', 'Species', '9606', (239, 244))	('prostate cancer', 'Phenotype', 'HP:0012125', (245, 260))
31389	33658847	Conversely, Lugade et al found that single dose (15 Gyx1) results in great numbers of immune cells than fractionated dose (5 Gyx3) in mice with B16 melanoma tumors.	('mice', 'Species', '10090', (134, 138))	('melanoma tumors', 'Disease', (148, 163))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('15 Gyx1', 'Var', (49, 56))	('immune cells', 'CPA', (86, 98))	('melanoma tumors', 'Disease', 'MESH:D008545', (148, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
31390	33658847	However, Lee et al found comparable progressive growth of B16 melanoma tumors irrespective of being treated with single dose (20 Gyx1) or fractionated dose (5 Gyx4).	('20 Gyx1', 'Var', (126, 133))	('melanoma tumors', 'Disease', 'MESH:D008545', (62, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('melanoma tumors', 'Disease', (62, 77))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
31396	33658847	It was found that radiotherapy and anti-OX40 had the best survival rate if immunotherapy was carried out 1 day after radiotherapy, while radiotherapy and anti-CTLA4 had the best survival rate if immunotherapy was carried out 7 days before radiotherapy.	('CTLA4', 'Gene', '12477', (159, 164))	('OX40', 'Gene', '22163', (40, 44))	('CTLA4', 'Gene', (159, 164))	('OX40', 'Gene', (40, 44))	('radiotherapy', 'Var', (18, 30))
31436	27993170	As with primary RCC tumors, the mutation status of cancer including VLH, cMET and TP53 and a general marker immunohistochemistry profile may serve to define the histotype of RCC cell lines (Table 1).	('cMET', 'Gene', '4233', (73, 77))	('TP53', 'Gene', (82, 86))	('primary RCC tumors', 'Disease', (8, 26))	('TP53', 'Gene', '7157', (82, 86))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('cMET', 'Gene', (73, 77))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('RCC', 'Disease', (16, 19))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('RCC', 'Disease', (174, 177))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('primary RCC tumors', 'Disease', 'MESH:C538614', (8, 26))	('mutation', 'Var', (32, 40))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
31451	27993170	Germline met proto-oncogene (MET) and fumarate hydratase (FH) alterations are the hallmark of these cancer syndromes, but are infrequent in sporadic cases.	('MET', 'Gene', (29, 32))	('fumarate hydratase', 'Gene', '2271', (38, 56))	('cancer syndromes', 'Disease', 'MESH:D009369', (100, 116))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer syndromes', 'Disease', (100, 116))	('fumarate hydratase', 'Gene', (38, 56))	('alterations', 'Var', (62, 73))	('FH', 'Gene', '2271', (58, 60))
31459	27993170	The von Hippel-Lindau (VHL) gene is known to be most often mutated in renal cell carcinoma of clear cell type (ccRCC) in up to 90% of sporadic ccRCC cases and multiple surprising and contradictory reports on the VHL gene status in common RCC cell lines have been published (Additional file 1: Table S1).	('RCC', 'Phenotype', 'HP:0005584', (238, 241))	('von Hippel-Lindau', 'Gene', (4, 21))	('renal cell carcinoma', 'Disease', (70, 90))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('RCC', 'Disease', 'MESH:C538614', (238, 241))	('RCC', 'Disease', (238, 241))	('VHL', 'Gene', (23, 26))	('renal cell carcinoma of clear cell type', 'Phenotype', 'HP:0006770', (70, 109))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (70, 90))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (70, 90))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('von Hippel-Lindau', 'Gene', '7428', (4, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('mutated', 'Var', (59, 66))
31464	27993170	Mutations in BAP1 and PBRM1 in ccRCC tend to be mutually exclusive.	('BAP1', 'Gene', (13, 17))	('PBRM1', 'Gene', '55193', (22, 27))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (13, 17))	('PBRM1', 'Gene', (22, 27))
31478	27993170	Moreover, this cell line harbors a c-met polymorphism that is specific for papillary RCC.	('polymorphism', 'Var', (41, 53))	('c-met', 'Gene', (35, 40))	('papillary RCC', 'Gene', (75, 88))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('c-met', 'Gene', '4233', (35, 40))	('papillary RCC', 'Gene', '5546', (75, 88))
31481	27993170	No mutations in VHL and HIF-1alpha mRNA in ACHN cell line, could confirm non-clear cell histology.	('ACHN', 'Gene', '55323', (43, 47))	('VHL', 'Gene', (16, 19))	('HIF-1alpha', 'Gene', '3091', (24, 34))	('ACHN', 'Gene', (43, 47))	('mutations', 'Var', (3, 12))	('HIF-1alpha', 'Gene', (24, 34))
31486	27993170	The 786-O RCC line is defective in VHL expression, as it harbors mutated VHL with altered HIF and VEGF (Vascular endothelial growth factor) pathways and gives rise to clear cell tumors in nude mice.	('VHL', 'Gene', (73, 76))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('Vascular endothelial growth factor', 'Gene', (104, 138))	('Vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('104', '138'))	('Vascular endothelial growth factor', 'Gene', '22339', (104, 138))	('clear cell tumors', 'Disease', 'MESH:D008649', (167, 184))	('nude mice', 'Species', '10090', (188, 197))	('clear cell tumors', 'Disease', (167, 184))	('RCC', 'Disease', 'MESH:C538614', (10, 13))	('gives rise to', 'Reg', (153, 166))	('RCC', 'Disease', (10, 13))	('RCC', 'Phenotype', 'HP:0005584', (10, 13))	('altered', 'Reg', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('mutated', 'Var', (65, 72))
31487	27993170	In this RCC model the vast majority (122/160) of genes induced by hypoxia in wt-VHL transfected 786-O (VHL +) cells are not significantly up-regulated in VHL mutated 786-O cells, confirming that the loss of VHL is not equivalent to hypoxic exposure and that in RCC, the VHL tumor suppressor has a distinct role from its activity in the hypoxia-inducible pathway.	('RCC', 'Disease', 'MESH:C538614', (261, 264))	('RCC', 'Disease', (8, 11))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('274', '290'))	('loss', 'Var', (199, 203))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('VHL tumor', 'Disease', (270, 279))	('tumor suppressor', 'biological_process', 'GO:0051726', ('274', '290'))	('hypoxia', 'Disease', 'MESH:D000860', (336, 343))	('hypoxia', 'Disease', (336, 343))	('hypoxic', 'Disease', (232, 239))	('hypoxia', 'Disease', (66, 73))	('VHL tumor', 'Disease', 'MESH:D006623', (270, 279))	('hypoxic', 'Disease', 'MESH:D000860', (232, 239))	('hypoxia', 'Disease', 'MESH:D000860', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('RCC', 'Disease', (261, 264))	('RCC', 'Phenotype', 'HP:0005584', (261, 264))
31505	27993170	The 769-P cell line, established along with 786-O by, harbors mutated vhl and secretes high levels of VEGF, suggesting a ccRCC phenotype (Additional file 1: Table S1 for ref).	('suggesting', 'Reg', (108, 118))	('secretes', 'MPA', (78, 86))	('harbors', 'Reg', (54, 61))	('RCC', 'Disease', (123, 126))	('vhl', 'Gene', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('mutated', 'Var', (62, 69))
31508	27993170	Another interesting cell line is RCC4, a vhl mutant derived from a primary tumor widely used as a model for VHL-dependant mechanisms, witha commercially available counterpart cell line with restored wild-type gene.	('mutant', 'Var', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
31512	27993170	Vhl is mutated in cell lines SMKT-R2 and SMKT-R3, and in SMKT-R2 and SMKT-R3 HIF-alpha proteins are expressed.	('mutated', 'Var', (7, 14))	('Vhl', 'Gene', '7428', (0, 3))	('Vhl', 'Gene', (0, 3))
31518	27993170	The MSKCC panel covers cell lines obtained from tumors that developed in the most common RCC metastases loci, including the adrenal glands (SK-RC-45), lymph nodes (SK-RC-18, SK-RC-26b), lungs (SK-RC-26a SK-RC-31, SK-RC-38 SK-RC-54), bones (SK-RC-42, SK-RC-46), soft tissue (SK-RC-17, SK-RC-39), and the brain (SK-RC-9, SK-RC-13).	('SK-RC-46', 'CellLine', 'CVCL:6193', (250, 258))	('SK-RC-38 SK-RC-54', 'CellLine', 'CVCL:6200', (213, 230))	('RCC metastases', 'Disease', (89, 103))	('SK-RC-42', 'CellLine', 'CVCL:6192', (240, 248))	('SK-RC-26', 'CellLine', 'CVCL:6183', (193, 201))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('SK-RC-13', 'CellLine', 'CVCL:6178', (319, 327))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('RCC metastases', 'Disease', 'MESH:D009362', (89, 103))	('SK-RC-39', 'CellLine', 'CVCL:4021', (284, 292))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('SK-RC-26', 'CellLine', 'CVCL:6183', (174, 182))	('SK-RC-9', 'CellLine', 'CVCL:6174', (310, 317))	('SK-RC-42', 'Var', (240, 248))	('SK-RC-17', 'Var', (274, 282))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('SK-RC-26a SK-RC-31', 'CellLine', 'CVCL:6183', (193, 211))
31526	27993170	In particular, five cell lines were derived from clear cell RCC (SNU-228, -267, -328, -349, and -1272), one from granular RCC (SNU-482), and one from mixed clear and granular RCC (SNU-333).	('SNU-228', 'Var', (65, 72))	('RCC', 'Disease', 'MESH:C538614', (175, 178))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('RCC', 'Disease', (175, 178))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))
31550	27993170	The former was transduced with human papilloma virus (HPV 16) E6/E7 genes while the latter ectopically expresses the catalytic subunit of telomerase (TERT).	('TERT', 'Gene', (150, 154))	('HPV 16', 'Species', '333760', (54, 60))	('papilloma', 'Phenotype', 'HP:0012740', (37, 46))	('TERT', 'Gene', '7015', (150, 154))	('E6/E7 genes', 'Var', (62, 73))	('human papilloma virus', 'Species', '10566', (31, 52))
31551	27993170	These modifications enable the cells to be cultured continuously constituting a convenient control for RCC cell lines.	('modifications', 'Var', (6, 19))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('RCC', 'Disease', 'MESH:C538614', (103, 106))
31563	27993170	SK-RC-42 and SK-RC-46 also represent bone metastasis-derived cell lines, as well as the CRBM-1990 cell line, while ACHN and 786-O cells transplanted into the left ventricle establish bone metastases.	('CRBM-1990', 'CellLine', 'CVCL:6893', (88, 97))	('SK-RC-46', 'Var', (13, 21))	('ACHN', 'Gene', (115, 119))	('SK-RC-46', 'CellLine', 'CVCL:6193', (13, 21))	('ACHN', 'Gene', '55323', (115, 119))	('metastases', 'Disease', (188, 198))	('metastases', 'Disease', 'MESH:D009362', (188, 198))	('SK-RC-42', 'CellLine', 'CVCL:6192', (0, 8))
31576	27993170	Apart from gene mutation, vhl promoter region methylation often occurs in ccRCC samples which effects in no protein expression.	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('methylation', 'Var', (46, 57))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('occurs', 'Reg', (64, 70))	('protein expression', 'MPA', (108, 126))	('vhl', 'Gene', (26, 29))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
31579	27993170	The ACHN cell line expresses the protein, but harbors a heterozygous nonsense mutation, while 786-O, 769-P, Caki-1, and A-498 express wild-type PBRM1.	('769-P', 'Var', (101, 106))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('PBRM1', 'Gene', (144, 149))	('ACHN', 'Gene', '55323', (4, 8))	('PBRM1', 'Gene', '55193', (144, 149))	('ACHN', 'Gene', (4, 8))	('786-O', 'Var', (94, 99))
31580	27993170	The PBRM1 mutation is also reported in Caki-2 and A-704 lines; loss-of-function gene mutations in A-704 and the deletion in exon 17 of the PBRM1 gene in Caki-2 results in no protein expression.	('PBRM1', 'Gene', '55193', (139, 144))	('protein expression', 'MPA', (174, 192))	('deletion in', 'Var', (112, 123))	('PBRM1', 'Gene', (4, 9))	('loss-of-function', 'NegReg', (63, 79))	('PBRM1', 'Gene', '55193', (4, 9))	('mutations', 'Var', (85, 94))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))	('PBRM1', 'Gene', (139, 144))
31583	27993170	The knockdown of PBRM1 in cells with wild-type gene increased the proliferation, migration and colony formation abilities, supporting this gene's important role in RCC progression, as the loss of PBRM1 was correlated with a worse disease outcome in patients.	('increased', 'PosReg', (52, 61))	('patients', 'Species', '9606', (249, 257))	('proliferation', 'CPA', (66, 79))	('PBRM1', 'Gene', (17, 22))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))	('PBRM1', 'Gene', (196, 201))	('formation', 'biological_process', 'GO:0009058', ('102', '111'))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('PBRM1', 'Gene', '55193', (17, 22))	('RCC', 'Disease', (164, 167))	('PBRM1', 'Gene', '55193', (196, 201))	('loss', 'Var', (188, 192))	('knockdown', 'Var', (4, 13))	('colony formation abilities', 'CPA', (95, 121))
31584	27993170	BAP1 mutants are available as UM-RC-6, 769-P, and SN12C cell lines; however, 769-P cells still produce the protein.	('BAP1', 'Gene', (0, 4))	('769-P', 'Var', (77, 82))	('SN12C', 'CellLine', 'CVCL:1705', (50, 55))	('BAP1', 'Gene', '8314', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
31585	27993170	The reintroduction of the wild-type gene reduced cell proliferation and sensitized cells to treatment, and it was proposed that BAP1 is a tumor suppressor, as gene loss is associated with patients with higher-grade RCC.	('tumor', 'Disease', (138, 143))	('BAP1', 'Gene', '8314', (128, 132))	('RCC', 'Disease', 'MESH:C538614', (215, 218))	('cell proliferation', 'biological_process', 'GO:0008283', ('49', '67'))	('RCC', 'Disease', (215, 218))	('RCC', 'Phenotype', 'HP:0005584', (215, 218))	('tumor suppressor', 'biological_process', 'GO:0051726', ('138', '154'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('138', '154'))	('cell proliferation', 'CPA', (49, 67))	('gene loss', 'Var', (159, 168))	('BAP1', 'Gene', (128, 132))	('higher-grade', 'Disease', (202, 214))	('patients', 'Species', '9606', (188, 196))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
31586	27993170	SETD2 mutations have also been detected in A-498, A-704, Caki-1, and RCC-ER, PTEN mutations in 786-O, and OS-RC-2, while no mutated RCC cell lines could be found for KDM5C.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('KDM5C', 'Gene', '8242', (166, 171))	('RCC', 'Disease', (69, 72))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('SETD2', 'Gene', '29072', (0, 5))	('PTEN', 'Gene', (77, 81))	('mutations', 'Var', (82, 91))	('SETD2', 'Gene', (0, 5))	('PTEN', 'Gene', '5728', (77, 81))	('OS-RC-2', 'CellLine', 'CVCL:1626', (106, 113))	('KDM5C', 'Gene', (166, 171))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('mutations', 'Var', (6, 15))
31587	27993170	An mTOR mutation was found for SNU349 and RCC-ER cell lines only (see Additional file 1: Table S1 for ref).	('mTOR', 'Gene', '2475', (3, 7))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('mutation', 'Var', (8, 16))	('RCC', 'Disease', (42, 45))	('mTOR', 'Gene', (3, 7))
31588	27993170	Studies on SETD2-defective RCC cells proved that the mutation of this gene affects DNA repair and may correlate with in vivo disease progression.	('affects', 'Reg', (75, 82))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('mutation', 'Var', (53, 61))	('DNA repair', 'biological_process', 'GO:0006281', ('83', '93'))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('SETD2', 'Gene', '29072', (11, 16))	('SETD2', 'Gene', (11, 16))	('DNA repair', 'MPA', (83, 93))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('correlate with', 'Reg', (102, 116))
31595	27993170	This cell line was also shown to contain an NF2 mutation, together with SN12C, while Caki-1, A-704, 769-P, TK10, 786-O, A-498, and OS-RC-2 were confirmed to be wild-type for NF2.	('NF2', 'Gene', '4771', (44, 47))	('SN12C', 'CellLine', 'CVCL:1705', (72, 77))	('OS-RC-2', 'CellLine', 'CVCL:1626', (131, 138))	('NF2', 'Gene', '4771', (174, 177))	('A-704', 'Var', (93, 98))	('mutation', 'Var', (48, 56))	('NF2', 'Gene', (44, 47))	('NF2', 'Gene', (174, 177))
31597	27993170	A FAT1 mutation was found in Caki-1, OS-RC-2, SN12C, RCC-FG2, and TK10 (COSMIC database) but no functional analysis of this gene in in vitro RCC was reported.	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('SN12C', 'CellLine', 'CVCL:1705', (46, 51))	('FAT1', 'Gene', '2195', (2, 6))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('mutation', 'Var', (7, 15))	('FAT1', 'Gene', (2, 6))	('OS-RC-2', 'CellLine', 'CVCL:1626', (37, 44))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
31598	27993170	Chromosome aberrations present in pRCC include chromosomes 7 and 17 gains and 9p loss.	('chromosomes', 'Var', (47, 58))	('pRCC', 'Gene', (34, 38))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('loss', 'NegReg', (81, 85))	('gains', 'PosReg', (68, 73))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('pRCC', 'Gene', '5546', (34, 38))
31600	27993170	TP53 tumor-suppressor mutations, present in 50% of tumor cases in general, are less frequent in RCC (around 20% cases), but confirmed in 786-O, A-498 (COSMIC and CCLE databases),,SN12C, TK10 and reported as wild-type in ACHN, Caki-1, and Caki-2.	('RCC', 'Disease', (96, 99))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('5', '21'))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('5', '21'))	('tumor', 'Disease', (51, 56))	('ACHN', 'Gene', '55323', (220, 224))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mutations', 'Var', (22, 31))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('SN12C', 'CellLine', 'CVCL:1705', (179, 184))	('ACHN', 'Gene', (220, 224))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
31607	27993170	Athymic nude mice are hairless, an effect of the Foxn1nu (Forkhead box protein N1) mutation, but more importantly they lack a thymus and are T-cell deficient but produce functional B-cells.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('Foxn1', 'Gene', (49, 54))	('nude mice', 'Species', '10090', (8, 17))	('Foxn1', 'Gene', '15218', (49, 54))	('mutation', 'Var', (83, 91))	('lack', 'NegReg', (119, 123))
31620	27993170	Ectopic xenograft models of athymic nude mice with various genetic backgrounds have been extensively used for studying established RCC lines, including 769-P, 786-O, Caki-1, SK-RC-38, SK-RC-42, SK-RC-44, SK-RC-45, SK-RC-46, and others.	('SK-RC-44', 'CellLine', 'CVCL:4022', (194, 202))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('SK-RC-42', 'Var', (184, 192))	('nude mice', 'Species', '10090', (36, 45))	('SK-RC-38', 'Var', (174, 182))	('SK-RC-42', 'CellLine', 'CVCL:6192', (184, 192))	('SK-RC-44', 'Var', (194, 202))	('SK-RC-38', 'CellLine', 'CVCL:6189', (174, 182))	('SK-RC-46', 'CellLine', 'CVCL:6193', (214, 222))
31675	32591370	Interestingly, clear cell ovarian cancer shares more similarity in gene expression profiles with clear cell renal cell carcinoma rather than to other subtypes of epithelial ovarian cancer, and is characterized by frequent somatic mutations in ARID1A, overexpression of MDM2, and upregulation of the phosphoinositide 3-kinase (PI3K)- protein kinase B (Akt)- mammalian target of rapamycin (mTOR) and mitogen-activated protein kiase (MAPK) signaling axes.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (108, 128))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (97, 128))	('ARID1A', 'Gene', (243, 249))	('mammalian target of rapamycin', 'Gene', (357, 386))	('protein', 'cellular_component', 'GO:0003675', ('416', '423'))	('mutations', 'Var', (230, 239))	('ovarian cancer', 'Phenotype', 'HP:0100615', (173, 187))	('overexpression', 'PosReg', (251, 265))	('MDM2', 'Gene', '4193', (269, 273))	('clear cell ovarian cancer', 'Disease', 'MESH:D008649', (15, 40))	('clear cell renal cell carcinoma', 'Disease', (97, 128))	('MAPK) signaling', 'biological_process', 'GO:0000165', ('431', '446'))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (162, 187))	('clear cell ovarian cancer', 'Disease', (15, 40))	('upregulation', 'PosReg', (279, 291))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (97, 128))	('protein', 'cellular_component', 'GO:0003675', ('333', '340'))	('mTOR', 'Gene', (388, 392))	('mitogen-activated protein kiase', 'Pathway', (398, 429))	('ovarian cancer', 'Phenotype', 'HP:0100615', (26, 40))	('PI3K', 'molecular_function', 'GO:0016303', ('326', '330'))	('epithelial ovarian cancer', 'Disease', (162, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('Akt', 'Gene', (351, 354))	('mammalian target of rapamycin', 'Gene', '2475', (357, 386))	('gene expression', 'biological_process', 'GO:0010467', ('67', '82'))	('MAPK', 'molecular_function', 'GO:0004707', ('431', '435'))	('MDM2', 'Gene', (269, 273))	('Akt', 'Gene', '207', (351, 354))	('mTOR', 'Gene', '2475', (388, 392))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (162, 187))
31677	32591370	Increased expression of lymphocyte activation gene 3 (LAG3), T-cell immunoglobulin mucin-3 (TIM-3), and PD-1 in ovarian clear cell carcinoma has been linked to increased immune suppression, while PIK3CA mutations and ARID1A loss of function, together with upregulation of HNF1-beta and activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signaling pathways, lead to increased interleukin-6 (IL6) and -8 expression, and further immune suppression.	('interleukin-6', 'Gene', '100628202', (476, 489))	('LAG3', 'Gene', (54, 58))	('PD-1 in ovarian clear cell carcinoma', 'Disease', (104, 140))	('ARID1A', 'Gene', (217, 223))	('PIK3CA', 'Gene', (196, 202))	('STAT3', 'Gene', '733648', (352, 357))	('lymphocyte activation gene 3', 'Gene', (24, 52))	('PD-1 in ovarian clear cell carcinoma', 'Disease', 'MESH:D020734', (104, 140))	('increased', 'PosReg', (466, 475))	('upregulation', 'PosReg', (256, 268))	('IL6', 'molecular_function', 'GO:0005138', ('491', '494'))	('immune suppression', 'CPA', (170, 188))	('loss of function', 'NegReg', (224, 240))	('immune suppression', 'CPA', (527, 545))	('signaling', 'biological_process', 'GO:0023052', ('438', '447'))	('LAG3', 'Gene', '100125962', (54, 58))	('increased', 'PosReg', (160, 169))	('IL6', 'Gene', (491, 494))	('lymphocyte activation', 'biological_process', 'GO:0046649', ('24', '45'))	('signal transducer and activator of transcription 3', 'Gene', '733648', (300, 350))	('mutations', 'Var', (203, 212))	('increased interleukin-6', 'Phenotype', 'HP:0030783', (466, 489))	('transcription', 'biological_process', 'GO:0006351', ('335', '348'))	('interleukin-6', 'Gene', (476, 489))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('IL6', 'Gene', '100628202', (491, 494))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('68', '82'))	('STAT3', 'Gene', (352, 357))	('lymphocyte activation gene 3', 'Gene', '100125962', (24, 52))	('expression', 'MPA', (503, 513))
31705	32591370	Potential biomarkers of response and resistance that will be studied include: PTEN loss, PIK3CA, ARID1A mutations, MMR status, PD-1/PD-L1 overexpression, cytokines, lymphocyte activation markers, human leukocyte antigen class I/II, and immune regulator status and expression.	('lymphocyte activation', 'biological_process', 'GO:0046649', ('165', '186'))	('mutations', 'Var', (104, 113))	('MMR', 'biological_process', 'GO:0006298', ('115', '118'))	('PIK3CA', 'Gene', (89, 95))	('PTEN loss', 'Disease', 'MESH:D006223', (78, 87))	('ARID1A', 'Gene', (97, 103))	('PTEN loss', 'Disease', (78, 87))	('PD-1/PD-L1', 'Gene', (127, 137))	('overexpression', 'PosReg', (138, 152))
31725	30783205	While APLN showed only very weak association with tumour histological grade (TCGA cohort), APLNR/mRNA protein expression correlate significantly with ccRCC aggressiveness.	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Disease', (50, 56))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('aggressiveness', 'Phenotype', 'HP:0000718', (156, 170))	('aggressiveness', 'CPA', (156, 170))	('ccRCC', 'Disease', (150, 155))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('ccRCC', 'Disease', 'MESH:D002292', (150, 155))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('APLNR/mRNA', 'Var', (91, 101))
31734	30783205	Given the paucity of data concerning the role of APLN and APLNR in renal cell carcinoma and the importance of immune evasion mechanisms of this tumour, our study aimed to investigate the expression of APLN and APLNR in RCC and its association with clinicopathological parameters and survival.	('RCC', 'Disease', 'MESH:D002292', (219, 222))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (67, 87))	('renal cell carcinoma', 'Disease', (67, 87))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (67, 87))	('APLN', 'Var', (201, 205))	('immune evasion', 'biological_process', 'GO:0051842', ('110', '124'))	('APLNR', 'Var', (210, 215))	('tumour', 'Disease', (144, 150))	('RCC', 'Disease', (219, 222))	('RCC', 'Phenotype', 'HP:0005584', (219, 222))	('immune evasion', 'biological_process', 'GO:0042783', ('110', '124'))
31763	30783205	In contrast, APLNR was predictive for overall (OS) and cancer-specific survival (CSS) in Kaplan-Meier (Fig.	('APLNR', 'Var', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Kaplan-Meier', 'Disease', (89, 101))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
31768	30783205	However, independent prognostic significance in multivariate Cox analysis (gene mRNA expression, histologic grade, pT-stage, pN-status) was only observed for APLNR expression (HR 1.8, 95% CI 1.3-2.5, p = 0.0009; see also Suppl.	('Cox', 'Gene', (61, 64))	('Cox', 'Gene', '1351', (61, 64))	('APLNR', 'Var', (158, 163))
31801	30783205	In a cholangiocarcinoma cell model and in in vitro/in vivo experiments with glioblastoma cells, inhibition of the APLN/APLNR axis has resulted in decreased proliferation and angiogenesis.	('glioblastoma', 'Disease', 'MESH:D005909', (76, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (5, 23))	('angiogenesis', 'biological_process', 'GO:0001525', ('174', '186'))	('angiogenesis', 'CPA', (174, 186))	('proliferation', 'CPA', (156, 169))	('decreased', 'NegReg', (146, 155))	('cholangiocarcinoma cell', 'Disease', (5, 28))	('inhibition', 'Var', (96, 106))	('glioblastoma', 'Disease', (76, 88))	('cholangiocarcinoma cell', 'Disease', 'MESH:D018281', (5, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
31803	30783205	ccRCC is a highly vascularised tumour with high levels of intratumoural HIF, which accumulates due to inactivation of the von Hippel-Lindau gene.	('inactivation', 'Var', (102, 114))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (122, 139))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('ccRCC', 'Disease', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('ccRCC', 'Disease', 'MESH:D002292', (0, 5))	('vascularised tumour', 'Phenotype', 'HP:0100742', (18, 37))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('von Hippel-Lindau', 'Disease', (122, 139))	('tumour', 'Disease', (31, 37))	('tumour', 'Disease', (63, 69))
31806	30783205	One possible explanation could be that APLN/APLNR activation induces maturation of the tumour vasculature and improves the efficiency of immune therapy, while immature vessels could help the tumour to evade the immune response.	('maturation', 'CPA', (69, 79))	('tumour', 'Disease', 'MESH:D009369', (191, 197))	('immune response', 'biological_process', 'GO:0006955', ('211', '226'))	('tumour', 'Disease', (87, 93))	('induces', 'Reg', (61, 68))	('tumour', 'Disease', (191, 197))	('evade', 'CPA', (201, 206))	('immune therapy', 'CPA', (137, 151))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('tumour', 'Disease', 'MESH:D009369', (87, 93))	('improves', 'PosReg', (110, 118))	('tumour vasculature', 'Disease', (87, 105))	('APLN/APLNR activation', 'Var', (39, 60))	('tumour vasculature', 'Disease', 'MESH:C565633', (87, 105))	('help', 'PosReg', (182, 186))
31812	30783205	Although our study provides the first thorough characterisation of APLN/APLNR expression in renal cell carcinoma (especially in ccRCC as the dominant subtype) and its association with clinicopathological variables and outcome, functional studies, especially those related to the associated immune processes, were not within the scope of our project and warrant further investigations.	('ccRCC', 'Disease', (128, 133))	('ccRCC', 'Disease', 'MESH:D002292', (128, 133))	('renal cell carcinoma', 'Disease', (92, 112))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (92, 112))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (92, 112))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('APLN/APLNR', 'Var', (67, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
31817	33061618	miR-758-3p Inhibits Proliferation, Migration, and Invasion of Clear Cell Renal Cell Carcinoma and Predicts Favorable Prognosis Although miR-758-3p has been reported to be associated with multiple cancers, including hepatocellular carcinoma, bladder cancer, gastric cancer and papillary thyroid cancer, its role in clear cell renal cell carcinoma (ccRCC) remains unclear.	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (276, 300))	('thyroid cancer', 'Phenotype', 'HP:0002890', (286, 300))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (314, 345))	('bladder cancer', 'Phenotype', 'HP:0009725', (241, 255))	('miR-758-3p', 'Chemical', '-', (136, 146))	('Clear Cell Renal Cell Carcinoma', 'Disease', (62, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('hepatocellular carcinoma', 'Disease', (215, 239))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('Inhibits', 'NegReg', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('Invasion', 'CPA', (50, 58))	('Carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('gastric cancer', 'Phenotype', 'HP:0012126', (257, 271))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (62, 93))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (73, 93))	('papillary thyroid cancer', 'Disease', (276, 300))	('miR-758-3p', 'Var', (136, 146))	('miR-758-3p', 'Chemical', '-', (0, 10))	('Proliferation', 'CPA', (20, 33))	('associated', 'Reg', (171, 181))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (314, 345))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (215, 239))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (325, 345))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('ccRCC', 'Phenotype', 'HP:0006770', (347, 352))	('RCC', 'Disease', (349, 352))	('RCC', 'Phenotype', 'HP:0005584', (349, 352))	('cancers', 'Disease', (196, 203))	('gastric cancer', 'Disease', (257, 271))	('miR-758-3p', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (276, 300))	('Migration', 'CPA', (35, 44))	('clear cell renal cell carcinoma', 'Disease', (314, 345))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (62, 93))	('RCC', 'Disease', 'MESH:C538614', (349, 352))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (215, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (336, 345))	('bladder cancer', 'Disease', 'MESH:D001749', (241, 255))	('bladder cancer', 'Disease', (241, 255))	('gastric cancer', 'Disease', 'MESH:D013274', (257, 271))
31823	33061618	The expression levels of miR-758-3p were down-regulated in human ccRCC tissues and cell lines.	('expression levels', 'MPA', (4, 21))	('miR-758-3p', 'Var', (25, 35))	('human', 'Species', '9606', (59, 64))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('down-regulated', 'NegReg', (41, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('miR-758-3p', 'Chemical', '-', (25, 35))
31824	33061618	Moreover, the expression of miR-758-3p was closely associated with histological grade, TNM stage and vascular invasion.	('miR-758-3p', 'Var', (28, 38))	('vascular invasion', 'CPA', (101, 118))	('TNM', 'Gene', '10178', (87, 90))	('associated', 'Reg', (51, 61))	('expression', 'MPA', (14, 24))	('TNM', 'Gene', (87, 90))	('miR-758-3p', 'Chemical', '-', (28, 38))	('histological grade', 'CPA', (67, 85))
31825	33061618	High expression of miR-758-3p was found to be capable of predicting favorable clinical prognosis in ccRCC patients.	('miR-758-3p', 'Chemical', '-', (19, 29))	('miR-758-3p', 'Var', (19, 29))	('RCC', 'Disease', (102, 105))	('patients', 'Species', '9606', (106, 114))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))
31826	33061618	Additionally, whilst the proliferation, migration and invasion of ccRCC cells were inhibited upon overexpression of miR-758-3p, the effects were reversed upon miR-758-3p knockdown.	('miR-758-3p', 'Chemical', '-', (159, 169))	('overexpression', 'PosReg', (98, 112))	('inhibited', 'NegReg', (83, 92))	('miR-758-3p', 'Chemical', '-', (116, 126))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('migration', 'CPA', (40, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('miR-758-3p', 'Var', (116, 126))
31828	33061618	This study demonstrated that miR-758-3p is a potential prognostic biomarker for ccRCC patients.	('miR-758-3p', 'Chemical', '-', (29, 39))	('miR-758-3p', 'Var', (29, 39))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('patients', 'Species', '9606', (86, 94))
31829	33061618	Data from this study showed that miR-758-3p exhibits different biological functions that inhibit the progression of ccRCC cells, hence it can be a potential therapeutic target candidate for treating ccRCC.	('progression of', 'CPA', (101, 115))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('RCC', 'Disease', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (199, 204))	('miR-758-3p', 'Var', (33, 43))	('miR-758-3p', 'Chemical', '-', (33, 43))	('inhibit', 'NegReg', (89, 96))
31841	33061618	In particular, abnormal miRNA expression has been found to be highly involved in some critical cellular processes of multiple cancers, including proliferation, differentiation, development and apoptosis.	('development', 'CPA', (177, 188))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('apoptosis', 'CPA', (193, 202))	('involved', 'Reg', (69, 77))	('proliferation', 'CPA', (145, 158))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('apoptosis', 'biological_process', 'GO:0097194', ('193', '202'))	('apoptosis', 'biological_process', 'GO:0006915', ('193', '202'))	('abnormal', 'Var', (15, 23))	('miR', 'Gene', '220972', (24, 27))	('cancers', 'Disease', (126, 133))	('miR', 'Gene', (24, 27))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('differentiation', 'CPA', (160, 175))
31843	33061618	It has been widely reported in recent years, that miR-758-3p plays critical roles in different cancer types, including hepatocellular carcinoma, bladder cancer, gastric cancer, and papillary thyroid cancer.	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', (153, 159))	('miR-758-3p', 'Chemical', '-', (50, 60))	('thyroid cancer', 'Phenotype', 'HP:0002890', (191, 205))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (181, 205))	('bladder cancer', 'Phenotype', 'HP:0009725', (145, 159))	('cancer', 'Disease', (199, 205))	('gastric cancer', 'Disease', 'MESH:D013274', (161, 175))	('hepatocellular carcinoma', 'Disease', (119, 143))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('miR-758-3p', 'Var', (50, 60))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('gastric cancer', 'Phenotype', 'HP:0012126', (161, 175))	('papillary thyroid cancer', 'Disease', (181, 205))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (119, 143))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('gastric cancer', 'Disease', (161, 175))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (181, 205))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (119, 143))	('roles', 'Reg', (76, 81))	('bladder cancer', 'Disease', 'MESH:D001749', (145, 159))	('bladder cancer', 'Disease', (145, 159))
31845	33061618	In this study, we explored the prognostic and biological functions of miR-758-3p in the progression of ccRCC.	('miR-758-3p', 'Var', (70, 80))	('miR-758-3p', 'Chemical', '-', (70, 80))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))
31846	33061618	We found that miR-758-3p was down-regulated in human primary ccRCC tissues and cell lines.	('miR-758-3p', 'Chemical', '-', (14, 24))	('RCC', 'Disease', (63, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('miR-758-3p', 'Var', (14, 24))	('down-regulated', 'NegReg', (29, 43))	('human', 'Species', '9606', (47, 52))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
31848	33061618	Additionally, our data revealed that miR-758-3p inhibited the proliferation, migration and invasion of ccRCC cells in vitro via targeting MDM2.	('proliferation', 'CPA', (62, 75))	('miR-758-3p', 'Chemical', '-', (37, 47))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('miR-758-3p', 'Var', (37, 47))	('migration', 'CPA', (77, 86))	('invasion of', 'CPA', (91, 102))	('inhibited', 'NegReg', (48, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('MDM2', 'Gene', '4193', (138, 142))	('MDM2', 'Gene', (138, 142))	('targeting', 'Reg', (128, 137))
31876	33061618	To primarily explore whether the miR-758-3p expression is associated with ccRCC progression, the expression levels of miR-758-3p in 68 pairs of ccRCC tissues and corresponding normal tissues were evaluated using RT-qPCR.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (76, 79))	('associated', 'Reg', (58, 68))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('miR-758-3p', 'Chemical', '-', (118, 128))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('miR-758-3p', 'Var', (33, 43))	('miR-758-3p', 'Chemical', '-', (33, 43))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))
31877	33061618	Our results showed that the expression of miR-758-3p was significantly down-regulated in the primary ccRCC tissues compared to that of the normal tissues (all P< 0.001, Figure 1A and B).	('down-regulated', 'NegReg', (71, 85))	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('expression', 'MPA', (28, 38))	('miR-758-3p', 'Chemical', '-', (42, 52))	('miR-758-3p', 'Var', (42, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))
31880	33061618	As shown in Figure 1D, the expression of miR-758-3p was markedly lower in the ccRCC cell lines, especially in 786-O cells, than that in HK-2 cells (all P< 0.001).	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('lower', 'NegReg', (65, 70))	('miR-758-3p', 'Chemical', '-', (41, 51))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('expression', 'MPA', (27, 37))	('HK-2', 'CellLine', 'CVCL:0302', (136, 140))	('miR-758-3p', 'Var', (41, 51))	('HK-2', 'molecular_function', 'GO:0008256', ('136', '140'))
31883	33061618	As shown in Table 1, a higher proportion of G3-G4 histological grade was observed in the low miR-758-3p expression group than that in the high miR-758-3p expression group (P = 0.026).	('miR-758-3p', 'Chemical', '-', (93, 103))	('miR-758-3p', 'Chemical', '-', (143, 153))	('G3-G4 histological grade', 'CPA', (44, 68))	('low miR-758-3p expression', 'Var', (89, 114))
31884	33061618	There was a higher number of patients with TNM stage III-IV in the low miR-758-3p expression group than that in the high miR-758-3p expression group (P = 0.027).	('low miR-758-3p expression', 'Var', (67, 92))	('patients', 'Species', '9606', (29, 37))	('TNM', 'Gene', (43, 46))	('miR-758-3p', 'Chemical', '-', (71, 81))	('TNM', 'Gene', '10178', (43, 46))	('miR-758-3p', 'Chemical', '-', (121, 131))
31885	33061618	In addition, vascular invasion was more common in patients in the miR-758-3p low expression group than that in the high expression group (P = 0.028).	('miR-758-3p', 'Var', (66, 76))	('patients', 'Species', '9606', (50, 58))	('low expression', 'NegReg', (77, 91))	('common', 'Reg', (40, 46))	('vascular invasion', 'CPA', (13, 30))	('miR-758-3p', 'Chemical', '-', (66, 76))
31886	33061618	However, no significant difference was found between miR-758-3p expression and other characteristics, such as age, gender, tumor size and lymph nodes metastasis (all P > 0.05).	('tumor', 'Disease', (123, 128))	('miR-758-3p', 'Chemical', '-', (53, 63))	('miR-758-3p', 'Var', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
31888	33061618	In ccRCC patients, high miR-758-3p expression was found to be associated with better OS (Figure 2A; P = 0.017) and RFS (Figure 2B; P = 0.019) compared to those with low miR-758-3p expression.	('patients', 'Species', '9606', (9, 17))	('high miR-758-3p expression', 'Var', (19, 45))	('better', 'PosReg', (78, 84))	('miR-758-3p', 'Chemical', '-', (169, 179))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('miR-758-3p', 'Chemical', '-', (24, 34))	('RFS', 'Disease', (115, 118))	('RFS', 'Disease', 'MESH:D005198', (115, 118))
31890	33061618	For prognostic factors for OS (Table 2), the following results were obtained: TNM stage (hazard ratio (HR): 1.71, 95% confidence interval (CI): 1.23-2.02, P =0.011); vascular invasion (HR: 2.12, 95% CI: 1.65-3.01, P= 0.001); miR-758-3p expression (HR: 0.53, 95% CI: 0.46-0.88, P= 0.013).	('vascular invasion', 'CPA', (166, 183))	('TNM', 'Gene', (78, 81))	('miR-758-3p', 'Chemical', '-', (225, 235))	('miR-758-3p expression', 'Var', (225, 246))	('TNM', 'Gene', '10178', (78, 81))
31891	33061618	Meanwhile, for prognostic factors for RFS (Table 3), the following data were obtained: TNM stage (HR: 1.82, 95% CI: 1.31-2.13, P= 0.001); vascular invasion (HR: 2.12, 95% CI: 1.65-3.01, P =0.003); miR-758-3p expression (HR: 0.57, 95% CI: 0.44-0.84, P =0.033).	('vascular invasion', 'CPA', (138, 155))	('TNM', 'Gene', '10178', (87, 90))	('miR-758-3p', 'Chemical', '-', (197, 207))	('RFS', 'Disease', (38, 41))	('miR-758-3p expression', 'Var', (197, 218))	('TNM', 'Gene', (87, 90))	('RFS', 'Disease', 'MESH:D005198', (38, 41))
31892	33061618	Taken together, our results showed that high expression of miR-758-3p was correlated with favorable prognosis in ccRCC patients.	('miR-758-3p', 'Var', (59, 69))	('miR-758-3p', 'Chemical', '-', (59, 69))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('patients', 'Species', '9606', (119, 127))	('RCC', 'Disease', (115, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (113, 118))	('expression', 'MPA', (45, 55))
31893	33061618	Based on the findings above, we further investigated the biological functions of miR-758-3p in the progression of ccRCC cells.	('miR-758-3p', 'Chemical', '-', (81, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('miR-758-3p', 'Var', (81, 91))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))
31895	33061618	As shown in Figure 3A, qRT-PCR analysis indicated that miR-758-3p mimics successfully induced efficient miR-758-3p overexpression in 786-O cells (P < 0.001).	('miR-758-3p', 'Var', (104, 114))	('miR-758-3p', 'Chemical', '-', (104, 114))	('overexpression', 'PosReg', (115, 129))	('miR-758-3p', 'Chemical', '-', (55, 65))
31896	33061618	Results from CCK-8 assays as shown in Figure 3B revealed that the absorbance values of 786-O cells at 3 and 4 days after transfection with miR-758-3p mimics were significantly lower than those of the untreated cells (all P < 0.01).	('CCK-8', 'Chemical', '-', (13, 18))	('miR-758-3p', 'Chemical', '-', (139, 149))	('absorbance values', 'MPA', (66, 83))	('miR-758-3p', 'Var', (139, 149))	('lower', 'NegReg', (176, 181))
31897	33061618	Moreover, data from crystal violet assays (Figure 3C) indicated that overexpression of miR-758-3p significantly inhibited the proliferation of 786-O cells (P < 0.001).	('overexpression', 'PosReg', (69, 83))	('proliferation', 'CPA', (126, 139))	('inhibited', 'NegReg', (112, 121))	('miR-758-3p', 'Var', (87, 97))	('miR-758-3p', 'Chemical', '-', (87, 97))	('crystal violet', 'Chemical', 'MESH:D005840', (20, 34))
31898	33061618	Results as shown in Figure 3D and E demonstrated that the migration and invasion of 786-O cells were notably inhibited by miR-758-3p overexpression (all P < 0.001).	('inhibited', 'NegReg', (109, 118))	('miR-758-3p', 'Chemical', '-', (122, 132))	('overexpression', 'PosReg', (133, 147))	('miR-758-3p', 'Var', (122, 132))	('invasion of 786-O cells', 'CPA', (72, 95))	('migration', 'CPA', (58, 67))
31899	33061618	To down-regulate the expression of miR-758-3p, miR-758-3p inhibitor was used in ACHN cell lines with relatively high miR-758-3p expression and the knockdown efficacy was confirmed by qRT-PCR (P < 0.001, Figure 4A).	('miR-758-3p', 'Var', (117, 127))	('miR-758-3p', 'Chemical', '-', (117, 127))	('miR-758-3p', 'Chemical', '-', (35, 45))	('miR-758-3p', 'Chemical', '-', (47, 57))	('expression', 'MPA', (21, 31))	('down-regulate', 'NegReg', (3, 16))	('expression', 'MPA', (128, 138))
31900	33061618	Results from CCK-8 assays and crystal violet assays as shown in Figure 4B and C revealed that knockdown of miR-758-3p significantly promoted the proliferation ability of ACHN cells (all P< 0.01).	('CCK-8', 'Chemical', '-', (13, 18))	('knockdown', 'Var', (94, 103))	('miR-758-3p', 'Var', (107, 117))	('crystal violet', 'Chemical', 'MESH:D005840', (30, 44))	('proliferation ability', 'CPA', (145, 166))	('promoted', 'PosReg', (132, 140))	('miR-758-3p', 'Chemical', '-', (107, 117))
31901	33061618	In addition, transwell assays indicated that ACHN cells transfected with miR-758-3p inhibitor exhibited a significantly increased cell migratory and invasive capacity compared with that of the negative control (all P < 0.001, Figure 4D and E).	('miR-758-3p inhibitor', 'Var', (73, 93))	('increased', 'PosReg', (120, 129))	('miR-758-3p', 'Chemical', '-', (73, 83))
31902	33061618	We screened that MDM2 may act as the potential target gene of miR-758-3p via bioinformatics prediction using Targetscan tool.	('miR-758-3p', 'Var', (62, 72))	('miR-758-3p', 'Chemical', '-', (62, 72))	('MDM2', 'Gene', '4193', (17, 21))	('MDM2', 'Gene', (17, 21))
31904	33061618	Then, we examined the luciferase activity of reporter containing wild-type MDM2 (MDM2-WT) or mutant-type MDM2 (MDM2-MUT) in cells transfected with miR-758-3p mimics.	('luciferase activity', 'molecular_function', 'GO:0047077', ('22', '41'))	('MDM2-MUT', 'Gene', (111, 119))	('luciferase activity', 'molecular_function', 'GO:0045289', ('22', '41'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('22', '41'))	('activity', 'MPA', (33, 41))	('MDM2', 'Gene', (105, 109))	('MDM2-MUT', 'Gene', '4193', (111, 119))	('luciferase', 'Enzyme', (22, 32))	('luciferase activity', 'molecular_function', 'GO:0050397', ('22', '41'))	('MDM2', 'Gene', (75, 79))	('luciferase activity', 'molecular_function', 'GO:0050248', ('22', '41'))	('examined', 'Reg', (9, 17))	('MDM2', 'Gene', '4193', (105, 109))	('MDM2', 'Gene', '4193', (75, 79))	('MDM2', 'Gene', (81, 85))	('MDM2', 'Gene', (111, 115))	('mutant-type', 'Var', (93, 104))	('MDM2', 'Gene', '4193', (81, 85))	('MDM2', 'Gene', '4193', (111, 115))	('miR-758-3p', 'Chemical', '-', (147, 157))
31906	33061618	Moreover, the protein levels of MDM2 were decreased in 786-O cells transfected with miR-758-3p mimics and increased in ACHN cells transfected with miR-758-3p inhibitors (Figure 5C and D).	('protein levels', 'MPA', (14, 28))	('decreased', 'NegReg', (42, 51))	('miR-758-3p', 'Chemical', '-', (84, 94))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('miR-758-3p', 'Var', (84, 94))	('miR-758-3p', 'Chemical', '-', (147, 157))	('increased', 'PosReg', (106, 115))	('MDM2', 'Gene', '4193', (32, 36))	('MDM2', 'Gene', (32, 36))
31914	33061618	Moreover, the expression of miR-758-3p was found to be closely associated with histological grade, TNM stage and vascular invasion.	('miR-758-3p', 'Var', (28, 38))	('TNM', 'Gene', (99, 102))	('associated', 'Reg', (63, 73))	('histological grade', 'CPA', (79, 97))	('vascular invasion', 'CPA', (113, 130))	('expression', 'MPA', (14, 24))	('miR-758-3p', 'Chemical', '-', (28, 38))	('TNM', 'Gene', '10178', (99, 102))
31915	33061618	Notably, high expression of miR-758-3p was shown to be able to predict favorable clinical prognosis in ccRCC patients.	('miR-758-3p', 'Var', (28, 38))	('patients', 'Species', '9606', (109, 117))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('miR-758-3p', 'Chemical', '-', (28, 38))	('high', 'Var', (9, 13))
31916	33061618	These findings indicated the prognostic capability of miR-758-3p in ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('patients', 'Species', '9606', (74, 82))	('miR-758-3p', 'Chemical', '-', (54, 64))	('miR-758-3p', 'Var', (54, 64))
31917	33061618	In addition, our functional assays indicated that, whilst the proliferation, migration and invasion of ccRCC cells were inhibited when miR-758-3p was overexpressed; opposite effects were observed upon knockdown of miR-758-3p.	('miR-758-3p', 'Chemical', '-', (135, 145))	('proliferation', 'CPA', (62, 75))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('miR-758-3p', 'Var', (135, 145))	('inhibited', 'NegReg', (120, 129))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('miR-758-3p', 'Chemical', '-', (214, 224))	('migration', 'CPA', (77, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('overexpressed', 'PosReg', (150, 163))
31918	33061618	Through binding partner predication, we found the possible interaction between miR-758-3p and the 3'UTR of MDM2 and validated their binding through mutation analysis.	('binding', 'molecular_function', 'GO:0005488', ('8', '15'))	('interaction', 'Interaction', (59, 70))	('binding', 'molecular_function', 'GO:0005488', ('132', '139'))	('miR-758-3p', 'Chemical', '-', (79, 89))	('binding', 'Interaction', (132, 139))	('MDM2', 'Gene', '4193', (107, 111))	('miR-758-3p', 'Var', (79, 89))	('MDM2', 'Gene', (107, 111))
31919	33061618	miR-758-3p overexpression likely led to a decrease in MDM2 expression at both of transcriptional and translational levels.	('miR-758-3p', 'Var', (0, 10))	('MDM2', 'Gene', '4193', (54, 58))	('MDM2', 'Gene', (54, 58))	('expression', 'MPA', (59, 69))	('decrease', 'NegReg', (42, 50))	('miR-758-3p', 'Chemical', '-', (0, 10))	('overexpression', 'PosReg', (11, 25))
31920	33061618	Thus, MDM2 might be a functional target of miR-758-3p in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('miR-758-3p', 'Chemical', '-', (43, 53))	('miR-758-3p', 'Var', (43, 53))	('MDM2', 'Gene', '4193', (6, 10))	('MDM2', 'Gene', (6, 10))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
31921	33061618	Previous studies have demonstrated that miR-758-3p plays a tumor suppressor role in multiple human cancers.	('tumor', 'Disease', (59, 64))	('human', 'Species', '9606', (93, 98))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('miR-758-3p', 'Chemical', '-', (40, 50))	('cancers', 'Disease', (99, 106))	('miR-758-3p', 'Var', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor suppressor', 'biological_process', 'GO:0051726', ('59', '75'))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('59', '75'))
31922	33061618	For example, in hepatocellular carcinoma, overexpression of miR-758-3p has been reported to play a critical role in the inhibition of proliferation, migration and invasion of hepatocellular carcinoma cells via MDM2 and mTOR.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (175, 199))	('mTOR', 'Gene', (219, 223))	('MDM2', 'Gene', (210, 214))	('hepatocellular carcinoma', 'Disease', (16, 40))	('miR-758-3p', 'Var', (60, 70))	('proliferation', 'CPA', (134, 147))	('mTOR', 'Gene', '2475', (219, 223))	('invasion', 'CPA', (163, 171))	('hepatocellular carcinoma', 'Disease', (175, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('migration', 'CPA', (149, 158))	('MDM2', 'Gene', '4193', (210, 214))	('overexpression', 'PosReg', (42, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (16, 40))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (175, 199))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (16, 40))	('miR-758-3p', 'Chemical', '-', (60, 70))	('inhibition', 'NegReg', (120, 130))
31923	33061618	In addition, Wu and colleagues have demonstrated that miR-758-3p can suppress the proliferation, migration and invasion of bladder cancer cells by targeting NOTCH2.	('NOTCH2', 'Gene', (157, 163))	('bladder cancer', 'Phenotype', 'HP:0009725', (123, 137))	('NOTCH2', 'Gene', '4853', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('miR-758-3p', 'Chemical', '-', (54, 64))	('bladder cancer', 'Disease', 'MESH:D001749', (123, 137))	('miR-758-3p', 'Var', (54, 64))	('targeting', 'Reg', (147, 156))	('proliferation', 'CPA', (82, 95))	('bladder cancer', 'Disease', (123, 137))	('invasion', 'CPA', (111, 119))	('suppress', 'NegReg', (69, 77))
31924	33061618	Meanwhile, Guo and colleagues have reported that miR-758-3p can serve as a tumor suppressor, playing a crucial inhibitory role in the proliferation, migration and invasion of gastric cancer via chromobox 5.	('miR-758-3p', 'Chemical', '-', (49, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (175, 189))	('miR-758-3p', 'Var', (49, 59))	('migration', 'CPA', (149, 158))	('tumor suppressor', 'biological_process', 'GO:0051726', ('75', '91'))	('gastric cancer', 'Disease', (175, 189))	('inhibitory', 'NegReg', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('gastric cancer', 'Disease', 'MESH:D013274', (175, 189))	('chromobox 5', 'Gene', '23468', (194, 205))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('75', '91'))	('chromobox 5', 'Gene', (194, 205))	('proliferation', 'CPA', (134, 147))	('tumor', 'Disease', (75, 80))	('invasion', 'CPA', (163, 171))
31925	33061618	Moreover, miR-758-3p has also been shown to act as a tumor suppressor in the initiation of papillary thyroid cancer via inhibition of cell proliferation and invasion, and promotion of cell apoptosis.	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (91, 115))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('apoptosis', 'biological_process', 'GO:0097194', ('189', '198'))	('apoptosis', 'biological_process', 'GO:0006915', ('189', '198'))	('initiation of papillary thyroid cancer', 'Disease', 'MESH:D000077273', (77, 115))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('120', '152'))	('cell apoptosis', 'CPA', (184, 198))	('miR-758-3p', 'Chemical', '-', (10, 20))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cell proliferation', 'CPA', (134, 152))	('miR-758-3p', 'Var', (10, 20))	('initiation of papillary thyroid cancer', 'Disease', (77, 115))	('thyroid cancer', 'Phenotype', 'HP:0002890', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('promotion', 'PosReg', (171, 180))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('53', '69'))	('invasion', 'CPA', (157, 165))	('inhibition', 'NegReg', (120, 130))	('tumor', 'Disease', (53, 58))	('tumor suppressor', 'biological_process', 'GO:0051726', ('53', '69'))
31926	33061618	Overall, for the first time, this study determined the prognostic and tumor suppressor role of miR-758-3p in the progression of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('tumor', 'Disease', (70, 75))	('miR-758-3p', 'Chemical', '-', (95, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('miR-758-3p', 'Var', (95, 105))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
31927	33061618	In conclusion, this study demonstrated that miR-758-3p is associated with clinical prognosis of ccRCC patients, and that miR-758-3p inhibits the progression of ccRCC cells.	('miR-758-3p', 'Var', (121, 131))	('RCC', 'Disease', (162, 165))	('RCC', 'Phenotype', 'HP:0005584', (162, 165))	('associated', 'Reg', (58, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (160, 165))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('patients', 'Species', '9606', (102, 110))	('inhibits', 'NegReg', (132, 140))	('RCC', 'Disease', (98, 101))	('miR-758-3p', 'Var', (44, 54))	('miR-758-3p', 'Chemical', '-', (44, 54))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('progression', 'CPA', (145, 156))	('miR-758-3p', 'Chemical', '-', (121, 131))
31928	33061618	Thus, miR-758-3p may be a potential prognostic and therapeutic target for ccRCC patients.	('miR-758-3p', 'Var', (6, 16))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('patients', 'Species', '9606', (80, 88))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('miR-758-3p', 'Chemical', '-', (6, 16))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))
31934	31911271	Clinically, SH3BGRL2 was identified as an independent prognostic factor for ccRCC patients.	('SH3BGRL2', 'Var', (12, 20))	('patients', 'Species', '9606', (82, 90))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:D002292', (78, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))
31936	31911271	Our findings established that SH3BGRL2 performed as a tumor suppressor and modulator via Hippo/TEAD1-Twist1 signaling in ccRCC, and the alteration of SH3BGRL2 could serve as a functional response biomarker of tumor progression and metastasis in ccRCC.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('54', '70'))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('signaling', 'biological_process', 'GO:0023052', ('108', '117'))	('ccRCC', 'Phenotype', 'HP:0006770', (121, 126))	('tumor suppressor', 'biological_process', 'GO:0051726', ('54', '70'))	('tumor', 'Disease', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('RCC', 'Phenotype', 'HP:0005584', (247, 250))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('RCC', 'Disease', 'MESH:D002292', (123, 126))	('RCC', 'Disease', (247, 250))	('ccRCC', 'Phenotype', 'HP:0006770', (245, 250))	('Hippo/TEAD1-Twist1 signaling', 'MPA', (89, 117))	('SH3BGRL2', 'Gene', (150, 158))	('alteration', 'Var', (136, 146))	('RCC', 'Disease', 'MESH:D002292', (247, 250))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('SH3BGRL2', 'Gene', (30, 38))	('tumor', 'Disease', (54, 59))
31942	31911271	Our findings identified SH3BGRL2 as a novel tumor suppressor gene that modulates the metastatic potentials of ccRCC, and suggested that SH3BGRL2 servered as a clinical biomarker and SH3BGRL2/ Hippo/TEAD1/ Twist1 signaling pathway might be a promising therapeutic target for ccRCC.	('clinical', 'Species', '191496', (159, 167))	('RCC', 'Disease', 'MESH:D002292', (276, 279))	('ccRCC', 'Phenotype', 'HP:0006770', (274, 279))	('modulates', 'Reg', (71, 80))	('tumor', 'Disease', (44, 49))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('44', '60'))	('SH3BGRL2', 'Gene', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('SH3BGRL2', 'Var', (136, 144))	('tumor suppressor', 'biological_process', 'GO:0051726', ('44', '60'))	('metastatic potentials', 'CPA', (85, 106))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))	('signaling pathway', 'biological_process', 'GO:0007165', ('212', '229'))	('RCC', 'Disease', (276, 279))	('RCC', 'Phenotype', 'HP:0005584', (276, 279))	('RCC', 'Disease', 'MESH:D002292', (112, 115))
31965	31911271	Further studies found that SH3BGRL2 could inhibit the metastasis of ccRCC by regulating Hippo/TEAD1 signaling pathway, then TEAD1 altered Twist1 expression at the transcriptional level via directly binding to its promoter region.	('RCC', 'Disease', 'MESH:D002292', (70, 73))	('RCC', 'Disease', (70, 73))	('regulating', 'Reg', (77, 87))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('signaling pathway', 'biological_process', 'GO:0007165', ('100', '117'))	('Hippo/TEAD1 signaling pathway', 'Pathway', (88, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('Twist1', 'Gene', (138, 144))	('expression', 'MPA', (145, 155))	('metastasis', 'CPA', (54, 64))	('SH3BGRL2', 'Var', (27, 35))	('inhibit', 'NegReg', (42, 49))	('binding', 'molecular_function', 'GO:0005488', ('198', '205'))	('binding', 'Interaction', (198, 205))
32003	31911271	To evaluate whether the expression levels of SH3BGRL2 was associated with prognosis of ccRCC patients, based on the optimal cut-off values of SH3BGRL2 (Supplementary Fig.	('SH3BGRL2', 'Gene', (45, 53))	('associated', 'Reg', (58, 68))	('expression', 'MPA', (24, 34))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('RCC', 'Disease', 'MESH:D002292', (89, 92))	('patients', 'Species', '9606', (93, 101))	('SH3BGRL2', 'Var', (142, 150))
32023	31911271	3g and 3i), whereas the A498 OE-SH3BGRL2 cells had a slower migratory and less invasive capacity than vector control cells(Fig.	('invasive capacity', 'CPA', (79, 96))	('less', 'NegReg', (74, 78))	('A498', 'CellLine', 'CVCL:1056', (24, 28))	('A498', 'Var', (24, 28))	('slower', 'NegReg', (53, 59))
32027	31911271	As In Vivo Imaging Systems (IVIS) showed, SH3BGRL2 knocked-down significantly promoted tumor proliferation (Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('SH3BGRL2', 'Gene', (42, 50))	('promoted', 'PosReg', (78, 86))	('tumor', 'Disease', (87, 92))	('knocked-down', 'Var', (51, 63))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
32031	31911271	Increased luciferase signal in tumors of the sh-SH3BGRL2 group was detected by the IVIS, showing SH3BGRL2 knocked-down promoted ccRCC cell metastases (Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('metastases', 'Disease', (139, 149))	('promoted', 'PosReg', (119, 127))	('tumors', 'Disease', (31, 37))	('knocked-down', 'Var', (106, 118))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('SH3BGRL2', 'Gene', (97, 105))	('RCC', 'Disease', (130, 133))	('metastases', 'Disease', 'MESH:D009362', (139, 149))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('RCC', 'Disease', 'MESH:D002292', (130, 133))
32032	31911271	4g and 4h), and more lung and liver metastases occurred in sh-SH3BGRL2 group (Fig.	('metastases', 'Disease', 'MESH:D009362', (36, 46))	('more', 'PosReg', (16, 20))	('sh-SH3BGRL2', 'Var', (59, 70))	('metastases', 'Disease', (36, 46))
32033	31911271	More importantly, SH3BGRL2 knocked-down impaired mouse survival (Fig.	('SH3BGRL2', 'Gene', (18, 26))	('mouse survival', 'CPA', (49, 63))	('impaired', 'NegReg', (40, 48))	('mouse', 'Species', '10090', (49, 54))	('knocked-down', 'Var', (27, 39))
32034	31911271	Collectively, these observations demonstrated that inhibition of SH3BGRL2 might promote the growth and metastasis of ccRCC cells in vivo.	('SH3BGRL2', 'Gene', (65, 73))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('RCC', 'Disease', 'MESH:D002292', (119, 122))	('RCC', 'Disease', (119, 122))	('inhibition', 'Var', (51, 61))	('promote', 'PosReg', (80, 87))
32064	31911271	Moreover, overexpression or knockdown SH3BGRL2 could suppress or promote ccRCC cells proliferation and metastasis both in vitro and in vivo.	('SH3BGRL2', 'Gene', (38, 46))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', 'MESH:D002292', (75, 78))	('RCC', 'Disease', (75, 78))	('suppress', 'NegReg', (53, 61))	('promote', 'PosReg', (65, 72))	('knockdown', 'Var', (28, 37))	('overexpression', 'PosReg', (10, 24))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))
32141	32457844	Moreover, studies demonstrated that retrotransposon elements, oncogene amplifications, and other functional DNA fragments that reflected the genetic status of the parent tumor cells were found in EVs.	('amplifications', 'Var', (71, 85))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('N', 'Chemical', 'MESH:D009584', (109, 110))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('oncogene', 'Gene', (62, 70))
32154	32457844	found the levels of EVs-contained miR-30c-5p in RCC cell lines 786-O and ACHN were significant lower than that in human renal proximal tubular cell line HK-2.	('lower', 'NegReg', (95, 100))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('miR-30c-5p', 'Chemical', '-', (34, 44))	('HK-2', 'CellLine', 'CVCL:0302', (153, 157))	('HK-2', 'molecular_function', 'GO:0008256', ('153', '157'))	('human', 'Species', '9606', (114, 119))	('miR-30c-5p', 'Var', (34, 44))	('N', 'Chemical', 'MESH:D009584', (76, 77))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
32155	32457844	Consistently, the expression pattern of miR-30c-5p was significant different in urinary EVs from healthy controls and patients of clear cell RCC (ccRCC), which is the predominant RCC type.	('miR-30c-5p', 'Chemical', '-', (40, 50))	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('RCC', 'Disease', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('RCC', 'Disease', 'MESH:C538614', (141, 144))	('expression', 'MPA', (18, 28))	('miR-30c-5p', 'Var', (40, 50))	('different', 'Reg', (67, 76))	('RCC', 'Phenotype', 'HP:0005584', (179, 182))	('patients', 'Species', '9606', (118, 126))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('RCC', 'Disease', (179, 182))
32157	32457844	Gain-of-function study showed that overexpression of miR-30c-5p inhibited ccRCC progression both in vitro and in vivo.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('inhibited', 'NegReg', (64, 73))	('miR-30c-5p', 'Var', (53, 63))	('overexpression', 'PosReg', (35, 49))	('miR-30c-5p', 'Chemical', '-', (53, 63))
32160	32457844	Carbonic anhydrase IX (CAIX), a cellular hypoxia biomarker that overexpress in RCC with von Hippel-Lindau (VHL) gene mutation, is involved in proliferation and transformation of RCC cells.	('overexpress', 'PosReg', (64, 75))	('VHL', 'Gene', '7428', (107, 110))	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('von Hippel-Lindau', 'Gene', '7428', (88, 105))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('CAIX', 'Gene', (23, 27))	('Carbonic anhydrase IX', 'Gene', (0, 21))	('hypoxia', 'Disease', (41, 48))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('CAIX', 'Gene', '768', (23, 27))	('RCC', 'Disease', (178, 181))	('hypoxia', 'Disease', 'MESH:D000860', (41, 48))	('mutation', 'Var', (117, 125))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('VHL', 'Gene', (107, 110))	('von Hippel-Lindau', 'Gene', (88, 105))	('Carbonic anhydrase IX', 'Gene', '768', (0, 21))	('RCC', 'Disease', (79, 82))
32172	32457844	They found that EVs released by renal CD105+ CSCs could trigger angiogenesis both in vitro and in vivo, and enhanced the lung metastases induced by injection of renal tumor cells intravenously.	('renal tumor', 'Disease', 'MESH:D007674', (161, 172))	('angiogenesis', 'biological_process', 'GO:0001525', ('64', '76'))	('renal tumor', 'Phenotype', 'HP:0009726', (161, 172))	('angiogenesis', 'CPA', (64, 76))	('renal tumor', 'Disease', (161, 172))	('trigger', 'PosReg', (56, 63))	('enhanced', 'PosReg', (108, 116))	('CD105+ CSCs', 'Var', (38, 49))	('metastases', 'Disease', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('metastases', 'Disease', 'MESH:D009362', (126, 136))
32198	32457844	Immune checkpoint protein inhibitors, especially antibodies against programmed cell death-1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1), have elicited anti-cancer effects and long-lasting alleviation in melanoma, lymphoma, bladder cancer, non-small-cell lung cancer, RCC, and many other malignancies.	('bladder cancer', 'Phenotype', 'HP:0009725', (235, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('lymphoma', 'Phenotype', 'HP:0002665', (225, 233))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('ligand', 'molecular_function', 'GO:0005488', ('131', '137'))	('programmed death-ligand 1', 'Gene', (114, 139))	('cancer', 'Disease', (168, 174))	('PD-1', 'Gene', (93, 97))	('alleviation', 'NegReg', (200, 211))	('cancer', 'Disease', (271, 277))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('programmed death-ligand 1', 'Gene', '29126', (114, 139))	('antibodies', 'Var', (49, 59))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))	('RCC', 'Disease', (279, 282))	('RCC', 'Phenotype', 'HP:0005584', (279, 282))	('long-lasting alleviation', 'Phenotype', 'HP:0012532', (187, 211))	('PD-L1', 'Gene', (141, 146))	('PD-L1', 'Gene', '29126', (141, 146))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('malignancies', 'Disease', 'MESH:D009369', (299, 311))	('malignancies', 'Disease', (299, 311))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('programmed cell death', 'biological_process', 'GO:0012501', ('68', '89'))	('RCC', 'Disease', 'MESH:C538614', (279, 282))	('non-small-cell lung cancer', 'Disease', (251, 277))	('ligand', 'molecular_function', 'GO:0005488', ('107', '113'))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (251, 277))	('bladder cancer', 'Disease', 'MESH:D001749', (235, 249))	('bladder cancer', 'Disease', (235, 249))	('cancer', 'Disease', (243, 249))	('melanoma, lymphoma', 'Disease', 'MESH:D008545', (215, 233))	('PD-1', 'Gene', '5133', (93, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (266, 277))
32202	32457844	A recent work demonstrated that EVs could support tumor growth by carrying PD-L1 and suppressing T cell activation in draining lymph nodes.	('T cell activation', 'biological_process', 'GO:0042110', ('97', '114'))	('suppressing', 'NegReg', (85, 96))	('PD-L1', 'Gene', (75, 80))	('suppressing T cell activation', 'Phenotype', 'HP:0005419', (85, 114))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('carrying', 'Var', (66, 74))	('T cell activation in draining lymph nodes', 'CPA', (97, 138))	('PD-L1', 'Gene', '29126', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('support', 'PosReg', (42, 49))	('tumor', 'Disease', (50, 55))
32203	32457844	Genetic blockade of EVs-contained PD-L1 induced long-term and systemic anti-tumor effects.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('PD-L1', 'Gene', (34, 39))	('Genetic blockade', 'Var', (0, 16))	('PD-L1', 'Gene', '29126', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
32206	32457844	Above findings enlighten us that inhibition of EVs-contained PD-L1 may be an alternative therapy for RCC treatment, especially for RCC patients that are resistant to anti-PD-L1 antibodies.	('inhibition', 'Var', (33, 43))	('patients', 'Species', '9606', (135, 143))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('PD-L1', 'Gene', (61, 66))	('RCC', 'Disease', (131, 134))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('PD-L1', 'Gene', (171, 176))	('RCC', 'Disease', (101, 104))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('PD-L1', 'Gene', '29126', (61, 66))	('PD-L1', 'Gene', '29126', (171, 176))
32210	32457844	established and characterized docetaxel-resistant variants of two prostate cancer cell lines by a serial assays including cross-resistance, morphology, multi-category phenotypes, and EVs secretion.	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('secretion', 'biological_process', 'GO:0046903', ('187', '196'))	('variants', 'Var', (50, 58))	('prostate cancer', 'Disease', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('docetaxel', 'Chemical', 'MESH:D000077143', (30, 39))
32214	32457844	Since several receptor tyrosine kinases relevant to angiogenesis and homeostasis of TME are overexpressed predominantly due to inactivation of VHL gene in ccRCC, inhibitors targeted receptor tyrosine kinases such as sunitinib have become the one of first-line therapies for RCC treatment.	('inactivation', 'Var', (127, 139))	('angiogenesis', 'biological_process', 'GO:0001525', ('52', '64'))	('RCC', 'Disease', (274, 277))	('RCC', 'Phenotype', 'HP:0005584', (274, 277))	('homeostasis', 'biological_process', 'GO:0042592', ('69', '80'))	('RCC', 'Disease', 'MESH:C538614', (274, 277))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('VHL', 'Gene', (143, 146))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('overexpressed', 'PosReg', (92, 105))	('RCC', 'Disease', (157, 160))	('VHL', 'Gene', '7428', (143, 146))	('sunitinib', 'Chemical', 'MESH:D000077210', (216, 225))
32243	32457844	It has also claimed that the level of miR-30c-5p within the urinary EVs was significantly decreased in ccRCC patients but not in other urological malignancies samples.	('patients', 'Species', '9606', (109, 117))	('miR-30c-5p', 'Chemical', '-', (38, 48))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('decreased', 'NegReg', (90, 99))	('malignancies', 'Disease', 'MESH:D009369', (146, 158))	('miR-30c-5p', 'Var', (38, 48))	('malignancies', 'Disease', (146, 158))
32245	32457844	Our previous work showed that the lost expression of organic cation transporter 2 were partly due to the downregulation by miR-489-3p and miR-630.	('organic cation transporter 2', 'Gene', '6582', (53, 81))	('miR-630', 'Gene', '693215', (138, 145))	('miR-489-3p', 'Var', (123, 133))	('downregulation', 'NegReg', (105, 119))	('lost', 'NegReg', (34, 38))	('miR-489-3p', 'Chemical', '-', (123, 133))	('miR-630', 'Gene', (138, 145))	('expression', 'MPA', (39, 49))	('organic cation transporter 2', 'Gene', (53, 81))
32246	32457844	Interestingly, miR-489-3p and miR-630 were more abundant in EVs than donor cells.	('miR-630', 'Gene', (30, 37))	('miR-489-3p', 'Chemical', '-', (15, 25))	('miR-630', 'Gene', '693215', (30, 37))	('miR-489-3p', 'Var', (15, 25))
32272	32457844	It has been shown that modified RCC cells released EVs expressing both glycolipid-anchored-IL-12 and G250, which efficiently promoted the proliferation of antigen-specific cytotoxic T lymphocytes and enhanced cytotoxic effects.	('G250', 'Var', (101, 105))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('IL-12', 'molecular_function', 'GO:0005143', ('91', '96'))	('proliferation', 'CPA', (138, 151))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('glycolipid-anchored-IL-12', 'Var', (71, 96))	('lipid', 'Chemical', 'MESH:D008055', (76, 81))	('enhanced', 'PosReg', (200, 208))	('antigen-specific cytotoxic T lymphocytes', 'CPA', (155, 195))	('promoted', 'PosReg', (125, 133))	('cytotoxic effects', 'CPA', (209, 226))
32280	32457844	One is compounds that specifically inhibit EVs trafficking, including calpeptin, manumycin A, and Y27632.	('Y27632', 'Chemical', 'MESH:C108830', (98, 104))	('manumycin A', 'Chemical', 'MESH:C054474', (81, 92))	('calpeptin', 'Chemical', 'MESH:C071482', (70, 79))	('EVs trafficking', 'MPA', (43, 58))	('Y27632', 'Var', (98, 104))	('inhibit', 'NegReg', (35, 42))
32281	32457844	Another group is compounds that specifically disrupt lipid metabolism, including pantethine, imipramine, and GW4869.	('imipramine', 'Chemical', 'MESH:D007099', (93, 103))	('lipid metabolism', 'MPA', (53, 69))	('lipid metabolism', 'biological_process', 'GO:0006629', ('53', '69'))	('lipid', 'Chemical', 'MESH:D008055', (53, 58))	('pantethine', 'Chemical', 'MESH:C005425', (81, 91))	('GW4869', 'Chemical', 'MESH:C468773', (109, 115))	('GW4869', 'Var', (109, 115))	('disrupt', 'Reg', (45, 52))
32338	33322163	These drugs work particularly well for cancers with increased mutational load and highly expressed neo-antigens.	('increased', 'PosReg', (52, 61))	('mutational load', 'Var', (62, 77))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('cancers', 'Disease', (39, 46))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('neo-antigens', 'Protein', (99, 111))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
32436	33322163	It is associated with TFE3, TFEB, or MITF gene fusions, with various associated targetable signaling pathways.	('gene fusions', 'Var', (42, 54))	('associated', 'Reg', (6, 16))	('MITF', 'Gene', '4286', (37, 41))	('MITF', 'Gene', (37, 41))	('TFE3', 'Gene', (22, 26))	('TFEB', 'Gene', '7942', (28, 32))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('TFEB', 'Gene', (28, 32))	('TFE3', 'Gene', '7030', (22, 26))
32437	33322163	An example is the presence of an SFPQ-TFE fusion [t(X;1) (p11.2; p34)] resulting in "Xp11.2 translocation carcinoma", in which TFE3 chromatin immunoprecipitation followed by deep sequencing analysis indicated a strong enrichment for the PI3K/AKT/mTOR pathway.	('carcinoma', 'Disease', (106, 115))	('p11', 'Gene', '6281', (86, 89))	('p34', 'Gene', (65, 68))	('SFPQ-TFE', 'Var', (33, 41))	('p11', 'Gene', (86, 89))	('p11', 'Gene', (58, 61))	('TFE3', 'Gene', (127, 131))	('carcinoma', 'Disease', 'MESH:D009369', (106, 115))	('PI3K/AKT/mTOR pathway', 'Pathway', (237, 258))	('p34', 'Gene', '2967', (65, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('p11', 'Gene', '6281', (58, 61))	('TFE3', 'Gene', '7030', (127, 131))
32438	33322163	The novel inhibitor SN202, a dual inhibitor of PI3K and mTOR pathways, has been studied in vitro and in mice, with a decrease in the phosphorylation of PI3K downstream signaling molecules AKT and S6K in renal cancer cells seen.	('phosphorylation', 'MPA', (133, 148))	('renal cancer', 'Disease', (203, 215))	('SN202', 'Var', (20, 25))	('mice', 'Species', '10090', (104, 108))	('AKT', 'Pathway', (188, 191))	('renal cancer', 'Phenotype', 'HP:0009726', (203, 215))	('PI3K', 'molecular_function', 'GO:0016303', ('152', '156'))	('S6K', 'Pathway', (196, 199))	('renal cancer', 'Disease', 'MESH:D007680', (203, 215))	('phosphorylation', 'biological_process', 'GO:0016310', ('133', '148'))	('PI3K downstream signaling', 'Pathway', (152, 177))	('decrease', 'NegReg', (117, 125))	('signaling', 'biological_process', 'GO:0023052', ('168', '177'))	('SN202', 'Chemical', '-', (20, 25))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
32518	33322163	ccRCC is characterized by the inactivation of Von Hippel-Lindau (VHL) tumor suppressor protein and subsequent VHL mutation in essentially all cases, which results in the accumulation of hypoxia-inducible factor (HIF) and subsequent downstream activation of pathways involved in cell metabolism, proliferation and angiogenesis.	('VHL', 'Gene', '7428', (65, 68))	('activation', 'PosReg', (243, 253))	('mutation', 'Var', (114, 122))	('accumulation', 'PosReg', (170, 182))	('hypoxia', 'Disease', 'MESH:D000860', (186, 193))	('VHL', 'Gene', '7428', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('inactivation', 'Var', (30, 42))	('RCC', 'Disease', (2, 5))	('angiogenesis', 'biological_process', 'GO:0001525', ('313', '325'))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('pathways', 'Pathway', (257, 265))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('Von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (46, 75))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('met', 'Gene', '79811', (283, 286))	('met', 'Gene', (283, 286))	('VHL', 'Gene', (65, 68))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('metabolism', 'biological_process', 'GO:0008152', ('283', '293'))	('VHL', 'Gene', (110, 113))	('hypoxia', 'Disease', (186, 193))
32522	33322163	In patients with ccRCC, PBRM1 is the second most commonly altered gene, with up to 40% of these cancers having somatic loss-of-function mutations.	('loss-of-function', 'NegReg', (119, 135))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('RCC', 'Disease', (19, 22))	('PBRM1', 'Gene', (24, 29))	('PBRM1', 'Gene', '55193', (24, 29))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (136, 145))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))	('altered', 'Reg', (58, 65))
32523	33322163	In the localized disease setting, loss of PBRM1 is associated with unfavorable clinical outcomes, with these patients more likely to have stage III disease at presentation, as well as more aggressive pathology, and a higher likelihood of developing stage IV disease in the future.	('loss', 'Var', (34, 38))	('patients', 'Species', '9606', (109, 117))	('stage IV disease', 'Disease', 'MESH:D058625', (249, 265))	('stage III disease', 'Disease', 'MESH:D058625', (138, 155))	('PBRM1', 'Gene', (42, 47))	('PBRM1', 'Gene', '55193', (42, 47))	('stage IV disease', 'Disease', (249, 265))	('stage III disease', 'Disease', (138, 155))
32525	33322163	In the metastatic setting, however, loss of PBRM1 is associated with both improved PFS and OS, and may be explained by tumors harboring PBRM1 mutations being strongly angiogenic, resulting in the upregulation of targets of VEGF-directed therapies (e.g., HIF).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('mutations', 'Var', (142, 151))	('PFS', 'Disease', (83, 86))	('PBRM1', 'Gene', (136, 141))	('PBRM1', 'Gene', (44, 49))	('tumors', 'Disease', (119, 125))	('met', 'Gene', (7, 10))	('VEGF', 'Gene', '7422', (223, 227))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('PBRM1', 'Gene', '55193', (136, 141))	('PBRM1', 'Gene', '55193', (44, 49))	('loss', 'Var', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('improved', 'PosReg', (74, 82))	('upregulation', 'PosReg', (196, 208))	('met', 'Gene', '79811', (7, 10))	('VEGF', 'Gene', (223, 227))
32526	33322163	The favorable outcome associated with loss of PBRM1 is also found in the RECORD-3 and ImMotion150 trials, irrespective of treatment choice in each trial.	('loss', 'Var', (38, 42))	('PBRM1', 'Gene', (46, 51))	('PBRM1', 'Gene', '55193', (46, 51))
32528	33322163	Type 1 PRCC has been associated with both alterations in the MET gene and a gain in chromosome 7 (where the MET gene is located).	('PRCC', 'Gene', '5546', (7, 11))	('MET', 'Gene', (61, 64))	('alterations', 'Var', (42, 53))	('PRCC', 'Gene', (7, 11))	('gain', 'PosReg', (76, 80))	('MET', 'Gene', '79811', (108, 111))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('MET', 'Gene', (108, 111))	('MET', 'Gene', '79811', (61, 64))
32535	33322163	Foretinib had a 50.0% response rate among patients with a germline MET mutation, and Savolitinib had a 18.0% ORR in MET-driven tumors (compared to 0% ORR in non-MET driven tumors) with a median PFS of 6.2 months against 1.4 months in the respective arms (HR 0.33, 95% CI 0.20-0.52).	('MET', 'Gene', '79811', (161, 164))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (127, 133))	('tumors', 'Disease', (172, 178))	('mutation', 'Var', (71, 79))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('MET', 'Gene', (116, 119))	('MET', 'Gene', (161, 164))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('MET', 'Gene', '79811', (67, 70))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('Foretinib', 'Chemical', 'MESH:C544831', (0, 9))	('Savolitinib', 'Chemical', 'MESH:C000593259', (85, 96))	('MET', 'Gene', (67, 70))	('patients', 'Species', '9606', (42, 50))	('MET', 'Gene', '79811', (116, 119))
32541	33322163	Type 2 PRCC has been linked to mutations in CDKN2A, SETD2, BAP1, PBRM1, TERT, NF2, FH, and NRF2-ARE pathway genes (among others), as well as a CpG island methylator phenotype.	('CDKN2A', 'Gene', (44, 50))	('PRCC', 'Gene', (7, 11))	('PBRM1', 'Gene', (65, 70))	('NRF2', 'Gene', '4780', (91, 95))	('SETD2', 'Gene', '29072', (52, 57))	('NF2', 'Gene', '4771', (78, 81))	('CDKN2A', 'Gene', '1029', (44, 50))	('SETD2', 'Gene', (52, 57))	('NRF2', 'Gene', (91, 95))	('BAP1', 'Gene', '8314', (59, 63))	('NF2', 'Gene', (78, 81))	('mutations', 'Var', (31, 40))	('PRCC', 'Gene', '5546', (7, 11))	('met', 'Gene', '79811', (154, 157))	('met', 'Gene', (154, 157))	('linked', 'Reg', (21, 27))	('BAP1', 'Gene', (59, 63))	('PBRM1', 'Gene', '55193', (65, 70))	('TERT', 'Gene', (72, 76))	('TERT', 'Gene', '7015', (72, 76))
32542	33322163	Various mutations in CDK2NA have also been seen frequently in CDCs although it is unclear whether and how this knowledge may be harnessed in future therapy selection.	('CDK2NA', 'Gene', '1017', (21, 27))	('CDCs', 'Disease', (62, 66))	('mutations', 'Var', (8, 17))	('CDK', 'molecular_function', 'GO:0004693', ('21', '24'))	('seen', 'Reg', (43, 47))	('CDK2NA', 'Gene', (21, 27))
32546	33322163	As an example, given the known association, the presence of FH may lead to the use of treatment regimens efficacious in patients with hereditary leiomyomata and renal cell cancer (HLRCC) or PRCC.	('lead to', 'Reg', (67, 74))	('presence', 'Var', (48, 56))	('renal cell cancer', 'Phenotype', 'HP:0005584', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('hereditary leiomyomata and renal cell cancer', 'Disease', 'MESH:C538614', (134, 178))	('PRCC', 'Gene', '5546', (190, 194))	('HLRCC', 'Disease', (180, 185))	('patients', 'Species', '9606', (120, 128))	('PRCC', 'Gene', (190, 194))	('HLRCC', 'Disease', 'MESH:C535516', (180, 185))
32547	33322163	An association between mutation status for TSC1/TSC2/mTOR and therapeutic outcome with Everolimus was tested, but not confirmed.	('Everolimus', 'Chemical', 'MESH:D000068338', (87, 97))	('TSC1', 'Gene', '7248', (43, 47))	('TSC2', 'Gene', '7249', (48, 52))	('TSC2', 'Gene', (48, 52))	('TSC1', 'Gene', (43, 47))	('mutation status', 'Var', (23, 38))	('tested', 'Reg', (102, 108))
32553	33322163	Though treatment efficacy is greater in PD-L1 positive patients, it has been repeatedly demonstrated that ICI also provide clinical benefit to PD-L1 negative patients.	('PD-L1', 'Gene', (40, 45))	('PD-L1', 'Gene', (143, 148))	('PD-L1', 'Gene', '29126', (40, 45))	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (158, 166))	('positive', 'Var', (46, 54))	('PD-L1', 'Gene', '29126', (143, 148))
32556	33322163	Interestingly however, an association with high PD-L1 and poor outcome when treated with VEGFr inhibitors has been shown.	('VEGFr', 'Gene', (89, 94))	('PD-L1', 'Gene', '29126', (48, 53))	('high', 'Var', (43, 47))	('VEGFr', 'Gene', '3791', (89, 94))	('PD-L1', 'Gene', (48, 53))
32558	33322163	However, the mutational load in RCC is usually very low and as yet, it is not in routine clinical use as a predictive biomarker in any setting.	('mutational load', 'Var', (13, 28))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))
32559	33322163	The generation of tumor neoantigens may come from higher frequencies of frameshift insertion and deletion mutations, and the ongoing TRACERx Renal study has shown secondary mutations and chromosomal changes involved in tumor evolution, outlining their clinical relevance.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', (219, 224))	('deletion mutations', 'Var', (97, 115))	('frameshift insertion', 'Var', (72, 92))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
32563	33322163	As mentioned previously, tumors harboring PBRM1 mutations tend to be strongly angiogenic while BAP1 mutation is associated with poorly angiogenic tumors.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('BAP1', 'Gene', (95, 99))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('PBRM1', 'Gene', (42, 47))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('BAP1', 'Gene', '8314', (95, 99))	('PBRM1', 'Gene', '55193', (42, 47))	('tumors', 'Disease', (146, 152))	('mutations', 'Var', (48, 57))
32584	33322163	It demonstrated a statistically significant improvement in ORR, PFS, and OS with Nivolumab, compared to Everolimus.	('PFS', 'MPA', (64, 67))	('Everolimus', 'Chemical', 'MESH:D000068338', (104, 114))	('Nivolumab', 'Chemical', 'MESH:D000077594', (81, 90))	('ORR', 'MPA', (59, 62))	('improvement', 'PosReg', (44, 55))	('Nivolumab', 'Var', (81, 90))
32647	31788046	In addition, GABRQ copy numbers are decreased in several types of cancers, including kidney cancers, leukemia, multiple myeloma and prostate cancers (Fig.	('kidney cancer', 'Phenotype', 'HP:0009726', (85, 98))	('copy numbers', 'Var', (19, 31))	('multiple myeloma', 'Disease', 'MESH:D009101', (111, 127))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('multiple myeloma', 'Disease', (111, 127))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('cancers', 'Disease', (141, 148))	('myeloma and prostate cancers', 'Disease', 'MESH:D011471', (120, 148))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('leukemia', 'Disease', (101, 109))	('leukemia', 'Disease', 'MESH:D007938', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('decreased', 'NegReg', (36, 45))	('kidney cancers', 'Disease', 'MESH:D007680', (85, 99))	('kidney cancers', 'Disease', (85, 99))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('multiple myeloma', 'Phenotype', 'HP:0006775', (111, 127))	('prostate cancer', 'Phenotype', 'HP:0012125', (132, 147))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (92, 99))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('prostate cancers', 'Phenotype', 'HP:0012125', (132, 148))	('GABRQ', 'Gene', '55879', (13, 18))	('kidney cancers', 'Phenotype', 'HP:0009726', (85, 99))	('GABRQ', 'Gene', (13, 18))
32674	31788046	In addition, GABRQ copy numbers were much lower in numerous types of cancer, including kidney cancer, leukemia, multiple myeloma and prostate cancer, according to genomic analyses from Oncomine (Fig.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('copy numbers', 'Var', (19, 31))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('leukemia', 'Phenotype', 'HP:0001909', (102, 110))	('multiple myeloma', 'Disease', (112, 128))	('kidney cancer', 'Disease', 'MESH:D007680', (87, 100))	('lower', 'NegReg', (42, 47))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', (142, 148))	('leukemia', 'Disease', 'MESH:D007938', (102, 110))	('leukemia', 'Disease', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('kidney cancer', 'Phenotype', 'HP:0009726', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('kidney cancer', 'Disease', (87, 100))	('prostate cancer', 'Disease', 'MESH:D011471', (133, 148))	('multiple myeloma', 'Phenotype', 'HP:0006775', (112, 128))	('cancer', 'Disease', (69, 75))	('prostate cancer', 'Phenotype', 'HP:0012125', (133, 148))	('GABRQ', 'Gene', (13, 18))	('prostate cancer', 'Disease', (133, 148))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('multiple myeloma', 'Disease', 'MESH:D009101', (112, 128))	('GABRQ', 'Gene', '55879', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
32699	33296352	These tumors are highly angiogenic and are frequently associated with von Hippel-Lindau (VHL) gene mutations.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('von Hippel-Lindau', 'Gene', (70, 87))	('VHL', 'Gene', (89, 92))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('mutations', 'Var', (99, 108))	('VHL', 'Gene', '7428', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('von Hippel-Lindau', 'Gene', '7428', (70, 87))	('associated', 'Reg', (54, 64))
32700	33296352	Inactivation of the VHL gene increases hypoxia-inducible factor activity, eventually leading to overexpression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor.	('hypoxia', 'Disease', (39, 46))	('hypoxia', 'Disease', 'MESH:D000860', (39, 46))	('VEGF', 'Gene', '7422', (150, 154))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('114', '148'))	('leading to', 'Reg', (85, 95))	('VHL', 'Gene', (20, 23))	('increases', 'PosReg', (29, 38))	('vascular endothelial growth factor', 'Gene', (114, 148))	('overexpression', 'PosReg', (96, 110))	('VHL', 'Gene', '7428', (20, 23))	('VEGF', 'Gene', (150, 154))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('160', '190'))	('Inactivation', 'Var', (0, 12))	('vascular endothelial growth factor', 'Gene', '7422', (114, 148))
32725	33296352	Additionally, the time-dependent ROC curve showed that the AUCs associated with the 6-DEGs signatures at 1, 3, and 5 years were 0.785, 0.756, and 0.748, respectively (Figure 2B).	('6-DEGs', 'Chemical', '-', (84, 90))	('AUCs', 'MPA', (59, 63))	('0.748', 'Var', (146, 151))
32734	33296352	As a further confirmation of the clinical value of the 6-DEGs risk score model, we performed a stratified analysis with patients divided into different subgroups based on demographics and clinical characteristics, including age (<60 or >=60), sex (female vs. male), survival (living vs. deceased), pathological grade (I+II vs. III+IV), clinical stage (I+II vs. III+IV), T stage (T1+T2 vs. T3+T4), N stage (N0 vs. N1), and M stage (M0 vs. M1).	('T3+T4', 'Var', (389, 394))	('T1+T2', 'Var', (379, 384))	('N stage', 'CPA', (397, 404))	('T stage', 'CPA', (370, 377))	('6-DEGs', 'Chemical', '-', (55, 61))	('I+II vs.', 'Var', (352, 360))	('patients', 'Species', '9606', (120, 128))
32735	33296352	A Mann-Whitney test revealed that deceased patients, those with high pathological grades (III, IV), high clinical stages (III, IV), and high TNM diagnoses (T3, T4, M1, N1) were assigned higher risk scores.	('patients', 'Species', '9606', (43, 51))	('T3', 'Var', (156, 158))	('TNM', 'Gene', (141, 144))	('TNM', 'Gene', '10178', (141, 144))
32744	33296352	The mechanisms underlying TKI resistance may be related to the development of proangiogenic pathways, the tumor microenvironment, epithelial-mesenchymal transition (EMT), single-nucleotide polymorphisms, and/or other induced genetic alterations.	('epithelial-mesenchymal transition', 'CPA', (130, 163))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('130', '163'))	('proangiogenic pathways', 'Pathway', (78, 100))	('single-nucleotide polymorphisms', 'Var', (171, 202))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('EMT', 'biological_process', 'GO:0001837', ('165', '168'))	('tumor', 'Disease', (106, 111))
32763	33296352	demonstrated that inhibiting SLC44A4 expression results in reduced secretion of acetylcholine, which inhibits the growth of lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('reduced', 'NegReg', (59, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('SLC44A4', 'Gene', (29, 36))	('growth of', 'CPA', (114, 123))	('SLC44A4', 'Gene', '80736', (29, 36))	('inhibiting', 'Var', (18, 28))	('acetylcholine', 'Chemical', 'MESH:D000109', (80, 93))	('secretion of acetylcholine', 'MPA', (67, 93))	('inhibits', 'NegReg', (101, 109))	('lung cancer', 'Disease', (124, 135))	('secretion', 'biological_process', 'GO:0046903', ('67', '76'))	('expression', 'MPA', (37, 47))
32765	33296352	In the tumor microenvironment, complement activation could enhance tumor growth and accelerate metastasis.	('complement activation', 'Var', (31, 52))	('complement activation', 'biological_process', 'GO:0006956', ('31', '52'))	('tumor', 'Disease', (7, 12))	('enhance', 'PosReg', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('metastasis', 'CPA', (95, 105))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('accelerate', 'PosReg', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
32769	33296352	Previous studies demonstrated that a mutant form of C1ORF194 protein disrupted signaling pathways involving Ca2+ homeostasis, ultimately resulting in Charcot-Marie-Tooth disease.	('resulting in', 'Reg', (137, 149))	('signaling pathways', 'Pathway', (79, 97))	('C1ORF194', 'Gene', '127003', (52, 60))	('Ca2+', 'Chemical', 'MESH:D000069285', (108, 112))	('C1ORF194', 'Gene', (52, 60))	('mutant', 'Var', (37, 43))	('Charcot-Marie-Tooth disease', 'Disease', 'MESH:D000699', (150, 177))	('homeostasis', 'biological_process', 'GO:0042592', ('113', '124'))	('Charcot-Marie-Tooth disease', 'Disease', (150, 177))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('disrupted', 'NegReg', (69, 78))	('protein', 'Protein', (61, 68))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
32784	31747963	Upregulation of ERp57 promotes clear cell renal cell carcinoma progression by initiating a STAT3/ILF3 feedback loop ERp57 dysfunction has been shown to contribute to tumorigenesis in multiple malignances.	('ERp57', 'Gene', '2923', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (31, 62))	('ERp57', 'Gene', (16, 21))	('promotes', 'PosReg', (22, 30))	('ILF3', 'Gene', '3609', (97, 101))	('initiating', 'Reg', (78, 88))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (42, 62))	('dysfunction', 'Var', (122, 133))	('ERp57', 'Gene', (116, 121))	('clear cell renal cell carcinoma', 'Disease', (31, 62))	('tumor', 'Disease', (166, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('ERp57', 'Gene', '2923', (16, 21))	('STAT3', 'Gene', (91, 96))	('Upregulation', 'PosReg', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('ILF3', 'Gene', (97, 101))	('contribute', 'Reg', (152, 162))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (31, 62))	('STAT3', 'Gene', '6774', (91, 96))
32788	31747963	In vivo and in vitro experiments showed that ccRCC cell proliferation was enhanced by ERp57 overexpression and inhibited by ERp57 deletion.	('ccRCC cell proliferation', 'CPA', (45, 69))	('cell proliferation', 'biological_process', 'GO:0008283', ('51', '69'))	('overexpression', 'PosReg', (92, 106))	('deletion', 'Var', (130, 138))	('ERp57', 'Gene', (86, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('ERp57', 'Gene', (124, 129))	('inhibited', 'NegReg', (111, 120))	('men', 'Species', '9606', (27, 30))	('enhanced', 'PosReg', (74, 82))
32789	31747963	Mechanically, ERp57 was shown to bind to STAT3 protein and enhance the STAT3-mediated transcriptional activity of ILF3.	('STAT3', 'Gene', (41, 46))	('enhance', 'PosReg', (59, 66))	('ILF3', 'Gene', (114, 118))	('bind', 'Interaction', (33, 37))	('STAT3', 'Gene', '6774', (71, 76))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('STAT3', 'Gene', (71, 76))	('STAT3', 'Gene', '6774', (41, 46))	('ERp57', 'Var', (14, 19))
32801	31747963	In the nucleus, ERp57 directly interacts with DNA or enhances the DNA-binding of the signal transducer and activator of transcription 3 (STAT3) complex, influencing binding of the transcription factor to DNA, and facilitating nuclear import and export of transcription factor.	('STAT3', 'Gene', (137, 142))	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('binding', 'Interaction', (165, 172))	('STAT3', 'Gene', '6774', (137, 142))	('binding', 'molecular_function', 'GO:0005488', ('165', '172'))	('transcription', 'biological_process', 'GO:0006351', ('255', '268'))	('influencing', 'Reg', (153, 164))	('ERp57', 'Var', (16, 21))	('transcription', 'biological_process', 'GO:0006351', ('120', '133'))	('export', 'MPA', (245, 251))	('transcription', 'biological_process', 'GO:0006351', ('180', '193'))	('nuclear import', 'MPA', (226, 240))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('66', '77'))	('DNA-binding', 'Protein', (66, 77))	('signal transducer and activator of transcription 3', 'Gene', '6774', (85, 135))	('transcription factor', 'molecular_function', 'GO:0000981', ('180', '200'))	('interacts', 'Interaction', (31, 40))	('facilitating', 'Reg', (213, 225))	('DNA', 'cellular_component', 'GO:0005574', ('204', '207'))	('nucleus', 'cellular_component', 'GO:0005634', ('7', '14'))	('enhances', 'PosReg', (53, 61))	('transcription factor', 'molecular_function', 'GO:0000981', ('255', '275'))	('DNA-binding', 'Interaction', (66, 77))	('nuclear import', 'biological_process', 'GO:0051170', ('226', '240'))
32805	31747963	Previous studies have found that ILF3 was dysregulated in breast tumor, hepatocellular carcinoma, non-small cell lung carcinoma and ovarian cancer, indicating its potential functions in oncogenesis.	('breast tumor', 'Disease', (58, 70))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (102, 127))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (72, 96))	('ILF3', 'Gene', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('hepatocellular carcinoma', 'Disease', (72, 96))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (72, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('breast tumor', 'Phenotype', 'HP:0100013', (58, 70))	('oncogenesis', 'biological_process', 'GO:0007048', ('186', '197'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (132, 146))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (98, 127))	('non-small cell lung carcinoma and ovarian cancer', 'Disease', 'MESH:D002289', (98, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast tumor', 'Disease', 'MESH:D001943', (58, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('dysregulated', 'Var', (42, 54))
32830	31747963	Briefly, cultured cells were lysed by RIPA and then lysates were immunoprecipitated with anti-ERp57 or anti-ILF3 for 1 h at 37  C. Protein A-agarose were added to the lysates for incubating overnight.	('anti-ERp57', 'Var', (89, 99))	('anti-ILF3', 'Var', (103, 112))	('agarose', 'Chemical', 'MESH:D012685', (141, 148))
32837	31747963	5 x 106 A498 cells stably knocked down ILF3 and ERp57 or knocked down both of them were mixed with 50% Matrigel matrix then this suspension was injected subcutaneously into the left dorsal flanks of nude mice.	('knocked down', 'Var', (26, 38))	('ILF3', 'Gene', (39, 43))	('ERp57', 'Gene', (48, 53))	('A498', 'CellLine', 'CVCL:1056', (8, 12))	('nude mice', 'Species', '10090', (199, 208))
32849	31747963	Following incubating with primary antibodies anti-ILF3 (Abcam, ab89100) and anti-ERp57 (Abcam, ab13248) and fluorescent-labeled secondary antibodies, then DAPI (157,574, MB biomedical) was used to stain nuclear counter.	('anti-ERp57', 'Var', (76, 86))	('anti-ILF3', 'Var', (45, 54))	('DAPI', 'Chemical', 'MESH:C007293', (155, 159))
32861	31747963	Next, we knocked down ERp57 in SW839 cells using specific shRNA and overexpressed ERp57 in A498 cells by transfecting cells with a pWPI-ERp57 overexpression vector.	('SW839', 'CellLine', 'CVCL:3604', (31, 36))	('A498', 'CellLine', 'CVCL:1056', (91, 95))	('knocked', 'Var', (9, 16))	('ERp57', 'Gene', (22, 27))
32862	31747963	Western blotting results showed that transfection of shERp57 led to significantly downregulated levels of ERp57 and the proliferation maker gene, Cyclin E1, in A498 cells compared with the shRNA control vector, while transfection of pWPI-ERp57 in SW839 cells led to upregulated ERp57 and Cyclin E1 protein levels compared with empty vector (Fig.	('levels', 'MPA', (96, 102))	('downregulated', 'NegReg', (82, 95))	('SW839', 'CellLine', 'CVCL:3604', (247, 252))	('pWPI-ERp57', 'Var', (233, 243))	('Cyclin E1', 'Gene', '898', (288, 297))	('Cyclin E1', 'Gene', (288, 297))	('ERp57', 'MPA', (106, 111))	('protein', 'cellular_component', 'GO:0003675', ('298', '305'))	('Cyclin', 'molecular_function', 'GO:0016538', ('146', '152'))	('A498', 'CellLine', 'CVCL:1056', (160, 164))	('Cyclin', 'molecular_function', 'GO:0016538', ('288', '294'))	('Cyclin E1', 'Gene', '898', (146, 155))	('shERp57', 'Gene', (53, 60))	('Cyclin E1', 'Gene', (146, 155))	('upregulated', 'PosReg', (266, 277))
32865	31747963	Consistently, knockdown of ERp57 in SW839 cells led to markedly reduced cell migration ability (Fig.	('ERp57', 'Gene', (27, 32))	('cell migration', 'biological_process', 'GO:0016477', ('72', '86'))	('reduced', 'NegReg', (64, 71))	('knockdown', 'Var', (14, 23))	('cell migration ability', 'CPA', (72, 94))	('SW839', 'CellLine', 'CVCL:3604', (36, 41))
32873	31747963	We found that suppression of STAT3 expression decreased ILF3 mRNA levels, while enhanced STAT3 expression increased ILF3 mRNA levels in ccRCC cells (Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('STAT3', 'Gene', '6774', (29, 34))	('ILF3 mRNA levels', 'MPA', (56, 72))	('STAT3', 'Gene', (29, 34))	('STAT3', 'Gene', '6774', (89, 94))	('decreased', 'NegReg', (46, 55))	('enhanced', 'PosReg', (80, 88))	('ILF3 mRNA levels', 'MPA', (116, 132))	('STAT3', 'Gene', (89, 94))	('increased', 'PosReg', (106, 115))	('suppression', 'Var', (14, 25))	('expression', 'MPA', (95, 105))
32878	31747963	And these suppression effects could strengthen by knocking down STAT3 and ERp57 together.	('STAT3', 'Gene', (64, 69))	('ERp57', 'Gene', (74, 79))	('knocking down', 'Var', (50, 63))	('STAT3', 'Gene', '6774', (64, 69))
32885	31747963	Meanwhile, we performed luciferase reporter assays to determine whether ERp57 combined with STAT3 could promote ILF3 transcription.	('ERp57', 'Var', (72, 77))	('transcription', 'biological_process', 'GO:0006351', ('117', '130'))	('STAT3', 'Gene', '6774', (92, 97))	('transcription', 'MPA', (117, 130))	('ILF3', 'Gene', (112, 116))	('STAT3', 'Gene', (92, 97))	('promote', 'PosReg', (104, 111))
32888	31747963	These results indicate that ERp57 interacts with STAT3 and promotes the transcription factor activity of STAT3.	('STAT3', 'Gene', (49, 54))	('transcription factor activity', 'molecular_function', 'GO:0000988', ('72', '101'))	('transcription factor activity', 'MPA', (72, 101))	('STAT3', 'Gene', '6774', (105, 110))	('promotes', 'PosReg', (59, 67))	('interacts', 'Interaction', (34, 43))	('transcription', 'biological_process', 'GO:0006351', ('72', '85'))	('STAT3', 'Gene', (105, 110))	('STAT3', 'Gene', '6774', (49, 54))	('transcription factor activity', 'molecular_function', 'GO:0003700', ('72', '101'))	('ERp57', 'Var', (28, 33))
32891	31747963	We found that depletion of ILF3 in SW839 cells inhibited the effects of ActD on ERp57 mRNA stability, whereas ILF3 overexpression promoted the effects of ActD, indicating that ILF3 promoted ERp57 expression by enhancing its mRNA stability (Fig.	('effects', 'MPA', (61, 68))	('inhibited', 'NegReg', (47, 56))	('ActD', 'MPA', (72, 76))	('expression', 'MPA', (196, 206))	('SW839', 'CellLine', 'CVCL:3604', (35, 40))	('mRNA stability', 'MPA', (224, 238))	('promoted', 'PosReg', (181, 189))	('ERp57', 'Gene', (190, 195))	('enhancing', 'PosReg', (210, 219))	('ERp57 mRNA stability', 'MPA', (80, 100))	('ILF3', 'Var', (176, 180))	('depletion', 'MPA', (14, 23))
32896	31747963	This inhibitory effect could be enhanced by simultaneous knockdown of ILF3 in SW839 cells and reversed by overexpression of ILF3 in A498 cells.	('knockdown', 'Var', (57, 66))	('A498', 'CellLine', 'CVCL:1056', (132, 136))	('enhanced', 'PosReg', (32, 40))	('SW839', 'CellLine', 'CVCL:3604', (78, 83))	('ILF3', 'Gene', (70, 74))
32897	31747963	Moreover, BrdU staining showed that niclosamide treatment of SW839 cells reduced BrdU-positive cells, and this effect could be enhanced by silencing ILF3 (Fig.	('enhanced', 'PosReg', (127, 135))	('BrdU-positive cells', 'CPA', (81, 100))	('ILF3', 'Gene', (149, 153))	('reduced', 'NegReg', (73, 80))	('silencing', 'Var', (139, 148))	('niclosamide', 'Chemical', 'MESH:D009534', (36, 47))	('men', 'Species', '9606', (53, 56))	('SW839', 'CellLine', 'CVCL:3604', (61, 66))
32898	31747963	Similarly, transfection of ccRCC cells with shSTAT3 inhibited cell growth compared with negative control, as determined by colony formation assays.	('STAT3', 'Gene', '6774', (46, 51))	('STAT3', 'Gene', (46, 51))	('ccRCC', 'Phenotype', 'HP:0006770', (27, 32))	('inhibited', 'NegReg', (52, 61))	('transfection', 'Var', (11, 23))	('cell growth', 'biological_process', 'GO:0016049', ('62', '73'))	('formation', 'biological_process', 'GO:0009058', ('130', '139'))	('cell growth', 'CPA', (62, 73))
32902	31747963	To test this, SW839 cells with stably depleted ERp57 or ILF3 alone, or knockdown of both were implanted into nude mice.	('SW839', 'CellLine', 'CVCL:3604', (14, 19))	('knockdown', 'Var', (71, 80))	('ERp57', 'Gene', (47, 52))	('nude mice', 'Species', '10090', (109, 118))	('depleted', 'NegReg', (38, 46))	('ILF3', 'Gene', (56, 60))
32904	31747963	Furthermore, the tumor volume was much smaller in mice implanted with cells with simultaneous knockdown of ERp57 and ILF3 compared with those with depletion of either ERp57 or ILF3 alone (Figs.	('knockdown', 'Var', (94, 103))	('tumor', 'Disease', (17, 22))	('ERp57', 'Gene', (107, 112))	('mice', 'Species', '10090', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('ILF3', 'Gene', (117, 121))	('smaller', 'NegReg', (39, 46))
32905	31747963	Consistent with these findings, the mean wet weights of the tumors were significantly lower in mice with combined knockdown of ERp57 and ILF3 compared with those with knockdown of either ERp57 or ILF3 alone (Fig.	('mice', 'Species', '10090', (95, 99))	('ERp57', 'Gene', (127, 132))	('knockdown', 'Var', (114, 123))	('lower', 'NegReg', (86, 91))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('ILF3', 'Gene', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumors', 'Disease', (60, 66))
32906	31747963	Western blot analysis demonstrated that silencing of either ERp57 or ILF3 alone significantly downregulated levels of p-STAT3, ERp57, ILF3, and Cyclin E1, and was accompanied by an increase in cleaved caspase-3 expression compared with vehicle control.	('ERp57', 'Gene', (60, 65))	('levels', 'MPA', (108, 114))	('caspase-3', 'Gene', (201, 210))	('Cyclin', 'molecular_function', 'GO:0016538', ('144', '150'))	('ILF3', 'Gene', (69, 73))	('ERp57', 'Gene', (127, 132))	('Cyclin E1', 'Gene', '898', (144, 153))	('caspase-3', 'Gene', '836', (201, 210))	('ILF3', 'Gene', (134, 138))	('Cyclin E1', 'Gene', (144, 153))	('STAT3', 'Gene', '6774', (120, 125))	('silencing', 'Var', (40, 49))	('downregulated', 'NegReg', (94, 107))	('STAT3', 'Gene', (120, 125))	('expression', 'MPA', (211, 221))	('increase', 'PosReg', (181, 189))
32907	31747963	TUNEL staining was used to measure cell apoptosis in xenograft tumors and showed that depletion of either ERp57 or ILF3 promoted apoptosis and was enhanced by combined suppression of ERp57 and ILF3 (Fig.	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('enhanced', 'PosReg', (147, 155))	('ILF3', 'Gene', (115, 119))	('apoptosis', 'CPA', (129, 138))	('ERp57', 'Gene', (106, 111))	('depletion', 'MPA', (86, 95))	('ILF3', 'Gene', (193, 197))	('promoted', 'PosReg', (120, 128))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('apoptosis', 'biological_process', 'GO:0097194', ('40', '49'))	('apoptosis', 'biological_process', 'GO:0006915', ('40', '49'))	('ERp57', 'Var', (183, 188))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('suppression', 'NegReg', (168, 179))
32909	31747963	The tumor volumes were significantly decreased in the shSTAT3 groups compared with vehicle control group, indicating that knockdown of shSTAT3 inhibited ccRCC cell growth in vivo.	('tumor', 'Disease', (4, 9))	('ccRCC', 'Disease', (153, 158))	('STAT3', 'Gene', (137, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (153, 158))	('cell growth', 'biological_process', 'GO:0016049', ('159', '170'))	('STAT3', 'Gene', (56, 61))	('inhibited', 'NegReg', (143, 152))	('knockdown', 'Var', (122, 131))	('STAT3', 'Gene', '6774', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('decreased', 'NegReg', (37, 46))	('STAT3', 'Gene', '6774', (56, 61))
32919	31747963	There is growing evidence to show dysregulation of ERp57 in various malignant cells including ovarian cancer, breast cancer, melanoma, laryngeal cancer and leukemia.	('ovarian cancer', 'Disease', (94, 108))	('cancer', 'Disease', (145, 151))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('ovarian cancer', 'Phenotype', 'HP:0100615', (94, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('dysregulation', 'Var', (34, 47))	('leukemia', 'Phenotype', 'HP:0001909', (156, 164))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('breast cancer', 'Disease', (110, 123))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (102, 108))	('leukemia', 'Disease', 'MESH:D007938', (156, 164))	('ovarian cancer', 'Disease', 'MESH:D010051', (94, 108))	('leukemia', 'Disease', (156, 164))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('ERp57', 'Gene', (51, 56))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (135, 151))
32920	31747963	For example, depletion of ERp57 in breast cancer cell reduces cell proliferation by regulating PERK-mediated activation of the unfolded protein response.	('ERp57', 'Gene', (26, 31))	('unfolded protein response', 'MPA', (127, 152))	('PERK', 'Gene', '9451', (95, 99))	('cell proliferation', 'biological_process', 'GO:0008283', ('62', '80'))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('depletion', 'Var', (13, 22))	('cell proliferation', 'CPA', (62, 80))	('activation', 'PosReg', (109, 119))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('breast cancer', 'Disease', (35, 48))	('reduces', 'NegReg', (54, 61))	('regulating', 'Reg', (84, 94))	('PERK', 'Gene', (95, 99))
32921	31747963	Moreover, ERp57 affects mTORC1 activation by interacting with mTOR, and is associated with cell proliferation.	('mTOR', 'Gene', '2475', (62, 66))	('mTOR', 'Gene', (62, 66))	('mTORC1', 'Gene', '382056', (24, 30))	('activation', 'MPA', (31, 41))	('mTORC1', 'cellular_component', 'GO:0031931', ('24', '30'))	('mTORC1', 'Gene', (24, 30))	('mTOR', 'Gene', '2475', (24, 28))	('cell proliferation', 'biological_process', 'GO:0008283', ('91', '109'))	('interacting', 'Interaction', (45, 56))	('associated', 'Reg', (75, 85))	('mTOR', 'Gene', (24, 28))	('ERp57', 'Var', (10, 15))	('cell proliferation', 'CPA', (91, 109))
32930	31747963	In the present study, we revealed that ERp57 could interact with STAT3 and form a complex.	('interact', 'Interaction', (51, 59))	('complex', 'Interaction', (82, 89))	('ERp57', 'Var', (39, 44))	('STAT3', 'Gene', '6774', (65, 70))	('STAT3', 'Gene', (65, 70))	('form', 'Reg', (75, 79))
32941	31747963	ILF3, also as known as NF90, NF110, and CBTF in humans, is an important double-stranded RNA-binding protein generated via splicing of the ILF3 gene.	('NF110', 'Gene', (29, 34))	('CBTF', 'Gene', '3609', (40, 44))	('double-stranded RNA-binding', 'molecular_function', 'GO:0003725', ('72', '99'))	('CBTF', 'Gene', (40, 44))	('RNA', 'cellular_component', 'GO:0005562', ('88', '91'))	('NF90', 'Gene', (23, 27))	('RNA-binding protein', 'Gene', '27303', (88, 107))	('splicing', 'biological_process', 'GO:0045292', ('122', '130'))	('RNA-binding protein', 'Gene', (88, 107))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('ILF3', 'Gene', (138, 142))	('humans', 'Species', '9606', (48, 54))	('splicing', 'Var', (122, 130))	('NF90', 'Gene', '3609', (23, 27))	('NF110', 'Gene', '3609', (29, 34))
32949	31747963	In summary, the present study demonstrated that dysregulation of ERp57 enhanced ccRCC cell survival by initiating a STAT3/ILF3 feedback loop that was correlated with prognosis in patients with ccRCC.	('ccRCC', 'Disease', (80, 85))	('enhanced', 'PosReg', (71, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (193, 198))	('ERp57', 'Gene', (65, 70))	('initiating', 'Reg', (103, 113))	('dysregulation', 'Var', (48, 61))	('STAT3', 'Gene', '6774', (116, 121))	('patients', 'Species', '9606', (179, 187))	('STAT3', 'Gene', (116, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))
32957	29721091	Prospective multi-center trials were used to define plasmatic sCD146 as a predictive marker of sunitinib or bevacizumab efficacy for M1 patients.	('bevacizumab', 'Chemical', 'MESH:D000068258', (108, 119))	('sCD146', 'Chemical', '-', (62, 68))	('plasmatic', 'Var', (52, 61))	('sCD146', 'Gene', (62, 68))	('patients', 'Species', '9606', (136, 144))	('sunitinib', 'Chemical', 'MESH:D000077210', (95, 104))
32959	29721091	ccRCC patients from prospective cohorts with plasmatic sCD146 variation <120% following the first cycle of sunitinib treatment had a longer progression-free survival (PFS) and OS.	('progression-free survival', 'CPA', (140, 165))	('OS', 'Chemical', '-', (176, 178))	('sunitinib', 'Chemical', 'MESH:D000077210', (107, 116))	('longer', 'PosReg', (133, 139))	('variation', 'Var', (62, 71))	('ccRCC', 'Disease', (0, 5))	('sCD146', 'Chemical', '-', (55, 61))	('patients', 'Species', '9606', (6, 14))	('sCD146', 'Gene', (55, 61))
32960	29721091	The plasmatic sCD146 variation did not correlate with PFS or OS for the bevacizumab-based treatment.	('variation', 'Var', (21, 30))	('sCD146', 'Chemical', '-', (14, 20))	('PFS', 'Disease', (54, 57))	('OS', 'Chemical', '-', (61, 63))	('bevacizumab', 'Chemical', 'MESH:D000068258', (72, 83))
32964	29721091	Metastatic clear cell renal cell carcinomas (ccRCC) are highly angiogenic tumors bearing a mutation, deletion or methylation in the VHL gene.	('deletion', 'Var', (101, 109))	('VHL', 'Gene', (132, 135))	('mutation', 'Var', (91, 99))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (11, 42))	('methylation', 'biological_process', 'GO:0032259', ('113', '124'))	('Metastatic clear cell renal cell carcinomas', 'Disease', 'MESH:C538445', (0, 43))	('VHL', 'Gene', '7428', (132, 135))	('methylation', 'Var', (113, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (22, 43))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (22, 42))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (11, 43))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (33, 43))	('Metastatic clear cell renal cell carcinomas', 'Disease', (0, 43))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
32965	29721091	Inactivation of VHL leads to over-expression of VEGF.	('VHL', 'Gene', (16, 19))	('VEGF', 'Gene', (48, 52))	('VHL', 'Gene', '7428', (16, 19))	('VEGF', 'Gene', '7422', (48, 52))	('over-expression', 'MPA', (29, 44))	('Inactivation', 'Var', (0, 12))
32975	29721091	In prostate cancer, neo-expression results from hypermethylation of the CD146 promoter.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('CD146', 'Gene', '4162', (72, 77))	('neo-expression', 'MPA', (20, 34))	('hypermethylation', 'Var', (48, 64))	('CD146', 'Gene', (72, 77))	('results from', 'Reg', (35, 47))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
33049	29721091	Variations in the sCD146 levels were identified as an independent prognostic parameter for PFS (p = 0.001, HR 8.298 (CI 95% 2.221 - 31); Table S2B).	('sCD146', 'Chemical', '-', (18, 24))	('Variations', 'Var', (0, 10))	('sCD146 levels', 'MPA', (18, 31))	('PFS', 'Disease', (91, 94))
33057	29721091	The difference in median PFS of patients with sCD146 < 120% (10.7 months, n=25/34) and of patients with sCD146 >= 120% (10.5 months, n=9/34) was not significant (p = 0.6467, Figure 3A).	('patients', 'Species', '9606', (32, 40))	('PFS', 'MPA', (25, 28))	('sCD146', 'Chemical', '-', (104, 110))	('sCD146', 'Chemical', '-', (46, 52))	('sCD146 < 120%', 'Var', (46, 59))	('patients', 'Species', '9606', (90, 98))
33071	29721091	Moreover, the increase of CD146 level in 786R in basal conditions relies on activation of the c-Jun N-terminal Kinase (JNK) pathway (Figure S7).	('JNK', 'molecular_function', 'GO:0004705', ('119', '122'))	('JNK', 'Gene', (119, 122))	('c-Jun N-terminal Kinase', 'Gene', (94, 117))	('786R', 'Var', (41, 45))	('c-Jun N-terminal Kinase', 'Gene', '5599', (94, 117))	('CD146', 'Gene', '4162', (26, 31))	('CD146', 'Gene', (26, 31))	('JNK', 'Gene', '5599', (119, 122))	('activation', 'PosReg', (76, 86))	('increase', 'PosReg', (14, 22))
33072	29721091	Indeed, inhibition of JNK by SP600125 (Figure S7A) decreased CD146 expression at the mRNA (Figure S7B-D) and protein levels (membrane CD146 analyzed by FACS (Figure S7E), sCD146 analyzed by ELISA (Figure S7F)).	('CD146', 'Gene', '4162', (172, 177))	('sCD146', 'Chemical', '-', (171, 177))	('inhibition', 'NegReg', (8, 18))	('JNK', 'Gene', (22, 25))	('AC', 'Chemical', 'MESH:D000186', (153, 155))	('SP600125', 'Chemical', 'MESH:C432165', (29, 37))	('JNK', 'molecular_function', 'GO:0004705', ('22', '25'))	('CD146', 'Gene', (172, 177))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('SP600125', 'Var', (29, 37))	('decreased', 'NegReg', (51, 60))	('JNK', 'Gene', '5599', (22, 25))	('CD146', 'Gene', '4162', (61, 66))	('CD146', 'Gene', '4162', (134, 139))	('expression', 'MPA', (67, 77))	('CD146', 'Gene', (61, 66))	('membrane', 'cellular_component', 'GO:0016020', ('125', '133'))	('CD146', 'Gene', (134, 139))
33080	29721091	Their mRNA (total, long, short forms, Figure S10B-D) and protein (membrane CD146 analyzed by FACS (Figure S10E), sCD146 analyzed by ELISA (Figure S10F)) levels are expressed to a higher extent as compared to control 786 cells and are further stimulated by sunitinib.	('S10E', 'Mutation', 'p.S10E', (106, 110))	('S10B', 'Var', (45, 49))	('sCD146', 'Chemical', '-', (113, 119))	('membrane', 'cellular_component', 'GO:0016020', ('66', '74'))	('CD146', 'Gene', '4162', (114, 119))	('AC', 'Chemical', 'MESH:D000186', (94, 96))	('S10F', 'Mutation', 'p.S10F', (146, 150))	('CD146', 'Gene', (114, 119))	('CD146', 'Gene', '4162', (75, 80))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('CD146', 'Gene', (75, 80))	('sunitinib', 'Chemical', 'MESH:D000077210', (256, 265))	('mRNA', 'MPA', (6, 10))	('S10B', 'SUBSTITUTION', 'None', (45, 49))
33082	29721091	sCD146 increased cell viability in a dose-dependent manner in 786 cells.	('sCD146', 'Chemical', '-', (0, 6))	('sCD146', 'Var', (0, 6))	('increased', 'PosReg', (7, 16))	('cell viability', 'CPA', (17, 31))
33084	29721091	sCD146 also prevented the sunitinib-dependent decreased cell viability in another ccRCC cell line (RCC10, Figure S8C).	('sCD146', 'Var', (0, 6))	('sCD146', 'Chemical', '-', (0, 6))	('cell viability', 'CPA', (56, 70))	('RCC10', 'CellLine', 'CVCL:6265', (99, 104))	('decreased', 'NegReg', (46, 55))	('sunitinib', 'Chemical', 'MESH:D000077210', (26, 35))	('prevented', 'NegReg', (12, 21))
33085	29721091	sCD146 stimulated the proliferation of HUVEC but did not protect HUVEC from sunitinib (Figure S9E).	('sCD146', 'Var', (0, 6))	('sCD146', 'Chemical', '-', (0, 6))	('sunitinib', 'Chemical', 'MESH:D000077210', (76, 85))	('HUVEC', 'CPA', (39, 44))	('proliferation', 'CPA', (22, 35))	('stimulated', 'PosReg', (7, 17))
33208	32747913	Clear large-cell lymphoma may simulate an epithelial tumor but displays a distinctive IHC lymphoma panel including positivity for leukocyte common antigen (CD45) and negativity for pan-CK.	('lymphoma', 'Phenotype', 'HP:0002665', (90, 98))	('lymphoma', 'Disease', (17, 25))	('lymphoma', 'Disease', 'MESH:D008223', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('CD45', 'Gene', (156, 160))	('CD45', 'Gene', '5788', (156, 160))	('IHC lymphoma', 'Disease', (86, 98))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('positivity', 'Var', (115, 125))	('IHC lymphoma', 'Disease', 'MESH:D008223', (86, 98))	('CK', 'Gene', '51727', (185, 187))	('lymphoma', 'Disease', (90, 98))	('cell lymphoma', 'Phenotype', 'HP:0012191', (12, 25))	('tumor', 'Disease', (53, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (17, 25))	('epithelial tumor', 'Phenotype', 'HP:0031492', (42, 58))	('lymphoma', 'Disease', 'MESH:D008223', (90, 98))
33221	33435262	The standard of care for mccRCC has changed dramatically over the past decades with the emergence of new treatments: anti-VEGFR tyrosine kinase inhibitors, mTOR Inhibitors and immune checkpoint inhibitors (ICI) such as anti-Programmed cell-Death 1 (PD-1) and anti-anti-Programmed Death Ligand-1 (PD-L1) used as monotherapy or as a combination with anti CTLA-4 or anti angiogenic therapies.	('VEGFR', 'Gene', '3791', (122, 127))	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('PD-L1', 'Gene', '29126', (296, 301))	('anti-Programmed', 'Var', (219, 234))	('anti-anti-Programmed', 'Var', (259, 279))	('mTOR', 'Gene', (156, 160))	('mTOR', 'Gene', '2475', (156, 160))	('RCC', 'Disease', (28, 31))	('CTLA-4', 'Gene', '1493', (353, 359))	('VEGFR', 'Gene', (122, 127))	('PD-L1', 'Gene', (296, 301))	('Programmed cell-Death', 'biological_process', 'GO:0012501', ('224', '245'))	('CTLA-4', 'Gene', (353, 359))
33270	33435262	Genomic signatures may play such an important role in other malignancy, especially mccRCC.	('malignancy', 'Disease', (60, 70))	('Genomic signatures', 'Var', (0, 18))	('play', 'Reg', (23, 27))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('malignancy', 'Disease', 'MESH:D009369', (60, 70))	('RCC', 'Disease', (86, 89))
33301	33435262	showed that the co-expression of TIM-3 and PD-1 on CD8 T cells was correlated with a higher TNM stage, larger tumor size and lower progression-free survival (PFS) in mccRCC.	('co-expression', 'Var', (16, 29))	('PD-1', 'Gene', (43, 47))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('higher', 'PosReg', (85, 91))	('RCC', 'Disease', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('TNM stage', 'CPA', (92, 101))	('TIM-3', 'Gene', (33, 38))	('CD8', 'Gene', (51, 54))	('progression-free survival', 'CPA', (131, 156))	('CD8', 'Gene', '925', (51, 54))	('lower', 'NegReg', (125, 130))	('TIM-3', 'Gene', '84868', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
33307	33435262	Several studies evaluating an anti-TIM-3 antibody are ongoing in different tumor types, such as Sym023, TSR-022 and MBG453, for patients with advanced solid tumor and/or hematologic malignancies (NCT 03489343, NCT 02817633, NCT02608268, NCT03066648, NCT03680508 and NCT03961971).	('NCT02608268', 'Var', (224, 235))	('TSR', 'molecular_function', 'GO:0047362', ('104', '107'))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', (75, 80))	('antibody', 'molecular_function', 'GO:0003823', ('41', '49'))	('malignancies', 'Disease', 'MESH:D009369', (182, 194))	('antibody', 'cellular_component', 'GO:0042571', ('41', '49'))	('malignancies', 'Disease', (182, 194))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('NCT03680508', 'Var', (250, 261))	('NCT 02817633', 'Var', (210, 222))	('TIM-3', 'Gene', '84868', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('antibody', 'cellular_component', 'GO:0019815', ('41', '49'))	('patients', 'Species', '9606', (128, 136))	('NCT03961971', 'Var', (266, 277))	('tumor', 'Disease', (157, 162))	('NCT03066648', 'Var', (237, 248))	('TIM-3', 'Gene', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('NCT 03489343', 'Var', (196, 208))	('antibody', 'cellular_component', 'GO:0019814', ('41', '49'))
33325	33435262	Cyclophosphamide, an alkylating drug, is known to deplete T-regs.	('Cyclophosphamide', 'Chemical', 'MESH:D003520', (0, 16))	('deplete', 'NegReg', (50, 57))	('T-regs', 'Chemical', '-', (58, 64))	('T-regs', 'CPA', (58, 64))	('Cyclophosphamide', 'Var', (0, 16))
33363	33435262	In renal cancer, CAF-derived enzymes MMP 1, 9, 11 and 19 and LOXL 2 and 3 are associated with unfavorable prognostics.	('MMP 1', 'molecular_function', 'GO:0004232', ('37', '42'))	('renal cancer', 'Disease', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('renal cancer', 'Phenotype', 'HP:0009726', (3, 15))	('MMP 1', 'Var', (37, 42))	('renal cancer', 'Disease', 'MESH:D007680', (3, 15))	('LOXL 2 and 3', 'Gene', '4017;84695', (61, 73))
33402	33435262	Within the sunitinib arm, an Angiohigh signature was associated with an improved PFS: 10.12 months versus 5.95 months for patients with an Angiolow signature, HR = 0.59 (CI (confidence interval) 95% = 0.47-0.75).	('sunitinib', 'Chemical', 'MESH:D000077210', (11, 20))	('improved', 'PosReg', (72, 80))	('Angiohigh signature', 'Var', (29, 48))	('patients', 'Species', '9606', (122, 130))	('PFS', 'MPA', (81, 84))
33416	33435262	A Teffhigh signature was numerically associated with an improved PFS in the avelumab-axitinib arm versus the sunitinib one, but statistical significance was not reached (HR = 0.79, CI 95% = 0.58-1.08 p = 0.14).	('PFS', 'MPA', (65, 68))	('axitinib', 'Chemical', 'MESH:D000077784', (85, 93))	('improved', 'PosReg', (56, 64))	('avelumab', 'Chemical', 'MESH:C000609138', (76, 84))	('Teffhigh', 'Var', (2, 10))	('sunitinib', 'Chemical', 'MESH:D000077210', (109, 118))
33431	33435262	They also reported that a single biopsy is not representative of the entire tumor bulk, as a single biopsy revealed approximately 55% of all mutations detected in the corresponding tumor.	('tumor', 'Disease', (181, 186))	('mutations', 'Var', (141, 150))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('revealed', 'Reg', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
33474	31772671	Mutation and abnormal expression of genes contribute to the initiation and progression of tumors.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Disease', (90, 96))	('contribute', 'Reg', (42, 52))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('abnormal', 'Var', (13, 21))	('expression', 'MPA', (22, 32))
33476	31772671	Numerous studies have confirmed that VHL mutations are key drivers of ccRCC initiation and development, and that VHL mutations can serve as prognostic markers for ccRCC.	('mutations', 'Var', (41, 50))	('mutations', 'Var', (117, 126))	('VHL', 'Disease', (37, 40))	('VHL', 'Disease', (113, 116))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('RCC', 'Disease', 'MESH:D002292', (72, 75))	('RCC', 'Disease', (72, 75))	('VHL', 'Disease', 'MESH:D006623', (113, 116))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('VHL', 'Disease', 'MESH:D006623', (37, 40))	('RCC', 'Disease', 'MESH:D002292', (165, 168))	('RCC', 'Disease', (165, 168))
33477	31772671	A separate VHL mutation is not enough to cause ccRCC, as the formation of ccRCC is a complex biological process involving multiple genes.	('RCC', 'Disease', 'MESH:D002292', (49, 52))	('RCC', 'Disease', (49, 52))	('mutation', 'Var', (15, 23))	('formation', 'biological_process', 'GO:0009058', ('61', '70'))	('RCC', 'Disease', 'MESH:D002292', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('VHL', 'Disease', 'MESH:D006623', (11, 14))	('VHL', 'Disease', (11, 14))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('biological process', 'biological_process', 'GO:0008150', ('93', '111'))
33478	31772671	Previous studies have identified that mutations and abnormal expression of PBRM1, TCEB1 and PP5 contribute to the progression of ccRCC.	('PP5', 'Gene', (92, 95))	('TCEB1', 'Gene', '6921', (82, 87))	('TCEB1', 'Gene', (82, 87))	('PBRM1', 'Gene', (75, 80))	('PBRM1', 'Gene', '55193', (75, 80))	('RCC', 'Disease', 'MESH:D002292', (131, 134))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('contribute', 'Reg', (96, 106))	('PP5', 'Gene', '7980', (92, 95))	('mutations', 'Var', (38, 47))	('expression', 'MPA', (61, 71))
33514	31772671	From the above analysis, we found that the expression of CCND1, TGFB1, TIMP1 and VIM predicted a consistent overall survival and disease-free survival prognosis, in which high CCND1 expression predicted a good prognosis, while high expression of the other three genes predicted poor Prognosis.	('CCND1', 'Gene', (176, 181))	('VIM', 'Gene', '7431', (81, 84))	('TGFB1', 'Gene', (64, 69))	('CCND1', 'Gene', (57, 62))	('TIMP1', 'Gene', (71, 76))	('CCND1', 'Gene', '595', (176, 181))	('high', 'Var', (171, 175))	('VIM', 'Gene', (81, 84))	('TIMP1', 'Gene', '7076', (71, 76))	('CCND1', 'Gene', '595', (57, 62))	('TGFB1', 'Gene', '7040', (64, 69))
33530	31772671	According to the NES (normalized enrichment score) > 2, FDR (the false discovery rate) < 0.05 and the nominal P value < 0.05, high TGFB1, TIMP1 and VIM expression were mainly enriched in "primary immunodeficiency", "ECM receptor interaction", "cytokine receptor interaction" and "natural killer cell-mediated cytotoxicity" pathways (Fig.	('ECM', 'Gene', '22915', (216, 219))	('primary immunodeficiency', 'Disease', 'MESH:D007153', (188, 212))	('cytokine receptor', 'Gene', '8809', (244, 261))	('VIM', 'Gene', (148, 151))	('false', 'biological_process', 'GO:0071877', ('65', '70'))	('TGFB1', 'Gene', '7040', (131, 136))	('ECM', 'Gene', (216, 219))	('false', 'biological_process', 'GO:0071878', ('65', '70'))	('primary immunodeficiency', 'Disease', (188, 212))	('cytotoxicity', 'Disease', (309, 321))	('high', 'Var', (126, 130))	('TGFB1', 'Gene', (131, 136))	('cytokine receptor', 'Gene', (244, 261))	('VIM', 'Gene', '7431', (148, 151))	('TIMP1', 'Gene', (138, 143))	('immunodeficiency', 'Phenotype', 'HP:0002721', (196, 212))	('TIMP1', 'Gene', '7076', (138, 143))	('cytotoxicity', 'Disease', 'MESH:D064420', (309, 321))
33552	31772671	The inhibition of TIMP1 expression reduced proliferation and metastasis but increased apoptosis by activating TIMP1 mediated FAK-PI3K/AKT and MAPK pathway.	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('reduced', 'NegReg', (35, 42))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('inhibition', 'Var', (4, 14))	('PI3K', 'molecular_function', 'GO:0016303', ('129', '133'))	('FAK', 'Gene', '5747', (125, 128))	('TIMP1', 'Gene', (110, 115))	('apoptosis', 'CPA', (86, 95))	('AKT', 'Gene', (134, 137))	('increased', 'PosReg', (76, 85))	('MAPK', 'molecular_function', 'GO:0004707', ('142', '146'))	('MAPK pathway', 'Pathway', (142, 154))	('TIMP1', 'Gene', '7076', (110, 115))	('FAK', 'molecular_function', 'GO:0004717', ('125', '128'))	('AKT', 'Gene', '207', (134, 137))	('proliferation', 'CPA', (43, 56))	('TIMP1', 'Gene', (18, 23))	('activating', 'PosReg', (99, 109))	('TIMP1', 'Gene', '7076', (18, 23))	('FAK', 'Gene', (125, 128))
33577	27426025	Autosomal dominant inheritance of the mutant VHL gene predisposes persons to the development of pheochromocytomas, hemangioblastomas, and, through family linkage studies, was connected to frequent loss of chromosome 3p in ccRCC.	('RCC', 'Disease', (224, 227))	('mutant', 'Var', (38, 44))	('VHL', 'Gene', '7428', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (224, 227))	('hemangioblastomas', 'Disease', 'MESH:D018325', (115, 132))	('persons', 'Species', '9606', (66, 73))	('hemangioblastomas', 'Disease', (115, 132))	('pheochromocytomas', 'Disease', 'MESH:D010673', (96, 113))	('predisposes', 'Reg', (54, 65))	('pheochromocytomas', 'Disease', (96, 113))	('loss', 'NegReg', (197, 201))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (96, 113))	('chromosome', 'cellular_component', 'GO:0005694', ('205', '215'))	('VHL', 'Gene', (45, 48))	('RCC', 'Disease', 'MESH:C538614', (224, 227))
33580	27426025	Therefore, loss of VHL in ccRCC allows for constitutive activity of HIF2a to upregulate pathways involved in angiogenesis through vascular endothelial growth factor (VEGF).	('pathways', 'Pathway', (88, 96))	('vascular endothelial growth factor', 'Gene', (130, 164))	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('upregulate', 'PosReg', (77, 87))	('VEGF', 'Gene', (166, 170))	('HIF2a', 'Gene', (68, 73))	('loss', 'Var', (11, 15))	('VHL', 'Gene', (19, 22))	('vascular endothelial growth factor', 'Gene', '7422', (130, 164))	('angiogenesis', 'biological_process', 'GO:0001525', ('109', '121'))	('VHL', 'Gene', '7428', (19, 22))	('VEGF', 'Gene', '7422', (166, 170))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('130', '164'))	('RCC', 'Disease', (28, 31))	('RCC', 'Phenotype', 'HP:0005584', (28, 31))	('HIF2a', 'Gene', '2034', (68, 73))
33581	27426025	Another commonly altered pathway includes the mammalian target of rapamycin (mTOR) which is involved in cell growth and metabolism and is activated in 60-80% of ccRCC.. Lastly, a majority of the >400 ccRCC tumors in the TCGA showed epigenetic changes of hypomethylation associated with a mutation in the SET domain containing 2 (SETD2) gene.	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('epigenetic changes', 'Var', (232, 250))	('RCC', 'Disease', (163, 166))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('mTOR', 'Gene', '2475', (77, 81))	('SETD2', 'Gene', (329, 334))	('RCC', 'Disease', (202, 205))	('RCC', 'Phenotype', 'HP:0005584', (202, 205))	('mammalian target of rapamycin', 'Gene', (46, 75))	('mutation', 'Var', (288, 296))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('SETD2', 'Gene', '29072', (329, 334))	('tumors', 'Disease', (206, 212))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('metabolism', 'biological_process', 'GO:0008152', ('120', '130'))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('cell growth', 'biological_process', 'GO:0016049', ('104', '115'))	('hypomethylation', 'MPA', (254, 269))	('mTOR', 'Gene', (77, 81))	('mammalian target of rapamycin', 'Gene', '2475', (46, 75))
33609	27426025	Only 36% of patients had any degree of PD-L1 tumor expressing cells; the subset of patients with high PD-L1 expression (~13%, n=59) had a significantly shorter overall survival with a median OS of 15.1 vs 35.6 months and 15.3 vs 27.8 months for patients treated with pazopanib or sunitinib, respectively.	('patients', 'Species', '9606', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('patients', 'Species', '9606', (245, 253))	('overall survival', 'MPA', (160, 176))	('PD-L1', 'Gene', (102, 107))	('sunitinib', 'Chemical', 'MESH:D000077210', (280, 289))	('PD-L1 tumor', 'Disease', (39, 50))	('shorter', 'NegReg', (152, 159))	('patients', 'Species', '9606', (83, 91))	('PD-L1 tumor', 'Disease', 'MESH:D010300', (39, 50))	('high', 'Var', (97, 101))	('pazopanib', 'Chemical', 'MESH:C516667', (267, 276))
33619	27426025	showed that depletion of regulatory T cells induced regression of subcutaneous tumors but not intra-renal RCC tumors by using a spontaneously derived renal adenocarcinoma mouse cell line (RENCA) and comparing intra-renal injected RCC to a subcutaneous orthotopic model of RCC.	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('renal adenocarcinoma', 'Disease', (150, 170))	('renal adenocarcinoma', 'Phenotype', 'HP:0005584', (150, 170))	('depletion', 'Var', (12, 21))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('mouse', 'Species', '10090', (171, 176))	('RCC', 'Phenotype', 'HP:0005584', (272, 275))	('RCC', 'Disease', (272, 275))	('intra-renal RCC tumors', 'Disease', 'MESH:C538614', (94, 116))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (66, 85))	('intra-renal RCC tumors', 'Disease', (94, 116))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (66, 85))	('RCC', 'Disease', (230, 233))	('RCC', 'Phenotype', 'HP:0005584', (230, 233))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('RCC', 'Disease', 'MESH:C538614', (272, 275))	('renal adenocarcinoma', 'Disease', 'MESH:C538614', (150, 170))	('subcutaneous tumors', 'Disease', (66, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('RCC', 'Disease', 'MESH:C538614', (230, 233))	('renal RCC', 'Phenotype', 'HP:0030409', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
33644	27426025	Nivolumab was only rarely associated with colitis, but did produce immune mediated pneumonitis in a low percentage of patients (~1%).	('colitis', 'Disease', 'MESH:D003092', (42, 49))	('colitis', 'Disease', (42, 49))	('Nivolumab', 'Chemical', 'MESH:D000077594', (0, 9))	('pneumonitis', 'Disease', 'MESH:D011014', (83, 94))	('colitis', 'Phenotype', 'HP:0002583', (42, 49))	('Nivolumab', 'Var', (0, 9))	('patients', 'Species', '9606', (118, 126))	('pneumonitis', 'Disease', (83, 94))	('produce', 'Reg', (59, 66))
33795	31754403	Inhibition of SMYD2 suppresses tumor progression by down-regulating microRNA-125b and attenuates multi-drug resistance in renal cell carcinoma SMYD2 is a histone methyltransferase that has been reported to be an important epigenetic regulator.	('SMYD2', 'Gene', '56950', (14, 19))	('SMYD2', 'Gene', '56950', (143, 148))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (122, 142))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('down-regulating', 'NegReg', (52, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('renal cell carcinoma', 'Disease', (122, 142))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (122, 142))	('drug resistance', 'biological_process', 'GO:0009315', ('103', '118'))	('drug resistance', 'biological_process', 'GO:0042493', ('103', '118'))	('multi-drug resistance', 'MPA', (97, 118))	('Inhibition', 'Var', (0, 10))	('microRNA-125b', 'Gene', (68, 81))	('tumor', 'Disease', (31, 36))	('attenuates', 'NegReg', (86, 96))	('SMYD2', 'Gene', (14, 19))	('suppresses', 'NegReg', (20, 30))	('SMYD2', 'Gene', (143, 148))	('drug resistance', 'Phenotype', 'HP:0020174', (103, 118))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
33798	31754403	MicroRNA (miRNA)-microarray profiling identified differentially expressed miRNAs in renal cancer cells subjected to SMYD2 knockdown or treatment with the SMYD2 inhibitor AZ505.	('renal cancer', 'Disease', 'MESH:D007680', (84, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('SMYD2', 'Gene', (116, 121))	('N', 'Chemical', 'MESH:D009584', (77, 78))	('N', 'Chemical', 'MESH:D009584', (6, 7))	('knockdown', 'Var', (122, 131))	('N', 'Chemical', 'MESH:D009584', (13, 14))	('differentially', 'Reg', (49, 63))	('renal cancer', 'Disease', (84, 96))	('miRNAs', 'MPA', (74, 80))	('renal cancer', 'Phenotype', 'HP:0009726', (84, 96))
33803	31754403	AZ505 inhibited the binding of SMYD2 to the miR-125b promoter region (based on chromatin immunoprecipitation assays) and suppressed ccRCC cell migration and invasion by inhibiting the SMYD2/miR-125b/DKK3 pathway.	('miR', 'Gene', '220972', (44, 47))	('DKK3', 'Gene', '27122', (199, 203))	('RCC', 'Disease', 'MESH:D002292', (134, 137))	('miR', 'Gene', (44, 47))	('binding', 'Interaction', (20, 27))	('RCC', 'Phenotype', 'HP:0005584', (134, 137))	('inhibiting', 'NegReg', (169, 179))	('chromatin', 'cellular_component', 'GO:0000785', ('79', '88'))	('miR', 'Gene', '220972', (190, 193))	('DKK3', 'Gene', (199, 203))	('invasion', 'CPA', (157, 165))	('suppressed', 'NegReg', (121, 131))	('AZ505', 'Var', (0, 5))	('inhibited', 'NegReg', (6, 15))	('cell migration', 'biological_process', 'GO:0016477', ('138', '152'))	('RCC', 'Disease', (134, 137))	('binding', 'molecular_function', 'GO:0005488', ('20', '27'))	('ccRCC', 'Phenotype', 'HP:0006770', (132, 137))	('miR', 'Gene', (190, 193))
33813	31754403	Inhibiting P-gP as a method to reverse MDR in cancer patients has been studied extensively, but the results in RCC patients have been disappointing thus far.	('MDR', 'molecular_function', 'GO:0004745', ('39', '42'))	('patients', 'Species', '9606', (115, 123))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('Inhibiting', 'Var', (0, 10))	('patients', 'Species', '9606', (53, 61))	('RCC', 'Disease', 'MESH:D002292', (111, 114))	('cancer', 'Disease', (46, 52))	('RCC', 'Disease', (111, 114))	('P-gP', 'Gene', (11, 15))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('P-gP', 'Gene', '5243', (11, 15))
33815	31754403	SET and MYND domain-containing protein 2 (SMYD2) is a member of the SMYD-methyltransferase family of proteins and methylates the histone on lysine 36 and 4 (H3K36 and H3K4).	('H3K4', 'Var', (167, 171))	('SET and MYND domain-containing protein 2', 'Gene', '56950', (0, 40))	('H3K4', 'Chemical', 'MESH:C024755', (167, 171))	('lysine', 'Chemical', 'MESH:C114808', (140, 146))	('SMYD2', 'Gene', (42, 47))	('methylate', 'Chemical', 'MESH:C098207', (114, 123))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))
33816	31754403	SMYD2 can also methylate non-histone proteins, such as the tumor-suppresser proteins P53, RB1, and PTEN, and can activate the oncoprotein PARP1 at K370, K860, K313, and K528.	('PARP1', 'Gene', '142', (138, 143))	('RB1', 'Gene', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('PARP1', 'Gene', (138, 143))	('P53', 'Gene', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('non-histone proteins', 'Protein', (25, 45))	('K528', 'Var', (169, 173))	('P53', 'Gene', '7157', (85, 88))	('RB1', 'Gene', '5925', (90, 93))	('K860', 'Var', (153, 157))	('methylate', 'Chemical', 'MESH:C098207', (15, 24))	('PTEN', 'Gene', (99, 103))	('methylate', 'MPA', (15, 24))	('PTEN', 'Gene', '5728', (99, 103))	('activate', 'PosReg', (113, 121))	('K313', 'Var', (159, 163))
33838	31754403	Antibodies against the following proteins were used: SMYD2 (ab195365), STAT3 (ab68153), phospho-STAT3 (Y705, ab76315), DKK3 (ab186409), and P-gP (ab170904) from Abcam; beta-tubulin (10068-1-AP), CDK6 (14052-1-AP), N-cadherin (22018-1-AP), and GAPDH (60004-1-lg) from Proteintech; and E-cadherin (11A24) and vimentin (BM0135) from Boster (Wuhan, China).	('STAT3', 'Gene', (96, 101))	('phospho', 'Chemical', 'MESH:C033601', (88, 95))	('E-cadherin', 'Gene', (284, 294))	('E-cadherin', 'Gene', '999', (284, 294))	('STAT3', 'Gene', (71, 76))	('STAT3', 'Gene', '6774', (96, 101))	('GAPDH', 'Gene', (243, 248))	('vimentin', 'cellular_component', 'GO:0045098', ('307', '315'))	('STAT3', 'Gene', '6774', (71, 76))	('CDK', 'molecular_function', 'GO:0004693', ('195', '198'))	('cadherin', 'molecular_function', 'GO:0008014', ('286', '294'))	('P-gP', 'Gene', '5243', (140, 144))	('10068-1-AP', 'Var', (182, 192))	('CDK6', 'Gene', '1021', (195, 199))	('DKK3', 'Gene', (119, 123))	('N-cadherin', 'Gene', (214, 224))	('P-gP', 'Gene', (140, 144))	('vimentin', 'cellular_component', 'GO:0045099', ('307', '315'))	('N-cadherin', 'Gene', '1000', (214, 224))	('CDK6', 'Gene', (195, 199))	('cadherin', 'molecular_function', 'GO:0008014', ('216', '224'))	('14052-1-AP', 'Chemical', 'None', (201, 211))	('10068-1-AP', 'Chemical', 'None', (182, 192))	('DKK3', 'Gene', '27122', (119, 123))	('GAPDH', 'Gene', '2597', (243, 248))
33839	31754403	The following reagents were used in this research: AZ505 (HY-15226), cisplatin (HY-17394), and sunitinib (HY-10255A) from MedChemExpress (Monmouth Junction, NJ, USA); and doxorubicin (A3966), 5-fluorouracil (5-FU) (A4071), and docetaxel (A4394) from APExBIO (Boston, MA, USA).	('HY-17394', 'Var', (80, 88))	('A3966', 'Var', (184, 189))	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('HY-15226', 'Chemical', 'MESH:C006004', (58, 66))	('sunitinib', 'Chemical', 'MESH:C473478', (95, 104))	('N', 'Chemical', 'MESH:D009584', (157, 158))	('APExBIO', 'Chemical', 'MESH:D001964', (250, 257))	('doxorubicin', 'Chemical', 'MESH:D004317', (171, 182))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (192, 206))	('docetaxel', 'Chemical', 'MESH:C067311', (227, 236))	('HY-10255A', 'Chemical', 'MESH:C077327', (106, 115))	('HY-10255A', 'Var', (106, 115))	('5-FU', 'Chemical', 'MESH:D005472', (208, 212))	('HY-17394', 'Chemical', 'MESH:C006004', (80, 88))
33850	31754403	SMYD2 methylates histone H3 on K4, which is known to be an activating modification.	('methylate', 'Chemical', 'MESH:C098207', (6, 15))	('histone H3', 'Protein', (17, 27))	('K4', 'Chemical', 'MESH:D011188', (31, 33))	('methylates', 'Var', (6, 16))
33884	31754403	Notably, high SMYD2 expression was associated with an increased rate of tumor recurrence and disease-related death (P = 0.032 and 0.002, respectively).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('expression', 'MPA', (20, 30))	('tumor', 'Disease', (72, 77))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('SMYD2', 'Gene', (14, 19))	('disease-related death', 'CPA', (93, 114))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('high', 'Var', (9, 13))
33890	31754403	The results of the MTS and EdU assays demonstrated that the viability and proliferation of renal cancer cells decreased significantly after the inhibition of SMYD2 via AZ505 treatment or siSMYD2-mediated knockdown (Figure 2B-C).	('viability', 'CPA', (60, 69))	('proliferation of renal cancer', 'Disease', 'MESH:D007680', (74, 103))	('knockdown', 'Var', (204, 213))	('proliferation of renal cancer', 'Disease', (74, 103))	('SMYD2', 'Gene', (158, 163))	('decreased', 'NegReg', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('inhibition', 'NegReg', (144, 154))	('renal cancer', 'Phenotype', 'HP:0009726', (91, 103))
33891	31754403	We also found that AZ505 treatment and SMYD2 knockdown inhibited the migration and invasion of 786-O cells, compared to the case for the DMSO or negative control siRNA treated cells, by performing the wound-healing and Transwell assays (Figure 2D-E).	('SMYD2', 'Gene', (39, 44))	('DMSO', 'Chemical', 'MESH:D004121', (137, 141))	('knockdown', 'Var', (45, 54))	('N', 'Chemical', 'MESH:D009584', (165, 166))	('wound-healing', 'biological_process', 'GO:0042060', ('201', '214'))	('inhibited', 'NegReg', (55, 64))	('migration', 'CPA', (69, 78))
33893	31754403	We further verified the antitumor effects of AZ505 in an orthotopic xenograft model, which was established using BALB/c nude mice.	('tumor', 'Disease', (28, 33))	('nude mice', 'Species', '10090', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('AZ505', 'Var', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
33895	31754403	Tumor growth in the 786-O cell-implanted nude mice was significantly attenuated by the intraperitoneal injection of AZ505, and the Ki67 expression levels in the tumors from the AZ505-treated mice were significantly suppressed compared to those in the tumors from the mice in the control group (Figure 2G).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', (161, 167))	('Ki67', 'Gene', '17345', (131, 135))	('nude mice', 'Species', '10090', (41, 50))	('mice', 'Species', '10090', (267, 271))	('suppressed', 'NegReg', (215, 225))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('AZ505', 'Var', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('tumors', 'Disease', (251, 257))	('mice', 'Species', '10090', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('Tumor growth', 'CPA', (0, 12))	('Ki67', 'Gene', (131, 135))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('attenuated', 'NegReg', (69, 79))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('AZ505-treated', 'Var', (177, 190))	('mice', 'Species', '10090', (46, 50))	('expression levels', 'MPA', (136, 153))
33908	31754403	Analysis of TCGA data showed that a high miR-125b expression was significantly associated with a worse survival and high tumor stage in ccRCC patients (Figure 3E).	('RCC', 'Disease', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('expression', 'MPA', (50, 60))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('RCC', 'Disease', 'MESH:D002292', (138, 141))	('miR', 'Gene', '220972', (41, 44))	('tumor', 'Disease', (121, 126))	('miR', 'Gene', (41, 44))	('worse', 'NegReg', (97, 102))	('survival', 'CPA', (103, 111))	('patients', 'Species', '9606', (142, 150))	('high', 'Var', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
33909	31754403	The miR-125b expression levels in the six tumor samples each with the highest and lowest SMYD2 expression levels were detected by ISH (Figure S1); the results indicated that the miR-125b expression was elevated in the samples from the high SMYD2 expression group, compared to those in the low SMYD2 expression group (Figure 4A).	('tumor', 'Disease', (42, 47))	('miR', 'Gene', '220972', (178, 181))	('miR', 'Gene', (178, 181))	('miR', 'Gene', (4, 7))	('miR', 'Gene', '220972', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('expression', 'MPA', (187, 197))	('high SMYD2 expression', 'Var', (235, 256))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('elevated', 'PosReg', (202, 210))
33910	31754403	The qPCR results also showed that the miR-125b expression decreased after AZ505 treatment or siSMYD2-mediated SMYD2 knockdown (Figure 4B).	('decreased', 'NegReg', (58, 67))	('knockdown', 'Var', (116, 125))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (38, 41))	('expression', 'MPA', (47, 57))
33914	31754403	Based on our findings, we evaluated whether SMYD2 knockdown could reduce miR-125b expression, which would be consistent with the observation of DKK3 overexpression.	('DKK3', 'Gene', '27122', (144, 148))	('DKK3', 'Gene', (144, 148))	('expression', 'MPA', (82, 92))	('miR', 'Gene', (73, 76))	('SMYD2', 'Gene', (44, 49))	('knockdown', 'Var', (50, 59))	('miR', 'Gene', '220972', (73, 76))	('reduce', 'NegReg', (66, 72))
33917	31754403	Moreover, we found that miR-125b knockdown inhibited the tumor growth in vivo and that miR-125b overexpression partially reversed the inhibitory effects of AZ505 on the colonization of lung metastatic tumors in the tail vein xenograft model (Figure 4J-M).	('colonization of lung metastatic tumors', 'Disease', 'MESH:D008175', (169, 207))	('miR', 'Gene', (87, 90))	('colonization of lung metastatic tumors', 'Disease', (169, 207))	('inhibited', 'NegReg', (43, 52))	('knockdown', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('miR', 'Gene', '220972', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('miR', 'Gene', (24, 27))	('miR', 'Gene', '220972', (87, 90))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', (57, 62))
33921	31754403	The estimated IC50 values of cisplatin, doxorubicin, or 5-FU (but not docetaxel) for AZ505-treated RCC cells were significantly lower than those for the control cells, indicating that the SMYD2 inhibition enhanced the drug sensitivity in renal cancer cells (Figure 5A).	('inhibition', 'NegReg', (194, 204))	('doxorubicin', 'Chemical', 'MESH:D004317', (40, 51))	('renal cancer', 'Phenotype', 'HP:0009726', (238, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('drug sensitivity', 'Phenotype', 'HP:0020174', (218, 234))	('SMYD2', 'Gene', (188, 193))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('docetaxel', 'Chemical', 'MESH:C067311', (70, 79))	('renal cancer', 'Disease', (238, 250))	('renal cancer', 'Disease', 'MESH:D007680', (238, 250))	('RCC', 'Disease', (99, 102))	('lower', 'NegReg', (128, 133))	('AZ505-treated', 'Var', (85, 98))	('enhanced', 'PosReg', (205, 213))	('drug', 'CPA', (218, 222))	('RCC', 'Disease', 'MESH:D002292', (99, 102))	('5-FU', 'Chemical', 'MESH:D005472', (56, 60))
33922	31754403	Next, a subcutaneous xenograft model was used to evaluate the antitumor efficacy of the co-treatment with AZ505 and doxorubicin.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('doxorubicin', 'Chemical', 'MESH:D004317', (116, 127))	('AZ505', 'Var', (106, 111))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
33924	31754403	On the other hand, AZ505 treatment resulted in the decrease of the tumor sizes and weights in the mice.	('AZ505', 'Var', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('decrease', 'NegReg', (51, 59))	('tumor', 'Disease', (67, 72))	('mice', 'Species', '10090', (98, 102))
33925	31754403	Following the combination treatment with AZ505 and doxorubicin, the tumor volumes and weights were significantly reduced (Figure 5B), and the number of Ki67-positive cells was decreased (Figure 5C-D).	('tumor', 'Disease', (68, 73))	('Ki67', 'Gene', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('decreased', 'NegReg', (176, 185))	('Ki67', 'Gene', '17345', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('combination', 'Interaction', (14, 25))	('doxorubicin', 'Chemical', 'MESH:D004317', (51, 62))	('reduced', 'NegReg', (113, 120))	('AZ505', 'Var', (41, 46))
33928	31754403	The IC50 of sunitinib for AZ505-treated cells was significantly lower than that for the control cells (Figure 5F).	('lower', 'NegReg', (64, 69))	('IC50', 'MPA', (4, 8))	('sunitinib', 'Chemical', 'MESH:C473478', (12, 21))	('AZ505-treated', 'Var', (26, 39))
33929	31754403	AZ505 and sunitinib treatment alone in the tumor-bearing nude mice suppressed the growth of renal tumors (Figure 5G).	('renal tumors', 'Phenotype', 'HP:0009726', (92, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('renal tumors', 'Disease', 'MESH:D007680', (92, 104))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('nude mice', 'Species', '10090', (57, 66))	('renal tumors', 'Disease', (92, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('sunitinib', 'Chemical', 'MESH:C473478', (10, 19))	('AZ505', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (43, 48))	('suppressed', 'NegReg', (67, 77))
33930	31754403	Moreover, a significant reduction in renal cancer growth was observed following the combination treatment with AZ505 and sunitinib, compared to the case for the samples from the control and monotherapy groups, as demonstrated by the decreased number of Ki67-positive cells (Figure 5H-I).	('reduction in renal cancer', 'Disease', (24, 49))	('Ki67', 'Gene', '17345', (253, 257))	('reduction in renal cancer', 'Disease', 'MESH:D007680', (24, 49))	('decreased', 'NegReg', (233, 242))	('Ki67', 'Gene', (253, 257))	('combination', 'Interaction', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('sunitinib', 'Chemical', 'MESH:C473478', (121, 130))	('renal cancer', 'Phenotype', 'HP:0009726', (37, 49))	('AZ505', 'Var', (111, 116))
33931	31754403	Therefore, combining an SMYD2 inhibitor with a chemotherapeutic agent resulted in synergistic therapeutic effects against renal cancer in vivo.	('renal cancer', 'Disease', (122, 134))	('renal cancer', 'Phenotype', 'HP:0009726', (122, 134))	('inhibitor', 'Var', (30, 39))	('renal cancer', 'Disease', 'MESH:D007680', (122, 134))	('SMYD2', 'Gene', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))
33933	31754403	The P-gP expression levels in six ccRCC specimens each with the highest and lowest SMYD2 expression levels were measured by IHC (Figure S1); the results indicated that P-gP was upregulated in the tumor tissues with high SMYD2 expression (Figure 5K).	('upregulated', 'PosReg', (177, 188))	('P-gP', 'Gene', (4, 8))	('tumor', 'Disease', (196, 201))	('P-gP', 'Gene', (168, 172))	('RCC', 'Disease', 'MESH:D002292', (36, 39))	('RCC', 'Disease', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('expression', 'MPA', (226, 236))	('ccRCC', 'Phenotype', 'HP:0006770', (34, 39))	('P-gP', 'Gene', '5243', (4, 8))	('P-gP', 'Gene', '5243', (168, 172))	('SMYD2', 'Gene', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('high', 'Var', (215, 219))
33946	31754403	Previous findings have also confirmed that the dysregulation of miRNAs, including miR-125b, plays important roles in the protective effects of chemotherapy against cancer.	('miR', 'Gene', '220972', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('miR', 'Gene', (82, 85))	('dysregulation', 'Var', (47, 60))	('miR', 'Gene', '220972', (64, 67))	('miR', 'Gene', (64, 67))	('cancer', 'Disease', (164, 170))	('protective effects', 'CPA', (121, 139))	('cancer', 'Disease', 'MESH:D009369', (164, 170))
33951	31754403	Our study also revealed that SMYD2 inhibition led to the down-regulation of P-gP, which is an ATP-binding cassette multidrug transporter, thus enhancing the chemotherapeutic drug sensitivity in RCC cells.	('SMYD2', 'Gene', (29, 34))	('enhancing', 'PosReg', (143, 152))	('down-regulation', 'NegReg', (57, 72))	('P-gP', 'Gene', (76, 80))	('chemotherapeutic drug sensitivity', 'MPA', (157, 190))	('RCC', 'Disease', (194, 197))	('RCC', 'Disease', 'MESH:D002292', (194, 197))	('RCC', 'Phenotype', 'HP:0005584', (194, 197))	('drug sensitivity', 'Phenotype', 'HP:0020174', (174, 190))	('ATP-binding', 'molecular_function', 'GO:0005524', ('94', '105'))	('ATP', 'Chemical', 'MESH:D000255', (94, 97))	('inhibition', 'Var', (35, 45))	('regulation', 'biological_process', 'GO:0065007', ('62', '72'))	('P-gP', 'Gene', '5243', (76, 80))
33958	31754403	Inhibition of SMYD2 suppressed the progression of ccRCC in vivo and in vitro by dysregulating miR-125b, which acted as a tumor promoting factor in ccRCC.	('RCC', 'Disease', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (50, 55))	('RCC', 'Disease', 'MESH:D002292', (52, 55))	('RCC', 'Disease', (52, 55))	('suppressed', 'NegReg', (20, 30))	('tumor', 'Disease', (121, 126))	('SMYD2', 'Gene', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('miR', 'Gene', '220972', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (147, 152))	('Inhibition', 'Var', (0, 10))	('dysregulating', 'Var', (80, 93))	('miR', 'Gene', (94, 97))	('RCC', 'Disease', 'MESH:D002292', (149, 152))
34010	32128917	#202673, MG132 Selleck Cat.	('Cat', 'Gene', (23, 26))	('Cat', 'Gene', '847', (23, 26))	('MG132', 'Var', (9, 14))	('MG132', 'Chemical', 'MESH:C072553', (9, 14))	('Cat', 'molecular_function', 'GO:0004096', ('23', '26'))
34061	32128917	In the renal clear cell carcinoma (KIRC) group, high BMP8A expression indicates a poor prognosis, and the difference is statistically significant (P < 0.001; Figure 1C).	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (7, 33))	('BMP8A', 'Gene', (53, 58))	('si', 'Chemical', 'MESH:D012825', (93, 95))	('renal clear cell carcinoma', 'Disease', (7, 33))	('si', 'Chemical', 'MESH:D012825', (134, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('expression', 'MPA', (59, 69))	('BMP8A', 'Gene', '353500', (53, 58))	('high', 'Var', (48, 52))	('si', 'Chemical', 'MESH:D012825', (65, 67))
34081	32128917	It was worth noting that casp.3/7 activity increased significantly after treatment with As2O3 in BMP8A KD cells (Figure 2I).	('activity', 'MPA', (34, 42))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('BMP8A', 'Gene', '353500', (97, 102))	('As2O3', 'Chemical', 'MESH:D000077237', (88, 93))	('casp.3/7', 'Gene', (25, 33))	('As2O3', 'Var', (88, 93))	('increased', 'PosReg', (43, 52))	('casp.3/7', 'Gene', '836;840', (25, 33))	('BMP8A', 'Gene', (97, 102))
34101	32128917	By analyzing the quantitative curve, we found that the half-life of Nrf2 in the si-Ctl group was approximately 4 hours, and in the BMP8A KD group it was probably down to 1 hour in 786-O (Figure 3J).	('Nrf2', 'Gene', (68, 72))	('si-Ctl', 'Var', (80, 86))	('BMP8A', 'Gene', '353500', (131, 136))	('Nrf2', 'Gene', '4780', (68, 72))	('BMP8A', 'Gene', (131, 136))	('si', 'Chemical', 'MESH:D012825', (80, 82))
34111	32128917	This suggests that in addition to the mechanism of apoptosis caused by Nrf2-mediated ROS imbalance, there are other regulatory pathways.	('Nrf2', 'Gene', (71, 75))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('apoptosis', 'biological_process', 'GO:0097194', ('51', '60'))	('apoptosis', 'biological_process', 'GO:0006915', ('51', '60'))	('imbalance', 'Var', (89, 98))	('ROS', 'MPA', (85, 88))	('imbalance', 'Phenotype', 'HP:0002172', (89, 98))	('Nrf2', 'Gene', '4780', (71, 75))	('ROS', 'Chemical', 'MESH:D017382', (85, 88))
34127	32128917	In addition, we analyzed the proliferation of cells with the above treatment and found that BMP8A stimulation also accelerated the proliferation of 786-O and ACHN, while the knockdown of Nrf2 restored this change (Figure 4L).	('BMP8A', 'Gene', (92, 97))	('accelerated', 'PosReg', (115, 126))	('ACHN', 'Gene', '55323', (158, 162))	('proliferation', 'CPA', (131, 144))	('Nrf2', 'Gene', '4780', (187, 191))	('BMP8A', 'Gene', '353500', (92, 97))	('knockdown', 'Var', (174, 183))	('ACHN', 'Gene', (158, 162))	('Nrf2', 'Gene', (187, 191))
34154	32128917	Si-Ctl xenografts grew more rapidly than those with BMP8A KD, and the difference in average tumor volume continued to increase to approximately 2.5-fold at the experimental endpoint (Figure 6F, G).	('grew', 'CPA', (18, 22))	('BMP8A', 'Gene', '353500', (52, 57))	('increase', 'PosReg', (118, 126))	('Si-Ctl', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('BMP8A', 'Gene', (52, 57))	('tumor', 'Disease', (92, 97))
34161	32128917	In view of the above-identified antioxidant activity of BMP8A, we further examined whether the ROS can increase the chemosensitivity of ccRCC to As2O3.	('RCC', 'Disease', (138, 141))	('increase', 'PosReg', (103, 111))	('As2O3', 'Chemical', 'MESH:D000077237', (145, 150))	('BMP8A', 'Gene', '353500', (56, 61))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('antioxidant activity', 'molecular_function', 'GO:0016209', ('32', '52'))	('chemosensitivity', 'MPA', (116, 132))	('ROS', 'Var', (95, 98))	('BMP8A', 'Gene', (56, 61))	('antioxidant', 'MPA', (32, 43))	('ROS', 'Chemical', 'MESH:D017382', (95, 98))	('si', 'Chemical', 'MESH:D012825', (124, 126))
34163	32128917	Similarly, As2O3 upregulated the dead cell ratio in BMP8A KD cells by Trypan Blue Staining (Figure 7B).	('BMP8A', 'Gene', '353500', (52, 57))	('As2O3', 'Chemical', 'MESH:D000077237', (11, 16))	('As2O3', 'Var', (11, 16))	('upregulated', 'PosReg', (17, 28))	('BMP8A', 'Gene', (52, 57))	('dead cell ratio', 'CPA', (33, 48))	('Trypan Blue', 'Chemical', 'MESH:D014343', (70, 81))
34166	32128917	Previous studies have shown that As2O3 has an inhibitory effect on the Wnt pathway in blood tumors.	('blood tumors', 'Disease', 'MESH:D007022', (86, 98))	('blood tumors', 'Disease', (86, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('As2O3', 'Var', (33, 38))	('As2O3', 'Chemical', 'MESH:D000077237', (33, 38))	('blood tumors', 'Phenotype', 'HP:0004377', (86, 98))	('inhibitory', 'NegReg', (46, 56))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('Wnt pathway', 'Pathway', (71, 82))
34169	32128917	Conversely, BMP8A KD reversed this process and As2O3 can inhibit the activity of Wnt pathway to a greater extent (Figure 7D, E).	('Wnt pathway', 'Pathway', (81, 92))	('activity', 'MPA', (69, 77))	('BMP8A', 'Gene', (12, 17))	('inhibit', 'NegReg', (57, 64))	('BMP8A', 'Gene', '353500', (12, 17))	('As2O3', 'Var', (47, 52))	('As2O3', 'Chemical', 'MESH:D000077237', (47, 52))
34171	32128917	In contrast, BMP8A KD inhibits the EMT process, and As2O3 further strengthens this therapeutic effect (Figure 7F, G).	('As2O3', 'Var', (52, 57))	('As2O3', 'Chemical', 'MESH:D000077237', (52, 57))	('EMT', 'Gene', (35, 38))	('BMP8A', 'Gene', (13, 18))	('EMT', 'Gene', '3702', (35, 38))	('EMT', 'biological_process', 'GO:0001837', ('35', '38'))	('inhibits', 'NegReg', (22, 30))	('strengthens', 'PosReg', (66, 77))	('BMP8A', 'Gene', '353500', (13, 18))
34172	32128917	The above data indicated that BMP8A stabilized the ROS balance and activated the Wnt pathway by regulating Nrf2-TRIM24, and As2O3 can break the ROS balance and inhibit Wnt pathway activity.	('TRIM24', 'Gene', '8805', (112, 118))	('Wnt pathway', 'Pathway', (81, 92))	('activated', 'PosReg', (67, 76))	('inhibit', 'NegReg', (160, 167))	('BMP8A', 'Gene', (30, 35))	('TRIM24', 'Gene', (112, 118))	('As2O3', 'Var', (124, 129))	('break', 'NegReg', (134, 139))	('Wnt pathway', 'Pathway', (168, 179))	('ROS', 'Chemical', 'MESH:D017382', (51, 54))	('Nrf2', 'Gene', '4780', (107, 111))	('As2O3', 'Chemical', 'MESH:D000077237', (124, 129))	('regulating', 'Reg', (96, 106))	('ROS', 'Chemical', 'MESH:D017382', (144, 147))	('ROS balance', 'MPA', (144, 155))	('BMP8A', 'Gene', '353500', (30, 35))	('Nrf2', 'Gene', (107, 111))	('ROS balance', 'MPA', (51, 62))
34173	32128917	Therefore, BMP8A KD with As2O3 has a better therapeutic effect at the in vitro level of ccRCC.	('As2O3', 'Var', (25, 30))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('As2O3', 'Chemical', 'MESH:D000077237', (25, 30))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('BMP8A', 'Gene', (11, 16))	('therapeutic effect', 'CPA', (44, 62))	('BMP8A', 'Gene', '353500', (11, 16))	('RCC', 'Disease', (90, 93))
34174	32128917	Substantially consistent with the results of in vitro experiments, the subcutaneous tumor model further showed that As2O3 had a mild inhibitory effect on tumor growth derived from ACHN/si-Ctl, but completely delayed the growth of BMP8A KD tumors (Figure 7H, I).	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('KD tumors', 'Disease', (236, 245))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('As2O3', 'Var', (116, 121))	('ACHN', 'Gene', '55323', (180, 184))	('growth', 'MPA', (220, 226))	('si', 'Chemical', 'MESH:D012825', (185, 187))	('BMP8A', 'Gene', '353500', (230, 235))	('KD tumors', 'Disease', 'MESH:C537017', (236, 245))	('tumor', 'Disease', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (71, 89))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('As2O3', 'Chemical', 'MESH:D000077237', (116, 121))	('tumor', 'Disease', (239, 244))	('delayed', 'NegReg', (208, 215))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('inhibitory effect', 'MPA', (133, 150))	('BMP8A', 'Gene', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('ACHN', 'Gene', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Disease', (84, 89))
34175	32128917	As2O3 had no significant effect on body weight, suggesting that BMP8A KD cells became more sensitive to As2O3 treatment and had good biological safety (Figures S2J and 7J).	('si', 'Chemical', 'MESH:D012825', (13, 15))	('As2O3', 'Var', (104, 109))	('As2O3', 'Chemical', 'MESH:D000077237', (104, 109))	('sensitive', 'MPA', (91, 100))	('BMP8A', 'Gene', (64, 69))	('As2O3', 'Chemical', 'MESH:D000077237', (0, 5))	('BMP8A', 'Gene', '353500', (64, 69))	('si', 'Chemical', 'MESH:D012825', (94, 96))
34177	32128917	In BMP8A KD xenografts, As2O3 obviously induced the expression of proapoptotic makers.	('As2O3', 'Var', (24, 29))	('BMP8A', 'Gene', (3, 8))	('expression of', 'MPA', (52, 65))	('induced', 'PosReg', (40, 47))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('As2O3', 'Chemical', 'MESH:D000077237', (24, 29))	('BMP8A', 'Gene', '353500', (3, 8))
34179	32128917	These results show that BMP8A inhibition enhances the As2O3 efficacy of elevated ROS levels and inhibits the Wnt pathway in chemotherapy for ccRCC by inhibiting Nrf2.	('elevated', 'PosReg', (72, 80))	('inhibits', 'NegReg', (96, 104))	('Wnt pathway', 'Pathway', (109, 120))	('inhibiting', 'NegReg', (150, 160))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('inhibition', 'Var', (30, 40))	('Nrf2', 'Gene', '4780', (161, 165))	('ccRCC', 'Phenotype', 'HP:0006770', (141, 146))	('Nrf2', 'Gene', (161, 165))	('As2O3', 'Chemical', 'MESH:D000077237', (54, 59))	('BMP8A', 'Gene', (24, 29))	('enhances', 'PosReg', (41, 49))	('elevated ROS levels', 'Phenotype', 'HP:0025464', (72, 91))	('ROS levels', 'MPA', (81, 91))	('RCC', 'Disease', (143, 146))	('ROS', 'Chemical', 'MESH:D017382', (81, 84))	('BMP8A', 'Gene', '353500', (24, 29))	('As2O3 efficacy', 'MPA', (54, 68))
34288	30799949	The differences in the expression of Nrf2 and HO-1 in ccRCC were associated with a statistically significant difference in survival curves (Nrf2: chi2=4.127, P=0.042; HO-1: chi2=4.846, P=0.028) (Figure 4 and Table 4).	('Nrf2', 'Gene', '4780', (140, 144))	('difference', 'Reg', (109, 119))	('HO-1', 'Gene', '3162', (167, 171))	('RCC', 'Disease', (56, 59))	('differences', 'Var', (4, 15))	('Nrf2', 'Gene', (37, 41))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('Nrf2', 'Gene', (140, 144))	('HO-1', 'Gene', (46, 50))	('HO-1', 'Gene', (167, 171))	('HO-1', 'Gene', '3162', (46, 50))	('Nrf2', 'Gene', '4780', (37, 41))	('expression', 'MPA', (23, 33))
34318	30799949	Kaplan-Meier survival estimates suggested that patients with high expression of Nrf2 or HO-1 tended to have a worse prognosis than those with low expression levels of the two proteins, whereas patients with high expression levels of Nrf2 or HO-1 in cancer tissues but not in paracancerous tissues had the worst prognosis of all the subgroups analyzed.	('Nrf2', 'Gene', '4780', (233, 237))	('HO-1', 'Gene', '3162', (241, 245))	('patients', 'Species', '9606', (47, 55))	('cancer', 'Disease', (249, 255))	('HO-1', 'Gene', '3162', (88, 92))	('cancer', 'Disease', (279, 285))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('HO-1', 'Gene', (241, 245))	('HO-1', 'Gene', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('Nrf2', 'Gene', '4780', (80, 84))	('Nrf2', 'Gene', (233, 237))	('patients', 'Species', '9606', (193, 201))	('or', 'Chemical', 'MESH:C034130', (238, 240))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('Nrf2', 'Gene', (80, 84))	('or', 'Chemical', 'MESH:C034130', (111, 113))	('high expression', 'Var', (61, 76))	('or', 'Chemical', 'MESH:C034130', (85, 87))	('or', 'Chemical', 'MESH:C034130', (306, 308))
34324	30799949	Shibata et al found that mutant Nrf2 promoted cell growth and insensitivity to 5-fluorouracil and gamma-irradiation.	('Nrf2', 'Gene', (32, 36))	('mutant', 'Var', (25, 31))	('promoted', 'PosReg', (37, 45))	('cell growth', 'CPA', (46, 57))	('Nrf2', 'Gene', '4780', (32, 36))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (79, 93))	('cell growth', 'biological_process', 'GO:0016049', ('46', '57'))	('insensitivity', 'MPA', (62, 75))
34338	33947447	Methylation of GREM1, GATA5, LAD1, NEFH, NEURL, and SFRP1 was associated with poor ccRCC-specific survival, independent of age, sex, tumor size, TNM stage or tumor grade.	('SFRP1', 'Gene', '6422', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('NEURL', 'Gene', (41, 46))	('associated', 'Reg', (62, 72))	('Methylation', 'Var', (0, 11))	('TNM', 'Gene', '10178', (145, 148))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('TNM', 'Gene', (145, 148))	('GREM1', 'Gene', '26585', (15, 20))	('NEFH', 'Gene', '4744', (35, 39))	('GREM1', 'Gene', (15, 20))	('SFRP1', 'Gene', (52, 57))	('NEURL', 'Gene', '9148', (41, 46))	('tumor', 'Disease', (133, 138))	('GATA5', 'Gene', (22, 27))	('NEFH', 'Gene', (35, 39))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('poor', 'NegReg', (78, 82))	('RCC', 'Disease', (85, 88))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('GATA5', 'Gene', '140628', (22, 27))	('LAD1', 'Gene', (29, 33))
34339	33947447	Moreover, the association between GREM1, NEFH, and NEURL methylation and outcome was shown to be dependent on the genomic region.	('methylation', 'Var', (57, 68))	('GREM1', 'Gene', '26585', (34, 39))	('NEFH', 'Gene', '4744', (41, 45))	('NEFH', 'Gene', (41, 45))	('NEURL', 'Gene', '9148', (51, 56))	('GREM1', 'Gene', (34, 39))	('methylation', 'biological_process', 'GO:0032259', ('57', '68'))	('NEURL', 'Gene', (51, 56))
34361	33947447	We therefore applied the approach that we recently developed using publicly available DNA methylation data from The Cancer Genome Atlas (TCGA) to determine the genomic location of methylation that is most likely to be clinically relevant and thus represents the optimal location for methylation assay development.	('Cancer', 'Disease', (116, 122))	('Cancer', 'Phenotype', 'HP:0002664', (116, 122))	('Cancer', 'Disease', 'MESH:D009369', (116, 122))	('methylation', 'biological_process', 'GO:0032259', ('180', '191'))	('methylation', 'biological_process', 'GO:0032259', ('283', '294'))	('men', 'Species', '9606', (308, 311))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('DNA methylation', 'biological_process', 'GO:0006306', ('86', '101'))	('methylation', 'Var', (180, 191))
34418	33947447	The methylation status of GREM1 (region i), LAD1 (region i and ii), NEFH (region i), NEURL (region ii), SFRP1, and GATA5 was significantly associated with poorer ccRCC-specific survival (log-rank test, P <= 0.0001-0.0117, Additional file 1: Fig.	('LAD1', 'Gene', (44, 48))	('GREM1', 'Gene', (26, 31))	('NEFH', 'Gene', (68, 72))	('NEFH', 'Gene', '4744', (68, 72))	('SFRP1', 'Gene', '6422', (104, 109))	('NEURL', 'Gene', '9148', (85, 90))	('NEURL', 'Gene', (85, 90))	('GATA5', 'Gene', (115, 120))	('poorer', 'NegReg', (155, 161))	('GATA5', 'Gene', '140628', (115, 120))	('SFRP1', 'Gene', (104, 109))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('RCC', 'Disease', (164, 167))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('methylation status', 'Var', (4, 22))	('GREM1', 'Gene', '26585', (26, 31))
34419	33947447	Notably, the association between methylation of GREM1, NEFH, NEURL and patient outcome was dependent on the region that is methylated.	('methylation', 'biological_process', 'GO:0032259', ('33', '44'))	('NEURL', 'Gene', '9148', (61, 66))	('methylation', 'Var', (33, 44))	('NEURL', 'Gene', (61, 66))	('GREM1', 'Gene', '26585', (48, 53))	('GREM1', 'Gene', (48, 53))	('NEFH', 'Gene', (55, 59))	('NEFH', 'Gene', '4744', (55, 59))	('patient', 'Species', '9606', (71, 78))
34420	33947447	For GREM1, only methylation of the region located most upstream of the TSS (GREM1-i) was associated with patient outcome (log-rank test, P = 0.0022), while for the other two regions no significant association with survival was found (log-rank test, GREM1-ii P = 0.5662 and GREM1-iii P = 0.2102).	('associated with', 'Reg', (89, 104))	('GREM1', 'Gene', (249, 254))	('patient', 'Species', '9606', (105, 112))	('GREM1', 'Gene', (273, 278))	('GREM1', 'Gene', '26585', (4, 9))	('methylation', 'biological_process', 'GO:0032259', ('16', '27'))	('GREM1', 'Gene', '26585', (249, 254))	('GREM1', 'Gene', (4, 9))	('GREM1', 'Gene', '26585', (76, 81))	('GREM1', 'Gene', '26585', (273, 278))	('GREM1', 'Gene', (76, 81))	('methylation', 'Var', (16, 27))
34421	33947447	Also, for NEFH and NEURL, methylation of only one of the two studied regions was associated with ccRCC-specific survival (log-rank test, NEFH-i P = 0.0067 versus NEFH-ii P = 0.9680 and NEURL-i P = 0.1533 versus NEURL-ii P = 0.0010).	('methylation', 'Var', (26, 37))	('associated with', 'Reg', (81, 96))	('NEURL', 'Gene', (19, 24))	('NEFH', 'Gene', (137, 141))	('NEFH', 'Gene', '4744', (137, 141))	('NEURL', 'Gene', '9148', (211, 216))	('NEURL', 'Gene', (211, 216))	('NEURL', 'Gene', '9148', (185, 190))	('NEFH', 'Gene', (10, 14))	('NEFH', 'Gene', '4744', (10, 14))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('NEURL', 'Gene', (185, 190))	('RCC', 'Disease', (99, 102))	('NEFH', 'Gene', (162, 166))	('NEFH', 'Gene', '4744', (162, 166))	('NEURL', 'Gene', '9148', (19, 24))
34423	33947447	In multivariate analyses, methylation of GREM1-i, LAD1-i, LAD1-ii, NEFH-i, NEURL-ii, SFRP1, and GATA5 remained statistically significant predictors of poor survival (HRGREM1-i 1.86 (95% CI 1.16-2.97), HRLAD1-i 2.26 (95% CI 1.47-3.48), HRLAD1-ii 1.71 (95% CI 1.12-2.61), HRNEFH-i 1.74 (95% CI 1.11-2.74), HRNEURL-ii 1.94 (95% CI 1.21-3.13), HRSFRP1 1.89 (95% CI 1.16-3.08), and HRGATA5 1.67 (95% CI 1.08-2.60) (Additional file 1: Table S11).	('NEURL', 'Gene', '9148', (306, 311))	('NEURL', 'Gene', '9148', (75, 80))	('NEFH', 'Gene', '4744', (67, 71))	('GATA5', 'Gene', (96, 101))	('GREM1', 'Gene', '26585', (168, 173))	('poor survival', 'CPA', (151, 164))	('GREM1', 'Gene', '26585', (41, 46))	('SFRP1', 'Gene', '6422', (342, 347))	('GREM1', 'Gene', (168, 173))	('NEFH', 'Gene', '4744', (272, 276))	('GREM1', 'Gene', (41, 46))	('NEFH', 'Gene', (67, 71))	('SFRP1', 'Gene', (85, 90))	('GATA5', 'Gene', '140628', (96, 101))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('GATA5', 'Gene', (379, 384))	('NEFH', 'Gene', (272, 276))	('NEURL', 'Gene', (306, 311))	('methylation', 'Var', (26, 37))	('NEURL', 'Gene', (75, 80))	('GATA5', 'Gene', '140628', (379, 384))	('SFRP1', 'Gene', '6422', (85, 90))	('SFRP1', 'Gene', (342, 347))
34426	33947447	TNM stage, Fuhrman grade, and methylation of LAD1-ii were the most significant predictors of survival.	('LAD1-ii', 'Gene', (45, 52))	('TNM', 'Gene', '10178', (0, 3))	('methylation', 'Var', (30, 41))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('TNM', 'Gene', (0, 3))
34452	33947447	It has been reported that hypermethylation of GATA5 is associated with metastasis and progression-free survival of RCC patients.	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('patients', 'Species', '9606', (119, 127))	('associated', 'Reg', (55, 65))	('RCC', 'Disease', (115, 118))	('metastasis', 'CPA', (71, 81))	('GATA5', 'Gene', (46, 51))	('GATA5', 'Gene', '140628', (46, 51))	('hypermethylation', 'Var', (26, 42))	('progression-free survival', 'CPA', (86, 111))
34469	33941190	Inhibition of KIF20A by transcription factor IRF6 affects the progression of renal clear cell carcinoma Renal clear cell carcinoma (ccRCC) is one of the most common malignant tumors, whose incidence is increasing year by year.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('transcription factor', 'molecular_function', 'GO:0000981', ('24', '44'))	('malignant tumors', 'Disease', (165, 181))	('malignant tumors', 'Disease', 'MESH:D009369', (165, 181))	('IRF6', 'Gene', (45, 49))	('IRF6', 'Gene', '3664', (45, 49))	('Renal clear cell carcinoma', 'Disease', (104, 130))	('KIF20A', 'Gene', (14, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('affects', 'Reg', (50, 57))	('KIF20A', 'Gene', '10112', (14, 20))	('Inhibition', 'Var', (0, 10))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (77, 103))	('Renal clear cell carcinoma', 'Disease', 'MESH:C538614', (104, 130))	('renal clear cell carcinoma', 'Disease', (77, 103))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('clear cell carcinoma Renal clear cell carcinoma', 'Phenotype', 'HP:0006770', (83, 130))	('progression', 'MPA', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('transcription', 'biological_process', 'GO:0006351', ('24', '37'))
34488	33941190	Six hub genes (CCNB2, CDC20, CEP55, KIF20A, TOP2A and UBE2C) of ccRCC, identified through the co-expression network of GSE40435 and GSE53757 database and PPI, are closely correlated with pathological stage and poor prognosis.	('CEP55', 'Gene', '55165', (29, 34))	('CEP55', 'Gene', (29, 34))	('GSE40435', 'Var', (119, 127))	('CCNB2', 'Gene', '9133', (15, 20))	('UBE2C', 'Gene', '11065', (54, 59))	('CEP', 'molecular_function', 'GO:0047849', ('29', '32'))	('hub', 'Gene', '1993', (4, 7))	('CDC20', 'Gene', (22, 27))	('CDC20', 'Gene', '991', (22, 27))	('KIF20A', 'Gene', (36, 42))	('correlated', 'Reg', (171, 181))	('PPI', 'biological_process', 'GO:0060134', ('154', '157'))	('TOP2A', 'Gene', '7153', (44, 49))	('KIF20A', 'Gene', '10112', (36, 42))	('CCNB2', 'Gene', (15, 20))	('TOP2A', 'Gene', (44, 49))	('hub', 'Gene', (4, 7))	('UBE2C', 'Gene', (54, 59))
34491	33941190	However, none of these studies functionally described the role of KIF20A overexpression and knockout in ccRCC.	('knockout', 'Var', (92, 100))	('KIF20A', 'Gene', '10112', (66, 72))	('KIF20A', 'Gene', (66, 72))	('ccRCC', 'Disease', (104, 109))
34510	33941190	The membrane was blocked with 5% milk in Tris-buffered saline/Tween-20 for 1 h at room temperature, and then probed overnight at 4  C with the following primary antibodies: anti-IRF6 (1:1000; ab123880; Abcam, Cambridge, MA), anti- KIF20A (1:1000; ab7091; Abcam, Cambridge, MA) (Santa Cruz Biotechnology, Santa Cruz, CA), and anti-GAPDH (ab75478; Abcam, Cambridge, MA).	('ab123880', 'Var', (192, 200))	('Tris-buffered saline', 'Chemical', '-', (41, 61))	('Tween-20', 'Chemical', 'MESH:D011136', (62, 70))	('GAPDH', 'Gene', '2597', (330, 335))	('1:1000', 'Var', (184, 190))	('GAPDH', 'Gene', (330, 335))	('KIF20A', 'Gene', (231, 237))	('KIF20A', 'Gene', '10112', (231, 237))	('membrane', 'cellular_component', 'GO:0016020', ('4', '12'))
34535	33941190	Interference with KIF20A can significantly inhibit proliferation, invasion and migration of renal clear cell carcinoma (Additional file 1: Fig S2-4).	('KIF20A', 'Gene', (18, 24))	('migration', 'CPA', (79, 88))	('inhibit', 'NegReg', (43, 50))	('proliferation', 'CPA', (51, 64))	('KIF20A', 'Gene', '10112', (18, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (92, 118))	('Interference', 'Var', (0, 12))	('invasion', 'CPA', (66, 74))	('renal clear cell carcinoma', 'Disease', (92, 118))
34539	33941190	Luciferase assay detected the transcriptional activity of KIF20A promoter mutant in ccRCC cells (Fig.	('ccRCC', 'Disease', (84, 89))	('KIF20A', 'Gene', '10112', (58, 64))	('mutant', 'Var', (74, 80))	('transcriptional activity', 'MPA', (30, 54))	('KIF20A', 'Gene', (58, 64))
34546	33941190	7c) were found as the interference with IRF6 expression up-regulated the expression of KIF20A.	('IRF6', 'Gene', (40, 44))	('KIF20A', 'Gene', (87, 93))	('up-regulated', 'PosReg', (56, 68))	('interference', 'Var', (22, 34))	('KIF20A', 'Gene', '10112', (87, 93))	('expression', 'MPA', (73, 83))
34556	33941190	In addition, the expression of Ki67 was detected by IHC and was found to be significantly decreased in the Oe-IRF6 group, compared with Oe-NC (Fig.	('Ki67', 'Gene', (31, 35))	('expression', 'MPA', (17, 27))	('Ki67', 'Gene', '17345', (31, 35))	('decreased', 'NegReg', (90, 99))	('Oe-IRF6', 'Var', (107, 114))
34567	33941190	These results indicate that IRF6 can inhibit the proliferation, invasion and migration of tumor cells in a variety of tumors.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('invasion', 'CPA', (64, 72))	('proliferation', 'CPA', (49, 62))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('inhibit', 'NegReg', (37, 44))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Disease', (118, 123))	('tumors', 'Disease', (118, 124))	('IRF6', 'Var', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
34573	33941190	In soft tissue sarcoma, KIF20A gene knockout can inhibit the proliferation, migration and invasion of soft tissue sarcoma cells, promote cell apoptosis, and inhibit tumor growth.	('knockout', 'Var', (36, 44))	('promote', 'PosReg', (129, 136))	('sarcoma', 'Disease', 'MESH:D012509', (15, 22))	('sarcoma', 'Disease', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('apoptosis', 'biological_process', 'GO:0097194', ('142', '151'))	('apoptosis', 'biological_process', 'GO:0006915', ('142', '151'))	('cell apoptosis', 'CPA', (137, 151))	('inhibit', 'NegReg', (157, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (15, 22))	('proliferation', 'CPA', (61, 74))	('invasion', 'CPA', (90, 98))	('sarcoma', 'Disease', 'MESH:D012509', (114, 121))	('sarcoma', 'Disease', (114, 121))	('migration', 'CPA', (76, 85))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (102, 121))	('KIF20A', 'Gene', (24, 30))	('tumor', 'Disease', (165, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (3, 22))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('inhibit', 'NegReg', (49, 56))	('KIF20A', 'Gene', '10112', (24, 30))
34575	33941190	In our study, we found that the expression of KIF20A was significantly increased in ccRCC, and that interfering with KIF20A inhibited cell proliferation, invasion and migration.	('cell proliferation', 'CPA', (134, 152))	('ccRCC', 'Disease', (84, 89))	('KIF20A', 'Gene', '10112', (117, 123))	('KIF20A', 'Gene', (46, 52))	('interfering', 'Var', (100, 111))	('KIF20A', 'Gene', '10112', (46, 52))	('increased', 'PosReg', (71, 80))	('expression', 'MPA', (32, 42))	('inhibited', 'NegReg', (124, 133))	('cell proliferation', 'biological_process', 'GO:0008283', ('134', '152'))	('KIF20A', 'Gene', (117, 123))
34588	31655797	Overexpression of steroid SULT genes was associated with worsened prognosis.	('steroid', 'Chemical', 'MESH:D013256', (18, 25))	('steroid SULT genes', 'Gene', (18, 36))	('Overexpression', 'Var', (0, 14))
34589	31655797	Steroid SULT gene-upregulated ccRCC cases showed mutual exclusivity with mutations of VHL, SETD2 and PBRM1, and with focal deletions of 3p and 9p, respectively.	('SETD2', 'Gene', '29072', (91, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('gene-upregulated', 'PosReg', (13, 29))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('SETD2', 'Gene', (91, 96))	('Steroid', 'Chemical', 'MESH:D013256', (0, 7))	('VHL', 'Disease', (86, 89))	('ccRCC', 'Disease', (30, 35))	('VHL', 'Disease', 'MESH:D006623', (86, 89))	('ccRCC', 'Disease', 'MESH:D002292', (30, 35))	('PBRM1', 'Gene', (101, 106))	('mutations', 'Var', (73, 82))	('PBRM1', 'Gene', '55193', (101, 106))
34593	31655797	Conclusion: Steroid SULT genes were associated with worsened prognosis and with immune exclusion in ccRCC.	('Steroid', 'Var', (12, 19))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('worsened', 'PosReg', (52, 60))	('Steroid', 'Chemical', 'MESH:D013256', (12, 19))	('ccRCC', 'Disease', (100, 105))	('prognosis', 'MPA', (61, 70))	('ccRCC', 'Disease', 'MESH:D002292', (100, 105))
34604	31655797	34324q `123 disease-free and overall survival in patients with pancreatic ductal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('34324q `', 'Var', (0, 8))	('disease-free', 'Disease', (12, 24))	('overall survival', 'CPA', (29, 45))	('patients', 'Species', '9606', (49, 57))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (63, 95))	('pancreatic ductal adenocarcinoma', 'Disease', (63, 95))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (63, 95))
34621	31655797	We found that alteration of steroid of SULT genes was mutually exclusive with mutations of VHL, SETD2, and PBRM1, respectively, but not with that of BAP1 (Figure 2A).	('alteration', 'Reg', (14, 24))	('BAP1', 'Gene', '8314', (149, 153))	('steroid', 'Chemical', 'MESH:D013256', (28, 35))	('PBRM1', 'Gene', '55193', (107, 112))	('mutations', 'Var', (78, 87))	('steroid', 'MPA', (28, 35))	('BAP1', 'Gene', (149, 153))	('PBRM1', 'Gene', (107, 112))	('SULT genes', 'Gene', (39, 49))	('SETD2', 'Gene', '29072', (96, 101))	('VHL', 'Disease', 'MESH:D006623', (91, 94))	('SETD2', 'Gene', (96, 101))	('VHL', 'Disease', (91, 94))
34623	31655797	We found that neither 3p loss nor 5q gain showed mutual exclusivity or co-occurrence, whereas loss of 9p showed significant mutual exclusivity with steroid SULT gene alteration (Figure 2A).	('loss', 'NegReg', (25, 29))	('steroid', 'Chemical', 'MESH:D013256', (148, 155))	('loss', 'Var', (94, 98))
34642	31655797	SULT2B1 silencing significantly increased population in G1 phase and SULT2B1 overexpression significantly decreased population in G1 phase in both cell lines (Figure 4E).	('decreased', 'NegReg', (106, 115))	('SULT2B1', 'Gene', (0, 7))	('silencing', 'Var', (8, 17))	('SULT2B1', 'Gene', '6820', (0, 7))	('SULT2B1', 'Gene', (69, 76))	('increased', 'PosReg', (32, 41))	('G1 phase', 'biological_process', 'GO:0051318', ('130', '138'))	('SULT2B1', 'Gene', '6820', (69, 76))	('G1 phase', 'biological_process', 'GO:0051318', ('56', '64'))
34643	31655797	SULT2B1 silencing significantly decreased apoptosis and SULT2B1 overexpression significantly increased apoptosis (Figure 4F).	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('SULT2B1', 'Gene', (0, 7))	('SULT2B1', 'Gene', '6820', (56, 63))	('silencing', 'Var', (8, 17))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('SULT2B1', 'Gene', '6820', (0, 7))	('apoptosis', 'CPA', (42, 51))	('SULT2B1', 'Gene', (56, 63))	('apoptosis', 'biological_process', 'GO:0097194', ('42', '51'))	('apoptosis', 'biological_process', 'GO:0006915', ('42', '51'))	('apoptosis', 'CPA', (103, 112))	('decreased', 'NegReg', (32, 41))
34644	31655797	Transwell assays showed SULT2B1 silencing significantly decreased invasion and migration in both cell lines and SULT2B1 overexpression significantly increased invasion and migration (Figure 4G) as well as anchorage-independent growth profiled by colony formation assay (Figure 4H).	('SULT2B1', 'Gene', (112, 119))	('formation', 'biological_process', 'GO:0009058', ('253', '262'))	('overexpression', 'PosReg', (120, 134))	('increased', 'PosReg', (149, 158))	('SULT2B1', 'Gene', '6820', (112, 119))	('decreased', 'NegReg', (56, 65))	('SULT2B1', 'Gene', (24, 31))	('silencing', 'Var', (32, 41))	('SULT2B1', 'Gene', '6820', (24, 31))	('invasion', 'CPA', (159, 167))	('anchorage-independent growth', 'CPA', (205, 233))
34663	31655797	Loss of 9p which features CDKN2A deletion has been established to confer very poor prognosis in ccRCC and this population harbors a series of other genetic alterations that may be secondary to the chromosomal alteration.	('CDKN2A', 'Gene', (26, 32))	('deletion', 'Var', (33, 41))	('CDKN2A', 'Gene', '1029', (26, 32))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('ccRCC', 'Disease', (96, 101))	('ccRCC', 'Disease', 'MESH:D002292', (96, 101))
34702	33759329	Abstract   From:  Furthermore, the aberrant translational efficiency of some codons in cancer, exemplified by ProCCA and GlyGGT, is associated with poor patient survival.	('cancer', 'Disease', (87, 93))	('poor', 'NegReg', (148, 152))	('aberrant', 'Var', (35, 43))	('GlyGGT', 'Chemical', '-', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ProCCA', 'Chemical', '-', (110, 116))	('patient', 'Species', '9606', (153, 160))	('associated', 'Reg', (132, 142))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('translational efficiency', 'MPA', (44, 68))
34703	33759329	To:  Furthermore, the aberrant translational efficiency of some codons in cancer, exemplified by ArgAGA, is associated with poor patient survival.	('aberrant', 'Var', (22, 30))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('translational efficiency', 'MPA', (31, 55))	('cancer', 'Disease', (74, 80))	('associated', 'Reg', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('poor', 'NegReg', (124, 128))	('patient', 'Species', '9606', (129, 136))
34709	33759329	Results, section "Aberrant translational efficiencies drive tumor progression"   From:  Among the most consistent changes, the ProCCA codon is significantly more favored in tumors for 8 out of 10 cancer types, while the ProCCG is disfavored in 14 out of 16 cancers (Fig 4B).	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('ProCCA', 'Chemical', '-', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('Aberrant', 'Var', (18, 26))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Disease', (60, 65))	('favored', 'PosReg', (162, 169))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('tumors', 'Disease', (173, 179))	('cancers', 'Disease', 'MESH:D009369', (257, 264))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cancer', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', (257, 263))	('tumor', 'Disease', (173, 178))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('cancers', 'Disease', (257, 264))
34711	33759329	Among the most consistent changes, the ArgAGA codon is significantly more favored in tumors for 15 out of 15 cancer types, while the ArgCGG is disfavored in 7 out of 11 cancers (Fig 4B).	('cancers', 'Disease', (169, 176))	('cancer', 'Disease', (169, 175))	('cancers', 'Disease', 'MESH:D009369', (169, 176))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ArgAGA', 'Var', (39, 45))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('favored', 'PosReg', (74, 81))	('ArgCGG', 'Chemical', '-', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('tumors', 'Disease', (85, 91))
34717	33759329	Arginine limitation in the kidney cell line HEK293T has been shown to compromise tRNAArg aminoacylation, leading to codon pausing and reduced cell viability (Darnell et al, 2018).	('Arginine limitation', 'Var', (0, 19))	('HEK293T', 'CellLine', 'CVCL:0063', (44, 51))	('codon pausing', 'MPA', (116, 129))	('Arginine', 'Chemical', 'MESH:D001120', (0, 8))	('cell viability', 'CPA', (142, 156))	('tRNAArg', 'Protein', (81, 88))	('compromise', 'NegReg', (70, 80))	('reduced', 'NegReg', (134, 141))	('aminoacylation', 'MPA', (89, 103))	('Arginine limitation', 'Phenotype', 'HP:0005961', (0, 19))
34718	33759329	In addition, low SDAw of ArgAGG and SerAGT lead to longer survival in kidney renal clear cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (70, 103))	('kidney renal clear cell carcinoma', 'Disease', (70, 103))	('longer', 'PosReg', (51, 57))	('low', 'Var', (13, 16))	('survival', 'MPA', (58, 66))
34738	33759329	To:  In particular, we detect the ArgAGA codon to be significantly more favored in proliferative cells and leading to poor cancer prognosis in kidney carcinoma, specifically driven by an overexpression of tRNAArgTCT in cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('overexpression', 'PosReg', (187, 201))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('kidney carcinoma', 'Disease', (143, 159))	('more', 'PosReg', (67, 71))	('poor', 'NegReg', (118, 122))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Disease', (123, 129))	('kidney carcinoma', 'Disease', 'MESH:D007680', (143, 159))	('cancer', 'Disease', (219, 225))	('ArgAGA codon', 'Var', (34, 46))	('kidney carcinoma', 'Phenotype', 'HP:0005584', (143, 159))
34739	33759329	Arginine limitation in the kidney cell line HEK293T has indeed been shown to compromise tRNAArg aminoacylation, leading to arginine codon pausing and reduced cell viability (Darnell et al, 2018).	('tRNAArg aminoacylation', 'MPA', (88, 110))	('cell viability', 'CPA', (158, 172))	('compromise', 'NegReg', (77, 87))	('arginine', 'Chemical', 'MESH:D001120', (123, 131))	('Arginine limitation', 'Var', (0, 19))	('arginine codon pausing', 'MPA', (123, 145))	('leading to', 'Reg', (112, 122))	('HEK293T', 'CellLine', 'CVCL:0063', (44, 51))	('Arginine', 'Chemical', 'MESH:D001120', (0, 8))	('reduced', 'NegReg', (150, 157))	('Arginine limitation', 'Phenotype', 'HP:0005961', (0, 19))
34752	33759329	To:  Differential promoter methylation (bisulfite sequencing) between healthy and tumor samples of genes expressing arginine tRNAs, as measured by Delta%Me=(%MeTumor- %MeHealthy).	('methylation', 'biological_process', 'GO:0032259', ('27', '38'))	('promoter methylation', 'MPA', (18, 38))	('arginine', 'Chemical', 'MESH:D001120', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('Differential', 'Reg', (5, 17))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('arginine tRNAs', 'Var', (116, 130))	('tumor', 'Disease', (82, 87))
34754	33759329	To:  Differential gene copy number between healthy and tumor samples of genes expressing arginine tRNAs, as measured by DeltaCNA.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('arginine', 'Chemical', 'MESH:D001120', (89, 97))	('tumor', 'Disease', (55, 60))	('arginine tRNAs', 'Var', (89, 103))
34771	28459850	The clonal theory of cancer is based on Darwinian models of natural selection in which genetically unstable cells acquire a somatic single nucleotide variant (SSNV), and selective pressure results in tumors with a biological fitness advantage for survival.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('biological fitness advantage', 'CPA', (214, 242))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (21, 27))	('single nucleotide variant', 'Var', (132, 157))	('results in', 'Reg', (189, 199))
34814	28459850	We obtained nine classes that represent a combination of cases in simulations I and II, named polyclonal-low trunk-accumulation (PL-TR), polyclonal-low balanced-accumulation (PL-BL), polyclonal-low branch-accumulation (PL-BR), polyclonal-middle trunk-accumulation (PM-TR), polyclonal-middle balanced-accumulation (PM-BL), polyclonal-middle branch-accumulation (PM-BR), polyclonal-high trunk-accumulation (PH-TR), polyclonal-high balanced-accumulation (PH-BL), and polyclonal-high branch-accumulation (PH-BR).	('trunk', 'cellular_component', 'GO:0043198', ('109', '114'))	('polyclonal-middle branch-accumulation', 'Disease', (322, 359))	('trunk', 'cellular_component', 'GO:0043198', ('385', '390'))	('polyclonal-middle branch-accumulation', 'Disease', 'MESH:D020244', (322, 359))	('trunk', 'cellular_component', 'GO:0043198', ('245', '250'))	('polyclonal-high', 'Var', (413, 428))	('polyclonal-high', 'Var', (369, 384))
34826	28459850	Cluster 1 reflects the drug-sensitive sub-clones group, and the result corresponds to the interpretation provided by Gerlinger et al.. Cases EV005, EV007, RMH004, RMH008, RK26, and RMH002 in cluster 2 acquired a large fraction of SSNVs in the sub-clones (Fig 4B-1).	('RK26', 'Var', (171, 175))	('RK26', 'CellLine', 'CVCL:3155', (171, 175))	('EV007', 'Var', (148, 153))	('EV005', 'Var', (141, 146))	('RMH004', 'Var', (155, 161))	('RMH008', 'Var', (163, 169))	('RMH002', 'Var', (181, 187))
34834	28459850	Some of the trees were classified with different cancer types, including case 330, case 4990, and case 356 in cluster 2, and EV003 and EV006 in cluster 1.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('EV006', 'Var', (135, 140))	('cancer type', 'Disease', (49, 60))	('EV003', 'Var', (125, 130))	('cancer type', 'Disease', 'MESH:D009369', (49, 60))
34836	28459850	EV003 and EV006 in the ccRCC dataset are samples of drug-sensitive tumors, and their tree shapes resemble those of NSCLC trees, which further supports that the drug interrupts the accumulation of SSNVs in the sub-clones.	('EV006', 'Var', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('NSCLC', 'Disease', (115, 120))	('EV003', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('interrupts', 'NegReg', (165, 175))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('accumulation', 'MPA', (180, 192))	('tumors', 'Disease', (67, 73))
34841	28459850	Second, we have here only considered the SSNVs accumulating in the evolutionary trees, ignoring potential copy number or epigenetic aberrations; however, these factors may also affect heterogeneity within a tumor.	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('affect', 'Reg', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('heterogeneity', 'MPA', (184, 197))	('tumor', 'Disease', (207, 212))	('epigenetic aberrations', 'Var', (121, 143))
34888	27891093	The CD133+ cell population can influence tumor vascularization and angiogenesis, and it is also expressed in normal adult human kidney cells.	('human', 'Species', '9606', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('angiogenesis', 'CPA', (67, 79))	('CD133+', 'Var', (4, 10))	('influence', 'Reg', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('angiogenesis', 'biological_process', 'GO:0001525', ('67', '79'))
34906	27891093	Undoubtedly, metastatic potential is improved by the expression of CD44, and metastatic properties are often linked to CSCs.	('CD44', 'Gene', '960', (67, 71))	('expression', 'Var', (53, 63))	('CD44', 'Gene', (67, 71))	('CSCs', 'Disease', (119, 123))	('improved', 'PosReg', (37, 45))	('metastatic potential', 'CPA', (13, 33))	('linked', 'Reg', (109, 115))	('metastatic properties', 'CPA', (77, 98))
34909	27891093	Meanwhile, a meta-analysis of the literature showed that CD44 was a poor prognostic marker for 5-year overall survival and that high CD44 expression levels were associated with high Fuhrman grade and recurrence.	('CD44', 'Gene', '960', (57, 61))	('CD44', 'Gene', '960', (133, 137))	('associated', 'Reg', (161, 171))	('expression levels', 'MPA', (138, 155))	('high Fuhrman grade', 'CPA', (177, 195))	('CD44', 'Gene', (57, 61))	('CD44', 'Gene', (133, 137))	('high', 'Var', (128, 132))	('recurrence', 'CPA', (200, 210))
34919	27891093	recently reported that the self-renewing ability of CXCR4+ spheres was enhanced before the upregulation of hypoxia-inducible factor 2alpha (HIF-2alpha) in the RCC cell lines Caki-1, Caki-2, 786-O, and 769-P. Knockdown of HIF-2alpha abolished CXCR4+ sphere formation and expression, and inhibition of HIF-2alpha abrogated tumor growth in vivo, proving that HIF-2alpha activation plays an important role in CSC expansion.	('Caki-2', 'CellLine', 'CVCL:0235', (182, 188))	('HIF-2alpha', 'Gene', (300, 310))	('HIF-2alpha', 'Gene', (221, 231))	('HIF-2alpha', 'Gene', (140, 150))	('Caki-1', 'CellLine', 'CVCL:0234', (174, 180))	('hypoxia-inducible factor 2alpha', 'Gene', (107, 138))	('HIF-2alpha abrogated tumor', 'Disease', (300, 326))	('CXCR4', 'molecular_function', 'GO:0038147', ('52', '57'))	('CXCR4', 'molecular_function', 'GO:0038147', ('242', '247'))	('HIF-2alpha abrogated tumor', 'Disease', 'MESH:D009369', (300, 326))	('inhibition', 'Var', (286, 296))	('CXCR4', 'Gene', '7852', (52, 57))	('CXCR4', 'Gene', '7852', (242, 247))	('RCC', 'Disease', (159, 162))	('expression', 'MPA', (270, 280))	('HIF-2alpha', 'Gene', '2034', (356, 366))	('enhanced', 'PosReg', (71, 79))	('self-renewing ability of', 'CPA', (27, 51))	('CXCR4', 'Gene', (52, 57))	('hypoxia-inducible factor 2alpha', 'Gene', '2034', (107, 138))	('CXCR4', 'Gene', (242, 247))	('HIF-2alpha', 'Gene', '2034', (300, 310))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('HIF-2alpha', 'Gene', '2034', (221, 231))	('HIF-2alpha', 'Gene', '2034', (140, 150))	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('formation', 'biological_process', 'GO:0009058', ('256', '265'))	('HIF-2alpha', 'Gene', (356, 366))
34928	27891093	Of note, a recent study found that high expression of the PIK3R1 protein was associated with RCC progression and metastasis.	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('PIK3R1', 'Gene', (58, 64))	('RCC', 'Disease', (93, 96))	('PIK3R1', 'Gene', '5295', (58, 64))	('protein', 'Protein', (65, 72))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('metastasis', 'CPA', (113, 123))	('high', 'Var', (35, 39))	('associated', 'Reg', (77, 87))
34931	27891093	In primary RCC-Caki-2 cells, silencing of the DCLK1 gene using DCLK1 siRNA resulted not only in decreased expression of EMT transcription factors (SNAI1, SNAI2, TWIST1, ZEB1, and Vimentin), but also reduced expression of the pluripotency and stemness factors MYC, Nanog, Oct-4, Sox-2, and aldehyde dehydrogenase (ALDH) 1A1.	('SNAI2', 'Gene', '6591', (154, 159))	('TWIST1', 'Gene', (161, 167))	('pluripotency and stemness factors MYC', 'Disease', 'MESH:D020295', (225, 262))	('Caki-2', 'CellLine', 'CVCL:0235', (15, 21))	('SNAI1', 'Gene', '6615', (147, 152))	('SNAI1', 'Gene', (147, 152))	('aldehyde dehydrogenase (ALDH) 1A1', 'Gene', '216', (289, 322))	('RCC', 'Disease', (11, 14))	('transcription', 'biological_process', 'GO:0006351', ('124', '137'))	('TWIST1', 'Gene', '7291', (161, 167))	('decreased', 'NegReg', (96, 105))	('DCLK1', 'Gene', (63, 68))	('silencing', 'Var', (29, 38))	('expression', 'MPA', (106, 116))	('ZEB1', 'Gene', '6935', (169, 173))	('Vimentin', 'cellular_component', 'GO:0045098', ('179', '187'))	('DCLK1', 'Gene', (46, 51))	('DCLK1', 'Gene', '9201', (63, 68))	('expression', 'MPA', (207, 217))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('DCLK1', 'Gene', '9201', (46, 51))	('reduced', 'NegReg', (199, 206))	('Vimentin', 'Gene', '7431', (179, 187))	('ALDH', 'molecular_function', 'GO:0004030', ('313', '317'))	('Vimentin', 'cellular_component', 'GO:0045099', ('179', '187'))	('Nanog', 'Gene', '79923', (264, 269))	('Nanog', 'Gene', (264, 269))	('Vimentin', 'Gene', (179, 187))	('SNAI2', 'Gene', (154, 159))	('ZEB1', 'Gene', (169, 173))	('Oct-4', 'Gene', '5460', (271, 276))	('Sox-2', 'Gene', (278, 283))	('Sox-2', 'Gene', '6657', (278, 283))	('EMT', 'biological_process', 'GO:0001837', ('120', '123'))	('Oct-4', 'Gene', (271, 276))
34932	27891093	These results corroborated the finding that DCLK1 knockdown can inhibit the invasive and metastatic ability of RCC cells.	('DCLK1', 'Gene', (44, 49))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('knockdown', 'Var', (50, 59))	('DCLK1', 'Gene', '9201', (44, 49))	('inhibit', 'NegReg', (64, 71))
34933	27891093	Recently, SP cells from an RCC cell line were genetically modified to knock out DnaJ (Hsp40) homolog, subfamily B, member 8 (DNAJB8) and examine its function in the tumorigenicity of RCC.	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('SP', 'Chemical', '-', (10, 12))	('RCC', 'Disease', (183, 186))	('DnaJ (Hsp40) homolog, subfamily B, member 8', 'Gene', '165721;11080', (80, 123))	('DNAJB8', 'Gene', '165721', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('knock', 'Var', (70, 75))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))	('DNAJB8', 'Gene', (125, 131))	('tumor', 'Disease', (165, 170))
34944	27891093	Interestingly, miR-17 inhibition led to increased colony formation in ACHN and Caki-1 cell lines, which demonstrated that miR-17 could regulate the self-renewing properties of the cells; inhibition also enhanced expression of mesenchymal markers and cancer stem markers.	('inhibition', 'Var', (22, 32))	('regulate', 'Reg', (135, 143))	('formation', 'biological_process', 'GO:0009058', ('57', '66'))	('mesenchymal markers', 'CPA', (226, 245))	('colony formation', 'CPA', (50, 66))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', (250, 256))	('enhanced', 'PosReg', (203, 211))	('expression', 'MPA', (212, 222))	('miR-17', 'Gene', (15, 21))	('self-renewing properties of the cells', 'CPA', (148, 185))	('miR-17', 'Gene', (122, 128))	('increased', 'PosReg', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('miR-17', 'Gene', '406952', (15, 21))	('inhibition', 'Var', (187, 197))	('miR-17', 'Gene', '406952', (122, 128))	('Caki-1', 'CellLine', 'CVCL:0234', (79, 85))
34948	27891093	Over the past several years, more and more encouraging data have demonstrated proof of principle that targeting CSCs could block the pathways associated with drug resistance, disease progression, aggressiveness, and metastasis, and may lead to complete and durable regression; this could improve treatment outcomes for patients with RCC and affect prognosis (Figure 1).	('lead to', 'Reg', (236, 243))	('aggressiveness', 'Disease', 'MESH:D001523', (196, 210))	('pathways', 'Pathway', (133, 141))	('CSCs', 'Protein', (112, 116))	('prognosis', 'MPA', (348, 357))	('block', 'NegReg', (123, 128))	('targeting', 'Var', (102, 111))	('drug resistance', 'MPA', (158, 173))	('RCC', 'Disease', (333, 336))	('treatment outcomes', 'CPA', (296, 314))	('disease progression', 'CPA', (175, 194))	('drug resistance', 'biological_process', 'GO:0009315', ('158', '173'))	('drug resistance', 'biological_process', 'GO:0042493', ('158', '173'))	('affect', 'Reg', (341, 347))	('drug resistance', 'Phenotype', 'HP:0020174', (158, 173))	('improve', 'PosReg', (288, 295))	('aggressiveness', 'Disease', (196, 210))	('patients', 'Species', '9606', (319, 327))	('RCC', 'Disease', 'MESH:C538614', (333, 336))	('aggressiveness', 'Phenotype', 'HP:0000718', (196, 210))	('metastasis', 'CPA', (216, 226))
34951	27891093	Abnormal tyrosine kinase signaling leads to various cancers, as well as other diseases.	('tyrosine kinase', 'Gene', (9, 24))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('leads to', 'Reg', (35, 43))	('Abnormal', 'Var', (0, 8))	('tyrosine kinase', 'Gene', '7294', (9, 24))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('Abnormal tyrosine kinase', 'Phenotype', 'HP:0010917', (0, 24))	('signaling', 'biological_process', 'GO:0023052', ('25', '34'))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
34958	27891093	Recent studies have demonstrated that TKIs can decrease the proliferation rate of renal CSCs, but that the efficacy of the growth inhibition was limited by hypoxic conditions and 3D intratumoral cell-cell interactions.	('hypoxic conditions', 'Disease', 'MESH:D009135', (156, 174))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('renal CSCs', 'CPA', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('decrease', 'NegReg', (47, 55))	('TKIs', 'Var', (38, 42))	('tumor', 'Disease', (187, 192))	('proliferation rate', 'CPA', (60, 78))	('hypoxic conditions', 'Disease', (156, 174))
34967	27891093	Interestingly, some clues can be found from a number of recent studies on mTOR inhibitors that eradicated the CSC populations in nasopharyngeal carcinoma, colon cancer, and glioblastoma multiforme, among other cancers, which may indicate future directions for designing novel drugs targeting mTOR for renal CSCs.	('mTOR', 'Gene', '2475', (292, 296))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('mTOR', 'Gene', (74, 78))	('inhibitors', 'Var', (79, 89))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (129, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('colon cancer', 'Disease', (155, 167))	('glioblastoma multiforme', 'Disease', (173, 196))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('nasopharyngeal carcinoma', 'Disease', (129, 153))	('glioblastoma', 'Phenotype', 'HP:0012174', (173, 185))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (173, 196))	('mTOR', 'Gene', '2475', (74, 78))	('cancers', 'Disease', 'MESH:D009369', (210, 217))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (129, 153))	('CSC populations', 'CPA', (110, 125))	('colon cancer', 'Phenotype', 'HP:0003003', (155, 167))	('eradicated', 'NegReg', (95, 105))	('mTOR', 'Gene', (292, 296))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('colon cancer', 'Disease', 'MESH:D015179', (155, 167))	('cancers', 'Disease', (210, 217))
34973	27891093	Additional combinations using mTOR inhibitors together with other targeted agents can more effectively inhibit mTOR and/or block signaling in multiple pathways, such as the PI3K/Akt/mTOR and Ras/Raf/MEK/Erk pathways.	('PI3K', 'molecular_function', 'GO:0016303', ('173', '177'))	('Erk', 'Gene', (203, 206))	('mTOR', 'Gene', '2475', (182, 186))	('MEK', 'Gene', (199, 202))	('Erk', 'molecular_function', 'GO:0004707', ('203', '206'))	('Erk', 'Gene', '5594', (203, 206))	('mTOR', 'Gene', '2475', (30, 34))	('inhibit', 'NegReg', (103, 110))	('Raf', 'Gene', '22882', (195, 198))	('Akt', 'Gene', (178, 181))	('block', 'NegReg', (123, 128))	('mTOR', 'Gene', (111, 115))	('Akt', 'Gene', '207', (178, 181))	('combinations', 'Interaction', (11, 23))	('mTOR', 'Gene', (182, 186))	('mTOR', 'Gene', '2475', (111, 115))	('MEK', 'Gene', '5609', (199, 202))	('signaling', 'biological_process', 'GO:0023052', ('129', '138'))	('Raf', 'Gene', (195, 198))	('inhibitors', 'Var', (35, 45))	('mTOR', 'Gene', (30, 34))	('signaling', 'MPA', (129, 138))
34999	27891093	IL-21, a novel cytokine with structural and sequence homology to IL-2 and IL-15, has been studied extensively both in vitro and in vivo and evaluated in Phase 1 and 2 trials (NCT00617253, NCT00389285, and NCT00095108) in mRCC.	('IL-15', 'molecular_function', 'GO:0016170', ('74', '79'))	('IL-21', 'Gene', (0, 5))	('IL-2', 'Gene', (0, 4))	('IL-2', 'Gene', '3558', (0, 4))	('IL-2', 'Gene', '3558', (65, 69))	('IL-2', 'molecular_function', 'GO:0005134', ('65', '69'))	('IL-2', 'Gene', (65, 69))	('NCT00389285', 'Var', (188, 199))	('RCC', 'Disease', 'MESH:C538614', (222, 225))	('IL-21', 'Gene', '59067', (0, 5))	('RCC', 'Disease', (222, 225))	('NCT00095108', 'Var', (205, 216))	('IL-21', 'molecular_function', 'GO:0001531', ('0', '5'))	('NCT00617253', 'Var', (175, 186))
35009	27891093	Notably, the angiogenesis inhibition of TRC105 was much more impressive than the inhibition of human endothelial proliferation in vitro, emphasizing the importance of assays that mimic the interplay between endothelium and perivascular cells during angiogenesis.	('human', 'Species', '9606', (95, 100))	('angiogenesis', 'biological_process', 'GO:0001525', ('249', '261'))	('TRC105', 'Var', (40, 46))	('angiogenesis', 'CPA', (13, 25))	('inhibition', 'NegReg', (26, 36))	('angiogenesis', 'biological_process', 'GO:0001525', ('13', '25'))
35013	27891093	Most importantly, the combination of TRC105 and axitinib increased the overall response rate and doubled PFS compared with axitinib as a single agent.	('PFS', 'CPA', (105, 108))	('TRC105', 'Var', (37, 43))	('combination', 'Interaction', (22, 33))	('axitinib', 'Chemical', 'MESH:D000077784', (123, 131))	('doubled', 'PosReg', (97, 104))	('increased', 'PosReg', (57, 66))	('axitinib', 'Chemical', 'MESH:D000077784', (48, 56))	('response', 'CPA', (79, 87))
35020	27891093	LY2510924 is a peptide antagonist of CXCR4 from Eli Lilly and Company and is currently in Phases 1 and 2 testing to evaluate its safety and efficacy in RCC (NCT01391130)3.	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('LY2510924', 'Var', (0, 9))	('RCC', 'Disease', (152, 155))	('CXCR4', 'Gene', (37, 42))	('LY2510924', 'Chemical', 'MESH:C000595455', (0, 9))	('CXCR4', 'molecular_function', 'GO:0038147', ('37', '42'))	('CXCR4', 'Gene', '7852', (37, 42))
35021	27891093	Preliminary data suggested that adding the CXCR4 inhibitor LY2510924 to sunitinib as a first-line treatment for metastatic RCC was tolerated but did not improve efficacy (.	('CXCR4', 'Gene', '7852', (43, 48))	('sunitinib', 'Chemical', 'MESH:D000077210', (72, 81))	('CXCR4', 'Gene', (43, 48))	('LY2510924', 'Var', (59, 68))	('RCC', 'Disease', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('CXCR4', 'molecular_function', 'GO:0038147', ('43', '48'))	('LY2510924', 'Chemical', 'MESH:C000595455', (59, 68))
35035	27891093	However, the poor absorption and instability of BMP-2 means that further research is needed to improve its drugability by pharmaceutical technologies; this could include PEGylation or packaging into liposomes or nanoparticles.	('BMP-2', 'Gene', (48, 53))	('PEG', 'Chemical', '-', (170, 173))	('PEGylation', 'Var', (170, 180))	('BMP-2', 'Gene', '650', (48, 53))	('drugability', 'MPA', (107, 118))
35061	27891093	The preliminary data showed that CRLX101 combined with bevacizumab is a safe treatment in mRCC.	('bevacizumab', 'Chemical', 'MESH:D000068258', (55, 66))	('CRLX101', 'Var', (33, 40))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))
35099	32235551	In contrast, male transgenic mice with IMPA2 knockout exhibited a lithium-resistant phenotype.	('transgenic mice', 'Species', '10090', (18, 33))	('IMPA2', 'Gene', (39, 44))	('lithium-resistant', 'Disease', (66, 83))	('exhibited', 'Reg', (54, 63))	('knockout', 'Var', (45, 53))	('lithium', 'Chemical', 'MESH:D008094', (66, 73))
35103	32235551	A previous report revealed that lithium induces autophagy which is a spherical structure with double layer membranes and involved in the intracellular degradation system for abnormal proteins or damaged organelles independent of the activity of mTOR, a negative regulator of autophagy, by inhibiting inositol monophosphatase in neural cells.	('intracellular', 'cellular_component', 'GO:0005622', ('137', '150'))	('induces', 'Reg', (40, 47))	('lithium', 'Var', (32, 39))	('degradation', 'biological_process', 'GO:0009056', ('151', '162'))	('lithium', 'Chemical', 'MESH:D008094', (32, 39))	('autophagy', 'biological_process', 'GO:0016236', ('275', '284'))	('autophagy', 'CPA', (48, 57))	('autophagy', 'biological_process', 'GO:0016236', ('48', '57'))	('mTOR', 'Gene', '2475', (245, 249))	('inositol monophosphatase', 'Gene', (300, 324))	('mTOR', 'Gene', (245, 249))	('autophagy', 'biological_process', 'GO:0006914', ('275', '284'))	('autophagy', 'biological_process', 'GO:0006914', ('48', '57'))	('inhibiting', 'NegReg', (289, 299))	('inositol monophosphatase', 'Gene', '3612', (300, 324))
35107	32235551	Pharmaceutical inhibition of mTORC1 with rapamycin restored autophagy initiation and ultimately suppressed the metastatic potential of IMPA2-silenced ccRCC cells in vitro and in vivo.	('mTORC1', 'Gene', (29, 35))	('autophagy', 'biological_process', 'GO:0016236', ('60', '69'))	('metastatic potential', 'CPA', (111, 131))	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('RCC', 'Disease', (152, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('ccRCC', 'Phenotype', 'HP:0006770', (150, 155))	('restored', 'PosReg', (51, 59))	('autophagy initiation', 'CPA', (60, 80))	('autophagy', 'biological_process', 'GO:0006914', ('60', '69'))	('mTORC1', 'cellular_component', 'GO:0031931', ('29', '35'))	('suppressed', 'NegReg', (96, 106))	('mTORC1', 'Gene', '382056', (29, 35))	('inhibition', 'Var', (15, 25))	('rapamycin', 'Chemical', 'MESH:D020123', (41, 50))
35128	32235551	For the in vivo lung metastatic colonization assay, cell suspensions (1 x 105 cells in 100 muL PBS) derived from A498 cells without or with IMPA2 knockdown and ACHN cells without or with IMPA2 overexpression were implanted into the mice through tail vein injection.	('knockdown', 'Var', (146, 155))	('PBS', 'Chemical', 'MESH:D007854', (95, 98))	('lung metastatic colonization assay', 'CPA', (16, 50))	('ACHN', 'Gene', (160, 164))	('IMPA2', 'Gene', (140, 145))	('A498', 'CellLine', 'CVCL:1056', (113, 117))	('ACHN', 'Gene', '55323', (160, 164))	('mice', 'Species', '10090', (232, 236))
35133	32235551	Previously, we demonstrated that low-level IMPA2 expression is associated with high risk for cancer metastasis and poor prognosis in TCGA ccRCC patients.	('cancer metastasis', 'Disease', (93, 110))	('IMPA2', 'Gene', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('low-level', 'Var', (33, 42))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('patients', 'Species', '9606', (144, 152))	('cancer metastasis', 'Disease', 'MESH:D009362', (93, 110))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('expression', 'Var', (49, 59))
35139	32235551	Kaplan-Meier analysis demonstrated that high mTORC1 gene set levels are associated with poor overall survival probability in the TCGA ccRCC cohort (Figure 1E).	('high', 'Var', (40, 44))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('poor', 'NegReg', (88, 92))	('overall', 'MPA', (93, 100))	('mTORC1', 'Gene', '382056', (45, 51))	('mTORC1', 'cellular_component', 'GO:0031931', ('45', '51'))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('mTORC1', 'Gene', (45, 51))	('RCC', 'Disease', (136, 139))
35142	32235551	In addition, the Chi-square test showed that the signature that combines low-level IMPA2 and high-level mTORC1 gene set expression is extensively detected in ccRCC derived from male patients who are classified as having higher pathologic T status (T3 and T4), pathologic M1, higher pathologic stage (III and IV) or higher neoplasm grade (G3 and G4) (Table S2).	('neoplasm', 'Disease', 'MESH:D009369', (322, 330))	('mTORC1', 'cellular_component', 'GO:0031931', ('104', '110'))	('detected', 'Reg', (146, 154))	('mTORC1', 'Gene', '382056', (104, 110))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('RCC', 'Disease', (160, 163))	('IMPA2', 'Gene', (83, 88))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('ccRCC', 'Phenotype', 'HP:0006770', (158, 163))	('patients', 'Species', '9606', (182, 190))	('neoplasm', 'Disease', (322, 330))	('mTORC1', 'Gene', (104, 110))	('neoplasm', 'Phenotype', 'HP:0002664', (322, 330))	('pathologic M1', 'Var', (260, 273))
35149	32235551	Conversely, the enforced expression of exogenous IMPA2 reduced the phosphorylation levels of Akt and mTORC1 proteins in highly metastatic ACHN cells (Figure 2E).	('ACHN', 'Gene', (138, 142))	('phosphorylation levels', 'MPA', (67, 89))	('Akt', 'Gene', (93, 96))	('mTORC1', 'Gene', '382056', (101, 107))	('mTORC1', 'cellular_component', 'GO:0031931', ('101', '107'))	('mTORC1', 'Gene', (101, 107))	('reduced', 'NegReg', (55, 62))	('phosphorylation', 'biological_process', 'GO:0016310', ('67', '82'))	('exogenous', 'Var', (39, 48))	('ACHN', 'Gene', '55323', (138, 142))	('Akt', 'Gene', '207', (93, 96))	('IMPA2', 'Gene', (49, 54))
35152	32235551	Robustly, autophagosome accumulation was dominant in A498 cells but not ACHN cells (Figure 3B).	('ACHN', 'Gene', (72, 76))	('autophagosome accumulation', 'CPA', (10, 36))	('A498', 'Var', (53, 57))	('autophagosome', 'cellular_component', 'GO:0005776', ('10', '23'))	('A498', 'CellLine', 'CVCL:1056', (53, 57))	('ACHN', 'Gene', '55323', (72, 76))
35154	32235551	IMPA2 knockdown reduced Beclin 1 expression and LC3-II production in poorly metastatic A498 cells (Figure 3D).	('LC3-II production', 'MPA', (48, 65))	('LC3-II', 'Chemical', '-', (48, 54))	('A498', 'CellLine', 'CVCL:1056', (87, 91))	('reduced', 'NegReg', (16, 23))	('Beclin 1', 'Gene', '8678', (24, 32))	('IMPA2', 'Gene', (0, 5))	('expression', 'MPA', (33, 43))	('knockdown', 'Var', (6, 15))	('Beclin 1', 'Gene', (24, 32))
35157	32235551	In poorly metastatic A498 cells, IMPA2 knockdown abrogated the production of LC3-II (Figure 4A) but promoted cellular migration ability (Figure 4B,C) and lung metastatic potential (Figure 4D,E).	('A498', 'CellLine', 'CVCL:1056', (21, 25))	('IMPA2', 'Gene', (33, 38))	('abrogated', 'NegReg', (49, 58))	('knockdown', 'Var', (39, 48))	('production of LC3-II', 'MPA', (63, 83))	('lung metastatic potential', 'CPA', (154, 179))	('cellular migration ability', 'CPA', (109, 135))	('promoted', 'PosReg', (100, 108))	('LC3-II', 'Chemical', '-', (77, 83))
35164	32235551	Regarding overall survival probability, low-level autophagy gene set expression was strongly associated with poor prognosis in the Kaplan -Meier analysis of the TCGA ccRCC cohort (Figure 6C).	('autophagy', 'biological_process', 'GO:0016236', ('50', '59'))	('autophagy gene set', 'Gene', (50, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (166, 171))	('autophagy', 'biological_process', 'GO:0006914', ('50', '59'))	('low-level', 'Var', (40, 49))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('RCC', 'Disease', (168, 171))
35165	32235551	Importantly, another Kaplan-Meier analysis revealed that the signature that combines low-level IMPA2 and autophagy gene set predicted a poor overall survival rate in TCGA ccRCC patients (Figure 6D).	('RCC', 'Disease', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('patients', 'Species', '9606', (177, 185))	('ccRCC', 'Phenotype', 'HP:0006770', (171, 176))	('autophagy', 'biological_process', 'GO:0016236', ('105', '114'))	('IMPA2', 'Gene', (95, 100))	('poor', 'NegReg', (136, 140))	('autophagy', 'CPA', (105, 114))	('low-level', 'Var', (85, 94))	('autophagy', 'biological_process', 'GO:0006914', ('105', '114'))
35181	32235551	Furthermore, in 2007, the United States Food and Drug Administration and the European Medicines Agency approved mTOR inhibitor temsirolimus as a first-line therapy for poor-risk patients with metastatic ccRCC, and the National Comprehensive Cancer Network (NCCN) Kidney Cancer Panel has listed temsirolimus as category 1 for front-line treatment of poor-risk patients since temsirolimus, in the phase III NCT0065468 trial which included 626 patients (69% with poor- and 31% with intermediate-risk characteristics), achieved longer progression-free and overall survival.	('progression-free', 'CPA', (531, 547))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('Cancer', 'Phenotype', 'HP:0002664', (241, 247))	('patients', 'Species', '9606', (441, 449))	('Kidney Cancer', 'Phenotype', 'HP:0009726', (263, 276))	('patients', 'Species', '9606', (178, 186))	('overall survival', 'CPA', (552, 568))	('mTOR', 'Gene', (112, 116))	('Cancer', 'Phenotype', 'HP:0002664', (270, 276))	('mTOR', 'Gene', '2475', (112, 116))	('patients', 'Species', '9606', (359, 367))	('longer', 'PosReg', (524, 530))	('temsirolimus', 'Var', (374, 386))	('RCC', 'Disease', (205, 208))	('RCC', 'Phenotype', 'HP:0005584', (205, 208))	('ccRCC', 'Phenotype', 'HP:0006770', (203, 208))	('Cancer Network (NCCN) Kidney Cancer', 'Disease', 'MESH:D009369', (241, 276))	('temsirolimus', 'Chemical', 'MESH:C401859', (294, 306))	('temsirolimus', 'Chemical', 'MESH:C401859', (127, 139))	('temsirolimus', 'Chemical', 'MESH:C401859', (374, 386))
35184	32235551	This finding may provide a new strategy for establishing personalized therapy by suggesting that metastatic ccRCC patients with IMPA2 deficiency should receive temsirolimus therapy.	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('IMPA2', 'Gene', (128, 133))	('deficiency', 'Var', (134, 144))	('temsirolimus', 'Chemical', 'MESH:C401859', (160, 172))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('patients', 'Species', '9606', (114, 122))
35185	32235551	It has been shown that the activation of the Akt/mTOR pathway by the long noncoding RNAs OECC and MetaLnc9 and the transmembrane 7 superfamily member 4 promotes cancer metastasis; conversely, the suppression of the Akt/mTOR pathway in the presence of the ferulic acid derivative FXS-3, cardamonin and microRNA-520a-3p inhibits cancer metastatic potential.	('mTOR', 'Gene', (219, 223))	('transmembrane', 'cellular_component', 'GO:0044214', ('115', '128'))	('transmembrane 7 superfamily member 4', 'Gene', (115, 151))	('cancer', 'Disease', (161, 167))	('mTOR', 'Gene', '2475', (219, 223))	('cancer metastasis', 'Disease', (161, 178))	('mTOR', 'Gene', (49, 53))	('Akt', 'Gene', (45, 48))	('cancer', 'Disease', (327, 333))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('Akt', 'Gene', '207', (45, 48))	('ferulic acid', 'Chemical', 'MESH:C004999', (255, 267))	('suppression', 'NegReg', (196, 207))	('mTOR', 'Gene', '2475', (49, 53))	('cancer metastasis', 'Disease', 'MESH:D009362', (161, 178))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('transmembrane 7 superfamily member 4', 'Gene', '81501', (115, 151))	('promotes', 'PosReg', (152, 160))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('microRNA-520a-3p', 'Var', (301, 317))	('Akt', 'Gene', (215, 218))	('transmembrane', 'cellular_component', 'GO:0016021', ('115', '128'))	('inhibits', 'NegReg', (318, 326))	('Akt', 'Gene', '207', (215, 218))
35188	32235551	Here, we further explored whether RCC cells with high-level IMPA2 expression displayed poor Akt/mTOR activity, as judged by their phosphorylation level.	('mTOR', 'Gene', (96, 100))	('phosphorylation level', 'MPA', (130, 151))	('Akt', 'Gene', '207', (92, 95))	('high-level', 'Var', (49, 59))	('IMPA2', 'Gene', (60, 65))	('phosphorylation', 'biological_process', 'GO:0016310', ('130', '145'))	('Akt', 'Gene', (92, 95))	('mTOR', 'Gene', '2475', (96, 100))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('poor', 'NegReg', (87, 91))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('RCC', 'Disease', (34, 37))
35207	30899441	Of these candidates, low maximum intensity ratio (cancerous/normal) values of ions of oleic acid, m/z 389.2, and 391.3 significantly correlated with shorter progression-free survival compared with high maximum intensity ratio values (P = 0.011, P = 0.022, and P < 0.001, respectively).	('oleic acid', 'Chemical', 'MESH:D019301', (86, 96))	('progression-free survival', 'CPA', (157, 182))	('cancerous', 'Disease', (50, 59))	('391.3', 'Var', (113, 118))	('low', 'NegReg', (21, 24))	('shorter', 'NegReg', (149, 156))	('cancerous', 'Disease', 'MESH:D009369', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('m/z 389.2', 'Var', (98, 107))
35216	30899441	Metabolomics studies have shown that metabolic changes affect the proliferation of cancer cells, cancer cell survival in conditions of nutrient depletion and hypoxia, and the immune system.	('affect', 'Reg', (55, 61))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('proliferation', 'CPA', (66, 79))	('hypoxia', 'Disease', (158, 165))	('hypoxia', 'Disease', 'MESH:D000860', (158, 165))	('changes', 'Var', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('survival', 'CPA', (109, 117))	('cancer', 'Disease', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
35234	30899441	DESI-IMS in negative ion mode revealed that the ion of m/z 885.6 was highly abundant in the cancerous tissue (Figure 1A).	('cancerous', 'Disease', (92, 101))	('DESI', 'Gene', '51029', (0, 4))	('DESI', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancerous', 'Disease', 'MESH:D009369', (92, 101))	('m/z 885.6', 'Var', (55, 64))
35237	30899441	The ion of m/z 281.2 was the most abundant in the cancerous tissue.	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancerous', 'Disease', (50, 59))	('m/z 281.2', 'Var', (11, 20))	('cancerous', 'Disease', 'MESH:D009369', (50, 59))
35251	30899441	The ions of biomarker candidates were m/z 187.1 (azelaic acid), 253.2 [FA(16:1)] (palmitoleic acid), 279.2 [FA(18:2)] (linoleic acid), 281.2 [FA(18:1)] (oleic acid), 329.2 [FA(22:5)] (docosapentaenoic acid: DPA), 389.2 (not assigned), 391.3 (not assigned), and 773.5 [PG(18:1/18:1)] (glycerophosphoglycerol 36:2).	('PG', 'Chemical', '-', (268, 270))	('m/z', 'Var', (38, 41))	('oleic acid', 'Chemical', 'MESH:D019301', (153, 163))	('oleic acid', 'Chemical', 'MESH:D019301', (88, 98))	('azelaic acid', 'Chemical', 'MESH:C010038', (49, 61))	('oleic acid', 'Chemical', 'MESH:D019301', (122, 132))	('279.2 [FA', 'Var', (101, 110))	('palmitoleic acid', 'Chemical', 'MESH:C008757', (82, 98))	('DPA', 'Chemical', 'MESH:C026219', (207, 210))	('glycerophosphoglycerol', 'Chemical', 'MESH:C409185', (284, 306))	('linoleic acid', 'Chemical', 'MESH:D019787', (119, 132))
35260	30899441	We found that the MIR values of the ions of oleic acid, m/z 389.2, and 391.3 were significantly correlated with disease progression, with low-MIR patients having a significantly shorter PFS (Figure 5D, 5F, and 5G; P = 0.011, P = 0.022 and P < 0.001, respectively).	('correlated', 'Reg', (96, 106))	('shorter', 'NegReg', (178, 185))	('low-MIR', 'Var', (138, 145))	('MIR', 'MPA', (18, 21))	('disease', 'Disease', (112, 119))	('oleic acid', 'Chemical', 'MESH:D019301', (44, 54))	('PFS', 'MPA', (186, 189))	('patients', 'Species', '9606', (146, 154))
35263	30899441	The ions of oleic acid, m/z 389.2, and 391.3 are possible novel lipid biomarkers that predict disease progression.	('m/z 389.2', 'Var', (24, 33))	('391.3', 'Var', (39, 44))	('oleic acid', 'Chemical', 'MESH:D019301', (12, 22))	('lipid', 'Chemical', 'MESH:D008055', (64, 69))
35265	30899441	Sixteen patients had disease progression or low MIR levels of oleic acid, m/z 389.2, or 391.3.	('low', 'NegReg', (44, 47))	('MIR levels of oleic acid', 'MPA', (48, 72))	('m/z 389.2', 'Var', (74, 83))	('oleic acid', 'Chemical', 'MESH:D019301', (62, 72))	('patients', 'Species', '9606', (8, 16))
35279	30899441	In this study, MIR values of the ions of azelaic acid and m/z 391.3 were significantly correlated with tumor grade and pathological stage, respectively.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('correlated', 'Reg', (87, 97))	('tumor', 'Disease', (103, 108))	('azelaic acid', 'Chemical', 'MESH:C010038', (41, 53))	('m/z 391.3', 'Var', (58, 67))	('azelaic', 'Protein', (41, 48))	('MIR', 'MPA', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
35281	30899441	Moreover, we found that oleic acid, m/z 389.2, and 391.3 showed decreased levels in cancerous tissues from patients showing shorter PFS, although the total lipid storage level increased in all patients.	('lipid', 'Chemical', 'MESH:D008055', (156, 161))	('patients', 'Species', '9606', (193, 201))	('lipid storage', 'biological_process', 'GO:0019915', ('156', '169'))	('increased', 'PosReg', (176, 185))	('cancerous', 'Disease', (84, 93))	('oleic acid', 'MPA', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('391.3', 'Var', (51, 56))	('levels', 'MPA', (74, 80))	('oleic acid', 'Chemical', 'MESH:D019301', (24, 34))	('cancerous', 'Disease', 'MESH:D009369', (84, 93))	('patients', 'Species', '9606', (107, 115))	('m/z 389.2', 'Var', (36, 45))	('decreased', 'NegReg', (64, 73))
35285	30899441	Surprisingly, low MIR levels of ions of m/z 281.2 (oleic acid), 389.2 (not assigned), and 391.3 (not assigned) were significantly correlated with disease progression.	('MIR levels', 'MPA', (18, 28))	('correlated with', 'Reg', (130, 145))	('m/z 281.2', 'Var', (40, 49))	('oleic acid', 'Chemical', 'MESH:D019301', (51, 61))	('disease', 'Disease', (146, 153))	('389.2', 'Var', (64, 69))
35287	30899441	The currently unassigned ion of m/z 391.3 was identified as a biomarker of viable tissue in breast cancer, and lack of this ion, which indicates tumor necrosis, predicts poor prognosis.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('necrosis', 'biological_process', 'GO:0008220', ('151', '159'))	('tumor necrosis', 'Disease', 'MESH:D009336', (145, 159))	('breast cancer', 'Disease', (92, 105))	('necrosis', 'biological_process', 'GO:0001906', ('151', '159'))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('necrosis', 'biological_process', 'GO:0019835', ('151', '159'))	('tumor necrosis', 'Disease', (145, 159))	('necrosis', 'biological_process', 'GO:0008219', ('151', '159'))	('necrosis', 'biological_process', 'GO:0070265', ('151', '159'))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('lack', 'Var', (111, 115))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
35288	30899441	Similarly, our study showed that the ion of m/z 391.3 was abundant in cancerous tissue, whereas it was lower in ccRCC patients with poor progression.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('cancerous', 'Disease', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('m/z 391.3', 'Var', (44, 53))	('cancerous', 'Disease', 'MESH:D009369', (70, 79))	('lower', 'NegReg', (103, 108))	('patients', 'Species', '9606', (118, 126))
35291	30899441	Finally, patients with one risk factor, for example a low MIR level in the three biomarkers (oleic acid, m/z 389.2, and 391.3) predicting disease progression, might not always have the other two risk factors.	('patients', 'Species', '9606', (9, 17))	('oleic acid', 'Chemical', 'MESH:D019301', (93, 103))	('low', 'NegReg', (54, 57))	('MIR level', 'MPA', (58, 67))	('m/z', 'Var', (105, 108))
35295	30899441	Low cancerous/normal MIRs of ions of oleic acid, m/z 389.2 (not assigned), and 391.3 (not assigned) were shown to be significantly associated with disease progression.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('oleic acid', 'Chemical', 'MESH:D019301', (37, 47))	('Low cancerous', 'Disease', 'MESH:D009369', (0, 13))	('m/z 389.2', 'Var', (49, 58))	('associated', 'Reg', (131, 141))	('391.3', 'Var', (79, 84))	('Low cancerous', 'Disease', (0, 13))	('oleic acid', 'Protein', (37, 47))	('disease progression', 'CPA', (147, 166))
35335	30796197	Thus, we hypothesized about different functions of IP3R3 compared to IP3R1 and IP3R2 in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('IP3R1', 'Gene', '3708', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('IP3R3', 'Var', (51, 56))	('tumor', 'Disease', (88, 93))	('IP3R2', 'Gene', '3709', (79, 84))	('IP3R1', 'Gene', (69, 74))	('IP3R2', 'Gene', (79, 84))
35336	30796197	Silencing of IP3R1 prevented apoptosis induction in colorectal cancer DLD1 cells, ovarian cancer A2780 cells, and clear cell renal cell carcinoma RCC4 cells, compared to apoptosis in cells treated with scrambled siRNA.	('clear cell renal cell carcinoma', 'Disease', (114, 145))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (125, 145))	('RCC4', 'Gene', (146, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('Silencing', 'Var', (0, 9))	('apoptosis', 'CPA', (29, 38))	('RCC4', 'Gene', '84925', (146, 150))	('ovarian cancer', 'Disease', 'MESH:D010051', (82, 96))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (114, 145))	('apoptosis', 'biological_process', 'GO:0097194', ('170', '179'))	('apoptosis', 'biological_process', 'GO:0006915', ('170', '179'))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('ovarian cancer', 'Disease', (82, 96))	('IP3R1', 'Gene', (13, 18))	('prevented', 'NegReg', (19, 28))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (114, 145))	('ovarian cancer', 'Phenotype', 'HP:0100615', (82, 96))	('IP3R1', 'Gene', '3708', (13, 18))	('apoptosis', 'biological_process', 'GO:0097194', ('29', '38'))	('colorectal cancer', 'Disease', (52, 69))	('apoptosis', 'biological_process', 'GO:0006915', ('29', '38'))
35338	30796197	Lower volume of tumors originated from DLD1/IP3R3_del cells was observed after 12 days, compared to wild type DLD1 cells.	('tumors', 'Disease', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('DLD1/IP3R3_del', 'Var', (39, 53))
35339	30796197	Apoptosis under hypoxic conditions was more pronounced in DLD1/IP3R3_del cells than in DLD1 cells.	('hypoxic conditions', 'Disease', (16, 34))	('DLD1/IP3R3_del', 'Var', (58, 72))	('Apoptosis', 'CPA', (0, 9))	('hypoxic conditions', 'Disease', 'MESH:D009135', (16, 34))
35340	30796197	These results clearly show that IP3R3 has proliferative and anti-apoptotic effect in tumor cells, on contrary to the pro-apoptotic effect of IP3R1.	('IP3R1', 'Gene', (141, 146))	('tumor', 'Disease', (85, 90))	('proliferative', 'CPA', (42, 55))	('anti-apoptotic effect', 'CPA', (60, 81))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('IP3R3', 'Var', (32, 37))	('IP3R1', 'Gene', '3708', (141, 146))
35350	30796197	Inhibition of the IP3R3 subtype reduced breast cancer cell proliferation, migration, invasion, and survival of glioblastoma cells and revealed an oscillating Ca2+ signature along with a slowing down cell migration in human breast cancer cells.	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('human', 'Species', '9606', (217, 222))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('breast cancer', 'Disease', 'MESH:D001943', (223, 236))	('breast cancer', 'Disease', (223, 236))	('invasion', 'CPA', (85, 93))	('cell migration', 'biological_process', 'GO:0016477', ('199', '213'))	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('breast cancer', 'Disease', (40, 53))	('reduced', 'NegReg', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('oscillating Ca2+ signature', 'MPA', (146, 172))	('cell migration', 'CPA', (199, 213))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('migration', 'CPA', (74, 83))	('Inhibition', 'Var', (0, 10))	('glioblastoma', 'Disease', 'MESH:D005909', (111, 123))	('Ca2+', 'Chemical', 'MESH:D000069285', (158, 162))	('survival', 'CPA', (99, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (223, 236))	('cell proliferation', 'biological_process', 'GO:0008283', ('54', '72'))	('glioblastoma', 'Disease', (111, 123))
35365	30796197	Subsequently labeling reaction using Quick Amp Labeling kit, where Cy3-dCTP (unaffected tissue samples) and Cy5-dCTP (tumor samples) were used to obtained cRNA.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('Amp', 'Chemical', 'MESH:D000249', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Cy5-dCTP', 'Chemical', 'MESH:C544355', (108, 116))	('Cy5-dCTP', 'Var', (108, 116))	('tumor', 'Disease', (118, 123))	('Cy3-dCTP', 'Chemical', '-', (67, 75))
35394	30796197	Mouse monoclonal antibody IP3R1 (407140, Calbiochem, USA) and rabbit polyclonal IP3R3 (HPA003915, Sigma-Aldrich, USA) were used in the experiment.	('407140', 'Var', (33, 39))	('antibody', 'cellular_component', 'GO:0019814', ('17', '25'))	('antibody', 'molecular_function', 'GO:0003823', ('17', '25'))	('IP3R1', 'Gene', (26, 31))	('IP3R1', 'Gene', '3708', (26, 31))	('Mouse', 'Species', '10090', (0, 5))	('antibody', 'cellular_component', 'GO:0042571', ('17', '25'))	('antibody', 'cellular_component', 'GO:0019815', ('17', '25'))	('rabbit', 'Species', '9986', (62, 68))
35395	30796197	Hypoxia was induced by 100 microM dimethyloxalylglycine (DMOG; Cayman Chemical Company, USA) for 24 and 48 h. DMOG is a cell permeable competitive inhibitor of HIF-alpha prolyl hydroxylase (HIF-PH) leading to the stabilization of HIF and subsequent angiogenesis and glucose metabolism at concentrations between 0.1 and 1 mM.	('DMOG', 'Var', (110, 114))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('angiogenesis', 'biological_process', 'GO:0001525', ('249', '261'))	('glucose metabolism', 'biological_process', 'GO:0006006', ('266', '284'))	('glucose metabolism', 'CPA', (266, 284))	('angiogenesis', 'CPA', (249, 261))	('Hypoxia', 'Disease', (0, 7))	('dimethyloxalylglycine', 'Chemical', 'MESH:C040947', (34, 55))	('glucose', 'Chemical', 'MESH:D005947', (266, 273))	('DMOG', 'Chemical', 'MESH:C040947', (57, 61))	('stabilization', 'MPA', (213, 226))	('DMOG', 'Chemical', 'MESH:C040947', (110, 114))	('HIF', 'MPA', (230, 233))
35407	30796197	In a group of 18 patients, we evaluated the expression of the IP3R1, IP3R2, and IP3R3 in ccRCC tumors compared to the unaffected part of tissue from the same patient (Fig.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('IP3R2', 'Gene', (69, 74))	('patient', 'Species', '9606', (158, 165))	('patient', 'Species', '9606', (17, 24))	('IP3R1', 'Gene', '3708', (62, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (89, 94))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('patients', 'Species', '9606', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('IP3R1', 'Gene', (62, 67))	('IP3R3', 'Var', (80, 85))	('tumors', 'Disease', (95, 101))	('IP3R2', 'Gene', '3709', (69, 74))
35412	30796197	Silencing of the IP3R1 in all above-mentioned cells has no effect on apoptosis compared to control cells, but silencing of the IP3R3 resulted in upregulation of apoptosis in RCC4, A2780, and DLD1 cells.	('RCC4', 'Gene', (174, 178))	('RCC4', 'Gene', '84925', (174, 178))	('upregulation', 'PosReg', (145, 157))	('apoptosis', 'biological_process', 'GO:0006915', ('69', '78'))	('silencing', 'Var', (110, 119))	('apoptosis', 'CPA', (161, 170))	('IP3R1', 'Gene', '3708', (17, 22))	('IP3R3', 'Gene', (127, 132))	('IP3R1', 'Gene', (17, 22))	('upregulation of apoptosis', 'biological_process', 'GO:0043065', ('145', '170'))	('apoptosis', 'biological_process', 'GO:0097194', ('69', '78'))
35413	30796197	Silencing of the IP3R1 and subsequent treatment with AIK resulted in lower level of apoptosis compared to groups treated with only AIK.	('level of apoptosis', 'MPA', (75, 93))	('lower', 'NegReg', (69, 74))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('IP3R1', 'Gene', '3708', (17, 22))	('IP3R1', 'Gene', (17, 22))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('Silencing', 'Var', (0, 9))
35415	30796197	To evaluate the physiological relevance of the IP3R3, we decided to knockout the IP3R3 and compare tumor induction of knockout IP3R3 cells with normal cells.	('tumor', 'Disease', (99, 104))	('knockout', 'Var', (68, 76))	('IP3R3', 'Gene', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
35419	30796197	We observed a significant decrease of tumor volume, when mice were inoculated with DLD1/IP3R3_del cells, compared to DLD1 cells (Fig.	('mice', 'Species', '10090', (57, 61))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('decrease', 'NegReg', (26, 34))	('DLD1/IP3R3_del cells', 'Var', (83, 103))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
35420	30796197	Xenografts were used for determination IP3R1 and IP3R3 proteins (Fig.	('IP3R1', 'Gene', '3708', (39, 44))	('IP3R1', 'Gene', (39, 44))	('IP3R3', 'Var', (49, 54))
35421	30796197	We observed increased expression of the IP3R1 in xenografts from DLD1/IP3R3_del cells, compared to DLD1 cells (Fig.	('IP3R1', 'Gene', '3708', (40, 45))	('IP3R1', 'Gene', (40, 45))	('increased', 'PosReg', (12, 21))	('DLD1/IP3R3_del', 'Var', (65, 79))	('expression', 'MPA', (22, 32))
35422	30796197	Also, apoptosis determined in tumor's slices by TUNEL assay was visible in DLD1/IP3R3_del cells, but not in DLD1 cells (Fig.	('apoptosis', 'biological_process', 'GO:0097194', ('6', '15'))	('apoptosis', 'biological_process', 'GO:0006915', ('6', '15'))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('apoptosis', 'CPA', (6, 15))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('DLD1/IP3R3_del', 'Var', (75, 89))
35426	30796197	To evaluate mutual interaction of IP3R1 and IP3R3, we compared apoptosis induction in DLD1 and DLD1/IP3R3_del cells after silencing of the IP3R1 and subsequent induction of apoptosis by AIK (Fig.	('induction of apoptosis', 'biological_process', 'GO:0006915', ('160', '182'))	('IP3R1', 'Gene', (139, 144))	('IP3R1', 'Gene', '3708', (139, 144))	('IP3R1', 'Gene', (34, 39))	('apoptosis', 'CPA', (63, 72))	('IP3R1', 'Gene', '3708', (34, 39))	('silencing', 'Var', (122, 131))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))
35427	30796197	Silencing of the IP3R1 decreased the basal apoptosis compared to cells treated with scrRNA in both, DLD1 and DLD1/IP3R3_del cells.	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('basal apoptosis', 'CPA', (37, 52))	('IP3R1', 'Gene', (17, 22))	('IP3R1', 'Gene', '3708', (17, 22))	('Silencing', 'Var', (0, 9))	('decreased', 'NegReg', (23, 32))
35428	30796197	In DLD1 cells we observed co-localization of IP3R1 and IP3R3 (Fig.	('IP3R3', 'Var', (55, 60))	('localization', 'biological_process', 'GO:0051179', ('29', '41'))	('IP3R1', 'Gene', '3708', (45, 50))	('IP3R1', 'Gene', (45, 50))	('co-localization', 'MPA', (26, 41))
35429	30796197	Silencing of the IP3R1 and/or IP3R3 revealed a decrease in levels of cytosolic calcium in RCC4, A2780, and DLD1 cells (Fig.	('decrease', 'NegReg', (47, 55))	('RCC4', 'Gene', '84925', (90, 94))	('RCC4', 'Gene', (90, 94))	('IP3R1', 'Gene', (17, 22))	('IP3R1', 'Gene', '3708', (17, 22))	('levels of cytosolic calcium', 'MPA', (59, 86))	('Silencing', 'Var', (0, 9))	('calcium', 'Chemical', 'MESH:D002118', (79, 86))
35433	30796197	Depletion of the IP3R3 resulted in rapid increase of apoptosis both, in normoxia and hypoxia.	('apoptosis', 'CPA', (53, 62))	('hypoxia', 'Disease', 'MESH:D000860', (85, 92))	('hypoxia', 'Disease', (85, 92))	('IP3R3', 'Var', (17, 22))	('Depletion', 'Var', (0, 9))	('apoptosis', 'biological_process', 'GO:0097194', ('53', '62'))	('apoptosis', 'biological_process', 'GO:0006915', ('53', '62'))	('increase', 'PosReg', (41, 49))
35443	30796197	These results clearly point to the different function of the IP3R3 compared to IP3R1 and IP3R2 in tumors:at least in ccRCC.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('IP3R1', 'Gene', (79, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('ccRCC', 'Disease', (117, 122))	('IP3R1', 'Gene', '3708', (79, 84))	('IP3R2', 'Gene', '3709', (89, 94))	('IP3R2', 'Gene', (89, 94))	('IP3R3', 'Var', (61, 66))
35445	30796197	As expected, silencing of the IP3R1 resulted in suppressing AIK-induced apoptosis, which is in line with the proapoptotic effect of this receptor described in the literature.	('AIK-induced apoptosis', 'CPA', (60, 81))	('IP3R1', 'Gene', '3708', (30, 35))	('IP3R1', 'Gene', (30, 35))	('apoptosis', 'biological_process', 'GO:0097194', ('72', '81'))	('apoptosis', 'biological_process', 'GO:0006915', ('72', '81'))	('suppressing', 'NegReg', (48, 59))	('silencing', 'Var', (13, 22))
35446	30796197	The AIK-induced apoptosis after silencing of the IP3R3 was increased in all three cell lines:A2780, DLD1, and RCC4, which points to the anti-apoptotic effect of the IP3R3.	('A2780', 'Var', (93, 98))	('apoptosis', 'CPA', (16, 25))	('RCC4', 'Gene', (110, 114))	('RCC4', 'Gene', '84925', (110, 114))	('silencing', 'Var', (32, 41))	('apoptosis', 'biological_process', 'GO:0097194', ('16', '25'))	('increased', 'PosReg', (59, 68))	('apoptosis', 'biological_process', 'GO:0006915', ('16', '25'))	('IP3R3', 'Gene', (49, 54))	('AIK-induced', 'Gene', (4, 15))
35448	30796197	We injected the same amount of DLD1 and/or DLD1/IP3R3_del cells into nude mice and evaluated the tumor's growth.	('DLD1/IP3R3_del', 'Var', (43, 57))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('nude mice', 'Species', '10090', (69, 78))
35449	30796197	We observed that the volume of tumors from DLD1/IP3R3_del cells was significantly lower compared to DLD1 cells.	('DLD1/IP3R3_del', 'Var', (43, 57))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('lower', 'NegReg', (82, 87))
35450	30796197	Moreover, xenografts from DLD1/IP3R3_del cells were apoptotic, probably due to rapidly increased expression of the IP3R1.	('DLD1/IP3R3_del', 'Var', (26, 40))	('increased', 'PosReg', (87, 96))	('IP3R1', 'Gene', '3708', (115, 120))	('expression', 'MPA', (97, 107))	('IP3R1', 'Gene', (115, 120))
35453	30796197	Silencing of the IP3R3 led to a significant decrease of cell migration capacities of all three breast cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('decrease', 'NegReg', (44, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('IP3R3', 'Gene', (17, 22))	('cell migration capacities', 'CPA', (56, 81))	('Silencing', 'Var', (0, 9))	('cell migration', 'biological_process', 'GO:0016477', ('56', '70'))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
35463	30796197	The loss of VHL leads to HIF accumulation and translocation into the nucleus, which subsequently activates the transcription of HIF target genes that are involved in critical oncogenic pathways.	('nucleus', 'cellular_component', 'GO:0005634', ('69', '76'))	('HIF accumulation', 'Disease', 'MESH:C579880', (25, 41))	('activates', 'PosReg', (97, 106))	('transcription', 'MPA', (111, 124))	('transcription', 'biological_process', 'GO:0006351', ('111', '124'))	('VHL', 'Disease', 'MESH:D006623', (12, 15))	('translocation', 'MPA', (46, 59))	('VHL', 'Disease', (12, 15))	('HIF accumulation', 'Disease', (25, 41))	('loss', 'Var', (4, 8))
35467	30796197	In summary, all our experiments, which were performed either on human samples or in vitro by silencing and apoptosis determination or in vivo on nude mice strongly suggest the anti-apoptotic role of the IP3R3.	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('human', 'Species', '9606', (64, 69))	('nude mice', 'Species', '10090', (145, 154))	('IP3R3', 'Var', (203, 208))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))	('anti-apoptotic', 'CPA', (176, 190))
35468	28536496	Link between dysregulated hypoxia signaling and aberrant methylation in clear cell renal cell carcinoma?	('clear cell renal cell carcinoma', 'Disease', (72, 103))	('methylation', 'Var', (57, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (83, 103))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (72, 103))	('dysregulated hypoxia', 'Disease', (13, 33))	('methylation', 'biological_process', 'GO:0032259', ('57', '68'))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (72, 103))	('aberrant methylation', 'Var', (48, 68))	('dysregulated hypoxia', 'Disease', 'MESH:D000860', (13, 33))
35469	28536496	Dysregulated pseudo-hypoxia (through its effects on cell survival, angiogenesis, metabolism, invasion) and epigenetic dysregulation [through widespread suppression of tumor suppressor genes involved in cell cycle, apoptosis, adhesion, immune evasion, etc. ]	('effects', 'Reg', (41, 48))	('angiogenesis', 'CPA', (67, 79))	('tumor suppressor', 'biological_process', 'GO:0051726', ('167', '183'))	('cell survival', 'CPA', (52, 65))	('suppression', 'NegReg', (152, 163))	('metabolism', 'CPA', (81, 91))	('hypoxia', 'Disease', 'MESH:D000860', (20, 27))	('tumor', 'Disease', (167, 172))	('immune evasion', 'biological_process', 'GO:0042783', ('235', '249'))	('cell cycle', 'biological_process', 'GO:0007049', ('202', '212'))	('immune evasion', 'biological_process', 'GO:0051842', ('235', '249'))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('epigenetic dysregulation', 'Var', (107, 131))	('angiogenesis', 'biological_process', 'GO:0001525', ('67', '79'))	('apoptosis', 'biological_process', 'GO:0097194', ('214', '223'))	('apoptosis', 'biological_process', 'GO:0006915', ('214', '223'))	('metabolism', 'biological_process', 'GO:0008152', ('81', '91'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('167', '183'))	('hypoxia', 'Disease', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))
35472	28536496	provides one mechanistic reason for the previously reported genome wide aberrant methylation seen in ccRCC, leading to the suppression of various important tumor suppressor genes.	('methylation', 'biological_process', 'GO:0032259', ('81', '92'))	('methylation', 'Var', (81, 92))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor suppressor', 'biological_process', 'GO:0051726', ('156', '172'))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('156', '172'))	('tumor', 'Disease', (156, 161))	('suppression', 'NegReg', (123, 134))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('ccRCC', 'Disease', (101, 106))	('aberrant methylation', 'Var', (72, 92))
35473	28536496	Strikingly, this finding may also establish a link between the driver hypoxia inducible factor (HIF) pathway and aberrant methylation seen in von Hippel-Lindau (VHL) defective ccRCC.	('methylation', 'MPA', (122, 133))	('ccRCC', 'Disease', (176, 181))	('VHL', 'Disease', (161, 164))	('methylation', 'biological_process', 'GO:0032259', ('122', '133'))	('VHL', 'Disease', 'MESH:D006623', (161, 164))	('von Hippel-Lindau', 'Gene', (142, 159))	('hypoxia', 'Disease', 'MESH:D000860', (70, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (176, 181))	('hypoxia', 'Disease', (70, 77))	('von Hippel-Lindau', 'Gene', '7428', (142, 159))	('defective', 'NegReg', (166, 175))	('aberrant', 'Var', (113, 121))
35474	28536496	BiallelicVHL gene defects are seen in up to 75% of patients with sporadic ccRCC.	('ccRCC', 'Disease', (74, 79))	('defects', 'Var', (18, 25))	('patients', 'Species', '9606', (51, 59))	('VHL', 'Disease', 'MESH:D006623', (9, 12))	('VHL', 'Disease', (9, 12))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))
35480	28536496	This potential link between dysregulated hypoxia signaling and aberrant methylation in ccRCC needs to be further studied with correlative studies on HIF-1alpha/HIF-2alpha expression and DNMT1 expression in ccRCC and with HIF-alpha knockdown impact on DNMT1 expression and genome wide methylation in ccRCC.	('DNMT1', 'Gene', '1786', (186, 191))	('HIF-1alpha', 'Gene', (149, 159))	('expression', 'MPA', (257, 267))	('methylation', 'biological_process', 'GO:0032259', ('284', '295'))	('impact', 'Reg', (241, 247))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('methylation', 'biological_process', 'GO:0032259', ('72', '83'))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('HIF-2alpha', 'Gene', '2034', (160, 170))	('DNMT1', 'Gene', (251, 256))	('DNMT1', 'Gene', (186, 191))	('knockdown', 'Var', (231, 240))	('dysregulated hypoxia', 'Disease', 'MESH:D000860', (28, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (206, 211))	('ccRCC', 'Phenotype', 'HP:0006770', (299, 304))	('HIF-1alpha', 'Gene', '3091', (149, 159))	('dysregulated hypoxia', 'Disease', (28, 48))	('HIF-2alpha', 'Gene', (160, 170))	('DNMT1', 'Gene', '1786', (251, 256))
35506	33390792	In the human colon cancer cell line HT29, HSC70 knockdown decreases cell viability and leads to cell death.	('cell viability', 'CPA', (68, 82))	('HSC70', 'Gene', '3312', (42, 47))	('decreases', 'NegReg', (58, 67))	('colon cancer', 'Phenotype', 'HP:0003003', (13, 25))	('HT29', 'CellLine', 'CVCL:0320', (36, 40))	('colon cancer', 'Disease', 'MESH:D015179', (13, 25))	('human', 'Species', '9606', (7, 12))	('HSC', 'cellular_component', 'GO:0035301', ('42', '45'))	('cell death', 'biological_process', 'GO:0008219', ('96', '106'))	('leads to', 'Reg', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('HSC70', 'Gene', (42, 47))	('colon cancer', 'Disease', (13, 25))	('death', 'Disease', (101, 106))	('death', 'Disease', 'MESH:D003643', (101, 106))	('knockdown', 'Var', (48, 57))
35540	33390792	Survival curves showed that renal cancers patients with positive HSC70 expression had a significantly shorter OS than those with negative HSC70 expression.	('shorter', 'NegReg', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('HSC70', 'Gene', '3312', (65, 70))	('renal cancers', 'Disease', (28, 41))	('HSC', 'cellular_component', 'GO:0035301', ('65', '68'))	('expression', 'Var', (71, 81))	('HSC70', 'Gene', '3312', (138, 143))	('HSC', 'cellular_component', 'GO:0035301', ('138', '141'))	('renal cancer', 'Phenotype', 'HP:0009726', (28, 40))	('positive', 'Var', (56, 64))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('HSC70', 'Gene', (65, 70))	('HSC70', 'Gene', (138, 143))	('patients', 'Species', '9606', (42, 50))	('renal cancers', 'Disease', 'MESH:D007680', (28, 41))
35541	33390792	HSC70 positivity is associated with a shorter OS and poor prognosis (Figure 2).	('HSC70', 'Gene', '3312', (0, 5))	('positivity', 'Var', (6, 16))	('HSC', 'cellular_component', 'GO:0035301', ('0', '3'))	('HSC70', 'Gene', (0, 5))
35548	33390792	HSC70 copy number increased only 1.007-fold (P = 0.005) in kidney cancer samples compared to that in normal tissues in a dataset of 1071 samples from The Cancer Genome Atlas (TCGA) (Supplementary Figure 1E).	('HSC70', 'Gene', '3312', (0, 5))	('increased', 'PosReg', (18, 27))	('kidney cancer', 'Phenotype', 'HP:0009726', (59, 72))	('Cancer', 'Disease', (154, 160))	('kidney cancer', 'Disease', 'MESH:D007680', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Cancer', 'Disease', 'MESH:D009369', (154, 160))	('Cancer', 'Phenotype', 'HP:0002664', (154, 160))	('kidney cancer', 'Disease', (59, 72))	('HSC70', 'Gene', (0, 5))	('HSC', 'cellular_component', 'GO:0035301', ('0', '3'))	('copy number', 'Var', (6, 17))
35572	33390792	We believe that HSC70 expression is an independent risk factor for higher distant metastasis rates, higher death rates, and shorter OS.	('higher', 'PosReg', (67, 73))	('expression', 'Var', (22, 32))	('HSC70', 'Gene', (16, 21))	('HSC', 'cellular_component', 'GO:0035301', ('16', '19'))	('death', 'Disease', 'MESH:D003643', (107, 112))	('HSC70', 'Gene', '3312', (16, 21))	('death', 'Disease', (107, 112))	('distant metastasis rates', 'CPA', (74, 98))
35640	33061644	As summarized in Table 3, patients were divided into two subgroups based on TCEAL2 expression level: low-expression group (n = 510) and high-expression group (n = 24).	('TCEAL2', 'Gene', '140597', (76, 82))	('TCEAL2', 'Gene', (76, 82))	('patients', 'Species', '9606', (26, 34))	('high-expression', 'Var', (136, 151))
35674	32014821	SH3BGRL2, a new downregulated tumor suppressor in clear cell renal cell carcinomas In this article of EBioMedicine, Bo Peng and colleagues show that the loss of SH3BGRL2, a novel tumor suppressor gene, activated Hippo / TEAD1 / Twist1 signaling pathway and promote aggressiveness of clear cell renal cell carcinomas (ccRCC).	('signaling pathway', 'biological_process', 'GO:0007165', ('235', '252'))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('ccRCC', 'Disease', (317, 322))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (50, 82))	('aggressiveness', 'Phenotype', 'HP:0000718', (265, 279))	('clear cell renal cell carcinomas', 'Disease', 'MESH:D002292', (283, 315))	('clear cell renal cell carcinomas', 'Disease', (50, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('SH3BGRL2', 'Gene', (0, 8))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (61, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (317, 322))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('activated', 'PosReg', (202, 211))	('aggressiveness of clear cell renal cell carcinomas', 'Disease', 'MESH:D002292', (265, 315))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('SH3BGRL2', 'Gene', '83699', (161, 169))	('tumor', 'Disease', (179, 184))	('Twist1', 'Gene', (228, 234))	('TEAD1', 'Gene', (220, 225))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (283, 315))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('179', '195'))	('clear cell renal cell carcinomas', 'Disease', 'MESH:D002292', (50, 82))	('SH3BGRL2', 'Gene', '83699', (0, 8))	('Twist1', 'Gene', '7291', (228, 234))	('TEAD1', 'Gene', '7003', (220, 225))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (294, 315))	('loss', 'Var', (153, 157))	('promote', 'PosReg', (257, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('carcinomas', 'Phenotype', 'HP:0030731', (305, 315))	('tumor suppressor', 'biological_process', 'GO:0051726', ('179', '195'))	('ccRCC', 'Disease', 'MESH:D002292', (317, 322))	('tumor', 'Disease', (30, 35))	('SH3BGRL2', 'Gene', (161, 169))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))	('aggressiveness of clear cell renal cell carcinomas', 'Disease', (265, 315))
35677	32014821	The loss of SH3BGRL2 induce (i) increase of LATS1/2 expression leading to YAP phosphorylation, activation and its translocation in nucleus, (ii) activated YAP in the nucleus bind its co-transcriptional factor TEAD and (iii) TEAD directly bind Twist promoter to favor its expression and induce EMT.	('activation', 'MPA', (95, 105))	('EMT', 'CPA', (293, 296))	('YAP', 'Gene', '10413', (74, 77))	('nucleus', 'cellular_component', 'GO:0005634', ('131', '138'))	('LATS1/2', 'Gene', (44, 51))	('favor', 'PosReg', (261, 266))	('YAP', 'Gene', (155, 158))	('nucleus', 'cellular_component', 'GO:0005634', ('166', '173'))	('expression', 'MPA', (271, 281))	('induce', 'PosReg', (286, 292))	('phosphorylation', 'biological_process', 'GO:0016310', ('78', '93'))	('EMT', 'biological_process', 'GO:0001837', ('293', '296'))	('translocation', 'MPA', (114, 127))	('loss', 'Var', (4, 8))	('SH3BGRL2', 'Gene', (12, 20))	('YAP', 'Gene', (74, 77))	('YAP', 'Gene', '10413', (155, 158))	('increase', 'PosReg', (32, 40))	('expression', 'MPA', (52, 62))
35695	32014821	In Kaposi's Sarcoma, the loss of SH3BGR is due to expression of miR-K6-3p and induces cell migration and angiogenesis.	('induces', 'Reg', (78, 85))	('SH3BGR', 'Gene', (33, 39))	('angiogenesis', 'CPA', (105, 117))	("Kaposi's Sarcoma", 'Disease', 'MESH:D012514', (3, 19))	('Sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('cell migration', 'CPA', (86, 100))	('angiogenesis', 'biological_process', 'GO:0001525', ('105', '117'))	('SH3BGR', 'Gene', '6450', (33, 39))	('loss', 'NegReg', (25, 29))	('cell migration', 'biological_process', 'GO:0016477', ('86', '100'))	('miR-K6-3p', 'Var', (64, 73))	("Kaposi's Sarcoma", 'Disease', (3, 19))	("Kaposi's Sarcoma", 'Phenotype', 'HP:0100726', (3, 19))
35697	32014821	Nerveless, when SH3BGRL is mutated (R76C), it binds and activates SRC and promotes metastasis.	('promotes', 'PosReg', (74, 82))	('activates', 'PosReg', (56, 65))	('R76C', 'SUBSTITUTION', 'None', (36, 40))	('metastasis', 'CPA', (83, 93))	('binds', 'Interaction', (46, 51))	('SH3BGRL', 'Gene', '6451', (16, 23))	('SH3BGRL', 'Gene', (16, 23))	('SRC', 'Protein', (66, 69))	('R76C', 'Var', (36, 40))
35699	32014821	In bladder cancer, high expression of SH3BGRL3 is related to lower survival rate.	('lower', 'NegReg', (61, 66))	('high', 'Var', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('expression', 'MPA', (24, 34))	('SH3BGRL3', 'Gene', (38, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('SH3BGRL3', 'Gene', '83442', (38, 46))	('survival rate', 'CPA', (67, 80))
35715	29665322	Median/high expression of IL6Ralpha showed significant association with median/high expression of VEGF-A and HSP27.	('VEGF-A', 'Gene', (98, 104))	('IL6Ralpha', 'Gene', '3570', (26, 35))	('IL6Ralpha', 'Gene', (26, 35))	('median/high', 'Var', (72, 83))	('IL6', 'molecular_function', 'GO:0005138', ('26', '29'))	('association', 'Interaction', (55, 66))	('VEGF-A', 'Gene', '7422', (98, 104))	('HSP27', 'Gene', (109, 114))	('HSP27', 'Gene', '3315', (109, 114))
35723	29665322	Among many, the focus has been on angiogenesis markers 5, 6, markers of hypoxia 5, 6, 7, clinical markers 8, 9, 10, VHL mutation status 11, and single nucleotide polymorphisms 12, 13, but immune response-related markers are less studied.	('immune response', 'biological_process', 'GO:0006955', ('188', '203'))	('angiogenesis', 'biological_process', 'GO:0001525', ('34', '46'))	('mutation', 'Var', (120, 128))	('VHL', 'Gene', (116, 119))	('hypoxia', 'Disease', (72, 79))	('hypoxia', 'Disease', 'MESH:D000860', (72, 79))	('VHL', 'Gene', '7428', (116, 119))	('angiogenesis', 'CPA', (34, 46))	('single nucleotide polymorphisms', 'Var', (144, 175))
35760	29665322	Further, with high power magnification (x200 or x400), staining intensity and the proportion of positive tumour cells were recorded using a semi-quantitative grading.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('x200', 'Var', (40, 44))	('x400', 'Var', (48, 52))	('tumour', 'Disease', (105, 111))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
35776	29665322	Median/high expression of IL6Ralpha was significantly associated with median/high expression of HSP27 (Fisher's exact test, p = 0.01) (Table 4).	('HSP27', 'Gene', (96, 101))	('HSP27', 'Gene', '3315', (96, 101))	('IL6Ralpha', 'Gene', '3570', (26, 35))	('IL6Ralpha', 'Gene', (26, 35))	('IL6', 'molecular_function', 'GO:0005138', ('26', '29'))	('median/high', 'Var', (70, 81))
35805	29665322	Dysregulation of the cytokine IL6 and its receptor is involved in the pathogenesis of several diseases, such as autoimmune conditions and cancer 39.	('IL6', 'Gene', (30, 33))	('pathogenesis', 'biological_process', 'GO:0009405', ('70', '82'))	('cancer', 'Disease', (138, 144))	('IL6', 'molecular_function', 'GO:0005138', ('30', '33'))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('autoimmune conditions', 'Disease', 'MESH:D001327', (112, 133))	('autoimmune conditions', 'Phenotype', 'HP:0002960', (112, 133))	('autoimmune conditions', 'Disease', (112, 133))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('IL6', 'Gene', '3569', (30, 33))	('involved', 'Reg', (54, 62))
35826	29665322	When correlating IL6Ralpha to the other biomarkers under investigation, we found that median/high expression of IL6Ralpha was significantly associated with median/high expression of HSP27.	('HSP27', 'Gene', (182, 187))	('associated', 'Reg', (140, 150))	('IL6', 'molecular_function', 'GO:0005138', ('112', '115'))	('HSP27', 'Gene', '3315', (182, 187))	('IL6Ralpha', 'Gene', '3570', (112, 121))	('IL6Ralpha', 'Gene', (112, 121))	('IL6Ralpha', 'Gene', '3570', (17, 26))	('IL6Ralpha', 'Gene', (17, 26))	('median/high', 'Var', (156, 167))	('IL6', 'molecular_function', 'GO:0005138', ('17', '20'))
35842	29665322	Dornbush et al found an association between high expression of VEGFR2 and good treatment response 6, and Terakawa et al also found high expression of VEGFR2 to be beneficial to sunitinib treatment 52.	('VEGFR2', 'Gene', (150, 156))	('high', 'Var', (44, 48))	('association', 'Interaction', (24, 35))	('VEGFR2', 'Gene', '3791', (63, 69))	('beneficial', 'PosReg', (163, 173))	('VEGFR2', 'Gene', (63, 69))	('high expression', 'Var', (131, 146))	('VEGFR2', 'Gene', '3791', (150, 156))	('sunitinib', 'Chemical', 'MESH:D000077210', (177, 186))	('good treatment response 6', 'CPA', (74, 99))
35845	29665322	In cancers, an association between high stromal PDGFRbeta expression or signalling and poor prognosis is reported 53.	('PDGFRbeta', 'Gene', (48, 57))	('signalling', 'MPA', (72, 82))	('expression', 'MPA', (58, 68))	('signalling', 'biological_process', 'GO:0023052', ('72', '82'))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('PDGFRbeta', 'Gene', '5159', (48, 57))	('high', 'Var', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
35891	27877211	The primers used for the qRT-PCR analysis of GSTA1, CEBPA, PCBD1, PDCD6IP, GAPDH were purchased from QuantiTect Primer Assays (Qiagen, Hilden, Germany); the product numbers of the used primers were QT01671530, QT00203357, QT00001841, QT00067942, and QT00079247, respectively.	('GSTA1', 'Gene', (45, 50))	('QT00001841', 'Var', (222, 232))	('PCBD1', 'Gene', (59, 64))	('QT00203357', 'Var', (210, 220))	('PCBD1', 'Gene', '5092', (59, 64))	('GSTA1', 'Gene', '2938', (45, 50))	('QT00067942', 'Var', (234, 244))	('QT01671530', 'Var', (198, 208))	('QT00079247', 'Var', (250, 260))	('GAPDH', 'Gene', '2597', (75, 80))	('GAPDH', 'Gene', (75, 80))	('PDCD6IP', 'Gene', (66, 73))	('CEBPA', 'Gene', (52, 57))	('PDCD6IP', 'Gene', '10015', (66, 73))	('CEBPA', 'Gene', '1050', (52, 57))
35980	31763513	ccRCC cells were transfected with mimic of miR-22 or non-targeting control, and total RNA was isolated 24 and 48 hrs post-transfection.	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('RNA', 'cellular_component', 'GO:0005562', ('86', '89'))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('ccRCC', 'Disease', (0, 5))	('mimic', 'Var', (34, 39))	('ccRCC', 'Disease', 'MESH:D002292', (0, 5))	('miR-22', 'Gene', '407004', (43, 49))	('N', 'Chemical', 'MESH:D009584', (87, 88))	('miR-22', 'Gene', (43, 49))
36006	31763513	When a hypergeometric test was performed using the predicted miRNA target genes downloaded from TargetScan (version 6.2), 66 miRNAs regulated significantly more gene targets than random in the list of 2,621 genes (Supplemental Table 4).	('N', 'Chemical', 'MESH:D009584', (128, 129))	('regulated', 'Reg', (132, 141))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('gene targets', 'MPA', (161, 173))	('miRNAs', 'Var', (125, 131))	('more', 'PosReg', (156, 160))
36022	31763513	Specifically, 210 out of the 220 cases that were classified as group 1 tumors using the 2,621 genes were also placed in group 1 when the 308 genes were used.	('genes', 'Var', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
36028	31763513	Cells transfected with scrambled RNA showed no difference in invasion compared to cells without transfection, whereas cells transfected with miR-22 mimics showed significantly higher invasiveness compared to cells transfected with scrambled RNA as well as cells without transfection (Fig.	('N', 'Chemical', 'MESH:D009584', (242, 243))	('invasiveness', 'CPA', (183, 195))	('miR-22', 'Gene', '407004', (141, 147))	('miR-22', 'Gene', (141, 147))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('RNA', 'cellular_component', 'GO:0005562', ('241', '244'))	('mimics', 'Var', (148, 154))	('higher', 'PosReg', (176, 182))	('RNA', 'cellular_component', 'GO:0005562', ('33', '36'))
36033	31763513	reported that cancer-specific survival of the TCGA ccRCC patients was significantly associated with gene expression similarity to the proximal tubules.	('cancer', 'Disease', (14, 20))	('ccRCC', 'Disease', 'MESH:D002292', (51, 56))	('gene expression similarity', 'Var', (100, 126))	('patients', 'Species', '9606', (57, 65))	('gene expression', 'biological_process', 'GO:0010467', ('100', '115'))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('associated', 'Reg', (84, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('ccRCC', 'Disease', (51, 56))
36044	31763513	observed in 69 ccRCC patients that those with high miR-210 expression had an improved overall survival post nephrectomy compared to those with medium and low levels of miR-210.	('high', 'Var', (46, 50))	('miR-210', 'Gene', '406992', (51, 58))	('ccRCC', 'Disease', (15, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (15, 20))	('ccRCC', 'Disease', 'MESH:D002292', (15, 20))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('patients', 'Species', '9606', (21, 29))	('miR-210', 'Gene', (51, 58))	('miR-210', 'Gene', (168, 175))	('miR-210', 'Gene', '406992', (168, 175))	('overall survival', 'MPA', (86, 102))	('improved', 'PosReg', (77, 85))
36100	30944649	193300; ) is an autosomal dominant inherited multisystemic tumor syndrome, which causes mutations of the tumor suppressor gene VHL located on chromosome 3p25-26.	('tumor', 'Disease', (59, 64))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('105', '121'))	('causes', 'Reg', (81, 87))	('autosomal dominant inherited multisystemic tumor syndrome', 'Disease', 'MESH:D030342', (16, 73))	('chromosome', 'cellular_component', 'GO:0005694', ('142', '152'))	('mutations', 'Var', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('VHL', 'Gene', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('VHL', 'Gene', '7428', (127, 130))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor suppressor', 'biological_process', 'GO:0051726', ('105', '121'))	('tumor', 'Disease', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
36125	30944649	The expression levels of RCC-associated molecular markers were divided into two groups according to the aforementioned scores as follows: Low/negative expression (-, +) and high expression (++, +++).	('high expression', 'MPA', (173, 188))	('++', 'Var', (190, 192))	('men', 'Species', '9606', (109, 112))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('RCC', 'Disease', (25, 28))
36130	30944649	Additional genetic testing clarified that the number of patients who presented with VHL mutation on exon 1, 2 or 3 and on introns was nine (33.3%), seven (25.9%), 10 (37.0%) and two (7.4%), respectively.	('patients', 'Species', '9606', (56, 64))	('mutation', 'Var', (88, 96))	('VHL', 'Gene', '7428', (84, 87))	('VHL', 'Gene', (84, 87))
36131	30944649	The majority of patients (14/27, 51.9%) had missense mutations, six (22.2%) had large deletions, three (11.1%) had nonsense mutations, two (7.4%) had frameshift mutations and two (7.4%) had splicing mutations.	('splicing', 'biological_process', 'GO:0045292', ('190', '198'))	('missense mutations', 'Var', (44, 62))	('patients', 'Species', '9606', (16, 24))	('large deletions', 'Var', (80, 95))	('frameshift mutations', 'Var', (150, 170))
36138	30944649	2), whereas the fourth tumor was diagnosed as clear cell papillary RCC (CCPRCC), according to IHC staining that indicated the following: CAIX (+++, goblet cell staining), CK7 (+++), CD10 (-) and P504S (-) (Fig.	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('CAIX', 'Gene', (137, 141))	('CD10 (-', 'Var', (182, 189))	('RCC', 'Disease', (67, 70))	('P504S', 'Mutation', 'p.P504S', (195, 200))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('RCC', 'Disease', (75, 78))	('CK7', 'Gene', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('CD10', 'molecular_function', 'GO:0004245', ('182', '186'))	('CAIX', 'Gene', '768', (137, 141))	('tumor', 'Disease', (23, 28))	('P504S (-', 'Var', (195, 203))	('CK7', 'Gene', '3855', (171, 174))
36139	30944649	The number of patients with TNM stages T1aN0M0, T1bN0M0, T2N0M0 and T3N0M0 was 14 (51.9%), seven (25.9%), two (7.4%) and four (14.8%), respectively.	('T3N0M0', 'Var', (68, 74))	('T1bN0M0', 'Var', (48, 55))	('T2N0M0', 'Var', (57, 63))	('patients', 'Species', '9606', (14, 22))	('T1aN0M0', 'Var', (39, 46))
36185	30944649	VHL inactivation through genetic mutation is a common and early trigger that is followed by various additional mutations in different renal tumor lesions.	('renal tumor lesions', 'Disease', 'MESH:D007674', (134, 153))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('VHL', 'Gene', (0, 3))	('renal tumor lesions', 'Disease', (134, 153))	('genetic mutation', 'Var', (25, 41))	('VHL', 'Gene', '7428', (0, 3))	('renal tumor', 'Phenotype', 'HP:0009726', (134, 145))	('inactivation', 'NegReg', (4, 16))
36248	33232269	After dividing ccRCC patients into three equal quantile divisions based on selected gene expression, we found that compared with the low expression group, the high BPTF expression group exhibited better OS (P< 0.0001) and PFS (P< 0.0001) (Figure 3A, 3B).	('PFS', 'MPA', (222, 225))	('better', 'PosReg', (196, 202))	('gene expression', 'biological_process', 'GO:0010467', ('84', '99'))	('patients', 'Species', '9606', (21, 29))	('BPTF', 'Gene', (164, 168))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('BPTF', 'Gene', '2186', (164, 168))	('RCC', 'Disease', (17, 20))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (15, 20))	('high', 'Var', (159, 163))
36277	33232269	Furthermore, patients with high expression level of BPTF and SIN3A have significantly better OS but the result of CNOT1 was insignificant.	('SIN3A', 'Gene', (61, 66))	('high expression level', 'Var', (27, 48))	('patients', 'Species', '9606', (13, 21))	('CNOT1', 'Gene', '23019', (114, 119))	('better', 'PosReg', (86, 92))	('SIN', 'biological_process', 'GO:0031028', ('61', '64'))	('SIN3A', 'Gene', '25942', (61, 66))	('BPTF', 'Gene', '2186', (52, 56))	('BPTF', 'Gene', (52, 56))	('CNOT1', 'Gene', (114, 119))
36282	33232269	High expression of CBL and HUWE1 indicated significantly better OS while the similar prognostic tendency could be obtained in PIAS1, TRAF6 and UBE4B but were not significant.	('High expression', 'Var', (0, 15))	('CBL', 'Gene', '867', (19, 22))	('PIAS1', 'Gene', '8554', (126, 131))	('UBE4B', 'Gene', (143, 148))	('UBE4B', 'Gene', '10277', (143, 148))	('HUWE1', 'Gene', (27, 32))	('PIAS1', 'Gene', (126, 131))	('HUWE1', 'Gene', '10075', (27, 32))	('TRAF6', 'Gene', (133, 138))	('TRAF6', 'Gene', '7189', (133, 138))	('better', 'PosReg', (57, 63))	('CBL', 'Gene', (19, 22))
36299	33232269	In breast cancer cells, interference with SIN3A function induces epigenetic reprogramming and differentiation, and the SIN3A/HDAC complex plays an important role in maintaining sensitivity to chemotherapy in breast cancer.	('induces', 'Reg', (57, 64))	('epigenetic reprogramming', 'CPA', (65, 89))	('SIN3A', 'Gene', '25942', (119, 124))	('HDAC complex', 'cellular_component', 'GO:0000118', ('125', '137'))	('SIN3A', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('SIN', 'biological_process', 'GO:0031028', ('119', '122'))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('SIN3A', 'Gene', '25942', (42, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('SIN3A', 'Gene', (119, 124))	('breast cancer', 'Disease', (3, 16))	('SIN', 'biological_process', 'GO:0031028', ('42', '45'))	('differentiation', 'CPA', (94, 109))	('breast cancer', 'Disease', 'MESH:D001943', (208, 221))	('interference', 'Var', (24, 36))	('breast cancer', 'Disease', (208, 221))
36300	33232269	In this study, we demonstrated for the first time that high SIN3A expression suggests a good prognosis in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('expression', 'MPA', (66, 76))	('SIN', 'biological_process', 'GO:0031028', ('60', '63'))	('high', 'Var', (55, 59))	('SIN3A', 'Gene', '25942', (60, 65))	('SIN3A', 'Gene', (60, 65))
36317	33232269	Interestingly, consistent with the prognostic value of BPTF, SIN3A, CNOT1, and YY1, high expression of any of the five E3 ubiquitin ligases indicated a good prognosis in ccRCC.	('SIN3A', 'Gene', (61, 66))	('E3 ubiquitin ligases', 'Protein', (119, 139))	('high', 'Var', (84, 88))	('ubiquitin', 'molecular_function', 'GO:0031386', ('122', '131'))	('YY1', 'Gene', '7528', (79, 82))	('CNOT1', 'Gene', (68, 73))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('ccRCC', 'Phenotype', 'HP:0006770', (170, 175))	('SIN', 'biological_process', 'GO:0031028', ('61', '64'))	('SIN3A', 'Gene', '25942', (61, 66))	('YY1', 'Gene', (79, 82))	('BPTF', 'Gene', (55, 59))	('CNOT1', 'Gene', '23019', (68, 73))	('RCC', 'Disease', (172, 175))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))	('BPTF', 'Gene', '2186', (55, 59))
36327	33232269	CNOT1, a transcriptional repressor, is crucial for maintaining embryonic stem cells in a pluripotent state, and a specific CNOT1 mutation can lead to holoprosencephaly and the novel syndrome of pancreatic agenesis.	('CNOT1', 'Gene', '23019', (123, 128))	('syndrome', 'Disease', (182, 190))	('lead to', 'Reg', (142, 149))	('mutation', 'Var', (129, 137))	('CNOT1', 'Gene', (0, 5))	('CNOT1', 'Gene', (123, 128))	('holoprosencephaly', 'Phenotype', 'HP:0001360', (150, 167))	('holoprosencephaly', 'Disease', 'MESH:D016142', (150, 167))	('pancreatic agenesis', 'Disease', 'MESH:C564908', (194, 213))	('CNOT1', 'Gene', '23019', (0, 5))	('pancreatic agenesis', 'Disease', (194, 213))	('holoprosencephaly', 'Disease', (150, 167))	('pancreatic agenesis', 'Phenotype', 'HP:0100801', (194, 213))
36329	33232269	In our study, we found that CNOT1 played an important role in chromatin remodeling, and we demonstrated for the first time that high CNOT1 expression suggested a good prognosis in ccRCC.	('CNOT1', 'Gene', (133, 138))	('chromatin', 'cellular_component', 'GO:0000785', ('62', '71'))	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('high', 'Var', (128, 132))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('62', '82'))	('CNOT1', 'Gene', (28, 33))	('CNOT1', 'Gene', '23019', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('RCC', 'Disease', (182, 185))	('CNOT1', 'Gene', '23019', (28, 33))
36405	29472550	In addition, PIM1-mediated phosphorylation of c-Myc activates the expression of the above transcription factors to synergistically promote EMT but does not activate Smads.	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('c-Myc', 'Gene', '4609', (46, 51))	('activates', 'PosReg', (52, 61))	('Smad', 'Gene', '4089;4089;4092', (165, 169))	('EMT', 'biological_process', 'GO:0001837', ('139', '142'))	('c-Myc', 'Gene', (46, 51))	('expression', 'MPA', (66, 76))	('EMT', 'CPA', (139, 142))	('phosphorylation', 'Var', (27, 42))	('transcription', 'biological_process', 'GO:0006351', ('90', '103'))	('Smad', 'Gene', (165, 169))	('promote', 'PosReg', (131, 138))
36406	29472550	Collectively, our results demonstrate that aberrant expression of PIM1 contributes to ccRCC development and progression.	('aberrant expression', 'Var', (43, 62))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('progression', 'CPA', (108, 119))	('contributes', 'Reg', (71, 82))	('PIM1', 'Gene', (66, 70))
36417	29472550	In addition, PIM1 exerts its tumorigenicity by regulating c-Myc; PIM1 phosphorylates c-Myc at S62, which increases c-Myc protein stability, thereby enhancing the transcriptional activity of c-Myc.	('c-Myc', 'Gene', (85, 90))	('c-Myc', 'Gene', (58, 63))	('c-Myc', 'Gene', '4609', (190, 195))	('c-Myc', 'Gene', '4609', (115, 120))	('c-Myc', 'Gene', (115, 120))	('transcriptional activity', 'MPA', (162, 186))	('enhancing', 'PosReg', (148, 157))	('c-Myc', 'Gene', (190, 195))	('c-Myc', 'Gene', '4609', (85, 90))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('increases', 'PosReg', (105, 114))	('PIM1', 'Var', (65, 69))	('c-Myc', 'Gene', '4609', (58, 63))
36421	29472550	EMT is characterised by several key events: cell polarity changes, including loss-of-apical-basal polarity and the establishment of front-rear polarity; reorganisation of the cytoskeleton; downregulation of the epithelial marker E-cadherin to disassemble cell junctions; upregulation of the mesenchymal markers N-cadherin and Vimentin to increase cell protrusions and motility; and degradation of the extracellular matrix (ECM) to acquire invasive properties.	('E-cadherin', 'Gene', (229, 239))	('downregulation', 'NegReg', (189, 203))	('Vimentin', 'Gene', (326, 334))	('E-cadherin', 'Gene', '999', (229, 239))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('401', '421'))	('increase', 'PosReg', (338, 346))	('cell polarity', 'biological_process', 'GO:0007163', ('44', '57'))	('loss-of-apical-basal', 'NegReg', (77, 97))	('Vimentin', 'cellular_component', 'GO:0045099', ('326', '334'))	('changes', 'Var', (58, 65))	('N-cadherin', 'Gene', (311, 321))	('invasive properties', 'CPA', (439, 458))	('degradation', 'biological_process', 'GO:0009056', ('382', '393'))	('N-cadherin', 'Gene', '1000', (311, 321))	('EMT', 'biological_process', 'GO:0001837', ('0', '3'))	('degradation of the extracellular matrix', 'CPA', (382, 421))	('cell protrusions and motility', 'CPA', (347, 376))	('cadherin', 'molecular_function', 'GO:0008014', ('313', '321'))	('cadherin', 'molecular_function', 'GO:0008014', ('231', '239'))	('Vimentin', 'cellular_component', 'GO:0045098', ('326', '334'))	('upregulation', 'PosReg', (271, 283))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('175', '187'))	('Vimentin', 'Gene', '7431', (326, 334))
36422	29472550	Furthermore, EMT is orchestrated and highly modulated by a number of upstream transcription factors, such as ZEB1, ZEB2, Snail1, Snail2 and Twist, and other regulators and processes, including non-coding miRNAs and alternative splicing.	('Twist', 'Gene', (140, 145))	('ZEB2', 'Gene', (115, 119))	('EMT', 'biological_process', 'GO:0001837', ('13', '16'))	('Snail1', 'Gene', '6615', (121, 127))	('alternative splicing', 'Var', (215, 235))	('ZEB1', 'Gene', (109, 113))	('ZEB1', 'Gene', '6935', (109, 113))	('Snail2', 'Gene', (129, 135))	('Snail2', 'Gene', '6591', (129, 135))	('modulated', 'Reg', (44, 53))	('non-coding miRNAs', 'Var', (193, 210))	('Snail1', 'Gene', (121, 127))	('ZEB2', 'Gene', '9839', (115, 119))	('splicing', 'biological_process', 'GO:0045292', ('227', '235'))	('Twist', 'Gene', '7291', (140, 145))	('transcription', 'biological_process', 'GO:0006351', ('78', '91'))
36427	29472550	A series of in vitro and in vivo experiments indicated that stable knockdown of PIM1 expression in ccRCC cells significantly impaired their capacity for proliferation, migration, invasion and angiogenesis.	('impaired', 'NegReg', (125, 133))	('PIM1', 'Gene', (80, 84))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('knockdown', 'Var', (67, 76))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Disease', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('angiogenesis', 'CPA', (192, 204))	('angiogenesis', 'biological_process', 'GO:0001525', ('192', '204'))
36433	29472550	In addition, survival curve analysis revealed that patients with high PIM1 expression (>median H-scores) had a dramatically lower survival rate than patients with low-PIM1 expression (<median H-scores) (Fig.	('survival rate', 'CPA', (130, 143))	('PIM1', 'Gene', (70, 74))	('patients', 'Species', '9606', (149, 157))	('lower', 'NegReg', (124, 129))	('high', 'Var', (65, 69))	('patients', 'Species', '9606', (51, 59))
36434	29472550	The median survival time of kidney cancer patients with high-PIM1 expression was significantly shorter than that of those with low-PIM1 expression.	('kidney cancer', 'Phenotype', 'HP:0009726', (28, 41))	('kidney cancer', 'Disease', 'MESH:D007680', (28, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('high-PIM1 expression', 'Var', (56, 76))	('kidney cancer', 'Disease', (28, 41))	('patients', 'Species', '9606', (42, 50))	('shorter', 'NegReg', (95, 102))
36438	29472550	To verify that PIM1 overexpression promotes kidney cancer, we generated four ccRCC cell lines using both ACHN and 786-O cells to measure proliferation in vitro.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('overexpression', 'Var', (20, 34))	('ACHN', 'Chemical', '-', (105, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('PIM1', 'Gene', (15, 19))	('kidney cancer', 'Disease', (44, 57))	('promotes', 'PosReg', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('kidney cancer', 'Phenotype', 'HP:0009726', (44, 57))	('kidney cancer', 'Disease', 'MESH:D007680', (44, 57))	('RCC', 'Disease', (79, 82))
36439	29472550	As shown by the Edu assay results, depletion of PIM1 with the lentiviral shRNA interference technique dramatically attenuated the number of Edu-positive ACHN and 786-O cells, suggesting that silencing of PIM1 effectively inhibits cell proliferation in vitro (Fig.	('Edu', 'Chemical', '-', (16, 19))	('cell proliferation in vitro', 'CPA', (230, 257))	('PIM1', 'Gene', (204, 208))	('cell proliferation', 'biological_process', 'GO:0008283', ('230', '248'))	('attenuated', 'NegReg', (115, 125))	('silencing', 'Var', (191, 200))	('Edu', 'Chemical', '-', (140, 143))	('inhibits', 'NegReg', (221, 229))	('PIM1', 'Gene', (48, 52))	('depletion', 'MPA', (35, 44))	('ACHN', 'Chemical', '-', (153, 157))
36440	29472550	To examine whether knockdown of PIM1 could affect the long-term proliferation of ccRCC cells, the cells were used in colony formation assays for the indicated interval.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('formation', 'biological_process', 'GO:0009058', ('124', '133'))	('knockdown', 'Var', (19, 28))	('PIM1', 'Gene', (32, 36))	('affect', 'Reg', (43, 49))
36441	29472550	We observed that the ability of ACHN and 786-O cells to form colonies was remarkably impaired when PIM1 was knocked down (Fig.	('ACHN', 'Chemical', '-', (32, 36))	('PIM1', 'Gene', (99, 103))	('knocked down', 'Var', (108, 120))	('impaired', 'NegReg', (85, 93))	('form colonies', 'CPA', (56, 69))
36443	29472550	Having observed a dramatic change in cell proliferation following the depletion of PIM1, we utilised a series of assays to detect whether knockdown of PIM1 affected ccRCC cell migration, invasion and angiogenesis.	('cell proliferation', 'biological_process', 'GO:0008283', ('37', '55'))	('angiogenesis', 'CPA', (200, 212))	('knockdown', 'Var', (138, 147))	('change', 'Reg', (27, 33))	('ccRCC', 'Phenotype', 'HP:0006770', (165, 170))	('angiogenesis', 'biological_process', 'GO:0001525', ('200', '212'))	('PIM1', 'Gene', (151, 155))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('cell migration', 'biological_process', 'GO:0016477', ('171', '185'))	('invasion', 'CPA', (187, 195))	('affected', 'Reg', (156, 164))
36445	29472550	Next, Matrigel Transwell assays showed that PIM1 depletion greatly inhibited the invasion capacity of ACHN and 786-O cells (Fig.	('ACHN', 'Chemical', '-', (102, 106))	('PIM1', 'Gene', (44, 48))	('inhibited', 'NegReg', (67, 76))	('depletion', 'Var', (49, 58))
36447	29472550	Immunoblotting assays showed that PIM1 silencing clearly decreased MMP2 and MMP9 expression (Fig.	('MMP2', 'Gene', '4313', (67, 71))	('MMP2', 'Gene', (67, 71))	('MMP9', 'Gene', (76, 80))	('MMP9', 'molecular_function', 'GO:0004229', ('76', '80'))	('MMP9', 'Gene', '4318', (76, 80))	('MMP2', 'molecular_function', 'GO:0004228', ('67', '71'))	('PIM1', 'Gene', (34, 38))	('silencing', 'Var', (39, 48))	('decreased', 'NegReg', (57, 66))	('expression', 'MPA', (81, 91))
36450	29472550	To determine the underlying molecular signalling pathways through which depletion of PIM1 elicits anti-proliferation, anti-migration and anti-invasion effects on cancer cells, we examined the effects of PIM1 depletion on EMT in ccRCC cells.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('anti-migration', 'CPA', (118, 132))	('cancer', 'Disease', (162, 168))	('elicits', 'Reg', (90, 97))	('anti-proliferation', 'CPA', (98, 116))	('PIM1', 'Gene', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('signalling', 'biological_process', 'GO:0023052', ('38', '48'))	('depletion', 'Var', (72, 81))	('EMT', 'biological_process', 'GO:0001837', ('221', '224'))	('RCC', 'Disease', 'MESH:C538614', (230, 233))	('RCC', 'Disease', (230, 233))	('RCC', 'Phenotype', 'HP:0005584', (230, 233))	('ccRCC', 'Phenotype', 'HP:0006770', (228, 233))
36451	29472550	Immunofluorescence assays showed dramatic upregulation of the epithelial phenotype marker E-cadherin and downregulation of the mesenchymal phenotype marker N-cadherin in both ACHN and 786-O cells transfected with PIM1shRNA or control-shRNA (Fig.	('downregulation', 'NegReg', (105, 119))	('ACHN', 'Chemical', '-', (175, 179))	('mesenchymal phenotype', 'CPA', (127, 148))	('epithelial phenotype', 'CPA', (62, 82))	('cadherin', 'molecular_function', 'GO:0008014', ('158', '166'))	('E-cadherin', 'Gene', '999', (90, 100))	('PIM1shRNA', 'Var', (213, 222))	('cadherin', 'molecular_function', 'GO:0008014', ('92', '100'))	('N-cadherin', 'Gene', (156, 166))	('E-cadherin', 'Gene', (90, 100))	('upregulation', 'PosReg', (42, 54))	('N-cadherin', 'Gene', '1000', (156, 166))
36452	29472550	Furthermore, immunoblotting assays showed that knockdown of PIM1 significantly increased E-cadherin protein expression levels and decreased N-cadherin and Vimentin protein expression levels (Fig.	('N-cadherin', 'Gene', (140, 150))	('increased', 'PosReg', (79, 88))	('Vimentin', 'Gene', (155, 163))	('cadherin', 'molecular_function', 'GO:0008014', ('91', '99'))	('Vimentin', 'cellular_component', 'GO:0045099', ('155', '163'))	('PIM1', 'Gene', (60, 64))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('E-cadherin', 'Gene', (89, 99))	('Vimentin', 'Gene', '7431', (155, 163))	('knockdown', 'Var', (47, 56))	('N-cadherin', 'Gene', '1000', (140, 150))	('E-cadherin', 'Gene', '999', (89, 99))	('cadherin', 'molecular_function', 'GO:0008014', ('142', '150'))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('Vimentin', 'cellular_component', 'GO:0045098', ('155', '163'))	('decreased', 'NegReg', (130, 139))
36454	29472550	Collectively, these data reveal that depletion of PIM1 attenuates EMT in ccRCC cells via downregulation of the above transcription factors.	('PIM1', 'Gene', (50, 54))	('depletion', 'Var', (37, 46))	('attenuates', 'NegReg', (55, 65))	('downregulation', 'NegReg', (89, 103))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('transcription', 'biological_process', 'GO:0006351', ('117', '130'))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('EMT', 'biological_process', 'GO:0001837', ('66', '69'))	('EMT in', 'CPA', (66, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))
36455	29472550	To investigate the molecular mechanism underlying EMT in ccRCC cells, immunoblotting assays were performed to quantify the expression levels of Smad2, Smad3, p-Smad2 and p-Smad3 in both ACHN and 786-O cells transfected with PIM1shRNA or control-shRNA.	('ACHN', 'Chemical', '-', (186, 190))	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('Smad2', 'Gene', '4087', (160, 165))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('EMT', 'biological_process', 'GO:0001837', ('50', '53'))	('Smad3', 'Gene', '4088', (172, 177))	('Smad2', 'Gene', (160, 165))	('Smad2', 'Gene', '4087', (144, 149))	('Smad3', 'Gene', '4088', (151, 156))	('PIM1shRNA', 'Var', (224, 233))	('Smad2', 'Gene', (144, 149))	('Smad3', 'Gene', (172, 177))	('Smad3', 'Gene', (151, 156))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
36457	29472550	However, depletion of PIM1 strongly reduced the levels of phosphorylated Smad2 and Smad3 (Fig.	('Smad2', 'Gene', (73, 78))	('PIM1', 'Gene', (22, 26))	('Smad3', 'Gene', '4088', (83, 88))	('levels of phosphorylated', 'MPA', (48, 72))	('reduced', 'NegReg', (36, 43))	('Smad3', 'Gene', (83, 88))	('Smad2', 'Gene', '4087', (73, 78))	('depletion', 'Var', (9, 18))
36460	29472550	The results clearly showed interactions between endogenous PIM1 and endogenous p-Smad2 in the nuclei of both ACHN and 786-O cells, whereas knockdown of PIM1 remarkably attenuated the interaction between PIM1 and p-Smad2 in the nucleus (Fig.	('attenuated', 'NegReg', (168, 178))	('ACHN', 'Chemical', '-', (109, 113))	('Smad2', 'Gene', '4087', (214, 219))	('interactions', 'Interaction', (27, 39))	('PIM1', 'Gene', (152, 156))	('nucleus', 'cellular_component', 'GO:0005634', ('227', '234'))	('Smad2', 'Gene', (214, 219))	('knockdown', 'Var', (139, 148))	('Smad2', 'Gene', (81, 86))	('Smad2', 'Gene', '4087', (81, 86))	('interaction', 'Interaction', (183, 194))
36462	29472550	Next, co-immunoprecipitation (co-IP) assays with a PIM1-specific antibody revealed that p-Smad2 co-immunoprecipitated with PIM1 and that the interaction between endogenous PIM1 and endogenous p-Smad2 was significantly decreased following knockdown of PIM1 (Fig.	('Smad2', 'Gene', (194, 199))	('Smad2', 'Gene', '4087', (194, 199))	('antibody', 'cellular_component', 'GO:0042571', ('65', '73'))	('interaction', 'Interaction', (141, 152))	('knockdown', 'Var', (238, 247))	('antibody', 'cellular_component', 'GO:0019815', ('65', '73'))	('PIM1', 'Gene', (251, 255))	('antibody', 'cellular_component', 'GO:0019814', ('65', '73'))	('antibody', 'molecular_function', 'GO:0003823', ('65', '73'))	('Smad2', 'Gene', '4087', (90, 95))	('decreased', 'NegReg', (218, 227))	('Smad2', 'Gene', (90, 95))
36464	29472550	Additionally, an in vitro PIM1 kinase assay revealed that PIM1 directly phosphorylated Smad2 and Smad3 and that inhibition of PIM1 kinase activity with SGI-1776 significantly reduced the protein levels of p-Smad2 and p-Smad3 (Supplementary Figure 1A and B).	('Smad3', 'Gene', (97, 102))	('inhibition', 'Var', (112, 122))	('reduced', 'NegReg', (175, 182))	('Smad2', 'Gene', '4087', (207, 212))	('Smad3', 'Gene', (219, 224))	('Smad3', 'Gene', '4088', (219, 224))	('Smad2', 'Gene', (207, 212))	('protein levels', 'MPA', (187, 201))	('SGI-1776', 'Gene', (152, 160))	('Smad2', 'Gene', '4087', (87, 92))	('Smad3', 'Gene', '4088', (97, 102))	('kinase activity', 'molecular_function', 'GO:0016301', ('131', '146'))	('PIM1', 'Gene', (126, 130))	('Smad2', 'Gene', (87, 92))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))
36468	29472550	Immunoblotting and co-IP assays were performed, and the results indicated that PIM1 interacts with c-Myc and phosphorylates c-Myc at S62 moreover, knockdown of PIM1 strongly decreased the level of p-c-Myc but not total c-Myc (Fig.	('PIM1', 'Gene', (160, 164))	('c-Myc', 'Gene', (199, 204))	('decreased', 'NegReg', (174, 183))	('c-Myc', 'Gene', '4609', (124, 129))	('c-Myc', 'Gene', (219, 224))	('c-Myc', 'Gene', (124, 129))	('c-Myc', 'Gene', '4609', (219, 224))	('knockdown', 'Var', (147, 156))	('c-Myc', 'Gene', '4609', (99, 104))	('c-Myc', 'Gene', '4609', (199, 204))	('c-Myc', 'Gene', (99, 104))
36470	29472550	Immunofluorescence assays showed that 10058-F4 treatment further upregulated E-cadherin expression and downregulated N-cadherin expression (Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('79', '87'))	('N-cadherin', 'Gene', (117, 127))	('E-cadherin', 'Gene', (77, 87))	('E-cadherin', 'Gene', '999', (77, 87))	('downregulated', 'NegReg', (103, 116))	('N-cadherin', 'Gene', '1000', (117, 127))	('10058-F4', 'Var', (38, 46))	('cadherin', 'molecular_function', 'GO:0008014', ('119', '127'))	('upregulated', 'PosReg', (65, 76))	('expression', 'MPA', (88, 98))
36471	29472550	Furthermore, immunoblotting assays revealed that the presence of 10058-F4 significantly increased E-cadherin protein levels and repressed N-cadherin and Vimentin expression levels (Fig.	('Vimentin', 'cellular_component', 'GO:0045099', ('153', '161'))	('cadherin', 'molecular_function', 'GO:0008014', ('100', '108'))	('E-cadherin', 'Gene', (98, 108))	('repressed', 'NegReg', (128, 137))	('E-cadherin', 'Gene', '999', (98, 108))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('cadherin', 'molecular_function', 'GO:0008014', ('140', '148'))	('increased', 'PosReg', (88, 97))	('Vimentin', 'Gene', (153, 161))	('N-cadherin', 'Gene', (138, 148))	('Vimentin', 'Gene', '7431', (153, 161))	('10058-F4', 'Var', (65, 73))	('Vimentin', 'cellular_component', 'GO:0045098', ('153', '161'))	('N-cadherin', 'Gene', '1000', (138, 148))
36472	29472550	Additionally, 10058-F4 treatment remarkably reduced the expression of transcription factors ZEB1, ZEB2, Snail1, Snail2 and Twist (Fig.	('ZEB2', 'Gene', '9839', (98, 102))	('Twist', 'Gene', '7291', (123, 128))	('Snail2', 'Gene', (112, 118))	('Twist', 'Gene', (123, 128))	('ZEB1', 'Gene', '6935', (92, 96))	('Snail2', 'Gene', '6591', (112, 118))	('ZEB1', 'Gene', (92, 96))	('ZEB2', 'Gene', (98, 102))	('expression', 'MPA', (56, 66))	('reduced', 'NegReg', (44, 51))	('10058-F4', 'Var', (14, 22))	('transcription', 'biological_process', 'GO:0006351', ('70', '83'))	('Snail1', 'Gene', (104, 110))	('Snail1', 'Gene', '6615', (104, 110))
36473	29472550	However, 10058-F4 treatment had no obvious effect on Smad proteins (Fig.	('Smad', 'Gene', '4089;4089;4092', (53, 57))	('10058-F4 treatment', 'Var', (9, 27))	('Smad', 'Gene', (53, 57))
36474	29472550	We thereby speculated that phosphorylation of c-Myc via interactions with PIM1 activates the expression of the above transcription factors to promote EMT without activating Smads.	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('Smad', 'Gene', '4089;4089;4092', (173, 177))	('c-Myc', 'Gene', '4609', (46, 51))	('PIM1', 'Gene', (74, 78))	('transcription', 'biological_process', 'GO:0006351', ('117', '130'))	('c-Myc', 'Gene', (46, 51))	('Smad', 'Gene', (173, 177))	('EMT', 'CPA', (150, 153))	('interactions', 'Interaction', (56, 68))	('expression', 'MPA', (93, 103))	('EMT', 'biological_process', 'GO:0001837', ('150', '153'))	('phosphorylation', 'Var', (27, 42))	('promote', 'PosReg', (142, 149))	('activates', 'PosReg', (79, 88))
36476	29472550	Immunofluorescence assays showed that depletion of PIM1 blocked EMT by inhibiting crosstalk between signalling pathways, including independent Smads and c-Myc, and that this process was reversed by TGF-beta treatment, which led to the downregulation of E-cadherin expression and upregulation of N-cadherin expression compared to untreated cells (Fig.	('expression', 'MPA', (264, 274))	('E-cadherin', 'Gene', (253, 263))	('E-cadherin', 'Gene', '999', (253, 263))	('c-Myc', 'Gene', (153, 158))	('cadherin', 'molecular_function', 'GO:0008014', ('255', '263'))	('c-Myc', 'Gene', '4609', (153, 158))	('Smad', 'Gene', (143, 147))	('N-cadherin', 'Gene', (295, 305))	('signalling', 'biological_process', 'GO:0023052', ('100', '110'))	('N-cadherin', 'Gene', '1000', (295, 305))	('downregulation', 'NegReg', (235, 249))	('TGF-beta', 'Gene', '7040', (198, 206))	('crosstalk', 'MPA', (82, 91))	('inhibiting', 'NegReg', (71, 81))	('Smad', 'Gene', '4089;4089;4092', (143, 147))	('depletion', 'Var', (38, 47))	('expression', 'MPA', (306, 316))	('cadherin', 'molecular_function', 'GO:0008014', ('297', '305'))	('EMT', 'biological_process', 'GO:0001837', ('64', '67'))	('TGF-beta', 'Gene', (198, 206))	('PIM1', 'Gene', (51, 55))	('EMT', 'CPA', (64, 67))	('blocked', 'NegReg', (56, 63))	('upregulation', 'PosReg', (279, 291))
36477	29472550	Taken together, our data suggest that phosphorylation of c-Myc via interactions with PIM1 activates the expression of downstream transcription factors (ZEB1, ZEB2, Snail1, Snail2 and Twist), without activating Smads, to synergistically promote EMT.	('Snail2', 'Gene', (172, 178))	('ZEB2', 'Gene', (158, 162))	('Snail1', 'Gene', '6615', (164, 170))	('Twist', 'Gene', '7291', (183, 188))	('Snail2', 'Gene', '6591', (172, 178))	('c-Myc', 'Gene', (57, 62))	('interactions', 'Interaction', (67, 79))	('ZEB1', 'Gene', '6935', (152, 156))	('EMT', 'CPA', (244, 247))	('ZEB2', 'Gene', '9839', (158, 162))	('c-Myc', 'Gene', '4609', (57, 62))	('Smad', 'Gene', '4089;4089;4092', (210, 214))	('Snail1', 'Gene', (164, 170))	('expression', 'MPA', (104, 114))	('EMT', 'biological_process', 'GO:0001837', ('244', '247'))	('promote', 'PosReg', (236, 243))	('phosphorylation', 'Var', (38, 53))	('Twist', 'Gene', (183, 188))	('activates', 'PosReg', (90, 99))	('ZEB1', 'Gene', (152, 156))	('PIM1', 'Gene', (85, 89))	('phosphorylation', 'biological_process', 'GO:0016310', ('38', '53'))	('transcription', 'biological_process', 'GO:0006351', ('129', '142'))	('Smad', 'Gene', (210, 214))
36483	29472550	In addition, IHC for p-Smad2, p-Smad3 and p-c-Myc was performed on the tumour edge tissues of the PIM1 knockdown mice and control mice to confirm tumour invasiveness.	('mice', 'Species', '10090', (130, 134))	('tumour', 'Disease', 'MESH:D009369', (71, 77))	('tumour', 'Disease', (71, 77))	('tumour', 'Disease', (146, 152))	('Smad2', 'Gene', (23, 28))	('Smad2', 'Gene', '4087', (23, 28))	('Smad3', 'Gene', (32, 37))	('PIM1', 'Gene', (98, 102))	('c-Myc', 'Gene', '4609', (44, 49))	('tumour invasiveness', 'Disease', (146, 165))	('tumour invasiveness', 'Disease', 'MESH:D009361', (146, 165))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('mice', 'Species', '10090', (113, 117))	('Smad3', 'Gene', '4088', (32, 37))	('knockdown', 'Var', (103, 112))	('c-Myc', 'Gene', (44, 49))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
36485	29472550	Collectively, these results demonstrate that PIM1 functions as a tumour promoter in ccRCC and that depletion of PIM1 dramatically attenuates ccRCC oncogenic properties in vivo.	('oncogenic properties', 'CPA', (147, 167))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('ccRCC', 'Phenotype', 'HP:0006770', (141, 146))	('PIM1', 'Gene', (112, 116))	('depletion', 'Var', (99, 108))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('RCC', 'Disease', (143, 146))	('attenuates', 'NegReg', (130, 140))	('RCC', 'Disease', (86, 89))	('tumour', 'Disease', (65, 71))
36491	29472550	In addition, phosphorylation of c-Myc through its interaction with PIM1 activated the expression of the above transcription factors to synergistically promote EMT without activating Smads.	('Smad', 'Gene', (182, 186))	('EMT', 'biological_process', 'GO:0001837', ('159', '162'))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('EMT', 'CPA', (159, 162))	('PIM1', 'Gene', (67, 71))	('c-Myc', 'Gene', '4609', (32, 37))	('phosphorylation', 'Var', (13, 28))	('expression', 'MPA', (86, 96))	('Smad', 'Gene', '4089;4089;4092', (182, 186))	('interaction', 'Interaction', (50, 61))	('promote', 'PosReg', (151, 158))	('c-Myc', 'Gene', (32, 37))	('activated', 'PosReg', (72, 81))	('transcription', 'biological_process', 'GO:0006351', ('110', '123'))
36492	29472550	These findings revealed a potential molecular mechanism in which PIM1 mediates crosstalk between signalling pathways, including independent Smads and c-Myc, which then target downstream transcription factors (ZEB1, ZEB2, Snail1, Snail2 and Twist) to trigger EMT; moreover, hyperactivation of EMT was shown to be associated with ccRCC cell proliferation, motility and invasion, as well as angiogenesis (Fig.	('RCC', 'Disease', (330, 333))	('associated', 'Reg', (312, 322))	('Snail1', 'Gene', '6615', (221, 227))	('EMT', 'biological_process', 'GO:0001837', ('258', '261'))	('ccRCC', 'Phenotype', 'HP:0006770', (328, 333))	('Snail2', 'Gene', (229, 235))	('Snail2', 'Gene', '6591', (229, 235))	('transcription', 'biological_process', 'GO:0006351', ('186', '199'))	('hyperactivation', 'Var', (273, 288))	('ZEB1', 'Gene', '6935', (209, 213))	('RCC', 'Disease', 'MESH:C538614', (330, 333))	('Snail1', 'Gene', (221, 227))	('Smad', 'Gene', '4089;4089;4092', (140, 144))	('invasion', 'CPA', (367, 375))	('Twist', 'Gene', (240, 245))	('c-Myc', 'Gene', (150, 155))	('EMT', 'Gene', (292, 295))	('motility', 'CPA', (354, 362))	('c-Myc', 'Gene', '4609', (150, 155))	('ZEB1', 'Gene', (209, 213))	('cell proliferation', 'biological_process', 'GO:0008283', ('334', '352'))	('angiogenesis', 'CPA', (388, 400))	('angiogenesis', 'biological_process', 'GO:0001525', ('388', '400'))	('Twist', 'Gene', '7291', (240, 245))	('ZEB2', 'Gene', (215, 219))	('signalling', 'biological_process', 'GO:0023052', ('97', '107'))	('RCC', 'Phenotype', 'HP:0005584', (330, 333))	('ZEB2', 'Gene', '9839', (215, 219))	('Smad', 'Gene', (140, 144))	('EMT', 'biological_process', 'GO:0001837', ('292', '295'))
36496	29472550	Furthermore, we showed that depletion of PIM1 effectively blocked EMT through the upregulation of E-cadherin expression and downregulation of N-cadherin and Vimentin expression in ccRCC cells.	('Vimentin', 'cellular_component', 'GO:0045099', ('157', '165'))	('EMT', 'biological_process', 'GO:0001837', ('66', '69'))	('depletion', 'Var', (28, 37))	('PIM1', 'Gene', (41, 45))	('Vimentin', 'Gene', '7431', (157, 165))	('E-cadherin', 'Gene', (98, 108))	('E-cadherin', 'Gene', '999', (98, 108))	('blocked', 'NegReg', (58, 65))	('Vimentin', 'Gene', (157, 165))	('downregulation', 'NegReg', (124, 138))	('EMT', 'CPA', (66, 69))	('Vimentin', 'cellular_component', 'GO:0045098', ('157', '165'))	('cadherin', 'molecular_function', 'GO:0008014', ('100', '108'))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('RCC', 'Disease', (182, 185))	('expression', 'MPA', (166, 176))	('expression', 'MPA', (109, 119))	('upregulation', 'PosReg', (82, 94))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('N-cadherin', 'Gene', (142, 152))	('cadherin', 'molecular_function', 'GO:0008014', ('144', '152'))	('N-cadherin', 'Gene', '1000', (142, 152))
36497	29472550	We further showed that knockdown of PIM1 significantly repressed the expression of EMT-inducing transcription factors (ZEB1, ZEB2, Snail1, Snail2 and Twist).	('Snail2', 'Gene', (139, 145))	('Snail1', 'Gene', '6615', (131, 137))	('Twist', 'Gene', '7291', (150, 155))	('Snail2', 'Gene', '6591', (139, 145))	('PIM1', 'Gene', (36, 40))	('Twist', 'Gene', (150, 155))	('repressed', 'NegReg', (55, 64))	('transcription', 'biological_process', 'GO:0006351', ('96', '109'))	('knockdown', 'Var', (23, 32))	('ZEB1', 'Gene', (119, 123))	('expression', 'MPA', (69, 79))	('ZEB1', 'Gene', '6935', (119, 123))	('ZEB2', 'Gene', '9839', (125, 129))	('EMT', 'biological_process', 'GO:0001837', ('83', '86'))	('Snail1', 'Gene', (131, 137))	('ZEB2', 'Gene', (125, 129))
36498	29472550	Taken together, our results suggest that depletion of PIM1 attenuates EMT in ccRCC cells by downregulating EMT-promoting transcription factor expression.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('PIM1', 'Gene', (54, 58))	('EMT-promoting transcription factor expression', 'MPA', (107, 152))	('attenuates', 'NegReg', (59, 69))	('EMT', 'biological_process', 'GO:0001837', ('70', '73'))	('transcription', 'biological_process', 'GO:0006351', ('121', '134'))	('EMT', 'biological_process', 'GO:0001837', ('107', '110'))	('transcription factor', 'molecular_function', 'GO:0000981', ('121', '141'))	('depletion', 'Var', (41, 50))	('downregulating', 'NegReg', (92, 106))	('EMT in', 'CPA', (70, 76))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
36500	29472550	In this study, we demonstrated that both MMP2 and MMP9 proteins were significantly decreased when EMT was attenuated by the depletion of PIM1, indicating that knockdown of PIM1 potentially impairs the abovementioned MMP2 and MMP9 regulatory loop, thereby blocking EMT.	('impairs', 'NegReg', (189, 196))	('blocking', 'NegReg', (255, 263))	('MMP2', 'Gene', (216, 220))	('MMP2', 'Gene', (41, 45))	('EMT', 'biological_process', 'GO:0001837', ('98', '101'))	('MMP9', 'Gene', (50, 54))	('MMP2', 'Gene', '4313', (216, 220))	('MMP2', 'Gene', '4313', (41, 45))	('MMP9', 'Gene', '4318', (225, 229))	('MMP9', 'Gene', '4318', (50, 54))	('MMP9', 'Gene', (225, 229))	('MMP2', 'molecular_function', 'GO:0004228', ('41', '45'))	('EMT', 'biological_process', 'GO:0001837', ('264', '267'))	('MMP2', 'molecular_function', 'GO:0004228', ('216', '220'))	('knockdown', 'Var', (159, 168))	('EMT', 'CPA', (264, 267))	('decreased', 'NegReg', (83, 92))	('MMP9', 'molecular_function', 'GO:0004229', ('50', '54'))	('MMP9', 'molecular_function', 'GO:0004229', ('225', '229'))	('PIM1', 'Gene', (172, 176))
36506	29472550	The current results reveal that phosphorylation of c-Myc via interactions with PIM1 activates the expression of transcription factors (ZEB1, ZEB2, Snail1, Snail2 and Twist) to synergistically promote EMT without activating Smads.	('ZEB1', 'Gene', (135, 139))	('promote', 'PosReg', (192, 199))	('Twist', 'Gene', '7291', (166, 171))	('c-Myc', 'Gene', (51, 56))	('Snail2', 'Gene', (155, 161))	('ZEB2', 'Gene', (141, 145))	('c-Myc', 'Gene', '4609', (51, 56))	('Snail2', 'Gene', '6591', (155, 161))	('activates', 'PosReg', (84, 93))	('ZEB2', 'Gene', '9839', (141, 145))	('Snail1', 'Gene', '6615', (147, 153))	('PIM1', 'Gene', (79, 83))	('Smad', 'Gene', (223, 227))	('ZEB1', 'Gene', '6935', (135, 139))	('phosphorylation', 'Var', (32, 47))	('Snail1', 'Gene', (147, 153))	('Twist', 'Gene', (166, 171))	('EMT', 'biological_process', 'GO:0001837', ('200', '203'))	('phosphorylation', 'biological_process', 'GO:0016310', ('32', '47'))	('Smad', 'Gene', '4089;4089;4092', (223, 227))	('EMT', 'CPA', (200, 203))	('transcription', 'biological_process', 'GO:0006351', ('112', '125'))	('interactions', 'Interaction', (61, 73))	('expression', 'MPA', (98, 108))
36508	29472550	In addition, we found that depletion of PIM1 and the subsequent blockage of signalling pathway crosstalk and EMT is reversed by TGF-beta, which activates the canonical TGF-beta-induced signalling pathway to enhance the phosphorylation of both Smad2 and Smad3 in the nucleus; this further confirmed the molecular mechanism of PIM1 in our study.	('TGF-beta', 'Gene', (168, 176))	('TGF-beta', 'Gene', '7040', (128, 136))	('signalling pathway', 'biological_process', 'GO:0007165', ('76', '94'))	('TGF-beta', 'Gene', (128, 136))	('Smad3', 'Gene', (253, 258))	('phosphorylation', 'MPA', (219, 234))	('PIM1', 'Gene', (40, 44))	('signalling pathway crosstalk', 'Pathway', (76, 104))	('EMT', 'biological_process', 'GO:0001837', ('109', '112'))	('Smad2', 'Gene', '4087', (243, 248))	('signalling pathway', 'biological_process', 'GO:0007165', ('185', '203'))	('phosphorylation', 'biological_process', 'GO:0016310', ('219', '234'))	('Smad2', 'Gene', (243, 248))	('depletion', 'Var', (27, 36))	('enhance', 'PosReg', (207, 214))	('Smad3', 'Gene', '4088', (253, 258))	('nucleus', 'cellular_component', 'GO:0005634', ('266', '273'))	('TGF-beta', 'Gene', '7040', (168, 176))
36509	29472550	Mutation of the von Hippel-Lindau (VHL) tumour suppressor plays an essential role in the cellular oxygen-sensing pathway, which is correlated with poor prognosis in ccRCC patients.	('von Hippel-Lindau (VHL) tumour', 'Disease', 'MESH:D006623', (16, 46))	('oxygen', 'Chemical', 'MESH:D010100', (98, 104))	('Mutation', 'Var', (0, 8))	('cellular oxygen-sensing pathway', 'Pathway', (89, 120))	('patients', 'Species', '9606', (171, 179))	('ccRCC', 'Phenotype', 'HP:0006770', (165, 170))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))
36510	29472550	VHL, which is located on chromosome 3p, is mutated in 52% of ccRCCs, and the mutation generally leads to dysfunction.	('RCC', 'Disease', (63, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('VHL', 'Disease', 'MESH:D006623', (0, 3))	('mutation', 'Var', (77, 85))	('leads to', 'Reg', (96, 104))	('chromosome', 'cellular_component', 'GO:0005694', ('25', '35'))	('dysfunction', 'Disease', (105, 116))	('VHL', 'Disease', (0, 3))	('mutated', 'Var', (43, 50))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
36511	29472550	VHL targets hypoxia-inducible factor (HIF) for degradation under normal physiological conditions, whereas in the tumour cell microenvironment, mutation of VHL enables HIF to accumulate in the tumour cells.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('degradation', 'biological_process', 'GO:0009056', ('47', '58'))	('VHL', 'Disease', 'MESH:D006623', (0, 3))	('VHL', 'Disease', 'MESH:D006623', (155, 158))	('VHL', 'Disease', (0, 3))	('mutation', 'Var', (143, 151))	('tumour', 'Disease', 'MESH:D009369', (192, 198))	('VHL', 'Disease', (155, 158))	('tumour', 'Disease', (113, 119))	('tumour', 'Disease', (192, 198))	('hypoxia', 'Disease', 'MESH:D000860', (12, 19))	('degradation', 'MPA', (47, 58))	('hypoxia', 'Disease', (12, 19))
36516	29472550	Moreover, our results showed that depletion of PIM1 strongly impaired angiogenesis and blocked EMT in ccRCC cells.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('EMT in', 'CPA', (95, 101))	('PIM1', 'Gene', (47, 51))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('angiogenesis', 'biological_process', 'GO:0001525', ('70', '82'))	('impaired', 'NegReg', (61, 69))	('depletion', 'Var', (34, 43))	('EMT', 'biological_process', 'GO:0001837', ('95', '98'))	('angiogenesis', 'CPA', (70, 82))	('blocked', 'NegReg', (87, 94))
36520	29472550	Therefore, further investigations are required to determine whether depletion of PIM1 impairs the dynamic phenotypic transition of ccRCC cells.	('dynamic phenotypic transition of', 'CPA', (98, 130))	('depletion', 'Var', (68, 77))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('impairs', 'NegReg', (86, 93))	('PIM1', 'Gene', (81, 85))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))
36524	29472550	Antibodies against PIM1, p-Smad2 (S467), p-Smad3 (S423 and S425) and p-c-Myc (S62) were purchased from Abcam (Cambridge, MA, USA).	('Smad3', 'Gene', (43, 48))	('PIM1', 'Gene', (19, 23))	('Smad3', 'Gene', '4088', (43, 48))	('c-Myc', 'Gene', '4609', (71, 76))	('S423', 'Var', (50, 54))	('Smad2', 'Gene', '4087', (27, 32))	('Smad2', 'Gene', (27, 32))	('c-Myc', 'Gene', (71, 76))
36571	29472550	The edge tissues of the mouse tumours from the PIM1 knockdown and control groups were subjected to IHC for p-Smad2, p-Smad3 and p-c-Myc.	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('mouse', 'Species', '10090', (24, 29))	('Smad3', 'Gene', (118, 123))	('Smad2', 'Gene', '4087', (109, 114))	('PIM1', 'Gene', (47, 51))	('tumours', 'Disease', 'MESH:D009369', (30, 37))	('tumours', 'Disease', (30, 37))	('Smad2', 'Gene', (109, 114))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('Smad3', 'Gene', '4088', (118, 123))	('c-Myc', 'Gene', '4609', (130, 135))	('knockdown', 'Var', (52, 61))	('c-Myc', 'Gene', (130, 135))
36574	32021684	There are diverse clues showing H3K36me3 participates in DNA damage response by directly recruiting DNA repair machinery to set the chromatin at a "ready" status, leading to a quick response upon damage.	('quick response upon damage', 'MPA', (176, 202))	('chromatin', 'cellular_component', 'GO:0000785', ('132', '141'))	('recruiting', 'PosReg', (89, 99))	('DNA damage response', 'biological_process', 'GO:0006974', ('57', '76'))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('DNA repair', 'biological_process', 'GO:0006281', ('100', '110'))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('H3K36me3', 'Var', (32, 40))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('N', 'Chemical', 'MESH:D009584', (101, 102))
36576	32021684	This review will also place a main emphasis on the H3K36me3-mediated DNA damage repair in the tumorigenesis of the newly found oncohistone mutant tumors.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('H3K36me3-mediated', 'Var', (51, 68))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (146, 151))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Disease', (94, 99))	('mutant', 'Var', (139, 145))	('tumors', 'Disease', (146, 152))	('N', 'Chemical', 'MESH:D009584', (70, 71))	('oncohistone', 'Gene', (127, 138))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
36582	32021684	Histone methylations usually occur on the arginine or lysine residues.	('methylations', 'Var', (8, 20))	('Histone', 'Protein', (0, 7))	('lysine', 'Chemical', 'MESH:C114808', (54, 60))	('arginine', 'Chemical', 'MESH:D001127', (42, 50))	('occur', 'Reg', (29, 34))
36583	32021684	Histone H3 is methylated at lysine 36 (H3K36) with mono-, di- and tri-methylations (H3K36me1/me2/me3).	('H3K36me1/me2/me3', 'Var', (84, 100))	('lysine', 'Chemical', 'MESH:C114808', (28, 34))	('Histone H3', 'Protein', (0, 10))
36586	32021684	SETD2, the paralogous protein of Set2, is the only enzyme found to catalyze the formation of H3K36me3, while there are still arguments that it also methylates H3K36 to H3K36me1 and H3K36me2 in vivo.	('SETD2', 'Gene', '29072', (0, 5))	('H3K36me2', 'Var', (181, 189))	('SETD2', 'Gene', (0, 5))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('formation', 'biological_process', 'GO:0009058', ('80', '89'))	('H3K36me3', 'Var', (93, 101))	('H3K36', 'Protein', (159, 164))
36587	32021684	SETD2, the methyltransferase for H3K36me3, is recruited through the Ser2 phosphorylated C-terminal domain (CTD) of RNA polymerase II (RNAPII) during gene transcription elongation, while the Ser5 phosphorylation of RNAPII is the characteristic of the paused polymerases at promoters.	('H3K36me3', 'Var', (33, 41))	('C', 'Chemical', 'MESH:D002244', (107, 108))	('recruited', 'PosReg', (46, 55))	('N', 'Chemical', 'MESH:D009584', (116, 117))	('N', 'Chemical', 'MESH:D009584', (215, 216))	('SETD2', 'Gene', '29072', (0, 5))	('Ser', 'cellular_component', 'GO:0005790', ('68', '71'))	('phosphorylation', 'biological_process', 'GO:0016310', ('195', '210'))	('C', 'Chemical', 'MESH:D002244', (88, 89))	('RNA', 'cellular_component', 'GO:0005562', ('115', '118'))	('SETD2', 'Gene', (0, 5))	('Ser', 'cellular_component', 'GO:0005790', ('190', '193'))	('Ser', 'Chemical', 'MESH:C530429', (190, 193))	('Ser2', 'Gene', (68, 72))	('Ser2', 'Gene', '3714', (68, 72))	('transcription', 'biological_process', 'GO:0006351', ('154', '167'))	('N', 'Chemical', 'MESH:D009584', (135, 136))	('Ser', 'Chemical', 'MESH:C530429', (68, 71))
36592	32021684	However, depletion of SETD2 does not affect the histone acetylation across the gene coding regions, indicating that the H3K36me3 preserves the repressive chromatin status independent of histone acetylation.	('SETD2', 'Gene', '29072', (22, 27))	('H3K36me3', 'Var', (120, 128))	('acetyl', 'Chemical', 'MESH:C011632', (56, 62))	('SETD2', 'Gene', (22, 27))	('histone acetylation', 'biological_process', 'GO:0016573', ('186', '205'))	('acetyl', 'Chemical', 'MESH:C011632', (194, 200))	('repressive chromatin status', 'MPA', (143, 170))	('histone acetylation', 'biological_process', 'GO:0016573', ('48', '67'))	('chromatin', 'cellular_component', 'GO:0000785', ('154', '163'))
36594	32021684	To regulate the RNA splicing machinery, H3K36me3 forms an adapter system with MORF-related gene 15 (MRG15) to recruit splicing regulator polypyrimidine tract-binding protein (PTB).	('binding', 'molecular_function', 'GO:0005488', ('158', '165'))	('recruit', 'PosReg', (110, 117))	('MORF-related gene 15', 'Gene', (78, 98))	('polypyrimidine tract-binding protein', 'Gene', (137, 173))	('polypyrimidine tract-binding protein', 'Gene', '5725', (137, 173))	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('RNA splicing', 'biological_process', 'GO:0008380', ('16', '28'))	('splicing', 'biological_process', 'GO:0045292', ('118', '126'))	('MORF-related gene 15', 'Gene', '10933', (78, 98))	('MRG15', 'Gene', '10933', (100, 105))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('PTB', 'Gene', '5725', (175, 178))	('PTB', 'Gene', (175, 178))	('MRG15', 'Gene', (100, 105))	('RNA', 'cellular_component', 'GO:0005562', ('16', '19'))	('H3K36me3', 'Var', (40, 48))
36595	32021684	Deletion of 3' splice site of genes causes a shift of H3K36me3 from 5' ends to 3' ends, despite the fact that mutations of poly(A) site have no apparent effects on H3K36me3.	('poly(A)', 'Chemical', 'MESH:C017937', (123, 130))	('shift', 'Reg', (45, 50))	('H3K36me3', 'Protein', (54, 62))	('Deletion', 'Var', (0, 8))
36600	32021684	DNA double strand breaks (DSBs) usually arise by the attack of electrophilic molecules like reactive oxygen species, leading to lesions in both DNA strands of the double helix.	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('lesions', 'Var', (128, 135))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('N', 'Chemical', 'MESH:D009584', (145, 146))	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))	('oxygen', 'Chemical', 'MESH:D010100', (101, 107))	('double strand breaks', 'Disease', (4, 24))
36619	32021684	Psip1 encodes two protein isoforms by alternative splicing, p52 and p75.	('p75', 'Gene', '11168', (68, 71))	('Psip1', 'Gene', '11168', (0, 5))	('p52', 'Var', (60, 63))	('Psip1', 'Gene', (0, 5))	('splicing', 'biological_process', 'GO:0045292', ('50', '58'))	('p75', 'Gene', (68, 71))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))
36624	32021684	A PWWP-mutated (W21A) p75 which does not bind histones or chromatin compromises the camptothecin-induced association of p75 and CtIP.	('p75', 'Gene', '11168', (22, 25))	('p75', 'Gene', (22, 25))	('CtIP', 'Gene', (128, 132))	('CtIP', 'Gene', '5932', (128, 132))	('p75', 'Gene', '11168', (120, 123))	('chromatin', 'cellular_component', 'GO:0000785', ('58', '67'))	('compromises', 'NegReg', (68, 79))	('camptothecin-induced', 'MPA', (84, 104))	('p75', 'Gene', (120, 123))	('camptothecin', 'Chemical', 'MESH:D002166', (84, 96))	('W21A', 'Var', (16, 20))	('W21A', 'SUBSTITUTION', 'None', (16, 20))	('association', 'Interaction', (105, 116))
36625	32021684	The ability of p75 to protect cells against camptothecin-induced cytotoxicity is also diminished by the W21A mutation.	('W21A', 'Var', (104, 108))	('cytotoxicity', 'Disease', 'MESH:D064420', (65, 77))	('W21A', 'SUBSTITUTION', 'None', (104, 108))	('p75', 'Gene', (15, 18))	('diminished', 'NegReg', (86, 96))	('cytotoxicity', 'Disease', (65, 77))	('camptothecin', 'Chemical', 'MESH:D002166', (44, 56))	('p75', 'Gene', '11168', (15, 18))
36626	32021684	The finding of p75 associated with H3K36me3 in DNA repair highlights the direct role of H3K36me3 in the regulation of HR.	('associated', 'Reg', (19, 29))	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('DNA repair', 'biological_process', 'GO:0006281', ('47', '57'))	('p75', 'Gene', (15, 18))	('regulation of HR', 'biological_process', 'GO:0010363', ('104', '120'))	('H3K36me3', 'Var', (35, 43))	('N', 'Chemical', 'MESH:D009584', (48, 49))	('p75', 'Gene', '11168', (15, 18))
36632	32021684	Together, despite of a similar N-terminal PWWP domain like p75, p52 plays a critical role in modulating mRNA splicing.	('mRNA splicing', 'biological_process', 'GO:0000374', ('104', '117'))	('mRNA splicing', 'biological_process', 'GO:0006371', ('104', '117'))	('p75', 'Gene', '11168', (59, 62))	('p75', 'Gene', (59, 62))	('N', 'Chemical', 'MESH:D009584', (106, 107))	('p52', 'Var', (64, 67))	('mRNA splicing', 'biological_process', 'GO:0000398', ('104', '117'))	('mRNA splicing', 'biological_process', 'GO:0000372', ('104', '117'))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('modulating', 'Reg', (93, 103))	('mRNA splicing', 'biological_process', 'GO:0000394', ('104', '117'))	('mRNA splicing', 'biological_process', 'GO:0000373', ('104', '117'))	('mRNA splicing', 'MPA', (104, 117))
36633	32021684	In this study by Pradeepa et al., the function of p52 in DNA damage repair pathway is not tested because the depletion systems used are gene trap or knock out of Psip1 which deplete both p52 and p75.	('p75', 'Gene', (195, 198))	('deplete', 'NegReg', (174, 181))	('p75', 'Gene', '11168', (195, 198))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('Psip1', 'Gene', '11168', (162, 167))	('Psip1', 'Gene', (162, 167))	('knock out', 'Var', (149, 158))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('p52', 'Var', (187, 190))
36634	32021684	Whether depletion of p52 affects the HR pathway or complementation of p52 in the Psip1 knockout system would rescue the HR pathway needs to be further analyzed.	('Psip1', 'Gene', '11168', (81, 86))	('Psip1', 'Gene', (81, 86))	('HR pathway', 'Pathway', (37, 47))	('complementation', 'Var', (51, 66))	('rescue', 'PosReg', (109, 115))	('affects', 'Reg', (25, 32))	('HR pathway', 'Pathway', (120, 130))	('p52', 'Var', (70, 73))
36639	32021684	Moreover, this recruitment of RAD51 is also H3K36me3-dependent in laser-induced DNA damage and I-SceI-induced DSBs.	('RAD51', 'Gene', '5888', (30, 35))	('laser-induced DNA damage', 'Disease', (66, 90))	('H3K36me3-dependent', 'Var', (44, 62))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('recruitment', 'MPA', (15, 26))	('RAD', 'biological_process', 'GO:1990116', ('30', '33'))	('RAD51', 'Gene', (30, 35))
36640	32021684	Besides RAD51, the H3K36me3:p75 axis also facilitates the RPA binding to DNA damage sites to promote HR.	('H3K36me3', 'Var', (19, 27))	('RAD', 'biological_process', 'GO:1990116', ('8', '11'))	('N', 'Chemical', 'MESH:D009584', (74, 75))	('facilitates', 'PosReg', (42, 53))	('RAD51', 'Gene', (8, 13))	('RPA', 'cellular_component', 'GO:0005662', ('58', '61'))	('p75', 'Gene', '11168', (28, 31))	('RPA', 'Protein', (58, 61))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('p75', 'Gene', (28, 31))	('RAD51', 'Gene', '5888', (8, 13))	('promote', 'PosReg', (93, 100))	('binding', 'molecular_function', 'GO:0005488', ('62', '69'))
36642	32021684	In addition, H3K36me3 cross-talks with other histone marks, like H4K16ac, by facilitating the interactions of corresponding histone acetyl transferase with DNA repair complex.	('H3K36me3', 'Var', (13, 21))	('N', 'Chemical', 'MESH:D009584', (157, 158))	('acetyl', 'Chemical', 'MESH:C011632', (132, 138))	('facilitating', 'PosReg', (77, 89))	('interactions', 'Interaction', (94, 106))	('DNA repair', 'biological_process', 'GO:0006281', ('156', '166'))	('DNA repair complex', 'cellular_component', 'GO:1990391', ('156', '174'))	('cross-talks', 'Reg', (22, 33))
36646	32021684	Although the detail mechanism is not clear, ATM activation, which is the direct sensor in early DNA damage signaling, is impaired by the depletion of SETD2.	('impaired', 'NegReg', (121, 129))	('depletion', 'Var', (137, 146))	('signaling', 'biological_process', 'GO:0023052', ('107', '116'))	('ATM', 'Gene', (44, 47))	('SETD2', 'Gene', '29072', (150, 155))	('SETD2', 'Gene', (150, 155))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('ATM', 'Gene', '472', (44, 47))	('N', 'Chemical', 'MESH:D009584', (97, 98))
36651	32021684	H3K36 methylation reduces chromatin accessibility and promotes NHEJ, while H3K36 acetylation increases chromatin accessibility and induces HR.	('chromatin accessibility', 'MPA', (26, 49))	('chromatin', 'cellular_component', 'GO:0000785', ('103', '112'))	('chromatin', 'cellular_component', 'GO:0000785', ('26', '35'))	('H3K36', 'Protein', (75, 80))	('acetylation', 'MPA', (81, 92))	('NHEJ', 'Disease', (63, 67))	('reduces', 'NegReg', (18, 25))	('H3K36', 'Protein', (0, 5))	('increases', 'PosReg', (93, 102))	('methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('chromatin accessibility', 'MPA', (103, 126))	('N', 'Chemical', 'MESH:D009584', (63, 64))	('methylation', 'Var', (6, 17))	('NHEJ', 'biological_process', 'GO:0006303', ('63', '67'))	('acetyl', 'Chemical', 'MESH:C011632', (81, 87))	('induces', 'Reg', (131, 138))	('promotes', 'PosReg', (54, 62))
36652	32021684	Depletion of either Set2 or Gcn5 primes DNA repair to the other pathway.	('DNA repair', 'biological_process', 'GO:0006281', ('40', '50'))	('DNA repair', 'MPA', (40, 50))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('Depletion', 'Var', (0, 9))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('Gcn5', 'Gene', (28, 32))	('primes', 'PosReg', (33, 39))
36653	32021684	In fission yeast, H3K36me3 levels increase to a peak in G1 phase when NHEJ prevails, while H3K36me2 and H3K36ac increases after G1 release when HR predominates.	('fission yeast', 'Species', '4896', (3, 16))	('H3K36ac', 'Var', (104, 111))	('H3K36me3 levels', 'MPA', (18, 33))	('NHEJ', 'biological_process', 'GO:0006303', ('70', '74'))	('increase', 'PosReg', (34, 42))	('N', 'Chemical', 'MESH:D009584', (70, 71))	('G1 phase', 'biological_process', 'GO:0051318', ('56', '64'))	('H3K36me2', 'Var', (91, 99))
36654	32021684	Moreover, base excision repair (BER) of alkylation damage induced by methyl methanesulfonate is regulated by H3K36me3 in budding yeast.	('alkylation damage', 'Disease', 'MESH:D009422', (40, 57))	('yeast', 'Species', '4932', (129, 134))	('methyl methanesulfonate', 'Chemical', 'MESH:D008741', (69, 92))	('BER', 'biological_process', 'GO:0006284', ('32', '35'))	('budding', 'biological_process', 'GO:0007114', ('121', '128'))	('base excision repair', 'MPA', (10, 30))	('base excision repair', 'biological_process', 'GO:0006284', ('10', '30'))	('alkylation damage', 'Disease', (40, 57))	('H3K36me3', 'Var', (109, 117))
36656	32021684	In consistent with the distinct functions of H3K36me2 and H3K36m3, SETMAR-mediated H3K36me2 is generated after ionizing radiation and recruits NBS1 and Ku to promote NHEJ in the response of DSBs in human cells.	('promote', 'PosReg', (158, 165))	('NHEJ', 'Gene', (166, 170))	('NBS1', 'Gene', (143, 147))	('H3K36me2', 'Var', (83, 91))	('SETMAR', 'Gene', (67, 73))	('response', 'MPA', (178, 186))	('human', 'Species', '9606', (198, 203))	('N', 'Chemical', 'MESH:D009584', (143, 144))	('NHEJ', 'biological_process', 'GO:0006303', ('166', '170'))	('NBS1', 'Gene', '4683', (143, 147))	('SETMAR', 'Gene', '6419', (67, 73))	('N', 'Chemical', 'MESH:D009584', (166, 167))
36662	32021684	Moreover, depletion of PHF1 sensitizes cells to X-ray induced DNA damage and increases HR frequency.	('PHF1', 'Gene', '5252', (23, 27))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('PHF1', 'Gene', (23, 27))	('depletion', 'Var', (10, 19))	('N', 'Chemical', 'MESH:D009584', (63, 64))	('increases', 'PosReg', (77, 86))	('sensitizes', 'Reg', (28, 38))	('HR frequency', 'CPA', (87, 99))
36664	32021684	The Tudor domain of PHF1 preferentially binds to H3K36me3 peptides among H3K4, H3K9, H3K36 methylated and unmodified peptides.	('preferentially', 'PosReg', (25, 39))	('H3K36me3 peptides', 'Protein', (49, 66))	('PHF1', 'Gene', (20, 24))	('H3K36', 'Protein', (85, 90))	('H3K9', 'Var', (79, 83))	('PHF1', 'Gene', '5252', (20, 24))	('H3K4', 'Protein', (73, 77))	('binds', 'Interaction', (40, 45))	('H3K4', 'Chemical', 'MESH:C024755', (73, 77))
36665	32021684	A 1.9 A X-ray crystallographic structure shows that the side chain of H3K36me3 peptide interacts with W41, Y47, F65 and F71 residues of PHF1.	('PHF1', 'Gene', '5252', (136, 140))	('F65', 'Var', (112, 115))	('F71 residues', 'Var', (120, 132))	('H3K36me3', 'Var', (70, 78))	('interacts', 'Interaction', (87, 96))	('Y47', 'Var', (107, 110))	('W41', 'Var', (102, 105))	('PHF1', 'Gene', (136, 140))
36667	32021684	In the sense that H3K27me3 is the mark for silenced genomic loci, these findings suggest that the retention of PHF1 at DNA damage sites maintains an open chromatin.	('retention', 'biological_process', 'GO:0051235', ('98', '107'))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('N', 'Chemical', 'MESH:D009584', (120, 121))	('open chromatin', 'MPA', (149, 163))	('maintains', 'Reg', (136, 145))	('PHF1', 'Gene', (111, 115))	('PHF1', 'Gene', '5252', (111, 115))	('retention', 'Var', (98, 107))	('chromatin', 'cellular_component', 'GO:0000785', ('154', '163'))
36673	32021684	H3K36me3 regulates both HR and NHEJ pathways, where LEDGF/p75 and MRG15 are the major readers for HR and PHF1 is the major reader for NHEJ in mammalian cells.	('NHEJ', 'biological_process', 'GO:0006303', ('134', '138'))	('mammalian', 'Species', '9606', (142, 151))	('NHEJ', 'biological_process', 'GO:0006303', ('31', '35'))	('H3K36me3', 'Var', (0, 8))	('LEDGF', 'Gene', (52, 57))	('p75', 'Gene', '11168', (58, 61))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('p75', 'Gene', (58, 61))	('MRG15', 'Gene', '10933', (66, 71))	('LEDGF', 'Gene', '11168', (52, 57))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('NHEJ pathways', 'Pathway', (31, 44))	('PHF1', 'Gene', (105, 109))	('MRG15', 'Gene', (66, 71))	('regulates', 'Reg', (9, 18))	('PHF1', 'Gene', '5252', (105, 109))
36675	32021684	For instance, H3K36me2, H4K20me1/me2, H3K79me2 and H4K16ac are involved in the DSB repair to promote NHEJ.	('H4K16ac', 'Var', (51, 58))	('H3K36me2, H4K20me1/me2, H3K79me2', 'Chemical', 'MESH:C024755', (14, 46))	('NHEJ', 'biological_process', 'GO:0006303', ('101', '105'))	('NHEJ', 'Disease', (101, 105))	('H3K36me2', 'Var', (14, 22))	('H3K79me2', 'Var', (38, 46))	('promote', 'PosReg', (93, 100))	('N', 'Chemical', 'MESH:D009584', (101, 102))	('H4K20me1/me2', 'Var', (24, 36))
36686	32021684	Disruption of H3K36me3 coupled DSBs repair inhibits the immunoglobulin V(D)J rearrangement in B cells and promotes tumorigenesis of aggressive cancers, such as clear cell renal cell carcinoma (ccRCC), acute myeloid leukemia (AML), and diffuse intrinsic pontine glioma (DIPG).	('ccRCC', 'Disease', (193, 198))	('aggressive cancers', 'Disease', (132, 150))	('tumor', 'Disease', (115, 120))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (201, 223))	('AML', 'Phenotype', 'HP:0004808', (225, 228))	('glioma', 'Phenotype', 'HP:0009733', (261, 267))	('AML', 'Disease', (225, 228))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('56', '70'))	('H3K36me3', 'Protein', (14, 22))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (171, 191))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (201, 223))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (160, 191))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('Disruption', 'Var', (0, 10))	('ccRCC', 'Phenotype', 'HP:0006770', (193, 198))	('clear cell renal cell carcinoma', 'Disease', (160, 191))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('aggressive cancers', 'Disease', 'MESH:D009369', (132, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('promotes', 'PosReg', (106, 114))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (160, 191))	('inhibits', 'NegReg', (43, 51))	('glioma', 'Disease', (261, 267))	('acute myeloid leukemia', 'Disease', (201, 223))	('glioma', 'Disease', 'MESH:D005910', (261, 267))	('ccRCC', 'Disease', 'MESH:D002292', (193, 198))	('leukemia', 'Phenotype', 'HP:0001909', (215, 223))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (207, 223))	('AML', 'Disease', 'MESH:D015470', (225, 228))
36687	32021684	SETD2 mutations are identified in ccRCC cells as homozygous truncating mutations and copy number loss.	('SETD2', 'Gene', '29072', (0, 5))	('ccRCC', 'Phenotype', 'HP:0006770', (34, 39))	('ccRCC', 'Disease', (34, 39))	('SETD2', 'Gene', (0, 5))	('copy number loss', 'Var', (85, 101))	('ccRCC', 'Disease', 'MESH:D002292', (34, 39))	('mutations', 'Var', (6, 15))
36688	32021684	Besides reduced DNA damage repair by HR, SETD2 mutant ccRCC tumors show altered chromatin organization occurred primarily at actively transcribed genes, leading to intron retention and aberrant splicing.	('altered', 'Reg', (72, 79))	('DNA', 'cellular_component', 'GO:0005574', ('16', '19'))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('ccRCC', 'Disease', (54, 59))	('chromatin', 'cellular_component', 'GO:0000785', ('80', '89'))	('ccRCC', 'Disease', 'MESH:D002292', (54, 59))	('chromatin organization', 'biological_process', 'GO:0006325', ('80', '102'))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('retention', 'biological_process', 'GO:0051235', ('171', '180'))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('intron retention', 'MPA', (164, 180))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('SETD2', 'Gene', '29072', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('splicing', 'biological_process', 'GO:0045292', ('194', '202'))	('mutant', 'Var', (47, 53))	('SETD2', 'Gene', (41, 46))	('tumors', 'Disease', (60, 66))
36690	32021684	Moreover, the genes exhibiting aberrant splicing, including TP53, ATR, PTEN, and CCNB1, are tumor suppressors whose inactivation will promote tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('inactivation', 'Var', (116, 128))	('promote', 'PosReg', (134, 141))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (142, 147))	('CCNB1', 'Gene', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('PTEN', 'Gene', (71, 75))	('TP53', 'Gene', '7157', (60, 64))	('ATR', 'Gene', '545', (66, 69))	('ATR', 'Gene', (66, 69))	('PTEN', 'Gene', '5728', (71, 75))	('aberrant splicing', 'Var', (31, 48))	('tumor', 'Disease', (92, 97))	('CCNB1', 'Gene', '891', (81, 86))	('TP53', 'Gene', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('splicing', 'biological_process', 'GO:0045292', ('40', '48'))
36692	32021684	These findings elucidate the observation that, despite a low frequency of TP53 mutation, the p53 cell-cycle checkpoint is usually defected in ccRCC tumors.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('defected', 'NegReg', (130, 138))	('ccRCC', 'Disease', (142, 147))	('TP53', 'Gene', '7157', (74, 78))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('mutation', 'Var', (79, 87))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('cell-cycle checkpoint', 'biological_process', 'GO:0000075', ('97', '118'))	('TP53', 'Gene', (74, 78))	('ccRCC', 'Disease', 'MESH:D002292', (142, 147))
36694	32021684	AML cells usually bear SETD2 mutations which abolish the preload DDR components.	('SETD2', 'Gene', '29072', (23, 28))	('preload DDR components', 'MPA', (57, 79))	('abolish', 'NegReg', (45, 52))	('SETD2', 'Gene', (23, 28))	('mutations', 'Var', (29, 38))	('AML', 'Disease', 'MESH:D015470', (0, 3))	('AML', 'Phenotype', 'HP:0004808', (0, 3))	('AML', 'Disease', (0, 3))
36696	32021684	Treatment of KDM4A (H3K9 and H3K36 demethylase) inhibitors restores H3K36me3 levels and sensitizes AML cells to DNA damaging agents.	('KDM4A', 'Gene', '9682', (13, 18))	('sensitizes', 'Reg', (88, 98))	('AML', 'Disease', 'MESH:D015470', (99, 102))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('KDM4A', 'Gene', (13, 18))	('AML', 'Phenotype', 'HP:0004808', (99, 102))	('restores', 'PosReg', (59, 67))	('AML', 'Disease', (99, 102))	('inhibitors', 'Var', (48, 58))	('H3K36me3 levels', 'MPA', (68, 83))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))
36698	32021684	Pharmacologic inhibition of DOT1L, the H3K79 methyltransferase, synergizes with SETD2 mutations to induce DNA damage, growth arrest, and apoptosis, indicating a cross-talk of H3K36me3 and H3K79me2 in AML cells.	('induce', 'PosReg', (99, 105))	('mutations', 'Var', (86, 95))	('growth arrest', 'Disease', 'MESH:D006323', (118, 131))	('growth arrest', 'Disease', (118, 131))	('SETD2', 'Gene', (80, 85))	('apoptosis', 'CPA', (137, 146))	('AML', 'Disease', 'MESH:D015470', (200, 203))	('apoptosis', 'biological_process', 'GO:0097194', ('137', '146'))	('apoptosis', 'biological_process', 'GO:0006915', ('137', '146'))	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('AML', 'Phenotype', 'HP:0004808', (200, 203))	('growth arrest', 'Phenotype', 'HP:0001510', (118, 131))	('AML', 'Disease', (200, 203))	('DOT1L', 'Gene', (28, 33))	('N', 'Chemical', 'MESH:D009584', (107, 108))	('DNA damage', 'MPA', (106, 116))	('DOT1L', 'Gene', '84444', (28, 33))	('SETD2', 'Gene', '29072', (80, 85))
36699	32021684	MMR-deficient tumors selectively acquire single-nucleotide variants (SNV) in regions with active histone marks, especially H3K36me3, indicating a role of H3K36me3-dependent MMR in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('H3K36me3', 'Var', (123, 131))	('tumor', 'Disease', (14, 19))	('acquire', 'PosReg', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('MMR', 'biological_process', 'GO:0006298', ('173', '176'))	('MMR', 'biological_process', 'GO:0006298', ('0', '3'))	('tumor', 'Disease', (180, 185))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('MMR-deficient', 'Gene', (0, 13))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('single-nucleotide variants', 'Var', (41, 67))	('N', 'Chemical', 'MESH:D009584', (70, 71))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
36701	32021684	These histone mutations play a role like oncogenes to promote tumorigenesis, so that the high frequent histone mutations are also called oncohistones.	('promote', 'PosReg', (54, 61))	('mutations', 'Var', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
36703	32021684	Biochemistry studies have shown that these H3G34 mutations, which substitute non-side chain residues with large side chain residues, reduce the corresponding H3K36me3 on the H3G34R/V histone proteins particularly through the inhibition of H3K36 methyltransferase SETD2.	('SETD2', 'Gene', '29072', (263, 268))	('H3K36me3', 'MPA', (158, 166))	('mutations', 'Var', (49, 58))	('SETD2', 'Gene', (263, 268))	('inhibition', 'NegReg', (225, 235))	('reduce', 'NegReg', (133, 139))	('H3G34', 'Gene', (43, 48))
36704	32021684	In human cells, there are 15 copies of genes encoding canonical histone H3.1/H3.2 and histone H3.3 variants while H3K36 is conserved in all histone H3 proteins.	('histone H3.1', 'Gene', (64, 76))	('histone H3.1', 'Gene', '8350', (64, 76))	('histone H3.3', 'Gene', (86, 98))	('variants', 'Var', (99, 107))	('human', 'Species', '9606', (3, 8))	('histone H3.3', 'Gene', '3021', (86, 98))
36705	32021684	How does this single heterozygous mutation in 15 genes lead to tumorigenesis?	('tumor', 'Disease', (63, 68))	('single heterozygous mutation', 'Var', (14, 42))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('lead to', 'Reg', (55, 62))
36706	32021684	In fission yeast that expresses only mutant H3G34R, DNA damage repair by HR is diminished and the DNA repair dynamics at the compromised replication fork are delayed.	('fission yeast', 'Species', '4896', (3, 16))	('N', 'Chemical', 'MESH:D009584', (53, 54))	('delayed', 'NegReg', (158, 165))	('DNA repair', 'biological_process', 'GO:0006281', ('98', '108'))	('N', 'Chemical', 'MESH:D009584', (99, 100))	('replication fork', 'cellular_component', 'GO:0005657', ('137', '153'))	('mutant', 'Var', (37, 43))	('diminished', 'NegReg', (79, 89))	('H3G34R', 'Gene', (44, 50))	('DNA damage repair', 'MPA', (52, 69))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('DNA', 'cellular_component', 'GO:0005574', ('98', '101'))
36708	32021684	The H3G34R mutation may lead to the observed defects of HR in an indirect way.	('defects', 'NegReg', (45, 52))	('H3G34R', 'Var', (4, 10))	('G34R', 'Mutation', 'p.G34R', (6, 10))
36709	32021684	Although this model does not mimic the in-situ status of H3G34R mutation in DIPG cases because these yeast cells are modified to express only the mutant H3, it sheds light on the functions of reduced DNA damage repair and increased genome instability in the tumorigenesis of DIPG.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('N', 'Chemical', 'MESH:D009584', (201, 202))	('genome instability', 'CPA', (232, 250))	('tumor', 'Disease', (258, 263))	('H3G34R', 'Gene', (57, 63))	('increased', 'PosReg', (222, 231))	('DNA', 'cellular_component', 'GO:0005574', ('200', '203'))	('mutant', 'Var', (146, 152))	('G34R', 'Mutation', 'p.G34R', (59, 63))	('DNA damage repair', 'MPA', (200, 217))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('reduced', 'NegReg', (192, 199))	('yeast', 'Species', '4932', (101, 106))
36710	32021684	In human cells, H3G34R/V mutations block the interactions of H3K36me3 and hMutSalpha, preventing the loading of MMR complex to chromatin.	('MMR complex', 'cellular_component', 'GO:0032389', ('112', '123'))	('MMR complex', 'cellular_component', 'GO:0032302', ('112', '123'))	('mutations', 'Var', (25, 34))	('MMR complex', 'cellular_component', 'GO:0032390', ('112', '123'))	('MMR complex', 'Protein', (112, 123))	('H3K36me3', 'Protein', (61, 69))	('human', 'Species', '9606', (3, 8))	('block', 'NegReg', (35, 40))	('interactions', 'Interaction', (45, 57))	('H3G34R/V', 'Gene', (16, 24))	('MMR', 'biological_process', 'GO:0006298', ('112', '115'))	('loading', 'MPA', (101, 108))	('MMR complex', 'cellular_component', 'GO:0032301', ('112', '123'))	('chromatin', 'cellular_component', 'GO:0000785', ('127', '136'))	('hMutSalpha', 'Protein', (74, 84))	('preventing', 'NegReg', (86, 96))
36711	32021684	Cells bearing H3G34R/V mutations display a week mutator phenotype, such as increased MSI and higher drug-induced mutation rate.	('higher', 'PosReg', (93, 99))	('H3G34R/V mutations', 'Var', (14, 32))	('mutations', 'Var', (23, 32))	('MSI', 'CPA', (85, 88))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('increased', 'PosReg', (75, 84))	('drug-induced', 'CPA', (100, 112))
36712	32021684	Therefore, H3G34 mutations promote genome instability and possibly tumorigenesis by impeding MMR activity.	('H3G34', 'Gene', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('promote', 'PosReg', (27, 34))	('impeding', 'NegReg', (84, 92))	('MMR activity', 'CPA', (93, 105))	('mutations', 'Var', (17, 26))	('tumor', 'Disease', (67, 72))	('MMR', 'biological_process', 'GO:0006298', ('93', '96'))	('genome instability', 'CPA', (35, 53))
36713	32021684	Besides these known results, one very interesting hypothesis is that whether the G34R mutation itself would generate a new site for methylation on the histone tail.	('G34R', 'Var', (81, 85))	('methylation', 'MPA', (132, 143))	('G34R', 'Mutation', 'p.G34R', (81, 85))	('methylation', 'biological_process', 'GO:0032259', ('132', '143'))	('site', 'MPA', (123, 127))	('histone', 'Protein', (151, 158))
36714	32021684	H3G34R/W/L mutations are also found in the giant cell tumor of bone, indicating a DNA damage repair deficiency in these tumors.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('H3G34R/W/L mutations', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('tumor of bone', 'Phenotype', 'HP:0010622', (54, 67))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('giant cell tumor of bone', 'Phenotype', 'HP:0011847', (43, 67))	('N', 'Chemical', 'MESH:D009584', (83, 84))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('damage repair deficiency', 'Disease', (86, 110))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('damage repair deficiency', 'Disease', 'MESH:D049914', (86, 110))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', (120, 125))
36715	32021684	In addition to the H3G34 mutations, H3K36M mutations, found in over 90% of chondroblastoma cases and in large subgroup of head and neck sarcomas, function as dominant negative regulators to reduce H3K36me2 and H3K36me3 on wild type histone H3.	('mutations', 'Var', (25, 34))	('H3K36me3', 'MPA', (210, 218))	('neck', 'cellular_component', 'GO:0044326', ('131', '135'))	('neck sarcomas', 'Disease', 'MESH:D012509', (131, 144))	('H3G34', 'Gene', (19, 24))	('H3K36M', 'Gene', (36, 42))	('chondroblastoma', 'Disease', (75, 90))	('neck sarcomas', 'Disease', (131, 144))	('H3K36me2', 'MPA', (197, 205))	('chondroblastoma', 'Phenotype', 'HP:0030432', (75, 90))	('head and', 'Disease', (122, 130))	('reduce', 'NegReg', (190, 196))	('sarcomas', 'Phenotype', 'HP:0100242', (136, 144))	('chondroblastoma', 'Disease', 'MESH:D002804', (75, 90))
36716	32021684	H3K36M oncohistones reduces H3K36me2 and H3K36me3 genome-wide through the inhibition of at least two histone H3K36 methyltransferases, NSD2 and SETD2.	('H3K36me2', 'MPA', (28, 36))	('reduces', 'NegReg', (20, 27))	('H3K36me3', 'Var', (41, 49))	('inhibition', 'NegReg', (74, 84))	('NSD2', 'Gene', '7468', (135, 139))	('SETD2', 'Gene', '29072', (144, 149))	('SETD2', 'Gene', (144, 149))	('H3K36M', 'Var', (0, 6))	('NSD2', 'Gene', (135, 139))
36717	32021684	Knock-in of heterozygous H3.3K36M mutation into chondrocytes reduces the H3K36 methylation and subsequent expression of cancer related genes.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('expression', 'MPA', (106, 116))	('methylation', 'MPA', (79, 90))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('H3K36', 'Protein', (73, 78))	('methylation', 'biological_process', 'GO:0032259', ('79', '90'))	('reduces', 'NegReg', (61, 68))	('H3.3K36M mutation', 'Var', (25, 42))
36718	32021684	In mouse mesenchymal progenitor cells, the heterozygous H3.3K36M mutation causes the global decrease of H3K36 methylation as well as defects of cell differentiation.	('methylation', 'biological_process', 'GO:0032259', ('110', '121'))	('cell differentiation', 'CPA', (144, 164))	('cell differentiation', 'biological_process', 'GO:0030154', ('144', '164'))	('H3.3K36M mutation', 'Var', (56, 73))	('mouse', 'Species', '10090', (3, 8))	('decrease', 'NegReg', (92, 100))	('methylation', 'MPA', (110, 121))	('H3K36', 'Protein', (104, 109))
36719	32021684	How this H3K36M mutation controls DNA damage repair is still unknown.	('H3K36M', 'Var', (9, 15))	('controls', 'Reg', (25, 33))	('DNA damage repair', 'MPA', (34, 51))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('N', 'Chemical', 'MESH:D009584', (35, 36))
36721	32021684	One well known inhibitor for H3K36me3 deficient ccRCC is the WEE1 inhibitor AZD1775, which acts synthetically with H3K36me3 depletion to reduce the tumor cell growth.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cell growth', 'biological_process', 'GO:0016049', ('154', '165'))	('tumor', 'Disease', (148, 153))	('reduce', 'NegReg', (137, 143))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('AZD1775', 'Chemical', 'MESH:C549567', (76, 83))	('ccRCC', 'Disease', (48, 53))	('WEE1', 'Gene', (61, 65))	('WEE1', 'Gene', '7465', (61, 65))	('ccRCC', 'Disease', 'MESH:D002292', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('H3K36me3', 'Var', (29, 37))
36722	32021684	AZD1775 and H3K36me3 both target RPM2 which is the ribonucleotide reductase subunit responsible for dNTP uptake.	('uptake', 'biological_process', 'GO:0098739', ('105', '111'))	('RPM2', 'Gene', (33, 37))	('AZD1775', 'Var', (0, 7))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('uptake', 'biological_process', 'GO:0098657', ('105', '111'))	('target', 'Reg', (26, 32))	('ribonucleotide', 'Chemical', 'MESH:D012265', (51, 65))	('H3K36me3', 'Var', (12, 20))	('dNTP', 'Chemical', 'MESH:C065818', (100, 104))
36726	32021684	In AML model with the SETD2 mutations, RPM2 protein levels are unaffected, indicating the cell-context dependent effects of SETD2 loss on gene expression.	('SETD2', 'Gene', (124, 129))	('SETD2', 'Gene', '29072', (22, 27))	('RPM2', 'MPA', (39, 43))	('SETD2', 'Gene', (22, 27))	('AML', 'Disease', 'MESH:D015470', (3, 6))	('AML', 'Phenotype', 'HP:0004808', (3, 6))	('gene expression', 'biological_process', 'GO:0010467', ('138', '153'))	('loss', 'NegReg', (130, 134))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('SETD2', 'Gene', '29072', (124, 129))	('mutations', 'Var', (28, 37))	('AML', 'Disease', (3, 6))
36727	32021684	Because SETD2 binds to and regulates different subsets of genes in distinct cells, depletion of SETD2 causes direct and indirect gene expression changes which may also affect specific cellular processes including DNA damage repair.	('SETD2', 'Gene', (8, 13))	('gene expression', 'MPA', (129, 144))	('SETD2', 'Gene', '29072', (8, 13))	('DNA damage repair', 'MPA', (213, 230))	('gene expression', 'biological_process', 'GO:0010467', ('129', '144'))	('SETD2', 'Gene', '29072', (96, 101))	('DNA', 'cellular_component', 'GO:0005574', ('213', '216'))	('depletion', 'Var', (83, 92))	('changes', 'Reg', (145, 152))	('affect', 'Reg', (168, 174))	('SETD2', 'Gene', (96, 101))	('N', 'Chemical', 'MESH:D009584', (214, 215))
36728	32021684	In consistent with this hypnosis, loss of Msh2 and a single-radiation hit in mice induce H3K36me3 alternations at the originally H3K4me3 marked genes, which are enriched in DNA repair, RNA processing, and ribosome biogenesis.	('mice', 'Species', '10090', (77, 81))	('induce', 'Reg', (82, 88))	('loss', 'Var', (34, 38))	('ribosome biogenesis', 'biological_process', 'GO:0042254', ('205', '224'))	('ribosome', 'cellular_component', 'GO:0005840', ('205', '213'))	('RNA processing', 'biological_process', 'GO:0006396', ('185', '199'))	('H3K36me3 alternations', 'MPA', (89, 110))	('Msh2', 'Gene', (42, 46))	('N', 'Chemical', 'MESH:D009584', (174, 175))	('RNA', 'cellular_component', 'GO:0005562', ('185', '188'))	('Msh2', 'Gene', '17685', (42, 46))	('H3K4me3', 'Chemical', 'MESH:C024755', (129, 136))	('N', 'Chemical', 'MESH:D009584', (186, 187))	('DNA', 'cellular_component', 'GO:0005574', ('173', '176'))	('DNA repair', 'biological_process', 'GO:0006281', ('173', '183'))
36729	32021684	There are still no druggable targets found in other tumors, like DIPGs bearing H3G34R/V mutation and chondroblastomas with H3K36M mutation (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('chondroblastomas', 'Disease', 'MESH:D002804', (101, 117))	('chondroblastomas', 'Disease', (101, 117))	('H3K36M mutation', 'Var', (123, 138))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('chondroblastoma', 'Phenotype', 'HP:0030432', (101, 116))	('H3G34R/V mutation', 'Var', (79, 96))
36731	32021684	Other screens, such as large-scale inhibitor screens and genetic screens, may lead to further understandings of how these aggressive SETD2 mutant cells can be targeted.	('SETD2', 'Gene', (133, 138))	('SETD2', 'Gene', '29072', (133, 138))	('mutant', 'Var', (139, 145))
36737	32021684	In the sense that H3K36me3 can also regulate the gene expression and RNA splicing, H3K36me3 may participate in the DSR by disturbing the gene expressions of DNA repair proteins.	('RNA splicing', 'MPA', (69, 81))	('H3K36me3', 'Var', (83, 91))	('DSR', 'Disease', (115, 118))	('DNA repair', 'MPA', (157, 167))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('N', 'Chemical', 'MESH:D009584', (158, 159))	('gene expression', 'MPA', (49, 64))	('RNA', 'cellular_component', 'GO:0005562', ('69', '72'))	('RNA splicing', 'biological_process', 'GO:0008380', ('69', '81'))	('gene expression', 'biological_process', 'GO:0010467', ('49', '64'))	('DNA repair', 'biological_process', 'GO:0006281', ('157', '167'))	('disturbing', 'NegReg', (122, 132))	('N', 'Chemical', 'MESH:D009584', (70, 71))	('regulate', 'Reg', (36, 44))	('gene expressions', 'MPA', (137, 153))	('participate', 'Reg', (96, 107))
36815	29041930	The presence of high molecular weight cytokeratin, such as CK5/6, P63, and 34betaE12, in the clear cells is the best way to establish the squamous nature of the tumor.	('CK5/6', 'Gene', (59, 64))	('P63', 'Gene', '8626', (66, 69))	('34betaE12', 'Var', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('CK5/6', 'Gene', '3852', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('P63', 'Gene', (66, 69))	('squamous nature', 'CPA', (138, 153))	('tumor', 'Disease', (161, 166))
36844	31690629	CRISPR/Cas9-mediated deletion of the hypoxia-response element revealed co-regulation of NICI and the neighboring protein-coding gene, solute carrier family 2 member 3 (SLC2A3) which encodes the high-affinity glucose transporter 3 (GLUT3).	('carrier', 'molecular_function', 'GO:0005215', ('141', '148'))	('glucose transporter', 'Gene', (208, 227))	('glucose transporter', 'Gene', '6513', (208, 227))	('NICI', 'Gene', (88, 92))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('solute carrier family 2 member 3', 'Gene', (134, 166))	('hypoxia', 'Disease', (37, 44))	('hypoxia', 'Disease', 'MESH:D000860', (37, 44))	('co-regulation', 'Reg', (71, 84))	('Cas', 'cellular_component', 'GO:0005650', ('7', '10'))	('regulation', 'biological_process', 'GO:0065007', ('74', '84'))	('deletion', 'Var', (21, 29))	('GLUT3', 'Gene', '6515', (231, 236))	('SLC2A3', 'Gene', (168, 174))	('solute carrier family 2 member 3', 'Gene', '6515', (134, 166))	('GLUT3', 'Gene', (231, 236))
36845	31690629	Knockdown or knockout of NICI attenuated hypoxic induction of SLC2A3, indicating a direct regulatory role of NICI in SLC2A3 expression, which was further evidenced by CRISPR/Cas9-VPR-mediated activation of NICI expression.	('NICI attenuated hypoxic', 'Disease', 'MESH:C538265', (25, 48))	('knockout', 'Var', (13, 21))	('Cas', 'cellular_component', 'GO:0005650', ('174', '177'))	('SLC2A3', 'Gene', (62, 68))	('NICI attenuated hypoxic', 'Disease', (25, 48))
36862	31690629	For example, the micro-RNA mir210 has been identified as a direct target of HIF, and its expression is associated with poor or favorable prognosis, respectively, depending on the type of cancer examined.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('expression', 'MPA', (89, 99))	('mir210', 'Gene', (27, 33))	('micro-RNA', 'Var', (17, 26))	('cancer', 'Disease', (187, 193))	('mir210', 'Gene', '406992', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('RNA', 'cellular_component', 'GO:0005562', ('23', '26'))	('HIF', 'Chemical', '-', (76, 79))
36878	31690629	We also screened existing databases of long noncoding RNAs derived from cancer transcriptomes and discovered that three cancer-associated transcripts (CAT) overlap this region (CAT1466.1, CAT1466.2, and CAT1466.3).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('CAT', 'molecular_function', 'GO:0004096', ('151', '154'))	('CAT1466.1', 'Var', (177, 186))	('CAT', 'molecular_function', 'GO:0004096', ('188', '191'))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('CAT', 'molecular_function', 'GO:0004096', ('177', '180'))	('CAT1466.3', 'Var', (203, 212))	('CAT1466.2', 'Var', (188, 197))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('CAT', 'molecular_function', 'GO:0004096', ('203', '206'))	('cancer', 'Disease', (72, 78))
36881	31690629	We exposed a broad selection of different human cell lines to the HIF stabilizer dimethyloxalylglycine (DMOG) or 1% hypoxia for 16 h and measured expression of SLC2A3 and CAT1466.1 by quantitative PCR (qPCR) (Fig.	('dimethyloxalylglycine', 'Chemical', 'MESH:C040947', (81, 102))	('SLC2A3', 'Gene', (160, 166))	('CAT1466.1', 'Var', (171, 180))	('human', 'Species', '9606', (42, 47))	('hypoxia', 'Disease', (116, 123))	('hypoxia', 'Disease', 'MESH:D000860', (116, 123))	('HIF', 'Chemical', '-', (66, 69))	('CAT', 'molecular_function', 'GO:0004096', ('171', '174'))	('DMOG', 'Chemical', 'MESH:C040947', (104, 108))	('expression', 'MPA', (146, 156))
36896	31690629	Interestingly, in the TCGA kidney renal clear cell carcinoma cohort high SLC2A3 mRNA expression was associated with an adverse prognosis (Fig.	('SLC2A3', 'Gene', (73, 79))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (27, 60))	('high', 'Var', (68, 72))	('kidney renal clear cell carcinoma', 'Disease', (27, 60))	('mRNA expression', 'MPA', (80, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
36902	31690629	In HIF-ChIP assays in HeLa cells, mutation of these core HREs significantly reduced HIF binding compared with control clones of cells or WT HeLa cells (Fig.	('HIF', 'Protein', (84, 87))	('HIF', 'Chemical', '-', (3, 6))	('binding', 'molecular_function', 'GO:0005488', ('88', '95'))	('mutation', 'Var', (34, 42))	('reduced', 'NegReg', (76, 83))	('HeLa', 'CellLine', 'CVCL:0030', (22, 26))	('HeLa', 'CellLine', 'CVCL:0030', (140, 144))	('core', 'cellular_component', 'GO:0019013', ('52', '56'))	('HIF', 'Chemical', '-', (84, 87))
36903	31690629	Importantly, these effects were specific because HIF-binding to the EGLN3 intronic enhancer at chromosome 14 was not affected by mutations at the NICI HRE indicating a preserved HIF response at another locus in the mutated cells (Fig.	('EGLN3', 'Gene', '112399', (68, 73))	('EGLN3', 'Gene', (68, 73))	('HIF', 'Chemical', '-', (178, 181))	('binding', 'molecular_function', 'GO:0005488', ('53', '60'))	('mutations', 'Var', (129, 138))	('HIF', 'Chemical', '-', (49, 52))	('chromosome', 'cellular_component', 'GO:0005694', ('95', '105'))	('HIF', 'MPA', (178, 181))
36907	31690629	Therefore, the single HIF-binding site on chr12p.13.31 could transactivate both NICI and SLC2A3 independently.	('NICI', 'Gene', (80, 84))	('chr12p.13.31', 'Var', (42, 54))	('SLC2A3', 'Gene', (89, 95))	('transactivate', 'MPA', (61, 74))	('binding', 'molecular_function', 'GO:0005488', ('26', '33'))	('HIF', 'Chemical', '-', (22, 25))
36912	31690629	Despite the lack of direct interaction between the HIF-binding site and the SLC2A3 promoter the strong association between HIF-binding and expression of both genes as well as the delayed induction of SLC2A3 compared with NICI (Fig.	('HIF', 'Chemical', '-', (123, 126))	('HIF', 'Chemical', '-', (51, 54))	('association', 'Interaction', (103, 114))	('binding', 'molecular_function', 'GO:0005488', ('127', '134'))	('binding', 'molecular_function', 'GO:0005488', ('55', '62'))	('expression', 'MPA', (139, 149))	('SLC2A3', 'Var', (200, 206))
36918	31690629	To further dissect the mechanism of hypoxic SLC2A3 regulation and the role of NICI, we performed CRISPR/Cas9-mediated deletion of the NICI transcript in HeLa cells (Fig.	('HeLa', 'CellLine', 'CVCL:0030', (153, 157))	('regulation', 'biological_process', 'GO:0065007', ('51', '61'))	('NICI', 'Gene', (134, 138))	('Cas', 'cellular_component', 'GO:0005650', ('104', '107'))	('deletion', 'Var', (118, 126))
36919	31690629	Importantly, mutations in the gene body of NICI did not alter HIF binding to the NICI HRE or the EGLN3 HRE (Fig.	('binding', 'molecular_function', 'GO:0005488', ('66', '73'))	('HIF', 'Chemical', '-', (62, 65))	('binding', 'Interaction', (66, 73))	('NICI', 'Gene', (43, 47))	('NICI', 'Gene', (81, 85))	('EGLN3', 'Gene', '112399', (97, 102))	('EGLN3', 'Gene', (97, 102))	('mutations', 'Var', (13, 22))
36920	31690629	However, mutation of NICI led to significantly reduced induction of both NICI and SLC2A3 RNA by DMOG when compared with control clones (Fig.	('mutation', 'Var', (9, 17))	('SLC2A3 RNA', 'Gene', (82, 92))	('RNA', 'cellular_component', 'GO:0005562', ('89', '92'))	('NICI', 'Gene', (21, 25))	('NICI', 'Gene', (73, 77))	('DMOG', 'Chemical', 'MESH:C040947', (96, 100))	('reduced', 'NegReg', (47, 54))	('induction', 'MPA', (55, 64))
36924	31690629	Importantly however, recruitment of RNApol2 to the SLC2A3 promoter by DMOG was significantly reduced in NICI-mutated clones, indicating a direct role of NICI in transcriptional activation of SLC2A3 expression (Fig.	('SLC2A3', 'Gene', (191, 197))	('activation', 'PosReg', (177, 187))	('DMOG', 'Var', (70, 74))	('reduced', 'NegReg', (93, 100))	('RNApol2', 'Gene', (36, 43))	('DMOG', 'Chemical', 'MESH:C040947', (70, 74))	('recruitment', 'MPA', (21, 32))
36926	31690629	Interestingly, mutations in either the NICI HRE or the NICI gene body caused a remarkable reduction in glucose consumption, lactate production, and proliferation in HeLa cells under hypoxic conditions.	('reduction', 'NegReg', (90, 99))	('glucose', 'Chemical', 'MESH:D005947', (103, 110))	('NICI HRE', 'Gene', (39, 47))	('proliferation', 'CPA', (148, 161))	('lactate production', 'MPA', (124, 142))	('mutations', 'Var', (15, 24))	('glucose consumption', 'MPA', (103, 122))	('HeLa', 'CellLine', 'CVCL:0030', (165, 169))	('lactate', 'Chemical', 'MESH:D019344', (124, 131))	('NICI', 'Gene', (55, 59))
36927	31690629	Importantly, hypoxic induction of SLC2A1 (GLUT1), the other glucose transporter targeted by HIF, was not compromised by mutations in the NICI gene (Fig.	('HIF', 'Chemical', '-', (92, 95))	('glucose transporter', 'Gene', (60, 79))	('GLUT1', 'Gene', (42, 47))	('NICI', 'Gene', (137, 141))	('glucose transporter', 'Gene', '6513', (60, 79))	('SLC2A1', 'Gene', '6513', (34, 40))	('GLUT1', 'Gene', '6513', (42, 47))	('mutations', 'Var', (120, 129))	('SLC2A1', 'Gene', (34, 40))
36935	31690629	Recent reports have highlighted this way of fine-tuning transcriptional activity with important relevance for human diseases.	('transcriptional activity', 'MPA', (56, 80))	('human', 'Species', '9606', (110, 115))	('fine-tuning', 'Var', (44, 55))
36942	31690629	Of note, and in contrast to SLC2A1 and most glycolytic genes which are regulated by HIF-1 in many species including humans and mice, SLC2A3 is not regulated by loss of VHL in the renal epithelium of mice (Fig.	('mice', 'Species', '10090', (127, 131))	('HIF-1', 'Gene', '3091', (84, 89))	('SLC2A1', 'Gene', (28, 34))	('mice', 'Species', '10090', (199, 203))	('humans', 'Species', '9606', (116, 122))	('loss', 'Var', (160, 164))	('VHL', 'Gene', (168, 171))	('HIF-1', 'Gene', (84, 89))	('SLC2A1', 'Gene', '6513', (28, 34))
36951	31690629	A recent study has highlighted this approach in glioblastoma patients in which high GLUT3 expression associates with an unfavorable outcome.	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('patients', 'Species', '9606', (61, 69))	('expression', 'MPA', (90, 100))	('high', 'Var', (79, 83))	('GLUT3', 'Gene', '6515', (84, 89))	('glioblastoma', 'Disease', (48, 60))	('glioblastoma', 'Disease', 'MESH:D005909', (48, 60))	('GLUT3', 'Gene', (84, 89))
37007	31490389	In multivariate analysis, high VM and CIP2A, tumor grade, LNM stage, TNM stage, and low PRRX1 levels were identified as potential independent prognostic factors for OST in CCRCC patients.	('TNM', 'Disease', (69, 72))	('CCRCC', 'Disease', 'MESH:D002292', (172, 177))	('TNM', 'Disease', 'MESH:D009362', (69, 72))	('low', 'NegReg', (84, 87))	('CIP2A', 'Gene', (38, 43))	('PRRX1', 'Gene', (88, 93))	('PRRX1', 'Gene', '5396', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('CCRCC', 'Disease', (172, 177))	('tumor', 'Disease', (45, 50))	('patients', 'Species', '9606', (178, 186))	('CIP2A', 'Gene', '57650', (38, 43))	('CCRCC', 'Phenotype', 'HP:0006770', (172, 177))	('high VM', 'Var', (26, 33))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('OST', 'Disease', (165, 168))
37056	31490389	Follow-up data suggested that OST was significantly shorter in CCRCC patients with VM+ specimens (48.62 +- 16.362 months) than in those with VM- specimens (71.25 +- 13.183 months; log-rank = 47.583, P < .001; Fig.	('VM+ specimens', 'Var', (83, 96))	('CCRCC', 'Disease', (63, 68))	('CCRCC', 'Phenotype', 'HP:0006770', (63, 68))	('shorter', 'NegReg', (52, 59))	('OST', 'Disease', (30, 33))	('CCRCC', 'Disease', 'MESH:D002292', (63, 68))	('patients', 'Species', '9606', (69, 77))
37062	31490389	Moreover, multivariate analysis demonstrated that VM+, CIP2A+, PRRX1- specimens, tumor grade, TNM stage, and LNM were independent prognostic factors for CCRCC (Table 4).	('TNM', 'Disease', (94, 97))	('CCRCC', 'Disease', 'MESH:D002292', (153, 158))	('TNM', 'Disease', 'MESH:D009362', (94, 97))	('CIP2A', 'Gene', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('PRRX1', 'Gene', (63, 68))	('VM+', 'Var', (50, 53))	('PRRX1', 'Gene', '5396', (63, 68))	('CIP2A', 'Gene', '57650', (55, 60))	('CCRCC', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CCRCC', 'Phenotype', 'HP:0006770', (153, 158))	('tumor', 'Disease', (81, 86))
37098	30896867	The receiver operating characteristic curve analysis revealed that CEP55 may be considered a diagnostic biomarker for ccRCC with an area under the curve of >0.85 in the training and validation sets.	('CEP', 'molecular_function', 'GO:0047849', ('67', '70'))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('CEP55', 'Var', (67, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))
37100	30896867	In addition, gene set enrichment analysis indicated that high CEP55 expression was associated with immunization, cell adhesion, inflammation, the Janus kinase/signal transducer and activator of transcription signaling pathway and cell proliferation.	('cell adhesion', 'CPA', (113, 126))	('CEP', 'molecular_function', 'GO:0047849', ('62', '65'))	('cell proliferation', 'CPA', (230, 248))	('men', 'Species', '9606', (28, 31))	('high', 'Var', (57, 61))	('inflammation', 'Disease', (128, 140))	('signaling pathway', 'biological_process', 'GO:0007165', ('208', '225'))	('cell proliferation', 'biological_process', 'GO:0008283', ('230', '248'))	('inflammation', 'biological_process', 'GO:0006954', ('128', '140'))	('immunization', 'Disease', (99, 111))	('associated', 'Reg', (83, 93))	('CEP55', 'Gene', (62, 67))	('Janus kinase/signal transducer and', 'Pathway', (146, 180))	('transcription', 'biological_process', 'GO:0006351', ('194', '207'))	('cell adhesion', 'biological_process', 'GO:0007155', ('113', '126'))	('inflammation', 'Disease', 'MESH:D007249', (128, 140))
37113	30896867	In the present study, four ccRCC datasets (GSE46699, GSE36895, GSE53000 and GSE53757) were downloaded from the GEO.	('GSE36895', 'Var', (53, 61))	('GSE53000', 'Var', (63, 71))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (27, 32))	('GSE53757', 'Var', (76, 84))	('GSE46699', 'Var', (43, 51))
37115	30896867	Tumor-associated genetic alterations are known to result in tumorigenesis and the progression of ccRCC.	('result in', 'Reg', (50, 59))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('progression', 'CPA', (82, 93))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('RCC', 'Disease', (99, 102))	('genetic alterations', 'Var', (17, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('tumor', 'Disease', (60, 65))
37125	30896867	The platform used to obtain the GSE36895 data was also GPL570, and this dataset consisted of 23 adjacent normal kidney samples and 29 ccRCC samples.	('GPL570', 'Chemical', '-', (55, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('GPL570', 'Var', (55, 61))	('RCC', 'Disease', (136, 139))
37127	30896867	The platform used to obtain the GSE53757 data was GPL570, and this dataset consisted of 72 adjacent normal kidney samples and 72 ccRCC samples.	('GPL570', 'Var', (50, 56))	('ccRCC', 'Phenotype', 'HP:0006770', (129, 134))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('GPL570', 'Chemical', '-', (50, 56))
37137	30896867	The primers used were as follows: CEP55, forward 5'-GCCATTGGGCGAGACCTACCT-3', reverse 5'-GTTCGGGACTTCGCTCACCTT-3'; and GAPDH, forward 5'-ACAACTTTGGTATCGTGGAAGG-3' and reverse 5'-GCCATCACGCCACAGTTTC-3'.	('CEP', 'molecular_function', 'GO:0047849', ('34', '37'))	('GAPDH', 'Gene', '2597', (119, 124))	('GAPDH', 'Gene', (119, 124))	('CEP55', 'Var', (34, 39))
37143	30896867	The ccRCC expression microarray datasets GSE46699, GSE36895, GSE53000 and GSE53757 were downloaded from the GEO and were analyzed using limma package (adjusted P<0.05,  logFC >1).	('GSE53000', 'Var', (61, 69))	('ccRCC', 'Phenotype', 'HP:0006770', (4, 9))	('GSE46699', 'Var', (41, 49))	('GSE36895', 'Var', (51, 59))	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('GSE53757', 'Var', (74, 82))	('RCC', 'Disease', (6, 9))
37156	30896867	These results revealed a potential association between high CEP55 expression levels and the aggressive clinical characteristics of ccRCC, and also with sex.	('expression levels', 'MPA', (66, 83))	('aggressive clinical characteristics', 'CPA', (92, 127))	('CEP', 'molecular_function', 'GO:0047849', ('60', '63'))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('CEP55', 'Protein', (60, 65))	('RCC', 'Disease', (133, 136))	('high', 'Var', (55, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))
37158	30896867	Cox regression analysis was performed to determine whether CEP55 could be a potential predictive and prognostic factor.	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('CEP', 'molecular_function', 'GO:0047849', ('59', '62'))	('CEP55', 'Var', (59, 64))
37159	30896867	As shown in Table V, high CEP55 expression was associated with a significantly increased risk of mortality in patients with ccRCC (P=0.006) when compared to those with low CEP55 expression, as determined by univariate Cox regression analysis.	('Cox', 'Gene', (218, 221))	('mortality', 'Disease', (97, 106))	('CEP55', 'Gene', (26, 31))	('CEP', 'molecular_function', 'GO:0047849', ('172', '175'))	('high', 'Var', (21, 25))	('Cox', 'Gene', '1351', (218, 221))	('ccRCC', 'Phenotype', 'HP:0006770', (124, 129))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('expression', 'MPA', (32, 42))	('CEP', 'molecular_function', 'GO:0047849', ('26', '29'))	('patients', 'Species', '9606', (110, 118))
37160	30896867	Multivariate Cox regression analysis also revealed that CEP55 expression (P=0.011) and M classification (P<0.001) could be factors for predicting poor prognosis in ccRCC (Table V).	('CEP', 'molecular_function', 'GO:0047849', ('56', '59'))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('Cox', 'Gene', (13, 16))	('RCC', 'Disease', (166, 169))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('ccRCC', 'Phenotype', 'HP:0006770', (164, 169))	('CEP55 expression', 'Var', (56, 72))	('Cox', 'Gene', '1351', (13, 16))
37169	30896867	Furthermore, only CEP55 was closely associated with ccRCC progression and prognosis as determined by GEPIA, an online method based on TCGA.	('CEP55', 'Var', (18, 23))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('CEP', 'molecular_function', 'GO:0047849', ('18', '21'))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('associated', 'Reg', (36, 46))
37173	30896867	High CEP55 expression results in disordered cytokinesis and an increased number of unstable binucleated cells; these are oncogenic characteristics in tumorigenesis.	('disordered', 'Disease', 'MESH:D030342', (33, 43))	('increased', 'PosReg', (63, 72))	('CEP55', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('CEP', 'molecular_function', 'GO:0047849', ('5', '8'))	('disordered', 'Disease', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('cytokinesis', 'biological_process', 'GO:0000910', ('44', '55'))
37175	30896867	In addition, high CEP55 expression in colorectal cancer downregulates the tumor susceptibility 101 gene in a post-transcriptional manner, and knockdown of CEP55 inhibits cell growth and increases apoptosis.	('colorectal cancer', 'Phenotype', 'HP:0003003', (38, 55))	('cell growth', 'CPA', (170, 181))	('increases', 'PosReg', (186, 195))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('high', 'Var', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('CEP', 'molecular_function', 'GO:0047849', ('18', '21'))	('apoptosis', 'CPA', (196, 205))	('colorectal cancer', 'Disease', 'MESH:D015179', (38, 55))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('colorectal cancer', 'Disease', (38, 55))	('CEP', 'molecular_function', 'GO:0047849', ('155', '158'))	('downregulates', 'NegReg', (56, 69))	('apoptosis', 'biological_process', 'GO:0006915', ('196', '205'))	('knockdown', 'Var', (142, 151))	('CEP55', 'Gene', (155, 160))	('inhibits', 'NegReg', (161, 169))	('apoptosis', 'biological_process', 'GO:0097194', ('196', '205'))	('CEP55', 'Gene', (18, 23))	('cell growth', 'biological_process', 'GO:0016049', ('170', '181'))
37187	30896867	The univariate and multivariate analyses also demonstrated that CEP55 may be an independent prognostic factor in patients with ccRCC.	('CEP55', 'Var', (64, 69))	('CEP', 'molecular_function', 'GO:0047849', ('64', '67'))	('patients', 'Species', '9606', (113, 121))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('RCC', 'Disease', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))
37196	30896867	Tissue expression levels of CEP55, which can distinguish ccRCC patients from normal patients, only provides the potential diagnostic value of CEP55 in ccRCC and cannot be put into clinical application.	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('CEP', 'molecular_function', 'GO:0047849', ('28', '31'))	('patients', 'Species', '9606', (84, 92))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('CEP55', 'Var', (142, 147))	('CEP', 'molecular_function', 'GO:0047849', ('142', '145'))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('RCC', 'Disease', (153, 156))	('CEP55', 'Gene', (28, 33))	('ccRCC', 'Phenotype', 'HP:0006770', (151, 156))	('patients', 'Species', '9606', (63, 71))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
37221	32245446	While adding back the CD45+ cells alone was insufficient to increase engraftment success, the CD45+ cells comprised the predominant proportion of viable cells in engrafted tumour specimens.	('CD45+ cells', 'Var', (94, 105))	('tumour', 'Disease', (172, 178))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('tumour', 'Disease', 'MESH:D009369', (172, 178))
37235	32245446	The specimens were stained using CD45-APC-Cy7 (1:200), CD31-PE-Cy7 (1:200), CD34-PerCP-Cy5.5 (1:50) (all BioLegend) and 1.2 mg/ml TE7-biotin (in-house production from hybridoma obtained from ATCC) followed by Streptavidin-eFluor450 (1:400; eBioscience).	('CD31', 'Gene', '5175', (55, 59))	('1:200', 'Var', (68, 73))	('TE7-biotin', 'Chemical', '-', (130, 140))	('CD34-PerCP-Cy5.5', 'Var', (76, 92))	('CD45-APC-Cy7', 'Var', (33, 45))	('APC', 'cellular_component', 'GO:0005680', ('38', '41'))	('CD31', 'Gene', (55, 59))
37265	32245446	Among the stem/progenitor markers, expression of CD10, CD29 and CD44 in the LIN-negative sub-population showed particularly strong positive correlation with higher proportion of CD45+ cells expressing a number of T-cell surface markers (i.e.	('CD45+', 'Var', (178, 183))	('cell surface', 'cellular_component', 'GO:0009986', ('215', '227'))	('CD10', 'Gene', '4311', (49, 53))	('CD44', 'Gene', '960', (64, 68))	('CD10', 'molecular_function', 'GO:0004245', ('49', '53'))	('CD29', 'Gene', '3688', (55, 59))	('CD44', 'Gene', (64, 68))	('CD29', 'Gene', (55, 59))	('CD10', 'Gene', (49, 53))
37271	32245446	When we examined the expression patterns of the immune checkpoint proteins on different sub-populations, CD140B and CD90 positivity in the LIN-negative sub-population showed generally positive correlation with the expression of most of the immune checkpoint proteins examined (Fig.	('CD140B', 'Gene', '5159', (105, 111))	('CD140B', 'Gene', (105, 111))	('positivity', 'Var', (121, 131))	('CD90', 'Gene', '7070', (116, 120))	('CD90', 'Gene', (116, 120))	('expression', 'MPA', (214, 224))	('positive', 'PosReg', (184, 192))
37272	32245446	On the other hand, CD133, SSEA/3 and SSEA-4 correlated negatively with most of the immune checkpoint proteins examined, and these correlations were more striking in the CD45+ and CD34+ sub-populations.	('negatively', 'NegReg', (55, 65))	('immune checkpoint proteins', 'MPA', (83, 109))	('CD133', 'Gene', (19, 24))	('CD34+', 'Var', (179, 184))	('CD45+', 'Var', (169, 174))	('SSEA/3', 'Gene', (26, 32))	('CD133', 'Gene', '8842', (19, 24))	('SSEA-4', 'Gene', (37, 43))
37305	32245446	When aberrantly expressed in carcinoma cells, vimentin is seen as a marker of EMT.	('vimentin', 'cellular_component', 'GO:0045098', ('46', '54'))	('carcinoma', 'Disease', 'MESH:D009369', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('vimentin', 'Gene', '7431', (46, 54))	('vimentin', 'Gene', (46, 54))	('aberrantly', 'Var', (5, 15))	('carcinoma', 'Disease', (29, 38))	('vimentin', 'cellular_component', 'GO:0045099', ('46', '54'))	('EMT', 'biological_process', 'GO:0001837', ('78', '81'))
37309	32245446	Increased CD44 expression has been associated with sarcomatoid differentiation and aberrant p53 expression in renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (110, 130))	('associated', 'Reg', (35, 45))	('aberrant', 'Var', (83, 91))	('sarcomatoid differentiation', 'Disease', (51, 78))	('expression', 'MPA', (96, 106))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (110, 130))	('CD44', 'Gene', '960', (10, 14))	('Increased', 'PosReg', (0, 9))	('p53', 'Gene', (92, 95))	('expression', 'MPA', (15, 25))	('sarcomatoid differentiation', 'Disease', 'MESH:C538614', (51, 78))	('CD44', 'Gene', (10, 14))	('p53', 'Gene', '7157', (92, 95))	('renal cell carcinoma', 'Disease', (110, 130))
37341	32260578	Indeed, ccRCC are hallmarked by a frequent alteration of the VHL gene, a tumour suppressor gene, leading to angiogenesis through the transcription of genes regulated by HIF such as VEGF.	('tumour', 'Disease', (73, 79))	('alteration', 'Var', (43, 53))	('transcription', 'biological_process', 'GO:0006351', ('133', '146'))	('leading to', 'Reg', (97, 107))	('VEGF', 'Gene', '7422', (181, 185))	('ccRCC', 'Phenotype', 'HP:0006770', (8, 13))	('VHL', 'Gene', (61, 64))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('VEGF', 'Gene', (181, 185))	('angiogenesis', 'biological_process', 'GO:0001525', ('108', '120'))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('VHL', 'Gene', '7428', (61, 64))	('RCC', 'Disease', (10, 13))	('angiogenesis', 'CPA', (108, 120))	('transcription', 'MPA', (133, 146))	('RCC', 'Disease', 'MESH:C538614', (10, 13))
37345	32260578	However, alterations of SETD2, CDKN2A, EGFR, NF2 and TERT have been described in type 2 and suggest the activation of MAP kinases pathway, cell cycle and deregulation of chromatin remodeling.	('chromatin remodeling', 'CPA', (170, 190))	('MAP', 'molecular_function', 'GO:0004239', ('118', '121'))	('EGFR', 'molecular_function', 'GO:0005006', ('39', '43'))	('EGFR', 'Gene', '1956', (39, 43))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('170', '190'))	('chromatin', 'cellular_component', 'GO:0000785', ('170', '179'))	('TERT', 'Gene', (53, 57))	('TERT', 'Gene', '7015', (53, 57))	('NF2', 'Gene', '4771', (45, 48))	('SETD2', 'Gene', (24, 29))	('activation', 'PosReg', (104, 114))	('NF2', 'Gene', (45, 48))	('MAP kinases pathway', 'Pathway', (118, 137))	('alterations', 'Var', (9, 20))	('SETD2', 'Gene', '29072', (24, 29))	('EGFR', 'Gene', (39, 43))	('cell cycle', 'biological_process', 'GO:0007049', ('139', '149'))	('CDKN2A', 'Gene', (31, 37))	('cell cycle', 'CPA', (139, 149))	('CDKN2A', 'Gene', '1029', (31, 37))
37346	32260578	Chromophobe RCC (cRCC) are rarely metastatic and characterize mitochondrial alterations, frequently mutated p53 and activation of mTOR pathway.	('mitochondrial', 'MPA', (62, 75))	('RCC', 'Disease', (18, 21))	('Chromophobe RCC', 'Disease', 'MESH:C538614', (0, 15))	('mutated', 'Var', (100, 107))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('mitochondrial alterations', 'Phenotype', 'HP:0012103', (62, 87))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('RCC', 'Disease', (12, 15))	('activation', 'PosReg', (116, 126))	('mTOR', 'Gene', (130, 134))	('Chromophobe RCC', 'Disease', (0, 15))	('mTOR', 'Gene', '2475', (130, 134))	('RCC', 'Disease', 'MESH:C538614', (18, 21))
37347	32260578	Translocation RCC (tRCC) harbor gene fusions involve TFE3 and TFEB, members of the MiTF family.	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('RCC', 'Disease', (14, 17))	('TFE3', 'Gene', (53, 57))	('gene fusions', 'Var', (32, 44))	('TFEB', 'Gene', '7942', (62, 66))	('TFEB', 'Gene', (62, 66))	('TFE3', 'Gene', '7030', (53, 57))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('RCC', 'Disease', (20, 23))
37351	32260578	Among familial RCC syndromes, patients with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome harbor Fumarate Hydratase (FH) germline mutation and develop clinical aggressive tumours.	('develop', 'PosReg', (165, 172))	('familial RCC syndromes', 'Disease', 'MESH:C538614', (6, 28))	('aggressive tumours', 'Disease', (182, 200))	('germline mutation', 'Var', (143, 160))	('hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome harbor Fumarate Hydratase', 'Disease', 'MESH:C538191', (44, 137))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (74, 94))	('patients', 'Species', '9606', (30, 38))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('familial RCC syndromes', 'Disease', (6, 28))	('aggressive tumours', 'Disease', 'MESH:D009369', (182, 200))	('tumours', 'Phenotype', 'HP:0002664', (193, 200))
37352	32260578	The FH mutation by inactivating the enzyme alters the function of the Krebs cycle.	('enzyme', 'Enzyme', (36, 42))	('alters', 'Reg', (43, 49))	('inactivating', 'Var', (19, 31))	('Krebs', 'Chemical', '-', (70, 75))	('Krebs cycle', 'Enzyme', (70, 81))	('Krebs cycle', 'biological_process', 'GO:0006099', ('70', '81'))	('function', 'MPA', (54, 62))
37353	32260578	The sarcomatoid component can be found in all the histologic subtypes and demonstrates an increased tumour mutation burden (TMB) with high frequency of p53, CDKN2A and NF2 mutations and also genes involved the chromatin remodeling such as ARID1A and BAP1.	('p53', 'Gene', '7157', (152, 155))	('TMB', 'Chemical', '-', (124, 127))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('CDKN2A', 'Gene', '1029', (157, 163))	('tumour', 'Disease', (100, 106))	('p53', 'Gene', (152, 155))	('sarcomatoid component', 'Disease', (4, 25))	('sarcomatoid component', 'Disease', 'MESH:C538614', (4, 25))	('ARID1A', 'Gene', (239, 245))	('increased', 'PosReg', (90, 99))	('BAP1', 'Gene', '8314', (250, 254))	('mutations', 'Var', (172, 181))	('ARID1A', 'Gene', '8289', (239, 245))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('210', '230'))	('NF2', 'Gene', '4771', (168, 171))	('CDKN2A', 'Gene', (157, 163))	('chromatin', 'cellular_component', 'GO:0000785', ('210', '219'))	('BAP1', 'Gene', (250, 254))	('NF2', 'Gene', (168, 171))
37356	32260578	The emergence of immune checkpoint inhibitors (ICI) alone or in combination (anti-cytotoxic T-lymphocyte antigen-4 (CTLA4) and anti-programmed death 1 (PD-1)) showed interesting results.	('CTLA4', 'Gene', (116, 121))	('lymphocyte antigen', 'molecular_function', 'GO:0005557', ('94', '112'))	('anti-programmed', 'Var', (127, 142))	('PD-1', 'Gene', (152, 156))	('PD-1', 'Gene', '5133', (152, 156))	('CTLA4', 'Gene', '1493', (116, 121))
37358	32260578	Recent trials proposed antiangiogenics in association with targeted immunotherapy to overcome resistance emphasizing the role of the tumour microenvironment (TME) and this strategy is currently an option in first line treatment.	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('men', 'Species', '9606', (223, 226))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('men', 'Species', '9606', (152, 155))	('tumour', 'Disease', (133, 139))	('antiangiogenics', 'Var', (23, 38))	('TME', 'Chemical', '-', (158, 161))
37417	32260578	Moreover, the LAG3 blockade leads to an increased production of interferon gamma (INFgamma), tumour necrosis factor alpha (TNFalpha) and pro-inflammatory interleukins.	('production', 'MPA', (50, 60))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('LAG3', 'Gene', (14, 18))	('increased production of interferon', 'Phenotype', 'HP:0009709', (40, 74))	('blockade', 'Var', (19, 27))	('TNFalpha', 'Gene', '7124', (123, 131))	('necrosis', 'biological_process', 'GO:0008219', ('100', '108'))	('tumour necrosis', 'Disease', 'MESH:D009336', (93, 108))	('tumour necrosis', 'Disease', (93, 108))	('interferon gamma', 'Gene', (64, 80))	('necrosis', 'biological_process', 'GO:0008220', ('100', '108'))	('TNFalpha', 'Gene', (123, 131))	('necrosis', 'biological_process', 'GO:0070265', ('100', '108'))	('interferon gamma', 'molecular_function', 'GO:0005133', ('64', '80'))	('interferon gamma', 'Gene', '3458', (64, 80))	('necrosis', 'biological_process', 'GO:0019835', ('100', '108'))	('increased', 'PosReg', (40, 49))	('necrosis', 'biological_process', 'GO:0001906', ('100', '108'))	('LAG3', 'Gene', '3902', (14, 18))
37433	32260578	Metabolic changes influence the TME by providing immunosuppressive metabolites and favoring tumour growth in hypoxic conditions, as shown in Figure 3.	('favoring', 'PosReg', (83, 91))	('providing', 'PosReg', (39, 48))	('TME', 'CPA', (32, 35))	('TME', 'Chemical', '-', (32, 35))	('tumour growth in hypoxic conditions', 'Disease', 'MESH:D006130', (92, 127))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('changes', 'Var', (10, 17))	('tumour growth in hypoxic conditions', 'Disease', (92, 127))	('immunosuppressive metabolites', 'MPA', (49, 78))
37436	32260578	The tryptophan depletion induced by IDO1 expression leads to T cell exhaustion and apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('tryptophan', 'Chemical', 'MESH:D014364', (4, 14))	('IDO1', 'Gene', '3620', (36, 40))	('T cell exhaustion', 'Phenotype', 'HP:0005435', (61, 78))	('IDO', 'molecular_function', 'GO:0033754', ('36', '39'))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('leads to', 'Reg', (52, 60))	('tryptophan depletion', 'MPA', (4, 24))	('IDO', 'molecular_function', 'GO:0047719', ('36', '39'))	('apoptosis', 'CPA', (83, 92))	('IDO1', 'Gene', (36, 40))	('expression', 'Var', (41, 51))	('T cell exhaustion', 'CPA', (61, 78))
37437	32260578	Moreover, high concentration of kynurenine promotes immune-tolerant dendritic cells and regulatory T cell proliferation.	('kynurenine', 'Chemical', 'MESH:D007737', (32, 42))	('regulatory T cell proliferation', 'CPA', (88, 119))	('promotes', 'PosReg', (43, 51))	('kynurenine', 'Var', (32, 42))	('T cell proliferation', 'biological_process', 'GO:0042098', ('99', '119'))	('immune-tolerant dendritic cells', 'CPA', (52, 83))
37444	32260578	Histone deacetylase (HDAC) inhibitors modify the chromatin accessibility and play a crucial role in cycle arrest and apoptosis and could eventually enhance tumour antigens release and indirectly improve antigen presentation by APC and T cells priming.	('APC', 'cellular_component', 'GO:0005680', ('227', '230'))	('modify', 'Reg', (38, 44))	('apoptosis', 'CPA', (117, 126))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('arrest', 'Disease', 'MESH:D006323', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('Histone deacetylase', 'Gene', (0, 19))	('tumour', 'Disease', (156, 162))	('antigen presentation', 'biological_process', 'GO:0019882', ('203', '223'))	('enhance', 'PosReg', (148, 155))	('HDAC', 'Gene', '9734', (21, 25))	('chromatin accessibility', 'MPA', (49, 72))	('improve', 'PosReg', (195, 202))	('Histone deacetylase', 'Gene', '9734', (0, 19))	('APC', 'Disease', 'MESH:D011125', (227, 230))	('APC', 'Disease', (227, 230))	('HDAC', 'Gene', (21, 25))	('arrest', 'Disease', (106, 112))	('antigen presentation', 'MPA', (203, 223))	('inhibitors', 'Var', (27, 37))	('apoptosis', 'biological_process', 'GO:0097194', ('117', '126'))	('apoptosis', 'biological_process', 'GO:0006915', ('117', '126'))	('chromatin', 'cellular_component', 'GO:0000785', ('49', '58'))
37466	32260578	Cluster 3 had the best prognosis with high angiogenic gene expression being associated with a better outcome under antiangiogenic therapy and similar to ccrcc2 cluster reported by Beuselinck et al.. Of note, PBRM1 mutation was frequently associated with angiogenic gene expression.	('mutation', 'Var', (214, 222))	('PBRM1', 'Gene', '55193', (208, 213))	('angiogenic gene', 'Gene', (254, 269))	('gene expression', 'biological_process', 'GO:0010467', ('54', '69'))	('associated', 'Reg', (238, 248))	('PBRM1', 'Gene', (208, 213))	('gene expression', 'biological_process', 'GO:0010467', ('265', '280'))
37470	32260578	Interestingly, high T effector/IFNgamma signature was associated with a better outcome to atezolizumab plus bevacizumab and a high myeloid inflammation signature was associated with reduced survival in the atezolizumab alone arm.	('high', 'Var', (15, 19))	('atezolizumab plus bevacizumab', 'Disease', (90, 119))	('inflammation', 'Disease', 'MESH:D007249', (139, 151))	('atezolizumab', 'Chemical', 'MESH:C000594389', (206, 218))	('inflammation', 'Disease', (139, 151))	('inflammation', 'biological_process', 'GO:0006954', ('139', '151'))	('better', 'PosReg', (72, 78))	('IFNgamma', 'Gene', (31, 39))	('IFNgamma', 'Gene', '3458', (31, 39))	('atezolizumab', 'Chemical', 'MESH:C000594389', (90, 102))	('atezolizumab plus bevacizumab', 'Disease', 'MESH:D007625', (90, 119))	('reduced', 'NegReg', (182, 189))
37475	32260578	Even if RCC are not considered to be in the spectrum of hereditary non-polyposis colon cancer (HNPCC) or Lynch syndrome, loss of mismatch repair (MMR) proteins leading to microsatellite instability is frequently observed.	('RCC', 'Disease', (8, 11))	('colon cancer', 'Phenotype', 'HP:0003003', (81, 93))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('MMR', 'biological_process', 'GO:0006298', ('146', '149'))	('mismatch repair', 'biological_process', 'GO:0006298', ('129', '144'))	('loss', 'Var', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('microsatellite instability', 'MPA', (171, 197))	('hereditary non-polyposis colon cancer (HNPCC) or Lynch syndrome', 'Disease', 'MESH:D003123', (56, 119))
37476	32260578	MMR deficient tumours demonstrate a higher rate of mutations but on specific genes.	('mutations', 'Var', (51, 60))	('MMR deficient tumours', 'Disease', 'MESH:C536143', (0, 21))	('tumours', 'Phenotype', 'HP:0002664', (14, 21))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('MMR', 'biological_process', 'GO:0006298', ('0', '3'))	('MMR deficient tumours', 'Disease', (0, 21))
37481	32260578	Conversely, they identified that some bacteria such as B. salyersiae or A. muciniphila could restore the efficacy of ICI.	('efficacy', 'MPA', (105, 113))	('restore', 'PosReg', (93, 100))	('B. salyersiae', 'Var', (55, 68))	('B. salyersiae', 'Species', '291644', (55, 68))	('A. muciniphila', 'Species', '239935', (72, 86))
37500	32260578	Other methods are based on RT-PCR targeting VHL gene alteration and size-based blood filtration associated with genetic and morphological analyses.	('alteration', 'Var', (53, 63))	('VHL', 'Gene', (44, 47))	('VHL', 'Gene', '7428', (44, 47))
37587	32316524	Recent studies, in fact, have demonstrated PAX8 positivity in up to 90% of metastatic CCRCCs.	('PAX8', 'Gene', (43, 47))	('positivity', 'Var', (48, 58))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('CCRCC', 'Phenotype', 'HP:0006770', (86, 91))	('PAX8', 'Gene', '7849', (43, 47))
37593	32443455	Both compounds caused cell cycle arrest and apoptosis but only 5F 203 potently inhibited the migration of TK-10, Caki-1 and SN12C cells as well as the migration signal transduction cascade, involving c-Met signaling, in TK-10 cells.	('migration', 'CPA', (151, 160))	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('signal transduction', 'biological_process', 'GO:0007165', ('161', '180'))	('signaling', 'biological_process', 'GO:0023052', ('206', '215'))	('5F 203', 'Chemical', 'MESH:C425784', (63, 69))	('migration', 'CPA', (93, 102))	('c-Met', 'Gene', (200, 205))	('arrest', 'Disease', 'MESH:D006323', (33, 39))	('SN12C', 'CellLine', 'CVCL:1705', (124, 129))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (22, 39))	('c-Met', 'Gene', '4233', (200, 205))	('5F 203', 'Var', (63, 69))	('inhibited', 'NegReg', (79, 88))	('cell cycle', 'CPA', (22, 32))	('arrest', 'Disease', (33, 39))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('22', '39'))
37601	32443455	Bi-allelic loss of function of the Von Hippel Lindau (VHL) tumor suppressor gene, as a consequence of mutations, deletions or epigenetic silencing, is found in the vast majority of ccRCC and is usually the most precocious truncal molecular driving event.	('RCC', 'Phenotype', 'HP:0005584', (183, 186))	('epigenetic silencing', 'Var', (126, 146))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('deletions', 'Var', (113, 122))	('RCC', 'Disease', (183, 186))	('loss of function', 'NegReg', (11, 27))	('mutations', 'Var', (102, 111))	('tumor suppressor', 'biological_process', 'GO:0051726', ('59', '75'))	('Von Hippel Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (35, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('59', '75'))
37603	32443455	Type I papillary RCC is characterized by proto-oncogene c-Met over-expression/amplification as a result of activated mutations or copy number alterations.	('mutations', 'Var', (117, 126))	('c-Met', 'Gene', (56, 61))	('c-Met', 'Gene', '4233', (56, 61))	('Type I papillary RCC', 'Disease', (0, 20))	('over-expression/amplification', 'PosReg', (62, 91))	('over-expression/amplification', 'MPA', (62, 91))	('Type I papillary RCC', 'Disease', 'MESH:C538614', (0, 20))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('copy number alterations', 'Var', (130, 153))
37627	32443455	AhR interacts with multiple other signaling pathways and activates other cytosolic proteins, including beta-catenin, Smads, ERK, p38MAPK, JNK, NF-kappaB and RB.	('ERK', 'Gene', (124, 127))	('JNK', 'Gene', '5599', (138, 141))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('NF-kappaB', 'Gene', '4790', (143, 152))	('beta-catenin', 'Gene', (103, 115))	('ERK', 'molecular_function', 'GO:0004707', ('124', '127'))	('beta-catenin', 'Gene', '1499', (103, 115))	('MAPK', 'molecular_function', 'GO:0004707', ('132', '136'))	('activates', 'PosReg', (57, 66))	('NF-kappaB', 'Gene', (143, 152))	('JNK', 'molecular_function', 'GO:0004705', ('138', '141'))	('ERK', 'Gene', '5594', (124, 127))	('cytosolic proteins', 'MPA', (73, 91))	('JNK', 'Gene', (138, 141))	('p38MAPK', 'Var', (129, 136))
37682	32443455	We concluded that AhR translocation could be included as a marker of sensitivity to AF in sensitive renal tumor cells of different histological origin, in Phase II clinical trials.	('AhR', 'Gene', (18, 21))	('renal tumor', 'Phenotype', 'HP:0009726', (100, 111))	('renal tumor', 'Disease', 'MESH:D007674', (100, 111))	('renal tumor', 'Disease', (100, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('translocation', 'Var', (22, 35))
37688	32443455	As previous results indicate that AFP 464 (NSC710404) induced DNA damage and apoptosis in renal cancer cells and 5F 203 evoked DNA damage in breast and ovarian cancer cells, we investigated perturbations in the cell cycle after treatment of renal cells with these compounds.	('DNA damage', 'MPA', (62, 72))	('cell cycle', 'biological_process', 'GO:0007049', ('211', '221'))	('induced', 'Reg', (54, 61))	('apoptosis', 'CPA', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (141, 166))	('renal cancer', 'Disease', (90, 102))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('ovarian cancer', 'Phenotype', 'HP:0100615', (152, 166))	('renal cancer', 'Phenotype', 'HP:0009726', (90, 102))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('AFP 464 (NSC710404', 'Var', (34, 52))	('men', 'Species', '9606', (233, 236))	('renal cancer', 'Disease', 'MESH:D007680', (90, 102))	('5F 203', 'Chemical', 'MESH:C425784', (113, 119))
37690	32443455	AFP 464 only caused an increase in phase G0/G1 in TK-10 cells at 24 h. In contrast, the ACHN cell cycle was not perturbed following treatment with AFP 464.	('men', 'Species', '9606', (137, 140))	('AFP 464', 'Var', (147, 154))	('ACHN cell cycle', 'CPA', (88, 103))	('cell cycle', 'biological_process', 'GO:0007049', ('93', '103'))
37691	32443455	5F 203 caused an increase in phase G0/G1 in SN12C and Caki-1 and TK-10 cells.	('phase G0/G1', 'MPA', (29, 40))	('5F 203', 'Chemical', 'MESH:C425784', (0, 6))	('SN12C', 'CellLine', 'CVCL:1705', (44, 49))	('5F 203', 'Var', (0, 6))	('increase', 'PosReg', (17, 25))
37697	32443455	In contrast, 5F 203 (1 microM) significantly suppressed cell migration in the three sensitive cell lines, namely, the TK-10, SN12C and Caki-1 cell lines, respectively.	('SN12C', 'CellLine', 'CVCL:1705', (125, 130))	('cell migration', 'CPA', (56, 70))	('5F 203', 'Var', (13, 19))	('suppressed', 'NegReg', (45, 55))	('5F 203', 'Chemical', 'MESH:C425784', (13, 19))	('cell migration', 'biological_process', 'GO:0016477', ('56', '70'))
37710	32443455	5F 203 is sequestered by TK-10 cells and induces CYP1A1 expression; 5F 203 potently inhibited the migration of TK-10, Caki-1, and SN12C cells, and inhibited c-Met receptor phosphorylation in TK-10 cells.	('CYP1A1', 'Gene', (49, 55))	('5F 203', 'Chemical', 'MESH:C425784', (0, 6))	('ester', 'Chemical', 'MESH:D004952', (14, 19))	('CYP1A1', 'Gene', '1543', (49, 55))	('SN12C', 'CellLine', 'CVCL:1705', (130, 135))	('5F 203', 'Var', (68, 74))	('phosphorylation', 'biological_process', 'GO:0016310', ('172', '187'))	('migration', 'CPA', (98, 107))	('inhibited', 'NegReg', (147, 156))	('5F 203', 'Chemical', 'MESH:C425784', (68, 74))	('c-Met', 'Gene', (157, 162))	('c-Met', 'Gene', '4233', (157, 162))	('inhibited', 'NegReg', (84, 93))
37730	32443455	A series of distinctive peaks corresponding to AFt (56-58 m/z) and 5F 203 (255-295 m/z) were detected.	('AFt', 'Gene', (47, 50))	('255-295', 'Var', (75, 82))	('5F 203', 'Chemical', 'MESH:C425784', (67, 73))	('AFt', 'Gene', '2495', (47, 50))
37743	32443455	We concluded that (i) the increased polarity of GW 608 (compared to GW 610) hinders encapsulation within the negatively charged cavity; and (ii) charge also impacts encapsulation, and (as in the case for Phortress) conjugation with positively-charged lysine (GW 608-Lys) resulted in enhanced encapsulation compared to GW 610, GW 608 and the serine (polar), glycine (non-polar) and aspartic acid (-ve) ester conjugates.	('GW 608', 'Chemical', '-', (259, 265))	('encapsulation', 'CPA', (165, 178))	('aspartic acid', 'Chemical', 'MESH:D001224', (381, 394))	('encapsulation', 'CPA', (292, 305))	('GW 610', 'Chemical', 'MESH:C507816', (68, 74))	('polarity', 'MPA', (36, 44))	('lysine', 'Chemical', 'MESH:D008239', (251, 257))	('conjugation', 'biological_process', 'GO:0000746', ('215', '226'))	('GW 610', 'Chemical', 'MESH:C507816', (318, 324))	('conjugation', 'Var', (215, 226))	('glycine', 'Chemical', 'MESH:D005998', (357, 364))	('hinders', 'NegReg', (76, 83))	('serine', 'Chemical', 'MESH:D012694', (341, 347))	('increased', 'PosReg', (26, 35))	('GW 608', 'Chemical', '-', (48, 54))	('enhanced', 'PosReg', (283, 291))	('GW 608-Lys', 'Var', (259, 269))	('Phortress', 'Chemical', 'MESH:C492651', (204, 213))	('impacts', 'Reg', (157, 164))	('Lys', 'Chemical', 'MESH:D008239', (266, 269))	('GW 608', 'Chemical', '-', (326, 332))	('encapsulation within the', 'CPA', (84, 108))	('ester', 'Chemical', 'MESH:D004952', (401, 406))
37749	32443455	However, AFt encapsulation of benzothiazole molecules enhanced their potency against TK10 carcinoma cells: AFt-5F 203 and AFt-GW 610 were ~4-fold more potent; lysyl-derivatives Phortress and GW 608-Lys demonstrated a ~60-fold enhanced activity following AFt encapsulation.	('AFt', 'Gene', (9, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinoma', 'Disease', (90, 99))	('AFt', 'Gene', (254, 257))	('5F 203', 'Chemical', 'MESH:C425784', (111, 117))	('Phortress', 'Chemical', 'MESH:C492651', (177, 186))	('potency', 'MPA', (69, 76))	('AFt', 'Gene', '2495', (107, 110))	('carcinoma', 'Disease', 'MESH:D009369', (90, 99))	('GW 608-Lys', 'Var', (191, 201))	('AFt', 'Gene', '2495', (122, 125))	('Lys', 'Chemical', 'MESH:D008239', (198, 201))	('activity', 'MPA', (235, 243))	('GW 610', 'Chemical', 'MESH:C507816', (126, 132))	('AFt', 'Gene', '2495', (9, 12))	('AFt', 'Gene', (107, 110))	('enhanced', 'PosReg', (226, 234))	('GW 608', 'Chemical', '-', (191, 197))	('benzothiazole', 'Chemical', 'MESH:C005465', (30, 43))	('AFt', 'Gene', (122, 125))	('AFt', 'Gene', '2495', (254, 257))
37753	32443455	Importantly, we can conclude that tumor selectivity displayed by 5F 203, GW 610 and their amino acid prodrugs is maintained following AFt encapsulation.	('5F 203', 'Chemical', 'MESH:C425784', (65, 71))	('tumor', 'Disease', (34, 39))	('GW 610', 'Chemical', 'MESH:C507816', (73, 79))	('AFt', 'Gene', '2495', (134, 137))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('5F 203', 'Var', (65, 71))	('AFt', 'Gene', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
37754	32443455	Neither GW 610 nor AFt-GW 610 inhibited growth of benzothiazole-insensitive MRC-5 fibroblasts.	('benzothiazole', 'Chemical', 'MESH:C005465', (50, 63))	('MRC-5', 'CellLine', 'CVCL:0440', (76, 81))	('GW 610', 'Chemical', 'MESH:C507816', (8, 14))	('inhibited', 'NegReg', (30, 39))	('AFt', 'Gene', '2495', (19, 22))	('AFt', 'Gene', (19, 22))	('GW 610', 'Chemical', 'MESH:C507816', (23, 29))	('growth', 'CPA', (40, 46))	('GW 610', 'Var', (8, 14))
37761	32443455	After 6 h and 9 h exposure, intracellular levels of GW 608-Lys were significantly greater (p < 0.01) following treatment of cells with AFt-GW 608-Lys (compared to naked agent).	('intracellular levels', 'MPA', (28, 48))	('Lys', 'Chemical', 'MESH:D008239', (59, 62))	('AFt', 'Gene', '2495', (135, 138))	('GW 608', 'Chemical', '-', (139, 145))	('AFt', 'Gene', (135, 138))	('Lys', 'Chemical', 'MESH:D008239', (146, 149))	('Aft', 'Gene', '2495', (0, 3))	('Aft', 'Gene', (0, 3))	('intracellular', 'cellular_component', 'GO:0005622', ('28', '41'))	('GW 608-Lys', 'Var', (52, 62))	('GW 608', 'Chemical', '-', (52, 58))	('men', 'Species', '9606', (116, 119))	('greater', 'PosReg', (82, 89))
37767	32443455	Previous studies in our research groups have shown that 5F 203 and AF caused growth inhibition in renal cells, which was accompanied by CYP1A1 induction and apoptosis in sensitive cells.	('5F 203', 'Chemical', 'MESH:C425784', (56, 62))	('induction', 'PosReg', (143, 152))	('growth inhibition', 'CPA', (77, 94))	('CYP1A1', 'Gene', (136, 142))	('apoptosis', 'biological_process', 'GO:0097194', ('157', '166'))	('5F 203', 'Var', (56, 62))	('apoptosis', 'biological_process', 'GO:0006915', ('157', '166'))	('CYP1A1', 'Gene', '1543', (136, 142))
37773	32443455	In contrast to AFP 464, 5F 203 significantly decreased cell migration in the three sensitive cell lines.	('cell migration', 'biological_process', 'GO:0016477', ('55', '69'))	('decreased', 'NegReg', (45, 54))	('5F 203', 'Var', (24, 30))	('cell migration in the three sensitive cell lines', 'CPA', (55, 103))	('5F 203', 'Chemical', 'MESH:C425784', (24, 30))
37774	32443455	Consistent with loss of migratory potential, a significant decrease in c-Met phosphorylation was observed at 1 h in TK-10 cells treated with 1 microM 5F 203.	('5F 203', 'Var', (150, 156))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('5F 203', 'Chemical', 'MESH:C425784', (150, 156))	('c-Met', 'Gene', (71, 76))	('decrease', 'NegReg', (59, 67))	('c-Met', 'Gene', '4233', (71, 76))
37775	32443455	Inhibition of c-Met activity by 5F 203 is consistent with previous observations: 5F 203 (1 microM; 24 h) decreased c-Met phosphorylation by 85% and 69 % in MCF-7 and MDA-MB-435 breast carcinoma cells, respectively.	('phosphorylation', 'biological_process', 'GO:0016310', ('121', '136'))	('5F 203', 'Var', (81, 87))	('c-Met', 'Gene', (14, 19))	('breast carcinoma', 'Disease', 'MESH:D001943', (177, 193))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (166, 176))	('c-Met', 'Gene', '4233', (14, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('c-Met', 'Gene', (115, 120))	('c-Met', 'Gene', '4233', (115, 120))	('5F 203', 'Chemical', 'MESH:C425784', (32, 38))	('breast carcinoma', 'Phenotype', 'HP:0003002', (177, 193))	('5F 203', 'Chemical', 'MESH:C425784', (81, 87))	('MCF-7', 'CellLine', 'CVCL:0031', (156, 161))	('decreased', 'NegReg', (105, 114))	('breast carcinoma', 'Disease', (177, 193))
37776	32443455	We speculate that 5F 203, a potent AhR ligand, triggers activation of a signaling cascade that potentially inhibits HIF signal transduction and hence the subsequent c-Met activation.	('c-Met', 'Gene', (165, 170))	('c-Met', 'Gene', '4233', (165, 170))	('5F 203', 'Chemical', 'MESH:C425784', (18, 24))	('signaling cascade', 'Pathway', (72, 89))	('activation', 'PosReg', (171, 181))	('inhibits', 'NegReg', (107, 115))	('HIF signal transduction', 'MPA', (116, 139))	('ligand', 'molecular_function', 'GO:0005488', ('39', '45'))	('5F 203', 'Var', (18, 24))	('signaling cascade', 'biological_process', 'GO:0007165', ('72', '89'))	('signal transduction', 'biological_process', 'GO:0007165', ('120', '139'))
37791	32443455	Differential expression of proteins that regulate AhR activation, such as HSP90, may also induce resistance to AF.	('expression', 'MPA', (13, 23))	('resistance to AF', 'MPA', (97, 113))	('Differential', 'Var', (0, 12))	('induce', 'Reg', (90, 96))	('proteins', 'Protein', (27, 35))	('HSP90', 'Gene', (74, 79))	('HSP90', 'Gene', '3320', (74, 79))
37809	32443455	We further examined the capacity of AF and AFP464 to exhibit anticancer activity and modulate the expression of the "stemness" genes, including alpha6-integrin.	('alpha6-integrin', 'Protein', (144, 159))	('AFP464', 'Chemical', '-', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('modulate', 'Reg', (85, 93))	('cancer', 'Disease', (65, 71))	('AFP464', 'Var', (43, 49))	('expression', 'MPA', (98, 108))
37812	32443455	AF andAFP464 reduced the expression and percentage of cells that stained for "stemness" markers, including alpha6-integrin in vitro and in vivo, respectively.	('expression', 'MPA', (25, 35))	('andAFP464', 'Var', (3, 12))	('alpha6-integrin', 'Protein', (107, 122))	('reduced', 'NegReg', (13, 20))	('AFP464', 'Chemical', '-', (6, 12))
37813	32443455	These data suggested AFP464 thwarts bulk breast tumor and TIC growth via AhR agonist-mediated alpha6-integrin inhibition.	('inhibition', 'NegReg', (110, 120))	('breast tumor', 'Disease', (41, 53))	('TIC', 'Phenotype', 'HP:0100033', (58, 61))	('thwarts', 'NegReg', (28, 35))	('TIC', 'Disease', 'None', (58, 61))	('AFP464', 'Var', (21, 27))	('breast tumor', 'Phenotype', 'HP:0100013', (41, 53))	('alpha6-integrin', 'Protein', (94, 109))	('TIC', 'Disease', (58, 61))	('AFP464', 'Chemical', '-', (21, 27))	('bulk', 'CPA', (36, 40))	('breast tumor', 'Disease', 'MESH:D001943', (41, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
37816	32443455	Considering that AhR has recently emerged as a physiological regulator of the innate and adaptive immune responses, in a previous publication we described that AFP 464 modulates the immune response in the estrogen-dependent, Tamoxifen-sensitive spontaneous M05 mammary carcinoma model.	('Tamoxifen', 'Chemical', 'MESH:D013629', (225, 234))	('modulates', 'Reg', (168, 177))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (261, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('immune response', 'CPA', (182, 197))	('carcinoma', 'Disease', (269, 278))	('AFP', 'Var', (160, 163))	('immune response', 'biological_process', 'GO:0006955', ('182', '197'))	('carcinoma', 'Disease', 'MESH:D009369', (269, 278))
37819	32443455	We found that AFP 464 increased splenic cytotoxic activity, diminished the number of systemic and local Treg lymphocytes and MDSCs as well as and induced a M1 phenotype in peritoneal macrophages of M05 tumor-bearing mice.	('diminished', 'NegReg', (60, 70))	('tumor', 'Disease', (202, 207))	('mice', 'Species', '10090', (216, 220))	('splenic cytotoxic activity', 'CPA', (32, 58))	('M1 phenotype', 'CPA', (156, 168))	('AFP 464', 'Var', (14, 21))	('increased', 'PosReg', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('induced', 'Reg', (146, 153))
37820	32443455	Therefore, we conclude that AFP 464 modulates immune responses, which collaborates with its anti-tumor activity.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('AFP', 'Var', (28, 31))	('tumor', 'Disease', (97, 102))	('immune responses', 'CPA', (46, 62))	('modulates', 'Reg', (36, 45))
37828	32443455	AFt encapsulation of 5F 203, GW 610 or their lysine-derivatives provides a robust formulation that enhances aqueous solubility (and bioavailability), increases intracellular uptake and significantly augments in vitro antitumor potency, whilst maintaining excellent tumor selectivity.	('men', 'Species', '9606', (202, 205))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('5F 203', 'Var', (21, 27))	('enhances', 'PosReg', (99, 107))	('intracellular uptake', 'MPA', (160, 180))	('AFt', 'Gene', (0, 3))	('lysine', 'Chemical', 'MESH:D008239', (45, 51))	('augments', 'NegReg', (199, 207))	('tumor', 'Disease', (265, 270))	('bioavailability', 'MPA', (132, 147))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('tumor', 'Disease', (221, 226))	('intracellular', 'cellular_component', 'GO:0005622', ('160', '173'))	('uptake', 'biological_process', 'GO:0098657', ('174', '180'))	('increases', 'PosReg', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('5F 203', 'Chemical', 'MESH:C425784', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('GW 610', 'Chemical', 'MESH:C507816', (29, 35))	('AFt', 'Gene', '2495', (0, 3))	('uptake', 'biological_process', 'GO:0098739', ('174', '180'))
37831	32443455	5F203 induced enhanced CYP1A1 expression; AhR translocation and reactive species formation (ROS) in IGROV-1 cells and ascites-isolated ovarian cancer cells that were sensitive to 5F203.	('reactive species formation', 'MPA', (64, 90))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('formation', 'biological_process', 'GO:0009058', ('81', '90'))	('AhR translocation', 'MPA', (42, 59))	('ascites-isolated ovarian cancer', 'Disease', 'MESH:D001201', (118, 149))	('5F203', 'Var', (0, 5))	('enhanced', 'PosReg', (14, 22))	('CYP1A1', 'Gene', (23, 29))	('ovarian cancer', 'Phenotype', 'HP:0100615', (135, 149))	('IGROV-1', 'CellLine', 'CVCL:1304', (100, 107))	('ROS', 'Chemical', '-', (92, 95))	('CYP1A1', 'Gene', '1543', (23, 29))	('ascites', 'Phenotype', 'HP:0001541', (118, 125))	('ascites-isolated ovarian cancer', 'Disease', (118, 149))
37832	32443455	In IGROV-1 cells, 5F203-induced ROS formation was accompanied by JNK, ERK and P38MAPK phosphorylation, as well as DNA damage and cell cycle arrest prior to apoptosis.	('JNK', 'Gene', '5599', (65, 68))	('ERK', 'Gene', (70, 73))	('ROS', 'MPA', (32, 35))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (129, 146))	('5F203-induced', 'Var', (18, 31))	('arrest', 'Disease', (140, 146))	('phosphorylation', 'biological_process', 'GO:0016310', ('86', '101'))	('DNA damage', 'MPA', (114, 124))	('ROS formation', 'biological_process', 'GO:1903409', ('32', '45'))	('IGROV-1', 'CellLine', 'CVCL:1304', (3, 10))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('129', '146'))	('phosphorylation', 'MPA', (86, 101))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('JNK', 'molecular_function', 'GO:0004705', ('65', '68'))	('P38MAPK', 'Var', (78, 85))	('arrest', 'Disease', 'MESH:D006323', (140, 146))	('ERK', 'molecular_function', 'GO:0004707', ('70', '73'))	('ERK', 'Gene', '5594', (70, 73))	('MAPK', 'molecular_function', 'GO:0004707', ('81', '85'))	('ROS', 'Chemical', '-', (32, 35))	('apoptosis', 'biological_process', 'GO:0097194', ('156', '165'))	('apoptosis', 'biological_process', 'GO:0006915', ('156', '165'))	('JNK', 'Gene', (65, 68))
37833	32443455	In contrast, 5F203 failed to induce CYP1A1 expression, AhR translocation or oxidative stress in 5F203-resistant SKOV-3 cells, or in ovarian cancer ascites cells inherently resistant to this agent.	('ovarian cancer ascites', 'Disease', 'MESH:D001201', (132, 154))	('ascites', 'Phenotype', 'HP:0001541', (147, 154))	('CYP1A1', 'Gene', (36, 42))	('AhR translocation', 'MPA', (55, 72))	('ovarian cancer ascites', 'Disease', (132, 154))	('ovarian cancer', 'Phenotype', 'HP:0100615', (132, 146))	('oxidative stress', 'Phenotype', 'HP:0025464', (76, 92))	('SKOV-3', 'CellLine', 'CVCL:0532', (112, 118))	('CYP1A1', 'Gene', '1543', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('5F203-resistant', 'Var', (96, 111))
37835	32443455	In future studies it could be of interest to measure ROS formation and JNK, ERK and P38MAPK phosphorylation in renal cancer cells treated ex vivo with 5F 203 as a putative additional biomarker of renal tumors suitable to be treated with this antitumor agent.	('MAPK', 'molecular_function', 'GO:0004707', ('87', '91'))	('JNK', 'Gene', (71, 74))	('renal tumors', 'Disease', 'MESH:D007674', (196, 208))	('ROS formation', 'biological_process', 'GO:1903409', ('53', '66'))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('JNK', 'Gene', '5599', (71, 74))	('renal cancer', 'Disease', 'MESH:D007680', (111, 123))	('renal tumors', 'Phenotype', 'HP:0009726', (196, 208))	('tumor', 'Disease', (202, 207))	('ERK', 'Gene', (76, 79))	('phosphorylation', 'biological_process', 'GO:0016310', ('92', '107'))	('JNK', 'molecular_function', 'GO:0004705', ('71', '74'))	('ROS', 'Chemical', '-', (53, 56))	('ROS formation', 'MPA', (53, 66))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('5F 203', 'Chemical', 'MESH:C425784', (151, 157))	('renal tumor', 'Phenotype', 'HP:0009726', (196, 207))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('ERK', 'molecular_function', 'GO:0004707', ('76', '79'))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('P38MAPK', 'Var', (84, 91))	('renal cancer', 'Disease', (111, 123))	('renal cancer', 'Phenotype', 'HP:0009726', (111, 123))	('renal tumors', 'Disease', (196, 208))	('ERK', 'Gene', '5594', (76, 79))
37850	28850564	Most of the cases harbour a mutation, deletion or methylation of the von Hippel Lindau gene, leading to overexpression of VEGF.	('VEGF', 'Gene', '7422', (122, 126))	('methylation', 'biological_process', 'GO:0032259', ('50', '61'))	('mutation', 'Var', (28, 36))	('von Hippel Lindau', 'Disease', (69, 86))	('VEGF', 'Gene', (122, 126))	('deletion', 'Var', (38, 46))	('von Hippel Lindau', 'Disease', 'MESH:D006623', (69, 86))	('overexpression', 'PosReg', (104, 118))	('methylation', 'Var', (50, 61))
37885	28850564	It is a combination of: (1) performance status (Karnofsky score)<80%, (2) time from diagnosis to systemic treatment<12 months, (3) haemoglobin less than the lower limit of normal, (4) lactate dehydrogenase>1.5 x upper limit of normal, (5) corrected calcium>10 mg dl-1 (2.5 mmol l-1).	('calcium', 'Chemical', 'MESH:D002118', (249, 256))	('corrected calcium', 'MPA', (239, 256))	('lactate', 'MPA', (184, 191))	('less', 'NegReg', (143, 147))	('haemoglobin', 'Var', (131, 142))
37950	28850564	However, tumour cells that also produce CXCL7 may participate in immune tolerance, inflammation and angiogenesis via attraction of neutrophils, differentiation of monocytes towards M2 macrophages and proliferation of endothelial cells (neutrophils, monocytes and endothelial cells physiologically expressed CXCL7 receptors).	('attraction', 'CPA', (117, 127))	('tumour', 'Disease', (9, 15))	('inflammation', 'Disease', (83, 95))	('participate', 'Reg', (50, 61))	('angiogenesis', 'biological_process', 'GO:0001525', ('100', '112'))	('proliferation', 'CPA', (200, 213))	('CXCL7', 'Var', (40, 45))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('angiogenesis', 'CPA', (100, 112))	('inflammation', 'biological_process', 'GO:0006954', ('83', '95'))	('tumour', 'Disease', 'MESH:D009369', (9, 15))	('differentiation', 'CPA', (144, 159))	('inflammation', 'Disease', 'MESH:D007249', (83, 95))	('immune tolerance', 'CPA', (65, 81))
37957	31202813	Dysregulation of the miR-25-IMPA2 axis promotes metastatic progression in clear cell renal cell carcinoma The molecular mechanism underlying clear cell renal cell carcinoma (ccRCC) metastasis remains unclear.	('promotes', 'PosReg', (39, 47))	('metastatic progression', 'CPA', (48, 70))	('Dysregulation', 'Var', (0, 13))	('miR-25', 'Gene', '407014', (21, 27))	('clear cell renal cell carcinoma', 'Disease', (74, 105))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (85, 105))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (141, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (74, 105))	('IMPA2', 'Gene', (28, 33))	('clear cell renal cell carcinoma', 'Disease', (141, 172))	('RCC', 'Disease', (176, 179))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (152, 172))	('miR-25', 'Gene', (21, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (74, 105))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (141, 172))	('IMPA2', 'Gene', '3613', (28, 33))
37965	31202813	We found that IMPA2 knockdown promotes, but overexpression suppresses, the cellular migration and lung colony-forming abilities of ccRCC cells.	('lung colony-forming abilities', 'CPA', (98, 127))	('promotes', 'PosReg', (30, 38))	('overexpression', 'PosReg', (44, 58))	('knockdown', 'Var', (20, 29))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('cellular migration', 'CPA', (75, 93))	('suppresses', 'NegReg', (59, 69))	('IMPA2', 'Gene', (14, 19))
37975	31202813	In addition, IMPA2 knockdown or overexpression negatively modulates the metastatic ability of ccRCC cells.	('RCC', 'Disease', (96, 99))	('overexpression', 'PosReg', (32, 46))	('knockdown', 'Var', (19, 28))	('modulates', 'Reg', (58, 67))	('IMPA2', 'Gene', (13, 18))	('negatively', 'NegReg', (47, 57))	('metastatic ability of', 'CPA', (72, 93))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
37976	31202813	Furthermore, we identified that a dysregulation of miR-25-3p determines the IMPA2-modulated metastatic progression in ccRCC.	('dysregulation', 'Var', (34, 47))	('miR-25', 'Gene', '407014', (51, 57))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('metastatic progression', 'CPA', (92, 114))	('miR-25', 'Gene', (51, 57))
37992	31202813	IP3 triggers the release of Ca2+ from intracellular stores and undergoes multistep dephosphorylation by multiple enzymes to enable the reuse of myo-inositol.	('myo-inositol', 'Chemical', 'MESH:D007294', (144, 156))	('Ca2', 'Gene', (28, 31))	('enable', 'PosReg', (124, 130))	('IP3', 'Var', (0, 3))	('dephosphorylation', 'biological_process', 'GO:0016311', ('83', '100'))	('reuse of myo-inositol', 'MPA', (135, 156))	('intracellular', 'cellular_component', 'GO:0005622', ('38', '51'))	('Ca2', 'Gene', '760', (28, 31))	('IP3', 'Chemical', 'MESH:D015544', (0, 3))
38001	31202813	For example, miR-338-3p has been found to target the sex-determining region Y-box 4 (SOX4) and inhibit cell proliferation and invasion in renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (138, 158))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (138, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('inhibit', 'NegReg', (95, 102))	('cell proliferation', 'CPA', (103, 121))	('invasion', 'CPA', (126, 134))	('SOX4', 'Gene', (85, 89))	('miR-338-3p', 'Var', (13, 23))	('cell proliferation', 'biological_process', 'GO:0008283', ('103', '121'))	('SOX4', 'Gene', '6659', (85, 89))	('renal cell carcinoma', 'Disease', (138, 158))
38038	31202813	The side-directed mutagenesis for the miR-25-3p DNA-binding site was performed by using pmiRGLO plasmid containing the full-length of IMPA2 3'-UTR as template in the standard PCR procedure with PfuUtra high-fidelity DNA polymerase (Agilent) and paired primers (forward_5'- CCCCCCGGAGTACTTCAGAATC -3'; reverse_5'- CCGCTCGAGTCTGAAGTACTCCGGGGGG-3').	('DNA-binding', 'molecular_function', 'GO:0003677', ('48', '59'))	('mutagenesis', 'biological_process', 'GO:0006280', ('18', '29'))	('DNA', 'cellular_component', 'GO:0005574', ('216', '219'))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('miR-25', 'Gene', '407014', (38, 44))	('miR-25', 'Gene', (38, 44))	("forward_5'- CCCCCCGGAGTACTTCAGAATC", 'Var', (261, 295))
38039	31202813	For determining luciferase activity, ACHN cells were seeded in 6-well plates and transfected with pmiRGLO or pmiRGLO containing the IMPA2 3' UTR variants.	('luciferase activity', 'molecular_function', 'GO:0047077', ('16', '35'))	('ACHN', 'Gene', '55323', (37, 41))	('luciferase activity', 'molecular_function', 'GO:0045289', ('16', '35'))	('variants', 'Var', (145, 153))	('luciferase activity', 'molecular_function', 'GO:0050248', ('16', '35'))	('ACHN', 'Gene', (37, 41))	('luciferase activity', 'molecular_function', 'GO:0047712', ('16', '35'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('16', '35'))	('activity', 'MPA', (27, 35))
38045	31202813	The data showed that the mRNA levels of IMPA2, but not IMPA1, were significantly (p < .05) downregulated in primary tumors compared to normal renal tissues (Fig.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('IMPA2', 'Var', (40, 45))	('downregulated', 'NegReg', (91, 104))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('IMPA1', 'Gene', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('IMPA1', 'Gene', '3612', (55, 60))	('mRNA levels', 'MPA', (25, 36))
38065	31202813	The lung colony-forming assay demonstrated that IMPA2 knockdown significantly (p = .00022) promoted the formation of tumor foci of A498 cells in the lungs of tumor-bearing mice (Fig.	('promoted', 'PosReg', (91, 99))	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('knockdown', 'Var', (54, 63))	('tumor', 'Disease', (117, 122))	('mice', 'Species', '10090', (172, 176))	('A498', 'CellLine', 'CVCL:1056', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('IMPA2', 'Gene', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('formation', 'biological_process', 'GO:0009058', ('104', '113'))
38067	31202813	Our data showed that IMPA2 knockdown promotes metastatic potentials of A498 cells by triggering EMT as judged by CDH1 downregulation but CDH2/Slug upregulation.	('downregulation', 'NegReg', (118, 132))	('metastatic potentials', 'CPA', (46, 67))	('EMT', 'CPA', (96, 99))	('knockdown', 'Var', (27, 36))	('CDH2', 'Gene', (137, 141))	('Slug', 'Gene', '6591', (142, 146))	('CDH2', 'Gene', '1000', (137, 141))	('Slug', 'Gene', (142, 146))	('CDH1', 'Gene', (113, 117))	('upregulation', 'PosReg', (147, 159))	('IMPA2', 'Gene', (21, 26))	('EMT', 'biological_process', 'GO:0001837', ('96', '99'))	('CDH1', 'Gene', '999', (113, 117))	('A498', 'CellLine', 'CVCL:1056', (71, 75))	('promotes', 'PosReg', (37, 45))
38069	31202813	5a) and then identified 2 miRNA candidates, miR-146 and miR-25-3p (Fig.	('miR-146', 'Var', (44, 51))	('miR-25', 'Gene', '407014', (56, 62))	('miR-25', 'Gene', (56, 62))
38088	31202813	Another recent study concluded that a potential association exists between single nucleotide polymorphisms in the IMPA2 gene and increased risk of ischemic stroke.	('ischemic stroke', 'Disease', 'MESH:D002544', (147, 162))	('ischemic stroke', 'Phenotype', 'HP:0002140', (147, 162))	('ischemic stroke', 'Disease', (147, 162))	('stroke', 'Phenotype', 'HP:0001297', (156, 162))	('single nucleotide polymorphisms', 'Var', (75, 106))	('IMPA2', 'Gene', (114, 119))
38098	31202813	Previous studies have demonstrated that IMPase increases free inositol and IP3.	('IP3', 'MPA', (75, 78))	('inositol', 'Chemical', 'MESH:D007294', (62, 70))	('IMPase', 'Var', (40, 46))	('IP3', 'Chemical', 'MESH:D015544', (75, 78))	('increases', 'PosReg', (47, 56))	('free inositol', 'MPA', (57, 70))
38100	31202813	indicated that knockdown of IP3R3 in colorectal carcinoma cells increased apoptosis, while overexpression of IP3R3 decreased apoptosis.	('apoptosis', 'CPA', (74, 83))	('knockdown', 'Var', (15, 24))	('IP3R3', 'Gene', '3710', (109, 114))	('colorectal carcinoma', 'Disease', (37, 57))	('IP3R3', 'Gene', (109, 114))	('apoptosis', 'biological_process', 'GO:0097194', ('125', '134'))	('IP3R3', 'Gene', '3710', (28, 33))	('apoptosis', 'biological_process', 'GO:0006915', ('125', '134'))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('IP3R3', 'Gene', (28, 33))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (37, 57))	('increased', 'PosReg', (64, 73))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
38101	31202813	Another recent study concluded that high levels of IP3R3 were associated with increased metastasis in the lymph nodes and liver and with decreased 5-year survival.	('5-year survival', 'CPA', (147, 162))	('metastasis in the lymph nodes', 'CPA', (88, 117))	('increased', 'PosReg', (78, 87))	('high levels', 'Var', (36, 47))	('IP3R3', 'Gene', '3710', (51, 56))	('IP3R3', 'Gene', (51, 56))	('decreased', 'NegReg', (137, 146))
38104	31202813	Silencing IMPA2 expression appeared to effectively increase the metastatic colonization of A498 cells in vitro and in the lungs of tumor-bearing mice (Fig.	('increase', 'PosReg', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('A498', 'CellLine', 'CVCL:1056', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('metastatic colonization', 'CPA', (64, 87))	('mice', 'Species', '10090', (145, 149))	('tumor', 'Disease', (131, 136))	('IMPA2', 'Gene', (10, 15))	('Silencing', 'Var', (0, 9))
38108	31202813	Moreover, inhibiting miR-25 suppressed the metastatic ability of ccRCC cells (Figs.	('metastatic ability of', 'CPA', (43, 64))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('inhibiting', 'Var', (10, 20))	('RCC', 'Disease', (67, 70))	('miR-25', 'Gene', '407014', (21, 27))	('suppressed', 'NegReg', (28, 38))	('miR-25', 'Gene', (21, 27))
38113	31202813	We found that patients with high miR-25 expression had significantly poorer OS than those with low miR-25 expression (Fig.	('miR-25', 'Gene', '407014', (99, 105))	('miR-25', 'Gene', (33, 39))	('miR-25', 'Gene', (99, 105))	('poorer', 'NegReg', (69, 75))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (14, 22))	('miR-25', 'Gene', '407014', (33, 39))
38114	31202813	Furthermore, both low miR-25 expression and high IMPA2 expression were good prognostic markers in ccRCC (Fig.	('miR-25', 'Gene', '407014', (22, 28))	('high', 'Var', (44, 48))	('miR-25', 'Gene', (22, 28))	('expression', 'MPA', (55, 65))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('expression', 'MPA', (29, 39))	('RCC', 'Disease', (100, 103))	('IMPA2', 'Gene', (49, 54))	('low', 'NegReg', (18, 21))
38116	31202813	In addition, the dysregulation of miR-25 may result in IMPA2 downregulation and thereby promote metastatic progression in ccRCC.	('RCC', 'Disease', (124, 127))	('downregulation', 'NegReg', (61, 75))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('metastatic progression', 'CPA', (96, 118))	('promote', 'PosReg', (88, 95))	('miR-25', 'Gene', '407014', (34, 40))	('dysregulation', 'Var', (17, 30))	('miR-25', 'Gene', (34, 40))	('IMPA2', 'Gene', (55, 60))
38189	32150988	These results are consistent with recently documented results showing 60% (6/10) positivity in TFE3 and 100% (7/7) in TFEB.	('TFE3', 'Gene', '7030', (95, 99))	('positivity', 'Var', (81, 91))	('TFE3', 'Gene', (95, 99))
38236	32150988	Therefore, both CK7 and CAIX positivity is unique in renal neoplasm of the low-malignant-potential group including multilocular cystic renal neoplasms and in CCPRCC.	('cystic renal neoplasm', 'Phenotype', 'HP:0000800', (128, 149))	('renal neoplasm', 'Phenotype', 'HP:0009726', (53, 67))	('neoplasm', 'Phenotype', 'HP:0002664', (141, 149))	('CAIX', 'Gene', (24, 28))	('positivity', 'Var', (29, 39))	('CAIX', 'Gene', '768', (24, 28))	('CCPRCC', 'Disease', (158, 164))	('neoplasm', 'Phenotype', 'HP:0002664', (59, 67))	('CK7', 'Gene', (16, 19))	('cystic renal neoplasms', 'Disease', (128, 150))	('cystic renal neoplasms', 'Disease', 'MESH:D052177', (128, 150))	('cystic renal neoplasms', 'Phenotype', 'HP:0000800', (128, 150))	('renal neoplasm', 'Disease', (53, 67))	('renal neoplasms', 'Phenotype', 'HP:0009726', (135, 150))	('CK7', 'Gene', '3855', (16, 19))	('CCPRCC', 'Chemical', '-', (158, 164))	('renal neoplasm', 'Disease', 'MESH:D007674', (135, 149))	('renal neoplasm', 'Phenotype', 'HP:0009726', (135, 149))	('renal neoplasm', 'Disease', 'MESH:D007674', (53, 67))	('neoplasms', 'Phenotype', 'HP:0002664', (141, 150))
38239	32150988	MiT RCC is a genetic fusion gene-associated malignant tumor caused by uncontrolled overexpression of MiT factors, followed by translocation with several partner genes, such as PRCC-TFE3 [t (X:1) (p11.2; q21.2)], ASPSCR1-TFE3, SFPQ-TFE3, and NONO-TFE3 fusion genes, and so on.	('translocation', 'Var', (126, 139))	('MiT RCC', 'Disease', (0, 7))	('p11', 'Gene', (196, 199))	('overexpression', 'PosReg', (83, 97))	('caused by', 'Reg', (60, 69))	('ASPSCR1', 'Gene', '79058', (212, 219))	('NONO', 'Gene', (241, 245))	('TFE3', 'Gene', (231, 235))	('PRCC-TFE3', 'Gene', '5546;7030', (176, 185))	('TFE3', 'Gene', '7030', (231, 235))	('PRCC-TFE3', 'Gene', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('malignant tumor', 'Disease', (44, 59))	('MiT RCC', 'Disease', 'MESH:C538614', (0, 7))	('TFE3', 'Gene', (246, 250))	('ASPSCR1', 'Gene', (212, 219))	('SFPQ', 'Gene', '6421', (226, 230))	('TFE3', 'Gene', (181, 185))	('TFE3', 'Gene', (220, 224))	('TFE3', 'Gene', '7030', (246, 250))	('SFPQ', 'Gene', (226, 230))	('malignant tumor', 'Disease', 'MESH:D009369', (44, 59))	('TFE3', 'Gene', '7030', (181, 185))	('NONO', 'Gene', '4841', (241, 245))	('TFE3', 'Gene', '7030', (220, 224))	('p11', 'Gene', '6281', (196, 199))
38251	32150988	When purely melanocytic differentiation occurs with MiT genetic translocation, melanotic MiT tumors may be same as PEComa.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('MiT genetic translocation', 'Var', (52, 77))	('PEComa', 'Disease', 'MESH:D054973', (115, 121))	('melanotic MiT tumors', 'Disease', 'MESH:D017600', (79, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('melanotic MiT tumors', 'Disease', (79, 99))	('PEComa', 'Disease', (115, 121))
38264	32150988	Although aberrant cytoplasmic beta-catenin is associated with unfavorable RCC, unlike one prior study, beta-catenin proved to be the least supportive marker for subtyping of renal cell tumors in the present study.	('beta-catenin', 'Gene', '1499', (30, 42))	('renal cell tumors', 'Disease', (174, 191))	('beta-catenin', 'Gene', (103, 115))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('RCC', 'Disease', (74, 77))	('beta-catenin', 'Gene', '1499', (103, 115))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('renal cell tumors', 'Disease', 'MESH:C538614', (174, 191))	('aberrant', 'Var', (9, 17))	('associated', 'Reg', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('beta-catenin', 'Gene', (30, 42))
38348	30256787	Three samples had mutations in TSC1; one in PTEN; and none in MTOR.	('MTOR', 'Gene', '2475', (62, 66))	('PTEN', 'Gene', (44, 48))	('PTEN', 'Gene', '5728', (44, 48))	('TSC1', 'Gene', '7248', (31, 35))	('MTOR', 'Gene', (62, 66))	('TSC1', 'Gene', (31, 35))	('mutations', 'Var', (18, 27))
38351	30256787	We conclude that mTOR pathway gene mutations did not contribute to rapalog resistance development in these six patients with advanced RCC.	('rapalog resistance', 'MPA', (67, 85))	('patients', 'Species', '9606', (111, 119))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('RCC', 'Disease', (134, 137))	('mTOR', 'Gene', (17, 21))	('mTOR', 'Gene', '2475', (17, 21))	('mutations', 'Var', (35, 44))
38355	30256787	We found that mutations in PBRM1 appeared to be enriched in post-treatment samples.	('PBRM1', 'Gene', (27, 32))	('PBRM1', 'Gene', '55193', (27, 32))	('mutations', 'Var', (14, 23))
38356	30256787	However, modulation of PBRM1 levels in vitro in cell lines had no apparent effect on rapalog sensitivity.	('PBRM1', 'Gene', (23, 28))	('modulation', 'Var', (9, 19))	('rapalog sensitivity', 'MPA', (85, 104))	('PBRM1', 'Gene', '55193', (23, 28))
38363	30256787	When both alleles of either TSC1 or TSC2 are mutated or lost, as is the rule in tumors occurring in individuals with the genetic disorder tuberous sclerosis complex, RHEB-GTP levels are high, leading to activation of mTORC1.	('GTP', 'Chemical', 'MESH:D006160', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('genetic disorder tuberous sclerosis', 'Disease', 'MESH:D030342', (121, 156))	('mTORC1', 'Gene', (217, 223))	('TSC2', 'Gene', '7249', (36, 40))	('tumors', 'Disease', (80, 86))	('lost', 'NegReg', (56, 60))	('RHEB', 'Gene', '6009', (166, 170))	('TSC1', 'Gene', (28, 32))	('mutated', 'Var', (45, 52))	('mTORC1', 'Gene', '382056', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('TSC2', 'Gene', (36, 40))	('TSC1', 'Gene', '7248', (28, 32))	('mTORC1', 'cellular_component', 'GO:0031931', ('217', '223'))	('genetic disorder tuberous sclerosis', 'Disease', (121, 156))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tuberous sclerosis complex', 'cellular_component', 'GO:0033596', ('138', '164'))	('RHEB', 'Gene', (166, 170))	('activation', 'PosReg', (203, 213))
38365	30256787	Activation of mTORC1 leads to protein synthesis, lipid synthesis, nucleotide synthesis, autophagy inhibition, leading to cell enlargement and preparation for cell division.	('mTORC1', 'Gene', (14, 20))	('cell enlargement', 'CPA', (121, 137))	('cell division', 'biological_process', 'GO:0051301', ('158', '171'))	('autophagy', 'biological_process', 'GO:0016236', ('88', '97'))	('protein synthesis', 'biological_process', 'GO:0006412', ('30', '47'))	('nucleotide synthesis', 'CPA', (66, 86))	('lipid synthesis', 'CPA', (49, 64))	('autophagy', 'biological_process', 'GO:0006914', ('88', '97'))	('autophagy', 'CPA', (88, 97))	('protein synthesis', 'CPA', (30, 47))	('lipid', 'Chemical', 'MESH:D008055', (49, 54))	('mTORC1', 'Gene', '382056', (14, 20))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('Activation', 'Var', (0, 10))	('lipid synthesis', 'biological_process', 'GO:0008610', ('49', '64'))	('nucleotide synthesis', 'biological_process', 'GO:0009165', ('66', '86'))	('mTORC1', 'cellular_component', 'GO:0031931', ('14', '20'))	('preparation for cell division', 'CPA', (142, 171))
38366	30256787	Somatic mutations in MTOR which deregulate and activate its kinase are known to occur in several cancer types, predominantly RCC in which mutation is seen in about 5%.	('MTOR', 'Gene', '2475', (21, 25))	('activate', 'PosReg', (47, 55))	('cancer', 'Disease', (97, 103))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('kinase', 'MPA', (60, 66))	('mutations', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('MTOR', 'Gene', (21, 25))	('deregulate', 'Reg', (32, 42))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
38367	30256787	Activating RHEB mutations which activate mTORC1 are quite rare but also known to occur in cancer.	('mTORC1', 'cellular_component', 'GO:0031931', ('41', '47'))	('mTORC1', 'Gene', '382056', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('RHEB', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('activate', 'PosReg', (32, 40))	('RHEB', 'Gene', '6009', (11, 15))	('mTORC1', 'Gene', (41, 47))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
38369	30256787	Previously we have reported that response to rapalog therapy in RCC is associated with mutation in the mTOR pathway genes: TSC1, TSC2, and MTOR.	('mTOR', 'Gene', (103, 107))	('MTOR', 'Gene', (139, 143))	('TSC1', 'Gene', '7248', (123, 127))	('RCC', 'Disease', (64, 67))	('TSC1', 'Gene', (123, 127))	('MTOR', 'Gene', '2475', (139, 143))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('TSC2', 'Gene', '7249', (129, 133))	('TSC2', 'Gene', (129, 133))	('mutation', 'Var', (87, 95))	('associated', 'Reg', (71, 81))	('mTOR', 'Gene', '2475', (103, 107))
38370	30256787	Another recent study reported that mutations in PBRM1 were associated with response to rapalog therapy in the RECORD-3 trial.	('response', 'MPA', (75, 83))	('PBRM1', 'Gene', (48, 53))	('associated with', 'Reg', (59, 74))	('PBRM1', 'Gene', '55193', (48, 53))	('mutations', 'Var', (35, 44))
38373	30256787	Five of these 6 patients had been studied in our earlier analysis of the association between mTOR pathway mutations and response to rapalogs in RCC.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('mTOR', 'Gene', (93, 97))	('mTOR', 'Gene', '2475', (93, 97))	('patients', 'Species', '9606', (16, 24))	('association', 'Interaction', (73, 84))	('mutations', 'Var', (106, 115))	('RCC', 'Disease', (144, 147))
38381	30256787	Three patients' tumors showed mutations in TSC1, while one had a mutation in PTEN, and some of these patients had been included in our previous study showing that there is enrichment for mutations in mTOR pathway genes in RCC patients who respond to rapalog therapy.	('patients', 'Species', '9606', (101, 109))	('TSC1', 'Gene', '7248', (43, 47))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('mTOR', 'Gene', (200, 204))	('mTOR', 'Gene', '2475', (200, 204))	('TSC1', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mutations', 'Var', (187, 196))	('PTEN', 'Gene', (77, 81))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('RCC', 'Disease', 'MESH:C538614', (222, 225))	('mutations', 'Var', (30, 39))	('RCC', 'Disease', (222, 225))	('patients', 'Species', '9606', (226, 234))	('PTEN', 'Gene', '5728', (77, 81))	('patients', 'Species', '9606', (6, 14))	('tumors', 'Disease', (16, 22))
38383	30256787	VHL mutations were seen in all 5 ccRCCs, as expected.	('RCC', 'Disease', (35, 38))	('VHL', 'Disease', 'MESH:D006623', (0, 3))	('VHL', 'Disease', (0, 3))	('seen', 'Reg', (19, 23))	('mutations', 'Var', (4, 13))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
38384	30256787	PBRM1 mutations were also seen in all 5 ccRCC samples.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('RCC', 'Disease', (42, 45))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('seen', 'Reg', (26, 30))	('mutations', 'Var', (6, 15))
38385	30256787	Three samples had inactivating mutations in TSC1, as noted; three including the chromophobe RCC had TP53 mutations; while two had BAP1 mutations.	('TP53', 'Gene', '7157', (100, 104))	('TSC1', 'Gene', '7248', (44, 48))	('BAP1', 'Gene', (130, 134))	('chromophobe RCC', 'Disease', 'MESH:C538614', (80, 95))	('inactivating mutations', 'Var', (18, 40))	('TP53', 'Gene', (100, 104))	('TSC1', 'Gene', (44, 48))	('mutations', 'Var', (105, 114))	('chromophobe RCC', 'Disease', (80, 95))	('BAP1', 'Gene', '8314', (130, 134))
38386	30256787	Several genes with recurrent mutations were likely chance events, enhanced by their large size: DNAH11 (4516aa), TTN (34350aa), PIEZO1 (2521aa), TRPM6 (2022aa); none are thought to be involved in the pathogenesis of any form of cancer.	('TTN', 'Gene', (113, 116))	('cancer', 'Disease', (228, 234))	('2022aa);', 'Var', (152, 160))	('TTN', 'Gene', '7273', (113, 116))	('4516aa', 'Var', (104, 110))	('pathogenesis', 'biological_process', 'GO:0009405', ('200', '212'))	('DNAH11', 'Gene', '8701', (96, 102))	('mutations', 'Var', (29, 38))	('2521aa', 'Var', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('PIEZO1', 'Gene', (128, 134))	('TRPM6', 'Gene', (145, 150))	('DNAH11', 'Gene', (96, 102))	('PIEZO1', 'Gene', '9780', (128, 134))	('34350aa', 'Var', (118, 125))	('TRPM6', 'Gene', '140803', (145, 150))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
38387	30256787	Recurrent mutations in PTPRN2 may have also been due to random chance, and one of those was also silent.	('mutations', 'Var', (10, 19))	('PTPRN2', 'Gene', '5799', (23, 29))	('PTPRN2', 'Gene', (23, 29))
38389	30256787	VHL mutations were clonal or high subclonal in all 5 ccRCC samples, as expected, and showed no significant change in clonal representation in the paired samples.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('VHL', 'Disease', 'MESH:D006623', (0, 3))	('VHL', 'Disease', (0, 3))	('mutations', 'Var', (4, 13))
38391	30256787	However, in another sample (MT_006), an inactivating TSC1 mutation went from zero cancer cell fraction in the pre-treatment sample to clonal in the post-treatment sample, in direct contrast to this model.	('TSC1', 'Gene', '7248', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('inactivating', 'Reg', (40, 52))	('cell fraction', 'cellular_component', 'GO:0000267', ('89', '102'))	('cancer', 'Disease', (82, 88))	('TSC1', 'Gene', (53, 57))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('mutation', 'Var', (58, 66))	('pre', 'molecular_function', 'GO:0003904', ('110', '113'))
38392	30256787	Mutations in each of TP53 and PTPRN2 also were enriched in one patient's post-treatment sample but lost in another patient's post-treatment sample.	('TP53', 'Gene', (21, 25))	('PTPRN2', 'Gene', '5799', (30, 36))	('Mutations', 'Var', (0, 9))	('patient', 'Species', '9606', (63, 70))	('PTPRN2', 'Gene', (30, 36))	('patient', 'Species', '9606', (115, 122))	('TP53', 'Gene', '7157', (21, 25))
38395	30256787	PBRM1 mutations were clonal in both pre-treatment and post-treatment samples from two patients, but went from zero to clonal in 3 patients samples' following treatment.	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('pre', 'molecular_function', 'GO:0003904', ('36', '39'))	('patients', 'Species', '9606', (130, 138))	('mutations', 'Var', (6, 15))	('patients', 'Species', '9606', (86, 94))
38397	30256787	PBRM1 mutations are seen in about 30% of ccRCC samples, and it is possible that the appearance of PBRM1 mutations in the post-treatment samples was due solely to tumor heterogeneity and/or sampling issues.	('PBRM1', 'Gene', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mutations', 'Var', (104, 113))	('PBRM1', 'Gene', '55193', (98, 103))	('tumor', 'Disease', (162, 167))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('mutations', 'Var', (6, 15))
38398	30256787	However, as noted above, VHL mutations were present at or near clonal frequency in all 5 ccRCC samples both pre- and post-treatment.	('VHL', 'Disease', 'MESH:D006623', (25, 28))	('mutations', 'Var', (29, 38))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('VHL', 'Disease', (25, 28))	('RCC', 'Disease', (91, 94))	('pre', 'molecular_function', 'GO:0003904', ('108', '111'))
38399	30256787	Hence, the finding that PBRM1 mutations were present in all 5 ccRCC samples at the time of resistance, including acquisition of mutations in 3 ccRCC samples led us to explore the hypothesis that PBRM1 loss is a mechanism of resistance to rapalog therapy in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('loss', 'NegReg', (201, 205))	('PBRM1', 'Gene', (195, 200))	('PBRM1', 'Gene', '55193', (195, 200))	('RCC', 'Disease', 'MESH:C538614', (259, 262))	('RCC', 'Disease', (259, 262))	('PBRM1', 'Gene', (24, 29))	('PBRM1', 'Gene', '55193', (24, 29))	('mutations', 'Var', (30, 39))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))
38402	30256787	The 3 lines with greatest knock-down showed somewhat variable growth rates in comparison to a similarly derived line expressing a control shRNA, and all lines showed moderate growth inhibition in response to rapamycin treatment at 20 nM for up to 3 days with no difference between the PBRM1 knock-down cells and those expressing control shRNAs (Fig 1B).	('knock-down', 'Var', (26, 36))	('rapamycin', 'Chemical', 'MESH:D020123', (208, 217))	('response to rapamycin', 'biological_process', 'GO:1901355', ('196', '217'))	('growth', 'MPA', (175, 181))	('response to rapamycin treatment at 20 nM', 'MPA', (196, 236))	('growth', 'MPA', (62, 68))	('PBRM1', 'Gene', (285, 290))	('PBRM1', 'Gene', '55193', (285, 290))
38404	30256787	We also studied RCC4 cells that are known to have biallelic mutation in PBRM1 that leads to a complete loss of expression of the protein.	('expression of the', 'MPA', (111, 128))	('biallelic mutation', 'Var', (50, 68))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('PBRM1', 'Gene', (72, 77))	('RCC4', 'Gene', '84925', (16, 20))	('RCC4', 'Gene', (16, 20))	('PBRM1', 'Gene', '55193', (72, 77))	('protein', 'Protein', (129, 136))	('loss', 'NegReg', (103, 107))
38408	30256787	We also performed the converse experiment, in that we examined rapalog sensitivity of derivatives of a native PBRM1 null cell line (A704) expressing either empty vector (A704_EV), wild type PBRM1 (A704_WT), or a mutant Q1298* PBRM1 (A704_Q1298*) under regulation of doxycycline (Fig 2A).	('Q1298*', 'SUBSTITUTION', 'None', (219, 225))	('PBRM1', 'Gene', '55193', (190, 195))	('Q1298*', 'Var', (219, 225))	('PBRM1', 'Gene', (226, 231))	('A704', 'Chemical', '-', (233, 237))	('regulation', 'biological_process', 'GO:0065007', ('252', '262'))	('A704', 'Chemical', '-', (132, 136))	('A704', 'Chemical', '-', (197, 201))	('PBRM1', 'Gene', '55193', (226, 231))	('doxycycline', 'Chemical', 'MESH:D004318', (266, 277))	('A704', 'Chemical', '-', (170, 174))	('Q1298*', 'SUBSTITUTION', 'None', (238, 244))	('Q1298*', 'Var', (238, 244))	('PBRM1', 'Gene', (190, 195))	('PBRM1', 'Gene', (110, 115))	('PBRM1', 'Gene', '55193', (110, 115))
38421	30256787	PBRM1 was the only gene to show gain of mutation in more than one patient in the post-treatment sample.	('mutation', 'Var', (40, 48))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('patient', 'Species', '9606', (66, 73))	('gain', 'PosReg', (32, 36))
38422	30256787	Two ccRCC patients showed gain of a nonsense mutation in PBRM1, while a third showed gain of a synonymous mutation, and all three were clonal in the post-treatment sample.	('gain', 'PosReg', (85, 89))	('PBRM1', 'Gene', (57, 62))	('nonsense', 'Var', (36, 44))	('synonymous mutation', 'MPA', (95, 114))	('PBRM1', 'Gene', '55193', (57, 62))	('patients', 'Species', '9606', (10, 18))	('gain', 'PosReg', (26, 30))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))
38425	30256787	Alternatively, tumor heterogeneity or sampling issues may account for these PBRM1 mutations seen only in the post-treatment samples.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mutations', 'Var', (82, 91))	('tumor', 'Disease', (15, 20))	('PBRM1', 'Gene', (76, 81))	('PBRM1', 'Gene', '55193', (76, 81))
38426	30256787	reported that PBRM1 mutations were associated with longer progression free survival (PFS) in metastatic RCC patients treated with first-line everolimus in the RECORD-3 trial.	('everolimus', 'Chemical', 'MESH:D000068338', (141, 151))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('PBRM1', 'Gene', (14, 19))	('progression', 'MPA', (58, 69))	('longer', 'PosReg', (51, 57))	('PBRM1', 'Gene', '55193', (14, 19))	('patients', 'Species', '9606', (108, 116))	('mutations', 'Var', (20, 29))	('RCC', 'Disease', (104, 107))
38427	30256787	Hence it is possible that the finding of PBRM1 mutations in our 5 ccRCC patients correlates with response to rapalog therapy, though not seen in the pre-treatment tumor specimen, rather than representing a mechanism of resistance.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('mutations', 'Var', (47, 56))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('tumor', 'Disease', (163, 168))	('pre', 'molecular_function', 'GO:0003904', ('149', '152'))	('PBRM1', 'Gene', (41, 46))	('PBRM1', 'Gene', '55193', (41, 46))	('patients', 'Species', '9606', (72, 80))
38428	30256787	On the other hand, if PBRM1 mutations cause response, then loss of PBRM1 mutation might be expected in the post-treatment resistance sample, given tumor heterogeneity in RCC, and we did not observe this.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('PBRM1', 'Gene', '55193', (22, 27))	('response', 'Disease', (44, 52))	('PBRM1', 'Gene', '55193', (67, 72))	('RCC', 'Disease', (170, 173))	('cause', 'Reg', (38, 43))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('loss', 'NegReg', (59, 63))	('mutation', 'Var', (73, 81))	('mutations', 'Var', (28, 37))	('PBRM1', 'Gene', (22, 27))	('PBRM1', 'Gene', (67, 72))
38430	30256787	Previous studies have identified MTOR mutations capable of preventing each of rapalog and ATP-competitive kinase inhibition of mTOR kinase activity in vivo and in vitro.	('preventing', 'NegReg', (59, 69))	('kinase activity', 'molecular_function', 'GO:0016301', ('132', '147'))	('MTOR', 'Gene', (33, 37))	('inhibition', 'NegReg', (113, 123))	('MTOR', 'Gene', '2475', (33, 37))	('ATP', 'Chemical', 'MESH:D000255', (90, 93))	('mTOR', 'Gene', (127, 131))	('mTOR', 'Gene', '2475', (127, 131))	('mutations', 'Var', (38, 47))
38431	30256787	Furthermore, a variety of activating mutations in MTOR are well-known in both RCC and other cancer types, and in some cases are associated with exceptional response to rapalog therapy.	('activating', 'PosReg', (26, 36))	('MTOR', 'Gene', (50, 54))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('RCC', 'Disease', (78, 81))	('mutations', 'Var', (37, 46))	('MTOR', 'Gene', '2475', (50, 54))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
38434	30256787	Transcriptional effects of PBRM1 mutation have recently been identified in analysis of the association of response of ccRCC to immune checkpoint therapies, and may have a similar effect in enhancing response to rapalogs.	('mutation', 'Var', (33, 41))	('enhancing', 'PosReg', (189, 198))	('PBRM1', 'Gene', (27, 32))	('response', 'MPA', (106, 114))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('PBRM1', 'Gene', '55193', (27, 32))	('response to rapalogs', 'MPA', (199, 219))
38443	30256787	We studied RCC cell lines SNU349, 786-O, RCC4, and several versions of the A704 cell line (A704+BAF180_WT, A704+BAF180_Q1298*, A704+BAF180_EV) previously generated by one of the co-authors (WG).	('A704+BAF180_Q1298*', 'Var', (107, 125))	('A704', 'Chemical', '-', (91, 95))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('A704', 'Chemical', '-', (127, 131))	('RCC4', 'Gene', (41, 45))	('RCC4', 'Gene', '84925', (41, 45))	('A704', 'Chemical', '-', (75, 79))	('A704', 'Chemical', '-', (107, 111))	('A704+BAF180_EV', 'Var', (127, 141))	('SNU349', 'CellLine', 'CVCL:5054', (26, 32))	('A704+BAF180_WT', 'Var', (91, 105))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (41, 44))	('RCC', 'Disease', (11, 14))
38465	30116722	Of note, several studies indicate that the HECT domain of NEDD4 E3s are also involved in substrate recognition.	('NEDD4', 'Gene', (58, 63))	('rat', 'Species', '10116', (94, 97))	('involved', 'Reg', (77, 85))	('HECT domain', 'MPA', (43, 54))	('NEDD4', 'Gene', '4734', (58, 63))	('substrate recognition', 'MPA', (89, 110))	('E3s', 'Var', (64, 67))
38466	30116722	Three isoforms of human Smurf1, resulting from alternative splicing, have been reported, and a single protein product has been confirmed for Smurf2.	('human', 'Species', '9606', (18, 23))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('splicing', 'biological_process', 'GO:0045292', ('59', '67'))	('alternative splicing', 'Var', (47, 67))	('Smurf1', 'Gene', (24, 30))
38487	30116722	Targeted disruption of Smurf2 in mice has also revealed that the protein levels and stability of the TGF-beta receptor and Smad proteins (i.e., Smad2/3) were unaffected by Smurf2 depletion, despite the enhanced cellular response to TGF-beta stimulation.	('protein levels', 'MPA', (65, 79))	('enhanced', 'PosReg', (202, 210))	('Smurf2', 'Gene', (172, 178))	('depletion', 'Var', (179, 188))	('Smad2/3', 'Gene', '17126;17127', (144, 151))	('mice', 'Species', '10090', (33, 37))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('TGF-beta', 'Protein', (101, 109))	('Smad2/3', 'Gene', (144, 151))	('stability', 'MPA', (84, 93))
38493	30116722	These findings suggest that NEDD4 E3s have overlapping functions in the TGF-beta signaling regulation.	('NEDD4', 'Gene', (28, 33))	('signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('TGF-beta signaling', 'Pathway', (72, 90))	('NEDD4', 'Gene', '4734', (28, 33))	('regulation', 'biological_process', 'GO:0065007', ('91', '101'))	('E3s', 'Var', (34, 37))
38495	30116722	Interestingly, a recent study shows that mice deficient for Smurf2 exhibit decreased bone mass due to severe osteoporosis.	('Smurf2', 'Gene', (60, 66))	('decreased bone mass', 'Phenotype', 'HP:0004349', (75, 94))	('mice', 'Species', '10090', (41, 45))	('osteoporosis', 'Phenotype', 'HP:0000939', (109, 121))	('bone mass', 'CPA', (85, 94))	('osteoporosis', 'Disease', (109, 121))	('severe osteoporosis', 'Phenotype', 'HP:0005897', (102, 121))	('osteoporosis', 'Disease', 'MESH:D010024', (109, 121))	('deficient', 'Var', (46, 55))	('decreased', 'NegReg', (75, 84))
38496	30116722	Moreover, the authors demonstrate that elimination of Smurf2, but not Smurf1, significantly increases the expression of RANKL, a key regulator in osteoclastogenesis and bone physiology.	('Smurf2', 'Gene', (54, 60))	('RANKL', 'Gene', (120, 125))	('expression', 'MPA', (106, 116))	('rat', 'Species', '10116', (29, 32))	('osteoclastogenesis', 'Disease', (146, 164))	('osteoclastogenesis', 'Disease', 'None', (146, 164))	('increases', 'PosReg', (92, 101))	('elimination', 'Var', (39, 50))
38511	30116722	Our subsequent studies revealed that inactivation of Smurf2 triggers a series of cascading events in cells, and creates the "mutator phenotype," which under the stress of aging leads to carcinogenesis.	('creates', 'Reg', (112, 119))	('triggers', 'Reg', (60, 68))	('cascading events', 'MPA', (81, 97))	('leads to', 'Reg', (177, 185))	('Smurf2', 'Gene', (53, 59))	('carcinogenesis', 'Disease', 'MESH:D063646', (186, 200))	('inactivation', 'Var', (37, 49))	('carcinogenesis', 'Disease', (186, 200))
38514	30116722	Furthermore, an interesting finding in Smurf2-/- cell genome was the accumulation of multiple chromosomal abnormalities, with translocations being the most notable hallmark.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (94, 119))	('chromosomal abnormalities', 'Disease', (94, 119))	('translocations', 'Var', (126, 140))	('multiple chromosomal abnormalities', 'Phenotype', 'HP:0040012', (85, 119))
38522	30116722	Smurf2 overexpression was reported to alter HSP27 subcellular distribution and induce its ubiquitin-dependent degradation in the human lung adenocarcinoma A549 cell model.	('ubiquitin-dependent degradation', 'MPA', (90, 121))	('degradation', 'biological_process', 'GO:0009056', ('110', '121'))	('lung adenocarcinoma A549', 'Disease', 'MESH:D000077192', (135, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('overexpression', 'Var', (7, 21))	('lung adenocarcinoma A549', 'Disease', (135, 159))	('subcellular distribution', 'MPA', (50, 74))	('Smurf2', 'Gene', (0, 6))	('induce', 'Reg', (79, 85))	('alter', 'Reg', (38, 43))	('ubiquitin', 'molecular_function', 'GO:0031386', ('90', '99'))	('HSP27', 'Gene', (44, 49))	('human', 'Species', '9606', (129, 134))	('HSP27', 'Gene', '3315', (44, 49))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (135, 154))
38528	30116722	Interestingly, KLF5 levels were specifically reduced by Smurf2, but not by Smurf1.	('KLF5', 'Gene', (15, 19))	('reduced', 'NegReg', (45, 52))	('Smurf2', 'Var', (56, 62))	('KLF5', 'Gene', '688', (15, 19))
38535	30116722	Overexpression of these IDs was shown to facilitate tumor growth, angiogenesis, stem cell maintenance, invasiveness, metastasis, as well as correlating with unfavorable clinical prognoses.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('invasiveness', 'CPA', (103, 115))	('facilitate', 'PosReg', (41, 51))	('angiogenesis', 'biological_process', 'GO:0001525', ('66', '78'))	('tumor', 'Disease', (52, 57))	('clinical', 'Species', '191496', (169, 177))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('Overexpression', 'Var', (0, 14))	('angiogenesis', 'CPA', (66, 78))	('stem cell maintenance', 'CPA', (80, 101))	('metastasis', 'CPA', (117, 127))
38542	30116722	Knockdown of Smurf2 or overexpression of its E3 ligase-deficient mutant generated misaligned and lagging chromosomes, premature anaphase onset, and defective cytokinesis in human cervix carcinoma HeLa cells.	('overexpression', 'PosReg', (23, 37))	('Smurf2', 'Gene', (13, 19))	('rat', 'Species', '10116', (76, 79))	('cytokinesis', 'biological_process', 'GO:0000910', ('158', '169'))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('anaphase', 'biological_process', 'GO:0051322', ('128', '136'))	('mutant', 'Var', (65, 71))	('carcinoma HeLa', 'Disease', 'MESH:D002277', (186, 200))	('cervix carcinoma', 'Phenotype', 'HP:0030079', (179, 195))	('carcinoma HeLa', 'Disease', (186, 200))	('human', 'Species', '9606', (173, 178))	('defective', 'NegReg', (148, 157))	('premature anaphase onset', 'CPA', (118, 142))
38543	30116722	Interestingly, in our study, Smurf2 depletion did not affect the formation of lagging chromosomes, but instead increased the formation of anaphase bridges in osteosarcoma U2OS cells.	('osteosarcoma', 'Phenotype', 'HP:0002669', (158, 170))	('U2OS', 'CellLine', 'CVCL:0042', (171, 175))	('increased', 'PosReg', (111, 120))	('osteosarcoma', 'Disease', (158, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('depletion', 'Var', (36, 45))	('osteosarcoma', 'Disease', 'MESH:D012516', (158, 170))	('formation', 'biological_process', 'GO:0009058', ('125', '134'))	('Smurf2', 'Gene', (29, 35))	('anaphase', 'biological_process', 'GO:0051322', ('138', '146'))	('formation', 'biological_process', 'GO:0009058', ('65', '74'))
38549	30116722	However, changes in Smurf2 expression are common in many cancers, similar to some other cancer-related genes such as the two TP53 paralogs, TP63 and TP73, and the members of the FOXO transcription factors family.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', (57, 63))	('expression', 'MPA', (27, 37))	('TP53', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('TP73', 'Gene', '7161', (149, 153))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('Smurf2', 'Gene', (20, 26))	('TP53', 'Gene', '7157', (125, 129))	('TP73', 'Gene', (149, 153))	('TP63', 'Gene', (140, 144))	('transcription', 'biological_process', 'GO:0006351', ('183', '196'))	('changes', 'Var', (9, 16))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('TP63', 'Gene', '8626', (140, 144))
38555	30116722	It is possible that overexpressed and mislocalized Smurf2 is employed by the carcinogenic machinery to promote oncogenesis, at least in some types of cancer.	('overexpressed', 'Var', (20, 33))	('carcinogenic', 'Disease', 'MESH:D063646', (77, 89))	('carcinogenic', 'Disease', (77, 89))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('oncogenesis', 'biological_process', 'GO:0007048', ('111', '122'))	('Smurf2', 'Gene', (51, 57))	('mislocalized', 'Var', (38, 50))	('promote', 'PosReg', (103, 110))	('oncogenesis', 'CPA', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
38560	30116722	In addition, the authors demonstrated that knockdown of Smurf2 reduces the clonogenic survival and prolongs tumor latency in the mutant KRAS-driven tumors generated in nude mice with either human colon or lung carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('rat', 'Species', '10116', (32, 35))	('Smurf2', 'Gene', (56, 62))	('rat', 'Species', '10116', (159, 162))	('tumor', 'Disease', (108, 113))	('prolongs', 'PosReg', (99, 107))	('nude mice', 'Species', '10090', (168, 177))	('human colon or lung carcinoma', 'Disease', 'MESH:D008175', (190, 219))	('mutant', 'Var', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('knockdown', 'Var', (43, 52))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('reduces', 'NegReg', (63, 70))	('human colon or lung carcinoma', 'Disease', (190, 219))	('tumors', 'Disease', (148, 154))	('KRAS-driven', 'Gene', (136, 147))	('tumor', 'Disease', (148, 153))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('clonogenic survival', 'CPA', (75, 94))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
38567	30116722	Inhibition of this degradation pathway by aberrant Wnt/beta-catenin signaling may contribute to Ras-induced transformation in colorectal tumorigenesis.	('beta-catenin', 'Gene', (55, 67))	('tumor', 'Disease', (137, 142))	('Inhibition', 'NegReg', (0, 10))	('colorectal', 'Disease', 'MESH:D015179', (126, 136))	('beta-catenin', 'Gene', '1499', (55, 67))	('degradation', 'biological_process', 'GO:0009056', ('19', '30'))	('aberrant', 'Var', (42, 50))	('contribute', 'Reg', (82, 92))	('colorectal', 'Disease', (126, 136))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('signaling', 'biological_process', 'GO:0023052', ('68', '77'))
38570	30116722	The authors also reported that the loss of Smurf2 destabilizes EGFR, and reduces the clonogenic survival of EGFR-expressing cancer cell strains.	('EGFR', 'Gene', '1956', (63, 67))	('cancer', 'Disease', (124, 130))	('EGFR', 'molecular_function', 'GO:0005006', ('108', '112'))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (63, 67))	('reduces', 'NegReg', (73, 80))	('EGFR', 'Gene', (108, 112))	('destabilizes', 'NegReg', (50, 62))	('loss', 'Var', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('clonogenic survival', 'CPA', (85, 104))	('Smurf2', 'Gene', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
38572	30116722	In addition, the authors demonstrated that knockdown of Smurf2 reduces the ability of human head and neck squamous cell carcinoma UMSCC74B cells to form tumors in vivo.	('UMSCC74B', 'CellLine', 'CVCL:7780', (130, 138))	('rat', 'Species', '10116', (32, 35))	('knockdown', 'Var', (43, 52))	('reduces', 'NegReg', (63, 70))	('Smurf2', 'Gene', (56, 62))	('human', 'Species', '9606', (86, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('neck squamous cell carcinoma', 'Disease', (101, 129))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (92, 129))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (101, 129))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('neck', 'cellular_component', 'GO:0044326', ('101', '105'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
38574	30116722	Of note, Wellbrock's group reported that Smurf2 depletion can significantly increase melanoma cell sensitivity to the cytotoxic effects of the MEK inhibitor selumetinib (AZD6244), both in vitro and in vivo.	('selumetinib', 'Chemical', 'MESH:C517975', (157, 168))	('MEK', 'Gene', (143, 146))	('increase', 'PosReg', (76, 84))	('MEK', 'Gene', '5609', (143, 146))	('Smurf2', 'Gene', (41, 47))	('AZD6244', 'Chemical', 'MESH:C517975', (170, 177))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('depletion', 'Var', (48, 57))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))
38575	30116722	This finding implies that at least in this type of tumor, inactivating Smurf2 might overcome tumor cell resistance to MAPK pathway inhibitors experienced in clinics.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('MAPK pathway', 'Pathway', (118, 130))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', (93, 98))	('MAPK', 'molecular_function', 'GO:0004707', ('118', '122'))	('overcome', 'PosReg', (84, 92))	('inactivating', 'Var', (58, 70))	('Smurf2', 'Gene', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
38579	30116722	Moreover, the authors demonstrated that Smurf2 E3 ligase-defective mutant (Cys716Gly) decreases the metastatic behavior of these cells.	('Cys716Gly', 'Var', (75, 84))	('rat', 'Species', '10116', (29, 32))	('decreases', 'NegReg', (86, 95))	('metastatic behavior of these cells', 'CPA', (100, 134))	('Cys716Gly', 'SUBSTITUTION', 'None', (75, 84))
38580	30116722	In contrast, Imamura's group showed that Smurf2 knockdown in MDA-MB-231 cells enhances cell migration in vitro and bone metastasis in vivo, implying that under these circumstances Smurf2 is a tumor suppressor.	('tumor', 'Disease', (192, 197))	('cell migration', 'CPA', (87, 101))	('enhances', 'PosReg', (78, 86))	('Smurf2', 'Gene', (41, 47))	('rat', 'Species', '10116', (95, 98))	('cell migration', 'biological_process', 'GO:0016477', ('87', '101'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('192', '208'))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('192', '208'))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('bone metastasis', 'CPA', (115, 130))	('knockdown', 'Var', (48, 57))
38582	30116722	In addition, a recent study showed that knock-down of Smurf2 increases the proportion of invasive MDA-MB-231 cell-derived organoids.	('Smurf2', 'Gene', (54, 60))	('knock-down', 'Var', (40, 50))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (98, 108))	('increases', 'PosReg', (61, 70))
38583	30116722	This group also demonstrated that PIAS3-dependent sumoylation of Smurf2 is important in suppressing the invasive behavior of these cells.	('sumoylation', 'biological_process', 'GO:0016925', ('50', '61'))	('suppressing', 'NegReg', (88, 99))	('PIAS3', 'Gene', (34, 39))	('rat', 'Species', '10116', (23, 26))	('sumoylation', 'Var', (50, 61))	('invasive behavior of these cells', 'CPA', (104, 136))	('Smurf2', 'Gene', (65, 71))	('PIAS3', 'Gene', '10401', (34, 39))
38594	30116722	Silencing of Smurf1 or expression of its interfering mutants inhibited cell migration.	('inhibited', 'NegReg', (61, 70))	('Silencing', 'Var', (0, 9))	('Smurf1', 'Gene', (13, 19))	('mutants', 'Var', (53, 60))	('cell migration', 'biological_process', 'GO:0016477', ('71', '85'))	('rat', 'Species', '10116', (79, 82))	('cell migration', 'CPA', (71, 85))
38662	29715308	Two recently introduced parameters were derived from the iodine concentration measurements and monochromatic images: (a) the normalized iodine concentration (NIC) was calculated as NIC = IClesion/ICaorta, where IClesion and ICaorta are the iodine levels in the lesions and the aorta; iodine concentrations in the lesions were normalized to those of the aorta to minimize variations in patients; (b) the slope of spectrum curve was calculated as slope = (CT40keV-CT70keV)/30, where CT40keV and CT70keV are the CT attenuation values of the tumors on 40 keV and 70 keV monochromatic images, respectively.	('tumors', 'Disease', (538, 544))	('tumors', 'Disease', 'MESH:D009369', (538, 544))	('tumors', 'Phenotype', 'HP:0002664', (538, 544))	('CT70keV', 'Var', (493, 500))	('iodine', 'Chemical', 'MESH:D007455', (240, 246))	('CT40keV', 'Var', (481, 488))	('tumor', 'Phenotype', 'HP:0002664', (538, 543))	('patients', 'Species', '9606', (385, 393))	('iodine', 'Chemical', 'MESH:D007455', (57, 63))	('iodine', 'Chemical', 'MESH:D007455', (136, 142))	('iodine', 'Chemical', 'MESH:D007455', (284, 290))
38742	27437764	In addition, [111In]XYIMSR-01 significantly improved both target-selective in vivo radiotracer uptake and pharmacokinetic properties compared to other reported ligands.	('uptake', 'biological_process', 'GO:0098739', ('95', '101'))	('pharmacokinetic', 'MPA', (106, 121))	('111In', 'Chemical', 'MESH:C000615551', (14, 19))	('[111In]XYIMSR-01', 'Var', (13, 29))	('target-selective', 'MPA', (58, 74))	('improved', 'PosReg', (44, 52))	('uptake', 'biological_process', 'GO:0098657', ('95', '101'))
38747	27437764	The binding of [Al19F]XYIMSR-04 to CAIX was evaluated using a competitive fluorescence polarization assay with a previously described FITC-labeled dual-motif ligand and 1 (Supplementary Figure S1).	('Supplementary Figure S1', 'Disease', 'MESH:D017034', (172, 195))	('Supplementary Figure S1', 'Disease', (172, 195))	('[Al19F]XYIMSR-04', 'Var', (15, 31))	('binding', 'Interaction', (4, 11))	('FITC', 'Chemical', 'MESH:D016650', (134, 138))	('ligand', 'molecular_function', 'GO:0005488', ('158', '164'))	('binding', 'molecular_function', 'GO:0005488', ('4', '11'))
38748	27437764	The IC50 values determined for 1 and [Al19F]XYIMSR-04 were 63.6 +- 2.8 and 96.7 +- 3.3 nM, respectively (Figure 2 and Supplementary Figure S1).	('Supplementary Figure S1', 'Disease', (118, 141))	('Supplementary Figure S1', 'Disease', 'MESH:D017034', (118, 141))	('[Al19F]XYIMSR-04', 'Var', (37, 53))
38749	27437764	PET imaging (Supplementary Figure S2) and biodistribution studies (Supplementary Table S1) at 1 h post-injection of [Al18F]XYIMSR-04 to mice bearing CAIX-expressing SK-RC-52 ccRCC tumor xenografts showed 14.4 +- 2.2 %ID/g tumor uptake.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('mice', 'Species', '10090', (136, 140))	('RCC', 'Disease', (176, 179))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('tumor', 'Disease', (180, 185))	('ccRCC', 'Phenotype', 'HP:0006770', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('uptake', 'biological_process', 'GO:0098657', ('228', '234'))	('SK-RC-52', 'CellLine', 'CVCL:6198', (165, 173))	('uptake', 'biological_process', 'GO:0098739', ('228', '234'))	('[Al18F]XYIMSR-04', 'Var', (116, 132))
38764	27437764	Compared with [111In]XYIMSR-01 (20.8 %ID/g at 4 h, 34.0 %ID/g at 8 h, 25.6 %ID/g at 24 h and 13.9%ID/g at 48 h), [64Cu]XYIMSR-06 demonstrated faster clearance, likely due to the more hydrophilic nature of NOTA-Cu(II), which has an additional non-coordinated free carboxylate not present for DOTA-In(III).	('carboxylate', 'Chemical', '-', (263, 274))	('faster', 'PosReg', (142, 148))	('64Cu', 'Chemical', 'MESH:C000615411', (114, 118))	('111In', 'Chemical', 'MESH:C000615551', (15, 20))	('[64Cu]XYIMSR-06', 'Var', (113, 128))	('clearance', 'MPA', (149, 158))
38770	27437764	Compared with [111In]XYIMSR-01 the faster clearance of [64Cu]XYIMSR-06 could be a result of its increased hydrophilicity, especially with the lack of internalization of CAIX upon ligand binding.	('increased', 'PosReg', (96, 105))	('ligand', 'molecular_function', 'GO:0005488', ('179', '185'))	('hydrophilicity', 'MPA', (106, 120))	('[64Cu]XYIMSR-06', 'Var', (55, 70))	('64Cu', 'Chemical', 'MESH:C000615411', (56, 60))	('faster', 'PosReg', (35, 41))	('lack', 'NegReg', (142, 146))	('clearance', 'MPA', (42, 51))	('111In', 'Chemical', 'MESH:C000615551', (15, 20))	('binding', 'molecular_function', 'GO:0005488', ('186', '193'))	('ligand binding', 'Interaction', (179, 193))	('internalization', 'MPA', (150, 165))
38774	27437764	Blocking studies with compound 1 at 8 h and 24 h, proved CAIX-mediated binding of [64Cu]XYIMSR-06.	('CAIX-mediated', 'Protein', (57, 70))	('64Cu', 'Chemical', 'MESH:C000615411', (83, 87))	('binding', 'Interaction', (71, 78))	('[64Cu]XYIMSR-06', 'Var', (82, 97))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))
38779	27437764	[64Cu]XYIMSR-06 demonstrated selective tumor uptake and pharmacokinetic properties suitable for clinical imaging.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('uptake', 'biological_process', 'GO:0098739', ('45', '51'))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('uptake', 'biological_process', 'GO:0098657', ('45', '51'))	('64Cu', 'Chemical', 'MESH:C000615411', (1, 5))	('tumor', 'Disease', (39, 44))	('[64Cu]', 'Var', (0, 6))
38780	27437764	[64Cu]XYIMSR-06 provides a clinically viable alternative for molecular imaging of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('64Cu', 'Chemical', 'MESH:C000615411', (1, 5))	('[64Cu', 'Var', (0, 5))
38826	30078736	ULK1 dysregulation has recently been found in several human cancers.	('dysregulation', 'Var', (5, 18))	('ULK1', 'Gene', '8408', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('found', 'Reg', (37, 42))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('ULK1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('human', 'Species', '9606', (54, 59))
38830	30078736	ULK1 activity was inhibited by SBI-0206965.	('ULK1', 'Gene', '8408', (0, 4))	('activity', 'MPA', (5, 13))	('inhibited', 'NegReg', (18, 27))	('ULK1', 'Gene', (0, 4))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (31, 42))	('SBI-0206965', 'Var', (31, 42))
38836	30078736	We demonstrated that SBI-0206965 triggered apoptosis by preventing autophagy and pentose phosphate pathway (PPP) flux.	('preventing', 'NegReg', (56, 66))	('apoptosis', 'CPA', (43, 52))	('autophagy', 'biological_process', 'GO:0006914', ('67', '76'))	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('autophagy', 'CPA', (67, 76))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('81', '106'))	('pentose phosphate', 'MPA', (81, 98))	('SBI-0206965', 'Var', (21, 32))	('pentose phosphate', 'Chemical', 'MESH:D010428', (81, 98))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (21, 32))	('autophagy', 'biological_process', 'GO:0016236', ('67', '76'))
38837	30078736	Furthermore, blocking the kinase activity of ULK1 with SBI-0206965 resulted in a level of anticancer effect in vivo.	('SBI-0206965', 'Var', (55, 66))	('kinase activity', 'molecular_function', 'GO:0016301', ('26', '41'))	('kinase activity', 'MPA', (26, 41))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('blocking', 'NegReg', (13, 21))	('ULK1', 'Gene', (45, 49))	('ULK1', 'Gene', '8408', (45, 49))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (55, 66))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
38839	30078736	Therefore, SBI-0206965 should be further considered as an anti-ccRCC agent.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (11, 22))	('SBI-0206965', 'Var', (11, 22))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
38842	30078736	They found that SBI-0206965 inhibits autophagy and enhances apoptosis in human glioblastoma and lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('inhibits', 'NegReg', (28, 36))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (16, 27))	('apoptosis', 'CPA', (60, 69))	('SBI-0206965', 'Var', (16, 27))	('lung cancer', 'Disease', (96, 107))	('human', 'Species', '9606', (73, 78))	('glioblastoma', 'Disease', (79, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (79, 91))	('autophagy', 'CPA', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('autophagy', 'biological_process', 'GO:0006914', ('37', '46'))	('autophagy', 'biological_process', 'GO:0016236', ('37', '46'))	('enhances', 'PosReg', (51, 59))	('apoptosis', 'biological_process', 'GO:0006915', ('60', '69'))	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))	('apoptosis', 'biological_process', 'GO:0097194', ('60', '69'))
38843	30078736	Recent studies showed that SBI-0206965 could suppress phosphorylation of the beta1-Ser108 of AMP-activated protein kinase (AMPK), and induce cell apoptosis and enhance the sensitivity of cisplatin against non-small cell lung cancer cells.	('Ser108', 'Chemical', '-', (83, 89))	('AMPK', 'molecular_function', 'GO:0050405', ('123', '127'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (209, 231))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))	('sensitivity of cisplatin', 'MPA', (172, 196))	('AMPK', 'molecular_function', 'GO:0004691', ('123', '127'))	('Ser', 'cellular_component', 'GO:0005790', ('83', '86'))	('lung cancer', 'Disease', (220, 231))	('phosphorylation', 'MPA', (54, 69))	('induce', 'PosReg', (134, 140))	('AMPK', 'molecular_function', 'GO:0047322', ('123', '127'))	('cell apoptosis', 'CPA', (141, 155))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))	('suppress', 'NegReg', (45, 53))	('AMP-activated protein kinase', 'MPA', (93, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('apoptosis', 'biological_process', 'GO:0097194', ('146', '155'))	('apoptosis', 'biological_process', 'GO:0006915', ('146', '155'))	('cisplatin', 'Chemical', 'MESH:D002945', (187, 196))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('enhance', 'PosReg', (160, 167))	('SBI-0206965', 'Var', (27, 38))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (27, 38))
38848	30078736	Then, we demonstrated that SBI-0206965 triggered apoptosis by preventing autophagy and pentose phosphate pathway (PPP) flux.	('autophagy', 'CPA', (73, 82))	('preventing', 'NegReg', (62, 72))	('pentose phosphate', 'MPA', (87, 104))	('pentose phosphate', 'Chemical', 'MESH:D010428', (87, 104))	('autophagy', 'biological_process', 'GO:0016236', ('73', '82'))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('87', '112'))	('apoptosis', 'biological_process', 'GO:0097194', ('49', '58'))	('apoptosis', 'biological_process', 'GO:0006915', ('49', '58'))	('autophagy', 'biological_process', 'GO:0006914', ('73', '82'))	('SBI-0206965', 'Var', (27, 38))	('apoptosis', 'CPA', (49, 58))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (27, 38))
38849	30078736	Furthermore, SBI-0206965 resulted in a level of anticancer effect in vivo in a murine xenograft model.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (13, 24))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('SBI-0206965', 'Var', (13, 24))	('murine', 'Species', '10090', (79, 85))
38850	30078736	Our results suggested that ULK1 may be a potential therapeutic target, and SBI-0206965 should be further considered as an anti-ccRCC agent.	('SBI-0206965', 'Chemical', 'MESH:C000601952', (75, 86))	('SBI-0206965', 'Var', (75, 86))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('RCC', 'Disease', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('ULK1', 'Gene', (27, 31))	('ULK1', 'Gene', '8408', (27, 31))
38864	30078736	SBI-0206965 inhibits autophagy and enhances apoptosis in human glioblastoma and lung cancer cells, suggesting it has therapeutic potential.	('autophagy', 'biological_process', 'GO:0006914', ('21', '30'))	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('autophagy', 'CPA', (21, 30))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('autophagy', 'biological_process', 'GO:0016236', ('21', '30'))	('apoptosis', 'CPA', (44, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('glioblastoma', 'Disease', (63, 75))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('inhibits', 'NegReg', (12, 20))	('glioblastoma', 'Disease', 'MESH:D005909', (63, 75))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (0, 11))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('enhances', 'PosReg', (35, 43))	('SBI-0206965', 'Var', (0, 11))	('human', 'Species', '9606', (57, 62))
38865	30078736	SBI-0206965 also suppresses phosphorylation of the beta1-Ser108 of AMP-activated protein kinase (AMPK), which has been demonstrated to upregulate pro-survival pathways.	('pro-survival pathways', 'Pathway', (146, 167))	('Ser108', 'Chemical', '-', (57, 63))	('phosphorylation', 'MPA', (28, 43))	('suppresses', 'NegReg', (17, 27))	('AMP-activated protein kinase', 'MPA', (67, 95))	('Ser', 'cellular_component', 'GO:0005790', ('57', '60'))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('AMPK', 'molecular_function', 'GO:0050405', ('97', '101'))	('pro-survival', 'biological_process', 'GO:0043066', ('146', '158'))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (0, 11))	('AMPK', 'molecular_function', 'GO:0004691', ('97', '101'))	('SBI-0206965', 'Var', (0, 11))	('phosphorylation', 'biological_process', 'GO:0016310', ('28', '43'))	('AMPK', 'molecular_function', 'GO:0047322', ('97', '101'))	('upregulate', 'PosReg', (135, 145))
38866	30078736	showed that SBI-0206965 induces cell apoptosis and enhances the sensitivity of cisplatin against non-small cell lung cancer cells.	('cell apoptosis', 'CPA', (32, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (101, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (12, 23))	('lung cancer', 'Disease', (112, 123))	('apoptosis', 'biological_process', 'GO:0097194', ('37', '46'))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('SBI-0206965', 'Var', (12, 23))	('apoptosis', 'biological_process', 'GO:0006915', ('37', '46'))	('sensitivity of cisplatin', 'MPA', (64, 88))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (97, 123))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('enhances', 'PosReg', (51, 59))	('non-small', 'MPA', (97, 106))
38869	30078736	SBI-0206965 appeared to increase apoptosis by inhibiting cell autophagy and by increasing the levels of reactive oxygen species (ROS) in ccRCC cells.	('inhibiting', 'NegReg', (46, 56))	('apoptosis', 'biological_process', 'GO:0097194', ('33', '42'))	('increase', 'PosReg', (24, 32))	('apoptosis', 'CPA', (33, 42))	('autophagy', 'biological_process', 'GO:0006914', ('62', '71'))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('apoptosis', 'biological_process', 'GO:0006915', ('33', '42'))	('increasing', 'PosReg', (79, 89))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('autophagy', 'biological_process', 'GO:0016236', ('62', '71'))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (0, 11))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (104, 127))	('ROS', 'Chemical', 'MESH:D017382', (129, 132))	('SBI-0206965', 'Var', (0, 11))	('cell autophagy', 'CPA', (57, 71))
38870	30078736	In a xenograft mouse model, SBI-0206965 inhibited tumour growth without producing any symptoms of toxicity.	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('SBI-0206965', 'Var', (28, 39))	('toxicity', 'Disease', 'MESH:D064420', (98, 106))	('toxicity', 'Disease', (98, 106))	('inhibited', 'NegReg', (40, 49))	('tumour', 'Disease', (50, 56))	('mouse', 'Species', '10090', (15, 20))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (28, 39))
38871	30078736	Results from this work revealed that ULK1 may be a novel prognostic marker and suggests that SBI-0206965 may be a potential therapeutic agent for ccRCC.	('RCC', 'Disease', (148, 151))	('SBI-0206965', 'Var', (93, 104))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (93, 104))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('ULK1', 'Gene', (37, 41))	('ULK1', 'Gene', '8408', (37, 41))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))
38887	30078736	A498 and ACHN cells (1 x 105/well) were evenly distributed and grown in 100-mm culture dishes overnight and then treated with Earle's Balanced Salt Solution (EBSS) and SBI-0206965 (Cat.	("Earle's Balanced Salt Solution", 'Chemical', '-', (126, 156))	('ACHN', 'Gene', (9, 13))	('Cat', 'molecular_function', 'GO:0004096', ('181', '184'))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (168, 179))	('EBSS', 'Chemical', '-', (158, 162))	('SBI-0206965', 'Var', (168, 179))	('ACHN', 'Gene', '55323', (9, 13))
38912	30078736	Analysis of the results showed that high ULK1 expression was related to shorter overall survival in ccRCC patients, indicating that overexpression of ULK1 mRNA was correlated with poor outcome (Fig.	('overexpression', 'PosReg', (132, 146))	('overall survival', 'MPA', (80, 96))	('shorter', 'NegReg', (72, 79))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('RCC', 'Disease', (102, 105))	('ULK1', 'Gene', (150, 154))	('patients', 'Species', '9606', (106, 114))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('ULK1', 'Gene', '8408', (150, 154))	('expression', 'MPA', (46, 56))	('ULK1', 'Gene', (41, 45))	('high', 'Var', (36, 40))	('ULK1', 'Gene', '8408', (41, 45))
38928	30078736	Flow cytometry analysis also demonstrated enhanced levels of cell death with increasing concentrations of SBI0206965 in ACHN and A498 cells (Fig.	('SBI0206965', 'Var', (106, 116))	('cell death', 'CPA', (61, 71))	('ACHN', 'Gene', '55323', (120, 124))	('cell death', 'biological_process', 'GO:0008219', ('61', '71'))	('enhanced', 'PosReg', (42, 50))	('ACHN', 'Gene', (120, 124))	('SBI0206965', 'Chemical', 'MESH:C000601952', (106, 116))
38929	30078736	Treatment with SBI0206965 attenuated the phosphorylation of Ser108 of the AMPK beta1 subunit, suggesting that ULK1 kinase activity was inhibited by SBI0206965 (Fig.	('ULK1', 'Gene', (110, 114))	('phosphorylation of', 'MPA', (41, 59))	('SBI0206965', 'Var', (148, 158))	('ULK1', 'Gene', '8408', (110, 114))	('phosphorylation', 'biological_process', 'GO:0016310', ('41', '56'))	('AMPK', 'molecular_function', 'GO:0050405', ('74', '78'))	('AMPK', 'molecular_function', 'GO:0004691', ('74', '78'))	('SBI0206965', 'Chemical', 'MESH:C000601952', (15, 25))	('Ser', 'cellular_component', 'GO:0005790', ('60', '63'))	('AMPK beta1', 'Gene', (74, 84))	('AMPK', 'molecular_function', 'GO:0047322', ('74', '78'))	('SBI0206965', 'Chemical', 'MESH:C000601952', (148, 158))	('Ser108', 'Chemical', '-', (60, 66))	('kinase activity', 'molecular_function', 'GO:0016301', ('115', '130'))	('attenuated', 'NegReg', (26, 36))	('inhibited', 'NegReg', (135, 144))	('AMPK beta1', 'Gene', '5564', (74, 84))
38932	30078736	SBI0206965 increased the levels of cleaved Caspase 8 and PARP, markers of apoptosis (Fig.	('SBI0206965', 'Chemical', 'MESH:C000601952', (0, 10))	('PARP', 'Gene', (57, 61))	('increased', 'PosReg', (11, 20))	('Caspase 8', 'Gene', '841', (43, 52))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('Caspase 8', 'Gene', (43, 52))	('PARP', 'Gene', '142', (57, 61))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('SBI0206965', 'Var', (0, 10))
38933	30078736	Under normal conditions, SBI0206965 was able to induce apoptosis (Fig.	('SBI0206965', 'Chemical', 'MESH:C000601952', (25, 35))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('induce', 'PosReg', (48, 54))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('SBI0206965', 'Var', (25, 35))	('apoptosis', 'CPA', (55, 64))
38934	30078736	S2b) but the activity of SBI0206965 was more pronounced under conditions of starvation.	('SBI0206965', 'Chemical', 'MESH:C000601952', (25, 35))	('activity', 'MPA', (13, 21))	('SBI0206965', 'Var', (25, 35))
38935	30078736	Our experimental findings demonstrated that SBI-0206965 inhibited autophagy, as evidenced by increased levels of LC3B I and the autophagy substrate p62 (Fig.	('autophagy', 'CPA', (66, 75))	('autophagy', 'biological_process', 'GO:0006914', ('128', '137'))	('increased', 'PosReg', (93, 102))	('LC3B', 'Gene', '81631', (113, 117))	('autophagy', 'biological_process', 'GO:0016236', ('66', '75'))	('inhibited', 'NegReg', (56, 65))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (44, 55))	('p62', 'Gene', '23636', (148, 151))	('autophagy', 'biological_process', 'GO:0006914', ('66', '75'))	('SBI-0206965', 'Var', (44, 55))	('LC3B', 'Gene', (113, 117))	('p62', 'Gene', (148, 151))	('autophagy', 'biological_process', 'GO:0016236', ('128', '137'))
38938	30078736	When ccRCC cells were treated with SBI-0206965 the autophagosomes were almost absent (Fig.	('SBI-0206965', 'Var', (35, 46))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (35, 46))	('autophagosomes', 'CPA', (51, 65))	('RCC', 'Disease', 'MESH:C538614', (7, 10))	('absent', 'NegReg', (78, 84))	('RCC', 'Disease', (7, 10))	('RCC', 'Phenotype', 'HP:0005584', (7, 10))	('ccRCC', 'Phenotype', 'HP:0006770', (5, 10))
38944	30078736	Moreover, SBI-0206965 clearly influenced ROS levels compared with that of the DMSO-treated control group (Fig.	('SBI-0206965', 'Var', (10, 21))	('ROS levels', 'MPA', (41, 51))	('ROS', 'Chemical', 'MESH:D017382', (41, 44))	('DMSO', 'Chemical', 'MESH:D004121', (78, 82))	('influenced', 'Reg', (30, 40))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (10, 21))
38945	30078736	Taken together, SBI-0206965 induced apoptosis of ccRCC cells through inhibiting autophagy and decreasing the rate of ROS clearance under conditions of starvation.	('decreasing', 'NegReg', (94, 104))	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('apoptosis', 'biological_process', 'GO:0097194', ('36', '45'))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (16, 27))	('autophagy', 'CPA', (80, 89))	('ROS', 'Chemical', 'MESH:D017382', (117, 120))	('apoptosis', 'biological_process', 'GO:0006915', ('36', '45'))	('SBI-0206965', 'Var', (16, 27))	('ROS', 'Protein', (117, 120))	('inhibiting', 'NegReg', (69, 79))	('autophagy', 'biological_process', 'GO:0016236', ('80', '89'))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('autophagy', 'biological_process', 'GO:0006914', ('80', '89'))	('RCC', 'Disease', (51, 54))
38946	30078736	To evaluate the anti-tumour efficacy in vivo, nude mice inoculated subcutaneously with A498 cells were intraperitoneally injected with either vehicle (DMSO) or SBI-0206965 (50 mg/kg) once every three days for 37 d starting 14 d after injection of the ccRCC cells.	('nude mice', 'Species', '10090', (46, 55))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (160, 171))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('SBI-0206965', 'Var', (160, 171))	('RCC', 'Disease', 'MESH:C538614', (253, 256))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('RCC', 'Disease', (253, 256))	('RCC', 'Phenotype', 'HP:0005584', (253, 256))	('ccRCC', 'Phenotype', 'HP:0006770', (251, 256))	('DMSO', 'Chemical', 'MESH:D004121', (151, 155))	('tumour', 'Disease', (21, 27))
38947	30078736	The A498 xenograft tumour growth rate was significantly suppressed by SBI-0206965 compared with that of the vehicle (Fig.	('SBI-0206965', 'Chemical', 'MESH:C000601952', (70, 81))	('tumour', 'Disease', 'MESH:D009369', (19, 25))	('tumour', 'Disease', (19, 25))	('suppressed', 'NegReg', (56, 66))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('SBI-0206965', 'Var', (70, 81))
38952	30078736	Treatment of mice with SBI-0206965 resulted in increased cell apoptosis in the tumour samples, as demonstrated by more green-coloured apoptotic cells (Fig.	('mice', 'Species', '10090', (13, 17))	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('cell apoptosis', 'CPA', (57, 71))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('SBI-0206965', 'Var', (23, 34))	('increased', 'PosReg', (47, 56))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (23, 34))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', (79, 85))
38955	30078736	It has been shown that ULK1 is induced by hypoxia and that ablation of ULK1 causes death of cancer cells under conditions of both normoxia and hypoxia.	('hypoxia', 'Disease', 'MESH:D000860', (143, 150))	('ULK1', 'Gene', (71, 75))	('death of cancer', 'Disease', (83, 98))	('hypoxia', 'Disease', (143, 150))	('ULK1', 'Gene', (23, 27))	('hypoxia', 'Disease', (42, 49))	('hypoxia', 'Disease', 'MESH:D000860', (42, 49))	('ULK1', 'Gene', '8408', (23, 27))	('ULK1', 'Gene', '8408', (71, 75))	('ablation', 'Var', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('death of cancer', 'Disease', 'MESH:D003643', (83, 98))
38959	30078736	Inhibition of ULK1 by knockdown or by treatment with SBI-0206965 promoted cell apoptosis in ccRCC cells.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('ULK1', 'Gene', '8408', (14, 18))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('Inhibition', 'NegReg', (0, 10))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (53, 64))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('cell apoptosis', 'CPA', (74, 88))	('knockdown', 'Var', (22, 31))	('promoted', 'PosReg', (65, 73))	('ULK1', 'Gene', (14, 18))
38961	30078736	Another important phenomenon observed in the current study was that treatment with SBI-0206965 inhibited autophagy and induced apoptosis in ccRCC cells, whereas chloroquine, a classic autophagy inhibitor, caused less Caspase 8 and PARP cleavage and cell death during EBSS treatment.	('SBI-0206965', 'Var', (83, 94))	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('autophagy', 'biological_process', 'GO:0016236', ('105', '114'))	('apoptosis', 'CPA', (127, 136))	('Caspase 8', 'Gene', (217, 226))	('autophagy', 'biological_process', 'GO:0006914', ('105', '114'))	('induced', 'Reg', (119, 126))	('cell death', 'CPA', (249, 259))	('chloroquine', 'Chemical', 'MESH:D002738', (161, 172))	('apoptosis', 'biological_process', 'GO:0097194', ('127', '136'))	('apoptosis', 'biological_process', 'GO:0006915', ('127', '136'))	('autophagy', 'biological_process', 'GO:0016236', ('184', '193'))	('PARP', 'Gene', '142', (231, 235))	('PARP', 'Gene', (231, 235))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('cell death', 'biological_process', 'GO:0008219', ('249', '259'))	('autophagy', 'biological_process', 'GO:0006914', ('184', '193'))	('EBSS', 'Chemical', '-', (267, 271))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('inhibited', 'NegReg', (95, 104))	('Caspase 8', 'Gene', '841', (217, 226))	('autophagy', 'CPA', (105, 114))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (83, 94))
38966	30078736	Dysregulation of PPP metabolic flux strikingly impacts cancer growth and cell survival.	('PPP', 'Gene', (17, 20))	('Dysregulation', 'Var', (0, 13))	('cell survival', 'CPA', (73, 86))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('impacts', 'Reg', (47, 54))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
38968	30078736	However, due to the inability to obtain antibodies, our results lack evidence that SBI-0206965 affects the level of glycolytic enzyme phosphorylation, which requires further study.	('SBI-0206965', 'Var', (83, 94))	('affects', 'Reg', (95, 102))	('phosphorylation', 'biological_process', 'GO:0016310', ('134', '149'))	('lack', 'NegReg', (64, 68))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (83, 94))	('level of glycolytic enzyme phosphorylation', 'MPA', (107, 149))
38969	30078736	In addition, SBI-0206965 has also been shown to inhibit the phosphorylation of AMPK beta1.	('phosphorylation', 'MPA', (60, 75))	('AMPK', 'molecular_function', 'GO:0050405', ('79', '83'))	('AMPK beta1', 'Gene', '5564', (79, 89))	('phosphorylation', 'biological_process', 'GO:0016310', ('60', '75'))	('AMPK', 'molecular_function', 'GO:0004691', ('79', '83'))	('AMPK', 'molecular_function', 'GO:0047322', ('79', '83'))	('AMPK beta1', 'Gene', (79, 89))	('SBI-0206965', 'Chemical', 'MESH:C000601952', (13, 24))	('SBI-0206965', 'Var', (13, 24))	('inhibit', 'NegReg', (48, 55))
38970	30078736	We cannot completely rule out the possibility that SBI-0206965 inhibits other kinases to promote apoptosis in this study.	('SBI-0206965', 'Chemical', 'MESH:C000601952', (51, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('97', '106'))	('SBI-0206965', 'Var', (51, 62))	('promote', 'PosReg', (89, 96))	('inhibits', 'NegReg', (63, 71))	('apoptosis', 'biological_process', 'GO:0006915', ('97', '106'))	('apoptosis', 'CPA', (97, 106))
38974	30078736	showed that ULK1 knockdown reduces fatty acid oxidation and elevates fatty acid uptake in adipocytes, whereas ULK2 knockdown has the opposite effects.	('fatty acid', 'Chemical', 'MESH:D005227', (35, 45))	('fatty acid', 'Chemical', 'MESH:D005227', (69, 79))	('uptake', 'biological_process', 'GO:0098739', ('80', '86'))	('fatty acid oxidation', 'MPA', (35, 55))	('reduces', 'NegReg', (27, 34))	('ULK2', 'Gene', (110, 114))	('ULK1', 'Gene', (12, 16))	('fatty acid uptake in adipocytes', 'MPA', (69, 100))	('ULK2', 'Gene', '9706', (110, 114))	('ULK1', 'Gene', '8408', (12, 16))	('knockdown', 'Var', (17, 26))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('35', '55'))	('elevates', 'PosReg', (60, 68))	('uptake', 'biological_process', 'GO:0098657', ('80', '86'))
38994	27506904	Inactivation of the tumor suppressor gene von Hippel Lindau, VHL, is a common alteration in sporadic clear cell renal cell carcinomas (ccRCCs).	('ccRCCs', 'Phenotype', 'HP:0006770', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (101, 132))	('VHL', 'Gene', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('RCC', 'Disease', (137, 140))	('Inactivation', 'Var', (0, 12))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (101, 132))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (112, 133))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('20', '36'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (112, 132))	('von Hippel Lindau', 'Disease', (42, 59))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('VHL', 'Gene', '7428', (61, 64))	('renal cell carcinomas', 'Disease', (112, 133))	('tumor suppressor', 'biological_process', 'GO:0051726', ('20', '36'))	('clear cell renal cell carcinoma', 'Disease', (101, 132))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (112, 133))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (101, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('von Hippel Lindau', 'Disease', 'MESH:D006623', (42, 59))	('tumor', 'Disease', (20, 25))
39005	27506904	HDAC 6 translocation to the plasma membrane is associated with membrane estrogen receptor alpha (ERalpha), and deacetylation of alpha-tubulin increases motility of breast tumor cells in vitro.	('HDAC 6', 'Gene', '10013', (0, 6))	('breast tumor', 'Disease', (164, 176))	('HDAC 6', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('increases', 'PosReg', (142, 151))	('alpha-tubulin', 'Gene', (128, 141))	('motility', 'CPA', (152, 160))	('breast tumor', 'Phenotype', 'HP:0100013', (164, 176))	('ERalpha', 'Gene', (97, 104))	('translocation', 'MPA', (7, 20))	('deacetylation', 'Var', (111, 124))	('plasma membrane', 'cellular_component', 'GO:0005886', ('28', '43'))	('estrogen receptor alpha', 'Gene', '2099', (72, 95))	('ERalpha', 'Gene', '2099', (97, 104))	('alpha-tubulin', 'Gene', '10376', (128, 141))	('breast tumor', 'Disease', 'MESH:D001943', (164, 176))	('estrogen receptor alpha', 'Gene', (72, 95))	('membrane', 'cellular_component', 'GO:0016020', ('63', '71'))
39058	27506904	G8898) was added to the media for quenching, followed by washing with PBS and harvesting of the cells with RIPA buffer.	('PBS', 'Disease', 'MESH:D011535', (70, 73))	('PBS', 'Disease', (70, 73))	('G8898', 'Var', (0, 5))	('RIPA buffer', 'Chemical', '-', (107, 118))
39087	27506904	To analyze whether HDAC 1 knockdown affected the invasive capacity of the cells, we utilized BD biocoat matrigel chambers and counted the tumor cells that migrated through the membrane.	('tumor', 'Disease', (138, 143))	('HDAC 1', 'Gene', '3065', (19, 25))	('membrane', 'cellular_component', 'GO:0016020', ('176', '184'))	('knockdown', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('HDAC 1', 'Gene', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
39088	27506904	The studies conducted with 786-0 and C2 renal cancer cell lines showed that knockdown of HDAC 1 led to reduced invasive capacity (Fig.	('HDAC 1', 'Gene', (89, 95))	('knockdown', 'Var', (76, 85))	('reduced', 'NegReg', (103, 110))	('invasive capacity', 'CPA', (111, 128))	('HDAC 1', 'Gene', '3065', (89, 95))	('C2 renal cancer', 'Disease', 'OMIM:217000', (37, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('C2 renal cancer', 'Disease', (37, 52))	('renal cancer', 'Phenotype', 'HP:0009726', (40, 52))
39099	27506904	Western blot analysis revealed that HDAC 1 was differentially expressed in renal tumor cell lines with wild type and non-functional VHL in vitro (Additional file 1: Figure S2a).	('renal tumor', 'Disease', (75, 86))	('VHL', 'Gene', (132, 135))	('HDAC 1', 'Gene', '3065', (36, 42))	('VHL', 'Gene', '7428', (132, 135))	('non-functional', 'Var', (117, 131))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('renal tumor', 'Phenotype', 'HP:0009726', (75, 86))	('renal tumor', 'Disease', 'MESH:D007674', (75, 86))	('HDAC 1', 'Gene', (36, 42))
39102	27506904	The reintroduction of VHL in both cell lines, however, did not significantly alter the proliferation rate (data not shown).	('reintroduction', 'Var', (4, 18))	('VHL', 'Gene', '7428', (22, 25))	('VHL', 'Gene', (22, 25))
39113	27506904	The HIF-2alpha only cell line, 786-0, also demonstrated enrichment for the HDAC 1 promoter region upon HIF-2alpha pull down (Fig.	('HIF-2alpha', 'Gene', (4, 14))	('HIF-2alpha', 'Gene', '2034', (103, 113))	('HIF-2alpha', 'Gene', '2034', (4, 14))	('HDAC 1', 'Gene', '3065', (75, 81))	('pull', 'Var', (114, 118))	('HDAC 1', 'Gene', (75, 81))	('HIF-2alpha', 'Gene', (103, 113))
39115	27506904	In order to explore the possibility of HIF-2alpha playing a dominant role in regulating the expression of HDAC 1, HIF-2alpha was knocked down in both C2 and 786-0 cells.	('HDAC 1', 'Gene', (106, 112))	('HIF-2alpha', 'Gene', (114, 124))	('HIF-2alpha', 'Gene', (39, 49))	('knocked', 'Var', (129, 136))	('HDAC 1', 'Gene', '3065', (106, 112))	('HIF-2alpha', 'Gene', '2034', (39, 49))	('HIF-2alpha', 'Gene', '2034', (114, 124))	('C2', 'Chemical', 'MESH:C023714', (150, 152))
39116	27506904	Silencing of HIF-2alpha in both cell lines dramatically reduced the protein levels of HDAC 1 that corresponded to increased acetylated histone H3, indicating loss of HDAC 1 activity in these cells (Fig.	('HDAC 1', 'Gene', '3065', (166, 172))	('HIF-2alpha', 'Gene', '2034', (13, 23))	('acetylated histone H3', 'MPA', (124, 145))	('reduced', 'NegReg', (56, 63))	('increased', 'PosReg', (114, 123))	('HDAC 1', 'Gene', (86, 92))	('activity', 'MPA', (173, 181))	('HIF-2alpha', 'Gene', (13, 23))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('protein levels', 'MPA', (68, 82))	('HDAC 1', 'Gene', '3065', (86, 92))	('HDAC 1', 'Gene', (166, 172))	('Silencing', 'Var', (0, 9))	('loss', 'NegReg', (158, 162))
39123	27506904	ERalpha knockdown led to increased acetylated alpha-tubulin levels in both 786-0 and C2 cells, as observed by immunofluorescence (Fig.	('increased', 'PosReg', (25, 34))	('ERalpha', 'Gene', (0, 7))	('alpha-tubulin', 'Gene', (46, 59))	('knockdown', 'Var', (8, 17))	('ERalpha', 'Gene', '2099', (0, 7))	('alpha-tubulin', 'Gene', '10376', (46, 59))	('C2', 'Chemical', 'MESH:C023714', (85, 87))
39124	27506904	ERalpha silencing did not have an effect on HDAC 6 expression (as measured by integrated density of immunofluorescent images) (Fig.	('ERalpha', 'Gene', (0, 7))	('ERalpha', 'Gene', '2099', (0, 7))	('silencing', 'Var', (8, 17))	('HDAC 6', 'Gene', '10013', (44, 50))	('HDAC 6', 'Gene', (44, 50))
39125	27506904	However, silencing ERalpha did not affect the proliferation rate of these cells (data not shown).	('silencing', 'Var', (9, 18))	('ERalpha', 'Gene', (19, 26))	('ERalpha', 'Gene', '2099', (19, 26))
39128	27506904	In C2H6 but not in parental C2 cells, single and combination treatments increased HDAC 6 expression (Fig.	('expression', 'MPA', (89, 99))	('increased', 'PosReg', (72, 81))	('C2', 'Chemical', 'MESH:C023714', (3, 5))	('C2H6', 'Chemical', 'MESH:D004980', (3, 7))	('C2', 'Chemical', 'MESH:C023714', (28, 30))	('C2H6', 'Var', (3, 7))	('HDAC 6', 'Gene', '10013', (82, 88))	('HDAC 6', 'Gene', (82, 88))
39144	27506904	The VHL-HIF axis deregulation has been implicated in the activation of several oncogenic pathways in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('VHL-HIF axis', 'Disease', (4, 16))	('VHL-HIF axis', 'Disease', 'MESH:D006623', (4, 16))	('activation', 'PosReg', (57, 67))	('oncogenic pathways', 'Pathway', (79, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('deregulation', 'Var', (17, 29))
39150	27506904	Our study demonstrates that HDAC 1 knockdown reduces the invasive capacity of renal tumor models through decreased MMP activity in these cells.	('MMP', 'molecular_function', 'GO:0004235', ('115', '118'))	('knockdown', 'Var', (35, 44))	('renal tumor', 'Disease', (78, 89))	('HDAC 1', 'Gene', (28, 34))	('reduces', 'NegReg', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('HDAC 1', 'Gene', '3065', (28, 34))	('MMP activity in these', 'CPA', (115, 136))	('renal tumor', 'Phenotype', 'HP:0009726', (78, 89))	('decreased', 'NegReg', (105, 114))	('renal tumor', 'Disease', 'MESH:D007674', (78, 89))
39159	27506904	Chromatin immunoprecipitation assay findings showed that the HDAC 1 promoter region is enriched upon pull down of both HIF isoforms and knockdown of HIF-2alpha in renal tumor cell lines reduced HDAC 1 expression in these cells.	('HDAC 1', 'Gene', '3065', (194, 200))	('Chromatin', 'cellular_component', 'GO:0000785', ('0', '9'))	('HDAC 1', 'Gene', '3065', (61, 67))	('renal tumor', 'Phenotype', 'HP:0009726', (163, 174))	('HIF-2alpha in renal tumor', 'Disease', (149, 174))	('reduced', 'NegReg', (186, 193))	('knockdown', 'Var', (136, 145))	('HIF-2alpha in renal tumor', 'Disease', 'MESH:D007674', (149, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('HDAC 1', 'Gene', (194, 200))	('expression', 'MPA', (201, 211))	('HDAC 1', 'Gene', (61, 67))
39199	31921344	Treatment with pazopanib was associated with inferior OS in comparison with sunitinib (median OS: 30.4 months versus 8.7 months; HR 2.71, 95% CI 1.31-5.58, P = 0.007).	('pazopanib', 'Var', (15, 24))	('pazopanib', 'Chemical', 'MESH:C516667', (15, 24))	('sunitinib', 'Chemical', 'MESH:C473478', (76, 85))	('inferior OS', 'Disease', (45, 56))
39202	31921344	In this patient cohort, pazopanib was associated with inferior OS in comparison with sunitinib for metastatic nccRCC.	('pazopanib', 'Chemical', 'MESH:C516667', (24, 33))	('sunitinib', 'Chemical', 'MESH:C473478', (85, 94))	('metastatic', 'Disease', (99, 109))	('RCC', 'Disease', 'MESH:D002292', (113, 116))	('RCC', 'Disease', (113, 116))	('patient', 'Species', '9606', (8, 15))	('pazopanib', 'Var', (24, 33))	('inferior OS', 'Disease', (54, 65))
39205	31921344	Other RCC variants are classified as non-clear cell RCC (nccRCC), a heterogeneous group of neoplasms composed of several histological variants.	('variants', 'Var', (10, 18))	('RCC', 'Disease', (52, 55))	('RCC', 'Disease', 'MESH:D002292', (52, 55))	('RCC', 'Disease', (60, 63))	('neoplasms', 'Phenotype', 'HP:0002664', (91, 100))	('RCC', 'Disease', 'MESH:D002292', (60, 63))	('neoplasms', 'Disease', 'MESH:D009369', (91, 100))	('RCC', 'Disease', 'MESH:D002292', (6, 9))	('RCC', 'Disease', (6, 9))	('neoplasms', 'Disease', (91, 100))
39266	31921344	The present study suggests that patients with metastatic nccRCC have inferior OS when treated with pazopanib in comparison with sunitinib (median OS: 30.4 months versus 8.7 months; P = 0.005).	('sunitinib', 'Chemical', 'MESH:C473478', (128, 137))	('pazopanib', 'Chemical', 'MESH:C516667', (99, 108))	('patients', 'Species', '9606', (32, 40))	('RCC', 'Disease', (60, 63))	('pazopanib', 'Var', (99, 108))	('RCC', 'Disease', 'MESH:D002292', (60, 63))
39268	31921344	This subgroup analysis showed that pazopanib was associated with inferior PFS (median: 8.9 months versus 5.1 months; P = 0.011) and OS (median: 38.7 months versus 14.7 months; P = 0.015) in patients with papillary, chromophobe and MiT family translocation subtypes.	('PFS', 'CPA', (74, 77))	('patients', 'Species', '9606', (190, 198))	('papillary', 'Disease', (204, 213))	('pazopanib', 'Chemical', 'MESH:C516667', (35, 44))	('chromophobe', 'Disease', (215, 226))	('MiT family translocation', 'Disease', (231, 255))	('inferior', 'NegReg', (65, 73))	('pazopanib', 'Var', (35, 44))
39293	31921344	In conclusion, in this single-centre retrospective cohort, pazopanib was associated with inferior OS in comparison with sunitinib as first-line treatment for metastatic nccRCC.	('pazopanib', 'Chemical', 'MESH:C516667', (59, 68))	('sunitinib', 'Chemical', 'MESH:C473478', (120, 129))	('pazopanib', 'Var', (59, 68))	('RCC', 'Disease', 'MESH:D002292', (172, 175))	('RCC', 'Disease', (172, 175))	('inferior OS', 'Disease', (89, 100))
39301	31294899	Inhibition of miR-34a-5p can rescue disruption of the p53-DAPK axis to suppress progression of clear cell renal cell carcinoma DAPK, a transcriptional target of the p53 protein, has long been characterized as a tumor suppressor that acts as a negative regulator in multiple cellular processes.	('miR-34a', 'Gene', (14, 21))	('tumor', 'Disease', (211, 216))	('miR-34a', 'Gene', '407040', (14, 21))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (95, 126))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('clear cell renal cell carcinoma', 'Disease', (95, 126))	('DAPK', 'Gene', (58, 62))	('p53', 'Gene', '7157', (54, 57))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (106, 126))	('p53', 'Gene', '7157', (165, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('DAPK', 'Gene', (127, 131))	('DAPK', 'Gene', '1612', (58, 62))	('p53', 'Gene', (54, 57))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('211', '227'))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('Inhibition', 'Var', (0, 10))	('suppress', 'NegReg', (71, 79))	('progression', 'MPA', (80, 91))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (95, 126))	('p53', 'Gene', (165, 168))	('tumor suppressor', 'biological_process', 'GO:0051726', ('211', '227'))	('DAPK', 'Gene', '1612', (127, 131))
39310	31294899	miR-34a-5p was identified as a novel repressor of DAPK acting downstream of p53.	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('miR-34a-5p', 'Var', (0, 10))	('DAPK', 'Gene', (50, 54))	('DAPK', 'Gene', '1612', (50, 54))
39311	31294899	Inhibition of miR-34a-5p can correct the p53-DAPK axis disruption by upregulating DAPK protein and may have potential to be used as a therapeutic target to improve outcomes for ccRCC patients.	('p53', 'Gene', '7157', (41, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (177, 182))	('DAPK', 'Gene', (82, 86))	('DAPK', 'Gene', '1612', (82, 86))	('DAPK', 'Gene', (45, 49))	('DAPK', 'Gene', '1612', (45, 49))	('miR-34a-5p', 'Gene', (14, 24))	('RCC', 'Disease', 'MESH:D002292', (179, 182))	('upregulating', 'PosReg', (69, 81))	('Inhibition', 'Var', (0, 10))	('patients', 'Species', '9606', (183, 191))	('RCC', 'Phenotype', 'HP:0005584', (179, 182))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('p53', 'Gene', (41, 44))	('RCC', 'Disease', (179, 182))
39315	31294899	Thus far, TP53 is the most studied tumor suppressor gene found to be mutated in approximately 50% of human cancers (Vousden and Lane, 2007).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('TP53', 'Gene', (10, 14))	('mutated', 'Var', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('tumor', 'Disease', (35, 40))	('human', 'Species', '9606', (101, 106))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('TP53', 'Gene', '7157', (10, 14))
39362	31294899	The pGL3 luciferase reporter constructs with the genomic region of human DAPK that contain the miR-34a-5p binding site were constructed by GenePharma, and pGL3 reporters with mutant miR-34a-5p binding sites and pGL3 reporters without binding sites were used as a control.	('miR-34a-5p', 'Gene', (182, 192))	('pGL3', 'Gene', (155, 159))	('binding', 'molecular_function', 'GO:0005488', ('193', '200'))	('binding', 'molecular_function', 'GO:0005488', ('106', '113'))	('binding', 'molecular_function', 'GO:0005488', ('234', '241'))	('pGL', 'molecular_function', 'GO:0004598', ('4', '7'))	('pGL3', 'Gene', (211, 215))	('pGL3', 'Gene', '6391', (4, 8))	('DAPK', 'Gene', (73, 77))	('DAPK', 'Gene', '1612', (73, 77))	('pGL3', 'Gene', '6391', (155, 159))	('pGL', 'molecular_function', 'GO:0004598', ('155', '158'))	('binding', 'Interaction', (193, 200))	('human', 'Species', '9606', (67, 72))	('pGL', 'molecular_function', 'GO:0004598', ('211', '214'))	('pGL3', 'Gene', '6391', (211, 215))	('mutant', 'Var', (175, 181))	('pGL3', 'Gene', (4, 8))
39363	31294899	The wild-type or mutant constructs (2.0 mug/well in 6-well plates) of DAPK were transfected into 293T cells together with miR-34a-5p mimics (50 nm) or the negative control (50 nm).	('mug', 'molecular_function', 'GO:0043739', ('40', '43'))	('mutant', 'Var', (17, 23))	('DAPK', 'Gene', (70, 74))	('DAPK', 'Gene', '1612', (70, 74))
39404	31294899	In the colony formation assay, cell colonies were stained and counted 10 days after plating 786-O cells infected with sh-DAPK vectors, DAPK-overexpressing cells, and control cells.	('DAPK', 'Gene', (121, 125))	('DAPK', 'Gene', '1612', (121, 125))	('vectors', 'Var', (126, 133))	('formation', 'biological_process', 'GO:0009058', ('14', '23'))	('DAPK', 'Gene', (135, 139))	('DAPK', 'Gene', '1612', (135, 139))
39406	31294899	Likewise, the EdU staining assay indicated that DAPK knockdown increased the percentage of EdU-positive cells, whereas DAPK overexpression reduced the percentage of EdU-positive cells (Fig.	('EdU-positive cells', 'CPA', (91, 109))	('DAPK', 'Gene', '1612', (119, 123))	('increased', 'PosReg', (63, 72))	('DAPK', 'Gene', (119, 123))	('knockdown', 'Var', (53, 62))	('DAPK', 'Gene', (48, 52))	('DAPK', 'Gene', '1612', (48, 52))	('expression', 'Species', '29278', (128, 138))
39411	31294899	The IHC results showed the percentage of Ki67-positive cells was highest in the sh-DAPK group, while the percentage of Ki67-positive cells was lowest in the DAPK-overexpressing group (Fig.	('Ki67-positive', 'Var', (41, 54))	('DAPK', 'Gene', (157, 161))	('DAPK', 'Gene', '1612', (157, 161))	('DAPK', 'Gene', '1612', (83, 87))	('DAPK', 'Gene', (83, 87))
39415	31294899	However, ectopic expression of DAPK inhibited the migration of renal cancer cells.	('ectopic expression', 'Var', (9, 27))	('inhibited', 'NegReg', (36, 45))	('expression', 'Species', '29278', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('renal cancer', 'Phenotype', 'HP:0009726', (63, 75))	('DAPK', 'Gene', (31, 35))	('DAPK', 'Gene', '1612', (31, 35))	('migration of renal cancer', 'Disease', (50, 75))	('migration of renal cancer', 'Disease', 'MESH:D007680', (50, 75))
39418	31294899	Of note, findings from the wound-healing assay showed that stable DAPK knockdown promoted the migration of both 786-O and ACHN cells irrespective of whether Z-VAD-FMK was used (Fig.	('Z-VAD-FMK', 'Chemical', 'MESH:C517629', (157, 166))	('wound-healing', 'biological_process', 'GO:0042060', ('27', '40'))	('ACHN', 'Gene', '55323', (122, 126))	('migration', 'CPA', (94, 103))	('promoted', 'PosReg', (81, 89))	('knockdown', 'Var', (71, 80))	('DAPK', 'Gene', (66, 70))	('DAPK', 'Gene', '1612', (66, 70))	('ACHN', 'Gene', (122, 126))
39438	31294899	However, the kinetics of DAPK mRNA were not subjected to the same regulation by p53 activation or knockdown.	('regulation', 'biological_process', 'GO:0065007', ('66', '76'))	('DAPK', 'Gene', (25, 29))	('DAPK', 'Gene', '1612', (25, 29))	('p53', 'Gene', (80, 83))	('knockdown', 'Var', (98, 107))	('p53', 'Gene', '7157', (80, 83))
39450	31294899	Among these miRNAs, miR-34a-5p is specifically regulated by the functional p53.	('miR', 'Gene', (12, 15))	('miR', 'Gene', '220972', (20, 23))	('miR', 'Gene', (20, 23))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('regulated by', 'Reg', (47, 59))	('miR', 'Gene', '220972', (12, 15))	('functional', 'Var', (64, 74))
39462	31294899	Then, we treated renal cancer cells with doxorubicin or both doxorubicin and miR-34 inhibitors, and we found that miR-34a inhibitors rescued the ability of doxorubicin to upregulate DAPK protein.	('miR-34', 'Gene', (114, 120))	('doxorubicin', 'Chemical', 'MESH:D004317', (156, 167))	('renal cancer', 'Disease', 'MESH:D007680', (17, 29))	('doxorubicin', 'Chemical', 'MESH:D004317', (61, 72))	('renal cancer', 'Phenotype', 'HP:0009726', (17, 29))	('upregulate', 'PosReg', (171, 181))	('inhibitors', 'Var', (122, 132))	('miR-34', 'Gene', '407040', (114, 120))	('miR-34', 'Gene', (77, 83))	('DAPK', 'Gene', (182, 186))	('DAPK', 'Gene', '1612', (182, 186))	('doxorubicin', 'Chemical', 'MESH:D004317', (41, 52))	('miR-34', 'Gene', '407040', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('renal cancer', 'Disease', (17, 29))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))
39465	31294899	The findings from these studies indicated that miR-34a can suppress the translation of DAPK protein by binding directly to the 3'-UTR of DAPK mRNA.	('translation', 'biological_process', 'GO:0006412', ('72', '83'))	('DAPK', 'Gene', (137, 141))	('DAPK', 'Gene', '1612', (137, 141))	('binding', 'Interaction', (103, 110))	('binding', 'molecular_function', 'GO:0005488', ('103', '110'))	('DAPK', 'Gene', (87, 91))	('DAPK', 'Gene', '1612', (87, 91))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('translation', 'MPA', (72, 83))	('suppress', 'NegReg', (59, 67))	('miR-34a', 'Var', (47, 54))
39469	31294899	Apoptotic assays showed that miR-34a inhibitors increased the percentage of cell death induced by doxorubicin or p53 overexpression (Fig.	('death', 'Disease', 'MESH:D003643', (81, 86))	('increased', 'PosReg', (48, 57))	('inhibitors', 'Var', (37, 47))	('expression', 'Species', '29278', (121, 131))	('death', 'Disease', (81, 86))	('doxorubicin', 'Chemical', 'MESH:D004317', (98, 109))	('miR-34a', 'Gene', (29, 36))	('p53', 'Gene', '7157', (113, 116))	('overexpression', 'PosReg', (117, 131))	('p53', 'Gene', (113, 116))	('cell death', 'biological_process', 'GO:0008219', ('76', '86'))
39476	31294899	Although tumors treated with antagomiR-34a were slightly smaller than tumors in the control group, the combined treatment inhibited the growth of tumor remarkably.	('smaller', 'NegReg', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('antagomiR-34a', 'Var', (29, 42))	('inhibited', 'NegReg', (122, 131))	('tumor', 'Disease', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (146, 151))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumor', 'Disease', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
39477	31294899	Furthermore, immunoblot analysis of the excised tumors showed antagomiR-34a with or without doxorubicin increased DAPK protein expression in xenograft tumors, and the combined treatment induced marked cleavage of the PARP (Fig.	('expression', 'Species', '29278', (127, 137))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('cleavage', 'MPA', (201, 209))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('PARP', 'Gene', '142', (217, 221))	('DAPK', 'Gene', (114, 118))	('antagomiR-34a', 'Var', (62, 75))	('expression', 'MPA', (127, 137))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('PARP', 'Gene', (217, 221))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('DAPK', 'Gene', '1612', (114, 118))	('increased', 'PosReg', (104, 113))	('doxorubicin', 'Chemical', 'MESH:D004317', (92, 103))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
39486	31294899	The upregulation of miR-34a induced by activated p53 inhibited the translation of DAPK protein, thus compromising the tumor-suppressive role of the p53-DAPK pathway.	('p53', 'Gene', '7157', (49, 52))	('inhibited', 'NegReg', (53, 62))	('translation', 'MPA', (67, 78))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('translation', 'biological_process', 'GO:0006412', ('67', '78'))	('p53', 'Gene', (49, 52))	('DAPK', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('DAPK', 'Gene', (152, 156))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('compromising', 'NegReg', (101, 113))	('DAPK', 'Gene', '1612', (82, 86))	('p53', 'Gene', '7157', (148, 151))	('DAPK', 'Gene', '1612', (152, 156))	('activated', 'Var', (39, 48))	('upregulation', 'PosReg', (4, 16))	('p53', 'Gene', (148, 151))	('tumor', 'Disease', (118, 123))	('miR-34a', 'Protein', (20, 27))
39504	31294899	Although most published studies have characterized miR-34a as a tumor suppressor, some studies have reported a contrasting function of miR-34a (Dutta et al., 2007; Krause et al., 2016; Pu et al., 2017).	('tumor', 'Disease', (64, 69))	('tumor suppressor', 'biological_process', 'GO:0051726', ('64', '80'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('64', '80'))	('miR-34a', 'Var', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
39505	31294899	In this study, DAPK was found to be a tumor suppressor in ccRCC; thus, miR-34a played a tumor-promoting role by inhibiting DAPK translation.	('DAPK', 'Gene', (123, 127))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('38', '54'))	('DAPK', 'Gene', '1612', (123, 127))	('RCC', 'Disease', 'MESH:D002292', (60, 63))	('tumor', 'Disease', (88, 93))	('tumor suppressor', 'biological_process', 'GO:0051726', ('38', '54'))	('inhibiting', 'NegReg', (112, 122))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('miR-34a', 'Var', (71, 78))	('DAPK', 'Gene', (15, 19))	('tumor', 'Disease', (38, 43))	('translation', 'biological_process', 'GO:0006412', ('128', '139'))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('DAPK', 'Gene', '1612', (15, 19))
39506	31294899	In addition, the tumor-promoting role of miR-34a was only evident when the p53 was activated or upregulated, whereas in unstressed cells, its effect on apoptosis or cell growth was nonsignificant.	('miR-34a', 'Var', (41, 48))	('tumor', 'Disease', (17, 22))	('apoptosis', 'biological_process', 'GO:0097194', ('152', '161'))	('apoptosis', 'biological_process', 'GO:0006915', ('152', '161'))	('upregulated', 'PosReg', (96, 107))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('activated', 'PosReg', (83, 92))	('cell growth', 'biological_process', 'GO:0016049', ('165', '176'))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
39509	31294899	miR-34 inhibitors can rescue the disrupted p53-DAPK pathway and be used as a potential therapeutic target to improve the treatment and prognosis of ccRCC patients.	('DAPK', 'Gene', (47, 51))	('DAPK', 'Gene', '1612', (47, 51))	('improve', 'PosReg', (109, 116))	('miR-34', 'Gene', '407040', (0, 6))	('RCC', 'Disease', 'MESH:D002292', (150, 153))	('RCC', 'Disease', (150, 153))	('inhibitors', 'Var', (7, 17))	('patients', 'Species', '9606', (154, 162))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('ccRCC', 'Phenotype', 'HP:0006770', (148, 153))	('rescue', 'PosReg', (22, 28))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('miR-34', 'Gene', (0, 6))
39525	31417274	When EZH2 was knocked down in 769P and OS-RC-2 cells overexpressing LINC-PINT, the effect of LINC-PINT on cell proliferation, cell cycle, and apoptosis was partially reversed.	('cell proliferation', 'CPA', (106, 124))	('cell cycle', 'CPA', (126, 136))	('LINC-PINT', 'Gene', '378805', (93, 102))	('OS-RC-2', 'CellLine', 'CVCL:1626', (39, 46))	('cell proliferation', 'biological_process', 'GO:0008283', ('106', '124'))	('LINC-PINT', 'Gene', (68, 77))	('knocked down', 'Var', (14, 26))	('LINC-PINT', 'Gene', (93, 102))	('EZH2', 'Gene', '2146', (5, 9))	('apoptosis', 'CPA', (142, 151))	('apoptosis', 'biological_process', 'GO:0097194', ('142', '151'))	('apoptosis', 'biological_process', 'GO:0006915', ('142', '151'))	('EZH2', 'Gene', (5, 9))	('cell cycle', 'biological_process', 'GO:0007049', ('126', '136'))	('LINC-PINT', 'Gene', '378805', (68, 77))
39526	31417274	Additionally, inducing p53 by doxorubicin (Dox) promoted LINC-PINT expression.	('LINC-PINT', 'Gene', (57, 66))	('doxorubicin', 'Chemical', 'MESH:D004317', (30, 41))	('inducing', 'Var', (14, 22))	('p53', 'Gene', '7157', (23, 26))	('p53', 'Gene', (23, 26))	('Dox', 'Chemical', 'MESH:D004317', (43, 46))	('promoted', 'PosReg', (48, 56))	('LINC-PINT', 'Gene', '378805', (57, 66))
39536	31417274	For example, high expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes migration by actively regulating the expression of a set of metastasis-associated genes and is highly predictive of poor outcome of early stage non-small cell lung cancer.	('cell lung cancer', 'Disease', 'MESH:D008175', (259, 275))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (54, 73))	('expression of a set of', 'MPA', (142, 164))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('regulating', 'Reg', (127, 137))	('high expression', 'Var', (13, 28))	('promotes', 'PosReg', (96, 104))	('MALAT1', 'Gene', '378938', (88, 94))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (253, 275))	('lung cancer', 'Phenotype', 'HP:0100526', (264, 275))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (249, 275))	('MALAT1', 'Gene', (88, 94))	('migration', 'CPA', (105, 114))	('cell lung cancer', 'Disease', (259, 275))	('metastasis-associated lung adenocarcinoma transcript 1', 'Gene', '378938', (32, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))
39538	31417274	Loss of HOTAIR in epithelial cancer cells inhibits invasiveness in a polycomb repressive complex 2 (PRC2)-dependent manner.	('epithelial cancer', 'Disease', (18, 35))	('epithelial cancer', 'Disease', 'MESH:D000077216', (18, 35))	('HOTAIR', 'Gene', (8, 14))	('inhibits', 'NegReg', (42, 50))	('HOTAIR', 'Gene', '100124700', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('epithelial cancer', 'Phenotype', 'HP:0031492', (18, 35))	('Loss', 'Var', (0, 4))	('invasiveness', 'CPA', (51, 63))
39584	31417274	Next, to identify the LINC-PINT transcript variant most potently upregulated in ccRCC, we performed reverse transcription (RT)-PCR using different primer pairs (Table 1; Figure 1A).	('LINC-PINT', 'Gene', (22, 31))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('variant', 'Var', (43, 50))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('upregulated', 'PosReg', (65, 76))	('reverse transcription', 'biological_process', 'GO:0001171', ('100', '121'))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('LINC-PINT', 'Gene', '378805', (22, 31))
39585	31417274	RT-PCR revealed that transcript variant 1 was the most abundant transcript variant in ccRCC (Figure 1B).	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('transcript variant 1', 'Var', (21, 41))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))
39588	31417274	Furthermore, the level of LINC-PINT was significantly higher in ccRCC cell lines (786-O, A498, 769P, Caki-2, Caki-1, ACHN, OS-RC-2, and SN12-PM6) than in human HKC renal proximal tubule epithelial cell line (Figure 2B).	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('ACHN', 'Gene', (117, 121))	('769P', 'Var', (95, 99))	('human', 'Species', '9606', (154, 159))	('higher', 'PosReg', (54, 60))	('LINC-PINT', 'Gene', (26, 35))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('ACHN', 'Gene', '55323', (117, 121))	('OS-RC-2', 'CellLine', 'CVCL:1626', (123, 130))	('LINC-PINT', 'Gene', '378805', (26, 35))	('RCC', 'Disease', (66, 69))	('A498', 'Var', (89, 93))
39589	31417274	Although there were no significant correlations between LINC-PINT expression level and age, body mass index, tumor size, or Fuhrman stage, aberrant expression level of LINC-PINT was more frequently observed in ccRCC patients with pT3 and pT4 or TNM-III and -IV stage tumors than in those with pT1 and pT2 or TNM-I and -II stage tumors and in males than in females (Table 2).	('TNM', 'Gene', (245, 248))	('LINC-PINT', 'Gene', '378805', (168, 177))	('TNM', 'Gene', (308, 311))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('LINC-PINT', 'Gene', '378805', (56, 65))	('pT3', 'Gene', '7694', (230, 233))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('RCC', 'Phenotype', 'HP:0005584', (212, 215))	('ccRCC', 'Phenotype', 'HP:0006770', (210, 215))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('tumor', 'Disease', (328, 333))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('observed', 'Reg', (198, 206))	('stage tumors', 'Disease', (261, 273))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('stage tumors', 'Disease', 'MESH:D062706', (261, 273))	('expression level', 'MPA', (148, 164))	('pT3', 'Gene', (230, 233))	('patients', 'Species', '9606', (216, 224))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('tumors', 'Phenotype', 'HP:0002664', (328, 334))	('pT1', 'Gene', '58492', (293, 296))	('stage tumors', 'Disease', (322, 334))	('pT1', 'Gene', (293, 296))	('LINC-PINT', 'Gene', (56, 65))	('stage tumors', 'Disease', 'MESH:D062706', (322, 334))	('LINC-PINT', 'Gene', (168, 177))	('tumor', 'Disease', (267, 272))	('RCC', 'Disease', (212, 215))	('TNM', 'Gene', '10178', (245, 248))	('TNM', 'Gene', '10178', (308, 311))	('aberrant', 'Var', (139, 147))	('tumor', 'Disease', (109, 114))
39596	31417274	LINC-PINT overexpression plasmids significantly increased LINC-PINT levels in 769P and OS-RC-2 cells (Figure 3A).	('increased', 'PosReg', (48, 57))	('OS-RC-2', 'CellLine', 'CVCL:1626', (87, 94))	('LINC-PINT', 'Gene', '378805', (58, 67))	('LINC-PINT', 'Gene', (0, 9))	('LINC-PINT', 'Gene', (58, 67))	('plasmids', 'Var', (25, 33))	('LINC-PINT', 'Gene', '378805', (0, 9))
39609	31417274	Next, we designed two EZH2-specific siRNAs to knockdown EZH2 in 769P and OS-RC-2 cells.	('OS-RC-2', 'CellLine', 'CVCL:1626', (73, 80))	('EZH2', 'Gene', (22, 26))	('knockdown', 'Var', (46, 55))	('EZH2', 'Gene', '2146', (56, 60))	('EZH2', 'Gene', (56, 60))	('EZH2', 'Gene', '2146', (22, 26))
39614	31417274	EZH2 silencing partially reversed changes in cell proliferation, cell cycle, and apoptosis induced by LINC-PINT overexpression (Figure 5E-G).	('apoptosis', 'biological_process', 'GO:0006915', ('81', '90'))	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('apoptosis', 'CPA', (81, 90))	('silencing', 'Var', (5, 14))	('cell proliferation', 'CPA', (45, 63))	('cell cycle', 'CPA', (65, 75))	('LINC-PINT', 'Gene', (102, 111))	('cell proliferation', 'biological_process', 'GO:0008283', ('45', '63'))	('apoptosis', 'biological_process', 'GO:0097194', ('81', '90'))	('LINC-PINT', 'Gene', '378805', (102, 111))	('cell cycle', 'biological_process', 'GO:0007049', ('65', '75'))
39622	31417274	Genetically, ccRCC has been characterized with a very high frequency of biallelic VHL inactivation occurring through allelic deletion or loss of heterozygosity on 3p.	('loss of heterozygosity', 'Var', (137, 159))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('RCC', 'Disease', (15, 18))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('VHL', 'Gene', (82, 85))	('inactivation', 'NegReg', (86, 98))	('VHL', 'Gene', '7428', (82, 85))	('biallelic', 'Var', (72, 81))
39623	31417274	Hypermethylation of enhancer and promoter CpGs of the genes encoding wingless/integrated (Wnt) antagonists in ccRCC, such as secreted frizzled related protein 1 (SFRP1), SFRP2, SFRP5, and WNT inhibitory factor 1 (WIF-1), decreases their expression and inhibits ccRCC cell proliferation.	('WIF-1', 'Gene', (213, 218))	('secreted frizzled related protein 1', 'Gene', '6422', (125, 160))	('SFRP5', 'Gene', '6425', (177, 182))	('SFRP1', 'Gene', '6422', (162, 167))	('Hypermethylation', 'Var', (0, 16))	('SFRP2', 'Gene', '6423', (170, 175))	('SFRP5', 'Gene', (177, 182))	('WNT inhibitory factor 1', 'Gene', '11197', (188, 211))	('WNT inhibitory factor 1', 'Gene', (188, 211))	('SFRP2', 'Gene', (170, 175))	('inhibits', 'NegReg', (252, 260))	('expression', 'MPA', (237, 247))	('RCC', 'Disease', (263, 266))	('RCC', 'Phenotype', 'HP:0005584', (263, 266))	('RCC', 'Disease', (112, 115))	('SFRP1', 'Gene', (162, 167))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (261, 266))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))	('cell proliferation', 'biological_process', 'GO:0008283', ('267', '285'))	('decreases', 'NegReg', (221, 230))	('WIF-1', 'Gene', '11197', (213, 218))	('RCC', 'Disease', 'MESH:C538614', (263, 266))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('secreted frizzled related protein 1', 'Gene', (125, 160))
39643	31417274	Further experiments revealed that knockdown of EZH2 partially rescued the effects induced by LINC-PINT overexpression.	('effects', 'MPA', (74, 81))	('EZH2', 'Gene', (47, 51))	('LINC-PINT', 'Gene', '378805', (93, 102))	('LINC-PINT', 'Gene', (93, 102))	('knockdown', 'Var', (34, 43))	('EZH2', 'Gene', '2146', (47, 51))
39709	31703694	We then examined the prognostic value of the expressions of the AQP family members in ccRCC and found that patients with high AQP9 expression had poor survival.	('patients', 'Species', '9606', (107, 115))	('AQP9', 'Gene', (126, 130))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('AQP9', 'Gene', '366', (126, 130))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('ccRCC', 'Disease', (86, 91))	('examined', 'Reg', (8, 16))	('high', 'Var', (121, 125))	('poor', 'NegReg', (146, 150))	('ccRCC', 'Disease', 'MESH:D002292', (86, 91))
39720	31703694	AQP9 expression was also significantly higher in ccRCC primary tumors in comparison with adjacent normal tissues in GSE11151 (Yusenko Renal dataset; ***p < 0.001), GSE14994 (Beroukhim Renal dataset; *p < 0.05) and GSE6344 (Gumz Renal dataset; *p < 0.05) (Fig.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('ccRCC', 'Disease', 'MESH:D002292', (49, 54))	('expression', 'MPA', (5, 15))	('higher', 'PosReg', (39, 45))	('AQP9', 'Gene', (0, 4))	('GSE6344', 'Chemical', 'MESH:C081303', (214, 221))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('AQP9', 'Gene', '366', (0, 4))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('ccRCC', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('GSE11151', 'Var', (116, 124))	('GSE14994', 'Var', (164, 172))
39733	31703694	Importantly, AQP9 amplification markedly correlated with poor PFS (TCGA: hazard ratio [HR] = 8.141, p < 0.001; FUSCC: HR = 2.593, p < 0.001) and poor OS (TCGA: HR = 2.262, p < 0.001, FUSCC: HR = 2.774, p < 0.001).	('poor', 'NegReg', (57, 61))	('PFS', 'MPA', (62, 65))	('AQP9', 'Gene', '366', (13, 17))	('poor', 'Disease', (145, 149))	('amplification', 'Var', (18, 31))	('AQP9', 'Gene', (13, 17))
39738	31703694	For high AQP9 expression patients, the median PFS was 39.5 months and the median OS was 59.5 months.	('AQP9', 'Gene', (9, 13))	('high', 'Var', (4, 8))	('patients', 'Species', '9606', (25, 33))	('AQP9', 'Gene', '366', (9, 13))
39739	31703694	For low AQP9 expression patients, the median PFS was 66 months and the median OS was 72 months.	('AQP9', 'Gene', '366', (8, 12))	('patients', 'Species', '9606', (24, 32))	('AQP9', 'Gene', (8, 12))	('low', 'Var', (4, 7))
39755	31703694	7b-g. Cancer genetics as well as abnormal epigenetic regulation have been found to participate in the progression and tumor environment for ccRCC.	('participate', 'Reg', (83, 94))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('ccRCC', 'Disease', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Cancer', 'Phenotype', 'HP:0002664', (6, 12))	('regulation', 'biological_process', 'GO:0065007', ('53', '63'))	('epigenetic regulation', 'MPA', (42, 63))	('tumor', 'Disease', (118, 123))	('abnormal', 'Var', (33, 41))	('ccRCC', 'Disease', 'MESH:D002292', (140, 145))
39760	31703694	Our data also indicated that high levels of AQP9 protein expression correlated with a high risk of recurrence and reduction in patient survival.	('reduction', 'NegReg', (114, 123))	('AQP9', 'Gene', '366', (44, 48))	('patient', 'Species', '9606', (127, 134))	('AQP9', 'Gene', (44, 48))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('high levels', 'Var', (29, 40))	('patient survival', 'CPA', (127, 143))
39761	31703694	These results reveal a new way for AQP9 expression to influence the pathogenesis of RCC through potential DNA damage variants.	('AQP9', 'Gene', '366', (35, 39))	('pathogenesis', 'biological_process', 'GO:0009405', ('68', '80'))	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('AQP9', 'Gene', (35, 39))	('variants', 'Var', (117, 125))	('RCC', 'Disease', (84, 87))	('RCC', 'Disease', 'MESH:D002292', (84, 87))	('influence', 'Reg', (54, 63))
39797	29335443	Multiple truncal alterations, including TP53 mutations and loss of CDKN2A and RB1, converge on cell cycle dysregulation, with late sector-specific high-amplitude amplifications and deletions that potentially beget drug resistant clones.	('RB1', 'Gene', '5925', (78, 81))	('mutations', 'Var', (45, 54))	('CDKN2A', 'Gene', (67, 73))	('cell', 'MPA', (95, 99))	('deletions', 'Var', (181, 190))	('CDKN2A', 'Gene', '1029', (67, 73))	('cell cycle', 'biological_process', 'GO:0007049', ('95', '105'))	('cell cycle dysregulation', 'Phenotype', 'HP:0011018', (95, 119))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('RB1', 'Gene', (78, 81))	('loss', 'NegReg', (59, 63))	('drug resistant clones', 'CPA', (214, 235))
39799	29335443	EGFR mutant lung adenocarcinoma (LUAD) exhibit diverse clinical outcomes in response to targeted therapies.	('EGFR', 'Gene', (0, 4))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (12, 31))	('lung adenocarcinoma', 'Disease', (12, 31))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (12, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('LUAD', 'Phenotype', 'HP:0030078', (33, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('mutant', 'Var', (5, 11))	('EGFR', 'Gene', '1956', (0, 4))
39802	29335443	Activating mutations in the epidermal growth factor receptor (EGFR) are the most common therapeutically tractable driver mutation in lung adenocarcinomas (LUAD) with distinct ethnic differences, occurring at higher frequencies in Asians (40-60%) compared to Caucasians (7-10%).	('EGFR', 'Gene', '1956', (62, 66))	('Activating mutations', 'Var', (0, 20))	('LUAD', 'Phenotype', 'HP:0030078', (155, 159))	('epidermal growth factor receptor', 'Gene', (28, 60))	('EGFR', 'Gene', (62, 66))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (133, 152))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('28', '51'))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))	('lung adenocarcinomas', 'Disease', (133, 153))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (133, 153))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (133, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('epidermal growth factor receptor', 'Gene', '1956', (28, 60))
39804	29335443	On the contrary, the copy number landscape has been shown to harbor considerable genomic complexity, although the extent to which these observations are confounded by intra-tumor heterogeneity (ITH) is unclear.	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('intra-tumor', 'Disease', (167, 178))	('intra-tumor', 'Disease', 'MESH:D009369', (167, 178))	('copy', 'Var', (21, 25))
39807	29335443	On the other hand, late diversification was contributed by branch/private driver alterations (mutations present in few but not all regions of tumor/present in single region of tumor) and increased APOBEC activity, representing evolutionary processes that are potentially amenable to therapeutic targeting.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('APOBEC', 'Protein', (197, 203))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (176, 181))	('alterations', 'Var', (81, 92))	('increased', 'PosReg', (187, 196))	('APOBEC', 'cellular_component', 'GO:0030895', ('197', '203'))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
39813	29335443	Through integrative genomics, we show that early EGFR and TP53 mutations are often followed by genome doubling events, with ongoing genomic instability typified by a variegated copy number landscape and late high-amplitude amplifications and deletions.	('mutations', 'Var', (63, 72))	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('TP53', 'Gene', '7157', (58, 62))	('EGFR', 'Gene', (49, 53))	('TP53', 'Gene', (58, 62))	('genome doubling', 'MPA', (95, 110))	('followed by', 'Reg', (83, 94))
39818	29335443	EGFR mutations were confirmed to be truncal events (mutations present in all sectors of a tumor) in every case regardless of the mutation type (L858R, exon 19 deletion or exon 20 insertion), underscoring its role as an early tumor initiating driver event (Fig.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('EGFR', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', (225, 230))	('L858R', 'Mutation', 'rs121434568', (144, 149))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
39819	29335443	Besides EGFR, TP53 was the most recurrently mutated gene with mutations in 9 out of 16 tumors, of which eight were truncal events (Fig.	('TP53', 'Gene', '7157', (14, 18))	('EGFR', 'molecular_function', 'GO:0005006', ('8', '12'))	('TP53', 'Gene', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('EGFR', 'Gene', '1956', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('EGFR', 'Gene', (8, 12))	('mutations', 'Var', (62, 71))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
39822	29335443	Interestingly, both CTNNB1 mutations (S37C and K335I, Supplementary Data 1) are known to be oncogenic and deregulate beta-catenin activity possibly contributing to EGFR-mediated tumorigenesis.	('K335I', 'Mutation', 'p.K335I', (47, 52))	('beta-catenin', 'Gene', (117, 129))	('tumor', 'Disease', (178, 183))	('EGFR', 'Gene', (164, 168))	('CTNNB1', 'Gene', (20, 26))	('EGFR', 'molecular_function', 'GO:0005006', ('164', '168'))	('S37C', 'Var', (38, 42))	('beta-catenin', 'Gene', '1499', (117, 129))	('CTNNB1', 'Gene', '1499', (20, 26))	('deregulate', 'NegReg', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('S37C', 'Mutation', 'rs121913403', (38, 42))	('EGFR', 'Gene', '1956', (164, 168))	('K335I', 'Var', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
39823	29335443	For example, the private mutation affecting D323 residue of AKT1 (found in A001, Fig.	('AKT1', 'Gene', '207', (60, 64))	('AKT1', 'Gene', (60, 64))	('D323 residue', 'Var', (44, 56))
39825	29335443	Loss-of-function of MED12 has been implicated in resistance to EGFR TKIs suggesting that the truncal MED12 frameshift deletions in A006 and the private MED12 mis-sense mutation (predicted to be damaging; Supplementary Data 1, 2) in A021 might be candidates for resistance inducing mutations.	('EGFR', 'Gene', '1956', (63, 67))	('Loss-of-function', 'NegReg', (0, 16))	('MED12', 'Gene', '9968', (152, 157))	('frameshift deletions', 'Var', (107, 127))	('MED12', 'Gene', '9968', (101, 106))	('EGFR', 'Gene', (63, 67))	('MED12', 'Gene', (20, 25))	('mis-sense', 'Var', (158, 167))	('MED12', 'Gene', (152, 157))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('MED12', 'Gene', '9968', (20, 25))	('MED12', 'Gene', (101, 106))
39826	29335443	However, we did not find any common resistance mutations like the T790M in EGFR, in any sector, likely due to their rare occurrence in treatment naive samples that are beyond the detection limits of our sequencing parameters.	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('EGFR', 'Gene', '1956', (75, 79))	('T790M', 'Mutation', 'rs121434569', (66, 71))	('EGFR', 'Gene', (75, 79))	('T790M', 'Var', (66, 71))
39829	29335443	Consistent with the higher pITH, we found an average increase of 37% in mutation burden upon sequencing three random sectors in EGFR mutation positive Asian LUAD compared to only 17% increase in smoker dominated Caucasian LUAD (Supplementary Fig.	('mutation burden', 'MPA', (72, 87))	('LUAD', 'Phenotype', 'HP:0030078', (157, 161))	('EGFR', 'molecular_function', 'GO:0005006', ('128', '132'))	('EGFR', 'Gene', '1956', (128, 132))	('Asian LUAD', 'Disease', (151, 161))	('EGFR', 'Gene', (128, 132))	('increase', 'PosReg', (53, 61))	('LUAD', 'Phenotype', 'HP:0030078', (222, 226))	('mutation positive', 'Var', (133, 150))
39834	29335443	However, 4 of 16 patients (A102, A103, A114, and A121) demonstrated relatively higher contribution of APOBEC activity (signature-2) in late subclonal events (Fig.	('A121', 'Var', (49, 53))	('A103', 'Var', (33, 37))	('higher contribution', 'PosReg', (79, 98))	('APOBEC activity', 'Protein', (102, 117))	('A114', 'Var', (39, 43))	('patients', 'Species', '9606', (17, 25))	('APOBEC', 'cellular_component', 'GO:0030895', ('102', '108'))
39835	29335443	Of note, marked spatial heterogeneity was observed in one patient (A102):a TP53 wild-type non-smoker, where two out of four sectors showed considerably increased contribution of APOBEC signature and disproportionately higher sector-specific mutational burden (Fig.	('APOBEC', 'cellular_component', 'GO:0030895', ('178', '184'))	('mutational', 'Var', (241, 251))	('patient', 'Species', '9606', (58, 65))	('increased', 'PosReg', (152, 161))	('APOBEC', 'Protein', (178, 184))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))
39839	29335443	2a), as well as frequent whole-genome doubling (WGD) events (12 of 15 tumors, except A006, A027, and A112; Fig.	('15 tumors', 'Disease', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('A027', 'Var', (91, 95))	('A006', 'Var', (85, 89))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('A112', 'Var', (101, 105))	('15 tumors', 'Disease', 'MESH:C567447', (67, 76))
39841	29335443	Using the eleven tumors with SCNA data in at least three sectors, we observed 40.5% of cytobands and 41.35% of genes to be affected by late branch or private copy number alterations (Supplementary Fig.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('copy number alterations', 'Var', (158, 181))	('affected', 'Reg', (123, 131))	('late branch', 'Disease', 'MESH:D002037', (135, 146))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('late branch', 'Disease', (135, 146))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
39845	29335443	The inferred cancer cell fractions and mutant allele copy numbers suggest that EGFR and TP53 mutations occurred prior to WGD and local SCNA (Supplementary Data 6), underscoring the founding role of these two drivers during tumorigenesis.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Disease', (223, 228))	('mutations', 'Var', (93, 102))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('TP53', 'Gene', '7157', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('TP53', 'Gene', (88, 92))
39846	29335443	Notably, in the nine tumors harboring mutations in TP53, all had undergone WGD (compared to 3 out of 6 in TP53 wild type (wt)) (Fig.	('WGD', 'Disease', (75, 78))	('TP53', 'Gene', (51, 55))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('mutations', 'Var', (38, 47))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', '7157', (51, 55))	('TP53', 'Gene', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
39854	29335443	In EGFR-mutant tumors with TP53 mutations, 6/9 tumors were found to have LOH and loss in copy number in RB1 region (3 tumors with potentially truncal LOH; Supplementary Fig.	('EGFR', 'molecular_function', 'GO:0005006', ('3', '7'))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('RB1', 'Gene', '5925', (104, 107))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumors', 'Disease', (47, 53))	('TP53', 'Gene', (27, 31))	('EGFR', 'Gene', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mutations', 'Var', (32, 41))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', (15, 21))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('copy number', 'MPA', (89, 100))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('loss', 'NegReg', (81, 85))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('TP53', 'Gene', '7157', (27, 31))	('RB1', 'Gene', (104, 107))	('EGFR', 'Gene', '1956', (3, 7))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
39856	29335443	4) can be explained by the higher number of smoking induced truncal mutations during the life history of a tumor (Fig.	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('truncal mutations', 'Var', (60, 77))	('tumor', 'Disease', (107, 112))
39858	29335443	In exploring potential reasons for the unexpectedly high-branch mutations in EGFR-mutant LUAD, we did not find enrichment for subclonal drivers (Fig.	('LUAD', 'Gene', (89, 93))	('EGFR', 'Gene', '1956', (77, 81))	('mutations', 'Var', (64, 73))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('EGFR', 'Gene', (77, 81))	('LUAD', 'Phenotype', 'HP:0030078', (89, 93))
39861	29335443	3d), we surmised that EGFR mutations may require fewer co-drivers for clonal expansion.	('mutations', 'Var', (27, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('22', '26'))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', (22, 26))
39870	29335443	4a, top panel), we found that TP53, EGFR double-mutant LUAD also harbored higher mutation and driver burdens, both on the trunk and branches (Fig.	('TP53', 'Gene', (30, 34))	('LUAD', 'Phenotype', 'HP:0030078', (55, 59))	('double-mutant', 'Var', (41, 54))	('higher', 'PosReg', (74, 80))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('EGFR', 'Gene', '1956', (36, 40))	('mutation', 'CPA', (81, 89))	('trunk', 'cellular_component', 'GO:0043198', ('122', '127'))	('EGFR', 'Gene', (36, 40))	('TP53', 'Gene', '7157', (30, 34))	('driver burdens', 'CPA', (94, 108))
39871	29335443	15), where out of 9 tumors with >=3 LUAD specific driver mutations, 8 were TP53-mutant.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (57, 66))	('LUAD', 'Phenotype', 'HP:0030078', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))
39872	29335443	Majority of these drivers were truncal (70.5%, 31/44) although some patients had disproportionately more branch/private mutations, such as patient A121 who harbored a branch TP53 mutation, and A065 who carried four different LUAD driver mutations in four different sectors (Fig.	('A065', 'Var', (193, 197))	('TP53', 'Gene', (174, 178))	('patient', 'Species', '9606', (68, 75))	('mutation', 'Var', (179, 187))	('patients', 'Species', '9606', (68, 76))	('LUAD', 'Phenotype', 'HP:0030078', (225, 229))	('mutations', 'Var', (120, 129))	('patient', 'Species', '9606', (139, 146))	('TP53', 'Gene', '7157', (174, 178))
39879	29335443	Taken together, our data suggest that in EGFR-mutant LUAD, an early TP53 mutation may impact clinical outcomes through facilitating genomic instability and the acquisition of additional co-occurring driver events.	('LUAD', 'Phenotype', 'HP:0030078', (53, 57))	('TP53', 'Gene', (68, 72))	('EGFR', 'Gene', (41, 45))	('EGFR', 'Gene', '1956', (41, 45))	('facilitating', 'PosReg', (119, 131))	('EGFR', 'molecular_function', 'GO:0005006', ('41', '45'))	('genomic', 'MPA', (132, 139))	('TP53', 'Gene', '7157', (68, 72))	('impact', 'Reg', (86, 92))	('mutation', 'Var', (73, 81))	('clinical outcomes', 'MPA', (93, 110))
39880	29335443	On the opposite end of the clinical spectrum, of the seven patients with TP53 wt tumors, five harbored only the activating EGFR mutation as the single-truncal driver.	('EGFR', 'Gene', (123, 127))	('tumors', 'Disease', (81, 87))	('TP53', 'Gene', '7157', (73, 77))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('TP53', 'Gene', (73, 77))	('patients', 'Species', '9606', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('EGFR', 'Gene', '1956', (123, 127))	('mutation', 'Var', (128, 136))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
39882	29335443	Despite the limited cohort size, these findings illustrate how a spectrum of clinical trajectories might be dictated by the course of genomic events and traits, including TP53 mutations, presence of multiple truncal drivers, aneuploidy, and associated genomic instability.	('TP53', 'Gene', (171, 175))	('aneuploidy', 'Disease', 'MESH:D000782', (225, 235))	('mutations', 'Var', (176, 185))	('presence', 'Var', (187, 195))	('aneuploidy', 'Disease', (225, 235))	('genomic', 'MPA', (252, 259))	('TP53', 'Gene', '7157', (171, 175))
39883	29335443	Through multi-region sequencing, we have, for the first time, characterized the clonal and subclonal genomic landscape of Asian EGFR mutation positive LUAD.	('LUAD', 'Phenotype', 'HP:0030078', (151, 155))	('EGFR', 'molecular_function', 'GO:0005006', ('128', '132'))	('mutation', 'Var', (133, 141))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))
39884	29335443	Despite the low somatic mutation burden, EGFR-mutant LUADs exhibit a heterogeneous genomic landscape characterized by (i) high proportion of late branch and private mutations and (ii) large proportion of genome altered through a combination of early genome doubling events and low-copy gains and losses, followed by late sector-specific copy number changes.	('late branch', 'Disease', (141, 152))	('gains', 'PosReg', (286, 291))	('EGFR', 'Gene', (41, 45))	('altered', 'Reg', (211, 218))	('low-copy', 'Var', (277, 285))	('EGFR', 'molecular_function', 'GO:0005006', ('41', '45'))	('LUAD', 'Phenotype', 'HP:0030078', (53, 57))	('EGFR', 'Gene', '1956', (41, 45))	('late branch', 'Disease', 'MESH:D002037', (141, 152))	('losses', 'NegReg', (296, 302))
39886	29335443	Founding mutations in EGFR and frequent early TP53 mutations coupled with other truncal alterations deregulating the cell cycle and evading cell death, facilitate tolerance of pervasive WGD and CIN.	('CIN', 'Disease', (194, 197))	('EGFR', 'molecular_function', 'GO:0005006', ('22', '26'))	('mutations', 'Var', (51, 60))	('CIN', 'Disease', 'MESH:D007674', (194, 197))	('cell cycle', 'biological_process', 'GO:0007049', ('117', '127'))	('deregulating', 'Reg', (100, 112))	('TP53', 'Gene', '7157', (46, 50))	('cell cycle', 'CPA', (117, 127))	('CIN', 'Phenotype', 'HP:0040012', (194, 197))	('cell death', 'biological_process', 'GO:0008219', ('140', '150'))	('TP53', 'Gene', (46, 50))	('facilitate', 'PosReg', (152, 162))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', (22, 26))
39887	29335443	Despite a relatively high fraction of branch mutations in these treatment naive tumors, we generally observed a low prevalence of subclonal drivers or putative resistance mutations (e.g., D323N in AKT1), consistent with a neutral evolution model.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('D323N', 'Mutation', 'p.D323N', (188, 193))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('AKT1', 'Gene', '207', (197, 201))	('D323N', 'Var', (188, 193))	('AKT1', 'Gene', (197, 201))
39888	29335443	While the truncal activating mutations in EGFR provide high-response rates to the targeted EGFR TKIs, these responses are often short-lived unlike those to Imatinib in BCR-ABL1 fusion driven chronic myeloid leukemia (CML).	('BCR-ABL1', 'Gene', '613;25', (168, 176))	('EGFR', 'molecular_function', 'GO:0005006', ('91', '95'))	('CML', 'Disease', 'MESH:D015464', (217, 220))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (199, 215))	('CML', 'Disease', (217, 220))	('EGFR', 'Gene', (91, 95))	('EGFR', 'Gene', (42, 46))	('chronic myeloid leukemia', 'Disease', (191, 215))	('mutations', 'Var', (29, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('CML', 'Phenotype', 'HP:0005506', (217, 220))	('EGFR', 'Gene', '1956', (91, 95))	('Imatinib', 'Chemical', 'MESH:D000068877', (156, 164))	('BCR-ABL1', 'Gene', (168, 176))	('EGFR', 'Gene', '1956', (42, 46))	('leukemia', 'Phenotype', 'HP:0001909', (207, 215))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (191, 215))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (191, 215))	('high-response rates', 'MPA', (55, 74))
39889	29335443	Although the determinants of durability of response in CML remain poorly understood, current studies suggest that the burden of point mutations and SCNAs is moderate in CML compared to solid tumors which possibly contributes to the longer TKI responses of CML compared to LUAD patients.	('CML', 'Disease', (169, 172))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('CML', 'Disease', (256, 259))	('solid tumors', 'Disease', (185, 197))	('LUAD', 'Phenotype', 'HP:0030078', (272, 276))	('CML', 'Disease', 'MESH:D015464', (55, 58))	('patients', 'Species', '9606', (277, 285))	('CML', 'Phenotype', 'HP:0005506', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('CML', 'Disease', 'MESH:D015464', (169, 172))	('point mutations', 'Var', (128, 143))	('CML', 'Phenotype', 'HP:0005506', (169, 172))	('solid tumors', 'Disease', 'MESH:D009369', (185, 197))	('CML', 'Disease', (55, 58))	('CML', 'Disease', 'MESH:D015464', (256, 259))	('CML', 'Phenotype', 'HP:0005506', (256, 259))
39891	29335443	In addition, the subclonal nature of high-amplitude amplifications and deletions underscores the challenge in interpreting gene copy number thresholds e.g., MET and ERBB2, from single biopsies in NSCLC.	('deletions', 'Var', (71, 80))	('NSCLC', 'Disease', (196, 201))	('MET', 'Gene', (157, 160))	('ERBB2', 'Gene', '2064', (165, 170))	('NSCLC', 'Disease', 'MESH:D002289', (196, 201))	('ERBB2', 'Gene', (165, 170))	('NSCLC', 'Phenotype', 'HP:0030358', (196, 201))
39894	29335443	However, larger sample sizes with more functional validations will be needed to test this and to decouple the effects of different genomic features like TP53 mutations, driver burdens and GII.	('mutations', 'Var', (158, 167))	('TP53', 'Gene', '7157', (153, 157))	('TP53', 'Gene', (153, 157))
39897	29335443	In the smoking scenario, a tumor-initiating cell population acquires mutations at a high rate and hence accumulates a large number of passenger and relatively weak driver mutations, with low likelihood for early acquisition of dominant drivers like EGFR (Fig.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (69, 78))	('EGFR', 'molecular_function', 'GO:0005006', ('249', '253'))	('tumor', 'Disease', (27, 32))	('EGFR', 'Gene', '1956', (249, 253))	('EGFR', 'Gene', (249, 253))	('mutations', 'Var', (171, 180))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
39898	29335443	In contrast, in an oncogene-driven never-smoker LUAD, a dominant driver e.g., EGFR mutation, in the context of low-mutation rates:is sufficient to allow expansion of early tumor cells with few co-drivers.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('LUAD', 'Phenotype', 'HP:0030078', (48, 52))	('tumor', 'Disease', (172, 177))	('mutation', 'Var', (83, 91))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('EGFR', 'Gene', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
39900	29335443	In summary, we have elucidated the distinct clonal architecture of EGFR mutation positive LUAD, providing insights as to how these may relate to the diverse clinical trajectories observed.	('positive', 'Reg', (81, 89))	('LUAD', 'Disease', (90, 94))	('LUAD', 'Phenotype', 'HP:0030078', (90, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('67', '71'))	('EGFR', 'Gene', '1956', (67, 71))	('mutation', 'Var', (72, 80))	('EGFR', 'Gene', (67, 71))
39901	29335443	While dominant truncal drivers, such as EGFR mutations are an important prerequisite for efficacious targeted therapies, the evolutionary trajectory for each tumor can be augmented by additional genomic events in the natural life history, enhancing clonal fitness with emergent drug resistance.	('tumor', 'Disease', (158, 163))	('mutations', 'Var', (45, 54))	('drug resistance', 'biological_process', 'GO:0009315', ('278', '293'))	('drug resistance', 'biological_process', 'GO:0042493', ('278', '293'))	('drug resistance', 'Phenotype', 'HP:0020174', (278, 293))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('clonal fitness', 'CPA', (249, 263))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('enhancing', 'PosReg', (239, 248))
39903	29335443	Among the patients diagnosed with LUAD at the National Cancer Centre Singapore, which underwent surgical resection of their tumors prior to receiving any form of therapy, 16 patients carrying EGFR mutations were selected for this study (relevant clinical information of each patient is provided in Supplementary Table 1).	('LUAD', 'Phenotype', 'HP:0030078', (34, 38))	('LUAD', 'Disease', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('EGFR', 'molecular_function', 'GO:0005006', ('192', '196'))	('patient', 'Species', '9606', (174, 181))	('mutations', 'Var', (197, 206))	('patient', 'Species', '9606', (10, 17))	('patient', 'Species', '9606', (275, 282))	('patients', 'Species', '9606', (174, 182))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('patients', 'Species', '9606', (10, 18))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('EGFR', 'Gene', '1956', (192, 196))	('EGFR', 'Gene', (192, 196))
39909	29335443	In addition, primers covering the T790M locus in EGFR were also added to the panel.	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('EGFR', 'Gene', (49, 53))	('T790M', 'Mutation', 'rs121434569', (34, 39))	('T790M', 'Var', (34, 39))
39917	29335443	Further, mutation calls were required to have a VAF five times higher in the tumor compared to the normal.	('mutation calls', 'Var', (9, 23))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('higher', 'PosReg', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('VAF', 'MPA', (48, 51))	('tumor', 'Disease', (77, 82))
39923	29335443	In order to uncover mutational processes active within the EGFR mutant LUAD patients, we combined somatic mutations from the Singapore cohort with two published large-scale data sets.	('patients', 'Species', '9606', (76, 84))	('EGFR', 'Gene', (59, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('59', '63'))	('LUAD', 'Phenotype', 'HP:0030078', (71, 75))	('mutant', 'Var', (64, 70))	('EGFR', 'Gene', '1956', (59, 63))
39930	29335443	For 5 of these 61 samples (namely A001-T-S03, A017-T-S10, A021-T-S02, A112-T-S28, and A112-T-S40), ASCAT solution was manually picked using second or third most optimal purity/ploidy solution since either the raw data suggested these sectors to be similar to other sectors from same patient or variant allele frequencies suggested alternate purity solution.	('A021-T-S02', 'Var', (58, 68))	('A001-T-S03', 'Var', (34, 44))	('A017-T-S10', 'Var', (46, 56))	('A112-T-S40', 'Var', (86, 96))	('patient', 'Species', '9606', (283, 290))	('A112-T-S28', 'Var', (70, 80))
39935	29335443	This was based on the logic that, for each cancer patient, the number of driver mutations found in each case implies the self-sufficiency of the drivers.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('mutations', 'Var', (80, 89))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('patient', 'Species', '9606', (50, 57))
39953	29295730	In conclusion, knockdown of Kim-1 inhibits the growth of 786-0 cells in vitro and in vivo, indicating that Kim-1 could be used as a potential target for clear cell renal cell carcinoma therapy.	('knockdown', 'Var', (15, 24))	('inhibits', 'NegReg', (34, 42))	('clear cell renal cell carcinoma', 'Disease', (153, 184))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (153, 184))	('growth of 786-0 cells', 'CPA', (47, 68))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (153, 184))	('Kim-1', 'Gene', (28, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (164, 184))
39969	29295730	Furthermore, silencing of Kim-1 inhibited the growth of ccRCC 786-0 cells in vivo.	('inhibited', 'NegReg', (32, 41))	('Kim-1', 'Gene', (26, 31))	('growth', 'CPA', (46, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('silencing', 'Var', (13, 22))
39972	29295730	pGCSIL-KIM-1-RNAi-LV and nontargeted control pGCSIL-neg-RNAi-LV were purchased from GeneChem Biomedical Co., Ltd. (Shanghai, P.R.	('KIM-1', 'Gene', '26762', (7, 12))	('Shanghai', 'Var', (115, 123))	('RNAi', 'biological_process', 'GO:0016246', ('13', '17'))	('RNAi', 'biological_process', 'GO:0016246', ('56', '60'))	('KIM-1', 'Gene', (7, 12))
40001	29295730	To further investigate the potential effects of reduced Kim-1 expression on the tumorigenic phenotype, 786-0 cells infected with pGCSIL-Kim-1-RNAi-LV (the KD group) or untreated (the CON group) were injected into nude mice to determine in vivo tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (244, 249))	('RNAi', 'biological_process', 'GO:0016246', ('142', '146'))	('reduced', 'NegReg', (48, 55))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('infected', 'Disease', 'MESH:D007239', (115, 123))	('pGCSIL-Kim-1-RNAi-LV', 'Var', (129, 149))	('nude mice', 'Species', '10090', (213, 222))	('Kim-1', 'Gene', (56, 61))	('infected', 'Disease', (115, 123))
40002	29295730	Tumors derived from cells treated with Kim-1-RNAi were significantly decreased in size compared with the CON group mice (p < 0.001) (Fig.	('RNAi', 'biological_process', 'GO:0016246', ('45', '49'))	('Kim-1-RNAi', 'Var', (39, 49))	('decreased', 'NegReg', (69, 78))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mice', 'Species', '10090', (115, 119))
40008	29295730	Mutation or silencing of Von Hippel-Lindau (VHL) tumor suppressor gene occurs in a majority of inherited and sporadic ccRCC, resulting in hypoxia inducible factor-alpha (HIF-alpha) stabilization, which causes abnormal expression of a series of growth factors.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('stabilization', 'MPA', (181, 194))	('silencing', 'NegReg', (12, 21))	('Mutation', 'Var', (0, 8))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('49', '65'))	('hypoxia', 'Disease', 'MESH:D000860', (138, 145))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('hypoxia', 'Disease', (138, 145))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('expression', 'MPA', (218, 228))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))	('Von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (25, 54))	('tumor suppressor', 'biological_process', 'GO:0051726', ('49', '65'))
40017	29295730	downmodulated KIM-1 in RCC cell lines using an siRNA lentiviral approach, which led to G1 cell cycle arrest phase and senescence.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('90', '107'))	('KIM-1', 'Gene', '26762', (14, 19))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (90, 107))	('led to', 'Reg', (80, 86))	('senescence', 'CPA', (118, 128))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('arrest', 'Disease', 'MESH:D006323', (101, 107))	('downmodulated', 'Var', (0, 13))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('KIM-1', 'Gene', (14, 19))	('senescence', 'biological_process', 'GO:0010149', ('118', '128'))	('arrest', 'Disease', (101, 107))
40018	29295730	They demonstrated that the expression of KIM-1 converts a normal epithelial cell into a "semiprofessional phagocyte" and facilitates the removal of apoptotic and necrotic cells.	('removal', 'CPA', (137, 144))	('KIM-1', 'Gene', '26762', (41, 46))	('facilitates', 'PosReg', (121, 132))	('necrotic', 'Disease', (162, 170))	('expression', 'Var', (27, 37))	('necrotic', 'Disease', 'MESH:D009336', (162, 170))	('KIM-1', 'Gene', (41, 46))
40019	29295730	We successfully constructed a highly efficient and stable lentivirus vector system, which could efficiently knock down Kim-1 gene in infected 786-0 cells.	('Kim-1 gene', 'Gene', (119, 129))	('infected', 'Disease', (133, 141))	('knock down', 'Var', (108, 118))	('infected', 'Disease', 'MESH:D007239', (133, 141))
40020	29295730	In this study, we investigated the correlated effects of Kim-1 silencing on the biological effects in ccRCC 786-0 cells in vitro and in vivo.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('Kim-1', 'Gene', (57, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('silencing', 'Var', (63, 72))	('RCC', 'Disease', (104, 107))
40021	29295730	Some studies demonstrated that expression of Kim-1 in ccRCC was able to provide advantages to EBV-mediated cell growth and transformation and enhance the malignant potential in vivo.	('cell growth', 'biological_process', 'GO:0016049', ('107', '118'))	('EBV-mediated cell growth', 'CPA', (94, 118))	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('enhance', 'PosReg', (142, 149))	('Kim-1', 'Gene', (45, 50))	('expression', 'Var', (31, 41))	('transformation', 'CPA', (123, 137))	('advantages', 'PosReg', (80, 90))	('malignant potential', 'CPA', (154, 173))
40023	29295730	Based on previous reports and our results, we suggest that silencing of Kim-1 weakens cell proliferation of ccRCC cells via increasing cell cycle arrest and inducing late apoptosis.	('RCC', 'Disease', (110, 113))	('inducing', 'NegReg', (157, 165))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('apoptosis', 'biological_process', 'GO:0097194', ('171', '180'))	('apoptosis', 'biological_process', 'GO:0006915', ('171', '180'))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (135, 152))	('late apoptosis', 'CPA', (166, 180))	('arrest', 'Disease', 'MESH:D006323', (146, 152))	('cell proliferation', 'biological_process', 'GO:0008283', ('86', '104'))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('arrest', 'Disease', (146, 152))	('Kim-1', 'Gene', (72, 77))	('weakens', 'NegReg', (78, 85))	('cell proliferation of', 'CPA', (86, 107))	('silencing', 'Var', (59, 68))	('increasing', 'PosReg', (124, 134))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('135', '152'))
40033	33692827	Method: We obtained renal clear cell carcinoma data from TCGA-KIRC-FPKM, GSE8050, GSE12606, GSE14762, and GSE3689.	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (20, 46))	('GSE12606', 'Var', (82, 90))	('GSE3689', 'Var', (106, 113))	('renal clear cell carcinoma', 'Disease', (20, 46))	('GSE14762', 'Var', (92, 100))	('GSE8050', 'Var', (73, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('GSE8050', 'Chemical', '-', (73, 80))	('GSE3689', 'Chemical', '-', (106, 113))
40055	33692827	GSE8050 (Weinzierl et al.,), GSE12606 (Stickel et al.,), GSE14762 (Wang et al.,), and GSE36895 (Pena-Llopis et al.,) were also downloaded from the GEO (http://www.ncbi.nlm.nih.gov/geo/) database.	('GSE8050', 'Chemical', '-', (0, 7))	('GSE14762', 'Var', (57, 65))	('GSE8050', 'Var', (0, 7))	('GSE12606', 'Var', (29, 37))	('GSE3689', 'Chemical', '-', (86, 93))	('GSE36895', 'Var', (86, 94))
40062	33692827	TMB (tumor mutation burden) per megabyte is calculated by dividing the total number of mutations by the size of the target coding region (Li et al.,; Yang et al.,).	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('TMB', 'Chemical', '-', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('mutations', 'Var', (87, 96))
40086	33692827	CAB012245 is an antibody against SDCBP, which showed a higher intensity in tumor tissue than in normal tissue.	('antibody', 'molecular_function', 'GO:0003823', ('16', '24'))	('CAB012245', 'Var', (0, 9))	('SDCBP', 'Gene', (33, 38))	('intensity', 'MPA', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('antibody', 'cellular_component', 'GO:0042571', ('16', '24'))	('SDCBP', 'Gene', '6386', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('antibody', 'cellular_component', 'GO:0019814', ('16', '24'))	('antibody', 'cellular_component', 'GO:0019815', ('16', '24'))	('higher', 'PosReg', (55, 61))	('tumor', 'Disease', (75, 80))
40121	32824856	CA9 Silencing Promotes Mitochondrial Biogenesis, Increases Putrescine Toxicity and Decreases Cell Motility to Suppress ccRCC Progression Carbonic anhydrase IX (CA9), a pH-regulating transmembrane protein, is highly expressed in solid tumors, and particularly in clear cell renal cell carcinoma (ccRCC).	('Carbonic anhydrase IX', 'Gene', (137, 158))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('Toxicity', 'Disease', (70, 78))	('CA9', 'Gene', (160, 163))	('Mitochondrial Biogenesis', 'MPA', (23, 47))	('pH', 'Gene', '2821', (168, 170))	('Cell Motility', 'biological_process', 'GO:0048870', ('93', '106'))	('Increases', 'PosReg', (49, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (295, 300))	('CA9', 'Gene', (0, 3))	('Cell Motility', 'CPA', (93, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('ccRCC', 'Disease', (119, 124))	('Promotes', 'PosReg', (14, 22))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (273, 293))	('Carbonic anhydrase IX', 'Gene', '768', (137, 158))	('Putrescine', 'Chemical', 'MESH:D011700', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('CA9', 'Gene', '768', (160, 163))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (262, 293))	('CA9', 'Gene', '768', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('Toxicity', 'Disease', 'MESH:D064420', (70, 78))	('Silencing', 'Var', (4, 13))	('transmembrane', 'cellular_component', 'GO:0016021', ('182', '195'))	('Decreases', 'NegReg', (83, 92))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (268, 293))	('tumors', 'Disease', (234, 240))	('cell renal cell carcinoma', 'Disease', (268, 293))	('transmembrane', 'cellular_component', 'GO:0044214', ('182', '195'))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))
40124	32824856	CA9 knockdown upregulated oxidative phosphorylation-associated proteins and increased mitochondrial biogenesis, resulting in the reversal of the Warburg phenotype and the inhibition of cell growth.	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('26', '51'))	('CA9', 'Gene', '768', (0, 3))	('CA9', 'Gene', (0, 3))	('increased', 'PosReg', (76, 85))	('mitochondrial biogenesis', 'MPA', (86, 110))	('inhibition of cell growth', 'biological_process', 'GO:0030308', ('171', '196'))	('oxidative phosphorylation-associated proteins', 'MPA', (26, 71))	('upregulated', 'PosReg', (14, 25))	('knockdown', 'Var', (4, 13))
40125	32824856	Our study revealed that CA9 knockdown upregulated mitochondrial arginase 2 (ARG2), leading to the accumulation of putrescine, which suppressed ccRCC proliferation.	('accumulation', 'PosReg', (98, 110))	('CA9', 'Gene', '768', (24, 27))	('CA9', 'Gene', (24, 27))	('upregulated', 'PosReg', (38, 49))	('ARG2', 'Gene', (76, 80))	('arginase 2', 'Gene', (64, 74))	('ccRCC', 'Disease', (143, 148))	('arginase 2', 'Gene', '384', (64, 74))	('putrescine', 'Chemical', 'MESH:D011700', (114, 124))	('ARG2', 'Gene', '384', (76, 80))	('ccRCC', 'Phenotype', 'HP:0006770', (143, 148))	('knockdown', 'Var', (28, 37))	('putrescine', 'MPA', (114, 124))	('suppressed', 'NegReg', (132, 142))
40126	32824856	Surfaceomics analysis revealed that CA9 knockdown downregulated proteins associated with extracellular matrix (ECM):receptor interaction and cell adhesion, resulting in decreased cell migration.	('cell migration', 'biological_process', 'GO:0016477', ('179', '193'))	('knockdown', 'Var', (40, 49))	('cell adhesion', 'CPA', (141, 154))	('proteins', 'Protein', (64, 72))	('CA9', 'Gene', (36, 39))	('cell adhesion', 'biological_process', 'GO:0007155', ('141', '154'))	('decreased', 'NegReg', (169, 178))	('downregulated', 'NegReg', (50, 63))	('CA9', 'Gene', '768', (36, 39))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('89', '109'))	('cell migration', 'CPA', (179, 193))
40127	32824856	CA9 silencing also downregulated amino acid transporters, leading to reduced cellular amino acids.	('CA9', 'Gene', '768', (0, 3))	('CA9', 'Gene', (0, 3))	('reduced', 'NegReg', (69, 76))	('amino acid transporters', 'MPA', (33, 56))	('cellular amino acids', 'MPA', (77, 97))	('silencing', 'Var', (4, 13))	('downregulated', 'NegReg', (19, 32))
40128	32824856	Collectively, our data show that CA9 knockdown suppresses proliferation via metabolic reprogramming and reduced cell migration, reaffirming that CA9 is a potential therapeutic target for ccRCC treatment.	('CA9', 'Gene', '768', (33, 36))	('ccRCC', 'Disease', (187, 192))	('reduced', 'NegReg', (104, 111))	('proliferation', 'CPA', (58, 71))	('suppresses', 'NegReg', (47, 57))	('knockdown', 'Var', (37, 46))	('CA9', 'Gene', '768', (145, 148))	('CA9', 'Gene', (145, 148))	('cell migration', 'biological_process', 'GO:0016477', ('112', '126'))	('metabolic reprogramming', 'CPA', (76, 99))	('cell migration', 'CPA', (112, 126))	('CA9', 'Gene', (33, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (187, 192))
40137	32824856	VHL (von Hippel:Lindau disease gene) is ubiquitously inactivated by mutation or promoter hypermethylation in ccRCC, which results in the persistent stabilization and activation of hypoxia-inducible factor (HIF).	('von Hippel', 'Disease', (5, 15))	('promoter hypermethylation', 'Var', (80, 105))	('activation', 'PosReg', (166, 176))	('Lindau disease', 'Disease', 'MESH:D006623', (16, 30))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('mutation', 'Var', (68, 76))	('hypoxia', 'Disease', 'MESH:D000860', (180, 187))	('ccRCC', 'Disease', (109, 114))	('VHL', 'Gene', (0, 3))	('inactivated', 'NegReg', (53, 64))	('stabilization', 'MPA', (148, 161))	('VHL', 'Gene', '7428', (0, 3))	('Lindau disease', 'Disease', (16, 30))	('hypoxia', 'Disease', (180, 187))	('von Hippel', 'Disease', 'MESH:D006623', (5, 15))
40141	32824856	Studies have shown that the high expression of CA9 promotes viability and growth of tumor cells in melanoma, breast, and colorectal cancers, and enhances tumor invasion and migration by promoting extracellular matrix degradation.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('colorectal cancers', 'Disease', 'MESH:D015179', (121, 139))	('high expression', 'Var', (28, 43))	('breast', 'Disease', (109, 115))	('growth', 'CPA', (74, 80))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('196', '216'))	('tumor', 'Disease', (154, 159))	('enhances', 'PosReg', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('promoting', 'PosReg', (186, 195))	('extracellular matrix', 'CPA', (196, 216))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('promotes', 'PosReg', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('CA9', 'Gene', (47, 50))	('colorectal cancers', 'Disease', (121, 139))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('CA9', 'Gene', '768', (47, 50))	('viability', 'CPA', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (84, 89))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('degradation', 'biological_process', 'GO:0009056', ('217', '228'))
40146	32824856	We found that CA9 silencing resulted in the accumulation of putrescine and increased mitochondrial biogenesis, leading to decreased cell proliferation.	('putrescine', 'Chemical', 'MESH:D011700', (60, 70))	('silencing', 'Var', (18, 27))	('CA9', 'Gene', (14, 17))	('mitochondrial biogenesis', 'MPA', (85, 109))	('decreased', 'NegReg', (122, 131))	('CA9', 'Gene', '768', (14, 17))	('putrescine', 'MPA', (60, 70))	('cell proliferation', 'CPA', (132, 150))	('cell proliferation', 'biological_process', 'GO:0008283', ('132', '150'))	('increased', 'PosReg', (75, 84))	('accumulation', 'PosReg', (44, 56))
40147	32824856	We carried out a quantitative surfaceomics analysis and found that CA9 silencing downregulated amino acid transporters and proteins associated with cell motility.	('cell motility', 'biological_process', 'GO:0048870', ('148', '161'))	('downregulated', 'NegReg', (81, 94))	('silencing', 'Var', (71, 80))	('CA9', 'Gene', '768', (67, 70))	('CA9', 'Gene', (67, 70))	('amino acid transporters and', 'MPA', (95, 122))	('proteins', 'Protein', (123, 131))
40149	32824856	We found that CA9 was significantly higher in KIRC tissues than in normal tissues (Figure 1B).	('CA9', 'Gene', (14, 17))	('higher', 'PosReg', (36, 42))	('KIRC', 'Var', (46, 50))	('CA9', 'Gene', '768', (14, 17))
40150	32824856	To examine the effects of CA9 on ccRCC progression, we knocked down (KD) or overexpressed (OE) CA9 in 786-O and 769-P to establish stable cell lines.	('ccRCC', 'Disease', (33, 38))	('overexpressed', 'PosReg', (76, 89))	('CA9', 'Gene', (95, 98))	('CA9', 'Gene', (26, 29))	('CA9', 'Gene', '768', (95, 98))	('knocked', 'Var', (55, 62))	('CA9', 'Gene', '768', (26, 29))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))
40154	32824856	Cell Counting Kit-8 (CCK-8) assays showed that CA9 knockdown inhibited cell growth (Figure 1E,F), while CA9 overexpression promoted cell proliferation (Figure 1G).	('CA9', 'Gene', '768', (47, 50))	('CA9', 'Gene', (47, 50))	('inhibited', 'NegReg', (61, 70))	('cell growth', 'biological_process', 'GO:0016049', ('71', '82'))	('CA9', 'Gene', (104, 107))	('cell growth', 'CPA', (71, 82))	('CA9', 'Gene', '768', (104, 107))	('overexpression promoted', 'PosReg', (108, 131))	('cell proliferation', 'CPA', (132, 150))	('cell proliferation', 'biological_process', 'GO:0008283', ('132', '150'))	('knockdown', 'Var', (51, 60))
40156	32824856	To elucidate CA9 function in the progression of ccRCC, quantitative proteomics analysis was carried out to characterize the proteome changes after CA9 knockdown in 786-O cells.	('CA9', 'Gene', (147, 150))	('CA9', 'Gene', '768', (13, 16))	('CA9', 'Gene', '768', (147, 150))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('CA9', 'Gene', (13, 16))	('ccRCC', 'Disease', (48, 53))	('knockdown', 'Var', (151, 160))
40161	32824856	Interestingly, most mitochondrial proteins were upregulated in CA9 knockdown cells (Figure 2D).	('knockdown', 'Var', (67, 76))	('CA9', 'Gene', '768', (63, 66))	('CA9', 'Gene', (63, 66))	('mitochondrial proteins', 'Protein', (20, 42))	('upregulated', 'PosReg', (48, 59))
40162	32824856	Ingenuity Pathway Analysis (IPA) further showed that proteins related to oxidative phosphorylation (OXPHOS), fatty acid beta-oxidation, and mitochondrial L-carnitine shuttle were upregulated, while proteins associated with the pentose phosphate pathway (PPP) were downregulated in CA9 knockdown cells (Figure 2E).	('oxidative phosphorylation', 'MPA', (73, 98))	('CA9', 'Gene', (281, 284))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('73', '98'))	('knockdown', 'Var', (285, 294))	('mitochondrial L-carnitine shuttle', 'MPA', (140, 173))	('CA9', 'Gene', '768', (281, 284))	('pentose phosphate', 'Chemical', 'MESH:D010428', (227, 244))	('carnitine shuttle', 'biological_process', 'GO:0006853', ('156', '173'))	('upregulated', 'PosReg', (179, 190))	('proteins', 'Protein', (198, 206))	('downregulated', 'NegReg', (264, 277))	('L-carnitine', 'Chemical', 'MESH:D002331', (154, 165))	('fatty acid', 'Chemical', 'MESH:D005227', (109, 119))	('proteins', 'Protein', (53, 61))	('fatty acid beta-oxidation', 'biological_process', 'GO:0006635', ('109', '134'))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('227', '252'))	('fatty acid beta-oxidation', 'MPA', (109, 134))	('OXPHOS', 'biological_process', 'GO:0002082', ('100', '106'))
40166	32824856	As predicted, CA9 knockdown increased MitoTracker staining intensity and enhanced the expressions of key factors in mitochondrial biogenesis, including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha), nuclear factor erythroid 2-related factor 2 (NRF2), and mitochondrial transcription factor 1 (TFAM) (Figure 3C,D and Figure S2A-C) in 786-O and 769-P cells.	('NRF2', 'Gene', '4780', (280, 284))	('PGC-1alpha', 'Gene', '10891', (222, 232))	('peroxisome', 'cellular_component', 'GO:0005777', ('152', '162'))	('mitochondrial transcription', 'biological_process', 'GO:0006390', ('291', '318'))	('expressions', 'MPA', (86, 97))	('enhanced', 'PosReg', (73, 81))	('PGC-1alpha', 'Gene', (222, 232))	('increased', 'PosReg', (28, 37))	('mitochondrial biogenesis', 'MPA', (116, 140))	('mitochondrial transcription factor 1', 'Gene', '7019', (291, 327))	('nuclear factor erythroid 2-related factor 2', 'Gene', '4780', (235, 278))	('NRF2', 'Gene', (280, 284))	('MitoTracker staining intensity', 'MPA', (38, 68))	('transcription factor', 'molecular_function', 'GO:0000981', ('305', '325'))	('knockdown', 'Var', (18, 27))	('mitochondrial transcription factor 1', 'Gene', (291, 327))	('CA9', 'Gene', (14, 17))	('peroxisome proliferator-activated receptor gamma coactivator 1-alpha', 'Gene', '10891', (152, 220))	('TFAM', 'Gene', (329, 333))	('CA9', 'Gene', '768', (14, 17))	('nuclear factor erythroid 2-related factor 2', 'Gene', (235, 278))
40167	32824856	Furthermore, mitochondrial DNA (mtDNA) content, which is proportional to the number of mitochondria, was also increased after CA9 knockdown in 786-O and 769-P cells (Figure S2D).	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('13', '30'))	('CA9', 'Gene', (126, 129))	('increased', 'PosReg', (110, 119))	('CA9', 'Gene', '768', (126, 129))	('knockdown', 'Var', (130, 139))	('mtDNA', 'cellular_component', 'GO:0000262', ('32', '37'))	('mitochondria', 'cellular_component', 'GO:0005739', ('87', '99'))
40168	32824856	Reactive oxygen species (ROS) are byproducts of electron transport chain activity, and we reasoned that an increase in the mitochondrial biogenesis could enhance the cellular ROS level after CA9 knockdown.	('ROS', 'Chemical', 'MESH:D017382', (175, 178))	('ROS', 'Chemical', 'MESH:D017382', (25, 28))	('increase', 'PosReg', (107, 115))	('mitochondrial biogenesis', 'MPA', (123, 147))	('electron transport chain', 'biological_process', 'GO:0022900', ('48', '72'))	('CA9', 'Gene', (191, 194))	('knockdown', 'Var', (195, 204))	('CA9', 'Gene', '768', (191, 194))	('cellular ROS level', 'MPA', (166, 184))	('enhance', 'PosReg', (154, 161))	('Reactive oxygen species', 'Chemical', 'MESH:D017382', (0, 23))
40170	32824856	Moreover, CA9 knockdown resulted in downregulation of glycolytic enzymes such as hexokinase-2 (HK2), glucose-6-phosphate 1-dehydrogenase (G6PD), ATP-dependent 6-phosphofructokinase (PFKM), and phosphoglycerate mutase 1 (PGAM1).	('CA9', 'Gene', (10, 13))	('HK2', 'molecular_function', 'GO:0008256', ('95', '98'))	('PGAM1', 'Gene', (220, 225))	('hexokinase-2', 'Gene', (81, 93))	('HK2', 'Gene', (95, 98))	('HK2', 'Gene', '3099', (95, 98))	('CA9', 'Gene', '768', (10, 13))	('G6PD', 'Gene', '2539', (138, 142))	('ATP', 'Chemical', 'MESH:D000255', (145, 148))	('glucose-6-phosphate 1-dehydrogenase', 'Gene', (101, 136))	('downregulation', 'NegReg', (36, 50))	('PGAM1', 'Gene', '5223', (220, 225))	('hexokinase-2', 'Gene', '3099', (81, 93))	('glycolytic enzymes', 'Enzyme', (54, 72))	('phosphoglycerate mutase 1', 'Gene', (193, 218))	('G6PD', 'Gene', (138, 142))	('PFKM', 'Gene', '5213', (182, 186))	('phosphoglycerate mutase 1', 'Gene', '5223', (193, 218))	('PFKM', 'Gene', (182, 186))	('knockdown', 'Var', (14, 23))	('glucose-6-phosphate 1-dehydrogenase', 'Gene', '2539', (101, 136))
40171	32824856	Consistently, levels of glucose-6-phosphate (G6P), lactate, Uridine-5'-diphosphate glucose (UDP-G), and 6-phosphpogluconate (6PG) were decreased after CA9 knockdown (Figure S3).	('glucose-6-phosphate', 'MPA', (24, 43))	("Uridine-5'-diphosphate glucose", 'Gene', (60, 90))	('knockdown', 'Var', (155, 164))	('lactate', 'MPA', (51, 58))	('CA9', 'Gene', (151, 154))	('6-phosphpogluconate', 'Chemical', '-', (104, 123))	('levels', 'MPA', (14, 20))	('glucose', 'Chemical', 'MESH:D005947', (24, 31))	('glucose', 'Chemical', 'MESH:D005947', (83, 90))	('CA9', 'Gene', '768', (151, 154))	("Uridine-5'-diphosphate glucose", 'Gene', '7360', (60, 90))	('6-phosphpogluconate', 'MPA', (104, 123))	('G6P', 'Chemical', 'MESH:D019298', (45, 48))	('decreased', 'NegReg', (135, 144))	('lactate', 'Chemical', 'MESH:D019344', (51, 58))
40172	32824856	These results demonstrated that CA9 knockdown increased mitochondrial biogenesis and reversed the Warburg metabolic phenotypes.	('increased', 'PosReg', (46, 55))	('knockdown', 'Var', (36, 45))	('Warburg metabolic phenotypes', 'MPA', (98, 126))	('CA9', 'Gene', (32, 35))	('mitochondrial biogenesis', 'MPA', (56, 80))	('CA9', 'Gene', '768', (32, 35))
40173	32824856	To confirm proteomics results suggesting that CA9 silencing reprogramed cellular metabolism, we performed metabolomics analysis in five biological replicates to investigate the effects of CA9 knockdown on cellular metabolism in 786-O cells.	('CA9', 'Gene', '768', (188, 191))	('reprogramed', 'Reg', (60, 71))	('silencing', 'Var', (50, 59))	('CA9', 'Gene', (46, 49))	('cellular metabolism', 'biological_process', 'GO:0044237', ('72', '91'))	('cellular', 'MPA', (72, 80))	('CA9', 'Gene', '768', (46, 49))	('cellular metabolism', 'biological_process', 'GO:0044237', ('205', '224'))	('CA9', 'Gene', (188, 191))
40174	32824856	Metabolomics analysis showed that CA9 knockdown increased the cellular contents of 24 metabolites while it decreased 127 metabolites (Tables S4 and S5).	('increased', 'PosReg', (48, 57))	('CA9', 'Gene', (34, 37))	('CA9', 'Gene', '768', (34, 37))	('cellular contents of 24 metabolites', 'MPA', (62, 97))	('decreased', 'NegReg', (107, 116))	('127 metabolites', 'MPA', (117, 132))	('knockdown', 'Var', (38, 47))
40175	32824856	Interestingly, we found that putrescine was increased seven-fold in CA9 knockdown cells compared with control cells (Figure 4A).	('knockdown', 'Var', (72, 81))	('CA9', 'Gene', '768', (68, 71))	('putrescine', 'MPA', (29, 39))	('increased', 'PosReg', (44, 53))	('putrescine', 'Chemical', 'MESH:D011700', (29, 39))	('CA9', 'Gene', (68, 71))
40177	32824856	Indeed, the metabolomics results show that CA9 knockdown decreased the abundance of arginine, whereas it increased the contents of putrescine, ornithine, and citrulline (Figure 4B).	('citrulline', 'Chemical', 'MESH:D002956', (158, 168))	('arginine', 'Chemical', 'MESH:D001120', (84, 92))	('arginine', 'MPA', (84, 92))	('putrescine', 'MPA', (131, 141))	('citrulline', 'MPA', (158, 168))	('abundance', 'MPA', (71, 80))	('knockdown', 'Var', (47, 56))	('ornithine', 'Chemical', 'MESH:D009952', (143, 152))	('putrescine', 'Chemical', 'MESH:D011700', (131, 141))	('decreased', 'NegReg', (57, 66))	('increased', 'PosReg', (105, 114))	('ornithine', 'MPA', (143, 152))	('CA9', 'Gene', '768', (43, 46))	('CA9', 'Gene', (43, 46))	('contents', 'MPA', (119, 127))
40178	32824856	Then, isotope tracing with 13C6-arginine was performed to determine the effects of CA9 knockdown on putrescine production from arginine.	('arginine', 'Chemical', 'MESH:D001120', (127, 135))	('13C6-arginine', 'Chemical', '-', (27, 40))	('CA9', 'Gene', (83, 86))	('putrescine production from arginine', 'MPA', (100, 135))	('putrescine', 'Chemical', 'MESH:D011700', (100, 110))	('CA9', 'Gene', '768', (83, 86))	('arginine', 'Chemical', 'MESH:D001120', (32, 40))	('knockdown', 'Var', (87, 96))
40180	32824856	13C6-arginine isotope tracing revealed that M+5 ornithine, M+5 citrulline, and M+4 putrescine increased after CA9 knockdown, suggesting putrescine synthesis was enhanced (Figure 4D).	('M+5 ornithine', 'MPA', (44, 57))	('13C6-arginine', 'Chemical', '-', (0, 13))	('putrescine synthesis', 'biological_process', 'GO:0009446', ('136', '156'))	('enhanced', 'PosReg', (161, 169))	('putrescine', 'Chemical', 'MESH:D011700', (136, 146))	('M+5 citrulline', 'MPA', (59, 73))	('M+4 putrescine', 'MPA', (79, 93))	('knockdown', 'Var', (114, 123))	('CA9', 'Gene', (110, 113))	('increased', 'PosReg', (94, 103))	('citrulline', 'Chemical', 'MESH:D002956', (63, 73))	('CA9', 'Gene', '768', (110, 113))	('ornithine', 'Chemical', 'MESH:D009952', (48, 57))	('putrescine synthesis', 'MPA', (136, 156))	('putrescine', 'Chemical', 'MESH:D011700', (83, 93))
40181	32824856	Arginase 2 (ARG2), a mitochondrial enzyme catalyzing the conversion of arginine to ornithine, was significantly upregulated after CA9 knockdown identified by quantitative proteomics data and Western blotting.	('CA9', 'Gene', '768', (130, 133))	('Arginase 2', 'Gene', (0, 10))	('arginine', 'Chemical', 'MESH:D001120', (71, 79))	('upregulated', 'PosReg', (112, 123))	('knockdown', 'Var', (134, 143))	('ornithine', 'Chemical', 'MESH:D009952', (83, 92))	('ARG2', 'Gene', (12, 16))	('ARG2', 'Gene', '384', (12, 16))	('Arginase 2', 'Gene', '384', (0, 10))	('CA9', 'Gene', (130, 133))
40182	32824856	ODC catalyzing ornithine decarboxylation was also upregulated, while argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL) catalyzing the conversion of citrulline to arginine were downregulated after CA9 knockdown (Figure 4E,F and Figure S4).	('argininosuccinate lyase', 'Gene', (109, 132))	('CA9', 'Gene', (216, 219))	('CA9', 'Gene', '768', (216, 219))	('argininosuccinate lyase', 'Gene', '435', (109, 132))	('argininosuccinate synthase 1', 'Gene', '445', (69, 97))	('ASL', 'Gene', '435', (134, 137))	('ODC', 'Gene', '4953', (0, 3))	('upregulated', 'PosReg', (50, 61))	('ornithine', 'Chemical', 'MESH:D009952', (15, 24))	('ASL', 'Gene', (134, 137))	('ASS1', 'Gene', (99, 103))	('ASS1', 'Gene', '445', (99, 103))	('ODC', 'Gene', (0, 3))	('argininosuccinate synthase 1', 'Gene', (69, 97))	('citrulline', 'Chemical', 'MESH:D002956', (168, 178))	('downregulated', 'NegReg', (196, 209))	('arginine', 'Chemical', 'MESH:D001120', (182, 190))	('ornithine decarboxylation', 'MPA', (15, 40))	('knockdown', 'Var', (220, 229))
40184	32824856	These results demonstrated that putrescine synthesis from arginine was increased by CA9 knockdown in ccRCC cells.	('putrescine synthesis from arginine', 'MPA', (32, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('knockdown', 'Var', (88, 97))	('arginine', 'Chemical', 'MESH:D001120', (58, 66))	('CA9', 'Gene', (84, 87))	('increased', 'PosReg', (71, 80))	('CA9', 'Gene', '768', (84, 87))	('putrescine', 'Chemical', 'MESH:D011700', (32, 42))	('putrescine synthesis from arginine', 'biological_process', 'GO:0033388', ('32', '66'))
40186	32824856	The viability of 786-O cells after putrescine treatment for 24 h was detected by CCK-8 kit, and putrescine was found to induce cell death with an IC50 (the half maximal inhibitory concentration) of 16.6 mM (Figure 4G), which is consistent with previous research.	('cell death', 'biological_process', 'GO:0008219', ('127', '137'))	('putrescine', 'Chemical', 'MESH:D011700', (96, 106))	('cell death', 'CPA', (127, 137))	('putrescine', 'Chemical', 'MESH:D011700', (35, 45))	('putrescine', 'Var', (96, 106))
40187	32824856	Metabolomics analysis also showed that most amino acids were reduced in CA9 knockdown cells (Figure 5A).	('knockdown', 'Var', (76, 85))	('CA9', 'Gene', (72, 75))	('amino acids', 'MPA', (44, 55))	('CA9', 'Gene', '768', (72, 75))	('reduced', 'NegReg', (61, 68))
40188	32824856	To explore whether CA9 silencing downregulates amino acid transporters, we performed a surfaceomics analysis to investigate changes in membrane proteins between 786-O-CA9-KD cells and control cells.	('downregulates', 'NegReg', (33, 46))	('CA9', 'Gene', (167, 170))	('CA9', 'Gene', '768', (19, 22))	('amino acid transporters', 'MPA', (47, 70))	('CA9', 'Gene', '768', (167, 170))	('silencing', 'Var', (23, 32))	('membrane', 'cellular_component', 'GO:0016020', ('135', '143'))	('CA9', 'Gene', (19, 22))
40191	32824856	These results indicate that the intake of amino acids was decreased in CA9 knockdown cells.	('intake of amino acids', 'MPA', (32, 53))	('decreased', 'NegReg', (58, 67))	('knockdown', 'Var', (75, 84))	('CA9', 'Gene', '768', (71, 74))	('CA9', 'Gene', (71, 74))
40193	32824856	Taking these results together, CA9 knockdown decreased cellular amino acid levels and protein synthesis, which contributed to suppressed cell proliferation in 786-O cells.	('protein synthesis', 'MPA', (86, 103))	('knockdown', 'Var', (35, 44))	('suppressed', 'NegReg', (126, 136))	('CA9', 'Gene', (31, 34))	('decreased', 'NegReg', (45, 54))	('CA9', 'Gene', '768', (31, 34))	('cell proliferation', 'biological_process', 'GO:0008283', ('137', '155'))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('protein synthesis', 'biological_process', 'GO:0006412', ('86', '103'))	('cellular amino acid levels', 'MPA', (55, 81))	('decreased cellular amino acid levels', 'Phenotype', 'HP:0040299', (45, 81))	('cell proliferation in 786-O cells', 'CPA', (137, 170))
40194	32824856	Furthermore, KEGG BlastKOALA analysis showed that the expression of most surface proteins involved in extracellular matrix (ECM)-receptor interaction and cell adhesion was decreased in CA9 knockdown cells, suggesting that CA9 silencing decreased cell migration (Figure 5E).	('CA9', 'Gene', (222, 225))	('expression', 'MPA', (54, 64))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('102', '122'))	('cell migration', 'CPA', (246, 260))	('CA9', 'Gene', '768', (185, 188))	('CA9', 'Gene', (185, 188))	('decreased', 'NegReg', (172, 181))	('cell migration', 'biological_process', 'GO:0016477', ('246', '260'))	('silencing', 'Var', (226, 235))	('cell adhesion', 'biological_process', 'GO:0007155', ('154', '167'))	('cell adhesion', 'CPA', (154, 167))	('knockdown', 'Var', (189, 198))	('decreased', 'NegReg', (236, 245))	('CA9', 'Gene', '768', (222, 225))
40198	32824856	As the major chaperonin for mitochondrial homeostasis, HSP60 (60 kDa heat shock protein, mitochondrial) knockdown switches the mitochondrial function from ATP production to biosynthesis to facilitate cell proliferation in ccRCC cells.	('HSP60', 'Gene', (55, 60))	('cell proliferation', 'biological_process', 'GO:0008283', ('200', '218'))	('HSP60', 'Gene', '3329', (55, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (222, 227))	('homeostasis', 'biological_process', 'GO:0042592', ('42', '53'))	('shock', 'Phenotype', 'HP:0031273', (74, 79))	('chaperonin', 'molecular_function', 'GO:0003763', ('13', '23'))	('facilitate', 'PosReg', (189, 199))	('biosynthesis', 'biological_process', 'GO:0009058', ('173', '185'))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('switches', 'Reg', (114, 122))	('ATP', 'Chemical', 'MESH:D000255', (155, 158))	('chaperonin', 'molecular_function', 'GO:0016887', ('13', '23'))	('cell proliferation', 'CPA', (200, 218))	('mitochondrial function', 'MPA', (127, 149))	('knockdown', 'Var', (104, 113))
40199	32824856	In contrast, CA9 was highly expressed in ccRCC and we proposed that CA9 silencing enhanced oxidative phosphorylation and decreased cell growth.	('cell growth', 'biological_process', 'GO:0016049', ('131', '142'))	('enhanced', 'PosReg', (82, 90))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('91', '116'))	('CA9', 'Gene', '768', (68, 71))	('CA9', 'Gene', '768', (13, 16))	('silencing', 'Var', (72, 81))	('cell growth', 'CPA', (131, 142))	('decreased', 'NegReg', (121, 130))	('oxidative phosphorylation', 'MPA', (91, 116))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('ccRCC', 'Disease', (41, 46))	('CA9', 'Gene', (68, 71))	('CA9', 'Gene', (13, 16))
40200	32824856	This was confirmed by results presented herein in which CA9 silencing increased mitochondrial biogenesis, reversed the Warburg phenotype, and inhibited cell growth, whereas CA9 overexpression promoted cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('201', '219'))	('increased', 'PosReg', (70, 79))	('promoted', 'PosReg', (192, 200))	('cell growth', 'CPA', (152, 163))	('CA9', 'Gene', (56, 59))	('CA9', 'Gene', (173, 176))	('reversed', 'PosReg', (106, 114))	('inhibited', 'NegReg', (142, 151))	('CA9', 'Gene', '768', (56, 59))	('CA9', 'Gene', '768', (173, 176))	('silencing', 'Var', (60, 69))	('mitochondrial biogenesis', 'MPA', (80, 104))	('cell proliferation', 'CPA', (201, 219))	('Warburg phenotype', 'CPA', (119, 136))	('cell growth', 'biological_process', 'GO:0016049', ('152', '163'))
40202	32824856	We investigated the effects of CA9 knockdown on pHi.	('knockdown', 'Var', (35, 44))	('CA9', 'Gene', (31, 34))	('pHi', 'Gene', '2821', (48, 51))	('CA9', 'Gene', '768', (31, 34))	('pHi', 'Gene', (48, 51))
40203	32824856	We found that CA9 knockdown resulted in a reduction in pHi in 786-O and 769-P cells (Figure S6), consistent with previous research.	('knockdown', 'Var', (18, 27))	('CA9', 'Gene', (14, 17))	('pHi', 'Gene', '2821', (55, 58))	('CA9', 'Gene', '768', (14, 17))	('pHi', 'Gene', (55, 58))	('reduction', 'NegReg', (42, 51))
40209	32824856	We found that CA9 silencing activated oxidative phosphorylation, fatty acid oxidation, and mitochondrial biogenesis, as confirmed by fluorescent MitoTracker analysis.	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('65', '85'))	('silencing', 'Var', (18, 27))	('fatty acid', 'Chemical', 'MESH:D005227', (65, 75))	('CA9', 'Gene', (14, 17))	('fatty acid oxidation', 'MPA', (65, 85))	('CA9', 'Gene', '768', (14, 17))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('38', '63'))	('activated', 'PosReg', (28, 37))	('oxidative phosphorylation', 'MPA', (38, 63))	('mitochondrial biogenesis', 'CPA', (91, 115))
40215	32824856	Polyamines can bind anionic complexes such as DNA, RNA, and proteins at physiological pH to modulate protein synthesis, gene expression, protection from oxidative damage, and maintenance of the structure of cellular macromolecules.	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('Polyamines', 'Var', (0, 10))	('protein synthesis', 'MPA', (101, 118))	('Polyamines', 'Chemical', 'MESH:D011073', (0, 10))	('bind', 'Interaction', (15, 19))	('pH', 'Gene', '2821', (86, 88))	('modulate', 'Reg', (92, 100))	('protein synthesis', 'biological_process', 'GO:0006412', ('101', '118'))	('gene expression', 'MPA', (120, 135))	('gene expression', 'biological_process', 'GO:0010467', ('120', '135'))	('RNA', 'cellular_component', 'GO:0005562', ('51', '54'))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('structure', 'MPA', (194, 203))
40217	32824856	Increased polyamine can promote pancreatic ductal adenocarcinoma and colon cancer cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('82', '100'))	('pancreatic ductal adenocarcinoma and colon cancer', 'Disease', 'MESH:D010190', (32, 81))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (32, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('polyamine', 'Chemical', 'MESH:D011073', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('promote', 'PosReg', (24, 31))	('colon cancer', 'Phenotype', 'HP:0003003', (69, 81))	('polyamine', 'Var', (10, 19))
40219	32824856	Polyamines contribute to uremic toxins and liver damage.	('uremic toxins', 'Disease', (25, 38))	('Polyamines', 'Var', (0, 10))	('Polyamines', 'Chemical', 'MESH:D011073', (0, 10))	('liver damage', 'Disease', (43, 55))	('uremic toxins', 'Disease', 'MESH:D006463', (25, 38))	('liver damage', 'Disease', 'MESH:D056486', (43, 55))	('contribute', 'Reg', (11, 21))
40222	32824856	Our work revealed that CA9 knockdown increased arginine-dependent putrescine production to inhibit cell growth.	('knockdown', 'Var', (27, 36))	('inhibit', 'NegReg', (91, 98))	('arginine', 'Chemical', 'MESH:D001120', (47, 55))	('cell growth', 'biological_process', 'GO:0016049', ('99', '110'))	('cell growth', 'CPA', (99, 110))	('putrescine', 'Chemical', 'MESH:D011700', (66, 76))	('increased', 'PosReg', (37, 46))	('arginine-dependent putrescine production', 'MPA', (47, 87))	('CA9', 'Gene', '768', (23, 26))	('CA9', 'Gene', (23, 26))	('increased arginine', 'Phenotype', 'HP:0500153', (37, 55))
40223	32824856	Furthermore, the polycationic nature of putrescine may be changed after CA9 knockdown due to a reduction in pHi.	('polycationic nature', 'MPA', (17, 36))	('putrescine', 'Chemical', 'MESH:D011700', (40, 50))	('knockdown', 'Var', (76, 85))	('CA9', 'Gene', (72, 75))	('pHi', 'Gene', '2821', (108, 111))	('CA9', 'Gene', '768', (72, 75))	('pHi', 'Gene', (108, 111))	('reduction', 'NegReg', (95, 104))	('changed', 'Reg', (58, 65))	('putrescine', 'Protein', (40, 50))
40225	32824856	Surfaceomics showed that CA9 silencing downregulated multiple amino acid transporters, resulting in the decreased cellular amino acids levels as confirmed by metabolomics analysis.	('CA9', 'Gene', (25, 28))	('CA9', 'Gene', '768', (25, 28))	('silencing', 'Var', (29, 38))	('cellular amino acids levels', 'MPA', (114, 141))	('decreased', 'NegReg', (104, 113))	('decreased cellular amino acids levels', 'Phenotype', 'HP:0040299', (104, 141))	('multiple amino acid transporters', 'MPA', (53, 85))	('downregulated', 'NegReg', (39, 52))
40226	32824856	It is worth mentioning that CA9 silencing also downregulated solute carrier family 4 member 4 (SLC4A4), a bicarbonate cotransporter, indicating that bicarbonate ions may regulate the expressions of these surface proteins.	('SLC4A4', 'Gene', '8671', (95, 101))	('downregulated', 'NegReg', (47, 60))	('solute carrier family 4 member 4', 'Gene', (61, 93))	('bicarbonate', 'Chemical', 'MESH:D001639', (106, 117))	('CA9', 'Gene', (28, 31))	('carrier', 'molecular_function', 'GO:0005215', ('68', '75'))	('CA9', 'Gene', '768', (28, 31))	('silencing', 'Var', (32, 41))	('expressions', 'MPA', (183, 194))	('bicarbonate', 'Chemical', 'MESH:D001639', (149, 160))	('SLC4A4', 'Gene', (95, 101))	('solute carrier family 4 member 4', 'Gene', '8671', (61, 93))
40228	32824856	Previous research found that inhibition of CA9 increases sensitivity of renal cell carcinoma to ionizing radiation.	('renal cell carcinoma to ionizing radiation', 'Disease', (72, 114))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (72, 92))	('CA9', 'Gene', '768', (43, 46))	('renal cell carcinoma to ionizing radiation', 'Disease', 'MESH:C538614', (72, 114))	('increases', 'PosReg', (47, 56))	('sensitivity', 'MPA', (57, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('inhibition', 'Var', (29, 39))	('CA9', 'Gene', (43, 46))
40230	32824856	Based on the results presented in this study in which CA9 knockdown downregulated programmed cell death 1 ligand 1 (PD-L1), we proposed that CA9-inhibition may enhance immunotherapy efficacy.	('programmed cell death 1 ligand 1', 'Gene', (82, 114))	('programmed cell death 1 ligand 1', 'Gene', '29126', (82, 114))	('downregulated', 'NegReg', (68, 81))	('CA9', 'Gene', '768', (141, 144))	('CA9', 'Gene', (141, 144))	('PD-L1', 'Gene', (116, 121))	('immunotherapy efficacy', 'CPA', (168, 190))	('CA9', 'Gene', (54, 57))	('enhance', 'PosReg', (160, 167))	('PD-L1', 'Gene', '29126', (116, 121))	('programmed cell death', 'biological_process', 'GO:0012501', ('82', '103'))	('knockdown', 'Var', (58, 67))	('CA9', 'Gene', '768', (54, 57))	('ligand', 'molecular_function', 'GO:0005488', ('106', '112'))
40231	32824856	Furthermore, CA9 inhibition increased mitochondrial biogenesis, which may enhance the efficacy of glutaminase inhibition for ccRCC treatment.	('increased', 'PosReg', (28, 37))	('CA9', 'Gene', '768', (13, 16))	('glutaminase', 'Gene', (98, 109))	('inhibition', 'Var', (17, 27))	('mitochondrial biogenesis', 'MPA', (38, 62))	('CA9', 'Gene', (13, 16))	('ccRCC', 'Phenotype', 'HP:0006770', (125, 130))	('ccRCC', 'Disease', (125, 130))	('glutaminase', 'Gene', '2744', (98, 109))	('enhance', 'PosReg', (74, 81))
40234	32824856	Minn et al., synthesized [64Cu] XYIMSR-06, a dual-motif CA9 ligand, and found it can image ccRCC by positron emission tomography.	('image', 'Reg', (85, 90))	('ccRCC', 'Disease', (91, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('ligand', 'molecular_function', 'GO:0005488', ('60', '66'))	('[64Cu] XYIMSR-06', 'Var', (25, 41))	('CA9', 'Gene', (56, 59))	('CA9', 'Gene', '768', (56, 59))
40246	32824856	The clone with intense and uniform GFP expression was selected and confirmed the efficiency of CA9 knockdown by Western blotting.	('CA9', 'Gene', '768', (95, 98))	('knockdown', 'Var', (99, 108))	('CA9', 'Gene', (95, 98))
40297	32824856	In summary, the present study demonstrated that CA9 knockdown increased mitochondrial biogenesis and putrescine production, and decreased the expression of surface proteins associated with amino acid transport and cell motility, leading to the reduced cell proliferation and migration in ccRCC.	('cell', 'MPA', (214, 218))	('increased', 'PosReg', (62, 71))	('migration', 'CPA', (275, 284))	('reduced', 'NegReg', (244, 251))	('cell proliferation', 'biological_process', 'GO:0008283', ('252', '270'))	('CA9', 'Gene', (48, 51))	('ccRCC', 'Disease', (288, 293))	('ccRCC', 'Phenotype', 'HP:0006770', (288, 293))	('knockdown', 'Var', (52, 61))	('amino acid transport', 'biological_process', 'GO:0006865', ('189', '209'))	('CA9', 'Gene', '768', (48, 51))	('decreased', 'NegReg', (128, 137))	('mitochondrial biogenesis', 'MPA', (72, 96))	('cell motility', 'biological_process', 'GO:0048870', ('214', '227'))	('putrescine', 'Chemical', 'MESH:D011700', (101, 111))	('putrescine production', 'MPA', (101, 122))	('cell proliferation', 'CPA', (252, 270))
40379	31540830	All ccLS data were collected prospectively on every patient that underwent mpMRI and was found to have a renal tumor.	('renal tumor', 'Disease', (105, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mpMRI', 'Var', (75, 80))	('patient', 'Species', '9606', (52, 59))	('renal tumor', 'Phenotype', 'HP:0009726', (105, 116))	('renal tumor', 'Disease', 'MESH:D007680', (105, 116))
40512	27821813	In the past decades, although the increased detection of small renal masses resulted in better survival (for example, 5-year survival rate increased from 50% in middle 1970s to over 70% in late 2000 s in the United States), over a quarter of patients present with metastasis at initial diagnosis.	('survival', 'MPA', (95, 103))	('small renal', 'Phenotype', 'HP:0000089', (57, 68))	('small', 'Var', (57, 62))	('renal masses', 'Phenotype', 'HP:0009726', (63, 75))	('better', 'PosReg', (88, 94))	('metastasis', 'CPA', (264, 274))	('patients', 'Species', '9606', (242, 250))
40541	27821813	As shown in Figure 5, the nomograms exhibited the largest AUC in ROC analyses of OS and RFS (AUC = 0.843, 0.720 and 0.6357 for OS; AUC = 0.802, 0.664 and 0.617 for RFS; Figure 5A-5B).	('ROC analyses', 'MPA', (65, 77))	('RFS', 'Chemical', '-', (88, 91))	('RFS', 'Chemical', '-', (164, 167))	('0.720', 'Var', (106, 111))	('0.664', 'Var', (144, 149))	('0.6357', 'Var', (116, 122))	('OS', 'Chemical', '-', (81, 83))	('OS', 'Chemical', '-', (127, 129))
40542	27821813	C-index validated this finding as our integrated nomograms reflected the highest c-index value (c-index = 0.8035, 0.7130 and 0.6057 for OS; c-index = 0.7775, 0.6688 and 0.5973 for RFS; Figure 5C).	('0.6057', 'Var', (125, 131))	('0.5973', 'Var', (169, 175))	('OS', 'Chemical', '-', (136, 138))	('RFS', 'Chemical', '-', (180, 183))	('0.6688', 'Var', (158, 164))	('0.7130', 'Var', (114, 120))
40549	27821813	Abolishing either C5a or C5aR could retard tumor growth and metastasis.	('C5a', 'Gene', '728', (18, 21))	('C5aR', 'Gene', (25, 29))	('retard tumor', 'Disease', 'MESH:D009369', (36, 48))	('C5a', 'Gene', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Abolishing', 'Var', (0, 10))	('C5a', 'Gene', '728', (25, 28))	('retard tumor', 'Disease', (36, 48))	('C5a', 'Gene', (18, 21))	('C5aR', 'Gene', '728', (25, 29))
40564	27821813	On the other hand, c-index of the axis was the highest(c-index = 0.6142, 0.5789 and 0.579 for C5a-C5aR, C5a and C5aR, respectively).	('C5a', 'Gene', '728', (104, 107))	('C5a', 'Gene', '728', (94, 97))	('C5aR', 'Gene', (98, 102))	('C5aR', 'Gene', (112, 116))	('0.579', 'Var', (84, 89))	('C5a', 'Gene', (98, 101))	('C5a', 'Gene', (112, 115))	('0.5789', 'Var', (73, 79))	('C5a', 'Gene', '728', (112, 115))	('C5a', 'Gene', '728', (98, 101))	('c-index', 'MPA', (19, 26))	('C5aR', 'Gene', '728', (98, 102))	('C5aR', 'Gene', '728', (112, 116))	('C5a', 'Gene', (104, 107))	('C5a', 'Gene', (94, 97))
40603	31180525	Based on the identified DElncR-DEmiR interactions and DEmiR-DEG interactions, a ceRNA-regulated network comprising 203 nodes and 221 edges was constructed (with MIC >0.15 and MIC-p2 >0.15).	('miR', 'Gene', '220972', (33, 36))	('miR', 'Gene', (33, 36))	('MIC', 'Var', (161, 164))	('MIC-p2', 'Var', (175, 181))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))
40610	31180525	These non-coding RNAs (ncRNAs) can be broadly classified as small ncRNAs (<200 nucleotides, including microRNAs (miRNAs), siRNAs, and piRNAs) or long non-coding (lncRNAs) (>200 nucleotides).	('<200 nucleotides', 'Var', (74, 90))	('miR', 'Gene', '220972', (113, 116))	('miR', 'Gene', (113, 116))
40611	31180525	miRNAs are the most widely studied subclass of small ncRNAs, and they can post-transcriptionally regulate the expression of multiple genes via the imperfect complementarity to their target mRNA transcripts.	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('expression', 'MPA', (110, 120))	('imperfect', 'Var', (147, 156))	('regulate', 'Reg', (97, 105))
40613	31180525	Alteration of lncRNA expression has been reported to be associated with tumor development, and certain lncRNAs have been used as cancer biomarkers and potential targets in several types of tumors.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (189, 194))	('lncRNA expression', 'Protein', (14, 31))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (72, 77))	('Alteration', 'Var', (0, 10))	('tumors', 'Disease', (189, 195))	('associated', 'Reg', (56, 66))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
40627	31180525	The clinical characteristics of patients with ccRCC were extracted from the downloaded data, including sex (female vs. male), age at diagnosis (>=61 years vs. <61 years), tumor grade (G3/G4 vs. G1/G2), tumor status (tumor-burden state vs. tumor-free state), American Joint Committee on Cancer pathologic stage (III/IV vs. I/II), tumor metastasis (yes vs. no), and overall survival time.	('tumor metastasis', 'Disease', 'MESH:D009362', (329, 345))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', (329, 334))	('tumor', 'Disease', (216, 221))	('tumor metastasis', 'Disease', (329, 345))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('Cancer', 'Phenotype', 'HP:0002664', (286, 292))	('tumor', 'Disease', (239, 244))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('Cancer', 'Disease', (286, 292))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('patients', 'Species', '9606', (32, 40))	('G3/G4 vs.', 'Var', (184, 193))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Disease', (171, 176))	('Cancer', 'Disease', 'MESH:D009369', (286, 292))
40633	31180525	Then, the interactions in the lncRNA-miRNA-mRNA network were further identified by calculating maximal information coefficients (MICs) with cut-off values of MIC >0.15 and MIC-p2 >0.15.	('MIC >0.15', 'Var', (158, 167))	('miR', 'Gene', '220972', (37, 40))	('MIC-p2 >0.15', 'Var', (172, 184))	('miR', 'Gene', (37, 40))
40643	31180525	In addition, tumor metastasis was related to the upregulated expression of BPESC1, C20orf203, C7orf71, C2orf48, DGCR9, DGCR5, and DKFZp434J0226 and the downregulated expression of MYCNOS, PP14571, TTTY4C, and PART1.	('PP14571', 'Gene', '100130449', (188, 195))	('C7orf71', 'Gene', '285941', (94, 101))	('C20orf203', 'Gene', (83, 92))	('tumor metastasis', 'Disease', (13, 29))	('DGCR9', 'Gene', '25787', (112, 117))	('downregulated', 'NegReg', (152, 165))	('DGCR5', 'Gene', (119, 124))	('TTTY4C', 'Gene', '474150', (197, 203))	('MYCNOS', 'Gene', '10408', (180, 186))	('BPESC1', 'Gene', (75, 81))	('DGCR5', 'Gene', '26220', (119, 124))	('C2orf48', 'Gene', '348738', (103, 110))	('C7orf71', 'Gene', (94, 101))	('C20orf203', 'Gene', '284805', (83, 92))	('PP14571', 'Gene', (188, 195))	('DGCR9', 'Gene', (112, 117))	('TTTY4C', 'Gene', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('C2orf48', 'Gene', (103, 110))	('DKFZp434J0226', 'Var', (130, 143))	('MYCNOS', 'Gene', (180, 186))	('upregulated', 'PosReg', (49, 60))	('BPESC1', 'Gene', '60467', (75, 81))	('expression', 'MPA', (166, 176))	('expression', 'MPA', (61, 71))	('tumor metastasis', 'Disease', 'MESH:D009362', (13, 29))
40670	31180525	First, the expression of certain differentially expressed lncRNAs, such as C2orf48, DGCR9, DGCR5, DKFZp434J0226, MYCNOS, PP14571, TTTY4C, and PART1, was correlated with tumor metastasis; moreover, the expression of TTTY4C, PSORS1C3, C2orf48, HPYR1, PWRN1, C15orf56, and PART1 was negatively correlated with patient overall survival.	('PP14571', 'Gene', (121, 128))	('HPYR1', 'Gene', (242, 247))	('expression', 'MPA', (11, 21))	('HPYR1', 'Gene', '93668', (242, 247))	('tumor metastasis', 'Disease', 'MESH:D009362', (169, 185))	('TTTY4C', 'Gene', (215, 221))	('MYCNOS', 'Gene', (113, 119))	('correlated', 'Reg', (153, 163))	('PSORS1C3', 'Gene', '100130889', (223, 231))	('negatively', 'NegReg', (280, 290))	('tumor metastasis', 'Disease', (169, 185))	('TTTY4C', 'Gene', '474150', (130, 136))	('C15orf56', 'Gene', (256, 264))	('DKFZp434J0226', 'Var', (98, 111))	('DGCR9', 'Gene', '25787', (84, 89))	('C15orf56', 'Gene', '644809', (256, 264))	('DGCR5', 'Gene', (91, 96))	('PP14571', 'Gene', '100130449', (121, 128))	('C2orf48', 'Gene', '348738', (75, 82))	('PWRN1', 'Gene', (249, 254))	('TTTY4C', 'Gene', (130, 136))	('patient', 'Species', '9606', (307, 314))	('C2orf48', 'Gene', '348738', (233, 240))	('DGCR5', 'Gene', '26220', (91, 96))	('PWRN1', 'Gene', '791114', (249, 254))	('C2orf48', 'Gene', (75, 82))	('correlated', 'Reg', (291, 301))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('DGCR9', 'Gene', (84, 89))	('MYCNOS', 'Gene', '10408', (113, 119))	('C2orf48', 'Gene', (233, 240))	('TTTY4C', 'Gene', '474150', (215, 221))	('PSORS1C3', 'Gene', (223, 231))
40699	33201837	DAPK1 overexpression enhances apoptosis in sunitinib-resistant ccRCC cells via the ATF6-dependent ER stress pathway.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('apoptosis', 'biological_process', 'GO:0006915', ('30', '39'))	('ATF6', 'Gene', (83, 87))	('overexpression', 'Var', (6, 20))	('apoptosis', 'CPA', (30, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('enhances', 'PosReg', (21, 29))	('sunitinib', 'Chemical', 'MESH:D000077210', (43, 52))	('DAPK1', 'Gene', (0, 5))	('ATF6', 'Gene', '22926', (83, 87))	('apoptosis', 'biological_process', 'GO:0097194', ('30', '39'))
40720	33201837	The ccRCC patients with low DAPK1 expression showed significantly shorter OS (N=537, P=0.0233) and DFS (N=434, P=0.0055) compared to patients with high DAPK1 expression (Figure 2A, 2D).	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('shorter', 'NegReg', (66, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (4, 9))	('patients', 'Species', '9606', (133, 141))	('ccRCC', 'Disease', (4, 9))	('DAPK1', 'Gene', (28, 33))	('low', 'Var', (24, 27))	('DFS', 'CPA', (99, 102))	('patients', 'Species', '9606', (10, 18))
40727	33201837	Moreover, ROC curve analysis of various subgroups of ccRCC patients showed that DAPK1 expression accurately distinguished early and advanced stage patients, including (T1 + T2)/(T3 + T4) stage (Figure 3B, AUC =0.5952, P<0.001), TNM (I + II)/(III + IV) stage (Figure 3C, AUC =0.6019, P<0.0001), (G1+G2)/(G3 + G4) stage (Figure 3D, AUC =0.5666, P=0.008527), M0/M1 (Figure 3E, AUC =0.5706, P=0.04636).	('T1', 'Var', (168, 170))	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('DAPK1', 'Gene', (80, 85))	('TNM', 'Gene', (228, 231))	('TNM', 'Gene', '10178', (228, 231))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (59, 67))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
40738	33201837	CCK-8 assay results show that DAPK1 overexpression significantly increases sunitinib sensitivity of 786O-R and ACHN-R cells, whereas, DAPK1 knockdown significantly increased sunitinib resistance of ACHN-R cells (Figure 6C, 6D).	('sunitinib', 'Chemical', 'MESH:D000077210', (174, 183))	('sunitinib resistance', 'MPA', (174, 194))	('increases', 'PosReg', (65, 74))	('DAPK1', 'Gene', (30, 35))	('DAPK1', 'Gene', (134, 139))	('sunitinib sensitivity', 'MPA', (75, 96))	('sunitinib', 'Chemical', 'MESH:D000077210', (75, 84))	('knockdown', 'Var', (140, 149))	('overexpression', 'Var', (36, 50))	('increased', 'PosReg', (164, 173))
40739	33201837	These results demonstrate that DAPK1 overexpression promotes sunitinib sensitivity in ccRCC cells.	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('overexpression', 'Var', (37, 51))	('promotes', 'PosReg', (52, 60))	('sunitinib sensitivity', 'MPA', (61, 82))	('sunitinib', 'Chemical', 'MESH:D000077210', (61, 70))	('ccRCC', 'Disease', (86, 91))	('DAPK1', 'Gene', (31, 36))
40744	33201837	Moreover, DAPK1 overexpression increases apoptosis in sunitinib-resistant 786O-R and ACHN-R cells compared to the corresponding controls (Figure 7C, 7D).	('apoptosis', 'biological_process', 'GO:0097194', ('41', '50'))	('apoptosis', 'biological_process', 'GO:0006915', ('41', '50'))	('increases', 'PosReg', (31, 40))	('sunitinib', 'Chemical', 'MESH:D000077210', (54, 63))	('overexpression', 'Var', (16, 30))	('apoptosis', 'CPA', (41, 50))	('DAPK1', 'Gene', (10, 15))
40745	33201837	Furthermore, recovery experiments show that after overexpression of DAPK1, the expression of Caspase-3 in 786O-R cell line increased significantly, while knocking down ATF6, on the basis of overexpression DAPK1, did not increase the expression of Caspase-3.	('knocking down', 'Var', (154, 167))	('increased', 'PosReg', (123, 132))	('Caspase-3', 'Gene', (247, 256))	('expression', 'MPA', (79, 89))	('ATF6', 'Gene', (168, 172))	('Caspase-3', 'Gene', (93, 102))	('Caspase-3', 'Gene', '836', (247, 256))	('DAPK1', 'Var', (68, 73))	('Caspase-3', 'Gene', '836', (93, 102))	('ATF6', 'Gene', '22926', (168, 172))
40746	33201837	This result showed that DAPK1 overexpression promoted apoptosis of sunitinib-resistant cells via upregulation of ATF6 (Figure 7E).	('apoptosis', 'CPA', (54, 63))	('upregulation', 'PosReg', (97, 109))	('ATF6', 'Gene', '22926', (113, 117))	('promoted', 'PosReg', (45, 53))	('apoptosis', 'biological_process', 'GO:0097194', ('54', '63'))	('ATF6', 'Gene', (113, 117))	('apoptosis', 'biological_process', 'GO:0006915', ('54', '63'))	('sunitinib', 'Chemical', 'MESH:D000077210', (67, 76))	('overexpression', 'Var', (30, 44))	('DAPK1', 'Gene', (24, 29))
40750	33201837	DAPK1 overexpression induces apoptosis in sunitinib-resistant ccRCC cell lines by enhancing ATF6-dependent ER stress pathway.	('sunitinib', 'Chemical', 'MESH:D000077210', (42, 51))	('ATF6', 'Gene', '22926', (92, 96))	('overexpression', 'Var', (6, 20))	('DAPK1', 'Gene', (0, 5))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('apoptosis', 'biological_process', 'GO:0097194', ('29', '38'))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('ATF6', 'Gene', (92, 96))	('apoptosis', 'biological_process', 'GO:0006915', ('29', '38'))	('enhancing', 'PosReg', (82, 91))
40754	33201837	Moreover, hypermethylation of the DAPK1 promoter is reported in tumor tissues and lymph nodes of patients with gastric cancer and head and neck tumors.	('hypermethylation', 'Var', (10, 26))	('gastric cancer', 'Disease', 'MESH:D013274', (111, 125))	('tumor', 'Disease', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumor', 'Disease', (64, 69))	('head and neck tumors', 'Disease', 'MESH:D006258', (130, 150))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('head and neck tumors', 'Phenotype', 'HP:0012288', (130, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('neck', 'cellular_component', 'GO:0044326', ('139', '143'))	('reported', 'Reg', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('DAPK1', 'Gene', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('gastric cancer', 'Disease', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('patients', 'Species', '9606', (97, 105))
40756	33201837	These studies showed that DAPK1 promoter hypermethylation was positively associated with advanced cancer stages and metastasis in several cancers, thereby suggesting that DAPK1 methylation is a potential prognostic marker in different human cancers.	('cancer', 'Disease', (138, 144))	('promoter hypermethylation', 'Var', (32, 57))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('associated', 'Reg', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('metastasis', 'CPA', (116, 126))	('cancers', 'Disease', 'MESH:D009369', (241, 248))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancers', 'Disease', 'MESH:D009369', (138, 145))	('methylation', 'biological_process', 'GO:0032259', ('177', '188'))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('human', 'Species', '9606', (235, 240))	('DAPK1', 'Gene', (26, 31))	('cancer', 'Disease', (241, 247))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancers', 'Phenotype', 'HP:0002664', (241, 248))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', (241, 248))
40757	33201837	In ccRCC, inhibition of miR-34a-5p upregulates DAPK1 protein expression and corrects the dysregulated p53-DAPK axis.	('DAPK', 'Gene', (47, 51))	('DAPK', 'Gene', '1612', (47, 51))	('corrects', 'NegReg', (76, 84))	('DAPK', 'Gene', (106, 110))	('DAPK', 'Gene', '1612', (106, 110))	('p53', 'Gene', '7157', (102, 105))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('miR-34a-5p', 'Var', (24, 34))	('ccRCC', 'Disease', (3, 8))	('protein', 'Protein', (53, 60))	('p53', 'Gene', (102, 105))	('inhibition', 'Var', (10, 20))	('upregulates', 'PosReg', (35, 46))	('expression', 'MPA', (61, 71))
40762	33201837	Deregulation of redox or calcium homoeostasis, glucose deficiency or viral infections can induce ER stress-mediated unfolded protein response or UPR.	('Deregulation', 'Var', (0, 12))	('homoeostasis, glucose deficiency', 'Disease', 'MESH:D018149', (33, 65))	('ER stress-mediated unfolded protein response', 'MPA', (97, 141))	('induce', 'Reg', (90, 96))	('calcium', 'Chemical', 'MESH:D002118', (25, 32))	('UPR', 'PosReg', (145, 148))	('viral infections', 'Disease', (69, 85))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('viral infections', 'Disease', 'MESH:D001102', (69, 85))
40772	33201837	DAPK1 overexpression reverses sunitinib resistance in sunitinib-resistant ccRCC cell lines by inducing ATF6-related ER stress and apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('apoptosis', 'CPA', (130, 139))	('overexpression', 'Var', (6, 20))	('ATF6', 'Gene', (103, 107))	('inducing', 'PosReg', (94, 102))	('ER stress', 'MPA', (116, 125))	('sunitinib', 'Chemical', 'MESH:D000077210', (54, 63))	('DAPK1', 'Gene', (0, 5))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('ATF6', 'Gene', '22926', (103, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))	('sunitinib', 'Chemical', 'MESH:D000077210', (30, 39))	('reverses', 'NegReg', (21, 29))
40779	33201837	Then, the blots were incubated overnight at 4  C with primary antibodies against DAPK1 (25136-1-AP; ProteinTech), ATF6 (ab227830; Abcam), GAPDH (ab198394; Abcam), and Caspase-3 (#9662; Cell Signaling Technology).	('Caspase-3', 'Gene', '836', (167, 176))	('GAPDH', 'Gene', '2597', (138, 143))	('ATF6', 'Gene', '22926', (114, 118))	('GAPDH', 'Gene', (138, 143))	('DAPK1', 'Gene', (81, 86))	('Signaling', 'biological_process', 'GO:0023052', ('190', '199'))	('ATF6', 'Gene', (114, 118))	('Caspase-3', 'Gene', (167, 176))	('25136-1-AP;', 'Var', (88, 99))
40803	28212566	Additionally, tumor specific somatic mutations in PBRM1, BAP1 and KDM5C were determined We confirmed a correlation between deletions at 9p and higher tumor size, and deletion of chromosome 20 and the survival time.	('KDM5C', 'Gene', '8242', (66, 71))	('deletion', 'Var', (166, 174))	('tumor', 'Disease', (14, 19))	('PBRM1', 'Gene', (50, 55))	('PBRM1', 'Gene', '55193', (50, 55))	('KDM5C', 'Gene', (66, 71))	('deletions', 'Var', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('BAP1', 'Gene', '8314', (57, 61))	('higher', 'PosReg', (143, 149))	('survival time', 'CPA', (200, 213))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('BAP1', 'Gene', (57, 61))	('tumor', 'Disease', (150, 155))	('chromosome', 'cellular_component', 'GO:0005694', ('178', '188'))
40805	28212566	In total 12 common and 94 rare variants were detected in PBRM1, BAP1 and KDM5C, with four potentially pathogenic variants.	('BAP1', 'Gene', (64, 68))	('PBRM1', 'Gene', (57, 62))	('variants', 'Var', (31, 39))	('KDM5C', 'Gene', '8242', (73, 78))	('PBRM1', 'Gene', '55193', (57, 62))	('BAP1', 'Gene', '8314', (64, 68))	('KDM5C', 'Gene', (73, 78))
40808	28212566	The functional studies on in BAP1, KDM5C, PBRM1 mutations in large, independent sample set would be necessary for the assessment of their prognostic and diagnostic potential.	('KDM5C', 'Gene', '8242', (35, 40))	('PBRM1', 'Gene', (42, 47))	('BAP1', 'Gene', '8314', (29, 33))	('PBRM1', 'Gene', '55193', (42, 47))	('KDM5C', 'Gene', (35, 40))	('mutations', 'Var', (48, 57))	('BAP1', 'Gene', (29, 33))
40812	28212566	In over 70% of sporadic ccRCC cases, von Hippel-Lindau (VHL) tumor suppressor gene inactivation through sequence alteration, promoter CpG hypermethylation or loss of heterozygosity has been reported.	('loss of heterozygosity', 'Var', (158, 180))	('hypermethylation', 'Var', (138, 154))	('inactivation', 'NegReg', (83, 95))	('ccRCC', 'Disease', (24, 29))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (37, 66))	('tumor suppressor', 'biological_process', 'GO:0051726', ('61', '77'))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('61', '77'))	('sequence alteration', 'Var', (104, 123))
40813	28212566	Germline VHL mutations are also linked to an increased risk of developing ccRCC in patients with the inherited disorder von Hippel-Lindau syndrome.	('inherited disorder von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (101, 146))	('ccRCC', 'Disease', (74, 79))	('VHL', 'Gene', (9, 12))	('inherited disorder von Hippel-Lindau syndrome', 'Disease', (101, 146))	('VHL', 'Gene', '7428', (9, 12))	('patients', 'Species', '9606', (83, 91))	('mutations', 'Var', (13, 22))
40816	28212566	pVHL inactivation results in constitutive HIFs activity leading to enhanced angiogenesis and cell proliferation thus stimulating tumor growth.	('angiogenesis', 'biological_process', 'GO:0001525', ('76', '88'))	('pVHL', 'Gene', (0, 4))	('tumor', 'Disease', (129, 134))	('angiogenesis', 'CPA', (76, 88))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('cell proliferation', 'CPA', (93, 111))	('cell proliferation', 'biological_process', 'GO:0008283', ('93', '111'))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('HIFs', 'Protein', (42, 46))	('stimulating', 'PosReg', (117, 128))	('activity', 'MPA', (47, 55))	('inactivation', 'Var', (5, 17))	('enhanced', 'PosReg', (67, 75))
40818	28212566	VHL mutations are not the only driving force in ccRCC tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('VHL', 'Gene', (0, 3))	('ccRCC', 'Disease', (48, 53))	('mutations', 'Var', (4, 13))	('tumor', 'Disease', (54, 59))	('VHL', 'Gene', '7428', (0, 3))
40819	28212566	Recent large-scale sequencing studies have revealed frequent mutations affecting chromatin modifying genes such as PBRM1, BAP1, SETD2, KDM5C and KMD6A.	('KDM5C', 'Gene', (135, 140))	('BAP1', 'Gene', (122, 126))	('SETD2', 'Gene', (128, 133))	('KDM5C', 'Gene', '8242', (135, 140))	('mutations', 'Var', (61, 70))	('PBRM1', 'Gene', (115, 120))	('chromatin', 'cellular_component', 'GO:0000785', ('81', '90'))	('BAP1', 'Gene', '8314', (122, 126))	('PBRM1', 'Gene', '55193', (115, 120))	('SETD2', 'Gene', '29072', (128, 133))
40820	28212566	PBRM1, SETD2 and BAP1, similarly to VHL, map to the 3p21 and this suggests that essential component of ccRCC pathogenesis may be allelic loss of 3p resulting in haploinsufficiency for four tumor suppressors simultaneously.	('tumor', 'Disease', (189, 194))	('pathogenesis', 'biological_process', 'GO:0009405', ('109', '121'))	('VHL', 'Gene', (36, 39))	('VHL', 'Gene', '7428', (36, 39))	('PBRM1', 'Gene', (0, 5))	('haploinsufficiency', 'Disease', 'MESH:D058495', (161, 179))	('PBRM1', 'Gene', '55193', (0, 5))	('SETD2', 'Gene', '29072', (7, 12))	('ccRCC', 'Disease', (103, 108))	('SETD2', 'Gene', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('loss', 'Var', (137, 141))	('BAP1', 'Gene', '8314', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('haploinsufficiency', 'Disease', (161, 179))	('BAP1', 'Gene', (17, 21))
40821	28212566	Moreover, mutations in BAP1 and SETD2 are probably secondary events to VHL or PBRM1 loss.	('BAP1', 'Gene', (23, 27))	('SETD2', 'Gene', '29072', (32, 37))	('SETD2', 'Gene', (32, 37))	('VHL', 'Gene', (71, 74))	('PBRM1', 'Gene', '55193', (78, 83))	('loss', 'NegReg', (84, 88))	('VHL', 'Gene', '7428', (71, 74))	('BAP1', 'Gene', '8314', (23, 27))	('mutations', 'Var', (10, 19))	('PBRM1', 'Gene', (78, 83))
40822	28212566	Sequencing projects have also identified potentially pathogenic mutations of the known tumor suppressor genes CDKN2A, TP53, NF2, and PTEN in a subset of ccRCC tumors as well as mutations in PI3K pathway regulators mTOR and PIK3CA, frequently abolished in many cancers.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('CDKN2A', 'Gene', '1029', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('PI3K pathway', 'Pathway', (190, 202))	('cancers', 'Disease', 'MESH:D009369', (260, 267))	('pathogenic', 'Reg', (53, 63))	('TP53', 'Gene', (118, 122))	('PIK3CA', 'Gene', '5290', (223, 229))	('PTEN', 'Gene', '5728', (133, 137))	('mutations', 'Var', (64, 73))	('NF2', 'Gene', '4771', (124, 127))	('ccRCC tumors', 'Disease', (153, 165))	('NF2', 'Gene', (124, 127))	('cancers', 'Phenotype', 'HP:0002664', (260, 267))	('tumor', 'Disease', (87, 92))	('cancers', 'Disease', (260, 267))	('mTOR', 'Gene', (214, 218))	('tumor', 'Disease', (159, 164))	('PIK3CA', 'Gene', (223, 229))	('TP53', 'Gene', '7157', (118, 122))	('PI3K', 'molecular_function', 'GO:0016303', ('190', '194'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('87', '103'))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('ccRCC tumors', 'Disease', 'MESH:D009369', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('CDKN2A', 'Gene', (110, 116))	('tumor suppressor', 'biological_process', 'GO:0051726', ('87', '103'))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('PTEN', 'Gene', (133, 137))	('mTOR', 'Gene', '2475', (214, 218))
40824	28212566	The most frequent genomic changes are deletion of chromosome 3p harboring VHL gene (70-80%) and/or loss of heterozygosity (LOH) at 3p, as well as gain of chromosome 5q (50-60%).	('chromosome', 'cellular_component', 'GO:0005694', ('154', '164'))	('VHL', 'Gene', (74, 77))	('gain', 'PosReg', (146, 150))	('VHL', 'Gene', '7428', (74, 77))	('loss', 'NegReg', (99, 103))	('deletion', 'Var', (38, 46))	('chromosome', 'cellular_component', 'GO:0005694', ('50', '60'))
40825	28212566	Other chromosomal imbalances have also been reported, in a large study encompassing 763 patients with ccRCC from Central and Eastern European population the most common were deletion of chromosome 14q (46.8%), 8p (38.1%), 4q (35.4%), 9p (32.3%), 6q (30.8%), 1p (23.5%) and gains of 7q (39.6%), 7p (30.6%), 20q (25.5%), 12q (24.8%) and 12p (22.8%).	('patients', 'Species', '9606', (88, 96))	('ccRCC', 'Disease', (102, 107))	('12q', 'Var', (319, 322))	('chromosome', 'cellular_component', 'GO:0005694', ('186', '196'))	('deletion', 'Var', (174, 182))	('imbalances', 'Phenotype', 'HP:0002172', (18, 28))	('gains', 'Var', (273, 278))
40826	28212566	VHL inactivation may serve an important diagnostic factor, however its prognostic relevance in patients with sporadic ccRCCs remains undetermined due to low number of studies performed and the conflicting results.	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', (0, 3))	('inactivation', 'Var', (4, 16))	('patients', 'Species', '9606', (95, 103))
40827	28212566	On the other hand, most of mutations of chromatin modulating genes are associated with advanced stage, metastases, and shorter overall survival.	('mutations', 'Var', (27, 36))	('shorter', 'NegReg', (119, 126))	('advanced stage', 'CPA', (87, 101))	('chromatin', 'cellular_component', 'GO:0000785', ('40', '49'))	('metastases', 'Disease', 'MESH:D009362', (103, 113))	('metastases', 'Disease', (103, 113))	('associated', 'Reg', (71, 81))	('overall', 'MPA', (127, 134))
40828	28212566	Copy number alterations in ccRCC tumors have also shown association with clinical parameters.	('ccRCC tumors', 'Disease', 'MESH:D009369', (27, 39))	('association', 'Reg', (56, 67))	('ccRCC tumors', 'Disease', (27, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('Copy number alterations', 'Var', (0, 23))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))
40829	28212566	Interestingly, deletion of 3p (accompanied by other chromosomal aberrations) is correlated with improved survival, low tumor stage and grade, and low risk of distant metastases.	('low tumor', 'Disease', 'MESH:D009800', (115, 124))	('improved', 'PosReg', (96, 104))	('metastases', 'Disease', (166, 176))	('low tumor', 'Disease', (115, 124))	('deletion', 'Var', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('metastases', 'Disease', 'MESH:D009362', (166, 176))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (52, 75))	('survival', 'CPA', (105, 113))
40842	28212566	We observed differences in the distribution of 28 most common genomic changes between high pT stage groups 3 and 4 (larger size of the primary tumor) and low pT stage groups (1 and 2), however only deletion of the 9p reached the level of significance (p=0.038).	('deletion', 'Var', (198, 206))	('low pT', 'Phenotype', 'HP:0032198', (154, 160))	('primary tumor', 'Disease', (135, 148))	('primary tumor', 'Disease', 'MESH:D009369', (135, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
40847	28212566	Regression analysis showed that chromosome 20 gain was significantly associated with survival rate, suggesting that its presence can be used as a prognostic factor for increased risk of death (HR 4.3; 95%CI 1.3-13.99; p=0.015), as suggested previously.	('death', 'Disease', 'MESH:D003643', (186, 191))	('chromosome 20', 'Gene', (32, 45))	('gain', 'PosReg', (46, 50))	('survival', 'MPA', (85, 93))	('presence', 'Var', (120, 128))	('death', 'Disease', (186, 191))	('chromosome', 'cellular_component', 'GO:0005694', ('32', '42'))
40849	28212566	Tumors at the lowest grade, G1, had typically only a few cytogenetic alterations: deletion of 3p, 1p, 8p, 10q and gain of 5q, 7, 13q and 16q (Figure 3, Supplementary Table 1).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('deletion', 'Var', (82, 90))	('gain', 'PosReg', (114, 118))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
40852	28212566	We observed that deletions of 9p (p=0.015) and 18q (p=0.034) were more common in tumors with high Fuhrman grade (3, 4).	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('deletions', 'Var', (17, 26))	('common', 'Reg', (71, 77))	('18q', 'Gene', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
40853	28212566	Value of these chromosomal alterations as potential predictors of Fuhrman tumor grade (as well as monosomy 14) was confirmed by univariate logistic regression which showed highest odds ratio to higher grades (G3, G4) in case of these three alterations (OR 4.5, 95%CI 1.42-17.74; OR 11.4, 95%CI, 2.01-215.7; OR 2.9, 95%CI, 1.06-8.54, respectively; Table 2).	('alterations', 'Var', (240, 251))	('Fuhrman tumor', 'Disease', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('Fuhrman tumor', 'Disease', 'MESH:D009369', (66, 79))	('alterations', 'Var', (27, 38))
40858	28212566	Sample 69 showed no chromosomal aberrations in cfDNA analysis (Figure 7), although microarray on tumor biopsy revealed 3p deletion and 5q gain.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('gain', 'PosReg', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('3p deletion', 'Var', (119, 130))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (20, 43))	('tumor', 'Disease', (97, 102))
40863	28212566	Only in one sample showing VHL and PBMR1 deletion we observed normal copy number of BAP1.	('BAP1', 'Gene', '8314', (84, 88))	('deletion', 'Var', (41, 49))	('PBMR1', 'Gene', (35, 40))	('VHL', 'Gene', (27, 30))	('BAP1', 'Gene', (84, 88))	('copy number', 'MPA', (69, 80))	('VHL', 'Gene', '7428', (27, 30))
40864	28212566	In one sample we detected normal copy number of VHL with BAP1, PBRM1 deletion, however the region 3p25 showed LOH (data not shown).	('VHL', 'Gene', '7428', (48, 51))	('PBRM1', 'Gene', (63, 68))	('BAP1', 'Gene', '8314', (57, 61))	('PBRM1', 'Gene', '55193', (63, 68))	('deletion', 'Var', (69, 77))	('VHL', 'Gene', (48, 51))	('BAP1', 'Gene', (57, 61))
40870	28212566	Common variants were found only in KDM5C (n=7) and PBRM1 (n=5) genes.	('KDM5C', 'Gene', '8242', (35, 40))	('variants', 'Var', (7, 15))	('PBRM1', 'Gene', (51, 56))	('KDM5C', 'Gene', (35, 40))	('PBRM1', 'Gene', '55193', (51, 56))
40871	28212566	As shown in Figure 9A the majority of rare variants were present in PBRM1 (69%, n=69), the remaining variants were present at nearly equal frequencies in KDM5C (16%, n=16) and BAP1 (15%, n=15).	('PBRM1', 'Gene', (68, 73))	('BAP1', 'Gene', '8314', (176, 180))	('KDM5C', 'Gene', (154, 159))	('PBRM1', 'Gene', '55193', (68, 73))	('KDM5C', 'Gene', '8242', (154, 159))	('BAP1', 'Gene', (176, 180))	('variants', 'Var', (43, 51))
40872	28212566	In 10 patients (12%) we found >3 variants in PBRM1, with prevalence of intronic mutations.	('PBRM1', 'Gene', '55193', (45, 50))	('PBRM1', 'Gene', (45, 50))	('variants', 'Var', (33, 41))	('patients', 'Species', '9606', (6, 14))
40873	28212566	One novel KDM5C variant is located outside of the peptidaseC12 functional domain leading to an amino acid change D376H (Figure 10).	('D376H', 'Var', (113, 118))	('KDM5C', 'Gene', '8242', (10, 15))	('D376H', 'SUBSTITUTION', 'None', (113, 118))	('KDM5C', 'Gene', (10, 15))
40874	28212566	The remaining three variants were found in PBRM1 gene (Figure 10), of which two are novel (p.S743P, p.K1016N).	('PBRM1', 'Gene', (43, 48))	('p.S743P', 'Mutation', 'p.S743P', (91, 98))	('p.K1016N', 'Mutation', 'p.K1016N', (100, 108))	('PBRM1', 'Gene', '55193', (43, 48))	('p.S743P', 'Var', (91, 98))	('p.K1016N', 'Var', (100, 108))
40875	28212566	Variant p.S605F was previously described in melanoma and kidney tumor samples (COSMIC database).	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('kidney tumor', 'Phenotype', 'HP:0009726', (57, 69))	('melanoma', 'Disease', (44, 52))	('kidney tumor', 'Disease', 'MESH:D007674', (57, 69))	('p.S605F', 'Var', (8, 15))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('p.S605F', 'Mutation', 'p.S605F', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('kidney tumor', 'Disease', (57, 69))
40876	28212566	All possibly/probably damaging PBRM1 variants were present in functional domains: bromodomain 5, bromo-adjacent homology domain 1 and bromodomain 4, respectively.	('variants', 'Var', (37, 45))	('PBRM1', 'Gene', (31, 36))	('PBRM1', 'Gene', '55193', (31, 36))	('damaging', 'Reg', (22, 30))
40878	28212566	Moreover, deletions at 1p, 4p, 4q, 8p, 9p, 9q, 13q, 14q, and 18q have been found to correlate with higher malignancy grades and tumor stages in ccRCC.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('higher', 'PosReg', (99, 105))	('malignancy', 'Disease', (106, 116))	('deletions', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('ccRCC', 'Disease', (144, 149))	('tumor', 'Disease', (128, 133))	('malignancy', 'Disease', 'MESH:D009369', (106, 116))
40879	28212566	Unfortunately we did not find a correlation between chromosomal rearrangements in metastatic tumors and patient survival, most probably due to relatively short 24 month patient follow-up.	('chromosomal rearrangements', 'Var', (52, 78))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('patient', 'Species', '9606', (104, 111))	('patient', 'Species', '9606', (169, 176))	('tumors', 'Disease', (93, 99))
40894	28212566	However, their contribution to cancer development and the functional consequences of the mutations still require further studies.	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('mutations', 'Var', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))
40896	28212566	In case of PBRM1 we observed markedly lower level of variants in Polish population (11%) than reviewed by Piva and colleagues (26-52%).	('PBRM1', 'Gene', (11, 16))	('PBRM1', 'Gene', '55193', (11, 16))	('variants', 'Var', (53, 61))	('lower', 'NegReg', (38, 43))
40898	28212566	We did not observe a significant co-occurrence of detected variants and VHL mutations (identified with standard Sanger sequencing, data not shown), as demonstrated on Figure 11.	('variants', 'Var', (59, 67))	('VHL', 'Gene', '7428', (72, 75))	('VHL', 'Gene', (72, 75))
40900	28212566	BAP1 loss was reported to correlate with high Fuhrman nuclear grade, higher tumor stage, and worst overall survival.	('BAP1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('high', 'Var', (41, 45))	('loss', 'NegReg', (5, 9))	('BAP1', 'Gene', '8314', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
40902	28212566	Three novel non-synonymous coding variants and one previously reported were predicted to be damaging and/or deleterious : one in KDM5C and three in PBRM1, suggesting possible correlation with the ccRCC phenotype.	('variants', 'Var', (34, 42))	('KDM5C', 'Gene', (129, 134))	('non-synonymous', 'Var', (12, 26))	('KDM5C', 'Gene', '8242', (129, 134))	('PBRM1', 'Gene', (148, 153))	('correlation', 'Reg', (175, 186))	('ccRCC', 'Disease', (196, 201))	('PBRM1', 'Gene', '55193', (148, 153))
40904	28212566	S605F and S743P substitutions are present in bromodomain 4 and 5, respectively, suggesting that they may impair chromatin targeting of PBRM1.	('chromatin', 'cellular_component', 'GO:0000785', ('112', '121'))	('S743P', 'Mutation', 'p.S743P', (10, 15))	('chromatin targeting', 'MPA', (112, 131))	('S743P', 'Var', (10, 15))	('S605F', 'Mutation', 'p.S605F', (0, 5))	('PBRM1', 'Gene', (135, 140))	('S605F', 'Var', (0, 5))	('impair', 'NegReg', (105, 111))	('PBRM1', 'Gene', '55193', (135, 140))
40905	28212566	Although not present in dbSNP database, p.S605F has been reported in COSMIC in ccRCC patients as well as alterations within residue 743: p.E742_I745del and p.S743F.	('p.E742_I745del', 'Var', (137, 151))	('p.S743F', 'Mutation', 'p.S743F', (156, 163))	('p.S743F', 'Var', (156, 163))	('p.E742_I745del', 'Mutation', 'p.742,745del_I', (137, 151))	('ccRCC', 'Disease', (79, 84))	('patients', 'Species', '9606', (85, 93))	('p.S605F', 'Var', (40, 47))	('p.S605F', 'Mutation', 'p.S605F', (40, 47))
40907	28212566	These domains are frequent targets of missense mutations in renal cancer, which suggest that K1016N substitution present in BAH1, although not reported before, may have functional impact on the protein function.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('protein', 'Protein', (194, 201))	('K1016N', 'SUBSTITUTION', 'None', (93, 99))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('BAH1', 'Gene', (124, 128))	('impact', 'Reg', (180, 186))	('renal cancer', 'Disease', (60, 72))	('K1016N', 'Var', (93, 99))	('renal cancer', 'Disease', 'MESH:D007680', (60, 72))	('renal cancer', 'Phenotype', 'HP:0009726', (60, 72))
40908	28212566	In contrast, D443H is located outside of KDM5C functional domains, however close to the PHD finger thus we can speculate that this variant could influence rather DNA binding than direct chromatin remodeling functions of this lysine-specific demethylase.	('KDM5C', 'Gene', '8242', (41, 46))	('DNA', 'cellular_component', 'GO:0005574', ('162', '165'))	('DNA binding', 'molecular_function', 'GO:0003677', ('162', '173'))	('DNA', 'Protein', (162, 165))	('lysine', 'Chemical', 'MESH:D008239', (225, 231))	('PHD', 'molecular_function', 'GO:0050175', ('88', '91'))	('D443H', 'Mutation', 'p.D443H', (13, 18))	('chromatin', 'cellular_component', 'GO:0000785', ('186', '195'))	('D443H', 'Var', (13, 18))	('KDM5C', 'Gene', (41, 46))	('influence', 'Reg', (145, 154))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('186', '206'))
40909	28212566	These include four novel variants leading to frameshift and one introducing premature stop codon within bromodomain 4 at position 602 of PBRM1.	('leading', 'Reg', (34, 41))	('frameshift', 'Var', (45, 55))	('PBRM1', 'Gene', (137, 142))	('PBRM1', 'Gene', '55193', (137, 142))	('premature stop codon', 'MPA', (76, 96))
40911	28212566	The catalytic peptidase C12 domain of BAP1 which has a deubiquitinase activity is often targeted by missense mutations in ccRCC.	('deubiquitinase activity', 'molecular_function', 'GO:0101005', ('55', '78'))	('BAP1', 'Gene', (38, 42))	('deubiquitinase activity', 'molecular_function', 'GO:0004843', ('55', '78'))	('targeted', 'Reg', (88, 96))	('missense mutations', 'Var', (100, 118))	('ccRCC', 'Gene', (122, 127))	('deubiquitinase activity', 'MPA', (55, 78))	('BAP1', 'Gene', '8314', (38, 42))
40912	28212566	One variant found in our patients is novel and leads to a frameshift (Figure 10).	('leads to', 'Reg', (47, 55))	('frameshift', 'Var', (58, 68))	('patients', 'Species', '9606', (25, 33))
40913	28212566	It should be also emphasized that in contrast to VHL, in case of PBRM1, BAP1 and KDM5C no gene silencing due to promoter hypermethylation has been reported suggesting that gene function impairment is rather entirely achieved through mutations within coding regions and regulatory elements.	('BAP1', 'Gene', '8314', (72, 76))	('gene silencing', 'biological_process', 'GO:0016458', ('90', '104'))	('KDM5C', 'Gene', (81, 86))	('PBRM1', 'Gene', (65, 70))	('PBRM1', 'Gene', '55193', (65, 70))	('BAP1', 'Gene', (72, 76))	('KDM5C', 'Gene', '8242', (81, 86))	('promoter hypermethylation', 'Var', (112, 137))	('VHL', 'Gene', (49, 52))	('mutations', 'Var', (233, 242))	('VHL', 'Gene', '7428', (49, 52))
40914	28212566	Therefore, functional studies on in BAP1, KDM5C, PBRM1 mutations impact on gene/protein function are required.	('gene/protein function', 'MPA', (75, 96))	('mutations', 'Var', (55, 64))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('BAP1', 'Gene', '8314', (36, 40))	('KDM5C', 'Gene', (42, 47))	('PBRM1', 'Gene', (49, 54))	('BAP1', 'Gene', (36, 40))	('PBRM1', 'Gene', '55193', (49, 54))	('impact', 'Reg', (65, 71))	('KDM5C', 'Gene', '8242', (42, 47))
40915	28212566	There is also necessity of population specific analysis of ccRCC mutations (germline and somatic) and their functional consequences, which is supported by our finding that as much as 38% of all identified variants in BAP1, KDMC5, and PBRM1 were not previously reported in dbSNP database.	('BAP1', 'Gene', '8314', (217, 221))	('BAP1', 'Gene', (217, 221))	('PBRM1', 'Gene', (234, 239))	('variants', 'Var', (205, 213))	('PBRM1', 'Gene', '55193', (234, 239))	('KDMC5', 'Gene', (223, 228))
40918	28212566	The functional studies on possibly pathogenic variant in BAP1, KDM5C, and PBRM1 as well as study of both somatic and germline variations in larger sample sets would be necessary for better risk assessment.	('pathogenic', 'Reg', (35, 45))	('variant', 'Var', (46, 53))	('PBRM1', 'Gene', '55193', (74, 79))	('BAP1', 'Gene', '8314', (57, 61))	('KDM5C', 'Gene', (63, 68))	('BAP1', 'Gene', (57, 61))	('PBRM1', 'Gene', (74, 79))	('KDM5C', 'Gene', '8242', (63, 68))
40937	33434215	Finally, by constructing the miRNA -mRNA interaction network, it was determined that five miRNAs (hsa-mir-199a-5p, hsa-mir-199b-5p, hsa-mir-532-3p and hsa-mir-429) and two key genes (ETS1 and hapln1) are significantly related to the overall survival rate of patients.	('hapln1', 'Gene', (192, 198))	('hsa-mir-429', 'Gene', '554210', (151, 162))	('related', 'Reg', (218, 225))	('hsa-mir-199b-5p', 'Var', (115, 130))	('ETS1', 'Gene', (183, 187))	('ETS1', 'Gene', '2113', (183, 187))	('hsa-mir-429', 'Gene', (151, 162))	('hsa-mir-199a-5p', 'Var', (98, 113))	('patients', 'Species', '9606', (258, 266))	('hsa-mir-532-3p', 'Var', (132, 146))	('hapln1', 'Gene', '1404', (192, 198))
40949	33434215	It include five miRNAs (hsa-mir-199a-5p, hsa-mir-199b-5p, hsa-mir-532-3p and hsa-mir-429) and two key genes (ETS1 and HAPLN1).	('hsa-mir-429', 'Gene', (77, 88))	('HAPLN1', 'Gene', (118, 124))	('hsa-mir-199b-5p', 'Var', (41, 56))	('hsa-mir-532-3p', 'Var', (58, 72))	('HAPLN1', 'Gene', '1404', (118, 124))	('hsa-mir-429', 'Gene', '554210', (77, 88))	('hsa-mir-199a-5p', 'Var', (24, 39))	('ETS1', 'Gene', '2113', (109, 113))	('ETS1', 'Gene', (109, 113))
40952	33434215	The gene expression profile GSE66270 includes 17 normal control samples and 17 clear renal cell carcinoma samples (S2 Table).	('GSE66270', 'Var', (28, 36))	('clear renal cell carcinoma', 'Disease', 'MESH:C538614', (79, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (85, 105))	('clear renal cell carcinoma', 'Phenotype', 'HP:0006770', (79, 105))	('clear renal cell carcinoma', 'Disease', (79, 105))	('gene expression', 'biological_process', 'GO:0010467', ('4', '19'))
40981	33434215	Now RNA sequencing technology has been used to screen out general genetic changes in tumorigenesis and predict potential biomarkers for prognosis.	('tumor', 'Disease', (85, 90))	('genetic', 'Var', (66, 73))	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
41002	33434215	The high expression of ETS1 is associated with a poor survival prognosis, which is consistent with our results.	('ETS1', 'Gene', (23, 27))	('high', 'Var', (4, 8))	('ETS1', 'Gene', '2113', (23, 27))
41008	33434215	HAPLN1 is negatively regulated by hsa-miR-133b, hsa-miR-199a-5p and hsa-miR-199b-5p.	('HAPLN1', 'Gene', '1404', (0, 6))	('hsa-miR-199b-5p', 'Var', (68, 83))	('negatively', 'NegReg', (10, 20))	('hsa-miR-133b', 'Gene', (34, 46))	('hsa-miR-133b', 'Gene', '442890', (34, 46))	('hsa-miR-199a-5p', 'Var', (48, 63))	('HAPLN1', 'Gene', (0, 6))
41011	33434215	found that knockout of the HAPLN1 gene downregulated the expression of key markers of liver progenitor cells, such as Snail, LGR5, type IV collagen, and alpha-SMA.	('expression', 'MPA', (57, 67))	('Snail', 'Gene', '6615', (118, 123))	('HAPLN1', 'Gene', '1404', (27, 33))	('alpha-SMA', 'Gene', (153, 162))	('LGR5', 'Gene', '8549', (125, 129))	('LGR5', 'Gene', (125, 129))	('HAPLN1', 'Gene', (27, 33))	('collagen', 'molecular_function', 'GO:0005202', ('139', '147'))	('knockout', 'Var', (11, 19))	('Snail', 'Gene', (118, 123))	('alpha-SMA', 'Gene', '58', (153, 162))	('downregulated', 'NegReg', (39, 52))
41012	33434215	also found that hapln1, hsa-mir-204 and hsa-mir-218 can be used as biomarkers of renal clear cell carcinoma, which further verified our prediction.	('renal clear cell carcinoma', 'Disease', (81, 107))	('hsa-mir-204', 'Gene', (24, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('hsa-mir-204', 'Gene', '406987', (24, 35))	('hsa-mir-218', 'Var', (40, 51))	('hapln1', 'Gene', '1404', (16, 22))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (81, 107))	('hapln1', 'Gene', (16, 22))
41017	33434215	In conclusion, with method of bioinformatics, five miRNAs (hsa-mir-199a-5p, hsa-mir-199b-5p, hsa-mir-532-3p and hsa-mir-429) and two key genes (ETS1 and HAPLN1) were found to be the potential biomarkers for the prognosis of patients with CCRCC.	('hsa-mir-429', 'Gene', '554210', (112, 123))	('HAPLN1', 'Gene', (153, 159))	('hsa-mir-199b-5p', 'Var', (76, 91))	('ETS1', 'Gene', (144, 148))	('ETS1', 'Gene', '2113', (144, 148))	('hsa-mir-429', 'Gene', (112, 123))	('HAPLN1', 'Gene', '1404', (153, 159))	('CCRCC', 'Disease', (238, 243))	('hsa-mir-532-3p', 'Var', (93, 107))	('patients', 'Species', '9606', (224, 232))	('hsa-mir-199a-5p', 'Var', (59, 74))
41036	32481352	Two datasets of GSE53757 and GSE16449, were chosen by carefully selected, we compared tumor tissue and normal tissue to get identify DEGs, and analyzed gene ontology (GO) and Kyoto Encyclopedia of Gene and Genomes (KEGG) to get genetic change trend, then obtained genes with clinical guiding significance by survival analysis.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('GSE53757', 'Var', (16, 24))	('tumor', 'Disease', (86, 91))	('GSE16449', 'Var', (29, 37))	('gene ontology', 'biological_process', 'GO:0003673', ('152', '165'))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
41056	32481352	In order to screen the key candidate proteins in ccRCC, we conducted the GEO database of GSE53757 and GSE16449, and 167 co-expression genes, including 72 upregulated DEGs and 95 downregulated DEGs, were identified finally.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('upregulated', 'PosReg', (154, 165))	('downregulated', 'NegReg', (178, 191))	('GSE53757', 'Gene', (89, 97))	('GSE16449', 'Var', (102, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
41067	32481352	Kusuhara Y et al, concluded that low TLR4 expression was correlated with tumor progression, and the expression of TLR4 was inversely associated with prognosis of patients with invasive bladder cancer (BCa), and depletion of TLR4 significantly enhanced the invasive capability of BCa cells.	('TLR4', 'Gene', (224, 228))	('TLR4', 'Gene', '7099', (114, 118))	('bladder cancer', 'Phenotype', 'HP:0009725', (185, 199))	('expression', 'MPA', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('TLR4', 'Gene', (114, 118))	('low', 'NegReg', (33, 36))	('depletion', 'Var', (211, 220))	('invasive capability of BCa cells', 'CPA', (256, 288))	('inversely', 'NegReg', (123, 132))	('invasive bladder', 'Phenotype', 'HP:0100645', (176, 192))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (176, 199))	('associated', 'Reg', (133, 143))	('patients', 'Species', '9606', (162, 170))	('TLR4', 'Gene', '7099', (37, 41))	('tumor', 'Disease', (73, 78))	('invasive bladder cancer', 'Disease', (176, 199))	('TLR4', 'Gene', (37, 41))	('enhanced', 'PosReg', (243, 251))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('BCa', 'Phenotype', 'HP:0009725', (201, 204))	('expression', 'MPA', (100, 110))	('TLR4', 'Gene', '7099', (224, 228))	('BCa', 'Phenotype', 'HP:0009725', (279, 282))
41069	32481352	IRF8 methylation may serve as a potential biomarker in NSCLC prognosis.	('IRF8', 'Gene', '3394', (0, 4))	('methylation', 'Var', (5, 16))	('NSCLC', 'Disease', (55, 60))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('IRF8', 'Gene', (0, 4))	('methylation', 'biological_process', 'GO:0032259', ('5', '16'))
41071	32481352	Aberrant expression of these protein were associated with the growth and progression of certain tumors, and may suppressed hematopoietic progenitor cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('148', '166'))	('suppressed', 'NegReg', (112, 122))	('hematopoietic progenitor cell proliferation', 'CPA', (123, 166))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('associated', 'Reg', (42, 52))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('expression', 'MPA', (9, 19))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))
41093	31364727	Receiver operating characteristic analysis indicated that high expression levels of RAC2 could be a diagnostic index for ccRCC (area under the curve, 0.9095; P<0.0001).	('RAC2', 'Gene', (84, 88))	('expression levels', 'MPA', (63, 80))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('RCC', 'Disease', (123, 126))	('high', 'Var', (58, 62))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('RAC2', 'Gene', '5880', (84, 88))	('si', 'Chemical', 'MESH:D012825', (69, 71))
41094	31364727	Furthermore, knockdown of RAC2 in vitro attenuated the proliferation, migration and invasion of renal carcinoma cells.	('renal carcinoma', 'Phenotype', 'HP:0005584', (96, 111))	('RAC2', 'Gene', (26, 30))	('proliferation', 'CPA', (55, 68))	('renal carcinoma', 'Disease', 'MESH:C538614', (96, 111))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('renal carcinoma', 'Disease', (96, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('RAC2', 'Gene', '5880', (26, 30))	('attenuated', 'NegReg', (40, 50))	('knockdown', 'Var', (13, 22))
41106	31364727	They are activated by guanine nucleotide exchange factors, which exchange GDP for GTP.	('GTP', 'Chemical', 'MESH:D006160', (82, 85))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (22, 40))	('GTP', 'MPA', (82, 85))	('exchange', 'Var', (65, 73))	('GDP', 'MPA', (74, 77))	('GDP', 'Chemical', 'MESH:D006153', (74, 77))
41151	31364727	ACHN and 786-O cells had been transfected with si-RAC2 or si-NC 48 h before subsequent experimentation.	('si-RAC2', 'Gene', (47, 54))	('si-NC', 'Var', (58, 63))	('ACHN', 'Gene', '55323', (0, 4))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('ACHN', 'Gene', (0, 4))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('si-RAC2', 'Gene', '5880', (47, 54))
41183	31364727	It was revealed that high expression levels of RAC2 were significantly associated with higher tumor T stage, distant metastasis, tumor lymph node metastasis (N stage), pathological TNM stage and advanced histological grade (G stage) in ccRCC (Fig.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('si', 'Chemical', 'MESH:D012825', (153, 155))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('tumor', 'Disease', (129, 134))	('higher', 'PosReg', (87, 93))	('RAC2', 'Gene', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('high', 'Var', (21, 25))	('RCC', 'Disease', (238, 241))	('distant metastasis', 'CPA', (109, 127))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor lymph node metastasis', 'Disease', (129, 156))	('tumor lymph node metastasis', 'Disease', 'MESH:D009362', (129, 156))	('si', 'Chemical', 'MESH:D012825', (124, 126))	('RAC2', 'Gene', '5880', (47, 51))	('RCC', 'Disease', 'MESH:C538614', (238, 241))	('tumor', 'Disease', (94, 99))	('expression levels', 'MPA', (26, 43))
41188	31364727	The results revealed that the OS of the high RAC2 expression group was poorer (P=0.006; Fig.	('high', 'Var', (40, 44))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('RAC2', 'Gene', '5880', (45, 49))	('RAC2', 'Gene', (45, 49))
41195	31364727	Furthermore, the diagnostic values of RAC2 expression levels were also analyzed in the subgroups as follows: G1 + G2 vs. G3 + G4 stage (AUC, 0.6337; P<0.0001; Fig.	('RAC2', 'Gene', '5880', (38, 42))	('RAC2', 'Gene', (38, 42))	('G1 + G2', 'Var', (109, 116))	('si', 'Chemical', 'MESH:D012825', (49, 51))
41213	31364727	Following transfection, cell proliferation assays, which were performed with the prior-transfected ACHN and 786-O cells, demonstrated that cell proliferation was significantly inhibited with RAC2 knockdown compared with the corresponding control (Fig.	('knockdown', 'Var', (196, 205))	('si', 'Chemical', 'MESH:D012825', (162, 164))	('ACHN', 'Gene', '55323', (99, 103))	('cell proliferation', 'biological_process', 'GO:0008283', ('24', '42'))	('RAC2', 'Gene', '5880', (191, 195))	('cell proliferation', 'CPA', (139, 157))	('ACHN', 'Gene', (99, 103))	('RAC2', 'Gene', (191, 195))	('inhibited', 'NegReg', (176, 185))	('cell proliferation', 'biological_process', 'GO:0008283', ('139', '157'))
41215	31364727	Furthermore, we compared cell proliferative, migration and invasive abilities between untransfected 786-O cells and transfected si-NC 786-O cells.	('si', 'Chemical', 'MESH:D012825', (128, 130))	('migration', 'CPA', (45, 54))	('cell proliferative', 'CPA', (25, 43))	('invasive abilities', 'CPA', (59, 77))	('si-NC', 'Var', (128, 133))	('si', 'Chemical', 'MESH:D012825', (63, 65))
41250	31364727	In conclusion, the results from the present study demonstrated that high expression levels of RAC2 were associated with poor overall survival and higher tumor grade in patients with ccRCC, which, to the best of our knowledge, is the first time this has been reported.	('higher', 'PosReg', (146, 152))	('si', 'Chemical', 'MESH:D012825', (79, 81))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('high', 'Var', (68, 72))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('overall survival', 'CPA', (125, 141))	('RCC', 'Disease', (184, 187))	('poor', 'NegReg', (120, 124))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('RAC2', 'Gene', '5880', (94, 98))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('patients', 'Species', '9606', (168, 176))	('RAC2', 'Gene', (94, 98))
41289	28286925	Inactivation of the VHL gene was commonly associated with clear cell renal cell carcinoma (ccRCC) and led to increased expression of hypoxia-inducible factors and the expression of multiple genes involved in cancer progression and metastasis, including the vascular endothelial growth factor (VEGF).	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (69, 89))	('cancer', 'Disease', (208, 214))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('257', '291'))	('increased', 'PosReg', (109, 118))	('expression', 'MPA', (167, 177))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (58, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('VHL', 'Gene', (20, 23))	('Inactivation', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('expression', 'MPA', (119, 129))	('hypoxia', 'Disease', (133, 140))	('ccRCC', 'Disease', 'MESH:D002292', (91, 96))	('vascular endothelial growth factor', 'Gene', '7422', (257, 291))	('VHL', 'Gene', '7428', (20, 23))	('ccRCC', 'Disease', (91, 96))	('associated', 'Reg', (42, 52))	('vascular endothelial growth factor', 'Gene', (257, 291))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (58, 89))	('hypoxia', 'Disease', 'MESH:D000860', (133, 140))	('clear cell renal cell carcinoma', 'Disease', (58, 89))
41290	28286925	VHL inactivation alone was insufficient for ccRCC development, and additional tumor-suppressor genes were later identified on chromosome 3p: BRCA1-associated protein1, SET domain-containing 2, and polybromo 1.	('tumor-suppressor', 'biological_process', 'GO:0051726', ('78', '94'))	('polybromo 1', 'Gene', '55193', (197, 208))	('inactivation', 'Var', (4, 16))	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('78', '94'))	('ccRCC', 'Disease', (44, 49))	('polybromo 1', 'Gene', (197, 208))	('ccRCC', 'Disease', 'MESH:D002292', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('VHL', 'Gene', (0, 3))	('chromosome', 'cellular_component', 'GO:0005694', ('126', '136'))	('tumor', 'Disease', (78, 83))	('VHL', 'Gene', '7428', (0, 3))	('BRCA1-associated protein1', 'Gene', '8314', (141, 166))	('protein', 'cellular_component', 'GO:0003675', ('158', '165'))	('BRCA1-associated protein1', 'Gene', (141, 166))
41291	28286925	Mutations in these genes have been described in different proportions in ccRCC.	('ccRCC', 'Disease', 'MESH:D002292', (73, 78))	('described', 'Reg', (35, 44))	('Mutations', 'Var', (0, 9))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))	('ccRCC', 'Disease', (73, 78))
41292	28286925	Additional mutations in genes regulating multiple other pathways within ccRCC include MTOR, tuberous sclerosis1, PI3K, and PTEN.	('mutations', 'Var', (11, 20))	('MTOR', 'Gene', (86, 90))	('MTOR', 'Gene', '2475', (86, 90))	('PI3K', 'molecular_function', 'GO:0016303', ('113', '117'))	('tuberous sclerosis1', 'Gene', (92, 111))	('tuberous sclerosis1', 'Gene', '7248', (92, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('PTEN', 'Gene', (123, 127))	('PTEN', 'Gene', '5728', (123, 127))	('ccRCC', 'Disease', (72, 77))	('ccRCC', 'Disease', 'MESH:D002292', (72, 77))	('PI3K', 'Disease', (113, 117))
41293	28286925	Intratumoral mutation heterogeneity abounds in ccRCC, both de novo and treatment-induced mutation changes, which lead to evolution of resistance pathways.	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('ccRCC', 'Disease', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('mutation changes', 'Var', (89, 105))	('changes', 'Var', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('ccRCC', 'Disease', 'MESH:D002292', (47, 52))	('resistance pathways', 'Pathway', (134, 153))	('lead to evolution', 'Reg', (113, 130))	('tumor', 'Disease', (5, 10))
41294	28286925	Mutations in MET proto-oncogene which is located on chromosome 7q21 is responsible for both types 1 and 2 hereditary papillary renal cell carcinoma (pRCC).	('chromosome', 'cellular_component', 'GO:0005694', ('52', '62'))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('responsible', 'Reg', (71, 82))	('pRCC', 'Phenotype', 'HP:0006766', (149, 153))	('pRCC', 'Gene', '5546', (149, 153))	('2 hereditary papillary renal cell carcinoma', 'Phenotype', 'HP:0006732', (104, 147))	('hereditary papillary renal cell carcinoma', 'Disease', (106, 147))	('Mutations', 'Var', (0, 9))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (117, 147))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (127, 147))	('hereditary papillary renal cell carcinoma', 'Disease', 'MESH:D002292', (106, 147))	('pRCC', 'Gene', (149, 153))
41299	28286925	In experiments conducted on two ccRCC mice models, one TKI sensitive and the other TKI resistant, combined blockade of VEGF and HGF-MET pathway increased the antitumor effect in both models (Fig.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('ccRCC', 'Disease', (32, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (32, 37))	('ccRCC', 'Disease', 'MESH:D002292', (32, 37))	('mice', 'Species', '10090', (38, 42))	('tumor', 'Disease', (162, 167))	('VEGF', 'Gene', (119, 123))	('HGF', 'Gene', (128, 131))	('blockade', 'Var', (107, 115))	('HGF', 'Gene', '3082', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('increased', 'PosReg', (144, 153))
41419	30486822	We provide evidence that low ALDH7A1 expression is a useful prognostic marker of poor clinical outcome for hepatocellular and renal clear cell carcinomas and hypothesize that patients with low ALDH7A1 might benefit from therapeutic approaches addressing PPARalpha activity.	('hepatocellular and renal clear cell carcinomas', 'Disease', 'MESH:C538614', (107, 153))	('ALDH', 'molecular_function', 'GO:0004030', ('193', '197'))	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('benefit', 'Reg', (207, 214))	('ALDH7A1', 'Gene', (193, 200))	('clinical', 'Species', '191496', (86, 94))	('ALDH', 'molecular_function', 'GO:0004030', ('29', '33'))	('low', 'NegReg', (25, 28))	('patients', 'Species', '9606', (175, 183))	('expression', 'MPA', (37, 47))	('low', 'Var', (189, 192))	('ALDH7A1', 'Gene', (29, 36))
41421	30486822	In addition to the well-known shift of cancer cells to aerobic glycolysis, mutations or changes in the expression of metabolic enzymes have been identified as potential cancer drivers.	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', (39, 45))	('changes', 'Reg', (88, 95))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('expression', 'MPA', (103, 113))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('mutations', 'Var', (75, 84))	('glycolysis', 'biological_process', 'GO:0006096', ('63', '73'))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
41422	30486822	Mutations and/or altered expression of metabolic enzymes such as succinate dehydrogenase, pyruvate kinase and isocitrate dehydrogenase are linked to tumor initiation, development and drug resistance.	('altered', 'Reg', (17, 24))	('tumor initiation', 'Disease', 'MESH:D009369', (149, 165))	('expression', 'MPA', (25, 35))	('linked', 'Reg', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('drug resistance', 'biological_process', 'GO:0009315', ('183', '198'))	('drug resistance', 'biological_process', 'GO:0042493', ('183', '198'))	('drug resistance', 'Phenotype', 'HP:0020174', (183, 198))	('Mutations', 'Var', (0, 9))	('tumor initiation', 'Disease', (149, 165))	('pyruvate', 'Chemical', 'MESH:D019289', (90, 98))
41430	30486822	We hypothesize that metabolic changes resulting from low ALDH7A1 expression may be linked to clinical outcome through their effects on PPAR activity.	('ALDH7A1', 'Gene', (57, 64))	('PPAR activity', 'MPA', (135, 148))	('effects', 'Reg', (124, 131))	('clinical', 'Species', '191496', (93, 101))	('linked', 'Reg', (83, 89))	('low', 'Var', (53, 56))	('expression', 'MPA', (65, 75))	('ALDH', 'molecular_function', 'GO:0004030', ('57', '61'))	('metabolic', 'MPA', (20, 29))
41438	30486822	One to two passages after thawing, BJ-4F3, HUH7, CAKI2 cells were transduced with control shRNAs (Sigma: SHC001 as empty vector, SHC002 as non-targeting shRNA control) or ALDH7A1-specific shRNAs (Sigma: TRCN0000028424 (sh1) and TRCN0000028447 (sh2)) for 24 h, allowed to recover for 24 h, and placed under puromycin selection (2 mug/ml) for 6 days.	('BJ-4F3', 'CellLine', 'CVCL:6573', (35, 41))	('HUH7', 'Gene', (43, 47))	('puromycin', 'Chemical', 'MESH:D011691', (306, 315))	('HUH7', 'Gene', '284424', (43, 47))	('CAKI2', 'CellLine', 'CVCL:0235', (49, 54))	('ALDH', 'molecular_function', 'GO:0004030', ('171', '175'))	('mug', 'molecular_function', 'GO:0043739', ('329', '332'))	('TRCN0000028447', 'Var', (228, 242))
41465	30486822	For Additional file 1: Figure S4 patients were divided into two equally sized groups based on ALDH7A1 expression, EGFR expression and sum of scaled and centered relative protein levels EGFR_pY1068 (CST; 2234), EGFR_pY1173 (Abcam; ab32578).	('EGFR', 'MPA', (114, 118))	('patients', 'Species', '9606', (33, 41))	('EGFR_pY1068', 'Var', (185, 196))	('EGFR_pY1173', 'Var', (210, 221))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('ALDH7A1', 'Gene', (94, 101))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('EGFR', 'molecular_function', 'GO:0005006', ('210', '214'))	('EGFR', 'molecular_function', 'GO:0005006', ('185', '189'))	('ALDH', 'molecular_function', 'GO:0004030', ('94', '98'))
41505	30486822	Within early and late stage groups, patients with low ALDH7A1 expression showed worse survival outcome: 5-year survival probability for the patients with late stage cancer and high ALDH7A1 expression was ~ 40% vs ~ 20% for patients with low ALDH7A1 (Fig.	('patients', 'Species', '9606', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('ALDH7A1', 'Gene', (181, 188))	('cancer', 'Disease', (165, 171))	('patients', 'Species', '9606', (140, 148))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('ALDH', 'molecular_function', 'GO:0004030', ('181', '185'))	('ALDH', 'molecular_function', 'GO:0004030', ('54', '58'))	('patients', 'Species', '9606', (223, 231))	('ALDH', 'molecular_function', 'GO:0004030', ('241', '245'))	('high', 'Var', (176, 180))
41511	30486822	For LIHC, survival was significantly worse for patients with low ALDH7A1 in the high EGFR activity group, while it was not significant in low EGFR group.	('EGFR', 'molecular_function', 'GO:0005006', ('85', '89'))	('patients', 'Species', '9606', (47, 55))	('low', 'Var', (61, 64))	('ALDH7A1', 'Gene', (65, 72))	('ALDH', 'molecular_function', 'GO:0004030', ('65', '69'))	('LIHC', 'Disease', 'None', (4, 8))	('EGFR', 'molecular_function', 'GO:0005006', ('142', '146'))	('worse', 'NegReg', (37, 42))	('LIHC', 'Disease', (4, 8))	('survival', 'MPA', (10, 18))
41512	30486822	This was not the case for KIRC: low ALDH7A1 expression was significantly associated with poor clinical outcome in both low and high EGFR RNA expression groups.	('low', 'NegReg', (32, 35))	('expression', 'MPA', (44, 54))	('high EGFR', 'Var', (127, 136))	('RNA', 'cellular_component', 'GO:0005562', ('137', '140'))	('clinical', 'Species', '191496', (94, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('132', '136'))	('ALDH', 'molecular_function', 'GO:0004030', ('36', '40'))	('ALDH7A1', 'Gene', (36, 43))
41515	30486822	To generate hypotheses about possible causes of the poor outcome in the low-ALDH7A1 LIHC and KIRC patient groups, we analyzed TCGA gene expression data and performed pathway analysis to compare tumors from the patient groups with top versus bottom third ALDH7A1 expression.	('ALDH', 'molecular_function', 'GO:0004030', ('76', '80'))	('tumors', 'Disease', (194, 200))	('patient', 'Species', '9606', (98, 105))	('LIHC', 'Disease', (84, 88))	('ALDH7A1', 'Gene', (254, 261))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('gene expression', 'biological_process', 'GO:0010467', ('131', '146'))	('LIHC', 'Disease', 'None', (84, 88))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('patient', 'Species', '9606', (210, 217))	('ALDH', 'molecular_function', 'GO:0004030', ('254', '258'))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('low-ALDH7A1', 'Var', (72, 83))
41531	30486822	If the effects of low ALDH7A1 activity are mediated though regulation of PPAR activity, we should find a corresponding correlation between PPAR transcriptional activity and survival outcome in patient datasets.	('activity', 'MPA', (78, 86))	('low', 'Var', (18, 21))	('regulation', 'biological_process', 'GO:0065007', ('59', '69'))	('ALDH', 'molecular_function', 'GO:0004030', ('22', '26'))	('patient', 'Species', '9606', (193, 200))	('activity', 'MPA', (30, 38))	('ALDH7A1', 'Gene', (22, 29))
41536	30486822	For LIHC patients the survival difference between the normal-like and low PPAR groups was significant (p = 0.006).	('LIHC', 'Disease', (4, 8))	('low', 'Var', (70, 73))	('patients', 'Species', '9606', (9, 17))	('LIHC', 'Disease', 'None', (4, 8))
41542	30486822	Nor does low PPAR activity always correlate with low survival in other cancers.	('low', 'Var', (9, 12))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('PPAR', 'Protein', (13, 17))	('low', 'NegReg', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
41546	30486822	The PPARbeta agonist GW501516 also restored migration to near normal levels, while the PPARgamma agonist Rosiglitazone did not (Additional file 1: Figure S6).	('GW501516', 'Chemical', 'MESH:C425931', (21, 29))	('Rosiglitazone', 'Chemical', 'MESH:D000077154', (105, 118))	('migration', 'MPA', (44, 53))	('PPARbeta', 'Gene', '5467', (4, 12))	('restored', 'PosReg', (35, 43))	('PPARbeta', 'Gene', (4, 12))	('GW501516', 'Var', (21, 29))	('PPARgamma', 'Gene', (87, 96))	('PPARgamma', 'Gene', '5468', (87, 96))
41561	30486822	Regression analysis showed a significantly increased hazard ratio for the patients with low ALDH7A1 scores and for those with higher stage for both cancers (Fig.	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('low', 'NegReg', (88, 91))	('cancers', 'Disease', (148, 155))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('scores', 'Var', (100, 106))	('ALDH', 'molecular_function', 'GO:0004030', ('92', '96'))	('ALDH7A1', 'Gene', (92, 99))
41574	30486822	Why are liver and kidney cancer sensitive to the effects of low ALDH7A1?	('liver', 'Disease', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('kidney cancer', 'Phenotype', 'HP:0009726', (18, 31))	('ALDH', 'molecular_function', 'GO:0004030', ('64', '68'))	('kidney cancer', 'Disease', 'MESH:D007680', (18, 31))	('low', 'Var', (60, 63))	('kidney cancer', 'Disease', (18, 31))	('ALDH7A1', 'Gene', (64, 71))
41590	30486822	Clinical trials are evaluating PPARalpha activation for treating non-alcoholic fatty liver disease and primary biliary cirrhosis, in combination with existing treatments (ClinicalTrials.gov identifier: NCT00262964, NCT00575042, NCT02823353, NCT02965911, NCT02823366).	('PPARalpha', 'Gene', (31, 40))	('Clinical', 'Species', '191496', (171, 179))	('alcoholic fatty liver', 'Phenotype', 'HP:0006573', (69, 90))	('non-alcoholic fatty liver disease', 'Disease', (65, 98))	('Clinical', 'Species', '191496', (0, 8))	('primary biliary cirrhosis', 'Phenotype', 'HP:0002613', (103, 128))	('primary biliary cirrhosis', 'Disease', 'MESH:D008105', (103, 128))	('cirrhosis', 'Phenotype', 'HP:0001394', (119, 128))	('NCT02965911', 'Var', (241, 252))	('liver disease', 'Phenotype', 'HP:0001392', (85, 98))	('fatty liver', 'Phenotype', 'HP:0001397', (79, 90))	('primary biliary cirrhosis', 'Disease', (103, 128))	('NCT02823353', 'Var', (228, 239))	('non-alcoholic fatty liver disease', 'Disease', 'MESH:D065626', (65, 98))	('NCT02823366', 'Var', (254, 265))
41604	33061459	Overexpression of HIF1A-AS2 presented an opposite effect that repressed the expression of miR-130a-5p, and miR-130a-5p inhibited the expression of HIF1A-AS2.	('miR-130a-5p', 'Var', (107, 118))	('miR-130a-5p', 'Chemical', '-', (107, 118))	('expression', 'MPA', (133, 143))	('miR-130a-5p', 'Chemical', '-', (90, 101))	('HIF1A-AS2', 'Gene', '100750247', (147, 156))	('HIF1A-AS2', 'Gene', '100750247', (18, 27))	('inhibited', 'NegReg', (119, 128))	('HIF1A-AS2', 'Gene', (18, 27))	('miR-130a-5p', 'Var', (90, 101))	('HIF1A-AS2', 'Gene', (147, 156))
41617	33061459	Unluckily, no complete narration has been made on the association of miR-130a-5p with lncRNAs.	('lncRNAs', 'Disease', (86, 93))	('miR-130a-5p', 'Var', (69, 80))	('miR-130a-5p', 'Chemical', '-', (69, 80))
41620	33061459	The disabled HIF1A-AS2 weakens the proliferation, migration, and invasion of the renal carcinoma cells.	('HIF1A-AS2', 'Gene', '100750247', (13, 22))	('proliferation', 'CPA', (35, 48))	('renal carcinoma', 'Disease', (81, 96))	('migration', 'CPA', (50, 59))	('renal carcinoma', 'Phenotype', 'HP:0005584', (81, 96))	('HIF1A-AS2', 'Gene', (13, 22))	('weakens', 'NegReg', (23, 30))	('disabled', 'Var', (4, 12))	('renal carcinoma', 'Disease', 'MESH:C538614', (81, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
41656	33061459	Primary antibodies included E-Cadherin (ab219332; Abcam, US), SNAIL (ab53519; Abcam), and ERBB2 (A2071; Abclonal).	('SNAIL', 'Gene', '6615', (62, 67))	('SNAIL', 'Gene', (62, 67))	('S', 'Chemical', 'MESH:D013455', (62, 63))	('S', 'Chemical', 'MESH:D013455', (58, 59))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('Cadherin', 'molecular_function', 'GO:0008014', ('30', '38'))	('E-Cadherin', 'Gene', (28, 38))	('ab53519;', 'Var', (69, 77))	('ERBB2', 'Gene', '2064', (90, 95))	('E-Cadherin', 'Gene', '999', (28, 38))	('ERBB2', 'Gene', (90, 95))	('ab219332', 'Var', (40, 48))
41659	33061459	For constructing HIF1A-AS2 reporter gene plasmids with a mutant miR-130a-5p binding site, the Site-Directed Mutagenesis System (Beyotime, China) was utilized in terms of the manufacturer's instructions of use.	('HIF1A-AS2', 'Gene', '100750247', (17, 26))	('miR-130a-5p', 'Gene', (64, 75))	('S', 'Chemical', 'MESH:D013455', (94, 95))	('binding', 'molecular_function', 'GO:0005488', ('76', '83'))	('miR-130a-5p', 'Chemical', '-', (64, 75))	('mutant', 'Var', (57, 63))	('HIF1A-AS2', 'Gene', (17, 26))	('S', 'Chemical', 'MESH:D013455', (120, 121))	('Mutagenesis', 'biological_process', 'GO:0006280', ('108', '119'))	('S', 'Chemical', 'MESH:D013455', (24, 25))
41670	33061459	Findings of MTT assay revealed that the interfered HIF1A-AS2 expression retarded the growth of ACHN and OSRC-2 cells (Figure 2B).	('OSRC-2', 'CellLine', 'CVCL:1901', (104, 110))	('retarded', 'NegReg', (72, 80))	('HIF1A-AS2', 'Gene', '100750247', (51, 60))	('expression', 'Var', (61, 71))	('interfered', 'NegReg', (40, 50))	('MTT', 'Chemical', 'MESH:C070243', (12, 15))	('HIF1A-AS2', 'Gene', (51, 60))
41673	33061459	To ascertain the association of HIF1A-AS2 with cycle of renal carcinoma cells, flow cytometry was performed to determine the percentage of cells in phase S, with results indicating that HIF1A-AS2 silence drastically decreased the cell percentage in phase S, while an increase exhibited in phase G2 (Figure 3A).	('HIF1A-AS2', 'Gene', (186, 195))	('S', 'Chemical', 'MESH:D013455', (255, 256))	('decreased', 'NegReg', (216, 225))	('silence', 'Var', (196, 203))	('renal carcinoma', 'Phenotype', 'HP:0005584', (56, 71))	('HIF1A-AS2', 'Gene', (32, 41))	('S', 'Chemical', 'MESH:D013455', (193, 194))	('cell percentage in', 'CPA', (230, 248))	('S', 'Chemical', 'MESH:D013455', (39, 40))	('renal carcinoma', 'Disease', 'MESH:C538614', (56, 71))	('HIF1A-AS2', 'Gene', '100750247', (186, 195))	('S', 'Chemical', 'MESH:D013455', (154, 155))	('HIF1A-AS2', 'Gene', '100750247', (32, 41))	('renal carcinoma', 'Disease', (56, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
41675	33061459	Notably, HIF1A-AS2 silence increased percentage of G2 phase in ACHN cells.	('HIF1A-AS2', 'Gene', (9, 18))	('increased', 'PosReg', (27, 36))	('G2 phase in ACHN cells', 'CPA', (51, 73))	('HIF1A-AS2', 'Gene', '100750247', (9, 18))	('G2 phase', 'biological_process', 'GO:0051319', ('51', '59'))	('silence', 'Var', (19, 26))
41679	33061459	Results exhibited that HIF1A-AS2 silencing dramatically alleviated cellular invasion and migration in ACHN and OSRC-2 cells (Figure 4A and B), whereas overexpressed HIF1A-AS2 was confirmed producing a role in promotion of the invasion and migration in ACHN and OSRC-2 cells (Figure 5A and B).	('cellular invasion', 'CPA', (67, 84))	('alleviated', 'NegReg', (56, 66))	('HIF1A-AS2', 'Gene', '100750247', (165, 174))	('HIF1A-AS2', 'Gene', (23, 32))	('silencing', 'Var', (33, 42))	('HIF1A-AS2', 'Gene', (165, 174))	('invasion', 'CPA', (226, 234))	('HIF1A-AS2', 'Gene', '100750247', (23, 32))	('promotion', 'PosReg', (209, 218))	('OSRC-2', 'CellLine', 'CVCL:1901', (261, 267))	('OSRC-2', 'CellLine', 'CVCL:1901', (111, 117))
41680	33061459	HIF1A-AS2 silencing disabled ACHN and OSRC-2 cell migration after being scratched (Figure 4A and B), and overexpressed HIF1A-AS2 displayed a diminished migratory capacity in ACHN and OSRC-2 cells (Figure 5A and B).	('HIF1A-AS2', 'Gene', '100750247', (119, 128))	('OSRC-2', 'CellLine', 'CVCL:1901', (183, 189))	('HIF1A-AS2', 'Gene', '100750247', (0, 9))	('migratory capacity', 'CPA', (152, 170))	('cell migration', 'biological_process', 'GO:0016477', ('45', '59'))	('HIF1A-AS2', 'Gene', (0, 9))	('HIF1A-AS2', 'Gene', (119, 128))	('OSRC-2', 'CellLine', 'CVCL:1901', (38, 44))	('diminished', 'NegReg', (141, 151))	('disabled', 'NegReg', (20, 28))	('silencing', 'Var', (10, 19))
41687	33061459	Importantly, miR-130a-5p was found possessing conserved complementary base pairings with HIF1A-AS2 (Figure 6A).	('complementary base pairings', 'MPA', (56, 83))	('HIF1A-AS2', 'Gene', '100750247', (89, 98))	('HIF1A-AS2', 'Gene', (89, 98))	('miR-130a-5p', 'Var', (13, 24))	('miR-130a-5p', 'Chemical', '-', (13, 24))
41688	33061459	Cloned HIF1A-AS2 Wild-type (WT) and mutation (MUT) structures containing miR-130a-5p binding sites were inserted into psiCHECK2 dual luciferase reporter plasmids, and transfected into 293T cells together with control miRNA mimics and miR-130a-5p mimics, respectively, through which the one regulated by HIF1A-AS2 was figured out.	('HIF1A-AS2', 'Gene', '100750247', (7, 16))	('HIF1A-AS2', 'Gene', '100750247', (303, 312))	('293T', 'CellLine', 'CVCL:0063', (184, 188))	('HIF1A-AS2', 'Gene', (7, 16))	('miR-130a-5p', 'Chemical', '-', (234, 245))	('HIF1A-AS2', 'Gene', (303, 312))	('binding', 'molecular_function', 'GO:0005488', ('85', '92'))	('mutation', 'Var', (36, 44))	('miR-130a-5p', 'Chemical', '-', (73, 84))
41689	33061459	Results of overexpressed miR-130a-5p exhibited robust diminution of luciferase activity in wild-type HIF1A-AS2 constructs (Figure 6C).	('activity', 'MPA', (79, 87))	('luciferase activity', 'molecular_function', 'GO:0050397', ('68', '87'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('68', '87'))	('luciferase', 'Enzyme', (68, 78))	('luciferase activity', 'molecular_function', 'GO:0045289', ('68', '87'))	('diminution', 'NegReg', (54, 64))	('HIF1A-AS2', 'Gene', '100750247', (101, 110))	('luciferase activity', 'molecular_function', 'GO:0047712', ('68', '87'))	('miR-130a-5p', 'Chemical', '-', (25, 36))	('miR-130a-5p', 'Var', (25, 36))	('luciferase activity', 'molecular_function', 'GO:0050248', ('68', '87'))	('HIF1A-AS2', 'Gene', (101, 110))
41691	33061459	These results of our assay demonstrated that mutation of binding sties muted the effects of miR-130a-5p on luciferase activity of HIF1A-AS2 (Figure 6C).	('effects', 'MPA', (81, 88))	('HIF1A-AS2', 'Gene', '100750247', (130, 139))	('luciferase activity', 'molecular_function', 'GO:0047077', ('107', '126'))	('activity', 'MPA', (118, 126))	('HIF1A-AS2', 'Gene', (130, 139))	('binding', 'molecular_function', 'GO:0005488', ('57', '64'))	('muted', 'NegReg', (71, 76))	('miR-130a-5p', 'Chemical', '-', (92, 103))	('mutation', 'Var', (45, 53))	('luciferase activity', 'molecular_function', 'GO:0045289', ('107', '126'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('107', '126'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('107', '126'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('107', '126'))	('luciferase', 'Enzyme', (107, 117))
41693	33061459	Meanwhile, there was a negative correlation between HIF1A-AS2 and miR-130a-5p in the mRNA level of the ccRCC tissues (Figure 6G).	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('HIF1A-AS2', 'Gene', '100750247', (52, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('miR-130a-5p', 'Var', (66, 77))	('miR-130a-5p', 'Chemical', '-', (66, 77))	('HIF1A-AS2', 'Gene', (52, 61))	('negative', 'NegReg', (23, 31))
41697	33061459	Luciferase reporter assay showed that miR-130a-5p overexpression substantially repressed activity of the reporter with WT rather than MUT 3'UTR of ERBB2 (Figure 6B and D).	("MUT 3'UTR", 'Var', (134, 143))	('miR-130a-5p', 'Var', (38, 49))	('ERBB2', 'Gene', (147, 152))	('ERBB2', 'Gene', '2064', (147, 152))	('miR-130a-5p', 'Chemical', '-', (38, 49))	('repressed', 'PosReg', (79, 88))	('activity', 'MPA', (89, 97))
41700	33061459	Based on these results, we argued that knockdown of HIF1A-AS2 released the repression to miR-130a-5p, thereby promoting the expression of ERRB2.	('knockdown', 'Var', (39, 48))	('promoting', 'PosReg', (110, 119))	('miR-130a-5p', 'Gene', (89, 100))	('miR-130a-5p', 'Chemical', '-', (89, 100))	('HIF1A-AS2', 'Gene', '100750247', (52, 61))	('expression', 'MPA', (124, 134))	('repression', 'MPA', (75, 85))	('HIF1A-AS2', 'Gene', (52, 61))	('ERRB2', 'Gene', (138, 143))
41701	33061459	We detected the effects of miR-130a-5p on RCC cells and determined whether miR-130a-5p overexpression could inhibit the proliferation and progression of renal cancer cells induced by HIF1A-AS2 overexpression.	('proliferation', 'CPA', (120, 133))	('renal cancer', 'Disease', 'MESH:D007680', (153, 165))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('miR-130a-5p', 'Var', (75, 86))	('miR-130a-5p', 'Chemical', '-', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('renal cancer', 'Disease', (153, 165))	('HIF1A-AS2', 'Gene', '100750247', (183, 192))	('progression', 'CPA', (138, 149))	('miR-130a-5p', 'Chemical', '-', (27, 38))	('renal cancer', 'Phenotype', 'HP:0009726', (153, 165))	('inhibit', 'NegReg', (108, 115))	('RCC', 'Disease', (42, 45))	('HIF1A-AS2', 'Gene', (183, 192))
41702	33061459	As illustrated in Figure 7A, miR-130a-5p and HIF1A-AS2 were successfully overexpressed in ACHN cells, respectively.	('HIF1A-AS2', 'Gene', '100750247', (45, 54))	('HIF1A-AS2', 'Gene', (45, 54))	('miR-130a-5p', 'Chemical', '-', (29, 40))	('miR-130a-5p', 'Var', (29, 40))
41704	33061459	Observation results revealed that ACHN cells with high miR-130a-5p expression declined the SNAIL levels but increased the E-cadherin levels.	('cadherin', 'molecular_function', 'GO:0008014', ('124', '132'))	('increased', 'PosReg', (108, 117))	('E-cadherin', 'Gene', (122, 132))	('E-cadherin', 'Gene', '999', (122, 132))	('declined', 'NegReg', (78, 86))	('SNAIL', 'Gene', (91, 96))	('miR-130a-5p expression', 'Var', (55, 77))	('SNAIL', 'Gene', '6615', (91, 96))	('miR-130a-5p', 'Chemical', '-', (55, 66))
41705	33061459	Meanwhile, overexpression of miR-130a-5p could weaken the regulation of HIF1A-AS2 to SNAIL and E-cadherin (Figure 7B and C).	('miR-130a-5p', 'Var', (29, 40))	('E-cadherin', 'Gene', (95, 105))	('weaken', 'NegReg', (47, 53))	('cadherin', 'molecular_function', 'GO:0008014', ('97', '105'))	('miR-130a-5p', 'Chemical', '-', (29, 40))	('HIF1A-AS2', 'Gene', '100750247', (72, 81))	('E-cadherin', 'Gene', '999', (95, 105))	('SNAIL', 'Gene', '6615', (85, 90))	('SNAIL', 'Gene', (85, 90))	('regulation', 'MPA', (58, 68))	('HIF1A-AS2', 'Gene', (72, 81))	('overexpression', 'PosReg', (11, 25))	('regulation', 'biological_process', 'GO:0065007', ('58', '68'))
41724	33061459	Luciferase assays showed that miR-130a-5p could depress ERBB2 and HIF1A-AS2 expression through direct binding to their promoter.	('binding', 'Interaction', (102, 109))	('depress', 'NegReg', (48, 55))	('HIF1A-AS2', 'Gene', '100750247', (66, 75))	('miR-130a-5p', 'Var', (30, 41))	('binding', 'molecular_function', 'GO:0005488', ('102', '109'))	('miR-130a-5p', 'Chemical', '-', (30, 41))	('expression', 'MPA', (76, 86))	('ERBB2', 'Gene', '2064', (56, 61))	('HIF1A-AS2', 'Gene', (66, 75))	('ERBB2', 'Gene', (56, 61))
41726	33061459	Inhibitors targeting the ERBB2 selective tyrosine kinase inhibit tumor growth including RCC.	('tumor', 'Disease', (65, 70))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('inhibit', 'NegReg', (57, 64))	('Inhibitors', 'Var', (0, 10))	('ERBB2', 'Gene', '2064', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('ERBB2', 'Gene', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
41730	33061459	Findings have proved that promoter hypermethylation elicits miR-130a-5p downregulation.	('miR-130a-5p', 'Chemical', '-', (60, 71))	('promoter hypermethylation', 'Var', (26, 51))	('miR-130a-5p', 'Gene', (60, 71))	('downregulation', 'NegReg', (72, 86))
41731	33061459	In line with extensive reports on the relationship between miR-130a-5p expression and its promoter methylation of renal carcinomas, miR-130a-5p CpG methylation may be a promising diagnostic marker for colorectal cancer, pancreatic cancer, breast cancer, kidney cancer, urothelial cancer, and soft tissue sarcoma.	('urothelial cancer', 'Disease', 'MESH:D014523', (269, 286))	('pancreatic cancer', 'Disease', 'MESH:D010190', (220, 237))	('breast cancer', 'Disease', (239, 252))	('urothelial cancer', 'Disease', (269, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('pancreatic cancer', 'Disease', (220, 237))	('kidney cancer', 'Disease', 'MESH:D007680', (254, 267))	('miR-130a-5p', 'Chemical', '-', (132, 143))	('renal carcinomas', 'Disease', (114, 130))	('renal carcinomas', 'Phenotype', 'HP:0005584', (114, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (201, 218))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (292, 311))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('miR-130a-5p', 'Chemical', '-', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (292, 311))	('renal carcinoma', 'Phenotype', 'HP:0005584', (114, 129))	('soft tissue sarcoma', 'Disease', (292, 311))	('kidney cancer', 'Phenotype', 'HP:0009726', (254, 267))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('kidney cancer', 'Disease', (254, 267))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (220, 237))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('miR-130a-5p', 'Var', (132, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (239, 252))	('colorectal cancer', 'Disease', 'MESH:D015179', (201, 218))	('methylation', 'biological_process', 'GO:0032259', ('99', '110'))	('sarcoma', 'Phenotype', 'HP:0100242', (304, 311))	('methylation', 'biological_process', 'GO:0032259', ('148', '159'))	('renal carcinomas', 'Disease', 'MESH:C538614', (114, 130))	('colorectal cancer', 'Disease', (201, 218))	('breast cancer', 'Disease', 'MESH:D001943', (239, 252))
41734	33061459	Consequently, we determined levels of HIF1A-AS2 and miR-130a-5p in wide-type renal carcinoma cells, with findings demonstrated that the deletion of p53 dramatically suppressed the expression of miR-130a-5p by elevating the level of HIF1A-AS2 indicating that p53 functioned as a potential upstream regulator of the HIF1A-AS2-miR-130a-5p/c axis.	('miR-130a-5p', 'Chemical', '-', (324, 335))	('p53', 'Gene', (258, 261))	('renal carcinoma', 'Disease', (77, 92))	('HIF1A-AS2', 'Gene', '100750247', (38, 47))	('renal carcinoma', 'Phenotype', 'HP:0005584', (77, 92))	('deletion', 'Var', (136, 144))	('HIF1A-AS2', 'Gene', (38, 47))	('HIF1A-AS2', 'Gene', '100750247', (314, 323))	('elevating', 'PosReg', (209, 218))	('HIF1A-AS2', 'Gene', (314, 323))	('miR-130a-5p', 'Chemical', '-', (52, 63))	('level', 'MPA', (223, 228))	('expression', 'MPA', (180, 190))	('miR-130a-5p', 'Chemical', '-', (194, 205))	('p53', 'Gene', '7157', (148, 151))	('suppressed', 'NegReg', (165, 175))	('HIF1A-AS2', 'Gene', '100750247', (232, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('p53', 'Gene', '7157', (258, 261))	('p53', 'Gene', (148, 151))	('HIF1A-AS2', 'Gene', (232, 241))	('renal carcinoma', 'Disease', 'MESH:C538614', (77, 92))
41735	33061459	Massive evidence has revealed that miR-130a-5p roles as more than a regulator in the processes of cellular proliferation, apoptosis, invasion and migration of tumors, it functions as a modulator of cancer cellular stemness and chemoresistance as well.	('apoptosis', 'biological_process', 'GO:0097194', ('122', '131'))	('apoptosis', 'biological_process', 'GO:0006915', ('122', '131'))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('chemoresistance', 'CPA', (227, 242))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('miR-130a-5p', 'Chemical', '-', (35, 46))	('migration', 'CPA', (146, 155))	('cellular proliferation', 'CPA', (98, 120))	('apoptosis', 'CPA', (122, 131))	('functions', 'Reg', (170, 179))	('stemness', 'Disease', 'MESH:D020295', (214, 222))	('stemness', 'Disease', (214, 222))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('invasion', 'CPA', (133, 141))	('modulator', 'Reg', (185, 194))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('miR-130a-5p', 'Var', (35, 46))
41746	30633175	The models ordered by their AUCs from large to small were CIF-CMP-minMSE (AUC: 0.986), CIF-PP-minMSE (AUC: 0.981), CIF-minMSE (AUC: 0.980), CMP-minMSE (AUC: 0.975), and PP-minMSE (AUC: 0.963).	('CIF', 'Chemical', '-', (58, 61))	('CIF-PP', 'Chemical', '-', (87, 93))	('CIF-minMSE', 'Var', (115, 125))	('CIF', 'Chemical', '-', (87, 90))	('CIF', 'Chemical', '-', (115, 118))	('CMP-minMSE', 'Var', (140, 150))	('CIF-PP-minMSE', 'Var', (87, 100))
41755	30633175	Kuthi et al found the 5-year survival rate of grade 1 or 2 ccRCC was significant better than that of grade 3 or 4.	('better', 'PosReg', (81, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('grade 1', 'Var', (46, 53))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))
41772	30633175	Finally, 227 patients remained in this study, of which 130 cases were male patients, 97 cases were female patients, the age range was 10 to 85 years old, the mean age was 57.3 +- 12.9 years, 136 cases were low-grade ccRCCs (WHO/ISUP grades 1 and 2), and 91 cases were high-grade ccRCCs (WHO/ISUP grades 3 and 4) (Table 1).	('low-grade', 'Var', (206, 215))	('patients', 'Species', '9606', (13, 21))	('ccRCC', 'Phenotype', 'HP:0006770', (216, 221))	('patients', 'Species', '9606', (75, 83))	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('RCC', 'Disease', (218, 221))	('RCC', 'Phenotype', 'HP:0005584', (218, 221))	('RCC', 'Disease', 'MESH:C538614', (281, 284))	('patients', 'Species', '9606', (106, 114))	('RCC', 'Disease', (281, 284))	('RCC', 'Phenotype', 'HP:0005584', (281, 284))	('ccRCC', 'Phenotype', 'HP:0006770', (279, 284))
41795	30633175	The cutoff values, sensitivities, specificities, and AUCs of the 5 predictive models (CIF-minMSE, CMP-minMSE, PP-minMSE, CIF-CMP-minMSE, and CIF-PP-minMSE) were shown in Table 4.	('CIF', 'Chemical', '-', (86, 89))	('CMP-minMSE', 'Disease', (98, 108))	('CIF', 'Chemical', '-', (141, 144))	('CIF', 'Chemical', '-', (121, 124))	('PP-minMSE', 'Var', (110, 119))	('CIF-CMP-minMSE', 'Var', (121, 135))	('CIF-PP', 'Chemical', '-', (141, 147))
41811	30633175	That was to say, when combined with CIF-minMSE, the RFs of MDCT images were conducive to the higher rate of correctly recognizing the low and high grade ccRCC, and moreover, the RFs of CMP-minMSE were more valuable than that of PP-minMSE.	('ccRCC', 'Phenotype', 'HP:0006770', (153, 158))	('RCC', 'Disease', (155, 158))	('CIF', 'Chemical', '-', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('CMP-minMSE', 'Var', (185, 195))	('RCC', 'Disease', 'MESH:C538614', (155, 158))
41812	30633175	However, we also found, when used alone, the AUC of CIF-minMSE was larger than that of CMP-minMSE or PP-minMSE.	('CIF-minMSE', 'Var', (52, 62))	('AUC', 'MPA', (45, 48))	('CIF', 'Chemical', '-', (52, 55))
41851	28623280	The results indicate that neuroprotective and beneficial effects on cognition are preserved in EV-3, whereas erythropoietic effects of EPO are not mediated by the EV-3 protein.	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('EV-3', 'Chemical', '-', (95, 99))	('neuroprotective', 'CPA', (26, 41))	('cognition', 'biological_process', 'GO:0050890', ('68', '77'))	('EV-3', 'Var', (95, 99))	('beneficial effects', 'CPA', (46, 64))	('EV-3', 'Chemical', '-', (163, 167))	('cognition', 'CPA', (68, 77))
41902	28623280	Standard curves were generated with linear regression as duplicates for each transition separately using peptide concentrations of 0.001, 0.01, 0.1, 1 and 10 fmol/mul.	('rat', 'Species', '10116', (92, 95))	('rat', 'Species', '10116', (25, 28))	('rat', 'Species', '10116', (120, 123))	('0.01', 'Var', (138, 142))	('0.1', 'Var', (144, 147))
41933	28623280	Electrophoretic separation of 2-step PCR amplification products revealed the expected PCR product at approximately 550 bp corresponding to EPO truncated by 17 nucleotides at 5' and by 16 nucleotides at 3' through the usage of the second primer pair lying in exon 2 and exon 5 of the EPO gene.	('EPO', 'Gene', (139, 142))	('truncated', 'Var', (143, 152))	('EPO', 'Gene', (283, 286))	('rat', 'Species', '10116', (20, 23))
42005	28623280	During the visual discrimination task, EPO-treated mice showed significantly faster learning as compared to the placebo-treated mice (chi2 = 4.178; p = 0.041; Fig.	('EPO-treated', 'Var', (39, 50))	('mice', 'Species', '10090', (51, 55))	('mice', 'Species', '10090', (128, 132))	('faster', 'PosReg', (77, 83))	('learning', 'CPA', (84, 92))
42007	28623280	EPO-treated mice showed a significantly better overall performance as compared to the placebo-treated mice (chi2 = 4.177; p = 0.041; Fig.	('mice', 'Species', '10090', (12, 16))	('mice', 'Species', '10090', (102, 106))	('better', 'PosReg', (40, 46))	('EPO-treated', 'Var', (0, 11))
42009	28623280	EV-3 mice were faster in the acquisition of the different stages of the touchscreen task compared to placebo.	('EV-3', 'Chemical', '-', (0, 4))	('acquisition', 'CPA', (29, 40))	('faster', 'PosReg', (15, 21))	('EV-3', 'Var', (0, 4))	('mice', 'Species', '10090', (5, 9))
42014	28623280	Haematocrit levels were increased in EPO-treated mice as compared to both EV-3 (T[27] = 10.27; p < 0.0001; t-test for independent samples) and placebo treated mice (T[28] = 10.29; p < 0.0001).	('EV-3', 'Chemical', '-', (74, 78))	('Haematocrit levels', 'MPA', (0, 18))	('mice', 'Species', '10090', (49, 53))	('mice', 'Species', '10090', (159, 163))	('EPO-treated', 'Var', (37, 48))	('increased', 'PosReg', (24, 33))
42044	28623280	Our results in cultured human CD34+ showed that EV-3, contrary to EPO, does not promote erythroid progenitors (BFU-E or CFU-E) in the early phase of erythropoiesis.	('EV-3', 'Var', (48, 52))	('human', 'Species', '9606', (24, 29))	('erythroid progenitors', 'CPA', (88, 109))	('erythropoiesis', 'biological_process', 'GO:0030218', ('149', '163'))	('CD34', 'Gene', (30, 34))	('CD34', 'Gene', '947', (30, 34))	('EV-3', 'Chemical', '-', (48, 52))	('BFU', 'Chemical', '-', (111, 114))	('promote', 'PosReg', (80, 87))
42062	28623280	The finding that EV-3 conserves EPO's neuroprotective and cognition-promoting effects without stimulating erythropoiesis further supports the independency of these effects from erythropoiesis.	('erythropoiesis', 'biological_process', 'GO:0030218', ('177', '191'))	('cognition', 'biological_process', 'GO:0050890', ('58', '67'))	('erythropoiesis', 'biological_process', 'GO:0030218', ('106', '120'))	('EV-3', 'Chemical', '-', (17, 21))	('neuroprotective', 'CPA', (38, 53))	('cognition-promoting effects', 'CPA', (58, 85))	('EV-3', 'Var', (17, 21))
42079	31528216	In addition, CD36 mRNA expression was significantly increased in patients with advanced TNM stage (p=0.003, p<0.001, p<0.001), and high VAT% (p=0.004).	('increased', 'PosReg', (52, 61))	('TNM', 'Gene', (88, 91))	('N', 'Chemical', 'MESH:D009584', (89, 90))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('CD36', 'Protein', (13, 17))	('patients', 'Species', '9606', (65, 73))	('high VAT', 'Var', (131, 139))	('TNM', 'Gene', '10178', (88, 91))	('CD36', 'Species', '42374', (13, 17))
42093	31528216	Interestingly, tumor cells completely stopped metastasis in mouse models when CD36 expression was knockdown.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('stopped', 'NegReg', (38, 45))	('knockdown', 'Var', (98, 107))	('CD36', 'Species', '42374', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('metastasis', 'CPA', (46, 56))	('CD36', 'Gene', (78, 82))	('tumor', 'Disease', (15, 20))	('mouse', 'Species', '10090', (60, 65))
42094	31528216	Therefore, CD36 may affect the tumorigenesis of ccRCC through underlying lipid metabolism variations.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('lipid metabolism', 'biological_process', 'GO:0006629', ('73', '89'))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('tumor', 'Disease', (31, 36))	('CD36', 'Species', '42374', (11, 15))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('lipid', 'Chemical', 'MESH:D008055', (73, 78))	('CD36', 'Var', (11, 15))	('affect', 'Reg', (20, 26))	('variations', 'Reg', (90, 100))	('lipid metabolism', 'MPA', (73, 89))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
42118	31528216	X-tile software was utilized to take the cut-off value: point of 5 and 10, in concordance of which overall participants were divided to three groups: CD36 expression high, middle and low.	('high', 'Var', (166, 170))	('CD36', 'Species', '42374', (150, 154))	('CD36', 'Protein', (150, 154))	('participants', 'Species', '9606', (107, 119))	('low', 'NegReg', (183, 186))
42130	31528216	Importantly, subgroups of CD36 expression (Low vs. middle) and CD36 expression (low vs. high) showed that CD36 amplification markedly associated with poor PFS (p<0.001) and OS (p<0.001) for ccRCC patients both in Cox logistic regression analysis.	('CD36', 'Species', '42374', (106, 110))	('amplification', 'Var', (111, 124))	('CD36', 'Species', '42374', (26, 30))	('Cox', 'Gene', (213, 216))	('CD36', 'Species', '42374', (63, 67))	('PFS', 'MPA', (155, 158))	('patients', 'Species', '9606', (196, 204))	('CD36', 'Gene', (106, 110))	('poor', 'NegReg', (150, 154))	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('RCC', 'Disease', (192, 195))	('RCC', 'Phenotype', 'HP:0005584', (192, 195))	('ccRCC', 'Phenotype', 'HP:0006770', (190, 195))	('Cox', 'Gene', '1351', (213, 216))
42143	31528216	Considering MRI scans were available only in 104 cases, in Supplementary Table 1 and Supplementary Table 2, multivariate Cox regression analyses of PFS and OS indicated that high VAT% was significantly related with poor PFS (HR=2.56, p=0.042) and OS (HR=3.291, p=0.044), while BMI was not independent covariate affecting survival.	('poor', 'NegReg', (215, 219))	('PFS', 'MPA', (220, 223))	('high VAT%', 'Var', (174, 183))	('Cox', 'Gene', '1351', (121, 124))	('Cox', 'Gene', (121, 124))
42146	31528216	To clarify the effect of elevated CD36 mRNA expression of ccRCC, we detected anthropometric measures of adipose distribution on MRI and observed that CD36 mRNA amplification was significantly associated with increased VAT%.	('CD36 mRNA amplification', 'Var', (150, 173))	('CD36', 'Species', '42374', (150, 154))	('N', 'Chemical', 'MESH:D009584', (157, 158))	('CD36', 'Species', '42374', (34, 38))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('VAT', 'Disease', (218, 221))	('increased', 'PosReg', (208, 217))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('N', 'Chemical', 'MESH:D009584', (41, 42))
42148	31528216	It opens up a novel way for CD36 mRNA expression to affect the pathogenesis of ccRCC by underlying adipose metabolism variation.	('underlying', 'Reg', (88, 98))	('adipose metabolism variation', 'MPA', (99, 127))	('pathogenesis', 'biological_process', 'GO:0009405', ('63', '75'))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('CD36', 'Species', '42374', (28, 32))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('mRNA expression', 'Var', (33, 48))	('RCC', 'Disease', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('N', 'Chemical', 'MESH:D009584', (35, 36))	('CD36', 'Protein', (28, 32))	('metabolism', 'biological_process', 'GO:0008152', ('107', '117'))	('affect', 'Reg', (52, 58))
42162	31528216	Despite the fact that computed tomography (CT) is used to be considered primarily standard imaging method for measurement of abdominal obesity, MRI is a highly predictive, accurate and safe modality to quantitatively assess body fat distribution, transcending the shortcomings of rough BMI cutoff.	('MRI', 'Var', (144, 147))	('abdominal obesity', 'Disease', 'MESH:D056128', (125, 142))	('obesity', 'Phenotype', 'HP:0001513', (135, 142))	('abdominal obesity', 'Phenotype', 'HP:0012743', (125, 142))	('abdominal obesity', 'Disease', (125, 142))	('fat', 'Gene', '948', (229, 232))	('fat', 'Gene', (229, 232))
42167	31528216	CD36 may also contribute to the activation of latent TGF-beta, to enhance inflammatory responses, and to suppress immune responses.	('suppress immune responses', 'Phenotype', 'HP:0002721', (105, 130))	('enhance', 'PosReg', (66, 73))	('CD36', 'Species', '42374', (0, 4))	('activation', 'PosReg', (32, 42))	('suppress', 'NegReg', (105, 113))	('CD36', 'Var', (0, 4))	('latent', 'Protein', (46, 52))	('inflammatory responses', 'CPA', (74, 96))	('immune responses', 'CPA', (114, 130))	('TGF-beta', 'Protein', (53, 61))
42173	31528216	Therefore, it also provides a provoking thought that underlying adipose metabolism variation concerning VAT% might clarify the correlation triggering carcinogenesis.	('adipose metabolism', 'MPA', (64, 82))	('carcinogenesis', 'Disease', 'MESH:D063646', (150, 164))	('metabolism', 'biological_process', 'GO:0008152', ('72', '82'))	('VAT', 'Gene', (104, 107))	('carcinogenesis', 'Disease', (150, 164))	('variation', 'Var', (83, 92))
42238	29721070	Standard of care surgery was performed, supplemented with gamma probe detection and near-infrared fluorescence imaging (NIRF) to assess accumulation of 111In-DOTA-girentuximab-IRDye800CW in the tumor.	('accumulation', 'PosReg', (136, 148))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('IRDye800CW', 'Chemical', 'MESH:C562366', (176, 186))	('111In-DOTA-girentuximab-IRDye800CW', 'Var', (152, 186))	('N', 'Chemical', 'MESH:D009584', (120, 121))	('111In-DOTA-girentuximab', 'Chemical', '-', (152, 175))	('tumor', 'Disease', (194, 199))
42258	29721070	False positive accumulation of 111In-DOTA-girentuximab-IRDye800CW was observed by SPECT/CT in a CAIX-negative adrenal adenoma and a cyst in the contralateral kidney in patient #12.	('adrenal adenoma', 'Disease', (110, 125))	('CAIX', 'Gene', '768', (96, 100))	('111In-DOTA-girentuximab-IRDye800CW', 'Var', (31, 65))	('111In-DOTA-girentuximab', 'Chemical', '-', (31, 54))	('patient', 'Species', '9606', (168, 175))	('IRDye800CW', 'Chemical', 'MESH:C562366', (55, 65))	('adrenal adenoma', 'Phenotype', 'HP:0008256', (110, 125))	('CAIX', 'Gene', (96, 100))	('adrenal adenoma', 'Disease', 'MESH:D018246', (110, 125))
42279	29721070	The average blood levels of 111In-DOTA-girentuximab-IRDye800CW were 0.024+-0.009, 0.019+-0.007, 0.007+-0.003 and 0.004+-0.002 %ID/g at 5 min, 3 h, 4 d and 7 d post injection, respectively.	('blood levels', 'MPA', (12, 24))	('0.024+-0.009', 'Var', (68, 80))	('0.004+-0.002 %', 'Var', (113, 127))	('111In-DOTA-girentuximab', 'Chemical', '-', (28, 51))	('IRDye800CW', 'Chemical', 'MESH:C562366', (52, 62))	('0.019+-0.007', 'Var', (82, 94))	('0.007+-0.003', 'Var', (96, 108))
42322	29721070	Pharmacokinetics are faster with smaller molecules, but small molecules may have the disadvantage of high physiological renal clearance, thereby obscuring ccRCC tumors.	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('obscuring', 'NegReg', (145, 154))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('small molecules', 'Var', (56, 71))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', (157, 160))	('ccRCC', 'Phenotype', 'HP:0006770', (155, 160))
42329	29721070	Except for its use during NSS, the specific accumulation of 111In-DOTA-girentuximab-IRDye800CW in ccRCC implies that dual-modality imaging may also be advantageous for lymph node dissection or metastasectomy.	('lymph node dissection', 'CPA', (168, 189))	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('N', 'Chemical', 'MESH:D009584', (26, 27))	('metastasectomy', 'CPA', (193, 207))	('111In-DOTA-girentuximab', 'Chemical', '-', (60, 83))	('IRDye800CW', 'Chemical', 'MESH:C562366', (84, 94))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('111In-DOTA-girentuximab-IRDye800CW', 'Var', (60, 94))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
42334	28746769	The aims of the present study were to investigate the antitumor roles of miR-10a-5p and the novel cancer networks regulated by this miRNA in RCC cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('RCC', 'Disease', (141, 144))	('tumor', 'Disease', (58, 63))	('miR-10a-5p', 'Var', (73, 83))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('5p', 'Chemical', '-', (81, 83))	('cancer', 'Disease', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
42336	28746769	Ectopic expression of miR-10a-5p in RCC cell lines (786-O and A498 cells) inhibited cancer cell migration and invasion.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('inhibited', 'NegReg', (74, 83))	('miR-10a-5p', 'Var', (22, 32))	('cancer', 'Disease', (84, 90))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('5p', 'Chemical', '-', (30, 32))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('cell migration', 'biological_process', 'GO:0016477', ('91', '105'))	('A498', 'CellLine', 'CVCL:1056', (62, 66))	('Ectopic', 'MPA', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('invasion', 'CPA', (110, 118))
42344	28746769	miRNAs act as pivotal players that regulate the expression control of protein-coding/protein-noncoding RNAs in a sequence-dependent manner.13, 14 Notably, a single miRNA can directly control many mRNAs in human cells.15 Therefore, aberrantly expressed miRNAs can disrupt the tight control of RNA expression in cancer cells.	('miRNAs', 'Protein', (252, 258))	('cancer', 'Disease', (310, 316))	('aberrantly expressed', 'Var', (231, 251))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('RNA', 'cellular_component', 'GO:0005562', ('292', '295'))	('RNA expression', 'MPA', (292, 306))	('disrupt', 'NegReg', (263, 270))	('human', 'Species', '9606', (205, 210))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('tight control', 'MPA', (275, 288))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
42348	28746769	The aims of the present study were to investigate the functional significance of miR-10a-5p and to identify the molecular targets regulated by miR-10a-5p in ccRCC cells.	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('5p', 'Chemical', '-', (89, 91))	('miR-10a-5p', 'Var', (143, 153))	('5p', 'Chemical', '-', (151, 153))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))
42368	28746769	The partial wild-type sequence of the SKA1 3'-UTR or that with deletion of the miR-10a-5p target site was inserted between the XhoI-PmeI restriction sites in the 3'-UTR of the hRluc gene in the psiCHECK-2 vector (C8021; Promega, Madison, WI, USA).	('5p', 'Chemical', '-', (87, 89))	('SKA1', 'Gene', (38, 42))	('hRluc', 'Gene', (176, 181))	('SKA1', 'Gene', '220134', (38, 42))	('deletion', 'Var', (63, 71))	('C8021', 'Var', (213, 218))
42375	28746769	Expression levels of miR-10a-5p were significantly downregulated in primary cancer tissues and TKI-treated tissues compared with those in noncancerous tissues (P = 0.0010, P = 0.0009, respectively; Fig.	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('5p', 'Chemical', '-', (29, 31))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('Expression levels', 'MPA', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('downregulated', 'NegReg', (51, 64))	('miR-10a-5p', 'Var', (21, 31))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (141, 147))
42376	28746769	In 786-O and A498 cells, expression levels of miR-10a-5p were relatively low compared with those of clinical specimens (Fig.	('miR-10a-5p', 'Var', (46, 56))	('expression levels', 'MPA', (25, 42))	('5p', 'Chemical', '-', (54, 56))	('low', 'NegReg', (73, 76))	('A498', 'CellLine', 'CVCL:1056', (13, 17))
42378	28746769	XTT assays showed that cell proliferation was significantly inhibited in miR-10a-5p transfectants compared with that in mock or miR-control transfectants (Figs 2b; S1a).	('miR-10a-5p transfectants', 'Var', (73, 97))	('cell proliferation', 'biological_process', 'GO:0008283', ('23', '41'))	('inhibited', 'NegReg', (60, 69))	('5p', 'Chemical', '-', (81, 83))	('cell proliferation', 'CPA', (23, 41))
42379	28746769	Migration assays showed that cell migration activity was significantly inhibited in miR-10a-5p transfectants in comparison with those in mock or miR-control transfectants (Figs 2c; S2a).	('miR-10a-5p transfectants', 'Var', (84, 108))	('inhibited', 'NegReg', (71, 80))	('cell migration', 'biological_process', 'GO:0016477', ('29', '43'))	('5p', 'Chemical', '-', (92, 94))	('cell migration activity', 'CPA', (29, 52))
42381	28746769	To further elucidate the molecular mechanisms and pathways regulated by antitumor miR-10a-5p in ccRCC cells, we carried out a combination of in silico analyses and oligo microarray analyses using miR-10a-5p transfectants.	('5p', 'Chemical', '-', (204, 206))	('5p', 'Chemical', '-', (90, 92))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('miR-10a-5p', 'Var', (82, 92))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
42386	28746769	Kaplan-Meier survival curves showed that high expression of eight genes was associated with poor prognosis in ccRCC (Table3; Figs 4a, 5).	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('high', 'Var', (41, 45))
42387	28746769	Among these genes, we focused on SKA1, which was most downregulated by transfection of miR-10a-5p, and showed the most dramatic difference in OncoLnc prognostic analysis (P = 2.72E-08, Fig.	('miR-10a-5p', 'Var', (87, 97))	('transfection', 'Var', (71, 83))	('5p', 'Chemical', '-', (95, 97))	('difference', 'Reg', (128, 138))	('SKA1', 'Gene', (33, 37))	('downregulated', 'NegReg', (54, 67))	('SKA1', 'Gene', '220134', (33, 37))
42397	28746769	Expression of SKA1 mRNA was significantly suppressed by miR-10a-5p transfection compared with that in mock- or miR-control-transfected cells (Fig.	('SKA1', 'Gene', (14, 18))	('miR-10a-5p transfection', 'Var', (56, 79))	('Expression', 'MPA', (0, 10))	('suppressed', 'NegReg', (42, 52))	('5p', 'Chemical', '-', (64, 66))	('SKA1', 'Gene', '220134', (14, 18))
42398	28746769	Similarly, SKA1 protein expression was repressed in the miR-10a-5p transfectants (Fig.	('protein', 'cellular_component', 'GO:0003675', ('16', '23'))	('SKA1', 'Gene', (11, 15))	('5p', 'Chemical', '-', (64, 66))	('protein', 'Protein', (16, 23))	('SKA1', 'Gene', '220134', (11, 15))	('miR-10a-5p', 'Var', (56, 66))
42400	28746769	The TargetScan database predicted that miR-10a-5p bound at position 28-35 in the 3'-UTR of SKA1.	('5p', 'Chemical', '-', (47, 49))	('SKA1', 'Gene', '220134', (91, 95))	('miR-10a-5p', 'Var', (39, 49))	('SKA1', 'Gene', (91, 95))
42402	28746769	Luminescence intensity was significantly reduced by cotransfection with miR-10a-5p and the vector carrying the wild-type 3'-UTR of SKA1.	('reduced', 'NegReg', (41, 48))	('SKA1', 'Gene', '220134', (131, 135))	('5p', 'Chemical', '-', (80, 82))	('SKA1', 'Gene', (131, 135))	('Luminescence intensity', 'MPA', (0, 22))	('miR-10a-5p', 'Var', (72, 82))
42403	28746769	However, luminescence intensity was not suppressed when the target site of miR-10a-5p was deleted from the vectors (Fig.	('luminescence intensity', 'MPA', (9, 31))	('5p', 'Chemical', '-', (83, 85))	('miR-10a-5p', 'Var', (75, 85))
42408	28746769	Furthermore, functional assays indicated that si-SKA1 transfection markedly inhibited cell proliferation, migration, and invasion in comparison with mock- or si-control-transfected cells (Figs 8c; S1b, S3a, S4a).	('SKA1', 'Gene', (49, 53))	('cell proliferation', 'biological_process', 'GO:0008283', ('86', '104'))	('SKA1', 'Gene', '220134', (49, 53))	('cell proliferation', 'CPA', (86, 104))	('invasion', 'CPA', (121, 129))	('migration', 'CPA', (106, 115))	('inhibited', 'NegReg', (76, 85))	('transfection', 'Var', (54, 66))
42409	28746769	To validate whether the molecular pathway of SKA1/miR-10a-5p was critical for the progression of ccRCC, we carried out SKA1 rescue experiments by cotransfection with SKA1 and miR-10a-5p in 786-O cells.	('SKA1', 'Gene', (45, 49))	('5p', 'Chemical', '-', (183, 185))	('SKA1', 'Gene', '220134', (119, 123))	('miR-10a-5p', 'Var', (175, 185))	('SKA1', 'Gene', '220134', (45, 49))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('SKA1', 'Gene', (166, 170))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('5p', 'Chemical', '-', (58, 60))	('SKA1', 'Gene', (119, 123))	('SKA1', 'Gene', '220134', (166, 170))
42411	28746769	Functional assays showed that the migration and invasion abilities of ccRCC cells were recovered by SKA1 and miR-10a-5p transfection compared with cells with restored miR-10a-5p only (Figs 9b-d; S1c, S5a,b).	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('SKA1', 'Gene', (100, 104))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('invasion abilities', 'CPA', (48, 66))	('miR-10a-5p', 'Var', (109, 119))	('SKA1', 'Gene', '220134', (100, 104))	('5p', 'Chemical', '-', (175, 177))	('5p', 'Chemical', '-', (117, 119))	('migration', 'CPA', (34, 43))	('recovered', 'PosReg', (87, 96))
42414	28746769	Kaplan-Meier curves for DFS rates showed that the DFS of the high SKA1 expression group was significantly shorter than that of the low expression group in ccRCC (P < 0.0001, Fig.	('shorter', 'NegReg', (106, 113))	('high', 'Var', (61, 65))	('SKA1', 'Gene', (66, 70))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('SKA1', 'Gene', '220134', (66, 70))	('RCC', 'Disease', (157, 160))	('DFS', 'MPA', (50, 53))
42418	28746769	To explore the downstream survival pathways of miR-10a-5p/SKA1 axis, phosphorylation of ERK1/2 (Thr 202/Tyr 204), AKT (Ser 473), FAK (Tyr 397) and SRC (Tyr 416) was examined.	('AKT', 'Gene', '207', (114, 117))	('5p', 'Chemical', '-', (55, 57))	('Thr 202/Tyr 204', 'Var', (96, 111))	('ERK1', 'molecular_function', 'GO:0004707', ('88', '92'))	('ERK1/2', 'Gene', (88, 94))	('ERK1/2', 'Gene', '5595;5594', (88, 94))	('phosphorylation', 'biological_process', 'GO:0016310', ('69', '84'))	('FAK', 'Gene', (129, 132))	('Ser', 'cellular_component', 'GO:0005790', ('119', '122'))	('Tyr', 'Chemical', 'MESH:D014443', (104, 107))	('SKA1', 'Gene', (58, 62))	('FAK', 'Gene', '5747', (129, 132))	('Tyr', 'Chemical', 'MESH:D014443', (152, 155))	('AKT', 'Gene', (114, 117))	('SRC', 'Gene', '6714', (147, 150))	('Thr', 'Chemical', 'MESH:D013912', (96, 99))	('SKA1', 'Gene', '220134', (58, 62))	('Ser', 'Chemical', 'MESH:D012694', (119, 122))	('FAK', 'molecular_function', 'GO:0004717', ('129', '132'))	('SRC', 'Gene', (147, 150))	('Tyr', 'Chemical', 'MESH:D014443', (134, 137))
42422	28746769	To investigate the molecular mechanisms of drug resistance in RCC cells, we constructed a miRNA expression signature using autopsy specimens from patients with ccRCC who exhibited TKI-treatment failure.22 Our present data demonstrated that miR-10a-5p acted as an antitumor miRNA in RCC cells.	('RCC', 'Disease', 'MESH:C538614', (282, 285))	('RCC', 'Disease', (162, 165))	('RCC', 'Disease', (282, 285))	('RCC', 'Phenotype', 'HP:0005584', (282, 285))	('RCC', 'Phenotype', 'HP:0005584', (162, 165))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('drug resistance', 'Phenotype', 'HP:0020174', (43, 58))	('drug resistance', 'biological_process', 'GO:0009315', ('43', '58'))	('drug resistance', 'biological_process', 'GO:0042493', ('43', '58'))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', (267, 272))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('miR-10a-5p', 'Var', (240, 250))	('patients', 'Species', '9606', (146, 154))	('5p', 'Chemical', '-', (248, 250))
42439	28746769	Many reports have demonstrated that acquired resistance of RCC cells to molecular targeted therapies induces cancer-promoting genes and activates several alternative pathways.12, 56, 57 A previous study showed that sunitinib treatment significantly suppressed phosphorylation of ERK1/2 and AKT in TKI-sensitive RCC cells, whereas inhibition of phosphorylation was not observed in TKI-resistant RCC cells.58 In this study, phosphorylation of ERK1/2 and AKT was suppressed by knockdown of SKA1 and restoration of miR-10a-5p.	('phosphorylation', 'MPA', (422, 437))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('RCC', 'Disease', 'MESH:C538614', (394, 397))	('AKT', 'Gene', (452, 455))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))	('miR-10a-5p', 'MPA', (511, 521))	('ERK1', 'molecular_function', 'GO:0004707', ('279', '283'))	('ERK1/2', 'Gene', (279, 285))	('ERK1', 'molecular_function', 'GO:0004707', ('441', '445'))	('RCC', 'Disease', (311, 314))	('ERK1/2', 'Gene', '5595;5594', (279, 285))	('suppressed', 'NegReg', (460, 470))	('RCC', 'Phenotype', 'HP:0005584', (311, 314))	('AKT', 'Gene', (290, 293))	('SKA1', 'Gene', (487, 491))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('5p', 'Chemical', '-', (519, 521))	('SKA1', 'Gene', '220134', (487, 491))	('phosphorylation', 'biological_process', 'GO:0016310', ('260', '275'))	('RCC', 'Disease', 'MESH:C538614', (311, 314))	('cancer', 'Disease', (109, 115))	('AKT', 'Gene', '207', (452, 455))	('inhibition of phosphorylation', 'biological_process', 'GO:0042326', ('330', '359'))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('phosphorylation', 'biological_process', 'GO:0016310', ('422', '437'))	('AKT', 'Gene', '207', (290, 293))	('RCC', 'Disease', (394, 397))	('RCC', 'Phenotype', 'HP:0005584', (394, 397))	('ERK1/2', 'Gene', (441, 447))	('ERK1/2', 'Gene', '5595;5594', (441, 447))	('knockdown', 'Var', (474, 483))
42454	27845902	Taken together, our data implicate that dysregulated UQCRC1 and UQCRFS1 are involved in impaired mitochondrial electron transport chain function.	('UQCRC1', 'Gene', '7384', (53, 59))	('mitochondrial electron transport chain', 'cellular_component', 'GO:0005746', ('97', '135'))	('electron transport chain', 'biological_process', 'GO:0022900', ('111', '135'))	('impaired', 'NegReg', (88, 96))	('mitochondrial electron transport chain function', 'MPA', (97, 144))	('dysregulated', 'Var', (40, 52))	('mitochondrial electron transport', 'biological_process', 'GO:0042775', ('97', '129'))	('impaired mitochondrial electron transport chain function', 'Phenotype', 'HP:0200125', (88, 144))	('UQCRFS1', 'Gene', '7386', (64, 71))	('UQCRFS1', 'Gene', (64, 71))	('UQCRC1', 'Gene', (53, 59))
42491	27845902	The Kaplan Meier estimate indicated a non-significant trend towards poor outcome in patients with high UQCRFS1 levels, but failed to reach statistical significance (log rank p=0.093).	('UQCRFS1', 'Gene', '7386', (103, 110))	('UQCRFS1', 'Gene', (103, 110))	('high', 'Var', (98, 102))	('patients', 'Species', '9606', (84, 92))
42522	27845902	Subsequently, immunostaining was performed with antibodies against UQCRFS1 1:1000 (#ab14746, Abcam, Cambridge, UK), UQCRC1 1:1000 (#Ab197055, Abcam), GAPDH 1:2000 (#2118, Cell Signaling Technology), and beta-actin 1:5000 (#A5316, Sigma-Aldrich).	('UQCRC1', 'Gene', '7384', (116, 122))	('GAPDH', 'Gene', '2597', (150, 155))	('UQCRFS1', 'Gene', '7386', (67, 74))	('UQCRFS1', 'Gene', (67, 74))	('Signaling', 'biological_process', 'GO:0023052', ('176', '185'))	('#Ab197055', 'Var', (131, 140))	('#ab14746', 'Var', (83, 91))	('GAPDH', 'Gene', (150, 155))	('UQCRC1', 'Gene', (116, 122))
42540	32427869	Low-dose SF and MU combinations inhibited growth, motility, invasion and downregulated an invasive signature in RCC cells, patient-derived tumor explants and/or endothelial-RCC cell co-cultures; however, both agents individually were ineffective.	('growth', 'CPA', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('RCC', 'Disease', (173, 176))	('patient', 'Species', '9606', (123, 130))	('invasion', 'CPA', (60, 68))	('inhibited', 'NegReg', (32, 41))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('MU', 'Chemical', 'MESH:D006923', (16, 18))	('invasive signature', 'MPA', (90, 108))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('RCC', 'Disease', (112, 115))	('motility', 'CPA', (50, 58))	('downregulated', 'NegReg', (73, 86))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('combinations', 'Var', (19, 31))	('SF', 'Chemical', 'MESH:D000077157', (9, 11))
42573	32427869	The combinations (SF + MU: 5/0.1, 5/0.2) were equally effective in both VHL+ and VHL- RCC cell lines; VHL is a tumor suppressor that is frequently mutated or deleted in RCC.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('111', '127'))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('deleted', 'Var', (158, 165))	('VHL', 'Gene', '7428', (72, 75))	('VHL', 'Gene', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('RCC', 'Disease', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('VHL', 'Gene', '7428', (81, 84))	('SF +', 'Chemical', 'MESH:D000077157', (18, 22))	('tumor', 'Disease', (111, 116))	('VHL', 'Gene', (102, 105))	('MU', 'Chemical', 'MESH:D006923', (23, 25))	('VHL', 'Gene', '7428', (102, 105))	('tumor suppressor', 'biological_process', 'GO:0051726', ('111', '127'))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('VHL', 'Gene', (72, 75))
42583	32427869	A9 expression in the A9 transfectants was comparable to that found in RCC tissues (described below).	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('A9', 'Chemical', 'MESH:C518022', (0, 2))	('transfectants', 'Var', (24, 37))	('A9', 'Chemical', 'MESH:C518022', (21, 23))	('A9 transfectants', 'Var', (21, 37))
42592	32427869	Furthermore, Kaplan-Meier plots showed that high A9 levels significantly stratified patients into higher risk for metastasis (Fig.	('A9 levels', 'MPA', (49, 58))	('high', 'Var', (44, 48))	('metastasis', 'CPA', (114, 124))	('patients', 'Species', '9606', (84, 92))	('stratified', 'Reg', (73, 83))	('A9', 'Chemical', 'MESH:C518022', (49, 51))
42604	32427869	To examine whether downregulation of A9 would sensitize the RCC cells to SF treatment, we generated A9 shRNA transfectants of both 786-O and Caki-1 cells using two different shRNA constructs.	('A9', 'Chemical', 'MESH:C518022', (37, 39))	('transfectants', 'Var', (109, 122))	('RCC', 'Disease', (60, 63))	('SF', 'Chemical', 'MESH:D000077157', (73, 75))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('A9', 'Chemical', 'MESH:C518022', (100, 102))	('downregulation', 'NegReg', (19, 33))
42605	32427869	In these transfectants, A9 expression was downregulated by >=80% (Supplementary Fig.	('transfectants', 'Var', (9, 22))	('A9', 'Chemical', 'MESH:C518022', (24, 26))	('downregulated', 'NegReg', (42, 55))
42606	32427869	When compared to the control shRNA transfectants, IC50 for growth inhibition by SF alone was 2.5-3.1-fold lower in the A9 shRNA transfectants (Supplementary Fig.	('lower', 'NegReg', (106, 111))	('A9', 'Chemical', 'MESH:C518022', (119, 121))	('SF', 'Chemical', 'MESH:D000077157', (80, 82))	('growth', 'MPA', (59, 65))	('transfectants', 'Var', (128, 141))
42609	32427869	At these doses, SF + MU inhibited clonogenic survival by 86-98.8% in EV-transfectants, but A9-transfectants were resistant (Fig.	('clonogenic survival', 'CPA', (34, 53))	('A9', 'Chemical', 'MESH:C518022', (91, 93))	('inhibited', 'NegReg', (24, 33))	('MU', 'Chemical', 'MESH:D006923', (21, 23))	('SF +', 'Chemical', 'MESH:D000077157', (16, 20))	('SF + MU', 'Var', (16, 23))
42610	32427869	In A9-shRNA transfectants, SF alone inhibited clonogenic survival by >90% (Supplementary Fig.	('inhibited', 'NegReg', (36, 45))	('SF', 'Chemical', 'MESH:D000077157', (27, 29))	('A9', 'Chemical', 'MESH:C518022', (3, 5))	('clonogenic survival', 'CPA', (46, 65))	('transfectants', 'Var', (12, 25))
42617	32427869	Similarly, SF + MU caused >60% inhibition of TS2 growth in 2D-cultures (Fig.	('inhibition', 'NegReg', (31, 41))	('MU', 'Chemical', 'MESH:D006923', (16, 18))	('SF +', 'Chemical', 'MESH:D000077157', (11, 15))	('SF + MU', 'Var', (11, 18))	('TS2', 'Gene', (45, 48))	('TS2', 'Gene', '110292', (45, 48))
42619	32427869	Within 24-h of treatment, SF + MU mainly caused G2-M arrest in 786-O EV-transfectants.	('SF + MU', 'Var', (26, 33))	('caused', 'Reg', (41, 47))	('arrest', 'Disease', 'MESH:D006323', (53, 59))	('arrest', 'Disease', (53, 59))	('MU', 'Chemical', 'MESH:D006923', (31, 33))	('SF +', 'Chemical', 'MESH:D000077157', (26, 30))
42620	32427869	At 5/0.2 SF + MU dose, 1.74-fold more cells were in the G2-M phase.	('SF + MU dose', 'Var', (9, 21))	('M phase', 'biological_process', 'GO:0000279', ('59', '66'))	('SF +', 'Chemical', 'MESH:D000077157', (9, 13))	('more', 'PosReg', (33, 37))	('MU', 'Chemical', 'MESH:D006923', (14, 16))
42621	32427869	In Caki-1 EV-transfectants, SF + MU mainly induced cell cycle arrest in the G0-G1 phase, with a corresponding 1.6-fold decrease in the S-phase (Fig.	('arrest', 'Disease', 'MESH:D006323', (62, 68))	('MU', 'Chemical', 'MESH:D006923', (33, 35))	('decrease', 'NegReg', (119, 127))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (51, 68))	('S-phase', 'CPA', (135, 142))	('arrest', 'Disease', (62, 68))	('SF +', 'Chemical', 'MESH:D000077157', (28, 32))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('51', '68'))	('induced', 'Reg', (43, 50))	('Caki-1', 'Gene', (3, 9))	('G1 phase', 'biological_process', 'GO:0051318', ('79', '87'))	('SF + MU', 'Var', (28, 35))	('S-phase', 'biological_process', 'GO:0051320', ('135', '142'))
42627	32427869	After 48-h of treatment SF + MU induced apoptosis by >=8-fold in EV-transfectants, compared to untreated control (Fig.	('apoptosis', 'CPA', (40, 49))	('SF +', 'Chemical', 'MESH:D000077157', (24, 28))	('MU', 'Chemical', 'MESH:D006923', (29, 31))	('apoptosis', 'biological_process', 'GO:0097194', ('40', '49'))	('apoptosis', 'biological_process', 'GO:0006915', ('40', '49'))	('SF + MU', 'Var', (24, 31))
42629	32427869	Decreased levels of pro-survival marker Mcl-1, and increased levels of pro-apoptotic markers cleaved PARP and cleaved caspase-3 validated induction of apoptosis by SF + MU in EV-transfectants; no changes in these markers were observed in A9-transfectants (Fig.	('SF +', 'Chemical', 'MESH:D000077157', (164, 168))	('Mcl-1', 'Gene', (40, 45))	('MU', 'Chemical', 'MESH:D006923', (169, 171))	('caspase-3', 'Gene', (118, 127))	('increased', 'PosReg', (51, 60))	('levels of pro-apoptotic', 'MPA', (61, 84))	('Decreased', 'NegReg', (0, 9))	('SF + MU', 'Var', (164, 171))	('caspase-3', 'Gene', '836', (118, 127))	('PARP', 'Gene', '1302', (101, 105))	('Mcl-1', 'Gene', '4170', (40, 45))	('PARP', 'Gene', (101, 105))	('apoptosis', 'CPA', (151, 160))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('138', '160'))	('A9', 'Chemical', 'MESH:C518022', (238, 240))	('pro-survival', 'biological_process', 'GO:0043066', ('20', '32'))
42630	32427869	In our previous study, we demonstrated that SF + MU effectively inhibited RCC cell motility and invasion.	('MU', 'Chemical', 'MESH:D006923', (49, 51))	('SF + MU', 'Var', (44, 51))	('cell motility', 'biological_process', 'GO:0048870', ('78', '91'))	('inhibited', 'NegReg', (64, 73))	('RCC', 'Disease', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('SF +', 'Chemical', 'MESH:D000077157', (44, 48))
42632	32427869	Consistent with previous results, SF + MU inhibited chemotactic motility by 3-fold and invasion by 4-fold in EV-transfectants, compared to untreated control (Fig.	('chemotactic motility', 'CPA', (52, 72))	('MU', 'Chemical', 'MESH:D006923', (39, 41))	('SF +', 'Chemical', 'MESH:D000077157', (34, 38))	('inhibited', 'NegReg', (42, 51))	('SF + MU', 'Var', (34, 41))	('invasion', 'CPA', (87, 95))
42633	32427869	However, in A9-transfectants, SF + MU inhibited chemotactic motility only by 1.2-fold, with no inhibition of invasive activity (Fig.	('invasive activity', 'CPA', (109, 126))	('SF +', 'Chemical', 'MESH:D000077157', (30, 34))	('SF + MU', 'Var', (30, 37))	('inhibited', 'NegReg', (38, 47))	('MU', 'Chemical', 'MESH:D006923', (35, 37))	('A9', 'Chemical', 'MESH:C518022', (12, 14))	('chemotactic motility', 'CPA', (48, 68))
42637	32427869	Consistently, in EV-transfectants SF + MU downregulated CD44, RHAMM, phospho-MET, MMP-9, and Caveolin-1 levels by 2-10-fold (Fig.	('CD44', 'Gene', (56, 60))	('SF +', 'Chemical', 'MESH:D000077157', (34, 38))	('MU', 'Chemical', 'MESH:D006923', (39, 41))	('MMP-9', 'molecular_function', 'GO:0004229', ('82', '87'))	('Caveolin-1', 'Gene', '857', (93, 103))	('downregulated', 'NegReg', (42, 55))	('RHAMM', 'Gene', (62, 67))	('RHAMM', 'Gene', '3161', (62, 67))	('phospho-MET', 'MPA', (69, 80))	('SF + MU', 'Var', (34, 41))	('MMP-9', 'Gene', '4318', (82, 87))	('Caveolin-1', 'Gene', (93, 103))	('CD44', 'Gene', '960', (56, 60))	('MMP-9', 'Gene', (82, 87))
42646	32427869	As expected A9 was downregulated in the SF + MU treated EV tumors but the treatment did not affect the expression in A9 tumors (Fig.	('EV tumors', 'Disease', 'MESH:D004819', (56, 65))	('SF + MU', 'Var', (40, 47))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('A9 tumors', 'Disease', 'MESH:D009369', (117, 126))	('EV tumors', 'Disease', (56, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('A9', 'Chemical', 'MESH:C518022', (12, 14))	('A9', 'Chemical', 'MESH:C518022', (117, 119))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('SF +', 'Chemical', 'MESH:D000077157', (40, 44))	('A9 tumors', 'Disease', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('downregulated', 'NegReg', (19, 32))	('MU', 'Chemical', 'MESH:D006923', (45, 47))
42651	32427869	In SF + MU treated EV tumors, phospho-c-Raf (S338) levels were downregulated by 2.5-fold, whereas, the levels were not consistently affected in A9 tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('A9 tumors', 'Disease', 'MESH:D009369', (144, 153))	('MU', 'Chemical', 'MESH:D006923', (8, 10))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('SF +', 'Chemical', 'MESH:D000077157', (3, 7))	('A9 tumors', 'Disease', (144, 153))	('SF + MU', 'Var', (3, 10))	('EV tumors', 'Disease', 'MESH:D004819', (19, 28))	('downregulated', 'NegReg', (63, 76))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('EV tumors', 'Disease', (19, 28))	('c-Raf', 'Gene', '5894', (38, 43))	('c-Raf', 'Gene', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))
42693	32427869	SF + MU also inhibited the growth of patient-derived tumorspheres.	('SF +', 'Chemical', 'MESH:D000077157', (0, 4))	('patient', 'Species', '9606', (37, 44))	('SF + MU', 'Var', (0, 7))	('inhibited', 'NegReg', (13, 22))	('MU', 'Chemical', 'MESH:D006923', (5, 7))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
42705	32427869	Moreover, in both the present and our published studies, SF + MU did not cause serum or tissue toxicity and mice did not lose weight.	('SF + MU', 'Var', (57, 64))	('mice', 'Species', '10090', (108, 112))	('SF +', 'Chemical', 'MESH:D000077157', (57, 61))	('MU', 'Chemical', 'MESH:D006923', (62, 64))	('toxicity', 'Disease', 'MESH:D064420', (95, 103))	('toxicity', 'Disease', (95, 103))
42723	32427869	For A9 knockdown, RCC cells were transfected with A9-shRNA (Supplementary Table 6) or a non-targeting shRNA.	('RCC', 'Disease', (18, 21))	('A9', 'Chemical', 'MESH:C518022', (50, 52))	('A9-shRNA', 'Var', (50, 58))	('A9', 'Chemical', 'MESH:C518022', (4, 6))	('RCC', 'Disease', 'MESH:C538614', (18, 21))
42840	29342219	Higher levels of EEF2 were significantly associated with poor RFS and PPS in basal subtype, but better RFS and DMFS in luminal subtypes.	('EEF2', 'Gene', '1938', (17, 21))	('RFS', 'Disease', (62, 65))	('poor', 'NegReg', (57, 61))	('EEF2', 'Gene', (17, 21))	('PPS', 'MPA', (70, 73))	('DMFS', 'Var', (111, 115))	('RFS', 'Disease', (103, 106))	('DMFS', 'Chemical', '-', (111, 115))	('RFS', 'Disease', 'MESH:D005198', (62, 65))	('PPS', 'Chemical', '-', (70, 73))	('RFS', 'Disease', 'MESH:D005198', (103, 106))
43053	33602288	A 73-year-old White male was diagnosed with pT2NxMx clear cell RCC (ccRCC) and underwent radical nephrectomy in November of 2007.	('RCC', 'Disease', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('pT2NxMx', 'Var', (44, 51))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
43054	33602288	Given his family history of malignancy, he underwent genetic testing and was found to be positive for CHEK2, ATM, BLM and MLH1 mutations.	('BLM', 'Gene', (114, 117))	('positive', 'Reg', (89, 97))	('MLH1', 'Gene', (122, 126))	('malignancy', 'Disease', (28, 38))	('ATM', 'Gene', (109, 112))	('MLH1', 'Gene', '4292', (122, 126))	('ATM', 'Gene', '472', (109, 112))	('CHEK2', 'Gene', '11200', (102, 107))	('mutations', 'Var', (127, 136))	('BLM', 'Gene', '641', (114, 117))	('CHEK2', 'Gene', (102, 107))	('malignancy', 'Disease', 'MESH:D009369', (28, 38))
43104	33602288	Additionally, while there is little evidence of axitinib or its metabolites acting as oxidizers, axitinib is metabolized by multiple cytochrome P450 enzymes which could form oxidizing agents in a similar mechanism to a dapsone-induced methemoglobinemia.	('dapsone', 'Chemical', 'MESH:D003622', (219, 226))	('axitinib', 'Var', (97, 105))	('methemoglobinemia', 'Disease', (235, 252))	('cytochrome P450', 'molecular_function', 'GO:0005490', ('133', '148'))	('cytochrome P450', 'molecular_function', 'GO:0019825', ('133', '148'))	('axitinib', 'Chemical', 'MESH:D000077784', (48, 56))	('methemoglobinemia', 'Disease', 'MESH:D008708', (235, 252))	('methemoglobinemia', 'Phenotype', 'HP:0012119', (235, 252))	('axitinib', 'Chemical', 'MESH:D000077784', (97, 105))
43211	30999623	The discovery of Von Hippel Lindau (VHL) gene alterations that arouse in 50% of ccRCC patients, leads the identification of an intracellular accumulation of HIF and, consequently an increase of VEGFR expression.	('increase', 'PosReg', (182, 190))	('VEGFR', 'Gene', (194, 199))	('Von Hippel Lindau', 'Gene', '7428', (17, 34))	('VHL', 'Gene', (36, 39))	('intracellular', 'cellular_component', 'GO:0005622', ('127', '140'))	('alterations', 'Var', (46, 57))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('VEGFR', 'Gene', '3791', (194, 199))	('RCC', 'Disease', (82, 85))	('intracellular accumulation of HIF', 'MPA', (127, 160))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('expression', 'MPA', (200, 210))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('Von Hippel Lindau', 'Gene', (17, 34))	('patients', 'Species', '9606', (86, 94))
43232	30999623	Mutations in the PTEN/PI3K/mTOR axis lead to permanent activation of the mTORC complex, underlying ccRCC development and progression.	('mTOR', 'Gene', '2475', (73, 77))	('mTOR', 'Gene', (73, 77))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('RCC', 'Disease', (101, 104))	('Mutations', 'Var', (0, 9))	('PI3K', 'molecular_function', 'GO:0016303', ('22', '26'))	('PTEN', 'Gene', (17, 21))	('PTEN', 'Gene', '5728', (17, 21))	('men', 'Species', '9606', (112, 115))	('mTOR', 'Gene', (27, 31))	('mTOR', 'Gene', '2475', (27, 31))	('activation', 'PosReg', (55, 65))
43234	30999623	These gene alterations and the phenotypic results within the biology of kidney cancer cells are key to understanding the exact mechanisms responsible for ccRCC development and progression and the underlying mode of action of the treatment used for these patients in daily practice.	('alterations', 'Var', (11, 22))	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('ccRCC', 'Phenotype', 'HP:0006770', (154, 159))	('kidney cancer', 'Disease', 'MESH:D007680', (72, 85))	('RCC', 'Disease', (156, 159))	('men', 'Species', '9606', (234, 237))	('kidney cancer', 'Phenotype', 'HP:0009726', (72, 85))	('kidney cancer', 'Disease', (72, 85))	('patients', 'Species', '9606', (254, 262))	('men', 'Species', '9606', (167, 170))
43236	30999623	Somatic alterations (mutations or epigenetic alterations) have been described in a large number of sporadic cases of ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('RCC', 'Disease', (119, 122))	('epigenetic alterations', 'Var', (34, 56))	('described', 'Reg', (68, 77))
43239	30999623	This complex has the main function of ubiquitination after HIF hydroxylation, HIF-2alpha and HIF-1alpha.	('HIF', 'Var', (59, 62))	('hydroxylation', 'Var', (63, 76))	('ubiquitination', 'MPA', (38, 52))	('HIF-2alpha and HIF-1alpha', 'Disease', 'None', (78, 103))
43252	30999623	It seems that patients with these gene alterations develop more aggressive diseases, with highly heterogeneous tumors and, from a clinical point of view, those patients exhibit worse survival and response to oncological treatments.	('patients', 'Species', '9606', (160, 168))	('develop', 'PosReg', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('men', 'Species', '9606', (225, 228))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('gene alterations', 'Var', (34, 50))	('aggressive diseases', 'Disease', 'MESH:D001523', (64, 83))	('patients', 'Species', '9606', (14, 22))	('aggressive diseases', 'Disease', (64, 83))
43254	30999623	On the one hand, the activating mutations have been described in the tyrosine kinase domain involved in the development of papillary subtypes of renal cancer.	('papillary subtypes', 'Disease', (123, 141))	('tyrosine', 'Chemical', 'MESH:D014443', (69, 77))	('activating', 'PosReg', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('men', 'Species', '9606', (115, 118))	('renal cancer', 'Disease', (145, 157))	('mutations', 'Var', (32, 41))	('renal cancer', 'Phenotype', 'HP:0009726', (145, 157))	('renal cancer', 'Disease', 'MESH:D007680', (145, 157))
43276	30999623	This kinase family is in charge of cytoskeletal dynamics, intracellular junctions' maintenance and vascular permeability regulation by phosphorylation of focal adhesion kinase (FAK).	('regulation', 'biological_process', 'GO:0065007', ('121', '131'))	('FAK', 'Gene', (177, 180))	('focal adhesion kinase', 'Gene', (154, 175))	('phosphorylation', 'Var', (135, 150))	('phosphorylation', 'biological_process', 'GO:0016310', ('135', '150'))	('FAK', 'molecular_function', 'GO:0004717', ('177', '180'))	('intracellular', 'cellular_component', 'GO:0005622', ('58', '71'))	('FAK', 'Gene', '5747', (177, 180))	('focal adhesion', 'cellular_component', 'GO:0005925', ('154', '168'))	('focal adhesion kinase', 'Gene', '5747', (154, 175))
43277	30999623	Once Src has activated PI3K, it is able to phosphorylate the phosphatidyl inositol biphosphate (PIP2) of the cell membrane into the phosphatidyl inositol triphosphate (PIP3).	('Src', 'Gene', (5, 8))	('Src', 'Gene', '6714', (5, 8))	('phosphorylate', 'MPA', (43, 56))	('phosphatidyl inositol triphosphate', 'Chemical', '-', (132, 166))	('cell membrane', 'cellular_component', 'GO:0005886', ('109', '122'))	('PIP3', 'Chemical', '-', (168, 172))	('PIP2', 'Chemical', 'MESH:D019269', (96, 100))	('PI3K', 'molecular_function', 'GO:0016303', ('23', '27'))	('phosphatidyl inositol biphosphate', 'Chemical', '-', (61, 94))	('PI3K', 'Var', (23, 27))
43292	30999623	Moreover, all these cells also express PDGFRalpha and/or PDGFRbeta, so that PDGFs usually lead to autocrine regulation loops.	('autocrine regulation loops', 'MPA', (98, 124))	('PDGFs', 'Var', (76, 81))	('PDGFRbeta', 'Gene', '5159', (57, 66))	('PDGFRbeta', 'Gene', (57, 66))	('PDGFRalpha', 'Gene', '5156', (39, 49))	('regulation', 'biological_process', 'GO:0065007', ('108', '118'))	('lead to', 'Reg', (90, 97))	('PDGFRalpha', 'Gene', (39, 49))
43296	30999623	PI3K activation transforms PIP2 into PIP3, which is able to bind and activate AKT and, therefore, trigger the mTOR complex to regulate genes related to cell survival.	('mTOR', 'Gene', (110, 114))	('PIP2', 'Chemical', 'MESH:D019269', (27, 31))	('PI3K', 'Var', (0, 4))	('mTOR', 'Gene', '2475', (110, 114))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('PIP3', 'Chemical', '-', (37, 41))	('mTOR complex', 'cellular_component', 'GO:0038201', ('110', '122'))	('activate', 'PosReg', (69, 77))	('trigger', 'Reg', (98, 105))	('regulate', 'Reg', (126, 134))	('AKT', 'Gene', '207', (78, 81))	('bind', 'Interaction', (60, 64))	('AKT', 'Gene', (78, 81))
43297	30999623	In addition, the tyrosine kinase domain is also able to attract PLCgamma, which transforms PIP2 into IP3 and DAG, increasing intracellular calcium and activating PKC to ultimately regulate cell growth and survival.	('cell growth', 'CPA', (189, 200))	('intracellular', 'cellular_component', 'GO:0005622', ('125', '138'))	('tyrosine', 'Var', (17, 25))	('PKC', 'molecular_function', 'GO:0004697', ('162', '165'))	('activating', 'Reg', (151, 161))	('cell growth', 'biological_process', 'GO:0016049', ('189', '200'))	('calcium', 'Chemical', 'MESH:D002118', (139, 146))	('IP3', 'Chemical', 'MESH:D015544', (101, 104))	('intracellular calcium', 'MPA', (125, 146))	('PIP2', 'Chemical', 'MESH:D019269', (91, 95))	('PKC', 'Enzyme', (162, 165))	('tyrosine', 'Chemical', 'MESH:D014443', (17, 25))	('regulate', 'Reg', (180, 188))	('DAG', 'Chemical', 'MESH:D004075', (109, 112))	('increasing', 'PosReg', (114, 124))
43325	30999623	Axl can also be activated independently from the receptor: Under oxidative stress conditions, by interaction with another Axl receptor in the same cell or with the one of a nearby cell or by hetero-dimerization with other receptor families, such as VEGFR1 or other members of the TAM family.	('Axl', 'Gene', '558', (122, 125))	('Axl', 'Gene', '558', (0, 3))	('oxidative stress', 'Phenotype', 'HP:0025464', (65, 81))	('Axl', 'Gene', (122, 125))	('interaction', 'Interaction', (97, 108))	('Axl', 'Gene', (0, 3))	('VEGFR1', 'Gene', '2321', (249, 255))	('hetero-dimerization', 'Var', (191, 210))	('VEGFR1', 'Gene', (249, 255))
43342	30999623	Once FGF binds, FGFR dimerizes causing autophosphorylation of the tyrosine residues in the tyrosine kinase domain and triggers the intracellular signaling cascade.	('FGFR', 'Gene', (16, 20))	('intracellular signaling cascade', 'MPA', (131, 162))	('tyrosine', 'Chemical', 'MESH:D014443', (66, 74))	('FGFR', 'molecular_function', 'GO:0005007', ('16', '20'))	('autophosphorylation', 'MPA', (39, 58))	('binds', 'Interaction', (9, 14))	('tyrosine', 'Chemical', 'MESH:D014443', (91, 99))	('dimerizes', 'Var', (21, 30))	('intracellular', 'cellular_component', 'GO:0005622', ('131', '144'))	('triggers', 'Reg', (118, 126))	('intracellular signaling cascade', 'biological_process', 'GO:0035556', ('131', '162'))
43473	30999623	In this sense, alternative proangiogenic pathways that are involved in resistance mechanisms to VEGFR inhibitors have been evaluated, such as angiopoietin inhibitors or HIF-2alpha inhibitors.	('HIF-2alpha', 'Gene', (169, 179))	('VEGFR', 'Gene', '3791', (96, 101))	('inhibitors', 'Var', (102, 112))	('HIF-2alpha', 'Gene', '2034', (169, 179))	('VEGFR', 'Gene', (96, 101))
43476	30999623	Otherwise, Bruton's tyrosine kinase (BTK), as a key intracellular signaling both for B and T lymphocytes, is under current research in combination with nivolumab (NCT02899078) and everolimus (NCT02599324).	('everolimus', 'Chemical', 'MESH:D000068338', (180, 190))	('NCT02899078', 'Var', (163, 174))	('signaling', 'biological_process', 'GO:0023052', ('66', '75'))	('BTK', 'Gene', (37, 40))	('BTK', 'Gene', '695', (37, 40))	("Bruton's tyrosine kinase", 'Gene', (11, 35))	("Bruton's tyrosine kinase", 'Gene', '695', (11, 35))	('nivolumab', 'Chemical', 'MESH:D000077594', (152, 161))	('intracellular', 'cellular_component', 'GO:0005622', ('52', '65'))
43477	30999623	Finally, other relevant investigational strategies that are arising promising results are based on histone deacetylase (NCT02619253, NCT03024437), BET proteins (NCT02419417) or NOTCH inhibitors (NCT01198184).	('histone deacetylase', 'Protein', (99, 118))	('NCT01198184', 'Var', (195, 206))	('NCT02419417', 'Var', (161, 172))	('BET', 'Gene', '92737', (147, 150))	('NCT03024437', 'Var', (133, 144))	('BET', 'Gene', (147, 150))	('NCT02619253', 'Var', (120, 131))
43478	30999623	Special attention should be given to the role of non-coding RNAs as key mechanisms in ccRCC development and progression, accordingly with the importance of epigenetic alterations in this oncological context.	('mechanisms', 'Reg', (72, 82))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('men', 'Species', '9606', (99, 102))	('non-coding RNAs', 'Var', (49, 64))
43495	30755832	Genetic alteration of histone lysine methyltransferases and their significance in renal cell carcinoma Histone lysine methyltransferases (HMTs), a category of enzymes, play essential roles in regulating transcription, cellular differentiation, and chromatin construction.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('HMT', 'Gene', (138, 141))	('transcription', 'biological_process', 'GO:0006351', ('203', '216'))	('Genetic alteration', 'Var', (0, 18))	('HMT', 'Gene', '3176', (138, 141))	('renal cell carcinoma', 'Disease', (82, 102))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (82, 102))	('chromatin', 'cellular_component', 'GO:0000785', ('248', '257'))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (82, 102))
43497	30755832	We conducted an integrative analysis of 50 HMTs in RCC and discovered the internal relations among copy number alterations (CNAs), expressive abundance, mutations, and clinical outcome.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('expressive', 'MPA', (131, 141))	('copy', 'Var', (99, 103))	('HMT', 'Gene', (43, 46))	('HMT', 'Gene', '3176', (43, 46))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
43498	30755832	We confirmed 12 HMTs with the highest frequency of genetic alterations, including seven HMTs with high-level amplification, two HMTs with somatic mutation, and three HMTs with putative homozygous deletion.	('HMT', 'Gene', (128, 131))	('HMT', 'Gene', (166, 169))	('HMT', 'Gene', (16, 19))	('amp', 'Chemical', 'MESH:D000249', (109, 112))	('HMT', 'Gene', '3176', (128, 131))	('HMT', 'Gene', (88, 91))	('HMT', 'Gene', '3176', (166, 169))	('HMT', 'Gene', '3176', (16, 19))	('HMT', 'Gene', '3176', (88, 91))	('genetic alterations', 'Var', (51, 70))
43501	30755832	Systematic analysis identified six HMTs (ASH1L, PRDM6, NSD1, EZH2, WHSC1L1, SETD2) which were dysregulated by genetic alterations as candidate therapeutic targets.	('SETD2', 'Gene', (76, 81))	('HMT', 'Gene', (35, 38))	('EZH2', 'Gene', (61, 65))	('EZH2', 'Gene', '2146', (61, 65))	('WHSC1L1', 'Gene', '54904', (67, 74))	('NSD1', 'Gene', (55, 59))	('alterations', 'Var', (118, 129))	('HMT', 'Gene', '3176', (35, 38))	('ASH1L', 'Gene', '55870', (41, 46))	('WHSC1L1', 'Gene', (67, 74))	('ASH1L', 'Gene', (41, 46))	('NSD1', 'Gene', '64324', (55, 59))	('PRDM6', 'Gene', '93166', (48, 53))	('PRDM6', 'Gene', (48, 53))	('SETD2', 'Gene', '29072', (76, 81))
43502	30755832	In summary, our findings strongly evidenced that genetic alteration of HMTs may play an important role in generation and development of RCC, which lays a solid foundation for the mechanism for further research in the future.	('HMT', 'Gene', (71, 74))	('HMT', 'Gene', '3176', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('genetic alteration', 'Var', (49, 67))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))	('play', 'Reg', (80, 84))
43509	30755832	Recent researches have shown that HMT dysregulation leads to uncontrollable histone methylation pathways and contributes to the pathogenesis of many human cancers, including RCC.	('uncontrollable', 'MPA', (61, 75))	('contributes', 'Reg', (109, 120))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('HMT', 'Gene', '3176', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('histone methylation', 'biological_process', 'GO:0016571', ('76', '95'))	('human', 'Species', '9606', (149, 154))	('dysregulation', 'Var', (38, 51))	('leads to', 'Reg', (52, 60))	('RCC', 'Disease', (174, 177))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('pathogenesis', 'biological_process', 'GO:0009405', ('128', '140'))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('histone', 'Pathway', (76, 83))	('cancers', 'Disease', (155, 162))	('HMT', 'Gene', (34, 37))
43510	30755832	Several studies indicated that the methyltransferase gene SETD2 was frequently mutated during epigenetic progress in RCC.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('epigenetic progress', 'Var', (94, 113))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('SETD2', 'Gene', '29072', (58, 63))	('SETD2', 'Gene', (58, 63))
43513	30755832	Increasing evidences showed that genetic alterations of several HMTs play crucial roles in oncogenesis.	('oncogenesis', 'CPA', (91, 102))	('roles', 'Reg', (82, 87))	('genetic alterations', 'Var', (33, 52))	('HMT', 'Gene', (64, 67))	('oncogenesis', 'biological_process', 'GO:0007048', ('91', '102'))	('HMT', 'Gene', '3176', (64, 67))
43515	30755832	Furthermore, the clinical relevance of genetic alterations in each HMT in RCC remains unclear.	('HMT', 'Gene', (67, 70))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('genetic alterations', 'Var', (39, 58))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('HMT', 'Gene', '3176', (67, 70))
43519	30755832	In addition, 78 samples of Tokyo university downloaded from cBioportal were added to persuasively compare the tumor stage and overall survival between 62 SET-domain mutated patients and 16 non-SET-domain mutated patients.	('overall survival', 'CPA', (126, 142))	('patients', 'Species', '9606', (173, 181))	('SET-domain mutated', 'Var', (154, 172))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('patients', 'Species', '9606', (212, 220))	('amp', 'Chemical', 'MESH:D000249', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
43536	30755832	The shRNA plasmids for SETD2 and EZH2 knockdown were constructed from pSicoR (#11579; Addgene, Watertown, MA, USA) with target sequences of shSETD2: TAGTACACCAAGACTCCAG, and shEZH2: CCAACACAAGTCATCCCATTA.	('SETD2', 'Gene', '29072', (23, 28))	('SETD2', 'Gene', (23, 28))	('EZH2', 'Gene', '2146', (176, 180))	('EZH2', 'Gene', '2146', (33, 37))	('SETD2', 'Gene', '29072', (142, 147))	('EZH2', 'Gene', (176, 180))	('knockdown', 'Var', (38, 47))	('EZH2', 'Gene', (33, 37))	('SETD2', 'Gene', (142, 147))
43538	30755832	Copy number alteration and somatic mutations are crucial mechanisms for oncogenesis or inactivating tumor suppressor genes in the occurrence and development of cancer.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('100', '116'))	('inactivating', 'Var', (87, 99))	('Copy number alteration', 'Var', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('tumor', 'Disease', (100, 105))	('oncogenesis', 'biological_process', 'GO:0007048', ('72', '83'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('100', '116'))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
43539	30755832	We hypothesized that genetic alterations of HMTs play significant roles in the development and progression of RCC.	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('HMT', 'Gene', (44, 47))	('HMT', 'Gene', '3176', (44, 47))	('roles', 'Reg', (66, 71))	('genetic alterations', 'Var', (21, 40))
43542	30755832	We found a different pattern of altered copy number and mutation of HMTs in RCC.	('HMT', 'Gene', '3176', (68, 71))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('copy number', 'MPA', (40, 51))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('altered', 'Reg', (32, 39))	('HMT', 'Gene', (68, 71))	('mutation', 'Var', (56, 64))
43544	30755832	Three HMT genes, SETD2, SETD5, and SETMAR, showed homozygous deletion in more than 10% ccRCC samples.	('SETD5', 'Gene', '55209', (24, 29))	('HMT', 'Gene', '3176', (6, 9))	('SETMAR', 'Gene', (35, 41))	('deletion', 'Var', (61, 69))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('SETD2', 'Gene', '29072', (17, 22))	('SETMAR', 'Gene', '6419', (35, 41))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('SETD2', 'Gene', (17, 22))	('SETD5', 'Gene', (24, 29))	('amp', 'Chemical', 'MESH:D000249', (94, 97))	('HMT', 'Gene', (6, 9))
43547	30755832	Several studies revealed that SETD2 was frequently mutated in ccRCC and SETD2-mutated signal pathway played a vital role in the process of oncogenesis.	('SETD2', 'Gene', '29072', (30, 35))	('SETD2', 'Gene', (30, 35))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('SETD2', 'Gene', '29072', (72, 77))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('RCC', 'Disease', (64, 67))	('oncogenesis', 'biological_process', 'GO:0007048', ('139', '150'))	('SETD2', 'Gene', (72, 77))	('mutated', 'Var', (51, 58))
43549	30755832	Furthermore, HMTs showed different frequencies of CNA and mutation in different subtypes of RCC.	('RCC', 'Disease', (92, 95))	('mutation', 'Var', (58, 66))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('HMT', 'Gene', (13, 16))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('HMT', 'Gene', '3176', (13, 16))
43553	30755832	Additionally, in 213 ccRCC, 113 pRCC, and 65 chRCC, of the most commonly mutated HMTs, SETD2, and KMT2C were most frequently mutated in ccRCC and pRCC subtypes, whereas SETD2 was mutated in less than 1.54% of tumor samples and KMT2C did not exhibit mutation in chRCC (Fig.	('KMT2C', 'Gene', '58508', (98, 103))	('KMT2C', 'Gene', (98, 103))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('RCC', 'Disease', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('SETD2', 'Gene', (169, 174))	('tumor', 'Disease', (209, 214))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('mutated', 'Var', (125, 132))	('amp', 'Chemical', 'MESH:D000249', (216, 219))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('SETD2', 'Gene', (87, 92))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('SETD2', 'Gene', '29072', (169, 174))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('RCC', 'Disease', (263, 266))	('RCC', 'Disease', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('SETD2', 'Gene', '29072', (87, 92))	('HMT', 'Gene', '3176', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (21, 26))	('RCC', 'Disease', 'MESH:C538614', (263, 266))	('RCC', 'Disease', (23, 26))	('HMT', 'Gene', (81, 84))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('KMT2C', 'Gene', '58508', (227, 232))	('KMT2C', 'Gene', (227, 232))
43554	30755832	The above data indicates that the subtype of ccRCC has a higher CNA and somatic mutation frequency in several HMTs, including amplification of NSD1 and PRDM6, homozygous deletion of SETD2, SETD5, and SETMAR, and mutation of KMT2C and SETD2.	('PRDM6', 'Gene', (152, 157))	('SETD2', 'Gene', '29072', (234, 239))	('NSD1', 'Gene', '64324', (143, 147))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('HMT', 'Gene', (110, 113))	('HMT', 'Gene', '3176', (110, 113))	('KMT2C', 'Gene', '58508', (224, 229))	('KMT2C', 'Gene', (224, 229))	('SETD5', 'Gene', (189, 194))	('SETMAR', 'Gene', '6419', (200, 206))	('SETD2', 'Gene', (182, 187))	('NSD1', 'Gene', (143, 147))	('SETD5', 'Gene', '55209', (189, 194))	('PRDM6', 'Gene', '93166', (152, 157))	('higher', 'PosReg', (57, 63))	('SETMAR', 'Gene', (200, 206))	('mutation', 'Var', (212, 220))	('amp', 'Chemical', 'MESH:D000249', (126, 129))	('SETD2', 'Gene', (234, 239))	('amplification', 'Var', (126, 139))	('SETD2', 'Gene', '29072', (182, 187))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))
43567	30755832	Results showed that a total of 78 SETD2 mutations were found whereas 14 mutations were excluded because their data were untested.	('mutations', 'Var', (40, 49))	('SETD2', 'Gene', (34, 39))	('SETD2', 'Gene', '29072', (34, 39))
43568	30755832	In addition, 24 KMT2C gene mutations were identified, including 10 missense mutations, five nonsense mutations, three frameshift deletions, two splice, and four other mutations (Fig.	('KMT2C', 'Gene', (16, 21))	('frameshift deletions', 'Var', (118, 138))	('missense mutations', 'Var', (67, 85))	('KMT2C', 'Gene', '58508', (16, 21))
43569	30755832	A mutation map was performed to display the distribution of SETD2 and KMT2C mutations (Fig.	('mutations', 'Var', (76, 85))	('SETD2', 'Gene', '29072', (60, 65))	('SETD2', 'Gene', (60, 65))	('KMT2C', 'Gene', '58508', (70, 75))	('KMT2C', 'Gene', (70, 75))
43570	30755832	By systematic analysis of the mutation distribution, we found that SETD2 mutations were more likely to occur at SET domain area.	('SETD2', 'Gene', '29072', (67, 72))	('SETD2', 'Gene', (67, 72))	('mutations', 'Var', (73, 82))	('occur', 'Reg', (103, 108))
43571	30755832	Taking account of the crucial function of SET domain in SETD2, we predicted that mutations at the SET domain might result in the loss of methyltransferases features of SETD2 and poor prognosis of ccRCC patients.	('SETD2', 'Gene', (56, 61))	('methyltransferases', 'Enzyme', (137, 155))	('loss', 'NegReg', (129, 133))	('SETD2', 'Gene', '29072', (168, 173))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('patients', 'Species', '9606', (202, 210))	('RCC', 'Disease', (198, 201))	('SETD2', 'Gene', '29072', (56, 61))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('SETD2', 'Gene', (168, 173))	('ccRCC', 'Phenotype', 'HP:0006770', (196, 201))	('mutations', 'Var', (81, 90))
43575	30755832	First of all, samples were divided into the following three groups for each HMT: amp/gain (high-level amplification/low-level gain), diploid, and deletion.	('deletion', 'Var', (146, 154))	('amp', 'Chemical', 'MESH:D000249', (15, 18))	('HMT', 'Gene', (76, 79))	('amp', 'Chemical', 'MESH:D000249', (81, 84))	('amp', 'Chemical', 'MESH:D000249', (102, 105))	('HMT', 'Gene', '3176', (76, 79))	('diploid', 'Var', (133, 140))
43576	30755832	For six HMTs (EZH2, NSD1, PRDM6, SETD2, SETD5, and SETMAR), copy number amp/gain and deletion were significantly related to poorer survival in RCC patients (P < 0.05).	('survival', 'MPA', (131, 139))	('HMT', 'Gene', (8, 11))	('PRDM6', 'Gene', (26, 31))	('HMT', 'Gene', '3176', (8, 11))	('poorer', 'NegReg', (124, 130))	('NSD1', 'Gene', (20, 24))	('SETD2', 'Gene', (33, 38))	('patients', 'Species', '9606', (147, 155))	('SETD2', 'Gene', '29072', (33, 38))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('EZH2', 'Gene', (14, 18))	('SETD5', 'Gene', (40, 45))	('EZH2', 'Gene', '2146', (14, 18))	('SETMAR', 'Gene', '6419', (51, 57))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('deletion', 'Var', (85, 93))	('NSD1', 'Gene', '64324', (20, 24))	('RCC', 'Disease', (143, 146))	('SETD5', 'Gene', '55209', (40, 45))	('amp', 'Chemical', 'MESH:D000249', (72, 75))	('SETMAR', 'Gene', (51, 57))	('PRDM6', 'Gene', '93166', (26, 31))	('copy number amp/gain', 'Var', (60, 80))
43577	30755832	Deletions of KMT2C and PRDM6 were related to shorter survival, however, only amp/gain of EZH2 and PRDM14 was more likely related to poorer survival.	('EZH2', 'Gene', '2146', (89, 93))	('amp', 'Chemical', 'MESH:D000249', (77, 80))	('PRDM6', 'Gene', (23, 28))	('EZH2', 'Gene', (89, 93))	('PRDM14', 'Gene', (98, 104))	('shorter', 'NegReg', (45, 52))	('PRDM6', 'Gene', '93166', (23, 28))	('PRDM14', 'Gene', '63978', (98, 104))	('KMT2C', 'Gene', '58508', (13, 18))	('KMT2C', 'Gene', (13, 18))	('Deletions', 'Var', (0, 9))
43578	30755832	More importantly, deletion of NSD1 was significantly related to poorer survival; amp/gain of NSD1 was significantly related to longer survival, compared with diploid or deletion groups (Fig.	('NSD1', 'Gene', (30, 34))	('NSD1', 'Gene', '64324', (93, 97))	('amp', 'Chemical', 'MESH:D000249', (81, 84))	('NSD1', 'Gene', (93, 97))	('longer', 'PosReg', (127, 133))	('amp/gain', 'Var', (81, 89))	('NSD1', 'Gene', '64324', (30, 34))	('deletion', 'Var', (18, 26))
43582	30755832	Results indicated that amp/gain of ASH1L had a hazard radio (HR), a ratio of death probabilities, of 1.533 compared with non-amp/gain of ASH1L in RCC patients.	('ASH1L', 'Gene', (35, 40))	('ASH1L', 'Gene', '55870', (35, 40))	('amp', 'Chemical', 'MESH:D000249', (125, 128))	('amp/gain', 'Var', (23, 31))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('death', 'Disease', (77, 82))	('RCC', 'Disease', (146, 149))	('death', 'Disease', 'MESH:D003643', (77, 82))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('amp', 'Chemical', 'MESH:D000249', (23, 26))	('patients', 'Species', '9606', (150, 158))	('ASH1L', 'Gene', (137, 142))	('ASH1L', 'Gene', '55870', (137, 142))
43583	30755832	In addition, deletion of PRDM8 was significantly associated with shorter survival (HR = 1.516, P < 0.05) in RCC patients.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('survival', 'MPA', (73, 81))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('shorter', 'NegReg', (65, 72))	('patients', 'Species', '9606', (112, 120))	('deletion', 'Var', (13, 21))	('PRDM8', 'Gene', '56978', (25, 30))	('PRDM8', 'Gene', (25, 30))
43586	30755832	Also, amp/gain of PRDM6 (HR = 0.703), PRDM9 (HR = 0.662), PRDM7 (HR = 0.640), SETD1A (HR = 0.638), NSD1 (HR = 0.598), and DOT1L (HR = 0.592) was negative correlated with shorter survival in RCC patients (P < 0.05).	('PRDM9', 'Gene', '56979', (38, 43))	('PRDM7', 'Gene', '11105', (58, 63))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('PRDM7', 'Gene', (58, 63))	('DOT1L', 'Gene', (122, 127))	('amp/gain', 'Var', (6, 14))	('shorter', 'NegReg', (170, 177))	('SETD1A', 'Gene', (78, 84))	('NSD1', 'Gene', (99, 103))	('patients', 'Species', '9606', (194, 202))	('negative', 'NegReg', (145, 153))	('DOT1L', 'Gene', '84444', (122, 127))	('PRDM6', 'Gene', '93166', (18, 23))	('RCC', 'Disease', (190, 193))	('RCC', 'Phenotype', 'HP:0005584', (190, 193))	('NSD1', 'Gene', '64324', (99, 103))	('SETD1A', 'Gene', '9739', (78, 84))	('amp', 'Chemical', 'MESH:D000249', (6, 9))	('PRDM9', 'Gene', (38, 43))	('PRDM6', 'Gene', (18, 23))
43599	30755832	Assays showed a higher proliferative ability in 786-O cell line with SETD2 knockdown.	('higher', 'PosReg', (16, 22))	('proliferative ability in 786-O cell line', 'CPA', (23, 63))	('knockdown', 'Var', (75, 84))	('SETD2', 'Gene', '29072', (69, 74))	('SETD2', 'Gene', (69, 74))
43600	30755832	However, the migration and invasion ability showed no significant differences with or without SETD2 knockdown.	('knockdown', 'Var', (100, 109))	('SETD2', 'Gene', (94, 99))	('invasion ability', 'CPA', (27, 43))	('migration', 'CPA', (13, 22))	('SETD2', 'Gene', '29072', (94, 99))
43601	30755832	Meanwhile EZH2 knockdown reduced the ability of cell proliferation, migration, and invasion significantly.	('reduced', 'NegReg', (25, 32))	('knockdown', 'Var', (15, 24))	('EZH2', 'Gene', '2146', (10, 14))	('EZH2', 'Gene', (10, 14))	('invasion', 'CPA', (83, 91))	('migration', 'CPA', (68, 77))	('cell proliferation', 'biological_process', 'GO:0008283', ('48', '66'))
43605	30755832	Oncogenic alterations of HMTs, including amplification, homozygous deletion, and mutation, were associated with various human cancers, including RCC.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('human', 'Species', '9606', (120, 125))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('HMT', 'Gene', '3176', (25, 28))	('associated', 'Reg', (96, 106))	('mutation', 'Var', (81, 89))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('amplification', 'Var', (41, 54))	('amp', 'Chemical', 'MESH:D000249', (41, 44))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('homozygous deletion', 'Var', (56, 75))	('HMT', 'Gene', (25, 28))
43606	30755832	EZH2 is overexpressed and mutated frequently in RCC and other types of tumors, contributing to tumorigenic potential of cancer.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('cancer', 'Disease', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('contributing', 'Reg', (79, 91))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('mutated', 'Var', (26, 33))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', (95, 100))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))
43609	30755832	Taking chromosome 3p as an illustration, ccRCC was characterized by a high frequency of allelic deletion or loss of heterozygosity on chromosome 3p, causing biallelic mutation or promoter hypermethylation of von Hippel-Lindau (VHL) gene.	('VHL', 'Gene', '7428', (227, 230))	('chromosome', 'cellular_component', 'GO:0005694', ('7', '17'))	('promoter hypermethylation', 'MPA', (179, 204))	('causing', 'Reg', (149, 156))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('von Hippel-Lindau', 'Gene', (208, 225))	('allelic deletion', 'Var', (88, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('chromosome', 'cellular_component', 'GO:0005694', ('134', '144'))	('VHL', 'Gene', (227, 230))	('von Hippel-Lindau', 'Gene', '7428', (208, 225))	('biallelic', 'MPA', (157, 166))
43611	30755832	Several researches explored their relationship between methylation of VHL promoter, SETD2 mutation and CNA of other genes located at 3p, including SETD5 and BAP1.	('VHL', 'Gene', (70, 73))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))	('SETD2', 'Gene', (84, 89))	('VHL', 'Gene', '7428', (70, 73))	('BAP1', 'Gene', (157, 161))	('SETD5', 'Gene', '55209', (147, 152))	('BAP1', 'Gene', '8314', (157, 161))	('mutation', 'Var', (90, 98))	('SETD5', 'Gene', (147, 152))	('SETD2', 'Gene', '29072', (84, 89))
43614	30755832	SETD2 was most mutated in ccRCC with highest frequency rate of 11.51%.	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (26, 31))	('SETD2', 'Gene', '29072', (0, 5))	('SETD2', 'Gene', (0, 5))	('mutated', 'Var', (15, 22))	('RCC', 'Disease', (28, 31))	('RCC', 'Phenotype', 'HP:0005584', (28, 31))
43616	30755832	Clinical stage of patients with SETD2 mutations occurred in SET domain region were often higher than those of patients whose SETD2 mutations did not located in SET domain.	('SETD2', 'Gene', '29072', (32, 37))	('Clinical stage', 'CPA', (0, 14))	('SETD2', 'Gene', (32, 37))	('higher', 'PosReg', (89, 95))	('patients', 'Species', '9606', (18, 26))	('SETD2', 'Gene', '29072', (125, 130))	('mutations', 'Var', (38, 47))	('patients', 'Species', '9606', (110, 118))	('SETD2', 'Gene', (125, 130))
43617	30755832	Taking our results of the GO enrichment analysis into account, among all the predefined Hallmarks gene sets, DNA repair, E2F targets, G2M checkpoint, and mitotic spindle were found to be significantly associated with SET domain mutation, suggesting that SET domain mutation may be involved in ccRCC development and progression through the above cancer-associated biological processes.	('mitotic spindle', 'cellular_component', 'GO:0072686', ('154', '169'))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('involved', 'Reg', (281, 289))	('G2M checkpoint', 'biological_process', 'GO:0000075', ('134', '148'))	('SET domain mutation', 'Var', (254, 273))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('DNA repair', 'biological_process', 'GO:0006281', ('109', '119'))	('SET', 'Gene', (217, 220))	('RCC', 'Disease', 'MESH:C538614', (295, 298))	('associated', 'Reg', (201, 211))	('RCC', 'Disease', (295, 298))	('RCC', 'Phenotype', 'HP:0005584', (295, 298))	('cancer', 'Disease', 'MESH:D009369', (345, 351))	('ccRCC', 'Phenotype', 'HP:0006770', (293, 298))	('cancer', 'Disease', (345, 351))
43618	30755832	The above potential pathway involved in DNA repair, cell circle, dual chromatin, and cytoskeletal remodeling might constitute the reason for poor prognosis in patients with SETD2 mutations.	('SETD2', 'Gene', (173, 178))	('DNA repair', 'biological_process', 'GO:0006281', ('40', '50'))	('chromatin', 'cellular_component', 'GO:0000785', ('70', '79'))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('mutations', 'Var', (179, 188))	('patients', 'Species', '9606', (159, 167))	('SETD2', 'Gene', '29072', (173, 178))
43621	30755832	Targeting SETD2 is believed to be a promising strategy for cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('SETD2', 'Gene', '29072', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('SETD2', 'Gene', (10, 15))	('cancer', 'Disease', (59, 65))	('Targeting', 'Var', (0, 9))
43679	32610589	We observed that patients with metastatic disease and higher levels of TIMP-1 EV-derived mRNA presented a lower overall survival compared to patients presenting with lower levels (Log Rank test, p = 0.030) (Figure 4C).	('lower', 'NegReg', (106, 111))	('higher levels', 'Var', (54, 67))	('TIMP-1', 'Gene', '7076', (71, 77))	('TIMP-1', 'Gene', (71, 77))	('patients', 'Species', '9606', (17, 25))	('metastatic disease', 'Disease', (31, 49))	('overall survival', 'MPA', (112, 128))	('patients', 'Species', '9606', (141, 149))
43747	32610589	The A60-Micro-Plus machine is equipped with three spatially separated lasers (488 nm:Position C, 405 nm:Position A and 638 nm:Position B), seven fluorescence color detectors (525/50, LWP590, 530/30, 574/26, 590/40, 695/40, 676/36) and three light scatter detectors (SALS, MALS and LALS).	('525/50', 'Var', (175, 181))	('LWP590', 'Var', (183, 189))	('MALS', 'Gene', '259197', (272, 276))	('MALS', 'Gene', (272, 276))
43755	32610589	For mRNA expression normalization two housekeeping controls were used: GAPDH (Hs02758991_g1:Applied Biosystems, Foster City, CA, USA) and ACTB (Hs01060665_g1:Applied Biosystems, Foster City, CA, USA).	('Hs02758991_g1', 'Var', (78, 91))	('Hs01060665_g1', 'Var', (144, 157))	('GAPDH', 'Gene', '2597', (71, 76))	('GAPDH', 'Gene', (71, 76))	('ACTB', 'Gene', '60', (138, 142))	('ACTB', 'Gene', (138, 142))
43759	33882057	Spatial clustering of CD68+ tumor associated macrophages with tumor cells is associated with worse overall survival in metastatic clear cell renal cell carcinoma Immune infiltration is typically quantified using cellular density, not accounting for cellular clustering.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (141, 161))	('worse', 'NegReg', (93, 98))	('tumor', 'Disease', (62, 67))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (130, 161))	('CD68+', 'Var', (22, 27))	('clear cell renal cell carcinoma', 'Disease', (130, 161))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (130, 161))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
43762	33882057	CD68+ cells were found to be clustered with tumor cells and dispersed from stromal cells, while CD163+ and CD206+ cells were found to be clustered with stromal cells and dispersed from tumor cells.	('tumor', 'Disease', (185, 190))	('CD206', 'Gene', (107, 112))	('CD206', 'Gene', '4360', (107, 112))	('CD163', 'Gene', '9332', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('CD163', 'Gene', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('CD68+', 'Var', (0, 5))	('tumor', 'Disease', (44, 49))
43763	33882057	CD68+ density was not associated with OS, while high tumor/CD68+ cell clustering was associated with significantly worse OS.	('high', 'Var', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (53, 58))
43765	33882057	Significance: Increased clustering of CD68+ TAMs and tumor cells was associated with worse overall survival for patients with metastatic ccRCC.	('CD68+', 'Var', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('TAMs', 'Chemical', 'MESH:D013629', (44, 48))	('overall survival', 'MPA', (91, 107))	('patients', 'Species', '9606', (112, 120))	('RCC', 'Disease', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('worse', 'NegReg', (85, 90))
43797	33882057	CD68+ TAMs were found to be clustered with tumor cells and dispersed from stromal cells (nK(25) = 1.10 and 0.90, respectively, p<0.01).	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('TAMs', 'Chemical', 'MESH:D013629', (6, 10))	('CD68+', 'Var', (0, 5))
43802	33882057	After stratifying for both cell density and cell clustering, patients with high CD68+ density and high tumor/CD68+ clustering were found to have significantly worse OS (HR = 8.50, 95%CI 1.97-36.7, p = 0.004) (Fig 3D).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('high', 'Var', (75, 79))	('patients', 'Species', '9606', (61, 69))	('high', 'Var', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
43814	33882057	It has been suggested that TAMs with an M2-like phenotype (markers CD163, CD204, and CD206) have a pro-tumor effect while M1-like TAMs (CD68, CD80, and CD86) may have an anti-tumor effect.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('CD8', 'Gene', '925', (142, 145))	('CD163', 'Gene', '9332', (67, 72))	('CD68', 'Var', (136, 140))	('TAMs', 'Chemical', 'MESH:D013629', (27, 31))	('CD8', 'Gene', (152, 155))	('CD204', 'Gene', '4481', (74, 79))	('CD204', 'Gene', (74, 79))	('tumor', 'Disease', (175, 180))	('CD163', 'Gene', (67, 72))	('tumor', 'Disease', (103, 108))	('TAMs', 'Chemical', 'MESH:D013629', (130, 134))	('CD8', 'Gene', (142, 145))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('CD206', 'Gene', '4360', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('CD8', 'Gene', '925', (152, 155))	('CD206', 'Gene', (85, 90))
43816	33882057	Similarly, our analysis identified high CD68+ TAM/tumor cell clustering as having a strong association with worse OS.	('worse OS', 'Disease', (108, 116))	('TAM', 'Chemical', '-', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('high CD68+', 'Var', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('CD68+', 'Var', (40, 45))	('tumor', 'Disease', (50, 55))
43818	33882057	Together, these findings suggest that high TAM infiltration may portend a worse prognosis in metastatic ccRCC regardless of M1/M2 polarization.	('TAM', 'Chemical', '-', (43, 46))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('high', 'Var', (38, 42))	('RCC', 'Disease', (106, 109))
43819	33882057	Additionally, this analysis identified that CD68+ TAMs tend to cluster with tumor cells and away from stromal cells, while CD163+ and CD206+ TAMs tend to cluster with stromal cells and away from tumor cells (Fig 3B).	('tumor', 'Disease', (195, 200))	('TAMs', 'Chemical', 'MESH:D013629', (141, 145))	('TAMs', 'Chemical', 'MESH:D013629', (50, 54))	('CD163', 'Gene', '9332', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('CD163', 'Gene', (123, 128))	('CD68+', 'Var', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('CD206', 'Gene', '4360', (134, 139))	('CD206', 'Gene', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
43852	33882057	6 Apr 2021  Spatial Clustering of CD68+ Tumor Associated Macrophages with Tumor Cells is Associated with Worse Overall Survival in Metastatic Clear Cell Renal Cell Carcinoma PONE-D-20-39779R1 Dear Dr. Chakiryan, We're pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.	('Metastatic Clear Cell Renal Cell Carcinoma', 'Disease', (131, 173))	('Apr', 'Gene', '5366', (2, 5))	('Apr', 'Gene', (2, 5))	('Carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (142, 173))	('Metastatic Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538445', (131, 173))	('Tumor', 'Phenotype', 'HP:0002664', (74, 79))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (153, 173))	('PONE-D-20-', 'Chemical', '-', (174, 184))	('CD68+', 'Var', (34, 39))	('Tumor', 'Phenotype', 'HP:0002664', (40, 45))
43857	27389969	In the multivariate analysis, high tumoral podoplanin expression (using staining intensity as either a continuous or dichotomous variable) was still an independent adverse prognostic factor for patient survival (OS, P < 0.001, RFS, P < 0.001 for continuous; OS, P < 0.001, RFS, P = 0.002 for dichotomous).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('podoplanin', 'Gene', '10630', (43, 53))	('patient', 'Species', '9606', (194, 201))	('RFS', 'Chemical', '-', (273, 276))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('podoplanin', 'Gene', (43, 53))	('OS', 'Chemical', '-', (258, 260))	('tumor', 'Disease', (35, 40))	('high', 'Var', (30, 34))	('RFS', 'Chemical', '-', (227, 230))	('OS', 'Chemical', '-', (212, 214))
43860	27389969	In conclusion, high tumoral podoplanin expression could independently predict an adverse clinical outcome for ccRCC patients, and it might be useful in future for clinical decision-making and therapeutic developments.	('high', 'Var', (15, 19))	('predict', 'Reg', (70, 77))	('patients', 'Species', '9606', (116, 124))	('podoplanin', 'Gene', '10630', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('expression', 'MPA', (39, 49))	('podoplanin', 'Gene', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))	('tumor', 'Disease', (20, 25))
43908	27389969	As is evident from Figure 2f-h,j,l, high tumoral podoplanin expression was an adverse prognostic factor in the intermediate-risk and high-risk groups in both OS and RFS analyses (OS, P = 0.001, RFS, P = 0.005 in intermediate -risk groups; OS, P < 0.022, RFS, P < 0.012 in high-risk groups), while in the low-risk groups it did not meet statistical significance.	('RFS', 'Chemical', '-', (194, 197))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('RFS', 'Chemical', '-', (254, 257))	('OS', 'Chemical', '-', (158, 160))	('RFS', 'Chemical', '-', (165, 168))	('OS', 'Chemical', '-', (239, 241))	('podoplanin', 'Gene', '10630', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('podoplanin', 'Gene', (49, 59))	('high', 'Var', (36, 40))	('OS', 'Chemical', '-', (179, 181))
43916	27389969	In this study, high tumoral podoplanin expression has been identified as an independent adverse prognostic factor for ccRCC patients.	('high', 'Var', (15, 19))	('podoplanin', 'Gene', '10630', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('RCC', 'Disease', (120, 123))	('podoplanin', 'Gene', (28, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))	('patients', 'Species', '9606', (124, 132))	('tumor', 'Disease', (20, 25))
43928	27389969	In conclusion, our findings demonstrated that high tumoral podoplanin expression was an independent adverse prognostic factor for the RFS and OS of ccRCC patients.	('high', 'Var', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('RFS', 'Disease', (134, 137))	('RFS', 'Chemical', '-', (134, 137))	('OS', 'Chemical', '-', (142, 144))	('tumor', 'Disease', (51, 56))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('patients', 'Species', '9606', (154, 162))	('RCC', 'Disease', (150, 153))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('podoplanin', 'Gene', '10630', (59, 69))	('ccRCC', 'Phenotype', 'HP:0006770', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('podoplanin', 'Gene', (59, 69))
43945	33408516	For example, it has been demonstrated that VHL (Von Hippel-Lindau) deletion directly led to mRNA alteration and facilitated RCC development.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('VHL', 'Gene', (43, 46))	('deletion', 'Var', (67, 75))	('facilitated', 'PosReg', (112, 123))	('VHL', 'Gene', '7428', (43, 46))	('Von Hippel-Lindau', 'Gene', '7428', (48, 65))	('led to', 'Reg', (85, 91))	('Von Hippel-Lindau', 'Gene', (48, 65))	('mRNA alteration', 'MPA', (92, 107))
43950	33408516	In addition, data mining from high-throughput platforms can be conducted to identify significant genetic or epigenetic changes in carcinogenesis, which in turn help to select promising biomarkers for cancer diagnosis and prognosis.	('help', 'Reg', (160, 164))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('si', 'Chemical', 'MESH:D012825', (141, 143))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('si', 'Chemical', 'MESH:D012825', (213, 215))	('epigenetic changes', 'Var', (108, 126))	('si', 'Chemical', 'MESH:D012825', (227, 229))	('cancer', 'Disease', (200, 206))	('si', 'Chemical', 'MESH:D012825', (180, 182))
43952	33408516	In this study, we downloaded gene expression profiles GSE53757 and GSE84546 from the Gene Expression Omnibus (GEO) containing paired advanced-stage ccRCC and normal samples to identify the differentially expressed genes (DEGs).	('GSE84546', 'Var', (67, 75))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('si', 'Chemical', 'MESH:D012825', (40, 42))	('RCC', 'Disease', (150, 153))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('gene expression', 'biological_process', 'GO:0010467', ('29', '44'))	('si', 'Chemical', 'MESH:D012825', (96, 98))	('Gene Expression', 'biological_process', 'GO:0010467', ('85', '100'))	('GSE53757', 'Var', (54, 62))
43957	33408516	Two gene expression profiles (GSE53757 and GSE84546) were downloaded from the GEO database (https://www.ncbi.nlm.nih.gov/geo/).	('gene expression', 'biological_process', 'GO:0010467', ('4', '19'))	('si', 'Chemical', 'MESH:D012825', (15, 17))	('GSE53757', 'Var', (30, 38))	('GSE84546', 'Var', (43, 51))
43986	33408516	The primary antibodies used in this experiment were as follows: anti-KIF20A (ab70791, Abcam, USA), anti-CCNB2 (ab185622, Abcam, USA), and anti-CDCA8 antibody (ab67126, Abcam, USA).	('CDCA8', 'Gene', (143, 148))	('antibody', 'cellular_component', 'GO:0019814', ('149', '157'))	('CCNB2', 'Gene', '9133', (104, 109))	('KIF20A', 'Gene', (69, 75))	('antibody', 'molecular_function', 'GO:0003823', ('149', '157'))	('CDCA8', 'Gene', '55143', (143, 148))	('KIF20A', 'Gene', '10112', (69, 75))	('antibody', 'cellular_component', 'GO:0042571', ('149', '157'))	('CCNB2', 'Gene', (104, 109))	('ab185622', 'Var', (111, 119))	('antibody', 'cellular_component', 'GO:0019815', ('149', '157'))
43993	33408516	After the standardization of GSE53757 and GSE84546 profiles, Venn analysis was performed to obtain the DEG profiles intersection (2791 in GSE84546 and 923 in GSE53757).	('GSE84546', 'Var', (138, 146))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('GSE53757', 'Var', (158, 166))	('2791', 'Var', (130, 134))
44011	33408516	Firstly, we validated three hub genes in normal and RRCC cells were treated with the inhibitors of CCNB2, CDCA8, and KIF20A, respectively.	('hub', 'Gene', (28, 31))	('CDCA8', 'Gene', '55143', (106, 111))	('KIF20A', 'Gene', '10112', (117, 123))	('CCNB2', 'Gene', (99, 104))	('inhibitors', 'Var', (85, 95))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('CCNB2', 'Gene', '9133', (99, 104))	('hub', 'Gene', '1993', (28, 31))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('CDCA8', 'Gene', (106, 111))	('KIF20A', 'Gene', (117, 123))
44013	33408516	Western blot analysis was also conducted to measure the expression difference of hub genes after the knockdown (Figure 10B, D and F).	('si', 'Chemical', 'MESH:D012825', (18, 20))	('knockdown', 'Var', (101, 110))	('hub', 'Gene', (81, 84))	('expression', 'MPA', (56, 66))	('si', 'Chemical', 'MESH:D012825', (62, 64))	('hub', 'Gene', '1993', (81, 84))
44015	33408516	Expectedly, the knockdown of CCNB2, CDCA8, and KIF20A suppressed RCC cell growth and invasion ability compared with that of si-NC-transfected cells (Figure 11A-F).	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('suppressed', 'NegReg', (54, 64))	('CDCA8', 'Gene', '55143', (36, 41))	('invasion ability', 'CPA', (85, 101))	('CCNB2', 'Gene', '9133', (29, 34))	('cell growth', 'biological_process', 'GO:0016049', ('69', '80'))	('knockdown', 'Var', (16, 25))	('KIF20A', 'Gene', (47, 53))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('CDCA8', 'Gene', (36, 41))	('KIF20A', 'Gene', '10112', (47, 53))	('CCNB2', 'Gene', (29, 34))	('si', 'Chemical', 'MESH:D012825', (124, 126))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
44024	33408516	The correction between CCNB2, CDCA8 and KIF20A in RCC was also positively correlated with each other, illustrating that they might serve pivotal roles in the progression and metastasis of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('roles', 'Reg', (145, 150))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('KIF20A', 'Gene', '10112', (40, 46))	('CCNB2', 'Gene', (23, 28))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('correction', 'Var', (4, 14))	('RCC', 'Disease', (50, 53))	('correlated', 'Reg', (74, 84))	('CDCA8', 'Gene', '55143', (30, 35))	('serve', 'Reg', (131, 136))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('si', 'Chemical', 'MESH:D012825', (181, 183))	('si', 'Chemical', 'MESH:D012825', (165, 167))	('CCNB2', 'Gene', '9133', (23, 28))	('RCC', 'Disease', (190, 193))	('RCC', 'Phenotype', 'HP:0005584', (190, 193))	('KIF20A', 'Gene', (40, 46))	('CDCA8', 'Gene', (30, 35))
44033	33408516	It is commonly acknowledged that dysregulation of cell cycle and uncontrolled cell proliferation are hallmarks of cancer, and loss of CDCA8 leads to defective cell proliferation and early fetal death.	('death', 'Disease', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('defective', 'NegReg', (149, 158))	('CDCA8', 'Gene', '55143', (134, 139))	('cell proliferation', 'biological_process', 'GO:0008283', ('78', '96'))	('cell proliferation', 'biological_process', 'GO:0008283', ('159', '177'))	('dysregulation of cell cycle', 'Phenotype', 'HP:0011018', (33, 60))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cell proliferation', 'CPA', (159, 177))	('cell cycle', 'biological_process', 'GO:0007049', ('50', '60'))	('death', 'Disease', 'MESH:D003643', (194, 199))	('CDCA8', 'Gene', (134, 139))	('cell cycle', 'CPA', (50, 60))	('loss', 'Var', (126, 130))	('cancer', 'Disease', (114, 120))
44037	33408516	Previous studies have shown that KIF20A was essential for cell cycle mitosis, and its aberrant accumulation promoted cell proliferation.	('si', 'Chemical', 'MESH:D012825', (73, 75))	('cell cycle', 'biological_process', 'GO:0007049', ('58', '68'))	('KIF20A', 'Gene', (33, 39))	('cell proliferation', 'CPA', (117, 135))	('KIF20A', 'Gene', '10112', (33, 39))	('cell proliferation', 'biological_process', 'GO:0008283', ('117', '135'))	('promoted', 'PosReg', (108, 116))	('mitosis', 'biological_process', 'GO:0000278', ('69', '76'))	('aberrant accumulation', 'Var', (86, 107))
44038	33408516	In addition, abnormal expression of KIF20A participates in the carcinogenesis of multiple malignancies, including cell differentiation, invasion, and distant metastasis, which ultimately lead to drug resistance.	('si', 'Chemical', 'MESH:D012825', (28, 30))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('drug resistance', 'MPA', (195, 210))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('abnormal', 'Var', (13, 21))	('drug resistance', 'biological_process', 'GO:0009315', ('195', '210'))	('lead to', 'Reg', (187, 194))	('malignancies', 'Disease', (90, 102))	('drug resistance', 'Phenotype', 'HP:0020174', (195, 210))	('drug resistance', 'biological_process', 'GO:0042493', ('195', '210'))	('KIF20A', 'Gene', (36, 42))	('distant metastasis', 'CPA', (150, 168))	('cell differentiation', 'biological_process', 'GO:0030154', ('114', '134'))	('invasion', 'CPA', (136, 144))	('participates', 'Reg', (43, 55))	('si', 'Chemical', 'MESH:D012825', (140, 142))	('KIF20A', 'Gene', '10112', (36, 42))	('si', 'Chemical', 'MESH:D012825', (165, 167))	('expression', 'MPA', (22, 32))	('cell differentiation', 'CPA', (114, 134))	('si', 'Chemical', 'MESH:D012825', (202, 204))
44067	32547955	Dysregulation of autophagy is closely related to cancer.	('autophagy', 'CPA', (17, 26))	('autophagy', 'biological_process', 'GO:0006914', ('17', '26'))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('related', 'Reg', (38, 45))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('autophagy', 'biological_process', 'GO:0016236', ('17', '26'))	('cancer', 'Disease', (49, 55))
44136	32547955	After multivariate Cox regression analysis, we obtained 5 ARGs and constructed a prognostic signature: risk score = (0.5163 x BID) + (-0.4748 x BAG1) + (0.1084 x APOL1) + (-0.6522 x NKX2-3) + (0.3866 x EIF4EBP1).	('APOL1', 'Gene', (162, 167))	('ARGs', 'Chemical', '-', (58, 62))	('NKX2-3', 'Gene', '159296;4824', (182, 188))	('NKX2-3', 'Gene', (182, 188))	('APOL1', 'Gene', '8542', (162, 167))	('EIF4EBP1', 'Gene', (202, 210))	('BAG1', 'Gene', '573', (144, 148))	('BAG1', 'Gene', (144, 148))	('BID', 'Gene', '637', (126, 129))	('EIF4', 'cellular_component', 'GO:0008304', ('202', '206'))	('EIF4EBP1', 'Gene', '1978', (202, 210))	('0.5163 x', 'Var', (117, 125))	('BID', 'Gene', (126, 129))
44164	32547955	23 ARGs were found to be significantly associated with the prognosis of ccRCC.	('associated with', 'Reg', (39, 54))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('ARGs', 'Chemical', '-', (3, 7))	('ARGs', 'Var', (3, 7))
44166	32547955	In vivo and in vitro experiments showed that knockdown of CASP4 leads to cell migration and impairs cell-matrix adhesion.	('CASP4', 'Gene', '837', (58, 63))	('impairs', 'NegReg', (92, 99))	('cell migration', 'biological_process', 'GO:0016477', ('73', '87'))	('cell-matrix adhesion', 'CPA', (100, 120))	('cell-matrix adhesion', 'biological_process', 'GO:0007160', ('100', '120'))	('cell migration', 'CPA', (73, 87))	('CASP4', 'Gene', (58, 63))	('leads to', 'Reg', (64, 72))	('knockdown', 'Var', (45, 54))
44167	32547955	Silencing BAG1 in breast cancer cells increases resistance to tamoxifen and reduces apoptosis by activating the PI3K/Akt/mTOR signaling pathway, and the overexpression of ATG16L2 is related to poor prognosis in epithelial cancer.	('epithelial cancer', 'Phenotype', 'HP:0031492', (211, 228))	('reduces', 'NegReg', (76, 83))	('resistance to tamoxifen', 'MPA', (48, 71))	('BAG1', 'Gene', (10, 14))	('ATG16L2', 'Gene', (171, 178))	('activating', 'PosReg', (97, 107))	('cancer', 'Disease', (25, 31))	('Silencing', 'Var', (0, 9))	('apoptosis', 'CPA', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('mTOR', 'Gene', (121, 125))	('Akt', 'Gene', (117, 120))	('cancer', 'Disease', (222, 228))	('ATG16L2', 'Gene', '89849', (171, 178))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('tamoxifen', 'Chemical', 'MESH:D013629', (62, 71))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('Akt', 'Gene', '207', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('overexpression', 'PosReg', (153, 167))	('mTOR', 'Gene', '2475', (121, 125))	('signaling pathway', 'biological_process', 'GO:0007165', ('126', '143'))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('increases', 'PosReg', (38, 47))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('breast cancer', 'Disease', (18, 31))	('PI3K', 'molecular_function', 'GO:0016303', ('112', '116'))	('BAG1', 'Gene', '573', (10, 14))
44186	31118677	Patients with high RRM2 expression tend to have advanced pT stages, high Fuhrman grades, and shortened overall survival (OS).	('overall', 'MPA', (103, 110))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('pT stages', 'CPA', (57, 66))	('Fuhrman grades', 'CPA', (73, 87))	('shortened', 'NegReg', (93, 102))	('RRM2', 'Gene', '6241', (19, 23))	('RRM2', 'Gene', (19, 23))
44218	31118677	After transfection with siRNAs targeting RRM2 or treatment with Triapine for the indicated time, 10 muL of CCK-8 solution (Life Technologies) was added to each well, incubating for 1-2 h at 37  C. Then the optical density (OD) value was read at 450 nm on an ELISA plate reader.	('CCK-8', 'Chemical', 'MESH:D012844', (107, 112))	('RRM2', 'Gene', '6241', (41, 45))	('RRM2', 'Gene', (41, 45))	('transfection', 'Var', (6, 18))	('Triapine', 'Chemical', 'MESH:C078157', (64, 72))
44234	31118677	We found that patients with high RRM2 expression tended to have advanced pT stages (P<0.001; Table 2) and high Fuhrman grades (P=0.008; Table 2) as compared to those patients with low RRM2 expression.	('pT stages', 'CPA', (73, 82))	('RRM2', 'Gene', (33, 37))	('high Fuhrman grades', 'CPA', (106, 125))	('RRM2', 'Gene', (184, 188))	('RRM2', 'Gene', '6241', (184, 188))	('RRM2', 'Gene', '6241', (33, 37))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (166, 174))	('advanced', 'PosReg', (64, 72))
44242	31118677	To further investigate the role of RRM2 in RCC cells, two specific siRNAs targeting RRM2 were transfected into 786-O and 769-P cells to knockdown the expression of RRM2.	('RRM2', 'Gene', '6241', (164, 168))	('RRM2', 'Gene', (164, 168))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('RRM2', 'Gene', '6241', (35, 39))	('knockdown', 'Var', (136, 145))	('RRM2', 'Gene', (35, 39))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('RRM2', 'Gene', '6241', (84, 88))	('RRM2', 'Gene', (84, 88))
44245	31118677	After the CCK-8 assay, the knockdown of RRM2 significantly inhibited the cell proliferation in both 786-O and 769-P cells at 24, 48, and 72 h (Figure 2B).	('knockdown', 'Var', (27, 36))	('cell proliferation', 'biological_process', 'GO:0008283', ('73', '91'))	('inhibited', 'NegReg', (59, 68))	('cell proliferation in', 'CPA', (73, 94))	('RRM2', 'Gene', '6241', (40, 44))	('RRM2', 'Gene', (40, 44))	('CCK-8', 'Chemical', 'MESH:D012844', (10, 15))
44246	31118677	In addition, the knockdown of RRM2 also significantly induced G0/G1 cell cycle arrest by propidium iodide (PI) staining (Figure 2C).	('RRM2', 'Gene', '6241', (30, 34))	('induced', 'Reg', (54, 61))	('propidium iodide', 'Chemical', 'MESH:D011419', (89, 105))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (68, 85))	('G0/G1 cell cycle arrest', 'CPA', (62, 85))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('68', '85'))	('knockdown', 'Var', (17, 26))	('RRM2', 'Gene', (30, 34))
44247	31118677	Furthermore, the intracellular RRM2 activity is cell cycle dependent in mammalian cells, with activities rising at the border of G1 to S phase transition, which contributes to the dNTP pool expansion during the S phase Herein, we demonstrated that knockdown of RRM2 led to the depletion of the dNTP pool, as indicated by a decrease in a specific dNTP: dATP and dGTP (Figure 2D).	('mammalian', 'Species', '9606', (72, 81))	('dGTP', 'MPA', (361, 365))	('dATP', 'Chemical', 'MESH:C026600', (352, 356))	('dNTP', 'Chemical', '-', (346, 350))	('S phase', 'biological_process', 'GO:0051320', ('211', '218'))	('decrease', 'NegReg', (323, 331))	('S phase', 'biological_process', 'GO:0051320', ('135', '142'))	('specific dNTP: dATP', 'MPA', (337, 356))	('intracellular', 'cellular_component', 'GO:0005622', ('17', '30'))	('RRM2', 'Gene', '6241', (261, 265))	('RRM2', 'Gene', '6241', (31, 35))	('dGTP', 'Chemical', 'MESH:C029603', (361, 365))	('knockdown', 'Var', (248, 257))	('cell cycle', 'biological_process', 'GO:0007049', ('48', '58'))	('RRM2', 'Gene', (261, 265))	('dNTP', 'Chemical', '-', (294, 298))	('RRM2', 'Gene', (31, 35))	('depletion', 'MPA', (277, 286))	('dNTP pool', 'MPA', (294, 303))	('dNTP', 'Chemical', '-', (180, 184))
44248	31118677	These results indicated that the knockdown of RRM2 inhibits the proliferation and induces the G0/G1 arrest in RCC cells via attenuation of the dNTP pool.	('RCC', 'Disease', (110, 113))	('induces', 'Reg', (82, 89))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('dNTP pool', 'MPA', (143, 152))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('inhibits', 'NegReg', (51, 59))	('knockdown', 'Var', (33, 42))	('G0/G1 arrest', 'CPA', (94, 106))	('dNTP', 'Chemical', '-', (143, 147))	('RRM2', 'Gene', (46, 50))	('proliferation', 'CPA', (64, 77))	('RRM2', 'Gene', '6241', (46, 50))	('attenuation', 'NegReg', (124, 135))
44256	31118677	More than 80% of ccRCC harbors the VHL gene mutation or methylation inactivation, which regulates the metabolic alteration through the hypoxia-inducible factor (HIF) pathway.	('hypoxia', 'Disease', (135, 142))	('mutation', 'Var', (44, 52))	('regulates', 'Reg', (88, 97))	('hypoxia', 'Disease', 'MESH:D000860', (135, 142))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('ccRCC', 'Phenotype', 'HP:0006770', (17, 22))	('RCC', 'Disease', (19, 22))	('methylation inactivation', 'Var', (56, 80))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('metabolic alteration', 'MPA', (102, 122))	('VHL', 'Gene', (35, 38))	('VHL', 'Gene', '7428', (35, 38))
44258	31118677	The genetic knockdown or pharmacological inhibition of SCD1 decreased the proliferation of RCC cells Sufficient supply of dNTPs is required for the uncontrolled replication of cancers, which is a defining feature.	('cancers', 'Disease', (176, 183))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('decreased', 'NegReg', (60, 69))	('SCD1', 'Gene', '6319', (55, 59))	('knockdown', 'Var', (12, 21))	('pharmacological', 'Var', (25, 40))	('RCC', 'Disease', (91, 94))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('inhibition', 'Var', (41, 51))	('proliferation', 'CPA', (74, 87))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('dNTPs', 'Chemical', '-', (122, 127))	('SCD1', 'Gene', (55, 59))
44262	31118677	Similarly, in glioma patients, RRM2 is a negative prognostic factor that worsens the survival and is correlated with the malignancy degree as defined by WHO In the present study, both genetic and pharmacological inhibition of RRM2 in RCC cells significantly decreased tumor cell proliferation by inducing the G0/G1 cell cycle arrest.	('glioma', 'Disease', (14, 20))	('cell proliferation', 'biological_process', 'GO:0008283', ('274', '292'))	('patients', 'Species', '9606', (21, 29))	('glioma', 'Disease', 'MESH:D005910', (14, 20))	('RCC', 'Phenotype', 'HP:0005584', (234, 237))	('RCC', 'Disease', (234, 237))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('315', '332'))	('inducing', 'PosReg', (296, 304))	('RRM2', 'Gene', '6241', (31, 35))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('RCC', 'Disease', 'MESH:C538614', (234, 237))	('RRM2', 'Gene', '6241', (226, 230))	('malignancy', 'Disease', 'MESH:D009369', (121, 131))	('RRM2', 'Gene', (31, 35))	('worsens', 'NegReg', (73, 80))	('RRM2', 'Gene', (226, 230))	('decreased', 'NegReg', (258, 267))	('malignancy', 'Disease', (121, 131))	('tumor', 'Disease', (268, 273))	('inhibition', 'Var', (212, 222))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (315, 332))	('G0/G1 cell cycle arrest', 'CPA', (309, 332))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
44263	31118677	Consistent with this phenomenon, RRM2-siRNAs or RRM2 inhibitor significantly represses the cell viability by inducing cell-cycle arrest at the G0/G1 phase in glioblastoma, neuroblastoma, primary effusion lymphoma, adrenocortical cancer, or at the sub G0/G1 phase in melanoma However, the role of RRM2 may differ in different types of cancers.	('RRM2', 'Gene', (296, 300))	('RRM2', 'Gene', '6241', (48, 52))	('melanoma', 'Disease', 'MESH:D008545', (266, 274))	('glioblastoma', 'Disease', (158, 170))	('RRM2', 'Gene', (33, 37))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('118', '135'))	('glioblastoma', 'Phenotype', 'HP:0012174', (158, 170))	('represses', 'NegReg', (77, 86))	('cancers', 'Phenotype', 'HP:0002664', (334, 341))	('cancers', 'Disease', (334, 341))	('G1 phase', 'biological_process', 'GO:0051318', ('146', '154'))	('RRM2', 'Gene', (48, 52))	('cell-cycle arrest', 'CPA', (118, 135))	('adrenocortical cancer', 'Disease', (214, 235))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('primary effusion lymphoma', 'Phenotype', 'HP:0030069', (187, 212))	('inhibitor', 'Var', (53, 62))	('G1 phase', 'biological_process', 'GO:0051318', ('254', '262'))	('melanoma', 'Phenotype', 'HP:0002861', (266, 274))	('melanoma', 'Disease', (266, 274))	('inducing', 'PosReg', (109, 117))	('primary effusion lymphoma', 'Disease', (187, 212))	('primary effusion lymphoma', 'Disease', 'MESH:D054685', (187, 212))	('cancers', 'Disease', 'MESH:D009369', (334, 341))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('neuroblastoma', 'Disease', (172, 185))	('neuroblastoma', 'Phenotype', 'HP:0003006', (172, 185))	('lymphoma', 'Phenotype', 'HP:0002665', (204, 212))	('RRM2', 'Gene', '6241', (296, 300))	('glioblastoma', 'Disease', 'MESH:D005909', (158, 170))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (214, 235))	('neuroblastoma', 'Disease', 'MESH:D009447', (172, 185))	('RRM2', 'Gene', '6241', (33, 37))	('cell viability', 'CPA', (91, 105))
44264	31118677	RRM2-siRNAs dramatically decreased the formation of cell colonies by inducing the significant cell-cycle arrest at the S phase in pancreatic cancer In addition, the inhibition of RRM2 regulates the RCC cell growth and cell cycle transition through the attenuation of dNTP pool.	('attenuation', 'NegReg', (252, 263))	('RRM2', 'Gene', '6241', (0, 4))	('dNTP', 'Chemical', '-', (267, 271))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (130, 147))	('cell growth', 'biological_process', 'GO:0016049', ('202', '213'))	('cell-cycle arrest at the S phase', 'CPA', (94, 126))	('cell cycle transition', 'biological_process', 'GO:0044770', ('218', '239'))	('RRM2', 'Gene', (0, 4))	('decreased', 'NegReg', (25, 34))	('cell cycle transition', 'CPA', (218, 239))	('regulates', 'Reg', (184, 193))	('RRM2', 'Gene', '6241', (179, 183))	('pancreatic cancer', 'Disease', 'MESH:D010190', (130, 147))	('cell cycle transition', 'biological_process', 'GO:0044771', ('218', '239'))	('inducing', 'Reg', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('S phase', 'biological_process', 'GO:0051320', ('119', '126'))	('formation', 'biological_process', 'GO:0009058', ('39', '48'))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('94', '111'))	('pancreatic cancer', 'Disease', (130, 147))	('RRM2', 'Gene', (179, 183))	('RCC', 'Disease', (198, 201))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('inhibition', 'Var', (165, 175))	('dNTP pool', 'MPA', (267, 276))
44314	28280347	Kaplan-Meier survival curves for OS, stratified by the ALDOA levels, are shown in Figure 2, the OS being significantly decreased in patients with high levels of ALDOA (Log-rank test, P<0.001).	('decreased', 'NegReg', (119, 128))	('high levels', 'Var', (146, 157))	('ALDOA', 'Gene', '226', (55, 60))	('ALDOA', 'Gene', (161, 166))	('ALDOA', 'Gene', '226', (161, 166))	('patients', 'Species', '9606', (132, 140))	('ALDOA', 'Gene', (55, 60))
44390	33613765	The time of renal ischemia was 27.2+-3.6 mins for the group of fluorescence laparoscopy, and 27.9+-3.2 mins for the group of general laparoscopy (p=0.45) (Table 2).	('renal ischemia', 'Disease', (12, 26))	('renal ischemia', 'Disease', 'MESH:D007511', (12, 26))	('fluorescence', 'Var', (63, 75))	('renal ischemia', 'Phenotype', 'HP:0002637', (12, 26))
44393	33613765	The average volume of the tumor for the group of fluorescence laparoscopy was 28.8+-9.8 cm3, while the group of general laparoscopy had a smaller average volume (26.9+-8.2 cm3, p=0.43).	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('fluorescence', 'Var', (49, 61))
44435	32236626	However, ZNF710-AS1-202 overexpression promoted the proliferation of RCC cells and inhibited apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))	('promoted', 'PosReg', (39, 47))	('ZNF710', 'Gene', (9, 15))	('AS1', 'Gene', (16, 19))	('proliferation', 'CPA', (52, 65))	('ZNF710', 'Gene', '374655', (9, 15))	('AS1', 'Gene', '5729', (16, 19))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('inhibited', 'NegReg', (83, 92))	('RCC cells', 'CPA', (69, 78))	('apoptosis', 'CPA', (93, 102))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('overexpression', 'Var', (24, 38))
44504	32236626	Furthermore, ZNF710-AS1-202 knockdown significantly decreased the proliferation rate in 786-O and 769-P cells (Fig.	('decreased', 'NegReg', (52, 61))	('AS1', 'Gene', (20, 23))	('knockdown', 'Var', (28, 37))	('ZNF710', 'Gene', '374655', (13, 19))	('AS1', 'Gene', '5729', (20, 23))	('ZNF710', 'Gene', (13, 19))
44505	32236626	The colony formation assay revealed that the colony formation ability of ccRCC cells was impaired after ZNF710-AS1-202 knockdown (Fig.	('formation', 'biological_process', 'GO:0009058', ('52', '61'))	('ZNF710', 'Gene', '374655', (104, 110))	('AS1', 'Gene', '5729', (111, 114))	('AS1', 'Gene', (111, 114))	('colony formation ability of ccRCC cells', 'CPA', (45, 84))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('knockdown', 'Var', (119, 128))	('formation', 'biological_process', 'GO:0009058', ('11', '20'))	('impaired', 'NegReg', (89, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))	('ZNF710', 'Gene', (104, 110))
44506	32236626	Furthermore, ZNF710-AS1-202 knockdown increased the number of cells in the G2/M phase and decreased the number of cells in the S phase (Fig.	('S phase', 'biological_process', 'GO:0051320', ('127', '134'))	('M phase', 'biological_process', 'GO:0000279', ('78', '85'))	('ZNF710', 'Gene', '374655', (13, 19))	('AS1', 'Gene', (20, 23))	('decreased', 'NegReg', (90, 99))	('knockdown', 'Var', (28, 37))	('AS1', 'Gene', '5729', (20, 23))	('ZNF710', 'Gene', (13, 19))	('increased', 'PosReg', (38, 47))
44520	32236626	Furthermore, in the ccRCC cell lines investigated in vitro, the cell lines with high ZNF710-AS1-202 expression exhibited faster proliferation rates.	('faster', 'PosReg', (121, 127))	('RCC', 'Phenotype', 'HP:0005584', (22, 25))	('AS1', 'Gene', (92, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (20, 25))	('ZNF710', 'Gene', '374655', (85, 91))	('AS1', 'Gene', '5729', (92, 95))	('ZNF710', 'Gene', (85, 91))	('high', 'Var', (80, 84))
44530	32236626	While there was no significant difference in the levels of ZNF710 mRNA expression between ccRCC and PC tissues from TCGA database, low levels of ZNF710 mRNA expression were associated with poor prognosis in patients with ccRCC.	('ZNF710', 'Gene', '374655', (59, 65))	('patients', 'Species', '9606', (207, 215))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('ZNF710', 'Gene', (145, 151))	('ZNF710', 'Gene', (59, 65))	('ZNF710', 'Gene', '374655', (145, 151))	('low levels', 'Var', (131, 141))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (221, 226))	('ccRCC', 'Disease', (221, 226))	('RCC', 'Phenotype', 'HP:0005584', (223, 226))
44550	31743108	FOXM1 copy number amplification (115/500, 23% of patients), occurred in an amplified peak in chromosome 12q13.3, was enriched in late-stage ccRCC samples and was associated with worse survival.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('associated', 'Reg', (162, 172))	('copy number', 'Var', (6, 17))	('FOXM1', 'Gene', '2305', (0, 5))	('patients', 'Species', '9606', (49, 57))	('FOXM1', 'Gene', (0, 5))
44552	31743108	The eQTM-gene hybrid signature (cg00044170 and FOXM1), superior to either gene expression or DNA methylation alone, showed great potential in diagnosing localized ccRCC in training (area under curve = 0.958) and validation datasets.	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('DNA methylation', 'biological_process', 'GO:0006306', ('93', '108'))	('ccRCC', 'Phenotype', 'HP:0006770', (163, 168))	('FOXM1', 'Gene', (47, 52))	('gene expression', 'biological_process', 'GO:0010467', ('74', '89'))	('FOXM1', 'Gene', '2305', (47, 52))	('cg00044170', 'Var', (32, 42))	('diagnosing', 'Reg', (142, 152))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('RCC', 'Disease', (165, 168))
44574	31743108	Taken together, identified 756 genes were widely involved in EMT-associated pathways and their dysregulation may contribute to the progression of tumors through downstream pathways.	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('dysregulation', 'Var', (95, 108))	('contribute', 'Reg', (113, 123))	('involved', 'Reg', (49, 57))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('EMT', 'biological_process', 'GO:0001837', ('61', '64'))	('tumors', 'Disease', (146, 152))
44578	31743108	Furthermore, the number of patients with stage III/IV (chi2 test, P = 2.70e-06), G3/G4 (chi2 test, P = 8.74e-07), higher pathological primary tumor stage (T3/T4, chi2 test, P = 3.06e-05), invasive regional lymph nodes (N1, chi2 test, P = 0.002) and distant metastasis (M1, chi2 test, P = 0.002) in sC4 were significantly larger than those in sC2 (Figure 3A).	('distant metastasis', 'CPA', (249, 267))	('sC4', 'Var', (298, 301))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('invasive regional lymph nodes', 'CPA', (188, 217))	('tumor', 'Disease', (142, 147))	('larger', 'PosReg', (321, 327))	('patients', 'Species', '9606', (27, 35))	('sC2', 'Gene', '9524', (342, 345))	('sC2', 'Gene', (342, 345))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('higher', 'PosReg', (114, 120))	('G3/G4', 'Var', (81, 86))
44595	31743108	The expression of 44 genes were associated with multiple CpGs, such as the EMT marker CDH1 (hypermethylation) and ZEB1 (hypomethylation), while others (46 genes) were affected by single CpG, such as FOXM1 (cg00044170, hypomethylation, Figure 4A) and VIM (hypomethylation).	('VIM', 'Gene', '7431', (250, 253))	('cg00044170', 'Var', (206, 216))	('ZEB1', 'Gene', (114, 118))	('CDH1', 'Gene', (86, 90))	('affected', 'Reg', (167, 175))	('VIM', 'Gene', (250, 253))	('expression', 'MPA', (4, 14))	('ZEB1', 'Gene', '6935', (114, 118))	('EMT', 'biological_process', 'GO:0001837', ('75', '78'))	('CDH1', 'Gene', '999', (86, 90))	('FOXM1', 'Gene', '2305', (199, 204))	('associated', 'Reg', (32, 42))	('FOXM1', 'Gene', (199, 204))	('hypomethylation', 'Var', (218, 233))
44596	31743108	Given that the abnormal methylation of eQTMs is associated with the expression change of EDCGs, we investigated their DNA methylation patterns in ccRCC based on eleven grouping methods (see Materials and Methods).	('EDCGs', 'Gene', (89, 94))	('RCC', 'Disease', (148, 151))	('methylation', 'MPA', (24, 35))	('expression', 'MPA', (68, 78))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('associated', 'Reg', (48, 58))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('DNA', 'cellular_component', 'GO:0005574', ('118', '121'))	('DNA methylation', 'biological_process', 'GO:0006306', ('118', '133'))	('abnormal', 'Var', (15, 23))	('EDCGs', 'Chemical', '-', (89, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))
44599	31743108	These results suggested that the differential methylation of EDCGs were more likely to associate with tumorigenesis of ccRCC, rather than its progression.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('methylation', 'Var', (46, 57))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('associate with', 'Reg', (87, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('EDCGs', 'Chemical', '-', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('differential methylation', 'Var', (33, 57))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('EDCGs', 'Gene', (61, 66))
44602	31743108	The hypermethylation of CDH1 and hypomethylation of its transcriptional repressors (such as ZEB1 and TCF3) were consistent with EMT activation (FDR < 0.25, Figure 4B).	('CDH1', 'Gene', (24, 28))	('CDH1', 'Gene', '999', (24, 28))	('EMT activation', 'CPA', (128, 142))	('TCF3', 'Gene', '6929', (101, 105))	('ZEB1', 'Gene', '6935', (92, 96))	('ZEB1', 'Gene', (92, 96))	('EMT', 'biological_process', 'GO:0001837', ('128', '131'))	('TCF3', 'Gene', (101, 105))	('hypomethylation', 'Var', (33, 48))	('hypermethylation', 'Var', (4, 20))
44610	31743108	CN amplification of FOXM1 (115/500, 23%) was affected by CN amplifications (FDR = 2.83e-09, Figure 5B), and associated with high stage (OR = 2.701, 95% CI: 1.766-4.162, FDR = 5.36e-06, Figure 5C).	('high stage', 'CPA', (124, 134))	('associated', 'Reg', (108, 118))	('affected', 'Reg', (45, 53))	('FOXM1', 'Gene', '2305', (20, 25))	('FOXM1', 'Gene', (20, 25))	('CN amplifications', 'Var', (57, 74))
44614	31743108	In addition, upregulation of FOXM1 affected by CN amplifications (t-test, P < 0.05) was observed both in patients with regional and distant metastasis as well (Figure 5F).	('patients', 'Species', '9606', (105, 113))	('FOXM1', 'Gene', (29, 34))	('FOXM1', 'Gene', '2305', (29, 34))	('upregulation', 'PosReg', (13, 25))	('CN amplifications', 'Var', (47, 64))
44624	31743108	A logistic model of the methylation levels of eQTM (cg00044170 of FOXM1) showed high sensitivity and specificity for identifying tumors (area under curve [AUC] = 0.778) and localized tumors (AUC = 0.778) in the training dataset and validation dataset (GEO methylation dataset, AUC = 0.684 and 0.665 respectively, Figure 7A).	('FOXM1', 'Gene', (66, 71))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('cg00044170', 'Var', (52, 62))	('localized tumors', 'Disease', 'MESH:D009364', (173, 189))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('methylation', 'biological_process', 'GO:0032259', ('256', '267'))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('tumors', 'Disease', (183, 189))	('localized tumors', 'Disease', (173, 189))	('FOXM1', 'Gene', '2305', (66, 71))
44633	31743108	FOXM1 copy number amplification (115/500, 23% of patients), occurred in an amplified peak in chromosome 12q13.3, was enriched in late-stage ccRCC samples and associated with worse overall survival and progression-free survival.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('associated with', 'Reg', (158, 173))	('worse', 'NegReg', (174, 179))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('progression-free survival', 'CPA', (201, 226))	('overall survival', 'CPA', (180, 196))	('copy number', 'Var', (6, 17))	('FOXM1', 'Gene', '2305', (0, 5))	('patients', 'Species', '9606', (49, 57))	('FOXM1', 'Gene', (0, 5))
44635	31743108	Our eQTM-gene signature (FOXM1 and cg00044170) showed high sensitivity and specificity in diagnosis of ccRCC, especially for localized tumors.	('FOXM1', 'Gene', '2305', (25, 30))	('localized tumors', 'Disease', 'MESH:D009364', (125, 141))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('cg00044170', 'Var', (35, 45))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('localized tumors', 'Disease', (125, 141))	('FOXM1', 'Gene', (25, 30))
44649	31743108	Multi-omics data containing transcriptome, genome and epigenome that from the same subjects was valuable and may be critical for dissecting the potential factors of dynamic behaviors of EDCGs in cancer, and identifying the association between gene expression and DNA methylation or copy number alterations.	('methylation', 'Var', (267, 278))	('EDCGs', 'Chemical', '-', (186, 191))	('copy number alterations', 'Var', (282, 305))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('association', 'Reg', (223, 234))	('DNA methylation', 'biological_process', 'GO:0006306', ('263', '278'))	('DNA', 'cellular_component', 'GO:0005574', ('263', '266'))	('gene expression', 'biological_process', 'GO:0010467', ('243', '258'))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
44652	31743108	The same phenomenon was observed in all CpGs of EDCGs, which implied the close relevance between aberrant DNA methylation and tumorigenesis in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('ccRCC', 'Phenotype', 'HP:0006770', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('aberrant', 'Var', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('DNA methylation', 'biological_process', 'GO:0006306', ('106', '121'))	('EDCGs', 'Chemical', '-', (48, 53))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('tumor', 'Disease', (126, 131))
44653	31743108	Based on eQTMs analysis, rigorously speaking, FOXM1 upregulation and promoter hypomethylation are significantly correlated (FDR < 0.05), while if hypomethylation leads to upregulation of FOXM1 or upregulation of FOXM1 leads to hypomethylation are unclear and require further functional experiments.	('upregulation', 'PosReg', (52, 64))	('FOXM1', 'Gene', '2305', (46, 51))	('FOXM1', 'Gene', (46, 51))	('FOXM1', 'Gene', '2305', (187, 192))	('FOXM1', 'Gene', (187, 192))	('FOXM1', 'Gene', (212, 217))	('upregulation', 'PosReg', (171, 183))	('hypomethylation', 'Var', (146, 161))	('FOXM1', 'Gene', '2305', (212, 217))	('upregulation', 'PosReg', (196, 208))
44654	31743108	Previous evidences showed that loss of H3K36me3 demethylase SETD2 due to genomic alterations and hypermethylation was identified in both primary and metastases of ccRCC, while decreased methylation in regional H3K36me3 was only observed in lesions of distant metastases.	('metastases of ccRCC', 'Disease', (149, 168))	('metastases', 'Disease', (149, 159))	('loss', 'NegReg', (31, 35))	('metastases', 'Disease', (259, 269))	('SETD2', 'Gene', '29072', (60, 65))	('H3K36me3', 'Protein', (39, 47))	('metastases', 'Disease', 'MESH:D009362', (149, 159))	('hypermethylation', 'Var', (97, 113))	('SETD2', 'Gene', (60, 65))	('methylation', 'biological_process', 'GO:0032259', ('186', '197'))	('metastases', 'Disease', 'MESH:D009362', (259, 269))	('metastases of ccRCC', 'Disease', 'MESH:D009362', (149, 168))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('ccRCC', 'Phenotype', 'HP:0006770', (163, 168))
44655	31743108	In fact, hypomethylated CpGs among ~420,000 probes were observed in tumors with distant metastasis, while hypomethylation of EDCGs affected by eQTMs were not identified.	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('hypomethylated', 'Var', (9, 23))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('EDCGs', 'Chemical', '-', (125, 130))
44664	31743108	In summary, we identified that the signature (FOXM1 and cg00044170) and FOXM1 may be valuable for early diagnosis of ccRCC and OS prognosis for pT3 patients with distant metastasis respectively.	('patients', 'Species', '9606', (148, 156))	('FOXM1', 'Gene', (72, 77))	('FOXM1', 'Gene', '2305', (46, 51))	('FOXM1', 'Gene', (46, 51))	('pT3', 'Gene', '7694', (144, 147))	('cg00044170', 'Var', (56, 66))	('pT3', 'Gene', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('RCC', 'Disease', (119, 122))	('FOXM1', 'Gene', '2305', (72, 77))
44686	31743108	In the early diagnosis analysis of FOXM1 methylation, cg00044170 methylation level was used as a classifier to distinguish localized ccRCC tumors (even pT1a tumors) and normal samples.	('FOXM1', 'Gene', '2305', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('cg00044170', 'Var', (54, 64))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('localized ccRCC tumors', 'Disease', (123, 145))	('FOXM1', 'Gene', (35, 40))	('pT1', 'Gene', '58492', (152, 155))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('tumors', 'Disease', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('pT1', 'Gene', (152, 155))	('tumors', 'Disease', (139, 145))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('localized ccRCC tumors', 'Disease', 'MESH:D009364', (123, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('methylation', 'biological_process', 'GO:0032259', ('65', '76'))
44687	31743108	In the early diagnosis analysis of FOXM1-cg00044170 signature, the epsilon values calculated from FOXM1 expression levels and cg00044170 methylation levels by our formula (Figure 7C) was served as a new classifier for early diagnosis.	('FOXM1', 'Gene', (35, 40))	('cg00044170', 'Var', (126, 136))	('methylation', 'biological_process', 'GO:0032259', ('137', '148'))	('FOXM1', 'Gene', '2305', (35, 40))	('FOXM1', 'Gene', (98, 103))	('FOXM1', 'Gene', '2305', (98, 103))
44688	31743108	The logistic regression was used to determine whether CN deletion/amplification was associated with advanced tumors.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('CN deletion/amplification', 'Var', (54, 79))	('associated', 'Reg', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))
44689	31743108	A deleted gene with odds ratio (OR) <1 and FDR <0.05 represents that its deletion was associated with advanced tumors.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('associated', 'Reg', (86, 96))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('advanced', 'Disease', (102, 110))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('deletion', 'Var', (73, 81))
44692	33324682	More and more evidence showed that the aberrant expression of CXCRs is closely related to the prognosis of various cancers.	('aberrant expression', 'Var', (39, 58))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('related', 'Reg', (79, 86))
44697	33324682	23.14% mutation rate (118/510) of CXCR1-7 was observed in ccRCC patients, and the genetic alterations in CXCRs were related to worse OS and progression-free survival in ccRCC patients.	('observed', 'Reg', (46, 54))	('patients', 'Species', '9606', (64, 72))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('CXCR1-7', 'Gene', (34, 41))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('genetic alterations', 'Var', (82, 101))	('patients', 'Species', '9606', (175, 183))	('mutation', 'Var', (7, 15))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('CXCR1-7', 'Gene', '3577;3579;2833;7852;643;10663;57007', (34, 41))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('RCC', 'Disease', (171, 174))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))
44732	33324682	Moreover, the prognostic values of CpG methylation in CXCR1-7 were evaluated, and the survival outcome was OS.	('CXCR1-7', 'Gene', '3577;3579;2833;7852;643;10663;57007', (54, 61))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('CXCR1-7', 'Gene', (54, 61))	('CpG methylation', 'Var', (35, 50))
44764	33324682	Genetic alterations in CXCRs and their correlations with OS and PFS of ccRCC patients were explored by cBioPortal database.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('RCC', 'Disease', (73, 76))	('Genetic', 'Var', (0, 7))	('patients', 'Species', '9606', (77, 85))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
44766	33324682	As shown in Figure 6A, the percentages of genetic alterations in CXCRs of ccRCC ranged from 1.8 to 10% for single genes (CXCR1, 1.8%; CXCR2, 1.8%; CXCR3, 6%; CXCR4, 6%; CXCR5, 4%; CXCR6, 10%; CXCR7, 7%).	('CXCR7', 'molecular_function', 'GO:0038147', ('192', '197'))	('CXCR4', 'Gene', '7852', (158, 163))	('CXCR4', 'Gene', (158, 163))	('CXCR6', 'Gene', (180, 185))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('CXCR3', 'Gene', (147, 152))	('CXCR5', 'Gene', (169, 174))	('CXCR3', 'Gene', '2833', (147, 152))	('CXCR5', 'Gene', '643', (169, 174))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('CXCR4', 'molecular_function', 'GO:0038147', ('158', '163'))	('CXCR7', 'Gene', (192, 197))	('CXCR6', 'Gene', '10663', (180, 185))	('CXCR7', 'Gene', '57007', (192, 197))	('CXCR2', 'Gene', (134, 139))	('CXCR1', 'Gene', (121, 126))	('genetic alterations', 'Var', (42, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))	('CXCR1', 'Gene', '3577', (121, 126))	('CXCR2', 'Gene', '3579', (134, 139))
44767	33324682	The results of KM curves and log-rank test suggested that genetic alterations in CXCRs were correlated with worse OS (p = 0.0204) and PFS (p = 4.009e-3) of patients with ccRCC (Figures 6B,C).	('patients', 'Species', '9606', (156, 164))	('ccRCC', 'Phenotype', 'HP:0006770', (170, 175))	('RCC', 'Disease', (172, 175))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('genetic alterations', 'Var', (58, 77))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))
44768	33324682	In short, genetic alterations in CXCRs could significantly influence the prognosis of ccRCC patients.	('genetic alterations', 'Var', (10, 29))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('patients', 'Species', '9606', (92, 100))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('influence', 'Reg', (59, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))
44770	33324682	The results of MethSurv suggested that cg07016356 of CXCR1, cg14652717 of CXCR2, cg14296598 of CXCR3, cg07784959 of CXCR4, cg20208523 of CXCR5, cg05705212 of CXCR6, and cg05693814 of CXCR7 had the highest DNA methylation (Supplementary Figures 1, 2).	('CXCR5', 'Gene', (137, 142))	('CXCR6', 'Gene', (158, 163))	('CXCR2', 'Gene', (74, 79))	('CXCR4', 'Gene', '7852', (116, 121))	('CXCR7', 'molecular_function', 'GO:0038147', ('183', '188'))	('DNA methylation', 'biological_process', 'GO:0006306', ('205', '220'))	('CXCR1', 'Gene', (53, 58))	('CXCR4', 'Gene', (116, 121))	('CXCR2', 'Gene', '3579', (74, 79))	('CXCR4', 'molecular_function', 'GO:0038147', ('116', '121'))	('cg20208523', 'Var', (123, 133))	('cg07784959', 'Var', (102, 112))	('cg05693814', 'Var', (169, 179))	('cg05705212', 'Var', (144, 154))	('DNA methylation', 'MPA', (205, 220))	('CXCR1', 'Gene', '3577', (53, 58))	('cg07016356', 'Var', (39, 49))	('CXCR5', 'Gene', '643', (137, 142))	('cg14296598', 'Var', (81, 91))	('CXCR6', 'Gene', '10663', (158, 163))	('DNA', 'cellular_component', 'GO:0005574', ('205', '208'))	('CXCR7', 'Gene', (183, 188))	('CXCR3', 'Gene', (95, 100))	('CXCR7', 'Gene', '57007', (183, 188))	('MethSurv', 'Chemical', '-', (15, 23))	('CXCR3', 'Gene', '2833', (95, 100))	('cg14652717', 'Var', (60, 70))
44773	33324682	In addition, BPs such as GO: 0060326 (cell chemotaxis), GO:0046649 (lymphocyte activation), GO: 0002274 (myeloid leukocyte activation), GO: 0032649 (regulation of interferon-gamma production), and GO: 0032496 (response to lipopolysaccharide) were prominently related to CXCRs and their similar genes.	('GO: 0060326', 'Var', (25, 36))	('interferon-gamma', 'Gene', (163, 179))	('related', 'Reg', (259, 266))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (222, 240))	('regulation of interferon-gamma production', 'biological_process', 'GO:0032649', ('149', '190'))	('myeloid leukocyte activation', 'biological_process', 'GO:0002274', ('105', '133'))	('cell chemotaxis', 'biological_process', 'GO:0060326', ('38', '53'))	('GO: 0032496', 'Var', (197, 208))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('163', '179'))	('GO: 0002274', 'Var', (92, 103))	('response to lipopolysaccharide', 'biological_process', 'GO:0032496', ('210', '240'))	('lymphocyte activation', 'biological_process', 'GO:0046649', ('68', '89'))	('GO:0046649', 'Var', (56, 66))	('interferon-gamma', 'Gene', '3458', (163, 179))	('GO: 0032649', 'Var', (136, 147))
44774	33324682	Pathways such as has: 04060 (cytokine-cytokine receptor interaction), has: 05340 (primary immunodeficiency), has: 04650 (natural killer cell-mediated cytotoxicity), and has: 05200 (pathways in cancer) were correlated with the functions of CXCRs and their similar genes in ccRCC.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('has: 04060', 'Var', (17, 27))	('cancer', 'Disease', (193, 199))	('has: 05340', 'Var', (70, 80))	('cytotoxicity', 'Disease', (150, 162))	('RCC', 'Disease', (274, 277))	('primary immunodeficiency', 'Disease', 'MESH:D000081207', (82, 106))	('RCC', 'Phenotype', 'HP:0005584', (274, 277))	('natural killer cell-mediated cytotoxicity', 'biological_process', 'GO:0042267', ('121', '162'))	('primary immunodeficiency', 'Disease', (82, 106))	('RCC', 'Disease', 'MESH:C538614', (274, 277))	('ccRCC', 'Phenotype', 'HP:0006770', (272, 277))	('has: 05200', 'Var', (169, 179))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cytotoxicity', 'Disease', 'MESH:D064420', (150, 162))	('has: 04650', 'Var', (109, 119))	('immunodeficiency', 'Phenotype', 'HP:0002721', (90, 106))
44787	33324682	Furthermore, 23.14% mutation rate (118/510) of CXCR1-7 was observed in ccRCC patients and the genetic alterations in CXCR family members were related to worse OS and PFS in patients with ccRCC.	('genetic alterations', 'Var', (94, 113))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('RCC', 'Disease', (73, 76))	('CXCR1-7', 'Gene', (47, 54))	('PFS', 'Disease', (166, 169))	('patients', 'Species', '9606', (173, 181))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))	('mutation', 'Var', (20, 28))	('CXCR1-7', 'Gene', '3577;3579;2833;7852;643;10663;57007', (47, 54))	('patients', 'Species', '9606', (77, 85))	('worse OS', 'Disease', (153, 161))	('observed', 'Reg', (59, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (187, 192))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('RCC', 'Disease', (189, 192))	('related', 'Reg', (142, 149))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
44788	33324682	Besides, although mRNA expression of CXCR1 and CXCR7 was not significantly correlated with OS in ccRCC, 53 CpGs of CXCR1-7 showed significant prognostic values.	('CXCR1', 'Gene', '3577', (37, 42))	('CpGs', 'Var', (107, 111))	('CXCR1', 'Gene', (115, 120))	('CXCR7', 'Gene', (47, 52))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('CXCR1', 'Gene', (37, 42))	('CXCR7', 'Gene', '57007', (47, 52))	('CXCR7', 'molecular_function', 'GO:0038147', ('47', '52'))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('CXCR1', 'Gene', '3577', (115, 120))	('CXCR1-7', 'Gene', (115, 122))	('CXCR1-7', 'Gene', '3577;3579;2833;7852;643;10663;57007', (115, 122))
44805	33324682	Moreover, high mRNA expression CXCR3 was correlated with poor prognosis in ccRCC, and one CpG (cg17678039) of CXCR3 was related to favorable survival.	('CXCR3', 'Gene', '2833', (31, 36))	('cg17678039', 'Var', (95, 105))	('CXCR3', 'Gene', '2833', (110, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('CXCR3', 'Gene', (31, 36))	('high', 'Var', (10, 14))	('CXCR3', 'Gene', (110, 115))
44812	33324682	In our study, an association was observed between high CXCR4 expression and worse prognosis for OS time, which was consistent with the previous research, and 15 CpGs of CXCR4 have also been found to be related to OS time.	('CXCR4', 'Gene', (55, 60))	('CXCR4', 'molecular_function', 'GO:0038147', ('169', '174'))	('CXCR4', 'Gene', (169, 174))	('OS time', 'Disease', (213, 220))	('CXCR4', 'molecular_function', 'GO:0038147', ('55', '60'))	('related', 'Reg', (202, 209))	('CXCR4', 'Gene', '7852', (55, 60))	('OS time', 'Disease', (96, 103))	('CXCR4', 'Gene', '7852', (169, 174))	('high', 'Var', (50, 54))
44814	33324682	High plasmacytoid dendritic cells could promote the expression of CXCR4 by TNF-alpha/NF-kappaB pathway (Gadalla et al.,), and blocking CXCR4 could effectively inhibit cancer progression and enhanced the curative effect of immune checkpoint blockers by up-regulating Treg cells infiltration (Chen I. X. et al.,).	('CXCR4', 'Gene', (135, 140))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('promote', 'PosReg', (40, 47))	('blocking', 'Var', (126, 134))	('TNF-alpha', 'Gene', '7124', (75, 84))	('enhanced', 'PosReg', (190, 198))	('CXCR4', 'molecular_function', 'GO:0038147', ('66', '71'))	('TNF-alpha', 'Gene', (75, 84))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('Treg cells infiltration', 'CPA', (266, 289))	('NF-kappaB', 'Gene', (85, 94))	('CXCR4', 'Gene', '7852', (66, 71))	('CXCR4', 'Gene', (66, 71))	('NF-kappaB', 'Gene', '4790', (85, 94))	('up-regulating', 'PosReg', (252, 265))	('curative effect', 'CPA', (203, 218))	('expression', 'MPA', (52, 62))	('CXCR4', 'molecular_function', 'GO:0038147', ('135', '140'))	('CXCR4', 'Gene', '7852', (135, 140))	('inhibit', 'NegReg', (159, 166))
44844	33324682	Additionally, we found that mRNA expression of CXCR3/4/5/6 and CpGs methylation in all CXCRs members were significantly associated with OS in ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('patients', 'Species', '9606', (148, 156))	('associated', 'Reg', (120, 130))	('CXCR3/4/5/6', 'Gene', '2833;7852;643;10663', (47, 58))	('CpGs', 'Gene', (63, 67))	('methylation', 'Var', (68, 79))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('mRNA expression', 'MPA', (28, 43))	('CXCR3/4/5/6', 'Gene', (47, 58))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))
44845	33324682	Besides, genetic alterations in CXCRs were remarkably related to shorter OS and PFS in ccRCC patients.	('patients', 'Species', '9606', (93, 101))	('genetic alterations', 'Var', (9, 28))	('shorter', 'Disease', (65, 72))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('PFS', 'CPA', (80, 83))
44884	33178275	Based on the tumor size, all patients were categorized into four groups: "<=4 cm," "4-7 cm," "7-10 cm," and ">10 cm."	('tumor', 'Disease', (13, 18))	('patients', 'Species', '9606', (29, 37))	('4-7 cm', 'Var', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
44891	33178275	Generally, all four tumor size groups were highly representative, and the tumor size distribution was as follows: <=4 cm: n = 1,212 (14.62%), 4-7 cm: n = 2,278 (27.47%), 7-10 cm: n = 2,428 (29.93%), and >10 cm: n = 2,320 (27.98%).	('4-7 cm', 'Var', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('<=4 cm', 'Var', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
44941	32325871	ccRCC is highly associated with biallelic mutations in the von Hippel-Lindau (VHL) tumor suppressor gene.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('biallelic mutations', 'Var', (32, 51))	('tumor suppressor', 'biological_process', 'GO:0051726', ('83', '99'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('83', '99'))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('ccRCC', 'Disease', (0, 5))	('associated', 'Reg', (16, 26))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (59, 88))
44943	32325871	Furthermore, we show that blocking miRNA-212/132 with anti-miRs can significantly alleviate the excessive vascular branching phenotype characteristic of vhl-/- mutant zebrafish.	('miR', 'Gene', '335888', (35, 38))	('vhl-/-', 'Gene', (153, 159))	('miR', 'Gene', '335888', (59, 62))	('alleviate', 'NegReg', (82, 91))	('zebrafish', 'Species', '7955', (167, 176))	('miRNA-212/132', 'Gene', '406921', (35, 48))	('miR', 'Gene', (59, 62))	('mutant', 'Var', (160, 166))	('miR', 'Gene', (35, 38))	('miRNA-212/132', 'Gene', (35, 48))	('vascular branching', 'Disease', (106, 124))	('vascular branching', 'Disease', 'MESH:D000783', (106, 124))
44944	32325871	Moreover, using human umbilical vascular endothelial cells (HUVECs) and an endothelial cell/pericyte coculture system, we observed that VHL knockdown promotes endothelial cells neovascularization capacity in vitro, an effect which can be inhibited by anti-miR-212/132 treatment.	('endothelial cells neovascularization capacity', 'CPA', (159, 204))	('promotes', 'PosReg', (150, 158))	('human', 'Species', '9606', (16, 21))	('VHL', 'Gene', (136, 139))	('knockdown', 'Var', (140, 149))
44945	32325871	Taken together, our results demonstrate an important role for miRNA-212/132 in angiogenesis induced by loss of VHL.	('miRNA-212/132', 'Gene', '406921', (62, 75))	('VHL', 'Gene', (111, 114))	('loss', 'Var', (103, 107))	('angiogenesis', 'biological_process', 'GO:0001525', ('79', '91'))	('miRNA-212/132', 'Gene', (62, 75))	('angiogenesis', 'CPA', (79, 91))	('rat', 'Species', '10116', (35, 38))
44946	32325871	Intriguingly, this also presents a possibility for the pharmaceutical manipulation of angiogenesis by modulating levels of MiR212/132.	('angiogenesis', 'biological_process', 'GO:0001525', ('86', '98'))	('modulating', 'Var', (102, 112))	('MiR212', 'Gene', '100033725', (123, 129))	('MiR212', 'Gene', (123, 129))
44947	32325871	Clear cell renal cell carcinoma (ccRCC), the most common form of sporadic and inherited kidney cancer, is highly associated with mutations in the von Hippel-Lindau (VHL) gene.	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('von Hippel-Lindau', 'Gene', '791202', (146, 163))	('mutations', 'Var', (129, 138))	('von Hippel-Lindau', 'Gene', (146, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('VHL', 'Gene', (165, 168))	('kidney cancer', 'Phenotype', 'HP:0009726', (88, 101))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('inherited kidney cancer', 'Disease', (78, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('inherited kidney cancer', 'Disease', 'MESH:D007680', (78, 101))	('associated', 'Reg', (113, 123))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))
44950	32325871	Upon hypoxia or loss of functional pVHL, HIF1alpha-subunits can no longer be hydroxylated and begin to accumulate.	('HIF1alpha', 'Gene', '797150', (41, 50))	('accumulate', 'PosReg', (103, 113))	('hypoxia', 'Disease', (5, 12))	('hypoxia', 'Disease', 'MESH:D000860', (5, 12))	('pVHL', 'Gene', '7428', (35, 39))	('pVHL', 'Gene', (35, 39))	('HIF1alpha', 'Gene', (41, 50))	('loss', 'Var', (16, 20))
44952	32325871	However, many of the changes initiated by the stabilization of HIF1alpha, such as increased angiogenesis, an upregulation of antiapoptotic signaling, and a shift to anaerobic glycolosis, can contribute to tumor growth and survival.	('survival', 'CPA', (222, 230))	('contribute', 'Reg', (191, 201))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('angiogenesis', 'CPA', (92, 104))	('upregulation', 'PosReg', (109, 121))	('HIF1alpha', 'Gene', (63, 72))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('increased', 'PosReg', (82, 91))	('HIF1alpha', 'Gene', '797150', (63, 72))	('stabilization', 'Var', (46, 59))	('antiapoptotic signaling', 'MPA', (125, 148))	('angiogenesis', 'biological_process', 'GO:0001525', ('92', '104'))
44953	32325871	People born with a mutation in one VHL allele may acquire somatic mutations in the second allele, resulting in consequent angiogenic symptoms and a variety of tumors, including ccRCC.	('mutation', 'Var', (19, 27))	('ccRCC', 'Disease', (177, 182))	('ccRCC', 'Phenotype', 'HP:0006770', (177, 182))	('angiogenic symptoms', 'CPA', (122, 141))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('People', 'Species', '9606', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('VHL', 'Gene', (35, 38))	('tumors', 'Disease', 'MESH:D009369', (159, 165))
44959	32325871	In this study, using a combination of cellular models, patient ccRCC material with biallelic loss of VHL and a previously described vhl-/- mutant zebrafish model, we show that miR-212/132 is upregulated after VHL knockdown or mutation and that this upregulation is at least partially responsible for pro-angiogenic effects.	('upregulated', 'PosReg', (191, 202))	('VHL', 'Gene', (101, 104))	('miR-212/132', 'Gene', (176, 187))	('loss', 'NegReg', (93, 97))	('zebrafish', 'Species', '7955', (146, 155))	('mutation', 'Var', (226, 234))	('VHL', 'Gene', (209, 212))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('patient', 'Species', '9606', (55, 62))	('knockdown', 'Var', (213, 222))
44963	32325871	A scarcity of functional pVHL induces excessive vascular outgrowth, which further is enhanced by miR-212/132 expression, providing an exciting target for the modulation of angiogenesis.	('pVHL', 'Gene', '7428', (25, 29))	('pVHL', 'Gene', (25, 29))	('enhanced', 'PosReg', (85, 93))	('angiogenesis', 'biological_process', 'GO:0001525', ('172', '184'))	('miR-212/132 expression', 'Var', (97, 119))	('vascular outgrowth', 'CPA', (48, 66))
44965	32325871	However, in ccRCC #1, in addition to the already known germline deletion of VHL exons 1 and 2, an additional somatic mutation was found in the tumor (c.277delG/p.Gly93Ala_fs_x158).	('VHL', 'Gene', (76, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (12, 17))	('p.Gly93Ala', 'Mutation', 'p.G93A', (160, 170))	('tumor', 'Disease', (143, 148))	('c.277delG', 'Mutation', 'c.277delG', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('c.277delG/p.Gly93Ala_fs_x158', 'Var', (150, 178))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
44966	32325871	ccRCC #2 has a germline mutation c.266T> p.Leu89Pro and a somatic mutation of c.419-420delTC/p.Leu140Gln_fs_x142.	('p.Leu140Gln', 'Mutation', 'p.L140Q', (93, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('c.419-420delTC', 'Mutation', 'rs869025649', (78, 92))	('c.266T> p.Leu89Pro', 'Var', (33, 51))	('c.419-420delTC/p.Leu140Gln_fs_x142', 'Var', (78, 112))	('p.Leu89Pro', 'Mutation', 'rs5030807', (41, 51))
44968	32325871	Paraffin samples were first deparaffinized with tissue clear (Cat# 1426, SAKURA) followed with 10 min of proteinase K treatment (5mug/ml, Cat# 03115828001, Roche).	('proteinase', 'molecular_function', 'GO:0004175', ('105', '115'))	('Cat', 'molecular_function', 'GO:0004096', ('62', '65'))	('Paraffin', 'Chemical', 'MESH:D010232', (0, 8))	('Cat# 1426', 'Var', (62, 71))	('Cat# 03115828001', 'Var', (138, 154))	('Cat', 'molecular_function', 'GO:0004096', ('138', '141'))	('paraffin', 'Chemical', 'MESH:D010232', (30, 38))	('mug', 'molecular_function', 'GO:0043739', ('130', '133'))
44983	32325871	Mutant zebrafish possessed the previously described vhlhu2117 mutation.	('Mutant', 'Var', (0, 6))	('zebrafish', 'Species', '7955', (7, 16))	('vhlhu2117', 'Gene', (52, 61))
44985	32325871	Wild-type and mutant Zebrafish embryos were injected at the 1-2-cell stage with 1 nL of 5 uM of the same miRNA mimics and antagonists used for the cell culture experiments described above.	('miR', 'Gene', (105, 108))	('Zebrafish', 'Species', '7955', (21, 30))	('mutant', 'Var', (14, 20))	('miR', 'Gene', '335888', (105, 108))
44999	32325871	PTEN has been predicted to be a potential target of miR-212/132 in humans by targetscan (Supplemental Figure S1B), and the rat homologue of PTEN has been shown to be targeted by miR-212/132 in rat vascular smooth muscle cells.	('rat', 'Species', '10116', (193, 196))	('humans', 'Species', '9606', (67, 73))	('miR-212/132', 'Var', (178, 189))	('rat', 'Species', '10116', (123, 126))	('targetscan', 'MPA', (77, 87))
45003	32325871	In agreement with our previous qPCR results, we observed widespread overexpression of miR-132 in tumor material from ccRCC samples with biallelic VHL mutations proven by sequencing (Figure 1E).	('VHL', 'Gene', (146, 149))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('miR-132', 'Gene', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('overexpression', 'PosReg', (68, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('mutations', 'Var', (150, 159))	('ccRCC', 'Disease', (117, 122))
45004	32325871	These results demonstrate that miR-132 is increased in response to the pseudo-hypoxia induced by the lack of functional pVHL, which eventually leads to overexpression of miR-132.	('increased', 'PosReg', (42, 51))	('leads to', 'Reg', (143, 151))	('overexpression', 'PosReg', (152, 166))	('miR-132', 'Gene', (31, 38))	('hypoxia', 'Disease', (78, 85))	('hypoxia', 'Disease', 'MESH:D000860', (78, 85))	('miR-132', 'Gene', (170, 177))	('rat', 'Species', '10116', (21, 24))	('lack', 'Var', (101, 105))	('pVHL', 'Gene', '7428', (120, 124))	('pVHL', 'Gene', (120, 124))
45010	32325871	Anti-miR injections against miR-212/132 significantly reduced the extent of intersomitic vessel sprouting in vhl-/- fish (Figure 3C,D).	('miR', 'Gene', (5, 8))	('miR', 'Gene', '335888', (28, 31))	('reduced', 'NegReg', (54, 61))	('miR', 'Gene', (28, 31))	('miR', 'Gene', '335888', (5, 8))	('injections', 'Var', (9, 19))
45011	32325871	In addition, injecting wild-type zebrafish with miR-212/132 mimics partially recapitulated the vhl mutant vessel sprouting phenotype (Supplemental Figure S1C,D).	('vhl', 'Gene', (95, 98))	('mutant', 'Var', (99, 105))	('zebrafish', 'Species', '7955', (33, 42))
45015	32325871	ptenb is a predicted target of miR-212/132 in targetscan but not ptena (Supplemental Figure S1E).	('ptena', 'Gene', (65, 70))	('ptena', 'Gene', '794088', (65, 70))	('ptenb', 'Gene', '368415', (0, 5))	('miR-212/132', 'Var', (31, 42))	('ptenb', 'Gene', (0, 5))
45018	32325871	We observed that miR-212/132 is upregulated in response to VHL mutation both in zebrafish model systems and in human patient ccRCC tumor material carrying biallelic inactivating VHL mutations.	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('human', 'Species', '9606', (111, 116))	('ccRCC tumor', 'Disease', (125, 136))	('miR-212/132', 'Gene', (17, 28))	('mutation', 'Var', (63, 71))	('zebrafish', 'Species', '7955', (80, 89))	('ccRCC tumor', 'Disease', 'MESH:D009369', (125, 136))	('patient', 'Species', '9606', (117, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (125, 130))	('VHL', 'Gene', (59, 62))	('upregulated', 'PosReg', (32, 43))
45019	32325871	We demonstrated that the excessive angiogenesis attributable to VHL mutation is strongly affected by miR-212/132.	('mutation', 'Var', (68, 76))	('affected', 'Reg', (89, 97))	('VHL', 'Gene', (64, 67))	('rat', 'Species', '10116', (10, 13))	('angiogenesis', 'biological_process', 'GO:0001525', ('35', '47'))	('miR-212/132', 'Var', (101, 112))	('angiogenesis', 'CPA', (35, 47))
45028	32325871	miR-212/132 frequently act as a promoter of cell proliferation, and increases in their expression levels have also been suggested as contributors to tumorigenesis in addition to their angiogenic role.	('promoter', 'PosReg', (32, 40))	('increases', 'PosReg', (68, 77))	('rat', 'Species', '10116', (56, 59))	('cell proliferation', 'CPA', (44, 62))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('expression levels', 'MPA', (87, 104))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('contributors', 'Reg', (133, 145))	('miR-212/132', 'Var', (0, 11))	('tumor', 'Disease', (149, 154))	('cell proliferation', 'biological_process', 'GO:0008283', ('44', '62'))
45029	32325871	In addition, anti-miR-132 has also been shown to reduce tumor burden in a mouse xenograft model of human breast carcinoma.	('breast carcinoma', 'Disease', (105, 121))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('breast carcinoma', 'Phenotype', 'HP:0003002', (105, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('mouse', 'Species', '10090', (74, 79))	('reduce', 'NegReg', (49, 55))	('anti-miR-132', 'Var', (13, 25))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('human', 'Species', '9606', (99, 104))	('breast carcinoma', 'Disease', 'MESH:D001943', (105, 121))
45030	32325871	This study supports the previously reported role of miR-212/132 in angiogenesis and expands upon its role in the context of VHL-regulated hypoxia signaling.	('angiogenesis', 'CPA', (67, 79))	('hypoxia', 'Disease', (138, 145))	('miR-212/132', 'Var', (52, 63))	('hypoxia', 'Disease', 'MESH:D000860', (138, 145))	('signaling', 'biological_process', 'GO:0023052', ('146', '155'))	('angiogenesis', 'biological_process', 'GO:0001525', ('67', '79'))
45031	32325871	For example, in the case of PTEN, PI3K may activate AKT, leading to an increase in proliferation.	('activate', 'PosReg', (43, 51))	('PTEN', 'Gene', (28, 32))	('PI3K', 'Var', (34, 38))	('proliferation', 'CPA', (83, 96))	('AKT', 'Gene', (52, 55))	('PI3K', 'molecular_function', 'GO:0016303', ('34', '38'))	('increase', 'PosReg', (71, 79))	('AKT', 'Gene', '207', (52, 55))	('rat', 'Species', '10116', (90, 93))
45035	32325871	Uncontrolled proliferation and angiogenesis are hallmarks of cancer, and many tumors contain mutations leading to hyperactivation of signaling networks which act to promote these processes.	('angiogenesis', 'biological_process', 'GO:0001525', ('31', '43'))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('mutations', 'Var', (93, 102))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('hyperactivation', 'PosReg', (114, 129))	('signaling', 'biological_process', 'GO:0023052', ('133', '142'))	('cancer', 'Disease', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('promote', 'PosReg', (165, 172))	('angiogenesis', 'CPA', (31, 43))	('signaling networks', 'Pathway', (133, 151))	('rat', 'Species', '10116', (20, 23))	('Uncontrolled proliferation', 'CPA', (0, 26))
45041	32325871	Antiapoptotic signaling is upregulated after HIF1alpha hyper-stabilization in ccRCC tumors.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('signaling', 'biological_process', 'GO:0023052', ('14', '23'))	('HIF1alpha', 'Gene', '797150', (45, 54))	('ccRCC tumors', 'Disease', (78, 90))	('Antiapoptotic signaling', 'MPA', (0, 23))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('HIF1alpha', 'Gene', (45, 54))	('upregulated', 'PosReg', (27, 38))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('hyper-stabilization', 'Var', (55, 74))	('ccRCC tumors', 'Disease', 'MESH:D009369', (78, 90))
45043	32325871	Our results and the results of other studies suggest that miR-212/132 may act as a promoter of tumorigenesis by targeting inhibitors of proliferation, survival, and angiogenesis, presenting an interesting opportunity for pharmaceutical intervention.	('angiogenesis', 'biological_process', 'GO:0001525', ('165', '177'))	('inhibitors', 'MPA', (122, 132))	('survival', 'CPA', (151, 159))	('miR-212/132', 'Var', (58, 69))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('rat', 'Species', '10116', (143, 146))	('promoter', 'PosReg', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('angiogenesis', 'CPA', (165, 177))	('targeting', 'NegReg', (112, 121))	('tumor', 'Disease', (95, 100))	('proliferation', 'CPA', (136, 149))
45045	32325871	Here, we have shown that antagonizing the activity of this miRNA family can reduce angiogenesis in relevant models of VHL deficiency.	('miR', 'Gene', '335888', (59, 62))	('activity', 'MPA', (42, 50))	('VHL deficiency', 'Disease', 'MESH:D006623', (118, 132))	('antagonizing', 'Var', (25, 37))	('angiogenesis', 'biological_process', 'GO:0001525', ('83', '95'))	('miR', 'Gene', (59, 62))	('reduce', 'NegReg', (76, 82))	('VHL deficiency', 'Disease', (118, 132))	('angiogenesis', 'CPA', (83, 95))
45046	32325871	PTEN, which we have confirmed to be a target of the miR-212/132 family in these models, is frequently mutated in cancer.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('miR-212/132', 'Var', (52, 63))	('PTEN', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
45048	32325871	Loss of PTEN leads to upregulation of mTOR signaling, and mTOR inhibitors have been used to treat multiple cancer types.	('mTOR', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('signaling', 'biological_process', 'GO:0023052', ('43', '52'))	('PTEN', 'Gene', (8, 12))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('upregulation', 'PosReg', (22, 34))	('Loss', 'Var', (0, 4))	('mTOR', 'Gene', (38, 42))	('cancer', 'Disease', (107, 113))	('mTOR', 'Gene', '2475', (38, 42))	('mTOR', 'Gene', '2475', (58, 62))
45050	32325871	Conversely, treatments with miR-212/132 might also be a useful method to promote angiogenesis and to increase neovascularization in the cases where neovascularization would be helpful, such as certain ischemic tissues or newly transplanted engineered tissue constructs.	('ischemic', 'Disease', 'MESH:D007511', (201, 209))	('angiogenesis', 'biological_process', 'GO:0001525', ('81', '93'))	('increase', 'PosReg', (101, 109))	('angiogenesis', 'CPA', (81, 93))	('neovascularization', 'CPA', (110, 128))	('ischemic', 'Disease', (201, 209))	('miR-212/132', 'Var', (28, 39))	('promote', 'PosReg', (73, 80))
45051	32325871	In fact, ex vivo transfection of mir-132 into endothelial cells has been shown to be beneficial for transplantation and vascularization of transplanted endothelial cells.	('transplantation', 'CPA', (100, 115))	('vascularization', 'CPA', (120, 135))	('mir-132', 'Gene', '100033650', (33, 40))	('transfection', 'Var', (17, 29))	('mir-132', 'Gene', (33, 40))	('beneficial', 'PosReg', (85, 95))
45054	27774982	Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer Clear cell renal cell carcinoma (ccRCC) is characterized by loss of function of the von Hippel-Lindau tumour suppressor (VHL) and unrestrained activation of hypoxia-inducible transcription factors (HIFs).	('renal cancer', 'Disease', 'MESH:D007680', (33, 45))	('HIF', 'Protein', (75, 78))	('Clear cell renal cell carcinoma', 'Disease', (105, 136))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (116, 136))	('RCC', 'Disease', (140, 143))	('transcription', 'biological_process', 'GO:0006351', ('280', '293'))	('affects', 'Reg', (67, 74))	('von Hippel-Lindau tumour', 'Disease', (189, 213))	('MYC', 'Gene', '4609', (92, 95))	('MYC', 'Gene', (92, 95))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (105, 136))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('hypoxia', 'Disease', (262, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('binding', 'molecular_function', 'GO:0005488', ('79', '86'))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('renal cancer', 'Disease', (33, 45))	('renal cancer', 'Phenotype', 'HP:0009726', (33, 45))	('hypoxia', 'Disease', 'MESH:D000860', (262, 269))	('von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (189, 213))	('loss of function', 'NegReg', (165, 181))	('binding', 'Interaction', (79, 86))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (105, 136))	('variation', 'Var', (8, 17))
45055	27774982	A recent genome-wide association study on renal cancer susceptibility identified single-nucleotide polymorphisms (SNPs) in an intergenic region located between the oncogenes MYC and PVT1.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('renal cancer', 'Disease', (42, 54))	('MYC', 'Gene', '4609', (174, 177))	('single-nucleotide polymorphisms', 'Var', (81, 112))	('renal cancer', 'Disease', 'MESH:D007680', (42, 54))	('renal cancer', 'Phenotype', 'HP:0009726', (42, 54))	('PVT1', 'Gene', (182, 186))	('PVT1', 'Gene', '5820', (182, 186))	('MYC', 'Gene', (174, 177))
45057	27774982	These findings provide further evidence that genetic variation at HIF-binding sites modulates the oncogenic transcriptional output of the VHL-HIF axis and provide a functional explanation for the disease-associated effects of SNPs in ccRCC.	('RCC', 'Disease', (236, 239))	('binding', 'molecular_function', 'GO:0005488', ('70', '77'))	('VHL-HIF axis', 'Disease', (138, 150))	('VHL-HIF axis', 'Disease', 'MESH:D006623', (138, 150))	('RCC', 'Disease', 'MESH:C538614', (236, 239))	('modulates', 'Reg', (84, 93))	('genetic variation', 'Var', (45, 62))
45060	27774982	In clear cell renal cell carcinoma (ccRCC), but few other cancers, somatic loss-of-function mutations, chromosomal aberrations or promoter hypermethylation lead to decreased activity of von Hippel-Lindau tumour suppressor protein (pVHL).	('RCC', 'Disease', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (186, 210))	('activity', 'MPA', (174, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('RCC', 'Disease', 'MESH:C538614', (38, 41))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (3, 34))	('loss-of-function', 'NegReg', (75, 91))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('protein', 'cellular_component', 'GO:0003675', ('222', '229'))	('mutations', 'Var', (92, 101))	('von Hippel-Lindau tumour', 'Disease', (186, 210))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (103, 126))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 34))	('decreased', 'NegReg', (164, 173))	('pVHL', 'Gene', (231, 235))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('promoter hypermethylation', 'Var', (130, 155))	('pVHL', 'Gene', '7428', (231, 235))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('cancers', 'Disease', (58, 65))	('clear cell renal cell carcinoma', 'Disease', (3, 34))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (14, 34))
45062	27774982	Dysfunctional pVHL therefore disrupts proteasomal degradation of HIF-alpha subunits (HIF-1alpha and HIF-2alpha) and increases expression of HIF target genes.	('pVHL', 'Gene', '7428', (14, 18))	('HIF-alpha', 'Gene', (65, 74))	('pVHL', 'Gene', (14, 18))	('expression', 'MPA', (126, 136))	('degradation', 'biological_process', 'GO:0009056', ('50', '61'))	('HIF-alpha', 'Gene', '43580', (65, 74))	('increases', 'PosReg', (116, 125))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (85, 110))	('disrupts', 'NegReg', (29, 37))	('Dysfunctional', 'Var', (0, 13))	('proteasomal degradation', 'MPA', (38, 61))
45063	27774982	VHL mutations are considered to be 'truncal' mutations in ccRCC and HIF stabilization can already be detected in early pre-cancerous lesions in tubular segments bearing biallelic VHL mutations within kidneys of patients with von Hippel-Lindau disease.	('cancerous lesions', 'Disease', 'MESH:D009062', (123, 140))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('pre', 'molecular_function', 'GO:0003904', ('119', '122'))	('cancerous lesions', 'Disease', (123, 140))	('patients', 'Species', '9606', (211, 219))	('mutations', 'Var', (183, 192))	('RCC', 'Disease', (60, 63))	('von Hippel-Lindau disease', 'Disease', (225, 250))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('VHL', 'Gene', (179, 182))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (225, 250))	('mutations', 'Var', (4, 13))
45065	27774982	In this context, genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) that are specifically associated with renal cancer susceptibility.	('single-nucleotide polymorphisms', 'Var', (65, 96))	('associated', 'Reg', (126, 136))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('renal cancer', 'Disease', (142, 154))	('renal cancer', 'Disease', 'MESH:D007680', (142, 154))	('renal cancer', 'Phenotype', 'HP:0009726', (142, 154))
45066	27774982	So far, two genetic regions with ccRCC-related SNPs may have an impact on the VHL-HIF signalling axis.	('RCC', 'Disease', (35, 38))	('SNPs', 'Var', (47, 51))	('impact', 'Reg', (64, 70))	('VHL-HIF', 'Disease', (78, 85))	('signalling', 'biological_process', 'GO:0023052', ('86', '96'))	('VHL-HIF', 'Disease', 'MESH:D006623', (78, 85))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
45067	27774982	SNPs on chromosome 2 are located within the first intron of the EPAS1 gene coding for HIF-2alpha and SNPs on chromosome 11 associate with a HIF-2-binding enhancer, which trans-activates the CCND1 oncogene.	('CCND1', 'Gene', (190, 195))	('HIF-2alpha', 'Gene', (86, 96))	('EPAS1', 'Gene', '2034', (64, 69))	('binding', 'molecular_function', 'GO:0005488', ('146', '153'))	('EPAS1', 'Gene', (64, 69))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('HIF-2alpha', 'Gene', '2034', (86, 96))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))	('CCND1', 'Gene', '595', (190, 195))	('trans-activates', 'PosReg', (170, 185))	('SNPs', 'Var', (101, 105))
45069	27774982	rs35252396 is strongly associated with renal cancer risk in Icelandic and other populations of European descent (odds ratio 1.27, P-value 5.4 x 10-11, minor allele frequency 0.46 in the combined analysis).	('renal cancer', 'Disease', 'MESH:D007680', (39, 51))	('renal cancer', 'Phenotype', 'HP:0009726', (39, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('renal cancer', 'Disease', (39, 51))	('associated', 'Reg', (23, 33))	('rs35252396', 'Mutation', 'rs35252396', (0, 10))	('rs35252396', 'Var', (0, 10))
45071	27774982	MYC orchestrates metabolic and growth-promoting pathways, and dysregulation is a hallmark of tumour initiation.	('MYC', 'Gene', (0, 3))	('dysregulation', 'Var', (62, 75))	('growth-promoting', 'CPA', (31, 47))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('MYC', 'Gene', '4609', (0, 3))	('hallmark of tumour initiation', 'Disease', (81, 110))	('metabolic', 'Pathway', (17, 26))	('hallmark of tumour initiation', 'Disease', 'MESH:D009369', (81, 110))
45073	27774982	Across all cancers, the MYC locus displays the highest susceptibility to somatic copy-number gains and both, MYC and PVT1, are co-amplified in most cases (>98%).	('MYC', 'Gene', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('copy-number gains', 'Var', (81, 98))	('MYC', 'Gene', '4609', (109, 112))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('PVT1', 'Gene', (117, 121))	('cancers', 'Disease', (11, 18))	('MYC', 'Gene', '4609', (24, 27))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('MYC', 'Gene', (109, 112))	('PVT1', 'Gene', '5820', (117, 121))
45076	27774982	Despite this high density of multiple cancer-associated variants in the 8q24.21 region, functional analyses have mainly been restricted to the SNP rs6983267, which is associated with colorectal and prostate cancer.	('rs6983267', 'Var', (147, 156))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (207, 213))	('rs6983267', 'Mutation', 'rs6983267', (147, 156))	('variants', 'Var', (56, 64))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', (38, 44))	('colorectal and prostate cancer', 'Disease', 'MESH:D015179', (183, 213))	('associated', 'Reg', (167, 177))	('prostate cancer', 'Phenotype', 'HP:0012125', (198, 213))
45078	27774982	However, the renal cancer-associated variant rs35252396 observed in the Icelandic population is not in linkage with any other disease-associated SNP in the 8q24.21 region (r2<0.02) (ref.	('renal cancer', 'Disease', (13, 25))	('renal cancer', 'Phenotype', 'HP:0009726', (13, 25))	('renal cancer', 'Disease', 'MESH:D007680', (13, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('rs35252396', 'Mutation', 'rs35252396', (45, 55))	('rs35252396', 'Var', (45, 55))
45080	27774982	In contrast with many other cancers, copy-number gains at the MYC locus are relatively infrequent in ccRCC.	('cancers', 'Disease', (28, 35))	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('copy-number gains', 'Var', (37, 54))	('MYC', 'Gene', (62, 65))	('RCC', 'Disease', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('MYC', 'Gene', '4609', (62, 65))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('cancers', 'Disease', 'MESH:D009369', (28, 35))
45081	27774982	As a first step in analysing mechanisms associated with variant rs35252396, we therefore sought to define the frequency of dysregulated MYC and PVT1 expression in renal cancer.	('MYC', 'Gene', (136, 139))	('variant rs35252396', 'Var', (56, 74))	('renal cancer', 'Disease', (163, 175))	('PVT1', 'Gene', (144, 148))	('MYC', 'Gene', '4609', (136, 139))	('rs35252396', 'Mutation', 'rs35252396', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('renal cancer', 'Phenotype', 'HP:0009726', (163, 175))	('PVT1', 'Gene', '5820', (144, 148))	('renal cancer', 'Disease', 'MESH:D007680', (163, 175))
45083	27774982	In line with the results from RNA analyses, positive MYC protein staining was strongly associated with the clear cell phenotype in a tissue microarray containing 453 unselected renal cancer specimens (Erlangen RCC Cohort, Supplementary Fig.	('renal cancer', 'Disease', 'MESH:D007680', (177, 189))	('RCC', 'Disease', (210, 213))	('MYC', 'Gene', '4609', (53, 56))	('RCC', 'Disease', 'MESH:C538614', (210, 213))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('RNA', 'cellular_component', 'GO:0005562', ('30', '33'))	('clear cell phenotype', 'Disease', (107, 127))	('associated with', 'Reg', (87, 102))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('renal cancer', 'Disease', (177, 189))	('MYC', 'Gene', (53, 56))	('positive', 'Var', (44, 52))	('renal cancer', 'Phenotype', 'HP:0009726', (177, 189))
45085	27774982	In pVHL re-expressing RCC4 cells with low HIF, levels of both transcripts were reduced compared with the pVHL-defective parental cells (Fig.	('pVHL', 'Gene', '7428', (3, 7))	('levels of both transcripts', 'MPA', (47, 73))	('reduced', 'NegReg', (79, 86))	('pVHL', 'Gene', (3, 7))	('pVHL', 'Gene', '7428', (105, 109))	('pVHL', 'Gene', (105, 109))	('low', 'Var', (38, 41))	('RCC4', 'Gene', '84925', (22, 26))	('RCC4', 'Gene', (22, 26))
45086	27774982	When exposed to the hypoxia mimetic and HIF stabilizer dimethyl oxalylglycine (DMOG), we measured an increase of MYC and PVT1 RNA in pVHL re-expressing RCC4 transfectants, whereas no difference was determined in the respective pVHL-defective cells (Fig.	('PVT1', 'Gene', '5820', (121, 125))	('RNA', 'cellular_component', 'GO:0005562', ('126', '129'))	('transfectants', 'Var', (157, 170))	('MYC', 'Gene', (113, 116))	('pVHL', 'Gene', '7428', (133, 137))	('pVHL', 'Gene', '7428', (227, 231))	('increase', 'PosReg', (101, 109))	('MYC', 'Gene', '4609', (113, 116))	('pVHL', 'Gene', (227, 231))	('RCC4', 'Gene', '84925', (152, 156))	('hypoxia', 'Disease', (20, 27))	('hypoxia', 'Disease', 'MESH:D000860', (20, 27))	('RCC4', 'Gene', (152, 156))	('PVT1', 'Gene', (121, 125))	('DMOG', 'Chemical', 'MESH:C040947', (79, 83))	('dimethyl oxalylglycine', 'Chemical', 'MESH:C040947', (55, 77))	('pVHL', 'Gene', (133, 137))
45094	27774982	To directly examine the role of HIF in MYC/PVT1 regulation, we performed short interfering RNA (siRNA)-mediated knockdown of HIF-alpha subunits in pVHL-competent RCC cells.	('pVHL', 'Gene', (147, 151))	('PVT1', 'Gene', (43, 47))	('RCC', 'Disease', (162, 165))	('HIF-alpha', 'Gene', '43580', (125, 134))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('MYC', 'Gene', '4609', (39, 42))	('HIF-alpha', 'Gene', (125, 134))	('PVT1', 'Gene', '5820', (43, 47))	('regulation', 'biological_process', 'GO:0065007', ('48', '58'))	('knockdown', 'Var', (112, 121))	('MYC', 'Gene', (39, 42))	('RNA', 'cellular_component', 'GO:0005562', ('91', '94'))	('pVHL', 'Gene', '7428', (147, 151))
45095	27774982	In pVHL re-expressing RCC4 or 786-O and VHL wild-type RCC L34 cells, induction of MYC and PVT1 by DMOG was significantly reduced after HIF depletion (Fig.	('pVHL', 'Gene', '7428', (3, 7))	('PVT1', 'Gene', '5820', (90, 94))	('pVHL', 'Gene', (3, 7))	('RCC', 'Disease', (22, 25))	('RCC', 'Disease', (54, 57))	('reduced', 'NegReg', (121, 128))	('RCC', 'Disease', 'MESH:C538614', (22, 25))	('MYC', 'Gene', '4609', (82, 85))	('RCC4', 'Gene', '84925', (22, 26))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('DMOG', 'Chemical', 'MESH:C040947', (98, 102))	('induction', 'MPA', (69, 78))	('PVT1', 'Gene', (90, 94))	('DMOG', 'Var', (98, 102))	('L34', 'CellLine', 'CVCL:J663', (58, 61))	('MYC', 'Gene', (82, 85))	('RCC4', 'Gene', (22, 26))
45099	27774982	Inspection of epigenetic data from our laboratories and the ENCODE consortium revealed enriched signals for open (FAIRE, formaldehyde-assisted isolation of regulatory elements) and active chromatin (H3K4me1 and H3K27ac) at this site in pVHL-defective 786-O cells that are homozygous for the risk allele at rs35252396 (Fig.	('chromatin', 'cellular_component', 'GO:0000785', ('188', '197'))	('pVHL', 'Gene', (236, 240))	('H3K27ac', 'Var', (211, 218))	('formaldehyde', 'Chemical', 'MESH:D005557', (121, 133))	('pVHL', 'Gene', '7428', (236, 240))	('rs35252396', 'Mutation', 'rs35252396', (306, 316))	('rs35252396', 'Var', (306, 316))
45107	27774982	Further confirming the transactivation potential of this site, MYC and PVT1 RNA expression was significantly reduced by 40% and 32%, respectively, in comparison with the control HPRT gene, in cells with mutations that affected the HRE when compared with non-mutant clones of cells (Fig.	('MYC', 'Gene', (63, 66))	('PVT1', 'Gene', (71, 75))	('RNA', 'cellular_component', 'GO:0005562', ('76', '79'))	('HPRT', 'Gene', '3251', (178, 182))	('MYC', 'Gene', '4609', (63, 66))	('transactivation potential', 'MPA', (23, 48))	('PVT1', 'Gene', '5820', (71, 75))	('HPRT', 'molecular_function', 'GO:0004422', ('178', '182'))	('expression', 'MPA', (80, 90))	('reduced', 'NegReg', (109, 116))	('HPRT', 'Gene', (178, 182))	('mutations', 'Var', (203, 212))	('transactivation', 'biological_process', 'GO:2000144', ('23', '38'))
45115	27774982	For these experiments, we identified primary tubular cells as well as pVHL-defective RCC4 and RCC L13 renal cancer cells that are heterozygous for rs35252396.	('renal cancer', 'Disease', (102, 114))	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (94, 97))	('RCC4', 'Gene', (85, 89))	('renal cancer', 'Phenotype', 'HP:0009726', (102, 114))	('pVHL', 'Gene', '7428', (70, 74))	('RCC4', 'Gene', '84925', (85, 89))	('pVHL', 'Gene', (70, 74))	('renal cancer', 'Disease', 'MESH:D007680', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', (85, 88))	('rs35252396', 'Mutation', 'rs35252396', (147, 157))	('rs35252396', 'Var', (147, 157))
45116	27774982	In genotype-specific qPCR assays, the risk allele at rs35252396 was significantly enriched in chromatin fragments that bound HIF and had marks of active chromatin (Fig.	('bound', 'Interaction', (119, 124))	('rs35252396', 'Mutation', 'rs35252396', (53, 63))	('rs35252396', 'Var', (53, 63))	('chromatin', 'cellular_component', 'GO:0000785', ('153', '162'))	('active', 'MPA', (146, 152))	('chromatin', 'cellular_component', 'GO:0000785', ('94', '103'))	('HIF', 'Protein', (125, 128))
45122	27774982	To examine this, we identified primary renal tubular cells from 12 individuals who are heterozygous for rs11604, a SNP in the coding region of PVT1.	('rs11604', 'Mutation', 'rs11604', (104, 111))	('PVT1', 'Gene', (143, 147))	('PVT1', 'Gene', '5820', (143, 147))	('rs11604', 'Var', (104, 111))
45129	27774982	rs35252396 was not genotyped in this cohort, but we identified SNPs in the TCGA cohort (rs10111989, rs4733579 and rs17775239) that were genotyped and are in LD with rs35252396 (ref.).	('rs35252396', 'Var', (165, 175))	('rs17775239', 'Mutation', 'rs17775239', (114, 124))	('rs10111989', 'Var', (88, 98))	('rs17775239', 'Var', (114, 124))	('rs35252396', 'Mutation', 'rs35252396', (0, 10))	('rs4733579', 'Mutation', 'rs4733579', (100, 109))	('CG', 'Chemical', 'MESH:C028505', (76, 78))	('rs4733579', 'Var', (100, 109))	('rs10111989', 'Mutation', 'rs10111989', (88, 98))	('rs35252396', 'Mutation', 'rs35252396', (165, 175))
45130	27774982	Analysis of genotype expression correlations revealed that the risk allele of SNP rs10111989 (pairwise LD with rs35252396: r2=0.33, D'=0.98 (ref.))	('rs35252396', 'Mutation', 'rs35252396', (111, 121))	('rs35252396', 'Var', (111, 121))	('rs10111989', 'Mutation', 'rs10111989', (82, 92))	('rs10111989', 'Var', (82, 92))	('SNP', 'Gene', (78, 81))
45133	27774982	Though this analysis itself cannot implicate any specific polymorphism in the regulation of MYC in renal cancer, it is consistent with the data above implicating an rs35252396-associated phenotype.	('regulation', 'biological_process', 'GO:0065007', ('78', '88'))	('rs35252396-associated', 'Var', (165, 186))	('renal cancer', 'Disease', 'MESH:D007680', (99, 111))	('MYC', 'Gene', '4609', (92, 95))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('renal cancer', 'Disease', (99, 111))	('MYC', 'Gene', (92, 95))	('rs35252396', 'Mutation', 'rs35252396', (165, 175))	('renal cancer', 'Phenotype', 'HP:0009726', (99, 111))
45135	27774982	HIF binding, activity and accessibility of the enhancer as well as MYC/PVT1 induction are restricted to cells from renal tubular origin and dependent on the genotype of rs35252396, a polymorphism associated with renal cancer susceptibility.	('renal cancer', 'Disease', (212, 224))	('MYC', 'Gene', '4609', (67, 70))	('PVT1', 'Gene', (71, 75))	('rs35252396', 'Mutation', 'rs35252396', (169, 179))	('renal cancer', 'Disease', 'MESH:D007680', (212, 224))	('binding', 'Interaction', (4, 11))	('rs35252396', 'Var', (169, 179))	('renal cancer', 'Phenotype', 'HP:0009726', (212, 224))	('MYC', 'Gene', (67, 70))	('PVT1', 'Gene', '5820', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('activity', 'MPA', (13, 21))	('binding', 'molecular_function', 'GO:0005488', ('4', '11'))
45137	27774982	Modulation of HIF activity and MYC/PVT1 expression by polymorphisms located in this intergenic region could then promote or retard renal tumorigenesis.	('expression', 'MPA', (40, 50))	('polymorphisms', 'Var', (54, 67))	('Modulation', 'Var', (0, 10))	('PVT1', 'Gene', '5820', (35, 39))	('retard renal tumorigenesis', 'Disease', (124, 150))	('MYC', 'Gene', (31, 34))	('promote', 'PosReg', (113, 120))	('retard renal tumorigenesis', 'Disease', 'MESH:D007674', (124, 150))	('MYC', 'Gene', '4609', (31, 34))	('PVT1', 'Gene', (35, 39))
45138	27774982	That many of the currently known renal cancer-associated SNPs (EPAS1, CCND1 and MYC/PVT1) can be linked to modulation of a single pathway (that is, the HIF pathway) is striking and to our knowledge unique in tumour biology.	('renal cancer', 'Disease', 'MESH:D007680', (33, 45))	('MYC', 'Gene', '4609', (80, 83))	('tumour', 'Disease', (208, 214))	('modulation', 'Var', (107, 117))	('EPAS1', 'Gene', '2034', (63, 68))	('CCND1', 'Gene', '595', (70, 75))	('EPAS1', 'Gene', (63, 68))	('PVT1', 'Gene', '5820', (84, 88))	('renal cancer', 'Phenotype', 'HP:0009726', (33, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('MYC', 'Gene', (80, 83))	('renal cancer', 'Disease', (33, 45))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('tumour', 'Disease', 'MESH:D009369', (208, 214))	('CCND1', 'Gene', (70, 75))	('PVT1', 'Gene', (84, 88))
45140	27774982	We conclude that the predisposing or protective effects of renal cancer-associated polymorphisms are explained at least in part by their ability to promote or inhibit, respectively, HIF expression or HIF-mediated transactivation of key oncogenic pathways.	('renal cancer', 'Disease', (59, 71))	('renal cancer', 'Phenotype', 'HP:0009726', (59, 71))	('HIF', 'Protein', (182, 185))	('transactivation', 'CPA', (213, 228))	('renal cancer', 'Disease', 'MESH:D007680', (59, 71))	('polymorphisms', 'Var', (83, 96))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('transactivation', 'biological_process', 'GO:2000144', ('213', '228'))	('key oncogenic pathways', 'Pathway', (232, 254))	('expression', 'MPA', (186, 196))	('promote', 'PosReg', (148, 155))	('inhibit', 'NegReg', (159, 166))
45165	27774982	After transferring the proteins onto polyvinylidene difluoride membranes, HIF or MYC proteins were detected using anti-HIF-1alpha (1:1,000, rabbit polyclonal, Cayman Chemicals, Cay10006421), anti-HIF-2alpha (1:1,000 goat polyclonal, R/D, AF2997) and anti-MYC (1:1,000, rabbit monoclonal (Y69), Abcam, ab32072) antibodies.	('anti-HIF-1alpha', 'Var', (114, 129))	('transferrin', 'Gene', '7018', (6, 17))	('rabbit', 'Species', '9986', (269, 275))	('transferrin', 'Gene', (6, 17))	('HIF-2alpha', 'Gene', '2034', (196, 206))	('MYC', 'Gene', '4609', (81, 84))	('goat', 'Species', '9925', (216, 220))	('MYC', 'Gene', '4609', (255, 258))	('MYC', 'Gene', (81, 84))	('rabbit', 'Species', '9986', (140, 146))	('HIF-2alpha', 'Gene', (196, 206))	('MYC', 'Gene', (255, 258))	('polyvinylidene difluoride', 'Chemical', 'MESH:C024865', (37, 62))
45174	27774982	We used data from a meta-analysis of UK and NCI RCC cohorts to identify risk variants of SNPs in the 8q24.21 region that are in LD with rs35252396 (C for rs10111989, P<0.05; G for rs4733579, P<0.01; A for rs17775239).	('rs17775239', 'Mutation', 'rs17775239', (205, 215))	('rs10111989', 'Mutation', 'rs10111989', (154, 164))	('SNPs', 'Gene', (89, 93))	('rs35252396', 'Mutation', 'rs35252396', (136, 146))	('rs35252396', 'Var', (136, 146))	('NCI RCC', 'Disease', 'MESH:C538614', (44, 51))	('rs4733579', 'Mutation', 'rs4733579', (180, 189))	('NCI RCC', 'Disease', (44, 51))
45176	27774982	SNP reference rs10111989 was mapped to SNP_A-8366368, rs4733579 to SNP_A-8558309 and rs17775239 to SNP_A-8682521 in the Affymetrix array.	('rs17775239', 'Mutation', 'rs17775239', (85, 95))	('rs4733579', 'Mutation', 'rs4733579', (54, 63))	('rs17775239', 'Var', (85, 95))	('rs10111989', 'Mutation', 'rs10111989', (14, 24))	('rs4733579', 'Var', (54, 63))
45185	27774982	Genomic DNA of clones of cells with putative indel mutations was PCR amplified and cloned into pGL3 vector (Promega) and subjected to Sanger sequencing.	('pGL3', 'Gene', '6391', (95, 99))	('indel', 'Var', (45, 50))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('pGL3', 'Gene', (95, 99))	('pGL', 'molecular_function', 'GO:0004598', ('95', '98'))
45187	27774982	To identify samples heterozygous for the common and rare alleles at rs35252396 and rs11604, DNA from cell lines and primary tubular cells was genotyped using customized Taqman assays (Life Technologies).	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('rs35252396', 'Mutation', 'rs35252396', (68, 78))	('rs11604', 'Mutation', 'rs11604', (83, 90))	('rs35252396', 'Var', (68, 78))	('rs11604', 'Var', (83, 90))
45188	27774982	Homozygous cell lines for both alleles were used as positive controls (rs35252396: AC/AC-Caki1 cells, CG/CG-786-O cells; rs11604: T/T-RCC L15, C/C-RCC L13) in all allele-specific assays.	('CG', 'Chemical', 'MESH:C028505', (105, 107))	('CG', 'Chemical', 'MESH:C028505', (102, 104))	('rs35252396', 'Mutation', 'rs35252396', (71, 81))	('AC', 'Chemical', 'MESH:D000186', (83, 85))	('AC', 'Chemical', 'MESH:D000186', (86, 88))	('L15, C/C-RCC L13', 'Gene', '28901', (138, 154))	('rs11604', 'Mutation', 'rs11604', (121, 128))	('RCC', 'Disease', (147, 150))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('RCC', 'Disease', (134, 137))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('rs11604', 'Var', (121, 128))
45197	27774982	Antibodies were anti-MYC (1:200, rabbit monoclonal (Y69), Abcam, ab32072), anti-HIF-1alpha (1:10,000, rabbit polyclonal, Cayman Chemicals, Cay10006421) and anti-HIF-2alpha (1:10,000, rabbit polyclonal, PM8), and were applied after an antigen retrieval procedure (Dako).	('HIF-2alpha', 'Gene', '2034', (161, 171))	('rabbit', 'Species', '9986', (183, 189))	('rabbit', 'Species', '9986', (33, 39))	('HIF-2alpha', 'Gene', (161, 171))	('PM8', 'Species', '1214577', (202, 205))	('MYC', 'Gene', '4609', (21, 24))	('rabbit', 'Species', '9986', (102, 108))	('Cay10006421', 'Var', (139, 150))	('MYC', 'Gene', (21, 24))
45203	27774982	After quantile normalization, signals for Myc, Pvt1 and Egln3 were compared between tubular-specific VHL knockout and control mice.	('VHL', 'Gene', (101, 104))	('Pvt1', 'Gene', '19296', (47, 51))	('mice', 'Species', '10090', (126, 130))	('knockout', 'Var', (105, 113))	('Egln3', 'Gene', (56, 61))	('Pvt1', 'Gene', (47, 51))	('Myc', 'Gene', (42, 45))	('Myc', 'Gene', '17869', (42, 45))	('Egln3', 'Gene', '112407', (56, 61))
45206	27774982	Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer.	('renal cancer', 'Disease', 'MESH:D007680', (33, 45))	('Genetic variation', 'Var', (0, 17))	('affects', 'Reg', (67, 74))	('MYC', 'Gene', '4609', (92, 95))	('binding', 'molecular_function', 'GO:0005488', ('79', '86'))	('HIF binding', 'Interaction', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('renal cancer', 'Disease', (33, 45))	('renal cancer', 'Phenotype', 'HP:0009726', (33, 45))	('MYC', 'Gene', (92, 95))
45213	31582532	In our metastatic ccRCC PDX model, RP-R-02LM, trebananib alone and in combination with a MET kinase inhibitor significantly reduced lung metastases and M2 macrophage infiltration (p=0.0075 and p=0.0205 respectively).	('kinase inhibitor', 'biological_process', 'GO:0033673', ('93', '109'))	('reduced', 'NegReg', (124, 131))	('M2 macrophage infiltration', 'CPA', (152, 178))	('lung metastases', 'Disease', (132, 147))	('lung metastases', 'Disease', 'MESH:D009362', (132, 147))	('ccRCC', 'Phenotype', 'HP:0006770', (18, 23))	('RP-R-02LM', 'Var', (35, 44))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('RCC', 'Disease', (20, 23))
45220	31582532	Among those patients diagnosed with sporadic ccRCC, the majority has loss of function mutations in the VHL (von Hippel-Landau) tumor suppressor gene resulting in an inability to functionally degrade the transcription factors HIFs (hypoxia inducible factors).	('hypoxia', 'Disease', 'MESH:D000860', (231, 238))	('mutations', 'Var', (86, 95))	('patients', 'Species', '9606', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('HIFs', 'Disease', 'None', (225, 229))	('transcription', 'biological_process', 'GO:0006351', ('203', '216'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('127', '143'))	('hypoxia', 'Disease', (231, 238))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('127', '143'))	('HIFs', 'Disease', (225, 229))	('loss of function', 'NegReg', (69, 85))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('VHL (von Hippel-Landau) tumor', 'Disease', 'MESH:D006623', (103, 132))	('RCC', 'Disease', (47, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('degrade', 'NegReg', (191, 198))
45234	31582532	Preclinical studies in colorectal cancer, breast cancer, and melanoma models have shown that inhibition of Ang2 resulted in reduced blood vessels, increased pericyte coverage, blood vessel stabilization, and altered EMT pathway activation.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Ang2', 'Gene', (107, 111))	('blood vessels', 'CPA', (132, 145))	('pericyte coverage', 'CPA', (157, 174))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('altered', 'Reg', (208, 215))	('colorectal cancer', 'Disease', 'MESH:D015179', (23, 40))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('EMT', 'biological_process', 'GO:0001837', ('216', '219'))	('EMT pathway', 'CPA', (216, 227))	('colorectal cancer', 'Disease', (23, 40))	('increased', 'PosReg', (147, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('activation', 'PosReg', (228, 238))	('reduced', 'NegReg', (124, 131))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Disease', (42, 55))	('colorectal cancer', 'Phenotype', 'HP:0003003', (23, 40))	('inhibition', 'Var', (93, 103))	('blood vessel stabilization', 'CPA', (176, 202))
45237	31582532	Recent reviews of MET addicted tumors indicate that MET/HGF inhibitors impact both the stroma and cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('MET/HGF', 'Gene', '15234', (52, 59))	('impact', 'Reg', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('addicted tumors', 'Disease', 'MESH:D000437', (22, 37))	('MET/HGF', 'Gene', (52, 59))	('inhibitors', 'Var', (60, 70))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('addicted tumors', 'Disease', (22, 37))
45242	31582532	The concept of combining inhibitors of both the MET and Ang/Tie2 pathways as treatment for metastatic ccRCC is postulated to be efficacious on both the tumor niche and the TME.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('tumor', 'Disease', (152, 157))	('inhibitors', 'Var', (25, 35))	('Ang', 'Gene', (56, 59))	('Ang', 'Gene', '11727', (56, 59))	('men', 'Species', '9606', (82, 85))	('RCC', 'Disease', (104, 107))
45254	31582532	Upon arrival and acclimation mice were implanted orthotopically or subcutaneously (~1mm2 tumor piece) with RP-R-01, RP-R-02, or RP-R02LM which, were established from the skin metastasis of a patient with sporadic ccRCC which developed sunitinib resistance and skin metastasis from a patient with hereditary VHL syndrome ccRCC, respectively.	('RP-R02LM', 'Var', (128, 136))	('RP-R-01', 'Var', (107, 114))	('hereditary VHL syndrome ccRCC', 'Disease', (296, 325))	('patient', 'Species', '9606', (191, 198))	('RCC', 'Disease', 'MESH:C538614', (215, 218))	('ccRCC', 'Phenotype', 'HP:0006770', (213, 218))	('RCC', 'Disease', (215, 218))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('RCC', 'Disease', 'MESH:C538614', (322, 325))	('hereditary VHL syndrome ccRCC', 'Disease', 'MESH:D006623', (296, 325))	('RCC', 'Disease', (322, 325))	('sunitinib', 'Chemical', 'MESH:D000077210', (235, 244))	('mice', 'Species', '10090', (29, 33))	('patient', 'Species', '9606', (283, 290))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (320, 325))
45284	31582532	The PDX models have been detailed previously as maintaining their original clear cell morphology, VHL-negative status, human Alu positive status, and containing common ccRCC gene mutations.	('Alu', 'Chemical', '-', (125, 128))	('RCC', 'Disease', (170, 173))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('ccRCC', 'Phenotype', 'HP:0006770', (168, 173))	('mutations', 'Var', (179, 188))	('human', 'Species', '9606', (119, 124))
45288	31582532	Our preliminary experiments assessed the primary tumor growth of RP-R-01, RP-R-02LM (intrinsically sunitinib resistant) and RENCA-Luc tumors.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumors', 'Disease', (134, 140))	('RP-R-02LM', 'Var', (74, 83))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('men', 'Species', '9606', (22, 25))	('RP-R-01', 'Var', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('sunitinib', 'Chemical', 'MESH:D000077210', (99, 108))	('tumor', 'Disease', (134, 139))
45297	31582532	In summary, these data suggest that inhibition of the angiopoietin-TIE2-MET kinase axis may result in tumor microenvironment alterations which may hinder tumor metastasis.	('inhibition', 'Var', (36, 46))	('hinder', 'NegReg', (147, 153))	('result in', 'Reg', (92, 101))	('tumor metastasis', 'Disease', 'MESH:D009362', (154, 170))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor metastasis', 'Disease', (154, 170))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('men', 'Species', '9606', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', (154, 159))
45306	31582532	In addition, we observed a significant delay in the development of lung metastases in the combination cohort and strikingly less macro-metastases in the trebananib and combination cohorts as compared to the control and MET kinase inhibitor cohorts congruent with our initial studies (Supplementary Figure S4).	('metastases', 'Disease', (72, 82))	('combination', 'Var', (168, 179))	('metastases', 'Disease', (135, 145))	('metastases', 'Disease', 'MESH:D009362', (72, 82))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('223', '239'))	('metastases', 'Disease', 'MESH:D009362', (135, 145))	('lung metastases', 'Disease', 'MESH:D009362', (67, 82))	('lung metastases', 'Disease', (67, 82))	('men', 'Species', '9606', (290, 293))	('delay', 'NegReg', (39, 44))	('less', 'NegReg', (124, 128))	('men', 'Species', '9606', (59, 62))
45319	31582532	We also examined p-STAT3, a marker of aggressiveness and proliferation, and noted that while there was an overall trend of p-STAT3 inhibition in the single agent and combination groups, there was no significant change from the vehicle (Supplemental Figure S7D).	('aggressiveness', 'Disease', 'MESH:D001523', (38, 52))	('STAT3', 'Gene', (125, 130))	('STAT3', 'Gene', '20848', (19, 24))	('STAT3', 'Gene', '20848', (125, 130))	('aggressiveness', 'Disease', (38, 52))	('men', 'Species', '9606', (242, 245))	('STAT3', 'Gene', (19, 24))	('combination', 'Var', (166, 177))	('aggressiveness', 'Phenotype', 'HP:0000718', (38, 52))	('inhibition', 'NegReg', (131, 141))
45331	31582532	Taken together, these data indicate that inhibition of the angiopoietin-TIE2-MET axis in our PDX model stabilizes blood vessels in the primary tumor and potently inhibits tumor cells metastases.	('tumor', 'Disease', (143, 148))	('metastases', 'Disease', (183, 193))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('stabilizes blood vessels', 'CPA', (103, 127))	('inhibits', 'NegReg', (162, 170))	('inhibition', 'Var', (41, 51))	('metastases', 'Disease', 'MESH:D009362', (183, 193))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
45342	31582532	Additionally, inhibition of MET has been shown to be sufficient to subdue HGF dependent migration and downstream targets, such as ERK and AKT.	('AKT', 'Gene', '11651', (138, 141))	('ERK', 'molecular_function', 'GO:0004707', ('130', '133'))	('subdue', 'NegReg', (67, 73))	('AKT', 'Gene', (138, 141))	('MET', 'Gene', (28, 31))	('ERK', 'Gene', (130, 133))	('HGF', 'Gene', '15234', (74, 77))	('inhibition', 'Var', (14, 24))	('ERK', 'Gene', '26413', (130, 133))	('HGF', 'Gene', (74, 77))
45348	31582532	In contrast, trebananib treatment combined with MET kinase inhibition in our metastatic PDX model, RP-R-02LM, not only decreased the presence of tumor metastases to the lungs but also significantly enhanced survival.	('tumor metastases', 'Disease', 'MESH:D009362', (145, 161))	('decreased', 'NegReg', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('RP-R-02LM', 'Var', (99, 108))	('men', 'Species', '9606', (29, 32))	('survival', 'CPA', (207, 215))	('enhanced', 'PosReg', (198, 206))	('tumor metastases', 'Disease', (145, 161))
45349	31582532	In our initial short term treatment study with the highly metastatic RP-R-02LM model, we noted a significant decrease in metastases to the lungs, indicating that we were impairing the metastatic potential of the tumor.	('decrease', 'NegReg', (109, 117))	('metastases', 'Disease', 'MESH:D009362', (121, 131))	('men', 'Species', '9606', (31, 34))	('impairing', 'NegReg', (170, 179))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('RP-R-02LM', 'Var', (69, 78))	('tumor', 'Disease', (212, 217))	('metastases', 'Disease', (121, 131))
45350	31582532	In our orthotropic study, we noted that when RP-R-02LM tumor pieces were implanted into the kidney and treated for at least 4 months a significant improvement in survival in the combination groups were observed.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('improvement', 'PosReg', (147, 158))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('men', 'Species', '9606', (154, 157))	('survival', 'CPA', (162, 170))	('RP-R-02LM', 'Var', (45, 54))
45359	31582532	These results further emphasize the potential of MET kinase and angiopoietin inhibition to affect the tumor microenvironment in a manner that significantly inhibits the metastatic phenotype of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (193, 198))	('inhibition', 'Var', (77, 87))	('metastatic phenotype', 'CPA', (169, 189))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('affect', 'Reg', (91, 97))	('inhibits', 'NegReg', (156, 164))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('RCC', 'Disease', (195, 198))	('men', 'Species', '9606', (120, 123))
45368	28386724	Shaping the Cellular Landscape with Set2/SETD2 Methylation Chromatin structure is a major barrier to gene transcription that must be disrupted and re-set during each round of transcription.	('Chromatin', 'cellular_component', 'GO:0000785', ('59', '68'))	('transcription', 'biological_process', 'GO:0006351', ('175', '188'))	('Set2', 'Gene', (36, 40))	('SETD2', 'Gene', '29072', (41, 46))	('Methylation', 'biological_process', 'GO:0032259', ('47', '58'))	('transcription', 'biological_process', 'GO:0006351', ('106', '119'))	('Set2', 'Gene', '853271', (36, 40))	('Methylation', 'Var', (47, 58))	('SETD2', 'Gene', (41, 46))
45370	28386724	Consistent with the importance of Set2/SETD2 in chromatin biology, mutations of SETD2, or mutations at or near H3K36 in H3.3, have recently been found to underlie cancer development.	('mutations at', 'Var', (90, 102))	('SETD2', 'Gene', (80, 85))	('mutations', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('underlie', 'Reg', (154, 162))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('chromatin', 'cellular_component', 'GO:0000785', ('48', '57'))
45383	28386724	For example, in Drosophila melanogaster, dMes-4 is responsible for H3K36me1 and H3K36me2, whereas dSet2 is primarily responsible for H3K36me3.	('dMes-4', 'Gene', '37560', (41, 47))	('Drosophila melanogaster', 'Species', '7227', (16, 39))	('H3K36me1', 'Var', (67, 75))	('dSet2', 'Gene', (98, 103))	('dSet2', 'Gene', '32301', (98, 103))	('responsible', 'Reg', (51, 62))	('dMes-4', 'Gene', (41, 47))	('H3K36me2', 'Var', (80, 88))
45384	28386724	In humans, NSD1, NSD2, NSD3, SETMAR, SMYD2 and ASH1L are responsible for mediating H3K36me1 and H3K36me2, and SETD2, the human Set2 homolog, mediates H3K36me3.	('SETD2', 'Gene', (110, 115))	('NSD1', 'Gene', '64324', (11, 15))	('NSD2', 'Gene', (17, 21))	('ASH1L', 'Gene', (47, 52))	('NSD3', 'Gene', (23, 27))	('human', 'Species', '9606', (3, 8))	('NSD1', 'Gene', (11, 15))	('SETMAR', 'Gene', (29, 35))	('H3K36me2', 'Var', (96, 104))	('ASH1L', 'Gene', '55870', (47, 52))	('humans', 'Species', '9606', (3, 9))	('SETMAR', 'Gene', '6419', (29, 35))	('human', 'Species', '9606', (121, 126))	('NSD3', 'Gene', '54904', (23, 27))	('SMYD2', 'Gene', '56950', (37, 42))	('NSD2', 'Gene', '7468', (17, 21))	('H3K36me1', 'Var', (83, 91))	('SMYD2', 'Gene', (37, 42))
45385	28386724	Because Set2 is responsible for all H3K36me in yeast, and strains in which SET2 has been deleted are viable, yeast has become a premiere model system for studying the function of H3K36me.	('SET2', 'Gene', (75, 79))	('yeast', 'Species', '4932', (47, 52))	('yeast', 'Species', '4932', (109, 114))	('SET2', 'Gene', '853271', (75, 79))	('deleted', 'Var', (89, 96))
45391	28386724	Notably, a precise deletion of the WW domain in yeast does not affect the association of Set2 with RNAPII or alter H3K36 methylation, thus we speculate that the WW domain participates in the association of Set2 with proteins that contribute to methylation of non-histone substrates (see below).	('methylation', 'biological_process', 'GO:0032259', ('121', '132'))	('methylation', 'MPA', (121, 132))	('methylation', 'biological_process', 'GO:0032259', ('244', '255'))	('deletion', 'Var', (19, 27))	('yeast', 'Species', '4932', (48, 53))	('participates', 'Reg', (171, 183))	('association', 'Interaction', (191, 202))	('association', 'Interaction', (74, 85))	('H3K36', 'Protein', (115, 120))
45396	28386724	Deletion of the AID results in a hyperactive Set2, increasing the amount of H3K36me on nucleosomes and at genes.	('Set2', 'Gene', (45, 49))	('amount', 'MPA', (66, 72))	('AID', 'Disease', (16, 19))	('AID', 'Disease', 'None', (16, 19))	('increasing', 'PosReg', (51, 61))	('hyperactive', 'PosReg', (33, 44))	('H3K36me', 'Protein', (76, 83))	('Deletion', 'Var', (0, 8))
45397	28386724	Further, the AID influences Set2 interactions RNAPII, as AID mutant versions of Set2 are able to bind to the unphosphorylated CTD of RNAPII, whereas wild-type Set2 can bind to only the hyperphosphorylated form of the CTD.	('AID', 'Disease', (13, 16))	('AID', 'Disease', 'None', (57, 60))	('AID', 'Disease', 'None', (13, 16))	('bind', 'Interaction', (97, 101))	('Set2', 'Gene', (80, 84))	('mutant', 'Var', (61, 67))	('AID', 'Disease', (57, 60))
45400	28386724	This domain, which is highly conserved from yeast to humans (Figure 1), binds to serine 2 (Ser2) and serine 5 (Ser5) doubly phosphorylated CTD repeats of RNAPII.	('serine', 'Chemical', 'MESH:D012694', (81, 87))	('Ser', 'cellular_component', 'GO:0005790', ('111', '114'))	('yeast', 'Species', '4932', (44, 49))	('binds', 'Interaction', (72, 77))	('humans', 'Species', '9606', (53, 59))	('Ser', 'cellular_component', 'GO:0005790', ('91', '94'))	('Ser5', 'Chemical', '-', (111, 115))	('RNAPII', 'Gene', (154, 160))	('serine', 'Var', (101, 107))	('serine', 'Chemical', 'MESH:D012694', (101, 107))	('Ser2', 'Chemical', '-', (91, 95))
45403	28386724	In Schizosaccharomyces pombe, however, the SRI domain is completely dispensable for H3K36me2, but is required for H3K36me3 and plays a role in post-transcriptional gene silencing at subtelomeric regions of the genome.	('post-transcriptional gene silencing', 'biological_process', 'GO:0016441', ('143', '178'))	('Schizosaccharomyces pombe', 'Species', '4896', (3, 28))	('H3K36me3', 'Var', (114, 122))	('plays', 'Reg', (127, 132))
45404	28386724	However, mutants of Spt6 and Ctk1 that prevent CTD phosphorylation at Ser2 render chromatin incapable of being trimethylated by full-length recombinant Set2.	('Spt', 'molecular_function', 'GO:0004758', ('20', '23'))	('Ser', 'cellular_component', 'GO:0005790', ('70', '73'))	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('Ctk1', 'Gene', (29, 33))	('CTD phosphorylation', 'MPA', (47, 66))	('Spt', 'molecular_function', 'GO:0004760', ('20', '23'))	('mutants', 'Var', (9, 16))	('chromatin', 'cellular_component', 'GO:0000785', ('82', '91'))	('Ctk1', 'Gene', '853718', (29, 33))	('Spt6', 'Gene', (20, 24))	('Ser2', 'Chemical', '-', (70, 74))
45405	28386724	Early studies in yeast found that deletion of the major kinase complex that mediates Ser2 CTD phosphorylation, CTDK-1 (CDK12 in metazoans), results in an ablation of H3K36 methylation.	('methylation', 'MPA', (172, 183))	('CTDK-1', 'Gene', (111, 117))	('CDK', 'molecular_function', 'GO:0004693', ('119', '122'))	('phosphorylation', 'biological_process', 'GO:0016310', ('94', '109'))	('Ser2', 'Chemical', '-', (85, 89))	('methylation', 'biological_process', 'GO:0032259', ('172', '183'))	('deletion', 'Var', (34, 42))	('Ser', 'cellular_component', 'GO:0005790', ('85', '88'))	('yeast', 'Species', '4932', (17, 22))	('H3K36', 'Protein', (166, 171))	('ablation', 'NegReg', (154, 162))
45406	28386724	Consistent with this finding, deletions of the CTD or mutations of Ser2 residues (but not Ser5) in the CTD also caused a loss of H3K36 methylation.	('H3K36', 'Protein', (129, 134))	('Ser', 'cellular_component', 'GO:0005790', ('90', '93'))	('Ser', 'cellular_component', 'GO:0005790', ('67', '70'))	('loss', 'NegReg', (121, 125))	('Ser5', 'Chemical', '-', (90, 94))	('deletions', 'Var', (30, 39))	('mutations', 'Var', (54, 63))	('methylation', 'MPA', (135, 146))	('Ser2', 'Chemical', '-', (67, 71))	('Ser2', 'Gene', (67, 71))	('methylation', 'biological_process', 'GO:0032259', ('135', '146'))
45410	28386724	Consistent with a role of Ser2 CTD phosphorylation in regulating H3K36me, bur1 temperature sensitive alleles, or a deletion of BUR2 (the Bur1 cyclin), reduce H3K36me3 levels in yeast.	('deletion', 'Var', (115, 123))	('Bur1', 'Gene', '856290', (137, 141))	('Ser', 'cellular_component', 'GO:0005790', ('26', '29'))	('BUR2', 'Gene', '850923', (127, 131))	('yeast', 'Species', '4932', (177, 182))	('Ser2', 'Chemical', '-', (26, 30))	('cyclin', 'molecular_function', 'GO:0016538', ('142', '148'))	('H3K36me', 'Protein', (65, 72))	('Bur1', 'Gene', (137, 141))	('reduce', 'NegReg', (151, 157))	('bur1', 'Gene', '856290', (74, 78))	('phosphorylation', 'biological_process', 'GO:0016310', ('35', '50'))	('bur1', 'Gene', (74, 78))	('BUR2', 'Gene', (127, 131))	('H3K36me3 levels', 'MPA', (158, 173))
45416	28386724	Similar to Ctk1, mutations in Spt6 also reduce Set2 protein stability.	('Spt', 'molecular_function', 'GO:0004758', ('30', '33'))	('reduce', 'NegReg', (40, 46))	('Ctk1', 'Gene', '853718', (11, 15))	('Spt', 'molecular_function', 'GO:0004760', ('30', '33'))	('Spt6', 'Gene', (30, 34))	('Set2 protein', 'Protein', (47, 59))	('mutations', 'Var', (17, 26))	('Ctk1', 'Gene', (11, 15))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
45422	28386724	Specifically, the Paf1 complex is required for H3K36me3 in addition to H2BK123 mono-ubiquitylation (H2BK123ub1) - a chromatin mark that is necessary for H3K4 and H3K79 methylation.	('H2BK123', 'Var', (71, 78))	('methylation', 'biological_process', 'GO:0032259', ('168', '179'))	('H3K36me3', 'Var', (47, 55))	('Paf1 complex', 'cellular_component', 'GO:0016593', ('18', '30'))	('chromatin', 'cellular_component', 'GO:0000785', ('116', '125'))	('Paf1', 'Gene', (18, 22))	('Paf1', 'Gene', '852582', (18, 22))
45423	28386724	In the case of H2BK123ub1, the histone modification domain of Rtf1 (a member of the Paf1 complex that links Paf1 to RNAPII) directly associates with Rad6/Bre1, thus providing a molecular basis for how Paf1 regulates H2Bub1.	('Rtf1', 'Gene', (62, 66))	('Paf1', 'Gene', (84, 88))	('Paf1', 'Gene', '852582', (108, 112))	('Paf1', 'Gene', '852582', (201, 205))	('histone modification', 'biological_process', 'GO:0016570', ('31', '51'))	('Paf1', 'Gene', '852582', (84, 88))	('Rtf1', 'Gene', '852607', (62, 66))	('Paf1 complex', 'cellular_component', 'GO:0016593', ('84', '96'))	('Rad', 'biological_process', 'GO:1990116', ('149', '152'))	('histone modification domain', 'MPA', (31, 58))	('associates', 'Interaction', (133, 143))	('Bre1', 'Gene', (154, 158))	('Rad6', 'Gene', '852822', (149, 153))	('Rad6', 'Gene', (149, 153))	('Paf1', 'Gene', (108, 112))	('Bre1', 'Gene', '851485', (154, 158))	('Paf1', 'Gene', (201, 205))	('H2BK123ub1', 'Var', (15, 25))
45424	28386724	However, in the case of Set2 methylation, the role of Paf1 is likely indirect.	('methylation', 'Var', (29, 40))	('methylation', 'biological_process', 'GO:0032259', ('29', '40'))	('Paf1', 'Gene', (54, 58))	('Set2', 'Gene', (24, 28))	('Paf1', 'Gene', '852582', (54, 58))
45430	28386724	In budding yeast, there are two predominant H3K36me demethylase enzymes, Jhd1, which acts on H3K36me1/2, and Rph1, which acts on H3K36me2/3.	('acts', 'Reg', (85, 89))	('H3K36me demethylase', 'Enzyme', (44, 63))	('Jhd1', 'Gene', '856777', (73, 77))	('H3K36me1/2', 'Var', (93, 103))	('Rph1', 'Gene', (109, 113))	('budding', 'biological_process', 'GO:0007114', ('3', '10'))	('yeast', 'Species', '4932', (11, 16))	('Rph', 'molecular_function', 'GO:0047520', ('109', '112'))	('Rph1', 'Gene', '856916', (109, 113))	('Jhd1', 'Gene', (73, 77))
45437	28386724	The long noncoding RNA HOTAIR can bind to the promoter region of SETD2 and inhibit the recruitment of pro-transcription factors such as CREB, P300, and RNAPII.	('recruitment', 'MPA', (87, 98))	('inhibit', 'NegReg', (75, 82))	('RNA', 'cellular_component', 'GO:0005562', ('19', '22'))	('P300', 'Var', (142, 146))	('SETD2', 'Gene', (65, 70))	('HOTAIR', 'Gene', (23, 29))	('HOTAIR', 'Gene', '100124700', (23, 29))	('transcription', 'biological_process', 'GO:0006351', ('106', '119'))	('bind', 'Interaction', (34, 38))
45440	28386724	Thus, miR-106b-5p and HOTAIR, which themselves play roles in cancer development, may do so also, in part, through SETD2 inactivation and loss of H3K36me3.	('SETD2', 'Gene', (114, 119))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('HOTAIR', 'Gene', (22, 28))	('cancer', 'Disease', (61, 67))	('miR-106b-5p', 'Var', (6, 17))	('loss', 'NegReg', (137, 141))	('HOTAIR', 'Gene', '100124700', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('H3K36me3', 'Protein', (145, 153))	('inactivation', 'NegReg', (120, 132))
45444	28386724	Further, cells deleted for SET2 (set2Delta) show increased H3K56ac at the 3'-ends of genes in G1-arrested cells, indicating increased levels of histone exchange.	('SET2', 'Gene', (27, 31))	('set2Delta', 'Gene', (33, 42))	('SET2', 'Gene', '853271', (27, 31))	('histone exchange', 'biological_process', 'GO:0043486', ('144', '160'))	('increased', 'PosReg', (124, 133))	('increased', 'PosReg', (49, 58))	('levels', 'MPA', (134, 140))	('H3K56ac', 'Var', (59, 66))	('set2Delta', 'Gene', '853271', (33, 42))	('histone exchange', 'MPA', (144, 160))
45446	28386724	Critically, Asf1, and to a lesser extent Spt6 and Spt16, show decreased affinity for peptides that are marked with H3K36me, suggesting a model wherein Set2-mediated H3K36me may actively inhibit histone exchange after transcription by preventing Asf1 (and other histone chaperones) from binding to and removing H3K36me histones (Figure 1B).	('Spt', 'molecular_function', 'GO:0004758', ('50', '53'))	('transcription', 'biological_process', 'GO:0006351', ('217', '230'))	('H3K36me histones', 'Protein', (310, 326))	('Asf1', 'Gene', (12, 16))	('Asf1', 'Gene', '853327', (12, 16))	('H3K36me', 'Var', (165, 172))	('binding', 'molecular_function', 'GO:0005488', ('286', '293'))	('removing', 'NegReg', (301, 309))	('Spt16', 'Gene', '852665', (50, 55))	('preventing', 'NegReg', (234, 244))	('Spt', 'molecular_function', 'GO:0004760', ('41', '44'))	('Spt16', 'Gene', (50, 55))	('Spt', 'molecular_function', 'GO:0004760', ('50', '53'))	('histone exchange', 'biological_process', 'GO:0043486', ('194', '210'))	('histone exchange after transcription', 'MPA', (194, 230))	('Asf1', 'Gene', (245, 249))	('peptides', 'Chemical', 'MESH:D010455', (85, 93))	('Asf1', 'Gene', '853327', (245, 249))	('inhibit', 'NegReg', (186, 193))	('binding', 'Interaction', (286, 293))	('Spt', 'molecular_function', 'GO:0004758', ('41', '44'))
45460	28386724	Eaf3 contains a chromo domain that recognizes H3K36me2/3, and Rco1 contains a dual plant homeodomain (PHD) finger motif that is necessary for chromatin engagement and a homo-dimerization domain.	('Rco1', 'Gene', (62, 66))	('PHD', 'Disease', 'MESH:D011547', (102, 105))	('Eaf3', 'Gene', (0, 4))	('PHD', 'Disease', (102, 105))	('H3K36me2/3', 'Var', (46, 56))	('Rco1', 'Gene', '855097', (62, 66))	('Eaf3', 'Gene', '856134', (0, 4))	('chromatin', 'cellular_component', 'GO:0000785', ('142', '151'))	('PHD', 'molecular_function', 'GO:0050175', ('102', '105'))
45463	28386724	Like the Isw1b complex, Eaf3's recognition of H3K36me helps to localize the Rpd3S complex to the 3'-ends of gene bodies where it can deacetylate histone tails.	('Isw1', 'Gene', (9, 13))	('deacetylate', 'MPA', (133, 144))	('Eaf3', 'Gene', (24, 28))	('Rpd3', 'Gene', '855386', (76, 80))	('Eaf3', 'Gene', '856134', (24, 28))	('Isw1', 'Gene', '852547', (9, 13))	('Rpd3', 'Gene', (76, 80))	('H3K36me', 'Var', (46, 53))	('histone tails', 'Protein', (145, 158))	('Rpd3S complex', 'cellular_component', 'GO:0032221', ('76', '89'))	('Isw1b complex', 'cellular_component', 'GO:0036437', ('9', '22'))
45471	28386724	The correct spacing is likely ensured by the nucleosome sliding activity of Isw1b, which could explain the increased histone acetylation levels in isw1Delta and ioc4Delta cells.	('histone acetylation', 'biological_process', 'GO:0016573', ('117', '136'))	('ioc4Delta', 'Var', (161, 170))	('increased', 'PosReg', (107, 116))	('histone acetylation levels', 'MPA', (117, 143))	('Isw1', 'Gene', '852547', (76, 80))	('nucleosome sliding', 'biological_process', 'GO:0042766', ('45', '63'))	('isw1Delta', 'Var', (147, 156))	('Isw1', 'Gene', (76, 80))	('nucleosome', 'cellular_component', 'GO:0000786', ('45', '55'))
45472	28386724	Without proper spacing, and even with proper H3K36me, the affinity of Rpd3S for chromatin is decreased to a degree where the naturally low binding affinity of Eaf3 for H3K36me2/3 is not able to sufficiently engage nucleosomes and stimulate Rpd3's deacetylase activity.	('Eaf3', 'Gene', '856134', (159, 163))	('deacetylase', 'Enzyme', (247, 258))	('binding', 'Interaction', (139, 146))	('H3K36me', 'Var', (45, 52))	('stimulate', 'PosReg', (230, 239))	('activity', 'MPA', (259, 267))	('Rpd3', 'Gene', '855386', (70, 74))	('chromatin', 'cellular_component', 'GO:0000785', ('80', '89'))	('decreased', 'NegReg', (93, 102))	('Rpd3', 'Gene', (240, 244))	('Eaf3', 'Gene', (159, 163))	('Rpd3', 'Gene', (70, 74))	('engage', 'Interaction', (207, 213))	('affinity', 'MPA', (58, 66))	('deacetylase activity', 'molecular_function', 'GO:0019213', ('247', '267'))	('binding', 'molecular_function', 'GO:0005488', ('139', '146'))	('Rpd3', 'Gene', '855386', (240, 244))
45474	28386724	Collectively, these findings indicate that at least one function of H3K36me is to maintain nucleosome stability by repelling histone chaperones like Asf1 and ensure low levels of histone acetylation by recruiting the Isw1b chromatin-remodeling complex and the Rpd3S HDAC.	('Asf1', 'Gene', (149, 153))	('Rpd3', 'Gene', (260, 264))	('Asf1', 'Gene', '853327', (149, 153))	('low levels', 'MPA', (165, 175))	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('223', '243'))	('repelling', 'NegReg', (115, 124))	('chromatin-remodeling complex', 'cellular_component', 'GO:0016585', ('223', '251'))	('recruiting', 'PosReg', (202, 212))	('Isw1', 'Gene', (217, 221))	('histone acetylation', 'MPA', (179, 198))	('H3K36me', 'Var', (68, 75))	('maintain', 'PosReg', (82, 90))	('ensure', 'PosReg', (158, 164))	('nucleosome stability', 'MPA', (91, 111))	('Isw1', 'Gene', '852547', (217, 221))	('histone acetylation', 'biological_process', 'GO:0016573', ('179', '198'))	('histone chaperones', 'MPA', (125, 143))	('nucleosome', 'cellular_component', 'GO:0000786', ('91', '101'))	('Rpd3', 'Gene', '855386', (260, 264))
45477	28386724	Similar to yeast, H3K36me3 recruits an Rpd3S-related HDAC complex that associates via the Eaf3 homolog MRG15; MRG15 also maintains reduced histone acetylation levels and functions in alternative mRNA splicing.	('MRG15', 'Gene', '10933', (103, 108))	('reduced', 'NegReg', (131, 138))	('histone acetylation levels', 'MPA', (139, 165))	('H3K36me3', 'Var', (18, 26))	('mRNA splicing', 'biological_process', 'GO:0000398', ('195', '208'))	('Eaf3', 'Gene', '856134', (90, 94))	('alternative mRNA splicing', 'MPA', (183, 208))	('Eaf3', 'Gene', (90, 94))	('mRNA splicing', 'biological_process', 'GO:0006371', ('195', '208'))	('MRG15', 'Gene', '10933', (110, 115))	('mRNA splicing', 'biological_process', 'GO:0000394', ('195', '208'))	('mRNA splicing', 'biological_process', 'GO:0000374', ('195', '208'))	('Rpd3', 'Gene', '855386', (39, 43))	('functions', 'Reg', (170, 179))	('HDAC complex', 'cellular_component', 'GO:0000118', ('53', '65'))	('histone acetylation', 'biological_process', 'GO:0016573', ('139', '158'))	('MRG15', 'Gene', (103, 108))	('Rpd3', 'Gene', (39, 43))	('yeast', 'Species', '4932', (11, 16))	('mRNA splicing', 'biological_process', 'GO:0000373', ('195', '208'))	('mRNA splicing', 'biological_process', 'GO:0000372', ('195', '208'))	('MRG15', 'Gene', (110, 115))
45480	28386724	One of the best-understood functions of Set2 and H3K36me in yeast is prevention of cryptic transcription across the genome.	('transcription', 'biological_process', 'GO:0006351', ('91', '104'))	('yeast', 'Species', '4932', (60, 65))	('H3K36me', 'Var', (49, 56))	('Set2', 'Gene', (40, 44))	('cryptic', 'Gene', (83, 90))	('cryptic', 'Gene', '55997', (83, 90))
45491	28386724	A deletion of ISW1 or IOC4 results in increased histone acetylation and increased cryptic transcription.	('IOC4', 'Gene', (22, 26))	('increased', 'PosReg', (72, 81))	('histone acetylation', 'MPA', (48, 67))	('deletion', 'Var', (2, 10))	('cryptic', 'Gene', (82, 89))	('ISW1', 'Gene', '852547', (14, 18))	('cryptic', 'Gene', '55997', (82, 89))	('IOC4', 'Gene', '855061', (22, 26))	('histone acetylation', 'biological_process', 'GO:0016573', ('48', '67'))	('increased', 'PosReg', (38, 47))	('ISW1', 'Gene', (14, 18))	('transcription', 'biological_process', 'GO:0006351', ('90', '103'))
45496	28386724	In total, H3K36me serves to both activate Rpd3S activity through the binding of Eaf3's chromodomain and, through Isw1b recruitment via the PWWP domain of Ioc4, ensure that nucleosome spacing is ideal for Rdp3S binding.	('Ioc4', 'Gene', '855061', (154, 158))	('Isw1', 'Gene', (113, 117))	('Rpd3', 'Gene', '855386', (42, 46))	('activity', 'MPA', (48, 56))	('binding', 'molecular_function', 'GO:0005488', ('210', '217'))	('nucleosome spacing', 'biological_process', 'GO:0016584', ('172', '190'))	('H3K36me', 'Var', (10, 17))	('Ioc4', 'Gene', (154, 158))	('Rpd3', 'Gene', (42, 46))	('Eaf3', 'Gene', (80, 84))	('binding', 'Interaction', (69, 76))	('Isw1', 'Gene', '852547', (113, 117))	('nucleosome', 'cellular_component', 'GO:0000786', ('172', '182'))	('binding', 'molecular_function', 'GO:0005488', ('69', '76'))	('activate', 'PosReg', (33, 41))	('Eaf3', 'Gene', '856134', (80, 84))
45503	28386724	Deletions of many chromatin modifying, remodeling, and maintenance factors promote cryptic transcription.	('cryptic', 'Gene', '55997', (83, 90))	('promote', 'PosReg', (75, 82))	('transcription', 'biological_process', 'GO:0006351', ('91', '104'))	('cryptic', 'Gene', (83, 90))	('Deletions', 'Var', (0, 9))	('chromatin', 'cellular_component', 'GO:0000785', ('18', '27'))
45504	28386724	Interestingly, the types of cryptic transcripts produced from these different deletion mutants are different, offering further support for different underlying mechanisms regulating cryptic transcript production.	('deletion mutants', 'Var', (78, 94))	('cryptic', 'Gene', (182, 189))	('cryptic', 'Gene', '55997', (182, 189))	('cryptic', 'Gene', '55997', (28, 35))	('cryptic', 'Gene', (28, 35))
45506	28386724	set2Delta cells are viable, as are many other deletions that lead to the production of cryptic transcripts.	('cryptic', 'Gene', '55997', (87, 94))	('set2Delta', 'Gene', '853271', (0, 9))	('set2Delta', 'Gene', (0, 9))	('production', 'MPA', (73, 83))	('deletions', 'Var', (46, 55))	('cryptic', 'Gene', (87, 94))
45507	28386724	Further, under normal laboratory conditions, a deletion of SET2 or other chromatin factors results in relatively few changes to the transcriptome, i.e., only ~80 genes are up- or down-regulated in a SET2 deletion; thus, production of cryptic transcripts does not drive large-scale transcriptional change.	('down-regulated', 'NegReg', (179, 193))	('SET2', 'Gene', (59, 63))	('deletion', 'Var', (204, 212))	('SET2', 'Gene', (199, 203))	('SET2', 'Gene', '853271', (199, 203))	('chromatin', 'cellular_component', 'GO:0000785', ('73', '82'))	('up-', 'PosReg', (172, 175))	('deletion', 'Var', (47, 55))	('cryptic', 'Gene', '55997', (234, 241))	('cryptic', 'Gene', (234, 241))	('SET2', 'Gene', '853271', (59, 63))
45514	28386724	Using Spt6 mutation that produces a very strong cryptic transcription phenotype, the Winston lab observed the translation of a select few cryptic transcripts.	('cryptic', 'Gene', (138, 145))	('Spt', 'molecular_function', 'GO:0004760', ('6', '9'))	('Spt', 'molecular_function', 'GO:0004758', ('6', '9'))	('Spt6', 'Gene', (6, 10))	('transcription', 'biological_process', 'GO:0006351', ('56', '69'))	('mutation', 'Var', (11, 19))	('translation', 'biological_process', 'GO:0006412', ('110', '121'))	('cryptic', 'Gene', '55997', (48, 55))	('cryptic', 'Gene', '55997', (138, 145))	('cryptic', 'Gene', (48, 55))
45519	28386724	Specifically, the Berger group showed that a loss of Set2 or a mutation of H3K36 decreased the lifespan of yeast cells and, critically, removal of Rph1, an H3K36me3 demethylase, significantly extended the lifespan of wild-type cells.	('decreased', 'NegReg', (81, 90))	('Rph1', 'Gene', '856916', (147, 151))	('lifespan of yeast cells', 'CPA', (95, 118))	('lifespan', 'CPA', (205, 213))	('yeast', 'Species', '4932', (107, 112))	('Rph', 'molecular_function', 'GO:0047520', ('147', '150'))	('mutation', 'Var', (63, 71))	('extended', 'PosReg', (192, 200))	('Rph1', 'Gene', (147, 151))	('loss', 'NegReg', (45, 49))	('removal', 'Var', (136, 143))	('Set2', 'Gene', (53, 57))	('H3K36', 'Gene', (75, 80))
45524	28386724	In summary, in yeast and worms, H3K36me regulates the transcriptome by preventing cryptic transcription, thus decreasing transcriptional noise.	('yeast', 'Species', '4932', (15, 20))	('cryptic', 'Gene', (82, 89))	('preventing', 'NegReg', (71, 81))	('cryptic', 'Gene', '55997', (82, 89))	('transcriptional noise', 'MPA', (121, 142))	('H3K36me', 'Var', (32, 39))	('decreasing', 'NegReg', (110, 120))	('transcription', 'biological_process', 'GO:0006351', ('90', '103'))
45528	28386724	Interestingly, nucleosome positioning was altered at many sites of RNA processing defects, suggesting that H3K36me's chromatin remodeling function and repression of histone exchange may also be conserved in human cells.	('nucleosome positioning', 'MPA', (15, 37))	('RNA', 'cellular_component', 'GO:0005562', ('67', '70'))	('RNA processing', 'biological_process', 'GO:0006396', ('67', '81'))	('altered', 'Reg', (42, 49))	('histone exchange', 'biological_process', 'GO:0043486', ('165', '181'))	('nucleosome', 'cellular_component', 'GO:0000786', ('15', '25'))	('chromatin', 'cellular_component', 'GO:0000785', ('117', '126'))	('nucleosome positioning', 'biological_process', 'GO:0016584', ('15', '37'))	('human', 'Species', '9606', (207, 212))	('defects', 'Var', (82, 89))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('117', '137'))	('H3K36me', 'Gene', (107, 114))
45532	28386724	The necessity of the SRI domain for proper splicing suggests that Set2 may act co-transcriptionally to recruit splicing factors, and the requirement of H3K36me2 suggests that Rpd3S may also play an important role in splicing.	('Rpd3', 'Gene', (175, 179))	('splicing', 'biological_process', 'GO:0045292', ('43', '51'))	('splicing factors', 'MPA', (111, 127))	('splicing', 'biological_process', 'GO:0045292', ('111', '119'))	('splicing', 'biological_process', 'GO:0045292', ('216', '224'))	('Rpd3', 'Gene', '855386', (175, 179))	('H3K36me2', 'Var', (152, 160))
45536	28386724	In human cells, HR is defective in SETD2 mutant cells.	('human', 'Species', '9606', (3, 8))	('SETD2', 'Gene', (35, 40))	('mutant', 'Var', (41, 47))
45539	28386724	H3K36me regulates Polycomb-mediated gene silencing during mammalian development by recruiting Polycomb repressive complex 2 (PRC2) components PHF19 and PHF1.	('regulates', 'Reg', (8, 17))	('recruiting', 'PosReg', (83, 93))	('gene silencing', 'biological_process', 'GO:0016458', ('36', '50'))	('H3K36me', 'Var', (0, 7))	('PRC2', 'Gene', (125, 129))	('PRC2', 'Gene', '852873', (125, 129))	('PHF1', 'Gene', (142, 146))	('PHF19', 'Gene', '26147', (142, 147))	('PHF1', 'Gene', (152, 156))	('PHF19', 'Gene', (142, 147))	('PHF1', 'Gene', '5252', (142, 146))	('PHF1', 'Gene', '5252', (152, 156))	('Polycomb-mediated', 'MPA', (18, 35))	('mammalian', 'Species', '9606', (58, 67))
45540	28386724	PHF19 and PHF1 both have Tudor domains that recognize H3K36me3 and bring PRC2 to actively transcribed and developmentally regulated regions of the genome, which then allows for H3K27me3 to spread across the genes to induce transcriptional repression.	('allows', 'Reg', (166, 172))	('PHF19', 'Gene', (0, 5))	('PHF1', 'Gene', (10, 14))	('H3K36me3', 'Protein', (54, 62))	('PRC2', 'Gene', (73, 77))	('PHF1', 'Gene', (0, 4))	('PHF19', 'Gene', '26147', (0, 5))	('PRC2', 'Gene', '852873', (73, 77))	('H3K27me3', 'Var', (177, 185))	('PHF1', 'Gene', '5252', (10, 14))	('induce', 'PosReg', (216, 222))	('PHF1', 'Gene', '5252', (0, 4))	('transcriptional repression', 'MPA', (223, 249))
45542	28386724	DNA methylation is an essential regulator of gene expression; hyper-methylation of gene promoters results in repression and is a hallmark of cancer.	('hyper-methylation', 'Var', (62, 79))	('gene expression', 'biological_process', 'GO:0010467', ('45', '60'))	('hallmark of cancer', 'Disease', 'MESH:D009369', (129, 147))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('results in', 'Reg', (98, 108))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('repression', 'MPA', (109, 119))	('hallmark of cancer', 'Disease', (129, 147))
45544	28386724	In addition, and as mentioned above, DNA methylation also prevents spurious transcription initiation within the gene body in mammalian cells.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('mammalian', 'Species', '9606', (125, 134))	('spurious transcription initiation', 'MPA', (67, 100))	('DNA methylation', 'biological_process', 'GO:0006306', ('37', '52'))	('methylation', 'Var', (41, 52))	('transcription', 'biological_process', 'GO:0006351', ('76', '89'))	('prevents', 'NegReg', (58, 66))
45546	28386724	During mitosis, SETD2 methylates tubulin at K40, and ablation of SETD2 leads to a plethora of mitotic defects.	('mitosis', 'biological_process', 'GO:0000278', ('7', '14'))	('ablation', 'Var', (53, 61))	('tubulin', 'Protein', (33, 40))	('plethora', 'Phenotype', 'HP:0001050', (82, 90))	('SETD2', 'Gene', (65, 70))	('mitosis', 'Disease', (7, 14))	('mitotic defects', 'Disease', 'MESH:C536987', (94, 109))	('mitosis', 'Disease', 'None', (7, 14))	('mitotic defects', 'Disease', (94, 109))	('leads to', 'Reg', (71, 79))
45547	28386724	Most likely, some of the oncogenic phenotypes observed in SETD2-mutated cells are due to the genomic instability caused by tubulin defects during mitosis.	('mitosis', 'Disease', (146, 153))	('mitosis', 'Disease', 'None', (146, 153))	('mitosis', 'biological_process', 'GO:0000278', ('146', '153'))	('defects', 'Var', (131, 138))	('due', 'Reg', (82, 85))	('tubulin', 'Protein', (123, 130))	('SETD2-mutated', 'Gene', (58, 71))
45548	28386724	The requirement for SETD2 and H3K36me was first shown for Drosophila; RNAi knockdown of dSet2 caused lethality during the larval stage of development.	('caused', 'Reg', (94, 100))	('Drosophila', 'Species', '7227', (58, 68))	('knockdown', 'Var', (75, 84))	('dSet2', 'Gene', '32301', (88, 93))	('dSet2', 'Gene', (88, 93))	('RNAi', 'biological_process', 'GO:0016246', ('70', '74'))	('lethality', 'MPA', (101, 110))
45549	28386724	Additionally, when all of the canonical H3K36 residues in the genome were mutated to arginine, flies were unable to complete development.	('unable', 'NegReg', (106, 112))	('H3K36', 'Protein', (40, 45))	('mutated', 'Var', (74, 81))	('arginine', 'Chemical', 'MESH:D001120', (85, 93))
45551	28386724	SETD2 -/- knock-out mice die as embryos at E10.5-E11.5 due to defects in angiogenesis.	('mice', 'Species', '10090', (20, 24))	('defects', 'NegReg', (62, 69))	('E10.5-E11.5', 'Var', (43, 54))	('angiogenesis', 'biological_process', 'GO:0001525', ('73', '85'))	('angiogenesis', 'CPA', (73, 85))
45553	28386724	RNAi knock-down experiments in murine embryonic stem cells also reveal defects in differentiation due to misregulation of the Fgfr3/Erk pathway.	('Erk', 'Gene', '26413', (132, 135))	('defects', 'NegReg', (71, 78))	('Fgfr', 'molecular_function', 'GO:0005007', ('126', '130'))	('Erk', 'Gene', (132, 135))	('RNAi', 'biological_process', 'GO:0016246', ('0', '4'))	('Fgfr3', 'Gene', '14184', (126, 131))	('Erk', 'molecular_function', 'GO:0004707', ('132', '135'))	('Fgfr3', 'Gene', (126, 131))	('misregulation', 'Var', (105, 118))	('murine', 'Species', '10090', (31, 37))	('differentiation', 'CPA', (82, 97))
45556	28386724	ccRCC tumors are very heterogeneous, but mutations in SETD2 arise frequently and independently in a single tumor.	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('SETD2', 'Gene', (54, 59))	('ccRCC', 'Disease', (0, 5))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
45557	28386724	SETD2 mutations have also been observed in acute leukemias, in bladder cancer, and in glioblastoma, indicating a broad need for maintaining SETD2 to prevent tumorigenesis.	('tumor', 'Disease', (157, 162))	('bladder cancer', 'Disease', 'MESH:D001749', (63, 77))	('bladder cancer', 'Disease', (63, 77))	('leukemias', 'Phenotype', 'HP:0001909', (49, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (86, 98))	('leukemias', 'Disease', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('bladder cancer', 'Phenotype', 'HP:0009725', (63, 77))	('SETD2', 'Gene', (0, 5))	('leukemias', 'Disease', 'MESH:D007938', (49, 58))	('glioblastoma', 'Disease', (86, 98))	('acute leukemias', 'Phenotype', 'HP:0002488', (43, 58))	('observed', 'Reg', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mutations', 'Var', (6, 15))	('glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))
45558	28386724	Although, it is not known, biochemically, exactly how SETD2 functions as a tumor suppressor, the abilities of SETD2 and H3K36me3 to regulate splicing, DNA methylation, chromosome segregation, and DNA damage repair are likely candidates that underlie SETD2's role in tumor suppression.	('tumor suppressor', 'biological_process', 'GO:0051726', ('75', '91'))	('regulate', 'Reg', (132, 140))	('tumor', 'Disease', (266, 271))	('chromosome segregation', 'CPA', (168, 190))	('tumor', 'Disease', (75, 80))	('H3K36me3', 'Var', (120, 128))	('DNA', 'MPA', (151, 154))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('DNA', 'cellular_component', 'GO:0005574', ('196', '199'))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('chromosome segregation', 'biological_process', 'GO:0007059', ('168', '190'))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('splicing', 'biological_process', 'GO:0045292', ('141', '149'))	('SETD2', 'Gene', (110, 115))	('chromosome', 'cellular_component', 'GO:0005694', ('168', '178'))	('DNA methylation', 'biological_process', 'GO:0006306', ('151', '166'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('75', '91'))	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))	('splicing', 'MPA', (141, 149))
45560	28386724	These termination defects lead to the creation of chimeric transcripts, some involving oncogenes, providing yet another potential mechanism that could lead to cancer development.	('cancer', 'Disease', (159, 165))	('defects', 'Var', (18, 25))	('lead to', 'Reg', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('lead to', 'Reg', (151, 158))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('chimeric transcripts', 'Var', (50, 70))
45562	28386724	Finally, it has recently been shown through exome sequencing that recurrent mutations at or near H3K36 can also lead to cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (76, 85))	('lead to', 'Reg', (112, 119))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('H3K36', 'Gene', (97, 102))
45563	28386724	In particular, H3K36 in the context of the H3.3 variant has been found mutated to methionine in chondroblastomas and in other cancer types including head and neck squamous cell carcinoma and colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('H3K36', 'Protein', (15, 20))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (149, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('chondroblastomas', 'Disease', 'MESH:D002804', (96, 112))	('neck squamous cell carcinoma', 'Disease', (158, 186))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (158, 186))	('colorectal cancer', 'Disease', 'MESH:D015179', (191, 208))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('variant', 'Var', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('colorectal cancer', 'Disease', (191, 208))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (163, 186))	('neck', 'cellular_component', 'GO:0044326', ('158', '162'))	('methionine', 'Chemical', 'MESH:D008715', (82, 92))	('chondroblastomas', 'Disease', (96, 112))	('mutated', 'Var', (71, 78))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Disease', (202, 208))	('colorectal cancer', 'Phenotype', 'HP:0003003', (191, 208))
45564	28386724	Mutations at H3.3K36 result in genome-wide loss of H3K36 tri-methylation and can directly stimulate tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('tri-methylation', 'MPA', (57, 72))	('Mutations', 'Var', (0, 9))	('loss', 'NegReg', (43, 47))	('formation', 'biological_process', 'GO:0009058', ('106', '115'))	('stimulate', 'PosReg', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('H3K36', 'Protein', (51, 56))	('H3.3K36', 'Gene', (13, 20))
45565	28386724	Similar to the mechanism by which K M mutations at H3K9 and H3K27 "trap" or "poison" their respective methyltransferase enzymes, the H3.3K36M mutation rearranges the active center of SETD2 to provide a high affinity binding site for the H3.3K36M histone tail, thus explaining how a single histone mutation can impart a tumor phenotype.	('tumor', 'Disease', (319, 324))	('binding', 'Interaction', (216, 223))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('binding', 'molecular_function', 'GO:0005488', ('212', '219'))	('methyltransferase enzymes', 'Enzyme', (102, 127))	('H3.3K36M mutation', 'Var', (133, 150))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('mutation', 'Var', (142, 150))	('mutations', 'Var', (38, 47))	('poison', 'NegReg', (77, 83))
45567	28386724	In addition to mutations at H3.3K36, mutations at adjacent residues (i.e., G34-to-R/V and G34-to-W/L) have also been reported in a variety of cancers including pediatric non-brain stem gliomas and tumors of the bone.	('gliomas', 'Phenotype', 'HP:0009733', (185, 192))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('G34-to-W/L', 'Var', (90, 100))	('tumors of the bone', 'Phenotype', 'HP:0010622', (197, 215))	('cancers', 'Disease', (142, 149))	('reported', 'Reg', (117, 125))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('G34-to-R/V', 'Var', (75, 85))	('brain stem gliomas', 'Phenotype', 'HP:0010796', (174, 192))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('gliomas and tumors', 'Disease', 'MESH:D005910', (185, 203))
45568	28386724	Unlike the H3.3K36M mutation, however, G34W/L and G34R/V mutations do not abolish global levels of H3K36me3.	('global levels of H3K36me3', 'MPA', (82, 107))	('G34W', 'Var', (39, 43))	('G34R', 'SUBSTITUTION', 'None', (50, 54))	('G34W', 'SUBSTITUTION', 'None', (39, 43))	('G34R', 'Var', (50, 54))	('abolish', 'NegReg', (74, 81))
45569	28386724	Rather, they impact the nucleosomes that contain this mutation and result in a redistribution of the H3K36me3 mark across the genome that reprograms the transcriptome in ways that promote tumorigenesis.	('tumor', 'Disease', (188, 193))	('mutation', 'Var', (54, 62))	('redistribution', 'MPA', (79, 93))	('nucleosomes', 'MPA', (24, 35))	('impact', 'Reg', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('promote', 'PosReg', (180, 187))	('H3K36me3', 'Protein', (101, 109))
45570	28386724	Collectively, these findings show that mutating either SETD2 or H3K36 is sufficient to promote cancer progression.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('H3K36', 'Protein', (64, 69))	('mutating', 'Var', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('promote', 'PosReg', (87, 94))	('SETD2', 'Gene', (55, 60))
45576	28386724	Along these lines, although SETD2 and H3.3K36 are mutated in multiple types of cancer, we do not fully understand H3.3K36's role as a tumor suppressor.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('134', '150'))	('H3.3K36', 'Var', (114, 121))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor suppressor', 'biological_process', 'GO:0051726', ('134', '150'))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('SETD2', 'Gene', (28, 33))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('tumor', 'Disease', (134, 139))
45590	32002016	Biomarkers used to predict overall survival (OS) can range from clinical parameters, endogenous substances and pathohistological characteristics of tumor to specific mutated gene.	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('mutated', 'Var', (166, 173))
45643	32002016	Amplification was common in ATP6V0D2, DPP6 and C9orf135, while deep deletion was common in PADI1, C9orf135 and PLG in ccRCC patients.	('ATP6V0D2', 'Gene', '245972', (28, 36))	('C9orf135', 'Gene', '138255', (47, 55))	('DPP6', 'Gene', (38, 42))	('ATP6V0D2', 'Gene', (28, 36))	('patients', 'Species', '9606', (124, 132))	('PADI1', 'Gene', (91, 96))	('ccRCC', 'Disease', 'MESH:D002292', (118, 123))	('C9orf135', 'Gene', (98, 106))	('C9orf135', 'Gene', '138255', (98, 106))	('PADI1', 'Gene', '29943', (91, 96))	('ccRCC', 'Disease', (118, 123))	('PLG', 'Gene', '5340', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))	('deep deletion', 'Var', (63, 76))	('Amplification', 'Var', (0, 13))	('common', 'Reg', (18, 24))	('DPP6', 'Gene', '1804', (38, 42))	('PLG', 'Gene', (111, 114))	('C9orf135', 'Gene', (47, 55))
45673	32002016	Our GSEA analysis showed that low expression of PLG also probably negatively mediates p53 signaling pathway to promote ccRCC progression.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('negatively', 'NegReg', (66, 76))	('PLG', 'Gene', (48, 51))	('p53', 'Gene', '7157', (86, 89))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('ccRCC', 'Disease', (119, 124))	('p53 signaling pathway', 'biological_process', 'GO:0030330', ('86', '107'))	('low expression', 'Var', (30, 44))	('mediates', 'Reg', (77, 85))	('ccRCC', 'Disease', 'MESH:D002292', (119, 124))	('PLG', 'Gene', '5340', (48, 51))	('promote', 'PosReg', (111, 118))	('p53', 'Gene', (86, 89))
45675	32002016	Nevertheless, recent research has found that DPP6 could regulate various biological functions, maintain cell-specific phenotype and dysregulated expression of DPP6 would result in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (180, 194))	('DPP6', 'Gene', (159, 163))	('result in', 'Reg', (170, 179))	('DPP6', 'Gene', '1804', (45, 49))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('dysregulated expression', 'Var', (132, 155))	('DPP6', 'Gene', (45, 49))	('regulate', 'Reg', (56, 64))	('DPP6', 'Gene', '1804', (159, 163))	('carcinogenesis', 'Disease', (180, 194))
45688	32002016	Downregulated ATP6V0D2 probably functions through increasing HIF-2alpha expression produced by macrophage to enhance tumor vascularization and growth.	('Downregulated', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('growth', 'CPA', (143, 149))	('increasing', 'PosReg', (50, 60))	('ATP6V0D2', 'Gene', '245972', (14, 22))	('tumor', 'Disease', (117, 122))	('HIF-2alpha', 'Gene', (61, 71))	('expression', 'MPA', (72, 82))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('ATP6V0D2', 'Gene', (14, 22))	('HIF-2alpha', 'Gene', '2034', (61, 71))	('enhance', 'PosReg', (109, 116))
45695	32002016	Our GSEA suggests that low expression of C9orf135 probably promote ccRCC formation through affecting PPAR signaling pathway.	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('PPAR signaling pathway', 'biological_process', 'GO:0035357', ('101', '123'))	('PPAR', 'Gene', (101, 105))	('C9orf135', 'Gene', '138255', (41, 49))	('affecting', 'Reg', (91, 100))	('ccRCC', 'Disease', (67, 72))	('formation', 'biological_process', 'GO:0009058', ('73', '82'))	('ccRCC', 'Disease', 'MESH:D002292', (67, 72))	('promote', 'PosReg', (59, 66))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('PPAR', 'Gene', '5465', (101, 105))	('C9orf135', 'Gene', (41, 49))	('low expression', 'Var', (23, 37))
45705	32002016	Other types of data like single nucleotide polymorphisms (SNP), copy number variation (CNV) and DNA methylation are provided by the public dataset.	('N', 'Chemical', 'MESH:D009584', (88, 89))	('copy number variation', 'Var', (64, 85))	('single nucleotide polymorphisms', 'Var', (25, 56))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('DNA methylation', 'biological_process', 'GO:0006306', ('96', '111'))
45722	30037856	Transient knockdown of MALAT-1 mimicked the effects of miR-182-5p overexpression.	('MALAT-1', 'Gene', '378938', (23, 30))	('miR-182-5p', 'Gene', (55, 65))	('MALAT-1', 'Gene', (23, 30))	('miR-182-5p', 'Gene', '100302183', (55, 65))	('knockdown', 'Var', (10, 19))
45734	30037856	Its overexpression enhances the tumorigenic potential of renal cancer cells and knockdown of MALAT-1 is known to induce G2/M phase arrest in many types of cancer.	('renal cancer', 'Disease', 'MESH:D007680', (57, 69))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('induce', 'Reg', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('G2/M phase arrest', 'CPA', (120, 137))	('overexpression enhances', 'PosReg', (4, 27))	('M phase', 'biological_process', 'GO:0000279', ('123', '130'))	('cancer', 'Disease', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('renal cancer', 'Disease', (57, 69))	('tumor', 'Disease', (32, 37))	('MALAT-1', 'Gene', '378938', (93, 100))	('cancer', 'Disease', (155, 161))	('knockdown', 'Var', (80, 89))	('MALAT-1', 'Gene', (93, 100))	('renal cancer', 'Phenotype', 'HP:0009726', (57, 69))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
45764	30037856	For MALAT-1, we used antisense oligonucleotides (ASO) from IDT (Integrated DNA technologies).	('antisense', 'Var', (21, 30))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('MALAT-1', 'Gene', (4, 11))	('MALAT-1', 'Gene', '378938', (4, 11))
45833	30037856	We found that knockdown of MALAT-1 decreased cell and colony formation in both ACHN and Caki-1 cells (Fig.	('Caki-1', 'CellLine', 'CVCL:0234', (88, 94))	('decreased', 'NegReg', (35, 44))	('MALAT-1', 'Gene', '378938', (27, 34))	('knockdown', 'Var', (14, 23))	('formation', 'biological_process', 'GO:0009058', ('61', '70'))	('MALAT-1', 'Gene', (27, 34))
45835	30037856	We found that both ACHN (12.5% vs 17.6%, p-value= 0.03) and Caki-1 cells (7.3% vs 10.5%, p-value= 0.004) showed G2/M arrest after MALAT-1 knockdown compared to controls (Fig.	('knockdown', 'Var', (138, 147))	('MALAT-1', 'Gene', '378938', (130, 137))	('MALAT-1', 'Gene', (130, 137))	('Caki-1', 'CellLine', 'CVCL:0234', (60, 66))	('G2/M arrest', 'CPA', (112, 123))
45846	30037856	On the other hand, the levels of CDC 20 and AURKA decreased significantly in p53 overexpressing cells confirming involvement of p53 (Fig 7D).	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (128, 131))	('CDC 20', 'Gene', '991', (33, 39))	('overexpressing', 'Var', (81, 95))	('p53', 'Gene', (77, 80))	('decreased', 'NegReg', (50, 59))	('AURKA', 'Gene', (44, 49))	('levels', 'MPA', (23, 29))	('p53', 'Gene', '7157', (77, 80))	('AURKA', 'Gene', '6790', (44, 49))	('CDC 20', 'Gene', (33, 39))
45860	30037856	Further, a demethylating agent Aza-CdR treatment has been reported to rescue the expression of hypermethylated miRNAs in cancers.	('cancers', 'Disease', (121, 128))	('rescue', 'PosReg', (70, 76))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('hypermethylated', 'Var', (95, 110))	('miR', 'Gene', '220972', (111, 114))	('miR', 'Gene', (111, 114))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('expression', 'MPA', (81, 91))
45861	30037856	Our results indicated that treatment with Aza-CdR restored miR-182-5p expression and decreased the expression of key methylation regulating genes such as DNMT1, DNMT3a and DNMT3b in ccRCC cell lines.	('expression', 'MPA', (99, 109))	('decreased', 'NegReg', (85, 94))	('DNMT3a', 'Gene', (161, 167))	('methylation', 'biological_process', 'GO:0032259', ('117', '128'))	('miR-182-5p', 'Gene', (59, 69))	('DNMT3b', 'Gene', (172, 178))	('methylation regulating genes', 'MPA', (117, 145))	('miR-182-5p', 'Gene', '100302183', (59, 69))	('DNMT3a', 'Gene', '1788', (161, 167))	('DNMT1', 'Gene', (154, 159))	('ccRCC', 'Disease', (182, 187))	('DNMT1', 'Gene', '1786', (154, 159))	('ccRCC', 'Disease', 'MESH:D002292', (182, 187))	('Aza-CdR', 'Var', (42, 49))	('restored', 'PosReg', (50, 58))	('DNMT3b', 'Gene', '1789', (172, 178))
45862	30037856	Thus, confirming that CpG island hyper-methylation is responsible for suppressed miR-182-5p expression in ccRCC.	('hyper-methylation', 'Var', (33, 50))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('ccRCC', 'Disease', (106, 111))	('suppressed', 'NegReg', (70, 80))	('ccRCC', 'Disease', 'MESH:D002292', (106, 111))	('miR-182-5p', 'Gene', '100302183', (81, 91))	('miR-182-5p', 'Gene', (81, 91))
45866	30037856	In addition, miR-182-5p had tumor suppressor effects in in vivo mouse model, highlighting the fact that restoration of miR-182-5p expression may be an attractive therapeutic modality in ccRCC.	('ccRCC', 'Disease', (186, 191))	('ccRCC', 'Disease', 'MESH:D002292', (186, 191))	('tumor', 'Disease', (28, 33))	('miR-182-5p', 'Gene', (13, 23))	('restoration', 'Var', (104, 115))	('miR-182-5p', 'Gene', '100302183', (13, 23))	('miR-182-5p', 'Gene', '100302183', (119, 129))	('tumor suppressor', 'biological_process', 'GO:0051726', ('28', '44'))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('28', '44'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('mouse', 'Species', '10090', (64, 69))	('miR-182-5p', 'Gene', (119, 129))
45871	30037856	Consistent with our finding, silencing of both genes (CDC20, AURKA) has been known to induce G2/M arrest in various cancers, whereas, induction of p53 has been reported to induce cell cycle arrest, cellular senescence or apoptosis and is known to suppress the expression of both CDC20 and AURKA.	('cellular senescence', 'CPA', (198, 217))	('CDC20', 'Gene', (54, 59))	('induction', 'Var', (134, 143))	('AURKA', 'Gene', '6790', (289, 294))	('silencing', 'Var', (29, 38))	('AURKA', 'Gene', (289, 294))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cellular senescence', 'biological_process', 'GO:0090398', ('198', '217'))	('G2/M arrest', 'MPA', (93, 104))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (179, 196))	('CDC20', 'Gene', '991', (279, 284))	('cell cycle arrest', 'CPA', (179, 196))	('induce', 'Reg', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('apoptosis', 'biological_process', 'GO:0006915', ('221', '230'))	('AURKA', 'Gene', (61, 66))	('p53', 'Gene', '7157', (147, 150))	('CDC20', 'Gene', (279, 284))	('induce', 'Reg', (172, 178))	('AURKA', 'Gene', '6790', (61, 66))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('CDC20', 'Gene', '991', (54, 59))	('apoptosis', 'biological_process', 'GO:0097194', ('221', '230'))	('cancers', 'Disease', (116, 123))	('apoptosis', 'CPA', (221, 230))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('179', '196'))	('p53', 'Gene', (147, 150))
45876	30037856	To summarize, we provide evidence that miR-182 is silenced by CpG hypermethylation and may possess diagnostic potential in ccRCC.	('miR-182', 'Gene', (39, 46))	('hypermethylation', 'Var', (66, 82))	('silenced', 'NegReg', (50, 58))	('ccRCC', 'Disease', (123, 128))	('ccRCC', 'Disease', 'MESH:D002292', (123, 128))
45909	33208553	Mutations in several other 3p genes occur secondarily in SETD2, PBRM1, and BAP1, all identified via high-throughput sequencing studies.	('SETD2', 'Gene', '29072', (57, 62))	('BAP1', 'Gene', (75, 79))	('PBRM1', 'Gene', (64, 69))	('PBRM1', 'Gene', '55193', (64, 69))	('SETD2', 'Gene', (57, 62))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (75, 79))
45934	33208553	High-throughput exon sequencing revealed an average of 190 mutations (range, 100-240) in each tumor, which were recorded for each pre- and posttreatment specimen using the whole blood sample sequence as a reference.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('pre', 'molecular_function', 'GO:0003904', ('130', '133'))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('mutations', 'Var', (59, 68))	('revealed', 'Reg', (32, 40))
45937	33208553	Private mutations are defined here as mutations that are uniquely observed in a single tumor sample and not shared by any other tumor sample from the same subject.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('mutations', 'Var', (8, 17))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
45938	33208553	This may suggest that there is a selective reduction in genetic diversity in samples collected following treatment with pazopanib.	('genetic diversity', 'MPA', (56, 73))	('reduction', 'NegReg', (43, 52))	('pazopanib', 'Var', (120, 129))	('pazopanib', 'Chemical', 'MESH:C516667', (120, 129))
45947	33208553	We hypothesized that neoadjuvant pazopanib may elicit changes in the tumor immune microenvironment that would be evaluable via immunogenomics analysis.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('pazopanib', 'Var', (33, 42))	('tumor', 'Disease', (69, 74))	('pazopanib', 'Chemical', 'MESH:C516667', (33, 42))	('elicit changes', 'Reg', (47, 61))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
45970	33208553	Whether this adaptation involves a selective elimination of cells bearing passenger mutations, or an enrichment for a clonally derived set of tumor cells, it would appear that the exposure to a relatively short period of anti-VEGFR therapy selects for a unique set of tumor cells in each tumor.	('tumor', 'Disease', (288, 293))	('VEGFR', 'Gene', '3791', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (268, 273))	('mutations', 'Var', (84, 93))	('VEGFR', 'Gene', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
45973	33208553	The concept that tumor selection can enrich for important driver mutations is not new in RCC.	('tumor', 'Disease', (17, 22))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('mutations', 'Var', (65, 74))
45978	33208553	We show that neoadjuvant pazopanib led to decreased genetic diversity via a contraction of tumor clonotypes recovered from whole exome sequencing (Figure 3).	('contraction', 'NegReg', (76, 87))	('decreased', 'NegReg', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('pazopanib', 'Chemical', 'MESH:C516667', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('pazopanib', 'Var', (25, 34))	('tumor', 'Disease', (91, 96))	('genetic diversity', 'MPA', (52, 69))
45979	33208553	In a recent analysis of genomics data from melanoma patients treated with PD-1 inhibition (nivolumab), genomic contraction on therapy was significantly associated with achievement of partial or complete response.	('PD-1', 'Gene', '5133', (74, 78))	('nivolumab', 'Chemical', 'MESH:D000077594', (91, 100))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', (43, 51))	('inhibition', 'Var', (79, 89))	('genomic', 'MPA', (103, 110))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('patients', 'Species', '9606', (52, 60))	('PD-1', 'Gene', (74, 78))
45983	33208553	First, samples within a tumor, even temporally separated by a therapeutic intervention, cluster together, revealing that each tumor has a fairly unique profile of mutations that separates it from other tumors with similar histological features.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mutations', 'Var', (163, 172))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', (24, 29))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', (126, 131))
45987	33208553	Second, the low frequency of VHL mutations in our set may seem surprising in light of the high frequency of these mutations that is seen in some series.	('VHL', 'Gene', (29, 32))	('VHL', 'Gene', '7428', (29, 32))	('mutations', 'Var', (33, 42))
46000	33208553	Primary alignments were then realigned using ABRA; somatic variants were called using Strelka and were annotated with SnpEff.	('ABRA', 'Gene', (45, 49))	('variants', 'Var', (59, 67))	('ABRA', 'Gene', '137735', (45, 49))
46043	30385260	We identify variability in PD-L1 expression in six patients with renal tumor thrombus.	('renal tumor thrombus', 'Disease', 'MESH:D013927', (65, 85))	('renal tumor', 'Phenotype', 'HP:0009726', (65, 76))	('renal tumor thrombus', 'Disease', (65, 85))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('patients', 'Species', '9606', (51, 59))	('expression', 'MPA', (33, 43))	('variability', 'Var', (12, 23))	('PD-L1', 'Gene', (27, 32))	('PD-L1', 'Gene', '29126', (27, 32))
46073	30385260	Therefore, the presence of complex genomic heterogeneity and a wide range of mutational load in RCC may predict better responses to recently approved checkpoint inhibitors in patients with RCC with tumor thrombus.	('RCC', 'Disease', (96, 99))	('RCC', 'Disease', 'MESH:D002292', (189, 192))	('RCC', 'Disease', 'MESH:D002292', (96, 99))	('tumor thrombus', 'Disease', 'MESH:D013927', (198, 212))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor thrombus', 'Disease', (198, 212))	('patients', 'Species', '9606', (175, 183))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('mutational load', 'Var', (77, 92))	('RCC', 'Disease', (189, 192))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))	('better', 'PosReg', (112, 118))	('responses', 'MPA', (119, 128))
46107	30799953	The effects of COL5A1 silencing on cell proliferation, apoptosis, migration, invasion in vitro, and tumor growth in vivo were investigated.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('tumor', 'Disease', (100, 105))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('silencing', 'Var', (22, 31))	('cell proliferation', 'biological_process', 'GO:0008283', ('35', '53'))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('COL5A1', 'Gene', (15, 21))
46111	30799953	COL5A1 knockdown significantly inhibited cell proliferation, induced cell apoptosis, inhibited cell migration and invasion in vitro, and inhibited tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('cell proliferation', 'biological_process', 'GO:0008283', ('41', '59'))	('inhibited', 'NegReg', (137, 146))	('inhibited', 'NegReg', (85, 94))	('cell proliferation', 'CPA', (41, 59))	('COL5A1', 'Gene', (0, 6))	('induced', 'Reg', (61, 68))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('inhibited', 'NegReg', (31, 40))	('knockdown', 'Var', (7, 16))	('cell apoptosis', 'CPA', (69, 83))	('cell migration', 'biological_process', 'GO:0016477', ('95', '109'))
46119	30799953	Importantly, high expression of COL5A1 is independently significantly associated with poor survival according to survival analysis of The Cancer Genome Atlas (TCGA) data from renal cell carcinoma samples.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (175, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('high expression', 'Var', (13, 28))	('associated', 'Reg', (70, 80))	('renal cell carcinoma', 'Disease', (175, 195))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (175, 195))	('Cancer Genome Atlas', 'Disease', (138, 157))	('Cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (138, 157))	('COL5A1', 'Gene', (32, 38))	('poor', 'NegReg', (86, 90))
46166	30799953	Kaplan-Meier analysis demonstrated that ccRCC patients with high COL5A1 expression had a significantly worse OS probability than those with low COL5A1 expression (log-rank test, P<0.001; Figure 2B).	('patients', 'Species', '9606', (46, 54))	('high', 'Var', (60, 64))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('ccRCC', 'Disease', (40, 45))	('COL5A1', 'Gene', (65, 71))	('expression', 'Var', (72, 82))
46175	30799953	The cell line Caki-1 (highest level of COL5A1 expression; Figure 1B and C) was selected to examine whether COL5A1 knockdown could affect the growth of ccRCC cells.	('growth', 'CPA', (141, 147))	('knockdown', 'Var', (114, 123))	('affect', 'Reg', (130, 136))	('COL5A1', 'Gene', (107, 113))	('ccRCC', 'Phenotype', 'HP:0006770', (151, 156))	('ccRCC', 'Disease', (151, 156))	('Caki-1', 'CellLine', 'CVCL:0234', (14, 20))
46177	30799953	MTT assay showed that COL5A1 knockdown inhibited cell growth in a time-dependent manner compared with controls (Figure 3B).	('COL5A1', 'Gene', (22, 28))	('inhibited', 'NegReg', (39, 48))	('knockdown', 'Var', (29, 38))	('cell growth', 'biological_process', 'GO:0016049', ('49', '60'))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('cell growth', 'CPA', (49, 60))
46178	30799953	Apoptosis analysis revealed that knockdown of COL5A1 significantly increased apoptosis of Caki-1 cells (Figure 3D).	('apoptosis', 'CPA', (77, 86))	('knockdown', 'Var', (33, 42))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('increased', 'PosReg', (67, 76))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('COL5A1', 'Gene', (46, 52))	('Caki-1', 'CellLine', 'CVCL:0234', (90, 96))
46181	30799953	As shown in Figure 5A, the tumor was significantly smaller in mice which received siRNA-COL5A1 intratumoral injection than in mice which received siRNA-control intratumoral injection.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('siRNA-COL5A1', 'Var', (82, 94))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mice', 'Species', '10090', (126, 130))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', (100, 105))	('mice', 'Species', '10090', (62, 66))	('smaller', 'NegReg', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', (165, 170))
46183	30799953	The abnormal change of BM or ECM could lead to detachment of tumor cells, which is the first stage of tumor metastasis.	('lead to', 'Reg', (39, 46))	('detachment', 'CPA', (47, 57))	('tumor metastasis', 'Disease', 'MESH:D009362', (102, 118))	('tumor metastasis', 'Disease', (102, 118))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('abnormal change', 'Var', (4, 19))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', (61, 66))
46201	30799953	Moreover, deletion of COL5A1 expression significantly inhibited tumor growth in vivo using siRNA technique.	('COL5A1', 'Gene', (22, 28))	('inhibited', 'NegReg', (54, 63))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('deletion', 'Var', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
46202	30799953	In addition, COL5A1 knockdown also significantly inhibited cell migration and invasion in vitro, suggesting that COL5A1 is involved in malignancy of ccRCC.	('involved', 'Reg', (123, 131))	('COL5A1', 'Gene', (13, 19))	('malignancy', 'Disease', 'MESH:D009369', (135, 145))	('cell migration', 'biological_process', 'GO:0016477', ('59', '73'))	('malignancy', 'Disease', (135, 145))	('knockdown', 'Var', (20, 29))	('inhibited', 'NegReg', (49, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (149, 154))	('ccRCC', 'Disease', (149, 154))
46214	33154194	Method: Gene expression matrix and clinical data were obtained from TCGA (The Cancer Genome Atlas), GSE26574, GSE2048, and GSE7023.	('GSE2048', 'Var', (110, 117))	('Cancer', 'Disease', (78, 84))	('GSE', 'Chemical', '-', (100, 103))	('GSE', 'Chemical', '-', (110, 113))	('Cancer', 'Disease', 'MESH:D009369', (78, 84))	('GSE26574', 'Var', (100, 108))	('GSE7023', 'Var', (123, 130))	('GSE2048', 'Chemical', '-', (110, 117))	('TCGA', 'Gene', (68, 72))	('Cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Gene expression', 'biological_process', 'GO:0010467', ('8', '23'))	('GSE7023', 'Chemical', '-', (123, 130))	('GSE', 'Chemical', '-', (123, 126))
46268	33154194	The results of transwell assays showed that Knockdown of TPX2 inhibited cell migration (Figure 11G and 11H).	('Knockdown', 'Var', (44, 53))	('TPX2', 'Gene', (57, 61))	('cell migration', 'CPA', (72, 86))	('cell migration', 'biological_process', 'GO:0016477', ('72', '86'))	('TPX2', 'Gene', '22974', (57, 61))	('inhibited', 'NegReg', (62, 71))
46285	33154194	In the TPX2 co-expression module, the synergistic effect between CENPF and FOXM1 were found to activate prostate malignancies; experimental verification showed that the synergistic effect of FOXM1 and CENPF promoted tumor growth by activating key signaling pathways and acted as an important marker of tumor prognosis and survival.	('prostate malignancies', 'Disease', (104, 125))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('key signaling pathways', 'Pathway', (243, 265))	('tumor', 'Disease', (216, 221))	('prostate malignancies', 'Disease', 'MESH:D011471', (104, 125))	('FOXM1', 'Gene', '2305', (191, 196))	('FOXM1', 'Gene', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('signaling', 'biological_process', 'GO:0023052', ('247', '256'))	('synergistic', 'Var', (169, 180))	('prostate malignancies', 'Phenotype', 'HP:0100787', (104, 125))	('CENPF', 'Gene', (65, 70))	('tumor', 'Disease', (302, 307))	('CENPF', 'Gene', '1063', (65, 70))	('TPX2', 'Gene', (7, 11))	('activate', 'PosReg', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('CENPF', 'Gene', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('TPX2', 'Gene', '22974', (7, 11))	('CENPF', 'Gene', '1063', (201, 206))	('activating', 'PosReg', (232, 242))	('FOXM1', 'Gene', '2305', (75, 80))	('FOXM1', 'Gene', (191, 196))	('promoted', 'PosReg', (207, 215))
46290	33154194	suggested TXNRD2 polymorphisms acted as the protective factors of gastric cancer.	('TXNRD2', 'Gene', '10587', (10, 16))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('polymorphisms', 'Var', (17, 30))	('TXNRD2', 'Gene', (10, 16))	('gastric cancer', 'Disease', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
46299	33154194	It is currently believed that tumors with high mutation burden are more likely to be detected and killed by the immune system, and to generate a stronger immune response.	('high mutation burden', 'Var', (42, 62))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('immune response', 'CPA', (154, 169))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('stronger', 'PosReg', (145, 153))	('immune response', 'biological_process', 'GO:0006955', ('154', '169'))
46340	33460239	And further investigations showed that KLF6, which collected from the intersection of databases, was the potential conjugated mRNAs of miR-513a-5p.	('KLF6', 'Gene', (39, 43))	('miR-513a-5p', 'Var', (135, 146))	('KLF6', 'Gene', '1316', (39, 43))	('miR-513a-5p', 'Chemical', '-', (135, 146))
46381	33460239	769-P cells were hybridized in hybridization buffer with the DNA oligo probes labelled with Cy5 for MIR4435-2HG and FAM for miR-513a-5p.	('Cy5', 'Var', (92, 95))	('MIR4435-2HG', 'Gene', '541471', (100, 111))	('Cy5', 'Chemical', 'MESH:C085321', (92, 95))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('MIR4435-2HG', 'Gene', (100, 111))	('miR-513a-5p', 'Chemical', '-', (124, 135))
46410	33460239	Initially, we used TCGA database to further identify the target genes modulated by MIR4435-2HG, among which miR-513a-5p was found significantly down-regulated (fold change >=2 or <=0.5, P < 0.05) (Figure 3A).	('miR-513a-5p', 'Var', (108, 119))	('down-regulated', 'NegReg', (144, 158))	('MIR4435-2HG', 'Gene', '541471', (83, 94))	('miR-513a-5p', 'Chemical', '-', (108, 119))	('MIR4435-2HG', 'Gene', (83, 94))
46411	33460239	Furthermore, we confirmed the expression level of miR-513a-5p in ccRCC tissues by applying qRT-PCR (Figure 3B).	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('miR-513a-5p', 'Chemical', '-', (50, 61))	('miR-513a-5p', 'Var', (50, 61))
46412	33460239	And we also validated the expression of MIR4435-2HG and miR-513a-5p in 40 fresh ccRCC tissues and obtained a negative correlation between MIR4435-2HG and miR-513a-5p (gamma = -0.3762, P < 0.01) (Figure 3C).	('miR-513a-5p', 'Chemical', '-', (154, 165))	('miR-513a-5p', 'Gene', (56, 67))	('miR-513a-5p', 'Chemical', '-', (56, 67))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('MIR4435-2HG', 'Gene', '541471', (40, 51))	('RCC', 'Disease', (82, 85))	('MIR4435-2HG', 'Gene', '541471', (138, 149))	('miR-513a-5p', 'Var', (154, 165))	('MIR4435-2HG', 'Gene', (138, 149))	('negative', 'NegReg', (109, 117))	('MIR4435-2HG', 'Gene', (40, 51))
46416	33460239	We further performed co-localization experiment to confirm the above results, which was consistent with the interaction of MIR4435-2HG and miR-513a-5p (Figure 3F).	('miR-513a-5p', 'Chemical', '-', (139, 150))	('MIR4435-2HG', 'Gene', '541471', (123, 134))	('MIR4435-2HG', 'Gene', (123, 134))	('interaction', 'Interaction', (108, 119))	('miR-513a-5p', 'Var', (139, 150))	('localization', 'biological_process', 'GO:0051179', ('24', '36'))
46423	33460239	Then, we detected the expression of KLF6 in 769-P and ACHN cells transfected with miR-513a-5p mimics or miR-513a-5p inhibitor, and the results revealed that miR-513a-5p could regulate the expression of KLF6 (Figure 4G).	('miR-513a-5p', 'Chemical', '-', (82, 93))	('KLF6', 'Gene', '1316', (202, 206))	('expression', 'MPA', (188, 198))	('KLF6', 'Gene', (36, 40))	('miR-513a-5p', 'Chemical', '-', (157, 168))	('regulate', 'Reg', (175, 183))	('miR-513a-5p', 'Chemical', '-', (104, 115))	('KLF6', 'Gene', (202, 206))	('KLF6', 'Gene', '1316', (36, 40))	('miR-513a-5p', 'Var', (157, 168))
46425	33460239	The overexpression of miR-513a-5p decreased the luciferase activity driven by KLF6-WT in HEK293FT cells, but did not change the activity of KLF6-MUT, which suggested that KLF6 was a direct target of miR-513a-5p (Figure 4H).	('activity', 'MPA', (59, 67))	('miR-513a-5p', 'Chemical', '-', (22, 33))	('KLF6', 'Gene', '1316', (171, 175))	('decreased', 'NegReg', (34, 43))	('luciferase activity', 'molecular_function', 'GO:0047077', ('48', '67'))	('KLF6', 'Gene', '1316', (140, 144))	('KLF6', 'Gene', (78, 82))	('miR-513a-5p', 'Chemical', '-', (199, 210))	('luciferase', 'Enzyme', (48, 58))	('HEK293FT', 'CellLine', 'CVCL:6911', (89, 97))	('miR-513a-5p', 'Var', (22, 33))	('luciferase activity', 'molecular_function', 'GO:0050397', ('48', '67'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('48', '67'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('48', '67'))	('KLF6', 'Gene', (140, 144))	('KLF6', 'Gene', (171, 175))	('luciferase activity', 'molecular_function', 'GO:0047712', ('48', '67'))	('KLF6', 'Gene', '1316', (78, 82))
46427	33460239	The up-regulation of KLF6 expression in ccRCC cells could reverse the promotion on cell viability (Figure 5A,B) and invasive capacity (Figure 5C) caused by miR-513a-5p up-expression.	('expression', 'MPA', (26, 36))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('up-expression', 'PosReg', (168, 181))	('KLF6', 'Gene', '1316', (21, 25))	('cell viability', 'CPA', (83, 97))	('promotion', 'PosReg', (70, 79))	('miR-513a-5p', 'Var', (156, 167))	('invasive capacity', 'CPA', (116, 133))	('up-regulation', 'PosReg', (4, 17))	('KLF6', 'Gene', (21, 25))	('miR-513a-5p', 'Chemical', '-', (156, 167))	('RCC', 'Disease', (42, 45))	('regulation', 'biological_process', 'GO:0065007', ('7', '17'))
46428	33460239	Accordingly, the down-regulation of KLF6 could reverse inhibition on cell viability (Figure 5A,B) and invasive capacity caused by miR-513a-5p knockdown Figure 5C).	('miR-513a-5p', 'Chemical', '-', (130, 141))	('KLF6', 'Gene', (36, 40))	('cell viability', 'CPA', (69, 83))	('regulation', 'biological_process', 'GO:0065007', ('22', '32'))	('miR-513a-5p', 'Var', (130, 141))	('invasive capacity', 'CPA', (102, 119))	('down-regulation', 'NegReg', (17, 32))	('KLF6', 'Gene', '1316', (36, 40))
46429	33460239	In addition, KLF6, the target gene of miR-513a-5p, in different transfection groups of 769-P and ACHN cells, was detected by Western blot, and the results are displayed in Figure 5D.	('KLF6', 'Gene', '1316', (13, 17))	('miR-513a-5p', 'Var', (38, 49))	('KLF6', 'Gene', (13, 17))	('miR-513a-5p', 'Chemical', '-', (38, 49))
46430	33460239	Moreover, tumours of miR-513a-5p antagonists groups presented higher positive rate of KLF6 compared with NC antagonist groups (Figure 5E).	('tumours', 'Disease', (10, 17))	('positive', 'MPA', (69, 77))	('miR-513a-5p antagonists', 'Var', (21, 44))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('KLF6', 'Gene', (86, 90))	('miR-513a-5p', 'Chemical', '-', (21, 32))	('higher', 'PosReg', (62, 68))	('tumours', 'Phenotype', 'HP:0002664', (10, 17))	('KLF6', 'Gene', '1316', (86, 90))	('tumours', 'Disease', 'MESH:D009369', (10, 17))
46431	33460239	These results highlighted that miR-513a-5p could suppress tumorigenesis of ccRCC by down-regulating KLF6.	('suppress', 'NegReg', (49, 57))	('miR-513a-5p', 'Var', (31, 42))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('KLF6', 'Gene', '1316', (100, 104))	('miR-513a-5p', 'Chemical', '-', (31, 42))	('down-regulating', 'NegReg', (84, 99))	('tumorigenesis', 'CPA', (58, 71))	('KLF6', 'Gene', (100, 104))
46438	33460239	MIR4435-2HG knockdown caused less tumour formation and significantly decreased tumour size compared with sh-NC+pcDNA3.1 group, whereas results demonstrated that the effect of MIR4435-2HG knockdown on tumour growth was reversed by KLF6 overexpression (Figure 7A,B).	('KLF6', 'Gene', (230, 234))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('knockdown', 'Var', (12, 21))	('MIR4435-2HG', 'Gene', '541471', (175, 186))	('MIR4435-2HG', 'Gene', '541471', (0, 11))	('tumour', 'Disease', (34, 40))	('tumour', 'Phenotype', 'HP:0002664', (200, 206))	('tumour', 'Disease', 'MESH:D009369', (200, 206))	('tumour growth', 'Disease', 'MESH:D006130', (200, 213))	('tumour', 'Disease', (200, 206))	('formation', 'biological_process', 'GO:0009058', ('41', '50'))	('KLF6', 'Gene', '1316', (230, 234))	('decreased', 'NegReg', (69, 78))	('MIR4435-2HG', 'Gene', (175, 186))	('MIR4435-2HG', 'Gene', (0, 11))	('less', 'NegReg', (29, 33))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('tumour growth', 'Disease', (200, 213))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', (79, 85))
46458	33460239	In our investigation, bioinformatic analysis showed that miR-513a-5p bound to MIR4435-2HG, which was confirmed by qRT-PCR and dual-luciferase reporter assay.	('MIR4435-2HG', 'Gene', '541471', (78, 89))	('MIR4435-2HG', 'Gene', (78, 89))	('bound', 'Interaction', (69, 74))	('miR-513a-5p', 'Var', (57, 68))	('miR-513a-5p', 'Chemical', '-', (57, 68))
46462	33460239	35  Bioinformatic analysis showed that miR-513a-5p bound to KLF6, which was also confirmed by qRT-PCR and dual-luciferase reporter assay.	('KLF6', 'Gene', '1316', (60, 64))	('miR-513a-5p', 'Chemical', '-', (39, 50))	('bound', 'Interaction', (51, 56))	('miR-513a-5p', 'Var', (39, 50))	('KLF6', 'Gene', (60, 64))
46463	33460239	The results revealed that miR-513a-5p could interact with KLF6, therefore modulated the expression of KLF6.	('KLF6', 'Gene', (58, 62))	('KLF6', 'Gene', '1316', (102, 106))	('modulated', 'Reg', (74, 83))	('KLF6', 'Gene', '1316', (58, 62))	('miR-513a-5p', 'Var', (26, 37))	('interact', 'Interaction', (44, 52))	('KLF6', 'Gene', (102, 106))	('expression', 'MPA', (88, 98))	('miR-513a-5p', 'Chemical', '-', (26, 37))
46470	30781655	Loss of MYBBP1A Induces Cancer Stem Cell Activity in Renal Cancer Tumors are cellular ecosystems where different populations and subpopulations of cells coexist.	('Cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Renal Cancer', 'Phenotype', 'HP:0009726', (53, 65))	('Induces', 'Reg', (16, 23))	('Renal Cancer', 'Disease', 'MESH:D007680', (53, 65))	('MYBBP1A', 'Gene', (8, 15))	('MYBBP1A', 'Gene', '10514', (8, 15))	('Renal Cancer', 'Disease', (53, 65))	('Tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Cancer', 'Phenotype', 'HP:0002664', (24, 30))	('Tumors', 'Phenotype', 'HP:0002664', (66, 72))	('Tumors', 'Disease', (66, 72))	('Tumors', 'Disease', 'MESH:D009369', (66, 72))	('Loss', 'Var', (0, 4))	('Cancer Stem Cell Activity', 'CPA', (24, 49))
46488	30781655	The capacity for which MYBBP1A binds several transcription factors involved in various biological processes, and the fact that MYBBP1A deletion in mice leads to embryonic death prior to blastocyst formation, suggest that MYBBP1A is a multifunctional protein involved in several essential biologic processes, such as early embryonic development and cell proliferation.	('deletion', 'Var', (135, 143))	('mice', 'Species', '10090', (147, 151))	('embryonic death', 'Disease', 'MESH:D003643', (161, 176))	('blastocyst', 'Disease', (186, 196))	('transcription', 'biological_process', 'GO:0006351', ('45', '58'))	('protein', 'cellular_component', 'GO:0003675', ('250', '257'))	('leads to', 'Reg', (152, 160))	('blastocyst formation', 'biological_process', 'GO:0001825', ('186', '206'))	('MYBBP1A', 'Gene', (127, 134))	('blastocyst', 'Disease', 'MESH:D020964', (186, 196))	('embryonic death', 'Disease', (161, 176))	('cell proliferation', 'biological_process', 'GO:0008283', ('348', '366'))
46497	30781655	The antisense against MYBBP1A was found in a loss of function screen to identify new genes involved in tumorigenesis, but if the loss of MYBBP1A is an important trait required for the evolution of tumor cells, it must be maintained throughout tumor growth; therefore, we should be able to identify it in human tumors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('human', 'Species', '9606', (304, 309))	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('tumors', 'Disease', (310, 316))	('loss', 'Var', (129, 133))	('tumor', 'Disease', (310, 315))	('MYBBP1A', 'Gene', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (310, 316))	('tumors', 'Disease', 'MESH:D009369', (310, 316))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
46510	30781655	It has been described that MYBBP1A binds to the leucine zipper motif within the NRD of c-MYB, being the c-MYB interacting doming in the N-terminus of MYBBP1A (Figure S3).	('c-MYB', 'Gene', '4602', (104, 109))	('binds', 'Interaction', (35, 40))	('leucine zipper motif', 'Var', (48, 68))	('c-MYB', 'Gene', (87, 92))	('c-MYB', 'Gene', (104, 109))	('NRD', 'biological_process', 'GO:0070651', ('80', '83'))	('c-MYB', 'Gene', '4602', (87, 92))	('MYBBP1A', 'Gene', (27, 34))
46518	30781655	We found that these genes have increased levels of transcription in A498 or 786-O MYBBP1A knock down cells related to the levels in control cells but not in ACHN or Caki-1 cells (Figure 2C).	('increased', 'PosReg', (31, 40))	('knock down', 'Var', (90, 100))	('ACHN', 'Gene', '55323', (157, 161))	('levels of transcription', 'MPA', (41, 64))	('MYBBP1A', 'Gene', (82, 89))	('transcription', 'biological_process', 'GO:0006351', ('51', '64'))	('ACHN', 'Gene', (157, 161))
46519	30781655	To confirm the increased expression of c-MYB target genes by MYBBP1A knock down, we measured the percentage of CD34+ cells.	('c-MYB', 'Gene', (39, 44))	('CD34', 'Gene', (111, 115))	('c-MYB', 'Gene', '4602', (39, 44))	('knock down', 'Var', (69, 79))	('expression', 'MPA', (25, 35))	('increased', 'PosReg', (15, 24))	('MYBBP1A', 'Gene', (61, 68))	('CD34', 'Gene', '947', (111, 115))
46521	30781655	Again, MYBBP1A knock down in A498 and 786-O cells increased the percentage of CD34+ cells (Figure 2D), while this increment was not observed in Caki-1 or ACHN cells.	('knock down', 'Var', (15, 25))	('CD34', 'Gene', (78, 82))	('ACHN', 'Gene', '55323', (154, 158))	('increased', 'PosReg', (50, 59))	('CD34', 'Gene', '947', (78, 82))	('MYBBP1A', 'Gene', (7, 14))	('ACHN', 'Gene', (154, 158))
46526	30781655	We observed that 786-O and A498 MYBBP1A knock down cells formed a higher percentage of tumorspheres than cells expressing the scramble vector (Figure 3A).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('MYBBP1A', 'Gene', (32, 39))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('higher', 'PosReg', (66, 72))	('knock down', 'Var', (40, 50))	('tumors', 'Disease', (87, 93))	('A498', 'Var', (27, 31))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
46527	30781655	However, the number of tumorspheres formed by Caki-1 and ACHN were the same in MYBBP1A knock down cells and cells expressing the scramble vector (Figure 3A).	('MYBBP1A', 'Gene', (79, 86))	('tumors', 'Disease', (23, 29))	('ACHN', 'Gene', '55323', (57, 61))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('knock down', 'Var', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('ACHN', 'Gene', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('Caki-1', 'Gene', (46, 52))
46529	30781655	After 50 days, we observed that tumorspheres from both cell lines formed tumors but tumorspheres from MYBBP1A knock down cells formed larger tumors (Figure 3B).	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('MYBBP1A', 'Gene', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('knock down', 'Var', (110, 120))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
46532	30781655	We observed increases in the number and size of tumorspheres formed in A498 MYBBP1A knock down cells compared to control cells, while there was no difference in the number of tumorspheres formed in ACHN MYBBP1A knock down cells (Figure 3C).	('tumors', 'Disease', (175, 181))	('ACHN', 'Gene', '55323', (198, 202))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('MYBBP1A', 'Gene', (76, 83))	('tumors', 'Disease', (48, 54))	('ACHN', 'Gene', (198, 202))	('A498', 'Var', (71, 75))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('knock down', 'Var', (84, 94))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('increases', 'PosReg', (12, 21))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
46534	30781655	We found that NANOG and TWIST1 expression were increased in 786-O and A498 MYBBP1A knock down cells related to the levels in control cells but were not increased in ACHN or Caki-1 cells (Figure 4A).	('A498', 'Var', (70, 74))	('TWIST1', 'Gene', (24, 30))	('knock down', 'Var', (83, 93))	('TWIST1', 'Gene', '7291', (24, 30))	('ACHN', 'Gene', '55323', (165, 169))	('NANOG', 'Gene', '79923', (14, 19))	('MYBBP1A', 'Gene', (75, 82))	('expression', 'MPA', (31, 41))	('increased', 'PosReg', (47, 56))	('NANOG', 'Gene', (14, 19))	('ACHN', 'Gene', (165, 169))
46538	30781655	We observed an increase in CXCR4 mRNA levels in 786-O MYBBP1A knock down cells either in the whole population or in tumorspheres only, but this increase was not observed in the ACHN cell line.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('knock down', 'Var', (62, 72))	('ACHN', 'Gene', '55323', (177, 181))	('CXCR4', 'molecular_function', 'GO:0038147', ('27', '32'))	('ACHN', 'Gene', (177, 181))	('increase', 'PosReg', (15, 23))	('MYBBP1A', 'Gene', (54, 61))	('CXCR4', 'Gene', '7852', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('CXCR4', 'Gene', (27, 32))
46540	30781655	Finally, we wondered if MYBBP1A knock down altered c-MYB levels, so we measured c-MYB protein levels in our cellular model by western blot.	('c-MYB', 'Gene', '4602', (51, 56))	('c-MYB', 'Gene', '4602', (80, 85))	('knock', 'Var', (32, 37))	('c-MYB', 'Gene', (51, 56))	('c-MYB', 'Gene', (80, 85))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('MYBBP1A', 'Gene', (24, 31))	('altered', 'Reg', (43, 50))
46541	30781655	Interestingly, we did not observed significant variations in c-MYB protein levels after MYBBP1A knock down (Figure S7), suggesting that MYBBP1A knock down alters c-MYB target genes expression but does not have a strong effect in c-MYB levels.	('expression', 'MPA', (181, 191))	('c-MYB', 'Gene', (61, 66))	('c-MYB', 'Gene', '4602', (229, 234))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('c-MYB', 'Gene', '4602', (61, 66))	('alters', 'Reg', (155, 161))	('MYBBP1A', 'Gene', (136, 143))	('c-MYB', 'Gene', (162, 167))	('knock down', 'Var', (144, 154))	('c-MYB', 'Gene', (229, 234))	('c-MYB', 'Gene', '4602', (162, 167))
46542	30781655	Our data clearly showed that MYBBP1A knock down increased the stem cell-like phenotype in some tumor cells and that these tumor cells seemed to have significant levels of c-MYB.	('increased', 'PosReg', (48, 57))	('c-MYB', 'Gene', (171, 176))	('stem cell-like phenotype', 'CPA', (62, 86))	('c-MYB', 'Gene', '4602', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('knock down', 'Var', (37, 47))	('MYBBP1A', 'Gene', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('levels', 'MPA', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', (95, 100))
46544	30781655	The previous data suggest that in our model, MYBBP1A knock down increases stem properties in cells that express high levels of c-MYB, so we wondered if this increase was translated into an increment in tumorigenic properties.	('tumor', 'Disease', (202, 207))	('knock down', 'Var', (53, 63))	('c-MYB', 'Gene', (127, 132))	('stem properties', 'CPA', (74, 89))	('c-MYB', 'Gene', '4602', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('MYBBP1A', 'Gene', (45, 52))	('increases', 'PosReg', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
46545	30781655	To confirm this hypothesis, we performed a soft agar assay and we found that A498 MYBBP1A knock down cells formed more colonies than cells expressing the scramble vector (Figure 5A).	('knock down', 'Var', (90, 100))	('colonies', 'CPA', (119, 127))	('agar', 'Chemical', 'MESH:D000362', (48, 52))	('MYBBP1A', 'Gene', (82, 89))
46546	30781655	However, ACHN and CaKi-1 MYBBP1A knock down cells formed the same number of colonies or an even lower number than the control cells (Figure 5A).	('CaKi-1 MYBBP1A', 'Gene', (18, 32))	('ACHN', 'Gene', '55323', (9, 13))	('ACHN', 'Gene', (9, 13))	('knock down', 'Var', (33, 43))
46548	30781655	However, ACHN and CaKi-1 MYBBP1A knock down cells formed xenograft tumors that were smaller than those of the control cells (Figure 5B).	('CaKi-1 MYBBP1A', 'Gene', (18, 32))	('ACHN', 'Gene', '55323', (9, 13))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('ACHN', 'Gene', (9, 13))	('knock down', 'Var', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('smaller', 'NegReg', (84, 91))	('tumors', 'Disease', (67, 73))
46549	30781655	In addition, we observed that A498 and 786-O MYBBP1A knock down cells also metastasized in some host mice before the primary tumors reached large sizes (Figure 5C), while the control cells did not.	('primary tumors', 'Disease', (117, 131))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('knock down', 'Var', (53, 63))	('primary tumors', 'Disease', 'MESH:D009369', (117, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('metastasized', 'CPA', (75, 87))	('mice', 'Species', '10090', (101, 105))	('MYBBP1A', 'Gene', (45, 52))
46551	30781655	However, the expression of genes related to EMT, such as SERPINE1, TWIST, VIM or SNAI1 are increased in metastasis showing an important correlation with MYBBP1A knock down.	('MYBBP1A', 'Gene', (153, 160))	('metastasis', 'CPA', (104, 114))	('expression', 'MPA', (13, 23))	('SNAI1', 'Gene', '6615', (81, 86))	('SNAI1', 'Gene', (81, 86))	('TWIST', 'Gene', '7291', (67, 72))	('TWIST', 'Gene', (67, 72))	('VIM', 'Gene', (74, 77))	('SERPINE1', 'Gene', '5054', (57, 65))	('increased', 'PosReg', (91, 100))	('SERPINE1', 'Gene', (57, 65))	('EMT', 'biological_process', 'GO:0001837', ('44', '47'))	('VIM', 'Gene', '7431', (74, 77))	('knock down', 'Var', (161, 171))
46553	30781655	These data confirm the tumor suppressor activity of MYBBP1A and points to a connection between MYBBP1A knock down and the induction of a metastatic phenotype in cell lines that express c-MYB (786-O and A498).	('knock down', 'Var', (103, 113))	('induction', 'Reg', (122, 131))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('23', '39'))	('c-MYB', 'Gene', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('MYBBP1A', 'Gene', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('c-MYB', 'Gene', '4602', (185, 190))	('tumor suppressor', 'biological_process', 'GO:0051726', ('23', '39'))	('tumor', 'Disease', (23, 28))	('metastatic', 'CPA', (137, 147))
46557	30781655	Patients with low levels of MYBBP1A protein have worse prognosis for both disease-free survival and overall survival (Figure 6F).	('MYBBP1A', 'Gene', (28, 35))	('disease-free survival', 'CPA', (74, 95))	('overall survival', 'CPA', (100, 116))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('low levels', 'Var', (14, 24))	('Patients', 'Species', '9606', (0, 8))	('protein', 'Protein', (36, 43))
46558	30781655	In addition, in order to confirm the association of MYBBP1A loss with worse prognosis, we analyzed the overall survival of patients with ccRCC on TCGA database and we observed that patients with tumors with low levels of MYBBP1A showed worse overall survival (Figure 6G).	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('MYBBP1A', 'Gene', (221, 228))	('overall survival', 'MPA', (242, 258))	('patients', 'Species', '9606', (123, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('patients', 'Species', '9606', (181, 189))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('low levels', 'Var', (207, 217))
46559	30781655	In sporadic ccRCC, VHL is mutated, deleted or epigenetically silenced in around 85-90% of tumors.	('ccRCC', 'Phenotype', 'HP:0006770', (12, 17))	('ccRCC', 'Disease', (12, 17))	('epigenetically silenced', 'Var', (46, 69))	('deleted', 'Var', (35, 42))	('VHL', 'Gene', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('mutated', 'Var', (26, 33))	('VHL', 'Gene', '7428', (19, 22))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))
46568	30781655	Our data suggest that MYBBP1A knock down de-represses c-MYB, inducing transcriptional activation of its target genes and an increase in the CSC pool.	('increase', 'PosReg', (124, 132))	('c-MYB', 'Gene', (54, 59))	('MYBBP1A', 'Gene', (22, 29))	('c-MYB', 'Gene', '4602', (54, 59))	('knock down', 'Var', (30, 40))	('CSC pool', 'MPA', (140, 148))	('de-represses', 'NegReg', (41, 53))	('transcriptional activation', 'MPA', (70, 96))
46570	30781655	The human MYBBP1A gene maps to chromosome 17p13.3 between markers D17S1828 and D17S938.	('chromosome', 'cellular_component', 'GO:0005694', ('31', '41'))	('human', 'Species', '9606', (4, 9))	('D17S938', 'Var', (79, 86))	('D17S1828', 'Var', (66, 74))	('MYBBP1A', 'Gene', (10, 17))
46578	30781655	In this case, MYBBP1A may play a role in tumor prevention by enhancing p53 activation.	('activation', 'MPA', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('MYBBP1A', 'Var', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('enhancing', 'PosReg', (61, 70))
46583	30781655	We have also found that MYBBP1A knock down increases the expression of CD34, NANOG and CXCR4, which are target genes of c-MYB, exclusively in renal carcinoma cell lines that express high levels of c-MYB.	('NANOG', 'Gene', '79923', (77, 82))	('NANOG', 'Gene', (77, 82))	('CD34', 'Gene', '947', (71, 75))	('renal carcinoma', 'Phenotype', 'HP:0005584', (142, 157))	('knock down', 'Var', (32, 42))	('c-MYB', 'Gene', '4602', (120, 125))	('increases', 'PosReg', (43, 52))	('MYBBP1A', 'Gene', (24, 31))	('expression', 'MPA', (57, 67))	('c-MYB', 'Gene', (120, 125))	('CXCR4', 'molecular_function', 'GO:0038147', ('87', '92'))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('c-MYB', 'Gene', '4602', (197, 202))	('CD34', 'Gene', (71, 75))	('c-MYB', 'Gene', (197, 202))	('renal carcinoma', 'Disease', 'MESH:C538614', (142, 157))	('CXCR4', 'Gene', '7852', (87, 92))	('renal carcinoma', 'Disease', (142, 157))	('CXCR4', 'Gene', (87, 92))
46590	30781655	Therefore, we propose that loss of MYBBP1A leads to an increase in c-MYB activity, which controls self-renewal and differentiation of cells and induces the transcription of genes involved in the stem phenotype, thus increasing and potentiating stemness.	('c-MYB', 'Gene', (67, 72))	('loss', 'Var', (27, 31))	('increase', 'PosReg', (55, 63))	('potentiating', 'PosReg', (231, 243))	('activity', 'MPA', (73, 81))	('transcription', 'biological_process', 'GO:0006351', ('156', '169'))	('c-MYB', 'Gene', '4602', (67, 72))	('induces', 'Reg', (144, 151))	('transcription', 'MPA', (156, 169))	('stemness', 'Disease', 'MESH:D020295', (244, 252))	('stemness', 'Disease', (244, 252))	('increasing', 'PosReg', (216, 226))	('MYBBP1A', 'Gene', (35, 42))
46593	30781655	The deregulation or overexpression of c-MYB has been detected in a wide variety of human cancers and is associated with poorly differentiated tumors, including leukemia, colon and breast tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('colon and breast tumors', 'Disease', 'MESH:D015179', (170, 193))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('overexpression', 'PosReg', (20, 34))	('associated', 'Reg', (104, 114))	('detected', 'Reg', (53, 61))	('cancers', 'Disease', (89, 96))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('leukemia', 'Disease', 'MESH:D007938', (160, 168))	('leukemia', 'Disease', (160, 168))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', (142, 148))	('c-MYB', 'Gene', '4602', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('deregulation', 'Var', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('c-MYB', 'Gene', (38, 43))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('breast tumors', 'Phenotype', 'HP:0100013', (180, 193))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', (187, 193))	('human', 'Species', '9606', (83, 88))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('leukemia', 'Phenotype', 'HP:0001909', (160, 168))
46596	30781655	Here we show that MYBBP1A acts as a negative regulator of c-MYB, as loss of MYBBP1A leads to an increase of c-MYB activity in renal carcinoma cell lines.	('c-MYB', 'Gene', '4602', (108, 113))	('activity', 'MPA', (114, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('MYBBP1A', 'Gene', (76, 83))	('renal carcinoma', 'Disease', 'MESH:C538614', (126, 141))	('c-MYB', 'Gene', (58, 63))	('renal carcinoma', 'Disease', (126, 141))	('c-MYB', 'Gene', '4602', (58, 63))	('c-MYB', 'Gene', (108, 113))	('loss', 'Var', (68, 72))	('increase', 'PosReg', (96, 104))	('renal carcinoma', 'Phenotype', 'HP:0005584', (126, 141))
46605	30781655	We also found that loss of MYBBP1A is associated with a metastatic tendency and poorer prognosis in human tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('associated', 'Reg', (38, 48))	('metastatic tendency', 'CPA', (56, 75))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('human', 'Species', '9606', (100, 105))	('loss', 'Var', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('MYBBP1A', 'Gene', (27, 34))
46629	30781655	We used the following probes (Applied biosystems, Foster City, CA, USA): beta-Actin (Hs0160665_g1), MYBBP1A (Hs00959671_m1), NANOG (Hs04260366_g1), OCT4 (Hs00999632_g1), SOX2 (Hs01053049_s1), TWIST1 (Hs01675818_s1), CD34 (Hs00990732_m1), CXCR4 (Hs00607978_s1), MYB (Hs00920556_m1), SNAI1 (Hs00195591_m1), VIM (Hs00958111_m1) and SERPINE1 (Hs00167155_m1).	('CXCR4', 'Gene', '7852', (238, 243))	('Hs00920556_m1', 'Var', (266, 279))	('SNAI1', 'Gene', '6615', (282, 287))	('TWIST1', 'Gene', (192, 198))	('VIM', 'Gene', (305, 308))	('SOX2', 'Gene', (170, 174))	('Hs01053049_s1', 'Var', (176, 189))	('CXCR4', 'Gene', (238, 243))	('SOX2', 'Gene', '6657', (170, 174))	('CD34', 'Gene', (216, 220))	('SERPINE1', 'Gene', (329, 337))	('Hs00958111_m1', 'Var', (310, 323))	('OCT4', 'Gene', '5460', (148, 152))	('TWIST1', 'Gene', '7291', (192, 198))	('Hs00195591_m1', 'Var', (289, 302))	('Hs00167155_m1', 'Var', (339, 352))	('CXCR4', 'molecular_function', 'GO:0038147', ('238', '243'))	('Hs01675818_s1', 'Var', (200, 213))	('SERPINE1', 'Gene', '5054', (329, 337))	('MYB', 'Gene', '4602', (261, 264))	('OCT4', 'Gene', (148, 152))	('MYB', 'Gene', (261, 264))	('beta-Actin', 'Gene', (73, 83))	('beta-Actin', 'Gene', '728378', (73, 83))	('CD34', 'Gene', '947', (216, 220))	('Hs00607978_s1', 'Var', (245, 258))	('MYB', 'Gene', '4602', (100, 103))	('Hs00999632_g1', 'Var', (154, 167))	('Hs00959671_m1', 'Var', (109, 122))	('MYB', 'Gene', (100, 103))	('Hs04260366_g1', 'Var', (132, 145))	('Hs00990732_m1', 'Var', (222, 235))	('NANOG', 'Gene', '79923', (125, 130))	('NANOG', 'Gene', (125, 130))	('SNAI1', 'Gene', (282, 287))	('VIM', 'Gene', '7431', (305, 308))
46642	30781655	MYBBP1A knock down in renal carcinoma cell lines results into an increase in c-MYB target genes expression, leading to an increase in the stem population.	('increase', 'PosReg', (65, 73))	('renal carcinoma', 'Disease', (22, 37))	('c-MYB', 'Gene', (77, 82))	('c-MYB', 'Gene', '4602', (77, 82))	('renal carcinoma', 'Phenotype', 'HP:0005584', (22, 37))	('knock down', 'Var', (8, 18))	('expression', 'MPA', (96, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('MYBBP1A', 'Gene', (0, 7))	('stem population', 'CPA', (138, 153))	('increase', 'PosReg', (122, 130))	('renal carcinoma', 'Disease', 'MESH:C538614', (22, 37))
46646	30781655	Table S1: Patient clinical characteristics of the cohort used in our study, Table S2: Percentage of cases of each renal cell carcinoma subtype in low MYBBP1A and normal MYBBP1A groups.	('Patient', 'Species', '9606', (10, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('low MYBBP1A', 'Var', (146, 157))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (114, 134))	('renal cell carcinoma subtype', 'Disease', (114, 142))	('renal cell carcinoma subtype', 'Disease', 'MESH:C538614', (114, 142))
46653	33863293	High expression of GMFG predicted worse OS in GBM (HR = 1.5, P = 0.017), LGG (HR = 2.2, P < 0.001), LUSC (HR = 1.4, P = 0.022) and ocular melanomas (UVM) (HR = 7, P < 0.001), as well as worse DFS in LGG (HR = 1.8, P < 0.001) and prostate cancer (PRAD) (HR = 1.9, P = 0.004).	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('High expression', 'Var', (0, 15))	('LUSC', 'Disease', (100, 104))	('ocular melanomas', 'Phenotype', 'HP:0025534', (131, 147))	('prostate cancer', 'Disease', (229, 244))	('LGG', 'Disease', (199, 202))	('ocular melanomas', 'Disease', 'MESH:D008545', (131, 147))	('LGG', 'Disease', (73, 76))	('GMFG', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('GBM', 'Disease', (46, 49))	('ocular melanomas', 'Disease', (131, 147))	('prostate cancer', 'Disease', 'MESH:D011471', (229, 244))	('prostate cancer', 'Phenotype', 'HP:0012125', (229, 244))	('melanomas', 'Phenotype', 'HP:0002861', (138, 147))	('GBM', 'Phenotype', 'HP:0012174', (46, 49))	('LUSC', 'Phenotype', 'HP:0030359', (100, 104))
46654	33863293	In contrast, high expression of GMFG was associated with better OS in skin cutaneous melanoma (SKCM) (HR = 0.59, P < 0.001) and thymoma (THYM) (HR = 0.098, P = 0.031), as well as better DFS in bile duct cancer (CHOL) (HR = 0.2, P = 0.003).	('THYM', 'Phenotype', 'HP:0100522', (137, 141))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (70, 93))	('GMFG', 'Gene', (32, 36))	('bile duct cancer', 'Phenotype', 'HP:0030153', (193, 209))	('high expression', 'Var', (13, 28))	('bile duct cancer', 'Disease', (193, 209))	('thymoma', 'Phenotype', 'HP:0100522', (128, 135))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('skin cutaneous melanoma', 'Disease', (70, 93))	('thymoma', 'Disease', 'MESH:D013945', (128, 135))	('bile duct cancer', 'Disease', 'MESH:D001650', (193, 209))	('thymoma', 'Disease', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (75, 93))	('CHOL', 'Disease', (211, 215))	('CHOL', 'Disease', 'None', (211, 215))
46656	33863293	Our study preliminarily identified that GMFG may cause different survivals for different cancers through modulating tumor progression, immune response status and tissue-specific tumor microenvironment (TME).	('iron', 'Chemical', 'MESH:D007501', (192, 196))	('immune response', 'biological_process', 'GO:0006955', ('135', '150'))	('immune response', 'CPA', (135, 150))	('tumor', 'Disease', (178, 183))	('GMFG', 'Var', (40, 44))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('survivals', 'Disease', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cause', 'Reg', (49, 54))	('tumor', 'Disease', (116, 121))	('modulating', 'Reg', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
46662	33863293	These two studies demonstrated that GMFG could promote the migration and proliferation of ovarian and colorectal cancer cells, and the high expression of GMFG was related to poor survival outcome for ovarian cancer patients.	('ovarian', 'Disease', 'MESH:D010049', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('ovarian cancer', 'Disease', 'MESH:D010051', (200, 214))	('related', 'Reg', (163, 170))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('GMFG', 'Gene', (154, 158))	('high', 'Var', (135, 139))	('ovarian', 'Disease', (90, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('migration', 'CPA', (59, 68))	('ovarian cancer', 'Disease', (200, 214))	('colorectal cancer', 'Disease', (102, 119))	('promote', 'PosReg', (47, 54))	('ovarian cancer', 'Phenotype', 'HP:0100615', (200, 214))	('ovarian', 'Disease', (200, 207))	('patients', 'Species', '9606', (215, 223))	('ovarian', 'Disease', 'MESH:D010049', (90, 97))	('proliferation', 'CPA', (73, 86))	('rectal cancer', 'Phenotype', 'HP:0100743', (106, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))
46680	33863293	1c, high expression of GMFG was correlated with early pathological stage in bladder cancer (BLCA) (P = 0.016), LUAD (P = 0.015), skin cutaneous melanoma (SKCM) (P = 0.006) and thyroid cancer (THCA) (P = 0.01), but was linked with advanced pathological stage in stomach cancer (STAD) (P = 0.028).	('skin cutaneous melanoma', 'Disease', (129, 152))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('high expression', 'Var', (4, 19))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (134, 152))	('thyroid cancer', 'Disease', (176, 190))	('stomach cancer', 'Disease', 'MESH:D013274', (261, 275))	('stomach cancer', 'Phenotype', 'HP:0012126', (261, 275))	('LUAD', 'Phenotype', 'HP:0030078', (111, 115))	('THCA', 'Phenotype', 'HP:0002890', (192, 196))	('thyroid cancer', 'Disease', 'MESH:D013964', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('correlated', 'Reg', (32, 42))	('LUAD', 'Disease', (111, 115))	('GMFG', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))	('bladder cancer', 'Disease', (76, 90))	('thyroid cancer', 'Phenotype', 'HP:0002890', (176, 190))	('stomach cancer', 'Disease', (261, 275))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (129, 152))	('BLCA', 'Phenotype', 'HP:0009725', (92, 96))
46681	33863293	For survival outcome, high expression of GMFG predicted worse OS in GBM (HR = 1.5, P = 0.017), LGG (HR = 2.2, P < 0.001), LUSC (HR = 1.4, P = 0.022) and UVM (HR = 7, P < 0.001), as well as worse DFS in LGG (HR = 1.8, P < 0.001) and prostate cancer (PRAD) (HR = 1.9, P = 0.004).	('high expression', 'Var', (22, 37))	('prostate cancer', 'Disease', (232, 247))	('LGG', 'Disease', (202, 205))	('GBM', 'Phenotype', 'HP:0012174', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('GMFG', 'Gene', (41, 45))	('GBM', 'Disease', (68, 71))	('prostate cancer', 'Disease', 'MESH:D011471', (232, 247))	('prostate cancer', 'Phenotype', 'HP:0012125', (232, 247))	('LUSC', 'Phenotype', 'HP:0030359', (122, 126))	('LGG', 'Disease', (95, 98))	('UVM', 'Disease', (153, 156))	('LUSC', 'Disease', (122, 126))
46682	33863293	In contrast, high expression of GMFG was associated with better OS in SKCM (HR = 0.59, P < 0.001) and THYM (HR = 0.098, P = 0.031), as well as better DFS in bile duct cancer (CHOL) (HR = 0.2, P = 0.003) (Fig.	('bile duct cancer', 'Disease', 'MESH:D001650', (157, 173))	('CHOL', 'Disease', 'None', (175, 179))	('THYM', 'Phenotype', 'HP:0100522', (102, 106))	('SKCM', 'Disease', (70, 74))	('CHOL', 'Disease', (175, 179))	('GMFG', 'Gene', (32, 36))	('high expression', 'Var', (13, 28))	('THYM', 'Disease', (102, 106))	('bile duct cancer', 'Phenotype', 'HP:0030153', (157, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('bile duct cancer', 'Disease', (157, 173))
46688	33863293	We also summarized the top 10 most significant items of GO/KEGG pathways for each individual cancer (Supplementary file 1-4: Table S1-S4), and we found that GMFG was notably associated with the biological process of immune response in most cancers, so we decided to analyze the correlation between GMFG and its immunomodulators co-expression genes.	('cancer', 'Disease', (93, 99))	('associated with', 'Reg', (174, 189))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('immune response', 'biological_process', 'GO:0006955', ('216', '231'))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('GMFG', 'Var', (157, 161))	('cancers', 'Disease', (240, 247))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('biological process', 'biological_process', 'GO:0008150', ('194', '212'))	('cancer', 'Disease', (240, 246))	('cancers', 'Disease', 'MESH:D009369', (240, 247))
46690	33863293	As for co-stimulators, GMFG was highly associated with CD80 and CD28 in most cancers.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('CD28', 'Gene', (64, 68))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('GMFG', 'Var', (23, 27))	('cancers', 'Disease', (77, 84))	('CD28', 'Gene', '940', (64, 68))	('CD80', 'Gene', (55, 59))	('associated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('CD80', 'Gene', '941', (55, 59))
46700	33863293	In addition, high expression of GMFG was associated with early pathological stage in four cancers (BLCA, LUAD, SKCM, and THCA), but was correlated with advanced pathological stage in STAD.	('cancers', 'Disease', (90, 97))	('associated', 'Reg', (41, 51))	('SKCM', 'Disease', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('high', 'Var', (13, 17))	('BLCA', 'Phenotype', 'HP:0009725', (99, 103))	('GMFG', 'Gene', (32, 36))	('LUAD', 'Disease', (105, 109))	('THCA', 'Phenotype', 'HP:0002890', (121, 125))	('correlated', 'Reg', (136, 146))	('LUAD', 'Phenotype', 'HP:0030078', (105, 109))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
46701	33863293	Moreover, the associations of GMFG expression with OS and DFS were also investigated, and high expression of GMFG predicted worse OS in four cancers (GBM, LGG, LUSC, and UVM), and worse DFS for LGG and PRAD, but was associated with better OS in SKCM and THYM, better DFS in CHOL.	('better OS', 'Disease', (232, 241))	('PRAD', 'Disease', (202, 206))	('LUSC', 'Phenotype', 'HP:0030359', (160, 164))	('high expression', 'Var', (90, 105))	('SKCM', 'Disease', (245, 249))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('CHOL', 'Disease', 'None', (274, 278))	('cancers', 'Disease', (141, 148))	('LGG', 'Disease', (155, 158))	('THYM', 'Phenotype', 'HP:0100522', (254, 258))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('GMFG', 'Gene', (109, 113))	('CHOL', 'Disease', (274, 278))	('GBM', 'Phenotype', 'HP:0012174', (150, 153))	('worse OS', 'Disease', (124, 132))	('LUSC', 'Disease', (160, 164))	('LGG', 'Disease', (194, 197))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('THYM', 'Disease', (254, 258))
46709	33863293	Taken together, that GMFG enhances both the cancer progression and the immune defense, and patients' survival outcome may depend on the balance between the speed of cancer development and the ability of immune system against cancer tissues.	('immune defense', 'CPA', (71, 85))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('patients', 'Species', '9606', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (225, 231))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('GMFG', 'Var', (21, 25))	('enhances', 'PosReg', (26, 34))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
46712	33863293	Recent studies reported that GMFG regulates monocyte migration by modulating ITGB1, and functions as a negative regulator of Toll-like receptor 4 (TLR4) signaling through facilitating TLR4 endocytic trafficking in macrophages.	('ITGB1', 'Gene', (77, 82))	('signaling', 'biological_process', 'GO:0023052', ('153', '162'))	('GMFG', 'Var', (29, 33))	('TLR4', 'Gene', (147, 151))	('TLR4', 'Gene', '7099', (184, 188))	('modulating', 'Reg', (66, 76))	('regulates', 'Reg', (34, 43))	('facilitating', 'PosReg', (171, 183))	('ITGB1', 'Gene', '3688', (77, 82))	('TLR4', 'Gene', (184, 188))	('Toll-like receptor 4', 'Gene', '7099', (125, 145))	('TLR4', 'Gene', '7099', (147, 151))	('Toll-like receptor 4', 'Gene', (125, 145))	('monocyte migration', 'CPA', (44, 62))
46745	30061365	Upregulation of PI3/AKT/mTOR pathway in additional TFE3-tRCC models were confirmed by significantly higher expression of phospho-S6 (P<0.0001) and phospho-4EBP1 (P<0.0001) in established tRCC cell lines compared to clear cell RCC cells.	('phospho', 'Chemical', 'MESH:C033601', (121, 128))	('RCC', 'Disease', (226, 229))	('RCC', 'Disease', 'MESH:D002292', (188, 191))	('PI3', 'Gene', '5266', (16, 19))	('higher', 'PosReg', (100, 106))	('phospho-S6', 'Var', (121, 131))	('mTOR', 'Gene', (24, 28))	('RCC', 'Disease', 'MESH:D002292', (226, 229))	('AKT', 'Gene', (20, 23))	('PI3', 'Gene', (16, 19))	('phospho', 'Chemical', 'MESH:C033601', (147, 154))	('RCC', 'Disease', (57, 60))	('mTOR', 'Gene', '2475', (24, 28))	('Upregulation', 'PosReg', (0, 12))	('BP1', 'Gene', '474256', (157, 160))	('expression', 'MPA', (107, 117))	('RCC', 'Disease', 'MESH:D002292', (57, 60))	('RCC', 'Disease', (188, 191))	('BP1', 'Gene', (157, 160))	('AKT', 'Gene', '207', (20, 23))
46749	30061365	Micropthalmia transcription factor (MiT) family tRCC is a distinct subtype of kidney cancer characterized by gene fusions resulting from translocations involving TFE3 (Xp11.2 locus or TFEB (6p21 locus) with various partner gene.	('RCC', 'Disease', 'MESH:D002292', (49, 52))	('RCC', 'Disease', (49, 52))	('TFEB', 'Gene', (184, 188))	('Micropthalmia transcription factor', 'Disease', (0, 34))	('p11', 'Gene', '6281', (169, 172))	('transcription factor', 'molecular_function', 'GO:0000981', ('14', '34'))	('transcription', 'biological_process', 'GO:0006351', ('14', '27'))	('Micropthalmia transcription factor', 'Disease', 'OMIM:602482', (0, 34))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('kidney cancer', 'Phenotype', 'HP:0009726', (78, 91))	('p11', 'Gene', (169, 172))	('kidney cancer', 'Disease', 'MESH:D007680', (78, 91))	('translocations', 'Var', (137, 151))	('TFEB', 'Gene', '7942', (184, 188))	('kidney cancer', 'Disease', (78, 91))
46754	30061365	Genetically engineered cell lines, as well mouse models, have been generated to study the biology of various tumors harboring TFE3 fusions.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('fusions', 'Var', (131, 138))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('TFE3', 'Gene', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mouse', 'Species', '10090', (43, 48))	('tumors', 'Disease', (109, 115))
46766	30061365	Furthermore, dysregulated miRNAs have been frequently implicated in carcinogenesis.	('miRNAs', 'Protein', (26, 32))	('carcinogenesis', 'Disease', 'MESH:D063646', (68, 82))	('implicated', 'Reg', (54, 64))	('carcinogenesis', 'Disease', (68, 82))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('dysregulated', 'Var', (13, 25))
46819	30061365	Approximately six-week old NSG mice were implanted subcutaneously with ~ 3 mm3 pieces of RP-R07 tumor and allowed to grow until tumors reached 200 mm3 in volume prior to treatment with either vehicle, Rapamycin (EMD chemicals, USA), MLN0128 (kindly provided by Millenium Pharmaceuticals, USA) or BEZ-235 (kindly provided by Novartis Pharmaceuticals, USA).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('mice', 'Species', '10090', (31, 35))	('tumors', 'Disease', (128, 134))	('Millenium', 'Chemical', 'None', (261, 270))	('EMD', 'Disease', (212, 215))	('N', 'Chemical', 'MESH:D009584', (235, 236))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('N', 'Chemical', 'MESH:D009584', (27, 28))	('EMD', 'Disease', 'None', (212, 215))	('MLN0128', 'Var', (233, 240))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('BEZ-235', 'Chemical', 'MESH:C531198', (296, 303))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('MLN0128', 'Chemical', 'MESH:C572449', (233, 240))	('Rapamycin', 'Chemical', 'MESH:D020123', (201, 210))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('N', 'Chemical', 'MESH:D009584', (324, 325))
46847	30061365	We identified enhanced nuclear immunoreactivity of C-terminal TFE3 in three different tRCC models: RP-R07 (SFPQ-TFE3), UOK-109 (NONO-TFE3), and UOK-146 (PRCC-TFE3).	('RP-R07', 'Var', (99, 105))	('NONO-TFE3', 'Gene', (128, 137))	('RCC', 'Disease', 'MESH:D002292', (87, 90))	('RCC', 'Disease', (87, 90))	('SFPQ-TFE3', 'Gene', (107, 116))	('C-terminal', 'Protein', (51, 61))	('nuclear immunoreactivity', 'MPA', (23, 47))	('enhanced', 'PosReg', (14, 22))	('SFPQ-TFE3', 'Gene', '6421;7030', (107, 116))	('PRCC-TFE3', 'Gene', '5546;7030', (153, 162))	('UOK-146', 'CellLine', 'CVCL:B123', (144, 151))	('RCC', 'Disease', (154, 157))	('UOK-109', 'Var', (119, 126))	('RCC', 'Disease', 'MESH:D002292', (154, 157))	('PRCC-TFE3', 'Gene', (153, 162))	('UOK-146', 'Var', (144, 151))	('NONO-TFE3', 'Gene', '4841;7030', (128, 137))	('TFE3', 'Gene', (62, 66))
46861	30061365	Expression profile analysis of the whole microRNAome in tRCC (RP-R07t), ccRCC and pRCC PDX models (also established in our lab) was performed using TaqMan  low-density array human microRNA card set A+B.	('RCC', 'Disease', 'MESH:D002292', (83, 86))	('RCC', 'Disease', (83, 86))	('human', 'Species', '9606', (174, 179))	('pRCC', 'Gene', (82, 86))	('N', 'Chemical', 'MESH:D009584', (47, 48))	('RP-R07t', 'Var', (62, 69))	('RCC', 'Disease', (74, 77))	('RCC', 'Disease', 'MESH:D002292', (57, 60))	('RCC', 'Disease', (57, 60))	('RCC', 'Disease', 'MESH:D002292', (74, 77))	('N', 'Chemical', 'MESH:D009584', (186, 187))	('pRCC', 'Gene', '5546', (82, 86))
46868	30061365	Hierarchical clustering heatmap revealed significantly targeted pathways by the miRNA signature in cluster 3 (Fig.	('N', 'Chemical', 'MESH:D009584', (83, 84))	('targeted', 'Reg', (55, 63))	('miRNA signature', 'Var', (80, 95))
46871	30061365	A complete list of the statistically enriched pathways targeted by differential expression of miRNA in cluster 3 is available in Supplementary Table S6.	('N', 'Chemical', 'MESH:D009584', (97, 98))	('miRNA', 'Gene', (94, 99))	('differential expression', 'Var', (67, 90))
46873	30061365	S5) shows that almost all predicted genes in this pathway are targeted by aberrantly expressed miRNA in cluster 3, including PI3KCA, AKT1, IRS1, RPS6, TSC1, eIF4BP1, and mTOR among others.	('eIF4BP1', 'Gene', (157, 164))	('RPS6', 'Gene', '6194', (145, 149))	('PI3', 'Gene', (125, 128))	('N', 'Chemical', 'MESH:D009584', (98, 99))	('TSC1', 'Gene', '7248', (151, 155))	('mTOR', 'Gene', (170, 174))	('mTOR', 'Gene', '2475', (170, 174))	('IRS1', 'Gene', '3667', (139, 143))	('aberrantly', 'Var', (74, 84))	('IRS1', 'Gene', (139, 143))	('RPS6', 'Gene', (145, 149))	('eIF4BP1', 'Gene', '319118', (157, 164))	('PI3', 'Gene', '5266', (125, 128))	('TSC1', 'Gene', (151, 155))	('eIF4', 'cellular_component', 'GO:0008304', ('157', '161'))	('AKT1', 'Gene', '207', (133, 137))	('miRNA', 'Gene', (95, 100))	('AKT1', 'Gene', (133, 137))
46886	30061365	We designed three vertical inhibition schemas to target the PI3K/AKT/mTOR axis at different points within the pathway: 1) PI3K/AKT axis inhibition with the P13K inhibitor BKM-120, 2) m-TOR axis inhibition with the pan-mTOR inhibitor MLN0128, and 3) simultaneous inhibition of the PI3K/AKT and mTOR axis with the dual P13K/mTOR inhibitor BEZ-235.	('mTOR', 'Gene', '2475', (69, 73))	('TOR', 'Gene', (323, 326))	('TOR', 'Gene', (70, 73))	('AKT', 'Gene', (285, 288))	('PI3', 'Gene', '5266', (122, 125))	('PI3', 'Gene', (60, 63))	('P13K', 'Var', (156, 160))	('mTOR', 'Gene', '2475', (322, 326))	('mTOR', 'Gene', (218, 222))	('AKT', 'Gene', '207', (65, 68))	('TOR', 'Gene', '6097', (185, 188))	('TOR', 'Gene', '6097', (219, 222))	('TOR', 'Gene', (219, 222))	('P13K', 'Mutation', 'p.P13K', (156, 160))	('PI3', 'Gene', (280, 283))	('mTOR', 'Gene', '2475', (218, 222))	('BKM-120', 'Var', (171, 178))	('PI3', 'Gene', '5266', (280, 283))	('PI3K', 'molecular_function', 'GO:0016303', ('280', '284'))	('AKT', 'Gene', '207', (127, 130))	('TOR', 'Gene', '6097', (294, 297))	('PI3', 'Gene', (122, 125))	('AKT', 'Gene', '207', (285, 288))	('MLN0128', 'Var', (233, 240))	('TOR', 'Gene', (185, 188))	('inhibition', 'NegReg', (194, 204))	('mTOR', 'Gene', (293, 297))	('TOR', 'Gene', (294, 297))	('mTOR', 'Gene', (69, 73))	('PI3', 'Gene', '5266', (60, 63))	('TOR', 'Gene', '6097', (323, 326))	('TOR', 'Gene', '6097', (70, 73))	('BEZ-235', 'Chemical', 'MESH:C531198', (337, 344))	('mTOR', 'Gene', '2475', (293, 297))	('AKT', 'Gene', (65, 68))	('MLN0128', 'Chemical', 'MESH:C572449', (233, 240))	('PI3K', 'molecular_function', 'GO:0016303', ('60', '64'))	('mTOR', 'Gene', (322, 326))	('inhibition', 'NegReg', (136, 146))	('PI3K', 'molecular_function', 'GO:0016303', ('122', '126'))	('P13K', 'Mutation', 'p.P13K', (317, 321))	('AKT', 'Gene', (127, 130))
46891	30061365	An MTT assay was performed after cells were treated with different concentrations of BKM-120, MLN0128, rapamycin or BEZ-235 for 96 hours to assess the anti-tumor activity of these agents (Fig.	('MLN0128', 'Var', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('BKM-120', 'Var', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('MLN0128', 'Chemical', 'MESH:C572449', (94, 101))	('BEZ-235', 'Chemical', 'MESH:C531198', (116, 123))	('tumor', 'Disease', (156, 161))	('rapamycin', 'Chemical', 'MESH:D020123', (103, 112))	('MTT', 'Chemical', 'MESH:C022616', (3, 6))
46892	30061365	BKM-120 treatment inhibited cellular proliferation in a concentration-dependent manner with IC50 values of 420, 373.6 and 714 nM for RP-R07, UOK-109, and UOK-146, respectively (Fig.	('RP-R07', 'Var', (133, 139))	('UOK-146', 'CellLine', 'CVCL:B123', (154, 161))	('UOK-146', 'Var', (154, 161))	('cellular proliferation', 'CPA', (28, 50))	('inhibited', 'NegReg', (18, 27))	('UOK-109', 'Var', (141, 148))
46893	30061365	The dual TORC1/TORC2 inhibitor MLN0128 demonstrated greater anti-proliferative effect than the PI3K inhibitor BKM-120 with 10-fold lower IC50 values (RP-R07: IC50=49.4 nM, UOK-109: IC50=24.3 nM, and UOK-146: IC50=8.18 nM).	('PI3', 'Gene', '5266', (95, 98))	('MLN0128', 'Var', (31, 38))	('IC50 values', 'MPA', (137, 148))	('anti-proliferative effect', 'CPA', (60, 85))	('TORC2', 'cellular_component', 'GO:0031932', ('15', '20'))	('TORC1', 'Gene', '23373', (9, 14))	('PI3K', 'molecular_function', 'GO:0016303', ('95', '99'))	('MLN0128', 'Chemical', 'MESH:C572449', (31, 38))	('TORC1', 'cellular_component', 'GO:0031931', ('9', '14'))	('PI3', 'Gene', (95, 98))	('TORC1', 'Gene', (9, 14))	('lower', 'NegReg', (131, 136))	('TORC2', 'Gene', '200186', (15, 20))	('UOK-146', 'CellLine', 'CVCL:B123', (199, 206))	('TORC2', 'Gene', (15, 20))
46896	30061365	To validate whether the anti-proliferative effect of BEZ-235 in RP-R07 cells was associated with biochemical attenuation of the PI3K/AKT/mTOR pathway, we assessed the phosphorylation and expression levels of selected key nodes by immunofluorescence.	('PI3', 'Gene', (128, 131))	('BEZ-235', 'Chemical', 'MESH:C531198', (53, 60))	('attenuation', 'NegReg', (109, 120))	('AKT', 'Gene', '207', (133, 136))	('PI3K', 'molecular_function', 'GO:0016303', ('128', '132'))	('mTOR', 'Gene', (137, 141))	('phospho', 'Chemical', 'MESH:C033601', (167, 174))	('anti-proliferative effect', 'MPA', (24, 49))	('mTOR', 'Gene', '2475', (137, 141))	('PI3', 'Gene', '5266', (128, 131))	('phosphorylation', 'biological_process', 'GO:0016310', ('167', '182'))	('AKT', 'Gene', (133, 136))	('BEZ-235', 'Var', (53, 60))
46902	30061365	First, we confirmed the efficacy of our siRNA treatment by assessing TFE3 endogenous mRNA transcript level and protein expression after cells treatment with TFE3-siRNA and negative control-siRNA, scramble RNA (Fig.	('endogenous mRNA transcript level', 'MPA', (74, 106))	('N', 'Chemical', 'MESH:D009584', (43, 44))	('protein expression', 'MPA', (111, 129))	('N', 'Chemical', 'MESH:D009584', (165, 166))	('RNA', 'cellular_component', 'GO:0005562', ('205', '208'))	('N', 'Chemical', 'MESH:D009584', (192, 193))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('N', 'Chemical', 'MESH:D009584', (87, 88))	('TFE3-siRNA', 'Var', (157, 167))	('TFE3', 'Gene', (69, 73))	('N', 'Chemical', 'MESH:D009584', (206, 207))
46904	30061365	Next, we assessed whether inhibition of TFE3 provides regulatory feedback on PI3K/AKT/mTOR signaling axis.	('PI3K', 'molecular_function', 'GO:0016303', ('77', '81'))	('TFE3', 'Gene', (40, 44))	('mTOR', 'Gene', '2475', (86, 90))	('PI3', 'Gene', '5266', (77, 80))	('mTOR', 'Gene', (86, 90))	('inhibition', 'Var', (26, 36))	('PI3', 'Gene', (77, 80))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('AKT', 'Gene', '207', (82, 85))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('AKT', 'Gene', (82, 85))
46912	30061365	SiRNA mediated silencing of TFE3 decreased endogenous expression of IRS-1 mRNA transcript compared to scramble RNA treatment (P<0.01) (Fig.	('RNA', 'cellular_component', 'GO:0005562', ('111', '114'))	('N', 'Chemical', 'MESH:D009584', (112, 113))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('silencing', 'Var', (15, 24))	('IRS-1', 'Gene', '3667', (68, 73))	('TFE3', 'Gene', (28, 32))	('decreased', 'NegReg', (33, 42))	('endogenous expression of', 'MPA', (43, 67))	('IRS-1', 'Gene', (68, 73))	('N', 'Chemical', 'MESH:D009584', (76, 77))
46913	30061365	Next, the analysis of immunofluorescence images further demonstrated the decrease of IRS-1 protein expression following TFE3-siRNA treatment compared to scramble RNA treatment (P<0.001) (Fig.	('N', 'Chemical', 'MESH:D009584', (128, 129))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('TFE3-siRNA', 'Var', (120, 130))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('decrease', 'NegReg', (73, 81))	('IRS-1', 'Gene', '3667', (85, 90))	('IRS-1', 'Gene', (85, 90))	('N', 'Chemical', 'MESH:D009584', (163, 164))	('RNA', 'cellular_component', 'GO:0005562', ('162', '165'))
46914	30061365	Following TFE3-siRNA treatment at 96 hrs and 110 hrs, the cell number was significantly reduced (96 hrs P=0.04, 110 hrs P< 0.00001) in RP-R07 compared to the non-silencing control siRNA transfected cells and non-treated cells.	('TFE3-siRNA', 'Gene', (10, 20))	('cell number', 'CPA', (58, 69))	('RP-R07', 'Var', (135, 141))	('N', 'Chemical', 'MESH:D009584', (18, 19))	('reduced', 'NegReg', (88, 95))	('N', 'Chemical', 'MESH:D009584', (183, 184))
46915	30061365	Next, we investigated the anti-proliferative effect of MLN0128 and BEZ-235 in vivo.	('N', 'Chemical', 'MESH:D009584', (57, 58))	('BEZ-235', 'Chemical', 'MESH:C531198', (67, 74))	('anti-proliferative effect', 'MPA', (26, 51))	('MLN0128', 'Var', (55, 62))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('MLN0128', 'Chemical', 'MESH:C572449', (55, 62))	('BEZ-235', 'Gene', (67, 74))
46918	30061365	Therefore, we postulated that MLN0128 and BEZ-235 could provide superior anti-tumor effects as compared to rapamycin given their ability to impact this resistance pathway.	('resistance pathway', 'Pathway', (152, 170))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('BEZ-235', 'Var', (42, 49))	('impact', 'Reg', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MLN0128', 'Var', (30, 37))	('tumor', 'Disease', (78, 83))	('rapamycin', 'Chemical', 'MESH:D020123', (107, 116))	('MLN0128', 'Chemical', 'MESH:C572449', (30, 37))	('BEZ-235', 'Chemical', 'MESH:C531198', (42, 49))
46921	30061365	Treatment of RP-R07 xenografts with MLN0128, rapamycin, and BEZ-235 resulted in decreased tumor weight (Fig.	('decreased tumor weight', 'Disease', 'MESH:D015431', (80, 102))	('BEZ-235', 'Chemical', 'MESH:C531198', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('MLN0128', 'Var', (36, 43))	('decreased tumor weight', 'Disease', (80, 102))	('rapamycin', 'Chemical', 'MESH:D020123', (45, 54))	('MLN0128', 'Chemical', 'MESH:C572449', (36, 43))
46930	30061365	Therapeutic strategies to effectively treat MiT family translocation renal cell carcinoma have yet to be established.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (69, 89))	('MiT family translocation', 'Var', (44, 68))	('renal cell carcinoma', 'Disease', (69, 89))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (69, 89))
46941	30061365	Consistent with our ChiP-seq data, PI3K/AKT/mTOR was identified once again as a pathway with significant (P=4.91E-9) association with the miRNA signatures in RP-R07.	('PI3', 'Gene', (35, 38))	('RP-R07', 'Var', (158, 164))	('miRNA signatures', 'Var', (138, 154))	('AKT', 'Gene', '207', (40, 43))	('association', 'Interaction', (117, 128))	('mTOR', 'Gene', (44, 48))	('PI3', 'Gene', '5266', (35, 38))	('mTOR', 'Gene', '2475', (44, 48))	('AKT', 'Gene', (40, 43))	('N', 'Chemical', 'MESH:D009584', (141, 142))	('PI3K', 'molecular_function', 'GO:0016303', ('35', '39'))
46943	30061365	It is noteworthy that some pathways associated with differential miRNA expression identified in our study are the same miRNA associated pathways identified in previous work using larger panel of tRCC tumors.	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('N', 'Chemical', 'MESH:D009584', (122, 123))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tRCC tumors', 'Disease', 'MESH:D009369', (195, 206))	('N', 'Chemical', 'MESH:D009584', (68, 69))	('differential', 'Var', (52, 64))	('miRNA expression', 'MPA', (65, 81))	('tRCC tumors', 'Disease', (195, 206))
46951	30061365	Then, we enacted a variable, multi-nodal P13K/AKT/mTOR inhibition strategy using three treatment arms to examine the effects of blocking this pathway at different points in vitro and in vivo: 1) PI3K inhibition with BKM-120, 2) pan-mTOR inhibition with MLN0128, and 3) simultaneous vertical inhibition of PI3K and mTOR with BEZ-235.	('PI3K', 'molecular_function', 'GO:0016303', ('305', '309'))	('mTOR', 'Gene', (50, 54))	('PI3', 'Gene', (305, 308))	('AKT', 'Gene', (46, 49))	('mTOR', 'Gene', (314, 318))	('MLN0128', 'Var', (253, 260))	('inhibition', 'NegReg', (237, 247))	('PI3', 'Gene', (195, 198))	('BEZ-235', 'Chemical', 'MESH:C531198', (324, 331))	('mTOR', 'Gene', '2475', (314, 318))	('mTOR', 'Gene', '2475', (50, 54))	('PI3K', 'molecular_function', 'GO:0016303', ('195', '199'))	('mTOR', 'Gene', (232, 236))	('MLN0128', 'Chemical', 'MESH:C572449', (253, 260))	('AKT', 'Gene', '207', (46, 49))	('mTOR', 'Gene', '2475', (232, 236))	('P13K', 'Mutation', 'p.P13K', (41, 45))	('BKM-120', 'Var', (216, 223))	('PI3', 'Gene', '5266', (305, 308))	('inhibition', 'NegReg', (200, 210))	('PI3', 'Gene', '5266', (195, 198))
46952	30061365	While all three treatment arms had a greater anti-proliferative effect as compared to the MET inhibitor crizotinib, BKM-120 had a modest effect, which is possibly due to inadequate inhibition by targeting PI3K axis alone.	('PI3', 'Gene', (205, 208))	('PI3K', 'molecular_function', 'GO:0016303', ('205', '209'))	('BKM-120', 'Var', (116, 123))	('anti-proliferative effect', 'MPA', (45, 70))	('crizotinib', 'Chemical', 'MESH:C551994', (104, 114))	('PI3', 'Gene', '5266', (205, 208))
46953	30061365	In contrast, MLN0128 and BEZ-235 potently inhibited proliferation of all tRCC cells models tested in a concentration-dependent fashion, with BEZ-235 exerting the greatest effect.	('proliferation', 'CPA', (52, 65))	('MLN0128', 'Chemical', 'MESH:C572449', (13, 20))	('BEZ-235', 'Gene', (25, 32))	('RCC', 'Disease', (74, 77))	('inhibited', 'NegReg', (42, 51))	('RCC', 'Disease', 'MESH:D002292', (74, 77))	('BEZ-235', 'Chemical', 'MESH:C531198', (25, 32))	('BEZ-235', 'Chemical', 'MESH:C531198', (141, 148))	('MLN0128', 'Var', (13, 20))
46960	30061365	BEZ-235 was the only treatment that resulted in significant tumor reduction in vivo compared to the modest tumor growth inhibition by rapamycin or MLN0128 alone.	('BEZ-235', 'Var', (0, 7))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('MLN0128', 'Chemical', 'MESH:C572449', (147, 154))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('rapamycin', 'Chemical', 'MESH:D020123', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('BEZ-235', 'Chemical', 'MESH:C531198', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (60, 65))	('reduction', 'NegReg', (66, 75))
46961	30061365	Even though dual mTOR inhibition with MLN0128 conferred greater efficacy of tumor growth inhibition compared to partial mTOR inhibition, possibly due to attenuation of the mTORC2-AKT reactivation mechanism, our results suggest that neither form of mTOR blockade in isolation is sufficient to elicit significant tumor control in TFE3-tRCC.	('mTOR', 'Gene', (172, 176))	('tumor', 'Disease', (76, 81))	('mTOR', 'Gene', (17, 21))	('mTOR', 'Gene', '2475', (172, 176))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('MLN0128', 'Var', (38, 45))	('mTOR', 'Gene', (248, 252))	('mTOR', 'Gene', (120, 124))	('mTOR', 'Gene', '2475', (17, 21))	('tumor', 'Disease', (311, 316))	('mTOR', 'Gene', '2475', (248, 252))	('AKT', 'Gene', (179, 182))	('RCC', 'Disease', (334, 337))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('MLN0128', 'Chemical', 'MESH:C572449', (38, 45))	('mTORC2', 'Gene', (172, 178))	('mTORC2', 'cellular_component', 'GO:0031932', ('172', '178'))	('mTOR', 'Gene', '2475', (120, 124))	('RCC', 'Disease', 'MESH:D002292', (334, 337))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('AKT', 'Gene', '207', (179, 182))	('mTORC2', 'Gene', '74343', (172, 178))
46966	30061365	By using siRNA mediated TFE3 silencing strategy, we showed that attenuated wild type TFE3 expression exerts inhibitory effect on RP-R07 cell proliferation.	('N', 'Chemical', 'MESH:D009584', (12, 13))	('TFE3', 'Gene', (85, 89))	('attenuated', 'Var', (64, 74))	('inhibitory', 'NegReg', (108, 118))	('cell proliferation', 'biological_process', 'GO:0008283', ('136', '154'))	('RP-R07 cell proliferation', 'CPA', (129, 154))
46971	30061365	Furthermore, we showed that TFE3 silencing inhibits IRS-1 expression.	('IRS-1', 'Gene', '3667', (52, 57))	('expression', 'MPA', (58, 68))	('IRS-1', 'Gene', (52, 57))	('silencing', 'Var', (33, 42))	('TFE3', 'Gene', (28, 32))	('inhibits', 'NegReg', (43, 51))
46981	30061365	The abbreviations used are: tRCC translocation renal cell carcinoma ccRCC clear cell renal cell carcinoma pRCC papillary renal cell carcinoma PDX patient-derived xenograft PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ChIP-Seq chromatin immune precipitation sequencing miRNA microRNA MiT Micropthalmia transcription factor NGS next generation sequencing RT-qPCR quantitative reverse transcription polymerase chain reaction IRS-1 insulin receptor substrate 1 NSG NOD-SCID gamma Despite the significant progress achieved by targeted therapies in renal cell carcinoma, patients with translocation RCC continue do have a poor outcome.	('RCC', 'Disease', (70, 73))	('transcription', 'biological_process', 'GO:0006351', ('334', '347'))	('RCC', 'Disease', 'MESH:D002292', (626, 629))	('RCC', 'Disease', (29, 32))	('N', 'Chemical', 'MESH:D009584', (490, 491))	('PIK3CA', 'Gene', (172, 178))	('N', 'Chemical', 'MESH:D009584', (313, 314))	('renal cell carcinoma', 'Disease', (85, 105))	('renal cell carcinoma', 'Disease', (576, 596))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (85, 105))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (576, 596))	('papillary renal cell carcinoma', 'Disease', (111, 141))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (121, 141))	('N', 'Chemical', 'MESH:D009584', (304, 305))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('RCC', 'Disease', 'MESH:D002292', (70, 73))	('RCC', 'Disease', (107, 110))	('pRCC', 'Gene', (106, 110))	('Micropthalmia transcription factor', 'Disease', (320, 354))	('IRS-1', 'Gene', (455, 460))	('RCC', 'Disease', 'MESH:D002292', (29, 32))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (74, 105))	('Micropthalmia transcription factor', 'Disease', 'OMIM:602482', (320, 354))	('carcinoma', 'Phenotype', 'HP:0030731', (587, 596))	('patients', 'Species', '9606', (598, 606))	('transcription factor', 'molecular_function', 'GO:0000981', ('334', '354'))	('RCC', 'Disease', 'MESH:D002292', (107, 110))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (121, 141))	('N', 'Chemical', 'MESH:D009584', (494, 495))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (47, 67))	('chromatin', 'cellular_component', 'GO:0000785', ('259', '268'))	('translocation', 'Var', (612, 625))	('PIK3CA', 'Gene', '5290', (172, 178))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (111, 141))	('reverse transcription', 'biological_process', 'GO:0001171', ('407', '428'))	('IRS-1', 'Gene', '3667', (455, 460))	('NGS', 'Disease', 'None', (355, 358))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('RCC', 'Disease', (626, 629))	('insulin', 'molecular_function', 'GO:0016088', ('461', '468'))	('papillary renal cell carcinoma', 'Disease', 'MESH:D002292', (111, 141))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (576, 596))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:C106336', (179, 216))	('renal cell carcinoma', 'Disease', (47, 67))	('NGS', 'Disease', (355, 358))	('patient', 'Species', '9606', (598, 605))	('pRCC', 'Gene', '5546', (106, 110))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (85, 105))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (47, 67))	('patient', 'Species', '9606', (146, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('N', 'Chemical', 'MESH:D009584', (355, 356))
47024	29207195	Enriched biological themes of DEGs in hub module, particularly GO terms and visualization of those on KEGG pathway maps were performed using DAVID database.	('DEGs', 'Var', (30, 34))	('hub', 'Gene', (38, 41))	('hub', 'Gene', '1993', (38, 41))
47049	29207195	To obtain further insight into the function of DEGs in hub module, they were uploaded to the DAVID database.	('hub', 'Gene', '1993', (55, 58))	('DEGs', 'Var', (47, 51))	('hub', 'Gene', (55, 58))
47059	29207195	Seth et al supposed that higher levels of ATP5A1 were associated with certain SNPs and with TP53 mutation.	('ATP5A1', 'Gene', (42, 48))	('SNPs', 'Disease', (78, 82))	('TP53', 'Gene', (92, 96))	('ATP5A1', 'Gene', '498', (42, 48))	('TP53', 'Gene', '7157', (92, 96))	('mutation', 'Var', (97, 105))
47060	29207195	Moreover, highly-expressed ATP5A1 occurs in chromosomal instability and may facilitate tumor development along this pathway.	('chromosomal instability', 'Phenotype', 'HP:0040012', (44, 67))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('occurs', 'Reg', (34, 40))	('facilitate', 'PosReg', (76, 86))	('tumor', 'Disease', (87, 92))	('ATP5A1', 'Gene', (27, 33))	('highly-expressed', 'Var', (10, 26))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('ATP5A1', 'Gene', '498', (27, 33))
47061	29207195	Conversely, low levels of ATP5A1 may facilitate development of tumors with microsatellite instability.	('ATP5A1', 'Gene', (26, 32))	('low', 'Var', (12, 15))	('ATP5A1', 'Gene', '498', (26, 32))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('facilitate', 'PosReg', (37, 47))	('tumors', 'Disease', (63, 69))	('microsatellite instability', 'Var', (75, 101))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
47062	29207195	As mitochondrial dysfunction often occurs in encephalopathy, Jonckheere et al discovered a complex V ATP5A1 which could cause fatal neonatal mitochondrial encephalopathy.	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (3, 28))	('ATP5A1', 'Gene', (101, 107))	('encephalopathy', 'Disease', 'MESH:D001927', (155, 169))	('encephalopathy', 'Phenotype', 'HP:0001298', (45, 59))	('encephalopathy', 'Phenotype', 'HP:0001298', (155, 169))	('encephalopathy', 'Disease', (45, 59))	('mitochondrial dysfunction', 'Disease', (3, 28))	('encephalopathy', 'Disease', (155, 169))	('cause', 'Reg', (120, 125))	('ATP5A1', 'Gene', '498', (101, 107))	('complex', 'Var', (91, 98))	('mitochondrial encephalopathy', 'Phenotype', 'HP:0006789', (141, 169))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (3, 28))	('encephalopathy', 'Disease', 'MESH:D001927', (45, 59))
47081	29207195	Many studies had reported that mitochondrial DNA mutations leading to changes in enzymes, may affect the process of oxidative phosphorylation, and ultimately cause the occurrence of tumors.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('mutations', 'Var', (49, 58))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('31', '48'))	('affect', 'Reg', (94, 100))	('tumors', 'Disease', (182, 188))	('mitochondrial DNA', 'Gene', (31, 48))	('cause', 'Reg', (158, 163))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('changes', 'Reg', (70, 77))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('116', '141'))	('enzymes', 'MPA', (81, 88))	('process of oxidative phosphorylation', 'MPA', (105, 141))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
47085	27564117	High CLEC-2 expression associates with unfavorable postoperative prognosis of patients with clear cell renal cell carcinoma We enrolled a total of 277 patients who received nephrectomy due to clear cell renal cell carcinoma (ccRCC) in Zhongshan Hospital from Jan 2005 to Jun 2007.	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('patients', 'Species', '9606', (78, 86))	('clear cell renal cell carcinoma', 'Disease', (192, 223))	('CLEC-2', 'Gene', (5, 11))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (203, 223))	('RCC', 'Disease', (227, 230))	('RCC', 'Phenotype', 'HP:0005584', (227, 230))	('High', 'Var', (0, 4))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (92, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (192, 223))	('RCC', 'Disease', 'MESH:C538614', (227, 230))	('clear cell renal cell carcinoma', 'Disease', (92, 123))	('CLEC-2', 'Gene', '51266', (5, 11))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (103, 123))	('patients', 'Species', '9606', (151, 159))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (192, 223))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (92, 123))	('ccRCC', 'Phenotype', 'HP:0006770', (225, 230))
47101	27564117	Ligation of CLEC-2 with podoplanin elicits strong platelet activation, and it is identified that platelet activation is known to promote tumor metastasis, which may be triggered by podoplanin up-regulation.	('tumor metastasis', 'Disease', 'MESH:D009362', (137, 153))	('elicits', 'Reg', (35, 42))	('Ligation', 'Var', (0, 8))	('promote', 'PosReg', (129, 136))	('tumor metastasis', 'Disease', (137, 153))	('podoplanin', 'Gene', '10630', (181, 191))	('regulation', 'biological_process', 'GO:0065007', ('195', '205'))	('CLEC-2', 'Gene', '51266', (12, 18))	('podoplanin', 'Gene', '10630', (24, 34))	('podoplanin', 'Gene', (181, 191))	('platelet activation', 'biological_process', 'GO:0030168', ('97', '116'))	('CLEC-2', 'Gene', (12, 18))	('platelet activation', 'MPA', (50, 69))	('podoplanin', 'Gene', (24, 34))	('up-regulation', 'PosReg', (192, 205))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('platelet activation', 'biological_process', 'GO:0030168', ('50', '69'))
47119	27564117	To evaluate the robustness of the prognostic value of CLEC-2 positive cell infiltration and control for confounders, we performed Cox multivariate regression analyses and found that high CLEC-2 positive cell infiltration was still an independent risk factor for both OS and RFS (OS, p = 0.004; RFS, p = 0.009) (Table 1), together with other clinicopathological parameters like pathological T stage, Fuhrman grade, Necrosis, ECOG PS and distant metastasis.	('CLEC-2', 'Gene', (187, 193))	('Necrosis', 'biological_process', 'GO:0001906', ('414', '422'))	('Necrosis', 'biological_process', 'GO:0070265', ('414', '422'))	('RFS', 'Chemical', '-', (294, 297))	('OS', 'Chemical', '-', (279, 281))	('high', 'Var', (182, 186))	('CLEC-2', 'Gene', '51266', (54, 60))	('RFS', 'Disease', (274, 277))	('Cox', 'Gene', '1351', (130, 133))	('Necrosis', 'biological_process', 'GO:0008219', ('414', '422'))	('CLEC-2', 'Gene', '51266', (187, 193))	('OS', 'Chemical', '-', (267, 269))	('Necrosis', 'Disease', (414, 422))	('RFS', 'Chemical', '-', (274, 277))	('Cox', 'Gene', (130, 133))	('Necrosis', 'Disease', 'MESH:D009336', (414, 422))	('Necrosis', 'biological_process', 'GO:0019835', ('414', '422'))	('CLEC-2', 'Gene', (54, 60))	('Necrosis', 'biological_process', 'GO:0008220', ('414', '422'))
47120	27564117	We also found that CLEC-2 positive cell infiltration could stratify ccRCC patients' survival in the UISS mediate-risk and high-risk groups, in which high CLEC-2 positive cell infiltration turned out to be an independent risk factor in both OS and RFS analyses (OS, p = 0.009, RFS, p = 0.008 in mediate-risk groups; OS, p = 0.016, RFS, p = 0.012 in high-risk groups) (Figure 2C and 2G, Figure 2D and 2H), while in the low-risk groups it is not statistically significant (Figure 2B and 2E).	('high', 'Var', (149, 153))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('OS', 'Chemical', '-', (261, 263))	('RCC', 'Disease', (70, 73))	('OS', 'Chemical', '-', (240, 242))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('patients', 'Species', '9606', (74, 82))	('RFS', 'Chemical', '-', (247, 250))	('CLEC-2', 'Gene', '51266', (19, 25))	('RFS', 'Chemical', '-', (330, 333))	('stratify', 'Reg', (59, 67))	('CLEC-2', 'Gene', (19, 25))	('OS', 'Chemical', '-', (315, 317))	('CLEC-2', 'Gene', '51266', (154, 160))	('CLEC-2', 'Gene', (154, 160))	('RFS', 'Chemical', '-', (276, 279))
47139	27564117	Therefore, ligation of CLEC-2 might promote cancer progression by creating an immunosuppressive environment and help cancer cell escape from immune surveillance.	('promote', 'PosReg', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (44, 50))	('men', 'Species', '9606', (103, 106))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('immunosuppressive', 'MPA', (78, 95))	('CLEC-2', 'Gene', '51266', (23, 29))	('CLEC-2', 'Gene', (23, 29))	('ligation', 'Var', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
47222	27807511	Inhibition of uPA activity was demonstrated to suppress tumor invasion and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('suppress', 'NegReg', (47, 55))	('Inhibition', 'Var', (0, 10))	('uPA', 'Gene', (14, 17))	('uPA', 'molecular_function', 'GO:0008243', ('14', '17'))	('uPA', 'Gene', '5328', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
47239	27807511	Though unexpected, another specific property of TAMs in RCC is expression of CCR8 associated with higher activity of Stat3-mediated signaling, which is rather typical for inflammatory phenotype.	('Stat3', 'Gene', (117, 122))	('associated', 'Reg', (82, 92))	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('CCR8', 'Gene', '1237', (77, 81))	('TAMs', 'Chemical', '-', (48, 52))	('CCR8', 'Gene', (77, 81))	('activity', 'MPA', (105, 113))	('higher', 'PosReg', (98, 104))	('CCR', 'molecular_function', 'GO:0043880', ('77', '80'))	('signaling', 'biological_process', 'GO:0023052', ('132', '141'))	('Stat3', 'Gene', '6774', (117, 122))	('expression', 'Var', (63, 73))
47256	27807511	Statistical analysis revealed that CD68 alone has a poor predictive value, while low CD11+ and high CD206+ as single variables correlated with reduced survival.	('CD206', 'Gene', '4360', (100, 105))	('CD206', 'Gene', (100, 105))	('CD68', 'Gene', (35, 39))	('low', 'Var', (81, 84))	('survival', 'MPA', (151, 159))	('CD68', 'Gene', '968', (35, 39))	('CD11+', 'MPA', (85, 90))	('reduced', 'NegReg', (143, 150))
47267	27807511	These data are supported by the study, demonstrating that VEGFR1 knockdown leads to a reduced macrophage infiltration in the tumor.	('VEGFR1', 'Gene', '2321', (58, 64))	('reduced', 'NegReg', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('VEGFR1', 'Gene', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('knockdown', 'Var', (65, 74))
47291	32020234	Aberrations in anaplastic lymphoma kinase (ALK), a rational therapeutic target, as verified in lung cancer with ALK rearrangement, have been implicated in the pathogenesis of multiple human cancers.	('lung cancer', 'Disease', (95, 106))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('anaplastic lymphoma kinase', 'Gene', (15, 41))	('cancers', 'Disease', (190, 197))	('ALK', 'Gene', (43, 46))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (15, 34))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lymphoma', 'Phenotype', 'HP:0002665', (26, 34))	('pathogenesis', 'biological_process', 'GO:0009405', ('159', '171'))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('human', 'Species', '9606', (184, 189))	('anaplastic lymphoma kinase', 'Gene', '238', (15, 41))	('Aberrations', 'Var', (0, 11))	('implicated', 'Reg', (141, 151))
47296	32020234	Notably, we first showed that enforced EML4-ALK expression could significantly promote in vitro proliferation, clonogenic colony formation and apoptosis resistance in HK2 immortalized normal renal tubal epithelial cells and their in vivo outgrowth when injected into immunocompromised nude mice.	('nude mice', 'Species', '10090', (285, 294))	('apoptosis resistance', 'CPA', (143, 163))	('formation', 'biological_process', 'GO:0009058', ('129', '138'))	('HK2', 'Gene', (167, 170))	('EML4-ALK expression', 'Var', (39, 58))	('promote', 'PosReg', (79, 86))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))	('HK2', 'molecular_function', 'GO:0008256', ('167', '170'))	('clonogenic colony formation', 'CPA', (111, 138))
47297	32020234	Importantly, this pro-tumorigenic effect was completely abolished by the ALK-specific inhibitor crizotinib, indicating the potential effectiveness of ALK-specific inhibitors in treating ALK-rearranged ccRCC patients.	('ccRCC', 'Phenotype', 'HP:0006770', (201, 206))	('ccRCC', 'Disease', (201, 206))	('patients', 'Species', '9606', (207, 215))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('ccRCC', 'Disease', 'MESH:C538614', (201, 206))	('abolished', 'NegReg', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('crizotinib', 'Chemical', 'MESH:D000077547', (96, 106))	('ALK-rearranged', 'Var', (186, 200))	('RCC', 'Phenotype', 'HP:0005584', (203, 206))
47305	32020234	Since then, various ALK fusion genes mediated by translocation have been identified in multiple malignancies, including inflammatory myofibroblastic tumor (IMT), non-small cell lung cancer (NSCLC) and ovarian cancer.	('non-small cell lung cancer', 'Disease', (162, 188))	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (133, 154))	('myofibroblastic tumor', 'Disease', 'MESH:D009369', (133, 154))	('malignancies', 'Disease', (96, 108))	('NSCLC', 'Disease', (190, 195))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('ovarian cancer', 'Disease', 'MESH:D010051', (201, 215))	('NSCLC', 'Phenotype', 'HP:0030358', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (162, 188))	('identified', 'Reg', (73, 83))	('ALK', 'Gene', (20, 23))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (166, 188))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('ovarian cancer', 'Disease', (201, 215))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (162, 188))	('ovarian cancer', 'Phenotype', 'HP:0100615', (201, 215))	('myofibroblastic tumor', 'Disease', (133, 154))	('translocation', 'Var', (49, 62))	('IMT', 'biological_process', 'GO:1990953', ('156', '159'))	('NSCLC', 'Disease', 'MESH:D002289', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
47306	32020234	In the scope of the kinase domain, activating mutations with ALK have also been identified in neuroblastoma and anaplastic thyroid cancer.	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (112, 137))	('mutations', 'Var', (46, 55))	('neuroblastoma and anaplastic thyroid cancer', 'Disease', 'MESH:D065646', (94, 137))	('ALK', 'Gene', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('activating', 'PosReg', (35, 45))	('neuroblastoma', 'Phenotype', 'HP:0003006', (94, 107))	('thyroid cancer', 'Phenotype', 'HP:0002890', (123, 137))
47307	32020234	In addition, amplification of the ALK gene has been discovered in neuroblastoma, inflammatory breast cancer, and esophageal cancer.	('inflammatory breast cancer', 'Disease', (81, 107))	('neuroblastoma', 'Disease', (66, 79))	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('neuroblastoma', 'Phenotype', 'HP:0003006', (66, 79))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('ALK', 'Gene', (34, 37))	('amplification', 'Var', (13, 26))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('inflammatory breast cancer', 'Disease', 'MESH:D058922', (81, 107))	('esophageal cancer', 'Disease', (113, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('discovered', 'Reg', (52, 62))	('neuroblastoma', 'Disease', 'MESH:D009447', (66, 79))
47309	32020234	Therefore, an aberration in ALK could be used therapeutically as an 'Achilles heel' for tumors.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('ALK', 'Gene', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('aberration', 'Var', (14, 24))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
47310	32020234	Indeed, it has been reported that there is significant clinical efficacy with ALK inhibitors for NSCLC, ALCL and IMT with ALK fusions, including crizotinib and ceritinib, ALK-targeting small-molecule tyrosine kinase inhibitors (TKIs).	('NSCLC', 'Disease', (97, 102))	('ceritinib', 'Chemical', 'MESH:C586847', (160, 169))	('ALCL', 'Phenotype', 'HP:0012193', (104, 108))	('IMT', 'biological_process', 'GO:1990953', ('113', '116'))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('fusions', 'Var', (126, 133))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('crizotinib', 'Chemical', 'MESH:D000077547', (145, 155))
47312	32020234	The above findings illustrate that an ALK fusion associated with an oncogene would be one of the most hopeful targets in cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ALK', 'Var', (38, 41))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))
47322	32020234	The H2228 lung cancer cell line with confirmed EML4-ALK rearrangement was purchased from ATCC.	('rearrangement', 'Var', (56, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (10, 21))	('H2228 lung cancer', 'Disease', (4, 21))	('H2228 lung cancer', 'Disease', 'MESH:D008175', (4, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
47331	32020234	ALK-rearranged NSCLC patients served as positive controls and were contained in each staining batch.	('NSCLC', 'Phenotype', 'HP:0030358', (15, 20))	('ALK-rearranged', 'Var', (0, 14))	('patients', 'Species', '9606', (21, 29))	('NSCLC', 'Disease', (15, 20))	('NSCLC', 'Disease', 'MESH:D002289', (15, 20))
47373	32020234	An anaplastic lymphoma kinase (ALK) rearrangement is a key molecular event resulting in the emergence of functional ALK fusion genes capable of driving carcinogenesis, and approximately 30 ALK fusion genes with different partners have been identified in a plethora of tumor types.	('carcinogenesis', 'Disease', (152, 166))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('anaplastic lymphoma kinase', 'Gene', '238', (3, 29))	('carcinogenesis', 'Disease', 'MESH:D063646', (152, 166))	('tumor', 'Disease', (268, 273))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (3, 22))	('ALK', 'Gene', (116, 119))	('plethora', 'Phenotype', 'HP:0001050', (256, 264))	('anaplastic lymphoma kinase', 'Gene', (3, 29))	('lymphoma', 'Phenotype', 'HP:0002665', (14, 22))	('rearrangement', 'Var', (36, 49))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
47374	32020234	Importantly, the targeted inhibition of ALK fusion genes by small-molecule tyrosine kinase inhibitors (TKIs) has demonstrated an impressive clinical outcome in treating cancer patients with ALK rearrangements confirmed by RT-PCR, immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH).	('ALK', 'Gene', (190, 193))	('patients', 'Species', '9606', (176, 184))	('cancer', 'Disease', (169, 175))	('inhibition', 'NegReg', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('rearrangements', 'Var', (194, 208))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('ALK fusion genes', 'Gene', (40, 56))
47390	31921677	Dysregulation of Ketone Body Metabolism Is Associated With Poor Prognosis for Clear Cell Renal Cell Carcinoma Patients Kidney is an important organ for ketone body metabolism.	('Ketone Body Metabolism', 'MPA', (17, 39))	('Clear Cell Renal Cell Carcinoma', 'Disease', (78, 109))	('ketone body', 'Phenotype', 'HP:0001946', (152, 163))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (89, 109))	('Dysregulation', 'Var', (0, 13))	('Ketone Body Metabolism', 'biological_process', 'GO:1902224', ('17', '39'))	('ketone body metabolism', 'biological_process', 'GO:1902224', ('152', '174'))	('ketone', 'Chemical', 'MESH:D007659', (152, 158))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:D002292', (78, 109))	('Ketone Body', 'Phenotype', 'HP:0001946', (17, 28))	('Ketone', 'Chemical', 'MESH:D007659', (17, 23))	('Carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (78, 109))
47394	31921677	In addition, we demonstrated that ectopic expression of each of these genes inhibited the proliferation of ccRCC cells.	('proliferation of', 'CPA', (90, 106))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('ectopic expression', 'Var', (34, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('ccRCC', 'Disease', (107, 112))	('inhibited', 'NegReg', (76, 85))	('ccRCC', 'Disease', 'MESH:D002292', (107, 112))
47396	31921677	Furthermore, exogenous beta-hydroxybutyrate suppressed the growth of ccRCC cells in vitro in a dose-dependent manner.	('suppressed', 'NegReg', (44, 54))	('growth', 'CPA', (59, 65))	('beta-hydroxybutyrate', 'Chemical', 'MESH:D020155', (23, 43))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (69, 74))	('ccRCC', 'Disease', (69, 74))	('exogenous', 'Var', (13, 22))	('ccRCC', 'Disease', 'MESH:D002292', (69, 74))
47400	31921677	The metabolites produced by altered metabolism serve as an important biochemical driver to maintain the malignant phenotype of cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('altered', 'Var', (28, 35))	('metabolism', 'biological_process', 'GO:0008152', ('36', '46'))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))
47401	31921677	Alteration in glycometabolism, known as the "Warburg effect," described as the preferential fermentation of glucose to lactate even under sufficient oxygen supply, is common in malignancies.	('glucose', 'Chemical', 'MESH:D005947', (108, 115))	('glycometabolism', 'MPA', (14, 29))	('Alteration', 'Var', (0, 10))	('malignancies', 'Disease', (177, 189))	('lactate', 'Chemical', 'MESH:D019344', (119, 126))	('oxygen', 'Chemical', 'MESH:D010100', (149, 155))	('malignancies', 'Disease', 'MESH:D009369', (177, 189))
47437	31921677	A tissue microarray including 85 primary ccRCC tissues and matched adjacent non-cancerous kidney tissues was purchased from Shanghai Outdo Biotech Co., Ltd. (Shanghai, China; Cat no: HPro-Ade180PG-01).	('HPro-Ade180PG', 'Chemical', 'MESH:C115673', (183, 196))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('non-cancerous kidney', 'Disease', 'MESH:D007680', (76, 96))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('cancerous kidney', 'Phenotype', 'HP:0009726', (80, 96))	('Cat', 'molecular_function', 'GO:0004096', ('175', '178'))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('ccRCC', 'Disease', (41, 46))	('non-cancerous kidney', 'Disease', (76, 96))	('ccRCC', 'Disease', 'MESH:D002292', (41, 46))	('Shanghai', 'Var', (158, 166))
47438	31921677	Paraffin sections (4 mm) of samples were deparaffinized and antigen retrieval was performed in citrate buffer for 3 min at 100 C. The samples were subjected to proteolytic digestion and blockage of an endogenous peroxidase, then slides were incubated overnight with primary antibody against ACAT1 (HPA004428), BDH2 (HPA036028), and HMGCL (HPA004727) from Sigma Aldrich (St. Louis, MO, USA), at a dilution of 1:200, 1:800, 1:600, respectively at 4 C. Then, secondary antibody (ZB-2305, ZSGB-BIO, Beijing) labeled with horseradish peroxidase (HP) was applied for 1 h at room temperature.	('ZSGB-BIO', 'Chemical', 'MESH:C483321', (485, 493))	('citrate', 'Chemical', 'MESH:C102006', (95, 102))	('antibody', 'cellular_component', 'GO:0042571', ('466', '474'))	('ACAT1', 'Gene', (291, 296))	('ACAT1', 'Gene', '38', (291, 296))	('HPA004727', 'Chemical', 'MESH:C047158', (339, 348))	('digestion', 'biological_process', 'GO:0007586', ('172', '181'))	('antibody', 'cellular_component', 'GO:0019814', ('274', '282'))	('HMGCL', 'Gene', (332, 337))	('horseradish', 'Species', '3704', (517, 528))	('antibody', 'cellular_component', 'GO:0019815', ('466', '474'))	('antibody', 'molecular_function', 'GO:0003823', ('274', '282'))	('antibody', 'cellular_component', 'GO:0042571', ('274', '282'))	('HPA036028', 'Var', (316, 325))	('BDH2', 'Gene', '56898', (310, 314))	('HPA004428', 'Chemical', 'MESH:C047158', (298, 307))	('antibody', 'cellular_component', 'GO:0019814', ('466', '474'))	('BDH2', 'Gene', (310, 314))	('HMGCL', 'Gene', '3155', (332, 337))	('antibody', 'cellular_component', 'GO:0019815', ('274', '282'))	('HPA036028', 'Chemical', 'MESH:C047158', (316, 325))	('HPA004727', 'Var', (339, 348))	('antibody', 'molecular_function', 'GO:0003823', ('466', '474'))
47508	31921677	The biallelic mutation of SDH results in inactivation of the SDH enzyme, which is a mitochondrial complex of type II, associated with the respiratory chain and the Krebs cycle, and is now considered to have tumor suppressor properties.	('inactivation', 'NegReg', (41, 53))	('SDH', 'Gene', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('biallelic mutation', 'Var', (4, 22))	('tumor suppressor', 'biological_process', 'GO:0051726', ('207', '223'))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('respiratory chain', 'cellular_component', 'GO:0070469', ('138', '155'))	('Krebs cycle', 'biological_process', 'GO:0006099', ('164', '175'))	('SDH', 'Gene', '6390', (26, 29))	('SDH', 'Gene', '6390', (61, 64))	('tumor', 'Disease', (207, 212))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('207', '223'))	('SDH', 'Gene', (26, 29))
47519	31921677	There are abundant epigenetic alterations in RCC, due to abnormal histone modification, DNA methylation and deregulated microRNAs expression, all of which have been considered as important factors in the occurrence and progression of RCC.	('abnormal', 'Reg', (57, 65))	('RCC', 'Disease', 'MESH:D002292', (45, 48))	('epigenetic alterations', 'Var', (19, 41))	('DNA methylation', 'MPA', (88, 103))	('DNA', 'cellular_component', 'GO:0005574', ('88', '91'))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))	('histone modification', 'MPA', (66, 86))	('histone modification', 'biological_process', 'GO:0016570', ('66', '86'))	('RCC', 'Phenotype', 'HP:0005584', (234, 237))	('DNA methylation', 'biological_process', 'GO:0006306', ('88', '103'))	('RCC', 'Disease', 'MESH:D002292', (234, 237))	('RCC', 'Disease', (234, 237))	('RCC', 'Disease', (45, 48))	('deregulated microRNAs expression', 'MPA', (108, 140))
47523	31921677	Mutations in ACAT1 gene lead to 3-ketothiolase deficiency (3KTD).	('deficiency', 'Disease', 'None', (47, 57))	('ACAT1', 'Gene', '38', (13, 18))	('ACAT1', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('lead to', 'Reg', (24, 31))	('deficiency', 'Disease', (47, 57))
47571	30884815	The HEF1-Ca2+/CaM-AURKA complex in turn activates the tubulin deacetylase histone deacetylase 6 (HDAC6), which destabilizes axonemal microtubules, inducing cilium disassembly.	('inducing', 'Reg', (147, 155))	('HDAC6', 'Gene', (97, 102))	('destabilizes', 'NegReg', (111, 123))	('cilium disassembly', 'CPA', (156, 174))	('activates', 'PosReg', (40, 49))	('HDAC6', 'Gene', '15185', (97, 102))	('histone deacetylase 6', 'Gene', '15185', (74, 95))	('cilium', 'cellular_component', 'GO:0005929', ('156', '162'))	('cilium disassembly', 'biological_process', 'GO:0061523', ('156', '174'))	('axonemal microtubules', 'Protein', (124, 145))	('histone deacetylase 6', 'Gene', (74, 95))	('HEF1-Ca2+/CaM-AURKA', 'Var', (4, 23))
47576	30884815	NEK2 and KIF24 were found to be overexpressed in breast cancer cells, and ablation of these proteins restored ciliation, thereby reducing proliferation.	('KIF24', 'Gene', '109242', (9, 14))	('ablation', 'Var', (74, 82))	('NEK2', 'Gene', '18005', (0, 4))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('proliferation', 'CPA', (138, 151))	('NEK2', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ciliation', 'MPA', (110, 119))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('KIF24', 'Gene', (9, 14))	('restored', 'PosReg', (101, 109))	('overexpressed', 'PosReg', (32, 45))	('reducing', 'NegReg', (129, 137))
47579	30884815	According to the double function of the centrosome (as the MTOC, during mitosis, and basal body, the template for ciliogenesis), defects in cilium formation can deregulate the cell cycle, or inversely, the persistence of the primary cilium can put a brake on it, forcing the cells to enter a quiescent state.	('mitosis', 'Disease', 'None', (72, 79))	('cilium', 'cellular_component', 'GO:0005929', ('140', '146'))	('mitosis', 'biological_process', 'GO:0000278', ('72', '79'))	('deregulate', 'Reg', (161, 171))	('primary cilium', 'cellular_component', 'GO:0097731', ('225', '239'))	('cell cycle', 'CPA', (176, 186))	('defects', 'Var', (129, 136))	('primary cilium', 'cellular_component', 'GO:0005929', ('225', '239'))	('MTOC', 'cellular_component', 'GO:0005815', ('59', '63'))	('cell cycle', 'biological_process', 'GO:0007049', ('176', '186'))	('basal body', 'cellular_component', 'GO:0036064', ('85', '95'))	('mitosis', 'Disease', (72, 79))	('ciliogenesis', 'biological_process', 'GO:0060271', ('114', '126'))	('centrosome', 'cellular_component', 'GO:0005813', ('40', '50'))	('cilium formation', 'biological_process', 'GO:0060271', ('140', '156'))
47586	30884815	The IFT-A subcomplex is made up of six proteins (IFT144, 140, 139, 122, 121, and 43), whereas 16 subunits are found in IFT-B (IFT172, 88, 81, 80, 74, 70, 57, 56, 54, 52, 46, 38, 27, 25, 22, and 20).	('IFT', 'biological_process', 'GO:0042073', ('49', '52'))	('IFT', 'biological_process', 'GO:0042073', ('126', '129'))	('IFT172', 'Var', (126, 132))	('IFT144', 'Gene', '213081', (49, 55))	('IFT144', 'Gene', (49, 55))	('IFT', 'biological_process', 'GO:0042073', ('4', '7'))	('IFT', 'biological_process', 'GO:0042073', ('119', '122'))
47587	30884815	Mutagenesis experiments in green alga have been able to identify kinesin-2 and dynein 1b as the molecular motors catalyzing, respectively, the anterograde and retrograde transport of IFT particles, with IFTB contributing to the anterograde, and IFTA to the retrograde transport.	('kinesin', 'molecular_function', 'GO:0003777', ('65', '72'))	('Mutagenesis', 'biological_process', 'GO:0006280', ('0', '11'))	('kinesin-2', 'Gene', (65, 74))	('retrograde transport', 'MPA', (159, 179))	('anterograde', 'MPA', (143, 154))	('Mutagenesis', 'Var', (0, 11))	('transport', 'biological_process', 'GO:0006810', ('268', '277'))	('transport', 'biological_process', 'GO:0006810', ('170', '179'))	('IFT', 'biological_process', 'GO:0042073', ('183', '186'))	('dynein', 'molecular_function', 'GO:0003777', ('79', '85'))	('kinesin-2', 'Gene', '16563', (65, 74))
47590	30884815	It has been shown that the knock-down of the IFT27 protein affected both flagellar assembly and the cell cycle, causing defects in cytokinesis.	('cell cycle', 'biological_process', 'GO:0007049', ('100', '110'))	('flagellar assembly', 'CPA', (73, 91))	('IFT', 'biological_process', 'GO:0042073', ('45', '48'))	('protein', 'Protein', (51, 58))	('cell cycle', 'CPA', (100, 110))	('knock-down', 'Var', (27, 37))	('cytokinesis', 'biological_process', 'GO:0000910', ('131', '142'))	('cytokinesis', 'CPA', (131, 142))	('affected', 'Reg', (59, 67))	('defects', 'NegReg', (120, 127))	('IFT27', 'Gene', '67042', (45, 50))	('IFT27', 'Gene', (45, 50))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
47592	30884815	came the first observation that disruption of ciliary formation by targeting IFT results in the development of polycystic kidney disease (PKD), a disorder that is characterized by the onset of kidney cysts with increased proliferation.	('kidney cysts', 'Disease', (193, 205))	('targeting', 'Var', (67, 76))	('kidney disease', 'Phenotype', 'HP:0000112', (122, 136))	('IFT', 'Gene', (77, 80))	('results in', 'Reg', (81, 91))	('polycystic kidney disease', 'Disease', (111, 136))	('PKD', 'Disease', 'MESH:C537180', (138, 141))	('PKD', 'Disease', (138, 141))	('polycystic kidney disease', 'Disease', 'MESH:D007690', (111, 136))	('kidney cysts', 'Phenotype', 'HP:0000107', (193, 205))	('IFT', 'biological_process', 'GO:0042073', ('77', '80'))	('polycystic kidney', 'Phenotype', 'HP:0000113', (111, 128))	('formation', 'biological_process', 'GO:0009058', ('54', '63'))	('kidney cysts', 'Disease', 'MESH:D007674', (193, 205))
47593	30884815	Additional evidence for IFT-induced ciliary assembly defects in PKD was provided by an analysis of targeted knockouts of the KIF3A subunit of kinesin2 anterograde motor in kidney epithelium.	('PKD', 'Disease', (64, 67))	('kinesin2', 'Gene', (142, 150))	('knockouts', 'Var', (108, 117))	('KIF3A', 'Gene', (125, 130))	('PKD', 'Disease', 'MESH:C537180', (64, 67))	('KIF3A', 'Gene', '16568', (125, 130))	('defects', 'NegReg', (53, 60))	('kinesin', 'molecular_function', 'GO:0003777', ('142', '149'))	('ciliary assembly', 'CPA', (36, 52))	('kinesin2', 'Gene', '16563', (142, 150))	('IFT', 'biological_process', 'GO:0042073', ('24', '27'))
47610	30884815	Wimple, flexo, and Kif3a mouse mutants showed abnormal embryonic morphologies at the neural tube level, which recalled the phenotype induced by deficient hedgehog signaling.	('mutants', 'Var', (31, 38))	('signaling', 'biological_process', 'GO:0023052', ('163', '172'))	('Kif3a', 'Gene', (19, 24))	('mouse', 'Species', '10090', (25, 30))	('embryonic morphologies at the neural tube level', 'CPA', (55, 102))
47611	30884815	Wimple and flexo mutations corresponded to genes homologous to Chlamydomonas IFT88 and IFT172, two components of the IFTB subcomplex.	('IFT172', 'Gene', (87, 93))	('IFT', 'biological_process', 'GO:0042073', ('77', '80'))	('mutations', 'Var', (17, 26))	('Chlamydomonas', 'Species', '3055', (63, 76))	('IFT', 'biological_process', 'GO:0042073', ('87', '90'))
47612	30884815	All mutants showed a reduction in hedgehog signaling, and all three proteins were identified to be required in the pathway at a step downstream to Ptch1, but upstream to Glis.	('mutants', 'Var', (4, 11))	('Ptch1', 'Gene', '19206', (147, 152))	('Ptch1', 'Gene', (147, 152))	('reduction', 'NegReg', (21, 30))	('hedgehog signaling', 'Pathway', (34, 52))	('signaling', 'biological_process', 'GO:0023052', ('43', '52'))
47613	30884815	A similar aberrant phenotype during embryonic development was caused by a partial loss of function of Ift52, or by mutations in two subunits of the retrograde dynein IFT motor.	('Ift52', 'Gene', '245866', (102, 107))	('loss of function', 'NegReg', (82, 98))	('mutations', 'Var', (115, 124))	('dynein', 'molecular_function', 'GO:0003777', ('159', '165'))	('IFT', 'biological_process', 'GO:0042073', ('166', '169'))	('Ift52', 'Gene', (102, 107))	('Ift', 'biological_process', 'GO:0042073', ('102', '105'))
47615	30884815	Recent findings based on a rapamycin-induced in-cell dimerization system to sequester IFT proteins into mitochondria showed that disrupted IFT did not affect SMO accumulation in the cilium, suggesting that SMO enters the cilium in an IFT-independent manner.	('SMO', 'Gene', '319757', (206, 209))	('cilium', 'cellular_component', 'GO:0005929', ('221', '227'))	('SMO', 'Gene', (206, 209))	('IFT', 'biological_process', 'GO:0042073', ('234', '237'))	('mitochondria', 'cellular_component', 'GO:0005739', ('104', '116'))	('disrupted', 'Var', (129, 138))	('IFT', 'biological_process', 'GO:0042073', ('139', '142'))	('IFT', 'biological_process', 'GO:0042073', ('86', '89'))	('SMO', 'Gene', '319757', (158, 161))	('cilium', 'cellular_component', 'GO:0005929', ('182', '188'))	('SMO', 'Gene', (158, 161))	('rapamycin', 'Chemical', 'MESH:D020123', (27, 36))
47618	30884815	Mutant Arl13bhnn MEFs failed to increase the Hedgehog response after Shh stimulation, and displayed an altered distribution of Hedgehog components, such as Gli2, Gli3, Sufu, and also Smo, which was found to be enriched in the cilia, even in the absence of Hedgehog stimulation.	('Arl13b', 'Gene', (7, 13))	('Smo', 'Gene', (183, 186))	('Shh', 'Gene', '20423', (69, 72))	('Gli2', 'Gene', '14633', (156, 160))	('Sufu', 'Gene', '24069', (168, 172))	('altered', 'Reg', (103, 110))	('MEFs', 'CellLine', 'CVCL:9115', (17, 21))	('Smo', 'Gene', '319757', (183, 186))	('Gli3', 'Gene', (162, 166))	('distribution', 'MPA', (111, 123))	('Hedgehog response', 'MPA', (45, 62))	('Sufu', 'Gene', (168, 172))	('Arl13b', 'Gene', '68146', (7, 13))	('Gli3', 'Gene', '14634', (162, 166))	('Mutant', 'Var', (0, 6))	('Shh', 'Gene', (69, 72))	('Gli2', 'Gene', (156, 160))
47620	30884815	Inactivating mutations in PTCH, SUFU, and GNAS or activating mutations of SMO, indicative of Hedgehog pathway misregulation, have been described for sporadic basal cell carcinoma and medulloblastoma tumors.	('medulloblastoma tumors', 'Disease', 'MESH:D008527', (183, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('activating', 'PosReg', (50, 60))	('PTCH', 'Gene', (26, 30))	('Inactivating mutations', 'Var', (0, 22))	('SMO', 'Gene', '319757', (74, 77))	('GNAS', 'Gene', '14683', (42, 46))	('medulloblastoma tumors', 'Disease', (183, 205))	('SUFU', 'Gene', (32, 36))	('SMO', 'Gene', (74, 77))	('sporadic basal cell carcinoma', 'Disease', (149, 178))	('SUFU', 'Gene', '24069', (32, 36))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('PTCH', 'Gene', '19206', (26, 30))	('described', 'Reg', (135, 144))	('GNAS', 'Gene', (42, 46))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (158, 178))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('medulloblastoma', 'Phenotype', 'HP:0002885', (183, 198))	('sporadic basal cell carcinoma', 'Disease', 'MESH:D002280', (149, 178))
47621	30884815	On the basis of these findings, which support a role for the cilium in correct pathway activation, we may assert that, for the Hedgehog-driven tumor, the presence of the primary cilium can boost tumorigenesis and cancer progression (Figure 2, panel "HYPER ON"), contrary to the example in the previous section.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', (143, 148))	('primary cilium', 'cellular_component', 'GO:0005929', ('170', '184'))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cilium', 'cellular_component', 'GO:0005929', ('61', '67'))	('cancer', 'Disease', (213, 219))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('presence', 'Var', (154, 162))	('boost', 'PosReg', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('primary cilium', 'cellular_component', 'GO:0097731', ('170', '184'))
47622	30884815	demonstrated in a recent study that loss of Arl13b abolished cilia-mediated Hedgehog signaling in vitro, but also in vivo in Ptch-deficient mice, where the development of medulloblastoma was arrested.	('cilia-mediated Hedgehog signaling', 'MPA', (61, 94))	('mice', 'Species', '10090', (140, 144))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('medulloblastoma', 'Disease', 'MESH:D008527', (171, 186))	('arrest', 'Disease', 'MESH:D006323', (191, 197))	('Arl13b', 'Gene', '68146', (44, 50))	('Ptch', 'Gene', (125, 129))	('abolished', 'NegReg', (51, 60))	('medulloblastoma', 'Phenotype', 'HP:0002885', (171, 186))	('loss', 'Var', (36, 40))	('medulloblastoma', 'Disease', (171, 186))	('Arl13b', 'Gene', (44, 50))	('arrest', 'Disease', (191, 197))	('Ptch', 'Gene', '19206', (125, 129))
47624	30884815	assessed the role of primary cilia in mouse basal cell carcinoma and found that the expression of a conditional allele of a constitutive active form of Smo induced a highly proliferative and ciliated basal cell carcinoma, in which the constitutive active Smo was localized to the cilia.	('Smo', 'Gene', (152, 155))	('expression', 'Var', (84, 94))	('mouse', 'Species', '10090', (38, 43))	('Smo', 'Gene', '319757', (255, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (200, 220))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (200, 220))	('basal cell carcinoma', 'Disease', (200, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('Smo', 'Gene', '319757', (152, 155))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (44, 64))	('Smo', 'Gene', (255, 258))	('basal cell carcinoma', 'Disease', (44, 64))	('induced', 'PosReg', (156, 163))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (44, 64))
47626	30884815	However, the expression of a constitutively-active human GLI2, in concomitance with the loss of Kif3a-induced cilia resorption, did not protect against tumor formation, but instead drove faster neoplastic growth, with a hyperactivation of Hedgehog signaling (Figure 2, panel "HYPER ON").	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('hyperactivation', 'PosReg', (220, 235))	('neoplastic growth', 'CPA', (194, 211))	('signaling', 'biological_process', 'GO:0023052', ('248', '257'))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('human', 'Species', '9606', (51, 56))	('expression', 'Var', (13, 23))	('drove faster', 'PosReg', (181, 193))	('Hedgehog signaling', 'Pathway', (239, 257))	('formation', 'biological_process', 'GO:0009058', ('158', '167'))
47645	30884815	However, cilia-lacking fibroblasts derived from Tg737orpk mice with mutated Ift88 were not able to increase PDGFRalpha levels and activity, neither in the case of serum-induced growth arrest, nor ligand stimulation (Figure 3B (i)).	('PDGFRalpha levels', 'MPA', (108, 125))	('growth arrest', 'Disease', 'MESH:D006323', (177, 190))	('growth arrest', 'Disease', (177, 190))	('Ift88', 'Gene', (76, 81))	('ligand', 'molecular_function', 'GO:0005488', ('196', '202'))	('mice', 'Species', '10090', (58, 62))	('growth arrest', 'Phenotype', 'HP:0001510', (177, 190))	('Ift', 'biological_process', 'GO:0042073', ('76', '79'))	('mutated', 'Var', (68, 75))	('increase', 'PosReg', (99, 107))	('activity', 'MPA', (130, 138))
47646	30884815	Since aberrant PDGFRalpha signaling is linked to many human tumors, such as gliomas, osteosarcoma, and gastrointestinal stromal tumors, it can be argued that the suppression of the primary cilium can be beneficial for cancer regression.	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (103, 134))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (103, 134))	('tumors', 'Disease', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('osteosarcoma', 'Disease', (85, 97))	('gliomas', 'Disease', (76, 83))	('osteosarcoma', 'Disease', 'MESH:D012516', (85, 97))	('linked', 'Reg', (39, 45))	('signaling', 'biological_process', 'GO:0023052', ('26', '35'))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('gastrointestinal stromal tumors', 'Disease', (103, 134))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('aberrant', 'Var', (6, 14))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('human', 'Species', '9606', (54, 59))	('tumors', 'Disease', (60, 66))	('osteosarcoma', 'Phenotype', 'HP:0002669', (85, 97))	('cancer', 'Disease', (218, 224))	('primary cilium', 'cellular_component', 'GO:0005929', ('181', '195'))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('PDGFRalpha', 'Gene', (15, 25))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('primary cilium', 'cellular_component', 'GO:0097731', ('181', '195'))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
47648	30884815	However, IFT20 depletion caused the autoubiquitination and degradation of c-Cbl, with a mislocalizaton of PDGFRalpha to the plasma membrane, thus impairing negative feedback for pathway regulation.	('depletion', 'Var', (15, 24))	('degradation', 'MPA', (59, 70))	('caused', 'Reg', (25, 31))	('impairing', 'NegReg', (146, 155))	('negative feedback', 'MPA', (156, 173))	('IFT', 'biological_process', 'GO:0042073', ('9', '12'))	('PDGFRalpha', 'Gene', (106, 116))	('regulation', 'biological_process', 'GO:0065007', ('186', '196'))	('mislocalizaton', 'MPA', (88, 102))	('pathway', 'Pathway', (178, 185))	('c-Cbl', 'Gene', '12402', (74, 79))	('plasma membrane', 'cellular_component', 'GO:0005886', ('124', '139'))	('IFT20', 'Gene', (9, 14))	('c-Cbl', 'Gene', (74, 79))	('degradation', 'biological_process', 'GO:0009056', ('59', '70'))	('autoubiquitination', 'MPA', (36, 54))
47652	30884815	In the canonical Wnt/beta-catenin pathway, binding to Frizzled proteins activates the Dvl protein, and this results in the inhibition of the destruction complex containing Adenomatous polyposis coli (Apc), Axin2, Glycogen synthase kinase 3 (Gsk3), and Casein Kinase 1a (CK1a), that constantly degrades beta-catenin in the cytoplasm.	('activates', 'PosReg', (72, 81))	('Gsk3', 'Gene', (241, 245))	('Dvl', 'Gene', '13542', (86, 89))	('binding', 'molecular_function', 'GO:0005488', ('43', '50'))	('CK1', 'Species', '2498238', (270, 273))	('beta-catenin in the', 'MPA', (302, 321))	('Gsk', 'molecular_function', 'GO:0050321', ('241', '244'))	('binding', 'Var', (43, 50))	('cytoplasm', 'cellular_component', 'GO:0005737', ('322', '331'))	('Dvl', 'Gene', (86, 89))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('Apc', 'Gene', (200, 203))	('Apc', 'Gene', '11789', (200, 203))	('Apc', 'cellular_component', 'GO:0005680', ('200', '203'))	('Adenomatous polyposis coli', 'Disease', (172, 198))	('Adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (172, 198))	('Adenomatous polyposis coli', 'Disease', 'MESH:D011125', (172, 198))	('inhibition', 'NegReg', (123, 133))	('Apc', 'Phenotype', 'HP:0005227', (200, 203))	('degrades', 'NegReg', (293, 301))
47658	30884815	In addition, Axin2, Apc, and Vangl2 were found to be localized at the basal body and mutations in the genes encoding basal body proteins impaired both Wnt pathways.	('Vangl2', 'Gene', (29, 35))	('Vangl2', 'Gene', '93840', (29, 35))	('Wnt pathways', 'Pathway', (151, 163))	('Apc', 'Phenotype', 'HP:0005227', (20, 23))	('impaired', 'NegReg', (137, 145))	('Apc', 'cellular_component', 'GO:0005680', ('20', '23'))	('basal body', 'cellular_component', 'GO:0036064', ('117', '127'))	('mutations', 'Var', (85, 94))	('Apc', 'Gene', (20, 23))	('basal body', 'cellular_component', 'GO:0036064', ('70', '80'))	('Apc', 'Gene', '11789', (20, 23))
47660	30884815	In these models, a loss of primary cilia induced by mutations affecting Kif3a, Ift88, or oral-facial-digital syndrome 1 (Ofd1) caused Wnt hyper-responsiveness.	('mutations', 'Var', (52, 61))	('oral-facial-digital syndrome 1', 'Gene', '237222', (89, 119))	('primary cilia', 'CPA', (27, 40))	('Kif3a', 'Gene', (72, 77))	('oral-facial-digital syndrome 1', 'Gene', (89, 119))	('loss', 'NegReg', (19, 23))	('Ift88', 'Gene', (79, 84))	('Ift', 'biological_process', 'GO:0042073', ('79', '82'))	('hyper-responsiveness', 'Disease', 'MESH:D012130', (138, 158))	('hyper-responsiveness', 'Disease', (138, 158))
47661	30884815	The loss of Kif3a led to the constitutive phosphorylation of Dvl by CK1, and the subsequent cytoplasmic stabilization of beta-catenin was responsible for Wnt pathway hyperactivation.	('CK1', 'Species', '2498238', (68, 71))	('CK1', 'Protein', (68, 71))	('Kif3a', 'Gene', (12, 17))	('Dvl', 'Gene', '13542', (61, 64))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))	('constitutive phosphorylation', 'MPA', (29, 57))	('Dvl', 'Gene', (61, 64))	('loss', 'Var', (4, 8))
47662	30884815	Similarly, it was shown that MEFs treated with Kif3a small interfering RNA (siRNA), or with a mutation in the retrograde transport motor dynein cytoplasmic heavy chain 2 (Dnchc2) gene showed no ciliation, and an increase in nuclear translocation of beta-catenin, by a mechanism involving the Jouberin (Jbn) protein, which is normally restricted to the primary cilium, thus limiting beta-catenin nuclear entry.	('Dnchc2', 'Gene', (171, 177))	('primary cilium', 'cellular_component', 'GO:0097731', ('352', '366'))	('transport', 'biological_process', 'GO:0006810', ('121', '130'))	('dynein', 'molecular_function', 'GO:0003777', ('137', '143'))	('RNA', 'cellular_component', 'GO:0005562', ('71', '74'))	('ciliation', 'CPA', (194, 203))	('beta-catenin nuclear entry', 'MPA', (382, 408))	('increase', 'PosReg', (212, 220))	('limiting', 'NegReg', (373, 381))	('Jbn', 'Gene', '52906', (302, 305))	('Jouberin', 'Gene', (292, 300))	('nuclear translocation', 'MPA', (224, 245))	('MEFs', 'CellLine', 'CVCL:9115', (29, 33))	('beta-catenin', 'Protein', (249, 261))	('Jbn', 'Gene', (302, 305))	('dynein cytoplasmic heavy chain 2', 'Gene', (137, 169))	('dynein cytoplasmic heavy chain 2', 'Gene', '110350', (137, 169))	('Dnchc2', 'Gene', '110350', (171, 177))	('primary cilium', 'cellular_component', 'GO:0005929', ('352', '366'))	('Jouberin', 'Gene', '52906', (292, 300))	('protein', 'cellular_component', 'GO:0003675', ('307', '314'))	('mutation', 'Var', (94, 102))
47669	30884815	A defective cilium can lead to signaling impairments, causing the induction of tumorigenesis.	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('lead', 'Reg', (23, 27))	('tumor', 'Disease', (79, 84))	('signaling impairments', 'MPA', (31, 52))	('induction', 'Reg', (66, 75))	('cilium', 'cellular_component', 'GO:0005929', ('12', '18'))	('defective', 'Var', (2, 11))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
47670	30884815	In cancer, the presence or absence of the primary cilium can trigger or inhibit cancer progression, depending on the type of cancer, the cancer-initiating mutations, and on the altered molecular pathway responsible for tumor insurgence.	('tumor', 'Disease', (219, 224))	('cancer', 'Disease', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('cancer', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('trigger', 'Reg', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('presence', 'Var', (15, 23))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('primary cilium', 'cellular_component', 'GO:0005929', ('42', '56'))	('cancer', 'Disease', (3, 9))	('primary cilium', 'cellular_component', 'GO:0097731', ('42', '56'))	('inhibit', 'NegReg', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('absence', 'Var', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
47678	30884815	The positive role of cilia in autophagy activation was also confirmed by Wang et al., where cilia shortening induced by IFT88 knockdown in human kidney proximal tubular cells impaired autophagy through the activation of mTOR signaling.	('autophagy', 'biological_process', 'GO:0006914', ('184', '193'))	('cilia', 'CPA', (92, 97))	('signaling', 'biological_process', 'GO:0023052', ('225', '234'))	('autophagy', 'biological_process', 'GO:0016236', ('30', '39'))	('mTOR signaling', 'Pathway', (220, 234))	('autophagy', 'CPA', (184, 193))	('IFT', 'biological_process', 'GO:0042073', ('120', '123'))	('IFT88', 'Gene', (120, 125))	('autophagy', 'biological_process', 'GO:0006914', ('30', '39'))	('human', 'Species', '9606', (139, 144))	('impaired', 'NegReg', (175, 183))	('shortening', 'NegReg', (98, 108))	('knockdown', 'Var', (126, 135))	('activation', 'PosReg', (206, 216))	('autophagy', 'biological_process', 'GO:0016236', ('184', '193'))
47679	30884815	did not observe an activation of the mTOR pathway upon cilia-related autophagy inhibition, disruption of ciliogenesis was shown to lead to an increase in the phosphorylation of mTOR and AKT1, the downstream substrates of the mTOR pathway.	('increase', 'PosReg', (142, 150))	('disruption', 'Var', (91, 101))	('phosphorylation', 'MPA', (158, 173))	('mTOR', 'Protein', (177, 181))	('autophagy', 'biological_process', 'GO:0016236', ('69', '78'))	('phosphorylation', 'biological_process', 'GO:0016310', ('158', '173'))	('AKT1', 'Gene', '11651', (186, 190))	('ciliogenesis', 'biological_process', 'GO:0060271', ('105', '117'))	('autophagy', 'biological_process', 'GO:0006914', ('69', '78'))	('ciliogenesis', 'CPA', (105, 117))	('AKT1', 'Gene', (186, 190))
47681	30884815	Moreover, the knockdown of Ofd1 was able to restore ciliogenesis, even in the presence of serum in both the MEFs and MCF7 breast cell lines, thus indicating that OFD1 has a suppressive role on ciliogenesis and that autophagy, by degrading the satellite OFD1, is instead a positive regulator.	('Ofd1', 'Gene', (27, 31))	('suppressive', 'NegReg', (173, 184))	('OFD1', 'Gene', (162, 166))	('degrading', 'NegReg', (229, 238))	('MCF7', 'CellLine', 'CVCL:0031', (117, 121))	('autophagy', 'biological_process', 'GO:0016236', ('215', '224'))	('ciliogenesis', 'biological_process', 'GO:0060271', ('52', '64'))	('ciliogenesis', 'CPA', (52, 64))	('autophagy', 'biological_process', 'GO:0006914', ('215', '224'))	('satellite OFD1', 'MPA', (243, 257))	('ciliogenesis', 'CPA', (193, 205))	('knockdown', 'Var', (14, 23))	('MEFs', 'CellLine', 'CVCL:9115', (108, 112))	('autophagy', 'CPA', (215, 224))	('ciliogenesis', 'biological_process', 'GO:0060271', ('193', '205'))
47691	30884815	Peroxisome proliferator-activated receptor alpha (PPARA), a hormone transcription factor that is activated during starvation, was shown to be another positive regulator of ciliogenesis, by activating autophagy both in vivo and in vitro; thus, the pharmacological inhibition of autophagy repressed ciliogenesis.	('Peroxisome proliferator-activated receptor alpha', 'Gene', (0, 48))	('ciliogenesis', 'biological_process', 'GO:0060271', ('172', '184'))	('transcription', 'biological_process', 'GO:0006351', ('68', '81'))	('autophagy', 'CPA', (277, 286))	('autophagy', 'biological_process', 'GO:0016236', ('200', '209'))	('ciliogenesis', 'biological_process', 'GO:0060271', ('297', '309'))	('Peroxisome proliferator-activated receptor alpha', 'Gene', '19013', (0, 48))	('autophagy', 'biological_process', 'GO:0016236', ('277', '286'))	('pharmacological', 'Var', (247, 262))	('activating', 'PosReg', (189, 199))	('Peroxisome', 'cellular_component', 'GO:0005777', ('0', '10'))	('autophagy', 'biological_process', 'GO:0006914', ('200', '209'))	('ciliogenesis', 'CPA', (297, 309))	('transcription factor', 'molecular_function', 'GO:0000981', ('68', '88'))	('PPARA', 'Gene', '19013', (50, 55))	('autophagy', 'CPA', (200, 209))	('repressed', 'NegReg', (287, 296))	('autophagy', 'biological_process', 'GO:0006914', ('277', '286'))	('PPARA', 'Gene', (50, 55))
47695	30884815	In fact, the ligand activation of NR1H4 impaired ciliogenesis in RPE1 and HK2 cells, while the knockdown of NR1H4 restored ciliogenesis and activated autophagy genes, even in media containing serum.	('autophagy', 'biological_process', 'GO:0006914', ('150', '159'))	('ciliogenesis', 'CPA', (49, 61))	('HK2', 'molecular_function', 'GO:0008256', ('74', '77'))	('ligand', 'molecular_function', 'GO:0005488', ('13', '19'))	('autophagy genes', 'CPA', (150, 165))	('impaired', 'NegReg', (40, 48))	('restored', 'PosReg', (114, 122))	('NR1H4', 'Gene', (34, 39))	('knockdown', 'Var', (95, 104))	('HK2', 'CellLine', 'CVCL:0302', (74, 77))	('ciliogenesis', 'biological_process', 'GO:0060271', ('49', '61'))	('activated', 'PosReg', (140, 149))	('activation', 'PosReg', (20, 30))	('autophagy', 'biological_process', 'GO:0016236', ('150', '159'))	('NR1H4', 'Gene', (108, 113))	('ciliogenesis', 'biological_process', 'GO:0060271', ('123', '135'))	('RPE1', 'CellLine', 'CVCL:4388', (65, 69))	('ciliogenesis', 'CPA', (123, 135))
47700	30884815	Studies on autophagy-deficient mice lacking the Atg5 gene or harboring an Atg7 liver-specific deletion developed benign liver tumors, whose size was further reduced with the depletion of the ubiquitin-binding protein p62, thus indicating a suppressive role for autophagy in cell transformation.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('liver tumors', 'Disease', 'MESH:D008113', (120, 132))	('liver tumors', 'Phenotype', 'HP:0002896', (120, 132))	('mice', 'Species', '10090', (31, 35))	('autophagy', 'biological_process', 'GO:0006914', ('261', '270'))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('protein', 'cellular_component', 'GO:0003675', ('209', '216'))	('p62', 'Gene', '18226', (217, 220))	('liver tumors', 'Disease', (120, 132))	('autophagy', 'biological_process', 'GO:0006914', ('11', '20'))	('deletion', 'Var', (94, 102))	('depletion', 'MPA', (174, 183))	('Atg5', 'Gene', '11793', (48, 52))	('ubiquitin-binding', 'MPA', (191, 208))	('autophagy-deficient', 'Disease', (11, 30))	('reduced', 'NegReg', (157, 164))	('Atg7', 'Gene', '74244', (74, 78))	('autophagy-deficient', 'Disease', 'MESH:C564093', (11, 30))	('ubiquitin-binding', 'molecular_function', 'GO:0043130', ('191', '208'))	('autophagy', 'biological_process', 'GO:0016236', ('261', '270'))	('Atg5', 'Gene', (48, 52))	('Atg7', 'Gene', (74, 78))	('developed', 'Reg', (103, 112))	('p62', 'Gene', (217, 220))	('autophagy', 'biological_process', 'GO:0016236', ('11', '20'))
47715	30884815	With high PO2, PHDs hydroxylate HIFs-alpha in the oxygen-dependent degradation domain (ODDD), thus enabling rapid interaction with the ubiquitin E3-containing ligase, von Hippel-Lindau (pVHL).	('pVHL', 'Gene', '22346', (186, 190))	('enabling', 'PosReg', (99, 107))	('ubiquitin', 'molecular_function', 'GO:0031386', ('135', '144'))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (167, 184))	('PHD', 'Disease', 'MESH:D011547', (15, 18))	('ODDD', 'Disease', (87, 91))	('degradation', 'biological_process', 'GO:0009056', ('67', '78'))	('interaction', 'Interaction', (114, 125))	('pVHL', 'Gene', (186, 190))	('high PO2', 'Var', (5, 13))	('von Hippel-Lindau', 'Disease', (167, 184))	('PO2', 'Var', (10, 13))	('oxygen', 'Chemical', 'MESH:D010100', (50, 56))	('ODDD', 'Disease', 'MESH:C563160', (87, 91))	('PO2', 'Chemical', 'MESH:C093415', (10, 13))	('PHD', 'Disease', (15, 18))
47721	30884815	The oncogenic event characterizing both the hereditary and the sporadic form of ccRCC is the biallelic inactivation of the VHL gene, which, among its functions, is crucial in addressing HIF-alpha proteins for proteasomal degradation.	('degradation', 'biological_process', 'GO:0009056', ('221', '232'))	('VHL', 'Gene', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('biallelic', 'Var', (93, 102))
47733	30884815	Finally, severe cilia disruption was observed in tumors from patients with germline mutations in the pseudohypoxia-linked genes succinate dehydrogenase (SDHx) and VHL, indicating a possible role for the HIFs.	('succinate', 'Chemical', 'MESH:D019802', (128, 137))	('hypoxia', 'Disease', 'MESH:D000860', (107, 114))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('germline mutations', 'Var', (75, 93))	('cilia disruption', 'Disease', 'MESH:D019958', (16, 32))	('patients', 'Species', '9606', (61, 69))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('SDH', 'Gene', (153, 156))	('SDH', 'Gene', '231691', (153, 156))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('VHL', 'Gene', (163, 166))	('hypoxia', 'Disease', (107, 114))	('cilia disruption', 'Disease', (16, 32))
47739	30884815	Hypoxia seems to mostly counteract primary cilia formation through the stabilization of HIF transcription factors, following the inactivation of pVHL, which is a structural component of the cilium, and it is essential for ciliogenesis.	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('Hypoxia', 'Disease', (0, 7))	('HIF transcription factors', 'Gene', (88, 113))	('pVHL', 'Gene', (145, 149))	('primary cilia formation', 'CPA', (35, 58))	('transcription', 'biological_process', 'GO:0006351', ('92', '105'))	('cilium', 'cellular_component', 'GO:0005929', ('190', '196'))	('ciliogenesis', 'biological_process', 'GO:0060271', ('222', '234'))	('formation', 'biological_process', 'GO:0009058', ('49', '58'))	('inactivation', 'Var', (129, 141))	('pVHL', 'Gene', '22346', (145, 149))
47746	30884815	LOF-IFT88/primary cilia resulted in mitochondrial fragmentation, impaired oxidative phosphorylation (OXPHOS), diminished mitochondrial membrane potential, and reduced ATP synthesis.	('OXPHOS', 'biological_process', 'GO:0002082', ('101', '107'))	('ATP', 'Chemical', 'MESH:D000255', (167, 170))	('diminished mitochondrial membrane potential', 'Phenotype', 'HP:0040013', (110, 153))	('reduced', 'NegReg', (159, 166))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('74', '99'))	('mitochondrial membrane potential', 'MPA', (121, 153))	('LOF-IFT88/primary', 'Var', (0, 17))	('oxidative phosphorylation', 'MPA', (74, 99))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('121', '143'))	('ATP synthesis', 'biological_process', 'GO:0006754', ('167', '180'))	('ATP synthesis', 'MPA', (167, 180))	('IFT', 'biological_process', 'GO:0042073', ('4', '7'))	('diminished', 'NegReg', (110, 120))	('impaired', 'NegReg', (65, 73))	('mitochondrial fragmentation', 'CPA', (36, 63))
47748	30884815	The results were further confirmed for two out of three thyroid cancer cell lines knocked down for KIF3A, indicating that the shift towards glycolytic metabolism was specifically dependent on the loss of primary cilia.	('metabolism', 'biological_process', 'GO:0008152', ('151', '161'))	('knocked down', 'Var', (82, 94))	('thyroid cancer', 'Disease', 'MESH:D013964', (56, 70))	('primary cilia', 'CPA', (204, 217))	('glycolytic metabolism', 'MPA', (140, 161))	('loss', 'NegReg', (196, 200))	('KIF3A', 'Gene', '16568', (99, 104))	('KIF3A', 'Gene', (99, 104))	('thyroid cancer', 'Phenotype', 'HP:0002890', (56, 70))	('thyroid cancer', 'Disease', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
47758	30884815	As discussed in   3.1, medulloblastoma insurgence is associated with mutations in the Hedgehog pathway, which is tightly regulated throughout the primary cilium.	('mutations', 'Var', (69, 78))	('medulloblastoma', 'Disease', 'MESH:D008527', (23, 38))	('medulloblastoma', 'Phenotype', 'HP:0002885', (23, 38))	('Hedgehog pathway', 'Pathway', (86, 102))	('medulloblastoma', 'Disease', (23, 38))	('primary cilium', 'cellular_component', 'GO:0097731', ('146', '160'))	('associated', 'Reg', (53, 63))	('primary cilium', 'cellular_component', 'GO:0005929', ('146', '160'))
47763	30884815	By using HMLE human mammary epithelial cells engineered for the acquisition of an epithelial-to-mesenchymal (EMT) signature, they demonstrated that this HMLE variant was able to strongly increase the expression of primary cilia.	('increase', 'PosReg', (187, 195))	('epithelia', 'Disease', 'None', (82, 91))	('EMT', 'biological_process', 'GO:0001837', ('109', '112'))	('human', 'Species', '9606', (14, 19))	('primary cilia', 'Protein', (214, 227))	('variant', 'Var', (158, 165))	('epithelia', 'Disease', (82, 91))	('expression', 'MPA', (200, 210))	('epithelia', 'Disease', (28, 37))	('epithelia', 'Disease', 'None', (28, 37))
47767	30884815	In fact, EMT in the kidney is promoted by ARL13B and IFT20 knockdown-induced impairment of ciliogenesis, but the study was carried out on the non-cancerous Madin Darby Canine Kidney (MDCK) cell line.	('cancerous', 'Disease', (146, 155))	('knockdown-induced', 'Var', (59, 76))	('EMT in the', 'CPA', (9, 19))	('cancerous', 'Disease', 'MESH:D009369', (146, 155))	('IFT', 'biological_process', 'GO:0042073', ('53', '56'))	('promoted', 'PosReg', (30, 38))	('EMT', 'biological_process', 'GO:0001837', ('9', '12'))	('impairment', 'NegReg', (77, 87))	('ciliogenesis', 'CPA', (91, 103))	('MDCK', 'CellLine', 'CVCL:0422', (183, 187))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ARL13B', 'Var', (42, 48))	('IFT20', 'Gene', (53, 58))	('ciliogenesis', 'biological_process', 'GO:0060271', ('91', '103'))	('Canine', 'Species', '9615', (168, 174))
47775	30884815	However, another study has proposed the role of cilia loss in the context of drug resistance to SMO inhibitors in vitro and in vivo, in which the loss of cilia in medulloblastoma cells was associated with mutations in OFD1, and a basal level of activated Hedgehog pathway sustained tumor growth, indicating that the role of cilia in promoting cell death resistance depends on the oncogenic context.	('medulloblastoma', 'Disease', (163, 178))	('SMO', 'Gene', (96, 99))	('loss', 'NegReg', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('cell death', 'biological_process', 'GO:0008219', ('343', '353'))	('cilia loss', 'Disease', 'MESH:C536287', (48, 58))	('drug resistance', 'biological_process', 'GO:0042493', ('77', '92'))	('OFD1', 'Gene', (218, 222))	('tumor', 'Disease', (282, 287))	('cilia', 'CPA', (154, 159))	('mutations', 'Var', (205, 214))	('drug resistance', 'biological_process', 'GO:0009315', ('77', '92'))	('medulloblastoma', 'Disease', 'MESH:D008527', (163, 178))	('cilia loss', 'Disease', (48, 58))	('medulloblastoma', 'Phenotype', 'HP:0002885', (163, 178))	('SMO', 'Gene', '319757', (96, 99))	('drug resistance', 'Phenotype', 'HP:0020174', (77, 92))	('tumor', 'Disease', 'MESH:D009369', (282, 287))
47781	30884815	Mutation or morpholino-induced loss of ift172 and ift81 developed cranial hemorrhages in zebrafish embryos, and the phenotype was rescued with the overexpression of ift81.	('cranial hemorrhages', 'Disease', 'MESH:D002543', (66, 85))	('loss', 'NegReg', (31, 35))	('ift81', 'Gene', (165, 170))	('ift', 'biological_process', 'GO:0042073', ('50', '53'))	('ift172', 'Gene', '432389', (39, 45))	('Mutation', 'Var', (0, 8))	('cranial hemorrhages', 'Phenotype', 'HP:0002170', (66, 85))	('ift', 'biological_process', 'GO:0042073', ('165', '168'))	('ift172', 'Gene', (39, 45))	('ift81', 'Gene', '432390', (50, 55))	('ift81', 'Gene', '432390', (165, 170))	('cranial hemorrhages', 'Disease', (66, 85))	('ift', 'biological_process', 'GO:0042073', ('39', '42'))	('ift81', 'Gene', (50, 55))	('zebrafish', 'Species', '7955', (89, 98))
47783	30884815	The latter in vivo research on mice demonstrated that the inducible deletion of primary cilia via loss of Ift88 in retinal endothelial cells triggered premature and random vessel regression, indicating that primary cilia are crucial for proper vascular remodeling.	('primary cilia', 'Gene', (80, 93))	('Ift88', 'Gene', (106, 111))	('deletion', 'Var', (68, 76))	('mice', 'Species', '10090', (31, 35))	('loss', 'NegReg', (98, 102))	('Ift', 'biological_process', 'GO:0042073', ('106', '109'))
47790	30884815	On the other hand, primary cilia of ciliated cancer cells may also confer drug resistance to specific kinase inhibitors through the activation of the Hedgehog pathway, and targeting the primary cilium sensitizes cancer cells to cell death.	('activation', 'PosReg', (132, 142))	('sensitizes', 'Reg', (201, 211))	('primary cilium', 'cellular_component', 'GO:0005929', ('186', '200'))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('primary cilium', 'cellular_component', 'GO:0097731', ('186', '200'))	('Hedgehog pathway', 'Pathway', (150, 166))	('drug resistance', 'Phenotype', 'HP:0020174', (74, 89))	('drug resistance', 'biological_process', 'GO:0009315', ('74', '89'))	('drug resistance', 'biological_process', 'GO:0042493', ('74', '89'))	('confer', 'Reg', (67, 73))	('cancer', 'Disease', (212, 218))	('drug resistance to', 'MPA', (74, 92))	('cancer', 'Disease', (45, 51))	('cell death', 'CPA', (228, 238))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cell death', 'biological_process', 'GO:0008219', ('228', '238'))	('targeting', 'Var', (172, 181))
47806	28494778	In cell line experiments, LPCAT1 knockdown depleted PCs, inhibited cell proliferation, migration and invasion and induced cell cycle arrest at the G0/G1 phase.	('depleted', 'NegReg', (43, 51))	('LPCAT1', 'Gene', (26, 32))	('PC', 'Chemical', 'MESH:D010713', (52, 54))	('PC', 'Chemical', 'MESH:D010713', (27, 29))	('inhibited', 'NegReg', (57, 66))	('knockdown', 'Var', (33, 42))	('si', 'Chemical', 'MESH:D012825', (105, 107))	('G1 phase', 'biological_process', 'GO:0051318', ('150', '158'))	('LPCAT1', 'Gene', '79888', (26, 32))	('cell cycle arrest at the G0/G1 phase', 'CPA', (122, 158))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('122', '139'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (122, 139))	('cell proliferation', 'CPA', (67, 85))	('induced', 'Reg', (114, 121))	('PCs', 'Protein', (52, 55))	('invasion', 'CPA', (101, 109))
47840	28494778	After blotting with 5% non-fat milk or BSA, the membranes were incubated with anti-LPCAT1 (1:1000; Proteintech, Chicago, IL, USA) or anti-GAPDH (1:3000; Cell Signalling Technology, Danvers, MA, USA) overnight at 4  C, followed by incubation with horseradish peroxidase-conjugated secondary antibodies for 1 h at room temperature.	('GAPDH', 'Gene', '2597', (138, 143))	('LPCAT1', 'Gene', '79888', (83, 89))	('GAPDH', 'Gene', (138, 143))	('horseradish', 'Species', '3704', (246, 257))	('Signalling', 'biological_process', 'GO:0023052', ('158', '168'))	('1:1000', 'Var', (91, 97))	('LPCAT1', 'Gene', (83, 89))
47849	28494778	The intensity was quantified by two pathologists blinded to the clinical status of the patients, and the results were categorized according to the staining intensity of LPCAT1 as follows: -, negative; +, weak; ++, moderate; and +++, intense.	('LPCAT1', 'Gene', (169, 175))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('LPCAT1', 'Gene', '79888', (169, 175))	('si', 'Chemical', 'MESH:D012825', (161, 163))	('+++', 'Var', (228, 231))	('patients', 'Species', '9606', (87, 95))
47853	28494778	The following sequences were used for the two LPCAT1 siRNAs and the non-specific control siRNA (NC): si-LPCAT1-1: 5'-GAUCCAGUAUAUACGGCCUTT-3' (sense), 5'-AGGCCGUAUAUACUGGAUCTT-3' (antisense); si-LPCAT1-2: 5'-CCUGCCUAAUUACCUUCAATT-3' (sense), 5'-UUGAAGGUAAUUAGGCAGGTT-3' (antisense); and si-NC: 5'-UUCUCCGAACGUGUCACGUTT-3' (sense), 5'-ACGUGACACGUUCGGAGAATT-3' (antisense).	('si-NC', 'Var', (287, 292))	('LPCAT1', 'Gene', (46, 52))	('si', 'Chemical', 'MESH:D012825', (287, 289))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('LPCAT1', 'Gene', '79888', (104, 110))	('LPCAT1', 'Gene', (195, 201))	('LPCAT1', 'Gene', '79888', (46, 52))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('LPCAT1', 'Gene', (104, 110))	('si', 'Chemical', 'MESH:D012825', (192, 194))	('LPCAT1', 'Gene', '79888', (195, 201))
47891	28494778	Kaplan-Meier survival curves showed that the high expression of LPCAT1 in tumours correlated with worse survival in ccRCC patients (log-rank test, p = 0.018) (Fig.	('expression', 'MPA', (50, 60))	('survival', 'MPA', (104, 112))	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('LPCAT1', 'Gene', '79888', (64, 70))	('RCC', 'Disease', (118, 121))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('tumours', 'Disease', 'MESH:D009369', (74, 81))	('LPCAT1', 'Gene', (64, 70))	('high', 'Var', (45, 49))	('tumours', 'Disease', (74, 81))	('patients', 'Species', '9606', (122, 130))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('worse', 'NegReg', (98, 103))
47893	28494778	To investigate the function of LPCAT1 in ccRCC, we used specific siRNAs to knockdown the expression of LPCAT1 in the ccRCC cell lines 769P and ACHN.	('LPCAT1', 'Gene', '79888', (31, 37))	('ACHN', 'Gene', '55323', (143, 147))	('LPCAT1', 'Gene', '79888', (103, 109))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('knockdown', 'Var', (75, 84))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('ACHN', 'Gene', (143, 147))	('RCC', 'Disease', (43, 46))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))	('LPCAT1', 'Gene', (103, 109))	('LPCAT1', 'Gene', (31, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('si', 'Chemical', 'MESH:D012825', (65, 67))
47898	28494778	At 48 h after transfection, we examined the PC compositions of ccRCC cells, and confirmed the reductions of some PCs after LPCAT1 knockdown in ACHN and 769P (Fig.	('reductions', 'NegReg', (94, 104))	('PC', 'Chemical', 'MESH:D010713', (124, 126))	('ACHN', 'Gene', '55323', (143, 147))	('knockdown', 'Var', (130, 139))	('LPCAT1', 'Gene', (123, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('ACHN', 'Gene', (143, 147))	('PCs', 'Disease', (113, 116))	('PC', 'Chemical', 'MESH:D010713', (113, 115))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('PC', 'Chemical', 'MESH:D010713', (44, 46))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('LPCAT1', 'Gene', '79888', (123, 129))	('RCC', 'Disease', (65, 68))
47904	28494778	Taken together, these results indicated that the knockdown of LPCAT1 suppresses the proliferation of ACHN and 769P ccRCC cells.	('knockdown', 'Var', (49, 58))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('ACHN', 'Gene', (101, 105))	('LPCAT1', 'Gene', '79888', (62, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('ACHN', 'Gene', '55323', (101, 105))	('LPCAT1', 'Gene', (62, 68))	('suppresses', 'NegReg', (69, 79))
47907	28494778	5, the knockdown of LPCAT1 led to a significant increase in the proportion of cells at the G0/G1 phase and a decrease in the proportion of cells at the S and G2/M phases.	('decrease', 'NegReg', (109, 117))	('G1 phase', 'biological_process', 'GO:0051318', ('94', '102'))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('LPCAT1', 'Gene', (20, 26))	('knockdown', 'Var', (7, 16))	('LPCAT1', 'Gene', '79888', (20, 26))	('increase', 'PosReg', (48, 56))
47908	28494778	These results indicated that the knockdown of LPCAT1 could induce cell cycle arrest at the G0/G1 phase in the ACHN and 769P ccRCC cells.	('ACHN', 'Gene', (110, 114))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (66, 83))	('G1 phase', 'biological_process', 'GO:0051318', ('94', '102'))	('LPCAT1', 'Gene', (46, 52))	('knockdown', 'Var', (33, 42))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('66', '83'))	('induce', 'Reg', (59, 65))	('cell cycle arrest at the G0/G1 phase', 'CPA', (66, 102))	('ACHN', 'Gene', '55323', (110, 114))	('LPCAT1', 'Gene', '79888', (46, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (124, 129))	('RCC', 'Disease', (126, 129))	('RCC', 'Disease', 'MESH:C538614', (126, 129))
47911	28494778	The migration assay revealed that the knockdown of LPCAT1 could inhibit the motility of ccRCC cells.	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('LPCAT1', 'Gene', '79888', (51, 57))	('motility of', 'CPA', (76, 87))	('inhibit', 'NegReg', (64, 71))	('knockdown', 'Var', (38, 47))	('LPCAT1', 'Gene', (51, 57))	('RCC', 'Disease', (90, 93))
47913	28494778	The invasion assay showed the inhibition of cell invasion after LPCAT1 knockdown.	('cell invasion', 'CPA', (44, 57))	('si', 'Chemical', 'MESH:D012825', (8, 10))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('knockdown', 'Var', (71, 80))	('LPCAT1', 'Gene', (64, 70))	('inhibition', 'NegReg', (30, 40))	('LPCAT1', 'Gene', '79888', (64, 70))
47916	28494778	Overall, these results indicated that the knockdown of LPCAT1 could inhibit the migration and invasion of ACHN and 769P ccRCC cells.	('ccRCC', 'Phenotype', 'HP:0006770', (120, 125))	('LPCAT1', 'Gene', '79888', (55, 61))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('ACHN', 'Gene', '55323', (106, 110))	('inhibit', 'NegReg', (68, 75))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('ACHN', 'Gene', (106, 110))	('LPCAT1', 'Gene', (55, 61))	('RCC', 'Disease', (122, 125))	('knockdown', 'Var', (42, 51))
47917	28494778	As a relatively new concept in oncogenesis, lipid profile alterations have been implicated in the development and progression of various cancers, such as breast cancer, hepatocellular carcinoma and prostate cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('lipid profile', 'MPA', (44, 57))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('lipid', 'Chemical', 'MESH:D008055', (44, 49))	('alterations', 'Var', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (169, 193))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('implicated', 'Reg', (80, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('prostate cancer', 'Phenotype', 'HP:0012125', (198, 213))	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('hepatocellular carcinoma and prostate cancer', 'Disease', 'MESH:D006528', (169, 213))	('breast cancer', 'Disease', (154, 167))	('oncogenesis', 'biological_process', 'GO:0007048', ('31', '42'))	('si', 'Chemical', 'MESH:D012825', (121, 123))
47951	28494778	Alterations of membrane PC levels can influence cell proliferation and membrane fluidity, which facilitate cancer cell growth and metastases.	('membrane fluidity', 'CPA', (71, 88))	('PC', 'Chemical', 'MESH:D010713', (24, 26))	('facilitate', 'PosReg', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Alterations', 'Var', (0, 11))	('influence', 'Reg', (38, 47))	('cell proliferation', 'CPA', (48, 66))	('cell growth', 'biological_process', 'GO:0016049', ('114', '125'))	('metastases', 'Disease', (130, 140))	('membrane', 'cellular_component', 'GO:0016020', ('71', '79'))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('metastases', 'Disease', 'MESH:D009362', (130, 140))	('cancer', 'Disease', (107, 113))	('cell proliferation', 'biological_process', 'GO:0008283', ('48', '66'))	('membrane', 'cellular_component', 'GO:0016020', ('15', '23'))
47952	28494778	In the present study, we observed significant phospholipid alterations and the accumulation of several PC species in ccRCC tissues, and knockdown of LPCAT1 could deplete PCs and inhibited proliferation, migration and invasion abilities of ccRCC cell lines.	('invasion abilities', 'CPA', (217, 235))	('accumulation', 'MPA', (79, 91))	('RCC', 'Disease', (241, 244))	('proliferation', 'CPA', (188, 201))	('LPCAT1', 'Gene', (149, 155))	('ccRCC', 'Phenotype', 'HP:0006770', (239, 244))	('deplete', 'NegReg', (162, 169))	('LPCAT1', 'Gene', '79888', (149, 155))	('inhibited', 'NegReg', (178, 187))	('PC', 'Chemical', 'MESH:D010713', (170, 172))	('RCC', 'Disease', 'MESH:C538614', (241, 244))	('PC', 'Chemical', 'MESH:D010713', (103, 105))	('phospholipid alterations', 'Phenotype', 'HP:0040176', (46, 70))	('si', 'Chemical', 'MESH:D012825', (221, 223))	('knockdown', 'Var', (136, 145))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('RCC', 'Disease', (119, 122))	('PC', 'Chemical', 'MESH:D010713', (150, 152))	('phospholipid alterations', 'MPA', (46, 70))	('PCs', 'MPA', (170, 173))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('phospholipid', 'Chemical', 'MESH:D010743', (46, 58))
47954	28494778	Alterations of phospholipids enhance cell proliferation and membrane fluidity and eventually lead to the development and progression of ccRCC.	('RCC', 'Disease', (138, 141))	('cell proliferation', 'biological_process', 'GO:0008283', ('37', '55'))	('membrane fluidity', 'CPA', (60, 77))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('membrane', 'cellular_component', 'GO:0016020', ('60', '68'))	('Alterations', 'Var', (0, 11))	('phospholipids', 'Chemical', 'MESH:D010743', (15, 28))	('enhance', 'PosReg', (29, 36))	('lead to', 'Reg', (93, 100))	('cell proliferation', 'CPA', (37, 55))
47963	27741505	We identified mutations in the VHL, PTEN, JAK3, MET, ERBB4, APC, CDKN2A, FGFR3, EGFR, RB1, TP53 genes.	('RB1', 'Gene', (86, 89))	('PTEN', 'Gene', (36, 40))	('FGFR3', 'Gene', '2261', (73, 78))	('EGFR', 'Gene', '1956', (80, 84))	('JAK3', 'Gene', '3718', (42, 46))	('VHL', 'Gene', '7428', (31, 34))	('RB1', 'Gene', '5925', (86, 89))	('TP53', 'Gene', '7157', (91, 95))	('PTEN', 'Gene', '5728', (36, 40))	('MET', 'Gene', (48, 51))	('ERBB4', 'Gene', '2066', (53, 58))	('CDKN2A', 'Gene', (65, 71))	('mutations', 'Var', (14, 23))	('ERBB4', 'Gene', (53, 58))	('APC', 'Disease', 'MESH:D011125', (60, 63))	('TP53', 'Gene', (91, 95))	('APC', 'Disease', (60, 63))	('FGFR', 'molecular_function', 'GO:0005007', ('73', '77'))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('EGFR', 'Gene', (80, 84))	('JAK', 'molecular_function', 'GO:0004713', ('42', '45'))	('CDKN2A', 'Gene', '1029', (65, 71))	('APC', 'cellular_component', 'GO:0005680', ('60', '63'))	('FGFR3', 'Gene', (73, 78))	('VHL', 'Gene', (31, 34))	('JAK3', 'Gene', (42, 46))
47964	27741505	Most mutations hit VHL1 (31,8%) followed by PTEN (13,6%), JAK3, FGFR and TP53 (9% each).	('JAK3', 'Gene', (58, 62))	('TP53', 'Gene', '7157', (73, 77))	('JAK3', 'Gene', '3718', (58, 62))	('VHL1', 'Gene', (19, 23))	('FGFR', 'molecular_function', 'GO:0005007', ('64', '68'))	('TP53', 'Gene', (73, 77))	('mutations', 'Var', (5, 14))	('PTEN', 'Gene', (44, 48))	('PTEN', 'Gene', '5728', (44, 48))	('JAK', 'molecular_function', 'GO:0004713', ('58', '61'))	('VHL1', 'Gene', '7428', (19, 23))	('hit', 'Reg', (15, 18))
47968	27741505	Among the 4 partial responders, 1 (25%) was wild-type and 3 (75%) harbored different VHL1 variants.	('variants', 'Var', (90, 98))	('VHL1', 'Gene', (85, 89))	('VHL1', 'Gene', '7428', (85, 89))	('harbored', 'Reg', (66, 74))
47969	27741505	Among the 7 patients with disease stabilization 2 (29%) were wild-type, 2 (29%) PTEN mutated, and single patients (14% each) displayed mutations in VHL1, JAK3 and APC/CDKN2A.	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (105, 113))	('PTEN', 'Gene', (80, 84))	('JAK', 'molecular_function', 'GO:0004713', ('154', '157'))	('PTEN', 'Gene', '5728', (80, 84))	('CDKN2A', 'Gene', (167, 173))	('CDKN2A', 'Gene', '1029', (167, 173))	('mutations', 'Var', (135, 144))	('APC', 'Disease', (163, 166))	('VHL1', 'Gene', '7428', (148, 152))	('APC', 'Disease', 'MESH:D011125', (163, 166))	('JAK3', 'Gene', (154, 158))	('APC', 'cellular_component', 'GO:0005680', ('163', '166'))	('JAK3', 'Gene', '3718', (154, 158))	('VHL1', 'Gene', (148, 152))
47982	27741505	According to the Cancer Genome Atlas database the most frequent somatic mutations in ccRCC include mainly alterations of the VHL gene and its partners involved in neo-angiogenesis and response to hypoxia, followed by alterations of the PI(3)K/AKT/mTOR pathway.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('mTOR', 'Gene', (247, 251))	('mutations', 'Var', (72, 81))	('VHL', 'Gene', (125, 128))	('angiogenesis', 'biological_process', 'GO:0001525', ('167', '179'))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('mTOR', 'Gene', '2475', (247, 251))	('alterations', 'Reg', (217, 228))	('AKT', 'Gene', (243, 246))	('response to hypoxia', 'biological_process', 'GO:0001666', ('184', '203'))	('Cancer', 'Disease', (17, 23))	('VHL', 'Gene', '7428', (125, 128))	('hypoxia', 'Disease', (196, 203))	('alterations', 'Reg', (106, 117))	('RCC', 'Disease', (87, 90))	('AKT', 'Gene', '207', (243, 246))	('PI(3)K', 'molecular_function', 'GO:0016303', ('236', '242'))	('hypoxia', 'Disease', 'MESH:D000860', (196, 203))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))
47983	27741505	Conversely, the most frequent somatic genetic changes in non-ccRCC such as the papillary histotype (pRCC) involve mutations or copy number variations of the MET oncogene or loss of the tumor suppressor gene CDKN2A.	('RCC', 'Disease', (63, 66))	('loss of the tumor', 'Disease', (173, 190))	('pRCC', 'Gene', '5546', (100, 104))	('CDKN2A', 'Gene', (207, 213))	('CDKN2A', 'Gene', '1029', (207, 213))	('mutations', 'Var', (114, 123))	('tumor suppressor', 'biological_process', 'GO:0051726', ('185', '201'))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('papillary histotype', 'Phenotype', 'HP:0007482', (79, 98))	('RCC', 'Disease', (101, 104))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('185', '201'))	('pRCC', 'Gene', (100, 104))	('MET oncogene', 'Gene', (157, 169))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('copy number variations', 'Var', (127, 149))	('papillary histotype', 'Disease', (79, 98))	('loss of the tumor', 'Disease', 'MESH:D009369', (173, 190))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
48013	27741505	We identified mutations in the genes VHL, PTEN, JAK3, MET, ERBB4, APC, CDKN2A, FGFR3, EGFR, RB1 and TP53.	('FGFR3', 'Gene', '2261', (79, 84))	('TP53', 'Gene', (100, 104))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('JAK3', 'Gene', (48, 52))	('VHL', 'Gene', (37, 40))	('EGFR', 'Gene', '1956', (86, 90))	('APC', 'cellular_component', 'GO:0005680', ('66', '69'))	('RB1', 'Gene', (92, 95))	('JAK', 'molecular_function', 'GO:0004713', ('48', '51'))	('MET', 'Gene', (54, 57))	('mutations', 'Var', (14, 23))	('JAK3', 'Gene', '3718', (48, 52))	('PTEN', 'Gene', (42, 46))	('TP53', 'Gene', '7157', (100, 104))	('ERBB4', 'Gene', '2066', (59, 64))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('CDKN2A', 'Gene', (71, 77))	('VHL', 'Gene', '7428', (37, 40))	('ERBB4', 'Gene', (59, 64))	('APC', 'Disease', 'MESH:D011125', (66, 69))	('APC', 'Disease', (66, 69))	('RB1', 'Gene', '5925', (92, 95))	('PTEN', 'Gene', '5728', (42, 46))	('FGFR3', 'Gene', (79, 84))	('CDKN2A', 'Gene', '1029', (71, 77))	('EGFR', 'Gene', (86, 90))
48015	27741505	In particular, the most frequent mutations (7/22 patients 31,8%) affected the VHL1 gene, all were in different loci and except for 3 cases were always associated with other mutations.	('associated', 'Reg', (151, 161))	('VHL1', 'Gene', (78, 82))	('mutations', 'Var', (33, 42))	('affected', 'Reg', (65, 73))	('patients', 'Species', '9606', (49, 57))	('VHL1', 'Gene', '7428', (78, 82))
48016	27741505	VHL1 was mutated in 6 primary RCC, in 2 metastatic sites and in 1 sarcomatoid and 2 rhabdoid components of primary RCCs.	('rhabdoid component', 'Disease', (84, 102))	('VHL1', 'Gene', '7428', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('mutated', 'Var', (9, 16))	('RCC', 'Disease', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('sarcomatoid', 'Disease', 'MESH:C538614', (66, 77))	('RCC', 'Disease', (30, 33))	('VHL1', 'Gene', (0, 4))	('rhabdoid component', 'Disease', 'MESH:D018335', (84, 102))	('sarcomatoid', 'Disease', (66, 77))
48017	27741505	The VHL1 mutation variant was concordant between primary and the corresponding metastasis in 1 out of 2 cases.	('variant', 'Var', (18, 25))	('VHL1', 'Gene', (4, 8))	('VHL1', 'Gene', '7428', (4, 8))	('mutation variant', 'Var', (9, 25))
48018	27741505	PTEN was found mutated in 3/22 (13,6%) patients and only in 1 case was associated with mutations of VHL 1 and FGFR3.	('patients', 'Species', '9606', (39, 47))	('FGFR', 'molecular_function', 'GO:0005007', ('110', '114'))	('PTEN', 'Gene', '5728', (0, 4))	('FGFR3', 'Gene', '2261', (110, 115))	('VHL 1', 'Gene', '7428', (100, 105))	('VHL 1', 'Gene', (100, 105))	('PTEN', 'Gene', (0, 4))	('FGFR3', 'Gene', (110, 115))	('mutations', 'Var', (87, 96))
48020	27741505	Two patients (2/22) ( 9%) showed the same JAK3 mutation variant (V722I); it was associated with a VHL 1 mutation and was revealed both in the sarcomatoid and rhadboid component of the same patient, while in the other patient it was present as a single mutation in the primary RCC and the metastatic lesion.	('VHL 1', 'Gene', '7428', (98, 103))	('RCC', 'Disease', 'MESH:C538614', (276, 279))	('VHL 1', 'Gene', (98, 103))	('sarcomatoid', 'Disease', (142, 153))	('V722I);', 'Var', (65, 72))	('RCC', 'Disease', (276, 279))	('V722I', 'Mutation', 'rs3213409', (65, 70))	('patient', 'Species', '9606', (217, 224))	('patient', 'Species', '9606', (4, 11))	('patient', 'Species', '9606', (189, 196))	('associated', 'Reg', (80, 90))	('mutation', 'Var', (104, 112))	('sarcomatoid', 'Disease', 'MESH:C538614', (142, 153))	('patients', 'Species', '9606', (4, 12))	('JAK', 'molecular_function', 'GO:0004713', ('42', '45'))	('JAK3', 'Gene', (42, 46))	('JAK3', 'Gene', '3718', (42, 46))
48021	27741505	Two patients (9%) harboured a mutation of the FGFR3 gene (F386L); in both cases it was associated with a VHL1 mutation (1 cases also with a PTEN mutation) and each patient presented respectively the mutation both in the primary RCC and the corresponding metastasis and the clear cell and in the rhabdoid component.	('VHL1', 'Gene', (105, 109))	('rhabdoid component', 'Disease', (295, 313))	('RCC', 'Disease', (228, 231))	('RCC', 'Disease', 'MESH:C538614', (228, 231))	('patient', 'Species', '9606', (164, 171))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('patient', 'Species', '9606', (4, 11))	('associated', 'Reg', (87, 97))	('FGFR3', 'Gene', '2261', (46, 51))	('PTEN', 'Gene', '5728', (140, 144))	('rhabdoid component', 'Disease', 'MESH:D018335', (295, 313))	('mutation', 'Var', (110, 118))	('patients', 'Species', '9606', (4, 12))	('F386L);', 'Var', (58, 65))	('VHL1', 'Gene', '7428', (105, 109))	('FGFR3', 'Gene', (46, 51))	('PTEN', 'Gene', (140, 144))	('F386L', 'Mutation', 'rs17881656', (58, 63))
48023	27741505	Mutation in MET gene was found in 1/22 patients (4,5%) in the primary RCC and in association with VHL1 mutation.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('VHL1', 'Gene', '7428', (98, 102))	('RCC', 'Disease', (70, 73))	('patients', 'Species', '9606', (39, 47))	('Mutation', 'Var', (0, 8))	('VHL1', 'Gene', (98, 102))	('MET', 'Gene', (12, 15))	('found', 'Reg', (25, 30))
48024	27741505	ERBB4 mutation were discovered in 1/22 (4,5%) patients in both primary and metastatic RCC sites, in association with VHL1 mutation.	('ERBB4', 'Gene', '2066', (0, 5))	('VHL1', 'Gene', (117, 121))	('patients', 'Species', '9606', (46, 54))	('mutation', 'Var', (6, 14))	('ERBB4', 'Gene', (0, 5))	('VHL1', 'Gene', '7428', (117, 121))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))
48025	27741505	Double mutations in the APC and DCKN2A genes was found in the same patient in the primary RCC.	('found', 'Reg', (49, 54))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('APC', 'cellular_component', 'GO:0005680', ('24', '27'))	('Double mutations', 'Var', (0, 16))	('DCKN2A', 'Gene', (32, 38))	('APC', 'Disease', 'MESH:D011125', (24, 27))	('APC', 'Disease', (24, 27))	('patient', 'Species', '9606', (67, 74))	('RCC', 'Disease', (90, 93))
48026	27741505	Mutations of EGFR and RB1genes were both detected in 1 patients in the rhabdoid component of the primary RCC.	('rhabdoid component of the primary RCC', 'Disease', 'MESH:C538614', (71, 108))	('RB1', 'Gene', (22, 25))	('rhabdoid component of the primary RCC', 'Disease', (71, 108))	('Mutations', 'Var', (0, 9))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('patients', 'Species', '9606', (55, 63))	('RB1', 'Gene', '5925', (22, 25))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('detected', 'Reg', (41, 49))
48029	27741505	In particular the four pRCC harbored mutations in the APC, DCKN2A, PTEN and TP53 genes but not in VHL1.	('APC', 'Disease', 'MESH:D011125', (54, 57))	('DCKN2A', 'Gene', (59, 65))	('APC', 'Disease', (54, 57))	('VHL1', 'Gene', '7428', (98, 102))	('pRCC', 'Gene', (23, 27))	('TP53', 'Gene', '7157', (76, 80))	('mutations', 'Var', (37, 46))	('harbored', 'Reg', (28, 36))	('TP53', 'Gene', (76, 80))	('PTEN', 'Gene', (67, 71))	('VHL1', 'Gene', (98, 102))	('pRCC', 'Gene', '5546', (23, 27))	('PTEN', 'Gene', '5728', (67, 71))	('APC', 'cellular_component', 'GO:0005680', ('54', '57'))
48030	27741505	Eight (42%) out of the remaining 19 ccRCC tumors habored at least one VHL1 mutation although with different variants.	('RCC', 'Disease', (38, 41))	('VHL1', 'Gene', (70, 74))	('tumors habored', 'Disease', (42, 56))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mutation', 'Var', (75, 83))	('tumors habored', 'Disease', 'MESH:D009369', (42, 56))	('VHL1', 'Gene', '7428', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
48031	27741505	As depicted in Table 3, the concordance between the primary RCC and its rhadboid/sarcomatoid component was seen in 2/3 cases: FGFR3 F386L and VHL1 V13fs*7 (rhabdoid and primary RCC) and VHL1 P97R and JAK3 (rhabdoid and sarcomatoid component of RCC).	('RCC', 'Disease', (244, 247))	('JAK', 'molecular_function', 'GO:0004713', ('200', '203'))	('JAK3', 'Gene', (200, 204))	('FGFR3', 'Gene', (126, 131))	('RCC', 'Disease', (60, 63))	('F386L', 'Mutation', 'rs17881656', (132, 137))	('FGFR3', 'Gene', '2261', (126, 131))	('VHL1', 'Gene', (142, 146))	('rhabdoid', 'Disease', (206, 214))	('RCC', 'Disease', 'MESH:C538614', (244, 247))	('RCC', 'Disease', (177, 180))	('JAK3', 'Gene', '3718', (200, 204))	('sarcomatoid component', 'Disease', (219, 240))	('VHL1', 'Gene', '7428', (142, 146))	('sarcomatoid component', 'Disease', 'MESH:C538614', (219, 240))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('rhabdoid', 'Disease', 'MESH:D018335', (206, 214))	('FGFR', 'molecular_function', 'GO:0005007', ('126', '130'))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('P97R', 'Mutation', 'rs587782886', (191, 195))	('rhabdoid', 'Disease', (156, 164))	('F386L', 'Var', (132, 137))	('rhabdoid', 'Disease', 'MESH:D018335', (156, 164))	('sarcomatoid component', 'Disease', (81, 102))	('sarcomatoid component', 'Disease', 'MESH:C538614', (81, 102))	('VHL1', 'Gene', (186, 190))	('VHL1', 'Gene', '7428', (186, 190))	('rhabdoid and sarcomatoid component of RCC', 'Disease', 'MESH:C538614', (206, 247))
48038	27741505	Among the 4 partial responders, 1 (25%) was wild-type for all genes and 3 (75%) harbored different VHL1 variants.	('VHL1', 'Gene', '7428', (99, 103))	('VHL1', 'Gene', (99, 103))	('variants', 'Var', (104, 112))	('harbored', 'Reg', (80, 88))
48042	27741505	Among the 11 non-responders 7 (64%) were wild-type for all genes, 2 (18%) were TP53 mutated (in different loci) and 2 (18%) were VHL1 mutated.	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('VHL1', 'Gene', (129, 133))	('mutated', 'Var', (84, 91))	('VHL1', 'Gene', '7428', (129, 133))
48045	27741505	Two patients harbouring just the same PTEN L320S mutation survived for at least 27 or 30 months.	('PTEN', 'Gene', '5728', (38, 42))	('L320S', 'Mutation', 'p.L320S', (43, 48))	('L320S', 'Var', (43, 48))	('patients', 'Species', '9606', (4, 12))	('PTEN', 'Gene', (38, 42))
48047	27741505	The ccRCC is largely the most common histotype and it is tightly associated with alteration of the VHL1-HIF pathway, while non-clear cell tumors are characterized by alterations of the PI3K and MET pathways.	('VHL1', 'Gene', '7428', (99, 103))	('PI3K', 'molecular_function', 'GO:0016303', ('185', '189'))	('alteration', 'Var', (81, 91))	('cell tumors', 'Disease', 'MESH:D005935', (133, 144))	('alterations', 'Reg', (166, 177))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('VHL1', 'Gene', (99, 103))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))	('cell tumors', 'Disease', (133, 144))
48050	27741505	Although we did not find a significant association between histotype and mutation variants we found that approximately 40% of ccRCC harboured mutations of VHL1 gene compared to none in the pRCC group.	('VHL1', 'Gene', (155, 159))	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('mutations', 'Var', (142, 151))	('RCC', 'Disease', (128, 131))	('pRCC', 'Gene', '5546', (189, 193))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Disease', (190, 193))	('pRCC', 'Gene', (189, 193))	('VHL1', 'Gene', '7428', (155, 159))
48051	27741505	Mutations in some genes such as VHL1, PTEN, JAK3 and TP53 are well recognized.	('PTEN', 'Gene', '5728', (38, 42))	('TP53', 'Gene', (53, 57))	('JAK', 'molecular_function', 'GO:0004713', ('44', '47'))	('VHL1', 'Gene', (32, 36))	('JAK3', 'Gene', (44, 48))	('JAK3', 'Gene', '3718', (44, 48))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (53, 57))	('VHL1', 'Gene', '7428', (32, 36))	('PTEN', 'Gene', (38, 42))
48052	27741505	By contrast, mutations in the genes APC, ERBB4, RB1, EGFR, FGFR3 have been rarely or never found in RCC but were encountered in our series.	('FGFR3', 'Gene', '2261', (59, 64))	('RB1', 'Gene', (48, 51))	('FGFR', 'molecular_function', 'GO:0005007', ('59', '63'))	('FGFR3', 'Gene', (59, 64))	('ERBB4', 'Gene', '2066', (41, 46))	('RB1', 'Gene', '5925', (48, 51))	('EGFR', 'Gene', (53, 57))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('APC', 'cellular_component', 'GO:0005680', ('36', '39'))	('EGFR', 'Gene', '1956', (53, 57))	('ERBB4', 'Gene', (41, 46))	('mutations', 'Var', (13, 22))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('APC', 'Disease', 'MESH:D011125', (36, 39))	('APC', 'Disease', (36, 39))
48054	27741505	Taken together all these data bring to the conclusion that more gene variants than expected are associated with mRCC, and are non-mutually exclusive.	('variants', 'Var', (69, 77))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('associated', 'Reg', (96, 106))	('RCC', 'Disease', (113, 116))
48055	27741505	Mutations of VHL1 are the most frequent but involve wide number of loci.	('frequent', 'Reg', (31, 39))	('Mutations', 'Var', (0, 9))	('VHL1', 'Gene', (13, 17))	('VHL1', 'Gene', '7428', (13, 17))
48057	27741505	In addition, our mutational analysis is based on a panel generating 207 amplicons covering approximately 2,800 COSMIC mutations from 50 of the most altered oncogenes and tumor suppressor genes in solid tumors.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('170', '186'))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Disease', (202, 207))	('solid tumors', 'Disease', (196, 208))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('mutations', 'Var', (118, 127))	('tumor', 'Disease', (170, 175))	('solid tumors', 'Disease', 'MESH:D009369', (196, 208))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor suppressor', 'biological_process', 'GO:0051726', ('170', '186'))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
48062	27741505	In fact, we found that three of the four patients experiencing partial response after first-line therapy were treated with a TKI with anti-angiogenetic activity and actually harbored mutations of the pro-angiogenic gene VHL1, although in different loci.	('mutations', 'Var', (183, 192))	('harbored', 'Reg', (174, 182))	('VHL1', 'Gene', '7428', (220, 224))	('patients', 'Species', '9606', (41, 49))	('VHL1', 'Gene', (220, 224))
48063	27741505	By contrast, other three patients with tumors harboring VHL1 mutations experienced progressive disease with similar therapies.	('VHL1', 'Gene', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('experienced', 'Reg', (71, 82))	('mutations', 'Var', (61, 70))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('VHL1', 'Gene', '7428', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('patients', 'Species', '9606', (25, 33))	('progressive', 'Disease', (83, 94))	('tumors', 'Disease', (39, 45))
48064	27741505	Although in few patients, this finding is in line with other studies reporting no association between VHL1 mutations and objective responses to anti-angiogenic TKIs.	('patients', 'Species', '9606', (16, 24))	('VHL1', 'Gene', (102, 106))	('mutations', 'Var', (107, 116))	('VHL1', 'Gene', '7428', (102, 106))
48068	27741505	It is also noteworthy that our data do not seem to confirm the well known role of mutations within the mTOR patway components to predict long term benefit from mTOR inhibitors.	('mTOR', 'Gene', (103, 107))	('mTOR', 'Gene', '2475', (160, 164))	('mTOR', 'Gene', (160, 164))	('mutations', 'Var', (82, 91))	('mTOR', 'Gene', '2475', (103, 107))
48070	27741505	An interesting aspect of our work is the finding of rare potentially actionable mutations such as FGFR3 and JAK3 for which effective targeted agents are available and currently under investigation in other tumor types We can therefore conclude that in the absence of established molecular predictors of response to targeted therapies in mRCC an NGS approach may address single patients to basket trials enrolling according to molecular specific alterations regardless of the pathological features.	('JAK3', 'Gene', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('JAK3', 'Gene', '3718', (108, 112))	('RCC', 'Disease', 'MESH:C538614', (338, 341))	('FGFR3', 'Gene', (98, 103))	('mutations', 'Var', (80, 89))	('tumor', 'Disease', (206, 211))	('JAK', 'molecular_function', 'GO:0004713', ('108', '111'))	('patients', 'Species', '9606', (377, 385))	('FGFR', 'molecular_function', 'GO:0005007', ('98', '102'))	('FGFR3', 'Gene', '2261', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('RCC', 'Disease', (338, 341))
48104	30092766	For breast cancer cell lines, two datasets were analysed for expression of CPT1A: (i) quantile normalised with gene level summary data from E-MTAB-181 was accessed from ArrayExpress, and (ii) GSE57083 accessed from NCBI GEO where the RMA-normalised expression matrix was used to calculate the average expression of CPT1A for each cell line based on the values from four probesets: 203633_at, 203634_s_at, 210687_at and 210688_s_at on the Affymetrix Human Genome U133 Plus 2.0 array.	('CPT1A', 'Gene', (315, 320))	('Human', 'Species', '9606', (449, 454))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('CPT', 'molecular_function', 'GO:0004142', ('315', '318'))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('210687_at', 'Var', (405, 414))	('210688_s_at', 'Var', (419, 430))	('CPT', 'molecular_function', 'GO:0004095', ('315', '318'))	('breast cancer', 'Disease', (4, 17))	('203634_s_at', 'Var', (392, 403))	('CPT', 'molecular_function', 'GO:0004142', ('75', '78'))	('CPT', 'molecular_function', 'GO:0004095', ('75', '78'))	('MTAB', 'molecular_function', 'GO:0047152', ('142', '146'))	('203633_at', 'Var', (381, 390))
48145	30092766	We also analysed clear cell renal cell carcinoma (ccRCC) and melanoma cohorts from TCGA and observed high FAO signature expression to be associated with better prognosis (Fig.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (17, 48))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (23, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (50, 55))	('FAO signature', 'Gene', (106, 119))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('high', 'Var', (101, 105))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (28, 48))	('cell renal cell carcinoma', 'Disease', (23, 48))	('FAO', 'Chemical', '-', (106, 109))
48157	30092766	Of note, genetic modulation and pharmacologic inhibition of CPT1A has been shown to alter FAO flux.	('CPT', 'molecular_function', 'GO:0004142', ('60', '63'))	('FAO', 'Chemical', '-', (90, 93))	('genetic modulation', 'Var', (9, 27))	('CPT', 'molecular_function', 'GO:0004095', ('60', '63'))	('FAO flux', 'MPA', (90, 98))	('alter', 'Reg', (84, 89))	('CPT1A', 'Gene', (60, 65))
48177	30092766	Breast cancer cells treated with etomoxir to inhibit CPT1A resulted in cell death, while in vivo, mutant KRAS lung tumours were dependent on ACSL3-dependent FAO for tumour initiation and progression.	('KRAS lung tumours', 'Disease', 'MESH:D008175', (105, 122))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('ACSL3', 'Gene', '2181', (141, 146))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('tumour initiation', 'Disease', 'MESH:D009369', (165, 182))	('mutant', 'Var', (98, 104))	('CPT', 'molecular_function', 'GO:0004095', ('53', '56'))	('etomoxir', 'Chemical', 'MESH:C054207', (33, 41))	('CPT1A', 'Gene', (53, 58))	('inhibit', 'NegReg', (45, 52))	('cell death', 'CPA', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumour initiation', 'Disease', (165, 182))	('cell death', 'biological_process', 'GO:0008219', ('71', '81'))	('ACSL3', 'Gene', (141, 146))	('FAO', 'Chemical', '-', (157, 160))	('CPT', 'molecular_function', 'GO:0004142', ('53', '56'))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('KRAS lung tumours', 'Disease', (105, 122))	('Breast cancer', 'Disease', (0, 13))
48178	30092766	However, findings from recent studies focused on human tumour samples and in vivo animal models suggest that activating FAO negatively affects tumour growth and progression.	('activating', 'Var', (109, 119))	('tumour', 'Disease', (55, 61))	('tumour growth', 'Disease', (143, 156))	('affects', 'Reg', (135, 142))	('negatively', 'NegReg', (124, 134))	('tumour growth', 'Disease', 'MESH:D006130', (143, 156))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('human', 'Species', '9606', (49, 54))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('FAO', 'Gene', (120, 123))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('tumour', 'Disease', (143, 149))	('FAO', 'Chemical', '-', (120, 123))
48185	30092766	In the neoadjuvant treatment setting, we found that ER-positive tumours from patients with high FAO signature expression had a better response to short-term oestrogen deprivation therapy.	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('ER', 'Gene', '2099', (52, 54))	('better', 'PosReg', (127, 133))	('high', 'Var', (91, 95))	('FAO', 'Chemical', '-', (96, 99))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('patients', 'Species', '9606', (77, 85))	('FAO signature', 'Gene', (96, 109))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
48186	30092766	Additionally, patients with tumours that had low FAO signature expression that received pre-surgical chemotherapy had better odds of achieving complete response.	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('FAO', 'Chemical', '-', (49, 52))	('pre', 'molecular_function', 'GO:0003904', ('88', '91'))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('tumours', 'Disease', (28, 35))	('tumours', 'Disease', 'MESH:D009369', (28, 35))	('low', 'Var', (45, 48))	('FAO signature', 'Gene', (49, 62))	('patients', 'Species', '9606', (14, 22))
48188	30092766	In support of this finding, we analysed publicly available gene expression data from MCF7 cells with knockdown of ER expression, and observed higher expression of the MKS signature, and a trend towards decreased expression of the FAO signature, in cells with ER knockdown compared to control (Additional file 7: Fig.	('FAO', 'Chemical', '-', (230, 233))	('decreased', 'NegReg', (202, 211))	('expression', 'MPA', (212, 222))	('ER', 'Gene', '2099', (259, 261))	('ER', 'Gene', '2099', (114, 116))	('gene expression', 'biological_process', 'GO:0010467', ('59', '74'))	('expression', 'MPA', (149, 159))	('MCF7', 'CellLine', 'CVCL:0031', (85, 89))	('MKS', 'Gene', (167, 170))	('higher', 'PosReg', (142, 148))	('knockdown', 'Var', (262, 271))	('knockdown', 'Var', (101, 110))
48203	30092766	This is supported by the findings of Balaban et al., who reported the rate of oxidation of radiolabelled palmitate to be over 5-fold higher in MCF7 cells compared to the MDA-MB231 cell line.	('MDA-MB231', 'CellLine', 'CVCL:0062', (170, 179))	('palmitate', 'Chemical', 'MESH:D010168', (105, 114))	('higher', 'PosReg', (133, 139))	('MCF7', 'CellLine', 'CVCL:0031', (143, 147))	('oxidation', 'MPA', (78, 87))	('MCF7', 'Var', (143, 147))
48207	30092766	These data suggest that modulating the rate-limiting enzyme of FAO can significantly alter the proliferation and migration rates of cancer cells.	('cancer', 'Disease', (132, 138))	('modulating', 'Var', (24, 34))	('FAO', 'Chemical', '-', (63, 66))	('alter', 'Reg', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('FAO', 'Gene', (63, 66))	('proliferation', 'CPA', (95, 108))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
48215	30092766	As such, future efforts could focus on modulating this pathway in cell lines from breast, as well as other cancer types, which could shed light on the common mechanisms as to how alterations in FAO affects cancer cell biology.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('affects', 'Reg', (198, 205))	('FAO', 'Chemical', '-', (194, 197))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('alterations', 'Var', (179, 190))	('cancer', 'Disease', (107, 113))	('FAO', 'Gene', (194, 197))
48229	29167760	Furthermore, subsequent studies have begun to elucidate the prognostic and predictive values of prevalent mutations in ccRCC, which is likely to impact clinical management of kidney cancer patients in the near future.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('kidney cancer', 'Disease', (175, 188))	('mutations', 'Var', (106, 115))	('patients', 'Species', '9606', (189, 197))	('impact', 'Reg', (145, 151))	('kidney cancer', 'Phenotype', 'HP:0009726', (175, 188))	('kidney cancer', 'Disease', 'MESH:D007680', (175, 188))
48240	29167760	Before the advent of next generation sequencing technology, studies directly comparing matched sarcomatous and carcinomatous components of ccRCC include assessing the mutation status of TP53 and H-RAS, determining pattern of allelic loss, and immunohistochemistry of EMT markers.	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('sarcomatous', 'Disease', 'MESH:D018316', (95, 106))	('EMT', 'biological_process', 'GO:0001837', ('267', '270'))	('mutation', 'Var', (167, 175))	('TP53', 'Gene', '7157', (186, 190))	('carcinomatous', 'Disease', 'MESH:D055756', (111, 124))	('H-RAS', 'Gene', '3265', (195, 200))	('sarcomatous', 'Disease', (95, 106))	('TP53', 'Gene', (186, 190))	('H-RAS', 'Gene', (195, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('carcinomatous', 'Disease', (111, 124))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
48251	29167760	One of these tumors had a mutation in mutS homolog 2 (MSH2), and the other had a mutation in polymerase epsilon (POLE).	('MSH2', 'Gene', '4436', (54, 58))	('tumors', 'Disease', (13, 19))	('mutation', 'Var', (26, 34))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('mutation', 'Var', (81, 89))	('mutS homolog 2', 'Gene', (38, 52))	('mutS homolog 2', 'Gene', '4436', (38, 52))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('MSH2', 'Gene', (54, 58))
48252	29167760	Their mutational signatures were consistent with mismatch repair deficiency, and they were excluded from the grouped analysis of the other 19 tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('mismatch', 'Var', (49, 57))	('mismatch repair', 'biological_process', 'GO:0006298', ('49', '64'))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', (142, 148))
48259	29167760	They reported 6 out of 19 (31.6%) sarcomatoid elements had TP53 mutations compared to zero in the matched carcinomatous elements.	('carcinomatous', 'Disease', 'MESH:D055756', (106, 119))	('TP53', 'Gene', (59, 63))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('sarcomatoid', 'Disease', 'MESH:C538614', (34, 45))	('carcinomatous', 'Disease', (106, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('mutations', 'Var', (64, 73))	('sarcomatoid', 'Disease', (34, 45))	('TP53', 'Gene', '7157', (59, 63))
48260	29167760	also highlighted sarcomatoid-specific mutations in BRACA1 associated protein 1 (BAP1) in 2/19 (10.5%) and AT-rich interaction domain 1A (ARID1A) in 3/19 (15.7%) samples.	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('BRACA1 associated protein 1', 'Gene', '8314', (51, 78))	('ARID1A', 'Gene', '8289', (137, 143))	('BRACA1 associated protein 1', 'Gene', (51, 78))	('ARID1A', 'Gene', (137, 143))	('sarcomatoid', 'Disease', 'MESH:C538614', (17, 28))	('BAP1', 'Gene', '8314', (80, 84))	('BAP1', 'Gene', (80, 84))	('sarcomatoid', 'Disease', (17, 28))	('mutations', 'Var', (38, 47))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))
48261	29167760	They also observed that mutations in TP53, BAP1, and ARID1A were all mutually exclusive among the 19 tumors.	('BAP1', 'Gene', (43, 47))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('BAP1', 'Gene', '8314', (43, 47))	('mutations', 'Var', (24, 33))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('ARID1A', 'Gene', '8289', (53, 59))	('tumors', 'Disease', (101, 107))	('ARID1A', 'Gene', (53, 59))
48262	29167760	Sarcomatoid elements were also found to have more frequent LOH events among chromosomes 1p, 9, 10, 17p, 18 and 22.	('Sarcomatoid', 'Disease', (0, 11))	('Sarcomatoid', 'Disease', 'MESH:C538614', (0, 11))	('LOH events', 'Var', (59, 69))
48263	29167760	reported a similar enrichment for such copy number events in sRCC.	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('copy number events', 'Var', (39, 57))
48271	29167760	In the third sample they saw similar homozygous deletions in VHL but found multiple distinct inactivating mutations in TP53 and phosphatase and tensin homolog (PTEN) that differed between the two elements.	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('128', '158'))	('PTEN', 'Gene', (160, 164))	('phosphatase', 'molecular_function', 'GO:0016791', ('128', '139'))	('PTEN', 'Gene', '5728', (160, 164))	('VHL', 'Gene', (61, 64))	('deletions', 'Var', (48, 57))	('mutations', 'Var', (106, 115))	('VHL', 'Gene', '7428', (61, 64))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))
48283	29167760	Next, the notion that the sarcomatoid element represents a dedifferentiated progression of RCC is supported by the increased overall mutational burden and copy number aberrations seen in the sarcomatoid elements compared to the carcinomatous elements from Bi et al.	('carcinomatous', 'Disease', (228, 241))	('increased', 'PosReg', (115, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('copy', 'MPA', (155, 159))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))	('sarcomatoid', 'Disease', (191, 202))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('sarcomatoid', 'Disease', (26, 37))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('mutational', 'Var', (133, 143))	('sarcomatoid', 'Disease', 'MESH:C538614', (191, 202))	('carcinomatous', 'Disease', 'MESH:D055756', (228, 241))	('sarcomatoid', 'Disease', 'MESH:C538614', (26, 37))
48285	29167760	published a study in 1995 reporting a mutation rate of 78.6% (11 of 14) for TP53 in the sarcomatoid elements of sRCC tumors using polymerase chain reaction.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('sarcomatoid', 'Disease', 'MESH:C538614', (88, 99))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('TP53', 'Gene', '7157', (76, 80))	('sRCC tumors', 'Disease', (112, 123))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('TP53', 'Gene', (76, 80))	('sarcomatoid', 'Disease', (88, 99))	('mutation', 'Var', (38, 46))	('sRCC tumors', 'Disease', 'MESH:D009369', (112, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
48287	29167760	clearly show an enrichment of TP53 aberrations (31.6%) in the sarcomatoid elements among primary ccRCC tumors, caution must be used when interpreting the even more enriched results (42.3%) from the 26 sRCC tumors reported in the Malouf et al.	('sarcomatoid', 'Disease', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('tumors', 'Disease', (103, 109))	('RCC', 'Disease', (99, 102))	('RCC', 'Disease', (202, 205))	('RCC', 'Phenotype', 'HP:0005584', (202, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('TP53', 'Gene', (30, 34))	('sarcomatoid', 'Disease', 'MESH:C538614', (62, 73))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('TP53', 'Gene', '7157', (30, 34))	('sRCC tumors', 'Disease', (201, 212))	('aberrations', 'Var', (35, 46))	('sRCC tumors', 'Disease', 'MESH:D009369', (201, 212))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))
48288	29167760	The latter study included diverse primary RCC histologies and also included metastatic tumors, which previously have been shown to be enriched for TP53 aberrations irrespective of sarcomatoid features.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('TP53', 'Gene', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('aberrations', 'Var', (152, 163))	('sarcomatoid', 'Disease', (180, 191))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('sarcomatoid', 'Disease', 'MESH:C538614', (180, 191))	('TP53', 'Gene', '7157', (147, 151))	('RCC', 'Disease', (42, 45))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
48289	29167760	Similarly the finding of increased NF2 mutations occurring in sRCC may also be limited due to the diverse background of primary RCC histologies in this cohort.	('RCC', 'Disease', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('increased', 'PosReg', (25, 34))	('NF2', 'Gene', (35, 38))	('mutations', 'Var', (39, 48))	('NF2', 'Gene', '4771', (35, 38))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
48291	29167760	As a significant number of the NF2 and TP53 aberrations occurred in these unclassified tumors, attributing the results to sRCC may be problematic.	('occurred', 'Reg', (56, 64))	('NF2', 'Gene', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('NF2', 'Gene', '4771', (31, 34))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('aberrations', 'Var', (44, 55))	('TP53', 'Gene', '7157', (39, 43))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('tumors', 'Disease', (87, 93))	('TP53', 'Gene', (39, 43))
48301	29167760	They have also identified key genomic aberrations (e.g., TP53, CDKN2A, copy number changes) present in sRCC that may explain its aggressive clinical course and may become potential targets for therapy.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('CDKN2A', 'Gene', '1029', (63, 69))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('copy number changes', 'Var', (71, 90))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('CDKN2A', 'Gene', (63, 69))	('RCC', 'Disease', (104, 107))
48317	33221754	Aberrant regulation of the tricarboxylic acid (TCA) cycle, glutamine metabolism, and lipid metabolism are associated with the growth and progression of RCC.	('regulation', 'biological_process', 'GO:0065007', ('9', '19'))	('lipid', 'Chemical', 'MESH:D008055', (85, 90))	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('Aberrant', 'Var', (0, 8))	('RCC', 'Disease', (152, 155))	('associated', 'Reg', (106, 116))	('TCA', 'Chemical', 'MESH:D014233', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('lipid metabolism', 'MPA', (85, 101))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('59', '79'))	('glutamine', 'Chemical', 'MESH:D005973', (59, 68))	('TCA) cycle', 'biological_process', 'GO:0006099', ('47', '57'))	('lipid metabolism', 'biological_process', 'GO:0006629', ('85', '101'))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (27, 45))	('glutamine metabolism', 'MPA', (59, 79))
48333	33221754	We observed mutations in these 10 candidate hub genes in 39% (172 of 446) of the ccRCC patients (Figure 5A).	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('mutations', 'Var', (12, 21))	('hub', 'Gene', (44, 47))	('patients', 'Species', '9606', (87, 95))	('hub', 'Gene', '1993', (44, 47))
48335	33221754	Kaplan- Meier survival curve analysis showed that the overall survival (OS) was significantly shorter in the ccRCC patients with mutations in the candidate hub genes compared to the ccRCC patients without mutations in the candidate hub genes (Figure 5C).	('patients', 'Species', '9606', (115, 123))	('hub', 'Gene', (156, 159))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('hub', 'Gene', (232, 235))	('RCC', 'Disease', (111, 114))	('RCC', 'Disease', (184, 187))	('mutations', 'Var', (129, 138))	('overall survival', 'MPA', (54, 70))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('shorter', 'NegReg', (94, 101))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('patients', 'Species', '9606', (188, 196))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (182, 187))	('hub', 'Gene', '1993', (156, 159))	('hub', 'Gene', '1993', (232, 235))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))
48357	33221754	Furthermore, oncogenic mutations cause changes in glycolysis, fatty acid biosynthesis, and amino acid metabolism in the ccRCC tissues.	('glycolysis', 'biological_process', 'GO:0006096', ('50', '60'))	('ccRCC', 'Phenotype', 'HP:0006770', (120, 125))	('fatty acid biosynthesis', 'biological_process', 'GO:0006633', ('62', '85'))	('fatty acid biosynthesis', 'MPA', (62, 85))	('changes', 'Reg', (39, 46))	('metabolism', 'biological_process', 'GO:0008152', ('102', '112'))	('glycolysis', 'MPA', (50, 60))	('mutations', 'Var', (23, 32))	('amino acid metabolism', 'MPA', (91, 112))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))	('fatty acid', 'Chemical', 'MESH:D005227', (62, 72))
48370	33221754	Therefore, alterations in the expression of metabolic genes modulate several metabolic pathways involved in the synthesis and breakdown of amino acids, fatty acids, and nucleotides, mitochondrial oxidative phosphorylation, and other pathways.	('alterations', 'Var', (11, 22))	('breakdown', 'biological_process', 'GO:0009056', ('126', '135'))	('expression', 'MPA', (30, 40))	('mitochondrial oxidative phosphorylation', 'MPA', (182, 221))	('metabolic genes', 'Gene', (44, 59))	('modulate', 'Reg', (60, 68))	('fatty acids', 'Chemical', 'MESH:D005227', (152, 163))	('metabolic pathways', 'Pathway', (77, 95))	('breakdown of amino acids', 'MPA', (126, 150))	('synthesis', 'biological_process', 'GO:0009058', ('112', '121'))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('196', '221'))	('synthesis', 'MPA', (112, 121))
48383	33221754	ALAD gene variants are associated with the risk of genitourinary tumors.	('variants', 'Var', (10, 18))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('ALAD', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('genitourinary tumors', 'Phenotype', 'HP:0007379', (51, 71))	('ALAD', 'Gene', '210', (0, 4))	('associated', 'Reg', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
48385	33221754	ALDH3B2 polymorphisms are related to the esophageal squamous cell carcinoma in the Chinese population.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (41, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('related', 'Reg', (26, 33))	('ALDH', 'molecular_function', 'GO:0004030', ('0', '4'))	('ALDH3B2', 'Gene', (0, 7))	('ALDH3B2', 'Gene', '222', (0, 7))	('esophageal squamous cell carcinoma', 'Disease', (41, 75))	('polymorphisms', 'Var', (8, 21))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))
48390	33221754	showed that inhibition of ACDAM activity accelerated breast cancer progression in the mouse model.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('inhibition', 'Var', (12, 22))	('ACDAM activity', 'Protein', (26, 40))	('mouse', 'Species', '10090', (86, 91))	('accelerated', 'PosReg', (41, 52))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', (53, 66))
48395	33221754	reported that high expression of IPTKA correlates with higher vascular infiltration and shorter survival time of liver cancer patients.	('IPTKA', 'Protein', (33, 38))	('shorter', 'NegReg', (88, 95))	('expression', 'MPA', (19, 29))	('liver cancer', 'Disease', (113, 125))	('vascular infiltration', 'CPA', (62, 83))	('high', 'Var', (14, 18))	('survival time', 'CPA', (96, 109))	('patients', 'Species', '9606', (126, 134))	('liver cancer', 'Phenotype', 'HP:0002896', (113, 125))	('liver cancer', 'Disease', 'MESH:D006528', (113, 125))	('higher', 'PosReg', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
48400	33221754	also reported that high IMPDH1 expression is associated with shorter overall survival and disease-free survival of RCC patients.	('shorter', 'NegReg', (61, 68))	('high', 'Var', (19, 23))	('overall survival', 'CPA', (69, 85))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('patients', 'Species', '9606', (119, 127))	('RCC', 'Disease', (115, 118))	('expression', 'MPA', (31, 41))	('disease-free survival', 'CPA', (90, 111))	('IMPDH1', 'Gene', (24, 30))
48401	33221754	In a mouse model of non-small cell lung cancer (NSCLC), inhibition of IMPDH1 expression reduced the expression of RNA polymerase-I-dependent pre-ribosomal RNA expression, inhibited the growth of tumor cells, and improved the survival of NSCLC model mice treated with chemotherapy.	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('tumor', 'Disease', (195, 200))	('NSCLC', 'Disease', (48, 53))	('ribosomal RNA', 'molecular_function', 'GO:0005566', ('145', '158'))	('NSCLC', 'Disease', 'MESH:D002289', (237, 242))	('inhibited', 'NegReg', (171, 180))	('RNA', 'cellular_component', 'GO:0005562', ('114', '117'))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('pre', 'molecular_function', 'GO:0003904', ('141', '144'))	('NSCLC', 'Disease', (237, 242))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (20, 46))	('inhibition', 'Var', (56, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (237, 242))	('mouse', 'Species', '10090', (5, 10))	('mice', 'Species', '10090', (249, 253))	('reduced', 'NegReg', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (24, 46))	('improved', 'PosReg', (212, 220))	('ribosomal RNA', 'molecular_function', 'GO:0003735', ('145', '158'))	('lung cancer', 'Disease', (35, 46))	('ribosomal RNA', 'cellular_component', 'GO:0005840', ('145', '158'))	('survival', 'CPA', (225, 233))	('IMPDH1', 'Gene', (70, 76))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('expression', 'MPA', (100, 110))
48414	33221754	demonstrated that ACHE gene variants were associated with the aggressiveness of human astrocytomas.	('associated with', 'Reg', (42, 57))	('variants', 'Var', (28, 36))	('aggressiveness', 'Phenotype', 'HP:0000718', (62, 76))	('aggressiveness of human astrocytomas', 'Disease', 'MESH:D001254', (62, 98))	('aggressiveness of human astrocytomas', 'Disease', (62, 98))
48425	33221754	This has resulted in the development of new targeted therapies and cancer-related biomarkers, including, proliferation markers such as Ki-67, p53 and PTEN, hypoxia-inducible factor pathways, carbonic anhydrase IX, vascular endothelial growth factor (VEGF) and others.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('hypoxia', 'Disease', (156, 163))	('hypoxia', 'Disease', 'MESH:D000860', (156, 163))	('carbonic anhydrase IX', 'Gene', (191, 212))	('VEGF', 'Gene', '7422', (250, 254))	('PTEN', 'Gene', '5728', (150, 154))	('p53', 'Gene', (142, 145))	('cancer', 'Disease', (67, 73))	('p53', 'Gene', '7157', (142, 145))	('carbonic anhydrase IX', 'Gene', '768', (191, 212))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('214', '248'))	('Ki-67', 'Var', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('VEGF', 'Gene', (250, 254))	('PTEN', 'Gene', (150, 154))	('vascular endothelial growth factor', 'Gene', (214, 248))	('vascular endothelial growth factor', 'Gene', '7422', (214, 248))
48426	33221754	Several studies have investigated the relationship between the somatic mutations, variations in gene methylation, differential gene expression, germline variations, and the status of immune biomarkers such as CD8 and PD-L1 with prognosis of ccRCC, and several different prognosis models have been proposed.	('CD8', 'Gene', (209, 212))	('variations', 'Var', (82, 92))	('gene expression', 'biological_process', 'GO:0010467', ('127', '142'))	('CD8', 'Gene', '925', (209, 212))	('RCC', 'Disease', 'MESH:C538614', (243, 246))	('ccRCC', 'Phenotype', 'HP:0006770', (241, 246))	('RCC', 'Disease', (243, 246))	('RCC', 'Phenotype', 'HP:0005584', (243, 246))	('methylation', 'biological_process', 'GO:0032259', ('101', '112'))
48445	33221754	The cBioPortal (https://www.cbioportal.org/) database was used to determine the gene mutations (missense mutations, gene amplifications, and deletions) and copy-number alterations of the hub genes.	('hub', 'Gene', (187, 190))	('gene amplifications', 'Var', (116, 135))	('missense mutations', 'Var', (96, 114))	('deletions', 'Var', (141, 150))	('hub', 'Gene', '1993', (187, 190))
48446	33221754	Then, the correlation between the hub gene mutations and survival time were determined by the survival module in the cBioPortal database.	('hub', 'Gene', (34, 37))	('hub', 'Gene', '1993', (34, 37))	('mutations', 'Var', (43, 52))
48460	33147753	A significant decrease in progression-free survival (PFS), determined by Kaplan-Meier curves, was observed for patients with higher PC CPA status compared with those with lower PC CPA status (p < 0.05).	('PC CPA', 'Chemical', '-', (132, 138))	('PC CPA status', 'Var', (132, 145))	('PC CPA', 'Chemical', '-', (177, 183))	('decrease', 'NegReg', (14, 22))	('progression-free survival', 'CPA', (26, 51))	('patients', 'Species', '9606', (111, 119))
48516	33147753	In addition, a greater median DisCPA was observed in patients with high Fuhrman grade (p = 0.004) and tumor size (p = 0.044).	('high', 'Var', (67, 71))	('patients', 'Species', '9606', (53, 61))	('DisCPA', 'MPA', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('DisCPA', 'Chemical', '-', (30, 36))	('greater', 'PosReg', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
48570	33147753	However, there was a meaningfully increased risk of PC invasion in tumors with Fuhrman grades > G2 compared with tumors in Fuhrman grade G1 (OR 3.343; 95% CI 1.194-9.363; p = 0.022).	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('PC', 'Gene', '5091', (52, 54))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('Fuhrman grades > G2', 'Var', (79, 98))
48612	31817988	Additionally, knockdown of RASSF10 or ASPP2 induced constitutive phosphorylation of SMAD2 (Smad family member 2).	('ASPP2', 'Gene', (38, 43))	('phosphorylation', 'biological_process', 'GO:0016310', ('65', '80'))	('RASSF10', 'Gene', (27, 34))	('constitutive phosphorylation', 'MPA', (52, 80))	('SMAD2', 'Gene', (84, 89))	('knockdown', 'Var', (14, 23))	('phospho', 'Chemical', 'MESH:C033601', (65, 72))
48613	31817988	Moreover, we found that epigenetic reduction of RASSF10 levels correlates with tumor progression and poor survival in human cancers.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('epigenetic reduction', 'Var', (24, 44))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('RASSF10', 'Gene', (48, 55))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('human', 'Species', '9606', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
48614	31817988	This data suggests that epigenetic loss of RASSF10 contributes to tumorigenesis by promoting EMT induced by TGFbeta.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('EMT', 'biological_process', 'GO:0001837', ('93', '96'))	('promoting', 'PosReg', (83, 92))	('RASSF10', 'Gene', (43, 50))	('tumor', 'Disease', (66, 71))	('contributes', 'Reg', (51, 62))	('EMT', 'Gene', (93, 96))	('EMT', 'Gene', '3702', (93, 96))	('epigenetic loss', 'Var', (24, 39))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
48615	31817988	Cancer is caused by a multistep genetic and epigenetic transformation of normal cells into highly invasive and immortal tumor cells.	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('epigenetic', 'Var', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
48618	31817988	Different genetic and epigenetic alterations have been identified that are associated with EMT.	('rat', 'Species', '10116', (37, 40))	('EMT', 'Gene', '3702', (91, 94))	('epigenetic alterations', 'Var', (22, 44))	('EMT', 'biological_process', 'GO:0001837', ('91', '94'))	('EMT', 'Gene', (91, 94))	('associated', 'Reg', (75, 85))
48619	31817988	Epithelial cadherin (CDH1) is a master mediator of cell-cell adherens junctions and loss of CDH1 expression is associated with disruption of apical-basal polarity and integrity of epithelial cells.	('apical-basal polarity', 'CPA', (141, 162))	('CDH1', 'Gene', '999', (21, 25))	('associated', 'Reg', (111, 121))	('CDH1', 'Gene', (92, 96))	('expression', 'Species', '29278', (97, 107))	('loss', 'Var', (84, 88))	('cadherin', 'molecular_function', 'GO:0008014', ('11', '19'))	('CDH1', 'Gene', (21, 25))	('CDH1', 'Gene', '999', (92, 96))	('integrity of epithelial', 'CPA', (167, 190))
48628	31817988	Epigenetic inactivation of RASSF10 through promoter hypermethylation has been reported in various tumor entities including lung cancer, thyroid cancer, melanoma and several others.	('thyroid cancer', 'Disease', 'MESH:D013964', (136, 150))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('tumor entities', 'Disease', (98, 112))	('RASSF10', 'Gene', (27, 34))	('thyroid cancer', 'Disease', (136, 150))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor entities', 'Disease', 'MESH:D009369', (98, 112))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('thyroid cancer', 'Phenotype', 'HP:0002890', (136, 150))	('promoter', 'MPA', (43, 51))	('Epigenetic inactivation', 'Var', (0, 23))	('reported', 'Reg', (78, 86))
48633	31817988	Furthermore, we found that RASSF10, but not ASPP2, is frequently hypermethylated in human cancers and the loss of RASSF10 is associated with advanced tumor stages and impaired survival of cancer patients.	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('RASSF10', 'Gene', (27, 34))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('RASSF10', 'Gene', (114, 121))	('associated', 'Reg', (125, 135))	('patients', 'Species', '9606', (195, 203))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('impaired', 'NegReg', (167, 175))	('human', 'Species', '9606', (84, 89))	('cancer', 'Disease', (188, 194))	('tumor', 'Disease', (150, 155))	('loss', 'Var', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('survival', 'CPA', (176, 184))	('cancer', 'Disease', (90, 96))
48634	31817988	We studied human cancer cell lines (CCLE, cancer cell line encyclopedia, Broad Institute, n = 917,) and found that expression of RASSF10 (238755_at) significantly correlated with the expression of genes associated with the GO (gene ontology) terms cell periphery, plasma membrane (apical), epidermal/epithelial cell differentiation and cell-cell junction (Table 1).	('epithelial cell differentiation', 'biological_process', 'GO:0030855', ('300', '331'))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('correlated', 'Reg', (163, 173))	('human', 'Species', '9606', (11, 16))	('cancer', 'Disease', (17, 23))	('gene ontology', 'biological_process', 'GO:0003673', ('227', '240'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('264', '279'))	('RASSF10', 'Gene', (129, 136))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('cell periphery', 'cellular_component', 'GO:0071944', ('248', '262'))	('expression', 'Species', '29278', (115, 125))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('expression', 'MPA', (183, 193))	('cell-cell junction', 'cellular_component', 'GO:0005911', ('336', '354'))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('238755_at', 'Var', (138, 147))	('expression', 'Species', '29278', (183, 193))	('cancer', 'Disease', (42, 48))	('cell periphery', 'cellular_component', 'GO:0005938', ('248', '262'))
48638	31817988	Therefore, we generated a RASSF10 knockout in the prototypic epithelial cell line A549 by CRISPR/Cas9 (Figure 1c; frameshift deletion mutation).	('rat', 'Species', '10116', (18, 21))	('frameshift deletion mutation', 'Var', (114, 142))	('Cas', 'cellular_component', 'GO:0005650', ('97', '100'))	('A549', 'CellLine', 'CVCL:0023', (82, 86))	('RASSF10', 'Gene', (26, 33))
48641	31817988	In contrast, RASSF10 re-expression in HeLa cells with epigenetically inactivated endogenous RASSF10 halted cell proliferation (G1/G0 induction) measured by flow cytometry (Figure 1h).	('expression', 'Species', '29278', (24, 34))	('RASSF10', 'Gene', (92, 99))	('cell proliferation', 'biological_process', 'GO:0008283', ('107', '125'))	('rat', 'Species', '10116', (119, 122))	('cell proliferation', 'CPA', (107, 125))	('halted', 'NegReg', (100, 106))	('HeLa', 'CellLine', 'CVCL:0030', (38, 42))	('epigenetically inactivated', 'Var', (54, 80))
48646	31817988	We assumed that loss of the tumor-suppressor RASSF10 in cancer contributes to the transition of epithelial to mesenchymal cell phenotypes.	('tumor', 'Disease', (28, 33))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('28', '44'))	('RASSF10', 'Gene', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('28', '44'))	('loss', 'Var', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
48648	31817988	However, this induction was not significant (p-value >= 0.14) in the wtRASSF10 cells suggesting that depletion of RASSF10 enhances significantly the ability of A549 cells to invade an ECM.	('depletion', 'Var', (101, 110))	('A549', 'CellLine', 'CVCL:0023', (160, 164))	('RASSF10', 'Gene', (114, 121))	('enhances', 'PosReg', (122, 130))
48649	31817988	RASSF10 knockdown revealed that RASSF10 inhibits induced TGFbeta-target gene expression associated with extracellular matrix (COL5A1) and matrix metallopeptidase 2 (MMP2) or direct induction of EMT (SNAI2 and SPOCK1) (Figure 3a).	('SNAI2', 'Gene', '6591', (199, 204))	('SNAI2', 'Gene', (199, 204))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('104', '124'))	('TGFbeta-target gene', 'Gene', (57, 76))	('EMT', 'biological_process', 'GO:0001837', ('194', '197'))	('CO', 'Chemical', 'MESH:D002245', (126, 128))	('EMT', 'Gene', '3702', (194, 197))	('inhibits', 'NegReg', (40, 48))	('gene expression', 'biological_process', 'GO:0010467', ('72', '87'))	('EMT', 'Gene', (194, 197))	('MMP2', 'molecular_function', 'GO:0004228', ('165', '169'))	('RASSF10', 'Var', (32, 39))	('expression', 'Species', '29278', (77, 87))
48651	31817988	Interestingly, we observed that CDH1 levels are reduced by RASSF10 knockdown (Figure 3b,c) and CDH1 expression is significantly positively correlated with RASSF10 expression (CCLE correlation analysis; Figure 3g).	('CDH1', 'Gene', '999', (95, 99))	('knockdown', 'Var', (67, 76))	('RASSF10', 'Gene', (59, 66))	('reduced', 'NegReg', (48, 55))	('expression', 'Species', '29278', (100, 110))	('CDH1', 'Gene', (32, 36))	('expression', 'Species', '29278', (163, 173))	('expression', 'MPA', (100, 110))	('expression', 'MPA', (163, 173))	('correlated', 'Interaction', (139, 149))	('CDH1', 'Gene', (95, 99))	('CDH1', 'Gene', '999', (32, 36))
48652	31817988	RASSF10 deletion by CRISPR/Cas9 further reduced TGFbeta driven CDH1 repression (Figure 3d).	('CDH1', 'Gene', (63, 67))	('RASSF10', 'Gene', (0, 7))	('Cas', 'cellular_component', 'GO:0005650', ('27', '30'))	('CDH1', 'Gene', '999', (63, 67))	('reduced', 'NegReg', (40, 47))	('TGFbeta', 'Gene', (48, 55))	('deletion', 'Var', (8, 16))
48659	31817988	RASSF10 co-localized with ASPP1 and ASPP2, whereas the latter was altered in its localization by RASSF10 (Figure S2).	('altered', 'Reg', (66, 73))	('RASSF10', 'Gene', (0, 7))	('localization', 'biological_process', 'GO:0051179', ('81', '93'))	('ASPP1', 'Gene', '21981', (26, 31))	('RASSF10', 'Var', (97, 104))	('ASPP1', 'Gene', (26, 31))
48664	31817988	We used CRISPR/Cas9 to generate three RASSF10 negative clones in A549 ( RX-A,B,C), which we controlled by PCR and sequencing the deletion within the coding region of RASSF10 (Figure 1).	('RX-A,B,C', 'Chemical', 'MESH:C096849', (72, 80))	('Cas', 'cellular_component', 'GO:0005650', ('15', '18'))	('A549', 'CellLine', 'CVCL:0023', (65, 69))	('RASSF10', 'Gene', (38, 45))	('deletion', 'Var', (129, 137))	('RASSF10', 'Gene', (166, 173))	('rat', 'Species', '10116', (27, 30))
48665	31817988	Using three A549 RASSF10-negative clones and three RASSF10-positive wt clones (wt-A,B,C), we could show that knockout of endogenous RASSF10 abolishes its co-precipitation with ASPP2 (Figure 4f).	('co-precipitation', 'MPA', (154, 170))	('knockout', 'Var', (109, 117))	('abolishes', 'NegReg', (140, 149))	('RASSF10', 'Gene', (132, 139))	('A549', 'CellLine', 'CVCL:0023', (12, 16))
48673	31817988	Induction of RASSF10 strongly increased endogenous ASPP2 protein levels (Figure 5b), which was not due to increased ASPP2 RNA expression (Figure 5c).	('expression', 'Species', '29278', (126, 136))	('RASSF10', 'Gene', (13, 20))	('RNA', 'cellular_component', 'GO:0005562', ('122', '125'))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('endogenous ASPP2 protein levels', 'MPA', (40, 71))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('increased', 'PosReg', (30, 39))	('Induction', 'Var', (0, 9))
48677	31817988	We only found minimal genomic alterations of RASSF10 (2.4%) and ASPP2 (4.7%) compared to 62% of TP53 mutations in cancer cell lines (n = 881; Broad CCLE/Cancer Cell Line Encyclopedia; analyzed using).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('Cancer', 'Disease', 'MESH:D009369', (153, 159))	('mutations', 'Var', (101, 110))	('TP53', 'Gene', (96, 100))	('RASSF10', 'Var', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('rat', 'Species', '10116', (34, 37))	('Cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Cancer', 'Disease', (153, 159))	('cancer', 'Disease', (114, 120))
48682	31817988	In summary, we are not convinced that mutations of RASSF10 and ASPP2 are likely to contribute to tumorigenesis, whereas occurrence of TP53 mutations in cancer is consistent with literature.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('ASPP2', 'Gene', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('RASSF10', 'Gene', (51, 58))	('tumor', 'Disease', (97, 102))	('rat', 'Species', '10116', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('mutations', 'Var', (38, 47))	('contribute', 'Reg', (83, 93))
48697	31817988	In breast cancer we can show that high RASSF10 methylation is associated with reduced RASSF10 expression, we observed that loss of RASSF10 expression correlates with progressed breast cancer grade and reduced overall survival of breast cancer patients (Figure 8e-g, Table S2).	('breast cancer', 'Disease', (177, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('expression', 'Species', '29278', (94, 104))	('reduced', 'NegReg', (201, 208))	('loss', 'NegReg', (123, 127))	('breast cancer', 'Disease', 'MESH:D001943', (229, 242))	('RASSF10', 'Gene', (131, 138))	('breast cancer', 'Disease', (229, 242))	('patients', 'Species', '9606', (243, 251))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('methylation', 'Var', (47, 58))	('expression', 'Species', '29278', (139, 149))	('RASSF10', 'Gene', (86, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (229, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('reduced', 'NegReg', (78, 85))	('expression', 'MPA', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('RASSF10', 'Gene', (39, 46))	('overall survival', 'CPA', (209, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))	('progressed', 'PosReg', (166, 176))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (3, 16))	('methylation', 'biological_process', 'GO:0032259', ('47', '58'))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))
48700	31817988	Supplementary Table S2 summarizes that low RASSF10 expression is associated with reduced 5 year survival rates of cancers: kidney cancer, 24% (papillary, significant) and 12% (clear cell, significant); head and neck cancer, 18% (significant); lymphoma, 22% (mantle cell, significant) and 5% (B-cell); thymoma, 8%; liver cancer, 34% (significant); lung cancer, 18% (significant); gastric cancer, 7%; and breast cancer, 21% (significant).	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('lung cancer', 'Disease', (347, 358))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('liver cancer', 'Disease', 'MESH:D006528', (314, 326))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('reduced', 'NegReg', (81, 88))	('lymphoma', 'Disease', (243, 251))	('thymoma', 'Disease', 'MESH:D013945', (301, 308))	('breast cancer', 'Phenotype', 'HP:0003002', (403, 416))	('gastric cancer', 'Disease', (379, 393))	('lymphoma', 'Disease', 'MESH:D008223', (243, 251))	('RASSF10', 'Gene', (43, 50))	('head and neck cancer', 'Phenotype', 'HP:0012288', (202, 222))	('kidney cancer', 'Phenotype', 'HP:0009726', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('kidney cancer', 'Disease', (123, 136))	('liver cancer', 'Phenotype', 'HP:0002896', (314, 326))	('breast cancer', 'Disease', 'MESH:D001943', (403, 416))	('liver cancer', 'Disease', (314, 326))	('lung cancer', 'Disease', 'MESH:D008175', (347, 358))	('breast cancer', 'Disease', (403, 416))	('thymoma', 'Disease', (301, 308))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('thymoma', 'Phenotype', 'HP:0100522', (301, 308))	('gastric cancer', 'Disease', 'MESH:D013274', (379, 393))	('lung cancer', 'Phenotype', 'HP:0100526', (347, 358))	('expression', 'Species', '29278', (51, 61))	('head and neck cancer', 'Disease', 'MESH:D006258', (202, 222))	('neck', 'cellular_component', 'GO:0044326', ('211', '215'))	('rat', 'Species', '10116', (105, 108))	('lymphoma', 'Phenotype', 'HP:0002665', (243, 251))	('low', 'Var', (39, 42))	('gastric cancer', 'Phenotype', 'HP:0012126', (379, 393))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('kidney cancer', 'Disease', 'MESH:D007680', (123, 136))
48704	31817988	Interestingly, we found an enhanced phosphorylation of SMAD2 after TGFbeta treatment and knockdown of ASPP2.	('ASPP2', 'Gene', (102, 107))	('TGFbeta', 'Gene', (67, 74))	('phosphorylation', 'biological_process', 'GO:0016310', ('36', '51'))	('phospho', 'Chemical', 'MESH:C033601', (36, 43))	('enhanced', 'PosReg', (27, 35))	('SMAD2', 'Protein', (55, 60))	('knockdown', 'Var', (89, 98))	('phosphorylation', 'MPA', (36, 51))
48706	31817988	However, YAP1 levels were rather unaffected after RASSF10 or ASPP2 knockdown.	('knockdown', 'Var', (67, 76))	('rat', 'Species', '10116', (26, 29))	('YAP1 levels', 'MPA', (9, 20))	('ASPP2', 'Gene', (61, 66))	('RASSF10', 'Gene', (50, 57))
48709	31817988	These data indicated that loss of RASSF10 or ASPP2 induced constitutive activation of TGFbeta signaling and EMT.	('activation', 'PosReg', (72, 82))	('EMT', 'biological_process', 'GO:0001837', ('108', '111'))	('ASPP2', 'Gene', (45, 50))	('RASSF10', 'Gene', (34, 41))	('EMT', 'Gene', (108, 111))	('signaling', 'biological_process', 'GO:0023052', ('94', '103'))	('EMT', 'Gene', '3702', (108, 111))	('TGFbeta signaling', 'Pathway', (86, 103))	('loss', 'Var', (26, 30))
48716	31817988	Loss of RASSF10 altered the TGFbeta gene expression profile and induced expression of COL5A1, MMP2, SNAI2 and SPOCK1 (Figure 3a) and constitutive SMAD2 phosphorylation (Figure 9a), suggesting that RASSF10 plays a suppressive role in TGFbeta signaling and EMT.	('phospho', 'Chemical', 'MESH:C033601', (152, 159))	('MMP2', 'molecular_function', 'GO:0004228', ('94', '98'))	('altered', 'Reg', (16, 23))	('COL5A1', 'Gene', (86, 92))	('phosphorylation', 'MPA', (152, 167))	('signaling', 'biological_process', 'GO:0023052', ('241', '250'))	('EMT', 'Gene', (255, 258))	('EMT', 'Gene', '3702', (255, 258))	('induced', 'Reg', (64, 71))	('expression', 'MPA', (72, 82))	('RASSF10', 'Gene', (8, 15))	('EMT', 'biological_process', 'GO:0001837', ('255', '258'))	('phosphorylation', 'biological_process', 'GO:0016310', ('152', '167'))	('SPOCK1', 'Gene', (110, 116))	('SNAI2', 'Gene', (100, 105))	('Loss', 'Var', (0, 4))	('gene expression', 'biological_process', 'GO:0010467', ('36', '51'))	('expression', 'Species', '29278', (41, 51))	('expression', 'Species', '29278', (72, 82))	('SNAI2', 'Gene', '6591', (100, 105))	('MMP2', 'Gene', (94, 98))	('TGFbeta gene', 'Gene', (28, 40))	('expression profile', 'MPA', (41, 59))	('CO', 'Chemical', 'MESH:D002245', (86, 88))
48718	31817988	Additionally, we observed that depletion of RASSF10 significantly promotes TGFbeta induced invasion of A549 cells in an extracellular matrix (Table 2).	('invasion of A549 cells in an extracellular matrix', 'CPA', (91, 140))	('A549', 'CellLine', 'CVCL:0023', (103, 107))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('120', '140'))	('promotes', 'PosReg', (66, 74))	('depletion', 'Var', (31, 40))	('RASSF10', 'Gene', (44, 51))	('TGFbeta', 'Gene', (75, 82))
48720	31817988	Interestingly, we observed that RASSF10 induced E-cadherin (CDH1) levels and loss of RASSF10 expression reduced CDH1 levels (Figure 3).	('RASSF10', 'Gene', (85, 92))	('induced', 'Reg', (40, 47))	('reduced', 'NegReg', (104, 111))	('CDH1', 'Gene', '999', (60, 64))	('expression', 'Species', '29278', (93, 103))	('cadherin', 'molecular_function', 'GO:0008014', ('50', '58'))	('expression', 'MPA', (93, 103))	('CDH1', 'Gene', (60, 64))	('CDH1', 'Gene', (112, 116))	('RASSF10', 'Gene', (32, 39))	('loss', 'Var', (77, 81))	('CDH1', 'Gene', '999', (112, 116))
48727	31817988	Our data indicate that knockdown of ASPP2 induces beta-Catenin levels and phospho-SMAD2 under TGFbeta treatment (Figure 9a).	('phospho-SMAD2', 'MPA', (74, 87))	('induces', 'PosReg', (42, 49))	('phospho', 'Chemical', 'MESH:C033601', (74, 81))	('knockdown', 'Var', (23, 32))	('beta-Catenin levels', 'MPA', (50, 69))	('ASPP2', 'Gene', (36, 41))
48733	31817988	We found that knockdown and knockout of RASSF10 increased mitosis and increased cell proliferation (Figure 1) and significantly promotes TGFbeta induced ECM invasion (Table 2), as well as RASSF10 re-expression halted proliferation (Figure 1).	('increased', 'PosReg', (48, 57))	('expression', 'Species', '29278', (199, 209))	('increased', 'PosReg', (70, 79))	('mitosis', 'biological_process', 'GO:0000278', ('58', '65'))	('TGFbeta', 'Gene', (137, 144))	('rat', 'Species', '10116', (92, 95))	('cell proliferation', 'CPA', (80, 98))	('cell proliferation', 'biological_process', 'GO:0008283', ('80', '98'))	('halted', 'NegReg', (210, 216))	('mitosis', 'CPA', (58, 65))	('knockout', 'Var', (28, 36))	('promotes', 'PosReg', (128, 136))	('rat', 'Species', '10116', (224, 227))	('RASSF10', 'Gene', (40, 47))
48734	31817988	As RASSF10 and ASPP2 are both linked to the cell polarity network, their presence would negatively regulate the mitotic/proliferative potential.	('cell polarity', 'biological_process', 'GO:0007163', ('44', '57'))	('presence', 'Var', (73, 81))	('RASSF10', 'Gene', (3, 10))	('regulate', 'Reg', (99, 107))	('negatively', 'NegReg', (88, 98))	('ASPP2', 'Gene', (15, 20))	('mitotic/proliferative potential', 'CPA', (112, 143))	('rat', 'Species', '10116', (127, 130))
48735	31817988	Loss of the RASSF10-ASPP2 complex would lead to disturbance of cell polarity and thereby would interfere with the coordination of mitosis, as it is known that the positioning of the spindle apparatus is coordinated with polarity signals at the cell cortex.	('coordination of mitosis', 'Disease', (114, 137))	('spindle', 'cellular_component', 'GO:0005819', ('182', '189'))	('cell polarity', 'CPA', (63, 76))	('disturbance', 'MPA', (48, 59))	('lead to', 'Reg', (40, 47))	('rat', 'Species', '10116', (194, 197))	('cell polarity', 'biological_process', 'GO:0007163', ('63', '76'))	('interfere', 'NegReg', (95, 104))	('RASSF10-ASPP2', 'Gene', (12, 25))	('cell cortex', 'cellular_component', 'GO:0005938', ('244', '255'))	('Loss', 'Var', (0, 4))	('coordination of mitosis', 'Disease', 'MESH:D001259', (114, 137))	('mitosis', 'biological_process', 'GO:0000278', ('130', '137'))
48737	31817988	In our study we found a significant epigenetic silencing of RASSF10, but not ASPP2 in different tumor entities (Figure 6 and Figure 7).	('RASSF10', 'Gene', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor entities', 'Disease', 'MESH:D009369', (96, 110))	('epigenetic silencing', 'Var', (36, 56))	('tumor entities', 'Disease', (96, 110))
48738	31817988	Promoter hypermethylation of tumor suppressor genes is an established mechanism of their silencing in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (102, 116))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor suppressor', 'biological_process', 'GO:0051726', ('29', '45'))	('carcinogenesis', 'Disease', (102, 116))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('29', '45'))	('tumor', 'Disease', (29, 34))	('silencing', 'NegReg', (89, 98))	('Promoter hypermethylation', 'Var', (0, 25))
48742	31817988	Our clinical data set revealed that hypermethylation of the CpG island of RASSF10 is a common and general event in human tumorigenesis (Figure 7 and Figure 8).	('RASSF10', 'Gene', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('hypermethylation', 'Var', (36, 52))	('human', 'Species', '9606', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
48743	31817988	We could broadly show that in independent data sets loss of RASSF10 correlated not only with reduced patient survival rates in various tumor types (kidney cancer, thymoma, lymphoma, breast cancer, colon carcinoma, head and neck cancer, liver cancer, lung cancer and gastric cancer), but also with tumor stage/grade (thymoma, breast cancer) and tumor types (kidney cancer, melanoma and colon carcinoma) (Figure 8 and Table S2).	('RASSF10', 'Gene', (60, 67))	('liver cancer', 'Disease', 'MESH:D006528', (236, 248))	('lung cancer', 'Phenotype', 'HP:0100526', (250, 261))	('thymoma', 'Phenotype', 'HP:0100522', (163, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (325, 338))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('colon carcinoma', 'Disease', 'MESH:D015179', (385, 400))	('breast cancer', 'Phenotype', 'HP:0003002', (182, 195))	('tumor', 'Disease', (297, 302))	('breast cancer', 'Disease', 'MESH:D001943', (325, 338))	('gastric cancer', 'Phenotype', 'HP:0012126', (266, 280))	('liver cancer', 'Phenotype', 'HP:0002896', (236, 248))	('patient survival rates', 'CPA', (101, 123))	('breast cancer', 'Disease', (325, 338))	('melanoma', 'Phenotype', 'HP:0002861', (372, 380))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('liver cancer', 'Disease', (236, 248))	('rat', 'Species', '10116', (118, 121))	('breast cancer', 'Disease', 'MESH:D001943', (182, 195))	('head and neck cancer', 'Disease', 'MESH:D006258', (214, 234))	('breast cancer', 'Disease', (182, 195))	('tumor', 'Disease', (344, 349))	('thymoma, lymphoma', 'Disease', 'MESH:D013945', (163, 180))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('thymoma', 'Disease', 'MESH:D013945', (316, 323))	('colon carcinoma', 'Disease', (197, 212))	('lung cancer', 'Disease', (250, 261))	('tumor', 'Disease', 'MESH:D009369', (344, 349))	('kidney cancer', 'Disease', 'MESH:D007680', (357, 370))	('loss', 'Var', (52, 56))	('kidney cancer', 'Disease', 'MESH:D007680', (148, 161))	('tumor', 'Disease', (135, 140))	('gastric cancer', 'Disease', (266, 280))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('thymoma', 'Disease', 'MESH:D013945', (163, 170))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('thymoma', 'Disease', (316, 323))	('neck', 'cellular_component', 'GO:0044326', ('223', '227'))	('melanoma and colon carcinoma', 'Disease', 'MESH:D015179', (372, 400))	('colon carcinoma', 'Disease', 'MESH:D015179', (197, 212))	('patient', 'Species', '9606', (101, 108))	('thymoma', 'Phenotype', 'HP:0100522', (316, 323))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('kidney cancer', 'Phenotype', 'HP:0009726', (357, 370))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('lung cancer', 'Disease', 'MESH:D008175', (250, 261))	('gastric cancer', 'Disease', 'MESH:D013274', (266, 280))	('colon carcinoma', 'Disease', (385, 400))	('kidney cancer', 'Disease', (357, 370))	('reduced', 'NegReg', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('kidney cancer', 'Phenotype', 'HP:0009726', (148, 161))	('kidney cancer', 'Disease', (148, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (391, 400))	('head and neck cancer', 'Phenotype', 'HP:0012288', (214, 234))	('lymphoma', 'Phenotype', 'HP:0002665', (172, 180))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('thymoma', 'Disease', (163, 170))
48745	31817988	Our present comprehensive work is the finalization of our previous research in smaller data sets in which we have shown that the promoter of RASSF10 is methylated in patient tumors samples of the adrenal gland, head and neck, sarcoma, pancreas carcinoma and Merkel cell carcinoma.	('sarcoma', 'Phenotype', 'HP:0100242', (226, 233))	('tumors', 'Disease', (174, 180))	('pancreas carcinoma', 'Disease', 'MESH:D010190', (235, 253))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('RASSF10', 'Gene', (141, 148))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (258, 279))	('pancreas carcinoma', 'Disease', (235, 253))	('sarcoma', 'Disease', 'MESH:D012509', (226, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('Merkel cell carcinoma', 'Disease', (258, 279))	('neck', 'cellular_component', 'GO:0044326', ('220', '224'))	('methylated', 'Var', (152, 162))	('patient', 'Species', '9606', (166, 173))	('sarcoma', 'Disease', (226, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
48746	31817988	We showed the epigenetic inactivation of RASSF10 in thyroid cancer, lung cancer, skin cancer, breast cancer and showed that RASSF10 inhibited growth of breast cancer, pancreas carcinoma and sarcoma cell lines.	('thyroid cancer', 'Disease', (52, 66))	('sarcoma', 'Disease', 'MESH:D012509', (190, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('sarcoma', 'Disease', (190, 197))	('epigenetic inactivation', 'Var', (14, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('skin cancer', 'Disease', (81, 92))	('inhibited', 'NegReg', (132, 141))	('pancreas carcinoma', 'Disease', 'MESH:D010190', (167, 185))	('pancreas carcinoma', 'Disease', (167, 185))	('thyroid cancer', 'Disease', 'MESH:D013964', (52, 66))	('RASSF10', 'Gene', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Disease', (94, 107))	('skin cancer', 'Phenotype', 'HP:0008069', (81, 92))	('thyroid cancer', 'Phenotype', 'HP:0002890', (52, 66))	('lung cancer', 'Disease', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('growth', 'CPA', (142, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('skin cancer', 'Disease', 'MESH:D012878', (81, 92))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('RASSF10', 'Gene', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', (152, 165))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
48749	31817988	It is obvious to measure methylated tumor DNA instead of RNA due to its superior stability in cells and body fluids (circulating DNA).	('N', 'Chemical', 'MESH:D009584', (43, 44))	('N', 'Chemical', 'MESH:D009584', (130, 131))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('DNA', 'cellular_component', 'GO:0005574', ('129', '132'))	('methylated', 'Var', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('RNA', 'cellular_component', 'GO:0005562', ('57', '60'))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
48751	31817988	However, in DNA, we observed that already low levels of methylation inactivated RASSF10 and therefore a common threshold level could abrogate RASSF10 expression irrespective of the tissue.	('expression', 'MPA', (150, 160))	('DNA', 'cellular_component', 'GO:0005574', ('12', '15'))	('abrogate', 'NegReg', (133, 141))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('N', 'Chemical', 'MESH:D009584', (13, 14))	('RASSF10', 'Gene', (142, 149))	('methylation', 'Var', (56, 67))	('RASSF10', 'Gene', (80, 87))	('expression', 'Species', '29278', (150, 160))	('inactivated', 'NegReg', (68, 79))
48754	31817988	Liquid biopsies are FDA approved for lung cancer EGFR mutation tests as companion diagnostic.	('lung cancer', 'Disease', (37, 48))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('EGFR', 'Gene', (49, 53))	('mutation tests', 'Var', (54, 68))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))
48772	31817988	The following antibodies were used: a-GAPDH (FL335, sc-25778 from Santa Cruz), a-GFP from Rainer Renkawitz (Giessen, Germany), a-RASSF10 (AP12444c-ev2020, Abgent, San Diego, United States), a-p65 (610868, BD Biosciences, Heidelberg, Germany), a-ASPP1 (sc50890, Santa Cruz, Santa Cruz, United States), a-ASPP2 (sc53861, Santa Cruz), a-YAP1 (sc15407, Santa Cruz), a-ss-Catenin (9562S, Cell Signaling), a-phospho-SMAD2 ser465/467 (3101, Cell signaling), a-Flag (M2, Sigma), a-GST (B-14 sc138, Santa Cruz), a-V5 Tag (ab9116, Abcam, Cambridge, United Kingdom), HRP-coupled secondary antibodies anti-rabbit (sc2004, sc2357, Santa Cruz), anti-mouse (sc2005, sc516102, Santa Cruz) and anti-goat (sc2021, Santa Cruz), alexafluor568 (Thermo Fisher Scientific).	('signaling', 'biological_process', 'GO:0023052', ('439', '448'))	('sc2021', 'Var', (688, 694))	('alexafluor568', 'Chemical', 'MESH:C107873', (709, 722))	('9562S', 'CellLine', 'CVCL:Z231', (376, 381))	('sc2004', 'Var', (602, 608))	('p65', 'Gene', (192, 195))	('phospho', 'Chemical', 'MESH:C033601', (402, 409))	('BD Biosciences', 'Disease', 'MESH:D001528', (205, 219))	('ASPP1', 'Gene', '21981', (245, 250))	('GAPDH', 'Gene', (38, 43))	('sc-25778', 'Chemical', 'MESH:D012538', (52, 60))	('ser', 'cellular_component', 'GO:0005790', ('416', '419'))	('p65', 'Gene', '19697', (192, 195))	('Signaling', 'biological_process', 'GO:0023052', ('388', '397'))	('sc2005', 'Var', (643, 649))	('ASPP1', 'Gene', (245, 250))	('mouse', 'Species', '10090', (636, 641))	('BD Biosciences', 'Disease', (205, 219))	('GAPDH', 'Gene', '14433', (38, 43))
48782	31817988	RASSF10's coding sequence was amplified from genomic DNA, ASPP1 (IRAVp968F02130D) and ASPP2 (IRATp970A06136D) were obtained from the former Deutschen Ressourcenzentrum fur Genomforschung (RZPD) now THE I.M.A.G.E.	('IRATp970A06136D', 'Var', (93, 108))	('ASPP1', 'Gene', (58, 63))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('ASPP1', 'Gene', '21981', (58, 63))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('IRAVp968F02130D', 'Var', (65, 80))	('IRAVp968F02130D', 'Chemical', 'MESH:C000900', (65, 80))
48785	31817988	Susanne Maaz cloned p53 (IRALp962F088Q) into pCDNA3.1/nV5-DEST (Thermo Fisher Scientific) and YAP1 (IRAKp961L0779) was cloned into EYFP (Clontech) by Desiree Block and A.J.	('IRALp962F088Q', 'Var', (25, 38))	('N', 'Chemical', 'MESH:D009584', (48, 49))	('p53', 'Gene', '2768677', (20, 23))	('p53', 'Gene', (20, 23))
48787	31817988	Deletion mutants and domain mutants of RASSF10 were generated by site directed mutations as above.	('rat', 'Species', '10116', (56, 59))	('RASSF10', 'Gene', (39, 46))	('Deletion', 'Var', (0, 8))
48791	31817988	For the evaluation of the invasion capacity of A549 wildtype and RASSF10 deletion clones transwell extracellular matrix (ECM) invasion assays were performed.	('extracellular matrix', 'cellular_component', 'GO:0031012', ('99', '119'))	('deletion', 'Var', (73, 81))	('RASSF10', 'Gene', (65, 72))	('A549', 'CellLine', 'CVCL:0023', (47, 51))
48796	31817988	We are now showing that RASSF10 expression inhibits signs of EMT in cancer cell lines, but we are also reporting its mode of action as a tumor suppressor.	('EMT', 'Gene', '3702', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', (137, 142))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('137', '153'))	('expression', 'Var', (32, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('137', '153'))	('RASSF10', 'Gene', (24, 31))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('expression', 'Species', '29278', (32, 42))	('EMT', 'biological_process', 'GO:0001837', ('61', '64'))	('cancer', 'Disease', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('inhibits', 'NegReg', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('EMT', 'Gene', (61, 64))
48799	31817988	We show that RASSF10 induces the protein levels of ASPP2 that is also an inhibitor of EMT.	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('EMT', 'Gene', (86, 89))	('induces', 'Reg', (21, 28))	('RASSF10', 'Var', (13, 20))	('EMT', 'Gene', '3702', (86, 89))	('protein levels', 'MPA', (33, 47))	('ASPP2', 'Protein', (51, 56))	('EMT', 'biological_process', 'GO:0001837', ('86', '89'))
48800	31817988	In human cancers, RASSF10, but not ASPP2, is epigenetically inactivated by promoter hypermethylation.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('human', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('promoter hypermethylation', 'Var', (75, 100))	('RASSF10', 'Gene', (18, 25))
48803	31817988	The following are available online at , Figure S1: Structure of RASSF10., Figure S2: RASSF10 (RX) localizes with overexpressed ASPP1/2 (A1/A2) and induces endogenous ASPP2, Figure S3: Characterization of RASSF10 binding to ASPP1/2 and competition; Figure S4: ASPP2 is not epigenetically regulated in human cancers; Figure S5: No SMAD2 and SMAD3 binding at the RASSF10 promoter.	('cancers', 'Phenotype', 'HP:0002664', (306, 313))	('RASSF10', 'Var', (85, 92))	('SMAD3', 'Gene', '4088', (339, 344))	('cancers', 'Disease', (306, 313))	('binding', 'Interaction', (212, 219))	('N', 'Chemical', 'MESH:D009584', (326, 327))	('cancers', 'Disease', 'MESH:D009369', (306, 313))	('binding', 'molecular_function', 'GO:0005488', ('212', '219'))	('RASSF10', 'Gene', (360, 367))	('SMAD3', 'Gene', (339, 344))	('human', 'Species', '9606', (300, 305))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('binding', 'Interaction', (345, 352))	('binding', 'molecular_function', 'GO:0005488', ('345', '352'))
48807	31817988	Figure 8: Methylation Expression Correlation: RASSF10, Dataset Project: TCGA, Data Type: 450k Methylation Array 450k Infinium chip, Select: cg05817758, beta value and log2 (normalized rsem+1) of RASSF10, Correlation method: Spearman, Fit linear regression, for Breast invasive carcinoma.	('Breast invasive carcinoma', 'Disease', 'MESH:D001943', (261, 286))	('Methylation', 'biological_process', 'GO:0032259', ('10', '21'))	('Methylation', 'biological_process', 'GO:0032259', ('94', '105'))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('cg05817758', 'Var', (140, 150))	('Breast invasive carcinoma', 'Disease', (261, 286))	('Expression', 'Species', '29278', (22, 32))
48822	31513923	Nearly all ccRCC tumor cells contain mutations inactivating Von Hippel-Lindau syndrome protein (VHL), an E3 ubiquitin ligase required for degradation of the alpha subunits of hypoxia-inducible factors (HIFalphas).	('ccRCC tumor', 'Disease', (11, 22))	('ccRCC tumor', 'Disease', 'MESH:D009369', (11, 22))	('hypoxia', 'Disease', 'MESH:D000860', (175, 182))	('degradation', 'biological_process', 'GO:0009056', ('138', '149'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('108', '117'))	('hypoxia', 'Disease', (175, 182))	('inactivating', 'Var', (47, 59))	('mutations inactivating', 'Var', (37, 59))	('VHL', 'Gene', (96, 99))	('Von Hippel-Lindau syndrome', 'Disease', (60, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (11, 16))	('Von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (60, 86))	('VHL', 'Gene', '22346', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
48824	31513923	The aberrant activation of HIFalphas, particularly HIF2alpha, is believed to be the major mechanism to trigger development of ccRCC.	('HIF2alpha', 'Gene', (51, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('aberrant', 'Var', (4, 12))	('ccRCC', 'Disease', (126, 131))	('activation', 'PosReg', (13, 23))	('HIF2alpha', 'Gene', '13819', (51, 60))
48899	31513923	A possible explanation for the dilemma is that cholesterol accumulation may facilitate ccRCC development in human but this effect is unable to be reproduced in mouse-based experiments.	('cholesterol accumulation', 'Var', (47, 71))	('cholesterol', 'Chemical', 'MESH:D002784', (47, 58))	('facilitate', 'PosReg', (76, 86))	('human', 'Species', '9606', (108, 113))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('ccRCC', 'Disease', (87, 92))	('mouse', 'Species', '10090', (160, 165))
48905	31513923	A more likely scenario is that SR-B1 overexpression may cooperates with loss of VHL to further stimulate HIFalpha transcriptional activity in ccRCC cells.	('VHL', 'Gene', (80, 83))	('HIFalpha transcriptional activity', 'MPA', (105, 138))	('stimulate', 'PosReg', (95, 104))	('VHL', 'Gene', '22346', (80, 83))	('loss', 'Var', (72, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('ccRCC', 'Disease', (142, 147))
48907	31513923	If this is indeed the case, then cholesterol accumulation is the consequence of SR-B1 overexpression, but may contribute little to cancer development.	('cancer', 'Disease', (131, 137))	('cholesterol accumulation', 'MPA', (33, 57))	('cholesterol', 'Chemical', 'MESH:D002784', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('overexpression', 'Var', (86, 100))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('SR-B1', 'Gene', (80, 85))
48913	31513923	Thus, it will be interesting to determine whether inhibiting ACAT activity will cause selective cytotoxicity to ccRCC cells that contain excess cholesterol, thereby providing a novel targeted therapy against these cancers.	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('ACAT', 'Gene', '110446', (61, 65))	('ACAT', 'Gene', (61, 65))	('cholesterol', 'MPA', (144, 155))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('ACAT activity', 'molecular_function', 'GO:0004313', ('61', '74'))	('ACAT activity', 'molecular_function', 'GO:0034736', ('61', '74'))	('ccRCC', 'Disease', (112, 117))	('activity', 'MPA', (66, 74))	('cancers', 'Disease', (214, 221))	('cholesterol', 'Chemical', 'MESH:D002784', (144, 155))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('cytotoxicity', 'Disease', (96, 108))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('excess cholesterol', 'Phenotype', 'HP:0003124', (137, 155))	('inhibiting', 'Var', (50, 60))	('cytotoxicity', 'Disease', 'MESH:D064420', (96, 108))
48986	28832979	Frequency of genomic alteration events including mutations, putative copy-number alteration from GISTIC, mRNA expression Z-scores (RNA Seq V2 RSEM) with Z-score thresholds +-2.0, and protein expression (RPPA) with Z-score thresholds +-2.0 were evaluated in the 469 patients with mRNA data (RNA Seq V2).	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('RNA', 'cellular_component', 'GO:0005562', ('131', '134'))	('mutations', 'Var', (49, 58))	('RNA', 'cellular_component', 'GO:0005562', ('290', '293'))	('mRNA expression Z-scores', 'MPA', (105, 129))	('patients', 'Species', '9606', (265, 273))	('protein', 'MPA', (183, 190))
48995	28832979	All cases of sRCC with PD-L1 positivity on manual evaluation showed an H-score of >=10.	('positivity', 'Var', (29, 39))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('RCC', 'Disease', (14, 17))	('PD-L1', 'Gene', (23, 28))
49021	28832979	collected 26 sRCCs and 29 non-sarcomatoid ccRCCs, performed immunohistochemical analysis for PD-1 and PD-L1 in whole sections, and found increased expression of PD-L1 on tumor cells (54% of sRCCs and 17% of non-sarcomatoid ccRCCs; P=0.006) concurrent with PD-1-positive TILs in sRCC (96% of sRCCs and 62% of non-sarcomatoid ccRCCs; P=0.003).	('RCC', 'Disease', (14, 17))	('expression', 'MPA', (147, 157))	('sarcomatoid', 'Disease', 'MESH:C538614', (312, 323))	('RCC', 'Disease', (44, 47))	('tumor', 'Disease', (170, 175))	('sarcomatoid', 'Disease', (30, 41))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('RCC', 'Disease', (225, 228))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('sarcomatoid', 'Disease', (211, 222))	('increased', 'PosReg', (137, 146))	('RCC', 'Disease', (279, 282))	('PD-1', 'Gene', (256, 260))	('sarcomatoid', 'Disease', 'MESH:C538614', (30, 41))	('RCC', 'Disease', 'MESH:C538614', (292, 295))	('PD-1', 'Gene', '5133', (256, 260))	('RCC', 'Disease', (191, 194))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('RCC', 'Disease', (326, 329))	('sarcomatoid', 'Disease', (312, 323))	('RCC', 'Disease', (292, 295))	('RCC', 'Disease', 'MESH:C538614', (279, 282))	('sarcomatoid', 'Disease', 'MESH:C538614', (211, 222))	('RCC', 'Disease', 'MESH:C538614', (191, 194))	('PD-L1', 'Var', (161, 166))	('RCC', 'Disease', 'MESH:C538614', (326, 329))	('PD-1', 'Gene', (93, 97))	('PD-1', 'Gene', '5133', (93, 97))
49059	32508031	DNA methylation could negatively regulate gene expression in the development of tumors, and be also used as biomarkers for prognostic prediction.	('regulate', 'Reg', (33, 41))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('gene expression', 'MPA', (42, 57))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('methylation', 'Var', (4, 15))	('negatively', 'NegReg', (22, 32))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('gene expression', 'biological_process', 'GO:0010467', ('42', '57'))
49084	32541526	According to AKIP1 expression in tumor tissues, all patients were grouped as AKIP1 low and high expression (AKIP1 high expression were further divided into AKIP1 high+, high++, and high+++ expression).	('high+++ expression', 'Var', (181, 199))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('AKIP1', 'Gene', '56672', (108, 113))	('AKIP1', 'Gene', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('AKIP1', 'Gene', '56672', (156, 161))	('patients', 'Species', '9606', (52, 60))	('tumor', 'Disease', (33, 38))	('AKIP1', 'Gene', '56672', (77, 82))	('AKIP1', 'Gene', (77, 82))	('AKIP1', 'Gene', (156, 161))	('AKIP1', 'Gene', '56672', (13, 18))	('AKIP1', 'Gene', (13, 18))
49108	32541526	Moreover, AKIP1 high expression tissues were further divided into tissues with AKIP1 high+ expression (total IHC score ranging from 4 to 6), tissues with AKIP1 high++ expression (total IHC score range from 7 to 9), tissues with AKIP1 high+++ expression (total IHC score ranging from 10 to 12).	('AKIP1', 'Gene', '56672', (79, 84))	('AKIP1', 'Gene', (79, 84))	('AKIP1', 'Gene', '56672', (10, 15))	('AKIP1', 'Gene', (10, 15))	('high+ expression', 'Var', (85, 101))	('AKIP1', 'Gene', '56672', (228, 233))	('AKIP1', 'Gene', (228, 233))	('AKIP1', 'Gene', '56672', (154, 159))	('AKIP1', 'Gene', (154, 159))
49109	32541526	In addition, according to AKIP1 expression in tumor tissues, all patients were grouped as patients with AKIP1 low expression (n = 98), patients with AKIP1 high expression (n = 112), patients with AKIP1 high+ expression (n = 60), patients with AKIP1 high++ expression (n = 37), and patients with AKIP1 high+++ expression (n = 15).	('patients', 'Species', '9606', (229, 237))	('patients', 'Species', '9606', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('AKIP1', 'Gene', '56672', (149, 154))	('AKIP1', 'Gene', (104, 109))	('patients', 'Species', '9606', (182, 190))	('AKIP1', 'Gene', '56672', (196, 201))	('AKIP1', 'Gene', (149, 154))	('AKIP1', 'Gene', '56672', (243, 248))	('low', 'NegReg', (110, 113))	('AKIP1', 'Gene', (196, 201))	('patients', 'Species', '9606', (281, 289))	('tumor', 'Disease', (46, 51))	('AKIP1', 'Gene', '56672', (26, 31))	('patients', 'Species', '9606', (65, 73))	('AKIP1', 'Gene', '56672', (295, 300))	('patients', 'Species', '9606', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('AKIP1', 'Gene', (243, 248))	('AKIP1', 'Gene', '56672', (104, 109))	('high expression', 'Var', (155, 170))	('AKIP1', 'Gene', (295, 300))	('AKIP1', 'Gene', (26, 31))
49122	32541526	AKIP1 high expression tissues were further divided into AKIP1 high+ (total IHC score 4-6), AKIP1 high++ (total IHC score 7-9), and AKIP1 high+++ (total IHC score 10-12) expression.	('AKIP1', 'Gene', (0, 5))	('high+++', 'Var', (137, 144))	('AKIP1', 'Gene', '56672', (56, 61))	('AKIP1', 'Gene', (56, 61))	('AKIP1', 'Gene', '56672', (131, 136))	('AKIP1', 'Gene', (131, 136))	('AKIP1', 'Gene', '56672', (0, 5))	('AKIP1', 'Gene', '56672', (91, 96))	('AKIP1', 'Gene', (91, 96))	('high++', 'Var', (97, 103))
49123	32541526	Representative IHC images illustrated AKIP1 low expression in adjacent tissues, AKIP1 low expression in tumor tissues, AKIP1 high+ expression in tumor tissues, AKIP1 high++ expression in tumor tissues, and AKIP1 high+++ expression in tumor tissues (Fig.	('tumor', 'Disease', (234, 239))	('AKIP1', 'Gene', '56672', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('AKIP1', 'Gene', (80, 85))	('tumor', 'Disease', (187, 192))	('expression', 'MPA', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('AKIP1', 'Gene', (160, 165))	('AKIP1', 'Gene', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('AKIP1', 'Gene', (38, 43))	('AKIP1', 'Gene', (206, 211))	('tumor', 'Disease', (145, 150))	('low', 'NegReg', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('high+++ expression', 'Var', (212, 230))	('tumor', 'Disease', (104, 109))	('high++ expression', 'Var', (166, 183))	('high+ expression', 'Var', (125, 141))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('low', 'NegReg', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('AKIP1', 'Gene', '56672', (80, 85))	('AKIP1', 'Gene', '56672', (160, 165))	('AKIP1', 'Gene', '56672', (38, 43))	('AKIP1', 'Gene', '56672', (119, 124))
49131	32541526	The second method was that tumor AKIP1 expression was classified as tumor AKIP1 high+++, high++, high+, low.	('tumor', 'Disease', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('high++', 'Var', (89, 95))	('AKIP1', 'Gene', '56672', (74, 79))	('AKIP1', 'Gene', (74, 79))	('high+', 'Var', (97, 102))	('AKIP1', 'Gene', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('AKIP1', 'Gene', '56672', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('high+++', 'Var', (80, 87))	('low', 'Var', (104, 107))
49134	32541526	Univariate Cox regression indicated that tumor AKIP1 high expression (hazard ratio [HR] = 2.085, P = .005), age (>60 years) (HR = 1.954, P = .007), pathological grade (G2/G3 vs G1) (HR = 2.568, P < .001), and TNM stage (II/III vs I) (HR = 4.145, P < .001) were correlated with decreased OS in ccRCC patients (Table 3).	('high expression', 'PosReg', (53, 68))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('G2/G3', 'Var', (168, 173))	('tumor', 'Disease', (41, 46))	('TNM', 'Gene', (209, 212))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('RCC', 'Disease', 'MESH:C538614', (295, 298))	('patients', 'Species', '9606', (299, 307))	('RCC', 'Disease', (295, 298))	('RCC', 'Phenotype', 'HP:0005584', (295, 298))	('AKIP1', 'Gene', '56672', (47, 52))	('AKIP1', 'Gene', (47, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (293, 298))	('decreased', 'NegReg', (277, 286))	('TNM', 'Gene', '10178', (209, 212))
49140	32541526	For example, 1 functional and molecular experiment exhibits that AKIP1 knockdown suppresses cell proliferation, invasion, and metastasis via regulating slug-induced EMT in gastric cancer.	('slug', 'Gene', (152, 156))	('AKIP1', 'Gene', '56672', (65, 70))	('AKIP1', 'Gene', (65, 70))	('gastric cancer', 'Disease', 'MESH:D013274', (172, 186))	('gastric cancer', 'Phenotype', 'HP:0012126', (172, 186))	('slug', 'Gene', '6591', (152, 156))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('invasion', 'CPA', (112, 120))	('suppresses', 'NegReg', (81, 91))	('knockdown', 'Var', (71, 80))	('cell proliferation', 'biological_process', 'GO:0008283', ('92', '110'))	('metastasis', 'CPA', (126, 136))	('gastric cancer', 'Disease', (172, 186))	('regulating', 'Reg', (141, 151))	('cell proliferation', 'CPA', (92, 110))	('EMT', 'biological_process', 'GO:0001837', ('165', '168'))
49145	32541526	The possible reasons might include that: Considering the close association of EMT with epithelial and carcinoma stem cell properties, AKIP1 high expression might increase the population of self-renewing tumor initiating cells, further generating tumors; therefore, AKIP1 was upregulated in ccRCC tumor tissues compared with adjacent tissues.	('tumor', 'Disease', (203, 208))	('ccRCC', 'Phenotype', 'HP:0006770', (290, 295))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('upregulated', 'PosReg', (275, 286))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('AKIP1', 'Gene', (134, 139))	('tumors', 'Disease', (246, 252))	('tumor', 'Disease', (296, 301))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('ccRCC tumor', 'Disease', (290, 301))	('carcinoma', 'Disease', (102, 111))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('tumor', 'Disease', 'MESH:D009369', (296, 301))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('increase', 'PosReg', (162, 170))	('AKIP1', 'Gene', '56672', (265, 270))	('generating', 'PosReg', (235, 245))	('tumor', 'Disease', (246, 251))	('RCC', 'Phenotype', 'HP:0005584', (292, 295))	('EMT', 'biological_process', 'GO:0001837', ('78', '81'))	('population', 'CPA', (175, 185))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('ccRCC tumor', 'Disease', 'MESH:D009369', (290, 301))	('AKIP1', 'Gene', (265, 270))	('high expression', 'Var', (140, 155))	('carcinoma', 'Disease', 'MESH:D009369', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('AKIP1', 'Gene', '56672', (134, 139))
49150	32541526	For example, NSCLC patients whose tumor tissues presents high level of AKIP1 have worse 5-year survival and disease-free survival.	('NSCLC', 'Disease', (13, 18))	('5-year survival', 'CPA', (88, 103))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('NSCLC', 'Disease', 'MESH:D002289', (13, 18))	('patients', 'Species', '9606', (19, 27))	('high level', 'Var', (57, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (13, 18))	('AKIP1', 'Gene', '56672', (71, 76))	('disease-free survival', 'CPA', (108, 129))	('AKIP1', 'Gene', (71, 76))	('worse', 'NegReg', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
49154	32541526	Besides, TNM stage was observed to be a predictive factor for unfavorable prognosis in ccRCC patients; therefore, patients with tumor AKPI1 high expression were more likely to have undesirable prognosis.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('high expression', 'Var', (140, 155))	('AKPI1', 'Gene', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('RCC', 'Disease', (89, 92))	('TNM', 'Gene', '10178', (9, 12))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('tumor', 'Disease', (128, 133))	('patients', 'Species', '9606', (114, 122))	('patients', 'Species', '9606', (93, 101))	('TNM', 'Gene', (9, 12))
49156	32541526	According to these prior evidence, AKIP1 high expression might upregulate the expression of mesenchymal markers, but downregulate the expression of epithelial marker, which might activate EMT program and introduce the anti-apoptotic as well as drug-tolerant properties of ccRCC cells, hence, ccRCC patients with tumor AKIP1 high expression might have poor response to anticancer therapy and unfavorable prognosis.	('EMT', 'biological_process', 'GO:0001837', ('188', '191'))	('RCC', 'Disease', (274, 277))	('RCC', 'Phenotype', 'HP:0005584', (274, 277))	('ccRCC', 'Phenotype', 'HP:0006770', (272, 277))	('EMT', 'CPA', (188, 191))	('tumor', 'Disease', (312, 317))	('downregulate', 'NegReg', (117, 129))	('upregulate', 'PosReg', (63, 73))	('activate', 'PosReg', (179, 187))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('high expression', 'Var', (41, 56))	('patients', 'Species', '9606', (298, 306))	('RCC', 'Disease', 'MESH:C538614', (274, 277))	('cancer', 'Disease', (372, 378))	('expression', 'MPA', (134, 144))	('AKIP1', 'Gene', '56672', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (372, 378))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('ccRCC', 'Phenotype', 'HP:0006770', (292, 297))	('AKIP1', 'Gene', '56672', (318, 323))	('RCC', 'Disease', (294, 297))	('RCC', 'Phenotype', 'HP:0005584', (294, 297))	('expression', 'MPA', (78, 88))	('AKIP1', 'Gene', (35, 40))	('RCC', 'Disease', 'MESH:C538614', (294, 297))	('AKIP1', 'Gene', (318, 323))	('cancer', 'Disease', 'MESH:D009369', (372, 378))
49185	32102400	Regarding molecular analyses, the issue remains incomplete when considering VHL gene malfunctions as the hallmark of CCRCC, and the trisomy of chromosomes 7 and 17 as the signature for PRCC.	('VHL', 'Gene', (76, 79))	('VHL', 'Gene', '7428', (76, 79))	('PRCC', 'Disease', 'MESH:C538614', (185, 189))	('CCRCC', 'Disease', (117, 122))	('trisomy', 'Var', (132, 139))	('CCRCC', 'Phenotype', 'HP:0006770', (117, 122))	('PRCC', 'Phenotype', 'HP:0006766', (185, 189))	('CCRCC', 'Disease', 'MESH:C538614', (117, 122))	('malfunctions', 'Var', (85, 97))	('PRCC', 'Disease', (185, 189))
49220	31915049	Chromosomal alterations are usually related with ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('ccRCC', 'Disease', 'MESH:D002292', (49, 54))	('related', 'Reg', (36, 43))	('Chromosomal alterations', 'Var', (0, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('ccRCC', 'Disease', (49, 54))
49221	31915049	The VHL tumor suppressor gene, located in chromosome 3p25.3, is frequently inactivated by deletion, microdeletion, or epigenetic mechanisms in approximately 80% of ccRCC cases.	('deletion', 'Var', (90, 98))	('epigenetic', 'Var', (118, 128))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('VHL', 'Disease', (4, 7))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('VHL', 'Disease', 'MESH:D006623', (4, 7))	('ccRCC', 'Phenotype', 'HP:0006770', (164, 169))	('ccRCC', 'Disease', 'MESH:D002292', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('8', '24'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('8', '24'))	('ccRCC', 'Disease', (164, 169))	('tumor', 'Disease', (8, 13))	('microdeletion', 'Var', (100, 113))	('inactivated', 'NegReg', (75, 86))	('chromosome', 'cellular_component', 'GO:0005694', ('42', '52'))
49223	31915049	Other chromosomal alterations involving translocations and deletions might also be seen in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('ccRCC', 'Disease', (91, 96))	('deletions', 'Var', (59, 68))	('ccRCC', 'Disease', 'MESH:D002292', (91, 96))	('translocations', 'Var', (40, 54))
49240	31915049	Treatment for LS was initiated with a first-line chemotherapy cocktail containing epirubicin (an antineoplastic agent belonging to the group of anthracyclines that intercalates between deoxyribonucleic acid (DNA) base pairs, inhibiting DNA replication and transcription), ifosfamide (an antineoplastic agent belonging to the group of alkylating agents that acts in phase S of the cell cycle, interfering with DNA replication), and mesna (a chemoprotective agent that reduce the risk of developing hemorrhagic cystitis after ifosfamide therapy) (first cycle = 34 days; second cycle = 59 days; third cycle = 85 days).	('DNA', 'cellular_component', 'GO:0005574', ('236', '239'))	('transcription', 'MPA', (256, 269))	('ifosfamide', 'Chemical', 'MESH:D007069', (272, 282))	('intercalates', 'Var', (164, 176))	('DNA', 'cellular_component', 'GO:0005574', ('208', '211'))	('DNA replication', 'biological_process', 'GO:0006260', ('409', '424'))	('deoxyribonucleic acid', 'Chemical', 'MESH:D000596', (185, 206))	('LS', 'Phenotype', 'HP:0012034', (14, 16))	('cell cycle', 'biological_process', 'GO:0007049', ('380', '390'))	('mesna', 'Chemical', 'MESH:D015080', (431, 436))	('DNA', 'cellular_component', 'GO:0005574', ('409', '412'))	('hemorrhagic cystitis', 'Disease', (497, 517))	('inhibiting', 'NegReg', (225, 235))	('transcription', 'biological_process', 'GO:0006351', ('256', '269'))	('hemorrhagic cystitis', 'Disease', 'MESH:D003556', (497, 517))	('ifosfamide', 'Chemical', 'MESH:D007069', (524, 534))	('DNA', 'MPA', (236, 239))	('LS', 'Disease', 'MESH:D008080', (14, 16))	('interfering', 'NegReg', (392, 403))	('epirubicin', 'Chemical', 'MESH:D015251', (82, 92))	('anthracyclines', 'Chemical', 'MESH:D018943', (144, 158))	('DNA replication', 'biological_process', 'GO:0006260', ('236', '251'))	('DNA replication', 'MPA', (409, 424))
49252	31915049	Four mutations were detected in BRCA2: L638FS*9, NF1: R1846FS*17, RB1: deletion exon 24, and TP53: R282W.	('R282W', 'Mutation', 'rs28934574', (99, 104))	('NF1', 'Gene', '4763', (49, 52))	('BRCA2', 'Gene', (32, 37))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('RB1', 'Gene', '5925', (66, 69))	('L638FS*9', 'Var', (39, 47))	('BRCA2', 'Gene', '675', (32, 37))	('deletion exon 24', 'Var', (71, 87))	('NF1', 'Gene', (49, 52))	('R1846FS*17', 'Var', (54, 64))	('RB1', 'Gene', (66, 69))
49253	31915049	None of these mutations has an action indicating a clinical benefit of these histological types of tumors (sarcoma and ccRCC).	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('sarcoma', 'Disease', 'MESH:D012509', (107, 114))	('sarcoma', 'Disease', (107, 114))	('ccRCC', 'Disease', (119, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('tumors', 'Disease', (99, 105))	('ccRCC', 'Disease', 'MESH:D002292', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('mutations', 'Var', (14, 23))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
49269	31915049	Even though its etiology is unknown, it is related to some genetic alterations in the MDM2, HMGA2, and CDK4 genes, which our patient did not have.	('CDK4', 'Gene', '1019', (103, 107))	('HMGA2', 'Gene', '8091', (92, 97))	('HMGA2', 'Gene', (92, 97))	('CDK', 'molecular_function', 'GO:0004693', ('103', '106'))	('patient', 'Species', '9606', (125, 132))	('MDM2', 'Gene', '4193', (86, 90))	('MDM2', 'Gene', (86, 90))	('CDK4', 'Gene', (103, 107))	('genetic alterations', 'Var', (59, 78))
49367	27883021	Identification of aberrant tRNA-halves expression patterns in clear cell renal cell carcinoma Small non-coding RNAs (sncRNA; <200 nt) regulate various cellular processes and modify gene expression.	('gene expression', 'biological_process', 'GO:0010467', ('181', '196'))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (62, 93))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (73, 93))	('cellular processes', 'CPA', (151, 169))	('regulate', 'Reg', (134, 142))	('aberrant', 'Var', (18, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('modify', 'Reg', (174, 180))	('gene expression', 'MPA', (181, 196))	('tRNA', 'molecular_function', 'GO:0030533', ('27', '31'))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (62, 93))	('clear cell renal cell carcinoma', 'Disease', (62, 93))
49391	27883021	miR-142-3p, miR-885-5p, miR-1910-5p, miR-186-3p, miR-4652-5p, miR-6737-3p, miR-508-5p, miR-513c-5p, miR-4485-3p, miR-513a-5p, miR-4461).	('miR-508-5p', 'Var', (75, 85))	('miR-513c', 'Gene', (87, 95))	('miR-1910-5p', 'Var', (24, 35))	('miR-142', 'Gene', (0, 7))	('miR-4461', 'Gene', (126, 134))	('miR-4652-5p', 'Var', (49, 60))	('miR-4485-3p', 'Var', (100, 111))	('miR-186-3p', 'Var', (37, 47))	('miR-4461', 'Gene', '100616209', (126, 134))	('miR-6737-3p', 'Var', (62, 73))	('miR-513c', 'Gene', '100302114', (87, 95))	('miR-513a-5p', 'Var', (113, 124))	('miR-885-5p', 'Var', (12, 22))	('miR-142', 'Gene', '406934', (0, 7))
49398	27883021	As expected from the small RNA sequencing experiments, we noticed significant upregulation of miRNA-122-5p and miRNA-142-3p in ccRCC samples (p < 0.001).	('miRNA-122', 'Gene', '406906', (94, 103))	('RNA', 'cellular_component', 'GO:0005562', ('27', '30'))	('miRNA-122', 'Gene', (94, 103))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('upregulation', 'PosReg', (78, 90))	('RCC', 'Disease', (129, 132))	('miRNA-142-3p', 'Var', (111, 123))
49418	27883021	In eukaryotes, the RNAse Angiogenin produces tRNA-halves through specific cleavage near or in the anticodon loop.	('Angiogenin', 'Gene', (25, 35))	('Angiogenin', 'Gene', '283', (25, 35))	('cleavage', 'Var', (74, 82))	('tRNA', 'molecular_function', 'GO:0030533', ('45', '49'))
49457	27883021	A pre-designed miScript Primer Assay was used to quantify the reference gene SNORD43 (MS00007476) and the target gene miR-122-5p (MS00003416) and miR-142-3p (MS00031451); a custom made miScript Primer Assay (MSC0074992) was used to detect 5'tRNA4-Val-AAC.	('MS00007476', 'Var', (86, 96))	('miR-142', 'Gene', '406934', (146, 153))	('tRNA', 'molecular_function', 'GO:0030533', ('241', '245'))	('miR-142', 'Gene', (146, 153))	('miR-122-5p', 'Gene', (118, 128))	('SNORD43', 'Gene', '26807', (77, 84))	('pre', 'molecular_function', 'GO:0003904', ('2', '5'))	('MS00031451', 'Var', (158, 168))	('AAC', 'Gene', (251, 254))	('AAC', 'Gene', '10249', (251, 254))	('SNORD43', 'Gene', (77, 84))	('miR-122-5p', 'Gene', '100188847', (118, 128))	('MS00003416', 'Var', (130, 140))
49460	27883021	Identification of aberrant tRNA-halves expression patterns in clear cell renal cell carcinoma.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (62, 93))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (73, 93))	('aberrant', 'Var', (18, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('expression', 'MPA', (39, 49))	('tRNA-halves', 'Protein', (27, 38))	('tRNA', 'molecular_function', 'GO:0030533', ('27', '31'))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (62, 93))	('clear cell renal cell carcinoma', 'Disease', (62, 93))
49468	33591959	The high expression of APOC1 was associated with unfavorable prognosis of female patients (P<0.01), but not of male patients.	('APOC1', 'Gene', (23, 28))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (81, 89))	('APOC1', 'Gene', '341', (23, 28))	('high', 'Var', (4, 8))
49469	33591959	APOC1 high expression also shortened the survival time of ccRCC patients age >=60 years old (P<0.05).	('age', 'Gene', '5973', (73, 76))	('survival time', 'CPA', (41, 54))	('patients', 'Species', '9606', (64, 72))	('RCC', 'Disease', (60, 63))	('high expression', 'Var', (6, 21))	('shortened', 'NegReg', (27, 36))	('APOC1', 'Gene', (0, 5))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('age', 'Gene', (73, 76))	('APOC1', 'Gene', '341', (0, 5))
49487	33591959	It was revealed that APOC1 is highly expressed in gastric cancer (GC), and high expression of APOC1 decreased the overall survival (OS) time of patients.	('high expression', 'Var', (75, 90))	('APOC1', 'Gene', '341', (21, 26))	('overall survival', 'MPA', (114, 130))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('gastric cancer', 'Disease', (50, 64))	('APOC1', 'Gene', '341', (94, 99))	('gastric cancer', 'Disease', 'MESH:D013274', (50, 64))	('patients', 'Species', '9606', (144, 152))	('decreased', 'NegReg', (100, 109))	('APOC1', 'Gene', (21, 26))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))	('APOC1', 'Gene', (94, 99))
49527	33591959	The survival analysis showed that high expression of APOC1 was associated with shorter survival time and poor prognosis of patients with kidney cancer (Figure 3C, P=0.024).	('kidney cancer', 'Disease', (137, 150))	('survival', 'MPA', (87, 95))	('APOC1', 'Gene', (53, 58))	('high expression', 'Var', (34, 49))	('shorter', 'NegReg', (79, 86))	('APOC1', 'Gene', '341', (53, 58))	('patients', 'Species', '9606', (123, 131))	('kidney cancer', 'Phenotype', 'HP:0009726', (137, 150))	('kidney cancer', 'Disease', 'MESH:D007680', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
49529	33591959	Our result suggested that the survival time was similar in male and female patients (Figure 4A), high expression of APOC1 was associated with poor prognosis of female patients (P=0.001), but APOC1 high expression was not associated with male survival (P=0.601).	('APOC1', 'Gene', (191, 196))	('patients', 'Species', '9606', (75, 83))	('patients', 'Species', '9606', (167, 175))	('APOC1', 'Gene', (116, 121))	('APOC1', 'Gene', '341', (191, 196))	('APOC1', 'Gene', '341', (116, 121))	('high expression', 'Var', (97, 112))
49530	33591959	Survival time was associated by the age of patients (Figure 4B), high expression of APOC1 was associated with shorter survival time of ccRCC patients age >=60 years (P=0.032), OS was not different in patients with age <60 years (P=0.542).	('age', 'Gene', (150, 153))	('age', 'Gene', (214, 217))	('survival', 'MPA', (118, 126))	('patients', 'Species', '9606', (200, 208))	('APOC1', 'Gene', (84, 89))	('age', 'Gene', '5973', (36, 39))	('patients', 'Species', '9606', (43, 51))	('shorter', 'NegReg', (110, 117))	('APOC1', 'Gene', '341', (84, 89))	('age', 'Gene', '5973', (150, 153))	('age', 'Gene', '5973', (214, 217))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('high expression', 'Var', (65, 80))	('RCC', 'Disease', (137, 140))	('age', 'Gene', (36, 39))	('patients', 'Species', '9606', (141, 149))
49545	33591959	Taken together, these results indicated that the expression of APOC1 was associated with many key clinical features of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('associated', 'Reg', (73, 83))	('expression', 'Var', (49, 59))	('APOC1', 'Gene', (63, 68))	('APOC1', 'Gene', '341', (63, 68))
49555	33591959	A recent study by Cui et al revealed that high expression of APOC1 was correlated with shorter overall survival (P=0.022) and progression-free survival (P=0.007), and APOC1 may serve as a novel diagnostic biomarker for ccRCC.	('progression-free survival', 'CPA', (126, 151))	('RCC', 'Disease', 'MESH:C538614', (221, 224))	('APOC1', 'Gene', (167, 172))	('APOC1', 'Gene', (61, 66))	('RCC', 'Disease', (221, 224))	('shorter', 'NegReg', (87, 94))	('overall survival', 'CPA', (95, 111))	('APOC1', 'Gene', '341', (61, 66))	('APOC1', 'Gene', '341', (167, 172))	('high', 'Var', (42, 46))
49557	33591959	The APOC1 expression was also much higher in prostate cancer tissues than in normal tissues, and APOC1 silencing could inhibit cell proliferation and colony formation, and arrested cell cycle progression.	('silencing', 'Var', (103, 112))	('cell proliferation', 'biological_process', 'GO:0008283', ('127', '145'))	('prostate cancer', 'Disease', 'MESH:D011471', (45, 60))	('APOC1', 'Gene', '341', (97, 102))	('prostate cancer', 'Phenotype', 'HP:0012125', (45, 60))	('formation', 'biological_process', 'GO:0009058', ('157', '166'))	('APOC1', 'Gene', (4, 9))	('inhibit', 'NegReg', (119, 126))	('expression', 'MPA', (10, 20))	('arrested', 'NegReg', (172, 180))	('cell cycle', 'biological_process', 'GO:0007049', ('181', '191'))	('APOC1', 'Gene', '341', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('prostate cancer', 'Disease', (45, 60))	('higher', 'PosReg', (35, 41))	('APOC1', 'Gene', (97, 102))	('cell cycle progression', 'CPA', (181, 203))
49572	33591959	For example, Staphylococcus aureus can induce cell apoptosis, which can trim the immune response by influencing cytokine production and T cell differentiation.	('Staphylococcus aureus', 'Species', '1280', (13, 34))	('immune response', 'CPA', (81, 96))	('cell apoptosis', 'CPA', (46, 60))	('influencing', 'Reg', (100, 111))	('apoptosis', 'biological_process', 'GO:0097194', ('51', '60'))	('apoptosis', 'biological_process', 'GO:0006915', ('51', '60'))	('immune response', 'biological_process', 'GO:0006955', ('81', '96'))	('cytokine production', 'biological_process', 'GO:0001816', ('112', '131'))	('T cell differentiation', 'CPA', (136, 158))	('induce', 'Reg', (39, 45))	('cytokine production', 'MPA', (112, 131))	('Staphylococcus aureus', 'Var', (13, 34))	('trim', 'Reg', (72, 76))	('T cell differentiation', 'biological_process', 'GO:0030217', ('136', '158'))
49585	33591959	It was revealed that APOC1 was highly expressed in ccRCC tissue, and high expression of APOC1 was associated with poor prognosis of patients.	('APOC1', 'Gene', '341', (21, 26))	('APOC1', 'Gene', (88, 93))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('APOC1', 'Gene', '341', (88, 93))	('APOC1', 'Gene', (21, 26))	('high', 'Var', (69, 73))	('associated', 'Reg', (98, 108))	('patients', 'Species', '9606', (132, 140))
49596	33139776	The multivariate analysis revealed mRNA expression of PINK1 and PARK2 as well as PINK1 protein expression as independent prognostic factors for shorter overall survival.	('PINK1', 'Gene', (54, 59))	('mRNA expression', 'Var', (35, 50))	('PARK2', 'Gene', (64, 69))	('PINK1', 'Gene', (81, 86))	('overall survival', 'MPA', (152, 168))	('shorter', 'NegReg', (144, 151))	('protein', 'Protein', (87, 94))	('PINK1', 'Gene', '65018', (81, 86))	('PINK1', 'Gene', '65018', (54, 59))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('PARK2', 'Gene', '5071', (64, 69))
49604	33139776	Type 1 pRCC (basophilic pRCC) often carries MET gene alterations, whereas type 2 (eosinophilic) tumors are associated with CDKN2A silencing, SETD2 mutations, and an increased expression of the NRF2-antioxidant response element (ARE) pathway.	('mutations', 'Var', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('carries', 'Reg', (36, 43))	('NRF2', 'Gene', '4780', (193, 197))	('tumors', 'Disease', (96, 102))	('CDKN2A', 'Gene', (123, 129))	('MET', 'Gene', '79811', (44, 47))	('pRCC', 'Gene', '5546', (24, 28))	('expression', 'MPA', (175, 185))	('silencing', 'NegReg', (130, 139))	('NRF2', 'Gene', (193, 197))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('CDKN2A', 'Gene', '1029', (123, 129))	('pRCC', 'Gene', '5546', (7, 11))	('pRCC', 'Phenotype', 'HP:0006766', (24, 28))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('pRCC', 'Gene', (24, 28))	('SETD2', 'Gene', (141, 146))	('MET', 'Gene', (44, 47))	('pRCC', 'Phenotype', 'HP:0006766', (7, 11))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('pRCC', 'Gene', (7, 11))	('SETD2', 'Gene', '29072', (141, 146))	('increased', 'PosReg', (165, 174))
49610	33139776	Von Hippel-Lindau (VHL) gene inactivation is the most common alteration in sporadic ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('Von Hippel-Lindau', 'Gene', '7428', (0, 17))	('VHL', 'Gene', (19, 22))	('Von Hippel-Lindau', 'Gene', (0, 17))	('VHL', 'Gene', '7428', (19, 22))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('inactivation', 'Var', (29, 41))
49617	33139776	Mitochondrial depolarization causes PINK1 accumulation on the outer mitochondrial membrane, which induces (cytosolic) PARK2 recruitment.	('Mitochondrial depolarization', 'biological_process', 'GO:0051882', ('0', '28'))	('PINK1', 'Gene', (36, 41))	('recruitment', 'MPA', (124, 135))	('induces', 'Reg', (98, 105))	('accumulation', 'PosReg', (42, 54))	('depolarization', 'Var', (14, 28))	('Mitochondrial depolarization', 'Var', (0, 28))	('outer mitochondrial membrane', 'cellular_component', 'GO:0005741', ('62', '90'))	('PARK2', 'Gene', (118, 123))	('PARK2', 'Gene', '5071', (118, 123))	('PINK1', 'Gene', '65018', (36, 41))
49660	33139776	Patients with an increased PINK1 and PARK2 expression (using cutoff dichotomization) had a significantly longer overall survival compared to patients with downregulated PINK1 and PARK2 levels in Kaplan Meier and univariate Cox-analysis (Fig.	('increased', 'PosReg', (17, 26))	('PARK2', 'Gene', '5071', (179, 184))	('longer', 'PosReg', (105, 111))	('PINK1', 'Gene', '65018', (27, 32))	('PARK2', 'Gene', (179, 184))	('expression', 'Var', (43, 53))	('PINK1', 'Gene', (27, 32))	('PINK1', 'Gene', '65018', (169, 174))	('Patients', 'Species', '9606', (0, 8))	('PARK2', 'Gene', '5071', (37, 42))	('PARK2', 'Gene', (37, 42))	('overall survival', 'CPA', (112, 128))	('PINK1', 'Gene', (169, 174))	('patients', 'Species', '9606', (141, 149))
49693	33139776	The consequences of PARK2 and PINK1 dysregulation in cancer are not fully elucidated.	('dysregulation', 'Var', (36, 49))	('PINK1', 'Gene', (30, 35))	('PARK2', 'Gene', (20, 25))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('PINK1', 'Gene', '65018', (30, 35))	('PARK2', 'Gene', '5071', (20, 25))
49695	33139776	PARK2 mutations affect the PINK1/PARK2 mitophagy axis in lung cancer due to slower clearance of damaged mitochondria.	('PINK1', 'Gene', '65018', (27, 32))	('PARK2', 'Gene', (0, 5))	('mitophagy', 'biological_process', 'GO:0000423', ('39', '48'))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mitochondria', 'cellular_component', 'GO:0005739', ('104', '116'))	('lung cancer', 'Disease', (57, 68))	('clearance of damaged mitochondria', 'MPA', (83, 116))	('PINK1', 'Gene', (27, 32))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('affect', 'Reg', (16, 22))	('PARK2', 'Gene', '5071', (33, 38))	('slower', 'NegReg', (76, 82))	('PARK2', 'Gene', (33, 38))	('mitophagy', 'biological_process', 'GO:0000422', ('39', '48'))	('mutations', 'Var', (6, 15))	('PARK2', 'Gene', '5071', (0, 5))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
49696	33139776	Morever, dysregulation of the PINK1/PARK2 axis accelerates KRAS-mediated carcinogenesis in pancreatic cancer.	('KRAS', 'Gene', '3845', (59, 63))	('carcinogenesis', 'Disease', (73, 87))	('PINK1', 'Gene', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('KRAS', 'Gene', (59, 63))	('accelerates', 'PosReg', (47, 58))	('PARK2', 'Gene', (36, 41))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('carcinogenesis', 'Disease', 'MESH:D063646', (73, 87))	('PARK2', 'Gene', '5071', (36, 41))	('pancreatic cancer', 'Disease', (91, 108))	('dysregulation', 'Var', (9, 22))	('PINK1', 'Gene', '65018', (30, 35))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))
49720	32688345	In this study, we systematically analyzed the differential expression and genetic alterations in ferroptosis-related genes (FRGs) in 32 cancer types.	('ferroptosis', 'biological_process', 'GO:0097707', ('97', '108'))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('FRGs', 'Gene', (124, 128))	('cancer', 'Disease', (136, 142))	('genetic alterations', 'Var', (74, 93))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
49726	32688345	Ferroptosis is also triggered by perturbations in lipid metabolism.	('lipid metabolism', 'biological_process', 'GO:0006629', ('50', '66'))	('perturbations', 'Var', (33, 46))	('triggered by', 'Reg', (20, 32))	('lipid metabolism', 'MPA', (50, 66))	('Ferroptosis', 'Disease', (0, 11))	('Ferroptosis', 'biological_process', 'GO:0097707', ('0', '11'))	('lipid', 'Chemical', 'MESH:D008055', (50, 55))
49727	32688345	We then used the GSCA database to determine the single nucleotide variations (SNV) and copy number variations (CNV) in the 36 FRGs in the 32 cancer types.	('copy number variations', 'Var', (87, 109))	('FRGs', 'Gene', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('single nucleotide variations', 'Var', (48, 76))	('cancer', 'Disease', (141, 147))
49729	32688345	The average mutation rate of TP53 was the highest among all FRGs at 82%; majority of the genetic aberrations were missense mutations and were more common in lung adenocarcinoma (LUAD) and squamous cell carcinoma(LUSC) (Supplementary Figure 1A, 1B).	('common', 'Reg', (147, 153))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (188, 211))	('LUAD', 'Phenotype', 'HP:0030078', (178, 182))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (157, 176))	('TP53', 'Gene', '7157', (29, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('TP53', 'Gene', (29, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (188, 211))	('lung adenocarcinoma', 'Disease', (157, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('squamous cell carcinoma', 'Disease', (188, 211))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (157, 176))	('missense mutations', 'Var', (114, 132))
49730	32688345	We also analyzed the CNVs in the FRGs among the 32 cancer types and found heterozygous mutations in TP53 and ALOX15B and heterozygous amplifications in RPL8 and PTGS2 (Supplementary Figure 1C).	('RPL8', 'Gene', (152, 156))	('TP53', 'Gene', '7157', (100, 104))	('PTGS2', 'Gene', '5743', (161, 166))	('RPL8', 'Gene', '6132', (152, 156))	('PTGS', 'biological_process', 'GO:0016441', ('161', '165'))	('ALOX15B', 'Gene', (109, 116))	('TP53', 'Gene', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('ALOX15B', 'Gene', '247', (109, 116))	('cancer', 'Disease', (51, 57))	('PTGS2', 'Gene', (161, 166))	('mutations', 'Var', (87, 96))
49763	32688345	CCK8 proliferation assay shows that CARS knockdown 786-O cells showed significant reduction in proliferation compared to the control 786-O cells (Figure 7D).	('reduction', 'NegReg', (82, 91))	('CARS', 'Gene', (36, 40))	('proliferation', 'CPA', (95, 108))	('knockdown', 'Var', (41, 50))	('CARS', 'Gene', '833', (36, 40))
49799	30792476	This hypervascularity is attributed to the frequent inactivation of the Von Hippel-Lindau gene, which leads to activation of the Hypoxia Inducible Factor (HIF) pathway and the subsequent release of vascularizing growth factors: Vascular Endothelial Growth Factor (VEGF), platelet-derived growth factor beta (PDGFbeta), and transforming growth factor alpha (TGFalpha).	('Hypoxia', 'Disease', 'MESH:D000860', (129, 136))	('Hypoxia', 'Disease', (129, 136))	('Vascular Endothelial Growth Factor', 'Gene', '7422', (228, 262))	('release', 'MPA', (187, 194))	('VEGF', 'Gene', '7422', (264, 268))	('inactivation', 'Var', (52, 64))	('transforming growth factor alpha', 'Gene', (323, 355))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('271', '301'))	('transforming growth factor alpha', 'Gene', '7124', (323, 355))	('activation', 'PosReg', (111, 121))	('VEGF', 'Gene', (264, 268))	('PDGFbeta', 'Gene', '5155', (308, 316))	('Von Hippel-Lindau', 'Disease', (72, 89))	('PDGFbeta', 'Gene', (308, 316))	('Vascular Endothelial Growth Factor', 'Gene', (228, 262))	('Von Hippel-Lindau', 'Disease', 'MESH:D006623', (72, 89))	('TGFalpha', 'Gene', (357, 365))	('Vascular Endothelial Growth Factor', 'molecular_function', 'GO:0005172', ('228', '262'))	('transforming growth factor alpha', 'molecular_function', 'GO:0005154', ('323', '355'))
49824	30792476	The input for these analyses were: VHL mutation/methylation status, tumour stage, mRNA subtype (as identified in the original TCGA analysis using hierarchical clustering analysis), and the 3 most frequent chromosomal alterations observed in ccRCC: loss of chromosome 3p (i.a.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('loss', 'Var', (248, 252))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (241, 246))	('tumour', 'Disease', (68, 74))	('chromosome', 'cellular_component', 'GO:0005694', ('256', '266'))	('RCC', 'Phenotype', 'HP:0005584', (243, 246))	('VHL', 'Gene', (35, 38))	('ccRCC', 'Disease', (241, 246))	('VHL', 'Gene', '7428', (35, 38))
49832	30792476	The 4 variables mRNA subtype, loss of chromosome 3p, gain of chromosome 5q and loss of chromosome 14q are significantly associated with the mean connectivity score of PX-12/CAY-10585 and estimated tumour purity (Adj.	('CAY-10585', 'Chemical', '-', (173, 182))	('chromosome', 'cellular_component', 'GO:0005694', ('87', '97'))	('loss', 'Var', (79, 83))	('tumour purity', 'Disease', 'MESH:D009369', (197, 210))	('connectivity score', 'MPA', (145, 163))	('chromosome', 'cellular_component', 'GO:0005694', ('38', '48'))	('tumour purity', 'Disease', (197, 210))	('gain', 'PosReg', (53, 57))	('chromosome', 'cellular_component', 'GO:0005694', ('61', '71'))	('PX-12', 'Chemical', 'MESH:C412893', (167, 172))	('loss', 'Var', (30, 34))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))
49833	30792476	Furthermore, the number of chromosomally altered genes which regulate p53 and the G1/S cell cycle transition is associated with the mean connectivity score of PX-12/CAY-10585 (Adj.	('PX-12', 'Chemical', 'MESH:C412893', (159, 164))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('CAY-10585', 'Chemical', '-', (165, 174))	('G1/S cell cycle transition', 'CPA', (82, 108))	('PX-12/CAY-10585', 'Var', (159, 174))	('cell cycle transition', 'biological_process', 'GO:0044770', ('87', '108'))	('associated', 'Reg', (112, 122))	('cell cycle transition', 'biological_process', 'GO:0044771', ('87', '108'))
49837	30792476	In addition, each chromosomal alteration in p53 associated genes increases the mean connectivity score by an average of 0.013 points per alteration (P = 1.8 x 10-9).	('increases', 'PosReg', (65, 74))	('connectivity', 'MPA', (84, 96))	('chromosomal alteration', 'Var', (18, 40))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))
49838	30792476	This is likely caused by the fact that the number of chromosomal alterations in p53 associated genes is strongly positively associated with the number of genes in the tumour sample signature (Fig.	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('tumour', 'Disease', (167, 173))	('p53', 'Gene', (80, 83))	('positively', 'PosReg', (113, 123))	('associated', 'Reg', (124, 134))	('chromosomal alterations', 'Var', (53, 76))	('p53', 'Gene', '7157', (80, 83))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))
49840	30792476	Furthermore, note that although VHL mutation/methylation was not predictive when all samples were analysed together, it was predictive in the subset of 36 samples which did not lose chromosome 3p and which had mutation/methylation data available (Fig.	('VHL', 'Gene', (32, 35))	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('methylation', 'biological_process', 'GO:0032259', ('219', '230'))	('VHL', 'Gene', '7428', (32, 35))	('chromosome', 'cellular_component', 'GO:0005694', ('182', '192'))	('predictive', 'Reg', (124, 134))	('mutation/methylation', 'Var', (36, 56))
49842	30792476	The 2nd strongest effect size with regard to predicting estimated tumour purity was loss of chromosome 3p, estimated to decrease the estimated tumour purity by an average of 4.2% (P = 0.02).	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('tumour purity', 'Disease', 'MESH:D009369', (143, 156))	('tumour purity', 'Disease', (66, 79))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('decrease', 'NegReg', (120, 128))	('chromosome', 'cellular_component', 'GO:0005694', ('92', '102'))	('tumour purity', 'Disease', 'MESH:D009369', (66, 79))	('loss', 'Var', (84, 88))	('tumour purity', 'Disease', (143, 156))
49843	30792476	Loss of chromosome 14q (-2.5%, P = 0.03) and loss of chromosome 14q (-3.1%, P = 0.007) further contribute to decreases in estimated tumour purity.	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('loss', 'Var', (45, 49))	('tumour purity', 'Disease', (132, 145))	('Loss', 'NegReg', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('chromosome', 'cellular_component', 'GO:0005694', ('53', '63'))	('tumour purity', 'Disease', 'MESH:D009369', (132, 145))	('decreases', 'NegReg', (109, 118))
49845	30792476	In summary, the 2 most frequent chromosomal alterations observed in ccRCC (3p loss and 5q gain, observed in 87% and 59% of samples respectively) are associated with both HIF activation (as evidenced by on average more negative connectivity scores with HIF inhibitors) and decreased estimated tumour purity regardless of analysis method (univariate non-parametric, multivariable regression using backward elimination and multivariable regression with all 7 preselected variables in the model including all possible sources of batch effects).	('connectivity scores', 'MPA', (227, 246))	('HIF', 'CPA', (170, 173))	('tumour purity', 'Disease', (292, 305))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('decreased', 'NegReg', (272, 281))	('tumour', 'Phenotype', 'HP:0002664', (292, 298))	('gain', 'PosReg', (90, 94))	('ccRCC', 'Disease', (68, 73))	('alterations', 'Var', (44, 55))	('loss', 'NegReg', (78, 82))	('tumour purity', 'Disease', 'MESH:D009369', (292, 305))	('activation', 'PosReg', (174, 184))	('negative', 'NegReg', (218, 226))
49850	30792476	Lastly, the 12 samples which upon histopathological re-evaluation were still considered ccRCC or unconventional ccRCC had lower median connectivity scores with PX-12 and CAY-10585 than the 12 samples deemed non-ccRCC (P = 0.03, Wilcoxon rank-sum test).	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('lower', 'NegReg', (122, 127))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('ccRCC', 'Disease', (88, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (211, 216))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('CAY-10585', 'Var', (170, 179))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	('PX-12', 'Chemical', 'MESH:C412893', (160, 165))	('CAY-10585', 'Chemical', '-', (170, 179))
49856	30792476	By studying predictors of the probability of HIF-activation in samples (with the mean connectivity score of PX-12 and CAY-10585 as the dependent variable), we learned that it can be attributed to two main underlying causes: Firstly, observing HIF-activation depends on inactivation of the VHL gene due to loss of chromosome 3p (Table 2) or, in samples with an intact chromosome 3p, mutation or methylation of the VHL gene (Fig.	('VHL', 'Gene', (413, 416))	('VHL', 'Gene', '7428', (289, 292))	('inactivation', 'NegReg', (269, 281))	('VHL', 'Gene', '7428', (413, 416))	('PX-12', 'Chemical', 'MESH:C412893', (108, 113))	('methylation', 'Var', (394, 405))	('methylation', 'biological_process', 'GO:0032259', ('394', '405'))	('chromosome', 'cellular_component', 'GO:0005694', ('313', '323'))	('mutation', 'Var', (382, 390))	('chromosome', 'cellular_component', 'GO:0005694', ('367', '377'))	('CAY-10585', 'Chemical', '-', (118, 127))	('VHL', 'Gene', (289, 292))
49857	30792476	Secondly, observing HIF-activation can be interfered with by other factors, the most biologically plausible factor being deletions of negative regulators and gains of positive regulators in the genes that regulate p53 and the G1/S cell cycle transition.	('cell cycle transition', 'biological_process', 'GO:0044771', ('231', '252'))	('p53', 'Gene', (214, 217))	('cell cycle transition', 'biological_process', 'GO:0044770', ('231', '252'))	('deletions', 'Var', (121, 130))	('G1/S cell cycle transition', 'CPA', (226, 252))	('p53', 'Gene', '7157', (214, 217))	('gains', 'PosReg', (158, 163))
49858	30792476	These copy number alterations result in many more genes differentially expressed in the tumour samples (Fig.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('result', 'Reg', (30, 36))	('tumour', 'Disease', (88, 94))	('copy number alterations', 'Var', (6, 29))	('differentially', 'Reg', (56, 70))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))
49864	30792476	After mRNA subtype, loss of chromosome 3p, associated with increased HIF-activation, had the strongest single effect of any variable (4.2% reduction in estimated tumour purity).	('HIF-activation', 'MPA', (69, 83))	('loss', 'Var', (20, 24))	('reduction', 'NegReg', (139, 148))	('tumour purity', 'Disease', (162, 175))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('tumour purity', 'Disease', 'MESH:D009369', (162, 175))	('increased', 'PosReg', (59, 68))	('chromosome', 'cellular_component', 'GO:0005694', ('28', '38'))
49865	30792476	When we compared our gene expression-based results to the methylome clustering results produced by Winter et al., we found that the 24 samples with papillary-like and chromophobe-like methylomes, similar to samples with lower probability of HIF-activation, had a higher median estimated tumour purity as well as a lower rate of chromosome 3p loss.	('higher', 'PosReg', (263, 269))	('tumour purity', 'Disease', 'MESH:D009369', (287, 300))	('methylomes', 'Var', (184, 194))	('chromosome', 'cellular_component', 'GO:0005694', ('328', '338'))	('papillary-like', 'Var', (148, 162))	('lower', 'NegReg', (314, 319))	('gene expression', 'biological_process', 'GO:0010467', ('21', '36'))	('loss', 'NegReg', (342, 346))	('tumour', 'Phenotype', 'HP:0002664', (287, 293))	('tumour purity', 'Disease', (287, 300))	('chromosome 3p', 'CPA', (328, 341))
49870	30792476	To conclusively answer this question and explore new hypotheses, it would require a large single cell RNA-seq dataset of the ccRCC tumour micro-environment from many different patients, so that the impact of variation in cancer cell genetic identity (i.e.	('patients', 'Species', '9606', (176, 184))	('tumour', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', (221, 227))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('RNA', 'cellular_component', 'GO:0005562', ('102', '105'))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('ccRCC', 'Phenotype', 'HP:0006770', (125, 130))	('variation', 'Var', (208, 217))
49879	30792476	In summary, CPE is based on 3 different data types and algorithms: copy number data (ABSOLUTE), methylation data (LUMP) and transcriptomic data (ESTIMATE).	('methylation', 'MPA', (96, 107))	('copy number', 'Var', (67, 78))	('methylation', 'biological_process', 'GO:0032259', ('96', '107'))	('CPE', 'Gene', (12, 15))	('CPE', 'Gene', '1363', (12, 15))
49892	30792476	VHL was considered methylated if the beta value for probe cg15267345 exceeded 0.2 (as in previous methylation analyses).	('VHL', 'Gene', '7428', (0, 3))	('methylation', 'biological_process', 'GO:0032259', ('98', '109'))	('VHL', 'Gene', (0, 3))	('cg15267345', 'Var', (58, 68))
49894	30792476	The following variables were investigated for their association with observed HIF activation (for which we used negative connectivity scores with the HIF inhibitors PX-12 and CAY-10585 as a proxy) and estimated tumour purity: Estimated tumour purity, VHL mutation/methylation status, tumour stage, mRNA subtype, loss of chromosome 3p, gain of chromosome 5q, loss of chromosome 14q and number of chromosomal alterations in the p53 and the G1/S cell cycle transition pathway.	('tumour', 'Disease', 'MESH:D009369', (236, 242))	('tumour', 'Disease', 'MESH:D009369', (284, 290))	('chromosomal alterations', 'Var', (395, 418))	('tumour', 'Disease', (236, 242))	('tumour', 'Disease', (284, 290))	('tumour purity', 'Disease', (211, 224))	('chromosome', 'cellular_component', 'GO:0005694', ('320', '330'))	('VHL', 'Gene', (251, 254))	('tumour purity', 'Disease', (236, 249))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))	('tumour', 'Disease', 'MESH:D009369', (211, 217))	('cell cycle transition', 'biological_process', 'GO:0044771', ('443', '464'))	('mutation/methylation', 'Var', (255, 275))	('tumour', 'Disease', (211, 217))	('G1/S cell cycle transition pathway', 'Pathway', (438, 472))	('loss', 'NegReg', (312, 316))	('chromosome', 'cellular_component', 'GO:0005694', ('366', '376'))	('VHL', 'Gene', '7428', (251, 254))	('gain', 'PosReg', (335, 339))	('p53', 'Gene', '7157', (426, 429))	('CAY-10585', 'Chemical', '-', (175, 184))	('tumour purity', 'Disease', 'MESH:D009369', (211, 224))	('methylation', 'biological_process', 'GO:0032259', ('264', '275'))	('PX-12', 'Chemical', 'MESH:C412893', (165, 170))	('p53', 'Gene', (426, 429))	('tumour purity', 'Disease', 'MESH:D009369', (236, 249))	('loss', 'Var', (358, 362))	('chromosome', 'cellular_component', 'GO:0005694', ('343', '353'))	('tumour', 'Phenotype', 'HP:0002664', (236, 242))	('cell cycle transition', 'biological_process', 'GO:0044770', ('443', '464'))	('tumour', 'Phenotype', 'HP:0002664', (284, 290))
49908	28918350	In human RCC tumor samples, high cytoplasmic BNIP3 expression was associated with high-grade RCCs and regional lymph node metastasis.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC tumor', 'Disease', (9, 18))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Disease', (93, 96))	('human', 'Species', '9606', (3, 8))	('RCC', 'Disease', 'MESH:C538614', (9, 12))	('RCCs', 'Phenotype', 'HP:0005584', (93, 97))	('RCC', 'Disease', (9, 12))	('associated', 'Reg', (66, 76))	('RCC', 'Phenotype', 'HP:0005584', (9, 12))	('high cytoplasmic', 'Var', (28, 44))	('regional lymph node metastasis', 'CPA', (102, 132))	('RCC tumor', 'Disease', 'MESH:C538614', (9, 18))	('BNIP3', 'Gene', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('BNIP3', 'Gene', '664', (45, 50))
49913	28918350	Moreover, BNIP3 overexpression was reported to induce delayed cell death in cell lines.	('BNIP3', 'Gene', (10, 15))	('BNIP3', 'Gene', '664', (10, 15))	('overexpression', 'Var', (16, 30))	('cell death', 'biological_process', 'GO:0008219', ('62', '72'))	('delayed cell death', 'CPA', (54, 72))
49919	28918350	Overexpression of BNIP3 is frequently observed in human malignancies and association with aggressive tumor biology, and poor clinical outcome has been described in salivary gland adenoid cystic carcinoma, endometrial cancer, ductal carcinoma in situ of the breast, and cervical cancer.	('aggressive tumor', 'Disease', 'MESH:D001523', (90, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('Overexpression', 'Var', (0, 14))	('cervical cancer', 'Disease', 'MESH:D002583', (269, 284))	('endometrial cancer', 'Phenotype', 'HP:0012114', (205, 223))	('human', 'Species', '9606', (50, 55))	('cervical cancer', 'Disease', (269, 284))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('aggressive tumor', 'Disease', (90, 106))	('endometrial cancer', 'Disease', (205, 223))	('BNIP3', 'Gene', (18, 23))	('malignancies', 'Disease', (56, 68))	('endometrial cancer', 'Disease', 'MESH:D016889', (205, 223))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (225, 249))	('salivary gland adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (164, 203))	('BNIP3', 'Gene', '664', (18, 23))	('ductal carcinoma', 'Disease', (225, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('association', 'Reg', (73, 84))	('salivary gland adenoid cystic carcinoma', 'Disease', (164, 203))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('ductal carcinoma', 'Disease', 'MESH:D044584', (225, 241))
49920	28918350	In contrast, high BNIP3 expression is associated with favorable outcome in invasive human breast cancer and laryngeal cancer.	('laryngeal cancer', 'Disease', (108, 124))	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (108, 124))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('BNIP3', 'Gene', (18, 23))	('human', 'Species', '9606', (84, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('BNIP3', 'Gene', '664', (18, 23))	('laryngeal cancer', 'Disease', 'MESH:D007822', (108, 124))
49931	28918350	Antibodies were obtained as follows: anti-actin (Sigma Aldrich, Munich, Germany; A5441) and anti-BNIP3 (R&D Systems, Wiesbaden, Germany, AF4147).	('BNIP3', 'Gene', '664', (97, 102))	('A5441', 'Var', (81, 86))	('BNIP3', 'Gene', (97, 102))
49932	28918350	CoCl2 (60818), etoposide (E1383), and staurosporine (4400) were obtained from Sigma Aldrich.	('E1383', 'Chemical', '-', (26, 31))	('etoposide', 'Chemical', 'MESH:D005047', (15, 24))	('CoCl2', 'Chemical', 'MESH:C018021', (0, 5))	('staurosporine', 'Chemical', 'MESH:D019311', (38, 51))	('E1383', 'Var', (26, 31))	('60818', 'Var', (7, 12))
49963	28918350	We observed a statistically significant association of high cytoplasmic BNIP3 expression (defined as IHS >= 6) with reduced cancer specific survival compared to tumors with low cytoplasmic or nuclear BNIP3 expression (Figure 2A).	('BNIP3', 'Gene', '664', (200, 205))	('cancer', 'Disease', (124, 130))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('BNIP3', 'Gene', '664', (72, 77))	('high cytoplasmic', 'Var', (55, 71))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('BNIP3', 'Gene', (72, 77))	('reduced', 'NegReg', (116, 123))	('BNIP3', 'Gene', (200, 205))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
49971	28918350	These results suggest that high BNIP3 expression is an independent prognostic factor for poor cancer-specific survival in ccRCC patients with nonmetastasized disease.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('BNIP3', 'Gene', '664', (32, 37))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('expression', 'MPA', (38, 48))	('high', 'Var', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('poor', 'NegReg', (89, 93))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('patients', 'Species', '9606', (128, 136))	('cancer', 'Disease', (94, 100))	('BNIP3', 'Gene', (32, 37))
49974	28918350	Silencing of BNIP3 by siRNA increased cell death induced by serum depletion, staurosporine, etoposide, and CoCl2, a hypoxia-mimetic agent (Figure 3B).	('increased', 'PosReg', (28, 37))	('hypoxia', 'Disease', (116, 123))	('hypoxia', 'Disease', 'MESH:D000860', (116, 123))	('BNIP3', 'Gene', (13, 18))	('etoposide', 'Chemical', 'MESH:D005047', (92, 101))	('staurosporine', 'Chemical', 'MESH:D019311', (77, 90))	('cell death', 'CPA', (38, 48))	('serum depletion', 'MPA', (60, 75))	('BNIP3', 'Gene', '664', (13, 18))	('CoCl2', 'Chemical', 'MESH:C018021', (107, 112))	('Silencing', 'Var', (0, 9))	('cell death', 'biological_process', 'GO:0008219', ('38', '48'))
49981	28918350	Importantly, multivariate analysis revealed that high BNIP3 expression was an independent prognostic factor for cancer-specific survival in ccRCC patients without distant metastasis.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('BNIP3', 'Gene', (54, 59))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('BNIP3', 'Gene', '664', (54, 59))	('high', 'Var', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('patients', 'Species', '9606', (146, 154))
49983	28918350	Our functional analysis showed increased cell death and reduced clonogenicity upon silencing of BNIP3 and vice versa increased clonogenicity upon stable overexpression, indicating protumorigenic effects of BNIP3 in RCC cell lines.	('increased', 'PosReg', (117, 126))	('increased', 'PosReg', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('RCC', 'Disease', 'MESH:C538614', (215, 218))	('reduced', 'NegReg', (56, 63))	('RCC', 'Disease', (215, 218))	('clonogenicity', 'CPA', (127, 140))	('RCC', 'Phenotype', 'HP:0005584', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cell death', 'biological_process', 'GO:0008219', ('41', '51'))	('cell death', 'CPA', (41, 51))	('BNIP3', 'Gene', (96, 101))	('tumor', 'Disease', (183, 188))	('BNIP3', 'Gene', (206, 211))	('BNIP3', 'Gene', '664', (96, 101))	('clonogenicity', 'CPA', (64, 77))	('BNIP3', 'Gene', '664', (206, 211))	('silencing', 'Var', (83, 92))
49992	33510822	A Risk Score Model Based on Nine Differentially Methylated mRNAs for Predicting Prognosis of Patients with Clear Cell Renal Cell Carcinoma DNA methylation alterations play important roles in initiation and progression of clear cell renal cell carcinoma (ccRCC).	('Patients', 'Species', '9606', (93, 101))	('Carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (107, 138))	('alterations', 'Var', (155, 166))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (221, 252))	('clear cell renal cell carcinoma', 'Disease', (221, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('Clear Cell Renal Cell Carcinoma', 'Disease', (107, 138))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (107, 138))	('ccRCC', 'Phenotype', 'HP:0006770', (254, 259))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (118, 138))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (221, 252))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (232, 252))	('DNA methylation', 'biological_process', 'GO:0006306', ('139', '154'))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (232, 252))
50003	33510822	Methylation of DMRTA2 is associated with survival of patients with triple-negative breast cancer.	('associated', 'Reg', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Methylation', 'Var', (0, 11))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('DMRTA2', 'Gene', (15, 21))	('breast cancer', 'Disease', (83, 96))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))
50006	33510822	FAM167A, also namely C8orf13, belongs to the FAM167 (SEC) family.	('FAM167A', 'Var', (0, 7))	('C8orf13', 'Gene', '83648', (21, 28))	('C8orf13', 'Gene', (21, 28))
50007	33510822	The polymorphisms of FAM167A-BLK region are linked to susceptibility of autoimmune diseases.	('autoimmune diseases', 'Disease', 'MESH:D001327', (72, 91))	('autoimmune diseases', 'Disease', (72, 91))	('polymorphisms', 'Var', (4, 17))	('BLK', 'Gene', '640', (29, 32))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (72, 91))	('linked', 'Reg', (44, 50))	('BLK', 'Gene', (29, 32))
50016	33510822	Aberrant methylation of UBE2QL1 has been found in HBV-related hepatocellular carcinoma.	('found', 'Reg', (41, 46))	('hepatocellular carcinoma', 'Disease', (62, 86))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (62, 86))	('Aberrant', 'Var', (0, 8))	('HBV-related', 'Gene', (50, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('UBE2QL1', 'Gene', (24, 31))	('methylation', 'MPA', (9, 20))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (62, 86))
50023	31713264	Kaplan-Meier curve showed that patients with integrin alpha7 high expression (mean OS = 69.8, 95%CI: 60.5-79.1 months) presented with worse OS compared to patients with integrin alpha7 low expression (mean OS = 101.8, 95%CI: 96.0-107.7 months; P < .001).	('integrin alpha7', 'Gene', '3679', (45, 60))	('high expression', 'Var', (61, 76))	('integrin alpha7', 'Gene', (169, 184))	('integrin alpha7', 'Gene', '3679', (169, 184))	('patients', 'Species', '9606', (31, 39))	('patients', 'Species', '9606', (155, 163))	('integrin alpha7', 'Gene', (45, 60))
50064	31713264	For example, integrin alpha7 interacts with S100P to promote cells migration and cells invasion in lung carcinoma.10 Another mechanistic study discloses that integrin alpha7 induces cells migration and invasion abilities via the activation of epithelial-mesenchymal transition (EMT) in OSCC.6 In addition, parts of previous studies have revealed that integrin alpha7 possesses effect on regulating stemness of cancer cells.	('invasion abilities', 'CPA', (202, 220))	('cells migration', 'CPA', (182, 197))	('integrin alpha7', 'Gene', (158, 173))	('cancer', 'Phenotype', 'HP:0002664', (410, 416))	('induces', 'PosReg', (174, 181))	('integrin alpha7', 'Gene', '3679', (351, 366))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('S100P', 'SUBSTITUTION', 'None', (44, 49))	('integrin alpha7', 'Gene', (13, 28))	('lung carcinoma', 'Disease', (99, 113))	('integrin alpha7', 'Gene', '3679', (158, 173))	('integrin alpha7', 'Gene', (351, 366))	('S100P', 'Var', (44, 49))	('stemness of cancer', 'Disease', 'MESH:D009369', (398, 416))	('lung carcinoma', 'Disease', 'MESH:D008175', (99, 113))	('EMT', 'biological_process', 'GO:0001837', ('278', '281'))	('integrin alpha7', 'Gene', '3679', (13, 28))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('243', '276'))	('stemness of cancer', 'Disease', (398, 416))
50095	31661117	Dysregulated miRNAs have been demonstrated to influence multiple processes in cancer cells, such as proliferation, migration and chemoresistance.	('influence', 'Reg', (46, 55))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('migration', 'CPA', (115, 124))	('cancer', 'Disease', (78, 84))	('proliferation', 'CPA', (100, 113))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('chemoresistance', 'CPA', (129, 144))	('Dysregulated', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
50096	31661117	Recently, several investigations found that differentially expressed miRNAs in cancer cells could also affect the steady abundance of stable miRNAs in the peripheral blood.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('differentially', 'Var', (44, 58))	('miR', 'Gene', '220972', (141, 144))	('miR', 'Gene', '220972', (69, 72))	('miR', 'Gene', (141, 144))	('miR', 'Gene', (69, 72))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('affect', 'Reg', (103, 109))
50102	31661117	We identified dysregulated serum miR-508-3p and miR-885-5p as novel potential diagnostic biomarkers for ccRCC.	('ccRCC', 'Disease', 'MESH:D002292', (104, 109))	('dysregulated', 'Var', (14, 26))	('miR-885', 'Gene', '100126334', (48, 55))	('miR-508', 'Gene', (33, 40))	('miR-508', 'Gene', '574513', (33, 40))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('miR-885', 'Gene', (48, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))	('ccRCC', 'Disease', (104, 109))
50115	31661117	miRNAs with log FC  >1 and P<0.05 were regarded as dysregulated miRNAs.	('miR', 'Gene', '220972', (64, 67))	('miR', 'Gene', (64, 67))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('log FC  >1', 'Var', (12, 22))
50125	31661117	1, 82 upregulated miRNAs and 122 downregulated miRNAs were found in GSE109368.	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('upregulated', 'PosReg', (6, 17))	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (18, 21))	('GSE109368', 'Var', (68, 77))	('downregulated', 'NegReg', (33, 46))
50178	30824757	The uremic toxin p-cresyl sulfate induces proliferation and migration of clear cell renal cell carcinoma via microRNA-21/ HIF-1alpha axis signals p-Cresyl sulfate (pCS), a uremic toxin, can cause renal damage and dysfunction.	('microRNA-21', 'Gene', '406991', (109, 120))	('cresyl sulfate', 'Chemical', '-', (19, 33))	('clear cell renal cell carcinoma', 'Disease', (73, 104))	('pCS', 'Chemical', 'MESH:C408690', (164, 167))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (73, 104))	('HIF-1alpha', 'Gene', '3091', (122, 132))	('p-Cresyl sulfate', 'Chemical', 'MESH:C408690', (146, 162))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (84, 104))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (73, 104))	('renal damage and dysfunction', 'Disease', 'MESH:D007674', (196, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('p-Cresyl', 'Var', (146, 154))	('migration', 'CPA', (60, 69))	('HIF-1alpha', 'Gene', (122, 132))	('microRNA-21', 'Gene', (109, 120))	('cause', 'Reg', (190, 195))
50181	30824757	Clear cell renal cell carcinoma (ccRCC) expresses mutant von Hippel-Lindau gene and is difficult to treat.	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (57, 74))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('mutant', 'Var', (50, 56))	('von Hippel-Lindau', 'Disease', (57, 74))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))
50187	30824757	Specifically, inhibition of miR-21 blocked pCS-induced proliferation and migration.	('migration', 'CPA', (73, 82))	('rat', 'Species', '10116', (76, 79))	('miR-21', 'Gene', (28, 34))	('pCS-induced', 'Disease', (43, 54))	('inhibition', 'Var', (14, 24))	('rat', 'Species', '10116', (62, 65))	('pCS', 'Chemical', 'MESH:C408690', (43, 46))	('blocked', 'NegReg', (35, 42))	('miR-21', 'Gene', '406991', (28, 34))
50194	30824757	However, in most ccRCC cases, VHL is mutated and deficient.	('VHL', 'Gene', (30, 33))	('VHL', 'Gene', '7428', (30, 33))	('deficient', 'NegReg', (49, 58))	('ccRCC', 'Disease', (17, 22))	('mutated', 'Var', (37, 44))
50204	30824757	Accumulation of pCS causes renal dysfunction and disease progression by inducing oxidative damage and endothelial dysfunction.	('oxidative damage', 'MPA', (81, 97))	('Accumulation', 'Var', (0, 12))	('disease', 'Disease', (49, 56))	('renal dysfunction', 'Disease', (27, 44))	('causes', 'Reg', (20, 26))	('endothelial dysfunction', 'Disease', (102, 125))	('renal dysfunction', 'Disease', 'MESH:D007674', (27, 44))	('inducing', 'Reg', (72, 80))	('pCS', 'Gene', (16, 19))	('pCS', 'Chemical', 'MESH:C408690', (16, 19))	('endothelial dysfunction', 'Disease', 'MESH:C536439', (102, 125))	('renal dysfunction', 'Phenotype', 'HP:0000083', (27, 44))
50206	30824757	pCS can induce proliferation and migration of rat aortic vascular smooth muscle cells and epithelial-mesenchymal transition (EMT) in kidney fibrosis.	('kidney fibrosis', 'Disease', (133, 148))	('pCS', 'Chemical', 'MESH:C408690', (0, 3))	('rat', 'Species', '10116', (46, 49))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('90', '123'))	('rat', 'Species', '10116', (22, 25))	('rat', 'Species', '10116', (36, 39))	('migration', 'CPA', (33, 42))	('proliferation', 'CPA', (15, 28))	('kidney fibrosis', 'Phenotype', 'HP:0030760', (133, 148))	('epithelial-mesenchymal transition', 'CPA', (90, 123))	('kidney fibrosis', 'Disease', 'MESH:D005355', (133, 148))	('pCS', 'Var', (0, 3))	('EMT', 'biological_process', 'GO:0001837', ('125', '128'))
50212	30824757	Additionally, inhibition of HIF-1alpha can reduce the migration of ccRCC cells.	('HIF-1alpha', 'Gene', (28, 38))	('reduce', 'NegReg', (43, 49))	('ccRCC', 'Disease', (67, 72))	('migration of', 'CPA', (54, 66))	('HIF-1alpha', 'Gene', '3091', (28, 38))	('rat', 'Species', '10116', (57, 60))	('inhibition', 'Var', (14, 24))
50235	30824757	The results showed that fibronectin, twist, and vimentin expression was increased, while E-cadherin was decreased in pCS-treated 786-O and A498 cells (Fig.	('expression', 'MPA', (57, 67))	('vimentin', 'Gene', '7431', (48, 56))	('fibronectin', 'Gene', (24, 35))	('cadherin', 'molecular_function', 'GO:0008014', ('91', '99'))	('increased', 'PosReg', (72, 81))	('vimentin', 'Gene', (48, 56))	('vimentin', 'cellular_component', 'GO:0045099', ('48', '56'))	('twist', 'MPA', (37, 42))	('E-cadherin', 'Gene', (89, 99))	('decreased', 'NegReg', (104, 113))	('E-cadherin', 'Gene', '999', (89, 99))	('pCS', 'Chemical', 'MESH:C408690', (117, 120))	('vimentin', 'cellular_component', 'GO:0045098', ('48', '56'))	('pCS-treated', 'Var', (117, 128))	('fibronectin', 'Gene', '2335', (24, 35))	('A498', 'CellLine', 'CVCL:1056', (139, 143))
50238	30824757	3k, pCS promoted the migration of 786-O cells as compared to the control.	('pCS', 'Var', (4, 7))	('migration of 786-O cells', 'CPA', (21, 45))	('pCS', 'Chemical', 'MESH:C408690', (4, 7))	('rat', 'Species', '10116', (24, 27))	('promoted', 'PosReg', (8, 16))
50240	30824757	Similarly, pCS promoted the migration of A498 cells (data not shown).	('promoted', 'PosReg', (15, 23))	('migration of A498 cells', 'CPA', (28, 51))	('pCS', 'Chemical', 'MESH:C408690', (11, 14))	('A498', 'CellLine', 'CVCL:1056', (41, 45))	('pCS', 'Var', (11, 14))	('rat', 'Species', '10116', (31, 34))
50241	30824757	These results indicate that pCS induces EMT and migration of ccRCC cells.	('migration', 'CPA', (48, 57))	('pCS', 'Var', (28, 31))	('ccRCC', 'Disease', (61, 66))	('pCS', 'Chemical', 'MESH:C408690', (28, 31))	('EMT', 'biological_process', 'GO:0001837', ('40', '43'))	('EMT', 'CPA', (40, 43))	('induces', 'Reg', (32, 39))	('rat', 'Species', '10116', (51, 54))
50244	30824757	However, knockdown of HIF-1alpha significantly inhibited VHL expression in pCS-treated 786-O cells only at day 5 (Fig.	('HIF-1alpha', 'Gene', '3091', (22, 32))	('inhibited', 'NegReg', (47, 56))	('knockdown', 'Var', (9, 18))	('VHL', 'Gene', (57, 60))	('HIF-1alpha', 'Gene', (22, 32))	('VHL', 'Gene', '7428', (57, 60))	('pCS', 'Chemical', 'MESH:C408690', (75, 78))
50245	30824757	Additionally, knockdown of HIF-1alpha inhibited the expression of fibronectin, twist, and vimentin and promoted the expression of E-cadherin (Fig.	('expression', 'MPA', (116, 126))	('vimentin', 'Gene', '7431', (90, 98))	('fibronectin', 'Gene', (66, 77))	('HIF-1alpha', 'Gene', (27, 37))	('vimentin', 'cellular_component', 'GO:0045099', ('90', '98'))	('vimentin', 'Gene', (90, 98))	('E-cadherin', 'Gene', (130, 140))	('knockdown', 'Var', (14, 23))	('E-cadherin', 'Gene', '999', (130, 140))	('inhibited', 'NegReg', (38, 47))	('expression', 'MPA', (52, 62))	('twist', 'Protein', (79, 84))	('fibronectin', 'Gene', '2335', (66, 77))	('vimentin', 'cellular_component', 'GO:0045098', ('90', '98'))	('HIF-1alpha', 'Gene', '3091', (27, 37))	('promoted', 'PosReg', (103, 111))	('cadherin', 'molecular_function', 'GO:0008014', ('132', '140'))
50246	30824757	pCS-induced cell migration (Figs 3k and 5f) was inhibited by knockdown of HIF-1alpha (Fig.	('pCS', 'Chemical', 'MESH:C408690', (0, 3))	('HIF-1alpha', 'Gene', '3091', (74, 84))	('knockdown', 'Var', (61, 70))	('pCS-induced', 'Disease', (0, 11))	('cell migration', 'CPA', (12, 26))	('inhibited', 'NegReg', (48, 57))	('HIF-1alpha', 'Gene', (74, 84))	('rat', 'Species', '10116', (20, 23))	('cell migration', 'biological_process', 'GO:0016477', ('12', '26'))
50255	30824757	Overall, our results suggest that pCS increases miR-21 to cause cell proliferation and EMT in ccRCC cells.	('ccRCC', 'Disease', (94, 99))	('increases', 'PosReg', (38, 47))	('pCS', 'Chemical', 'MESH:C408690', (34, 37))	('rat', 'Species', '10116', (76, 79))	('cell proliferation', 'CPA', (64, 82))	('miR-21', 'Gene', (48, 54))	('EMT', 'CPA', (87, 90))	('EMT', 'biological_process', 'GO:0001837', ('87', '90'))	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('cause', 'PosReg', (58, 63))	('miR-21', 'Gene', '406991', (48, 54))	('pCS', 'Var', (34, 37))
50264	30824757	A study showed that pCS activated the renin angiotensin aldosterone system and induced EMT.	('renin', 'Gene', (38, 43))	('pCS', 'Chemical', 'MESH:C408690', (20, 23))	('angiotensin aldosterone', 'Phenotype', 'HP:0000859', (44, 67))	('EMT', 'CPA', (87, 90))	('EMT', 'biological_process', 'GO:0001837', ('87', '90'))	('induced', 'PosReg', (79, 86))	('renin', 'Gene', '5972', (38, 43))	('activated', 'PosReg', (24, 33))	('pCS', 'Var', (20, 23))
50272	30824757	Our results showed that pCS induced HIF-1alpha overexpression and promoted the proliferation of ccRCC cells.	('pCS', 'Var', (24, 27))	('proliferation', 'CPA', (79, 92))	('rat', 'Species', '10116', (86, 89))	('pCS', 'Chemical', 'MESH:C408690', (24, 27))	('HIF-1alpha overexpression', 'Disease', (36, 61))	('HIF-1alpha overexpression', 'Disease', 'None', (36, 61))	('ccRCC', 'Disease', (96, 101))	('promoted', 'PosReg', (66, 74))
50274	30824757	Our results on pCS-induced HIF-1alpha and reduced HIF-2alpha expression agreed with those of previous studies.	('pCS', 'Chemical', 'MESH:C408690', (15, 18))	('pCS-induced', 'Var', (15, 26))	('expression', 'MPA', (61, 71))	('HIF-1alpha and reduced HIF-2alpha', 'Disease', 'MESH:D015354', (27, 60))
50276	30824757	However, mutant VHL genes are found in most ccRCC cells, including in 786-O and A498 cells.	('VHL', 'Gene', (16, 19))	('mutant', 'Var', (9, 15))	('VHL', 'Gene', '7428', (16, 19))	('found', 'Reg', (30, 35))	('ccRCC', 'Disease', (44, 49))	('A498', 'CellLine', 'CVCL:1056', (80, 84))
50277	30824757	A study indicated that mutant VHL does not regulate HIF-alpha signals.	('VHL', 'Gene', '7428', (30, 33))	('VHL', 'Gene', (30, 33))	('mutant', 'Var', (23, 29))
50278	30824757	Our results showed that pCS induced HIF-1alpha and VHL and suppressed HIF-2alpha expression.	('pCS', 'Var', (24, 27))	('VHL', 'Gene', '7428', (51, 54))	('pCS', 'Chemical', 'MESH:C408690', (24, 27))	('induced', 'PosReg', (28, 35))	('HIF-2alpha', 'Gene', '2034', (70, 80))	('HIF-1alpha', 'Gene', '3091', (36, 46))	('suppressed', 'NegReg', (59, 69))	('HIF-1alpha', 'Gene', (36, 46))	('VHL', 'Gene', (51, 54))	('HIF-2alpha', 'Gene', (70, 80))
50279	30824757	We found that overexpression of mutant VHL in pCS-treated 786-O and A498 cells did not inhibit HIF-1alpha-induced proliferation.	('HIF-1alpha', 'Gene', '3091', (95, 105))	('VHL', 'Gene', (39, 42))	('mutant', 'Var', (32, 38))	('HIF-1alpha', 'Gene', (95, 105))	('inhibit', 'NegReg', (87, 94))	('VHL', 'Gene', '7428', (39, 42))	('pCS', 'Chemical', 'MESH:C408690', (46, 49))	('A498', 'CellLine', 'CVCL:1056', (68, 72))	('rat', 'Species', '10116', (121, 124))
50280	30824757	This may be explained by the data showing that overexpression of mutant VHL in ccRCC prevented UV-induced apoptosis.	('prevented', 'NegReg', (85, 94))	('VHL', 'Gene', '7428', (72, 75))	('UV-induced apoptosis', 'CPA', (95, 115))	('mutant', 'Var', (65, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('VHL', 'Gene', (72, 75))
50284	30824757	Our results showed that inhibition of miR-21 decreased HIF-1alpha expression in pCS-treated ccRCC cells.	('miR-21', 'Gene', (38, 44))	('HIF-1alpha', 'Gene', (55, 65))	('decreased', 'NegReg', (45, 54))	('expression', 'MPA', (66, 76))	('inhibition', 'Var', (24, 34))	('pCS', 'Chemical', 'MESH:C408690', (80, 83))	('miR-21', 'Gene', '406991', (38, 44))	('HIF-1alpha', 'Gene', '3091', (55, 65))
50290	30824757	In contrast, our results showed that inhibition of miR-21 decreased the expression of VHL and inhibited pCS-induced proliferation in ccRCC cells.	('inhibition', 'Var', (37, 47))	('decreased', 'NegReg', (58, 67))	('pCS', 'Chemical', 'MESH:C408690', (104, 107))	('miR-21', 'Gene', (51, 57))	('expression', 'MPA', (72, 82))	('rat', 'Species', '10116', (123, 126))	('VHL', 'Gene', '7428', (86, 89))	('VHL', 'Gene', (86, 89))	('miR-21', 'Gene', '406991', (51, 57))	('inhibited', 'NegReg', (94, 103))	('pCS-induced proliferation', 'CPA', (104, 129))
50291	30824757	Because wild-type VHL in glioblastoma inhibits cell growth while mutant VHL in ccRCC inhibits apoptosis, miR-21 has distinct effects on VHL expression and regulates cell growth in different cells.	('VHL', 'Gene', '7428', (18, 21))	('VHL', 'Gene', '7428', (136, 139))	('regulates', 'Reg', (155, 164))	('cell growth', 'biological_process', 'GO:0016049', ('165', '176'))	('apoptosis', 'CPA', (94, 103))	('VHL', 'Gene', '7428', (72, 75))	('inhibits', 'NegReg', (38, 46))	('mutant', 'Var', (65, 71))	('miR-21', 'Gene', '406991', (105, 111))	('glioblastoma', 'Disease', 'MESH:D005909', (25, 37))	('inhibits', 'NegReg', (85, 93))	('cell growth', 'biological_process', 'GO:0016049', ('47', '58'))	('effects', 'Reg', (125, 132))	('glioblastoma', 'Disease', (25, 37))	('cell growth', 'CPA', (47, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (25, 37))	('VHL', 'Gene', (18, 21))	('miR-21', 'Gene', (105, 111))	('apoptosis', 'biological_process', 'GO:0097194', ('94', '103'))	('apoptosis', 'biological_process', 'GO:0006915', ('94', '103'))	('expression', 'MPA', (140, 150))	('VHL', 'Gene', (136, 139))	('VHL', 'Gene', (72, 75))
50359	31577719	Prognostic significance of long non-coding RNAs in clear cell renal cell carcinoma Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer in adults, and patients with advanced ccRCC have a 5-year survival rate of <30%.	('Clear cell renal cell carcinoma', 'Disease', (83, 114))	('RCC', 'Phenotype', 'HP:0005584', (204, 207))	('ccRCC', 'Phenotype', 'HP:0006770', (202, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (83, 114))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (51, 82))	('ccRCC', 'Disease', 'MESH:D002292', (116, 121))	('patients', 'Species', '9606', (179, 187))	('long non-coding RNAs', 'Var', (27, 47))	('kidney cancer', 'Disease', 'MESH:D007680', (150, 163))	('ccRCC', 'Disease', (116, 121))	('ccRCC', 'Disease', 'MESH:D002292', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (94, 114))	('kidney cancer', 'Phenotype', 'HP:0009726', (150, 163))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('kidney cancer', 'Disease', (150, 163))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (51, 82))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (83, 114))	('ccRCC', 'Disease', (202, 207))	('clear cell renal cell carcinoma', 'Disease', (51, 82))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (62, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
50384	31577719	And ENSG241684, NONHSAT123350, lnc-ZNF180-2, neuroblastoma associated transcript-1 (NBAT1), and cell adhesion molecule 1 anti-sense transcript-1 (CADM1-AS1) were down-regulated.	('AS1', 'Gene', '5729', (152, 155))	('AS1', 'Gene', (152, 155))	('NONHSAT123350', 'Var', (16, 29))	('cell adhesion', 'biological_process', 'GO:0007155', ('96', '109'))	('NONHSAT123350', 'Chemical', 'None', (16, 29))	('neuroblastoma', 'Phenotype', 'HP:0003006', (45, 58))	('ENSG241684', 'Chemical', 'MESH:C065462', (4, 14))	('CADM1', 'Gene', (146, 151))	('NBAT1', 'Gene', (84, 89))	('down-regulated', 'NegReg', (162, 176))	('CADM1', 'Gene', '23705', (146, 151))	('neuroblastoma associated transcript-1', 'Gene', (45, 82))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('96', '118'))	('NBAT1', 'Gene', '729177', (84, 89))	('lnc-ZNF180-2', 'Gene', (31, 43))	('ENSG241684', 'Var', (4, 14))	('neuroblastoma associated transcript-1', 'Gene', '729177', (45, 82))
50387	31577719	Two studies revealed that clinicopathological characteristics were not significantly associated with the expression levels of NONHSAT123350 and lnc-ZNF180-2.	('NONHSAT123350', 'Chemical', 'None', (126, 139))	('NONHSAT123350', 'Var', (126, 139))	('lnc-ZNF180-2', 'Gene', (144, 156))
50391	31577719	The overexpression of PANDAR, lncRNA H19, PVT1, linc00152, LUCAT1, MRCCAT1, MALAT1, and SPRY4-IT1 were associated with poor prognosis; meanwhile the low expressions of CADM1-AS1, ENSG241684, lnc-ZNF180-2, NONHSAT123350, NBAT1 were related to poor prognosis.	('CADM1', 'Gene', '23705', (168, 173))	('NBAT1', 'Gene', '729177', (220, 225))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (88, 97))	('RCC', 'Disease', 'MESH:D002292', (68, 71))	('AS1', 'Gene', '5729', (174, 177))	('overexpression', 'PosReg', (4, 18))	('ENSG241684', 'Gene', (179, 189))	('NONHSAT123350', 'Chemical', 'None', (205, 218))	('SPRY4-IT1', 'Gene', (88, 97))	('lnc-ZNF180-2', 'Gene', (191, 203))	('MALAT1', 'Gene', (76, 82))	('linc00152', 'Gene', '112597', (48, 57))	('H19', 'Gene', (37, 40))	('PANDAR', 'Gene', '101154753', (22, 28))	('NONHSAT123350', 'Var', (205, 218))	('PANDAR', 'Gene', (22, 28))	('NBAT1', 'Gene', (220, 225))	('ENSG241684', 'Chemical', 'MESH:C065462', (179, 189))	('MALAT1', 'Gene', '378938', (76, 82))	('CADM1', 'Gene', (168, 173))	('linc00152', 'Gene', (48, 57))	('PVT1', 'Gene', (42, 46))	('AS1', 'Gene', (174, 177))	('H19', 'Gene', '283120', (37, 40))	('PVT1', 'Gene', '5820', (42, 46))	('LUCAT1', 'Gene', '100505994', (59, 65))	('LUCAT1', 'Gene', (59, 65))
50400	31577719	The results showed that expression of lncRNAs was significantly associated with poor OS outcome in patients with ccRCC, with a pooled HR of 1.71 (95% CI = 1.40-2.01; Fig.	('associated', 'Reg', (64, 74))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (113, 118))	('ccRCC', 'Disease', (113, 118))	('patients', 'Species', '9606', (99, 107))	('lncRNAs', 'Protein', (38, 45))	('poor OS', 'Disease', (80, 87))	('ccRCC', 'Disease', 'MESH:D002292', (113, 118))	('expression', 'Var', (24, 34))
50407	31577719	Moreover, the low expressions of NONHSAT123350 and lnc-ZNF180-2 were significantly associated with poor DFS/PFS outcome in patients with ccRCC, with a pooled HR of 0.79 (95% CI = 0.69-0.88; Fig.	('NONHSAT123350', 'Var', (33, 46))	('NONHSAT123350', 'Chemical', 'None', (33, 46))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('patients', 'Species', '9606', (123, 131))	('ccRCC', 'Disease', (137, 142))	('poor', 'NegReg', (99, 103))	('DFS/PFS', 'Disease', (104, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('expressions', 'MPA', (18, 29))	('low', 'NegReg', (14, 17))	('ccRCC', 'Disease', 'MESH:D002292', (137, 142))	('lnc-ZNF180-2', 'Gene', (51, 63))
50411	31577719	During carcinogenesis, genetic alterations could drive tumor evolution toward higher grades of malignancy, however, the extent to how the lncRNAs alterations influence this process remains incompletely understood.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('carcinogenesis', 'Disease', 'MESH:D063646', (7, 21))	('genetic alterations', 'Var', (23, 42))	('drive', 'Reg', (49, 54))	('carcinogenesis', 'Disease', (7, 21))	('malignancy', 'Disease', 'MESH:D009369', (95, 105))	('malignancy', 'Disease', (95, 105))
50424	31577719	The dysregulated PANDAR, NBAT-1, H19, LUCAT1, lnc-ZNF180-2, MALAT1, SPRY4-IT1 might be used as biomarkers of lymph node metastasis.	('PANDAR', 'Gene', '101154753', (17, 23))	('PANDAR', 'Gene', (17, 23))	('LUCAT1', 'Gene', (38, 44))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (68, 77))	('SPRY4-IT1', 'Gene', (68, 77))	('NBAT-1', 'Gene', '729177', (25, 31))	('LUCAT1', 'Gene', '100505994', (38, 44))	('MALAT1', 'Gene', '378938', (60, 66))	('H19', 'Gene', '283120', (33, 36))	('H19', 'Gene', (33, 36))	('dysregulated', 'Var', (4, 16))	('MALAT1', 'Gene', (60, 66))	('NBAT-1', 'Gene', (25, 31))
50429	31577719	Among these 14 lncRNAs, the overexpression of PANDAR, lncRNA H19, PVT1, linc00152, LUCAT1, MRCCAT1, MALAT1, SPRY4-IT1, and lncRNA MIAT were associated with poor prognosis; meanwhile the low expression of CADM1-AS1, ENSG241684, lnc-ZNF180-2, NONHSAT123350, NBAT1 were related to poor prognosis.	('LUCAT1', 'Gene', (83, 89))	('low', 'NegReg', (186, 189))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('CADM1', 'Gene', (204, 209))	('ENSG241684', 'Gene', (215, 225))	('NBAT1', 'Gene', (256, 261))	('SPRY4-IT1', 'Gene', (108, 117))	('overexpression', 'PosReg', (28, 42))	('NONHSAT123350', 'Chemical', 'None', (241, 254))	('lnc-ZNF180-2', 'Gene', (227, 239))	('NONHSAT123350', 'Var', (241, 254))	('RCC', 'Disease', 'MESH:D002292', (92, 95))	('expression', 'MPA', (190, 200))	('ENSG241684', 'Chemical', 'MESH:C065462', (215, 225))	('AS1', 'Gene', (210, 213))	('CADM1', 'Gene', '23705', (204, 209))	('NBAT1', 'Gene', '729177', (256, 261))	('MIAT', 'Gene', '440823', (130, 134))	('MALAT1', 'Gene', (100, 106))	('AS1', 'Gene', '5729', (210, 213))	('MIAT', 'Gene', (130, 134))	('linc00152', 'Gene', '112597', (72, 81))	('PANDAR', 'Gene', '101154753', (46, 52))	('H19', 'Gene', (61, 64))	('PANDAR', 'Gene', (46, 52))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (108, 117))	('MALAT1', 'Gene', '378938', (100, 106))	('linc00152', 'Gene', (72, 81))	('PVT1', 'Gene', (66, 70))	('H19', 'Gene', '283120', (61, 64))	('PVT1', 'Gene', '5820', (66, 70))	('LUCAT1', 'Gene', '100505994', (83, 89))
50439	31577719	Li et al revealed that the expression of PVT1 was up-regulated in ccRCC tissues, and knockdown of PVT1 induced apoptosis by increasing the expression of poly ADP ribose polymerase and Bcl-2-associated X protein, and promoted cell cycle arrest at the G1 phase by decreasing the expression of cyclin D1.	('PVT1', 'Gene', '5820', (41, 45))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (225, 242))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('225', '242'))	('poly ADP ribose polymerase', 'Gene', (153, 179))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('knockdown', 'Var', (85, 94))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('Bcl-2', 'molecular_function', 'GO:0015283', ('184', '189'))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('G1 phase', 'biological_process', 'GO:0051318', ('250', '258'))	('increasing', 'PosReg', (124, 134))	('induced', 'Reg', (103, 110))	('expression', 'MPA', (277, 287))	('poly ADP ribose polymerase', 'Gene', '142', (153, 179))	('Bcl-2', 'Gene', (184, 189))	('up-regulated', 'PosReg', (50, 62))	('cyclin D1', 'Gene', (291, 300))	('decreasing', 'NegReg', (262, 272))	('ccRCC', 'Disease', 'MESH:D002292', (66, 71))	('cell cycle arrest at the G1 phase', 'CPA', (225, 258))	('PVT1', 'Gene', (98, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('cyclin D1', 'Gene', '595', (291, 300))	('Bcl-2', 'Gene', '596', (184, 189))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('PVT1', 'Gene', (41, 45))	('promoted', 'PosReg', (216, 224))	('PVT1', 'Gene', '5820', (98, 102))	('cyclin', 'molecular_function', 'GO:0016538', ('291', '297'))	('expression', 'MPA', (139, 149))	('ccRCC', 'Disease', (66, 71))	('apoptosis', 'CPA', (111, 120))
50447	31577719	This meta-analysis summarized current researches on the relationship between aberrant lncRNAs expression and prognosis of patients with ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('ccRCC', 'Disease', (136, 141))	('ccRCC', 'Disease', 'MESH:D002292', (136, 141))	('patients', 'Species', '9606', (122, 130))	('lncRNAs expression', 'Protein', (86, 104))	('aberrant', 'Var', (77, 85))
50526	30233214	In this study, we found that patients who received partial nephrectomy showed a better OS and DSS than those with RN.	('DSS', 'CPA', (94, 97))	('patients', 'Species', '9606', (29, 37))	('OS', 'Chemical', '-', (87, 89))	('DSS', 'Chemical', '-', (94, 97))	('better', 'PosReg', (80, 86))	('partial nephrectomy', 'Var', (51, 70))
50559	30233214	Sex-specific mutation of genes such as BAP1, is evident in ccRCC, which may affect the OS of the patient.	('affect', 'Reg', (76, 82))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('mutation', 'Var', (13, 21))	('OS', 'Chemical', '-', (87, 89))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('BAP1', 'Gene', '8314', (39, 43))	('RCC', 'Disease', (61, 64))	('patient', 'Species', '9606', (97, 104))	('BAP1', 'Gene', (39, 43))
50570	29357946	The effects of FSTL1 on cell activity and cell cycle were investigated in ccRCC cell lines with altered FSTL1 expression.	('cell cycle', 'biological_process', 'GO:0007049', ('42', '52'))	('altered', 'Var', (96, 103))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('FSTL1', 'Gene', (104, 109))	('FSTL1', 'Gene', '11167', (104, 109))	('FSTL1', 'Gene', (15, 20))	('FSTL1', 'Gene', '11167', (15, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))
50571	29357946	Gene expression microarray assays were performed to identify the major signaling pathways affected by FSTL1 knockdown.	('signaling', 'biological_process', 'GO:0023052', ('71', '80'))	('knockdown', 'Var', (108, 117))	('FSTL1', 'Gene', (102, 107))	('FSTL1', 'Gene', '11167', (102, 107))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))
50573	29357946	FSTL1 knockdown promoted anchorage-independent growth, migration, invasion, and cell cycle of ccRCC cell lines, whereas FSTL1 overexpression attenuated cell migration.	('RCC', 'Disease', (96, 99))	('FSTL1', 'Gene', (0, 5))	('FSTL1', 'Gene', (120, 125))	('FSTL1', 'Gene', '11167', (120, 125))	('attenuated', 'NegReg', (141, 151))	('promoted', 'PosReg', (16, 24))	('migration', 'CPA', (55, 64))	('FSTL1', 'Gene', '11167', (0, 5))	('cell migration', 'biological_process', 'GO:0016477', ('152', '166'))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('cell cycle', 'CPA', (80, 90))	('anchorage-independent growth', 'CPA', (25, 53))	('cell cycle', 'biological_process', 'GO:0007049', ('80', '90'))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('knockdown', 'Var', (6, 15))	('invasion', 'CPA', (66, 74))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
50574	29357946	FSTL1 knockdown up-regulated nuclear factor-kappaB (NF-kappaB) and hypoxia-inducible factor (HIF) signaling pathways, increased epithelial-to-mesenchymal transition, up-regulated interleukin-6 expression, and promoted tumor necrosis factor-alpha-induced degradation of NF-kappaB inhibitor (IkappaBalpha) in ccRCC cell lines.	('degradation', 'MPA', (254, 265))	('hypoxia', 'Disease', 'MESH:D000860', (67, 74))	('RCC', 'Disease', 'MESH:C538614', (309, 312))	('interleukin-6', 'Gene', (179, 192))	('up-regulated', 'PosReg', (166, 178))	('increased', 'PosReg', (118, 127))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('218', '239'))	('necrosis', 'biological_process', 'GO:0008219', ('224', '232'))	('tumor necrosis factor-alpha', 'Gene', (218, 245))	('expression', 'MPA', (193, 203))	('NF-kappaB inhibitor', 'biological_process', 'GO:0032088', ('269', '288'))	('degradation', 'biological_process', 'GO:0009056', ('254', '265'))	('nuclear factor-kappaB', 'Gene', '4790', (29, 50))	('FSTL1', 'Gene', '11167', (0, 5))	('IkappaBalpha', 'Gene', (290, 302))	('nuclear factor-kappaB', 'Gene', (29, 50))	('NF-kappaB', 'Gene', (269, 278))	('necrosis', 'biological_process', 'GO:0008220', ('224', '232'))	('FSTL1', 'Gene', (0, 5))	('IkappaBalpha', 'Gene', '4792', (290, 302))	('epithelial-to-mesenchymal transition', 'CPA', (128, 164))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('necrosis', 'biological_process', 'GO:0070265', ('224', '232'))	('tumor necrosis factor-alpha', 'Gene', '7124', (218, 245))	('NF-kappaB', 'Gene', (52, 61))	('NF-kappaB', 'Gene', '4790', (269, 278))	('necrosis', 'biological_process', 'GO:0019835', ('224', '232'))	('RCC', 'Disease', (309, 312))	('RCC', 'Phenotype', 'HP:0005584', (309, 312))	('necrosis', 'biological_process', 'GO:0001906', ('224', '232'))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('128', '164'))	('hypoxia', 'Disease', (67, 74))	('up-regulated', 'PosReg', (16, 28))	('interleukin-6', 'Gene', '3569', (179, 192))	('promoted', 'PosReg', (209, 217))	('NF-kappaB', 'Gene', '4790', (52, 61))	('knockdown', 'Var', (6, 15))	('ccRCC', 'Phenotype', 'HP:0006770', (307, 312))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))
50589	29357946	D9S168 microsatellite alteration in tumors, intratumoral neutrophil, intratumoral expression of proteins including chemokine (C-X-C motif) receptor 8 (CXCR8), CD44, CXCR3, insulin-like growth factor mRNA-binding protein 3, survivin, B7 homolog 1, glycolytic enzymes, circulating molecules such as human telomerase reverse transcriptase, spermine/spermidine, urinary cathepsin D, and co-expression of interleukin-6 (IL-6) and its receptor have been associated with poor prognosis in RCC patients.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('RCC', 'Disease', 'MESH:C538614', (482, 485))	('cathepsin D', 'Gene', (366, 377))	('tumor', 'Disease', (74, 79))	('interleukin-6', 'Gene', (400, 413))	('IL-6', 'molecular_function', 'GO:0005138', ('415', '419'))	('tumor', 'Disease', (36, 41))	('B7 homolog 1', 'Gene', '29126', (233, 245))	('transcriptase', 'molecular_function', 'GO:0003968', ('322', '335'))	('chemokine ', 'Gene', '1237', (115, 125))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('telomerase reverse transcriptase', 'Gene', (303, 335))	('transcriptase', 'molecular_function', 'GO:0034062', ('322', '335'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('cathepsin D', 'Gene', '1509', (366, 377))	('CD44', 'Gene', '960', (159, 163))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('IL-6', 'Gene', '3569', (415, 419))	('CD44', 'Gene', (159, 163))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('telomerase reverse transcriptase', 'Gene', '7015', (303, 335))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('IL-6', 'Gene', (415, 419))	('tumors', 'Disease', (36, 42))	('co-expression', 'Var', (383, 396))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('transcriptase', 'molecular_function', 'GO:0003899', ('322', '335'))	('B7 homolog 1', 'Gene', (233, 245))	('CXCR3', 'Gene', (165, 170))	('RCC', 'Disease', (482, 485))	('RCC', 'Phenotype', 'HP:0005584', (482, 485))	('chemokine ', 'Gene', (115, 125))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('patients', 'Species', '9606', (486, 494))	('mRNA-binding', 'molecular_function', 'GO:0003729', ('199', '211'))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('172', '198'))	('CXCR3', 'Gene', '2833', (165, 170))	('human', 'Species', '9606', (297, 302))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('D9S168', 'Gene', (0, 6))	('interleukin-6', 'Gene', '3569', (400, 413))
50592	29357946	In our previous study investigating global profiling of gene expression in RCC cells with different metastatic potential, we found that follistatin-like protein 1 (FSTL1) was frequently down-regulated in metastatic ccRCC; and the C allele of rs1259293 in the coding region of FSLT1 was associated with an increased risk and unfavorable postoperative prognosis of RCC, possibly by down-regulating FSTL1 expression in renal tissues.	('FSTL1', 'Gene', (164, 169))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (363, 366))	('protein', 'cellular_component', 'GO:0003675', ('153', '160'))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('FSTL1', 'Gene', '11167', (396, 401))	('RCC', 'Phenotype', 'HP:0005584', (217, 220))	('ccRCC', 'Phenotype', 'HP:0006770', (215, 220))	('RCC', 'Disease', (217, 220))	('FSTL1', 'Gene', (396, 401))	('down-regulating', 'NegReg', (380, 395))	('down-regulated', 'NegReg', (186, 200))	('rs1259293', 'Var', (242, 251))	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('rs1259293', 'Mutation', 'rs1259293', (242, 251))	('FSLT1', 'Gene', (276, 281))	('follistatin-like protein 1', 'Gene', (136, 162))	('FSTL1', 'Gene', '11167', (164, 169))	('expression', 'MPA', (402, 412))	('follistatin-like protein 1', 'Gene', '11167', (136, 162))	('RCC', 'Disease', (363, 366))	('RCC', 'Phenotype', 'HP:0005584', (363, 366))	('gene expression', 'biological_process', 'GO:0010467', ('56', '71'))
50603	29357946	In the present study, we aimed to clarify the effects of aberrant FSTL1 expression on the growth and aggressiveness of RCC cells, identify the signaling pathways that were affected by FSTL1, and validate the prognostic functions of FSTL1 with a cohort of RCC patients.	('aggressiveness', 'Phenotype', 'HP:0000718', (101, 115))	('aggressiveness of RCC', 'Disease', 'MESH:C538614', (101, 122))	('FSTL1', 'Gene', '11167', (66, 71))	('FSTL1', 'Gene', '11167', (184, 189))	('aberrant', 'Var', (57, 65))	('FSTL1', 'Gene', '11167', (232, 237))	('patients', 'Species', '9606', (259, 267))	('FSTL1', 'Gene', (66, 71))	('effects', 'Reg', (46, 53))	('FSTL1', 'Gene', (184, 189))	('RCC', 'Disease', (255, 258))	('RCC', 'Phenotype', 'HP:0005584', (255, 258))	('signaling', 'biological_process', 'GO:0023052', ('143', '152'))	('FSTL1', 'Gene', (232, 237))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RCC', 'Disease', (119, 122))	('RCC', 'Disease', 'MESH:C538614', (255, 258))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('aggressiveness of RCC', 'Disease', (101, 122))
50618	29357946	Anchorage-independent growth of RCC cells with aberrant FSTL1 expression was evaluated with a double-layered soft agarose culture system, as previously described.	('aberrant', 'Var', (47, 55))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('FSTL1', 'Gene', (56, 61))	('FSTL1', 'Gene', '11167', (56, 61))	('agarose', 'Chemical', 'MESH:D012685', (114, 121))
50636	29357946	AP10534b, San Diego, CA, USA), anti-IkappaBalpha (1:1000 dilution; Cell Signaling Technology No.	('Signaling', 'biological_process', 'GO:0023052', ('72', '81'))	('IkappaBalpha', 'Gene', (36, 48))	('AP10534b', 'Var', (0, 8))	('IkappaBalpha', 'Gene', '4792', (36, 48))
50669	29357946	FSTL1 knockdown significantly promoted anchorage-independent growth (Fig.	('FSTL1', 'Gene', (0, 5))	('anchorage-independent growth', 'CPA', (39, 67))	('FSTL1', 'Gene', '11167', (0, 5))	('promoted', 'PosReg', (30, 38))	('knockdown', 'Var', (6, 15))
50679	29357946	After filtered with absent/present calls, 105 differentially expressed genes with a fold change of > 2 were identified in FSTL1 knockdown NRCC cells, including 57 up-regulated genes and 48 down-regulated genes.	('FSTL1', 'Gene', (122, 127))	('up-regulated', 'PosReg', (163, 175))	('down-regulated', 'NegReg', (189, 203))	('knockdown', 'Var', (128, 137))	('FSTL1', 'Gene', '11167', (122, 127))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('differentially expressed genes', 'MPA', (46, 76))
50681	29357946	We applied GSEA software package to enrich the gene sets from the global gene expression in response to FSTL1 knockdown in NRCC cells.	('RCC', 'Disease', (124, 127))	('knockdown', 'Var', (110, 119))	('GSEA', 'Chemical', '-', (11, 15))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('FSTL1', 'Gene', (104, 109))	('gene expression', 'biological_process', 'GO:0010467', ('73', '88'))	('FSTL1', 'Gene', '11167', (104, 109))
50684	29357946	Our qRT-PCR assays indicated that IL-6 transcription was significantly up-regulated following FSTL1 knockdown in ACHN, 786-O, and NRCC cells (P < 0.05) (Fig.	('knockdown', 'Var', (100, 109))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('transcription', 'biological_process', 'GO:0006351', ('39', '52'))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('IL-6', 'Gene', '3569', (34, 38))	('IL-6', 'Gene', (34, 38))	('FSTL1', 'Gene', (94, 99))	('FSTL1', 'Gene', '11167', (94, 99))	('up-regulated', 'PosReg', (71, 83))	('IL-6', 'molecular_function', 'GO:0005138', ('34', '38'))	('transcription', 'MPA', (39, 52))
50710	29357946	However, related evidence was mostly obtained from FSTL1 knockdown assays.	('FSTL1', 'Gene', (51, 56))	('FSTL1', 'Gene', '11167', (51, 56))	('knockdown', 'Var', (57, 66))
50714	29357946	Our cytometry results indicated that FSTL1 knockdown up-regulated CD99, a cellular marker related to ccRCC aggressiveness, and down-regulated CD24 expression in NRCC cells.	('CD24', 'Gene', (142, 146))	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('expression', 'MPA', (147, 157))	('CD99', 'Gene', (66, 70))	('RCC', 'Disease', (162, 165))	('CD99', 'Gene', '4267', (66, 70))	('RCC', 'Phenotype', 'HP:0005584', (162, 165))	('down-regulated', 'NegReg', (127, 141))	('knockdown', 'Var', (43, 52))	('up-regulated', 'PosReg', (53, 65))	('CD24', 'Gene', '100133941', (142, 146))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('ccRCC aggressiveness', 'Disease', 'MESH:D001523', (101, 121))	('ccRCC aggressiveness', 'Disease', (101, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('FSTL1', 'Gene', '11167', (37, 42))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('FSTL1', 'Gene', (37, 42))	('aggressiveness', 'Phenotype', 'HP:0000718', (107, 121))
50719	29357946	Thus, it is possible that FSTL1 knockdown increases CSC-like properties of ccRCC cells.	('FSTL1', 'Gene', (26, 31))	('increases', 'PosReg', (42, 51))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('FSTL1', 'Gene', '11167', (26, 31))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('knockdown', 'Var', (32, 41))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('CSC-like properties of', 'CPA', (52, 74))
50720	29357946	We also found that FSTL1 knockdown promoted EMT process via up-regulating N-cadherin and down-regulating E-cadherin in ccRCC cells.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('N-cadherin', 'Gene', (74, 84))	('cadherin', 'molecular_function', 'GO:0008014', ('76', '84'))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('EMT process', 'CPA', (44, 55))	('RCC', 'Disease', (121, 124))	('cadherin', 'molecular_function', 'GO:0008014', ('107', '115'))	('N-cadherin', 'Gene', '1000', (74, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('E-cadherin', 'Gene', (105, 115))	('up-regulating', 'PosReg', (60, 73))	('E-cadherin', 'Gene', '999', (105, 115))	('down-regulating', 'NegReg', (89, 104))	('promoted', 'PosReg', (35, 43))	('EMT', 'biological_process', 'GO:0001837', ('44', '47'))	('knockdown', 'Var', (25, 34))	('FSTL1', 'Gene', (19, 24))	('FSTL1', 'Gene', '11167', (19, 24))
50722	29357946	Using global gene expression profiling, we found NF-kappaB- and HIF-related functional gene sets were the predominant signaling pathways affected by FSTL1 knockdown.	('knockdown', 'Var', (155, 164))	('affected', 'Reg', (137, 145))	('FSTL1', 'Gene', '11167', (149, 154))	('gene expression', 'biological_process', 'GO:0010467', ('13', '28'))	('NF-kappaB', 'Gene', '4790', (49, 58))	('signaling', 'biological_process', 'GO:0023052', ('118', '127'))	('FSTL1', 'Gene', (149, 154))	('NF-kappaB', 'Gene', (49, 58))
50728	29357946	FSTL1 knockdown up-regulated the expression of IL-6 in ccRCC cells.	('IL-6', 'molecular_function', 'GO:0005138', ('47', '51'))	('FSTL1', 'Gene', (0, 5))	('IL-6', 'Gene', (47, 51))	('FSTL1', 'Gene', '11167', (0, 5))	('up-regulated', 'PosReg', (16, 28))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('expression', 'MPA', (33, 43))	('IL-6', 'Gene', '3569', (47, 51))	('knockdown', 'Var', (6, 15))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))
50730	29357946	FSTL1 knockdown promotes the NF-kappaB signaling pathway in ccRCC cells (Fig.	('NF-kappaB', 'Gene', (29, 38))	('promotes', 'PosReg', (16, 24))	('FSTL1', 'Gene', (0, 5))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('FSTL1', 'Gene', '11167', (0, 5))	('knockdown', 'Var', (6, 15))	('signaling pathway', 'biological_process', 'GO:0007165', ('39', '56'))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('NF-kappaB', 'Gene', '4790', (29, 38))
50732	29357946	FSTL1 knockdown also affect the HIF signaling pathway.	('HIF signaling pathway', 'Pathway', (32, 53))	('FSTL1', 'Gene', (0, 5))	('FSTL1', 'Gene', '11167', (0, 5))	('signaling pathway', 'biological_process', 'GO:0007165', ('36', '53'))	('knockdown', 'Var', (6, 15))	('affect', 'Reg', (21, 27))
50736	29357946	Therefore, we believe that FSTL1 knockdown may derepress NF-kappaB and HIF-2alpha signaling in ccRCC cells, thus promoting cancer invasion and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('signaling', 'biological_process', 'GO:0023052', ('82', '91'))	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('NF-kappaB', 'Gene', (57, 66))	('knockdown', 'Var', (33, 42))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('HIF-2alpha', 'Gene', (71, 81))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('FSTL1', 'Gene', (27, 32))	('FSTL1', 'Gene', '11167', (27, 32))	('NF-kappaB', 'Gene', '4790', (57, 66))	('cancer', 'Disease', (123, 129))	('derepress', 'NegReg', (47, 56))	('HIF-2alpha', 'Gene', '2034', (71, 81))	('metastasis', 'CPA', (143, 153))	('promoting', 'PosReg', (113, 122))
50753	30405850	EZH2 Expression is increased in BAP1-mutant renal clear cell carcinoma and is related to poor prognosis Aim: BAP1 is frequently mutated in clear cell renal cell carcinoma (ccRCC) with a definitive role still unclear.	('Expression', 'MPA', (5, 15))	('BAP1', 'Gene', '8314', (109, 113))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (139, 170))	('BAP1', 'Gene', (32, 36))	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('increased', 'PosReg', (19, 28))	('BAP1', 'Gene', (109, 113))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (139, 170))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (150, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('RCC', 'Disease', (174, 177))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('clear cell renal cell carcinoma', 'Disease', (139, 170))	('mutated', 'Var', (128, 135))	('BAP1', 'Gene', '8314', (32, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (172, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (44, 70))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('renal clear cell carcinoma', 'Disease', (44, 70))
50755	30405850	BAP1 was frequently mutated and more frequently downregulated in ccRCC compared to normal kidney tissue or benign renal tumors.	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('BAP1', 'Gene', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('renal tumors', 'Phenotype', 'HP:0009726', (114, 126))	('downregulated', 'NegReg', (48, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('benign renal tumors', 'Disease', 'MESH:D007674', (107, 126))	('mutated', 'Var', (20, 27))	('benign renal tumors', 'Disease', (107, 126))
50756	30405850	In the analysis between samples with BAP1 mutation (N = 33) and pan-negative (N = 33), we found that cancers with BAP1 mutation was significantly enriched for 14 pathways, of which 3 were DNA repair pathways, in which EZH2 played a role.	('mutation', 'Var', (119, 127))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('DNA', 'cellular_component', 'GO:0005574', ('188', '191'))	('cancers', 'Disease', (101, 108))	('mutation', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('pathways', 'Pathway', (162, 170))	('DNA repair', 'biological_process', 'GO:0006281', ('188', '198'))	('BAP1', 'Gene', (37, 41))	('BAP1', 'Gene', (114, 118))	('DNA repair pathways', 'Pathway', (188, 207))	('enriched', 'Reg', (146, 154))
50758	30405850	Genetic and pharmaceutical inhibition of EZH2 not only inhibited BAP1-mutatn ccRCC cell viability and invasion but also abrogated genetic replenishing of BAP1 expression.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('BAP1-mutatn', 'Gene', (65, 76))	('inhibited', 'NegReg', (55, 64))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('BAP1', 'Gene', (154, 158))	('EZH2', 'Gene', (41, 45))	('inhibition', 'Var', (27, 37))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('abrogated', 'NegReg', (120, 129))	('genetic replenishing', 'MPA', (130, 150))	('RCC', 'Disease', (79, 82))
50765	30405850	Recent next-generation sequencing has revealed predominant genetic disposition for distinctive histological subtypes including frequent mutations in VHL, PBRM1, SETD2, BAP1, in some series KDM5C.	('VHL', 'Gene', '7428', (149, 152))	('PBRM1', 'Gene', (154, 159))	('PBRM1', 'Gene', '55193', (154, 159))	('SETD2', 'Gene', '29072', (161, 166))	('BAP1', 'Gene', (168, 172))	('KDM5C', 'Gene', (189, 194))	('SETD2', 'Gene', (161, 166))	('mutations', 'Var', (136, 145))	('KDM5C', 'Gene', '8242', (189, 194))	('VHL', 'Gene', (149, 152))
50767	30405850	Mutation in BAP1 has been reported in a variety of cancers.	('reported', 'Reg', (26, 34))	('Mutation', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('BAP1', 'Gene', (12, 16))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
50769	30405850	Later in uveal melanomas (UM), BAP1 is also reported to be mutated in ~50% of cases with functional impairment in case of missense mutation within UCH and ULD deubiquitinase domain.	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('ULD', 'Disease', 'MESH:D020194', (155, 158))	('UCH', 'Gene', (147, 150))	('ULD', 'Disease', (155, 158))	('uveal melanomas', 'Disease', 'MESH:C536494', (9, 24))	('BAP1', 'Gene', (31, 35))	('UM', 'Phenotype', 'HP:0007716', (26, 28))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('159', '173'))	('uveal melanomas', 'Disease', (9, 24))	('uveal melanomas', 'Phenotype', 'HP:0007716', (9, 24))	('missense mutation', 'Var', (122, 139))
50771	30405850	In ccRCC, BAP1 loss is characterized with both mutation and loss of heterozygosity, the latter owing to its proximity to 3p25 region that is often deleted in kidney cancer.	('kidney cancer', 'Phenotype', 'HP:0009726', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('BAP1', 'Gene', (10, 14))	('kidney cancer', 'Disease', (158, 171))	('mutation', 'Var', (47, 55))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('loss', 'NegReg', (15, 19))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('kidney cancer', 'Disease', 'MESH:D007680', (158, 171))
50772	30405850	It is now suggested that loss of VHL function by mutation with and without LOH or methylation occurs in almost if not all ccRCC and VHL loss is accepted as a truncal genetic alteration in ccRCC.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('loss of VHL function', 'Disease', 'MESH:D006623', (25, 45))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('ccRCC', 'Phenotype', 'HP:0006770', (188, 193))	('RCC', 'Disease', (190, 193))	('RCC', 'Phenotype', 'HP:0005584', (190, 193))	('VHL loss', 'Disease', 'MESH:D006623', (132, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (122, 127))	('loss of VHL function', 'Disease', (25, 45))	('mutation', 'Var', (49, 57))	('methylation', 'biological_process', 'GO:0032259', ('82', '93'))	('VHL loss', 'Disease', (132, 140))
50773	30405850	PBRM1 and BAP1 mutations are shown to be mutually exclusive in ccRCC and are suggested to be later-on events due to selectivity.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('BAP1', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
50774	30405850	CcRCC patients with BAP1 mutations have worse prognosis compared with the rest.	('mutations', 'Var', (25, 34))	('BAP1', 'Gene', (20, 24))	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('patients', 'Species', '9606', (6, 14))
50778	30405850	We then captured samples with BAP1 mutation and excluded samples with mutations of any of the genes including VHL, PBRM1, SETD2 and KDM5C, generating a 'pan-negative' cohort (Control 1).	('VHL', 'Gene', '7428', (110, 113))	('BAP1', 'Gene', (30, 34))	('KDM5C', 'Gene', (132, 137))	('SETD2', 'Gene', '29072', (122, 127))	('KDM5C', 'Gene', '8242', (132, 137))	('SETD2', 'Gene', (122, 127))	('PBRM1', 'Gene', (115, 120))	('mutation', 'Var', (35, 43))	('VHL', 'Gene', (110, 113))	('PBRM1', 'Gene', '55193', (115, 120))
50780	30405850	The primary antibodies were EZH2 (Abcam, ab186006, Shanghai, China), BAP1 (sc-28383, Santa Cruz Biotechnology, OR, USA), VHL (sc-135657, Santa Cruz Biotechnology, OR, USA), PBRM1 (SAB1409486, Sigma-Aldrich), SETD2 (AV47617, Sigma-Aldrich), and KDM5C (SAB4301634, Sigma-Aldrich).	('PBRM1', 'Gene', (173, 178))	('VHL', 'Gene', '7428', (121, 124))	('PBRM1', 'Gene', '55193', (173, 178))	('SETD2', 'Gene', '29072', (208, 213))	('KDM5C', 'Gene', '8242', (244, 249))	('sc-135657', 'Var', (126, 135))	('SAB1409486', 'Var', (180, 190))	('SETD2', 'Gene', (208, 213))	('AV47617', 'Var', (215, 222))	('KDM5C', 'Gene', (244, 249))	('VHL', 'Gene', (121, 124))	('SAB4301634', 'Var', (251, 261))
50810	30405850	Control 1 (pan-negative) included 33 cases with no mutation or copy number loss in VHL, PBRM1, SETD2 or KDM5C.	('KDM5C', 'Gene', (104, 109))	('PBRM1', 'Gene', (88, 93))	('VHL', 'Gene', '7428', (83, 86))	('PBRM1', 'Gene', '55193', (88, 93))	('KDM5C', 'Gene', '8242', (104, 109))	('SETD2', 'Gene', '29072', (95, 100))	('SETD2', 'Gene', (95, 100))	('copy number loss', 'Var', (63, 79))	('VHL', 'Gene', (83, 86))
50815	30405850	All these results indicate that the low level of BAP1 positively correlates with ccRCC progression and poor prognosis in ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('BAP1', 'Gene', (49, 53))	('RCC', 'Disease', (123, 126))	('patients', 'Species', '9606', (127, 135))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (121, 126))	('low level', 'Var', (36, 45))
50818	30405850	To investigate the function of BAP1 in ccRCC, by analyzing the enrichment of mRNA expression between BAP1 mutated cases and pan-negative cases, we acquired 2,132 genes that were significantly enriched according to both P and Q value thresholds.	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('BAP1', 'Gene', (101, 105))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))	('mutated', 'Var', (106, 113))
50826	30405850	To address our hypothesis, we used 769-P ccRCC cell line that harbored BAP1 mutation and 786-O ccRCC cell line that was BAP-wildtype (WT).	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('mutation', 'Var', (76, 84))	('BAP1', 'Gene', (71, 75))
50828	30405850	These findings supported the notion that BAP1-loss ccRCC were at least in part addictive to EZH2 overexpression which warrant further pharmaceutical investigation.	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))	('BAP1-loss', 'Var', (41, 50))
50829	30405850	EPZ011989 significantly and selectively inhibited cell invasion, migration, and anchorage-independent growth in ccRCC cells with BAP1 mutation (Fig 5A-C).	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('migration', 'CPA', (65, 74))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('inhibited', 'NegReg', (40, 49))	('mutation', 'Var', (134, 142))	('cell invasion', 'CPA', (50, 63))	('BAP1', 'Gene', (129, 133))	('anchorage-independent growth', 'CPA', (80, 108))
50830	30405850	EPZ011989 at 500 mg/kg twice a day showed tolerable toxicity in all mice and significant inhibition of tumor growth of BAP1-mutant tumors (Fig 5D).	('mice', 'Species', '10090', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Disease', (131, 136))	('inhibition', 'NegReg', (89, 99))	('toxicity', 'Disease', 'MESH:D064420', (52, 60))	('tumors', 'Disease', (131, 137))	('toxicity', 'Disease', (52, 60))	('BAP1-mutant', 'Gene', (119, 130))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('EPZ011989', 'Var', (0, 9))
50832	30405850	As germline BAP1 mutation is associated with increased risk and earlier onset of a variety of cancers and somatic BAP1 mutation is noted in a series of cancers, BAP1-defficient tumors are now recognized as a specific entity that characterize a unique tumor profile.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('tumor', 'Disease', (251, 256))	('germline', 'Var', (3, 11))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('BAP1-defficient tumors', 'Disease', 'MESH:D009369', (161, 183))	('cancers', 'Disease', (152, 159))	('mutation', 'Var', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('tumor', 'Disease', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('cancers', 'Disease', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('BAP1-defficient tumors', 'Disease', (161, 183))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('BAP1', 'Gene', (12, 16))
50834	30405850	Contemporary understanding of the kidney tumorigenesis points out that VHL mutations are truncal and its inactivation and subsequent hyperactivity of HIF2 axis is almost ubiquitous in ccRCC, other frequently mutated genes including BAP1 are considered branch events in response to selection.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('ccRCC', 'Phenotype', 'HP:0006770', (184, 189))	('tumor', 'Disease', (41, 46))	('VHL', 'Gene', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('hyperactivity of HIF2 axis', 'Disease', (133, 159))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('RCC', 'Disease', (186, 189))	('VHL', 'Gene', '7428', (71, 74))	('hyperactivity of HIF2 axis', 'Disease', 'MESH:C566610', (133, 159))	('hyperactivity', 'Phenotype', 'HP:0000752', (133, 146))	('mutations', 'Var', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
50835	30405850	Many studies have shown that BAP1 mutation confers worsened prognosis in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('mutation', 'Var', (34, 42))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('worsened', 'NegReg', (51, 59))	('BAP1', 'Gene', (29, 33))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))	('prognosis', 'MPA', (60, 69))
50838	30405850	Also, as there is a small proportion of ccRCC that is VHL/HIF2 independent, which are expected to fit our pan-negative category, the similar prognosis of such to BAP1 mutated cases also suggest that BAP1 deficient tumor is a standalone entity.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('VHL', 'Gene', (54, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('VHL', 'Gene', '7428', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('deficient tumor', 'Disease', 'MESH:D009369', (204, 219))	('mutated', 'Var', (167, 174))	('deficient tumor', 'Disease', (204, 219))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))
50841	30405850	Our annotation showed notably that BAP1 mutation is associated with Fc gamma R-mediated phagocytosis, Apoptosis, Amino sugar and nucleotide sugar metabolism, Base excision repair, Glycerophospholipid metabolism, Insulin signaling pathway, Homologous recombination, and Nucleotide excision repair.	('phagocytosis', 'biological_process', 'GO:0006909', ('88', '100'))	('BAP1', 'Gene', (35, 39))	('Amino sugar', 'Chemical', 'MESH:D000606', (113, 124))	('signaling pathway', 'biological_process', 'GO:0007165', ('220', '237'))	('Glycerophospholipid metabolism', 'biological_process', 'GO:0006650', ('180', '210'))	('nucleotide sugar metabolism', 'biological_process', 'GO:0009225', ('129', '156'))	('Insulin', 'molecular_function', 'GO:0016088', ('212', '219'))	('Glycerophospholipid', 'Chemical', 'MESH:D020404', (180, 199))	('nucleotide sugar', 'Chemical', '-', (129, 145))	('mutation', 'Var', (40, 48))	('Base excision repair', 'biological_process', 'GO:0006284', ('158', '178'))	('associated', 'Reg', (52, 62))	('Homologous', 'CPA', (239, 249))	('Homologous recombination', 'biological_process', 'GO:0035825', ('239', '263'))	('Insulin signaling pathway', 'Pathway', (212, 237))	('Glycerophospholipid metabolism', 'MPA', (180, 210))	('Apoptosis', 'CPA', (102, 111))	('Nucleotide excision repair', 'biological_process', 'GO:0006289', ('269', '295'))	('Base excision repair', 'MPA', (158, 178))
50842	30405850	For example, the immunomodulation annotation may indicate that BAP1 mutated ccRCC is specially associated with tumor infiltrated immunoresponse and may predict the effect of current novel PD1/PD-L1 therapies.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('BAP1', 'Gene', (63, 67))	('predict', 'Reg', (152, 159))	('RCC', 'Disease', (78, 81))	('tumor', 'Disease', (111, 116))	('PD-L1', 'Gene', '29126', (192, 197))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('PD-L1', 'Gene', (192, 197))	('PD1', 'Gene', '5133', (188, 191))	('mutated', 'Var', (68, 75))	('associated', 'Reg', (95, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('PD1', 'Gene', (188, 191))
50847	30405850	DNA repair is a highly conservative mechanism and impairment of such function may trigger tumorigenesis.	('DNA repair', 'biological_process', 'GO:0006281', ('0', '10'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('trigger', 'Reg', (82, 89))	('impairment', 'Var', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
50850	30405850	The most promising report of developing a transgenic kidney cancer model is by simultaneous inactivation of VHL an BAP1.	('inactivation', 'Var', (92, 104))	('VHL', 'Gene', '7428', (108, 111))	('kidney cancer', 'Phenotype', 'HP:0009726', (53, 66))	('kidney cancer', 'Disease', 'MESH:D007680', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('VHL', 'Gene', (108, 111))	('kidney cancer', 'Disease', (53, 66))
50857	30405850	LaFave et al reported Loss of BAP1 function leads to EZH2-dependent transformation, showing mesothelioma cells that lack BAP1 are sensitive to EZH2 pharmacologic inhibition, suggesting a novel therapeutic approach for BAP1-mutant malignancies.	('lack', 'NegReg', (116, 120))	('BAP1', 'Gene', (30, 34))	('malignancies', 'Disease', 'MESH:D009369', (230, 242))	('mesothelioma', 'Disease', 'MESH:D008654', (92, 104))	('Loss', 'Var', (22, 26))	('BAP1', 'Gene', (121, 125))	('malignancies', 'Disease', (230, 242))	('leads to', 'Reg', (44, 52))	('mesothelioma', 'Disease', (92, 104))
50859	30405850	BAP1 is frequently mutated in ccRCC and its function remains unknown.	('BAP1', 'Gene', (0, 4))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('mutated', 'Var', (19, 26))
50860	30405850	We performed in silico analysis of TCGA ccRCC database for expressional enrichments between BAP1 mutated and pan-negative cases.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('mutated', 'Var', (97, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('BAP1', 'Gene', (92, 96))
50887	30023241	One of the diagnostic criteria of ChRCC is Hale colloidal iron, and another is intracytoplasmic microvesicles observed by electron microscopy, but the eosinophilic variant of ChRCC is particularly difficult to distinguish from renal oncocytoma and CCRCC.	('renal oncocytoma', 'Disease', (227, 243))	('eosin', 'Chemical', 'MESH:D004801', (151, 156))	('eosinophilic', 'Var', (151, 163))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('RCC', 'Disease', (177, 180))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('iron', 'Chemical', 'MESH:D007501', (58, 62))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (177, 180))	('RCC', 'Disease', 'MESH:C538614', (250, 253))	('RCC', 'Phenotype', 'HP:0005584', (250, 253))	('RCC', 'Disease', (250, 253))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (227, 243))	('CCRCC', 'Phenotype', 'HP:0006770', (248, 253))	('renal oncocytoma', 'Disease', 'MESH:C537750', (227, 243))
50892	30023241	It is well known that KIT pathological activation through mutations may lead to neoplasia.	('mutations', 'Var', (58, 67))	('neoplasia', 'Disease', (80, 89))	('activation', 'PosReg', (39, 49))	('neoplasia', 'Disease', 'MESH:D009369', (80, 89))	('neoplasia', 'Phenotype', 'HP:0002664', (80, 89))	('KIT', 'molecular_function', 'GO:0005020', ('22', '25'))	('lead to', 'Reg', (72, 79))
50943	30023241	A few studies have documented vimentin positivity in 20% of ChRCCs and 9.7% of oncocytomas.	('oncocytomas', 'Disease', 'MESH:D018249', (79, 90))	('vimentin', 'cellular_component', 'GO:0045099', ('30', '38'))	('vimentin', 'Gene', '7431', (30, 38))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('vimentin', 'cellular_component', 'GO:0045098', ('30', '38'))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('oncocytomas', 'Disease', (79, 90))	('RCC', 'Disease', (62, 65))	('positivity', 'Var', (39, 49))	('vimentin', 'Gene', (30, 38))
50953	30023241	Our results coincided with those of Pradhan et al, who detected CK7 positivity in all cases of ChRCC, whereas all cases of CCRCCs and renal oncocytoma were negative.	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('positivity', 'Var', (68, 78))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('CCRCC', 'Phenotype', 'HP:0006770', (123, 128))	('CK7', 'Gene', (64, 67))	('renal oncocytoma', 'Disease', 'MESH:C537750', (134, 150))	('CK7', 'Gene', '3855', (64, 67))	('renal oncocytoma', 'Disease', (134, 150))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (134, 150))
50955	30023241	By contrast, Garcia and Li detected CK7 positivity in all cases of ChRCC and in 96% of renal oncocytomas.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (87, 103))	('renal oncocytomas', 'Disease', (87, 104))	('CK7', 'Gene', (36, 39))	('renal oncocytomas', 'Disease', 'MESH:C537750', (87, 104))	('CK7', 'Gene', '3855', (36, 39))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (87, 104))	('Garcia', 'Disease', (13, 19))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('Garcia', 'Disease', 'MESH:C536767', (13, 19))	('positivity', 'Var', (40, 50))
50972	29245961	To functionally investigate the role of XPNPEP-1 in ccRCC, we performed small-hairpin RNA mediated XPNPEP-1 expression silencing in 786-O ccRCC cells harboring a mutated VHL gene.	('XPNPEP-1', 'Gene', (99, 107))	('VHL', 'Gene', (170, 173))	('XPNPEP-1', 'Gene', '7511', (99, 107))	('mutated', 'Var', (162, 169))	('VHL', 'Gene', '7428', (170, 173))	('RNA', 'cellular_component', 'GO:0005562', ('86', '89'))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('XPNPEP-1', 'Gene', (40, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('XPNPEP-1', 'Gene', '7511', (40, 48))
50973	29245961	We found that XPNPEP-1 expression dampens cellular proliferation and migration.	('dampens', 'NegReg', (34, 41))	('XPNPEP-1', 'Gene', (14, 22))	('XPNPEP-1', 'Gene', '7511', (14, 22))	('expression', 'Var', (23, 33))	('cellular proliferation', 'CPA', (42, 64))
50979	29245961	Likewise, somatic mutation of the VHL gene is also a frequent event in sporadic ccRCC (occurring in non-VHL patients).	('ccRCC', 'Disease', (80, 85))	('VHL', 'Gene', '7428', (104, 107))	('somatic mutation', 'Var', (10, 26))	('VHL', 'Gene', (34, 37))	('patients', 'Species', '9606', (108, 116))	('VHL', 'Gene', '7428', (34, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('VHL', 'Gene', (104, 107))
50982	29245961	However, several in vitro and in vivo studies highlight that VHL inactivation alone is insufficient to cause the development of overt malignancies.	('malignancies', 'Disease', 'MESH:D009369', (134, 146))	('inactivation', 'Var', (65, 77))	('malignancies', 'Disease', (134, 146))	('VHL', 'Gene', (61, 64))	('cause', 'Reg', (103, 108))	('VHL', 'Gene', '7428', (61, 64))
51035	29245961	To this end, we chose the human renal cell adenocarcinoma cell line 786-O, which contains a mutated VHL gene.	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('renal cell adenocarcinoma', 'Disease', (32, 57))	('renal cell adenocarcinoma', 'Phenotype', 'HP:0005584', (32, 57))	('mutated', 'Var', (92, 99))	('VHL', 'Gene', (100, 103))	('human', 'Species', '9606', (26, 31))	('VHL', 'Gene', '7428', (100, 103))	('renal cell adenocarcinoma', 'Disease', 'MESH:C538614', (32, 57))
51082	29245961	The human renal cell adenocarcinoma cell line 786-O, which contains a mutated VHL gene, was purchased from Cell Line Services (Heidelberg, Germany) and cultured in Dulbecco's modified Eagle's medium (PAN) supplemented with 10 % fetal calf serum (PAN), 1 % non-essential amino acids, 1 % MEM vitamins and 1 % penicillin/streptomycin (all Gibco/Invitrogen) at 37  C in humidified air, containing 5 % CO2.	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (164, 198))	('human', 'Species', '9606', (4, 9))	('renal cell adenocarcinoma', 'Disease', (10, 35))	('VHL', 'Gene', (78, 81))	('renal cell adenocarcinoma', 'Disease', 'MESH:C538614', (10, 35))	('calf', 'Species', '9913', (234, 238))	('PAN', 'cellular_component', 'GO:0022623', ('246', '249'))	('penicillin', 'Chemical', 'MESH:D010406', (308, 318))	('VHL', 'Gene', '7428', (78, 81))	('renal cell adenocarcinoma', 'Phenotype', 'HP:0005584', (10, 35))	('CO2', 'Chemical', '-', (398, 401))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('PAN', 'cellular_component', 'GO:0022623', ('200', '203'))	('MEM vitamins', 'Chemical', '-', (287, 299))	('streptomycin', 'Chemical', 'MESH:D013307', (319, 331))	('mutated', 'Var', (70, 77))
51083	29245961	To reduce the expression of XPNPEP1, three different shRNA constructs were used: shRNA-ctrl (non-targeting shRNA, SHC002), shRNA-1 (TRCN 0000073927), shRNA-2 (TRCN 0000073923) (all Sigma-Aldrich).	('XPNPEP1', 'Gene', '7511', (28, 35))	('XPNPEP1', 'Gene', (28, 35))	('TRCN 0000073927', 'Var', (132, 147))	('TRCN 0000073923', 'Var', (159, 174))
51094	31034483	One start codon variant of unknown clinical significance (VUS) (c.3G>A, p.Met1Ile) and one missense VUS (c.631A>C, p.Met211Leu) was found in VHL in a patient with RCC-onset at twenty-eight years of age but without other manifestations or family history of von Hippel-Lindau (VHL).	('c.3G>A', 'Mutation', 'rs578091032', (64, 70))	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('VHL', 'Gene', '7428', (141, 144))	('patient', 'Species', '9606', (150, 157))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (256, 273))	('VUS', 'Chemical', '-', (58, 61))	('VUS', 'Chemical', '-', (100, 103))	('RCC-onset', 'Disease', 'MESH:C538614', (163, 172))	('p.Met211Leu', 'Mutation', 'rs200019083', (115, 126))	('von Hippel-Lindau', 'Disease', (256, 273))	('c.3G>A', 'Var', (64, 70))	('c.631A>C', 'Var', (105, 113))	('VHL', 'Gene', (275, 278))	('RCC-onset', 'Disease', (163, 172))	('c.631A>C', 'Mutation', 'rs200019083', (105, 113))	('VHL', 'Gene', (141, 144))	('p.Met1Ile', 'Mutation', 'rs578091032', (72, 81))	('VHL', 'Gene', '7428', (275, 278))
51095	31034483	Furthermore, in three families we found three different variants in BAP1, one of which was a novel non-segregating missense variant (c.1502G>A, p.Ser501Asn) in a family with two brothers affected with RCC.	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('p.Ser501Asn', 'Mutation', 'rs587777964', (144, 155))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('Ser', 'cellular_component', 'GO:0005790', ('146', '149'))	('BAP1', 'Gene', '8314', (68, 72))	('BAP1', 'Gene', (68, 72))	('c.1502G>A', 'Var', (133, 142))	('c.1502G>A', 'Mutation', 'rs587777964', (133, 142))
51096	31034483	Finally, we found the known E318K-substitution in MITF in a RCC-affected member of a family with multiple melanomas.	('MITF', 'Gene', '4286', (50, 54))	('MITF', 'Gene', (50, 54))	('E318K-substitution', 'Var', (28, 46))	('E318K', 'Mutation', 'rs149617956', (28, 33))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('multiple melanomas', 'Disease', (97, 115))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('melanomas', 'Phenotype', 'HP:0002861', (106, 115))	('multiple melanomas', 'Disease', 'MESH:D008545', (97, 115))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))
51098	31034483	Although we did find three VUS's in BAP1 in three families and a pathogenic variant in MITF in one family, pathogenic germline variants in BAP1, MITF or CDKN2B are not frequent causes of hereditary renal cancer in Denmark.	('MITF', 'Gene', '4286', (145, 149))	('variant', 'Var', (76, 83))	('CDKN2B', 'Gene', '1030', (153, 159))	('MITF', 'Gene', '4286', (87, 91))	('MITF', 'Gene', (145, 149))	('BAP1', 'Gene', '8314', (36, 40))	('MITF', 'Gene', (87, 91))	('variants', 'Var', (127, 135))	('hereditary renal cancer', 'Disease', 'MESH:D007680', (187, 210))	('hereditary renal cancer', 'Disease', (187, 210))	('BAP1', 'Gene', '8314', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	("VUS's", 'Disease', 'MESH:D010300', (27, 32))	('VUS', 'Disease', (27, 30))	('BAP1', 'Gene', (36, 40))	('CDKN2B', 'Gene', (153, 159))	('BAP1', 'Gene', (139, 143))	('renal cancer', 'Phenotype', 'HP:0009726', (198, 210))	('causes', 'Reg', (177, 183))
51110	31034483	The majority of hereditary RCCs are caused by pathogenic germline variants in the VHL gene (OMIM #608537) that causes von Hippel-Lindau syndrome (VHL), while other predisposing syndromes include hereditary leiomyomatosis and RCC (FH, OMIM#136850), Birt-Hogg-Dube (FLCN, OMIM #607273), hereditary papillary RCC (MET, OMIM#164860), hereditary paraganglioma and RCC (SDHB, OMIM#185470) and constitutional chromosome 3 translocations of t(3;8)(p14.2;q24.1) (reviewed in, OMIM#14470).	('hereditary leiomyomatosis', 'Disease', 'MESH:D018231', (195, 220))	('hereditary paraganglioma', 'Disease', 'MESH:D010235', (330, 354))	('SDHB', 'Gene', '6390', (364, 368))	('causes', 'Reg', (111, 117))	('paraganglioma', 'Phenotype', 'HP:0002668', (341, 354))	('t(3;8)(p14.2;q24.1)', 'STRUCTURAL_ABNORMALITY', 'None', (433, 452))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (306, 309))	('RCC', 'Disease', (225, 228))	('RCC', 'Disease', (306, 309))	('von Hippel-Lindau syndrome', 'Disease', (118, 144))	('RCC', 'Phenotype', 'HP:0005584', (225, 228))	('variants', 'Var', (66, 74))	('von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (118, 144))	('hereditary paraganglioma', 'Disease', (330, 354))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('SDHB', 'Gene', (364, 368))	('VHL', 'Gene', (146, 149))	('hereditary papillary RCC', 'Disease', 'MESH:C538614', (285, 309))	('RCC', 'Disease', 'MESH:C538614', (306, 309))	('RCC', 'Disease', (359, 362))	('RCC', 'Phenotype', 'HP:0005584', (359, 362))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('VHL', 'Gene', (82, 85))	('FLCN', 'Gene', '201163', (264, 268))	('hereditary leiomyomatosis', 'Disease', (195, 220))	('RCCs', 'Phenotype', 'HP:0005584', (27, 31))	('hereditary papillary RCC', 'Disease', (285, 309))	('RCC', 'Disease', 'MESH:C538614', (359, 362))	('FLCN', 'Gene', (264, 268))	('VHL', 'Gene', '7428', (146, 149))	('caused', 'Reg', (36, 42))	('VHL', 'Gene', '7428', (82, 85))	('chromosome', 'cellular_component', 'GO:0005694', ('402', '412'))
51111	31034483	However, for several multi-case or early onset RCC families, screening for known pathogenic variants in the most frequent causative genes VHL, FH, FLCN, and MET yields no eligible explanation for the accumulation of RCC in the family, suggesting that unknown genes predisposing for RCC most likely exist.	('FLCN', 'Gene', (147, 151))	('VHL', 'Gene', '7428', (138, 141))	('RCC', 'Disease', 'MESH:C538614', (282, 285))	('RCC', 'Disease', (282, 285))	('RCC', 'Phenotype', 'HP:0005584', (282, 285))	('FLCN', 'Gene', '201163', (147, 151))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('RCC', 'Disease', (216, 219))	('RCC', 'Phenotype', 'HP:0005584', (216, 219))	('VHL', 'Gene', (138, 141))	('variants', 'Var', (92, 100))
51114	31034483	A broad tumor spectrum accompanies BAP1 pathogenic germline variants and although this spectrum has not yet been fully elucidated, pathogenic variants in BAP1 is known to predispose to cutaneous and uveal melanoma and mesothelioma and is suspected of playing a role in the development of other cancers such as breast cancer, cholangiocarcinoma, cancer of the pancreas and basal cell carcinoma.	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (372, 392))	('BAP1', 'Gene', (154, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (383, 392))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('breast cancer', 'Disease', 'MESH:D001943', (310, 323))	('men', 'Species', '9606', (280, 283))	('BAP1', 'Gene', (35, 39))	('breast cancer', 'Disease', (310, 323))	('role', 'Reg', (261, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (334, 343))	('basal cell carcinoma', 'Disease', (372, 392))	('uveal melanoma and mesothelioma', 'Disease', 'MESH:C536494', (199, 230))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('cancers', 'Disease', (294, 301))	('cancer of the pancreas', 'Disease', (345, 367))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('cancer of the pancreas', 'Phenotype', 'HP:0002894', (345, 367))	('variants', 'Var', (142, 150))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (325, 343))	('playing', 'Reg', (251, 258))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('tumor', 'Disease', (8, 13))	('uveal melanoma', 'Phenotype', 'HP:0007716', (199, 213))	('cholangiocarcinoma', 'Disease', (325, 343))	('BAP1', 'Gene', '8314', (154, 158))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (325, 343))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (372, 392))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('BAP1', 'Gene', '8314', (35, 39))	('cancers', 'Disease', 'MESH:D009369', (294, 301))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('predispose', 'Reg', (171, 181))	('variants', 'Var', (60, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (310, 323))	('cancer of the pancreas', 'Disease', 'MESH:D010190', (345, 367))
51115	31034483	Furthermore BAP1 has been found to be mutated in tissue from sporadic malignant renal tumors, which are associated with a high tumor grade and bad prognosis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mutated', 'Var', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('malignant renal tumors', 'Disease', 'MESH:D007674', (70, 92))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (86, 91))	('renal tumor', 'Phenotype', 'HP:0009726', (80, 91))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('BAP1', 'Gene', '8314', (12, 16))	('renal tumors', 'Phenotype', 'HP:0009726', (80, 92))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('BAP1', 'Gene', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('malignant renal tumors', 'Disease', (70, 92))
51116	31034483	Pathogenic germline variants have been found to segregate with the disease in high risk RCC families in France and the US, indicating that RCC might be an integral part of the BAP1 tumor spectrum.	('variants', 'Var', (20, 28))	('tumor', 'Disease', (181, 186))	('BAP1', 'Gene', '8314', (176, 180))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('RCC', 'Disease', (139, 142))	('BAP1', 'Gene', (176, 180))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
51118	31034483	In 2011 Bertolotto et al discovered a germline amino acid substitution (E318K) in MITF (OMIM#156845) that occurred with a significantly higher frequency in patients with melanoma, RCC or both cancers when compared to controls.	('patients', 'Species', '9606', (156, 164))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('melanoma', 'Disease', (170, 178))	('RCC', 'Disease', (180, 183))	('RCC', 'Phenotype', 'HP:0005584', (180, 183))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('MITF', 'Gene', (82, 86))	('MITF', 'Gene', '4286', (82, 86))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('cancers', 'Disease', (192, 199))	('E318K', 'Mutation', 'rs149617956', (72, 77))	('E318K', 'Var', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
51119	31034483	The E318K variant has been found to increase growth, proliferation and migration of melanocytes and renal cells, and although the full picture of MITFs contribution to oncogenesis is yet unknown, the variant is thought to enable MITF to act as an oncogene and thereby predispose to melanoma and RCC.	('melanoma', 'Disease', (282, 290))	('MITF', 'Gene', '4286', (229, 233))	('MITF', 'Gene', (229, 233))	('E318K', 'Mutation', 'rs149617956', (4, 9))	('melanoma', 'Disease', 'MESH:D008545', (282, 290))	('oncogenesis', 'biological_process', 'GO:0007048', ('168', '179'))	('growth', 'CPA', (45, 51))	('increase', 'PosReg', (36, 44))	('E318K', 'Var', (4, 9))	('RCC', 'Phenotype', 'HP:0005584', (295, 298))	('enable', 'PosReg', (222, 228))	('RCC', 'Disease', 'MESH:C538614', (295, 298))	('RCC', 'Disease', (295, 298))	('MITF', 'Gene', (146, 150))	('predispose to', 'Reg', (268, 281))	('MITF', 'Gene', '4286', (146, 150))	('melanoma', 'Phenotype', 'HP:0002861', (282, 290))
51120	31034483	CDKN2B (OMIM#600431) is located close to the tumor suppressor gene CDKN2A in region 9p21.3 on the short arm of chromosome 9; a region that often contains genetic alterations and is involved in the development of several types of tumors.	('CDKN2A', 'Gene', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (45, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('111', '121'))	('CDKN2B', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('short arm', 'Phenotype', 'HP:0009824', (98, 107))	('CDKN2A', 'Gene', '1029', (67, 73))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('45', '61'))	('tumors', 'Disease', (229, 235))	('CDKN2B', 'Gene', '1030', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor suppressor', 'biological_process', 'GO:0051726', ('45', '61'))	('contains', 'Reg', (145, 153))	('involved', 'Reg', (181, 189))	('tumor', 'Disease', (229, 234))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('men', 'Species', '9606', (204, 207))	('genetic alterations', 'Var', (154, 173))
51124	31034483	DNA was available from five family members of whom the variant was found in two affected brothers and not in three of their cancer free siblings.	('variant', 'Var', (55, 62))	('cancer', 'Disease', (124, 130))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
51125	31034483	Furthermore, two novel missense variants in CDKN2B were found in a cohort of fifty individuals with features of nonsyndromic hereditary RCC.	('missense variants', 'Var', (23, 40))	('CDKN2B', 'Gene', (44, 50))	('nonsyndromic hereditary RCC', 'Disease', (112, 139))	('nonsyndromic hereditary RCC', 'Disease', 'MESH:C538614', (112, 139))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('CDKN2B', 'Gene', '1030', (44, 50))	('found', 'Reg', (56, 61))
51126	31034483	In this study we have examined whether pathogenic variants in BAP1, MITF or CDKN2B play a role in the development of RCC.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('BAP1', 'Gene', '8314', (62, 66))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('CDKN2B', 'Gene', '1030', (76, 82))	('MITF', 'Gene', '4286', (68, 72))	('MITF', 'Gene', (68, 72))	('BAP1', 'Gene', (62, 66))	('variants', 'Var', (50, 58))	('men', 'Species', '9606', (109, 112))	('CDKN2B', 'Gene', (76, 82))
51127	31034483	In Denmark, patients with early onset RCC and families with accumulation of RCCs are usually screened for variants in four genes: VHL, FH, FLCN and MET.	('RCC', 'Disease', (38, 41))	('patients', 'Species', '9606', (12, 20))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('variants', 'Var', (106, 114))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('RCCs', 'Phenotype', 'HP:0005584', (76, 80))	('FLCN', 'Gene', (139, 143))	('VHL', 'Gene', (130, 133))	('VHL', 'Gene', '7428', (130, 133))	('MET', 'Gene', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('FLCN', 'Gene', '201163', (139, 143))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
51128	31034483	At Copenhagen University Hospital SDHB-screening is also performed, since pathogenic variants in SDHB are correlated with an increased risk of paraganglioma, pheochromocytoma and RCC and standard chromosome analysis is performed to examine for the known chromosome translocation t(3;8)(p14.2;q24.1).	('SDHB', 'Gene', (97, 101))	('pheochromocytoma', 'Disease', 'MESH:D010673', (158, 174))	('chromosome', 'cellular_component', 'GO:0005694', ('196', '206'))	('SDHB', 'Gene', '6390', (97, 101))	('variants', 'Var', (85, 93))	('paraganglioma', 'Phenotype', 'HP:0002668', (143, 156))	('paraganglioma', 'Disease', (143, 156))	('chromosome', 'cellular_component', 'GO:0005694', ('254', '264'))	('pheochromocytoma', 'Disease', (158, 174))	('SDHB', 'Gene', '6390', (34, 38))	('t(3;8)(p14.2;q24.1)', 'STRUCTURAL_ABNORMALITY', 'None', (279, 298))	('SDHB', 'Gene', (34, 38))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (158, 174))	('RCC', 'Phenotype', 'HP:0005584', (179, 182))	('paraganglioma', 'Disease', 'MESH:D010235', (143, 156))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('RCC', 'Disease', (179, 182))
51129	31034483	We have performed analyses of the aforementioned RCC causative genes and screened for variants in the putative RCC genes BAP1, MITF and CDKN2B.	('RCC', 'Disease', (49, 52))	('BAP1', 'Gene', '8314', (121, 125))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('MITF', 'Gene', '4286', (127, 131))	('MITF', 'Gene', (127, 131))	('CDKN2B', 'Gene', (136, 142))	('BAP1', 'Gene', (121, 125))	('variants', 'Var', (86, 94))	('CDKN2B', 'Gene', '1030', (136, 142))	('men', 'Species', '9606', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
51134	31034483	Patients with a previously identified pathogenic variant in a renal cancer predisposition gene were not included.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('renal cancer', 'Disease', (62, 74))	('renal cancer', 'Phenotype', 'HP:0009726', (62, 74))	('Patients', 'Species', '9606', (0, 8))	('renal cancer', 'Disease', 'MESH:D007680', (62, 74))	('variant', 'Var', (49, 56))
51138	31034483	Cohort 1 comprises thirty-two families, who had already been through genetic counselling and hence been screened for variants in one or more of the RCC predisposition genes VHL, FH, FLCN and MET without identification of any pathogenic mutations.	('VHL', 'Gene', (173, 176))	('RCC', 'Disease', (148, 151))	('FLCN', 'Gene', (182, 186))	('VHL', 'Gene', '7428', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('variants', 'Var', (117, 125))	('FLCN', 'Gene', '201163', (182, 186))	('screened', 'Reg', (104, 112))
51143	31034483	These patients only consented to screening for variants in BAP1 and the known E318K-variant in MITF, which was performed prior to this study.	('variants', 'Var', (47, 55))	('BAP1', 'Gene', (59, 63))	('MITF', 'Gene', '4286', (95, 99))	('MITF', 'Gene', (95, 99))	('patients', 'Species', '9606', (6, 14))	('E318K', 'Mutation', 'rs149617956', (78, 83))	('BAP1', 'Gene', '8314', (59, 63))	('E318K-variant', 'Var', (78, 91))
51164	31034483	MITF was screened for the E318K variant by TaqMan analysis as recently described.	('E318K', 'Mutation', 'rs149617956', (26, 31))	('MITF', 'Gene', '4286', (0, 4))	('E318K', 'Var', (26, 31))	('MITF', 'Gene', (0, 4))
51166	31034483	BAP1, MITF and VHL variants are numbered according to accession number NM_004656.3, NM_000248.3 and NM_000551.3, respectively, following the guidelines from the Human Genome Variation Society (http://www.hgvs.org/varnomen).	('Human', 'Species', '9606', (161, 166))	('BAP1', 'Gene', (0, 4))	('VHL', 'Gene', (15, 18))	('NM_000248.3', 'Var', (84, 95))	('VHL', 'Gene', '7428', (15, 18))	('BAP1', 'Gene', '8314', (0, 4))	('men', 'Species', '9606', (218, 221))	('MITF', 'Gene', '4286', (6, 10))	('MITF', 'Gene', (6, 10))	('NM_000551.3', 'Var', (100, 111))	('variants', 'Var', (19, 27))	('NM_004656.3', 'Var', (71, 82))
51168	31034483	'Likely benign' and 'benign' variants have a low probability of actually being pathogenic (0.001-0.049 and lower than 0.001, respectively) and are treated as 'no mutation detected' for RCC.	('RCC', 'Disease', (185, 188))	('variants', 'Var', (29, 37))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('RCC', 'Disease', 'MESH:C538614', (185, 188))
51176	31034483	Sixteen patients were screened for variants in one or more of the RCC predisposition genes VHL, FH, FLCN, MET or SDHB (Table 2).	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('FLCN', 'Gene', (100, 104))	('SDHB', 'Gene', '6390', (113, 117))	('MET', 'Gene', (106, 109))	('variants', 'Var', (35, 43))	('VHL', 'Gene', (91, 94))	('SDHB', 'Gene', (113, 117))	('screened', 'Reg', (22, 30))	('VHL', 'Gene', '7428', (91, 94))	('FLCN', 'Gene', '201163', (100, 104))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('patients', 'Species', '9606', (8, 16))
51177	31034483	No pathogenic variants were found in FH, FLCN, MET or SDHB, but we did find a start codon variant (c.3G>A, p.Met1Ile) and a missense variant (c.631A>C, p.Met211Leu) in VHL in a patient from cohort 2 (Fig 3).	('FLCN', 'Gene', (41, 45))	('c.631A>C', 'Var', (142, 150))	('SDHB', 'Gene', '6390', (54, 58))	('SDHB', 'Gene', (54, 58))	('VHL', 'Gene', (168, 171))	('p.Met1Ile', 'Mutation', 'rs578091032', (107, 116))	('c.3G>A', 'Var', (99, 105))	('FLCN', 'Gene', '201163', (41, 45))	('c.631A>C', 'Mutation', 'rs200019083', (142, 150))	('p.Met211Leu', 'Mutation', 'rs200019083', (152, 163))	('VHL', 'Gene', '7428', (168, 171))	('patient', 'Species', '9606', (177, 184))	('c.3G>A', 'Mutation', 'rs578091032', (99, 105))
51178	31034483	Both VHL variants are classified as class 3 variants (VUS) according to the classification guidelines from IARC.	('variants', 'Var', (9, 17))	('VUS', 'Chemical', '-', (54, 57))	('VHL', 'Gene', (5, 8))	('VHL', 'Gene', '7428', (5, 8))
51179	31034483	In three patients of forty-seven tested, we found variants in BAP1; two missense variants (c.944A>C, p.Glu315Ala, Fig 4) and (c.1502G>A, p.Ser501Asn, Fig 5) and one intron variant (c.1729+8T>C, Table 3).	('p.Ser501Asn', 'Mutation', 'rs587777964', (137, 148))	('patients', 'Species', '9606', (9, 17))	('BAP1', 'Gene', '8314', (62, 66))	('c.944A>C', 'Var', (91, 99))	('p.Glu315Ala', 'Mutation', 'rs149974450', (101, 112))	('c.1502G>A', 'Mutation', 'rs587777964', (126, 135))	('Ser', 'cellular_component', 'GO:0005790', ('139', '142'))	('BAP1', 'Gene', (62, 66))	('c.1729+8T>C', 'Mutation', 'rs150945583', (181, 192))	('c.944A>C', 'Mutation', 'rs149974450', (91, 99))	('c.1502G>A', 'Var', (126, 135))
51180	31034483	The missense variant c.944A>C, p.Glu315Ala is reported in the gnomAD database with a frequency of 0.016% in Europeans (non-Finnish).	('c.944A>C', 'Var', (21, 29))	('p.Glu315Ala', 'Var', (31, 42))	('p.Glu315Ala', 'Mutation', 'rs149974450', (31, 42))	('c.944A>C', 'Mutation', 'rs149974450', (21, 29))
51181	31034483	The intron variant c.1729+8T>C (rs150945583), which is identified in the patient with two VHL variants, is reported in the gnomAD database with a frequency of 0.60% in Europeans (non-Finnish).	('VHL', 'Gene', '7428', (90, 93))	('rs150945583', 'Mutation', 'rs150945583', (32, 43))	('c.1729+8T>C', 'Mutation', 'rs150945583', (19, 30))	('patient', 'Species', '9606', (73, 80))	('VHL', 'Gene', (90, 93))	('c.1729+8T>C', 'Var', (19, 30))
51182	31034483	Finally, the novel missense variant c.1502G>A, p.Ser501Asn is not reported in the gnomAD database and to our knowledge not in the literature, and is classified as a class 3 variant.	('Ser', 'cellular_component', 'GO:0005790', ('49', '52'))	('p.Ser501Asn', 'Mutation', 'rs587777964', (47, 58))	('p.Ser501Asn', 'Var', (47, 58))	('c.1502G>A', 'Var', (36, 45))	('c.1502G>A', 'Mutation', 'rs587777964', (36, 45))
51183	31034483	Sequencing for the E318K-variant in MITF was performed in forty-five patients with normal results.	('MITF', 'Gene', '4286', (36, 40))	('MITF', 'Gene', (36, 40))	('patients', 'Species', '9606', (69, 77))	('E318K', 'Mutation', 'rs149617956', (19, 24))	('E318K-variant', 'Var', (19, 32))
51184	31034483	In one family, we were able to collect DNA from two relatives with RCC and both were screened for the E318K variant with normal results.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('E318K', 'Mutation', 'rs149617956', (102, 107))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('E318K', 'Var', (102, 107))
51185	31034483	In one family, the patient diagnosed with RCC was found to carry the E318K variant.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('patient', 'Species', '9606', (19, 26))	('E318K', 'Mutation', 'rs149617956', (69, 74))	('E318K', 'Var', (69, 74))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))
51187	31034483	Two daughters were diagnosed with melanoma, one of whom was a carrier of the E318K-variant.	('E318K-variant', 'Var', (77, 90))	('carrier', 'molecular_function', 'GO:0005215', ('62', '69'))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))	('diagnosed', 'Reg', (19, 28))	('E318K', 'Mutation', 'rs149617956', (77, 82))
51201	31034483	Forty-six families in the current study, including thirteen families with melanoma, have been screened for the known E318K-variant in MITF, but the variant has only been found in one family, which has previously been published.	('E318K', 'Mutation', 'rs149617956', (117, 122))	('MITF', 'Gene', '4286', (134, 138))	('MITF', 'Gene', (134, 138))	('E318K-variant', 'Var', (117, 130))	('melanoma', 'Disease', (74, 82))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))
51204	31034483	The c.1502G>A, p.Ser501Asn variant in BAP1 in family 1013 has not previously been reported.	('c.1502G>A', 'Var', (4, 13))	('p.Ser501Asn', 'Var', (15, 26))	('BAP1', 'Gene', (38, 42))	('c.1502G>A', 'Mutation', 'rs587777964', (4, 13))	('Ser', 'cellular_component', 'GO:0005790', ('17', '20'))	('p.Ser501Asn', 'Mutation', 'rs587777964', (15, 26))	('BAP1', 'Gene', '8314', (38, 42))
51205	31034483	Pathogenic clues include the highly conserved nucleotide and amino acid involved, and a SIFT and MutationTaster prediction as 'deleterious'.	('MutationTaster', 'Var', (97, 111))	('SIFT', 'Disease', (88, 92))	('SIFT', 'Disease', 'None', (88, 92))
51206	31034483	However, the variant was not found in two cancer-free FFPE samples collected from the proband's brother also diagnosed with RCC (II:1, Fig 5) and thus did not segregate with RCC in the family.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('variant', 'Var', (13, 20))	('cancer', 'Disease', (42, 48))	('RCC', 'Disease', (174, 177))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('RCC', 'Disease', 'MESH:C538614', (174, 177))
51209	31034483	The c.944A>C, p.Glu315Ala variant in BAP1 in family 5001 has not been reported in families with BAP1-associated cancers but has a population frequency of 0.016%.	('BAP1', 'Gene', (96, 100))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('c.944A>C', 'Var', (4, 12))	('p.Glu315Ala', 'Var', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('c.944A>C', 'Mutation', 'rs149974450', (4, 12))	('BAP1', 'Gene', '8314', (37, 41))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('BAP1', 'Gene', (37, 41))	('p.Glu315Ala', 'Mutation', 'rs149974450', (14, 25))	('BAP1', 'Gene', '8314', (96, 100))
51213	31034483	The start codon variant (c.3G>A, p.Met1Ile) and missense variant (c.631A>C, p.Met211Leu) in VHL in family 6002 was found in a patient (III:1, Fig 3), who was diagnosed with ccRCC at age twenty-eight, but neither he nor any family member have other VHL-manifestations.	('c.3G>A', 'Var', (25, 31))	('p.Met211Leu', 'Mutation', 'rs200019083', (76, 87))	('p.Met1Ile', 'Mutation', 'rs578091032', (33, 42))	('c.631A>C', 'Var', (66, 74))	('c.3G>A', 'Mutation', 'rs578091032', (25, 31))	('VHL', 'Gene', (92, 95))	('patient', 'Species', '9606', (126, 133))	('p.Met211Leu', 'Var', (76, 87))	('VHL', 'Gene', '7428', (92, 95))	('RCC', 'Disease', (175, 178))	('c.631A>C', 'Mutation', 'rs200019083', (66, 74))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('VHL', 'Gene', (248, 251))	('RCC', 'Disease', 'MESH:C538614', (175, 178))	('VHL', 'Gene', '7428', (248, 251))
51214	31034483	The start codon variant substitutes the initial methionine, thus skipping the native start codon with a yet unknown effect on VHL translation.	('translation', 'biological_process', 'GO:0006412', ('130', '141'))	('variant', 'Var', (16, 23))	('methionine', 'Chemical', 'MESH:D008715', (48, 58))	('VHL', 'Gene', (126, 129))	('methionine', 'MPA', (48, 58))	('skipping', 'NegReg', (65, 73))	('VHL', 'Gene', '7428', (126, 129))
51215	31034483	An alternative start codon at codon 54, which harbors the next methionine, is presumed to initiate VHL translation, thus forming an alternative protein product, which is thought to possess tumor suppressor properties partially similar to wildtype VHL.	('tumor', 'Disease', (189, 194))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('methionine', 'Var', (63, 73))	('VHL', 'Gene', (99, 102))	('tumor suppressor', 'biological_process', 'GO:0051726', ('189', '205'))	('VHL', 'Gene', '7428', (99, 102))	('VHL', 'Gene', (247, 250))	('translation', 'biological_process', 'GO:0006412', ('103', '114'))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('VHL', 'Gene', '7428', (247, 250))	('methionine', 'Chemical', 'MESH:D008715', (63, 73))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('189', '205'))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
51218	31034483	It is possible that mosaicism of a third, and pathogenic, variant in VHL could explain the mild VHL-phenotype.	('variant', 'Var', (58, 65))	('VHL', 'Gene', (96, 99))	('VHL', 'Gene', (69, 72))	('VHL', 'Gene', '7428', (96, 99))	('VHL', 'Gene', '7428', (69, 72))
51221	31034483	Evidence suggests that the E318K-variant plays a role in the development of melanoma but the role in the development of RCC is unclear.	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('E318K', 'Mutation', 'rs149617956', (27, 32))	('E318K-variant', 'Var', (27, 40))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('men', 'Species', '9606', (112, 115))	('men', 'Species', '9606', (68, 71))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
51222	31034483	Recent studies do not find an association between the E318K-variant and the development of RCC, neither does the current study.	('E318K', 'Mutation', 'rs149617956', (54, 59))	('men', 'Species', '9606', (83, 86))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('E318K-variant', 'Var', (54, 67))
51223	31034483	A possible association between the E318K-variant and the development of pheochromocytoma and paraganglioma has been proposed recently by Castro-Vega et al, illustrating that the cancer spectrum of the E318K-variant, if any, is not yet fully elucidated.	('pheochromocytoma', 'Disease', (72, 88))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('pheochromocytoma', 'Disease', 'MESH:D010673', (72, 88))	('paraganglioma', 'Disease', 'MESH:D010235', (93, 106))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (72, 88))	('E318K-variant', 'Var', (201, 214))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('E318K-variant', 'Var', (35, 48))	('paraganglioma', 'Disease', (93, 106))	('E318K', 'Mutation', 'rs149617956', (35, 40))	('paraganglioma', 'Phenotype', 'HP:0002668', (93, 106))	('men', 'Species', '9606', (64, 67))	('E318K', 'Mutation', 'rs149617956', (201, 206))
51224	31034483	Further studies should be performed in renal cancer families to elucidate the impact of the E318K-variant in the development of RCC.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('renal cancer', 'Disease', 'MESH:D007680', (39, 51))	('RCC', 'Disease', (128, 131))	('renal cancer', 'Phenotype', 'HP:0009726', (39, 51))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('renal cancer', 'Disease', (39, 51))	('E318K', 'Mutation', 'rs149617956', (92, 97))	('E318K-variant', 'Var', (92, 105))	('men', 'Species', '9606', (120, 123))
51225	31034483	We found no variants in CDKN2B and are therefore not able to confirm the findings of Jafri et al regarding CDKN2B as a RCC predisposing gene.	('CDKN2B', 'Gene', '1030', (107, 113))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('CDKN2B', 'Gene', (24, 30))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('variants', 'Var', (12, 20))	('RCC', 'Disease', (119, 122))	('CDKN2B', 'Gene', '1030', (24, 30))	('CDKN2B', 'Gene', (107, 113))
51226	31034483	Two different putative RCC-genes include PTEN known for its involvement in Cowden syndrome, in which patients have a genetic predisposition to RCC, and PBRM1 in which a heterozygote germline variant was found to segregate with RCC in four affected family members in a French RCC-family.	('involvement', 'Reg', (60, 71))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('PBRM1', 'Gene', (152, 157))	('Cowden syndrome', 'Disease', 'MESH:D006223', (75, 90))	('RCC', 'Disease', (227, 230))	('RCC', 'Disease', 'MESH:C538614', (275, 278))	('patients', 'Species', '9606', (101, 109))	('RCC', 'Phenotype', 'HP:0005584', (227, 230))	('variant', 'Var', (191, 198))	('PTEN', 'Gene', (41, 45))	('RCC', 'Disease', 'MESH:C538614', (227, 230))	('Cowden syndrome', 'Disease', (75, 90))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('RCC', 'Disease', (143, 146))	('PTEN', 'Gene', '5728', (41, 45))	('men', 'Species', '9606', (67, 70))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('RCC', 'Disease', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('PBRM1', 'Gene', '55193', (152, 157))	('RCC', 'Disease', (275, 278))	('RCC', 'Phenotype', 'HP:0005584', (275, 278))
51227	31034483	The proband of one family in the current study was screened for variants in PTEN prior to inclusion, but in the remaining families PTEN screening was not considered relevant by the Departments of Clinical Genetics initially performing the genetic counselling.	('PTEN', 'Gene', (131, 135))	('PTEN', 'Gene', (76, 80))	('PTEN', 'Gene', '5728', (131, 135))	('men', 'Species', '9606', (187, 190))	('PTEN', 'Gene', '5728', (76, 80))	('variants', 'Var', (64, 72))
51248	31034483	Here ten different histological subtypes of RCCs are described (clear cell, multilocular cystic, papillary, chromophobe, collecting duct carcinoma, medullary carcinoma, RCC associated with Xp11.2 translocations, RCC associated with neuroblastoma, mucinous, tubular and spindle cell carcinomas and the unclassified carcinomas).	('associated', 'Reg', (216, 226))	('neuroblastoma', 'Disease', (232, 245))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (212, 215))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('neuroblastoma', 'Phenotype', 'HP:0003006', (232, 245))	('spindle', 'cellular_component', 'GO:0005819', ('269', '276'))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('carcinoma', 'Disease', 'MESH:D002277', (282, 291))	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('neuroblastoma', 'Disease', 'MESH:D009447', (232, 245))	('RCC', 'Disease', (169, 172))	('carcinoma', 'Disease', 'MESH:D002277', (314, 323))	('carcinomas', 'Disease', (282, 292))	('carcinomas', 'Disease', (314, 324))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('carcinoma', 'Disease', 'MESH:D002277', (137, 146))	('associated', 'Reg', (173, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('carcinoma', 'Disease', (158, 167))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('mucinous', 'Disease', (247, 255))	('RCCs', 'Phenotype', 'HP:0005584', (44, 48))	('Xp11.2', 'Gene', (189, 195))	('translocations', 'Var', (196, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('carcinomas', 'Disease', 'MESH:D002277', (282, 292))	('carcinomas', 'Phenotype', 'HP:0030731', (282, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (314, 323))	('carcinomas', 'Phenotype', 'HP:0030731', (314, 324))	('carcinoma', 'Disease', (282, 291))	('carcinomas', 'Disease', 'MESH:D002277', (314, 324))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('carcinoma', 'Disease', 'MESH:D002277', (158, 167))	('RCC', 'Disease', (212, 215))	('carcinoma', 'Disease', (314, 323))	('carcinoma', 'Disease', (137, 146))
51253	31034483	Few E318K-carriers have been diagnosed with RCC, but the most prevalent histological subtype described in the literature is clear cell carcinoma.	('E318K', 'Mutation', 'rs149617956', (4, 9))	('carcinoma', 'Disease', 'MESH:D002277', (135, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('E318K-carriers', 'Var', (4, 18))	('carcinoma', 'Disease', (135, 144))
51260	31034483	We screened forty-nine family members in forty-eight families for variants in one or more of the RCC causative genes VHL (n = 10), FH (n = 11), FLCN (n = 10), MET (n = 11) and SDHB (n = 9) and the putative RCC-genes BAP1 (n = 47), MITF (n = 46) and CDKN2B (n = 43).	('MITF', 'Gene', '4286', (231, 235))	('FLCN', 'Gene', (144, 148))	('BAP1', 'Gene', (216, 220))	('SDHB', 'Gene', (176, 180))	('MET', 'Gene', (159, 162))	('CDKN2B', 'Gene', '1030', (249, 255))	('VHL', 'Gene', (117, 120))	('MITF', 'Gene', (231, 235))	('variants', 'Var', (66, 74))	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('VHL', 'Gene', '7428', (117, 120))	('BAP1', 'Gene', '8314', (216, 220))	('RCC', 'Phenotype', 'HP:0005584', (206, 209))	('RCC', 'Disease', (206, 209))	('SDHB', 'Gene', '6390', (176, 180))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('FLCN', 'Gene', '201163', (144, 148))	('CDKN2B', 'Gene', (249, 255))	('RCC', 'Disease', 'MESH:C538614', (206, 209))
51262	31034483	Furthermore, we found three VUS's in BAP1, of which one was novel and non-segregating in the family, and the E318K variant in MITF in one patient of a family with melanoma and RCC.	('E318K', 'Mutation', 'rs149617956', (109, 114))	('RCC', 'Disease', (176, 179))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('E318K', 'Var', (109, 114))	("VUS's", 'Disease', 'MESH:D010300', (28, 33))	('MITF', 'Gene', '4286', (126, 130))	('MITF', 'Gene', (126, 130))	('BAP1', 'Gene', '8314', (37, 41))	('patient', 'Species', '9606', (138, 145))	('BAP1', 'Gene', (37, 41))	('VUS', 'Disease', (28, 31))
51263	31034483	Since the BAP1 variants are classified as VUS's, a standardized surveillance program for variant carriers is not relevant.	('BAP1', 'Gene', (10, 14))	("VUS's", 'Disease', 'MESH:D010300', (42, 47))	('variants', 'Var', (15, 23))	('VUS', 'Disease', (42, 45))	('BAP1', 'Gene', '8314', (10, 14))
51264	31034483	A surveillance program has not been established for E318K variant carriers, but increased awareness of potentially malignant cutaneous lesions and symptoms of renal disease should be advised.	('renal disease', 'Disease', 'MESH:D007674', (159, 172))	('malignant cutaneous lesions', 'Disease', (115, 142))	('E318K', 'Mutation', 'rs149617956', (52, 57))	('malignant cutaneous lesions', 'Disease', 'MESH:D009369', (115, 142))	('renal disease', 'Disease', (159, 172))	('E318K', 'Var', (52, 57))	('renal disease', 'Phenotype', 'HP:0000112', (159, 172))
51266	31034483	The results of the study indicate that germline variants in BAP1, MITF and CDKN2B are not frequent in Danish families with suspected hereditary predisposition to renal cancer, and in the families of this study a possible genetic background of RCC is still unresolved.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('variants', 'Var', (48, 56))	('CDKN2B', 'Gene', (75, 81))	('renal cancer', 'Disease', (162, 174))	('RCC', 'Disease', 'MESH:C538614', (243, 246))	('RCC', 'Disease', (243, 246))	('BAP1', 'Gene', '8314', (60, 64))	('CDKN2B', 'Gene', '1030', (75, 81))	('renal cancer', 'Disease', 'MESH:D007680', (162, 174))	('renal cancer', 'Phenotype', 'HP:0009726', (162, 174))	('RCC', 'Phenotype', 'HP:0005584', (243, 246))	('MITF', 'Gene', '4286', (66, 70))	('MITF', 'Gene', (66, 70))	('BAP1', 'Gene', (60, 64))
51344	27549611	Based on CDH1, CK18 and CK19 negativity (low expression) and S100A4 and VIM positivity (high expression), patients were considered to be EMT positive (EMT+, n = 6).	('EMT', 'biological_process', 'GO:0001837', ('151', '154'))	('EMT', 'Gene', (151, 154))	('EMT', 'Gene', (137, 140))	('CK18', 'Gene', '3875', (15, 19))	('EMT', 'Gene', '3702', (137, 140))	('EMT', 'Gene', '3702', (151, 154))	('VIM', 'Gene', (72, 75))	('S100A4', 'Gene', (61, 67))	('CK19', 'Gene', '3880', (24, 28))	('CDH1', 'Gene', '999', (9, 13))	('S100A4', 'Gene', '6275', (61, 67))	('CDH1', 'Gene', (9, 13))	('patients', 'Species', '9606', (106, 114))	('CK18', 'Gene', (15, 19))	('EMT', 'biological_process', 'GO:0001837', ('137', '140'))	('VIM', 'Gene', '7431', (72, 75))	('CK19', 'Gene', (24, 28))	('negativity', 'Var', (29, 39))
51430	27549611	Interestingly, deregulation of these genes in RCC tumor tissue is highly significant and present in almost all cases (Fig.	('deregulation', 'Var', (15, 27))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('RCC tumor', 'Disease', (46, 55))	('RCC tumor', 'Disease', 'MESH:C538614', (46, 55))
51504	28972818	The following antibodies were used in this study: CgA (M0869, Dako, Glostrup, Denmark, 1:200), synaptophysin (M7315, Dako, 1:200), NSE (BBS/NC/VI-H14, Dako, 1:200), CD56 (123C3, Dako, 1:50), and secretagogin (MAb 4878, R&D Systems, Minneapolis, MN, 1:200).	('M0869', 'Var', (55, 60))	('M7315', 'Var', (110, 115))	('MN', 'CellLine', 'CVCL:U508', (245, 247))
51619	28972818	Interestingly, the carcinomas of the stomach with focal NSE expression also expressed one or more other NE markers in the same areas, thus supporting the finding of NE differentiation in these tumors.	('NSE', 'Gene', (56, 59))	('carcinomas of the stomach', 'Disease', 'MESH:D013274', (19, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('carcinomas', 'Phenotype', 'HP:0030731', (19, 29))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('focal', 'Var', (50, 55))	('carcinomas of the stomach', 'Disease', (19, 44))	('carcinomas of the stomach', 'Phenotype', 'HP:0006753', (19, 44))
51659	31920398	qRT-PCR showed IREB2 expression was downregulated in ccRCC cancer tissues and high IREB2 expression had a longer overall survival (OS) and disease-free survival (DFS).	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('ccRCC', 'Disease', (53, 58))	('expression', 'MPA', (89, 99))	('high', 'Var', (78, 82))	('IREB2', 'Gene', '3658', (83, 88))	('longer', 'PosReg', (106, 112))	('ccRCC', 'Disease', 'MESH:D002292', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('expression', 'MPA', (21, 31))	('IREB2', 'Gene', (83, 88))	('overall survival', 'CPA', (113, 129))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('disease-free survival', 'CPA', (139, 160))	('IREB2', 'Gene', (15, 20))	('cancer', 'Disease', (59, 65))	('IREB2', 'Gene', '3658', (15, 20))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('downregulated', 'NegReg', (36, 49))
51660	31920398	Silencing IREB2 could reverse the function of miR-935 inhibitor on cell proliferation and metastasis in renal cancer cells.	('miR-935', 'Gene', '100126325', (46, 53))	('IREB2', 'Gene', (10, 15))	('metastasis', 'CPA', (90, 100))	('IREB2', 'Gene', '3658', (10, 15))	('renal cancer', 'Disease', (104, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('renal cancer', 'Disease', 'MESH:D007680', (104, 116))	('renal cancer', 'Phenotype', 'HP:0009726', (104, 116))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('cell proliferation', 'CPA', (67, 85))	('Silencing', 'Var', (0, 9))	('miR-935', 'Gene', (46, 53))
51671	31920398	Abnormal miRNA expression found in many cancers and abnormal miRNA expression reveals some correlation between tumor type and stage and miRNA expression.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('miR', 'Gene', '220972', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('miR', 'Gene', (61, 64))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('miR', 'Gene', '220972', (136, 139))	('abnormal', 'Var', (52, 60))	('cancers', 'Disease', (40, 47))	('tumor', 'Disease', (111, 116))	('miR', 'Gene', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('miR', 'Gene', '220972', (9, 12))	('miR', 'Gene', (9, 12))
51684	31920398	Primers of mir-935 (MQPS0002274-1-100) and U6 (MQPS0000002-1-100) were purchased from RiboBio (RiboBio, Guangzhou, China) and gene primers of GAPDH and IREB2 were obtained from GENEWIZ (GENEWIZ, Suzhou, China).	('MQPS0000002-1-100', 'Var', (47, 64))	('GAPDH', 'Gene', '2597', (142, 147))	('mir-935', 'Gene', (11, 18))	('GAPDH', 'Gene', (142, 147))	('MQPS0002274-1-100', 'Var', (20, 37))	('IREB2', 'Gene', (152, 157))	('mir-935', 'Gene', '100126325', (11, 18))	('IREB2', 'Gene', '3658', (152, 157))
51695	31920398	Reporter plasmids of wild-type or mutant IREB2 3'UTR were purchased from RiboBio (RiboBio, Guangzhou, China).	('IREB2', 'Gene', '3658', (41, 46))	('mutant', 'Var', (34, 40))	('IREB2', 'Gene', (41, 46))
51700	31920398	After cleaning the membrane with PBS 3 times, incubated the membrane with antibody against GAPDH (1:2000; BM3876; Wuhan Boster Biological Technology, Ltd., Wuhan, China) or IREB2 (1:1000; 23829-1-AP; Proteintech, Rosemont, USA) at 4 C overnight.	('membrane', 'cellular_component', 'GO:0016020', ('60', '68'))	('antibody', 'cellular_component', 'GO:0042571', ('74', '82'))	('membrane', 'cellular_component', 'GO:0016020', ('19', '27'))	('GAPDH', 'Gene', '2597', (91, 96))	('antibody', 'cellular_component', 'GO:0019815', ('74', '82'))	('IREB2', 'Gene', (173, 178))	('IREB2', 'Gene', '3658', (173, 178))	('1:1000; 23829-1-AP;', 'Var', (180, 199))	('antibody', 'cellular_component', 'GO:0019814', ('74', '82'))	('GAPDH', 'Gene', (91, 96))	('antibody', 'molecular_function', 'GO:0003823', ('74', '82'))
51717	31920398	The results as shown in Figure 2B indicate that miR-935 inhibitors significantly impaired the proliferation and viability of 786-O and A498 cells.	('proliferation', 'CPA', (94, 107))	('miR-935', 'Gene', (48, 55))	('inhibitors', 'Var', (56, 66))	('impaired', 'NegReg', (81, 89))	('A498', 'CellLine', 'CVCL:1056', (135, 139))	('786-O', 'Chemical', 'MESH:C002925', (125, 130))	('miR-935', 'Gene', '100126325', (48, 55))	('viability', 'CPA', (112, 121))
51719	31920398	Wound healing experiments show that miR-935 inhibitors can significantly reduce the migration of 786-O and A498 cells, as shown in Figure 2C.	('786-O', 'Chemical', 'MESH:C002925', (97, 102))	('inhibitors', 'Var', (44, 54))	('miR-935', 'Gene', '100126325', (36, 43))	('migration', 'CPA', (84, 93))	('A498', 'CellLine', 'CVCL:1056', (107, 111))	('Wound healing', 'biological_process', 'GO:0042060', ('0', '13'))	('reduce', 'NegReg', (73, 79))	('miR-935', 'Gene', (36, 43))
51721	31920398	Transwell analysis showed that miR-935 inhibitors inhibited the migration and invasion of 786-O cells, while miR-935 mimicked enhanced migration and invasion, as shown in Figure 2E.	('inhibitors', 'Var', (39, 49))	('enhanced', 'PosReg', (126, 134))	('miR-935', 'Gene', '100126325', (109, 116))	('miR-935', 'Gene', (31, 38))	('miR-935', 'Gene', '100126325', (31, 38))	('786-O', 'Chemical', 'MESH:C002925', (90, 95))	('inhibited', 'NegReg', (50, 59))	('miR-935', 'Gene', (109, 116))
51725	31920398	Luciferase reporter constructs containing either the wild type (WT) or mutated (MUT) IREB2 binding sequences downstream of the firefly luciferase gene were generated (Figure 3B).	('IREB2', 'Gene', (85, 90))	('IREB2', 'Gene', '3658', (85, 90))	('mutated', 'Var', (71, 78))	('binding', 'molecular_function', 'GO:0005488', ('91', '98'))
51729	31920398	At last, we found high IREB2 expression had a longer survival on patient overall survival (OS) and disease-free survival (DFS) in renal cell carcinoma database from The Cancer Genome Atlas (TCGA) of ccRCC (TCGA_KIRC) (Figure 3F).	('longer', 'PosReg', (46, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('Cancer', 'Phenotype', 'HP:0002664', (169, 175))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('ccRCC', 'Phenotype', 'HP:0006770', (199, 204))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (130, 150))	('ccRCC', 'Disease', (199, 204))	('renal cell carcinoma', 'Disease', (130, 150))	('patient', 'Species', '9606', (65, 72))	('high', 'Var', (18, 22))	('ccRCC', 'Disease', 'MESH:D002292', (199, 204))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (130, 150))	('IREB2', 'Gene', (23, 28))	('IREB2', 'Gene', '3658', (23, 28))
51733	31920398	As shown in Figure 4E, knockdown IREB2 reversed the function of miR-935 inhibitor on the migration and invasion ability of A498 cells.	('A498', 'CellLine', 'CVCL:1056', (123, 127))	('miR-935', 'Gene', '100126325', (64, 71))	('invasion ability of A498 cells', 'CPA', (103, 133))	('knockdown', 'Var', (23, 32))	('IREB2', 'Gene', '3658', (33, 38))	('IREB2', 'Gene', (33, 38))	('miR-935', 'Gene', (64, 71))
51759	31920398	qRT-PCR showed IREB2 expression was downregulated in cancer tissues and high IREB2 expression had a longer OS and DFS.	('IREB2', 'Gene', (77, 82))	('IREB2', 'Gene', '3658', (77, 82))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('expression', 'MPA', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('expression', 'MPA', (83, 93))	('IREB2', 'Gene', (15, 20))	('IREB2', 'Gene', '3658', (15, 20))	('high', 'Var', (72, 76))	('downregulated', 'NegReg', (36, 49))
51760	31920398	Silencing IREB2 could reverse the function of miR-935 inhibitor in renal cancer cell proliferation and metastasis.	('renal cancer', 'Phenotype', 'HP:0009726', (67, 79))	('miR-935', 'Gene', '100126325', (46, 53))	('IREB2', 'Gene', (10, 15))	('renal cancer', 'Disease', 'MESH:D007680', (67, 79))	('IREB2', 'Gene', '3658', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cell proliferation', 'biological_process', 'GO:0008283', ('80', '98'))	('Silencing', 'Var', (0, 9))	('miR-935', 'Gene', (46, 53))	('renal cancer', 'Disease', (67, 79))
51797	31250518	The pGL3-control luciferase reporter gene vector (Promega, Madison, WI, USA) loaded with either MALAT1-wt or MALAT1-mut was co-transfected with miR-203 mimics or control into HEK293T cells using Lipofectamine 2000 reagent (Invitrogen).	('pGL', 'molecular_function', 'GO:0004598', ('4', '7'))	('pGL3', 'Gene', '6391', (4, 8))	('pGL3', 'Gene', (4, 8))	('MALAT1-mut', 'Var', (109, 119))
51807	31250518	Female athymic BALB/c nude mice at their subcutaneous tissue of the right flank were injected with p-MALAT1- or si-MALAT1-1-transfected A498 cells (six nude mice per group), and six nude mice were injected with si-control-transfected A498 cells as a control.	('p-MALAT1-', 'Var', (99, 108))	('MALAT1-1', 'Gene', (115, 123))	('MALAT1-1', 'Gene', '378938', (115, 123))
51808	31250518	KIRC (kidney renal clear cell carcinoma) is the most common type of renal cell carcinoma, accounting for 70%-80% of all renal cell carcinoma cases.27 KIRP (kidney renal papillary cell carcinoma) is the second most common histological subtype of RCC (renal cell carcinoma), and it accounts for 10% to 15% of all RCCs.28 The results of survival analysis illustrated that KIRC and KIRP patients expressing high levels of BIRC5 presented a significantly poorer prognosis than those expressing low levels of BIRC5 (Figure 1C,D).	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('kidney renal papillary cell carcinoma', 'Disease', (156, 193))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (250, 270))	('poorer', 'NegReg', (450, 456))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (68, 88))	('BIRC5', 'Var', (418, 423))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('KIRC', 'Disease', (369, 373))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (6, 39))	('RCC', 'Phenotype', 'HP:0005584', (311, 314))	('high levels', 'Var', (403, 414))	('KIRC', 'Disease', 'MESH:D002292', (369, 373))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('prognosis', 'MPA', (457, 466))	('KIRC', 'Disease', (0, 4))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D002292', (156, 193))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (163, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (120, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('kidney renal clear cell carcinoma', 'Disease', (6, 39))	('RCC', 'Phenotype', 'HP:0005584', (245, 248))	('KIRC', 'Disease', 'MESH:D002292', (0, 4))
51811	31250518	Wang et al demonstrated that miR-203 suppressed the proliferation and migration of lung cancer cells and promoted their apoptosis by targeting SRC.30 Zhang et al suggested that miR-203 inhibited tumour growth and invasion in oesophageal cancer by inhibiting Ran.6 These studies are generally consistent with our results.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('SRC', 'Gene', '6714', (143, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('tumour growth', 'CPA', (195, 208))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('oesophageal cancer', 'Disease', 'MESH:D009369', (225, 243))	('migration', 'CPA', (70, 79))	('miR-203', 'Var', (177, 184))	('inhibited', 'NegReg', (185, 194))	('SRC', 'Gene', (143, 146))	('suppressed', 'NegReg', (37, 47))	('proliferation', 'CPA', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('inhibiting', 'NegReg', (247, 257))	('apoptosis', 'biological_process', 'GO:0097194', ('120', '129'))	('lung cancer', 'Disease', (83, 94))	('apoptosis', 'biological_process', 'GO:0006915', ('120', '129'))	('invasion', 'CPA', (213, 221))	('Ran.6', 'MPA', (258, 263))	('oesophageal cancer', 'Disease', (225, 243))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
51841	29930760	Class I PI3Ks are heterodimeric proteins constituted by a catalytic subunit (4 isoforms with non redundant activities: p110alpha, p110beta, p110delta and p110gamma) and one or several regulatory subunits.	('p110gamma', 'Gene', (154, 163))	('p110beta', 'Var', (130, 138))	('p110delta', 'Gene', (140, 149))	('p110delta', 'Gene', '5293', (140, 149))	('p110alpha', 'Var', (119, 128))	('p110gamma', 'Gene', '5294', (154, 163))
51843	29930760	Blockade of the PI3K pathway sensitized tumor cells to platinum and taxanes, and combinatorial treatment with chemotherapy resulted in increased antitumor activity in multiple human xenograft models of breast, lung cancer, and glioblastoma grown in nude mice.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('human', 'Species', '9606', (176, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (210, 221))	('glioblastoma', 'Disease', 'MESH:D005909', (227, 239))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('glioblastoma', 'Disease', (227, 239))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('glioblastoma', 'Phenotype', 'HP:0012174', (227, 239))	('platinum', 'Chemical', 'MESH:D010984', (55, 63))	('Blockade', 'Var', (0, 8))	('taxanes', 'Chemical', 'MESH:D043823', (68, 75))	('tumor', 'Disease', (40, 45))	('nude mice', 'Species', '10090', (249, 258))	('PI3K pathway', 'Pathway', (16, 28))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('breast, lung cancer', 'Disease', 'MESH:D001943', (202, 221))	('increased', 'PosReg', (135, 144))	('tumor', 'Disease', (149, 154))	('PI3K', 'molecular_function', 'GO:0016303', ('16', '20'))
51847	29930760	We have previously demonstrated the specific implication of the p110alpha isoform of Class I PI3Ks in tumor initiation or progression in pancreatic cancers.	('tumor initiation', 'Disease', (102, 118))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('PI3Ks', 'Gene', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('pancreatic cancers', 'Disease', 'MESH:D010190', (137, 155))	('pancreatic cancers', 'Disease', (137, 155))	('p110alpha', 'Var', (64, 73))	('tumor initiation', 'Disease', 'MESH:D009369', (102, 118))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (137, 155))
51850	29930760	identified that p110alpha-specific inhibitors could counteract the chemoresistance shown by chronic lymphoid leukemia, by suppressing the protective effect of marrow stromal cells on fludarabine-induced apoptosis.	('p110alpha-specific', 'Var', (16, 34))	('fludarabine', 'Chemical', 'MESH:C024352', (183, 194))	('lymphoid leukemia', 'Disease', (100, 117))	('apoptosis', 'biological_process', 'GO:0006915', ('203', '212'))	('lymphoid leukemia', 'Disease', 'MESH:D007945', (100, 117))	('suppressing', 'NegReg', (122, 133))	('lymphoid leukemia', 'Phenotype', 'HP:0005526', (100, 117))	('fludarabine-induced apoptosis', 'MPA', (183, 212))	('leukemia', 'Phenotype', 'HP:0001909', (109, 117))	('protective effect of marrow stromal cells on', 'CPA', (138, 182))	('chronic lymphoid leukemia', 'Phenotype', 'HP:0005550', (92, 117))	('apoptosis', 'biological_process', 'GO:0097194', ('203', '212'))
51852	29930760	Genetic and pharmacological data from our laboratory demonstrate that PI3K signaling in other cancers where the stromal compartment plays a major role regulates the autocrine IL-6-STAT3 loop.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('STAT3', 'Gene', (180, 185))	('PI3K signaling', 'biological_process', 'GO:0014065', ('70', '84'))	('IL-6', 'molecular_function', 'GO:0005138', ('175', '179'))	('PI3K', 'Var', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('regulates', 'Reg', (151, 160))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('STAT3', 'Gene', '6774', (180, 185))	('PI3K', 'molecular_function', 'GO:0016303', ('70', '74'))	('cancers', 'Disease', (94, 101))
51857	29930760	The aim of our present study was to evaluate the implication of the p110alpha PI3K subunit in ovarian cancer chemoresistance acquisition, and to evaluate whether the JAK/STAT pathway could mediate resistance to PI3K inhibitors through secretion of IL-6.	('ovarian cancer', 'Disease', (94, 108))	('secretion', 'MPA', (235, 244))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('PI3K', 'molecular_function', 'GO:0016303', ('211', '215'))	('JAK', 'molecular_function', 'GO:0004713', ('166', '169'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (94, 108))	('secretion', 'biological_process', 'GO:0046903', ('235', '244'))	('ovarian cancer', 'Disease', 'MESH:D010051', (94, 108))	('p110alpha', 'Var', (68, 77))	('IL-6', 'molecular_function', 'GO:0005138', ('248', '252'))	('PI3K', 'molecular_function', 'GO:0016303', ('78', '82'))
51873	29930760	Without carboplatin, we found an increase of Akt S473 phosphorylation as well as Erk phosphorylation in IGROV-1 cells cultured with patient ascites (Figure 2).	('Erk', 'molecular_function', 'GO:0004707', ('81', '84'))	('Akt', 'Gene', (45, 48))	('ascites', 'Disease', (140, 147))	('ascites', 'Disease', 'MESH:D001201', (140, 147))	('ascites', 'Phenotype', 'HP:0001541', (140, 147))	('increase', 'PosReg', (33, 41))	('Akt', 'Gene', '207', (45, 48))	('carboplatin', 'Chemical', 'MESH:D016190', (8, 19))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('Erk phosphorylation', 'MPA', (81, 100))	('phosphorylation', 'biological_process', 'GO:0016310', ('85', '100'))	('patient', 'Species', '9606', (132, 139))	('S473', 'Var', (49, 53))
51884	29930760	The JHOC-5 clear cell carcinoma cell line bears the tumor suppressor gene ARID1A (encoding BAF250) and PIK3CA mutations, which cooperate to promote tumor growth through IL-6 overproduction.	('IL-6', 'molecular_function', 'GO:0005138', ('169', '173'))	('tumor', 'Disease', (52, 57))	('clear cell carcinoma', 'Disease', (11, 31))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('ARID1A', 'Gene', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (11, 31))	('JHOC-5', 'CellLine', 'CVCL:4640', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutations', 'Var', (110, 119))	('PIK3CA', 'Gene', (103, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('52', '68'))	('BAF250', 'Gene', '8289', (91, 97))	('tumor', 'Disease', (148, 153))	('promote', 'PosReg', (140, 147))	('BAF250', 'Gene', (91, 97))	('tumor suppressor', 'biological_process', 'GO:0051726', ('52', '68'))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
51890	29930760	We decided to test whether the combination of JAK/STAT and PI3K/Akt inhibition could abolish chemoresistance of HOCCs.	('chemoresistance', 'CPA', (93, 108))	('inhibition', 'Var', (68, 78))	('Akt', 'Gene', '207', (64, 67))	('JAK', 'molecular_function', 'GO:0004713', ('46', '49'))	('Akt', 'Gene', (64, 67))	('abolish', 'NegReg', (85, 92))	('PI3K', 'molecular_function', 'GO:0016303', ('59', '63'))
51892	29930760	As shown in Figure 5, both cell lines expressed p110alpha and p110beta, and to a lesser extent p110delta, though no p110gamma.	('p110gamma', 'Gene', (116, 125))	('p110delta', 'Gene', (95, 104))	('p110delta', 'Gene', '5293', (95, 104))	('p110beta', 'Var', (62, 70))	('p110gamma', 'Gene', '5294', (116, 125))	('p110alpha', 'Var', (48, 57))
51895	29930760	Since PI3KCA polymorphism has been observed in ovarian cancer and because this isoform is implicated in oncogenesis we decided to specifically inhibit this isoform.	('polymorphism', 'Var', (13, 25))	('ovarian cancer', 'Disease', 'MESH:D010051', (47, 61))	('oncogenesis', 'biological_process', 'GO:0007048', ('104', '115'))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('PI3KCA', 'Gene', (6, 12))	('ovarian cancer', 'Disease', (47, 61))	('inhibit', 'NegReg', (143, 150))	('observed', 'Reg', (35, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (47, 61))
51897	29930760	In addition, unlike shRNAalpha1, shRNAalpha3 and shRNAalpha4 the shRNAalpha2 effectively reduced downstream Akt signaling, as shown by a decrease in phosphoryled-Akt on S473 (p-Akt S473).	('Akt signaling', 'biological_process', 'GO:0043491', ('108', '121'))	('decrease', 'NegReg', (137, 145))	('Akt', 'Gene', (108, 111))	('Akt', 'Gene', (162, 165))	('shRNAalpha2', 'Var', (65, 76))	('downstream', 'MPA', (97, 107))	('Akt', 'Gene', (177, 180))	('reduced', 'NegReg', (89, 96))	('Akt', 'Gene', '207', (108, 111))	('Akt', 'Gene', '207', (177, 180))	('Akt', 'Gene', '207', (162, 165))
51898	29930760	Inhibition of PI3KCA alone was able to downregulate the Akt pathway in IGROV-1 cells.	('Akt', 'Gene', '207', (56, 59))	('Akt', 'Gene', (56, 59))	('downregulate', 'NegReg', (39, 51))	('PI3KCA', 'Var', (14, 20))
51900	29930760	We postulated upon the involvement of Akt phosphorylation on S473 in this phenomenon and hypothesized that ascites secretions may activate the anti-apoptotic signaling pathway through p110alpha activation.	('activate', 'PosReg', (130, 138))	('ascites secretions', 'Disease', (107, 125))	('activation', 'PosReg', (194, 204))	('apoptotic signaling pathway', 'biological_process', 'GO:0097190', ('148', '175'))	('p110alpha', 'Var', (184, 193))	('ascites secretions', 'Disease', 'MESH:D001201', (107, 125))	('anti-apoptotic signaling pathway', 'Pathway', (143, 175))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))	('Akt', 'Gene', '207', (38, 41))	('S473', 'Var', (61, 65))	('ascites', 'Phenotype', 'HP:0001541', (107, 114))	('Akt', 'Gene', (38, 41))
51904	29930760	Surprisingly, inhibition of the isoform p110alpha in fact increased resistance to carboplatin in the IGROV-1 cell line (Figure 7).	('resistance to carboplatin', 'MPA', (68, 93))	('inhibition', 'Var', (14, 24))	('carboplatin', 'Chemical', 'MESH:D016190', (82, 93))	('increased', 'PosReg', (58, 67))
51905	29930760	Taken together, our results show that treatment with an antibody against IL-6 did not reverse chemoresistance to carboplatin, even upon PI3KCA inhibition.	('antibody', 'cellular_component', 'GO:0019815', ('56', '64'))	('chemoresistance', 'CPA', (94, 109))	('carboplatin', 'Chemical', 'MESH:D016190', (113, 124))	('antibody', 'Var', (56, 64))	('antibody', 'cellular_component', 'GO:0019814', ('56', '64'))	('IL-6', 'molecular_function', 'GO:0005138', ('73', '77'))	('antibody', 'molecular_function', 'GO:0003823', ('56', '64'))	('antibody', 'cellular_component', 'GO:0042571', ('56', '64'))	('IL-6', 'Gene', (73, 77))
51925	29930760	Indeed, results from in vivo models show that neutralizing IL-6 enhances the therapeutic effect of paclitaxel in an ovarian cancer mouse model, leading to reduced tumor growth and angiogenesis.	('angiogenesis', 'CPA', (180, 192))	('ovarian cancer', 'Disease', 'MESH:D010051', (116, 130))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('reduced', 'NegReg', (155, 162))	('IL-6', 'molecular_function', 'GO:0005138', ('59', '63'))	('enhances', 'PosReg', (64, 72))	('mouse', 'Species', '10090', (131, 136))	('ovarian cancer', 'Disease', (116, 130))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('IL-6', 'Gene', (59, 63))	('tumor', 'Disease', (163, 168))	('angiogenesis', 'biological_process', 'GO:0001525', ('180', '192'))	('paclitaxel', 'Chemical', 'MESH:D017239', (99, 109))	('ovarian cancer', 'Phenotype', 'HP:0100615', (116, 130))	('therapeutic effect', 'MPA', (77, 95))	('neutralizing', 'Var', (46, 58))
51926	29930760	However, a phase I/II trial of siltuximab (anti-IL-6 monoclonal antibody) in ovarian cancer patients demonstrated a lack of clinical efficacy, arguing that IL-6 inhibition could eliminate IL-6 sensitive clones leading to the development of resistant clones whose growth is triggered by other pathways such as the gp130 family.	('IL-6', 'Gene', (188, 192))	('ovarian cancer', 'Disease', (77, 91))	('IL-6', 'molecular_function', 'GO:0005138', ('156', '160'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (77, 91))	('antibody', 'cellular_component', 'GO:0019815', ('64', '72'))	('eliminate', 'NegReg', (178, 187))	('IL-6', 'Gene', (156, 160))	('gp130', 'molecular_function', 'GO:0004921', ('313', '318'))	('gp130', 'molecular_function', 'GO:0004898', ('313', '318'))	('inhibition', 'Var', (161, 171))	('patients', 'Species', '9606', (92, 100))	('IL-6', 'molecular_function', 'GO:0005138', ('48', '52'))	('antibody', 'cellular_component', 'GO:0019814', ('64', '72'))	('gp130', 'molecular_function', 'GO:0004897', ('313', '318'))	('gp130', 'molecular_function', 'GO:0004915', ('313', '318'))	('siltuximab', 'Chemical', 'MESH:C504234', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('gp130', 'Gene', (313, 318))	('ovarian cancer', 'Disease', 'MESH:D010051', (77, 91))	('gp130', 'Gene', '3572', (313, 318))	('antibody', 'molecular_function', 'GO:0003823', ('64', '72'))	('IL-6', 'molecular_function', 'GO:0005138', ('188', '192'))	('antibody', 'cellular_component', 'GO:0042571', ('64', '72'))
51935	29930760	We next focused on the implication of the PI3K catalytic subunit p110alpha in platinum resistance, and on the combined inhibition of IL-6/STAT3 and PI3K/Akt pathways to revert chemotherapy resistance.	('revert', 'NegReg', (169, 175))	('STAT3', 'Gene', (138, 143))	('Akt', 'Gene', '207', (153, 156))	('chemotherapy resistance', 'CPA', (176, 199))	('platinum resistance', 'CPA', (78, 97))	('Akt', 'Gene', (153, 156))	('inhibition', 'NegReg', (119, 129))	('platinum', 'Chemical', 'MESH:D010984', (78, 86))	('PI3K', 'molecular_function', 'GO:0016303', ('148', '152'))	('IL-6', 'molecular_function', 'GO:0005138', ('133', '137'))	('STAT3', 'Gene', '6774', (138, 143))	('PI3K', 'molecular_function', 'GO:0016303', ('42', '46'))	('p110alpha', 'Var', (65, 74))
51938	29930760	Knockdown of p110alpha expression alone or in combination with IL-6/STAT3 inhibition did not reduce ovarian cancer cell resistance to carboplatin induced by ascites medium.	('ovarian cancer', 'Disease', (100, 114))	('carboplatin', 'Chemical', 'MESH:D016190', (134, 145))	('ascites', 'Disease', (157, 164))	('ascites', 'Phenotype', 'HP:0001541', (157, 164))	('IL-6', 'molecular_function', 'GO:0005138', ('63', '67'))	('ascites', 'Disease', 'MESH:D001201', (157, 164))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (100, 114))	('ovarian cancer', 'Disease', 'MESH:D010051', (100, 114))	('STAT3', 'Gene', '6774', (68, 73))	('STAT3', 'Gene', (68, 73))	('p110alpha', 'Var', (13, 22))	('reduce', 'NegReg', (93, 99))
51944	29930760	In one murine model of clear cell carcinoma of the ovary, PIK3CA mutations drove signaling loops to promote high levels of IL-6 production in the absence of negative regulation by ARID1A.	('clear cell carcinoma', 'Disease', (23, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('carcinoma of the ovary', 'Disease', 'MESH:D010051', (34, 56))	('clear cell carcinoma of the ovary', 'Phenotype', 'HP:0031522', (23, 56))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (23, 43))	('signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('regulation', 'biological_process', 'GO:0065007', ('166', '176'))	('mutations', 'Var', (65, 74))	('PIK3CA', 'Gene', (58, 64))	('carcinoma of the ovary', 'Disease', (34, 56))	('murine', 'Species', '10090', (7, 13))	('promote', 'PosReg', (100, 107))	('IL-6', 'molecular_function', 'GO:0005138', ('123', '127'))	('IL-6 production', 'biological_process', 'GO:0032635', ('123', '138'))	('high levels of IL-6 production', 'MPA', (108, 138))
51945	29930760	Indeed, as has been shown in leukemia models, PI3K chemoresistance could, at least in part, be mediated by other cells of the tumor microenvironment.	('PI3K', 'molecular_function', 'GO:0016303', ('46', '50'))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('PI3K', 'Var', (46, 50))	('leukemia', 'Phenotype', 'HP:0001909', (29, 37))	('leukemia', 'Disease', 'MESH:D007938', (29, 37))	('leukemia', 'Disease', (29, 37))	('tumor', 'Disease', (126, 131))
51947	29930760	Inhibition of p110alpha blocked bone marrow stromal cell-derived migration and survival and reduced drug resistance of chronic lymphocytic leukemia.	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (119, 147))	('bone marrow stromal cell-derived migration', 'CPA', (32, 74))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (119, 147))	('drug resistance', 'biological_process', 'GO:0009315', ('100', '115'))	('drug resistance', 'CPA', (100, 115))	('chronic lymphocytic leukemia', 'Disease', (119, 147))	('drug resistance', 'Phenotype', 'HP:0020174', (100, 115))	('drug resistance', 'biological_process', 'GO:0042493', ('100', '115'))	('survival', 'CPA', (79, 87))	('reduced', 'NegReg', (92, 99))	('leukemia', 'Phenotype', 'HP:0001909', (139, 147))	('blocked', 'NegReg', (24, 31))	('p110alpha', 'Var', (14, 23))
51964	29930760	Membranes were saturated for 1 h in TBS (50 mM Tris, 150 mM NaCl) / 0.1% Tween 20/ 5% milk or 5% bovine serum albumin (BSA) for phosphorylated protein analysis and incubated overnight at 4 C with a rabbit polyclonal primary antibody directed against p85 (1:1000, Millipore clone 06-195), p110alpha (1:1000, Cell Signaling 4249), p110beta (1:1000, Santacruz SC-602), p-AktS473 (1:1000, Cell Signaling #4060S); pan-Akt (1:1000, Cell Signaling #4691S); p-Erk (1:1000, Cell Signaling #4377S), p-Stat3 (1:1000, Cell Signaling #9145) or beta-Tubulin (1:1000, Cell Signaling # 2146S); or a mouse polyclonal primary antibody directed against Erk (1:1000, mouse, Cell Signaling #4696) or Stat3 (1:1000, Mouse, Cell Signaling #9139).	('Signaling', 'biological_process', 'GO:0023052', ('659', '668'))	('Signaling', 'biological_process', 'GO:0023052', ('706', '715'))	('Signaling', 'biological_process', 'GO:0023052', ('511', '520'))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('antibody', 'cellular_component', 'GO:0042571', ('224', '232'))	('Signaling', 'biological_process', 'GO:0023052', ('390', '399'))	('beta-Tubulin', 'Protein', (531, 543))	('p85', 'Gene', (250, 253))	('antibody', 'cellular_component', 'GO:0019815', ('224', '232'))	('antibody', 'cellular_component', 'GO:0019815', ('608', '616'))	('Erk (1', 'molecular_function', 'GO:0004707', ('452', '458'))	('Signaling', 'biological_process', 'GO:0023052', ('312', '321'))	('Signaling', 'biological_process', 'GO:0023052', ('470', '479'))	('bovine', 'Species', '9913', (97, 103))	('Signaling', 'biological_process', 'GO:0023052', ('558', '567'))	('Akt', 'Gene', (368, 371))	('p85', 'Gene', '21981', (250, 253))	('rabbit', 'Species', '9986', (198, 204))	('antibody', 'cellular_component', 'GO:0019814', ('224', '232'))	('antibody', 'cellular_component', 'GO:0019814', ('608', '616'))	('mouse', 'Species', '10090', (647, 652))	('Tween 20', 'Chemical', 'MESH:D011136', (73, 81))	('TBS', 'Disease', (36, 39))	('Erk (1', 'molecular_function', 'GO:0004707', ('634', '640'))	('Akt', 'Gene', '207', (368, 371))	('mouse', 'Species', '10090', (583, 588))	('Mouse', 'Species', '10090', (694, 699))	('Akt', 'Gene', (413, 416))	('antibody', 'molecular_function', 'GO:0003823', ('224', '232'))	('antibody', 'molecular_function', 'GO:0003823', ('608', '616'))	('TBS', 'Disease', 'None', (36, 39))	('Akt', 'Gene', '207', (413, 416))	('Signaling', 'biological_process', 'GO:0023052', ('431', '440'))	('1:1000', 'Var', (686, 692))	('antibody', 'cellular_component', 'GO:0042571', ('608', '616'))
51972	29754953	Reduced ARG2 activity promotes ccRCC tumor growth through at least two distinct mechanisms: conserving the critical biosynthetic cofactor pyridoxal phosphate, and avoiding toxic polyamine accumulation.	('promotes', 'PosReg', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('conserving', 'NegReg', (92, 102))	('pyridoxal phosphate', 'Chemical', 'MESH:D011732', (138, 157))	('polyamine', 'Chemical', 'MESH:D011073', (178, 187))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('ARG2', 'Gene', '384', (8, 12))	('Reduced', 'Var', (0, 7))	('ARG2', 'Gene', (8, 12))
51975	29754953	Loss of the urea cycle enzyme arginase2 (ARG2) promotes ccRCC tumor progression by conserving essential biosynthetic cofactor pools and preventing toxic polyamine build up.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('ARG2', 'Gene', (41, 45))	('ARG2', 'Gene', '384', (41, 45))	('arginase2', 'Gene', (30, 39))	('urea', 'Chemical', 'MESH:D014508', (12, 16))	('promotes', 'PosReg', (47, 55))	('tumor', 'Disease', (62, 67))	('preventing', 'NegReg', (136, 146))	('polyamine', 'Chemical', 'MESH:D011073', (153, 162))	('urea cycle', 'biological_process', 'GO:0000050', ('12', '22'))	('toxic polyamine build up', 'MPA', (147, 171))	('Loss', 'Var', (0, 4))	('arginase2', 'Gene', '384', (30, 39))	('conserving essential biosynthetic cofactor pools', 'MPA', (83, 131))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
51981	29754953	Consequently, pharmacological inhibition of specific metabolic pathways may preferentially limit tumor cell growth and proliferation, and multiple metabolism-based therapies are currently in development.	('limit', 'NegReg', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('metabolism', 'biological_process', 'GO:0008152', ('147', '157'))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('preferentially', 'PosReg', (76, 90))	('cell growth', 'biological_process', 'GO:0016049', ('103', '114'))	('tumor', 'Disease', (97, 102))	('pharmacological', 'Var', (14, 29))
51989	29754953	A hallmark genetic event in ccRCC is deletion or translocation of chromosome 3p (>90%), resulting in inactivation of the von Hippel-Lindau (VHL) gene.	('chromosome', 'cellular_component', 'GO:0005694', ('66', '76'))	('deletion', 'Var', (37, 45))	('von Hippel-Lindau', 'Gene', (121, 138))	('translocation', 'Var', (49, 62))	('inactivation', 'NegReg', (101, 113))	('VHL', 'Gene', (140, 143))	('ccRCC', 'Disease', (28, 33))	('von Hippel-Lindau', 'Gene', '7428', (121, 138))	('VHL', 'Gene', '7428', (140, 143))
51991	29754953	In VHL-deficient ccRCCs, constitutive HIF expression reprograms cellular metabolism and induces tumor angiogenesis, primarily through activation of downstream HIF target genes.	('cellular metabolism', 'biological_process', 'GO:0044237', ('64', '83'))	('expression', 'Species', '29278', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('HIF', 'Gene', (38, 41))	('tumor', 'Disease', (96, 101))	('activation', 'PosReg', (134, 144))	('cellular metabolism', 'CPA', (64, 83))	('angiogenesis', 'biological_process', 'GO:0001525', ('102', '114'))	('VHL-deficient', 'Disease', 'MESH:D006623', (3, 16))	('expression', 'Var', (42, 52))	('reprograms', 'Reg', (53, 63))	('VHL-deficient', 'Disease', (3, 16))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('induces', 'PosReg', (88, 95))
51993	29754953	Recent large-scale analyses identified frequent mutations in three genes, PBRM1 (~40%), SETD2 (~15%), and BAP1 (~15%), all of which encode epigenetic regulators and reside in a 43 Mb region on chromosome 3p that encompasses VHL.	('VHL', 'Gene', '7428', (224, 227))	('SETD2', 'Gene', '29072', (88, 93))	('PBRM1', 'Gene', '55193', (74, 79))	('BAP1', 'Gene', (106, 110))	('SETD2', 'Gene', (88, 93))	('chromosome', 'cellular_component', 'GO:0005694', ('193', '203'))	('BAP1', 'Gene', '8314', (106, 110))	('PBRM1', 'Gene', (74, 79))	('mutations', 'Var', (48, 57))	('VHL', 'Gene', (224, 227))
51994	29754953	In addition to these epigenetic factors, PI3K/mTOR signaling components are also mutated in a subset (<30%) of ccRCC tumors.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('PI3K', 'molecular_function', 'GO:0016303', ('41', '45'))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('mTOR', 'Gene', '2475', (46, 50))	('mTOR', 'Gene', (46, 50))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('mutated', 'Var', (81, 88))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))
52007	29754953	As such, urea cycle suppression promotes both ccRCC cell proliferation (where PLP conservation enhances anabolic metabolism), and viability (where polyamine uptake from the microenvironment results in toxic intracellular levels of putrescine and spermine).	('metabolism', 'biological_process', 'GO:0008152', ('113', '123'))	('intracellular', 'cellular_component', 'GO:0005622', ('207', '220'))	('polyamine', 'Chemical', 'MESH:D011073', (147, 156))	('toxic intracellular levels of putrescine', 'MPA', (201, 241))	('spermine', 'Chemical', 'MESH:D013096', (246, 254))	('ccRCC', 'Disease', (46, 51))	('putrescine', 'Chemical', 'MESH:D011700', (231, 241))	('urea cycle', 'Enzyme', (9, 19))	('enhances', 'PosReg', (95, 103))	('PLP', 'Gene', '57026', (78, 81))	('polyamine', 'Var', (147, 156))	('polyamine uptake', 'biological_process', 'GO:1902047', ('147', '163'))	('urea', 'Chemical', 'MESH:D014508', (9, 13))	('promotes', 'PosReg', (32, 40))	('urea cycle', 'biological_process', 'GO:0000050', ('9', '19'))	('suppression', 'NegReg', (20, 31))	('viability', 'CPA', (130, 139))	('cell proliferation', 'biological_process', 'GO:0008283', ('52', '70'))	('PLP', 'Gene', (78, 81))
52010	29754953	Data from The Cancer Genome Atlas (TCGA) also revealed ARG2 and ASS1 copy number loss in 38% and 24% of ccRCC patients, respectively, and copy number gain of ASL in 40% (Figure 1C).	('copy number gain', 'Var', (138, 154))	('patients', 'Species', '9606', (110, 118))	('ARG2', 'Gene', (55, 59))	('ARG2', 'Gene', '384', (55, 59))	('ASL', 'Gene', (158, 161))	('ASS1', 'Gene', (64, 68))	('ASL', 'Gene', '435', (158, 161))	('ASS1', 'Gene', '445', (64, 68))	('Cancer Genome Atlas', 'Disease', (14, 33))	('copy number', 'Var', (69, 80))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (14, 33))	('loss', 'NegReg', (81, 85))	('ccRCC', 'Disease', (104, 109))
52011	29754953	Of note, ARG2 copy number loss is accompanied by ASS1 deletion in approximately 40% of ARG2-deficient ccRCCs (n=184), and ARG2 and ASS1 mRNA expression in multiple cohorts was lower in ccRCC tumors compared to normal kidney, irrespective of disease stage (Figures 1D, S1A, and S1B).	('ARG2', 'Gene', (87, 91))	('expression', 'Species', '29278', (141, 151))	('ARG2-deficient', 'Disease', 'MESH:D007153', (87, 101))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))	('ARG2', 'Gene', '384', (122, 126))	('deletion', 'Var', (54, 62))	('lower', 'NegReg', (176, 181))	('ARG2', 'Gene', '384', (9, 13))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('ASS1', 'Gene', '445', (131, 135))	('ARG2', 'Gene', '384', (87, 91))	('ARG2-deficient', 'Disease', (87, 101))	('ASS1', 'Gene', (131, 135))	('loss', 'NegReg', (26, 30))	('ASS1', 'Gene', '445', (49, 53))	('ccRCCs', 'Disease', (102, 108))	('ARG2', 'Gene', (122, 126))	('ASS1', 'Gene', (49, 53))	('ARG2', 'Gene', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))
52020	29754953	Given the high frequency of gene copy number loss, reduced mRNA and protein expression, altered urea cycle metabolite levels, and correlative survival differences, we further explored the role of ARG2 and ASS1 as potential metabolic suppressors of ccRCC tumorigenesis.	('ARG2', 'Gene', (196, 200))	('ASS1', 'Gene', '445', (205, 209))	('tumor', 'Disease', (254, 259))	('reduced', 'NegReg', (51, 58))	('ASS1', 'Gene', (205, 209))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('gene copy number', 'Var', (28, 44))	('expression', 'Species', '29278', (76, 86))	('urea cycle', 'biological_process', 'GO:0000050', ('96', '106'))	('ccRCC', 'Disease', (248, 253))	('urea', 'Chemical', 'MESH:D014508', (96, 100))	('altered', 'Reg', (88, 95))	('urea cycle metabolite levels', 'MPA', (96, 124))	('loss', 'NegReg', (45, 49))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('ARG2', 'Gene', '384', (196, 200))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
52023	29754953	Stable knockdown of ARG2, ASS1, or both ARG2 and ASS1 (Double KD), mRNAs (Figure 2B) increased proliferation of control HK-2 cells in tissue culture (2D growth; Figure 2C) and anchorage-independent 3D soft agar growth assays (Figure 2D); moreover, the 3D growth effects were enhanced when both ARG2 and ASS1 were reduced simultaneously.	('ARG2', 'Gene', '384', (20, 24))	('agar', 'Chemical', 'MESH:D000362', (206, 210))	('increased', 'PosReg', (85, 94))	('proliferation', 'CPA', (95, 108))	('HK-2', 'Gene', '3099', (120, 124))	('ARG2', 'Gene', '384', (40, 44))	('ARG2', 'Gene', '384', (294, 298))	('HK-2', 'molecular_function', 'GO:0008256', ('120', '124'))	('ARG2', 'Gene', (20, 24))	('enhanced', 'PosReg', (275, 283))	('ASS1', 'Gene', '445', (49, 53))	('ASS1', 'Gene', '445', (303, 307))	('ASS1', 'Gene', (49, 53))	('HK-2', 'Gene', (120, 124))	('ASS1', 'Gene', (303, 307))	('anchorage-independent 3D soft agar growth assays', 'CPA', (176, 224))	('ASS1', 'Gene', (26, 30))	('ASS1', 'Gene', '445', (26, 30))	('ARG2', 'Gene', (40, 44))	('knockdown', 'Var', (7, 16))	('ARG2', 'Gene', (294, 298))
52025	29754953	These results were subsequently confirmed using clonally selected HK-2 cells with CRISPR/Cas9 mediated deletion of ARG2 or ASS1 (Figure 2E).	('HK-2', 'Gene', '3099', (66, 70))	('HK-2', 'molecular_function', 'GO:0008256', ('66', '70'))	('HK-2', 'Gene', (66, 70))	('Cas', 'cellular_component', 'GO:0005650', ('89', '92'))	('ARG2', 'Gene', '384', (115, 119))	('ASS1', 'Gene', (123, 127))	('ASS1', 'Gene', '445', (123, 127))	('ARG2', 'Gene', (115, 119))	('deletion', 'Var', (103, 111))
52028	29754953	Conversely, ectopic ARG2 and/or ASS1 re-expression in polyclonal 786-O and A498 ccRCC cells reduced 3D spheroid volume, the number of cells per spheroid, soft agar colony formation, and 2D growth (Figures 3A-B, and S2A).	('ARG2', 'Gene', '384', (20, 24))	('ASS1', 'Gene', (32, 36))	('expression', 'Species', '29278', (40, 50))	('ARG2', 'Gene', (20, 24))	('ASS1', 'Gene', '445', (32, 36))	('formation', 'biological_process', 'GO:0009058', ('171', '180'))	('3D spheroid volume', 'CPA', (100, 118))	('reduced', 'NegReg', (92, 99))	('soft agar colony formation', 'CPA', (154, 180))	('2D growth', 'CPA', (186, 195))	('agar', 'Chemical', 'MESH:D000362', (159, 163))	('ectopic', 'Var', (12, 19))
52033	29754953	Combined ARG2 and ASS1 expression decreased the abundance of all three urea cycle metabolites, most notably citrulline and aspartate.	('ASS1', 'Gene', (18, 22))	('ASS1', 'Gene', '445', (18, 22))	('citrulline', 'MPA', (108, 118))	('decreased', 'NegReg', (34, 43))	('urea', 'Chemical', 'MESH:D014508', (71, 75))	('urea cycle', 'biological_process', 'GO:0000050', ('71', '81'))	('expression', 'Var', (23, 33))	('aspartate', 'Chemical', 'MESH:D001224', (123, 132))	('citrulline', 'Chemical', 'MESH:D002956', (108, 118))	('ARG2', 'Gene', (9, 13))	('ARG2', 'Gene', '384', (9, 13))	('expression', 'Species', '29278', (23, 33))	('abundance of', 'MPA', (48, 60))
52035	29754953	To test whether this was true for ARG2, we generated a missense mutation (ARG2 H160F) that abolished enzymatic activity (Figure 3D), consistent with previous reports.	('H160F', 'Mutation', 'p.H160F', (79, 84))	('ARG2', 'Gene', '384', (34, 38))	('ARG2', 'Gene', (34, 38))	('H160F', 'Var', (79, 84))	('enzymatic activity', 'MPA', (101, 119))	('ARG2', 'Gene', '384', (74, 78))	('ARG2', 'Gene', (74, 78))	('abolished', 'NegReg', (91, 100))
52036	29754953	In a 3D spheroid growth assay, expression of wild type ARG2 dramatically reduced ccRCC spheroid volume and the number of cells per spheroid, whereas ARG2 H160F failed to suppress spheroid growth (Figure 3E) and soft agar colony formation (Figure 3F).	('spheroid growth', 'CPA', (179, 194))	('agar', 'Chemical', 'MESH:D000362', (216, 220))	('ccRCC spheroid volume', 'CPA', (81, 102))	('reduced', 'NegReg', (73, 80))	('ARG2', 'Gene', (55, 59))	('soft agar colony formation', 'CPA', (211, 237))	('ARG2', 'Gene', '384', (55, 59))	('expression', 'Species', '29278', (31, 41))	('H160F', 'Mutation', 'p.H160F', (154, 159))	('ARG2', 'Gene', '384', (149, 153))	('ARG2', 'Gene', (149, 153))	('formation', 'biological_process', 'GO:0009058', ('228', '237'))	('expression', 'Var', (31, 41))
52045	29754953	Ectopic ARG2 expression in 786-O ccRCC xenografts reduced tumor growth in vivo, which was further suppressed by co-expression of ARG2 and ASS1 (Figures 4A and S3A).	('ASS1', 'Gene', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('expression', 'Species', '29278', (13, 23))	('suppressed', 'NegReg', (98, 108))	('ASS1', 'Gene', '445', (138, 142))	('expression', 'Species', '29278', (115, 125))	('ARG2', 'Gene', '384', (8, 12))	('Ectopic', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('reduced', 'NegReg', (50, 57))	('ARG2', 'Gene', '384', (129, 133))	('ARG2', 'Gene', (8, 12))	('ARG2', 'Gene', (129, 133))
52061	29754953	We also introduced two constitutively active mTORC1 mutants (R2505P and L1460P) into 786-O cells with and without ARG2 reconstitution.	('L1460P', 'Var', (72, 78))	('L1460P', 'Mutation', 'rs1057519779', (72, 78))	('mTORC1', 'Gene', '382056', (45, 51))	('R2505P', 'Var', (61, 67))	('R2505P', 'Mutation', 'rs1057519777', (61, 67))	('mTORC1', 'cellular_component', 'GO:0031931', ('45', '51'))	('ARG2', 'Gene', (114, 118))	('ARG2', 'Gene', '384', (114, 118))	('mTORC1', 'Gene', (45, 51))
52063	29754953	Intriguingly, mTORC1 R2505P and L1460P, if anything, suppress growth of while failing to fully restore the growth of ARG2-expressing cells (Figure S4E).	('mTORC1', 'Gene', (14, 20))	('growth of', 'MPA', (62, 71))	('ARG2', 'Gene', (117, 121))	('ARG2', 'Gene', '384', (117, 121))	('mTORC1', 'Gene', '382056', (14, 20))	('L1460P', 'Var', (32, 38))	('suppress', 'NegReg', (53, 61))	('R2505P', 'Mutation', 'rs1057519777', (21, 27))	('R2505P', 'Var', (21, 27))	('L1460P', 'Mutation', 'rs1057519779', (32, 38))	('mTORC1', 'cellular_component', 'GO:0031931', ('14', '20'))
52064	29754953	A direct comparison is control cells in soft agar colony formation assays, provided when one assesses the vector plus mTORC1 R2505P- transduced cells to ARG2 plus mTORC1 R2505P- expressing cells.	('mTORC1', 'Gene', (118, 124))	('mTORC1', 'Gene', (163, 169))	('R2505P', 'Mutation', 'rs1057519777', (170, 176))	('mTORC1', 'cellular_component', 'GO:0031931', ('163', '169'))	('formation', 'biological_process', 'GO:0009058', ('57', '66'))	('agar', 'Chemical', 'MESH:D000362', (45, 49))	('mTORC1', 'cellular_component', 'GO:0031931', ('118', '124'))	('mTORC1', 'Gene', '382056', (118, 124))	('ARG2', 'Gene', (153, 157))	('mTORC1', 'Gene', '382056', (163, 169))	('ARG2', 'Gene', '384', (153, 157))	('R2505P', 'Mutation', 'rs1057519777', (125, 131))	('R2505P-', 'Var', (125, 132))
52070	29754953	demonstrated that ASS1 deficiency increases cytoplasmic aspartate levels, which are critical for maintaining pyrimidine biosynthesis in multiple cancer cell lines.	('ASS1', 'Gene', (18, 22))	('deficiency', 'Var', (23, 33))	('cancer', 'Disease', (145, 151))	('ASS1', 'Gene', '445', (18, 22))	('pyrimidine', 'Chemical', 'MESH:C030986', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('aspartate', 'Chemical', 'MESH:D001224', (56, 65))	('cytoplasmic aspartate levels', 'MPA', (44, 72))	('biosynthesis', 'biological_process', 'GO:0009058', ('120', '132'))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('increases', 'PosReg', (34, 43))
52077	29754953	If anything, SLC1A3/hEAAT1 overexpression resulted in decreased rates of ARG2/786-O cell proliferation relative to control cells.	('hEAAT1', 'Gene', (20, 26))	('overexpression', 'Var', (27, 41))	('ARG2', 'Gene', (73, 77))	('ARG2', 'Gene', '384', (73, 77))	('cell proliferation', 'biological_process', 'GO:0008283', ('84', '102'))	('expression', 'Species', '29278', (31, 41))	('SLC1A3', 'Gene', (13, 19))	('decreased', 'NegReg', (54, 63))	('SLC1A3', 'Gene', '6507', (13, 19))	('hEAAT1', 'Gene', '6507', (20, 26))
52081	29754953	recently determined that increased expression of the urea cycle enzyme carbamoyl phosphate-1 in Kras/LKB1 mutant lung cancer cells is essential to maintain their intracellular pyrimidine pools, DNA synthesis, and genome integrity.	('DNA', 'cellular_component', 'GO:0005574', ('194', '197'))	('urea', 'Chemical', 'MESH:D014508', (53, 57))	('expression', 'MPA', (35, 45))	('LKB1', 'Gene', (101, 105))	('Kras', 'Gene', (96, 100))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('intracellular', 'cellular_component', 'GO:0005622', ('162', '175'))	('DNA synthesis', 'biological_process', 'GO:0071897', ('194', '207'))	('mutant', 'Var', (106, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('pyrimidine', 'Chemical', 'MESH:C030986', (176, 186))	('expression', 'Species', '29278', (35, 45))	('intracellular pyrimidine pools', 'MPA', (162, 192))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('urea cycle', 'biological_process', 'GO:0000050', ('53', '63'))	('LKB1', 'Gene', '6794', (101, 105))	('DNA synthesis', 'MPA', (194, 207))	('lung cancer', 'Disease', (113, 124))	('increased', 'PosReg', (25, 34))	('Kras', 'Gene', '3845', (96, 100))
52087	29754953	Conversely, ectopic ARG2 expression in 786-O ccRCC cells dramatically increased 15N4-arginine incorporation into glutamate and proline (Figure 5B, right panel), suggesting that ARG2 directly controls the levels of downstream ornithine metabolites by increasing substrate availability for OAT.	('ARG2', 'Gene', '384', (20, 24))	('15N4-arginine', 'Chemical', '-', (80, 93))	('substrate availability', 'MPA', (261, 283))	('increasing', 'PosReg', (250, 260))	('proline', 'Chemical', 'MESH:D011392', (127, 134))	('ornithine', 'Chemical', 'MESH:D009952', (225, 234))	('OAT', 'Disease', (288, 291))	('ARG2', 'Gene', (20, 24))	('increased', 'PosReg', (70, 79))	('glutamate', 'Chemical', 'MESH:D018698', (113, 122))	('expression', 'Species', '29278', (25, 35))	('OAT', 'Disease', 'MESH:D015799', (288, 291))	('OAT', 'molecular_function', 'GO:0004587', ('288', '291'))	('ARG2', 'Gene', (177, 181))	('ectopic', 'Var', (12, 19))	('ARG2', 'Gene', '384', (177, 181))
52096	29754953	Ectopic ARG2 expression significantly reduced the concentration of PLP, as expected, with no effect on the precursors PL, PN, etc.	('expression', 'Species', '29278', (13, 23))	('PN', 'Chemical', 'MESH:D011736', (122, 124))	('reduced', 'NegReg', (38, 45))	('PLP', 'Gene', '57026', (67, 70))	('PLP', 'Gene', (67, 70))	('ARG2', 'Gene', '384', (8, 12))	('Ectopic', 'Var', (0, 7))	('PL', 'Chemical', 'MESH:D011730', (118, 120))	('PL', 'Chemical', 'MESH:D011730', (67, 69))	('ARG2', 'Gene', (8, 12))
52097	29754953	Conversely, deletion of ARG2 in HK-2 cells produced significantly elevated concentrations of PLP (Figure 5E, left panel), demonstrating that ARG2 activity modulates the pool of available PLP.	('deletion', 'Var', (12, 20))	('ARG2', 'Gene', (24, 28))	('ARG2', 'Gene', '384', (24, 28))	('ARG2', 'Gene', '384', (141, 145))	('HK-2', 'Gene', '3099', (32, 36))	('PLP', 'Gene', (93, 96))	('ARG2', 'Gene', (141, 145))	('PLP', 'Gene', (187, 190))	('PLP', 'Gene', '57026', (93, 96))	('HK-2', 'molecular_function', 'GO:0008256', ('32', '36'))	('HK-2', 'Gene', (32, 36))	('PLP', 'Gene', '57026', (187, 190))	('elevated', 'PosReg', (66, 74))
52100	29754953	To demonstrate that ectopic PDXK was having the predicted effects on intracellular levels of pyridoxine pathway components, we employed LC/MS for their quantification in ARG2- and PDXK-expressing 786-O cells (see Experimental Procedures).	('intracellular levels of pyridoxine', 'MPA', (69, 103))	('PDXK', 'Gene', (180, 184))	('effects', 'Reg', (58, 65))	('pyridoxine', 'Chemical', 'MESH:D011736', (93, 103))	('intracellular', 'cellular_component', 'GO:0005622', ('69', '82'))	('ARG2', 'Gene', (170, 174))	('ectopic', 'Var', (20, 27))	('PDXK', 'Gene', '8566', (28, 32))	('PDXK', 'Gene', (28, 32))	('ARG2', 'Gene', '384', (170, 174))	('PDXK', 'Gene', '8566', (180, 184))
52104	29754953	However, ectopic PDXK expression increases PLP levels in ARG2-expressing cells, albeit not to the levels observed in controls (Figure 5G).	('ectopic', 'Var', (9, 16))	('PLP', 'Gene', '57026', (43, 46))	('expression', 'Var', (22, 32))	('PDXK', 'Gene', '8566', (17, 21))	('ARG2', 'Gene', '384', (57, 61))	('increases', 'PosReg', (33, 42))	('PDXK', 'Gene', (17, 21))	('expression', 'Species', '29278', (22, 32))	('PLP', 'Gene', (43, 46))	('ARG2', 'Gene', (57, 61))
52108	29754953	While polyamines promote tumor progression in some contexts, they cause cellular toxicity in other tumor cells, although the precise mechanisms by which polyamines either promote or inhibit tumor growth are not well characterized.	('tumor', 'Disease', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('toxicity', 'Disease', 'MESH:D064420', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('toxicity', 'Disease', (81, 89))	('tumor', 'Disease', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('promote', 'PosReg', (17, 24))	('polyamines', 'Chemical', 'MESH:D011073', (6, 16))	('promote', 'PosReg', (171, 178))	('cause', 'Reg', (66, 71))	('inhibit', 'NegReg', (182, 189))	('tumor', 'Disease', (190, 195))	('polyamines', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('polyamines', 'Chemical', 'MESH:D011073', (153, 163))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
52109	29754953	Treatment of 786-O ccRCC cells with exogenous putrescine resulted in a dose-dependent toxicity, whereas putrescine had no effect on the growth of control HK-2 cells, even at relatively high (10 mM) concentrations (Figure 6B).	('HK-2', 'molecular_function', 'GO:0008256', ('154', '158'))	('HK-2', 'Gene', (154, 158))	('exogenous', 'Var', (36, 45))	('putrescine', 'Chemical', 'MESH:D011700', (104, 114))	('toxicity', 'Disease', 'MESH:D064420', (86, 94))	('toxicity', 'Disease', (86, 94))	('putrescine', 'Chemical', 'MESH:D011700', (46, 56))	('HK-2', 'Gene', '3099', (154, 158))
52125	29754953	Taken together, these data support the hypothesis that altered expression of genes encoding polyamine pathway enzymes reduces endogenous polyamine synthesis in ccRCC as an adaptive response to the accumulation of toxic polyamines.	('endogenous polyamine synthesis', 'MPA', (126, 156))	('polyamines', 'Chemical', 'MESH:D011073', (219, 229))	('polyamine', 'Chemical', 'MESH:D011073', (137, 146))	('expression', 'Species', '29278', (63, 73))	('altered', 'Var', (55, 62))	('ccRCC', 'Disease', (160, 165))	('polyamine', 'Chemical', 'MESH:D011073', (219, 228))	('reduces', 'NegReg', (118, 125))	('polyamine synthesis', 'biological_process', 'GO:0006596', ('137', '156'))	('polyamine', 'Chemical', 'MESH:D011073', (92, 101))
52130	29754953	Absolute levels of putrescine in 786-O and HK-2 cells were determined to be 2-4 mM in media lacking exogenous polyamines (Figure S6A), with ARG2 deletion reducing levels by 8X in HK-2 cells, and ARG2 re-expression increasing putrescine levels 4X in 786-O cells in these conditions.	('ARG2', 'Gene', '384', (195, 199))	('ARG2', 'Gene', '384', (140, 144))	('increasing', 'PosReg', (214, 224))	('putrescine', 'Chemical', 'MESH:D011700', (19, 29))	('reducing', 'NegReg', (154, 162))	('HK-2', 'Gene', '3099', (43, 47))	('HK-2', 'Gene', (179, 183))	('expression', 'Species', '29278', (203, 213))	('HK-2', 'molecular_function', 'GO:0008256', ('43', '47'))	('putrescine levels', 'MPA', (225, 242))	('HK-2', 'Gene', (43, 47))	('ARG2', 'Gene', (195, 199))	('ARG2', 'Gene', (140, 144))	('HK-2', 'molecular_function', 'GO:0008256', ('179', '183'))	('levels', 'MPA', (163, 169))	('polyamines', 'Chemical', 'MESH:D011073', (110, 120))	('putrescine', 'Chemical', 'MESH:D011700', (225, 235))	('HK-2', 'Gene', '3099', (179, 183))	('deletion', 'Var', (145, 153))
52135	29754953	On the other hand, ARG2 knockout in HK-2 cells reduced the levels of putrescine (Figure S7A), while hypoxia had no effect (S7A), likely due to the lack of constitutive HIF activity in a VHL wild type setting.	('VHL', 'Gene', (186, 189))	('knockout', 'Var', (24, 32))	('levels of putrescine', 'MPA', (59, 79))	('VHL', 'Gene', '7428', (186, 189))	('HK-2', 'Gene', '3099', (36, 40))	('putrescine', 'Chemical', 'MESH:D011700', (69, 79))	('ARG2', 'Gene', '384', (19, 23))	('hypoxia', 'Disease', 'MESH:D000860', (100, 107))	('HK-2', 'Gene', (36, 40))	('HK-2', 'molecular_function', 'GO:0008256', ('36', '40'))	('ARG2', 'Gene', (19, 23))	('hypoxia', 'Disease', (100, 107))	('reduced', 'NegReg', (47, 54))
52141	29754953	To determine if ODC1 deficiency reverses polyamine overproduction in ARG2-reconstituted 786-O cells (see Figure 7A), CRISPR/Cas9 was used to achieve 70% deficiency in ODC1 protein in 786-O cell pools using ODC1 sgRNA-3 (Figure 7F).	('protein', 'Protein', (172, 179))	('Cas', 'cellular_component', 'GO:0005650', ('124', '127'))	('deficiency', 'NegReg', (153, 163))	('ARG2', 'Gene', '384', (69, 73))	('ODC1', 'Gene', (167, 171))	('ODC1', 'Gene', '4953', (16, 20))	('ARG2', 'Gene', (69, 73))	('ODC1', 'Gene', '4953', (167, 171))	('polyamine overproduction', 'MPA', (41, 65))	('ODC1', 'Gene', (206, 210))	('deficiency', 'Var', (21, 31))	('polyamine', 'Chemical', 'MESH:D011073', (41, 50))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('ODC1', 'Gene', '4953', (206, 210))	('ODC1', 'Gene', (16, 20))
52142	29754953	Soft agar colony assays revealed a significant rescue of colony formation when ARG2 expression and ODC1 deficiency were combined (Figure 7G).	('ODC1', 'Gene', (99, 103))	('ARG2', 'Gene', (79, 83))	('ARG2', 'Gene', '384', (79, 83))	('colony formation', 'CPA', (57, 73))	('ODC1', 'Gene', '4953', (99, 103))	('expression', 'Species', '29278', (84, 94))	('formation', 'biological_process', 'GO:0009058', ('64', '73'))	('rescue', 'PosReg', (47, 53))	('deficiency', 'Var', (104, 114))	('agar', 'Chemical', 'MESH:D000362', (5, 9))
52164	29754953	ARG2 expression had significant effects on pyridoxine metabolism, in that its deletion in renal epithelial cells, or reconstitution in ccRCC cells, changed overall intracellular PLP levels by a surprising 25-35%.	('ARG2', 'Gene', '384', (0, 4))	('PLP', 'Gene', (178, 181))	('PLP', 'Gene', '57026', (178, 181))	('ARG2', 'Gene', (0, 4))	('changed', 'Reg', (148, 155))	('pyridoxine metabolism', 'MPA', (43, 64))	('deletion', 'Var', (78, 86))	('pyridoxine', 'Chemical', 'MESH:D011736', (43, 53))	('intracellular', 'cellular_component', 'GO:0005622', ('164', '177'))	('expression', 'Species', '29278', (5, 15))	('pyridoxine metabolism', 'biological_process', 'GO:0008614', ('43', '64'))
52172	29754953	While intracellular polyamines can support cell division and anabolic metabolism, they can also be converted to toxic byproducts like acrolein.	('polyamines', 'Chemical', 'MESH:D011073', (20, 30))	('anabolic metabolism', 'MPA', (61, 80))	('cell division', 'biological_process', 'GO:0051301', ('43', '56'))	('cell division', 'CPA', (43, 56))	('polyamines', 'Var', (20, 30))	('acrolein', 'Chemical', 'MESH:D000171', (134, 142))	('metabolism', 'biological_process', 'GO:0008152', ('70', '80'))	('support', 'PosReg', (35, 42))	('intracellular', 'cellular_component', 'GO:0005622', ('6', '19'))
52206	29754953	pLKO.1 lentiviral vectors expressing hairpins against ARG2 SH-1 (TRCN0000051018), ARG2 SH-2 (TRCN0000051020), ASS1 SH-3 (TRCN0000045554), and ASS1 SH-4 (TRCN0000045553) were obtained from The RNAi Consortium (TRC) at the Broad Institute and GE Dharmacon.	('ASS1', 'Gene', (110, 114))	('ARG2', 'Gene', '384', (82, 86))	('ASS1', 'Gene', (142, 146))	('TRCN0000051020', 'Var', (93, 107))	('TRCN0000051018', 'Var', (65, 79))	('TRCN0000045554', 'Var', (121, 135))	('RNAi', 'biological_process', 'GO:0016246', ('192', '196'))	('TRCN0000045553', 'Var', (153, 167))	('ARG2', 'Gene', (54, 58))	('ARG2', 'Gene', '384', (54, 58))	('ASS1', 'Gene', '445', (110, 114))	('ARG2', 'Gene', (82, 86))	('ASS1', 'Gene', '445', (142, 146))
52209	29754953	Stable cell line generation with multiple cDNA's was achieved using either of two additional mammalian expression vectors with different selectable markers: pCDH-CMV-MCS-Hygromycin or pCDH-CMV-MCS-Neomycin (System Biosciences).	('MCS', 'cellular_component', 'GO:0044232', ('166', '169'))	('mammalian', 'Species', '9606', (93, 102))	('MCS', 'cellular_component', 'GO:0044232', ('193', '196'))	('pCDH-CMV-MCS-Hygromycin', 'Var', (157, 180))	('pCDH-CMV-MCS-Neomycin', 'Var', (184, 205))	('Hygromycin', 'Chemical', 'MESH:C026273', (170, 180))	('Neomycin', 'Chemical', 'MESH:D009355', (197, 205))	('expression vectors', 'Species', '29278', (103, 121))
52210	29754953	ARG2 cDNA construct: MHS6278-202800846 (Accession BC029050).	('ARG2', 'Gene', '384', (0, 4))	('MHS6278-202800846', 'Var', (21, 38))	('ARG2', 'Gene', (0, 4))
52228	29754953	Normal and ccRCC kidney tissue sections (from Cooperative Human Tissue Network) and tissue microarray slides (KD802, KD804, KD481, KD482, KD244, KD901, KD601, KD701 from US Biomax) were deparaffinized by baking slides at 50 C for 20 min.	('KD802', 'Var', (110, 115))	('KD244', 'Var', (138, 143))	('KD804', 'Var', (117, 122))	('KD701', 'Var', (159, 164))	('KD481', 'Var', (124, 129))	('Human', 'Species', '9606', (58, 63))	('KD482', 'Var', (131, 136))	('KD601', 'Var', (152, 157))	('KD901', 'Var', (145, 150))
52239	29754953	Predesigned Taqman primers were obtained from Life Technologies for the following genes: ACTB (HS01060665_G1), 18S (HS03928985_G1), ASS1 (HS01597989_G1), and ARG2 (HS00982833_M1).	('ASS1', 'Gene', '445', (132, 136))	('ARG2', 'Gene', (158, 162))	('ASS1', 'Gene', (132, 136))	('ARG2', 'Gene', '384', (158, 162))	('HS03928985_G1', 'Var', (116, 129))	('ACTB', 'Gene', (89, 93))	('ACTB', 'Gene', '60', (89, 93))	('HS01060665_G1', 'Var', (95, 108))	('HS01597989_G1', 'Var', (138, 151))	('HS00982833_M1', 'Var', (164, 177))
52270	29754953	For measurement of 15N enrichment we used the MRM, ion-pair links 275-70 and 279-70 for arginine; 276-70 and 278-70 for citrulline; 233-187 and 235-189 for putrescine; and 305-70and 307-70 for ornithine.	('279-70', 'Var', (77, 83))	('arginine', 'Chemical', 'MESH:D001120', (88, 96))	('305-70and 307-70', 'Var', (172, 188))	('citrulline', 'Chemical', 'MESH:D002956', (120, 130))	('278-70', 'Var', (109, 115))	('putrescine', 'MPA', (156, 166))	('ornithine', 'Chemical', 'MESH:D009952', (193, 202))	('arginine', 'MPA', (88, 96))	('15N', 'Chemical', '-', (19, 22))	('citrulline', 'MPA', (120, 130))	('ornithine', 'MPA', (193, 202))	('276-70', 'Var', (98, 104))	('233-187', 'Var', (132, 139))	('putrescine', 'Chemical', 'MESH:D011700', (156, 166))	('275-70', 'Var', (66, 72))
52292	28408295	Mutations in SETD2 (p=0.027) and KDM5C (p=0.019) were associated with reduced risk of death (HR 0.58 [95% CI 0.35-0.94] and HR 0.43 [95% CI 0.22-0.85] respectively).	('KDM5C', 'Gene', (33, 38))	('reduced', 'NegReg', (70, 77))	('KDM5C', 'Gene', '8242', (33, 38))	('SETD2', 'Gene', '29072', (13, 18))	('Mutations', 'Var', (0, 9))	('death', 'Disease', 'MESH:D003643', (86, 91))	('death', 'Disease', (86, 91))	('SETD2', 'Gene', (13, 18))
52293	28408295	BAP1 mutations (p=0.008) were associated with increased risk of death (HR 1.81 [95% CI 1.16-2.83].	('BAP1', 'Gene', (0, 4))	('death', 'Disease', 'MESH:D003643', (64, 69))	('mutations', 'Var', (5, 14))	('death', 'Disease', (64, 69))	('BAP1', 'Gene', '8314', (0, 4))
52294	28408295	There were significantly more female patients with a BAP1 mutation than females in the overall cohort (p=0.001).	('mutation', 'Var', (58, 66))	('BAP1', 'Gene', '8314', (53, 57))	('patients', 'Species', '9606', (37, 45))	('BAP1', 'Gene', (53, 57))
52295	28408295	Mutations in BAP1 negatively affected overall survival, while SETD2 and KDM5C mutations were associated with prolonged overall survival in our pooled cohort of 167 metastatic ccRCC patients.	('affected', 'Reg', (29, 37))	('BAP1', 'Gene', (13, 17))	('overall survival', 'MPA', (38, 54))	('KDM5C', 'Gene', '8242', (72, 77))	('negatively', 'NegReg', (18, 28))	('mutations', 'Var', (78, 87))	('Mutations', 'Var', (0, 9))	('SETD2', 'Gene', '29072', (62, 67))	('patients', 'Species', '9606', (181, 189))	('BAP1', 'Gene', '8314', (13, 17))	('overall', 'MPA', (119, 126))	('SETD2', 'Gene', (62, 67))	('KDM5C', 'Gene', (72, 77))	('prolonged', 'PosReg', (109, 118))
52302	28408295	One such stratification scheme has been based on the mutation status of PBRM1 and BAP1 in patients with ccRCC.	('BAP1', 'Gene', (82, 86))	('mutation status', 'Var', (53, 68))	('PBRM1', 'Gene', (72, 77))	('BAP1', 'Gene', '8314', (82, 86))	('PBRM1', 'Gene', '55193', (72, 77))	('patients', 'Species', '9606', (90, 98))	('ccRCC', 'Disease', (104, 109))
52304	28408295	They found that patients with neither mutation had the best clinical outcomes, while patients with mutations in PBRM1, BAP1, or both, had sequentially worse outcomes.	('PBRM1', 'Gene', (112, 117))	('PBRM1', 'Gene', '55193', (112, 117))	('patients', 'Species', '9606', (16, 24))	('patients', 'Species', '9606', (85, 93))	('mutations', 'Var', (99, 108))	('BAP1', 'Gene', '8314', (119, 123))	('BAP1', 'Gene', (119, 123))
52305	28408295	Numerous other studies have identified inferior overall survival (OS) in patients carrying BAP1 mutations.	('BAP1', 'Gene', (91, 95))	('overall survival', 'MPA', (48, 64))	('inferior', 'NegReg', (39, 47))	('BAP1', 'Gene', '8314', (91, 95))	('patients', 'Species', '9606', (73, 81))	('mutations', 'Var', (96, 105))
52326	28408295	Mutations in SETD2 (p=0.027) and KDM5C (p=0.019) were associated with a reduced risk of death, with hazard ratios (HR) of 0.58 (95% CI 0.35-0.94) and 0.45 (95% CI 0.23-0.89), respectively.	('reduced', 'NegReg', (72, 79))	('KDM5C', 'Gene', (33, 38))	('death', 'Disease', (88, 93))	('KDM5C', 'Gene', '8242', (33, 38))	('SETD2', 'Gene', '29072', (13, 18))	('Mutations', 'Var', (0, 9))	('SETD2', 'Gene', (13, 18))	('death', 'Disease', 'MESH:D003643', (88, 93))
52327	28408295	BAP1 (p=0.008) mutations were associated with increased risk of death: HR 1.85 (95% CI 1.17-2.92).	('BAP1', 'Gene', (0, 4))	('death', 'Disease', 'MESH:D003643', (64, 69))	('mutations', 'Var', (15, 24))	('death', 'Disease', (64, 69))	('BAP1', 'Gene', '8314', (0, 4))
52330	28408295	There was a significant association within our cohort between BAP1 mutations and sex.	('BAP1', 'Gene', '8314', (62, 66))	('significant association', 'Reg', (12, 35))	('BAP1', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))
52331	28408295	Females made up 24.6% of all those without a BAP1 mutation, but 58.6% of those with a BAP1 mutation (p=0.001).	('BAP1', 'Gene', '8314', (86, 90))	('BAP1', 'Gene', (45, 49))	('BAP1', 'Gene', (86, 90))	('BAP1', 'Gene', '8314', (45, 49))	('mutation', 'Var', (50, 58))
52332	28408295	No significant association was found between BAP1 mutation status and changes in OS when stratified by sex.	('mutation status', 'Var', (50, 65))	('BAP1', 'Gene', '8314', (45, 49))	('BAP1', 'Gene', (45, 49))
52335	28408295	Our analysis found no statistically significant association with OS when patients were stratified by their combined BAP1/PBRM1 mutational status, though the results may be trending towards significance (p=0.054) (Table 4 and Figure 2).	('BAP1', 'Gene', (116, 120))	('mutational', 'Var', (127, 137))	('PBRM1', 'Gene', (121, 126))	('BAP1', 'Gene', '8314', (116, 120))	('patients', 'Species', '9606', (73, 81))	('PBRM1', 'Gene', '55193', (121, 126))
52340	28408295	We found BAP1 mutations were associated with inferior OS, whereas SETD2 and KDM5C were associated with improved OS.	('KDM5C', 'Gene', (76, 81))	('KDM5C', 'Gene', '8242', (76, 81))	('associated with', 'Reg', (29, 44))	('inferior OS', 'Disease', (45, 56))	('BAP1', 'Gene', '8314', (9, 13))	('SETD2', 'Gene', '29072', (66, 71))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('SETD2', 'Gene', (66, 71))
52341	28408295	Using a BAP1/PBRM1 stratification scheme for prognosis, we found no statistically significant difference in OS according to the four subgroups based on BAP1 and PBRM1 mutations.	('PBRM1', 'Gene', (161, 166))	('PBRM1', 'Gene', (13, 18))	('BAP1', 'Gene', '8314', (152, 156))	('BAP1', 'Gene', '8314', (8, 12))	('PBRM1', 'Gene', '55193', (161, 166))	('mutations', 'Var', (167, 176))	('PBRM1', 'Gene', '55193', (13, 18))	('BAP1', 'Gene', (152, 156))	('BAP1', 'Gene', (8, 12))
52343	28408295	This result is likely due to the fact that PBRM1 mutations did not have prognostic value in this cohort of cytoreductive patients.	('PBRM1', 'Gene', (43, 48))	('PBRM1', 'Gene', '55193', (43, 48))	('patients', 'Species', '9606', (121, 129))	('mutations', 'Var', (49, 58))
52344	28408295	It is also worth noting that patients with PBRM1 loss may possess some element of clinical benefit from their mutational status, as being a PBRM1 mutant often precludes the existence of BAP1 mutations, given these two mutations' tendency towards mutual exclusivity.	('PBRM1', 'Gene', (43, 48))	('loss', 'NegReg', (49, 53))	('patients', 'Species', '9606', (29, 37))	('precludes', 'NegReg', (159, 168))	('PBRM1', 'Gene', (140, 145))	('PBRM1', 'Gene', '55193', (43, 48))	('BAP1', 'Gene', '8314', (186, 190))	('PBRM1', 'Gene', '55193', (140, 145))	('mutant', 'Var', (146, 152))	('BAP1', 'Gene', (186, 190))
52345	28408295	Interestingly, females made up a significantly disproportionate number of patients with BAP1 mutations than they did BAP1 wild type or the cohort overall.	('mutations', 'Var', (93, 102))	('BAP1', 'Gene', '8314', (117, 121))	('patients', 'Species', '9606', (74, 82))	('BAP1', 'Gene', '8314', (88, 92))	('BAP1', 'Gene', (117, 121))	('BAP1', 'Gene', (88, 92))
52346	28408295	A previous study suggested that BAP1 mutations only carry significance for decreased OS among females, as well as increased frequency between female sex and BAP1 mutations.	('mutations', 'Var', (162, 171))	('BAP1', 'Gene', (157, 161))	('BAP1', 'Gene', '8314', (32, 36))	('mutations', 'Var', (37, 46))	('BAP1', 'Gene', (32, 36))	('BAP1', 'Gene', '8314', (157, 161))	('decreased', 'NegReg', (75, 84))
52348	28408295	Mutations in SETD2 and KDM5C conferred improved OS in our cohort.	('KDM5C', 'Gene', (23, 28))	('KDM5C', 'Gene', '8242', (23, 28))	('SETD2', 'Gene', '29072', (13, 18))	('Mutations', 'Var', (0, 9))	('SETD2', 'Gene', (13, 18))	('improved', 'PosReg', (39, 47))
52349	28408295	One possible reason for a survival advantage in patients with KDM5C mutations may be an improved response to VEGF inhibitor therapy.	('survival', 'CPA', (26, 34))	('KDM5C', 'Gene', '8242', (62, 67))	('VEGF', 'Gene', (109, 113))	('advantage', 'PosReg', (35, 44))	('improved', 'PosReg', (88, 96))	('mutations', 'Var', (68, 77))	('KDM5C', 'Gene', (62, 67))	('patients', 'Species', '9606', (48, 56))	('VEGF', 'Gene', '7422', (109, 113))	('response', 'MPA', (97, 105))
52350	28408295	We have recently published data showing prolonged progression-free survival among these patients (20.6 months for patients with KDM5C mutations vs 8.3 months for KDM5C wild-type), and other recent research has yielded similar results.	('KDM5C', 'Gene', (128, 133))	('KDM5C', 'Gene', '8242', (162, 167))	('KDM5C', 'Gene', '8242', (128, 133))	('patients', 'Species', '9606', (88, 96))	('mutations', 'Var', (134, 143))	('patients', 'Species', '9606', (114, 122))	('KDM5C', 'Gene', (162, 167))
52351	28408295	In regard to SETD2 mutations, previous studies have indicated these mutations are associated with advanced or recurrent disease.	('associated', 'Reg', (82, 92))	('mutations', 'Var', (19, 28))	('SETD2', 'Gene', '29072', (13, 18))	('advanced', 'Disease', (98, 106))	('SETD2', 'Gene', (13, 18))	('mutations', 'Var', (68, 77))	('recurrent disease', 'Disease', (110, 127))
52352	28408295	However, in our study, SETD2 mutated patients had a survival advantage.	('SETD2', 'Gene', '29072', (23, 28))	('SETD2', 'Gene', (23, 28))	('survival advantage', 'CPA', (52, 70))	('patients', 'Species', '9606', (37, 45))	('mutated', 'Var', (29, 36))
52355	28408295	The frequency of patients with VHL mutations in our study (61.1%) is less than what is commonly found in other large cohorts of ccRCC patients (74%).	('VHL', 'Gene', '7428', (31, 34))	('patients', 'Species', '9606', (134, 142))	('patients', 'Species', '9606', (17, 25))	('VHL', 'Gene', (31, 34))	('mutations', 'Var', (35, 44))
52360	28408295	In our study of 167 cytoreductive ccRCC patients, we found that mutations in BAP1 negatively affected OS, while SETD2 and KDM5C mutations were associated with prolonged OS.	('associated', 'Reg', (143, 153))	('SETD2', 'Gene', '29072', (112, 117))	('patients', 'Species', '9606', (40, 48))	('SETD2', 'Gene', (112, 117))	('KDM5C', 'Gene', (122, 127))	('BAP1', 'Gene', '8314', (77, 81))	('mutations', 'Var', (64, 73))	('KDM5C', 'Gene', '8242', (122, 127))	('negatively', 'NegReg', (82, 92))	('BAP1', 'Gene', (77, 81))
52362	28408295	The favorable prognostic influence of PBRM1 mutations seen in multiple studies of localized ccRCC appears to be lost in the Stage IV setting.	('PBRM1', 'Gene', (38, 43))	('PBRM1', 'Gene', '55193', (38, 43))	('mutations', 'Var', (44, 53))
52363	28408295	While examining the combined influence of PBRM1 and BAP1 mutations, the BAP1 mutations appeared to be the catalyst of worsening OS among this cohort of cytoreductive ccRCC patients.	('BAP1', 'Gene', '8314', (52, 56))	('BAP1', 'Gene', '8314', (72, 76))	('PBRM1', 'Gene', (42, 47))	('BAP1', 'Gene', (52, 56))	('BAP1', 'Gene', (72, 76))	('mutations', 'Var', (77, 86))	('worsening', 'PosReg', (118, 127))	('PBRM1', 'Gene', '55193', (42, 47))	('patients', 'Species', '9606', (172, 180))	('ccRCC', 'Disease', (166, 171))
52368	31771219	MTA2 knockdown inhibited the migration, invasion, and in vivo metastasis of RCC cells without effects on cell proliferation.	('inhibited', 'NegReg', (15, 24))	('cell proliferation', 'biological_process', 'GO:0008283', ('105', '123'))	('RCC', 'Disease', 'MESH:D002292', (76, 79))	('invasion', 'CPA', (40, 48))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('knockdown', 'Var', (5, 14))	('MTA2', 'Gene', (0, 4))	('migration', 'CPA', (29, 38))
52369	31771219	Regarding molecular mechanisms, MTA2 knockdown reduced the activity, protein level, and mRNA expression of matrix metalloproteinase-9 (MMP-9) in RCC cells.	('activity', 'MPA', (59, 67))	('protein level', 'MPA', (69, 82))	('RCC', 'Disease', (145, 148))	('matrix metalloproteinase-9', 'Gene', '4318', (107, 133))	('RCC', 'Disease', 'MESH:D002292', (145, 148))	('mRNA expression', 'MPA', (88, 103))	('MMP-9', 'Gene', '4318', (135, 140))	('knockdown', 'Var', (37, 46))	('MMP-9', 'Gene', (135, 140))	('MMP-9', 'molecular_function', 'GO:0004229', ('135', '140'))	('matrix metalloproteinase-9', 'Gene', (107, 133))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('reduced', 'NegReg', (47, 54))	('MTA2', 'Gene', (32, 36))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))
52371	31771219	Moreover, miR-133b modulated the 3'untranslated region (UTR) of MMP-9 promoter activities and subsequently the migratory and invasive abilities of these dysregulated expressions of MTA2 in RCC cells.	('RCC', 'Disease', 'MESH:D002292', (189, 192))	('modulated', 'Reg', (19, 28))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))	('miR-133b', 'Gene', (10, 18))	('MMP-9', 'molecular_function', 'GO:0004229', ('64', '69'))	('MTA2', 'Gene', (181, 185))	('dysregulated', 'Var', (153, 165))	('MMP-9', 'Gene', '4318', (64, 69))	('invasive abilities', 'CPA', (125, 143))	('RCC', 'Disease', (189, 192))	('miR-133b', 'Gene', '442890', (10, 18))	('MMP-9', 'Gene', (64, 69))
52382	31771219	In estrogen receptor-alpha-negative breast cancer, MTA2 expression is associated with poor prognosis and enhanced metastasis in vitro and in vivo through Rho pathway activation.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('activation', 'PosReg', (166, 176))	('metastasis', 'CPA', (114, 124))	('breast cancer', 'Disease', (36, 49))	('estrogen receptor-alpha', 'Gene', (3, 26))	('Rho pathway', 'Pathway', (154, 165))	('MTA2', 'Gene', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('estrogen receptor-alpha', 'Gene', '2099', (3, 26))	('expression', 'Var', (56, 66))	('enhanced', 'PosReg', (105, 113))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
52390	31771219	Moreover, aberrant miR-133b expression plays a role in RCC development by suppressing cell proliferation and migratory and invasive abilities by modulating MMP-9 expression, but the molecular mechanism of MTA2 regulating miR-133b involvement in RCC metastasis has not yet been elucidated.	('RCC', 'Disease', 'MESH:D002292', (55, 58))	('modulating', 'Reg', (145, 155))	('aberrant', 'Var', (10, 18))	('RCC', 'Disease', 'MESH:D002292', (245, 248))	('miR-133b', 'Gene', '442890', (221, 229))	('miR-133b', 'Gene', (19, 27))	('MMP-9', 'Gene', '4318', (156, 161))	('MMP-9', 'Gene', (156, 161))	('suppressing', 'NegReg', (74, 85))	('cell proliferation', 'biological_process', 'GO:0008283', ('86', '104'))	('cell proliferation', 'CPA', (86, 104))	('miR-133b', 'Gene', '442890', (19, 27))	('MMP-9', 'molecular_function', 'GO:0004229', ('156', '161'))	('miR-133b', 'Gene', (221, 229))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('RCC', 'Disease', (55, 58))	('RCC', 'Disease', (245, 248))	('RCC', 'Phenotype', 'HP:0005584', (245, 248))	('expression', 'MPA', (162, 172))
52400	31771219	Patients with RCC who had high MTA2 expression had a significantly lower survival rate compared with those with low MTA2 expression (p = 0.014, Figure 1D).	('RCC', 'Disease', 'MESH:D002292', (14, 17))	('RCC', 'Disease', (14, 17))	('high', 'Var', (26, 30))	('survival rate', 'CPA', (73, 86))	('expression', 'Var', (36, 46))	('Patients', 'Species', '9606', (0, 8))	('MTA2', 'Gene', (31, 35))	('lower', 'NegReg', (67, 72))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
52405	31771219	To further explore the influence of MTA2 on cell proliferation, we determined whether MTA2 knockdown had a cytotoxic effect on RCC cells using an (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MTT) MTT assay.	('knockdown', 'Var', (91, 100))	('MTT', 'Chemical', 'MESH:C022616', (214, 217))	('MTT', 'Chemical', 'MESH:C022616', (209, 212))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide', 'Chemical', 'MESH:C022616', (147, 207))	('MTA2', 'Gene', (86, 90))	('RCC', 'Disease', 'MESH:D002292', (127, 130))	('RCC', 'Disease', (127, 130))	('cell proliferation', 'biological_process', 'GO:0008283', ('44', '62'))
52408	31771219	Hence, MTA2 knockdown did not affect the proliferation of RCC cells.	('knockdown', 'Var', (12, 21))	('MTA2', 'Gene', (7, 11))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:D002292', (58, 61))
52409	31771219	After MTA2 knockdown, RCC cells (786-O, Caki-1, and ACHN) exhibited significantly reduced MTA2 expression using western blot analysis (Figure 3A).	('786-O', 'Chemical', 'MESH:C002925', (33, 38))	('RCC', 'Disease', (22, 25))	('RCC', 'Phenotype', 'HP:0005584', (22, 25))	('Caki-1', 'CellLine', 'CVCL:0234', (40, 46))	('MTA2', 'Gene', (6, 10))	('RCC', 'Disease', 'MESH:D002292', (22, 25))	('reduced', 'NegReg', (82, 89))	('MTA2', 'Gene', (90, 94))	('knockdown', 'Var', (11, 20))	('expression', 'MPA', (95, 105))
52413	31771219	Lung nodules were counted after sacrificing these mice, and markedly fewer nodules were observed in the shMTA2-786-O and shMTA2-Caki-1 cells than in shLuc-786-O and shLuc-Caki-1 cells (Figure 3D).	('786-O', 'Chemical', 'MESH:C002925', (111, 116))	('shMTA2-786-O', 'Var', (104, 116))	('Caki-1', 'CellLine', 'CVCL:0234', (128, 134))	('fewer', 'NegReg', (69, 74))	('Caki-1', 'CellLine', 'CVCL:0234', (171, 177))	('shMTA2-786-O', 'Chemical', 'MESH:C085586', (104, 116))	('nodules', 'CPA', (75, 82))	('mice', 'Species', '10090', (50, 54))	('786-O', 'Chemical', 'MESH:C002925', (155, 160))
52415	31771219	To identify the molecular mechanism of MTA2 in the invasive behaviour of RCC, western blot analysis, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay, and gelatin zymography demonstrated that MTA2 knockdown significantly decreased the protein, mRNA, and activity expression of MMP-9 in 786-O, Caki-1, and ACHN cells, but was not involved in MMP-2 (Figure 4A-C).	('reverse transcription', 'biological_process', 'GO:0001171', ('114', '135'))	('protein', 'cellular_component', 'GO:0003675', ('263', '270'))	('behaviour', 'biological_process', 'GO:0007610', ('60', '69'))	('mRNA', 'MPA', (272, 276))	('MMP-9', 'molecular_function', 'GO:0004229', ('305', '310'))	('MMP-2', 'Gene', '4313', (369, 374))	('activity expression', 'MPA', (282, 301))	('protein', 'MPA', (263, 270))	('knockdown', 'Var', (225, 234))	('MMP-9', 'Gene', '4318', (305, 310))	('MMP-9', 'Gene', (305, 310))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))	('MMP-2', 'molecular_function', 'GO:0004228', ('369', '374'))	('RCC', 'Disease', (73, 76))	('Caki-1', 'CellLine', 'CVCL:0234', (321, 327))	('MTA2', 'Gene', (220, 224))	('MMP-2', 'Gene', (369, 374))	('RCC', 'Disease', 'MESH:D002292', (73, 76))	('decreased', 'NegReg', (249, 258))	('786-O', 'Chemical', 'MESH:C002925', (314, 319))
52418	31771219	In addition, Kaplan-Meier survival and log rank analyses suggested that patients with RCC and high MMP-9 expression had lower survival rates compared with those with low MMP-9 expression (p < 0.001, Figure 4E).	('lower', 'NegReg', (120, 125))	('RCC', 'Disease', (86, 89))	('MMP-9', 'Gene', (99, 104))	('MMP-9', 'Gene', '4318', (170, 175))	('MMP-9', 'molecular_function', 'GO:0004229', ('170', '175'))	('MMP-9', 'Gene', '4318', (99, 104))	('MMP-9', 'Gene', (170, 175))	('MMP-9', 'molecular_function', 'GO:0004229', ('99', '104'))	('high', 'Var', (94, 98))	('RCC', 'Disease', 'MESH:D002292', (86, 89))	('survival', 'MPA', (126, 134))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('patients', 'Species', '9606', (72, 80))
52434	31771219	A western blotting assay revealed a significantly higher MMP-9 expression in antagomir-133b-transfected HK2 cells than in NC-transfected cells (Supplementary Figure S2A) and inhibition of endogenous miR-133b expression by using RT-qPCR assay (Supplementary Figure S2B).	('HK2', 'molecular_function', 'GO:0008256', ('104', '107'))	('higher', 'PosReg', (50, 56))	('HK2', 'Gene', '3099', (104, 107))	('miR-133b', 'Gene', '442890', (199, 207))	('miR-133b', 'Gene', (199, 207))	('expression', 'MPA', (63, 73))	('MMP-9', 'molecular_function', 'GO:0004229', ('57', '62'))	('expression', 'MPA', (208, 218))	('inhibition', 'NegReg', (174, 184))	('MMP-9', 'Gene', '4318', (57, 62))	('antagomir-133b-transfected', 'Var', (77, 103))	('HK2', 'Gene', (104, 107))	('MMP-9', 'Gene', (57, 62))
52438	31771219	Our results indicated that (1) MTA2 expression was increased in RCC cells and was markedly correlated with high grade and poor survival rates of patients with RCC; (2) MTA2 did not affect RCC cell proliferation or cell cycle distribution; (3) MTA2 regulated the tumour metastasis of RCC cells and modulation of MMP-9 expression in vitro and in vivo; (4) miR-133b and MMP-9 expression in patients with RCC was negatively correlated with poor survival rates; (5) MTA2 knockdown inhibited RCC metastasis by targeting miR-133b and MMP-9 pathways.	('MMP-9', 'molecular_function', 'GO:0004229', ('311', '316'))	('tumour metastasis', 'Disease', (262, 279))	('knockdown', 'Var', (466, 475))	('RCC', 'Disease', (283, 286))	('patients', 'Species', '9606', (387, 395))	('RCC', 'Phenotype', 'HP:0005584', (283, 286))	('miR-133b', 'Gene', '442890', (514, 522))	('cell proliferation', 'biological_process', 'GO:0008283', ('192', '210'))	('RCC', 'Disease', (401, 404))	('RCC', 'Phenotype', 'HP:0005584', (401, 404))	('RCC', 'Disease', 'MESH:D002292', (188, 191))	('miR-133b', 'Gene', '442890', (354, 362))	('targeting', 'Reg', (504, 513))	('RCC', 'Disease', (486, 489))	('MMP-9', 'Gene', '4318', (527, 532))	('RCC', 'Disease', 'MESH:D002292', (283, 286))	('RCC', 'Disease', 'MESH:D002292', (401, 404))	('MTA2', 'Gene', (461, 465))	('MMP-9', 'Gene', (527, 532))	('MMP-9', 'molecular_function', 'GO:0004229', ('527', '532'))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))	('tumour metastasis', 'Disease', 'MESH:D009362', (262, 279))	('cell cycle', 'biological_process', 'GO:0007049', ('214', '224'))	('MMP-9', 'molecular_function', 'GO:0004229', ('367', '372'))	('RCC', 'Disease', 'MESH:D002292', (486, 489))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('MMP-9', 'Gene', '4318', (311, 316))	('RCC', 'Disease', (64, 67))	('MTA2', 'Gene', (31, 35))	('miR-133b', 'Gene', (514, 522))	('MMP-9', 'Gene', (311, 316))	('MMP-9', 'Gene', '4318', (367, 372))	('patients', 'Species', '9606', (145, 153))	('RCC', 'Disease', 'MESH:D002292', (159, 162))	('MMP-9', 'Gene', (367, 372))	('inhibited', 'NegReg', (476, 485))	('miR-133b', 'Gene', (354, 362))	('tumour', 'Phenotype', 'HP:0002664', (262, 268))	('RCC', 'Disease', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('RCC', 'Disease', 'MESH:D002292', (64, 67))
52442	31771219	Moreover, high MTA2 expression was markedly correlated with tumour grades and indicated low survival rates in accordance with the clinical pathologic data from our patients and TCGA database (Figure 1).	('MTA2', 'Gene', (15, 19))	('expression', 'MPA', (20, 30))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('low', 'NegReg', (88, 91))	('tumour', 'Disease', (60, 66))	('correlated', 'Reg', (44, 54))	('survival rates', 'CPA', (92, 106))	('high', 'Var', (10, 14))	('patients', 'Species', '9606', (164, 172))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))
52448	31771219	On the basis of these studies, we demonstrated that MTA2 knockdown could decrease the expression of MMP-9 and the invasive, migratory, and metastatic abilities of RCC cells.	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('MMP-9', 'Gene', '4318', (100, 105))	('RCC', 'Disease', 'MESH:D002292', (163, 166))	('RCC', 'Disease', (163, 166))	('MMP-9', 'Gene', (100, 105))	('MMP-9', 'molecular_function', 'GO:0004229', ('100', '105'))	('knockdown', 'Var', (57, 66))	('expression', 'MPA', (86, 96))	('decrease', 'NegReg', (73, 81))	('MTA2', 'Gene', (52, 56))	('invasive', 'CPA', (114, 122))
52449	31771219	Therefore, MTA2 could influence the malignant factor that modulates MMP-9 expression for RCC.	('expression', 'MPA', (74, 84))	('MMP-9', 'Gene', (68, 73))	('MMP-9', 'molecular_function', 'GO:0004229', ('68', '73'))	('modulates', 'Reg', (58, 67))	('influence', 'Reg', (22, 31))	('MTA2', 'Var', (11, 15))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('RCC', 'Disease', 'MESH:D002292', (89, 92))	('MMP-9', 'Gene', '4318', (68, 73))
52457	31771219	Consistent with the aforementioned results, MTA2 knockdown inhibited RCC metastasis by targeting MMP-9 expression.	('knockdown', 'Var', (49, 58))	('RCC', 'Disease', (69, 72))	('RCC', 'Disease', 'MESH:D002292', (69, 72))	('MTA2', 'Gene', (44, 48))	('expression', 'MPA', (103, 113))	('MMP-9', 'Gene', '4318', (97, 102))	('inhibited', 'NegReg', (59, 68))	('MMP-9', 'molecular_function', 'GO:0004229', ('97', '102'))	('MMP-9', 'Gene', (97, 102))	('targeting', 'Reg', (87, 96))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
52459	31771219	Similarly, inhibition of miR-133b in HK2 cells, which exhibit relatively high levels of miR-133b, significantly enhanced HK2 cell migration and invasion when treated with miR-133b antagomir.	('enhanced', 'PosReg', (112, 120))	('HK2', 'Gene', (121, 124))	('miR-133b', 'Gene', (171, 179))	('HK2', 'Gene', '3099', (121, 124))	('miR-133b', 'Gene', '442890', (25, 33))	('miR-133b', 'Gene', (25, 33))	('cell migration', 'biological_process', 'GO:0016477', ('125', '139'))	('invasion', 'CPA', (144, 152))	('HK2', 'Gene', (37, 40))	('HK2', 'Gene', '3099', (37, 40))	('miR-133b', 'Gene', '442890', (88, 96))	('HK2', 'molecular_function', 'GO:0008256', ('37', '40'))	('HK2', 'molecular_function', 'GO:0008256', ('121', '124'))	('inhibition', 'Var', (11, 21))	('miR-133b', 'Gene', '442890', (171, 179))	('miR-133b', 'Gene', (88, 96))
52464	31771219	Moreover, MTA2 knockdown inhibited RCC metastasis by regulating miR-133b targeting of MMP-9, and miR-133b was negatively correlated with RCC progression.	('miR-133b', 'Gene', (64, 72))	('RCC', 'Disease', (35, 38))	('RCC', 'Disease', 'MESH:D002292', (35, 38))	('MMP-9', 'Gene', '4318', (86, 91))	('knockdown', 'Var', (15, 24))	('targeting', 'MPA', (73, 82))	('negatively', 'NegReg', (110, 120))	('MMP-9', 'Gene', (86, 91))	('miR-133b', 'Gene', '442890', (97, 105))	('inhibited', 'NegReg', (25, 34))	('MTA2', 'Gene', (10, 14))	('miR-133b', 'Gene', (97, 105))	('miR-133b', 'Gene', '442890', (64, 72))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('MMP-9', 'molecular_function', 'GO:0004229', ('86', '91'))	('RCC', 'Disease', 'MESH:D002292', (137, 140))	('RCC', 'Disease', (137, 140))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))
52507	31771219	Moreover, we highlighted that MTA2 could regulate the RCC process by modulating miR-133b targeting MMP-9 expression.	('modulating', 'Var', (69, 79))	('MMP-9', 'Gene', (99, 104))	('miR-133b', 'Gene', '442890', (80, 88))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('regulate', 'Reg', (41, 49))	('RCC', 'Disease', 'MESH:D002292', (54, 57))	('miR-133b', 'Gene', (80, 88))	('MMP-9', 'molecular_function', 'GO:0004229', ('99', '104'))	('MMP-9', 'Gene', '4318', (99, 104))
52534	31268155	Although HIF1A and HIF2A represent different proteins, and they partially overlap in the activation of target genes; for example, the gene expression of C-X-C chemokine receptor type 4 (CXCR4) and solute carrier family 2 member 1 (SLC2A1) has been shown to be activated by either HIF1A or HIF2A.	('HIF1A', 'Gene', (280, 285))	('HIF1A', 'Gene', '3091', (280, 285))	('solute carrier family 2 member 1', 'Gene', '6513', (197, 229))	('solute carrier family 2 member 1', 'Gene', (197, 229))	('carrier', 'molecular_function', 'GO:0005215', ('204', '211'))	('CXCR4', 'Gene', (186, 191))	('CXCR4', 'molecular_function', 'GO:0038147', ('186', '191'))	('HIF1A', 'Gene', '3091', (9, 14))	('gene expression', 'biological_process', 'GO:0010467', ('134', '149'))	('SLC2A1', 'Gene', '6513', (231, 237))	('activated', 'PosReg', (260, 269))	('C-X-C chemokine receptor type 4', 'Gene', (153, 184))	('SLC2A1', 'Gene', (231, 237))	('C-X-C chemokine receptor type 4', 'Gene', '7852', (153, 184))	('HIF2A', 'Var', (289, 294))	('CXCR4', 'Gene', '7852', (186, 191))	('HIF1A', 'Gene', (9, 14))
52578	31268155	Of the 36 patients with ccRCC aged 60.6+-11.9 years [mean +- standard deviation (SD); Table I], 21 were diagnosed [according to the tumor-necrosis-metastasis (TNM) staging system] as stage I (T1-2N0M0), 7 as stage III (T1-2N1M0 or T3N0-1M0) and 8 as stage IV (T4N0-2M0 or T1-4N2M0 or T1-4N0-2M1), according to anatomic stage and prognostic groups based on the 2010 TNM 7th classification of RCC.	('T1-4N2M0', 'Var', (272, 280))	('necrosis', 'biological_process', 'GO:0070265', ('138', '146'))	('necrosis', 'biological_process', 'GO:0008219', ('138', '146'))	('tumor-necrosis-metastasis', 'Disease', (132, 157))	('RCC', 'Disease', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('necrosis', 'biological_process', 'GO:0019835', ('138', '146'))	('necrosis', 'biological_process', 'GO:0008220', ('138', '146'))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('necrosis', 'biological_process', 'GO:0001906', ('138', '146'))	('RCC', 'Disease', 'MESH:C538614', (391, 394))	('RCC', 'Disease', (391, 394))	('tumor-necrosis-metastasis', 'Disease', 'MESH:D009362', (132, 157))	('patients', 'Species', '9606', (10, 18))
52584	31268155	Post-operative treatment included sunitinib (an anti-VEGFA agent), which was administered to 9 patients with clinically advanced ccRCC (T1-2N1M0, T3N0-1M0, T1-4N2M0 and T1-4N0-2M1), and to 2 patients with early ccRCC (T1-2N0M0), according to a generally accepted schedule of 1 cycle: 50 mg/day for 4 weeks, followed by a 2-week interval.	('VEGFA', 'Gene', '7422', (53, 58))	('sunitinib', 'Chemical', 'MESH:D000077210', (34, 43))	('to 9', 'Species', '1214577', (90, 94))	('T3N0-1M0', 'Var', (146, 154))	('patients', 'Species', '9606', (191, 199))	('patients', 'Species', '9606', (95, 103))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (131, 134))	('T1-4N2M0', 'Var', (156, 164))	('VEGFA', 'Gene', (53, 58))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('T1-2N1M0', 'Var', (136, 144))	('RCC', 'Disease', (213, 216))
52612	31268155	There was also a medium-to-strong positive correlation between either HIF1A or HIF2A and VEGFA (at both the mRNA and protein level); the associations were stronger for HIF1A mRNA-VEGFA mRNA and HIF2A mRNA-VEGFA mRNA (rs=0.71 and 0.73, respectively; P<0.05) compared with HIF1A protein-VEGFA protein or HIF2A protein-VEGFA protein (rs=0.58 and 0.69, respectively; Table V).	('VEGFA', 'Gene', '7422', (205, 210))	('HIF1A', 'Gene', (168, 173))	('protein', 'cellular_component', 'GO:0003675', ('277', '284'))	('VEGFA', 'Gene', '7422', (179, 184))	('HIF1A', 'Gene', (271, 276))	('VEGFA', 'Gene', (89, 94))	('associations', 'Interaction', (137, 149))	('protein', 'cellular_component', 'GO:0003675', ('291', '298'))	('HIF1A', 'Gene', (70, 75))	('HIF2A', 'Var', (194, 199))	('VEGFA', 'Gene', (285, 290))	('VEGFA', 'Gene', (316, 321))	('HIF1A', 'Gene', '3091', (168, 173))	('VEGFA', 'Gene', '7422', (89, 94))	('protein', 'cellular_component', 'GO:0003675', ('308', '315'))	('stronger', 'PosReg', (155, 163))	('VEGFA', 'Gene', (205, 210))	('HIF1A', 'Gene', '3091', (271, 276))	('VEGFA', 'Gene', (179, 184))	('protein', 'cellular_component', 'GO:0003675', ('322', '329'))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('HIF1A', 'Gene', '3091', (70, 75))	('VEGFA', 'Gene', '7422', (316, 321))	('VEGFA', 'Gene', '7422', (285, 290))
52626	31268155	Patients with increased levels of HIF1A (mRNA and protein), HIF2A (mRNA and protein), as well as VEGFA (mRNA and protein) were characterized by a shorter PFS (Fig.	('increased', 'PosReg', (14, 23))	('HIF2A', 'Var', (60, 65))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('VEGFA', 'Gene', (97, 102))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('HIF1A', 'Gene', (34, 39))	('HIF1A', 'Gene', '3091', (34, 39))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (146, 153))	('VEGFA', 'Gene', '7422', (97, 102))	('PFS', 'MPA', (154, 157))
52649	31268155	It has been demonstrated that pVHL may trigger various processes, such as glucose uptake and metabolism, angiogenesis, the suppression of epithelial-to-mesenchymal transition, cell proliferation, survival or apoptosis, or activation of the P53 pathway.	('angiogenesis', 'CPA', (105, 117))	('trigger', 'Reg', (39, 46))	('cell proliferation', 'CPA', (176, 194))	('glucose uptake', 'CPA', (74, 88))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('138', '174'))	('survival', 'CPA', (196, 204))	('epithelial-to-mesenchymal transition', 'CPA', (138, 174))	('angiogenesis', 'biological_process', 'GO:0001525', ('105', '117'))	('pVHL', 'Var', (30, 34))	('cell proliferation', 'biological_process', 'GO:0008283', ('176', '194'))	('metabolism', 'biological_process', 'GO:0008152', ('93', '103'))	('glucose', 'Chemical', 'MESH:D005947', (74, 81))	('suppression', 'NegReg', (123, 134))	('apoptosis', 'CPA', (208, 217))	('glucose uptake', 'biological_process', 'GO:0046323', ('74', '88'))	('metabolism', 'CPA', (93, 103))	('P53 pathway', 'Pathway', (240, 251))	('apoptosis', 'biological_process', 'GO:0097194', ('208', '217'))	('apoptosis', 'biological_process', 'GO:0006915', ('208', '217'))
52651	31268155	Although the contribution of the mutated VHL gene to ccRCC initiated in the course of Von Hippel-Lindau disease has been described, further studies of this gene in sporadic ccRCC are warranted.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('mutated', 'Var', (33, 40))	('Von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (86, 111))	('RCC', 'Disease', (175, 178))	('VHL', 'Gene', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (175, 178))	('VHL', 'Gene', '7428', (41, 44))	('Von Hippel-Lindau disease', 'Disease', (86, 111))
52657	31268155	On the contrary to the listed studies, deep-genome and mRNA studies on 48 ccRCC cases conducted by Girgis et al did not reveal any changes in VHL mRNA levels, despite the observed hypermethylation of the VHL genomic locus.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('VHL', 'Gene', '7428', (142, 145))	('VHL', 'Gene', (204, 207))	('VHL', 'Gene', '7428', (204, 207))	('hypermethylation', 'Var', (180, 196))	('VHL', 'Gene', (142, 145))
52658	31268155	Other studies on VHL gene expression were mainly based on DNA analysis focusing on the hypermethylation status of the VHL gene promoter locus or mutational analysis of the VHL exons.	('VHL', 'Gene', (118, 121))	('mutational', 'Var', (145, 155))	('VHL', 'Gene', '7428', (118, 121))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('VHL', 'Gene', (17, 20))	('gene expression', 'biological_process', 'GO:0010467', ('21', '36'))	('VHL', 'Gene', (172, 175))	('VHL', 'Gene', '7428', (17, 20))	('VHL', 'Gene', '7428', (172, 175))
52659	31268155	Since previous investigations of the tumor tissues from patients with ccRCC treated with sunitinib focused on VHL mutations, to the best of our knowledge, the present study is the first to investigate the expression of VHL at both the mRNA and protein level in patients with ccRCC treated with first-line sunitinib.	('patients', 'Species', '9606', (261, 269))	('patients', 'Species', '9606', (56, 64))	('VHL', 'Gene', '7428', (110, 113))	('VHL', 'Gene', '7428', (219, 222))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('sunitinib', 'Chemical', 'MESH:D000077210', (89, 98))	('mutations', 'Var', (114, 123))	('RCC', 'Disease', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('protein', 'cellular_component', 'GO:0003675', ('244', '251'))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('RCC', 'Disease', (277, 280))	('VHL', 'Gene', (219, 222))	('RCC', 'Disease', 'MESH:C538614', (277, 280))	('VHL', 'Gene', (110, 113))	('sunitinib', 'Chemical', 'MESH:D000077210', (305, 314))
52667	31268155	The increased levels of HIF1A and HIF2A at both the mRNA and protein level in ccRCC samples observed in the present study confirm previous findings.	('RCC', 'Disease', (80, 83))	('HIF1A', 'Gene', (24, 29))	('HIF2A', 'Var', (34, 39))	('HIF1A', 'Gene', '3091', (24, 29))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('increased', 'PosReg', (4, 13))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
52673	31268155	Using IHC in a group of 72 ccRCC patients, they observed a strong association between shorter OS and high expression of HIF1A, HIF2 and VEGFA, as well as Ki-67 protein and microvessel density.	('microvessel density', 'CPA', (172, 191))	('HIF1A', 'Gene', (120, 125))	('patients', 'Species', '9606', (33, 41))	('HIF1A', 'Gene', '3091', (120, 125))	('protein', 'cellular_component', 'GO:0003675', ('160', '167'))	('Ki-67 protein', 'Protein', (154, 167))	('RCC', 'Disease', (29, 32))	('VEGFA', 'Gene', '7422', (136, 141))	('HIF2', 'Gene', (127, 131))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('high', 'Var', (101, 105))	('VEGFA', 'Gene', (136, 141))	('shorter OS', 'Disease', (86, 96))
52675	31268155	High levels of HIF2A, but not HIF1A, were found to be associated with the risk of death and cancer recurrence, independent of sunitinib treatment.	('sunitinib', 'Chemical', 'MESH:D000077210', (126, 135))	('HIF1A', 'Gene', (30, 35))	('HIF1A', 'Gene', '3091', (30, 35))	('death', 'Disease', (82, 87))	('cancer', 'Disease', (92, 98))	('death', 'Disease', 'MESH:D003643', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('associated', 'Reg', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('HIF2A', 'Var', (15, 20))
52676	31268155	The stronger impact of HIF2A, rather than HIF1A, on ccRCC progression has also been previously reported.	('HIF1A', 'Gene', (42, 47))	('HIF1A', 'Gene', '3091', (42, 47))	('RCC', 'Disease', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('HIF2A', 'Var', (23, 28))
52686	31268155	Furthermore, new-generation dual mammalian target of rapamycin inhibitors (GDC-0980 and BKM120), which block both TORC1 and TORC2 activity, including HIF2A expression, have been introduced to phase I trials of advanced RCC.	('BKM120', 'Chemical', 'MESH:C571178', (88, 94))	('TORC1', 'Gene', '23373', (114, 119))	('block', 'NegReg', (103, 108))	('TORC1', 'cellular_component', 'GO:0031931', ('114', '119'))	('mammalian', 'Species', '9606', (33, 42))	('BKM120', 'Var', (88, 94))	('TORC2', 'Gene', '200186', (124, 129))	('GDC-0980', 'Chemical', 'MESH:C569670', (75, 83))	('TORC1', 'Gene', (114, 119))	('TORC2', 'Gene', (124, 129))	('RCC', 'Disease', (219, 222))	('TORC2', 'cellular_component', 'GO:0031932', ('124', '129'))	('RCC', 'Disease', 'MESH:C538614', (219, 222))
52690	31268155	It has been widely confirmed that HIF1A, as well as HIF2A, trigger transcription of the VEGFA gene to VEGFA, and its receptors (VEGFRs) play pivotal roles in vasculogenesis and angiogenesis under physiological conditions, as well as in cancer, including ccRCC.	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('vasculogenesis', 'CPA', (158, 172))	('VEGFA', 'Gene', (88, 93))	('VEGFRs', 'Gene', (128, 134))	('HIF1A', 'Gene', '3091', (34, 39))	('angiogenesis', 'CPA', (177, 189))	('RCC', 'Disease', (256, 259))	('HIF2A', 'Var', (52, 57))	('VEGFA', 'Gene', (102, 107))	('VEGFRs', 'Gene', '3791', (128, 134))	('VEGFA', 'Gene', '7422', (88, 93))	('cancer', 'Disease', (236, 242))	('RCC', 'Disease', 'MESH:C538614', (256, 259))	('vasculogenesis', 'biological_process', 'GO:0001570', ('158', '172'))	('transcription', 'biological_process', 'GO:0006351', ('67', '80'))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('transcription', 'MPA', (67, 80))	('roles', 'Reg', (149, 154))	('angiogenesis', 'biological_process', 'GO:0001525', ('177', '189'))	('VEGFA', 'Gene', '7422', (102, 107))	('HIF1A', 'Gene', (34, 39))
52692	31268155	Additionally, Cox analysis revealed that ccRCC patients with high levels of VEGFA mRNA in tumor tissues had an increased risk of cancer progression, while an increased risk of death was associated with high levels of the VEGFA protein in tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('patients', 'Species', '9606', (47, 55))	('cancer', 'Disease', (129, 135))	('Cox', 'Gene', '1351', (14, 17))	('VEGFA', 'Gene', '7422', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('protein', 'cellular_component', 'GO:0003675', ('227', '234'))	('VEGFA', 'Gene', (221, 226))	('tumor', 'Disease', (90, 95))	('Cox', 'Gene', (14, 17))	('RCC', 'Disease', (43, 46))	('death', 'Disease', 'MESH:D003643', (176, 181))	('high levels', 'Var', (61, 72))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('tumor', 'Disease', (238, 243))	('VEGFA', 'Gene', '7422', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('VEGFA', 'Gene', (76, 81))	('death', 'Disease', (176, 181))
52693	31268155	Other studies have also reported the important effect of VEGFA expression on the progression of ccRCC, while Wang et al also revealed that high levels of VEGFA mRNA may serve as a prognostic marker in ccRCC.	('VEGFA', 'Gene', '7422', (57, 62))	('VEGFA', 'Gene', '7422', (154, 159))	('RCC', 'Disease', (98, 101))	('effect', 'Reg', (47, 53))	('VEGFA', 'Gene', (57, 62))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('VEGFA', 'Gene', (154, 159))	('RCC', 'Disease', 'MESH:C538614', (203, 206))	('RCC', 'Disease', (203, 206))	('high', 'Var', (139, 143))
52709	31268155	The results of this study demonstrated that patients who were treated with sunitinib post-operatively had significantly shorter OS and PFS compared with ccRCC patients who did not receive such treatment.	('PFS', 'CPA', (135, 138))	('RCC', 'Disease', (155, 158))	('shorter', 'NegReg', (120, 127))	('patients', 'Species', '9606', (44, 52))	('sunitinib', 'Chemical', 'MESH:D000077210', (75, 84))	('patients', 'Species', '9606', (159, 167))	('sunitinib', 'Var', (75, 84))	('RCC', 'Disease', 'MESH:C538614', (155, 158))
52751	33935779	Moreover, highly expressed LOX-1 is a significant prognosis factor of tumor progression in advanced-stage of prostate cancer and colorectal cancer.	('highly expressed', 'Var', (10, 26))	('colorectal cancer', 'Disease', (129, 146))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('prostate cancer', 'Disease', (109, 124))	('LOX-1', 'Gene', '4973', (27, 32))	('tumor', 'Disease', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('colorectal cancer', 'Disease', 'MESH:D015179', (129, 146))	('colorectal cancer', 'Phenotype', 'HP:0003003', (129, 146))	('LOX-1', 'Gene', (27, 32))	('prostate cancer', 'Disease', 'MESH:D011471', (109, 124))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('prostate cancer', 'Phenotype', 'HP:0012125', (109, 124))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
52874	33935779	Instead, oxidized LDL (ox-LDL), a pathologically modified lipoprotein, induces pronounced accumulation of cholesterol via its receptors LOX-1.	('oxidized', 'Var', (9, 17))	('LOX-1', 'Gene', '4973', (136, 141))	('cholesterol', 'MPA', (106, 117))	('LDL', 'molecular_function', 'GO:0005322', ('18', '21'))	('cholesterol', 'Chemical', 'MESH:D002784', (106, 117))	('LOX-1', 'Gene', (136, 141))	('accumulation', 'PosReg', (90, 102))	('pronounced accumulation of cholesterol', 'Phenotype', 'HP:0003124', (79, 117))	('LDL', 'molecular_function', 'GO:0005322', ('26', '29'))
52893	33935779	Besides, silencing CAV-1 in 786-O cells impaired the potential for tumor sphere formation and the levels of stemness markers (Supplementary Figure S3C, Figure 5E).	('silencing', 'Var', (9, 18))	('levels of stemness markers', 'MPA', (98, 124))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('CAV-1', 'Gene', '857', (19, 24))	('impaired', 'NegReg', (40, 48))	('men', 'Species', '9606', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('formation', 'biological_process', 'GO:0009058', ('80', '89'))	('tumor', 'Disease', (67, 72))	('CAV-1', 'Gene', (19, 24))
52902	33935779	Furthermore, compared with knockdown CAV-1 or LOX-1 alone, double knockdown of CAV-1 and LOX-1 showed better interference efficiency (Supplementary Figure S4B).	('men', 'Species', '9606', (140, 143))	('LOX-1', 'Gene', (46, 51))	('LOX-1', 'Gene', '4973', (89, 94))	('better', 'PosReg', (102, 108))	('CAV-1', 'Gene', (79, 84))	('CAV-1', 'Gene', '857', (37, 42))	('interference', 'MPA', (109, 121))	('LOX-1', 'Gene', '4973', (46, 51))	('LOX-1', 'Gene', (89, 94))	('double knockdown', 'Var', (59, 75))	('CAV-1', 'Gene', (37, 42))	('CAV-1', 'Gene', '857', (79, 84))
52905	33935779	In addition, celastrol attenuated the stem-like properties and stemness markers expression after knockdown of CAV-1 and LOX-1 (Figures 6D,E).	('LOX-1', 'Gene', '4973', (120, 125))	('knockdown', 'Var', (97, 106))	('stemness markers', 'CPA', (63, 79))	('CAV-1', 'Gene', '857', (110, 115))	('LOX-1', 'Gene', (120, 125))	('celastrol', 'Chemical', 'MESH:C050414', (13, 22))	('expression', 'MPA', (80, 90))	('CAV-1', 'Gene', (110, 115))	('attenuated', 'NegReg', (23, 33))	('stem-like properties', 'CPA', (38, 58))
52917	33935779	In recent years, increasing evidence has indicated that alterations in the lipid profile are associated with the occurrence, progression, and prognosis of various cancers, including RCC.	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancers', 'Disease', (163, 170))	('lipid profile', 'MPA', (75, 88))	('alterations', 'Var', (56, 67))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('associated', 'Reg', (93, 103))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('RCC', 'Disease', (182, 185))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('lipid', 'Chemical', 'MESH:D008055', (75, 80))
52946	33935779	Remarkably, GSK-3beta activity is increased by the site-specific phosphorylation of Tyr216, whereas the phosphorylation of Ser9 inhibits GSK-3beta activity.	('phosphorylation', 'biological_process', 'GO:0016310', ('65', '80'))	('Ser', 'cellular_component', 'GO:0005790', ('123', '126'))	('GSK-3beta', 'Gene', '2931', (12, 21))	('inhibits', 'NegReg', (128, 136))	('Tyr216', 'Chemical', '-', (84, 90))	('phosphorylation', 'biological_process', 'GO:0016310', ('104', '119'))	('GSK-3beta', 'Gene', (12, 21))	('Ser9', 'Chemical', '-', (123, 127))	('GSK-3beta', 'Gene', '2931', (137, 146))	('GSK', 'molecular_function', 'GO:0050321', ('12', '15'))	('Tyr216', 'Var', (84, 90))	('GSK', 'molecular_function', 'GO:0050321', ('137', '140'))	('GSK-3beta', 'Gene', (137, 146))	('activity', 'MPA', (22, 30))	('increased', 'PosReg', (34, 43))	('activity', 'MPA', (147, 155))
52954	33935779	The name of the repository and accession numbers are as follows: https://www.ncbi.nlm.nih.gov/sra (PRJNA705508, PRJNA705508, SAMN18090835, SAMN18090836, SAMN18090837).	('PRJNA705508', 'Var', (112, 123))	('SAMN18090836', 'Var', (139, 151))	('sra', 'Gene', (94, 97))	('sra', 'Gene', '10011', (94, 97))	('SAMN18090835', 'Var', (125, 137))	('SAMN18090837', 'Var', (153, 165))	('PRJNA705508', 'Var', (99, 110))
52982	30082842	Moreover, coexpression of OCT4 and NANOG is a strong independent predictor of unfavorable outcome and tumor recurrence in HCC patients and is associated with enhanced lung cancer malignancy and pancreatic carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('pancreatic carcinogenesis', 'Disease', (194, 219))	('lung cancer malignancy', 'Disease', (167, 189))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('enhanced', 'PosReg', (158, 166))	('HCC', 'Phenotype', 'HP:0001402', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('OCT4', 'Gene', '5460', (26, 30))	('coexpression', 'Var', (10, 22))	('NANOG', 'Gene', '79923', (35, 40))	('patients', 'Species', '9606', (126, 134))	('lung cancer malignancy', 'Disease', 'MESH:D008175', (167, 189))	('NANOG', 'Gene', (35, 40))	('OCT4', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (194, 219))
53040	30082842	The 5-year DSS and PFS survival rates were 82.0% and 49.0% in low nuclear OCT4 expression, and 84.0% and 30.0% in high nuclear OCT4 expression.	('DSS', 'Chemical', '-', (11, 14))	('DSS', 'CPA', (11, 14))	('OCT4', 'Gene', '5460', (127, 131))	('OCT4', 'Gene', '5460', (74, 78))	('OCT4', 'Gene', (74, 78))	('OCT4', 'Gene', (127, 131))	('PFS survival', 'CPA', (19, 31))	('high nuclear', 'Var', (114, 126))	('low nuclear', 'Var', (62, 73))
53069	30082842	Most ccRCCs cases have deletions in the short arm of Chromosome 3, which are highly specific for ccRCC, and are not observed in any other RCC subtypes.	('deletions', 'Var', (23, 32))	('RCC', 'Disease', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('Chromosome', 'cellular_component', 'GO:0005694', ('53', '63'))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('short arm', 'Phenotype', 'HP:0009824', (40, 49))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (7, 10))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('RCC', 'Disease', (7, 10))	('RCC', 'Phenotype', 'HP:0005584', (7, 10))	('ccRCC', 'Phenotype', 'HP:0006770', (5, 10))
53080	30082842	Interestingly, cytoplasmic NANOG expression was an independent prognostic factor for poor PFS in RCC patients, which was a novel finding of our study, raising the possibility of its utility as a prognostic biomarker for RCC.	('RCC', 'Disease', (97, 100))	('patients', 'Species', '9606', (101, 109))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('PFS', 'Disease', (90, 93))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('cytoplasmic', 'Var', (15, 26))	('NANOG', 'Gene', '79923', (27, 32))	('NANOG', 'Gene', (27, 32))	('RCC', 'Phenotype', 'HP:0005584', (220, 223))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('RCC', 'Disease', (220, 223))
53086	30082842	Similar to our observations, coexpression of OCT4 and NANOG was found to be significantly associated with tumor aggressiveness and poor prognosis of several malignances including breast and lung cancers and glioma.	('tumor aggressiveness', 'Disease', (106, 126))	('lung cancers', 'Phenotype', 'HP:0100526', (190, 202))	('coexpression', 'Var', (29, 41))	('breast and lung cancers', 'Disease', 'MESH:D001943', (179, 202))	('aggressiveness', 'Phenotype', 'HP:0000718', (112, 126))	('NANOG', 'Gene', (54, 59))	('glioma', 'Disease', (207, 213))	('associated with', 'Reg', (90, 105))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (106, 126))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('OCT4', 'Gene', '5460', (45, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('OCT4', 'Gene', (45, 49))	('NANOG', 'Gene', '79923', (54, 59))
53091	30082842	demonstrated that knockdown of both OCT4 and NANOG expressions inhibit spontaneous changes in the expression of EMT-related genes and the migration of breast CSC in vitro.	('knockdown', 'Var', (18, 27))	('OCT4', 'Gene', '5460', (36, 40))	('migration of breast CSC', 'CPA', (138, 161))	('OCT4', 'Gene', (36, 40))	('NANOG', 'Gene', '79923', (45, 50))	('NANOG', 'Gene', (45, 50))	('EMT-related genes', 'Gene', (112, 129))	('inhibit', 'NegReg', (63, 70))	('EMT', 'biological_process', 'GO:0001837', ('112', '115'))	('expression', 'MPA', (98, 108))
53109	29463811	Here, we show that the methylation status of the CpG dinucleotide within the consensus hypoxia-responsive element (HRE) markedly influences the binding of HIF and that the loss of VHL results in significant alterations in the DNA methylome.	('DNA methylome', 'MPA', (226, 239))	('VHL', 'Gene', (180, 183))	('loss', 'Var', (172, 176))	('alterations', 'Reg', (207, 218))	('VHL', 'Gene', '7428', (180, 183))	('binding', 'Interaction', (144, 151))	('rat', 'Species', '10116', (211, 214))	('binding', 'molecular_function', 'GO:0005488', ('144', '151'))	('methylation', 'biological_process', 'GO:0032259', ('23', '34'))	('CpG dinucleotide', 'Chemical', 'MESH:C015772', (49, 65))	('DNA', 'cellular_component', 'GO:0005574', ('226', '229'))	('HIF', 'Protein', (155, 158))	('hypoxia', 'Disease', 'MESH:D000860', (87, 94))	('hypoxia', 'Disease', (87, 94))	('methylation', 'MPA', (23, 34))	('influences', 'Reg', (129, 139))
53112	29463811	These results suggest that the loss of VHL alters DNA methylation profile across the genome, commonly associated with and contributing to ccRCC progression.	('contributing', 'Reg', (122, 134))	('alters', 'Reg', (43, 49))	('associated', 'Reg', (102, 112))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('loss', 'Var', (31, 35))	('DNA methylation', 'biological_process', 'GO:0006306', ('50', '65'))	('VHL', 'Gene', (39, 42))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('VHL', 'Gene', '7428', (39, 42))	('DNA methylation profile', 'MPA', (50, 73))	('ccRCC', 'Disease', (138, 143))
53115	29463811	This highly aggressive, chemotherapy resistant tumour type is characterised genetically by loss or mutation of von Hippel-Lindau (VHL) gene, proposed to occur in up to 80% of all ccRCC.	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('von Hippel-Lindau', 'Disease', (111, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (179, 184))	('tumour', 'Disease', (47, 53))	('mutation', 'Var', (99, 107))	('ccRCC', 'Disease', (179, 184))	('VHL', 'Gene', (130, 133))	('occur', 'Reg', (153, 158))	('loss', 'NegReg', (91, 95))	('VHL', 'Gene', '7428', (130, 133))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (111, 128))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
53120	29463811	Thus, an important consequence of VHL loss or mutation in ccRCC is HIF stabilisation.	('VHL loss', 'Disease', 'MESH:D006623', (34, 42))	('VHL loss', 'Disease', (34, 42))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('ccRCC', 'Disease', (58, 63))	('mutation', 'Var', (46, 54))
53126	29463811	Hypoxic environments are classic features of solid tumors, including ccRCC, where hyperactive, dysregulated vascular growth results in poorly oxygenated regions and subsequent HIFalpha stabilisation.	('hyperactive', 'PosReg', (82, 93))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('solid tumors', 'Disease', (45, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('poorly oxygenated regions', 'MPA', (135, 160))	('dysregulated', 'Var', (95, 107))	('ccRCC', 'Disease', (69, 74))	('oxygen', 'Chemical', 'MESH:D010100', (142, 148))	('ccRCC', 'Phenotype', 'HP:0006770', (69, 74))	('solid tumors', 'Disease', 'MESH:D009369', (45, 57))
53129	29463811	The likelihood of transcription factor binding is often determined by epigenetic factors and previous studies have demonstrated that changes to epigenetic code surrounding HREs can augment HIF mediated transcription.	('HREs', 'Gene', (172, 176))	('transcription', 'biological_process', 'GO:0006351', ('202', '215'))	('augment', 'NegReg', (181, 188))	('changes', 'Var', (133, 140))	('epigenetic code', 'MPA', (144, 159))	('rat', 'Species', '10116', (122, 125))	('transcription', 'biological_process', 'GO:0006351', ('18', '31'))	('HIF mediated transcription', 'MPA', (189, 215))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('18', '46'))
53141	29463811	These results demonstrate that the affinities of both HIF1alpha and HIF2alpha for HRE sequence are markedly reduced when the CpG within HRE is methylated.	('HIF1alpha', 'Gene', '3091', (54, 63))	('reduced', 'NegReg', (108, 115))	('HIF2alpha', 'Gene', '2034', (68, 77))	('methylated', 'Var', (143, 153))	('HRE', 'Disease', (82, 85))	('rat', 'Species', '10116', (21, 24))	('HIF2alpha', 'Gene', (68, 77))	('HIF1alpha', 'Gene', (54, 63))	('affinities', 'MPA', (35, 45))
53142	29463811	Previous studies have also alluded to this and HIF responsive genes such as CAIX and EPO are both repressed if their respective HREs or areas in the vicinity of the HRE are methylated.	('EPO', 'Gene', '2056', (85, 88))	('CAIX', 'Gene', '768', (76, 80))	('EPO', 'Gene', (85, 88))	('methylated', 'Var', (173, 183))	('CAIX', 'Gene', (76, 80))
53149	29463811	While demethylation of tissue-specific enhancers or epigenetically silenced trans-acting transcription factors could impact transcription of HRE-containing genes, it is equally likely that that regardless of oxygen tension, a certain degree of methylation may exist at or near many of these HREs, which acts to dampen HIF mediated transcription and that removal of DNA methylation enhances HIF mediated transcription.	('transcription', 'biological_process', 'GO:0006351', ('124', '137'))	('oxygen', 'Chemical', 'MESH:D010100', (208, 214))	('methylation', 'biological_process', 'GO:0032259', ('244', '255'))	('removal', 'Var', (354, 361))	('DNA', 'cellular_component', 'GO:0005574', ('365', '368'))	('HIF mediated transcription', 'MPA', (390, 416))	('HIF mediated transcription', 'MPA', (318, 344))	('enhances', 'PosReg', (381, 389))	('demethylation', 'Var', (6, 19))	('dampen', 'NegReg', (311, 317))	('transcription', 'MPA', (124, 137))	('impact', 'Reg', (117, 123))	('demethylation', 'biological_process', 'GO:0070988', ('6', '19'))	('transcription', 'biological_process', 'GO:0006351', ('331', '344'))	('transcription', 'biological_process', 'GO:0006351', ('89', '102'))	('DNA methylation', 'biological_process', 'GO:0006306', ('365', '380'))	('HRE-containing genes', 'Gene', (141, 161))	('transcription', 'biological_process', 'GO:0006351', ('403', '416'))
53157	29463811	Similar to our results from RCC4 cells, we identified a large number of CpG sites with significant differential DNA methylation patterns between 786-mock and 786-VHL cells; 57,122 hypermethylated and 41,163 hypomethylated in 786-VHL cells relative to 786-mock cells (Supplementary Table 2; Fig.	('VHL', 'Gene', (162, 165))	('VHL', 'Gene', '7428', (162, 165))	('VHL', 'Gene', (229, 232))	('RCC4', 'Gene', '84925', (28, 32))	('hypomethylated', 'Var', (207, 221))	('RCC4', 'Gene', (28, 32))	('VHL', 'Gene', '7428', (229, 232))	('to 7', 'Species', '1214577', (248, 252))	('DNA methylation', 'biological_process', 'GO:0006306', ('112', '127'))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))	('hypermethylated', 'Var', (180, 195))
53159	29463811	Differential methylation analysis identified 91 and 2523 loci as being significantly hyper- and hypomethylated, respectively, following VHL knockdown (Supplementary Table 3; Fig.	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('hyper-', 'PosReg', (85, 91))	('VHL', 'Gene', (136, 139))	('VHL', 'Gene', '7428', (136, 139))	('knockdown', 'Var', (140, 149))	('hypomethylated', 'Var', (96, 110))
53164	29463811	When combining data of 786 and RCC4 cell lines, we identified 20,834 loci that exhibited similar changes in these two cell lines upon ectopic expression of VHL; 16,902 with hyper- and 3,932 with hypomethylation.	('hyper-', 'Var', (173, 179))	('hypomethylation', 'Var', (195, 210))	('VHL', 'Gene', '7428', (156, 159))	('RCC4', 'Gene', (31, 35))	('RCC4', 'Gene', '84925', (31, 35))	('VHL', 'Gene', (156, 159))
53165	29463811	To investigate the potential contribution of DNA methylation of these loci to the hypoxia-mediated transcription, we examined the coincidence of these loci with canonical HRE and observed 2-fold enrichment of hypermethylated loci in HREs (p = 2.2 x 10-16, Fisher's exact test) compared to hypomethylated loci (Fig.	('hypoxia', 'Disease', 'MESH:D000860', (82, 89))	('hypoxia', 'Disease', (82, 89))	('transcription', 'biological_process', 'GO:0006351', ('99', '112'))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('hypermethylated', 'Var', (209, 224))	('DNA methylation', 'biological_process', 'GO:0006306', ('45', '60'))
53166	29463811	These results suggest that VHL-dependent DNA hypermethylation may affect HIF-mediated gene expression by altering epigenetic status of HREs, thereby modulating HIF binding to HREs.	('expression', 'MPA', (91, 101))	('affect', 'Reg', (66, 72))	('hypermethylation', 'Var', (45, 61))	('gene expression', 'biological_process', 'GO:0010467', ('86', '101'))	('modulating', 'Reg', (149, 159))	('binding', 'molecular_function', 'GO:0005488', ('164', '171'))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('epigenetic status', 'MPA', (114, 131))	('VHL', 'Gene', (27, 30))	('HIF-mediated gene', 'Gene', (73, 90))	('altering', 'Reg', (105, 113))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('41', '61'))	('VHL', 'Gene', '7428', (27, 30))	('binding', 'Interaction', (164, 171))
53178	29463811	These results suggest that hypoxia does not have a profound effect on 5MeC status while loss of VHL in the same cell type promotes dramatic changes in global DNA methylation (Fig.	('global DNA methylation', 'MPA', (151, 173))	('MeC', 'Gene', (71, 74))	('DNA', 'cellular_component', 'GO:0005574', ('158', '161'))	('DNA methylation', 'biological_process', 'GO:0006306', ('158', '173'))	('hypoxia', 'Disease', (27, 34))	('loss', 'Var', (88, 92))	('changes', 'Reg', (140, 147))	('VHL', 'Gene', (96, 99))	('hypoxia', 'Disease', 'MESH:D000860', (27, 34))	('MeC', 'Gene', '56477', (71, 74))	('VHL', 'Gene', '7428', (96, 99))
53184	29463811	There were slight changes in DNA methylation (999 loci) upon DNMT1 knockdown in RCC4-VHL cells maintained in normoxia (Fig.	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('knockdown', 'Var', (67, 76))	('DNMT1', 'Gene', (61, 66))	('changes in DNA methylation', 'biological_process', 'GO:0044728', ('18', '44'))	('DNMT1', 'Gene', '1786', (61, 66))	('changes', 'Reg', (18, 25))	('DNA methylation', 'MPA', (29, 44))
53187	29463811	We next compared the results from methylation profiling of ccRCC cell lines to the methylome of human primary ccRCC specimens, which are characterised by inactivation of VHL due to somatic mutations or promoter hypermethylation.	('inactivation', 'NegReg', (154, 166))	('VHL', 'Gene', (170, 173))	('human', 'Species', '9606', (96, 101))	('VHL', 'Gene', '7428', (170, 173))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('promoter hypermethylation', 'Var', (202, 227))	('mutations', 'Var', (189, 198))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))
53189	29463811	It is notable that this fraction represents CpG loci with high-confidence methylation changes observed recurrently across multiple tumors.	('methylation', 'Var', (74, 85))	('multiple tumors', 'Disease', (122, 137))	('multiple tumors', 'Disease', 'MESH:D009369', (122, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('methylation', 'biological_process', 'GO:0032259', ('74', '85'))
53191	29463811	However, among 18,191 CpGs that were hypomethylated in ccRCC as compared to patient-matched normal kidney tissues, 2,037 loci (11.2%) become hypermethylated upon ectopic expression of VHL in ccRCC cell lines.	('ccRCC', 'Phenotype', 'HP:0006770', (191, 196))	('VHL', 'Gene', (184, 187))	('VHL', 'Gene', '7428', (184, 187))	('hypermethylated', 'MPA', (141, 156))	('patient', 'Species', '9606', (76, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))	('ccRCC', 'Disease', (55, 60))	('ectopic expression', 'Var', (162, 180))
53192	29463811	In contrast, among 16,407 CpG sites that exhibited hypermethylation in ccRCC tumors, only 160 loci (~1%) showed hypomethylation in VHL-reconstituted cell lines.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('hypermethylation', 'Var', (51, 67))	('VHL', 'Gene', (131, 134))	('ccRCC tumors', 'Disease', (71, 83))	('VHL', 'Gene', '7428', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ccRCC tumors', 'Disease', 'MESH:D009369', (71, 83))
53194	29463811	4A, Supplementary Table 6) We further investigated possible correlation between abnormal methylation of these loci and cancer associated expression of the genes associated with them.	('expression', 'MPA', (137, 147))	('methylation', 'biological_process', 'GO:0032259', ('89', '100'))	('investigated', 'Reg', (38, 50))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('abnormal', 'Var', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
53201	29463811	According to the role of DNA methylation of promoter CpG islands on the regulation of gene expression, we also investigated associations between changes of DNA methylation of promoter CpG islands and alterations in expression of nearby genes in ccRCC, and the potential involvement of VHL.	('ccRCC', 'Phenotype', 'HP:0006770', (245, 250))	('ccRCC', 'Disease', (245, 250))	('VHL', 'Gene', '7428', (285, 288))	('DNA methylation', 'biological_process', 'GO:0006306', ('156', '171'))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))	('DNA', 'cellular_component', 'GO:0005574', ('156', '159'))	('rat', 'Species', '10116', (204, 207))	('regulation of gene expression', 'biological_process', 'GO:0010468', ('72', '101'))	('changes', 'Var', (145, 152))	('VHL', 'Gene', (285, 288))	('DNA methylation', 'biological_process', 'GO:0006306', ('25', '40'))	('expression', 'MPA', (215, 225))
53202	29463811	We observed that methylation of clusters associated with fourteen of these 42 genes is changed upon expression of VHL in either 786-O or RCC-4 cell lines (Supplementary Table 8).	('methylation', 'MPA', (17, 28))	('changed', 'Reg', (87, 94))	('VHL', 'Gene', '7428', (114, 117))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('expression', 'Var', (100, 110))	('VHL', 'Gene', (114, 117))
53209	29463811	Despite the fact that ectopic VHL expression in the cell lines tested could result in promoting supraphysiological effects on the DNA methylome, many of the changes we recorded in the cell lines were evident in ccRCC patient samples where loss or mutation of VHL is the most common and earliest genetic perturbation.	('VHL', 'Gene', (259, 262))	('ccRCC', 'Disease', (211, 216))	('ectopic', 'Var', (22, 29))	('ccRCC', 'Phenotype', 'HP:0006770', (211, 216))	('mutation', 'Var', (247, 255))	('patient', 'Species', '9606', (217, 224))	('VHL', 'Gene', (30, 33))	('promoting', 'PosReg', (86, 95))	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('loss', 'NegReg', (239, 243))	('VHL', 'Gene', '7428', (259, 262))	('VHL', 'Gene', '7428', (30, 33))	('supraphysiological effects on the DNA methylome', 'MPA', (96, 143))
53220	29463811	Loss of DNMT1 results in passive removal of 5MeC during cell replication although other reports implicate that loss of DNMT1 may also have consequences independent of its catalytic activity.	('catalytic activity', 'molecular_function', 'GO:0003824', ('171', '189'))	('DNMT1', 'Gene', (8, 13))	('loss', 'Var', (111, 115))	('MeC', 'Gene', '56477', (45, 48))	('DNMT1', 'Gene', '1786', (119, 124))	('DNMT1', 'Gene', '1786', (8, 13))	('DNMT1', 'Gene', (119, 124))	('Loss', 'Var', (0, 4))	('MeC', 'Gene', (45, 48))
53225	29463811	For example, many ccRCC tumors harbour mutations, predominantly of epigenetic regulators such as PBRM1 and SETD2.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('ccRCC tumors', 'Disease', 'MESH:D009369', (18, 30))	('mutations', 'Var', (39, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (18, 23))	('SETD2', 'Gene', '29072', (107, 112))	('PBRM1', 'Gene', (97, 102))	('ccRCC tumors', 'Disease', (18, 30))	('PBRM1', 'Gene', '55193', (97, 102))	('SETD2', 'Gene', (107, 112))
53226	29463811	Recently it has been demonstrated that SETD2 inactivation results in global redistribution of 5MeC in renal cells.	('SETD2', 'Gene', (39, 44))	('inactivation', 'Var', (45, 57))	('MeC', 'Gene', (95, 98))	('MeC', 'Gene', '56477', (95, 98))	('rat', 'Species', '10116', (28, 31))	('SETD2', 'Gene', '29072', (39, 44))
53233	29463811	It is widely acknowledged that loss or mutation of VHL occurs early in tumourigenesis, while hypoxic regions of tumours are associated with later disease stages when avascular or dysregulated angiogenesis, primarily mediated by VEGF, are commonplace.	('VHL', 'Gene', '7428', (51, 54))	('tumour', 'Disease', 'MESH:D009369', (71, 77))	('hypoxic regions of tumours', 'Disease', 'MESH:D009369', (93, 119))	('tumour', 'Disease', (71, 77))	('mutation', 'Var', (39, 47))	('loss', 'NegReg', (31, 35))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('tumour', 'Disease', (112, 118))	('VEGF', 'Gene', (228, 232))	('associated', 'Reg', (124, 134))	('angiogenesis', 'biological_process', 'GO:0001525', ('192', '204'))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('VHL', 'Gene', (51, 54))	('hypoxic regions of tumours', 'Disease', (93, 119))	('VEGF', 'Gene', '7422', (228, 232))
53237	29463811	Taken together, we demonstrate that loss of VHL dramatically impacts the DNA methylation landscape of renal cancer cells while in contrast there are relatively few changes to 5MeC in hypoxia.	('renal cancer', 'Disease', (102, 114))	('MeC', 'Gene', (176, 179))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('renal cancer', 'Phenotype', 'HP:0009726', (102, 114))	('impacts', 'Reg', (61, 68))	('VHL', 'Gene', (44, 47))	('renal cancer', 'Disease', 'MESH:D007680', (102, 114))	('MeC', 'Gene', '56477', (176, 179))	('DNA methylation landscape', 'MPA', (73, 98))	('loss', 'Var', (36, 40))	('rat', 'Species', '10116', (26, 29))	('VHL', 'Gene', '7428', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('DNA methylation', 'biological_process', 'GO:0006306', ('73', '88'))	('hypoxia', 'Disease', 'MESH:D000860', (183, 190))	('hypoxia', 'Disease', (183, 190))
53238	29463811	These findings are in support of previous studies that have implicated an association between VHL loss and epigenetic modifications that promote cancer progression.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('promote', 'PosReg', (137, 144))	('VHL loss', 'Disease', 'MESH:D006623', (94, 102))	('epigenetic modifications', 'Var', (107, 131))	('VHL loss', 'Disease', (94, 102))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
53257	29463811	Anti-HIF1alpha (610958) was obtained from BD Transduction Laboratories.	('HIF1alpha', 'Gene', '3091', (5, 14))	('610958', 'Var', (16, 22))	('Transduction', 'biological_process', 'GO:0009293', ('45', '57'))	('rat', 'Species', '10116', (62, 65))	('HIF1alpha', 'Gene', (5, 14))
53269	29463811	Supershift was performed using 1 mug of anti-HIF1alpha or anti-HA antibodies and incubating the reaction for an additional 15 min.	('anti-HA', 'Var', (58, 65))	('HIF1alpha', 'Gene', '3091', (45, 54))	('mug', 'molecular_function', 'GO:0043739', ('33', '36'))	('HIF1alpha', 'Gene', (45, 54))
53285	33231603	Analyses of the data from The Cancer Genome Atlas (TCGA) illustrated that ARHGEF39 expression was upregulated in ccRCC and high ARHGEF39 expression was correlated with a worse prognosis.	('ARHGEF39', 'Gene', (128, 136))	('ARHGEF39', 'Gene', '84904', (128, 136))	('expression', 'MPA', (137, 147))	('Cancer', 'Disease', 'MESH:D009369', (30, 36))	('Cancer', 'Disease', (30, 36))	('ARHGEF39', 'Gene', (74, 82))	('ccRCC', 'Disease', (113, 118))	('upregulated', 'PosReg', (98, 109))	('high', 'Var', (123, 127))	('ccRCC', 'Phenotype', 'HP:0006770', (113, 118))	('Cancer', 'Phenotype', 'HP:0002664', (30, 36))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('ARHGEF39', 'Gene', '84904', (74, 82))	('si', 'Chemical', 'MESH:D012825', (143, 145))	('si', 'Chemical', 'MESH:D012825', (182, 184))
53288	33231603	CCK8 and clonogenic assays were used to measure the viability of ccRCC cells after knockdown or overexpression of ARHGEF39.	('ARHGEF39', 'Gene', (114, 122))	('ARHGEF39', 'Gene', '84904', (114, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('overexpression', 'PosReg', (96, 110))	('knockdown', 'Var', (83, 92))
53289	33231603	Transwell assays were used to examine the changes in cell motility after alterations in ARHGEF39 expression and treatment with LY294002 (an AKT inhibitor) or PD98059 (an ERK inhibitor).	('AKT', 'Gene', (140, 143))	('PD98059', 'Var', (158, 165))	('alterations', 'Reg', (73, 84))	('ERK', 'Gene', '5594', (170, 173))	('ARHGEF39', 'Gene', (88, 96))	('LY294002', 'Chemical', 'MESH:C085911', (127, 135))	('ERK', 'Gene', (170, 173))	('PD98059', 'Chemical', 'MESH:C093973', (158, 165))	('ERK', 'molecular_function', 'GO:0004707', ('170', '173'))	('ARHGEF39', 'Gene', '84904', (88, 96))	('AKT', 'Gene', '207', (140, 143))	('changes', 'Reg', (42, 49))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('cell motility', 'biological_process', 'GO:0048870', ('53', '66'))	('expression', 'MPA', (97, 107))	('LY294002', 'Var', (127, 135))	('cell motility', 'CPA', (53, 66))
53301	33231603	According to the research results, ectopic expression of ARHGEF39 is conducive to the proliferation of hepatocellular carcinoma cells by affecting the G2/M phase.	('G2/M phase', 'CPA', (151, 161))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (103, 127))	('affecting', 'Reg', (137, 146))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (103, 127))	('ARHGEF39', 'Gene', (57, 65))	('M phase', 'biological_process', 'GO:0000279', ('154', '161'))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('hepatocellular carcinoma', 'Disease', (103, 127))	('ARHGEF39', 'Gene', '84904', (57, 65))	('si', 'Chemical', 'MESH:D012825', (49, 51))	('ectopic expression', 'Var', (35, 53))
53321	33231603	Briefly, the following two different ARHGEF39-siRNA sequences (si-ARHGEF39#1: 5'-TCCATACTATTGGTCAGAAAC-3' and si-ARHGEF39#2: 5'- CCAATTTGCTGCCAACTCAGA-3') were designed to knock down ARHGEF39 in ccRCC cells.	('ARHGEF39', 'Gene', (66, 74))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('si', 'Chemical', 'MESH:D012825', (162, 164))	('ARHGEF39', 'Gene', (37, 45))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('ARHGEF39', 'Gene', (113, 121))	('ARHGEF39', 'Gene', '84904', (183, 191))	('ARHGEF39', 'Gene', '84904', (66, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (195, 200))	('ARHGEF39', 'Gene', '84904', (37, 45))	('ARHGEF39', 'Gene', '84904', (113, 121))	('knock', 'Var', (172, 177))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('ARHGEF39', 'Gene', (183, 191))
53326	33231603	Then, the mixed solution was added in the 6-well plate and the transfection efficiency was detected after incubating for 48 h. UT33A cells were treated with the AKT inhibitor LY294002 (20 muM; Cell Signaling Technology, USA) or the ERK inhibitor PD98059 (20 muM; MedChem Express, USA) for 12 h to explore whether inhibition of AKT or ERK would reverse the phenotypes of ccRCC cells induced by ARHGEF39.	('ERK', 'Gene', '5594', (232, 235))	('UT33A', 'Mutation', 'rs867310524', (127, 132))	('AKT', 'Gene', '207', (161, 164))	('ERK', 'molecular_function', 'GO:0004707', ('232', '235'))	('ERK', 'Gene', '5594', (334, 337))	('AKT', 'Gene', '207', (327, 330))	('ERK', 'Gene', (232, 235))	('Signaling', 'biological_process', 'GO:0023052', ('198', '207'))	('ARHGEF39', 'Gene', '84904', (393, 401))	('ccRCC cells', 'Disease', (370, 381))	('LY294002', 'Var', (175, 183))	('ERK', 'Gene', (334, 337))	('PD98059', 'Chemical', 'MESH:C093973', (246, 253))	('ARHGEF39', 'Gene', (393, 401))	('ERK', 'molecular_function', 'GO:0004707', ('334', '337'))	('AKT', 'Gene', (161, 164))	('ccRCC', 'Phenotype', 'HP:0006770', (370, 375))	('LY294002', 'Chemical', 'MESH:C085911', (175, 183))	('AKT', 'Gene', (327, 330))
53368	33231603	It was revealed that the survival rate in high ARHGEF39 mRNA expression group was notably lower than that in the low expression group (p = 0.004, Figure 2).	('si', 'Chemical', 'MESH:D012825', (67, 69))	('survival rate', 'CPA', (25, 38))	('lower', 'NegReg', (90, 95))	('ARHGEF39', 'Gene', (47, 55))	('si', 'Chemical', 'MESH:D012825', (123, 125))	('ARHGEF39', 'Gene', '84904', (47, 55))	('high', 'Var', (42, 46))
53374	33231603	The result of CCK8 assay showed that the OD value was significantly decreased after depletion of ARHGEF39 in Caki-1, 786-O and UT33A cells (p < 0.01, Figure 3D-F), indicating that depletion of ARHGEF39 suppressed the viability of ccRCC cells.	('OD value', 'MPA', (41, 49))	('ARHGEF39', 'Gene', (193, 201))	('decreased', 'NegReg', (68, 77))	('depletion', 'Var', (84, 93))	('si', 'Chemical', 'MESH:D012825', (54, 56))	('UT33A', 'Mutation', 'rs867310524', (127, 132))	('viability', 'CPA', (217, 226))	('Caki-1', 'CellLine', 'CVCL:0234', (109, 115))	('ARHGEF39', 'Gene', '84904', (193, 201))	('ARHGEF39', 'Gene', '84904', (97, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (230, 235))	('suppressed', 'NegReg', (202, 212))	('ARHGEF39', 'Gene', (97, 105))
53376	33231603	Clonogenic assay revealed that the number of colonies in si-ARHGEF39 group was notably smaller than that of the si-con group, which further indicated that knockdown of ARHGEF39 notably restricted the viability of Caki-1 and 786-O cells (p < 0.01, Figure 3G-H).	('knockdown', 'Var', (155, 164))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('ARHGEF39', 'Gene', (60, 68))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('Caki-1', 'CellLine', 'CVCL:0234', (213, 219))	('smaller', 'NegReg', (87, 94))	('ARHGEF39', 'Gene', '84904', (60, 68))	('viability', 'CPA', (200, 209))	('restricted', 'NegReg', (185, 195))	('ARHGEF39', 'Gene', (168, 176))	('ARHGEF39', 'Gene', '84904', (168, 176))
53378	33231603	The results illustrated that the knockdown of ARHGEF39 notably prevented migration and invasion of the Caki-1 and 786-O cells (p < 0.01, Figure 3I-J).	('ARHGEF39', 'Gene', (46, 54))	('knockdown', 'Var', (33, 42))	('prevented', 'NegReg', (63, 72))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('ARHGEF39', 'Gene', '84904', (46, 54))	('Caki-1', 'CellLine', 'CVCL:0234', (103, 109))
53400	33231603	In addition, cytological experiments showed that ARHGEF39 overexpression could significantly promote the viability, invasion and migration of ccRCC cells.	('overexpression', 'Var', (58, 72))	('ARHGEF39', 'Gene', '84904', (49, 57))	('viability', 'CPA', (105, 114))	('si', 'Chemical', 'MESH:D012825', (79, 81))	('invasion', 'CPA', (116, 124))	('migration', 'CPA', (129, 138))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('ccRCC', 'Disease', (142, 147))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('ARHGEF39', 'Gene', (49, 57))	('promote', 'PosReg', (93, 100))
53457	29134564	The genomic study defined by the Cancer Genome Atlas (TCGA) of more than 400 ccRCC samples revealed the importance of mutations of genes related to angiogenesis, mainly the von Hippel Lindau (VHL) gene, together with mutations altering the chromatin remodelling complexes (PBRM1, ARID1A, and SMARCA4) and other epigenetic regulators such as SETD2 and BAP1.	('angiogenesis', 'biological_process', 'GO:0001525', ('148', '160'))	('PBRM1', 'Gene', (273, 278))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (33, 52))	('BAP1', 'Gene', (351, 355))	('chromatin', 'cellular_component', 'GO:0000785', ('240', '249'))	('ARID1A', 'Gene', (280, 286))	('Cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Cancer Genome Atlas', 'Disease', (33, 52))	('VHL', 'Disease', (192, 195))	('SMARCA4', 'Gene', (292, 299))	('von Hippel Lindau', 'Gene', '7428', (173, 190))	('ARID1A', 'Gene', '8289', (280, 286))	('von Hippel Lindau', 'Gene', (173, 190))	('SETD2', 'Gene', (341, 346))	('mutations', 'Var', (118, 127))	('SETD2', 'Gene', '29072', (341, 346))	('RCC', 'Disease', (79, 82))	('VHL', 'Disease', 'MESH:D006623', (192, 195))	('BAP1', 'Gene', '8314', (351, 355))	('PBRM1', 'Gene', '55193', (273, 278))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('240', '261'))	('SMARCA4', 'Gene', '6597', (292, 299))	('mutations', 'Var', (217, 226))	('RCC', 'Disease', 'MESH:C538614', (79, 82))
53458	29134564	It was also observed that 28% of the samples are harbouring mutations affecting the PI3K/Akt pathway that directly affect metabolic intracellular routes.	('affect', 'Reg', (115, 121))	('Akt', 'Gene', '207', (89, 92))	('metabolic intracellular routes', 'MPA', (122, 152))	('Akt', 'Gene', (89, 92))	('intracellular', 'cellular_component', 'GO:0005622', ('132', '145'))	('PI3K', 'molecular_function', 'GO:0016303', ('84', '88'))	('mutations', 'Var', (60, 69))
53461	29134564	Type I pRCC is mostly associated with mutations in the MET oncogene and exerts a more favorable prognosis, while type II patients use to harbour aberrations in the Krebs cycle gene fumarate hydratase (FH) that confer a very poor prognosis in most cases.	('RCC', 'Disease', (8, 11))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('fumarate hydratase', 'Gene', '2271', (181, 199))	('fumarate hydratase', 'Gene', (181, 199))	('FH', 'Gene', '2271', (201, 203))	('Krebs cycle', 'biological_process', 'GO:0006099', ('164', '175'))	('mutations', 'Var', (38, 47))	('associated', 'Reg', (22, 32))	('MET oncogene', 'Gene', (55, 67))	('patients', 'Species', '9606', (121, 129))
53463	29134564	Other non-ccRCC subtypes include chromophobe (chRCC) tumors with an incidence rate of ~ 5%, collecting duct tumors (< 1%) and more rare cases like Xp11 translocation (tRCC) or medullary subtypes that exert a poor clinical outcome despite of systemic treatment.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('RCC', 'Disease', (12, 15))	('Xp11 translocation', 'Var', (147, 165))	('duct tumors', 'Disease', 'MESH:D057091', (103, 114))	('chromophobe (chRCC) tumors', 'Disease', 'MESH:D000238', (33, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('duct tumors', 'Disease', (103, 114))	('RCC', 'Disease', (168, 171))	('men', 'Species', '9606', (255, 258))	('RCC', 'Disease', (48, 51))
53500	29134564	The International Metastatic Database Consortium (IMDC) retrospectively assessed 645 patients with mRCC treated with sorafenib, sunitinib or bevacizumab-IFNalpha and identified six variables to classify cases into favorable, intermediate and poor prognosis groups: KPS less than 80%, time from nephrectomy less than 1 year, hemoglobin less than LLN, serum corrected calcium greater than ULN, platelets greater than ULN and absolute neutrophil count greater than ULN.	('LLN', 'MPA', (345, 348))	('serum corrected calcium', 'MPA', (350, 373))	('RCC', 'Disease', (100, 103))	('less', 'NegReg', (269, 273))	('IFNalpha', 'Gene', '3439', (153, 161))	('sorafenib', 'Chemical', 'MESH:D000077157', (117, 126))	('hemoglobin', 'MPA', (324, 334))	('platelets', 'MPA', (392, 401))	('patients', 'Species', '9606', (85, 93))	('calcium', 'Chemical', 'MESH:D002118', (366, 373))	('sunitinib', 'Chemical', 'MESH:D000077210', (128, 137))	('less', 'NegReg', (335, 339))	('KPS', 'Var', (265, 268))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('IFNalpha', 'Gene', (153, 161))	('ULN', 'MPA', (387, 390))	('bevacizumab', 'Chemical', 'MESH:D000068258', (141, 152))
53525	29134564	Nivolumab, an antibody against PD-1, and cabozantinib, an oral TKI targeting VEGFR, MET and AXL, were compared with everolimus, an mTOR inhibitor previously approved in second line of treatment of mRCC, in two different randomized phase III trial including 821 and 658 patients with mRCC patients previously treated with at least one prior antiangiogenic therapy one prior antiangiogenic therapy Both cabozantinib and nivolumab increased OS (figures of 21.4 and 25.0 months, respectively) and response rate (RR), while PFS was significantly better for the former and no differences were observed for the latter.	('AXL', 'Gene', '558', (92, 95))	('mTOR', 'Gene', (131, 135))	('OS', 'Chemical', '-', (438, 440))	('RCC', 'Disease', 'MESH:C538614', (284, 287))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('cabozantinib', 'Chemical', 'MESH:C558660', (401, 413))	('patients', 'Species', '9606', (269, 277))	('VEGFR', 'Gene', '3791', (77, 82))	('antibody', 'molecular_function', 'GO:0003823', ('14', '22'))	('VEGFR', 'Gene', (77, 82))	('antibody', 'cellular_component', 'GO:0042571', ('14', '22'))	('mTOR', 'Gene', '2475', (131, 135))	('AXL', 'Gene', (92, 95))	('better', 'PosReg', (541, 547))	('cabozantinib', 'Chemical', 'MESH:C558660', (41, 53))	('patients', 'Species', '9606', (288, 296))	('nivolumab', 'Chemical', 'MESH:D000077594', (418, 427))	('response rate', 'MPA', (493, 506))	('antibody', 'cellular_component', 'GO:0019815', ('14', '22'))	('cabozantinib', 'Var', (401, 413))	('men', 'Species', '9606', (189, 192))	('nivolumab', 'Gene', (418, 427))	('Nivolumab', 'Chemical', 'MESH:D000077594', (0, 9))	('RCC', 'Disease', (284, 287))	('RCC', 'Disease', (198, 201))	('increased', 'PosReg', (428, 437))	('everolimus', 'Chemical', 'MESH:D000068338', (116, 126))	('antibody', 'cellular_component', 'GO:0019814', ('14', '22'))
53570	28049408	Detailed simulation of cancer exome sequencing data reveals differences and common limitations of variant callers Next-generation sequencing of matched tumor and normal biopsy pairs has become a technology of paramount importance for precision cancer treatment.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('tumor', 'Disease', (152, 157))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('variant', 'Var', (98, 105))	('cancer', 'Disease', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
53572	28049408	This particularly concerns the reliable identification of subclonal mutations in a cancer tissue sample with very low frequencies, which may be clinically relevant.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', (83, 89))	('subclonal mutations', 'Var', (58, 77))
53580	28049408	Unfortunately, even very low-frequency variants may be critical for treatment outcome, because (i) it may be sufficient if a small portion of the cells promotes tumor growth, e.g.	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('promotes', 'PosReg', (152, 160))	('tumor', 'Disease', (161, 166))	('variants', 'Var', (39, 47))
53586	28049408	The set of ground truth mutations was generated using variants detected in the same matched tumor and normal sample, but at a higher coverage of approximately 300x.	('variants', 'Var', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (92, 97))
53587	28049408	We carefully designed a simulation study based on one diploid normal and eight diploid cancer genomes, where we introduced variants found in a real tumor-normal sample pair (clear cell renal cell carcinoma).	('diploid cancer', 'Disease', 'MESH:C548012', (79, 93))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (174, 205))	('clear cell renal cell carcinoma', 'Disease', (174, 205))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (185, 205))	('diploid cancer', 'Disease', (79, 93))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('variants', 'Var', (123, 131))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (174, 205))
53592	28049408	After running one or more variant callers on the pair of tumor and normal aligned reads, confidence cutoffs have to be defined depending on the requirements of the downstream analysis.	('tumor', 'Disease', (57, 62))	('variant', 'Var', (26, 33))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))
53595	28049408	Variants detected in a WES tumor-normal sample pair of human clear cell renal cell carcinoma (ccRCC) were placed into these genomes using the software library SeqAn.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (72, 92))	('Variants', 'Var', (0, 8))	('tumor', 'Disease', (27, 32))	('human', 'Species', '9606', (55, 60))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (61, 92))	('clear cell renal cell carcinoma', 'Disease', (61, 92))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (61, 92))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
53597	28049408	The cancer clones are related by a clonal ancestry tree, shown in Additional file 1: Figure A. Variants detected only in the real tumor sample are randomly assigned to one of the nodes of the tree.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('Variants', 'Var', (95, 103))	('tumor', 'Disease', (130, 135))	('cancer', 'Disease', (4, 10))
53605	28049408	To this end, we ran the callers separately on the tumor and the normal bam file, and removed all mutations that were found in the normal sample.	('mutations', 'Var', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))
53606	28049408	The resulting filtered variant calls for the tumor sample should contain only somatic mutations.	('variant', 'Var', (23, 30))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))
53607	28049408	2 a were generated when restricting the ground truth variant set to locations with a coverage of at least 25x, which is displayed in Additional file 1: Figure C. Next, we assessed how the performance of the variant callers depends on the coverage and the contamination of tumor samples with normal tissue.	('tumor', 'Disease', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('variant', 'Var', (207, 214))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))
53609	28049408	We define the following error categories: If the coverage at the variant loci was less than 25x reads in the cancer sample, the category low coverage applies.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('less', 'NegReg', (82, 86))	('variant', 'Var', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
53628	28049408	This might be explained by the relatively small number of indels that were introduced in the simulated cancer sample: Among the introduced mutations, there were 0.67% indels, since this study focuses on SNVs.	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('indels', 'Var', (167, 173))
53637	28049408	We simulated cancer and normal read data starting from variants that had been identified in a real tumor-normal pair of clear cell renal cell carcinoma.	('tumor', 'Disease', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('variants', 'Var', (55, 63))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (131, 151))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (120, 151))	('clear cell renal cell carcinoma', 'Disease', (120, 151))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (120, 151))
53639	28049408	Variants that were found only in the tumor sample were randomly assigned to 8 diploid clones (randomly deciding for each variants zygosity).	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('Variants', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (37, 42))
53642	28049408	auPRC Area under precision-recall curve ccRCC Clear cell renal cell carcinoma CNV Copy number variant EM Expectation-maximization FDR False discovery rate GATK Genome Analysis Toolkit HP HaplotypeCaller LOH Loss of heterozygosity MAP Maximum a posteriori probability MNV Multi-nucleotide variant SNV Single-nucleotide variant UG UnifiedGenotyper VAF Variant allele frequency VCF Variant call format WES Whole exome sequencing	('Clear cell renal cell carcinoma', 'Disease', (46, 77))	('Variant', 'Var', (379, 386))	('Multi-nucleotide', 'Chemical', '-', (271, 287))	('MAP', 'molecular_function', 'GO:0004239', ('230', '233'))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (46, 77))	('SNV', 'Gene', (296, 299))	('VAF', 'Chemical', '-', (346, 349))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (46, 77))	('Single-nucleotide variant', 'Var', (300, 325))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (57, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))
53661	30365137	Mutations or heterozygous deletions of the tumor suppressor gene, VHL, are known to occur in the majority of ccRCCs, leading to reduced expression of VHL protein (pVHL).	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('VHL', 'Gene', '7428', (150, 153))	('VHL', 'Gene', (164, 167))	('tumor', 'Disease', (43, 48))	('expression', 'MPA', (136, 146))	('RCCs', 'Phenotype', 'HP:0005584', (111, 115))	('reduced', 'NegReg', (128, 135))	('ccRCCs', 'Phenotype', 'HP:0006770', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('Mutations', 'Var', (0, 9))	('VHL', 'Gene', (66, 69))	('VHL', 'Gene', '7428', (164, 167))	('pVHL', 'Gene', '7428', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('pVHL', 'Gene', (163, 167))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('43', '59'))	('VHL', 'Gene', '7428', (66, 69))	('RCC', 'Disease', (111, 114))	('VHL', 'Gene', (150, 153))	('tumor suppressor', 'biological_process', 'GO:0051726', ('43', '59'))
53662	30365137	pVHL is able to specifically bind to HIF and induce its ubiquitination under physiological conditions, and also under hypoxic conditions; low expression levels of VHL can also lead to HIF accumulation.	('pVHL', 'Gene', '7428', (0, 4))	('accumulation', 'PosReg', (188, 200))	('VHL', 'Gene', '7428', (163, 166))	('pVHL', 'Gene', (0, 4))	('induce', 'Reg', (45, 51))	('VHL', 'Gene', (1, 4))	('low expression levels', 'Var', (138, 159))	('bind', 'Interaction', (29, 33))	('HIF', 'MPA', (184, 187))	('ubiquitination', 'MPA', (56, 70))	('VHL', 'Gene', '7428', (1, 4))	('hypoxic conditions', 'Disease', (118, 136))	('VHL', 'Gene', (163, 166))	('hypoxic conditions', 'Disease', 'MESH:D009135', (118, 136))	('lead to', 'Reg', (176, 183))
53664	30365137	Hence, HIF accumulation activates downstream genes, including vascular endothelial growth factor (VEGF), transforming growth factor-alpha and platelet-derived growth factor, which have important roles in tumor growth and progression.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('VEGF', 'Gene', '7422', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('transforming', 'MPA', (105, 117))	('vascular endothelial growth factor', 'Gene', (62, 96))	('accumulation', 'Var', (11, 23))	('transforming growth factor-alpha', 'molecular_function', 'GO:0005154', ('105', '137'))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('62', '96'))	('tumor', 'Disease', (204, 209))	('vascular endothelial growth factor', 'Gene', '7422', (62, 96))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('142', '172'))	('VEGF', 'Gene', (98, 102))	('activates', 'PosReg', (24, 33))
53742	30365137	In the presence of a methylated BNIP3 promoter region in RCC cells, treatment with 5-aza-C would be expected to induce the upregulation of BNIP3, and the consequential promotion of apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('181', '190'))	('BNIP3', 'Gene', '664', (139, 144))	('BNIP3', 'Gene', '664', (32, 37))	('apoptosis', 'biological_process', 'GO:0006915', ('181', '190'))	('methylated', 'Var', (21, 31))	('5-aza-C', 'Chemical', 'MESH:D001374', (83, 90))	('apoptosis', 'CPA', (181, 190))	('upregulation', 'PosReg', (123, 135))	('RCC', 'Disease', (57, 60))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('BNIP3', 'Gene', (139, 144))	('BNIP3', 'Gene', (32, 37))	('promotion', 'PosReg', (168, 177))
53746	30365137	This led us to hypothesize that the inhibition of deacetylation might activate BNIP3 expression.	('expression', 'MPA', (85, 95))	('inhibition', 'Var', (36, 46))	('BNIP3', 'Gene', (79, 84))	('deacetylation', 'MPA', (50, 63))	('BNIP3', 'Gene', '664', (79, 84))	('activate', 'PosReg', (70, 78))
53752	30365137	Consequently, it appears that the inhibition of deacetylation may suppress tumor growth, and promote apoptosis.	('suppress', 'NegReg', (66, 74))	('inhibition', 'Var', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('apoptosis', 'biological_process', 'GO:0097194', ('101', '110'))	('deacetylation', 'Protein', (48, 61))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('apoptosis', 'biological_process', 'GO:0006915', ('101', '110'))	('apoptosis', 'CPA', (101, 110))	('promote', 'PosReg', (93, 100))	('tumor', 'Disease', (75, 80))
53771	30365137	Either BNIP3 activation or silencing has been shown to promote tumor invasion, delay cell death, and subsequently lead to poor prognosis in different types of tumor.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('silencing', 'Var', (27, 36))	('delay cell death', 'Disease', 'MESH:D003643', (79, 95))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('delay cell death', 'Disease', (79, 95))	('activation', 'PosReg', (13, 23))	('tumor', 'Disease', (159, 164))	('BNIP3', 'Gene', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('promote', 'PosReg', (55, 62))	('BNIP3', 'Gene', '664', (7, 12))	('cell death', 'biological_process', 'GO:0008219', ('85', '95'))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
53777	30365137	As previously described, BNIP3 silencing might facilitate tumor survival.	('silencing', 'Var', (31, 40))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('facilitate', 'PosReg', (47, 57))	('BNIP3', 'Gene', (25, 30))	('BNIP3', 'Gene', '664', (25, 30))
53784	30365137	DNA methylation and histone deacetylation are two epigenetic mechanisms with crucial roles in tumorigenesis and tumor progression.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('histone', 'MPA', (20, 27))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('histone deacetylation', 'biological_process', 'GO:0016575', ('20', '41'))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('methylation', 'Var', (4, 15))	('tumor', 'Disease', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))
53786	30365137	DNA methylation is a proven mechanism of BNIP3 downregulation in tumors.	('downregulation', 'NegReg', (47, 61))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('methylation', 'Var', (4, 15))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('BNIP3', 'Gene', (41, 46))	('BNIP3', 'Gene', '664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
53787	30365137	In a previous study, Murai and coworkers demonstrated that BNIP3 was methylated in 65.6% of colorectal cancer tissues, although it was not methylated in adjacent normal tissue samples.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('BNIP3', 'Gene', (59, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (92, 109))	('methylated', 'Var', (69, 79))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('BNIP3', 'Gene', '664', (59, 64))	('colorectal cancer', 'Disease', (92, 109))
53788	30365137	Similarly, Cleven et al also demonstrated the occurrence of BNIP3 methylation in 52.8% of colorectal cancer cells, and that treatment with 5-aza-C restored the expression of BNIP3 and led to increased apoptosis and autophagy, with enhanced sensitivity to chemotherapy.	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('methylation', 'biological_process', 'GO:0032259', ('66', '77'))	('autophagy', 'biological_process', 'GO:0006914', ('215', '224'))	('BNIP3', 'Gene', '664', (174, 179))	('enhanced', 'PosReg', (231, 239))	('colorectal cancer', 'Disease', (90, 107))	('autophagy', 'CPA', (215, 224))	('BNIP3', 'Gene', (60, 65))	('apoptosis', 'CPA', (201, 210))	('expression', 'MPA', (160, 170))	('BNIP3', 'Gene', '664', (60, 65))	('methylation', 'Var', (66, 77))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('restored', 'PosReg', (147, 155))	('autophagy', 'biological_process', 'GO:0016236', ('215', '224'))	('BNIP3', 'Gene', (174, 179))	('increased', 'PosReg', (191, 200))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('apoptosis', 'biological_process', 'GO:0097194', ('201', '210'))	('apoptosis', 'biological_process', 'GO:0006915', ('201', '210'))	('5-aza-C', 'Chemical', 'MESH:D001374', (139, 146))
53797	30365137	Bacon et al previously found that BNIP3 was upregulated following either 5-aza-C or TSA treatment in certain types of colorectal cancer cells, which had no initial methylation or histone deacetylation in the BNIP3 promoter region.	('BNIP3', 'Gene', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('methylation', 'biological_process', 'GO:0032259', ('164', '175'))	('TSA', 'molecular_function', 'GO:0033984', ('84', '87'))	('BNIP3', 'Gene', '664', (208, 213))	('upregulated', 'PosReg', (44, 55))	('5-aza-C', 'Var', (73, 80))	('colorectal cancer', 'Disease', 'MESH:D015179', (118, 135))	('BNIP3', 'Gene', (34, 39))	('colorectal cancer', 'Phenotype', 'HP:0003003', (118, 135))	('5-aza-C', 'Chemical', 'MESH:D001374', (73, 80))	('BNIP3', 'Gene', '664', (34, 39))	('histone deacetylation', 'biological_process', 'GO:0016575', ('179', '200'))	('colorectal cancer', 'Disease', (118, 135))	('TSA', 'Chemical', 'MESH:C012589', (84, 87))
53802	30365137	Along with the increased expression of several genes, TSA is able to activate a range of signaling pathways, including the c-Jun N-terminal kinase (JNK) signaling pathway, to promote cell apoptosis, or it can suppress pathways, such as the Wnt/beta catenin signaling pathway.	('signaling pathways', 'Pathway', (89, 107))	('activate', 'PosReg', (69, 77))	('suppress', 'NegReg', (209, 217))	('c-Jun N-terminal kinase', 'Gene', '5599', (123, 146))	('apoptosis', 'biological_process', 'GO:0097194', ('188', '197'))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('apoptosis', 'biological_process', 'GO:0006915', ('188', '197'))	('TSA', 'Var', (54, 57))	('promote', 'PosReg', (175, 182))	('JNK', 'molecular_function', 'GO:0004705', ('148', '151'))	('TSA', 'molecular_function', 'GO:0033984', ('54', '57'))	('cell apoptosis', 'CPA', (183, 197))	('c-Jun N-terminal kinase', 'Gene', (123, 146))	('JNK', 'Gene', (148, 151))	('JNK', 'Gene', '5599', (148, 151))	('JNK) signaling pathway', 'biological_process', 'GO:0031098', ('148', '170'))	('pathways', 'Pathway', (218, 226))	('Wnt/beta catenin signaling pathway', 'Pathway', (240, 274))	('signaling pathway', 'biological_process', 'GO:0007165', ('257', '274'))	('TSA', 'Chemical', 'MESH:C012589', (54, 57))
53808	30365137	Agents acting on targets in the VHL-HIF hypoxia-response gene pathway have increased the rate of disease control to almost 80%; however, according to the Response Evaluation Criteria In Solid Tumors (RECIST), targeted therapies mostly lead to stable disease, with low objective response rates.	('Solid Tumors', 'Disease', 'MESH:D009369', (186, 198))	('Solid Tumors', 'Disease', (186, 198))	('lead to', 'Reg', (235, 242))	('Tumors', 'Phenotype', 'HP:0002664', (192, 198))	('stable disease', 'Disease', (243, 257))	('VHL-HIF hypoxia', 'Disease', (32, 47))	('VHL-HIF hypoxia', 'Disease', 'MESH:D000860', (32, 47))	('targeted therapies', 'Var', (209, 227))
53813	30365137	In conclusion, in the present study low levels of expression of the pro-apoptosis gene, BNIP3, were demonstrated in RCC cells with VHL inactivation and HIF upregulation, and BNIP3 promoter methylation did not contribute to BNIP3 suppression.	('BNIP3', 'Gene', (88, 93))	('VHL', 'Gene', (131, 134))	('BNIP3', 'Gene', '664', (88, 93))	('upregulation', 'PosReg', (156, 168))	('BNIP3', 'Gene', (174, 179))	('VHL', 'Gene', '7428', (131, 134))	('pro-apoptosis', 'biological_process', 'GO:0043065', ('68', '81'))	('BNIP3', 'Gene', (223, 228))	('BNIP3', 'Gene', '664', (174, 179))	('methylation', 'biological_process', 'GO:0032259', ('189', '200'))	('BNIP3', 'Gene', '664', (223, 228))	('inactivation', 'Var', (135, 147))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))	('expression', 'MPA', (50, 60))
53814	30365137	TSA treatment was demonstrated to restore the acetylated status of the BNIP3 gene, increase BNIP3 expression at both the mRNA and protein levels, inhibit cell proliferation, and induce RCC cell death, thereby indicating that deacetylation of the promoter region histone appears to be a mechanism of BNIP3 inactivation, and that BNIP3 could be a potential new target for RCC treatment.	('cell proliferation', 'CPA', (154, 172))	('BNIP3', 'Gene', (92, 97))	('induce', 'Reg', (178, 184))	('BNIP3', 'Gene', '664', (71, 76))	('cell death', 'biological_process', 'GO:0008219', ('189', '199'))	('BNIP3', 'Gene', '664', (299, 304))	('RCC', 'Disease', (370, 373))	('BNIP3', 'Gene', (328, 333))	('BNIP3', 'Gene', '664', (92, 97))	('RCC', 'Disease', 'MESH:C538614', (370, 373))	('RCC', 'Disease', (185, 188))	('TSA', 'molecular_function', 'GO:0033984', ('0', '3'))	('increase', 'PosReg', (83, 91))	('BNIP3', 'Gene', '664', (328, 333))	('RCC', 'Disease', 'MESH:C538614', (185, 188))	('inhibit', 'NegReg', (146, 153))	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('acetylated status', 'MPA', (46, 63))	('BNIP3', 'Gene', (71, 76))	('TSA', 'Chemical', 'MESH:C012589', (0, 3))	('cell proliferation', 'biological_process', 'GO:0008283', ('154', '172'))	('restore', 'PosReg', (34, 41))	('BNIP3', 'Gene', (299, 304))	('deacetylation', 'Var', (225, 238))	('expression', 'MPA', (98, 108))
53862	33229506	When assessed by histology, patients with metastatic ccRCC had numerically longer PFS (7.3 vs 2.5 months, HR 1.39, 95% CI 0.86 to 2.25, p=0.18) and OS (31.6 vs 23.9 months, HR 1.26, 95% CI 0.71 to 2.23, p=0.44) with wide CIs indicating substantial uncertainty (table 2, figure 2A, B).	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('longer', 'PosReg', (75, 81))	('PFS', 'CPA', (82, 85))	('metastatic', 'Var', (42, 52))	('patients', 'Species', '9606', (28, 36))
53886	32826868	VHL is well-recognized as essential tumor suppressor gene, and dysfunction of which intimately associates with malignancy-predisposing von Hipple-Lindau disease.	('tumor suppressor', 'biological_process', 'GO:0051726', ('36', '52'))	('malignancy', 'Disease', 'MESH:D009369', (111, 121))	('dysfunction', 'Var', (63, 74))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('36', '52'))	('malignancy', 'Disease', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('VHL', 'Gene', (0, 3))	('associates', 'Reg', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('von Hipple-Lindau disease', 'Disease', 'MESH:D006623', (135, 160))	('von Hipple-Lindau disease', 'Disease', (135, 160))	('tumor', 'Disease', (36, 41))
53887	32826868	Assembling investigations uncover that loss-of-function of VHL via loss of alleles, somatic mutation or epigenetic inhibition accounts for the majority of clear cell renal cell carcinomas (ccRCCs) incidence clinically.	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (166, 187))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (155, 186))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (166, 186))	('epigenetic inhibition', 'Var', (104, 125))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (155, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('loss of alleles', 'Var', (67, 82))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (155, 187))	('clear cell renal cell carcinomas', 'Disease', (155, 187))	('VHL', 'Gene', (59, 62))	('ccRCCs', 'Phenotype', 'HP:0006770', (189, 195))	('loss-of-function', 'NegReg', (39, 55))
53900	32826868	All shRNAs were purchased from Origene (Beijing, China) and overexpressing plasmids for VHL, hnRNPA2B1, c-myc, HA-eIF2A, HA-eIF4A were ordered from Vigenebio (Jinan, China).	('eIF4', 'cellular_component', 'GO:0008304', ('124', '128'))	('hnRNPA2B1', 'Gene', (93, 102))	('VHL', 'Gene', (88, 91))	('eIF4A', 'Gene', '1973', (124, 129))	('eIF4A', 'Gene', (124, 129))	('c-myc', 'Gene', '4609', (104, 109))	('c-myc', 'Gene', (104, 109))	('HA-eIF2A', 'Var', (111, 119))	('eIF2', 'cellular_component', 'GO:0005850', ('114', '118'))
53936	32826868	Point-directed mutagenesis was employed to generate putative c-myc-recognizing site mutants.	('mutants', 'Var', (84, 91))	('c-myc', 'Gene', '4609', (61, 66))	('c-myc', 'Gene', (61, 66))	('mutagenesis', 'biological_process', 'GO:0006280', ('15', '26'))
53957	32826868	VHLalpha was slightly upregulated only in the context of eIF4A knockdown (Fig.	('upregulated', 'PosReg', (22, 33))	('VHLalpha', 'Gene', (0, 8))	('eIF4', 'cellular_component', 'GO:0008304', ('57', '61'))	('eIF4A', 'Gene', '1973', (57, 62))	('knockdown', 'Var', (63, 72))	('eIF4A', 'Gene', (57, 62))
53964	32826868	Taken together, our results identified the CUG-initiated VHLalpha translation, which was subjected to modulation by both eIF2A and eIF4A.	('VHLalpha', 'Gene', (57, 65))	('eIF4', 'cellular_component', 'GO:0008304', ('131', '135'))	('eIF4A', 'Gene', (131, 136))	('CUG', 'Chemical', '-', (43, 46))	('translation', 'biological_process', 'GO:0006412', ('66', '77'))	('eIF4A', 'Gene', '1973', (131, 136))	('eIF2A', 'Var', (121, 126))	('eIF2', 'cellular_component', 'GO:0005850', ('121', '125'))
53966	32826868	We also noticed that MG132 treatment caused increase of VHLalpha in addition to accumulation of hnRNPA2B1, which implicated the possible feedback regulation on VHLalpha.	('hnRNPA2B1', 'Gene', (96, 105))	('MG132', 'Chemical', 'MESH:C072553', (21, 26))	('MG132', 'Var', (21, 26))	('increase', 'PosReg', (44, 52))	('VHLalpha', 'MPA', (56, 64))	('accumulation', 'PosReg', (80, 92))	('regulation', 'biological_process', 'GO:0065007', ('146', '156'))
53970	32826868	Addition of MG132, which stabilized hnRNPA2B1 and therefore continuously stimulated VHLalpha translation up to 24 h in our system (Fig.	('stimulated', 'PosReg', (73, 83))	('translation', 'biological_process', 'GO:0006412', ('93', '104'))	('hnRNPA2B1', 'Protein', (36, 45))	('MG132', 'Var', (12, 17))	('VHLalpha translation', 'MPA', (84, 104))	('MG132', 'Chemical', 'MESH:C072553', (12, 17))
53971	32826868	Our previous study demonstrated VHLalpha other than both VHL-19 and VHL-24 was capable of degrading hnRNPA2B1 in renal cancer cells.	('degrading', 'NegReg', (90, 99))	('hnRNPA2B1', 'Protein', (100, 109))	('renal cancer', 'Disease', 'MESH:D007680', (113, 125))	('renal cancer', 'Phenotype', 'HP:0009726', (113, 125))	('renal cancer', 'Disease', (113, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('VHLalpha', 'Var', (32, 40))
53973	32826868	3b, c. The immunoprecipitated hnRNPA2B1 was ubiquitinated to greater extent in the presence of MG132 while 293T cells were co-transfected with either full-length of VHLalpha or 20-270aa fragment in comparison with 39-270 fragment, VHL-19 or VHL-24, respectively (Fig.	('ubiquitinated', 'MPA', (44, 57))	('MG132', 'Var', (95, 100))	('20-270aa', 'Var', (177, 185))	('293T', 'CellLine', 'CVCL:0063', (107, 111))	('hnRNPA2B1', 'Gene', (30, 39))	('MG132', 'Chemical', 'MESH:C072553', (95, 100))
53974	32826868	Sequence analysis performed with UbPred algorithm (http://www.ubpred.org/) predicted that lysine residue-5, residue-174, and residue-305 as potential ubiquitination sites.	('lysine', 'Chemical', 'MESH:D008239', (90, 96))	('residue-305', 'Var', (125, 136))	('lysine residue-5', 'Var', (90, 106))	('residue-174', 'Var', (108, 119))	('ubiquitination', 'MPA', (150, 164))
53975	32826868	Co-transfection with VHLalpha led to tremendous decrease of hnRNPA2B1 (wild-type and K5R), which was greatly canceled by K174R and K305R mutation individually or in combination (Fig.	('K174R', 'Var', (121, 126))	('K305R', 'Mutation', 'p.K305R', (131, 136))	('K305R', 'Var', (131, 136))	('decrease', 'NegReg', (48, 56))	('hnRNPA2B1', 'Gene', (60, 69))	('K174R', 'Mutation', 'p.K174R', (121, 126))
53989	32826868	We first established stable cell with ectopic c-myc alone or in combination with either shhnRNPA2B1 or VHLalpha, and ectopic hnRNPA2B1 alone or in combination with VHLalpha.	('c-myc', 'Gene', '4609', (46, 51))	('ectopic', 'Var', (117, 124))	('hnRNPA2B1', 'Gene', (125, 134))	('c-myc', 'Gene', (46, 51))
53991	32826868	Ectopic introduction of c-myc significantly stimulated cell viability in comparison with empty control, which was greatly compromised by shRNA-mediated knockdown of hnRNPA2B1 (Fig.	('hnRNPA2B1', 'Gene', (165, 174))	('knockdown', 'Var', (152, 161))	('c-myc', 'Gene', '4609', (24, 29))	('c-myc', 'Gene', (24, 29))	('stimulated', 'PosReg', (44, 54))	('cell viability', 'CPA', (55, 69))
53994	32826868	The pro-proliferative activities of hnRNPA2B1 was also uncovered by colony formation assay, wherein c-myc overexpression dramatically increased the colony number which was greatly reduced by either hnRNPA2B1 depletion or VHLalpha-proficiency (representative images and statistical data were provided in Fig.	('depletion', 'Var', (208, 217))	('c-myc', 'Gene', '4609', (100, 105))	('formation', 'biological_process', 'GO:0009058', ('75', '84'))	('reduced', 'NegReg', (180, 187))	('colony number', 'CPA', (148, 161))	('c-myc', 'Gene', (100, 105))	('hnRNPA2B1', 'Gene', (198, 207))	('increased', 'PosReg', (134, 143))
53996	32826868	Consistently, the migrative measurement with wound healing demonstrated that ectopic c-myc significantly accelerated gap closure, which was slowed by hnRNPA2B1 silencing and further decelerated by VHLalpha.	('c-myc', 'Gene', (85, 90))	('ectopic', 'Var', (77, 84))	('silencing', 'NegReg', (160, 169))	('slowed', 'NegReg', (140, 146))	('accelerated', 'PosReg', (105, 116))	('wound healing', 'biological_process', 'GO:0042060', ('45', '58'))	('hnRNPA2B1', 'Gene', (150, 159))	('c-myc', 'Gene', '4609', (85, 90))	('gap closure', 'CPA', (117, 128))
54000	32826868	5j, and growth curve of xenograft tumor in the context of c-myc overexpression in combination with hnRNPA2B1 knockdown and ectopic VHLalpha was provided in Fig.	('tumor', 'Disease', (34, 39))	('c-myc', 'Gene', '4609', (58, 63))	('c-myc', 'Gene', (58, 63))	('overexpression', 'PosReg', (64, 78))	('knockdown', 'Var', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('hnRNPA2B1', 'Gene', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
54001	32826868	5k, growth curve of xenograft tumor in the context of hnRNPA2B1 overexpression in combination with VHLalpha overexpression was shown in Fig.	('hnRNPA2B1', 'Gene', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('overexpression', 'Var', (64, 78))	('tumor', 'Disease', (30, 35))
54002	32826868	We further analyzed functional relevance of VHLalpha, hnRNPA2B1 and c-myc in ccRCC tissue samples, and noticed relatively high abundance of hnRNPA2B1 in Myc+/VHLmt patients in comparison with Myc+/VHLwt ones (Fig.	('hnRNPA2B1', 'Gene', (140, 149))	('Myc+/VHLmt', 'Var', (153, 163))	('c-myc', 'Gene', (68, 73))	('patients', 'Species', '9606', (164, 172))	('c-myc', 'Gene', '4609', (68, 73))
54011	32826868	Via retrieval of the Catalogue of Somatic Mutations in Cancer database (COSMIC, cancer.sanger.ac.uk/cosmic), we noticed that -134G > C point mutation locating in the N terminal of VHLalpha protein caused arginine to proline transition and therefore might disrupt interaction between VHLalpha and hnRNPA2B1 and VHLalpha-mediated hnRNPA2B1 degradation through ubiquitin-proteasome pathway.	('hnRNPA2B1', 'Protein', (296, 305))	('VHLalpha', 'Gene', (180, 188))	('hnRNPA2B1', 'Gene', (328, 337))	('ubiquitin', 'molecular_function', 'GO:0031386', ('358', '367'))	('Cancer', 'Disease', 'MESH:D009369', (55, 61))	('disrupt', 'Reg', (255, 262))	('cancer', 'Disease', (80, 86))	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('degradation', 'MPA', (338, 349))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('proteasome pathway', 'biological_process', 'GO:0043161', ('368', '386'))	('degradation', 'biological_process', 'GO:0009056', ('338', '349'))	('-134G > C', 'Mutation', 'c.-134G>C', (125, 134))	('proteasome', 'molecular_function', 'GO:0004299', ('368', '378'))	('ubiquitin-proteasome pathway', 'Pathway', (358, 386))	('proline', 'Chemical', 'MESH:D011392', (216, 223))	('VHLalpha', 'Protein', (283, 291))	('caused', 'Reg', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('-134G > C', 'Var', (125, 134))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('proteasome', 'cellular_component', 'GO:0000502', ('368', '378'))	('Cancer', 'Disease', (55, 61))	('arginine to proline transition', 'MPA', (204, 234))	('interaction', 'Interaction', (263, 274))	('arginine', 'Chemical', 'MESH:D001120', (204, 212))
54017	32826868	Via bioinformatic prediction and experimental validation, we identified -281~275 nt fragment as cis-element of c-myc and mutation of which greatly abolished the luciferase reporter activity of hnRNPA2B1.	('abolished', 'NegReg', (147, 156))	('c-myc', 'Gene', '4609', (111, 116))	('c-myc', 'Gene', (111, 116))	('hnRNPA2B1', 'Gene', (193, 202))	('mutation', 'Var', (121, 129))	('luciferase', 'Enzyme', (161, 171))
54021	32826868	The current results suggested the specificity of VHLalpha exerting anti-tumoral function against activated hnRNPA2B1 in renal tumors, and therefore somatic mutations in VHLalpha which interrupted the feedback loop might compromise its tumor suppressor activity, which worthied further investigations to fully understand the novel isoform of VHL.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('renal tumor', 'Phenotype', 'HP:0009726', (120, 131))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('VHLalpha', 'Gene', (49, 57))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('235', '251'))	('VHLalpha', 'Gene', (169, 177))	('tumor', 'Disease', (72, 77))	('mutations', 'Var', (156, 165))	('tumor suppressor', 'biological_process', 'GO:0051726', ('235', '251'))	('compromise', 'NegReg', (220, 230))	('renal tumors', 'Disease', (120, 132))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (126, 131))	('hnRNPA2B1', 'Protein', (107, 116))	('renal tumors', 'Disease', 'MESH:D007674', (120, 132))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', (235, 240))	('renal tumors', 'Phenotype', 'HP:0009726', (120, 132))
54091	31936274	The accumulation of HIF1alpha also occurs due to inactivation of the VHL gene.	('HIF1alpha', 'Gene', (20, 29))	('inactivation', 'Var', (49, 61))	('HIF1alpha', 'Gene', '3091', (20, 29))	('VHL', 'Gene', (69, 72))	('VHL', 'Gene', '7428', (69, 72))
54112	31936274	Increased expression of BHLHE41 stimulated the proliferation of tumor cells of ccRCC, and a knockdown led to a significant decrease in this feature.	('tumor', 'Disease', (64, 69))	('stimulated', 'PosReg', (32, 42))	('BHLHE41', 'Gene', (24, 31))	('knockdown', 'Var', (92, 101))	('expression', 'MPA', (10, 20))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('Increased', 'PosReg', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('BHLHE41', 'Gene', '79365', (24, 31))	('proliferation', 'CPA', (47, 60))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
54134	31936274	Increased expression of IGFBP3 inhibits the growth of metastatic cells in the lungs, but does not inhibit the growth of primary tumor cells and normal kidney cells.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('Increased expression of IGFBP3', 'Phenotype', 'HP:0030269', (0, 30))	('inhibits', 'NegReg', (31, 39))	('IGFBP3', 'Gene', (24, 30))	('IGFBP3', 'Gene', '3486', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('growth of metastatic cells in the lungs', 'CPA', (44, 83))	('tumor', 'Disease', (128, 133))	('expression', 'Var', (10, 20))
54334	31649850	Upregulation of miR-489-3p and miR-630 inhibits oxaliplatin uptake in renal cell carcinoma by targeting OCT2 Renal cell carcinoma (RCC) is one of the most common malignant tumors affecting the urogenital system, accounting for 90% of renal malignancies.	('renal cell carcinoma', 'Disease', (70, 90))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (70, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('Renal cell carcinoma', 'Disease', (109, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('inhibits', 'NegReg', (39, 47))	('renal malignancies', 'Disease', (234, 252))	('uptake', 'biological_process', 'GO:0098739', ('60', '66'))	('Renal cell carcinoma', 'Disease', 'MESH:D002292', (109, 129))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('tumors affecting the urogenital system', 'Phenotype', 'HP:0007379', (172, 210))	('miR-489', 'Gene', '574442', (16, 23))	('miR-630', 'Gene', (31, 38))	('malignant tumors', 'Disease', (162, 178))	('malignant tumors', 'Disease', 'MESH:D009369', (162, 178))	('oxaliplatin', 'Chemical', 'MESH:C030110', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('Renal cell carcinoma', 'Phenotype', 'HP:0005584', (109, 129))	('RCC', 'Disease', 'MESH:D002292', (131, 134))	('OCT2', 'Var', (104, 108))	('oxaliplatin uptake', 'MPA', (48, 66))	('miR-489', 'Gene', (16, 23))	('renal malignancies', 'Disease', 'MESH:D007674', (234, 252))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (70, 90))	('miR-630', 'Gene', '693215', (31, 38))	('OCT2 Renal cell carcinoma', 'Phenotype', 'HP:0006732', (104, 129))	('affecting the urogenital system', 'Phenotype', 'HP:0000119', (179, 210))	('renal malignancies', 'Phenotype', 'HP:0009726', (234, 252))	('targeting', 'Reg', (94, 103))	('uptake', 'biological_process', 'GO:0098657', ('60', '66'))
54342	31649850	MiR-489-3p, c-Myc and miR-630 mediate OCT2 downregulation in RCC cells.	('miR-630', 'Gene', (22, 29))	('downregulation', 'NegReg', (43, 57))	('OCT2', 'Protein', (38, 42))	('c-Myc', 'Gene', '4609', (12, 17))	('miR-630', 'Gene', '693215', (22, 29))	('c-Myc', 'Gene', (12, 17))	('RCC', 'Disease', 'MESH:D002292', (61, 64))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('MiR-489-3p', 'Var', (0, 10))
54345	31649850	A previous study revealed that miRNAs are pivotal regulators of cancer development and work by influencing the main cancer hallmarks.	('cancer hallmarks', 'Disease', 'MESH:D009369', (116, 132))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('miRNAs', 'Var', (31, 37))	('influencing', 'Reg', (95, 106))	('cancer hallmarks', 'Disease', (116, 132))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
54348	31649850	A combination treatment, with specifical antagomir or agomir of the dysregulated miRNAs, can provide insight into better and more efficacious clinical chemotherapy options.	('agomir', 'Var', (54, 60))	('antagomir', 'Var', (41, 50))	('clinical', 'Species', '191496', (142, 150))
54353	31649850	In a previous study, we revealed that aberrant DNA methylation at OCT2 promoter caused OCT2 repression in RCC, which drives oxaliplatin resistance in RCC.	('oxaliplatin', 'Chemical', 'MESH:C030110', (124, 135))	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('OCT2 repression', 'MPA', (87, 102))	('DNA methylation', 'biological_process', 'GO:0006306', ('47', '62'))	('caused', 'Reg', (80, 86))	('RCC', 'Disease', 'MESH:D002292', (150, 153))	('RCC', 'Disease', (150, 153))	('oxaliplatin resistance', 'MPA', (124, 146))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('drives', 'Reg', (117, 123))	('RCC', 'Disease', 'MESH:D002292', (106, 109))	('aberrant DNA methylation', 'Var', (38, 62))
54367	31649850	Wild type or mutated OCT2 3'-UTR were homologous recombined to PGL3 promoter vector (Promega, Wisconsin, USA) for the construction of reporter plasmids.	('PGL3', 'Gene', '6391', (63, 67))	('OCT2', 'Gene', (21, 25))	('PGL3', 'Gene', (63, 67))	('PGL', 'molecular_function', 'GO:0004598', ('63', '66'))	('mutated', 'Var', (13, 20))
54388	31649850	Each female BALB/c nude mouse (National Rodent Laboratory Animal Resource, Shanghai, China) was injected subcutaneously with 107 786-O-pCDH, 786-O-OCT2-NC, 786-O-OCT2-489 or 786-O-OCT2-630.	('mouse', 'Species', '10090', (24, 29))	('786-O-pCDH', 'Chemical', 'MESH:C002925', (129, 139))	('786-O-OCT2-NC', 'Var', (141, 154))	('786-O-OCT2-489', 'Var', (156, 170))	('786-O-OCT2-630', 'Var', (174, 188))
54394	31649850	Exosomes used for protein immunoblotting were resuspended in PBS, quantified by bicinchoninic acid assays (P0011, Beyotime) and mixed with SDS loading buffer (C516031, Sangon Biotech, China).	('C516031', 'Var', (159, 166))	('bicinchoninic acid assays', 'MPA', (80, 105))	('bicinchoninic acid', 'Chemical', 'MESH:C047117', (80, 98))	('C516031', 'Chemical', 'MESH:D002244', (159, 166))	('SDS', 'Chemical', 'MESH:C001114', (139, 142))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))
54402	31649850	The significantly decreased luciferase activity between NC and miR-489-3p in HEK-293 cells, cotransfected with pGL3-OCT2 3'-UTR, was partially reversed by cotransfecting with mutant pGL3-OCT2 3'-UTR (Fig.	('pGL3', 'Gene', (182, 186))	('pGL', 'molecular_function', 'GO:0004598', ('182', '185'))	('pGL3', 'Gene', (111, 115))	('luciferase activity', 'molecular_function', 'GO:0045289', ('28', '47'))	('miR-489', 'Gene', '574442', (63, 70))	('luciferase activity', 'molecular_function', 'GO:0050248', ('28', '47'))	('decreased', 'NegReg', (18, 27))	('pGL3', 'Gene', '6391', (182, 186))	('luciferase activity', 'molecular_function', 'GO:0047712', ('28', '47'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('28', '47'))	('activity', 'MPA', (39, 47))	('luciferase', 'Enzyme', (28, 38))	('pGL3', 'Gene', '6391', (111, 115))	('miR-489', 'Gene', (63, 70))	('pGL', 'molecular_function', 'GO:0004598', ('111', '114'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('28', '47'))	('mutant', 'Var', (175, 181))
54403	31649850	Given that two miR-630 MREs distributed at different locations in OCT2 3'-UTR, deleted either did not affect luciferase activity inhibition by miR-630, while mutated both simultaneously, the inhibitory effect was negligible (Fig.	('luciferase activity', 'molecular_function', 'GO:0050248', ('109', '128'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('109', '128'))	('miR-630', 'Gene', (15, 22))	('luciferase', 'Enzyme', (109, 119))	('miR-630', 'Gene', (143, 150))	('miR-630', 'Gene', '693215', (143, 150))	('luciferase activity', 'molecular_function', 'GO:0047077', ('109', '128'))	('miR-630', 'Gene', '693215', (15, 22))	('mutated', 'Var', (158, 165))	('activity', 'MPA', (120, 128))	('luciferase activity', 'molecular_function', 'GO:0045289', ('109', '128'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('109', '128'))
54410	31649850	Compared with cells transfected with the parent vector (786-O-pCDH), both mRNA and protein expression levels and the uptake of MPP+ in 786-O-OCT2 were significantly upregulated (Fig.	('786-O-OCT2', 'Var', (135, 145))	('uptake', 'biological_process', 'GO:0098657', ('117', '123'))	('uptake', 'biological_process', 'GO:0098739', ('117', '123'))	('MPP+', 'Chemical', 'MESH:C026560', (127, 131))	('786-O-pCDH', 'Chemical', 'MESH:C002925', (56, 66))	('uptake of MPP+', 'MPA', (117, 131))	('upregulated', 'PosReg', (165, 176))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('MPP', 'molecular_function', 'GO:0004240', ('127', '130'))
54414	31649850	Like DAC-induced renal cancer cells, overexpression of miR489-3p and miR-630 in OCT2 stably overexpressed cells resulted in inhibition of OCT2 RNA, protein expression level, and uptake ability of MPP+, compared to those in 786-O-OCT2-NC cells (Fig.	('uptake', 'biological_process', 'GO:0098657', ('178', '184'))	('miR-630', 'Gene', '693215', (69, 76))	('uptake', 'MPA', (178, 184))	('uptake', 'biological_process', 'GO:0098739', ('178', '184'))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('renal cancer', 'Disease', (17, 29))	('inhibition', 'NegReg', (124, 134))	('OCT2 RNA', 'MPA', (138, 146))	('renal cancer', 'Phenotype', 'HP:0009726', (17, 29))	('MPP+', 'Chemical', 'MESH:C026560', (196, 200))	('DAC', 'Gene', (5, 8))	('RNA', 'cellular_component', 'GO:0005562', ('143', '146'))	('miR-630', 'Gene', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('renal cancer', 'Disease', 'MESH:D007680', (17, 29))	('protein expression level', 'MPA', (148, 172))	('MPP', 'molecular_function', 'GO:0004240', ('196', '199'))	('miR489-3p', 'Var', (55, 64))	('DAC', 'Gene', '6468', (5, 8))
54423	31649850	To simulate the inhibitory effect of miR-489-3p and miR630 on OCT2 in vivo, a xenograft mouse model was established to monitor the therapeutic effect of oxaliplatin.	('oxaliplatin', 'Chemical', 'MESH:C030110', (153, 164))	('miR-489', 'Gene', (37, 44))	('mouse', 'Species', '10090', (88, 93))	('miR630', 'Var', (52, 58))	('miR-489', 'Gene', '574442', (37, 44))
54426	31649850	Regarding tumor growth, mice bearing tumors originating from 786-O-OCT2 cells demonstrated a remarkably delayed tumor growth, or even tumor shrinkage, with prolonged administration compared with 786-O-pCDH cells.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Disease', (10, 15))	('delayed', 'NegReg', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('786-O-pCDH', 'Chemical', 'MESH:C002925', (195, 205))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('tumor', 'Disease', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mice', 'Species', '10090', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (37, 42))	('786-O-OCT2', 'Var', (61, 71))
54430	31649850	Together we conclude that epigenetic suppression of OCT2 by miR-489-3p and miR-630 reduces intracellular platinum accumulation and consequently enhances chemoresistance of RCC cells to oxaliplatin, both in vitro and in xenografts.	('miR-489', 'Gene', (60, 67))	('chemoresistance', 'CPA', (153, 168))	('miR-630', 'Gene', (75, 82))	('intracellular platinum accumulation', 'MPA', (91, 126))	('platinum', 'Chemical', 'MESH:D010984', (105, 113))	('reduces', 'NegReg', (83, 90))	('epigenetic suppression', 'Var', (26, 48))	('miR-630', 'Gene', '693215', (75, 82))	('oxaliplatin', 'Chemical', 'MESH:C030110', (185, 196))	('enhances', 'PosReg', (144, 152))	('intracellular', 'cellular_component', 'GO:0005622', ('91', '104'))	('OCT2', 'Gene', (52, 56))	('miR-489', 'Gene', '574442', (60, 67))	('RCC', 'Disease', 'MESH:D002292', (172, 175))	('RCC', 'Disease', (172, 175))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))
54432	31649850	MiR-489-3p and miR-630 were also found to be uniquely upregulated in RCC, via microarray analysis and RT-PCR verification.	('RCC', 'Disease', 'MESH:D002292', (69, 72))	('RCC', 'Disease', (69, 72))	('upregulated', 'PosReg', (54, 65))	('miR-630', 'Gene', (15, 22))	('miR-630', 'Gene', '693215', (15, 22))	('MiR-489-3p', 'Var', (0, 10))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
54445	31649850	Two c-Myc binding motifs (E-Box: CACGTG) were identified inside the putative miR-630 promoter region named E1 (-1638 to -1632) and E2 (-1034 to -1040) (Supporting Information Fig.	('miR-630', 'Gene', (77, 84))	('c-Myc', 'Gene', (4, 9))	('-1638 to -1632', 'Var', (111, 125))	('c-Myc', 'Gene', '4609', (4, 9))	('-1034 to -1040', 'Var', (135, 149))	('miR-630', 'Gene', '693215', (77, 84))	('binding', 'molecular_function', 'GO:0005488', ('10', '17'))
54456	31649850	Together we conclude that the aberrant upregulation of miR-630 was partly due to the enrichment of c-Myc at E2 motif of miR-630 promoter in RCC.	('RCC', 'Disease', 'MESH:D002292', (140, 143))	('miR-630', 'Gene', '693215', (55, 62))	('miR-630', 'Gene', (120, 127))	('upregulation', 'PosReg', (39, 51))	('c-Myc', 'Gene', '4609', (99, 104))	('miR-630', 'Gene', (55, 62))	('E2 motif', 'Var', (108, 116))	('RCC', 'Disease', (140, 143))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('c-Myc', 'Gene', (99, 104))	('miR-630', 'Gene', '693215', (120, 127))
54458	31649850	To investigate whether miR-489-3p and miR-630 can be secreted through exosomes and used as biomarkers, we isolated exosomes from culture media of three stable transfected cell lines (786-O-OCT2-NC, 786-O-OCT2-489 and 786-O-OCT2-630).	('miR-630', 'Gene', '693215', (38, 45))	('miR-489', 'Gene', (23, 30))	('786-O-OCT2-NC', 'Var', (183, 196))	('786-O-OCT2-489', 'Var', (198, 212))	('miR-630', 'Gene', (38, 45))	('miR-489', 'Gene', '574442', (23, 30))	('786-O-OCT2-630', 'Var', (217, 231))
54465	31649850	showed a significant increase of miR-197a-3p, miR-362, and miR-572 and a marked decrease of miR-378 and miR-28-5p in the serum of RCC patients compared to those in normal volunteers.	('miR-378', 'Gene', '494327', (92, 99))	('miR-378', 'Gene', (92, 99))	('patients', 'Species', '9606', (134, 142))	('miR-28', 'Gene', '407020', (104, 110))	('miR-28', 'Gene', (104, 110))	('miR-572', 'Gene', '693157', (59, 66))	('RCC', 'Disease', (130, 133))	('miR-362', 'Gene', '574030', (46, 53))	('miR-197a-3p', 'Var', (33, 44))	('miR-572', 'Gene', (59, 66))	('miR-362', 'Gene', (46, 53))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('RCC', 'Disease', 'MESH:D002292', (130, 133))	('increase', 'PosReg', (21, 29))	('decrease', 'NegReg', (80, 88))
54473	31649850	Previously, the dysregulation of miR-630 has been widely identified in various cancers, including gastric cancer, hepatocellular carcinoma (HCC), ovarian carcinoma, pancreatic cancer and renal cell carcinoma, associated with cancer invasion, metastasis and cell apoptosis.	('renal cell carcinoma', 'Disease', (187, 207))	('pancreatic cancer', 'Disease', 'MESH:D010190', (165, 182))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (187, 207))	('ovarian carcinoma', 'Disease', (146, 163))	('cancer', 'Disease', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('HCC', 'Disease', 'MESH:D006528', (140, 143))	('cancer', 'Disease', (106, 112))	('identified', 'Reg', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('pancreatic cancer', 'Disease', (165, 182))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (146, 163))	('miR-630', 'Gene', (33, 40))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (114, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancers', 'Disease', (79, 86))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (114, 138))	('metastasis', 'CPA', (242, 252))	('gastric cancer', 'Disease', (98, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (165, 182))	('HCC', 'Disease', (140, 143))	('miR-630', 'Gene', '693215', (33, 40))	('HCC', 'Phenotype', 'HP:0001402', (140, 143))	('dysregulation', 'Var', (16, 29))	('associated', 'Reg', (209, 219))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (187, 207))	('hepatocellular carcinoma', 'Disease', (114, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('gastric cancer', 'Disease', 'MESH:D013274', (98, 112))	('apoptosis', 'biological_process', 'GO:0097194', ('262', '271'))	('apoptosis', 'biological_process', 'GO:0006915', ('262', '271'))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (146, 163))
54479	31649850	S4), which implies that epigenetic regulation of histone acetylation may account for the increase of miR-630.	('miR-630', 'Gene', (101, 108))	('miR-630', 'Gene', '693215', (101, 108))	('regulation of histone acetylation', 'biological_process', 'GO:0035065', ('35', '68'))	('histone', 'Protein', (49, 56))	('epigenetic regulation', 'Var', (24, 45))	('increase', 'PosReg', (89, 97))
54485	31649850	MiR-489 is thought to be induced via hypoxia-inducible factor-1 during ischemic AKI to protect the kidneys in mice.	('ischemic', 'Disease', (71, 79))	('hypoxia', 'Disease', 'MESH:D000860', (37, 44))	('hypoxia', 'Disease', (37, 44))	('mice', 'Species', '10090', (110, 114))	('ischemic', 'Disease', 'MESH:D007511', (71, 79))	('MiR-489', 'Var', (0, 7))
54495	31649850	Combinations of miRNA antagomirs in RCC therapy could sensitize cells to oxaliplatin and have important significance in guiding clinical chemotherapy.	('clinical', 'Species', '191496', (128, 136))	('sensitize', 'Reg', (54, 63))	('RCC', 'Disease', 'MESH:D002292', (36, 39))	('RCC', 'Disease', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('Combinations', 'Var', (0, 12))	('cells to oxaliplatin', 'MPA', (64, 84))	('oxaliplatin', 'Chemical', 'MESH:C030110', (73, 84))
54516	32333642	In contrast to its typical role as a miRNA sponge, circHIAT1 was shown to act as a miRNA storage device to improve the stability of mir-195-5p/29a-3p/29c-3p and partially reverse or block the migration and invasion of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('stability', 'MPA', (119, 128))	('block', 'NegReg', (182, 187))	('cancer', 'Disease', (218, 224))	('storage', 'biological_process', 'GO:0051235', ('89', '96'))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('rat', 'Species', '10116', (195, 198))	('improve', 'PosReg', (107, 114))	('mir-195-5p/29a-3p/29c-3p', 'Var', (132, 156))	('reverse', 'NegReg', (171, 178))
54552	32333642	49  The function of circ-AKT3 was confirmed to suppress ccRCC metastasis by increasing E-cadherin expression via competitively binding miR-296-3p.	('E-cadherin', 'Gene', (87, 97))	('E-cadherin', 'Gene', '999', (87, 97))	('AKT3', 'Gene', '10000', (25, 29))	('miR-296-3p', 'Var', (135, 145))	('suppress', 'NegReg', (47, 55))	('AKT3', 'Gene', (25, 29))	('increasing', 'PosReg', (76, 86))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('binding', 'molecular_function', 'GO:0005488', ('127', '134'))	('cadherin', 'molecular_function', 'GO:0008014', ('89', '97'))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('miR-296-3p', 'Chemical', '-', (135, 145))	('expression', 'MPA', (98, 108))
54566	32333642	The knockdown of circRNA-15698 by small interfering RNAs (siRNAs) led to a significant decrease in these fibrosis-related proteins.	('small', 'Var', (34, 39))	('fibrosis', 'Disease', (105, 113))	('decrease', 'NegReg', (87, 95))	('fibrosis', 'Disease', 'MESH:D005355', (105, 113))
54567	32333642	Mechanistically, circRNA-15698 acted as an miR-185 sponge, increasing TGF-beta1 protein levels and stimulating ECM-related protein synthesis in DN.	('miR-185', 'Gene', (43, 50))	('stimulating', 'PosReg', (99, 110))	('protein synthesis', 'biological_process', 'GO:0006412', ('123', '140'))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('TGF-beta1', 'Gene', '7040', (70, 79))	('TGF-beta1', 'Gene', (70, 79))	('ECM-related protein synthesis', 'MPA', (111, 140))	('increasing', 'PosReg', (59, 69))	('miR-185', 'Gene', '406961', (43, 50))	('circRNA-15698', 'Var', (17, 30))
54590	32333642	38  Recently, a bioinformatic analysis showed that high hsa_circ_0000479 levels were correlated with low albumin levels, positive urine protein and low haemoglobin, which indicated that it might be involved in SLE-associated renal injury.	('SLE', 'Disease', 'MESH:D008180', (210, 213))	('SLE', 'Disease', (210, 213))	('high hsa_circ_0000479 levels', 'Var', (51, 79))	('renal injury', 'Disease', (225, 237))	('haemoglobin', 'MPA', (152, 163))	('SLE', 'Phenotype', 'HP:0002725', (210, 213))	('low haemoglobin', 'Phenotype', 'HP:0001903', (148, 163))	('albumin levels', 'MPA', (105, 119))	('positive urine protein', 'MPA', (121, 143))	('urine protein', 'Phenotype', 'HP:0000093', (130, 143))	('renal injury', 'Disease', 'MESH:D007674', (225, 237))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('low albumin', 'Phenotype', 'HP:0003073', (101, 112))	('involved', 'Reg', (198, 206))	('low', 'NegReg', (148, 151))	('low', 'NegReg', (101, 104))
54602	32333642	85  Furthermore, by modulating miR-671, circRar1 induced the transcriptional activity of apoptosis-linked factors, such as caspase-8, in lead-induced neurotoxicity.	('circRar1', 'Gene', (40, 48))	('transcriptional activity', 'MPA', (61, 85))	('induced', 'PosReg', (49, 56))	('miR-671', 'Gene', (31, 38))	('neurotoxicity', 'Disease', 'MESH:D020258', (150, 163))	('caspase-8', 'Gene', '841', (123, 132))	('miR-671', 'Gene', '768213', (31, 38))	('modulating', 'Var', (20, 30))	('neurotoxicity', 'Disease', (150, 163))	('apoptosis', 'biological_process', 'GO:0097194', ('89', '98'))	('apoptosis', 'biological_process', 'GO:0006915', ('89', '98'))	('caspase-8', 'Gene', (123, 132))
54609	32333642	89  Rno-miR-138-5p and rno-miR-672-5p, which are co-expressed with miRNAs, have been proven to be involved in kidney calculi.	('rno-miR-672', 'Gene', (23, 34))	('involved', 'Reg', (98, 106))	('kidney calculi', 'Disease', 'MESH:D007669', (110, 124))	('Rno-miR-138-5p', 'Var', (4, 18))	('kidney calculi', 'Phenotype', 'HP:0000787', (110, 124))	('kidney calculi', 'Disease', (110, 124))	('rno-miR-672', 'Gene', '100314175', (23, 34))
54611	32333642	This study showed that circSamd4a exerts an anti-calcification role, via functioning as an miRNA sponge in a vascular calcification model, to reduce the complications of CKD.	('complications', 'MPA', (153, 166))	('calcification', 'Disease', 'MESH:D002114', (49, 62))	('vascular calcification', 'Phenotype', 'HP:0004934', (109, 131))	('calcification', 'Disease', 'MESH:D002114', (118, 131))	('vascular calcification', 'Disease', (109, 131))	('CKD', 'Disease', 'MESH:D012080', (170, 173))	('calcification', 'Disease', (49, 62))	('vascular calcification', 'Disease', 'MESH:D061205', (109, 131))	('CKD', 'Disease', (170, 173))	('calcification', 'Disease', (118, 131))	('circSamd4a', 'Var', (23, 33))	('reduce', 'NegReg', (142, 148))	('CKD', 'Phenotype', 'HP:0012622', (170, 173))
54618	32333642	92  A recent study demonstrated that hsa_circ_0014243 was elevated in blood samples derived from hypertensive patients, and it could be used as a diagnostic marker for hypertension.	('hypertension', 'Disease', 'MESH:D006973', (168, 180))	('hypertension', 'Phenotype', 'HP:0000822', (168, 180))	('hsa_circ_0014243', 'Var', (37, 53))	('rat', 'Species', '10116', (26, 29))	('hypertensive', 'Disease', 'MESH:D006973', (97, 109))	('hypertension', 'Disease', (168, 180))	('hypertensive', 'Disease', (97, 109))	('elevated', 'PosReg', (58, 66))	('patients', 'Species', '9606', (110, 118))
54625	32333642	The levels of circ_101319 were significantly higher and exhibited promising diagnostic value in patients with IMN.	('IMN', 'Disease', (110, 113))	('levels', 'MPA', (4, 10))	('circ_101319', 'Var', (14, 25))	('patients', 'Species', '9606', (96, 104))	('higher', 'PosReg', (45, 51))
54639	32547313	Further study found that knockdown of circ-APBB1IP up-regulated protein expression of cleaved caspase-3, cleaved caspase-7, cleaved caspase-8, cleaved caspase-9, Bax, Bad, Bak, E-cadherin and down-regulated expression of Bcl-2, N-cadherin, MMP-2, MMP-9, p-ERK1/2.	('Bax', 'Gene', (162, 165))	('caspase-7', 'Gene', (113, 122))	('N-cadherin', 'Gene', '1000', (228, 238))	('down-regulated', 'NegReg', (192, 206))	('Bcl-2', 'Gene', '596', (221, 226))	('MMP-9', 'molecular_function', 'GO:0004229', ('247', '252'))	('caspase-8', 'Gene', (132, 141))	('Bax', 'Gene', '581', (162, 165))	('Bcl-2', 'molecular_function', 'GO:0015283', ('221', '226'))	('cadherin', 'molecular_function', 'GO:0008014', ('179', '187'))	('caspase-9', 'Gene', (151, 160))	('ERK1', 'molecular_function', 'GO:0004707', ('256', '260'))	('caspase-3', 'Gene', '836', (94, 103))	('MMP-2', 'molecular_function', 'GO:0004228', ('240', '245'))	('APBB1IP', 'Gene', (43, 50))	('MMP-2', 'Gene', '4313', (240, 245))	('cleaved', 'MPA', (124, 131))	('expression', 'MPA', (207, 217))	('cleaved', 'Var', (143, 150))	('Bak', 'Gene', (172, 175))	('caspase-3', 'Gene', (94, 103))	('up-regulated', 'PosReg', (51, 63))	('E-cadherin', 'Gene', (177, 187))	('caspase-7', 'Gene', '840', (113, 122))	('E-cadherin', 'Gene', '999', (177, 187))	('caspase-8', 'Gene', '841', (132, 141))	('knockdown', 'Var', (25, 34))	('protein expression', 'MPA', (64, 82))	('cadherin', 'molecular_function', 'GO:0008014', ('230', '238'))	('MMP-9', 'Gene', (247, 252))	('MMP-9', 'Gene', '4318', (247, 252))	('cleaved', 'MPA', (105, 112))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('Bcl-2', 'Gene', (221, 226))	('MMP-2', 'Gene', (240, 245))	('APBB1IP', 'Gene', '54518', (43, 50))	('caspase-9', 'Gene', '842', (151, 160))	('N-cadherin', 'Gene', (228, 238))	('Bak', 'Gene', '578', (172, 175))
54646	32547313	For example, circular RNA ABCB10 was related to apoptosis in ccRCC cells.	('RNA', 'cellular_component', 'GO:0005562', ('22', '25'))	('ABCB10', 'Gene', '23456', (26, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('ccRCC', 'Disease', (61, 66))	('ABCB10', 'Gene', (26, 32))	('apoptosis', 'biological_process', 'GO:0006915', ('48', '57'))	('related', 'Reg', (37, 44))	('apoptosis', 'CPA', (48, 57))	('circular', 'Var', (13, 21))	('apoptosis', 'biological_process', 'GO:0097194', ('48', '57'))
54649	32547313	Circ-0000284 arouses the malignant phenotype of cholangiocarcinoma cells and regulates the biological functions of peripheral cells through cellular communication.	('cholangiocarcinoma', 'Disease', (48, 66))	('regulates', 'Reg', (77, 86))	('cellular communication', 'CPA', (140, 162))	('Circ-0000284', 'Var', (0, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('malignant phenotype of', 'CPA', (25, 47))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (48, 66))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (48, 66))	('biological functions of peripheral cells', 'MPA', (91, 131))	('arouses', 'PosReg', (13, 20))
54683	32547313	Primary Antibody Dilution Buffer (Beyotime) were used to dilute primary antibody cleaved caspase-3 (#9665S; dilution 1: 1,000), cleaved caspase-7 (#9494S; dilution 1: 1,000), cleaved caspase-8 (#4790S; dilution 1: 1,000), cleaved caspase-9 (#9502S; dilution 1: 1,000), Bax (#2772S; dilution 1: 1,000), Bad (#9239; dilution 1: 1,000), Bak (#12105S; dilution 1: 1,000), Bcl-2 (#2876S; dilution 1: 1,000), E-cadherin (#3195S; dilution 1: 1,000), N-cadherin (#4061S; dilution 1: 1,000), MMP-2 (#87809S; dilution 1: 1,000), MMP-9 (#2270S; dilution 1: 1,000), ERK1/2 (#4695S; dilution 1: 1,000), p-ERK1/2 (#4370S; dilution 1: 1,000) (all Cell Signaling Technology, Inc., Danvers, MA, USA).	('caspase-7', 'Gene', (136, 145))	('caspase-3', 'Gene', '836', (89, 98))	('antibody', 'cellular_component', 'GO:0042571', ('72', '80'))	('E-cadherin', 'Gene', (403, 413))	('E-cadherin', 'Gene', '999', (403, 413))	('Signaling', 'biological_process', 'GO:0023052', ('637', '646'))	('cadherin', 'molecular_function', 'GO:0008014', ('445', '453'))	('#87809S;', 'Var', (490, 498))	('#2270S;', 'Var', (526, 533))	('caspase-3', 'Gene', (89, 98))	('MMP-2', 'molecular_function', 'GO:0004228', ('483', '488'))	('caspase-8', 'Gene', '841', (183, 192))	('MMP-2', 'Gene', (483, 488))	('Bcl-2', 'Gene', (368, 373))	('antibody', 'cellular_component', 'GO:0019815', ('72', '80'))	('#4370S;', 'Var', (600, 607))	('Bcl-2', 'molecular_function', 'GO:0015283', ('368', '373'))	('#4061S; dilution', 'Var', (455, 471))	('#3195S', 'Var', (415, 421))	('ERK1', 'molecular_function', 'GO:0004707', ('592', '596'))	('Bax', 'Gene', (269, 272))	('ERK1', 'molecular_function', 'GO:0004707', ('554', '558'))	('Bcl-2', 'Gene', '596', (368, 373))	('Bak', 'Gene', '578', (334, 337))	('caspase-9', 'Gene', '842', (230, 239))	('caspase-7', 'Gene', '840', (136, 145))	('Bax', 'Gene', '581', (269, 272))	('caspase-8', 'Gene', (183, 192))	('MMP-9', 'Gene', (519, 524))	('MMP-9', 'Gene', '4318', (519, 524))	('antibody', 'cellular_component', 'GO:0019814', ('72', '80'))	('MMP-9', 'molecular_function', 'GO:0004229', ('519', '524'))	('#4695S; dilution', 'Var', (562, 578))	('N-cadherin', 'Gene', (443, 453))	('MMP-2', 'Gene', '4313', (483, 488))	('N-cadherin', 'Gene', '1000', (443, 453))	('cadherin', 'molecular_function', 'GO:0008014', ('405', '413'))	('caspase-9', 'Gene', (230, 239))	('antibody', 'molecular_function', 'GO:0003823', ('72', '80'))	('Bak', 'Gene', (334, 337))
54698	32547313	The proliferation of 786-O and Caki-1 was significantly inhibited after silencing circ-APBB1IP (Fig.	('APBB1IP', 'Gene', (87, 94))	('proliferation', 'CPA', (4, 17))	('silencing', 'Var', (72, 81))	('Caki-1', 'CellLine', 'CVCL:0234', (31, 37))	('inhibited', 'NegReg', (56, 65))	('APBB1IP', 'Gene', '54518', (87, 94))
54700	32547313	The results showed that the apoptosis rate of the cells increased significantly after knockdown circ-APBB1IP (Fig.	('knockdown', 'Var', (86, 95))	('APBB1IP', 'Gene', '54518', (101, 108))	('increased', 'PosReg', (56, 65))	('APBB1IP', 'Gene', (101, 108))	('apoptosis', 'biological_process', 'GO:0097194', ('28', '37'))	('apoptosis', 'biological_process', 'GO:0006915', ('28', '37'))	('apoptosis rate of the cells', 'CPA', (28, 55))
54701	32547313	To investigate the possible mechanism of circ-APBB1IP in ccRCC, circ-APBB1IP was knockdown by a specific siRNA targeting circ-APBB1IP.	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('APBB1IP', 'Gene', (69, 76))	('APBB1IP', 'Gene', '54518', (46, 53))	('ccRCC', 'Disease', (57, 62))	('APBB1IP', 'Gene', (46, 53))	('knockdown', 'Var', (81, 90))	('APBB1IP', 'Gene', '54518', (126, 133))	('APBB1IP', 'Gene', '54518', (69, 76))	('APBB1IP', 'Gene', (126, 133))
54705	32547313	The results showed that the invasion of 786-O and Caki-1 cells was inhibited prominently after knockdown the expression of circ-APBB1IP (Fig.	('inhibited', 'NegReg', (67, 76))	('APBB1IP', 'Gene', (128, 135))	('Caki-1', 'CellLine', 'CVCL:0234', (50, 56))	('knockdown', 'Var', (95, 104))	('APBB1IP', 'Gene', '54518', (128, 135))
54715	32547313	The data showed that the expression of p-ERK1/2 was reduced significantly after knocking down circ-APBB1IP (Fig.	('reduced', 'NegReg', (52, 59))	('knocking down', 'Var', (80, 93))	('expression', 'MPA', (25, 35))	('APBB1IP', 'Gene', '54518', (99, 106))	('APBB1IP', 'Gene', (99, 106))	('ERK1', 'molecular_function', 'GO:0004707', ('41', '45'))
54722	32547313	Our results suggested that knockdown of circ-APBB1IP could suppress the proliferation, migration and invasion, whereas promoted the apoptosis in ccRCC cells.	('apoptosis', 'CPA', (132, 141))	('APBB1IP', 'Gene', (45, 52))	('knockdown', 'Var', (27, 36))	('apoptosis', 'biological_process', 'GO:0097194', ('132', '141'))	('promoted', 'PosReg', (119, 127))	('apoptosis', 'biological_process', 'GO:0006915', ('132', '141'))	('ccRCC', 'Phenotype', 'HP:0006770', (145, 150))	('APBB1IP', 'Gene', '54518', (45, 52))	('suppress', 'NegReg', (59, 67))	('ccRCC', 'Disease', (145, 150))	('invasion', 'CPA', (101, 109))
54723	32547313	Deregulation of apoptosis was a hallmark of cancer and got related to tumor development and progression.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Deregulation', 'Var', (0, 12))	('apoptosis', 'CPA', (16, 25))	('cancer', 'Disease', (44, 50))	('tumor', 'Disease', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('related', 'Reg', (59, 66))	('apoptosis', 'biological_process', 'GO:0097194', ('16', '25'))	('apoptosis', 'biological_process', 'GO:0006915', ('16', '25'))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
54729	32547313	The result showed that the expression of p-ERK1/2 was suppressed after the silencing of circ-APBB1IP.	('APBB1IP', 'Gene', (93, 100))	('suppressed', 'NegReg', (54, 64))	('expression', 'MPA', (27, 37))	('ERK1', 'molecular_function', 'GO:0004707', ('43', '47'))	('silencing', 'Var', (75, 84))	('APBB1IP', 'Gene', '54518', (93, 100))
54754	31788053	Aberrant expression of SHH, PTCH1, SMO and GLI1 genes associated with cancer progression and patients survival has been reported in a broad range of human malignancies such as basal cell carcinoma, breast cancer and other neoplasms.	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('basal cell carcinoma', 'Disease', (176, 196))	('neoplasms', 'Disease', 'MESH:D009369', (222, 231))	('breast cancer', 'Disease', 'MESH:D001943', (198, 211))	('patients', 'Species', '9606', (93, 101))	('PTCH1', 'Gene', '5727', (28, 33))	('breast cancer', 'Disease', (198, 211))	('SMO', 'Gene', '6608', (35, 38))	('Aberrant', 'Var', (0, 8))	('GLI1', 'Gene', '2735', (43, 47))	('neoplasms', 'Disease', (222, 231))	('cancer', 'Disease', (70, 76))	('associated', 'Reg', (54, 64))	('reported', 'Reg', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('SMO', 'Gene', (35, 38))	('cancer', 'Disease', (205, 211))	('malignancies', 'Disease', 'MESH:D009369', (155, 167))	('PTCH1', 'Gene', (28, 33))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (176, 196))	('human', 'Species', '9606', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('malignancies', 'Disease', (155, 167))	('SHH', 'Gene', (23, 26))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (176, 196))	('neoplasms', 'Phenotype', 'HP:0002664', (222, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('GLI1', 'Gene', (43, 47))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
54781	31788053	Final semi-quantitative results for tumor samples were obtained as a ratio=mean unitsTumor/mean unitsControl for full-length or C-terminal SHH protein.	('SHH protein', 'Protein', (139, 150))	('unitsTumor', 'Disease', 'None', (80, 90))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('unitsTumor', 'Disease', (80, 90))	('C-terminal', 'Var', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
54784	31788053	According to AJCC/UICC TNM classification of malignant tumors, 17 patients were diagnosed as stage I (T1N0M0), 3 as stage II (T2N0M0), 13 as stage III (T1-2N1M0 or T3N0-2M0) and 4 as stage IV (T4N0-2M0 or T1-4N0-2M1).	('T3N0-2M0', 'Var', (164, 172))	('TNM', 'Gene', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('malignant tumors', 'Disease', (45, 61))	('malignant tumors', 'Disease', 'MESH:D009369', (45, 61))	('TNM', 'Gene', '10178', (23, 26))	('T1-2N1M0', 'Var', (152, 160))	('patients', 'Species', '9606', (66, 74))
54825	31788053	Furthermore, aberrant SHH gene expression was indicated not only in cancers derived from epithelial cells but also other types of malignancies such as retinoblastoma.	('retinoblastoma', 'Disease', 'MESH:D012175', (151, 165))	('retinoblastoma', 'Disease', (151, 165))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('malignancies', 'Disease', (130, 142))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('expression', 'MPA', (31, 41))	('retinoblastoma', 'Phenotype', 'HP:0009919', (151, 165))	('gene expression', 'biological_process', 'GO:0010467', ('26', '41'))	('SHH gene', 'Gene', (22, 30))	('malignancies', 'Disease', 'MESH:D009369', (130, 142))	('aberrant', 'Var', (13, 21))
54834	31788053	However, Dormoy et al observed that cyclopamine, the substance that acts as an SMO protein inhibitor, decreases ccRCC cells proliferation and stimulates their apoptosis in vitro as well as in vivo.	('cyclopamine', 'Var', (36, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('cyclopamine', 'Chemical', 'MESH:C000541', (36, 47))	('apoptosis', 'biological_process', 'GO:0097194', ('159', '168'))	('SMO', 'Gene', (79, 82))	('ccRCC', 'Disease', (112, 117))	('ccRCC', 'Disease', 'MESH:D002292', (112, 117))	('apoptosis', 'biological_process', 'GO:0006915', ('159', '168'))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('decreases', 'NegReg', (102, 111))	('stimulates', 'PosReg', (142, 152))	('apoptosis', 'CPA', (159, 168))	('SMO', 'Gene', '6608', (79, 82))
54856	29215599	Systematic Analysis of Transcriptomic Profile of Renal Cell Carcinoma under Long-Term Hypoxia Using Next-Generation Sequencing and Bioinformatics Patients with clear cell renal cell carcinoma (ccRCC) are often diagnosed with both von Hippel-Lindau (VHL) mutations and the constitutive activation of hypoxia-inducible factor-dependent signaling.	('Patients', 'Species', '9606', (146, 154))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (49, 69))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (160, 191))	('von Hippel-Lindau', 'Gene', '7428', (230, 247))	('RCC', 'Phenotype', 'HP:0005584', (195, 198))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (171, 191))	('RCC', 'Disease', (195, 198))	('mutations', 'Var', (254, 263))	('ccRCC', 'Phenotype', 'HP:0006770', (193, 198))	('clear cell renal cell carcinoma', 'Disease', (160, 191))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (49, 69))	('signaling', 'biological_process', 'GO:0023052', ('334', '343'))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('Hypoxia', 'Disease', 'MESH:D000860', (86, 93))	('VHL', 'Gene', (249, 252))	('Carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('Hypoxia', 'Disease', (86, 93))	('diagnosed', 'Reg', (210, 219))	('hypoxia', 'Disease', (299, 306))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (160, 191))	('von Hippel-Lindau', 'Gene', (230, 247))	('VHL', 'Gene', '7428', (249, 252))	('Renal Cell Carcinoma', 'Disease', (49, 69))	('hypoxia', 'Disease', 'MESH:D000860', (299, 306))
54863	29215599	We also found that long-term hypoxia in 786-O resulted in decreased expressions of hsa-mir-100 and hsa-mir-378 and this effect was also observed in samples of metastatic ccRCC compared to samples of non-metastatic ccRCC.	('expressions', 'MPA', (68, 79))	('hsa-mir-378', 'Gene', (99, 110))	('hypoxia', 'Disease', (29, 36))	('hypoxia', 'Disease', 'MESH:D000860', (29, 36))	('hsa-mir-100', 'Gene', '406892', (83, 94))	('786-O', 'Var', (40, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (170, 175))	('hsa-mir-100', 'Gene', (83, 94))	('decreased', 'NegReg', (58, 67))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('hsa-mir-378', 'Gene', '494327', (99, 110))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('RCC', 'Disease', (216, 219))	('RCC', 'Phenotype', 'HP:0005584', (216, 219))	('RCC', 'Disease', (172, 175))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))	('ccRCC', 'Phenotype', 'HP:0006770', (214, 219))
54873	29215599	The risk factors for RCC have been reported to be associated with carcinogens, chronic kidney inflammation and genetic alterations, however further studies are needed to elucidate the etiology.	('chronic kidney', 'Phenotype', 'HP:0012622', (79, 93))	('RCC', 'Disease', (21, 24))	('genetic alterations', 'Var', (111, 130))	('chronic kidney inflammation', 'Disease', (79, 106))	('chronic kidney inflammation', 'Disease', 'MESH:D007249', (79, 106))	('inflammation', 'biological_process', 'GO:0006954', ('94', '106'))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('associated', 'Reg', (50, 60))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('kidney inflammation', 'Phenotype', 'HP:0000123', (87, 106))
54880	29215599	VHL mutations in ccRCC have been found in sporadic (46-82%) and inherited cases.	('found', 'Reg', (33, 38))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('ccRCC', 'Phenotype', 'HP:0006770', (17, 22))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('VHL', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('VHL', 'Gene', '7428', (0, 3))
54908	29215599	GSE66272 provides 27 clinical samples of ccRCC with grade 1 (n = 1), grade 2 (n = 16), grade 3 (n = 8) and grade 4 (n = 2).	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('GSE66272', 'Var', (0, 8))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('clinical samples', 'Species', '191496', (21, 37))
54909	29215599	GSE73731 provides 256 clinical samples of ccRCC with grade 1 (n = 22), grade 2 (n = 90), grade 3 (n = 95) and grade 4 (n = 49).	('clinical samples', 'Species', '191496', (22, 38))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (42, 47))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('GSE73731', 'Var', (0, 8))
54946	29215599	We therefore hypothesized that short-term hypoxia-specific genes may be rapidly regulated to adapt to stress in response to sudden exposure to hypoxia and that the genes associated with long-term hypoxia may be mostly regulated by the accumulation of reactive oxygen species (ROS) or genetic instability.	('regulated', 'Reg', (218, 227))	('hypoxia', 'Disease', 'MESH:D000860', (143, 150))	('genetic instability', 'Var', (284, 303))	('hypoxia', 'Disease', (143, 150))	('hypoxia', 'Disease', (196, 203))	('hypoxia', 'Disease', 'MESH:D000860', (196, 203))	('ROS', 'Chemical', 'MESH:D017382', (276, 279))	('hypoxia', 'Disease', (42, 49))	('hypoxia', 'Disease', 'MESH:D000860', (42, 49))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (251, 274))
54959	29215599	In addition, depletion of IL18R1, an IL18 receptor, has been shown to enhance tumor growth due to inhibitory recruitment of tumor-infiltrating lymphocytes.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('enhance', 'PosReg', (70, 77))	('IL18', 'Gene', (37, 41))	('inhibitory recruitment', 'MPA', (98, 120))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (124, 129))	('depletion', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('IL18R', 'molecular_function', 'GO:0042008', ('26', '31'))	('IL18', 'Gene', (26, 30))	('IL18', 'Gene', '3606', (37, 41))	('IL18', 'molecular_function', 'GO:0045515', ('37', '41'))	('tumor', 'Disease', (78, 83))	('IL18R1', 'Gene', '8809', (26, 32))	('IL18', 'Gene', '3606', (26, 30))	('IL18R1', 'Gene', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
54960	29215599	Silencing of MAPK13 has also been shown to promote cell growth in triple-negative breast cancer.	('breast cancer', 'Disease', (82, 95))	('cell growth', 'CPA', (51, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('cell growth', 'biological_process', 'GO:0016049', ('51', '62'))	('promote', 'PosReg', (43, 50))	('MAPK', 'molecular_function', 'GO:0004707', ('13', '17'))	('MAPK13', 'Gene', '5603', (13, 19))	('MAPK13', 'Gene', (13, 19))	('Silencing', 'Var', (0, 9))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
54961	29215599	The expression of VCAM1 on the cell surface has been shown to increase the survival of tumor cells by decreasing the number of infiltrating lymphocytes.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('VCAM1', 'Gene', (18, 23))	('cell surface', 'cellular_component', 'GO:0009986', ('31', '43'))	('tumor', 'Disease', (87, 92))	('decreasing', 'NegReg', (102, 112))	('VCAM1', 'Gene', '7412', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('expression', 'Var', (4, 14))	('number', 'CPA', (117, 123))	('increase', 'PosReg', (62, 70))
54970	29215599	With regards to the clinical analysis of ccRCC samples from microarrays of GSE66272 and GSE73731, the upregulation of L1CAM and FBN1 and downregulation of AUTS2, MAPT, AGT and USH1C were observed along with an increase in tumor grade.	('USH1C', 'Gene', (176, 181))	('GSE73731', 'Var', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('MAPT', 'Gene', '4137', (162, 166))	('FBN1', 'Gene', '2200', (128, 132))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('RCC', 'Disease', (43, 46))	('L1CAM', 'Gene', '3897', (118, 123))	('upregulation', 'PosReg', (102, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('increase', 'PosReg', (210, 218))	('AUTS2', 'Gene', (155, 160))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('tumor', 'Disease', (222, 227))	('USH1C', 'Gene', '10083', (176, 181))	('AGT', 'Gene', '183', (168, 171))	('clinical', 'Species', '191496', (20, 28))	('FBN1', 'Gene', (128, 132))	('AUTS2', 'Gene', '26053', (155, 160))	('MAPT', 'Gene', (162, 166))	('L1CAM', 'Gene', (118, 123))	('GSE66272', 'Var', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('downregulation', 'NegReg', (137, 151))	('AGT', 'Gene', (168, 171))
54975	29215599	In endometrial cancer, the expression of L1CAM has been shown to be a predictor of poor survival and this has been shown to be associated with an advanced stage.	('associated', 'Reg', (127, 137))	('endometrial cancer', 'Phenotype', 'HP:0012114', (3, 21))	('L1CAM', 'Gene', '3897', (41, 46))	('endometrial cancer', 'Disease', 'MESH:D016889', (3, 21))	('poor survival', 'CPA', (83, 96))	('expression', 'Var', (27, 37))	('endometrial cancer', 'Disease', (3, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('L1CAM', 'Gene', (41, 46))
54977	29215599	In addition, the identification of hypermethylated FBN1 in stool samples has been used to detect colorectal cancer.	('detect', 'Reg', (90, 96))	('FBN1', 'Gene', '2200', (51, 55))	('colorectal cancer', 'Disease', 'MESH:D015179', (97, 114))	('colorectal cancer', 'Phenotype', 'HP:0003003', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('FBN1', 'Gene', (51, 55))	('colorectal cancer', 'Disease', (97, 114))	('hypermethylated', 'Var', (35, 50))
54992	29215599	GSE37989 has also been associated with the significant downregulation of hsa-mir-100 in metastatic ccRCC.	('GSE37989', 'Var', (0, 8))	('hsa-mir-100', 'Gene', '406892', (73, 84))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('hsa-mir-100', 'Gene', (73, 84))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('RCC', 'Disease', (101, 104))	('downregulation', 'NegReg', (55, 69))
55061	31867475	Type 2 PRCC tends to have mutations in CDKN2A, SETD2, BAP1, PBRM1, TERT, NF2, FH, and NRF2-ARE pathway genes.	('TERT', 'Gene', (67, 71))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('Type 2 PRCC', 'Disease', (0, 11))	('CDKN2A', 'Gene', (39, 45))	('NRF2', 'Gene', '4780', (86, 90))	('SETD2', 'Gene', '29072', (47, 52))	('TERT', 'Gene', '7015', (67, 71))	('PBRM1', 'Gene', (60, 65))	('SETD2', 'Gene', (47, 52))	('NF2', 'Gene', (73, 76))	('PBRM1', 'Gene', '55193', (60, 65))	('CDKN2A', 'Gene', '1029', (39, 45))	('NRF2', 'Gene', (86, 90))	('BAP1', 'Gene', '8314', (54, 58))	('mutations', 'Var', (26, 35))	('PRCC', 'Phenotype', 'HP:0006766', (7, 11))	('NF2', 'Gene', '4771', (73, 76))	('BAP1', 'Gene', (54, 58))
55063	31867475	MET mutations are also found in other malignancies, such as hepatocellular carcinomas (HCC), lung cancer, breast cancer, colorectal cancer (CRC), head and neck squamous cell cancers (HNSCC), gastric carcinomas (GC), and cancers of unknown primary origin.	('CRC', 'Disease', (140, 143))	('colorectal cancer', 'Disease', (121, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('HCC', 'Phenotype', 'HP:0001402', (87, 90))	('MET mutations', 'Var', (0, 13))	('neck squamous cell cancers', 'Disease', 'MESH:D002294', (155, 181))	('CRC', 'Phenotype', 'HP:0003003', (140, 143))	('gastric carcinomas', 'Disease', 'MESH:D013274', (191, 209))	('gastric carcinomas', 'Disease', (191, 209))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancers', 'Disease', (174, 181))	('lung cancer', 'Disease', (93, 104))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('neck squamous cell cancers', 'Disease', (155, 181))	('CRC', 'Disease', 'MESH:D015179', (140, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('found', 'Reg', (23, 28))	('malignancies', 'Disease', 'MESH:D009369', (38, 50))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('malignancies', 'Disease', (38, 50))	('mutations', 'Var', (4, 13))	('cancers', 'Disease', (220, 227))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (60, 85))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))	('breast cancer', 'Disease', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('neck', 'cellular_component', 'GO:0044326', ('155', '159'))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (160, 181))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (60, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))	('hepatocellular carcinomas', 'Disease', (60, 85))
55067	31867475	This interaction is further evidenced in non-small cell lung carcinomas (NSCLC) with acquired resistance to EGFR inhibitors due to amplifications in MET.	('EGFR', 'molecular_function', 'GO:0005006', ('108', '112'))	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (41, 71))	('MET', 'Var', (149, 152))	('SCLC', 'Disease', 'MESH:D018288', (74, 78))	('SCLC', 'Disease', (74, 78))	('lung carcinomas', 'Disease', (56, 71))	('NSCLC', 'Disease', (73, 78))	('amplifications', 'Var', (131, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('SCLC', 'Phenotype', 'HP:0030357', (74, 78))	('lung carcinomas', 'Disease', 'MESH:D008175', (56, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (45, 71))
55075	31867475	For ccRCC, nivolumab improves OS with patients surviving 25 months with nivolumab versus 19.6 months with everolimus.	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('nivolumab', 'Var', (72, 81))	('ccRCC', 'Disease', (4, 9))	('nivolumab', 'Chemical', 'MESH:D000077594', (72, 81))	('nivolumab', 'Chemical', 'MESH:D000077594', (11, 20))
55082	31867475	The phase 3 trial, METEOR, found significant improvement in OS for advanced ccRCC patients who received cabozantinib compared to everolimus (OS 21.4 months vs 17.1 months).	('cabozantinib', 'Chemical', 'MESH:C558660', (104, 116))	('cabozantinib', 'Var', (104, 116))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('improvement', 'PosReg', (45, 56))
55096	31867475	LY3164530 is an anti-EGFR/MET bispecific antibody created by fusing a cetuximab variable fragment to an emibetuzumab heavy chain.	('LY3164530', 'Var', (0, 9))	('cetuximab', 'Chemical', 'MESH:D000068818', (70, 79))	('cetuximab', 'Gene', (70, 79))	('LY3164530', 'Chemical', '-', (0, 9))	('antibody', 'cellular_component', 'GO:0042571', ('41', '49'))	('emibetuzumab', 'Chemical', 'MESH:C000599789', (104, 116))	('antibody', 'cellular_component', 'GO:0019814', ('41', '49'))	('antibody', 'cellular_component', 'GO:0019815', ('41', '49'))	('EGFR', 'molecular_function', 'GO:0005006', ('21', '25'))	('antibody', 'molecular_function', 'GO:0003823', ('41', '49'))
55112	30184495	Here we show that disrupting triglyceride synthesis compromises the growth of both ccRCC tumors and ccRCC cells exposed to tumor-like conditions.	('triglyceride synthesis', 'MPA', (29, 51))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', (123, 128))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('triglyceride', 'Chemical', 'MESH:D014280', (29, 41))	('growth', 'MPA', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('disrupting', 'Var', (18, 28))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('ccRCC', 'Disease', (83, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('triglyceride synthesis', 'biological_process', 'GO:0019432', ('29', '51'))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('compromises', 'NegReg', (52, 63))
55115	30184495	Disrupting this process derails lipid homeostasis, causing overproduction of toxic saturated ceramides and acyl-carnitines as well as activation of the NF-kappaB transcription factor.	('derails', 'Reg', (24, 31))	('acyl-carnitines', 'Chemical', 'MESH:C116917', (107, 122))	('saturated', 'Chemical', '-', (83, 92))	('overproduction of', 'MPA', (59, 76))	('activation', 'PosReg', (134, 144))	('NF-kappaB', 'Gene', '4790', (152, 161))	('Disrupting', 'Var', (0, 10))	('transcription', 'biological_process', 'GO:0006351', ('162', '175'))	('lipid homeostasis', 'MPA', (32, 49))	('lipid homeostasis', 'biological_process', 'GO:0055088', ('32', '49'))	('transcription factor', 'molecular_function', 'GO:0000981', ('162', '182'))	('ceramides', 'Chemical', 'MESH:D002518', (93, 102))	('lipid', 'Chemical', 'MESH:D008055', (32, 37))	('NF-kappaB', 'Gene', (152, 161))	('acyl-carnitines', 'MPA', (107, 122))
55120	30184495	Inhibiting triglyceride synthesis compromises solid tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('triglyceride', 'Chemical', 'MESH:D014280', (11, 23))	('Inhibiting', 'Var', (0, 10))	('triglyceride synthesis', 'biological_process', 'GO:0019432', ('11', '33'))	('tumor', 'Disease', (52, 57))	('compromises', 'NegReg', (34, 45))	('triglyceride synthesis', 'MPA', (11, 33))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
55131	30184495	We have previously shown that induction of HIF2alpha specifically promotes lipid accumulation through upregulation of PLIN2, the gene encoding the LD coat protein perilipin-2.	('induction', 'Var', (30, 39))	('lipid', 'Chemical', 'MESH:D008055', (75, 80))	('L', 'Chemical', '-', (119, 120))	('perilipin-2', 'Gene', '123', (163, 174))	('L', 'Chemical', '-', (147, 148))	('perilipin-2', 'Gene', (163, 174))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('HIF2alpha', 'Gene', (43, 52))	('promotes', 'PosReg', (66, 74))	('upregulation', 'PosReg', (102, 114))	('lipid accumulation', 'MPA', (75, 93))	('PLIN2', 'Gene', '123', (118, 123))	('HIF2alpha', 'Gene', '2034', (43, 52))	('PLIN2', 'Gene', (118, 123))
55133	30184495	In a separate study, HIF-dependent repression of FA beta-oxidation has also been demonstrated to contribute to LD accumulation.	('contribute', 'Reg', (97, 107))	('FA beta', 'Gene', (49, 56))	('L', 'Chemical', '-', (111, 112))	('LD accumulation', 'CPA', (111, 126))	('FA beta', 'Gene', '2187', (49, 56))	('repression', 'Var', (35, 45))
55149	30184495	We investigated how direct disruption of TG synthesis by loss of DGAT enzymes affects lipid homeostasis.	('TG', 'Chemical', 'MESH:D014280', (41, 43))	('affects', 'Reg', (78, 85))	('lipid homeostasis', 'MPA', (86, 103))	('lipid', 'Chemical', 'MESH:D008055', (86, 91))	('DGAT enzymes', 'Gene', (65, 77))	('loss', 'Var', (57, 61))	('lipid homeostasis', 'biological_process', 'GO:0055088', ('86', '103'))	('synthesis', 'biological_process', 'GO:0009058', ('44', '53'))
55152	30184495	Although a combination of CRISPR/Cas9-mediated DGAT2 deletion and DGAT1 pharmacological inhibition fully abrogated this, loss of neither DGAT individually was sufficient (Figure S1A).	('DGAT1', 'Gene', '8694', (66, 71))	('DGAT2', 'Gene', (47, 52))	('deletion', 'Var', (53, 61))	('abrogated', 'NegReg', (105, 114))	('DGAT2', 'Gene', '84649', (47, 52))	('DGAT1', 'Gene', (66, 71))	('Cas', 'cellular_component', 'GO:0005650', ('33', '36'))
55153	30184495	This approach provides the opportunity to precisely control the timing of DGAT inhibition by adding the DGAT1 inhibitor T863 (DGAT1i) to cells with DGAT2 deletion.	('DGAT1', 'Gene', '8694', (104, 109))	('T863', 'Chemical', '-', (120, 124))	('DGAT1', 'Gene', (126, 131))	('DGAT2', 'Gene', '84649', (148, 153))	('deletion', 'Var', (154, 162))	('DGAT2', 'Gene', (148, 153))	('DGAT1', 'Gene', '8694', (126, 131))	('DGAT1', 'Gene', (104, 109))
55162	30184495	Thus, DGAT silencing disrupts TG FA composition and causes both increased apoptosis and reduced proliferation of ccRCC tumor cells in vivo.	('silencing', 'Var', (11, 20))	('apoptosis', 'CPA', (74, 83))	('tumor', 'Disease', (119, 124))	('proliferation', 'CPA', (96, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (113, 118))	('disrupts', 'NegReg', (21, 29))	('ccRCC', 'Disease', (113, 118))	('composition', 'MPA', (36, 47))	('TG', 'Chemical', 'MESH:D014280', (30, 32))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('DGAT', 'Gene', (6, 10))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('increased', 'PosReg', (64, 73))	('reduced', 'NegReg', (88, 95))	('TG FA', 'Protein', (30, 35))
55165	30184495	Of note, combined serum and O2 limitation led to deteriorated cell viability upon DGAT knockdown (Figure 2A).	('O2 limitation', 'Phenotype', 'HP:0012418', (28, 41))	('O2', 'Chemical', 'MESH:D010100', (28, 30))	('cell viability', 'CPA', (62, 76))	('deteriorated', 'NegReg', (49, 61))	('knockdown', 'Var', (87, 96))
55167	30184495	Cells were exposed to the SCD inhibitor CAY10566, which phenocopied the effect of O2 deprivation (Figure 2B).	('SCD', 'Gene', '6319', (26, 29))	('CAY10566', 'Var', (40, 48))	('CAY10566', 'Chemical', '-', (40, 48))	('O2', 'Chemical', 'MESH:D010100', (82, 84))	('SCD', 'Gene', (26, 29))
55174	30184495	Moreover, TGs may also harbor polyunsaturated FAs to protect them against peroxidation.	('TGs', 'Chemical', 'MESH:D014280', (10, 13))	('TGs', 'biological_process', 'GO:0006342', ('10', '13'))	('polyunsaturated', 'Var', (30, 45))	('unsaturated FAs', 'Chemical', 'MESH:D005231', (34, 49))	('peroxidation', 'MPA', (74, 86))
55176	30184495	Strikingly, TG composition was affected much more profoundly than other lipid classes (Figures 2E and S2C), including a loss of TGs harboring unsaturated FAs and a shift toward increased TG saturation (Figure S2D).	('TGs', 'Var', (128, 131))	('TGs', 'biological_process', 'GO:0006342', ('128', '131'))	('unsaturated FAs', 'Chemical', 'MESH:D005231', (142, 157))	('affected', 'Reg', (31, 39))	('TGs', 'Chemical', 'MESH:D014280', (128, 131))	('increased', 'PosReg', (177, 186))	('TG', 'Chemical', 'MESH:D014280', (128, 130))	('TG', 'Chemical', 'MESH:D014280', (12, 14))	('lipid', 'Chemical', 'MESH:D008055', (72, 77))	('TG composition', 'MPA', (12, 26))	('TG', 'Chemical', 'MESH:D014280', (187, 189))	('loss', 'NegReg', (120, 124))	('TG saturation', 'MPA', (187, 200))
55182	30184495	As demonstrated with in vivo tumor growth (Figures 1E and 1F), DGAT silencing in vitro also caused a further decrease in TG abundance (Figure 2G) and selective depletion of unsaturated TGs (Figure 2H).	('decrease', 'NegReg', (109, 117))	('TGs', 'biological_process', 'GO:0006342', ('185', '188'))	('depletion', 'MPA', (160, 169))	('TG abundance', 'MPA', (121, 133))	('TG', 'Chemical', 'MESH:D014280', (185, 187))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('TGs', 'Chemical', 'MESH:D014280', (185, 188))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('TG', 'Chemical', 'MESH:D014280', (121, 123))	('tumor', 'Disease', (29, 34))	('silencing', 'Var', (68, 77))	('DGAT', 'Gene', (63, 67))	('unsaturated', 'Chemical', '-', (173, 184))
55183	30184495	Given that both hypoxia and DGAT depletion cause increased saturation of the TG pool under low-serum conditions, we asked whether combination of the two leads to a cumulative effect; i.e., an even more saturated TG pool.	('depletion', 'Var', (33, 42))	('TG', 'Chemical', 'MESH:D014280', (212, 214))	('hypoxia', 'Disease', 'MESH:D000860', (16, 23))	('increased', 'PosReg', (49, 58))	('TG pool', 'MPA', (212, 219))	('saturated', 'Chemical', '-', (202, 211))	('saturation', 'MPA', (59, 69))	('TG pool', 'MPA', (77, 84))	('TG', 'Chemical', 'MESH:D014280', (77, 79))	('hypoxia', 'Disease', (16, 23))
55186	30184495	Additional DGAT knockdown further lowered TG levels (Figure 2G), resulting in an even more saturated TG pool (Figures 2I and 2J).	('TG', 'Chemical', 'MESH:D014280', (42, 44))	('knockdown', 'Var', (16, 25))	('lowered', 'NegReg', (34, 41))	('saturated TG pool', 'MPA', (91, 108))	('TG', 'Chemical', 'MESH:D014280', (101, 103))	('lowered TG levels', 'Phenotype', 'HP:0012153', (34, 51))	('more', 'PosReg', (86, 90))	('DGAT', 'Gene', (11, 15))	('saturated', 'Chemical', '-', (91, 100))	('TG levels', 'MPA', (42, 51))
55190	30184495	Because monounsaturated oleate (C18:1) is the single most abundant FA in TG pools (Figure S3A), its mobilization during periods of unsaturated lipid deprivation should ameliorate stress by preventing the synthesis of fully saturated, potentially toxic lipids.	('synthesis', 'biological_process', 'GO:0009058', ('204', '213'))	('saturated', 'Chemical', '-', (223, 232))	('saturated', 'Chemical', '-', (14, 23))	('monounsaturated oleate', 'Chemical', '-', (8, 30))	('preventing', 'NegReg', (189, 199))	('TG', 'Chemical', 'MESH:D014280', (73, 75))	('C18:1', 'Var', (32, 37))	('lipids', 'Chemical', 'MESH:D008055', (252, 258))	('unsaturated lipid', 'Chemical', '-', (131, 148))	('synthesis of fully saturated', 'MPA', (204, 232))	('saturated', 'Chemical', '-', (133, 142))
55211	30184495	By reducing the TG pool, DGAT inhibition prevents the subsequent flow of oleate from TGs to other lipid classes during periods of unsaturated lipid deprivation Adipose triglyceride lipase (ATGL) and monoacylglycerol lipase (MAGL) have been shown previously to play supportive roles in cancer progression, suggesting that mobilization of TG stores is critical for tumor cell metabolism.	('TGs', 'biological_process', 'GO:0006342', ('85', '88'))	('MAGL', 'Gene', (224, 228))	('reducing', 'NegReg', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('DGAT', 'Gene', (25, 29))	('lipid', 'Chemical', 'MESH:D008055', (98, 103))	('MAGL', 'Gene', '11343', (224, 228))	('Adipose triglyceride lipase', 'Gene', '57104', (160, 187))	('metabolism', 'biological_process', 'GO:0008152', ('374', '384'))	('TG', 'Chemical', 'MESH:D014280', (190, 192))	('monoacylglycerol lipase', 'Gene', (199, 222))	('ATGL', 'Gene', (189, 193))	('cancer', 'Disease', (285, 291))	('TG', 'Chemical', 'MESH:D014280', (16, 18))	('Adipose triglyceride lipase', 'Gene', (160, 187))	('TGs', 'Chemical', 'MESH:D014280', (85, 88))	('monoacylglycerol lipase', 'Gene', '11343', (199, 222))	('oleate', 'Chemical', 'MESH:D019301', (73, 79))	('unsaturated lipid', 'Chemical', '-', (130, 147))	('lipid', 'Chemical', 'MESH:D008055', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('prevents', 'NegReg', (41, 49))	('flow of oleate', 'MPA', (65, 79))	('TG pool', 'MPA', (16, 23))	('tumor', 'Disease', (363, 368))	('ATGL', 'Gene', '57104', (189, 193))	('TG', 'Chemical', 'MESH:D014280', (85, 87))	('inhibition', 'Var', (30, 40))	('TG', 'Chemical', 'MESH:D014280', (337, 339))	('tumor', 'Disease', 'MESH:D009369', (363, 368))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
55224	30184495	DGAT depletion resulted in a large increase in ceramide levels in A498 cells treated with SCD inhibitor under serum-deprived conditions (Figure 4A) and A498 xenograft tumors (Figure 4B), along with acyl-ceramides (Figure 4C).	('increase', 'PosReg', (35, 43))	('depletion', 'Var', (5, 14))	('ceramide', 'Chemical', 'MESH:D002518', (203, 211))	('A498 xenograft tumors', 'Disease', (152, 173))	('A498', 'CellLine', 'CVCL:1056', (66, 70))	('SCD', 'Gene', (90, 93))	('A498 xenograft tumors', 'Disease', 'MESH:D009369', (152, 173))	('ceramide levels', 'MPA', (47, 62))	('SCD', 'Gene', '6319', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('A498', 'CellLine', 'CVCL:1056', (152, 156))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('acyl-ceramides', 'Chemical', '-', (198, 212))	('ceramide', 'Chemical', 'MESH:D002518', (47, 55))
55225	30184495	Acyl-carnitines have recently been shown to be elevated upon DGAT inhibition, contributing to mitochondrial dysfunction.	('Acyl-carnitines', 'MPA', (0, 15))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (94, 119))	('elevated', 'PosReg', (47, 55))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (94, 119))	('Acyl-carnitines', 'Chemical', 'MESH:C116917', (0, 15))	('inhibition', 'Var', (66, 76))	('DGAT', 'Protein', (61, 65))	('mitochondrial dysfunction', 'Disease', (94, 119))	('contributing', 'Reg', (78, 90))
55226	30184495	In line with this, we observed elevated acyl-carnitine upon DGAT knockdown in the context of in vitro hypoxia (Figure 4D), in vitro SCD inhibition (Figure 4E), and in vivo xenograft tumors (Figure 4F).	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('xenograft tumors', 'Disease', 'MESH:D009369', (172, 188))	('hypoxia', 'Disease', 'MESH:D000860', (102, 109))	('acyl-carnitine', 'MPA', (40, 54))	('DGAT', 'Gene', (60, 64))	('acyl-carnitine', 'Chemical', 'MESH:C116917', (40, 54))	('hypoxia', 'Disease', (102, 109))	('SCD', 'Gene', (132, 135))	('elevated', 'PosReg', (31, 39))	('xenograft tumors', 'Disease', (172, 188))	('SCD', 'Gene', '6319', (132, 135))	('elevated acyl-carnitine', 'Phenotype', 'HP:0045045', (31, 54))	('knockdown', 'Var', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
55227	30184495	These changes indicate that disrupted TG synthesis widely affects lipid homeostasis and accumulation of toxic lipid species.	('TG', 'Chemical', 'MESH:D014280', (38, 40))	('lipid homeostasis', 'MPA', (66, 83))	('TG synthesis', 'Gene', (38, 50))	('affects', 'Reg', (58, 65))	('lipid', 'Chemical', 'MESH:D008055', (66, 71))	('lipid homeostasis', 'biological_process', 'GO:0055088', ('66', '83'))	('synthesis', 'biological_process', 'GO:0009058', ('41', '50'))	('disrupted', 'Var', (28, 37))	('lipid', 'Chemical', 'MESH:D008055', (110, 115))	('accumulation of toxic lipid species', 'MPA', (88, 123))
55232	30184495	In vivo, DGAT depletion led to a significant increase in NF-kappaB target gene expression (Figure 4G).	('NF-kappaB', 'Gene', (57, 66))	('increase', 'PosReg', (45, 53))	('depletion', 'Var', (14, 23))	('NF-kappaB', 'Gene', '4790', (57, 66))	('gene expression', 'biological_process', 'GO:0010467', ('74', '89'))
55268	30184495	Pre-designed Taqman primers were obtained from Life Technologies for the following genes: TBP (HS01060665_G1), ACTB (HS01060665_G1), DGAT1 (HS01017541_M1), and DGAT2 (HS01045913_M1).	('ACTB', 'Gene', (111, 115))	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('HS01045913_M1', 'Var', (167, 180))	('DGAT2', 'Gene', (160, 165))	('ACTB', 'Gene', '60', (111, 115))	('DGAT1', 'Gene', (133, 138))	('TBP', 'Gene', (90, 93))	('TBP', 'Gene', '6908', (90, 93))	('DGAT1', 'Gene', '8694', (133, 138))	('HS01060665_G1', 'Var', (117, 130))	('HS01017541_M1', 'Var', (140, 153))	('DGAT2', 'Gene', '84649', (160, 165))	('L', 'Chemical', '-', (47, 48))	('HS01060665_G1', 'Var', (95, 108))
55269	30184495	DGAT1 and DGAT2 shRNA (specified as DGAT shRNA unless stated otherwise) was achieved by expressing Dox-inducible shDGAT2_5 (TRCN0000005195) using the Tet-pLKO-puro plasmid and shDGAT1_1 (TRCN0000036151) using the Tet-pLKO-neo.	('DGAT2', 'Gene', '84649', (10, 15))	('Tet', 'Chemical', 'MESH:C010349', (213, 216))	('DGAT2', 'Gene', '84649', (115, 120))	('DGAT1', 'Gene', (178, 183))	('DGAT1', 'Gene', (0, 5))	('TRCN0000005195', 'Var', (124, 138))	('DGAT2', 'Gene', (10, 15))	('L', 'Chemical', '-', (155, 156))	('DGAT1', 'Gene', '8694', (0, 5))	('Tet', 'Chemical', 'MESH:C010349', (150, 153))	('DGAT1', 'Gene', '8694', (178, 183))	('DGAT2', 'Gene', (115, 120))	('L', 'Chemical', '-', (218, 219))
55273	30184495	PCR of the DGAT2 locus was performed using DA182 (TCCTCTTGTCCCAGGAATCTGC) forward and DA184 CACTCAGGATGAGGCCCTTCAG reverse primers.	('DGAT2', 'Gene', '84649', (11, 16))	('DA184', 'Var', (86, 91))	('TG', 'Chemical', 'MESH:D014280', (56, 58))	('TG', 'Chemical', 'MESH:D014280', (69, 71))	('TG', 'Chemical', 'MESH:D014280', (101, 103))	('DGAT2', 'Gene', (11, 16))	('PC', 'Chemical', 'MESH:D010713', (0, 2))
55277	30184495	Clones containing mutations in both alleles were tested phenotypically by Bodipy neutral lipid staining, and LC/MS confirmed reduced TG production (data not shown), as expected.	('TG', 'Chemical', 'MESH:D014280', (133, 135))	('lipid', 'Chemical', 'MESH:D008055', (89, 94))	('reduced', 'NegReg', (125, 132))	('reduced TG production', 'Phenotype', 'HP:0012153', (125, 146))	('L', 'Chemical', '-', (109, 110))	('TG production', 'MPA', (133, 146))	('mutations', 'Var', (18, 27))
55280	30184495	Rescue of DGAT2 loss was performed by cloning DGAT2 cDNA from the pcDNA3.1 vector (GeneCopoeia) into the pCDH lentiviral expression plasmid pCDH-CMV-MCS-EF1-Neo using the primers DA199 (GTTTCTgctagcATGAAGACCCTCATAGCCGC), DA200 (GTTTCTgcggccgcTCAATGGTGATGGTGATGATG) as well as DA199 and DA201 (gtttctGCGGCCGCtcaGTTCACCTCCAGGACCTCAG) for expression with and without V5 and Histags.	('DGAT2', 'Gene', '84649', (10, 15))	('TG', 'Chemical', 'MESH:D014280', (249, 251))	('TG', 'Chemical', 'MESH:D014280', (199, 201))	('TG', 'Chemical', 'MESH:D014280', (255, 257))	('TG', 'Chemical', 'MESH:D014280', (261, 263))	('DA201', 'Var', (286, 291))	('DGAT2', 'Gene', '84649', (46, 51))	('TG', 'Chemical', 'MESH:D014280', (258, 260))	('DGAT2', 'Gene', (10, 15))	('DA199', 'Var', (276, 281))	('DGAT2', 'Gene', (46, 51))	('TG', 'Chemical', 'MESH:D014280', (246, 248))	('TG', 'Chemical', 'MESH:D014280', (252, 254))	('MCS', 'cellular_component', 'GO:0044232', ('149', '152'))
55313	30184495	Some minor odd-labeled isotopes (M+19, M+37, M+55) were observed; these are most likely caused by imperfect corrections for 13C-natural abundance by the algorithm.	('M+55', 'Var', (45, 49))	('M+19', 'Var', (33, 37))	('13C', 'Chemical', '-', (124, 127))	('M+37', 'Var', (39, 43))	('odd-labeled', 'MPA', (11, 22))	('13C-natural abundance', 'MPA', (124, 145))
55316	30184495	This is arguably best demonstrated by the MS2 pattern of TG(48:0) M+18 (one labeled FA, Figure S5B).	('S5B', 'Gene', (95, 98))	('MS2', 'Gene', (42, 45))	('TG(48:0) M+18', 'Var', (57, 70))	('MS2', 'Gene', '100271694', (42, 45))	('TG', 'Chemical', 'MESH:D014280', (57, 59))	('S5B', 'Gene', '5711', (95, 98))
55320	30184495	We did find that Labeled stearate is desaturated and elongated leading to FAs such as [U13C]-18:1 and [13C18]-20:0 as well as longer chain FAs, as evidenced by the direct observation of their acylium ions in MS2 (FAs are observed as their acylium ions in positive mode MS2, Figure S5C).	('U13C', 'Chemical', '-', (87, 91))	('acylium', 'Chemical', '-', (192, 199))	('acylium', 'Chemical', '-', (239, 246))	('FAs', 'Chemical', 'MESH:D005227', (213, 216))	('MS2', 'Gene', '100271694', (208, 211))	('MS2', 'Gene', (269, 272))	('FAs', 'Chemical', 'MESH:D005227', (74, 77))	('L', 'Chemical', '-', (17, 18))	('[13C18]-20:0', 'Var', (102, 114))	('FAs', 'Chemical', 'MESH:D005227', (139, 142))	('MS2', 'Gene', (208, 211))	('13C18', 'Chemical', '-', (103, 108))	('MS2', 'Gene', '100271694', (269, 272))	('saturated', 'Chemical', '-', (39, 48))	('stearate', 'Chemical', 'MESH:D013228', (25, 33))	('leading to', 'Reg', (63, 73))
55332	30184495	The A498 DGAT shRNA in vivo microarray experiment and the A498 DGAT shRNA in vitro microarray experiment data were deposited at NCBI GEO (https://www.ncbi.nlm.nih.gov/geo/) under accession numbers GEO: GSE117774 and GSE117775 respectively.	('A498', 'CellLine', 'CVCL:1056', (4, 8))	('A498', 'CellLine', 'CVCL:1056', (58, 62))	('GSE117774', 'Var', (202, 211))	('GSE117775', 'Var', (216, 225))
55348	31767020	Eighty percent of ccRCC have inactivating mutations in the Von Hippel Lindau gene which stabilizes hypoxia inducible factors and leads to overexpression of vascular endothelial growth factor receptor and platelet-derived growth factor receptor which promote angiogenesis, tumor growth and metastasis.	('hypoxia', 'Disease', 'MESH:D000860', (99, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (18, 23))	('vascular endothelial growth factor', 'Gene', '7422', (156, 190))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('156', '190'))	('angiogenesis', 'biological_process', 'GO:0001525', ('258', '270'))	('tumor', 'Disease', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('vascular endothelial growth factor', 'Gene', (156, 190))	('overexpression', 'PosReg', (138, 152))	('Von Hippel Lindau', 'Disease', (59, 76))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('204', '234'))	('ccRCC', 'Disease', 'MESH:D002292', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('metastasis', 'CPA', (289, 299))	('promote', 'PosReg', (250, 257))	('hypoxia', 'Disease', (99, 106))	('inactivating mutations', 'Var', (29, 51))	('ccRCC', 'Disease', (18, 23))	('Von Hippel Lindau', 'Disease', 'MESH:D006623', (59, 76))	('angiogenesis', 'CPA', (258, 270))	('leads to', 'Reg', (129, 137))
55410	31767020	By t-test and Chi squared tests, patients with primary resistance were more likely to have a worse ECOG performance status at the start of immunotherapy (p = 0.03), have an earlier stage at diagnosis (p = 0.04), have not undergone nephrectomy (p = 0.04) and not experience an immune-related adverse event (p = 0.02).	('patients', 'Species', '9606', (33, 41))	('ECOG performance status', 'MPA', (99, 122))	('primary resistance', 'Var', (47, 65))
55421	31767020	In all 90 patients in the cohort, we observed significant correlation between PFS and experiencing clinical benefit and BMI status (Additional file 1: Table S1).	('BMI', 'MPA', (120, 123))	('PFS', 'Var', (78, 81))	('patients', 'Species', '9606', (10, 18))
55429	31767020	Angio-Q1 patients showed significantly lower PFI and OS compared to Angio-Q2/3/4 (Fig.	('patients', 'Species', '9606', (9, 17))	('Angio-Q1', 'Var', (0, 8))	('PFI', 'molecular_function', 'GO:0034016', ('45', '48'))	('lower', 'NegReg', (39, 44))
55454	31767020	Our analysis of the TCGA revealed an inverse correlation between angiogenesis and T-cell inflammation signatures in tumors of high T cell-inflamed gene expression, a pattern not observed in non-T cell-inflamed tumors.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('angiogenesis', 'biological_process', 'GO:0001525', ('65', '77'))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('inverse', 'NegReg', (37, 44))	('tumors', 'Disease', (210, 216))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('gene expression', 'biological_process', 'GO:0010467', ('147', '162'))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('high', 'Var', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('T-cell inflammation', 'Disease', 'MESH:D007249', (82, 101))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('angiogenesis', 'MPA', (65, 77))	('inflammation', 'biological_process', 'GO:0006954', ('89', '101'))	('T-cell inflammation', 'Disease', (82, 101))
55458	31767020	Benefit from ICI in the adjuvant and neoadjuvant setting has been observed in multiple cancers including NSCLC, breast cancer and melanoma and multiple phase III clinical trials evaluating ICI in ccRCC in both adjuvant and neoadjuvant settings are ongoing (NCT03024996, NCT03142334, NCT03055013).	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('N', 'Chemical', 'MESH:D009584', (283, 284))	('breast cancer', 'Disease', (112, 125))	('NCT03142334', 'Chemical', 'MESH:C079985', (270, 281))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('N', 'Chemical', 'MESH:D009584', (257, 258))	('ccRCC', 'Disease', 'MESH:D002292', (196, 201))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancers', 'Disease', (87, 94))	('N', 'Chemical', 'MESH:D009584', (105, 106))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('NCT03142334', 'Var', (270, 281))	('ccRCC', 'Disease', (196, 201))	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('NCT03024996', 'Var', (257, 268))	('N', 'Chemical', 'MESH:D009584', (270, 271))	('ccRCC', 'Phenotype', 'HP:0006770', (196, 201))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('melanoma', 'Disease', (130, 138))	('NSCLC', 'Disease', (105, 110))	('NCT03055013', 'Var', (283, 294))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
55586	30031457	A recent study by the authors confirmed segmental inversion enhancement as an independent predictor of oncocytoma.	('men', 'Species', '9606', (67, 70))	('segmental inversion', 'Var', (40, 59))	('men', 'Species', '9606', (43, 46))	('oncocytoma', 'Disease', (103, 113))	('oncocytoma', 'Disease', 'MESH:D018249', (103, 113))
55626	31955490	Synthetic lethal therapy based on targeting the vulnerability of SWI/SNF chromatin remodeling complex-deficient cancers The SWI/SNF chromatin remodeling complex is composed of approximately 15 subunits, and approximately 20% of all cancers carry mutations in the genes encoding these subunits.	('chromatin remodeling', 'biological_process', 'GO:0006338', ('132', '152'))	('cancers', 'Disease', 'MESH:D009369', (232, 239))	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('73', '101'))	('cancers', 'Disease', (232, 239))	('complex-deficient cancers', 'Disease', 'MESH:D009369', (94, 119))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('73', '93'))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('132', '160'))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('mutations', 'Var', (246, 255))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('complex-deficient cancers', 'Disease', (94, 119))
55633	31955490	Inhibition of the synthesis or activity of these oncogenes results in cell death, specifically in cells expressing the activated oncogene; the dependence of cells on an oncogene for survival is defined as "oncogene addiction".4 Only a fraction of cancers have an activated oncogene, whereas many cancers have other genetic aberrations such as loss-of-function (LOF) mutations.	('loss-of-function', 'NegReg', (343, 359))	('cell death', 'biological_process', 'GO:0008219', ('70', '80'))	('activated', 'PosReg', (263, 272))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('oncogene', 'Protein', (273, 281))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('mutations', 'Var', (366, 375))	('cancers', 'Disease', 'MESH:D009369', (247, 254))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('cancers', 'Disease', 'MESH:D009369', (296, 303))	('cancers', 'Disease', (247, 254))	('cancers', 'Phenotype', 'HP:0002664', (296, 303))	('synthesis', 'biological_process', 'GO:0009058', ('18', '27'))	('cancers', 'Disease', (296, 303))
55634	31955490	Certain LOF gene mutations of tumor suppressor genes confer druggable vulnerabilities on cancer cells.	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('cancer', 'Disease', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutations', 'Var', (17, 26))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', (30, 35))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))	('LOF', 'NegReg', (8, 11))
55636	31955490	This strategy is based on the assumption that a cancer patient has a LOF mutation of "gene A" and gene A is synthetic lethal with gene B (Figure 2).	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('patient', 'Species', '9606', (55, 62))	('mutation', 'Var', (73, 81))	('LOF', 'NegReg', (69, 72))
55641	31955490	Recent advances in genome-wide sequencing technologies have contributed to the identification of most gene mutations associated with cancer.	('mutations', 'Var', (107, 116))	('associated', 'Reg', (117, 127))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('genome', 'Disease', (19, 25))	('cancer', 'Disease', (133, 139))	('genome', 'Disease', 'MESH:D042822', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
55642	31955490	Comprehensive genome studies identified mutations in genes involved in chromatin regulation in approximately 50% of cancers.11, 12, 13, 14 Most of the mutations in chromatin regulating genes are LOF mutations such as deleterious missense mutations, frameshift mutations, and chromosomal deletions.	('regulation', 'biological_process', 'GO:0065007', ('81', '91'))	('genome', 'Disease', (14, 20))	('missense mutations', 'Var', (229, 247))	('chromosomal', 'Disease', (275, 286))	('genome', 'Disease', 'MESH:D042822', (14, 20))	('chromatin', 'cellular_component', 'GO:0000785', ('71', '80'))	('frameshift mutations', 'Var', (249, 269))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('chromatin', 'cellular_component', 'GO:0000785', ('164', '173'))	('LOF', 'NegReg', (195, 198))	('mutations', 'Var', (151, 160))	('chromatin regulating genes', 'Gene', (164, 190))
55644	31955490	Specifically, LOF genetic aberrations of SMARCA4, ARID1A, ARID2, PBRM1, and SMARCB1 are common in various cancers such as lung cancer, ovarian clear cell carcinoma, skin cancer, renal clear cell carcinoma, and rhabdoid tumors, respectively.	('renal clear cell carcinoma', 'Disease', (178, 204))	('SMARCA4', 'Gene', (41, 48))	('skin cancer', 'Phenotype', 'HP:0008069', (165, 176))	('PBRM1', 'Gene', (65, 70))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancers', 'Disease', (106, 113))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('ARID1A', 'Gene', (50, 56))	('ARID2', 'Gene', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('genetic aberrations', 'Var', (18, 37))	('SMARCB1', 'Gene', '6598', (76, 83))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('SMARCB1', 'Gene', (76, 83))	('rhabdoid tumors', 'Disease', (210, 225))	('skin cancer', 'Disease', 'MESH:D012878', (165, 176))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (210, 225))	('ARID1A', 'Gene', '8289', (50, 56))	('ovarian clear cell carcinoma', 'Disease', (135, 163))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('SMARCA4', 'Gene', '6597', (41, 48))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('lung cancer', 'Disease', (122, 133))	('skin cancer', 'Disease', (165, 176))	('renal clear cell carcinoma', 'Disease', 'MESH:D002292', (178, 204))	('PBRM1', 'Gene', '55193', (65, 70))	('ARID2', 'Gene', '196528', (58, 63))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D010051', (135, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('LOF', 'NegReg', (14, 17))
55646	31955490	In this review, we introduce a synthetic lethal therapy strategy for the treatment of cancers with genetic aberrations of SWI/SNF chromatin remodeling genes (Figures 4 and 5).	('SWI/SNF', 'Gene', (122, 129))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('130', '150'))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('chromatin', 'cellular_component', 'GO:0000785', ('130', '139'))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('genetic aberrations', 'Var', (99, 118))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('cancers', 'Disease', (86, 93))
55659	31955490	Loss of both ARID1A and ARID1B causes collapse of the BAF complex and leads to loss of functional activity of the BAF complex.24 Therefore, inhibition of ARID1B function is a promising strategy for ARID1A-deficient cancers.	('ARID1A-deficient cancers', 'Disease', 'MESH:D009369', (198, 222))	('ARID1B', 'Gene', '57492', (154, 160))	('ARID1B', 'Gene', '57492', (24, 30))	('ARID1A', 'Gene', '8289', (13, 19))	('ARID1A', 'Gene', (13, 19))	('inhibition', 'Var', (140, 150))	('BAF', 'Gene', '8815', (114, 117))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('BAF', 'Gene', (114, 117))	('BAF', 'Gene', '8815', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('ARID1A-deficient cancers', 'Disease', (198, 222))	('ARID1A', 'Gene', '8289', (198, 204))	('ARID1A', 'Gene', (198, 204))	('ARID1B', 'Gene', (154, 160))	('ARID1B', 'Gene', (24, 30))	('BAF', 'Gene', (54, 57))
55661	31955490	A modified approach to the inhibition of ARID1B may be the use of BRD2 inhibitors because inhibition of BRD2 represses the transcriptional expression of ARID1B.	('ARID1B', 'Gene', '57492', (153, 159))	('ARID1B', 'Gene', (41, 47))	('BRD2', 'Gene', '6046', (104, 108))	('BRD2', 'Gene', (104, 108))	('ARID1B', 'Gene', (153, 159))	('BRD2', 'Gene', (66, 70))	('transcriptional expression', 'MPA', (123, 149))	('ARID1B', 'Gene', '57492', (41, 47))	('BRD2', 'Gene', '6046', (66, 70))	('inhibition', 'Var', (90, 100))	('represses', 'NegReg', (109, 118))
55662	31955490	In fact, ARID1A-deficient cancer cells are more sensitive to BRD2 inhibitors than ARID1A-proficient cancer cells.25 Therefore, BRD2 inhibitors would be promising for the treatment of ARID1A-deficient cancers because of induction of synthetic lethality through suppression of ARID1B.	('cancer', 'Disease', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('ARID1A', 'Gene', (9, 15))	('BRD2', 'Gene', (127, 131))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('ARID1A', 'Gene', (82, 88))	('suppression', 'NegReg', (260, 271))	('ARID1A-deficient cancer', 'Disease', (9, 32))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('ARID1A', 'Gene', '8289', (9, 15))	('ARID1A-deficient cancers', 'Disease', 'MESH:D009369', (183, 207))	('ARID1A', 'Gene', (183, 189))	('BRD2', 'Gene', '6046', (61, 65))	('ARID1A', 'Gene', '8289', (82, 88))	('ARID1A-deficient cancers', 'Disease', (183, 207))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('ARID1B', 'Gene', (275, 281))	('ARID1A', 'Gene', '8289', (183, 189))	('ARID1B', 'Gene', '57492', (275, 281))	('cancer', 'Disease', (100, 106))	('ARID1A-deficient cancer', 'Disease', 'MESH:D009369', (183, 206))	('BRD2', 'Gene', (61, 65))	('inhibitors', 'Var', (132, 142))	('ARID1A-deficient cancer', 'Disease', 'MESH:D009369', (9, 32))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (200, 206))	('BRD2', 'Gene', '6046', (127, 131))
55664	31955490	SMARCB1 is genetically aberrant because of LOF gene mutation or chromosomal deletion in pediatric and juvenile cancers such as rhabdoid tumor and epithelioid sarcoma.26, 27 SS18 is genetically aberrant because of fusion with SSXs (SSX1, SSX2, or SSX4) in synovial sarcoma.	('SSX4', 'Gene', (246, 250))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (127, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (264, 271))	('synovial sarcoma', 'Disease', (255, 271))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('SS18', 'Gene', '6760', (173, 177))	('SSX2', 'Gene', (237, 241))	('synovial sarcoma', 'Disease', 'MESH:D013584', (255, 271))	('SSX', 'Gene', '6757', (225, 228))	('SSX4', 'Gene', '6759', (246, 250))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (146, 165))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('rhabdoid tumor', 'Disease', (127, 141))	('SSX2', 'Gene', '6757', (237, 241))	('juvenile cancers', 'Disease', 'MESH:D009369', (102, 118))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (255, 271))	('SSX', 'Gene', '6757', (246, 249))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('SSX', 'Gene', '6757', (231, 234))	('SSX', 'Gene', (225, 228))	('epithelioid sarcoma', 'Disease', (146, 165))	('SSX', 'Gene', '6757', (237, 240))	('SMARCB1', 'Gene', '6598', (0, 7))	('juvenile cancers', 'Disease', (102, 118))	('SSX1', 'Gene', '6756', (231, 235))	('SMARCB1', 'Gene', (0, 7))	('SSX', 'Gene', (246, 249))	('SSX1', 'Gene', (231, 235))	('SSX', 'Gene', (231, 234))	('fusion', 'Var', (213, 219))	('SS18', 'Gene', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('SSX', 'Gene', (237, 240))
55675	31955490	ARID1A deficiency upregulates HDAC6 expression through derepression caused by deficiency in the SWI/SNF chromatin remodeling complex.	('HDAC6', 'Gene', '10013', (30, 35))	('upregulates', 'PosReg', (18, 29))	('HDAC6', 'Gene', (30, 35))	('derepression', 'MPA', (55, 67))	('deficiency', 'Var', (78, 88))	('ARID1A', 'Gene', '8289', (0, 6))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('104', '132'))	('deficiency', 'Var', (7, 17))	('ARID1A', 'Gene', (0, 6))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('104', '124'))	('expression', 'MPA', (36, 46))
55680	31955490	ARID1A mediates the physical interaction between the BAF complex and TOP2.42 Thus, TOP2 dysfunction in BAF complex-deficient tumors, such as ARID1A-deficient cancers, results in aberrant DNA replication and chromosomal segregation.	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('BAF', 'Gene', (103, 106))	('chromosomal segregation', 'CPA', (207, 230))	('complex-deficient tumors', 'Disease', 'MESH:D018193', (107, 131))	('DNA replication', 'biological_process', 'GO:0006260', ('187', '202'))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('DNA', 'cellular_component', 'GO:0005574', ('187', '190'))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('results in', 'Reg', (167, 177))	('TOP2', 'Gene', (83, 87))	('BAF', 'Gene', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('BAF', 'Gene', '8815', (103, 106))	('ARID1A', 'Gene', (141, 147))	('ARID1A', 'Gene', (0, 6))	('complex-deficient tumors', 'Disease', (107, 131))	('ARID1A-deficient cancers', 'Disease', 'MESH:D009369', (141, 165))	('dysfunction', 'Var', (88, 99))	('ARID1A-deficient cancers', 'Disease', (141, 165))	('aberrant DNA replication', 'CPA', (178, 202))	('ARID1A', 'Gene', '8289', (0, 6))	('ARID1A', 'Gene', '8289', (141, 147))	('BAF', 'Gene', '8815', (53, 56))
55698	31955490	Ovarian clear cell carcinoma has the highest rate of ARID1A mutation among cancers.	('mutation', 'Var', (60, 68))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('cancers', 'Disease', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Ovarian clear cell carcinoma', 'Disease', (0, 28))	('Ovarian clear cell carcinoma', 'Disease', 'MESH:D010051', (0, 28))	('ARID1A', 'Gene', '8289', (53, 59))	('ARID1A', 'Gene', (53, 59))
55705	31955490	Frequently mutated genes tend to be characteristic of different tumor types, such as SMARCA4 in lung adenocarcinoma (10% frequency), ARID1A in ovarian clear cell carcinoma (50% frequency), PBRM1 in renal clear cell carcinoma (40% frequency), and SMARCB1 in rhabdoid tumors (100% frequency).	('ARID1A', 'Gene', '8289', (133, 139))	('SMARCA4', 'Gene', '6597', (85, 92))	('tumor', 'Disease', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('renal clear cell carcinoma', 'Disease', 'MESH:D002292', (198, 224))	('ovarian clear cell carcinoma', 'Disease', (143, 171))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('rhabdoid tumors', 'Disease', (257, 272))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (257, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('PBRM1', 'Gene', '55193', (189, 194))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (96, 115))	('renal clear cell carcinoma', 'Disease', (198, 224))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('mutated', 'Var', (11, 18))	('SMARCA4', 'Gene', (85, 92))	('lung adenocarcinoma', 'Disease', (96, 115))	('SMARCB1', 'Gene', (246, 253))	('PBRM1', 'Gene', (189, 194))	('SMARCB1', 'Gene', '6598', (246, 253))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D010051', (143, 171))	('ARID1A', 'Gene', (133, 139))	('tumor', 'Disease', (64, 69))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (96, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
55706	31955490	Mutation of each gene is important for carcinogenesis in every tumor type.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('carcinogenesis', 'Disease', (39, 53))	('Mutation', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('carcinogenesis', 'Disease', 'MESH:D063646', (39, 53))
55707	31955490	The mechanism underlying the effect of cancer-specific gene mutations can be elucidated by determining the functional relationship based on synthetic lethality.	('mutations', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))
55708	31955490	ARID1A mutation occurs in the early stage of precancerous endometriosis and clear cell adenofibroma.55, 56 In addition, ROS could contribute to cancer transformation by promoting gene mutation or by stimulating cellular signaling.57, 58, 59, 60 The basal level of ROS increases as a result of a decrease of GSH in ARID1A-deficient ovarian cancer cells.49 These findings suggest that ARID1A abrogation is involved in oncogenesis by contributing to a dysregulated balance between ROS and GSH homeostasis.	('GSH homeostasis', 'MPA', (486, 501))	('ROS', 'Chemical', 'MESH:D017382', (478, 481))	('ROS', 'Chemical', 'MESH:D017382', (264, 267))	('oncogenesis', 'biological_process', 'GO:0007048', ('416', '427'))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (339, 345))	('cancer', 'Disease', (48, 54))	('ARID1A', 'Gene', '8289', (314, 320))	('ARID1A', 'Gene', (383, 389))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('ROS', 'Chemical', 'MESH:D017382', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('ARID1A-deficient ovarian cancer', 'Disease', (314, 345))	('GSH', 'Chemical', 'MESH:D005978', (307, 310))	('ovarian cancer', 'Phenotype', 'HP:0100615', (331, 345))	('ARID1A', 'Gene', '8289', (383, 389))	('involved', 'Reg', (404, 412))	('clear cell adenofibroma', 'Disease', (76, 99))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (339, 345))	('ARID1A', 'Gene', (0, 6))	('GSH', 'Chemical', 'MESH:D005978', (486, 489))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('precancerous endometriosis', 'Disease', (45, 71))	('precancerous endometriosis', 'Disease', 'MESH:D004715', (45, 71))	('dysregulated balance', 'Phenotype', 'HP:0002172', (449, 469))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('clear cell adenofibroma', 'Disease', 'MESH:D062625', (76, 99))	('ARID1A', 'Gene', '8289', (0, 6))	('dysregulated balance', 'MPA', (449, 469))	('ARID1A-deficient ovarian cancer', 'Disease', 'MESH:D010051', (314, 345))	('abrogation', 'Var', (390, 400))	('endometriosis', 'Phenotype', 'HP:0030127', (58, 71))	('signaling', 'biological_process', 'GO:0023052', ('220', '229'))	('ARID1A', 'Gene', (314, 320))	('homeostasis', 'biological_process', 'GO:0042592', ('490', '501'))	('ROS', 'MPA', (478, 481))
55712	28546525	Although several inhibitors of vascular endothelial growth factor have recently shown efficacy against nccRCC, the clinical benefit of pazopanib in nccRCC has not been analyzed.	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('31', '65'))	('vascular endothelial growth factor', 'Gene', (31, 65))	('vascular endothelial growth factor', 'Gene', '7422', (31, 65))	('inhibitors', 'Var', (17, 27))	('pazopanib', 'Chemical', 'MESH:C516667', (135, 144))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (106, 109))	('RCC', 'Disease', (151, 154))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('RCC', 'Disease', 'MESH:C538614', (106, 109))
55813	28900502	In the current study, we comprehensively analyzed the genome-wide microRNA (miRNA) expression profiles in ccRCC, with the aim to identify the differentially expressed miRNAs between BAP1 mutant and wild-type tumors, and generate a BAP1 mutation-specific miRNA signature for ccRCC patients with wild-type BAP1.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('patients', 'Species', '9606', (280, 288))	('BAP1', 'Gene', '8314', (182, 186))	('RCC', 'Disease', 'MESH:C538614', (276, 279))	('RCC', 'Disease', (276, 279))	('BAP1', 'Gene', '8314', (231, 235))	('BAP1', 'Gene', (182, 186))	('BAP1', 'Gene', '8314', (304, 308))	('mutant', 'Var', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('BAP1', 'Gene', (231, 235))	('BAP1', 'Gene', (304, 308))	('tumors', 'Disease', 'MESH:D009369', (208, 214))
55814	28900502	Methods: The BAP1 mutation status and miRNA profiles in BAP1 mutant and wild-type tumors were analyzed.	('BAP1', 'Gene', (13, 17))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('BAP1', 'Gene', '8314', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BAP1', 'Gene', (56, 60))	('mutant', 'Var', (61, 67))	('BAP1', 'Gene', '8314', (13, 17))
55816	28900502	Results: A total of 350 treatment-naive primary ccRCC patients were selected from The Cancer Genome Atlas project, among which 35 (10.0%) subjects carried mutant BAP1 and had a shorter overall survival (OS) time.	('BAP1', 'Gene', '8314', (162, 166))	('patients', 'Species', '9606', (54, 62))	('mutant', 'Var', (155, 161))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('shorter', 'NegReg', (177, 184))	('BAP1', 'Gene', (162, 166))	('Cancer Genome Atlas', 'Disease', (86, 105))	('Cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (86, 105))	('overall survival', 'MPA', (185, 201))	('carried', 'Reg', (147, 154))
55817	28900502	Furthermore, 33 miRNAs were found to be differentially expressed between BAP1 mutant and wild-type tumors, among which 11 (miR-149, miR-29b-2, miR-182, miR-183, miR-21, miR-365-2, miR-671, miR-365-1, miR-10b, miR-139, and miR-181a-2) were significantly associated with OS in ccRCC patients with wild-type BAP1.	('BAP1', 'Gene', (305, 309))	('miR-365-2', 'Gene', '100500842', (169, 178))	('miR-139', 'Gene', '406931', (209, 216))	('miR-149', 'Gene', '406941', (123, 130))	('miR-182', 'Gene', (143, 150))	('BAP1', 'Gene', (73, 77))	('miR-365-1', 'Gene', '100500918', (189, 198))	('miR-182', 'Gene', '406958', (143, 150))	('miR-181a-2', 'Gene', (222, 232))	('RCC', 'Disease', 'MESH:C538614', (277, 280))	('miR-139', 'Gene', (209, 216))	('miR-671', 'Gene', '768213', (180, 187))	('miR-183', 'Gene', '406959', (152, 159))	('miR-365-2', 'Gene', (169, 178))	('miR-29b-2', 'Gene', '407025', (132, 141))	('miR-21', 'Gene', '406991', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('associated', 'Reg', (253, 263))	('miR-29b-2', 'Gene', (132, 141))	('miR-183', 'Gene', (152, 159))	('patients', 'Species', '9606', (281, 289))	('BAP1', 'Gene', '8314', (305, 309))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mutant', 'Var', (78, 84))	('tumors', 'Disease', (99, 105))	('miR-671', 'Gene', (180, 187))	('miR-365-1', 'Gene', (189, 198))	('BAP1', 'Gene', '8314', (73, 77))	('miR-21', 'Gene', (161, 167))	('miR-10b', 'Gene', (200, 207))	('miR-149', 'Gene', (123, 130))	('RCC', 'Disease', (277, 280))	('miR-10b', 'Gene', '406903', (200, 207))	('miR-181a-2', 'Gene', '406954', (222, 232))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
55819	28900502	Conclusions: In summary, our study identified a total of 33 miRNAs differentially expressed between BAP1 mutant and wild-type tumors, and generated a BAP1 mutation-specific miRNA signature including eleven miRNAs, which could serve as a novel prognostic biomarker for ccRCC patients with wild-type BAP1.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('BAP1', 'Gene', '8314', (150, 154))	('mutant', 'Var', (105, 111))	('mutation-specific', 'Reg', (155, 172))	('BAP1', 'Gene', '8314', (100, 104))	('tumors', 'Disease', (126, 132))	('patients', 'Species', '9606', (274, 282))	('expressed', 'MPA', (82, 91))	('BAP1', 'Gene', '8314', (298, 302))	('miRNAs', 'MPA', (206, 212))	('BAP1', 'Gene', (150, 154))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('BAP1', 'Gene', (100, 104))	('RCC', 'Disease', (270, 273))	('BAP1', 'Gene', (298, 302))	('RCC', 'Disease', 'MESH:C538614', (270, 273))	('miRNAs', 'MPA', (60, 66))	('differentially', 'Reg', (67, 81))
55829	28900502	The BAP1 mutant ccRCC patients have a worse prognosis than those with wild-type BAP1 , and the BAP1 mutant tumors exhibit a specific gene expression signature, which overall suggests that BAP1 mutation status could serve as a novel molecular classification parameter of ccRCC.	('mutant', 'Var', (9, 15))	('BAP1', 'Gene', '8314', (80, 84))	('BAP1', 'Gene', '8314', (188, 192))	('BAP1', 'Gene', '8314', (95, 99))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('patients', 'Species', '9606', (22, 30))	('BAP1', 'Gene', (80, 84))	('gene expression', 'biological_process', 'GO:0010467', ('133', '148'))	('BAP1', 'Gene', '8314', (4, 8))	('RCC', 'Disease', (18, 21))	('RCC', 'Disease', (272, 275))	('BAP1', 'Gene', (188, 192))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('BAP1', 'Gene', (95, 99))	('tumors', 'Disease', (107, 113))	('RCC', 'Disease', 'MESH:C538614', (18, 21))	('RCC', 'Disease', 'MESH:C538614', (272, 275))	('mutant', 'Var', (100, 106))	('BAP1', 'Gene', (4, 8))	('tumors', 'Disease', 'MESH:D009369', (107, 113))
55830	28900502	Increased data suggests that miRNAs exert important functions in the development and progression of human malignancies, and could serve as potential biomarkers for the early diagnosis, prognosis prediction, and therapy decision.	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('miRNAs', 'Var', (29, 35))	('malignancies', 'Disease', (106, 118))	('human', 'Species', '9606', (100, 105))	('development', 'CPA', (69, 80))
55833	28900502	However, to date, no study has been conducted to compare the miRNA expression profiles between BAP1 mutant and wild-type tumors, and no specific miRNA signature was establsished for ccRCC patients with wild-type BAP1.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('BAP1', 'Gene', (95, 99))	('BAP1', 'Gene', (212, 216))	('mutant', 'Var', (100, 106))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('RCC', 'Disease', (184, 187))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('patients', 'Species', '9606', (188, 196))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('BAP1', 'Gene', '8314', (95, 99))	('BAP1', 'Gene', '8314', (212, 216))	('miRNA', 'MPA', (61, 66))
55834	28900502	Hence, we stringently designed a stepwise study using the data from TCGA project to: 1) ascertain the differential miRNA expression profiles between wild-type and mutant BAP1 tumors; 2) identify the miRNAs with prognostic potential from the differential expression profiles; 3) generate a BAP1 mutation-specific miRNA signature for ccRCC patients with wild-type BAP1; and 4) predict target genes and potential involved biological pathways for selected miRNAs.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('RCC', 'Disease', (334, 337))	('RCC', 'Disease', 'MESH:C538614', (334, 337))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('predict', 'Reg', (375, 382))	('BAP1', 'Gene', '8314', (170, 174))	('BAP1', 'Gene', '8314', (362, 366))	('mutant', 'Var', (163, 169))	('BAP1', 'Gene', (289, 293))	('BAP1', 'Gene', (362, 366))	('BAP1', 'Gene', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('patients', 'Species', '9606', (338, 346))	('BAP1', 'Gene', '8314', (289, 293))
55843	28900502	The miRNA expression levels between BAP1 mutant and wild-type tumors were ascertained with Student's t-test embedded in BRB-Array tools (significance level set as 0.01), and the unsupervised hierarchical cluster analysis was performed by Euclidian distance and average linkage methods.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mutant', 'Var', (41, 47))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('BAP1', 'Gene', '8314', (36, 40))	('miRNA expression levels', 'MPA', (4, 27))	('BAP1', 'Gene', (36, 40))
55849	28900502	Among all 350 ccRCC patients, a summary of 35 (10.0%) mutations were detected, which included 9 (2.6%) nonsense, 15 (4.3%) missense, 3 (0.8%) splice site, and 8 (2.3%) frameshift mutations (Figure 1 and Supplementary Table S1).	('frameshift mutations', 'Var', (168, 188))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('RCC', 'Disease', (16, 19))	('splice site', 'Var', (142, 153))	('patients', 'Species', '9606', (20, 28))	('missense', 'Var', (123, 131))	('nonsense', 'Var', (103, 111))
55850	28900502	The ccRCC patients with mutated BAP1 showed a trend towards higher AJCC stage (P=0.006), pathologic T stage (P=0.009), Fuhrman grade (P=0.003) and distant metastasis (P=0.029) compared with those with wild-type BAP1 (Table 1).	('mutated', 'Var', (24, 31))	('higher', 'PosReg', (60, 66))	('BAP1', 'Gene', '8314', (32, 36))	('BAP1', 'Gene', '8314', (211, 215))	('Fuhrman grade', 'CPA', (119, 132))	('AJCC', 'Disease', (67, 71))	('patients', 'Species', '9606', (10, 18))	('BAP1', 'Gene', (32, 36))	('BAP1', 'Gene', (211, 215))	('distant metastasis', 'CPA', (147, 165))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))
55851	28900502	As depicted in Figure 1, the patients with BAP1 mutant tumors had a worse prognosis in terms of median overall survival (OS; BAP1 mutant vs. wild type: 31.7 vs. 86.7 months; P=0.008).	('BAP1', 'Gene', (43, 47))	('patients', 'Species', '9606', (29, 37))	('mutant', 'Var', (48, 54))	('BAP1', 'Gene', '8314', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('BAP1', 'Gene', '8314', (43, 47))	('BAP1', 'Gene', (125, 129))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('mutant', 'Var', (130, 136))
55852	28900502	Furthermore, the univariate Cox regression analysis confirmed that patients with mutant BAP1 had a significantly higher probability of death (HR =1.909, 95% CI: 1.175-3.102; P=0.009); however, unfortunately, it did not pass the multivariate analysis after adjusting for the other significant prognostic variables (Supplementary Table S2).	('patients', 'Species', '9606', (67, 75))	('Cox', 'Gene', '1351', (28, 31))	('Cox', 'Gene', (28, 31))	('BAP1', 'Gene', '8314', (88, 92))	('mutant', 'Var', (81, 87))	('death', 'Disease', 'MESH:D003643', (135, 140))	('death', 'Disease', (135, 140))	('BAP1', 'Gene', (88, 92))
55853	28900502	The miRNA expression in BAP1 mutated (n=35) and wild-type (n=315) tumors was profiled, and a total of 33 miRNAs were found to be expressed differentially after adjustment for multiple testing (Supplementary Table S3).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('BAP1', 'Gene', (24, 28))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('mutated', 'Var', (29, 36))	('BAP1', 'Gene', '8314', (24, 28))
55854	28900502	Among all the 33 miRNAs, 15 miRNAs (45.5%) were up-regulated and the remaining 18 (54.5%) were down-regulated in tumors with mutated BAP1 compared with those with wild-type BAP1.	('down-regulated', 'NegReg', (95, 109))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('mutated', 'Var', (125, 132))	('up-regulated', 'PosReg', (48, 60))	('BAP1', 'Gene', '8314', (173, 177))	('BAP1', 'Gene', '8314', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('BAP1', 'Gene', (173, 177))	('BAP1', 'Gene', (133, 137))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
55855	28900502	In addition, the unsupervised hierarchical clustering with the 33 miRNAs expression data could clearly separate the tumors with mutated and wild-type BAP1 (Figure 2).	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('BAP1', 'Gene', (150, 154))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('mutated', 'Var', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('BAP1', 'Gene', '8314', (150, 154))
55870	28900502	To the best of our knowledge, this is the first study to explore the genome-wide miRNA expression in BAP1 mutant and wild-type ccRCC tumors, which could help predict patient prognosis in the era of precision medicine.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('mutant', 'Var', (106, 112))	('ccRCC tumors', 'Disease', 'MESH:D009369', (127, 139))	('BAP1', 'Gene', '8314', (101, 105))	('ccRCC tumors', 'Disease', (127, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('BAP1', 'Gene', (101, 105))	('patient', 'Species', '9606', (166, 173))
55872	28900502	The immunohistochemistry assays of RCC tumor tissues have demonstrated that loss of BAP1 protein expression was specific for ccRCC compared with other histological subtypes of RCC, and could function as a potent prognostic factor for ccRCC.	('RCC tumor', 'Disease', (35, 44))	('RCC', 'Disease', (35, 38))	('RCC', 'Disease', (176, 179))	('RCC', 'Disease', (236, 239))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('RCC', 'Disease', (127, 130))	('loss', 'Var', (76, 80))	('RCC', 'Disease', 'MESH:C538614', (236, 239))	('BAP1', 'Gene', '8314', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))	('RCC tumor', 'Disease', 'MESH:C538614', (35, 44))	('BAP1', 'Gene', (84, 88))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('protein', 'Protein', (89, 96))	('expression', 'MPA', (97, 107))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
55873	28900502	In the current study, we observed that BAP1 was mutated in 10.0% of the 350 ccRCC patients, with the similar frequency as the previous immunohistochemistry and mutational analyses studies.	('mutated', 'Var', (48, 55))	('patients', 'Species', '9606', (82, 90))	('RCC', 'Disease', (78, 81))	('BAP1', 'Gene', '8314', (39, 43))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('BAP1', 'Gene', (39, 43))
55874	28900502	The ccRCC patients with mutated BAP1 were more likely to present high AJCC stage, pathologic T stage, Fuhrman grade and distant metastasis, and had a shorter median OS (BAP1 mutant vs. wild type: 31.7 vs. 86.7 months; P=0.008).	('mutated', 'Var', (24, 31))	('BAP1', 'Gene', '8314', (32, 36))	('BAP1', 'Gene', '8314', (169, 173))	('distant metastasis', 'CPA', (120, 138))	('BAP1', 'Gene', (32, 36))	('BAP1', 'Gene', (169, 173))	('patients', 'Species', '9606', (10, 18))	('shorter', 'NegReg', (150, 157))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))
55875	28900502	In the Cox regression analysis, a HR of 1.909 (95% CI: 1.175-3.102; P=0.009) was obtained from the univariate analysis; however, no significant result for the prognostic value of BAP1 mutation was found after including the other variables for multivariate analysis, which could be explained by the limited sample size.	('Cox', 'Gene', '1351', (7, 10))	('BAP1', 'Gene', (179, 183))	('Cox', 'Gene', (7, 10))	('BAP1', 'Gene', '8314', (179, 183))	('mutation', 'Var', (184, 192))
55876	28900502	It is conceivable that BAP1 mutation could serve as a potent prognostic parameter, as previous studies and the current study have indicated that ccRCC patients with mutated BAP1 had a shorter median survival time.	('BAP1', 'Gene', (23, 27))	('patients', 'Species', '9606', (151, 159))	('BAP1', 'Gene', '8314', (173, 177))	('BAP1', 'Gene', '8314', (23, 27))	('RCC', 'Disease', (147, 150))	('shorter', 'NegReg', (184, 191))	('BAP1', 'Gene', (173, 177))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('mutated', 'Var', (165, 172))
55877	28900502	Previous studies have demonstrated that BAP1 mutant tumors exhibit a highly specific gene expression signature; however, to date, the miRNA expression profiles between BAP1 mutant and wild-type tumor have never been compared.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('gene expression', 'biological_process', 'GO:0010467', ('85', '100'))	('mutant', 'Var', (45, 51))	('BAP1', 'Gene', '8314', (168, 172))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Disease', (52, 57))	('tumors', 'Disease', (52, 58))	('BAP1', 'Gene', (168, 172))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('BAP1', 'Gene', '8314', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('BAP1', 'Gene', (40, 44))
55879	28900502	In the current study, we explored the genome-wide miRNA expression profiles in BAP1 mutant and wild-type ccRCC tumors, and found a total of 33 differentially expressed miRNAs.	('ccRCC tumors', 'Disease', (105, 117))	('BAP1', 'Gene', '8314', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('BAP1', 'Gene', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('mutant', 'Var', (84, 90))	('ccRCC tumors', 'Disease', 'MESH:D009369', (105, 117))
55890	28900502	Second, in the multivariate Cox regression analysis, BAP1 mutation was not proved as an independent prognostic factor, which could be partially attributed to the limited sample size.	('Cox', 'Gene', '1351', (28, 31))	('Cox', 'Gene', (28, 31))	('mutation', 'Var', (58, 66))	('BAP1', 'Gene', '8314', (53, 57))	('BAP1', 'Gene', (53, 57))
55891	28900502	In summary, by employing a large independent ccRCC patient cohort, our study identified a total of 33 miRNAs differentially expressed between BAP1 mutant and wild-type tumors, and generated a BAP1 mutation-specific miRNA signature consisting of eleven miRNAs, which could serve as a novel prognostic biomarker for ccRCC patients with wild-type BAP1.	('mutant', 'Var', (147, 153))	('BAP1', 'Gene', (192, 196))	('BAP1', 'Gene', '8314', (142, 146))	('tumors', 'Disease', (168, 174))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('BAP1', 'Gene', (344, 348))	('expressed', 'MPA', (124, 133))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('BAP1', 'Gene', (142, 146))	('miRNAs', 'MPA', (252, 258))	('BAP1', 'Gene', '8314', (192, 196))	('patients', 'Species', '9606', (320, 328))	('RCC', 'Disease', (316, 319))	('miRNAs', 'MPA', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('differentially', 'Reg', (109, 123))	('BAP1', 'Gene', '8314', (344, 348))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('patient', 'Species', '9606', (320, 327))	('patient', 'Species', '9606', (51, 58))	('RCC', 'Disease', (47, 50))	('RCC', 'Disease', 'MESH:C538614', (316, 319))
55892	33627663	Proteolysis-targeting chimera against BCL-XL destroys tumor-infiltrating regulatory T cells Regulatory T cells (Tregs) play an important role in maintaining immune homeostasis and, within tumors, their upregulation is common and promotes an immunosuppressive microenvironment.	('tumor', 'Disease', (188, 193))	('tumors', 'Disease', (188, 194))	('Tregs', 'Chemical', '-', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('BCL-XL', 'Gene', (38, 44))	('chimera', 'Var', (22, 29))	('immune homeostasis', 'MPA', (157, 175))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('BCL-XL', 'Gene', '12048', (38, 44))	('homeostasis', 'biological_process', 'GO:0042592', ('164', '175'))	('Proteolysis', 'biological_process', 'GO:0006508', ('0', '11'))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', (54, 59))	('upregulation', 'PosReg', (202, 214))
55900	33627663	Here the authors show that pharmacological degradation of BCL-XL preferentially induces apoptosis of tumor-infiltrating Treg, promoting CD8 T cell activation and anti-tumor immune responses in preclinical cancer models.	('promoting', 'PosReg', (126, 135))	('apoptosis', 'biological_process', 'GO:0006915', ('88', '97'))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('degradation', 'biological_process', 'GO:0009056', ('43', '54'))	('CD8', 'Gene', '925', (136, 139))	('induces', 'Reg', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('pharmacological degradation', 'Var', (27, 54))	('Treg', 'Chemical', '-', (120, 124))	('T cell activation', 'biological_process', 'GO:0042110', ('140', '157'))	('tumor', 'Disease', (167, 172))	('CD8', 'Gene', (136, 139))	('cancer', 'Disease', (205, 211))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('apoptosis', 'CPA', (88, 97))	('BCL-XL', 'Gene', (58, 64))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('apoptosis', 'biological_process', 'GO:0097194', ('88', '97'))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
55909	33627663	The inhibition of BCL-XL with an inhibitor, however, induces severe thrombocytopenia, an on-target and dose-limiting toxicity, which limits the use of ABT263 and other BCL-XL inhibitors as safe and effective anticancer drugs in clinic.	('thrombocytopenia', 'Disease', (68, 84))	('BCL-XL', 'Enzyme', (18, 24))	('toxicity', 'Disease', 'MESH:D064420', (117, 125))	('toxicity', 'Disease', (117, 125))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('thrombocytopenia', 'Disease', 'MESH:D013921', (68, 84))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (68, 84))	('ABT263', 'Chemical', 'MESH:C528561', (151, 157))	('inhibitor', 'Var', (33, 42))	('inhibition', 'NegReg', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
55911	33627663	Because platelets express a low level of VHL E3 ligase, DT2216 has minimal effect on platelets but exhibits an improved cytotoxicity against various cancer cells that are dependent on BCL-XL for survival.	('cancer', 'Disease', (149, 155))	('DT2216', 'Var', (56, 62))	('improved', 'PosReg', (111, 119))	('cytotoxicity', 'Disease', (120, 132))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('VHL', 'Gene', '22346', (41, 44))	('VHL', 'Gene', (41, 44))	('cytotoxicity', 'Disease', 'MESH:D064420', (120, 132))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('DT2216', 'Chemical', '-', (56, 62))
55914	33627663	Using the two PROTACs (DT2166 and PZ15227) to degrade BCL-XL, we are able to define the critical pro-survival function of BCL-XL within TI-Tregs, which represents a potential method to deplete TI-Tregs for cancer immunotherapy.	('TI-Tregs', 'Chemical', '-', (136, 144))	('degrade', 'NegReg', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('pro-survival', 'biological_process', 'GO:0043066', ('97', '109'))	('TI-Tregs', 'Chemical', '-', (193, 201))	('DT2166', 'Var', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', (206, 212))	('BCL-XL', 'MPA', (54, 60))	('PZ15227', 'Var', (34, 41))	('PZ15227', 'Chemical', '-', (34, 41))
55935	33627663	Although PB-Tregs exhibited subpopulations of naive (CD45RA+CCR7+), effector (EMRA, CD45RA+CCR7-), central memory (CM, CD45RA-CCR7+), and effector memory (EM, CD45RA-CCR7-), TI-Tregs only consisted of the EM population (Supplementary Fig.	('CCR', 'molecular_function', 'GO:0043880', ('126', '129'))	('memory', 'biological_process', 'GO:0007613', ('107', '113'))	('CD45RA-CCR7', 'Gene', (119, 130))	('CD45RA-CCR7', 'Gene', (159, 170))	('CCR', 'molecular_function', 'GO:0043880', ('60', '63'))	('PB-Tregs', 'Chemical', '-', (9, 17))	('CD45RA+CCR7+', 'Var', (53, 65))	('CD45RA-CCR7', 'Gene', '1236', (119, 130))	('CCR', 'molecular_function', 'GO:0043880', ('166', '169'))	('TI-Tregs', 'Chemical', '-', (174, 182))	('CD45RA-CCR7', 'Gene', '1236', (159, 170))	('CD45RA+CCR7-', 'Var', (84, 96))	('CCR', 'molecular_function', 'GO:0043880', ('91', '94'))	('memory', 'biological_process', 'GO:0007613', ('147', '153'))
55937	33627663	Using flow cytometry, we found that the levels of BCL-XL protein:determined by intracellular staining of BCL-XL:were much higher in TI-Tregs versus PB-Tregs in both human BrCa (Fig.	('TI-Tregs', 'Var', (132, 140))	('human', 'Species', '9606', (165, 170))	('BrCa', 'Gene', '672', (171, 175))	('higher', 'PosReg', (122, 128))	('TI-Tregs', 'Chemical', '-', (132, 140))	('PB-Tregs', 'Chemical', '-', (148, 156))	('levels', 'MPA', (40, 46))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('intracellular', 'cellular_component', 'GO:0005622', ('79', '92'))	('BrCa', 'Gene', (171, 175))
55941	33627663	BCL-XL levels were also higher, though to a lesser extent, in conventional TI-CD4+ Tconv versus their PB-counterparts (Fig.	('Tconv', 'Chemical', '-', (83, 88))	('higher', 'PosReg', (24, 30))	('TI', 'Chemical', '-', (75, 77))	('BCL-XL levels', 'MPA', (0, 13))	('TI-CD4+ Tconv', 'Var', (75, 88))
55952	33627663	DT2216, the lead BCL-XL PROTAC, targets BCL-XL to the VHL E3 ligase for polyubiquitination and degradation.	('DT2216', 'Var', (0, 6))	('VHL', 'Gene', (54, 57))	('VHL', 'Gene', '22346', (54, 57))	('degradation', 'MPA', (95, 106))	('degradation', 'biological_process', 'GO:0009056', ('95', '106'))	('polyubiquitination', 'MPA', (72, 90))	('DT2216', 'Chemical', '-', (0, 6))
55953	33627663	DT2216 did not cause the platelet toxicity observed when other BCL-XL inhibitors were used to inhibit BCL-XL, because of the poor expression of VHL in platelets.	('expression', 'MPA', (130, 140))	('DT2216', 'Var', (0, 6))	('toxicity', 'Disease', 'MESH:D064420', (34, 42))	('toxicity', 'Disease', (34, 42))	('VHL', 'Gene', (144, 147))	('VHL', 'Gene', '22346', (144, 147))	('DT2216', 'Chemical', '-', (0, 6))
55955	33627663	Treatment with DT2216 led to a significant decrease in BCL-XL levels within TI-Tregs from human BrCa (Fig.	('BCL-XL levels', 'MPA', (55, 68))	('decrease', 'NegReg', (43, 51))	('BrCa', 'Gene', (96, 100))	('TI-Tregs', 'Chemical', '-', (76, 84))	('BrCa', 'Gene', '672', (96, 100))	('DT2216', 'Chemical', '-', (15, 21))	('human', 'Species', '9606', (90, 95))	('DT2216', 'Var', (15, 21))
55962	33627663	and PZ15227 (a second BCL-XL PROTAC that targets BCL-XL to the CRBN E3 ligase for polyubiquitination and degradation) treatments each resulted in dose-dependent reduction of BCL-XL levels (Fig.	('PZ15227', 'Chemical', '-', (4, 11))	('treatments', 'Var', (118, 128))	('CRBN', 'Gene', '58799', (63, 67))	('CRBN', 'Gene', (63, 67))	('degradation', 'biological_process', 'GO:0009056', ('105', '116'))	('reduction', 'NegReg', (161, 170))	('PZ15227', 'Var', (4, 11))	('BCL-XL levels', 'MPA', (174, 187))
55963	33627663	Treatment of mice bearing tumors originated from MC38 and Renca cells with DT2216 resulted in reduced BCL-XL levels in the tumors, regardless of whether the mice were wild-type (WT) (Fig.	('mice', 'Species', '10090', (13, 17))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('mice', 'Species', '10090', (157, 161))	('reduced', 'NegReg', (94, 101))	('Renca', 'Chemical', '-', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('DT2216', 'Chemical', '-', (75, 81))	('BCL-XL levels', 'MPA', (102, 115))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('DT2216', 'Var', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumors', 'Disease', (26, 32))
55966	33627663	We found that in vitro treatment of MC38, Renca, Py8119, or 4T1 cells with DT2216 or PZ15227 had little effect on cell survival (Supplementary Fig.	('PZ15227', 'Var', (85, 92))	('Renca', 'Chemical', '-', (42, 47))	('DT2216', 'Chemical', '-', (75, 81))	('PZ15227', 'Chemical', '-', (85, 92))	('cell survival', 'CPA', (114, 127))	('DT2216', 'Var', (75, 81))
55969	33627663	BCL-XL deficiency, caused by either treatment with DT2216 or genetic knockout (KO), influenced neither apoptosis nor colony-forming efficiency of cancer cells in vitro (Supplementary Fig.	('DT2216', 'Chemical', '-', (51, 57))	('cancer', 'Disease', (146, 152))	('colony-forming efficiency', 'CPA', (117, 142))	('influenced', 'Reg', (84, 94))	('BCL-XL deficiency', 'Disease', 'MESH:D000080345', (0, 17))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('DT2216', 'Var', (51, 57))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('BCL-XL deficiency', 'Disease', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('apoptosis', 'CPA', (103, 112))
55970	33627663	Although BCL-XL PROTACs did not kill the above cancer cells in vitro, DT2216 treatment resulted in significantly reduced tumor growth of the tested models:including Renca (Fig.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('DT2216', 'Var', (70, 76))	('Renca', 'Chemical', '-', (165, 170))	('cancer', 'Disease', (47, 53))	('tumor', 'Disease', (121, 126))	('DT2216', 'Chemical', '-', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('reduced', 'NegReg', (113, 120))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
55974	33627663	Also, DT2216 lost its tumor-inhibitory effect in the same tumor cell lines when injected into NSG mice, which lack T and B lymphocytes, as well as natural killer cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('lost', 'NegReg', (13, 17))	('DT2216', 'Var', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', (22, 27))	('mice', 'Species', '10090', (98, 102))	('DT2216', 'Chemical', '-', (6, 12))
55975	33627663	Collectively, our results suggest that DT2216 exerts its antitumor activity via a mechanism that is dependent on immune cells.	('DT2216', 'Chemical', '-', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('DT2216', 'Var', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
55977	33627663	6b), supporting the notion that DT2216-mediated inhibition of tumor growth in syngeneic models is via CD8+ T cells.	('DT2216-mediated', 'Var', (32, 47))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('CD8', 'Gene', (102, 105))	('CD8', 'Gene', '925', (102, 105))	('tumor', 'Disease', (62, 67))	('DT2216', 'Chemical', '-', (32, 38))	('inhibition', 'NegReg', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
55979	33627663	The percentages of lymphocytes in the spleen, draining lymph node (DLN), and tumors were assessed in mice that had been treated once weekly for 3 weeks with DT2216 after tumors were palpable.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('DT2216', 'Var', (157, 163))	('tumors', 'Disease', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('mice', 'Species', '10090', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('DT2216', 'Chemical', '-', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (170, 176))
55981	33627663	To determine whether this DT2216-mediated Treg depletion was due to increased apoptosis, we injected MC38 tumor-bearing mice with a fluorescent probe that detects active caspases.	('apoptosis', 'biological_process', 'GO:0006915', ('78', '87'))	('mice', 'Species', '10090', (120, 124))	('DT2216-mediated', 'Var', (26, 41))	('DT2216', 'Chemical', '-', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('Treg', 'Chemical', '-', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('apoptosis', 'biological_process', 'GO:0097194', ('78', '87'))	('tumor', 'Disease', (106, 111))	('depletion', 'NegReg', (47, 56))
55982	33627663	A significant increase in median fluorescence intensity (MFI) was observed in TI-Tregs upon DT2216 treatment (Fig.	('DT2216', 'Chemical', '-', (92, 98))	('TI-Tregs', 'Chemical', '-', (78, 86))	('DT2216', 'Var', (92, 98))	('median fluorescence intensity', 'MPA', (26, 55))	('increase', 'PosReg', (14, 22))
55986	33627663	CD39+ TI-Tregs:shown to have suppressive capacity when undergoing apoptosis:exhibited similar levels of cell death after DT2216 treatment (Supplementary Fig.	('apoptosis', 'biological_process', 'GO:0006915', ('66', '75'))	('DT2216', 'Chemical', '-', (121, 127))	('CD3', 'Gene', (0, 3))	('DT2216', 'Var', (121, 127))	('CD3', 'Gene', '28134', (0, 3))	('cell death', 'biological_process', 'GO:0008219', ('104', '114'))	('TI-Tregs', 'Chemical', '-', (6, 14))	('apoptosis', 'biological_process', 'GO:0097194', ('66', '75'))
55987	33627663	Although DT2216 had a small effect on the frequency on total CD8+ T cells (Fig.	('CD8', 'Gene', (61, 64))	('CD8', 'Gene', '925', (61, 64))	('DT2216', 'Chemical', '-', (9, 15))	('DT2216', 'Var', (9, 15))
55990	33627663	Similar increase of Gzmb+ CD8+ T cells was also seen in blood and DLN from tumor-bearing mice, but not spleen and other non-draining lymph nodes (NDLN) after DT2216 treatment (Supplementary Fig.	('Gzmb', 'Gene', '14939', (20, 24))	('increase', 'PosReg', (8, 16))	('CD8', 'Gene', '925', (26, 29))	('mice', 'Species', '10090', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('Gzmb', 'Gene', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('DT2216', 'Chemical', '-', (158, 164))	('tumor', 'Disease', (75, 80))	('CD8', 'Gene', (26, 29))	('DT2216', 'Var', (158, 164))
55991	33627663	This finding supports the notion that treatment with DT2216 leads to an immune active tumor microenvironment due to the elimination of TI-Tregs, resulting in tumor-specific CD8 T cell activation as seen from tumor, blood, and DLNs.	('CD8', 'Gene', '925', (173, 176))	('activation', 'PosReg', (184, 194))	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Disease', (86, 91))	('TI-Tregs', 'Chemical', '-', (135, 143))	('DT2216', 'Chemical', '-', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('T cell activation', 'biological_process', 'GO:0042110', ('177', '194'))	('DT2216', 'Var', (53, 59))	('tumor', 'Disease', (208, 213))	('CD8', 'Gene', (173, 176))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
55992	33627663	TI-Treg depletion by DT2216 was confirmed in ex vivo cancer slice cultures generated from mouse Py8119 BrCa (Supplementary Fig.	('TI-Treg', 'Chemical', '-', (0, 7))	('DT2216', 'Var', (21, 27))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('BrCa', 'Gene', (103, 107))	('mouse', 'Species', '10090', (90, 95))	('BrCa', 'Gene', '672', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('DT2216', 'Chemical', '-', (21, 27))
55999	33627663	The impact of DT2216 was minimal to the majority of myeloid cell populations in tumor-bearing mice, including granulocytic or monocytic MDSC (CD11b+Ly6G+ G-MDSC or CD11b+Ly6C+Ly6G- M-MDSC), macrophages (F4/80+), dendritic cells (CD11c+MHCII+ DC), or CD8+ DCs, with the exception of DC where DT02216 treatment led to slightly decreased TI-DC population (Supplementary Fig.	('CD8', 'Gene', (250, 253))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('CD11b', 'Gene', '16409', (142, 147))	('Ly6G', 'Gene', '546644', (148, 152))	('Ly6C', 'Gene', '17067', (170, 174))	('mice', 'Species', '10090', (94, 98))	('CD11c', 'Gene', (229, 234))	('Ly6G', 'Gene', (148, 152))	('CD11b', 'Gene', (142, 147))	('Ly6C', 'Gene', (170, 174))	('CD11c', 'Gene', '16411', (229, 234))	('decreased', 'NegReg', (325, 334))	('CD8', 'Gene', '925', (250, 253))	('DT2216', 'Chemical', '-', (14, 20))	('DT02216', 'Var', (291, 298))	('CD11b', 'Gene', '16409', (164, 169))	('tumor', 'Disease', (80, 85))	('Ly6G', 'Gene', '546644', (175, 179))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('CD11b', 'Gene', (164, 169))	('Ly6G', 'Gene', (175, 179))	('TI', 'Chemical', '-', (335, 337))	('TI-DC population', 'CPA', (335, 351))
56000	33627663	Treatment with DT2216 had no global effect on the overall levels of Treg, CD4+ Tconv, CD8+ T, NK cells, and B cells from various tissues within non-tumor bearing mice (Supplementary Fig.	('Tconv', 'Chemical', '-', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('CD4+', 'MPA', (74, 78))	('Treg', 'Chemical', '-', (68, 72))	('tumor', 'Disease', (148, 153))	('DT2216', 'Chemical', '-', (15, 21))	('CD8', 'Gene', (86, 89))	('CD8', 'Gene', '925', (86, 89))	('mice', 'Species', '10090', (162, 166))	('DT2216', 'Var', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
56003	33627663	These findings suggest that DT2216 may selectively deplete TI-Treg in an individual tumor/mouse-dependent manner.	('DT2216', 'Var', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('TI-Treg', 'Chemical', '-', (59, 66))	('deplete', 'NegReg', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('mouse', 'Species', '10090', (90, 95))	('tumor', 'Disease', (84, 89))	('TI-Treg', 'CPA', (59, 66))	('DT2216', 'Chemical', '-', (28, 34))
56009	33627663	Histological analysis did not reveal tissue damage in the lung, pancreas, or intestines of Renca-tumor-bearing mice treated with either DT2216 or PZ15227 (Supplementary Fig.	('DT2216', 'Var', (136, 142))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('PZ15227', 'Var', (146, 153))	('Renca', 'Chemical', '-', (91, 96))	('PZ15227', 'Chemical', '-', (146, 153))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mice', 'Species', '10090', (111, 115))	('tumor', 'Disease', (97, 102))	('DT2216', 'Chemical', '-', (136, 142))
56010	33627663	9m), indicating that Treg depletion and CD8+ T cell activation are relatively specific to the tumor microenvironment rather than being systemic and that targeting BCL-XL by PROTACs is a relatively safe and effective way to treat cancer.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Disease', (229, 235))	('CD8', 'Gene', '925', (40, 43))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('T cell activation', 'biological_process', 'GO:0042110', ('45', '62'))	('Treg', 'Chemical', '-', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('targeting', 'Var', (153, 162))	('CD8', 'Gene', (40, 43))
56017	33627663	In the current study, we determined the kinetics of DT2216-induced caspase activation within TI-Tregs and found that caspase activation was detectable at 24 h after DT2216 treatment of MC38 tumor-bearing mice, but completely disappeared after 48 h of treatment (Supplementary Fig.	('DT2216', 'Chemical', '-', (165, 171))	('DT2216', 'Var', (165, 171))	('TI-Tregs', 'Chemical', '-', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (190, 195))	('DT2216', 'Chemical', '-', (52, 58))	('mice', 'Species', '10090', (204, 208))	('caspase activation', 'biological_process', 'GO:0006919', ('67', '85'))	('caspase', 'Enzyme', (67, 74))	('caspase activation', 'biological_process', 'GO:0006919', ('117', '135'))
56023	33627663	Cancer types that are likely to be most susceptible to treatment with DT2216 include: (1) those in which TI-Tregs are critical for immune regulation and cancer progression; and (2) those that rely on BCL-XL for survival and in which high BCL-XL levels and poor outcome are positively correlated.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('DT2216', 'Var', (70, 76))	('TI-Tregs', 'Chemical', '-', (105, 113))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('regulation', 'biological_process', 'GO:0065007', ('138', '148'))	('DT2216', 'Chemical', '-', (70, 76))
56025	33627663	In these cancer types, DT2216 may be able to eliminate TI-Tregs and thereby boost immunity against cancers.	('cancer', 'Disease', (9, 15))	('eliminate', 'NegReg', (45, 54))	('boost', 'PosReg', (76, 81))	('TI-Tregs', 'CPA', (55, 63))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', (99, 105))	('cancers', 'Disease', (99, 106))	('DT2216', 'Chemical', '-', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('DT2216', 'Var', (23, 29))	('TI-Tregs', 'Chemical', '-', (55, 63))
56028	33627663	These are cancers for which DT2216 treatment might lead to direct killing of cancer cells and/or sensitization to anti-tumor immunity (Supplementary Fig.	('DT2216', 'Var', (28, 34))	('tumor', 'Disease', (119, 124))	('sensitization', 'biological_process', 'GO:0046960', ('97', '110'))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('lead to', 'Reg', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('cancers', 'Disease', (10, 17))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancers', 'Disease', 'MESH:D009369', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Disease', (10, 16))	('DT2216', 'Chemical', '-', (28, 34))
56050	33627663	Single-cell suspension of splenic cells was obtained by pressing spleens from the same tumor bearing mice through a 40-microm nylon strainer and lysing red blood cells using ACK lysis buffer (150 mM NH4Cl, 10 mM KHCO3, 0.1 mM EDTA).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('nylon', 'Chemical', 'MESH:D009757', (126, 131))	('lysis', 'biological_process', 'GO:0019835', ('178', '183'))	('ACK', 'Gene', (174, 177))	('NH4Cl', 'Chemical', '-', (199, 204))	('tumor', 'Disease', (87, 92))	('ACK', 'Gene', '107482', (174, 177))	('150', 'Var', (192, 195))	('mice', 'Species', '10090', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('4Cl', 'molecular_function', 'GO:0016207', ('201', '204'))	('EDTA', 'Chemical', 'MESH:D004492', (226, 230))	('KHCO3', 'Chemical', 'MESH:C026329', (212, 217))
56069	33627663	For all studies involving DT2216 or PZ15227 (ref.	('PZ15227', 'Var', (36, 43))	('PZ15227', 'Chemical', '-', (36, 43))	('DT2216', 'Chemical', '-', (26, 32))	('DT2216', 'Var', (26, 32))
56083	33627663	Cells were stained with a combination of the following antibodies: anti-mouse FOXP3-APC (clone FJK-16S, 1:50, eBioscience), anti-mouse Granzyme B-Pacific Blue (clone GB11), anti-mouse Perforin-PE (clone S16009B), anti-mouse Ki-67-PerCP-Cy5.5 (clone 16A8), and anti-mouse/human BCL-XL-PE (clone S486, 1:50, Cell Signaling Technologies, Danvers, MA).	('Ki-67', 'Gene', '17345', (224, 229))	('Granzyme B', 'Gene', (135, 145))	('mouse', 'Species', '10090', (178, 183))	('Granzyme B', 'Gene', '14939', (135, 145))	('APC', 'cellular_component', 'GO:0005680', ('84', '87'))	('human', 'Species', '9606', (271, 276))	('Ki-67', 'Gene', (224, 229))	('S16009B', 'SUBSTITUTION', 'None', (203, 210))	('mouse', 'Species', '10090', (72, 77))	('mouse', 'Species', '10090', (129, 134))	('mouse', 'Species', '10090', (265, 270))	('Signaling', 'biological_process', 'GO:0023052', ('311', '320'))	('APC', 'Gene', '11789', (84, 87))	('mouse', 'Species', '10090', (218, 223))	('APC', 'Gene', (84, 87))	('S16009B', 'Var', (203, 210))
56086	33627663	Cells were further stained with a combination of the following antibodies: anti-human FOXP3-FITC (clone 206D), anti-mouse/human BCL-XL-PE (clone S486, Cell Signaling Technologies).	('human', 'Species', '9606', (122, 127))	('Signaling', 'biological_process', 'GO:0023052', ('156', '165'))	('FITC', 'Chemical', 'MESH:D016650', (92, 96))	('human', 'Species', '9606', (80, 85))	('anti-mouse/human', 'Var', (111, 127))	('mouse', 'Species', '10090', (116, 121))	('FOXP3-FITC', 'Gene', (86, 96))
56092	33627663	Cells were incubated with the following antibodies: anti-mouse CD45-AF532 (clone 30F.11), anti-mouse CD3-APC (clone 17A2), anti-mouse CD4-BV605 (clone GK1.5), anti-mouse CD8 (clone MEL-14), CD11B-PE-dazzle (clone M1/70, 1:200), and FVD-eFluor-780.	('mouse', 'Species', '10090', (164, 169))	('CD8', 'Gene', '925', (170, 173))	('CD45', 'Gene', '5788', (63, 67))	('mouse', 'Species', '10090', (95, 100))	('mouse', 'Species', '10090', (128, 133))	('APC', 'Gene', '11789', (105, 108))	('APC', 'cellular_component', 'GO:0005680', ('105', '108'))	('APC', 'Gene', (105, 108))	('CD3', 'Gene', (101, 104))	('mouse', 'Species', '10090', (57, 62))	('CD8', 'Gene', (170, 173))	('CD3', 'Gene', '28134', (101, 104))	('CD45', 'Gene', (63, 67))	('anti-mouse', 'Var', (123, 133))
56099	33627663	The single-cell RNA sequencing result for renal cancer is deposited as GSE121638 and for the TI-Tregs from MC38 tumor model, it is deposited as GSE150420.	('TI-Tregs', 'Chemical', '-', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('renal cancer', 'Disease', (42, 54))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('GSE121638', 'Var', (71, 80))	('renal cancer', 'Disease', 'MESH:D007680', (42, 54))	('renal cancer', 'Phenotype', 'HP:0009726', (42, 54))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('RNA', 'cellular_component', 'GO:0005562', ('16', '19'))
56108	27494890	Differences in expression of three of the lncRNAs (ENSG00000177133, TCL6, and ENSG00000244020) were validated in this analysis.	('ENSG00000177133', 'Var', (51, 66))	('TCL6', 'Gene', '27004', (68, 72))	('ENSG00000244020', 'Var', (78, 93))	('expression', 'MPA', (15, 25))	('TCL6', 'Gene', (68, 72))
56138	27494890	We next examined the expression of these lncRNAs in the E-TABM-282 dataset and confirmed differential expression of five lncRNAs (fold change > 2, P < 0.05): ENSG00000247225, ENSG00000241732, ENSG00000177133, ENSG00000244020, and TCL6.	('ENSG00000241732', 'Var', (175, 190))	('TCL6', 'Gene', '27004', (230, 234))	('ENSG00000247225', 'Var', (158, 173))	('ENSG00000244020', 'Var', (209, 224))	('TCL6', 'Gene', (230, 234))	('ENSG00000177133', 'Var', (192, 207))
56139	27494890	Because ENSG00000247225 and ENSG00000241732 had been removed from Ensembl, we investigated ENSG00000177133, ENSG00000244020, and TCL6 in this study (Table 2).	('TCL6', 'Gene', '27004', (129, 133))	('TCL6', 'Gene', (129, 133))	('ENSG00000241732', 'Var', (28, 43))
56142	27494890	Decreased expression of three lncRNAs (ENSG00000177133, TCL6, and ENSG00000244020) was observed in ccRCC compared to adjacent normal tissue (P < 0.05) (Figure 3).	('TCL6', 'Gene', (56, 60))	('TCL6', 'Gene', '27004', (56, 60))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('Decreased', 'NegReg', (0, 9))	('RCC', 'Disease', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('expression', 'MPA', (10, 20))	('ENSG00000177133', 'Var', (39, 54))	('ENSG00000244020', 'Var', (66, 81))
56152	27494890	Conversely, knockdown of TCL6 promoted proliferation (Figure 6D).	('knockdown', 'Var', (12, 21))	('promoted', 'PosReg', (30, 38))	('proliferation', 'CPA', (39, 52))	('TCL6', 'Gene', '27004', (25, 29))	('TCL6', 'Gene', (25, 29))
56220	33959493	The inactivation of von Hippel Lindau tumor-suppressor gene, found in up to 90% of patients, is a representative biomarker, and its downstream signaling pathways are influenced accordingly, leading to tumor angiogenesis, cell migration, and proliferation.	('von Hippel Lindau tumor-suppressor', 'Gene', '7428', (20, 54))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('leading to', 'Reg', (190, 200))	('inactivation', 'Var', (4, 16))	('cell migration', 'biological_process', 'GO:0016477', ('221', '235'))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('38', '54'))	('patients', 'Species', '9606', (83, 91))	('tumor', 'Disease', (201, 206))	('signaling', 'biological_process', 'GO:0023052', ('143', '152'))	('angiogenesis', 'biological_process', 'GO:0001525', ('207', '219'))	('influenced', 'Reg', (166, 176))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('38', '54'))	('tumor', 'Disease', (38, 43))	('von Hippel Lindau tumor-suppressor', 'Gene', (20, 54))	('proliferation', 'CPA', (241, 254))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('cell migration', 'CPA', (221, 235))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
56282	33959493	However, the outcomes of OS analyses in ccRCC patients indicated that low STAM1 level was an ideal biomarker in predicting worse survival in early-stage ccRCC patients (pT1 and 2: P < 0.0001; grade 1 and 2: P < 0.0001; AJCC stage I and II: P < 0.0001) (Figure 4).	('ccRCC', 'Phenotype', 'HP:0006770', (153, 158))	('ccRCC', 'Disease', (153, 158))	('low', 'Var', (70, 73))	('patients', 'Species', '9606', (46, 54))	('STAM1', 'Gene', (74, 79))	('STAM1', 'Gene', '8027', (74, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('pT1 and 2', 'Gene', '58492', (169, 178))	('patients', 'Species', '9606', (159, 167))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))
56323	33959493	The dysregulation or mutation of the ESCRT system is linked to hyperproliferation of cells, apoptosis failure, and tumorigenesis.	('apoptosis', 'biological_process', 'GO:0097194', ('92', '101'))	('apoptosis failure', 'Disease', 'MESH:D006333', (92, 109))	('apoptosis', 'biological_process', 'GO:0006915', ('92', '101'))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('dysregulation', 'Var', (4, 17))	('ESCRT system', 'Gene', (37, 49))	('tumor', 'Disease', (115, 120))	('mutation', 'Var', (21, 29))	('hyperproliferation', 'Disease', (63, 81))	('linked', 'Reg', (53, 59))	('apoptosis failure', 'Disease', (92, 109))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
56328	33959493	Depletion of Hrs by knocking down its RNA expression pointed out that EGFR accumulated in cells, further activating MAPK/ERK signaling and its downstream receptors.	('ERK', 'Gene', '5594', (121, 124))	('ERK', 'Gene', (121, 124))	('RNA', 'cellular_component', 'GO:0005562', ('38', '41'))	('EGFR', 'Gene', '1956', (70, 74))	('MAPK', 'molecular_function', 'GO:0004707', ('116', '120'))	('EGFR', 'molecular_function', 'GO:0005006', ('70', '74'))	('EGFR', 'Gene', (70, 74))	('RNA expression', 'MPA', (38, 52))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('ERK', 'molecular_function', 'GO:0004707', ('121', '124'))	('activating', 'PosReg', (105, 115))	('knocking down', 'Var', (20, 33))
56329	33959493	A mutant Hrs also resulted in abnormal EGFR degradation, causing similar pathological processes.	('Hrs', 'Gene', (9, 12))	('mutant', 'Var', (2, 8))	('EGFR', 'molecular_function', 'GO:0005006', ('39', '43'))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('causing', 'Reg', (57, 64))	('degradation', 'biological_process', 'GO:0009056', ('44', '55'))	('resulted in', 'Reg', (18, 29))
56355	31781477	This would upregulate membrane cholesterol content making inhibitors of cholesterol synthesis to act for stabilizing lipid rafts, reducing membrane fluidity, and therefore opposing EMT phenomena.	('membrane fluidity', 'MPA', (139, 156))	('EMT', 'biological_process', 'GO:0001837', ('181', '184'))	('membrane', 'cellular_component', 'GO:0016020', ('22', '30'))	('reducing', 'NegReg', (130, 138))	('EMT phenomena', 'CPA', (181, 194))	('stabilizing lipid rafts', 'MPA', (105, 128))	('membrane', 'cellular_component', 'GO:0016020', ('139', '147'))	('inhibitors', 'Var', (58, 68))	('cholesterol', 'Chemical', 'MESH:D002784', (72, 83))	('upregulate', 'PosReg', (11, 21))	('cholesterol', 'Chemical', 'MESH:D002784', (31, 42))	('cholesterol synthesis', 'biological_process', 'GO:0006695', ('72', '93'))	('membrane cholesterol content', 'MPA', (22, 50))
56363	31781477	Thus, Erk signalling activation and histone H3K27me3 posttranslational modification were the most significantly upregulated marks in TGF-beta-induced EMT that could be turned in therapeutic strategies for EMT-related diseases.	('posttranslational modification', 'biological_process', 'GO:0043687', ('53', '83'))	('Erk', 'Gene', '5594', (6, 9))	('upregulated', 'PosReg', (112, 123))	('TGF-beta', 'Gene', '7040', (133, 141))	('signalling', 'biological_process', 'GO:0023052', ('10', '20'))	('EMT', 'biological_process', 'GO:0001837', ('150', '153'))	('Erk', 'molecular_function', 'GO:0004707', ('6', '9'))	('TGF-beta', 'Gene', (133, 141))	('histone H3K27me', 'biological_process', 'GO:0070734', ('36', '51'))	('activation', 'PosReg', (21, 31))	('histone H3K27me3', 'Var', (36, 52))	('Erk', 'Gene', (6, 9))	('EMT', 'biological_process', 'GO:0001837', ('205', '208'))
56381	31781477	Moreover, SNAIL upregulation is favoured by HDAC1 inhibition suggesting an interrelation between these two proteins in EMT initiation.	('inhibition', 'Var', (50, 60))	('HDAC1', 'Gene', (44, 49))	('upregulation', 'PosReg', (16, 28))	('EMT', 'biological_process', 'GO:0001837', ('119', '122'))	('SNAIL', 'Gene', (10, 15))	('HDAC1', 'Gene', '3065', (44, 49))	('SNAIL', 'Gene', '6615', (10, 15))
56387	31781477	Inactivating ILK, FAK, MAPK, or PI3K/AKT signalling would also suppress EMT, so the ITGB1-FAK/ILK axis revealed by proteomic inquires conducts the TWIST-induced EMT in human breast cancer cells.	('ITGB1', 'Gene', '3688', (84, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('EMT', 'CPA', (72, 75))	('EMT', 'biological_process', 'GO:0001837', ('161', '164'))	('FAK', 'Gene', (90, 93))	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('PI3K', 'molecular_function', 'GO:0016303', ('32', '36'))	('human', 'Species', '9606', (168, 173))	('breast cancer', 'Disease', (174, 187))	('Inactivating', 'Var', (0, 12))	('FAK', 'molecular_function', 'GO:0004717', ('18', '21'))	('AKT', 'Gene', (37, 40))	('FAK', 'Gene', '5747', (90, 93))	('FAK', 'Gene', (18, 21))	('suppress', 'NegReg', (63, 71))	('signalling', 'biological_process', 'GO:0023052', ('41', '51'))	('MAPK', 'molecular_function', 'GO:0004707', ('23', '27'))	('FAK', 'Gene', '5747', (18, 21))	('ITGB1', 'Gene', (84, 89))	('ILK', 'Gene', (94, 97))	('TWIST', 'Gene', (147, 152))	('FAK', 'molecular_function', 'GO:0004717', ('90', '93'))	('ILK', 'Gene', '3611', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('AKT', 'Gene', '207', (37, 40))	('EMT', 'biological_process', 'GO:0001837', ('72', '75'))	('ILK', 'Gene', (13, 16))	('ILK', 'Gene', '3611', (13, 16))	('TWIST', 'Gene', '7291', (147, 152))
56388	31781477	More recently, breast cancer metastasis was associated with alterations in genes encoding for complex I components of mitochondria.	('associated', 'Reg', (44, 54))	('breast cancer metastasis', 'Disease', (15, 39))	('breast cancer metastasis', 'Disease', 'MESH:D001943', (15, 39))	('complex I', 'cellular_component', 'GO:0030964', ('94', '103'))	('alterations', 'Var', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('mitochondria', 'cellular_component', 'GO:0005739', ('118', '130'))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
56390	31781477	Using the iTRAQ labelling, it was found that NDUFB9, one of the respiratory complex I subunits, was downregulated; moreover, NDUFB9 knockdown cells MDA-MB-231 exhibit decreased expression of E-cadherin and an increased expression of vimentin and fibronectin-1, as assessed by immunoblotting analysis.	('vimentin', 'cellular_component', 'GO:0045099', ('233', '241'))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (148, 158))	('expression', 'MPA', (177, 187))	('vimentin', 'Gene', '7431', (233, 241))	('decreased', 'NegReg', (167, 176))	('cadherin', 'molecular_function', 'GO:0008014', ('193', '201'))	('vimentin', 'Gene', (233, 241))	('knockdown', 'Var', (132, 141))	('NDUFB9', 'Gene', (125, 131))	('increased', 'PosReg', (209, 218))	('NDUFB9', 'Gene', (45, 51))	('NDUFB9', 'Gene', '4715', (125, 131))	('complex I', 'cellular_component', 'GO:0030964', ('76', '85'))	('vimentin', 'cellular_component', 'GO:0045098', ('233', '241'))	('E-cadherin', 'Gene', (191, 201))	('NDUFB9', 'Gene', '4715', (45, 51))	('expression', 'MPA', (219, 229))	('E-cadherin', 'Gene', '999', (191, 201))	('fibronectin-1', 'Gene', '2335', (246, 259))	('fibronectin-1', 'Gene', (246, 259))
56402	31781477	EMT process could guide the therapy options in cancer cells expressing oncogenic Ras mutants.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('EMT', 'biological_process', 'GO:0001837', ('0', '3'))	('cancer', 'Disease', (47, 53))	('Ras', 'Gene', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutants', 'Var', (85, 92))
56408	31781477	Using shotgun proteomics, the levels of several proteins were compared in human ENC cells with high and low ALDH1 expressions; it was noticed that serum deprivation-response protein (SDPR) was particularly expressed in cells with high ALDH1 expression.	('human', 'Species', '9606', (74, 79))	('ENC cells', 'Disease', (80, 89))	('ALDH1', 'Gene', (108, 113))	('SDPR', 'Gene', '8436', (183, 187))	('serum deprivation-response protein', 'Gene', '8436', (147, 181))	('ALDH1', 'Gene', (235, 240))	('ALDH1', 'Gene', '216', (108, 113))	('high', 'Var', (230, 234))	('ENC cells', 'Disease', 'MESH:D018269', (80, 89))	('serum deprivation-response protein', 'Gene', (147, 181))	('ENC', 'Phenotype', 'HP:0012114', (80, 83))	('ALDH', 'molecular_function', 'GO:0004030', ('235', '239'))	('ALDH', 'molecular_function', 'GO:0004030', ('108', '112'))	('ALDH1', 'Gene', '216', (235, 240))	('SDPR', 'Gene', (183, 187))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))
56420	31781477	Multiomic platforms were enrolled also in exploring EMT in renal carcinoma through modulators of transcription factors such as SNAIL, well known to be involved in EMT initiation.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('EMT', 'biological_process', 'GO:0001837', ('52', '55'))	('SNAIL', 'Gene', (127, 132))	('EMT', 'biological_process', 'GO:0001837', ('163', '166'))	('renal carcinoma', 'Disease', (59, 74))	('renal carcinoma', 'Disease', 'MESH:D002292', (59, 74))	('transcription', 'biological_process', 'GO:0006351', ('97', '110'))	('SNAIL', 'Gene', '6615', (127, 132))	('modulators', 'Var', (83, 93))	('renal carcinoma', 'Phenotype', 'HP:0005584', (59, 74))
56421	31781477	Thus, BRCA1-associated protein 1 (BAP1) is an enzyme from the ubiquitinase family whose encoding gene BAP1 is mutated in almost 10% of clear cell renal cell carcinomas (ccRCC).	('BRCA1-associated protein 1', 'Gene', (6, 32))	('BAP1', 'Gene', (34, 38))	('mutated', 'Var', (110, 117))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('BAP1', 'Gene', '8314', (102, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))	('clear cell renal cell carcinomas', 'Disease', 'MESH:D002292', (135, 167))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (146, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (146, 167))	('BAP1', 'Gene', (102, 106))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (135, 166))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (135, 167))	('BAP1', 'Gene', '8314', (34, 38))	('BRCA1-associated protein 1', 'Gene', '8314', (6, 32))	('clear cell renal cell carcinomas', 'Disease', (135, 167))	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('ccRCC', 'Disease', 'MESH:D002292', (169, 174))	('ccRCC', 'Disease', (169, 174))
56430	31781477	In A549 lung cancer cells, it was found that knockdown KAP1 arrested cells in the G0/G1 phase and decreased growth, metastasis, and EMT process; thus, Raf-MEK-ERK pathway represents a source of therapeutic inquires and regulate lung cancer development.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('A549', 'CellLine', 'CVCL:0023', (3, 7))	('MEK', 'Gene', '5609', (155, 158))	('EMT process', 'CPA', (132, 143))	('ERK', 'Gene', '5594', (159, 162))	('ERK', 'molecular_function', 'GO:0004707', ('159', '162'))	('lung cancer', 'Disease', (228, 239))	('KAP1', 'Gene', (55, 59))	('knockdown', 'Var', (45, 54))	('lung cancer', 'Disease', 'MESH:D008175', (8, 19))	('MEK', 'Gene', (155, 158))	('Raf', 'Gene', (151, 154))	('cells in the G0/G1 phase', 'CPA', (69, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (8, 19))	('ERK', 'Gene', (159, 162))	('lung cancer', 'Disease', 'MESH:D008175', (228, 239))	('decreased growth', 'Phenotype', 'HP:0001510', (98, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (228, 239))	('Raf', 'Gene', '22882', (151, 154))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('growth', 'CPA', (108, 114))	('EMT', 'biological_process', 'GO:0001837', ('132', '135'))	('KAP1', 'Gene', '1033', (55, 59))	('G1 phase', 'biological_process', 'GO:0051318', ('85', '93'))	('lung cancer', 'Disease', (8, 19))	('decreased', 'NegReg', (98, 107))
56447	31781477	Further functional evaluation in BAP1 wild-type, BAP1 knocked down, and BAP1 noncatalytically expressing NCI-H226 mesothelioma cells indicate that BAP1 enzymatic activity was a requisite to maintain these proteomic and genomic phenotypes.	('BAP1', 'Gene', (147, 151))	('knocked', 'Var', (54, 61))	('BAP1', 'Gene', '8314', (72, 76))	('BAP1', 'Gene', (49, 53))	('BAP1', 'Gene', '8314', (33, 37))	('NCI-H226', 'CellLine', 'CVCL:1544', (105, 113))	('mesothelioma', 'Disease', (114, 126))	('BAP1', 'Gene', (72, 76))	('mesothelioma', 'Disease', 'MESH:D008654', (114, 126))	('BAP1', 'Gene', (33, 37))	('BAP1', 'Gene', '8314', (147, 151))	('BAP1', 'Gene', '8314', (49, 53))
56452	31781477	These proteomic data highlight the antitumour properties and EMT inhibitors of hBMSCs with the potential to be explored in glioma therapy.	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('tumour', 'Disease', (39, 45))	('hBMSCs', 'Gene', (79, 85))	('EMT', 'biological_process', 'GO:0001837', ('61', '64'))	('inhibitors', 'Var', (65, 75))	('glioma', 'Disease', (123, 129))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('C', 'Chemical', 'MESH:D002244', (83, 84))
56486	31781477	A high level of GDF15 prognosticated reduced overall survival in CRC.	('GDF15', 'Gene', (16, 21))	('GDF15', 'Gene', '9518', (16, 21))	('CRC', 'Phenotype', 'HP:0003003', (65, 68))	('CRC', 'Disease', 'MESH:D015179', (65, 68))	('high level', 'Var', (2, 12))	('reduced', 'NegReg', (37, 44))	('CRC', 'Disease', (65, 68))	('overall survival', 'MPA', (45, 61))
56493	31781477	Furthermore, FGFR1 expression was associated with peritoneal dissemination of the tumour and with EMT that was reflected in poor prognosis for GC patients.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('associated', 'Reg', (34, 44))	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('GC', 'Phenotype', 'HP:0012126', (143, 145))	('FGFR1', 'Gene', (13, 18))	('expression', 'Var', (19, 29))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))	('FGFR1', 'Gene', '2260', (13, 18))	('GC', 'Disease', 'MESH:D013274', (143, 145))	('EMT', 'biological_process', 'GO:0001837', ('98', '101'))	('EMT', 'CPA', (98, 101))	('patients', 'Species', '9606', (146, 154))
56531	31781477	When comparing these data to standard breast cancer cell lines (MDA-MB-231, MCF7, and BT-474), the authors have shown that MBrCa have a clear mesenchymal pattern and that surface proteome is different when compared to standard BC cell lines.	('BT-474', 'Chemical', 'MESH:C400102', (86, 92))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('MCF7', 'CellLine', 'CVCL:0031', (76, 80))	('breast cancer', 'Disease', (38, 51))	('mesenchymal pattern', 'CPA', (142, 161))	('C', 'Chemical', 'MESH:D002244', (228, 229))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('BC', 'Phenotype', 'HP:0003002', (227, 229))	('MBrCa', 'Var', (123, 128))	('BC', 'Disease', 'MESH:D001943', (227, 229))	('C', 'Chemical', 'MESH:D002244', (126, 127))	('C', 'Chemical', 'MESH:D002244', (77, 78))
56558	31781477	In human oral squamous cell carcinomas (OSCCs), nucleosome remodelling and deacetylase (NuRD) complex regulates tumourigenesis processes, and the loss of the subunit Deleted in Oral Cancer 1 (DOC1) associates with protumourigenesis and EMT processes.	('human', 'Species', '9606', (3, 8))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (14, 38))	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('NuRD) complex', 'cellular_component', 'GO:0016581', ('88', '101'))	('tumour', 'Disease', 'MESH:D009369', (217, 223))	('OSCC', 'CellLine', 'CVCL:L894', (40, 44))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (14, 38))	('DOC1', 'Gene', (192, 196))	('tumour', 'Disease', (217, 223))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('DOC1', 'Gene', '8099', (192, 196))	('nucleosome', 'cellular_component', 'GO:0000786', ('48', '58'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('EMT', 'biological_process', 'GO:0001837', ('236', '239'))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('tumour', 'Disease', (112, 118))	('EMT processes', 'CPA', (236, 249))	('Cancer', 'Phenotype', 'HP:0002664', (182, 188))	('loss', 'Var', (146, 150))	('squamous cell carcinomas', 'Disease', (14, 38))	('Deleted in Oral Cancer 1', 'Gene', '8099', (166, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('Deleted in Oral Cancer 1', 'Gene', (166, 190))	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))
56577	31781477	Upon applying this proteomic analysis, multiple protumoural processes were shown to be hindered by this inhibitor; thus, KHS101 can be foreseen as a multitargeting inhibitor in BC.	('BC', 'Phenotype', 'HP:0003002', (177, 179))	('BC', 'Disease', 'MESH:D001943', (177, 179))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('KHS101', 'Var', (121, 127))	('tumour', 'Disease', (51, 57))
56586	31781477	But when introducing also metformin, EMT and metastasis were inhibited, and moreover, metformin could inhibit AKT/GSK-3beta signalling induced by bFGF-mediated activation.	('EMT', 'biological_process', 'GO:0001837', ('37', '40'))	('inhibited', 'NegReg', (61, 70))	('signalling', 'biological_process', 'GO:0023052', ('124', '134'))	('AKT', 'Gene', (110, 113))	('metformin', 'Chemical', 'MESH:D008687', (26, 35))	('GSK-3beta', 'Gene', '2932', (114, 123))	('GSK-3beta', 'Gene', (114, 123))	('bFGF', 'Gene', '2247', (146, 150))	('bFGF', 'Gene', (146, 150))	('inhibit', 'NegReg', (102, 109))	('metformin', 'Var', (86, 95))	('GSK', 'molecular_function', 'GO:0050321', ('114', '117'))	('metformin', 'Chemical', 'MESH:D008687', (86, 95))	('AKT', 'Gene', '207', (110, 113))
56632	31781477	The acetylated version of mutant p53 protein is enlisted on the EFNB2 promoter and upregulates its expression in conjunction with coactivator p300.	('expression', 'MPA', (99, 109))	('EFNB2', 'Gene', (64, 69))	('EFNB2', 'Gene', '1948', (64, 69))	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('p300', 'Gene', (142, 146))	('upregulates', 'PosReg', (83, 94))	('p53', 'Gene', (33, 36))	('p300', 'Gene', '2033', (142, 146))	('p53', 'Gene', '7157', (33, 36))	('mutant', 'Var', (26, 32))	('protein', 'Protein', (37, 44))
56633	31781477	Silencing EFNB2 induces chemosensitivity in tumours that display mutant p53.	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('tumours', 'Disease', 'MESH:D009369', (44, 51))	('EFNB2', 'Gene', (10, 15))	('EFNB2', 'Gene', '1948', (10, 15))	('mutant', 'Var', (65, 71))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('tumours', 'Disease', (44, 51))	('chemosensitivity', 'MPA', (24, 40))	('induces', 'Reg', (16, 23))	('Silencing', 'Var', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
56635	31781477	Targeting the ephrin-B2 axes can increase the therapeutic capacity of cytostatics in tumours that display mutant p53.	('therapeutic capacity of cytostatics', 'MPA', (46, 81))	('mutant', 'Var', (106, 112))	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('ephrin-B2', 'Gene', (14, 23))	('tumours', 'Disease', 'MESH:D009369', (85, 92))	('ephrin', 'molecular_function', 'GO:0005106', ('14', '20'))	('increase', 'PosReg', (33, 41))	('tumours', 'Disease', (85, 92))	('p53', 'Gene', '7157', (113, 116))	('ephrin-B2', 'Gene', '1948', (14, 23))	('p53', 'Gene', (113, 116))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('ephrin', 'molecular_function', 'GO:0046875', ('14', '20'))
56653	31781477	In BRAFV600E-mutated melanoma tumours, the acquired resistance to MEK1/2 inhibitors (MEKi) reinstalls ERK1/2 signalling.	('melanoma tumours', 'Disease', (21, 37))	('MEK', 'Gene', '5609', (85, 88))	('BRAFV600E-mutated', 'Var', (3, 20))	('MEK', 'Gene', (85, 88))	('MEK', 'Gene', '5609', (66, 69))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('MEK1/2', 'Gene', '5604;5605', (66, 72))	('MEK1/2', 'Gene', (66, 72))	('reinstalls', 'PosReg', (91, 101))	('MEK', 'Gene', (66, 69))	('MEK1', 'molecular_function', 'GO:0004708', ('66', '70'))	('melanoma tumours', 'Disease', 'MESH:D008545', (21, 37))	('ERK1/2', 'Gene', (102, 108))	('ERK1', 'molecular_function', 'GO:0004707', ('102', '106'))	('BRAFV600E', 'Mutation', 'rs113488022', (3, 12))	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('ERK1/2', 'Gene', '5595;5594', (102, 108))	('signalling', 'biological_process', 'GO:0023052', ('109', '119'))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
56664	31781477	Knocking down ANXA2 induced an inverse EMT phenotype.	('EMT', 'biological_process', 'GO:0001837', ('39', '42'))	('ANXA2', 'Gene', (14, 19))	('ANXA2', 'Gene', '302', (14, 19))	('Knocking down', 'Var', (0, 13))
56665	31781477	Thus, if a new therapeutical approach is to be designed in the future, inhibition of tandem HGF/c-met and IGF-1/IGF-1R networks could reduce EMT and gefitinib resistance.	('HGF', 'Gene', (92, 95))	('c-met', 'Gene', (96, 101))	('inhibition', 'Var', (71, 81))	('EMT', 'CPA', (141, 144))	('reduce EMT', 'Phenotype', 'HP:0032198', (134, 144))	('reduce', 'NegReg', (134, 140))	('EMT', 'biological_process', 'GO:0001837', ('141', '144'))	('HGF', 'Gene', '3082', (92, 95))	('IGF-1', 'Gene', '3479', (112, 117))	('IGF-1', 'Gene', (112, 117))	('IGF-1R', 'Gene', '3480', (112, 118))	('c-met', 'Gene', '4233', (96, 101))	('IGF-1', 'Gene', '3479', (106, 111))	('IGF-1R', 'Gene', (112, 118))	('IGF-1', 'Gene', (106, 111))	('gefitinib', 'Chemical', 'MESH:C419708', (149, 158))
56671	31781477	Within the glycolysis pathway, lactate dehydrogenase A enzyme (LDHA) is a crucial node, and if knocked down (e.g., with siRNA or with a LDHA specific inhibitor like FX-11), PC-3RR cells would develop radiosensitivity, reduced EMT phenotype, hypoxia, and apoptosis.	('apoptosis', 'biological_process', 'GO:0006915', ('254', '263'))	('radiosensitivity', 'CPA', (200, 216))	('hypoxia', 'Disease', 'MESH:D000860', (241, 248))	('EMT', 'biological_process', 'GO:0001837', ('226', '229'))	('reduced', 'NegReg', (218, 225))	('LDHA', 'Gene', (136, 140))	('LDHA', 'Gene', (63, 67))	('knocked down', 'Var', (95, 107))	('lactate dehydrogenase A', 'Gene', '3939', (31, 54))	('glycolysis', 'biological_process', 'GO:0006096', ('11', '21'))	('EMT phenotype', 'CPA', (226, 239))	('PC', 'Phenotype', 'HP:0012125', (173, 175))	('lactate dehydrogenase A', 'Gene', (31, 54))	('LDHA', 'Gene', '3939', (136, 140))	('reduced EMT', 'Phenotype', 'HP:0032198', (218, 229))	('LDHA', 'Gene', '3939', (63, 67))	('hypoxia', 'Disease', (241, 248))	('apoptosis', 'CPA', (254, 263))	('develop', 'PosReg', (192, 199))	('PC', 'Disease', 'MESH:D011471', (173, 175))	('apoptosis', 'biological_process', 'GO:0097194', ('254', '263'))
56675	31781477	If this receptor is knocked down in this cell line, proteins p53 and p21 are reduced.	('proteins', 'Protein', (52, 60))	('p21', 'Gene', (69, 72))	('p21', 'Gene', '644914', (69, 72))	('reduced', 'NegReg', (77, 84))	('knocked', 'Var', (20, 27))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))
56679	31781477	Indeed, the NgBR knockdown of NSCLC cells inhibited EMT process, while NgBR overexpression induced EMT, through EMT-related proteins, mainly Snail1, the transcription factor repressing E-cadherin expression.	('NgBR', 'Gene', '116150', (12, 16))	('Snail1', 'Gene', (141, 147))	('transcription', 'biological_process', 'GO:0006351', ('153', '166'))	('NgBR', 'Gene', (71, 75))	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('transcription factor', 'molecular_function', 'GO:0000981', ('153', '173'))	('E-cadherin', 'Gene', (185, 195))	('inhibited', 'NegReg', (42, 51))	('E-cadherin', 'Gene', '999', (185, 195))	('EMT', 'biological_process', 'GO:0001837', ('52', '55'))	('EMT', 'CPA', (99, 102))	('EMT process', 'CPA', (52, 63))	('NSCLC', 'Disease', (30, 35))	('EMT', 'biological_process', 'GO:0001837', ('99', '102'))	('NgBR', 'Gene', '116150', (71, 75))	('knockdown', 'Var', (17, 26))	('induced', 'PosReg', (91, 98))	('EMT', 'biological_process', 'GO:0001837', ('112', '115'))	('NgBR', 'Gene', (12, 16))	('cadherin', 'molecular_function', 'GO:0008014', ('187', '195'))	('Snail1', 'Gene', '6615', (141, 147))
56698	27686732	Studies also suggest that lncRNA aberrant expression is associated with numerous diseases including cancer.	('lncRNA', 'Protein', (26, 32))	('numerous diseases', 'Disease', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('associated', 'Reg', (56, 66))	('numerous diseases', 'Disease', 'MESH:D004194', (72, 89))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('aberrant expression', 'Var', (33, 52))
56708	27686732	However, recent studies have linked specific lncRNA gene mutations with cancer, raising the possibility of lncRNA-based cancer diagnostics and therapy.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('mutations', 'Var', (57, 66))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('lncRNA gene', 'Gene', (45, 56))	('cancer', 'Disease', (72, 78))
56724	27686732	HOTAIR knockdown efficiently inhibits cell proliferation and matrix invasiveness in gastric cancer cells in vitro.	('cell proliferation', 'CPA', (38, 56))	('gastric cancer', 'Disease', (84, 98))	('gastric cancer', 'Disease', 'MESH:D013274', (84, 98))	('gastric cancer', 'Phenotype', 'HP:0012126', (84, 98))	('matrix invasiveness', 'CPA', (61, 80))	('inhibits', 'NegReg', (29, 37))	('cell proliferation', 'biological_process', 'GO:0008283', ('38', '56'))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('knockdown', 'Var', (7, 16))
56726	27686732	The five-year survival rate of patients with positive HOTAIR expression was greatly reduced compared with patients with negative expression.	('reduced', 'NegReg', (84, 91))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (31, 39))	('HOTAIR expression', 'Var', (54, 71))
56727	27686732	In vitro, HOTAIR facilitates ESCC cell proliferation, colony formation, and migration, while silencing of HOTAIR in ESCC KYSE30 cells reduced cell invasion and migration but enhances apoptosis rate.	('apoptosis rate', 'CPA', (183, 197))	('silencing', 'Var', (93, 102))	('facilitates', 'PosReg', (17, 28))	('colony formation', 'CPA', (54, 70))	('migration', 'CPA', (76, 85))	('migration', 'CPA', (160, 169))	('KYSE30', 'CellLine', 'CVCL:1351', (121, 127))	('cell invasion', 'CPA', (142, 155))	('enhances', 'PosReg', (174, 182))	('ESCC cell proliferation', 'CPA', (29, 52))	('cell proliferation', 'biological_process', 'GO:0008283', ('34', '52'))	('reduced', 'NegReg', (134, 141))	('HOTAIR', 'Gene', (106, 112))	('apoptosis', 'biological_process', 'GO:0097194', ('183', '192'))	('formation', 'biological_process', 'GO:0009058', ('61', '70'))	('apoptosis', 'biological_process', 'GO:0006915', ('183', '192'))
56728	27686732	In nude mice ESCC models, HOTAIR promoted cell proliferation and tumor metastasis, while knockout reduced the metastasis of ESCC cells.	('HOTAIR', 'Var', (26, 32))	('promoted', 'PosReg', (33, 41))	('metastasis', 'CPA', (110, 120))	('ESCC', 'Disease', (13, 17))	('cell proliferation', 'CPA', (42, 60))	('tumor metastasis', 'Disease', (65, 81))	('tumor metastasis', 'Disease', 'MESH:D009362', (65, 81))	('cell proliferation', 'biological_process', 'GO:0008283', ('42', '60'))	('nude mice', 'Species', '10090', (3, 12))	('reduced', 'NegReg', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
56732	27686732	Additionally, HOTAIR impedes RNA binding motif 38 (RBM38) protein expression and initiates HCC cell invasion and migration.	('protein', 'Protein', (58, 65))	('RBM38', 'Gene', (51, 56))	('RBM38', 'Gene', '55544', (51, 56))	('HCC', 'Gene', '619501', (91, 94))	('HCC', 'Phenotype', 'HP:0001402', (91, 94))	('impedes', 'NegReg', (21, 28))	('expression', 'MPA', (66, 76))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('RNA binding', 'molecular_function', 'GO:0003723', ('29', '40'))	('RNA binding motif 38', 'Gene', '55544', (29, 49))	('RNA', 'cellular_component', 'GO:0005562', ('29', '32'))	('HOTAIR', 'Var', (14, 20))	('initiates', 'PosReg', (81, 90))	('RNA binding motif 38', 'Gene', (29, 49))	('HCC', 'Gene', (91, 94))
56738	27686732	Facilitation of matrix invasion and migration has been ascribed to HOTAIR-mediated activation of VEGF, MMP-9, and genes associated with epithelial-to-mesenchymal transition (EMT) as well as inhibition of p21.	('MMP-9', 'Gene', '4318', (103, 108))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('136', '172'))	('VEGF', 'Gene', (97, 101))	('MMP-9', 'Gene', (103, 108))	('matrix invasion', 'CPA', (16, 31))	('p21', 'Gene', (204, 207))	('epithelial-to-mesenchymal transition', 'CPA', (136, 172))	('VEGF', 'Gene', '7422', (97, 101))	('MMP-9', 'molecular_function', 'GO:0004229', ('103', '108'))	('EMT', 'biological_process', 'GO:0001837', ('174', '177'))	('inhibition', 'Var', (190, 200))	('p21', 'Gene', '644914', (204, 207))	('genes', 'Gene', (114, 119))	('activation', 'PosReg', (83, 93))
56743	27686732	Ip1, HO8910-PM, and HEY-A8) in vitro depresses cell migration and invasion.	('depresses', 'NegReg', (37, 46))	('Ip1', 'Gene', '8517', (0, 3))	('HO8910-PM', 'Var', (5, 14))	('HO8910', 'CellLine', 'CVCL:6868', (5, 11))	('Ip1', 'Gene', (0, 3))	('cell migration', 'biological_process', 'GO:0016477', ('47', '61'))
56753	27686732	MALAT1 is associated with EMT, which confers invasive capacity to malignant cells, and the depletion of MALAT1 can reduce the migration of glioblastoma cells.	('glioblastoma', 'Disease', 'MESH:D005909', (139, 151))	('glioblastoma', 'Phenotype', 'HP:0012174', (139, 151))	('depletion', 'Var', (91, 100))	('EMT', 'biological_process', 'GO:0001837', ('26', '29'))	('MALAT1', 'Gene', (104, 110))	('glioblastoma', 'Disease', (139, 151))	('reduce', 'NegReg', (115, 121))
56763	27686732	Post-transcriptional silencing of MALAT1 can reduce ESCC cell proliferation through cell cycle block, and this may relate to suppression of MALAT1-mediated upregulation of p21 and p27 as well as inhibition of the cell cycle-associated transcription factor B-MYB.	('B-MYB', 'Gene', (256, 261))	('B-MYB', 'Gene', '4605', (256, 261))	('ESCC', 'Disease', (52, 56))	('cell proliferation', 'biological_process', 'GO:0008283', ('57', '75'))	('cell cycle block', 'CPA', (84, 100))	('cell cycle', 'biological_process', 'GO:0007049', ('84', '94'))	('inhibition', 'NegReg', (195, 205))	('reduce', 'NegReg', (45, 51))	('p27', 'Gene', '3429', (180, 183))	('p27', 'Gene', (180, 183))	('p21', 'Gene', (172, 175))	('transcription factor', 'molecular_function', 'GO:0000981', ('235', '255'))	('p21', 'Gene', '644914', (172, 175))	('upregulation', 'PosReg', (156, 168))	('suppression', 'NegReg', (125, 136))	('MALAT1-mediated', 'Gene', (140, 155))	('cell cycle', 'biological_process', 'GO:0007049', ('213', '223'))	('MALAT1', 'Gene', (34, 40))	('transcription', 'biological_process', 'GO:0006351', ('235', '248'))	('Post-transcriptional', 'Var', (0, 20))
56765	27686732	Stable knockout of MALAT1 prevents cell proliferation and motility, which is associated with G2/M arrest, enhanced apoptosis, disrupted EMT, and weakened cancer stem-like properties in vitro, consistent with a putative oncogenic role for MALAT1 in this usually fatal disease.	('EMT', 'biological_process', 'GO:0001837', ('136', '139'))	('enhanced', 'PosReg', (106, 114))	('apoptosis', 'biological_process', 'GO:0097194', ('115', '124'))	('prevents', 'NegReg', (26, 34))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cell proliferation', 'CPA', (35, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('115', '124'))	('disrupted', 'NegReg', (126, 135))	('cell proliferation', 'biological_process', 'GO:0008283', ('35', '53'))	('knockout', 'Var', (7, 15))	('apoptosis', 'CPA', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('weakened', 'NegReg', (145, 153))	('MALAT1', 'Gene', (19, 25))	('EMT', 'CPA', (136, 139))
56772	27686732	In castrated male nude mice, siRNA-mediated silencing of MALAT1 delayed tumor growth and inhibited PCa cell metastasis.	('delayed', 'NegReg', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('PCa cell metastasis', 'CPA', (99, 118))	('PCa', 'Phenotype', 'HP:0012125', (99, 102))	('tumor', 'Disease', (72, 77))	('inhibited', 'NegReg', (89, 98))	('nude mice', 'Species', '10090', (18, 27))	('silencing', 'Var', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('MALAT1', 'Gene', (57, 63))
56781	27686732	Furthermore, high expression of MALAT1 was found exclusively in metastatic tissues developed in lymph node, and knockout of MALAT1 inhibits melanoma cell migration in vitro.	('knockout', 'Var', (112, 120))	('MALAT1', 'Gene', (124, 130))	('cell migration', 'biological_process', 'GO:0016477', ('149', '163'))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('inhibits', 'NegReg', (131, 139))	('melanoma', 'Disease', (140, 148))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))
56783	27686732	Ectopic expression of MALAT2 enhanced the motility of the human GC cell line SGC-7901 in vitro, whereas silencing of MALAT2 impairs tumor metastasis.	('impairs tumor metastasis', 'Disease', 'MESH:D009362', (124, 148))	('human', 'Species', '9606', (58, 63))	('motility', 'CPA', (42, 50))	('silencing', 'Var', (104, 113))	('GC', 'Phenotype', 'HP:0012126', (78, 80))	('MALAT2', 'Gene', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('GC', 'Phenotype', 'HP:0012126', (64, 66))	('SGC-7901', 'CellLine', 'CVCL:0520', (77, 85))	('MALAT2', 'Gene', (117, 123))	('enhanced', 'PosReg', (29, 37))	('impairs tumor metastasis', 'Disease', (124, 148))
56788	27686732	The oncogenic properties of H19 were strongly associated with antagonism of the tumor suppressor miRNA let-7 and forced EMT mediated by the non-histone chromosomal transcriptional regulator HMGA2.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('H19', 'Gene', '283120', (28, 31))	('oncogenic properties', 'CPA', (4, 24))	('HMGA2', 'Gene', (190, 195))	('H19', 'Gene', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))	('tumor', 'Disease', (80, 85))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('antagonism', 'Var', (62, 72))	('associated', 'Reg', (46, 56))	('EMT', 'biological_process', 'GO:0001837', ('120', '123'))	('HMGA2', 'Gene', '8091', (190, 195))	('miR', 'Gene', '220972', (97, 100))	('miR', 'Gene', (97, 100))	('forced EMT mediated', 'CPA', (113, 132))
56798	27686732	In retinoblastoma tissues, high BANCR expression was correlated with tumor size and invasion of choroid and optic nerve.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('correlated', 'Reg', (53, 63))	('BANCR', 'Gene', '100885775', (32, 37))	('retinoblastoma', 'Phenotype', 'HP:0009919', (3, 17))	('high', 'Var', (27, 31))	('BANCR', 'Gene', (32, 37))	('retinoblastoma', 'Disease', 'MESH:D012175', (3, 17))	('retinoblastoma', 'Disease', (3, 17))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
56815	27686732	As expected, the ectopic expression of UCA1 induced a marked increase in lymph node metastasis.	('UCA1', 'Gene', '652995', (39, 43))	('UCA1', 'Gene', (39, 43))	('ectopic expression', 'Var', (17, 35))	('increase', 'PosReg', (61, 69))	('lymph node metastasis', 'CPA', (73, 94))
56822	27686732	UCA1 upregulation was correlated with poor differentiation, advanced lymph node classification, and metastasis of melanoma cells, while invasive and migratory capacities were remarkably diminished by UCA1 knockdown.	('metastasis of melanoma cells', 'Disease', 'MESH:D009362', (100, 128))	('advanced lymph node classification', 'CPA', (60, 94))	('UCA1', 'Gene', '652995', (200, 204))	('UCA1', 'Gene', (200, 204))	('knockdown', 'Var', (205, 214))	('upregulation', 'PosReg', (5, 17))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('UCA1', 'Gene', '652995', (0, 4))	('UCA1', 'Gene', (0, 4))	('diminished', 'NegReg', (186, 196))	('metastasis of melanoma cells', 'Disease', (100, 128))	('poor differentiation', 'CPA', (38, 58))
56826	27686732	Conversely, inhibition of FOXCUT impaired the invasion and migration capabilities of the breast cancer cell lines MDA-MB-231 and MDA-MB-468.	('FOXCUT', 'Gene', '101927703', (26, 32))	('inhibition', 'Var', (12, 22))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('impaired', 'NegReg', (33, 41))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (114, 124))	('FOXCUT', 'Gene', (26, 32))
56832	27686732	On the contrary, knockdown of these lncRNAs lead to diminished cell viability and increased anoikis in EAC EC9706 and KYSE150 cells compared to cells transfected with empty vector.	('KYSE150', 'CellLine', 'CVCL:1348', (118, 125))	('cell viability', 'CPA', (63, 77))	('EC9706', 'CellLine', 'CVCL:E307', (107, 113))	('diminished', 'NegReg', (52, 62))	('increased', 'PosReg', (82, 91))	('knockdown', 'Var', (17, 26))	('anoikis', 'CPA', (92, 99))	('anoikis', 'biological_process', 'GO:0043276', ('92', '99'))
56836	27686732	found that local infiltration depth of neuroblastoma was correlated with dysregulated expression of SPRY4-IT1, leading to repressed proliferation and extensive apoptosis.	('apoptosis', 'CPA', (160, 169))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('dysregulated', 'Var', (73, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('neuroblastoma', 'Disease', 'MESH:D009447', (39, 52))	('expression', 'MPA', (86, 96))	('neuroblastoma', 'Disease', (39, 52))	('neuroblastoma', 'Phenotype', 'HP:0003006', (39, 52))	('SPRY4-IT1', 'Gene', (100, 109))	('repressed proliferation', 'CPA', (122, 145))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (100, 109))
56845	27686732	In one study, patients with high ATB expression had strikingly shorter overall survivals than those with low expression.	('shorter', 'NegReg', (63, 70))	('ATB', 'Protein', (33, 36))	('overall survivals', 'MPA', (71, 88))	('ATB', 'Chemical', 'MESH:C042207', (33, 36))	('high', 'Var', (28, 32))	('expression', 'MPA', (37, 47))	('patients', 'Species', '9606', (14, 22))
56852	27686732	In vitro, knockdown of ZXF1 by siRNA depressed the invasion and migration of A549 cells, whereas no remarkable effect was observed on cell growth.	('cell growth', 'biological_process', 'GO:0016049', ('134', '145'))	('depressed', 'NegReg', (37, 46))	('ZXF1', 'Gene', (23, 27))	('ZXF1', 'Gene', '100132116', (23, 27))	('knockdown', 'Var', (10, 19))	('A549', 'CellLine', 'CVCL:0023', (77, 81))
56858	27686732	In vitro experiment, knockdown of CARLo-5 inhibited the proliferative activity, infiltration, and migration of NSCLC cell lines.	('infiltration', 'CPA', (80, 92))	('NSCLC', 'Disease', (111, 116))	('men', 'Species', '9606', (15, 18))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('inhibited', 'NegReg', (42, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('CARLo-5', 'Gene', (34, 41))	('CARLo-5', 'Gene', '100507056', (34, 41))	('knockdown', 'Var', (21, 30))	('proliferative activity', 'CPA', (56, 78))
56859	27686732	Additionally, inhibition of CARLo-5 could reverse EMT in a NSCLC cell line.	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('EMT', 'biological_process', 'GO:0001837', ('50', '53'))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('EMT', 'CPA', (50, 53))	('CARLo-5', 'Gene', (28, 35))	('CARLo-5', 'Gene', '100507056', (28, 35))	('inhibition', 'Var', (14, 24))	('NSCLC', 'Disease', (59, 64))
56865	27686732	XIST expression is upregulated in glioma tissues and human glioblastoma stem cells (GSCs), while knockdown of XIST reduced cell proliferation, migration, and invasion, and induced apoptosis.	('cell proliferation', 'CPA', (123, 141))	('reduced', 'NegReg', (115, 122))	('glioblastoma', 'Disease', 'MESH:D005909', (59, 71))	('migration', 'CPA', (143, 152))	('apoptosis', 'CPA', (180, 189))	('apoptosis', 'biological_process', 'GO:0097194', ('180', '189'))	('cell proliferation', 'biological_process', 'GO:0008283', ('123', '141'))	('glioblastoma', 'Disease', (59, 71))	('apoptosis', 'biological_process', 'GO:0006915', ('180', '189'))	('glioblastoma', 'Phenotype', 'HP:0012174', (59, 71))	('upregulated', 'PosReg', (19, 30))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('knockdown', 'Var', (97, 106))	('glioma tissues', 'Disease', (34, 48))	('glioma tissues', 'Disease', 'MESH:D005910', (34, 48))	('human', 'Species', '9606', (53, 58))	('induced', 'Reg', (172, 179))	('invasion', 'CPA', (158, 166))	('XIST', 'Gene', (0, 4))	('XIST', 'Gene', (110, 114))
56866	27686732	In vivo knockdown of XIST restrained tumor growth and produced higher survival in nude mice.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('knockdown', 'Var', (8, 17))	('nude mice', 'Species', '10090', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('restrained', 'NegReg', (26, 36))	('XIST', 'Gene', (21, 25))	('survival', 'CPA', (70, 78))	('higher', 'PosReg', (63, 69))
56870	27686732	HIT expression is dramatically increased in the highly metastatic 4 T1 cell line, and knockout of HIT in 4 T1 cells resulted in decreased cell migration and invasion.	('knockout', 'Var', (86, 94))	('HIT', 'Disease', 'MESH:D013921', (0, 3))	('HIT', 'Disease', (0, 3))	('increased', 'PosReg', (31, 40))	('4 T1', 'CellLine', 'CVCL:0125', (105, 109))	('decreased', 'NegReg', (128, 137))	('cell migration', 'biological_process', 'GO:0016477', ('138', '152'))	('HIT', 'Disease', 'MESH:D013921', (98, 101))	('4 T1', 'CellLine', 'CVCL:0125', (66, 70))	('HIT', 'Disease', (98, 101))
56878	27686732	Loc554202 is expressed at markedly higher levels in breast cancer tissues than in normal controls and is associated with advanced pathologic stage and greater tumor size.	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('tumor', 'Disease', (159, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('Loc554202', 'Var', (0, 9))	('higher', 'PosReg', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('associated', 'Reg', (105, 115))
56881	27686732	Increased BCAR4 level was correlated with progressive mammary cancer, and targeting BCAR4 based on knockout of specific gene intensively suppressed breast cancer spread in an animal model.	('targeting', 'Var', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('suppressed', 'NegReg', (137, 147))	('BCAR4', 'Gene', (10, 15))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('BCAR4', 'Gene', '400500', (10, 15))	('breast cancer', 'Disease', (148, 161))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('BCAR4', 'Gene', (84, 89))	('cancer', 'Disease', (155, 161))	('BCAR4', 'Gene', '400500', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
56883	27686732	Furthermore, siRNA-induced depletion of RCCRT1 expression diminished migration and invasion in ACHN and A498 RCC cell lines.	('A498', 'CellLine', 'CVCL:1056', (104, 108))	('ACHN', 'Gene', '55323', (95, 99))	('RCC', 'Disease', (40, 43))	('diminished', 'NegReg', (58, 68))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('depletion', 'Var', (27, 36))	('ACHN', 'Gene', (95, 99))
56894	27686732	PCGEM1 polymorphisms may contribute to PCa risk in Chinese men.	('PCGEM1', 'Gene', '64002', (0, 6))	('PCa', 'Phenotype', 'HP:0012125', (39, 42))	('contribute', 'Reg', (25, 35))	('polymorphisms', 'Var', (7, 20))	('PCGEM1', 'Gene', (0, 6))	('PCa', 'Disease', (39, 42))	('men', 'Species', '9606', (59, 62))
56895	27686732	LncRNA PCAT18 is specifically expressed in PCa, and PCAT18 silencing significantly inhibited PCa cell proliferation, migration, and invasion, and triggered caspase 3/7 activation with no effect on non-neoplastic cells.	('cell proliferation', 'biological_process', 'GO:0008283', ('97', '115'))	('migration', 'CPA', (117, 126))	('PCa', 'Phenotype', 'HP:0012125', (43, 46))	('caspase 3', 'Gene', (156, 165))	('PCAT18', 'Gene', '728606', (7, 13))	('PCAT18', 'Gene', '728606', (52, 58))	('inhibited', 'NegReg', (83, 92))	('caspase 3', 'Gene', '836', (156, 165))	('PCa', 'Disease', (93, 96))	('activation', 'PosReg', (168, 178))	('PCa', 'Phenotype', 'HP:0012125', (93, 96))	('silencing', 'Var', (59, 68))	('PCAT18', 'Gene', (7, 13))	('PCAT18', 'Gene', (52, 58))	('invasion', 'CPA', (132, 140))
56902	27686732	In particular, the antitumor effects of targeted knockdown highlight the potential of lncRNA-based cancer therapies for patients at high risk for metastasis, an outcome currently lacking effective chemotherapeutic options.	('knockdown', 'Var', (49, 58))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('cancer', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('patients', 'Species', '9606', (120, 128))	('targeted knockdown', 'Var', (40, 58))	('tumor', 'Disease', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
56933	27686732	The lncRNA FENDRR controls the expression of target genes epigenetically by binding to PRC2.	('FENDRR', 'Gene', '400550', (11, 17))	('PRC2', 'Gene', (87, 91))	('epigenetically', 'Var', (58, 72))	('binding', 'molecular_function', 'GO:0005488', ('76', '83'))	('expression', 'MPA', (31, 41))	('FENDRR', 'Gene', (11, 17))	('binding', 'Interaction', (76, 83))
56937	27686732	ENST00000480739 level was negatively related to tumor node metastasis stage and lymph node metastasis, indicating that it could be an independent prognostic factor of survival time in PDAC patients following surgery.	('lymph node metastasis', 'CPA', (80, 101))	('tumor node metastasis', 'Disease', 'MESH:D009362', (48, 69))	('PDAC', 'Chemical', '-', (184, 188))	('negatively', 'NegReg', (26, 36))	('tumor node metastasis', 'Disease', (48, 69))	('patients', 'Species', '9606', (189, 197))	('ENST00000480739', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('PDAC', 'Phenotype', 'HP:0006725', (184, 188))
56941	27686732	Microarray studies have found that upregulated expression of Meg3 in MIN6 cells can attenuate the level of the proto-oncogene c-Met and reduce cell migration and invasion.	('Meg3', 'Gene', (61, 65))	('reduce', 'NegReg', (136, 142))	('expression', 'Var', (47, 57))	('cell migration', 'biological_process', 'GO:0016477', ('143', '157'))	('proto-oncogene c-Met', 'Gene', '17295', (111, 131))	('upregulated', 'PosReg', (35, 46))	('attenuate', 'NegReg', (84, 93))	('MIN6', 'CellLine', 'CVCL:0431', (69, 73))	('level of the', 'MPA', (98, 110))	('proto-oncogene c-Met', 'Gene', (111, 131))
56945	27686732	Moreover, the aberrant expression of BANCR was positively associated with clinical stage, tumor depth, lymph node metastasis, and distant metastasis, and was an independent prognostic factor for GC/NSCLC in survival analysis.	('lymph node metastasis', 'CPA', (103, 124))	('clinical stage', 'CPA', (74, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (198, 203))	('associated', 'Reg', (58, 68))	('BANCR', 'Gene', '100885775', (37, 42))	('distant metastasis', 'CPA', (130, 148))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('aberrant expression', 'Var', (14, 33))	('NSCLC', 'Disease', (198, 203))	('BANCR', 'Gene', (37, 42))	('GC', 'Phenotype', 'HP:0012126', (195, 197))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
56970	33985542	The in vitro studies showed that knockdown and overexpression of METTL13 respectively led to increase and decrease in ccRCC cells' proliferation, viability, migratory ability and invasiveness as well as epithelial-mesenchymal transition (EMT).	('rat', 'Species', '10116', (138, 141))	('EMT', 'biological_process', 'GO:0001837', ('238', '241'))	('rat', 'Species', '10116', (160, 163))	('overexpression', 'PosReg', (47, 61))	('migratory ability', 'CPA', (157, 174))	('knockdown', 'Var', (33, 42))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('203', '236'))	('epithelial-mesenchymal transition', 'CPA', (203, 236))	('viability', 'CPA', (146, 155))	('decrease', 'NegReg', (106, 114))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('METTL13', 'Gene', (65, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))	('invasiveness', 'CPA', (179, 191))
56973	33985542	In general, our finding suggests that high expression of METTL13 is associated with favorable prognosis of ccRCC patients.	('associated', 'Reg', (68, 78))	('patients', 'Species', '9606', (113, 121))	('high expression', 'Var', (38, 53))	('METTL13', 'Gene', (57, 64))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))
56985	33985542	As a methyltransferase protein, it can specifically methylate the Lys55 of eEF1A, resulting in the increase of its translational output and tumorigenesis of lung and pancreatic cancer.	('eEF1A', 'Gene', (75, 80))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('eEF1A', 'Gene', '1915', (75, 80))	('Lys55', 'Var', (66, 71))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (166, 183))	('pancreatic cancer', 'Disease', (166, 183))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('pancreatic cancer', 'Disease', 'MESH:D010190', (166, 183))	('methylate', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('translational output', 'MPA', (115, 135))	('increase', 'PosReg', (99, 107))	('lung', 'Disease', (157, 161))	('Lys55', 'Chemical', '-', (66, 71))	('tumor', 'Disease', (140, 145))
57040	33985542	According to the result, two cell lines, 786-O and Caki-1, in which METTL13 was expressed relatively high, were selected to perform functional experiments with by knocking down METTL13 expression.	('METTL13', 'Gene', (177, 184))	('expression', 'MPA', (185, 195))	('Caki-1', 'CellLine', 'CVCL:0234', (51, 57))	('knocking', 'Var', (163, 171))
57041	33985542	After transfecting the siRNA, we found that proliferation and viability of the two cell lines were significantly enhanced (Fig.	('transfecting', 'Var', (6, 18))	('viability', 'CPA', (62, 71))	('proliferation', 'CPA', (44, 57))	('enhanced', 'PosReg', (113, 121))	('rat', 'Species', '10116', (51, 54))
57042	33985542	In addition, knockdown of METTL13 respectively led to increase in wound healing rates of 786-O cells and Caki-1 cells (Fig.	('wound healing rates', 'CPA', (66, 85))	('METTL13', 'Gene', (26, 33))	('rat', 'Species', '10116', (80, 83))	('wound healing', 'biological_process', 'GO:0042060', ('66', '79'))	('increase', 'PosReg', (54, 62))	('Caki-1', 'CellLine', 'CVCL:0234', (105, 111))	('Caki-1 cells', 'CPA', (105, 117))	('knockdown', 'Var', (13, 22))
57045	33985542	In general, inhibition of METTL13 expression facilitated proliferation, viability, migration and invasion of ccRCC cells as well as epithelial-mesenchymal transition.	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('132', '165'))	('inhibition', 'Var', (12, 22))	('METTL13', 'Gene', (26, 33))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('viability', 'CPA', (72, 81))	('rat', 'Species', '10116', (64, 67))	('facilitated', 'PosReg', (45, 56))	('epithelial-mesenchymal transition', 'CPA', (132, 165))	('proliferation', 'CPA', (57, 70))	('invasion', 'CPA', (97, 105))	('rat', 'Species', '10116', (86, 89))	('migration', 'CPA', (83, 92))
57060	33985542	Results showed that silencing METTL13 resulted in significantly increase in HIF-1alpha protein levels in Caki-1 cells and on the contrary in OS-RC-2 cells, the overexpression of METTL13 led to an opposite effect (Fig.	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('HIF-1alpha', 'Gene', (76, 86))	('METTL13', 'Gene', (30, 37))	('Caki-1', 'CellLine', 'CVCL:0234', (105, 111))	('increase', 'PosReg', (64, 72))	('HIF-1alpha', 'Gene', '3091', (76, 86))	('silencing', 'Var', (20, 29))	('OS-RC-2', 'CellLine', 'CVCL:1626', (141, 148))
57061	33985542	However, HIF-1alpha mRNA expressions were not influenced by METTL13 expression alterations (Fig.	('alterations', 'Var', (79, 90))	('rat', 'Species', '10116', (83, 86))	('HIF-1alpha', 'Gene', (9, 19))	('METTL13', 'Gene', (60, 67))	('HIF-1alpha', 'Gene', '3091', (9, 19))
57067	33985542	Furthermore, results showed that silencing METTL13 resulted in increase in c-Myc protein levels in Caki-1 cells and on the contrary in OS-RC-2 cells, the overexpression of METTL13 led to an opposite phenomenon (Fig.	('increase', 'PosReg', (63, 71))	('OS-RC-2', 'CellLine', 'CVCL:1626', (135, 142))	('silencing', 'Var', (33, 42))	('Caki-1', 'CellLine', 'CVCL:0234', (99, 105))	('METTL13', 'Gene', (43, 50))	('c-Myc', 'Gene', '4609', (75, 80))	('c-Myc', 'Gene', (75, 80))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))
57068	33985542	7c), which indicated an inhibitory effect that METT13 had on c-Myc protein expression.	('c-Myc', 'Gene', (61, 66))	('c-Myc', 'Gene', '4609', (61, 66))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('METT13', 'Var', (47, 53))
57090	33985542	However, it still requires further efforts to determine whether METTL13 regulates HIF-1alpha expression via other mechanisms or not and how METTL13 specifically participates in the whole HIF-1 signaling pathway.	('HIF-1', 'Gene', '3091', (187, 192))	('METTL13', 'Var', (140, 147))	('METTL13', 'Gene', (64, 71))	('HIF-1alpha', 'Gene', '3091', (82, 92))	('HIF-1', 'Gene', '3091', (82, 87))	('HIF-1', 'Gene', (187, 192))	('participates', 'Reg', (161, 173))	('signaling pathway', 'biological_process', 'GO:0007165', ('193', '210'))	('regulates', 'Reg', (72, 81))	('expression', 'MPA', (93, 103))	('HIF-1', 'Gene', (82, 87))	('HIF-1alpha', 'Gene', (82, 92))
57097	33985542	Via our experiments, we evidenced not only the physical interaction between METTL13 and c-Myc but also the restraining effect that METTL13 had on c-Myc protein expression.	('METTL13', 'Gene', (76, 83))	('c-Myc', 'Gene', '4609', (146, 151))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('c-Myc', 'Gene', (146, 151))	('interaction', 'Interaction', (56, 67))	('c-Myc', 'Gene', '4609', (88, 93))	('c-Myc', 'Gene', (88, 93))	('METTL13', 'Var', (131, 138))
57114	29416602	Furthermore, multivariate analysis showed that the combination of PHF2 and C/EBPalpha expression as an independent prognostic factor for cancer-specific and progression-free survival.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('progression-free survival', 'CPA', (157, 182))	('C/EBPalpha', 'Gene', (75, 85))	('combination', 'Var', (51, 62))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('PHF2', 'Gene', (66, 70))	('cancer', 'Disease', (137, 143))
57122	29416602	In considering the genetic alteration levels, mutations in the Von Hippel-Lindau (VHL) gene, which acts as tumour suppressor gene by stabilizing hypoxia inducible factors (HIF-1alpha and HIF-2alpha) and the polybromo-1 (PBRM1) gene, which are associated with chromatin remodelling are the most common alterations in ccRCC.	('polybromo-1', 'Gene', '55193', (207, 218))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('hypoxia', 'Disease', 'MESH:D000860', (145, 152))	('tumour', 'Disease', (107, 113))	('VHL', 'Disease', (82, 85))	('mutations', 'Var', (46, 55))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (172, 197))	('polybromo-1', 'Gene', (207, 218))	('RCC', 'Disease', (318, 321))	('RCC', 'Phenotype', 'HP:0005584', (318, 321))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('259', '280'))	('PBRM1', 'Gene', '55193', (220, 225))	('chromatin', 'cellular_component', 'GO:0000785', ('259', '268'))	('ccRCC', 'Phenotype', 'HP:0006770', (316, 321))	('VHL', 'Disease', 'MESH:D006623', (82, 85))	('RCC', 'Disease', 'MESH:C538614', (318, 321))	('PBRM1', 'Gene', (220, 225))	('hypoxia', 'Disease', (145, 152))	('common', 'Reg', (294, 300))
57123	29416602	Based on comprehensive molecular studies, oncogenic metabolic shifts and epigenetic alterations have been considered the major pathogenic components of ccRCC.	('oncogenic metabolic shifts', 'CPA', (42, 68))	('epigenetic alterations', 'Var', (73, 95))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('RCC', 'Disease', (154, 157))	('RCC', 'Phenotype', 'HP:0005584', (154, 157))	('ccRCC', 'Phenotype', 'HP:0006770', (152, 157))
57129	29416602	These molecules induce transcription of genes related to adipogenesis by demethylating dimethylated histone H3 lysine 9 (H3K9me2).	('adipogenesis', 'biological_process', 'GO:0045444', ('57', '69'))	('transcription', 'biological_process', 'GO:0006351', ('23', '36'))	('genes', 'Gene', (40, 45))	('adipogenesis', 'biological_process', 'GO:0060612', ('57', '69'))	('demethylating', 'Var', (73, 86))	('transcription', 'MPA', (23, 36))	('induce', 'PosReg', (16, 22))	('lysine', 'Chemical', 'MESH:D008239', (111, 117))
57130	29416602	Alterations in PHF2 have been identified in several cancer types, including breast, oesophageal, stomach and colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (109, 121))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('colon cancer', 'Disease', 'MESH:D015179', (109, 121))	('oesophageal', 'Disease', (84, 95))	('Alterations', 'Var', (0, 11))	('stomach', 'Disease', (97, 104))	('breast', 'Disease', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('colon cancer', 'Disease', (109, 121))	('cancer', 'Disease', (52, 58))	('identified', 'Reg', (30, 40))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('PHF2', 'Gene', (15, 19))
57131	29416602	Additionally, C/EBPalpha has a role in tumourigenesis in various cancers, including acute myeloid leukaemia (AML) and cancers of the lungs, liver, breast, skin and ovaries.	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))	('acute myeloid leukaemia', 'Disease', (84, 107))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('C/EBPalpha', 'Var', (14, 24))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('cancers', 'Disease', (118, 125))	('AML', 'Disease', 'MESH:D015470', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('AML', 'Disease', (109, 112))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('AML', 'Phenotype', 'HP:0004808', (109, 112))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('ovaries', 'Disease', 'MESH:D010051', (164, 171))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (90, 107))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (84, 107))	('tumour', 'Disease', (39, 45))	('ovaries', 'Disease', (164, 171))	('cancers of the lungs', 'Phenotype', 'HP:0100526', (118, 138))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (84, 107))
57157	29416602	Univariate analysis showed that high ADFP expression was related to a better prognosis for cancer-specific survival, and high ADFP expression was identified as an independent prognostic factor of a better outcome by multivariate analysis.	('high', 'Var', (32, 36))	('ADFP', 'Gene', '123', (37, 41))	('ADFP', 'Gene', (37, 41))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('ADFP', 'Gene', (126, 130))	('ADFP', 'Gene', '123', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
57165	29416602	In breast cancer, alterations in the PHF2 gene were observed in up to 60% of patients and reduction in the PHF2 mRNA expression was identified.	('reduction', 'NegReg', (90, 99))	('PHF2 gene', 'Gene', (37, 46))	('alterations', 'Var', (18, 29))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('mRNA expression', 'MPA', (112, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('patients', 'Species', '9606', (77, 85))	('PHF2', 'Gene', (107, 111))
57166	29416602	Additionally, PHF2 deletion or methylation showed a poor prognosis in the patient group > 40 years of age.	('patient', 'Species', '9606', (74, 81))	('deletion', 'Var', (19, 27))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('PHF2', 'Gene', (14, 18))	('methylation', 'Var', (31, 42))
57169	29416602	In a study on HCT116 cancer cells, the authors showed that PHF2 is essential for p53 signalling pathway activation and demethylates H3K9me2 at p53 target promoters.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('activation', 'PosReg', (104, 114))	('signalling pathway', 'biological_process', 'GO:0007165', ('85', '103'))	('p53', 'Gene', '7157', (143, 146))	('demethylates', 'Var', (119, 131))	('PHF2', 'Gene', (59, 63))	('H3K9me2', 'Protein', (132, 139))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('HCT116', 'CellLine', 'CVCL:0291', (14, 20))	('p53', 'Gene', (143, 146))
57170	29416602	Based on these findings, the authors suggested that PHF2 regulates p53-target gene expression by demethylating methylated H3K9 and showed that PHF2 acts as a tumour suppressor.	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('regulates', 'Reg', (57, 66))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('H3K9', 'Protein', (122, 126))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('tumour', 'Disease', (158, 164))	('PHF2', 'Gene', (52, 56))	('gene expression', 'biological_process', 'GO:0010467', ('78', '93'))	('expression', 'MPA', (83, 93))	('demethylating', 'Var', (97, 110))	('methylated', 'MPA', (111, 121))
57172	29416602	C/EBPalpha is important for myeloid differentiation, and dysregulation of its expression is observed in AML and other haemato-lymphoid malignancies.	('haemato-lymphoid malignancies', 'Disease', (118, 147))	('expression', 'MPA', (78, 88))	('dysregulation', 'Var', (57, 70))	('AML', 'Phenotype', 'HP:0004808', (104, 107))	('AML', 'Disease', (104, 107))	('haemato-lymphoid malignancies', 'Disease', 'MESH:D008223', (118, 147))	('observed', 'Reg', (92, 100))	('AML', 'Disease', 'MESH:D015470', (104, 107))	('lymphoid malignancies', 'Phenotype', 'HP:0002665', (126, 147))
57174	29416602	In a breast cancer study, low expression levels of C/EBPalpha mRNA and protein were identified, and induction of C/EBPalpha inhibited growth.	('C/EBPalpha', 'Var', (113, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (5, 18))	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('growth', 'CPA', (134, 140))	('induction', 'Var', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('breast cancer', 'Disease', 'MESH:D001943', (5, 18))	('C/EBPalpha', 'Gene', (51, 61))	('inhibited', 'NegReg', (124, 133))	('expression levels', 'MPA', (30, 47))	('breast cancer', 'Disease', (5, 18))
57177	29416602	C/EBPalpha is thought to act as a tumour suppressor, which interacts with various molecules, including p21, CDK2, CDK4, E2F, SWI/SNF chromatin-remodelling complex, and p53.	('CDK', 'molecular_function', 'GO:0004693', ('108', '111'))	('CDK4', 'Gene', (114, 118))	('C/EBPalpha', 'Var', (0, 10))	('p21', 'Gene', (103, 106))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('p53', 'Gene', '7157', (168, 171))	('CDK2', 'Gene', (108, 112))	('tumour', 'Disease', (34, 40))	('CDK4', 'Gene', '1019', (114, 118))	('chromatin-remodelling', 'biological_process', 'GO:0006338', ('133', '154'))	('interacts', 'Interaction', (59, 68))	('p21', 'Gene', '644914', (103, 106))	('CDK2', 'Gene', '1017', (108, 112))	('chromatin-remodelling complex', 'cellular_component', 'GO:0016585', ('133', '162'))	('p53', 'Gene', (168, 171))	('CDK', 'molecular_function', 'GO:0004693', ('114', '117'))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
57181	29416602	Those results were consistent with previous reports that an eosinophilic cytoplasm is associated with high-grade tumours, necrosis or haemorrhage.	('necrosis', 'biological_process', 'GO:0019835', ('122', '130'))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('haemorrhage', 'Disease', (134, 145))	('cytoplasm', 'cellular_component', 'GO:0005737', ('73', '82'))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('necrosis', 'biological_process', 'GO:0008220', ('122', '130'))	('necrosis', 'Disease', 'MESH:D009336', (122, 130))	('haemorrhage', 'Disease', 'MESH:D006470', (134, 145))	('tumours', 'Disease', 'MESH:D009369', (113, 120))	('necrosis', 'biological_process', 'GO:0001906', ('122', '130'))	('associated', 'Reg', (86, 96))	('tumours', 'Disease', (113, 120))	('eosinophilic', 'Var', (60, 72))	('eosin', 'Chemical', 'MESH:D004801', (60, 65))	('necrosis', 'biological_process', 'GO:0070265', ('122', '130'))	('necrosis', 'biological_process', 'GO:0008219', ('122', '130'))	('necrosis', 'Disease', (122, 130))
57183	29416602	In TCGA data for ccRCC, genetic alterations in PHF2 and C/EBPalpha were found in a single patient case (0.2%) for each.	('found', 'Reg', (72, 77))	('genetic alterations', 'Var', (24, 43))	('PHF2', 'Gene', (47, 51))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('ccRCC', 'Phenotype', 'HP:0006770', (17, 22))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('patient', 'Species', '9606', (90, 97))	('C/EBPalpha', 'Gene', (56, 66))
57184	29416602	The patients had a PHF2 missense mutation and CEBPA truncating mutation, respectively.	('PHF2', 'Gene', (19, 23))	('missense mutation', 'Var', (24, 41))	('CEBPA', 'Gene', '1050', (46, 51))	('patients', 'Species', '9606', (4, 12))	('CEBPA', 'Gene', (46, 51))
57190	29416602	As VHL mutation is the most common genetic alteration in ccRCC and VHL affects cellular energy metabolism through HIF-1alpha, ccRCC cases have received substantial attention at the metabolic level.	('affects', 'Reg', (71, 78))	('cellular energy metabolism', 'MPA', (79, 105))	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('VHL', 'Disease', (3, 6))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('VHL', 'Disease', 'MESH:D006623', (3, 6))	('HIF-1alpha', 'Gene', (114, 124))	('metabolism', 'biological_process', 'GO:0008152', ('95', '105'))	('mutation', 'Var', (7, 15))	('VHL', 'Disease', 'MESH:D006623', (67, 70))	('HIF-1alpha', 'Gene', '3091', (114, 124))	('VHL', 'Disease', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
57240	30890701	von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME Renal cell carcinoma (RCC) is the major cause of death among patients with von Hippel-Lindau (VHL) disease.	('renal cell carcinoma', 'Disease', (29, 49))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (29, 49))	('von Hippel-Lindau', 'Gene', '7428', (0, 17))	('Renal cell carcinoma', 'Disease', 'MESH:C538614', (97, 117))	('death', 'Disease', 'MESH:D003643', (146, 151))	('patients', 'Species', '9606', (158, 166))	('expression', 'Species', '29278', (77, 87))	('Renal cell carcinoma', 'Phenotype', 'HP:0005584', (97, 117))	('von Hippel-Lindau', 'Gene', (172, 189))	('increased', 'PosReg', (67, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('mutants', 'Var', (18, 25))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (29, 49))	('RCC', 'Disease', (119, 122))	('death', 'Disease', (146, 151))	('von Hippel-Lindau', 'Gene', '7428', (172, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('von Hippel-Lindau', 'Gene', (0, 17))	('Renal cell carcinoma', 'Disease', (97, 117))	('von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (172, 203))	('RCC', 'Disease', 'MESH:C538614', (119, 122))
57242	30890701	Previously we have described that RWDD3 or RSUME (RWD domain-containing protein SUMO Enhancer) sumoylates and binds VHL protein and negatively regulates HIF degradation, leading to xenograft RCC tumor growth in mice.	('RCC tumor', 'Disease', (191, 200))	('leading to', 'Reg', (170, 180))	('RCC', 'Phenotype', 'HP:0005584', (191, 194))	('degradation', 'biological_process', 'GO:0009056', ('157', '168'))	('VHL protein', 'Protein', (116, 127))	('binds', 'Interaction', (110, 115))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('RCC tumor', 'Disease', 'MESH:C538614', (191, 200))	('negatively', 'NegReg', (132, 142))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('regulates', 'Reg', (143, 152))	('RWDD3', 'Var', (34, 39))	('mice', 'Species', '10090', (211, 215))	('HIF degradation', 'MPA', (153, 168))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
57243	30890701	In this study, we performed a bioinformatics analysis in a ccRCC dataset showing an association of RSUME levels with VHL mutations and tumor progression, and we demonstrate the molecular mechanism by which RSUME regulates the pathologic angiogenic phenotype of VHL missense mutations.	('association', 'Interaction', (84, 95))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('mutations', 'Var', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('regulates', 'Reg', (212, 221))	('tumor', 'Disease', (135, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('VHL', 'Gene', (261, 264))	('missense mutations', 'Var', (265, 283))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
57244	30890701	We report that VHL mutants fail to downregulate RSUME protein levels accounting for the increased RSUME expression found in RCC tumors.	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('RCC tumors', 'Disease', (124, 134))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('VHL', 'Gene', (15, 18))	('expression', 'Species', '29278', (104, 114))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('increased', 'PosReg', (88, 97))	('RSUME', 'MPA', (98, 103))	('RCC tumors', 'Disease', 'MESH:C538614', (124, 134))	('expression', 'MPA', (104, 114))	('downregulate', 'NegReg', (35, 47))	('RSUME protein levels', 'MPA', (48, 68))	('mutants', 'Var', (19, 26))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
57245	30890701	Furthermore, we prove that targeting RSUME in RCC cell line clones carrying missense VHL mutants results in decreased early tumor angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('RCC', 'Disease', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('VHL', 'Gene', (85, 88))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('tumor', 'Disease', (124, 129))	('decreased', 'NegReg', (108, 117))	('missense', 'Var', (76, 84))	('angiogenesis', 'biological_process', 'GO:0001525', ('130', '142'))	('mutants', 'Var', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
57246	30890701	The mechanism we describe is that RSUME sumoylates VHL mutants and beyond its sumoylation capacity, interacts with Type 2 VHL mutants, reduces HIF-2alpha-VHL mutants binding, and negatively regulates the assembly of the Type 2 VHL, Elongins and Cullins (ECV) complex.	('Cullins', 'Gene', '8453', (245, 252))	('assembly', 'MPA', (204, 212))	('binding', 'molecular_function', 'GO:0005488', ('166', '173'))	('mutants', 'Var', (55, 62))	('binding', 'Interaction', (166, 173))	('VHL', 'Gene', (122, 125))	('HIF-2alpha-VHL', 'Disease', (143, 157))	('Cullins', 'Gene', (245, 252))	('HIF-2alpha-VHL', 'Disease', 'MESH:D006623', (143, 157))	('sumoylation', 'biological_process', 'GO:0016925', ('78', '89'))	('mutants', 'Var', (158, 165))	('negatively', 'NegReg', (179, 189))	('reduces', 'NegReg', (135, 142))	('interacts', 'Interaction', (100, 109))	('VHL', 'Gene', (51, 54))	('regulates', 'Reg', (190, 199))	('mutants', 'Var', (126, 133))	('Type', 'Gene', (115, 119))
57247	30890701	Altogether these results show RSUME involvement in VHL mutants deregulation that leads to the angiogenic phenotype of RCC tumors.	('leads to', 'Reg', (81, 89))	('deregulation', 'Var', (63, 75))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('RCC tumors', 'Disease', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('RCC tumors', 'Disease', 'MESH:C538614', (118, 128))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('VHL', 'Gene', (51, 54))	('mutants deregulation', 'Var', (55, 75))
57250	30890701	It is caused by mutations in the tumor suppressor gene VHL.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('33', '49'))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('mutations', 'Var', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor suppressor', 'biological_process', 'GO:0051726', ('33', '49'))	('tumor', 'Disease', (33, 38))	('VHL', 'Gene', (55, 58))	('caused by', 'Reg', (6, 15))
57252	30890701	When VHL gene is mutated and its function is modified or lost, HIF-1/2-alpha subunits are stabilized and HIF target genes become activated.	('VHL gene', 'Gene', (5, 13))	('activated', 'PosReg', (129, 138))	('HIF-1', 'Gene', '3091', (63, 68))	('function', 'MPA', (33, 41))	('mutated', 'Var', (17, 24))	('HIF-1', 'Gene', (63, 68))
57258	30890701	The proteins translated from some of missense mutated VHL gene retain the functional ability to downregulate HIF, suggesting additional mechanisms underlying VHL mutation impact on tumorigenesis.	('tumor', 'Disease', (181, 186))	('impact', 'Reg', (171, 177))	('HIF', 'CPA', (109, 112))	('missense mutated', 'Var', (37, 53))	('downregulate', 'NegReg', (96, 108))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('VHL gene', 'Gene', (54, 62))
57265	30890701	We show that RSUME acts on missense VHL mutants promoting HIF-2alpha stabilization.	('VHL', 'Gene', (36, 39))	('HIF-2alpha', 'Gene', '2034', (58, 68))	('promoting', 'PosReg', (48, 57))	('missense', 'Var', (27, 35))	('mutants', 'Var', (40, 47))	('HIF-2alpha', 'Gene', (58, 68))
57266	30890701	RSUME, in a sumoylation independent manner, displaces HIF-2-Type 2 VHL mutants interaction and regulates the loss of function of VHL mutants on HIF-2alpha regulation, leading to enhanced VEGF action and, thus promoting higher vascularized tumors.	('tumors', 'Disease', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('VEGF', 'Gene', (187, 191))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('enhanced', 'PosReg', (178, 186))	('HIF-2alpha', 'Gene', '2034', (144, 154))	('sumoylation', 'biological_process', 'GO:0016925', ('12', '23'))	('interaction', 'Interaction', (79, 90))	('VHL', 'Gene', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('regulation', 'biological_process', 'GO:0065007', ('155', '165'))	('HIF-2-Type 2 VHL', 'Disease', 'MESH:D006623', (54, 70))	('HIF-2-Type 2 VHL', 'Disease', (54, 70))	('HIF-2alpha', 'Gene', (144, 154))	('VEGF', 'Gene', '7422', (187, 191))	('mutants', 'Var', (133, 140))	('displaces', 'NegReg', (44, 53))	('promoting higher', 'PosReg', (209, 225))
57267	30890701	RSUME levels are higher in tumor patients with VHL mutations and associated with poor prognosis in RCC tumors.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mutations', 'Var', (51, 60))	('patients', 'Species', '9606', (33, 41))	('RCC tumors', 'Disease', 'MESH:C538614', (99, 109))	('tumor', 'Disease', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (103, 108))	('RSUME levels', 'MPA', (0, 12))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('higher', 'PosReg', (17, 23))	('VHL', 'Gene', (47, 50))	('RCC tumors', 'Disease', (99, 109))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
57268	30890701	Altogether these results support a key role for RSUME on the early angiogenesis needed for tumor establishment by Type 2 VHL mutants.	('VHL', 'Gene', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('mutants', 'Var', (125, 132))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('angiogenesis', 'biological_process', 'GO:0001525', ('67', '79'))
57275	30890701	For MG-132 treatment, cells were incubated in DMEM 2% FBS with 5 muM MG-132 for 6 h. The following plasmids were kindly provided and described as follows pCEFL, O. Coso; Flag-pcDNA3 and Flag-VHL, S. Lee; HA-HIF-2alpha, W. Kaelin; pBI-GLV4R HRE-LUC, E. Van Meir; V5-Ubc-9 and 6xHis-SUMO-2, R. Hay; siRSUME and siScramble; shRSUME and shScramble (#KH14185N, SABiosciences, Hilden, Germany); V5-RSUME, V5-RSUMEY61A/P62A were described previously.	('V5-RSUME', 'Var', (389, 397))	('MG-132', 'Chemical', 'MESH:C072553', (69, 75))	('muM', 'Gene', '56925', (65, 68))	('HIF-2alpha', 'Gene', (207, 217))	('DMEM', 'Chemical', '-', (46, 50))	('P62A', 'Var', (412, 416))	('muM', 'Gene', (65, 68))	('SUMO-2', 'Gene', '6613', (281, 287))	('HIF-2alpha', 'Gene', '2034', (207, 217))	('SUMO-2', 'Gene', (281, 287))	('P62A', 'SUBSTITUTION', 'None', (412, 416))	('MG-132', 'Chemical', 'MESH:C072553', (4, 10))	('Ubc-9', 'Gene', (265, 270))	('Ubc-9', 'Gene', '7329', (265, 270))
57276	30890701	Flag-VHLY112H, Flag-VHLR167Q, Flag-VHLL188V, and Flag-VHLK171R mutants were generated with directed mutagenesis PCR standard protocol and cloned in frame into Flag-VHL plasmids with NotI and HindIII restriction enzymes.	('Flag-VHLK171R', 'Var', (49, 62))	('VHLL', 'Gene', (35, 39))	('K171R', 'Mutation', 'p.K171R', (57, 62))	('mutagenesis', 'biological_process', 'GO:0006280', ('100', '111'))	('VHLL', 'Gene', '391104', (35, 39))
57277	30890701	After confirming VHL mutations by DNA sequencing, Flag-VHLY112H, Flag-VHLR167Q, Flag-VHLL188V, primers containing missense mutation were used in a PCR to generate Flag-VHLY112H/K171R, Flag-VHLR167Q/K171R, and Flag-VHLL188V/K171R plasmids.	('K171R', 'Mutation', 'p.K171R', (177, 182))	('VHLL', 'Gene', (214, 218))	('K171R', 'Mutation', 'p.K171R', (198, 203))	('VHLL', 'Gene', '391104', (214, 218))	('Flag-VHLR167Q/K171R', 'Var', (184, 203))	('VHLL', 'Gene', (85, 89))	('K171R', 'Mutation', 'p.K171R', (223, 228))	('Flag-VHLY112H/K171R', 'Var', (163, 182))	('VHL', 'Gene', (17, 20))	('VHLL', 'Gene', '391104', (85, 89))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('mutations', 'Var', (21, 30))
57280	30890701	Stable clones were obtained as described, RCC 786-O VHL-negative cells were transfected with Flag-VHLY112H/K171R-shScramble/shRSUME, Flag-VHLR167Q/K171R-shScramble/shRSUME, Flag-VHLL188V/K171R-shScramble/shRSUME or pcDNA3-Flag-VHLK171R-shScramble/shRSUME.	('Flag-VHLR167Q/K171R-shScramble/shRSUME', 'Var', (133, 171))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('pcDNA3-Flag-VHLK171R-shScramble/shRSUME', 'Var', (215, 254))	('K171R', 'Mutation', 'p.K171R', (230, 235))	('K171R', 'Mutation', 'p.K171R', (147, 152))	('Flag-VHLY112H/K171R-shScramble/shRSUME', 'Var', (93, 131))	('K171R', 'Mutation', 'p.K171R', (107, 112))	('VHLL', 'Gene', '391104', (178, 182))	('VHLL', 'Gene', (178, 182))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('K171R', 'Mutation', 'p.K171R', (187, 192))
57282	30890701	Mutated VHL and RSUME expression levels were checked by western blot (WB) and RT-PCR, respectively.	('Mutated', 'Var', (0, 7))	('VHL', 'Gene', (8, 11))	('expression', 'Species', '29278', (22, 32))
57323	30890701	The bioespecimen data of somatic variants identified from exome sequencing studies of ccRCC tumors correspond to the TCGA Kidney Renal Clear Cell Carcinoma (Project ID: TCGA-KIRC) of the TCGA Resource Network.	('Kidney Renal Clear Cell Carcinoma', 'Disease', 'MESH:C538614', (122, 155))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('ccRCC tumors', 'Disease', 'MESH:D009369', (86, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('Kidney Renal Clear Cell Carcinoma', 'Disease', (122, 155))	('Carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('ccRCC tumors', 'Disease', (86, 98))	('variants', 'Var', (33, 41))
57329	30890701	RCC samples were stratified in two groups according to the presence of VHL mutation (See Additional file 8: Table S1).	('VHL', 'Gene', (71, 74))	('mutation', 'Var', (75, 83))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('RCC', 'Disease', (0, 3))
57330	30890701	VHL mutated samples were then stratified in sub-groups according to tumor stage.	('tumor', 'Disease', (68, 73))	('mutated', 'Var', (4, 11))	('VHL', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
57339	30890701	Kaplan-Meier survival analysis shows that patients exhibiting high RSUME expression within this cohort had significantly worse overall survival compared to those with low RSUME gene expression (Fig.	('expression', 'Species', '29278', (182, 192))	('gene expression', 'biological_process', 'GO:0010467', ('177', '192'))	('high RSUME expression', 'Var', (62, 83))	('worse', 'NegReg', (121, 126))	('expression', 'Species', '29278', (73, 83))	('overall survival', 'MPA', (127, 143))	('patients', 'Species', '9606', (42, 50))
57340	30890701	We next interrogated the TCGA dataset to assess RSUME gene expression levels comparing between patients with VHL mutations (VHLmut) and those without VHL mutations (VHLwt) and observed significant augmented RSUME levels in those with VHLmut (P = 0.048; Fig.	('patients', 'Species', '9606', (95, 103))	('RSUME gene expression levels', 'MPA', (48, 76))	('expression', 'Species', '29278', (59, 69))	('VHL', 'Gene', (109, 112))	('mutations', 'Var', (113, 122))	('augmented', 'PosReg', (197, 206))	('gene expression', 'biological_process', 'GO:0010467', ('54', '69'))	('RSUME levels', 'MPA', (207, 219))
57343	30890701	Patients with VHL mutations show higher RSUME levels compared to those without VHL mutations (P = 0.012; Fig.	('higher', 'PosReg', (33, 39))	('Patients', 'Species', '9606', (0, 8))	('VHL', 'Gene', (14, 17))	('RSUME levels', 'MPA', (40, 52))	('mutations', 'Var', (18, 27))
57344	30890701	When we interrogated the datasets for the levels of RSUME in patients within this group carrying missense VHL mutations, they also displayed a significant difference with respect to patients without VHL mutations (P = 0.027; Fig.	('RSUME', 'MPA', (52, 57))	('mutations', 'Var', (110, 119))	('patients', 'Species', '9606', (61, 69))	('missense', 'Var', (97, 105))	('difference', 'Reg', (155, 165))	('VHL', 'Gene', (106, 109))	('patients', 'Species', '9606', (182, 190))
57345	30890701	Altogether these results indicate an association of RSUME levels with VHL mutations and tumor progression.	('VHL', 'Gene', (70, 73))	('association', 'Interaction', (37, 48))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('mutations', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('RSUME levels', 'MPA', (52, 64))	('tumor', 'Disease', (88, 93))
57346	30890701	To understand the basis for the augmented RSUME levels in patients with VHL mutations (Fig.	('mutations', 'Var', (76, 85))	('RSUME levels', 'MPA', (42, 54))	('patients', 'Species', '9606', (58, 66))	('augmented', 'PosReg', (32, 41))	('VHL', 'Gene', (72, 75))
57347	30890701	1c) we investigated the regulation of RSUME by VHL mutants in a RCC cell line.	('mutants', 'Var', (51, 58))	('regulation', 'biological_process', 'GO:0065007', ('24', '34'))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('VHL', 'Gene', (47, 50))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))
57348	30890701	VHL type 2 representative mutants (Tyr112His, Arg167Gln, and Leu188Val) contrasting to VHLWT, do not reduce RSUME expression (Fig.	('Arg167Gln', 'Var', (46, 55))	('reduce', 'NegReg', (101, 107))	('Leu188Val', 'SUBSTITUTION', 'None', (61, 70))	('VHL type 2', 'Gene', (0, 10))	('RSUME expression', 'MPA', (108, 124))	('Leu188Val', 'Var', (61, 70))	('Arg167Gln', 'SUBSTITUTION', 'None', (46, 55))	('Tyr112His', 'SUBSTITUTION', 'None', (35, 44))	('expression', 'Species', '29278', (114, 124))	('Tyr112His', 'Var', (35, 44))
57349	30890701	RSUME overexpression in the presence of VHL Type 2 mutants causes increased stabilization of HIF-2alpha (Fig.	('increased', 'PosReg', (66, 75))	('mutants', 'Var', (51, 58))	('HIF-2alpha', 'Gene', (93, 103))	('VHL Type 2', 'Disease', (40, 50))	('HIF-2alpha', 'Gene', '2034', (93, 103))	('expression', 'Species', '29278', (10, 20))	('VHL Type 2', 'Disease', 'MESH:D006623', (40, 50))	('stabilization', 'MPA', (76, 89))
57350	30890701	In cells previously cultured under HPX and next exposed to NMX, RSUME blocks HIF-2alpha degradation produced by the incomplete action of VHL mutants (Fig.	('mutants', 'Var', (141, 148))	('VHL', 'Gene', (137, 140))	('HIF-2alpha', 'Gene', (77, 87))	('blocks', 'NegReg', (70, 76))	('degradation', 'biological_process', 'GO:0009056', ('88', '99'))	('HIF-2alpha', 'Gene', '2034', (77, 87))
57351	30890701	To verify that HIF-alpha stabilization due to RSUME action on VHL type 2 mutants produces an increase in HIF transcriptional activity, COS-7 cells were transfected with HIF transcriptional activity reporter (HRE-LUC) in combination with the different variants of VHL.	('increase', 'PosReg', (93, 101))	('mutants', 'Var', (73, 80))	('VHL type 2', 'Gene', (62, 72))	('COS-7', 'CellLine', 'CVCL:0224', (135, 140))	('HIF transcriptional activity', 'MPA', (105, 133))
57352	30890701	By affinity purification of sumoylated proteins from transiently transfected cells expressing His-SUMO-2, Ubc-9 and the different Type 2 VHL mutants, we observed that VHL mutants are sumoylation substrates (Fig.	('sumoylation', 'biological_process', 'GO:0016925', ('183', '194'))	('mutants', 'Var', (141, 148))	('Ubc-9', 'Gene', (106, 111))	('mutants', 'Var', (171, 178))	('Ubc-9', 'Gene', '7329', (106, 111))	('VHL', 'Gene', (167, 170))	('SUMO-2', 'Gene', '6613', (98, 104))	('SUMO-2', 'Gene', (98, 104))
57353	30890701	Knock-down of endogenous RSUME expression with a small-interfering RNA (siRNA), produced a significant decrease of sumoylation of transiently expressed variants of VHL (Fig.	('sumoylation', 'MPA', (115, 126))	('RNA', 'cellular_component', 'GO:0005562', ('67', '70'))	('expression', 'Species', '29278', (31, 41))	('VHL', 'Gene', (164, 167))	('variants', 'Var', (152, 160))	('decrease', 'NegReg', (103, 111))	('sumoylation', 'biological_process', 'GO:0016925', ('115', '126'))
57354	30890701	Thus, RSUME acts on VHL disease representative mutants as a positive modulator of their sumoylation.	('VHL disease', 'Disease', (20, 31))	('sumoylation', 'MPA', (88, 99))	('VHL disease', 'Disease', 'MESH:D006623', (20, 31))	('sumoylation', 'biological_process', 'GO:0016925', ('88', '99'))	('mutants', 'Var', (47, 54))
57355	30890701	RSUME increased HIF-2alpha stability both when VHL WT or VHLK171R (VHL defective in sumoylation) were expressed (Supplementary Fig.	('increased', 'PosReg', (6, 15))	('VHLK171R', 'Var', (57, 65))	('stability', 'MPA', (27, 36))	('VHL WT', 'Disease', 'MESH:D006623', (47, 53))	('VHL WT', 'Disease', (47, 53))	('sumoylation', 'biological_process', 'GO:0016925', ('84', '95'))	('HIF-2alpha', 'Gene', (16, 26))	('HIF-2alpha', 'Gene', '2034', (16, 26))
57357	30890701	Given that the consensus site for sumoylation and the Type 2 mutations are near and in order to confirm that RSUME retains its action on VHL mutants when their sumoylation is affected, we generated plasmids expressing both VHL disease variants and the K171R mutation (VHL Y112H/K171R, VHLR167Q/K171R and VHLL188V/K171R), which showed impaired sumoylation (Supplementary Fig.	('Y112H', 'SUBSTITUTION', 'None', (272, 277))	('sumoylation', 'MPA', (343, 354))	('VHLL', 'Gene', (304, 308))	('K171R', 'Mutation', 'p.K171R', (252, 257))	('VHLL', 'Gene', '391104', (304, 308))	('VHL disease', 'Disease', 'MESH:D006623', (223, 234))	('sumoylation', 'biological_process', 'GO:0016925', ('160', '171'))	('sumoylation', 'biological_process', 'GO:0016925', ('34', '45'))	('K171R', 'Mutation', 'p.K171R', (294, 299))	('sumoylation', 'biological_process', 'GO:0016925', ('343', '354'))	('K171R', 'Mutation', 'p.K171R', (278, 283))	('K171R', 'Mutation', 'p.K171R', (313, 318))	('VHLR167Q/K171R', 'Var', (285, 299))	('VHL disease', 'Disease', (223, 234))	('Y112H', 'Var', (272, 277))
57358	30890701	In line with this, in RCC 786-O cells transfected with each single mutant or its corresponding sumoylation defective variant VHLY112H and VHLY112H/K171R (Fig.	('sumoylation', 'MPA', (95, 106))	('RCC', 'Disease', (22, 25))	('VHLY112H/K171R', 'Var', (138, 152))	('RCC', 'Phenotype', 'HP:0005584', (22, 25))	('RCC', 'Disease', 'MESH:C538614', (22, 25))	('K171R', 'Mutation', 'p.K171R', (147, 152))	('sumoylation', 'biological_process', 'GO:0016925', ('95', '106'))	('VHLY112H', 'Var', (125, 133))
57359	30890701	3f), VHLR167Q and VHLR167Q/K171R (Fig.	('VHLR167Q/K171R', 'Var', (18, 32))	('K171R', 'Mutation', 'p.K171R', (27, 32))	('VHLR167Q', 'Var', (5, 13))
57361	30890701	3h), RSUME overexpression stabilized HIF-2alpha, potentiating simple and double mutants loss of function (Fig.	('simple', 'Var', (62, 68))	('HIF-2alpha', 'Gene', (37, 47))	('expression', 'Species', '29278', (15, 25))	('HIF-2alpha', 'Gene', '2034', (37, 47))	('double mutants', 'Var', (73, 87))	('loss of function', 'NegReg', (88, 104))
57363	30890701	To explore the molecular mechanism by which RSUME impacts on VHL mutants function, we next addressed whether RSUME would coexist with VHL variants and HIF-2alpha in a complex.	('HIF-2alpha', 'Gene', '2034', (151, 161))	('VHL', 'Gene', (134, 137))	('variants', 'Var', (138, 146))	('HIF-2alpha', 'Gene', (151, 161))
57364	30890701	We performed tandem immunoprecipitation (first purification: VHL-associated proteins; second purification: RSUME-associated proteins), showing that in addition to binding to VHL Type 2 mutants RSUME participates in a VHL-HIF-RSUME complex for all Type 2 mutants (Fig.	('mutants', 'Var', (254, 261))	('mutants', 'Var', (185, 192))	('binding', 'molecular_function', 'GO:0005488', ('163', '170'))	('VHL Type 2', 'Disease', (174, 184))	('VHL-HIF', 'Disease', (217, 224))	('VHL-HIF', 'Disease', 'MESH:D006623', (217, 224))	('VHL Type 2', 'Disease', 'MESH:D006623', (174, 184))
57365	30890701	RSUME decreases the binding of HIF-2alpha to all disease VHL mutants analyzed (Fig.	('decreases', 'NegReg', (6, 15))	('HIF-2alpha to all disease', 'Disease', 'MESH:C536496', (31, 56))	('binding', 'Interaction', (20, 27))	('HIF-2alpha to all disease', 'Disease', (31, 56))	('binding', 'molecular_function', 'GO:0005488', ('20', '27'))	('mutants', 'Var', (61, 68))
57366	30890701	Moreover, when sumoylation was inhibited by Gam-1 or in presence of VHL defective for sumoylation, RSUME also impaired VHL-HIF-2alpha interaction (Fig.	('sumoylation', 'MPA', (15, 26))	('sumoylation', 'biological_process', 'GO:0016925', ('15', '26'))	('sumoylation', 'biological_process', 'GO:0016925', ('86', '97'))	('RSUME', 'Var', (99, 104))	('impaired VHL-HIF-2alpha', 'Disease', 'MESH:D006623', (110, 133))	('inhibited', 'NegReg', (31, 40))	('interaction', 'Interaction', (134, 145))	('impaired VHL-HIF-2alpha', 'Disease', (110, 133))
57367	30890701	4c, d), further confirming that RSUME-mediated decrease in HIF-VHL mutant binding is the mechanism responsible for HIF stabilization.	('HIF-VHL', 'Disease', 'MESH:D006623', (59, 66))	('decrease', 'NegReg', (47, 55))	('binding', 'molecular_function', 'GO:0005488', ('74', '81'))	('mutant', 'Var', (67, 73))	('HIF-VHL', 'Disease', (59, 66))	('binding', 'Interaction', (74, 81))
57368	30890701	Furthermore, the interaction of RSUME with VHL type 2 mutants impacts on the ECV complex assembly, affecting VHL variants binding to Elongin C and Elongin B (Fig.	('Elongin C', 'Gene', (133, 142))	('interaction', 'Interaction', (17, 28))	('binding', 'Interaction', (122, 129))	('binding', 'molecular_function', 'GO:0005488', ('122', '129'))	('VHL', 'Gene', (43, 46))	('VHL', 'Gene', (109, 112))	('Elongin B', 'Gene', '6923', (147, 156))	('mutants', 'Var', (54, 61))	('impacts', 'Reg', (62, 69))	('Elongin C', 'Gene', '6921', (133, 142))	('variants', 'Var', (113, 121))	('ECV complex assembly', 'MPA', (77, 97))	('Elongin B', 'Gene', (147, 156))
57371	30890701	In RCC 786-O clones expressing VHL, VHLK171R, VHLL188V or VHLL188V/K171R, co-expression of shRNA against RSUME resulted in a decrease of VEGF mRNA, indicating that through the mechanism described above, RSUME impacts on VHL function (Fig.	('expression', 'Species', '29278', (77, 87))	('VHLL', 'Gene', (46, 50))	('K171R', 'Mutation', 'p.K171R', (39, 44))	('K171R', 'Mutation', 'p.K171R', (67, 72))	('VHLL', 'Gene', '391104', (46, 50))	('VEGF', 'Gene', '7422', (137, 141))	('impacts', 'Reg', (209, 216))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('VHL function', 'MPA', (220, 232))	('VEGF', 'Gene', (137, 141))	('RCC', 'Disease', 'MESH:C538614', (3, 6))	('RCC', 'Disease', (3, 6))	('decrease', 'NegReg', (125, 133))	('VHLL', 'Gene', (58, 62))	('VHLL', 'Gene', '391104', (58, 62))	('VHLK171R', 'Var', (36, 44))
57372	30890701	Similar results were obtained for VHLY112H/K171R and VHLR167Q/K171R co-expressing RSUME shRNA clones (Supplementary Fig.	('K171R', 'Mutation', 'p.K171R', (43, 48))	('VHLY112H/K171R', 'Var', (34, 48))	('VHLR167Q/K171R', 'Var', (53, 67))	('K171R', 'Mutation', 'p.K171R', (62, 67))
57373	30890701	To determine how these changes in VEGF may contribute to differential tumoral vessel formation, we first performed in vitro tube formation assays.	('contribute', 'Reg', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('VEGF', 'Gene', '7422', (34, 38))	('changes', 'Var', (23, 30))	('tumoral', 'Disease', (70, 77))	('tumoral', 'Disease', 'MESH:D009369', (70, 77))	('tube formation', 'biological_process', 'GO:0035148', ('124', '138'))	('formation', 'biological_process', 'GO:0009058', ('85', '94'))	('VEGF', 'Gene', (34, 38))
57374	30890701	When EA.hy926 endothelial cells were cultured in conditioned media of clones in which RSUME was silenced, there was a significant decrease in capillary-like structures formation (Fig.	('capillary-like structures formation', 'CPA', (142, 177))	('silenced', 'Var', (96, 104))	('RSUME', 'Gene', (86, 91))	('decrease', 'NegReg', (130, 138))	('formation', 'biological_process', 'GO:0009058', ('168', '177'))	('EA.hy926', 'CellLine', 'CVCL:3901', (5, 13))
57376	30890701	This confirms, in vivo, that in absence of RSUME, VHL Type 2 mutant become more potent and might limit early tumoral angiogenesis.	('tumoral', 'Disease', (109, 116))	('tumoral', 'Disease', 'MESH:D009369', (109, 116))	('angiogenesis', 'biological_process', 'GO:0001525', ('117', '129'))	('VHL Type 2', 'Disease', (50, 60))	('more', 'PosReg', (75, 79))	('potent', 'MPA', (80, 86))	('VHL Type 2', 'Disease', 'MESH:D006623', (50, 60))	('mutant', 'Var', (61, 67))	('limit', 'NegReg', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))
57381	30890701	Our findings support a model in which RSUME is not downregulated in presence of VHL mutants, achieving high RSUME expression in specific tissues, were RSUME becomes critical for potentiating the missense VHL loss of function on HIF-2-alpha degradation, providing a permissive setting for the development of VHL tumors and promoting deregulated angiogenesis needed for tumor progression (Fig.	('tumor', 'Disease', (368, 373))	('missense', 'Var', (195, 203))	('VHL tumors', 'Disease', (307, 317))	('mutants', 'Var', (84, 91))	('VHL tumors', 'Disease', 'MESH:D006623', (307, 317))	('promoting', 'PosReg', (322, 331))	('tumor', 'Disease', 'MESH:D009369', (368, 373))	('VHL loss', 'Disease', (204, 212))	('deregulated', 'MPA', (332, 343))	('VHL loss', 'Disease', 'MESH:D006623', (204, 212))	('tumor', 'Disease', (311, 316))	('tumor', 'Phenotype', 'HP:0002664', (368, 373))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('expression', 'Species', '29278', (114, 124))	('angiogenesis', 'biological_process', 'GO:0001525', ('344', '356'))	('tumors', 'Phenotype', 'HP:0002664', (311, 317))	('degradation', 'biological_process', 'GO:0009056', ('240', '251'))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('angiogenesis', 'CPA', (344, 356))
57382	30890701	There are mutant VHL isoforms that seem to behave similarly to wild-type VHL in terms of HIFalpha stabilization opening the question about the mechanisms by which these mutations impact on tumor phenotype.	('tumor', 'Disease', (189, 194))	('mutations', 'Var', (169, 178))	('HIFalpha stabilization', 'MPA', (89, 111))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('impact', 'Reg', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
57383	30890701	Other alterations associated with VHL missense mutations, such as loss of PBRM1 or BAP1, or changes in proteostasis of VHL, have been proposed to support VHL pathological function.	('support', 'PosReg', (146, 153))	('loss', 'NegReg', (66, 70))	('PBRM1', 'Gene', '55193', (74, 79))	('missense mutations', 'Var', (38, 56))	('changes', 'Reg', (92, 99))	('BAP1', 'Gene', (83, 87))	('VHL', 'Gene', (34, 37))	('proteostasis', 'MPA', (103, 115))	('PBRM1', 'Gene', (74, 79))	('BAP1', 'Gene', '8314', (83, 87))
57384	30890701	In this landscape RSUME emerges as a VHL modulator: it is expressed in VHL syndrome tumors, interacts with VHL mutants and promotes HIF-2alpha stabilization by disruption of the VHL interactions.	('VHL syndrome tumors', 'Disease', (71, 90))	('promotes', 'PosReg', (123, 131))	('interacts', 'Interaction', (92, 101))	('HIF-2alpha', 'Gene', (132, 142))	('VHL syndrome tumors', 'Disease', 'MESH:D006623', (71, 90))	('interactions', 'Interaction', (182, 194))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('VHL', 'Protein', (178, 181))	('stabilization', 'MPA', (143, 156))	('disruption', 'NegReg', (160, 170))	('mutants', 'Var', (111, 118))	('HIF-2alpha', 'Gene', '2034', (132, 142))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('VHL', 'Gene', (107, 110))
57385	30890701	An in silico analysis of the effect of VHL mutations found in RCC samples shows that missense loss of function could be achieved by an impaired interaction between VHL mutants and interacting proteins.	('interaction', 'Interaction', (144, 155))	('loss of function', 'NegReg', (94, 110))	('missense', 'Var', (85, 93))	('interacting', 'Interaction', (180, 191))	('impaired', 'NegReg', (135, 143))	('VHL', 'Gene', (39, 42))	('mutations', 'Var', (43, 52))	('VHL', 'Gene', (164, 167))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('proteins', 'Protein', (192, 200))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('mutants', 'Var', (168, 175))
57386	30890701	The interaction of VHL mutants with HIF and RSUME show that RSUME overexpression disrupts HIF-2alpha-VHL mutants binding, shedding light onto the underlying mechanism behind HIF-2 stabilization.	('binding', 'molecular_function', 'GO:0005488', ('113', '120'))	('disrupts', 'NegReg', (81, 89))	('expression', 'Species', '29278', (70, 80))	('mutants', 'Var', (105, 112))	('mutants', 'Var', (23, 30))	('binding', 'Interaction', (113, 120))	('HIF-2alpha-VHL', 'Disease', (90, 104))	('HIF-2alpha-VHL', 'Disease', 'MESH:D006623', (90, 104))
57388	30890701	The reduced but still partial ability of some VHL mutants to bind to Elongin C and B has been shown to explain in part their capacity to still partially degrade HIF.	('VHL', 'Gene', (46, 49))	('bind', 'Interaction', (61, 65))	('mutants', 'Var', (50, 57))	('degrade', 'NegReg', (153, 160))	('Elongin C and B', 'Gene', '6921;6923', (69, 84))	('HIF', 'MPA', (161, 164))
57392	30890701	Sumoylation of VHL is relevant to affect its function as tumor suppressor.	('Sumoylation', 'Var', (0, 11))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('57', '73'))	('VHL', 'Gene', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('tumor suppressor', 'biological_process', 'GO:0051726', ('57', '73'))	('Sumoylation', 'biological_process', 'GO:0016925', ('0', '11'))
57393	30890701	Sumoylation/ubiquitination on Lysines 171 and 196 actively regulate VHL spatial distribution and decrease HIF-alpha inhibition.	('HIF-alpha inhibition', 'MPA', (106, 126))	('Lysines 171', 'Var', (30, 41))	('ubiquitination', 'Disease', (12, 26))	('VHL', 'Protein', (68, 71))	('ubiquitination', 'Disease', 'MESH:C563003', (12, 26))	('regulate', 'Reg', (59, 67))	('Lysines', 'Chemical', 'MESH:D008239', (30, 37))	('decrease', 'NegReg', (97, 105))	('Sumoylation', 'biological_process', 'GO:0016925', ('0', '11'))
57394	30890701	Using a VHL sumoylation-deficient, which is mutated in Lysine 171, we observed that RSUME diminishes the binding between HIF and Type 2 VHL mutants defective in sumoylation and increases HIF-2alpha stability and transcriptional response, proving that this action of RSUME is mediated by a VHL sumoylation independent mechanism.	('increases HIF-2alpha stability', 'Disease', (177, 207))	('sumoylation', 'biological_process', 'GO:0016925', ('12', '23'))	('binding', 'molecular_function', 'GO:0005488', ('105', '112'))	('transcriptional response', 'CPA', (212, 236))	('sumoylation', 'biological_process', 'GO:0016925', ('161', '172'))	('increases HIF-2alpha stability', 'Disease', 'MESH:D043171', (177, 207))	('diminishes', 'NegReg', (90, 100))	('mutants', 'Var', (140, 147))	('sumoylation', 'MPA', (161, 172))	('VHL', 'Gene', (136, 139))	('sumoylation', 'biological_process', 'GO:0016925', ('293', '304'))	('defective', 'NegReg', (148, 157))	('Lysine', 'Chemical', 'MESH:D008239', (55, 61))	('binding', 'Interaction', (105, 112))
57396	30890701	RSUME expression levels are higher in patients with VHL mutations, particularly in those in stage IV of the disease.	('mutations', 'Var', (56, 65))	('expression', 'Species', '29278', (6, 16))	('higher', 'PosReg', (28, 34))	('RSUME expression levels', 'MPA', (0, 23))	('patients', 'Species', '9606', (38, 46))	('VHL', 'Gene', (52, 55))
57397	30890701	Among those mutations, patients with missense VHL mutations showed increased RSUME levels.	('VHL', 'Gene', (46, 49))	('RSUME levels', 'MPA', (77, 89))	('mutations', 'Var', (50, 59))	('patients', 'Species', '9606', (23, 31))	('increased', 'PosReg', (67, 76))	('missense', 'Var', (37, 45))
57399	30890701	The mutations create a permissive context for RSUME increased levels that regulate their loss of function and worsens the rate of survival of the patients.	('rate', 'MPA', (122, 126))	('loss of function', 'NegReg', (89, 105))	('mutations', 'Var', (4, 13))	('worsens', 'NegReg', (110, 117))	('patients', 'Species', '9606', (146, 154))
57402	30890701	Mutations in VHL that impact on its function generate a permissive setting for deregulation of VEGF.	('VEGF', 'Gene', '7422', (95, 99))	('VHL', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('VEGF', 'Gene', (95, 99))	('deregulation', 'MPA', (79, 91))	('permissive setting', 'MPA', (56, 74))
57405	30890701	One strategy would be to act upstream HIF stability regulation, since HIF deregulation has been associated to the imbalance of factors that induce a proangiogenic scenario, thus triggering the tumoral angiogenic switch.	('induce', 'PosReg', (140, 146))	('associated', 'Reg', (96, 106))	('imbalance of factors', 'MPA', (114, 134))	('triggering', 'Reg', (178, 188))	('imbalance', 'Phenotype', 'HP:0002172', (114, 123))	('regulation', 'biological_process', 'GO:0065007', ('52', '62'))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('proangiogenic scenario', 'MPA', (149, 171))	('deregulation', 'Var', (74, 86))	('tumoral', 'Disease', (193, 200))	('tumoral', 'Disease', 'MESH:D009369', (193, 200))
57407	30890701	RSUME binds missense VHL mutant proteins in normoxic conditions in which VHL is active and RSUME, mutant VHL and HIF-2alpha coexist in the same protein complex, suggesting that RSUME could act on HIF-2alpha deregulation by missense VHL mutants previous to the tumoral hypoxic state development.	('VHL', 'Gene', (232, 235))	('tumoral hypoxic', 'Disease', 'MESH:D009369', (260, 275))	('act', 'Reg', (189, 192))	('deregulation', 'MPA', (207, 219))	('missense', 'Var', (223, 231))	('HIF-2alpha', 'Gene', '2034', (196, 206))	('tumoral hypoxic', 'Disease', (260, 275))	('protein complex', 'cellular_component', 'GO:0032991', ('144', '159'))	('HIF-2alpha', 'Gene', (113, 123))	('mutants', 'Var', (236, 243))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('HIF-2alpha', 'Gene', (196, 206))	('HIF-2alpha', 'Gene', '2034', (113, 123))
57409	30890701	Taking together, our results reveal a protein-protein interaction mechanism involved in the VHL Type 2 mutants' loss of function phenotype through the action of RSUME, both in vitro and in vivo.	('protein-protein', 'Protein', (38, 53))	('loss of function', 'NegReg', (112, 128))	('mutants', 'Var', (103, 110))	('VHL Type 2', 'Disease', (92, 102))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('VHL Type 2', 'Disease', 'MESH:D006623', (92, 102))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))
57410	30890701	Supporting this, the bioinformatics analysis from TCGA dataset showing that RSUME increased levels are associated with VHL mutations and poor patients prognosis highlight the key role of RSUME as a possible biomarker of RCC VHL disease outcome.	('RSUME', 'MPA', (76, 81))	('VHL', 'Gene', (119, 122))	('RCC VHL disease', 'Disease', (220, 235))	('RCC VHL disease', 'Disease', 'MESH:C538614', (220, 235))	('levels', 'MPA', (92, 98))	('increased', 'PosReg', (82, 91))	('RCC', 'Phenotype', 'HP:0005584', (220, 223))	('patients', 'Species', '9606', (142, 150))	('mutations', 'Var', (123, 132))
57418	27866460	Conclusions: Our data showed that morphine promotes RCC growth and increases RCC progression via over-expression of Survivin.	('Survivin', 'Gene', '100689366', (116, 124))	('morphine', 'Chemical', 'MESH:D009020', (34, 42))	('Survivin', 'Gene', (116, 124))	('promotes', 'PosReg', (43, 51))	('over-expression', 'PosReg', (97, 112))	('RCC', 'Disease', (77, 80))	('RCC growth', 'CPA', (52, 62))	('increases', 'PosReg', (67, 76))	('morphine', 'Var', (34, 42))
57431	27866460	On the other hand, morphine can inhibit migration of tumor-infiltrating leukocytes and suppresses angiogenesis associated with tumor growth in mice.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('inhibit', 'NegReg', (32, 39))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('angiogenesis', 'biological_process', 'GO:0001525', ('98', '110'))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('morphine', 'Var', (19, 27))	('mice', 'Species', '10090', (143, 147))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('morphine', 'Chemical', 'MESH:D009020', (19, 27))	('suppresses', 'NegReg', (87, 97))
57432	27866460	In addition to these well-recognized effects, various studies have suggested that morphine elicits a variety of biological effects that appear to be independent of its analgesic properties and may affect cell survival or proliferation.	('affect', 'Reg', (197, 203))	('morphine', 'Chemical', 'MESH:D009020', (82, 90))	('cell survival', 'CPA', (204, 217))	('morphine', 'Var', (82, 90))
57454	27866460	We first confirmed the effect of morphine, D50488H, DAMGO, and DPDPE on 786-O cells.	('DPDPE', 'Var', (63, 68))	('D50488H', 'Mutation', 'p.D50488H', (43, 50))	('morphine', 'Chemical', 'MESH:D009020', (33, 41))	('D50488H', 'Var', (43, 50))
57455	27866460	Our results show morphine as well as MOR, DOR, and KOR agonists (at 50 muM) induced significant 786-O proliferation under both serum-free and serum-replete conditions (Figure 1(A)).	('muM', 'Gene', (71, 74))	('morphine', 'Chemical', 'MESH:D009020', (17, 25))	('MOR', 'Gene', '4988', (37, 40))	('DOR', 'Gene', (42, 45))	('KOR', 'Gene', '4986', (51, 54))	('MOR', 'Gene', (37, 40))	('DOR', 'Gene', '58476', (42, 45))	('muM', 'Gene', '56925', (71, 74))	('786-O proliferation', 'CPA', (96, 115))	('morphine', 'Var', (17, 25))	('KOR', 'Gene', (51, 54))
57485	27866460	On the contrary, other studies have shown that morphine increases tumor cell growth in vivo and in vitro.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('morphine', 'Chemical', 'MESH:D009020', (47, 55))	('morphine', 'Var', (47, 55))	('increases tumor', 'Disease', (56, 71))	('cell growth', 'biological_process', 'GO:0016049', ('72', '83'))	('increases tumor', 'Disease', 'MESH:D009369', (56, 71))
57490	27866460	Over-expression of Survivin protein could inhibit tumor cell apoptosis, promote metastatic ability of tumor cells, and increase genomic instability, thereby boosting malignant phenotypes, such as local invasion and distant metastasis Recent studies demonstrated that Survivin expression was associated with advanced clinico-pathological stages and grades of ccRCC, while ccRCC patients with low Survivin levels had a better survival rate compared to patients with high Survivin-expressed tumor.	('Survivin', 'Gene', (469, 477))	('tumor', 'Disease', (488, 493))	('patients', 'Species', '9606', (450, 458))	('promote', 'PosReg', (72, 79))	('boosting', 'PosReg', (157, 165))	('Over-expression', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (488, 493))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('Survivin', 'Gene', '100689366', (19, 27))	('genomic instability', 'MPA', (128, 147))	('ccRCC', 'Disease', (358, 363))	('Survivin', 'Gene', (395, 403))	('patients', 'Species', '9606', (377, 385))	('Survivin', 'Gene', '100689366', (469, 477))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))	('tumor', 'Disease', (50, 55))	('associated', 'Reg', (291, 301))	('Survivin', 'Gene', (267, 275))	('tumor', 'Phenotype', 'HP:0002664', (488, 493))	('ccRCC', 'Phenotype', 'HP:0006770', (358, 363))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', (102, 107))	('expression', 'MPA', (276, 286))	('Survivin', 'Gene', (19, 27))	('Survivin', 'Gene', '100689366', (395, 403))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (371, 376))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('increase', 'PosReg', (119, 127))	('inhibit', 'NegReg', (42, 49))	('Survivin', 'Gene', '100689366', (267, 275))
57494	27866460	Morphine also induces phosphorylation of epidermal growth factor receptor (EGFR) via opioid receptors, promotes cell proliferation and increases cell invasion.	('cell proliferation', 'CPA', (112, 130))	('opioid receptors', 'Protein', (85, 101))	('Morphine', 'Chemical', 'MESH:D009020', (0, 8))	('epidermal growth factor receptor', 'Gene', (41, 73))	('increases', 'PosReg', (135, 144))	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('Morphine', 'Var', (0, 8))	('epidermal growth factor receptor', 'Gene', '1956', (41, 73))	('induces', 'Reg', (14, 21))	('cell invasion', 'CPA', (145, 158))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('EGFR', 'Gene', '1956', (75, 79))	('promotes', 'PosReg', (103, 111))	('cell proliferation', 'biological_process', 'GO:0008283', ('112', '130'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('41', '64'))	('phosphorylation', 'MPA', (22, 37))	('EGFR', 'Gene', (75, 79))
57502	27866460	Our results show morphine augments the growth and aggressive phenotype of renal cancer cells in vitro.	('aggressive phenotype of', 'CPA', (50, 73))	('morphine', 'Chemical', 'MESH:D009020', (17, 25))	('renal cancer', 'Disease', 'MESH:D007680', (74, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('augments', 'PosReg', (26, 34))	('renal cancer', 'Disease', (74, 86))	('morphine', 'Var', (17, 25))	('renal cancer', 'Phenotype', 'HP:0009726', (74, 86))
57531	33182233	In comparison to other malignancies, ccRCC is characterized by a high prevalence of somatic copy number alterations (SCNAs) and a low burden of somatic substitutions.	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('malignancies', 'Disease', (23, 35))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('malignancies', 'Disease', 'MESH:D009369', (23, 35))	('copy number alterations', 'Var', (92, 115))
57532	33182233	The integrative analysis of the genetic and clinical data led to the identification of certain alterations with prognostic value, such as mutually exclusive mutations of BAP1 and PBRM1.	('BAP1', 'Gene', '8314', (170, 174))	('PBRM1', 'Gene', (179, 184))	('PBRM1', 'Gene', '55193', (179, 184))	('mutations', 'Var', (157, 166))	('BAP1', 'Gene', (170, 174))
57536	33182233	Cancer cells continuously undergo adaptive changes, and insensitivity to drugs arises due to genetic and epigenetic alterations that offer a survival advantage.	('epigenetic alterations', 'Var', (105, 127))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('genetic', 'Var', (93, 100))
57539	33182233	Loss of the short arm of chromosome 3 is a nearly universal driver of ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('short arm', 'Phenotype', 'HP:0009824', (12, 21))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('chromosome', 'cellular_component', 'GO:0005694', ('25', '35'))	('ccRCC', 'Phenotype', 'HP:0006770', (70, 75))	('Loss', 'Var', (0, 4))
57542	33182233	Chromosomal copies of deleted suppressor genes are often affected afterward, with inactivation of the second allele of VHL being the most common (65-80% of patients).	('patients', 'Species', '9606', (156, 164))	('VHL', 'Gene', '7428', (119, 122))	('VHL', 'Gene', (119, 122))	('inactivation', 'Var', (82, 94))
57543	33182233	In some cases, there are different driver mutations on the trunk of the phylogenetic tree, which, in contrast to 3p loss and VHL inactivation, trigger a substantial expansion.	('VHL', 'Gene', (125, 128))	('trunk', 'cellular_component', 'GO:0043198', ('59', '64'))	('VHL', 'Gene', '7428', (125, 128))	('trigger', 'Reg', (143, 150))	('mutations', 'Var', (42, 51))
57546	33182233	Group 1 consists of primary tumors with VHL alteration as the sole driver event.	('alteration', 'Var', (44, 54))	('VHL', 'Gene', (40, 43))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('VHL', 'Gene', '7428', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
57547	33182233	Group 2 includes tumors in which early PBRM1 mutation and subsequent SETD2 mutation or PI3K pathway mutation or acquisition of SCNAs result in a "branched" evolutionary pattern.	('PBRM1', 'Gene', '55193', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('PI3K pathway', 'Pathway', (87, 99))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('mutation', 'Var', (75, 83))	('SETD2', 'Gene', '29072', (69, 74))	('mutation', 'Var', (100, 108))	('mutation', 'Var', (45, 53))	('PI3K', 'molecular_function', 'GO:0016303', ('87', '91'))	('SETD2', 'Gene', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('PBRM1', 'Gene', (39, 44))
57549	33182233	Clonal acquisition of multiple driver mutations (VHL plus >=2 BAP1, PBRM1, SETD2, or PTEN) or the parallel BAP1 mutation results in "punctuated" evolution.	('BAP1', 'Gene', '8314', (62, 66))	('BAP1', 'Gene', '8314', (107, 111))	('SETD2', 'Gene', '29072', (75, 80))	('mutation', 'Var', (112, 120))	('PBRM1', 'Gene', (68, 73))	('SETD2', 'Gene', (75, 80))	('BAP1', 'Gene', (62, 66))	('BAP1', 'Gene', (107, 111))	('PBRM1', 'Gene', '55193', (68, 73))	('VHL', 'Gene', (49, 52))	('PTEN', 'Gene', (85, 89))	('PTEN', 'Gene', '5728', (85, 89))	('VHL', 'Gene', '7428', (49, 52))
57552	33182233	These alterations provide a permissive genomic background for the selection of hallmark drivers of ccRCC metastasis and the loss of 9p and 14q.	('ccRCC metastasis', 'Disease', (99, 115))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('loss', 'Var', (124, 128))	('ccRCC metastasis', 'Disease', 'MESH:D009362', (99, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))
57584	33182233	The ability to target alteration present in all tumor cells is expected to diminish the odds of the escape of clonal branches.	('alteration', 'Var', (22, 32))	('tumor', 'Disease', (48, 53))	('escape of clonal branches', 'CPA', (100, 125))	('diminish', 'NegReg', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
57585	33182233	As previously described, inactivation of VHL constitutes the trunk event in ccRCC development while most of the other driver aberrations are subclonal.	('inactivation', 'Var', (25, 37))	('trunk', 'cellular_component', 'GO:0043198', ('61', '66'))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('VHL', 'Gene', (41, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('VHL', 'Gene', '7428', (41, 44))
57586	33182233	Apart from large chromosomal aberrations as in the cytogenetic 3p abnormalities, VHL inactivation may be caused by small deletions affecting the locus, or promoter methylation and epigenetic silencing.	('inactivation', 'NegReg', (85, 97))	('promoter methylation', 'Var', (155, 175))	('methylation', 'biological_process', 'GO:0032259', ('164', '175'))	('VHL', 'Gene', (81, 84))	('VHL', 'Gene', '7428', (81, 84))	('caused by', 'Reg', (105, 114))	('epigenetic silencing', 'Var', (180, 200))	('deletions', 'Var', (121, 130))	('large chromosomal aberrations', 'Phenotype', 'HP:0040012', (11, 40))
57593	33182233	In a phase I dose-escalation clinical trial, PT2385 was found to be well-tolerated and demonstrated clinical activity in extensively pretreated ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('PT2385', 'Var', (45, 51))	('PT2385', 'Chemical', 'MESH:C000614279', (45, 51))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('patients', 'Species', '9606', (150, 158))
57604	33182233	The ongoing phase III clinical trials are currently testing different combinations of a checkpoint inhibitor plus a tyrosine kinase inhibitor (NCT02811861, NCT03937219) or IL-2 derivate (NCT03729245).	('kinase inhibitor', 'biological_process', 'GO:0033673', ('125', '141'))	('NCT02811861', 'Var', (143, 154))	('IL-2', 'Gene', '3558', (172, 176))	('IL-2', 'Gene', (172, 176))	('NCT03729245', 'Var', (187, 198))	('NCT03937219', 'Var', (156, 167))	('IL-2', 'molecular_function', 'GO:0005134', ('172', '176'))
57605	33182233	Earlier phase studies are evaluating the potential of combining PD-1/PD-L1 inhibitors and antibodies directed against LAG-3 (NCT02996110, NCT03849469), TIM-3 (NCT02608268), or ICOS (NCT03693612, NCT03829501).	('NCT03829501', 'Var', (195, 206))	('PD-1', 'Gene', (64, 68))	('combining', 'Interaction', (54, 63))	('ICOS', 'Gene', (176, 180))	('PD-L1', 'Gene', '29126', (69, 74))	('LAG-3', 'Gene', '3902', (118, 123))	('TIM-3', 'Gene', (152, 157))	('LAG-3', 'Gene', (118, 123))	('ICOS', 'Gene', '29851', (176, 180))	('NCT02996110', 'Var', (125, 136))	('NCT02608268', 'Var', (159, 170))	('TIM-3', 'Gene', '84868', (152, 157))	('PD-1', 'Gene', '6622', (64, 68))	('NCT03693612', 'Var', (182, 193))	('NCT03849469', 'Var', (138, 149))	('PD-L1', 'Gene', (69, 74))
57606	33182233	An alternative approach is represented by the use of different cytokines (NCT02799095, NCT03063762) or personalized cancer vaccines (NCT03633110, NCT02950766).	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('NCT03063762', 'Var', (87, 98))	('NCT02799095', 'Var', (74, 85))	('NCT02950766', 'Var', (146, 157))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('NCT03633110', 'Var', (133, 144))
57611	33182233	Miao and colleagues found that truncating mutations in PBRM1 were associated with significantly extended progression-free survival (PFS) and OS of patients with metastatic ccRCC treated with immune checkpoint inhibitors.	('truncating mutations', 'Var', (31, 51))	('patients', 'Species', '9606', (147, 155))	('RCC', 'Disease', (174, 177))	('extended', 'PosReg', (96, 104))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('ccRCC', 'Phenotype', 'HP:0006770', (172, 177))	('progression-free survival', 'CPA', (105, 130))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('PBRM1', 'Gene', '55193', (55, 60))	('PBRM1', 'Gene', (55, 60))
57617	33182233	RCC is characterized by a moderate level of genomic instability and the absence of mutations in canonical DNA damage response (DDR) genes, such as RAD9, BRCA1, or TP53.	('mutations', 'Var', (83, 92))	('DDR) genes', 'Gene', (127, 137))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('DNA damage response', 'biological_process', 'GO:0006974', ('106', '125'))	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('TP53', 'Gene', '7157', (163, 167))	('BRCA1', 'Gene', '672', (153, 158))	('absence', 'NegReg', (72, 79))	('TP53', 'Gene', (163, 167))	('RAD9', 'Gene', '5883', (147, 151))	('BRCA1', 'Gene', (153, 158))	('RAD9', 'Gene', (147, 151))	('RAD', 'biological_process', 'GO:1990116', ('147', '150'))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('RCC', 'Disease', (0, 3))
57624	33182233	Moreover, cells harboring SETD2 mutation undergo synthetic lethal interaction with WEE1 blockade due to the depletion of nucleotide pools.	('WEE1', 'Gene', (83, 87))	('SETD2', 'Gene', '29072', (26, 31))	('SETD2', 'Gene', (26, 31))	('synthetic lethal', 'CPA', (49, 65))	('depletion of nucleotide pools', 'MPA', (108, 137))	('mutation', 'Var', (32, 40))	('WEE1', 'Gene', '7465', (83, 87))
57625	33182233	AZD1775, an experimental inhibitor of WEE1, is currently being evaluated for patients with SETD2-deficient tumors, including RCC (NCT03284385).	('SETD2', 'Gene', '29072', (91, 96))	('AZD1775', 'Var', (0, 7))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('SETD2', 'Gene', (91, 96))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('WEE1', 'Gene', '7465', (38, 42))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('deficient tumors', 'Disease', (97, 113))	('patients', 'Species', '9606', (77, 85))	('deficient tumors', 'Disease', 'MESH:D009369', (97, 113))	('WEE1', 'Gene', (38, 42))
57640	33182233	Tumors from Group 1, in which VHL mutation is the sole driver event, are the best candidates for targeting trunk mutations.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('trunk', 'cellular_component', 'GO:0043198', ('107', '112'))	('VHL', 'Gene', (30, 33))	('mutation', 'Var', (34, 42))	('Tumors', 'Disease', (0, 6))	('mutations', 'Var', (113, 122))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('VHL', 'Gene', '7428', (30, 33))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
57641	33182233	As a general rule, ITH diminishes immune responses but tumors harboring PBRM1 mutations (Group 2) could be highly vulnerable to immunotherapeutic agents.	('diminishes', 'NegReg', (23, 33))	('immune responses', 'CPA', (34, 50))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('mutations', 'Var', (78, 87))	('PBRM1', 'Gene', (72, 77))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('diminishes immune responses', 'Phenotype', 'HP:0002721', (23, 50))	('PBRM1', 'Gene', '55193', (72, 77))
57642	33182233	The predictive value of PBRM1 mutation, however, is under debate and requires further investigation.	('PBRM1', 'Gene', (24, 29))	('mutation', 'Var', (30, 38))	('PBRM1', 'Gene', '55193', (24, 29))
57643	33182233	In Figure 2, we illustrate how modulating genomic instability may affect ccRCC fitness.	('affect', 'Reg', (66, 72))	('modulating', 'Var', (31, 41))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('ccRCC fitness', 'Disease', 'MESH:D012640', (73, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))	('ccRCC fitness', 'Disease', (73, 86))
57645	33182233	As a general rule, trunk alterations are found in all tumor cells and represent an ancestral event, while other modifications constitute the branches.	('alterations', 'Var', (25, 36))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('trunk', 'cellular_component', 'GO:0043198', ('19', '24'))
57646	33182233	The gain in driver detection per additional sampling declines after eight, which is usually still not enough in cases with PBRM1 mutation.	('driver detection', 'MPA', (12, 28))	('gain', 'PosReg', (4, 8))	('mutation', 'Var', (129, 137))	('PBRM1', 'Gene', (123, 128))	('PBRM1', 'Gene', '55193', (123, 128))
57648	33182233	Analysis of ctDNA enables identification of both clonal and subclonal tumor-specific mutations with high sensitivity and specificity, with detection rates comparable with those of traditional biopsies.	('mutations', 'Var', (85, 94))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))
57662	33182233	The ongoing phase 2 clinical trials, A-PREDICT (NCT01693822) and ADAPTeR (NCT02446860), incorporate a multiregional sampling of metastatic RCC prior to and during therapy to evaluate biomarkers of treatment response.	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('NCT01693822', 'Var', (48, 59))	('NCT02446860', 'Var', (74, 85))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))
57676	32793310	ARNT disruption using siRNA knockdown inhibited the migratory abilities and cell proliferation, potentially by altering the glycolysis pathway in vitro, as evidenced by decreased M2 type acetone kinase, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 and hexokinase 2 expression.	('hexokinase 2', 'Gene', '3099', (262, 274))	('cell proliferation', 'biological_process', 'GO:0008283', ('76', '94'))	('disruption', 'Var', (5, 15))	('altering', 'Reg', (111, 119))	('cell proliferation', 'CPA', (76, 94))	('hexokinase 2', 'Gene', (262, 274))	('inhibited', 'NegReg', (38, 47))	('glycolysis pathway', 'Pathway', (124, 142))	('expression', 'MPA', (275, 285))	('glycolysis', 'biological_process', 'GO:0006096', ('124', '134'))	('6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3', 'Gene', '5209', (203, 257))	('decreased', 'NegReg', (169, 178))	('M2 type acetone kinase', 'MPA', (179, 201))	('migratory abilities', 'CPA', (52, 71))
57764	32793310	Furthermore, it has been reported that mutations of the von Hippel-Lindau (VHL) gene are the main driver events in ccRCC, and loss of VHL products will alter the expression of HIF-1alpha/2alpha and their downstream targets.	('HIF-1alpha/2alpha', 'Gene', '3091;2034', (176, 193))	('VHL', 'Gene', '7428', (134, 137))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('VHL', 'Gene', (75, 78))	('VHL', 'Gene', '7428', (75, 78))	('von Hippel-Lindau', 'Gene', (56, 73))	('mutations', 'Var', (39, 48))	('expression', 'MPA', (162, 172))	('VHL', 'Gene', (134, 137))	('HIF-1alpha/2alpha', 'Gene', (176, 193))	('alter', 'Reg', (152, 157))	('von Hippel-Lindau', 'Gene', '7428', (56, 73))	('ccRCC', 'Disease', (115, 120))	('loss', 'Var', (126, 130))
57776	32315986	LNC00160 was significantly upregulated in ccRCC and high expression predicted poor prognosis; higher expression of LNC00160 was associated with advanced clinic pathological parameters in TCGA_KIRC Cohort.	('LNC00160', 'Var', (115, 123))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (42, 47))	('RCC', 'Disease', (44, 47))	('upregulated', 'PosReg', (27, 38))	('expression', 'MPA', (101, 111))	('higher', 'PosReg', (94, 100))
57779	32315986	In conclusion, our results demonstrated that LNC00160 acted as an oncogenic gene and a specific prognostic indicator for patients with ccRCC, and that LNC00160 might be a targeted intervention for ccRCC patients in the future.	('ccRCC', 'Phenotype', 'HP:0006770', (197, 202))	('LNC00160', 'Gene', (45, 53))	('patients', 'Species', '9606', (203, 211))	('LNC00160', 'Var', (151, 159))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('RCC', 'Disease', (137, 140))	('RCC', 'Disease', (199, 202))	('patients', 'Species', '9606', (121, 129))	('RCC', 'Disease', 'MESH:C538614', (199, 202))
57789	32315986	Three independent cancer progression-related gene sets (namely GSE40435, GSE89563 and GSE105261) and two independent sunitinib resistance-related gene sets (namely GSE69535 and GSE76068) (Figure 1A) were used for screening after GEO2R analysis.	('GSE69535', 'Var', (164, 172))	('sunitinib', 'Chemical', 'MESH:D000077210', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('GSE89563', 'Var', (73, 81))	('GSE40435', 'Var', (63, 71))	('GSE76068', 'Var', (177, 185))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('GSE105261', 'Var', (86, 95))
57795	32315986	To obtain more detailed information about LINC00160, ROC curves were used to distinguish between the G1+G2 and G3+G4, M0 and M1, N0 and N1, T1+T2 and T3+T4, and Stage I+II and Stage III+IV patient samples (Supplementary Figure 2A-2E).	('LINC00160', 'Gene', (42, 51))	('patient', 'Species', '9606', (189, 196))	('LINC00160', 'Gene', '54064', (42, 51))	('T3+T4', 'Var', (150, 155))	('G1+G2', 'Var', (101, 106))	('T1+T2', 'Var', (140, 145))	('G3+G4', 'Var', (111, 116))
57797	32315986	various subgroups OS and DFS analysis demonstrated that LINC00160 expression could acted as a potential prognostic factor for patients including T1+T2 stage (Figure 2A, 2H), G1+G2 stage (Figure 2B, 2I), M0 (Figure 2C, 2J), N0 (Figure 2D, 2K), Age <=60 (Figure 2E, 2L), Age >60 (Figure 2F, 2M), Female (Figure 2G), and Male (Figure 2N).	('LINC00160', 'Gene', '54064', (56, 65))	('patients', 'Species', '9606', (126, 134))	('LINC00160', 'Gene', (56, 65))	('G1+G2 stage', 'Var', (174, 185))	('T1+T2 stage', 'Var', (145, 156))
57800	32315986	To visualize and clarify these relationships, we divided patient samples into two subgroups (alive vs dead, female vs male, T1+T2 vs T3+T4, N0 vs N1, G1+G2 vs G3+G4, Stage I+II vs Stage III+IV).	('T1+T2 vs T3+T4', 'Var', (124, 138))	('G1+G2 vs G3+G4', 'Var', (150, 164))	('patient', 'Species', '9606', (57, 64))
57807	32315986	LINC00160 dysregulation in RCC suggested that LINC00160 might influence the progression of RCC.	('LINC00160', 'Gene', (46, 55))	('LINC00160', 'Gene', (0, 9))	('dysregulation', 'Var', (10, 23))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('LINC00160', 'Gene', '54064', (0, 9))	('RCC', 'Disease', (91, 94))	('influence', 'Reg', (62, 71))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))	('LINC00160', 'Gene', '54064', (46, 55))
57808	32315986	To test this hypothesis, we successfully constructed ACHN and 786-O cell lines with knocked down LINC00160 by transfecting short hairpin RNA (shRNA) and also constructed ACHN and 786-O with overexpressed LINC00160 by transfecting plasmid (Figure 5A-5D).	('ACHN', 'Gene', '55323', (53, 57))	('RNA', 'cellular_component', 'GO:0005562', ('137', '140'))	('knocked', 'Var', (84, 91))	('ACHN', 'Gene', (170, 174))	('ACHN', 'Gene', (53, 57))	('LINC00160', 'Gene', (97, 106))	('LINC00160', 'Gene', (204, 213))	('LINC00160', 'Gene', '54064', (97, 106))	('LINC00160', 'Gene', '54064', (204, 213))	('ACHN', 'Gene', '55323', (170, 174))
57810	32315986	As shown in Figure 5E, 5F, proliferation rate of ACHN and 786-O cells was significantly repressed when knocking down LINC00160 levels.	('ACHN', 'Gene', (49, 53))	('proliferation rate', 'CPA', (27, 45))	('knocking down', 'Var', (103, 116))	('repressed', 'NegReg', (88, 97))	('ACHN', 'Gene', '55323', (49, 53))	('LINC00160', 'Gene', (117, 126))	('LINC00160', 'Gene', '54064', (117, 126))
57811	32315986	Conversely, proliferation rates have increased in LINC00160 overexpressing cells (Figure 5G, 5H).	('overexpressing', 'Var', (60, 74))	('increased', 'PosReg', (37, 46))	('proliferation rates', 'CPA', (12, 31))	('LINC00160', 'Gene', (50, 59))	('LINC00160', 'Gene', '54064', (50, 59))
57812	32315986	It was obvious that migration and invasion capabilities were suppressed in LINC00160 knocked down cells (Figure 5I, 5J, 5M, 5N, 5Q, 5R, 5U, 5V), while cells with overexpressed LINC00160 showed enhanced migration and invasion abilities (Figure 5K, 5L, 5O, 5P, 5S, 5T, 5W, 5X).	('suppressed', 'NegReg', (61, 71))	('LINC00160', 'Gene', '54064', (75, 84))	('LINC00160', 'Gene', (75, 84))	('knocked down', 'Var', (85, 97))	('LINC00160', 'Gene', '54064', (176, 185))	('enhanced', 'PosReg', (193, 201))	('LINC00160', 'Gene', (176, 185))
57820	32315986	We uncovered that LINC00160 knockdown in 786-O cells significantly decreased tumor weight and tumor volume (Figure 7A-7C).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', (94, 99))	('LINC00160', 'Gene', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('LINC00160', 'Gene', '54064', (18, 27))	('knockdown', 'Var', (28, 37))	('decreased', 'NegReg', (67, 76))	('tumor', 'Disease', (77, 82))
57822	32315986	Collectively, these results indicated that LINC00160 silencing could inhibit renal cancer growth.	('LINC00160', 'Gene', '54064', (43, 52))	('LINC00160', 'Gene', (43, 52))	('renal cancer', 'Disease', 'MESH:D007680', (77, 89))	('renal cancer', 'Phenotype', 'HP:0009726', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('silencing', 'Var', (53, 62))	('renal cancer', 'Disease', (77, 89))	('inhibit', 'NegReg', (69, 76))
57828	32315986	showed that silencing of LINC00160 resulted in reduced proliferation.	('proliferation', 'CPA', (55, 68))	('silencing', 'Var', (12, 21))	('LINC00160', 'Gene', '54064', (25, 34))	('LINC00160', 'Gene', (25, 34))	('reduced', 'NegReg', (47, 54))
57829	32315986	In the present study, public database and our experimental evidence revealed that LINC00160 was significantly upregulated in ccRCC, and that high expression of LINC00160 predicted poor outcome and was correlated with high T stage, grades, and TNM stage in TCGA_KIRC cohort; moreover, knockdown of lncRNAs in ACHN and 786-O cells impaired cell proliferation, migration, and invasion, whereas overexpression of lncRNAs accelerated cell proliferation, migration, and invasion in vitro; the xenograft tumor model in vivo indicated that the knockdown of LINC00160 level inhibits tumorigenesis.	('ACHN', 'Gene', '55323', (308, 312))	('migration', 'CPA', (358, 367))	('LINC00160', 'Gene', (549, 558))	('tumor', 'Disease', 'MESH:D009369', (497, 502))	('invasion', 'CPA', (464, 472))	('TNM', 'Gene', '10178', (243, 246))	('cell proliferation', 'biological_process', 'GO:0008283', ('338', '356'))	('knockdown', 'Var', (536, 545))	('TNM', 'Gene', (243, 246))	('cell proliferation', 'CPA', (429, 447))	('cell proliferation', 'biological_process', 'GO:0008283', ('429', '447'))	('tumor', 'Disease', (574, 579))	('tumor', 'Phenotype', 'HP:0002664', (497, 502))	('impaired', 'NegReg', (329, 337))	('LINC00160', 'Gene', '54064', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (574, 579))	('ACHN', 'Gene', (308, 312))	('invasion', 'CPA', (373, 381))	('migration', 'CPA', (449, 458))	('ccRCC', 'Phenotype', 'HP:0006770', (125, 130))	('RCC', 'Disease', (127, 130))	('LINC00160', 'Gene', '54064', (160, 169))	('LINC00160', 'Gene', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (574, 579))	('LINC00160', 'Gene', '54064', (549, 558))	('inhibits', 'NegReg', (565, 573))	('cell proliferation', 'CPA', (338, 356))	('LINC00160', 'Gene', (160, 169))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('tumor', 'Disease', (497, 502))
57846	32315986	High expression of LINC00160 is significantly positively associated with ccRCC progression.	('High', 'Var', (0, 4))	('positively', 'PosReg', (46, 56))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('LINC00160', 'Gene', (19, 28))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))	('LINC00160', 'Gene', '54064', (19, 28))	('associated', 'Reg', (57, 67))
57871	31212796	Copy number profiles of the index patient showed two distinct subgroups: one consisted of three primary tumours with relatively minor copy number changes, the other of a primary tumour, the thrombus, and the lung metastases, all with a similar copy number pattern and tetraploid-like characteristics.	('changes', 'Reg', (146, 153))	('primary tumour', 'Disease', 'MESH:D009369', (96, 110))	('primary tumour', 'Disease', (170, 184))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('lung metastases', 'Disease', (208, 223))	('primary tumour', 'Disease', 'MESH:D009369', (170, 184))	('lung metastases', 'Disease', 'MESH:D009362', (208, 223))	('primary tumours', 'Disease', 'MESH:D009369', (96, 111))	('copy number', 'Var', (134, 145))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('primary tumours', 'Disease', (96, 111))	('patient', 'Species', '9606', (34, 41))
57880	31212796	In the few reported cases, intra primary tumour and metastasis heterogeneity was identified based on differences in copy number aberrations (CNAs), single nucleotide variants (SNVs) and RNA expression patterns.	('single nucleotide variants', 'Var', (148, 174))	('intra primary tumour', 'Disease', (27, 47))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('copy number', 'MPA', (116, 127))	('RNA', 'MPA', (186, 189))	('RNA', 'cellular_component', 'GO:0005562', ('186', '189'))	('intra primary tumour', 'Disease', 'MESH:D009369', (27, 47))
57882	31212796	As the majority of metastases are thought to establish through hematogenous dissemination, studying venous tumour thrombus samples may reveal the mutations of at least some of the cancer cells on their road to distant metastasis.	('venous tumour thrombus', 'Phenotype', 'HP:0004936', (100, 122))	('mutations', 'Var', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('metastases', 'Disease', (19, 29))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('venous tumour thrombus', 'Disease', 'MESH:D013927', (100, 122))	('metastases', 'Disease', 'MESH:D009362', (19, 29))	('cancer', 'Disease', (180, 186))	('venous tumour thrombus', 'Disease', (100, 122))
57893	31212796	The lung metastasis that developed after treatment with pegylated (PEG)-interferon, M4, was distinct from other metastases by several copy number alterations, most prominently the loss of 11q.	('PEG', 'Chemical', '-', (67, 70))	('loss', 'Var', (180, 184))	('metastases', 'Disease', (112, 122))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('lung metastasis', 'Disease', 'MESH:D009362', (4, 19))	('pegylated', 'Var', (56, 65))	('lung metastasis', 'Disease', (4, 19))
57905	31212796	Indeed, the BAF plots of the germline variants for chromosomes 8, 14, and 15 indicated an odd number of copies in the tumour cells in Pr4, VT, and the lung metastases, consistent with the presence of three copies.	('copies', 'Var', (104, 110))	('lung metastases', 'Disease', 'MESH:D009362', (151, 166))	('tumour', 'Disease', (118, 124))	('variants', 'Var', (38, 46))	('VT', 'Disease', 'MESH:D017180', (139, 141))	('BAF', 'Gene', '8815', (12, 15))	('VT', 'Phenotype', 'HP:0031041', (139, 141))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('BAF', 'Gene', (12, 15))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('lung metastases', 'Disease', (151, 166))
57908	31212796	A total of 146 non-synonymous somatic mutations identified in 138 genes were defined as a major clone mutation in at least one tumour sample, adding up to 390 events of major clone mutations in nine tumour samples (Figure 3).	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (199, 205))	('non-synonymous', 'Var', (15, 29))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('tumour', 'Disease', (199, 205))	('tumour', 'Disease', (127, 133))
57910	31212796	Eighteen of the 146 non-synonymous somatic mutations (12.3%) were shared by all tumour samples.	('tumour', 'Disease', (80, 86))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('non-synonymous', 'Var', (20, 34))
57911	31212796	Among these were mutations in two well-known ccRCC cancer driver genes (VHL and PBRM1) and in EPHA4, a lung adenocarcinoma driver gene.	('PBRM1', 'Gene', '55193', (80, 85))	('EPHA4', 'Gene', (94, 99))	('lung adenocarcinoma', 'Disease', (103, 122))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (103, 122))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('EPHA4', 'Gene', '2043', (94, 99))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('VHL', 'Disease', 'MESH:D006623', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('PBRM1', 'Gene', (80, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('VHL', 'Disease', (72, 75))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (103, 122))	('cancer', 'Disease', (51, 57))	('mutations', 'Var', (17, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))
57912	31212796	Fifty-one mutations (35%) were present in a subset of the primary tumours but not detected in the VT nor in the lung metastases.	('VT', 'Phenotype', 'HP:0031041', (98, 100))	('primary tumours', 'Disease', 'MESH:D009369', (58, 73))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('primary tumours', 'Disease', (58, 73))	('lung metastases', 'Disease', 'MESH:D009362', (112, 127))	('lung metastases', 'Disease', (112, 127))	('VT', 'Disease', 'MESH:D017180', (98, 100))	('mutations', 'Var', (10, 19))
57913	31212796	This included a mutation in a known ccRCC cancer driver gene, ARID1A.	('RCC', 'Disease', (38, 41))	('mutation', 'Var', (16, 24))	('included', 'Reg', (5, 13))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('ARID1A', 'Gene', '8289', (62, 68))	('ARID1A', 'Gene', (62, 68))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
57944	31212796	The lung metastasis that developed after treatment of PEG-interferon, M4, featured additional structural alteration in 11q and more copy number levels than the rest of the metastases.	('PEG', 'Chemical', '-', (54, 57))	('copy number levels', 'MPA', (132, 150))	('metastases', 'Disease', 'MESH:D009362', (172, 182))	('more', 'PosReg', (127, 131))	('11q', 'Protein', (119, 122))	('lung metastasis', 'Disease', 'MESH:D009362', (4, 19))	('PEG-interferon', 'Var', (54, 68))	('metastases', 'Disease', (172, 182))	('lung metastasis', 'Disease', (4, 19))
57951	31212796	These included mutations in the well-known ccRCC-specific cancer driver genes VHL and PBRM1, which were, therefore, most likely involved in the initiation of tumour development in this patient.	('VHL', 'Disease', 'MESH:D006623', (78, 81))	('initiation of tumour', 'Disease', 'MESH:D009369', (144, 164))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('VHL', 'Disease', (78, 81))	('mutations', 'Var', (15, 24))	('patient', 'Species', '9606', (185, 192))	('initiation of tumour', 'Disease', (144, 164))	('PBRM1', 'Gene', (86, 91))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('involved', 'Reg', (128, 136))	('cancer', 'Disease', (58, 64))	('PBRM1', 'Gene', '55193', (86, 91))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))
57952	31212796	A low number of shared mutations between primary tumours and their metastasis was also reported in a study where single primary tumour samples were compared with a single metastatic sample per patient.	('primary tumour', 'Disease', 'MESH:D009369', (41, 55))	('metastasis', 'CPA', (67, 77))	('primary tumours', 'Disease', (41, 56))	('primary tumours', 'Disease', 'MESH:D009369', (41, 56))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('mutations', 'Var', (23, 32))	('primary tumour', 'Disease', (120, 134))	('primary tumour', 'Disease', 'MESH:D009369', (120, 134))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('patient', 'Species', '9606', (193, 200))
57953	31212796	Instead, both the primary tumour sections and metastases we analysed show a more-or-less equal number of unique mutations.	('primary tumour', 'Disease', (18, 32))	('primary tumour', 'Disease', 'MESH:D009369', (18, 32))	('metastases', 'Disease', (46, 56))	('mutations', 'Var', (112, 121))	('metastases', 'Disease', 'MESH:D009362', (46, 56))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))
57954	31212796	The presence of these private mutations might reflect on-going parallel clonal evolution in each of the primary tumour sections and in metastasis regions.	('primary tumour', 'Disease', 'MESH:D009369', (104, 118))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (30, 39))	('primary tumour', 'Disease', (104, 118))
57956	31212796	The combined data suggest punctuated evolution of structural variations occurred within a short window of time, after which the mutational load of different parts of the primary tumour and all the individual metastasis further increased independently.	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('primary tumour', 'Disease', (170, 184))	('primary tumour', 'Disease', 'MESH:D009369', (170, 184))	('mutational load', 'MPA', (128, 143))	('variations', 'Var', (61, 71))
57957	31212796	We identified several somatic mutations restricted to the different metastatic sites in the lungs, but none of these mutations were shared between all lung metastasis sites.	('lung metastasis', 'Disease', (151, 166))	('mutations', 'Var', (30, 39))	('lung metastasis', 'Disease', 'MESH:D009362', (151, 166))
57960	31212796	With respect to the mutations that may have facilitated the process of metastasis, we found it interesting that we observed a missense mutation of ARHGAP12 and a frameshift deletion of CENPN in the VT and all lung metastatic samples.	('missense mutation', 'Var', (126, 143))	('frameshift deletion', 'Var', (162, 181))	('ARHGAP12', 'Gene', '94134', (147, 155))	('CENPN', 'Gene', '55839', (185, 190))	('VT', 'Disease', 'MESH:D017180', (198, 200))	('VT', 'Phenotype', 'HP:0031041', (198, 200))	('ARHGAP12', 'Gene', (147, 155))	('CENPN', 'Gene', (185, 190))
57962	31212796	These processes regulate invasive growth, and when aberrantly expressed in cancer cells, leads to cancer invasion and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('invasive growth', 'CPA', (25, 40))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('invasive growth', 'biological_process', 'GO:0007125', ('25', '40'))	('metastasis', 'CPA', (118, 128))	('leads to', 'Reg', (89, 97))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('invasive growth', 'biological_process', 'GO:0001404', ('25', '40'))	('invasive growth', 'biological_process', 'GO:0036267', ('25', '40'))	('invasive growth', 'biological_process', 'GO:0044412', ('25', '40'))	('cancer', 'Disease', (98, 104))	('invasive growth', 'biological_process', 'GO:0044409', ('25', '40'))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('invasive growth', 'biological_process', 'GO:0051831', ('25', '40'))	('aberrantly expressed', 'Var', (51, 71))
57967	31212796	Few mutations were only present in area Pr4 of the primary tumour and were shared with VT and all lung metastases, including one missense mutation of CUBN.	('CUBN', 'Gene', '8029', (150, 154))	('primary tumour', 'Disease', 'MESH:D009369', (51, 65))	('VT', 'Disease', 'MESH:D017180', (87, 89))	('CUBN', 'Gene', (150, 154))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('VT', 'Phenotype', 'HP:0031041', (87, 89))	('lung metastases', 'Disease', (98, 113))	('lung metastases', 'Disease', 'MESH:D009362', (98, 113))	('missense', 'Var', (129, 137))	('primary tumour', 'Disease', (51, 65))
57972	31212796	In fact, none of the genes that showed differential expression between primary tumour and metastases carried a mutation in any of the tumour samples.	('metastases', 'Disease', (90, 100))	('metastases', 'Disease', 'MESH:D009362', (90, 100))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('primary tumour', 'Disease', (71, 85))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('tumour', 'Disease', (134, 140))	('primary tumour', 'Disease', 'MESH:D009369', (71, 85))	('mutation', 'Var', (111, 119))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', (79, 85))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
57973	31212796	Conversely, the mutations that occurred in these tumours, apparently did not influence mRNA levels of the mutated genes.	('tumours', 'Disease', (49, 56))	('mRNA levels', 'MPA', (87, 98))	('mutations', 'Var', (16, 25))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('tumours', 'Disease', 'MESH:D009369', (49, 56))
57992	31212796	Copy number alteration and somatic mutation profiling from multi-region sampling of the primary tumour and metastases facilitates the identification of somatic alterations that underlie early events in tumour evolution and subsequent events in metastatic development.	('primary tumour', 'Disease', (88, 102))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('tumour', 'Disease', (96, 102))	('Copy', 'Var', (0, 4))	('metastases', 'Disease', 'MESH:D009362', (107, 117))	('tumour', 'Disease', 'MESH:D009369', (202, 208))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('alterations', 'Var', (160, 171))	('primary tumour', 'Disease', 'MESH:D009369', (88, 102))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('tumour', 'Disease', (202, 208))	('metastases', 'Disease', (107, 117))
58018	32180553	It is important to note that MBOAT7, unlike other lysophospholipid acyltransferses, only diversifies the fatty acid composition of membrane PI species and not phospholipids with other head groups.	('phospholipids', 'Chemical', 'MESH:D010743', (159, 172))	('lysophospholipid', 'Chemical', 'MESH:D008246', (50, 66))	('membrane', 'cellular_component', 'GO:0016020', ('131', '139'))	('fatty acid', 'Chemical', 'MESH:D005227', (105, 115))	('fatty acid composition', 'MPA', (105, 127))	('MBOAT7', 'Var', (29, 35))	('diversifies', 'Reg', (89, 100))
58020	32180553	The data support the hypothesis that limiting MBOAT7-driven PI diversification may hold therapeutic promise in ccRCC and potentially other cancers.	('ccRCC', 'Disease', 'MESH:D002292', (111, 116))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('PI diversification', 'Var', (60, 78))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('ccRCC', 'Disease', (111, 116))	('MBOAT7-driven', 'Var', (46, 59))
58035	32180553	Standard solutions: The standards used in this assay were purchased from Avanti Polar Lipids (LPI-16:0, LPI-18:0, LPI-18:1, LPI-20:4, and PI-38:4).	('LPI-16:0', 'Var', (94, 102))	('LPI', 'Chemical', 'MESH:C025449', (124, 127))	('LPI-18:1', 'Var', (114, 122))	('Lipids', 'Chemical', 'MESH:D008055', (86, 92))	('LPI', 'Chemical', 'MESH:C025449', (104, 107))	('LPI-20:4', 'Var', (124, 132))	('LPI-18:0', 'Var', (104, 112))	('LPI', 'Chemical', 'MESH:C025449', (94, 97))	('LPI', 'Chemical', 'MESH:C025449', (114, 117))
58040	32180553	The SRM transitions (m/z) were 571   255 for LPI-16:0, 599   283 for LPI-18:0, 597   281 for LPI-18:1, 619   303 for LPI-20:4, 885   241 for PI-38:4, and 583   267 for internal standard LPI-17:1 and 866   281 for internal standard PI-34:1-d31.	('LPI', 'Chemical', 'MESH:C025449', (93, 96))	('LPI', 'Chemical', 'MESH:C025449', (186, 189))	('LPI-16:0', 'Var', (45, 53))	('LPI', 'Chemical', 'MESH:C025449', (69, 72))	('LPI', 'Chemical', 'MESH:C025449', (45, 48))	('571   255', 'Var', (31, 40))	('LPI', 'Chemical', 'MESH:C025449', (117, 120))
58051	32180553	The percent change in area was quantified using ImageJ software by using the following formula: MBOAT7+/+ and MBOAT7-/- Caki-1 cell lines were injected into the subcutaneous flank of NSG mice (Jackson Laboratory) at 2.5 million cells per mouse in PBS (n = 10 per group).	('MBOAT7+/+', 'Var', (96, 105))	('PBS', 'Chemical', 'MESH:D007854', (247, 250))	('MBOAT7-/-', 'Var', (110, 119))	('mice', 'Species', '10090', (187, 191))	('mouse', 'Species', '10090', (238, 243))
58072	32180553	To assess the role of MBOAT7 in ccRCC, we utilized CRISPR/Cas9 to knockout MBOAT7 in the Caki-1 and 786-O ccRCC cell lines.	('knockout', 'Var', (66, 74))	('Cas', 'cellular_component', 'GO:0005650', ('58', '61'))	('ccRCC', 'Phenotype', 'HP:0006770', (32, 37))	('ccRCC', 'Disease', (32, 37))	('ccRCC', 'Disease', 'MESH:D002292', (32, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('ccRCC', 'Disease', (106, 111))	('ccRCC', 'Disease', 'MESH:D002292', (106, 111))	('MBOAT7', 'Gene', (75, 81))
58075	32180553	Thus, because of MBOAT7deletion, the levels of LPI substrates were significantly increased in the MBOAT7-/- clones (Figure 3B) and the set of AA-PI (36:4, 38:4, 38:5) products were significantly attenuated (Figure 3C).	('AA-PI', 'Chemical', '-', (142, 147))	('levels of LPI substrates', 'MPA', (37, 61))	('MBOAT7deletion', 'Var', (17, 31))	('LPI', 'Chemical', 'MESH:C025449', (47, 50))	('MBOAT7-/-', 'Var', (98, 107))	('increased', 'PosReg', (81, 90))	('attenuated', 'NegReg', (195, 205))
58076	32180553	MBOAT7 deficiency led to a 4-fold increase in the total LPI species and an approximately 50% reduction in the total PI (Supplementary Fig.	('LPI', 'Chemical', 'MESH:C025449', (56, 59))	('reduction', 'NegReg', (93, 102))	('MBOAT7', 'Gene', (0, 6))	('deficiency', 'Var', (7, 17))	('increase', 'PosReg', (34, 42))	('LPI species', 'MPA', (56, 67))
58079	32180553	Pharmacological inhibition of MBOAT7 with thimerosal showed striking reductions in the in vitro cell viability (Supplementary Fig.	('MBOAT7', 'Gene', (30, 36))	('thimerosal', 'Chemical', 'MESH:D013849', (42, 52))	('in vitro cell viability', 'CPA', (87, 110))	('thimerosal', 'Var', (42, 52))	('reductions', 'NegReg', (69, 79))
58081	32180553	Approximately 8 weeks post-injection, the MBOAT7+/+ cells had reached the endpoint in the tumor growth experiment, but the MBOAT7-/- failed to develop a palpable tumor (Figure 3F).	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('MBOAT7+/+', 'Var', (42, 51))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
58083	32180553	In an asynchronous culture, the MBOAT7-/- cells had reduced phospho-ERK1/2 levels (Figure 3G).	('ERK1/2', 'Gene', '5595;5594', (68, 74))	('ERK1', 'molecular_function', 'GO:0004707', ('68', '72'))	('reduced', 'NegReg', (52, 59))	('MBOAT7-/-', 'Var', (32, 41))	('ERK1/2', 'Gene', (68, 74))
58084	32180553	Upon synchronizing the cells, the Caki-1 MBOAT7-/- cells demonstrated a blunted platelet-derived growth factor stimulated response in phospho-ERK1/2 activation (Supplementary Fig.	('MBOAT7-/-', 'Var', (41, 50))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('80', '110'))	('Caki-1', 'Gene', (34, 40))	('ERK1/2', 'Gene', (142, 148))	('ERK1/2', 'Gene', '5595;5594', (142, 148))	('blunted', 'NegReg', (72, 79))	('ERK1', 'molecular_function', 'GO:0004707', ('142', '146'))
58085	32180553	The MBOAT7-/- cells had reduced P-S6K activation (Figure 3H).	('P-S6K', 'Gene', '6198', (32, 37))	('MBOAT7-/-', 'Var', (4, 13))	('reduced', 'NegReg', (24, 31))	('activation', 'MPA', (38, 48))	('P-S6K', 'Gene', (32, 37))
58086	32180553	MBOAT7-/- ccRCC cells had differentially regulated motility, proliferation, and matrix organization.	('motility', 'CPA', (51, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (10, 15))	('ccRCC', 'Disease', (10, 15))	('proliferation', 'CPA', (61, 74))	('MBOAT7-/-', 'Var', (0, 9))	('ccRCC', 'Disease', 'MESH:D002292', (10, 15))	('matrix organization', 'CPA', (80, 99))
58088	32180553	MBOAT7-/- ccRCC cells showed decreased migration and less mesenchymal phenotype.	('less', 'NegReg', (53, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (10, 15))	('ccRCC', 'Disease', (10, 15))	('decreased', 'NegReg', (29, 38))	('MBOAT7-/-', 'Var', (0, 9))	('ccRCC', 'Disease', 'MESH:D002292', (10, 15))
58090	32180553	The MBOAT7-/- had decreased expression of mesenchymal genes SNAIL, ZEB1, and ACTA2, yet increased expression of the epithelial marker E-cadherin (CDH1) (Figure 5C).	('MBOAT7-/-', 'Var', (4, 13))	('CDH1', 'Gene', (146, 150))	('cadherin', 'molecular_function', 'GO:0008014', ('136', '144'))	('decreased', 'NegReg', (18, 27))	('expression', 'MPA', (28, 38))	('ZEB1', 'Gene', '6935', (67, 71))	('SNAIL', 'Gene', '6615', (60, 65))	('ZEB1', 'Gene', (67, 71))	('E-cadherin', 'Gene', (134, 144))	('SNAIL', 'Gene', (60, 65))	('increased', 'PosReg', (88, 97))	('ACTA2', 'Gene', (77, 82))	('E-cadherin', 'Gene', '999', (134, 144))	('ACTA2', 'Gene', '59', (77, 82))	('CDH1', 'Gene', '999', (146, 150))	('expression', 'MPA', (98, 108))
58093	32180553	Closely associated with these genetic alterations, lipid metabolic processes are dramatically altered in the ccRCC tumor microenvironment.	('lipid metabolic processes', 'MPA', (51, 76))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('altered', 'Reg', (94, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('tumor', 'Disease', (115, 120))	('lipid', 'Chemical', 'MESH:D008055', (51, 56))	('ccRCC', 'Disease', (109, 114))	('genetic alterations', 'Var', (30, 49))	('ccRCC', 'Disease', 'MESH:D002292', (109, 114))	('alterations', 'Var', (38, 49))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
58096	32180553	The key findings from this study are (1) in addition to the accumulation of cholesteryl ester, metastatic ccRCC is characterized by the accumulation of AA-PI lipids and the elevated expression of AA-PI synthesizing enzyme MBOAT7; (2) MBOAT7 expression is elevated in high grade ccRCC, and high MBOAT7 expression is associated with poor survival; (3) the genetic deletion of MBOAT7 in ccRCC cells results in reduced AA-PI levels and reciprocal increases in substrate LPIs; (4) MBOAT7 null ccRCC cells exhibit reduced proliferation associated with cell cycle arrest and fail to form tumors in vivo; (5) MBOAT7 null ccRCC cells have reduced growth factor-driven MAPK activation; and (6) unbiased RNA sequencing reveals that MBOAT7/AA-PI may play a role in regulating ccRCC migration and epithelial to mesenchymal transition (EMT).	('ccRCC', 'Disease', (613, 618))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('LPI', 'Chemical', 'MESH:C025449', (466, 469))	('MAPK activation', 'biological_process', 'GO:0000187', ('659', '674'))	('MAPK', 'molecular_function', 'GO:0004707', ('659', '663'))	('ccRCC', 'Phenotype', 'HP:0006770', (384, 389))	('ccRCC', 'Disease', (278, 283))	('epithelial to mesenchymal transition', 'CPA', (784, 820))	('ccRCC', 'Phenotype', 'HP:0006770', (613, 618))	('RNA', 'cellular_component', 'GO:0005562', ('693', '696'))	('AA-PI', 'Chemical', '-', (728, 733))	('MAPK', 'Gene', '5595;5594;5595', (659, 663))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('546', '563'))	('tumor', 'Disease', (581, 586))	('ccRCC', 'Phenotype', 'HP:0006770', (278, 283))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('784', '820'))	('ccRCC', 'Disease', 'MESH:D002292', (488, 493))	('AA-PI', 'Chemical', '-', (196, 201))	('deletion', 'Var', (362, 370))	('tumor', 'Disease', 'MESH:D009369', (581, 586))	('tumors', 'Phenotype', 'HP:0002664', (581, 587))	('MAPK', 'Gene', (659, 663))	('ccRCC', 'Disease', 'MESH:D002292', (106, 111))	('ccRCC', 'Disease', (488, 493))	('ccRCC', 'Disease', 'MESH:D002292', (384, 389))	('AA-PI', 'Chemical', '-', (415, 420))	('ccRCC', 'Disease', 'MESH:D002292', (764, 769))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (546, 563))	('AA-PI', 'Chemical', '-', (152, 157))	('ccRCC', 'Disease', 'MESH:D002292', (613, 618))	('tumor', 'Phenotype', 'HP:0002664', (581, 586))	('EMT', 'biological_process', 'GO:0001837', ('822', '825'))	('ccRCC', 'Disease', (384, 389))	('ccRCC', 'Phenotype', 'HP:0006770', (488, 493))	('AA-PI', 'MPA', (415, 420))	('ccRCC', 'Disease', (106, 111))	('ccRCC', 'Disease', 'MESH:D002292', (278, 283))	('lipids', 'Chemical', 'MESH:D008055', (158, 164))	('ccRCC', 'Disease', (764, 769))
58105	32180553	Supporting this hypothesis, it was recently demonstrated that MBOAT7 knockout mice have a selective reduction in arachidonic acid-containing PIP species.	('reduction', 'NegReg', (100, 109))	('arachidonic acid-containing PIP species', 'MPA', (113, 152))	('MBOAT7', 'Gene', (62, 68))	('arachidonic acid', 'Chemical', 'MESH:D016718', (113, 129))	('PIP', 'Chemical', 'MESH:D018129', (141, 144))	('knockout', 'Var', (69, 77))	('mice', 'Species', '10090', (78, 82))
58122	32180553	Collectively, our work suggests that selective MBOAT7 inhibitors may hold promise to blunt the progression of metastatic ccRCC, and these findings may be broadly related to other cancer types in which the PI3K-AKT-mTOR axis is hyperactive.	('ccRCC', 'Disease', 'MESH:D002292', (121, 126))	('AKT', 'Gene', (210, 213))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('inhibitors', 'Var', (54, 64))	('mTOR', 'Gene', (214, 218))	('mTOR', 'Gene', '2475', (214, 218))	('blunt', 'NegReg', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('ccRCC', 'Phenotype', 'HP:0006770', (121, 126))	('AKT', 'Gene', '207', (210, 213))	('MBOAT7', 'Gene', (47, 53))	('PI3K', 'molecular_function', 'GO:0016303', ('205', '209'))	('ccRCC', 'Disease', (121, 126))	('cancer', 'Disease', (179, 185))
58202	28681074	pixels with higher Ktrans would also had higher Kep and higher iAUC).	('Kep', 'MPA', (48, 51))	('higher', 'PosReg', (41, 47))	('Ktrans', 'Chemical', '-', (19, 25))	('Ktrans', 'Var', (19, 25))
58248	33953569	Genetic Analysis and Targeted Therapy Using Buparlisib and MK2206 in a Patient with Triple Metachronous Cancers of the Kidney, Prostate, and Squamous Cell Carcinoma of the Lung: A Case Report Multiple primary cancers (MPC) occurring in the same individual is considered rare but being increasingly recognized owing to the longer cancer survival nowadays.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('Cancers of the Kidney', 'Phenotype', 'HP:0009726', (104, 125))	('Triple Metachronous Cancers of the Kidney', 'Disease', 'MESH:D007680', (84, 125))	('Buparlisib', 'Chemical', 'MESH:C571178', (44, 54))	('Triple Metachronous Cancers of the Kidney', 'Disease', (84, 125))	('cancer', 'Disease', 'MESH:D009369', (329, 335))	('MK2206', 'Chemical', 'MESH:C548887', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (141, 164))	('Carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Squamous Cell Carcinoma of the Lung', 'Phenotype', 'HP:0030359', (141, 176))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (141, 164))	('Carcinoma of the Lung', 'Phenotype', 'HP:0100526', (155, 176))	('MK2206', 'Var', (59, 65))	('Squamous Cell Carcinoma', 'Disease', (141, 164))	('cancer', 'Disease', (329, 335))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('Patient', 'Species', '9606', (71, 78))	('MPC', 'Chemical', '-', (218, 221))	('cancers', 'Disease', (209, 216))	('cancer', 'Disease', (209, 215))	('Cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
58255	33953569	Briefly, the results identified VHL, EGFR, PIK3CA, TP53, and AKT1 mutations in lung cancer, AKT1, FGFR2, and TP53 mutations in renal cancer, and FGFR2 mutations in prostate cancer.	('mutations', 'Var', (66, 75))	('mutations', 'Var', (114, 123))	('VHL', 'Gene', '7428', (32, 35))	('renal cancer', 'Disease', 'MESH:D007680', (127, 139))	('lung cancer', 'Disease', (79, 90))	('FGFR2', 'Gene', (98, 103))	('AKT1', 'Gene', '207', (92, 96))	('AKT1', 'Gene', '207', (61, 65))	('PIK3CA', 'Gene', (43, 49))	('TP53', 'Gene', (51, 55))	('FGFR2', 'Gene', (145, 150))	('TP53', 'Gene', '7157', (109, 113))	('EGFR', 'Gene', '1956', (37, 41))	('FGFR2', 'Gene', '2263', (98, 103))	('mutations', 'Var', (151, 160))	('AKT1', 'Gene', (92, 96))	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('AKT1', 'Gene', (61, 65))	('FGFR2', 'Gene', '2263', (145, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TP53', 'Gene', '7157', (51, 55))	('prostate cancer', 'Disease', 'MESH:D011471', (164, 179))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('renal cancer', 'Disease', (127, 139))	('prostate cancer', 'Phenotype', 'HP:0012125', (164, 179))	('VHL', 'Gene', (32, 35))	('PIK3CA', 'Gene', '5290', (43, 49))	('renal cancer', 'Phenotype', 'HP:0009726', (127, 139))	('FGFR', 'molecular_function', 'GO:0005007', ('98', '102'))	('prostate cancer', 'Disease', (164, 179))	('TP53', 'Gene', (109, 113))	('EGFR', 'Gene', (37, 41))	('FGFR', 'molecular_function', 'GO:0005007', ('145', '149'))
58256	33953569	A combined medication targeting PIK3CA and AKT1 signaling was recommended and the patient was given BKM120 (PIK3CA, Phase III clinical trial) and MK2206 (AKT, phase III clinical trial).	('MK2206', 'Var', (146, 152))	('AKT1', 'Gene', (43, 47))	('BKM120', 'Var', (100, 106))	('PIK3CA', 'Gene', '5290', (32, 38))	('patient', 'Species', '9606', (82, 89))	('AKT', 'Gene', '207', (154, 157))	('AKT', 'Gene', '207', (43, 46))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('PIK3CA', 'Gene', (108, 114))	('AKT', 'Gene', (154, 157))	('AKT', 'Gene', (43, 46))	('MK2206', 'Chemical', 'MESH:C548887', (146, 152))	('AKT1', 'Gene', '207', (43, 47))	('BKM120', 'Chemical', 'MESH:C571178', (100, 106))	('PIK3CA', 'Gene', '5290', (108, 114))	('PIK3CA', 'Gene', (32, 38))
58287	33953569	Lung SQCC was found to have mutations in VHL, PIK3CA, EGFR, HRAS, TP53, BRAF, CDH1, and AKT1.	('VHL', 'Gene', '7428', (41, 44))	('EGFR', 'molecular_function', 'GO:0005006', ('54', '58'))	('PIK3CA', 'Gene', '5290', (46, 52))	('BRAF', 'Gene', (72, 76))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('CDH1', 'Gene', '999', (78, 82))	('HRAS', 'Gene', '3265', (60, 64))	('BRAF', 'Gene', '673', (72, 76))	('EGFR', 'Gene', '1956', (54, 58))	('VHL', 'Gene', (41, 44))	('CDH1', 'Gene', (78, 82))	('AKT1', 'Gene', '207', (88, 92))	('HRAS', 'Gene', (60, 64))	('EGFR', 'Gene', (54, 58))	('mutations', 'Var', (28, 37))	('AKT1', 'Gene', (88, 92))	('PIK3CA', 'Gene', (46, 52))
58288	33953569	CCRCC harbored mutations in VHL, FGFR2 and AKT1, and TP53.	('AKT1', 'Gene', (43, 47))	('CCRCC', 'Disease', (0, 5))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))	('mutations', 'Var', (15, 24))	('FGFR2', 'Gene', (33, 38))	('FGFR2', 'Gene', '2263', (33, 38))	('TP53', 'Gene', '7157', (53, 57))	('AKT1', 'Gene', '207', (43, 47))	('VHL', 'Gene', (28, 31))	('TP53', 'Gene', (53, 57))	('VHL', 'Gene', '7428', (28, 31))
58290	33953569	The metastatic bone tumor of CCRCC origin showed mutations in VHL, FGFR2, and TP53.	('bone tumor', 'Disease', (15, 25))	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('bone tumor', 'Disease', 'MESH:D001859', (15, 25))	('mutations', 'Var', (49, 58))	('bone tumor', 'Phenotype', 'HP:0010622', (15, 25))	('CCRCC', 'Disease', (29, 34))	('metastatic', 'Disease', (4, 14))	('FGFR2', 'Gene', (67, 72))	('VHL', 'Gene', (62, 65))	('TP53', 'Gene', (78, 82))	('FGFR2', 'Gene', '2263', (67, 72))	('TP53', 'Gene', '7157', (78, 82))	('VHL', 'Gene', '7428', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
58291	33953569	The VHL, FGFR2, and TP53 mutations were the most common ones, with the VHL mutations in lung, renal and bone tumors, and the FGFR2 mutations in renal and metastatic bone tumors.	('bone tumors', 'Disease', (165, 176))	('FGFR2', 'Gene', '2263', (125, 130))	('bone tumors', 'Phenotype', 'HP:0010622', (165, 176))	('VHL', 'Gene', '7428', (71, 74))	('lung', 'Disease', (88, 92))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (25, 34))	('renal', 'Disease', (144, 149))	('TP53', 'Gene', (20, 24))	('bone tumors', 'Disease', 'MESH:D001859', (165, 176))	('FGFR', 'molecular_function', 'GO:0005007', ('125', '129'))	('FGFR2', 'Gene', (9, 14))	('bone tumor', 'Phenotype', 'HP:0010622', (165, 175))	('VHL', 'Gene', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('bone tumors', 'Disease', (104, 115))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('FGFR2', 'Gene', '2263', (9, 14))	('FGFR', 'molecular_function', 'GO:0005007', ('9', '13'))	('bone tumors', 'Phenotype', 'HP:0010622', (104, 115))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('VHL', 'Gene', '7428', (4, 7))	('TP53', 'Gene', '7157', (20, 24))	('mutations', 'Var', (131, 140))	('common', 'Reg', (49, 55))	('FGFR2', 'Gene', (125, 130))	('VHL', 'Gene', (71, 74))	('bone tumors', 'Disease', 'MESH:D001859', (104, 115))	('mutations', 'Var', (75, 84))	('bone tumor', 'Phenotype', 'HP:0010622', (104, 114))
58292	33953569	Several PIK3CA and AKT1 mutations are canonical and had been reported in various cancers according to COSMIC and Clinvar database, including PIK3CA c.3142C>T p.His1048Tyr (COSM249875), AKT1 c.68G>A p.Arg23Gln (COSM3770600), and c.49G>A p.Glu17Lys (COSM33765).	('c.68G>A', 'SUBSTITUTION', 'None', (190, 197))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('COSM33765', 'Chemical', '-', (248, 257))	('cancers', 'Disease', (81, 88))	('p.His1048Tyr', 'Var', (158, 170))	('c.49G>A', 'Var', (228, 235))	('mutations', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('PIK3CA', 'Gene', '5290', (8, 14))	('p.Arg23Gln', 'SUBSTITUTION', 'None', (198, 208))	('p.Glu17Lys', 'SUBSTITUTION', 'None', (236, 246))	('AKT1', 'Gene', '207', (19, 23))	('PIK3CA', 'Gene', '5290', (141, 147))	('AKT1', 'Gene', '207', (185, 189))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('AKT1', 'Gene', (19, 23))	('c.68G>A', 'Var', (190, 197))	('PIK3CA', 'Gene', (8, 14))	('c.49G>A', 'SUBSTITUTION', 'None', (228, 235))	('c.3142C>T', 'Var', (148, 157))	('c.3142C>T', 'SUBSTITUTION', 'None', (148, 157))	('AKT1', 'Gene', (185, 189))	('p.Glu17Lys', 'Var', (236, 246))	('p.Arg23Gln', 'Var', (198, 208))	('PIK3CA', 'Gene', (141, 147))	('COSM3770600', 'Chemical', '-', (210, 221))	('COSM249875', 'Chemical', '-', (172, 182))	('p.His1048Tyr', 'SUBSTITUTION', 'None', (158, 170))	('reported', 'Reg', (61, 69))
58295	33953569	A combination of PIK3CA inhibitor BKM120 (80mg PO QD) and AKT1 inhibitor MK2206 (45mg PO QOD) on a 28-day cycle was initiated starting from February, 2015.	('AKT1', 'Gene', '207', (58, 62))	('PIK3CA', 'Gene', (17, 23))	('BKM120', 'Chemical', 'MESH:C571178', (34, 40))	('PIK3CA', 'Gene', '5290', (17, 23))	('AKT1', 'Gene', (58, 62))	('MK2206', 'Chemical', 'MESH:C548887', (73, 79))	('BKM120', 'Var', (34, 40))
58296	33953569	The combination of BKM120 and MK2206 was expected to suppress growth of both CCRCC and lung SQCC.	('BKM120', 'Chemical', 'MESH:C571178', (19, 25))	('MK2206', 'Var', (30, 36))	('lung SQCC', 'Disease', (87, 96))	('growth', 'MPA', (62, 68))	('suppress', 'NegReg', (53, 61))	('BKM120', 'Var', (19, 25))	('CCRCC', 'Disease', (77, 82))	('MK2206', 'Chemical', 'MESH:C548887', (30, 36))
58313	33953569	According to the Cancer Genome Atlas (TCGA), the hot- spot mutations reported in SQCC are TP53, CDKN2A, PTEN, PIK3CA, KEAP1, MLL2, AKT1, NFE2L2, NOTCH1, and RB1.	('TP53', 'Gene', '7157', (90, 94))	('RB1', 'Gene', (157, 160))	('SQCC', 'Gene', (81, 85))	('AKT1', 'Gene', '207', (131, 135))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('MLL2', 'Gene', '8085', (125, 129))	('CDKN2A', 'Gene', (96, 102))	('PTEN', 'Gene', (104, 108))	('PIK3CA', 'Gene', '5290', (110, 116))	('NFE2L2', 'Gene', '4780', (137, 143))	('RB1', 'Gene', '5925', (157, 160))	('MLL2', 'Gene', (125, 129))	('Cancer', 'Disease', (17, 23))	('KEAP1', 'Gene', '9817', (118, 123))	('TP53', 'Gene', (90, 94))	('mutations', 'Var', (59, 68))	('AKT1', 'Gene', (131, 135))	('KEAP1', 'Gene', (118, 123))	('NOTCH1', 'Gene', (145, 151))	('PTEN', 'Gene', '5728', (104, 108))	('CDKN2A', 'Gene', '1029', (96, 102))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('NFE2L2', 'Gene', (137, 143))	('PIK3CA', 'Gene', (110, 116))	('NOTCH1', 'Gene', '4851', (145, 151))
58314	33953569	Our findings are consistent with the TCGA reports, with PIK3CA and AKT1 mutations being identified and employed as drug targets, along with the other mutations on EGFR, BRAF, CDH1, HRAS, and TP53 (Table 1).	('AKT1', 'Gene', (67, 71))	('mutations', 'Var', (72, 81))	('BRAF', 'Gene', (169, 173))	('HRAS', 'Gene', (181, 185))	('CDH1', 'Gene', '999', (175, 179))	('BRAF', 'Gene', '673', (169, 173))	('TP53', 'Gene', '7157', (191, 195))	('EGFR', 'Gene', '1956', (163, 167))	('TP53', 'Gene', (191, 195))	('HRAS', 'Gene', '3265', (181, 185))	('PIK3CA', 'Gene', (56, 62))	('EGFR', 'Gene', (163, 167))	('AKT1', 'Gene', '207', (67, 71))	('EGFR', 'molecular_function', 'GO:0005006', ('163', '167'))	('PIK3CA', 'Gene', '5290', (56, 62))	('CDH1', 'Gene', (175, 179))
58315	33953569	A combination of PIK3CA inhibitor Buparlisib (BKM120) and AKT inhibitor MK2206 was used to treat the lung SQCC of our patient presented here.	('BKM120', 'Chemical', 'MESH:C571178', (46, 52))	('AKT', 'Gene', (58, 61))	('PIK3CA', 'Gene', (17, 23))	('Buparlisib', 'Chemical', 'MESH:C571178', (34, 44))	('MK2206', 'Chemical', 'MESH:C548887', (72, 78))	('PIK3CA', 'Gene', '5290', (17, 23))	('AKT', 'Gene', '207', (58, 61))	('lung SQCC', 'Disease', (101, 110))	('patient', 'Species', '9606', (118, 125))	('MK2206', 'Var', (72, 78))
58316	33953569	BKM120 and MK2206, as newer targeted drugs inhibiting the PI3K-Akt signaling pathway, are currently on clinical trials for NSCLC.	('inhibiting', 'NegReg', (43, 53))	('PI3K', 'molecular_function', 'GO:0016303', ('58', '62'))	('NSCLC', 'Disease', (123, 128))	('BKM120', 'Var', (0, 6))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('MK2206', 'Chemical', 'MESH:C548887', (11, 17))	('signaling pathway', 'biological_process', 'GO:0007165', ('67', '84'))	('BKM120', 'Chemical', 'MESH:C571178', (0, 6))	('Akt', 'Gene', '207', (63, 66))	('Akt signaling', 'biological_process', 'GO:0043491', ('63', '76'))	('MK2206', 'Var', (11, 17))	('Akt', 'Gene', (63, 66))
58319	33953569	The phase-II BASALT-1 study failed to show increased PFS in receiving BKM120.	('BKM120', 'Chemical', 'MESH:C571178', (70, 76))	('PFS', 'MPA', (53, 56))	('BKM120', 'Var', (70, 76))
58320	33953569	The NCT01911325 Phase II trial showed only a marginal anti-tumor activity by BKM120 plus docetaxel.	('BKM120', 'Chemical', 'MESH:C571178', (77, 83))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('BKM120', 'Var', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('docetaxel', 'Chemical', 'MESH:D000077143', (89, 98))
58322	33953569	Similarly, in a study of Erlotinib-resistant NSCLC, the AKT inhibitor MK2206 seemed unable to potentiate the efficacy of Erlotinib.	('AKT', 'Gene', '207', (56, 59))	('NSCLC', 'Disease', (45, 50))	('Erlotinib', 'Chemical', 'MESH:D000069347', (25, 34))	('MK2206', 'Chemical', 'MESH:C548887', (70, 76))	('AKT', 'Gene', (56, 59))	('Erlotinib', 'Chemical', 'MESH:D000069347', (121, 130))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('potentiate', 'PosReg', (94, 104))	('MK2206', 'Var', (70, 76))
58323	33953569	The BATTLE-2 trial aimed to compare the efficacy of MK2206 in NSCLC with mutant or wild type KRAS and the study remained ongoing.	('KRAS', 'Gene', (93, 97))	('NSCLC', 'Disease', (62, 67))	('MK2206', 'Chemical', 'MESH:C548887', (52, 58))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('KRAS', 'Gene', '3845', (93, 97))	('MK2206', 'Var', (52, 58))
58324	33953569	Currently there have been no studies using combined MK2206 and BKM120 in NSCLC/SQCC treatment.	('BKM120', 'Var', (63, 69))	('MK2206', 'Var', (52, 58))	('MK2206', 'Chemical', 'MESH:C548887', (52, 58))	('NSCLC', 'Disease', (73, 78))	('BKM120', 'Chemical', 'MESH:C571178', (63, 69))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))
58325	33953569	Our case demonstrated a good combination of BKM120 and MK2206 to combat lung SQCC and possibly CCRCC with actionable AKT1 mutation, which is worth further clinical investigations.	('BKM120', 'Chemical', 'MESH:C571178', (44, 50))	('AKT1', 'Gene', '207', (117, 121))	('mutation', 'Var', (122, 130))	('combat lung SQCC', 'Disease', (65, 81))	('CCRCC', 'Disease', (95, 100))	('MK2206', 'Chemical', 'MESH:C548887', (55, 61))	('AKT1', 'Gene', (117, 121))	('BKM120', 'Var', (44, 50))	('MK2206', 'Var', (55, 61))
58328	33953569	Smoking is the major risk factor for CCRCC and gene mutation including VHL gene and genes on the PI3K-Akt-mTOR axis is another known risk factor.	('Akt', 'Gene', (102, 105))	('Akt', 'Gene', '207', (102, 105))	('VHL', 'Gene', (71, 74))	('gene mutation', 'Var', (47, 60))	('PI3K', 'molecular_function', 'GO:0016303', ('97', '101'))	('VHL', 'Gene', '7428', (71, 74))	('mTOR', 'Gene', (106, 110))	('CCRCC', 'Disease', (37, 42))	('mTOR', 'Gene', '2475', (106, 110))
58330	33953569	While clinical interest in PI3K-Akt inhibitors is rising rapidly, certain phase I/II trials demonstrated a great potential of BKM120 and MK2206 in CCRCC treatment.	('MK2206', 'Chemical', 'MESH:C548887', (137, 143))	('Akt', 'Gene', '207', (32, 35))	('PI3K', 'molecular_function', 'GO:0016303', ('27', '31'))	('BKM120', 'Chemical', 'MESH:C571178', (126, 132))	('CCRCC', 'Disease', (147, 152))	('Akt', 'Gene', (32, 35))	('MK2206', 'Var', (137, 143))	('BKM120', 'Var', (126, 132))
58331	33953569	A Phase I study of BKM120 plus bevacizumab showed partial response in 13% metastatic CCRCC patients, with increased efficacy in those harboring activating PI3K mutations.	('metastatic CCRCC', 'Disease', (74, 90))	('BKM120', 'Chemical', 'MESH:C571178', (19, 25))	('patients', 'Species', '9606', (91, 99))	('activating', 'PosReg', (144, 154))	('PI3K', 'molecular_function', 'GO:0016303', ('155', '159'))	('BKM120', 'Var', (19, 25))	('bevacizumab', 'Chemical', 'MESH:D000068258', (31, 42))	('increased', 'PosReg', (106, 115))	('PI3K mutations', 'Var', (155, 169))
58333	33953569	Although in our case, the patient's renal cancer could have been cured by Sorafenib and no further bone metastasis had been reported for years, our decision to use BKM120 combined with MK2206 may exert certain protective function against the CCRCC in overt stage.	('patient', 'Species', '9606', (26, 33))	('renal cancer', 'Disease', 'MESH:D007680', (36, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('MK2206', 'Chemical', 'MESH:C548887', (185, 191))	('BKM120', 'Chemical', 'MESH:C571178', (164, 170))	('Sorafenib', 'Chemical', 'MESH:D000077157', (74, 83))	('renal cancer', 'Disease', (36, 48))	('CCRCC', 'Disease', (242, 247))	('renal cancer', 'Phenotype', 'HP:0009726', (36, 48))	('MK2206', 'Var', (185, 191))	('BKM120', 'Var', (164, 170))
58335	33953569	Genome-guided targeted therapy identified mutations aberrantly affecting the PI3K-Akt pathway across different tumors and a combination of PI3K inhibitor BKM120 and AKT inhibitor MK2206 achieved good efficacy prolonging the patient's survival for more than a year.	('PI3K', 'molecular_function', 'GO:0016303', ('77', '81'))	('AKT', 'Gene', (165, 168))	('BKM120', 'Chemical', 'MESH:C571178', (154, 160))	('MK2206', 'Chemical', 'MESH:C548887', (179, 185))	('Akt', 'Gene', '207', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('patient', 'Species', '9606', (224, 231))	('affecting', 'Reg', (63, 72))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('AKT', 'Gene', '207', (165, 168))	('PI3K', 'molecular_function', 'GO:0016303', ('139', '143'))	('Akt', 'Gene', (82, 85))	('prolonging', 'PosReg', (209, 219))	('mutations', 'Var', (42, 51))
58344	27751729	With first-line everolimus, PBRM1 and BAP1 mutations were associated with longer (median [95% confidence interval {CI}] 12.8 [8.1, 18.4] vs 5.5 [3.1, 8.4] mo) and shorter (median [95% CI] 4.9 [2.9, 8.1] vs 10.5 [7.3, 12.9] mo) PFS1L, respectively.	('BAP1', 'Gene', (38, 42))	('PBRM1', 'Gene', (28, 33))	('everolimus', 'Chemical', 'MESH:D000068338', (16, 26))	('mutations', 'Var', (43, 52))	('PBRM1', 'Gene', '55193', (28, 33))	('BAP1', 'Gene', '8314', (38, 42))
58345	27751729	With first-line sunitinib, KDM5C mutations were associated with longer PFS1L (median [95% CI] of 20.6 [12.4, 27.3] vs 8.3 [7.8, 11.0] mo).	('PFS1L', 'Gene', (71, 76))	('mutations', 'Var', (33, 42))	('KDM5C', 'Gene', (27, 32))	('sunitinib', 'Chemical', 'MESH:D000077210', (16, 25))	('KDM5C', 'Gene', '8242', (27, 32))
58346	27751729	Molecular subgroups of metastatic ccRCC based on PBRM1, BAP1, and KDM5C mutations could have predictive values for patients treated with VEGF or mTOR inhibitors.	('mutations', 'Var', (72, 81))	('patients', 'Species', '9606', (115, 123))	('KDM5C', 'Gene', '8242', (66, 71))	('VEGF', 'Gene', '7422', (137, 141))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('BAP1', 'Gene', '8314', (56, 60))	('RCC', 'Disease', (36, 39))	('mTOR', 'Gene', (145, 149))	('mTOR', 'Gene', '2475', (145, 149))	('ccRCC', 'Phenotype', 'HP:0006770', (34, 39))	('VEGF', 'Gene', (137, 141))	('BAP1', 'Gene', (56, 60))	('PBRM1', 'Gene', (49, 54))	('PBRM1', 'Gene', '55193', (49, 54))	('KDM5C', 'Gene', (66, 71))
58348	27751729	PBRM1, BAP1, and KDM5C mutations impact outcomes of targeted therapies in metastatic ccRCC patients.	('outcomes', 'MPA', (40, 48))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('patients', 'Species', '9606', (91, 99))	('BAP1', 'Gene', (7, 11))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('mutations', 'Var', (23, 32))	('KDM5C', 'Gene', (17, 22))	('BAP1', 'Gene', '8314', (7, 11))	('KDM5C', 'Gene', '8242', (17, 22))	('impact', 'Reg', (33, 39))
58349	27751729	Large-scale genomic kidney cancer studies reported novel mutations and heterogeneous features among individual tumors, which could contribute to varied clinical outcomes.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('kidney cancer', 'Phenotype', 'HP:0009726', (20, 33))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('kidney cancer', 'Disease', (20, 33))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (57, 66))	('contribute', 'Reg', (131, 141))	('kidney cancer', 'Disease', 'MESH:D007680', (20, 33))
58352	27751729	The genetic inactivation of Von Hippel Lindau (VHL) tumor suppressor gene was the only known prevalent oncogenic driver event in ccRCC for decades.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (129, 134))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (131, 134))	('genetic inactivation', 'Var', (4, 24))	('Von Hippel Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (28, 57))	('tumor suppressor', 'biological_process', 'GO:0051726', ('52', '68'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('52', '68'))
58354	27751729	These genes encode proteins that regulate chromatin and most reported somatic mutations result in loss of function, indicating that these proteins function as tumor suppressors.	('loss of function', 'NegReg', (98, 114))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('mutations', 'Var', (78, 87))	('tumor', 'Disease', (159, 164))	('chromatin', 'cellular_component', 'GO:0000785', ('42', '51'))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
58355	27751729	Thus far, analyses of published cohorts encompassing Stages I-IV kidney cancer patients have suggested prognostic values of individual mutations.	('I-IV kidney cancer', 'Disease', (60, 78))	('kidney cancer', 'Phenotype', 'HP:0009726', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (135, 144))	('patients', 'Species', '9606', (79, 87))	('I-IV kidney cancer', 'Disease', 'MESH:D007680', (60, 78))
58357	27751729	Inhibitors of vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) signaling pathways are standard treatment options for patients with metastatic RCC (mRCC).	('signaling', 'biological_process', 'GO:0023052', ('96', '105'))	('mTOR', 'Gene', (90, 94))	('VEGF', 'Gene', (50, 54))	('mTOR', 'Gene', '2475', (90, 94))	('vascular endothelial growth factor', 'Gene', (14, 48))	('Inhibitors', 'Var', (0, 10))	('mammalian target of rapamycin', 'Gene', '2475', (59, 88))	('mammalian target of rapamycin', 'Gene', (59, 88))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('14', '48'))	('patients', 'Species', '9606', (150, 158))	('vascular endothelial growth factor', 'Gene', '7422', (14, 48))	('RCC', 'Disease', (175, 178))	('men', 'Species', '9606', (133, 136))	('VEGF', 'Gene', '7422', (50, 54))	('RCC', 'Disease', 'MESH:C538614', (175, 178))	('RCC', 'Disease', 'MESH:C538614', (181, 184))	('RCC', 'Disease', (181, 184))
58362	27751729	Case studies involving cancer gene mutations of advanced (Stage IV or recurrent metastatic) ccRCC have indicated a potential correlation between mutations and treatment response to targeted therapy; however, these associations have not been evaluated in a large clinical trial setting.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Disease', (94, 97))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('men', 'Species', '9606', (164, 167))	('mutations', 'Var', (35, 44))
58371	27751729	Associations between PFS1L (and OS), first-line treatment (treatment regimen), and gene alteration status (mutant type [MT] or wild type [WT]) were investigated.	('mutant type', 'Var', (107, 118))	('men', 'Species', '9606', (73, 76))	('men', 'Species', '9606', (53, 56))	('PFS1L', 'Gene', (21, 26))	('men', 'Species', '9606', (64, 67))
58384	27751729	Six genes:VHL, PBRM1, SETD2, BAP1, KDM5C, and PTEN:were mutated at >=10% in our cohort, and there was no association between these mutations and MSKCC risk groups (Supplementary Table 2).	('MSK', 'Gene', '150094', (145, 148))	('KDM5C', 'Gene', '8242', (35, 40))	('MSK', 'Gene', (145, 148))	('PBRM1', 'Gene', '55193', (15, 20))	('PBRM1', 'Gene', (15, 20))	('SETD2', 'Gene', '29072', (22, 27))	('VHL', 'Disease', (10, 13))	('PTEN', 'Gene', (46, 50))	('SETD2', 'Gene', (22, 27))	('mutated', 'Var', (56, 63))	('KDM5C', 'Gene', (35, 40))	('PTEN', 'Gene', '5728', (46, 50))	('BAP1', 'Gene', '8314', (29, 33))	('VHL', 'Disease', 'MESH:D006623', (10, 13))	('men', 'Species', '9606', (170, 173))	('BAP1', 'Gene', (29, 33))
58385	27751729	Most mutations were truncating (VHL, 64%; PBRM1, 79%; SETD2, 89%; BAP1, 69%; KDM5C, 75%; PTEN, 81%), consistent with previous reports.	('BAP1', 'Gene', '8314', (66, 70))	('SETD2', 'Gene', '29072', (54, 59))	('KDM5C', 'Gene', (77, 82))	('PBRM1', 'Gene', (42, 47))	('SETD2', 'Gene', (54, 59))	('truncating', 'Var', (20, 30))	('BAP1', 'Gene', (66, 70))	('mutations', 'Var', (5, 14))	('KDM5C', 'Gene', '8242', (77, 82))	('PBRM1', 'Gene', '55193', (42, 47))	('VHL', 'Disease', 'MESH:D006623', (32, 35))	('PTEN', 'Gene', '5728', (89, 93))	('PTEN', 'Gene', (89, 93))	('VHL', 'Disease', (32, 35))
58392	27751729	The mutation status of KDM5C appears to have no effect on PFS1L in the everolimus arm (HR: 1.06; 95% CI: 0.5, 2.1; median PFS1L [95%CI], 9.8 [2.2, 16.6] vs 8.2 [5.3, 10.9]); whereas patients in the sunitinib arm with KDM5C MT appear to have lower risk of progression than those with WT tumors (HR: 0.57; 95% CI: 0.3, 1.1; median PFS1L [95%CI], 20.6 [12.4, 27.3] vs 8.3 [7.8, 11.0]).	('KDM5C', 'Gene', (23, 28))	('WT tumors', 'Disease', (283, 292))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('KDM5C', 'Gene', '8242', (23, 28))	('everolimus', 'Chemical', 'MESH:D000068338', (71, 81))	('mutation', 'Var', (4, 12))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('sunitinib', 'Chemical', 'MESH:D000077210', (198, 207))	('patients', 'Species', '9606', (182, 190))	('KDM5C', 'Gene', (217, 222))	('WT tumors', 'Disease', 'MESH:C536751', (283, 292))	('KDM5C', 'Gene', '8242', (217, 222))
58394	27751729	TSC1 and MTOR were mutated in 13% of our cohort, and no clear association between PFS1L outcomes and everolimus (HR: 0.91; 95% CI: 0.4, 2.2) or sunitinib (HR: 1.24; 95% CI: 0.7, 2.4) was observed.	('PFS1L', 'Gene', (82, 87))	('MTOR', 'Gene', (9, 13))	('everolimus', 'Chemical', 'MESH:D000068338', (101, 111))	('mutated', 'Var', (19, 26))	('TSC1', 'Gene', '7248', (0, 4))	('MTOR', 'Gene', '2475', (9, 13))	('TSC1', 'Gene', (0, 4))	('sunitinib', 'Chemical', 'MESH:D000077210', (144, 153))
58395	27751729	Of note, seven patients with MTOR tumor mutations were treated with first-line everolimus.	('patients', 'Species', '9606', (15, 23))	('tumor', 'Disease', (34, 39))	('MTOR', 'Gene', (29, 33))	('mutations', 'Var', (40, 49))	('MTOR', 'Gene', '2475', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('everolimus', 'Chemical', 'MESH:D000068338', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
58400	27751729	Among patients with KDM5C tumor mutations, although not statistically significant, patients receiving first-line everolimus have a high risk of progression than those receiving sunitinib (HR: 2.23; 95% CI: 0.9, 5.5; median PFS1L [95% CI], 9.8 [2.2, 16.2] vs 20.6 [12.4, 27.3] mo; Fig.	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('KDM5C tumor', 'Disease', (20, 31))	('mutations', 'Var', (32, 41))	('everolimus', 'Chemical', 'MESH:D000068338', (113, 123))	('patients', 'Species', '9606', (6, 14))	('sunitinib', 'Chemical', 'MESH:D000077210', (177, 186))	('patients', 'Species', '9606', (83, 91))	('KDM5C tumor', 'Disease', 'MESH:D009369', (20, 31))
58401	27751729	There was no significant difference in the risk of progression and median PFS1L among patients with PBRM1 tumor mutations who received first-line everolimus versus sunitinib (HR: 1.02; 95% CI: 0.6, 1.7; median PFS1L [95% CI] 12.8 [8.1, 18.4] vs 11.0 [8.3, 13.8] mo; Fig.	('PBRM1 tumor', 'Disease', (100, 111))	('everolimus', 'Chemical', 'MESH:D000068338', (146, 156))	('mutations', 'Var', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('PBRM1 tumor', 'Disease', 'MESH:D009369', (100, 111))	('sunitinib', 'Chemical', 'MESH:D000077210', (164, 173))	('patients', 'Species', '9606', (86, 94))
58402	27751729	The shortest median PFS1L was found among patients with BAP1 tumor mutations in both treatment arms (median [95% CI], sunitinib 8.1 [3.1, 11.3] vs everolimus 4.9 [2.9, 8.1] mo; Fig.	('men', 'Species', '9606', (90, 93))	('PFS1L', 'MPA', (20, 25))	('BAP1 tumor', 'Disease', 'MESH:D009369', (56, 66))	('sunitinib', 'Chemical', 'MESH:D000077210', (118, 127))	('mutations', 'Var', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('shortest', 'NegReg', (4, 12))	('patients', 'Species', '9606', (42, 50))	('everolimus', 'Chemical', 'MESH:D000068338', (147, 157))	('BAP1 tumor', 'Disease', (56, 66))
58408	27751729	Mutual exclusivity was detected between PBRM1 and BAP1 (p < 0.001) mutations with only seven (3%) cases carrying both mutations in our NGS ccRCC cohort (Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (139, 144))	('RCC', 'Disease', (141, 144))	('PBRM1', 'Gene', (40, 45))	('PBRM1', 'Gene', '55193', (40, 45))	('BAP1', 'Gene', '8314', (50, 54))	('mutations', 'Var', (67, 76))	('BAP1', 'Gene', (50, 54))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
58410	27751729	As the mutation status of PBRM1 and BAP1 was shown to associate with RCC-specific survival among ccRCC patients of all stages without taking consideration of treatment information, we classified patients into three molecular groups based on their combined PBRM1 and BAP1 mutation status and assessed the impact of genotypes on OS of patients with ccRCC in each treatment arm.	('RCC', 'Disease', (69, 72))	('PBRM1', 'Gene', '55193', (256, 261))	('associate', 'Reg', (54, 63))	('PBRM1', 'Gene', '55193', (26, 31))	('patients', 'Species', '9606', (333, 341))	('RCC', 'Disease', (99, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('PBRM1', 'Gene', (256, 261))	('PBRM1', 'Gene', (26, 31))	('BAP1', 'Gene', '8314', (266, 270))	('BAP1', 'Gene', '8314', (36, 40))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('patients', 'Species', '9606', (195, 203))	('men', 'Species', '9606', (366, 369))	('ccRCC', 'Phenotype', 'HP:0006770', (347, 352))	('RCC', 'Disease', (349, 352))	('BAP1', 'Gene', (266, 270))	('BAP1', 'Gene', (36, 40))	('men', 'Species', '9606', (163, 166))	('RCC', 'Disease', 'MESH:C538614', (349, 352))	('mutation', 'Var', (7, 15))	('patients', 'Species', '9606', (103, 111))
58412	27751729	Of note, patients with mutations in both PBRM1 and BAP1 have been shown to fare poorly, and were assigned to the BAP1 group in our analysis.	('patients', 'Species', '9606', (9, 17))	('poorly', 'NegReg', (80, 86))	('BAP1', 'Gene', '8314', (51, 55))	('BAP1', 'Gene', (51, 55))	('mutations', 'Var', (23, 32))	('BAP1', 'Gene', '8314', (113, 117))	('PBRM1', 'Gene', (41, 46))	('PBRM1', 'Gene', '55193', (41, 46))	('BAP1', 'Gene', (113, 117))
58417	27751729	As patients with KDM5C mutations appear to have longer PFS1L with first-line sunitinib but not with first-line everolimus (Fig.	('everolimus', 'Chemical', 'MESH:D000068338', (111, 121))	('longer', 'PosReg', (48, 54))	('mutations', 'Var', (23, 32))	('patients', 'Species', '9606', (3, 11))	('PFS1L', 'MPA', (55, 60))	('sunitinib', 'Chemical', 'MESH:D000077210', (77, 86))	('KDM5C', 'Gene', (17, 22))	('KDM5C', 'Gene', '8242', (17, 22))
58418	27751729	3A), and PBRM1 mutations exhibited comparable PFS1L (Fig.	('PBRM1', 'Gene', (9, 14))	('mutations', 'Var', (15, 24))	('PBRM1', 'Gene', '55193', (9, 14))
58423	27751729	The discoveries of intratumor heterogeneity and novel prevalent mutations in ccRCC suggest a potential genetic basis for observed diverse clinical outcome.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('tumor', 'Disease', (24, 29))	('mutations', 'Var', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
58424	27751729	Consistent with previous studies, we did not detect an association between VHL mutation and clinical outcome in ccRCC.	('VHL', 'Disease', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('RCC', 'Disease', (114, 117))	('mutation', 'Var', (79, 87))	('VHL', 'Disease', 'MESH:D006623', (75, 78))
58426	27751729	KDM5C is located at the X-chromosome, and single-allele mutation of KDM5C in male patients would result in complete genetic loss of KDM5C.	('loss', 'NegReg', (124, 128))	('KDM5C', 'Gene', (132, 137))	('patients', 'Species', '9606', (82, 90))	('KDM5C', 'Gene', '8242', (132, 137))	('KDM5C', 'Gene', (0, 5))	('KDM5C', 'Gene', (68, 73))	('single-allele mutation', 'Var', (42, 64))	('KDM5C', 'Gene', '8242', (0, 5))	('KDM5C', 'Gene', '8242', (68, 73))	('X-chromosome', 'cellular_component', 'GO:0000805', ('24', '36'))
58427	27751729	The extended benefit in patients (especially men) with KDM5C mutations who received VEGF inhibitor therapy was noted in a smaller study where statistical significance was not detected.	('KDM5C', 'Gene', '8242', (55, 60))	('men', 'Species', '9606', (45, 48))	('mutations', 'Var', (61, 70))	('VEGF', 'Gene', (84, 88))	('patients', 'Species', '9606', (24, 32))	('KDM5C', 'Gene', (55, 60))	('VEGF', 'Gene', '7422', (84, 88))	('benefit', 'PosReg', (13, 20))
58431	27751729	Interestingly, in our NGS ccRCC cohort, four of six patients with mTOR mutations benefited from first-line everolimus with PFS1L >12 mo.	('everolimus', 'Chemical', 'MESH:D000068338', (107, 117))	('mTOR', 'Gene', (66, 70))	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('mTOR', 'Gene', '2475', (66, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (26, 31))	('benefited', 'PosReg', (81, 90))	('mutations', 'Var', (71, 80))	('RCC', 'Disease', (28, 31))	('patients', 'Species', '9606', (52, 60))
58432	27751729	The association of a PBRM1 or BAP1 mutation with better or worse PFS1L, respectively, with everolimus is surprising because higher mTORC1 activity was reported for patients with BAP1 versus PBRM1 mutant ccRCC.	('mTORC1', 'Gene', (131, 137))	('BAP1', 'Gene', (178, 182))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('everolimus', 'Chemical', 'MESH:D000068338', (91, 101))	('mTORC1', 'Gene', '382056', (131, 137))	('mutation', 'Var', (35, 43))	('PBRM1', 'Gene', '55193', (190, 195))	('PFS1L', 'Gene', (65, 70))	('patients', 'Species', '9606', (164, 172))	('PBRM1', 'Gene', (190, 195))	('BAP1', 'Gene', '8314', (30, 34))	('higher', 'PosReg', (124, 130))	('PBRM1', 'Gene', '55193', (21, 26))	('mTORC1', 'cellular_component', 'GO:0031931', ('131', '137'))	('mutant', 'Var', (196, 202))	('BAP1', 'Gene', '8314', (178, 182))	('activity', 'MPA', (138, 146))	('BAP1', 'Gene', (30, 34))	('RCC', 'Disease', (205, 208))	('PBRM1', 'Gene', (21, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (203, 208))
58434	27751729	In this study, when patients with metastatic ccRCC were stratified into three genotypic groups based on PBRM1 and BAP1 mutations, median OS (mo) was longer in the PBRM1 group (43.5) than in the BAP1 (9.8) or WT (18.1) group in the everolimus-sunitinib arm, whereas median OS was similar in all three groups (BAP1, 29.9; PBRM1, 33.2; WT, 33.1) in the sunitinib-everolimus arm.	('BAP1', 'Gene', '8314', (308, 312))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('PBRM1', 'Gene', (320, 325))	('BAP1', 'Gene', (114, 118))	('everolimus', 'Chemical', 'MESH:D000068338', (360, 370))	('PBRM1', 'Gene', '55193', (104, 109))	('PBRM1', 'Gene', (104, 109))	('patients', 'Species', '9606', (20, 28))	('mutations', 'Var', (119, 128))	('BAP1', 'Gene', (308, 312))	('everolimus', 'Chemical', 'MESH:D000068338', (231, 241))	('sunitinib', 'Chemical', 'MESH:D000077210', (242, 251))	('BAP1', 'Gene', '8314', (194, 198))	('PBRM1', 'Gene', '55193', (163, 168))	('BAP1', 'Gene', '8314', (114, 118))	('longer', 'PosReg', (149, 155))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('RCC', 'Disease', (47, 50))	('BAP1', 'Gene', (194, 198))	('PBRM1', 'Gene', '55193', (320, 325))	('PBRM1', 'Gene', (163, 168))	('sunitinib', 'Chemical', 'MESH:D000077210', (350, 359))
58437	27751729	Our analysis puts common RCC mutations into clinical context for patients treated with VEGF and mTOR inhibitors in a clinical trial at the frontline setting and suggests correlative clinical outcome signals for sunitinib and everolimus that warrant further investigation.	('mTOR', 'Gene', (96, 100))	('RCC', 'Disease', (25, 28))	('mutations', 'Var', (29, 38))	('everolimus', 'Chemical', 'MESH:D000068338', (225, 235))	('VEGF', 'Gene', '7422', (87, 91))	('patients', 'Species', '9606', (65, 73))	('sunitinib', 'Chemical', 'MESH:D000077210', (211, 220))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('mTOR', 'Gene', '2475', (96, 100))	('VEGF', 'Gene', (87, 91))
58439	27751729	Nevertheless, we confirmed that VHL, PBRM1, SETD2, BAP1, and KDM5C are the most commonly mutated genes in ccRCC and found that PBRM1 and KDM5C mutations could be associated with better clinical outcomes with everolimus and sunitinib, respectively.	('RCC', 'Disease', (108, 111))	('sunitinib', 'Chemical', 'MESH:D000077210', (223, 232))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('SETD2', 'Gene', (44, 49))	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('everolimus', 'Chemical', 'MESH:D000068338', (208, 218))	('KDM5C', 'Gene', (61, 66))	('SETD2', 'Gene', '29072', (44, 49))	('PBRM1', 'Gene', '55193', (127, 132))	('KDM5C', 'Gene', '8242', (137, 142))	('BAP1', 'Gene', '8314', (51, 55))	('VHL', 'Disease', (32, 35))	('mutations', 'Var', (143, 152))	('PBRM1', 'Gene', '55193', (37, 42))	('PBRM1', 'Gene', (127, 132))	('PBRM1', 'Gene', (37, 42))	('BAP1', 'Gene', (51, 55))	('KDM5C', 'Gene', '8242', (61, 66))	('KDM5C', 'Gene', (137, 142))	('VHL', 'Disease', 'MESH:D006623', (32, 35))
58442	27751729	Our results confirmed prevalent ccRCC mutations, demonstrated distinct mutation enrichment in metastatic ccRCC, showed mutual exclusivity between BAP1 and PBRM1 or KDM5C mutations, and suggested distinct molecular subtypes based on PBRM1, BAP1, and KDM5C mutations could potentially have different efficacy genomic biomarker values for patients with metastatic ccRCC treated with targeted therapies.	('PBRM1', 'Gene', '55193', (232, 237))	('KDM5C', 'Gene', '8242', (249, 254))	('RCC', 'Disease', 'MESH:C538614', (363, 366))	('BAP1', 'Gene', (239, 243))	('PBRM1', 'Gene', (232, 237))	('ccRCC', 'Phenotype', 'HP:0006770', (105, 110))	('RCC', 'Disease', (107, 110))	('KDM5C', 'Gene', (164, 169))	('mutations', 'Var', (38, 47))	('RCC', 'Disease', (34, 37))	('BAP1', 'Gene', '8314', (146, 150))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('men', 'Species', '9606', (86, 89))	('ccRCC', 'Phenotype', 'HP:0006770', (32, 37))	('KDM5C', 'Gene', (249, 254))	('patients', 'Species', '9606', (336, 344))	('PBRM1', 'Gene', '55193', (155, 160))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('BAP1', 'Gene', (146, 150))	('RCC', 'Disease', (363, 366))	('BAP1', 'Gene', '8314', (239, 243))	('PBRM1', 'Gene', (155, 160))	('ccRCC', 'Phenotype', 'HP:0006770', (361, 366))	('KDM5C', 'Gene', '8242', (164, 169))
58443	27751729	Targeted next-generation sequencing and clinical correlation analyses of a randomized metastatic renal cell carcinoma first-line targeted therapy trial (RECORD-3) demonstrated enrichment of tumor suppressor gene mutations, showed mutual exclusivity among mutations, and presented distinct molecular subtypes based on PBRM1/BAP1/KDM5C mutations that could have predictive/prognostic values.	('mutations', 'Var', (334, 343))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (97, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('BAP1', 'Gene', '8314', (323, 327))	('KDM5C', 'Gene', (328, 333))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('190', '206'))	('KDM5C', 'Gene', '8242', (328, 333))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (97, 117))	('PBRM1', 'Gene', (317, 322))	('BAP1', 'Gene', (323, 327))	('tumor', 'Disease', (190, 195))	('tumor suppressor', 'biological_process', 'GO:0051726', ('190', '206'))	('mutations', 'Var', (212, 221))	('PBRM1', 'Gene', '55193', (317, 322))	('men', 'Species', '9606', (182, 185))	('renal cell carcinoma', 'Disease', (97, 117))
58448	31493764	In addition, multivariate Cox analysis indicated that MIXIPL and PPARGC1A were the most significant prognostic signatures, and were closely related to immune infiltration in TCGA cohort.	('PPARGC1A', 'Gene', '10891', (65, 73))	('MIXIPL', 'Var', (54, 60))	('related', 'Reg', (140, 147))	('PPARGC1A', 'Gene', (65, 73))	('Cox', 'Gene', '1351', (26, 29))	('Cox', 'Gene', (26, 29))
58531	31493764	Peroxisome proliferator-activated receptor gamma coactivator-1 (PPARGC1A; PGC-1alpha) is a transcriptional co-regulator, and its polymorphisms are proposed as obesity metabolic regulators and to be involved in epithelial-mesenchymal transition.	('polymorphisms', 'Var', (129, 142))	('obesity metabolic', 'Disease', (159, 176))	('PGC-1alpha', 'Gene', (74, 84))	('PPARGC1A', 'Gene', (64, 72))	('obesity metabolic', 'Disease', 'MESH:D009765', (159, 176))	('obesity', 'Phenotype', 'HP:0001513', (159, 166))	('PGC-1alpha', 'Gene', '10891', (74, 84))	('Peroxisome', 'cellular_component', 'GO:0005777', ('0', '10'))	('transcriptional co-regulator', 'molecular_function', 'GO:0003712', ('91', '119'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('210', '243'))	('involved', 'Reg', (198, 206))	('PPARGC1A', 'Gene', '10891', (64, 72))
58572	29312615	DNA repair plays a vital role in maintaining genetic integrity, and deficiencies in DNA damage repair enzymes, which are connected to many different types of diseases, specifically increase a person's risk for developing cancer.	('deficiencies', 'Var', (68, 80))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('DNA repair', 'biological_process', 'GO:0006281', ('0', '10'))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('cancer', 'Disease', (221, 227))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('increase', 'Reg', (181, 189))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('person', 'Species', '9606', (192, 198))	('DNA', 'Gene', (84, 87))
58604	29312615	In the CCK-8 cell proliferation assay, we found that there was no effect of XRCC1 on ccRCC cell proliferation after XRCC1 silencing in both 786-O and ACHN cells (Figure 2B).	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('XRCC1', 'Gene', (116, 121))	('cell proliferation', 'biological_process', 'GO:0008283', ('13', '31'))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('XRCC1', 'Gene', '7515', (76, 81))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('cell proliferation', 'biological_process', 'GO:0008283', ('91', '109'))	('XRCC1', 'Gene', '7515', (116, 121))	('XRCC1', 'Gene', (76, 81))	('silencing', 'Var', (122, 131))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
58606	29312615	In the transwell filter assay, we found that XRCC1 knockdown significantly enhanced the ability of ccRCC cells to migrate through transwell filter inserts (Figure 3A, 3B).	('enhanced', 'PosReg', (75, 83))	('RCC', 'Disease', (46, 49))	('XRCC1', 'Gene', '7515', (45, 50))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('RCC', 'Disease', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('XRCC1', 'Gene', (45, 50))	('knockdown', 'Var', (51, 60))
58608	29312615	In the cell invasion assay, we got a similar conclusion: XRCC1 knockdown significantly enhanced the ability of ccRCC cells to invade through the transwell filter inserts (Figure 3C, 3D).	('invade', 'CPA', (126, 132))	('XRCC1', 'Gene', (57, 62))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('RCC', 'Disease', (58, 61))	('enhanced', 'PosReg', (87, 95))	('XRCC1', 'Gene', '7515', (57, 62))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('knockdown', 'Var', (63, 72))
58617	29312615	Above all, our results confirmed that XRCC1 expression inhibited the migration and invasion of ccRCC cells by suppressing MMP-2 and MMP-9 expression and activity.	('XRCC1', 'Gene', (38, 43))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('activity', 'MPA', (153, 161))	('expression', 'MPA', (138, 148))	('MMP-9', 'molecular_function', 'GO:0004229', ('132', '137'))	('expression', 'Var', (44, 54))	('MMP-9', 'Gene', '4318', (132, 137))	('MMP-2', 'Gene', '4313', (122, 127))	('MMP-9', 'Gene', (132, 137))	('XRCC1', 'Gene', '7515', (38, 43))	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('MMP-2', 'Gene', (122, 127))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('RCC', 'Disease', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('suppressing', 'NegReg', (110, 121))	('inhibited', 'NegReg', (55, 64))	('MMP-2', 'molecular_function', 'GO:0004228', ('122', '127'))
58622	29312615	Our results showed that the expression of both TIMP-2 and TIMP-1 decreased when MMP-2 and MMP-9 were up-regulated following XRCC1 knockdown (Figure 4A), which indicated that XRCC1 can regulate MMP-2 and MMP-9 expression through TIMP-2 and TIMP-1 in ccRCC.	('expression', 'MPA', (209, 219))	('decreased', 'NegReg', (65, 74))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('XRCC1', 'Gene', (174, 179))	('TIMP-2', 'Gene', '7077', (47, 53))	('TIMP-1', 'Gene', (239, 245))	('MMP-2', 'Gene', (80, 85))	('TIMP-1', 'Gene', '7076', (239, 245))	('RCC', 'Disease', 'MESH:C538614', (251, 254))	('MMP-9', 'Gene', '4318', (203, 208))	('TIMP-2', 'Gene', (47, 53))	('MMP-9', 'Gene', (203, 208))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('TIMP-2', 'Gene', '7077', (228, 234))	('up-regulated', 'PosReg', (101, 113))	('knockdown', 'Var', (130, 139))	('MMP-2', 'molecular_function', 'GO:0004228', ('193', '198'))	('XRCC1', 'Gene', (124, 129))	('TIMP-2', 'Gene', (228, 234))	('XRCC1', 'Gene', '7515', (174, 179))	('MMP-9', 'Gene', '4318', (90, 95))	('MMP-2', 'Gene', '4313', (193, 198))	('MMP-2', 'molecular_function', 'GO:0004228', ('80', '85'))	('MMP-9', 'Gene', (90, 95))	('MMP-9', 'molecular_function', 'GO:0004229', ('90', '95'))	('RCC', 'Disease', (175, 178))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('TIMP-1', 'Gene', '7076', (58, 64))	('regulate', 'Reg', (184, 192))	('TIMP-1', 'Gene', (58, 64))	('MMP-2', 'Gene', '4313', (80, 85))	('MMP-9', 'molecular_function', 'GO:0004229', ('203', '208'))	('XRCC1', 'Gene', '7515', (124, 129))	('expression', 'MPA', (28, 38))	('RCC', 'Disease', (251, 254))	('RCC', 'Phenotype', 'HP:0005584', (251, 254))	('MMP-2', 'Gene', (193, 198))	('RCC', 'Disease', 'MESH:C538614', (175, 178))	('ccRCC', 'Phenotype', 'HP:0006770', (249, 254))
58625	29312615	However, a recent publication showed a lack of correlation between XRCC1 gene polymorphisms and colorectal cancer susceptibility in a Malaysian cohort.	('XRCC1', 'Gene', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('XRCC1', 'Gene', '7515', (67, 72))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('colorectal cancer', 'Disease', (96, 113))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))	('polymorphisms', 'Var', (78, 91))
58634	29312615	A recent publication studied the impact of plasmacytoid variant histology on the survival of patients with urothelial carcinoma of the bladder after radical cystectomy; a large cohort of patients indicated that the plasmacytoid variant was associated with adverse pathologic features but was not associated with worse overall mortality in multivariable analyses.	('variant', 'Var', (228, 235))	('patients', 'Species', '9606', (187, 195))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (107, 142))	('urothelial carcinoma of the bladder', 'Disease', (107, 142))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (107, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('plasmacytoid', 'Gene', (215, 227))	('patients', 'Species', '9606', (93, 101))
58637	29312615	A recent publication showed that vascular invasion was significantly more frequent in patients with biliary tract cancers with a low expression of XRCC1.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('low expression', 'Var', (129, 143))	('XRCC1', 'Gene', '7515', (147, 152))	('frequent', 'Reg', (74, 82))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('XRCC1', 'Gene', (147, 152))	('biliary tract cancers', 'Disease', 'MESH:D001661', (100, 121))	('vascular invasion', 'CPA', (33, 50))	('biliary tract cancers', 'Disease', (100, 121))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('patients', 'Species', '9606', (86, 94))
58642	29312615	Our studies have found that silencing XRCC1 expression had no effect on cell proliferation ability in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('cell proliferation', 'biological_process', 'GO:0008283', ('72', '90'))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('XRCC1', 'Gene', (38, 43))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('XRCC1', 'Gene', '7515', (38, 43))	('silencing', 'Var', (28, 37))	('cell proliferation ability', 'CPA', (72, 98))	('RCC', 'Disease', (104, 107))
58691	29312589	Our previous study indicated that G6PD is overexpressed in clear cell renal cell carcinoma (ccRCC), the most common subtype of RCC.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Disease', (94, 97))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (70, 90))	('overexpressed', 'PosReg', (42, 55))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (59, 90))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (59, 90))	('G6PD', 'Var', (34, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('clear cell renal cell carcinoma', 'Disease', (59, 90))
58693	29312589	Here, we demonstrate that G6PD is not only up-regulated in all types of RCC specimens but also displays higher activities in RCC cell lines.	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('G6PD', 'Var', (26, 30))	('RCC', 'Disease', (72, 75))	('RCC', 'Disease', (125, 128))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('activities', 'MPA', (111, 121))	('up-regulated', 'PosReg', (43, 55))	('higher', 'PosReg', (104, 110))
58694	29312589	G6PD overexpression promoted RCC cell proliferation, altered cell cycle distribution, and enhanced xenografted RCC development.	('cell cycle', 'biological_process', 'GO:0007049', ('61', '71'))	('cell proliferation', 'biological_process', 'GO:0008283', ('33', '51'))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('cell cycle distribution', 'CPA', (61, 84))	('RCC', 'Disease', (29, 32))	('G6PD', 'Var', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('promoted', 'PosReg', (20, 28))	('altered', 'Reg', (53, 60))	('enhanced', 'PosReg', (90, 98))
58695	29312589	G6PD up-regulated ROS generation by facilitating NADPH-dependent NOX4 activation, which led to increased expression of p-STAT3 and CyclinD1.	('STAT3', 'Gene', '6774', (121, 126))	('CyclinD1', 'Gene', (131, 139))	('STAT3', 'Gene', (121, 126))	('NOX4', 'Gene', (65, 69))	('G6PD', 'Var', (0, 4))	('ROS generation', 'biological_process', 'GO:1903409', ('18', '32'))	('NADPH', 'Chemical', 'MESH:D009249', (49, 54))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('CyclinD1', 'Gene', '595', (131, 139))	('NOX4', 'Gene', '50507', (65, 69))	('up-regulated', 'PosReg', (5, 17))	('ROS generation', 'MPA', (18, 32))	('increased', 'PosReg', (95, 104))	('expression', 'MPA', (105, 115))
58699	29312589	Therefore, G6PD may be an effective RCC therapeutic target.	('G6PD', 'Var', (11, 15))	('RCC', 'Disease', (36, 39))	('RCC', 'Disease', 'MESH:C538614', (36, 39))
58701	29312589	Lately, increasing evidences show that high expression of G6PD predicts poor overall survival of patients with numbers of cancers, indicating that G6PD may play important roles in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('G6PD', 'Var', (58, 62))	('patients', 'Species', '9606', (97, 105))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('overall survival', 'MPA', (77, 93))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('poor', 'NegReg', (72, 76))
58702	29312589	In addition to the so-called Warburg effect, G6PD was aberrantly activated in order to generate sufficient building blocks required for rapid proliferation and adaptation of cancer cells to the altered internal and external environment.	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('G6PD', 'Var', (45, 49))	('cancer', 'Disease', (174, 180))
58703	29312589	Our recent studies demonstrate that G6PD is significantly higher expressed in advanced status of clear cell renal cell carcinoma (ccRCC) and closely correlates to the tumor extent, lymph node metastasis, Fuhrman grade, TNM stage and poor overall survival of ccRCC.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (108, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (130, 135))	('RCC', 'Disease', (132, 135))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (97, 128))	('RCC', 'Disease', 'MESH:C538614', (260, 263))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('clear cell renal cell carcinoma', 'Disease', (97, 128))	('TNM', 'Gene', '10178', (219, 222))	('TNM', 'Gene', (219, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('tumor', 'Disease', (167, 172))	('G6PD', 'Var', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (97, 128))	('higher', 'PosReg', (58, 64))	('ccRCC', 'Phenotype', 'HP:0006770', (258, 263))	('RCC', 'Disease', (260, 263))	('correlates', 'Reg', (149, 159))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))
58712	29312589	Based on these facts, we tentatively hypothesize that there must be a close underlying correlation between G6PD and RCC tumorigenesis.	('RCC tumor', 'Disease', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('G6PD', 'Var', (107, 111))	('RCC tumor', 'Disease', 'MESH:C538614', (116, 125))
58722	29312589	Accordingly, both G6PD and NOX4 are important in cellular ROS metabolism and may synergistically act in regulation of redox homeostasis in RCC.	('regulation of redox homeostasis', 'biological_process', 'GO:0045454', ('104', '135'))	('regulation', 'MPA', (104, 114))	('ROS', 'Chemical', 'MESH:D017382', (58, 61))	('NOX4', 'Gene', (27, 31))	('metabolism', 'biological_process', 'GO:0008152', ('62', '72'))	('act', 'Reg', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('G6PD', 'Var', (18, 22))	('NOX4', 'Gene', '50507', (27, 31))	('redox homeostasis', 'MPA', (118, 135))
58724	29312589	Before the experiment carried out, we could not assume that G6PD overexpression will increase or decrease ROS generation.	('ROS generation', 'biological_process', 'GO:1903409', ('106', '120'))	('G6PD', 'Var', (60, 64))	('ROS', 'Chemical', 'MESH:D017382', (106, 109))	('decrease', 'NegReg', (97, 105))	('ROS generation', 'CPA', (106, 120))
58725	29312589	Because it has been clarified that G6PD could probably promote ROS production through the process we described, but may also have the abilities to eliminate ROS via the reduced form of glutathione.	('ROS', 'Chemical', 'MESH:D017382', (157, 160))	('eliminate', 'NegReg', (147, 156))	('glutathione', 'Chemical', 'MESH:D005978', (185, 196))	('ROS', 'Chemical', 'MESH:D017382', (63, 66))	('ROS production', 'MPA', (63, 77))	('ROS', 'MPA', (157, 160))	('promote', 'PosReg', (55, 62))	('G6PD', 'Var', (35, 39))
58728	29312589	Furthermore, the potential molecular mechanisms underlying G6PD-promoted tumorigenesis and the reason for aberrant G6PD expression in RCC were investigated.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('RCC', 'Disease', (134, 137))	('G6PD-promoted', 'Var', (59, 72))	('G6PD-promoted', 'PosReg', (59, 72))
58729	29312589	We previously reported the aberrant expression of G6PD in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('RCC', 'Disease', (60, 63))	('G6PD', 'Var', (50, 54))
58732	29312589	This conclusion is not totally the same as our previous statistical analyses of The Cancer Genome Atlas (TCGA) datasets, but provides sufficient information for further unravelling the correlation between G6PD overexpression and RCC tumor initiation and progression.	('RCC tumor initiation', 'Disease', 'MESH:C538614', (229, 249))	('Cancer Genome Atlas', 'Disease', (84, 103))	('RCC tumor initiation', 'Disease', (229, 249))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (84, 103))	('overexpression', 'PosReg', (210, 224))	('Cancer', 'Phenotype', 'HP:0002664', (84, 90))	('G6PD', 'Var', (205, 209))
58736	29312589	Though there were no obvious expression differences between the different subtypes, the results have showed that the expression of G6PD was significantly increased in the total of 74 RCC specimens (p < 0.001, Table 1).	('G6PD', 'Var', (131, 135))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('RCC', 'Disease', (183, 186))	('expression', 'MPA', (117, 127))	('increased', 'PosReg', (154, 163))
58737	29312589	High expression level of G6PD was detected in 18.92% (14/74) of the non-cancerous renal tissues but in 67.57% (50/74) of the RCC tissues.	('detected', 'Reg', (34, 42))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('G6PD', 'Var', (25, 29))	('expression level', 'MPA', (5, 21))	('cancerous renal tissues', 'Disease', (72, 95))	('cancerous renal tissues', 'Disease', 'MESH:D007680', (72, 95))
58738	29312589	Moreover, G6PD expression was significantly higher in the RCC metastasis than that detected in normal adjacent tissues or primary RCC without lymph node or distant metastasis (Figure 1B).	('higher', 'PosReg', (44, 50))	('G6PD', 'Var', (10, 14))	('RCC', 'Disease', (130, 133))	('RCC', 'Disease', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
58739	29312589	Additionally, G6PD was mainly localized in the cytoplasm of the renal tumor cells, with different staining intensities in different TNM stages of RCC (Figure 1C2-C4).	('TNM', 'Gene', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('renal tumor', 'Disease', (64, 75))	('cytoplasm', 'cellular_component', 'GO:0005737', ('47', '56'))	('G6PD', 'Var', (14, 18))	('TNM', 'Gene', '10178', (132, 135))	('renal tumor', 'Phenotype', 'HP:0009726', (64, 75))	('renal tumor', 'Disease', 'MESH:D007674', (64, 75))
58741	29312589	These results indicate that G6PD is highly expressed and overactive in RCC and might be tightly correlated to renal tumorigenesis.	('correlated', 'Reg', (96, 106))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('renal tumor', 'Phenotype', 'HP:0009726', (110, 121))	('RCC', 'Disease', (71, 74))	('overactive', 'PosReg', (57, 67))	('renal tumor', 'Disease', 'MESH:D007674', (110, 121))	('G6PD', 'Var', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('renal tumor', 'Disease', (110, 121))
58745	29312589	Consistently, the colony formation assay also revealed that G6PD overexpression in ACHN cells showed significantly increased colony formation index compared with the control cells (Figure 2C, 2D), while reduced colony formation index were observed in G6PD-knockdown 786-O cells (Figure 2E, 2F).	('G6PD', 'Var', (60, 64))	('formation', 'biological_process', 'GO:0009058', ('218', '227'))	('increased', 'PosReg', (115, 124))	('colony formation index', 'CPA', (125, 147))	('formation', 'biological_process', 'GO:0009058', ('132', '141'))	('formation', 'biological_process', 'GO:0009058', ('25', '34'))	('ACHN', 'Gene', '55323', (83, 87))	('overexpression', 'PosReg', (65, 79))	('ACHN', 'Gene', (83, 87))
58747	29312589	The results revealed that G6PD-overexpressing ACHN and 786-O cells had a decreased cell population in the G0/G1 phase and a significant increase in the S and G2/M phase compared with the control cells (Figure 2G, 2H).	('cell population in the G0/G1 phase', 'CPA', (83, 117))	('ACHN', 'Gene', (46, 50))	('decreased', 'NegReg', (73, 82))	('M phase', 'biological_process', 'GO:0000279', ('161', '168'))	('increase', 'PosReg', (136, 144))	('G1 phase', 'biological_process', 'GO:0051318', ('109', '117'))	('ACHN', 'Gene', '55323', (46, 50))	('G6PD-overexpressing', 'Var', (26, 45))
58748	29312589	These results indicate that G6PD facilitates the cell cycle and promotes RCC cell proliferation.	('promotes', 'PosReg', (64, 72))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('cell proliferation', 'biological_process', 'GO:0008283', ('77', '95'))	('cell cycle', 'CPA', (49, 59))	('cell cycle', 'biological_process', 'GO:0007049', ('49', '59'))	('G6PD', 'Var', (28, 32))	('facilitates', 'PosReg', (33, 44))
58749	29312589	The above in vitro results demonstrate that G6PD may play an oncogenic role in RCC.	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('G6PD', 'Var', (44, 48))	('RCC', 'Disease', (79, 82))
58750	29312589	Therefore, we subsequently used xenograft models in nude mice to investigate whether G6PD promotes RCC tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('RCC tumor', 'Disease', 'MESH:C538614', (99, 108))	('G6PD', 'Var', (85, 89))	('RCC tumor', 'Disease', (99, 108))	('promotes', 'PosReg', (90, 98))	('nude mice', 'Species', '10090', (52, 61))
58752	29312589	We found that the growth of tumor and tumor size were significantly faster and larger with G6PD-overexpressing cells compared with the control cells (Figure 3A-3C).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', (28, 33))	('larger', 'PosReg', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('G6PD-overexpressing cells', 'Var', (91, 116))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('faster', 'PosReg', (68, 74))
58753	29312589	Conversely, the G6PD-knockdown cells produced slower and smaller tumors than those with the Non-silencer cells (Figure 3D-3F).	('Non-silencer', 'Disease', 'MESH:C580335', (92, 104))	('smaller', 'NegReg', (57, 64))	('slower', 'NegReg', (46, 52))	('G6PD-knockdown', 'Var', (16, 30))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('Non-silencer', 'Disease', (92, 104))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
58754	29312589	These results confirm that G6PD potentiates RCC tumorigenesis in vivo.	('potentiates', 'PosReg', (32, 43))	('G6PD', 'Var', (27, 31))	('RCC tumor', 'Disease', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('RCC tumor', 'Disease', 'MESH:C538614', (44, 53))
58755	29312589	Taken together, in vitro and in vivo results indicate that G6PD overexpression increases RCC cell proliferation and enhances RCC tumorigenesis, whereas G6PD silencing reduces RCC cells growth and inhibits xenograft development.	('reduces', 'NegReg', (167, 174))	('inhibits', 'NegReg', (196, 204))	('RCC tumor', 'Disease', (125, 134))	('xenograft development', 'CPA', (205, 226))	('increases', 'PosReg', (79, 88))	('G6PD silencing', 'Var', (152, 166))	('RCC', 'Disease', (125, 128))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC tumor', 'Disease', 'MESH:C538614', (125, 134))	('G6PD', 'Var', (59, 63))	('enhances', 'PosReg', (116, 124))	('cell proliferation', 'biological_process', 'GO:0008283', ('93', '111'))	('RCC', 'Disease', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('RCC', 'Disease', (175, 178))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (175, 178))
58756	29312589	As the key enzyme of the pentose phosphate pathway, G6PD plays an important role in the maintenance of the cellular redox balance by cooperating with NADPH oxidase 4 (NOX4) and synergistically regulating the production of reactive oxygen species (ROS), which is often closely correlated with tumor initiation and development.	('NOX4', 'Gene', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('NADPH oxidase 4', 'Gene', (150, 165))	('regulating', 'Reg', (193, 203))	('tumor initiation', 'Disease', 'MESH:D009369', (292, 308))	('pentose phosphate', 'Chemical', 'MESH:D010428', (25, 42))	('ROS', 'Chemical', 'MESH:D017382', (247, 250))	('production of reactive oxygen species', 'MPA', (208, 245))	('NADPH oxidase', 'molecular_function', 'GO:0008753', ('150', '163'))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (222, 245))	('NADPH oxidase 4', 'Gene', '50507', (150, 165))	('cellular', 'MPA', (107, 115))	('tumor initiation', 'Disease', (292, 308))	('NOX4', 'Gene', '50507', (167, 171))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('25', '50'))	('NADPH oxidase', 'molecular_function', 'GO:0016174', ('150', '163'))	('G6PD', 'Var', (52, 56))
58760	29312589	Additional results indicated that overexpression of G6PD increased the levels of NADPH (Figure 4C), NOX4 enzyme activities (Figure 4E) and ROS production (Figure 4G, 4H) in ACHN cells, whereas, a significant decrease in NADPH levels (Figure 4D), NOX4 activity (Figure 4F) and ROS accumulation (Figure 4I, 4J) were associated with the knockdown of G6PD in comparison to the Non-silencer cells.	('levels', 'MPA', (71, 77))	('NADPH', 'Chemical', 'MESH:D009249', (81, 86))	('G6PD increased', 'Phenotype', 'HP:0410186', (52, 66))	('ACHN', 'Gene', '55323', (173, 177))	('NADPH', 'MPA', (81, 86))	('ROS', 'Chemical', 'MESH:D017382', (276, 279))	('ROS production', 'MPA', (139, 153))	('G6PD', 'Var', (347, 351))	('activity', 'MPA', (251, 259))	('NADPH levels', 'MPA', (220, 232))	('Non-silencer', 'Disease', 'MESH:C580335', (373, 385))	('NOX4', 'Gene', '50507', (246, 250))	('ROS accumulation', 'MPA', (276, 292))	('G6PD', 'Var', (52, 56))	('increased', 'PosReg', (57, 66))	('Non-silencer', 'Disease', (373, 385))	('NOX4', 'Gene', '50507', (100, 104))	('decrease', 'NegReg', (208, 216))	('NOX4', 'Gene', (246, 250))	('knockdown', 'Var', (334, 343))	('NOX4', 'Gene', (100, 104))	('ACHN', 'Gene', (173, 177))	('NADPH', 'Chemical', 'MESH:D009249', (220, 225))	('ROS', 'Chemical', 'MESH:D017382', (139, 142))
58761	29312589	These results show that G6PD could alter the redox status and promote ROS production partly by increasing NADPH levels and NOX4 activity in RCC cells.	('NOX4', 'Gene', (123, 127))	('NADPH', 'Chemical', 'MESH:D009249', (106, 111))	('increasing', 'PosReg', (95, 105))	('G6PD', 'Var', (24, 28))	('ROS production', 'MPA', (70, 84))	('NOX4', 'Gene', '50507', (123, 127))	('promote', 'PosReg', (62, 69))	('ROS', 'Chemical', 'MESH:D017382', (70, 73))	('NADPH levels', 'MPA', (106, 118))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('alter', 'Reg', (35, 40))	('redox status', 'MPA', (45, 57))
58764	29312589	These evidences lead us to suspect that p-STAT3 excessive activation may contribute to G6PD-stimulated RCC cell proliferation via up-regulated CyclinD1 expression.	('STAT3', 'Gene', (42, 47))	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('G6PD-stimulated', 'Var', (87, 102))	('cell proliferation', 'biological_process', 'GO:0008283', ('107', '125'))	('up-regulated', 'PosReg', (130, 142))	('CyclinD1', 'Gene', (143, 151))	('STAT3', 'Gene', '6774', (42, 47))	('activation', 'PosReg', (58, 68))	('expression', 'MPA', (152, 162))	('CyclinD1', 'Gene', '595', (143, 151))
58765	29312589	To test this hypothesis, Western blot analysis was firstly performed to identify the expression changes of p-STAT3 in RCC cells with G6PD overexpression or knockdown.	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('knockdown', 'Var', (156, 165))	('RCC', 'Disease', (118, 121))	('STAT3', 'Gene', '6774', (109, 114))	('STAT3', 'Gene', (109, 114))
58766	29312589	The results showed that G6PD knockdown could notably attenuate the levels of p-STAT3, STAT3 and the ratio of p-STAT3/STAT3 in 786-O cells, whereas, with the G6PD overexpression, the protein level of both p-STAT3 and STAT3 were obviously increased in ACHN cells (Figure 5A, 5B).	('increased', 'PosReg', (237, 246))	('STAT3', 'Gene', (111, 116))	('knockdown', 'Var', (29, 38))	('ACHN', 'Gene', (250, 254))	('STAT3', 'Gene', '6774', (79, 84))	('attenuate', 'NegReg', (53, 62))	('STAT3', 'Gene', '6774', (111, 116))	('overexpression', 'PosReg', (162, 176))	('STAT3', 'Gene', (117, 122))	('STAT3', 'Gene', (86, 91))	('STAT3', 'Gene', (206, 211))	('protein level', 'MPA', (182, 195))	('G6PD', 'Var', (157, 161))	('protein', 'cellular_component', 'GO:0003675', ('182', '189'))	('STAT3', 'Gene', '6774', (206, 211))	('STAT3', 'Gene', '6774', (117, 122))	('STAT3', 'Gene', '6774', (86, 91))	('ACHN', 'Gene', '55323', (250, 254))	('levels', 'MPA', (67, 73))	('ratio', 'MPA', (100, 105))	('STAT3', 'Gene', (216, 221))	('STAT3', 'Gene', '6774', (216, 221))	('STAT3', 'Gene', (79, 84))	('G6PD knockdown', 'Var', (24, 38))
58767	29312589	Meanwhile, the mRNA and protein levels of CyclinD1 were also down or up-regulated when G6PD was knockdown or overexpressed in RCC cells (Figure 5A, Supplementary Figure 2).	('CyclinD1', 'Gene', '595', (42, 50))	('down', 'NegReg', (61, 65))	('up-regulated', 'PosReg', (69, 81))	('G6PD', 'Var', (87, 91))	('CyclinD1', 'Gene', (42, 50))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('RCC', 'Disease', (126, 129))	('RCC', 'Disease', 'MESH:C538614', (126, 129))
58768	29312589	These results indicate that G6PD may have the potential to increase p-STAT3 signaling activities and promote CyclinD1 transcription.	('promote', 'PosReg', (101, 108))	('CyclinD1', 'Gene', (109, 117))	('transcription', 'biological_process', 'GO:0006351', ('118', '131'))	('STAT3', 'Gene', (70, 75))	('signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('CyclinD1', 'Gene', '595', (109, 117))	('STAT3', 'Gene', '6774', (70, 75))	('G6PD', 'Var', (28, 32))	('increase', 'PosReg', (59, 67))
58769	29312589	Our previous reports indicated that the aberrant ROS level could influence melanoma cell proliferation by regulating the DNA-binding activity of p-STAT3.	('DNA-binding', 'molecular_function', 'GO:0003677', ('121', '132'))	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('aberrant', 'Var', (40, 48))	('ROS', 'Chemical', 'MESH:D017382', (49, 52))	('cell proliferation', 'biological_process', 'GO:0008283', ('84', '102'))	('regulating', 'Reg', (106, 116))	('DNA-binding activity', 'MPA', (121, 141))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('ROS level', 'MPA', (49, 58))	('influence', 'Reg', (65, 74))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('STAT3', 'Gene', '6774', (147, 152))	('STAT3', 'Gene', (147, 152))
58773	29312589	Significantly reduced or elevated CyclinD1 expression at both mRNA and protein levels was also observed when 786-O cell was treated with NAC or H2O2 (Figure 5C, Supplementary Figure 4B-4C).	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('H2O2', 'Var', (144, 148))	('reduced', 'NegReg', (14, 21))	('CyclinD1', 'Gene', (34, 42))	('NAC', 'cellular_component', 'GO:0005854', ('137', '140'))	('NAC', 'Chemical', 'MESH:D000111', (137, 140))	('elevated', 'PosReg', (25, 33))	('H2O2', 'Chemical', 'MESH:D006861', (144, 148))	('expression', 'MPA', (43, 53))	('CyclinD1', 'Gene', '595', (34, 42))
58774	29312589	The above results imply that G6PD mediates p-STAT3 signaling activities, CyclinD1 overexpression and promoted RCC proliferation may be dependent on the up-regulation of cellular ROS accumulation.	('promoted', 'PosReg', (101, 109))	('RCC', 'Disease', (110, 113))	('G6PD', 'Var', (29, 33))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('up-regulation', 'PosReg', (152, 165))	('STAT3', 'Gene', (45, 50))	('STAT3', 'Gene', '6774', (45, 50))	('CyclinD1', 'Gene', '595', (73, 81))	('regulation', 'biological_process', 'GO:0065007', ('155', '165'))	('overexpression', 'PosReg', (82, 96))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('CyclinD1', 'Gene', (73, 81))	('ROS', 'Chemical', 'MESH:D017382', (178, 181))
58776	29312589	The results of Supplementary Figure 5 showed that H2O2 addition could rescue the ROS down-regulation by G6PD knockdown in 786-O cells, whereas, NAC in ACHN cells could reverse the ROS up-regulation by G6PD overexpression.	('G6PD knockdown', 'Var', (104, 118))	('ROS', 'Gene', (81, 84))	('ACHN', 'Gene', '55323', (151, 155))	('regulation', 'biological_process', 'GO:0065007', ('187', '197'))	('H2O2', 'Chemical', 'MESH:D006861', (50, 54))	('H2O2', 'Var', (50, 54))	('down-regulation', 'NegReg', (85, 100))	('knockdown', 'Var', (109, 118))	('ROS', 'Chemical', 'MESH:D017382', (180, 183))	('NAC', 'cellular_component', 'GO:0005854', ('144', '147'))	('regulation', 'biological_process', 'GO:0065007', ('90', '100'))	('NAC', 'Chemical', 'MESH:D000111', (144, 147))	('ACHN', 'Gene', (151, 155))	('ROS', 'Chemical', 'MESH:D017382', (81, 84))
58777	29312589	Moreover, the p-STAT3 and CyclinD1 expression reduction, mediated by G6PD knockdown, could be rescued by H2O2 addition in G6PD-knockdown 786-O cells (Figure 5D, 5E), while the up-regulated p-STAT3 signaling activities and CyclinD1 expression could be reversed by NAC stimulation in G6PD-overexpressing ACHN cells (Figure 5F, 5G).	('reduction', 'NegReg', (46, 55))	('ACHN', 'Gene', (302, 306))	('NAC', 'Chemical', 'MESH:D000111', (263, 266))	('STAT3', 'Gene', '6774', (191, 196))	('STAT3', 'Gene', '6774', (16, 21))	('H2O2', 'Chemical', 'MESH:D006861', (105, 109))	('H2O2', 'Var', (105, 109))	('CyclinD1', 'Gene', (222, 230))	('NAC', 'cellular_component', 'GO:0005854', ('263', '266'))	('STAT3', 'Gene', (191, 196))	('STAT3', 'Gene', (16, 21))	('G6PD', 'Var', (69, 73))	('CyclinD1', 'Gene', (26, 34))	('signaling', 'biological_process', 'GO:0023052', ('197', '206'))	('ACHN', 'Gene', '55323', (302, 306))	('CyclinD1', 'Gene', '595', (222, 230))	('CyclinD1', 'Gene', '595', (26, 34))
58778	29312589	These results proved that G6PD might promote p-STAT3 activation by mediating ROS accumulation.	('ROS accumulation', 'MPA', (77, 93))	('promote', 'PosReg', (37, 44))	('G6PD', 'Var', (26, 30))	('STAT3', 'Gene', '6774', (47, 52))	('STAT3', 'Gene', (47, 52))	('ROS', 'Chemical', 'MESH:D017382', (77, 80))
58779	29312589	We then analyzed the expression of G6PD and p-STAT3 in human RCC and paired adjacent non-cancer renal tissues (n=10) by immunohistochemistry.	('STAT3', 'Gene', '6774', (46, 51))	('STAT3', 'Gene', (46, 51))	('human', 'Species', '9606', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('G6PD', 'Var', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
58780	29312589	As shown in Figure 5H, 5I, the staining of both G6PD and p-STAT3 was stronger in RCC than in the adjacent tissues.	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('staining', 'MPA', (31, 39))	('RCC', 'Disease', (81, 84))	('STAT3', 'Gene', '6774', (59, 64))	('G6PD', 'Var', (48, 52))	('stronger', 'PosReg', (69, 77))	('STAT3', 'Gene', (59, 64))
58781	29312589	Moreover, the Pearson correlation analysis revealed that the expression levels of G6PD protein are strongly correlated with p-STAT3 in human RCC samples (r = 0.521, p < 0.01).	('RCC', 'Disease', (141, 144))	('correlated', 'Reg', (108, 118))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('G6PD', 'Var', (82, 86))	('protein', 'Protein', (87, 94))	('human', 'Species', '9606', (135, 140))	('STAT3', 'Gene', '6774', (126, 131))	('STAT3', 'Gene', (126, 131))	('expression levels', 'MPA', (61, 78))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
58782	29312589	These results reveal that up-regulated co-expression of G6PD and p-STAT3 may synergistically contribute to the tumorigenesis of RCC.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('contribute', 'Reg', (93, 103))	('RCC', 'Disease', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('STAT3', 'Gene', '6774', (67, 72))	('tumor', 'Disease', (111, 116))	('co-expression', 'MPA', (39, 52))	('STAT3', 'Gene', (67, 72))	('up-regulated', 'PosReg', (26, 38))	('G6PD', 'Var', (56, 60))
58783	29312589	Taken together, G6PD promotes tumor cell proliferation possibly through ROS-stimulated persistent activation of p-STAT3 signaling and up-regulated CyclinD1 expression in RCC.	('G6PD', 'Var', (16, 20))	('STAT3', 'Gene', '6774', (114, 119))	('activation', 'PosReg', (98, 108))	('RCC', 'Disease', (170, 173))	('STAT3', 'Gene', (114, 119))	('promotes', 'PosReg', (21, 29))	('CyclinD1', 'Gene', (147, 155))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('cell proliferation', 'biological_process', 'GO:0008283', ('36', '54'))	('ROS', 'Chemical', 'MESH:D017382', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('expression', 'MPA', (156, 166))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))	('up-regulated', 'PosReg', (134, 146))	('CyclinD1', 'Gene', '595', (147, 155))	('tumor', 'Disease', (30, 35))
58785	29312589	Interestingly, after the 786-O cells were treated with NAC or H2O2 as above, we could observe a significant decrease or increase of G6PD expression at both mRNA and protein levels (Supplementary Figure 4D-4E and Figure 5C), which was consistent with the p-STAT3 signaling activity changes.	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('H2O2', 'Chemical', 'MESH:D006861', (62, 66))	('H2O2', 'Var', (62, 66))	('expression', 'MPA', (137, 147))	('STAT3', 'Gene', '6774', (256, 261))	('increase', 'PosReg', (120, 128))	('increase of G6PD expression', 'Phenotype', 'HP:0410186', (120, 147))	('NAC', 'cellular_component', 'GO:0005854', ('55', '58'))	('G6PD', 'Gene', (132, 136))	('decrease', 'NegReg', (108, 116))	('STAT3', 'Gene', (256, 261))	('NAC', 'Chemical', 'MESH:D000111', (55, 58))	('signaling', 'biological_process', 'GO:0023052', ('262', '271'))
58786	29312589	Therefore, we hypothesize that p-STAT3 may be a novel transcriptional regulator of G6PD gene expression, and thus form a positive feedback loop to contribute to G6PD up-regulation in RCC.	('STAT3', 'Gene', '6774', (33, 38))	('gene expression', 'biological_process', 'GO:0010467', ('88', '103'))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('up-regulation', 'PosReg', (166, 179))	('RCC', 'Disease', (183, 186))	('regulation', 'biological_process', 'GO:0065007', ('169', '179'))	('G6PD', 'Var', (161, 165))	('STAT3', 'Gene', (33, 38))
58788	29312589	The results showed that the transcriptional regulatory region of G6PD had conserved p-STAT3 binding TTN5AA sequences (Figure 6A).	('G6PD', 'Var', (65, 69))	('STAT3', 'Gene', '6774', (86, 91))	('STAT3', 'Gene', (86, 91))	('binding', 'molecular_function', 'GO:0005488', ('92', '99'))
58790	29312589	Following the transfection of G6PD-luc and vectors encoding either the mutant STAT3 C or STAT3 DN, which actively up or down-regulates STAT3 signaling pathway persistently, the stimulated increase or reduction of G6PD-luc activity occurred in a dose-dependent manner in 786-O cells (Figure 6B).	('STAT3', 'Gene', '6774', (135, 140))	('down-regulates', 'NegReg', (120, 134))	('STAT3', 'Gene', (135, 140))	('reduction of G6PD-luc', 'Disease', 'MESH:D005955', (200, 221))	('reduction of G6PD-luc', 'Disease', (200, 221))	('STAT3', 'Gene', '6774', (78, 83))	('STAT3', 'Gene', '6774', (89, 94))	('mutant', 'Var', (71, 77))	('STAT3', 'Gene', (78, 83))	('increase', 'PosReg', (188, 196))	('signaling pathway', 'biological_process', 'GO:0007165', ('141', '158'))	('activity', 'MPA', (222, 230))	('STAT3', 'Gene', (89, 94))
58791	29312589	The G6PD-luc mutant, or deletion containing the mutant or deleted p-STAT3 binding site (Figure 6A), exhibited significantly decreased p-STAT3 activity as compared to the wild type (Figure 6C), indicating that p-STAT3 plays an important role in activating G6PD mRNA expression.	('STAT3', 'Gene', '6774', (211, 216))	('G6PD-luc', 'Var', (4, 12))	('activating', 'PosReg', (244, 254))	('decreased', 'NegReg', (124, 133))	('STAT3', 'Gene', '6774', (136, 141))	('STAT3', 'Gene', (211, 216))	('binding', 'molecular_function', 'GO:0005488', ('74', '81'))	('STAT3', 'Gene', '6774', (68, 73))	('STAT3', 'Gene', (136, 141))	('STAT3', 'Gene', (68, 73))
58797	29312589	Whereas, the expression of G6PD at the mRNA level was notably reduced by the p-STAT3 signaling inhibitor STATTIC in both ACHN and 786-O cells (Figure 7C, 7D).	('STAT', 'Gene', '6774;20848', (105, 109))	('ACHN', 'Gene', (121, 125))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('expression', 'MPA', (13, 23))	('STAT', 'Gene', (105, 109))	('G6PD', 'Var', (27, 31))	('STAT3', 'Gene', '6774', (79, 84))	('ACHN', 'Gene', '55323', (121, 125))	('STAT', 'Gene', (79, 83))	('STAT3', 'Gene', (79, 84))	('STAT', 'Gene', '6774;20848', (79, 83))	('reduced', 'NegReg', (62, 69))
58799	29312589	Conversely, after stimulated with STATTIC, the expression of G6PD obviously decreased in RCC cells (Figure 7G, 7H).	('G6PD', 'Var', (61, 65))	('decreased', 'NegReg', (76, 85))	('RCC', 'Disease', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('STAT', 'Gene', '6774;20848', (34, 38))	('STAT', 'Gene', (34, 38))	('expression', 'MPA', (47, 57))
58800	29312589	Taken together, these results show that persistent activation of p-STAT3 could act as a positive feedback regulator and lead to the aberrant transcription of G6PD in RCC.	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('RCC', 'Disease', (166, 169))	('G6PD', 'Var', (158, 162))	('lead to', 'Reg', (120, 127))	('STAT3', 'Gene', '6774', (67, 72))	('STAT3', 'Gene', (67, 72))	('transcription', 'biological_process', 'GO:0006351', ('141', '154'))	('transcription', 'MPA', (141, 154))	('activation', 'PosReg', (51, 61))
58801	29312589	In the present study, we aimed to clarify the function of G6PD in promoting RCC proliferation and unravel the potential mechanisms underlying this regulation.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('promoting', 'PosReg', (66, 75))	('RCC', 'Disease', (76, 79))	('G6PD', 'Var', (58, 62))	('regulation', 'biological_process', 'GO:0065007', ('147', '157'))
58805	29312589	ROS have been implicated in cancer development through regulation of the redox state of target cells and exert diverse effects on cellular function, by promoting either cell proliferation and tumor progression, or cell death and tumor regression, suggesting that ROS increment is a double-edged sword in tumor cells.	('cell proliferation', 'biological_process', 'GO:0008283', ('169', '187'))	('increment', 'Var', (267, 276))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('regulation', 'biological_process', 'GO:0065007', ('55', '65'))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cell proliferation', 'CPA', (169, 187))	('tumor', 'Disease', (304, 309))	('ROS', 'Chemical', 'MESH:D017382', (263, 266))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('cell death', 'CPA', (214, 224))	('tumor', 'Disease', (192, 197))	('promoting', 'PosReg', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancer', 'Disease', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cell death', 'biological_process', 'GO:0008219', ('214', '224'))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
58808	29312589	Our present report unravel that G6PD plays a critical role in the regulation of RCC redox homeostasis and the elevated levels of NADPH might be an indispensable mediator of NOX4-regulated ROS accumulation.	('regulation', 'biological_process', 'GO:0065007', ('66', '76'))	('homeostasis', 'biological_process', 'GO:0042592', ('90', '101'))	('ROS', 'Chemical', 'MESH:D017382', (188, 191))	('RCC', 'Disease', (80, 83))	('NOX4', 'Gene', '50507', (173, 177))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('NOX4', 'Gene', (173, 177))	('NADPH', 'Chemical', 'MESH:D009249', (129, 134))	('G6PD', 'Var', (32, 36))	('regulation', 'MPA', (66, 76))
58809	29312589	Inducting the exogenous G6PD overexpression up-regulates the production of NADPH, as well as the enzymatic activity of NOX4, and thus leads to the increment of G6PD-NADPH-NOX4-dependent ROS generation in the G6PD promoted RCC carcinogenesis.	('NOX4', 'Gene', (119, 123))	('RCC carcinogenesis', 'Disease', (222, 240))	('G6PD', 'Var', (208, 212))	('NADPH', 'MPA', (75, 80))	('NOX4', 'Gene', (171, 175))	('NADPH', 'Chemical', 'MESH:D009249', (165, 170))	('ROS generation', 'biological_process', 'GO:1903409', ('186', '200'))	('NOX4', 'Gene', '50507', (119, 123))	('increment', 'PosReg', (147, 156))	('NOX4', 'Gene', '50507', (171, 175))	('up-regulates', 'PosReg', (44, 56))	('ROS', 'Chemical', 'MESH:D017382', (186, 189))	('RCC carcinogenesis', 'Disease', 'MESH:C538614', (222, 240))	('NADPH', 'Chemical', 'MESH:D009249', (75, 80))
58818	29312589	Here we demonstrate that STAT3, and its active form p-STAT3, are significantly promoted by G6PD-triggered increased ROS production.	('ROS production', 'MPA', (116, 130))	('ROS', 'Chemical', 'MESH:D017382', (116, 119))	('STAT3', 'Gene', (25, 30))	('G6PD-triggered', 'Var', (91, 105))	('STAT3', 'Gene', '6774', (54, 59))	('promoted', 'PosReg', (79, 87))	('STAT3', 'Gene', (54, 59))	('increased', 'PosReg', (106, 115))	('increased ROS production', 'Phenotype', 'HP:0025464', (106, 130))	('STAT3', 'Gene', '6774', (25, 30))
58820	29312589	Aberrant p-STAT3 directly binds to the promoter and regulates the expression of a series of cell-cycle genes including CyclinD1 that mediates cell survival, proliferation and chemotherapeutic sensitivity.	('Aberrant', 'Var', (0, 8))	('STAT3', 'Gene', '6774', (11, 16))	('CyclinD1', 'Gene', (119, 127))	('expression', 'MPA', (66, 76))	('regulates', 'Reg', (52, 61))	('cell-cycle genes', 'Gene', (92, 108))	('cell-cycle', 'biological_process', 'GO:0007049', ('92', '102'))	('binds', 'Interaction', (26, 31))	('CyclinD1', 'Gene', '595', (119, 127))	('STAT3', 'Gene', (11, 16))
58821	29312589	The high frequency of CyclinD1 overexpression observed in RCC patients suggesting that CyclinD1 might contribute to the tumorigenesis and aberrations in the G1/S transition of the cell cycle.	('CyclinD1', 'Gene', (22, 30))	('aberrations', 'Var', (138, 149))	('G1/S transition of the cell cycle', 'CPA', (157, 190))	('CyclinD1', 'Gene', '595', (87, 95))	('contribute', 'Reg', (102, 112))	('CyclinD1', 'Gene', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cell cycle', 'biological_process', 'GO:0007049', ('180', '190'))	('RCC', 'Disease', (58, 61))	('CyclinD1', 'Gene', '595', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('patients', 'Species', '9606', (62, 70))	('overexpression', 'PosReg', (31, 45))	('tumor', 'Disease', (120, 125))
58824	29312589	Moreover, G6PD could regulate CyclinD1 but had a minimal effect on CDK2 expression in regulating cell cycle distribution of RCC cells (data not shown), implying that CyclinD1 must be a more potential downstream target of G6PD.	('CyclinD1', 'Gene', (166, 174))	('RCC', 'Disease', (124, 127))	('CDK2', 'Gene', '1017', (67, 71))	('cell cycle distribution', 'MPA', (97, 120))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('regulate', 'Reg', (21, 29))	('CyclinD1', 'Gene', (30, 38))	('CyclinD1', 'Gene', '595', (166, 174))	('G6PD', 'Var', (10, 14))	('cell cycle', 'biological_process', 'GO:0007049', ('97', '107'))	('CDK', 'molecular_function', 'GO:0004693', ('67', '70'))	('CyclinD1', 'Gene', '595', (30, 38))	('CDK2', 'Gene', (67, 71))
58825	29312589	Although further investigations are required to elucidate the mechanism involved in this regulation, our results definitely support the oncogenic role of G6PD in promoting RCC proliferation.	('promoting', 'PosReg', (162, 171))	('G6PD', 'Var', (154, 158))	('regulation', 'biological_process', 'GO:0065007', ('89', '99'))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('RCC', 'Disease', (172, 175))
58826	29312589	In this study, the biological functions and underlying molecular mechanisms of G6PD overexpression in RCC tumorigenesis have partially been clarified.	('RCC tumor', 'Disease', 'MESH:C538614', (102, 111))	('RCC tumor', 'Disease', (102, 111))	('G6PD', 'Var', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
58827	29312589	However, the question why G6PD is highly expressed and exhibits aberrant activities in a number of human cancers is far from being answered.	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('G6PD', 'Var', (26, 30))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('activities', 'MPA', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('human', 'Species', '9606', (99, 104))
58828	29312589	Previous studies have revealed that G6PD over-activation in human tumors may be attributed to the tumor suppressor p53, the most frequently mutated gene in human tumors, which binds to G6PD, inhibits formation of the active G6PD dimer, and suppresses NADPH production, as well as glucose consumption and biosynthesis.	('tumor', 'Disease', (162, 167))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('p53', 'Gene', (115, 118))	('tumor suppressor', 'biological_process', 'GO:0051726', ('98', '114'))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('formation', 'MPA', (200, 209))	('tumor', 'Disease', (98, 103))	('glucose consumption', 'Disease', (280, 299))	('biosynthesis', 'biological_process', 'GO:0009058', ('304', '316'))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Disease', (66, 71))	('binds', 'Interaction', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('glucose consumption', 'Disease', 'MESH:D014397', (280, 299))	('suppresses', 'NegReg', (240, 250))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('G6PD', 'Var', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('NADPH production', 'MPA', (251, 267))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('biosynthesis', 'MPA', (304, 316))	('over-activation', 'PosReg', (41, 56))	('NADPH', 'Chemical', 'MESH:D009249', (251, 256))	('tumors', 'Disease', (66, 72))	('formation', 'biological_process', 'GO:0009058', ('200', '209'))	('p53', 'Gene', '7157', (115, 118))	('inhibits', 'NegReg', (191, 199))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('98', '114'))	('tumors', 'Disease', (162, 168))	('human', 'Species', '9606', (156, 161))	('active G6PD dimer', 'MPA', (217, 234))	('human', 'Species', '9606', (60, 65))
58829	29312589	In RCC cells, we find that both the expression level and the activity of G6PD enzyme are up-regulated.	('expression level', 'MPA', (36, 52))	('G6PD', 'Var', (73, 77))	('RCC', 'Disease', (3, 6))	('activity', 'MPA', (61, 69))	('up-regulated', 'PosReg', (89, 101))	('RCC', 'Disease', 'MESH:C538614', (3, 6))
58830	29312589	Nevertheless, given the fact that only 4% of ccRCCs present with p53 mutations, enhanced G6PD activities to direct glucose toward biosynthesis and increased tumor cells growth may not be due to p53 inactivation in RCC.	('p53', 'Gene', '7157', (65, 68))	('p53', 'Gene', (194, 197))	('RCC', 'Disease', 'MESH:C538614', (214, 217))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('p53', 'Gene', (65, 68))	('enhanced', 'PosReg', (80, 88))	('mutations', 'Var', (69, 78))	('biosynthesis', 'biological_process', 'GO:0009058', ('130', '142'))	('increased', 'PosReg', (147, 156))	('glucose', 'Chemical', 'MESH:D005947', (115, 122))	('tumor', 'Disease', (157, 162))	('enhanced G6PD activities', 'Phenotype', 'HP:0410186', (80, 104))	('G6PD', 'Enzyme', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('RCC', 'Disease', (214, 217))	('p53', 'Gene', '7157', (194, 197))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('RCC', 'Disease', (47, 50))
58831	29312589	Liu B et al reported that G6PD is highly expressed in chronic hepatitis B virus (HBV)-associated liver cancers and up-regulated by HBx-mediated activation of Nrf2, which may be of importance in the reprogramming of glucose metabolism and development of hepatocarcinoma.	('G6PD', 'Var', (26, 30))	('hepatocarcinoma', 'Disease', 'None', (253, 268))	('liver cancers', 'Disease', 'MESH:D006528', (97, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('glucose metabolism', 'Disease', (215, 233))	('Nrf2', 'Gene', '2551', (158, 162))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (54, 71))	('liver cancers', 'Phenotype', 'HP:0002896', (97, 110))	('hepatocarcinoma', 'Disease', (253, 268))	('chronic hepatitis B virus', 'Disease', (54, 79))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('hepatitis B virus', 'Species', '10407', (62, 79))	('HBV', 'Species', '10407', (81, 84))	('hepatitis', 'Phenotype', 'HP:0012115', (62, 71))	('up-regulated', 'PosReg', (115, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('glucose metabolism', 'biological_process', 'GO:0006006', ('215', '233'))	('liver cancers', 'Disease', (97, 110))	('HBx', 'Gene', '944566', (131, 134))	('glucose metabolism', 'Disease', 'MESH:D044882', (215, 233))	('HBx', 'Gene', (131, 134))	('Nrf2', 'Gene', (158, 162))
58834	29312589	In this report, we find that G6PD expression in metastatic RCC patients is significantly higher than that of RCC specimens without lymph node or distant metastasis, indicating that G6PD might play an important role in mediating the progression of RCC to metastasis.	('G6PD', 'Var', (29, 33))	('expression', 'MPA', (34, 44))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('higher', 'PosReg', (89, 95))	('patients', 'Species', '9606', (63, 71))	('RCC', 'Disease', 'MESH:C538614', (247, 250))	('RCC', 'Disease', (247, 250))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))
58835	29312589	Although the mechanism of G6PD in RCC is not fully clarified, we believe that in addition to the proliferation-promoting effect, G6PD may have other functions, especially the potential to facilitate migration and invasion of RCC.	('facilitate', 'PosReg', (188, 198))	('G6PD', 'Var', (129, 133))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('RCC', 'Disease', (225, 228))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('invasion', 'CPA', (213, 221))	('migration', 'CPA', (199, 208))	('RCC', 'Disease', (34, 37))
58836	29312589	In conclusion, our findings demonstrate that G6PD is highly expressed in RCC.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('G6PD', 'Var', (45, 49))
58837	29312589	Aberrant G6PD could stimulate cell proliferation and tumor growth by activating the G6PD-ROS-p-STAT3-CyclinD1 signaling pathway.	('ROS', 'Chemical', 'MESH:D017382', (89, 92))	('G6PD', 'Var', (9, 13))	('CyclinD1', 'Gene', (101, 109))	('cell proliferation', 'CPA', (30, 48))	('Aberrant G6PD', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('stimulate', 'PosReg', (20, 29))	('activating', 'PosReg', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('STAT3', 'Gene', '6774', (95, 100))	('CyclinD1', 'Gene', '595', (101, 109))	('signaling pathway', 'biological_process', 'GO:0007165', ('110', '127'))	('tumor', 'Disease', (53, 58))	('STAT3', 'Gene', (95, 100))	('cell proliferation', 'biological_process', 'GO:0008283', ('30', '48'))
58839	29312589	Taken together, our research supports the oncogenic role of G6PD in human tumorigenesis, unveils new mechanisms underlying RCC carcinogenesis, and points to strategies of designing innovative therapeutic agents to improve RCC treatment.	('G6PD', 'Var', (60, 64))	('RCC carcinogenesis', 'Disease', (123, 141))	('human', 'Species', '9606', (68, 73))	('RCC carcinogenesis', 'Disease', 'MESH:C538614', (123, 141))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('RCC', 'Disease', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (222, 225))	('tumor', 'Disease', (74, 79))	('RCC', 'Disease', (222, 225))	('RCC', 'Disease', 'MESH:C538614', (123, 126))
58840	29312589	To identify the expression profile of G6PD in human RCC, data mining was performed using the Gene Expression Omnibus (GEO, National Center Biotechnology information, Bethesda, MD, USA).	('Gene Expression', 'biological_process', 'GO:0010467', ('93', '108'))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('G6PD', 'Var', (38, 42))	('human', 'Species', '9606', (46, 51))
58844	29312589	The RCC cell lines ACHN (ATCC CRL-1611 ), 786-O (ATCC CRL-1932 ), Caki-1 (ATCC CRL-1611 ) and the normal renal tubular epithelial cell line HK-2 (ATCC CRL-2190 ) were purchased from Kunming Institute of Zoology (Chinese Academy of Sciences, China) and routinely cultured in MEM (#10370-021, Gibco  Life Technologies, Grand Island, NY), RPMI-1640 (#11875-085, Gibco), McCOY's 5A media (M9309, Sigma-Aldrich, Louis, MO, USA) and K-SFM medium (#17005-042, Gibco) containing 10% FBS, respectively.	('ACHN', 'Gene', '55323', (19, 23))	('ACHN', 'Gene', (19, 23))	('#11875-085', 'Var', (347, 357))	('HK-2', 'CellLine', 'CVCL:0302', (140, 144))	('#10370-021', 'Var', (279, 289))	('HK-2', 'molecular_function', 'GO:0008256', ('140', '144'))	('RCC', 'Disease', (4, 7))	('RCC', 'Disease', 'MESH:C538614', (4, 7))	('M9309', 'Var', (385, 390))
58848	29312589	To establish stable G6PD knockdown cell lines, the 786-O cells were transfected with pSR-GFP/Neo-G6PD shRNA (G6PD KD) or pSR-GFP/Neo-Non-silencer (Non-silencer) plasmid as the control and then selected using G418 resistance screening (1000 mug/ml) for 21 days.	('Non-silencer', 'Disease', 'MESH:C580335', (147, 159))	('pSR-GFP/Neo-G6PD', 'Var', (85, 101))	('Non-silencer', 'Disease', (133, 145))	('mug', 'molecular_function', 'GO:0043739', ('240', '243'))	('Non-silencer', 'Disease', (147, 159))	('G418', 'Chemical', 'MESH:C010680', (208, 212))	('Non-silencer', 'Disease', 'MESH:C580335', (133, 145))
58849	29312589	STATTIC and H2O2 (sc-202818 and sc-203336) were purchased from Santa Cruz Biotechnology (SantaCruz, CA, USA).	('sc-202818', 'Var', (18, 27))	('sc-203336', 'Var', (32, 41))	('H2O2', 'Chemical', 'MESH:D006861', (12, 16))	('STAT', 'Gene', '6774;20848', (0, 4))	('STAT', 'Gene', (0, 4))
58859	29312589	Additionally, anti-STAT3 antibody (#4904), anti-beta-actin (#4967) antibody, and anti-GAPDH antibody (#2118) were purchased from Cell Signaling Technology (Beverly, MA, USA).	('antibody', 'cellular_component', 'GO:0019814', ('92', '100'))	('Signaling', 'biological_process', 'GO:0023052', ('134', '143'))	('antibody', 'cellular_component', 'GO:0019815', ('67', '75'))	('antibody', 'cellular_component', 'GO:0019815', ('25', '33'))	('#4904', 'Var', (35, 40))	('antibody', 'molecular_function', 'GO:0003823', ('92', '100'))	('antibody', 'cellular_component', 'GO:0042571', ('92', '100'))	('GAPDH', 'Gene', '2597', (86, 91))	('#4967', 'Var', (60, 65))	('antibody', 'cellular_component', 'GO:0019814', ('67', '75'))	('antibody', 'cellular_component', 'GO:0019814', ('25', '33'))	('STAT3', 'Gene', (19, 24))	('antibody', 'cellular_component', 'GO:0019815', ('92', '100'))	('STAT3', 'Gene', '6774', (19, 24))	('GAPDH', 'Gene', (86, 91))	('antibody', 'molecular_function', 'GO:0003823', ('67', '75'))	('antibody', 'molecular_function', 'GO:0003823', ('25', '33'))	('antibody', 'cellular_component', 'GO:0042571', ('67', '75'))	('antibody', 'cellular_component', 'GO:0042571', ('25', '33'))
58860	29312589	G6PD and NOX4 activities were analyzed using the G6PD or NOX4 assay kit (GMS70013.1 and GMS50096.1, GENMED, Shanghai, China) according to the manufacturer instructions.	('NOX4', 'Gene', '50507', (9, 13))	('GMS50096.1', 'Var', (88, 98))	('NOX4', 'Gene', '50507', (57, 61))	('NOX4', 'Gene', (9, 13))	('NOX4', 'Gene', (57, 61))
58874	29312589	STAT3 C and STAT3 DN were purchased from Addgene (#24983 and #24984, Addgene, MA, USA).	('STAT3', 'Gene', '6774', (12, 17))	('#24983', 'Var', (50, 56))	('#24984', 'Var', (61, 67))	('STAT3', 'Gene', (12, 17))	('STAT3', 'Gene', '6774', (0, 5))	('STAT3', 'Gene', (0, 5))
58888	33468079	High TV was an independent predictor of poor CSS, OS, FFLR and FFM of localized ccRCC.	('CSS', 'Chemical', '-', (45, 48))	('High', 'Var', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))
58921	33468079	TV was graded as group 1 (TV < 17 cm3), group 2 (17 <= TV < 40 cm3), group 3 (40 <= TV < 134 cm3), and group 4 (TV >= 134 cm3) and there were 267 (35.6%), 172 (23.0%), 156 (20.8%), and 154 (20.6%) patients in each group, respectively.	('TV >= 134 cm3', 'Var', (112, 125))	('patients', 'Species', '9606', (197, 205))	('40 <= TV < 134 cm3', 'Var', (78, 96))	('17 <= TV < 40 cm3', 'Var', (49, 66))	('TV < 17 cm3', 'Var', (26, 37))
58926	33468079	Log rank test revealed that high TV, high Fuhrman grade and advanced pT classification were associated with poor OS, CSS, FFLR and FFM of patients after surgery (P < 0.001 for all) (Figs.	('FFLR', 'Disease', (122, 126))	('high', 'Var', (37, 41))	('CSS', 'Chemical', '-', (117, 120))	('poor OS', 'Disease', (108, 115))	('CSS', 'Disease', (117, 120))	('patients', 'Species', '9606', (138, 146))
58927	33468079	Univariable Cox proportional hazards analysis showed that high Fuhrman grade, high TV and advanced pT classification were all associated with poor OS, CSS, FFLR and FFM of localized ccRCC after surgery, but tumor necrosis and Ki-67 did not predict the oncological outcome independently (P < 0.05 for all; Tables 2, 3, 4 and 5).	('tumor necrosis', 'Disease', (207, 221))	('high', 'Var', (78, 82))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('RCC', 'Disease', (184, 187))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('tumor necrosis', 'Disease', 'MESH:D009336', (207, 221))	('necrosis', 'biological_process', 'GO:0070265', ('213', '221'))	('necrosis', 'biological_process', 'GO:0008219', ('213', '221'))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('necrosis', 'biological_process', 'GO:0019835', ('213', '221'))	('high', 'Var', (58, 62))	('necrosis', 'biological_process', 'GO:0008220', ('213', '221'))	('necrosis', 'biological_process', 'GO:0001906', ('213', '221'))	('CSS', 'Chemical', '-', (151, 154))
58939	33468079	Jorns et al.. concluded that TV could provide valuable prognostic information for patients with pT1a ccRCC rather than pT1b ccRCC.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('patients', 'Species', '9606', (82, 90))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('pT1a', 'Var', (96, 100))
58976	31519159	We investigated Akt/mTOR pathway activation and the preclinical efficacy of dual mTORC1/2 versus selective mTORC1 inhibition in TfRCC.	('activation', 'PosReg', (33, 43))	('mTORC1/2', 'Gene', (81, 89))	('Akt/mTOR pathway', 'Pathway', (16, 32))	('mTORC1', 'Gene', '382056', (107, 113))	('mTORC1', 'Gene', (81, 87))	('dual', 'Var', (76, 80))	('mTORC1', 'cellular_component', 'GO:0031931', ('81', '87'))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('mTORC1', 'cellular_component', 'GO:0031931', ('107', '113'))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('mTORC1/2', 'Gene', '74343;382056', (81, 89))	('mTORC1', 'Gene', (107, 113))	('mTORC1', 'Gene', '382056', (81, 87))
58979	31519159	TfRCC xenograft tumor growth in mice was evaluated after 3-week treatment with oral AZD8055, intraperitoneal sirolimus and respective vehicle controls.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mice', 'Species', '10090', (32, 36))	('tumor', 'Disease', (16, 21))	('AZD8055', 'Var', (84, 91))	('sirolimus', 'Chemical', 'MESH:D020123', (109, 118))	('AZD8055', 'Chemical', 'MESH:C546624', (84, 91))
58981	31519159	Dual mTORC1/2 inhibition with AZD8055 potently inhibited TfRCC viability (IC50 = 20-50 nM) due at least in part to cell cycle arrest, while benign renal epithelial cells were relatively resistant (IC50 = 400 nM).	('inhibited', 'NegReg', (47, 56))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (115, 132))	('inhibition', 'NegReg', (14, 24))	('AZD8055', 'Chemical', 'MESH:C546624', (30, 37))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))	('mTORC1', 'cellular_component', 'GO:0031931', ('5', '11'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('115', '132'))	('cell cycle arrest', 'CPA', (115, 132))	('mTORC1/2', 'Gene', '74343;382056', (5, 13))	('AZD8055', 'Var', (30, 37))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('mTORC1/2', 'Gene', (5, 13))
58982	31519159	Maximal viability reduction was greater with AZD8055 than sirolimus (80-90% versus 30-50%), as was the extent of Akt/mTOR pathway inhibition, based on significantly greater suppression of P-Akt (Ser473), P-4EBP1, P-mTOR and HIF1alpha.	('sirolimus', 'Chemical', 'MESH:D020123', (58, 67))	('4EBP1', 'Gene', (206, 211))	('AZD8055', 'Var', (45, 52))	('HIF1alpha', 'Gene', (224, 233))	('AZD8055', 'Chemical', 'MESH:C546624', (45, 52))	('Akt/mTOR pathway', 'Pathway', (113, 129))	('suppression', 'NegReg', (173, 184))	('P-Akt', 'Protein', (188, 193))	('inhibition', 'NegReg', (130, 140))	('HIF1alpha', 'Gene', '3091', (224, 233))	('Ser', 'cellular_component', 'GO:0005790', ('195', '198'))	('Ser473', 'Chemical', '-', (195, 201))	('P-mTOR', 'Protein', (213, 219))	('4EBP1', 'Gene', '1978', (206, 211))	('reduction', 'NegReg', (18, 27))
58983	31519159	In mouse xenograft models, AZD8055 achieved significantly better tumor growth inhibition and prolonged mouse survival compared to sirolimus or vehicle controls.	('mouse', 'Species', '10090', (3, 8))	('tumor', 'Disease', (65, 70))	('AZD8055', 'Var', (27, 34))	('better', 'PosReg', (58, 64))	('mouse survival', 'CPA', (103, 117))	('AZD8055', 'Chemical', 'MESH:C546624', (27, 34))	('mouse', 'Species', '10090', (103, 108))	('prolonged', 'PosReg', (93, 102))	('sirolimus', 'Chemical', 'MESH:D020123', (130, 139))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
58988	31519159	Rearrangements include an inversion or translocation of the TFE3 gene (Xp11.2), which is a member of the Microphthalmia-associated transcription factor (MiT) family that regulates growth and differentiation.	('Microphthalmia', 'Phenotype', 'HP:0000568', (105, 119))	('inversion', 'Var', (26, 35))	('transcription factor', 'molecular_function', 'GO:0000981', ('131', '151'))	('Microphthalmia-associated transcription factor', 'Gene', '4286', (105, 151))	('transcription', 'biological_process', 'GO:0006351', ('131', '144'))	('TFE3', 'Gene', (60, 64))	('MiT', 'Gene', '4286', (153, 156))	('Microphthalmia-associated transcription factor', 'Gene', (105, 151))	('TFE3', 'Gene', '7030', (60, 64))	('translocation', 'Var', (39, 52))	('MiT', 'Gene', (153, 156))
58994	31519159	The diagnosis is suggested by young age, tumor histology and nuclear immunoreactivity for the TFE3 C-terminus; however, confirmation of diagnosis requires cytogenetic or molecular evidence of an Xp11 rearrangement or fusion transcript.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('Xp11 rearrangement', 'Var', (195, 213))	('tumor', 'Disease', (41, 46))	('fusion transcript', 'Var', (217, 234))	('TFE3', 'Gene', '7030', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('TFE3', 'Gene', (94, 98))
58999	31519159	A variety of cellular functions are governed by wild-type TFE3, and the simultaneous dysregulation of these functions might be sufficient to promote carcinogenesis.	('carcinogenesis', 'Disease', (149, 163))	('dysregulation', 'Var', (85, 98))	('TFE3', 'Gene', '7030', (58, 62))	('promote', 'PosReg', (141, 148))	('carcinogenesis', 'Disease', 'MESH:D063646', (149, 163))	('TFE3', 'Gene', (58, 62))
59004	31519159	Activation of mTORC1 is thought to promote ccRCC carcinogenesis, at least in part, through increased cap-dependent translation of the hypoxia-inducible factor alpha (HIFalpha) transcript.	('mTORC1', 'Gene', (14, 20))	('hypoxia', 'Disease', 'MESH:D000860', (134, 141))	('hypoxia', 'Disease', (134, 141))	('cap-dependent translation', 'MPA', (101, 126))	('carcinogenesis', 'Disease', (49, 63))	('carcinogenesis', 'Disease', 'MESH:D063646', (49, 63))	('mTORC1', 'Gene', '382056', (14, 20))	('mTORC1', 'cellular_component', 'GO:0031931', ('14', '20'))	('Activation', 'Var', (0, 10))	('promote', 'PosReg', (35, 42))	('increased', 'PosReg', (91, 100))	('translation', 'biological_process', 'GO:0006412', ('115', '126'))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
59006	31519159	However, clinical resistance to mTORC1 inhibition limits its long-term efficacy and may be mediated by several mechanisms, including a feedback loop involving a second mTOR-containing complex, mTORC2, which phosphorylates Akt in response to mTORC1 inhibition.	('mediated', 'Reg', (91, 99))	('mTORC2', 'Gene', (193, 199))	('inhibition', 'Var', (39, 49))	('mTORC1', 'cellular_component', 'GO:0031931', ('32', '38'))	('long-term', 'MPA', (61, 70))	('mTORC1', 'Gene', (32, 38))	('mTORC2', 'Gene', '74343', (193, 199))	('limits', 'NegReg', (50, 56))	('mTORC1', 'Gene', '382056', (241, 247))	('mTORC1', 'Gene', (241, 247))	('mTORC1', 'cellular_component', 'GO:0031931', ('241', '247'))	('mTORC1', 'Gene', '382056', (32, 38))	('mTORC2', 'cellular_component', 'GO:0031932', ('193', '199'))
59012	31519159	The UOK111, UOK139 and UOK150 cell lines had been derived from ccRCC tumors excised from RCC patients treated at the NCI and were shown to harbor VHL gene mutations.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('VHL', 'Gene', (146, 149))	('harbor', 'Reg', (139, 145))	('mutations', 'Var', (155, 164))	('VHL', 'Gene', '7428', (146, 149))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('UOK150', 'CellLine', 'CVCL:B125', (23, 29))	('patients', 'Species', '9606', (93, 101))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
59020	31519159	Akt kinase activation was evaluated by measurement of phosphorylated levels of Akt (Thr308) and Akt (Ser473), the latter also served as a reporter for mTORC2 activation, in addition to levels of phosphorylated GSK3beta, which is an Akt kinase target.	('GSK3beta', 'Gene', '2932', (210, 218))	('mTORC2', 'cellular_component', 'GO:0031932', ('151', '157'))	('Ser', 'cellular_component', 'GO:0005790', ('101', '104'))	('Ser473', 'Var', (101, 107))	('Ser473', 'Chemical', '-', (101, 107))	('Thr308', 'Chemical', '-', (84, 90))	('mTORC2', 'Gene', (151, 157))	('GSK', 'molecular_function', 'GO:0050321', ('210', '213'))	('mTORC2', 'Gene', '74343', (151, 157))	('GSK3beta', 'Gene', (210, 218))
59041	31519159	Briefly, 5 x 106 cells in PBS suspension with 30% (UOK120) or 50% (UOK146) Matrigel (BD Biosciences, Franklin Lakes, NY) were injected subcutaneously into the mouse right flank.	('UOK120', 'Chemical', '-', (51, 57))	('PBS', 'Chemical', 'MESH:D007854', (26, 29))	('UOK146', 'Var', (67, 73))	('mouse', 'Species', '10090', (159, 164))	('UOK146', 'Chemical', '-', (67, 73))	('UOK120', 'Var', (51, 57))
59042	31519159	When UOK120 (N = 34) or UOK146 (N = 40) tumors were palpable (volume 0.05-0.20 cm3), treatment was initiated with doses of 4 mg/kg sirolimus intraperitoneal (IP) weekly, IP vehicle control weekly (5% Tween-80 and 5% PEG-400), AZD8055 20 mg/kg oral (PO) daily, or PO vehicle control daily (30% Captisol, pH 5.0).	('Tween-80', 'Chemical', 'MESH:D011136', (200, 208))	('UOK120', 'Var', (5, 11))	('AZD8055', 'Var', (226, 233))	('UOK146', 'Chemical', '-', (24, 30))	('AZD8055', 'Chemical', 'MESH:C546624', (226, 233))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('sirolimus', 'Chemical', 'MESH:D020123', (131, 140))	('UOK146', 'Var', (24, 30))	('UOK120', 'Chemical', '-', (5, 11))	('Captisol', 'Chemical', 'MESH:C093196', (293, 301))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('PEG-400', 'Chemical', 'MESH:C000595213', (216, 223))	('tumors', 'Disease', (40, 46))
59047	31519159	An additional 8 mice xenografted with UOK120 or UOK146 tumors underwent the same treatments (N = 2 mice per treatment) and were sacrificed at 6 h after their first drug dose for analysis of tumor protein.	('mice', 'Species', '10090', (99, 103))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('UOK146', 'Chemical', '-', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', (190, 195))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('UOK146', 'Var', (48, 54))	('mice', 'Species', '10090', (16, 20))	('UOK120', 'Chemical', '-', (38, 44))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))
59050	31519159	Activation of mTORC2 and Akt based on phosphorylated Akt (Ser473) or Akt (Thr308) and phosphorylated GSK3beta was more consistently detected in TfRCC than in ccRCC cell lines.	('mTORC2', 'Gene', '74343', (14, 20))	('Thr308', 'Var', (74, 80))	('Ser473', 'Var', (58, 64))	('Ser473', 'Chemical', '-', (58, 64))	('Ser', 'cellular_component', 'GO:0005790', ('58', '61'))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('GSK', 'molecular_function', 'GO:0050321', ('101', '104'))	('GSK3beta', 'Gene', '2932', (101, 109))	('Thr308', 'Chemical', '-', (74, 80))	('Akt', 'Pathway', (25, 28))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('mTORC2', 'cellular_component', 'GO:0031932', ('14', '20'))	('RCC', 'Disease', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('Activation', 'PosReg', (0, 10))	('mTORC2', 'Gene', (14, 20))	('GSK3beta', 'Gene', (101, 109))	('RCC', 'Disease', 'MESH:C538614', (160, 163))
59053	31519159	Simultaneous phosphorylation of mTOR at both the Ser2448 and Ser2481 residues was detected in all TfRCC cell lines compared to only a minority of ccRCC cell lines.	('Ser', 'cellular_component', 'GO:0005790', ('61', '64'))	('Ser', 'cellular_component', 'GO:0005790', ('49', '52'))	('RCC', 'Disease', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('phosphorylation', 'MPA', (13, 28))	('mTOR', 'Protein', (32, 36))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('Ser2481', 'Chemical', '-', (61, 68))	('Ser2448', 'Var', (49, 56))	('detected', 'Reg', (82, 90))	('Ser2448', 'Chemical', '-', (49, 56))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('Ser2481', 'Var', (61, 68))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
59058	31519159	Phosphorylation of mTOR at Ser2448 and Ser2481 was also largely preserved upon serum starvation.	('Ser2481', 'Chemical', '-', (39, 46))	('mTOR', 'Protein', (19, 23))	('Ser2448', 'Var', (27, 34))	('Ser', 'cellular_component', 'GO:0005790', ('27', '30'))	('Phosphorylation', 'MPA', (0, 15))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('Ser2448', 'Chemical', '-', (27, 34))	('Ser2481', 'Var', (39, 46))	('Ser', 'cellular_component', 'GO:0005790', ('39', '42'))
59061	31519159	AZD8055 potently suppressed viability in all TfRCC cell lines (IC50 range = 20-50 nM), with maximal viability reduction of approximately 80-90% at 500-1000 nM (Fig.	('reduction', 'NegReg', (110, 119))	('AZD8055', 'Var', (0, 7))	('AZD8055', 'Chemical', 'MESH:C546624', (0, 7))	('suppressed', 'NegReg', (17, 27))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('viability', 'MPA', (28, 37))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))
59062	31519159	In contrast, AZD8055 caused relatively little reduction in viability in benign renal cells, with an approximately ten-fold higher IC50 (400 nM) and only 50% maximal viability reduction at 500-1000 nM.	('AZD8055', 'Chemical', 'MESH:C546624', (13, 20))	('higher', 'PosReg', (123, 129))	('AZD8055', 'Var', (13, 20))
59068	31519159	First, we examined the mechanism by which AZD8055 and sirolimus inhibited TfRCC cell viability.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('AZD8055', 'Var', (42, 49))	('AZD8055', 'Chemical', 'MESH:C546624', (42, 49))	('inhibited', 'NegReg', (64, 73))	('sirolimus', 'Chemical', 'MESH:D020123', (54, 63))
59071	31519159	No cytotoxicity was observed in UOK146 cells and only slight cytotoxicity was observed in UOK120 cells after 1000 nM AZD8055 treatment, despite substantial growth reduction of both cell lines with this dose in MTT assays (Fig.	('cytotoxicity', 'Disease', 'MESH:D064420', (3, 15))	('UOK120', 'Chemical', '-', (90, 96))	('reduction', 'NegReg', (163, 172))	('growth', 'MPA', (156, 162))	('cytotoxicity', 'Disease', (61, 73))	('AZD8055', 'Var', (117, 124))	('MTT', 'Chemical', 'MESH:C070243', (210, 213))	('AZD8055', 'Chemical', 'MESH:C546624', (117, 124))	('cytotoxicity', 'Disease', 'MESH:D064420', (61, 73))	('cytotoxicity', 'Disease', (3, 15))	('UOK146', 'Chemical', '-', (32, 38))
59072	31519159	These data suggested that inhibition of cell proliferation rather than induction of cytotoxicity might be the mechanism of TfRCC suppression by AZD8055 and sirolimus.	('cytotoxicity', 'Disease', (84, 96))	('AZD8055', 'Var', (144, 151))	('AZD8055', 'Chemical', 'MESH:C546624', (144, 151))	('RCC', 'Disease', (125, 128))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('sirolimus', 'Chemical', 'MESH:D020123', (156, 165))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('cytotoxicity', 'Disease', 'MESH:D064420', (84, 96))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('26', '58'))	('cell proliferation', 'CPA', (40, 58))
59074	31519159	A dose-dependent decrease in S-phase was observed in both cell lines upon treatment with AZD8055, and, to a lower extent, with sirolimus (Fig.	('sirolimus', 'Chemical', 'MESH:D020123', (127, 136))	('S-phase', 'biological_process', 'GO:0051320', ('29', '36'))	('decrease', 'NegReg', (17, 25))	('AZD8055', 'Chemical', 'MESH:C546624', (89, 96))	('S-phase', 'MPA', (29, 36))	('AZD8055', 'Var', (89, 96))
59076	31519159	These findings support cell cycle arrest as a primary mechanism by which AZD8055 and sirolimus suppress TfRCC growth.	('cell cycle', 'CPA', (23, 33))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (23, 40))	('suppress', 'NegReg', (95, 103))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('23', '40'))	('AZD8055', 'Var', (73, 80))	('AZD8055', 'Chemical', 'MESH:C546624', (73, 80))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('sirolimus', 'Chemical', 'MESH:D020123', (85, 94))	('RCC', 'Disease', 'MESH:C538614', (106, 109))
59078	31519159	Akt/mTOR pathway suppression was more effective with AZD8055 than sirolimus, as demonstrated by more complete downregulation of phosphorylated pathway members (Akt (Ser473), GSK3beta, mTOR, 4EBP1) and HIF1alpha, although S6 phosphorylation was suppressed equally by the two drugs.	('sirolimus', 'Chemical', 'MESH:D020123', (66, 75))	('HIF1alpha', 'Gene', '3091', (201, 210))	('GSK3beta', 'Gene', '2932', (174, 182))	('4EBP1', 'Gene', '1978', (190, 195))	('phosphorylated', 'MPA', (128, 142))	('mTOR', 'Pathway', (184, 188))	('4EBP1', 'Gene', (190, 195))	('GSK3beta', 'Gene', (174, 182))	('Ser', 'cellular_component', 'GO:0005790', ('165', '168'))	('phosphorylation', 'biological_process', 'GO:0016310', ('224', '239'))	('GSK', 'molecular_function', 'GO:0050321', ('174', '177'))	('AZD8055', 'Var', (53, 60))	('HIF1alpha', 'Gene', (201, 210))	('Akt/mTOR pathway', 'Pathway', (0, 16))	('AZD8055', 'Chemical', 'MESH:C546624', (53, 60))	('suppression', 'NegReg', (17, 28))	('downregulation', 'NegReg', (110, 124))	('Ser473', 'Chemical', '-', (165, 171))
59079	31519159	While AZD8055 suppressed phosphorylated Akt (Ser473), GSK3beta and 4EBP1, sirolimus had the opposite effect, increasing each of these phosphorylated proteins in a dose- and time-dependent fashion.	('increasing', 'PosReg', (109, 119))	('phosphorylated', 'MPA', (25, 39))	('Ser', 'cellular_component', 'GO:0005790', ('45', '48'))	('AZD8055', 'Var', (6, 13))	('AZD8055', 'Chemical', 'MESH:C546624', (6, 13))	('GSK', 'molecular_function', 'GO:0050321', ('54', '57'))	('GSK3beta and 4EBP1', 'Gene', '2932', (54, 72))	('suppressed', 'NegReg', (14, 24))	('sirolimus', 'Chemical', 'MESH:D020123', (74, 83))	('Ser473', 'Chemical', '-', (45, 51))
59082	31519159	In contrast to sirolimus, AZD8055 treatment suppressed phosphorylation of all key Akt/mTOR pathway members to completion in a time- and dose-dependent fashion and achieved nearly 100% reduction in HIF1alpha protein levels.	('HIF1alpha', 'Gene', (197, 206))	('reduction', 'NegReg', (184, 193))	('suppressed', 'NegReg', (44, 54))	('phosphorylation', 'biological_process', 'GO:0016310', ('55', '70'))	('HIF1alpha', 'Gene', '3091', (197, 206))	('protein', 'cellular_component', 'GO:0003675', ('207', '214'))	('sirolimus', 'Chemical', 'MESH:D020123', (15, 24))	('AZD8055', 'Chemical', 'MESH:C546624', (26, 33))	('phosphorylation', 'MPA', (55, 70))	('AZD8055', 'Var', (26, 33))
59084	31519159	In both models, treatment with AZD8055 resulted in significant inhibition of tumor growth (UOK146: p < 0.0001; UOK120: p < 0.0001).	('UOK120', 'Chemical', '-', (111, 117))	('AZD8055', 'Var', (31, 38))	('AZD8055', 'Chemical', 'MESH:C546624', (31, 38))	('UOK146', 'Chemical', '-', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('inhibition', 'NegReg', (63, 73))
59085	31519159	The mean tumor volume after the 3-week AZD8055 treatment period was reduced by 56% (UOK120) and 64% (UOK146) compared to mice treated with the vehicle control (Fig.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('AZD8055', 'Chemical', 'MESH:C546624', (39, 46))	('UOK120', 'Chemical', '-', (84, 90))	('tumor', 'Disease', (9, 14))	('mice', 'Species', '10090', (121, 125))	('reduced', 'NegReg', (68, 75))	('UOK146', 'Chemical', '-', (101, 107))	('AZD8055', 'Var', (39, 46))
59089	31519159	Mouse survival, which was driven by tumor size, was significantly longer in AZD8055-treated mice compared to oral vehicle control-treated mice (UOK146: p < 0.0001; UOK120: p = 0.021) or sirolimus-treated mice (UOK146: p < 0.0001; UOK120: p = 0.076) (Fig.	('Mouse survival', 'CPA', (0, 14))	('UOK146', 'Chemical', '-', (144, 150))	('UOK120', 'Chemical', '-', (230, 236))	('AZD8055', 'Chemical', 'MESH:C546624', (76, 83))	('sirolimus', 'Chemical', 'MESH:D020123', (186, 195))	('mice', 'Species', '10090', (92, 96))	('mice', 'Species', '10090', (138, 142))	('UOK146', 'Chemical', '-', (210, 216))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('Mouse', 'Species', '10090', (0, 5))	('longer', 'PosReg', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mice', 'Species', '10090', (204, 208))	('UOK120', 'Chemical', '-', (164, 170))	('tumor', 'Disease', (36, 41))	('AZD8055-treated', 'Var', (76, 91))
59090	31519159	Immunoblot analysis of Akt/mTOR pathway members in tumor lysates confirmed on-target effects for both sirolimus and AZD8055 at 6 h after treatment (Fig.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('AZD8055', 'Chemical', 'MESH:C546624', (116, 123))	('AZD8055', 'Var', (116, 123))	('tumor', 'Disease', (51, 56))	('Akt/mTOR pathway', 'Pathway', (23, 39))	('sirolimus', 'Chemical', 'MESH:D020123', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
59091	31519159	Both drugs achieved complete suppression of S6 phosphorylation indicative of mTORC1 inhibition, while AZD8055 additionally suppressed phosphorylation of Akt (Ser473) indicative of mTORC2 inhibition.	('mTORC2', 'cellular_component', 'GO:0031932', ('180', '186'))	('phosphorylation', 'MPA', (134, 149))	('inhibition', 'NegReg', (84, 94))	('AZD8055', 'Var', (102, 109))	('AZD8055', 'Chemical', 'MESH:C546624', (102, 109))	('Ser', 'cellular_component', 'GO:0005790', ('158', '161'))	('mTORC1', 'Gene', (77, 83))	('suppressed', 'NegReg', (123, 133))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('mTORC1', 'cellular_component', 'GO:0031931', ('77', '83'))	('suppression', 'NegReg', (29, 40))	('Akt', 'Pathway', (153, 156))	('Ser473', 'Chemical', '-', (158, 164))	('phosphorylation', 'biological_process', 'GO:0016310', ('134', '149'))	('mTORC2', 'Gene', (180, 186))	('mTORC1', 'Gene', '382056', (77, 83))	('mTORC2', 'Gene', '74343', (180, 186))
59094	31519159	Retrospective identification of TFE3-fusion gene mutations by the TCGA project in several patients diagnosed originally with ccRCC or papillary RCC is consistent with the 1-5% incidence of retrospective identification reported among nephrectomy patients by others and may be even higher among metastatic RCC patients.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('papillary RCC', 'Disease', 'MESH:C538614', (134, 147))	('TFE3', 'Gene', (32, 36))	('papillary RCC', 'Disease', (134, 147))	('mutations', 'Var', (49, 58))	('patients', 'Species', '9606', (245, 253))	('RCC', 'Disease', (127, 130))	('patients', 'Species', '9606', (308, 316))	('RCC', 'Phenotype', 'HP:0005584', (304, 307))	('RCC', 'Disease', (144, 147))	('RCC', 'Disease', 'MESH:C538614', (304, 307))	('RCC', 'Disease', (304, 307))	('TFE3', 'Gene', '7030', (32, 36))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('TCGA', 'Gene', (66, 70))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('patients', 'Species', '9606', (90, 98))
59102	31519159	These results suggest that dysregulated Akt and mTOR activation may play an important role in TfRCC carcinogenesis.	('TfRCC carcinogenesis', 'Disease', 'MESH:D063646', (94, 114))	('activation', 'PosReg', (53, 63))	('mTOR', 'CPA', (48, 52))	('Akt', 'Pathway', (40, 43))	('dysregulated', 'Var', (27, 39))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('TfRCC carcinogenesis', 'Disease', (94, 114))
59104	31519159	The inhibitory mechanism for both AZD8055 and sirolimus included cell cycle arrest without significant cytotoxicity induction, consistent with the effect of rapalogs reported in other cancer types.	('cancer', 'Disease', (184, 190))	('cell cycle arrest', 'CPA', (65, 82))	('cytotoxicity', 'Disease', 'MESH:D064420', (103, 115))	('AZD8055', 'Var', (34, 41))	('AZD8055', 'Chemical', 'MESH:C546624', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('sirolimus', 'Chemical', 'MESH:D020123', (46, 55))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('65', '82'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (65, 82))	('cytotoxicity', 'Disease', (103, 115))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
59106	31519159	Greater growth suppression with AZD8055 than sirolimus in vitro was validated in vivo using two separate mouse xenograft models of TfRCC.	('sirolimus', 'Chemical', 'MESH:D020123', (45, 54))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('AZD8055', 'Chemical', 'MESH:C546624', (32, 39))	('AZD8055', 'Var', (32, 39))	('mouse', 'Species', '10090', (105, 110))	('growth', 'MPA', (8, 14))
59108	31519159	Greater TfRCC suppression with AZD8055 relative to sirolimus is likely due to more complete suppression of the Akt/mTOR pathway.	('sirolimus', 'Chemical', 'MESH:D020123', (51, 60))	('suppression', 'NegReg', (14, 25))	('Akt/mTOR pathway', 'Pathway', (111, 127))	('AZD8055', 'Var', (31, 38))	('AZD8055', 'Chemical', 'MESH:C546624', (31, 38))	('suppression', 'NegReg', (92, 103))	('RCC', 'Disease', (10, 13))	('RCC', 'Phenotype', 'HP:0005584', (10, 13))	('RCC', 'Disease', 'MESH:C538614', (10, 13))
59109	31519159	AZD8055- versus sirolimus-treated TfRCC cell lines and mouse xenografts demonstrated clear differences in Akt/mTOR pathway activation.	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('AZD8055', 'Chemical', 'MESH:C546624', (0, 7))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('mouse', 'Species', '10090', (55, 60))	('activation', 'PosReg', (123, 133))	('sirolimus', 'Chemical', 'MESH:D020123', (16, 25))	('Akt/mTOR pathway', 'Pathway', (106, 122))	('AZD8055-', 'Var', (0, 8))
59110	31519159	Selective mTORC1 inhibition induced feedback activation of Akt kinase and, consequently, less effective inhibition of downstream S6 phosphorylation, whereas dual mTORC1/2 inhibition suppressed both upstream Akt activation and downstream S6 phosphorylation.	('mTORC1', 'Gene', (162, 168))	('mTORC1/2', 'Gene', '74343;382056', (162, 170))	('suppressed', 'NegReg', (182, 192))	('mTORC1', 'Gene', '382056', (10, 16))	('inhibition', 'MPA', (104, 114))	('inhibition', 'Var', (17, 27))	('mTORC1/2', 'Gene', (162, 170))	('Akt kinase', 'Pathway', (59, 69))	('phosphorylation', 'biological_process', 'GO:0016310', ('132', '147'))	('downstream S6 phosphorylation', 'MPA', (118, 147))	('mTORC1', 'cellular_component', 'GO:0031931', ('10', '16'))	('mTORC1', 'Gene', '382056', (162, 168))	('phosphorylation', 'biological_process', 'GO:0016310', ('240', '255'))	('activation', 'PosReg', (45, 55))	('mTORC1', 'cellular_component', 'GO:0031931', ('162', '168'))	('mTORC1', 'Gene', (10, 16))
59112	31519159	Dual mTORC1/2 inhibition blocks this feedback activation and hence provides a promising strategy for overcoming clinical resistance to selective mTORC1 inhibition.	('mTORC1', 'Gene', (145, 151))	('feedback activation', 'MPA', (37, 56))	('mTORC1', 'Gene', (5, 11))	('mTORC1', 'Gene', '382056', (145, 151))	('blocks', 'NegReg', (25, 31))	('mTORC1/2', 'Gene', '74343;382056', (5, 13))	('mTORC1', 'cellular_component', 'GO:0031931', ('145', '151'))	('inhibition', 'Var', (14, 24))	('mTORC1', 'Gene', '382056', (5, 11))	('mTORC1', 'cellular_component', 'GO:0031931', ('5', '11'))	('mTORC1/2', 'Gene', (5, 13))
59119	31519159	Dual mTORC1/2 inhibitors such as AZD8055 or Ku0063794 suppress growth of ccRCC cell lines, including those resistant to angiogenesis inhibitors.	('angiogenesis', 'biological_process', 'GO:0001525', ('120', '132'))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('Ku0063794', 'Var', (44, 53))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('suppress', 'NegReg', (54, 62))	('RCC', 'Disease', (75, 78))	('AZD8055', 'Chemical', 'MESH:C546624', (33, 40))	('mTORC1/2', 'Gene', '74343;382056', (5, 13))	('growth', 'MPA', (63, 69))	('AZD8055', 'Var', (33, 40))	('Ku0063794', 'Chemical', 'MESH:C541932', (44, 53))	('mTORC1', 'cellular_component', 'GO:0031931', ('5', '11'))	('mTORC1/2', 'Gene', (5, 13))
59120	31519159	Although dual mTORC1/2 inhibition with AZD2014 proved inferior to everolimus in metastatic ccRCC patients, preclinical studies from our group and others suggest that AZD8055 is superior to rapalogs in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('mTORC1/2', 'Gene', '74343;382056', (14, 22))	('everolimus', 'Chemical', 'MESH:D000068338', (66, 76))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Disease', (93, 96))	('AZD8055', 'Var', (166, 173))	('mTORC1/2', 'Gene', (14, 22))	('AZD8055', 'Chemical', 'MESH:C546624', (166, 173))	('AZD2014', 'Var', (39, 46))	('AZD2014', 'Chemical', 'MESH:C585537', (39, 46))	('mTORC1', 'cellular_component', 'GO:0031931', ('14', '20'))	('RCC', 'Disease', 'MESH:C538614', (203, 206))	('RCC', 'Disease', (203, 206))	('RCC', 'Phenotype', 'HP:0005584', (203, 206))	('patients', 'Species', '9606', (97, 105))
59123	31519159	Activating mutations in the MTOR gene have not yet been detected in patient tumors harboring a TFE3 gene fusion, nor have mutations in PIK3CA or PTEN.	('fusion', 'Var', (105, 111))	('MTOR', 'Gene', '2475', (28, 32))	('PTEN', 'Gene', (145, 149))	('patient', 'Species', '9606', (68, 75))	('PTEN', 'Gene', '5728', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('TFE3', 'Gene', (95, 99))	('tumors', 'Disease', (76, 82))	('PIK3CA', 'Gene', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('PIK3CA', 'Gene', '5290', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('MTOR', 'Gene', (28, 32))	('TFE3', 'Gene', '7030', (95, 99))
59126	31519159	Given the potential ability of PI3K to activate both mTORC2 and PDK-1, dysregulated PI3K could theoretically explain the high phosphorylation at both Akt (Ser473) and Akt (Thr308) observed in TfRCC.	('PDK-1', 'Gene', '5163', (64, 69))	('Thr308', 'Chemical', '-', (172, 178))	('Ser473', 'Chemical', '-', (155, 161))	('PI3K', 'molecular_function', 'GO:0016303', ('84', '88'))	('activate', 'PosReg', (39, 47))	('mTORC2', 'cellular_component', 'GO:0031932', ('53', '59'))	('RCC', 'Disease', (194, 197))	('RCC', 'Phenotype', 'HP:0005584', (194, 197))	('PDK-1', 'Gene', (64, 69))	('PI3K', 'molecular_function', 'GO:0016303', ('31', '35'))	('PDK-1', 'molecular_function', 'GO:0004740', ('64', '69'))	('mTORC2', 'Gene', (53, 59))	('phosphorylation', 'MPA', (126, 141))	('RCC', 'Disease', 'MESH:C538614', (194, 197))	('phosphorylation', 'biological_process', 'GO:0016310', ('126', '141'))	('Akt', 'Pathway', (150, 153))	('Ser', 'cellular_component', 'GO:0005790', ('155', '158'))	('Akt', 'Pathway', (167, 170))	('mTORC2', 'Gene', '74343', (53, 59))	('Ser473', 'Var', (155, 161))
59132	31519159	Adding to recently published results that suggest therapeutic potential for PI3K/mTOR inhibition in TfRCC, our work shows dual mTORC1/2 inhibition suppresses the Akt/mTOR pathway and tumor growth in TfRCC preclinical models more effectively than selective mTORC1 inhibition.	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('suppresses', 'NegReg', (147, 157))	('mTORC1/2', 'Gene', '74343;382056', (127, 135))	('RCC', 'Disease', (201, 204))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('inhibition', 'Var', (136, 146))	('mTORC1', 'cellular_component', 'GO:0031931', ('256', '262'))	('mTORC1', 'Gene', (256, 262))	('mTORC1', 'Gene', '382056', (256, 262))	('PI3K', 'molecular_function', 'GO:0016303', ('76', '80'))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('mTORC1/2', 'Gene', (127, 135))	('tumor', 'Disease', (183, 188))	('mTORC1', 'Gene', (127, 133))	('Akt/mTOR pathway', 'Pathway', (162, 178))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('mTORC1', 'Gene', '382056', (127, 133))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('mTORC1', 'cellular_component', 'GO:0031931', ('127', '133'))
59154	31138299	indicated that the presence of CD4+ but not CD8+ T-cell infiltrate is associated with poor survival.	('CD8', 'Gene', (44, 47))	('CD4+', 'Var', (31, 35))	('CD8', 'Gene', '925', (44, 47))	('poor', 'NegReg', (86, 90))
59214	31138299	In cases with high NanoString T cell expression, strong expression of CD3+ and CD8+ T cells was noted on IHC.	('CD8', 'Gene', (79, 82))	('high NanoString', 'Var', (14, 29))	('CD8', 'Gene', '925', (79, 82))
59235	31138299	Several ongoing trials are studying (neo) adjuvant immunotherapy for ccRCC and results are awaited (NCT03341845, NCT03142334, NCT03024996).	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('NCT03341845', 'Var', (100, 111))	('RCC', 'Disease', (71, 74))
59273	28457802	At the authors' institution mpMRI includes the following sequences: T2-weighted images in coronal and axial (with fat-suppression) planes (4-8mm slice thickness, 256x154 to 348x280 matrix, 70-120ms echo time (TE), and 964-4820ms repetition time (TR)), axial chemical shift T1-weighted images (5-8mm thickness, 193x168 to 500x286 matrix, 2.38/4.87ms (1.5T) or 1.1/2.3ms (3.0T) TE, and 100-216ms TR), and fat-suppressed dynamic contrast-enhanced (DCE) T1-weighted imaging, including corticomedullary and late nephrographic and/or excretory phases in either axial or coronal planes (3-6mm slice thickness, 176x149 to 320x259 matrix size, 1.6-2.4ms TE, and 3.4-5.4ms TR).	('DCE', 'Gene', '1718', (445, 448))	('DCE', 'Gene', (445, 448))	('176x149', 'Var', (603, 610))
59329	29286165	In the present study, we used renal cell carcinoma (RCC) cells and bronchial epithelial cells, representing metastasis target organ cells, conditioned medium and co-culture models to identify specific gene expression changes responsible for cancer cell viability in a metastatic microenvironment.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('renal cell carcinoma', 'Disease', (30, 50))	('changes', 'Var', (217, 224))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (30, 50))	('gene expression', 'biological_process', 'GO:0010467', ('201', '216'))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (30, 50))	('men', 'Species', '9606', (291, 294))
59397	29286165	A significant difference in expression was found between normal cells induced by different cancer cells (N + C vs. N + A, Tables I-V), cancer cell lines induced by normal cells (C + N vs. A + N, Tables VI-IX), as well as between co-cultures and Caki-2 monoculture or NL-20 monoculture (Fig.	('cancer', 'Disease', (135, 141))	('C + N', 'Chemical', '-', (178, 183))	('cancer', 'Disease', (91, 97))	('expression', 'MPA', (28, 38))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('C + N vs.', 'Var', (178, 187))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Caki-2', 'CellLine', 'CVCL:0235', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
59402	29286165	8), when compared to genes deregulated in Caki-2 cells interacting with NL-20 cells (C + N), as well as ACHN cells induced by NL-20 cells (A + N) and NL-20 cells induced by ACHN cells (N + A).	('ACHN', 'Gene', '55323', (173, 177))	('C + N', 'Chemical', '-', (85, 90))	('ACHN', 'Gene', (173, 177))	('ACHN', 'Gene', '55323', (104, 108))	('NL-20', 'Var', (126, 131))	('ACHN', 'Gene', (104, 108))	('Caki-2', 'CellLine', 'CVCL:0235', (42, 48))
59406	29286165	If C + N was compared with Caki-2 monoculture, 326 genes were deregulated.	('C + N', 'Chemical', '-', (3, 8))	('deregulated', 'PosReg', (62, 73))	('C + N', 'Var', (3, 8))	('Caki-2', 'CellLine', 'CVCL:0235', (27, 33))
59410	29286165	Prolactin receptor signaling with the major downstream signaling modules JAK/STAT, RAS/RAF/MAPK, PI3-Kinase/AKT and RAC was also deregulated in the metastatic target organ normal cells (pleural epithelial cells) (Table II).	('AKT', 'Gene', '207', (108, 111))	('JAK', 'molecular_function', 'GO:0004713', ('73', '76'))	('MAPK', 'molecular_function', 'GO:0004707', ('91', '95'))	('RAF', 'Gene', '22882', (87, 90))	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('AKT', 'Gene', (108, 111))	('RAF', 'Gene', (87, 90))	('Prolactin receptor', 'Gene', '5618', (0, 18))	('Prolactin', 'molecular_function', 'GO:0005148', ('0', '9'))	('JAK/STAT', 'Var', (73, 81))	('signaling', 'biological_process', 'GO:0023052', ('55', '64'))	('Prolactin receptor', 'Gene', (0, 18))	('deregulated', 'Reg', (129, 140))	('RAC', 'Gene', (116, 119))
59416	29286165	At the same time genes deregulated in Caki-2 cells from C + N co-culture, compared with Caki-2 monoculture were clustered in and 276 GO pathways and 17 WikiPathways (P<=0.05) (Tables V and VI).	('C + N', 'Var', (56, 61))	('276', 'Reg', (129, 132))	('WikiPathways', 'Pathway', (152, 164))	('GO pathways', 'Pathway', (133, 144))	('Caki-2', 'CellLine', 'CVCL:0235', (88, 94))	('C + N', 'Chemical', '-', (56, 61))	('genes', 'Gene', (17, 22))	('Caki-2', 'CellLine', 'CVCL:0235', (38, 44))
59433	29286165	19), both under normoxic and hypoxic conditions, with a trend towards a higher expression in 21% O2 (Fig.	('O2', 'Chemical', '-', (97, 99))	('expression', 'MPA', (79, 89))	('21%', 'Var', (93, 96))	('hypoxic conditions', 'Disease', (29, 47))	('higher', 'PosReg', (72, 78))	('hypoxic conditions', 'Disease', 'MESH:D009135', (29, 47))
59441	29286165	Our analysis of cDNA array data indicated that crosstalk between healthy NL-20 cells and RCC cells mostly results in the deregulation of cell-cell signaling, mitosis and cell cycling, cell motility pathways, as well as intracellular transport and metabolism, including the regulation of RNA biosynthesis (Tables I-IX).	('mitosis', 'Disease', 'None', (158, 165))	('regulation of RNA biosynthesis', 'biological_process', 'GO:2001141', ('273', '303'))	('RCC', 'Disease', (89, 92))	('metabolism', 'MPA', (247, 257))	('deregulation', 'MPA', (121, 133))	('cell-cell signaling', 'biological_process', 'GO:0007267', ('137', '156'))	('crosstalk', 'Var', (47, 56))	('cell-cell signaling', 'MPA', (137, 156))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('RNA', 'cellular_component', 'GO:0005562', ('287', '290'))	('metabolism', 'biological_process', 'GO:0008152', ('247', '257'))	('cell motility', 'CPA', (184, 197))	('intracellular transport', 'biological_process', 'GO:0046907', ('219', '242'))	('mitosis', 'biological_process', 'GO:0000278', ('158', '165'))	('cell cycling', 'CPA', (170, 182))	('intracellular transport', 'MPA', (219, 242))	('cell motility', 'biological_process', 'GO:0048870', ('184', '197'))	('mitosis', 'Disease', (158, 165))	('intracellular', 'cellular_component', 'GO:0005622', ('219', '232'))
59447	29286165	As terpenoids are useful in the prevention and therapy of several diseases, including cancer, and also have anti-spasmodic, antimicrobial, anti-parasitic, anti-fungal, anti-viral, anti-allergenic, anti-hyperglycemic, anti-inflammatory, and immunomodulatory properties, the deregulation of their transport into the cells may significantly impact RCC treatment, but may also represent a novel therapeutic target.	('terpenoids', 'Chemical', 'MESH:D013729', (3, 13))	('transport into the cells', 'MPA', (295, 319))	('men', 'Species', '9606', (354, 357))	('RCC', 'Disease', 'MESH:C538614', (345, 348))	('RCC', 'Disease', (345, 348))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('transport', 'biological_process', 'GO:0006810', ('295', '304'))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('impact', 'Reg', (338, 344))	('deregulation', 'Var', (273, 285))	('cancer', 'Disease', (86, 92))
59478	29286165	It was previously shown that signaling via the sIL-6R is often observed in chronic inflammatory disorders, such as rheumatoid arthritis, Crohn's disease and colon cancer.	('arthritis', 'Phenotype', 'HP:0001369', (126, 135))	('signaling', 'biological_process', 'GO:0023052', ('29', '38'))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (115, 135))	("Crohn's disease", 'Disease', 'MESH:D003424', (137, 152))	('sIL-6R', 'Chemical', '-', (47, 53))	('inflammatory disorders', 'Disease', 'MESH:D015212', (83, 105))	('colon cancer', 'Phenotype', 'HP:0003003', (157, 169))	('sIL-6R', 'Var', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('colon cancer', 'Disease', 'MESH:D015179', (157, 169))	('rheumatoid arthritis', 'Disease', (115, 135))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (115, 135))	('colon cancer', 'Disease', (157, 169))	("Crohn's disease", 'Phenotype', 'HP:0100280', (137, 152))	('observed', 'Reg', (63, 71))	('inflammatory disorders', 'Disease', (83, 105))	("Crohn's disease", 'Disease', (137, 152))
59479	29286165	IL-6 trans-signaling promotes pro-inflammatory pathways via the inhibition of lamina propria T-cell apoptosis, the stimulation of enhanced IEC proliferation and maintenance of the TH17 phenotype in inflamed tissues.	('signaling', 'biological_process', 'GO:0023052', ('11', '20'))	('lamina propria T-cell apoptosis', 'CPA', (78, 109))	('IL-6', 'molecular_function', 'GO:0005138', ('0', '4'))	('enhanced', 'PosReg', (130, 138))	('promotes', 'PosReg', (21, 29))	('IEC proliferation', 'CPA', (139, 156))	('TH17 phenotype', 'CPA', (180, 194))	('IL-6', 'Gene', '3570', (0, 4))	('IL-6', 'Gene', (0, 4))	('inhibition', 'NegReg', (64, 74))	('T-cell apoptosis', 'biological_process', 'GO:0070231', ('93', '109'))	('pro-inflammatory pathways', 'Pathway', (30, 55))	('trans-signaling', 'Var', (5, 20))
59484	29286165	These authors also claimed that this may be an additional mechanism by which IL6 signaling influences the progression of ovarian cancer, and they suggest that blocking LY75 may be a beneficial clinical strategy for inhibiting the early metastasis of cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('IL6', 'Gene', '3569', (77, 80))	('ovarian cancer', 'Disease', (121, 135))	('IL6', 'molecular_function', 'GO:0005138', ('77', '80'))	('signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('ovarian cancer', 'Phenotype', 'HP:0100615', (121, 135))	('blocking', 'Var', (159, 167))	('metastasis of cancer', 'Disease', (236, 256))	('LY75', 'Gene', '4065', (168, 172))	('ovarian cancer', 'Disease', 'MESH:D010051', (121, 135))	('metastasis of cancer', 'Disease', 'MESH:D009362', (236, 256))	('influences', 'Reg', (91, 101))	('LY75', 'Gene', (168, 172))	('inhibiting', 'NegReg', (215, 225))	('IL6', 'Gene', (77, 80))
59496	29286165	The deregulated genes are implicated in invasion and metastasis in other cancer types.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('invasion', 'CPA', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('implicated', 'Reg', (26, 36))	('deregulated', 'Var', (4, 15))
59515	28418903	Pharmacologic inhibition of FAK1 with GSK2256098 suppresses in vitro tumor phenotypes.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('FAK', 'molecular_function', 'GO:0004717', ('28', '31'))	('GSK2256098', 'Chemical', 'MESH:C000600809', (38, 48))	('FAK1', 'Gene', '5747', (28, 32))	('tumor', 'Disease', (69, 74))	('GSK', 'molecular_function', 'GO:0050321', ('38', '41'))	('FAK1', 'Gene', (28, 32))	('inhibition', 'Var', (14, 24))	('GSK2256098', 'Var', (38, 48))	('suppresses', 'NegReg', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
59516	28418903	In turn, FAK1 knockdown in RCC cells suppresses both in vitro phenotypes and in vivo tumor growth.	('tumor', 'Disease', (85, 90))	('FAK1', 'Gene', (9, 13))	('suppresses', 'NegReg', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('FAK', 'molecular_function', 'GO:0004717', ('9', '12'))	('FAK1', 'Gene', '5747', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('knockdown', 'Var', (14, 23))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))
59529	28418903	The peptide with the highest phosphorylation by metastatic tumor lysates is derived from FGF receptor (FGFR)-1 with the phosphorylation site corresponding to tyrosine residue 766 (Y766).	('tyrosine residue 766', 'Var', (158, 178))	('FGFR', 'molecular_function', 'GO:0005007', ('103', '107'))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('phosphorylation', 'biological_process', 'GO:0016310', ('29', '44'))	('FGFR)-1', 'Gene', (103, 110))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('phosphorylation', 'biological_process', 'GO:0016310', ('120', '135'))	('tyrosine', 'Chemical', 'MESH:D014443', (158, 166))	('phosphorylation', 'MPA', (29, 44))
59530	28418903	There are 7 autophosphorylation sites in FGFR1, Y463 (juxtamembrane), Y583/Y585 (kinase insert), Y653/Y654 (the activation loop), Y730 (kinase domain) and Y766 (C-terminal tail).	('juxtamembrane', 'cellular_component', 'GO:0009898', ('54', '67'))	('Y730', 'Var', (130, 134))	('juxtamembrane', 'cellular_component', 'GO:0005886', ('54', '67'))	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('juxtamembrane', 'cellular_component', 'GO:0009897', ('54', '67'))	('juxtamembrane', 'cellular_component', 'GO:0019897', ('54', '67'))	('Y463', 'Var', (48, 52))	('Y766', 'Var', (155, 159))	('Y583/Y585', 'Var', (70, 79))	('FGFR1', 'Gene', (41, 46))	('FGFR1', 'Gene', '2260', (41, 46))	('Y653/Y654', 'Var', (97, 106))
59532	28418903	For example, upon phosphorylation the C-terminal Y766 binds PLCgamma and Shb, which leads to recruitment of FRS2.	('Y766', 'Var', (49, 53))	('Shb', 'Gene', (73, 76))	('FRS2', 'Gene', (108, 112))	('recruitment', 'MPA', (93, 104))	('PLCgamma', 'Protein', (60, 68))	('Shb', 'Gene', '6461', (73, 76))	('binds', 'Interaction', (54, 59))	('FRS2', 'Gene', '10818', (108, 112))	('leads to', 'Reg', (84, 92))	('phosphorylation', 'biological_process', 'GO:0016310', ('18', '33'))
59537	28418903	Several sites of tyrosine phosphorylation have been identified in FAK which serve to modulate FAK kinase activity or mediate FAK interaction with SH2-domain containing proteins, including the major autophosphorylation site Y397 essential for the majority of FAK functions.	('FAK', 'Gene', (258, 261))	('FAK', 'Gene', (66, 69))	('modulate', 'Reg', (85, 93))	('FAK', 'Gene', '5747', (125, 128))	('kinase activity', 'molecular_function', 'GO:0016301', ('98', '113'))	('FAK', 'Gene', '5747', (258, 261))	('FAK', 'Gene', '5747', (66, 69))	('FAK', 'molecular_function', 'GO:0004717', ('94', '97'))	('FAK', 'molecular_function', 'GO:0004717', ('125', '128'))	('phosphorylation', 'biological_process', 'GO:0016310', ('26', '41'))	('FAK', 'molecular_function', 'GO:0004717', ('258', '261'))	('tyrosine', 'Chemical', 'MESH:D014443', (17, 25))	('Y397', 'Var', (223, 227))	('interaction', 'Interaction', (129, 140))	('FAK', 'Gene', (94, 97))	('FAK', 'molecular_function', 'GO:0004717', ('66', '69'))	('activity', 'MPA', (105, 113))	('FAK', 'Gene', '5747', (94, 97))	('FAK', 'Gene', (125, 128))
59538	28418903	FAK auto-phosphorylation at Y397 leads to binding of Src-family kinases to the phosphorylated site and subsequent Src-mediated phosphorylation of the FAK kinase domain activation loop (Y576/577 culminating in the formation of an activated FAK-Src complex.	('FAK', 'molecular_function', 'GO:0004717', ('150', '153'))	('leads to', 'Reg', (33, 41))	('FAK', 'molecular_function', 'GO:0004717', ('239', '242'))	('FAK', 'molecular_function', 'GO:0004717', ('0', '3'))	('formation', 'biological_process', 'GO:0009058', ('213', '222'))	('Src', 'Gene', (53, 56))	('Src', 'Gene', (243, 246))	('phosphorylation', 'biological_process', 'GO:0016310', ('127', '142'))	('Y576/577', 'Var', (185, 193))	('FAK', 'Gene', (239, 242))	('FAK', 'Gene', (150, 153))	('binding', 'Interaction', (42, 49))	('FAK', 'Gene', (0, 3))	('Src', 'Gene', (114, 117))	('binding', 'molecular_function', 'GO:0005488', ('42', '49'))	('Src', 'Gene', '6714', (53, 56))	('Src', 'Gene', '6714', (243, 246))	('phosphorylation', 'biological_process', 'GO:0016310', ('9', '24'))	('FAK', 'Gene', '5747', (239, 242))	('FAK', 'Gene', '5747', (150, 153))	('FAK', 'Gene', '5747', (0, 3))	('Src', 'Gene', '6714', (114, 117))
59544	28418903	While FAK1 activation is associated with FAK1 autophosphorylation at Y397 and subsequent FAK1 phosphorylation at residues Y576 and Y577, it is also implicated in the phosphorylation of several other phosphopetides identified in the array demonstrated by the high Kinexus score and Hit % (Table 2 and Supplementary File).	('Y577', 'Var', (131, 135))	('FAK1', 'Gene', '5747', (41, 45))	('phosphorylation', 'biological_process', 'GO:0016310', ('94', '109'))	('FAK', 'molecular_function', 'GO:0004717', ('6', '9'))	('FAK1', 'Gene', '5747', (89, 93))	('FAK1', 'Gene', (41, 45))	('FAK', 'molecular_function', 'GO:0004717', ('41', '44'))	('FAK1', 'Gene', (89, 93))	('FAK1', 'Gene', (6, 10))	('phosphorylation', 'MPA', (94, 109))	('FAK', 'molecular_function', 'GO:0004717', ('89', '92'))	('phosphorylation', 'MPA', (166, 181))	('activation', 'PosReg', (11, 21))	('phosphorylation', 'biological_process', 'GO:0016310', ('166', '181'))	('autophosphorylation', 'MPA', (46, 65))	('FAK1', 'Gene', '5747', (6, 10))
59552	28418903	As noted, Y397 is an autocatalytic site of FAK1 and phosphorylation at this residue is associated with higher FAK1 kinase activity.	('FAK1', 'Gene', '5747', (43, 47))	('FAK1', 'Gene', (43, 47))	('kinase activity', 'MPA', (115, 130))	('FAK1', 'Gene', '5747', (110, 114))	('FAK', 'molecular_function', 'GO:0004717', ('43', '46'))	('FAK1', 'Gene', (110, 114))	('FAK', 'molecular_function', 'GO:0004717', ('110', '113'))	('kinase activity', 'molecular_function', 'GO:0016301', ('115', '130'))	('higher', 'PosReg', (103, 109))	('Y397', 'Var', (10, 14))	('phosphorylation', 'biological_process', 'GO:0016310', ('52', '67'))	('phosphorylation', 'MPA', (52, 67))
59555	28418903	Treatment of 786-O and RXF-393 cells with GSK2256098 resulted in a dose-dependent decrease in Y397 phosphorylation without effects on total FAK1 levels (Figure 2B).	('Y397 phosphorylation', 'MPA', (94, 114))	('FAK1', 'Gene', '5747', (140, 144))	('GSK2256098', 'Chemical', 'MESH:C000600809', (42, 52))	('decrease', 'NegReg', (82, 90))	('RXF-393', 'CellLine', 'CVCL:1673', (23, 30))	('FAK', 'molecular_function', 'GO:0004717', ('140', '143'))	('FAK1', 'Gene', (140, 144))	('GSK2256098', 'Var', (42, 52))	('GSK', 'molecular_function', 'GO:0050321', ('42', '45'))	('phosphorylation', 'biological_process', 'GO:0016310', ('99', '114'))
59556	28418903	We measured the change in the proliferative rates of RCC cells in response to GSK2256098.	('GSK2256098', 'Chemical', 'MESH:C000600809', (78, 88))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('proliferative rates', 'CPA', (30, 49))	('GSK', 'molecular_function', 'GO:0050321', ('78', '81'))	('GSK2256098', 'Var', (78, 88))
59557	28418903	786-O and RXF393 cells treated with GSK2256098 demonstrated reduced proliferation relative to untreated cells (Figure 2C).	('proliferation', 'CPA', (68, 81))	('GSK', 'molecular_function', 'GO:0050321', ('36', '39'))	('GSK2256098', 'Var', (36, 46))	('reduced', 'NegReg', (60, 67))	('RXF393', 'CellLine', 'CVCL:1673', (10, 16))	('GSK2256098', 'Chemical', 'MESH:C000600809', (36, 46))
59558	28418903	To assess the effect of inhibiting FAK kinase activity on the clonogenic potential of these cells, we performed a colony formation assay in 786-O and RXF393 cells in the presence of increasing concentrations of GSK2256098 and compared the results to vehicle treated cells.	('GSK', 'molecular_function', 'GO:0050321', ('211', '214'))	('FAK', 'molecular_function', 'GO:0004717', ('35', '38'))	('RXF393', 'CellLine', 'CVCL:1673', (150, 156))	('GSK2256098', 'Var', (211, 221))	('kinase activity', 'molecular_function', 'GO:0016301', ('39', '54'))	('FAK', 'Gene', (35, 38))	('FAK', 'Gene', '5747', (35, 38))	('GSK2256098', 'Chemical', 'MESH:C000600809', (211, 221))	('colony formation assay', 'CPA', (114, 136))	('formation', 'biological_process', 'GO:0009058', ('121', '130'))
59559	28418903	GSK2256098 treatment resulted in a concentration-dependent decrease in colony formation (Figure 2D).	('formation', 'biological_process', 'GO:0009058', ('78', '87'))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('GSK2256098', 'Chemical', 'MESH:C000600809', (0, 10))	('colony formation', 'CPA', (71, 87))	('decrease', 'NegReg', (59, 67))	('GSK2256098', 'Var', (0, 10))
59561	28418903	We therefore tested the effects on GSK2256098 on RCC migration via wound healing assay as previously described.	('GSK2256098', 'Var', (35, 45))	('RCC', 'Disease', (49, 52))	('GSK', 'molecular_function', 'GO:0050321', ('35', '38'))	('GSK2256098', 'Chemical', 'MESH:C000600809', (35, 45))	('tested', 'Reg', (13, 19))	('wound healing', 'biological_process', 'GO:0042060', ('67', '80'))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
59562	28418903	Inhibition of FAK kinase activity by GSK2256098 decreased wound healing in both 786-O and RXF-393 cells (Figure 2E and Supplementary Figure 1).	('wound healing', 'CPA', (58, 71))	('Inhibition', 'NegReg', (0, 10))	('wound healing', 'biological_process', 'GO:0042060', ('58', '71'))	('FAK', 'Gene', '5747', (14, 17))	('kinase activity', 'molecular_function', 'GO:0016301', ('18', '33'))	('GSK2256098', 'Var', (37, 47))	('decreased', 'NegReg', (48, 57))	('GSK2256098', 'Chemical', 'MESH:C000600809', (37, 47))	('RXF-393', 'CellLine', 'CVCL:1673', (90, 97))	('FAK', 'molecular_function', 'GO:0004717', ('14', '17'))	('FAK', 'Gene', (14, 17))	('decreased wound healing', 'Phenotype', 'HP:0001058', (48, 71))	('GSK', 'molecular_function', 'GO:0050321', ('37', '40'))	('activity', 'MPA', (25, 33))
59563	28418903	Importantly, FAK1 inhibition reduced wound healing at relatively low doses of GSK2256098.	('GSK2256098', 'Chemical', 'MESH:C000600809', (78, 88))	('inhibition reduced', 'NegReg', (18, 36))	('FAK1', 'Gene', (13, 17))	('wound healing', 'biological_process', 'GO:0042060', ('37', '50'))	('GSK', 'molecular_function', 'GO:0050321', ('78', '81'))	('reduced wound healing', 'Phenotype', 'HP:0001058', (29, 50))	('GSK2256098', 'Var', (78, 88))	('FAK', 'molecular_function', 'GO:0004717', ('13', '16'))	('wound healing', 'CPA', (37, 50))	('FAK1', 'Gene', '5747', (13, 17))
59569	28418903	In contrast, both FAK1 knockdown clones demonstrated reduced colony formation relative to control vector cells (Figure 3C).	('FAK1', 'Gene', '5747', (18, 22))	('knockdown', 'Var', (23, 32))	('reduced', 'NegReg', (53, 60))	('colony formation', 'CPA', (61, 77))	('FAK', 'molecular_function', 'GO:0004717', ('18', '21'))	('formation', 'biological_process', 'GO:0009058', ('68', '77'))	('FAK1', 'Gene', (18, 22))
59570	28418903	In addition, FAK1 knockdown in RCC cells reduced wound healing (Figure 3D and Supplementary Figure 2).	('knockdown', 'Var', (18, 27))	('reduced', 'NegReg', (41, 48))	('FAK1', 'Gene', '5747', (13, 17))	('reduced wound healing', 'Phenotype', 'HP:0001058', (41, 62))	('FAK', 'molecular_function', 'GO:0004717', ('13', '16'))	('FAK1', 'Gene', (13, 17))	('wound healing', 'CPA', (49, 62))	('wound healing', 'biological_process', 'GO:0042060', ('49', '62'))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))
59587	28418903	Indeed, FAK1 inhibition using GSK2256098 suppressed in vitro ccRCC cell line proliferation and FAK1 knockdown in ccRCC cells suppressed both in vitro and in vivo tumor growth.	('tumor', 'Disease', (162, 167))	('suppressed', 'NegReg', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('knockdown', 'Var', (100, 109))	('FAK', 'molecular_function', 'GO:0004717', ('95', '98'))	('RCC', 'Disease', (115, 118))	('suppressed', 'NegReg', (125, 135))	('inhibition', 'NegReg', (13, 23))	('FAK1', 'Gene', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('FAK1', 'Gene', (95, 99))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('FAK', 'molecular_function', 'GO:0004717', ('8', '11'))	('FAK1', 'Gene', '5747', (8, 12))	('GSK', 'molecular_function', 'GO:0050321', ('30', '33'))	('FAK1', 'Gene', '5747', (95, 99))	('RCC', 'Disease', (63, 66))	('GSK2256098', 'Chemical', 'MESH:C000600809', (30, 40))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
59591	28418903	In addition to suggesting the potential importance of FGFR1 and FAK1 inhibitors in metastatic disease, these agents may also warrant investigation as adjuvant therapy following surgical resection of localized high-risk disease to prevent metastasis.	('inhibitors', 'Var', (69, 79))	('FAK', 'molecular_function', 'GO:0004717', ('64', '67'))	('FGFR', 'molecular_function', 'GO:0005007', ('54', '58'))	('FGFR1', 'Gene', (54, 59))	('FAK1', 'Gene', (64, 68))	('FGFR1', 'Gene', '2260', (54, 59))	('metastatic disease', 'Disease', (83, 101))	('FAK1', 'Gene', '5747', (64, 68))
59609	28418903	In particular, FGFR1 and FAK1 warrant special attention, given that inhibition of these kinases has already demonstrated preclinical or clinical activity in RCC or other malignancies.	('malignancies', 'Disease', (170, 182))	('FGFR1', 'Gene', '2260', (15, 20))	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('inhibition', 'Var', (68, 78))	('FAK1', 'Gene', (25, 29))	('FAK', 'molecular_function', 'GO:0004717', ('25', '28'))	('malignancies', 'Disease', 'MESH:D009369', (170, 182))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', (157, 160))	('FGFR1', 'Gene', (15, 20))	('FAK1', 'Gene', '5747', (25, 29))
59630	28418903	RCC cells were treated with increasing concentrations of GSK2256098 (GlaxoSmithKline), a small molecule FAK1 inhibitor, for variable lengths of time to determine toxic concentrations of the drug.	('FAK1', 'Gene', '5747', (104, 108))	('FAK', 'molecular_function', 'GO:0004717', ('104', '107'))	('FAK1', 'Gene', (104, 108))	('GSK2256098', 'Var', (57, 67))	('GSK2256098', 'Chemical', 'MESH:C000600809', (57, 67))	('GSK', 'molecular_function', 'GO:0050321', ('57', '60'))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('RCC', 'Disease', (0, 3))
59637	28418903	Antibodies were obtained from the following sources: phospho-FAK1 (Y397) and total FAK1 (Invitrogen); Actin (Sigma).	('FAK1', 'Gene', '5747', (83, 87))	('FAK', 'molecular_function', 'GO:0004717', ('61', '64'))	('FAK1', 'Gene', (61, 65))	('FAK', 'molecular_function', 'GO:0004717', ('83', '86'))	('Y397', 'Var', (67, 71))	('FAK1', 'Gene', (83, 87))	('FAK1', 'Gene', '5747', (61, 65))
59761	30262800	TIGIT is a new immunomodulatory molecule and has the following characteristics: (1) TIGIT is an immunosuppressive molecule of effector T cells and can antagonize the CD226 mediated costimulatory signals.	('CD226', 'Gene', '10666', (166, 171))	('TIGIT', 'Var', (84, 89))	('antagonize', 'NegReg', (151, 161))	('CD226', 'Gene', (166, 171))
59770	30262800	After CD155 stimulates human NK cells, the Tyr225 close to the ITIM motif in the tail of TIGIT in the cytoplasm is phosphorylated and then binds to adapter protein Grb2.	('Grb2', 'Gene', (164, 168))	('CD155', 'Gene', '5817', (6, 11))	('cytoplasm', 'cellular_component', 'GO:0005737', ('102', '111'))	('binds', 'Interaction', (139, 144))	('Grb2', 'Gene', '2885', (164, 168))	('Tyr225', 'Var', (43, 49))	('Tyr225', 'Chemical', '-', (43, 49))	('human', 'Species', '9606', (23, 28))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('CD155', 'Gene', (6, 11))
59822	28991235	Mutation of these binding sites or circRNA knockdown resulted in less pull-down of p53 with an MDM2 antibody and vice versa supporting the notion that circFoxo3 can function as a protein scaffold.	('binding', 'molecular_function', 'GO:0005488', ('18', '25'))	('circFoxo3', 'Chemical', '-', (151, 160))	('antibody', 'molecular_function', 'GO:0003823', ('100', '108'))	('antibody', 'cellular_component', 'GO:0019815', ('100', '108'))	('Mutation', 'Var', (0, 8))	('antibody', 'cellular_component', 'GO:0042571', ('100', '108'))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('less', 'NegReg', (65, 69))	('pull-down', 'MPA', (70, 79))	('antibody', 'cellular_component', 'GO:0019814', ('100', '108'))	('p53', 'Protein', (83, 86))
59826	28991235	Thus perturbation of the balance between circular and linear splicing could promote aberrant transcription of oncogenes and tumor-suppressor genes.	('transcription', 'biological_process', 'GO:0006351', ('93', '106'))	('promote', 'PosReg', (76, 83))	('tumor-suppressor', 'Gene', (124, 140))	('oncogenes', 'Gene', (110, 119))	('splicing', 'biological_process', 'GO:0045292', ('61', '69'))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('perturbation', 'Var', (5, 17))	('aberrant transcription', 'MPA', (84, 106))	('tumor-suppressor', 'Gene', '7248', (124, 140))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('124', '140'))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('124', '140'))
59833	28991235	Unlike circFoxo3, circRNAs derived from TTBK2 and UBAP2 have been shown to inhibit apoptosis, and similar to circFoxo3, circZNF292 has been shown to have tumor-suppressor properties by negatively regulating cell cycle progression.	('TTBK2', 'Gene', '146057', (40, 45))	('tumor-suppressor', 'Gene', (154, 170))	('negatively', 'NegReg', (185, 195))	('cell cycle', 'biological_process', 'GO:0007049', ('207', '217'))	('circFoxo3', 'Chemical', '-', (7, 16))	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('circFoxo3', 'Chemical', '-', (109, 118))	('apoptosis', 'CPA', (83, 92))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('154', '170'))	('inhibit', 'NegReg', (75, 82))	('UBAP2', 'Gene', '55833', (50, 55))	('circZNF292', 'Var', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('154', '170'))	('UBAP2', 'Gene', (50, 55))	('TTBK2', 'Gene', (40, 45))	('tumor-suppressor', 'Gene', '7248', (154, 170))	('cell cycle progression', 'CPA', (207, 229))
59841	28991235	Finally, aberrant expression of several circRNAs have been associated with a late-stage diagnosis and metastases, and a few (circZKSCAN1, circCCDC66, circKCNH1 and circHIAT1) have been shown to affect metastasis both in vitro and in vivo.	('KCNH1', 'Gene', (154, 159))	('circHIAT1', 'Disease', (164, 173))	('ZKSCAN1', 'Gene', '7586', (129, 136))	('metastasis', 'CPA', (201, 211))	('circHIAT1', 'Disease', 'None', (164, 173))	('CCDC66', 'Gene', (142, 148))	('metastases', 'Disease', 'MESH:D009362', (102, 112))	('affect', 'Reg', (194, 200))	('CCDC66', 'Gene', '285331', (142, 148))	('associated', 'Reg', (59, 69))	('metastases', 'Disease', (102, 112))	('ZKSCAN1', 'Gene', (129, 136))	('aberrant expression', 'Var', (9, 28))	('KCNH1', 'Gene', '3756', (154, 159))
59842	28991235	It is likely that many more circRNAs are involved in the hallmarks of cancer as many studies have shown an effect of circRNA knockdown or overexpression on proliferation rates of cancer cells in culture without exploring the molecular mechanisms behind.	('knockdown', 'Var', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('hallmarks of cancer', 'Disease', (57, 76))	('involved', 'Reg', (41, 49))	('proliferation rates', 'CPA', (156, 175))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', (179, 185))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (57, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
59855	28991235	Most interestingly, a circRNA derived from TCF25 was observed to promote proliferation and migration of bladder cancer cells by sponging miR-103a-3p and miR-107.	('bladder cancer', 'Disease', (104, 118))	('miR-107', 'Gene', '406901', (153, 160))	('sponging', 'Var', (128, 136))	('TCF25', 'Gene', '22980', (43, 48))	('proliferation', 'CPA', (73, 86))	('TCF25', 'Gene', (43, 48))	('miR-107', 'Gene', (153, 160))	('miR-103a-3p', 'Var', (137, 148))	('promote', 'PosReg', (65, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (104, 118))	('migration', 'CPA', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (104, 118))
59884	28991235	Overexpression of ciRS-7 was shown to be a risk factor for hepatic microvascular invasion and was inversely correlated with miR-7 expression in a study including 108 patients.	('expression', 'MPA', (130, 140))	('hepatic microvascular', 'Disease', (59, 80))	('risk', 'Reg', (43, 47))	('miR-7', 'Gene', (124, 129))	('ciRS-7', 'Gene', '103611090', (18, 24))	('miR-7', 'Gene', '10859', (124, 129))	('Overexpression', 'Var', (0, 14))	('ciRS-7', 'Gene', (18, 24))	('patients', 'Species', '9606', (166, 174))
59913	28991235	To their surprise, they found hundreds of genes that produced circRNAs in the ALL patient samples.	('produced', 'Reg', (53, 61))	('genes', 'Var', (42, 47))	('ALL', 'Phenotype', 'HP:0006721', (78, 81))	('patient', 'Species', '9606', (82, 89))
59920	28991235	As illustrated above, deregulation of circRNAs may influence proliferative signaling, epithelial-to-mesenchymal transition, angiogenesis, apoptosis or drug resistance and, in this manner, directly have a causative role in the development of cancer.	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('causative', 'Reg', (204, 213))	('drug resistance', 'CPA', (151, 166))	('proliferative signaling', 'CPA', (61, 84))	('angiogenesis', 'biological_process', 'GO:0001525', ('124', '136'))	('apoptosis', 'CPA', (138, 147))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('86', '122'))	('deregulation', 'Var', (22, 34))	('circRNAs', 'Gene', (38, 46))	('angiogenesis', 'CPA', (124, 136))	('drug resistance', 'biological_process', 'GO:0009315', ('151', '166'))	('epithelial-to-mesenchymal transition', 'CPA', (86, 122))	('drug resistance', 'biological_process', 'GO:0042493', ('151', '166'))	('drug resistance', 'Phenotype', 'HP:0020174', (151, 166))	('apoptosis', 'biological_process', 'GO:0097194', ('138', '147'))	('apoptosis', 'biological_process', 'GO:0006915', ('138', '147'))	('cancer', 'Disease', (241, 247))	('influence', 'Reg', (51, 60))
59941	28991235	Here methylation and downregulation of many tumor-suppressor genes were discovered before much was known about what was causing these aberrant epigenetic changes.	('tumor-suppressor', 'Gene', '7248', (44, 60))	('methylation', 'Var', (5, 16))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('44', '60'))	('downregulation', 'NegReg', (21, 35))	('tumor-suppressor', 'Gene', (44, 60))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('44', '60'))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('methylation', 'biological_process', 'GO:0032259', ('5', '16'))
59942	28991235	Only later, mutations in epigenetic regulators such as DNMT3A, TET2, IDH1, IDH2, EZH2 and ASXL1 were discovered and linked to aberrant epigenetic landscapes in cancer.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('ASXL1', 'Gene', (90, 95))	('EZH2', 'Gene', (81, 85))	('TET2', 'Gene', (63, 67))	('IDH1', 'Gene', '3417', (69, 73))	('EZH2', 'Gene', '2146', (81, 85))	('cancer', 'Disease', (160, 166))	('mutations', 'Var', (12, 21))	('ASXL1', 'Gene', '171023', (90, 95))	('IDH2', 'Gene', (75, 79))	('epigenetic landscapes', 'MPA', (135, 156))	('linked to', 'Reg', (116, 125))	('TET2', 'Gene', '54790', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('IDH2', 'Gene', '3418', (75, 79))	('DNMT3A', 'Gene', (55, 61))	('DNMT3A', 'Gene', '1788', (55, 61))	('IDH1', 'Gene', (69, 73))
59944	28991235	Mutations in spliceosome genes, such as SF3B1, SRSF2 and U2AF1, are prevalent in cancer where they influence alternative splicing and miRNA expression.	('SF3B1', 'Gene', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('SRSF2', 'Gene', (47, 52))	('splicing', 'biological_process', 'GO:0045292', ('121', '129'))	('SF3B1', 'Gene', '23451', (40, 45))	('spliceosome', 'cellular_component', 'GO:0005681', ('13', '24'))	('cancer', 'Disease', (81, 87))	('influence', 'Reg', (99, 108))	('alternative splicing', 'MPA', (109, 129))	('Mutations', 'Var', (0, 9))	('U2AF1', 'Gene', (57, 62))	('U2AF1', 'Gene', '7307', (57, 62))	('prevalent', 'Reg', (68, 77))	('miRNA expression', 'MPA', (134, 150))	('SRSF2', 'Gene', '6427', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('U2AF', 'cellular_component', 'GO:0089701', ('57', '61'))
59945	28991235	Altered expression or mutation of other trans-acting factors, such as QKI, may also cause the differential expression of circRNAs observed in most human cancers.	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('QKI', 'Gene', '9444', (70, 73))	('mutation', 'Var', (22, 30))	('cancers', 'Disease', (153, 160))	('human', 'Species', '9606', (147, 152))	('circRNAs', 'Gene', (121, 129))	('differential expression', 'MPA', (94, 117))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('cause', 'Reg', (84, 89))	('QKI', 'Gene', (70, 73))
59947	28991235	Thus it is tempting to speculate that the aberrant expression of circRNAs observed in cancer may, in part, be explained by genetic and/or epigenetic changes of genes involved in their biogenesis.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('expression', 'MPA', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('epigenetic changes', 'Var', (138, 156))	('cancer', 'Disease', (86, 92))
59948	28991235	Mutations in cis regulatory elements such as inverted repeats or protein-binding motifs could, in theory, also influence circRNA expression in cancer, but this is also still an open research question that could be pursued in future.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('protein-binding', 'molecular_function', 'GO:0005515', ('65', '80'))	('Mutations', 'Var', (0, 9))	('protein-binding', 'Protein', (65, 80))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('circRNA expression', 'MPA', (121, 139))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('influence', 'Reg', (111, 120))
59949	28991235	Chemical modifications of RNA such as N6-methyladenosine, N1-methyladenosine, 5-methylcytosine, 5-hydroxymethylcytosine, pseudouridine (Psi) and inosine-to-adenine editing are central in the control of coding as well as noncoding RNA activity and stability.	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (96, 119))	('N1-methyladenosine', 'Var', (58, 76))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (38, 56))	('Psi', 'Chemical', 'MESH:D011560', (136, 139))	('N6-methyladenosine', 'Var', (38, 56))	('RNA', 'cellular_component', 'GO:0005562', ('230', '233'))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (78, 94))	('N1-methyladenosine', 'Chemical', 'MESH:C002230', (58, 76))	('pseudouridine', 'Chemical', 'MESH:D011560', (121, 134))	('RNA', 'cellular_component', 'GO:0005562', ('26', '29'))	('inosine-to-adenine', 'Chemical', '-', (145, 163))
59950	28991235	Many of the writers and erasers of these modifications are mutated or aberrantly expressed in cancer.	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('modifications', 'Var', (41, 54))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
59953	28991235	However, to our knowledge, only one study has investigated such relationships and found that the upregulation of circPVT1 in gastric cancer can be explained, in part, by genomic DNA amplification.	('gastric cancer', 'Disease', 'MESH:D013274', (125, 139))	('upregulation', 'PosReg', (97, 109))	('DNA', 'cellular_component', 'GO:0005574', ('178', '181'))	('DNA amplification', 'biological_process', 'GO:0006277', ('178', '195'))	('gastric cancer', 'Phenotype', 'HP:0012126', (125, 139))	('genomic DNA amplification', 'Var', (170, 195))	('gastric cancer', 'Disease', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('circPVT1', 'Gene', (113, 121))
59955	28991235	A preliminary study found circRNA expression and KRAS mutations to be linked in lung and colorectal cancer, and another recent study found that the oncogenic transcription factor c-Myc to regulate the expression of a large number of circRNAs.	('c-Myc', 'Gene', (179, 184))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('KRAS', 'Gene', '3845', (49, 53))	('linked', 'Reg', (70, 76))	('mutations', 'Var', (54, 63))	('colorectal cancer', 'Disease', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung', 'Disease', (80, 84))	('transcription', 'biological_process', 'GO:0006351', ('158', '171'))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('expression', 'MPA', (201, 211))	('transcription factor', 'molecular_function', 'GO:0000981', ('158', '178'))	('c-Myc', 'Gene', '4609', (179, 184))	('KRAS', 'Gene', (49, 53))
59971	28662155	While the interactions of environmental factors, genetic and epigenetic alterations on ccRCC development are still unclear, therapeutic options for ccRCCs are still limited.	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('epigenetic alterations', 'Var', (61, 83))	('RCC', 'Disease', (150, 153))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))
59973	28662155	After the human genome sequencing era, the discovery of an extremely large number of non-coding RNAs conceptually transformed cancer research.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('transformed', 'Reg', (114, 125))	('human', 'Species', '9606', (10, 15))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('non-coding RNAs', 'Var', (85, 100))
60066	31592165	High expression of RUNX1 was significantly associated with gender (p = 0.003), clinical stage (p < 0.001), tissue infiltration (p < 0.001), lymph node metastasis (p = 0.037) and histological grade (p < 0.001).	('tissue infiltration', 'CPA', (107, 126))	('clinical stage', 'CPA', (79, 93))	('High', 'Var', (0, 4))	('RUNX1', 'Gene', (19, 24))	('RUNX1', 'Gene', '861', (19, 24))	('lymph node metastasis', 'CPA', (140, 161))	('associated', 'Reg', (43, 53))
60068	31592165	Kaplan-Meier survival curves revealed that the prognosis of patients with ccRCC with high RUNX1 expression was worse than that of patients with ccRCC with low RUNX1 expression (p < 0.001).	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))	('RUNX1', 'Gene', (159, 164))	('RUNX1', 'Gene', (90, 95))	('ccRCC', 'Disease', (74, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('ccRCC', 'Disease', 'MESH:D002292', (74, 79))	('patients', 'Species', '9606', (60, 68))	('RUNX1', 'Gene', '861', (159, 164))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('RUNX1', 'Gene', '861', (90, 95))	('high', 'Var', (85, 89))	('patients', 'Species', '9606', (130, 138))	('ccRCC', 'Disease', (144, 149))	('ccRCC', 'Disease', 'MESH:D002292', (144, 149))	('expression', 'Var', (96, 106))
60069	31592165	Univariate Cox regression analysis showed that high RUNX1 expression was strongly correlated with poor prognosis (HR = 1.60, 95% CI [1.31-1.97], p < 0.001).	('RUNX1', 'Gene', (52, 57))	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('expression', 'MPA', (58, 68))	('high', 'Var', (47, 51))	('RUNX1', 'Gene', '861', (52, 57))
60070	31592165	In addition, high expression of RUNX1 was an independent prognostic factor for poor overall survival (OS), with an HR of 1.50 (95% CI [1.20-1.87], p < 0.001) in multivariate Cox analysis.	('Cox', 'Gene', '1351', (174, 177))	('Cox', 'Gene', (174, 177))	('RUNX1', 'Gene', (32, 37))	('high expression', 'Var', (13, 28))	('overall survival', 'MPA', (84, 100))	('RUNX1', 'Gene', '861', (32, 37))	('poor', 'NegReg', (79, 83))
60081	31592165	In the ER+ subtype of breast cancer, RUNX1 has been implicated as a tumour suppressor through the stabilization of Axis inhibition protein 1 (AXIN1) expression, but high RUNX1 expression correlates with poor prognosis in triple-negative breast cancers.	('RUNX1', 'Gene', (37, 42))	('AXIN1', 'Gene', (142, 147))	('expression', 'MPA', (176, 186))	('RUNX1', 'Gene', '861', (37, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('RUNX1', 'Gene', (170, 175))	('RUNX1', 'Gene', '861', (170, 175))	('high', 'Var', (165, 169))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('tumour', 'Disease', (68, 74))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))	('breast cancer', 'Disease', (22, 35))	('AXIN1', 'Gene', '8312', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Axis inhibition protein 1', 'Gene', '8312', (115, 140))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('breast cancers', 'Disease', 'MESH:D001943', (237, 251))	('breast cancers', 'Disease', (237, 251))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('Axis inhibition protein 1', 'Gene', (115, 140))	('breast cancers', 'Phenotype', 'HP:0003002', (237, 251))
60082	31592165	Additionally, loss of RUNX1 resulted in enhanced proliferation, migration, and invasion in lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('loss', 'Var', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('proliferation', 'CPA', (49, 62))	('RUNX1', 'Gene', (22, 27))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('RUNX1', 'Gene', '861', (22, 27))	('invasion', 'CPA', (79, 87))	('migration', 'CPA', (64, 73))	('enhanced', 'PosReg', (40, 48))	('lung cancer', 'Disease', (91, 102))
60102	31592165	2A-2E, high expression of RUNX1 was significantly associated with gender (p = 0.003), clinical stage (p < 0.001), tissue infiltration (p < 0.001), lymph node metastasis (p = 0.037) and histological grade (p < 0.001).	('clinical stage', 'CPA', (86, 100))	('RUNX1', 'Gene', (26, 31))	('high expression', 'Var', (7, 22))	('RUNX1', 'Gene', '861', (26, 31))	('lymph node metastasis', 'CPA', (147, 168))	('associated', 'Reg', (50, 60))	('tissue infiltration', 'CPA', (114, 133))
60103	31592165	The logistic regression analysis results showed that high RUNX1 expression was significantly correlated with gender (odds ratio [OR] = 1.71 for male vs. female, p = 0.004), histologic grade (OR = 11.61 for grade IV vs.	('RUNX1', 'Gene', (58, 63))	('expression', 'MPA', (64, 74))	('high', 'Var', (53, 57))	('RUNX1', 'Gene', '861', (58, 63))
60104	31592165	Kaplan-Meier survival curves revealed that the prognosis of patients with ccRCC with high RUNX1 expression was worse than that of patients with ccRCC with low RUNX1 expression (p < 0.001) (Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))	('RUNX1', 'Gene', (159, 164))	('RUNX1', 'Gene', (90, 95))	('ccRCC', 'Disease', (74, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('ccRCC', 'Disease', 'MESH:D002292', (74, 79))	('patients', 'Species', '9606', (60, 68))	('RUNX1', 'Gene', '861', (159, 164))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('RUNX1', 'Gene', '861', (90, 95))	('high', 'Var', (85, 89))	('patients', 'Species', '9606', (130, 138))	('ccRCC', 'Disease', (144, 149))	('ccRCC', 'Disease', 'MESH:D002292', (144, 149))	('expression', 'Var', (96, 106))
60105	31592165	The univariate Cox regression analysis results showed that high RUNX1 expression was strongly correlated with poor prognosis (hazard ratio [HR] = 1.60, 95% confidence interval CI [1.31-1.97], p < 0.001; Table 3A).	('high', 'Var', (59, 63))	('expression', 'MPA', (70, 80))	('RUNX1', 'Gene', (64, 69))	('Cox', 'Gene', '1351', (15, 18))	('RUNX1', 'Gene', '861', (64, 69))	('Cox', 'Gene', (15, 18))
60106	31592165	Moreover, in multivariate analysis, high expression of RUNX1 (HR =1.50, 95% CI [1.20-1.87], p < 0.001), age (HR =1.03, 95% CI [1.01-1.05], p = 0.002) and distant metastasis (HR =2.42, 95% CI [1.14-5.16], p = 0.022) still implied a poor prognosis (Table 3A).	('RUNX1', 'Gene', (55, 60))	('distant metastasis', 'CPA', (154, 172))	('high', 'Var', (36, 40))	('RUNX1', 'Gene', '861', (55, 60))
60108	31592165	GSEA was conducted to identify the differentially activated signalling pathways in the high RUNX1 expression ccRCC data sets.	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('RUNX1', 'Gene', (92, 97))	('ccRCC', 'Disease', (109, 114))	('RUNX1', 'Gene', '861', (92, 97))	('high', 'Var', (87, 91))	('ccRCC', 'Disease', 'MESH:D002292', (109, 114))	('signalling', 'biological_process', 'GO:0023052', ('60', '70'))
60111	31592165	Researchers have demonstrated differential expression of RUNX1 in several cancers, and deregulation of RUNX1 correlates with tumour progression, which could ultimately lead to its dual role.	('RUNX1', 'Gene', '861', (103, 108))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('deregulation', 'Var', (87, 99))	('cancers', 'Disease', (74, 81))	('RUNX1', 'Gene', (57, 62))	('RUNX1', 'Gene', '861', (57, 62))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('tumour', 'Disease', (125, 131))	('RUNX1', 'Gene', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
60116	31592165	RUNX1 has been shown to be androgen-dependent, and loss of RUNX1 may contribute to prostate cancer progression.	('contribute', 'Reg', (69, 79))	('loss', 'Var', (51, 55))	('prostate cancer', 'Disease', 'MESH:D011471', (83, 98))	('prostate cancer', 'Phenotype', 'HP:0012125', (83, 98))	('androgen', 'Chemical', 'MESH:D000728', (27, 35))	('RUNX1', 'Gene', (0, 5))	('prostate cancer', 'Disease', (83, 98))	('RUNX1', 'Gene', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('RUNX1', 'Gene', '861', (0, 5))	('RUNX1', 'Gene', '861', (59, 64))
60125	31592165	RUNX1 gene silencing induces p53-promoted core binding factor-beta (CBFB) expression, and upregulated CBFB stabilizes RUNX1 expression in acute myeloid leukaemia cells, resulting in a compensatory RUNX1-p53-CBFB feedback loop.	('core binding', 'MPA', (42, 54))	('myeloid leukaemia', 'Disease', (144, 161))	('CBFB', 'Gene', '865', (207, 211))	('RUNX1', 'Gene', (118, 123))	('RUNX1', 'Gene', (197, 202))	('RUNX1', 'Gene', '861', (118, 123))	('gene silencing', 'Var', (6, 20))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (138, 161))	('gene silencing', 'biological_process', 'GO:0016458', ('6', '20'))	('RUNX1', 'Gene', '861', (197, 202))	('CBFB', 'Gene', (68, 72))	('expression', 'MPA', (74, 84))	('p53', 'Gene', (203, 206))	('CBFB', 'Gene', '865', (102, 106))	('upregulated', 'PosReg', (90, 101))	('induces', 'PosReg', (21, 28))	('CBFB', 'Gene', '865', (68, 72))	('CBFB', 'Gene', (207, 211))	('RUNX1', 'Gene', (0, 5))	('p53', 'Gene', '7157', (29, 32))	('RUNX1', 'Gene', '861', (0, 5))	('p53', 'Gene', '7157', (203, 206))	('p53', 'Gene', (29, 32))	('core', 'cellular_component', 'GO:0019013', ('42', '46'))	('binding', 'molecular_function', 'GO:0005488', ('47', '54'))	('expression', 'MPA', (124, 134))	('myeloid leukaemia', 'Disease', 'MESH:D007951', (144, 161))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (144, 161))	('CBFB', 'Gene', (102, 106))
60140	32468053	The analysis of the enriched pathway results suggested that SALL4 may act via translation initiation, and that the related genes promoted the progression of RCC.	('SALL4', 'Gene', '57167', (60, 65))	('promoted', 'PosReg', (129, 137))	('SALL4', 'Gene', (60, 65))	('translation initiation', 'biological_process', 'GO:0006413', ('78', '100'))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('genes', 'Var', (123, 128))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', (157, 160))	('progression', 'CPA', (142, 153))
60144	32468053	Furthermore, targeting of SALL4 may improve RCC therapy and prolong the survival of patients with ccRCC or pRCC.	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('pRCC', 'Phenotype', 'HP:0006766', (107, 111))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('survival', 'CPA', (72, 80))	('prolong', 'NegReg', (60, 67))	('pRCC', 'Gene', (107, 111))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('patients', 'Species', '9606', (84, 92))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('improve', 'PosReg', (36, 43))	('SALL4', 'Gene', '57167', (26, 31))	('pRCC', 'Gene', '5546', (107, 111))	('SALL4', 'Gene', (26, 31))	('targeting', 'Var', (13, 22))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
60210	32468053	Therefore, the present results suggested that patients with pRCC and low SALL4 mRNA expression have a longer survival time compared with patients with high SALL4 expression.	('SALL4', 'Gene', '57167', (156, 161))	('survival time', 'CPA', (109, 122))	('patients', 'Species', '9606', (46, 54))	('SALL4', 'Gene', (73, 78))	('pRCC', 'Gene', (60, 64))	('longer', 'PosReg', (102, 108))	('SALL4', 'Gene', (156, 161))	('patients', 'Species', '9606', (137, 145))	('pRCC', 'Phenotype', 'HP:0006766', (60, 64))	('pRCC', 'Gene', '5546', (60, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('low', 'Var', (69, 72))	('SALL4', 'Gene', '57167', (73, 78))
60252	32468053	An invasion assay was performed in OSRC-2 cells, and the results indicated that knockdown of SALL4 decreased cell invasion compared with pLKO (3.32+-0.08 vs. 1.05+-0.11; P<0.01; Fig.	('knockdown', 'Var', (80, 89))	('decreased', 'NegReg', (99, 108))	('OSRC-2', 'CellLine', 'CVCL:1901', (35, 41))	('SALL4', 'Gene', '57167', (93, 98))	('SALL4', 'Gene', (93, 98))	('cell invasion', 'CPA', (109, 122))
60254	32468053	It was demonstrated that SALL4 knockdown decreased cell viability compared with the pLKO group (P=0.003 in OSRC-2 and P=0.001 in SW839 at day 3; Fig.	('decreased', 'NegReg', (41, 50))	('cell viability', 'CPA', (51, 65))	('SALL4', 'Gene', '57167', (25, 30))	('SW839', 'CellLine', 'CVCL:3604', (129, 134))	('OSRC-2', 'CellLine', 'CVCL:1901', (107, 113))	('SALL4', 'Gene', (25, 30))	('knockdown', 'Var', (31, 40))
60270	32468053	Other studies have also confirmed a critical role of SALL4 in cell survival and tumorigenicity by knocking down SALL4.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('SALL4', 'Gene', '57167', (112, 117))	('SALL4', 'Gene', (53, 58))	('SALL4', 'Gene', '57167', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cell survival', 'CPA', (62, 75))	('SALL4', 'Gene', (112, 117))	('tumor', 'Disease', (80, 85))	('knocking', 'Var', (98, 106))
60283	32468053	Additionally, the copy number of SALL4 was positively associated with the survival curve.	('SALL4', 'Gene', '57167', (33, 38))	('SALL4', 'Gene', (33, 38))	('survival curve', 'CPA', (74, 88))	('copy number', 'Var', (18, 29))	('associated', 'Reg', (54, 64))
60296	32468053	Thus, targeting SALL4 may improve RCC therapy and prolong the survival of patients with ccRCC and pRCC.	('SALL4', 'Gene', (16, 21))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', (99, 102))	('pRCC', 'Phenotype', 'HP:0006766', (98, 102))	('RCC', 'Disease', (90, 93))	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('pRCC', 'Gene', (98, 102))	('survival', 'CPA', (62, 70))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('prolong', 'NegReg', (50, 57))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('RCC', 'Disease', (34, 37))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('patients', 'Species', '9606', (74, 82))	('targeting', 'Var', (6, 15))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('improve', 'PosReg', (26, 33))	('SALL4', 'Gene', '57167', (16, 21))	('pRCC', 'Gene', '5546', (98, 102))
60337	29434939	Single nucleotide polymorphisms in ADCY2 and ADCY8 are associated with glioma risk.	('Single nucleotide polymorphisms', 'Var', (0, 31))	('glioma', 'Disease', (71, 77))	('associated', 'Reg', (55, 65))	('ADCY8', 'Gene', (45, 50))	('ADCY8', 'Gene', '114', (45, 50))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('ADCY2', 'Gene', '108', (35, 40))	('ADCY2', 'Gene', (35, 40))
60350	29434939	As aforementioned, the majority of enzymes that are encoded by these genes are known to metabolize xenobiotics, including the anticancer drugs cyclophosphamide and ifosphamide.	('cyclophosphamide', 'Chemical', 'MESH:D003520', (143, 159))	('ifosphamide', 'Chemical', 'MESH:D007069', (164, 175))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('metabolize', 'MPA', (88, 98))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('genes', 'Var', (69, 74))
60369	29434939	Previous studies have revealed that abnormalities in CYP1B1, CYP1A1, CYP3A4 or CYP3A5 expression are associated with ccRCC, particularly drug resistance.	('CYP1B1', 'Gene', '1545', (53, 59))	('drug resistance', 'biological_process', 'GO:0009315', ('137', '152'))	('CYP1B1', 'Gene', (53, 59))	('drug resistance', 'biological_process', 'GO:0042493', ('137', '152'))	('CYP3A4', 'molecular_function', 'GO:0033780', ('69', '75'))	('CYP1A1', 'Gene', (61, 67))	('abnormalities', 'Var', (36, 49))	('drug resistance', 'Phenotype', 'HP:0020174', (137, 152))	('drug resistance', 'Disease', (137, 152))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('RCC', 'Disease', (119, 122))	('associated', 'Reg', (101, 111))	('CYP3A4', 'Gene', '1576', (69, 75))	('CYP1A1', 'Gene', '1543', (61, 67))	('CYP3A4', 'Gene', (69, 75))	('CYP3A5', 'Gene', '1577', (79, 85))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('CYP3A5', 'Gene', (79, 85))
60370	29434939	The present study demonstrated that the overall disorder of the cytochrome P450 family genes may be the primary cause of marked drug resistance in patients with ccRCC.	('drug resistance', 'biological_process', 'GO:0009315', ('128', '143'))	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('cause', 'Reg', (112, 117))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('ccRCC', 'Phenotype', 'HP:0006770', (161, 166))	('RCC', 'Disease', (163, 166))	('cytochrome P450 family', 'Enzyme', (64, 86))	('cytochrome P450', 'molecular_function', 'GO:0019825', ('64', '79'))	('drug resistance', 'biological_process', 'GO:0042493', ('128', '143'))	('patients', 'Species', '9606', (147, 155))	('drug resistance', 'Phenotype', 'HP:0020174', (128, 143))	('disorder', 'Var', (48, 56))	('cytochrome P450', 'molecular_function', 'GO:0005490', ('64', '79'))
60383	33766002	CA19-9 (P = 0.025) and ascites (P = 0.001) were significantly associated with OS, while HE4 (P = 0.027) and ascites (P = 0.001) were significantly associated with PFS.	('ascites', 'Disease', (23, 30))	('ascites', 'Phenotype', 'HP:0001541', (23, 30))	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('associated', 'Reg', (147, 157))	('PFS', 'Disease', (163, 166))	('ascites', 'Disease', 'MESH:D001201', (23, 30))	('HE4', 'Gene', (88, 91))	('associated', 'Reg', (62, 72))	('HE4', 'Gene', '10406', (88, 91))	('ascites', 'Disease', (108, 115))	('ascites', 'Phenotype', 'HP:0001541', (108, 115))	('CA19-9', 'Var', (0, 6))	('ascites', 'Disease', 'MESH:D001201', (108, 115))
60386	33766002	CA19-9, HE4, massive ascites, and positive lymph node are independent prognostic factors.	('HE4', 'Gene', '10406', (8, 11))	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('HE4', 'Gene', (8, 11))	('ascites', 'Disease', (21, 28))	('ascites', 'Phenotype', 'HP:0001541', (21, 28))	('ascites', 'Disease', 'MESH:D001201', (21, 28))	('CA19-9', 'Var', (0, 6))
60394	33766002	OCCC shows little association with family history, and BRCA1 and BRCA2 germline mutations are rare in OCCC, however, somatic mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and AT-rich interactive domain-containing protein 1A (ARID1A) are present in 20-51% and 40-57% respectively.	('mutations', 'Var', (125, 134))	('BRCA2', 'Gene', '675', (65, 70))	('ARID1A', 'Gene', '8289', (272, 278))	('AT-rich interactive domain-containing protein 1A', 'Gene', (222, 270))	('phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha', 'Gene', '5290', (138, 208))	('ARID1A', 'Gene', (272, 278))	('BRCA1', 'Gene', '672', (55, 60))	('PIK3CA', 'Gene', (210, 216))	('ml', 'Gene', '21832', (74, 76))	('BRCA1', 'Gene', (55, 60))	('PIK3CA', 'Gene', '5290', (210, 216))	('BRCA2', 'Gene', (65, 70))	('AT-rich interactive domain-containing protein 1A', 'Gene', '8289', (222, 270))	('protein', 'cellular_component', 'GO:0003675', ('260', '267'))
60398	33766002	Suboptimal cytoreduction, lymph node (LN) metastasis, and occurrence of VTE are also prognostic predictors of poor outcome.	('VTE', 'Disease', 'MESH:D054556', (72, 75))	('VTE', 'Disease', (72, 75))	('Suboptimal', 'Var', (0, 10))
60463	33766002	We also compared the median survival time of patients with IC1 or IC2/3 of OCCC, and the median PFS and OS of them are shown in sTable3 and sTable4.	('IC2/3', 'Gene', '1781', (66, 71))	('patients', 'Species', '9606', (45, 53))	('IC2/3', 'Gene', (66, 71))	('IC1', 'Var', (59, 62))
60476	33766002	2) were generated which showed that AJCC stage (P < 0.001), SEER summary stage (P < 0.001), >= 4 LN removed (P = 0.003), and positive LN (P < 0.001) were significantly associated OS in patients with OCCC.	('OCCC', 'Disease', (199, 203))	('associated', 'Reg', (168, 178))	('positive LN', 'Var', (125, 136))	('ER', 'Gene', '2099', (62, 64))	('AJCC', 'Disease', (36, 40))	('patients', 'Species', '9606', (185, 193))
60514	33766002	Elevated postoperative CA19-9 has been reported as an independent risk factor for reduced survival outcomes in OCCC patients with normal postoperative CA125 levels.	('CA125', 'Gene', (151, 156))	('survival outcomes', 'CPA', (90, 107))	('CA19-9', 'Chemical', 'MESH:C086528', (23, 29))	('patients', 'Species', '9606', (116, 124))	('CA19-9', 'Var', (23, 29))	('CA125', 'Gene', '94025', (151, 156))	('reduced', 'NegReg', (82, 89))
60536	33783991	CA9 is a metalloenzyme overexpressed in almost all ccRCC following hypoxia (via HIF1) and inactivation of the VHL gene, but absent in benign tumors and normal renal tissue.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('HIF1', 'Gene', (80, 84))	('hypoxia', 'Disease', (67, 74))	('hypoxia', 'Disease', 'MESH:D000860', (67, 74))	('VHL', 'Gene', '7428', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumor', 'Disease', (141, 146))	('benign tumors', 'Disease', 'MESH:D009369', (134, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('HIF1', 'Gene', '3091', (80, 84))	('inactivation', 'Var', (90, 102))	('overexpressed', 'PosReg', (23, 36))	('VHL', 'Gene', (110, 113))	('ccRCC', 'Disease', (51, 56))	('benign tumors', 'Disease', (134, 147))
60595	31431624	Due to its role as an E3 ubiquitin ligase complex, loss of VHL leads to stabilization and activation of the TFs HIF1alpha and HIF2alpha that control angiogenesis, glycolysis, and apoptosis.	('glycolysis', 'biological_process', 'GO:0006096', ('163', '173'))	('apoptosis', 'biological_process', 'GO:0097194', ('179', '188'))	('control', 'Reg', (141, 148))	('stabilization', 'MPA', (72, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('179', '188'))	('activation', 'PosReg', (90, 100))	('HIF1alpha', 'Gene', '3091', (112, 121))	('angiogenesis', 'MPA', (149, 161))	('HIF2alpha', 'Gene', '2034', (126, 135))	('apoptosis', 'CPA', (179, 188))	('angiogenesis', 'biological_process', 'GO:0001525', ('149', '161'))	('VHL', 'Gene', (59, 62))	('HIF1alpha', 'Gene', (112, 121))	('loss', 'Var', (51, 55))	('glycolysis', 'MPA', (163, 173))	('ubiquitin ligase complex', 'cellular_component', 'GO:0000151', ('25', '49'))	('VHL', 'Gene', '7428', (59, 62))	('HIF2alpha', 'Gene', (126, 135))	('ubiquitin', 'molecular_function', 'GO:0031386', ('25', '34'))
60604	31431624	In order to characterize the landscape of active enhancers and promoters in kidney cancer cells we conducted ChIP-sequencing for H3K27ac and ATAC-sequencing of four ccRCC cell lines (Fig.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('kidney cancer', 'Phenotype', 'HP:0009726', (76, 89))	('kidney cancer', 'Disease', 'MESH:D007680', (76, 89))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('kidney cancer', 'Disease', (76, 89))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('H3K27ac', 'Var', (129, 136))
60610	31431624	PAX8 knockdown induced an accumulation of cells in the G1-S phase of the cell cycle and a concomitant reduction of BrdU labeled cells indicating decreased proliferation (Fig.	('accumulation', 'PosReg', (26, 38))	('cells', 'CPA', (42, 47))	('BrdU labeled cells', 'MPA', (115, 133))	('cell cycle', 'biological_process', 'GO:0007049', ('73', '83'))	('knockdown', 'Var', (5, 14))	('proliferation', 'CPA', (155, 168))	('PAX8', 'Gene', (0, 4))	('reduction', 'NegReg', (102, 111))	('decreased', 'NegReg', (145, 154))	('S phase', 'biological_process', 'GO:0051320', ('58', '65'))	('BrdU', 'Chemical', 'MESH:D001973', (115, 119))
60614	31431624	In order to characterize the transcriptional program imposed by PAX8 in kidney cancer cells, we sought to quantify gene expression changes by RNA-seq upon PAX8 knockdown across multiple RCC models (Fig.	('knockdown', 'Var', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('kidney cancer', 'Disease', 'MESH:D007680', (72, 85))	('gene expression', 'biological_process', 'GO:0010467', ('115', '130'))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('RCC', 'Disease', (186, 189))	('kidney cancer', 'Phenotype', 'HP:0009726', (72, 85))	('RNA', 'cellular_component', 'GO:0005562', ('142', '145'))	('PAX8', 'Gene', (155, 159))	('kidney cancer', 'Disease', (72, 85))
60616	31431624	2a), consistent with decreased viability of RCC cells upon PAX8 knockdown and as previously reported.	('decreased', 'NegReg', (21, 30))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('PAX8', 'Gene', (59, 63))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('knockdown', 'Var', (64, 73))
60625	31431624	3a) and this effect is irrespective of relevant genetic aberrations such as VHL mutations (Supplementary Fig.	('VHL', 'Gene', (76, 79))	('VHL', 'Gene', '7428', (76, 79))	('mutations', 'Var', (80, 89))
60626	31431624	In addition, tumors with different levels of CP expression display similar mutation frequency in most frequently mutated genes in RCC (Supplementary Fig.	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('mutation', 'Var', (75, 83))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('CP', 'Gene', '1356', (45, 47))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
60627	31431624	We readily validated the regulation of CP upon PAX8 knockdown (with siRNA and shRNA) by qRT-PCR across multiple cell lines of renal and ovarian lineage (Fig.	('renal and ovarian lineage', 'Disease', 'MESH:D007674', (126, 151))	('CP', 'Gene', '1356', (39, 41))	('PAX8', 'Gene', (47, 51))	('regulation', 'biological_process', 'GO:0065007', ('25', '35'))	('knockdown', 'Var', (52, 61))
60628	31431624	We also observed the downregulation of CP upon PAX8 knockdown at the protein level.	('CP', 'Gene', '1356', (39, 41))	('PAX8', 'Gene', (47, 51))	('knockdown', 'Var', (52, 61))	('downregulation', 'NegReg', (21, 35))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))
60634	31431624	Due to the reported interaction between PAX8 and p300, we characterized the impact of PAX8 knockdown on histone acetylation at the e-CP locus.	('histone acetylation', 'MPA', (104, 123))	('e-CP', 'Gene', '6037', (131, 135))	('p300', 'Gene', (49, 53))	('knockdown', 'Var', (91, 100))	('histone acetylation', 'biological_process', 'GO:0016573', ('104', '123'))	('PAX8', 'Gene', (86, 90))	('p300', 'Gene', '2033', (49, 53))	('e-CP', 'Gene', (131, 135))
60640	31431624	Moreover, knockdown of PAX8 by inducible shRNAs induced a decrease in NanoLuc signal comparable to that of the endogenous CP gene (Fig.	('PAX8', 'Gene', (23, 27))	('shRNAs', 'Gene', (41, 47))	('NanoLuc signal', 'MPA', (70, 84))	('decrease', 'NegReg', (58, 66))	('CP', 'Gene', '1356', (122, 124))	('knockdown', 'Var', (10, 19))
60646	31431624	We then analyzed conditioned media from cell lines bearing doxycycline-inducible shPAX8 and observed that knockdown of PAX8 led to a reduction in the level of CP secreted in the media (Supplementary Fig.	('PAX8', 'Gene', (119, 123))	('reduction', 'NegReg', (133, 142))	('knockdown', 'Var', (106, 115))	('doxycycline', 'Chemical', 'MESH:D004318', (59, 70))	('CP', 'Gene', '1356', (159, 161))
60650	31431624	In fact, segregation of the CCLE RCC and ovarian models based on PAX8 expression revealed low expression of CP in cellular models expressing low PAX8 (Fig.	('CCLE RCC', 'Disease', 'MESH:C538614', (28, 36))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('CCLE RCC', 'Disease', (28, 36))	('expression', 'MPA', (94, 104))	('low', 'Var', (141, 144))	('low', 'NegReg', (90, 93))	('PAX8', 'Gene', (145, 149))	('CP', 'Gene', '1356', (108, 110))
60651	31431624	Such concept held true also in vivo, as shown by RNA-seq analysis of our internal RCC patient-derived xenografts collection, which displayed remarkably low expression of CP in models bearing low PAX8 expression (Supplementary Fig.	('low', 'NegReg', (152, 155))	('low', 'Var', (191, 194))	('CP', 'Gene', '1356', (170, 172))	('PAX8', 'Gene', (195, 199))	('patient', 'Species', '9606', (86, 93))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('expression', 'MPA', (156, 166))	('RNA', 'cellular_component', 'GO:0005562', ('49', '52'))
60657	31431624	In addition, we characterize the epigenomic landscape controlled by PAX8 in RCC cells and show that PAX8 activates a large set of genes involved in cell cycle and metabolism mainly through distal enhancer elements.	('PAX8', 'Gene', (68, 72))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('PAX8', 'Var', (100, 104))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('metabolism', 'biological_process', 'GO:0008152', ('163', '173'))	('activates', 'PosReg', (105, 114))	('cell cycle', 'biological_process', 'GO:0007049', ('148', '158'))
60666	31431624	However, HNF1B mutations/deletions have been shown to lead to a variety of renal malignancies such as polycystic kidney disease or even supporting chromophobe renal cell carcinoma development.	('HNF1B', 'Gene', '6928', (9, 14))	('polycystic kidney disease', 'Disease', (102, 127))	('polycystic kidney', 'Phenotype', 'HP:0000113', (102, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('lead to', 'Reg', (54, 61))	('mutations/deletions', 'Var', (15, 34))	('polycystic kidney disease', 'Disease', 'MESH:D007690', (102, 127))	('kidney disease', 'Phenotype', 'HP:0000112', (113, 127))	('chromophobe renal cell carcinoma', 'Disease', (147, 179))	('HNF1B', 'Gene', (9, 14))	('renal malignancies', 'Phenotype', 'HP:0009726', (75, 93))	('renal malignancies', 'Disease', (75, 93))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (159, 179))	('renal malignancies', 'Disease', 'MESH:D007674', (75, 93))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (147, 179))
60669	31431624	In addition, germline mutations in PAX8 DNA-binding domain in humans (abolishing PAX8 transcriptional activity), lead to hypoplasia and a compensatory thyroid hyperactivity.	('hyperactivity', 'Phenotype', 'HP:0000752', (159, 172))	('PAX8', 'Gene', (81, 85))	('lead to', 'Reg', (113, 120))	('hypoplasia', 'Disease', 'MESH:C535916', (121, 131))	('abolishing', 'NegReg', (70, 80))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('germline mutations', 'Var', (13, 31))	('PAX8', 'Gene', (35, 39))	('hypoplasia', 'Disease', (121, 131))	('humans', 'Species', '9606', (62, 68))	('thyroid hyperactivity', 'Disease', 'MESH:D013959', (151, 172))	('DNA-binding', 'molecular_function', 'GO:0003677', ('40', '51'))	('thyroid hyperactivity', 'Disease', (151, 172))
60671	31431624	This data indicates that PAX8 is largely dispensable for adult tissue homeostasis, suggesting a high therapeutic index for modulators of PAX8 functions in the context of cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('PAX8', 'Gene', (137, 141))	('modulators', 'Var', (123, 133))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('tissue homeostasis', 'biological_process', 'GO:0001894', ('63', '81'))
60675	31431624	Importantly, VHL inactivation, when combined with other genetic lesions in Pax8-expressing cells, leads to neoplastic lesions of different stage and penetrance suggesting proximal tubules as a potential source of RCC.	('inactivation', 'Var', (17, 29))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (107, 125))	('neoplastic lesions', 'CPA', (107, 125))	('VHL', 'Gene', (13, 16))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('RCC', 'Disease', (213, 216))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	('VHL', 'Gene', '7428', (13, 16))	('leads to', 'Reg', (98, 106))
60678	31431624	To date there are no models available for conditional inactivation or ectopic expression of PAX8, which hampers the understanding of sufficiency and dependency of PAX8 for tumorigenesis.	('sufficiency', 'Disease', (133, 144))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('conditional inactivation', 'Var', (42, 66))	('sufficiency', 'Disease', 'None', (133, 144))	('ectopic expression', 'Var', (70, 88))	('PAX8', 'Gene', (92, 96))
60679	31431624	PAX8 knockdown leads to profound decrease of proliferation in RCC cells, most likely by regulating cell cycle genes as we and others reported.	('decrease', 'NegReg', (33, 41))	('proliferation', 'CPA', (45, 58))	('cell cycle', 'biological_process', 'GO:0007049', ('99', '109'))	('knockdown', 'Var', (5, 14))	('PAX8', 'Gene', (0, 4))	('cell cycle genes', 'Gene', (99, 115))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('regulating', 'Reg', (88, 98))
60686	31431624	In the latter setting, instead, PAX8 drives expression of proteins such as CP and RHEX directly involved in iron homeostasis, further corroborating the importance of the tubulointerstitial cellular crosstalk.	('RHEX', 'Gene', '440712', (82, 86))	('expression', 'MPA', (44, 54))	('iron homeostasis', 'biological_process', 'GO:0055072', ('108', '124'))	('CP', 'Gene', '1356', (75, 77))	('iron', 'Chemical', 'MESH:D007501', (108, 112))	('PAX8', 'Var', (32, 36))	('iron homeostasis', 'biological_process', 'GO:0006879', ('108', '124'))	('RHEX', 'Gene', (82, 86))
60692	31431624	Doxycycline-inducible shRNA cells were obtained by lentiviral transduction of pLKO-TET-ON constructs containing the following shRNA sequences: sh784 5'-ccgactaagcattgactcaca-3'; sh1355 5'-ggaagtgaatactctggcaat-3'; sh1581 5'-gagagtcacacaaaggaatct-3' and shPLK1 5'-ggtatcagctctgtgataaca-3'.	('transduction', 'biological_process', 'GO:0009293', ('62', '74'))	("sh784 5'-ccgactaagcattgactcaca-3", 'Var', (143, 175))	('TET', 'Chemical', 'MESH:C010349', (83, 86))	("sh1355 5'-ggaagtgaatactctggcaat-3", 'Var', (178, 211))	('Doxycycline', 'Chemical', 'MESH:D004318', (0, 11))
60710	31431624	We identified super-enhancers using the rank ordering of super-enhancers (ROSE) meta algorithm (https://github.com/BradnerLab/pipeline), excluding H3K27ac peaks within 2500 bp of a transcription start site and stitching together peaks from any RCC cell line within 1638 bp.	('RCC', 'Disease', (244, 247))	('RCC', 'Phenotype', 'HP:0005584', (244, 247))	('H3K27ac', 'Var', (147, 154))	('excluding', 'NegReg', (137, 146))	('transcription', 'biological_process', 'GO:0006351', ('181', '194'))	('RCC', 'Disease', 'MESH:C538614', (244, 247))
60735	28252459	Inactivation of VHL either by mutation or epigenetic silencing occurs in over 90% cases of sporadic ccRCC.	('VHL', 'Gene', (16, 19))	('epigenetic silencing', 'Var', (42, 62))	('mutation', 'Var', (30, 38))	('VHL', 'Gene', '7428', (16, 19))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('Inactivation', 'NegReg', (0, 12))
60736	28252459	Additionally, TCGA analysis has demonstrated recurrent mutations in several chromatin remodeling genes, including PBRM1 (32.9%), SETD2 (11.5%), and BAP1 (10.1%).	('SETD2', 'Gene', '29072', (129, 134))	('PBRM1', 'Gene', '55193', (114, 119))	('chromatin', 'cellular_component', 'GO:0000785', ('76', '85'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('76', '96'))	('mutations', 'Var', (55, 64))	('SETD2', 'Gene', (129, 134))	('BAP1', 'Gene', '8314', (148, 152))	('BAP1', 'Gene', (148, 152))	('PBRM1', 'Gene', (114, 119))
60740	28252459	The study affirmed differences in type 1 and type 2 pRCC, and found 4 distinct molecular subgroups with progressively worse survival (C1, C2a, C2b, and C2c).	('C2a', 'Var', (138, 141))	('pRCC', 'Gene', '5546', (52, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('pRCC', 'Gene', (52, 56))	('C2b', 'Var', (143, 146))	('worse', 'NegReg', (118, 123))
60741	28252459	C1 consisted of mostly type 1 pRCC tumors, characterized by gain of chromosome 7 and 17, as well as alterations in MET.	('MET', 'MPA', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('chromosome', 'cellular_component', 'GO:0005694', ('68', '78'))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('pRCC', 'Gene', (30, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('gain', 'PosReg', (60, 64))	('pRCC', 'Gene', '5546', (30, 34))	('alterations', 'Var', (100, 111))
60742	28252459	In contrast to the hereditary form of pRCC, Hereditary Papillary Renal Cancer (HPRC) which is characterized by germline MET mutations, somatic alterations of MET in non-hereditary pRCC was less common, occurring in ~15% of cases.	('pRCC', 'Gene', '5546', (38, 42))	('MET', 'Gene', (158, 161))	('pRCC', 'Gene', (38, 42))	('pRCC', 'Gene', '5546', (180, 184))	('Renal Cancer', 'Phenotype', 'HP:0009726', (65, 77))	('Hereditary Papillary Renal Cancer', 'Disease', 'MESH:D007681', (44, 77))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('Hereditary Papillary Renal Cancer', 'Disease', (44, 77))	('Papillary Renal Cancer', 'Phenotype', 'HP:0006766', (55, 77))	('pRCC', 'Gene', (180, 184))	('alterations', 'Var', (143, 154))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
60744	28252459	C2a consisted of early stage tumors, while C2b consisted of later stage tumors and was characterized by mutations in SETD2.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mutations', 'Var', (104, 113))	('tumors', 'Disease', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('SETD2', 'Gene', '29072', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('SETD2', 'Gene', (117, 122))	('C2a', 'Disease', (0, 3))
60745	28252459	Other alterations in type 2 pRCC included loss of CDKN2a, activation of the NRF2 oxidative stress pathway, mutations of FH, gene fusions involving the MiTF gene family members TFE3 and TFEB, and mutations in chromatin remodeling genes.	('NRF2', 'Gene', '4780', (76, 80))	('oxidative stress', 'Phenotype', 'HP:0025464', (81, 97))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('pRCC', 'Gene', (28, 32))	('activation', 'PosReg', (58, 68))	('TFE3', 'Gene', (176, 180))	('gene fusions', 'Var', (124, 136))	('MiTF gene', 'Gene', (151, 160))	('NRF2', 'Gene', (76, 80))	('TFE3', 'Gene', '7030', (176, 180))	('CDKN2a', 'Gene', (50, 56))	('loss', 'NegReg', (42, 46))	('mutations', 'Var', (195, 204))	('TFEB', 'Gene', (185, 189))	('chromatin', 'cellular_component', 'GO:0000785', ('208', '217'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('208', '228'))	('pRCC', 'Gene', '5546', (28, 32))	('mutations', 'Var', (107, 116))	('CDKN2a', 'Gene', '1029', (50, 56))	('TFEB', 'Gene', '7942', (185, 189))
60748	28252459	The analysis from TCGA demonstrated that chRCC exhibit alterations in mitochondrial DNA and that 10% of cases had rearrangement in the TERT promoter.	('TERT', 'Gene', '7015', (135, 139))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('70', '87'))	('mitochondrial DNA', 'MPA', (70, 87))	('alterations', 'Reg', (55, 66))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('rearrangement', 'Var', (114, 127))	('TERT', 'Gene', (135, 139))
60749	28252459	Furthermore, TP53 was mutated in 32% of cases, and mTOR pathway changes occurred in 23% of cases.	('mTOR', 'Gene', (51, 55))	('TP53', 'Gene', (13, 17))	('changes', 'Reg', (64, 71))	('mutated', 'Var', (22, 29))	('TP53', 'Gene', '7157', (13, 17))	('mTOR', 'Gene', '2475', (51, 55))
60757	28252459	AXL is activated by HIF-1 and HIF-2, and inactivation of AXL decreases lung metastases in mice xenograft models of RCC.	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('HIF-1 and HIF-2', 'Disease', 'MESH:D003924', (20, 35))	('inactivation', 'Var', (41, 53))	('RCC', 'Disease', (115, 118))	('AXL decreases lung metastases', 'Disease', 'MESH:D009362', (57, 86))	('mice', 'Species', '10090', (90, 94))	('AXL decreases lung metastases', 'Disease', (57, 86))
60765	28252459	In a randomized phase II trial comparing cabozantinib and sunitinib in the first-line setting (CABOSUN) in 157 patients with intermediate or poor-risk mRCC, cabozantinib was associated with increased median PFS (8.2 v 5.6 months; HR 0.66; 95% CI, 0.46-0.95; one-sided p= .012), OS (30.3 vs 21.8 months; HR 0.8; 95% CI 0.5-1.26) and ORR (46%; 95% CI, 34-57 versus 18%; 95% CI, 10-28) with a similar incidence of grade 3-4 AEs (67% for cabozantinib and 68% for sunitinib).	('PFS', 'CPA', (207, 210))	('sunitinib', 'Chemical', 'MESH:D000077210', (58, 67))	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('cabozantinib', 'Chemical', 'MESH:C558660', (41, 53))	('RCC', 'Disease', (152, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('ORR', 'Disease', (332, 335))	('sunitinib', 'Chemical', 'MESH:D000077210', (459, 468))	('cabozantinib', 'Chemical', 'MESH:C558660', (434, 446))	('cabozantinib', 'Var', (157, 169))	('cabozantinib', 'Chemical', 'MESH:C558660', (157, 169))	('patients', 'Species', '9606', (111, 119))
60773	28252459	Cho and colleagues showed that PT2300 inhibits growth of VHL-deficient ccRCC cell lines in vitro and in mouse xenografts.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('VHL-deficient', 'Disease', 'MESH:D006623', (57, 70))	('inhibits', 'NegReg', (38, 46))	('growth', 'MPA', (47, 53))	('VHL-deficient', 'Disease', (57, 70))	('mouse', 'Species', '10090', (104, 109))	('PT2300', 'Var', (31, 37))	('Cho', 'molecular_function', 'GO:0043848', ('0', '3'))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
60793	28252459	There is significant interest in combining PD1/PDL-1 inhibitors with other agents, including other checkpoint inhibitors, VEGF inhibitors, HDAC inhibitors, and vaccines (Table 3).	('inhibitors', 'Var', (53, 63))	('VEGF', 'Gene', '7422', (122, 126))	('PDL-1', 'Gene', (47, 52))	('PD1', 'Gene', '5133', (43, 46))	('VEGF', 'Gene', (122, 126))	('PD1', 'Gene', (43, 46))	('PDL-1', 'Gene', '29126', (47, 52))
60802	28252459	Indeed, VEGF-pathway inhibitors seem to have an immunomodulatory effect.	('inhibitors', 'Var', (21, 31))	('VEGF-', 'Gene', '7422', (8, 13))	('VEGF-', 'Gene', (8, 13))
60827	28252459	A second randomized phase 2 study, ASPEN (Phase II Study of Afinitor Vs. Sutent in Patients with Metastatic Non-Clear Cell Renal Cell Carcinoma), in 108 patients with treatment-naive metastatic pRCC, chRCC or unclassified non-ccRCC subtypes demonstrated that Sunitnib was associated with an improved PFS (8.3 vs 5.6 mo; HR 1.4; p=0.16) compared to everolimus.	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (123, 143))	('Carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('RCC', 'Disease', 'MESH:C538614', (228, 231))	('Metastatic Non-Clear Cell Renal Cell Carcinoma', 'Disease', (97, 143))	('PFS', 'MPA', (300, 303))	('RCC', 'Phenotype', 'HP:0005584', (195, 198))	('Sunitnib', 'Chemical', '-', (259, 267))	('RCC', 'Disease', (202, 205))	('RCC', 'Phenotype', 'HP:0005584', (202, 205))	('RCC', 'Disease', (195, 198))	('pRCC', 'Gene', (194, 198))	('Metastatic Non-Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538445', (97, 143))	('-Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (111, 143))	('Sutent', 'Chemical', 'MESH:D000077210', (73, 79))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('Sunitnib', 'Var', (259, 267))	('improved', 'PosReg', (291, 299))	('patients', 'Species', '9606', (153, 161))	('RCC', 'Disease', (228, 231))	('everolimus', 'Chemical', 'MESH:D000068338', (348, 358))	('RCC', 'Phenotype', 'HP:0005584', (228, 231))	('pRCC', 'Gene', '5546', (194, 198))	('Patients', 'Species', '9606', (83, 91))
60831	28252459	Other ongoing trials in pRCC include phase 2 studies of selective Met inhibitors, including INC280 and AZD6094, and the combination of the EGFR inhibitor erlotinib with bevacizumab, as summarized in Table 4.	('pRCC', 'Gene', '5546', (24, 28))	('bevacizumab', 'Chemical', 'MESH:D000068258', (169, 180))	('AZD6094', 'Var', (103, 110))	('INC280', 'Chemical', 'MESH:C000613976', (92, 98))	('EGFR', 'molecular_function', 'GO:0005006', ('139', '143'))	('pRCC', 'Gene', (24, 28))	('EGFR', 'Gene', '1956', (139, 143))	('AZD6094', 'Chemical', 'MESH:C000593259', (103, 110))	('erlotinib', 'Chemical', 'MESH:D000069347', (154, 163))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('EGFR', 'Gene', (139, 143))
60835	28252459	This phase III trial of 1943 patients with high-grade T1b or higher non-metastatic RCC randomized to receive 54 weeks of sunitinib, sorafenib or placebo demonstrated no improvement in outcome with adjuvant VEGFR TKIs (median PFS 5.8 years; HR 1.02; p=0.8 for sunitinib vs 6.1 years; HR 0.97; p=0.7 for sorafenib vs 6.6 years for placebo).	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('patients', 'Species', '9606', (29, 37))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('sorafenib', 'Chemical', 'MESH:D000077157', (302, 311))	('T1b', 'Gene', (54, 57))	('sunitinib', 'Chemical', 'MESH:D000077210', (121, 130))	('sorafenib', 'Chemical', 'MESH:D000077157', (132, 141))	('high-grade', 'Var', (43, 53))	('VEGFR', 'Gene', '3791', (206, 211))	('sunitinib', 'Chemical', 'MESH:D000077210', (259, 268))	('VEGFR', 'Gene', (206, 211))
60837	28252459	In contrast, results from S-TRAC (Sunitinib as Adjuvant treatment for patients at high risk of recurrence of renal cell carcinoma following nephrectomy), a phase III trial that randomized 615 patients with T3 or greater RCC to sunitinib vs placebo for 1 year suggest that sunitinib was associated with improved DFS compared to placebo (6.8 vs 5.8 years, p = 0.03).	('patients', 'Species', '9606', (70, 78))	('sunitinib', 'Chemical', 'MESH:D000077210', (272, 281))	('DFS', 'MPA', (311, 314))	('renal cell carcinoma', 'Disease', (109, 129))	('sunitinib', 'Var', (272, 281))	('sunitinib', 'Chemical', 'MESH:D000077210', (227, 236))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (109, 129))	('patients', 'Species', '9606', (192, 200))	('improved', 'PosReg', (302, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('RCC', 'Phenotype', 'HP:0005584', (220, 223))	('Sunitinib', 'Chemical', 'MESH:D000077210', (34, 43))	('TRAC', 'Gene', '28755', (28, 32))	('TRAC', 'Gene', (28, 32))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (109, 129))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('RCC', 'Disease', (220, 223))
60849	28252459	In 104 patients who received pazopanib, 61% went on to undergo nephrectomy.	('pazopanib', 'Var', (29, 38))	('nephrectomy', 'Disease', (63, 74))	('pazopanib', 'Chemical', 'MESH:C516667', (29, 38))	('patients', 'Species', '9606', (7, 15))
60854	28252459	While VEGFR inhibitors remain the standard first-line treatment for the majority of patients, this paradigm is being challenged by ongoing studies.	('patients', 'Species', '9606', (84, 92))	('inhibitors', 'Var', (12, 22))	('VEGFR', 'Gene', (6, 11))	('VEGFR', 'Gene', '3791', (6, 11))
60874	32140530	After an extensive immunohistochemical analysis, the most relevant finding was an ARID1A loss that was corroborated by molecular analysis showing an ARID1A deletion.	('ARID1A', 'Gene', '8289', (82, 88))	('ARID1A', 'Gene', (82, 88))	('loss', 'NegReg', (89, 93))	('ARID1A', 'Gene', '8289', (149, 155))	('ARID1A', 'Gene', (149, 155))	('deletion', 'Var', (156, 164))
60909	32140530	Immunohistochemical stainings showed positivity for CK7, NapsinA, AMACR, PAX8, vimentin, CK34BE12, Ber-EP4, p16, and CEA.	('AMACR', 'Gene', (66, 71))	('CK7', 'Gene', (52, 55))	('vimentin', 'Gene', (79, 87))	('CEA', 'Gene', (117, 120))	('p16', 'Gene', '1029', (108, 111))	('AMACR', 'Gene', '23600', (66, 71))	('CK7', 'Gene', '3855', (52, 55))	('PAX8', 'Gene', '7849', (73, 77))	('CEA', 'Gene', '5670', (117, 120))	('vimentin', 'cellular_component', 'GO:0045099', ('79', '87'))	('vimentin', 'cellular_component', 'GO:0045098', ('79', '87'))	('Ber', 'biological_process', 'GO:0006284', ('99', '102'))	('PAX8', 'Gene', (73, 77))	('CK34BE12', 'Var', (89, 97))	('p16', 'Gene', (108, 111))	('vimentin', 'Gene', '7431', (79, 87))
60913	32140530	NGS results showed a pathogenic deletion in ARID1A -p.Ala162GlyfsTer234 (c.485_495del)-.	('ARID1A', 'Gene', '8289', (44, 50))	('ARID1A', 'Gene', (44, 50))	('c.485_495del', 'Mutation', 'c.485_495del', (73, 85))	('p.Ala162Gly', 'Var', (52, 63))	('pathogenic', 'Reg', (21, 31))	('p.Ala162Gly', 'SUBSTITUTION', 'None', (52, 63))
60914	32140530	In addition, two germline mutations were observed in both MKI67 (L1806V) and BRCA2 (T1915M), and somatic mutations in GSDMB (V197A) and KMT2C (S772L/K339N/T316S/L291F).	('S772L', 'SUBSTITUTION', 'None', (143, 148))	('S772L', 'Var', (143, 148))	('L291F', 'SUBSTITUTION', 'None', (161, 166))	('L1806V', 'Var', (65, 71))	('L291F', 'Var', (161, 166))	('GSDMB', 'Gene', (118, 123))	('KMT2C', 'Gene', '58508', (136, 141))	('KMT2C', 'Gene', (136, 141))	('K339N', 'SUBSTITUTION', 'None', (149, 154))	('V197A', 'Mutation', 'p.V197A', (125, 130))	('T1915M', 'Mutation', 'rs4987117', (84, 90))	('MKI67', 'Gene', (58, 63))	('BRCA2', 'Gene', (77, 82))	('K339N', 'Var', (149, 154))	('MKI67', 'Gene', '4288', (58, 63))	('T316S', 'Var', (155, 160))	('T316S', 'SUBSTITUTION', 'None', (155, 160))	('V197A', 'Var', (125, 130))	('T1915M', 'Var', (84, 90))	('L1806V', 'Mutation', 'rs61729193', (65, 71))	('BRCA2', 'Gene', '675', (77, 82))	('GSDMB', 'Gene', '55876', (118, 123))
60935	32140530	Interestingly, Kim et al by using NGS showed increased mutations in PIK3CA, ARID1A, and KRAS in ovarian CCC regardless of the association with endometriosis.	('CCC', 'cellular_component', 'GO:0030896', ('104', '107'))	('ovarian', 'Disease', (96, 103))	('endometriosis', 'Disease', 'MESH:D004715', (143, 156))	('PIK3CA', 'Gene', (68, 74))	('increased', 'PosReg', (45, 54))	('mutations', 'Var', (55, 64))	('endometriosis', 'Disease', (143, 156))	('ovarian', 'Disease', 'MESH:D010049', (96, 103))	('CCC', 'Disease', (104, 107))	('endometriosis', 'Phenotype', 'HP:0030127', (143, 156))	('PIK3CA', 'Gene', '5290', (68, 74))	('ARID1A', 'Gene', '8289', (76, 82))	('KRAS', 'Gene', (88, 92))	('ARID1A', 'Gene', (76, 82))	('CCC', 'Disease', 'MESH:D002292', (104, 107))	('KRAS', 'Gene', '3845', (88, 92))
60936	32140530	Our case presented a pathogenic deletion in ARID1A, leading to a loss of ARID1A expression.	('loss', 'NegReg', (65, 69))	('deletion', 'Var', (32, 40))	('ARID1A', 'Gene', '8289', (44, 50))	('ARID1A', 'Gene', (44, 50))	('expression', 'MPA', (80, 90))	('ARID1A', 'Gene', '8289', (73, 79))	('ARID1A', 'Gene', (73, 79))	('pathogenic', 'Reg', (21, 31))
60938	32140530	Finally, it also presented a series of somatic mutations in GSDMB and KMT2C, which appear as unreported or of uncertain significance.	('GSDMB', 'Gene', '55876', (60, 65))	('mutations', 'Var', (47, 56))	('GSDMB', 'Gene', (60, 65))	('KMT2C', 'Gene', '58508', (70, 75))	('KMT2C', 'Gene', (70, 75))
60959	32042317	In fact, most pseudogenes are expressed in parallel with their parental genes, e.g., loss of phosphatase and tensin homolog pseudogene 1 (PTENP1), a processed pseudogene of PTEN at chromosome 9p13.3, can lead to a remarkable reduction in the level of PTEN .	('loss', 'Var', (85, 89))	('PTEN', 'MPA', (251, 255))	('reduction', 'NegReg', (225, 234))	('phosphatase', 'molecular_function', 'GO:0016791', ('93', '104'))	('chromosome', 'cellular_component', 'GO:0005694', ('181', '191'))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('93', '123'))	('tensin', 'Chemical', 'MESH:C406010', (109, 115))	('level', 'MPA', (242, 247))	('PTENP1', 'Gene', (138, 144))
60964	32042317	performed an RNA-seq analysis on samples from 13 cancers and their corresponding normal tissues and found 218 pseudogenes and 40 pseudogenes that were only present in the cancer samples and a single cancer subtype, respectively.	('cancer', 'Disease', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (171, 177))	('pseudogenes', 'Var', (110, 121))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('cancer', 'Disease', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancers', 'Disease', (49, 56))
60967	32042317	Moreover, single-nucleotide polymorphisms (SNPs) can occur in pseudogene sequences to induce variants, such as alleles of poly(ADP-ribose) polymerase (PADPRP)-processed pseudogene , E2F transcription factor 3 pseudogene 1 (E2F3P1)  and OCT4-pg1 .	('poly(ADP-ribose)', 'Chemical', 'MESH:D011064', (122, 138))	('transcription factor', 'molecular_function', 'GO:0000981', ('186', '206'))	('transcription', 'biological_process', 'GO:0006351', ('186', '199'))	('single-nucleotide polymorphisms', 'Var', (10, 41))	('E2F3P1', 'Gene', (223, 229))
60969	32042317	2) Retrotransposon: reversely transcribed cDNA may randomly reintegrate into the genome by forming an inappropriate locus or mutation, leading to the biogenesis of a functionally insufficient pseudogene.	('inappropriate', 'Disease', 'MESH:D007177', (102, 115))	('inappropriate', 'Disease', (102, 115))	('cDNA', 'Gene', (42, 46))	('biogenesis', 'MPA', (150, 160))	('mutation', 'Var', (125, 133))
60971	32042317	1) Epigenetic silencing: By inserting into the upstream regulatory regions, particularly a promoter, a pseudogene may destroy its "landing site" and prevent host gene transcription, e.g., pseudogene protein tyrosine phosphatase non-receptor type 12 (PTPN12) inserts into the promoter region of MAX dimerization protein MGA (MGA), which acts as a potential lung cancer suppressor, to inactivate its expression and promote a malignant phenotype in NCI-H2009 cells.	('NCI-H2009', 'CellLine', 'CVCL:1514', (446, 455))	('malignant phenotype in', 'CPA', (423, 445))	('host', 'MPA', (157, 161))	('expression', 'MPA', (398, 408))	('lung cancer', 'Disease', (356, 367))	('destroy', 'NegReg', (118, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (356, 367))	('PTPN12', 'Gene', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('prevent', 'NegReg', (149, 156))	('inserting', 'Var', (28, 37))	('promote', 'PosReg', (413, 420))	('tyrosine', 'Chemical', 'None', (207, 215))	('inactivate', 'NegReg', (383, 393))	('lung cancer', 'Disease', 'MESH:D008175', (356, 367))
60972	32042317	Given that mutation occurring in antitumor genes is a key trigger of tumorigenesis, pseudogene-induced epigenetic silencing of antitumor genes provides a new form of mutation during tumor development.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('epigenetic silencing', 'Var', (103, 123))	('tumor', 'Disease', (131, 136))	('pseudogene-induced', 'Var', (84, 102))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('mutation', 'Var', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
60973	32042317	Because SEC1P can be detected in multiple cancer cell lines, expression of the FUT2 and SEC1P fusion is expected in tumors in vivo.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('FUT2', 'Gene', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('fusion', 'Var', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('SEC1P', 'Gene', (88, 93))
60976	32042317	For instance, intron 2 of BRCA1 DNA repair associated (BRCA1) and intron 2 of its pseudogene PsiBRCA1 can be exchanged by recombination, transferring BRCA1 into a "nonfunctional" gene without a tumor suppressive effect, which constitutes a new mechanism for inactivating antitumor genes.	('BRCA1', 'Gene', (150, 155))	('BRCA1', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Disease', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('DNA repair', 'biological_process', 'GO:0006281', ('32', '42'))	('transferring', 'Var', (137, 149))
60977	32042317	A canonical example of this function is the pseudogene of neuronal nitric oxide synthase (nNOS), which is a natural antisense regulator and transcribed with a significant antisense region to nNOS, resulting in the formation of a double-stranded RNA-RNA duplex and a decline in nNOS protein synthesis.	('protein', 'cellular_component', 'GO:0003675', ('282', '289'))	('nNOS protein synthesis', 'MPA', (277, 299))	('formation', 'biological_process', 'GO:0009058', ('214', '223'))	('nitric oxide', 'Chemical', 'MESH:D009569', (67, 79))	('decline', 'NegReg', (266, 273))	('RNA', 'cellular_component', 'GO:0005562', ('245', '248'))	('RNA', 'cellular_component', 'GO:0005562', ('249', '252'))	('protein synthesis', 'biological_process', 'GO:0006412', ('282', '299'))	('formation', 'MPA', (214, 223))	('pseudogene', 'Var', (44, 54))
60990	32042317	6) A single pseudogene in multiple disease regulation: Intriguingly, several pseudogenes can regulate and correlate closely with the diagnosis and prognosis of more than a single disease, e.g., PTENP1 in HCC, BC, GC, ccRCC and AD, SUMO1P3 in HCC, GC, CRC and PDAC, and HMGA1P6/7 in EEC, PT, TC, BC, UCS and OCS.	('HCC', 'Disease', (242, 245))	('RCC', 'Disease', 'MESH:D002292', (219, 222))	('HCC', 'Disease', (204, 207))	('HCC', 'Disease', 'MESH:D006528', (242, 245))	('HCC', 'Disease', 'MESH:D006528', (204, 207))	('OCS', 'Disease', (307, 310))	('regulation', 'biological_process', 'GO:0065007', ('43', '53'))	('EEC', 'Disease', (282, 285))	('SUMO1P3', 'Gene', (231, 238))	('UCS', 'Disease', (299, 302))	('HMGA1P6/7', 'Gene', (269, 278))	('RCC', 'Disease', (219, 222))	('GC', 'Disease', 'MESH:D013274', (213, 215))	('AD', 'Var', (227, 229))	('GC', 'Disease', 'MESH:D013274', (247, 249))	('CRC', 'Disease', (251, 254))	('PTENP1', 'Var', (194, 200))
60991	32042317	For example, ccRCC patients with low levels of PTENP1 show a shorter OS rate than do those with high PTENP1 levels; overexpression of OCT4-pg1 in GC due to aberrant amplification can result in a poor rate of life expectancy in GC patients.	('aberrant amplification', 'Var', (156, 178))	('GC', 'Disease', 'MESH:D013274', (146, 148))	('RCC', 'Disease', 'MESH:D002292', (15, 18))	('overexpression', 'PosReg', (116, 130))	('RCC', 'Disease', (15, 18))	('life expectancy', 'CPA', (208, 223))	('GC', 'Disease', 'MESH:D013274', (227, 229))
60992	32042317	In addition, SNPs in the pseudogene sequence correlate with prognosis; e.g., HCC patients who carry the GG allele of E2F3P1 show a worse OS than do those carrying the GA/AA allele.	('HCC', 'Disease', (77, 80))	('E2F3P1', 'Var', (117, 123))	('HCC', 'Disease', 'MESH:D006528', (77, 80))
60993	32042317	Moreover, by combining pseudogene expression with the tumor grade or stage, pseudogenes can indirectly predict OS in several diseases, especially cancer.	('pseudogene', 'Var', (23, 33))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('predict', 'Reg', (103, 110))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('pseudogenes', 'Var', (76, 87))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Disease', (54, 59))
60994	32042317	Intriguingly, a certain number of pseudogenes can be combined as a signature that helps stratify disease risk, as do the clues provided by research in kidney renal clear cell carcinoma (KIRC).	('pseudogenes', 'Var', (34, 45))	('KIRC', 'Disease', (186, 190))	('kidney renal clear cell carcinoma', 'Disease', (151, 184))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (151, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('KIRC', 'Disease', 'MESH:D002292', (186, 190))
60997	32042317	3) The majority of current pseudogene studies concentrate on the correlation between pseudogenes and cancer, and a shortage of evidence on other diseases is notable in this field.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('correlation', 'Interaction', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('pseudogenes', 'Var', (85, 96))
61009	30975094	Functionally, knockdown of YAP inhibited cell proliferation, migration and invasion.	('YAP', 'Gene', (27, 30))	('YAP', 'Gene', '10413', (27, 30))	('invasion', 'CPA', (75, 83))	('cell proliferation', 'CPA', (41, 59))	('knockdown', 'Var', (14, 23))	('inhibited', 'NegReg', (31, 40))	('cell proliferation', 'biological_process', 'GO:0008283', ('41', '59'))
61023	30975094	HOXA3, the HOXA gene near the 3' end of the cluster was found to induce cell migration in endothelial and epithelial cells possibly through cancer-associated hypermethylation.	('hypermethylation', 'Var', (158, 174))	('HOXA', 'Gene', '3197', (11, 15))	('cell migration', 'biological_process', 'GO:0016477', ('72', '86'))	('cancer', 'Disease', (140, 146))	('HOXA', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('induce', 'PosReg', (65, 71))	('HOXA', 'Gene', (11, 15))	('HOXA3', 'Gene', (0, 5))	('HOXA', 'Gene', '3197', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('HOXA3', 'Gene', '3200', (0, 5))
61037	30975094	The primary non-metastasis human ccRCC 786-O, and A498 cells, renal tubular HK-2 cells, and non- von Hippel-Lindau (VHL) mutated cancer CAKI cells were purchased from the American Type Culture Collection (ATCC) (Rockville, MD, USA).	('RCC', 'Disease', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('HK-2', 'CellLine', 'CVCL:0302', (76, 80))	('VHL', 'Disease', 'MESH:D006623', (116, 119))	('VHL', 'Disease', (116, 119))	('human', 'Species', '9606', (27, 32))	('mutated', 'Var', (121, 128))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('von Hippel-Lindau', 'Gene', (97, 114))	('HK-2', 'molecular_function', 'GO:0008256', ('76', '80'))	('A498', 'CellLine', 'CVCL:1056', (50, 54))	('von Hippel-Lindau', 'Gene', '7428', (97, 114))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
61043	30975094	Primary antibodies used were antibodies specific against HOXA3 (1:200, Sigma-Aldrich), YAP (1:500, Sigma-Aldrich), MMP-9 (1:500, Sigma-Aldrich), MMP-2 (1:500, ab37150, Abcam), FAK (1:500, Sigma-Aldrich), and Slug-1 (1:500, ab106077, Abcam).	('1:500', 'Var', (216, 221))	('FAK', 'Gene', '5747', (176, 179))	('MMP-2', 'Gene', '4313', (145, 150))	('MMP-9', 'Gene', '4318', (115, 120))	('YAP', 'Gene', (87, 90))	('1:200', 'Var', (64, 69))	('MMP-9', 'Gene', (115, 120))	('1:500', 'Var', (152, 157))	('MMP-2', 'Gene', (145, 150))	('HOXA3', 'Gene', (57, 62))	('MMP-9', 'molecular_function', 'GO:0004229', ('115', '120'))	('MMP-2', 'molecular_function', 'GO:0004228', ('145', '150'))	('FAK', 'molecular_function', 'GO:0004717', ('176', '179'))	('HOXA3', 'Gene', '3200', (57, 62))	('YAP', 'Gene', '10413', (87, 90))	('FAK', 'Gene', (176, 179))
61069	30975094	qRT-PCR reveled a marked reduction of YAP level in 786-O and A498 cells after YAP knockdown (Fig.	('reduction', 'NegReg', (25, 34))	('YAP', 'Gene', (38, 41))	('knockdown', 'Var', (82, 91))	('YAP', 'Gene', '10413', (78, 81))	('YAP', 'Gene', '10413', (38, 41))	('YAP', 'Gene', (78, 81))	('A498', 'CellLine', 'CVCL:1056', (61, 65))
61071	30975094	Furthermore, YAP knockdown suppressed colony formation, decelerated the wound closure rate and reduced migration and invasiveness of ccRCC cells, as detected by colony formation assay, wound-healing assay and transwell assay, respectively (Fig.	('invasiveness of', 'CPA', (117, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('knockdown', 'Var', (17, 26))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('suppressed', 'NegReg', (27, 37))	('RCC', 'Disease', (135, 138))	('formation', 'biological_process', 'GO:0009058', ('168', '177'))	('YAP', 'Gene', '10413', (13, 16))	('colony formation', 'CPA', (38, 54))	('reduced', 'NegReg', (95, 102))	('formation', 'biological_process', 'GO:0009058', ('45', '54'))	('wound closure rate', 'CPA', (72, 90))	('YAP', 'Gene', (13, 16))	('wound-healing', 'biological_process', 'GO:0042060', ('185', '198'))	('decelerated', 'NegReg', (56, 67))	('migration', 'CPA', (103, 112))
61072	30975094	These various observations suggest that knockdown of YAP could inhibit proliferation, migration and invasion of ccRCC cells.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('RCC', 'Disease', (114, 117))	('migration', 'CPA', (86, 95))	('invasion of', 'CPA', (100, 111))	('knockdown', 'Var', (40, 49))	('YAP', 'Gene', '10413', (53, 56))	('YAP', 'Gene', (53, 56))	('proliferation', 'CPA', (71, 84))	('inhibit', 'NegReg', (63, 70))
61073	30975094	Apart from a marked reduction of YAP level in ccRCC cells with YAP knockdown, expression levels of HOXA3 and the metastasis-associated gene MMP-9 were also significantly reduced, as detected by qRT-PCR (Fig.	('MMP-9', 'Gene', (140, 145))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('YAP', 'Gene', (63, 66))	('HOXA3', 'Gene', '3200', (99, 104))	('knockdown', 'Var', (67, 76))	('YAP', 'Gene', '10413', (33, 36))	('reduced', 'NegReg', (170, 177))	('MMP-9', 'molecular_function', 'GO:0004229', ('140', '145'))	('reduction', 'NegReg', (20, 29))	('YAP', 'Gene', (33, 36))	('expression levels', 'MPA', (78, 95))	('YAP', 'Gene', '10413', (63, 66))	('HOXA3', 'Gene', (99, 104))	('MMP-9', 'Gene', '4318', (140, 145))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('RCC', 'Disease', (48, 51))
61075	30975094	To investigate the influence of FAK activity on YAP activation in ccRCC cell lines, we used shRNA to knock down the endogenous expression of FAK in 786-O and A498 cells, and observed a significant decrease in FAK expression in ccRCC cells with FAK shRNA.	('RCC', 'Disease', 'MESH:C538614', (229, 232))	('YAP', 'Gene', (48, 51))	('FAK', 'Gene', (209, 212))	('FAK', 'molecular_function', 'GO:0004717', ('244', '247'))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('RCC', 'Disease', (68, 71))	('FAK', 'Gene', '5747', (244, 247))	('FAK', 'Gene', '5747', (209, 212))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('FAK', 'molecular_function', 'GO:0004717', ('141', '144'))	('YAP', 'Gene', '10413', (48, 51))	('FAK', 'Gene', (32, 35))	('FAK', 'molecular_function', 'GO:0004717', ('32', '35'))	('A498', 'CellLine', 'CVCL:1056', (158, 162))	('expression', 'MPA', (213, 223))	('FAK', 'Gene', (141, 144))	('knock', 'Var', (101, 106))	('FAK', 'Gene', '5747', (32, 35))	('RCC', 'Disease', (229, 232))	('ccRCC', 'Phenotype', 'HP:0006770', (227, 232))	('FAK', 'Gene', (244, 247))	('FAK', 'Gene', '5747', (141, 144))	('FAK', 'molecular_function', 'GO:0004717', ('209', '212'))	('decrease', 'NegReg', (197, 205))
61077	30975094	Collectively, our data indicate that FAK inactivation represses the YAP expression, which further down-regulates HOXA3 and MMP-9 in ccRCC cells.	('MMP-9', 'Gene', '4318', (123, 128))	('MMP-9', 'molecular_function', 'GO:0004229', ('123', '128'))	('FAK', 'Gene', (37, 40))	('MMP-9', 'Gene', (123, 128))	('FAK', 'Gene', '5747', (37, 40))	('HOXA3', 'Gene', (113, 118))	('inactivation', 'Var', (41, 53))	('YAP', 'Gene', '10413', (68, 71))	('represses', 'NegReg', (54, 63))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('RCC', 'Disease', (134, 137))	('YAP', 'Gene', (68, 71))	('HOXA3', 'Gene', '3200', (113, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (132, 137))	('FAK', 'molecular_function', 'GO:0004717', ('37', '40'))	('down-regulates', 'NegReg', (98, 112))
61084	30975094	In support of these results, we found an apparent decrease in HOXA3 protein expression in cells transfected with the miR-10b mimic, to an extent comparable to that achieved by transfected the cells with shHOXA3.	('HOXA3', 'Gene', (62, 67))	('HOXA3', 'Gene', '3200', (62, 67))	('miR-10b', 'Gene', '406903', (117, 124))	('HOXA3', 'Gene', (205, 210))	('HOXA3', 'Gene', '3200', (205, 210))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('miR-10b', 'Gene', (117, 124))	('mimic', 'Var', (125, 130))	('decrease', 'NegReg', (50, 58))
61090	30975094	Furthermore, HOXA3 knockdown significantly inhibited cell invasion and promoted cell apoptosis, while concomitant administration with miR-10b mimic had a pronounced synergistic effect (Fig.	('HOXA3', 'Gene', '3200', (13, 18))	('apoptosis', 'biological_process', 'GO:0006915', ('85', '94'))	('promoted', 'PosReg', (71, 79))	('inhibited', 'NegReg', (43, 52))	('knockdown', 'Var', (19, 28))	('miR-10b', 'Gene', (134, 141))	('miR-10b', 'Gene', '406903', (134, 141))	('apoptosis', 'biological_process', 'GO:0097194', ('85', '94'))	('cell invasion', 'CPA', (53, 66))	('HOXA3', 'Gene', (13, 18))	('cell apoptosis', 'CPA', (80, 94))
61093	30975094	MicroRNAs have been associated with tumor progression in various cancers including RCC, which is one of the most common malignant tumors.	('MicroRNAs', 'Var', (0, 9))	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('cancers', 'Disease', (65, 72))	('malignant tumors', 'Disease', (120, 136))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('associated with', 'Reg', (20, 35))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('malignant tumors', 'Disease', 'MESH:D018198', (120, 136))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', (36, 41))
61108	30975094	Overexpressed miR-10b reduced HOXA3 expression to levels similar to those in ccRCC cells treated with shHOXA3, whereas miR-10b depletion dramatically enhanced HOXA3 expression (Fig.	('HOXA3', 'Gene', (104, 109))	('enhanced', 'PosReg', (150, 158))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('HOXA3', 'Gene', (159, 164))	('HOXA3', 'Gene', '3200', (159, 164))	('miR-10b', 'Gene', (119, 126))	('HOXA3', 'Gene', '3200', (104, 109))	('miR-10b', 'Gene', '406903', (14, 21))	('depletion', 'Var', (127, 136))	('miR-10b', 'Gene', '406903', (119, 126))	('HOXA3', 'Gene', (30, 35))	('reduced', 'NegReg', (22, 29))	('miR-10b', 'Gene', (14, 21))	('HOXA3', 'Gene', '3200', (30, 35))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
61110	30975094	In addition, inhibition of miR-10 could completely rescue the decreased proliferation, migration and invasion by HOXA3 knockdown.	('migration', 'CPA', (87, 96))	('decreased', 'NegReg', (62, 71))	('miR-10', 'Gene', '10288', (27, 33))	('inhibition', 'Var', (13, 23))	('miR-10', 'Gene', (27, 33))	('knockdown', 'Var', (119, 128))	('HOXA3', 'Gene', (113, 118))	('HOXA3', 'Gene', '3200', (113, 118))	('invasion', 'CPA', (101, 109))
61116	30975094	In line with previous findings, knockdown of YAP dramatically inhibited proliferation, migration and invasion capabilities of ccRCC cells (Fig.	('migration', 'CPA', (87, 96))	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('YAP', 'Gene', (45, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('proliferation', 'CPA', (72, 85))	('knockdown', 'Var', (32, 41))	('inhibited', 'NegReg', (62, 71))	('invasion capabilities', 'CPA', (101, 122))	('YAP', 'Gene', '10413', (45, 48))
61117	30975094	Moreover, YAP depletion resulted in a marked reduction in HOXA3 expression (Fig.	('HOXA3', 'Gene', '3200', (58, 63))	('YAP', 'Gene', (10, 13))	('depletion', 'Var', (14, 23))	('YAP', 'Gene', '10413', (10, 13))	('HOXA3', 'Gene', (58, 63))	('reduction', 'NegReg', (45, 54))
61118	30975094	3), while FAK knockdown reduced both YAP and HOXA3 expression in ccRCC cells (Fig.	('HOXA3', 'Gene', (45, 50))	('reduced', 'NegReg', (24, 31))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('YAP', 'Gene', '10413', (37, 40))	('RCC', 'Disease', (67, 70))	('HOXA3', 'Gene', '3200', (45, 50))	('FAK', 'molecular_function', 'GO:0004717', ('10', '13'))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('FAK', 'Gene', (10, 13))	('FAK', 'Gene', '5747', (10, 13))	('knockdown', 'Var', (14, 23))	('YAP', 'Gene', (37, 40))
61146	29568504	It is estimated that 50-60% of patients with sporadic ccRCC have an abnormality of the VHL gene - .	('VHL', 'Gene', '7428', (87, 90))	('RCC', 'Disease', (56, 59))	('abnormality', 'Var', (68, 79))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('patients', 'Species', '9606', (31, 39))	('VHL', 'Gene', (87, 90))
61147	29568504	Other, more sophisticated studies have suggested that VHL gene alterations through genetic and epigenetic mechanisms can be found in up to 90% of ccRCC cases .	('RCC', 'Disease', (148, 151))	('alterations', 'Var', (63, 74))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('VHL', 'Gene', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('VHL', 'Gene', '7428', (54, 57))
61155	29568504	These growth factors play a vital role in the development of highly vascular tumors (such as ccRCC) associated with VHL gene alterations.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('highly', 'Disease', (61, 67))	('vascular tumors', 'Disease', 'MESH:D019043', (68, 83))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('alterations', 'Var', (125, 136))	('associated', 'Reg', (100, 110))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('VHL', 'Gene', (116, 119))	('RCC', 'Disease', (95, 98))	('vascular tumors', 'Phenotype', 'HP:0100742', (68, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('gene alterations', 'Var', (120, 136))	('VHL', 'Gene', '7428', (116, 119))	('vascular tumors', 'Disease', (68, 83))
61159	29568504	From a therapeutic standpoint, inhibitors of VEGF are typically used as first-line therapy for the treatment of metastatic ccRCC.	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('VEGF', 'Gene', '7422', (45, 49))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('inhibitors', 'Var', (31, 41))	('VEGF', 'Gene', (45, 49))
61164	29568504	Selective HIF2 antagonists PT2399, PT2385, and PT2977 are under investigation - .	('PT2385', 'Var', (35, 41))	('PT2385', 'Chemical', 'MESH:C000614279', (35, 41))	('PT2977', 'Chemical', '-', (47, 53))	('PT2399', 'Var', (27, 33))	('PT2399', 'Chemical', 'MESH:C000614278', (27, 33))
61165	29568504	PT2399 has been shown to cause regression in preclinical models (cell line and tumorgraft/patient-derived xenograft) of pVHL-defective ccRCC , .	('PT2399', 'Chemical', 'MESH:C000614278', (0, 6))	('tumor', 'Disease', (79, 84))	('pVHL', 'Gene', '7428', (120, 124))	('patient', 'Species', '9606', (90, 97))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('PT2399', 'Var', (0, 6))	('RCC', 'Disease', (137, 140))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('regression', 'NegReg', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('pVHL', 'Gene', (120, 124))
61166	29568504	PT2385 has been evaluated as monotherapy in a phase 1 study in patients with metastatic ccRCC and has been shown to have a favorable safety profile and early evidence of efficacy .	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('PT2385', 'Var', (0, 6))	('PT2385', 'Chemical', 'MESH:C000614279', (0, 6))	('patients', 'Species', '9606', (63, 71))	('RCC', 'Disease', (90, 93))
61171	29568504	Re-introduction of PBRM-1 in PBRM-1-deficient cell lines typically produces cell cycle arrest.	('PBRM-1', 'Gene', '55193', (19, 25))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (76, 93))	('PBRM-1', 'Gene', (29, 35))	('cell cycle arrest', 'CPA', (76, 93))	('PBRM-1-deficient', 'Disease', (29, 45))	('PBRM-1-deficient', 'Disease', 'MESH:C565162', (29, 45))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('76', '93'))	('PBRM-1', 'Gene', (19, 25))	('Re-introduction', 'Var', (0, 15))	('produces', 'Reg', (67, 75))	('PBRM-1', 'Gene', '55193', (29, 35))
61172	29568504	Thus, a mutated PBRM-1 gene would result in an abnormal/malfunctioning BAF180, which would result in unchecked cell growth and subsequent tumorigenesis , .	('cell growth', 'biological_process', 'GO:0016049', ('111', '122'))	('tumor', 'Disease', (138, 143))	('BAF180', 'Gene', (71, 77))	('mutated', 'Var', (8, 15))	('BAF180', 'Gene', '55193', (71, 77))	('result in', 'Reg', (91, 100))	('PBRM-1', 'Gene', (16, 22))	('result in', 'Reg', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('PBRM-1', 'Gene', '55193', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
61179	29568504	A mutated BAP-1 protein is unable to interact with HCF-1; as a result, the inhibitory effects of HCF-1 on cell proliferation are lost .	('cell proliferation', 'CPA', (106, 124))	('inhibitory', 'MPA', (75, 85))	('protein', 'cellular_component', 'GO:0003675', ('16', '23'))	('HCF-1', 'Gene', (51, 56))	('mutated', 'Var', (2, 9))	('HCF-1', 'Gene', (97, 102))	('HCF-1', 'Gene', '3054', (51, 56))	('protein', 'Protein', (16, 23))	('HCF-1', 'Gene', '3054', (97, 102))	('BAP-1', 'Gene', '8314', (10, 15))	('BAP-1', 'Gene', (10, 15))	('lost', 'NegReg', (129, 133))	('cell proliferation', 'biological_process', 'GO:0008283', ('106', '124'))
61184	29568504	The phosphorylated P70SK migrates to the nucleus and initiates the transcription of mRNA coding for the HIFA protein, which, as mentioned above, has the ability to increase the production of angiogenic proteins such as VEGF, PDGF, and TGFB - .	('VEGF', 'Gene', (219, 223))	('HIFA', 'Chemical', '-', (104, 108))	('PDGF', 'molecular_function', 'GO:0005161', ('225', '229'))	('nucleus', 'cellular_component', 'GO:0005634', ('41', '48'))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('VEGF', 'Gene', '7422', (219, 223))	('TGFB', 'Gene', '7040', (235, 239))	('production of angiogenic proteins', 'MPA', (177, 210))	('P70SK', 'Var', (19, 24))	('transcription', 'biological_process', 'GO:0006351', ('67', '80'))	('increase', 'PosReg', (164, 172))	('TGFB', 'Gene', (235, 239))
61220	29568504	Therefore, inhibition of this pathway results in both cell cycle arrest (by decreasing pyrimidine synthesis required for DNA formation) and an inability of these cells to fight oxidative stress.	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('synthesis', 'biological_process', 'GO:0009058', ('98', '107'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (54, 71))	('DNA formation', 'biological_process', 'GO:0071897', ('121', '134'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('54', '71'))	('cell cycle arrest', 'CPA', (54, 71))	('inhibition', 'Var', (11, 21))	('inability', 'NegReg', (143, 152))	('decreasing', 'NegReg', (76, 86))	('pyrimidine', 'Chemical', 'MESH:C030986', (87, 97))	('oxidative stress', 'Phenotype', 'HP:0025464', (177, 193))
61238	28329682	However, the biological consequences of PBRM1 mutations for kidney tumorigenesis are unknown.	('kidney tumor', 'Phenotype', 'HP:0009726', (60, 72))	('mutations', 'Var', (46, 55))	('PBRM1', 'Gene', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
61239	28329682	Here, we find that kidney-specific deletion of Vhl and Pbrm1, but not either gene alone, results in bilateral, multifocal, transplantable clear cell kidney cancers.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('Vhl', 'Gene', '22346', (47, 50))	('Pbrm1', 'Gene', '66923', (55, 60))	('clear cell kidney cancer', 'Disease', 'MESH:D008649', (138, 162))	('clear cell kidney cancer', 'Phenotype', 'HP:0006770', (138, 162))	('results in', 'Reg', (89, 99))	('Vhl', 'Gene', (47, 50))	('kidney cancers', 'Phenotype', 'HP:0009726', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('kidney cancers', 'Disease', 'MESH:D007680', (149, 163))	('kidney cancer', 'Phenotype', 'HP:0009726', (149, 162))	('kidney cancers', 'Disease', (149, 163))	('deletion', 'Var', (35, 43))	('Pbrm1', 'Gene', (55, 60))	('clear cell kidney cancer', 'Disease', (138, 162))
61242	28329682	Our study reports a physiological preclinical ccRCC mouse model that recapitulates somatic mutations in human ccRCC and provides mechanistic and therapeutic insights into PBRM1 mutated subtypes of human ccRCC.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('RCC', 'Disease', (205, 208))	('PBRM1', 'Gene', (171, 176))	('mouse', 'Species', '10090', (52, 57))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('mutated', 'Var', (177, 184))	('human', 'Species', '9606', (104, 109))	('RCC', 'Disease', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('human', 'Species', '9606', (197, 202))	('RCC', 'Disease', (48, 51))
61244	28329682	After the loss of VHL, the loss of SWI/SNF tumor suppressor protein PBRM1/BAF180 further activates HIF1/STAT3 signaling in mouse kidney and positions mTORC1 activation as the preferred third driver event.	('STAT3', 'Gene', (104, 109))	('loss', 'Var', (27, 31))	('SWI/SNF tumor', 'Disease', (35, 48))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('mTORC1', 'Gene', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('43', '59'))	('VHL', 'Gene', (18, 21))	('HIF1', 'Gene', '3091', (99, 103))	('mTORC1', 'Gene', '382056', (150, 156))	('STAT3', 'Gene', '20848', (104, 109))	('mouse', 'Species', '10090', (123, 128))	('SWI/SNF tumor', 'Disease', 'MESH:D009369', (35, 48))	('BAF180', 'Gene', '66923', (74, 80))	('BAF180', 'Gene', (74, 80))	('HIF1', 'Gene', (99, 103))	('activates', 'PosReg', (89, 98))	('tumor suppressor', 'biological_process', 'GO:0051726', ('43', '59'))	('signaling', 'biological_process', 'GO:0023052', ('110', '119'))	('mTORC1', 'cellular_component', 'GO:0031931', ('150', '156'))
61252	28329682	Remarkably, these genes encode chromatin and epigenetic regulatory proteins, and most mutations are predicted to result in functional loss, favoring their roles as tumor suppressors.	('mutations', 'Var', (86, 95))	('tumor', 'Disease', (164, 169))	('epigenetic', 'Protein', (45, 55))	('chromatin', 'cellular_component', 'GO:0000785', ('31', '40'))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('loss', 'NegReg', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
61255	28329682	Interestingly, pan-cancer genomics have uncovered epigenetic regulators including SWI/SNF proteins as a major class of cancer genes.	('SWI/SNF proteins', 'Gene', (82, 98))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('epigenetic', 'Var', (50, 60))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
61256	28329682	Mutations of individual SWI/SNF subunits have been detected in ~20% of human cancers and they displayed preferential enrichment of mutations among cancer types.	('detected', 'Reg', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('SWI/SNF', 'Gene', (24, 31))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancer', 'Disease', (77, 83))	('cancers', 'Disease', (77, 84))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', (147, 153))	('human', 'Species', '9606', (71, 76))
61257	28329682	For example, PBRM1 is most highly mutated in ccRCC, SMARCB1 (BAF47) in pediatric rhabdoid tumors, and ARID1A (BAF250A) in ovarian clear-cell carcinoma, implicating underlying tissue tropism for disarming specific tumor suppressor gene (TSG) during tumorigenesis.	('pediatric rhabdoid tumors', 'Disease', (71, 96))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('BAF47', 'Gene', '20587', (61, 66))	('tumor', 'Disease', (248, 253))	('SMARCB1', 'Gene', (52, 59))	('tropism', 'biological_process', 'GO:0009606', ('182', '189'))	('tumor', 'Disease', (90, 95))	('SMARCB1', 'Gene', '20587', (52, 59))	('BAF250A', 'Gene', '93760', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('BAF47', 'Gene', (61, 66))	('ovarian clear-cell carcinoma', 'Disease', 'MESH:D008649', (122, 150))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('213', '229'))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('BAF250A', 'Gene', (110, 117))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('mutated', 'Var', (34, 41))	('tumor', 'Disease', (213, 218))	('TSG', 'Gene', '65960', (236, 239))	('tumor suppressor', 'biological_process', 'GO:0051726', ('213', '229'))	('ARID1A', 'Gene', (102, 108))	('TSG', 'Gene', (236, 239))	('PBRM1', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('ARID1A', 'Gene', '93760', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('RCC', 'Disease', (47, 50))	('ovarian clear-cell carcinoma', 'Disease', (122, 150))	('pediatric rhabdoid tumors', 'Disease', 'MESH:D018335', (71, 96))
61260	28329682	In vitro studies demonstrated that PBRM1 activated p21 upon irradiation in breast cancer cell lines and participated in p53-induced replicative senescence in fibroblasts, and PBRM1 knockdown enhanced proliferation and migration of kidney cancer cell lines.	('migration of kidney cancer', 'Disease', 'MESH:D007680', (218, 244))	('enhanced', 'PosReg', (191, 199))	('PBRM1', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('replicative senescence', 'biological_process', 'GO:0090399', ('132', '154'))	('migration of kidney cancer', 'Disease', (218, 244))	('PBRM1', 'Gene', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('kidney cancer', 'Phenotype', 'HP:0009726', (231, 244))	('participated', 'Reg', (104, 116))	('p53', 'Gene', (120, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('p53', 'Gene', '22060', (120, 123))	('activated', 'PosReg', (41, 50))	('replicative', 'MPA', (132, 143))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('breast cancer', 'Disease', (75, 88))	('p21', 'Gene', (51, 54))	('proliferation', 'CPA', (200, 213))	('p21', 'Gene', '237052', (51, 54))	('knockdown', 'Var', (181, 190))
61264	28329682	Here, we created kidney-specific deletion of Pbrm1 and/or Vhl mice to study the tumor suppressor role of PBRM1 and sought to establish a physiological mouse kidney cancer model that recapitulates human ccRCC.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('deletion', 'Var', (33, 41))	('RCC', 'Disease', (204, 207))	('mice', 'Species', '10090', (62, 66))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))	('mouse', 'Species', '10090', (151, 156))	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('Vhl', 'Gene', (58, 61))	('kidney cancer', 'Disease', 'MESH:D007680', (157, 170))	('tumor', 'Disease', (80, 85))	('Pbrm1', 'Gene', (45, 50))	('kidney cancer', 'Phenotype', 'HP:0009726', (157, 170))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('kidney cancer', 'Disease', (157, 170))	('human', 'Species', '9606', (196, 201))	('Vhl', 'Gene', '22346', (58, 61))	('Pbrm1', 'Gene', '66923', (45, 50))
61265	28329682	As Pbrm1 (BAF180) deletion in mice incurred embryonic lethality, we deleted the conditional Pbrm1F allele in the mouse kidney using a transgenic Cre recombinase line Ksp-Cre that has been widely utilized to model kidney cancer in mice.	('kidney cancer', 'Disease', 'MESH:D007680', (213, 226))	('mice', 'Species', '10090', (30, 34))	('embryonic lethality', 'Disease', 'MESH:D020964', (44, 63))	('Pbrm1', 'Gene', (92, 97))	('embryonic lethality', 'Disease', (44, 63))	('Pbrm1', 'Gene', '66923', (92, 97))	('mice', 'Species', '10090', (230, 234))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('kidney cancer', 'Disease', (213, 226))	('BAF180', 'Gene', '66923', (10, 16))	('Pbrm1', 'Gene', (3, 8))	('Pbrm1', 'Gene', '66923', (3, 8))	('BAF180', 'Gene', (10, 16))	('mouse', 'Species', '10090', (113, 118))	('deletion', 'Var', (18, 26))	('kidney cancer', 'Phenotype', 'HP:0009726', (213, 226))
61272	28329682	As neither Vhl nor Pbrm1 deletion alone caused kidney tumors, VhlF/FPbrm1F/FKsp-Cre mice were generated to investigate the genetic interaction between Vhl and Pbrm1 deficiency in kidney cancer pathogenesis.	('kidney tumors', 'Disease', 'MESH:D007674', (47, 60))	('Pbrm1', 'Gene', '66923', (19, 24))	('kidney cancer', 'Phenotype', 'HP:0009726', (179, 192))	('kidney tumors', 'Phenotype', 'HP:0009726', (47, 60))	('Pbrm1', 'Gene', '66923', (68, 73))	('Pbrm1', 'Gene', (159, 164))	('mice', 'Species', '10090', (84, 88))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('Vhl', 'Gene', '22346', (151, 154))	('deficiency in kidney cancer', 'Disease', (165, 192))	('Vhl', 'Gene', '22346', (62, 65))	('kidney tumor', 'Phenotype', 'HP:0009726', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('Vhl', 'Gene', (11, 14))	('caused', 'Reg', (40, 46))	('Pbrm1', 'Gene', '66923', (159, 164))	('kidney tumors', 'Disease', (47, 60))	('deficiency in kidney cancer', 'Disease', 'MESH:D007680', (165, 192))	('Pbrm1', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('Vhl', 'Gene', '22346', (11, 14))	('Pbrm1', 'Gene', (68, 73))	('pathogenesis', 'biological_process', 'GO:0009405', ('193', '205'))	('Vhl', 'Gene', (62, 65))	('Vhl', 'Gene', (151, 154))	('deletion', 'Var', (25, 33))	('deficiency in kidney', 'Phenotype', 'HP:0000089', (165, 185))
61296	28329682	Higher proliferation index (Ki-67 staining) was observed in these Vhl and Pbrm1 doubly deficient clear cell kidney tumors whereas no alteration in cell death was detected by immunohistochemistry for cleaved caspase-3 and TUNEL assays (Figures S5B, S5C).	('Pbrm1', 'Gene', (74, 79))	('deficient clear cell kidney tumors', 'Disease', 'MESH:D008649', (87, 121))	('Pbrm1', 'Gene', '66923', (74, 79))	('clear cell kidney tumors', 'Phenotype', 'HP:0006770', (97, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('Vhl', 'Gene', '22346', (66, 69))	('deficient clear cell kidney tumors', 'Disease', (87, 121))	('S5C', 'Mutation', 'p.S5C', (248, 251))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('Higher', 'PosReg', (0, 6))	('Vhl', 'Gene', (66, 69))	('cell death', 'biological_process', 'GO:0008219', ('147', '157'))	('kidney tumor', 'Phenotype', 'HP:0009726', (108, 120))	('kidney tumors', 'Phenotype', 'HP:0009726', (108, 121))	('doubly', 'Var', (80, 86))
61321	28329682	Remarkably, the effects of Pbrm1 deletion on HIF1 and STAT3 targets manifested only under the premise of Vhl loss, resulting in a further increase of the HIF1 (P = 0.035) and STAT3 (P = 0.0022) motif activities when comparing VhlF/FPbrm1F/FKsp-Cre to VhlF/FKsp-Cre kidneys (Figure 5C).	('Pbrm1', 'Gene', (232, 237))	('deletion', 'Var', (33, 41))	('STAT3', 'Gene', '20848', (54, 59))	('Vhl', 'Gene', (251, 254))	('Pbrm1', 'Gene', '66923', (27, 32))	('Pbrm1', 'Gene', '66923', (232, 237))	('HIF1', 'Gene', '3091', (45, 49))	('STAT3', 'Gene', (54, 59))	('Vhl', 'Gene', (226, 229))	('HIF1', 'Gene', (45, 49))	('increase', 'PosReg', (138, 146))	('Vhl', 'Gene', '22346', (251, 254))	('Vhl', 'Gene', (105, 108))	('STAT3', 'Gene', '20848', (175, 180))	('HIF1', 'Gene', '3091', (154, 158))	('Vhl', 'Gene', '22346', (226, 229))	('loss', 'NegReg', (109, 113))	('HIF1', 'Gene', (154, 158))	('Pbrm1', 'Gene', (27, 32))	('STAT3', 'Gene', (175, 180))	('Vhl', 'Gene', '22346', (105, 108))
61325	28329682	To further interrogate this working hypothesis, qRT-PCR was performed on NIH3T3 cells with knockout of Vhl, Pbrm1, or both using CRISPR-Cas9.	('knockout', 'Var', (91, 99))	('Cas', 'cellular_component', 'GO:0005650', ('136', '139'))	('Vhl', 'Gene', '22346', (103, 106))	('NIH3T3', 'CellLine', 'CVCL:0594', (73, 79))	('Vhl', 'Gene', (103, 106))	('Pbrm1', 'Gene', '66923', (108, 113))	('Pbrm1', 'Gene', (108, 113))
61326	28329682	Indeed, the loss of PBRM1 further enhances HIF1 and the STAT3 signaling that was primed upon the loss of VHL (Figure S6G).	('STAT3', 'Gene', '20848', (56, 61))	('PBRM1', 'Gene', (20, 25))	('STAT3', 'Gene', (56, 61))	('HIF1', 'Gene', (43, 47))	('signaling', 'biological_process', 'GO:0023052', ('62', '71'))	('loss', 'Var', (12, 16))	('enhances', 'PosReg', (34, 42))	('HIF1', 'Gene', '3091', (43, 47))
61337	28329682	Significantly, dysregulation of the mTOR signaling pathway was shown in the Vhl and Pbrm1 doubly deficient tumors but not in the 12-week-old VhlF/FPbrm1F/FKsp-Cre renal cortices (Figures 5B, 6B, and 6C, and Table S4).	('doubly', 'Var', (90, 96))	('Pbrm1', 'Gene', '66923', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('Pbrm1', 'Gene', (147, 152))	('deficient tumors', 'Disease', (97, 113))	('Vhl', 'Gene', '22346', (141, 144))	('mTOR signaling pathway', 'Pathway', (36, 58))	('Pbrm1', 'Gene', '66923', (147, 152))	('Vhl', 'Gene', (76, 79))	('Vhl', 'Gene', '22346', (76, 79))	('signaling pathway', 'biological_process', 'GO:0007165', ('41', '58'))	('deficient tumors', 'Disease', 'MESH:D009369', (97, 113))	('Vhl', 'Gene', (141, 144))	('Pbrm1', 'Gene', (84, 89))
61343	28329682	It is noteworthy that Ddit4 or Redd1, a transcriptional target of HIF1, was significantly upregulated in Vhl and Pbrm1 doubly deficient kidney tumors (Figure 6E).	('Ddit4', 'Gene', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('Pbrm1', 'Gene', (113, 118))	('deficient kidney tumors', 'Disease', 'MESH:D007680', (126, 149))	('kidney tumor', 'Phenotype', 'HP:0009726', (136, 148))	('deficient kidney', 'Phenotype', 'HP:0000089', (126, 142))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('Redd1', 'Gene', '74747', (31, 36))	('doubly', 'Var', (119, 125))	('Pbrm1', 'Gene', '66923', (113, 118))	('upregulated', 'PosReg', (90, 101))	('Redd1', 'Gene', (31, 36))	('deficient kidney tumors', 'Disease', (126, 149))	('Ddit4', 'Gene', '74747', (22, 27))	('Vhl', 'Gene', (105, 108))	('HIF1', 'Gene', '3091', (66, 70))	('kidney tumors', 'Phenotype', 'HP:0009726', (136, 149))	('HIF1', 'Gene', (66, 70))	('Vhl', 'Gene', '22346', (105, 108))
61345	28329682	Several lines of clinical evidence support the importance of mTORC1 activation in the pathobiology of human ccRCC, including the known therapeutic benefit of administering mTORC1 inhibitors in treating metastatic ccRCC and the observed prevalent mTORC1 pathway activation in human ccRCC.	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('mTORC1', 'Gene', '382056', (172, 178))	('RCC', 'Disease', (283, 286))	('mTORC1', 'cellular_component', 'GO:0031931', ('246', '252'))	('mTORC1', 'cellular_component', 'GO:0031931', ('61', '67'))	('RCC', 'Disease', 'MESH:C538614', (283, 286))	('mTORC1', 'cellular_component', 'GO:0031931', ('172', '178'))	('human', 'Species', '9606', (102, 107))	('mTORC1', 'Gene', (246, 252))	('RCC', 'Disease', (215, 218))	('inhibitors', 'Var', (179, 189))	('mTORC1', 'Gene', '382056', (246, 252))	('activation', 'PosReg', (261, 271))	('RCC', 'Disease', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (215, 218))	('mTORC1', 'Gene', (61, 67))	('human', 'Species', '9606', (275, 280))	('mTORC1', 'Gene', (172, 178))	('mTORC1', 'Gene', '382056', (61, 67))
61347	28329682	Hence, activation of mTORC1 activity through additional genetic/epigenetic events may be required for the initiation of ccRCC in Vhl and Pbrm1 doubly deficient renal epithelial cells.	('Vhl', 'Gene', '22346', (129, 132))	('activity', 'MPA', (28, 36))	('mTORC1', 'Gene', '382056', (21, 27))	('mTORC1', 'cellular_component', 'GO:0031931', ('21', '27'))	('Vhl', 'Gene', (129, 132))	('Pbrm1', 'Gene', (137, 142))	('doubly', 'Var', (143, 149))	('Pbrm1', 'Gene', '66923', (137, 142))	('deficient renal epithelial', 'Disease', 'MESH:D007674', (150, 176))	('mTORC1', 'Gene', (21, 27))	('activation', 'PosReg', (7, 17))	('deficient renal epithelial', 'Disease', (150, 176))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))
61348	28329682	In fact, significant down-regulation of Tsc1 and Tsc2 was demonstrated in Vhl and Pbrm1 doubly deficient kidney tumors (Figure 6F), which would activate mTORC1 even when REDD1 was upregulated.	('REDD1', 'Gene', '74747', (170, 175))	('doubly', 'Var', (88, 94))	('Pbrm1', 'Gene', '66923', (82, 87))	('deficient kidney tumors', 'Disease', (95, 118))	('mTORC1', 'Gene', (153, 159))	('Tsc2', 'Gene', '22084', (49, 53))	('down-regulation', 'NegReg', (21, 36))	('mTORC1', 'Gene', '382056', (153, 159))	('kidney tumors', 'Phenotype', 'HP:0009726', (105, 118))	('Vhl', 'Gene', (74, 77))	('Tsc1', 'Gene', '64930', (40, 44))	('REDD1', 'Gene', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('mTORC1', 'cellular_component', 'GO:0031931', ('153', '159'))	('regulation', 'biological_process', 'GO:0065007', ('26', '36'))	('Tsc1', 'Gene', (40, 44))	('deficient kidney', 'Phenotype', 'HP:0000089', (95, 111))	('deficient kidney tumors', 'Disease', 'MESH:D007680', (95, 118))	('kidney tumor', 'Phenotype', 'HP:0009726', (105, 117))	('Pbrm1', 'Gene', (82, 87))	('activate', 'PosReg', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Tsc2', 'Gene', (49, 53))	('Vhl', 'Gene', '22346', (74, 77))
61349	28329682	In summary, the emergent mTORC1 activation detected in the Vhl and Pbrm1 doubly deficient ccRCC may represent a prerequisite oncogenic driver event in the pathogenesis of ccRCC once kidney epithelial cells lost VHL and PBRM1.	('Pbrm1', 'Gene', (67, 72))	('RCC', 'Disease', (173, 176))	('Pbrm1', 'Gene', '66923', (67, 72))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('activation', 'PosReg', (32, 42))	('mTORC1', 'Gene', '382056', (25, 31))	('Vhl', 'Gene', '22346', (59, 62))	('RCC', 'Disease', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('Vhl', 'Gene', (59, 62))	('mTORC1', 'Gene', (25, 31))	('mTORC1', 'cellular_component', 'GO:0031931', ('25', '31'))	('pathogenesis', 'biological_process', 'GO:0009405', ('155', '167'))	('doubly', 'Var', (73, 79))
61350	28329682	Contrary to the inability of Vhl deficiency to initiate ccRCC in mice, the Hif1alpha-M3 transgenic model (Hif1alpha-M3 TRACK) where kidney-specific overexpression of a non-degradable as well as transcriptionally active mutant HIF1alpha-M3 (P402A, F564A, N803A) resulted in renal cysts and small clear cell tumors in aged (14-22 months) mice.	('HIF1alpha', 'Gene', (226, 235))	('F564A', 'Var', (247, 252))	('N803A', 'Var', (254, 259))	('P402A', 'Var', (240, 245))	('RCC', 'Disease', (58, 61))	('overexpression', 'PosReg', (148, 162))	('inability of Vhl deficiency', 'Disease', (16, 43))	('tumors', 'Phenotype', 'HP:0002664', (306, 312))	('P402A', 'Mutation', 'p.P402A', (240, 245))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('mice', 'Species', '10090', (336, 340))	('renal cysts', 'Disease', (273, 284))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('inability of Vhl deficiency', 'Disease', 'MESH:D016388', (16, 43))	('mice', 'Species', '10090', (65, 69))	('tumors', 'Disease', (306, 312))	('renal cysts', 'Phenotype', 'HP:0000107', (273, 284))	('renal cysts', 'Disease', 'MESH:D007674', (273, 284))	('F564A', 'Mutation', 'p.F564A', (247, 252))	('Hif1alpha', 'Gene', '15251', (75, 84))	('tumors', 'Disease', 'MESH:D009369', (306, 312))	('Hif1alpha', 'Gene', '15251', (106, 115))	('resulted in', 'Reg', (261, 272))	('Hif1alpha', 'Gene', (75, 84))	('Hif1alpha', 'Gene', (106, 115))	('N803A', 'Mutation', 'p.N803A', (254, 259))	('HIF1alpha', 'Gene', '15251', (226, 235))
61351	28329682	Of note, oxygen-dependent hydroxylation of P402 and F564 of HIF1alpha by prolyl hydroxylase domain enzymes (PHDs) and of N803 by Factor Inhibiting HIF (FIH) enhances the HIF-VHL interaction, leading to its degradation.	('degradation', 'MPA', (206, 217))	('HIF1alpha', 'Gene', (60, 69))	('P402', 'Var', (43, 47))	('HIF-VHL', 'Disease', (170, 177))	('Factor Inhibiting HIF', 'Disease', (129, 150))	('FIH', 'Gene', (152, 155))	('F564', 'Var', (52, 56))	('enhances', 'PosReg', (157, 165))	('oxygen', 'Chemical', 'MESH:D010100', (9, 15))	('Factor Inhibiting HIF', 'Disease', 'MESH:C565433', (129, 150))	('degradation', 'biological_process', 'GO:0009056', ('206', '217'))	('HIF-VHL', 'Disease', 'MESH:D006623', (170, 177))	('FIH', 'Gene', '319594', (152, 155))	('HIF1alpha', 'Gene', '15251', (60, 69))
61352	28329682	Furthermore, hydroxylation of N803 by FIH also disrupts the interaction between HIF and transcription coactivator p300/CBP, thereby inhibiting HIF1-mediated transcription.	('HIF', 'Protein', (80, 83))	('p300', 'Gene', (114, 118))	('FIH', 'Gene', (38, 41))	('N803', 'Var', (30, 34))	('disrupts', 'NegReg', (47, 55))	('transcription', 'biological_process', 'GO:0006351', ('157', '170'))	('CBP', 'molecular_function', 'GO:0008140', ('119', '122'))	('HIF1', 'Gene', (143, 147))	('transcription', 'biological_process', 'GO:0006351', ('88', '101'))	('CBP', 'Gene', '12914', (119, 122))	('p300', 'Gene', '328572', (114, 118))	('FIH', 'Gene', '319594', (38, 41))	('interaction', 'Interaction', (60, 71))	('inhibiting', 'NegReg', (132, 142))	('CBP', 'Gene', (119, 122))	('hydroxylation', 'MPA', (13, 26))	('HIF1', 'Gene', '3091', (143, 147))
61359	28329682	The shared mTOR pathway aberration between these two different mouse ccRCC models supports the convergence on mTORC1 activation once HIF1 becomes hyperactive (Figures 7A, 7B, and 7C).	('HIF1', 'Gene', '3091', (133, 137))	('mTORC1', 'cellular_component', 'GO:0031931', ('110', '116'))	('mouse', 'Species', '10090', (63, 68))	('mTORC1', 'Gene', (110, 116))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('HIF1', 'Gene', (133, 137))	('aberration', 'Var', (24, 34))	('hyperactive', 'PosReg', (146, 157))	('mTOR pathway', 'Pathway', (11, 23))	('mTORC1', 'Gene', '382056', (110, 116))	('activation', 'PosReg', (117, 127))
61360	28329682	To determine whether this observation could be extended into human ccRCC bearing both VHL and PBRM1 mutations, we first compiled differentially expressed genes in human VHL and PBRM1 mutated ccRCC from the TCGA-KIRC dataset.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('PBRM1', 'Gene', (177, 182))	('RCC', 'Disease', (193, 196))	('mutated', 'Var', (183, 190))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('human', 'Species', '9606', (163, 168))	('human', 'Species', '9606', (61, 66))	('VHL', 'Gene', (169, 172))
61362	28329682	Next, we compared the differentially expressed genes identified in human VHL and PBRM1 mutated ccRCC to those shared between the two mouse models, which resulted in the identification of 1772 genes that were shared among these three ccRCC models (Figure 7B).	('VHL', 'Gene', (73, 76))	('RCC', 'Disease', (97, 100))	('mutated', 'Var', (87, 94))	('PBRM1', 'Gene', (81, 86))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (235, 238))	('RCC', 'Disease', (235, 238))	('mouse', 'Species', '10090', (133, 138))	('human', 'Species', '9606', (67, 72))
61364	28329682	Taken together, our study favors a scenario in which a sequence of at least three distinct genetic/epigenetic events including the loss of VHL, the loss of PBRM1, and the subsequent activation of mTORC1 are required for the development of ccRCC (Figure 7F).	('mTORC1', 'cellular_component', 'GO:0031931', ('196', '202'))	('VHL', 'Gene', (139, 142))	('mTORC1', 'Gene', '382056', (196, 202))	('loss', 'Var', (148, 152))	('loss', 'Var', (131, 135))	('mTORC1', 'Gene', (196, 202))	('activation', 'PosReg', (182, 192))	('RCC', 'Disease', 'MESH:C538614', (241, 244))	('RCC', 'Disease', (241, 244))	('PBRM1', 'Gene', (156, 161))
61365	28329682	VHL is the most commonly mutated gene in human ccRCC and its mutation serves as the initial driver event in the pathogenesis of ccRCC.	('pathogenesis', 'biological_process', 'GO:0009405', ('112', '124'))	('RCC', 'Disease', (49, 52))	('mutation', 'Var', (61, 69))	('human', 'Species', '9606', (41, 46))	('VHL', 'Gene', (0, 3))	('RCC', 'Disease', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
61366	28329682	However, genetic deletion of Vhl in mice is insufficient to initiate kidney tumors, favoring the involvement of additional genetic/epigenetic events.	('Vhl', 'Gene', '22346', (29, 32))	('insufficient to initiate kidney tumors', 'Disease', (44, 82))	('insufficient to initiate kidney tumors', 'Disease', 'MESH:D051437', (44, 82))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('Vhl', 'Gene', (29, 32))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('genetic deletion', 'Var', (9, 25))	('kidney tumors', 'Phenotype', 'HP:0009726', (69, 82))	('mice', 'Species', '10090', (36, 40))	('kidney tumor', 'Phenotype', 'HP:0009726', (69, 81))
61370	28329682	Through tissue-specific deletion of both Vhl and Pbrm1 (VhlF/FPbrm1F/FKsp-Cre), we created a clear cell kidney cancer mouse model that recapitulates histopathological and molecular features of human ccRCC and elucidated how PBRM1 functions as a tumor suppressor in ccRCC.	('Vhl', 'Gene', '22346', (41, 44))	('clear cell kidney cancer', 'Disease', 'MESH:D008649', (93, 117))	('RCC', 'Disease', (267, 270))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('Pbrm1', 'Gene', (49, 54))	('deletion', 'Var', (24, 32))	('human', 'Species', '9606', (193, 198))	('RCC', 'Disease', (201, 204))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('RCC', 'Disease', 'MESH:C538614', (267, 270))	('Pbrm1', 'Gene', (62, 67))	('Vhl', 'Gene', '22346', (56, 59))	('mouse', 'Species', '10090', (118, 123))	('Pbrm1', 'Gene', '66923', (49, 54))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('clear cell kidney cancer', 'Disease', (93, 117))	('kidney cancer', 'Phenotype', 'HP:0009726', (104, 117))	('clear cell kidney cancer', 'Phenotype', 'HP:0006770', (93, 117))	('Vhl', 'Gene', (41, 44))	('tumor', 'Disease', (245, 250))	('Pbrm1', 'Gene', '66923', (62, 67))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('245', '261'))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor suppressor', 'biological_process', 'GO:0051726', ('245', '261'))	('Vhl', 'Gene', (56, 59))
61371	28329682	The VhlF/FPbrm1F/FKsp-Cre mice developed preneoplastic polycystic kidney lesions at ~6 months and multifocal ccRCC at ~10 months, suggesting that loss of Vhl and Pbrm1 in kidney predisposes to ccRCC.	('Vhl', 'Gene', '22346', (154, 157))	('preneoplastic polycystic kidney lesions', 'Disease', 'MESH:D007690', (41, 80))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('Vhl', 'Gene', '22346', (4, 7))	('RCC', 'Disease', (111, 114))	('Vhl', 'Gene', (154, 157))	('loss', 'Var', (146, 150))	('Pbrm1', 'Gene', (10, 15))	('polycystic kidney', 'Phenotype', 'HP:0000113', (55, 72))	('preneoplastic polycystic kidney lesions', 'Disease', (41, 80))	('predisposes', 'Reg', (178, 189))	('Vhl', 'Gene', (4, 7))	('Pbrm1', 'Gene', '66923', (10, 15))	('Pbrm1', 'Gene', (162, 167))	('Pbrm1', 'Gene', '66923', (162, 167))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('RCC', 'Disease', (195, 198))	('mice', 'Species', '10090', (26, 30))
61382	28329682	Moreover, mTORC1 pathway activation was also observed in human ccRCC carrying mutations of VHL and PBRM1 (Figure 6E).	('PBRM1', 'Gene', (99, 104))	('VHL', 'Gene', (91, 94))	('mTORC1', 'Gene', '382056', (10, 16))	('mutations', 'Var', (78, 87))	('mTORC1', 'cellular_component', 'GO:0031931', ('10', '16'))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('activation', 'PosReg', (25, 35))	('mTORC1', 'Gene', (10, 16))	('human', 'Species', '9606', (57, 62))	('RCC', 'Disease', (65, 68))
61383	28329682	Of note, multi-regional sequencing of a hereditary VHL syndrome patient also detected the mutations of PBRM1 and the convergence of mTORC1 pathway activation.	('hereditary VHL syndrome', 'Disease', (40, 63))	('mTORC1', 'Gene', (132, 138))	('mutations', 'Var', (90, 99))	('patient', 'Species', '9606', (64, 71))	('PBRM1', 'Gene', (103, 108))	('mTORC1', 'Gene', '382056', (132, 138))	('hereditary VHL syndrome', 'Disease', 'MESH:D006623', (40, 63))	('activation', 'PosReg', (147, 157))	('mTORC1', 'cellular_component', 'GO:0031931', ('132', '138'))
61386	28329682	It was recently reported that homozygous deletion of Vhl and Bap1 in mouse kidney resulted in early lethality (<1 month), and some mice (within a cohort of 7) carrying homozygous deletion of Vhl and heterozygous deletion of Bap1 developed tumor micronodules (0.25-1.8mm) with unknown tumor incidence, transplantability, and molecular characteristics.	('Bap1', 'Gene', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('developed', 'PosReg', (229, 238))	('Vhl', 'Gene', '22346', (191, 194))	('Bap1', 'Gene', (224, 228))	('Vhl', 'Gene', (53, 56))	('mouse', 'Species', '10090', (69, 74))	('deletion', 'Var', (212, 220))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('tumor', 'Disease', (239, 244))	('mice', 'Species', '10090', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('deletion', 'Var', (179, 187))	('Bap1', 'Gene', '104416', (61, 65))	('Vhl', 'Gene', '22346', (53, 56))	('Vhl', 'Gene', (191, 194))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Disease', (284, 289))	('Bap1', 'Gene', '104416', (224, 228))
61390	28329682	Inhibitors of mTORC1, the key cellular complex integrating nutrient and growth factor signaling to promote anabolic metabolism, are standard of care for metastatic ccRCC.	('mTORC1', 'Gene', (14, 20))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('RCC', 'Disease', (166, 169))	('Inhibitors', 'Var', (0, 10))	('mTORC1', 'Gene', '382056', (14, 20))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('mTORC1', 'cellular_component', 'GO:0031931', ('14', '20'))	('anabolic metabolism', 'MPA', (107, 126))	('metabolism', 'biological_process', 'GO:0008152', ('116', '126'))
61391	28329682	Interestingly, genomic study of RECORD-3, a large clinical trial randomized kidney cancer patients to either VEGFR or mTORC1 inhibitors, demonstrated that ccRCC with mutant PBRM1 associates with longer progression free survival (PFS) on everolimus, an mTORC1 inhibitor, at 12.8 months than those with wild-type PBRM1 at 5.5 months.	('longer', 'PosReg', (195, 201))	('mTORC1', 'cellular_component', 'GO:0031931', ('118', '124'))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('kidney cancer', 'Phenotype', 'HP:0009726', (76, 89))	('kidney cancer', 'Disease', (76, 89))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('VEGFR', 'Gene', '3791', (109, 114))	('mTORC1', 'cellular_component', 'GO:0031931', ('252', '258'))	('VEGFR', 'Gene', (109, 114))	('progression free survival', 'CPA', (202, 227))	('mutant', 'Var', (166, 172))	('patients', 'Species', '9606', (90, 98))	('everolimus', 'Chemical', 'MESH:D000068338', (237, 247))	('PBRM1', 'Gene', (173, 178))	('mTORC1', 'Gene', (118, 124))	('mTORC1', 'Gene', (252, 258))	('kidney cancer', 'Disease', 'MESH:D007680', (76, 89))	('mTORC1', 'Gene', '382056', (118, 124))	('RCC', 'Disease', (157, 160))	('mTORC1', 'Gene', '382056', (252, 258))
61392	28329682	In parallel, the VhlF/FPbrm1F/FKsp-Cre ccRCC and human VHL and PBRM1 mutated ccRCC shared mTORC1 pathway aberration.	('Pbrm1', 'Gene', '66923', (23, 28))	('Vhl', 'Gene', '22346', (17, 20))	('RCC', 'Disease', (79, 82))	('mTORC1', 'Gene', (90, 96))	('mutated', 'Var', (69, 76))	('mTORC1', 'Gene', '382056', (90, 96))	('human', 'Species', '9606', (49, 54))	('PBRM1', 'Gene', (63, 68))	('Vhl', 'Gene', (17, 20))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('mTORC1', 'cellular_component', 'GO:0031931', ('90', '96'))	('RCC', 'Disease', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('Pbrm1', 'Gene', (23, 28))
61393	28329682	Both clinical data and this study support a model in which mTORC1 activation constitutes the preferred third driver event during ccRCC tumorigenesis immediately after genetic inactivation of VHL and PBRM1 (Figure 7F), which serves as an example of preferential pathway convergent evolution of a given cancer type that could have predictive values for selecting patients of a given cancer genotype with matched targeted therapies.	('VHL', 'Gene', (191, 194))	('patients', 'Species', '9606', (361, 369))	('cancer', 'Phenotype', 'HP:0002664', (381, 387))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('PBRM1', 'Gene', (199, 204))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (131, 134))	('mTORC1', 'Gene', '382056', (59, 65))	('genetic inactivation', 'Var', (167, 187))	('tumor', 'Disease', (135, 140))	('cancer', 'Disease', (301, 307))	('mTORC1', 'cellular_component', 'GO:0031931', ('59', '65'))	('cancer', 'Disease', 'MESH:D009369', (381, 387))	('cancer', 'Disease', (381, 387))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('mTORC1', 'Gene', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
61402	28329682	Loss of Vhl and Pbrm1 in mouse kidney results in multifocal, transplantable ccRCC.	('Vhl', 'Gene', (8, 11))	('Pbrm1', 'Gene', (16, 21))	('Pbrm1', 'Gene', '66923', (16, 21))	('mouse', 'Species', '10090', (25, 30))	('RCC', 'Disease', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('Vhl', 'Gene', '22346', (8, 11))	('Loss', 'Var', (0, 4))
61403	28329682	In ccRCC, mTORC1 activation is the third driver event after loss of VHL and PBRM1.	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('mTORC1', 'Gene', '382056', (10, 16))	('VHL', 'Gene', (68, 71))	('RCC', 'Disease', (5, 8))	('loss', 'Var', (60, 64))	('mTORC1', 'cellular_component', 'GO:0031931', ('10', '16'))	('PBRM1', 'Gene', (76, 81))	('mTORC1', 'Gene', (10, 16))
61407	28329682	PBRM1, a SWI/SNF complex gene, is mutated in ~40% of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('PBRM1', 'Gene', (0, 5))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('9', '24'))	('mutated', 'Var', (34, 41))
61441	33510354	Next, we knocked down the AR expression via adding two AR-shRNA (shAR1# and shAR2#) in RCC AR-positive SW839 cells (Fig.	('shAR1', 'Var', (65, 70))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('SW839', 'CellLine', 'CVCL:3604', (103, 108))	('shAR2#', 'Var', (76, 82))	('knocked', 'Reg', (9, 16))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
61448	33510354	Consistent with this, western blot assay further showed that knocking down AR in SW839 cells could decrease TWIST1, a dominant VM-promoting gene, and overexpressing AR in 786O cells had the opposite effect (Fig.	('decrease', 'NegReg', (99, 107))	('TWIST1', 'Gene', (108, 114))	('TWIST1', 'Gene', '7291', (108, 114))	('knocking down', 'Var', (61, 74))	('SW839', 'CellLine', 'CVCL:3604', (81, 86))
61451	33510354	In contrast, oeTWIST1 in SW839 cells increased VM formation, especially after knocking down the endogenous AR (Fig.	('formation', 'biological_process', 'GO:0009058', ('50', '59'))	('endogenous AR', 'MPA', (96, 109))	('SW839', 'CellLine', 'CVCL:3604', (25, 30))	('increased', 'PosReg', (37, 46))	('VM formation', 'MPA', (47, 59))	('knocking', 'Var', (78, 86))	('TWIST1', 'Gene', (15, 21))	('TWIST1', 'Gene', '7291', (15, 21))
61459	33510354	1b, VM occurred more frequently in the TWIST1 high expression group.	('TWIST1', 'Gene', (39, 45))	('TWIST1', 'Gene', '7291', (39, 45))	('high expression', 'Var', (46, 61))
61466	33510354	As miRNA usually destabilizes its target genes in the Ago2-containing RISC complex (RNA-induced silencing complex), we performed immunoprecipitation of Ago2 followed by detection of TWIST1 mRNA.	('TWIST1', 'Gene', (182, 188))	('miRNA', 'Var', (3, 8))	('TWIST1', 'Gene', '7291', (182, 188))	('Ago2', 'Gene', '27161', (152, 156))	('RISC', 'Gene', (70, 74))	('Ago2', 'Gene', '27161', (54, 58))	('Ago2', 'Gene', (152, 156))	('destabilizes', 'NegReg', (17, 29))	('RISC', 'Gene', '59342', (70, 74))	('RISC complex', 'cellular_component', 'GO:0016442', ('70', '82'))	('Ago2', 'Gene', (54, 58))	('RNA-induced silencing complex', 'cellular_component', 'GO:0016442', ('84', '113'))
61470	33510354	Furthermore, results from the RNA pull-down assay via TWIST1 mRNA showed that overexpressing AR in 786O cells could lead to ENST00000425110.1 and ENST00000377977.3 binding more to TWIST1 mRNA compared with pWPI group (Fig.	('ENST00000377977.3', 'Var', (146, 163))	('ENST00000425110.1', 'Var', (124, 141))	('TWIST1', 'Gene', (180, 186))	('TWIST1', 'Gene', '7291', (180, 186))	('binding', 'molecular_function', 'GO:0005488', ('164', '171'))	('RNA', 'cellular_component', 'GO:0005562', ('30', '33'))	('more', 'PosReg', (172, 176))	('TWIST1', 'Gene', (54, 60))	('TWIST1', 'Gene', '7291', (54, 60))	('binding', 'Interaction', (164, 171))
61471	33510354	2c) indicated that knockdown of ENST00000425110.1 and ENST00000377977.3 could suppress TWIST1 expression more in the oeAR group than in the control group (Fig.	('ENST00000377977.3', 'Var', (54, 71))	('TWIST1', 'Gene', (87, 93))	('TWIST1', 'Gene', '7291', (87, 93))	('suppress', 'NegReg', (78, 86))	('expression', 'MPA', (94, 104))	('ENST00000425110.1', 'Var', (32, 49))
61472	33510354	In addition, western blot assays revealed that only ENST00000425110.1 overexpression could rescue the decline in TWIST1 protein induced by knocking down AR.	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('knocking down', 'Var', (139, 152))	('decline', 'NegReg', (102, 109))	('TWIST1', 'Gene', (113, 119))	('TWIST1', 'Gene', '7291', (113, 119))
61473	33510354	As expected, the overexpressed AR-elevated TWIST 1 protein level decreased drastically via knockdown of ENST00000425110.1 (TANAR) (Fig.	('decreased', 'NegReg', (65, 74))	('ENST00000425110.1', 'Gene', (104, 121))	('knockdown', 'Var', (91, 100))	('TWIST 1', 'Gene', (43, 50))	('TWIST 1', 'Gene', '7291', (43, 50))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
61474	33510354	Consistent with these results, we also found that overexpressing ENST00000425110.1 in SW839 cells could increase VM formation, especially after knocking down the endogenous AR (Fig.	('increase', 'PosReg', (104, 112))	('knocking', 'Var', (144, 152))	('ENST00000425110.1', 'Var', (65, 82))	('VM formation', 'CPA', (113, 125))	('endogenous', 'MPA', (162, 172))	('overexpressing', 'PosReg', (50, 64))	('SW839', 'CellLine', 'CVCL:3604', (86, 91))	('formation', 'biological_process', 'GO:0009058', ('116', '125'))
61479	33510354	Furthermore, we mutated the critical sequences of ARE II/III and inserted the mutant (MT) promoter region of TANAR into pGL3 luciferase plasmid as well as the wild-type (WT) promoter (Fig.	('pGL3', 'Gene', '6391', (120, 124))	('pGL', 'molecular_function', 'GO:0004598', ('120', '123'))	('mutated', 'Var', (16, 23))	('pGL3', 'Gene', (120, 124))	('mutant', 'Var', (78, 84))
61480	33510354	As expected, the luciferase assay results showed that knocking down AR or adding Enz 10 microM significantly lessened luciferase activity in SW839 cells transfected with WT reporter, but not in the cells with the MT reporter (Fig.	('luciferase', 'Enzyme', (118, 128))	('luciferase activity', 'molecular_function', 'GO:0050248', ('118', '137'))	('lessened', 'NegReg', (109, 117))	('SW839', 'CellLine', 'CVCL:3604', (141, 146))	('luciferase activity', 'molecular_function', 'GO:0047077', ('118', '137'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('118', '137'))	('knocking down', 'Var', (54, 67))	('activity', 'MPA', (129, 137))	('luciferase activity', 'molecular_function', 'GO:0047712', ('118', '137'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('118', '137'))	('Enz', 'Chemical', 'MESH:C540278', (81, 84))
61481	33510354	In contrast, overexpressing AR or adding DHT 10 nM could drastically increase luciferase activity in 786O or SW839 cells with the WT reporter, but not in the cells with the reporter containing the MT ARE (Fig.	('luciferase activity', 'molecular_function', 'GO:0050397', ('78', '97'))	('increase', 'PosReg', (69, 77))	('SW839', 'CellLine', 'CVCL:3604', (109, 114))	('luciferase activity', 'molecular_function', 'GO:0047077', ('78', '97'))	('luciferase', 'Enzyme', (78, 88))	('DHT 10 nM', 'Var', (41, 50))	('luciferase activity', 'molecular_function', 'GO:0045289', ('78', '97'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('78', '97'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('78', '97'))	('DHT', 'Chemical', 'MESH:D013196', (41, 44))	('activity', 'MPA', (89, 97))
61484	33510354	Indeed, mRNA stability assay, using treatment with actinomycin, revealed that knocking down TANAR could block the overexpressing AR-increased TWIST1 mRNA stability (Fig.	('TANAR', 'Gene', (92, 97))	('block', 'NegReg', (104, 109))	('TWIST1', 'Gene', (142, 148))	('knocking down', 'Var', (78, 91))	('TWIST1', 'Gene', '7291', (142, 148))	('actinomycin', 'Chemical', 'MESH:D003609', (51, 62))	('overexpressing AR-increased', 'MPA', (114, 141))
61485	33510354	Furthermore, to test whether this binding is crucial for TANAR's regulation on TWIST1 mRNA, we constructed WT TANAR cDNA sequence and mutated it by deleting the TANAR-TWIST presumptive binding region (Fig.	('binding', 'molecular_function', 'GO:0005488', ('34', '41'))	('deleting', 'NegReg', (148, 156))	('TWIST1', 'Gene', (79, 85))	('binding', 'molecular_function', 'GO:0005488', ('185', '192'))	('TWIST', 'Gene', '7291', (167, 172))	('TWIST1', 'Gene', '7291', (79, 85))	('mutated', 'Var', (134, 141))	('regulation', 'biological_process', 'GO:0065007', ('65', '75'))	('TWIST', 'Gene', '7291', (79, 84))	('TWIST', 'Gene', (167, 172))	('TWIST', 'Gene', (79, 84))
61487	33510354	Moreover, mRNA stability assay, using actinomycin treatment, showed that AR knockdown-decreased TWIST1 mRNA stability could be rescued only by adding wild-type TANAR (Fig.	('TWIST1', 'Gene', (96, 102))	('TWIST1', 'Gene', '7291', (96, 102))	('actinomycin', 'Chemical', 'MESH:D003609', (38, 49))	('knockdown-decreased', 'Var', (76, 95))
61494	33510354	Consistent with that, overexpressing wild-type TANAR, but not mutant TANAR, reduced TWIST1 level in the UPF1 immunoprecipitation (Fig.	('mutant', 'Var', (62, 68))	('UPF1', 'Gene', (104, 108))	('reduced', 'NegReg', (76, 83))	('TWIST1', 'Gene', (84, 90))	('TWIST1', 'Gene', '7291', (84, 90))	('TANAR', 'Gene', (69, 74))	('UPF1', 'Gene', '5976', (104, 108))
61495	33510354	Knocking down TANAR significantly increases the TWIST1 level in UPF1 immunoprecipitation (Fig.	('UPF1', 'Gene', (64, 68))	('Knocking down', 'Var', (0, 13))	('TWIST1', 'Gene', (48, 54))	('TWIST1', 'Gene', '7291', (48, 54))	('UPF1', 'Gene', '5976', (64, 68))	('TANAR', 'Gene', (14, 19))	('increases', 'PosReg', (34, 43))
61498	33510354	Consistent with this, knocking down AR significantly reduced luciferase activity in SW839 cells transfected with pWPI-luc-TWIST1, but not in the cells with either of the 2 mutant plasmids (Fig.	('TWIST1', 'Gene', '7291', (122, 128))	('activity', 'MPA', (72, 80))	('luciferase', 'Enzyme', (61, 71))	('luciferase activity', 'molecular_function', 'GO:0047712', ('61', '80'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('61', '80'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('61', '80'))	('reduced', 'NegReg', (53, 60))	('luciferase activity', 'molecular_function', 'GO:0050397', ('61', '80'))	('SW839', 'CellLine', 'CVCL:3604', (84, 89))	('knocking down', 'Var', (22, 35))	('TWIST1', 'Gene', (122, 128))	('luciferase activity', 'molecular_function', 'GO:0047077', ('61', '80'))
61501	33510354	The luciferase activity decreased only when knocking down TANAR in SW839 cells transfected with pWPI-luc-TWIST1 (Fig.	('SW839', 'CellLine', 'CVCL:3604', (67, 72))	('luciferase activity', 'molecular_function', 'GO:0047077', ('4', '23'))	('activity', 'MPA', (15, 23))	('luciferase activity', 'molecular_function', 'GO:0050248', ('4', '23'))	('TANAR', 'Gene', (58, 63))	('luciferase activity', 'molecular_function', 'GO:0045289', ('4', '23'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('4', '23'))	('TWIST1', 'Gene', (105, 111))	('luciferase activity', 'molecular_function', 'GO:0050397', ('4', '23'))	('luciferase', 'Enzyme', (4, 14))	('knocking down', 'Var', (44, 57))	('TWIST1', 'Gene', '7291', (105, 111))
61507	33510354	7a-d), as well as in the left kidney in the oeAR xenografted groups while knocking down TANAR could partly reverse the oeAR-increased high chemiluminescence in ccRCC xenografts.	('TANAR', 'Gene', (88, 93))	('RCC', 'Disease', (162, 165))	('RCC', 'Phenotype', 'HP:0005584', (162, 165))	('ccRCC', 'Phenotype', 'HP:0006770', (160, 165))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('high chemiluminescence', 'MPA', (134, 156))	('knocking down', 'Var', (74, 87))
61517	33510354	Consistent with pathological data, ectopic expression or DHT-induced activation of AR increases, whereas knockdown of AR or Enz-induced inactivation of AR decreases, the classical Matrigel-coated 2D VM formation.	('DHT-induced', 'Var', (57, 68))	('increases', 'PosReg', (86, 95))	('decreases', 'NegReg', (155, 164))	('formation', 'biological_process', 'GO:0009058', ('202', '211'))	('Enz', 'Chemical', 'MESH:C540278', (124, 127))	('ectopic expression', 'MPA', (35, 53))	('DHT', 'Chemical', 'MESH:D013196', (57, 60))	('activation', 'PosReg', (69, 79))
61537	33510354	6a-k), we show lncRNA-TANAR increases TWIST1 mRNA stability via directly binding to its 5'UTR with disruption of UPF1 initiating nonsense-mediate TWIST1 mRNA decay.	('TWIST1', 'Gene', (38, 44))	('increases', 'PosReg', (28, 37))	('TWIST1', 'Gene', '7291', (38, 44))	('disruption', 'Var', (99, 109))	('UPF1', 'Gene', '5976', (113, 117))	('binding', 'Interaction', (73, 80))	('lncRNA-TANAR', 'Var', (15, 27))	('mRNA decay', 'biological_process', 'GO:0006402', ('153', '163'))	('TWIST1', 'Gene', (146, 152))	('TWIST1', 'Gene', '7291', (146, 152))	('binding', 'molecular_function', 'GO:0005488', ('73', '80'))	('UPF1', 'Gene', (113, 117))
61550	33510354	786-O cells transfected with Scr-luc, oeAR-luc, shTANAR-luc, or oeAR+shTANAR, were injected at 1 x 106 cells/mouse, into the left renal capsule of 8-week-old male athymic nude mice (n = 5 mice/group).	('mice', 'Species', '10090', (188, 192))	('Scr', 'Gene', '109559', (29, 32))	('mice', 'Species', '10090', (176, 180))	('nude mice', 'Species', '10090', (171, 180))	('Scr', 'Gene', (29, 32))	('capsule', 'cellular_component', 'GO:0042603', ('136', '143'))	('oeAR+shTANAR', 'Var', (64, 76))	('mouse', 'Species', '10090', (109, 114))
61572	32419773	RNA m6A modification, similar to traditional types of DNA and protein modification, can regulate RNA splicing, translocation, stability, and translation into protein.	('regulate', 'Reg', (88, 96))	('stability', 'MPA', (126, 135))	('m6A', 'Gene', '56339', (4, 7))	('protein modification', 'biological_process', 'GO:0036211', ('62', '82'))	('RNA splicing', 'biological_process', 'GO:0008380', ('97', '109'))	('RNA splicing', 'MPA', (97, 109))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))	('RNA', 'Gene', (0, 3))	('translation into protein', 'MPA', (141, 165))	('translocation', 'MPA', (111, 124))	('protein', 'cellular_component', 'GO:0003675', ('158', '165'))	('RNA', 'cellular_component', 'GO:0005562', ('97', '100'))	('m6A', 'Gene', (4, 7))	('translation', 'biological_process', 'GO:0006412', ('141', '152'))	('modification', 'Var', (8, 20))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))
61574	32419773	Currently, accumulative evidence have demonstrated that aberrant expression of those m6A RNA methylation regulators is associated with multiple diseases such as infertility, obesity, and even cancer.	('infertility', 'Phenotype', 'HP:0000789', (161, 172))	('obesity', 'Phenotype', 'HP:0001513', (174, 181))	('infertility', 'Disease', (161, 172))	('RNA methylation', 'biological_process', 'GO:0001510', ('89', '104'))	('obesity', 'Disease', 'MESH:D009765', (174, 181))	('RNA', 'cellular_component', 'GO:0005562', ('89', '92'))	('obesity', 'Disease', (174, 181))	('cancer', 'Disease', (192, 198))	('m6A', 'Gene', (85, 88))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('m6A', 'Gene', '56339', (85, 88))	('infertility', 'Disease', 'MESH:D007247', (161, 172))	('aberrant expression', 'Var', (56, 75))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('associated', 'Reg', (119, 129))
61626	32419773	The results exhibited that 5 out of 16 regulators were significantly associated with OS (p < 0.05), among which two regulators (HNRNPA2B1 and METTL3) were risky genes with HR > 1 whereas three regulators (METTL14, YTHDC1, YTHDF2) acted as protective genes with HR < 1 (Fig.	('YTHDF2', 'Gene', (222, 228))	('METTL3', 'Gene', '56339', (142, 148))	('YTHDC1', 'Gene', (214, 220))	('HR > 1', 'Var', (172, 178))	('YTHDC1', 'Gene', '91746', (214, 220))	('HNRNPA2B1', 'Gene', '3181', (128, 137))	('HNRNPA2B1', 'Gene', (128, 137))	('METTL14', 'Gene', '57721', (205, 212))	('METTL14', 'Gene', (205, 212))	('METTL3', 'Gene', (142, 148))	('YTHDF2', 'Gene', '51441', (222, 228))
61630	32419773	Coefficients generated from multivariate Cox analysis were applied to calculate each ccRCC patient's risk score using the following formula: risk score = (- 0.385) x METTL14 + (0.121) x METTL3.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('- 0.385', 'Var', (155, 162))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('METTL3', 'Gene', '56339', (186, 192))	('METTL14', 'Gene', (166, 173))	('METTL14', 'Gene', '57721', (166, 173))	('METTL3', 'Gene', (186, 192))	('patient', 'Species', '9606', (91, 98))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
61646	32419773	On the contrary, anti-oncogenic role of m6A methylation have also been reported by various studies.	('methylation', 'Var', (44, 55))	('anti-oncogenic', 'CPA', (17, 31))	('m6A', 'Gene', (40, 43))	('m6A', 'Gene', '56339', (40, 43))	('methylation', 'biological_process', 'GO:0032259', ('44', '55'))
61647	32419773	reported that reduced m6A methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer, implying its tumor suppressive role especially in endometrial cancer.	('endometrial cancer', 'Disease', 'MESH:D016889', (112, 130))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('AKT', 'Gene', (48, 51))	('endometrial cancer', 'Phenotype', 'HP:0012114', (182, 200))	('m6A', 'Gene', '56339', (22, 25))	('endometrial cancer', 'Disease', (182, 200))	('promote', 'PosReg', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('m6A', 'Gene', (22, 25))	('endometrial cancer', 'Disease', 'MESH:D016889', (182, 200))	('tumor', 'Disease', (145, 150))	('AKT', 'Gene', '207', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('proliferation', 'CPA', (76, 89))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('endometrial cancer', 'Phenotype', 'HP:0012114', (112, 130))	('methylation', 'Var', (26, 37))	('reduced', 'NegReg', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('activity', 'MPA', (52, 60))	('tumor', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('endometrial cancer', 'Disease', (112, 130))
61648	32419773	Moreover, m6A modifications were found to be decreased in hepatocellular carcinoma and involved in suppressing the tumor metastasis.	('hepatocellular carcinoma', 'Disease', (58, 82))	('modifications', 'Var', (14, 27))	('m6A', 'Gene', '56339', (10, 13))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (58, 82))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('suppressing', 'NegReg', (99, 110))	('tumor', 'Disease', (115, 120))	('decreased', 'NegReg', (45, 54))	('m6A', 'Gene', (10, 13))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (58, 82))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
61655	32419773	Previous studies reported that RNA m6A methylation could affect various biological processes and signaling pathways, such as self-renewal and tumorigenesis of cancer stem cells, RNA metabolism, the FTO/m6A/MYC/CEBPA signaling, and the IL-7/STAT5/SOCS pathways.	('STAT5', 'Gene', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('CEBPA', 'Gene', '1050', (210, 215))	('RNA metabolism', 'biological_process', 'GO:0016070', ('178', '192'))	('RNA', 'cellular_component', 'GO:0005562', ('31', '34'))	('IL-7', 'Gene', (235, 239))	('signaling pathways', 'Pathway', (97, 115))	('self-renewal', 'CPA', (125, 137))	('CEBPA', 'Gene', (210, 215))	('cancer', 'Disease', (159, 165))	('methylation', 'Var', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('RNA', 'MPA', (178, 181))	('signaling', 'biological_process', 'GO:0023052', ('216', '225'))	('RNA', 'cellular_component', 'GO:0005562', ('178', '181'))	('IL-7', 'molecular_function', 'GO:0005139', ('235', '239'))	('MYC', 'Gene', (206, 209))	('m6A', 'Gene', '56339', (202, 205))	('m6A', 'Gene', '56339', (35, 38))	('tumor', 'Disease', (142, 147))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('affect', 'Reg', (57, 63))	('m6A', 'Gene', (202, 205))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('FTO', 'Gene', '79068', (198, 201))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('m6A', 'Gene', (35, 38))	('FTO', 'Gene', (198, 201))	('SOCS', 'Gene', '1154', (246, 250))	('SOCS', 'Gene', (246, 250))	('IL-7', 'Gene', '3574', (235, 239))	('signaling', 'biological_process', 'GO:0023052', ('97', '106'))	('MYC', 'Gene', '4609', (206, 209))	('STAT5', 'Gene', '6776', (240, 245))	('biological processes', 'CPA', (72, 92))
61657	32419773	These results, taken together, uncovered that RNA m6A methylation could play a vital role in regulating the malignant process of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (129, 134))	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('methylation', 'Var', (54, 65))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('m6A', 'Gene', (50, 53))	('malignant process', 'CPA', (108, 125))	('RNA', 'cellular_component', 'GO:0005562', ('46', '49'))	('m6A', 'Gene', '56339', (50, 53))
61658	32419773	Previous study indicated that ccRCC patients with any copy number variations (CNVs) of the m6A RNA methylation regulators had worse OS and DFS than those with diploid genes.	('RNA', 'cellular_component', 'GO:0005562', ('95', '98'))	('worse', 'NegReg', (126, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('patients', 'Species', '9606', (36, 44))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('RNA methylation', 'biological_process', 'GO:0001510', ('95', '110'))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('m6A', 'Gene', (91, 94))	('RCC', 'Disease', (32, 35))	('copy number variations', 'Var', (54, 76))	('m6A', 'Gene', '56339', (91, 94))	('DFS', 'MPA', (139, 142))
61714	31831737	In particular, proteome-based versus mRNA-based subtyping associations, respectively, included (proteome-based) k1 to (mRNA-based) c1, k2 to both c3 and c10, k3 to c3, k4 to c5, k5 to c6, k6 to c7, and k7 to c8.	('k4 to c5', 'Var', (168, 176))	('k3 to c3', 'Var', (158, 166))	('c10', 'Gene', (153, 156))	('k5 to c6', 'Var', (178, 186))	('c10', 'Gene', '3226', (153, 156))
61729	31831737	2e), other tumors that were not breast could also manifest a k4-associated signature pattern.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('k4-associated', 'Var', (61, 74))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))
61958	33654583	Genetically, it is most characterized by deletions of the short arm of chromosome 3 and mutations of the VHL gene.	('VHL', 'Gene', (105, 108))	('mutations', 'Var', (88, 97))	('VHL', 'Gene', '7428', (105, 108))	('short arm', 'Phenotype', 'HP:0009824', (58, 67))	('chromosome', 'cellular_component', 'GO:0005694', ('71', '81'))	('deletions', 'Var', (41, 50))
61987	33654583	Some of them include treatment effects of the first cancer, age, lifestyle, environmental exposures, genetic mutations, and certain cytokines.	('genetic mutations', 'Var', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('men', 'Species', '9606', (83, 86))	('men', 'Species', '9606', (26, 29))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
62010	33654583	Most CCRCC is characterized by deletions and/or mutations on the short arm of chromosome 3 (3p), but PCM has not been found to bear 3p abnormalities.	('PCM', 'Phenotype', 'HP:0006775', (101, 104))	('chromosome', 'cellular_component', 'GO:0005694', ('78', '88'))	('deletions', 'Var', (31, 40))	('short arm', 'Phenotype', 'HP:0009824', (65, 74))	('RCC', 'Disease', 'MESH:C538614', (7, 10))	('RCC', 'Disease', (7, 10))	('RCC', 'Phenotype', 'HP:0005584', (7, 10))	('mutations', 'Var', (48, 57))	('CCRCC', 'Phenotype', 'HP:0006770', (5, 10))
62055	31150395	To this aim we first compare the variances between T1 and T3 tumors using Levene's test and detect six probes (ILMN_1762410 (SLC22A2), ILMN_1716246 (FRZB), ILMN_1677851 (RARRES1), ILMN_1746128 (ACSM2B), ILMN_3311035 (miR-1251) and ILMN_1793309 (BEND4)) with FDR below the standard 0.05 significance threshold.	('ILMN_1793309', 'Var', (231, 243))	('BEND4', 'Gene', (245, 250))	('T3 tumors', 'Disease', 'MESH:C537047', (58, 67))	('SLC22A2', 'Gene', (125, 132))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('RARRES1', 'Gene', '5918', (170, 177))	('T3 tumors', 'Disease', (58, 67))	('FRZB', 'Gene', (149, 153))	('RARRES1', 'Gene', (170, 177))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('ILMN_1716246', 'Var', (135, 147))	('ILMN_1762410', 'Var', (111, 123))	('ILMN_1746128', 'Var', (180, 192))	('ACSM2B', 'Gene', (194, 200))	('BEND4', 'Gene', '389206', (245, 250))	('FRZB', 'Gene', '2487', (149, 153))	('ILMN_1677851', 'Var', (156, 168))	('ACSM2B', 'Gene', '348158', (194, 200))	('ILMN_3311035', 'Var', (203, 215))	('SLC22A2', 'Gene', '6582', (125, 132))
62069	31150395	Overexpression of IL-6 is associated with enhanced invasiveness and epithelial-mesenchymal transition (EMT) and IL-6 is involved in a JAK/STAT signaling pathway.	('IL-6', 'Gene', '3569', (18, 22))	('epithelial-mesenchymal transition', 'CPA', (68, 101))	('involved', 'Reg', (120, 128))	('JAK', 'molecular_function', 'GO:0004713', ('134', '137'))	('enhanced', 'PosReg', (42, 50))	('IL-6', 'Gene', (112, 116))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('68', '101'))	('IL-6', 'molecular_function', 'GO:0005138', ('112', '116'))	('IL-6', 'Gene', '3569', (112, 116))	('EMT', 'biological_process', 'GO:0001837', ('103', '106'))	('Overexpression', 'Var', (0, 14))	('signaling pathway', 'biological_process', 'GO:0007165', ('143', '160'))	('IL-6', 'molecular_function', 'GO:0005138', ('18', '22'))	('IL-6', 'Gene', (18, 22))	('invasiveness', 'CPA', (51, 63))
62142	29069747	For example, ccRCC is characterized by silencing of the VHL gene and alteration of the hypoxia-inducible factor pathway; mutations of the MET and FH genes are commonly observed in type I and type II PCC, respectively; and abnormal TP53 and BHD genes have been implicated in Chromophobe.	('VHL', 'Gene', (56, 59))	('mutations', 'Var', (121, 130))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('TP53', 'Gene', '7157', (231, 235))	('PCC', 'Phenotype', 'HP:0006766', (199, 202))	('observed', 'Reg', (168, 176))	('alteration', 'Reg', (69, 79))	('BHD', 'Gene', (240, 243))	('PCC', 'cellular_component', 'GO:0120205', ('199', '202'))	('VHL', 'Gene', '7428', (56, 59))	('hypoxia', 'Disease', (87, 94))	('Chromophobe', 'Disease', (274, 285))	('hypoxia', 'Disease', 'MESH:D000860', (87, 94))	('TP53', 'Gene', (231, 235))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('RCC', 'Disease', (15, 18))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('implicated', 'Reg', (260, 270))	('silencing', 'NegReg', (39, 48))	('MET', 'Gene', (138, 141))	('BHD', 'Gene', '50947', (240, 243))
62153	29069747	In addition, we were not able to obtain complete clinical records regarding the patients' sporadic RCC risk factors, such as their BMI, hypertension, diabetes, and smoking, TNM stage, Furhman grade, gene-mutation results, and family history.	('hypertension', 'Disease', 'MESH:D006973', (136, 148))	('diabetes', 'Disease', 'MESH:D003920', (150, 158))	('patients', 'Species', '9606', (80, 88))	('hypertension', 'Disease', (136, 148))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('hypertension', 'Phenotype', 'HP:0000822', (136, 148))	('gene-mutation', 'Var', (199, 212))	('TNM', 'Gene', '10178', (173, 176))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('TNM', 'Gene', (173, 176))	('diabetes', 'Disease', (150, 158))
62154	29069747	We also excluded relatively rare RCC histological subtypes and benign tumors, such as angioleiomyolipoma, Xp11.2 translocation, and some others from our study.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('benign tumors', 'Disease', (63, 76))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('benign tumors', 'Disease', 'MESH:D009369', (63, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('angioleiomyolipoma', 'Disease', (86, 104))	('Xp11.2 translocation', 'Var', (106, 126))	('angioleiomyolipoma', 'Disease', 'None', (86, 104))
62193	29251173	A high percentage of ccRCCs has been shown to be associated with the inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('associated', 'Reg', (49, 59))	('inactivation', 'Var', (69, 81))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('von Hippel-Lindau (VHL) tumour', 'Disease', 'MESH:D006623', (89, 119))	('ccRCC', 'Phenotype', 'HP:0006770', (21, 26))	('ccRCC', 'Disease', (21, 26))	('ccRCC', 'Disease', 'MESH:D002292', (21, 26))
62195	29251173	Under hypoxic conditions, as well as in case of VHL inactivation, HIF-1alpha is stabilised and accumulates in the nucleus leading to subsequent over-expression of genes which are critical for tumour angiogenesis, glucose transport, epithelial proliferation, cell migration, and pH control.	('over-expression', 'PosReg', (144, 159))	('hypoxic conditions', 'Disease', (6, 24))	('VHL', 'Gene', '7428', (48, 51))	('glucose transport', 'biological_process', 'GO:1904659', ('213', '230'))	('HIF-1alpha', 'Gene', (66, 76))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('hypoxic conditions', 'Disease', 'MESH:D009135', (6, 24))	('glucose', 'Chemical', 'MESH:D005947', (213, 220))	('tumour', 'Disease', 'MESH:D009369', (192, 198))	('inactivation', 'Var', (52, 64))	('nucleus', 'cellular_component', 'GO:0005634', ('114', '121'))	('tumour', 'Disease', (192, 198))	('HIF-1alpha', 'Gene', '3091', (66, 76))	('cell migration', 'biological_process', 'GO:0016477', ('258', '272'))	('VHL', 'Gene', (48, 51))	('angiogenesis', 'biological_process', 'GO:0001525', ('199', '211'))
62199	29251173	In particular, CA IX is a downstream gene activated following either hypoxia (via HIF-1alpha) or VHL inactivation.	('VHL', 'Gene', '7428', (97, 100))	('CA IX', 'Gene', (15, 20))	('hypoxia', 'Disease', 'MESH:D000860', (69, 76))	('HIF-1alpha', 'Gene', '3091', (82, 92))	('inactivation', 'Var', (101, 113))	('hypoxia', 'Disease', (69, 76))	('HIF-1alpha', 'Gene', (82, 92))	('CA IX', 'Gene', '768', (15, 20))	('VHL', 'Gene', (97, 100))
62203	29251173	This difference could be a reflection of molecular mechanisms responsible for CA IX expression: high CA IX expression in other tumours than ccRCC is hypoxia-related, whereas, is linked to VHL inactivation in ccRCC, where the latter is itself a marker of good prognosis.	('ccRCC', 'Disease', (208, 213))	('CA IX', 'Gene', (78, 83))	('VHL', 'Gene', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (210, 213))	('CA IX', 'Gene', (101, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (208, 213))	('tumours', 'Disease', (127, 134))	('ccRCC', 'Disease', 'MESH:D002292', (140, 145))	('VHL', 'Gene', '7428', (188, 191))	('hypoxia', 'Disease', (149, 156))	('inactivation', 'Var', (192, 204))	('CA IX', 'Gene', '768', (78, 83))	('tumours', 'Phenotype', 'HP:0002664', (127, 134))	('ccRCC', 'Disease', (140, 145))	('tumours', 'Disease', 'MESH:D009369', (127, 134))	('CA IX', 'Gene', '768', (101, 106))	('hypoxia', 'Disease', 'MESH:D000860', (149, 156))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('ccRCC', 'Disease', 'MESH:D002292', (208, 213))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('expression', 'MPA', (107, 117))
62240	29251173	Similarly to CA IX, VEGF is a downstream gene activated following hypoxia and/or VHL inactivation.	('activated', 'PosReg', (46, 55))	('inactivation', 'Var', (85, 97))	('VHL', 'Gene', (81, 84))	('VEGF', 'Gene', '7422', (20, 24))	('CA IX', 'Gene', '768', (13, 18))	('VHL', 'Gene', '7428', (81, 84))	('hypoxia', 'Disease', (66, 73))	('CA IX', 'Gene', (13, 18))	('hypoxia', 'Disease', 'MESH:D000860', (66, 73))	('VEGF', 'Gene', (20, 24))
62255	29251173	A low pH has been associated with tumorigenic transformation, chromosomal rearrangements, extracellular matrix breakdown, tumour cell migration and invasion.	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('breakdown', 'biological_process', 'GO:0009056', ('111', '120'))	('low', 'Var', (2, 5))	('tumorigenic transformation', 'CPA', (34, 60))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('90', '110'))	('chromosomal', 'Disease', (62, 73))	('men', 'Species', '9606', (83, 86))	('tumour', 'Disease', (122, 128))	('associated', 'Reg', (18, 28))	('extracellular matrix breakdown', 'CPA', (90, 120))	('cell migration', 'biological_process', 'GO:0016477', ('129', '143'))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('invasion', 'CPA', (148, 156))
62262	29251173	Similarly to CA IX, VEGF is one of the HIF-1 target genes induced by either intratumoral hypoxia or VHL inactivation.	('intratumoral hypoxia', 'Disease', (76, 96))	('intratumoral hypoxia', 'Disease', 'MESH:D000860', (76, 96))	('HIF-1', 'Gene', '3091', (39, 44))	('VEGF', 'Gene', '7422', (20, 24))	('CA IX', 'Gene', '768', (13, 18))	('inactivation', 'Var', (104, 116))	('CA IX', 'Gene', (13, 18))	('HIF-1', 'Gene', (39, 44))	('VHL', 'Gene', (100, 103))	('VEGF', 'Gene', (20, 24))	('VHL', 'Gene', '7428', (100, 103))
62268	29251173	Tumour cell responses to hypoxic stress can be enhanced by proteomic and genomic changes, resulting in loss of apoptotic potential.	('hypoxic stress', 'Disease', (25, 39))	('enhanced', 'PosReg', (47, 55))	('changes', 'Var', (81, 88))	('Tumour cell responses', 'CPA', (0, 21))	('hypoxic stress', 'Disease', 'MESH:D054549', (25, 39))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('apoptotic potential', 'CPA', (111, 130))	('loss', 'NegReg', (103, 107))
62296	31527133	HIF accumulation drives the cellular hypoxic response leading to increased angiogenesis, glycolysis and aberrant fatty acid metabolism thus bestowing ccRCC with its characteristic glycogen and lipid-rich cytoplasmic deposits and hyper-vascularity.	('increased', 'PosReg', (65, 74))	('fatty acid metabolism', 'MPA', (113, 134))	('hyper-vascularity', 'Disease', (229, 246))	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('RCC', 'Disease', (152, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('glycolysis', 'biological_process', 'GO:0006096', ('89', '99'))	('glycolysis', 'MPA', (89, 99))	('glycogen', 'Chemical', 'MESH:D006003', (180, 188))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('113', '134'))	('angiogenesis', 'MPA', (75, 87))	('aberrant', 'Var', (104, 112))	('fatty acid', 'Chemical', 'MESH:D005227', (113, 123))	('angiogenesis', 'biological_process', 'GO:0001525', ('75', '87'))	('lipid', 'Chemical', 'MESH:D008055', (193, 198))	('hyper-vascularity', 'Disease', 'MESH:D000783', (229, 246))	('aberrant fatty acid metabolism', 'Phenotype', 'HP:0004359', (104, 134))
62297	31527133	It is well appreciated that angiogenesis and immunity are closely interlinked, and targeting VEGF can promote immune surveillance by normalising dysfunctional tumor vessels.	('angiogenesis', 'biological_process', 'GO:0001525', ('28', '40'))	('VEGF', 'Gene', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('promote', 'PosReg', (102, 109))	('dysfunctional tumor', 'Disease', (145, 164))	('VEGF', 'Gene', '7422', (93, 97))	('dysfunctional tumor', 'Disease', 'MESH:D009369', (145, 164))	('targeting', 'Var', (83, 92))	('immune surveillance', 'MPA', (110, 129))
62320	31527133	It is generally thought that tumor-specific mutations give rise to immunogenic neo-antigens that can drive immune infiltration, a prerequisite for ICI efficacy.	('immune infiltration', 'CPA', (107, 126))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('mutations', 'Var', (44, 53))	('drive', 'PosReg', (101, 106))	('give rise to', 'Reg', (54, 66))	('immunogenic neo-antigens', 'MPA', (67, 91))
62326	31527133	Although non-synonymous single nucleotide variants (nsSNVs) are the most established readout of TMB, frameshifts caused by small nucleotide insertions or deletions (indels) are predicted to generate more immunogenic neoantigens than nsSNVs.	('immunogenic neoantigens', 'MPA', (204, 227))	('small nucleotide insertions', 'Var', (123, 150))	('TMB', 'Chemical', '-', (96, 99))	('deletions', 'Var', (154, 163))	('frameshifts', 'Var', (101, 112))	('generate more', 'PosReg', (190, 203))
62327	31527133	In pan-cancer comparisons, indels are strikingly abundant in ccRCC perhaps explaining the disparity between low SNVs and high immune infiltration.	('RCC', 'Disease', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('indels', 'Var', (27, 33))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
62328	31527133	However in the IMmotion-150 phase II trial, indels and frameshift burdens were not significantly associated with response to atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF).	('PD-L1', 'Gene', '29126', (144, 149))	('VEGF', 'Gene', '7422', (192, 196))	('indels', 'Var', (44, 50))	('bevacizumab', 'Chemical', 'MESH:D000068258', (174, 185))	('frameshift burdens', 'Var', (55, 73))	('VEGF', 'Gene', (192, 196))	('PD-L1', 'Gene', (144, 149))	('atezolizumab', 'Chemical', 'MESH:C000594389', (125, 137))	('associated', 'Reg', (97, 107))
62349	31527133	This suggests that the CD38+ M5 macrophage subset may be pro-inflammatory in nature, promoting initial T cell activation and eventual exhaustion in ccRCC, but further functional characterisation is required.	('activation', 'PosReg', (110, 120))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('RCC', 'Disease', (150, 153))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('T cell', 'CPA', (103, 109))	('CD38+ M5', 'Var', (23, 31))	('T cell activation', 'biological_process', 'GO:0042110', ('103', '120'))	('promoting', 'PosReg', (85, 94))
62351	31527133	It is tempting to speculate that these M11 TAMs may be involved in T cell exclusion, a phenomena recently reported in human lung tumors and mouse breast cancer models.	('mouse', 'Species', '10090', (140, 145))	('TAMs', 'Chemical', '-', (43, 47))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('T cell exclusion', 'Disease', (67, 83))	('involved', 'Reg', (55, 63))	('lung tumors', 'Disease', 'MESH:D008175', (124, 135))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Disease', (146, 159))	('M11 TAMs', 'Var', (39, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('human', 'Species', '9606', (118, 123))	('lung tumors', 'Phenotype', 'HP:0100526', (124, 135))	('lung tumors', 'Disease', (124, 135))
62352	31527133	In fitting with this hypothesis, low M5, high M11 and high M13 macrophages corresponded to poor survival in ccRCC, but validation is required in larger cohorts.	('RCC', 'Disease', (110, 113))	('high M11', 'Var', (41, 49))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('high M13', 'Var', (54, 62))	('low M5', 'Var', (33, 39))	('poor', 'NegReg', (91, 95))
62363	31527133	Pre-surgical pazopanib is associated with a reduction in CD8+ T cell infiltration, increased PD-L1 expression, and enhanced DC activation proposed through downregulation of the p-ERK/beta-catenin pathway.	('expression', 'MPA', (99, 109))	('beta-catenin', 'Gene', (183, 195))	('CD8', 'Gene', '925', (57, 60))	('pazopanib', 'Chemical', 'MESH:C516667', (13, 22))	('beta-catenin', 'Gene', '1499', (183, 195))	('ERK', 'Gene', (179, 182))	('increased', 'PosReg', (83, 92))	('ERK', 'molecular_function', 'GO:0004707', ('179', '182'))	('reduction', 'NegReg', (44, 53))	('downregulation', 'NegReg', (155, 169))	('PD-L1', 'Gene', (93, 98))	('ERK', 'Gene', '2048', (179, 182))	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('PD-L1', 'Gene', '29126', (93, 98))	('CD8', 'Gene', (57, 60))	('DC activation', 'MPA', (124, 137))	('pazopanib', 'Var', (13, 22))	('enhanced', 'PosReg', (115, 123))	('increased PD', 'Phenotype', 'HP:0008151', (83, 95))
62364	31527133	Sunitinib is associated with a reduction in Tregs and myeloid-derived suppressor cells (MDSCs) with an improved Th1 response.	('Tregs', 'CPA', (44, 49))	('reduction', 'NegReg', (31, 40))	('Th1 response', 'CPA', (112, 124))	('improved', 'PosReg', (103, 111))	('Sunitinib', 'Chemical', 'MESH:D000077210', (0, 9))	('Sunitinib', 'Var', (0, 9))
62375	31527133	Forty-one percent of ccRCC patients harbor PBRM1 loss of function mutations.	('mutations', 'Var', (66, 75))	('PBRM1', 'Gene', (43, 48))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('loss of function', 'NegReg', (49, 65))	('patients', 'Species', '9606', (27, 35))	('RCC', 'Disease', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (23, 26))
62376	31527133	PBRM1 mutations were enriched in cluster 3 and were also associated with improved response to sunitinib in a separate cohort, in fitting with its known roles in augmenting the HIF-mediated hypoxia response signature of VHL-deficient tumors.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('sunitinib', 'Chemical', 'MESH:D000077210', (94, 103))	('PBRM1', 'Gene', (0, 5))	('VHL-deficient tumors', 'Disease', (219, 239))	('improved', 'PosReg', (73, 81))	('VHL-deficient tumors', 'Disease', 'MESH:D006623', (219, 239))	('hypoxia', 'Disease', 'MESH:D000860', (189, 196))	('response to', 'MPA', (82, 93))	('hypoxia', 'Disease', (189, 196))	('augmenting', 'PosReg', (161, 171))	('mutations', 'Var', (6, 15))
62377	31527133	Cluster 4 had the worst OS and was enriched for BAP1 and TP53 mutations.	('BAP1', 'Gene', '8314', (48, 52))	('BAP1', 'Gene', (48, 52))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
62399	31527133	Recently, PBRM1 was discovered to confer resistance to T-cell induced apoptosis and deletion in a B16F10 melanoma mouse model increases susceptibility to anti-PD-1 and anti-CTLA-4.	('increases', 'PosReg', (126, 135))	('deletion', 'Var', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('apoptosis', 'biological_process', 'GO:0097194', ('70', '79'))	('melanoma', 'Disease', (105, 113))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('PBRM1', 'Gene', (10, 15))	('mouse', 'Species', '10090', (114, 119))	('apoptosis', 'biological_process', 'GO:0006915', ('70', '79'))	('susceptibility', 'MPA', (136, 150))
62408	31527133	Further, pegilodecakin, a pegylated IL-10 which increases CD8+ T cells and reduces TGF-beta, has shown preliminary efficacy when combined with an anti-PD-1 agent, but interestingly has shown hemophagocytic lymphohysticytosis (HLH) (7.9% any grade, n=38) as a reported treatment side effect.	('TGF-beta', 'Gene', (83, 91))	('increases', 'PosReg', (48, 57))	('CD8', 'Gene', (58, 61))	('pegilodecakin', 'Var', (9, 22))	('IL-10', 'molecular_function', 'GO:0005141', ('36', '41'))	('IL-10', 'Gene', (36, 41))	('CD8', 'Gene', '925', (58, 61))	('TGF-beta', 'Gene', '7039', (83, 91))	('reduces', 'NegReg', (75, 82))	('hemophagocytic lymphohysticytosis', 'Disease', (191, 224))	('hemophagocytic lymphohysticytosis', 'Disease', 'MESH:D051359', (191, 224))	('IL-10', 'Gene', '3586', (36, 41))
62432	31148584	The feasibility of our approach is demonstrated by performing aptamer selection against a clear cell renal cell carcinoma (ccRCC) RCC-MF cell line using the RC-124 cell line from healthy kidney tissue for negative selection.	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (90, 121))	('clear cell renal cell carcinoma', 'Disease', (90, 121))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (90, 121))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (101, 121))	('aptamer', 'Var', (62, 69))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))
62449	31148584	Enrichment analysis between the 4th and 11th pools by log2CPM enrichment identified sequences EN-1, EN-2 and EN-3.	('EN-2', 'Gene', '2020', (100, 104))	('EN-1', 'Gene', (94, 98))	('EN-3', 'Var', (109, 113))	('EN-1', 'Gene', '2019', (94, 98))	('EN-2', 'Gene', (100, 104))
62503	33535553	We concentrated on potentially oncocytoma-specific miRNAs (miRNA-424-5p, miRNA-146b-5p, miRNA-183-5p, miRNA-218-5p), pRCC-specific (miRNA-127-3p, miRNA-139-5p) and ccRCC-specific miRNAs (miRNA-200c-3p, miRNA-362-5p, miRNA-363-3p and miRNA-204-5p, 21-5p, miRNA-224-5p, miRNA-155-5p, miRNA-210-3p) and validated their expression in an independent sample set.	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('miRNA-204', 'Gene', (233, 242))	('miRNA-146b', 'Gene', '574447', (73, 83))	('oncocytoma', 'Disease', (31, 41))	('miRNA-155', 'Gene', (268, 277))	('miRNA-21', 'Gene', '406991', (102, 110))	('miRNA-363-3p', 'Var', (216, 228))	('miRNA-204', 'Gene', '406987', (233, 242))	('oncocytoma-', 'Phenotype', 'HP:0011798', (31, 42))	('miRNA-21', 'Gene', (102, 110))	('miRNA-200c-3p', 'Var', (187, 200))	('miRNA-146b', 'Gene', (73, 83))	('miRNA-224', 'Gene', '407009', (254, 263))	('pRCC', 'Gene', '5546', (117, 121))	('miRNA-127-3p', 'Var', (132, 144))	('21-5p', 'Var', (247, 252))	('miRNA-21', 'Gene', '406991', (282, 290))	('oncocytoma', 'Disease', 'MESH:D018249', (31, 41))	('miRNA-183', 'Gene', '406959', (88, 97))	('miRNA-424', 'Gene', (59, 68))	('RCC', 'Disease', (118, 121))	('RCC', 'Disease', (166, 169))	('miRNA-362-5p', 'Var', (202, 214))	('miRNA-183', 'Gene', (88, 97))	('miRNA-21', 'Gene', (282, 290))	('pRCC', 'Gene', (117, 121))	('miRNA-155', 'Gene', '406947', (268, 277))	('miRNA-224', 'Gene', (254, 263))	('miRNA-424', 'Gene', '494336', (59, 68))
62526	33535553	Mature miRNA can occur in isoforms (iso-miRNA) processed from the same pri-miRNA and different at 5' and 3' ends as a result of inaccurate cleavage by DROSHA and DICER1.	('cleavage', 'MPA', (139, 147))	('inaccurate', 'Var', (128, 138))	('DROSHA', 'Gene', '29102', (151, 157))	('DICER1', 'Gene', (162, 168))	('DICER1', 'Gene', '23405', (162, 168))	('DROSHA', 'Gene', (151, 157))
62527	33535553	Deregulations of miRNA expression have been previously correlated with changes in protein levels engaged in proliferation, motility or cell invasiveness and in consequence promotion of tumor development and growth.	('tumor', 'Disease', (185, 190))	('changes', 'Reg', (71, 78))	('promotion', 'PosReg', (172, 181))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('Deregulations', 'Var', (0, 13))	('growth', 'CPA', (207, 213))	('proliferation', 'CPA', (108, 121))	('miRNA', 'Protein', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('protein levels engaged', 'MPA', (82, 104))	('motility', 'CPA', (123, 131))	('cell invasiveness', 'CPA', (135, 152))
62529	33535553	The most commonly identified as downregulated in ccRCC tumor samples were miR-141, miRNA-200c.	('downregulated', 'NegReg', (32, 45))	('ccRCC tumor', 'Disease', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('ccRCC tumor', 'Disease', 'MESH:D009369', (49, 60))	('miR-141', 'Gene', (74, 81))	('miRNA-200c', 'Var', (83, 93))	('miR-141', 'Gene', '406933', (74, 81))
62553	33535553	Specific "iso-miRNA primers," which discriminate miRNA-363-3p or miRNA-224-5p shorter isoforms and amplify longer isoforms, were used in qPCR.	('miRNA-224', 'Gene', '407009', (65, 74))	('miRNA-224', 'Gene', (65, 74))	('miRNA-363-3p', 'Var', (49, 61))
62563	33535553	After comparison of all available data sets eight commonly deregulated miRNAs in ccRCC were selected (Figure 1c) and those included: miR-200c-3p, miR-362-5p, miR-363-3p and miR-204-5p as downregulated and miR-21-5p, miR-224-5p, miR-155-5p and miR-210-3p as upregulated (Figure 1d).	('downregulated', 'NegReg', (187, 200))	('miR-210-3p', 'Chemical', '-', (243, 253))	('miR-200c', 'Gene', (133, 141))	('miR-363-3p', 'Var', (158, 168))	('miR-362', 'Gene', (146, 153))	('miR-210-3p', 'Var', (243, 253))	('miR-155', 'Gene', (228, 235))	('RCC', 'Disease', (83, 86))	('miR-155', 'Gene', '406947', (228, 235))	('miR-363-3p', 'Chemical', '-', (158, 168))	('miR-362', 'Gene', '574030', (146, 153))	('miR-21-5p', 'Gene', (205, 214))	('upregulated', 'PosReg', (257, 268))	('miR-21-5p', 'Gene', '406997', (205, 214))	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('miR-204-5p', 'Chemical', '-', (173, 183))	('miR-204-5p', 'Var', (173, 183))	('miR-224', 'Gene', '407009', (216, 223))	('miR-224', 'Gene', (216, 223))	('miR-200c', 'Gene', '406985', (133, 141))
62565	33535553	Additionally, this analysis suggests that deregulation of miR-21-5p, miR-155-5p and miR-210-3p could be ccRCC-specific.	('deregulation', 'Var', (42, 54))	('miR-21-5p', 'Gene', (58, 67))	('miR-21-5p', 'Gene', '406997', (58, 67))	('miR-155', 'Gene', '406947', (69, 76))	('miR-210-3p', 'Var', (84, 94))	('RCC', 'Disease', (106, 109))	('miR-155', 'Gene', (69, 76))	('miR-210-3p', 'Chemical', '-', (84, 94))	('RCC', 'Disease', 'MESH:C538614', (106, 109))
62574	33535553	According to high-throughput data miRNA-127-3p and miRNA-139-5p should be downregulated in pRCC tumors.	('miRNA-139-5p', 'Var', (51, 63))	('pRCC tumors', 'Disease', 'MESH:D009369', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('miRNA-127-3p', 'Var', (34, 46))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('pRCC tumors', 'Disease', (91, 102))	('downregulated', 'NegReg', (74, 87))
62575	33535553	Although, in contrast to previous reports, in our sample set miRNA-127-3p appears to be significantly upregulated in pRCC (29-fold change, p < 0.01).	('pRCC', 'Gene', (117, 121))	('pRCC', 'Gene', '5546', (117, 121))	('miRNA-127-3p', 'Var', (61, 73))	('upregulated', 'PosReg', (102, 113))
62576	33535553	Increase in expression of miRNA-139-5p does not significantly differ in pRCC and oncocytoma (Figure 2b), however miRNA-139-5p appears to be downregulated in ccRCC (0.2-fold change, p = 0.04).	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('downregulated', 'NegReg', (140, 153))	('pRCC', 'Gene', '5546', (72, 76))	('oncocytoma', 'Disease', (81, 91))	('oncocytoma', 'Disease', 'MESH:D018249', (81, 91))	('miRNA-139-5p', 'Var', (113, 125))	('pRCC', 'Gene', (72, 76))	('RCC', 'Disease', (159, 162))
62582	33535553	Only miR-204-5p, was significantly downregulated in all RCC tumor types as compared to controls (ccRCC, 0.09-fold change, p = 0.011; pRCC, 0.006-fold change, p < 0.01; oncocytoma, 0.03-fold change, p < 0.001).	('RCC', 'Disease', (56, 59))	('pRCC', 'Gene', (133, 137))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('RCC tumor', 'Disease', 'MESH:C538614', (56, 65))	('miR-204-5p', 'Var', (5, 15))	('miR-204-5p', 'Chemical', '-', (5, 15))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('RCC', 'Disease', (99, 102))	('pRCC', 'Gene', '5546', (133, 137))	('oncocytoma', 'Disease', (168, 178))	('RCC', 'Disease', (134, 137))	('downregulated', 'NegReg', (35, 48))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('oncocytoma', 'Disease', 'MESH:D018249', (168, 178))	('RCC tumor', 'Disease', (56, 65))
62585	33535553	There was no significant change in the expression of miR-21-5p, miR-224-5p and miR-210-3p among the subtypes (Figure 2d).	('miR-210-3p', 'Chemical', '-', (79, 89))	('miR-224', 'Gene', (64, 71))	('miR-224', 'Gene', '407009', (64, 71))	('miR-21-5p', 'Gene', (53, 62))	('miR-21-5p', 'Gene', '406997', (53, 62))	('miR-210-3p', 'Var', (79, 89))
62588	33535553	Figure 2e shows no significant changes in different tumor grades in case of miRNA-200c-3p.	('tumor', 'Disease', (52, 57))	('miRNA-200c-3p', 'Var', (76, 89))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))
62589	33535553	miRNA-200c-3p is one of most commonly identified as ccRCC downregulated miRNA.	('miRNA-200c-3p', 'Var', (0, 13))	('RCC', 'Disease', (54, 57))	('miRNA', 'MPA', (72, 77))	('downregulated', 'NegReg', (58, 71))	('RCC', 'Disease', 'MESH:C538614', (54, 57))
62593	33535553	Consistent downregulation throughout all tumor grades were observed in case of miR-362-5p (G1, 0.09-fold change, p < 0.01; G3, 0.03-fold change, p < 0.001; G4, 0.09-fold change, p = 0.013), miR-363-3p (G1, 0.3-fold change, p = 0.019; G3, 0.08-fold change, p < 0.001; G4, 0.07-fold change, p < 0.01) and miR-204-5p (G1, 0.3-fold change, p = 0.042; G3, 0.01-fold change, p < 0.001; G4, 0.05-fold change, p = 0.02) (Figure 2e).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('miR-204-5p', 'Var', (303, 313))	('miR-204-5p', 'Chemical', '-', (303, 313))	('miR-362', 'Gene', '574030', (79, 86))	('tumor', 'Disease', (41, 46))	('miR-362', 'Gene', (79, 86))	('downregulation', 'NegReg', (11, 25))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('miR-363-3p', 'Var', (190, 200))	('miR-363-3p', 'Chemical', '-', (190, 200))
62595	33535553	The following miRNAs displayed elevated expression in all samples: miR-210-3p (G1, 21-fold change, p < 0.001; G2, 7.4-fold change, p = 0.013; G3, 12-fold change, p < 0.01; G4, 11-fold change, p < 0.01) and miR-155-5p (G1, 22-fold change, p < 0.01; G2, 7.4-fold change, p = 0.02; G3, 8-fold change, p = 0.03; G4, 47-fold change, p < 0.001).	('expression', 'MPA', (40, 50))	('miR-155', 'Gene', '406947', (206, 213))	('miR-155', 'Gene', (206, 213))	('miR-210-3p', 'Var', (67, 77))	('elevated', 'PosReg', (31, 39))	('miR-210-3p', 'Chemical', '-', (67, 77))
62601	33535553	pRCC could be classified using miRNA-362-5p (AUC = 0.87, p < 0.001), miRNA-363-3p (AUC = 0.75, p = 0.03), miRNA-204-5p (AUC = 0.9, p < 0.001), miRNA-21-5p (AUC = 0.79, p = 0.02) and miRNA-210-3p (AUC = 0.86, p = 0.01) while oncocytoma with miRNA-204-5p (AUC = 0.9, p < 0.001) and miRNA-224-5p (AUC = 0.79, p < 0.01).	('oncocytoma', 'Disease', 'MESH:D018249', (224, 234))	('miRNA-21', 'Gene', (182, 190))	('miRNA-204', 'Gene', (106, 115))	('miRNA-224', 'Gene', (280, 289))	('miRNA-204', 'Gene', '406987', (106, 115))	('pRCC', 'Gene', (0, 4))	('miRNA-204', 'Gene', (240, 249))	('miRNA-224', 'Gene', '407009', (280, 289))	('miRNA-21', 'Gene', '406991', (143, 151))	('miRNA-21', 'Gene', (143, 151))	('miRNA-204', 'Gene', '406987', (240, 249))	('miRNA-21', 'Gene', '406991', (182, 190))	('pRCC', 'Gene', '5546', (0, 4))	('oncocytoma', 'Disease', (224, 234))	('miRNA-363-3p', 'Var', (69, 81))
62602	33535553	Furthermore, ccRCC could be significantly distinguished from pRCC with miRNA-362-5p (AUC = 0.76, p < 0.01) and miRNA-155-5p (AUC = 0.79, p < 0.01) or from oncocytoma with miRNA-155-5p (AUC = 0.81, p < 0.01).	('miRNA-362-5p', 'Var', (71, 83))	('oncocytoma', 'Disease', 'MESH:D018249', (155, 165))	('pRCC', 'Gene', (61, 65))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('RCC', 'Disease', (15, 18))	('miRNA-155', 'Gene', (111, 120))	('miRNA-155', 'Gene', '406947', (171, 180))	('miRNA-155', 'Gene', (171, 180))	('pRCC', 'Gene', '5546', (61, 65))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('miRNA-155', 'Gene', '406947', (111, 120))	('oncocytoma', 'Disease', (155, 165))
62609	33535553	Mature miRNA could occur in isoforms that vary in length or presence of poly(A) or poly(U) tails on 3' end.	('poly(A)', 'Chemical', 'MESH:D011061', (72, 79))	('poly(U) tails', 'Var', (83, 96))	('poly(U)', 'Chemical', 'MESH:D011072', (83, 90))	('poly(A', 'Protein', (72, 78))
62613	33535553	As shown in Figure 4a (upper panel), among four downregulated miRNAs, two: miR-363-3p and miR-204-5p exhibit significantly different isoform expression pattern in ccRCC tumors.	('miR-204-5p', 'Chemical', '-', (90, 100))	('miR-363-3p', 'Chemical', '-', (75, 85))	('isoform expression', 'MPA', (133, 151))	('different', 'Reg', (123, 132))	('miR-204-5p', 'Var', (90, 100))	('miR-363-3p', 'Var', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('ccRCC tumors', 'Disease', 'MESH:D009369', (163, 175))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('ccRCC tumors', 'Disease', (163, 175))
62614	33535553	In case of miR-363-3p, shortening of 3' end is more frequent with simultaneous reduction of elongation, with 67% and 14% contribution as compared to control: 52% and 20%, respectively (p < 0.01 and p = 0.047, respectively).	("3' end", 'MPA', (37, 43))	('shortening', 'Var', (23, 33))	('miR-363-3p', 'Var', (11, 21))	('miR-363-3p', 'Chemical', '-', (11, 21))	('reduction', 'NegReg', (79, 88))	('elongation', 'CPA', (92, 102))
62615	33535553	Similarly, poly(U) addition is more common in non-ccRCC tissue (control 15%, ccRCC 7.3%; p < 0.01).	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('poly(U)', 'Chemical', 'MESH:D011072', (11, 18))	('poly(U) addition', 'Var', (11, 27))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
62617	33535553	In the group of potentially ccRCC-specific, upregulated miRNAs (Figure 4a lower panel) miRNAs miR-21-5p displayed slight, less frequent, though statistically significant modifications, with addition of poly(A) (control 4%, ccRCC 3%; p < 0.001) and poly(U) (control 0.3%, ccRCC 0.2%).	('poly(U)', 'Chemical', 'MESH:D011072', (248, 255))	('miRNAs', 'MPA', (56, 62))	('poly(U', 'Var', (248, 254))	('RCC', 'Disease', (225, 228))	('upregulated', 'PosReg', (44, 55))	('miR-21-5p', 'Gene', (94, 103))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('RCC', 'Disease', (30, 33))	('RCC', 'Disease', (273, 276))	('RCC', 'Disease', 'MESH:C538614', (273, 276))	('miR-21-5p', 'Gene', '406997', (94, 103))	('poly(A', 'Var', (202, 208))	('poly(A)', 'Chemical', 'MESH:D011061', (202, 209))
62621	33535553	Specific primers used in qPCR ("iso-miRNA primer") (Figure 4b,e) discriminate miRNA-363-3p and miRNA-224-5p shorter isoforms and amplify longer isoforms.	('miRNA-224', 'Gene', '407009', (95, 104))	('miRNA-363-3p', 'Var', (78, 90))	('miRNA-224', 'Gene', (95, 104))	('amplify', 'MPA', (129, 136))
62645	33535553	Chromosomal rearrangements which are ccRCC drivers occur decades before diagnosis in childhood or adolescence which makes early detection of the diseases difficult.	('RCC', 'Disease', (39, 42))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('Chromosomal rearrangements', 'Var', (0, 26))
62651	33535553	Based on the meta-analysis ccRCC could be potentially classified by the comparison of expression levels of eight miRNAs: miRNA-200c-3p, miRNA-362-5p, miRNA-363-3p, miRNA-204-5p, miRNA-21-5p, miRNA-224-5p, miRNA-155-5p and miRNA-210-3p.	('miRNA-362-5p', 'Var', (136, 148))	('miRNA-155', 'Gene', '406947', (205, 214))	('miRNA-21', 'Gene', '406991', (222, 230))	('RCC', 'Disease', (29, 32))	('miRNA-21', 'Gene', '406991', (178, 186))	('miRNA-204', 'Gene', (164, 173))	('miRNA-363-3p', 'Var', (150, 162))	('miRNA-155', 'Gene', (205, 214))	('miRNA-200c-3p', 'Var', (121, 134))	('miRNA-224', 'Gene', (191, 200))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('miRNA-224', 'Gene', '407009', (191, 200))	('miRNA-204', 'Gene', '406987', (164, 173))	('miRNA-21', 'Gene', (222, 230))	('miRNA-21', 'Gene', (178, 186))
62662	33535553	Many miRNA-210-3p targets are engaged in angiogenesis, cell survival and differentiation miRNA-200c-3p is one of the most significantly downregulated miRNAs in ccRCC tumors.	('downregulated', 'NegReg', (136, 149))	('miRNA-21', 'Gene', '406991', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('miRNA-200c-3p', 'Var', (89, 102))	('angiogenesis', 'biological_process', 'GO:0001525', ('41', '53'))	('miRNA-21', 'Gene', (5, 13))	('ccRCC tumors', 'Disease', 'MESH:D009369', (160, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('ccRCC tumors', 'Disease', (160, 172))
62663	33535553	miRNA-200c is member of miRNA-200 family (miRNA-200a, miRNA-200b, miRNA-200c, miRNA-141 and miRNA-429), commonly deregulated in other cancer types.	('miRNA-200b', 'Var', (54, 64))	('miRNA-141', 'Var', (78, 87))	('cancer', 'Disease', (134, 140))	('deregulated', 'PosReg', (113, 124))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('miRNA-200c', 'Var', (66, 76))	('miRNA-429', 'Var', (92, 101))	('miRNA-200c', 'Gene', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
62665	33535553	miRNA-362-5p has been classified as oncogenic in solid tumors and could be a potential therapeutic target or prognostic factor for human cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('miRNA-362-5p', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('human', 'Species', '9606', (131, 136))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))	('cancers', 'Disease', (137, 144))
62667	33535553	Its downregulation was reported in cervical cancer promotes vascular invasion and metastasis miRNA-363-3p is well known as miRNA with an anti-tumor role in many human cancers such as hepatocellular carcinoma and lung cancer.	('human', 'Species', '9606', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancer', 'Disease', (167, 173))	('hepatocellular carcinoma', 'Disease', (183, 207))	('vascular invasion', 'CPA', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('lung cancer', 'Disease', (212, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('cancers', 'Disease', (167, 174))	('promotes', 'PosReg', (51, 59))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (183, 207))	('tumor', 'Disease', (142, 147))	('downregulation', 'NegReg', (4, 18))	('lung cancer', 'Disease', 'MESH:D008175', (212, 223))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (212, 223))	('cancer', 'Disease', (44, 50))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (183, 207))	('cancer', 'Disease', (217, 223))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('metastasis', 'CPA', (82, 92))	('miRNA-363-3p', 'Var', (93, 105))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
62675	33535553	Other interesting examples are potential targets of miRNA-362-3p belong to homotypic fusion and vacuole protein sorting (HOPS) complex (Table 1, Table S3 and Figure S4a), controlling cell homeostasis, which dysfunctions are associated with various cancer types including renal cancers.	('cancer', 'Disease', (248, 254))	('renal cancers', 'Disease', (271, 284))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('renal cancer', 'Phenotype', 'HP:0009726', (271, 283))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('miRNA-362-3p', 'Var', (52, 64))	('HOPS) complex', 'cellular_component', 'GO:0030897', ('121', '134'))	('vacuole', 'cellular_component', 'GO:0005773', ('96', '103'))	('associated', 'Reg', (224, 234))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('homeostasis', 'biological_process', 'GO:0042592', ('188', '199'))	('renal cancers', 'Disease', 'MESH:D007680', (271, 284))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))
62682	33535553	As a result of our meta-analysis, we would like to propose a miRNA panel that could potentially aid RCC classification, with miRNA-362-5p, miRNA-363-3p, miRNA-224-5p, miRNA-155-5p and miRNA-210-3p as classifiers of ccRCC, miRNA-362-5p, miRNA-363-3p, miRNA-21-5p, miRNA-204-5p as characteristic for pRCC and miRNA-204-5p and miRNA-224-5p for oncocytoma (Figure 1, Figure 2 and Figure 3).	('miRNA-204', 'Gene', '406987', (307, 316))	('miRNA-21', 'Gene', '406991', (184, 192))	('pRCC', 'Gene', (298, 302))	('miRNA-21', 'Gene', (184, 192))	('miRNA-363-3p', 'Var', (236, 248))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', 'MESH:C538614', (299, 302))	('miRNA-204', 'Gene', (263, 272))	('miRNA-224', 'Gene', (324, 333))	('miRNA-224', 'Gene', '407009', (153, 162))	('miRNA-362-5p', 'Var', (222, 234))	('oncocytoma', 'Disease', 'MESH:D018249', (341, 351))	('RCC', 'Disease', (217, 220))	('miRNA-204', 'Gene', '406987', (263, 272))	('miRNA-155', 'Gene', '406947', (167, 176))	('pRCC', 'Gene', '5546', (298, 302))	('miRNA-204', 'Gene', (307, 316))	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('miRNA-224', 'Gene', '407009', (324, 333))	('miRNA-21', 'Gene', '406991', (250, 258))	('miRNA-224', 'Gene', (153, 162))	('miRNA-21', 'Gene', (250, 258))	('miRNA-155', 'Gene', (167, 176))	('RCC', 'Disease', (100, 103))	('oncocytoma', 'Disease', (341, 351))	('RCC', 'Disease', (299, 302))
62687	33535553	Regrettably, we did not validate the alteration of miRNA-200c-3p expression in ccRCC tumors likely due to low specificity of the qPCR primer.	('ccRCC tumors', 'Disease', 'MESH:D009369', (79, 91))	('ccRCC tumors', 'Disease', (79, 91))	('miRNA-200c-3p', 'Var', (51, 64))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
62763	31782902	Result from Figure 5A-F indicated that the risk gene signature still had the ability to distinguish that the outcome of patients with high-risk score was dramatically worse than that with low-risk score both in the early-stage and late-stage stratums.	('high-risk score', 'Var', (134, 149))	('patients', 'Species', '9606', (120, 128))	('worse', 'NegReg', (167, 172))	('F', 'Chemical', 'MESH:D005461', (12, 13))	('F', 'Chemical', 'MESH:D005461', (22, 23))
62791	29656895	Evolutionary study of matched primary metastasis biopsies from 100 ccRCC cases Metastasis competence is afforded by chromosome complexity, but not driver mutation load The hallmark genomic drivers of ccRCC metastasis are loss of 9p and 14q Punctuated and branched evolution result in distinct patterns of metastases  A multi-center prospective study and two validation cohorts of matched primary metastasis biopsies from 100 patients with clear-cell renal cell carcinoma provides a comprehensive picture of the genetic underpinnings and the evolutionary patterns of metastasis.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (461, 470))	('RCC', 'Disease', (69, 72))	('Metastasis', 'Disease', 'MESH:D009362', (79, 89))	('Metastasis', 'Disease', (79, 89))	('loss', 'Var', (221, 225))	('metastases', 'Disease', (305, 315))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (439, 470))	('patients', 'Species', '9606', (425, 433))	('chromosome', 'cellular_component', 'GO:0005694', ('116', '126'))	('clear-cell renal cell carcinoma', 'Disease', (439, 470))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (439, 470))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (450, 470))	('metastases', 'Disease', 'MESH:D009362', (305, 315))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('RCC', 'Disease', (202, 205))
62795	29656895	The well-established molecular landscape of primary clear-cell renal cell carcinoma (ccRCC), defined by the loss of 3p and VHL mutations/methylation as early events, provides an excellent model for the study of cancer evolution.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (63, 83))	('methylation', 'biological_process', 'GO:0032259', ('137', '148'))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (52, 83))	('RCC', 'Disease', (87, 90))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Disease', (211, 217))	('VHL', 'Gene', (123, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('VHL', 'Gene', '7428', (123, 126))	('mutations/methylation', 'Var', (127, 148))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (52, 83))	('clear-cell renal cell carcinoma', 'Disease', (52, 83))
62817	29656895	The overall number of driver events (mutations and SCNAs as presented in Figure 1A) was lower in metastases (mean = 9), compared to primary tumors (mean = 12, p = 0.05, adjusted for the varying number of profiled regions; STAR Methods) (Figure 1A).	('STAR', 'Gene', '6770', (222, 226))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('metastases', 'Disease', (97, 107))	('STAR', 'Gene', (222, 226))	('mutations', 'Var', (37, 46))	('metastases', 'Disease', 'MESH:D009362', (97, 107))	('primary tumors', 'Disease', (132, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('lower', 'NegReg', (88, 93))	('primary tumors', 'Disease', 'MESH:D009369', (132, 146))
62818	29656895	Consistent with evolutionary bottlenecking, metastases were significantly more homogeneous (proportion of clonal variants = 0.87) compared to primary tumors (proportion of clonal variants = 0.32, p = 3.6 x 10-13, adjusted for the varying number of profiled regions) (Figure 1B).	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('more', 'PosReg', (74, 78))	('primary tumors', 'Disease', 'MESH:D009369', (142, 156))	('metastases', 'Disease', (44, 54))	('primary tumors', 'Disease', (142, 156))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('homogeneous', 'MPA', (79, 90))	('metastases', 'Disease', 'MESH:D009362', (44, 54))	('variants', 'Var', (113, 121))
62833	29656895	Finally, we observed increased allelic imbalance at the human leukocyte antigen (HLA) locus in selected versus non-selected clones (HLA allelic imbalance observed in n = 12 "selected" vs. n = 2 "not selected" clones; Table S3), consistent with the recent findings in non-small-cell lung cancer.	('increased', 'PosReg', (21, 30))	('n =', 'Var', (166, 169))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('HLA', 'Gene', (81, 84))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (271, 293))	('human', 'Species', '9606', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('imbalance', 'Phenotype', 'HP:0002172', (39, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (282, 293))	('imbalance', 'Phenotype', 'HP:0002172', (144, 153))	('allelic imbalance', 'MPA', (31, 48))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (267, 293))
62844	29656895	In the TRACERx Renal cohort 33/100 ccRCC cases presented with venous tumor extension, only one of which was classified as a "VHL monodriver" tumor, which harbored 9p loss (K253) (Figure 3).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('presented', 'Reg', (47, 56))	('VHL', 'Gene', (125, 128))	('venous tumor', 'Phenotype', 'HP:0012721', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('venous tumor', 'Disease', (62, 74))	('tumor', 'Disease', (69, 74))	('venous tumor', 'Disease', 'MESH:D054556', (62, 74))	('VHL', 'Gene', '7428', (125, 128))	('tumor', 'Disease', (141, 146))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('K253', 'Var', (172, 176))
62845	29656895	Median survival in patients with TT was 17.8 months (Table S1) with 3 patients dying within 6 months of surgery due to disease progression (K328, K263, and K390); classified as "multiple clonal" driver (2 cases) and "VHL wild-type" (1 case) subtypes (Table S1).	('patients', 'Species', '9606', (70, 78))	('K390)', 'Var', (156, 161))	('TT', 'Chemical', '-', (33, 35))	('patients', 'Species', '9606', (19, 27))	('K328', 'Chemical', '-', (140, 144))	('K328', 'Var', (140, 144))	('VHL', 'Gene', (217, 220))	('K263', 'Var', (146, 150))	('VHL', 'Gene', '7428', (217, 220))
62847	29656895	The TT was seeded directly by the most recent common ancestor (MRCA, the clone which harbors the full complement of alterations common to all the clones in the tumor; denoted by the first node in the phylogenetic tree) in 10 cases (K239, K118, K250, K207, K059, K167, K276, K107, K253, and K191) (Figure 3), suggesting intravascular growth was an early event.	('K191', 'Var', (290, 294))	('K059', 'Var', (256, 260))	('K253', 'Var', (280, 284))	('K250', 'Var', (244, 248))	('K167', 'Var', (262, 266))	('K239', 'Var', (232, 236))	('K118', 'Var', (238, 242))	('K207', 'Var', (250, 254))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('K107', 'Var', (274, 278))	('K276', 'Var', (268, 272))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))	('TT', 'Chemical', '-', (4, 6))
62848	29656895	In other cases, the TT emerged from the more advanced subclones in the primary tumor, which harbored additional drivers, including 9p loss.	('TT', 'Chemical', '-', (20, 22))	('primary tumor', 'Disease', (71, 84))	('9p loss', 'Var', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('primary tumor', 'Disease', 'MESH:D009369', (71, 84))
62853	29656895	In some cases distinct clones in the primary tumor seeded the TT and the metastasis (K326 and K390; Figure S3B).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('K390', 'Var', (94, 98))	('metastasis', 'CPA', (73, 83))	('K326', 'Var', (85, 89))	('primary tumor', 'Disease', (37, 50))	('TT', 'Chemical', '-', (62, 64))	('primary tumor', 'Disease', 'MESH:D009369', (37, 50))
62854	29656895	Consistent with the poor prognosis conferred by lymph node involvement in ccRCC, the lymph node seeding clone in K390 harbored 9p loss, whereas the TT clone did not.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('K390', 'Var', (113, 117))	('RCC', 'Disease', (76, 79))	('TT', 'Chemical', '-', (148, 150))
62855	29656895	The same primary clone seeded both TT and metastasis in K096 and K427 (Figure S3B), whereas in K107 and K263 (Figure S3B) the metastasizing clone appeared to first seed the thrombus and then lymph node and adrenal sites, respectively.	('K427', 'Var', (65, 69))	('thrombus', 'Disease', (173, 181))	('K263', 'Var', (104, 108))	('K107', 'Var', (95, 99))	('thrombus', 'Disease', 'MESH:D013927', (173, 181))	('metastasis', 'CPA', (42, 52))	('TT', 'Chemical', '-', (35, 37))	('K096', 'Var', (56, 60))
62865	29656895	Consequently, in some patients metastatic disease was controlled with further surgery (K029) or radiotherapy (K096, K228, K208 and K243), consistent with the lack of other occult metastases.	('K228', 'Var', (116, 120))	('K029', 'Var', (87, 91))	('patients', 'Species', '9606', (22, 30))	('K096', 'Var', (110, 114))	('K243', 'Var', (131, 135))	('K208 and K243', 'Var', (122, 135))	('metastases', 'Disease', (179, 189))	('metastatic disease', 'Disease', (31, 49))	('metastases', 'Disease', 'MESH:D009362', (179, 189))
62866	29656895	This group was enriched for "PBRM1 SETD2" and "PBRM1 PI3K" evolutionary subtypes, with the primary tumors characterized by higher ITH index and lower wGII, as compared to the "rapid progression" group (Figure 4C).	('wGII', 'CPA', (150, 154))	('PBRM1', 'Gene', (47, 52))	('PBRM1', 'Gene', '55193', (29, 34))	('lower', 'NegReg', (144, 149))	('PBRM1', 'Gene', '55193', (47, 52))	('higher', 'PosReg', (123, 129))	('ITH index', 'MPA', (130, 139))	('SETD2', 'Gene', '29072', (35, 40))	('primary tumors', 'Disease', (91, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('PBRM1', 'Gene', (29, 34))	('SETD2', 'Gene', (35, 40))	('PI3K', 'Var', (53, 57))	('primary tumors', 'Disease', 'MESH:D009369', (91, 105))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
62867	29656895	For example, case K029 ("PBRM1 PI3K") presented with spatially separate bone metastases 3 years apart; the metastasizing clone harbored a PBRM1 mutation, but not 9p loss (Figure S4).	('metastases', 'Disease', (77, 87))	('PBRM1', 'Gene', (138, 143))	('mutation', 'Var', (144, 152))	('PBRM1', 'Gene', '55193', (138, 143))	('PBRM1', 'Gene', (25, 30))	('metastases', 'Disease', 'MESH:D009362', (77, 87))	('PBRM1', 'Gene', '55193', (25, 30))
62872	29656895	In the case of SP006, the pancreatic metastasis was diagnosed 17 years after the primary tumor was resected, and the latent clone was mapped directly back to the founding MRCA clone, suggesting early divergence from the primitive ancestral clone.	('pancreatic metastasis', 'Disease', 'MESH:D009362', (26, 47))	('primary tumor', 'Disease', 'MESH:D009369', (81, 94))	('SP006', 'Var', (15, 20))	('pancreatic metastasis', 'Disease', (26, 47))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('primary tumor', 'Disease', (81, 94))
62874	29656895	Finally, SP058 presented with pancreatic metastasis at 8 years, with a single additional driver event (SETD2 mutation) in metastasis, while we detected alternative subclones with a greater number of driver events in the primary tumor (Figure 5C).	('primary tumor', 'Disease', (220, 233))	('pancreatic metastasis', 'Disease', 'MESH:D009362', (30, 51))	('primary tumor', 'Disease', 'MESH:D009369', (220, 233))	('SP058', 'Var', (9, 14))	('pancreatic metastasis', 'Disease', (30, 51))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('SETD2', 'Gene', '29072', (103, 108))	('SETD2', 'Gene', (103, 108))
62884	29656895	In case K489 the patient presented with a primary ccRCC and underwent a nephrectomy with curative intent (Figure 6B).	('RCC', 'Disease', (52, 55))	('K489', 'Var', (8, 12))	('patient', 'Species', '9606', (17, 24))	('RCC', 'Disease', 'MESH:C538614', (52, 55))
62889	29656895	The primary tumor harbored a clonal VHL mutation and 3p loss, and a subclonal PBRM1 and multiple SETD2 mutations, indicating parallel evolution.	('mutation', 'Var', (40, 48))	('mutations', 'Var', (103, 112))	('VHL', 'Gene', (36, 39))	('loss', 'NegReg', (56, 60))	('primary tumor', 'Disease', 'MESH:D009369', (4, 17))	('PBRM1', 'Gene', '55193', (78, 83))	('SETD2', 'Gene', (97, 102))	('VHL', 'Gene', '7428', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('SETD2', 'Gene', '29072', (97, 102))	('primary tumor', 'Disease', (4, 17))	('PBRM1', 'Gene', (78, 83))
62892	29656895	By contrast, subsequent metastases to the lymph nodes, liver, lung, and kidney were seeded by a subclone harboring additional SCNA events, including loss of 9p.	('metastases', 'Disease', (24, 34))	('loss', 'Var', (149, 153))	('metastases', 'Disease', 'MESH:D009362', (24, 34))
62899	29656895	Loss of 14q also showed a trend towards significance, and taken together these two events represent hallmark genomic alterations in ccRCC metastasis (overall 36 of 38 TRACERx Renal cases had loss of at least one of these chromosome arms).	('loss', 'NegReg', (191, 195))	('chromosome', 'cellular_component', 'GO:0005694', ('221', '231'))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('RCC', 'Disease', (134, 137))	('Loss', 'Var', (0, 4))
62912	29656895	We note that the evolutionary trajectories in this group are underpinned by PBRM1 alterations, in keeping with the observation by Brugarolas and colleagues that loss of PBRM1 expression is associated with an increased risk of metastasis but not with decreased survival.	('metastasis', 'CPA', (226, 236))	('PBRM1', 'Gene', (169, 174))	('loss', 'Var', (161, 165))	('PBRM1', 'Gene', (76, 81))	('PBRM1', 'Gene', '55193', (76, 81))	('PBRM1', 'Gene', '55193', (169, 174))
62946	29656895	The milling tip blade size for the dissection was selected based on the estimated area of the ROI, where small ROIs less than 200mm2 used small blade sizes (200 or 400mum) and ROIs larger than 200mm2 used larger blade sizes (800 mum).	('200 or 400mum', 'Var', (157, 170))	('milling tip blade', 'Disease', 'MESH:D060725', (4, 21))	('milling tip blade', 'Disease', (4, 21))
62952	29656895	Primary antibody used was rabbit anti-Ki67 (AB16667, Abcam, Cambridge, UK) and secondary antibody was Discovery Omnimap anti-rabbit HRP RUO (760-4311, Roche, Rotkreuz, Switzerland).	('antibody', 'cellular_component', 'GO:0019815', ('8', '16'))	('Ki67', 'Gene', '17345', (38, 42))	('antibody', 'cellular_component', 'GO:0019814', ('8', '16'))	('antibody', 'cellular_component', 'GO:0019815', ('89', '97'))	('antibody', 'molecular_function', 'GO:0003823', ('8', '16'))	('antibody', 'cellular_component', 'GO:0019814', ('89', '97'))	('rabbit', 'Species', '9986', (26, 32))	('antibody', 'molecular_function', 'GO:0003823', ('89', '97'))	('antibody', 'cellular_component', 'GO:0042571', ('8', '16'))	('Ki67', 'Gene', (38, 42))	('antibody', 'cellular_component', 'GO:0042571', ('89', '97'))	('760-4311', 'Var', (141, 149))	('rabbit', 'Species', '9986', (125, 131))
62974	29656895	Single Nucleotide Variant (SNV) calling was performed using Mutect v1.1.7 and small scale insetion/deletions (INDELs) were called running VarScan v2.4.1 in somatic mode with a minimum variant frequency (--min-var-freq) of 0.005, a tumour purity estimate (--tumor-purity) of 0.75 and then validated using Scalpel v0.5.3 (scalpel-discovery in - -somatic mode) (intersection between two callers taken).	('tumor', 'Disease', (257, 262))	('tumour', 'Phenotype', 'HP:0002664', (231, 237))	('tumour purity', 'Disease', (231, 244))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('a minimum variant', 'Species', '181476', (174, 191))	('tumour purity', 'Disease', 'MESH:D009369', (231, 244))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('insetion/deletions', 'Var', (90, 108))
62979	29656895	Deleterious mutations were defined if two out of three algorithms - SIFT, PolyPhen2 and MutationTaster - predicted the mutation as deleterious.	('mutation', 'Var', (119, 127))	('algorithms - SIFT', 'Disease', (55, 72))	('algorithms - SIFT', 'Disease', 'None', (55, 72))
62981	29656895	Mutations detected in high-confidence driver genes (VHL, PBRM1, SETD2, PIK3CA, MTOR, PTEN, KDM5C, CSMD3, BAP1, TP53, TSC1, TSC2) were defined as driver mutations.	('PBRM1', 'Gene', '55193', (57, 62))	('KDM5C', 'Gene', '8242', (91, 96))	('TSC1', 'Gene', '7248', (117, 121))	('PTEN', 'Gene', (85, 89))	('TSC2', 'Gene', '7249', (123, 127))	('PBRM1', 'Gene', (57, 62))	('PIK3CA', 'Gene', '5290', (71, 77))	('TP53', 'Gene', '7157', (111, 115))	('CSMD3', 'Gene', '114788', (98, 103))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', '5728', (85, 89))	('MTOR', 'Gene', (79, 83))	('TSC2', 'Gene', (123, 127))	('VHL', 'Gene', (52, 55))	('KDM5C', 'Gene', (91, 96))	('MTOR', 'Gene', '2475', (79, 83))	('BAP1', 'Gene', '8314', (105, 109))	('SETD2', 'Gene', (64, 69))	('CSMD3', 'Gene', (98, 103))	('PIK3CA', 'Gene', (71, 77))	('VHL', 'Gene', '7428', (52, 55))	('SETD2', 'Gene', '29072', (64, 69))	('TP53', 'Gene', (111, 115))	('TSC1', 'Gene', (117, 121))	('BAP1', 'Gene', (105, 109))
62984	29656895	Copy number alterations were then called as losses or gains relative to overall sample wide estimated ploidy.	('gain', 'Disease', (54, 58))	('gain', 'Disease', 'MESH:D015430', (54, 58))	('Copy number alterations', 'Var', (0, 23))
62998	29656895	To estimate the clonality of a mutation in a region, we used the following formula:where  is the variant allele frequency at the mutation base;  is estimated tumour purity;  and  are the tumour locus specific copy number and the normal locus specific copy number which was assumed to be 2 for autosomal chromosomes; and  is the fraction of tumour cells carrying the mutation.	('variant', 'Var', (97, 104))	('tumour', 'Disease', (187, 193))	('tumour', 'Disease', 'MESH:D009369', (187, 193))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumour', 'Phenotype', 'HP:0002664', (340, 346))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('tumour purity', 'Disease', 'MESH:D009369', (158, 171))	('mutation', 'Var', (31, 39))	('tumour', 'Disease', 'MESH:D009369', (340, 346))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('tumour', 'Disease', (158, 164))	('tumour', 'Disease', (340, 346))	('tumour purity', 'Disease', (158, 171))
63005	29656895	However, two contingency measures are in place to mitigate against phylogenetic misconstruction: i) ultra-deep 500x sequencing coverage, which ensures stably derived cancer cell fraction estimates, ii) a bespoke gene panel which is enriched for driver events, increasing the likelihood that mutational markers are driving genuine clonal expansion.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('gain', 'Disease', (60, 64))	('gain', 'Disease', 'MESH:D015430', (60, 64))	('cell fraction', 'cellular_component', 'GO:0000267', ('173', '186'))	('mutational markers', 'Var', (291, 309))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
63035	27775259	Despite insignificant mortality reduction over years 0-14 of 15% (95% confidence interval [CI], -3 to 30; p=0.100) with MMS and 11% (95% CI, -7 to 27; p=0.210) with USS, a prespecified analysis of ovarian cancer death of MMS vs. no screening with exclusion of prevalent cases showed significant decrease of death rates (p=0.021), with an overall average mortality reduction of 20% (95% CI, -2 to 40) and a reduction of 8% (95% CI, -27 to 43) in years 0-7 and 28% (95% CI, -3 to 49) in years 7-14 in favor of MMS, suggesting the long-term effect of an MMS screening program.	('ovarian cancer death', 'Disease', 'MESH:D010051', (197, 217))	('MMS', 'Chemical', '-', (508, 511))	('decrease of death', 'Disease', (295, 312))	('MMS', 'Chemical', '-', (551, 554))	('reduction', 'NegReg', (406, 415))	('decrease of death', 'Disease', 'MESH:D003643', (295, 312))	('ovarian cancer death', 'Disease', (197, 217))	('MMS', 'Chemical', '-', (221, 224))	('MMS', 'Var', (508, 511))	('reduction', 'NegReg', (32, 41))	('ovarian cancer', 'Phenotype', 'HP:0100615', (197, 211))	('MMS', 'Var', (221, 224))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('reduction', 'NegReg', (364, 373))	('MMS', 'Chemical', '-', (120, 123))
63037	27775259	False-positive rate, that resulted in unnecessary surgery for which ovaries had benign pathology or were normal, was 2.3 times higher in the MMS group than in the no screening group.	('MMS', 'Var', (141, 144))	('MMS', 'Chemical', '-', (141, 144))	('higher', 'PosReg', (127, 133))
63041	27775259	First, oral contraceptives reduce the risk of ovarian cancer and are considered safe for BRCA1 and BRCA2 mutations carriers.	('ovarian cancer', 'Disease', 'MESH:D010051', (46, 60))	('carriers', 'Reg', (115, 123))	('BRCA1', 'Gene', (89, 94))	('ovarian cancer', 'Disease', (46, 60))	('reduce', 'NegReg', (27, 33))	('BRCA2', 'Gene', (99, 104))	('mutations', 'Var', (105, 114))	('contraceptives reduce the risk of ovarian cancer', 'Phenotype', 'HP:0008209', (12, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('BRCA1', 'Gene', '672', (89, 94))	('ovarian cancer', 'Phenotype', 'HP:0100615', (46, 60))	('BRCA2', 'Gene', '675', (99, 104))
63043	27775259	Although a recently published systematic review concluded that there is a small increased risk of breast cancer in oral pill users (odds ratio [OR], 1.08; 95% CI, 1.00 to 1.17), women with BRCA1 or BRCA2 mutations should consider taking oral pills to reduce their ovarian cancer risk not only because a significant reduction in the risk of ovarian cancer for BRCA1 and BRCA2 mutation carriers (summary relative risk [SRR], 0.50; 95% CI, 0.33 to 0.75), but also because there was no significant association between modern oral contraceptive use and breast cancer risk in these women (SRR, 1.13; 95% CI, 0.88 to 1.45).	('breast cancer', 'Disease', (548, 561))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('BRCA2', 'Gene', '675', (369, 374))	('ovarian cancer', 'Disease', 'MESH:D010051', (264, 278))	('reduction', 'NegReg', (315, 324))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ovarian cancer', 'Disease', (340, 354))	('cancer in oral', 'Phenotype', 'HP:0100649', (105, 119))	('BRCA2', 'Gene', (198, 203))	('BRCA1', 'Gene', '672', (359, 364))	('ovarian cancer', 'Phenotype', 'HP:0100615', (340, 354))	('reduce', 'NegReg', (251, 257))	('BRCA1', 'Gene', (359, 364))	('ovarian cancer', 'Disease', (264, 278))	('cancer', 'Phenotype', 'HP:0002664', (555, 561))	('mutation', 'Var', (375, 383))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('mutations', 'Var', (204, 213))	('ovarian cancer', 'Phenotype', 'HP:0100615', (264, 278))	('women', 'Species', '9606', (576, 581))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('BRCA2', 'Gene', '675', (198, 203))	('BRCA1', 'Gene', '672', (189, 194))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('BRCA2', 'Gene', (369, 374))	('breast cancer', 'Disease', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (548, 561))	('BRCA1', 'Gene', (189, 194))	('women', 'Species', '9606', (178, 183))	('ovarian cancer', 'Disease', 'MESH:D010051', (340, 354))	('breast cancer', 'Disease', 'MESH:D001943', (548, 561))
63044	27775259	Second, tubal ligation is associated with a reduction in ovarian cancer in both the general population (34%) and high-risk women (57% in BRCA1 mutations carriers).	('BRCA1', 'Gene', '672', (137, 142))	('carriers', 'Reg', (153, 161))	('BRCA1', 'Gene', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('reduction in ovarian cancer', 'Disease', 'MESH:D010051', (44, 71))	('women', 'Species', '9606', (123, 128))	('reduction in ovarian cancer', 'Disease', (44, 71))	('ovarian cancer', 'Phenotype', 'HP:0100615', (57, 71))	('mutations', 'Var', (143, 152))
63045	27775259	Third, risk-reducing salpingo-oophorectomy (RRSO), the most proven method so far for the prevention of ovarian cancer in women with BRCA1 or BRCA2 mutation, was shown to have a 70%-85% reduction in ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (198, 212))	('reduction in ovarian cancer', 'Disease', (185, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('reduction in ovarian cancer', 'Disease', 'MESH:D010051', (185, 212))	('mutation', 'Var', (147, 155))	('BRCA2', 'Gene', '675', (141, 146))	('women', 'Species', '9606', (121, 126))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('BRCA1', 'Gene', '672', (132, 137))	('salpingo-oophorectomy', 'Disease', (21, 42))	('ovarian cancer', 'Phenotype', 'HP:0100615', (198, 212))	('ovarian cancer', 'Disease', 'MESH:D010051', (103, 117))	('BRCA1', 'Gene', (132, 137))	('ovarian cancer', 'Disease', (103, 117))	('BRCA2', 'Gene', (141, 146))
63046	27775259	Because the cumulative incidence of ovarian cancer in BRCA1 mutation carrier is low under the age of 40 years but reaches more than 10% by the age of 50 years, all guidelines recommend RRSO be performed between 35 and 40 years.	('ovarian cancer', 'Disease', 'MESH:D010051', (36, 50))	('mutation', 'Var', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('carrier', 'molecular_function', 'GO:0005215', ('69', '76'))	('ovarian cancer', 'Disease', (36, 50))	('BRCA1', 'Gene', '672', (54, 59))	('ovarian cancer', 'Phenotype', 'HP:0100615', (36, 50))	('BRCA1', 'Gene', (54, 59))
63049	27775259	Lastly, by contrast of high-risk women, for average risk women, opportunistic salpingectomy at the time of elective pelvic surgeries including hysterectomy and as an alternative to other sterilization could theoretically reduce the incidence of type 2 ovarian cancer.	('type 2 ovarian cancer', 'Disease', (245, 266))	('hysterectomy', 'Disease', (143, 155))	('reduce', 'NegReg', (221, 227))	('type 2 ovarian cancer', 'Disease', 'MESH:D010051', (245, 266))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('women', 'Species', '9606', (33, 38))	('women', 'Species', '9606', (57, 62))	('opportunistic', 'Var', (64, 77))	('ovarian cancer', 'Phenotype', 'HP:0100615', (252, 266))
63073	27775259	Although the researchers did not detect recurrent point mutations that were actionable in recurrence samples, they found that at least four common molecular events were associated with acquired resistance: multiple independent reversions of germline BRCA1 or BRCA2 mutations, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1 in about 8% of HGSC relapse samples.	('MDR', 'molecular_function', 'GO:0004745', ('433', '436'))	('BRCA1', 'Gene', (250, 255))	('BRCA1', 'Gene', (284, 289))	('mutations', 'Var', (265, 274))	('associated', 'Reg', (378, 388))	('BRCA2', 'Gene', (259, 264))	('methylation', 'biological_process', 'GO:0032259', ('299', '310'))	('loss', 'Var', (276, 280))	('overexpression', 'PosReg', (394, 408))	('promoter fusion', 'Var', (362, 377))	('MDR1', 'Gene', (433, 437))	('BRCA2', 'Gene', '675', (259, 264))	('efflux', 'biological_process', 'GO:0140352', ('421', '427'))	('MDR1', 'Gene', '5243', (433, 437))	('efflux', 'biological_process', 'GO:0140115', ('421', '427'))	('BRCA1', 'Gene', '672', (250, 255))	('BRCA1', 'Gene', '672', (284, 289))	('efflux pump', 'cellular_component', 'GO:1990281', ('421', '432'))
63074	27775259	Gene breakage, which commonly inactivated tumor suppressor genes such as RB1, NF1, RAD51B, and PTEN, was also shown to contribute to acquired chemoresistance.	('acquired chemoresistance', 'CPA', (133, 157))	('RAD51B', 'Gene', '5890', (83, 89))	('tumor', 'Disease', (42, 47))	('RAD51B', 'Gene', (83, 89))	('RB1', 'Gene', (73, 76))	('contribute', 'Reg', (119, 129))	('tumor suppressor', 'biological_process', 'GO:0051726', ('42', '58'))	('RB1', 'Gene', '5925', (73, 76))	('NF1', 'Gene', (78, 81))	('Gene breakage', 'Var', (0, 13))	('PTEN', 'Gene', (95, 99))	('NF1', 'Gene', '4763', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('PTEN', 'Gene', '5728', (95, 99))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('42', '58'))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('RAD', 'biological_process', 'GO:1990116', ('83', '86'))
63075	27775259	On the other hand, CCNE1 amplification was common in primary resistant and refractory disease.	('common', 'Reg', (43, 49))	('refractory disease', 'Disease', (75, 93))	('primary resistant', 'Disease', (53, 70))	('amplification', 'Var', (25, 38))	('CCNE1', 'Gene', '898', (19, 24))	('CCNE1', 'Gene', (19, 24))
63077	27775259	Another outstanding study of chemoresistance in HGSC identified a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) mutations as a possible predictor of chemosensitivity in ovarian cancer without BRCA1 or BRCA2 mutations.	('ovarian cancer', 'Disease', 'MESH:D010051', (193, 207))	('BRCA2', 'Gene', (225, 230))	('BRCA1', 'Gene', (216, 221))	('ovarian cancer', 'Disease', (193, 207))	('BRCA2', 'Gene', '675', (225, 230))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('mutations', 'Var', (136, 145))	('ovarian cancer', 'Phenotype', 'HP:0100615', (193, 207))	('BRCA1', 'Gene', '672', (216, 221))
63079	27775259	Moreover, ADAMTS mutations were associated with longer OS (HR, 0.54; 95% CI, 0.42 to 0.89; p=0.010) and PFS (HR, 0.42; 95% CI, 0.38 to 0.70; p<0.001).	('OS', 'Chemical', '-', (55, 57))	('longer OS', 'CPA', (48, 57))	('ADAMTS', 'Gene', (10, 16))	('PFS', 'CPA', (104, 107))	('mutations', 'Var', (17, 26))
63080	27775259	The associations remained the same with OS (HR, 0.53; 95% CI 0.32 to 0.87; p=0.010) and PFS (HR, 0.40; 95% CI, 0.25 to 0.62; p<0.001) even after adjustment by BRCA1 or BRCA2 mutation, surgical stage, residual tumor, and patient age.	('BRCA2', 'Gene', '675', (168, 173))	('tumor', 'Disease', (209, 214))	('mutation', 'Var', (174, 182))	('BRCA1', 'Gene', '672', (159, 164))	('patient', 'Species', '9606', (220, 227))	('BRCA1', 'Gene', (159, 164))	('OS', 'Chemical', '-', (40, 42))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('BRCA2', 'Gene', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
63081	27775259	These findings suggested that there were still more events other than ADAMTS or BRCA1/2 mutations that predicted better chemotherapy response because those mutations accounted for only 30% (10% and 20%, respectively) out of 70% of the clinical chemosensitivity rates.	('mutations', 'Var', (88, 97))	('BRCA1/2', 'Gene', (80, 87))	('BRCA1/2', 'Gene', '672;675', (80, 87))
63087	27775259	identified the relationship between ARID1A and EZH2 as the first potential effective target for the treatment of ovarian clear cell carcinoma, of which more than 50% ARID1A is mutated and loses genomic instability, and typically shows low response rate to platinum-based chemotherapy, in particular, in its late stages.	('genomic instability', 'MPA', (194, 213))	('EZH2', 'Gene', (47, 51))	('ovarian clear cell carcinoma', 'Disease', (113, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('mutated', 'Var', (176, 183))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (113, 141))	('platinum', 'Chemical', 'MESH:D010984', (256, 264))	('ARID1A', 'Gene', '8289', (166, 172))	('ARID1A', 'Gene', '8289', (36, 42))	('ARID1A', 'Gene', (166, 172))	('EZH2', 'Gene', '2146', (47, 51))	('ARID1A', 'Gene', (36, 42))	('loses', 'NegReg', (188, 193))
63090	27775259	Authors showed that inhibition of the EZH2 methyltransferase caused regression of ARID1A mutated clear cell carcinoma in a synthetic lethal manner by inhibiting phosphatidylinositol 3-kinase (PI3K)/AKT signaling.	('inhibiting', 'NegReg', (150, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('ARID1A', 'Gene', '8289', (82, 88))	('ARID1A', 'Gene', (82, 88))	('EZH2', 'Gene', '2146', (38, 42))	('synthetic', 'Species', '32630', (123, 132))	('EZH2', 'Gene', (38, 42))	('AKT signaling', 'biological_process', 'GO:0043491', ('198', '211'))	('inhibition', 'NegReg', (20, 30))	('PI3K', 'molecular_function', 'GO:0016303', ('192', '196'))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (97, 117))	('mutated', 'Var', (89, 96))	('clear cell carcinoma', 'Disease', (97, 117))	('phosphatidylinositol', 'MPA', (161, 181))
63091	27775259	These findings were published in Nature Medicine for the promise of highly specific small molecule EZH2 inhibitors as a new paradigm for pharmacologically targeting ARID1A mutation in ovarian clear cell carcinoma.	('EZH2', 'Gene', '2146', (99, 103))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (184, 212))	('EZH2', 'Gene', (99, 103))	('ARID1A', 'Gene', '8289', (165, 171))	('ARID1A', 'Gene', (165, 171))	('mutation', 'Var', (172, 180))	('ovarian clear cell carcinoma', 'Disease', (184, 212))	('inhibitors', 'Var', (104, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))
63105	27775259	First, MR. Mirza presented the subgroups for clinical trials in recurrent ovarian cancer in terms of multiple treatment lines, refractory, resistant, platinum-sensitive, asymptomatic CA125 elevation, prior use of antiangiogenic therapy, BRCA mutation, etc.	('ovarian cancer', 'Phenotype', 'HP:0100615', (74, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('BRCA', 'Gene', '672', (237, 241))	('CA125 elevation', 'Phenotype', 'HP:0031030', (183, 198))	('CA125', 'Gene', (183, 188))	('ovarian cancer', 'Disease', 'MESH:D010051', (74, 88))	('BRCA', 'Gene', (237, 241))	('elevation', 'PosReg', (189, 198))	('ovarian cancer', 'Disease', (74, 88))	('recurrent ovarian cancer', 'Phenotype', 'HP:0008209', (64, 88))	('platinum', 'Chemical', 'MESH:D010984', (150, 158))	('CA125', 'Gene', '94025', (183, 188))	('mutation', 'Var', (242, 250))
63136	27775259	Adverse events related to the injection site such as pain, swelling, and erythema were more common in 9vHPV vaccine group than qHPV vaccine group (90.7% vs. 84.9%) although most of these events were mild to moderate.	('erythema', 'Disease', (73, 81))	('swelling', 'Disease', (59, 67))	('qHPV', 'Chemical', '-', (127, 131))	('9vHPV', 'Chemical', '-', (102, 107))	('pain', 'Phenotype', 'HP:0012531', (53, 57))	('9vHPV vaccine', 'Var', (102, 115))	('pain', 'Disease', 'MESH:D010146', (53, 57))	('pain', 'Disease', (53, 57))	('erythema', 'Phenotype', 'HP:0010783', (73, 81))	('erythema', 'Disease', 'MESH:D004890', (73, 81))
63192	27775259	Clinical benefit rate was significantly higher in trabectedin group than that of dacarbazine group (34% vs. 19%, HR, 2.3; 95% CI, 1.45 to 3.70; p<0.001).	('higher', 'PosReg', (40, 46))	('dacarbazine', 'Chemical', 'MESH:D003606', (81, 92))	('trabectedin', 'Chemical', 'MESH:D000077606', (50, 61))	('trabectedin', 'Var', (50, 61))	('Clinical', 'MPA', (0, 8))
63197	27775259	Lynch syndrome is an autosomal dominant disorder caused by a germline mutation in one of the DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, PMS2, and EPCAM.	('MLH1', 'Gene', (126, 130))	('EPCAM', 'Gene', '4072', (154, 159))	('mismatch repair', 'biological_process', 'GO:0006298', ('97', '112'))	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('autosomal dominant disorder', 'Disease', (21, 48))	('PMS2', 'Gene', '5395', (144, 148))	('MLH1', 'Gene', '4292', (126, 130))	('MSH2', 'Gene', (132, 136))	('caused by', 'Reg', (49, 58))	('MSH6', 'Gene', (138, 142))	('EPCAM', 'Gene', (154, 159))	('germline mutation', 'Var', (61, 78))	('MSH6', 'Gene', '2956', (138, 142))	('Lynch syndrome', 'Disease', (0, 14))	('MSH2', 'Gene', '4436', (132, 136))	('PMS2', 'Gene', (144, 148))	('MMR', 'biological_process', 'GO:0006298', ('114', '117'))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (21, 48))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))
63200	27775259	reported the associations of endometrial cancer risk with hormonal factors in women with Lynch syndrome were similar to those in the general population, providing directions in counseling women with a MMR gene mutation with regard to hormonal influences on endometrial cancer risk.	('endometrial cancer', 'Disease', (257, 275))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('MMR', 'Gene', (201, 204))	('endometrial cancer', 'Phenotype', 'HP:0012114', (257, 275))	('endometrial cancer', 'Disease', (29, 47))	('women', 'Species', '9606', (78, 83))	('Lynch syndrome', 'Disease', 'MESH:D003123', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('endometrial cancer', 'Disease', 'MESH:D016889', (257, 275))	('mutation', 'Var', (210, 218))	('women', 'Species', '9606', (188, 193))	('Lynch syndrome', 'Disease', (89, 103))	('endometrial cancer', 'Phenotype', 'HP:0012114', (29, 47))	('MMR', 'biological_process', 'GO:0006298', ('201', '204'))	('endometrial cancer', 'Disease', 'MESH:D016889', (29, 47))
63201	27775259	This retrospective cohort study included 1,128 women with a MMR gene mutation from the Colon Cancer Family Registry across the United States, Australia, Canada, and New Zealand between 1997 and 2012.	('Colon Cancer', 'Phenotype', 'HP:0003003', (87, 99))	('Colon Cancer', 'Disease', 'MESH:D015179', (87, 99))	('Colon Cancer', 'Disease', (87, 99))	('women', 'Species', '9606', (47, 52))	('mutation', 'Var', (69, 77))	('Cancer', 'Phenotype', 'HP:0002664', (93, 99))	('MMR', 'biological_process', 'GO:0006298', ('60', '63'))	('MMR gene', 'Gene', (60, 68))
63204	27775259	Later age at menarche >=13 years (vs. <13 years; HR per year 0.85; 95% CI, 0.73 to 0.99; p=0.04), multi-parity >=1 live births (vs. nulliparous; HR, 0.21; 95% CI, 0.10 to 0.42; p<0.001), and ever use of hormonal contraceptives >=1 years (vs. <1-year use; HR, 0.39; 95% CI, 0.23 to 0.64; p<0.001) were associated with a lower risk of endometrial cancer.	('multi-parity >=1', 'Var', (98, 114))	('menarche', 'biological_process', 'GO:0042696', ('13', '21'))	('endometrial cancer', 'Phenotype', 'HP:0012114', (333, 351))	('lower', 'NegReg', (319, 324))	('endometrial cancer', 'Disease', 'MESH:D016889', (333, 351))	('Later age at menarche', 'Phenotype', 'HP:0012569', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('endometrial cancer', 'Disease', (333, 351))
63209	27775259	A total of 1,002 tumors were analyzed for MSI, MLH1 methylation, and MMR protein expression, and then classified as normal MMR, defective MMR associated with MLH1 methylation (i.e., a sporadic epigenetic MMR defect), or probable MMR mutation (i.e., defective MMR but no methylation).	('tumors', 'Disease', (17, 23))	('MLH1', 'Gene', (47, 51))	('MLH1', 'Gene', (158, 162))	('MMR', 'Gene', (229, 232))	('methylation', 'biological_process', 'GO:0032259', ('270', '281'))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('MMR', 'biological_process', 'GO:0006298', ('204', '207'))	('MLH1', 'Gene', '4292', (47, 51))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('MLH1', 'Gene', '4292', (158, 162))	('mutation', 'Var', (233, 241))	('methylation', 'biological_process', 'GO:0032259', ('163', '174'))	('associated', 'Reg', (142, 152))	('methylation', 'Var', (163, 174))	('MMR', 'biological_process', 'GO:0006298', ('229', '232'))	('MMR', 'biological_process', 'GO:0006298', ('69', '72'))	('MMR', 'biological_process', 'GO:0006298', ('138', '141'))	('MMR', 'biological_process', 'GO:0006298', ('123', '126'))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('MMR', 'biological_process', 'GO:0006298', ('259', '262'))
63212	27775259	On the other hand, germline mutation test results for forty-seven DNA samples from probands whose tumor MMR status was probable MMR mutation demonstrated nineteen (40.4%) germline mutations.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('MMR', 'biological_process', 'GO:0006298', ('104', '107'))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('MMR', 'biological_process', 'GO:0006298', ('128', '131'))	('tumor', 'Disease', (98, 103))	('mutation', 'Var', (132, 140))	('MMR', 'Gene', (128, 131))
63215	27775259	Another interesting finding of this study was that some Lynch mutations were found in patients with endometrial cancer diagnosed at age >60 years.	('endometrial cancer', 'Disease', (100, 118))	('endometrial cancer', 'Phenotype', 'HP:0012114', (100, 118))	('found', 'Reg', (77, 82))	('endometrial cancer', 'Disease', 'MESH:D016889', (100, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (62, 71))	('patients', 'Species', '9606', (86, 94))
63216	27775259	Despite younger age at diagnosis of endometrial cancer of mutations carriers than non-carriers (54.3 years vs. 62.3 years; p<0.01), there were five carriers (0.94%) diagnosed at age >60 years, which represents 24% of Lynch cases presenting with endometrial cancer.	('mutations', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('endometrial cancer', 'Disease', (245, 263))	('endometrial cancer', 'Phenotype', 'HP:0012114', (245, 263))	('endometrial cancer', 'Disease', (36, 54))	('endometrial cancer', 'Phenotype', 'HP:0012114', (36, 54))	('endometrial cancer', 'Disease', 'MESH:D016889', (245, 263))	('endometrial cancer', 'Disease', 'MESH:D016889', (36, 54))
63218	27775259	Nevertheless, the authors concluded that these results from a large cohort of endometrioid endometrial cancer seemed to be enough to indicate that all women with endometrioid endometrial cancer including women diagnosed at age >60 years should undergo Lynch screening that included IHC, MLH1 methylation, and MSI tumor typing.	('endometrioid endometrial cancer', 'Disease', 'MESH:D016889', (162, 193))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('women', 'Species', '9606', (204, 209))	('MSI tumor', 'Disease', (309, 318))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('MLH1', 'Gene', '4292', (287, 291))	('endometrial cancer', 'Phenotype', 'HP:0012114', (175, 193))	('MLH1', 'Gene', (287, 291))	('endometrioid endometrial cancer', 'Disease', 'MESH:D016889', (78, 109))	('endometrioid endometrial cancer', 'Disease', (162, 193))	('methylation', 'Var', (292, 303))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('methylation', 'biological_process', 'GO:0032259', ('292', '303'))	('endometrioid endometrial cancer', 'Disease', (78, 109))	('MSI tumor', 'Disease', 'MESH:D009369', (309, 318))	('endometrial cancer', 'Phenotype', 'HP:0012114', (91, 109))	('women', 'Species', '9606', (151, 156))
63257	27775259	tVEGF-A also revealed a potential predictive value for OS (>Q3 tVEGF-A HR, 0.62 [95% CI, 0.43 to 0.91]; <=Q3 tVEGF-A HR, 1.01 [95% CI, 0.82 to 1.25]; interaction p=0.023) when comparing CPB15+ with CPP group.	('CPB15+', 'Var', (186, 192))	('OS', 'Chemical', '-', (55, 57))	('VEGF', 'Gene', (1, 5))	('VEGF', 'Gene', '7422', (110, 114))	('VEGF', 'Gene', (64, 68))	('VEGF', 'Gene', '7422', (1, 5))	('VEGF', 'Gene', '7422', (64, 68))	('VEGF', 'Gene', (110, 114))
63269	27775259	demonstrated that macrophage-targeted treatment with CSF-1R inhibitors lessen the number of pro-tumor macrophages and allow the vessels in the abdomen to become normal again, easing ascites accumulation without any concern about fatal side effects.	('easing', 'PosReg', (175, 181))	('CSF-1R', 'Gene', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('lessen', 'NegReg', (71, 77))	('CSF-1', 'molecular_function', 'GO:0005011', ('53', '58'))	('ascites accumulation', 'Disease', (182, 202))	('inhibitors', 'Var', (60, 70))	('CSF-1R', 'Gene', '1436', (53, 59))	('tumor', 'Disease', (96, 101))	('ascites', 'Phenotype', 'HP:0001541', (182, 189))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('ascites accumulation', 'Disease', 'MESH:D001201', (182, 202))
63273	27775259	However, CSF-1R inhibition by GW2580, a selective CSF-1R inhibitor, was shown to reverse the abnormal vascular features and reduce vascular dysfunction and in this ID8 model as well as human OVCAR3 xenograft model.	('CSF-1', 'molecular_function', 'GO:0005011', ('50', '55'))	('GW2580', 'Var', (30, 36))	('human', 'Species', '9606', (185, 190))	('CSF-1R', 'Gene', '1436', (9, 15))	('ID8', 'Disease', (164, 167))	('CSF-1R', 'Gene', '1436', (50, 56))	('GW2580', 'Chemical', 'MESH:C506269', (30, 36))	('CSF-1', 'molecular_function', 'GO:0005011', ('9', '14'))	('vascular dysfunction', 'Disease', 'MESH:D002561', (131, 151))	('reverse', 'NegReg', (81, 88))	('vascular dysfunction', 'Disease', (131, 151))	('abnormal vascular features', 'Phenotype', 'HP:0025015', (93, 119))	('CSF-1R', 'Gene', (9, 15))	('reduce', 'NegReg', (124, 130))	('CSF-1R', 'Gene', (50, 56))
63279	27775259	While at least 50% of HGSC was reported to have homologous recombination deficiency (HRD), germline BRCA1 and BRCA2 mutations (gBRCAmut) account for up to one third of the patients.	('HGSC', 'Disease', (22, 26))	('BRCA', 'Gene', '672', (110, 114))	('BRCA2', 'Gene', (110, 115))	('BRCA1', 'Gene', '672', (100, 105))	('BRCA', 'Gene', '672', (100, 104))	('homologous recombination', 'biological_process', 'GO:0035825', ('48', '72'))	('BRCA', 'Gene', (110, 114))	('BRCA', 'Gene', (100, 104))	('BRCA', 'Gene', (128, 132))	('deficiency', 'Disease', (73, 83))	('BRCA1', 'Gene', (100, 105))	('BRCA2', 'Gene', '675', (110, 115))	('HRD', 'Disease', (85, 88))	('BRCA', 'Gene', '672', (128, 132))	('mutations', 'Var', (116, 125))	('deficiency', 'Disease', 'MESH:D007153', (73, 83))	('patients', 'Species', '9606', (172, 180))	('HRD', 'Disease', 'None', (85, 88))
63284	27775259	There were only 15 (9%) BRCAwt tumors that had a loss-of-function mutation or homozygous deletion in a HR gene.	('BRCA', 'Gene', '672', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('BRCA', 'Gene', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('loss-of-function', 'NegReg', (49, 65))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('mutation', 'Var', (66, 74))
63289	27775259	presented the results of randomized phase II trial of AZD1775 plus paclitaxel and carboplatin for the treatment of women with platinum-sensitive, TP53-mutant ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (158, 172))	('TP53', 'Gene', '7157', (146, 150))	('carboplatin', 'Chemical', 'MESH:D016190', (82, 93))	('ovarian cancer', 'Disease', 'MESH:D010051', (158, 172))	('TP53', 'Gene', (146, 150))	('paclitaxel', 'Chemical', 'MESH:D017239', (67, 77))	('ovarian cancer', 'Disease', (158, 172))	('AZD1775', 'Var', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('platinum', 'Chemical', 'MESH:D010984', (126, 134))	('AZD1775', 'Chemical', 'MESH:C549567', (54, 61))	('women', 'Species', '9606', (115, 120))
63290	27775259	On the basis of synthetic lethality of the combination of genotoxic drugs and Wee1 inhibitor AZD1775 in TP53-deficient cell, the researchers evaluated the efficacy of AZD1775 plus paclitaxel and carboplatin compared with paclitaxel and carboplatin alone in women with TP53-mutant ovarian cancer.	('TP53', 'Gene', '7157', (104, 108))	('carboplatin', 'Chemical', 'MESH:D016190', (195, 206))	('TP53', 'Gene', (268, 272))	('AZD1775', 'Chemical', 'MESH:C549567', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('synthetic', 'Species', '32630', (16, 25))	('ovarian cancer', 'Disease', 'MESH:D010051', (280, 294))	('AZD1775', 'Gene', (93, 100))	('TP53', 'Gene', '7157', (268, 272))	('TP53', 'Gene', (104, 108))	('ovarian cancer', 'Disease', (280, 294))	('Wee1', 'Gene', (78, 82))	('carboplatin', 'Chemical', 'MESH:D016190', (236, 247))	('ovarian cancer', 'Phenotype', 'HP:0100615', (280, 294))	('AZD1775', 'Chemical', 'MESH:C549567', (167, 174))	('paclitaxel', 'Chemical', 'MESH:D017239', (180, 190))	('paclitaxel', 'Chemical', 'MESH:D017239', (221, 231))	('women', 'Species', '9606', (257, 262))	('Wee1', 'Gene', '7465', (78, 82))	('AZD1775', 'Var', (167, 174))
63291	27775259	A total of 121 patients with confirmed TP53 mutations were randomly assigned to receive either AZD1775 (225 mg bid) (n=59) or placebo (n=62) for 2.5 days plus paclitaxel (175 mg/m2) and carboplatin (AUC5) intravenously on day1 every three weeks until progression or the completion of six cycles.	('AZD1775', 'Chemical', 'MESH:C549567', (95, 102))	('patients', 'Species', '9606', (15, 23))	('paclitaxel', 'Chemical', 'MESH:D017239', (159, 169))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (39, 43))	('AZD1775', 'Gene', (95, 102))	('carboplatin', 'Chemical', 'MESH:D016190', (186, 197))	('TP53', 'Gene', (39, 43))
63292	27775259	PFS was significantly longer in AZD1775 group than placebo group (enhanced RECIST: HR, 0.63; 80% CI, 0.45 to 0.89; 95% CI, 0.38 to 1.06; p=0.080; median PFS, 34.14 vs. 31.86 weeks; RECIST: HR, 0.55; 80% CI, 0.39 to 0.79; 95% CI, 0.32 to 0.95; p=0.030; median PFS, 42.86 vs. 34.86 weeks).	('PFS', 'MPA', (0, 3))	('RECIST', 'MPA', (75, 81))	('AZD1775', 'Var', (32, 39))	('enhanced', 'PosReg', (66, 74))	('AZD1775', 'Chemical', 'MESH:C549567', (32, 39))
63294	27775259	The study results suggest that the addition of AZD1775 to paclitaxel and carboplatin could lengthen the PFS compared with paclitaxel and carboplatin alone with acceptable tolerability in women with TP53-mutant ovarian cancer.	('carboplatin', 'Chemical', 'MESH:D016190', (137, 148))	('women', 'Species', '9606', (187, 192))	('AZD1775', 'Chemical', 'MESH:C549567', (47, 54))	('ovarian cancer', 'Phenotype', 'HP:0100615', (210, 224))	('carboplatin', 'Chemical', 'MESH:D016190', (73, 84))	('ovarian cancer', 'Disease', (210, 224))	('TP53', 'Gene', '7157', (198, 202))	('PFS', 'MPA', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('paclitaxel', 'Chemical', 'MESH:D017239', (122, 132))	('ovarian cancer', 'Disease', 'MESH:D010051', (210, 224))	('TP53', 'Gene', (198, 202))	('lengthen', 'PosReg', (91, 99))	('paclitaxel', 'Chemical', 'MESH:D017239', (58, 68))	('AZD1775', 'Var', (47, 54))
63306	27775259	Based on these results, although more severe toxicity profiles were reported in the addition of bevacizumab than chemotherapy alone, the authors concluded that the incorporation of bevacizumab into the treatment of advanced cervical cancer were not accompanied by any significant deterioration in health-related quality of life.	('bevacizumab', 'Chemical', 'MESH:D000068258', (96, 107))	('incorporation', 'Var', (164, 177))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('toxicity', 'Disease', 'MESH:D064420', (45, 53))	('toxicity', 'Disease', (45, 53))	('bevacizumab', 'Chemical', 'MESH:D000068258', (181, 192))	('cervical cancer', 'Disease', (224, 239))	('cervical cancer', 'Disease', 'MESH:D002583', (224, 239))
63310	27775259	The HRs of death for bevacizumab were 0.96 (95% CI, 0.51 to 1.83; p=0.909), 0.673 (95% CI, 0.50 to 0.91; p=0.0094), and 0.536 (95% CI, 0.320 to 0.905; p=0.0196) in low-, mid-, and high-risk patients, respectively.	('patients', 'Species', '9606', (190, 198))	('0.536', 'Var', (120, 125))	('bevacizumab', 'Chemical', 'MESH:D000068258', (21, 32))	('0.673', 'Var', (76, 81))
63314	27775259	Given one of the mechanisms underlying resistance to hormonal treatment in endometrial cancer is PI3K pathway activation, targeting mTOR may overcome the resistance, and therefore could improve the poor survival of recurrent or advanced endometrial cancer.	('endometrial cancer', 'Disease', (237, 255))	('mTOR', 'Gene', '2475', (132, 136))	('activation', 'PosReg', (110, 120))	('endometrial cancer', 'Disease', 'MESH:D016889', (75, 93))	('mTOR', 'Gene', (132, 136))	('PI3K pathway', 'Pathway', (97, 109))	('targeting', 'Var', (122, 131))	('endometrial cancer', 'Disease', 'MESH:D016889', (237, 255))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('endometrial cancer', 'Phenotype', 'HP:0012114', (237, 255))	('PI3K', 'molecular_function', 'GO:0016303', ('97', '101'))	('endometrial cancer', 'Disease', (75, 93))	('poor', 'MPA', (198, 202))	('improve', 'PosReg', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('endometrial cancer', 'Phenotype', 'HP:0012114', (75, 93))
63320	27775259	Endometrioid histology and CTNNB1 mutations were associated with better response, while serous histology were associated with lack of response.	('Endometrioid', 'Disease', (0, 12))	('CTNNB1', 'Gene', (27, 33))	('mutations', 'Var', (34, 43))	('CTNNB1', 'Gene', '1499', (27, 33))
63349	27695045	Tumor Specific Epigenetic Silencing of Corticotropin Releasing Hormone -Binding Protein in Renal Cell Carcinoma: Association of Hypermethylation and Metastasis The relevance of Corticotropin Releasing Hormone (CRH)-system in human malignancies is a question of growing interest.	('Corticotropin Releasing Hormone', 'Gene', '1392', (39, 70))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('Corticotropin Releasing Hormone', 'Gene', '1392', (177, 208))	('Epigenetic Silencing', 'Var', (15, 35))	('Renal Cell Carcinoma', 'Disease', (91, 111))	('Corticotropin Releasing Hormone', 'Gene', (39, 70))	('human', 'Species', '9606', (225, 230))	('malignancies', 'Disease', 'MESH:D009369', (231, 243))	('Corticotropin Releasing Hormone', 'Gene', (177, 208))	('Corticotropin', 'molecular_function', 'GO:0017043', ('177', '190'))	('Hypermethylation', 'Var', (128, 144))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (91, 111))	('Corticotropin Releasing Hormone -Binding', 'molecular_function', 'GO:0051424', ('39', '79'))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (91, 111))	('malignancies', 'Disease', (231, 243))
63350	27695045	Here we investigated hypermethylation and epigenetic silencing of the CRH-Binding Protein (CRHBP) gene in clear cell renal cell cancer (ccRCC).	('RCC', 'Disease', (138, 141))	('CRHBP', 'Gene', (91, 96))	('CRH-Binding Protein', 'Gene', (70, 89))	('CRH-Binding', 'molecular_function', 'GO:0051424', ('70', '81'))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('clear cell renal cell cancer', 'Disease', (106, 134))	('epigenetic silencing', 'Var', (42, 62))	('CRHBP', 'Gene', '1393', (91, 96))	('clear cell renal cell cancer', 'Disease', 'MESH:C538614', (106, 134))	('CRH-Binding Protein', 'Gene', '1393', (70, 89))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('renal cell cancer', 'Phenotype', 'HP:0005584', (117, 134))	('clear cell renal cell cancer', 'Phenotype', 'HP:0006770', (106, 134))
63358	27695045	We describe for the first time tumor specific epigenetic silencing of CRHBP and statistical association with aggressive tumors thus suggesting the CRH system to contribute to the development of kidney cancer.	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('aggressive tumors', 'Disease', 'MESH:D001523', (109, 126))	('tumor', 'Disease', (31, 36))	('kidney cancer', 'Disease', 'MESH:D007680', (194, 207))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('CRHBP', 'Gene', (70, 75))	('epigenetic silencing', 'Var', (46, 66))	('contribute', 'Reg', (161, 171))	('aggressive tumors', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('kidney cancer', 'Phenotype', 'HP:0009726', (194, 207))	('CRHBP', 'Gene', '1393', (70, 75))	('kidney cancer', 'Disease', (194, 207))	('tumor', 'Disease', (120, 125))	('association', 'Interaction', (92, 103))
63369	27695045	The development of ccRCC is associated with loss and/or alteration of chromosome 3q and frequently observed gene mutations in the von Hippel-Lindau (VHL) and PBRM1 genes.	('PBRM1', 'Gene', (158, 163))	('von Hippel-Lindau', 'Gene', '7428', (130, 147))	('chromosome', 'cellular_component', 'GO:0005694', ('70', '80'))	('VHL', 'Disease', (149, 152))	('loss', 'NegReg', (44, 48))	('mutations', 'Var', (113, 122))	('PBRM1', 'Gene', '55193', (158, 163))	('VHL', 'Disease', 'MESH:D006623', (149, 152))	('alteration', 'Var', (56, 66))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('RCC', 'Disease', (21, 24))	('von Hippel-Lindau', 'Gene', (130, 147))	('ccRCC', 'Phenotype', 'HP:0006770', (19, 24))
63370	27695045	Exome wide mutational analyses in substantial number of tumors on the one hand revealed a great number of additional mutations occurring in RCC.	('mutations', 'Var', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))
63372	27695045	Interestingly, loss of VHL function was shown to associate with extended epigenetic alterations in RCC and, noteworthy, the most frequent mutations described so far affect genes maintaining the cellular chromatin and histone status, a process that is interrelated with DNA methylation.	('affect', 'Reg', (165, 171))	('VHL', 'Disease', (23, 26))	('DNA methylation', 'biological_process', 'GO:0006306', ('269', '284'))	('epigenetic alterations', 'MPA', (73, 95))	('loss', 'NegReg', (15, 19))	('DNA', 'cellular_component', 'GO:0005574', ('269', '272'))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('histone status', 'MPA', (217, 231))	('VHL', 'Disease', 'MESH:D006623', (23, 26))	('chromatin', 'cellular_component', 'GO:0000785', ('203', '212'))	('mutations', 'Var', (138, 147))
63375	27695045	Our study shows, to our knowledge for the first time, that a member of the CRH-system can undergo epigenetic silencing in a solid human cancer, hence providing new and strong evidence for a significant role of the CRH-system in human tumorigenesis.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Disease', (234, 239))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('human', 'Species', '9606', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('epigenetic silencing', 'Var', (98, 118))	('CRH-system', 'Gene', (75, 85))	('human', 'Species', '9606', (130, 135))
63380	27695045	Organ-confined RCC was defined as pT <= 2 and N0/M0 and advanced disease as pT >= 3 and/or N+/M+.	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('N0/M0', 'Var', (46, 51))	('RCC', 'Disease', (15, 18))
63403	27695045	Considering that all of these cell lines exhibited high CRHBP methylation and undetectable mRNA expression in QPCR analyses, we used both suppression of endogenously re-expressed CRHBP as well as targeted ectopic re-expression of CRHBP.	('methylation', 'biological_process', 'GO:0032259', ('62', '73'))	('CRHBP', 'Gene', (230, 235))	('mRNA expression', 'MPA', (91, 106))	('suppression', 'NegReg', (138, 149))	('CRHBP', 'Gene', (179, 184))	('methylation', 'Var', (62, 73))	('CRHBP', 'Gene', (56, 61))	('CRHBP', 'Gene', '1393', (230, 235))	('CRHBP', 'Gene', '1393', (179, 184))	('CRHBP', 'Gene', '1393', (56, 61))	('ectopic re-expression', 'Var', (205, 226))
63406	27695045	For example, the si-RNA treated RCC-GS cell line, originally derived from a metastatic primary tumor, showed a significantly increased capability to pass the matrigel-layer used as a measure for invasiveness (Fig 2A).	('increased', 'PosReg', (125, 134))	('RCC-GS', 'Disease', (32, 38))	('si-RNA', 'Var', (17, 23))	('RNA', 'cellular_component', 'GO:0005562', ('20', '23'))	('pass the matrigel-layer', 'CPA', (149, 172))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('RCC-GS', 'Disease', 'MESH:C538614', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
63426	27695045	Furthermore, we found that treatment of RCC cell lines with 5-aza-2 -deoxycytidine leads to a substantial reduction of methylation and concurrent increase in mRNA expression, indicating that methylation substantially contributes in expression regulation and silencing of CRHBP in RCC cell lines.	('contributes', 'Reg', (217, 228))	('regulation', 'biological_process', 'GO:0065007', ('243', '253'))	('silencing', 'NegReg', (258, 267))	('methylation', 'biological_process', 'GO:0032259', ('119', '130'))	('5-aza-2 -deoxycytidine', 'Var', (60, 82))	('RCC', 'Disease', (280, 283))	('reduction', 'NegReg', (106, 115))	('CRHBP', 'Gene', (271, 276))	('methylation', 'biological_process', 'GO:0032259', ('191', '202'))	('CRHBP', 'Gene', '1393', (271, 276))	('increase', 'PosReg', (146, 154))	('RCC', 'Disease', 'MESH:C538614', (280, 283))	('RCC', 'Disease', (40, 43))	('mRNA expression', 'MPA', (158, 173))	('methylation', 'MPA', (119, 130))	('5-aza-2 -deoxycytidine', 'Chemical', 'MESH:D000077209', (60, 82))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('expression regulation', 'MPA', (232, 253))	('methylation', 'Var', (191, 202))
63430	27695045	Statistical evaluation of tumor methylation levels and clinicopathological parameters of patients exhibited significant associations of CRHBP methylation with the presence of distant metastasis as well as the state of advanced disease therefore indicating a role in the development of more aggressive cancer subtypes.	('CRHBP', 'Gene', (136, 141))	('methylation', 'biological_process', 'GO:0032259', ('142', '153'))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('aggressive cancer', 'Disease', 'MESH:D009369', (290, 307))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('CRHBP', 'Gene', '1393', (136, 141))	('distant metastasis', 'CPA', (175, 193))	('patients', 'Species', '9606', (89, 97))	('aggressive cancer', 'Disease', (290, 307))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('methylation', 'Var', (142, 153))	('tumor', 'Disease', (26, 31))	('associations', 'Interaction', (120, 132))
63431	27695045	Moreover, in silico validation by use of the KIRC dataset provided by TCGA network study confirmed tumor specific hypermethylation of CRHBP, epigenetic silencing of CRHBP mRNA expression and association of CRHBP methylation with biological aggressive tumor characteristics.	('tumor', 'Disease', (251, 256))	('mRNA expression', 'MPA', (171, 186))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Disease', (99, 104))	('aggressive tumor', 'Disease', 'MESH:D001523', (240, 256))	('epigenetic silencing', 'Var', (141, 161))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('CRHBP', 'Gene', (134, 139))	('CRHBP', 'Gene', (165, 170))	('CRHBP', 'Gene', (206, 211))	('aggressive tumor', 'Disease', (240, 256))	('CRHBP', 'Gene', '1393', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('CRHBP', 'Gene', '1393', (165, 170))	('CRHBP', 'Gene', '1393', (206, 211))	('hypermethylation', 'Var', (114, 130))	('methylation', 'biological_process', 'GO:0032259', ('212', '223'))	('association', 'Interaction', (191, 202))
63432	27695045	Our analysis of the proliferation and invasion characteristics of RCC cancer cell lines following both si-RNA knock down of endogenously re-expressed CRHBP after 5-aza-2 -deoxycytidine treatment as well as ectopic re-expression of CRHBP in an epigenetically silenced RCC cell line interestingly revealed substantial alteration in the matri-gel invasion assay.	('alteration', 'Reg', (316, 326))	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('CRHBP', 'Gene', (150, 155))	('CRHBP', 'Gene', '1393', (231, 236))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('knock down', 'Var', (110, 120))	('RCC cancer', 'Disease', (66, 76))	('matri-gel invasion assay', 'CPA', (334, 358))	('RCC', 'Disease', 'MESH:C538614', (267, 270))	('RCC', 'Disease', (267, 270))	('CRHBP', 'Gene', '1393', (150, 155))	('si-RNA', 'Var', (103, 109))	('ectopic', 'Var', (206, 213))	('CRHBP', 'Gene', (231, 236))	('5-aza-2 -deoxycytidine', 'Chemical', 'MESH:D000077209', (162, 184))	('RCC cancer', 'Disease', 'MESH:C538614', (66, 76))	('RNA', 'cellular_component', 'GO:0005562', ('106', '109'))	('RCC', 'Disease', (66, 69))
63440	27695045	Conclusively, our analysis clearly demonstrated epigenetic silencing of CRHBP hence showing for the first time that a member of the CRH-system is epigenetically silenced in tumor cells and thus providing strong evidence for an involvement of CRH members in human tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('CRHBP', 'Gene', '1393', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('human', 'Species', '9606', (257, 262))	('epigenetic silencing', 'Var', (48, 68))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', (263, 268))	('involvement', 'Reg', (227, 238))	('CRHBP', 'Gene', (72, 77))
63441	27695045	Moreover, we found association of DNA methylation with aggressive ccRCC tumor subsets, a finding that appears in nearly perfect concordance with the in silico results provided by the TCGA network.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('DNA', 'Gene', (34, 37))	('methylation', 'Var', (38, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('aggressive ccRCC tumor', 'Disease', 'MESH:D001523', (55, 77))	('aggressive ccRCC tumor', 'Disease', (55, 77))	('DNA methylation', 'biological_process', 'GO:0006306', ('34', '49'))	('association', 'Interaction', (19, 30))
63442	27695045	Consequently, both analyses statistically point to CRHBP silencing as a factor contributing to the development of aggressive tumors.	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('aggressive tumors', 'Disease', (114, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('silencing', 'Var', (57, 66))	('CRHBP', 'Gene', (51, 56))	('aggressive tumors', 'Disease', 'MESH:D001523', (114, 131))	('CRHBP', 'Gene', '1393', (51, 56))
63445	27695045	To expand our pathophysiological understanding of CRHBP function in tumor biology and ccRCC as well, future studies will rely on identification of improved cell line models to resolve the interplay of CRH peptides, receptors, binding protein and epigenetic alteration in human tissues.	('tumor', 'Disease', (68, 73))	('protein', 'cellular_component', 'GO:0003675', ('234', '241'))	('CRHBP', 'Gene', (50, 55))	('binding', 'molecular_function', 'GO:0005488', ('226', '233'))	('human', 'Species', '9606', (271, 276))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('epigenetic', 'Var', (246, 256))	('CRHBP', 'Gene', '1393', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
63452	31788077	Further analyses revealed that patients with CCRCC and low Cyto C expression levels had a shorter survival time than those with high Cyto C expression.	('survival time', 'CPA', (98, 111))	('Cyto C', 'Gene', (133, 139))	('Cyto C', 'Gene', '54205', (133, 139))	('CCRCC', 'Disease', (45, 50))	('shorter', 'NegReg', (90, 97))	('Cyto C', 'Gene', (59, 65))	('Cyto C', 'Gene', '54205', (59, 65))	('patients', 'Species', '9606', (31, 39))	('CCRCC', 'Phenotype', 'HP:0006770', (45, 50))	('low', 'Var', (55, 58))	('CCRCC', 'Disease', 'MESH:D002292', (45, 50))
63454	31788077	Functionally, overexpression of Cyto C effectively suppressed the growth of CCRCC cells and induced cell apoptosis, and knockdown of Cyto C reversed these effects.	('CCRCC', 'Disease', 'MESH:D002292', (76, 81))	('Cyto C', 'Gene', '54205', (133, 139))	('Cyto C', 'Gene', (133, 139))	('growth', 'CPA', (66, 72))	('apoptosis', 'biological_process', 'GO:0097194', ('105', '114'))	('induced', 'Reg', (92, 99))	('apoptosis', 'biological_process', 'GO:0006915', ('105', '114'))	('suppressed', 'NegReg', (51, 61))	('knockdown', 'Var', (120, 129))	('CCRCC', 'Disease', (76, 81))	('CCRCC', 'Phenotype', 'HP:0006770', (76, 81))	('cell apoptosis', 'CPA', (100, 114))	('overexpression', 'PosReg', (14, 28))	('Cyto C', 'Gene', (32, 38))	('Cyto C', 'Gene', '54205', (32, 38))
63457	31788077	Clear cell renal cell carcinoma (CCRCC) represents the most common subtype of renal cancer, which is frequently observed to exhibit alterations in the von Hippel-Lindau gene.	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('renal cancer', 'Disease', 'MESH:D007680', (78, 90))	('renal cancer', 'Phenotype', 'HP:0009726', (78, 90))	('CCRCC', 'Disease', 'MESH:D002292', (33, 38))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (0, 31))	('alterations', 'Var', (132, 143))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (151, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('CCRCC', 'Disease', (33, 38))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('von Hippel-Lindau', 'Disease', (151, 168))	('renal cancer', 'Disease', (78, 90))	('CCRCC', 'Phenotype', 'HP:0006770', (33, 38))
63518	31788077	2D) suggested that patients with low Cyto C expression exhibited shorter overall survival rates compared with those with high Cyto C levels.	('Cyto C', 'Gene', '54205', (126, 132))	('Cyto C', 'Gene', (126, 132))	('patients', 'Species', '9606', (19, 27))	('shorter', 'NegReg', (65, 72))	('low', 'Var', (33, 36))	('Cyto C', 'Gene', '54205', (37, 43))	('Cyto C', 'Gene', (37, 43))	('overall survival', 'MPA', (73, 89))
63522	31788077	Western blotting confirmed that overexpression and knockdown of Cyto C protein levels in 786-O cells were achieved (Fig.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('Cyto C', 'Gene', (64, 70))	('Cyto C', 'Gene', '54205', (64, 70))	('knockdown', 'Var', (51, 60))
63523	31788077	As a control, the expression levels of COXIV, a house-keeping gene in mitochondria, were not significantly altered following Cyto C-overexpression or knockdown in 786-O cells (Fig.	('COXIV', 'Gene', '1327', (39, 44))	('mitochondria', 'cellular_component', 'GO:0005739', ('70', '82'))	('Cyto C', 'Gene', '54205', (125, 131))	('Cyto C', 'Gene', (125, 131))	('COXIV', 'Gene', (39, 44))	('knockdown', 'Var', (150, 159))
63565	27993630	Low level of PDZK1 in both mRNA and protein was associated with reduced overall survival (OS) and disease-free survival (DFS) in two independent sets.	('Low level', 'Var', (0, 9))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('overall survival', 'CPA', (72, 88))	('PDZK1', 'Gene', (13, 18))	('reduced', 'NegReg', (64, 71))	('PDZK1', 'Gene', '5174', (13, 18))	('disease-free survival', 'CPA', (98, 119))
63567	27993630	These findings indicated that low level of PDZK1 could predict poor clinical outcome in patients with ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('PDZK1', 'Gene', (43, 48))	('patients', 'Species', '9606', (88, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('PDZK1', 'Gene', '5174', (43, 48))	('low level', 'Var', (30, 39))
63570	27993630	Low level of PDZK1 could predict poor clinical outcome in patients with ccRCC.	('Low level', 'Var', (0, 9))	('RCC', 'Disease', (74, 77))	('PDZK1', 'Gene', (13, 18))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('PDZK1', 'Gene', '5174', (13, 18))	('patients', 'Species', '9606', (58, 66))
63604	27993630	Anti-PDZK1 and anti-beta-actin antibodies were purchased from BD Biosciences (Cat# 612660, RRID: AB_399904, San Jose, CA) and Sigma-Aldrich (Cat# A5441, RRID: AB_476744, St. Louis, MO), respectively.	('RRID', 'Disease', (153, 157))	('PDZK1', 'Gene', (5, 10))	('PDZK1', 'Gene', '5174', (5, 10))	('RRID', 'Disease', (91, 95))	('beta-actin', 'Gene', '728378', (20, 30))	('Cat', 'molecular_function', 'GO:0004096', ('78', '81'))	('beta-actin', 'Gene', (20, 30))	('RRID', 'Disease', 'None', (153, 157))	('Cat', 'molecular_function', 'GO:0004096', ('141', '144'))	('Cat# A5441', 'Var', (141, 151))	('RRID', 'Disease', 'None', (91, 95))
63637	27993630	Patients with low PDZK1 mRNA level had shorter OS and DFS time (Fig.	('DFS time', 'MPA', (54, 62))	('Patients', 'Species', '9606', (0, 8))	('PDZK1', 'Gene', (18, 23))	('low', 'Var', (14, 17))	('shorter', 'NegReg', (39, 46))	('PDZK1', 'Gene', '5174', (18, 23))
63699	30439581	In post-therapy HPD tumors, somatic mutations were found in known cancer genes, including tumor suppressor genes such as TSC2 and VHL, along with transcriptional upregulation of oncogenic pathways, including IGF-1, ERK/MAPK, PI3K/AKT, and TGF-beta.	('AKT', 'Gene', (230, 233))	('tumor suppressor', 'biological_process', 'GO:0051726', ('90', '106'))	('MAPK', 'molecular_function', 'GO:0004707', ('219', '223'))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', (20, 25))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('ERK', 'Gene', '5594', (215, 218))	('tumor', 'Disease', (90, 95))	('oncogenic pathways', 'Pathway', (178, 196))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('AKT', 'Gene', '207', (230, 233))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('IGF-1', 'Gene', (208, 213))	('ERK', 'Gene', (215, 218))	('PI3K', 'molecular_function', 'GO:0016303', ('225', '229'))	('VHL', 'Gene', (130, 133))	('TGF-beta', 'Gene', (239, 247))	('HPD tumors', 'Disease', 'MESH:D009369', (16, 26))	('upregulation', 'PosReg', (162, 174))	('IGF-1', 'Gene', '3479', (208, 213))	('HPD tumors', 'Disease', (16, 26))	('TSC2', 'Gene', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('ERK', 'molecular_function', 'GO:0004707', ('215', '218'))	('mutations', 'Var', (36, 45))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('90', '106'))	('cancer', 'Disease', (66, 72))
63707	30439581	Although accurate identification of the frequency of patients developing HPD has been limited by variability in diagnostic criteria, conservative estimates suggest that HPD may occur in as many as 10% of patients treated with anti-PD-1.	('HPD', 'Disease', (169, 172))	('anti-PD-1', 'Var', (226, 235))	('patients', 'Species', '9606', (204, 212))	('patients', 'Species', '9606', (53, 61))	('HPD', 'Disease', 'MESH:D004421', (73, 76))	('HPD', 'Disease', 'MESH:D004421', (169, 172))	('HPD', 'Disease', (73, 76))
63709	30439581	Although a pilot study suggested that some patients with MDM2 family amplification or EGFR aberrations developed HPD after treatment with PD-1 or PD-L1 inhibitors, it is likely that alterations beyond those identified in that study are important in facilitating accelerated disease progression.	('EGFR', 'Gene', '1956', (86, 90))	('MDM2', 'Gene', '4193', (57, 61))	('patients', 'Species', '9606', (43, 51))	('MDM2', 'Gene', (57, 61))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('HPD', 'Disease', (113, 116))	('developed', 'Reg', (103, 112))	('EGFR', 'Gene', (86, 90))	('aberrations', 'Var', (91, 102))	('HPD', 'Disease', 'MESH:D004421', (113, 116))
63724	30439581	There were 154 and 124 common somatic mutations shared by the HPD and pre-therapy tumors for Patients 1 and 2, respectively (Figure S1).	('Patients', 'Species', '9606', (93, 101))	('pre', 'molecular_function', 'GO:0003904', ('70', '73'))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('HPD', 'Disease', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mutations', 'Var', (38, 47))	('HPD', 'Disease', 'MESH:D004421', (62, 65))
63728	30439581	There were 47 cancer genes mutated in at least one of the tumors from Patient 1 and 40 cancer genes mutated in at least one of the tumors from Patient 2 (Figure 1, Table S2).	('cancer', 'Disease', (14, 20))	('cancer', 'Disease', (87, 93))	('mutated', 'Var', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('Patient', 'Species', '9606', (143, 150))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('Patient', 'Species', '9606', (70, 77))
63730	30439581	However, the HPD tumor of Patient 1 had somatic mutations in 20 cancer genes, including IGFBP2, KMT2C, MAP3K4, MUC16, MUC2, NCOR2, and NOTCH4, which were not present in the pre-therapy tumors.	('HPD tumor', 'Disease', (13, 22))	('tumors', 'Disease', (185, 191))	('IGFBP2', 'Gene', (88, 94))	('mutations', 'Var', (48, 57))	('NOTCH4', 'Gene', (135, 141))	('NOTCH4', 'Gene', '4855', (135, 141))	('cancer', 'Disease', (64, 70))	('HPD tumor', 'Disease', 'MESH:D009369', (13, 22))	('MUC16', 'Gene', '94025', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('NCOR2', 'Gene', (124, 129))	('MUC2', 'Gene', '4583', (118, 122))	('KMT2C', 'Gene', '58508', (96, 101))	('KMT2C', 'Gene', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('MAP3K4', 'Gene', '4216', (103, 109))	('NCOR2', 'Gene', '9612', (124, 129))	('Patient', 'Species', '9606', (26, 33))	('MAP3K', 'molecular_function', 'GO:0004709', ('103', '108'))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('MUC2', 'Gene', (118, 122))	('MUC16', 'Gene', (111, 116))	('IGFBP2', 'Gene', '3485', (88, 94))	('MAP3K4', 'Gene', (103, 109))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('pre', 'molecular_function', 'GO:0003904', ('173', '176'))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
63732	30439581	Four cancer genes (APC2, OBSCN, PHLPP1, and SATB1) that were mutated in the pre-therapy tumor of Patient 2 were not mutated in the post-treatment tumors, whereas the HPD tumor of Patient 2 had somatic mutations in 21 cancer genes, including IGFBP2, MUC4, NCOR2, NFE2L2, TSC2, and VHL, which were not present in the pre-therapy tumors.	('SATB1', 'Gene', (44, 49))	('IGFBP2', 'Gene', (241, 247))	('tumor', 'Disease', (146, 151))	('PHLPP1', 'Gene', '23239', (32, 38))	('tumor', 'Disease', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('tumors', 'Disease', (327, 333))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('NFE2L2', 'Gene', (262, 268))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('SATB1', 'Gene', '6304', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('MUC4', 'Gene', '4585', (249, 253))	('tumor', 'Disease', (327, 332))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('OBSCN', 'Gene', (25, 30))	('MUC4', 'Gene', (249, 253))	('Patient', 'Species', '9606', (179, 186))	('tumors', 'Disease', 'MESH:D009369', (327, 333))	('APC2', 'Gene', (19, 23))	('tumor', 'Disease', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (327, 333))	('tumor', 'Disease', 'MESH:D009369', (327, 332))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('OBSCN', 'Gene', '84033', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('VHL', 'Gene', (280, 283))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('HPD tumor', 'Disease', (166, 175))	('pre', 'molecular_function', 'GO:0003904', ('76', '79'))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('pre', 'molecular_function', 'GO:0003904', ('315', '318'))	('IGFBP2', 'Gene', '3485', (241, 247))	('APC', 'cellular_component', 'GO:0005680', ('19', '22'))	('mutations', 'Var', (201, 210))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('Patient', 'Species', '9606', (97, 104))	('cancer', 'Disease', (5, 11))	('PHLPP1', 'Gene', (32, 38))	('cancer', 'Disease', (217, 223))	('NFE2L2', 'Gene', '4780', (262, 268))	('HPD tumor', 'Disease', 'MESH:D009369', (166, 175))	('TSC2', 'Gene', (270, 274))	('NCOR2', 'Gene', (255, 260))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('tumors', 'Disease', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('APC2', 'Gene', '10297', (19, 23))	('NCOR2', 'Gene', '9612', (255, 260))
63735	30439581	For comparison in the context of corresponding cancer populations, we analyzed the numbers of somatic mutations of the esophageal carcinoma (ESCA, n = 184) and kidney renal clear cell carcinoma (KIRC, n = 384) samples from The Cancer Genome Atlas (TCGA).	('esophageal carcinoma', 'Disease', 'MESH:D004938', (119, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (119, 139))	('cancer', 'Disease', (47, 53))	('Cancer Genome Atlas', 'Disease', (227, 246))	('mutations', 'Var', (102, 111))	('kidney renal clear cell carcinoma', 'Disease', (160, 193))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (160, 193))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (227, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Cancer', 'Phenotype', 'HP:0002664', (227, 233))	('esophageal carcinoma', 'Disease', (119, 139))
63741	30439581	Bioinformatics analyses of these 161 mutations led to the identification of 11 potentially deleterious somatic variants in the HPD tumors, which were predicted to be "deleterious" by SIFT, "probably damaging" by PolyPhen-2, and "potentially associated with cancer" by FATHMM (Table 2).	('SIFT', 'Disease', (183, 187))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('associated with', 'Reg', (241, 256))	('cancer', 'Disease', (257, 263))	('PolyPhen-2', 'MPA', (212, 222))	('HPD tumors', 'Disease', 'MESH:D009369', (127, 137))	('variants', 'Var', (111, 119))	('SIFT', 'Disease', 'None', (183, 187))	('mutations', 'Var', (37, 46))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('damaging', 'NegReg', (199, 207))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('HPD tumors', 'Disease', (127, 137))
63742	30439581	The 11 genes having these deleterious mutations were TRPC4, POTEE, FBN2, KMT2C, FUT10, PQBP1, TSC2, MFSD6, CYP2D6, VHL, and RAD54B.	('MFSD6', 'Gene', (100, 105))	('CYP2D6', 'Gene', '1565', (107, 113))	('TRPC4', 'Gene', (53, 58))	('POTEE', 'Gene', '445582', (60, 65))	('RAD54B', 'Gene', (124, 130))	('PQBP1', 'Gene', '10084', (87, 92))	('CYP2D6', 'Gene', (107, 113))	('RAD', 'biological_process', 'GO:1990116', ('124', '127'))	('TRPC4', 'Gene', '7223', (53, 58))	('TSC2', 'Gene', (94, 98))	('FBN2', 'Gene', (67, 71))	('mutations', 'Var', (38, 47))	('PQBP1', 'Gene', (87, 92))	('VHL', 'Gene', (115, 118))	('KMT2C', 'Gene', '58508', (73, 78))	('KMT2C', 'Gene', (73, 78))	('FBN2', 'Gene', '2201', (67, 71))	('FUT10', 'Gene', '84750', (80, 85))	('RAD54B', 'Gene', '25788', (124, 130))	('MFSD6', 'Gene', '54842', (100, 105))	('FUT10', 'Gene', (80, 85))	('POTEE', 'Gene', (60, 65))
63743	30439581	Of the 11 mutations, 10 were located at evolutionarily conserved sites, as predicted by GERP++ (scores >2; Table 2).	('mutations', 'Var', (10, 19))	('GERP', 'Gene', '81603', (88, 92))	('GERP', 'Gene', (88, 92))
63745	30439581	The mutated TSC2 gene carrying a missense mutation, p.Y1611S, was in the center of this network and is linked to inhibition of the TP53 pathway and activation of the MYC, CCND1, and VEGF pathways (Figure S3).	('p.Y1611S', 'Mutation', 'p.Y1611S', (52, 60))	('p.Y1611S', 'Var', (52, 60))	('MYC', 'Gene', '4609', (166, 169))	('activation', 'PosReg', (148, 158))	('VEGF', 'Gene', '7422', (182, 186))	('inhibition', 'NegReg', (113, 123))	('CCND1', 'Gene', (171, 176))	('TP53', 'Gene', (131, 135))	('MYC', 'Gene', (166, 169))	('TP53', 'Gene', '7157', (131, 135))	('TSC2', 'Gene', (12, 16))	('CCND1', 'Gene', '595', (171, 176))	('VEGF', 'Gene', (182, 186))
63747	30439581	Previous studies showed that TSC2 knockdown transforms mouse and human renal epithelial cells into neoplastic stem cells that can serially propagate upon re-inoculation in mice.	('human', 'Species', '9606', (65, 70))	('knockdown', 'Var', (34, 43))	('mice', 'Species', '10090', (172, 176))	('mouse', 'Species', '10090', (55, 60))	('TSC2', 'Gene', (29, 33))
63748	30439581	Together, it is reasonable to hypothesize that the deleterious p.Y1611S mutation could result in the loss of function of the TSC2 protein, which in turn will lead to uncontrolled proliferation of cancer cells in the HPD tumors that survive anti-PD-1 treatment.	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('lead to', 'Reg', (158, 165))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('uncontrolled', 'MPA', (166, 178))	('HPD tumors', 'Disease', 'MESH:D009369', (216, 226))	('TSC2', 'Gene', (125, 129))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('loss of function', 'NegReg', (101, 117))	('cancer', 'Disease', (196, 202))	('p.Y1611S', 'Mutation', 'p.Y1611S', (63, 71))	('p.Y1611S', 'Var', (63, 71))	('protein', 'Protein', (130, 137))	('HPD tumors', 'Disease', (216, 226))
63752	30439581	Such concerted gene expression changes may synergistically contribute to the generation of the HPD tumors after anti-PD-1 immunotherapy.	('gene expression', 'biological_process', 'GO:0010467', ('15', '30'))	('HPD tumors', 'Disease', 'MESH:D009369', (95, 105))	('HPD tumors', 'Disease', (95, 105))	('changes', 'Var', (31, 38))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('contribute', 'Reg', (59, 69))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
63753	30439581	Based on mutation clustering results, we inferred the identity of three clones having distinct sets of mutations (clusters) in pre-therapy tumors when compared with post-therapy HPD tumors of the two patients.	('pre', 'molecular_function', 'GO:0003904', ('127', '130'))	('mutations', 'Var', (103, 112))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('patients', 'Species', '9606', (200, 208))	('HPD tumors', 'Disease', 'MESH:D009369', (178, 188))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('HPD tumors', 'Disease', (178, 188))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
63755	30439581	In Patient 1, the post-anti-PD-1 treatment HPD tumor was associated with the outgrowth of new clone(s) represented by mutations in cancer-associated genes including KMT2C, NCOR2, COL28A1, ING3, CAMKK2, and CARD8 (Figures 4A and 4C).	('CAMKK2', 'Gene', (194, 200))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('HPD tumor', 'Disease', (43, 52))	('ING3', 'Gene', (188, 192))	('CAMKK2', 'Gene', '10645', (194, 200))	('NCOR2', 'Gene', (172, 177))	('outgrowth of new clone', 'CPA', (77, 99))	('CARD8', 'Gene', (206, 211))	('Patient', 'Species', '9606', (3, 10))	('COL28A1', 'Gene', (179, 186))	('ING3', 'Gene', '54556', (188, 192))	('HPD tumor', 'Disease', 'MESH:D009369', (43, 52))	('NCOR2', 'Gene', '9612', (172, 177))	('mutations', 'Var', (118, 127))	('CARD8', 'Gene', '22900', (206, 211))	('KMT2C', 'Gene', '58508', (165, 170))	('KMT2C', 'Gene', (165, 170))	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('COL28A1', 'Gene', '340267', (179, 186))	('associated', 'Reg', (57, 67))
63756	30439581	The pre-therapy tumor clone(s) characterized by mutations in APH1A, ARHGEF12, GPER1, and KIF14 genes was eliminated by anti-PD-1 treatment (Figures 4A and 4C).	('APH1A', 'Gene', '51107', (61, 66))	('APH1A', 'Gene', (61, 66))	('KIF14', 'Gene', (89, 94))	('KIF14', 'Gene', '9928', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('ARHGEF12', 'Gene', '23365', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('GPER1', 'Gene', (78, 83))	('GPER1', 'Gene', '2852', (78, 83))	('ARHGEF12', 'Gene', (68, 76))	('pre', 'molecular_function', 'GO:0003904', ('4', '7'))	('mutations', 'Var', (48, 57))
63757	30439581	The clone(s) represented by mutations in the cancer genes EP400, CUBN, SPP1, PHLPP2, PALB2, ERCC1, TFRC, MARK4, and MDM4 remained stable under the selection pressure of anti-PD-1 treatment (Figures 4A and 4C).	('SPP1', 'Gene', (71, 75))	('CUBN', 'Gene', (65, 69))	('CUBN', 'Gene', '8029', (65, 69))	('TFRC', 'Gene', '7037', (99, 103))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('TFRC', 'Gene', (99, 103))	('PHLPP2', 'Gene', (77, 83))	('SPP1', 'Gene', '6696', (71, 75))	('PHLPP2', 'Gene', '23035', (77, 83))	('PALB2', 'Gene', (85, 90))	('MARK4', 'Gene', '57787', (105, 110))	('EP400', 'Gene', '57634', (58, 63))	('MARK4', 'Gene', (105, 110))	('PALB2', 'Gene', '79728', (85, 90))	('MDM4', 'Gene', '4194', (116, 120))	('ERCC1', 'Gene', '2067', (92, 97))	('cancer', 'Disease', (45, 51))	('mutations', 'Var', (28, 37))	('MDM4', 'Gene', (116, 120))	('EP400', 'Gene', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('SPP', 'molecular_function', 'GO:0042499', ('71', '74'))	('ERCC1', 'Gene', (92, 97))
63758	30439581	In Patient 2, the post-anti-PD-1 treatment HPD tumor was associated with the evolution of new clone(s) represented by mutations in the cancer genes including BAP1, CARD11, CBFA2T3, CYP2D6, PBRM1, TSC2, and VHL (Figures 4B and 4D), whereas the pre-therapy tumor clone with mutations in APC2, CDC27, OBSCN, PHLPP1, and SATB1 was not detectable after anti-PD-1 treatment (Figures 4B and 4D).	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('OBSCN', 'Gene', (298, 303))	('CYP2D6', 'Gene', '1565', (181, 187))	('CYP2D6', 'Gene', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('BAP1', 'Gene', '8314', (158, 162))	('OBSCN', 'Gene', '84033', (298, 303))	('HPD tumor', 'Disease', (43, 52))	('TSC2', 'Gene', (196, 200))	('cancer', 'Disease', (135, 141))	('CBFA2T3', 'Gene', (172, 179))	('SATB1', 'Gene', (317, 322))	('PHLPP1', 'Gene', (305, 311))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('APC2', 'Gene', '10297', (285, 289))	('PBRM1', 'Gene', '55193', (189, 194))	('Patient', 'Species', '9606', (3, 10))	('CBFA2T3', 'Gene', '863', (172, 179))	('HPD tumor', 'Disease', 'MESH:D009369', (43, 52))	('tumor', 'Disease', (255, 260))	('BAP1', 'Gene', (158, 162))	('mutations', 'Var', (118, 127))	('PBRM1', 'Gene', (189, 194))	('SATB1', 'Gene', '6304', (317, 322))	('CDC27', 'Gene', '996', (291, 296))	('PHLPP1', 'Gene', '23239', (305, 311))	('pre', 'molecular_function', 'GO:0003904', ('243', '246'))	('CARD11', 'Gene', (164, 170))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Disease', (47, 52))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('APC2', 'Gene', (285, 289))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('CARD11', 'Gene', '84433', (164, 170))	('APC', 'cellular_component', 'GO:0005680', ('285', '288'))	('VHL', 'Gene', (206, 209))	('CDC27', 'Gene', (291, 296))
63759	30439581	Other clones, including those represented by mutations in COL4A3, TTC40, NPHS1, UGT2A3, RYR1, AGGF1, and LANCL1, remained stable before and after anti-PD-1 treatment (Figures 4B and 4D).	('RYR', 'cellular_component', 'GO:1990425', ('88', '91'))	('COL4A3', 'Gene', '1285', (58, 64))	('mutations', 'Var', (45, 54))	('AGGF1', 'Gene', (94, 99))	('NPHS1', 'Gene', (73, 78))	('LANCL1', 'Gene', (105, 111))	('TTC40', 'Gene', (66, 71))	('NPHS1', 'Gene', '4868', (73, 78))	('COL4A3', 'Gene', (58, 64))	('RYR1', 'Gene', (88, 92))	('TTC40', 'Gene', '54777', (66, 71))	('LANCL1', 'Gene', '10314', (105, 111))	('AGGF1', 'Gene', '55109', (94, 99))	('UGT2A3', 'Gene', (80, 86))	('RYR1', 'Gene', '6261', (88, 92))	('UGT2A3', 'Gene', '79799', (80, 86))
63761	30439581	As can be seen from Figures S5 and S6, all four melanoma cases demonstrated allele clusters after anti-PD-1 therapy.	('allele clusters', 'Var', (76, 91))	('melanoma', 'Disease', (48, 56))	('demonstrated', 'Reg', (63, 75))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
63762	30439581	Variant allele frequencies (VAFs) of the Cluster 1 mutations were not significantly changed by PD-1 blockade; Cluster 2 mutations had reduced VAFs but were still prevalent in the relapsing tumor after PD-1 blockade; Cluster 3 mutations represented the newly evolved tumor clone(s) in the relapsing tumor after PD-1 blockade; Cluster 4 mutated genes represented the tumor clone(s) that diminished to undetectable levels after PD-1 blockade.	('tumor', 'Disease', (189, 194))	('tumor', 'Disease', (298, 303))	('tumor', 'Disease', 'MESH:D009369', (365, 370))	('tumor', 'Phenotype', 'HP:0002664', (365, 370))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumor', 'Disease', (365, 370))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('mutations', 'Var', (226, 235))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('tumor', 'Disease', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))
63788	30439581	However, it was reported that ILC3 may promote the growth of mutant tumor cells that express the receptors needed for oncogenic pathways.	('tumor', 'Disease', (68, 73))	('promote', 'PosReg', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('mutant', 'Var', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('growth', 'MPA', (51, 57))	('ILC3', 'Gene', (30, 34))
63793	30439581	To characterize the inflammation activity in post-anti-PD-1 treatment HPD tumors versus pre-treatment tumors, we again utilized GSVA, which identified four founder datasets of inflammation pathways that were significantly enhanced in the HPD tumors after anti-PD-1 treatment (Figure 8A).	('inflammation', 'biological_process', 'GO:0006954', ('20', '32'))	('inflammation', 'Disease', 'MESH:D007249', (20, 32))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('inflammation', 'Disease', (20, 32))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('enhanced', 'PosReg', (222, 230))	('inflammation', 'Disease', 'MESH:D007249', (176, 188))	('tumors', 'Disease', (102, 108))	('inflammation', 'biological_process', 'GO:0006954', ('176', '188'))	('anti-PD-1', 'Var', (255, 264))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('HPD tumors', 'Disease', 'MESH:D009369', (238, 248))	('tumors', 'Disease', (242, 248))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('inflammation', 'Disease', (176, 188))	('pre', 'molecular_function', 'GO:0003904', ('88', '91'))	('HPD tumors', 'Disease', (238, 248))	('HPD tumors', 'Disease', 'MESH:D009369', (70, 80))	('HPD tumors', 'Disease', (70, 80))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('GSVA', 'Chemical', '-', (128, 132))	('tumors', 'Disease', (74, 80))
63809	30439581	The mutation analysis highlighted 11 genes with deleterious mutations in the HPD tumors after anti-PD-1 therapy (Table 2).	('HPD tumors', 'Disease', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mutations', 'Var', (60, 69))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('HPD tumors', 'Disease', 'MESH:D009369', (77, 87))
63811	30439581	However, a query of this 11 mutated gene set in the cBioPortal website (http://www.cbioportal.org/) showed that this gene set has somatic mutations or copy number aberrations (CNAs) in 8,887 (22%) of the 41,320 sequenced patients.	('copy number aberrations', 'Var', (151, 174))	('patients', 'Species', '9606', (221, 229))	('mutations', 'Var', (138, 147))
63812	30439581	The alterations of these 11 genes were most frequent in the six major cancer types with an alteration frequency >30% (Figure S13), i.e., prostate cancer (70.8% tumor samples had mutations or CNAs in at least one of the 11 genes), melanoma (50.2% altered), renal cell carcinoma (45.3% altered), brain cancer (33.3% altered), breast cancer (31.1% altered), and colorectal adenocarcinoma (31.0% altered).	('cancer', 'Disease', (146, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (375, 384))	('brain cancer', 'Disease', (294, 306))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('melanoma', 'Phenotype', 'HP:0002861', (230, 238))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('altered', 'Reg', (246, 253))	('melanoma', 'Disease', (230, 238))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (359, 384))	('breast cancer', 'Phenotype', 'HP:0003002', (324, 337))	('prostate cancer', 'Disease', 'MESH:D011471', (137, 152))	('alterations', 'Var', (4, 15))	('prostate cancer', 'Phenotype', 'HP:0012125', (137, 152))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('renal cell carcinoma', 'Disease', (256, 276))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (256, 276))	('prostate cancer', 'Disease', (137, 152))	('breast cancer', 'Disease', 'MESH:D001943', (324, 337))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('breast cancer', 'Disease', (324, 337))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', (300, 306))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('brain cancer', 'Phenotype', 'HP:0030692', (294, 306))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('CNAs', 'MPA', (191, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('tumor', 'Disease', (160, 165))	('brain cancer', 'Disease', 'MESH:D001932', (294, 306))	('melanoma', 'Disease', 'MESH:D008545', (230, 238))	('cancer', 'Disease', (331, 337))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('colorectal adenocarcinoma', 'Disease', (359, 384))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (256, 276))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('mutations', 'Var', (178, 187))
63813	30439581	These data support the cancer linkage to these 11 genes, the mutations of which could contribute to the tumor hyperprogressive phenotype.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('cancer', 'Disease', (23, 29))	('mutations', 'Var', (61, 70))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('contribute', 'Reg', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
63815	30439581	Inactivating mutations in TSC2 that encode the protein tuberin lead to constitutive activation of mTOR kinase through the Rheb-GTP signaling axis, which in turn induces cell growth, motility, invasion, and development of tumors.	('cell growth', 'CPA', (169, 180))	('induces', 'PosReg', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('Rheb', 'Gene', (122, 126))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('mTOR', 'Gene', (98, 102))	('cell growth', 'biological_process', 'GO:0016049', ('169', '180'))	('Inactivating mutations', 'Var', (0, 22))	('invasion', 'CPA', (192, 200))	('mTOR', 'Gene', '2475', (98, 102))	('tumors', 'Disease', (221, 227))	('tuberin', 'Gene', '7249', (55, 62))	('motility', 'CPA', (182, 190))	('tuberin', 'Gene', (55, 62))	('GTP', 'Chemical', 'MESH:D006160', (127, 130))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('Rheb', 'Gene', '6009', (122, 126))	('activation', 'PosReg', (84, 94))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('TSC2', 'Gene', (26, 30))
63816	30439581	These outcomes were consistent with our observation that the deleterious pY1611S mutation in the key Rap/ran-GAP domain of the TSC2 protein (Table 2, Figure S4) occurred in the hyperprogressive tumors after anti-PD-1 therapy.	('TSC2', 'Gene', (127, 131))	('pY1611S', 'Var', (73, 80))	('hyperprogressive tumors', 'Disease', (177, 200))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('hyperprogressive tumors', 'Disease', 'MESH:D009369', (177, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('occurred', 'Reg', (161, 169))
63817	30439581	We also found that the VHL gene had a deleterious mutation:pL117V:in the ccRCC hyperprogressive tumors after anti-PD-1 treatment (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('VHL', 'Gene', (23, 26))	('hyperprogressive tumors', 'Disease', 'MESH:D009369', (79, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('pL117V', 'Var', (59, 65))	('hyperprogressive tumors', 'Disease', (79, 102))
63820	30439581	In our case, we found that only the post-anti-PD-1 therapy hyperprogressive ccRCC tumor had detectable deleterious VHL mutation, but the pre-therapy ccRCC tumor did not.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('VHL', 'Gene', (115, 118))	('mutation', 'Var', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('pre', 'molecular_function', 'GO:0003904', ('137', '140'))	('tumor', 'Disease', (82, 87))
63822	30439581	This has significant implications in that it suggests that ccRCC cells with an altered/mutated VHL gene may be a key factor leading to HPD after anti-PD-1 therapy.	('altered/mutated', 'Var', (79, 94))	('leading', 'Reg', (124, 131))	('HPD', 'Disease', (135, 138))	('VHL', 'Gene', (95, 98))	('HPD', 'Disease', 'MESH:D004421', (135, 138))
63825	30439581	Clonal evolution analysis (Figure 4) indicates that HPD tumor-specific mutations in TSC2 and VHL along with mutations in a number of other cancer genes including KMT2C, NCOR2, COL28A1, ING3, CAMKK2, CARD8, BAP1, CARD11, CBFA2T3, CYP2D6, and PBRM1 could be significant to the progression of nonaggressive pre-therapy tumors to the hyperprogressive state after anti-PD-1 treatment.	('CYP2D6', 'Gene', (229, 235))	('BAP1', 'Gene', '8314', (206, 210))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('significant', 'Reg', (256, 267))	('CARD8', 'Gene', (199, 204))	('ING3', 'Gene', '54556', (185, 189))	('HPD tumor', 'Disease', (52, 61))	('tumors', 'Phenotype', 'HP:0002664', (316, 322))	('PBRM1', 'Gene', (241, 246))	('COL28A1', 'Gene', '340267', (176, 183))	('VHL', 'Gene', (93, 96))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('CARD8', 'Gene', '22900', (199, 204))	('CBFA2T3', 'Gene', (220, 227))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('BAP1', 'Gene', (206, 210))	('HPD tumor', 'Disease', 'MESH:D009369', (52, 61))	('mutations', 'Var', (71, 80))	('tumors', 'Disease', (316, 322))	('TSC2', 'Gene', (84, 88))	('CBFA2T3', 'Gene', '863', (220, 227))	('CAMKK2', 'Gene', (191, 197))	('tumors', 'Disease', 'MESH:D009369', (316, 322))	('CARD11', 'Gene', (212, 218))	('NCOR2', 'Gene', (169, 174))	('cancer', 'Disease', (139, 145))	('COL28A1', 'Gene', (176, 183))	('NCOR2', 'Gene', '9612', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('ING3', 'Gene', (185, 189))	('CAMKK2', 'Gene', '10645', (191, 197))	('CARD11', 'Gene', '84433', (212, 218))	('PBRM1', 'Gene', '55193', (241, 246))	('pre', 'molecular_function', 'GO:0003904', ('304', '307'))	('CYP2D6', 'Gene', '1565', (229, 235))	('KMT2C', 'Gene', '58508', (162, 167))	('KMT2C', 'Gene', (162, 167))
63826	30439581	Figure S3 showed that the mutated KMT2C, TSC2, VHL, and CYP2D6 genes were involved in the gene-gene interaction network leading to suppression of the TP53 pathway activity.	('TP53', 'Gene', (150, 154))	('TSC2', 'Gene', (41, 45))	('suppression', 'NegReg', (131, 142))	('activity', 'MPA', (163, 171))	('CYP2D6', 'Gene', '1565', (56, 62))	('VHL', 'Gene', (47, 50))	('mutated', 'Var', (26, 33))	('CYP2D6', 'Gene', (56, 62))	('KMT2C', 'Gene', '58508', (34, 39))	('KMT2C', 'Gene', (34, 39))	('TP53', 'Gene', '7157', (150, 154))	('involved', 'Reg', (74, 82))
63829	30439581	Our RNA-seq data revealed that the IGF-1, ERK/MAPK, PI3K/AKT, and TGF-beta signaling pathways were activated in the HPD tumors after anti-PD-1 therapy (Figure 3).	('ERK', 'Gene', (42, 45))	('IGF-1', 'Gene', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('PI3K', 'molecular_function', 'GO:0016303', ('52', '56'))	('ERK', 'molecular_function', 'GO:0004707', ('42', '45'))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('HPD tumors', 'Disease', 'MESH:D009369', (116, 126))	('activated', 'PosReg', (99, 108))	('AKT', 'Gene', '207', (57, 60))	('MAPK', 'molecular_function', 'GO:0004707', ('46', '50'))	('HPD tumors', 'Disease', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('ERK', 'Gene', '5594', (42, 45))	('TGF-beta signaling pathways', 'Pathway', (66, 93))	('AKT', 'Gene', (57, 60))	('IGF-1', 'Gene', '3479', (35, 40))	('anti-PD-1', 'Var', (133, 142))
63831	30439581	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))
63835	30439581	A recent study demonstrated that the activity of PI3K/AKT signaling was crucial for lymphomas with PD-1 deletion.	('PD-1', 'Gene', (99, 103))	('AKT', 'Gene', '207', (54, 57))	('lymphomas', 'Disease', (84, 93))	('lymphomas', 'Disease', 'MESH:D008223', (84, 93))	('PI3K', 'molecular_function', 'GO:0016303', ('49', '53'))	('AKT', 'Gene', (54, 57))	('lymphomas', 'Phenotype', 'HP:0002665', (84, 93))	('AKT signaling', 'biological_process', 'GO:0043491', ('54', '67'))	('deletion', 'Var', (104, 112))
63836	30439581	Therefore, when the tumors are exposed to anti-PD-1 therapy, elevated PI3K/AKT signaling may be another important mechanism for the survival, progression, or even hyperprogression of the tumor cells.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('anti-PD-1', 'Var', (42, 51))	('AKT', 'Gene', '207', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('elevated', 'PosReg', (61, 69))	('hyperprogression', 'CPA', (163, 179))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', (187, 192))	('AKT', 'Gene', (75, 78))	('AKT signaling', 'biological_process', 'GO:0043491', ('75', '88'))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('survival', 'CPA', (132, 140))	('progression', 'CPA', (142, 153))	('PI3K', 'molecular_function', 'GO:0016303', ('70', '74'))	('tumor', 'Disease', (20, 25))
63845	30439581	It can be seen that five apoptosis gene sets were activated in the two patients after anti-PD-1 therapy (Figure S14A), of which 27 apoptotic genes including marker genes in caspase/bcl2 pathways (CASP3, CASP7, BNIP2, and BNIP3L) were significantly upregulated (Figure S14B).	('bcl2', 'Gene', '596', (181, 185))	('CASP3', 'Gene', '836', (196, 201))	('patients', 'Species', '9606', (71, 79))	('apoptosis', 'biological_process', 'GO:0097194', ('25', '34'))	('S14B', 'SUBSTITUTION', 'None', (268, 272))	('apoptosis', 'biological_process', 'GO:0006915', ('25', '34'))	('bcl2', 'Gene', (181, 185))	('bcl2', 'molecular_function', 'GO:0015283', ('181', '185'))	('activated', 'PosReg', (50, 59))	('CASP7', 'Gene', (203, 208))	('S14B', 'Var', (268, 272))	('apoptotic genes', 'Gene', (131, 146))	('BNIP3L', 'Gene', (221, 227))	('BNIP2', 'Gene', (210, 215))	('CASP7', 'Gene', '840', (203, 208))	('S14A', 'Mutation', 'p.S14A', (112, 116))	('BNIP2', 'Gene', '663', (210, 215))	('apoptosis gene sets', 'Gene', (25, 44))	('upregulated', 'PosReg', (248, 259))	('anti-PD-1', 'Gene', (86, 95))	('CASP3', 'Gene', (196, 201))	('BNIP3L', 'Gene', '665', (221, 227))
63857	30439581	We observed upregulated expression of ILC3 marker genes by anti-PD-1 immunotherapy in the two HPD patients, which may contribute to the suppression of T cell responses or the induction of T cell death.	('anti-PD-1', 'Var', (59, 68))	('ILC3 marker genes', 'Gene', (38, 55))	('cell death', 'biological_process', 'GO:0008219', ('190', '200'))	('expression', 'MPA', (24, 34))	('T cell responses', 'CPA', (151, 167))	('HPD', 'Disease', 'MESH:D004421', (94, 97))	('patients', 'Species', '9606', (98, 106))	('suppression', 'NegReg', (136, 147))	('suppression of T cell responses', 'Phenotype', 'HP:0005419', (136, 167))	('HPD', 'Disease', (94, 97))	('upregulated', 'PosReg', (12, 23))
63858	30439581	Our findings were in line with those of previous studies, indicating that inhibiting ILC3 may complement anti-PD-1 treatment to reduce the likelihood of developing hyperprogressive tumors after the therapy.	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('hyperprogressive tumors', 'Disease', 'MESH:D009369', (164, 187))	('hyperprogressive tumors', 'Disease', (164, 187))	('inhibiting', 'Var', (74, 84))	('reduce', 'NegReg', (128, 134))	('ILC3', 'Gene', (85, 89))
63864	30439581	If anti-PD-1 therapy is administered to HPD patients, it may contribute to tumor growth by further upregulating inflammatory pathway activities.	('contribute', 'PosReg', (61, 71))	('patients', 'Species', '9606', (44, 52))	('anti-PD-1', 'Var', (3, 12))	('HPD', 'Disease', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('inflammatory pathway', 'Pathway', (112, 132))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('HPD', 'Disease', 'MESH:D004421', (40, 43))	('upregulating', 'PosReg', (99, 111))	('tumor', 'Disease', (75, 80))	('activities', 'MPA', (133, 143))
63870	30439581	Specifically, these genes could be classified into the following six categories that were described above as important contributors to the HPD phenotype (Figure S9): (1) somatic mutated gene sets; (2) oncogenic pathways of IGF-1, ERK/MAPK, PI3K/AKT, and TGF-beta; (3) immune checkpoint genes; (4) ILC3 population marker genes; (5) marker genes for other immune populations like monocytes, CD4 T cells, and dendritic cells; and (6) differentially expressed genes in post-anti-PD-1 HPD tumors versus pre-anti-PD-1 non-HPD tumors.	('HPD', 'Disease', (139, 142))	('ERK', 'molecular_function', 'GO:0004707', ('230', '233'))	('AKT', 'Gene', (245, 248))	('HPD', 'Disease', 'MESH:D004421', (480, 483))	('post-anti-PD-1', 'Var', (465, 479))	('HPD tumors', 'Disease', 'MESH:D009369', (480, 490))	('pre', 'molecular_function', 'GO:0003904', ('498', '501'))	('HPD tumors', 'Disease', (480, 490))	('tumors', 'Phenotype', 'HP:0002664', (520, 526))	('ERK', 'Gene', '5594', (230, 233))	('non-HPD tumors', 'Disease', 'MESH:D009369', (512, 526))	('HPD', 'Disease', 'MESH:D004421', (139, 142))	('HPD', 'Disease', (516, 519))	('AKT', 'Gene', '207', (245, 248))	('tumor', 'Phenotype', 'HP:0002664', (520, 525))	('CD4', 'Gene', '920', (389, 392))	('PI3K', 'molecular_function', 'GO:0016303', ('240', '244'))	('HPD tumors', 'Disease', 'MESH:D009369', (516, 526))	('IGF-1', 'Gene', (223, 228))	('non-HPD tumors', 'Disease', (512, 526))	('ERK', 'Gene', (230, 233))	('HPD', 'Disease', (480, 483))	('MAPK', 'molecular_function', 'GO:0004707', ('234', '238'))	('tumors', 'Phenotype', 'HP:0002664', (484, 490))	('CD4', 'Gene', (389, 392))	('HPD', 'Disease', 'MESH:D004421', (516, 519))	('IGF-1', 'Gene', '3479', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (484, 489))
63876	30439581	Previous research demonstrated that MDM4 alteration was significantly associated with hyperprogression in patients subjected to immunotherapy, which was consistent with our results.	('hyperprogression', 'Disease', (86, 102))	('MDM4', 'Gene', '4194', (36, 40))	('associated with', 'Reg', (70, 85))	('alteration', 'Var', (41, 51))	('patients', 'Species', '9606', (106, 114))	('MDM4', 'Gene', (36, 40))
63881	30439581	The corresponding gene expression changes of the above significantly altered pathways were also shown (Figure S16B).	('S16B', 'SUBSTITUTION', 'None', (110, 114))	('S16B', 'Var', (110, 114))	('changes', 'Reg', (34, 41))	('gene expression', 'MPA', (18, 33))	('gene expression', 'biological_process', 'GO:0010467', ('18', '33'))
63890	30439581	Further larger patient samples involving more HPD patients treated with anti-PD-1 are needed to validate and extend our findings.	('patient', 'Species', '9606', (15, 22))	('patients', 'Species', '9606', (50, 58))	('HPD', 'Disease', (46, 49))	('anti-PD-1', 'Var', (72, 81))	('HPD', 'Disease', 'MESH:D004421', (46, 49))	('patient', 'Species', '9606', (50, 57))
63908	31570754	Current numerous research results concerning the mechanisms of ccRCC are based on the small sample, and the evidence of whole-genome sequencing only indicated some somatic mutant genes are linked with pathogenesis of ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('pathogenesis', 'biological_process', 'GO:0009405', ('201', '213'))	('linked', 'Reg', (189, 195))	('mutant genes', 'Var', (172, 184))	('RCC', 'Disease', 'MESH:C538614', (219, 222))	('RCC', 'Disease', (219, 222))	('RCC', 'Phenotype', 'HP:0005584', (219, 222))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
63913	31570754	Moreover, hypermethylation level of CRHBP was significantly negative with mRNA expression based on methylated microarray, and alteration of methylation level could affect ccRCC cell lines migration and invasion.	('negative', 'NegReg', (60, 68))	('CRHBP', 'Gene', (36, 41))	('RCC', 'Disease', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('mRNA expression', 'MPA', (74, 89))	('alteration', 'Var', (126, 136))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('invasion', 'CPA', (202, 210))	('methylation', 'biological_process', 'GO:0032259', ('140', '151'))	('hypermethylation level', 'MPA', (10, 32))	('methylation', 'MPA', (140, 151))	('affect', 'Reg', (164, 170))
63974	31570754	4d, the overexpression of CRHBP significantly inhibited proliferation of both 769P and ACHN in 72 h. Moreover, the results of wound healing assay indicated that the migration capacity of 769P and ACHN cells was significantly repressed in CRHBP-overexpressed group compared with that in vector group (Fig.	('769P', 'Chemical', '-', (78, 82))	('migration capacity', 'CPA', (165, 183))	('repressed', 'NegReg', (225, 234))	('ACHN', 'Gene', '55323', (196, 200))	('wound healing', 'biological_process', 'GO:0042060', ('126', '139'))	('769P', 'Var', (187, 191))	('ACHN', 'Gene', (196, 200))	('ACHN', 'Gene', '55323', (87, 91))	('769P', 'Chemical', '-', (187, 191))	('ACHN', 'Gene', (87, 91))
63980	31570754	The result revealed that CRHBP group significantly increase the protein levels of p-AKT, p-p65 and p-IkBalpha, as well as decrease the expression of IkBalpha compared with vector group both in 769P and ACHN cells (Fig.	('increase', 'PosReg', (51, 59))	('IkBalpha', 'Protein', (149, 157))	('p65', 'Gene', (91, 94))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('AKT', 'Gene', '207', (84, 87))	('decrease', 'NegReg', (122, 130))	('ACHN', 'Gene', '55323', (202, 206))	('CRHBP', 'Gene', (25, 30))	('p-IkBalpha', 'Var', (99, 109))	('p65', 'Gene', '5970', (91, 94))	('protein levels', 'MPA', (64, 78))	('expression', 'MPA', (135, 145))	('AKT', 'Gene', (84, 87))	('ACHN', 'Gene', (202, 206))	('769P', 'Chemical', '-', (193, 197))
63981	31570754	5c-f), indicating that CRHBP may be capable of promoting ccRCC inflammation in part via activating the NF-kB signaling pathway.	('CRHBP', 'Var', (23, 28))	('inflammation', 'biological_process', 'GO:0006954', ('63', '75'))	('NF-kB signaling pathway', 'Pathway', (103, 126))	('ccRCC inflammation', 'Disease', 'MESH:D007249', (57, 75))	('signaling pathway', 'biological_process', 'GO:0007165', ('109', '126'))	('ccRCC inflammation', 'Disease', (57, 75))	('activating', 'PosReg', (88, 98))	('promoting', 'PosReg', (47, 56))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
63984	31570754	The results showed that apoptotic cells of 769P and ACHN were significantly increased compared with vector cells especially in early apoptosis (annexin V + /PI, color = red) (Fig.	('769P', 'Var', (43, 47))	('ACHN', 'Gene', (52, 56))	('annexin V', 'Gene', (144, 153))	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('769P', 'Chemical', '-', (43, 47))	('increased', 'PosReg', (76, 85))	('apoptotic cells', 'CPA', (24, 39))	('ACHN', 'Gene', '55323', (52, 56))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('annexin V', 'Gene', '308', (144, 153))
63985	31570754	Moreover, immunofluorescence analysis showed that the expression of cleaved-caspase 3 was markedly increased in ccRCC cells of CRHBP group compared with control cells (Fig.	('expression', 'MPA', (54, 64))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('caspase 3', 'Gene', (76, 85))	('caspase 3', 'Gene', '836', (76, 85))	('CRHBP', 'Var', (127, 132))	('increased', 'PosReg', (99, 108))
63986	31570754	To further obtain insight into the possible mechanism by which CRHBP induced ccRCC cellular apoptosis, western blotting was employed to investigate apoptosis-related proteins (Fig.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('apoptosis', 'biological_process', 'GO:0097194', ('92', '101'))	('apoptosis', 'biological_process', 'GO:0006915', ('92', '101'))	('apoptosis', 'biological_process', 'GO:0097194', ('148', '157'))	('apoptosis', 'biological_process', 'GO:0006915', ('148', '157'))	('CRHBP', 'Var', (63, 68))	('induced', 'Reg', (69, 76))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
63995	31570754	Besides, the levels of CRHBP are closely related to patients' clinical stage and histologic grade, implying that it has important role in the pathogenesis of ccRCC.	('CRHBP', 'Var', (23, 28))	('pathogenesis', 'biological_process', 'GO:0009405', ('142', '154'))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('RCC', 'Disease', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('related', 'Reg', (41, 48))	('patients', 'Species', '9606', (52, 60))
64003	31570754	reported hypermethylation of CRHBP was correlative with its mRNA expression as well as clinicopathological parameters of RCC patients.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('mRNA expression', 'MPA', (60, 75))	('hypermethylation', 'Var', (9, 25))	('CRHBP', 'Gene', (29, 34))	('patients', 'Species', '9606', (125, 133))
64012	31570754	Besides, high expressions of p65 were correlated significantly with worse cancer-specific survival in ccRCC patients.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('p65', 'Gene', (29, 32))	('worse', 'NegReg', (68, 73))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('high', 'Var', (9, 13))	('cancer', 'Disease', (74, 80))	('p65', 'Gene', '5970', (29, 32))	('patients', 'Species', '9606', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('RCC', 'Disease', (104, 107))
64013	31570754	also reported that knockdown of NF-kappaB1 could suppress the growth and invasion of RCC in vitro and in vivo.	('NF-kappaB', 'Gene', (32, 41))	('knockdown', 'Var', (19, 28))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', (85, 88))	('NF-kappaB', 'Gene', '4790', (32, 41))	('suppress', 'NegReg', (49, 57))
64016	31570754	Overexpression of CRHBP upregulated the protein expression of p-AKT, p-p65 and p-IkBalpha, while downregulated IkBalpha in vitro, suggesting that NF-kappaB pathway was inhibited by CRHBP.	('p65', 'Gene', (71, 74))	('protein expression', 'MPA', (40, 58))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('CRHBP', 'Gene', (18, 23))	('AKT', 'Gene', '207', (64, 67))	('NF-kappaB', 'Gene', '4790', (146, 155))	('IkBalpha', 'MPA', (111, 119))	('downregulated', 'NegReg', (97, 110))	('upregulated', 'PosReg', (24, 35))	('inhibited', 'NegReg', (168, 177))	('p65', 'Gene', '5970', (71, 74))	('p-IkBalpha', 'Var', (79, 89))	('AKT', 'Gene', (64, 67))	('NF-kappaB', 'Gene', (146, 155))
64022	31570754	Our apoptotic analysis indicated overexpression of CRHBP significantly increased the percentage of apoptotic ccRCC cells, suggesting CRHBP could induce ccRCC apoptosis.	('CRHBP', 'Var', (133, 138))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('induce', 'PosReg', (145, 151))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('RCC', 'Disease', (154, 157))	('RCC', 'Phenotype', 'HP:0005584', (154, 157))	('apoptosis', 'biological_process', 'GO:0097194', ('158', '167'))	('apoptosis', 'biological_process', 'GO:0006915', ('158', '167'))
64024	31570754	During cellular apoptosis, phosphorylation of p53 reduces interaction between p53 and facilitate bax transcript into mitochondria to induce the release of cytochrome c, initiating the cascade amplification effect of caspase family.	('reduces', 'NegReg', (50, 57))	('phosphorylation', 'Var', (27, 42))	('cytochrome c', 'molecular_function', 'GO:0045155', ('155', '167'))	('bax', 'Gene', (97, 100))	('p53', 'Gene', '7157', (46, 49))	('p53', 'Gene', '7157', (78, 81))	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('cytochrome c', 'molecular_function', 'GO:0009461', ('155', '167'))	('interaction', 'Interaction', (58, 69))	('p53', 'Gene', (46, 49))	('cytochrome c', 'Gene', '54205', (155, 167))	('p53', 'Gene', (78, 81))	('bax', 'Gene', '581', (97, 100))	('induce', 'Reg', (133, 139))	('mitochondria', 'cellular_component', 'GO:0005739', ('117', '129'))	('facilitate', 'PosReg', (86, 96))	('apoptosis', 'biological_process', 'GO:0097194', ('16', '25'))	('apoptosis', 'biological_process', 'GO:0006915', ('16', '25'))	('cytochrome c', 'Gene', (155, 167))
64026	31570754	Together, these data are possible mechanisms of CRHBP may induce ccRCC cell apoptosis through activation of p53 mediated mitochondrial apoptosis pathway.	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('induce', 'PosReg', (58, 64))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('CRHBP', 'Var', (48, 53))	('apoptosis', 'biological_process', 'GO:0097194', ('76', '85'))	('apoptosis', 'biological_process', 'GO:0006915', ('76', '85'))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))	('activation', 'PosReg', (94, 104))
64029	31570754	Moreover, it is unclear how CRHBP regulates NF-kappaB signaling pathway and p53-mediated mitochondrial apoptosis pathway and whether it accepts the stimuli from environment and then still activates the pathways.	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('NF-kappaB', 'Gene', '4790', (44, 53))	('signaling pathway', 'biological_process', 'GO:0007165', ('54', '71'))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('regulates', 'Reg', (34, 43))	('NF-kappaB', 'Gene', (44, 53))	('CRHBP', 'Var', (28, 33))	('activates', 'PosReg', (188, 197))	('men', 'Species', '9606', (168, 171))
64037	32272660	PHAX knockdown in a ccRCC organ culture model impacted the ability of sunitinib to cause cancer cell death (p < 0.0001 untreated vs. treated), suggesting a role for PHAX in mediating the efficacy of sunitinib.	('sunitinib', 'Chemical', 'MESH:D000077210', (199, 208))	('RCC', 'Disease', (22, 25))	('knockdown', 'Var', (5, 14))	('PHAX', 'Gene', (0, 4))	('cell death', 'biological_process', 'GO:0008219', ('96', '106'))	('sunitinib', 'Chemical', 'MESH:D000077210', (70, 79))	('RCC', 'Disease', 'MESH:C538614', (22, 25))	('ability', 'MPA', (59, 66))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('impacted', 'Reg', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
64041	32272660	Von Hippel Lindau (VHL) mutation is the key driver mutation in >90% of ccRCCs, and hence targeting this axis was thought to exploit the disease's "Achilles heel."	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('VHL', 'Gene', (19, 22))	('VHL', 'Gene', '7428', (19, 22))	('Von Hippel Lindau', 'Gene', (0, 17))	('mutation', 'Var', (24, 32))	('Von Hippel Lindau', 'Gene', '7428', (0, 17))
64081	32272660	Successful siRNA-induced knockdown of PHAX protein was confirmed by immunofluorescence, co-immunostained with CD31 (Figure 6A).	('CD31', 'Gene', '5175', (110, 114))	('CD31', 'Gene', (110, 114))	('knockdown', 'Var', (25, 34))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))
64099	32272660	Using RNAi in a ccRCC organ culture system we have also shown that PHAX protein expression potentiates the efficacy of sunitinib, a key systemic therapy for the treatment of patients with metastatic ccRCC.	('RCC', 'Disease', (18, 21))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('RNAi', 'biological_process', 'GO:0016246', ('6', '10'))	('potentiates', 'PosReg', (91, 102))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('RCC', 'Disease', 'MESH:C538614', (18, 21))	('patients', 'Species', '9606', (174, 182))	('efficacy', 'MPA', (107, 115))	('sunitinib', 'Chemical', 'MESH:D000077210', (119, 128))	('PHAX', 'Gene', (67, 71))	('expression', 'Var', (80, 90))
64103	32272660	Further, in general terms, aberrations in the expression of small nucleolar RNA have previously been linked to cancer phenotypes.	('small nucleolar RNA', 'cellular_component', 'GO:0005733', ('60', '79'))	('small nucleolar RNA', 'Gene', (60, 79))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('small nucleolar RNA', 'molecular_function', 'GO:0005569', ('60', '79'))	('linked', 'Reg', (101, 107))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('expression', 'MPA', (46, 56))	('aberrations', 'Var', (27, 38))
64110	32272660	Finally, by knocking down PHAX using siRNA, we were able to evaluate the interplay between the cell killing effect of sunitinib and the induction of PHAX protein expression.	('cell killing', 'CPA', (95, 107))	('sunitinib', 'Chemical', 'MESH:D000077210', (118, 127))	('knocking', 'Var', (12, 20))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('cell killing', 'biological_process', 'GO:0001906', ('95', '107'))
64111	32272660	We successfully knocked down PHAX protein and showed that this reduction of expression resulted in a significantly reduced efficacy of sunitinib in the in vitro model.	('knocked', 'Var', (16, 23))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('protein', 'Protein', (34, 41))	('reduced', 'NegReg', (115, 122))	('efficacy', 'MPA', (123, 131))	('sunitinib', 'Chemical', 'MESH:D000077210', (135, 144))	('expression', 'MPA', (76, 86))	('reduction', 'NegReg', (63, 72))	('PHAX', 'Gene', (29, 33))
64159	32272660	ccRCC organ cultures were subjected to siRNA gene knockdown targeting the human PHAX gene.	('RCC', 'Disease', (2, 5))	('knockdown', 'Var', (50, 59))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('human', 'Species', '9606', (74, 79))	('PHAX gene', 'Gene', (80, 89))
64246	32432045	The results of KEGG pathway enrichment analysis showed that the dysfunction of the autophagy-related genes may contribute to the drug resistance of ccRCC, such as "platinum drug resistance" (gene count = 10, p = 9.44E-10), "endocrine resistance" (gene count = 9, p = 2.43E-07).	('drug resistance', 'Phenotype', 'HP:0020174', (129, 144))	('endocrine', 'MPA', (224, 233))	('drug resistance', 'MPA', (129, 144))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('RCC', 'Disease', (150, 153))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('drug resistance', 'biological_process', 'GO:0009315', ('129', '144'))	('autophagy', 'biological_process', 'GO:0016236', ('83', '92'))	('drug resistance', 'Phenotype', 'HP:0020174', (173, 188))	('ccRCC', 'Phenotype', 'HP:0006770', (148, 153))	('drug resistance', 'biological_process', 'GO:0042493', ('129', '144'))	('contribute', 'Reg', (111, 121))	('autophagy', 'biological_process', 'GO:0006914', ('83', '92'))	('autophagy-related genes', 'Gene', (83, 106))	('dysfunction', 'Var', (64, 75))	('platinum', 'Chemical', 'MESH:D010984', (164, 172))
64266	32432045	Single-gene GSEA of the seven genes has shown the potential roles of the genes in ccRCC (Figure 9).	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('GSEA', 'Chemical', '-', (12, 16))	('Single-gene', 'Var', (0, 11))
64267	32432045	For example, PINK1 was identified as a protective factor for ccRCC, the signal pathways of "TGF-beta signal pathway," "mTOR signal pathway," "VEGF signal pathway" are up-regulated in high-expression group (namely, relatively low risk group) of PINK1, and "Homologous recombination" down-regulated in high-expression group of PINK1.	('TGF-beta', 'Gene', '7039', (92, 100))	('PINK1', 'Gene', (325, 330))	('PINK1', 'Gene', (244, 249))	('signal pathways', 'Pathway', (72, 87))	('TGF-beta', 'Gene', (92, 100))	('PINK1', 'Gene', (13, 18))	('mTOR', 'Gene', (119, 123))	('PINK1', 'Gene', '65018', (325, 330))	('PINK1', 'Gene', '65018', (244, 249))	('down-regulated', 'NegReg', (282, 296))	('VEGF', 'Gene', '7422', (142, 146))	('mTOR', 'Gene', '2475', (119, 123))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('high-expression', 'Var', (183, 198))	('VEGF', 'Gene', (142, 146))	('RCC', 'Disease', (63, 66))	('PINK1', 'Gene', '65018', (13, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('up-regulated', 'PosReg', (167, 179))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
64283	32432045	In all, our work implied that dysfunction of autophagy plays a vital role in the process of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('autophagy', 'CPA', (45, 54))	('autophagy', 'biological_process', 'GO:0006914', ('45', '54'))	('dysfunction', 'Var', (30, 41))	('autophagy', 'biological_process', 'GO:0016236', ('45', '54'))
64288	32432045	On the contrary, some genes were DE-ARGs but their influences on OS were not such significant.	('ARGs', 'Gene', '390502', (36, 40))	('OS', 'Chemical', '-', (65, 67))	('genes', 'Var', (22, 27))	('ARGs', 'Gene', (36, 40))
64300	32432045	BID plays a major role in apoptosis and its dysfunction underlies the process of carcinogenesis.	('BID', 'Gene', (0, 3))	('apoptosis', 'CPA', (26, 35))	('carcinogenesis', 'Disease', 'MESH:D063646', (81, 95))	('apoptosis', 'biological_process', 'GO:0097194', ('26', '35'))	('carcinogenesis', 'Disease', (81, 95))	('apoptosis', 'biological_process', 'GO:0006915', ('26', '35'))	('BID', 'Gene', '637', (0, 3))	('dysfunction', 'Var', (44, 55))
64318	29905933	In contrast, RCC with translocations involving members of the microphthalmia transcription factor (MiT) family (TFE3 and TFEB) occur more frequently in younger patients.	('patients', 'Species', '9606', (160, 168))	('microphthalmia', 'Disease', 'MESH:D008850', (62, 76))	('microphthalmia', 'Disease', (62, 76))	('transcription factor', 'molecular_function', 'GO:0000981', ('77', '97'))	('TFE3', 'Gene', (112, 116))	('transcription', 'biological_process', 'GO:0006351', ('77', '90'))	('translocations', 'Var', (22, 36))	('RCC', 'Disease', (13, 16))	('TFE3', 'Gene', '7030', (112, 116))	('TFEB', 'Gene', '7942', (121, 125))	('microphthalmia', 'Phenotype', 'HP:0000568', (62, 76))	('TFEB', 'Gene', (121, 125))
64335	29905933	Further evidence of TFE3 gene rearrangement was present in 72/82, including all 5 cases in which TFE3 immunohistochemistry was not performed.	('TFE3', 'Gene', (97, 101))	('rearrangement', 'Var', (30, 43))	('TFE3', 'Gene', '7030', (20, 24))	('TFE3', 'Gene', '7030', (97, 101))	('TFE3', 'Gene', (20, 24))
64339	29905933	Most tumors (21/25) with ASPL-TFE3 fusion transcripts showed pattern 1 while pattern 2 predominated in PRCC-TFE3 tumors (19/24), similar to previous reports.	('pattern', 'MPA', (61, 68))	('tumors', 'Disease', (5, 11))	('PRCC-TFE3 tumors', 'Disease', (103, 119))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('TFE3', 'Gene', '7030', (108, 112))	('ASPL', 'Gene', '79058', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('ASPL', 'Gene', (25, 29))	('TFE3', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('fusion transcripts', 'Var', (35, 53))	('PRCC-TFE3 tumors', 'Disease', 'MESH:D009369', (103, 119))	('TFE3', 'Gene', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('TFE3', 'Gene', '7030', (30, 34))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
64343	29905933	Six cases had TFEB gene rearrangements documented by FISH.	('rearrangements', 'Var', (24, 38))	('TFEB', 'Gene', (14, 18))	('TFEB', 'Gene', '7942', (14, 18))
64362	29905933	One additional tumor was shown to have a translocation involving chromosome 3p13 (VHL gene locus) (Table 2).	('VHL', 'Disease', (82, 85))	('VHL', 'Disease', 'MESH:D006623', (82, 85))	('translocation', 'Var', (41, 54))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('chromosome', 'cellular_component', 'GO:0005694', ('65', '75'))
64364	29905933	Mutations in the fumarate hydratase (FH) gene were identified by NGS in 3 tumors (Table 2) initially classified as RCC-NOS, and the morphological features were similar to those previously described.	('identified', 'Reg', (51, 61))	('fumarate hydratase', 'Gene', '2271', (17, 35))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('fumarate hydratase', 'Gene', (17, 35))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('FH', 'Gene', '2271', (37, 39))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
64371	29905933	Nine cases had either a personal and/or familial history of tuberous sclerosis (TS, 5 cases) or were discovered during this study to have mutations in the TSC2 gene (4 cases) within tumor (Table 2) through NGS analysis (the mutations could therefore be either germline or somatic).	('tuberous sclerosis', 'Disease', 'MESH:D014402', (60, 78))	('tumor', 'Disease', (182, 187))	('TSC2', 'Gene', '7249', (155, 159))	('TSC2', 'Gene', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tuberous sclerosis', 'Disease', (60, 78))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('mutations', 'Var', (138, 147))
64390	29905933	Both cases were negative for TSC1/TSC2 mutations by NGS.	('TSC2', 'Gene', '7249', (34, 38))	('TSC2', 'Gene', (34, 38))	('TSC1', 'Gene', (29, 33))	('mutations', 'Var', (39, 48))	('TSC1', 'Gene', '7248', (29, 33))
64398	29905933	Among cases with confirmed TFE3 rearrangements, the ASPL and PRCC genes were the most common fusion partners, in keeping with the existing literature.	('TFE3', 'Gene', '7030', (27, 31))	('PRCC', 'Gene', (61, 65))	('common', 'Reg', (86, 92))	('ASPL', 'Gene', '79058', (52, 56))	('TFE3', 'Gene', (27, 31))	('rearrangements', 'Var', (32, 46))	('PRCC', 'Gene', '5546', (61, 65))	('ASPL', 'Gene', (52, 56))	('fusion', 'Interaction', (93, 99))
64401	29905933	We were unable to identify the TFE3 fusion partner in 16/72 (22%) cases with a documented TFE3 rearrangement; however, none of these 16 cases was able to be fully tested by both dual-probe FISH and NGS.	('TFE3', 'Gene', '7030', (31, 35))	('TFE3', 'Gene', '7030', (90, 94))	('TFE3', 'Gene', (31, 35))	('TFE3', 'Gene', (90, 94))	('rearrangement', 'Var', (95, 108))
64403	29905933	The combination of characteristic morphological features, underexpression of epithelial markers and diffuse and strong nuclear TFE3 immunohistochemical expression reliably detected RCC with TFE3 rearrangements in our series, without the need for molecular studies.	('TFE3', 'Gene', (190, 194))	('detected', 'Reg', (172, 180))	('TFE3', 'Gene', (127, 131))	('TFE3', 'Gene', '7030', (190, 194))	('TFE3', 'Gene', '7030', (127, 131))	('RCC', 'Disease', (181, 184))	('rearrangements', 'Var', (195, 209))
64405	29905933	These observations may explain why 2/82 tumors classified as TFE3 MiT-RCC (2.4%) showed TFE3 positivity, characteristic histologic and immunophenotypic features, yet were negative for a TFE3 rearrangement by FISH.	('MiT-RCC', 'Disease', (66, 73))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('TFE3', 'Gene', (88, 92))	('TFE3', 'Gene', (61, 65))	('TFE3', 'Gene', '7030', (186, 190))	('MiT-RCC', 'Disease', 'MESH:C538614', (66, 73))	('positivity', 'Var', (93, 103))	('TFE3', 'Gene', '7030', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('TFE3', 'Gene', '7030', (61, 65))	('tumors', 'Disease', (40, 46))	('TFE3', 'Gene', (186, 190))
64413	29905933	Of the 212 patients in this study, 9 had either a history of TS or a documented TSC2 mutation.	('patients', 'Species', '9606', (11, 19))	('TSC2', 'Gene', '7249', (80, 84))	('TSC2', 'Gene', (80, 84))	('mutation', 'Var', (85, 93))
64414	29905933	Two additional cases demonstrated morphologically similar tumors (one of which was bilateral), suggesting the possibility of mutations in related genes, or undetected mutations in TSC1/TSC2.	('TSC1', 'Gene', (180, 184))	('mutations', 'Var', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('TSC2', 'Gene', '7249', (185, 189))	('TSC2', 'Gene', (185, 189))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('TSC1', 'Gene', '7248', (180, 184))
64418	33461580	Neuropilin 1 and Neuropilin 2 gene invalidation or pharmacological inhibition reveals their relevance for the treatment of metastatic renal cell carcinoma Despite the improvement of relapse-free survival mediated by anti-angiogenic drugs like sunitinib (Sutent ), or by combinations of anti-angiogenic drugs with immunotherapy, metastatic clear cell Renal Cell Carcinoma (mccRCC) remain incurable.	('Sutent', 'Chemical', 'MESH:D000077210', (254, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (350, 370))	('Neuropilin 2', 'Gene', (17, 29))	('Neuropilin 1', 'Gene', '8829', (0, 12))	('Neuropilin 1', 'Gene', (0, 12))	('Neuropilin 2', 'Gene', '8828', (17, 29))	('invalidation', 'Var', (35, 47))	('clear cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (339, 370))	('renal cell carcinoma', 'Disease', (134, 154))	('sunitinib', 'Chemical', 'MESH:D000077210', (243, 252))	('Carcinoma', 'Phenotype', 'HP:0030731', (361, 370))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (134, 154))	('clear cell Renal Cell Carcinoma', 'Disease', (339, 370))	('clear cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (339, 370))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (134, 154))
64431	33461580	Our study strongly suggests that inhibiting NRPs is a relevant treatment for mccRCC patients in therapeutic impasses and NRPa-308 represents a relevant hit.	('patients', 'Species', '9606', (84, 92))	('NRPs', 'Protein', (44, 48))	('inhibiting', 'Var', (33, 43))	('mccRCC', 'Disease', (77, 83))	('NRPa', 'Chemical', '-', (121, 125))
64454	33461580	Sequencing of human genomic DNA to confirm the mutations leading to human NRP1 or NRP2 invalidation was performed using the following primers: Forward NRP1 5'- CACGAAGGACTTACGGGG-3' and Reverse NRP1 5'- AGACAGGCGTGACCAGTAG-3', and Forward NRP2 5'- TGAGCCGGAATAATCTCTTCCAC-3' and Reverse NRP2 5'- GGTGCTTACTTGCAGTCGTG-3'.	('NRP', 'biological_process', 'GO:0085015', ('74', '77'))	('NRP1', 'Gene', (74, 78))	('NRP', 'biological_process', 'GO:0085015', ('151', '154'))	('human', 'Species', '9606', (68, 73))	('NRP', 'biological_process', 'GO:0085015', ('239', '242'))	('NRP', 'biological_process', 'GO:0085015', ('287', '290'))	('human', 'Species', '9606', (14, 19))	('NRP', 'biological_process', 'GO:0085015', ('194', '197'))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('mutations', 'Var', (47, 56))	('NRP', 'biological_process', 'GO:0085015', ('82', '85'))	('NRP2', 'Gene', (82, 86))
64477	33461580	These results were surprising since they described that NRP1 knock-down decreased the AKT activity, a major pathway involved in cell proliferation/survival.	('knock-down', 'Var', (61, 71))	('AKT', 'Gene', (86, 89))	('decreased', 'NegReg', (72, 81))	('NRP', 'biological_process', 'GO:0085015', ('56', '59'))	('NRP1', 'Gene', (56, 60))	('AKT', 'Gene', '207', (86, 89))	('cell proliferation', 'biological_process', 'GO:0008283', ('128', '146'))
64480	33461580	These differences with the results of Cao Y et al incited us to decipher the role of NRP1 and NRP2 by knocking-out (KO) their genes by the CRISPR/Cas9 method in human (786-O) and mouse (RENCA) ccRCC cells.	('mouse', 'Species', '10090', (179, 184))	('human', 'Species', '9606', (161, 166))	('NRP', 'biological_process', 'GO:0085015', ('85', '88'))	('Cas', 'cellular_component', 'GO:0005650', ('146', '149'))	('NRP', 'biological_process', 'GO:0085015', ('94', '97'))	('knocking-out', 'Var', (102, 114))	('NRP2', 'Gene', (94, 98))	('NRP1', 'Gene', (85, 89))	('KO', 'Gene', '3856', (116, 118))
64502	33461580	Invalidation of NRP1 or NRP2 in RENCA cells delayed tumor incidence (percentage of mice with a tumor) as compared to the control group, in nude mice (Fig.	('delayed', 'NegReg', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('nude mice', 'Species', '10090', (139, 148))	('NRP2', 'Gene', (24, 28))	('tumor', 'Disease', (52, 57))	('mice', 'Species', '10090', (144, 148))	('Invalidation', 'Var', (0, 12))	('NRP1', 'Gene', (16, 20))	('NRP', 'biological_process', 'GO:0085015', ('24', '27'))	('NRP', 'biological_process', 'GO:0085015', ('16', '19'))	('mice', 'Species', '10090', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (95, 100))
64505	33461580	These results strongly suggest that, in addition to the intrinsic effects of NRPs on tumor cell metabolic activity, their expression on tumor cells inhibits the anti-tumor immune system.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('expression', 'Var', (122, 132))	('inhibits', 'NegReg', (148, 156))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('NRPs', 'Gene', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', (136, 141))
64506	33461580	The strong impact on tumor growth mediated by invalidation of NRPs encouraged us to test the relevance of the NRPs' pharmacological inhibitor NRPa-308 on different parameters characterizing ccRCC cells (786-O and A498) aggressiveness in comparison to its effect on normal dermal fibroblasts (HDF).	('ccRCC', 'Disease', (190, 195))	('aggressiveness', 'Disease', 'MESH:D001523', (219, 233))	('aggressiveness', 'Phenotype', 'HP:0000718', (219, 233))	('tumor', 'Disease', (21, 26))	('A498', 'CellLine', 'CVCL:1056', (213, 217))	('aggressiveness', 'Disease', (219, 233))	('impact', 'Reg', (11, 17))	('test', 'Reg', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('NRPa', 'Chemical', '-', (142, 146))	('invalidation', 'Var', (46, 58))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
64508	33461580	EG00229 was poorly efficient in inhibiting the metabolic activity of ccRCC cell lines (5 and 30% inhibition respectively for 786-O and A498 cells at the highest dose 2 muM, Fig.	('inhibiting', 'NegReg', (32, 42))	('EG00229', 'Var', (0, 7))	('inhibition', 'NegReg', (97, 107))	('metabolic activity', 'CPA', (47, 65))	('A498', 'CellLine', 'CVCL:1056', (135, 139))	('EG00229', 'Chemical', '-', (0, 7))
64535	33461580	In both cases, NRPa-308 is stabilized in the binding site through hydrogen bonds, pi-stacking and hydrophobic interactions (Fig.	('NRPa', 'Chemical', '-', (15, 19))	('hydrogen', 'Chemical', 'MESH:D006859', (66, 74))	('hydrophobic', 'CPA', (98, 109))	('hydrogen bonds', 'CPA', (66, 80))	('pi-stacking', 'Var', (82, 93))	('binding', 'molecular_function', 'GO:0005488', ('45', '52'))	('NRPa-308', 'Protein', (15, 23))
64536	33461580	Few residues involved in these interactions are conserved in NRP1 and NRP2 (W301/304, S346/349, E348/351, Y353/356 according to the NRP1/NRP2 numeration) but they establish interactions with different parts of NRPa-308.	('NRP1', 'Gene', (61, 65))	('E348/351', 'Var', (96, 104))	('interactions', 'Interaction', (31, 43))	('NRP', 'biological_process', 'GO:0085015', ('70', '73'))	('NRP', 'biological_process', 'GO:0085015', ('61', '64'))	('Y353/356', 'Var', (106, 114))	('NRP2', 'Gene', (70, 74))	('NRP', 'biological_process', 'GO:0085015', ('132', '135'))	('NRPa', 'Chemical', '-', (210, 214))	('interactions', 'Interaction', (173, 185))	('NRP', 'biological_process', 'GO:0085015', ('137', '140'))	('S346/349', 'Var', (86, 94))	('establish', 'Reg', (163, 172))	('W301/304', 'Var', (76, 84))
64631	32003757	High ISG20 expression was associated with poor overall survival and disease-free survival.	('disease-free survival', 'CPA', (68, 89))	('ISG20', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('overall survival', 'CPA', (47, 63))	('poor', 'NegReg', (42, 46))	('ISG20', 'Gene', '3669', (5, 10))
64633	32003757	Functional experiments proved that knockdown of ISG20 expression could obviously inhibit cell growth, migration, and invasion in ccRCC cells.	('knockdown', 'Var', (35, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (129, 134))	('ccRCC', 'Disease', (129, 134))	('inhibit', 'NegReg', (81, 88))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('ccRCC', 'Disease', 'MESH:D002292', (129, 134))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('ISG20', 'Gene', (48, 53))	('cell growth', 'CPA', (89, 100))	('ISG20', 'Gene', '3669', (48, 53))	('migration', 'CPA', (102, 111))	('cell growth', 'biological_process', 'GO:0016049', ('89', '100'))	('invasion', 'CPA', (117, 125))
64647	32003757	Interferon stimulated exonuclease Gene 20 (ISG20), also named as estrogen-regulated transcript 45 protein, is an RNA exonuclease which induced by interferons (IFN types I and II) or double-stranded RNA.	('ISG20', 'Gene', '3669', (43, 48))	('estrogen-regulated transcript 45 protein', 'Gene', '3669', (65, 105))	('ISG20', 'Gene', (43, 48))	('Interferon stimulated exonuclease Gene 20', 'Gene', (0, 41))	('double-stranded RNA', 'Var', (182, 201))	('Interferon stimulated exonuclease Gene 20', 'Gene', '3669', (0, 41))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('RNA', 'cellular_component', 'GO:0005562', ('113', '116'))	('estrogen-regulated transcript 45 protein', 'Gene', (65, 105))	('RNA', 'cellular_component', 'GO:0005562', ('198', '201'))
64655	32003757	The "clusterProfiler" package was used to perform GO and KEGG enrichment analysis in R. As shown in Figure 1C, biological process analysis indicated that the DEGs were significantly associated with organic anion transport, small molecule catabolic process, and leukocyte cell-cell adhesion.	('small molecule catabolic process', 'MPA', (223, 255))	('associated', 'Reg', (182, 192))	('si', 'Chemical', 'MESH:D012825', (285, 287))	('si', 'Chemical', 'MESH:D012825', (135, 137))	('leukocyte cell-cell adhesion', 'biological_process', 'GO:0007159', ('259', '287'))	('organic anion transport', 'MPA', (198, 221))	('leukocyte cell-cell adhesion', 'CPA', (261, 289))	('organic anion transport', 'biological_process', 'GO:0015711', ('196', '219'))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('si', 'Chemical', 'MESH:D012825', (168, 170))	('DEGs', 'Var', (158, 162))	('biological process', 'biological_process', 'GO:0008150', ('109', '127'))	('small molecule catabolic process', 'biological_process', 'GO:0044282', ('221', '253'))
64657	32003757	As shown in Figure 1D, KEGG analysis exhibited that the DEGs were significantly correlated to the PPAR signaling pathway, cell adhesion molecules and multiple metabolic pathways (fructose/mannose metabolism, glycolysis/gluconeogenesis, tyrosine metabolism, cholesterol metabolism and arachidonic acid metabolism).	('si', 'Chemical', 'MESH:D012825', (33, 35))	('glycolysis', 'biological_process', 'GO:0006096', ('208', '218'))	('tyrosine metabolism', 'biological_process', 'GO:0006570', ('236', '255'))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('si', 'Chemical', 'MESH:D012825', (240, 242))	('DEGs', 'Var', (56, 60))	('mannose', 'Chemical', 'MESH:D008358', (188, 195))	('gluconeogenesis', 'biological_process', 'GO:0006094', ('219', '234'))	('si', 'Chemical', 'MESH:D012825', (231, 233))	('si', 'Chemical', 'MESH:D012825', (215, 217))	('tyrosine', 'Chemical', 'MESH:D014443', (236, 244))	('PPAR signaling pathway', 'Pathway', (98, 120))	('cell adhesion', 'biological_process', 'GO:0007155', ('122', '135'))	('PPAR signaling pathway', 'biological_process', 'GO:0035357', ('98', '120'))	('correlated', 'Reg', (80, 90))	('mannose metabolism', 'biological_process', 'GO:0006013', ('188', '206'))	('cholesterol metabolism', 'MPA', (257, 279))	('glycolysis/gluconeogenesis', 'Phenotype', 'HP:0005959', (208, 234))	('si', 'Chemical', 'MESH:D012825', (131, 133))	('cholesterol metabolism', 'biological_process', 'GO:0008203', ('257', '279'))	('glycolysis/gluconeogenesis', 'MPA', (208, 234))	('tyrosine metabolism', 'MPA', (236, 255))	('tip', 'Gene', (153, 156))	('arachidonic acid metabolism', 'biological_process', 'GO:0019369', ('284', '311'))	('arachidonic acid', 'Chemical', 'MESH:D016718', (284, 300))	('cholesterol', 'Chemical', 'MESH:D002784', (257, 268))	('tip', 'Gene', '79828', (153, 156))	('cell', 'Protein', (122, 126))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('fructose', 'Chemical', 'MESH:D005632', (179, 187))
64675	32003757	The survival analysis (Figure 5F-5G) showed that high expression of ISG20 predicted poor OS (HR = 1.64, p = 0.001) and DFS (HR = 1.70, p = 0.003).	('si', 'Chemical', 'MESH:D012825', (18, 20))	('ISG20', 'Gene', (68, 73))	('ISG20', 'Gene', '3669', (68, 73))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('high expression', 'Var', (49, 64))	('poor OS', 'CPA', (84, 91))	('DFS', 'CPA', (119, 122))
64679	32003757	To verify the effect of ISG20 on the biological function of ccRCC cell, the siRNA targeting ISG20 (si-ISG20) was used to knockdown the expression of ISG20 in 786O, A498, and OSRC-2 cell lines.	('knockdown', 'Var', (121, 130))	('ISG20', 'Gene', (149, 154))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('ISG20', 'Gene', (92, 97))	('ISG20', 'Gene', (102, 107))	('OSRC', 'Gene', '5925', (174, 178))	('ccRCC', 'Disease', (60, 65))	('OSRC', 'Gene', (174, 178))	('ISG20', 'Gene', '3669', (102, 107))	('ccRCC', 'Disease', 'MESH:D002292', (60, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('ISG20', 'Gene', '3669', (24, 29))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('ISG20', 'Gene', (24, 29))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('ISG20', 'Gene', '3669', (149, 154))	('si', 'Chemical', 'MESH:D012825', (141, 143))	('ISG20', 'Gene', '3669', (92, 97))
64685	32003757	We also found that the silencing of ISG20 could significantly down-regulate the expression of MMP9 and CCND1 in ccRCC (Figure 8C).	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('MMP9', 'molecular_function', 'GO:0004229', ('94', '98'))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('ISG20', 'Gene', '3669', (36, 41))	('ccRCC', 'Disease', (112, 117))	('ISG20', 'Gene', (36, 41))	('ccRCC', 'Disease', 'MESH:D002292', (112, 117))	('MMP9', 'Gene', (94, 98))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('down-regulate', 'NegReg', (62, 75))	('silencing', 'Var', (23, 32))	('CCND1', 'Gene', '595', (103, 108))	('MMP9', 'Gene', '4318', (94, 98))	('expression', 'MPA', (80, 90))	('CCND1', 'Gene', (103, 108))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('si', 'Chemical', 'MESH:D012825', (86, 88))
64707	32003757	Furthermore, KEGG enrichment analysis revealed that the DEGs were obviously associated with multiple metabolic pathways.	('DEGs', 'Var', (56, 60))	('tip', 'Gene', (95, 98))	('associated', 'Reg', (76, 86))	('tip', 'Gene', '79828', (95, 98))	('si', 'Chemical', 'MESH:D012825', (34, 36))
64711	32003757	Multi-omics characterization also revealed that abnormal glycolysis and pentose phosphate pathway promoted tumor growth.	('glycolysis', 'biological_process', 'GO:0006096', ('57', '67'))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('glycolysis', 'MPA', (57, 67))	('promoted', 'PosReg', (98, 106))	('abnormal', 'Var', (48, 56))	('pentose phosphate', 'Chemical', 'MESH:D010428', (72, 89))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('72', '97'))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('pentose phosphate pathway', 'Pathway', (72, 97))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('abnormal glycolysis', 'Phenotype', 'HP:0004366', (48, 67))
64713	32003757	It was worth mentioning that the DEGs were significantly associated with the peroxisome proliferators-activated receptors (PPAR) signaling pathway.	('peroxisome proliferators-activated receptors', 'Gene', (77, 121))	('PPAR) signaling pathway', 'biological_process', 'GO:0035357', ('123', '146'))	('peroxisome', 'cellular_component', 'GO:0005777', ('77', '87'))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('DEGs', 'Var', (33, 37))	('si', 'Chemical', 'MESH:D012825', (129, 131))	('peroxisome proliferators-activated receptors', 'Gene', '5465', (77, 121))	('associated', 'Reg', (57, 67))
64727	32003757	In addition, high expression of ISG20 predicted poor overall survival in glioma.	('ISG20', 'Gene', '3669', (32, 37))	('glioma', 'Disease', (73, 79))	('ISG20', 'Gene', (32, 37))	('high', 'Var', (13, 17))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('overall', 'MPA', (53, 60))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('poor', 'NegReg', (48, 52))	('si', 'Chemical', 'MESH:D012825', (24, 26))
64728	32003757	Similarly, patients with high expression of ISG20 had shorter overall survival time in our present study.	('ISG20', 'Gene', '3669', (44, 49))	('ISG20', 'Gene', (44, 49))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('high expression', 'Var', (25, 40))	('shorter', 'NegReg', (54, 61))	('patients', 'Species', '9606', (11, 19))	('overall survival', 'MPA', (62, 78))
64733	32003757	Functional experiments also verified that knockdown of ISG20 could obviously inhibit proliferation, migration, and invasion of ccRCC cells.	('migration', 'CPA', (100, 109))	('inhibit', 'NegReg', (77, 84))	('ISG20', 'Gene', (55, 60))	('si', 'Chemical', 'MESH:D012825', (119, 121))	('ccRCC', 'Disease', (127, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('ccRCC', 'Disease', 'MESH:D002292', (127, 132))	('ISG20', 'Gene', '3669', (55, 60))	('invasion of', 'CPA', (115, 126))	('proliferation', 'CPA', (85, 98))	('knockdown', 'Var', (42, 51))
64742	32003757	Mutations, amplification and overexpression of CCND1 are observed frequently in a variety of tumors and these may contribute to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('overexpression', 'PosReg', (29, 43))	('si', 'Chemical', 'MESH:D012825', (138, 140))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Disease', (93, 98))	('CCND1', 'Gene', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (128, 133))	('tumors', 'Disease', (93, 99))	('CCND1', 'Gene', '595', (47, 52))	('amplification', 'Var', (11, 24))	('contribute', 'Reg', (114, 124))
64869	30026228	VHL Substrate Transcription Factor ZHX2 As An Oncogenic Driver In Clear Cell Renal Cell Carcinoma Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC).	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (187, 218))	('von Hippel-Lindau', 'Gene', (118, 135))	('Inactivation', 'Var', (98, 110))	('VHL', 'Gene', '7428', (0, 3))	('ZHX2', 'Gene', '22882', (35, 39))	('ubiquitin', 'molecular_function', 'GO:0031386', ('145', '154'))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (66, 97))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (187, 218))	('von Hippel-Lindau', 'Gene', '7428', (118, 135))	('VHL', 'Gene', (137, 140))	('Clear Cell Renal Cell Carcinoma', 'Disease', (66, 97))	('Carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('clear cell renal cell carcinoma', 'Disease', (187, 218))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (198, 218))	('ZHX2', 'Gene', (35, 39))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (66, 97))	('VHL', 'Gene', (0, 3))	('ccRCC', 'Phenotype', 'HP:0006770', (220, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('VHL', 'Gene', '7428', (137, 140))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (77, 97))
64873	30026228	Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2.	('mutations', 'Var', (58, 67))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('patients', 'Species', '9606', (23, 31))	('abundance', 'MPA', (90, 99))	('ZHX2', 'Gene', (128, 132))	('increased', 'PosReg', (80, 89))	('ccRCC', 'Phenotype', 'HP:0006770', (17, 22))	('ccRCC', 'Disease', (17, 22))	('ZHX2', 'Gene', '22882', (128, 132))	('localization', 'biological_process', 'GO:0051179', ('112', '124'))	('VHL loss', 'Disease', 'MESH:D006623', (37, 45))	('VHL loss', 'Disease', (37, 45))	('nuclear localization', 'MPA', (104, 124))
64883	30026228	We validated this by incubating 35S-labeled HIF2alpha protein with Glutathione S-transferase VBC (GST-VBC) in the presence of p-OH HIF1alpha peptide in a competition assay (fig.	('HIF2alpha', 'Gene', '2034', (44, 53))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('p-OH', 'Var', (126, 130))	('p-OH', 'Chemical', '-', (126, 130))	('HIF2alpha', 'Gene', (44, 53))	('HIF1alpha', 'Gene', (131, 140))	('35S', 'Chemical', 'MESH:C000615320', (32, 35))	('HIF1alpha', 'Gene', '3091', (131, 140))
64884	30026228	Next, a genome-wide human cDNA library was divided into approximately 700 pools with 24 cDNAs/pool, which were in vitro translated followed by binding assays with the GST-VBC in the presence of either unmodified or p-OH HIF1alpha peptide.	('p-OH', 'Var', (215, 219))	('binding', 'Interaction', (143, 150))	('p-OH', 'Chemical', '-', (215, 219))	('human', 'Species', '9606', (20, 25))	('HIF1alpha', 'Gene', (220, 229))	('binding', 'molecular_function', 'GO:0005488', ('143', '150'))	('HIF1alpha', 'Gene', '3091', (220, 229))
64895	30026228	Conversely, reintroduction of VHL into VHL-deficient ccRCC cells increased the ubiquitination and degradation of endogenous ZHX2 (Fig.1H).	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('increased', 'PosReg', (65, 74))	('VHL-deficient', 'Disease', 'MESH:D006623', (39, 52))	('reintroduction', 'Var', (12, 26))	('VHL-deficient', 'Disease', (39, 52))	('ubiquitination', 'MPA', (79, 93))	('VHL', 'Gene', (30, 33))	('VHL', 'Gene', (39, 42))	('ZHX2', 'Gene', (124, 128))	('degradation', 'biological_process', 'GO:0009056', ('98', '109'))	('VHL', 'Gene', '7428', (30, 33))	('VHL', 'Gene', '7428', (39, 42))	('ZHX2', 'Gene', '22882', (124, 128))	('degradation', 'MPA', (98, 109))
64898	30026228	Next, we performed mass spectrometry and identified three ZHX2 prolyl hydroxylation sites: proline 427, 440, and 464 (fig.	('proline 427', 'Var', (91, 102))	('ZHX2', 'Gene', (58, 62))	('464', 'Var', (113, 116))	('ZHX2', 'Gene', '22882', (58, 62))	('proline', 'Chemical', 'MESH:D011392', (91, 98))
64899	30026228	We generated single proline-to-alanine mutants (P427A, P440A, and P464A) and a triple mutant that harbors three mutations (P3A).	('P427A', 'Mutation', 'p.P427A', (48, 53))	('P440A', 'Mutation', 'p.P440A', (55, 60))	('P427A', 'Var', (48, 53))	('alanine', 'Chemical', 'MESH:D000409', (31, 38))	('proline', 'Chemical', 'MESH:D011392', (20, 27))	('P464A', 'Var', (66, 71))	('P440A', 'Var', (55, 60))	('P464A', 'Mutation', 'rs1471678738', (66, 71))
64900	30026228	The single mutants, and especially the P3A mutant, exhibited decreased VHL binding, ubiquitination and a concomitant increase of ZHX2 (Fig.1J-K, fig.	('increase', 'PosReg', (117, 125))	('VHL', 'Gene', (71, 74))	('decreased', 'NegReg', (61, 70))	('binding', 'molecular_function', 'GO:0005488', ('75', '82'))	('VHL', 'Gene', '7428', (71, 74))	('P3A', 'Var', (39, 42))	('ubiquitination', 'MPA', (84, 98))	('ZHX2', 'Gene', (129, 133))	('ZHX2', 'Gene', '22882', (129, 133))
64902	30026228	We obtained 7 tumors from ccRCC patients and confirmed VHL loss of function mutations important for HIFalpha regulation in all 7 by sequencing  (Table S1), most of which contained greater amounts of ZHX2, HIF1alpha and HIF2alpha than the paired normal tissues (Fig.	('patients', 'Species', '9606', (32, 40))	('mutations', 'Var', (76, 85))	('HIF1alpha', 'Gene', '3091', (205, 214))	('ZHX2', 'Gene', (199, 203))	('regulation', 'biological_process', 'GO:0065007', ('109', '119'))	('VHL loss', 'Disease', 'MESH:D006623', (55, 63))	('HIF2alpha', 'Gene', '2034', (219, 228))	('VHL loss', 'Disease', (55, 63))	('ZHX2', 'Gene', '22882', (199, 203))	('ccRCC', 'Phenotype', 'HP:0006770', (26, 31))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('greater', 'PosReg', (180, 187))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('HIF2alpha', 'Gene', (219, 228))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('HIF1alpha', 'Gene', (205, 214))
64903	30026228	For two tumors with VHL missense mutations (332 and 778), we did not observe distinctive upregulation of ZHX2 compared to normals, possibly because such mutations are less critical for ZHX2 regulation.	('ZHX2', 'Gene', '22882', (105, 109))	('332', 'Var', (44, 47))	('ZHX2', 'Gene', (185, 189))	('regulation', 'biological_process', 'GO:0065007', ('190', '200'))	('ZHX2', 'Gene', '22882', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('VHL', 'Gene', (20, 23))	('ZHX2', 'Gene', (105, 109))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('VHL', 'Gene', '7428', (20, 23))
64906	30026228	ZHX2, HIF1alpha and HIF2alpha upregulation were also found for another two pairs of ccRCC tumor tissues harboring VHL frameshift mutations (Table S1), but not ccRCC tumors with intact VHL (Fig.	('ZHX2', 'Gene', (0, 4))	('frameshift mutations', 'Var', (118, 138))	('VHL', 'Gene', '7428', (184, 187))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('HIF2alpha', 'Gene', (20, 29))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Disease', (90, 95))	('ZHX2', 'Gene', '22882', (0, 4))	('ccRCC', 'Phenotype', 'HP:0006770', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('VHL', 'Gene', (114, 117))	('ccRCC', 'Disease', (84, 89))	('HIF2alpha', 'Gene', '2034', (20, 29))	('tumors', 'Disease', (165, 171))	('HIF1alpha', 'Gene', '3091', (6, 15))	('upregulation', 'PosReg', (30, 42))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('tumor', 'Disease', (165, 170))	('VHL', 'Gene', '7428', (114, 117))	('VHL', 'Gene', (184, 187))	('HIF1alpha', 'Gene', (6, 15))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (165, 170))
64908	30026228	On the other hand, ZHX2 was exclusively in the nucleus of tumors harboring VHL frameshift mutations (fig.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('ZHX2', 'Gene', '22882', (19, 23))	('frameshift mutations', 'Var', (79, 99))	('VHL', 'Gene', (75, 78))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('VHL', 'Gene', '7428', (75, 78))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('ZHX2', 'Gene', (19, 23))	('nucleus', 'cellular_component', 'GO:0005634', ('47', '54'))
64910	30026228	Depletion of ZHX2 in multiple VHL-deficient ccRCC cells with several independent shRNAs or sgRNAs decreased cell proliferation and growth in soft agar (Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('decreased', 'NegReg', (98, 107))	('ZHX2', 'Gene', '22882', (13, 17))	('Depletion', 'Var', (0, 9))	('growth in soft agar', 'CPA', (131, 150))	('agar', 'Chemical', 'MESH:D000362', (146, 150))	('VHL-deficient', 'Disease', 'MESH:D006623', (30, 43))	('VHL-deficient', 'Disease', (30, 43))	('cell proliferation', 'CPA', (108, 126))	('ZHX2', 'Gene', (13, 17))	('cell proliferation', 'biological_process', 'GO:0008283', ('108', '126'))
64919	30026228	Next, we performed gene expression profiling of 786-O cells after ZHX2 knockdown followed by gene set enrichment analysis (GSEA) adjusted for gene function associated with oncogenic pathways.	('ZHX2', 'Gene', (66, 70))	('knockdown', 'Var', (71, 80))	('ZHX2', 'Gene', '22882', (66, 70))	('GSEA', 'Chemical', '-', (123, 127))	('gene expression', 'biological_process', 'GO:0010467', ('19', '34'))
64920	30026228	ZHX2 depletion caused decreased expression of multiple genes linked with anti-apoptosis, cell proliferation, invasion/metastasis, and metabolism (fig.	('anti-apoptosis', 'biological_process', 'GO:0043066', ('73', '87'))	('ZHX2', 'Gene', (0, 4))	('depletion', 'Var', (5, 14))	('cell proliferation', 'CPA', (89, 107))	('anti-apoptosis', 'CPA', (73, 87))	('ZHX2', 'Gene', '22882', (0, 4))	('cell proliferation', 'biological_process', 'GO:0008283', ('89', '107'))	('invasion/metastasis', 'CPA', (109, 128))	('metabolism', 'CPA', (134, 144))	('expression', 'MPA', (32, 42))	('metabolism', 'biological_process', 'GO:0008152', ('134', '144'))	('decreased', 'NegReg', (22, 31))
64921	30026228	Interestingly, GSEA analyses also demonstrated that NF-kappaB activity was suppressed by ZHX2 depletion (fig.	('suppressed', 'NegReg', (75, 85))	('ZHX2', 'Gene', (89, 93))	('GSEA', 'Chemical', '-', (15, 19))	('ZHX2', 'Gene', '22882', (89, 93))	('NF-kappaB', 'Gene', '4790', (52, 61))	('NF-kappaB', 'Gene', (52, 61))	('depletion', 'Var', (94, 103))
64922	30026228	Real time PCR (RT-PCR) analysis confirmed that ZHX2 depletion decreased the expression of canonical NF-kappaB target genes, including c-c motif chemokine ligand 2 (CCL2), interleukin-8 (IL8) and interleukin 6 (IL6) (Fig.	('IL6', 'molecular_function', 'GO:0005138', ('210', '213'))	('IL8', 'Gene', (186, 189))	('IL8', 'Gene', '3576', (186, 189))	('c-c motif chemokine ligand 2', 'Gene', '6347', (134, 162))	('IL6', 'Gene', (210, 213))	('depletion', 'Var', (52, 61))	('ligand', 'molecular_function', 'GO:0005488', ('154', '160'))	('ZHX2', 'Gene', (47, 51))	('IL8', 'molecular_function', 'GO:0005153', ('186', '189'))	('CCL2', 'Gene', (164, 168))	('interleukin-8', 'Gene', '3576', (171, 184))	('ZHX2', 'Gene', '22882', (47, 51))	('decreased', 'NegReg', (62, 71))	('interleukin-8', 'Gene', (171, 184))	('interleukin 6', 'Gene', (195, 208))	('CCL2', 'Gene', '6347', (164, 168))	('NF-kappaB', 'Gene', (100, 109))	('CCL', 'molecular_function', 'GO:0044101', ('164', '167'))	('IL6', 'Gene', '3569', (210, 213))	('NF-kappaB', 'Gene', '4790', (100, 109))	('expression', 'MPA', (76, 86))	('interleukin 6', 'Gene', '3569', (195, 208))	('c-c motif chemokine ligand 2', 'Gene', (134, 162))
64925	30026228	Loss of VHL constitutively activates the NF-kappaB pathway .	('VHL', 'Gene', '7428', (8, 11))	('NF-kappaB', 'Gene', '4790', (41, 50))	('NF-kappaB', 'Gene', (41, 50))	('Loss', 'Var', (0, 4))	('VHL', 'Gene', (8, 11))	('activates', 'PosReg', (27, 36))
64930	30026228	Inhibiting NF-kappaB with RelA/p65 shRNAs or with a specific IKK inhibitor compound A (CMPDA) suppressed VHL-deficient ccRCC cell proliferation and growth in soft agar (fig.	('CMPDA', 'Chemical', '-', (87, 92))	('p65', 'Gene', '5970', (31, 34))	('VHL-deficient', 'Disease', 'MESH:D006623', (105, 118))	('Inhibiting', 'Var', (0, 10))	('IKK', 'molecular_function', 'GO:0008384', ('61', '64'))	('VHL-deficient', 'Disease', (105, 118))	('RelA', 'Gene', (26, 30))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('ccRCC', 'Disease', (119, 124))	('NF-kappaB', 'Gene', '4790', (11, 20))	('RelA', 'Gene', '5970', (26, 30))	('suppressed', 'NegReg', (94, 104))	('p65', 'Gene', (31, 34))	('growth in soft agar', 'CPA', (148, 167))	('NF-kappaB', 'Gene', (11, 20))	('agar', 'Chemical', 'MESH:D000362', (163, 167))	('cell proliferation', 'biological_process', 'GO:0008283', ('125', '143'))
64948	30026228	ZHX2 depletion impaired RelA/p65 occupancy on IL6 and inhibitor of NF-kappaB kinase subunit epsilon (IKBKE) promoters (Fig.	('ZHX2', 'Gene', (0, 4))	('p65', 'Gene', (29, 32))	('depletion', 'Var', (5, 14))	('impaired', 'NegReg', (15, 23))	('IL6', 'molecular_function', 'GO:0005138', ('46', '49'))	('RelA', 'Gene', (24, 28))	('p65', 'Gene', '5970', (29, 32))	('ZHX2', 'Gene', '22882', (0, 4))	('NF-kappaB kinase subunit epsilon (IKBKE)', 'Gene', '9641', (67, 107))	('IL6', 'Gene', '3569', (46, 49))	('RelA', 'Gene', '5970', (24, 28))	('NF-kappaB kinase subunit epsilon (IKBKE', 'Gene', (67, 106))	('IL6', 'Gene', (46, 49))
64953	30026228	Etaowever, the HIF2alpha inhibitor PT2399 is effective in only a subset of ccRCC .	('PT2399', 'Var', (35, 41))	('PT2399', 'Chemical', 'MESH:C000614278', (35, 41))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('ccRCC', 'Disease', (75, 80))	('HIF2alpha', 'Gene', (15, 24))	('HIF2alpha', 'Gene', '2034', (15, 24))
64954	30026228	We found ZHX2 depletion or IKK inhibition inhibited soft agar growth of UMRC2 and UMRC6 cells (Fig.3, fig.	('agar', 'Chemical', 'MESH:D000362', (57, 61))	('IKK', 'Gene', (27, 30))	('ZHX2', 'Gene', (9, 13))	('depletion', 'Var', (14, 23))	('UMRC2', 'CellLine', 'CVCL:2739', (72, 77))	('IKK', 'molecular_function', 'GO:0008384', ('27', '30'))	('UMRC6', 'CellLine', 'CVCL:2741', (82, 87))	('inhibition inhibited', 'NegReg', (31, 51))	('ZHX2', 'Gene', '22882', (9, 13))
65005	29669553	reported that PD-L1 positivity in RCC with sarcomatoid differentiation is detected in 89% of patients with these tumors and they may be good candidates for treatment with anti-PD-1/PD-L1 therapy.	('PD-L1', 'Gene', '29126', (14, 19))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('positivity', 'Var', (20, 30))	('sarcomatoid', 'Disease', 'MESH:C538614', (43, 54))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('PD-L1', 'Gene', (181, 186))	('sarcomatoid', 'Disease', (43, 54))	('PD-1', 'Gene', (176, 180))	('PD-L1', 'Gene', (14, 19))	('PD-1', 'Gene', '5133', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('PD-L1', 'Gene', '29126', (181, 186))	('patients', 'Species', '9606', (93, 101))	('RCC', 'Disease', (34, 37))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
65037	31892969	The study on copy number alteration of clear cell renal cancer in Chinese population Objectives: Copy number alteration (CNA) is one of the important genetic variations.	('clear cell renal cancer', 'Disease', (39, 62))	('Copy number', 'Var', (97, 108))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('clear cell renal cancer', 'Phenotype', 'HP:0006770', (39, 62))	('clear cell renal cancer', 'Disease', 'MESH:C538614', (39, 62))	('renal cancer', 'Phenotype', 'HP:0009726', (50, 62))
65042	31892969	Results: We acquired the whole-genome CNA landscape by Oncoscan detection, and found out the high-frequency CNA regions which were not reported in previous studies, for example, 11P11, 22q11.23, 20q11.3 (PDRG1), and Xp22.33 so on.	('11P11', 'Var', (178, 183))	('22q11.23', 'Var', (185, 193))	('PDRG1', 'Gene', '81572', (204, 209))	('Xp22.33', 'Var', (216, 223))	('20q11.3', 'Var', (195, 202))	('PDRG1', 'Gene', (204, 209))
65043	31892969	During the analyzing of genes annotation and enrichment, we found out some ccRCC functional genes in the CNA regions which might play a role in the biological process, for example, the copy number loss of DNA repair genes (TTC5 PARP2, etc.)	('TTC5', 'Gene', '91875', (223, 227))	('PARP2', 'Gene', (228, 233))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('men', 'Species', '9606', (51, 54))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('DNA repair', 'biological_process', 'GO:0006281', ('205', '215'))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('loss', 'NegReg', (197, 201))	('biological process', 'biological_process', 'GO:0008150', ('148', '166'))	('copy number', 'Var', (185, 196))	('DNA', 'cellular_component', 'GO:0005574', ('205', '208'))	('PARP2', 'Gene', '10038', (228, 233))	('TTC5', 'Gene', (223, 227))
65045	31892969	), the copy number gain of oncogenes (ABL2, MET, HUWE1, etc.)	('HUWE1', 'Gene', (49, 54))	('HUWE1', 'Gene', '10075', (49, 54))	('copy number gain', 'Var', (7, 23))	('ABL2', 'Gene', '27', (38, 42))	('ABL2', 'Gene', (38, 42))	('MET', 'Gene', (44, 47))
65048	31892969	And between the different T stage patients affected by CNA, the T2+T3 group carried more high-frequency CNA regions (P-value was 0.012).	('high-frequency CNA regions', 'MPA', (89, 115))	('patients', 'Species', '9606', (34, 42))	('T2+T3', 'Var', (64, 69))
65056	31892969	For example, the copy number loss (CN loss) of tumor suppressor genes would affect the regulation of cell proliferation, leading to uncontrollable proliferation, and then cause cancer.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('47', '63'))	('affect', 'Reg', (76, 82))	('cancer', 'Disease', (177, 183))	('cause', 'Reg', (171, 176))	('tumor', 'Disease', (47, 52))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('regulation of cell proliferation', 'biological_process', 'GO:0042127', ('87', '119'))	('regulation of cell', 'MPA', (87, 105))	('tumor suppressor', 'biological_process', 'GO:0051726', ('47', '63'))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('copy number loss', 'Var', (17, 33))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('uncontrollable proliferation', 'MPA', (132, 160))	('leading to', 'Reg', (121, 131))
65057	31892969	In addition, the copy number gain (CN gain) of oncogenes also results in tumor occurrence, because of the accumulation of oncogenesis effect.	('oncogenesis', 'biological_process', 'GO:0007048', ('122', '133'))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('accumulation', 'PosReg', (106, 118))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('copy number', 'Var', (17, 28))	('tumor', 'Disease', (73, 78))	('gain', 'PosReg', (29, 33))	('results in', 'Reg', (62, 72))	('oncogenesis effect', 'CPA', (122, 140))
65071	31892969	In the first four columns of Table 2, we listed the high-frequency CNA regions we found from Ocoscan assay, among which the CN gain in 11p11 (MDK), 22q11.23 (PLA2G6), Xp22.33 (XGY3), and the CN loss in 20q11.3 (PDRG1), 16p11.2-p11.1 (SMG1P2), were found for the first time.	('p11', 'Gene', '6281', (227, 230))	('SMG1P2', 'Gene', '440354', (234, 240))	('PLA2G6', 'Gene', '8398', (158, 164))	('p11', 'Gene', (137, 140))	('p11', 'Gene', '6281', (221, 224))	('MDK', 'Gene', '4192', (142, 145))	('Xp22.33', 'Var', (167, 174))	('loss', 'NegReg', (194, 198))	('MDK', 'Gene', (142, 145))	('p11', 'Gene', '6281', (137, 140))	('PLA2G6', 'Gene', (158, 164))	('p11', 'Gene', (227, 230))	('PDRG1', 'Gene', '81572', (211, 216))	('p11', 'Gene', (221, 224))	('gain', 'PosReg', (127, 131))	('SMG1P2', 'Gene', (234, 240))	('PDRG1', 'Gene', (211, 216))
65072	31892969	Compared with TCGA database, the CNA frequency of some regions in Chinese was obviously higher, for example, 3p25.3 (VHL), 5q35.3 (SQSTM1), 13q21 (RB1), 17q21.33 (ABCC3), and Xq28 (SPRY3) so on.	('higher', 'PosReg', (88, 94))	('5q35.3', 'Var', (123, 129))	('VHL', 'Gene', '7428', (117, 120))	('RB1', 'Gene', '5925', (147, 150))	('SQSTM1', 'Gene', '8878', (131, 137))	('ABCC3', 'Gene', '8714', (163, 168))	('RB1', 'Gene', (147, 150))	('SQSTM1', 'Gene', (131, 137))	('SPRY3', 'Gene', '10251', (181, 186))	('ABCC3', 'Gene', (163, 168))	('SPRY3', 'Gene', (181, 186))	('13q21', 'Var', (140, 145))	('3p25.3', 'Var', (109, 115))	('Xq28', 'Var', (175, 179))	('CNA', 'MPA', (33, 36))	('17q21.33', 'Var', (153, 161))	('VHL', 'Gene', (117, 120))
65087	31892969	Although there were no significance in the group of CN loss, CN gain, LOH (loss of heterozygosity), the significant difference of total CNA between T1 group and T2+T3 group was noticed (P-value =0.012), which mean T2+T3 group carried more high-frequency CNA regions (Supplementary Table 2).	('men', 'Species', '9606', (273, 276))	('more', 'PosReg', (234, 238))	('T2+T3', 'Var', (214, 219))
65099	31892969	There was a study that showed 5q amplification led to overexpression of the SQSTM1 oncogene in ccRCC lines and tumors, and the gene product of which, p62, regulated known renal cancer suppressor genes such as VHL, TSC1and TSC2.	('TSC1', 'Gene', '7248', (214, 218))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('overexpression', 'PosReg', (54, 68))	('tumors', 'Disease', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('TSC2', 'Gene', (222, 226))	('renal cancer', 'Disease', (171, 183))	('renal cancer', 'Phenotype', 'HP:0009726', (171, 183))	('VHL', 'Gene', (209, 212))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('5q amplification', 'Var', (30, 46))	('TSC2', 'Gene', '7249', (222, 226))	('SQSTM1', 'Gene', (76, 82))	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('amplification', 'Var', (33, 46))	('renal cancer', 'Disease', 'MESH:D007680', (171, 183))	('VHL', 'Gene', '7428', (209, 212))	('SQSTM1', 'Gene', '8878', (76, 82))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('TSC1', 'Gene', (214, 218))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('p62', 'Gene', '8878', (150, 153))	('regulated', 'Reg', (155, 164))	('p62', 'Gene', (150, 153))
65103	31892969	The previous studies validated that the alterations in DNA repair genes were closely associated with tumorigenesis and prognosis, including renal cancer.	('renal cancer', 'Disease', 'MESH:D007680', (140, 152))	('renal cancer', 'Phenotype', 'HP:0009726', (140, 152))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('alterations', 'Var', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('DNA repair genes', 'Gene', (55, 71))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('DNA repair', 'biological_process', 'GO:0006281', ('55', '65'))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('renal cancer', 'Disease', (140, 152))	('associated', 'Reg', (85, 95))
65108	31892969	This outcome might be an evidence to prove that CN loss of FOXA1 at 14q11.2 was associated with ccRCC in our study.	('FOXA1', 'Gene', (59, 64))	('FOXA1', 'Gene', '3169', (59, 64))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('associated', 'Reg', (80, 90))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('CN loss', 'Var', (48, 55))
65110	31892969	Therefore, this result might be also a proof to verify that CN loss of PSME2, PSMB11, PSMB5 was associated with ccRCC in our study.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('PSME2', 'Gene', (71, 76))	('RCC', 'Disease', (114, 117))	('PSMB5', 'Gene', (86, 91))	('PSME2', 'Gene', '5721', (71, 76))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('PSMB11', 'Gene', (78, 84))	('associated', 'Reg', (96, 106))	('CN loss', 'Var', (60, 67))	('PSMB5', 'Gene', '5693', (86, 91))	('PSMB11', 'Gene', '122706', (78, 84))
65117	31892969	Moreover, more and more researches revealed that pseudogene could regulate normal genes or express a part of protein, and the alteration in pseudogene might result in cancer.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('normal genes', 'MPA', (75, 87))	('alteration', 'Var', (126, 136))	('pseudogene', 'Var', (49, 59))	('result in', 'Reg', (157, 166))	('cancer', 'Disease', (167, 173))	('pseudogene', 'Gene', (140, 150))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('express', 'MPA', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('regulate', 'Reg', (66, 74))	('protein', 'Protein', (109, 116))
65123	31892969	RCC renal cell cancer ccRCC clear cell renal cancer CNA copy number alteration bp base pair Mbp million bp CN loss copy number loss CN gain copy number gain BP biological process GO gene ontology BMI body mass index TCGA the Cancer Genome Atlas DAVID The Database for Annotation, Visualization and Integrated Discovery Chr chromosome Del delete LOH loss of heterozygosity Amp amplification	('renal cancer', 'Phenotype', 'HP:0009726', (39, 51))	('loss of', 'NegReg', (349, 356))	('Cancer', 'Phenotype', 'HP:0002664', (225, 231))	('clear cell renal cancer', 'Phenotype', 'HP:0006770', (28, 51))	('alteration', 'Var', (68, 78))	('chromosome', 'cellular_component', 'GO:0005694', ('323', '333'))	('gene ontology', 'biological_process', 'GO:0003673', ('182', '195'))	('Cancer', 'Disease', (225, 231))	('clear cell renal cancer', 'Disease', (28, 51))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('renal cell cancer', 'Disease', 'MESH:C538614', (4, 21))	('RCC', 'Phenotype', 'HP:0005584', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('RCC', 'Disease', (0, 3))	('renal cell cancer', 'Disease', (4, 21))	('ccRCC', 'Phenotype', 'HP:0006770', (22, 27))	('RCC', 'Disease', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Cancer', 'Disease', 'MESH:D009369', (225, 231))	('renal cell cancer', 'Phenotype', 'HP:0005584', (4, 21))	('biological process', 'biological_process', 'GO:0008150', ('160', '178'))	('clear cell renal cancer', 'Disease', 'MESH:C538614', (28, 51))	('LOH', 'Var', (345, 348))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('Amp', 'Chemical', 'MESH:D000249', (372, 375))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
65126	31822727	In renal cancer, where HIF is constitutively and un-physiologically activated by mutation of the von Hippel-Lindau tumour suppressor, we observed marked excess overlap, which extended to potential susceptibility polymorphisms that are below the conventional threshold applied in GWAS.	('overlap', 'MPA', (160, 167))	('renal cancer', 'Disease', (3, 15))	('von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (97, 121))	('mutation', 'Var', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('renal cancer', 'Phenotype', 'HP:0009726', (3, 15))	('von Hippel-Lindau tumour', 'Disease', (97, 121))	('renal cancer', 'Disease', 'MESH:D007680', (3, 15))
65131	31822727	Much of this work concerns the role of major tumour suppressors and oncogenes and has led to a now classical model in which mutational dysregulation of these molecules generates a discrete effect on a specific pathway that directly promotes the development of cancer.	('development', 'CPA', (245, 256))	('promotes', 'PosReg', (232, 240))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', (260, 266))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('mutational dysregulation', 'Var', (124, 148))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('tumour', 'Disease', (45, 51))
65133	31822727	However, the existence of extensive interconnected pathways, predicts that the mutational dysregulation of a pathway will lead to multiple effects that are unlikely to be neutral with respect to cancer development.	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('lead to', 'Reg', (122, 129))	('mutational dysregulation', 'Var', (79, 103))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
65138	31822727	Of these, the most striking is the constitutive activation of HIF that follows bi-allelic inactivation of the von Hippel-Lindau tumour suppressor (pVHL) in renal clear cell carcinoma (RCC), the most prevalent form of kidney cancer.	('von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (110, 134))	('kidney cancer', 'Phenotype', 'HP:0009726', (217, 230))	('pVHL', 'Gene', (147, 151))	('kidney cancer', 'Disease', 'MESH:D007680', (217, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('von Hippel-Lindau tumour', 'Disease', (110, 134))	('kidney cancer', 'Disease', (217, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('activation', 'PosReg', (48, 58))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (156, 182))	('bi-allelic', 'Var', (79, 89))	('renal clear cell carcinoma', 'Disease', (156, 182))	('pVHL', 'Gene', '7428', (147, 151))
65141	31822727	A priori, it might be expected that when such an extensive pathway is activated un-physiologically, then the numerous alterations in gene expression would have heterogeneous actions on oncogenesis, with selective pressure operating to modulate or tune these outputs during the evolution of the cancer.	('alterations', 'Var', (118, 129))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('oncogenesis', 'biological_process', 'GO:0007048', ('185', '196'))	('oncogenesis', 'CPA', (185, 196))	('cancer', 'Disease', (294, 300))	('gene expression', 'biological_process', 'GO:0010467', ('133', '148'))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))
65155	31822727	ChIP-seq analysis of histone H3K4me1, H3K4me3 and H3K27ac modifications together with formaldehyde-assisted isolation of regulatory elements (FAIRE)-seq analysis of DNA accessibility in 786-O RCC cells was used to identify functional elements within each supra-threshold RCC-susceptibility locus.	('modifications', 'Var', (58, 71))	('formaldehyde', 'Chemical', 'MESH:D005557', (86, 98))	('H3K27ac', 'Var', (50, 57))	('histone H3K4me', 'biological_process', 'GO:0051568', ('21', '35'))	('DNA', 'cellular_component', 'GO:0005574', ('165', '168'))
65161	31822727	Gene Set Enrichment Analysis (GSEA) of the 36-gene set showed enrichment for genes that are upregulated in VHL defective cells (Fig.	('upregulated', 'PosReg', (92, 103))	('VHL', 'Gene', (107, 110))	('GSEA', 'Chemical', '-', (30, 34))	('defective', 'Var', (111, 120))
65168	31822727	Finally, polymorphisms at the 11q13.3 locus have been shown to alter binding of HIF to a long-range enhancer of the CCND1 gene, polymorphisms at the 8q24.21 locus alter binding of HIF to an enhancer of MYC, and polymorphisms at the 12p12.1 locus also alter HIF binding and BHLHE41 expression.	('alter', 'Reg', (163, 168))	('MYC', 'Protein', (202, 205))	('BHLHE41', 'Gene', '79365', (273, 280))	('binding', 'molecular_function', 'GO:0005488', ('69', '76'))	('binding', 'Interaction', (261, 268))	('alter', 'Reg', (63, 68))	('alter', 'Reg', (251, 256))	('polymorphisms', 'Var', (128, 141))	('binding', 'Interaction', (69, 76))	('CCND1', 'Gene', (116, 121))	('HIF', 'Protein', (257, 260))	('binding', 'Interaction', (169, 176))	('binding', 'molecular_function', 'GO:0005488', ('169', '176'))	('polymorphisms', 'Var', (9, 22))	('binding', 'molecular_function', 'GO:0005488', ('261', '268'))	('CCND1', 'Gene', '595', (116, 121))	('expression', 'MPA', (281, 291))	('BHLHE41', 'Gene', (273, 280))
65175	31822727	Fourthly, in human tumors, high expression of SCARB1 is associated with adverse patient outcomes and in experimental models, inhibition of SCARB1 impairs the proliferation, invasion and migration of ccRCC cells.	('SCARB1', 'Gene', '949', (139, 145))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('invasion', 'CPA', (173, 181))	('human', 'Species', '9606', (13, 18))	('SCARB1', 'Gene', (139, 145))	('migration', 'CPA', (186, 195))	('SCARB1', 'Gene', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('high', 'Var', (27, 31))	('associated', 'Reg', (56, 66))	('ccRCC', 'Disease', (199, 204))	('patient', 'Species', '9606', (80, 87))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('inhibition', 'Var', (125, 135))	('impairs', 'NegReg', (146, 153))	('SCARB1', 'Gene', '949', (46, 52))	('proliferation', 'CPA', (158, 171))
65190	31822727	GSEA showed that this gene set was significantly enriched amongst genes up regulated in the absence of VHL (Fig.	('up regulated', 'PosReg', (72, 84))	('GSEA', 'Chemical', '-', (0, 4))	('absence', 'Var', (92, 99))	('VHL', 'Gene', (103, 106))
65206	31822727	Inactivation of VHL leads to un-physiological activation of hypoxia signalling pathways and is a common, early and truncal event in RCC.	('VHL', 'Gene', (16, 19))	('hypoxia', 'Disease', (60, 67))	('hypoxia', 'Disease', 'MESH:D000860', (60, 67))	('activation', 'PosReg', (46, 56))	('signalling', 'biological_process', 'GO:0023052', ('68', '78'))	('Inactivation', 'Var', (0, 12))
65211	31822727	We postulate that the contrast between RCC and non-RCC cancer types reflects the contrast between highly un-physiological HIF activation following inactivation of VHL in most RCC, and more physiological activation of HIF by micro-environmental hypoxia in other cancers (i.e.	('cancers', 'Phenotype', 'HP:0002664', (261, 268))	('non-RCC cancer', 'Disease', 'MESH:C538614', (47, 61))	('inactivation', 'Var', (147, 159))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('activation', 'PosReg', (126, 136))	('hypoxia', 'Disease', 'MESH:D000860', (244, 251))	('non-RCC cancer', 'Disease', (47, 61))	('RCC', 'Disease', (175, 178))	('hypoxia', 'Disease', (244, 251))	('cancers', 'Disease', 'MESH:D009369', (261, 268))	('VHL', 'Gene', (163, 166))	('cancers', 'Disease', (261, 268))
65214	31822727	This is consistent with the emerging picture from cancer genome sequencing studies of remarkably constrained tissue specific patterns of mutations even in pathways that, like the VHL-HIF pathway, have general cellular functions - i.e.	('mutations', 'Var', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))
65216	31822727	Such a model implies that a similar process of 'pathway accommodation' should occur by somatic or epigenetic changes during cancer evolution.	('epigenetic changes', 'Var', (98, 116))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))
65267	31509346	Cases with known histologic subtypes (histologic code, 8255, 8260, 8310, 8316, 8317, 8318, and 8319) were included, while patients with unknown RCC histologic subtype (not otherwise specified, NOS) were excluded.	('RCC', 'Disease', 'MESH:D002292', (144, 147))	('8310', 'Var', (67, 71))	('patients', 'Species', '9606', (122, 130))	('8316', 'Var', (73, 77))	('8317', 'Var', (79, 83))	('RCC', 'Disease', (144, 147))
65321	31509346	This project was supported by Urology Care Foundation Research Scholar Award, the National Cancer Institute Cancer Center Support Grant developmental funds of the University of Arizona (P30CA023074), and the Partnership for Native American Cancer Prevention (NACP), funded under parallel grants, U54CA143924 (University of Arizona Cancer Center) and U54CA143925 (Northern Arizona University).	('Cancer', 'Phenotype', 'HP:0002664', (331, 337))	('U54CA143925', 'Chemical', 'MESH:C072901', (350, 361))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('U54CA143925', 'Var', (350, 361))	('U54CA143924', 'Chemical', 'MESH:C072901', (296, 307))	('Cancer', 'Phenotype', 'HP:0002664', (240, 246))	('U54CA143924', 'Var', (296, 307))	('Cancer', 'Phenotype', 'HP:0002664', (108, 114))
65330	33232285	KIF20A knockdown was able to inhibite cell proliferation and invasion of kidney A498 and Caki-1 cells.	('cell proliferation', 'CPA', (38, 56))	('KIF20A', 'Gene', '10112', (0, 6))	('invasion of kidney A498', 'CPA', (61, 84))	('inhibite', 'NegReg', (29, 37))	('cell proliferation', 'biological_process', 'GO:0008283', ('38', '56'))	('knockdown', 'Var', (7, 16))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('KIF20A', 'Gene', (0, 6))
65370	33232285	The survival analysis revealed a shorter overall survival (OS) in patients with high KIF20 expression when compared to those with low KIF20 expression (P<0.0001) (Figure 3B).	('si', 'Chemical', 'MESH:D012825', (146, 148))	('KIF20', 'Gene', (85, 90))	('si', 'Chemical', 'MESH:D012825', (18, 20))	('si', 'Chemical', 'MESH:D012825', (97, 99))	('overall survival', 'MPA', (41, 57))	('shorter', 'NegReg', (33, 40))	('high', 'Var', (80, 84))	('patients', 'Species', '9606', (66, 74))
65385	33232285	So far, our result suggests that samples with high KIF20A expression were likely associated with high immune infiltration in the tumour microenvironment (Figure 6A).	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('high', 'Var', (46, 50))	('KIF20A', 'Gene', (51, 57))	('KIF20A', 'Gene', '10112', (51, 57))	('expression', 'MPA', (58, 68))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('tumour', 'Disease', (129, 135))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('associated', 'Reg', (81, 91))
65390	33232285	As such, western blotting and qPCR analysis revealed the successful knockdown of KIF20A in vitro upon transfection of small interfering RNAs (Figure 7C).	('small interfering RNAs', 'Var', (118, 140))	('si', 'Chemical', 'MESH:D012825', (40, 42))	('KIF20A', 'Gene', (81, 87))	('KIF20A', 'Gene', '10112', (81, 87))	('knockdown', 'NegReg', (68, 77))
65391	33232285	Western blotting analysis showed that KIF20A knockdown may significantly increase the protein level of Bax and cleaved-Cas3 and, contrarily, decrease Bcl-2 protein level (Figure 8A, 8B).	('KIF20A', 'Gene', '10112', (38, 44))	('increase', 'PosReg', (73, 81))	('Cas3', 'Gene', (119, 123))	('Cas3', 'Gene', '10278', (119, 123))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('protein level', 'MPA', (86, 99))	('Bax', 'Gene', '581', (103, 106))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('Bcl-2', 'molecular_function', 'GO:0015283', ('150', '155'))	('KIF20A', 'Gene', (38, 44))	('Bcl-2', 'Gene', '596', (150, 155))	('Bcl-2', 'Gene', (150, 155))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('Cas', 'cellular_component', 'GO:0005650', ('119', '122'))	('decrease', 'NegReg', (141, 149))	('knockdown', 'Var', (45, 54))	('Bax', 'Gene', (103, 106))
65393	33232285	Based on the results of transwell assays, a significant decrease on the content of migrating and invasive cells was detected in the si-KIF20 group (Figure 9A, 9B).	('si', 'Chemical', 'MESH:D012825', (132, 134))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('si-KIF20', 'Var', (132, 140))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('decrease', 'NegReg', (56, 64))
65395	33232285	Knockdown of KIF20A expression can also significantly decrease the number of colonies based on a clonogenic assay (Figure 10A).	('decrease', 'NegReg', (54, 62))	('Knockdown', 'Var', (0, 9))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('si', 'Chemical', 'MESH:D012825', (40, 42))	('KIF20A', 'Gene', (13, 19))	('KIF20A', 'Gene', '10112', (13, 19))
65396	33232285	Likewise, MTT assay result indicated that KIF20A knockdown is able to inhibit the proliferation of renal cancer cells (Figure 10B).	('knockdown', 'Var', (49, 58))	('renal cancer', 'Disease', (99, 111))	('renal cancer', 'Disease', 'MESH:D007680', (99, 111))	('MTT', 'Chemical', 'MESH:C070243', (10, 13))	('renal cancer', 'Phenotype', 'HP:0009726', (99, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('inhibit', 'NegReg', (70, 77))	('KIF20A', 'Gene', (42, 48))	('KIF20A', 'Gene', '10112', (42, 48))
65410	33232285	Moreover, patients with high KIF20A expression appear to have a poorer prognosis when compared with the low KIF20 expression group from the TCGA cohort, thus indicating that KIF20A has a reliable prognostic value.	('KIF20A', 'Gene', (29, 35))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('KIF20A', 'Gene', '10112', (29, 35))	('high', 'Var', (24, 28))	('KIF20A', 'Gene', (174, 180))	('patients', 'Species', '9606', (10, 18))	('si', 'Chemical', 'MESH:D012825', (42, 44))	('KIF20A', 'Gene', '10112', (174, 180))
65423	33232285	According to the retrospective analysis of 662 non-metastatic ccRCC samples, Fu and colleagues have suggested that patients with high mast cell infiltration might have a better OS, cancer-specific survival (CSS) and relapse-free survival (RFS).	('patients', 'Species', '9606', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('high', 'Var', (129, 133))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('relapse-free survival', 'CPA', (216, 237))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))	('cancer', 'Disease', (181, 187))	('better', 'PosReg', (170, 176))
65424	33232285	The evidence mentioned above may explain the poor prognosis of high KIF20A patients from the perspective of tumor immune microenvironment.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('KIF20A', 'Gene', '10112', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('patients', 'Species', '9606', (75, 83))	('tumor', 'Disease', (108, 113))	('high', 'Var', (63, 67))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('KIF20A', 'Gene', (68, 74))
65435	33232285	Chip data derived from ccRCC patients were downloaded from GSE40435 (Platform: GPL10558; 101 tumor samples and 101 adjacent no-tumor renal tissues), GSE36895 (Platform: GPL570; 29 tumor samples and 23 normal cortex tissues), GSE46699 (Platform: GPL570; 65 tumor samples and 65 normal normal tissues) and GSE53757 (Platform: GPL570; 72 tumor samples and 72 normal normal tissues).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('GSE36895', 'Var', (149, 157))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('patients', 'Species', '9606', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('GSE46699', 'Var', (225, 233))	('tumor', 'Disease', (256, 261))	('RCC', 'Disease', (25, 28))	('tumor', 'Disease', (335, 340))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Disease', 'MESH:D009369', (335, 340))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
65513	31666664	The area under curve (AUC) and 95% confidence interval was 0.924 (0.799-1.049), 0.991 (0.964-1.018), 1 (1-1), respectively, for ccRCC, papRCC and chroRCC (Fig.	('papRCC', 'Phenotype', 'HP:0006766', (135, 141))	('ccRCC', 'Disease', (128, 133))	('papRCC', 'Disease', (135, 141))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('ccRCC', 'Disease', 'MESH:D002292', (128, 133))	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('chroRCC', 'Disease', (146, 153))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('0.991', 'Var', (80, 85))	('papRCC', 'Disease', 'MESH:D002292', (135, 141))	('chroRCC', 'Disease', 'MESH:D002292', (146, 153))
65549	31666664	The dysregulation of amino acid metabolism is known to be a key event during cancer development and alterations in specific amino acid levels are emerging hallmarks of cancers.	('amino acid metabolism', 'MPA', (21, 42))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('metabolism', 'biological_process', 'GO:0008152', ('32', '42'))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('specific amino acid levels', 'MPA', (115, 141))	('dysregulation', 'MPA', (4, 17))	('cancers', 'Disease', (168, 175))	('cancer', 'Disease', (168, 174))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('alterations', 'Var', (100, 111))
65595	28220033	Additionally, specific tumor mutations have been found to correlate to overall patient survival.	('mutations', 'Var', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('patient', 'Species', '9606', (79, 86))	('tumor', 'Disease', (23, 28))
65596	28220033	Patients expressing wildtype BAP1 and PBRM1 have longer median survival than patients who harbor mutation in one or both of these genes.	('wildtype', 'Var', (20, 28))	('PBRM1', 'Gene', (38, 43))	('patients', 'Species', '9606', (77, 85))	('PBRM1', 'Gene', '55193', (38, 43))	('Patients', 'Species', '9606', (0, 8))	('BAP1', 'Gene', '8314', (29, 33))	('longer', 'PosReg', (49, 55))	('BAP1', 'Gene', (29, 33))	('median survival', 'MPA', (56, 71))
65605	28220033	Furthermore, knocking down HNRNPK recapitulated the proliferation defects as well as global transcriptional changes as the siRNA knockdowns of SLINKY.	('knocking down', 'Var', (13, 26))	('HNRNPK', 'Gene', (27, 33))	('proliferation defects', 'CPA', (52, 73))	('transcriptional changes', 'MPA', (92, 115))	('HNRNPK', 'Gene', '3190', (27, 33))
65614	33882870	DNA methylation of tumor associated calcium signal transducer 2 (TACSTD2) loci shows association with clinically aggressive renal cell cancers DNA methylation is frequently observed in the development and progression of many human tumors as well as renal cell cancer (RCC).	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('RCC', 'Disease', (268, 271))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumors', 'Disease', (231, 237))	('aggressive renal cell cancers', 'Disease', 'MESH:C538614', (113, 142))	('TACSTD2', 'Gene', (65, 72))	('RCC', 'Disease', 'MESH:C538614', (268, 271))	('tumor associated calcium signal transducer 2', 'Gene', '4070', (19, 63))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('association', 'Reg', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('renal cell cancer', 'Disease', 'MESH:C538614', (124, 141))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('observed', 'Reg', (173, 181))	('DNA methylation', 'biological_process', 'GO:0006306', ('143', '158'))	('methylation', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('renal cell cancer', 'Phenotype', 'HP:0005584', (124, 141))	('aggressive renal cell cancers', 'Disease', (113, 142))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('men', 'Species', '9606', (196, 199))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor associated calcium signal transducer 2', 'Gene', (19, 63))	('renal cell cancer', 'Disease', 'MESH:C538614', (249, 266))	('renal cell cancer', 'Disease', (249, 266))	('TACSTD2', 'Gene', '4070', (65, 72))	('human', 'Species', '9606', (225, 230))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('renal cell cancer', 'Phenotype', 'HP:0005584', (249, 266))
65616	33882870	Moreover, tumor-specific hypermethylation and association with aggressive cancer characteristics has been found for lung adenocarcinoma, hepatocellular carcinoma and cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('hypermethylation', 'Var', (25, 41))	('association', 'Interaction', (46, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (116, 135))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (116, 135))	('tumor', 'Disease', (10, 15))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (137, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('aggressive cancer', 'Disease', 'MESH:D009369', (63, 80))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (166, 184))	('cholangiocarcinoma', 'Disease', (166, 184))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (166, 184))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (137, 161))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('aggressive cancer', 'Disease', (63, 80))	('lung adenocarcinoma', 'Disease', (116, 135))	('hepatocellular carcinoma', 'Disease', (137, 161))
65619	33882870	In silico analysis of TACSTD2 methylation in the TCGA Kidney Renal Clear Cell Carcinoma (KIRC) dataset of 280 patients served as validation cohort.	('TACSTD2', 'Gene', '4070', (22, 29))	('TCGA Kidney Renal Clear Cell Carcinoma', 'Disease', 'MESH:C538614', (49, 87))	('methylation', 'Var', (30, 41))	('TCGA Kidney Renal Clear Cell Carcinoma', 'Disease', (49, 87))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('TACSTD2', 'Gene', (22, 29))	('patients', 'Species', '9606', (110, 118))	('Carcinoma', 'Phenotype', 'HP:0030731', (78, 87))
65622	33882870	TACSTD2 hypermethylation was associated with a shorter RFS of patients and demonstrate statistical independency from clinical parameters as state of metastasis, tumor stage, grade and state of advanced disease.	('tumor', 'Disease', (161, 166))	('shorter', 'NegReg', (47, 54))	('RFS', 'MPA', (55, 58))	('hypermethylation', 'Var', (8, 24))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('TACSTD2', 'Gene', '4070', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('patients', 'Species', '9606', (62, 70))	('TACSTD2', 'Gene', (0, 7))
65625	33882870	Our results suggest an association between TACSTD2 methylation and disease progression and clinical course of RCC.	('RCC', 'Disease', (110, 113))	('association', 'Interaction', (23, 34))	('TACSTD2', 'Gene', '4070', (43, 50))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('methylation', 'biological_process', 'GO:0032259', ('51', '62'))	('methylation', 'Var', (51, 62))	('TACSTD2', 'Gene', (43, 50))
65630	33882870	About 90% of sporadic ccRCC show mutation or loss of the Von Hippel-Lindau (VHL) gene function accompanied with subsequent activation of angiogenesis, cell migration and proliferation via the Hypoxia-inducible factor (HIF)-pathway.	('Hypoxia', 'Disease', (192, 199))	('VHL', 'Gene', (76, 79))	('RCC', 'Disease', (24, 27))	('HIF', 'Disease', 'None', (218, 221))	('mutation', 'Var', (33, 41))	('cell migration', 'CPA', (151, 165))	('VHL', 'Gene', '7428', (76, 79))	('proliferation', 'CPA', (170, 183))	('function', 'MPA', (86, 94))	('angiogenesis', 'CPA', (137, 149))	('cell migration', 'biological_process', 'GO:0016477', ('151', '165'))	('activation', 'PosReg', (123, 133))	('HIF', 'Disease', (218, 221))	('loss', 'NegReg', (45, 49))	('activation of angiogenesis', 'biological_process', 'GO:0045766', ('123', '149'))	('Hypoxia', 'Disease', 'MESH:D000860', (192, 199))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
65631	33882870	However, prospective use of gene mutations to enhanced diagnostic or personalized therapy approaches is uncertain as clinically aggressive cancers reveal an individual subset of gene mutations and individual mutation profiles for large part of tumors showed only comparatively weak associations with prognosis and prediction of ccRCC disease.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('mutations', 'Var', (183, 192))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('associations', 'Interaction', (282, 294))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('ccRCC disease', 'Disease', 'MESH:D003141', (328, 341))	('aggressive cancers', 'Disease', (128, 146))	('aggressive cancers', 'Disease', 'MESH:D009369', (128, 146))	('tumors', 'Disease', (244, 250))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('ccRCC disease', 'Disease', (328, 341))
65632	33882870	In contrast, several studies, including the work of our group, have identified a substantial number of hypermethylated genes in RCC which are moreover strongly associated with unfavorable histopathological characteristics and/or poor overall survival (OS).	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('hypermethylated genes', 'Var', (103, 124))	('RCC', 'Disease', (128, 131))	('associated with', 'Reg', (160, 175))
65633	33882870	So, we found hypermethylation of SFRP1, miR-124-3, GATA5, CRHBP, NELL1,TBR1 and NEFH in RCC and demonstrated statistically significant associations with adverse clinicopathology and clinical outcome.	('NELL1', 'Gene', '4745', (65, 70))	('miR-124-3', 'Gene', (40, 49))	('TBR1', 'Gene', '10716', (71, 75))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('SFRP1', 'Gene', '6422', (33, 38))	('RCC', 'Disease', (88, 91))	('GATA5', 'Gene', (51, 56))	('CRHBP', 'Gene', (58, 63))	('TBR1', 'Gene', (71, 75))	('NELL1', 'Gene', (65, 70))	('significant associations', 'Reg', (123, 147))	('GATA5', 'Gene', '140628', (51, 56))	('CRHBP', 'Gene', '1393', (58, 63))	('NEFH', 'Gene', '4744', (80, 84))	('hypermethylation', 'Var', (13, 29))	('NEFH', 'Gene', (80, 84))	('miR-124-3', 'Gene', '406909', (40, 49))	('SFRP1', 'Gene', (33, 38))
65644	33882870	Hypermethylation of TACSTD2 loci has been described in lung adenocarcinoma, HCC and cholangiocarcinoma.	('HCC', 'Gene', '619501', (76, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('described', 'Reg', (42, 51))	('TACSTD2', 'Gene', (20, 27))	('lung adenocarcinoma', 'Disease', (55, 74))	('Hypermethylation', 'Var', (0, 16))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (55, 74))	('cholangiocarcinoma', 'Disease', (84, 102))	('TACSTD2', 'Gene', '4070', (20, 27))	('HCC', 'Gene', (76, 79))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (55, 74))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
65645	33882870	Moreover, hypermethylation of TACSTD2 has been associated in all these tumor entities with subsequent epigenetic silencing and, in addition, coincided with adjacent organ invasion, poor differentiation and reduced OS.	('hypermethylation', 'Var', (10, 26))	('coincided', 'Reg', (141, 150))	('poor differentiation', 'CPA', (181, 201))	('TACSTD2', 'Gene', '4070', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('adjacent organ invasion', 'CPA', (156, 179))	('epigenetic silencing', 'MPA', (102, 122))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('TACSTD2', 'Gene', (30, 37))	('associated', 'Reg', (47, 57))	('tumor', 'Disease', (71, 76))	('reduced OS', 'CPA', (206, 216))
65647	33882870	Here, we investigated whether methylation of TACSTD2 gene loci in RCC associate with clinical parameters of tumor aggressiveness and recurrence free survival (RFS) of patients and identified hypermethylated TACSTD2 loci as a potential prognosticator for RCC.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('aggressiveness', 'Phenotype', 'HP:0000718', (114, 128))	('hypermethylated', 'Var', (191, 206))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('associate', 'Reg', (70, 79))	('TACSTD2', 'Gene', '4070', (207, 214))	('TACSTD2', 'Gene', (207, 214))	('tumor aggressiveness', 'Disease', (108, 128))	('patients', 'Species', '9606', (167, 175))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('TACSTD2', 'Gene', '4070', (45, 52))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (108, 128))	('RCC', 'Disease', (66, 69))	('RCC', 'Disease', 'MESH:C538614', (254, 257))	('TACSTD2', 'Gene', (45, 52))	('RCC', 'Disease', (254, 257))
65648	33882870	In silico analyses of the KIRC data indicated epigenetic silencing of TACSTD2 in RCC and confirmed an association of methylation of TACSTD2 with clinically aggressive subsets of ccRCC.	('association', 'Interaction', (102, 113))	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('RCC', 'Disease', (180, 183))	('methylation', 'MPA', (117, 128))	('TACSTD2', 'Gene', (132, 139))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('TACSTD2', 'Gene', '4070', (70, 77))	('RCC', 'Disease', (81, 84))	('epigenetic silencing', 'Var', (46, 66))	('TACSTD2', 'Gene', '4070', (132, 139))	('methylation', 'biological_process', 'GO:0032259', ('117', '128'))	('TACSTD2', 'Gene', (70, 77))
65673	33882870	Using an optimum cut point approximately corresponding to 0.1% relative methylation, patients with primary tumors exhibiting above cut point methylation demonstrated a significant faster disease progression (p = 0.005, logrank, Fig.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('methylation', 'biological_process', 'GO:0032259', ('72', '83'))	('tumors', 'Disease', (107, 113))	('disease progression', 'CPA', (187, 206))	('faster', 'PosReg', (180, 186))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('patients', 'Species', '9606', (85, 93))	('methylation', 'Var', (72, 83))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('methylation', 'Var', (141, 152))	('methylation', 'biological_process', 'GO:0032259', ('141', '152'))
65675	33882870	In view that a multivariate evaluation of the prognostic relevance of TACSTD2 methylation might be biased due to the limited size of subgroups, pairwise bivariate cox regressions were carried out as a methodical surrogate to define possible statistical dependencies on clinicopathological parameters.	('TACSTD2', 'Gene', '4070', (70, 77))	('TACSTD2', 'Gene', (70, 77))	('methylation', 'biological_process', 'GO:0032259', ('78', '89'))	('methylation', 'Var', (78, 89))
65676	33882870	Bivariate cox regression modelling considering state of metastasis, stage, grade and status of advanced disease as covariates revealed methylation as a significant variable indicating TACSTD2 methylation as an independent prognosticator (Table 3).	('methylation', 'Var', (135, 146))	('methylation', 'biological_process', 'GO:0032259', ('192', '203'))	('TACSTD2', 'Gene', (184, 191))	('TACSTD2', 'Gene', '4070', (184, 191))	('methylation', 'biological_process', 'GO:0032259', ('135', '146'))
65681	33882870	The results of in silico univariate cox regression survival analysis showed significant association of methylation of loci between the status of metastasis and survival of patients (Fig.	('survival', 'CPA', (160, 168))	('methylation', 'biological_process', 'GO:0032259', ('103', '114'))	('methylation', 'Var', (103, 114))	('patients', 'Species', '9606', (172, 180))
65687	33882870	So, DNA hypermethylation demonstrated statistically significant association with the presence of distant metastasis, one of the strongest prognosticators of RCC.	('significant', 'Reg', (52, 63))	('distant metastasis', 'CPA', (97, 115))	('hypermethylation', 'Var', (8, 24))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('4', '24'))	('DNA', 'Gene', (4, 7))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', (157, 160))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))	('association', 'Interaction', (64, 75))
65689	33882870	In line with a possible relevance of TACSTD2 methylation as a prognosticator for an unfavorable course of the disease we found that tumors showing increased methylation exhibit a significantly shorter period until tumor recurrence which, of interest, was likely independent from the strong prognosticators state of metastasis or advanced tumor classification.	('tumor', 'Disease', (338, 343))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('methylation', 'Var', (157, 168))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('shorter', 'NegReg', (193, 200))	('TACSTD2', 'Gene', '4070', (37, 44))	('increased', 'PosReg', (147, 156))	('methylation', 'biological_process', 'GO:0032259', ('157', '168'))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('tumor', 'Disease', (214, 219))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('TACSTD2', 'Gene', (37, 44))
65690	33882870	To gain additional and independent statistical evidence for the association between TACSTD2 DNA methylation and a worse clinical development of the disease we also carried out in silico analysis of the TCGA KIRC methylation data.	('DNA methylation', 'biological_process', 'GO:0006306', ('92', '107'))	('TACSTD2', 'Gene', '4070', (84, 91))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('methylation', 'biological_process', 'GO:0032259', ('212', '223'))	('TACSTD2', 'Gene', (84, 91))	('methylation', 'Var', (96, 107))	('men', 'Species', '9606', (136, 139))	('association', 'Interaction', (64, 75))
65692	33882870	Therefore, two independent cohorts each measured by a different methylation detection method, agree that TACSTD2 methylation is statistically associated with a clinically more aggressive phenotype of RCC.	('methylation', 'biological_process', 'GO:0032259', ('113', '124'))	('TACSTD2', 'Gene', '4070', (105, 112))	('RCC', 'Disease', (200, 203))	('methylation', 'Var', (113, 124))	('RCC', 'Disease', 'MESH:C538614', (200, 203))	('associated with', 'Reg', (142, 157))	('TACSTD2', 'Gene', (105, 112))	('methylation', 'biological_process', 'GO:0032259', ('64', '75'))
65693	33882870	In concordance with our analysis for RCC, an association of TACSTD2 hypermethylation and poor OS has been previously reported for patients suffering from aggressive HCC.	('poor', 'Disease', (89, 93))	('association', 'Interaction', (45, 56))	('TACSTD2', 'Gene', '4070', (60, 67))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('patients', 'Species', '9606', (130, 138))	('RCC', 'Disease', (37, 40))	('TACSTD2', 'Gene', (60, 67))	('aggressive HCC', 'Disease', 'MESH:D006528', (154, 168))	('hypermethylation', 'Var', (68, 84))	('aggressive HCC', 'Disease', (154, 168))
65694	33882870	Our in silico analysis showed a negative correlation of methylation and mRNA expression for all of the investigated 15 CpG sites thus indicating epigenetic silencing of TACSTD2 in RCC.	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('TACSTD2', 'Gene', (169, 176))	('RCC', 'Disease', (180, 183))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('methylation', 'MPA', (56, 67))	('epigenetic silencing', 'Var', (145, 165))	('mRNA expression', 'MPA', (72, 87))	('negative', 'NegReg', (32, 40))	('TACSTD2', 'Gene', '4070', (169, 176))
65695	33882870	Hypermethylation and concurrent loss of TACSTD2 mRNA expression as a potential mark for epigenetic silencing has already been demonstrated for a number of human malignancies such as cholangiocarcinoma, lung adenocarcinoma, malignant glioma and HCC.	('TACSTD2', 'Gene', '4070', (40, 47))	('Hypermethylation', 'Var', (0, 16))	('malignancies', 'Disease', (161, 173))	('malignant glioma', 'Disease', (223, 239))	('malignant glioma', 'Disease', 'MESH:D005910', (223, 239))	('lung adenocarcinoma', 'Disease', (202, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('TACSTD2', 'Gene', (40, 47))	('HCC', 'Gene', '619501', (244, 247))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (202, 221))	('glioma', 'Phenotype', 'HP:0009733', (233, 239))	('loss', 'NegReg', (32, 36))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (182, 200))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (202, 221))	('HCC', 'Gene', (244, 247))	('mRNA expression', 'MPA', (48, 63))	('cholangiocarcinoma', 'Disease', (182, 200))	('human', 'Species', '9606', (155, 160))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (182, 200))	('malignancies', 'Disease', 'MESH:D009369', (161, 173))
65705	33882870	miR-495 was previously described to suppress cell proliferation and migration in RCC and epigenetic regulation of miR-495 was linked to tumor suppression in breast cancer.	('tumor suppression in breast cancer', 'Disease', 'MESH:D001943', (136, 170))	('tumor suppression in breast cancer', 'Disease', (136, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('miR-495', 'Gene', (0, 7))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('suppress', 'NegReg', (36, 44))	('cell proliferation', 'CPA', (45, 63))	('cell proliferation', 'biological_process', 'GO:0008283', ('45', '63'))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('epigenetic regulation', 'Var', (89, 110))	('miR-495', 'Gene', (114, 121))	('miR-495', 'Gene', '574453', (0, 7))	('regulation', 'biological_process', 'GO:0065007', ('100', '110'))	('linked', 'Reg', (126, 132))	('miR-495', 'Gene', '574453', (114, 121))
65706	33882870	Moreover, post-transcriptional regulation of TACSTD2 expression by miR-125b as well as promotion of cell migration in RCC has been reported previously.	('cell migration', 'biological_process', 'GO:0016477', ('100', '114'))	('miR-125b', 'Var', (67, 75))	('promotion', 'PosReg', (87, 96))	('RCC', 'Disease', (118, 121))	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('cell migration', 'CPA', (100, 114))	('TACSTD2', 'Gene', '4070', (45, 52))	('miR-125b', 'Chemical', '-', (67, 75))	('TACSTD2', 'Gene', (45, 52))	('regulation', 'biological_process', 'GO:0065007', ('31', '41'))
65707	33882870	Also, functional in vitro and in vivo analyses for TACSTD2 in other human tumor entities like lung adenocarcinoma, HCC and cholangiocarcinoma, consistently demonstrated that silencing of TACSTD2 gene expression results in a significant increase of tumor growth and leads to cell proliferation and migration.	('cell proliferation', 'CPA', (274, 292))	('human', 'Species', '9606', (68, 73))	('TACSTD2', 'Gene', (51, 58))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (94, 113))	('cell proliferation', 'biological_process', 'GO:0008283', ('274', '292'))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (123, 141))	('tumor', 'Disease', (74, 79))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (94, 113))	('silencing', 'Var', (174, 183))	('tumor', 'Disease', (248, 253))	('cholangiocarcinoma', 'Disease', (123, 141))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (123, 141))	('increase', 'PosReg', (236, 244))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('TACSTD2', 'Gene', '4070', (187, 194))	('gene expression', 'biological_process', 'GO:0010467', ('195', '210'))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('TACSTD2', 'Gene', '4070', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('HCC', 'Gene', '619501', (115, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('lung adenocarcinoma', 'Disease', (94, 113))	('TACSTD2', 'Gene', (187, 194))	('leads to', 'Reg', (265, 273))	('HCC', 'Gene', (115, 118))
65710	33882870	Conclusively, a substantial number of epigenetic alterations were described in RCC in part showing statistically significant association with clinicopathological parameters of patients, but as yet no marker or marker-panel has been transferred into clinical routine.	('patients', 'Species', '9606', (176, 184))	('association', 'Reg', (125, 136))	('epigenetic alterations', 'Var', (38, 60))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
65711	33882870	Our analyses identify TACSTD2 DNA methylation as a new promising candidate marker associated with clinically aggressive RCC.	('TACSTD2', 'Gene', '4070', (22, 29))	('associated', 'Reg', (82, 92))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('methylation', 'Var', (34, 45))	('aggressive RCC', 'Disease', 'MESH:C538614', (109, 123))	('TACSTD2', 'Gene', (22, 29))	('aggressive RCC', 'Disease', (109, 123))	('DNA methylation', 'biological_process', 'GO:0006306', ('30', '45'))
65712	33882870	Our results suggest inclusion of TACSTD2 DNA methylation in corresponding future prospective biomarker candidate panel analyses and for detailed functional analysis in RCC.	('TACSTD2', 'Gene', '4070', (33, 40))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('methylation', 'Var', (45, 56))	('TACSTD2', 'Gene', (33, 40))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('RCC', 'Disease', (168, 171))	('DNA methylation', 'biological_process', 'GO:0006306', ('41', '56'))
65715	33882870	H.T., P.F.T, C.A.V.K and M.A.K.	('F.T', 'Disease', 'OMIM:102510', (8, 11))	('C.A.V.K', 'Var', (13, 20))	('F.T', 'Disease', (8, 11))
65772	31690270	Primary antibodies are anti-phospho-EGFR (#3777), anti-EGFR (#4267), anti-phospho-PDGFRbeta (#3161), anti-PDGFRbeta (#3169), anti-phospho-InsulinRbeta (#3024), anti-InsulinRbeta (#3025), anti-phospho-VEGFR2 (#2474), anti-VEGFR2 (#9698), anti-phospho-Met (#3077), anti-Met (#3148), anti-phospho-Akt (#4060), anti-phospho-Erk1/2 (#4370).	('#9698', 'Var', (229, 234))	('#2474', 'Var', (208, 213))	('Akt', 'Gene', '207', (294, 297))	('#3025', 'Var', (179, 184))	('#4370', 'Var', (328, 333))	('PDGFRbeta', 'Gene', (82, 91))	('#3148', 'Var', (273, 278))	('PDGFRbeta', 'Gene', (106, 115))	('VEGFR2', 'Gene', (200, 206))	('#3777', 'Var', (42, 47))	('Insulin', 'Gene', (138, 145))	('PDGFRbeta', 'Gene', '5159', (82, 91))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('VEGFR2', 'Gene', '3791', (200, 206))	('PDGFRbeta', 'Gene', '5159', (106, 115))	('#3024', 'Var', (152, 157))	('Insulin', 'Gene', '3630', (165, 172))	('#3169', 'Var', (117, 122))	('Met', 'Chemical', 'MESH:C034758', (268, 271))	('Met', 'Chemical', 'MESH:C034758', (250, 253))	('anti-Met (#3148', 'Var', (263, 278))	('#4060', 'Var', (299, 304))	('VEGFR2', 'Gene', (221, 227))	('Erk1', 'molecular_function', 'GO:0004707', ('320', '324'))	('Insulin', 'Gene', '3630', (138, 145))	('EGFR', 'molecular_function', 'GO:0005006', ('55', '59'))	('VEGFR2', 'Gene', '3791', (221, 227))	('Akt', 'Gene', (294, 297))	('#3077', 'Var', (255, 260))	('Insulin', 'Gene', (165, 172))
65782	31690270	After washed with PBS three times, the sections were incubated for 1 h at room temperature with Alexa Fluor 594-labeled donkey anti-rabbit IgG (A21207,1:400, Invitrogen), Alexa Fluor 488-labeled donkey anti-mouse IgG (A21202,1:400, Invitrogen) and Alexa Fluor 555-labeled rabbit anti-goat IgG (A21431,1:400, Invitrogen).	('A21431,1:400', 'Var', (294, 306))	('Alexa Fluor 488', 'Chemical', 'MESH:C504424', (171, 186))	('Alexa Fluor', 'Chemical', 'MESH:C569686', (171, 182))	('goat', 'Species', '9925', (284, 288))	('rabbit', 'Species', '9986', (132, 138))	('Alexa Fluor', 'Chemical', 'MESH:C569686', (96, 107))	('A21202,1:400', 'Var', (218, 230))	('Alexa Fluor', 'Chemical', 'MESH:C569686', (248, 259))	('rabbit', 'Species', '9986', (272, 278))	('donkey', 'Species', '9793', (195, 201))	('donkey', 'Species', '9793', (120, 126))	('mouse', 'Species', '10090', (207, 212))	('A21207,1:400', 'Var', (144, 156))
65799	31690270	The phosphorylation levels of Insulin Rbeta (Tyr1150/1151), PDGFRbeta (Tyr751), VEGFR2 (Tyr996), and HGFR (Met Tyr1234/1235) were found to be increased in the tumor tissues in comparison to the paired adjacent tissues (Fig.	('Tyr996', 'Var', (88, 94))	('increased', 'PosReg', (142, 151))	('Tyr1150/1151', 'Var', (45, 57))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('VEGFR2', 'Gene', '3791', (80, 86))	('Insulin', 'Gene', '3630', (30, 37))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('PDGFRbeta', 'Gene', '5159', (60, 69))	('Insulin', 'Gene', (30, 37))	('tumor', 'Disease', (159, 164))	('phosphorylation levels', 'MPA', (4, 26))	('Tyr751', 'Var', (71, 77))	('PDGFRbeta', 'Gene', (60, 69))	('VEGFR2', 'Gene', (80, 86))	('Insulin', 'molecular_function', 'GO:0016088', ('30', '37'))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('Met Tyr1234/1235', 'Chemical', 'MESH:C026545', (107, 123))
65843	31690270	More importantly, high PDGFRbeta expression in fibroblast-rich stroma is commonly associated with poor prognosis.	('PDGFRbeta', 'Gene', '5159', (23, 32))	('high', 'Var', (18, 22))	('PDGFRbeta', 'Gene', (23, 32))	('expression', 'MPA', (33, 43))
65870	32021266	Functional analyses demonstrated that siRNA silencing of UBE4B expression in SKRC39 and ACHN cells further reduced the growth, motility and invasiveness of RCC cells.	('UBE4B', 'Gene', (57, 62))	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('ACHN', 'Gene', '55323', (88, 92))	('RCC', 'Disease', 'MESH:D002292', (156, 159))	('RCC', 'Disease', (156, 159))	('reduced', 'NegReg', (107, 114))	('ACHN', 'Gene', (88, 92))	('silencing', 'Var', (44, 53))	('SKRC39', 'CellLine', 'CVCL:4021', (77, 83))	('growth', 'CPA', (119, 125))
65871	32021266	Moreover, siRNA silencing of UBE4B in the RCC cell lines did not induce apoptosis, and an increase in the cell population was observed during the G0/G1 phase of the cell cycle.	('RCC', 'Disease', 'MESH:D002292', (42, 45))	('increase', 'PosReg', (90, 98))	('cell population', 'CPA', (106, 121))	('cell cycle', 'biological_process', 'GO:0007049', ('165', '175'))	('apoptosis', 'biological_process', 'GO:0097194', ('72', '81'))	('silencing', 'Var', (16, 25))	('apoptosis', 'biological_process', 'GO:0006915', ('72', '81'))	('G1 phase', 'biological_process', 'GO:0051318', ('149', '157'))	('UBE4B', 'Gene', (29, 34))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))
65881	32021266	Ubiquitination is critical in cell functions such as proliferation, apoptosis, cell cycle regulation and DNA repair, and deregulation of certain types of protein that are involved in the tumorigenesis of many types of tumor.	('cell cycle', 'CPA', (79, 89))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('Ubiquitination', 'MPA', (0, 14))	('types of protein', 'Protein', (145, 161))	('DNA repair', 'biological_process', 'GO:0006281', ('105', '115'))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('deregulation', 'Var', (121, 133))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('79', '100'))	('tumor', 'Disease', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('apoptosis', 'biological_process', 'GO:0097194', ('68', '77'))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('tumor', 'Disease', (218, 223))	('apoptosis', 'biological_process', 'GO:0006915', ('68', '77'))
65883	32021266	Recent studies showed that UBE4B facilitated the polyubiquitination and degeneration of p53.	('UBE4B', 'Var', (27, 32))	('p53', 'Protein', (88, 91))	('polyubiquitination and degeneration', 'Disease', 'MESH:D009410', (49, 84))	('facilitated', 'PosReg', (33, 44))
65884	32021266	Moreover, UBE4B aberrant expression has been reported in several kinds of cancers, such as breast cancer, promyelocytic leukemia and nasopharyngeal carcinoma.	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (133, 157))	('nasopharyngeal carcinoma', 'Disease', 'MESH:C538339', (133, 157))	('promyelocytic leukemia', 'Disease', (106, 128))	('leukemia', 'Phenotype', 'HP:0001909', (120, 128))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('aberrant expression', 'Var', (16, 35))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('UBE4B', 'Gene', (10, 15))	('nasopharyngeal carcinoma', 'Disease', (133, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('promyelocytic leukemia', 'Disease', 'MESH:D015473', (106, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('breast cancer', 'Disease', (91, 104))	('reported', 'Reg', (45, 53))	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (106, 128))
65909	32021266	The sampled patients were divided into low UBE4B expression (UBE4B- or UBE4B+) or high UBE4B expression groups (UBE4B++ or UBE4B+++).	('UBE4B+++', 'Var', (123, 131))	('patients', 'Species', '9606', (12, 20))	('low UBE4B', 'Phenotype', 'HP:0045044', (39, 48))	('UBE4B++', 'Var', (112, 119))
65925	32021266	Moreover, the higher incidence of distant metastases was observed in the high UBE4B expression group (P=0.005), and none of other baseline features were related to UBE4B expression.	('metastases', 'Disease', 'MESH:D009362', (42, 52))	('expression', 'MPA', (84, 94))	('high', 'Var', (73, 77))	('metastases', 'Disease', (42, 52))	('UBE4B', 'Gene', (78, 83))
65927	32021266	Kaplan-Meier analyses indicated that worse OS was found in patients of the UBE4B high expression group (P<0.001, Figure 4A).	('high expression', 'Var', (81, 96))	('patients', 'Species', '9606', (59, 67))	('UBE4B', 'Gene', (75, 80))
65929	32021266	Multivariate Cox regression analyses showed that high UBE4B expression was an independent factor of poor outcome in RCC patients (P= 0.034, Table 3).	('expression', 'MPA', (60, 70))	('Cox', 'Gene', (13, 16))	('patients', 'Species', '9606', (120, 128))	('high', 'Var', (49, 53))	('RCC', 'Disease', 'MESH:D002292', (116, 119))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('UBE4B', 'Protein', (54, 59))	('RCC', 'Disease', (116, 119))	('Cox', 'Gene', '1351', (13, 16))
65936	32021266	These findings revealed that UBE4B may enhance the growth of RCC cells in vitro.	('growth', 'CPA', (51, 57))	('UBE4B', 'Var', (29, 34))	('RCC', 'Disease', 'MESH:D002292', (61, 64))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('enhance', 'PosReg', (39, 46))
65937	32021266	Apoptosis and cell cycle analyses were performed to examine whether the UBE4B knockdown-mediated inhibition of RCC cells growth is related to cell cycle arrest or an induction of apoptosis.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (142, 159))	('RCC', 'Disease', 'MESH:D002292', (111, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('inhibition', 'NegReg', (97, 107))	('arrest', 'Disease', 'MESH:D006323', (153, 159))	('cell cycle', 'biological_process', 'GO:0007049', ('14', '24'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('142', '159'))	('UBE4B', 'Gene', (72, 77))	('cell cycle', 'CPA', (142, 152))	('arrest', 'Disease', (153, 159))	('knockdown-mediated', 'Var', (78, 96))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('166', '188'))
65938	32021266	Results revealed that knockdown of UBE4B in SKRC39 and ACHN cells resulted in more percentages of cells in the G0/G1 phase and fewer percentages of cells in the S phase (P<0.05, Figure 6A and B), and no remarkable differences were found in the percentages of apoptotic cells between RCC cells transfected with siUBE4B and those transfected with siNC (both P>0.05, Figure 6C and D).	('ACHN', 'Gene', (55, 59))	('SKRC39', 'CellLine', 'CVCL:4021', (44, 50))	('G1 phase', 'biological_process', 'GO:0051318', ('114', '122'))	('more', 'PosReg', (78, 82))	('siUBE4B', 'Var', (310, 317))	('S phase', 'biological_process', 'GO:0051320', ('161', '168'))	('G0/G1 phase', 'CPA', (111, 122))	('S phase', 'CPA', (161, 168))	('RCC', 'Disease', (283, 286))	('UBE4B', 'Gene', (35, 40))	('knockdown', 'Var', (22, 31))	('SKRC39', 'Gene', (44, 50))	('RCC', 'Phenotype', 'HP:0005584', (283, 286))	('ACHN', 'Gene', '55323', (55, 59))	('RCC', 'Disease', 'MESH:D002292', (283, 286))	('cells', 'CPA', (98, 103))	('fewer', 'NegReg', (127, 132))
65941	32021266	Transwell assay displayed that the metastasis ability of ACHN and SKRC39 cells transfected with siUBE4B were significantly suppressed compared to controlled cells (all P<0.01, Figure 7A-D).	('ACHN', 'Gene', '55323', (57, 61))	('metastasis ability', 'CPA', (35, 53))	('SKRC39', 'CellLine', 'CVCL:4021', (66, 72))	('suppressed', 'NegReg', (123, 133))	('ACHN', 'Gene', (57, 61))	('siUBE4B', 'Var', (96, 103))
65948	32021266	This study revealed that high UBE4B expression may be related to a poor clinical outcome in RCC patients.	('expression', 'MPA', (36, 46))	('related', 'Reg', (54, 61))	('clinical', 'Species', '191496', (72, 80))	('RCC', 'Disease', (92, 95))	('high', 'Var', (25, 29))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('RCC', 'Disease', 'MESH:D002292', (92, 95))	('patients', 'Species', '9606', (96, 104))	('UBE4B', 'Protein', (30, 35))
65949	32021266	Similarly, our previous research had reported the relation between the magnifying expression of UBE4B and unfavorable prognosis in HCC.	('HCC', 'Disease', (131, 134))	('HCC', 'Phenotype', 'HP:0001402', (131, 134))	('UBE4B', 'Gene', (96, 101))	('magnifying expression', 'Var', (71, 92))	('HCC', 'Disease', 'MESH:D006528', (131, 134))
65958	32021266	Proliferation and colony formation assays confirmed that silencing of UBE4B suppressed RCC cells growth and motility.	('RCC', 'Disease', 'MESH:D002292', (87, 90))	('motility', 'CPA', (108, 116))	('RCC', 'Disease', (87, 90))	('silencing', 'Var', (57, 66))	('suppressed', 'NegReg', (76, 86))	('UBE4B', 'Gene', (70, 75))	('formation', 'biological_process', 'GO:0009058', ('25', '34'))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
65964	32021266	Many relative studies concur that the interaction between MDM2 and p53 is a primary mechanism for inhibition of the p53 function in cancers retaining wild-type p53, and they found that inhibiting the MDM2 expression could reactivate p53 function, triggering p53-dependent cell cycle arrest or apoptosis in tumor cells with functional p53.	('reactivate', 'NegReg', (222, 232))	('tumor', 'Disease', (306, 311))	('arrest', 'Disease', (283, 289))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (272, 289))	('apoptosis', 'CPA', (293, 302))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('MDM2', 'Gene', (200, 204))	('apoptosis', 'biological_process', 'GO:0097194', ('293', '302'))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('apoptosis', 'biological_process', 'GO:0006915', ('293', '302'))	('arrest', 'Disease', 'MESH:D006323', (283, 289))	('function', 'MPA', (237, 245))	('p53', 'Protein', (233, 236))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancers', 'Disease', (132, 139))	('inhibiting', 'Var', (185, 195))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('272', '289'))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('triggering', 'Reg', (247, 257))	('interaction', 'Interaction', (38, 49))
65965	32021266	Blocking the MDM2-p53 interaction to reactivate the p53 function has been recognized as a promising cancer therapeutic strategy, and a specific inhibitor of MDM2-p53 interaction is still under research.	('cancer', 'Disease', (100, 106))	('MDM2-p53', 'Protein', (13, 21))	('Blocking', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('p53 function', 'MPA', (52, 64))	('reactivate', 'MPA', (37, 47))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
65967	32021266	Wu et al founded that the reduction of UBE4B expression facilitated the ability of p53 to retard BJT fibroblasts in the G1 phase of the cell cycle, which was similar to our finding that lowering UBE4B expression in RCC cells blocked cell cycle progression.	('cell cycle progression', 'CPA', (233, 255))	('RCC', 'Disease', 'MESH:D002292', (215, 218))	('RCC', 'Disease', (215, 218))	('RCC', 'Phenotype', 'HP:0005584', (215, 218))	('reduction', 'NegReg', (26, 35))	('G1 phase', 'biological_process', 'GO:0051318', ('120', '128'))	('retard', 'NegReg', (90, 96))	('cell cycle', 'biological_process', 'GO:0007049', ('136', '146'))	('UBE4B', 'Gene', (39, 44))	('p53', 'Var', (83, 86))	('cell cycle', 'biological_process', 'GO:0007049', ('233', '243'))
65972	32021266	Apart from that, cellular function analysis indicated that inhibiting UBE4B expression could restrain RCC cell growth and motility ability, while inducing cell cycle arrest.	('inhibiting', 'Var', (59, 69))	('restrain', 'NegReg', (93, 101))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('155', '172'))	('arrest', 'Disease', 'MESH:D006323', (166, 172))	('UBE4B', 'Gene', (70, 75))	('inducing', 'Reg', (146, 154))	('RCC', 'Disease', (102, 105))	('expression', 'MPA', (76, 86))	('RCC', 'Disease', 'MESH:D002292', (102, 105))	('arrest', 'Disease', (166, 172))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('cell growth', 'biological_process', 'GO:0016049', ('106', '117'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (155, 172))
65996	29084770	The small-interfering RNAs (siRNAs) are considered promising anti-cancer compounds.	('RNAs', 'Protein', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('small-interfering', 'Var', (4, 21))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
66000	29084770	We found that siRNA-mediated silencing of BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (Bnip3), gelsolin (Gsn) and caveolin-1 (Cav1) diminished the growth and motility of mouse RCC (Renca) cells.	('BCL2/adenovirus E1B 19 kDa protein-interacting protein 3', 'Gene', '12176;12043', (42, 98))	('gelsolin', 'Gene', '227753', (108, 116))	('BCL2', 'molecular_function', 'GO:0015283', ('42', '46'))	('Bnip3', 'Gene', (100, 105))	('silencing', 'Var', (29, 38))	('mouse', 'Species', '10090', (183, 188))	('gelsolin', 'Gene', (108, 116))	('caveolin-1', 'Gene', '12389', (127, 137))	('diminished', 'NegReg', (145, 155))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('RCC', 'Disease', (189, 192))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))	('caveolin-1', 'Gene', (127, 137))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
66021	29084770	To assay whether siRNA-mediated gene silencing would have an impact on cell viability, the cells were stained with SYTOX Green nuclear acid dye, and the percentage of dead cells at 24 h after cell plating was illustrated.	('SYTOX Green nuclear acid', 'Chemical', '-', (115, 139))	('silencing', 'NegReg', (37, 46))	('gene silencing', 'biological_process', 'GO:0016458', ('32', '46'))	('gene', 'Var', (32, 36))	('cell viability', 'CPA', (71, 85))
66025	29084770	It turned out that transfection of the selected siRNAs, excluding Pax8 and Itgb2, significantly inhibited cell invasion across the filter compared to the controls (Fig.	('transfection', 'Var', (19, 31))	('Pax8', 'Gene', '18510', (66, 70))	('Itgb2', 'Gene', (75, 80))	('inhibited', 'NegReg', (96, 105))	('Pax8', 'Gene', (66, 70))	('cell invasion across the filter', 'CPA', (106, 137))
66026	29084770	Taken together, the data indicates that the siRNA-mediated silencing of Bnip3, Cav1, Gsn, Egfr and Lgals3 functions reduces the migratory and invasion capacity of RCC (Renca) cells, whereas silencing of the Pax8 or Itgb2 genes deregulates cell migration only.	('reduces', 'NegReg', (116, 123))	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('Lgals3', 'Gene', (99, 105))	('Egfr', 'Gene', (90, 94))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('Bnip3', 'Gene', (72, 77))	('Gsn', 'Gene', (85, 88))	('RCC', 'Disease', (163, 166))	('cell migration', 'biological_process', 'GO:0016477', ('239', '253'))	('Egfr', 'molecular_function', 'GO:0005006', ('90', '94'))	('Itgb2', 'Gene', (215, 220))	('Pax8', 'Gene', '18510', (207, 211))	('Cav1', 'Gene', (79, 83))	('Pax8', 'Gene', (207, 211))	('silencing', 'Var', (59, 68))
66031	29084770	Silencing of the Bnip3 function upregulated E-cadherin expression, but the mesenchymal marker analysis did not reveal any changes.	('Bnip3', 'Gene', (17, 22))	('E-cadherin', 'Gene', (44, 54))	('E-cadherin', 'Gene', '12550', (44, 54))	('expression', 'MPA', (55, 65))	('cadherin', 'molecular_function', 'GO:0008014', ('46', '54'))	('Silencing', 'Var', (0, 9))	('upregulated', 'PosReg', (32, 43))
66063	29084770	Loss of caveolae, as a result of mutations or gene expression changes in caveolins or cavins, results in the development of various diseases, including cancer.	('results in', 'Reg', (94, 104))	('cancer', 'Disease', (152, 158))	('caveolins', 'Gene', (73, 82))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('caveolae', 'cellular_component', 'GO:0005901', ('8', '16'))	('gene expression', 'biological_process', 'GO:0010467', ('46', '61'))	('caveolae', 'Protein', (8, 16))	('mutations', 'Var', (33, 42))	('Loss', 'NegReg', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('gene expression changes', 'Var', (46, 69))
66066	29084770	In the past 20 years, dysregulated Cav1 expression has consistently been detected in various cancers.	('expression', 'MPA', (40, 50))	('Cav1', 'Gene', (35, 39))	('cancers', 'Disease', (93, 100))	('detected', 'Reg', (73, 81))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('dysregulated', 'Var', (22, 34))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
66067	29084770	Still, there is no universal pattern linking Cav1 expression in cancer cells and patient outcomes: high Cav1 levels are associated with poor prognosis and aggressive disease in melanoma, breast, prostate and lung cancer, whereas, at the same time, high Cav1 expression is correlated with good clinical outcomes in head and neck cancer and extrahepatic biliary carcinoma cells.	('associated', 'Reg', (120, 130))	('aggressive disease', 'Disease', (155, 173))	('patient', 'Species', '9606', (81, 88))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('melanoma', 'Disease', (177, 185))	('cancer', 'Disease', (328, 334))	('aggressive disease', 'Disease', 'MESH:D001523', (155, 173))	('Cav1 levels', 'MPA', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('neck cancer', 'Disease', 'MESH:D006258', (323, 334))	('neck cancer', 'Disease', (323, 334))	('cancer', 'Disease', (64, 70))	('neck', 'cellular_component', 'GO:0044326', ('323', '327'))	('breast', 'Disease', (187, 193))	('lung cancer', 'Disease', 'MESH:D008175', (208, 219))	('head and neck cancer', 'Phenotype', 'HP:0012288', (314, 334))	('cancer', 'Disease', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (208, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('extrahepatic biliary carcinoma', 'Disease', (339, 369))	('melanoma', 'Disease', 'MESH:D008545', (177, 185))	('cancer', 'Disease', 'MESH:D009369', (328, 334))	('prostate', 'Disease', (195, 203))	('poor', 'Disease', (136, 140))	('extrahepatic biliary carcinoma', 'Disease', 'MESH:D001656', (339, 369))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('high', 'Var', (99, 103))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (360, 369))	('lung cancer', 'Disease', (208, 219))
66083	29084770	Depending on the cellular context, expression of Bnip3 either induces or delays cell death, and overexpression of Bnip3 has been reported in several types of cancer.	('cell death', 'biological_process', 'GO:0008219', ('80', '90'))	('Bnip3', 'Gene', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('induces', 'Reg', (62, 69))	('Bnip3', 'Gene', (114, 119))	('delays', 'NegReg', (73, 79))	('cancer', 'Disease', (158, 164))	('cell death', 'CPA', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('expression', 'Var', (35, 45))
66095	29084770	Thus, mutation of WT1 maintains progenitor characteristics of kidney cells.	('WT1', 'Gene', (18, 21))	('mutation', 'Var', (6, 14))	('WT1', 'Gene', '22431', (18, 21))	('progenitor characteristics of kidney cells', 'CPA', (32, 74))
66099	29084770	Interestingly, this model also provides a way to monitor how normal kidney cells influence cancer growth upon silencing of carcinogenesis-related genes.	('carcinogenesis', 'Disease', 'MESH:D063646', (123, 137))	('silencing', 'Var', (110, 119))	('cancer', 'Disease', (91, 97))	('influence', 'Reg', (81, 90))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('carcinogenesis', 'Disease', (123, 137))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
66135	31813279	MELK is Upregulated in Advanced Clear Cell Renal Cell Carcinoma and Promotes Disease Progression by Phosphorylating PRAS40 Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer.	('type of kidney cancer', 'Disease', (182, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('ccRCC', 'Phenotype', 'HP:0006770', (156, 161))	('Phosphorylating', 'Var', (100, 115))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (123, 154))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (43, 63))	('type of kidney cancer', 'Disease', 'MESH:D007680', (182, 203))	('PRAS40', 'Var', (116, 122))	('MELK', 'Gene', (0, 4))	('Advanced Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:D002292', (23, 63))	('Promotes', 'PosReg', (68, 76))	('ccRCC', 'Disease', 'MESH:D002292', (156, 161))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (32, 63))	('kidney cancer', 'Phenotype', 'HP:0009726', (190, 203))	('Advanced Clear Cell Renal Cell Carcinoma', 'Disease', (23, 63))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (123, 154))	('ccRCC', 'Disease', (156, 161))	('Clear cell renal cell carcinoma', 'Disease', (123, 154))	('MELK', 'Gene', '9833', (0, 4))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (134, 154))	('Carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('Upregulated', 'PosReg', (8, 19))
66145	31813279	Previous studies have shown that ccRCC is characterized by von Hippel-Lindau (VHL) inactivation, a governing event inducing transcription of hypoxia-inducible factors (HIF) target genes, including VEGF, EPO, GLUT-1 and EGFR, to accelerate ccRCC progression.	('ccRCC', 'Disease', (33, 38))	('VEGF', 'Gene', '7422', (197, 201))	('GLUT-1', 'Gene', '6513', (208, 214))	('ccRCC', 'Disease', (239, 244))	('EGFR', 'Gene', (219, 223))	('EGFR', 'molecular_function', 'GO:0005006', ('219', '223'))	('GLUT-1', 'Gene', (208, 214))	('VHL', 'Gene', (78, 81))	('VEGF', 'Gene', (197, 201))	('EPO', 'Gene', '2056', (203, 206))	('RCC', 'Phenotype', 'HP:0005584', (241, 244))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('EPO', 'Gene', (203, 206))	('ccRCC', 'Phenotype', 'HP:0006770', (239, 244))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('transcription', 'biological_process', 'GO:0006351', ('124', '137'))	('von Hippel-Lindau', 'Gene', (59, 76))	('inactivation', 'Var', (83, 95))	('transcription', 'MPA', (124, 137))	('VHL', 'Gene', '7428', (78, 81))	('hypoxia', 'Disease', (141, 148))	('accelerate', 'PosReg', (228, 238))	('EGFR', 'Gene', '1956', (219, 223))	('von Hippel-Lindau', 'Gene', '7428', (59, 76))	('hypoxia', 'Disease', 'MESH:D000860', (141, 148))	('ccRCC', 'Disease', 'MESH:D002292', (33, 38))	('ccRCC', 'Disease', 'MESH:D002292', (239, 244))
66146	31813279	Some studies have also reported that HIF-2 is implicated in angiogenesis and ccRCC metastasis, and obtaining PBRM1 or BAP1 mutation may set the process for ccRCC with different properties.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('PBRM1', 'Gene', (109, 114))	('mutation', 'Var', (123, 131))	('ccRCC', 'Disease', (156, 161))	('ccRCC', 'Phenotype', 'HP:0006770', (156, 161))	('ccRCC', 'Disease', 'MESH:D002292', (156, 161))	('ccRCC', 'Disease', (77, 82))	('PBRM1', 'Gene', '55193', (109, 114))	('ccRCC', 'Disease', 'MESH:D002292', (77, 82))	('BAP1', 'Gene', '8314', (118, 122))	('angiogenesis', 'biological_process', 'GO:0001525', ('60', '72'))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('BAP1', 'Gene', (118, 122))
66147	31813279	Metastatic ccRCC patients with truncated mutation of the PBRM1 gene gain more clinical benefits from immune checkpoint therapy.	('PBRM1', 'Gene', (57, 62))	('truncated mutation', 'Var', (31, 49))	('clinical benefits', 'CPA', (78, 95))	('PBRM1', 'Gene', '55193', (57, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (11, 16))	('ccRCC', 'Disease', (11, 16))	('patients', 'Species', '9606', (17, 25))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('gain', 'PosReg', (68, 72))	('ccRCC', 'Disease', 'MESH:D002292', (11, 16))
66148	31813279	Later research has validated that mutations in these genes were associated with advanced tumor stage.	('associated', 'Reg', (64, 74))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('mutations', 'Var', (34, 43))
66158	31813279	The RNA-seq data from GSE73731 consisted of 44 stage IV and 41 stage I ccRCC specimens from patients.	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('ccRCC', 'Disease', (71, 76))	('patients', 'Species', '9606', (92, 100))	('ccRCC', 'Disease', 'MESH:D002292', (71, 76))	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('GSE73731', 'Var', (22, 30))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
66160	31813279	We also used GEO2 R, a web tool applied to screen DEGs by comparing two groups of samples in a GEO series, to identify the DEGs between stage I and stage IV ccRCC samples in GSE73731.	('ccRCC', 'Phenotype', 'HP:0006770', (157, 162))	('ccRCC', 'Disease', (157, 162))	('ccRCC', 'Disease', 'MESH:D002292', (157, 162))	('GSE73731', 'Var', (174, 182))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))
66178	31813279	The primary antibodies were as follows: anti-MELK (ab108529), anti-alpha-tubulin (ab7291), and anti-mTOR (ab2732) from Abcam (Cambridge, UK); anti-4E-BP1 (#9644), anti-p-4E-BP1 (T37/46) (#2855), anti-S6 (#2317), anti-p-S6 (S235/236) (#4858), anti-p-PRAS40 (Thr246) (#13175), anti-p-PRAS40 (Ser183) (#5936), and anti-raptor (#2280) from Cell Signaling Technology (Danvers, MA, USA); and anti-Flag from Sigma (#3165, St Louis, MO, USA).	('4E-BP1', 'Gene', (170, 176))	('MELK', 'Gene', '9833', (45, 49))	('Thr246', 'Chemical', '-', (257, 263))	('#13175', 'Var', (266, 272))	('raptor', 'Gene', (316, 322))	('PRAS40', 'Gene', '84335', (249, 255))	('Ser', 'cellular_component', 'GO:0005790', ('290', '293'))	('PRAS40', 'Gene', (282, 288))	('Signaling', 'biological_process', 'GO:0023052', ('341', '350'))	('4E-BP1', 'Gene', '1978', (147, 153))	('#2280', 'Var', (324, 329))	('MELK', 'Gene', (45, 49))	('4E-BP1', 'Gene', (147, 153))	('4E-BP1', 'Gene', '1978', (170, 176))	('mTOR', 'Gene', (100, 104))	('raptor', 'Gene', '57521', (316, 322))	('PRAS40', 'Gene', (249, 255))	('PRAS40', 'Gene', '84335', (282, 288))	('mTOR', 'Gene', '2475', (100, 104))
66192	31813279	The successful over-expression and knock-down of MELK models were confirmed by western blot (Fig.	('knock-down', 'Var', (35, 45))	('MELK', 'Gene', (49, 53))	('MELK', 'Gene', '9833', (49, 53))
66194	31813279	3C), whereas knock-down of MELK in ACHN cells significantly reduced the viability (Fig.	('knock-down', 'Var', (13, 23))	('viability', 'CPA', (72, 81))	('reduced', 'NegReg', (60, 67))	('MELK', 'Gene', (27, 31))	('MELK', 'Gene', '9833', (27, 31))
66197	31813279	On the contrary, ACHN cells knocking-down MELK formed fewer colonies than shNC control cells (Fig.	('MELK', 'Gene', (42, 46))	('fewer', 'NegReg', (54, 59))	('MELK', 'Gene', '9833', (42, 46))	('knocking-down', 'Var', (28, 41))	('colonies', 'CPA', (60, 68))
66200	31813279	Knock-down of MELK in ACHN cells significantly inhibited migration (Fig.	('inhibited', 'NegReg', (47, 56))	('Knock-down', 'Var', (0, 10))	('migration', 'CPA', (57, 66))	('MELK', 'Gene', (14, 18))	('MELK', 'Gene', '9833', (14, 18))
66202	31813279	3K), whereas knock-down of MELK reduced levels of cyclin D1, cyclin A, N-Cadherin, and Vimentin, and increased levels of E-Cadherin compared with shNC control cells (Fig.	('levels', 'MPA', (111, 117))	('cyclin D1', 'Gene', '595', (50, 59))	('increased', 'PosReg', (101, 110))	('Cadherin', 'molecular_function', 'GO:0008014', ('123', '131'))	('Vimentin', 'Gene', '7431', (87, 95))	('cyclin A', 'Gene', '890', (61, 69))	('E-Cadherin', 'Gene', (121, 131))	('cyclin', 'molecular_function', 'GO:0016538', ('50', '56'))	('knock-down', 'Var', (13, 23))	('Vimentin', 'cellular_component', 'GO:0045098', ('87', '95'))	('Vimentin', 'Gene', (87, 95))	('cyclin A', 'Gene', (61, 69))	('reduced', 'NegReg', (32, 39))	('MELK', 'Gene', '9833', (27, 31))	('N-Cadherin', 'Gene', (71, 81))	('N-Cadherin', 'Gene', '1000', (71, 81))	('E-Cadherin', 'Gene', '999', (121, 131))	('cyclin D1', 'Gene', (50, 59))	('Vimentin', 'cellular_component', 'GO:0045099', ('87', '95'))	('MELK', 'Gene', (27, 31))	('Cadherin', 'molecular_function', 'GO:0008014', ('73', '81'))	('cyclin', 'molecular_function', 'GO:0016538', ('61', '67'))
66205	31813279	4A), the mTORC1 pathway was upregulated in the higher expression MELK group.	('mTORC1', 'Gene', (9, 15))	('mTORC1', 'cellular_component', 'GO:0031931', ('9', '15'))	('mTORC1', 'Gene', '382056', (9, 15))	('higher expression', 'Var', (47, 64))	('upregulated', 'PosReg', (28, 39))	('MELK', 'Gene', (65, 69))	('MELK', 'Gene', '9833', (65, 69))
66211	31813279	Conversely, knock-down of MELK in ACHN cells inhibited the activity of the mTORC1 pathway (Fig.	('activity', 'MPA', (59, 67))	('mTORC1', 'cellular_component', 'GO:0031931', ('75', '81'))	('MELK', 'Gene', (26, 30))	('mTORC1', 'Gene', (75, 81))	('MELK', 'Gene', '9833', (26, 30))	('mTORC1', 'Gene', '382056', (75, 81))	('inhibited', 'NegReg', (45, 54))	('knock-down', 'Var', (12, 22))
66213	31813279	4F, the rise in P-S6K1 and P-4EBP1 and the increase in the ratio of P-S6K1 to S6K1 mediated by MELK were significantly eliminated when we blocked the mTORC1 pathway with 100 nM rapamycin, a specific mTOR inhibitor.	('S6K1', 'Gene', (78, 82))	('mTOR', 'Gene', (199, 203))	('mTORC1', 'Gene', '382056', (150, 156))	('mTORC1', 'cellular_component', 'GO:0031931', ('150', '156'))	('rapamycin', 'Chemical', 'MESH:D020123', (177, 186))	('MELK', 'Gene', '9833', (95, 99))	('eliminated', 'NegReg', (119, 129))	('P-4EBP1', 'Var', (27, 34))	('MELK', 'Gene', (95, 99))	('S6K1', 'Gene', (18, 22))	('mTORC1', 'Gene', (150, 156))	('S6K1', 'Gene', '6198', (18, 22))	('S6K1', 'Gene', (70, 74))	('S6K1', 'Gene', '6198', (70, 74))	('mTOR', 'Gene', '2475', (150, 154))	('S6K1', 'Gene', '6198', (78, 82))	('mTOR', 'Gene', (150, 154))	('mTOR', 'Gene', '2475', (199, 203))
66219	31813279	We initially used western blot to evaluate levels of phosphorylating PRAS40, mTOR, and raptor in 769-P cells over-expressing MELK and ACHN cells knocking-down MELK.	('raptor', 'Gene', (87, 93))	('MELK', 'Gene', (159, 163))	('knocking-down', 'Var', (145, 158))	('raptor', 'Gene', '57521', (87, 93))	('mTOR', 'Gene', '2475', (77, 81))	('MELK', 'Gene', (125, 129))	('mTOR', 'Gene', (77, 81))	('PRAS40', 'Gene', '84335', (69, 75))	('PRAS40', 'Gene', (69, 75))	('MELK', 'Gene', '9833', (125, 129))	('MELK', 'Gene', '9833', (159, 163))
66221	31813279	In addition, over-expressing or knock-down of MELK had no effect on levels of mTOR, raptor, and p-PRAS40 (S183).	('MELK', 'Gene', '9833', (46, 50))	('raptor', 'Gene', (84, 90))	('PRAS40', 'Gene', '84335', (98, 104))	('over-expressing', 'PosReg', (13, 28))	('raptor', 'Gene', '57521', (84, 90))	('PRAS40', 'Gene', (98, 104))	('mTOR', 'Gene', (78, 82))	('mTOR', 'Gene', '2475', (78, 82))	('levels', 'MPA', (68, 74))	('knock-down', 'Var', (32, 42))	('MELK', 'Gene', (46, 50))
66249	31813279	reported that phosphorylation at Thr246 is sufficient to release PRAS40 from mTORC1, both in vitro and in vivo .	('phosphorylation', 'Var', (14, 29))	('Thr246', 'Chemical', '-', (33, 39))	('mTORC1', 'Gene', (77, 83))	('mTORC1', 'cellular_component', 'GO:0031931', ('77', '83'))	('release', 'MPA', (57, 64))	('phosphorylation', 'biological_process', 'GO:0016310', ('14', '29'))	('PRAS40', 'Gene', '84335', (65, 71))	('PRAS40', 'Gene', (65, 71))	('mTORC1', 'Gene', '382056', (77, 83))
66250	31813279	found that dissociation of PRAS40 from mTORC1 requires simultaneous phosphorylation of PRAS40 on T246 by Akt, and on S183 by mTOR itself.	('Akt', 'Gene', '207', (105, 108))	('mTOR', 'Gene', '2475', (125, 129))	('mTORC1', 'Gene', (39, 45))	('phosphorylation', 'MPA', (68, 83))	('mTOR', 'Gene', (125, 129))	('mTORC1', 'cellular_component', 'GO:0031931', ('39', '45'))	('Akt', 'Gene', (105, 108))	('mTOR', 'Gene', (39, 43))	('PRAS40', 'Gene', '84335', (27, 33))	('PRAS40', 'Gene', (27, 33))	('mTOR', 'Gene', '2475', (39, 43))	('S183', 'Var', (117, 121))	('T246', 'Var', (97, 101))	('mTORC1', 'Gene', '382056', (39, 45))	('phosphorylation', 'biological_process', 'GO:0016310', ('68', '83'))	('PRAS40', 'Gene', '84335', (87, 93))	('PRAS40', 'Gene', (87, 93))
66251	31813279	In our study, we observed that over-expression of MELK only increased the PRAS40 phosphorylation at Thr246, not at S183.	('MELK', 'Gene', (50, 54))	('PRAS40', 'Gene', '84335', (74, 80))	('Thr246', 'Var', (100, 106))	('MELK', 'Gene', '9833', (50, 54))	('over-expression', 'PosReg', (31, 46))	('PRAS40', 'Gene', (74, 80))	('Thr246', 'Chemical', '-', (100, 106))	('phosphorylation', 'biological_process', 'GO:0016310', ('81', '96'))	('increased', 'PosReg', (60, 69))
66252	31813279	Knock-down of MELK decreased the PRAS40 phosphorylation at Thr246 and had no effect on S183.	('PRAS40', 'Gene', (33, 39))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('Knock-down', 'Var', (0, 10))	('MELK', 'Gene', '9833', (14, 18))	('MELK', 'Gene', (14, 18))	('decreased', 'NegReg', (19, 28))	('Thr246', 'Chemical', '-', (59, 65))	('PRAS40', 'Gene', '84335', (33, 39))
66253	31813279	More importantly, we confirmed that over-expression of MELK:that is, phosphorylating PRAS40 at Thr246:could disrupt the interaction between PRAS40 and raptor whereas knock-down of MELK could not.	('raptor', 'Gene', '57521', (151, 157))	('interaction', 'Interaction', (120, 131))	('PRAS40', 'Gene', '84335', (85, 91))	('MELK', 'Gene', '9833', (180, 184))	('PRAS40', 'Gene', '84335', (140, 146))	('PRAS40', 'Gene', (140, 146))	('disrupt', 'NegReg', (108, 115))	('PRAS40', 'Gene', (85, 91))	('Thr246', 'Chemical', '-', (95, 101))	('Thr246', 'Var', (95, 101))	('MELK', 'Gene', '9833', (55, 59))	('MELK', 'Gene', (55, 59))	('raptor', 'Gene', (151, 157))	('MELK', 'Gene', (180, 184))
66257	30642274	DNA methylation associates with survival in non-metastatic clear cell renal cell carcinoma Clear cell renal cell carcinoma (ccRCC) is the most common subtype among renal cancer and is associated with poor prognosis if metastasized.	('renal cell carcinoma', 'Disease', (70, 90))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (70, 90))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (91, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('renal cancer', 'Disease', (164, 176))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (59, 90))	('renal cancer', 'Phenotype', 'HP:0009726', (164, 176))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (102, 122))	('associates with', 'Reg', (16, 31))	('DNA', 'Gene', (0, 3))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (70, 90))	('renal cancer', 'Disease', 'MESH:D007680', (164, 176))	('methylation', 'Var', (4, 15))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (91, 122))	('Clear cell renal cell carcinoma', 'Disease', (91, 122))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (102, 122))	('RCC', 'Disease', (126, 129))
66274	30642274	Loss of chromosome 3p and inactivation of the VHL (von Hippel-Lindau) gene are frequently observed.	('VHL', 'Gene', (46, 49))	('inactivation', 'Var', (26, 38))	('VHL', 'Gene', '7428', (46, 49))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('von Hippel-Lindau', 'Gene', (51, 68))	('Loss', 'NegReg', (0, 4))	('von Hippel-Lindau', 'Gene', '7428', (51, 68))
66278	30642274	DNA methylation on Cytosine-phosphate-Guanine (CpG) sites in promoter regions may alter the affinity of transcription factors for their binding sites, and may also, in combination with chromatin modifications, contribute to silencing of genomic regions.	('DNA methylation on Cytosine', 'biological_process', 'GO:0032776', ('0', '27'))	('transcription', 'Protein', (104, 117))	('silencing', 'MPA', (224, 233))	('alter', 'Reg', (82, 87))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('chromatin', 'cellular_component', 'GO:0000785', ('185', '194'))	('methylation', 'Var', (4, 15))	('affinity', 'Interaction', (92, 100))	('binding', 'molecular_function', 'GO:0005488', ('136', '143'))	('genomic', 'Protein', (237, 244))	('binding sites', 'Interaction', (136, 149))	('Cytosine-phosphate-Guanine', 'Chemical', '-', (19, 45))	('transcription', 'biological_process', 'GO:0006351', ('104', '117'))	('contribute to', 'Reg', (210, 223))
66279	30642274	Altered DNA methylation has been identified as a prognostic marker, as well as a potential target for therapy, in several malignancies.	('malignancies', 'Disease', 'MESH:D009369', (122, 134))	('malignancies', 'Disease', (122, 134))	('DNA', 'Protein', (8, 11))	('Altered', 'Var', (0, 7))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('methylation', 'Var', (12, 23))	('DNA methylation', 'biological_process', 'GO:0006306', ('8', '23'))
66280	30642274	De novo methylated CpGs in ccRCC assumed to be of relevance for RCC tumorigenesis have been identified, but their clinical value requires further validation.	('tumor', 'Disease', (68, 73))	('CpGs', 'Chemical', '-', (19, 23))	('RCC', 'Disease', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('methylated', 'Var', (8, 18))
66283	30642274	We have previously shown that genome-wide promotor methylation status can predict survival in ccRCC.	('RCC', 'Disease', (96, 99))	('methylation', 'biological_process', 'GO:0032259', ('51', '62'))	('predict', 'Reg', (74, 81))	('methylation', 'Var', (51, 62))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
66309	30642274	Hypermethylated CpGs showed increased methylation compared to TF whereas hypomethylated CpGs were less methylated.	('methylation', 'MPA', (38, 49))	('increased', 'PosReg', (28, 37))	('CpGs', 'Chemical', '-', (88, 92))	('CpGs', 'Chemical', '-', (16, 20))	('Hypermethylated', 'Var', (0, 15))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))
66314	30642274	The distribution of hyper- and hypomethylated CpGs within twelve genomic regions with frequent gain/loss in ccRCC (as defined by Kohn et al.	('RCC', 'Disease', (110, 113))	('hypomethylated', 'Var', (31, 45))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('hyper-', 'Var', (20, 26))	('gain/loss', 'PosReg', (95, 104))	('gain/loss', 'NegReg', (95, 104))	('CpGs', 'Chemical', '-', (46, 50))
66315	30642274	2014 and listed in Additional file 2: Table S3) was analysed to identify potential overrepresentation of hyper- and/or hypomethylated CpGs within these regions.	('hypomethylated', 'Var', (119, 133))	('hyper-', 'Var', (105, 111))	('CpGs', 'Chemical', '-', (134, 138))
66324	30642274	Gene expression levels of the MX2 (ILMN_2231928), SMAD6 (ILMN_1767068) and SOCS3 (ILMN_1781001) genes were extracted from the arrays.	('SMAD6', 'Gene', '4091', (50, 55))	('SOCS3', 'Gene', (75, 80))	('SMAD6', 'Gene', (50, 55))	('MX2', 'Gene', (30, 33))	('MX2', 'Gene', '4600', (30, 33))	('SOCS3', 'Gene', '9021', (75, 80))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('ILMN_2231928', 'Var', (35, 47))
66336	30642274	Cancer specific survival (pCSS) analysis confirmed the prognostic relevance of methylation cluster classification in ccRCC (pCSS5yr 80% for cluster A vs 27% for cluster B, p < 0.001) (Fig.	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('methylation', 'Var', (79, 90))	('RCC', 'Disease', (119, 122))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('methylation', 'biological_process', 'GO:0032259', ('79', '90'))
66350	30642274	The most common genetic aberration in ccRCC is loss of chromosome 3p (including the VHL gene).	('VHL', 'Gene', (84, 87))	('VHL', 'Gene', '7428', (84, 87))	('RCC', 'Disease', (40, 43))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('loss', 'Var', (47, 51))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))
66351	30642274	In our cohort, 84% of the ccRCCs showed a loss of 3p, and deletions were similarly distributed in clusters A and B (Fig.	('deletions', 'Var', (58, 67))	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('RCC', 'Disease', (28, 31))	('loss', 'NegReg', (42, 46))
66352	30642274	The chromosomal distribution of hyper- and hypomethylated CpGs was analysed in relation to the genomic aberrations in the 12 previously defined regions (Additional file 2: Table S3 and Additional file 6: Figure S4).	('hypomethylated', 'Var', (43, 57))	('CpGs', 'Chemical', '-', (58, 62))	('CpGs', 'Gene', (58, 62))
66353	30642274	Although genetic aberrations on chromosome 7p and 9q were associated with overrepresentation of hyper- and/or hypomethylated CpGs, there were no general enrichment of DM-CpGs within genomic regions harboring aberrations (Additional file 6: Figure S4).	('genetic aberrations', 'Disease', (9, 28))	('hypomethylated', 'Var', (110, 124))	('DM-CpGs', 'Chemical', '-', (167, 174))	('overrepresentation', 'PosReg', (74, 92))	('genetic aberrations', 'Disease', 'MESH:D030342', (9, 28))	('CpGs', 'Chemical', '-', (125, 129))	('CpGs', 'Chemical', '-', (170, 174))	('chromosome', 'cellular_component', 'GO:0005694', ('32', '42'))
66354	30642274	Importantly, loss of 3p which is frequently observed in ccRCC was not associated with significant accumulation of neither hyper- nor hypomethylated CpGs (Additional file 6: Figure S4).	('loss', 'Var', (13, 17))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('RCC', 'Disease', (58, 61))	('CpGs', 'Chemical', '-', (148, 152))
66357	30642274	The only genetic aberration that was more frequent in the M0-P compared to M0-PF patients, was the loss of 9q (43% vs. 20%, p = 0.031), which was even more frequent in the M1 patients (61%) (Table 2).	('M0-P', 'Var', (58, 62))	('patients', 'Species', '9606', (175, 183))	('loss of 9q', 'Var', (99, 109))	('patients', 'Species', '9606', (81, 89))
66360	30642274	The number of genetic aberrations were positively correlated to number of hypermethylated CpGs (p < 0.001), but not to the number of hypomethylated CpGs in promoters (Fig.	('genetic aberrations', 'Disease', 'MESH:D030342', (14, 33))	('hypermethylated', 'Var', (74, 89))	('CpGs', 'Chemical', '-', (148, 152))	('genetic aberrations', 'Disease', (14, 33))	('CpGs', 'Chemical', '-', (90, 94))
66361	30642274	The number of genetic aberrations and number of hypermethylated CpGs were both strongly positively associated with estimated mitotic age (R = 0.407, and R = 0.641, respectively, p < 0.001) (Fig.	('CpGs', 'Chemical', '-', (64, 68))	('genetic aberrations', 'Disease', 'MESH:D030342', (14, 33))	('genetic aberrations', 'Disease', (14, 33))	('CpGs', 'Gene', (64, 68))	('hypermethylated', 'Var', (48, 63))	('associated', 'Reg', (99, 109))
66364	30642274	M0-PF, M0-P and M1 patients showed gradually larger median tumor diameter (p < 0.001), higher TNM stage (p < 0.001), higher morphological grade (p < 0.001), increased number of hypermethylated CpGs (p = 0.015), higher mitotic age (p = 0.047), and a higher correlation to cluster B status (p < 0.001) (Table 2).	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('higher', 'PosReg', (117, 123))	('higher', 'PosReg', (87, 93))	('hypermethylated CpGs', 'CPA', (177, 197))	('morphological grade', 'CPA', (124, 143))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('larger', 'PosReg', (45, 51))	('M0-P', 'Var', (7, 11))	('mitotic age', 'CPA', (218, 229))	('patients', 'Species', '9606', (19, 27))	('higher', 'PosReg', (211, 217))	('M0-PF', 'Var', (0, 5))	('higher', 'Reg', (249, 255))	('correlation', 'Interaction', (256, 267))	('CpGs', 'Chemical', '-', (193, 197))	('TNM', 'Gene', '10178', (94, 97))	('increased', 'PosReg', (157, 166))	('TNM', 'Gene', (94, 97))
66372	30642274	Large inter-individual variations in the number of hyper/hypomethylated DM-CpGs was observed in the tumor samples (Fig.	('DM-CpGs', 'Gene', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('hyper/hypomethylated', 'Var', (51, 71))	('DM-CpGs', 'Chemical', '-', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
66378	30642274	DNA methylation alterations have been described as early events in tumor progression.	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('alterations', 'Var', (16, 27))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('methylation alterations', 'Var', (4, 27))
66380	30642274	CpGs that showed either hyper- or hypomethylation in at least 70% of samples in the M0-PF, M0-P and M1 groups of patients were selected and combined in a Venn diagram (Fig.	('hyper-', 'Var', (24, 30))	('patients', 'Species', '9606', (113, 121))	('CpGs', 'Chemical', '-', (0, 4))	('hypomethylation', 'Var', (34, 49))
66388	30642274	The prognostic relevance of PMC was confirmed in 230 ccRCC tumor samples from the TCGA-KIRC data set (PMC low (n = 144) pCIP5yr 16% vs. PMC high (n = 86) pCIP5yr 39%, p < 0.001; Fig.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('tumor', 'Disease', (59, 64))	('CIP', 'Disease', (155, 158))	('CIP', 'Disease', (121, 124))	('CIP', 'Disease', 'MESH:D010259', (155, 158))	('low', 'Var', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('CIP', 'Disease', 'MESH:D010259', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
66391	30642274	SMAD family member 6 (SMAD6, CpG cg10402698 and cg12476188), Suppressor of cytokine signaling 3 (SOCS3, CpG cg10279487 and cg27637521) and MX dynamin like GTPase 2 (MX2, CpG cg05656374 and cg15281283).	('Suppressor of cytokine signaling 3', 'Gene', (61, 95))	('SMAD6', 'Gene', '4091', (22, 27))	('cg15281283', 'Var', (189, 199))	('MX2', 'Gene', '4600', (165, 168))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('SMAD', 'Gene', '4091', (22, 26))	('SMAD6', 'Gene', (22, 27))	('SOCS3', 'Gene', '9021', (97, 102))	('SMAD', 'Gene', (22, 26))	('SMAD', 'Gene', '4091', (0, 4))	('cg10279487', 'Var', (108, 118))	('cg10402698', 'Var', (33, 43))	('SMAD', 'Gene', (0, 4))	('MX2', 'Gene', (165, 168))	('Suppressor of cytokine signaling 3', 'Gene', '9021', (61, 95))	('SOCS3', 'Gene', (97, 102))	('cg12476188', 'Var', (48, 58))	('cg27637521', 'Var', (123, 133))
66392	30642274	A significant increased gene expression was observed in M0-P and M1 samples compared to M0-PF samples in the SOCS3 (ILMN_1781001; p = 0.019 and 0.001) and MX2 (ILMN_2231928; p = 0.014 and 0.002) genes, whereas no significant difference in expression for SMAD6 (ILMN_1767068) was seen (Fig.	('increased', 'PosReg', (14, 23))	('gene expression', 'biological_process', 'GO:0010467', ('24', '39'))	('M0-P', 'Var', (56, 60))	('MX2', 'Gene', '4600', (155, 158))	('SOCS3', 'Gene', (109, 114))	('SMAD6', 'Gene', '4091', (254, 259))	('SMAD6', 'Gene', (254, 259))	('gene expression', 'MPA', (24, 39))	('SOCS3', 'Gene', '9021', (109, 114))	('MX2', 'Gene', (155, 158))
66409	30642274	There was a significantly higher frequency of deletions of 9p, 9q and 14q in cluster B tumors, and these three genetic aberrations have been associated with poorer outcome in ccRCC.	('genetic aberrations', 'Disease', (111, 130))	('cluster B tumors', 'Disease', (77, 93))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('RCC', 'Disease', (177, 180))	('cluster B tumors', 'Disease', 'MESH:D006509', (77, 93))	('genetic aberrations', 'Disease', 'MESH:D030342', (111, 130))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('associated', 'Reg', (141, 151))	('deletions', 'Var', (46, 55))
66411	30642274	Loss of chromosome 9q was the only genetic aberration that was more common in M0-P (and M1) patients compared to M0-PF patients.	('M0-P', 'Disease', (78, 82))	('patients', 'Species', '9606', (119, 127))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('patients', 'Species', '9606', (92, 100))	('M1', 'Var', (88, 90))	('Loss', 'Var', (0, 4))
66412	30642274	Previous studies have shown significant correlation of loss of chromosome 9q to both histological grade and TNM stage as well as to poor outcome.	('loss', 'Var', (55, 59))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('TNM', 'Gene', (108, 111))	('TNM', 'Gene', '10178', (108, 111))
66417	30642274	Correlation between genetic and epigenetic alterations was shown previously in both chronic lymphatic leukemia and in breast cancer cell lines, but less is known about correlations with mitotic age.	('chronic lymphatic leukemia', 'Disease', 'MESH:D015451', (84, 110))	('epigenetic alterations', 'Var', (32, 54))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('leukemia', 'Phenotype', 'HP:0001909', (102, 110))	('genetic', 'Var', (20, 27))	('chronic lymphatic leukemia', 'Disease', (84, 110))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('chronic lymphatic leukemia', 'Phenotype', 'HP:0005550', (84, 110))	('lymphatic leukemia', 'Phenotype', 'HP:0005526', (92, 110))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
66428	30642274	These findings indicate a functional relevance of the methylation alterations in ccRCC pathogenesis but needs to be confirmed in larger samples cohorts.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('methylation alterations', 'Var', (54, 77))	('pathogenesis', 'biological_process', 'GO:0009405', ('87', '99'))
66433	30642274	Genome-wide promoter-associated DNA methylation associated significantly with genetic aberrations, cellular mitotic age, and clinical parameters, including follow up status.	('associated', 'Reg', (48, 58))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('cellular mitotic age', 'CPA', (99, 119))	('genetic aberrations', 'Disease', (78, 97))	('DNA methylation', 'biological_process', 'GO:0006306', ('32', '47'))	('genetic aberrations', 'Disease', 'MESH:D030342', (78, 97))	('methylation', 'Var', (36, 47))
66436	30642274	DNA methylation status has the potential to identify non-metastatic patients with high risk of recurrence already at diagnosis.	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('methylation', 'Var', (4, 15))	('patients', 'Species', '9606', (68, 76))	('non-metastatic', 'Disease', (53, 67))
66453	30372395	This review will explore the major sources of metabolic impact in kidney tumors, through the classical biochemistry of cellular metabolism: highlighting features associated with the pseudohypoxia associated with clear cell renal cell carcinoma (ccRCC), disturbances of glucose regulation and glycolysis, factors influencing the Kreb's cycle in papillary renal cell carcinoma (pRCC), factors that fuel reductive carboxylation, and mitochondrial defects resulting from mutations in electron transport genes occurring in chromophobe renal cell carcinoma (chRCC).	('glucose', 'Chemical', 'MESH:D005947', (269, 276))	('papillary renal cell carcinoma', 'Disease', (344, 374))	('RCC', 'Disease', 'MESH:C538614', (554, 557))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (354, 374))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (530, 550))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (212, 243))	('pRCC', 'Phenotype', 'HP:0006766', (376, 380))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('kidney tumors', 'Disease', (66, 79))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (518, 550))	('carcinoma', 'Phenotype', 'HP:0030731', (541, 550))	('RCC', 'Disease', (377, 380))	('RCC', 'Phenotype', 'HP:0005584', (377, 380))	('pRCC', 'Gene', (376, 380))	('carcinoma', 'Phenotype', 'HP:0030731', (365, 374))	('cellular metabolism', 'biological_process', 'GO:0044237', ('119', '138'))	('regulation', 'biological_process', 'GO:0065007', ('277', '287'))	('kidney tumors', 'Disease', 'MESH:D007680', (66, 79))	('RCC', 'Phenotype', 'HP:0005584', (247, 250))	('RCC', 'Disease', 'MESH:C538614', (377, 380))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (344, 374))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (212, 243))	('RCC', 'Disease', (247, 250))	('mutations', 'Var', (467, 476))	('ccRCC', 'Phenotype', 'HP:0006770', (245, 250))	('electron transport genes', 'Gene', (480, 504))	('chromophobe renal cell carcinoma', 'Disease', (518, 550))	('hypoxia', 'Disease', (188, 195))	('mitochondrial defects', 'Disease', (430, 451))	('mitochondrial defects', 'Disease', 'MESH:D028361', (430, 451))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (344, 374))	('RCC', 'Disease', 'MESH:C538614', (247, 250))	('kidney tumors', 'Phenotype', 'HP:0009726', (66, 79))	('clear cell renal cell carcinoma', 'Disease', (212, 243))	('electron transport', 'biological_process', 'GO:0006118', ('480', '498'))	('RCC', 'Disease', (554, 557))	('RCC', 'Phenotype', 'HP:0005584', (554, 557))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (223, 243))	('glycolysis', 'biological_process', 'GO:0006096', ('292', '302'))	('pRCC', 'Gene', '5546', (376, 380))	('hypoxia', 'Disease', 'MESH:D000860', (188, 195))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))
66467	30372395	It is impossible to consider metabolism without examining the quintessential phenotype of ccRCC; dysregulation of hypoxia signaling via mutations in the VHL gene.	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('VHL', 'Gene', (153, 156))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('metabolism', 'biological_process', 'GO:0008152', ('29', '39'))	('mutations', 'Var', (136, 145))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('hypoxia', 'Disease', (114, 121))	('hypoxia', 'Disease', 'MESH:D000860', (114, 121))	('dysregulation', 'MPA', (97, 110))
66468	30372395	VHL is a key mediator of oxygen sensing, and absence or alteration of this protein is associated with stabilization of hypoxia inducible factor (HIF) family members.	('hypoxia', 'Disease', 'MESH:D000860', (119, 126))	('stabilization', 'MPA', (102, 115))	('hypoxia', 'Disease', (119, 126))	('oxygen', 'Chemical', 'MESH:D010100', (25, 31))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('VHL', 'Gene', (0, 3))	('alteration', 'Var', (56, 66))	('absence', 'Var', (45, 52))
66471	30372395	However, with mutation (or loss) of VHL, such as in ccRCC, VHL cannot target and degrade HIF, even in normoxia, and HIF accumulates.	('degrade', 'NegReg', (81, 88))	('VHL', 'Gene', (36, 39))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('mutation', 'Var', (14, 22))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('HIF', 'MPA', (89, 92))	('loss', 'NegReg', (27, 31))
66472	30372395	HIF accumulation then activates the expression of a broad repertoire of genes involved in the hypoxic response pathway, including notable regulators of glucose uptake and glycolytic metabolism.	('accumulation', 'Var', (4, 16))	('glucose', 'Chemical', 'MESH:D005947', (152, 159))	('glucose uptake', 'biological_process', 'GO:0046323', ('152', '166'))	('activates', 'PosReg', (22, 31))	('metabolism', 'biological_process', 'GO:0008152', ('182', '192'))	('expression', 'MPA', (36, 46))
66481	30372395	The growth of VHL mutated cancer cells is dependent on HIF upregulation.	('mutated', 'Var', (18, 25))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('growth', 'MPA', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('upregulation', 'PosReg', (59, 71))	('VHL', 'Gene', (14, 17))
66484	30372395	Multiple lines of evidence implied this was a high value target for RCC: upregulation of phosphor-AKT and phosphor-S6 in a subset of poor risk tumors, mTOR functioning as a regulator of HIF translation (and as a pathway activated as a result of HIF stabilization), and as a master regulator of glycolytic activity (Figure 3).	('translation', 'biological_process', 'GO:0006412', ('190', '201'))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('phosphor-S6', 'Var', (106, 117))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('AKT', 'Gene', '207', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('mTOR', 'Gene', (151, 155))	('mTOR', 'Gene', '2475', (151, 155))	('AKT', 'Gene', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('upregulation', 'PosReg', (73, 85))
66487	30372395	Although the demonstrated benefit of these drugs was brief, certain patients have been observed to demonstrate prolonged response, and harbor mutations in components of the overall mTOR signaling pathway, including PTEN, PIK3CA, and activating mutations in mTOR itself.	('mTOR', 'Gene', (257, 261))	('mutations', 'Var', (142, 151))	('PIK3CA', 'Gene', '5290', (221, 227))	('activating', 'Reg', (233, 243))	('signaling pathway', 'biological_process', 'GO:0007165', ('186', '203'))	('PTEN', 'Gene', (215, 219))	('patients', 'Species', '9606', (68, 76))	('PTEN', 'Gene', '5728', (215, 219))	('PIK3CA', 'Gene', (221, 227))	('mTOR', 'Gene', '2475', (181, 185))	('mTOR', 'Gene', '2475', (257, 261))	('mTOR', 'Gene', (181, 185))
66501	30372395	Type II pRCC includes a subset of tumors found to have driver mutations in the gene for the Krebs cycle enzyme, fumarate hydratase (FH), and presents with highly aggressive disease, similar to the germline syndrome of hereditary leiomyomatosis and renal cell carcinoma (HLRCC).	('fumarate hydratase', 'Gene', '2271', (112, 130))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('aggressive disease', 'Disease', 'MESH:D001523', (162, 180))	('pRCC', 'Gene', '5546', (8, 12))	('FH', 'Gene', '2271', (132, 134))	('RCC', 'Phenotype', 'HP:0005584', (272, 275))	('mutations', 'Var', (62, 71))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (248, 268))	('RCC', 'Disease', (272, 275))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('fumarate hydratase', 'Gene', (112, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('RCC', 'Disease', (9, 12))	('RCC', 'Phenotype', 'HP:0005584', (9, 12))	('pRCC', 'Phenotype', 'HP:0006766', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('RCC', 'Disease', 'MESH:C538614', (272, 275))	('pRCC', 'Gene', (8, 12))	('tumors', 'Disease', (34, 40))	('RCC', 'Disease', 'MESH:C538614', (9, 12))	('aggressive disease', 'Disease', (162, 180))	('Krebs cycle', 'biological_process', 'GO:0006099', ('92', '103'))	('hereditary leiomyomatosis and renal cell carcinoma', 'Disease', 'MESH:C538614', (218, 268))	('Krebs', 'Chemical', '-', (92, 97))
66524	30372395	One feature of chRCC, known as the eosinophilic variant, is recurrent mutations in genes involved in electron transport housed within the mitochondrial genome (Figure 4).	('mutations', 'Var', (70, 79))	('mitochondrial genome', 'cellular_component', 'GO:0000262', ('138', '158'))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('electron transport', 'biological_process', 'GO:0006118', ('101', '119'))
66525	30372395	The effect of these mutations is an accumulation of defective mitochondria, which may be a checkpoint limiting autophagy and inhibiting tumor progression.	('mitochondria', 'CPA', (62, 74))	('autophagy', 'CPA', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('autophagy', 'biological_process', 'GO:0016236', ('111', '120'))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('mitochondria', 'cellular_component', 'GO:0005739', ('62', '74'))	('inhibiting', 'NegReg', (125, 135))	('limiting', 'NegReg', (102, 110))	('accumulation', 'PosReg', (36, 48))	('autophagy', 'biological_process', 'GO:0006914', ('111', '120'))	('tumor', 'Disease', (136, 141))	('mutations', 'Var', (20, 29))
66534	30372395	These changes impact the balance of available nutrients, discarded metabolites, and secreted waste products and other local features, such as pH, oxygen tension, and redox state, that may directly or indirectly impact stromal and immune cells.	('balance of available nutrients', 'MPA', (25, 55))	('impact', 'Reg', (211, 217))	('changes', 'Var', (6, 13))	('oxygen', 'Chemical', 'MESH:D010100', (146, 152))	('impact', 'Reg', (14, 20))
66536	30372395	The earliest stages of VHL inactivation in precancerous cells can mount an inflammatory response, which sets the stage for later tumor cell-immune cell.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('mount', 'Reg', (66, 71))	('inactivation', 'Var', (27, 39))	('VHL', 'Gene', (23, 26))	('cancer', 'Disease', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('inflammatory response', 'biological_process', 'GO:0006954', ('75', '96'))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('inflammatory response', 'CPA', (75, 96))	('tumor', 'Disease', (129, 134))
66597	31768131	Further, 786-O cells stably transfected with lncRNA-LET overexpression (lncRNA-LET) or empty control (EV), 769-P cells stably transfected with lncRNA-LET knockdown (lncRNA-LET shRNA) or control (shRNA Ctrl) were established by selecting cells with 200 mug/ml or 300 mug/ml G418.	('lncRNA-LET', 'Gene', (165, 175))	('lncRNA-LET', 'Gene', (143, 153))	('lncRNA-LET', 'Gene', '101241892', (165, 175))	('lncRNA-LET', 'Gene', (72, 82))	('mug', 'molecular_function', 'GO:0043739', ('252', '255'))	('lncRNA-LET', 'Gene', (45, 55))	('lncRNA-LET', 'Gene', '101241892', (72, 82))	('lncRNA-LET', 'Gene', '101241892', (45, 55))	('mug', 'molecular_function', 'GO:0043739', ('266', '269'))	('G418', 'Var', (273, 277))	('lncRNA-LET', 'Gene', '101241892', (143, 153))
66621	31768131	The partial lncRNA-LET sequences containing wild-type (WT) and mutant (MUT) binding sites for miR-373-3p were synthesized and subcloned into pmirGLO luciferase reporter vectors.	('mutant', 'Var', (63, 69))	('lncRNA-LET', 'Gene', (12, 22))	('binding', 'molecular_function', 'GO:0005488', ('76', '83'))	('lncRNA-LET', 'Gene', '101241892', (12, 22))	('miR-373', 'Gene', '442918', (94, 101))	('miR-373', 'Gene', (94, 101))
66637	31768131	Moreover, lncRNA-LET overexpression down-regulated the expression of Cyclins D1 and E in 786-O cells, while lncRNA-LET knockdown up-regulated their expression in 769-P cells (Fig.	('lncRNA-LET', 'Gene', '101241892', (10, 20))	('lncRNA-LET', 'Gene', (10, 20))	('lncRNA-LET', 'Gene', (108, 118))	('expression', 'MPA', (55, 65))	('lncRNA-LET', 'Gene', '101241892', (108, 118))	('Cyclins D1 and E', 'Gene', '595', (69, 85))	('knockdown', 'Var', (119, 128))	('up-regulated', 'PosReg', (129, 141))	('expression', 'MPA', (148, 158))	('down-regulated', 'NegReg', (36, 50))
66649	31768131	Then, we carried out miR-373-3p overexpression or knockdown in ccRCC cells (Fig.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('knockdown', 'Var', (50, 59))	('miR-373', 'Gene', (21, 28))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('miR-373', 'Gene', '442918', (21, 28))	('ccRCC', 'Disease', (63, 68))	('ccRCC', 'Disease', 'MESH:D002292', (63, 68))
66694	31656019	All samples coexpressed CK7 and CA9; the TFE3 or TFEB reactions were negative; the CD10 and the AMACR stainings were negative in 27 cases and 30 cases, respectively.	('CD10', 'molecular_function', 'GO:0004245', ('83', '87'))	('TFE3', 'Gene', '7030', (41, 45))	('AMACR', 'Gene', '23600', (96, 101))	('CA9', 'Gene', (32, 35))	('TFE3', 'Gene', (41, 45))	('TFEB', 'Gene', '7942', (49, 53))	('CA9', 'Gene', '768', (32, 35))	('TFEB', 'Gene', (49, 53))	('CK7', 'Var', (24, 27))	('AMACR', 'Gene', (96, 101))
66695	31656019	The FISH assays for papillary RCC, available in 27 cases, and deletion of chromosome 3p, available in 29 cases, gave negative results.	('papillary RCC', 'Disease', 'MESH:C538614', (20, 33))	('papillary RCC', 'Disease', (20, 33))	('chromosome', 'cellular_component', 'GO:0005694', ('74', '84'))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('deletion', 'Var', (62, 70))
66703	31656019	Although CCPRCC shares histopathogical features with clear cell RCC (CCRCC), papillary RCC and Xp11.2 translocation RCC, its immunohistochemical coexpression of cytokeratin 7 (CK7) and carbonic anhydrase 9 (CA9), and negativity for CD10, alpha-methyl-CoA racemase (AMACR), and TFE3 usually clarifies the diagnosis.	('papillary RCC', 'Disease', (77, 90))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Phenotype', 'HP:0005584', (12, 15))	('RCC', 'Disease', (12, 15))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('CA9', 'Gene', (207, 210))	('RCC', 'Disease', (116, 119))	('carbonic anhydrase 9', 'Gene', (185, 205))	('CCPRCC', 'Chemical', '-', (9, 15))	('AMACR', 'Gene', (265, 270))	('cytokeratin 7', 'Gene', '3855', (161, 174))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('cytokeratin 7', 'Gene', (161, 174))	('negativity', 'Var', (217, 227))	('CA9', 'Gene', '768', (207, 210))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('AMACR', 'Gene', '23600', (265, 270))	('carbonic anhydrase 9', 'Gene', '768', (185, 205))	('TFE3', 'Gene', (277, 281))	('CD10', 'molecular_function', 'GO:0004245', ('232', '236'))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('CD10', 'Gene', (232, 236))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', (64, 67))	('TFE3', 'Gene', '7030', (277, 281))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))	('RCC', 'Disease', (87, 90))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('CCPRCC', 'Phenotype', 'HP:0006770', (9, 15))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('papillary RCC', 'Disease', 'MESH:C538614', (77, 90))
66705	31656019	Genetically, CCPRCCs lack chromosome 3p deletion or VHL gene mutation or VHL promoter hypermethylation, the hallmarks of CCRCC, and have no loss of chromosome Y or gain of chromosome 7 and 17, the hallmarks of papillary RCC.	('VHL', 'Gene', '7428', (73, 76))	('mutation', 'Var', (61, 69))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('chromosome 3p', 'Protein', (26, 39))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('hypermethylation', 'Var', (86, 102))	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('papillary RCC', 'Disease', 'MESH:C538614', (210, 223))	('papillary RCC', 'Disease', (210, 223))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('VHL', 'Gene', (52, 55))	('CCPRCC', 'Phenotype', 'HP:0006770', (13, 19))	('RCC', 'Disease', (16, 19))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('chromosome', 'cellular_component', 'GO:0005694', ('172', '182'))	('lack', 'NegReg', (21, 25))	('VHL', 'Gene', (73, 76))	('VHL', 'Gene', '7428', (52, 55))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('CCPRCC', 'Chemical', '-', (13, 19))	('RCC', 'Phenotype', 'HP:0005584', (220, 223))	('chromosome', 'cellular_component', 'GO:0005694', ('148', '158'))	('RCC', 'Disease', (220, 223))
66716	31656019	In the case of pathological mutation, the apparently tumor-free renal tissue was analyzed as well.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('mutation', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
66724	31656019	The FISH assays for papillary RCC, available in 27 cases, and deletion of chromosome 3p, available in 29 cases, yielded negative results.	('papillary RCC', 'Disease', 'MESH:C538614', (20, 33))	('papillary RCC', 'Disease', (20, 33))	('chromosome', 'cellular_component', 'GO:0005694', ('74', '84'))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('deletion', 'Var', (62, 70))
66725	31656019	The histomorphology, the results for VHL mutation and VHL methylation testing, and the immunophenotype confirmed 21 cases as CCPRCC and 10 cases as CCRCC.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('VHL', 'Gene', (37, 40))	('VHL', 'Gene', (54, 57))	('CCPRCC', 'Phenotype', 'HP:0006770', (125, 131))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('VHL', 'Gene', '7428', (37, 40))	('RCC', 'Disease', (150, 153))	('mutation', 'Var', (41, 49))	('VHL', 'Gene', '7428', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('methylation', 'biological_process', 'GO:0032259', ('58', '69'))	('CCPRCC', 'Chemical', '-', (125, 131))
66743	31656019	The mutation status of the VHL gene was investigated in 11 samples, and in Case 12, single nucleotide polymorphism (SNP) in untranslated region (UTR) was found.	('VHL', 'Gene', '7428', (27, 30))	('single nucleotide polymorphism', 'Var', (84, 114))	('VHL', 'Gene', (27, 30))
66766	31656019	CCRCCs are viewed as tumors that are CA9+ and CD10+, and display no more than a focal CK7 positivity.	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('CD10+', 'Var', (46, 51))	('CD10', 'molecular_function', 'GO:0004245', ('46', '50'))	('CA9', 'Gene', '768', (37, 40))	('CA9', 'Gene', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
66767	31656019	In contrast, the immunophenotype of CCPRCCs is CK7+, CA9+, and CD10-.	('CA9', 'Gene', '768', (53, 56))	('CCPRCC', 'Chemical', '-', (36, 42))	('CK7+', 'Var', (47, 51))	('CD10-', 'Var', (63, 68))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('CCPRCCs', 'Disease', (36, 43))	('CCPRCC', 'Phenotype', 'HP:0006770', (36, 42))	('CA9', 'Gene', (53, 56))	('CD10', 'molecular_function', 'GO:0004245', ('63', '67'))
66771	31656019	In another subset of our cases, the morphology and immunophenotype wholly favoured the diagnosis of CCPRCC; however, either VHL mutation (3 cases) or VHL promoter hypermethylation (7 cases) was present.	('VHL', 'Gene', '7428', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('CCPRCC', 'Disease', (100, 106))	('CCPRCC', 'Phenotype', 'HP:0006770', (100, 106))	('VHL', 'Gene', (150, 153))	('VHL', 'Gene', '7428', (150, 153))	('mutation', 'Var', (128, 136))	('VHL', 'Gene', (124, 127))	('CCPRCC', 'Chemical', '-', (100, 106))
66801	31656019	The VHL gene sequence analysis revealed pathologic mutations in cases 22, 23 and 31.	('VHL', 'Gene', '7428', (4, 7))	('mutations', 'Var', (51, 60))	('VHL', 'Gene', (4, 7))
66803	31656019	In seven samples, the histological and immunphenotypic data favoured the diagnosis of CCPRCC; however, the presence of the VHL gene promoter hypermethylation abnormality leads us to place these samples into the CCRCC group.	('presence', 'Var', (107, 115))	('CCPRCC', 'Phenotype', 'HP:0006770', (86, 92))	('VHL', 'Gene', (123, 126))	('RCC', 'Disease', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('VHL', 'Gene', '7428', (123, 126))	('RCC', 'Disease', (213, 216))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	('CCPRCC', 'Chemical', '-', (86, 92))
66806	31656019	The latter observation indicated that hypermethylation may inactivate the VHL gene even when both wild-type alleles are retained.	('hypermethylation', 'Var', (38, 54))	('VHL', 'Gene', (74, 77))	('inactivate', 'NegReg', (59, 69))	('VHL', 'Gene', '7428', (74, 77))
66807	31656019	In our analysis, hypermethylation was noted in seven cases; moreover coexisting VHL gene mutation and methylation was seen in Case 22.	('methylation', 'biological_process', 'GO:0032259', ('102', '113'))	('VHL', 'Gene', (80, 83))	('VHL', 'Gene', '7428', (80, 83))	('mutation', 'Var', (89, 97))	('hypermethylation', 'Var', (17, 33))
66809	31656019	Methylation analyses performed by others in the future may validate our assumption that a VHL promoter hypermethylation is definitely not compatible with the diagnosis of CCPRCC.	('VHL', 'Gene', '7428', (90, 93))	('hypermethylation', 'Var', (103, 119))	('CCPRCC', 'Chemical', '-', (171, 177))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('CCPRCC', 'Phenotype', 'HP:0006770', (171, 177))	('VHL', 'Gene', (90, 93))	('CCPRCC', 'Disease', (171, 177))
66811	31656019	Interestingly, in 8 cases the histological and immunphenotypic data were entirely consistent with the histopathological diagnosis of CCPRCC, but the presence of VHL abnormalities led us to place these samples into the group of low-grade CCRCC with CK7 immunoreactivity and no 3p loss.	('presence', 'Var', (149, 157))	('RCC', 'Disease', (239, 242))	('RCC', 'Phenotype', 'HP:0005584', (239, 242))	('CCPRCC', 'Chemical', '-', (133, 139))	('VHL abnormalities', 'Disease', 'MESH:D006623', (161, 178))	('RCC', 'Disease', 'MESH:C538614', (239, 242))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('VHL abnormalities', 'Disease', (161, 178))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('CCPRCC', 'Phenotype', 'HP:0006770', (133, 139))	('RCC', 'Disease', (136, 139))	('CK7', 'Var', (248, 251))
66813	31656019	Twenty-one cases were classified as CCPRCC (CK7+, CA9+; -3p absent, VHL abnormality not present) and 10 as CCRCC with diffuse CK7-positivity (CK7+, CA9+; -3p absent, VHL abnormality present).	('CK7+', 'Var', (142, 146))	('VHL abnormality', 'Disease', (166, 181))	('CCPRCC', 'Chemical', '-', (36, 42))	('VHL abnormality', 'Disease', 'MESH:D006623', (166, 181))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('CK7+', 'Var', (44, 48))	('RCC', 'Disease', (39, 42))	('RCC', 'Disease', (109, 112))	('CA9', 'Gene', (148, 151))	('VHL abnormality', 'Disease', (68, 83))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('CA9', 'Gene', '768', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('CCPRCC', 'Phenotype', 'HP:0006770', (36, 42))	('VHL abnormality', 'Disease', 'MESH:D006623', (68, 83))	('CA9', 'Gene', '768', (50, 53))	('CA9', 'Gene', (50, 53))
66817	31656019	And last but, not least the biological behavior of both CCPRCCs and CCRCCs with diffuse CK7 positivity seems to be indolent with a favorable clinical outcome.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('CCPRCC', 'Phenotype', 'HP:0006770', (56, 62))	('CK7', 'Gene', (88, 91))	('CCPRCC', 'Chemical', '-', (56, 62))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('positivity', 'Var', (92, 102))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
66834	31257481	A number of previous studies have demonstrated that multiple microRNAs (miRNAs) may act as oncogenes or tumor suppressor genes; therefore, the dysregulation of miRNAs was identified to be involved in the process of cancer development and progression.	('tumor suppressor', 'biological_process', 'GO:0051726', ('104', '120'))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('involved', 'Reg', (188, 196))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('104', '120'))	('dysregulation', 'Var', (143, 156))	('tumor', 'Disease', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
66840	31257481	Previous studies investigating the role of ZEB2 in cancer identified that the expression of ZEB2 is important for the development of cancer, and the inhibition of ZEB2 may suppress cancer cell growth, migration and invasion.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('ZEB2', 'Gene', (92, 96))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('ZEB2', 'Gene', '9839', (92, 96))	('invasion', 'CPA', (215, 223))	('ZEB2', 'Gene', (163, 167))	('ZEB2', 'Gene', (43, 47))	('cancer', 'Disease', (133, 139))	('ZEB2', 'Gene', '9839', (163, 167))	('inhibition', 'Var', (149, 159))	('cancer', 'Disease', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('ZEB2', 'Gene', '9839', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', (51, 57))	('cell growth', 'biological_process', 'GO:0016049', ('188', '199'))	('suppress', 'NegReg', (172, 180))
66881	31257481	The construction of the psiCHECK plasmid containing the mutated 3'-UTR of ZEB2 was performed as previously described.	('mutated', 'Var', (56, 63))	('ZEB2', 'Gene', '9839', (74, 78))	('ZEB2', 'Gene', (74, 78))
66912	31257481	Conversely, C666-1 cells transfected with miR-30a inhibitor exhibited an increased expression level of ZEB2 compared with cells transfected with the control miRNA (Fig.	('increased', 'PosReg', (73, 82))	('expression level', 'MPA', (83, 99))	('miR-30a', 'Gene', '407029', (42, 49))	('ZEB2', 'Gene', '9839', (103, 107))	('miR-30a', 'Gene', (42, 49))	('inhibitor', 'Var', (50, 59))	('C666-1', 'CellLine', 'CVCL:7949', (12, 18))	('ZEB2', 'Gene', (103, 107))
66915	31257481	Therefore, wild-type (WT) and mutant (Mut) 3'-UTRs of ZEB2 were cloned into psi-CHECK vectors, C666-1 cells were transfected, and dual-luciferase assay was performed.	('mutant', 'Var', (30, 36))	('ZEB2', 'Gene', '9839', (54, 58))	('ZEB2', 'Gene', (54, 58))	('C666-1', 'CellLine', 'CVCL:7949', (95, 101))
66921	31257481	The present results suggested that the number of proliferating cells was increased following ZEB2 overexpression.	('increased', 'PosReg', (73, 82))	('number of proliferating cells', 'CPA', (39, 68))	('ZEB2', 'Gene', '9839', (93, 97))	('overexpression', 'Var', (98, 112))	('ZEB2', 'Gene', (93, 97))
66924	31257481	miR-30a overexpression was identified to increase the percentage of cells in G0/G1 phase and decreased the percentage of cells in S phase and G2/M phase in NPC cells.	('S phase', 'biological_process', 'GO:0051320', ('130', '137'))	('G1 phase', 'biological_process', 'GO:0051318', ('80', '88'))	('miR-30a', 'Gene', (0, 7))	('decreased', 'NegReg', (93, 102))	('overexpression', 'Var', (8, 22))	('G0/G1 phase', 'CPA', (77, 88))	('NPC', 'cellular_component', 'GO:0005643', ('156', '159'))	('increase', 'PosReg', (41, 49))	('miR-30a', 'Gene', '407029', (0, 7))	('M phase', 'biological_process', 'GO:0000279', ('145', '152'))
66931	31257481	Conversely, ZEB2 transfection decreased the percentage of early-stage apoptotic cells in cells overexpressing miR-30a.	('ZEB2', 'Gene', (12, 16))	('miR-30a', 'Gene', '407029', (110, 117))	('transfection', 'Var', (17, 29))	('miR-30a', 'Gene', (110, 117))	('ZEB2', 'Gene', '9839', (12, 16))	('decreased', 'NegReg', (30, 39))
66943	31257481	The present results suggested that ZEB2 overexpression increased the weight and the volume of NPC and promoted tumor growth in vivo.	('ZEB2', 'Gene', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('ZEB2', 'Gene', '9839', (35, 39))	('promoted', 'PosReg', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('increased', 'PosReg', (55, 64))	('NPC', 'cellular_component', 'GO:0005643', ('94', '97'))	('weight', 'CPA', (69, 75))	('tumor', 'Disease', (111, 116))	('overexpression', 'Var', (40, 54))
66963	31257481	A previous study observed that the level of hypermethylation in the promoter of certain miRNAs increased in cancer cells, resulting in the downregulation of these miRNAs.	('miRNAs', 'MPA', (163, 169))	('cancer', 'Disease', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('hypermethylation', 'Var', (44, 60))	('downregulation', 'NegReg', (139, 153))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
66964	31257481	Therefore, the hypermethylation of miRNA promoters may serve an important role in the regulation of miRNAs, thus modulating the development and progression of cancer.	('cancer', 'Disease', (159, 165))	('modulating', 'Reg', (113, 123))	('progression', 'CPA', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('regulation', 'biological_process', 'GO:0065007', ('86', '96'))	('hypermethylation', 'Var', (15, 31))	('development', 'CPA', (128, 139))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
67001	29651023	Modern sequencing technology has shown a prevalence for biallelical inactivation of VHL in 92% of sporadic ccRCCs; additionally, the VHL mutation is supposed to occur at the earliest stage of tumorigensis.	('tumor', 'Disease', (192, 197))	('VHL', 'Gene', (84, 87))	('mutation', 'Var', (137, 145))	('VHL', 'Gene', (133, 136))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('biallelical inactivation', 'Var', (56, 80))
67002	29651023	The role of VHL as a tumor suppressor gene (TSG) in cancer has been established by the fact that reintroducing wide-type VHL into VHL-null RCC cell lines perturbs their capacity to form tumors in immune-compromised mice in vivo.	('tumor', 'Disease', (21, 26))	('TSG', 'Gene', '65960', (44, 47))	('tumor suppressor', 'biological_process', 'GO:0051726', ('21', '37'))	('reintroducing', 'Var', (97, 110))	('tumor', 'Disease', (186, 191))	('TSG', 'Gene', (44, 47))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('perturbs', 'NegReg', (154, 162))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('RCC', 'Disease', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('VHL-null', 'Gene', (130, 138))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('tumors', 'Disease', (186, 192))	('cancer', 'Disease', (52, 58))	('mice', 'Species', '10090', (215, 219))	('VHL', 'Gene', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('21', '37'))
67005	29651023	Further efforts have focused on the use of conditional inactivation of TSG or activation of oncogenes by the Cre-Lox system in adult renal tissue and cells of interest at the desired time.	('conditional inactivation', 'Var', (43, 67))	('TSG', 'Gene', '65960', (71, 74))	('Lox', 'Gene', (113, 116))	('oncogenes', 'Gene', (92, 101))	('TSG', 'Gene', (71, 74))	('Lox', 'Gene', '16948', (113, 116))
67008	29651023	Rankin and colleagues developed the first conditional knockout mouse model using the phosphoenolpyruvate carboxykinase-Cre system to inactivate VHL in renal proximal tubule cells.	('mouse', 'Species', '10090', (63, 68))	('inactivate', 'Var', (133, 143))	('VHL', 'Gene', (144, 147))
67015	29651023	performed a conditional knockout of Vhl in distal tubules and collecting ducts using the Ksp1.3-Cre system (also expressed in proximal tubules) and found no abnormalities other than hydronephrosis.	('Vhl', 'Gene', (36, 39))	('hydronephrosis', 'Disease', 'MESH:D006869', (182, 196))	('hydronephrosis', 'Disease', (182, 196))	('hydronephrosis', 'Phenotype', 'HP:0000126', (182, 196))	('knockout', 'Var', (24, 32))
67018	29651023	Other groups have also tested inactivation of Vhl in mice using the Pax8-Cre system, which targets the complete tubular system, or THP-Cre system, which targets the medullary thick ascending loop of Henle and the early distal tubule, but no RCC or even renal cysts have been induced.	('Pax8', 'Gene', (68, 72))	('renal cysts', 'Disease', (253, 264))	('renal cyst', 'Phenotype', 'HP:0000107', (253, 263))	('Vhl', 'Gene', (46, 49))	('inactivation', 'Var', (30, 42))	('tested', 'Reg', (23, 29))	('renal cysts', 'Disease', 'MESH:D007674', (253, 264))	('renal cysts', 'Phenotype', 'HP:0000107', (253, 264))	('Pax8', 'Gene', '18510', (68, 72))	('RCC', 'Disease', 'MESH:C538614', (241, 244))	('RCC', 'Disease', (241, 244))	('RCC', 'Phenotype', 'HP:0005584', (241, 244))	('mice', 'Species', '10090', (53, 57))
67020	29651023	Haase has provided several potential explanations for the inability of VHL inactivation to produce RCC in animals.	('inactivation', 'Var', (75, 87))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('Haase', 'Chemical', '-', (0, 5))
67021	29651023	For instance, he believes a specific gain-of-function mutation in VHL may be a requirement, the genetic background of mice may play a role, or VHL-associated renal lesions may only arise from a specific, rare type of kidney cell that is usually not targeted.	('mutation', 'Var', (54, 62))	('gain-of-function', 'PosReg', (37, 53))	('VHL', 'Gene', (66, 69))	('renal lesions', 'Disease', 'MESH:D007674', (158, 171))	('mice', 'Species', '10090', (118, 122))	('renal lesions', 'Disease', (158, 171))
67022	29651023	However, a more generally accepted reason is that additional mutations in other TSGs or oncogenes are required to form specific combinations of genetic alterations, together with the loss of VHL function, to initiate tumorigenesis.	('TSG', 'Gene', '65960', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('initiate', 'PosReg', (208, 216))	('alterations', 'Var', (152, 163))	('TSG', 'Gene', (80, 83))	('mutations', 'Var', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('loss of VHL function', 'Disease', 'MESH:D006623', (183, 203))	('loss of VHL function', 'Disease', (183, 203))
67023	29651023	In accordance with this hypothesis, researchers have combined the deletion of VHL with the deletion of other TSGs and/or activation of oncogenes in an attempt to provoke ccRCC development.	('deletion', 'Var', (91, 99))	('provoke', 'Reg', (162, 169))	('TSG', 'Gene', '65960', (109, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (170, 175))	('VHL', 'Gene', (78, 81))	('TSG', 'Gene', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('RCC', 'Disease', (172, 175))	('deletion', 'Var', (66, 74))
67024	29651023	The failure to produce ccRCC in mice by inactivating Vhl alone, together with the facts that ccRCC as well as renal cysts arise at a much lower frequency in relation to the total number of sites of VHL loss of function in the kidneys of VHL patients, support the idea of combining additional genetic alterations with inactivation of VHL to recapitulate the tumorigenesis of ccRCC.	('renal cysts', 'Disease', 'MESH:D007674', (110, 121))	('renal cyst', 'Phenotype', 'HP:0000107', (110, 120))	('VHL loss', 'Disease', 'MESH:D006623', (198, 206))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))	('RCC', 'Disease', (376, 379))	('RCC', 'Phenotype', 'HP:0005584', (376, 379))	('inactivating', 'Var', (40, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (374, 379))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('RCC', 'Disease', (25, 28))	('ccRCC', 'Phenotype', 'HP:0006770', (23, 28))	('RCC', 'Disease', 'MESH:C538614', (376, 379))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('RCC', 'Disease', (95, 98))	('mice', 'Species', '10090', (32, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('renal cysts', 'Phenotype', 'HP:0000107', (110, 121))	('patients', 'Species', '9606', (241, 249))	('tumor', 'Disease', (357, 362))	('VHL', 'Gene', (333, 336))	('renal cysts', 'Disease', (110, 121))	('inactivation', 'Var', (317, 329))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (357, 362))	('VHL loss', 'Disease', (198, 206))
67028	29651023	The involvement of PTEN and the PI3K/AKT pathway in ccRCC was recognized nearly 20 years ago and has been reconfirmed by recent comprehensive genomic studies that indicate that approximately one-fifth of patients harbor mutations in genes involved in this pathway.	('patients', 'Species', '9606', (204, 212))	('PI3K', 'molecular_function', 'GO:0016303', ('32', '36'))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('PI3K/AKT pathway', 'Pathway', (32, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('mutations', 'Var', (220, 229))
67030	29651023	Based on these facts, Frew and colleagues performed conditional co-deletion of Vhl and Pten in mouse kidney epithelial cells using the Ksp1.3-Cre system.	('co-deletion', 'Var', (64, 75))	('Pten', 'Gene', (87, 91))	('Vhl', 'Gene', (79, 82))	('Pten', 'Gene', '19211', (87, 91))	('mouse', 'Species', '10090', (95, 100))
67033	29651023	However, the combinatorial deletion of Vhl and Pten elicited cyst formation with a short latency, encouraging further exploration in this direction.	('formation', 'biological_process', 'GO:0009058', ('66', '75'))	('Pten', 'Gene', (47, 51))	('Vhl', 'Gene', (39, 42))	('Pten', 'Gene', '19211', (47, 51))	('elicited', 'Reg', (52, 60))	('deletion', 'Var', (27, 35))	('cyst formation', 'CPA', (61, 75))
67036	29651023	Unlike the PTEN gene, mutations of which usually only abrogate its tumor-suppressing function, mutations of TP53 usually confer it with oncogenic functions.	('confer', 'Reg', (121, 127))	('TP53', 'Gene', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('abrogate', 'NegReg', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('oncogenic functions', 'CPA', (136, 155))	('mutations', 'Var', (22, 31))	('mutations', 'Var', (95, 104))	('tumor', 'Disease', (67, 72))
67037	29651023	Although TP53 mutations only present in a small subset of ccRCC patients (2.08%), p53 pathway-related genes, including MDM2, CHEK2, ATM, and CDKN2A, are functionally mutated in approximately one-fourth of patients.	('ATM', 'Gene', (132, 135))	('CDKN2A', 'Gene', '1029', (141, 147))	('p53 pathway-related genes', 'Gene', (82, 107))	('patients', 'Species', '9606', (205, 213))	('patients', 'Species', '9606', (64, 72))	('MDM2', 'Gene', '4193', (119, 123))	('CHEK2', 'Gene', '11200', (125, 130))	('MDM2', 'Gene', (119, 123))	('RCC', 'Disease', (60, 63))	('ATM', 'Gene', '472', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('TP53', 'Gene', (9, 13))	('CHEK2', 'Gene', (125, 130))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('CDKN2A', 'Gene', (141, 147))	('mutations', 'Var', (14, 23))
67038	29651023	Moreover, TP53 mutations are much more prevalent in ccRCC with sarcomatoid dedifferentiation and in metastatic subclones of RCC, indicating the pivotal role of TP53 alterations in cancer aggressiveness.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('sarcomatoid', 'Disease', (63, 74))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (180, 201))	('dedifferentiation', 'biological_process', 'GO:0043696', ('75', '92'))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('TP53', 'Gene', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('aggressiveness', 'Phenotype', 'HP:0000718', (187, 201))	('mutations', 'Var', (15, 24))	('RCC', 'Disease', (54, 57))	('prevalent', 'Reg', (39, 48))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('sarcomatoid', 'Disease', 'MESH:C538614', (63, 74))	('cancer aggressiveness', 'Disease', (180, 201))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))
67039	29651023	To investigate the role of TP53 mutations in RCC tumorigenesis and progression, Albers and colleagues performed conditional co-inactivation of Vhl and Trp53 in the mouse kidney epithelium using the Ksp1.3-Cre system.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('TP53', 'Gene', (27, 31))	('mouse', 'Species', '10090', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Trp53', 'Gene', (151, 156))	('tumor', 'Disease', (49, 54))	('mutations', 'Var', (32, 41))	('Vhl', 'Gene', (143, 146))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
67040	29651023	They found that three-fourths of mice with the Vhl and Trp53 double deletion gave rise to renal cysts after 1 year; one-eighth of these was atypical lesions.	('gave rise', 'Reg', (77, 86))	('renal cysts', 'Disease', (90, 101))	('Trp53', 'Gene', (55, 60))	('renal cysts', 'Disease', 'MESH:D007674', (90, 101))	('renal cyst', 'Phenotype', 'HP:0000107', (90, 100))	('Vhl', 'Gene', (47, 50))	('mice', 'Species', '10090', (33, 37))	('renal cysts', 'Phenotype', 'HP:0000107', (90, 101))	('double deletion', 'Var', (61, 76))
67043	29651023	These findings collectively demonstrate that inactivation of Vhl and Trp53 together induces development of renal cysts and ultimately causes progression to dysplastic and malignant lesions, the cells of which recapitulate some of the cellular and molecular features that are characteristic of human ccRCC.	('Trp53', 'Gene', (69, 74))	('causes', 'Reg', (134, 140))	('inactivation', 'Var', (45, 57))	('renal cyst', 'Phenotype', 'HP:0000107', (107, 117))	('RCC', 'Disease', (301, 304))	('development of', 'CPA', (92, 106))	('RCC', 'Phenotype', 'HP:0005584', (301, 304))	('renal cysts', 'Disease', 'MESH:D007674', (107, 118))	('Vhl', 'Gene', (61, 64))	('RCC', 'Disease', 'MESH:C538614', (301, 304))	('renal cysts', 'Disease', (107, 118))	('dysplastic', 'Disease', (156, 166))	('human', 'Species', '9606', (293, 298))	('ccRCC', 'Phenotype', 'HP:0006770', (299, 304))	('dysplastic', 'Disease', 'MESH:D004416', (156, 166))	('renal cysts', 'Phenotype', 'HP:0000107', (107, 118))	('induces', 'Reg', (84, 91))
67044	29651023	Our realization of the importance of the primary cilium in renal cytogenesis and tumorigenesis, and the fact that at least one subset of ccRCC develops in a cyst-dependent manner, have driven scientists to investigate the effects of Vhl inactivation together with specifically ablating primary cilia in kidney.	('primary cilium', 'cellular_component', 'GO:0005929', ('41', '55'))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('inactivation', 'Var', (237, 249))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('Vhl', 'Gene', (233, 236))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('primary cilium', 'cellular_component', 'GO:0097731', ('41', '55'))	('tumor', 'Disease', (81, 86))
67045	29651023	To achieve this, the kinesin family member 3A (Kif3a) gene, which encodes a protein subunit of the kinesin-II microtubule motor complex that is essential for cilia formation, was conditionally deleted with Vhl in mouse kidney epithelial cells using the Ksp1.3-Cre system.	('mouse', 'Species', '10090', (213, 218))	('kinesin', 'molecular_function', 'GO:0003777', ('21', '28'))	('kinesin family member 3A', 'Gene', '16568', (21, 45))	('kinesin', 'molecular_function', 'GO:0003777', ('99', '106'))	('microtubule', 'cellular_component', 'GO:0005874', ('110', '121'))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('kinesin family member 3A', 'Gene', (21, 45))	('Kif3a', 'Gene', (47, 52))	('deleted', 'Var', (193, 200))	('Vhl', 'Gene', (206, 209))	('formation', 'biological_process', 'GO:0009058', ('164', '173'))
67047	29651023	Inspired by the facts that ablation of the primary cilium by deleting Kif3a accelerates renal cyst formation in Vhl-mutated kidney and that double inactivation of Vhl and Trp53 induces malignant lesions at a low frequency and long latency, a combination of mutations of Vhl, Trp53, and Kif3a in the mouse kidney was developed to investigate whether ablation of the primary cilium could accelerate tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (397, 402))	('formation', 'biological_process', 'GO:0009058', ('99', '108'))	('mouse', 'Species', '10090', (299, 304))	('renal', 'MPA', (88, 93))	('Trp53', 'Gene', (171, 176))	('Kif3a', 'Gene', (70, 75))	('primary cilium', 'cellular_component', 'GO:0005929', ('43', '57'))	('malignant lesions', 'CPA', (185, 202))	('primary cilium', 'cellular_component', 'GO:0005929', ('365', '379'))	('deleting', 'Var', (61, 69))	('primary cilium', 'cellular_component', 'GO:0097731', ('43', '57'))	('tumor', 'Disease', (397, 402))	('renal cyst', 'Phenotype', 'HP:0000107', (88, 98))	('accelerates', 'PosReg', (76, 87))	('formation', 'biological_process', 'GO:0009058', ('403', '412'))	('induces', 'Reg', (177, 184))	('primary cilium', 'cellular_component', 'GO:0097731', ('365', '379'))	('tumor', 'Disease', 'MESH:D009369', (397, 402))	('Vhl', 'Gene', (270, 273))
67048	29651023	The results showed that the triple-mutated kidney developed more cysts and neoplasms compared with double-mutated (Kif3a/Trp53) kidneys.	('more', 'PosReg', (60, 64))	('triple-mutated', 'Var', (28, 42))	('neoplasms', 'Phenotype', 'HP:0002664', (75, 84))	('neoplasms', 'Disease', (75, 84))	('neoplasms', 'Disease', 'MESH:D009369', (75, 84))
67051	29651023	This was disappointing because there is only one variable, the Kif3a mutation, that results in primary cilium deletion between the two mouse models, and comparing these two mouse models directly should be easier to draw a convincing conclusion.	('primary cilium', 'cellular_component', 'GO:0097731', ('95', '109'))	('mouse', 'Species', '10090', (135, 140))	('mutation', 'Var', (69, 77))	('mouse', 'Species', '10090', (173, 178))	('primary cilium', 'cellular_component', 'GO:0005929', ('95', '109'))	('primary cilium deletion', 'CPA', (95, 118))	('Kif3a', 'Gene', (63, 68))
67052	29651023	Recently, an exciting study from Harlander and colleagues showed success in developing an autochthonous mouse model of ccRCC by combining deletions of Vhl, Trp53, and Rb1 in renal epithelial cells.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('mouse', 'Species', '10090', (104, 109))	('Vhl', 'Gene', (151, 154))	('deletions', 'Var', (138, 147))	('Rb1', 'Gene', (167, 170))	('Trp53', 'Gene', (156, 161))
67053	29651023	More than 80% of the triple-mutant mice developed tumors within 25-61 weeks of somatic mutation, with an average of five tumors per mouse and a gender bias of more tumors in male mice, which is similar to the situation in human.	('developed', 'PosReg', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('mice', 'Species', '10090', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('mice', 'Species', '10090', (35, 39))	('mouse', 'Species', '10090', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('human', 'Species', '9606', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('triple-mutant', 'Var', (21, 34))
67060	29651023	Genomic sequencing confirmed the mutation of Vhl, Trp53, and Rb1, and demonstrated a similarity in the classes of mutations, mutational load, and inter- and intratumoral heterogeneity between the modeled ccRCC and human ccRCC.	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mutation', 'Var', (33, 41))	('tumor', 'Disease', (162, 167))	('RCC', 'Phenotype', 'HP:0005584', (222, 225))	('RCC', 'Disease', 'MESH:C538614', (222, 225))	('ccRCC', 'Phenotype', 'HP:0006770', (220, 225))	('RCC', 'Disease', (222, 225))	('Rb1', 'Gene', (61, 64))	('Vhl', 'Gene', (45, 48))	('Trp53', 'Gene', (50, 55))	('RCC', 'Phenotype', 'HP:0005584', (206, 209))	('human', 'Species', '9606', (214, 219))	('RCC', 'Disease', 'MESH:C538614', (206, 209))	('RCC', 'Disease', (206, 209))	('ccRCC', 'Phenotype', 'HP:0006770', (204, 209))
67066	29651023	At a minimum, this triple-mutant ccRCC model may reflect a subset of human ccRCCs.	('RCC', 'Disease', (35, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('human', 'Species', '9606', (69, 74))	('triple-mutant', 'Var', (19, 32))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
67067	29651023	The advent of next-generation sequencing technology has led to the identification of recurrent mutations that were previously unknown in human sporadic ccRCCs.	('human', 'Species', '9606', (137, 142))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('RCC', 'Disease', (154, 157))	('RCC', 'Phenotype', 'HP:0005584', (154, 157))	('mutations', 'Var', (95, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (152, 157))
67068	29651023	This distinguishing genetic feature of ccRCC has not only illuminated cancer biology to a further degree but also offered us a compelling rationale to assume that these genetic alterations might function cooperatively with VHL inactivation to cause ccRCC.	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('function', 'Reg', (195, 203))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cause', 'Reg', (243, 248))	('alterations', 'Var', (177, 188))	('ccRCC', 'Phenotype', 'HP:0006770', (249, 254))	('inactivation', 'Var', (227, 239))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('RCC', 'Disease', (251, 254))	('RCC', 'Phenotype', 'HP:0005584', (251, 254))	('VHL', 'Gene', (223, 226))	('cancer', 'Disease', (70, 76))	('RCC', 'Disease', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (251, 254))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
67070	29651023	Loss of BAP1 in sporadic ccRCC has been reported to be as high as 14% and defines a high-grade subset of ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (105, 110))	('RCC', 'Disease', (107, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (25, 30))	('RCC', 'Disease', (27, 30))	('BAP1', 'Gene', (8, 12))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('Loss', 'Var', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))
67071	29651023	To investigate the effects of the combined inactivation of the Vhl and Bap1 in the mouse kidney, Wang and colleagues developed a mouse model using the Six2-Cre system to specifically induce gene deletion in nephron progenitor cells.	('Bap1', 'Gene', (71, 75))	('Six2', 'Gene', (151, 155))	('mouse', 'Species', '10090', (83, 88))	('mouse', 'Species', '10090', (129, 134))	('Six2', 'Gene', '20472', (151, 155))	('induce', 'Reg', (183, 189))	('gene deletion', 'Var', (190, 203))	('Vhl', 'Gene', (63, 66))	('Bap1', 'Gene', '104416', (71, 75))
67072	29651023	However, mice deficient in Bap1 were obviously moribund and died before 1 month of age.	('Bap1', 'Gene', (27, 31))	('Bap1', 'Gene', '104416', (27, 31))	('deficient', 'Var', (14, 23))	('mice', 'Species', '10090', (9, 13))
67079	29651023	Loss of 3p in humans can simultaneously cause both VHL and BAP1 deletion, but this would not occur in mouse due to the location of these two genes on different chromosomes.	('humans', 'Species', '9606', (14, 20))	('cause', 'Reg', (40, 45))	('BAP1', 'Gene', (59, 63))	('Loss of 3p', 'Var', (0, 10))	('deletion', 'Var', (64, 72))	('VHL', 'Gene', (51, 54))	('mouse', 'Species', '10090', (102, 107))
67082	29651023	Six2-Cre-induced Vhl deletion and loss of heterozygosity of Bap1 in mice led to mice dying shortly after birth, and kidney tumors that were too small; Sglt2-Cre or Villin-Cre failed to induce tumors.	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Disease', (192, 198))	('mice', 'Species', '10090', (68, 72))	('Six2', 'Gene', (0, 4))	('kidney tumors', 'Disease', 'MESH:D007674', (116, 129))	('kidney tumors', 'Phenotype', 'HP:0009726', (116, 129))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('deletion', 'Var', (21, 29))	('loss', 'NegReg', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('Sglt2', 'Gene', '246787', (151, 156))	('kidney tumor', 'Phenotype', 'HP:0009726', (116, 128))	('Sglt2', 'Gene', (151, 156))	('Vhl', 'Gene', (17, 20))	('Bap1', 'Gene', '104416', (60, 64))	('Six2', 'Gene', '20472', (0, 4))	('kidney tumors', 'Disease', (116, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumors', 'Disease', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('mice', 'Species', '10090', (80, 84))	('Bap1', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
67086	29651023	On the other hand, mice deficient in Vhl and one allele of Bap1 had a median survival of 14.5 months, displaying cystic lesions and tumors at 10 and 11 months of age, respectively.	('cystic lesions', 'Disease', 'MESH:D052177', (113, 127))	('Bap1', 'Gene', (59, 63))	('Vhl', 'Gene', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('Bap1', 'Gene', '104416', (59, 63))	('deficient', 'Var', (24, 33))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', (132, 138))	('mice', 'Species', '10090', (19, 23))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('cystic lesions', 'Disease', (113, 127))
67092	29651023	Nargund and colleagues pioneered a project to investigate the role of Pbrm1 in the tumorigenesis of ccRCC by deletion of both Vhl and Pbrm1 to produce an autochthonous ccRCC mouse model.	('mouse', 'Species', '10090', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('deletion', 'Var', (109, 117))	('tumor', 'Disease', (83, 88))	('RCC', 'Disease', (170, 173))	('Pbrm1', 'Gene', (134, 139))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('Pbrm1', 'Gene', '66923', (134, 139))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('ccRCC', 'Phenotype', 'HP:0006770', (168, 173))	('Vhl', 'Gene', (126, 129))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('Pbrm1', 'Gene', (70, 75))	('Pbrm1', 'Gene', '66923', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
67094	29651023	Mice deficient in both Vhl and Pbrm1 developed preneoplastic polycystic kidney diseases at 6-9 months of age with a 30% incidence, and histologic examination displayed a 50% tumor incidence at 10 months of age.	('tumor', 'Disease', (174, 179))	('preneoplastic polycystic kidney diseases', 'Disease', 'MESH:D007690', (47, 87))	('kidney diseases', 'Phenotype', 'HP:0000112', (72, 87))	('polycystic kidney', 'Phenotype', 'HP:0000113', (61, 78))	('Vhl', 'Gene', (23, 26))	('developed', 'Reg', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('preneoplastic polycystic kidney diseases', 'Disease', (47, 87))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('Mice', 'Species', '10090', (0, 4))	('Pbrm1', 'Gene', (31, 36))	('Pbrm1', 'Gene', '66923', (31, 36))	('deficient', 'Var', (5, 14))
67097	29651023	Another group developed a RCC GEM model based on Pax8-Cre deletion of Vhl and Pbrm1.	('Pbrm1', 'Gene', (78, 83))	('Pax8', 'Gene', '18510', (49, 53))	('Pbrm1', 'Gene', '66923', (78, 83))	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('Pax8', 'Gene', (49, 53))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('deletion', 'Var', (58, 66))	('Vhl', 'Gene', (70, 73))
67098	29651023	Their results showed that approximately 85% of double-deleted mice presented bilateral, multiple, large, and homogeneous tumors at the age of 9 months and 100% at the age of 13 months.	('double-deleted', 'Var', (47, 61))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('mice', 'Species', '10090', (62, 66))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('multiple', 'CPA', (88, 96))
67101	29651023	Both of the studies confirmed the tumor suppressor role of PBRM1 and that loss of VHL and PBRM1 in the kidney predisposes mice to ccRCC that recapitulates key features of human ccRCC, which is potentially useful for further research.	('mice', 'Species', '10090', (122, 126))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('tumor', 'Disease', (34, 39))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (177, 182))	('ccRCC', 'Phenotype', 'HP:0006770', (130, 135))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('VHL', 'Gene', (82, 85))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))	('loss', 'Var', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('RCC', 'Phenotype', 'HP:0005584', (179, 182))	('PBRM1', 'Gene', (90, 95))	('human', 'Species', '9606', (171, 176))	('RCC', 'Disease', (179, 182))
67105	29651023	Interestingly, Gu and colleagues studied the simultaneous deletion of Vhl/Bap1 and Vhl/Pbrm1 in mice and found that Bap1 and Pbrm1 not only drives ccRCC formation but also plays an important role in determining the tumor grade.	('Bap1', 'Gene', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('Pbrm1', 'Gene', (87, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (147, 152))	('Bap1', 'Gene', (74, 78))	('formation', 'biological_process', 'GO:0009058', ('153', '162'))	('Pbrm1', 'Gene', '66923', (87, 92))	('Pbrm1', 'Gene', (125, 130))	('drives', 'PosReg', (140, 146))	('mice', 'Species', '10090', (96, 100))	('tumor', 'Disease', (215, 220))	('Bap1', 'Gene', '104416', (116, 120))	('Pbrm1', 'Gene', '66923', (125, 130))	('RCC', 'Disease', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('Bap1', 'Gene', '104416', (74, 78))	('deletion', 'Var', (58, 66))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
67106	29651023	This result is compatible with the fact that mutations of BAP1 and PBRM1 have been repeatedly confirmed to be associated with the tumor grade, aggressiveness, and patient survival in human ccRCC cohorts.	('aggressiveness', 'Disease', 'MESH:D001523', (143, 157))	('mutations', 'Var', (45, 54))	('RCC', 'Disease', (191, 194))	('RCC', 'Phenotype', 'HP:0005584', (191, 194))	('BAP1', 'Gene', (58, 62))	('RCC', 'Disease', 'MESH:C538614', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (189, 194))	('aggressiveness', 'Disease', (143, 157))	('associated', 'Reg', (110, 120))	('human', 'Species', '9606', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('patient', 'Species', '9606', (163, 170))	('aggressiveness', 'Phenotype', 'HP:0000718', (143, 157))	('tumor', 'Disease', (130, 135))	('PBRM1', 'Gene', (67, 72))
67109	29651023	Deletion of one copy of TSC1 to active mTORC1 drives to low-grade tumors in PBRM1-deficient ccRCC to high-grade tumors.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('Deletion', 'Var', (0, 8))	('mTORC1', 'Gene', (39, 45))	('drives', 'Reg', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('mTORC1', 'Gene', '382056', (39, 45))	('TSC1', 'Gene', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Disease', (94, 97))	('PBRM1-deficient', 'Gene', (76, 91))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('mTORC1', 'cellular_component', 'GO:0031931', ('39', '45'))	('tumors', 'Disease', (66, 72))	('TSC1', 'Gene', '64930', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', (112, 118))
67110	29651023	In addition to inactivation of TSGs, activation of oncogenes plays an equally important role in tumorigenesis.	('TSG', 'Gene', (31, 34))	('oncogenes', 'Protein', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('TSG', 'Gene', '65960', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('inactivation', 'Var', (15, 27))
67111	29651023	The most important molecular change in ccRCC is the inactivation of VHL, the product of which is a component of an E3 ubiquitin ligase complex that targets the a-subunits of the HIFs for ubiquitination and proteolytic degradation.	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('ubiquitination', 'MPA', (187, 201))	('degradation', 'biological_process', 'GO:0009056', ('218', '229'))	('VHL', 'Gene', (68, 71))	('inactivation', 'Var', (52, 64))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('ubiquitin ligase complex', 'cellular_component', 'GO:0000151', ('118', '142'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('118', '127'))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))
67114	29651023	The supplementary role of HIFs as oncogenes in ccRCC has been clearly shown by the fact that co-deletion of the Hif1a/Hif2a or Arnt genes can rescue cystic phenotypes in Vhl mutant kidneys and cystic and neoplastic phenotypes in Vhl/Trp53 mutant kidneys.	('RCC', 'Disease', (49, 52))	('Hif2a', 'Gene', (118, 123))	('Vhl', 'Gene', (170, 173))	('Hif1a', 'Gene', '15251', (112, 117))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('rescue', 'PosReg', (142, 148))	('co-deletion', 'Var', (93, 104))	('cystic phenotypes', 'CPA', (149, 166))	('Vhl/Trp53', 'Gene', (229, 238))	('Arnt', 'Gene', '11863', (127, 131))	('RCC', 'Disease', 'MESH:C538614', (49, 52))	('Arnt', 'Gene', (127, 131))	('Hif1a', 'Gene', (112, 117))	('mutant', 'Var', (239, 245))	('Hif2a', 'Gene', '13819', (118, 123))	('mutant', 'Var', (174, 180))
67116	29651023	Their results showed that Hif1alpha but not Hif2alpha activation drives the formation of "clear" cells and renal cysts, as well as other pathological and molecular features of early-stage human ccRCC.	('formation', 'biological_process', 'GO:0009058', ('76', '85'))	('human', 'Species', '9606', (188, 193))	('renal cyst', 'Phenotype', 'HP:0000107', (107, 117))	('renal cysts', 'Disease', 'MESH:D007674', (107, 118))	('renal cysts', 'Disease', (107, 118))	('Hif1alpha', 'Var', (26, 35))	('RCC', 'Disease', 'MESH:C538614', (196, 199))	('RCC', 'Disease', (196, 199))	('RCC', 'Phenotype', 'HP:0005584', (196, 199))	('renal cysts', 'Phenotype', 'HP:0000107', (107, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (194, 199))
67122	29651023	Johansson and colleagues performed an in vivo study to determine whether activating Notch signaling could induce tumor formation in renal proximal tubular epithelial cells.	('tumor', 'Disease', (113, 118))	('signaling', 'biological_process', 'GO:0023052', ('90', '99'))	('induce', 'PosReg', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('activating', 'Var', (73, 83))	('formation', 'biological_process', 'GO:0009058', ('119', '128'))	('Notch signaling', 'Gene', (84, 99))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
67123	29651023	They established a conditional mouse model with a concurrent deletion of the Vhl gene and ectopic expression of constitutively active Notch1 (NICD1) using the Kap2-iCre system to target proximal tubular cells.	('Notch1', 'Gene', '18128', (134, 140))	('Vhl', 'Gene', (77, 80))	('deletion', 'Var', (61, 69))	('mouse', 'Species', '10090', (31, 36))	('Notch1', 'Gene', (134, 140))
67125	29651023	A further in vivo study supported the role of activating Notch signaling in inducing cytoplasmic lipid accumulation in ccRCC, and inhibition of Notch signaling was able to reverse this process.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('signaling', 'biological_process', 'GO:0023052', ('63', '72'))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('inhibition', 'Var', (130, 140))	('RCC', 'Disease', (121, 124))	('signaling', 'biological_process', 'GO:0023052', ('150', '159'))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('inducing', 'Reg', (76, 84))	('lipid', 'Chemical', 'MESH:D008055', (97, 102))	('Notch signaling', 'Gene', (57, 72))	('cytoplasmic lipid accumulation', 'MPA', (85, 115))	('activating', 'PosReg', (46, 56))
67126	29651023	Another group developed a similar mouse model and also showed dysplastic changes in these tubular cells with deleted Vhl and activated Notch.	('mouse', 'Species', '10090', (34, 39))	('dysplastic', 'Disease', (62, 72))	('dysplastic', 'Disease', 'MESH:D004416', (62, 72))	('Notch', 'Gene', (135, 140))	('deleted', 'Var', (109, 116))	('Vhl', 'Gene', (117, 120))
67128	29651023	However, the above results seem to indicate that Notch activation together with Vhl deletion is not sufficient to cause ccRCC, at least in proximal tubular cells.	('deletion', 'Var', (84, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (120, 125))	('Vhl', 'Gene', (80, 83))	('cause', 'Reg', (114, 119))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))
67130	29651023	Overactivation of MYC confers a selective growth advantage to cells and orchestrates many hallmark features of cancer.	('MYC', 'Gene', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('growth advantage', 'CPA', (42, 58))	('Overactivation', 'Var', (0, 14))
67132	29651023	Increased levels of MYC gene expression have been found in most RCC and could result from different genetic and epigenetic mechanisms, including focal amplification of 8q24 harboring MYC and regulation of MYC expression by single-nucleotide polymorphisms.	('MYC', 'Gene', (20, 23))	('levels', 'MPA', (10, 16))	('gene expression', 'biological_process', 'GO:0010467', ('24', '39'))	('result from', 'Reg', (78, 89))	('MYC', 'Gene', (183, 186))	('focal amplification', 'Var', (145, 164))	('Increased', 'PosReg', (0, 9))	('single-nucleotide polymorphisms', 'Var', (223, 254))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('regulation', 'biological_process', 'GO:0065007', ('191', '201'))	('RCC', 'Disease', (64, 67))	('expression', 'MPA', (29, 39))	('MYC', 'Protein', (205, 208))
67134	29651023	Due to the crucial role of MYC activation in ccRCC, as well as the high prevalence of VHL deletion in ccRCC, it is easy to propose a hypothesis that VHL deletion might serve as the permissive context for MYC in ccRCC development.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('deletion', 'Var', (90, 98))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('deletion', 'Var', (153, 161))	('ccRCC', 'Phenotype', 'HP:0006770', (211, 216))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('RCC', 'Disease', (213, 216))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('VHL', 'Gene', (86, 89))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('activation', 'PosReg', (31, 41))	('VHL', 'Gene', (149, 152))	('RCC', 'Disease', (104, 107))
67135	29651023	Bailey and colleagues provided solid evidence for this hypothesis by developing a mouse model of RCC with a conditional deletion of Vhl and overexpression of Myc in renal tubular cells.	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('Myc', 'Gene', (158, 161))	('Myc', 'Gene', '17869', (158, 161))	('overexpression', 'PosReg', (140, 154))	('deletion', 'Var', (120, 128))	('mouse', 'Species', '10090', (82, 87))	('Vhl', 'Gene', (132, 135))
67137	29651023	In addition to Vhl deletion and MYC overexpression, inactivation of the Cdkn2a gene was added to the mouse model.	('Cdkn2a', 'Gene', (72, 78))	('Vhl', 'Gene', (15, 18))	('deletion', 'Var', (19, 27))	('mouse', 'Species', '10090', (101, 106))	('Cdkn2a', 'Gene', '12578', (72, 78))
67138	29651023	The Cdkn2a gene, the mutations of which are implicated in 31% of ccRCC, encodes the CDK4/6 inhibitor p16(ink4a), which is involved in cellular senescence by regulating the RB pathway, as well as a linked protein Arf that regulates the p53 pathway.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', (67, 70))	('implicated', 'Reg', (44, 54))	('RB pathway', 'Pathway', (172, 182))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('protein', 'cellular_component', 'GO:0003675', ('204', '211'))	('CDK4/6', 'Gene', (84, 90))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('CDK', 'molecular_function', 'GO:0004693', ('84', '87'))	('CDK4/6', 'Gene', '12567;12571', (84, 90))	('regulating', 'Reg', (157, 167))	('cellular senescence', 'biological_process', 'GO:0090398', ('134', '153'))	('Cdkn2a', 'Gene', '12578', (4, 10))	('p53 pathway', 'Pathway', (235, 246))	('ink4a', 'Gene', '12578', (105, 110))	('ink4a', 'Gene', (105, 110))	('p16', 'Gene', '12578', (101, 104))	('regulates', 'Reg', (221, 230))	('Cdkn2a', 'Gene', (4, 10))	('mutations', 'Var', (21, 30))	('p16', 'Gene', (101, 104))
67140	29651023	Additionally, Cdkn2a(Ink4a/Arf) deletion promoted macroscopic metastases of ccRCC to the liver in one-third of mice.	('Cdkn2a', 'Gene', (14, 20))	('deletion', 'Var', (32, 40))	('metastases', 'Disease', 'MESH:D009362', (62, 72))	('Ink4a/Arf', 'Gene', '12578', (21, 30))	('Ink4a/Arf', 'Gene', (21, 30))	('promoted', 'PosReg', (41, 49))	('RCC', 'Disease', (78, 81))	('mice', 'Species', '10090', (111, 115))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('Cdkn2a', 'Gene', '12578', (14, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('metastases', 'Disease', (62, 72))
67151	29651023	Another recurrent mutated TSG on chromosome 3p is SET domain-containing 2 (SETD2), which encodes a histone methyltransferase and mutated in ccRCC at a rate of 10-20%.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('chromosome', 'cellular_component', 'GO:0005694', ('33', '43'))	('RCC', 'Disease', (142, 145))	('SET domain-containing 2', 'Gene', '235626', (50, 73))	('TSG', 'Gene', '65960', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('SETD2', 'Gene', (75, 80))	('TSG', 'Gene', (26, 29))	('mutated', 'Var', (129, 136))	('SET domain-containing 2', 'Gene', (50, 73))
67161	29651023	A good example of this is about TP53 mutations: patient-relevant Trp53 hotspot mutations in mice are much more oncogenic than Trp53 knockouts.	('Trp53', 'Gene', (65, 70))	('oncogenic', 'CPA', (111, 120))	('patient', 'Species', '9606', (48, 55))	('mice', 'Species', '10090', (92, 96))	('mutations', 'Var', (79, 88))
67162	29651023	A similar story applies to Brca1 mutations and knockout in mice.	('Brca1', 'Gene', (27, 32))	('Brca1', 'Gene', '12189', (27, 32))	('mice', 'Species', '10090', (59, 63))	('mutations', 'Var', (33, 42))
67163	29651023	This suggestion is based on an observation that the tumor phenotype is directly shaped by the order of acquisition of genetic alterations and that the order of genetic mutations influences the clonal evolution of cancer.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('influences', 'Reg', (178, 188))	('tumor', 'Disease', (52, 57))	('clonal evolution', 'CPA', (193, 209))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (213, 219))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('alterations', 'Var', (126, 137))
67250	34046336	The activation of HIF-1 in the kidney is dependent on the prevalence of hypoxia as well as the presence of the VHL gene product (pVHL).	('VHL', 'Gene', (111, 114))	('HIF-1', 'Gene', (18, 23))	('HIF-1', 'Gene', '3091', (18, 23))	('VHL', 'Gene', '7428', (111, 114))	('VHL', 'Gene', (130, 133))	('presence', 'Var', (95, 103))	('hypoxia', 'Disease', (72, 79))	('hypoxia', 'Disease', 'MESH:D000860', (72, 79))	('pVHL', 'Gene', '7428', (129, 133))	('VHL', 'Gene', '7428', (130, 133))	('pVHL', 'Gene', (129, 133))	('activation', 'PosReg', (4, 14))
67254	34046336	The activation of those genes with increased expression in the early stages of tumor development is associated with HIF-1-mediated cellular adaptation to the oxygen-deprived microenvironment as well as due to the accumulation of HIF1alpha caused by the inactivation of the VHL gene.	('HIF1alpha', 'Gene', '3091', (229, 238))	('HIF1alpha', 'Gene', (229, 238))	('oxygen', 'Chemical', 'MESH:D010100', (158, 164))	('tumor', 'Disease', (79, 84))	('inactivation', 'Var', (253, 265))	('accumulation', 'PosReg', (213, 225))	('VHL', 'Gene', (273, 276))	('age', 'Gene', '5973', (71, 74))	('HIF-1', 'Gene', '3091', (116, 121))	('expression', 'MPA', (45, 55))	('VHL', 'Gene', '7428', (273, 276))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('HIF-1', 'Gene', (116, 121))	('activation', 'PosReg', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('age', 'Gene', (71, 74))
67278	34046336	NDUFA4L2 knockdown increased ROS production in NSCLC cell lines.	('knockdown', 'Var', (9, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('increased', 'PosReg', (19, 28))	('increased ROS production', 'Phenotype', 'HP:0025464', (19, 43))	('NSCLC', 'Disease', (47, 52))	('NDUFA4L2', 'Gene', '56901', (0, 8))	('ROS production', 'MPA', (29, 43))	('ROS', 'Chemical', '-', (29, 32))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))	('NDUFA4L2', 'Gene', (0, 8))
67300	34046336	In another study, the increased expression of BHLHE41 stimulated the proliferation of cultured ccRCC cells, and its knockdown led to a significant decrease in these indicators.	('BHLHE41', 'Gene', '79365', (46, 53))	('proliferation', 'CPA', (69, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('stimulated', 'PosReg', (54, 64))	('decrease', 'NegReg', (147, 155))	('knockdown', 'Var', (116, 125))	('increased', 'PosReg', (22, 31))	('expression', 'MPA', (32, 42))	('BHLHE41', 'Gene', (46, 53))
67301	34046336	Transfection of BHLHE41 into cultured cancer cells increased their proportion in the S and G2 phases and decreased them in the G1 phase.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('increased', 'PosReg', (51, 60))	('Transfection', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('BHLHE41', 'Gene', (16, 23))	('cancer', 'Disease', (38, 44))	('G1 phase', 'biological_process', 'GO:0051318', ('127', '135'))	('decreased', 'NegReg', (105, 114))	('BHLHE41', 'Gene', '79365', (16, 23))
67345	34046336	At the initial stage, in which the release of cells from the tumor for development is irrelevant, this gene can influence glycolytic processes and enhance proliferation.	('enhance', 'PosReg', (147, 154))	('age', 'Gene', (17, 20))	('gene', 'Var', (103, 107))	('proliferation', 'CPA', (155, 168))	('influence', 'Reg', (112, 121))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('age', 'Gene', '5973', (17, 20))	('glycolytic', 'MPA', (122, 132))	('tumor', 'Disease', (61, 66))
67368	34046336	These genes, as per the processes identified with GO, are associated with the activation of metabolic and inflammatory processes, indicating that these occur at an early stage of tumor development and persist throughout subsequent stages.	('genes', 'Var', (6, 11))	('age', 'Gene', (233, 236))	('age', 'Gene', (172, 175))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('activation', 'PosReg', (78, 88))	('age', 'Gene', '5973', (233, 236))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('metabolic', 'CPA', (92, 101))	('tumor', 'Disease', (179, 184))	('age', 'Gene', '5973', (172, 175))	('inflammatory processes', 'CPA', (106, 128))
67389	33668731	Moreover, gain of 5q34-q35.3 (FLT4 and NSD1) and loss of 6q23.2-q23.3 (MYB) and 9p21.3 (MLLT3) had gene expression levels that correlated with TCGA data and was also associated with advanced disease features, such as larger tumors, Fuhrman 3, metastasis at diagnosis and death.	('5q34-q35.3', 'Var', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('5q', 'Chemical', '-', (18, 20))	('tumors', 'Disease', (224, 230))	('death', 'Disease', (271, 276))	('gene expression', 'biological_process', 'GO:0010467', ('99', '114'))	('metastasis at diagnosis', 'Disease', (243, 266))	('gain', 'PosReg', (10, 14))	('MYB', 'Gene', '4602', (71, 74))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('9p21.3', 'Var', (80, 86))	('MYB', 'Gene', (71, 74))	('NSD1', 'Gene', '64324', (39, 43))	('associated', 'Reg', (166, 176))	('MLLT3', 'Gene', (88, 93))	('FLT4', 'Gene', '2324', (30, 34))	('FLT4', 'Gene', (30, 34))	('gene expression levels', 'MPA', (99, 121))	('death', 'Disease', 'MESH:D003643', (271, 276))	('loss', 'Var', (49, 53))	('Fuhrman 3', 'Disease', (232, 241))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('MLLT3', 'Gene', '4300', (88, 93))	('NSD1', 'Gene', (39, 43))
67390	33668731	The loss of region 14q22.1 which encompasses the NIN gene was associated with poor overall survival.	('overall', 'MPA', (83, 90))	('NIN', 'Gene', '51199', (49, 52))	('poor', 'NegReg', (78, 82))	('NIN', 'Gene', (49, 52))	('loss', 'Var', (4, 8))
67392	33668731	Our results highlight important genes that are associated with copy number changes involving large chromosomal regions that are potentially related to ccRCC tumorigenesis and disease biology for future clinical investigations.	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('ccRCC tumor', 'Disease', 'MESH:D009369', (151, 162))	('related', 'Reg', (140, 147))	('ccRCC', 'Phenotype', 'HP:0006770', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('copy number changes', 'Var', (63, 82))	('ccRCC tumor', 'Disease', (151, 162))
67400	33668731	Recurrent chromosomal abnormalities and copy number imbalances are related to clear-cell renal-cell carcinoma (ccRCC) tumorigenesis.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('related', 'Reg', (67, 74))	('imbalance', 'Phenotype', 'HP:0002172', (52, 61))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (10, 35))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('chromosomal abnormalities', 'Disease', (10, 35))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('renal-cell carcinoma', 'Phenotype', 'HP:0005584', (89, 109))	('imbalances', 'Phenotype', 'HP:0002172', (52, 62))	('clear-cell renal-cell carcinoma', 'Phenotype', 'HP:0006770', (78, 109))	('copy number imbalances', 'Var', (40, 62))	('Recurrent chromosomal abnormalities', 'Phenotype', 'HP:0040012', (0, 35))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('clear-cell renal-cell carcinoma (ccRCC) tumorigenesis', 'Disease', 'MESH:C538614', (78, 131))
67401	33668731	Most of the ccRCC copy number alterations (CNAs) consist of extensive chromosomal losses or gains that can involve multiple genes, in which changes of gene dosage may alter the levels of gene's expression.	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('ccRCC', 'Phenotype', 'HP:0006770', (12, 17))	('RCC', 'Disease', (14, 17))	('alter', 'Reg', (167, 172))	('gains', 'PosReg', (92, 97))	('changes', 'Var', (140, 147))	("levels of gene's expression", 'MPA', (177, 204))	('copy number alterations', 'Disease', (18, 41))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
67402	33668731	The impact of CNAs has been recently associated with changes in the metabolic activity since copy number losses of KEAP1 are involved in the transcriptional control of glutathione metabolism genes.	('glutathione metabolism', 'biological_process', 'GO:0006749', ('168', '190'))	('glutathione', 'Chemical', 'MESH:D005978', (168, 179))	('KEAP1', 'Gene', '9817', (115, 120))	('transcriptional control', 'biological_process', 'GO:0006355', ('141', '164'))	('KEAP1', 'Gene', (115, 120))	('metabolic', 'MPA', (68, 77))	('involved', 'Reg', (125, 133))	('copy number losses', 'Var', (93, 111))
67406	33668731	The loss or inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene at 3p25.3 is considered the crucial step in ccRCC carcinogenesis; however, other alterations are also required.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('ccRCC', 'Phenotype', 'HP:0006770', (122, 127))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (32, 61))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('56', '72'))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('56', '72'))	('inactivation', 'Var', (12, 24))	('loss', 'NegReg', (4, 8))
67409	33668731	Losses of chromosomes 14q, 9p and deletions on 6q and 8p are also reported and have been described to be correlated with advanced tumors and worse patient survival.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('advanced', 'Disease', (121, 129))	('Losses', 'NegReg', (0, 6))	('patient', 'Species', '9606', (147, 154))	('deletions', 'Var', (34, 43))	('correlated', 'Reg', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))
67425	33668731	An average of 10-12% of each patient's tumor genome had copy number imbalances.	('copy number imbalances', 'Var', (56, 78))	('patient', 'Species', '9606', (29, 36))	('imbalances', 'Phenotype', 'HP:0002172', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('imbalance', 'Phenotype', 'HP:0002172', (68, 77))
67427	33668731	According to Cancer Genome Interpreter (CGI) analysis, alterations in SETD2, BAP1, FLT4 and PTEN genes were reported as known drivers in several tumor types, and events in FGFR4 and NSD1 genes were classified as predicted drivers.	('FGFR4', 'Gene', (172, 177))	('Cancer', 'Disease', (13, 19))	('NSD1', 'Gene', (182, 186))	('PTEN', 'Gene', (92, 96))	('FGFR', 'molecular_function', 'GO:0005007', ('172', '176'))	('Cancer', 'Disease', 'MESH:D009369', (13, 19))	('PTEN', 'Gene', '5728', (92, 96))	('tumor', 'Disease', (145, 150))	('BAP1', 'Gene', '8314', (77, 81))	('NSD1', 'Gene', '64324', (182, 186))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('FLT4', 'Gene', (83, 87))	('FLT4', 'Gene', '2324', (83, 87))	('SETD2', 'Gene', (70, 75))	('BAP1', 'Gene', (77, 81))	('FGFR4', 'Gene', '2264', (172, 177))	('alterations', 'Var', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('SETD2', 'Gene', '29072', (70, 75))
67431	33668731	Except for 3p loss, all other alterations, i.e., deletions on 9p (9p-) and 14q (14q-), and gain on 7p (7p+) were significantly associated with features of advanced disease, such as tumor metastasis, T3/T4 stages, higher Fuhrman grade (3-4), larger tumors and dismal outcome (death).	('T3/T4 stages', 'CPA', (199, 211))	('associated with', 'Reg', (127, 142))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor metastasis', 'Disease', 'MESH:D009362', (181, 197))	('advanced disease', 'Disease', (155, 171))	('higher', 'PosReg', (213, 219))	('tumor metastasis', 'Disease', (181, 197))	('tumors', 'Disease', (248, 254))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('14q', 'Gene', (75, 78))	('death', 'Disease', 'MESH:D003643', (275, 280))	('deletions on 9p', 'Var', (49, 64))	('death', 'Disease', (275, 280))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('gain', 'PosReg', (91, 95))
67434	33668731	Patients with loss of 9p21.3 are more likely to have advanced staging (p = 0.005; 95% CI = 1.51-10.20) and with metastatic disease (p = 0.003; 95% IC = 1.72-16.02).	('loss of', 'Var', (14, 21))	('metastatic disease', 'Disease', (112, 130))	('advanced staging', 'CPA', (53, 69))	('metastatic disease', 'Disease', 'MESH:C538445', (112, 130))	('Patients', 'Species', '9606', (0, 8))	('9p21.3', 'Protein', (22, 28))
67435	33668731	Finally, patients with a loss of 14q22.1 had an increased risk of death approximately 3 times compared to patients without this event (p = 0.02; 95% CI = 1.12-7.84) (Table 4).	('14q22.1', 'Gene', (33, 40))	('patients', 'Species', '9606', (9, 17))	('loss', 'Var', (25, 29))	('death', 'Disease', 'MESH:D003643', (66, 71))	('death', 'Disease', (66, 71))	('patients', 'Species', '9606', (106, 114))
67436	33668731	In addition, loss of chromosome 14q, which encompasses the NIN gene was associated with shorter survival (p = 0.03) (Figure 3).	('shorter', 'NegReg', (88, 95))	('NIN', 'Gene', '51199', (59, 62))	('NIN', 'Gene', (59, 62))	('chromosome', 'cellular_component', 'GO:0005694', ('21', '31'))	('loss', 'Var', (13, 17))	('survival', 'MPA', (96, 104))
67442	33668731	According to TCGA data, loss of BAP1 in 3p, an oncogenic aberration known to be a biomarker of RCC was only associated with Fuhrman grade 1 (p = 0.02).	('loss', 'Var', (24, 28))	('BAP1', 'Gene', '8314', (32, 36))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('Fuhrman grade 1', 'Disease', (124, 139))	('RCC', 'Disease', (95, 98))	('BAP1', 'Gene', (32, 36))
67443	33668731	Losses of MYB and MLLT3, despite being predicted as passengers alterations were significantly associated with advanced disease: Loss of MLLT3 gene was associated with metastasis at diagnosis (p = 0.005), stage IV disease (p = 0.02), larger tumors (p = 0.01) and poor outcomes (p = 0.02), while loss of MYB was correlated with Fuhrman grade 3 (p = 0.02).	('Loss', 'Var', (128, 132))	('MLLT3', 'Gene', (136, 141))	('MYB', 'Gene', '4602', (302, 305))	('MYB', 'Gene', (10, 13))	('MLLT3', 'Gene', '4300', (136, 141))	('stage IV disease', 'Disease', 'MESH:D058625', (204, 220))	('MLLT3', 'Gene', '4300', (18, 23))	('MYB', 'Gene', (302, 305))	('poor', 'Disease', (262, 266))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('MLLT3', 'Gene', (18, 23))	('advanced disease', 'Disease', (110, 126))	('tumors', 'Disease', (240, 246))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('stage IV disease', 'Disease', (204, 220))	('MYB', 'Gene', '4602', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('metastasis at diagnosis', 'CPA', (167, 190))
67445	33668731	Loss of FTL4 was also associated with larger tumors (p = 0.007) and loss of NSD1, considered a predicted driver aberration was associated with larger tumors (p = 0.007) and advanced disease (stage IV; p = 0.01).	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('advanced disease', 'CPA', (173, 189))	('NSD1', 'Gene', '64324', (76, 80))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('NSD1', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('FTL4', 'Gene', (8, 12))	('loss', 'Var', (68, 72))	('Loss', 'Var', (0, 4))
67446	33668731	Aberrations of TFG and CDH11, despite showing changes on gene expression levels are still reported as predicted passenger alterations and did not show any clinicopathological associations.	('changes', 'Reg', (46, 53))	('gene expression levels', 'MPA', (57, 79))	('CDH11', 'Gene', (23, 28))	('CDH11', 'Gene', '1009', (23, 28))	('TFG', 'Gene', '10342', (15, 18))	('gene expression', 'biological_process', 'GO:0010467', ('57', '72'))	('TFG', 'Gene', (15, 18))	('Aberrations', 'Var', (0, 11))
67447	33668731	Copy number alterations (CNA) are important drivers of ccRCC tumorigenesis.	('ccRCC tumor', 'Disease', (55, 66))	('ccRCC tumor', 'Disease', 'MESH:D009369', (55, 66))	('Copy number alterations', 'Var', (0, 23))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))
67450	33668731	Some regions, including the gain of 5q34-q35.3 (FLT4 and NSD1) and loss of 6q23.2-q23.3 (MYB), 9p21.3 (MLLT3), and 14q22.1 (NIN) had gene expression levels validated by in silico re-analysis of TCGA data and were associated with patients clinicopathologic features.	('patients', 'Species', '9606', (229, 237))	('gain', 'PosReg', (28, 32))	('MLLT3', 'Gene', '4300', (103, 108))	('NSD1', 'Gene', '64324', (57, 61))	('MYB', 'Gene', '4602', (89, 92))	('FLT4', 'Gene', '2324', (48, 52))	('FLT4', 'Gene', (48, 52))	('MYB', 'Gene', (89, 92))	('14q22.1', 'Var', (115, 122))	('NIN', 'Gene', (124, 127))	('loss', 'NegReg', (67, 71))	('gene expression', 'biological_process', 'GO:0010467', ('133', '148'))	('9p21.3', 'Var', (95, 101))	('MLLT3', 'Gene', (103, 108))	('5q34-q35.3', 'Var', (36, 46))	('5q', 'Chemical', '-', (36, 38))	('NSD1', 'Gene', (57, 61))	('NIN', 'Gene', '51199', (124, 127))	('6q23.2-q23.3', 'Var', (75, 87))
67454	33668731	It has been reported that 3p loss is a truncal event in RCC.	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('RCC', 'Disease', (56, 59))	('3p loss', 'Var', (26, 33))
67459	33668731	Further studies on ccRCC mutations in the Brazilian population and local ancestry inference are necessary to estimates the number of copies at genomic sites to unravel such differences.	('mutations', 'Var', (25, 34))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('RCC', 'Disease', (21, 24))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('ccRCC', 'Phenotype', 'HP:0006770', (19, 24))
67467	33668731	It was also demonstrated that the loss of chromosome 14 leads to a decrease in HIF1-a protein levels since HIF1A gene maps at 14q23.2.	('HIF1-a', 'Gene', '3091', (79, 85))	('loss', 'Var', (34, 38))	('decrease', 'NegReg', (67, 75))	('HIF1A', 'Gene', (107, 112))	('HIF1A', 'Gene', '3091', (107, 112))	('HIF1-a', 'Gene', (79, 85))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('chromosome', 'cellular_component', 'GO:0005694', ('42', '52'))
67477	33668731	Deletions of PTEN, SETD2 and BAP1 genes, are described as biomarkers for RCC and are responsive to drugs of preclinical and clinical trials.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('SETD2', 'Gene', (19, 24))	('RCC', 'Disease', (73, 76))	('SETD2', 'Gene', '29072', (19, 24))	('PTEN', 'Gene', '5728', (13, 17))	('BAP1', 'Gene', '8314', (29, 33))	('PTEN', 'Gene', (13, 17))	('BAP1', 'Gene', (29, 33))	('Deletions', 'Var', (0, 9))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
67478	33668731	Also, deletions of JAK2, CD274 and MYD88 genes, and amplification of FGFR4 and NPM1 genes, are also involved in clinical trials for other tumor types.	('NPM1', 'Gene', '4869', (79, 83))	('FGFR4', 'Gene', '2264', (69, 74))	('FGFR4', 'Gene', (69, 74))	('JAK2', 'Gene', (19, 23))	('tumor', 'Disease', (138, 143))	('MYD88', 'Gene', (35, 40))	('MYD88', 'Gene', '4615', (35, 40))	('JAK', 'molecular_function', 'GO:0004713', ('19', '22'))	('FGFR', 'molecular_function', 'GO:0005007', ('69', '73'))	('deletions', 'Var', (6, 15))	('involved', 'Reg', (100, 108))	('CD274', 'Gene', '29126', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('NPM1', 'Gene', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('JAK2', 'Gene', '3717', (19, 23))	('CD274', 'Gene', (25, 30))
67479	33668731	Interestingly, alterations in JAK2, MYD88 and NPM1 genes, already have drugs FDA approved for other cancers.	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('JAK2', 'Gene', '3717', (30, 34))	('NPM1', 'Gene', '4869', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('alterations', 'Var', (15, 26))	('JAK', 'molecular_function', 'GO:0004713', ('30', '33'))	('JAK2', 'Gene', (30, 34))	('MYD88', 'Gene', '4615', (36, 41))	('MYD88', 'Gene', (36, 41))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('NPM1', 'Gene', (46, 50))	('cancers', 'Disease', (100, 107))
67484	33668731	These findings suggest that dysregulation of the epigenome could be one of the underlying mechanisms driving the translational response to CNAs, and further studies could help to understand the impact of the results regarding tumor suppressors involved in the chromatin modification mechanisms.	('dysregulation', 'Var', (28, 41))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('chromatin modification', 'biological_process', 'GO:0006325', ('260', '282'))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('chromatin', 'cellular_component', 'GO:0000785', ('260', '269'))	('chromatin modification', 'biological_process', 'GO:0016569', ('260', '282'))	('tumor', 'Disease', (226, 231))
67487	33668731	In our current study, the group of patients with less than 50 CNAs was significantly associated with evidence of localized diseases such as small tumors, early stages and histological grade, absence of metastases, and better outcomes.	('metastases', 'Disease', 'MESH:D009362', (202, 212))	('small tumors', 'Disease', (140, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('localized diseases', 'Disease', 'MESH:D012594', (113, 131))	('small tumors', 'Disease', 'MESH:D058405', (140, 152))	('localized diseases', 'Disease', (113, 131))	('less than 50 CNAs', 'Var', (49, 66))	('patients', 'Species', '9606', (35, 43))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('metastases', 'Disease', (202, 212))
67508	33668731	We found the most frequent aberrant regions were loss of 3p (87.3%), 14q (35.8%), and gains of 5q (59.7%) in accordance with previous studies.	('gains', 'Var', (86, 91))	('loss', 'NegReg', (49, 53))	('14q', 'CPA', (69, 72))	('5q', 'Chemical', '-', (95, 97))
67552	33036276	In the analysis of chromosomal change, the loss of chromosome 9 was reported to associate with metachronous ccRCC-BM.	('RCC', 'Disease', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('associate', 'Reg', (80, 89))	('chromosome', 'cellular_component', 'GO:0005694', ('51', '61'))	('loss', 'Var', (43, 47))
67571	33036276	analyzed 106 patients with RCC-BM in the TKI era and found that KPS < 80%, diagnosis to treatment with targeted therapy <1 year, and >4 BM were associated with shorter OS since BM diagnosis.	('KPS', 'Var', (64, 67))	('patients', 'Species', '9606', (13, 21))	('< 80%', 'Var', (68, 73))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))
67628	33036276	analyzed 81 patients with BM and also found that TKI was associated with a trend toward improved OS (with TKI: 6.71 months, without TKI: 4.4 months, p = 0.07 and significantly longer OS for patients who were TKI-naive at the time of BM development:23.6 months versus 2.08 months those who received TKI pre-BM, and 4.41 months for the never-TKI group (p = 0.0001).	('pre', 'molecular_function', 'GO:0003904', ('302', '305'))	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (190, 198))	('TKI', 'Var', (49, 52))	('longer', 'PosReg', (176, 182))	('improved', 'PosReg', (88, 96))
67682	32029828	In a different study, a pan-cancer analysis found renal cell carcinomas (RCC) to have the highest proportion of indel mutations, which can increase tumor neoantigen abundance.	('indel mutations', 'Var', (112, 127))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (50, 71))	('RCC', 'Disease', 'MESH:D002292', (73, 76))	('RCC', 'Disease', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (50, 70))	('tumor', 'Disease', (148, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('increase', 'PosReg', (139, 147))	('renal cell carcinomas', 'Disease', (50, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('renal cell carcinomas', 'Disease', 'MESH:D002292', (50, 71))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
67711	32029828	To understand the association of most frequently mutated genes in ccRCC, we analysed the mutation of VHL, BAP1, SETD2, PBRM1 and TP53 with the different patient clusters.	('BAP1', 'Gene', (106, 110))	('SETD2', 'Gene', '29072', (112, 117))	('PBRM1', 'Gene', (119, 124))	('mutation', 'Var', (89, 97))	('PBRM1', 'Gene', '55193', (119, 124))	('SETD2', 'Gene', (112, 117))	('TP53', 'Gene', '7157', (129, 133))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('RCC', 'Disease', 'MESH:D002292', (68, 71))	('RCC', 'Disease', (68, 71))	('BAP1', 'Gene', '8314', (106, 110))	('patient', 'Species', '9606', (153, 160))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('VHL', 'Disease', 'MESH:D006623', (101, 104))	('TP53', 'Gene', (129, 133))	('analysed', 'Reg', (76, 84))	('VHL', 'Disease', (101, 104))
67712	32029828	Statistically significant association was found in TP53, BAP1 and PBRM1 mutation with both Angio and T-eff groups, respectively (Supplementary Table ST3).	('Angio', 'Disease', (91, 96))	('TP53', 'Gene', (51, 55))	('T-eff groups', 'Disease', (101, 113))	('PBRM1', 'Gene', (66, 71))	('BAP1', 'Gene', '8314', (57, 61))	('mutation', 'Var', (72, 80))	('ST3', 'Gene', (149, 152))	('PBRM1', 'Gene', '55193', (66, 71))	('significant association', 'Reg', (14, 37))	('BAP1', 'Gene', (57, 61))	('TP53', 'Gene', '7157', (51, 55))	('ST3', 'Gene', '6762', (149, 152))
67713	32029828	Interestingly, higher proportion of mutation for both TP53 and BAP1 was observed in T-eff group compared to Angio group, and PBRM1 mutation with Angio compared to T-eff group of ccRCC patients (Supplementary Table ST3).	('RCC', 'Disease', 'MESH:D002292', (180, 183))	('ST3', 'Gene', (214, 217))	('RCC', 'Disease', (180, 183))	('BAP1', 'Gene', (63, 67))	('patients', 'Species', '9606', (184, 192))	('BAP1', 'Gene', '8314', (63, 67))	('PBRM1', 'Gene', '55193', (125, 130))	('ST3', 'Gene', '6762', (214, 217))	('RCC', 'Phenotype', 'HP:0005584', (180, 183))	('ccRCC', 'Phenotype', 'HP:0006770', (178, 183))	('TP53', 'Gene', '7157', (54, 58))	('T-eff', 'Disease', (84, 89))	('PBRM1', 'Gene', (125, 130))	('TP53', 'Gene', (54, 58))	('mutation', 'Var', (36, 44))	('mutation', 'Var', (131, 139))
67719	32029828	Furthermore, we identified a new "Mixed" cluster of patients who expressed genes from all the pathways (Angio, T-eff, Invasion, and Ca2+-flux).	('expressed', 'Reg', (65, 74))	('genes', 'Var', (75, 80))	('T-eff', 'Disease', (111, 116))	('Ca2+', 'Chemical', 'MESH:D002118', (132, 136))	('Invasion', 'CPA', (118, 126))	('Angio', 'Disease', (104, 109))	('patients', 'Species', '9606', (52, 60))
67721	32029828	Statistically significant association was found in TP53, BAP1 and PBRM1 mutation with both Angio and T-eff groups, respectively.	('Angio', 'Disease', (91, 96))	('TP53', 'Gene', (51, 55))	('T-eff groups', 'Disease', (101, 113))	('PBRM1', 'Gene', (66, 71))	('BAP1', 'Gene', '8314', (57, 61))	('mutation', 'Var', (72, 80))	('PBRM1', 'Gene', '55193', (66, 71))	('significant association', 'Reg', (14, 37))	('BAP1', 'Gene', (57, 61))	('TP53', 'Gene', '7157', (51, 55))
67722	32029828	TP53 and BAP1 mutations demonstrated an association with T-eff cluster, however, PBRM1 mutation associated to the Angio cluster (Supplementary Table ST4).	('TP53', 'Gene', '7157', (0, 4))	('ST4', 'Gene', (149, 152))	('TP53', 'Gene', (0, 4))	('PBRM1', 'Gene', (81, 86))	('Angio cluster', 'Disease', (114, 127))	('PBRM1', 'Gene', '55193', (81, 86))	('associated', 'Reg', (96, 106))	('T-eff cluster', 'Disease', (57, 70))	('BAP1', 'Gene', '8314', (9, 13))	('ST4', 'Gene', '6484', (149, 152))	('mutation', 'Var', (87, 95))	('BAP1', 'Gene', (9, 13))	('association', 'Interaction', (40, 51))	('mutations', 'Var', (14, 23))
67743	32029828	They also concluded that patients with enriched PBRM1 mutation associated with high angiogenic cluster, but BAP1 and TP53 mutations demonstrated a trend towards high immunogenic cluster.	('mutation', 'Var', (54, 62))	('BAP1', 'Gene', '8314', (108, 112))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('associated', 'Reg', (63, 73))	('PBRM1', 'Gene', (48, 53))	('BAP1', 'Gene', (108, 112))	('patients', 'Species', '9606', (25, 33))	('high angiogenic cluster', 'MPA', (79, 102))	('PBRM1', 'Gene', '55193', (48, 53))
67791	31540495	We found that a significant association between mRNA level of IL4Ralpha or IL13Ralpha1 and the poor prognosis of renal cell carcinoma (RCC) from the public database (http://www.oncolnc.org/).	('IL13', 'molecular_function', 'GO:0005144', ('75', '79'))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('renal cell carcinoma', 'Disease', (113, 133))	('IL4', 'molecular_function', 'GO:0005136', ('62', '65'))	('mRNA level', 'Var', (48, 58))	('RCC', 'Disease', (135, 138))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (113, 133))	('IL13Ralpha1', 'Gene', '3597', (75, 86))	('RCC', 'Disease', 'MESH:D002292', (135, 138))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (113, 133))	('IL13Ralpha1', 'Gene', (75, 86))	('IL4Ralpha', 'Gene', '3566', (62, 71))	('IL4Ralpha', 'Gene', (62, 71))
67797	31540495	Interestingly, JAK2 interacted with Forkhead box O3 (FOXO3) to cause tyrosine-phosphorylation of FOXO3.	('Forkhead box O3', 'Gene', (36, 51))	('JAK2', 'Var', (15, 19))	('cause', 'Reg', (63, 68))	('tyrosine-phosphorylation', 'MPA', (69, 93))	('phosphorylation', 'biological_process', 'GO:0016310', ('78', '93'))	('tyrosine', 'Chemical', 'None', (69, 77))	('JAK', 'molecular_function', 'GO:0004713', ('15', '18'))	('Forkhead box O3', 'Gene', '2309', (36, 51))	('FOXO3', 'Gene', (97, 102))
67798	31540495	Silencing IL4Ralpha or JAK2 in A498 and ACHN cells reduced the interaction between JAK2 and FOXO3.	('JAK2', 'Protein', (83, 87))	('reduced', 'NegReg', (51, 58))	('JAK2', 'Gene', (23, 27))	('JAK', 'molecular_function', 'GO:0004713', ('23', '26'))	('Silencing', 'Var', (0, 9))	('interaction', 'Interaction', (63, 74))	('ACHN', 'Gene', (40, 44))	('IL4', 'molecular_function', 'GO:0005136', ('10', '13'))	('IL4Ralpha', 'Gene', '3566', (10, 19))	('IL4Ralpha', 'Gene', (10, 19))	('FOXO3', 'Protein', (92, 97))	('JAK', 'molecular_function', 'GO:0004713', ('83', '86'))	('ACHN', 'Gene', '55323', (40, 44))
67820	31540495	Furthermore, several studies have reported that single nucleotide polymorphisms (SNPs) in the IL4R gene are closely associated with tumor progression.	('poly', 'Chemical', 'MESH:C017937', (66, 70))	('single nucleotide polymorphisms', 'Var', (48, 79))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('IL4R', 'molecular_function', 'GO:0004913', ('94', '98'))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('IL4R', 'Gene', (94, 98))	('tumor', 'Disease', (132, 137))	('associated', 'Reg', (116, 126))
67842	31540495	Interestingly, JAK2 interacted with FOXO3 to cause tyrosine-phosphorylation of FOXO3.	('JAK2', 'Var', (15, 19))	('tyrosine-phosphorylation', 'MPA', (51, 75))	('FOXO3', 'Gene', (79, 84))	('phosphorylation', 'biological_process', 'GO:0016310', ('60', '75'))	('cause', 'Reg', (45, 50))	('JAK', 'molecular_function', 'GO:0004713', ('15', '18'))	('tyrosine', 'Chemical', 'None', (51, 59))
67866	31540495	When we performed multivariate analysis with inclusion of co-expression pattern of IL4Ralpha and IL13Ralpha1 instead of the expression of IL4Ralpha and IL13Ralpha1, co-expression pattern of IL4Ralpha and IL13Ralpha1 was an independent prognostic indicator for CSS (hazard ratio; 3.286, 95% CI; 1.542-7.000, p = 0.002) and RFS (hazard ratio; 3.158, 95% CI; 1.662-6.000, p < 0.001) (Table 3, model 2).	('co-expression', 'Var', (165, 178))	('IL13Ralpha1', 'Gene', '3597', (204, 215))	('IL13', 'molecular_function', 'GO:0005144', ('204', '208'))	('IL4Ralpha', 'Gene', (190, 199))	('IL13Ralpha1', 'Gene', (97, 108))	('IL13', 'molecular_function', 'GO:0005144', ('97', '101'))	('IL4', 'molecular_function', 'GO:0005136', ('83', '86'))	('IL13Ralpha1', 'Gene', (152, 163))	('IL4Ralpha', 'Gene', '3566', (83, 92))	('IL4Ralpha', 'Gene', '3566', (138, 147))	('RFS', 'Disease', (322, 325))	('IL4', 'molecular_function', 'GO:0005136', ('138', '141'))	('IL13Ralpha1', 'Gene', (204, 215))	('IL4Ralpha', 'Gene', (83, 92))	('IL4Ralpha', 'Gene', (138, 147))	('CSS', 'Disease', (260, 263))	('IL13', 'molecular_function', 'GO:0005144', ('152', '156'))	('IL13Ralpha1', 'Gene', '3597', (152, 163))	('IL13Ralpha1', 'Gene', '3597', (97, 108))	('IL4Ralpha', 'Gene', '3566', (190, 199))	('IL4', 'molecular_function', 'GO:0005136', ('190', '193'))
67869	31540495	Therefore, we evaluated cell proliferation, arrest, and apoptosis after inducing knock-down of IL4Ralpha or IL13Ralpha1 in human RCC A498 and ACHN cells.	('IL4Ralpha', 'Gene', '3566', (95, 104))	('human', 'Species', '9606', (123, 128))	('arrest', 'CPA', (44, 50))	('cell proliferation', 'CPA', (24, 42))	('cell proliferation', 'biological_process', 'GO:0008283', ('24', '42'))	('IL4Ralpha', 'Gene', (95, 104))	('inducing', 'Reg', (72, 80))	('IL13Ralpha1', 'Gene', '3597', (108, 119))	('IL4', 'molecular_function', 'GO:0005136', ('95', '98'))	('RCC', 'Disease', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('ACHN', 'Gene', (142, 146))	('RCC', 'Disease', 'MESH:D002292', (129, 132))	('IL13', 'molecular_function', 'GO:0005144', ('108', '112'))	('knock-down', 'Var', (81, 91))	('IL13Ralpha1', 'Gene', (108, 119))	('ACHN', 'Gene', '55323', (142, 146))	('apoptosis', 'biological_process', 'GO:0097194', ('56', '65'))	('apoptosis', 'CPA', (56, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('56', '65'))
67873	31540495	The phosphorylation level of JAK2 was also downregulated by knockdown of IL4Ralpha or IL13Ralpha1 with siRNA.	('downregulated', 'NegReg', (43, 56))	('IL13Ralpha1', 'Gene', (86, 97))	('JAK2', 'Gene', (29, 33))	('IL13Ralpha1', 'Gene', '3597', (86, 97))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('phosphorylation level', 'MPA', (4, 25))	('JAK', 'molecular_function', 'GO:0004713', ('29', '32'))	('knockdown', 'Var', (60, 69))	('IL4Ralpha', 'Gene', '3566', (73, 82))	('IL4', 'molecular_function', 'GO:0005136', ('73', '76'))	('IL13', 'molecular_function', 'GO:0005144', ('86', '90'))	('IL4Ralpha', 'Gene', (73, 82))
67874	31540495	Collectively, these results suggest that knockdown of IL4Ralpha or IL13Ralpha1 with siRNA transfection is closely involved in proliferation, arrest, and apoptosis in A498 and ACHN cells as well as causing inhibition of JAK2 phosphorylation.	('apoptosis', 'biological_process', 'GO:0097194', ('153', '162'))	('IL4', 'molecular_function', 'GO:0005136', ('54', '57'))	('apoptosis', 'biological_process', 'GO:0006915', ('153', '162'))	('siRNA', 'Gene', (84, 89))	('IL13', 'molecular_function', 'GO:0005144', ('67', '71'))	('IL4Ralpha', 'Gene', (54, 63))	('inhibition', 'NegReg', (205, 215))	('ACHN', 'Gene', (175, 179))	('IL13Ralpha1', 'Gene', '3597', (67, 78))	('JAK2', 'Protein', (219, 223))	('phosphorylation', 'biological_process', 'GO:0016310', ('224', '239'))	('knockdown', 'Var', (41, 50))	('apoptosis', 'CPA', (153, 162))	('arrest', 'CPA', (141, 147))	('JAK', 'molecular_function', 'GO:0004713', ('219', '222'))	('ACHN', 'Gene', '55323', (175, 179))	('involved', 'Reg', (114, 122))	('IL13Ralpha1', 'Gene', (67, 78))	('IL4Ralpha', 'Gene', '3566', (54, 63))
67876	31540495	Therefore, we tested if JAK2 might interact with FOXO and contribute to a decrease in FOXO3 expression or not.	('decrease', 'NegReg', (74, 82))	('FOXO', 'Gene', (49, 53))	('FOXO', 'Gene', (86, 90))	('JAK', 'molecular_function', 'GO:0004713', ('24', '27'))	('interact', 'Reg', (35, 43))	('FOXO', 'Gene', '41709', (49, 53))	('FOXO', 'Gene', '41709', (86, 90))	('JAK2', 'Var', (24, 28))	('tested', 'Reg', (14, 20))	('expression', 'MPA', (92, 102))
67877	31540495	As shown in Figure 3A, we observed that JAK2 protein interacted with FOXO3 protein where the protein interaction was weakened by the transfection of IL4Ralpha siRNA in A498 and ACHN cells.	('transfection', 'Var', (133, 145))	('IL4Ralpha', 'Gene', (149, 158))	('ACHN', 'Gene', '55323', (177, 181))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('ACHN', 'Gene', (177, 181))	('interacted', 'Interaction', (53, 63))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('interaction', 'Interaction', (101, 112))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('FOXO3', 'Gene', (69, 74))	('protein', 'Protein', (75, 82))	('IL4', 'molecular_function', 'GO:0005136', ('149', '152'))	('weakened', 'NegReg', (117, 125))	('JAK', 'molecular_function', 'GO:0004713', ('40', '43'))	('IL4Ralpha', 'Gene', '3566', (149, 158))
67880	31540495	These results implicate that JAK2 interacts with FOXO3 to cause tyrosine-phosphorylation of FOXO3 and regulate the protein level of FOXO3.	('FOXO3', 'Gene', (92, 97))	('regulate', 'Reg', (102, 110))	('tyrosine', 'Chemical', 'None', (64, 72))	('JAK2', 'Var', (29, 33))	('cause', 'Reg', (58, 63))	('protein level', 'MPA', (115, 128))	('JAK', 'molecular_function', 'GO:0004713', ('29', '32'))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('phosphorylation', 'biological_process', 'GO:0016310', ('73', '88'))	('tyrosine-phosphorylation', 'MPA', (64, 88))
67881	31540495	Since we could find that FOXO3 protein interacts with JAK2 protein and the tyrosine-phosphorylation of FOXO3 was induced by JAK2, we tried to determine whether JAK2 affects the FOXO3 protein location, level, and ubiquitination status.	('FOXO3', 'Gene', (177, 182))	('induced', 'Reg', (113, 120))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('affects', 'Reg', (165, 172))	('FOXO3', 'Gene', (103, 108))	('FOXO3', 'Gene', (25, 30))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))	('protein', 'Protein', (31, 38))	('tyrosine', 'Chemical', 'None', (75, 83))	('tyrosine-phosphorylation', 'MPA', (75, 99))	('level', 'MPA', (201, 206))	('JAK', 'molecular_function', 'GO:0004713', ('160', '163'))	('interacts', 'Interaction', (39, 48))	('JAK', 'molecular_function', 'GO:0004713', ('124', '127'))	('JAK2', 'Var', (124, 128))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('JAK', 'molecular_function', 'GO:0004713', ('54', '57'))	('ubiquitination', 'MPA', (212, 226))
67882	31540495	As shown in Figure 4A, the cytoplasmic level of FOXO3 protein was decreased by AZD1480 treatment in A498 and ACHN cells, while the nuclear level of FOXO3 protein was significantly increased with a dose-dependent manner.	('ACHN', 'Gene', '55323', (109, 113))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('decreased', 'NegReg', (66, 75))	('increased', 'PosReg', (180, 189))	('ACHN', 'Gene', (109, 113))	('FOXO3', 'Gene', (48, 53))	('AZD1480', 'Var', (79, 86))	('AZD1480', 'Chemical', 'MESH:C545606', (79, 86))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('protein', 'Protein', (54, 61))	('cytoplasmic level of', 'MPA', (27, 47))	('nuclear level', 'MPA', (131, 144))
67884	31540495	These data were confirmed by the confocal analysis for staining FOXO3 protein in A498 and ACHN cells treated with AZD1480, which showed the nuclear accumulation of FOXO3 after treatment of AZD1480 (Figure 4B).	('ACHN', 'Gene', (90, 94))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('FOXO3', 'Gene', (164, 169))	('FOXO3', 'Gene', (64, 69))	('AZD1480', 'Var', (189, 196))	('ACHN', 'Gene', '55323', (90, 94))	('nuclear accumulation', 'CPA', (140, 160))	('AZD1480', 'Var', (114, 121))	('AZD1480', 'Chemical', 'MESH:C545606', (189, 196))	('AZD1480', 'Chemical', 'MESH:C545606', (114, 121))
67885	31540495	These results suggest that AZD1480 could trigger the translocation of the FOXO3 protein from the cytoplasm into the nucleus in A498 and ACHN cells.	('translocation', 'MPA', (53, 66))	('ACHN', 'Gene', '55323', (136, 140))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('nucleus', 'cellular_component', 'GO:0005634', ('116', '123'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('97', '106'))	('AZD1480', 'Var', (27, 34))	('protein', 'Protein', (80, 87))	('ACHN', 'Gene', (136, 140))	('trigger', 'Reg', (41, 48))	('AZD1480', 'Chemical', 'MESH:C545606', (27, 34))	('FOXO3', 'Gene', (74, 79))
67886	31540495	Then, we found that the expression level of FOXO3 was decreased within 2 h in 293T cells co-transfected with over-expressing plasmid DNAs (pECE Flag-FOXO3 and pCMV3-C-HA-JAK2) but the expression level of FOXO3 was increased up to 4 h in the same 293T cells treated with AZD1480 with/out the treatment of CHX and MG132 (Figure 4C) suggesting that the proteasomal degradation of FOXO3 is controlled by AZD1480 treatment.	('AZD1480', 'Var', (400, 407))	('expression level', 'MPA', (24, 40))	('degradation', 'biological_process', 'GO:0009056', ('362', '373'))	('AZD1480', 'Chemical', 'MESH:C545606', (400, 407))	('FOXO3', 'Gene', (44, 49))	('AZD1480', 'Chemical', 'MESH:C545606', (270, 277))	('CHX', 'Chemical', 'MESH:C085678', (304, 307))	('JAK', 'molecular_function', 'GO:0004713', ('170', '173'))	('FOXO3', 'Gene', (377, 382))	('decreased', 'NegReg', (54, 63))	('proteasomal degradation', 'MPA', (350, 373))
67887	31540495	Moreover, as shown in Figure 4D, immunoprecipitation analysis result with antibody against Flag after incubation of MG132 showed that poly-ubiquitination of FOXO3 was considerably weakened in 293T cells treated with AZD1480 compared to dimethyl sulfoxide (DMSO) vehicle control which is consistent with the above experimental results about the proteasomal degradation of FOXO3.	('weakened', 'NegReg', (180, 188))	('FOXO3', 'Gene', (157, 162))	('DMSO', 'Chemical', 'MESH:D004121', (256, 260))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (236, 254))	('AZD1480', 'Var', (216, 223))	('antibody', 'cellular_component', 'GO:0042571', ('74', '82'))	('AZD1480', 'Chemical', 'MESH:C545606', (216, 223))	('antibody', 'cellular_component', 'GO:0019815', ('74', '82'))	('degradation', 'biological_process', 'GO:0009056', ('356', '367'))	('poly-ubiquitination', 'MPA', (134, 153))	('antibody', 'cellular_component', 'GO:0019814', ('74', '82'))	('poly', 'Chemical', 'MESH:C017937', (134, 138))	('antibody', 'molecular_function', 'GO:0003823', ('74', '82'))
67888	31540495	To determine the anti-cancer effect of AZD1480 treatment, we performed cell proliferation, arrest, and apoptosis assays in A498 and ACHN cells treated with AZD1480.	('cell proliferation', 'biological_process', 'GO:0008283', ('71', '89'))	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('ACHN', 'Gene', (132, 136))	('AZD1480', 'Chemical', 'MESH:C545606', (156, 163))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('AZD1480', 'Chemical', 'MESH:C545606', (39, 46))	('cell proliferation', 'CPA', (71, 89))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('ACHN', 'Gene', '55323', (132, 136))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('AZD1480', 'Var', (156, 163))
67889	31540495	In vitro cell assays (WST-1, cell counting, colony formation, cell cycle analysis, TUNEL, and Annexin V staining assay) showed that AZD1480 treatment decreased cell proliferation rate and increased cell cycle arrest and apoptosis in A498 and ACHN cells with dose and time-dependent manner (Figure 5A-F).	('ACHN', 'Gene', '55323', (242, 246))	('cell cycle arrest', 'CPA', (198, 215))	('AZD1480', 'Chemical', 'MESH:C545606', (132, 139))	('apoptosis', 'biological_process', 'GO:0097194', ('220', '229'))	('cell cycle', 'biological_process', 'GO:0007049', ('62', '72'))	('apoptosis', 'biological_process', 'GO:0006915', ('220', '229'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (198, 215))	('Annexin V', 'Gene', '308', (94, 103))	('ACHN', 'Gene', (242, 246))	('cell proliferation rate', 'CPA', (160, 183))	('apoptosis', 'CPA', (220, 229))	('formation', 'biological_process', 'GO:0009058', ('51', '60'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('198', '215'))	('Annexin V', 'Gene', (94, 103))	('AZD1480', 'Var', (132, 139))	('increased', 'PosReg', (188, 197))	('cell proliferation', 'biological_process', 'GO:0008283', ('160', '178'))	('decreased', 'NegReg', (150, 159))
67890	31540495	Furthermore, knockdown of JAK2 with siRNA also decreased cell proliferation rate in A498 and ACHN cells (Figure S3A-C).	('ACHN', 'Gene', (93, 97))	('JAK2', 'Gene', (26, 30))	('JAK', 'molecular_function', 'GO:0004713', ('26', '29'))	('cell proliferation', 'biological_process', 'GO:0008283', ('57', '75'))	('ACHN', 'Gene', '55323', (93, 97))	('knockdown', 'Var', (13, 22))	('decreased', 'NegReg', (47, 56))
67891	31540495	Western blotting analysis indicated that AZD1480 treatment significantly increased cleaved PARP1, cleaved caspase3, Bax, p21, p27, Bim(EL) and FOXO3 expression but decreased Bcl2 expression with dose and time-dependent manner (Figure 5G).	('Bax', 'Gene', '581', (116, 119))	('Bcl2', 'Gene', (174, 178))	('p21', 'Gene', (121, 124))	('Bcl2', 'Gene', '596', (174, 178))	('p21', 'Gene', '644914', (121, 124))	('PARP1', 'Gene', (91, 96))	('Bcl2', 'molecular_function', 'GO:0015283', ('174', '178'))	('p27', 'Gene', '3429', (126, 129))	('p27', 'Gene', (126, 129))	('FOXO3', 'Gene', (143, 148))	('caspase3', 'Gene', (106, 114))	('AZD1480', 'Chemical', 'MESH:C545606', (41, 48))	('Bim', 'Gene', '10018', (131, 134))	('increased', 'PosReg', (73, 82))	('AZD1480', 'Var', (41, 48))	('expression', 'MPA', (149, 159))	('PARP1', 'Gene', '142', (91, 96))	('Bim', 'Gene', (131, 134))	('cleaved', 'MPA', (83, 90))	('caspase3', 'Gene', '836', (106, 114))	('decreased', 'NegReg', (164, 173))	('expression', 'MPA', (179, 189))	('Bax', 'Gene', (116, 119))
67902	31540495	It is reported that IL4Ralpha is overexpressed in human breast cancer and silencing of IL4Ralpha attenuated growth of metastatic breast cancer cells.	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('IL4', 'molecular_function', 'GO:0005136', ('87', '90'))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('IL4Ralpha', 'Gene', '3566', (20, 29))	('silencing', 'Var', (74, 83))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('IL4Ralpha', 'Gene', (20, 29))	('IL4Ralpha', 'Gene', '3566', (87, 96))	('attenuated', 'NegReg', (97, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('human', 'Species', '9606', (50, 55))	('IL4', 'molecular_function', 'GO:0005136', ('20', '23'))	('IL4Ralpha', 'Gene', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
67903	31540495	Moreover, IL4Ra expression activates colon tumor growth.	('expression', 'Var', (16, 26))	('IL4', 'molecular_function', 'GO:0005136', ('10', '13'))	('colon tumor', 'Disease', 'MESH:D015179', (37, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('IL4Ra', 'Gene', (10, 15))	('colon tumor', 'Phenotype', 'HP:0100273', (37, 48))	('IL4Ra', 'Gene', '3566', (10, 15))	('colon tumor', 'Disease', (37, 48))	('activates', 'PosReg', (27, 36))
67908	31540495	Overexpressed IL13Ralpha1 in tumor cells is closely related to patients with breast cancer.	('breast cancer', 'Disease', (77, 90))	('Overexpressed', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('IL13Ralpha1', 'Gene', (14, 25))	('IL13Ralpha1', 'Gene', '3597', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('patients', 'Species', '9606', (63, 71))	('related', 'Reg', (52, 59))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('IL13', 'molecular_function', 'GO:0005144', ('14', '18'))
67927	31540495	RNA aptamer-mediated inhibition of IL4Ralpha induces apoptosis of MDSC and tumor-associated macrophage (TAM) which is associated with the tumoral immune escape.	('apoptosis', 'CPA', (53, 62))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('TAM', 'Chemical', 'MESH:C419191', (104, 107))	('MDSC', 'CPA', (66, 70))	('IL4', 'molecular_function', 'GO:0005136', ('35', '38'))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('apoptosis', 'biological_process', 'GO:0006915', ('53', '62'))	('inhibition', 'Var', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('apoptosis', 'biological_process', 'GO:0097194', ('53', '62'))	('IL4Ralpha', 'Gene', '3566', (35, 44))	('tumoral', 'Disease', (138, 145))	('tumoral', 'Disease', 'MESH:D009369', (138, 145))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('tumor', 'Disease', (75, 80))	('IL4Ralpha', 'Gene', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
67935	31540495	Among these seven JHs, JH1 is the kinase domain responsible for a tyrosine kinase activity of JAKs and has the conserved tyrosine residues required for JAK activation (e.g., Y1007/Y1008 in JAK2).	('kinase activity', 'molecular_function', 'GO:0016301', ('75', '90'))	('tyrosine kinase activity', 'MPA', (66, 90))	('JAK', 'molecular_function', 'GO:0004713', ('152', '155'))	('Y1007/Y1008', 'Var', (174, 185))	('JAKs', 'Gene', '3716;3717;484185;16452;3718', (94, 98))	('tyrosine', 'Chemical', 'None', (66, 74))	('JAK', 'molecular_function', 'GO:0004713', ('189', '192'))	('JH1', 'Gene', (23, 26))	('JH1', 'Gene', '28483', (23, 26))	('JAKs', 'Gene', (94, 98))	('JAK2', 'Gene', (189, 193))	('tyrosine', 'Chemical', 'None', (121, 129))
67945	31540495	It is reported that the expression of IL13Ralpha1 induced STAT3 activation by IL4 and IL13 in the stimulated human B cells.	('IL13Ralpha1', 'Gene', (38, 49))	('IL13Ralpha1', 'Gene', '3597', (38, 49))	('human', 'Species', '9606', (109, 114))	('IL13', 'Gene', (38, 42))	('IL13', 'Gene', '3596', (38, 42))	('IL13', 'Gene', (86, 90))	('IL13', 'molecular_function', 'GO:0005144', ('38', '42'))	('IL4', 'molecular_function', 'GO:0005136', ('78', '81'))	('IL13', 'Gene', '3596', (86, 90))	('STAT3', 'Gene', '6774', (58, 63))	('expression', 'Var', (24, 34))	('IL13', 'molecular_function', 'GO:0005144', ('86', '90'))	('IL4', 'Gene', '3565', (78, 81))	('IL4', 'Gene', (78, 81))	('STAT3', 'Gene', (58, 63))
67947	31540495	Inhibition of JAK2/STAT3 signaling pathway induces apoptosis in ovarian cancer cells.	('JAK', 'molecular_function', 'GO:0004713', ('14', '17'))	('ovarian cancer', 'Disease', 'MESH:D010051', (64, 78))	('STAT3', 'Gene', '6774', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('apoptosis', 'biological_process', 'GO:0097194', ('51', '60'))	('apoptosis', 'biological_process', 'GO:0006915', ('51', '60'))	('STAT3', 'Gene', (19, 24))	('Inhibition', 'Var', (0, 10))	('ovarian cancer', 'Disease', (64, 78))	('signaling pathway', 'biological_process', 'GO:0007165', ('25', '42'))	('apoptosis', 'CPA', (51, 60))	('ovarian cancer', 'Phenotype', 'HP:0100615', (64, 78))
67948	31540495	Furthermore, inhibition of JAK2/STAT3 pathway suppresses the growth of gastric cancer in vitro and in vivo.	('gastric cancer', 'Disease', (71, 85))	('suppresses', 'NegReg', (46, 56))	('STAT3', 'Gene', '6774', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('gastric cancer', 'Disease', 'MESH:D013274', (71, 85))	('inhibition', 'Var', (13, 23))	('JAK', 'molecular_function', 'GO:0004713', ('27', '30'))	('STAT3', 'Gene', (32, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (71, 85))	('growth', 'CPA', (61, 67))
67951	31540495	According to Xin et al, treatment of 786-O human renal cancer cells with AZD1480 showed only limited decrease in cell viability.	('Xin', 'Gene', '165904', (13, 16))	('Xin', 'Gene', (13, 16))	('renal cancer', 'Disease', (49, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('renal cancer', 'Phenotype', 'HP:0009726', (49, 61))	('renal cancer', 'Disease', 'MESH:D007680', (49, 61))	('AZD1480', 'Var', (73, 80))	('AZD1480', 'Chemical', 'MESH:C545606', (73, 80))	('human', 'Species', '9606', (43, 48))
67953	31540495	However, we used 0, 2.5, 5, and 10 muM of AZD1480 to perform WST-1 assay and we could observe the dose-and time dependent cell toxicity effect of AZD1480 in A498 and ACHN cells.	('AZD1480', 'Chemical', 'MESH:C545606', (146, 153))	('muM', 'Gene', '56925', (35, 38))	('ACHN', 'Gene', (166, 170))	('toxicity', 'Disease', 'MESH:D064420', (127, 135))	('toxicity', 'Disease', (127, 135))	('muM', 'Gene', (35, 38))	('ACHN', 'Gene', '55323', (166, 170))	('AZD1480', 'Var', (146, 153))	('AZD1480', 'Chemical', 'MESH:C545606', (42, 49))
67954	31540495	When we tested the lower dose of AZD1480 (0.5 and 1 muM) for the cell viability assay, we also found the limited reduction of cell viability in A498 and ACHN cell.	('cell viability', 'CPA', (126, 140))	('AZD1480', 'Var', (33, 40))	('ACHN', 'Gene', (153, 157))	('muM', 'Gene', '56925', (52, 55))	('AZD1480', 'Chemical', 'MESH:C545606', (33, 40))	('reduction', 'NegReg', (113, 122))	('muM', 'Gene', (52, 55))	('ACHN', 'Gene', '55323', (153, 157))
67955	31540495	Thus, we thought that the range of AZD1480 dose might cause the different anti-cancer effect on the renal cancer cells.	('renal cancer', 'Disease', (100, 112))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('renal cancer', 'Disease', 'MESH:D007680', (100, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('renal cancer', 'Phenotype', 'HP:0009726', (100, 112))	('cancer', 'Disease', (106, 112))	('AZD1480', 'Var', (35, 42))	('AZD1480', 'Chemical', 'MESH:C545606', (35, 42))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
67958	31540495	As described in the results section, we demonstrated that AZD1489, a kind of JAK2 inhibitor, decreased cell proliferation rate and increases cell cycle arrest and apoptosis in A498 and ACHN cells with dose and time-dependent manner.	('apoptosis', 'biological_process', 'GO:0006915', ('163', '172'))	('apoptosis', 'CPA', (163, 172))	('apoptosis', 'biological_process', 'GO:0097194', ('163', '172'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (141, 158))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('141', '158'))	('increases', 'PosReg', (131, 140))	('cell cycle arrest', 'CPA', (141, 158))	('decreased', 'NegReg', (93, 102))	('JAK', 'molecular_function', 'GO:0004713', ('77', '80'))	('ACHN', 'Gene', '55323', (185, 189))	('cell proliferation rate', 'CPA', (103, 126))	('AZD1489', 'Chemical', 'MESH:C009217', (58, 65))	('AZD1489', 'Var', (58, 65))	('ACHN', 'Gene', (185, 189))	('cell proliferation', 'biological_process', 'GO:0008283', ('103', '121'))
67967	31540495	According to them, the introduction of Src42A, one of the constitutively active alleles, into the larval inhibited the starvation-mediated nuclear localization of dFOXO, and pharmacological inhibition of Src activity promoted the nuclear accumulation of dFOXO under the even high nutrient conditions.	('Src', 'Gene', (204, 207))	('Src42A', 'Var', (39, 45))	('localization', 'biological_process', 'GO:0051179', ('147', '159'))	('inhibited', 'NegReg', (105, 114))	('dFOXO', 'Gene', '41709', (254, 259))	('dFOXO', 'Gene', (254, 259))	('promoted', 'PosReg', (217, 225))	('dFOXO', 'Gene', '41709', (163, 168))	('dFOXO', 'Gene', (163, 168))	('nuclear accumulation', 'MPA', (230, 250))
67977	31540495	demonstrated that enhanced reactive oxygen species (ROS) level and aberrant PI3K signaling decreased the nuclear localization of FOXO3 and catalase expression in JAK2V617F mutant positive cells.	('oxygen', 'Chemical', 'MESH:D010100', (36, 42))	('mutant', 'Var', (172, 178))	('FOXO3', 'Gene', (129, 134))	('localization', 'biological_process', 'GO:0051179', ('113', '125'))	('PI3K signaling', 'biological_process', 'GO:0014065', ('76', '90'))	('PI3K signaling', 'Pathway', (76, 90))	('JAK2V617F mutant', 'Var', (162, 178))	('nuclear localization', 'MPA', (105, 125))	('enhanced', 'PosReg', (18, 26))	('catalase', 'Gene', (139, 147))	('PI3K', 'molecular_function', 'GO:0016303', ('76', '80'))	('JAK', 'molecular_function', 'GO:0004713', ('162', '165'))	('expression', 'MPA', (148, 158))	('aberrant', 'Var', (67, 75))	('decreased', 'NegReg', (91, 100))	('catalase', 'Gene', '847', (139, 147))
67978	31540495	In addition, they showed that JAK2V617F-positive erythroblasts derived from myeloproliferative neoplasm patients also displayed the increased ROS level and reduced nuclear FOXO3 compared with the control erythroblasts.	('myeloproliferative neoplasm', 'Disease', (76, 103))	('myeloproliferative neoplasm', 'Disease', 'MESH:D009196', (76, 103))	('increased ROS level', 'Phenotype', 'HP:0025464', (132, 151))	('JAK2V617F-positive', 'Var', (30, 48))	('ROS level', 'MPA', (142, 151))	('increased', 'PosReg', (132, 141))	('reduced', 'NegReg', (156, 163))	('JAK', 'molecular_function', 'GO:0004713', ('30', '33'))	('nuclear FOXO3', 'MPA', (164, 177))	('neoplasm', 'Phenotype', 'HP:0002664', (95, 103))	('patients', 'Species', '9606', (104, 112))	('myeloproliferative neoplasm', 'Phenotype', 'HP:0005547', (76, 103))
67979	31540495	Since JAK2 is known to phosphorylate and activate STATs in various kinds of cells, we might think about the possibility of the protein interaction between FOXO3 and STATs.	('STATs', 'Gene', '6774;6778', (165, 170))	('STATs', 'Gene', (50, 55))	('activate', 'PosReg', (41, 49))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('STATs', 'Gene', (165, 170))	('JAK2', 'Var', (6, 10))	('FOXO3', 'Gene', (155, 160))	('JAK', 'molecular_function', 'GO:0004713', ('6', '9'))	('STATs', 'Gene', '6774;6778', (50, 55))
67982	31540495	As described in the results section, we successfully showed that JAK2 interacts with FOXO3 to cause tyrosine-phosphorylation of FOXO3.	('interacts', 'Interaction', (70, 79))	('FOXO3', 'Gene', (128, 133))	('JAK', 'molecular_function', 'GO:0004713', ('65', '68'))	('tyrosine-phosphorylation', 'MPA', (100, 124))	('FOXO3', 'Gene', (85, 90))	('tyrosine', 'Chemical', 'None', (100, 108))	('cause', 'Reg', (94, 99))	('JAK2', 'Var', (65, 69))	('phosphorylation', 'biological_process', 'GO:0016310', ('109', '124'))
68039	31540495	The following are available online at , Figure S1: Higher expression of mRNA of both IL4Ralpha and IL13Ralpha1 are associated with shorter survival of clear cell renal cell carcinoma patients, Figure S2: Western blot analysis of IL4Ralpha expression in RCC cell lines, Figure S3: Anti-cancer effect by transfection of siRNA against JAK2 in A498 and ACHN cells.	('expression', 'MPA', (58, 68))	('RCC', 'Disease', 'MESH:D002292', (253, 256))	('transfection', 'Var', (302, 314))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (162, 182))	('IL4Ralpha', 'Gene', (229, 238))	('IL4Ralpha', 'Gene', '3566', (85, 94))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (151, 182))	('ACHN', 'Gene', (349, 353))	('IL4', 'molecular_function', 'GO:0005136', ('229', '232'))	('shorter', 'NegReg', (131, 138))	('Higher', 'PosReg', (51, 57))	('IL13Ralpha1', 'Gene', '3597', (99, 110))	('cancer', 'Disease', (285, 291))	('clear cell renal cell carcinoma', 'Disease', (151, 182))	('IL4', 'molecular_function', 'GO:0005136', ('85', '88'))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('IL4Ralpha', 'Gene', (85, 94))	('patients', 'Species', '9606', (183, 191))	('ACHN', 'Gene', '55323', (349, 353))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (151, 182))	('IL13', 'molecular_function', 'GO:0005144', ('99', '103'))	('IL4Ralpha', 'Gene', '3566', (229, 238))	('RCC', 'Disease', (253, 256))	('RCC', 'Phenotype', 'HP:0005584', (253, 256))	('JAK', 'molecular_function', 'GO:0004713', ('332', '335'))	('IL13Ralpha1', 'Gene', (99, 110))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
68040	31540495	M.-A.K., J.L., S.H.H., C.M.L., K.M.K., K.Y.J.	('S.H.H', 'Disease', (15, 20))	('C.M.L.', 'Var', (23, 29))	('K.M.K.', 'Var', (31, 37))	('S.H.H', 'Disease', 'MESH:D018455', (15, 20))
68047	29850494	However, the subgroup of ccRCC patients who presented with cytoplasmic YAP1 immunoexpression had significantly shorter OS (median = 26.8 months) than patients without cytoplasmic YAP1 expression (median undefined).	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('patients', 'Species', '9606', (150, 158))	('ccRCC', 'Phenotype', 'HP:0006770', (25, 30))	('patients', 'Species', '9606', (31, 39))	('cytoplasmic', 'Var', (59, 70))	('shorter', 'NegReg', (111, 118))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))	('YAP1', 'Gene', (71, 75))
68056	29850494	Yes-associated protein 1 (YAP1) may be considered as one of the oncoproteins that play an important role in ccRCC pathogenesis, since deregulation of this gene (either at mRNA or protein level) was associated with progression of other malignancies.	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('malignancies', 'Disease', (235, 247))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('pathogenesis', 'biological_process', 'GO:0009405', ('114', '126'))	('Yes-associated protein 1', 'Gene', (0, 24))	('Yes-associated protein 1', 'Gene', '10413', (0, 24))	('associated', 'Reg', (198, 208))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('YAP1', 'Gene', (26, 30))	('malignancies', 'Disease', 'MESH:D009369', (235, 247))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('deregulation', 'Var', (134, 146))
68115	29850494	Interestingly, the subgroup of ccRCC patients in whom cytoplasmic presence of YAP1 in cancer cells was observed exhibited the strongest correlation with patients' poor prognosis.	('patients', 'Species', '9606', (153, 161))	('patients', 'Species', '9606', (37, 45))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cytoplasmic', 'Var', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (31, 36))	('YAP1', 'Gene', (78, 82))	('cancer', 'Disease', (86, 92))
68116	29850494	The Cox statistical test, independently of Kaplan-Meier analysis, revealed high hazard ratio of death of ccRCC patients demonstrating cytoplasmic YAP1 presence.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('Cox', 'Gene', '1351', (4, 7))	('RCC', 'Disease', (107, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (105, 110))	('Cox', 'Gene', (4, 7))	('death', 'Disease', 'MESH:D003643', (96, 101))	('death', 'Disease', (96, 101))	('cytoplasmic YAP1 presence', 'Var', (134, 159))	('patients', 'Species', '9606', (111, 119))
68127	29850494	Although we did not check the association between LATS1 methylation and YAP1 protein content in our previous study, other authors in the study of ccRCC 786-O cell line observed that the demethylation of LATS1 promoter was strongly associated with upregulation of YAP1 protein in cells.	('demethylation', 'Var', (186, 199))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('RCC', 'Disease', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('protein', 'cellular_component', 'GO:0003675', ('268', '275'))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('protein', 'Protein', (268, 275))	('LATS1', 'Gene', (203, 208))	('upregulation', 'PosReg', (247, 259))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('demethylation', 'biological_process', 'GO:0070988', ('186', '199'))	('YAP1', 'Gene', (263, 267))
68132	29850494	The microarray study on 1028 patients with CRC indicated that high YAP1 mRNA levels were associated with shorter PFS and the upregulation of YAP1 mRNA was an independent prognostic factor of CRC (HR = 1.82, p = 0.034).	('PFS', 'MPA', (113, 116))	('patients', 'Species', '9606', (29, 37))	('upregulation', 'PosReg', (125, 137))	('CRC', 'Disease', (191, 194))	('CRC', 'Phenotype', 'HP:0003003', (43, 46))	('YAP1', 'Var', (141, 145))	('CRC', 'Phenotype', 'HP:0003003', (191, 194))	('high', 'PosReg', (62, 66))	('YAP1', 'Gene', (67, 71))	('shorter', 'NegReg', (105, 112))
68141	31258849	In multivariate Cox analyses, higher IHC expression of p eIF4E in ccRCC significantly predicted a longer recurrence-free interval.	('p eIF4E', 'Var', (55, 62))	('higher', 'PosReg', (30, 36))	('longer', 'PosReg', (98, 104))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('eIF4', 'cellular_component', 'GO:0008304', ('57', '61'))	('recurrence-free interval', 'CPA', (105, 129))
68145	31258849	Conclusions: MNK2a-induced eIF4E phosphorylation may suppress metastatic recurrence of ccRCC, partially due to vimentin downregulation at the translational level, consequently leading to inhibition of epithelial-mesenchymal transition.	('eIF4E', 'Gene', (27, 32))	('vimentin', 'cellular_component', 'GO:0045098', ('111', '119'))	('eIF4', 'cellular_component', 'GO:0008304', ('27', '31'))	('downregulation', 'NegReg', (120, 134))	('inhibition', 'NegReg', (187, 197))	('metastatic recurrence', 'CPA', (62, 83))	('MNK2', 'Gene', (13, 17))	('vimentin', 'Gene', '7431', (111, 119))	('phosphorylation', 'Var', (33, 48))	('vimentin', 'Gene', (111, 119))	('RCC', 'Disease', (89, 92))	('suppress', 'NegReg', (53, 61))	('epithelial-mesenchymal transition', 'CPA', (201, 234))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('201', '234'))	('phosphorylation', 'biological_process', 'GO:0016310', ('33', '48'))	('vimentin', 'cellular_component', 'GO:0045099', ('111', '119'))	('MNK2', 'Gene', '2872', (13, 17))
68151	31258849	However, the prognosis of patients with advanced-stage (T3-4, N+, M+) RCC remains extremely poor, with a 5-year overall survival (OS) rate of 10%-30%.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('M+', 'Var', (66, 68))	('patients', 'Species', '9606', (26, 34))	('T3-4', 'Var', (56, 60))	('OS', 'Chemical', '-', (130, 132))
68155	31258849	eIF4E is persistently hyperactivated due to genetic alterations of pathway components located upstream of the 4EBP1/eIF4E axis, as the genes encoding 4EBP1 and eIF4E remain normal in the vast majority of cancers, including RCC.	('RCC', 'Disease', 'MESH:C538614', (223, 226))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('RCC', 'Disease', (223, 226))	('eIF4', 'cellular_component', 'GO:0008304', ('0', '4'))	('cancers', 'Disease', (204, 211))	('4EBP1', 'Gene', '1978', (110, 115))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('4EBP1', 'Gene', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('genetic alterations', 'Var', (44, 63))	('4EBP1', 'Gene', '1978', (150, 155))	('eIF4E', 'Gene', (160, 165))	('hyperactivated', 'PosReg', (22, 36))	('4EBP1', 'Gene', (150, 155))	('eIF4', 'cellular_component', 'GO:0008304', ('160', '164'))	('eIF4', 'cellular_component', 'GO:0008304', ('116', '120'))
68156	31258849	Interacting with the scaffold eIF4G, eIF4E is phosphorylated at Ser209 by mitogen-activated protein kinase (MAPK) -interacting kinase 1/2 (MNK1/2).	('MNK1/2', 'Gene', (139, 145))	('eIF4E', 'Var', (37, 42))	('eIF4G', 'Gene', '1981', (30, 35))	('Ser209', 'Chemical', '-', (64, 70))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('eIF4', 'cellular_component', 'GO:0008304', ('37', '41'))	('eIF4', 'cellular_component', 'GO:0008304', ('30', '34'))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))	('eIF4G', 'Gene', (30, 35))	('MNK1/2', 'Gene', '8569;2872', (139, 145))	('Ser', 'cellular_component', 'GO:0005790', ('64', '67'))
68160	31258849	However, the oncological roles of p-eIF4E in malignancies are not completely understood.	('malignancies', 'Disease', 'MESH:D009369', (45, 57))	('eIF4', 'cellular_component', 'GO:0008304', ('36', '40'))	('p-eIF4E', 'Var', (34, 41))	('malignancies', 'Disease', (45, 57))
68161	31258849	Herein, we aim to investigate: (1) the clinical relevance of p-eIF4E in predicting tumour recurrence after curable resection of localized ccRCC, and (2) the effects of p-eIF4E on tumour behaviours by inhibiting MNKs in RCC cell lines.	('tumour', 'Disease', (83, 89))	('eIF4', 'cellular_component', 'GO:0008304', ('63', '67'))	('eIF4', 'cellular_component', 'GO:0008304', ('170', '174'))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (179, 185))	('p-eIF4E', 'Var', (61, 68))	('inhibiting', 'NegReg', (200, 210))	('MNKs', 'CPA', (211, 215))	('p-eIF4E', 'Var', (168, 175))	('RCC', 'Disease', (140, 143))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (219, 222))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('tumour', 'Disease', (179, 185))	('RCC', 'Disease', 'MESH:C538614', (219, 222))
68167	31258849	The potential clinical significance of eIF4E and p-eIF4E expression in the study cohorts is also presented in Table 1. eIF4E was expressed at significantly higher levels in patients with ccRCC recurrence than those without (p = 0.032).	('eIF4', 'cellular_component', 'GO:0008304', ('51', '55'))	('eIF4', 'cellular_component', 'GO:0008304', ('39', '43'))	('patients', 'Species', '9606', (173, 181))	('higher levels', 'PosReg', (156, 169))	('eIF4', 'cellular_component', 'GO:0008304', ('119', '123'))	('eIF4E', 'Var', (119, 124))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('RCC', 'Disease', (189, 192))
68169	31258849	In contrast, peIF4E expression in ccRCC was significantly lower in the recurrent patients than in the recurrence-free patients (p = 0.040).	('expression', 'MPA', (20, 30))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('lower', 'NegReg', (58, 63))	('RCC', 'Disease', (36, 39))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (118, 126))	('peIF4E', 'Var', (13, 19))
68170	31258849	The expression levels of p-eIF4E protein significantly differed in pT stage and pN (p < 0.001 and p = 0.030, respectively), whereas p-eIF4E protein was expressed at comparable levels in tumours of different Fuhrman grade, sarcomatoid differentiation, coagulative necrosis, and MVI.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('tumours', 'Disease', (186, 193))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('necrosis', 'biological_process', 'GO:0008220', ('263', '271'))	('necrosis', 'Disease', (263, 271))	('sarcomatoid', 'Disease', (222, 233))	('tumours', 'Phenotype', 'HP:0002664', (186, 193))	('pT stage', 'Disease', (67, 75))	('coagulative necrosis', 'Phenotype', 'HP:0010885', (251, 271))	('eIF4', 'cellular_component', 'GO:0008304', ('27', '31'))	('tumours', 'Disease', 'MESH:D009369', (186, 193))	('necrosis', 'biological_process', 'GO:0070265', ('263', '271'))	('differed', 'Reg', (55, 63))	('necrosis', 'biological_process', 'GO:0019835', ('263', '271'))	('necrosis', 'biological_process', 'GO:0001906', ('263', '271'))	('expression levels', 'MPA', (4, 21))	('sarcomatoid', 'Disease', 'MESH:C538614', (222, 233))	('eIF4', 'cellular_component', 'GO:0008304', ('134', '138'))	('necrosis', 'biological_process', 'GO:0008219', ('263', '271'))	('MVI', 'Disease', (277, 280))	('p-eIF4E', 'Var', (25, 32))	('necrosis', 'Disease', 'MESH:D009336', (263, 271))
68171	31258849	High eIF4E and low p-eIF4E expression was marginally associated with cancer-specific survival (CSS) (p = 0.105 and 0.114, respectively) but not with OS (Table 1).	('eIF4E', 'Var', (5, 10))	('High eIF4E', 'Var', (0, 10))	('eIF4', 'cellular_component', 'GO:0008304', ('21', '25'))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('OS', 'Chemical', '-', (149, 151))	('CSS', 'Chemical', '-', (95, 98))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('eIF4', 'cellular_component', 'GO:0008304', ('5', '9'))	('cancer', 'Disease', (69, 75))	('low', 'NegReg', (15, 18))
68173	31258849	The recurrence-free and CSS intervals were significantly shorter in patients who presented with high eIF4E expression than those with low expression ((p < 0.05 for both, log-rank test; Figure 1B and 1C).	('CSS', 'Chemical', '-', (24, 27))	('expression', 'MPA', (107, 117))	('patients', 'Species', '9606', (68, 76))	('high', 'Var', (96, 100))	('eIF4', 'cellular_component', 'GO:0008304', ('101', '105'))	('eIF4E', 'Protein', (101, 106))	('shorter', 'NegReg', (57, 64))
68174	31258849	In contrast, the recurrence-free interval (RFI) was significantly longer in patients who presented with high p-eIF4E expression than in those who did not (p < 0.05, log-rank test; Figure 1D), but Kaplan-Meier curves for CSS differed marginally between those with high and low peIF4E expression (p = 0.084, log-rank test; Figure 1E).	('patients', 'Species', '9606', (76, 84))	('eIF4', 'cellular_component', 'GO:0008304', ('111', '115'))	('longer', 'PosReg', (66, 72))	('high p-eIF4E expression', 'Var', (104, 127))	('CSS', 'Chemical', '-', (220, 223))	('recurrence-free interval', 'CPA', (17, 41))
68175	31258849	In univariate and multivariate (model 1) Cox regression analyses (Table 2), pT1b<= stage (vs. pT1a), Fuhrman grade 3/4 (vs. grade 1/2), presence of coagulative necrosis (vs. absence), and high eIF4E expression (vs. low) were significantly related to a high risk of recurrence and cancer-specific mortality.	('necrosis', 'Disease', 'MESH:D009336', (160, 168))	('necrosis', 'biological_process', 'GO:0070265', ('160', '168'))	('necrosis', 'biological_process', 'GO:0019835', ('160', '168'))	('cancer', 'Disease', (280, 286))	('necrosis', 'Disease', (160, 168))	('necrosis', 'biological_process', 'GO:0001906', ('160', '168'))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('presence', 'Var', (136, 144))	('expression', 'MPA', (199, 209))	('high', 'Var', (188, 192))	('coagulative necrosis', 'Phenotype', 'HP:0010885', (148, 168))	('eIF4E', 'Gene', (193, 198))	('eIF4', 'cellular_component', 'GO:0008304', ('193', '197'))	('recurrence', 'CPA', (265, 275))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('necrosis', 'biological_process', 'GO:0008219', ('160', '168'))	('pT1b', 'Gene', (76, 80))	('necrosis', 'biological_process', 'GO:0008220', ('160', '168'))	('related to', 'Reg', (239, 249))
68177	31258849	The combination of eIF4E (high vs. low) and p-eIF4E (high vs. low) expression levels significantly stratified Kaplan-Meier curves for recurrence-free status and CSS after curative surgery (p = 0.001 and 0.018, log-rank test, respectively; Supplementary Figure 4).	('CSS', 'CPA', (161, 164))	('eIF4', 'cellular_component', 'GO:0008304', ('19', '23'))	('stratified', 'Reg', (99, 109))	('recurrence-free status', 'CPA', (134, 156))	('eIF4', 'cellular_component', 'GO:0008304', ('46', '50'))	('p-eIF4E', 'Var', (44, 51))	('eIF4E', 'Gene', (19, 24))	('CSS', 'Chemical', '-', (161, 164))
68181	31258849	The expression levels of MNKs, eIF4E, and p-eIF4E (Ser209) were examined using fresh frozen tissue samples of ccRCC and normal kidney parenchyma from patients (n = 28 and 7, respectively).	('eIF4', 'cellular_component', 'GO:0008304', ('44', '48'))	('RCC', 'Disease', (112, 115))	('patients', 'Species', '9606', (150, 158))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('Ser', 'cellular_component', 'GO:0005790', ('51', '54'))	('p-eIF4E', 'Var', (42, 49))	('eIF4', 'cellular_component', 'GO:0008304', ('31', '35'))	('Ser209', 'Chemical', '-', (51, 57))
68183	31258849	On the immunoblot, MNK1/2 was more expressed in ccRCC tissues than in normal kidney parenchyma, while the variable expression of eIF4E and p-eIF4E proteins was observed in ccRCC and the normal kidney (Figure 2A).	('eIF4E', 'Var', (129, 134))	('MNK1/2', 'Gene', (19, 25))	('p-eIF4E', 'Var', (139, 146))	('MNK1/2', 'Gene', '8569;2872', (19, 25))	('more', 'PosReg', (30, 34))	('eIF4', 'cellular_component', 'GO:0008304', ('129', '133'))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('RCC', 'Disease', (174, 177))	('eIF4', 'cellular_component', 'GO:0008304', ('141', '145'))	('RCC', 'Disease', 'MESH:C538614', (174, 177))
68185	31258849	No differences in transcript levels of MNK1, 2, 2a and 2b were found between the four categories stratified with eIF4E + p-eIF4E immunohistochemical (IHC) expression in ccRCC.	('eIF4', 'cellular_component', 'GO:0008304', ('113', '117'))	('MNK1', 'Gene', (39, 43))	('MNK1', 'Gene', '8569', (39, 43))	('eIF4E + p-eIF4E', 'Var', (113, 128))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('RCC', 'Disease', (171, 174))	('eIF4', 'cellular_component', 'GO:0008304', ('123', '127'))
68188	31258849	Variabilities of protein levels of MNK1:p-eIF4E expression were observed on the immunoblot, implicating the potential involvement of MNK2-dependent eIF4E phosphorylation (Figure 2C).	('eIF4', 'cellular_component', 'GO:0008304', ('42', '46'))	('phosphorylation', 'biological_process', 'GO:0016310', ('154', '169'))	('p-eIF4E', 'Var', (40, 47))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('eIF4', 'cellular_component', 'GO:0008304', ('148', '152'))	('MNK1', 'Gene', '8569', (35, 39))	('MNK1', 'Gene', (35, 39))	('MNK2', 'Gene', '2872', (133, 137))	('MNK2', 'Gene', (133, 137))
68195	31258849	In 786-O cells, CGP57380 and ETP45835 prevented eIF4E phosphorylation in a concentration-dependent manner and at the same time increased vimentin and N-cadherin levels (Figure 3A, left).	('cadherin', 'molecular_function', 'GO:0008014', ('152', '160'))	('N-cadherin', 'Gene', (150, 160))	('eIF4E', 'Protein', (48, 53))	('prevented', 'NegReg', (38, 47))	('N-cadherin', 'Gene', '1000', (150, 160))	('CGP57380', 'Chemical', 'MESH:C466997', (16, 24))	('vimentin', 'Gene', '7431', (137, 145))	('vimentin', 'cellular_component', 'GO:0045099', ('137', '145'))	('ETP45835', 'Chemical', '-', (29, 37))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('eIF4', 'cellular_component', 'GO:0008304', ('48', '52'))	('CGP57380', 'Var', (16, 24))	('ETP45835', 'Var', (29, 37))	('vimentin', 'cellular_component', 'GO:0045098', ('137', '145'))	('vimentin', 'Gene', (137, 145))	('increased', 'PosReg', (127, 136))	('phosphorylation', 'MPA', (54, 69))
68196	31258849	Similarly, in A498 cells, p-eIF4E (vs. total eIF4E expression) was reduced in a concentrationdependent manner after CGP57380 or ETP45835 administration, with the reciprocal upregulation of vimentin and N-cadherin in parallel.	('vimentin', 'cellular_component', 'GO:0045099', ('189', '197'))	('eIF4', 'cellular_component', 'GO:0008304', ('28', '32'))	('vimentin', 'Gene', (189, 197))	('p-eIF4E', 'Var', (26, 33))	('ETP45835', 'Chemical', '-', (128, 136))	('CGP57380', 'Chemical', 'MESH:C466997', (116, 124))	('eIF4', 'cellular_component', 'GO:0008304', ('45', '49'))	('N-cadherin', 'Gene', (202, 212))	('reduced', 'NegReg', (67, 74))	('vimentin', 'cellular_component', 'GO:0045098', ('189', '197'))	('ETP45835', 'Var', (128, 136))	('N-cadherin', 'Gene', '1000', (202, 212))	('cadherin', 'molecular_function', 'GO:0008014', ('204', '212'))	('vimentin', 'Gene', '7431', (189, 197))	('CGP57380', 'Var', (116, 124))
68199	31258849	Under these conditions, MNK2 and 2a knockdown caused p-eIF4E reduction, although MNK1 knockdown had little effect on p-eIF4E expression (Figure 3C).	('MNK2', 'Gene', '2872', (24, 28))	('MNK1', 'Gene', '8569', (81, 85))	('MNK2', 'Gene', (24, 28))	('MNK1', 'Gene', (81, 85))	('reduction', 'NegReg', (61, 70))	('eIF4', 'cellular_component', 'GO:0008304', ('55', '59'))	('eIF4', 'cellular_component', 'GO:0008304', ('119', '123'))	('knockdown', 'Var', (36, 45))	('p-eIF4E', 'MPA', (53, 60))
68200	31258849	In parallel, E-cadherin faintly decreased and vimentin became overexpressed at the protein level in 786-O and A498 cells with MNK2 or 2a knockdown (Figure 3C).	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('MNK2', 'Gene', '2872', (126, 130))	('vimentin', 'cellular_component', 'GO:0045098', ('46', '54'))	('overexpressed', 'PosReg', (62, 75))	('MNK2', 'Gene', (126, 130))	('vimentin', 'Gene', '7431', (46, 54))	('vimentin', 'Gene', (46, 54))	('knockdown', 'Var', (137, 146))	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', '999', (13, 23))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('vimentin', 'cellular_component', 'GO:0045099', ('46', '54'))	('decreased', 'NegReg', (32, 41))
68201	31258849	Compared with RCC cells laden with a negative control (NC) of siRNA, however, no significant increase in vimentin mRNA was observed in the MNKs-knockdown cells, indicating that MNK knockdown may enhance translation of vimentin mRNA, but not its transcription (Figure 3D).	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('RCC', 'Disease', (14, 17))	('transcription', 'biological_process', 'GO:0006351', ('245', '258'))	('vimentin', 'cellular_component', 'GO:0045099', ('218', '226'))	('enhance', 'PosReg', (195, 202))	('translation', 'biological_process', 'GO:0006412', ('203', '214'))	('vimentin', 'cellular_component', 'GO:0045099', ('105', '113'))	('vimentin', 'Gene', '7431', (105, 113))	('vimentin', 'cellular_component', 'GO:0045098', ('218', '226'))	('vimentin', 'Gene', '7431', (218, 226))	('MNK', 'Gene', (177, 180))	('vimentin', 'Gene', (105, 113))	('vimentin', 'cellular_component', 'GO:0045098', ('105', '113'))	('vimentin', 'Gene', (218, 226))	('knockdown', 'Var', (181, 190))	('translation', 'MPA', (203, 214))
68210	31258849	In 786-O (but not in A498), knockdown with siMNK1 increased cell invasion approximately by twofold vs. the NC, comparable with that of siMNK2 or siMNK2a (Figure 4E and 4F).	('MNK2', 'Gene', (137, 141))	('MNK2', 'Gene', '2872', (147, 151))	('MNK2', 'Gene', (147, 151))	('increased', 'PosReg', (50, 59))	('MNK1', 'Gene', '8569', (45, 49))	('MNK1', 'Gene', (45, 49))	('knockdown', 'Var', (28, 37))	('MNK2', 'Gene', '2872', (137, 141))	('cell invasion', 'CPA', (60, 73))
68211	31258849	The pharmacological inhibition of MNK1/2 with CGP57380 suppressed cell viability in a concentration-dependent manner, but the maximal effects at 100 muM CGP57380 were approximately a 30% and 10% decrease from the baselines in 786O and A498, respectively (Figure 4G).	('CGP57380', 'Chemical', 'MESH:C466997', (46, 54))	('CGP57380', 'Chemical', 'MESH:C466997', (153, 161))	('cell viability', 'CPA', (66, 80))	('MNK1/2', 'Gene', '8569;2872', (34, 40))	('decrease', 'NegReg', (195, 203))	('MNK1/2', 'Gene', (34, 40))	('CGP57380', 'Var', (46, 54))	('CGP57380', 'Var', (153, 161))	('suppressed', 'NegReg', (55, 65))
68212	31258849	However, CGP57380 inhibits several kinases other than MNKs.	('inhibits', 'NegReg', (18, 26))	('CGP57380', 'Chemical', 'MESH:C466997', (9, 17))	('CGP57380', 'Var', (9, 17))	('kinases', 'Pathway', (35, 42))
68213	31258849	Another MNK1/2 inhibitor, ETP45835, had no effect on cell viability of 786-O and A498 at a concentration of 1 to 100 muM (Figure 4G).	('MNK1/2', 'Gene', (8, 14))	('ETP45835', 'Var', (26, 34))	('MNK1/2', 'Gene', '8569;2872', (8, 14))	('ETP45835', 'Chemical', '-', (26, 34))
68215	31258849	In contrast, cell viability decreased by 30% in A498 cells with MNK2 or 2a knocked down, but not in those with MNK1 knocked down (Figure 4I).	('MNK2', 'Gene', (64, 68))	('cell viability', 'CPA', (13, 27))	('knocked down', 'Var', (75, 87))	('decreased', 'NegReg', (28, 37))	('MNK2', 'Gene', '2872', (64, 68))	('MNK1', 'Gene', '8569', (111, 115))	('MNK1', 'Gene', (111, 115))
68219	31258849	Consistent with a previous report, our results show that high eIF4E expression is independently prognostic of poor recurrence-free rate and CSS in the patients with localized ccRCC.	('eIF4', 'cellular_component', 'GO:0008304', ('62', '66'))	('CSS', 'CPA', (140, 143))	('recurrence-free rate', 'CPA', (115, 135))	('eIF4E', 'Gene', (62, 67))	('high', 'Var', (57, 61))	('RCC', 'Disease', (177, 180))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('patients', 'Species', '9606', (151, 159))	('poor', 'NegReg', (110, 114))	('CSS', 'Chemical', '-', (140, 143))
68221	31258849	In the present study, we have demonstrated that higher expression of p-eIF4E is an independent predictor of longer RFI after curative nephrectomy for localized ccRCC.	('p-eIF4E', 'Var', (69, 76))	('eIF4', 'cellular_component', 'GO:0008304', ('71', '75'))	('RCC', 'Disease', (162, 165))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('expression', 'MPA', (55, 65))	('higher', 'PosReg', (48, 54))
68223	31258849	The present data suggest that MNK2a-induced p-eIF4E may suppress EMT, cell migration, and invasion, partially due to vimentin downregulation at the translational level, consequently inhibiting ccRCC recurrence.	('vimentin', 'Gene', '7431', (117, 125))	('vimentin', 'cellular_component', 'GO:0045099', ('117', '125'))	('EMT', 'CPA', (65, 68))	('eIF4', 'cellular_component', 'GO:0008304', ('46', '50'))	('MNK2', 'Gene', '2872', (30, 34))	('MNK2', 'Gene', (30, 34))	('vimentin', 'Gene', (117, 125))	('downregulation', 'NegReg', (126, 140))	('suppress', 'NegReg', (56, 64))	('vimentin', 'cellular_component', 'GO:0045098', ('117', '125'))	('cell migration', 'CPA', (70, 84))	('inhibiting', 'NegReg', (182, 192))	('p-eIF4E', 'Var', (44, 51))	('EMT', 'biological_process', 'GO:0001837', ('65', '68'))	('cell migration', 'biological_process', 'GO:0016477', ('70', '84'))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('RCC', 'Disease', (195, 198))	('invasion', 'CPA', (90, 98))
68225	31258849	However, in the present study, p-eIF4E may associate with the negative regulation of eIF4E activity, as indicated in some other tumours including ovarian, gastric, and colorectal cancers.	('tumours', 'Disease', 'MESH:D009369', (128, 135))	('tumours', 'Disease', (128, 135))	('colorectal cancers', 'Disease', 'MESH:D015179', (168, 186))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('gastric', 'Disease', (155, 162))	('regulation', 'biological_process', 'GO:0065007', ('71', '81'))	('ovarian', 'Disease', (146, 153))	('activity', 'MPA', (91, 99))	('colorectal cancers', 'Disease', (168, 186))	('negative', 'NegReg', (62, 70))	('eIF4E', 'Protein', (85, 90))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('eIF4', 'cellular_component', 'GO:0008304', ('85', '89'))	('eIF4', 'cellular_component', 'GO:0008304', ('33', '37'))	('p-eIF4E', 'Var', (31, 38))
68231	31258849	Recently, we demonstrated that the lower or higher expression of eIF4E reflected a weaker or stronger activation of the mTORC1/4EBP1/eIF4E signalling pathway, respectively.	('signalling pathway', 'biological_process', 'GO:0007165', ('139', '157'))	('mTORC1', 'Gene', '382056', (120, 126))	('higher', 'PosReg', (44, 50))	('eIF4', 'cellular_component', 'GO:0008304', ('65', '69'))	('mTORC1', 'Gene', (120, 126))	('activation', 'PosReg', (102, 112))	('eIF4E', 'Var', (65, 70))	('expression', 'MPA', (51, 61))	('eIF4', 'cellular_component', 'GO:0008304', ('133', '137'))	('mTORC1', 'cellular_component', 'GO:0031931', ('120', '126'))	('4EBP1', 'Gene', '1978', (127, 132))	('4EBP1', 'Gene', (127, 132))
68233	31258849	In the patients with better prognosis, hypofunction of mTORC1 may suppress mTORC1/4EBP1/eIF4E signalling to reduce eIF4E release from 4EBP1, and simultaneously may stimulate MNK2a to boost up eIF4E phosphorylation.	('MNK2', 'Gene', '2872', (174, 178))	('eIF4', 'cellular_component', 'GO:0008304', ('115', '119'))	('mTORC1', 'Gene', (75, 81))	('eIF4E', 'Protein', (192, 197))	('mTORC1', 'Gene', '382056', (75, 81))	('patients', 'Species', '9606', (7, 15))	('suppress', 'NegReg', (66, 74))	('MNK2', 'Gene', (174, 178))	('4EBP1', 'Gene', '1978', (134, 139))	('4EBP1', 'Gene', (82, 87))	('reduce', 'NegReg', (108, 114))	('hypofunction', 'Var', (39, 51))	('stimulate', 'PosReg', (164, 173))	('mTORC1', 'cellular_component', 'GO:0031931', ('55', '61'))	('signalling', 'biological_process', 'GO:0023052', ('94', '104'))	('mTORC1', 'Gene', (55, 61))	('mTORC1', 'cellular_component', 'GO:0031931', ('75', '81'))	('phosphorylation', 'biological_process', 'GO:0016310', ('198', '213'))	('4EBP1', 'Gene', '1978', (82, 87))	('eIF4E release from', 'MPA', (115, 133))	('mTORC1', 'Gene', '382056', (55, 61))	('boost up', 'PosReg', (183, 191))	('eIF4', 'cellular_component', 'GO:0008304', ('192', '196'))	('eIF4', 'cellular_component', 'GO:0008304', ('88', '92'))	('4EBP1', 'Gene', (134, 139))
68236	31258849	In the present study, MNK2 or 2a inhibition augmented migration, invasion and vimentin expression to promote EMT.	('MNK2', 'Gene', (22, 26))	('inhibition', 'Var', (33, 43))	('promote', 'PosReg', (101, 108))	('vimentin', 'cellular_component', 'GO:0045098', ('78', '86'))	('EMT', 'biological_process', 'GO:0001837', ('109', '112'))	('migration', 'CPA', (54, 63))	('vimentin', 'cellular_component', 'GO:0045099', ('78', '86'))	('expression', 'MPA', (87, 97))	('EMT', 'CPA', (109, 112))	('vimentin', 'Gene', '7431', (78, 86))	('invasion', 'CPA', (65, 73))	('vimentin', 'Gene', (78, 86))	('augmented', 'PosReg', (44, 53))	('MNK2', 'Gene', '2872', (22, 26))
68240	31258849	The overwhelming antagonism of abundant MNK2a against MNK2b in ccRCC may suppress EMT along with p-eIF4E upregulation (Figure 5).	('suppress', 'NegReg', (73, 81))	('eIF4', 'cellular_component', 'GO:0008304', ('99', '103'))	('upregulation', 'PosReg', (105, 117))	('MNK2', 'Gene', (40, 44))	('antagonism', 'Var', (17, 27))	('EMT', 'biological_process', 'GO:0001837', ('82', '85'))	('MNK2', 'Gene', '2872', (54, 58))	('EMT', 'CPA', (82, 85))	('MNK2', 'Gene', '2872', (40, 44))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('MNK2', 'Gene', (54, 58))	('RCC', 'Disease', (65, 68))
68243	31258849	Colony formation was greatly impaired in mesenchymal embryonic fibroblasts expressing eIF4E with mutation of Ser209 to alanine which MNKs cannot phosphorylate, but the fibroblasts proliferated comparably as those with wildtype eIF4E.	('eIF4E', 'Gene', (86, 91))	('impaired', 'NegReg', (29, 37))	('Ser209 to alanine', 'Mutation', 'p.S209A', (109, 126))	('eIF4', 'cellular_component', 'GO:0008304', ('86', '90'))	('formation', 'biological_process', 'GO:0009058', ('7', '16'))	('eIF4', 'cellular_component', 'GO:0008304', ('227', '231'))	('mutation', 'Var', (97, 105))	('Colony formation', 'CPA', (0, 16))	('Ser', 'cellular_component', 'GO:0005790', ('109', '112'))
68250	31258849	Fourthly, it was not possible to investigate the effects of specific MNK inhibition on p-eIF4E in mouse xenograft models, because stable MNK knockdown in RCC cell lines with short hairpin RNA significantly decreased eIF4E protein expression under our experimental conditions.	('protein', 'Protein', (222, 229))	('knockdown', 'Var', (141, 150))	('MNK', 'Gene', (137, 140))	('eIF4', 'cellular_component', 'GO:0008304', ('89', '93'))	('eIF4E protein', 'Protein', (216, 229))	('eIF4', 'cellular_component', 'GO:0008304', ('216', '220'))	('decreased', 'NegReg', (206, 215))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('RCC', 'Disease', (154, 157))	('protein', 'cellular_component', 'GO:0003675', ('222', '229'))	('mouse', 'Species', '10090', (98, 103))	('RNA', 'cellular_component', 'GO:0005562', ('188', '191'))
68275	31258849	Brown-coloured staining of tumour cells, regardless of the cytoplasmic or nuclear stainability, was judged as positive for anti- eIF4E and p-eIF4E antibodies.	('anti- eIF4E', 'Var', (123, 134))	('p-eIF4E', 'Var', (139, 146))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('eIF4', 'cellular_component', 'GO:0008304', ('129', '133'))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('eIF4', 'cellular_component', 'GO:0008304', ('141', '145'))	('tumour', 'Disease', (27, 33))
68286	31258849	The antibodies to the following chemicals were used: eIF4E, p-eIF4E (Ser209), MNK1, MNK2, vimentin, N-cadherin, and E-cadherin.	('eIF4E', 'Var', (53, 58))	('MNK1', 'Gene', '8569', (78, 82))	('Ser209', 'Chemical', '-', (69, 75))	('E-cadherin', 'Gene', (116, 126))	('E-cadherin', 'Gene', '999', (116, 126))	('N-cadherin', 'Gene', (100, 110))	('N-cadherin', 'Gene', '1000', (100, 110))	('MNK2', 'Gene', '2872', (84, 88))	('vimentin', 'Gene', '7431', (90, 98))	('eIF4', 'cellular_component', 'GO:0008304', ('62', '66'))	('vimentin', 'cellular_component', 'GO:0045099', ('90', '98'))	('vimentin', 'Gene', (90, 98))	('Ser', 'cellular_component', 'GO:0005790', ('69', '72'))	('eIF4', 'cellular_component', 'GO:0008304', ('53', '57'))	('MNK2', 'Gene', (84, 88))	('MNK1', 'Gene', (78, 82))	('p-eIF4E', 'Var', (60, 67))	('cadherin', 'molecular_function', 'GO:0008014', ('118', '126'))	('vimentin', 'cellular_component', 'GO:0045098', ('90', '98'))	('cadherin', 'molecular_function', 'GO:0008014', ('102', '110'))
68290	31258849	Targeting sequences of MNKs siRNA are as follows: siMNK11 (#161707029), 5'-GCCGUCAAAAUCAUCGAGAAACAAG-3'; siMNK12 (#161707032), 5'-GUUUACAGAUGGUAUCUUCUCAAAA-3'; siMNK21 (#158253115), 5'-GAAGUUUUCCUUUACACCAACUGTC-3'; siMNK22 (#158253118), 5'-GCCUUGGACUUUCUGCAUAACAAAG-3'; siMNK22 (#165395347), 5'-AGUGCAGACCUGCAUCAACCUCATC-3'; siMNK2a (#165395350), 5'-CUUGUCCCCAUGAUAGUUGACAATC-3' (all from Integrated DNA Technologies, Inc. Tokyo, Japan).	('#161707029', 'Var', (59, 69))	('DNA', 'cellular_component', 'GO:0005574', ('400', '403'))	('#165395347', 'Var', (279, 289))	('#158253118', 'Var', (224, 234))	('MNK2', 'Gene', '2872', (162, 166))	('MNK1', 'Gene', '8569', (52, 56))	('MNK1', 'Gene', '8569', (107, 111))	('#161707032', 'Var', (114, 124))	('MNK2', 'Gene', '2872', (217, 221))	('MNK2', 'Gene', '2872', (272, 276))	('MNK2', 'Gene', '2872', (327, 331))	('#165395350', 'Var', (334, 344))	('MNK2', 'Gene', (162, 166))	('MNK2', 'Gene', (272, 276))	('MNK2', 'Gene', (217, 221))	('#158253115', 'Var', (169, 179))	('MNK2', 'Gene', (327, 331))	('MNK1', 'Gene', (52, 56))	('MNK1', 'Gene', (107, 111))
68295	31258849	786-O and A498 RCC cells were cultured at 72 h in the presence and absence of MNK1/2 inhibitors, CGP57380 or ETP45835.	('CGP57380', 'Chemical', 'MESH:C466997', (97, 105))	('ETP45835', 'Var', (109, 117))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('CGP57380', 'Var', (97, 105))	('RCC', 'Disease', (15, 18))	('MNK1/2', 'Gene', '8569;2872', (78, 84))	('MNK1/2', 'Gene', (78, 84))	('ETP45835', 'Chemical', '-', (109, 117))
68306	32510176	Clearly, the tool helps visualize the enrichment of patients with BAP1 mutation and Chr14 deletion in CD8+ Inflamed group (Fig 1A).	('deletion', 'Var', (90, 98))	('BAP1', 'Gene', '8314', (66, 70))	('CD8', 'Gene', (102, 105))	('mutation', 'Var', (71, 79))	('CD8', 'Gene', '925', (102, 105))	('Chr14', 'Gene', (84, 89))	('BAP1', 'Gene', (66, 70))	('patients', 'Species', '9606', (52, 60))
68314	32510176	ProTrack organizes this data into top and bottom tracks of genetic and clinical annotations, including genomically confirmed ccRCC, non-ccRCC status; 3p copy number variation; immune subtype of each sample; copy number variation for chromosomes 5q, 7p, 14q; chromosomes 2,3 and 3,5 translocations; genome instability; CpG island methylator phenotype (CIMP) status; grade; stage; and gender.	('RCC', 'Disease', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('CIMP', 'Chemical', '-', (351, 355))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('genome instability', 'CPA', (298, 316))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('ccRCC', 'Phenotype', 'HP:0006770', (125, 130))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('copy number variation', 'Var', (207, 228))	('RCC', 'Disease', (127, 130))
68340	30536551	A total of 38 mutations across 16 (30%) patients were identified from cfDNA, including mutations in TP53 (n = 6) and VHL (n = 5), and median mutant allele frequency of ctDNA was 10%.	('TP53', 'Gene', '7157', (100, 104))	('patients', 'Species', '9606', (40, 48))	('TP53', 'Gene', (100, 104))	('cfDNA', 'Disease', (70, 75))	('VHL', 'Disease', (117, 120))	('VHL', 'Disease', 'MESH:D006623', (117, 120))	('mutations', 'Var', (87, 96))
68341	30536551	We designed specific ddPCR probes for 11 mutations and detected the same mutations in both cfDNA and tumor DNA.	('mutations', 'Var', (41, 50))	('cfDNA', 'Disease', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
68373	30536551	Probable PCR duplications, for which paired-end reads aligned to the same genomic position, were removed, and pileup files were generated as BAM files using SAMtools28 and our program developed in-house.	('BAM', 'Gene', (141, 144))	('BAM', 'Gene', '9126', (141, 144))	('duplications', 'Var', (13, 25))	('PCR', 'Gene', (9, 12))
68375	30536551	The ddPCR platform, Qx100 Droplet Digital PCR System (Bio-Rad Laboratories, Hercules, CA, USA), was used to validate the mutations detected by NGS using existing or customized Droplet Digital PCR Assays (Bio-Rad Laboratories) including primers and probes (FAM, mutant type; HEX, wild-type; Table S2), and ddPCR Supermix for Probes (No dUTP; Bio-Rad Laboratories) according to the manufacturer's instructions.	('mutations', 'Var', (121, 130))	('Rad', 'biological_process', 'GO:1990116', ('58', '61'))	('Rad', 'biological_process', 'GO:1990116', ('208', '211'))	('HEX', 'Gene', (274, 277))	('dUTP', 'Chemical', 'MESH:C027078', (335, 339))	('Rad', 'biological_process', 'GO:1990116', ('345', '348'))	('HEX', 'Gene', '3087', (274, 277))
68379	30536551	To evaluate the differences in size distribution of plasma cfDNA in each RCC patient, the proportion of cfDNA fragments (PCF) was defined as the ratio of small cfDNA fragments (50-166 bp) to large ones (167-250 bp).	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('50-166', 'Var', (177, 183))	('PCF', 'Chemical', '-', (121, 124))	('patient', 'Species', '9606', (77, 84))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
68380	30536551	For each of the mutations detected by NGS, fragment length was extracted using the integrative genomics viewer30 from BAM files of plasma cfDNA of between 50 and 250 bp and divided into two groups according to the presence of mutations.	('BAM', 'Gene', (118, 121))	('mutations', 'Var', (16, 25))	('BAM', 'Gene', '9126', (118, 121))
68398	30536551	In contrast, in case 53, the same MTOR mutation was identified in cfDNA and gDNA from cancer tissue, yet a TSC1 mutation was detected in the cfDNA sample only.	('MTOR', 'Gene', '2475', (34, 38))	('mutation', 'Var', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('TSC1', 'Gene', '7248', (107, 111))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('MTOR', 'Gene', (34, 38))	('cancer', 'Disease', (86, 92))	('TSC1', 'Gene', (107, 111))
68401	30536551	Importantly, 11 of 12 mutations were verified by ddPCR in both cfDNA and gDNA from tumor tissue.	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mutations', 'Var', (22, 31))
68403	30536551	Interestingly, in case 53, ddPCR enabled detection of the TSC1 mutation in both cfDNA and gDNA from tumor tissue, yet NGS showed the mutation only in the cfDNA sample.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mutation', 'Var', (63, 71))	('TSC1', 'Gene', '7248', (58, 62))	('TSC1', 'Gene', (58, 62))
68406	30536551	To evaluate cfDNA fragmentation in each RCC patient, we defined PCF as the ratio of short fragments (50-166 bp) to large ones (167-250 bp) using NGS (Figure 3B).	('patient', 'Species', '9606', (44, 51))	('RCC', 'Disease', (40, 43))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('50-166 bp', 'Var', (101, 110))	('PCF', 'Chemical', '-', (64, 67))
68410	30536551	These results suggest that RCC patients who had mutations in plasma cfDNA had significantly shorter cfDNA fragments than those without mutations.	('cfDNA fragments', 'CPA', (100, 115))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('patients', 'Species', '9606', (31, 39))	('plasma cfDNA', 'Gene', (61, 73))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))	('shorter', 'NegReg', (92, 99))	('mutations', 'Var', (48, 57))
68411	30536551	In case 10, mutations in plasma cfDNA were identified in the genes SETD2, BAP1 and NF2, and the cfDNA fragment sizes of mutant alleles were significantly shorter than those with wild-type alleles for SETD2 (P = .012) and NF2 (P = .008; Figure 4A-C).	('NF2', 'Gene', '4771', (221, 224))	('SETD2', 'Gene', '29072', (200, 205))	('SETD2', 'Gene', (200, 205))	('SETD2', 'Gene', '29072', (67, 72))	('NF2', 'Gene', (83, 86))	('SETD2', 'Gene', (67, 72))	('BAP1', 'Gene', '8314', (74, 78))	('NF2', 'Gene', (221, 224))	('NF2', 'Gene', '4771', (83, 86))	('BAP1', 'Gene', (74, 78))	('mutant', 'Var', (120, 126))	('shorter', 'NegReg', (154, 161))
68412	30536551	Likewise, in case 13, cfDNA fragment sizes of mutant alleles were significantly shorter than those with wild-type alleles for TP53 (P < .001; Figure 4D,E).	('TP53', 'Gene', (126, 130))	('cfDNA fragment sizes', 'CPA', (22, 42))	('mutant', 'Var', (46, 52))	('shorter', 'NegReg', (80, 87))	('TP53', 'Gene', '7157', (126, 130))
68413	30536551	In case 50, cfDNA fragments harboring a TSC1 mutation were significantly shorter than those of the corresponding wild-type allele (P < .001), with a similar trend for a FPGT mutation that did not reach significance (P = .095; Figure 4F-J).	('FPGT', 'Gene', '8790', (169, 173))	('TSC1', 'Gene', (40, 44))	('shorter', 'NegReg', (73, 80))	('mutation', 'Var', (45, 53))	('FPGT', 'Gene', (169, 173))	('TSC1', 'Gene', '7248', (40, 44))
68421	30536551	Similarly, in case 48, a rare TP53 mutation that was detected in the primary site was not detected in plasma cfDNA before and between initial treatments, whereas a BAP1 mutation that existed abundantly in the primary site was only identified in plasma cfDNA before treatment (Figure S2A).	('TP53', 'Gene', (30, 34))	('BAP1', 'Gene', (164, 168))	('mutation', 'Var', (35, 43))	('BAP1', 'Gene', '8314', (164, 168))	('TP53', 'Gene', '7157', (30, 34))
68424	30536551	In terms of predicting drug response, patients with short fragment sizes of cfDNA showed significantly worse responsiveness (long vs short, P = .011; Figure S3A).	('worse', 'NegReg', (103, 108))	('cfDNA', 'Gene', (76, 81))	('responsiveness', 'MPA', (109, 123))	('patients', 'Species', '9606', (38, 46))	('short fragment sizes', 'Var', (52, 72))
68428	30536551	Moreover, in RCC patients with metastasis, positive ctDNA, short fragment size of cfDNA and high PCF were significantly associated with worse CSS (P = .010, P = .011 and P = .007, respectively; Figure 6E,F and Figure S4C), whereas patients without metastasis had no association between prognosis and these parameters of cfDNA and ctDNA (P = .190, P = .485 and P = .677, respectively).	('PCF', 'Gene', (97, 100))	('high', 'Var', (92, 96))	('patients', 'Species', '9606', (231, 239))	('CSS', 'Chemical', '-', (142, 145))	('CSS', 'CPA', (142, 145))	('PCF', 'Chemical', '-', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', (13, 16))	('patients', 'Species', '9606', (17, 25))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('short fragment', 'Var', (59, 73))
68429	30536551	These data indicate that mutations and fragmentation of cfDNA could be used to identify more malignant tumors especially in patients with metastasis, warranting further study.	('mutations', 'Var', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('malignant tumors', 'Disease', 'MESH:D018198', (93, 109))	('cfDNA', 'Gene', (56, 61))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('malignant tumors', 'Disease', (93, 109))	('patients', 'Species', '9606', (124, 132))
68433	30536551	Regarding published mutation profiles from ccRCC tumor tissue, mutations in VHL (52.3%) is the most prominent, followed by PBRM1 (32.9%), SETD2 (11.5%) and BAP1 (10.1%), as well as TP53 (2.2%).25 In this study, TP53 mutations in cfDNA were most abundant, followed by VHL and BAP1, which is consistent with at least one previous report.23 The discrepancy between tumor DNA and cfDNA may be because TP53 mutations were induced by selection pressure from some drugs.	('TP53', 'Gene', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('PBRM1', 'Gene', (123, 128))	('SETD2', 'Gene', '29072', (138, 143))	('VHL', 'Disease', (76, 79))	('TP53', 'Gene', (211, 215))	('tumor', 'Disease', (362, 367))	('BAP1', 'Gene', '8314', (275, 279))	('BAP1', 'Gene', '8314', (156, 160))	('tumor', 'Disease', 'MESH:D009369', (362, 367))	('RCC tumor', 'Disease', 'MESH:C538614', (45, 54))	('TP53', 'Gene', '7157', (397, 401))	('TP53', 'Gene', '7157', (181, 185))	('VHL', 'Disease', 'MESH:D006623', (267, 270))	('BAP1', 'Gene', (275, 279))	('TP53', 'Gene', '7157', (211, 215))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (362, 367))	('DNA', 'cellular_component', 'GO:0005574', ('368', '371'))	('VHL', 'Disease', 'MESH:D006623', (76, 79))	('BAP1', 'Gene', (156, 160))	('mutations', 'Var', (402, 411))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('induced', 'Reg', (417, 424))	('PBRM1', 'Gene', '55193', (123, 128))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))	('TP53', 'Gene', (397, 401))	('SETD2', 'Gene', (138, 143))	('RCC tumor', 'Disease', (45, 54))	('VHL', 'Disease', (267, 270))
68436	30536551	We have previously reported that RCC patients tended to have shorter fragment sizes of cfDNA compared to healthy controls.38 Moreover, we showed that cfDNA fragments harboring mutant alleles were often shorter than those with corresponding wild-type alleles in RCC patients.	('RCC', 'Disease', 'MESH:C538614', (261, 264))	('shorter', 'NegReg', (202, 209))	('patients', 'Species', '9606', (37, 45))	('mutant', 'Var', (176, 182))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('patients', 'Species', '9606', (265, 273))	('RCC', 'Disease', (261, 264))	('RCC', 'Phenotype', 'HP:0005584', (261, 264))
68438	30536551	Second, some mutations could be detected in both cfDNA and gDNA from tumor tissue using the ddPCR platform.	('mutations', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))
68451	32355644	Determining the presence or absence of certain mutations through genetic testing may predict whether a patient with cancer may benefit from a particular chemotherapy regimen.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('mutations', 'Var', (47, 56))	('men', 'Species', '9606', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('patient', 'Species', '9606', (103, 110))
68461	32355644	Core tip: Specialized genetic testing determines the presence or absence of certain mutations which may predict whether a patient with cancer may benefit from a specific chemotherapy regimen.	('cancer', 'Disease', (135, 141))	('patient', 'Species', '9606', (122, 129))	('men', 'Species', '9606', (187, 190))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutations', 'Var', (84, 93))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
68471	32355644	Genetic testing for personalized and targeted cancer therapy detects mutations in the DNA of cancer cells.	('mutations', 'Var', (69, 78))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('detects', 'Reg', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))
68472	32355644	Determining the presence or absence of certain mutations may predict whether a patient with cancer may benefit from a particular chemotherapy regimen.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('men', 'Species', '9606', (146, 149))	('mutations', 'Var', (47, 56))	('patient', 'Species', '9606', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
68488	32355644	ERCCA positivity excluded platinum-based therapy, while BRCA1 positivity was the rationale for taxane-based therapy.	('BRCA1', 'Gene', '672', (56, 61))	('positivity', 'Var', (6, 16))	('taxane', 'Chemical', 'MESH:C080625', (95, 101))	('BRCA1', 'Gene', (56, 61))	('ERCCA', 'Gene', (0, 5))	('platinum', 'Chemical', 'MESH:D010984', (26, 34))
68495	32355644	The patient was treated with two cycles of doxorubicin as the specialized testing revealed Topo2alpha positivity.	('Topo2alpha positivity', 'Phenotype', 'HP:0030859', (91, 112))	('positivity', 'Var', (102, 112))	('revealed', 'Reg', (82, 90))	('doxorubicin', 'Chemical', 'MESH:D004317', (43, 54))	('patient', 'Species', '9606', (4, 11))	('Topo2alpha', 'Protein', (91, 101))	('Topo2alpha', 'Chemical', '-', (91, 101))
68586	30320241	The ClearCode34 assignment was independently correlated with outcome in multivariate analysis that included stage, grade, tumor size, presence of necrosis, and performance status.	('necrosis', 'biological_process', 'GO:0008220', ('146', '154'))	('necrosis', 'biological_process', 'GO:0001906', ('146', '154'))	('necrosis', 'Disease', (146, 154))	('ClearCode34', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('necrosis', 'biological_process', 'GO:0008219', ('146', '154'))	('necrosis', 'Disease', 'MESH:D009336', (146, 154))	('necrosis', 'biological_process', 'GO:0070265', ('146', '154'))	('tumor', 'Disease', (122, 127))	('correlated', 'Reg', (45, 55))	('necrosis', 'biological_process', 'GO:0019835', ('146', '154'))
68636	33576099	A single intravenous dose of 55 mug/mL of [113/115In]XYIMSR-01 was well-tolerated in male and female Sprague-Dawley rats.	('Sprague-Dawley rats', 'Species', '10116', (101, 120))	('[113/115In]', 'Var', (42, 53))	('mug', 'molecular_function', 'GO:0043739', ('32', '35'))	('XYIMSR-01', 'Gene', (53, 62))
68638	33576099	We have completed toxicity and dosimetry studies as well as validated a manufacturing process to test [111In]XYIMSR-01 in a phase I clinical trial.	('[111In]', 'Var', (102, 109))	('[111In]XYIMSR-01', 'Chemical', '-', (102, 118))	('toxicity', 'Disease', 'MESH:D064420', (18, 26))	('toxicity', 'Disease', (18, 26))
68647	33576099	Although anti-CAIX monoclonal antibodies (mAbs) radiolabeled with 124I, 89Zr and 111In for non-invasive PET and SPECT imaging of ccRCC have shown promising results, they suffer from slow blood and non-target tissue clearance and non-specific organ uptake.	('CAIX', 'Gene', '768', (14, 18))	('ccRCC', 'Disease', (129, 134))	('uptake', 'biological_process', 'GO:0098739', ('248', '254'))	('uptake', 'biological_process', 'GO:0098657', ('248', '254'))	('111In', 'Chemical', 'MESH:C000615551', (81, 86))	('CAIX', 'Gene', (14, 18))	('124I', 'Var', (66, 70))	('89Zr', 'Var', (72, 76))
68648	33576099	As opposed to mAbs, low-molecular-weight (LMW) CAIX inhibitors have rapid pharmacokinetics and have the advantages of potential same day imaging and lower radiation exposure to the patient.	('CAIX', 'Gene', '768', (47, 51))	('patient', 'Species', '9606', (181, 188))	('low-molecular-weight', 'Var', (20, 40))	('CAIX', 'Gene', (47, 51))
68649	33576099	We have reported dual-motif targeting LMW CAIX ligands [111In]XYIMSR-01, [64Cu] XYIMSR-06 and [177Lu]XYIMSR-01 for SPECT and PET imaging and therapy of ccRCC, respectively.	('CAIX', 'Gene', '768', (42, 46))	('[111In]XYIMSR-01', 'Chemical', '-', (55, 71))	('[177Lu]XYIMSR-01', 'Var', (94, 110))	('[64Cu] XYIMSR-06', 'Var', (73, 89))	('CAIX', 'Gene', (42, 46))	('ccRCC', 'Disease', (152, 157))	('[111In]XYIMSR-01', 'Var', (55, 71))
68695	33576099	Female rats treated with 11 mug/mL and 55 mug/mL [113/115In]XYIMSR-01 had a significant (P < 0.05) decrease in absolute lymphocyte count (Day 3 cohort) when compared to the vehicle control.	('[113/115In]', 'Var', (49, 60))	('rats', 'Species', '10116', (7, 11))	('XYIMSR-01', 'Gene', (60, 69))	('absolute lymphocyte count', 'CPA', (111, 136))	('decrease', 'NegReg', (99, 107))	('decrease in absolute lymphocyte count', 'Phenotype', 'HP:0001888', (99, 136))	('mug', 'molecular_function', 'GO:0043739', ('42', '45'))	('mug', 'molecular_function', 'GO:0043739', ('28', '31'))
68696	33576099	Female rats treated with 55 mug/mL [113/115In]XYIMSR-01 had a statistically significant increase of calcium (Day 15 cohort) and triglycerides (Day 3 cohort) when compared to the vehicle control.	('calcium', 'Chemical', 'MESH:D002118', (100, 107))	('rats', 'Species', '10116', (7, 11))	('mug', 'molecular_function', 'GO:0043739', ('28', '31'))	('triglycerides', 'Chemical', 'MESH:D014280', (128, 141))	('increase', 'PosReg', (88, 96))	('[113/115In]XYIMSR-01', 'Var', (35, 55))	('triglycerides', 'MPA', (128, 141))	('calcium', 'MPA', (100, 107))
68697	33576099	Male rats treated with 11 mug/mL and 55 mug/mL [113/115In]XYIMSR-01 had a statistically significant decrease in urine specific gravity (Day 3 cohort) when compared to the vehicle control.	('urine specific gravity', 'MPA', (112, 134))	('decrease in urine', 'Phenotype', 'HP:0011037', (100, 117))	('mug', 'molecular_function', 'GO:0043739', ('40', '43'))	('XYIMSR-01', 'Gene', (58, 67))	('decrease', 'NegReg', (100, 108))	('rats', 'Species', '10116', (5, 9))	('[113/115In]', 'Var', (47, 58))	('mug', 'molecular_function', 'GO:0043739', ('26', '29'))
68698	33576099	Male rats treated with 55 mug/mL [113/115In]XYIMSR-01 had a statistically significant increase of white blood cells (Day 15 cohort) when compared to the vehicle control.	('increase', 'PosReg', (86, 94))	('white blood cells', 'MPA', (98, 115))	('rats', 'Species', '10116', (5, 9))	('[113/115In]XYIMSR-01', 'Var', (33, 53))	('mug', 'molecular_function', 'GO:0043739', ('26', '29'))	('increase of white blood cells', 'Phenotype', 'HP:0001974', (86, 115))
68699	33576099	In summary, a single intravenous dose of 11 or 55 mug/mL [113/115In]XYIMSR-01 was well-tolerated in male and female Sprague-Dawley rats.	('XYIMSR-01', 'Gene', (68, 77))	('Sprague-Dawley rats', 'Species', '10116', (116, 135))	('[113/115In]', 'Var', (57, 68))	('mug', 'molecular_function', 'GO:0043739', ('50', '53'))
68708	33576099	The results for pharmacokinetics, radiation dosimetry and acute toxicity studies conducted in compliance with USP and FDA guidelines indicate that [111In]XYIMSR-01 injectable drug has no adverse effects with tested amounts of the agent.	('USP', 'molecular_function', 'GO:0051748', ('110', '113'))	('[111In]XYIMSR-01', 'Var', (147, 163))	('[111In]XYIMSR-01', 'Chemical', '-', (147, 163))	('toxicity', 'Disease', 'MESH:D064420', (64, 72))	('toxicity', 'Disease', (64, 72))
68718	33024069	High PKMYT1 expression was correlated with unsatisfactory survival (hazard ratio=1.67, P=0.001), indicating that it is a risk factor for ccRCC.	('PKMYT1', 'Gene', (5, 11))	('High', 'Var', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('RCC', 'Disease', (139, 142))	('expression', 'MPA', (12, 22))
68719	33024069	PKMYT1 was strongly positively correlated with the anti-silencing function of 1B histone chaperone (ASF1B) gene in ccRCC.	('histone chaperone', 'biological_process', 'GO:0043486', ('81', '98'))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('PKMYT1', 'Var', (0, 6))	('anti-silencing function', 'MPA', (51, 74))	('ASF1B', 'Gene', (100, 105))	('histone chaperone', 'biological_process', 'GO:0006334', ('81', '98'))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('ASF1B', 'Gene', '55723', (100, 105))
68720	33024069	PKMYT1 is upregulated in ccRCC and its presence indicates poor prognosis, making it a potential therapeutic target for ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('presence', 'Var', (39, 47))	('upregulated', 'PosReg', (10, 21))	('PKMYT1', 'Gene', (0, 6))	('ccRCC', 'Phenotype', 'HP:0006770', (25, 30))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))
68732	33024069	Because of the action of tumor-suppressor genes such as P53, mutations in which result in deactivation of the G1 checkpoint, most tumor cells are heavily dependent on the G2/M checkpoint, thus ensuring its genomic stability and survival advantage.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('G2/M checkpoint', 'biological_process', 'GO:0000075', ('171', '186'))	('P53', 'Gene', '7157', (56, 59))	('tumor', 'Disease', (25, 30))	('deactivation', 'NegReg', (90, 102))	('genomic stability', 'CPA', (206, 223))	('ensuring', 'PosReg', (193, 201))	('mutations', 'Var', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('25', '41'))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('25', '41'))	('survival advantage', 'CPA', (228, 246))	('P53', 'Gene', (56, 59))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
68735	33024069	In addition, PKMYT1 suppresses cDC2 activity by phosphorylating the Thr14/Thr15 residue on cDC2.	('Thr15', 'Chemical', '-', (74, 79))	('PKMYT1', 'Var', (13, 19))	('phosphorylating', 'MPA', (48, 63))	('activity', 'MPA', (36, 44))	('cDC2', 'Gene', (31, 35))	('cDC2', 'Gene', '379785', (91, 95))	('suppresses', 'NegReg', (20, 30))	('cDC2', 'Gene', '379785', (31, 35))	('Thr14', 'Chemical', '-', (68, 73))	('cDC2', 'Gene', (91, 95))
68738	33024069	Specifically, a study has demonstrated that PKMYT1 is positively associated with polo-like kinase 1 (PLK1) in breast cancer.	('PKMYT1', 'Var', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('PLK1', 'Gene', (101, 105))	('polo-like kinase 1', 'Gene', '5347', (81, 99))	('polo-like kinase 1', 'Gene', (81, 99))	('PLK1', 'Gene', '5347', (101, 105))	('associated', 'Reg', (65, 75))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('breast cancer', 'Disease', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
68740	33024069	PKMYT1 facilitates the progression of prostate cancer by targeting cyclin B1 and cyclin E1 expression.	('expression', 'MPA', (91, 101))	('prostate cancer', 'Disease', 'MESH:D011471', (38, 53))	('cyclin E1', 'Gene', '898', (81, 90))	('facilitates', 'PosReg', (7, 18))	('targeting', 'Reg', (57, 66))	('PKMYT1', 'Var', (0, 6))	('prostate cancer', 'Phenotype', 'HP:0012125', (38, 53))	('prostate cancer', 'Disease', (38, 53))	('cyclin B1', 'Gene', '891', (67, 76))	('cyclin E1', 'Gene', (81, 90))	('cyclin', 'molecular_function', 'GO:0016538', ('67', '73'))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cyclin B1', 'Gene', (67, 76))	('cyclin', 'molecular_function', 'GO:0016538', ('81', '87'))
68742	33024069	PKMYT1 can bind and inactivate glycogen synthase kinase 3beta and further activate beta-catenin/T-cell factor signaling, thus facilitating the development of hepatocellular carcinoma (HCC).	('bind', 'Interaction', (11, 15))	('PKMYT1', 'Var', (0, 6))	('beta-catenin', 'Gene', (83, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('HCC', 'Phenotype', 'HP:0001402', (184, 187))	('beta-catenin', 'Gene', '1499', (83, 95))	('inactivate', 'NegReg', (20, 30))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (158, 182))	('glycogen synthase kinase 3beta', 'Gene', '2932', (31, 61))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (158, 182))	('glycogen synthase kinase 3beta', 'Gene', (31, 61))	('signaling', 'biological_process', 'GO:0023052', ('110', '119'))	('men', 'Species', '9606', (150, 153))	('hepatocellular carcinoma', 'Disease', (158, 182))	('facilitating', 'Reg', (126, 138))	('activate', 'PosReg', (74, 82))
68743	33024069	PKMYT1 facilitates development of ovarian cancer (OC) by negatively modulating SIRT3.	('SIRT3', 'Gene', (79, 84))	('OC', 'Phenotype', 'HP:0100615', (50, 52))	('modulating', 'Reg', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('PKMYT1', 'Var', (0, 6))	('facilitates', 'PosReg', (7, 18))	('ovarian cancer', 'Phenotype', 'HP:0100615', (34, 48))	('ovarian cancer', 'Disease', 'MESH:D010051', (34, 48))	('men', 'Species', '9606', (26, 29))	('negatively', 'NegReg', (57, 67))	('ovarian cancer', 'Disease', (34, 48))	('SIRT3', 'Gene', '23410', (79, 84))
68744	33024069	Diminished expression of PKMYT1 is also accompanied by decreased levels of Notch1, p21, and Hes1, indicating that PKMYT1 has potential to strengthen the activity of the Notch signal pathway in non-small cell lung cancer (NSCLC).	('levels', 'MPA', (65, 71))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (193, 219))	('expression', 'MPA', (11, 21))	('NSCLC', 'Disease', (221, 226))	('Hes1', 'Gene', '3280', (92, 96))	('activity', 'MPA', (153, 161))	('Notch', 'Gene', '4851', (75, 80))	('Notch', 'Gene', (75, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (221, 226))	('Hes1', 'Gene', (92, 96))	('non-small cell lung cancer', 'Disease', (193, 219))	('Notch', 'Gene', '4851', (169, 174))	('Notch', 'Gene', (169, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (208, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('decreased', 'NegReg', (55, 64))	('PKMYT1', 'Var', (114, 120))	('strengthen', 'PosReg', (138, 148))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (193, 219))	('p21', 'Gene', (83, 86))	('Diminished', 'NegReg', (0, 10))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (197, 219))	('NSCLC', 'Disease', 'MESH:D002289', (221, 226))	('p21', 'Gene', '644914', (83, 86))	('Notch1', 'Gene', (75, 81))	('Notch1', 'Gene', '4851', (75, 81))
68745	33024069	Silencing PKMYT1 expression eliminates irradiation-induced G2/M phase arrest and enhances the sensitivity of cancer cells to radiation.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('arrest', 'Disease', (70, 76))	('eliminates', 'NegReg', (28, 38))	('enhances', 'PosReg', (81, 89))	('M phase', 'biological_process', 'GO:0000279', ('62', '69'))	('PKMYT1', 'Gene', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Silencing', 'Var', (0, 9))	('arrest', 'Disease', 'MESH:D006323', (70, 76))
68763	33024069	The cBioPortal database (https://www.cbioportal.org/) (last accessed May 20, 2020) was used to analyze the frequency of PKMYT1 mutations in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('PKMYT1', 'Gene', (120, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('mutations', 'Var', (127, 136))
68764	33024069	The Catalogue of Somatic Mutations in Cancer (COSMIC) (https://cancer.sanger.ac.uk/cosmic/) is a high-resolution database used to investigate the impact of somatic mutations on multiple human cancers, which was used to explore mutations in PKMYT1 in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (250, 255))	('RCC', 'Disease', 'MESH:C538614', (252, 255))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('cancers', 'Disease', (192, 199))	('cancer', 'Disease', (192, 198))	('Cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Disease', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('PKMYT1', 'Gene', (240, 246))	('mutations', 'Var', (227, 236))	('RCC', 'Phenotype', 'HP:0005584', (252, 255))	('RCC', 'Disease', (252, 255))	('Cancer', 'Disease', (38, 44))	('human', 'Species', '9606', (186, 191))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
68769	33024069	Gene Set Enrichment Analysis (GSEA) (https://www.broadinstitute.org/gsea/) was used to determine the significance of the potential biological mechanisms in the high and low PKMYT1 expression groups.	('high', 'Var', (160, 164))	('PKMYT1', 'Gene', (173, 179))	('men', 'Species', '9606', (15, 18))	('low', 'NegReg', (169, 172))	('GSEA', 'Chemical', '-', (30, 34))
68777	33024069	PKMYT1 was one of the most significant genes in the yellow module (GS=0.951435, MM=0.935643) (Figure 2G), which indicates that PKMYT1 is one of the DEGs that is the most significantly correlated with histological grade in ccRCC and it potentially predicts the prognosis of ccRCC based on histological grade.	('RCC', 'Disease', (224, 227))	('RCC', 'Disease', 'MESH:C538614', (275, 278))	('RCC', 'Phenotype', 'HP:0005584', (224, 227))	('correlated', 'Reg', (184, 194))	('PKMYT1', 'Var', (127, 133))	('ccRCC', 'Phenotype', 'HP:0006770', (222, 227))	('ccRCC', 'Phenotype', 'HP:0006770', (273, 278))	('GS', 'Disease', 'MESH:D011125', (67, 69))	('predicts', 'Reg', (247, 255))	('RCC', 'Disease', (275, 278))	('RCC', 'Phenotype', 'HP:0005584', (275, 278))	('RCC', 'Disease', 'MESH:C538614', (224, 227))
68781	33024069	As shown in Table 1, PKMYT1 was significantly correlated with T classification (P<0.0001), N classification (P=0.027), M classification (P=0.0058), TNM stage (P=0.0021), histologic grade (P=0.0002), tumor status (P=0.0037), status of relapse (P=0.0065), and vital status (P=0.0009).	('tumor', 'Disease', (199, 204))	('TNM stage', 'CPA', (148, 157))	('T classification', 'CPA', (62, 78))	('PKMYT1', 'Var', (21, 27))	('status', 'CPA', (224, 230))	('vital status', 'CPA', (258, 270))	('correlated', 'Reg', (46, 56))	('M classification', 'CPA', (119, 135))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('N classification', 'CPA', (91, 107))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
68786	33024069	In addition, the AUC values for the ability of PKMYT1 to distinguish between normal renal tissue and ccRCC at TNM stages I, II, III, and IV were 0.946 (95% CI: 0.908-0.985), 0.899 (95% CI: 0.833-0.965), 0.951 (95% CI: 0.914-0.988), and 0.971 (95% CI: 0.942-0.999), respectively (Figure 5B-5E).	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('PKMYT1', 'Gene', (47, 53))	('0.899', 'Var', (174, 179))	('0.946', 'Var', (145, 150))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))
68787	33024069	Similarly, PKMYT1 also demonstrated significant diagnostic value in distinguishing normal tissue from ccRCC of histological grades G1, G2, G3, and G4, with AUCs of 0.944 (95% CI: 0.897-0.991), 0.932 (95% CI: 0.890-0.973), 0.954 (95% CI: 0.919-0.989), and 0.971 (95% CI: 0.943-0.999), respectively (Figure 5F-5I).	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('PKMYT1', 'Var', (11, 17))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('0.932', 'Var', (193, 198))	('RCC', 'Disease', (104, 107))
68790	33024069	The Kaplan-Meier curve with log-rank test showed that prognosis of ccRCC was worse in those with high expression of PKMYT1 than in those with low expression of the gene (HR=1.67, 95% CI: 1.23-2.27, P=0.001) (Figure 6A).	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('RCC', 'Disease', (69, 72))	('PKMYT1', 'Gene', (116, 122))	('high expression', 'Var', (97, 112))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
68793	33024069	Thus, high PKMYT1 expression can be considered an independent risk factor for OS in ccRCC patients.	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('high', 'Var', (6, 10))	('PKMYT1', 'Gene', (11, 17))	('expression', 'MPA', (18, 28))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('patients', 'Species', '9606', (90, 98))	('RCC', 'Disease', (86, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))
68799	33024069	The AUC values for the nomogram, tumor status, histological grade, TNM stage, and PKMYT1 expression for 10-year OS were 0.739 (95% CI: 0.652-0.863), 0.678 (95% CI: 0.592-0.723), 0.661 (95% CI: 0.604-0.738), 0.653 (95% CI: 0.588-0.768), and 0.639 (95% CI: 0.572-0.743) (Figure 8C).	('0.661', 'Var', (178, 183))	('0.653', 'Var', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('PKMYT1', 'Gene', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('0.678', 'Var', (149, 154))	('0.639', 'Var', (240, 245))
68801	33024069	PKMYT1 expression had a slightly lower or similar predictive performance for predicting prognosis of ccRCC compared with that of the additional clinical indicators (including histologic grade, TNM stage, and tumor status).	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('PKMYT1 expression', 'Var', (0, 17))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (208, 213))	('lower', 'NegReg', (33, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))
68806	33024069	As shown in Figure 9B, missense mutation was the most frequent type of PKMYT1 mutation in ccRCC (27.91%), followed by synonymous mutation (11.63%), nonsense mutation (2.03%), and frameshift mutation (0.87%).	('PKMYT1', 'Gene', (71, 77))	('mutation', 'Var', (78, 86))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('missense mutation', 'Var', (23, 40))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('frameshift', 'Var', (179, 189))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))
68814	33024069	The regression analysis revealed that PKMYT1 and the anti-silencing function 1B (ASF1B) gene displayed the greatest correlation coefficient (Spearman's correlation=0.85, P=1.07e-145; Pearson's correlation=0.89, P=4.11e-174) (Figure 12A).	('correlation', 'Interaction', (116, 127))	('PKMYT1', 'Var', (38, 44))	('anti-silencing function 1B', 'Gene', '55723', (53, 79))	('ASF1B', 'Gene', (81, 86))	('ASF1B', 'Gene', '55723', (81, 86))	('anti-silencing function 1B', 'Gene', (53, 79))
68818	33024069	Furthermore, based on the Human Protein Atlas (HPA) database, a high ASF1B level was significantly correlated with diminished OS in ccRCC (P=0.006) (Figure 12E).	('high', 'Var', (64, 68))	('Human', 'Species', '9606', (26, 31))	('HPA', 'Disease', 'MESH:D010661', (47, 50))	('HPA', 'Disease', (47, 50))	('ASF1B', 'Gene', (69, 74))	('RCC', 'Disease', (134, 137))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('diminished', 'NegReg', (115, 125))	('RCC', 'Phenotype', 'HP:0005584', (134, 137))	('ccRCC', 'Phenotype', 'HP:0006770', (132, 137))	('ASF1B', 'Gene', '55723', (69, 74))
68828	33024069	PKMYT1 expression was further identified as an independent adverse factor for prognosis of ccRCC through a survival analysis that integrated a Cox analysis and a nomogram.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('PKMYT1 expression', 'Var', (0, 17))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('RCC', 'Disease', (93, 96))
68830	33024069	Consistent with the present results, PKMYT1 has been shown to be upregulated in oncogenesis and progression of multiple human tumors, including colorectal cancer, esophageal squamous cell carcinoma (ESCC), hepatocellular carcinoma (HCC), non-small-cell lung cancer (NSCLC), gastric cancer (GC), and breast cancer, as well as OC.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (206, 230))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (299, 312))	('PKMYT1', 'Var', (37, 43))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (174, 197))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('colorectal cancer', 'Disease', 'MESH:D015179', (144, 161))	('gastric cancer', 'Phenotype', 'HP:0012126', (274, 288))	('hepatocellular carcinoma', 'Disease', (206, 230))	('human', 'Species', '9606', (120, 125))	('tumors', 'Disease', (126, 132))	('lung cancer', 'Disease', (253, 264))	('breast cancer', 'Disease', 'MESH:D001943', (299, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('colorectal cancer', 'Disease', (144, 161))	('breast cancer', 'Disease', (299, 312))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (163, 197))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (238, 264))	('NSCLC', 'Disease', 'MESH:D002289', (266, 271))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('gastric cancer', 'Disease', (274, 288))	('lung cancer', 'Disease', 'MESH:D008175', (253, 264))	('oncogenesis', 'CPA', (80, 91))	('upregulated', 'PosReg', (65, 76))	('NSCLC', 'Disease', (266, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (242, 264))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (206, 230))	('GC', 'Phenotype', 'HP:0012126', (290, 292))	('colorectal cancer', 'Phenotype', 'HP:0003003', (144, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (253, 264))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('OC', 'Phenotype', 'HP:0100615', (325, 327))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('HCC', 'Phenotype', 'HP:0001402', (232, 235))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('NSCLC', 'Phenotype', 'HP:0030358', (266, 271))	('gastric cancer', 'Disease', 'MESH:D013274', (274, 288))	('esophageal squamous cell carcinoma', 'Disease', (163, 197))	('oncogenesis', 'biological_process', 'GO:0007048', ('80', '91'))
68832	33024069	One report revealed that mutation in the C-terminal domain of PKMYT1 influenced the prognosis of neuroblastoma by altering its catalytic activity.	('neuroblastoma', 'Disease', (97, 110))	('neuroblastoma', 'Phenotype', 'HP:0003006', (97, 110))	('PKMYT1', 'Gene', (62, 68))	('altering', 'Reg', (114, 122))	('catalytic activity', 'MPA', (127, 145))	('catalytic activity', 'molecular_function', 'GO:0003824', ('127', '145'))	('mutation in', 'Var', (25, 36))	('influenced', 'Reg', (69, 79))	('neuroblastoma', 'Disease', 'MESH:D009447', (97, 110))
68834	33024069	Thus, high PKMYT1 expression potentially indicates tumor progression and it may be a promising diagnostic and prognostic biomarker for ccRCC.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('indicates', 'Reg', (41, 50))	('tumor', 'Disease', (51, 56))	('high', 'Var', (6, 10))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('PKMYT1', 'Gene', (11, 17))	('expression', 'MPA', (18, 28))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('RCC', 'Disease', (137, 140))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
68839	33024069	Considering that EMT is a crucial determinant for tumor metastasis and progression, targeting the beta-catenin/TCF and Akt/mTOR pathway through PKMYT1 may be a promising strategy for tumor treatment.	('Akt', 'Gene', '207', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('TCF', 'Gene', '3172', (111, 114))	('men', 'Species', '9606', (194, 197))	('mTOR', 'Gene', '2475', (123, 127))	('EMT', 'biological_process', 'GO:0001837', ('17', '20'))	('tumor metastasis', 'Disease', 'MESH:D009362', (50, 66))	('tumor', 'Disease', (50, 55))	('tumor metastasis', 'Disease', (50, 66))	('TCF', 'Gene', (111, 114))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', (183, 188))	('PKMYT1', 'Var', (144, 150))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('Akt', 'Gene', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('beta-catenin', 'Gene', (98, 110))	('mTOR', 'Gene', (123, 127))	('beta-catenin', 'Gene', '1499', (98, 110))
68841	33024069	Studies of the pyridopyrimidine derivatives PD-0166285, PD-173952, and PD-173955 also are under way.	('PD-0166285', 'Chemical', 'MESH:C440869', (44, 54))	('PD-0166285', 'Var', (44, 54))	('pyridopyrimidine', 'Chemical', '-', (15, 31))	('PD-173952', 'Chemical', 'MESH:C511991', (56, 65))	('PD-173955', 'Var', (71, 80))	('PD-173955', 'Chemical', 'MESH:C403095', (71, 80))
68844	33024069	Importantly, high ASF1B expression correlates with faster disease development and metastasis in various tumors, including small-cell breast cancer, prostate cancer, and ccRCC.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('tumors', 'Disease', (104, 110))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('RCC', 'Disease', (171, 174))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))	('breast cancer', 'Disease', (133, 146))	('men', 'Species', '9606', (73, 76))	('high', 'Var', (13, 17))	('expression', 'MPA', (24, 34))	('ASF1B', 'Gene', (18, 23))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('ASF1B', 'Gene', '55723', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('faster', 'PosReg', (51, 57))	('prostate cancer', 'Disease', 'MESH:D011471', (148, 163))	('metastasis', 'CPA', (82, 92))	('prostate cancer', 'Phenotype', 'HP:0012125', (148, 163))	('prostate cancer', 'Disease', (148, 163))
68850	33024069	Co-targeting PKMYT1 and ASF1B may be a promising approach to preventing ccRCC progression.	('PKMYT1', 'Var', (13, 19))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('ASF1B', 'Gene', (24, 29))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('ASF1B', 'Gene', '55723', (24, 29))
68858	29088767	We found limited genetic concordance between primary and secondary tumor sites with private mutations in FLT4, MTOR, ITGA5, SETD2, PBRM1, and BRCA1 on progression.	('ITGA5', 'Gene', (117, 122))	('SETD2', 'Gene', (124, 129))	('FLT4', 'Gene', '2324', (105, 109))	('BRCA1', 'Gene', '672', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('MTOR', 'Gene', '2475', (111, 115))	('ITGA5', 'Gene', '3678', (117, 122))	('mutations', 'Var', (92, 101))	('BRCA1', 'Gene', (142, 147))	('SETD2', 'Gene', '29072', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('PBRM1', 'Gene', (131, 136))	('PBRM1', 'Gene', '55193', (131, 136))	('FLT4', 'Gene', (105, 109))	('MTOR', 'Gene', (111, 115))
68887	29088767	Sequencing of tumor and and matched buffy coat resulted in a mean target coverage of 124x and revealed an average of 486 non synonymous somatic mutations (Table 2, Supplementary Table 1) with a mean coverage of 104x at mutation sites.	('mutations', 'Var', (144, 153))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
68888	29088767	Mutations in RCC-associated genes, including VHL, BAP1, PBRM1, LRP1B, and KMT2C were further validated by Sanger sequencing.	('VHL', 'Gene', '7428', (45, 48))	('KMT2C', 'Gene', '58508', (74, 79))	('KMT2C', 'Gene', (74, 79))	('LRP1B', 'Gene', (63, 68))	('BAP1', 'Gene', '8314', (50, 54))	('Mutations', 'Var', (0, 9))	('PBRM1', 'Gene', (56, 61))	('RCC-associated genes', 'Gene', (13, 33))	('BAP1', 'Gene', (50, 54))	('LRP1B', 'Gene', '53353', (63, 68))	('VHL', 'Gene', (45, 48))	('PBRM1', 'Gene', '55193', (56, 61))
68891	29088767	We found remarkable heterogeneity between primary and metastatic lesions with only a small subset of alterations present in both sites (Figure 2): WES of the primary tumor from patient 1 identified private mutations in the tumor suppressor genes PTEN and APC as well as in HRAS, BCAR1 (COSM1479104), and SETD1A (COSM126103).	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('OS', 'Chemical', '-', (313, 315))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('OS', 'Chemical', '-', (287, 289))	('PTEN', 'Gene', '5728', (246, 250))	('BCAR1', 'Gene', (279, 284))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('223', '239'))	('HRAS', 'Gene', '3265', (273, 277))	('SETD1A', 'Gene', '9739', (304, 310))	('tumor suppressor', 'biological_process', 'GO:0051726', ('223', '239'))	('HRAS', 'Gene', (273, 277))	('mutations', 'Var', (206, 215))	('tumor', 'Disease', (223, 228))	('tumor', 'Disease', (166, 171))	('COSM126103', 'Var', (312, 322))	('APC', 'cellular_component', 'GO:0005680', ('255', '258'))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('BCAR1', 'Gene', '9564', (279, 284))	('COSM1479104', 'Var', (286, 297))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('APC', 'Disease', 'MESH:D011125', (255, 258))	('PTEN', 'Gene', (246, 250))	('APC', 'Disease', (255, 258))	('patient', 'Species', '9606', (177, 184))	('SETD1A', 'Gene', (304, 310))
68893	29088767	The metastasis upon progression under sunitinib carried mutations in FLT4, KMT2D, and BMP5, which were not detected in the primary tumor.	('BMP5', 'Gene', (86, 90))	('mutations', 'Var', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('sunitinib', 'Chemical', 'MESH:D000077210', (38, 47))	('BMP5', 'Gene', '653', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('KMT2D', 'Gene', (75, 80))	('KMT2D', 'Gene', '8085', (75, 80))	('tumor', 'Disease', (131, 136))	('FLT4', 'Gene', (69, 73))	('FLT4', 'Gene', '2324', (69, 73))	('metastasis', 'CPA', (4, 14))
68895	29088767	She had a private mutation in PIK3CA (COSM1041490) in the primary tumor.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('PIK3CA', 'Gene', (30, 36))	('tumor', 'Disease', (66, 71))	('PIK3CA', 'Gene', '5290', (30, 36))	('OS', 'Chemical', '-', (39, 41))	('COSM1041490', 'Var', (38, 49))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
68896	29088767	In line with previous findings suggesting that mTOR mutations occur predominantly at advanced stages of tumor evolution in subclonal metastatic populations, the metastasis revealed a private mTOR mutation.	('mutations', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('mutation', 'Var', (196, 204))	('mTOR', 'Gene', (191, 195))	('mTOR', 'Gene', '2475', (191, 195))	('tumor', 'Disease', (104, 109))	('mTOR', 'Gene', '2475', (47, 51))	('mTOR', 'Gene', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
68897	29088767	Additional mutations were found in FGFR1 and ERBB2 (Figure 2).	('mutations', 'Var', (11, 20))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('ERBB2', 'Gene', '2064', (45, 50))	('FGFR1', 'Gene', (35, 40))	('ERBB2', 'Gene', (45, 50))	('FGFR1', 'Gene', '2260', (35, 40))
68901	29088767	WES analysis showed an increase of mutational load between baseline (81 mutations) and progression (251 mutations), and 32 (39.5%) of the 81 baseline mutations were also found in the re-biopsy (Figure 3), including changes in VHL, BAP1, KMT2C, CSMD3, and FAT3.	('CSMD3', 'Gene', (244, 249))	('mutations', 'Var', (72, 81))	('CSMD3', 'Gene', '114788', (244, 249))	('VHL', 'Gene', '7428', (226, 229))	('mutational', 'Var', (35, 45))	('changes', 'Reg', (215, 222))	('FAT3', 'Gene', (255, 259))	('BAP1', 'Gene', '8314', (231, 235))	('increase', 'PosReg', (23, 31))	('VHL', 'Gene', (226, 229))	('FAT3', 'Gene', '120114', (255, 259))	('KMT2C', 'Gene', (237, 242))	('BAP1', 'Gene', (231, 235))	('KMT2C', 'Gene', '58508', (237, 242))
68902	29088767	The re-biopsy revealed additional private mutations in the epigenetic regulators KMT2D (COSM1299437) and KMT2E (COSM1083684) as well as in PBRM1, one of the most frequently mutated genes in ccRCC, which codes for a subunit of the BAF chromatin remodeling complex.	('BAF', 'Gene', '8815', (230, 233))	('PBRM1', 'Gene', '55193', (139, 144))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('234', '262'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('234', '254'))	('BAF', 'Gene', (230, 233))	('KMT2E', 'Gene', (105, 110))	('KMT2E', 'Gene', '55904', (105, 110))	('KMT2D', 'Gene', (81, 86))	('COSM1299437', 'Var', (88, 99))	('KMT2D', 'Gene', '8085', (81, 86))	('COSM1299437', 'CellLine', 'CVCL:C760', (88, 99))	('OS', 'Chemical', '-', (89, 91))	('OS', 'Chemical', '-', (113, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (190, 195))	('mutations', 'Var', (42, 51))	('PBRM1', 'Gene', (139, 144))
68903	29088767	Furthermore, we detected a mutation in BRCA1, which was not been present at baseline.	('mutation', 'Var', (27, 35))	('BRCA1', 'Gene', '672', (39, 44))	('BRCA1', 'Gene', (39, 44))
68906	29088767	Notably, the mutational spectrum of the primary tumor revealed a larger overlap with the chest wall metastasis than with the initial pelvic bone metastasis (30 vs. 5 mutations, respectively), including changes in VHL and PBRM1, possibly indicating an early separation of the cells giving rise to the latter metastasis.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('mutations', 'Var', (166, 175))	('VHL', 'Gene', (213, 216))	('changes', 'Var', (202, 209))	('VHL', 'Gene', '7428', (213, 216))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('PBRM1', 'Gene', (221, 226))	('PBRM1', 'Gene', '55193', (221, 226))
68907	29088767	The analysis of the chest wall metastasis identified further mutations in cancer-associated genes, including SETD2 and ERBB2.	('SETD2', 'Gene', '29072', (109, 114))	('ERBB2', 'Gene', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('ERBB2', 'Gene', '2064', (119, 124))	('mutations', 'Var', (61, 70))	('cancer', 'Disease', (74, 80))	('SETD2', 'Gene', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
68908	29088767	In addition, with 700 somatic variants, the mutational load of the chest wall metastasis was considerably higher than in the primary tumor and the metastasis located in the os ilium (371 and 342 mutations, respectively).	('variants', 'Var', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('higher', 'PosReg', (106, 112))	('mutational', 'Var', (44, 54))	('chest wall metastasis', 'CPA', (67, 88))	('tumor', 'Disease', (133, 138))
68912	29088767	Deletions of the VHL tumor suppressor gene are occuring early during tumorigenesis of ccRCC.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (21, 26))	('tumor suppressor', 'biological_process', 'GO:0051726', ('21', '37'))	('tumor', 'Disease', (69, 74))	('VHL tumor', 'Disease', (17, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('21', '37'))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('ccRCC', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('VHL tumor', 'Disease', 'MESH:D006623', (17, 26))	('Deletions', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
68913	29088767	We detected additional VHL mutations in baseline samples and metastatic sites in three out of four patients.	('mutations', 'Var', (27, 36))	('patients', 'Species', '9606', (99, 107))	('VHL', 'Gene', '7428', (23, 26))	('VHL', 'Gene', (23, 26))
68914	29088767	These included mutations in the ccRCC tumor-driving gene BAP1 in patients 1, 2, and 3.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('ccRCC', 'Phenotype', 'HP:0006770', (32, 37))	('ccRCC', 'Disease', (32, 37))	('mutations', 'Var', (15, 24))	('BAP1', 'Gene', '8314', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('patients', 'Species', '9606', (65, 73))	('BAP1', 'Gene', (57, 61))
68915	29088767	The clonality of the BAP1 mutation, which has been associated with poor prognosis and a high metastasizing potential supports BAP1 as a molecular marker for ccRCC sub-classification.	('mutation', 'Var', (26, 34))	('BAP1', 'Gene', (126, 130))	('BAP1', 'Gene', (21, 25))	('ccRCC', 'Disease', (157, 162))	('ccRCC', 'Phenotype', 'HP:0006770', (157, 162))	('BAP1', 'Gene', '8314', (126, 130))	('BAP1', 'Gene', '8314', (21, 25))
68916	29088767	In agreement with previous reports, our WES results revealed that mTOR mutations occur predominately in subclonal branches in advanced disease stages (patient 2).	('mTOR', 'Gene', (66, 70))	('mTOR', 'Gene', '2475', (66, 70))	('advanced disease', 'Disease', (126, 142))	('patient', 'Species', '9606', (151, 158))	('advanced disease', 'Disease', 'MESH:D020178', (126, 142))	('mutations', 'Var', (71, 80))	('occur', 'Reg', (81, 86))
68917	29088767	We also identified two different ITGA5 mutations in independent metastases, but not in the primary tumor, of patient 4, suggesting parallel evolution of the two metastatic clones.	('tumor', 'Disease', (99, 104))	('metastases', 'Disease', 'MESH:D009362', (64, 74))	('patient', 'Species', '9606', (109, 116))	('ITGA5', 'Gene', (33, 38))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('metastases', 'Disease', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('ITGA5', 'Gene', '3678', (33, 38))
68919	29088767	This might be due to several reasons: Either the initial molecular features present in the primary tumor were lost in the metastases, or multiple novel mutations accumulated in the metastases, or the sequenced tissue region in primary tumor did not contain the clones that gave rise to the metastases.	('tumor', 'Disease', (99, 104))	('metastases', 'Disease', 'MESH:D009362', (181, 191))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('mutations', 'Var', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('metastases', 'Disease', (290, 300))	('tumor', 'Disease', (235, 240))	('metastases', 'Disease', (122, 132))	('metastases', 'Disease', (181, 191))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('metastases', 'Disease', 'MESH:D009362', (122, 132))	('metastases', 'Disease', 'MESH:D009362', (290, 300))
68922	29088767	The identification of clinically relevant mutations upon tumor progression under TKI treatment suggests that it might be possible to derive alternative targeted therapies based on molecular changes in the metastases.	('metastases', 'Disease', (205, 215))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('metastases', 'Disease', 'MESH:D009362', (205, 215))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('mutations', 'Var', (42, 51))
68923	29088767	While we detected subclonal mutations in FLT4, ITGA5, SETD2, and BRCA1 in the metastases, one patient developed mutations in mTOR and several receptor tyrosine kinase genes, including ERBB2, ERBB4, and FGFR1.	('ERBB2', 'Gene', (184, 189))	('tyrosine kinase', 'Gene', '7294', (151, 166))	('mTOR', 'Gene', '2475', (125, 129))	('SETD2', 'Gene', '29072', (54, 59))	('mutations', 'Var', (112, 121))	('ITGA5', 'Gene', (47, 52))	('FGFR', 'molecular_function', 'GO:0005007', ('202', '206'))	('ERBB4', 'Gene', '2066', (191, 196))	('ERBB2', 'Gene', '2064', (184, 189))	('ITGA5', 'Gene', '3678', (47, 52))	('BRCA1', 'Gene', '672', (65, 70))	('ERBB4', 'Gene', (191, 196))	('BRCA1', 'Gene', (65, 70))	('patient', 'Species', '9606', (94, 101))	('FGFR1', 'Gene', '2260', (202, 207))	('metastases', 'Disease', 'MESH:D009362', (78, 88))	('FLT4', 'Gene', (41, 45))	('mTOR', 'Gene', (125, 129))	('SETD2', 'Gene', (54, 59))	('tyrosine kinase', 'Gene', (151, 166))	('FGFR1', 'Gene', (202, 207))	('FLT4', 'Gene', '2324', (41, 45))	('metastases', 'Disease', (78, 88))
68924	29088767	Moreover, the chest wall re-biopsy of patient 3 exhibited mutations in PBRM1 and BAP1, which are mostly mutually exclusive.	('mutations', 'Var', (58, 67))	('PBRM1', 'Gene', (71, 76))	('exhibited', 'Reg', (48, 57))	('BAP1', 'Gene', (81, 85))	('PBRM1', 'Gene', '55193', (71, 76))	('patient', 'Species', '9606', (38, 45))	('BAP1', 'Gene', '8314', (81, 85))
68926	29088767	The acquired BRCA1 mutation, which was not detected in the baseline of patient 3, represents another impairment of DNA repair, which might indicate that PARP inhibitors could be beneficial in this case.	('mutation', 'Var', (19, 27))	('BRCA1', 'Gene', (13, 18))	('DNA repair', 'biological_process', 'GO:0006281', ('115', '125'))	('DNA', 'cellular_component', 'GO:0005574', ('115', '118'))	('PARP', 'Gene', '1302', (153, 157))	('patient', 'Species', '9606', (71, 78))	('PARP', 'Gene', (153, 157))	('BRCA1', 'Gene', '672', (13, 18))
68929	29088767	Alternatively, BRCA1 mutations giving rise to impaired DNA repair may result in increased expression of neoantigens, a potential marker of sensitivity to immune checkpoint inhibitors.	('increased', 'PosReg', (80, 89))	('BRCA1', 'Gene', '672', (15, 20))	('neoantigens', 'Protein', (104, 115))	('expression', 'MPA', (90, 100))	('DNA repair', 'MPA', (55, 65))	('BRCA1', 'Gene', (15, 20))	('DNA repair', 'biological_process', 'GO:0006281', ('55', '65'))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('mutations', 'Var', (21, 30))
68930	29088767	Furthermore, VEGFR3/FLT4 inhibitors that are currently in early clinical development may be active in patients carrying VEGFR3/FLT4 mutations, respectively.	('FLT4', 'Gene', (127, 131))	('VEGFR3', 'Gene', (120, 126))	('FLT4', 'Gene', '2324', (127, 131))	('patients', 'Species', '9606', (102, 110))	('VEGFR3', 'Gene', (13, 19))	('mutations', 'Var', (132, 141))	('FLT4', 'Gene', (20, 24))	('VEGFR3', 'Gene', '2324', (120, 126))	('FLT4', 'Gene', '2324', (20, 24))	('active', 'PosReg', (92, 98))	('VEGFR3', 'Gene', '2324', (13, 19))
68931	29088767	Mutations in mTOR may be particularly sensitive to mTOR inhibitory drugs.	('mTOR', 'Gene', (51, 55))	('Mutations', 'Var', (0, 9))	('mTOR', 'Gene', (13, 17))	('mTOR', 'Gene', '2475', (13, 17))	('mTOR', 'Gene', '2475', (51, 55))
68967	33937014	The GSEA enrichment analysis showed that high SP1 expression positively correlates with TGF-beta signaling and inflammatory response, while negatively correlates with TNF-alpha signaling via NFKB.	('signaling', 'biological_process', 'GO:0023052', ('177', '186'))	('SP1', 'Gene', (46, 49))	('inflammatory response', 'CPA', (111, 132))	('correlates', 'Reg', (151, 161))	('men', 'Species', '9606', (15, 18))	('high', 'Var', (41, 45))	('correlates', 'Reg', (72, 82))	('signaling', 'biological_process', 'GO:0023052', ('97', '106'))	('inflammatory response', 'biological_process', 'GO:0006954', ('111', '132'))	('TNF-alpha', 'Gene', '7124', (167, 176))	('TGF-beta', 'Gene', (88, 96))	('negatively', 'NegReg', (140, 150))	('TNF-alpha', 'Gene', (167, 176))	('TGF-beta', 'Gene', '7039', (88, 96))	('GSEA', 'Chemical', '-', (4, 8))
68969	33937014	The abnormality of chromatin accessibility may play an important regulatory role in ccRCC immunity.	('abnormality', 'Var', (4, 15))	('chromatin accessibility', 'MPA', (19, 42))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('chromatin', 'cellular_component', 'GO:0000785', ('19', '28'))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))
69014	33937014	Overall survival analysis of every type of immune cells was performed ( Figure 1 ,  Supplementary Table 2 ), and we found that the presence of Treg, aDC, NK CD58 bright cells, and Th2 cells was associated with unfavorable prognosis (p < 0.001, p = 0.013, p < 0.001, and p = 0.00019), while Th 17 cells, neutrophils, mast cells, NK cells, Tgd, and Tcm were associated with favorable prognosis (p < 0.015, p = 0.00055, p < 0.0036, p = 0.0084, p = 0.04, and p = 0.0028) in ccRCC.	('Tgd', 'Gene', (338, 341))	('CD58', 'Gene', '965', (157, 161))	('RCC', 'Disease', (472, 475))	('men', 'Species', '9606', (90, 93))	('RCC', 'Phenotype', 'HP:0005584', (472, 475))	('CD58', 'Gene', (157, 161))	('presence', 'Var', (131, 139))	('RCC', 'Disease', 'MESH:C538614', (472, 475))	('ccRCC', 'Phenotype', 'HP:0006770', (470, 475))	('Tgd', 'Gene', '19', (338, 341))
69025	33937014	For example, Cluster 1 was enriched in IL-17 signaling pathway gene set (ES = -0.50, p = 0.003497, FDR = 0.021048), NK cell-mediated cytotoxicity gene set (ES = -0.63, p = 0.004237, FDR = 0.021048), PD-L1 expression and PD-1 checkpoint pathway (ES = -0.55, p = 0.00341297, FDR = 0.021048), Th1 and Th2 cell differentiation (ES = -0.61, p = 0.00341297, FDR = 0.021048), Th17 cell differentiation (ES = -0.65, p = 0.00349650, FDR = 0.021048) ( Figure 3D ), cAMP signaling pathway (ES = 0.46, p = 0.003571, FDR = 0.02108), chemical carcinogenesis gene set (ES = 0.54, p = 0.0042735, FDR = 0.021048), epithelial cell signaling in Helicobacter pylori infection (ES = 0.56, p = 0.004249, FDR = 0.021048), PPAR signaling pathway (ES = 0.56, p = 0.004267, FDR = 0.021048), and Vibrio cholerae infection (ES = 0.73, p = 0.001475, FDR = 0.021048) ( Figure 3E ).	('Vibrio cholerae infection', 'Disease', (769, 794))	('Vibrio cholerae infection', 'Disease', 'MESH:D002771', (769, 794))	('signaling', 'biological_process', 'GO:0023052', ('613', '622'))	('infection', 'Disease', (646, 655))	('NK cell-mediated cytotoxicity', 'biological_process', 'GO:0042267', ('116', '145'))	('infection', 'Disease', 'MESH:D007239', (646, 655))	('cAMP', 'Pathway', (455, 459))	('IL-17', 'Gene', (39, 44))	('PD-L1', 'Gene', (199, 204))	('IL-17', 'Gene', '3605', (39, 44))	('Helicobacter pylori', 'Species', '210', (626, 645))	('PD-L1', 'Gene', '29126', (199, 204))	('carcinogenesis', 'Disease', (529, 543))	('PPAR', 'Gene', '5465', (699, 703))	('signaling pathway', 'biological_process', 'GO:0007165', ('460', '477'))	('PPAR signaling pathway', 'biological_process', 'GO:0035357', ('699', '721'))	('cell differentiation', 'biological_process', 'GO:0030154', ('302', '322'))	('signaling pathway', 'biological_process', 'GO:0007165', ('45', '62'))	('carcinogenesis', 'Disease', 'MESH:D063646', (529, 543))	('epithelial', 'MPA', (597, 607))	('infection', 'Disease', (785, 794))	('cytotoxicity', 'Disease', (133, 145))	('infection', 'Disease', 'MESH:D007239', (785, 794))	('IL-17', 'molecular_function', 'GO:0030367', ('39', '44'))	('FDR = 0.021048', 'Var', (821, 835))	('cytotoxicity', 'Disease', 'MESH:D064420', (133, 145))	('cAMP signaling', 'biological_process', 'GO:0019933', ('455', '469'))	('cell differentiation', 'biological_process', 'GO:0030154', ('374', '394'))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (626, 655))	('PPAR', 'Gene', (699, 703))
69027	33937014	Interestingly, differential peaks and prognosis-related immune signal genes distributed across the genome in the 23 chromosomes were basically the same ( Figure 4C ), suggesting that the abnormality of chromatin accessibility plays an important regulatory role in ccRCC immunity.	('chromatin accessibility', 'MPA', (202, 225))	('chromatin', 'cellular_component', 'GO:0000785', ('202', '211'))	('RCC', 'Disease', 'MESH:C538614', (266, 269))	('RCC', 'Disease', (266, 269))	('RCC', 'Phenotype', 'HP:0005584', (266, 269))	('ccRCC', 'Phenotype', 'HP:0006770', (264, 269))	('abnormality', 'Var', (187, 198))
69036	33937014	The GSEA enrichment plot showed that high SP1 expression positively correlates with TGF-beta signaling and inflammatory response, while negatively correlates with TNF-alpha signaling via NFKB ( Figure 6C ).	('TGF-beta', 'Gene', '7039', (84, 92))	('high', 'Var', (37, 41))	('inflammatory response', 'CPA', (107, 128))	('correlates', 'Reg', (68, 78))	('correlates', 'Reg', (147, 157))	('TNF-alpha', 'Gene', '7124', (163, 172))	('men', 'Species', '9606', (15, 18))	('signaling', 'biological_process', 'GO:0023052', ('93', '102'))	('TNF-alpha', 'Gene', (163, 172))	('TGF-beta', 'Gene', (84, 92))	('negatively', 'NegReg', (136, 146))	('inflammatory response', 'biological_process', 'GO:0006954', ('107', '128'))	('signaling', 'biological_process', 'GO:0023052', ('173', '182'))	('SP1', 'Gene', (42, 45))	('GSEA', 'Chemical', '-', (4, 8))
69061	33937014	Differential peaks and prognosis-related immune signal cells were distributed across the genome in a similar manner, suggesting that the abnormality of chromatin accessibility plays an important regulatory role in ccRCC immunity.	('abnormality', 'Var', (137, 148))	('chromatin', 'cellular_component', 'GO:0000785', ('152', '161'))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('RCC', 'Disease', (216, 219))	('RCC', 'Phenotype', 'HP:0005584', (216, 219))	('ccRCC', 'Phenotype', 'HP:0006770', (214, 219))
69074	33937014	Further analysis of key transcription factors between the two clusters revealed that SP1, KLF12, KLF1, SP3, SP1, KLF3, SP2, KLF9, BACH1, FOSL1, and more may play an important role in these two different immunological subtypes.	('KLF1', 'Gene', '10661', (97, 101))	('FOSL1', 'Gene', (137, 142))	('SP1', 'Var', (108, 111))	('KLF1', 'Gene', '10661', (90, 94))	('BACH1', 'Gene', '571', (130, 135))	('KLF1', 'Gene', (90, 94))	('KLF3', 'Gene', '51274', (113, 117))	('KLF1', 'Gene', (97, 101))	('SP2', 'Gene', (119, 122))	('KLF3', 'Gene', (113, 117))	('FOSL1', 'Gene', '8061', (137, 142))	('KLF9', 'Gene', '687', (124, 128))	('play', 'Reg', (157, 161))	('BACH1', 'Gene', (130, 135))	('SP3', 'Gene', (103, 106))	('KLF9', 'Gene', (124, 128))	('SP2', 'Gene', '6668', (119, 122))	('SP3', 'Gene', '6670', (103, 106))	('transcription', 'biological_process', 'GO:0006351', ('24', '37'))
69079	31311810	ARID1A, encoding a subunit of the SWI/SNF complex, is the most frequently mutated epigenetic regulator in human cancers and is mutated in over 50% of ovarian clear cell carcinoma (OCCC), a disease that currently has no effective therapy.	('human', 'Species', '9606', (106, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (150, 178))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('ARID1A', 'Gene', (0, 6))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutated', 'Var', (127, 134))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('34', '49'))	('ovarian clear cell carcinoma', 'Disease', (150, 178))
69080	31311810	Inhibition of histone deacetylase 6 (HDAC6) suppresses the growth of ARID1A-mutated tumors and modulates tumor immune microenvironment.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('suppresses', 'NegReg', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('histone deacetylase 6', 'Gene', (14, 35))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('histone deacetylase 6', 'Gene', '15185', (14, 35))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Inhibition', 'Var', (0, 10))	('tumors', 'Disease', (84, 90))	('ARID1A-mutated', 'Gene', (69, 83))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('growth', 'MPA', (59, 65))	('HDAC6', 'Gene', (37, 42))	('tumor', 'Disease', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('modulates', 'Reg', (95, 104))
69081	31311810	Here we show that inhibition of HDAC6 synergizes with anti-PD-L1 immune-checkpoint blockade in ARID1A-inactivated ovarian cancer.	('ARID1A-inactivated ovarian cancer', 'Disease', 'MESH:C572568', (95, 128))	('inhibition', 'Var', (18, 28))	('ARID1A-inactivated ovarian cancer', 'Disease', (95, 128))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('HDAC6', 'Gene', (32, 37))
69082	31311810	Reduced tumor burden and improved survival was observed in ARID1Aflox/flox/PIK3CAH1047R OCCC mice treated with the HDAC6 inhibitor ACY1215 and anti-PD-L1 immune-checkpoint blockade as a result of activation and increased presence of interferon-gamma positive CD8 T cells.	('improved', 'PosReg', (25, 33))	('ACY1215', 'Var', (131, 138))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('survival', 'CPA', (34, 42))	('ACY1215', 'Chemical', 'MESH:C572255', (131, 138))	('Reduced', 'NegReg', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('interferon-gamma', 'Gene', '15978', (233, 249))	('increased', 'PosReg', (211, 220))	('increased presence of interferon', 'Phenotype', 'HP:0009709', (211, 243))	('mice', 'Species', '10090', (93, 97))	('interferon-gamma', 'Gene', (233, 249))	('tumor', 'Disease', (8, 13))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('233', '249'))
69090	31311810	In addition to inactivating mutations, ARID1A shows deletions in many tumor types in the cBioPortal datasets.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('deletions', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('ARID1A', 'Gene', (39, 45))
69091	31311810	Notably, inactivating mutations in ARID1A occur frequently in ovarian clear cell carcinomas (OCCC; >50%).	('inactivating mutations', 'Var', (9, 31))	('ovarian clear cell carcinomas', 'Disease', (62, 91))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (62, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('ARID1A', 'Gene', (35, 41))
69095	31311810	In addition, in clear cell renal cell cancer (ccRCC), patients who responded positively to anti-PD1/anti-PD-L1 therapy often carry a loss of function mutation in the PBRM1 subunit of the PBAF complex.	('PBAF complex', 'cellular_component', 'GO:0016586', ('187', '199'))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('loss of function', 'NegReg', (133, 149))	('BAF', 'Gene', (188, 191))	('clear cell renal cell cancer', 'Disease', 'MESH:C538614', (16, 44))	('BAF', 'Gene', '12016', (188, 191))	('patients', 'Species', '9606', (54, 62))	('mutation', 'Var', (150, 158))	('clear cell renal cell cancer', 'Phenotype', 'HP:0006770', (16, 44))	('renal cell cancer', 'Phenotype', 'HP:0005584', (27, 44))	('PBRM1', 'Gene', (166, 171))	('clear cell renal cell cancer', 'Disease', (16, 44))
69096	31311810	Likewise, inactivation of the PBAF subunits BRD7, ARID2, and PBRM1 confers susceptibility to T cell-mediated killing in melanoma.	('PBRM1', 'Gene', (61, 66))	('T cell-mediated killing', 'CPA', (93, 116))	('BAF', 'Gene', (31, 34))	('inactivation', 'Var', (10, 22))	('BRD7', 'Gene', (44, 48))	('BRD7', 'Gene', '26992', (44, 48))	('ARID2', 'Gene', '77044', (50, 55))	('BAF', 'Gene', '12016', (31, 34))	('ARID2', 'Gene', (50, 55))	('melanoma', 'Disease', (120, 128))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('susceptibility', 'Reg', (75, 89))
69103	31311810	Although most translational studies on HDAC6 inhibitors have focused on their effects on tumor cells, emerging evidence suggests that HDAC6 inhibitors have immunomodulatory effects on tumor immune microenvironment.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('HDAC6', 'Gene', (134, 139))	('inhibitors', 'Var', (140, 150))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
69187	31311810	As a negative control, ARID1A binding to the Cd274 promoter was reduced to a level observed in IgG controls in ARID1A knockout ID8-Defb29/Vegf cells (Figure 1C).	('Cd274', 'Gene', (45, 50))	('Cd274', 'Gene', '60533', (45, 50))	('ARID1A', 'Gene', (111, 117))	('binding', 'molecular_function', 'GO:0005488', ('30', '37'))	('reduced', 'NegReg', (64, 71))	('binding', 'Interaction', (30, 37))	('knockout', 'Var', (118, 126))
69188	31311810	Notably, SNF5, a core subunit of the SWI/SNF complex, was also associated with the Cd274 promoter and its association was reduced by ARID1A knockout (Figure 1C).	('ARID1A', 'Gene', (133, 139))	('core', 'cellular_component', 'GO:0019013', ('17', '21'))	('association', 'Interaction', (106, 117))	('Cd274', 'Gene', (83, 88))	('Cd274', 'Gene', '60533', (83, 88))	('SNF5', 'Gene', (9, 13))	('knockout', 'Var', (140, 148))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('37', '52'))	('associated', 'Interaction', (63, 73))	('SNF5', 'Gene', '20587', (9, 13))	('reduced', 'NegReg', (122, 129))
69189	31311810	Expression of ARID1B, the mutually exclusive subunit of the SWI/SNF complex with ARID1A, was upregulated in ARID1A knockout ID8-Defb29/Vegf cells (Figure 1B).	('knockout', 'Var', (115, 123))	('Expression', 'MPA', (0, 10))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('60', '75'))	('ARID1B', 'Gene', (14, 20))	('ARID1B', 'Gene', '239985', (14, 20))	('ARID1A', 'Gene', (108, 114))	('upregulated', 'PosReg', (93, 104))
69194	31311810	Compared with ARID1A wildtype control ID8-Defb29/Vegf cells, Cd274 mRNA was increased by ARID1A knockout (Figure 2A).	('ARID1A', 'Gene', (89, 95))	('increased', 'PosReg', (76, 85))	('knockout', 'Var', (96, 104))	('Cd274', 'Gene', (61, 66))	('Cd274', 'Gene', '60533', (61, 66))
69197	31311810	ARID1A knockout significantly enhanced the upregulation of Cd274 mRNA and PD-L1 expression induced by IFNgamma treatment (Figure 2A).	('Cd274', 'Gene', (59, 64))	('enhanced', 'PosReg', (30, 38))	('Cd274', 'Gene', '60533', (59, 64))	('PD-L1', 'Gene', (74, 79))	('IFNgamma', 'Gene', (102, 110))	('IFNgamma', 'Gene', '15978', (102, 110))	('ARID1A', 'Gene', (0, 6))	('upregulation', 'PosReg', (43, 55))	('expression', 'MPA', (80, 90))	('knockout', 'Var', (7, 15))
69200	31311810	Consistent with changes observed in Cd274 mRNA and PD-L1 expression, ARID1A knockout enhanced the association of Pol II and H3K4me3 with the Cd274 promoter with or without IFNgamma stimulation (Figure 2B).	('association', 'Interaction', (98, 109))	('Cd274', 'Gene', '60533', (36, 41))	('IFNgamma', 'Gene', (172, 180))	('H3K4me3', 'Protein', (124, 131))	('enhanced', 'PosReg', (85, 93))	('ARID1A', 'Gene', (69, 75))	('Cd274', 'Gene', (141, 146))	('Cd274', 'Gene', '60533', (141, 146))	('Pol II', 'Protein', (113, 119))	('IFNgamma', 'Gene', '15978', (172, 180))	('Cd274', 'Gene', (36, 41))	('knockout', 'Var', (76, 84))
69203	31311810	Notably, HDAC6 inhibitor ACY1215 significantly increased the CD69+ activated CD4 and CD8 T cells in the peritoneal wash (Figure S3B).	('CD8 T cells', 'CPA', (85, 96))	('CD69', 'Gene', (61, 65))	('increased', 'PosReg', (47, 56))	('CD69', 'Gene', '12515', (61, 65))	('CD4', 'Gene', (77, 80))	('CD4', 'Gene', '12504', (77, 80))	('ACY1215', 'Var', (25, 32))	('ACY1215', 'Chemical', 'MESH:C572255', (25, 32))
69204	31311810	Consistently, IFNgamma+ CD4 and CD8 T cells were also significantly increased by ACY1215 treatment (Figure 3A).	('CD4', 'Gene', (24, 27))	('CD4', 'Gene', '12504', (24, 27))	('ACY1215 treatment', 'Var', (81, 98))	('ACY1215', 'Chemical', 'MESH:C572255', (81, 88))	('IFNgamma', 'Gene', (14, 22))	('IFNgamma', 'Gene', '15978', (14, 22))	('CD8 T cells', 'CPA', (32, 43))	('increased', 'PosReg', (68, 77))
69205	31311810	In contrast, ACY1215 did not significantly affect Granzyme B+ CD8 T cells or Foxp3+ regulatory T cells (Figure S3C).	('Granzyme B', 'Gene', (50, 60))	('Granzyme B', 'Gene', '14939', (50, 60))	('Foxp3', 'Gene', '20371', (77, 82))	('ACY1215', 'Chemical', 'MESH:C572255', (13, 20))	('ACY1215', 'Var', (13, 20))	('Foxp3', 'Gene', (77, 82))
69206	31311810	These findings suggest that HDAC6 inhibition may boost antitumor immunity.	('boost', 'PosReg', (49, 54))	('tumor', 'Disease', (59, 64))	('inhibition', 'Var', (34, 44))	('HDAC6', 'Gene', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
69207	31311810	However, a combination of ACY1215 and anti-PD-L1 treatment only increased IFNgamma+ CD8, but not CD4 T cells (Figure 3A).	('IFNgamma', 'Gene', (74, 82))	('IFNgamma', 'Gene', '15978', (74, 82))	('CD4', 'Gene', (97, 100))	('ACY1215', 'Chemical', 'MESH:C572255', (26, 33))	('ACY1215', 'Var', (26, 33))	('CD4', 'Gene', '12504', (97, 100))	('increased', 'PosReg', (64, 73))
69211	31311810	); and 4) ACY1215 and anti-PD-L1 antibody combination for an additional three weeks.	('ACY1215', 'Chemical', 'MESH:C572255', (10, 17))	('anti-PD-L1', 'Protein', (22, 32))	('antibody', 'cellular_component', 'GO:0019815', ('33', '41'))	('antibody', 'cellular_component', 'GO:0019814', ('33', '41'))	('antibody', 'molecular_function', 'GO:0003823', ('33', '41'))	('antibody', 'cellular_component', 'GO:0042571', ('33', '41'))	('combination', 'Interaction', (42, 53))	('ACY1215', 'Var', (10, 17))
69214	31311810	As previously reported, both anti-PD-L1 antibody and ACY1215 significantly reduced the tumor weight in the OCCC model (Figure 3B).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('antibody', 'cellular_component', 'GO:0042571', ('40', '48'))	('tumor weight', 'Disease', 'MESH:D015431', (87, 99))	('ACY1215', 'Chemical', 'MESH:C572255', (53, 60))	('reduced', 'NegReg', (75, 82))	('ACY1215', 'Var', (53, 60))	('antibody', 'cellular_component', 'GO:0019814', ('40', '48'))	('antibody', 'cellular_component', 'GO:0019815', ('40', '48'))	('tumor weight', 'Disease', (87, 99))	('antibody', 'molecular_function', 'GO:0003823', ('40', '48'))
69215	31311810	We also examined effects of the ACY1215 and anti-PD-L1 combination in reducing ascites produced in the Arid1aflox/flox/Pik3caH1047R OCCC model.	('Arid1a', 'Gene', '93760', (103, 109))	('ACY1215', 'Chemical', 'MESH:C572255', (32, 39))	('ACY1215', 'Var', (32, 39))	('ascites', 'Disease', 'MESH:D001201', (79, 86))	('ascites', 'Disease', (79, 86))	('reducing', 'NegReg', (70, 78))	('ascites', 'Phenotype', 'HP:0001541', (79, 86))	('Arid1a', 'Gene', (103, 109))
69216	31311810	Both ACY1215 and anti-PD-L1 single treatment significantly reduced the amount of ascites produced in this model (Figure 3C).	('ascites', 'Disease', (81, 88))	('ascites', 'Phenotype', 'HP:0001541', (81, 88))	('reduced', 'NegReg', (59, 66))	('ascites', 'Disease', 'MESH:D001201', (81, 88))	('anti-PD-L1', 'Gene', (17, 27))	('ACY1215', 'Chemical', 'MESH:C572255', (5, 12))	('ACY1215', 'Var', (5, 12))
69217	31311810	The reduction in tumor weight and ascites production by ACY1215 or anti-PD-L1 single treatment correlated with an improvement of survival (Figure 3D).	('survival', 'CPA', (129, 137))	('ACY1215', 'Chemical', 'MESH:C572255', (56, 63))	('improvement', 'PosReg', (114, 125))	('ACY1215', 'Var', (56, 63))	('tumor weight', 'Disease', (17, 29))	('ascites', 'Disease', (34, 41))	('ascites', 'Phenotype', 'HP:0001541', (34, 41))	('ascites', 'Disease', 'MESH:D001201', (34, 41))	('reduction', 'NegReg', (4, 13))	('anti-PD-L1', 'Gene', (67, 77))	('tumor weight', 'Disease', 'MESH:D015431', (17, 29))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
69218	31311810	The HDAC6 inhibitor ACY1215 and anti-PD-L1 combination was synergistic in reducing the tumor burden and improving the survival of tumor-bearing mice (Figure 3B and D).	('ACY1215', 'Chemical', 'MESH:C572255', (20, 27))	('improving', 'PosReg', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('HDAC6', 'Gene', (4, 9))	('mice', 'Species', '10090', (144, 148))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('survival', 'CPA', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (130, 135))	('ACY1215', 'Var', (20, 27))	('reducing', 'NegReg', (74, 82))
69220	31311810	The doses of ACY1215 and anti-PD-L1 used in this study did not significantly affect the body weight of treated mice (Figure S3D), suggesting that effective combination doses can be achieved without gross toxicity.	('mice', 'Species', '10090', (111, 115))	('ACY1215', 'Chemical', 'MESH:C572255', (13, 20))	('toxicity', 'Disease', 'MESH:D064420', (204, 212))	('toxicity', 'Disease', (204, 212))	('ACY1215', 'Var', (13, 20))
69221	31311810	Together, we conclude that HDAC6 inhibitor ACY1215 and anti-PD-L1 are synergistic in reducing tumor burden, which correlated with an improvement of survival of mice bearing ARID1A-inactivated OCCCs.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('reducing', 'NegReg', (85, 93))	('tumor', 'Disease', (94, 99))	('anti-PD-L1', 'Gene', (55, 65))	('mice', 'Species', '10090', (160, 164))	('improvement', 'PosReg', (133, 144))	('ACY1215', 'Chemical', 'MESH:C572255', (43, 50))	('survival', 'CPA', (148, 156))	('ACY1215', 'Var', (43, 50))
69222	31311810	Since ACY1215 and anti-PD-L1 combination increases IFNgamma+ CD8, but not CD4, T cells (Figure 3A) and cytotoxic CD8 T cells play a critical role in mediating the antitumor effects of anti-PD-L1 treatment, we next sought to determine whether the combination limits the progression of ARID1A-mutated OCCCs through CD8 T cells.	('CD4', 'Gene', '12504', (74, 77))	('IFNgamma', 'Gene', '15978', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('OCCCs', 'Disease', (299, 304))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('CD4', 'Gene', (74, 77))	('ACY1215', 'Chemical', 'MESH:C572255', (6, 13))	('IFNgamma', 'Gene', (51, 59))	('ACY1215', 'Var', (6, 13))	('tumor', 'Disease', (167, 172))
69226	31311810	This result indicates that T cell activation induced by ACY1215 is not merely a reflection of reduction in tumor burden in the treated mice.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('ACY1215', 'Chemical', 'MESH:C572255', (56, 63))	('tumor', 'Disease', (107, 112))	('T cell activation', 'biological_process', 'GO:0042110', ('27', '44'))	('ACY1215', 'Var', (56, 63))	('T cell', 'CPA', (27, 33))	('mice', 'Species', '10090', (135, 139))	('activation', 'PosReg', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
69227	31311810	Together, these results support that the observed antitumor effects in ARID1A-inactivated OCCCs by ACY1215 and anti-PD-L1 combination is CD8 cytotoxic T cell dependent.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('ACY1215', 'Chemical', 'MESH:C572255', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('ACY1215', 'Var', (99, 106))	('tumor', 'Disease', (54, 59))	('OCCCs', 'Disease', (90, 95))
69228	31311810	Here we show that HDAC6 inhibitor ACY1215 activates both CD4 and CD8 T cells and increases IFNgamma+ CD4 and CD8 T cells.	('ACY1215', 'Chemical', 'MESH:C572255', (34, 41))	('CD4', 'Gene', '12504', (57, 60))	('IFNgamma', 'Gene', (91, 99))	('IFNgamma', 'Gene', '15978', (91, 99))	('ACY1215', 'Var', (34, 41))	('CD4', 'Gene', (101, 104))	('CD8 T cells', 'CPA', (65, 76))	('CD4', 'Gene', '12504', (101, 104))	('activates', 'PosReg', (42, 51))	('CD4', 'Gene', (57, 60))	('increases', 'PosReg', (81, 90))
69232	31311810	Indeed, ARID1A mutation correlated with an increase in PD-L1 expression and there was a trend toward improved response rate in clear cell ovarian cancer in which ARID1A is mutated in >50% of cases.	('mutation', 'Var', (15, 23))	('PD-L1', 'Protein', (55, 60))	('clear cell ovarian cancer', 'Disease', 'MESH:D008649', (127, 152))	('ovarian cancer', 'Phenotype', 'HP:0100615', (138, 152))	('improved', 'PosReg', (101, 109))	('increase', 'PosReg', (43, 51))	('clear cell ovarian cancer', 'Disease', (127, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ARID1A', 'Gene', (8, 14))	('ARID1A', 'Gene', (162, 168))	('expression', 'MPA', (61, 71))
69233	31311810	Further, there is evidence to suggest that inactivation of PBAF complex increased tumor cells sensitivity to IFNgamma, resulted in enhanced secretion of chemokines that recruit effector T cells.	('BAF', 'Gene', '12016', (60, 63))	('increased', 'PosReg', (72, 81))	('IFNgamma', 'Gene', (109, 117))	('IFNgamma', 'Gene', '15978', (109, 117))	('secretion of chemokines', 'MPA', (140, 163))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('PBAF complex', 'cellular_component', 'GO:0016586', ('59', '71'))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('enhanced', 'PosReg', (131, 139))	('tumor', 'Disease', (82, 87))	('secretion', 'biological_process', 'GO:0046903', ('140', '149'))	('inactivation', 'Var', (43, 55))	('BAF', 'Gene', (60, 63))
69234	31311810	Thus, inactivation of ARID1A containing BAF complex may increases PD-L1 expression directly at the CD274 gene promoter or indirectly through increasing mutation loads.	('mutation loads', 'Var', (152, 166))	('BAF', 'Gene', '12016', (40, 43))	('increases', 'PosReg', (56, 65))	('inactivation', 'Var', (6, 18))	('expression', 'MPA', (72, 82))	('increases PD', 'Phenotype', 'HP:0008151', (56, 68))	('increasing', 'PosReg', (141, 151))	('PD-L1', 'Gene', (66, 71))	('BAF', 'Gene', (40, 43))
69237	31311810	Interestingly, ARID1A mutation predicts clinical response to pan-HDAC inhibition in urothelial carcinoma and specific HDAC6 inhibition was most potent in suppressing the growth of ARID1A-mutated urothelial cells.	('ARID1A', 'Gene', (15, 21))	('mutation', 'Var', (22, 30))	('growth', 'MPA', (170, 176))	('suppressing', 'NegReg', (154, 165))	('urothelial carcinoma', 'Disease', (84, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (84, 104))
69238	31311810	The HDAC6 inhibitor ACY1215 is now in clinical development for other cancer types, and anti-PD-L1 is FDA-approved.	('ACY1215', 'Chemical', 'MESH:C572255', (20, 27))	('HDAC6', 'Gene', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('ACY1215', 'Var', (20, 27))	('cancer', 'Disease', (69, 75))
69261	31489722	Cell lines HK2 (CC4008), 769-P (CC1504) and ACHN (CC1505) were purchased from Cellcook, Guangzhou.	('ACHN', 'Gene', '55323', (44, 48))	('HK2', 'Gene', '3099', (11, 14))	('ACHN', 'Gene', (44, 48))	('CC1504', 'Chemical', 'MESH:C512248', (32, 38))	('HK2', 'Gene', (11, 14))	('HK2', 'molecular_function', 'GO:0008256', ('11', '14'))	('CC1505', 'Var', (50, 56))	('CC4008', 'Chemical', 'MESH:C483891', (16, 22))
69266	31489722	LC3 antibody (ab192890) was from Abcam, and P62 antibody (#88588) was from CST.	('LC3', 'Gene', '84557', (0, 3))	('antibody', 'molecular_function', 'GO:0003823', ('48', '56'))	('antibody', 'cellular_component', 'GO:0042571', ('4', '12'))	('ab192890', 'Var', (14, 22))	('LC3', 'Gene', (0, 3))	('P62', 'Gene', '8878', (44, 47))	('P62', 'Gene', (44, 47))	('antibody', 'cellular_component', 'GO:0019815', ('4', '12'))	('antibody', 'cellular_component', 'GO:0042571', ('48', '56'))	('antibody', 'cellular_component', 'GO:0019814', ('4', '12'))	('antibody', 'molecular_function', 'GO:0003823', ('4', '12'))	('antibody', 'cellular_component', 'GO:0019814', ('48', '56'))	('antibody', 'cellular_component', 'GO:0019815', ('48', '56'))
69297	31489722	Autophagy defects in the degradation of ADFP-associated lipid droplets may enhance the initiation and development of ccRCC and reduce the survival of ccRCC patients.19 Mul1 deficiency in ccRCC tissues predicted a blockade of autophagy degradation of lipid droplets and an accumulation of their associated ADFP.	('degradation', 'biological_process', 'GO:0009056', ('235', '246'))	('autophagy degradation', 'CPA', (225, 246))	('ccRCC', 'Disease', 'MESH:D002292', (150, 155))	('deficiency', 'Var', (173, 183))	('ccRCC', 'Disease', 'MESH:D002292', (117, 122))	('patients', 'Species', '9606', (156, 164))	('blockade', 'NegReg', (213, 221))	('ADFP', 'Gene', (305, 309))	('Autophagy', 'biological_process', 'GO:0016236', ('0', '9'))	('accumulation', 'PosReg', (272, 284))	('autophagy', 'biological_process', 'GO:0016236', ('225', '234'))	('ccRCC', 'Disease', (150, 155))	('ccRCC', 'Disease', (117, 122))	('ADFP', 'Gene', (40, 44))	('ccRCC', 'Disease', 'MESH:D002292', (187, 192))	('ccRCC', 'Phenotype', 'HP:0006770', (150, 155))	('ADFP', 'Gene', '123', (305, 309))	('autophagy', 'biological_process', 'GO:0006914', ('225', '234'))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('ADFP', 'Gene', '123', (40, 44))	('Mul1', 'Gene', (168, 172))	('Autophagy', 'biological_process', 'GO:0006914', ('0', '9'))	('ccRCC', 'Disease', (187, 192))	('Mul1', 'Gene', '79594', (168, 172))	('degradation', 'biological_process', 'GO:0009056', ('25', '36'))	('ccRCC', 'Phenotype', 'HP:0006770', (187, 192))
69312	29725475	Knockdown of long non-coding RNA PVT1 induces apoptosis and cell cycle arrest in clear cell renal cell carcinoma through the epidermal growth factor receptor pathway Previous years have witnessed the importance of long non-coding RNAs (lncRNAs) in cancer research.	('apoptosis', 'CPA', (46, 55))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('125', '148'))	('PVT1', 'Gene', '5820', (33, 37))	('clear cell renal cell carcinoma', 'Disease', (81, 112))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (92, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cancer', 'Disease', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cell cycle arrest', 'CPA', (60, 77))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (81, 112))	('apoptosis', 'biological_process', 'GO:0097194', ('46', '55'))	('epidermal growth factor receptor', 'Gene', (125, 157))	('apoptosis', 'biological_process', 'GO:0006915', ('46', '55'))	('epidermal growth factor receptor', 'Gene', '1956', (125, 157))	('long non-coding', 'Var', (13, 28))	('induces', 'PosReg', (38, 45))	('RNA', 'cellular_component', 'GO:0005562', ('29', '32'))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('60', '77'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (60, 77))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (81, 112))	('PVT1', 'Gene', (33, 37))
69317	29725475	Furthermore, the knockdown of PVT1 induced apoptosis by increasing the expression of poly ADP ribose polymerase and Bcl-2-associated X protein, and promoted cell cycle arrest at the G1 phase by decreasing the expression of cyclin D1.	('expression', 'MPA', (209, 219))	('poly ADP ribose polymerase', 'Gene', '142', (85, 111))	('Bcl-2', 'Gene', (116, 121))	('Bcl-2', 'molecular_function', 'GO:0015283', ('116', '121'))	('decreasing', 'NegReg', (194, 204))	('cyclin D1', 'Gene', (223, 232))	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('cell cycle arrest at the G1 phase', 'CPA', (157, 190))	('cyclin D1', 'Gene', '595', (223, 232))	('Bcl-2', 'Gene', '596', (116, 121))	('promoted', 'PosReg', (148, 156))	('expression', 'MPA', (71, 81))	('G1 phase', 'biological_process', 'GO:0051318', ('182', '190'))	('PVT1', 'Gene', (30, 34))	('apoptosis', 'CPA', (43, 52))	('PVT1', 'Gene', '5820', (30, 34))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (157, 174))	('knockdown', 'Var', (17, 26))	('poly ADP ribose polymerase', 'Gene', (85, 111))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('157', '174'))	('increasing', 'PosReg', (56, 66))	('cyclin', 'molecular_function', 'GO:0016538', ('223', '229'))
69324	29725475	Previous studies have highlighted the mutations of BRCA1 associated protein-1 and SET domain containing 2, which are inversely correlated with the outcome of patients with ccRCC.	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('BRCA1 associated protein-1', 'Gene', (51, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (172, 177))	('RCC', 'Disease', (174, 177))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('patients', 'Species', '9606', (158, 166))	('mutations', 'Var', (38, 47))	('correlated', 'Reg', (127, 137))	('BRCA1 associated protein-1', 'Gene', '8314', (51, 77))
69338	29725475	Copy number alterations were estimated by Genomics Identification of Significant Targets in Cancer 2.0 (GISTIC 2.0; provided by the Broad Institute of MIT and Harvard, Cambridge, MA, USA), which defined the copy-number alteration of each gene as -2, -1, 0, 1 or 2, representing homozygous deletion, heterozygous deletion, diploid normal copy number, low-level amplification (gain) and high-level amplification, respectively.	('Cancer', 'Disease', 'MESH:D009369', (92, 98))	('Cancer', 'Disease', (92, 98))	('Cancer', 'Phenotype', 'HP:0002664', (92, 98))	('low-level amplification', 'Var', (350, 373))	('diploid', 'Var', (322, 329))
69386	29725475	The result revealed that the overall survival time was significantly shorter in the high PVT1 expression group compared with that in the low PVT1 expression group (log-rank, P<0.01; Fig.	('PVT1', 'Gene', '5820', (89, 93))	('PVT1', 'Gene', '5820', (141, 145))	('high', 'Var', (84, 88))	('shorter', 'NegReg', (69, 76))	('PVT1', 'Gene', (89, 93))	('PVT1', 'Gene', (141, 145))	('survival time', 'CPA', (37, 50))
69389	29725475	786-O and Caki-1 cells were then transfected with si-PVT1s or si-NC using Lipofectamine RNAiMAX Transfection reagent, and the transfection efficiency was tested using RT-qPCR.	('PVT1', 'Gene', (53, 57))	('Lipofectamine', 'Chemical', 'MESH:C086724', (74, 87))	('PVT1', 'Gene', '5820', (53, 57))	('si-NC', 'Var', (62, 67))	('Caki-1', 'CellLine', 'CVCL:0234', (10, 16))
69392	29725475	The MTS assay revealed that the knockdown of PVT1 significantly inhibited the proliferation of 786-O and Caki-1 cells in a time-dependent manner compared with cells in the NC group (Fig.	('PVT1', 'Gene', (45, 49))	('inhibited', 'NegReg', (64, 73))	('knockdown', 'Var', (32, 41))	('Caki-1', 'CellLine', 'CVCL:0234', (105, 111))	('proliferation', 'CPA', (78, 91))	('PVT1', 'Gene', '5820', (45, 49))
69394	29725475	Cell apoptosis analysis indicated that the knockdown of PVT1 significantly increased the apoptosis rate in 786-O and Caki-1 cells, most notably in 786-O si-PVT1a group compared with the NC group (P<0.05; Fig.	('PVT1', 'Gene', '5820', (56, 60))	('apoptosis', 'biological_process', 'GO:0097194', ('5', '14'))	('apoptosis', 'biological_process', 'GO:0006915', ('5', '14'))	('PVT1', 'Gene', '5820', (156, 160))	('knockdown', 'Var', (43, 52))	('apoptosis rate', 'CPA', (89, 103))	('Caki-1', 'CellLine', 'CVCL:0234', (117, 123))	('PVT1', 'Gene', (56, 60))	('increased', 'PosReg', (75, 84))	('apoptosis', 'biological_process', 'GO:0097194', ('89', '98'))	('PVT1', 'Gene', (156, 160))	('apoptosis', 'biological_process', 'GO:0006915', ('89', '98'))
69395	29725475	Cell cycle analysis revealed that the knockdown of PVT1 also significantly promoted cell cycle arrest at the G0/G1 phase compared with the normal control (P<0.05; Fig.	('G1 phase', 'biological_process', 'GO:0051318', ('112', '120'))	('cell cycle arrest at the G0/G1 phase', 'CPA', (84, 120))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (84, 101))	('promoted', 'PosReg', (75, 83))	('PVT1', 'Gene', (51, 55))	('PVT1', 'Gene', '5820', (51, 55))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('84', '101'))	('knockdown', 'Var', (38, 47))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))
69397	29725475	The results demonstrated that the knockdown of PVT1 increased the level of Bax and the cleavage of PARP, which serve notable functions in the activation of cell apoptosis.	('PVT1', 'Gene', (47, 51))	('apoptosis', 'biological_process', 'GO:0097194', ('161', '170'))	('increased', 'PosReg', (52, 61))	('PARP', 'Gene', (99, 103))	('Bax', 'Gene', (75, 78))	('PVT1', 'Gene', '5820', (47, 51))	('apoptosis', 'biological_process', 'GO:0006915', ('161', '170'))	('Bax', 'Gene', '581', (75, 78))	('PARP', 'Gene', '142', (99, 103))	('cleavage', 'MPA', (87, 95))	('knockdown', 'Var', (34, 43))
69398	29725475	Meanwhile, the knockdown of PVT1 decreased the level of cyclin D1, a major mediator of the cell cycle, and increased the level of p21 (Fig.	('p21', 'Gene', (130, 133))	('PVT1', 'Gene', '5820', (28, 32))	('cyclin', 'molecular_function', 'GO:0016538', ('56', '62'))	('knockdown', 'Var', (15, 24))	('increased', 'PosReg', (107, 116))	('PVT1', 'Gene', (28, 32))	('p21', 'Gene', '1026', (130, 133))	('level', 'MPA', (121, 126))	('cell cycle', 'biological_process', 'GO:0007049', ('91', '101'))	('decreased', 'NegReg', (33, 42))	('cyclin D1', 'Gene', '595', (56, 65))	('cyclin D1', 'Gene', (56, 65))
69401	29725475	The results demonstrated that the mRNA expression level of EGFR was significantly downregulated following the knockdown of PVT1 compared with that of the NC (Fig.	('knockdown', 'Var', (110, 119))	('downregulated', 'NegReg', (82, 95))	('PVT1', 'Gene', (123, 127))	('EGFR', 'Gene', (59, 63))	('mRNA expression level', 'MPA', (34, 55))	('PVT1', 'Gene', '5820', (123, 127))	('EGFR', 'molecular_function', 'GO:0005006', ('59', '63'))	('EGFR', 'Gene', '1956', (59, 63))
69402	29725475	Furthermore, AKT and MYC, the downstream proteins of EGFR, were detected at the mRNA and protein level following the knockdown of PVT1.	('PVT1', 'Gene', (130, 134))	('PVT1', 'Gene', '5820', (130, 134))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('detected', 'Reg', (64, 72))	('AKT', 'Gene', (13, 16))	('MYC', 'Gene', '4609', (21, 24))	('AKT', 'Gene', '207', (13, 16))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('knockdown', 'Var', (117, 126))	('MYC', 'Gene', (21, 24))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
69403	29725475	It was revealed that the mRNA expression levels of AKT and MYC were significantly downregulated in si-PVT1 transfected groups compared with that in the NC groups (Fig.	('MYC', 'Gene', (59, 62))	('downregulated', 'NegReg', (82, 95))	('PVT1', 'Gene', (102, 106))	('AKT', 'Gene', (51, 54))	('transfected', 'Var', (107, 118))	('PVT1', 'Gene', '5820', (102, 106))	('mRNA expression levels', 'MPA', (25, 47))	('MYC', 'Gene', '4609', (59, 62))	('AKT', 'Gene', '207', (51, 54))
69404	29725475	5A), and the protein expression of AKT, phosphorylated (p-)AKT and MYC in cells transfected with si-PTV1 were notably downregulated compared with that in the NC groups (Fig.	('protein expression', 'MPA', (13, 31))	('AKT', 'Gene', (35, 38))	('MYC', 'Gene', '4609', (67, 70))	('AKT', 'Gene', (59, 62))	('MYC', 'Gene', (67, 70))	('si-PTV1', 'Var', (97, 104))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('AKT', 'Gene', '207', (59, 62))	('PTV', 'cellular_component', 'GO:1990257', ('100', '103'))	('AKT', 'Gene', '207', (35, 38))	('downregulated', 'NegReg', (118, 131))
69412	29725475	A previous study suggested that PVT1 expression was significantly higher in colorectal cancer tissues compared with that in normal tissues, and that the knockdown of PVT1 may inhibit cell proliferation.	('knockdown', 'Var', (153, 162))	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('PVT1', 'Gene', '5820', (166, 170))	('PVT1', 'Gene', '5820', (32, 36))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('PVT1', 'Gene', (166, 170))	('colorectal cancer', 'Disease', (76, 93))	('higher', 'PosReg', (66, 72))	('inhibit', 'NegReg', (175, 182))	('cell proliferation', 'CPA', (183, 201))	('PVT1', 'Gene', (32, 36))	('expression', 'MPA', (37, 47))	('cell proliferation', 'biological_process', 'GO:0008283', ('183', '201'))
69419	29725475	Furthermore, high PVT1 expression was associated with advanced ccRCC stage.	('associated', 'Reg', (38, 48))	('high', 'Var', (13, 17))	('expression', 'MPA', (23, 33))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('PVT1', 'Gene', (18, 22))	('PVT1', 'Gene', '5820', (18, 22))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
69422	29725475	Survival analysis revealed that the overall survival time was significantly shorter in the high PVT1 expression group compared with that in the low PVT1 expression group (P<0.01).	('PVT1', 'Gene', '5820', (148, 152))	('high', 'Var', (91, 95))	('PVT1', 'Gene', (96, 100))	('PVT1', 'Gene', (148, 152))	('shorter', 'NegReg', (76, 83))	('PVT1', 'Gene', '5820', (96, 100))
69425	29725475	Furthermore, the findings were confirmed by TCGA database, as its cohort size was large enough and the follow-up time was long enough to draw a conclusion without substantial bias, and it demonstrated that the survival time of patients with high PVT1 expression was shorter compared with that of patients with low PVT1 expression.	('PVT1', 'Gene', (246, 250))	('PVT1', 'Gene', '5820', (314, 318))	('PVT1', 'Gene', '5820', (246, 250))	('patients', 'Species', '9606', (296, 304))	('survival time', 'CPA', (210, 223))	('shorter', 'NegReg', (266, 273))	('PVT1', 'Gene', (314, 318))	('high', 'Var', (241, 245))	('patients', 'Species', '9606', (227, 235))
69433	29725475	It was revealed that the knockdown of PVT1 induced cell apoptosis and promoted cell cycle arrest at the G1 phase.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (79, 96))	('apoptosis', 'biological_process', 'GO:0097194', ('56', '65'))	('PVT1', 'Gene', (38, 42))	('G1 phase', 'biological_process', 'GO:0051318', ('104', '112'))	('PVT1', 'Gene', '5820', (38, 42))	('cell apoptosis', 'CPA', (51, 65))	('promoted', 'PosReg', (70, 78))	('apoptosis', 'biological_process', 'GO:0006915', ('56', '65'))	('cell cycle arrest at the G1 phase', 'CPA', (79, 112))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('79', '96'))	('knockdown', 'Var', (25, 34))
69435	29725475	Western blotting in the present study revealed that the knockdown of PVT1 increased the level of Bax and the cleavage of PARP, a marker of cells undergoing apoptosis.	('cleavage', 'MPA', (109, 117))	('PARP', 'Gene', '142', (121, 125))	('PVT1', 'Gene', '5820', (69, 73))	('increased', 'PosReg', (74, 83))	('Bax', 'Gene', '581', (97, 100))	('PVT1', 'Gene', (69, 73))	('apoptosis', 'biological_process', 'GO:0097194', ('156', '165'))	('apoptosis', 'biological_process', 'GO:0006915', ('156', '165'))	('PARP', 'Gene', (121, 125))	('knockdown', 'Var', (56, 65))	('Bax', 'Gene', (97, 100))
69436	29725475	Therefore, the results of the present study indicated that the knockdown of PVT1 induced cell apoptosis through the mitochondria-dependent pathway.	('PVT1', 'Gene', '5820', (76, 80))	('induced', 'Reg', (81, 88))	('cell apoptosis', 'CPA', (89, 103))	('mitochondria-dependent pathway', 'Pathway', (116, 146))	('mitochondria', 'cellular_component', 'GO:0005739', ('116', '128'))	('PVT1', 'Gene', (76, 80))	('knockdown', 'Var', (63, 72))	('apoptosis', 'biological_process', 'GO:0097194', ('94', '103'))	('apoptosis', 'biological_process', 'GO:0006915', ('94', '103'))
69437	29725475	In addition, the knockdown of PVT1 induced cell cycle arrest at the G1 phase by regulating the level of cyclin D1, which is an important protein for controlling cell transition through the G1 phase into the DNA synthesis S phase.	('cyclin D1', 'Gene', '595', (104, 113))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('43', '60'))	('cyclin D1', 'Gene', (104, 113))	('PVT1', 'Gene', (30, 34))	('DNA', 'cellular_component', 'GO:0005574', ('207', '210'))	('S phase', 'biological_process', 'GO:0051320', ('221', '228'))	('G1 phase', 'biological_process', 'GO:0051318', ('189', '197'))	('PVT1', 'Gene', '5820', (30, 34))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (43, 60))	('induced', 'Reg', (35, 42))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('G1 phase', 'biological_process', 'GO:0051318', ('68', '76'))	('cyclin', 'molecular_function', 'GO:0016538', ('104', '110'))	('knockdown', 'Var', (17, 26))	('DNA synthesis', 'biological_process', 'GO:0071897', ('207', '220'))	('regulating', 'Reg', (80, 90))	('cell cycle arrest', 'CPA', (43, 60))
69440	29725475	In the present study, it was revealed that silencing PVT1 decreased the expression of EGFR and its downstream protein AKT, and p-AKT.	('PVT1', 'Gene', (53, 57))	('AKT', 'Gene', '207', (118, 121))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('EGFR', 'Gene', '1956', (86, 90))	('AKT', 'Gene', '207', (129, 132))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('decreased', 'NegReg', (58, 67))	('PVT1', 'Gene', '5820', (53, 57))	('AKT', 'Gene', (118, 121))	('EGFR', 'Gene', (86, 90))	('silencing', 'Var', (43, 52))	('expression', 'MPA', (72, 82))	('AKT', 'Gene', (129, 132))
69442	29725475	The expression of MYC was confirmed and it was revealed that the expression of MYC was decreased subsequent to the silencing of PVT1.	('MYC', 'Gene', (79, 82))	('decreased', 'NegReg', (87, 96))	('silencing', 'Var', (115, 124))	('MYC', 'Gene', (18, 21))	('expression', 'MPA', (65, 75))	('PVT1', 'Gene', (128, 132))	('MYC', 'Gene', '4609', (79, 82))	('MYC', 'Gene', '4609', (18, 21))	('PVT1', 'Gene', '5820', (128, 132))
69444	29725475	In conclusion, the present study demonstrated that PVT1 expression was significantly upregulated in ccRCC compared with that in normal tissues, and that the high expression of PVT1 was associated with advanced stage and a poor prognosis.	('PVT1', 'Gene', '5820', (176, 180))	('associated', 'Reg', (185, 195))	('upregulated', 'PosReg', (85, 96))	('PVT1', 'Gene', (51, 55))	('high', 'Var', (157, 161))	('expression', 'MPA', (56, 66))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('PVT1', 'Gene', (176, 180))	('PVT1', 'Gene', '5820', (51, 55))
69445	29725475	Results also indicated that the knockdown of PVT1 induced the apoptosis and cell cycle arrest of ccRCC cells through activation of the EGFR pathway.	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (76, 93))	('EGFR', 'molecular_function', 'GO:0005006', ('135', '139'))	('PVT1', 'Gene', (45, 49))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('cell cycle arrest', 'CPA', (76, 93))	('knockdown', 'Var', (32, 41))	('EGFR', 'Gene', '1956', (135, 139))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('76', '93'))	('apoptosis', 'CPA', (62, 71))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('EGFR', 'Gene', (135, 139))	('PVT1', 'Gene', '5820', (45, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('activation', 'PosReg', (117, 127))
69450	28486536	Stratification of clear cell renal cell carcinoma (ccRCC) genomes by gene-directed copy number alteration (CNA) analysis Tumorigenic processes are understood to be driven by epi-/genetic and genomic alterations from single point mutations to chromosomal alterations such as insertions and deletions of nucleotides up to gains and losses of large chromosomal fragments including products of chromosomal rearrangements e.g.	('insertions', 'Var', (274, 284))	('clear cell renal cell carcinoma', 'Disease', (18, 49))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (29, 49))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (18, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (18, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))	('gains', 'Var', (320, 325))	('deletions', 'Var', (289, 298))	('losses', 'NegReg', (330, 336))
69458	28486536	Tumourigenic processes driven by epi-/genetic and genomic alterations consist of an interplay of individual events from single point mutations to chromosomal alterations such as insertions and deletions of nucleotides up to gains and losses of large chromosomal fragments including products of chromosomal rearrangements e.g.	('Tumour', 'Disease', (0, 6))	('deletions', 'Var', (193, 202))	('gains', 'PosReg', (224, 229))	('insertions', 'Var', (178, 188))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (133, 142))	('Tumour', 'Disease', 'MESH:D009369', (0, 6))	('losses', 'NegReg', (234, 240))
69465	28486536	Deletions and unbalanced translocations of chromosome 3p are the most frequent abnormalities associated with chromosomal loss of specific regions, involving among others the VHL gene locus.	('VHL', 'Disease', (174, 177))	('VHL', 'Disease', 'MESH:D006623', (174, 177))	('unbalanced translocations', 'Var', (14, 39))	('chromosome', 'cellular_component', 'GO:0005694', ('43', '53'))	('Deletions', 'Var', (0, 9))
69467	28486536	Losses and gains of certain gene segments in RCC tumour tissues are suspected to interfere with gene functionalities such as transcriptional gene expression and patient outcome.	('RCC tumour', 'Disease', 'MESH:C538614', (45, 55))	('interfere', 'Reg', (81, 90))	('patient', 'Species', '9606', (161, 168))	('gene functionalities', 'MPA', (96, 116))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('transcriptional gene expression', 'MPA', (125, 156))	('Losses', 'Var', (0, 6))	('gene expression', 'biological_process', 'GO:0010467', ('141', '156'))	('RCC tumour', 'Disease', (45, 55))	('gains', 'PosReg', (11, 16))
69473	28486536	The roadmap and workflow of the copy number analysis performed at the University Medicine of the Hansestadt Rostock (HRO) stratifies gene losses and gains in clear cell renal cell carcinoma (ccRCC) tumours.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (158, 189))	('tumours', 'Phenotype', 'HP:0002664', (198, 205))	('ccRCC', 'Phenotype', 'HP:0006770', (191, 196))	('clear cell renal cell carcinoma (ccRCC) tumours', 'Disease', 'MESH:C538614', (158, 205))	('gains', 'PosReg', (149, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (169, 189))	('gene losses', 'Var', (133, 144))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))
69476	28486536	Regarding the HRO study, gene members were categorized in a genome-wide unbiased gene-centred CNA approach comprising copy number alterations in at least 20 out of 48 ccRCC tumour samples.	('ccRCC', 'Phenotype', 'HP:0006770', (167, 172))	('RCC tumour', 'Disease', (169, 179))	('RCC tumour', 'Disease', 'MESH:C538614', (169, 179))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('copy number alterations', 'Var', (118, 141))
69483	28486536	The Workflow Branch WB I is focussed on selecting copy number alterations by molecular terms that are suitable to distinguish ccRCC tumours initially graded by pathologists using the Fuhrman classification.	('Workflow Branch WB I', 'Disease', (4, 24))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('ccRCC tumours', 'Disease', (126, 139))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('ccRCC tumours', 'Disease', 'MESH:D009369', (126, 139))	('copy number alterations', 'Var', (50, 73))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))	('Workflow Branch WB I', 'Disease', 'MESH:D002037', (4, 24))
69490	28486536	Furthermore, losses of VHL seemed to be associated more frequently with Fuhrman malignancy grade G1 independently of losses and gains of CNA genes at loci on 5q (Table B in S3 File).	('VHL', 'Disease', (23, 26))	('VHL', 'Disease', 'MESH:D006623', (23, 26))	('Fuhrman malignancy', 'Disease', 'MESH:D009369', (72, 90))	('Fuhrman malignancy', 'Disease', (72, 90))	('associated', 'Reg', (40, 50))	('losses', 'Var', (13, 19))
69491	28486536	that VHL wild-type ccRCC tumours were observed to have higher number of genetic instabilities suggesting a greater potential for tumour progression, as copy number alterations have been associated with tumour stage, grade and worse prognosis.	('ccRCC tumours', 'Disease', (19, 32))	('grade', 'CPA', (216, 221))	('genetic instabilities', 'Disease', (72, 93))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('tumour', 'Disease', 'MESH:D009369', (202, 208))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('copy number alterations', 'Var', (152, 175))	('tumour', 'Disease', (202, 208))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('VHL', 'Disease', 'MESH:D006623', (5, 8))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('ccRCC tumours', 'Disease', 'MESH:D009369', (19, 32))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('tumour', 'Disease', (129, 135))	('associated', 'Reg', (186, 196))	('tumour', 'Disease', (25, 31))	('genetic instabilities', 'Disease', 'MESH:D030342', (72, 93))	('VHL', 'Disease', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (19, 24))
69492	28486536	Median progression-free survival and ccRCC-specific survival were significantly reduced in patients with wild-type VHL expression.	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('patients', 'Species', '9606', (91, 99))	('wild-type', 'Var', (105, 114))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('reduced', 'NegReg', (80, 87))	('RCC', 'Disease', (39, 42))	('VHL', 'Disease', 'MESH:D006623', (115, 118))	('VHL', 'Disease', (115, 118))
69496	28486536	In cases CNA genes of grade G3 ccRCC tumours map to loci assigned as Fuhrman grade G1 as exemplified by locus 3p14.3, losses and gains at additional loci are most likely nominators for specifying final Fuhrman grades such as losses at 6q21 and gains at 7q22.1 in respect to losses common to chromosomal loci at 3p.	('ccRCC tumours', 'Disease', 'MESH:D009369', (31, 44))	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('gains', 'Var', (244, 249))	('losses', 'Var', (225, 231))	('ccRCC', 'Phenotype', 'HP:0006770', (31, 36))	('ccRCC tumours', 'Disease', (31, 44))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))
69497	28486536	CNAs at distinct chromosomal loci are shown to lead to G3 phenotypes as visualized by ccRCC G3-541 (Fig 4).	('lead to', 'Reg', (47, 54))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('CNAs', 'Var', (0, 4))
69498	28486536	Comparative analyses of losses and gains of individual loci indicate the presence of ordered processes of copy number alterations that occur in numerous HRO tumour genomes suspected to be guided by common mechanisms.	('numerous HRO tumour', 'Disease', (144, 163))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('copy number alterations', 'Var', (106, 129))	('numerous HRO tumour', 'Disease', 'MESH:D009369', (144, 163))
69506	28486536	B in S7 File) as well as chromosomal loci based on gene losses and gains in at least 20 or more ccRCC tumours (Fig.	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('losses', 'NegReg', (56, 62))	('ccRCC tumours', 'Disease', 'MESH:D009369', (96, 109))	('gene', 'Var', (51, 55))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('gains', 'PosReg', (67, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('ccRCC tumours', 'Disease', (96, 109))
69508	28486536	Gene losses seem by majority to be a common feature in ccRCC tumorigenesis.	('Gene losses', 'Var', (0, 11))	('tumorigenesis', 'CPA', (61, 74))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))
69511	28486536	Apparently, copy number alterations seem to obey and follow specific constraints in a non-random fashion that reoccur in a similar and comparable manner in numerous ccRCC tumours (S8 File).	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('numerous ccRCC tumours', 'Disease', 'MESH:D009369', (156, 178))	('tumours', 'Phenotype', 'HP:0002664', (171, 178))	('ccRCC', 'Phenotype', 'HP:0006770', (165, 170))	('copy number alterations', 'Var', (12, 35))	('numerous ccRCC tumours', 'Disease', (156, 178))
69528	28486536	Interestingly, BAP1 mutations in 15% of all ccRCC have been reported together with SETD2 mutations being more frequent in higher stage tumours and associated with worse prognosis.	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('RCC', 'Disease', (46, 49))	('associated', 'Reg', (147, 157))	('tumours', 'Disease', 'MESH:D009369', (135, 142))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('tumours', 'Disease', (135, 142))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('SETD2', 'Gene', '29072', (83, 88))	('BAP1', 'Gene', '8314', (15, 19))	('mutations', 'Var', (89, 98))	('SETD2', 'Gene', (83, 88))	('frequent', 'Reg', (110, 118))	('BAP1', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))	('tumours', 'Phenotype', 'HP:0002664', (135, 142))
69556	28486536	Renal Cell Carcinoma Pathway (Table I in S2 File) assigned of 49/66 CNA genes RAF1 (16/26) and VHL (14/26) as G1 top-ranks with Fisher's exact test p-values of 0.00228 and 0.0004437 (respectively) and SOS2 (7/20), HGF (4/20) and BRAF (3/20) as G3 top-ranks with p-values of 0.17, 0.51 and 0.075, respectively.	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (0, 20))	('VHL', 'Disease', (95, 98))	('BRAF', 'Gene', (229, 233))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (0, 20))	('RAF1', 'Gene', (78, 82))	('RAF1', 'Gene', '5894', (78, 82))	('Renal Cell Carcinoma', 'Disease', (0, 20))	('Carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('SOS2', 'Gene', '6655', (201, 205))	('0.0004437', 'Var', (172, 181))	('VHL', 'Disease', 'MESH:D006623', (95, 98))	('SOS2', 'Gene', (201, 205))	('BRAF', 'Gene', '673', (229, 233))
69561	28486536	As such, distinct gene losses and gains occurring in individual tumour genomes prioritize pathway assignments suitable to predict and evaluate functionalities of malignancy grades of individual tumours with the potential of offering more individualized treatment options.	('tumours', 'Phenotype', 'HP:0002664', (194, 201))	('gene losses', 'Var', (18, 29))	('malignancy', 'Disease', 'MESH:D009369', (162, 172))	('tumour', 'Disease', (194, 200))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumours', 'Disease', 'MESH:D009369', (194, 201))	('tumours', 'Disease', (194, 201))	('tumour', 'Disease', (64, 70))	('malignancy', 'Disease', (162, 172))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('gains', 'PosReg', (34, 39))	('tumour', 'Disease', 'MESH:D009369', (194, 200))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
69569	28486536	Noteworthy, in line with visualizations of diamond shapes and circles assigned to the PI3K pathway, PI3K signaling has previously been reported to be involved in complex processes with seemingly opposing functional effects such as cancer progression and anti-tumour response on one hand and escape mechanisms from immunological surveillance and immune suppression on the other hand.	('tumour', 'Disease', (259, 265))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('PI3K', 'Var', (100, 104))	('cancer', 'Disease', (231, 237))	('PI3K signaling', 'biological_process', 'GO:0014065', ('100', '114'))	('tumour', 'Phenotype', 'HP:0002664', (259, 265))	('involved in', 'Reg', (150, 161))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('PI3K', 'molecular_function', 'GO:0016303', ('86', '90'))	('PI3K', 'molecular_function', 'GO:0016303', ('100', '104'))	('tumour', 'Disease', 'MESH:D009369', (259, 265))
69577	28486536	Our initial CNA analysis performed on ccRCC tumour genomes was based on the conceptual understanding that copy number alterations start as lower malignant tumours and progress to higher malignant ccRCC tumours.	('malignant ccRCC tumours', 'Disease', 'MESH:D009369', (186, 209))	('progress', 'PosReg', (167, 175))	('copy number alterations', 'Var', (106, 129))	('malignant tumours', 'Disease', (145, 162))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('tumours', 'Phenotype', 'HP:0002664', (202, 209))	('RCC tumour', 'Disease', 'MESH:C538614', (198, 208))	('malignant ccRCC tumours', 'Disease', (186, 209))	('RCC tumour', 'Disease', 'MESH:C538614', (40, 50))	('RCC tumour', 'Disease', (40, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('tumours', 'Phenotype', 'HP:0002664', (155, 162))	('ccRCC', 'Phenotype', 'HP:0006770', (196, 201))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('malignant tumours', 'Disease', 'MESH:D009369', (145, 162))
69592	28486536	There, TGFBI (5q31) was reported to be amplified in 70% of ccRCC cases (7/10) with 5q23.2-q34 gain and CSF1R (5q32) to be upregulated in 30% of tumours (3/10).	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('CSF1R', 'Gene', '1436', (103, 108))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('upregulated', 'PosReg', (122, 133))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('gain', 'PosReg', (94, 98))	('TGFBI', 'Gene', '7045', (7, 12))	('CSF1', 'molecular_function', 'GO:0005011', ('103', '107'))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('amplified', 'PosReg', (39, 48))	('RCC', 'Disease', (61, 64))	('TGFBI', 'Gene', (7, 12))	('tumours', 'Disease', 'MESH:D009369', (144, 151))	('tumours', 'Disease', (144, 151))	('CSF1R', 'Gene', (103, 108))	('5q23.2-q34', 'Var', (83, 93))
69593	28486536	addressed CSF1R involvement in ccRCC pathogenesis based on CSF1R copy number gain, overexpression in cancer tissue on mRNA and protein level, plus two novel mutations identified in ccRCC tumours.	('CSF1R', 'Gene', '1436', (59, 64))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('overexpression', 'PosReg', (83, 97))	('ccRCC tumours', 'Disease', 'MESH:D009369', (181, 194))	('CSF1R', 'Gene', (59, 64))	('copy number', 'Var', (65, 76))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('CSF1R', 'Gene', '1436', (10, 15))	('CSF1R', 'Gene', (10, 15))	('RCC', 'Disease', (183, 186))	('ccRCC tumours', 'Disease', (181, 194))	('involvement', 'Reg', (16, 27))	('ccRCC', 'Phenotype', 'HP:0006770', (181, 186))	('RCC', 'Disease', (33, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (31, 36))	('CSF1', 'molecular_function', 'GO:0005011', ('10', '14'))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('cancer', 'Disease', (101, 107))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('pathogenesis', 'biological_process', 'GO:0009405', ('37', '49'))	('CSF1', 'molecular_function', 'GO:0005011', ('59', '63'))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gain', 'PosReg', (77, 81))	('tumours', 'Phenotype', 'HP:0002664', (187, 194))
69602	28486536	MYC (8q24.21) initially reported to be a potential target of 8q gain and a ccRCC candidate oncogene was not found to be amplified, but deleted once in 48 HRO cases.	('MYC', 'Gene', (0, 3))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('MYC', 'Gene', '4609', (0, 3))	('deleted', 'Var', (135, 142))
69609	28486536	SETD2 has been found to be mutated by 11.6%, respectively by 33.5% in ccRCC cohorts analysed by TCGA and by the Memorial-Sloan-Kettering Cancer Center.	('mutated', 'Var', (27, 34))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('Cancer', 'Phenotype', 'HP:0002664', (137, 143))	('SETD2', 'Gene', '29072', (0, 5))	('SETD2', 'Gene', (0, 5))	('ccRCC', 'Phenotype', 'HP:0006770', (70, 75))
69610	28486536	Haddad and Margulis published a meta-analysis of genes that are preferentially mutated in ccRCC tissues.	('RCC', 'Disease', (92, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('mutated', 'Var', (79, 86))
69611	28486536	Interestingly, the most common mutations are seen in genes that as well are predominantly found to be lost in ccRCC genomes of the HRO and Swiss data sets (Table 2).	('RCC', 'Disease', (112, 115))	('mutations', 'Var', (31, 40))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))
69615	28486536	Regarding losses of genes in chromosome 3p (Table L in S2 File), subsequent mutations in the remaining PBRM1 or BAP1 alleles were expected to result in ccRCC with different pathologic features and outcomes, see Table 2  The VHL gene showed losses in only 16/48 tumour genomes of which 14 represent grade G1, but only just 1 loss was detected in Fuhrman grades G2 and G3.	('BAP1', 'Gene', (112, 116))	('mutations', 'Var', (76, 85))	('losses', 'NegReg', (240, 246))	('tumour', 'Phenotype', 'HP:0002664', (261, 267))	('chromosome', 'cellular_component', 'GO:0005694', ('29', '39'))	('VHL', 'Disease', 'MESH:D006623', (224, 227))	('VHL', 'Disease', (224, 227))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('RCC', 'Disease', (154, 157))	('PBRM1', 'Gene', (103, 108))	('PBRM1', 'Gene', '55193', (103, 108))	('BAP1', 'Gene', '8314', (112, 116))	('tumour', 'Disease', 'MESH:D009369', (261, 267))	('ccRCC', 'Phenotype', 'HP:0006770', (152, 157))	('tumour', 'Disease', (261, 267))	('result in', 'Reg', (142, 151))
69616	28486536	showed absence of VHL mutations to be associated with tumour aggressiveness and poor survival.	('associated', 'Reg', (38, 48))	('aggressiveness', 'Phenotype', 'HP:0000718', (61, 75))	('absence', 'NegReg', (7, 14))	('VHL', 'Disease', (18, 21))	('VHL', 'Disease', 'MESH:D006623', (18, 21))	('mutations', 'Var', (22, 31))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumour aggressiveness', 'Disease', (54, 75))	('tumour aggressiveness', 'Disease', 'MESH:D001523', (54, 75))
69619	28486536	and Parker et al., VHL gene alterations are associated in sporadic clear cell renal carcinoma with better prognosis.	('associated', 'Reg', (44, 54))	('VHL', 'Disease', 'MESH:D006623', (19, 22))	('alterations', 'Var', (28, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('sporadic clear cell renal carcinoma', 'Disease', 'MESH:C538614', (58, 93))	('renal carcinoma', 'Phenotype', 'HP:0005584', (78, 93))	('sporadic clear cell renal carcinoma', 'Disease', (58, 93))	('VHL', 'Disease', (19, 22))
69620	28486536	Rini et al reported longer Kaplan-Meier time in disease progression in patients with VHL mutation or promoter methylation.	('methylation', 'biological_process', 'GO:0032259', ('110', '121'))	('Kaplan-Meier time in', 'MPA', (27, 47))	('VHL', 'Disease', (85, 88))	('patients', 'Species', '9606', (71, 79))	('mutation', 'Var', (89, 97))	('promoter methylation', 'Var', (101, 121))	('longer', 'PosReg', (20, 26))	('VHL', 'Disease', 'MESH:D006623', (85, 88))
69621	28486536	Genetic changes of VHL were reported by Kondo et al.	('VHL', 'Disease', 'MESH:D006623', (19, 22))	('Genetic changes', 'Var', (0, 15))	('VHL', 'Disease', (19, 22))
69625	28486536	Definitely, future studies are required to determine whether these different assignments of VHL gene losses in G1 and G3 ccRCC tumours were due to technical differences in scoring DNA losses or scientifically explainable by accompanied duplication of the remaining chromosomal region eventually resulting in copy-neutral loss of heterozygosity (LOH).	('VHL', 'Disease', (92, 95))	('duplication', 'Var', (236, 247))	('VHL', 'Disease', 'MESH:D006623', (92, 95))	('ccRCC tumours', 'Disease', 'MESH:D009369', (121, 134))	('tumours', 'Phenotype', 'HP:0002664', (127, 134))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('losses', 'NegReg', (101, 107))	('loss of', 'NegReg', (321, 328))	('ccRCC tumours', 'Disease', (121, 134))	('ccRCC', 'Phenotype', 'HP:0006770', (121, 126))	('chromosomal region', 'cellular_component', 'GO:0098687', ('265', '283'))	('DNA', 'cellular_component', 'GO:0005574', ('180', '183'))	('copy-neutral', 'Var', (308, 320))
69627	28486536	Note, gene losses at VHL locus favoring less malignant tumour progression are further supported by observations made in von-Hippel-Lindau disease.	('malignant tumour', 'Disease', (45, 61))	('VHL', 'Disease', 'MESH:D006623', (21, 24))	('VHL', 'Disease', (21, 24))	('von-Hippel-Lindau disease', 'Disease', (120, 145))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('malignant tumour', 'Disease', 'MESH:D009369', (45, 61))	('gene losses', 'Var', (6, 17))	('von-Hippel-Lindau disease', 'Disease', 'MESH:D006623', (120, 145))
69629	28486536	The latter observation might be related to the fact that secondary mutations of genes associated with losses at the VHL locus or protein mutations thereof might contribute leading to more malignant phenotypes in case of sporadic renal cell carcinoma.	('VHL', 'Disease', 'MESH:D006623', (116, 119))	('VHL', 'Disease', (116, 119))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (229, 249))	('mutations', 'Var', (67, 76))	('mutations', 'Var', (137, 146))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('sporadic renal cell carcinoma', 'Disease', 'MESH:C538614', (220, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('losses', 'NegReg', (102, 108))	('sporadic renal cell carcinoma', 'Disease', (220, 249))	('leading', 'Reg', (172, 179))
69637	28486536	Overall comparisons of CNAs resulted in ratios of gene losses versus gene gains between ccRCC grades G1 (ratio 1.25) and G3 (ratio 0.58) implying that gains of specific genes are most likely responsible for worse clinical outcomes of Fuhrman grade G3 versus grade G1 ccRCC tumours.	('losses', 'NegReg', (55, 61))	('RCC', 'Disease', (269, 272))	('ccRCC tumours', 'Disease', (267, 280))	('RCC', 'Disease', (90, 93))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('tumours', 'Phenotype', 'HP:0002664', (273, 280))	('ccRCC tumours', 'Disease', 'MESH:D009369', (267, 280))	('gains', 'PosReg', (74, 79))	('Fuhrman', 'Var', (234, 241))	('tumour', 'Phenotype', 'HP:0002664', (273, 279))	('ccRCC', 'Phenotype', 'HP:0006770', (267, 272))	('RCC', 'Disease', 'MESH:C538614', (269, 272))	('gains', 'PosReg', (151, 156))
69641	28486536	Interestingly, of 85 genes whose expressions were reduced in the HAP1 system, 23 genes showed copy number alterations detected in 14 ccRCC tumours (6 G1 and 8 G3 tumours).	('14 ccRCC tumours', 'Disease', 'MESH:C567448', (130, 146))	('tumours', 'Phenotype', 'HP:0002664', (139, 146))	('HAP1', 'Gene', '9001', (65, 69))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('G3 tumours', 'Disease', 'MESH:D009369', (159, 169))	('HAP1', 'Gene', (65, 69))	('copy number alterations', 'Var', (94, 117))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('G3 tumours', 'Disease', (159, 169))	('tumours', 'Phenotype', 'HP:0002664', (162, 169))	('14 ccRCC tumours', 'Disease', (130, 146))	('expressions', 'MPA', (33, 44))
69644	28486536	Initial ccRCC disease processes are dominated by gene losses resulting in Fuhrman grade G1 phenotypes.	('gene', 'Var', (49, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (8, 13))	('losses', 'NegReg', (54, 60))	('Fuhrman grade G1', 'Disease', (74, 90))	('RCC', 'Disease', (10, 13))	('RCC', 'Disease', 'MESH:C538614', (10, 13))
69648	28486536	The 849 CNA genes that encompassed Fisher's exact test p-values <0.1 (Table A in S13 File) in combination with the correlation matrix (Fig E in S13 File) stratify three patient groups: Patient Group 1, Patient Group 2 and Patient Group 3 (Fig E and Table F in S13 File).	('CNA genes', 'Gene', (8, 17))	('patient', 'Species', '9606', (169, 176))	('Patient', 'Species', '9606', (222, 229))	('Patient', 'Species', '9606', (185, 192))	('Patient', 'Species', '9606', (202, 209))	('p-values <0.1', 'Var', (55, 68))
69654	28486536	Losses of group B genes favoured G1 phenotypes by 558 CNA gene hits in G1 vs. 20 CNA hits in G3 tumours.	('Losses', 'NegReg', (0, 6))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('G3 tumours', 'Disease', 'MESH:D009369', (93, 103))	('hits', 'Var', (63, 67))	('group B genes', 'Gene', (10, 23))	('G3 tumours', 'Disease', (93, 103))
69662	28486536	Stratifyed the HRO cohort, patient group A was predominantly specified by G1 gene losses, patient group B by G3 gene losses, patient group C was identified by G3 gains and patient group F by a combination of G1 losses, G3 losses and G3 gains.	('gains', 'PosReg', (162, 167))	('patient', 'Species', '9606', (172, 179))	('losses', 'NegReg', (211, 217))	('losses', 'NegReg', (222, 228))	('gains', 'PosReg', (236, 241))	('patient', 'Species', '9606', (27, 34))	('patient', 'Species', '9606', (90, 97))	('patient', 'Species', '9606', (125, 132))	('losses', 'NegReg', (82, 88))	('gene', 'Var', (77, 81))	('losses', 'NegReg', (117, 123))
69665	28486536	Heterogeneities of HRO tumours seems to be less complex in the HRO data set that displays a lower average of copy number alterations per patient (Table A in S1 File).	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('patient', 'Species', '9606', (137, 144))	('HRO tumours', 'Disease', (19, 30))	('HRO tumours', 'Disease', 'MESH:D009369', (19, 30))	('copy number alterations', 'Var', (109, 132))
69669	28486536	Patient group F tumours are specified by G1 related gene losses and gains plus G3 related gene losses.	('gene', 'Var', (52, 56))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('F tumours', 'Disease', (14, 23))	('Patient', 'Species', '9606', (0, 7))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))	('F tumours', 'Disease', 'OMIM:102510', (14, 23))
69671	28486536	Interestingly, rates of deaths seem to increase with the total number of G3 related gene losses plus the number of gene gains (Table A in S16 File).	('death', 'Disease', 'MESH:D003643', (24, 29))	('gains', 'PosReg', (120, 125))	('death', 'Disease', (24, 29))	('losses', 'NegReg', (89, 95))	('gene', 'Var', (84, 88))	('G3 related', 'Gene', (73, 83))
69699	28486536	Distinct chromosomal loci reveal the existence of ordered processes of gene losses or gains associated with different stages of tumour progression.	('tumour', 'Disease', (128, 134))	('gains', 'PosReg', (86, 91))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('gene', 'Var', (71, 75))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('losses', 'NegReg', (76, 82))
69702	28486536	amplification of tumour driver genes) and/or losses (e.g.	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('tumour', 'Disease', (17, 23))	('amplification', 'Var', (0, 13))	('losses', 'NegReg', (45, 51))
69709	28486536	Our CNA analysis prioritized distinct low and high malignant ccRCC tumours that deploy low numbers of copy number alterations to be subjected to whole genome sequence analysis in order to determine causal gene mutations involved in initiating chromosomal instabilities in clear cell renal cellular carcinoma.	('clear cell renal cellular carcinoma', 'Disease', (272, 307))	('clear cell renal cellular carcinoma', 'Disease', 'MESH:C538614', (272, 307))	('mutations', 'Var', (210, 219))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('high malignant ccRCC tumours', 'Disease', (46, 74))	('high malignant ccRCC tumours', 'Disease', 'MESH:D009369', (46, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (298, 307))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('clear cell renal cellular carcinoma', 'Phenotype', 'HP:0006770', (272, 307))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))	('renal cellular carcinoma', 'Phenotype', 'HP:0005584', (283, 307))
69710	28486536	The application of genome-wide analysis of copy number alterations in concert with forthcoming whole genome sequencing data is expected to provide significant progress in biological understanding of ccRCC pathogenesis and oncogenesis in general.	('copy number alterations', 'Var', (43, 66))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('pathogenesis', 'biological_process', 'GO:0009405', ('205', '217'))	('RCC', 'Disease', (201, 204))	('ccRCC', 'Phenotype', 'HP:0006770', (199, 204))	('oncogenesis', 'biological_process', 'GO:0007048', ('222', '233'))
69712	28486536	One tempting challenge will be to define molecular features that initiate and promote chromosomal alterations in ccRCC tumour panels.	('RCC tumour', 'Disease', 'MESH:C538614', (115, 125))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('chromosomal alterations', 'Var', (86, 109))	('promote', 'PosReg', (78, 85))	('RCC tumour', 'Disease', (115, 125))	('ccRCC', 'Phenotype', 'HP:0006770', (113, 118))
69714	28486536	The final challenge will be to relate dynamics of mutations, translocations, copy number alterations and epigenetic modifications occurring in ccRCC to clinical outcome.	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('ccRCC', 'Phenotype', 'HP:0006770', (143, 148))	('translocations', 'Var', (61, 75))	('copy number alterations', 'Var', (77, 100))
69715	28486536	According to our own analysis, each ccRCC tumour subtype displays common and cancer subtype-specific copy number alterations (CNAs) possibly guiding or guided by mutational alterations (Table 2).	('tumour subtype displays', 'Disease', 'MESH:C535673', (42, 65))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('tumour subtype displays', 'Disease', (42, 65))	('copy number alterations', 'Var', (101, 124))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('RCC tumour', 'Disease', (38, 48))	('RCC tumour', 'Disease', 'MESH:C538614', (38, 48))
69760	33537247	In ccRCC, the inactivation of von Hippel Lindau tumor suppressor gene increases hypoxia-inducible factor, which in turn increases vascular endothelial growth factor, determining the high vascularization of ccRCC.	('vascular endothelial growth factor', 'Gene', (130, 164))	('tumor suppressor', 'biological_process', 'GO:0051726', ('48', '64'))	('von Hippel Lindau tumor suppressor', 'Gene', (30, 64))	('increases vascular endothelial growth factor', 'Phenotype', 'HP:0031052', (120, 164))	('hypoxia', 'Disease', 'MESH:D000860', (80, 87))	('vascular endothelial growth factor', 'Gene', '7422', (130, 164))	('increases', 'PosReg', (70, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('inactivation', 'Var', (14, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (206, 211))	('ccRCC', 'Disease', (206, 211))	('ccRCC', 'Disease', (3, 8))	('von Hippel Lindau tumor suppressor', 'Gene', '7428', (30, 64))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('130', '164'))	('increases', 'PosReg', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('48', '64'))	('hypoxia', 'Disease', (80, 87))
69783	33333852	We found that copy-number variation alterations in some olaparib-modulated lncRNAs had a statistically significant correlation with alterations in some key tumor suppressor genes.	('copy-number variation alterations', 'Var', (14, 47))	('olaparib-modulated', 'Gene', (56, 74))	('correlation', 'Reg', (115, 126))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('lncRNAs', 'Gene', (75, 82))	('tumor suppressor', 'biological_process', 'GO:0051726', ('156', '172'))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('156', '172'))	('olaparib', 'Chemical', 'MESH:C531550', (56, 64))	('tumor', 'Disease', (156, 161))
69792	33333852	VM describes the generation of perfusion pathways in tumors by highly aggressive and genetically deregulated tumor cells, independently of angiogenesis or pre-existing normal blood vessels.	('tumor', 'Disease', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('perfusion', 'MPA', (31, 40))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (53, 59))	('angiogenesis', 'biological_process', 'GO:0001525', ('139', '151'))	('genetically deregulated', 'Var', (85, 108))	('pre', 'molecular_function', 'GO:0003904', ('155', '158'))
69793	33333852	The presence of VM is reportedly correlated with increased metastasis, poor prognosis and decreased survival in cancer patients.	('metastasis', 'CPA', (59, 69))	('poor', 'CPA', (71, 75))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('increased', 'PosReg', (49, 58))	('patients', 'Species', '9606', (119, 127))	('decreased', 'NegReg', (90, 99))	('survival', 'CPA', (100, 108))	('presence', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
69802	33333852	In a previous study, we showed that PARP inhibition altered the ability of melanoma to undergo VM, interfering with the expression and phosphorylation of VE-cadherin.	('expression', 'MPA', (120, 130))	('ability', 'MPA', (64, 71))	('PARP', 'Gene', '142', (36, 40))	('phosphorylation', 'biological_process', 'GO:0016310', ('135', '150'))	('cadherin', 'molecular_function', 'GO:0008014', ('157', '165'))	('VE-cadherin', 'Gene', '1003', (154, 165))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('inhibition', 'Var', (41, 51))	('melanoma', 'Disease', (75, 83))	('VE-cadherin', 'Gene', (154, 165))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('phosphorylation', 'MPA', (135, 150))	('PARP', 'Gene', (36, 40))	('interfering', 'NegReg', (99, 110))
69824	33333852	We previously reported that PARP inhibition could hinder the potential of melanoma cells for VM formation on Matrigel.	('inhibition', 'Var', (33, 43))	('formation', 'biological_process', 'GO:0009058', ('96', '105'))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('PARP', 'Gene', (28, 32))	('melanoma', 'Disease', (74, 82))	('PARP', 'Gene', '142', (28, 32))	('hinder', 'NegReg', (50, 56))
69825	33333852	Moreover, PARP inhibition markedly reduced the expression of VE-cadherin, a well-known marker of VM, as well as the phosphorylation of VE-cadherin on Y658, which we reported to be crucial for VM signaling.	('cadherin', 'molecular_function', 'GO:0008014', ('138', '146'))	('phosphorylation', 'MPA', (116, 131))	('reduced', 'NegReg', (35, 42))	('VE-cadherin', 'Gene', (135, 146))	('Y658', 'Chemical', '-', (150, 154))	('cadherin', 'molecular_function', 'GO:0008014', ('64', '72'))	('VE-cadherin', 'Gene', (61, 72))	('PARP', 'Gene', (10, 14))	('VE-cadherin', 'Gene', '1003', (135, 146))	('expression', 'MPA', (47, 57))	('signaling', 'biological_process', 'GO:0023052', ('195', '204'))	('phosphorylation', 'biological_process', 'GO:0016310', ('116', '131'))	('VE-cadherin', 'Gene', '1003', (61, 72))	('PARP', 'Gene', '142', (10, 14))	('inhibition', 'Var', (15, 25))
69837	33333852	The generally large size of lncRNAs makes them prone to accumulate alterations in a genomically unstable context such as cancer, so it should be taken into account that most of the alterations that we found probably fall in the definition of passenger mutations.	('alterations', 'Var', (181, 192))	('fall', 'Phenotype', 'HP:0002527', (216, 220))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
69839	33333852	Out of 80 samples in the UM cohort, only one was altered, with a deletion in the SNHG4 gene.	('SNHG4', 'Gene', '724102', (81, 86))	('deletion', 'Var', (65, 73))	('UM', 'Phenotype', 'HP:0007716', (25, 27))	('SNHG4', 'Gene', (81, 86))
69850	33333852	Alterations in SMC5-AS1 and MAMDC2-AS1 have the highest co-occurrence, which can be easily explained by the fact that the loci for these lncRNAs partially overlap.	('SMC5-AS1', 'Gene', (15, 23))	('Alterations', 'Var', (0, 11))	('co-occurrence', 'Interaction', (56, 69))	('MAMDC2-AS1', 'Gene', '100507244;256691;5729', (28, 38))	('SMC5-AS1', 'Gene', '100507299;23137;5729', (15, 23))	('MAMDC2-AS1', 'Gene', (28, 38))	('SMC', 'cellular_component', 'GO:0016029', ('15', '18'))
69855	33333852	Alterations in TP53 were significantly enriched in samples harboring an amplification in FLG-AS1 (q-value = 2.761 x 10-3), while this amplification was negatively correlated with alterations in IDH1 (q-value = 0.0204) or PTEN (q-value = 0.0384) (Figure 5A).	('amplification', 'Var', (72, 85))	('PTEN', 'Gene', (221, 225))	('Alterations', 'Var', (0, 11))	('IDH1', 'Gene', (194, 198))	('PTEN', 'Gene', '5728', (221, 225))	('FLG-AS1', 'Gene', (89, 96))	('IDH1', 'Gene', '3417', (194, 198))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('FLG-AS1', 'Gene', '339400', (89, 96))
69856	33333852	Alterations in VHL were significantly enriched in samples with amplifications in SNHG4 (q-value = 5.98 x 10-9) (Figure 5B) or PRR7-AS1 (q-value = 2.94 x 10-7) (Figure 5D), and alterations in SPOP were significantly enriched in samples with deep deletion in RGMB-AS1 (q-value < 10-10) (Figure 5C).	('PRR7-AS1', 'Gene', '340037;80758;5729', (126, 134))	('VHL', 'Gene', (15, 18))	('SPOP', 'Gene', '8405', (191, 195))	('PRR', 'molecular_function', 'GO:0038187', ('126', '129'))	('SPOP', 'Gene', (191, 195))	('alterations', 'Var', (176, 187))	('SNHG4', 'Gene', (81, 86))	('VHL', 'Gene', '7428', (15, 18))	('RGMB-AS1', 'Gene', (257, 265))	('amplifications', 'Var', (63, 77))	('SNHG4', 'Gene', '724102', (81, 86))	('RGMB-AS1', 'Gene', '503569', (257, 265))	('deep deletion', 'Var', (240, 253))	('Alterations', 'Reg', (0, 11))	('PRR7-AS1', 'Gene', (126, 134))
69857	33333852	It is not surprising that samples with amplifications in SNHG4 and PRR7-AS1 have enrichment for alterations in the same gene since, as stated above, alterations in these two lncRNAs significantly co-occur in pan-cancer samples.	('alterations', 'Var', (149, 160))	('SNHG4', 'Gene', (57, 62))	('PRR', 'molecular_function', 'GO:0038187', ('67', '70'))	('PRR7-AS1', 'Gene', (67, 75))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('PRR7-AS1', 'Gene', '340037;80758;5729', (67, 75))	('SNHG4', 'Gene', '724102', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
69858	33333852	Assessing whether the co-occurrence of these alterations with the alterations in TP53, IDH1, PTEN, VHL and SPOP has a biological significance would require further research, which, while not within the scope of the present work, represents an interesting niche for future studies.	('PTEN', 'Gene', (93, 97))	('PTEN', 'Gene', '5728', (93, 97))	('IDH1', 'Gene', '3417', (87, 91))	('SPOP', 'Gene', '8405', (107, 111))	('VHL', 'Gene', (99, 102))	('SPOP', 'Gene', (107, 111))	('VHL', 'Gene', '7428', (99, 102))	('TP53', 'Gene', (81, 85))	('IDH1', 'Gene', (87, 91))	('TP53', 'Gene', '7157', (81, 85))	('alterations', 'Var', (66, 77))
69859	33333852	As for possible effects on survival, we checked how amplification or deep deletion of olaparib-modulated lncRNAs affected overall survival in pan-cancer patients (Figure S4).	('overall', 'MPA', (122, 129))	('deep deletion', 'Var', (69, 82))	('cancer', 'Disease', (146, 152))	('affected', 'Reg', (113, 121))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('olaparib-modulated', 'Gene', (86, 104))	('patients', 'Species', '9606', (153, 161))	('olaparib', 'Chemical', 'MESH:C531550', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('amplification', 'Var', (52, 65))
69860	33333852	Significant differences in survival can only be found for MAMDC2-AS1 (p = 0.0365 amplification vs. deletion; p = 0.002384 amplification vs. unaltered), SNHG15 (p = 2.23 x 10-5 amplification vs. unaltered) and LINC01135 (p = 0.0138 amplification vs. deletion; p = 5.72 x 10-8 amplification vs. unaltered).	('SNHG15', 'Gene', '285958', (152, 158))	('MAMDC2-AS1', 'Gene', '100507244;256691;5729', (58, 68))	('LINC01135', 'Gene', '100131060', (209, 218))	('LINC01135', 'Gene', (209, 218))	('deletion', 'Var', (99, 107))	('SNHG15', 'Gene', (152, 158))	('MAMDC2-AS1', 'Gene', (58, 68))
69862	33333852	However, it is important to point out that in many cases, samples with amplifications in olaparib-modulated lncRNAs have, in fact, whole chromosome amplifications.	('amplifications', 'Var', (71, 85))	('olaparib-modulated', 'Gene', (89, 107))	('olaparib', 'Chemical', 'MESH:C531550', (89, 97))	('chromosome', 'cellular_component', 'GO:0005694', ('137', '147'))	('lncRNAs', 'Gene', (108, 115))
69863	33333852	Therefore, many other genes are altered in these samples, and it is the global effect of these alterations that determines tumor aggressiveness and, eventually, patient survival.	('tumor aggressiveness', 'Disease', (123, 143))	('genes', 'Gene', (22, 27))	('determines', 'Reg', (112, 122))	('patient', 'Species', '9606', (161, 168))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (123, 143))	('altered', 'Reg', (32, 39))	('aggressiveness', 'Phenotype', 'HP:0000718', (129, 143))	('alterations', 'Var', (95, 106))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
69877	33333852	PARP inhibitors are a promising therapy in cancer treatment, having already demonstrated their beneficial effects in the treatment of ovarian cancer patients with specific deficiencies in homologous recombination-mediated DNA repair.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('patients', 'Species', '9606', (149, 157))	('ovarian cancer', 'Phenotype', 'HP:0100615', (134, 148))	('PARP', 'Gene', (0, 4))	('cancer', 'Disease', (43, 49))	('ovarian cancer', 'Disease', 'MESH:D010051', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('homologous recombination', 'biological_process', 'GO:0035825', ('188', '212'))	('DNA repair', 'biological_process', 'GO:0006281', ('222', '232'))	('deficiencies', 'Var', (172, 184))	('beneficial', 'PosReg', (95, 105))	('ovarian cancer', 'Disease', (134, 148))	('DNA', 'cellular_component', 'GO:0005574', ('222', '225'))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('PARP', 'Gene', '142', (0, 4))	('cancer', 'Disease', (142, 148))
69879	33333852	We have previously reported that PARP inhibition can decrease VM formation and VM markers (VE-cadherin and its phosphorylation on Y658) in melanoma.	('VM formation', 'CPA', (62, 74))	('decrease', 'NegReg', (53, 61))	('Y658', 'Chemical', '-', (130, 134))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('PARP', 'Gene', '142', (33, 37))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('VE-cadherin', 'Gene', (91, 102))	('inhibition', 'Var', (38, 48))	('cadherin', 'molecular_function', 'GO:0008014', ('94', '102'))	('VE-cadherin', 'Gene', '1003', (91, 102))	('formation', 'biological_process', 'GO:0009058', ('65', '74'))	('PARP', 'Gene', (33, 37))	('phosphorylation', 'MPA', (111, 126))	('phosphorylation', 'biological_process', 'GO:0016310', ('111', '126'))
69890	33333852	In many of these cancer types, high SNHG1 expression is correlated with poor prognosis and lower progression-free survival.	('lower', 'NegReg', (91, 96))	('expression', 'MPA', (42, 52))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('SNHG1', 'Gene', '23642', (36, 41))	('progression-free survival', 'CPA', (97, 122))	('cancer', 'Disease', (17, 23))	('high', 'Var', (31, 35))	('SNHG1', 'Gene', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
69901	33333852	A positive correlation, as the one found for SNHG4 and MIR17HG, would be expected in our model since inhibition of PARP1/2 leads to reduced lncRNA expression.	('PARP1/2', 'Gene', '64761;142;10038', (115, 122))	('inhibition', 'Var', (101, 111))	('MIR17HG', 'Gene', (55, 62))	('PARP1/2', 'Gene', (115, 122))	('lncRNA expression', 'MPA', (140, 157))	('reduced', 'NegReg', (132, 139))	('SNHG4', 'Gene', '724102', (45, 50))	('MIR17HG', 'Gene', '407975', (55, 62))	('SNHG4', 'Gene', (45, 50))
69905	33333852	Surprisingly, we found that CNV alterations in some olaparib-modulated lncRNAs had a statistically significant correlation with alterations in some key tumor suppressors genes (Figure 5 and Figure S3): samples harboring amplification in FLG-AS1 were frequently mutated in TP53, while there was a negative correlation with mutations in PTEN and IDH1; alterations in SPOP co-occurred with a deep deletion in RGMB-AS1, and alterations in VHL were enriched in samples containing amplification in SNHG4 or in PRR7-AS1.	('amplification', 'Var', (475, 488))	('TP53', 'Gene', '7157', (272, 276))	('VHL', 'Gene', (435, 438))	('IDH1', 'Gene', (344, 348))	('alterations', 'Reg', (420, 431))	('PRR7-AS1', 'Gene', (504, 512))	('FLG-AS1', 'Gene', (237, 244))	('co-occurred', 'Reg', (370, 381))	('VHL', 'Gene', '7428', (435, 438))	('tumor', 'Disease', (152, 157))	('IDH1', 'Gene', '3417', (344, 348))	('FLG-AS1', 'Gene', '339400', (237, 244))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('TP53', 'Gene', (272, 276))	('SPOP', 'Gene', '8405', (365, 369))	('PRR7-AS1', 'Gene', '340037;80758;5729', (504, 512))	('PTEN', 'Gene', (335, 339))	('RGMB-AS1', 'Gene', (406, 414))	('deep deletion', 'Var', (389, 402))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('SNHG4', 'Gene', '724102', (492, 497))	('SPOP', 'Gene', (365, 369))	('RGMB-AS1', 'Gene', '503569', (406, 414))	('olaparib', 'Chemical', 'MESH:C531550', (52, 60))	('PRR', 'molecular_function', 'GO:0038187', ('504', '507'))	('alterations', 'Reg', (350, 361))	('SNHG4', 'Gene', (492, 497))	('PTEN', 'Gene', '5728', (335, 339))
69909	33333852	Wildtype p53 can arrest cell cycle progression after DNA damage, hindering the accumulation of potentially oncogenic mutations in the cell.	('mutations', 'Var', (117, 126))	('cell cycle progression', 'CPA', (24, 46))	('hindering', 'NegReg', (65, 74))	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', (9, 12))	('cell cycle', 'biological_process', 'GO:0007049', ('24', '34'))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))
69910	33333852	Malfunction of p53 can lead to evasion of tumor cell death, which in turn allows tumor growth.	('tumor cell death', 'Disease', (42, 58))	('tumor', 'Disease', (42, 47))	('lead to', 'Reg', (23, 30))	('cell death', 'biological_process', 'GO:0008219', ('48', '58'))	('tumor cell death', 'Disease', 'MESH:D003643', (42, 58))	('evasion of', 'MPA', (31, 41))	('p53', 'Gene', (15, 18))	('Malfunction', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('p53', 'Gene', '7157', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('allows', 'PosReg', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', (81, 86))
69911	33333852	TP53 is altered in over half of the samples containing FLG-AS1 amplification (192 out of 376 samples) (Figure S3A), having a significant co-occurrence in the pan-cancer cohort.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('FLG-AS1', 'Gene', '339400', (55, 62))	('cancer', 'Disease', (162, 168))	('altered', 'Reg', (8, 15))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('amplification', 'Var', (63, 76))	('FLG-AS1', 'Gene', (55, 62))
69912	33333852	As expected for this gene, most TP53 alterations in those 192 samples are classed as putative drivers, most of the missense mutations, but also truncating mutations and a few in-frame mutations.	('TP53', 'Gene', '7157', (32, 36))	('TP53', 'Gene', (32, 36))	('alterations', 'Var', (37, 48))	('truncating', 'MPA', (144, 154))	('missense mutations', 'Var', (115, 133))
69913	33333852	Samples harboring alterations in both genes are mostly from non-small cell lung cancer and invasive breast carcinoma.	('lung cancer', 'Disease', (75, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('alterations', 'Var', (18, 29))	('invasive breast carcinoma', 'Disease', (91, 116))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (64, 86))	('invasive breast carcinoma', 'Disease', 'MESH:D001943', (91, 116))	('breast carcinoma', 'Phenotype', 'HP:0003002', (100, 116))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (60, 86))
69917	33333852	In the TCGA pan-cancer cohort, PTEN alterations occur most frequently in uterine corpus endometrial carcinoma (UCEC) (66.54% of all UCEC samples; data not shown), while FLG-AS1 amplification is most prevalent in hepatocellular carcinoma, lung adenocarcinoma and breast invasive carcinoma (Figure S2), with only two UCEC samples harboring an amplification in this lncRNA.	('PTEN', 'Gene', (31, 35))	('FLG-AS1', 'Gene', '339400', (169, 176))	('alterations', 'Var', (36, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('prevalent', 'Reg', (199, 208))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (212, 236))	('PTEN', 'Gene', '5728', (31, 35))	('cancer', 'Disease', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('endometrial carcinoma', 'Disease', (88, 109))	('hepatocellular carcinoma', 'Disease', (212, 236))	('amplification', 'Var', (177, 190))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (262, 287))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (238, 257))	('FLG-AS1', 'Gene', (169, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (88, 109))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (88, 109))	('lung adenocarcinoma and breast invasive carcinoma', 'Disease', 'MESH:D001943', (238, 287))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (212, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
69919	33333852	Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations are also frequent in several types of cancer, especially in a number of brain tumors.	('IDH1/2', 'Gene', '3417;3418', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('IDH1/2', 'Gene', (34, 40))	('frequent', 'Reg', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('brain tumors', 'Phenotype', 'HP:0030692', (124, 136))	('brain tumors', 'Disease', 'MESH:D001932', (124, 136))	('cancer', 'Disease', (90, 96))	('mutations', 'Var', (42, 51))	('brain tumors', 'Disease', (124, 136))
69920	33333852	In fact, IDH1/2 mutations are indicators of good prognosis in astrocytomas and glioblastomas since these mutations can lead to improved responses to irradiation and chemotherapy.	('IDH1/2', 'Gene', (9, 15))	('glioblastomas', 'Phenotype', 'HP:0012174', (79, 92))	('mutations', 'Var', (16, 25))	('responses to irradiation', 'MPA', (136, 160))	('astrocytomas', 'Disease', 'MESH:D001254', (62, 74))	('glioblastomas', 'Disease', 'MESH:D005909', (79, 92))	('IDH1/2', 'Gene', '3417;3418', (9, 15))	('glioblastomas', 'Disease', (79, 92))	('astrocytomas', 'Disease', (62, 74))	('improved', 'PosReg', (127, 135))
69921	33333852	IDH1 alterations were mostly found in the lower grade glioma (LGG) TCGA cohort in cBioPortal, with 78% of all LGG samples having alterations in this gene (data not shown).	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('glioma', 'Disease', (54, 60))	('alterations', 'Var', (5, 16))	('alterations', 'Var', (129, 140))	('IDH1', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('IDH1', 'Gene', '3417', (0, 4))
69922	33333852	However, as stated above, FLG-AS1 amplification is most common in other cancer types, and was only present in two LGG samples, hence the mutual exclusivity between alterations in these genes in the pan-cancer context.	('common', 'Reg', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('FLG-AS1', 'Gene', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('FLG-AS1', 'Gene', '339400', (26, 33))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('amplification', 'Var', (34, 47))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
69924	33333852	The co-occurrence between SPOP mutations and RGMB-AS1 deletion happened exclusively in prostate adenocarcinoma (PRAD).	('RGMB-AS1', 'Gene', '503569', (45, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('deletion', 'Var', (54, 62))	('prostate adenocarcinoma', 'Disease', (87, 110))	('happened', 'Reg', (63, 71))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (87, 110))	('RGMB-AS1', 'Gene', (45, 53))	('co-occurrence', 'Reg', (4, 17))	('SPOP', 'Gene', '8405', (26, 30))	('SPOP', 'Gene', (26, 30))
69926	33333852	SPOP alterations and RGMB-AS1 deletions significantly co-occurred in the PRAD cohort, with 20 out of 489 samples containing alterations in both genes (Figure S3E).	('SPOP', 'Gene', (0, 4))	('co-occurred', 'Reg', (54, 65))	('deletions', 'Var', (30, 39))	('RGMB-AS1', 'Gene', (21, 29))	('PRAD', 'Disease', (73, 77))	('RGMB-AS1', 'Gene', '503569', (21, 29))	('SPOP', 'Gene', '8405', (0, 4))
69927	33333852	RGMB-AS1 was deleted in all these 20 samples, while SPOP had suffered some kind of missense mutation, affecting the residues Y87, F102, F125, K129, W131 or F133.	('RGMB-AS1', 'Gene', '503569', (0, 8))	('SPOP', 'Gene', '8405', (52, 56))	('affecting', 'Reg', (102, 111))	('SPOP', 'Gene', (52, 56))	('W131', 'Var', (148, 152))	('RGMB-AS1', 'Gene', (0, 8))	('F102', 'Var', (130, 134))	('K129', 'Var', (142, 146))	('F125', 'Var', (136, 140))	('Y87', 'Var', (125, 128))	('F133', 'Var', (156, 160))
69928	33333852	Most of these residues are part of SPOP substrate-binding cleft, and all mutations were classed as putative drivers of cancer.	('SPOP', 'Gene', '8405', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('SPOP', 'Gene', (35, 39))	('binding', 'molecular_function', 'GO:0005488', ('50', '57'))	('mutations', 'Var', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
69929	33333852	Deletions in the chromodomain helicase DNA binding protein 1(CHD1) have also been associated with SPOP mutations.	('CHD1', 'Gene', (61, 65))	('associated', 'Reg', (82, 92))	('DNA binding', 'molecular_function', 'GO:0003677', ('39', '50'))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('SPOP', 'Gene', (98, 102))	('CHD1', 'Gene', '1105', (61, 65))	('chromodomain helicase DNA binding protein 1', 'Gene', (17, 60))	('chromodomain helicase DNA binding protein 1', 'Gene', '1105', (17, 60))	('SPOP', 'Gene', '8405', (98, 102))	('Deletions', 'Var', (0, 9))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
69930	33333852	A query for SPOP, CHD1 and deletions in RGMB-AS1 in the PRAD cohort (Figure S3F) confirmed a co-occurrence between alterations in all three genes.	('RGMB-AS1', 'Gene', (40, 48))	('SPOP', 'Gene', '8405', (12, 16))	('alterations', 'Var', (115, 126))	('RGMB-AS1', 'Gene', '503569', (40, 48))	('CHD1', 'Gene', (18, 22))	('deletions', 'Var', (27, 36))	('SPOP', 'Gene', (12, 16))	('CHD1', 'Gene', '1105', (18, 22))
69931	33333852	In fact, CHD1 and RGMB-AS1 are located in the same cytogenetic band (5q15) in the genome; hence a deletion in RGMB-AS1 always involves a deletion in CHD1 too.	('CHD1', 'Gene', '1105', (9, 13))	('RGMB-AS1', 'Gene', '503569', (18, 26))	('RGMB-AS1', 'Gene', '503569', (110, 118))	('deletion', 'Var', (137, 145))	('deletion', 'Var', (98, 106))	('RGMB-AS1', 'Gene', (18, 26))	('CHD1', 'Gene', (9, 13))	('CHD1', 'Gene', (149, 153))	('RGMB-AS1', 'Gene', (110, 118))	('CHD1', 'Gene', '1105', (149, 153))
69932	33333852	To our knowledge, there are no available publications analyzing the role of RGMB-AS1 in prostate cancer, though it would be of great interest to find out if the pro-tumoral effect of deletions in the 5q15 region is due exclusively to the loss of CHD1 or if RGMB-AS1 could be playing an important role as well.	('loss of CHD1', 'Disease', 'MESH:D014786', (238, 250))	('prostate cancer', 'Disease', (88, 103))	('RGMB-AS1', 'Gene', '503569', (76, 84))	('tumoral', 'Disease', (165, 172))	('tumoral', 'Disease', 'MESH:D009369', (165, 172))	('RGMB-AS1', 'Gene', (257, 265))	('prostate cancer', 'Disease', 'MESH:D011471', (88, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))	('RGMB-AS1', 'Gene', (76, 84))	('loss of CHD1', 'Disease', (238, 250))	('RGMB-AS1', 'Gene', '503569', (257, 265))	('deletions', 'Var', (183, 192))
69933	33333852	This is of particular interest since SPOP mutation in PRAD has been reported to impair homologous recombination-mediated DNA repair, sensitizing to PARP inhibitors, and CHD1 deletions have been associated with increased nonhomologous end joining (NHEJ) DNA-repair, which could lead to sensitivity to PARP inhibitors as well.	('NHEJ', 'biological_process', 'GO:0006303', ('247', '251'))	('PARP', 'Gene', '142', (148, 152))	('PARP', 'Gene', '142', (300, 304))	('PRAD', 'Gene', (54, 58))	('PARP', 'Gene', (300, 304))	('PARP', 'Gene', (148, 152))	('SPOP', 'Gene', (37, 41))	('CHD1', 'Gene', (169, 173))	('sensitizing', 'MPA', (133, 144))	('mutation', 'Var', (42, 50))	('homologous recombination', 'biological_process', 'GO:0035825', ('87', '111'))	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('increased', 'PosReg', (210, 219))	('DNA-repair', 'biological_process', 'GO:0006281', ('253', '263'))	('DNA', 'cellular_component', 'GO:0005574', ('253', '256'))	('nonhomologous end joining', 'MPA', (220, 245))	('DNA repair', 'biological_process', 'GO:0006281', ('121', '131'))	('homologous recombination-mediated DNA repair', 'MPA', (87, 131))	('deletions', 'Var', (174, 183))	('impair', 'NegReg', (80, 86))	('SPOP', 'Gene', '8405', (37, 41))	('CHD1', 'Gene', '1105', (169, 173))
69935	33333852	Loss of VHL interferes with the degradation of hypoxia-inducible factors HIF1alpha and HIF2alpha and therefore promotes the expression of hypoxic genes, which is directly associated with tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('VHL', 'Gene', '7428', (8, 11))	('HIF2alpha', 'Gene', (87, 96))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('hypoxia', 'Disease', (47, 54))	('HIF2alpha', 'Gene', '2034', (87, 96))	('HIF1alpha', 'Gene', (73, 82))	('tumor', 'Disease', (187, 192))	('interferes', 'NegReg', (12, 22))	('degradation', 'MPA', (32, 43))	('expression', 'MPA', (124, 134))	('promotes', 'PosReg', (111, 119))	('hypoxic genes', 'Gene', (138, 151))	('HIF1alpha', 'Gene', '3091', (73, 82))	('degradation', 'biological_process', 'GO:0009056', ('32', '43'))	('Loss', 'Var', (0, 4))	('VHL', 'Gene', (8, 11))
69936	33333852	VHL alterations were present in 16 samples with amplification in SNHG4 (Figure S3D), all of them ccRCC except a PRAD sample.	('SNHG4', 'Gene', '724102', (65, 70))	('alterations', 'Var', (4, 15))	('VHL', 'Gene', (0, 3))	('SNHG4', 'Gene', (65, 70))	('VHL', 'Gene', '7428', (0, 3))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('amplification', 'Var', (48, 61))
69939	33333852	VHL alterations in these samples were mainly truncating mutations classed as putative drivers.	('VHL', 'Gene', '7428', (0, 3))	('truncating mutations', 'Var', (45, 65))	('VHL', 'Gene', (0, 3))	('alterations', 'Reg', (4, 15))
69953	33333852	Amplifications in the MZF1 gene, as well as high MZF1 expression, are frequent in cancer, as shown by TCGA data, and MZF1 has been associated with cancer progression in a variety of solid tumors.	('MZF1', 'Gene', '7593', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('MZF1', 'Gene', (49, 53))	('MZF1', 'Gene', '7593', (22, 26))	('cancer', 'Disease', (82, 88))	('solid tumors', 'Disease', 'MESH:D009369', (182, 194))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('Amplifications', 'Var', (0, 14))	('MZF1', 'Gene', '7593', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('MZF1', 'Gene', (117, 121))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('expression', 'MPA', (54, 64))	('MZF1', 'Gene', (22, 26))	('high', 'PosReg', (44, 48))	('solid tumors', 'Disease', (182, 194))	('associated with', 'Reg', (131, 146))	('cancer', 'Disease', (147, 153))
69973	33333852	The following are available online at , Figure S1: Alteration of each olaparib-modulated lncRNAs across cancer types, Figure S2: Co-expression between olaparib-targeted PARPs and olaparib-modulated lncRNAs in SKCM, Figure S3: Co-alteration between olaparib-modulated lncRNAs and other genes in cancer (detailed), Figure S4: Survival of cancer patients with alterations in olaparib-modulated genes.	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('patients', 'Species', '9606', (343, 351))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('olaparib', 'Chemical', 'MESH:C531550', (179, 187))	('PARPs', 'Gene', (169, 174))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('olaparib', 'Chemical', 'MESH:C531550', (151, 159))	('PARPs', 'Gene', '142;10038;64761', (169, 174))	('olaparib', 'Chemical', 'MESH:C531550', (248, 256))	('cancer', 'Disease', (294, 300))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (336, 342))	('olaparib', 'Chemical', 'MESH:C531550', (372, 380))	('olaparib', 'Chemical', 'MESH:C531550', (70, 78))	('cancer', 'Disease', (336, 342))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('alterations', 'Var', (357, 368))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
69985	33277569	Not surprisingly, miRNAs are implicated in the development and progression of numerous tumours, including ccRCC.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('numerous tumours', 'Disease', 'MESH:D009369', (78, 94))	('miRNAs', 'Var', (18, 24))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('implicated', 'Reg', (29, 39))	('numerous tumours', 'Disease', (78, 94))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('men', 'Species', '9606', (54, 57))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))
70010	33277569	For this reason, in our algorithm, the value resulting from parameters #1, #2, and #3 was decreased by SD values of the miRNA expression in the kidney from HSs (parameter #4) and ccRCC (parameter #5).	('SD values', 'Var', (103, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (179, 184))	('decreased', 'NegReg', (90, 99))	('miRNA expression', 'MPA', (120, 136))	('RCC', 'Disease', 'MESH:C538614', (181, 184))	('RCC', 'Disease', (181, 184))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))
70098	33277569	RGS2 dysregulation is implicated in the development of solid tumours.	('dysregulation', 'Var', (5, 18))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('solid tumours', 'Disease', (55, 68))	('implicated', 'Reg', (22, 32))	('RGS2', 'Gene', (0, 4))	('men', 'Species', '9606', (47, 50))	('RGS', 'molecular_function', 'GO:0016299', ('0', '3'))	('RGS2', 'Gene', '5997', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('solid tumours', 'Disease', 'MESH:D009369', (55, 68))
70109	33277569	Normalization of miR-122 and miR-1271 with miR-16 slightly decreased the discriminating power of urinary miRNAs and normalization of miR-122, miR-1271, and miR-15b with cel-miR-39 and miRTC, increased the discriminating power but in an unexpected way (i.e.	('miR-1271', 'Gene', '100302203', (29, 37))	('miRTC', 'Chemical', '-', (184, 189))	('miR-15b', 'Gene', '406949', (156, 163))	('miR-122', 'Gene', '406906', (17, 24))	('discriminating power', 'MPA', (205, 225))	('miR-15b', 'Gene', (156, 163))	('miR-1271', 'Gene', (142, 150))	('miR-16', 'Gene', (43, 49))	('normalization', 'Var', (116, 129))	('miR-122', 'Gene', (17, 24))	('discriminating power of urinary miRNAs', 'MPA', (73, 111))	('miR-1271', 'Gene', (29, 37))	('miR-122', 'Gene', '406906', (133, 140))	('miR-16', 'Gene', '51573', (43, 49))	('miR-1271', 'Gene', '100302203', (142, 150))	('miR-39', 'Gene', (173, 179))	('miR-39', 'Gene', '266867', (173, 179))	('decreased', 'NegReg', (59, 68))	('increased', 'PosReg', (191, 200))	('miR-122', 'Gene', (133, 140))
70174	28969054	Unlike other oncoproteins, YAP and TAZ are rarely activated by mutations or amplified in cancer.	('mutations', 'Var', (63, 72))	('YAP', 'Gene', (27, 30))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('TAZ', 'Gene', (35, 38))	('cancer', 'Disease', (89, 95))	('TAZ', 'Gene', '6901', (35, 38))	('YAP', 'Gene', '10413', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
70177	28969054	Aberrant expression of ubiquitin ligase complexes that regulate the turnover of Hippo components and deubiquitylating enzymes that counteract these ubiquitin ligases have been implicated in human cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('Aberrant', 'Var', (0, 8))	('implicated', 'Reg', (176, 186))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('ubiquitin', 'molecular_function', 'GO:0031386', ('148', '157'))	('expression', 'MPA', (9, 19))	('cancer', 'Disease', (196, 202))	('human', 'Species', '9606', (190, 195))	('ubiquitin', 'molecular_function', 'GO:0031386', ('23', '32'))	('turnover', 'MPA', (68, 76))
70181	28969054	Hippo signaling represses the activity of the transcriptional co-activators YAP and TAZ, so that loss of pathway activity leads to increased YAP/TAZ activity.	('TAZ', 'Gene', (84, 87))	('YAP', 'Gene', '10413', (76, 79))	('increased', 'PosReg', (131, 140))	('YAP', 'Gene', (141, 144))	('loss', 'Var', (97, 101))	('YAP', 'Gene', (76, 79))	('TAZ', 'Gene', '6901', (145, 148))	('TAZ', 'Gene', (145, 148))	('activity', 'MPA', (113, 121))	('Hippo signaling', 'biological_process', 'GO:0035329', ('0', '15'))	('TAZ', 'Gene', '6901', (84, 87))	('activity', 'MPA', (30, 38))	('YAP', 'Gene', '10413', (141, 144))
70183	28969054	NF2, a promoter of Hippo signaling is the Hippo pathway component most often inactivated by mutation, as reported in the COSMIC database (reviewed in) and its loss is associated with a heritable cancer syndrome.	('NF2', 'Gene', (0, 3))	('Hippo signaling', 'biological_process', 'GO:0035329', ('19', '34'))	('mutation', 'Var', (92, 100))	('loss', 'NegReg', (159, 163))	('associated', 'Reg', (167, 177))	('NF2', 'Gene', '4771', (0, 3))	('cancer syndrome', 'Disease', 'MESH:D009369', (195, 210))	('inactivated', 'NegReg', (77, 88))	('cancer syndrome', 'Disease', (195, 210))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
70184	28969054	Inactivation of other Hippo genes such as RASSF1A, FAT1-4, RASSF2, RASSF4 through mutation or silencing was also observed in cancer (reviewed in).	('RASSF2', 'Gene', (59, 65))	('RASSF4', 'Gene', (67, 73))	('FAT1-4', 'Gene', '2195;2196;120114;79633', (51, 57))	('Hippo genes', 'Gene', (22, 33))	('silencing', 'Var', (94, 103))	('FAT1-4', 'Gene', (51, 57))	('mutation', 'Var', (82, 90))	('RASSF1A', 'Gene', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('observed', 'Reg', (113, 121))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('RASSF1A', 'Gene', '11186', (42, 49))	('cancer', 'Disease', (125, 131))	('Inactivation', 'NegReg', (0, 12))	('RASSF2', 'Gene', '9770', (59, 65))	('RASSF4', 'Gene', '83937', (67, 73))
70188	28969054	Using synthetic lethality screens or RNAi approaches, two groups have recently reported that activated YAP made B-Raf mutant or Ras-harboring tumor cells resistant to MEK-targeted cancer therapies.	('MEK', 'Gene', (167, 170))	('YAP', 'Gene', '10413', (103, 106))	('MEK', 'Gene', '5609', (167, 170))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('B-Raf', 'Gene', '673', (112, 117))	('B-Raf', 'Gene', (112, 117))	('RNAi', 'biological_process', 'GO:0016246', ('37', '41'))	('YAP', 'Gene', (103, 106))	('tumor', 'Disease', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('mutant', 'Var', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('cancer', 'Disease', (180, 186))
70206	28969054	USP21 protein was expressed at low levels in a majority of renal clear cell carcinoma (RCC) samples, suggesting that low USP21 activity could increase cancer relevant cellular phenotypes.	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (59, 85))	('low', 'Var', (117, 120))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('increase', 'PosReg', (142, 150))	('renal clear cell carcinoma', 'Disease', (59, 85))	('RCC', 'Disease', (87, 90))	('USP21', 'Gene', '27005', (121, 126))	('USP21', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('USP21', 'Gene', (121, 126))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('USP', 'molecular_function', 'GO:0051748', ('121', '124'))	('USP21', 'Gene', '27005', (0, 5))	('USP', 'molecular_function', 'GO:0051748', ('0', '3'))	('activity', 'MPA', (127, 135))
70208	28969054	Depletion of USP21 by two independent shRNAs or a pooled shRNA mixture significantly increased YAP reporter activity (Figure 1A) in HEK293T cells.	('YAP', 'Gene', '10413', (95, 98))	('USP21', 'Gene', (13, 18))	('Depletion', 'Var', (0, 9))	('USP', 'molecular_function', 'GO:0051748', ('13', '16'))	('increased', 'PosReg', (85, 94))	('YAP', 'Gene', (95, 98))	('USP21', 'Gene', '27005', (13, 18))	('HEK293T', 'CellLine', 'CVCL:0063', (132, 139))
70215	28969054	Expression of a catalytically inactive mutant form of USP21C221S showed no inhibitory effect on YAP reporter activity (Figure 1D), although the USP21C221S mutant protein was expressed at a comparable level to the native protein.	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('USP21C221S', 'Var', (54, 64))	('YAP', 'Gene', (96, 99))	('USP21C221S', 'Var', (144, 154))	('inhibitory', 'MPA', (75, 85))	('USP', 'molecular_function', 'GO:0051748', ('54', '57'))	('USP', 'molecular_function', 'GO:0051748', ('144', '147'))	('protein', 'cellular_component', 'GO:0003675', ('220', '227'))	('YAP', 'Gene', '10413', (96, 99))
70216	28969054	Instead, the USP21C221S mutant appeared to increase YAP reporter activity, perhaps suggesting a dominant negative effect; though we note that the effect was not strong enough to be statistically significant (p=0.07).	('USP21C221S', 'Var', (13, 23))	('YAP', 'Gene', (52, 55))	('increase', 'PosReg', (43, 51))	('USP', 'molecular_function', 'GO:0051748', ('13', '16'))	('YAP', 'Gene', '10413', (52, 55))
70224	28969054	This was accompanied by reduced YAP phosphorylation at Ser127 and S397 (Figure 2A), which are target sites of LATS kinases.	('phosphorylation', 'biological_process', 'GO:0016310', ('36', '51'))	('YAP', 'Gene', '10413', (32, 35))	('reduced', 'NegReg', (24, 31))	('YAP', 'Gene', (32, 35))	('Ser', 'cellular_component', 'GO:0005790', ('55', '58'))	('Ser127', 'Chemical', '-', (55, 61))	('S397', 'Var', (66, 70))
70227	28969054	Instead, phosphorylation of LATS1/2 (Thr1079/1041) was strongly reduced (Figure 2B), indicating reduced LATS kinase activity.	('phosphorylation', 'biological_process', 'GO:0016310', ('9', '24'))	('LATS kinase', 'Enzyme', (104, 115))	('kinase activity', 'molecular_function', 'GO:0016301', ('109', '124'))	('LATS1/2', 'Gene', '9113;26524', (28, 35))	('Thr1079/1041', 'Var', (37, 49))	('reduced', 'NegReg', (64, 71))	('activity', 'MPA', (116, 124))	('LATS1/2', 'Gene', (28, 35))	('Thr1079', 'Chemical', '-', (37, 44))	('phosphorylation', 'MPA', (9, 24))	('reduced', 'NegReg', (96, 103))
70235	28969054	USP21 depletion reduced the expression of MARK1 and 2 proteins (Figure 2C), but not the mRNA transcripts (Supplementary Figure 3A).	('USP21', 'Gene', (0, 5))	('expression', 'MPA', (28, 38))	('reduced', 'NegReg', (16, 23))	('MARK1 and 2', 'Gene', '4139;2011', (42, 53))	('depletion', 'Var', (6, 15))	('USP21', 'Gene', '27005', (0, 5))	('USP', 'molecular_function', 'GO:0051748', ('0', '3'))
70236	28969054	USP21 depletion also led to reduced phosphorylation of the MARK activation loop.	('MARK', 'Gene', '4139', (59, 63))	('phosphorylation', 'biological_process', 'GO:0016310', ('36', '51'))	('reduced', 'NegReg', (28, 35))	('USP21', 'Gene', (0, 5))	('MARK', 'Gene', (59, 63))	('USP', 'molecular_function', 'GO:0051748', ('0', '3'))	('depletion', 'Var', (6, 15))	('USP21', 'Gene', '27005', (0, 5))	('phosphorylation', 'MPA', (36, 51))
70238	28969054	Conversely, overexpression of USP21, but not of the catalytically inactive C221S mutant, stabilized MARK1 and MARK2 protein expression (Supplementary Figure 3B).	('stabilized', 'PosReg', (89, 99))	('overexpression', 'PosReg', (12, 26))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('USP21', 'Gene', (30, 35))	('MARK2', 'Gene', '2011', (110, 115))	('C221S', 'Mutation', 'rs1408890590', (75, 80))	('MARK2', 'Gene', (110, 115))	('USP21', 'Gene', '27005', (30, 35))	('USP', 'molecular_function', 'GO:0051748', ('30', '33'))	('C221S', 'Var', (75, 80))	('MARK1', 'Gene', '4139', (100, 105))	('MARK1', 'Gene', (100, 105))
70241	28969054	Depletion of MARK3 had little or no effect on YAP reporter activity; MARK1 and 4 depletion increased YAP activity 2-5 fold; and depletion of MARK2 caused over a 20 fold increase (Supplementary Figure 4B).	('YAP', 'Gene', '10413', (101, 104))	('YAP', 'Gene', '10413', (46, 49))	('depletion', 'Var', (81, 90))	('MARK2', 'Gene', (141, 146))	('MARK2', 'Gene', '2011', (141, 146))	('increase', 'PosReg', (169, 177))	('MARK3', 'Gene', '4140', (13, 18))	('YAP', 'Gene', (101, 104))	('YAP', 'Gene', (46, 49))	('MARK3', 'Gene', (13, 18))	('increased', 'PosReg', (91, 100))	('MARK1', 'Gene', (69, 74))	('MARK1', 'Gene', '4139', (69, 74))	('depletion', 'Var', (128, 137))
70243	28969054	Reducing MARK1, 2 levels attenuated the effect of USP21 depletion on YAP activity, while MARK4 depletion has a more limited effect (Supplementary Figure 5).	('MARK1', 'Gene', (9, 14))	('USP21', 'Gene', (50, 55))	('attenuated', 'NegReg', (25, 35))	('YAP', 'Gene', (69, 72))	('USP', 'molecular_function', 'GO:0051748', ('50', '53'))	('MARK4', 'Gene', (89, 94))	('USP21', 'Gene', '27005', (50, 55))	('depletion', 'Var', (56, 65))	('YAP', 'Gene', '10413', (69, 72))	('MARK4', 'Gene', '57787', (89, 94))	('MARK1', 'Gene', '4139', (9, 14))
70249	28969054	Under these conditions, we observed co-IP of MARK1 when performing IP with antibody to USP21 (Figure 2D).	('antibody', 'cellular_component', 'GO:0019815', ('75', '83'))	('USP21', 'Gene', '27005', (87, 92))	('antibody', 'cellular_component', 'GO:0019814', ('75', '83'))	('USP21', 'Gene', (87, 92))	('antibody', 'Var', (75, 83))	('antibody', 'molecular_function', 'GO:0003823', ('75', '83'))	('co-IP', 'Reg', (36, 41))	('MARK1', 'Gene', (45, 50))	('USP', 'molecular_function', 'GO:0051748', ('87', '90'))	('antibody', 'cellular_component', 'GO:0042571', ('75', '83'))	('MARK1', 'Gene', '4139', (45, 50))
70252	28969054	As shown in Figure 2E, USP21 depletion increased the amount of ubiquitin detected on MARK1 purified by IP.	('depletion', 'Var', (29, 38))	('ubiquitin', 'molecular_function', 'GO:0031386', ('63', '72'))	('MARK1', 'Gene', '4139', (85, 90))	('MARK1', 'Gene', (85, 90))	('USP21', 'Gene', '27005', (23, 28))	('amount of ubiquitin detected', 'MPA', (53, 81))	('increased', 'PosReg', (39, 48))	('USP', 'molecular_function', 'GO:0051748', ('23', '26'))	('USP21', 'Gene', (23, 28))
70253	28969054	The peptide sequence SGTSIAFKNIASKIA from MARK1 containing lysine 768 has been identified as a ubiquitylated substrate.	('lysine 768', 'Var', (59, 69))	('MARK1', 'Gene', (42, 47))	('SGTSIAFKNIASKIA', 'Disease', 'None', (21, 36))	('SGTSIAFKNIASKIA', 'Disease', (21, 36))	('MARK1', 'Gene', '4139', (42, 47))	('lysine', 'Chemical', 'MESH:D008239', (59, 65))
70254	28969054	The K768A mutant form of MARK1 showed considerably less ubiquitylation following USP21 depletion than the wild type MARK1 protein (Figure 2E), suggesting that K768 is a site at which USP21 dequbiquitylates MARK1.	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('USP21', 'Gene', (81, 86))	('K768', 'Var', (159, 163))	('USP', 'molecular_function', 'GO:0051748', ('81', '84'))	('K768A', 'Mutation', 'p.K768A', (4, 9))	('USP21', 'Gene', '27005', (183, 188))	('USP', 'molecular_function', 'GO:0051748', ('183', '186'))	('MARK1', 'Gene', '4139', (116, 121))	('MARK1', 'Gene', (116, 121))	('K768A', 'Var', (4, 9))	('less', 'NegReg', (51, 55))	('ubiquitylation', 'MPA', (56, 70))	('MARK1', 'Gene', (206, 211))	('MARK1', 'Gene', '4139', (206, 211))	('MARK1', 'Gene', (25, 30))	('USP21', 'Gene', (183, 188))	('USP21', 'Gene', '27005', (81, 86))	('MARK1', 'Gene', '4139', (25, 30))
70261	28969054	As a control, we verified that depletion of LATS2 kinase strongly increased soft agar colony formation in this experiment (Figure 3A and 3B).	('soft agar colony formation', 'CPA', (76, 102))	('increased', 'PosReg', (66, 75))	('agar', 'Chemical', 'MESH:D000362', (81, 85))	('LATS2', 'Gene', (44, 49))	('LATS2', 'Gene', '26524', (44, 49))	('formation', 'biological_process', 'GO:0009058', ('93', '102'))	('depletion', 'Var', (31, 40))
70263	28969054	USP21 depletion also led to increased soft agar colony formation in A549 and MDA-MB-231 cancer cell lines (Figures 3C and 4D: recall that YAP target gene expression was increased in these cancer cell lines following USP21 depletion, Supplementary Figure 1).	('cancer', 'Disease', (88, 94))	('USP21', 'Gene', (216, 221))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('soft agar colony formation', 'CPA', (38, 64))	('USP', 'molecular_function', 'GO:0051748', ('216', '219'))	('increased', 'PosReg', (28, 37))	('USP21', 'Gene', (0, 5))	('formation', 'biological_process', 'GO:0009058', ('55', '64'))	('USP', 'molecular_function', 'GO:0051748', ('0', '3'))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('increased', 'PosReg', (169, 178))	('YAP', 'Gene', (138, 141))	('cancer', 'Disease', (188, 194))	('USP21', 'Gene', '27005', (216, 221))	('A549', 'CellLine', 'CVCL:0023', (68, 72))	('gene expression', 'biological_process', 'GO:0010467', ('149', '164'))	('YAP', 'Gene', '10413', (138, 141))	('agar', 'Chemical', 'MESH:D000362', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('depletion', 'Var', (222, 231))	('depletion', 'Var', (6, 15))	('USP21', 'Gene', '27005', (0, 5))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (77, 87))	('expression', 'MPA', (154, 164))
70264	28969054	Thus, depletion of USP21 can increase YAP/TAZ activity and increase the ability of cells to grow in an anchorage independent manner.	('YAP', 'Gene', (38, 41))	('increase', 'PosReg', (29, 37))	('USP21', 'Gene', '27005', (19, 24))	('TAZ', 'Gene', '6901', (42, 45))	('depletion', 'Var', (6, 15))	('USP', 'molecular_function', 'GO:0051748', ('19', '22'))	('TAZ', 'Gene', (42, 45))	('YAP', 'Gene', '10413', (38, 41))	('USP21', 'Gene', (19, 24))	('increase', 'PosReg', (59, 67))
70282	28969054	Indeed, we observed that the intensity of USP21 protein down-regulation became less profound in more advanced cancers, suggesting that selection for regional amplification might lead to a secondary increase in USP21 concomitant with disease progression.	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('cancers', 'Disease', (110, 117))	('USP21', 'Gene', '27005', (210, 215))	('regulation', 'biological_process', 'GO:0065007', ('61', '71'))	('down-regulation', 'NegReg', (56, 71))	('protein', 'Protein', (48, 55))	('increase', 'PosReg', (198, 206))	('USP21', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('USP21', 'Gene', (210, 215))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('USP', 'molecular_function', 'GO:0051748', ('210', '213'))	('USP21', 'Gene', '27005', (42, 47))	('regional amplification', 'Var', (149, 171))	('USP', 'molecular_function', 'GO:0051748', ('42', '45'))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
70283	28969054	It is tempting to speculate that low USP21 may contribute to tumor formation early in cancer development, but that this effect might be obscured by secondary genetic changes including amplification of region 1q21.	('amplification', 'Var', (184, 197))	('contribute', 'Reg', (47, 57))	('USP21', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('low', 'Var', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('USP21', 'Gene', '27005', (37, 42))	('USP', 'molecular_function', 'GO:0051748', ('37', '40'))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('formation', 'biological_process', 'GO:0009058', ('67', '76'))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('tumor', 'Disease', (61, 66))	('cancer', 'Disease', (86, 92))
70291	28969054	Antibodies to MARK2 (#9118), phospho-MARK activation loop (#4836) YAP/TAZ (#8418), pYAP S127 (#4911), pYAP S397 (#13619), LATS1 (#9153), LATS2 (#13646), pLATS1/2 Thr1079/1041 (#8654), MOB1 (#3863), phosphor-MOB1 (Thr35, #8699), MST1 (#3682), phosho-MST1/2 (Thr183/180, #3681)) and Myc Tag (#2278) were from Cell Signaling Technology (Danvers, MA, USA).	('YAP', 'Gene', (103, 106))	('MARK2', 'Gene', (14, 19))	('LATS1', 'Gene', (122, 127))	('LATS1', 'Gene', (154, 159))	('#3863', 'Var', (190, 195))	('LATS1', 'Gene', '9113', (154, 159))	('LATS2', 'Gene', (137, 142))	('MST1', 'Gene', (249, 253))	('LATS2', 'Gene', '26524', (137, 142))	('LATS1', 'Gene', '9113', (122, 127))	('#13646', 'Var', (144, 150))	('TAZ', 'Gene', '6901', (70, 73))	('TAZ', 'Gene', (70, 73))	('Myc', 'Gene', '4609', (281, 284))	('LATS1/2', 'Gene', '9113;26524', (154, 161))	('#9153', 'Var', (129, 134))	('#3682', 'Var', (234, 239))	('MST1', 'Gene', '4485', (228, 232))	('LATS1/2', 'Gene', (154, 161))	('Signaling', 'biological_process', 'GO:0023052', ('312', '321'))	('#13619', 'Var', (113, 119))	('YAP', 'Gene', (84, 87))	('MOB1', 'Gene', '55233', (184, 188))	('MOB1', 'Gene', '55233', (207, 211))	('YAP', 'Gene', '10413', (103, 106))	('MARK2', 'Gene', '2011', (14, 19))	('MST1/2', 'Gene', '4485;6788', (249, 255))	('MARK', 'Gene', '4139', (14, 18))	('YAP', 'Gene', (66, 69))	('Thr1079', 'Chemical', '-', (162, 169))	('MST1', 'Gene', '4485', (249, 253))	('MST1/2', 'Gene', (249, 255))	('MOB1', 'Gene', (184, 188))	('MARK', 'Gene', (14, 18))	('MOB1', 'Gene', (207, 211))	('MARK', 'Gene', '4139', (37, 41))	('#2278', 'Var', (290, 295))	('Thr35', 'Var', (213, 218))	('MARK', 'Gene', (37, 41))	('YAP', 'Gene', '10413', (84, 87))	('Myc', 'Gene', (281, 284))	('MST1', 'Gene', (228, 232))	('Thr183/180', 'Var', (257, 267))	('YAP', 'Gene', '10413', (66, 69))
70292	28969054	Anti-USP21, anti-MARK1, anti-actin, HA-, and Myc-conjugated beads were from Sigma-Aldrich (St Louis, MO, USA).	('anti-actin', 'Var', (24, 34))	('Myc', 'Gene', '4609', (45, 48))	('USP21', 'Gene', '27005', (5, 10))	('USP', 'molecular_function', 'GO:0051748', ('5', '8'))	('Myc', 'Gene', (45, 48))	('MARK1', 'Gene', '4139', (17, 22))	('MARK1', 'Gene', (17, 22))	('USP21', 'Gene', (5, 10))
70320	32104684	In the present study, we found that LGK974 could inhibit proliferation and colony formation and induce apoptosis in ccRCC cells.	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('induce', 'Reg', (96, 102))	('ccRCC', 'Disease', (116, 121))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('ccRCC', 'Disease', 'MESH:D002292', (116, 121))	('colony formation', 'CPA', (75, 91))	('LGK974', 'Var', (36, 42))	('proliferation', 'CPA', (57, 70))	('apoptosis', 'CPA', (103, 112))	('inhibit', 'NegReg', (49, 56))	('formation', 'biological_process', 'GO:0009058', ('82', '91'))
70321	32104684	We also found that LGK974 could inhibit the migration and invasion of renal cell carcinoma and reduce the expression of mesenchymal markers.	('expression of', 'MPA', (106, 119))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (70, 90))	('reduce', 'NegReg', (95, 101))	('inhibit', 'NegReg', (32, 39))	('invasion of renal cell carcinoma', 'Disease', (58, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('LGK974', 'Var', (19, 25))	('migration', 'CPA', (44, 53))	('invasion of renal cell carcinoma', 'Disease', 'MESH:D002292', (58, 90))
70322	32104684	After treatment with LGK974, the expression level of beta-catenin, a key protein in the classical Wnt pathway, was significantly decreased, and the expression levels of the target genes cyclin D1, c-Myc, MMP9, and MMP2 in the Wnt signaling pathway were also significantly decreased, which represented a significant decrease in the activity of the Wnt signaling pathway.	('cyclin D1', 'Gene', '595', (186, 195))	('MMP2', 'Gene', '4313', (214, 218))	('decreased', 'NegReg', (272, 281))	('expression level', 'MPA', (33, 49))	('Wnt signaling pathway', 'Pathway', (347, 368))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('226', '247'))	('Wnt signaling pathway', 'Pathway', (226, 247))	('expression levels', 'MPA', (148, 165))	('decrease', 'NegReg', (315, 323))	('MMP9', 'Gene', (204, 208))	('MMP9', 'Gene', '4318', (204, 208))	('LGK974', 'Var', (21, 27))	('activity', 'MPA', (331, 339))	('beta-catenin', 'Gene', (53, 65))	('classical Wnt pathway', 'Pathway', (88, 109))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('347', '368'))	('c-Myc', 'Gene', (197, 202))	('MMP2', 'molecular_function', 'GO:0004228', ('214', '218'))	('MMP2', 'Gene', (214, 218))	('beta-catenin', 'Gene', '1499', (53, 65))	('MMP9', 'molecular_function', 'GO:0004229', ('204', '208'))	('cyclin', 'molecular_function', 'GO:0016538', ('186', '192'))	('cyclin D1', 'Gene', (186, 195))	('c-Myc', 'Gene', '4609', (197, 202))	('decreased', 'NegReg', (129, 138))
70324	32104684	In conclusion, our results indicate that LGK974 could significantly inhibit the progression of renal cancer cells in a safe concentration range, so PORCN may be a safe and effective target for patients with renal cancer.	('renal cancer', 'Disease', 'MESH:D007680', (95, 107))	('patients', 'Species', '9606', (193, 201))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('inhibit', 'NegReg', (68, 75))	('renal cancer', 'Disease', (207, 219))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('renal cancer', 'Disease', (95, 107))	('renal cancer', 'Phenotype', 'HP:0009726', (207, 219))	('renal cancer', 'Phenotype', 'HP:0009726', (95, 107))	('renal cancer', 'Disease', 'MESH:D007680', (207, 219))	('LGK974', 'Var', (41, 47))
70369	32104684	Gene mutations are often the cause of cancer.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('cause', 'Reg', (29, 34))	('Gene mutations', 'Var', (0, 14))
70370	32104684	In order to determine whether PORCN and its related genes have mutations in renal cell carcinoma, we conducted a study using the cBioportal online tool.	('mutations', 'Var', (63, 72))	('renal cell carcinoma', 'Disease', (76, 96))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (76, 96))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (76, 96))	('PORCN', 'Gene', (30, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
70371	32104684	The results showed that in addition to Wnt1 and Wnt2b, PORCN and other related genes have varying degrees of mutation in renal cell carcinoma (Figure 1(d)), which may mean that PORCN and its related genes will play an important role in renal cell carcinoma.	('renal cell carcinoma', 'Disease', 'MESH:D002292', (121, 141))	('renal cell carcinoma', 'Disease', (121, 141))	('Wnt2b', 'Gene', '7482', (48, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (121, 141))	('Wnt1', 'Gene', (39, 43))	('renal cell carcinoma', 'Disease', (236, 256))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (236, 256))	('PORCN', 'Gene', (55, 60))	('Wnt1', 'Gene', '7471', (39, 43))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (236, 256))	('Wnt2b', 'Gene', (48, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('mutation', 'Var', (109, 117))
70377	32104684	According to the research of Jun Liu et al., LGK974 did not show major cytotoxicity when the concentration was as high as 20 muM.	('LGK974', 'Var', (45, 51))	('cytotoxicity', 'Disease', (71, 83))	('muM', 'Gene', '56925', (125, 128))	('cytotoxicity', 'Disease', 'MESH:D064420', (71, 83))	('muM', 'Gene', (125, 128))
70378	32104684	We treated 786-O and ACHN cells with 5 muM, 10 muM, 15 muM, 20 muM LGK974, or vehicle control, respectively.	('muM', 'Gene', '56925', (63, 66))	('muM', 'Gene', (39, 42))	('muM', 'Gene', '56925', (55, 58))	('muM', 'Gene', (47, 50))	('ACHN', 'Gene', '55323', (21, 25))	('786-O', 'Chemical', '-', (11, 16))	('LGK974', 'Var', (67, 73))	('muM', 'Gene', (63, 66))	('muM', 'Gene', (55, 58))	('muM', 'Gene', '56925', (39, 42))	('ACHN', 'Gene', (21, 25))	('muM', 'Gene', '56925', (47, 50))
70379	32104684	We found that LGK974 significantly inhibits the growth of kidney cancer cells in a concentration-dependent manner (Figures 3(a) and 3(b)).	('growth', 'CPA', (48, 54))	('kidney cancer', 'Disease', 'MESH:D007680', (58, 71))	('LGK974', 'Var', (14, 20))	('kidney cancer', 'Phenotype', 'HP:0009726', (58, 71))	('inhibits', 'NegReg', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('kidney cancer', 'Disease', (58, 71))
70381	32104684	Our results showed that LGK974 kills ccRCC cells in a concentration-dependent and time-dependent manner.	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('ccRCC', 'Disease', (37, 42))	('ccRCC', 'Disease', 'MESH:D002292', (37, 42))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('LGK974', 'Var', (24, 30))
70383	32104684	We observed a significant decrease in colony-forming ability of 786-O and ACHN cells after LGK974 treatment (Figures 4(a) and 4(b)).	('treatment', 'Var', (98, 107))	('ACHN', 'Gene', '55323', (74, 78))	('decrease', 'NegReg', (26, 34))	('colony-forming ability', 'CPA', (38, 60))	('ACHN', 'Gene', (74, 78))	('LGK974 treatment', 'Var', (91, 107))	('786-O', 'Chemical', '-', (64, 69))
70384	32104684	Then, we demonstrated that LGK974 could significantly induce apoptosis in ACHN and 786 cell lines by flow cytometry (Figures 4(c) and 4(d)).	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('apoptosis', 'CPA', (61, 70))	('ACHN', 'Gene', '55323', (74, 78))	('ACHN', 'Gene', (74, 78))	('induce', 'PosReg', (54, 60))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))	('LGK974', 'Var', (27, 33))
70387	32104684	After drug treatment, the ratio of Bcl2/Bax decreased significantly (Figures 4(e) and 4(f)) which indicated that LGK974 induced apoptosis of ccRCC cells in vitro.	('ccRCC', 'Disease', 'MESH:D002292', (141, 146))	('Bcl2', 'molecular_function', 'GO:0015283', ('35', '39'))	('Bax', 'Gene', (40, 43))	('LGK974', 'Var', (113, 119))	('Bcl2', 'Gene', '596', (35, 39))	('decreased', 'NegReg', (44, 53))	('Bcl2', 'Gene', (35, 39))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('apoptosis', 'biological_process', 'GO:0097194', ('128', '137'))	('apoptosis', 'biological_process', 'GO:0006915', ('128', '137'))	('ccRCC', 'Phenotype', 'HP:0006770', (141, 146))	('ccRCC', 'Disease', (141, 146))	('Bax', 'Gene', '581', (40, 43))	('apoptosis', 'CPA', (128, 137))	('ratio', 'MPA', (26, 31))
70389	32104684	As shown by the wound healing assay, the results showed LGK974 could greatly inhibit the migration capacity of ACHN and 786-O cells (Figures 5(a)-5(c)).	('ACHN', 'Gene', (111, 115))	('LGK974', 'Var', (56, 62))	('inhibit', 'NegReg', (77, 84))	('ACHN', 'Gene', '55323', (111, 115))	('wound healing', 'biological_process', 'GO:0042060', ('16', '29'))	('786-O', 'Chemical', '-', (120, 125))
70390	32104684	In the transwell assay, we found that LGK974 could significantly inhibit the migration and invasion of renal cancer cells (Figures 5(d)-5(f)).	('invasion of renal cancer', 'Disease', 'MESH:D007680', (91, 115))	('invasion of renal cancer', 'Disease', (91, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('renal cancer', 'Phenotype', 'HP:0009726', (103, 115))	('inhibit', 'NegReg', (65, 72))	('LGK974', 'Var', (38, 44))
70392	32104684	As expected, LGK974 could significantly reduce the protein expression of N-cadherin, vimentin, and snail (Figures 5(g) and 5(h)).	('reduce', 'NegReg', (40, 46))	('vimentin', 'cellular_component', 'GO:0045099', ('85', '93'))	('protein expression', 'MPA', (51, 69))	('cadherin', 'molecular_function', 'GO:0008014', ('75', '83'))	('vimentin', 'cellular_component', 'GO:0045098', ('85', '93'))	('N-cadherin', 'Gene', (73, 83))	('vimentin', 'Gene', '7431', (85, 93))	('LGK974', 'Var', (13, 19))	('N-cadherin', 'Gene', '1000', (73, 83))	('snail', 'Protein', (99, 104))	('vimentin', 'Gene', (85, 93))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
70393	32104684	During this period, we found that the inhibitory effect of LGK974 on the invasion and migration of ACHN cells was not as obvious as that of 786-O at the same drug concentration.	('786-O', 'Chemical', '-', (140, 145))	('LGK974', 'Var', (59, 65))	('ACHN', 'Gene', '55323', (99, 103))	('ACHN', 'Gene', (99, 103))	('invasion', 'CPA', (73, 81))
70396	32104684	The results showed that LGK974 could reduce the expression of beta-catenin in cytoplasm, and LGK974 could significantly reduce the expression of cyclin D1, c-Myc (Figures 6(a)-6(c)), MMP9, and MMP2(Figure 6(d)).	('cyclin D1', 'Gene', (145, 154))	('MMP2', 'Gene', (193, 197))	('c-Myc', 'Gene', '4609', (156, 161))	('cytoplasm', 'cellular_component', 'GO:0005737', ('78', '87'))	('cyclin D1', 'Gene', '595', (145, 154))	('reduce', 'NegReg', (37, 43))	('expression', 'MPA', (48, 58))	('MMP2', 'Gene', '4313', (193, 197))	('beta-catenin', 'Gene', (62, 74))	('LGK974', 'Var', (93, 99))	('MMP2', 'molecular_function', 'GO:0004228', ('193', '197'))	('beta-catenin', 'Gene', '1499', (62, 74))	('MMP9', 'molecular_function', 'GO:0004229', ('183', '187'))	('MMP9', 'Gene', (183, 187))	('reduce', 'NegReg', (120, 126))	('MMP9', 'Gene', '4318', (183, 187))	('expression', 'MPA', (131, 141))	('LGK974', 'Var', (24, 30))	('c-Myc', 'Gene', (156, 161))	('cyclin', 'molecular_function', 'GO:0016538', ('145', '151'))
70399	32104684	The results of cell cycle analysis showed that compared with the control group, the number of 786-O cells and ACHN cells treated with LGK974 in the G1 phase was significantly increased (Figures 6(e) and 6(f)).	('ACHN', 'Gene', (110, 114))	('cell cycle', 'biological_process', 'GO:0007049', ('15', '25'))	('786-O', 'Chemical', '-', (94, 99))	('ACHN', 'Gene', '55323', (110, 114))	('G1 phase', 'biological_process', 'GO:0051318', ('148', '156'))	('LGK974', 'Var', (134, 140))	('increased', 'PosReg', (175, 184))
70401	32104684	In many other tumors, inhibition of PORCN has a good tumor-suppressing effect.	('inhibition', 'Var', (22, 32))	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('PORCN', 'Gene', (36, 41))
70406	32104684	In primary ovarian cancer ascites cells, the combination of LGK974 and carboplatin can significantly induce cytotoxicity and cell cycle arrest compared with monotherapy, not only that, LGK974 enhance the sensitivity of liver cancer to radiotherapy, and the combination of LGK974 and nilotinib (NIL) significantly enhances the ability to inhibit proliferation and colony formation of CML stem cells and progenitor cells and reduces their growth in immunodeficient mice in vivo.	('LGK974', 'Var', (185, 191))	('colony formation', 'CPA', (363, 379))	('liver cancer', 'Disease', 'MESH:D006528', (219, 231))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('nilotinib', 'Chemical', 'MESH:C498826', (283, 292))	('liver cancer', 'Phenotype', 'HP:0002896', (219, 231))	('reduces', 'NegReg', (423, 430))	('liver cancer', 'Disease', (219, 231))	('growth', 'CPA', (437, 443))	('carboplatin', 'Chemical', 'MESH:D016190', (71, 82))	('sensitivity', 'CPA', (204, 215))	('immunodeficient', 'Disease', 'MESH:D007153', (447, 462))	('mice', 'Species', '10090', (463, 467))	('proliferation', 'CPA', (345, 358))	('immunodeficient', 'Disease', (447, 462))	('ovarian cancer', 'Phenotype', 'HP:0100615', (11, 25))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('125', '142'))	('formation', 'biological_process', 'GO:0009058', ('370', '379'))	('cytotoxicity', 'Disease', (108, 120))	('LGK974', 'Var', (272, 278))	('enhance', 'PosReg', (192, 199))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (125, 142))	('ascites', 'Phenotype', 'HP:0001541', (26, 33))	('inhibit', 'NegReg', (337, 344))	('cytotoxicity', 'Disease', 'MESH:D064420', (108, 120))	('primary ovarian cancer ascites', 'Disease', (3, 33))	('primary ovarian cancer ascites', 'Disease', 'MESH:D010051', (3, 33))	('enhances', 'PosReg', (313, 321))
70408	32104684	found that PORCN inhibitors not only effectively induce tumor cell apoptosis but also inhibit their migration ability, and in many targets of Wnt pathway, PORCN and CBP are the most significant targets for tumor inhibition.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('CBP', 'Gene', '1387', (165, 168))	('CBP', 'Gene', (165, 168))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', (56, 61))	('PORCN', 'Gene', (11, 16))	('induce', 'PosReg', (49, 55))	('inhibitors', 'Var', (17, 27))	('inhibit', 'NegReg', (86, 93))	('migration ability', 'CPA', (100, 117))	('CBP', 'molecular_function', 'GO:0008140', ('165', '168'))	('apoptosis', 'biological_process', 'GO:0097194', ('67', '76'))	('apoptosis', 'biological_process', 'GO:0006915', ('67', '76'))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
70409	32104684	However, the antitumor effect produced by inhibiting PORCN is not obvious in some tumors and even produces a tumor-promoting effect.	('tumor', 'Disease', (17, 22))	('tumors', 'Disease', (82, 88))	('inhibiting', 'Var', (42, 52))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('PORCN', 'Gene', (53, 58))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (109, 114))
70410	32104684	For example, in Ewing sarcoma (ES), LGK974 inhibits cell migration ability well but does not inhibit tumor cell proliferation and primary tumor growth.	('ES', 'Phenotype', 'HP:0012254', (31, 33))	('ES', 'Disease', 'MESH:D012512', (31, 33))	('cell proliferation', 'biological_process', 'GO:0008283', ('107', '125'))	('tumor', 'Disease', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (16, 29))	('Ewing sarcoma', 'Disease', 'MESH:D012512', (16, 29))	('cell migration', 'biological_process', 'GO:0016477', ('52', '66'))	('LGK974', 'Var', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('cell migration ability', 'CPA', (52, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('inhibits', 'NegReg', (43, 51))	('Ewing sarcoma', 'Disease', (16, 29))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
70423	32104684	However, the inhibitory effect of LGK974 on ACHN is not as good as 786-O in inhibiting migration and invasion, which may be due to the fact that ACHN is a metastatic cell and conforms to the hypothesis that LGK974 suppresses the early steps of metastasis cascade reaction (such as migration and invasion).	('ACHN', 'Gene', '55323', (44, 48))	('suppresses', 'NegReg', (214, 224))	('ACHN', 'Gene', (145, 149))	('ACHN', 'Gene', (44, 48))	('invasion', 'CPA', (295, 303))	('LGK974', 'Var', (207, 213))	('inhibiting', 'NegReg', (76, 86))	('786-O', 'Chemical', '-', (67, 72))	('migration', 'CPA', (281, 290))	('ACHN', 'Gene', '55323', (145, 149))
70428	32104684	Further analysis showed that LGK974 could downregulate the activity of the Wnt/beta-catenin signaling pathway.	('activity', 'MPA', (59, 67))	('beta-catenin', 'Gene', '1499', (79, 91))	('LGK974', 'Var', (29, 35))	('signaling pathway', 'biological_process', 'GO:0007165', ('92', '109'))	('downregulate', 'NegReg', (42, 54))	('beta-catenin', 'Gene', (79, 91))
70463	29740587	When patients were stratified according to nodal status (namely, pN0 and pN1), pN0 patients had 1 year, 3 year and 5 year CSM-free survival rates of 89, 72 and 66%, conversely pN1 patients' CSM-free survival rates were 53, 20 and 9% (p < 0.01; Figure 2).	('pN1', 'Gene', (176, 179))	('patients', 'Species', '9606', (5, 13))	('pN0', 'Var', (79, 82))	('CSM-free', 'Disease', (122, 130))	('pN1', 'Gene', '5270', (176, 179))	('patients', 'Species', '9606', (83, 91))	('pN1', 'Gene', '5270', (73, 76))	('patients', 'Species', '9606', (180, 188))	('pN1', 'Gene', (73, 76))
70464	29740587	Median time to CSM in pN0 cM0 patients was 30 months.	('CSM', 'Disease', (15, 18))	('patients', 'Species', '9606', (30, 38))	('pN0 cM0', 'Var', (22, 29))
70480	29740587	According to Blute et al., among ccRCC patients, estimated CSM-free survival rates at 1-, 5- and 10 year follow-up were 95, 82 and 72.5% for pNx/pN0 patients and 52, 21 and 11% for pN +patients.	('CSM-free', 'Disease', (59, 67))	('RCC', 'Disease', (35, 38))	('patients', 'Species', '9606', (149, 157))	('patients', 'Species', '9606', (39, 47))	('pNx/pN0', 'Var', (141, 148))	('patients', 'Species', '9606', (185, 193))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
70525	29410711	In order to improve the current knowledge on circulating small non-coding RNAs and their diagnostic/prognostic relevance in ccRCC patients, we used small RNA sequencing to identify potential novel biomarkers and validated our findings in an independent cohort of ccRCC patients.	('ccRCC', 'Phenotype', 'HP:0006770', (263, 268))	('RNA', 'cellular_component', 'GO:0005562', ('154', '157'))	('patients', 'Species', '9606', (130, 138))	('small non-coding RNAs', 'Var', (57, 78))	('ccRCC', 'Phenotype', 'HP:0006770', (124, 129))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('patients', 'Species', '9606', (269, 277))	('RCC', 'Disease', 'MESH:C538614', (265, 268))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('RCC', 'Disease', (265, 268))	('RCC', 'Phenotype', 'HP:0005584', (265, 268))
70535	29410711	Additionally, 12 cycles of preamplification were performed with the Qiagen miScript PreAMP PCR Kit using a primer mix compiled of the pre-designed primer assays for the target miRNAs miR-122-5p (MS00003416), miR-193a-5p (MS00008932), and miR-206 (MS00003787) and the endogenous reference genes miR-16 (MS00006517), miR-191-5p (MS00003682), and miR-320a (MS00014707) and a custom designed primer assay for the piR-uc032och.1.	('miR-122-5p', 'Gene', '100188847', (183, 193))	('miR-320a', 'Gene', (344, 352))	('miR-16', 'Gene', '51573', (294, 300))	('MS00003416', 'Var', (195, 205))	('miR-206', 'Gene', '406989', (238, 245))	('miR-320a', 'Gene', '407037', (344, 352))	('MS00003682', 'Var', (327, 337))	('miR-122-5p', 'Gene', (183, 193))	('miR-191-5p', 'Gene', '100302129', (315, 325))	('miR-206', 'Gene', (238, 245))	('miR-191-5p', 'Gene', (315, 325))	('pre', 'molecular_function', 'GO:0003904', ('134', '137'))	('MS00003787', 'Var', (247, 257))	('miR-16', 'Gene', (294, 300))	('MS00014707', 'Var', (354, 364))	('MS00006517', 'Var', (302, 312))
70544	29410711	Most of these miRNAs have not been described dysregulated for RCC by now (e.g., miR-885-3p, miR-450a-2-3p, miR-483-5p, let-7f-1-3p, miR-193a-5p, miR-18a-3p, miR-1185-1-3p, miR-499a-5p, miR-485-3p, miR-125a-5p, miR-4446-3p).	('miR-18a-3p', 'Var', (145, 155))	('miR-499a-5p', 'Var', (172, 183))	('let-7f-1', 'Gene', (119, 127))	('miR-483-5p', 'Var', (107, 117))	('miR-193a-5p', 'Var', (132, 143))	('miR-885-3p', 'Var', (80, 90))	('miR-485-3p', 'Var', (185, 195))	('let-7f-1', 'Gene', '406888', (119, 127))	('miR-450a-2-3p', 'Var', (92, 105))	('miR-4446-3p', 'Var', (210, 221))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('miR-1185-1-3p', 'Var', (157, 170))	('miR-125a-5p', 'Var', (197, 208))
70547	29410711	Only piRNA uc032och.1 was significantly upregulated in serum of ccRCC patients (log2 FC 1.93, p < 0.001; see Additional file 1: Figure S1).	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('patients', 'Species', '9606', (70, 78))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('uc032och.1', 'Var', (11, 21))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('upregulated', 'PosReg', (40, 51))
70597	29410711	Thereby, they were able to point out a connection between modified miRNA expression in cancer tissues and the possibility to detect these miRNAs in serum samples.	('cancer', 'Disease', (87, 93))	('miRNA expression', 'MPA', (67, 83))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('modified', 'Var', (58, 66))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
70600	29410711	We were able to detect piRNA uc032och.1 at increased levels in serum of RCC patients via small RNA sequencing.	('patients', 'Species', '9606', (76, 84))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('RNA', 'cellular_component', 'GO:0005562', ('95', '98'))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('uc032och.1', 'Var', (29, 39))	('increased', 'PosReg', (43, 52))
70684	29656891	We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening.	('TERT', 'Gene', (53, 57))	('TERT', 'Gene', '7015', (53, 57))	('telomere', 'cellular_component', 'GO:0005696', ('110', '118'))	('MYC', 'Gene', '4609', (71, 74))	('MAD1', 'Gene', '4084', (79, 83))	('MAD1', 'Gene', (79, 83))	('targeting', 'Reg', (59, 68))	('MAD', 'biological_process', 'GO:0072671', ('79', '82'))	('point mutations', 'Var', (20, 35))	('MYC', 'Gene', (71, 74))	('telomere', 'cellular_component', 'GO:0000781', ('110', '118'))
70690	29656891	Novel hotspot of driver mutations in 5'-UTR repressor of TERT, expanding telomeres Most common cause of 3p loss is a chromothripsis event, generating concurrent 5q gain t(3;5) event occurs in childhood or adolescence, decades before tumor diagnosed Initial clonal expansion after 3p loss starts from only a few hundred cells  Combination of whole-genome sequencing analysis and a multi-region sampling approach provides insights into the nature and timing of key oncogenic events in clear cell renal cell carcinoma, depicts the evolutionary trajectories of tumors in patients and highlights the opportunity for early intervention.	('5q', 'Chemical', '-', (161, 163))	('tumors', 'Disease', (557, 563))	('mutations', 'Var', (24, 33))	('tumor', 'Disease', (233, 238))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (494, 514))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (483, 514))	('tumor', 'Disease', (557, 562))	('tumors', 'Disease', 'MESH:D009369', (557, 563))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor', 'Disease', 'MESH:D009369', (557, 562))	('patients', 'Species', '9606', (567, 575))	('clear cell renal cell carcinoma', 'Disease', (483, 514))	('carcinoma', 'Phenotype', 'HP:0030731', (505, 514))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('TERT', 'Gene', (57, 61))	('TERT', 'Gene', '7015', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (557, 562))	('tumors', 'Phenotype', 'HP:0002664', (557, 563))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (483, 514))
70695	29656891	The deleted region always encompasses four tumor suppressor genes that are frequent targets for inactivating point mutations on the other chromosomal copy: VHL (point mutations in 60%-70% patients; epigenetic silencing in a further 5%-10%), PBRM1 (40%), BAP1 (10%), and SETD2 (10%).	('point mutations', 'Var', (109, 124))	('SETD2', 'Gene', '29072', (270, 275))	('BAP1', 'Gene', (254, 258))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('43', '59'))	('SETD2', 'Gene', (270, 275))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('VHL', 'Gene', '7428', (156, 159))	('point mutations', 'Var', (161, 176))	('PBRM1', 'Gene', (241, 246))	('patients', 'Species', '9606', (188, 196))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor suppressor', 'biological_process', 'GO:0051726', ('43', '59'))	('epigenetic silencing', 'Var', (198, 218))	('PBRM1', 'Gene', '55193', (241, 246))	('tumor', 'Disease', (43, 48))	('BAP1', 'Gene', '8314', (254, 258))	('VHL', 'Gene', (156, 159))
70699	29656891	Interestingly, chromosome 3p loss and, when present, VHL point mutations are always on the trunk of the phylogenetic tree, suggesting that they are key early events in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('chromosome', 'cellular_component', 'GO:0005694', ('15', '25'))	('VHL', 'Gene', (53, 56))	('loss', 'NegReg', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('VHL', 'Gene', '7428', (53, 56))	('cancer', 'Disease', (168, 174))	('trunk', 'cellular_component', 'GO:0043198', ('91', '96'))	('point mutations', 'Var', (57, 72))
70703	29656891	In particular, multi-region sampling of the primary cancer and any metastases is used to generate high-resolution information on the timing of driver mutations, level of intratumoral heterogeneity, and presence of parallel evolution in each patient.	('tumor', 'Disease', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('metastases', 'Disease', (67, 77))	('patient', 'Species', '9606', (241, 248))	('mutations', 'Var', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('metastases', 'Disease', 'MESH:D009362', (67, 77))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
70709	29656891	The landscape of coding driver mutations and recurrent copy number alterations was typical for clear cell renal cell carcinoma (Figure 1B).	('mutations', 'Var', (31, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (95, 126))	('clear cell renal cell carcinoma', 'Disease', (95, 126))	('copy number alterations', 'Var', (55, 78))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (106, 126))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (95, 126))
70716	29656891	In chromophobe renal cancer, structural variants activating TERT are common, but we detected neither genomic rearrangements nor copy number aberrations near TERT in this cohort of clear cell renal cell carcinomas.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('carcinomas', 'Phenotype', 'HP:0030731', (202, 212))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (191, 212))	('TERT', 'Gene', '7015', (60, 64))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (191, 211))	('chromophobe renal cancer', 'Disease', 'MESH:D007680', (3, 27))	('TERT', 'Gene', (157, 161))	('TERT', 'Gene', '7015', (157, 161))	('activating', 'PosReg', (49, 59))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (180, 211))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (180, 212))	('chromophobe renal cancer', 'Disease', (3, 27))	('renal cancer', 'Phenotype', 'HP:0009726', (15, 27))	('variants', 'Var', (40, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (180, 212))	('clear cell renal cell carcinomas', 'Disease', (180, 212))	('TERT', 'Gene', (60, 64))
70724	29656891	In renal cancer cells, this element acts mainly as a repressor, a function that is abrogated by mutation of the binding site.	('repressor', 'MPA', (53, 62))	('renal cancer', 'Disease', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('mutation', 'Var', (96, 104))	('renal cancer', 'Phenotype', 'HP:0009726', (3, 15))	('binding', 'molecular_function', 'GO:0005488', ('112', '119'))	('renal cancer', 'Disease', 'MESH:D007680', (3, 15))
70725	29656891	The implication is that the mutations we observe diminish binding of a repressor, probably MAD1, to the E-box, leading to loss of the usual transcriptional suppression of TERT in kidney cells.	('transcriptional suppression', 'MPA', (140, 167))	('binding', 'Interaction', (58, 65))	('TERT', 'Gene', (171, 175))	('TERT', 'Gene', '7015', (171, 175))	('MAD1', 'Gene', '4084', (91, 95))	('binding', 'molecular_function', 'GO:0005488', ('58', '65'))	('MAD', 'biological_process', 'GO:0072671', ('91', '94'))	('loss', 'NegReg', (122, 126))	('mutations', 'Var', (28, 37))	('MAD1', 'Gene', (91, 95))	('diminish', 'NegReg', (49, 57))
70727	29656891	If the mutations act to abolish the active repression of TERT transcription, then samples carrying these mutations should have longer telomeres.	('TERT', 'Gene', (57, 61))	('abolish', 'NegReg', (24, 31))	('TERT', 'Gene', '7015', (57, 61))	('active repression', 'MPA', (36, 53))	('mutations', 'Var', (105, 114))	('transcription', 'biological_process', 'GO:0006351', ('62', '75'))	('mutations', 'Var', (7, 16))
70729	29656891	As predicted, samples with the canonical TERT promoter mutations and indeed those with 5' UTR mutations did, on average, have longer telomeres than wild-type samples (p = 0.031 and p = 0.0026, respectively) (Figure 2B, Table S5).	('longer', 'PosReg', (126, 132))	('mutations', 'Var', (55, 64))	('TERT', 'Gene', (41, 45))	('TERT', 'Gene', '7015', (41, 45))	('telomeres', 'CPA', (133, 142))
70733	29656891	The most frequent pattern of chromosome 3p loss in the cohort, affecting 13 (43%) of the 30 tumors with known 3p LOH breakpoints, was rearrangement between 3p and 5q.	('rearrangement', 'Var', (134, 147))	('5q', 'Chemical', '-', (163, 165))	('chromosome', 'cellular_component', 'GO:0005694', ('29', '39'))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('loss', 'NegReg', (43, 47))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (92, 98))
70743	29656891	In particular, clustered and interlocking rearrangements on chromosomes 3p and 5q confirm that chromothripsis is the predominant mechanism causing this critical driving event.	('chromothripsis', 'Disease', (95, 109))	('5q', 'Chemical', '-', (79, 81))	('rearrangements', 'Var', (42, 56))
70749	29656891	We were surprised that a complex event such as chromothripsis was the major process causing the copy number changes on chromosomes 3p and 5q, rather than say simple unbalanced translocation.	('5q', 'Chemical', '-', (138, 140))	('copy number changes', 'Var', (96, 115))	('causing', 'Reg', (84, 91))
70751	29656891	In fact, across patients, there was no obvious common region of chromothripsis on either 3p or 5q beyond the requirement to lose all four tumor suppressor genes on 3p and duplicate the terminal portion of 5q.	('lose', 'NegReg', (124, 128))	('duplicate', 'Var', (171, 180))	('tumor', 'Disease', (138, 143))	('tumor suppressor', 'biological_process', 'GO:0051726', ('138', '154'))	('patients', 'Species', '9606', (16, 24))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('138', '154'))	('5q', 'Chemical', '-', (205, 207))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('5q', 'Chemical', '-', (95, 97))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
70753	29656891	The key genes for the copy number gain on chromosome 5q remain mysterious, with several, including SQSTM1, proposed as targets.	('copy number', 'Var', (22, 33))	('SQSTM1', 'Gene', (99, 105))	('5q', 'Chemical', '-', (53, 55))	('SQSTM1', 'Gene', '8878', (99, 105))	('chromosome', 'cellular_component', 'GO:0005694', ('42', '52'))
70754	29656891	From the TCGA cohort, we identified genes with differential expression in patients with 5q gains versus those with baseline copy number (Figure S2B; Data S1).	('expression', 'MPA', (60, 70))	('patients', 'Species', '9606', (74, 82))	('5q gains', 'Var', (88, 96))	('5q', 'Chemical', '-', (88, 90))
70758	29656891	Third, within a given patient's tumor, different subclones have broadly similar mutation burdens (Figure 5A), suggesting that each subclone has been accumulating mutations at the same steady rate since clonal divergence.	('mutations', 'Var', (162, 171))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('patient', 'Species', '9606', (22, 29))
70760	29656891	The vast majority of mutations appear to arise from two mutational processes (so-called signatures 1 and 5) that are universal across cancer types and show linear correlation with age in both cancer and normal tissue.	('arise from', 'Reg', (41, 51))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('mutations', 'Var', (21, 30))
70763	29656891	We estimated the age at which the t(3;5) translocation events occurred from mutations on the duplicated region of chromosome 5q (Figures 5B and S4; Data S1).	('occurred', 'Reg', (62, 70))	('mutations', 'Var', (76, 85))	('chromosome', 'cellular_component', 'GO:0005694', ('114', '124'))	('5q', 'Chemical', '-', (125, 127))
70764	29656891	Mutations can be divided into four categories: those present on two copies of 5q (green points, Figure 5B), clonal mutations present on one copy of 5q (blue points), mutations that are subclonal in the cancer as a whole and are found in the given sample (orange points), and subclonal mutations absent from the given sample (purple points).	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('mutations', 'Var', (115, 124))	('mutations', 'Var', (166, 175))	('5q', 'Chemical', '-', (148, 150))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('5q', 'Chemical', '-', (78, 80))
70770	29656891	One patient (K135) had a t(3;9) unbalanced translocation with loss of 3p and gain of 9q, which we also estimated to have occurred early in childhood (Figure 5C).	('loss', 'NegReg', (62, 66))	('t(3', 'Var', (25, 28))	('gain', 'PosReg', (77, 81))	('patient', 'Species', '9606', (4, 11))
70772	29656891	Similarly, if we allowed for different periods of time for the clonal expansion between the occurrence of the last detectable mutation and tumor diagnosis, the estimated age of t(3;5) events did not increase.	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mutation', 'Var', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))
70778	29656891	If so, the clonal VHL and TERT driver mutations also seen in this tumor must have preceded the chromothripsis.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('VHL', 'Gene', '7428', (18, 21))	('TERT', 'Gene', (26, 30))	('tumor', 'Disease', (66, 71))	('TERT', 'Gene', '7015', (26, 30))	('mutations', 'Var', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('VHL', 'Gene', (18, 21))
70780	29656891	Germline mutations in VHL result in a syndrome known as von Hippel-Lindau disease, characterized by a high penetrance of clear cell renal cell carcinomas, together with hemangioblastomas of the retina, brain, and spine, and a handful of other tumor types.	('Germline mutations', 'Var', (0, 18))	('VHL', 'Gene', (22, 25))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (132, 152))	('hemangioblastomas', 'Disease', 'MESH:D018325', (169, 186))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (132, 153))	('tumor', 'Disease', (243, 248))	('spine', 'cellular_component', 'GO:0044309', ('213', '218'))	('VHL', 'Gene', '7428', (22, 25))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (121, 152))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (121, 153))	('clear cell renal cell carcinomas', 'Disease', (121, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (56, 81))	('result in', 'Reg', (26, 35))	('hemangioblastomas', 'Disease', (169, 186))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('von Hippel-Lindau disease', 'Disease', (56, 81))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (121, 153))
70785	29656891	As seen in the sporadic cases, we find clustered rearrangements between chromosomes 3p and 5q, reminiscent of chromothripsis and causing 3p loss and 5q gain (Figures 6A and S6).	('rearrangements', 'Var', (49, 63))	('5q', 'Chemical', '-', (149, 151))	('gain', 'PosReg', (152, 156))	('5q', 'Chemical', '-', (91, 93))	('loss', 'NegReg', (140, 144))
70787	29656891	Inactivating mutations were seen in the other key tumor suppressor genes on chromosome 3p, PBRM1, BAP1, and SETD2 (Figure 6B).	('BAP1', 'Gene', (98, 102))	('PBRM1', 'Gene', (91, 96))	('SETD2', 'Gene', (108, 113))	('PBRM1', 'Gene', '55193', (91, 96))	('chromosome', 'cellular_component', 'GO:0005694', ('76', '86'))	('Inactivating mutations', 'Var', (0, 22))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor suppressor', 'biological_process', 'GO:0051726', ('50', '66'))	('BAP1', 'Gene', '8314', (98, 102))	('SETD2', 'Gene', '29072', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('50', '66'))	('tumor', 'Disease', (50, 55))
70788	29656891	We identified one of the hotspot 5' UTR mutations in TERT in a VHL patient's tumor (Figure 2A).	('TERT', 'Gene', (53, 57))	('TERT', 'Gene', '7015', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('mutations', 'Var', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('VHL', 'Gene', (63, 66))	('tumor', 'Disease', (77, 82))	('VHL', 'Gene', '7428', (63, 66))	('patient', 'Species', '9606', (67, 74))
70789	29656891	Furthermore, as reported in the original paper, the overall burden of mutations increased linearly with age at a similar rate to our estimate in sporadic renal cancers, with similar inter-individual variation (Figure 6C).	('mutations', 'Var', (70, 79))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('renal cancer', 'Phenotype', 'HP:0009726', (154, 166))	('sporadic renal cancers', 'Disease', (145, 167))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('sporadic renal cancers', 'Disease', 'MESH:D007680', (145, 167))
70794	29656891	Knowing which mutations in VHL are driver mutations and the average rate of these mutations per cell per year, we can estimate how many cells with 3p loss must be present to generate the observed difference in age-incidence curves.	('mutations', 'Var', (14, 23))	('VHL', 'Gene', '7428', (27, 30))	('VHL', 'Gene', (27, 30))
70798	29656891	In our case, we know the target gene, VHL, and can directly estimate its rate of driver mutations: what we would like to know is the number of cells at risk after loss of chromosome 3p, namely the size of that initial clonal expansion after deletion of one copy of VHL, PBRM1, SETD2, and BAP1.	('VHL', 'Gene', '7428', (265, 268))	('chromosome', 'cellular_component', 'GO:0005694', ('171', '181'))	('PBRM1', 'Gene', (270, 275))	('PBRM1', 'Gene', '55193', (270, 275))	('loss', 'NegReg', (163, 167))	('SETD2', 'Gene', '29072', (277, 282))	('VHL', 'Gene', '7428', (38, 41))	('SETD2', 'Gene', (277, 282))	('BAP1', 'Gene', '8314', (288, 292))	('VHL', 'Gene', (38, 41))	('VHL', 'Gene', (265, 268))	('BAP1', 'Gene', (288, 292))	('deletion', 'Var', (241, 249))
70801	29656891	The incidence of sporadic clear cell renal cell carcinoma is treated as the sum of the same two waiting times plus an additional waiting time for acquisition of a somatic VHL driver mutation.	('sporadic clear cell renal cell carcinoma', 'Disease', (17, 57))	('sporadic clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (17, 57))	('VHL', 'Gene', (171, 174))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (37, 57))	('mutation', 'Var', (182, 190))	('VHL', 'Gene', '7428', (171, 174))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (26, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
70802	29656891	This latter waiting time is dependent on the number of susceptible cells, the variable of interest here, and the rate of acquisition of VHL driver mutations per year per cell.	('mutations', 'Var', (147, 156))	('VHL', 'Gene', (136, 139))	('VHL', 'Gene', '7428', (136, 139))
70803	29656891	We directly estimate this from the catalog of mutations in the COSMIC database, where we have a reasonably complete description of which point mutations in VHL can be drivers of clear cell renal cell carcinoma.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (178, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('point mutations', 'Var', (137, 152))	('VHL', 'Gene', '7428', (156, 159))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (178, 209))	('clear cell renal cell carcinoma', 'Disease', (178, 209))	('drivers', 'Reg', (167, 174))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (189, 209))	('VHL', 'Gene', (156, 159))
70804	29656891	Given this set of potential drivers, the sequence composition of the gene and the overall mutation rates and signatures observed in our study, we can calculate the rate at which VHL driver mutations occur per cell (STAR Methods).	('VHL', 'Gene', (178, 181))	('VHL', 'Gene', '7428', (178, 181))	('STAR', 'Gene', '6770', (215, 219))	('mutations', 'Var', (189, 198))	('STAR', 'Gene', (215, 219))
70805	29656891	This generates an estimate of 2.1 x 10-6 driver mutations in VHL per year per susceptible cell.	('VHL', 'Gene', '7428', (61, 64))	('VHL', 'Gene', (61, 64))	('mutations', 'Var', (48, 57))
70806	29656891	The waiting time from biallelic VHL inactivation to cancer diagnosis ranged from 15 to 30 years (Figure 7D), the wide range presumably reflecting differences in rate of tumor growth, acquisition of subclonal drivers, screening practices, and development of symptoms.	('VHL', 'Gene', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('VHL', 'Gene', '7428', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('inactivation', 'Var', (36, 48))
70807	29656891	We predict that after chromosome 3p loss in non-carriers, there would only be a few hundred cells with the potential to initiate a future clear cell renal cell carcinoma if a somatic VHL mutation were acquired (Figure 7C).	('VHL', 'Gene', '7428', (183, 186))	('chromosome', 'cellular_component', 'GO:0005694', ('22', '32'))	('clear cell renal cell carcinoma', 'Disease', (138, 169))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (149, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('loss', 'NegReg', (36, 40))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (138, 169))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (138, 169))	('mutation', 'Var', (187, 195))	('VHL', 'Gene', (183, 186))
70808	29656891	It is this population size that best explains the pronounced differences in penetrance and age of incidence between somatic and inherited cancers, given a VHL driver mutation rate of ~2 per million cells per year.	('VHL', 'Gene', '7428', (155, 158))	('inherited cancers', 'Disease', 'MESH:D009386', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('inherited cancers', 'Disease', (128, 145))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('mutation', 'Var', (166, 174))	('VHL', 'Gene', (155, 158))
70817	29656891	That the first somatic driver mutation would trigger only small clonal expansions has also been suggested by immunohistochemical studies in normal kidney tubules from von Hippel-Lindau disease.	('mutation', 'Var', (30, 38))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (167, 192))	('von Hippel-Lindau disease', 'Disease', (167, 192))
70818	29656891	The other critical event, always on the trunk of the phylogenetic tree, is inactivation of the second allele of VHL.	('inactivation', 'Var', (75, 87))	('VHL', 'Gene', '7428', (112, 115))	('trunk', 'cellular_component', 'GO:0043198', ('40', '45'))	('VHL', 'Gene', (112, 115))
70820	29656891	This suggests that point mutation of VHL typically occurs after 3p loss.	('VHL', 'Gene', '7428', (37, 40))	('point mutation', 'Var', (19, 33))	('occurs', 'Reg', (51, 57))	('VHL', 'Gene', (37, 40))
70821	29656891	Sometimes, there is another driver mutation on the trunk of the phylogenetic tree, drawn from a range of cancer genes, including PBRM1, SETD2, BAP1, TERT, the PI3K signaling pathway and other cytogenetic abnormalities.	('BAP1', 'Gene', (143, 147))	('PBRM1', 'Gene', (129, 134))	('PBRM1', 'Gene', '55193', (129, 134))	('TERT', 'Gene', '7015', (149, 153))	('PI3K signaling', 'biological_process', 'GO:0014065', ('159', '173'))	('cancer', 'Disease', (105, 111))	('PI3K signaling pathway', 'Pathway', (159, 181))	('SETD2', 'Gene', '29072', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('SETD2', 'Gene', (136, 141))	('trunk', 'cellular_component', 'GO:0043198', ('51', '56'))	('signaling pathway', 'biological_process', 'GO:0007165', ('164', '181'))	('mutation', 'Var', (35, 43))	('BAP1', 'Gene', '8314', (143, 147))	('TERT', 'Gene', (149, 153))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('PI3K', 'molecular_function', 'GO:0016303', ('159', '163'))
70823	29656891	Once acquired, these truncal driver mutations trigger a substantial clonal expansion:at this stage, the nascent tumor has a sufficient population size that mutation rate is no longer rate-limiting, which may explain why parallel evolution is so frequently observed in the later stages of renal cancer development.	('renal cancer', 'Disease', 'MESH:D007680', (288, 300))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('mutations', 'Var', (36, 45))	('renal cancer', 'Disease', (288, 300))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('renal cancer', 'Phenotype', 'HP:0009726', (288, 300))
70827	29656891	In support of this, several studies published recently have shown that bystander genes can be relevant therapeutic targets in cancers with deletions of specific tumor suppressor genes.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('161', '177'))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('tumor', 'Disease', (161, 166))	('tumor suppressor', 'biological_process', 'GO:0051726', ('161', '177'))	('deletions', 'Var', (139, 148))
70831	29656891	For those of us who have inherited a faulty VHL allele, the eventual germination of one or more of these seeds is virtually inevitable within the human lifespan.	('VHL', 'Gene', (44, 47))	('germination', 'biological_process', 'GO:0009844', ('69', '80'))	('human', 'Species', '9606', (146, 151))	('faulty', 'Var', (37, 43))	('VHL', 'Gene', '7428', (44, 47))
70839	29656891	Single-nucleotide substitutions were called using the CaVEMan (cancer variants through expectation maximization) algorithm (https://github.com/cancerit/CaVEMan).	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('Single-nucleotide substitutions', 'Var', (0, 31))	('cancer', 'Disease', (63, 69))
70860	29656891	The fraction of cells carrying a given mutation is modeled by a Dirichlet process with an adjustment for the decreased sensitivity in identifying mutations in lower tumor fractions.	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('mutation', 'Var', (39, 47))	('tumor', 'Disease', (165, 170))
70863	29656891	As an illustration, imagine a tumor with two major subclones that diverged at 50% of molecular time, with the two subclonal lineages accumulating mutations equally and at the same rate as before the most recent common ancestor (MRCA).	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('mutations', 'Var', (146, 155))	('tumor', 'Disease', 'MESH:D009369', (30, 35))
70870	29656891	From this, we calculate whether the mutation was acquired prior to the duplication of chromosome 5q (if it was, the CCF will be close to 2; if not, CCF ~ = 1).	('duplication', 'Var', (71, 82))	('CCF', 'Gene', (148, 151))	('CCF', 'Gene', '5307', (148, 151))	('chromosome', 'cellular_component', 'GO:0005694', ('86', '96'))	('CCF', 'Gene', (116, 119))	('5q', 'Chemical', '-', (97, 99))	('CCF', 'Gene', '5307', (116, 119))
70872	29656891	The first is to use the number of chromosome 5q mutations that are clonal and acquired before the 5q duplication relative to the number that are clonal but acquired after duplication (correcting for the fact that post-duplication there is an extra copy of 5q and hence the mutation burden accumulates more quickly).	('chromosome', 'cellular_component', 'GO:0005694', ('34', '44'))	('5q', 'Chemical', '-', (45, 47))	('5q', 'Chemical', '-', (256, 258))	('chromosome 5q', 'Gene', (34, 47))	('5q', 'Chemical', '-', (98, 100))	('mutations', 'Var', (48, 57))
70875	29656891	We apply two similar methods to estimate the age of occurrence of the t(3;5) gain: To estimate the average rate of driver mutations in VHL, we estimate separately the rate of substitutions and indels.	('VHL', 'Gene', '7428', (135, 138))	('VHL', 'Gene', (135, 138))	('mutations', 'Var', (122, 131))	('substitutions', 'Var', (175, 188))
70877	29656891	We then take the length and sequence composition of the coding DNA sequence (CDS) of VHL and generate all possible substitutions, and from this extract the set of all possible amino acid consequences arising from substitutions along the length of VHL.	('substitutions', 'Var', (115, 128))	('VHL', 'Gene', (85, 88))	('VHL', 'Gene', (247, 250))	('VHL', 'Gene', '7428', (247, 250))	('VHL', 'Gene', '7428', (85, 88))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('substitutions', 'Var', (213, 226))
70878	29656891	From this, we define the set of all possible driver substitutions as any substitutions that are: start-lost, stop-lost, stop-gained or a member of the set of previously observed amino acid substitutions in VHL recorded in clear cell renal cell carcinomas in the COSMIC database.	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (222, 254))	('substitutions', 'Var', (52, 65))	('clear cell renal cell carcinomas', 'Disease', (222, 254))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (222, 254))	('carcinomas', 'Phenotype', 'HP:0030731', (244, 254))	('VHL', 'Gene', (206, 209))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (233, 254))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (233, 253))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (222, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('VHL', 'Gene', '7428', (206, 209))
70881	29656891	We then assume that all indels within the CDS of VHL are driver mutations.	('indels', 'Var', (24, 30))	('VHL', 'Gene', '7428', (49, 52))	('VHL', 'Gene', (49, 52))
70884	29656891	The other key event that occurs early in the evolution of sporadic ccRCC is inactivation of the other allele of VHL, typically through point mutation (notwithstanding the role of epigenetic silencing) - this is an obligatory early event, because it is both highly recurrent across patients (> 75%) and always present on the trunk of the phylogenetic tree.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('RCC', 'Disease', (69, 72))	('patients', 'Species', '9606', (281, 289))	('point', 'Var', (135, 140))	('VHL', 'Gene', (112, 115))	('VHL', 'Gene', '7428', (112, 115))	('trunk', 'cellular_component', 'GO:0043198', ('324', '329'))
70885	29656891	Furthermore, exploring the genomic features of ccRCC that have occurred in the setting of inherited VHL mutations reveals many similarities with sporadic ccRCC, and analyzed further here.	('RCC', 'Disease', (49, 52))	('mutations', 'Var', (104, 113))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('ccRCC', 'Phenotype', 'HP:0006770', (154, 159))	('RCC', 'Disease', (156, 159))	('VHL', 'Gene', (100, 103))	('VHL', 'Gene', '7428', (100, 103))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
70892	29656891	From the difference in age-incidence curves between VHL carriers and sporadic kidney cancers, and the known VHL driver mutation rate per cell per year, we can estimate how many cells that are susceptible to initiating ccRCC carry chromosome 3p loss during adulthood.	('kidney cancers', 'Phenotype', 'HP:0009726', (78, 92))	('chromosome 3p', 'Var', (230, 243))	('VHL', 'Gene', '7428', (52, 55))	('VHL', 'Gene', '7428', (108, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (218, 223))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('chromosome', 'cellular_component', 'GO:0005694', ('230', '240'))	('sporadic kidney cancers', 'Disease', (69, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('sporadic kidney cancers', 'Disease', 'MESH:D007680', (69, 92))	('VHL', 'Gene', (52, 55))	('kidney cancer', 'Phenotype', 'HP:0009726', (78, 91))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('loss', 'NegReg', (244, 248))	('RCC', 'Disease', (220, 223))	('VHL', 'Gene', (108, 111))
70894	29656891	The broad concept for modeling the age-incidence curves is to treat sporadic ccRCC as the sum of three independent waiting times (time to 3p loss; time from 3p loss to VHL inactivation; time from biallelic VHL loss to diagnosed kidney cancer, Figure 7A).	('VHL', 'Gene', '7428', (206, 209))	('VHL loss', 'Disease', 'MESH:D006623', (206, 214))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('VHL loss', 'Disease', (206, 214))	('VHL', 'Gene', (168, 171))	('kidney cancer', 'Disease', 'MESH:D007680', (228, 241))	('VHL', 'Gene', (206, 209))	('VHL', 'Gene', '7428', (168, 171))	('biallelic', 'Var', (196, 205))	('kidney cancer', 'Phenotype', 'HP:0009726', (228, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('kidney cancer', 'Disease', (228, 241))	('RCC', 'Disease', (79, 82))
70895	29656891	We treat ccRCC in carriers of VHL as the sum of two independent waiting times, with the same distribution as in sporadic cases (time to 3p loss; time from 3p loss to diagnosed kidney cancer).	('carriers', 'Var', (18, 26))	('kidney cancer', 'Phenotype', 'HP:0009726', (176, 189))	('VHL', 'Gene', (30, 33))	('kidney cancer', 'Disease', 'MESH:D007680', (176, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('VHL', 'Gene', '7428', (30, 33))	('ccRCC', 'Phenotype', 'HP:0006770', (9, 14))	('kidney cancer', 'Disease', (176, 189))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))
70899	29656891	That is:where  with  as as the number of cells in the clone after chromosome 3p loss and  as the VHL driver mutation rate per cell per year.	('chromosome', 'cellular_component', 'GO:0005694', ('66', '76'))	('VHL', 'Gene', '7428', (97, 100))	('loss', 'NegReg', (80, 84))	('mutation', 'Var', (108, 116))	('VHL', 'Gene', (97, 100))
70903	29656891	Third, we do make the assumption that the order of events is chromosome 3p loss, followed by VHL point mutation, followed by other driver mutations, clonal expansion and diagnosis.	('VHL', 'Gene', '7428', (93, 96))	('chromosome', 'Var', (61, 71))	('point mutation', 'Var', (97, 111))	('loss', 'NegReg', (75, 79))	('chromosome', 'cellular_component', 'GO:0005694', ('61', '71'))	('VHL', 'Gene', (93, 96))
70904	29656891	Given that we are estimating a clone size of several hundred cells after chromosome 3p loss, it is statistically much more likely that the VHL mutation will occur after this clonal expansion than in the one cell before chromosome 3p loss (inherent in this is the assumption that the rate of chromosome 3p loss through, for example, chromothripsis involving chromosomes 3p and 5q is much lower than that of VHL driver point mutations).	('loss', 'NegReg', (87, 91))	('chromosome', 'cellular_component', 'GO:0005694', ('73', '83'))	('VHL', 'Gene', (406, 409))	('VHL', 'Gene', (139, 142))	('VHL', 'Gene', '7428', (406, 409))	('VHL', 'Gene', '7428', (139, 142))	('5q', 'Chemical', '-', (376, 378))	('mutation', 'Var', (143, 151))	('chromosome', 'cellular_component', 'GO:0005694', ('219', '229'))	('loss', 'NegReg', (305, 309))	('chromosome', 'cellular_component', 'GO:0005694', ('291', '301'))	('occur', 'Reg', (157, 162))
70908	29656891	Mathematical detail, code, and worked examples for the estimation of mutation rate per year and ages at which landmark events occur, the rate of VHL driver mutations, and the models of age-incidence curves for sporadic & inherited ccRCC are available in Data S1.	('mutations', 'Var', (156, 165))	('ccRCC', 'Phenotype', 'HP:0006770', (231, 236))	('RCC', 'Disease', 'MESH:C538614', (233, 236))	('VHL', 'Gene', (145, 148))	('RCC', 'Disease', (233, 236))	('inherited', 'Disease', (221, 230))	('VHL', 'Gene', '7428', (145, 148))
70911	31722744	BRM (BRAHMA) is a core, SWI2/SNF2-type ATPase subunit of SWI/SNF chromatin-remodelling complex (CRC) involved in various important regulatory processes including development.	('core', 'cellular_component', 'GO:0019013', ('18', '22'))	('chromatin-remodelling', 'biological_process', 'GO:0006338', ('65', '86'))	('SWI2', 'Gene', '6595', (24, 28))	('SWI2', 'Gene', (24, 28))	('ATPase', 'Gene', '1769', (39, 45))	('SWI/SNF', 'Var', (57, 64))	('BRAHMA', 'Gene', (5, 11))	('ATPase', 'Gene', (39, 45))	('chromatin-remodelling complex', 'cellular_component', 'GO:0016585', ('65', '94'))	('BRAHMA', 'Gene', '39744', (5, 11))
70912	31722744	Mutations in SMARCA2, a BRM-encoding gene as well as overexpression or epigenetic silencing were found in various human diseases including cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('found', 'Reg', (97, 102))	('SMARCA2', 'Gene', (13, 20))	('SMARCA2', 'Gene', '6595', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('Mutations', 'Var', (0, 9))	('human', 'Species', '9606', (114, 119))	('epigenetic silencing', 'Var', (71, 91))	('cancer', 'Disease', (139, 145))
70913	31722744	Missense mutations in SMARCA2 gene were recently connected with occurrence of Nicolaides-Baraitser genetics syndrome.	('SMARCA2', 'Gene', (22, 29))	('SMARCA2', 'Gene', '6595', (22, 29))	('Nicolaides-Baraitser genetics syndrome', 'Disease', (78, 116))	('connected', 'Reg', (49, 58))	('Missense mutations', 'Var', (0, 18))
70914	31722744	By contrast, SMARCA2 duplication rather than mutations is characteristic for Coffin-Siris syndrome.	('Coffin-Siris syndrome', 'Disease', (77, 98))	('Coffin-Siris syndrome', 'Disease', 'MESH:C536436', (77, 98))	('SMARCA2', 'Gene', (13, 20))	('SMARCA2', 'Gene', '6595', (13, 20))	('duplication', 'Var', (21, 32))
70918	31722744	Therefore, the summary of recent knowledge regarding BRM alteration in various types of cancer and highlighting of differences and commonalities between BRM and BRG1, another SWI2/SNF2 type ATPase, will lead to better understanding of SWI/SNF CRCs function in cancer development/progression.	('cancer', 'Disease', (88, 94))	('alteration', 'Var', (57, 67))	('SWI2', 'Gene', '6595', (175, 179))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('SWI2', 'Gene', (175, 179))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('ATPase', 'Gene', '1769', (190, 196))	('cancer', 'Disease', (260, 266))	('BRG1', 'Gene', (161, 165))	('ATPase', 'Gene', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))
70935	31722744	This hypothesis has been supported by mouse models where Brm-knockout (Brm-/-) mice lived until adulthood and developed tumours while Brg1-/- null mutants caused embryonic lethality.	('mouse', 'Species', '10090', (38, 43))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('mice', 'Species', '10090', (79, 83))	('Brg1-/-', 'Gene', (134, 141))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('tumours', 'Disease', (120, 127))	('embryonic lethality', 'Disease', 'MESH:D020964', (162, 181))	('embryonic lethality', 'Disease', (162, 181))	('mutants', 'Var', (147, 154))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
70940	31722744	In this case, the concomitant depletion of Brm and Brg1 resulted in severe cardiac dysfunction associated with glycogen accumulation and mitochondrial defects, eventually leading to death.	('resulted in', 'Reg', (56, 67))	('depletion', 'Var', (30, 39))	('Brm', 'Gene', (43, 46))	('glycogen accumulation', 'MPA', (111, 132))	('mitochondrial defects', 'Disease', (137, 158))	('cardiac dysfunction', 'Disease', (75, 94))	('mitochondrial defects', 'Disease', 'MESH:D028361', (137, 158))	('leading to', 'Reg', (171, 181))	('Brg1', 'Gene', (51, 55))	('cardiac dysfunction', 'Disease', 'MESH:D006331', (75, 94))
70942	31722744	The double-knockout mice Brm-/-/Brg1-/- exhibited an unexpected ability to overcome loss of both ATPases.	('ATPase', 'Gene', '1769', (97, 103))	('ATPase', 'Gene', (97, 103))	('mice', 'Species', '10090', (20, 24))	('Brm-/-/Brg1-/-', 'Var', (25, 39))
70945	31722744	The loss of human BRM or BRG1 consequently leads to the modified expression of genes that are significant for tumour development, e.g.	('modified', 'Reg', (56, 64))	('expression of genes', 'MPA', (65, 84))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('BRM', 'Gene', (18, 21))	('human', 'Species', '9606', (12, 17))	('BRG1', 'Gene', (25, 29))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Disease', (110, 116))	('leads to', 'Reg', (43, 51))	('loss', 'Var', (4, 8))
70949	31722744	In human heterozygous missense, mutations in BRM-encoding SMARCA2 gene were identified in patients with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes.	('identified', 'Reg', (76, 86))	('SMARCA2', 'Gene', (58, 65))	('SMARCA2', 'Gene', '6595', (58, 65))	('human', 'Species', '9606', (3, 8))	('Coffin-Siris', 'Disease', (104, 116))	('mutations', 'Var', (32, 41))	('Nicolaides-Baraitser', 'Disease', (127, 147))	('patients', 'Species', '9606', (90, 98))
70950	31722744	Although the last study performed on a large cohort of CSS patients proved that they carry the missense mutation in SMARCA4 (BRG1 encoding gene) gene but not in BRM-encoding SMARCA2 gene.	('SMARCA4', 'Gene', (116, 123))	('SMARCA2', 'Gene', (174, 181))	('SMARCA2', 'Gene', '6595', (174, 181))	('SMARCA4', 'Gene', '6597', (116, 123))	('patients', 'Species', '9606', (59, 67))	('missense mutation', 'Var', (95, 112))	('CSS', 'Disease', (55, 58))
70951	31722744	In some CSS patients, duplication of the SMARCA2 gene was detected.	('CSS', 'Disease', (8, 11))	('patients', 'Species', '9606', (12, 20))	('duplication', 'Var', (22, 33))	('detected', 'Reg', (58, 66))	('SMARCA2', 'Gene', (41, 48))	('SMARCA2', 'Gene', '6595', (41, 48))
70952	31722744	On the other hand, missense mutations in SMARCA2 were detected in NCBRS patients.	('NCBRS', 'Disease', (66, 71))	('detected', 'Reg', (54, 62))	('SMARCA2', 'Gene', (41, 48))	('SMARCA2', 'Gene', '6595', (41, 48))	('missense mutations', 'Var', (19, 37))	('patients', 'Species', '9606', (72, 80))
70953	31722744	Moreover, one individual with SMARCA2 mutation was previously diagnosed with CSS and after was reclassified for NCBRS.	('SMARCA2', 'Gene', '6595', (30, 37))	('SMARCA2', 'Gene', (30, 37))	('mutation', 'Var', (38, 46))	('CSS', 'Disease', (77, 80))
70954	31722744	This collectively suggests that missense mutations in SMARCA4 and SMARCA2 may cause different developmental disabilities, although both CSS and NCBRS syndromes share some similar developmental dysfunctions and their distinction is based mostly on foot and hand features (Fig.	('developmental dysfunctions', 'Disease', 'MESH:D012735', (179, 205))	('cause', 'Reg', (78, 83))	('missense mutations', 'Var', (32, 50))	('SMARCA4', 'Gene', '6597', (54, 61))	('SMARCA2', 'Gene', (66, 73))	('developmental disabilities', 'Disease', (94, 120))	('SMARCA2', 'Gene', '6595', (66, 73))	('developmental dysfunctions', 'Disease', (179, 205))	('CSS', 'Disease', (136, 139))	('SMARCA4', 'Gene', (54, 61))	('developmental disabilities', 'Disease', 'MESH:D002658', (94, 120))	('developmental disabilities', 'Phenotype', 'HP:0001263', (94, 120))
70956	31722744	Although, in CSS the duplication of SMARCA2 gene may lead to overexpression of BRM protein and as a consequence altered SWI/SNF stoichiometry caused by the pathological competition of BRM with BRG1 ATPase.	('SMARCA2', 'Gene', (36, 43))	('lead to', 'Reg', (53, 60))	('SMARCA2', 'Gene', '6595', (36, 43))	('BRM protein', 'Protein', (79, 90))	('overexpression', 'MPA', (61, 75))	('ATPase', 'Gene', '1769', (198, 204))	('SWI/SNF stoichiometry', 'MPA', (120, 141))	('duplication', 'Var', (21, 32))	('ATPase', 'Gene', (198, 204))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('altered', 'Reg', (112, 119))
70957	31722744	In NCBRS, the missense mutations in SMARCA2 may result in BRM gain-of-function or loss of function, i.e.	('loss of function', 'NegReg', (82, 98))	('SMARCA2', 'Gene', (36, 43))	('SMARCA2', 'Gene', '6595', (36, 43))	('NCBRS', 'Disease', (3, 8))	('missense mutations', 'Var', (14, 32))	('gain-of-function', 'PosReg', (62, 78))
70958	31722744	The exact role of SMARCA2 missense mutations or duplication during development is still unclear; however, the SMARCA2 polymorphisms may lead to higher cancer risk, suggesting the role of human BRM as a cancer susceptibility gene, similarly to mice.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lead to', 'Reg', (136, 143))	('higher', 'PosReg', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('SMARCA2', 'Gene', (110, 117))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', (202, 208))	('SMARCA2', 'Gene', (18, 25))	('SMARCA2', 'Gene', '6595', (110, 117))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('polymorphisms', 'Var', (118, 131))	('human', 'Species', '9606', (187, 192))	('SMARCA2', 'Gene', '6595', (18, 25))	('missense', 'Var', (26, 34))	('mice', 'Species', '10090', (243, 247))
70974	31722744	BRG1 knock-down handicaps TP53 binding to p21 promoter although BRM has ability to replace BRG1 in TP53 regulation.	('TP53', 'Gene', (26, 30))	('TP53', 'Gene', (99, 103))	('knock-down', 'Var', (5, 15))	('binding', 'Interaction', (31, 38))	('p21', 'Gene', (42, 45))	('p21', 'Gene', '644914', (42, 45))	('TP53', 'Gene', '7157', (99, 103))	('binding', 'molecular_function', 'GO:0005488', ('31', '38'))	('regulation', 'biological_process', 'GO:0065007', ('104', '114'))	('TP53', 'Gene', '7157', (26, 30))	('BRG1', 'Gene', (0, 4))
70975	31722744	Interestingly, mice lacking Brm did not present pathological Tp53 mutations in tumours, although such mutations were accumulated in Brm-positive tumours, suggesting that loss of Brm would restrain selection of Tp53-mutated variant in tumour evolution.	('Brm', 'Gene', (178, 181))	('tumours', 'Phenotype', 'HP:0002664', (145, 152))	('tumours', 'Disease', 'MESH:D009369', (145, 152))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('tumour', 'Disease', 'MESH:D009369', (234, 240))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('tumour', 'Disease', (234, 240))	('tumours', 'Disease', (79, 86))	('tumour', 'Disease', (145, 151))	('loss', 'Var', (170, 174))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('tumours', 'Disease', 'MESH:D009369', (79, 86))	('restrain', 'NegReg', (188, 196))	('Tp53', 'Gene', (61, 65))	('Tp53', 'Gene', (210, 214))	('Tp53', 'Gene', '22059', (61, 65))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('Tp53', 'Gene', '22059', (210, 214))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('mice', 'Species', '10090', (15, 19))	('selection', 'MPA', (197, 206))	('tumours', 'Disease', (145, 152))	('tumour', 'Disease', (79, 85))
70977	31722744	histone 2B phosphorylation on Ser36 which promotes BRM involvement in this process.	('promotes', 'PosReg', (42, 50))	('phosphorylation', 'biological_process', 'GO:0016310', ('11', '26'))	('BRM', 'Disease', (51, 54))	('Ser', 'cellular_component', 'GO:0005790', ('30', '33'))	('phosphorylation', 'Var', (11, 26))	('Ser', 'Chemical', 'MESH:C530429', (30, 33))	('histone 2B', 'Protein', (0, 10))
70984	31722744	The importance of an altered level and/or aberrant function of BRM in various cancers is not fully understood, although there is abundant evidence indicating the crucial BRM role in carcinogenesis.	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('carcinogenesis', 'Disease', 'MESH:D063646', (182, 196))	('aberrant', 'Var', (42, 50))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('carcinogenesis', 'Disease', (182, 196))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
70985	31722744	About 15% of all cancers display numerous aberrations in BRM abundance or impairment, that may lead to cancer development or progression (Fig.	('lead to', 'Reg', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('aberrations', 'Var', (42, 53))	('impairment', 'MPA', (74, 84))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancer', 'Disease', (17, 23))	('cancers', 'Disease', (17, 24))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
70987	31722744	The mutations in SMARCB1 an INI1/SNF5/BAF47-encoding gene were found in this type of cancer, suggesting the mutation in a gene encoding core SNF5-type subunit of SWI/SNF CRCs as a driving mutation for this cancer type.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('BAF47', 'Gene', '6598', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('SNF5', 'Gene', (141, 145))	('SNF5', 'Gene', (33, 37))	('BAF47', 'Gene', (38, 43))	('SNF5', 'Gene', '6598', (141, 145))	('cancer', 'Disease', (85, 91))	('INI1', 'Gene', (28, 32))	('SMARCB1', 'Gene', (17, 24))	('SMARCB1', 'Gene', '6598', (17, 24))	('mutation', 'Var', (108, 116))	('SNF5', 'Gene', '6598', (33, 37))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('core', 'cellular_component', 'GO:0019013', ('136', '140'))	('INI1', 'Gene', '6598', (28, 32))
70988	31722744	This INI1 alteration was accompanied by BRM epigenetic silencing in about 70% of MRT cases.	('INI1', 'Gene', (5, 9))	('INI1', 'Gene', '6598', (5, 9))	('MRT', 'Disease', 'MESH:D018335', (81, 84))	('MRT', 'Disease', (81, 84))	('alteration', 'Var', (10, 20))
70989	31722744	BRM was silenced by the HDAC-driven mechanism or by SMARCA2 promoter polymorphisms.	('HDAC', 'Gene', '9734', (24, 28))	('silenced', 'NegReg', (8, 16))	('HDAC', 'Gene', (24, 28))	('polymorphisms', 'Var', (69, 82))	('SMARCA2', 'Gene', (52, 59))	('SMARCA2', 'Gene', '6595', (52, 59))
71002	31722744	On the other hand, targeting BRM in the BRG1-deficient lung cancer (NSCLC) sensitised cancer cells (cell lines) to radiotherapy.	('targeting', 'Var', (19, 28))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('BRG1-deficient', 'Gene', (40, 54))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (60, 66))	('LC', 'Phenotype', 'HP:0100526', (71, 73))	('lung cancer', 'Disease', (55, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('deficient lung', 'Phenotype', 'HP:0002089', (45, 59))	('cancer', 'Disease', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('BRM', 'Gene', (29, 32))	('NSCLC', 'Disease', (68, 73))
71009	31722744	In BRM-deficient ccRCC tumours almost 90% cases displayed genetic alterations in the SMARCA2 gene, such as mutations, promoter methylation or chromosomal aberrations.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('mutations', 'Var', (107, 116))	('SMARCA2', 'Gene', (85, 92))	('tumours', 'Disease', 'MESH:D009369', (23, 30))	('SMARCA2', 'Gene', '6595', (85, 92))	('promoter', 'MPA', (118, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (17, 22))	('chromosomal aberrations', 'Var', (142, 165))	('tumours', 'Disease', (23, 30))	('ccRCC', 'Disease', (17, 22))	('ccRCC', 'Disease', 'MESH:D002292', (17, 22))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (142, 165))	('methylation', 'biological_process', 'GO:0032259', ('127', '138'))
71014	31722744	On the other hand, concomitant inactivation of BRM and INI1/SNF5/BAF47 frequently lost in rhabdoid carcinomas was reported.	('BAF47', 'Gene', '6598', (65, 70))	('lost', 'NegReg', (82, 86))	('BRM', 'Gene', (47, 50))	('inactivation', 'Var', (31, 43))	('BAF47', 'Gene', (65, 70))	('rhabdoid carcinomas', 'Disease', (90, 109))	('SNF5', 'Gene', (60, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('INI1', 'Gene', (55, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('INI1', 'Gene', '6598', (55, 59))	('SNF5', 'Gene', '6598', (60, 64))	('rhabdoid carcinomas', 'Disease', 'MESH:D018335', (90, 109))
71015	31722744	Inactivation of the BRM-encoding SMARCA2 gene by the presence of promoter indel polymorphisms correlates with higher risk of colorectal cancer.	('SMARCA2', 'Gene', (33, 40))	('SMARCA2', 'Gene', '6595', (33, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (125, 142))	('colorectal cancer', 'Phenotype', 'HP:0003003', (125, 142))	('presence', 'Var', (53, 61))	('colorectal cancer', 'Disease', (125, 142))	('Inactivation', 'NegReg', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
71019	31722744	In about 10% of gastric cancers, methylation of SMARCA2 promoter region was identified.	('gastric cancers', 'Phenotype', 'HP:0012126', (16, 31))	('methylation', 'biological_process', 'GO:0032259', ('33', '44'))	('gastric cancers', 'Disease', 'MESH:D013274', (16, 31))	('methylation', 'Var', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('identified', 'Reg', (76, 86))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('SMARCA2', 'Gene', (48, 55))	('SMARCA2', 'Gene', '6595', (48, 55))	('gastric cancers', 'Disease', (16, 31))
71021	31722744	High levels of BRM are associated with patients' poor survival, linked to larger tumour size, metastasis to other organs, lymphatic invasion and stage IV disease.	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('patients', 'Species', '9606', (39, 47))	('High levels', 'Var', (0, 11))	('tumour', 'Disease', (81, 87))	('lymphatic invasion', 'CPA', (122, 140))	('metastasis to other organs', 'CPA', (94, 120))	('stage IV disease', 'Disease', (145, 161))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
71023	31722744	BRM silencing in pancreatic cancer cell line correlates with lower cell viability, proliferation rate and growth both in vitro and in vivo.	('growth', 'CPA', (106, 112))	('lower', 'NegReg', (61, 66))	('pancreatic cancer', 'Disease', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('BRM', 'Gene', (0, 3))	('pancreatic cancer', 'Disease', 'MESH:D010190', (17, 34))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (17, 34))	('cell viability', 'CPA', (67, 81))	('silencing', 'Var', (4, 13))	('proliferation rate', 'CPA', (83, 101))
71027	31722744	It also transcriptionally regulates the miR-302a-3p and promotes pancreatic cancer metastasis by epigenetic modulation of SOCS5/STAT3 signalling axis.	('regulates', 'Reg', (26, 35))	('STAT3', 'Gene', '6774', (128, 133))	('pancreatic cancer', 'Disease', 'MESH:D010190', (65, 82))	('pancreatic cancer', 'Disease', (65, 82))	('epigenetic modulation', 'Var', (97, 118))	('miR-302a', 'Gene', (40, 48))	('STAT3', 'Gene', (128, 133))	('miR-302a', 'Gene', '407028', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (65, 82))	('SOCS5', 'Gene', (122, 127))	('promotes', 'PosReg', (56, 64))	('SOCS5', 'Gene', '9655', (122, 127))	('signalling', 'biological_process', 'GO:0023052', ('134', '144'))
71034	31722744	correlated this phenomenon with the occurrence of BRM promoter polymorphisms that were also found in other cancers, leading to poorer patient survival.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('poorer', 'NegReg', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('polymorphisms', 'Var', (63, 76))	('BRM', 'Gene', (50, 53))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('patient', 'Species', '9606', (134, 141))
71036	31722744	This indicates that changes in BRM localisation may also contribute to carcinogenesis, although the mechanism of this phenomenon remains unknown.	('BRM', 'Protein', (31, 34))	('carcinogenesis', 'Disease', (71, 85))	('contribute', 'Reg', (57, 67))	('localisation', 'biological_process', 'GO:0051179', ('35', '47'))	('changes', 'Var', (20, 27))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))
71039	31722744	Occurrence of SMARCA2 promoter region polymorphisms correlates with HNSCC risk, especially in HPV-positive oropharyngeal cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('polymorphisms', 'Var', (38, 51))	('HPV-positive oropharyngeal cancer', 'Disease', (94, 127))	('SMARCA2', 'Gene', (14, 21))	('SMARCA2', 'Gene', '6595', (14, 21))	('SCC', 'Phenotype', 'HP:0002860', (70, 73))	('HNSCC', 'Disease', 'MESH:C535575', (68, 73))	('HNSCC', 'Disease', (68, 73))	('HPV-positive oropharyngeal cancer', 'Disease', 'MESH:D009959', (94, 127))
71040	31722744	In 5% of cases of salivary gland adenoid cystic carcinoma (ACC), the SMARCA2 mutation was found.	('salivary gland adenoid cystic carcinoma', 'Disease', (18, 57))	('found', 'Reg', (90, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('mutation', 'Var', (77, 85))	('ACC', 'Disease', 'MESH:D003528', (59, 62))	('SMARCA2', 'Gene', (69, 76))	('SMARCA2', 'Gene', '6595', (69, 76))	('salivary gland adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (18, 57))	('ACC', 'Disease', (59, 62))
71044	31722744	described that the presence of both SWI/SNF ATPases is crucial for optimal cell cycle progression in non-malignant mammary epithelial cells and knock-down of either BRM or BRG1 affects cell cycle, while the double knock-down of BRM and BRG1 results in cell death.	('ATPase', 'Gene', (44, 50))	('affects', 'Reg', (177, 184))	('cell cycle', 'CPA', (185, 195))	('knock-down', 'Var', (144, 154))	('BRM', 'Gene', (165, 168))	('cell cycle', 'biological_process', 'GO:0007049', ('185', '195'))	('cell cycle', 'biological_process', 'GO:0007049', ('75', '85'))	('ATPase', 'Gene', '1769', (44, 50))	('BRG1', 'Gene', (172, 176))	('cell death', 'biological_process', 'GO:0008219', ('252', '262'))
71046	31722744	Additionally, it was observed that both BRG1 and BRM are required for the triple-negative breast cancer (TNBC) proliferation and that double SMARCA2 and SMARCA4 knock-down results in slowed tumour growth in xenografts.	('tumour', 'Disease', (190, 196))	('knock-down', 'Var', (161, 171))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('SMARCA4', 'Gene', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('SMARCA2', 'Gene', (141, 148))	('SMARCA2', 'Gene', '6595', (141, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('SMARCA4', 'Gene', '6597', (153, 160))	('double', 'Var', (134, 140))	('slowed', 'NegReg', (183, 189))	('tumour', 'Disease', 'MESH:D009369', (190, 196))
71049	31722744	Namely, decreased level of BRM was observed in MDA-MB-231 (TNBC cancer cell line) comparing to the less malignant MCF-7 (ER positive) cells.	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('MCF-7', 'CellLine', 'CVCL:0031', (114, 119))	('MDA-MB-231', 'Var', (47, 57))	('BRM', 'MPA', (27, 30))	('decreased', 'NegReg', (8, 17))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
71053	31722744	At first, loss of BRG1 protein caused by somatic and germline mutations in SMARCA4 gene (coding for BRG1 protein) in SCCOHT was identified by a few groups.	('SCC', 'Disease', 'MESH:D002294', (117, 120))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('germline mutations', 'Var', (53, 71))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('SCC', 'Phenotype', 'HP:0002860', (117, 120))	('SMARCA4', 'Gene', (75, 82))	('SCC', 'Disease', (117, 120))	('BRG1', 'Gene', (18, 22))	('loss', 'NegReg', (10, 14))	('SMARCA4', 'Gene', '6597', (75, 82))
71058	31722744	The mutations in the SMARCA2 gene, in about 2% of OCCC samples, were described.	('OCCC', 'Disease', 'MESH:D010051', (50, 54))	('OCCC', 'Disease', (50, 54))	('OCC', 'Phenotype', 'HP:0025318', (50, 53))	('SMARCA2', 'Gene', (21, 28))	('SMARCA2', 'Gene', '6595', (21, 28))	('mutations', 'Var', (4, 13))
71065	31722744	Alterations in BRM expression seem to be important for the non-melanoma skin cancer (NMSC) development, and in this case, the role of SMARCA2 as a susceptibility gene is strongly pronouncing.	('SMARCA2', 'Gene', (134, 141))	('important', 'Reg', (41, 50))	('SMARCA2', 'Gene', '6595', (134, 141))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (59, 83))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('Alterations', 'Var', (0, 11))	('skin cancer', 'Phenotype', 'HP:0008069', (72, 83))	('non-melanoma skin cancer', 'Disease', (59, 83))	('NMSC', 'Disease', 'MESH:D012878', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('NMSC', 'Disease', (85, 89))	('BRM', 'Gene', (15, 18))
71070	31722744	Additionally, a mutation in SMARCA2 gene was identified in 17% of NMSC.	('mutation', 'Var', (16, 24))	('NMSC', 'Disease', 'MESH:D012878', (66, 70))	('identified', 'Reg', (45, 55))	('NMSC', 'Disease', (66, 70))	('SMARCA2', 'Gene', (28, 35))	('SMARCA2', 'Gene', '6595', (28, 35))
71073	31722744	It was found that mouse keratinocytes with deleted Brm (Brm-/-) grew faster than normal (Brm+/+) after UV-irradiation.	('deleted', 'Var', (43, 50))	('faster', 'PosReg', (69, 75))	('mouse', 'Species', '10090', (18, 23))	('grew', 'CPA', (64, 68))	('Brm', 'Gene', (51, 54))
71074	31722744	All these effects result in the ability of Brm null mutant keratinocytes to undergo selective pressure that can cause overgrowth of cells with accumulated mutations over normal cells and hence lead to cancer development.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cause', 'Reg', (112, 117))	('mutations', 'Var', (155, 164))	('cancer', 'Disease', (201, 207))	('mutant', 'Var', (52, 58))	('Brm', 'Gene', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('overgrowth', 'PosReg', (118, 128))	('overgrowth', 'Phenotype', 'HP:0001548', (118, 128))	('lead to', 'Reg', (193, 200))
71083	31722744	who identified mutations in SMARCA2 gene in leukemic cells.	('SMARCA2', 'Gene', (28, 35))	('SMARCA2', 'Gene', '6595', (28, 35))	('mutations', 'Var', (15, 24))
71084	31722744	In acute myeloid leukaemia with monosomy, 7 (about 13% of cases) novel mutations of SMARCA2 gene were identified, although these are not thought to be driving mutations because the samples were collected at more advanced stages of carcinogenesis.	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (3, 26))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (9, 26))	('carcinogenesis', 'Disease', 'MESH:D063646', (231, 245))	('acute myeloid leukaemia', 'Disease', (3, 26))	('carcinogenesis', 'Disease', (231, 245))	('mutations', 'Var', (71, 80))	('acute myeloid leukaemia', 'Disease', 'MESH:D015470', (3, 26))	('monosomy', 'Var', (32, 40))	('SMARCA2', 'Gene', (84, 91))	('SMARCA2', 'Gene', '6595', (84, 91))
71086	31722744	Additionally, the occurrence of SNPs in the SMARCA2 gene seems to correlate with risk for oligodendroglioma development.	('SNPs', 'Var', (32, 36))	('SMARCA2', 'Gene', (44, 51))	('SMARCA2', 'Gene', '6595', (44, 51))	('oligodendroglioma', 'Disease', (90, 107))	('oligodendroglioma', 'Disease', 'MESH:D009837', (90, 107))
71092	31722744	Alterations of BRM were reported in various cancer types, but only in some of them, SMARCA2 mutations were found.	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('Alterations', 'Var', (0, 11))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('BRM', 'Gene', (15, 18))	('SMARCA2', 'Gene', (84, 91))	('SMARCA2', 'Gene', '6595', (84, 91))
71095	31722744	However, SMARCA2 mutations were found in 78.2% of BRM-deficient ccRCC cases, although about half of them were silent.	('SMARCA2', 'Gene', '6595', (9, 16))	('found', 'Reg', (32, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('ccRCC', 'Disease', (64, 69))	('ccRCC', 'Disease', 'MESH:D002292', (64, 69))	('mutations', 'Var', (17, 26))	('SMARCA2', 'Gene', (9, 16))
71096	31722744	All detected mutations were specific for cancerous tissue, especially low differentiated, and none or very low-level mutations were found in BRM-positive tissues as well as adjacent non-malignant tissues.	('cancerous', 'Disease', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancerous', 'Disease', 'MESH:D009369', (41, 50))	('low differentiated', 'CPA', (70, 88))	('mutations', 'Var', (13, 22))
71097	31722744	SMARCA2 gene mutations were also identified in about 10% of gastric cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('gastric cancers', 'Disease', (60, 75))	('gastric cancers', 'Disease', 'MESH:D013274', (60, 75))	('gastric cancers', 'Phenotype', 'HP:0012126', (60, 75))	('SMARCA2', 'Gene', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('identified', 'Reg', (33, 43))	('SMARCA2', 'Gene', '6595', (0, 7))	('mutations', 'Var', (13, 22))
71098	31722744	In NMSC, a mutation resulting in substitution of glutamine by lysine was discovered.	('glutamine', 'Chemical', 'MESH:C578860', (49, 58))	('NMSC', 'Disease', 'MESH:D012878', (3, 7))	('NMSC', 'Disease', (3, 7))	('lysine', 'MPA', (62, 68))	('substitution', 'Var', (33, 45))	('glutamine', 'MPA', (49, 58))	('lysine', 'Chemical', 'MESH:C114808', (62, 68))
71100	31722744	SMARCA2 mutations of unknown effect were also found in leukaemia.	('SMARCA2', 'Gene', (0, 7))	('leukaemia', 'Disease', (55, 64))	('mutations', 'Var', (8, 17))	('SMARCA2', 'Gene', '6595', (0, 7))	('found', 'Reg', (46, 51))	('leukaemia', 'Disease', 'MESH:D007938', (55, 64))
71101	31722744	Methylation of CpG sites on SMARCA2 promoter region is the key mechanism of BRM alterations.	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('Methylation', 'Var', (0, 11))	('SMARCA2', 'Gene', '6595', (28, 35))	('SMARCA2', 'Gene', (28, 35))
71103	31722744	In BRM, deficient ccRCC methylation refers to over 40% of cases and was found only in low-differentiated tumour areas.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('methylation', 'MPA', (24, 35))	('tumour', 'Disease', (105, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (18, 23))	('ccRCC', 'Disease', (18, 23))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('ccRCC', 'Disease', 'MESH:D002292', (18, 23))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('deficient', 'Var', (8, 17))
71106	31722744	Insertions in the promoter sequence of SMARCA2 gene (at positions -741 and -1321) was specified as silencing-type polymorphism, leading to development of many types of cancer.	('leading to', 'Reg', (128, 138))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('SMARCA2', 'Gene', (39, 46))	('SMARCA2', 'Gene', '6595', (39, 46))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('Insertions in', 'Var', (0, 13))	('cancer', 'Disease', (168, 174))
71107	31722744	Interestingly, the promoter insertions cause HDACs recruitment and result in SMARCA2 gene silencing.	('cause', 'Reg', (39, 44))	('SMARCA2', 'Gene', (77, 84))	('SMARCA2', 'Gene', '6595', (77, 84))	('recruitment', 'MPA', (51, 62))	('gene silencing', 'biological_process', 'GO:0016458', ('85', '99'))	('insertions', 'Var', (28, 38))	('gene', 'MPA', (85, 89))	('HDAC', 'Gene', (45, 49))	('HDAC', 'Gene', '9734', (45, 49))
71108	31722744	Such insertions were associated with higher risk of lung cancer, colorectal cancer, and head and neck squamous cell carcinoma.	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('insertions', 'Var', (5, 15))	('colorectal cancer', 'Phenotype', 'HP:0003003', (65, 82))	('neck', 'cellular_component', 'GO:0044326', ('97', '101'))	('colorectal cancer', 'Disease', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('lung cancer', 'Disease', (52, 63))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (88, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('colorectal cancer', 'Disease', 'MESH:D015179', (65, 82))
71110	31722744	In the case of pancreatic cancer, the presence of SMARCA2 promoter polymorphisms is associated with poor prognosis for patients with diagnosed cancer rather than specific cancer risk.	('presence', 'Var', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (15, 32))	('SMARCA2', 'Gene', '6595', (50, 57))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Disease', (171, 177))	('pancreatic cancer', 'Disease', 'MESH:D010190', (15, 32))	('pancreatic cancer', 'Disease', (15, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('SMARCA2', 'Gene', (50, 57))
71112	31722744	In ccRCC aberrations of chromosome, 9p (monosomy or deletion) was found in over 40% of analysed BRM-deficient tumours.	('found', 'Reg', (66, 71))	('chromosome', 'cellular_component', 'GO:0005694', ('24', '34'))	('tumours', 'Disease', 'MESH:D009369', (110, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('aberrations', 'Var', (9, 20))	('tumours', 'Phenotype', 'HP:0002664', (110, 117))	('ccRCC', 'Disease', (3, 8))	('ccRCC', 'Disease', 'MESH:D002292', (3, 8))	('deletion', 'Var', (52, 60))	('tumours', 'Disease', (110, 117))
71113	31722744	Currently, the loss of 9p chromosome is used as a prognostic marker for ccRCC.	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('loss of 9p chromosome', 'Var', (15, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('ccRCC', 'Disease', (72, 77))	('ccRCC', 'Disease', 'MESH:D002292', (72, 77))
71115	31722744	by mutation and CpG methylation that occur in the same cancer cell.	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mutation', 'Var', (3, 11))	('methylation', 'Var', (20, 31))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
71118	31722744	Overexpression of BRM correlated with poor survival and chemoresistance in pancreatic cancer.	('chemoresistance', 'CPA', (56, 71))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (75, 92))	('BRM', 'Gene', (18, 21))	('Overexpression', 'Var', (0, 14))	('pancreatic cancer', 'Disease', (75, 92))	('poor', 'NegReg', (38, 42))	('pancreatic cancer', 'Disease', 'MESH:D010190', (75, 92))
71119	31722744	Similarly, in ovarian cancer, high level of BRM promoted resistance to cisplatin.	('ovarian cancer', 'Disease', (14, 28))	('ovarian cancer', 'Phenotype', 'HP:0100615', (14, 28))	('resistance to cisplatin', 'MPA', (57, 80))	('ovarian cancer', 'Disease', 'MESH:D010051', (14, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (71, 80))	('high level', 'Var', (30, 40))	('promoted', 'PosReg', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
71127	31722744	Polymorphisms in SMARCA2 gene in position -747 and -1321 are suggested to be responsible for HDAC recruitment, and HDAC inhibitors (HDACi) cause upregulation of both BRM transcript and protein levels in cell lines.	('upregulation', 'PosReg', (145, 157))	('HDAC', 'Gene', (132, 136))	('HDAC', 'Gene', (93, 97))	('SMARCA2', 'Gene', (17, 24))	('Polymorphisms', 'Var', (0, 13))	('HDAC', 'Gene', '9734', (93, 97))	('HDAC', 'Gene', '9734', (132, 136))	('HDAC', 'Gene', (115, 119))	('SMARCA2', 'Gene', '6595', (17, 24))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('HDAC', 'Gene', '9734', (115, 119))	('protein levels', 'MPA', (185, 199))
71131	31722744	In tumours with SMARCA2 depletion caused by PRC2-driven methylation, usage of EZH2 inhibitors seems to be a promising therapy.	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('depletion', 'NegReg', (24, 33))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('SMARCA2', 'Gene', '6595', (16, 23))	('tumours', 'Disease', 'MESH:D009369', (3, 10))	('tumours', 'Disease', (3, 10))	('methylation', 'Var', (56, 67))	('SMARCA2', 'Gene', (16, 23))	('EZH2', 'Gene', (78, 82))	('EZH2', 'Gene', '2146', (78, 82))	('PRC2-driven', 'Gene', (44, 55))
71137	31722744	Therefore, BRM targeting in BRG1-deficient cancer is expected to cause synthetic lethality.	('BRM targeting', 'Var', (11, 24))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('BRG1-deficient', 'Gene', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
71140	31722744	BRM deficiency or downregulation was found in various types of cancer, although its function in cancer development and progression remains elusive.	('BRM', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('deficiency', 'Var', (4, 14))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('downregulation', 'NegReg', (18, 32))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', (63, 69))
71146	31722744	Additionally, some SMARCA2 missense mutations result not only in BRM loss of function but also may lead to production of gain-of-function BRM protein, likely influencing the whole BRM containing SWI/SNF CRC's activity.	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('SMARCA2', 'Gene', (19, 26))	('SMARCA2', 'Gene', '6595', (19, 26))	('BRM protein', 'Protein', (138, 149))	('missense mutations', 'Var', (27, 45))	('loss of function', 'NegReg', (69, 85))	('BRM', 'MPA', (65, 68))	('gain-of-function', 'PosReg', (121, 137))
71150	31722744	In such case, any BRM-targeting small molecule drugs can cause severe and unexpected negative effects on liver activity which may be impossible to detect during initial tests on cancer lines or in mice, as in this model, Brm seems to have a diverse function than in human liver.	('small molecule drugs', 'Var', (32, 52))	('BRM-targeting', 'Disease', (18, 31))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('negative', 'NegReg', (85, 93))	('drugs', 'Var', (47, 52))	('liver activity', 'MPA', (105, 119))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('mice', 'Species', '10090', (197, 201))	('human', 'Species', '9606', (266, 271))
71156	31722744	The relevance of BRM alternative splice variants in cancer is overlooked, although such a multiplicity of alternative BRM splicing variants suggests far more potential regulatory or pathological functions of the BRM protein which may be specific for certain cancer types or developmental stages.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('variants', 'Var', (131, 139))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('protein', 'cellular_component', 'GO:0003675', ('216', '223'))	('cancer', 'Disease', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('splicing', 'biological_process', 'GO:0045292', ('122', '130'))	('cancer', 'Disease', (52, 58))
71165	30349421	For both ccRCC and PRCC, the most frequent substitution in somatic missense mutations was T:A > A:T, which was different from that recorded in the COSMIC database.	('PRCC', 'Phenotype', 'HP:0006766', (19, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (9, 14))	('PRCC', 'Gene', (19, 23))	('T:A > A', 'Var', (90, 97))	('PRCC', 'Gene', '5546', (19, 23))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('RCC', 'Disease', (11, 14))	('RCC', 'Disease', (20, 23))
71167	30349421	All the mutations detected in those genes had not been reported in ccRCC before, except for alterations in VHL and PBRM1.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('VHL', 'Gene', '7428', (107, 110))	('RCC', 'Disease', (69, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('mutations', 'Var', (8, 17))	('PBRM1', 'Gene', (115, 120))	('VHL', 'Gene', (107, 110))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('PBRM1', 'Gene', '55193', (115, 120))
71168	30349421	Regarding the frequently mutated genes in PRCC in our study, DEPDC4 (p.E293A, p.T279A), PNLIP (p.N401Y, p.F342L) and SARDH (p.H554Q, p.M1T) were newly detected gene mutations predicted to be deleterious.	('p.F342L', 'Var', (104, 111))	('p.E293A', 'Mutation', 'p.E293A', (69, 76))	('PRCC', 'Gene', '5546', (42, 46))	('p.N401Y', 'Mutation', 'p.N401Y', (95, 102))	('p.H554Q', 'Mutation', 'rs891159195', (124, 131))	('PNLIP', 'Gene', (88, 93))	('p.E293A', 'Var', (69, 76))	('p.M1T', 'Mutation', 'rs1312268347', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('DEPDC4', 'Gene', '120863', (61, 67))	('p.M1T', 'Var', (133, 138))	('PNLIP', 'Gene', '5406', (88, 93))	('PRCC', 'Gene', (42, 46))	('p.N401Y', 'Var', (95, 102))	('p.F342L', 'Mutation', 'p.F342L', (104, 111))	('p.T279A', 'Var', (78, 85))	('p.H554Q', 'Var', (124, 131))	('PRCC', 'Phenotype', 'HP:0006766', (42, 46))	('p.T279A', 'Mutation', 'rs754882817', (78, 85))	('SARDH', 'Gene', '1757', (117, 122))	('SARDH', 'Gene', (117, 122))	('DEPDC4', 'Gene', (61, 67))
71173	30349421	Using WES, we identified somatic mutations in 26 Chinese patients with RCC, which enriched the racial diversity of the somatic mutation profiles of RCC subjects, and revealed a few discrepancies in molecular characterizations between our study and published datasets.	('RCC', 'Disease', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('patients', 'Species', '9606', (57, 65))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('mutations', 'Var', (33, 42))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))
71174	30349421	We also identified numerous newly detected somatic mutations, which further supplements the somatic mutation landscape of RCC.	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))	('mutations', 'Var', (51, 60))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))
71184	30349421	Notably, somatic mutations in MET are mainly found in type 1 PRCC, whereas type 2 PRCC is primarily associated with somatic mutations in SETD2, BAP1 and PBRM1, all of which are also frequently mutated in human ccRCC.	('PBRM1', 'Gene', '55193', (153, 158))	('ccRCC', 'Phenotype', 'HP:0006770', (210, 215))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('mutations', 'Var', (17, 26))	('PBRM1', 'Gene', (153, 158))	('PRCC', 'Gene', (61, 65))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('BAP1', 'Gene', (144, 148))	('PRCC', 'Phenotype', 'HP:0006766', (61, 65))	('SETD2', 'Gene', (137, 142))	('MET', 'Gene', (30, 33))	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('PRCC', 'Gene', (82, 86))	('SETD2', 'Gene', '29072', (137, 142))	('associated', 'Reg', (100, 110))	('PRCC', 'Phenotype', 'HP:0006766', (82, 86))	('human', 'Species', '9606', (204, 209))	('RCC', 'Disease', (62, 65))	('PRCC', 'Gene', '5546', (61, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('mutations', 'Var', (124, 133))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (212, 215))	('RCC', 'Phenotype', 'HP:0005584', (212, 215))	('found', 'Reg', (45, 50))	('PRCC', 'Gene', '5546', (82, 86))	('BAP1', 'Gene', '8314', (144, 148))
71185	30349421	Furthermore, TFE3 and TFEB gene fusion and loss of CNKD2A have been shown to be dominant in type 2 PRCC.	('CNKD2A', 'Gene', (51, 57))	('TFEB', 'Gene', '7942', (22, 26))	('PRCC', 'Gene', (99, 103))	('gene fusion', 'Var', (27, 38))	('TFE3', 'Gene', (13, 17))	('TFEB', 'Gene', (22, 26))	('PRCC', 'Phenotype', 'HP:0006766', (99, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('loss', 'NegReg', (43, 47))	('TFE3', 'Gene', '7030', (13, 17))	('PRCC', 'Gene', '5546', (99, 103))
71194	30349421	A recent study indicated that a longer progression-free survival was achieved with nivolumab plus ipilimumab than with sunitinib among advanced RCC patients with >= 1% PD-L1 expression but not among those with < 1% PD-L1 expression.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('longer', 'PosReg', (32, 38))	('patients', 'Species', '9606', (148, 156))	('PD-L1', 'Gene', (215, 220))	('expression', 'Var', (174, 184))	('nivolumab', 'Chemical', 'MESH:D000077594', (83, 92))	('PD-L1', 'Gene', (168, 173))	('PD-L1', 'Gene', '29126', (215, 220))	('ipilimumab', 'Chemical', 'MESH:D000074324', (98, 108))	('progression-free survival', 'CPA', (39, 64))	('sunitinib', 'Chemical', 'MESH:D000077210', (119, 128))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('PD-L1', 'Gene', '29126', (168, 173))
71206	30349421	The functional impacts of missense mutations were predicted by SIFT, PolyPhen2 HDIV, PolyPhen2 HVAR, LRT, MutationTaster, MutationAssessor, and FATHMM.	('missense mutations', 'Var', (26, 44))	('PolyPhen2', 'Var', (85, 94))	('SIFT', 'Disease', (63, 67))	('SIFT', 'Disease', 'None', (63, 67))
71219	30349421	In 15 ccRCC cases, we identified 1024 missense mutations, 81stop-gain mutations, 50 frameshift mutations, 48 splice mutations and 6 stop-loss mutations (Fig.	('RCC', 'Disease', (8, 11))	('mutations', 'Var', (70, 79))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('missense mutations', 'Var', (38, 56))	('ccRCC', 'Phenotype', 'HP:0006770', (6, 11))	('frameshift mutations', 'Var', (84, 104))	('81stop-gain', 'PosReg', (58, 69))
71220	30349421	The most frequent substitution in somatic missense mutations was exposed to be T:A > A:T, which was also the least common type in ChRCC cases (Fig.	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('missense mutations', 'Var', (42, 60))	('T:A > A', 'Var', (79, 86))
71222	30349421	These mutations contained five missense mutations (p.P86L, p.R120G, p.S80N, p.V130L, p.F136V), three frameshift deletions (p.G127fs, p.N141fs, p.N90fs) and two stop-gain mutations (p.E70X, p.Q145X).	('p.F136V', 'Mutation', 'p.F136V', (85, 92))	('p.N90fs', 'Mutation', 'rs869025623', (143, 150))	('p.P86L', 'Var', (51, 57))	('p.G127fs', 'Mutation', 'p.G127fsX', (123, 131))	('p.N90fs', 'Var', (143, 150))	('p.N141fs', 'Var', (133, 141))	('p.S80N', 'Mutation', 'rs5030805', (68, 74))	('p.Q145X', 'Mutation', 'rs749704215', (189, 196))	('p.P86L', 'Mutation', 'rs730882034', (51, 57))	('p.Q145X', 'Var', (189, 196))	('p.S80N', 'Var', (68, 74))	('p.E70X', 'Mutation', 'rs5030802', (181, 187))	('p.V130L', 'Var', (76, 83))	('p.F136V', 'Var', (85, 92))	('p.R120G', 'Var', (59, 66))	('p.N141fs', 'Mutation', 'p.N141fsX', (133, 141))	('p.G127fs', 'Var', (123, 131))	('p.V130L', 'Mutation', 'rs104893830', (76, 83))	('p.R120G', 'Mutation', 'rs5030818', (59, 66))	('p.E70X', 'Var', (181, 187))
71223	30349421	Those variants in VHL were located in the commonly known region of the VHL protein domain, all of which had been reported in the TCGA or COSMIC database (Fig.	('VHL', 'Gene', '7428', (18, 21))	('variants', 'Var', (6, 14))	('VHL', 'Gene', (71, 74))	('VHL', 'Gene', '7428', (71, 74))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('VHL', 'Gene', (18, 21))
71225	30349421	In the CDC42EP1 gene, the somatic missense mutation (S260P) was detected in three cases, which was not located in the protein domain for CDC42EP1 and was predicted to be benign.	('CDC42EP1', 'Gene', '11135', (137, 145))	('S260P', 'Mutation', 'rs62235034', (53, 58))	('CDC42EP1', 'Gene', (7, 15))	('S260P', 'Var', (53, 58))	('CDC42EP1', 'Gene', '11135', (7, 15))	('CDC42EP1', 'Gene', (137, 145))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))
71226	30349421	Regarding 5 PRCC cases, 537 missense mutations, 56 stop-gain mutations, 31 frameshift mutations, 34 splice mutations and 2 stop-loss mutations were detected (Fig.	('stop-gain', 'MPA', (51, 60))	('PRCC', 'Phenotype', 'HP:0006766', (12, 16))	('splice', 'MPA', (100, 106))	('missense mutations', 'Var', (28, 46))	('frameshift mutations', 'Var', (75, 95))	('PRCC', 'Gene', '5546', (12, 16))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('PRCC', 'Gene', (12, 16))
71227	30349421	Like in the ccRCC cases, the most common substitution in missense mutations was T:A > A:T (Fig.	('missense mutations', 'Var', (57, 75))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('ccRCC', 'Phenotype', 'HP:0006770', (12, 17))	('RCC', 'Disease', (14, 17))	('T:A > A', 'Var', (80, 87))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
71229	30349421	None of the variants detected in PER3 were located in its protein domain and they were all predicted to be neutral or benign.	('PER3', 'Gene', (33, 37))	('PER3', 'Gene', '8863', (33, 37))	('variants', 'Var', (12, 20))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))
71230	30349421	Among the remaining frequently mutated genes, DEPDC4 (p.E293A, p.T279A), PNLIP (p.N401Y, p.F342L) and SARDH (p.H554Q, p.M1T) had not been reported to correlate with PRCC before, and they were all predicted to be deleterious.	('p.E293A', 'Var', (54, 61))	('PRCC', 'Gene', (165, 169))	('PRCC', 'Phenotype', 'HP:0006766', (165, 169))	('PNLIP', 'Gene', (73, 78))	('p.N401Y', 'Mutation', 'p.N401Y', (80, 87))	('DEPDC4', 'Gene', '120863', (46, 52))	('PRCC', 'Gene', '5546', (165, 169))	('p.M1T', 'Mutation', 'rs1312268347', (118, 123))	('p.F342L', 'Mutation', 'p.F342L', (89, 96))	('p.H554Q', 'Var', (109, 116))	('p.T279A', 'Var', (63, 70))	('PNLIP', 'Gene', '5406', (73, 78))	('p.T279A', 'Mutation', 'rs754882817', (63, 70))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('SARDH', 'Gene', (102, 107))	('p.N401Y', 'Var', (80, 87))	('SARDH', 'Gene', '1757', (102, 107))	('p.E293A', 'Mutation', 'p.E293A', (54, 61))	('p.F342L', 'Var', (89, 96))	('DEPDC4', 'Gene', (46, 52))	('p.H554Q', 'Mutation', 'rs891159195', (109, 116))
71231	30349421	In the 6 ChRCC cases, 128 missense mutations, 2 stop-gain mutations, 3 frameshift mutations and 4 splice mutations were identified (Fig.	('missense mutations', 'Var', (26, 44))	('frameshift', 'Var', (71, 81))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))
71232	30349421	The most recurrent substitution in missense mutations was G:C > A:T, which was distinct from that in ccRCC and PRCC cases (Fig.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('G:C > A:T', 'Var', (58, 67))	('PRCC', 'Gene', '5546', (111, 115))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('PRCC', 'Gene', (111, 115))	('missense mutations', 'Var', (35, 53))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('PRCC', 'Phenotype', 'HP:0006766', (111, 115))
71234	30349421	It's worth noting that the ZNF814 gene was also mutated in 4 ccRCC cases and 2 PRCC cases.	('RCC', 'Disease', (63, 66))	('PRCC', 'Gene', '5546', (79, 83))	('mutated', 'Var', (48, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('PRCC', 'Phenotype', 'HP:0006766', (79, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('PRCC', 'Gene', (79, 83))	('ZNF814', 'Gene', '730051', (27, 33))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('ZNF814', 'Gene', (27, 33))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
71235	30349421	Among all these mutations in ZNF814 gene, p.P323H, p.R322K and p.G320E presented as a fixed combination occurring in three RCC types.	('p.G320E', 'Var', (63, 70))	('ZNF814', 'Gene', '730051', (29, 35))	('ZNF814', 'Gene', (29, 35))	('p.R322K', 'Mutation', 'rs113623532', (51, 58))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('p.P323H', 'Var', (42, 49))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('p.G320E', 'Mutation', 'rs760366488', (63, 70))	('p.P323H', 'Mutation', 'rs111727691', (42, 49))	('p.R322K', 'Var', (51, 58))
71236	30349421	Furthermore, p.P323H and p.G320E in ZNF814 were predicted to be deleterious, while p.R322K was predicted to be benign.	('ZNF814', 'Gene', '730051', (36, 42))	('p.R322K', 'Mutation', 'rs113623532', (83, 90))	('ZNF814', 'Gene', (36, 42))	('p.P323H', 'Mutation', 'rs111727691', (13, 20))	('p.P323H', 'Var', (13, 20))	('p.G320E', 'Mutation', 'rs760366488', (25, 32))	('p.G320E', 'Var', (25, 32))	('p.R322K', 'Var', (83, 90))
71238	30349421	Among the 4 missense mutations in KRTAP4-8, p.V71M and p.S68R were forecasted to be deleterious, while p.H91R and p.K76R were predicted to be benign.	('p.K76R', 'Mutation', 'rs1407887023', (114, 120))	('p.S68R', 'Mutation', 'rs200462175', (55, 61))	('p.H91R', 'Mutation', 'rs78132858', (103, 109))	('p.V71M', 'Var', (44, 50))	('KRTAP4-8', 'Gene', '728224', (34, 42))	('p.S68R', 'Var', (55, 61))	('KRTAP4-8', 'Gene', (34, 42))	('p.H91R', 'Var', (103, 109))	('p.V71M', 'Mutation', 'rs202107241', (44, 50))	('p.K76R', 'Var', (114, 120))
71239	30349421	In the COSMIC database, the most frequent substitution in missense mutations in ccRCC is G:C > A:T, which is different from what we found in this study (T:A > A:T).	('missense mutations', 'Var', (58, 76))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('G:C > A:T', 'Var', (89, 98))
71241	30349421	It's worth noting that the amino acid alterations p.P352fs and p.H193Q in BAP1, p.W1562C and p.S512X in SETD2, p.V343fs in PTEN and p.R882S in MTOR had not been reported previously in ccRCC, all of which were considered to be deleterious in this study.	('p.V343fs', 'Mutation', 'p.V343fsX', (111, 119))	('p.S512X', 'Mutation', 'p.S512X', (93, 100))	('p.H193Q', 'Var', (63, 70))	('PTEN', 'Gene', (123, 127))	('p.P352fs', 'Mutation', 'p.P352fsX', (50, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (184, 189))	('p.P352fs', 'Var', (50, 58))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('p.R882S', 'Mutation', 'p.R882S', (132, 139))	('MTOR', 'Gene', (143, 147))	('RCC', 'Disease', (186, 189))	('PTEN', 'Gene', '5728', (123, 127))	('MTOR', 'Gene', '2475', (143, 147))	('SETD2', 'Gene', (104, 109))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('p.V343fs', 'Var', (111, 119))	('BAP1', 'Gene', '8314', (74, 78))	('p.R882S', 'Var', (132, 139))	('p.H193Q', 'Mutation', 'p.H193Q', (63, 70))	('SETD2', 'Gene', '29072', (104, 109))	('p.W1562C', 'Var', (80, 88))	('p.W1562C', 'SUBSTITUTION', 'None', (80, 88))	('p.S512X', 'Var', (93, 100))	('BAP1', 'Gene', (74, 78))
71242	30349421	Figure 5 shows the distribution of somatic mutations identified in this study in functional domains for VHL, PBRM1, BAP1 and SETD2.	('VHL', 'Gene', '7428', (104, 107))	('BAP1', 'Gene', (116, 120))	('PBRM1', 'Gene', (109, 114))	('PBRM1', 'Gene', '55193', (109, 114))	('mutations', 'Var', (43, 52))	('SETD2', 'Gene', '29072', (125, 130))	('BAP1', 'Gene', '8314', (116, 120))	('VHL', 'Gene', (104, 107))	('SETD2', 'Gene', (125, 130))
71244	30349421	Notably, PBRM1 gene that was mutated in one ccRCC case was also altered in one PRCC case (type 2), which was reported to be mutated at a frequency of 2% in the COSMIC database and 3.9% in the TCGA database.	('PRCC', 'Gene', '5546', (79, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('RCC', 'Disease', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('PRCC', 'Gene', (79, 83))	('mutated', 'Var', (29, 36))	('PBRM1', 'Gene', (9, 14))	('altered', 'Reg', (64, 71))	('PBRM1', 'Gene', '55193', (9, 14))	('PRCC', 'Phenotype', 'HP:0006766', (79, 83))
71245	30349421	Moreover, in accordance with ccRCC, the most common substitution in missense mutations in PRCC in the COSMIC database is G:C > A:T, which is distinct from what we found in this study (T:A > A:T).	('PRCC', 'Phenotype', 'HP:0006766', (90, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('missense mutations', 'Var', (68, 86))	('G:C > A:T', 'Var', (121, 130))	('RCC', 'Disease', (91, 94))	('PRCC', 'Gene', '5546', (90, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('PRCC', 'Gene', (90, 94))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
71247	30349421	Moreover, the amino acid alteration p.R81Q in TP53 had not been reported before and was predicted to be deleterious.	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', (46, 50))	('p.R81Q', 'Var', (36, 42))	('p.R81Q', 'Mutation', 'rs587778720', (36, 42))
71248	30349421	In the COSMIC database, the most frequent substitution in missense mutations in ChRCC is G:C > A:T, which is consistent with our finding.	('missense mutations', 'Var', (58, 76))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('G:C > A:T', 'Var', (89, 98))
71252	30349421	In ChRCC, a few mutated genes were identified as components of the signaling pathways mentioned above, including the PI3K-Akt (3/6), MAPK (2/6) and HIF-1 (2/6) signaling pathway.	('MAPK', 'molecular_function', 'GO:0004707', ('133', '137'))	('signaling pathway', 'biological_process', 'GO:0007165', ('160', '177'))	('HIF-1', 'Gene', (148, 153))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('mutated', 'Var', (16, 23))	('RCC', 'Disease', (5, 8))	('Akt', 'Gene', '207', (122, 125))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('MAPK', 'Pathway', (133, 137))	('PI3K', 'molecular_function', 'GO:0016303', ('117', '121'))	('Akt', 'Gene', (122, 125))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))	('HIF-1', 'Gene', '3091', (148, 153))
71264	30349421	For instance, in a study focusing on racial differences in the sequencing results of hereditary malignancies, Caswell and colleagues reported that a higher proportion of whites than nonwhites carried deleterious CHEK2 mutations.	('hereditary malignancies', 'Disease', 'MESH:D009369', (85, 108))	('CHEK2', 'Gene', (212, 217))	('mutations', 'Var', (218, 227))	('CHEK2', 'Gene', '11200', (212, 217))	('hereditary malignancies', 'Disease', (85, 108))
71272	30349421	According to the TCGA database, the mutation frequency of VHL was 51.42%, which was much lower (20%) in the WES study performed on 10 Chinese patients with ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (156, 161))	('VHL', 'Gene', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('VHL', 'Gene', '7428', (58, 61))	('patients', 'Species', '9606', (142, 150))	('mutation', 'Var', (36, 44))
71273	30349421	In our study on 15 paired tumor-normal ccRCC samples from Chinese patients, the mutation frequency of VHL was 66.67%, which was much higher than that in the WES study performed on 10 Chinese with ccRCC previously.	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('VHL', 'Gene', (102, 105))	('RCC', 'Disease', (198, 201))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('ccRCC', 'Phenotype', 'HP:0006770', (196, 201))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('VHL', 'Gene', '7428', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('RCC', 'Disease', (41, 44))	('mutation', 'Var', (80, 88))	('patients', 'Species', '9606', (66, 74))
71275	30349421	In this study, all of the somatic mutations in VHL were located in the known domain for VHL and determined to be deleterious to protein function.	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('VHL', 'Gene', (88, 91))	('VHL', 'Gene', '7428', (88, 91))	('VHL', 'Gene', (47, 50))	('VHL', 'Gene', '7428', (47, 50))	('mutations', 'Var', (34, 43))
71280	30349421	Considering these published ideas together, we can speculate that the deleterious mutations in VHL identified in our study might play a leading role in the oncogenesis of ccRCC.	('oncogenesis', 'biological_process', 'GO:0007048', ('156', '167'))	('RCC', 'Disease', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('VHL', 'Gene', (95, 98))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('ccRCC', 'Phenotype', 'HP:0006770', (171, 176))	('VHL', 'Gene', '7428', (95, 98))	('mutations', 'Var', (82, 91))	('role', 'Reg', (144, 148))
71281	30349421	However, loss of VHL activity is unable to induce ccRCC by itself, as there are some other ingredients cooperating with that towards the oncogenesis of ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('oncogenesis', 'biological_process', 'GO:0007048', ('137', '148'))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (50, 55))	('RCC', 'Disease', (52, 55))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('loss', 'Var', (9, 13))	('RCC', 'Disease', (154, 157))	('VHL', 'Gene', (17, 20))	('RCC', 'Phenotype', 'HP:0005584', (154, 157))	('ccRCC', 'Phenotype', 'HP:0006770', (152, 157))	('VHL', 'Gene', '7428', (17, 20))	('activity', 'MPA', (21, 29))
71282	30349421	Amrita and colleagues demonstrated that the deficiencies of Vhl and Pbrm1 in the mouse kidney can lead to multifocal ccRCC with a tendency of metastasis.	('lead to', 'Reg', (98, 105))	('metastasis', 'CPA', (142, 152))	('Pbrm1', 'Gene', (68, 73))	('Vhl', 'Gene', (60, 63))	('Pbrm1', 'Gene', '66923', (68, 73))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('RCC', 'Disease', (119, 122))	('mouse', 'Species', '10090', (81, 86))	('Vhl', 'Gene', '22346', (60, 63))	('deficiencies', 'Var', (44, 56))
71283	30349421	Sabine and colleagues showed that the combined deletion of Vhl, Trp53 and Rb1 targeted in renal epithelial cells in mice caused ccRCC, which shared molecular markers and mRNA expression with human ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('mice', 'Species', '10090', (116, 120))	('caused', 'Reg', (121, 127))	('ccRCC', 'Phenotype', 'HP:0006770', (197, 202))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('Rb1', 'Gene', (74, 77))	('Trp53', 'Gene', '22059', (64, 69))	('Rb1', 'Gene', '19645', (74, 77))	('Vhl', 'Gene', '22346', (59, 62))	('deletion', 'Var', (47, 55))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('Vhl', 'Gene', (59, 62))	('human', 'Species', '9606', (191, 196))	('RCC', 'Disease', (199, 202))	('RCC', 'Phenotype', 'HP:0005584', (199, 202))	('RCC', 'Disease', 'MESH:C538614', (199, 202))	('Trp53', 'Gene', (64, 69))
71285	30349421	In this study, only a stop-gain mutation (p.E981X) in PBRM1 was detected in one ccRCC case, which had been reported previously.	('PBRM1', 'Gene', (54, 59))	('PBRM1', 'Gene', '55193', (54, 59))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('p.E981X', 'Mutation', 'p.E981X', (42, 49))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('p.E981X', 'Var', (42, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))
71286	30349421	Compared with the data documented in the TCGA (30.6%) and COSMIC datasets (31%), the mutation frequency of PBRM1 in ccRCC in this study was relatively lower (6.7%).	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('RCC', 'Disease', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('mutation', 'Var', (85, 93))	('lower', 'NegReg', (151, 156))	('PBRM1', 'Gene', (107, 112))	('PBRM1', 'Gene', '55193', (107, 112))
71290	30349421	It had been demonstrated that loss of Vhl and Pbrm1 in mouse kidney could generate ccRCC.	('generate', 'Reg', (74, 82))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('Vhl', 'Gene', '22346', (38, 41))	('mouse', 'Species', '10090', (55, 60))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('RCC', 'Disease', (85, 88))	('Pbrm1', 'Gene', (46, 51))	('loss', 'Var', (30, 34))	('Pbrm1', 'Gene', '66923', (46, 51))	('Vhl', 'Gene', (38, 41))
71291	30349421	As revealed in our study, PBRM1 and VHL were somatically mutated in the same ccRCC case.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('VHL', 'Gene', (36, 39))	('PBRM1', 'Gene', (26, 31))	('PBRM1', 'Gene', '55193', (26, 31))	('VHL', 'Gene', '7428', (36, 39))	('mutated', 'Var', (57, 64))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
71294	30349421	In addition, the PBRM1 mutation was also identified in one type 2 PRCC case in this study, which was consistent with the previous finding that mutated PBRM1 was mainly associated with type 2 PRCC.	('associated', 'Reg', (168, 178))	('identified', 'Reg', (41, 51))	('PRCC', 'Gene', '5546', (66, 70))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Phenotype', 'HP:0005584', (192, 195))	('PRCC', 'Phenotype', 'HP:0006766', (191, 195))	('PRCC', 'Gene', '5546', (191, 195))	('PBRM1', 'Gene', (17, 22))	('PRCC', 'Gene', (66, 70))	('PBRM1', 'Gene', (151, 156))	('PBRM1', 'Gene', '55193', (17, 22))	('PBRM1', 'Gene', '55193', (151, 156))	('mutated', 'Var', (143, 150))	('PRCC', 'Gene', (191, 195))	('PRCC', 'Phenotype', 'HP:0006766', (66, 70))
71295	30349421	Apart from VHL and PBRM1, there are some other genes significantly mutated in ccRCC based on the TCGA and COSMIC datasets, such as SETD2 and BAP1, which are both located at chromosome 3p21.	('PBRM1', 'Gene', '55193', (19, 24))	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('VHL', 'Gene', '7428', (11, 14))	('BAP1', 'Gene', '8314', (141, 145))	('chromosome', 'cellular_component', 'GO:0005694', ('173', '183'))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('BAP1', 'Gene', (141, 145))	('mutated', 'Var', (67, 74))	('VHL', 'Gene', (11, 14))	('SETD2', 'Gene', '29072', (131, 136))	('PBRM1', 'Gene', (19, 24))	('SETD2', 'Gene', (131, 136))
71296	30349421	For BAP1, a missense mutation (p.H193Q) and a frameshift-deletion (p.P352fs) were found in two different ccRCC cases in this study.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('p.P352fs', 'Var', (67, 75))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (105, 110))	('RCC', 'Disease', (107, 110))	('BAP1', 'Gene', (4, 8))	('found', 'Reg', (82, 87))	('p.H193Q', 'Var', (31, 38))	('p.H193Q', 'Mutation', 'p.H193Q', (31, 38))	('p.P352fs', 'Mutation', 'p.P352fsX', (67, 75))	('BAP1', 'Gene', '8314', (4, 8))
71297	30349421	Regarding SETD2, we also identified two somatic mutations in two distinct ccRCC cases consisting of a missense mutation (p.W1562C) and a stop-gain mutation (p.S512X).	('p.S512X', 'Mutation', 'p.S512X', (157, 164))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('SETD2', 'Gene', '29072', (10, 15))	('SETD2', 'Gene', (10, 15))	('p.W1562C', 'SUBSTITUTION', 'None', (121, 129))	('p.W1562C', 'Var', (121, 129))	('p.S512X', 'Var', (157, 164))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))
71298	30349421	All of those mutations in SETD2 and BAP1 had not been reported before and were predicted to be deleterious.	('SETD2', 'Gene', '29072', (26, 31))	('BAP1', 'Gene', '8314', (36, 40))	('SETD2', 'Gene', (26, 31))	('BAP1', 'Gene', (36, 40))	('mutations', 'Var', (13, 22))
71299	30349421	Serving as tumor suppressor genes in ccRCC, BAP1 and SETD2 mutations were related to worse cancer-specific survival.	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('worse', 'NegReg', (85, 90))	('tumor', 'Disease', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('BAP1', 'Gene', '8314', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('related', 'Reg', (74, 81))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('11', '27'))	('mutations', 'Var', (59, 68))	('BAP1', 'Gene', (44, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('SETD2', 'Gene', (53, 58))	('cancer', 'Disease', (91, 97))	('tumor suppressor', 'biological_process', 'GO:0051726', ('11', '27'))	('RCC', 'Disease', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('SETD2', 'Gene', '29072', (53, 58))
71300	30349421	In the TCGA database, only mutations in BAP1 were reported to be associated with poor survival outcome.	('mutations', 'Var', (27, 36))	('BAP1', 'Gene', (40, 44))	('associated', 'Reg', (65, 75))	('BAP1', 'Gene', '8314', (40, 44))
71302	30349421	Thus, ccRCC patients who were confirmed to have BAP1 and SETD2 mutations should be followed up regularly.	('mutations', 'Var', (63, 72))	('SETD2', 'Gene', '29072', (57, 62))	('RCC', 'Disease', (8, 11))	('BAP1', 'Gene', '8314', (48, 52))	('patients', 'Species', '9606', (12, 20))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('BAP1', 'Gene', (48, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (6, 11))	('SETD2', 'Gene', (57, 62))
71305	30349421	While Casuscelli and partners unraveled that TP53 was mutated at a frequency of 58% in 38 metastatic ChRCC cases, which was much higher than that unmasked by the TCGA project and our study.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('TP53', 'Gene', (45, 49))	('mutated', 'Var', (54, 61))	('TP53', 'Gene', '7157', (45, 49))
71306	30349421	In addition, those researchers found that mutations in TP53 and PTEN and imbalanced chromosome duplication in primary ChRCC were associated with worse survival.	('associated', 'Reg', (129, 139))	('PTEN', 'Gene', '5728', (64, 68))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('imbalanced chromosome duplication', 'Var', (73, 106))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('worse', 'NegReg', (145, 150))	('PTEN', 'Gene', (64, 68))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('mutations', 'Var', (42, 51))
71309	30349421	Thus, we hypothesised that somatically mutated TP53 might serve as an important factor contributing to the aggressiveness of ChRCC.	('somatically mutated', 'Var', (27, 46))	('contributing', 'Reg', (87, 99))	('aggressiveness', 'Disease', 'MESH:D001523', (107, 121))	('TP53', 'Gene', '7157', (47, 51))	('aggressiveness', 'Phenotype', 'HP:0000718', (107, 121))	('aggressiveness', 'Disease', (107, 121))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('TP53', 'Gene', (47, 51))
71318	30349421	None of those gene mutations were reported to correlate with PD-L1 expression in RCC tumor cells previously.	('RCC tumor', 'Disease', 'MESH:C538614', (81, 90))	('PD-L1', 'Gene', (61, 66))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('mutations', 'Var', (19, 28))	('RCC tumor', 'Disease', (81, 90))	('PD-L1', 'Gene', '29126', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
71322	30349421	Previous studies had revealed that PD-L1 expression had an association with poor overall survival in ccRCC, while the TCGA database indicated that only mutations in BAP1 were associated with poor survival in ccRCC.	('associated', 'Reg', (175, 185))	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('poor', 'NegReg', (76, 80))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (210, 213))	('PD-L1', 'Gene', '29126', (35, 40))	('mutations', 'Var', (152, 161))	('BAP1', 'Gene', (165, 169))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('overall survival', 'MPA', (81, 97))	('RCC', 'Disease', (210, 213))	('PD-L1', 'Gene', (35, 40))	('BAP1', 'Gene', '8314', (165, 169))	('RCC', 'Disease', 'MESH:C538614', (210, 213))	('ccRCC', 'Phenotype', 'HP:0006770', (208, 213))
71328	30349421	We identified somatic mutations in RCC from 26 Chinese patients using WES, which enriched the racial diversity of the somatic mutation profiles of RCC subjects.	('RCC', 'Disease', (35, 38))	('RCC', 'Disease', (147, 150))	('mutations', 'Var', (22, 31))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('patients', 'Species', '9606', (55, 63))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
71329	30349421	We also detected numerous novel somatic mutations in this study, which further supplements the somatic mutation profiles of RCC.	('RCC', 'Disease', (124, 127))	('mutations', 'Var', (40, 49))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))
71336	29202733	miR99a was overexpressed in most samples and its target gene mTOR was underexpressed, this also occurs for miRNAs 106a, 106b, and their target gene VHL.	('VHL', 'Gene', (148, 151))	('VHL', 'Gene', '7428', (148, 151))	('miR99a', 'Gene', (0, 6))	('miR99a', 'Gene', '407055', (0, 6))	('mTOR', 'Gene', (61, 65))	('mTOR', 'Gene', '2475', (61, 65))	('miRNAs', 'Var', (107, 113))
71342	29202733	Dysregulation of miRNAs has been shown to result in gene expression alteration and contributes to invasion and metastasis of many human tumors.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('Dysregulation', 'Var', (0, 13))	('invasion', 'CPA', (98, 106))	('miRNAs', 'Protein', (17, 23))	('result', 'Reg', (42, 48))	('contributes', 'Reg', (83, 94))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('alteration', 'Reg', (68, 78))	('gene expression', 'MPA', (52, 67))	('gene expression', 'biological_process', 'GO:0010467', ('52', '67'))	('human', 'Species', '9606', (130, 135))
71343	29202733	Prior studies indicated that miRNAs are also involved in other processes like tumor angiogenesis.	('miRNAs', 'Var', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('involved', 'Reg', (45, 53))	('tumor', 'Disease', (78, 83))	('angiogenesis', 'biological_process', 'GO:0001525', ('84', '96'))
71346	29202733	Remarkably, targeted disruption of angiogenesis-related miRNAs may be a potential target treatment for RCC and other cancers.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('targeted disruption', 'Var', (12, 31))	('angiogenesis-related miRNAs', 'Protein', (35, 62))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('angiogenesis', 'biological_process', 'GO:0001525', ('35', '47'))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
71347	29202733	ccRCC is characteristically highly vascularized and related to a germinative mutation of the von Hipple-Lindau (VHL) gene.	('RCC', 'Disease', (2, 5))	('mutation', 'Var', (77, 85))	('von Hipple-Lindau', 'Disease', (93, 110))	('VHL', 'Gene', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('VHL', 'Gene', '7428', (112, 115))	('related', 'Reg', (52, 59))	('von Hipple-Lindau', 'Disease', 'MESH:D006623', (93, 110))
71349	29202733	In the absence of the VHL protein, due to gene mutation and or deletion, even during normal oxygen conditions HIF1-alpha will bind to the constitutively expressed HIF1, thus forming a heterodimer (HIF-1) activating transcription of genes related to angiogenesis and cell survival as VEGF, EGFR, PDGF, TGF-alpha, erythropoietin ERK and mTOR.	('VEGF', 'Gene', '7422', (283, 287))	('PDGF', 'molecular_function', 'GO:0005161', ('295', '299'))	('erythropoietin ERK', 'Gene', (312, 330))	('VHL', 'Gene', (22, 25))	('HIF1-alpha', 'Gene', (110, 120))	('EGFR', 'Gene', (289, 293))	('HIF1', 'Gene', '3091', (110, 114))	('erythropoietin', 'molecular_function', 'GO:0005128', ('312', '326'))	('VEGF', 'Gene', (283, 287))	('deletion', 'Var', (63, 71))	('HIF1', 'Gene', (110, 114))	('oxygen', 'Chemical', 'MESH:D010100', (92, 98))	('PDGF', 'Gene', (295, 299))	('transcription', 'MPA', (215, 228))	('TGF-alpha', 'Gene', (301, 310))	('VHL', 'Gene', '7428', (22, 25))	('activating', 'PosReg', (204, 214))	('HIF1-alpha', 'Gene', '3091', (110, 120))	('mTOR', 'Gene', (335, 339))	('genes', 'Gene', (232, 237))	('EGFR', 'Gene', '1956', (289, 293))	('HIF-1', 'Gene', '3091', (197, 202))	('HIF1', 'Gene', '3091', (163, 167))	('bind', 'Interaction', (126, 130))	('HIF-1', 'Gene', (197, 202))	('mTOR', 'Gene', '2475', (335, 339))	('ERK', 'molecular_function', 'GO:0004707', ('327', '330'))	('EGFR', 'molecular_function', 'GO:0005006', ('289', '293'))	('HIF1', 'Gene', (163, 167))	('angiogenesis', 'biological_process', 'GO:0001525', ('249', '261'))	('mutation', 'Var', (47, 55))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('TGF-alpha', 'Gene', '7039', (301, 310))	('transcription', 'biological_process', 'GO:0006351', ('215', '228'))
71351	29202733	miR-126; miR-100,, miR-200 and miR-26a are some examples of this group of miRNAs.	('miR-200', 'Var', (19, 26))	('miR-26a', 'Gene', '407015', (31, 38))	('miR-126', 'Gene', '406913', (0, 7))	('miR-26a', 'Gene', (31, 38))	('miR-126', 'Gene', (0, 7))	('miR-100', 'Gene', (9, 16))	('miR-100', 'Gene', '406892', (9, 16))
71403	29202733	Actually, miRNAs are estimated to regulate 30% of all gene transcripts, it is highly possible that their aberrant expression will contribute to ccRCC formation by altering the balance between oncogenes and tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor suppressor', 'biological_process', 'GO:0051726', ('206', '222'))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('tumor', 'Disease', (206, 211))	('contribute', 'Reg', (130, 140))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('altering', 'Reg', (163, 171))	('formation', 'biological_process', 'GO:0009058', ('150', '159'))	('aberrant', 'Var', (105, 113))	('balance', 'MPA', (176, 183))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('206', '222'))
71498	31652588	The same treatment also induced other significant nuclear abnormalities (Supplementary Figure S6c, yellow arrow), mostly driven by CI-994.	('nuclear abnormalities', 'Disease', (50, 71))	('nuclear abnormalities', 'Disease', 'MESH:C564596', (50, 71))	('CI-994', 'Var', (131, 137))
71520	31652588	Interestingly, C2 inhibited cell viability much more efficiently in MDA-MB-435 than in M14 cells (90 +- 10%, vs. 40 +- 11%; Figure 5c).	('cell viability', 'CPA', (28, 42))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (68, 78))	('inhibited', 'NegReg', (18, 27))	('MDA-MB-435', 'Var', (68, 78))
71534	31652588	(2012) who demonstrated that HDAC6 treatment with trichostatin A or tubacin can effectively downregulate the activity of EGFR in the pdkd1-mutant epithelial cells, which in turn, results in the decreased phosphorylation of other targets downstream of EGFR, including ERK1/2.	('EGFR', 'Gene', '1956', (121, 125))	('EGFR', 'Gene', (251, 255))	('EGFR', 'Gene', '1956', (251, 255))	('HDAC6', 'Gene', '10013', (29, 34))	('EGFR', 'molecular_function', 'GO:0005006', ('251', '255'))	('downregulate', 'NegReg', (92, 104))	('trichostatin A', 'Chemical', 'MESH:C012589', (50, 64))	('EGFR', 'Gene', (121, 125))	('phosphorylation', 'biological_process', 'GO:0016310', ('204', '219'))	('EGFR', 'molecular_function', 'GO:0005006', ('121', '125'))	('activity', 'MPA', (109, 117))	('ERK1', 'molecular_function', 'GO:0004707', ('267', '271'))	('decreased', 'NegReg', (194, 203))	('phosphorylation', 'MPA', (204, 219))	('tubacin', 'Chemical', 'MESH:C474316', (68, 75))	('HDAC6', 'Gene', (29, 34))	('pdkd1-mutant', 'Gene', (133, 145))	('pdkd1-mutant', 'Var', (133, 145))
71536	31652588	The loss of VHL has been shown to extend the activation of EGFR and is associated with increased receptor half-life and retention in the endocytic pathway (the half-life time of EGFR is approx.	('extend', 'PosReg', (34, 40))	('increased', 'PosReg', (87, 96))	('EGFR', 'Gene', '1956', (178, 182))	('EGFR', 'Gene', (59, 63))	('retention', 'biological_process', 'GO:0051235', ('120', '129'))	('EGFR', 'molecular_function', 'GO:0005006', ('178', '182'))	('EGFR', 'Gene', (178, 182))	('activation', 'MPA', (45, 55))	('EGFR', 'molecular_function', 'GO:0005006', ('59', '63'))	('endocytic pathway', 'Pathway', (137, 154))	('receptor half-life', 'MPA', (97, 115))	('VHL', 'Disease', 'MESH:D006623', (12, 15))	('VHL', 'Disease', (12, 15))	('EGFR', 'Gene', '1956', (59, 63))	('loss', 'Var', (4, 8))
71542	31652588	Compounds that prevent pole clustering have emerged as a promising therapeutic agent, since they specifically target cancer cells that form multipolar spindles due to abnormal centrosome numbers, but do not affect mitotic progression in nonmalignant cells with normal centrosome numbers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('centrosome', 'cellular_component', 'GO:0005813', ('176', '186'))	('centrosome', 'cellular_component', 'GO:0005813', ('268', '278'))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('mis', 'Gene', '268', (60, 63))	('mis', 'Gene', (60, 63))	('cancer', 'Disease', (117, 123))	('abnormal', 'Var', (167, 175))
71546	31652588	So far, three HSET inhibitors have been reported: CW069, AZ82, and SR31527, but their clinical efficacy has not yet been reported.	('HSET', 'Gene', '3833', (14, 18))	('CW069', 'Var', (50, 55))	('SR31527', 'Var', (67, 74))	('HSET', 'Gene', (14, 18))	('AZ82', 'Var', (57, 61))	('SR31527', 'Chemical', 'MESH:C018147', (67, 74))
71580	31652588	The secondary antibodies (Invitrogen, Zug, Switzerland) used were Alexa Fluor 488 anti-mouse (A21202), Alexa Fluor 594 anti-rabbit (A11012), Alexa Fluor 568 anti-rabbit (A11036), and Alexa Fluor 647 anti-human (A21445), diluted 1:400 and incubated for 30 min at RT on cells.	('rabbit', 'Species', '9986', (124, 130))	('A21445', 'Var', (211, 217))	('rabbit', 'Species', '9986', (162, 168))	('Alexa Fluor', 'Chemical', 'MESH:C569686', (141, 152))	('Alexa Fluor', 'Chemical', 'MESH:C569686', (66, 77))	('mouse', 'Species', '10090', (87, 92))	('A21202', 'Var', (94, 100))	('Alexa Fluor', 'Chemical', 'MESH:C569686', (103, 114))	('Alexa Fluor', 'Chemical', 'MESH:C569686', (183, 194))	('human', 'Species', '9606', (204, 209))	('A11036', 'Var', (170, 176))	('A11012', 'Var', (132, 138))
71595	30877265	The association between alteration of m6A regulators and clinicopathological characteristics was examined using chi-square test.	('m6A', 'Gene', (38, 41))	('alteration', 'Var', (24, 34))	('m6A', 'Gene', '56339', (38, 41))
71596	30877265	The results showed that alteration of m6A regulators was associated with pathologic stage.	('m6A', 'Gene', (38, 41))	('alteration', 'Var', (24, 34))	('associated', 'Reg', (57, 67))	('m6A', 'Gene', '56339', (38, 41))
71597	30877265	Patients with any CNVs of the regulatory genes had worse OS and DFS than those with diploid genes.	('worse', 'NegReg', (51, 56))	('CNVs', 'Var', (18, 22))	('DFS', 'MPA', (64, 67))	('Patients', 'Species', '9606', (0, 8))
71598	30877265	Moreover, deletion of m6A "writer" genes was an independent risk factor for OS, and copy number gain of "eraser" genes could magnify the effect in a synergistic way.	('m6A', 'Gene', (22, 25))	('m6A', 'Gene', '56339', (22, 25))	('deletion', 'Var', (10, 18))	('copy number gain', 'Var', (84, 100))
71600	30877265	Thus, we for the first time determined genetic alterations of m6A regulators in ccRCC and found a significant relationship between the alterations and worse clinical characteristics.	('genetic alterations', 'Var', (39, 58))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('m6A', 'Gene', (62, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('m6A', 'Gene', '56339', (62, 65))
71601	30877265	The findings provide us clues to understand epigenetic modification of RNA in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('epigenetic modification', 'Var', (44, 67))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('RNA', 'cellular_component', 'GO:0005562', ('71', '74'))	('RNA', 'Protein', (71, 74))
71617	30877265	m6A dysregulation is involved in diverse cellular process and causes decreased cell proliferation, impaired self-renewal capacity, developmental defects and cell death.	('m6A', 'Gene', '56339', (0, 3))	('cell proliferation', 'CPA', (79, 97))	('self-renewal capacity', 'CPA', (108, 129))	('dysregulation', 'Var', (4, 17))	('involved', 'Reg', (21, 29))	('decreased', 'NegReg', (69, 78))	('cell proliferation', 'biological_process', 'GO:0008283', ('79', '97'))	('cell death', 'biological_process', 'GO:0008219', ('157', '167'))	('cellular process', 'cellular_component', 'GO:0042995', ('41', '57'))	('impaired', 'NegReg', (99, 107))	('developmental defects and cell death', 'Disease', 'MESH:D003643', (131, 167))	('cellular process', 'biological_process', 'GO:0009987', ('41', '57'))	('m6A', 'Gene', (0, 3))
71618	30877265	It has been reported that the alterations of m6A regulatory genes play an important role in the pathogenesis of a variety of human disease including obesity, impairment of spermatogenesis, neuronal disorders and immunological disease.	('immunological disease', 'Phenotype', 'HP:0002715', (212, 233))	('obesity', 'Disease', (149, 156))	('m6A', 'Gene', '56339', (45, 48))	('neuronal disorders', 'Disease', (189, 207))	('immunological disease', 'Disease', (212, 233))	('spermatogenesis', 'Disease', (172, 187))	('obesity', 'Disease', 'MESH:D009765', (149, 156))	('human', 'Species', '9606', (125, 130))	('obesity', 'Phenotype', 'HP:0001513', (149, 156))	('impairment of spermatogenesis', 'Phenotype', 'HP:0008669', (158, 187))	('alterations', 'Var', (30, 41))	('role', 'Reg', (84, 88))	('spermatogenesis', 'biological_process', 'GO:0007283', ('172', '187'))	('impairment', 'Disease', (158, 168))	('neuronal disorders', 'Disease', 'MESH:D009410', (189, 207))	('immunological disease', 'Disease', 'MESH:D007154', (212, 233))	('m6A', 'Gene', (45, 48))	('pathogenesis', 'biological_process', 'GO:0009405', ('96', '108'))
71619	30877265	More recently, the alterations of m6A regulatory genes have been shown to promote progression of both breast cancer and hematologic malignancies through cancer stem cell formation and abnormal differentiation state maintenance.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('breast cancer', 'Disease', (102, 115))	('m6A', 'Gene', '56339', (34, 37))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('promote', 'PosReg', (74, 81))	('progression', 'CPA', (82, 93))	('cancer', 'Disease', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('alterations', 'Var', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('hematologic malignancies', 'Disease', 'MESH:D019337', (120, 144))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('hematologic malignancies', 'Disease', (120, 144))	('m6A', 'Gene', (34, 37))	('formation', 'biological_process', 'GO:0009058', ('170', '179'))
71620	30877265	Another study also proves that METTL3, a major RNA N6-adenosine methyltransferase, promotes liver cancer progression through YTHDF2 dependent post-transcriptional silencing of SOCS2.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('liver cancer', 'Disease', (92, 104))	('SOCS2', 'Gene', (176, 181))	('METTL3', 'Gene', '56339', (31, 37))	('adenosine', 'Chemical', 'MESH:D000241', (54, 63))	('YTHDF2', 'Gene', '51441', (125, 131))	('promotes', 'PosReg', (83, 91))	('METTL3', 'Gene', (31, 37))	('RNA', 'cellular_component', 'GO:0005562', ('47', '50'))	('YTHDF2', 'Gene', (125, 131))	('SOCS2', 'Gene', '8835', (176, 181))	('liver cancer', 'Phenotype', 'HP:0002896', (92, 104))	('liver cancer', 'Disease', 'MESH:D006528', (92, 104))	('post-transcriptional silencing', 'Var', (142, 172))
71625	30877265	Furthermore, we also observed frequent CNVs of VHL (89.02%) and TP53 (14.58%) in this cohort in line with published literatures.	('VHL', 'Gene', (47, 50))	('CNVs', 'Var', (39, 43))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('VHL', 'Gene', '7428', (47, 50))
71626	30877265	Next, we evaluated the CNV patterns in ccRCC samples and found that most of the CNV events led to loss of copy number (737/1331) (Figure 1B, Table 2), which was similar as the CNV status in AML.	('737/1331', 'Var', (119, 127))	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('copy', 'MPA', (106, 110))	('AML', 'Disease', 'MESH:D015470', (190, 193))	('AML', 'Disease', (190, 193))	('loss', 'NegReg', (98, 102))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))
71627	30877265	Copy number gain of YTHDC2 was the most frequent alteration in all the CNVs of m6A regulatory genes (Figure 1C), and the simultaneous shallow deletions of METTL3 and YTHDC2 also ranked first among the concurrence of CNVs in two genes, implying the importance of m6A writer genes in the process of RNA m6A modification.	('m6A', 'Gene', (262, 265))	('YTHDC2', 'Gene', '64848', (20, 26))	('m6A', 'Gene', '56339', (79, 82))	('m6A', 'Gene', (301, 304))	('YTHDC2', 'Gene', (20, 26))	('m6A', 'Gene', '56339', (262, 265))	('METTL3', 'Gene', '56339', (155, 161))	('deletions', 'Var', (142, 151))	('m6A', 'Gene', '56339', (301, 304))	('gain', 'PosReg', (12, 16))	('METTL3', 'Gene', (155, 161))	('RNA', 'cellular_component', 'GO:0005562', ('297', '300'))	('Copy number', 'Var', (0, 11))	('YTHDC2', 'Gene', '64848', (166, 172))	('m6A', 'Gene', (79, 82))	('YTHDC2', 'Gene', (166, 172))
71628	30877265	Then, we assessed the relationship between alterations (CNV and/or mutation) of m6A regulatory genes and the clinicopathological characteristics of patients.	('patients', 'Species', '9606', (148, 156))	('mutation', 'Var', (67, 75))	('m6A', 'Gene', '56339', (80, 83))	('m6A', 'Gene', (80, 83))
71629	30877265	The results revealed that alterations of m6A regulatory genes were significantly associated with higher Fuhrman Nuclear Grade (Table 3).	('Fuhrman Nuclear Grade', 'CPA', (104, 125))	('higher', 'PosReg', (97, 103))	('m6A', 'Gene', '56339', (41, 44))	('alterations', 'Var', (26, 37))	('m6A', 'Gene', (41, 44))	('associated', 'Reg', (81, 91))
71632	30877265	The effects of alterations in m6A regulatory genes on the mRNA expression were next evaluated.	('m6A', 'Gene', '56339', (30, 33))	('m6A', 'Gene', (30, 33))	('alterations', 'Var', (15, 26))
71637	30877265	Furthermore, separate analysis of the ten genes revealed that patients affected by deletions of YTHDC1, METTL14 or METTL3 (one reader and two writer genes of m6A) had poorer OS and DFS (Figure 3C-H); while, no significant difference was observed between different subgroups based on the CNVs of the other ten m6A regulatory genes (Figure S2).	('DFS', 'CPA', (181, 184))	('m6A', 'Gene', '56339', (309, 312))	('YTHDC1', 'Gene', (96, 102))	('YTHDC1', 'Gene', '91746', (96, 102))	('METTL14', 'Gene', '57721', (104, 111))	('METTL14', 'Gene', (104, 111))	('deletions', 'Var', (83, 92))	('METTL3', 'Gene', '56339', (115, 121))	('patients', 'Species', '9606', (62, 70))	('METTL3', 'Gene', (115, 121))	('m6A', 'Gene', (158, 161))	('m6A', 'Gene', (309, 312))	('m6A', 'Gene', '56339', (158, 161))	('poorer', 'NegReg', (167, 173))
71638	30877265	Multivariate Cox regression analyses demonstrated that alteration of m6A regulator genes was an independent risk factor for overall survival (Table 5).	('alteration', 'Var', (55, 65))	('m6A', 'Gene', (69, 72))	('overall', 'MPA', (124, 131))	('m6A', 'Gene', '56339', (69, 72))
71640	30877265	In order to confirm the above conclusion, we next tested it among patients who were affected by two kinds of CNVs (deletions of writer genes and copy number gain of eraser genes).	('eraser genes', 'Gene', (165, 177))	('tested', 'Reg', (50, 56))	('copy number gain', 'Var', (145, 161))	('writer genes', 'Gene', (128, 140))	('deletions', 'Var', (115, 124))	('patients', 'Species', '9606', (66, 74))
71641	30877265	As the result showed, patients with deletions of writer genes in combination with copy number gain of eraser genes had worse OS and DFS than those with only deletions of writer genes (Figure 4A-B).	('worse', 'NegReg', (119, 124))	('writer genes', 'Gene', (49, 61))	('deletions', 'Var', (36, 45))	('patients', 'Species', '9606', (22, 30))	('gain', 'PosReg', (94, 98))	('DFS', 'MPA', (132, 135))
71652	30877265	In this ccRCC cohort, the frequency of alterations of the ten m6A related genes was much higher than that reported in AML, implying that dysregulation of m6A might play a more important role in ccRCC tumorigenesis compared with AML.	('m6A', 'Gene', (62, 65))	('RCC', 'Disease', 'MESH:C538614', (196, 199))	('dysregulation', 'Var', (137, 150))	('tumor', 'Disease', (200, 205))	('m6A', 'Gene', '56339', (154, 157))	('RCC', 'Disease', (10, 13))	('RCC', 'Phenotype', 'HP:0005584', (10, 13))	('AML', 'Disease', 'MESH:D015470', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (8, 13))	('AML', 'Disease', 'MESH:D015470', (228, 231))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('AML', 'Disease', (228, 231))	('AML', 'Disease', (118, 121))	('m6A', 'Gene', (154, 157))	('RCC', 'Disease', 'MESH:C538614', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('alterations', 'Var', (39, 50))	('RCC', 'Disease', (196, 199))	('RCC', 'Phenotype', 'HP:0005584', (196, 199))	('ccRCC', 'Phenotype', 'HP:0006770', (194, 199))	('m6A', 'Gene', '56339', (62, 65))
71654	30877265	In addition, the "writers" METTL3 and METTL14 were more predisposed to mutation or CNV than the other genes in ccRCC, while alterations of the "erasers" FTO and ALKBH5 were proved to be more important in breast cancer, glioblastoma and hematological malignancies.	('hematological malignancies', 'Disease', 'MESH:D019337', (236, 262))	('hematological malignancies', 'Phenotype', 'HP:0004377', (236, 262))	('CNV', 'Var', (83, 86))	('glioblastoma', 'Disease', 'MESH:D005909', (219, 231))	('ALKBH5', 'Gene', (161, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (204, 217))	('predisposed', 'Reg', (56, 67))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('ALKBH5', 'Gene', '54890', (161, 167))	('RCC', 'Disease', (113, 116))	('glioblastoma', 'Disease', (219, 231))	('breast cancer', 'Disease', 'MESH:D001943', (204, 217))	('breast cancer', 'Disease', (204, 217))	('FTO', 'Gene', '79068', (153, 156))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('glioblastoma', 'Phenotype', 'HP:0012174', (219, 231))	('hematological malignancies', 'Disease', (236, 262))	('FTO', 'Gene', (153, 156))	('METTL3', 'Gene', (27, 33))	('METTL14', 'Gene', '57721', (38, 45))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('METTL3', 'Gene', '56339', (27, 33))	('mutation', 'Var', (71, 79))	('METTL14', 'Gene', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
71657	30877265	Considering the opposite effect on m6A status for the two gene groups, these alterations eventually decreased the m6A level in ccRCC.	('m6A', 'Gene', (35, 38))	('m6A', 'Gene', (114, 117))	('m6A', 'Gene', '56339', (35, 38))	('m6A', 'Gene', '56339', (114, 117))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('alterations', 'Var', (77, 88))	('RCC', 'Disease', (129, 132))	('decreased', 'NegReg', (100, 109))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))
71662	30877265	The consequent decreased level of NANOG mRNA m6A modification resulted in the upregulation of NANOG expression, which was a key transcription factor that is associated with pluripotency.	('transcription', 'biological_process', 'GO:0006351', ('128', '141'))	('m6A', 'Gene', '56339', (45, 48))	('NANOG', 'Gene', '79923', (34, 39))	('NANOG', 'Gene', (34, 39))	('expression', 'MPA', (100, 110))	('upregulation', 'PosReg', (78, 90))	('modification', 'Var', (49, 61))	('decreased', 'NegReg', (15, 24))	('NANOG', 'Gene', '79923', (94, 99))	('NANOG', 'Gene', (94, 99))	('m6A', 'Gene', (45, 48))	('transcription factor', 'molecular_function', 'GO:0000981', ('128', '148'))
71664	30877265	Considering the high frequency of inactivation of von Hippel-Lindau (VHL) gene and the upregulated hypoxia induced factor-alpha (HIF- alpha) in ccRCC, we hypothesize that there may exist a m6A regulatory pathway (VHL-HIF-ZNF217-METTL3/METTL14) in ccRCC cells, leading to the formation and maintenance of ccRCC cancer stem cells.	('ccRCC', 'Phenotype', 'HP:0006770', (304, 309))	('formation', 'biological_process', 'GO:0009058', ('275', '284'))	('hypoxia', 'Disease', 'MESH:D000860', (99, 106))	('ZNF217', 'Gene', (221, 227))	('ZNF217', 'Gene', '7764', (221, 227))	('VHL-HIF', 'Disease', (213, 220))	('VHL', 'Gene', '7428', (213, 216))	('METTL3', 'Gene', (228, 234))	('VHL', 'Gene', (69, 72))	('cancer', 'Disease', (310, 316))	('m6A', 'Gene', '56339', (189, 192))	('RCC', 'Phenotype', 'HP:0005584', (306, 309))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('RCC', 'Disease', (306, 309))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('RCC', 'Phenotype', 'HP:0005584', (249, 252))	('formation', 'CPA', (275, 284))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('ccRCC', 'Phenotype', 'HP:0006770', (247, 252))	('RCC', 'Disease', (249, 252))	('METTL3', 'Gene', '56339', (228, 234))	('von Hippel-Lindau', 'Gene', (50, 67))	('m6A', 'Gene', (189, 192))	('VHL', 'Gene', '7428', (69, 72))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', 'MESH:C538614', (306, 309))	('inactivation', 'Var', (34, 46))	('METTL14', 'Gene', (235, 242))	('RCC', 'Disease', 'MESH:C538614', (249, 252))	('METTL14', 'Gene', '57721', (235, 242))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('von Hippel-Lindau', 'Gene', '7428', (50, 67))	('hypoxia', 'Disease', (99, 106))	('VHL', 'Gene', (213, 216))	('upregulated', 'PosReg', (87, 98))	('VHL-HIF', 'Disease', 'MESH:D006623', (213, 220))
71668	30877265	A worst overall survival in patients with writer gene loss of function in combination with eraser gene gain of function was observed, making it clear that decreased level of m6A plays a significant role in ccRCC progression.	('RCC', 'Phenotype', 'HP:0005584', (208, 211))	('writer gene', 'Var', (42, 53))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('RCC', 'Disease', (208, 211))	('m6A', 'Gene', '56339', (174, 177))	('m6A', 'Gene', (174, 177))	('ccRCC', 'Phenotype', 'HP:0006770', (206, 211))	('gain of function', 'PosReg', (103, 119))	('loss of function', 'NegReg', (54, 70))	('patients', 'Species', '9606', (28, 36))
71673	30877265	Similar as our results, a recent study showed knockdown of METTL3 in ccRCC cell lines led to obvious upregulation of PI3k, AKT and mTOR expression and patients with positive METTL3 expression had obviously longer survival time than those with negative METTL3 expression, implying that the mRNAs of molecules in mTOR pathway may be the target mRNA of m6A modification.	('m6A', 'Gene', '56339', (350, 353))	('METTL3', 'Gene', (174, 180))	('survival time', 'CPA', (213, 226))	('mTOR', 'Gene', (131, 135))	('m6A', 'Gene', (350, 353))	('METTL3', 'Gene', '56339', (174, 180))	('METTL3', 'Gene', (252, 258))	('expression', 'MPA', (136, 146))	('mTOR', 'Gene', '2475', (131, 135))	('mTOR', 'Gene', (311, 315))	('METTL3', 'Gene', '56339', (252, 258))	('AKT', 'Gene', (123, 126))	('PI3k', 'Pathway', (117, 121))	('upregulation', 'PosReg', (101, 113))	('RCC', 'Disease', (71, 74))	('positive', 'Var', (165, 173))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('METTL3', 'Gene', (59, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (69, 74))	('mTOR', 'Gene', '2475', (311, 315))	('knockdown', 'Var', (46, 55))	('PI3k', 'molecular_function', 'GO:0016303', ('117', '121'))	('METTL3', 'Gene', '56339', (59, 65))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('patients', 'Species', '9606', (151, 159))	('AKT', 'Gene', '207', (123, 126))	('longer', 'PosReg', (206, 212))
71675	30877265	In addition, we observed the alteration of m6A regulatory genes was significantly associated with VHL mutation and TP53 alteration.	('associated', 'Reg', (82, 92))	('alteration', 'Var', (120, 130))	('mutation', 'Var', (102, 110))	('TP53', 'Gene', '7157', (115, 119))	('VHL', 'Gene', (98, 101))	('m6A', 'Gene', (43, 46))	('TP53', 'Gene', (115, 119))	('VHL', 'Gene', '7428', (98, 101))	('m6A', 'Gene', '56339', (43, 46))	('alteration', 'Var', (29, 39))
71677	30877265	It has been reported in a human liver cancer cell line that loss of METTL3 leads to alternative splicing and gene expression changes of more than 20 genes involved in the p53 signaling pathway including MDM2, MDM4, and P21.	('MDM4', 'Gene', '4194', (209, 213))	('MDM4', 'Gene', (209, 213))	('MDM2', 'Gene', (203, 207))	('p53 signaling pathway', 'biological_process', 'GO:0030330', ('171', '192'))	('human', 'Species', '9606', (26, 31))	('P21', 'Gene', (219, 222))	('gene expression', 'biological_process', 'GO:0010467', ('109', '124'))	('gene expression', 'MPA', (109, 124))	('MDM2', 'Gene', '4193', (203, 207))	('liver cancer', 'Disease', 'MESH:D006528', (32, 44))	('loss', 'Var', (60, 64))	('splicing', 'biological_process', 'GO:0045292', ('96', '104'))	('changes', 'Reg', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('METTL3', 'Gene', (68, 74))	('alternative splicing', 'MPA', (84, 104))	('liver cancer', 'Phenotype', 'HP:0002896', (32, 44))	('liver cancer', 'Disease', (32, 44))	('p53', 'Gene', '7157', (171, 174))	('METTL3', 'Gene', '56339', (68, 74))	('P21', 'Gene', '644914', (219, 222))	('p53', 'Gene', (171, 174))
71679	30877265	Thus, it is likely that genetic alterations of m6A regulators, VHL-mediated hypoxia pathway and p53-mediated cell processes act in a synergistic way to promote the pathogenesis and progress of ccRCC.	('genetic alterations', 'Var', (24, 43))	('ccRCC', 'Phenotype', 'HP:0006770', (193, 198))	('hypoxia', 'Disease', (76, 83))	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('hypoxia', 'Disease', 'MESH:D000860', (76, 83))	('pathogenesis', 'biological_process', 'GO:0009405', ('164', '176'))	('RCC', 'Phenotype', 'HP:0005584', (195, 198))	('m6A', 'Gene', (47, 50))	('VHL', 'Gene', (63, 66))	('VHL', 'Gene', '7428', (63, 66))	('m6A', 'Gene', '56339', (47, 50))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('promote', 'PosReg', (152, 159))	('RCC', 'Disease', (195, 198))
71680	30877265	In conclusion, we for the first time determine the genetic alterations of m6A regulatory genes in ccRCC and find an obvious relationship between the alterations resulting in decreased m6A level and worse clinical characteristics including survival.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('decreased', 'NegReg', (174, 183))	('m6A', 'Gene', (184, 187))	('m6A', 'Gene', (74, 77))	('m6A', 'Gene', '56339', (184, 187))	('m6A', 'Gene', '56339', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('genetic alterations', 'Var', (51, 70))
71684	30877265	To investigate the clinicopathological significance of the status of CNV and/or mutation, this ccRCC cohort was divided into two subgroups; "with mutation and/or CNV of these ten m6A regulatory genes" and "without CNV and mutation".	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('m6A', 'Gene', '56339', (179, 182))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('mutation', 'Var', (146, 154))	('CNV', 'Var', (162, 165))	('m6A', 'Gene', (179, 182))
71689	30877265	Kaplan-Meier curve and log-rank test were used to evaluate the prognosis value of m6A regulatory gene's alteration.	('m6A', 'Gene', '56339', (82, 85))	('m6A', 'Gene', (82, 85))	('alteration', 'Var', (104, 114))
71695	30483771	Overexpression of miR-122 in 786-O cells improved cell proliferation, colony formation, migration and invasion, while knockdown of miR-122 in SN12-PM6 cells inhibited cell growth, colony formation, migration and invasion.	('colony formation', 'CPA', (180, 196))	('formation', 'biological_process', 'GO:0009058', ('187', '196'))	('improved', 'PosReg', (41, 49))	('knockdown', 'Var', (118, 127))	('inhibited', 'NegReg', (157, 166))	('migration', 'CPA', (198, 207))	('invasion', 'CPA', (102, 110))	('miR-122', 'Gene', (131, 138))	('invasion', 'CPA', (212, 220))	('migration', 'CPA', (88, 97))	('SN12-PM6', 'CellLine', 'CVCL:9549', (142, 150))	('cell growth', 'CPA', (167, 178))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('formation', 'biological_process', 'GO:0009058', ('77', '86'))	('colony formation', 'CPA', (70, 86))	('cell growth', 'biological_process', 'GO:0016049', ('167', '178'))	('cell proliferation', 'CPA', (50, 68))
71725	30483771	The miRNA expression profiles were downloaded from the GEO database (http://www.ncbi.nlm.nih.gov/geo/; accession numbers, GSE24457, GSE23085, GSE71302 and GSE95385), which yielded 33 ccRCC tissue samples and 33 paired normal samples in total.	('GSE95385', 'Var', (155, 163))	('GSE71302', 'Var', (142, 150))	('miR', 'Gene', (4, 7))	('miR', 'Gene', '220972', (4, 7))	('GSE23085', 'Var', (132, 140))	('GSE24457', 'Var', (122, 130))	('ccRCC', 'Disease', (183, 188))
71751	30483771	ab97051 and ab97023, respectively; Abcam) incubation for 1 h at 37 C. Immunoreactive bands of the proteins were normalized to beta-actin and visualized using enhanced chemiluminescence detection reagent (Thermo Fisher Scientific, Inc.).	('beta-actin', 'Gene', (126, 136))	('ab97023', 'Var', (12, 19))	('beta-actin', 'Gene', '728378', (126, 136))
71757	30483771	The wild-type or mutated 3'-UTR of FOXO3 containing the miR-122 binding site was cloned into a psiCHECK2 vector (Promega Corporation, Madison, WI, USA) provided by Genewiz, Inc. (Beijing, China).	('FOXO3', 'Gene', '2309', (35, 40))	('binding', 'molecular_function', 'GO:0005488', ('64', '71'))	('mutated', 'Var', (17, 24))	('FOXO3', 'Gene', (35, 40))
71758	30483771	To test the function of miR-122 on luciferase activity, 293T cells were co-transfected with luciferase reporter of wild-type (WT) or mutated (MUT) 3'-UTR and miR-122 mimics or control using Lipofectamine 2000.	('luciferase activity', 'molecular_function', 'GO:0045289', ('35', '54'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('35', '54'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('35', '54'))	('293T', 'CellLine', 'CVCL:0063', (56, 60))	('mutated', 'Var', (133, 140))	('luciferase activity', 'molecular_function', 'GO:0047077', ('35', '54'))	('miR-122', 'Gene', (158, 165))	('luciferase activity', 'molecular_function', 'GO:0047712', ('35', '54'))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (190, 208))
71769	30483771	miRNA expression profiles GSE24457, GSE23085, GSE71302 and GSE95385 were downloaded from GEO.	('GSE95385', 'Var', (59, 67))	('GSE71302', 'Var', (46, 54))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('GSE24457', 'Var', (26, 34))	('GSE23085', 'Var', (36, 44))
71773	30483771	It was determined that high levels of miR-21, miR-155 and miR-122 were significantly associated with poor overall survival time (Fig.	('overall', 'MPA', (106, 113))	('poor', 'NegReg', (101, 105))	('miR-21', 'Gene', (38, 44))	('miR-122', 'Var', (58, 65))	('miR-155', 'Gene', '406947', (46, 53))	('miR-21', 'Gene', '406991', (38, 44))	('miR-155', 'Gene', (46, 53))
71781	30483771	Kaplan-Meier analysis demonstrated that patients in the high miR-122 group had a reduced metastasis-free survival time, compared with those in the low miR-122 group (P<0.01; Fig.	('metastasis-free survival time', 'CPA', (89, 118))	('patients', 'Species', '9606', (40, 48))	('high miR-122', 'Var', (56, 68))	('reduced', 'NegReg', (81, 88))
71793	30483771	As FOXO3 was predicted to be the target of miR-122 and has been demonstrated to be downregulated in ccRCC.	('miR-122', 'Var', (43, 50))	('downregulated', 'NegReg', (83, 96))	('FOXO3', 'Gene', (3, 8))	('FOXO3', 'Gene', '2309', (3, 8))	('ccRCC', 'Disease', (100, 105))
71798	30483771	These data reveal that FOXO3 protein expression is negatively regulated by miR-122.	('FOXO3', 'Gene', (23, 28))	('FOXO3', 'Gene', '2309', (23, 28))	('negatively', 'NegReg', (51, 61))	('miR-122', 'Var', (75, 82))	('protein', 'Protein', (29, 36))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))
71801	30483771	4E), indicating that miR-122 directly binds to the predicted site in the FOXO3 3'-UTR and negatively regulates FOXO3 expression.	('FOXO3', 'Gene', '2309', (111, 116))	('FOXO3', 'Gene', '2309', (73, 78))	('negatively', 'NegReg', (90, 100))	('expression', 'MPA', (117, 127))	('miR-122', 'Var', (21, 28))	('regulates', 'Reg', (101, 110))	('FOXO3', 'Gene', (111, 116))	('FOXO3', 'Gene', (73, 78))	('binds', 'Interaction', (38, 43))
71804	30483771	RT-qPCR analysis confirmed that miR-122 mimics reduced FOXO3 expression, compared with mimics NC groups (P<0.001; Fig.	('FOXO3', 'Gene', '2309', (55, 60))	('mimics', 'Var', (40, 46))	('miR-122', 'Gene', (32, 39))	('FOXO3', 'Gene', (55, 60))	('reduced', 'NegReg', (47, 54))	('expression', 'MPA', (61, 71))
71805	30483771	Additionally, transfecting miR-122 inhibitor caused significant downregulation of miR-122 and significantly upregulation of FOXO3, compared with inhibitor NC groups (P<0.001; Fig.	('miR-122', 'Gene', (27, 34))	('FOXO3', 'Gene', '2309', (124, 129))	('downregulation', 'NegReg', (64, 78))	('inhibitor', 'Var', (35, 44))	('miR-122', 'Gene', (82, 89))	('upregulation', 'PosReg', (108, 120))	('FOXO3', 'Gene', (124, 129))
71808	30483771	In siFOXO3 groups, FOXO3 downregulation effectively reversed the attenuation of SN12-PM6 cell invasion and proliferation induced by the miR-122 inhibitor, compared with siNC groups (P<0.05; Fig.	('inhibitor', 'Var', (144, 153))	('SN12-PM6 cell invasion', 'CPA', (80, 102))	('proliferation', 'CPA', (107, 120))	('FOXO3', 'Gene', '2309', (19, 24))	('SN12-PM6', 'CellLine', 'CVCL:9549', (80, 88))	('FOXO3', 'Gene', '2309', (5, 10))	('miR-122', 'Gene', (136, 143))	('downregulation', 'NegReg', (25, 39))	('FOXO3', 'Gene', (5, 10))	('attenuation', 'NegReg', (65, 76))	('siFOXO3', 'Chemical', '-', (3, 10))	('FOXO3', 'Gene', (19, 24))
71817	30483771	Recent studies revealed that miRNAs may be secreted to circulation, assisting cancer cells in metastasis and colonization Reports demonstrated that miR-122 is dysregulated in numerous cancer types, including liver, breast and lung.	('numerous cancer', 'Disease', (175, 190))	('cancer', 'Disease', (184, 190))	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', (29, 32))	('dysregulated', 'Var', (159, 171))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('numerous cancer', 'Disease', 'MESH:D009369', (175, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('breast', 'Disease', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('miR', 'Gene', '220972', (148, 151))	('lung', 'Disease', (226, 230))	('miR', 'Gene', (148, 151))	('liver', 'Disease', (208, 213))
71821	30483771	However, in colorectal cancer (CRC), increased miR-122 levels were associated with a poor prognostic subtype, indicating that miR-122 may act as an oncogene in CRC.	('colorectal cancer', 'Disease', (12, 29))	('miR-122 levels', 'MPA', (47, 61))	('miR-122', 'Var', (126, 133))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('increased', 'PosReg', (37, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
71823	30483771	Lian et al demonstrated that miR-122 can promote the proliferation and invasion of renal cancer cell lines, but there was not further verification in clinical samples and in vivo experiments.	('miR-122', 'Var', (29, 36))	('renal cancer', 'Disease', (83, 95))	('invasion', 'CPA', (71, 79))	('promote', 'PosReg', (41, 48))	('clinical samples', 'Species', '191496', (150, 166))	('proliferation', 'CPA', (53, 66))	('renal cancer', 'Disease', 'MESH:D007680', (83, 95))	('Lian', 'Species', '155640', (0, 4))	('renal cancer', 'Phenotype', 'HP:0009726', (83, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
71826	30483771	The data recognized FOXO3 as a direct target of miR-122.	('FOXO3', 'Gene', '2309', (20, 25))	('miR-122', 'Var', (48, 55))	('FOXO3', 'Gene', (20, 25))
71840	32814829	Enhanced YB1/EphA2 axis signaling promotes acquired resistance to sunitinib and metastatic potential in renal cell carcinoma VHL mutations are the most common tumorigenic lesions in clear cell renal cell carcinoma (ccRCC) and result in continued activation of the HIF/VEGF pathway and uncontrolled cancer progression.	('VEGF', 'Gene', (268, 272))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (104, 124))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (182, 213))	('tumorigenic lesions', 'Disease', 'MESH:D002471', (159, 178))	('EphA2', 'Gene', (13, 18))	('EphA2', 'Gene', '1969', (13, 18))	('VHL', 'Gene', (125, 128))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (193, 213))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('YB1', 'Gene', (9, 12))	('YB1', 'Gene', '4904', (9, 12))	('renal cell carcinoma', 'Disease', (104, 124))	('RCC', 'Phenotype', 'HP:0005584', (217, 220))	('clear cell renal cell carcinoma', 'Disease', (182, 213))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (104, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (215, 220))	('RCC', 'Disease', (217, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('activation', 'PosReg', (246, 256))	('VHL', 'Gene', '7428', (125, 128))	('acquired', 'MPA', (43, 51))	('signaling', 'biological_process', 'GO:0023052', ('24', '33'))	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (182, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('mutations', 'Var', (129, 138))	('sunitinib', 'Chemical', 'MESH:D000077210', (66, 75))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (193, 213))	('VEGF', 'Gene', '7422', (268, 272))	('cancer', 'Disease', (298, 304))	('tumorigenic lesions', 'Disease', (159, 178))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
71848	32814829	Clear cell renal cell carcinoma (ccRCC), the most prevalent subtype of renal cell carcinoma (RCC), is characterized by VHL mutations in 70-80% of cases, high metastasis rate and mortality, and resistance to radiotherapy and chemotherapy.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', (93, 96))	('VHL', 'Gene', '7428', (119, 122))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (71, 91))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('metastasis', 'CPA', (158, 168))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('RCC', 'Disease', (35, 38))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('mortality', 'Disease', (178, 187))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('renal cell carcinoma', 'Disease', (71, 91))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (71, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (11, 31))	('VHL', 'Gene', (119, 122))	('mortality', 'Disease', 'MESH:D003643', (178, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('mutations', 'Var', (123, 132))
71865	32814829	High EphA2 levels are correlated with poor prognosis in oesophageal cancers and glioblastomas and promote the proliferation and metastasis of various malignant tumor cells.	('glioblastomas', 'Disease', (80, 93))	('EphA2 levels', 'MPA', (5, 17))	('malignant tumor', 'Disease', 'MESH:D009369', (150, 165))	('metastasis', 'CPA', (128, 138))	('oesophageal cancers', 'Disease', (56, 75))	('promote', 'PosReg', (98, 105))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('proliferation', 'CPA', (110, 123))	('glioblastomas', 'Phenotype', 'HP:0012174', (80, 93))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('malignant tumor', 'Disease', (150, 165))	('oesophageal cancers', 'Disease', 'MESH:D009369', (56, 75))	('glioblastomas', 'Disease', 'MESH:D005909', (80, 93))
71872	32814829	Furthermore, pharmacological inhibition of EphA2 by the small molecule inhibitor ALW-II-41-27 reduced the proliferation of SUN-resistant tumor cells, suppressed tumor growth in vivo, and restored the sensitivity of SUN-resistant tumor cells to SUN in vitro and in vivo.	('SUN-resistant tumor', 'Disease', 'MESH:D060467', (123, 142))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('sensitivity', 'MPA', (200, 211))	('SUN-resistant tumor', 'Disease', (123, 142))	('tumor', 'Disease', (161, 166))	('ALW-II-41-27', 'Chemical', 'MESH:C000605793', (81, 93))	('suppressed', 'NegReg', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('SUN', 'Chemical', 'MESH:D000077210', (215, 218))	('EphA2', 'Gene', (43, 48))	('ALW-II-41-27', 'Gene', (81, 93))	('SUN-resistant tumor', 'Disease', 'MESH:D060467', (215, 234))	('SUN-resistant tumor', 'Disease', (215, 234))	('tumor', 'Disease', (137, 142))	('reduced', 'NegReg', (94, 101))	('restored', 'PosReg', (187, 195))	('tumor', 'Disease', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('sensitivity of SUN', 'Phenotype', 'HP:0000992', (200, 218))	('proliferation', 'CPA', (106, 119))	('inhibition', 'Var', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('SUN', 'Chemical', 'MESH:D000077210', (244, 247))	('SUN', 'Chemical', 'MESH:D000077210', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
71875	32814829	1a, YB1 expression levels were higher in cancer tissues than in adjacent normal tissues, and high YB1 expression correlated with poor OS and disease-free survival (DFS).	('YB1', 'Gene', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('YB1', 'Gene', (4, 7))	('expression', 'MPA', (102, 112))	('YB1', 'Gene', '4904', (98, 101))	('YB1', 'Gene', '4904', (4, 7))	('disease-free survival', 'CPA', (141, 162))	('expression levels', 'MPA', (8, 25))	('cancer', 'Disease', (41, 47))	('higher', 'PosReg', (31, 37))	('poor OS', 'Disease', (129, 136))	('high', 'Var', (93, 97))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
71878	32814829	Gene set enrichment analysis (GSEA) performed using the ccRCC gene pool in the TCGA database showed that genes regulated by high YB1 expression were mainly concentrated in the EMT pathway (Fig.	('YB1', 'Gene', (129, 132))	('YB1', 'Gene', '4904', (129, 132))	('EMT', 'biological_process', 'GO:0001837', ('176', '179'))	('EMT pathway', 'Pathway', (176, 187))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('high', 'Var', (124, 128))	('GSEA', 'Chemical', '-', (30, 34))
71884	32814829	High YB1 expression levels were also significantly associated with higher TNM stage, T stage, M stage, G stage, and poorer OS and DFS (Supplementary Fig.	('T stage', 'CPA', (85, 92))	('higher', 'PosReg', (67, 73))	('M stage', 'CPA', (94, 101))	('High', 'Var', (0, 4))	('TNM', 'Gene', (74, 77))	('G stage', 'CPA', (103, 110))	('expression levels', 'MPA', (9, 26))	('TNM', 'Gene', '10178', (74, 77))	('YB1', 'Gene', (5, 8))	('YB1', 'Gene', '4904', (5, 8))
71891	32814829	We successfully constructed 786-O and ACHN cell lines with stable YB1 knockdown or stable YB1 overexpression (Fig.	('overexpression', 'PosReg', (94, 108))	('knockdown', 'Var', (70, 79))	('YB1', 'Gene', (66, 69))	('YB1', 'Gene', '4904', (66, 69))	('YB1', 'Gene', (90, 93))	('YB1', 'Gene', '4904', (90, 93))
71894	32814829	2a, VHL knockdown did not affect the expression of YB1 or EphA2 in Caki-1 cells.	('knockdown', 'Var', (8, 17))	('Caki-1', 'CellLine', 'CVCL:0234', (67, 73))	('EphA2', 'Gene', (58, 63))	('YB1', 'Gene', (51, 54))	('YB1', 'Gene', '4904', (51, 54))	('VHL', 'Gene', (4, 7))	('VHL', 'Gene', '7428', (4, 7))
71898	32814829	To validate this hypothesis, we performed high-throughput mRNA sequencing in 786-O cells with stable YB1 knockdown.	('YB1', 'Gene', (101, 104))	('YB1', 'Gene', '4904', (101, 104))	('knockdown', 'Var', (105, 114))
71899	32814829	Volcano plots show upregulated and downregulated genes in 786-O cells with YB1 knockdown according to the screening criteria (Fig.	('YB1', 'Gene', '4904', (75, 78))	('upregulated', 'PosReg', (19, 30))	('downregulated', 'NegReg', (35, 48))	('YB1', 'Gene', (75, 78))	('knockdown', 'Var', (79, 88))
71900	32814829	Subsequently, GO analysis revealed that genes downregulated by YB1 knockdown were involved in the cell surface receptor signaling pathway (Fig.	('cell surface receptor signaling pathway', 'biological_process', 'GO:0007166', ('98', '137'))	('YB1', 'Gene', (63, 66))	('knockdown', 'Var', (67, 76))	('cell surface receptor signaling pathway', 'Pathway', (98, 137))	('YB1', 'Gene', '4904', (63, 66))	('downregulated', 'NegReg', (46, 59))	('cell surface', 'cellular_component', 'GO:0009986', ('98', '110'))
71905	32814829	Our RNA-sequencing results showed that genes downregulated by YB1 knockdown were involved in the cell surface receptor signaling pathway (Fig.	('cell surface receptor signaling pathway', 'biological_process', 'GO:0007166', ('97', '136'))	('YB1', 'Gene', (62, 65))	('YB1', 'Gene', '4904', (62, 65))	('cell surface receptor signaling pathway', 'Pathway', (97, 136))	('cell surface', 'cellular_component', 'GO:0009986', ('97', '109'))	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('downregulated', 'NegReg', (45, 58))	('knockdown', 'Var', (66, 75))
71910	32814829	GSEA analysis showed that genes regulated by high EphA2 were enriched in cell migration, EMT, and multicancer invasiveness signature signaling pathways (Fig.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cell migration', 'biological_process', 'GO:0016477', ('73', '87'))	('signaling', 'biological_process', 'GO:0023052', ('133', '142'))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('EphA2', 'Gene', (50, 55))	('cell migration', 'CPA', (73, 87))	('high', 'Var', (45, 49))	('cancer', 'Disease', (103, 109))	('EMT', 'CPA', (89, 92))	('EMT', 'biological_process', 'GO:0001837', ('89', '92'))	('GSEA', 'Chemical', '-', (0, 4))
71912	32814829	Subsequently, we demonstrated that knockdown or overexpression of YB1 could downregulate or upregulate EphA2 expression in human renal cancer cells, respectively (Fig.	('knockdown', 'Var', (35, 44))	('renal cancer', 'Disease', 'MESH:D007680', (129, 141))	('expression', 'MPA', (109, 119))	('EphA2', 'Protein', (103, 108))	('upregulate', 'PosReg', (92, 102))	('YB1', 'Gene', (66, 69))	('human', 'Species', '9606', (123, 128))	('YB1', 'Gene', '4904', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('overexpression', 'PosReg', (48, 62))	('renal cancer', 'Disease', (129, 141))	('renal cancer', 'Phenotype', 'HP:0009726', (129, 141))	('downregulate', 'NegReg', (76, 88))
71916	32814829	4g-i, YB1 not only restored EphA2 protein expression but also rescued the metastatic phenotype of EphA2 knockdown in human renal cancer cells.	('EphA2 protein', 'Protein', (28, 41))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('renal cancer', 'Phenotype', 'HP:0009726', (123, 135))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('YB1', 'Gene', (6, 9))	('human', 'Species', '9606', (117, 122))	('renal cancer', 'Disease', 'MESH:D007680', (123, 135))	('YB1', 'Gene', '4904', (6, 9))	('EphA2', 'Gene', (98, 103))	('metastatic phenotype', 'CPA', (74, 94))	('rescued', 'PosReg', (62, 69))	('restored', 'PosReg', (19, 27))	('renal cancer', 'Disease', (123, 135))	('knockdown', 'Var', (104, 113))
71922	32814829	Moreover, our high-throughput sequencing results confirmed that knockdown of YB1 did not significantly change the levels of EphA2 mRNA (data not shown).	('EphA2 mRNA', 'MPA', (124, 134))	('YB1', 'Gene', (77, 80))	('YB1', 'Gene', '4904', (77, 80))	('knockdown', 'Var', (64, 73))
71927	32814829	5c, e), indicating constitutive EphA2 degradation in YB1 knockdown 786-O and ACHN cells.	('YB1', 'Gene', '4904', (53, 56))	('knockdown', 'Var', (57, 66))	('EphA2 degradation', 'MPA', (32, 49))	('YB1', 'Gene', (53, 56))	('degradation', 'biological_process', 'GO:0009056', ('38', '49'))
71928	32814829	Accordingly, we used cycloheximide to inhibit protein synthesis in 786-O and ACHN cells with stable YB1 knockdown, and EphA2 protein turnover was examined over time.	('protein synthesis', 'MPA', (46, 63))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('YB1', 'Gene', (100, 103))	('YB1', 'Gene', '4904', (100, 103))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('inhibit', 'NegReg', (38, 45))	('protein synthesis', 'biological_process', 'GO:0006412', ('46', '63'))	('cycloheximide', 'Chemical', 'MESH:D003513', (21, 34))	('knockdown', 'Var', (104, 113))
71929	32814829	Compared with that of the corresponding control cells, the half-life of EphA2 was dramatically reduced in 786-O and ACHN cells with stable YB1 knockdown (Fig.	('YB1', 'Gene', '4904', (139, 142))	('half-life', 'MPA', (59, 68))	('EphA2', 'Gene', (72, 77))	('reduced', 'NegReg', (95, 102))	('YB1', 'Gene', (139, 142))	('knockdown', 'Var', (143, 152))
71930	32814829	Furthermore, we also explored the effect of YB1 on the ubiquitin modification of EphA2 protein, and the experimental results showed that YB1 knockdown increased the ubiquitin modification of EphA2 protein in 786-O and ACHN cells (Fig.	('YB1', 'Gene', (137, 140))	('knockdown', 'Var', (141, 150))	('increased', 'PosReg', (151, 160))	('ubiquitin modification', 'MPA', (165, 187))	('YB1', 'Gene', '4904', (137, 140))	('ubiquitin', 'molecular_function', 'GO:0031386', ('165', '174'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('55', '64'))	('EphA2 protein', 'Protein', (191, 204))	('protein', 'cellular_component', 'GO:0003675', ('197', '204'))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('YB1', 'Gene', (44, 47))	('YB1', 'Gene', '4904', (44, 47))
71939	32814829	Knockdown of YB1 increased the sensitivity of SUN-resistant cells to SUN (Fig.	('increased', 'PosReg', (17, 26))	('YB1', 'Gene', (13, 16))	('YB1', 'Gene', '4904', (13, 16))	('Knockdown', 'Var', (0, 9))	('sensitivity', 'MPA', (31, 42))	('SUN', 'Chemical', 'MESH:D000077210', (69, 72))	('SUN', 'Chemical', 'MESH:D000077210', (46, 49))	('sensitivity of SUN', 'Phenotype', 'HP:0000992', (31, 49))
71940	32814829	Similarly, knockdown of EphA2 also increased the sensitivity of SUN-resistant cells to SUN (Fig.	('increased', 'PosReg', (35, 44))	('sensitivity', 'MPA', (49, 60))	('SUN', 'Chemical', 'MESH:D000077210', (87, 90))	('SUN', 'Chemical', 'MESH:D000077210', (64, 67))	('EphA2', 'Gene', (24, 29))	('knockdown', 'Var', (11, 20))	('sensitivity of SUN', 'Phenotype', 'HP:0000992', (49, 67))
71941	32814829	Moreover, rescue experiments showed that the compromised resistance phenotype by EphA2 knockdown could be restored by the reintroduction of YB1 in SUN-resistant cells (Fig.	('SUN', 'Chemical', 'MESH:D000077210', (147, 150))	('YB1', 'Gene', (140, 143))	('YB1', 'Gene', '4904', (140, 143))	('EphA2', 'Gene', (81, 86))	('resistance phenotype', 'MPA', (57, 77))	('knockdown', 'Var', (87, 96))
71950	32814829	7f, genes upregulated by high EphA2 expression were enriched in the MAPK and JNK/STAT3 signaling pathways.	('signaling', 'biological_process', 'GO:0023052', ('87', '96'))	('JNK', 'Gene', (77, 80))	('STAT3', 'Gene', '6774', (81, 86))	('JNK', 'molecular_function', 'GO:0004705', ('77', '80'))	('high', 'Var', (25, 29))	('upregulated', 'PosReg', (10, 21))	('STAT3', 'Gene', (81, 86))	('EphA2', 'Gene', (30, 35))	('JNK', 'Gene', '5599', (77, 80))	('MAPK', 'molecular_function', 'GO:0004707', ('68', '72'))
71954	32814829	Our results confirmed that ALW inhibited the activation and phosphorylation of these pathways, so we concluded that ALW suppressed the growth of parental and SUN-resistant cells by inhibiting these pathways.	('phosphorylation', 'MPA', (60, 75))	('suppressed', 'NegReg', (120, 130))	('ALW', 'Chemical', '-', (27, 30))	('ALW', 'Chemical', '-', (116, 119))	('inhibiting', 'NegReg', (181, 191))	('phosphorylation', 'biological_process', 'GO:0016310', ('60', '75'))	('ALW', 'Var', (116, 119))	('inhibited', 'NegReg', (31, 40))	('growth', 'MPA', (135, 141))	('SUN', 'Chemical', 'MESH:D000077210', (158, 161))
71955	32814829	To investigate the effect of EphA2 on the in vivo effects of SUN-resistant cells, we generated 786-O-R cells with stable EphA2 knockdown.	('knockdown', 'Var', (127, 136))	('SUN', 'Chemical', 'MESH:D000077210', (61, 64))	('EphA2', 'Gene', (121, 126))
71957	32814829	We found that EphA2 knockdown significantly reduced tumor size, tumor weight, and tumor volume in the 786-O-R subcutaneous tumor model (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor weight', 'Disease', (64, 76))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (123, 128))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (110, 128))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('reduced', 'NegReg', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('knockdown', 'Var', (20, 29))	('tumor', 'Disease', (82, 87))	('tumor weight', 'Disease', 'MESH:D015431', (64, 76))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('EphA2', 'Gene', (14, 19))
71958	32814829	IHC and haematoxylin and eosin (H&E) staining of subcutaneous tumor tissues demonstrated that EphA2 knockdown obviously decreased Ki-67 expression and tumor cell volume (Fig.	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (49, 67))	('eosin', 'Chemical', 'MESH:D004801', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('obviously', 'NegReg', (110, 119))	('EphA2', 'Var', (94, 99))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('Ki-67', 'Gene', '17345', (130, 135))	('haematoxylin', 'Chemical', 'MESH:D006416', (8, 20))	('H&E', 'Chemical', '-', (32, 35))	('that', 'Gene', (89, 93))	('decreased', 'Protein', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('Ki-67', 'Gene', (130, 135))
71960	32814829	The results showed that EphA2 knockdown inhibited the phosphorylation levels of the ERK/AKT/STAT3 pathway (Fig.	('ERK', 'Gene', '5594', (84, 87))	('inhibited', 'NegReg', (40, 49))	('phosphorylation levels', 'MPA', (54, 76))	('STAT3', 'Gene', '6774', (92, 97))	('ERK', 'Gene', (84, 87))	('AKT', 'Gene', '207', (88, 91))	('STAT3', 'Gene', (92, 97))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('knockdown', 'Var', (30, 39))	('AKT', 'Gene', (88, 91))	('EphA2', 'Gene', (24, 29))	('ERK', 'molecular_function', 'GO:0004707', ('84', '87'))
71961	32814829	In addition, we constructed a model of metastatic tumor in vivo via nude mouse tail vein injection of EphA2 knockdown 786-O-R cells.	('knockdown', 'Var', (108, 117))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('mouse', 'Species', '10090', (73, 78))	('EphA2', 'Gene', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
71962	32814829	Small animal imaging system and H&E staining showed that EphA2 knockdown decreased the liver metastasis of tumor cells (Fig.	('that', 'Gene', (52, 56))	('liver metastasis of tumor', 'Disease', 'MESH:D009362', (87, 112))	('knockdown', 'NegReg', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('liver metastasis of tumor', 'Disease', (87, 112))	('EphA2', 'Var', (57, 62))	('H&E', 'Chemical', '-', (32, 35))
71964	32814829	Considering that the pharmacological inhibition of EphA2 significantly inhibited the growth of SUN-resistant cells in vitro and that the stable knockdown of EphA2 significantly decreased the growth of SUN-resistant tumors in vivo, we wondered whether the pharmacological inhibition of EphA2 could block the growth of SUN-resistant tumors in vivo.	('growth', 'MPA', (191, 197))	('EphA2', 'Gene', (51, 56))	('SUN-resistant tumors', 'Disease', 'MESH:D060467', (317, 337))	('inhibited', 'NegReg', (71, 80))	('SUN', 'Chemical', 'MESH:D000077210', (317, 320))	('SUN', 'Chemical', 'MESH:D000077210', (201, 204))	('SUN-resistant tumors', 'Disease', (317, 337))	('SUN-resistant tumors', 'Disease', 'MESH:D060467', (201, 221))	('SUN-resistant tumors', 'Disease', (201, 221))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('EphA2', 'Gene', (157, 162))	('knockdown', 'Var', (144, 153))	('decreased', 'NegReg', (177, 186))	('SUN', 'Chemical', 'MESH:D000077210', (95, 98))	('tumors', 'Phenotype', 'HP:0002664', (331, 337))	('growth of SUN-resistant cells in vitro', 'CPA', (85, 123))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
71966	32814829	After the above treatment regimen was completed, ALW was found to significantly reduce the size and volume of SUN-resistant tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('SUN-resistant tumors', 'Disease', (110, 130))	('ALW', 'Chemical', '-', (49, 52))	('SUN-resistant tumors', 'Disease', 'MESH:D060467', (110, 130))	('reduce', 'NegReg', (80, 86))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('volume', 'CPA', (100, 106))	('ALW', 'Var', (49, 52))
71973	32814829	These findings indicate that pharmacological inhibition of EphA2 might be beneficial for SUN-resistant renal cancer, as inhibition of this protein could alleviate the phosphorylation and activation of key growth signaling pathway molecules and restore the sensitivity of SUN-resistant tumors to SUN.	('activation', 'PosReg', (187, 197))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('EphA2', 'Gene', (59, 64))	('sensitivity', 'MPA', (256, 267))	('SUN', 'Chemical', 'MESH:D000077210', (89, 92))	('SUN', 'Chemical', 'MESH:D000077210', (271, 274))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('inhibition', 'Var', (120, 130))	('phosphorylation', 'MPA', (167, 182))	('restore', 'PosReg', (244, 251))	('SUN', 'Chemical', 'MESH:D000077210', (295, 298))	('SUN-resistant tumors', 'Disease', 'MESH:D060467', (271, 291))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('SUN-resistant renal cancer', 'Disease', 'MESH:D007680', (89, 115))	('SUN-resistant tumors', 'Disease', (271, 291))	('alleviate', 'NegReg', (153, 162))	('signaling pathway', 'biological_process', 'GO:0007165', ('212', '229'))	('sensitivity of SUN', 'Phenotype', 'HP:0000992', (256, 274))	('renal cancer', 'Phenotype', 'HP:0009726', (103, 115))	('phosphorylation', 'biological_process', 'GO:0016310', ('167', '182'))	('SUN-resistant renal cancer', 'Disease', (89, 115))
71974	32814829	Renal cancer, one of the most common malignancies of the urinary system, is characterized by frequent VHL gene inactivation and activation of the HIF-VEGF pathway, leading to extensive vascularization around kidney cancer.	('activation', 'PosReg', (128, 138))	('vascularization around kidney', 'Phenotype', 'HP:0009741', (185, 214))	('vascularization', 'CPA', (185, 200))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('malignancies', 'Disease', (37, 49))	('VEGF', 'Gene', '7422', (150, 154))	('Renal cancer', 'Disease', 'MESH:D007680', (0, 12))	('Renal cancer', 'Phenotype', 'HP:0009726', (0, 12))	('kidney cancer', 'Disease', 'MESH:D007680', (208, 221))	('VHL', 'Gene', (102, 105))	('Renal cancer', 'Disease', (0, 12))	('inactivation', 'Var', (111, 123))	('kidney cancer', 'Phenotype', 'HP:0009726', (208, 221))	('VHL', 'Gene', '7428', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('VEGF', 'Gene', (150, 154))	('malignancies', 'Disease', 'MESH:D009369', (37, 49))	('kidney cancer', 'Disease', (208, 221))
71982	32814829	EphA2, a member of the RTK family, has been reported by us and other study groups to promote the dissemination and metastasis of tumors.	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('metastasis of tumors', 'Disease', (115, 135))	('promote', 'PosReg', (85, 92))	('metastasis of tumors', 'Disease', 'MESH:D009362', (115, 135))	('RTK', 'Gene', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('EphA2', 'Var', (0, 5))	('dissemination', 'CPA', (97, 110))	('RTK', 'Gene', '5979', (23, 26))
71995	32814829	EphA2 knockdown by shRNA counteracts YB1-mediated renal cancer SUN resistance in vitro, and this effect is also confirmed by EphA2 small molecule inhibitor ALW.	('renal cancer', 'Disease', 'MESH:D007680', (50, 62))	('YB1', 'Gene', '4904', (37, 40))	('SUN', 'Chemical', 'MESH:D000077210', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ALW', 'Chemical', '-', (156, 159))	('renal cancer', 'Disease', (50, 62))	('EphA2', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))	('YB1', 'Gene', (37, 40))	('renal cancer', 'Phenotype', 'HP:0009726', (50, 62))
71998	32814829	Functionally, high YB1 and EphA2 expression levels promote the invasion, metastasis, and SUN resistance of RCC.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('RCC', 'Disease', (107, 110))	('metastasis', 'CPA', (73, 83))	('high', 'Var', (14, 18))	('invasion', 'CPA', (63, 71))	('promote', 'PosReg', (51, 58))	('SUN resistance', 'CPA', (89, 103))	('expression levels', 'MPA', (33, 50))	('SUN', 'Chemical', 'MESH:D000077210', (89, 92))	('YB1', 'Gene', (19, 22))	('YB1', 'Gene', '4904', (19, 22))
72042	28721060	Among mTOR inhibitors, temsirolimus and everolimus have shown activity in mRCC: temsirolimus is recommended for the first-line therapy of poor prognosis ccRCC or non-ccRCC, whereas everolimus is a treatment option for second and subsequent lines.	('RCC', 'Disease', (155, 158))	('everolimus', 'Chemical', 'MESH:D000068338', (181, 191))	('RCC', 'Disease', 'MESH:C538614', (155, 158))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('temsirolimus', 'Chemical', 'MESH:C401859', (80, 92))	('RCC', 'Disease', (75, 78))	('temsirolimus', 'Chemical', 'MESH:C401859', (23, 35))	('everolimus', 'Chemical', 'MESH:D000068338', (40, 50))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('temsirolimus', 'Var', (80, 92))	('RCC', 'Disease', (168, 171))	('mTOR', 'Gene', '2475', (6, 10))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('mTOR', 'Gene', (6, 10))
72046	28721060	Lenvatinib (E7080, Lenvima ; Eisai, Hatfield, UK) is a multitarget kinase inhibitor firstly approved by US Food and Drug Administration (FDA) and European Medicine Agency (EMA) as monotherapy for the treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer, and more recently approved by FDA, in combination with everolimus, for the treatment of advanced RCC following one prior antiangiogenic therapy.	('everolimus', 'Chemical', 'MESH:D000068338', (375, 385))	('RCC', 'Phenotype', 'HP:0005584', (417, 420))	('RCC', 'Disease', 'MESH:C538614', (417, 420))	('radioactive iodine', 'Chemical', '-', (259, 277))	('RCC', 'Disease', (417, 420))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('67', '83'))	('thyroid cancer', 'Disease', (304, 318))	('Lenvatinib', 'Chemical', 'MESH:C531958', (0, 10))	('thyroid cancer', 'Phenotype', 'HP:0002890', (304, 318))	('E7080', 'Var', (12, 17))	('thyroid cancer', 'Disease', 'MESH:D013964', (304, 318))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))
72051	28721060	This event is crucial in RCC carcinogenesis; overexpressed growth factors induce pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions.	('induce', 'PosReg', (74, 80))	('cancer', 'Disease', (124, 130))	('angiogenesis', 'biological_process', 'GO:0001525', ('92', '104'))	('overexpressed', 'Var', (45, 58))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('RCC carcinogenesis', 'Disease', (25, 43))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('RCC carcinogenesis', 'Disease', 'MESH:C538614', (25, 43))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Disease', (106, 111))	('pathogenic angiogenesis', 'CPA', (81, 104))
72124	28721060	The value of the "VEGF pressure" theory is further supported by the results of the METEOR study, a randomized Phase III trial in which cabozantinib, a novel TKI, obtained a better PFS than those of everolimus in mRCC patients who progressed after >=1 prior TKIs (7.4 vs 3.8 months; HR: 0.51, 95% CI 0.41-0.62; P<0.0001).	('everolimus', 'Chemical', 'MESH:D000068338', (198, 208))	('cabozantinib', 'Var', (135, 147))	('VEGF', 'Gene', '7422', (18, 22))	('cabozantinib', 'Chemical', 'MESH:C558660', (135, 147))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('RCC', 'Disease', (213, 216))	('PFS', 'MPA', (180, 183))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	('better', 'PosReg', (173, 179))	('patients', 'Species', '9606', (217, 225))	('VEGF', 'Gene', (18, 22))
72142	28327152	We showed that TRIM8 is a target of miR-17-5p and miR-106b-5p, whose expression is promoted by N-MYC, and that alterations of their levels affect cell proliferation, acting on the TRIM8 transcripts stability, as confirmed in ccRCC patients and cell lines.	('ccRCC', 'Disease', (225, 230))	('N-MYC', 'Gene', (95, 100))	('miR-17-5p', 'Gene', (36, 45))	('affect', 'Reg', (139, 145))	('patients', 'Species', '9606', (231, 239))	('miR-106b', 'Gene', '406900', (50, 58))	('levels', 'MPA', (132, 138))	('alterations', 'Var', (111, 122))	('expression', 'MPA', (69, 79))	('promoted', 'PosReg', (83, 91))	('N-MYC', 'Gene', '4613', (95, 100))	('miR-17-5p', 'Gene', '406952', (36, 45))	('cell proliferation', 'biological_process', 'GO:0008283', ('146', '164'))	('miR-106b', 'Gene', (50, 58))	('cell proliferation', 'CPA', (146, 164))	('TRIM8', 'Gene', (180, 185))
72153	28327152	In this tumour, specific p53 pathways are inhibited by mechanisms, often unknown, other than mutations of the protein itself, resulting in a phenotype characterized by tumourigenesis, chemo-resistance, invasion and metastasis, that could be reverted by acting on the inhibiting factors.	('tumour', 'Disease', (8, 14))	('mutations', 'Var', (93, 102))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('chemo-resistance', 'CPA', (184, 200))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('p53 pathways', 'Pathway', (25, 37))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('metastasis', 'CPA', (215, 225))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('inhibited', 'NegReg', (42, 51))	('invasion', 'CPA', (202, 210))	('tumour', 'Disease', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (8, 14))
72167	28327152	The mechanisms through which the miRNAs-TRIM8-p53 axis - whose existence here we postulate based on the aforementioned observations - may impact chemo-resistance remain largely unknown.	('men', 'Species', '9606', (109, 112))	('chemo-resistance', 'CPA', (145, 161))	('impact', 'Reg', (138, 144))	('miRNAs-TRIM8-p53', 'Var', (33, 49))
72170	28327152	In this paper, using two independent cancer cell models, we unveiled a novel regulatory mechanism where inhibition of miR-17-5p and/or miR-106-5p leads to recover TRIM8-mediated p53 tumour suppressor activity and strong inhibition of N-MYC-dependent cell proliferation by p53-dependent N-MYC destabilization through miR-34a up-regulation.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('destabilization', 'NegReg', (292, 307))	('tumour', 'Disease', (182, 188))	('regulation', 'biological_process', 'GO:0065007', ('327', '337'))	('miR-106-5p', 'Var', (135, 145))	('N-MYC', 'Gene', (286, 291))	('inhibition', 'NegReg', (220, 230))	('N-MYC', 'Gene', '4613', (286, 291))	('cancer', 'Disease', (37, 43))	('up-regulation', 'PosReg', (324, 337))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('miR-34a', 'Gene', (316, 323))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('N-MYC', 'Gene', (234, 239))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('cell proliferation', 'biological_process', 'GO:0008283', ('250', '268'))	('miR-17-5p', 'Gene', '406952', (118, 127))	('N-MYC', 'Gene', '4613', (234, 239))	('recover', 'PosReg', (155, 162))	('miR-17-5p', 'Gene', (118, 127))	('miR-34a', 'Gene', '407040', (316, 323))
72172	28327152	The human proximal tubular epithelial cells HK-2 (wild type p53), the human renal cell carcinoma RCC-Shaw (ccRCC-derived cell line with wt-p53), the human renal carcinoma of BHD (Birt-Hogg-Dube) origin UOK-257 cells (RCC cell line with mutated p53) and the colon cancer cell line HCT116 were cultured in Dulbecco's modified Eagle's medium (D-MEM) plus 10% foetal bovine serum (FBS), L-Glutamine (2 mM), penicillin (100 U/ml) and streptomycin (100 mug/ml) at 37  C, 5% CO2.	('Birt-Hogg-Dube', 'Gene', '50947', (179, 193))	('mutated', 'Var', (236, 243))	('colon cancer', 'Disease', 'MESH:D015179', (257, 269))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('carcinoma of BHD', 'Disease', (161, 177))	('HK-2', 'Gene', (44, 48))	('HCT116', 'CellLine', 'CVCL:0291', (280, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('carcinoma of BHD', 'Disease', 'MESH:D058249', (161, 177))	('renal carcinoma', 'Phenotype', 'HP:0005584', (155, 170))	('renal cell carcinoma RCC-Shaw', 'Disease', (76, 105))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (76, 96))	('renal cell carcinoma RCC-Shaw', 'Disease', 'MESH:C538614', (76, 105))	('Birt-Hogg-Dube', 'Gene', (179, 193))	('colon cancer', 'Disease', (257, 269))	('human', 'Species', '9606', (70, 75))	('human', 'Species', '9606', (149, 154))	('UOK-257', 'CellLine', 'CVCL:S717', (202, 209))	('human', 'Species', '9606', (4, 9))	('bovine', 'Species', '9913', (363, 369))	('colon cancer', 'Phenotype', 'HP:0003003', (257, 269))	('HK-2', 'Gene', '3099', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('mug', 'molecular_function', 'GO:0043739', ('447', '450'))	('HK-2', 'molecular_function', 'GO:0008256', ('44', '48'))
72181	28327152	To assess miRNA/target interaction, the TRIM8 3'UTR fragment containing miR-17-5p/miR-106b-5p binding site wild type or mutant (wt or mut), and the p21 3'UTR fragment containing miR-17-5p/miR-106b-5p binding site wild type (wt) were cloned into pMIR Luciferase reporter vector (Life Technologies) downstream of the reporter luciferase gene.	('miR-17-5p', 'Gene', '406952', (178, 187))	('binding', 'molecular_function', 'GO:0005488', ('94', '101'))	('miR-106b', 'Gene', (188, 196))	('p21', 'Gene', '1026', (148, 151))	('miR-17-5p', 'Gene', (178, 187))	('miR-106b', 'Gene', '406900', (82, 90))	('miR-106b', 'Gene', '406900', (188, 196))	('men', 'Species', '9606', (162, 165))	('miR-17-5p', 'Gene', '406952', (72, 81))	('men', 'Species', '9606', (56, 59))	('miR-17-5p', 'Gene', (72, 81))	('p21', 'Gene', (148, 151))	('binding', 'molecular_function', 'GO:0005488', ('200', '207'))	('mutant', 'Var', (120, 126))	('miR-106b', 'Gene', (82, 90))
72184	28327152	12 h later cells were transfected with pMIR-TRIM8 3'UTR-wt, pMIR-TRIM8 3'UTR-mut or pMIR-p21 3'UTR and with the pRL SV40 renilla luciferase vector (transfection control).	('p21', 'Gene', '1026', (89, 92))	("pMIR-TRIM8 3'UTR-wt", 'Var', (39, 58))	('p21', 'Gene', (89, 92))	("pMIR-TRIM8 3'UTR-mut", 'Var', (60, 80))
72188	28327152	Four days later mice were randomized in three homogenized experimental groups; tumours thereby generated were treated with 1x109 MOI (multiplicity of infection) of each of the three recombinant adenoviruses expressing HA-TRIM8, HA-RING-TRIM8 or LacZ in sterile PBS, two times per week for three weeks.	('PBS', 'Gene', (261, 264))	('RING-TRIM8', 'Gene', '81603', (231, 241))	('RING-TRIM8', 'Gene', (231, 241))	('PBS', 'Gene', '1131', (261, 264))	('tumours', 'Disease', 'MESH:D009369', (79, 86))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('men', 'Species', '9606', (64, 67))	('mice', 'Species', '10090', (16, 20))	('HA-TRIM8', 'Var', (218, 226))	('tumours', 'Disease', (79, 86))
72215	28327152	On the contrary, miR-106b-5p expression level appeared to be dependent on the tumour grade, since it got significantly higher only in G3 Fuhrman grade samples (Fig.	('miR-106b', 'Gene', (17, 25))	('G3 Fuhrman', 'Var', (134, 144))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('miR-106b', 'Gene', '406900', (17, 25))	('tumour', 'Disease', (78, 84))	('higher', 'PosReg', (119, 125))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
72218	28327152	Intriguingly, the UOK-257 carcinoma cell line (harbouring a mutant p53) showed miR-17-5p expression levels comparable to cancer RCC-Shaw and HCT116 cells, while miR-106b-5p expression levels were comparable to non-cancer HK-2 cells (Fig.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('carcinoma', 'Disease', (26, 35))	('cancer', 'Disease', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('miR-17-5p', 'Gene', '406952', (79, 88))	('miR-106b', 'Gene', '406900', (161, 169))	('cancer RCC-Shaw', 'Disease', (121, 136))	('miR-17-5p', 'Gene', (79, 88))	('HK-2', 'Gene', '3099', (221, 225))	('carcinoma', 'Disease', 'MESH:D002277', (26, 35))	('HCT116', 'CellLine', 'CVCL:0291', (141, 147))	('HK-2', 'molecular_function', 'GO:0008256', ('221', '225'))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('cancer RCC-Shaw', 'Disease', 'MESH:C538614', (121, 136))	('miR-106b', 'Gene', (161, 169))	('p53', 'Gene', (67, 70))	('mutant', 'Var', (60, 66))	('HK-2', 'Gene', (221, 225))	('UOK-257', 'CellLine', 'CVCL:S717', (18, 25))	('cancer', 'Disease', (121, 127))	('expression levels', 'MPA', (89, 106))
72240	28327152	In UOK-257 cells, upon anti-miR-17-5p overexpression, p21 protein expression increased 2.3 fold compared to the control cells coherently with mRNA expression (Fig.	('miR-17-5p', 'Gene', '406952', (28, 37))	('miR-17-5p', 'Gene', (28, 37))	('UOK-257', 'CellLine', 'CVCL:S717', (3, 10))	('p21', 'Gene', '1026', (54, 57))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('increased', 'PosReg', (77, 86))	('p21', 'Gene', (54, 57))	('overexpression', 'Var', (38, 52))
72242	28327152	As a final important result of miR-17-5p and miR-106b-5p knocking-down, RCC and HCT116 cell proliferation rate decreased as demonstrated by MTT and colony-forming assays (Fig.	('cell proliferation', 'biological_process', 'GO:0008283', ('87', '105'))	('miR-106b', 'Gene', (45, 53))	('knocking-down', 'Var', (57, 70))	('decreased', 'NegReg', (111, 120))	('miR-17-5p', 'Gene', '406952', (31, 40))	('MTT', 'Chemical', 'MESH:C070243', (140, 143))	('miR-17-5p', 'Gene', (31, 40))	('miR-106b', 'Gene', '406900', (45, 53))	('HCT116', 'CellLine', 'CVCL:0291', (80, 86))
72245	28327152	Conversely, by inhibiting the action of miR-17-5p and miR-106b-5p on TRIM8, p53 becomes stable and activates miR-34a expression, which in turn quenches the N-MYC protein (Fig.	('p53', 'Var', (76, 79))	('N-MYC', 'Gene', (156, 161))	('miR-106b', 'Gene', '406900', (54, 62))	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('expression', 'MPA', (117, 127))	('quenches', 'NegReg', (143, 151))	('miR-34a', 'Gene', '407040', (109, 116))	('N-MYC', 'Gene', '4613', (156, 161))	('activates', 'PosReg', (99, 108))	('miR-17-5p', 'Gene', '406952', (40, 49))	('miR-34a', 'Gene', (109, 116))	('inhibiting', 'NegReg', (15, 25))	('miR-106b', 'Gene', (54, 62))	('miR-17-5p', 'Gene', (40, 49))
72249	28327152	MTT proliferation and colony suppression assays demonstrated that all the chemotherapeutic drugs used significantly reduced HK-2 cell proliferation rate, but had no effect at all on both RCC-Shaw and UOK-257, which have in common inactivated p53, the first due to TRIM8 deficit, the second to a mutation in the TP53 gene itself (Fig.	('UOK-257', 'CellLine', 'CVCL:S717', (200, 207))	('TP53', 'Gene', (311, 315))	('HK-2', 'Gene', '3099', (124, 128))	('HK-2', 'Gene', (124, 128))	('mutation', 'Var', (295, 303))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('cell proliferation', 'biological_process', 'GO:0008283', ('129', '147'))	('TP53', 'Gene', '7157', (311, 315))	('reduced', 'NegReg', (116, 123))	('HK-2', 'molecular_function', 'GO:0008256', ('124', '128'))
72271	28327152	Hence, three recombinant adenoviruses expressing HA-TRIM8, HA-RING-TRIM8 or LacZ (as control) were generated.	('RING-TRIM8', 'Gene', '81603', (62, 72))	('HA-TRIM8', 'Var', (49, 57))	('RING-TRIM8', 'Gene', (62, 72))
72275	28327152	9a, the xenograft growth curves revealed that the size of the tumours treated with Ad-HA-TRIM8 or Ad-HA-RING remained unchanged and, at the end of the experiment, they displayed mainly the same size they had at the moment of injection.	('tumours', 'Disease', (62, 69))	('men', 'Species', '9606', (217, 220))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('Ad-HA-RING', 'Var', (98, 108))	('tumours', 'Disease', 'MESH:D009369', (62, 69))	('men', 'Species', '9606', (157, 160))	('Ad-HA-TRIM8', 'Var', (83, 94))
72304	28327152	Previously, we observed that in ccRCC cell lines, differently from other cell lines, TRIM8 do not promote degradation of MDM2, the main negative regulator of p53.	('degradation', 'biological_process', 'GO:0009056', ('106', '117'))	('TRIM8', 'Var', (85, 90))	('degradation', 'MPA', (106, 117))	('MDM2', 'Gene', '4193', (121, 125))	('MDM2', 'Gene', (121, 125))
72306	28327152	In this scenario, TRIM8 recovery via miR-17-5p and miR-106b-5p silencing seems to be a winning move as it renders effective the tumour suppressor activity of p53, promoting the transcription of miR-34a that knocks out the oncogenic potential of N-MYC.	('tumour', 'Disease', (128, 134))	('N-MYC', 'Gene', '4613', (245, 250))	('miR-106b', 'Gene', (51, 59))	('miR-34a', 'Gene', '407040', (194, 201))	('promoting', 'PosReg', (163, 172))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('miR-34a', 'Gene', (194, 201))	('N-MYC', 'Gene', (245, 250))	('miR-106b', 'Gene', '406900', (51, 59))	('miR-17-5p', 'Gene', '406952', (37, 46))	('transcription', 'biological_process', 'GO:0006351', ('177', '190'))	('transcription', 'MPA', (177, 190))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('oncogenic potential', 'CPA', (222, 241))	('silencing', 'Var', (63, 72))	('miR-17-5p', 'Gene', (37, 46))
72309	28327152	This suggests that with the TRIM8-mediated recovery of the p53 tumour suppressor activity, a broader spectrum of chemotherapeutic agents may be taken into consideration to blunt tumorigenicity.	('p53', 'Gene', (59, 62))	('TRIM8-mediated', 'Var', (28, 42))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('tumorigenicity', 'CPA', (178, 192))	('blunt', 'NegReg', (172, 177))	('tumour', 'Disease', (63, 69))
72334	32103999	DUSPs are considered to be important regulators of key signaling pathways in many diseases, and signaling pathway abnormalities are essential for the development and progression of cancers.	('DUSP', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('abnormalities', 'Var', (114, 127))	('signaling', 'biological_process', 'GO:0023052', ('55', '64'))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('DUSP', 'Gene', '1847', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('cancers', 'Disease', (181, 188))	('signaling pathway', 'biological_process', 'GO:0007165', ('96', '113'))
72344	32103999	Mechanistically, we found DUSP9 to inhibit the activation of mTOR and expression of its downstream proteins.	('activation', 'MPA', (47, 57))	('DUSP9', 'Var', (26, 31))	('expression', 'MPA', (70, 80))	('mTOR', 'Gene', (61, 65))	('mTOR', 'Gene', '2475', (61, 65))	('inhibit', 'NegReg', (35, 42))
72384	32103999	Results of CCK-8 experiments showed the activity of cells overexpressing DUSP9, in both cell lines, to be lower than that in the negative control (NC) group (769-P and 786-O cells viability decreased by approximately 41.69% and 37.18% on the fifth day), thereby revealing that DUSP9 has the effect of inhibiting proliferation of ccRCC (Figure 2C).	('lower', 'NegReg', (106, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (329, 334))	('ccRCC', 'Disease', (329, 334))	('DUSP9', 'Gene', (73, 78))	('ccRCC', 'Disease', 'MESH:D002292', (329, 334))	('activity', 'MPA', (40, 48))	('proliferation', 'CPA', (312, 325))	('DUSP9', 'Var', (277, 282))	('inhibiting', 'NegReg', (301, 311))
72400	32103999	DUSP deregulation has been reported in a variety of cancers.	('reported', 'Reg', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('DUSP', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('DUSP', 'Gene', '1847', (0, 4))	('deregulation', 'Var', (5, 17))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
72403	32103999	For example, Liu et al had demonstrated DUSP9 reconstitution in squamous cell carcinoma to lead to G2-M phase-related cell death and microtubule disruption.	('M phase', 'biological_process', 'GO:0000279', ('102', '109'))	('cell death', 'biological_process', 'GO:0008219', ('118', '128'))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('reconstitution', 'Var', (46, 60))	('microtubule disruption', 'MPA', (133, 155))	('microtubule', 'cellular_component', 'GO:0005874', ('133', '144'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('DUSP9 reconstitution', 'Var', (40, 60))	('G2-M phase-related cell death', 'CPA', (99, 128))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 87))	('squamous cell carcinoma', 'Disease', (64, 87))
72405	32103999	Jenner et al had reported the establishment of a methylation screening method for DUSP9 in colorectal cancer, indicating the aberrant methylation of DUSP9 promoter as a phenotype of CPG island methylation.	('colorectal cancer', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('methylation', 'biological_process', 'GO:0032259', ('193', '204'))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('methylation', 'biological_process', 'GO:0032259', ('134', '145'))	('DUSP9', 'Gene', (149, 154))	('aberrant', 'Var', (125, 133))	('methylation', 'biological_process', 'GO:0032259', ('49', '60'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('methylation', 'MPA', (134, 145))
72428	32103999	Although we demonstrated decreased phosphorylation of mTOR (Ser2448) in ccRCC cells after DUSP9 overexpression, there could probably be other targets of DUSP9, which may also affect cancer cell growth and migration.	('ccRCC', 'Disease', (72, 77))	('cell growth', 'biological_process', 'GO:0016049', ('189', '200'))	('decreased', 'NegReg', (25, 34))	('Ser', 'cellular_component', 'GO:0005790', ('60', '63'))	('migration', 'CPA', (205, 214))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('cancer', 'Disease', (182, 188))	('phosphorylation', 'biological_process', 'GO:0016310', ('35', '50'))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('DUSP9', 'Gene', (90, 95))	('Ser2448', 'Chemical', '-', (60, 67))	('mTOR', 'Gene', (54, 58))	('overexpression', 'PosReg', (96, 110))	('affect', 'Reg', (175, 181))	('Ser2448', 'Var', (60, 67))	('mTOR', 'Gene', '2475', (54, 58))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('phosphorylation', 'MPA', (35, 50))	('ccRCC', 'Disease', 'MESH:D002292', (72, 77))
72432	31160694	Histone methylations have been implicated in renal tumorigenesis but their clinical significance and underlying pathology are unexplored.	('methylations', 'Var', (8, 20))	('implicated', 'Reg', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Histone', 'Protein', (0, 7))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
72436	31160694	The RCC cells exhibited reduced cell viability after knockdown of LSD2 and KDM5A genes with concomitant induction of apoptosis.	('induction of apoptosis', 'biological_process', 'GO:0006915', ('104', '126'))	('reduced', 'NegReg', (24, 31))	('knockdown', 'Var', (53, 62))	('induction', 'Reg', (104, 113))	('LSD2', 'Gene', (66, 70))	('KDM5A', 'Gene', (75, 80))	('cell viability', 'CPA', (32, 46))	('KDM5A', 'Gene', '5927', (75, 80))	('RCC', 'Disease', (4, 7))	('RCC', 'Phenotype', 'HP:0005584', (4, 7))	('LSD2', 'Gene', '221656', (66, 70))	('RCC', 'Disease', 'MESH:C538614', (4, 7))
72448	31160694	Histone methylation, which is the most prominent post-translational modification (PTM), can occur at lysine and arginine amino acids at the N-terminus of H3 and H4 by substitution of one, two or three methyl groups.	('Histone methylation', 'biological_process', 'GO:0016571', ('0', '19'))	('lysine', 'Chemical', 'MESH:D008239', (101, 107))	('PTM', 'biological_process', 'GO:0043687', ('82', '85'))	('post-translational modification', 'biological_process', 'GO:0043687', ('49', '80'))	('substitution', 'Var', (167, 179))	('arginine amino acids', 'Chemical', '-', (112, 132))	('Histone methylation', 'MPA', (0, 19))	('occur', 'Reg', (92, 97))
72459	31160694	Therefore, we have investigated the expression profile of H3K4 modifiers genes, including 13 histone methyltransferases and 7 histone demethylases, and observed the over-expression of HDMs as compared to HMTs, suggestive of their role in reduction of H3K4me patterns in ccRCC.	('RCC', 'Disease', (272, 275))	('over-expression', 'PosReg', (165, 180))	('HDMs', 'Var', (184, 188))	('RCC', 'Phenotype', 'HP:0005584', (272, 275))	('RCC', 'Disease', 'MESH:C538614', (272, 275))
72468	31160694	Although in general, all the three modifications were decreased with progression of cancer to higher stages and grades, a significant reduction was observed in the levels of H3K4me2 with tumor grades and H3K4me3 with stages and grades of ccRCC.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('H3K4me3', 'Var', (204, 211))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('cancer', 'Disease', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('H3K4me2', 'Protein', (174, 181))	('reduction', 'NegReg', (134, 143))	('tumor', 'Disease', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('RCC', 'Phenotype', 'HP:0005584', (240, 243))	('RCC', 'Disease', 'MESH:C538614', (240, 243))	('RCC', 'Disease', (240, 243))	('levels', 'MPA', (164, 170))
72472	31160694	Further, the performance of H3K4me1, H3K4me2 and H3K4me3 in predicting metastasis was assessed using Receiver operative characteristics (ROC) curve, which showed that H3K4me3 might be a fair predictor for tumor metastasis with Area under curve (AUC) of 0.713 (p = 0.023; Fig.	('tumor metastasis', 'Disease', (205, 221))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor metastasis', 'Disease', 'MESH:D009362', (205, 221))	('H3K4me3', 'Var', (167, 174))
72490	31160694	Further, cell cycle analysis was performed using PI staining which showed the arrest of A498 cells at S and sub-G1 phase in case of LSD2 (pA498 = 0.0001; pACHN = 0.0001) and KDM5A (pA498 = 0.0001; pACHN = 0.0001) knockdown, respectively (Fig.	('KDM5A', 'Gene', '5927', (174, 179))	('G1 phase', 'biological_process', 'GO:0051318', ('112', '120'))	('LSD2', 'Gene', '221656', (132, 136))	('cell cycle', 'biological_process', 'GO:0007049', ('9', '19'))	('LSD2', 'Gene', (132, 136))	('KDM5A', 'Gene', (174, 179))	('knockdown', 'Var', (213, 222))
72491	31160694	The ACHN cells were also arrested in S-phase and sub-G1 phase of the cell cycle on silencing of LSD2 (pA498 = 0.0001; pACHN = 0.0001) and KDM5A (pA498 = 0.0001; pACHN = 0.0001) genes (Fig.	('KDM5A', 'Gene', '5927', (138, 143))	('LSD2', 'Gene', (96, 100))	('S-phase', 'biological_process', 'GO:0051320', ('37', '44'))	('S-phase', 'CPA', (37, 44))	('cell cycle', 'biological_process', 'GO:0007049', ('69', '79'))	('sub-G1 phase of the cell cycle', 'CPA', (49, 79))	('G1 phase', 'biological_process', 'GO:0051318', ('53', '61'))	('LSD2', 'Gene', '221656', (96, 100))	('KDM5A', 'Gene', (138, 143))	('silencing', 'Var', (83, 92))
72492	31160694	In conclusion, these findings revealed that LSD2 and KDM5A silencing inhibited cell proliferation with the induction of apoptosis and corresponding arrest of cell cycle.	('LSD2', 'Gene', (44, 48))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('107', '129'))	('cell proliferation', 'CPA', (79, 97))	('apoptosis', 'CPA', (120, 129))	('LSD2', 'Gene', '221656', (44, 48))	('cell cycle', 'biological_process', 'GO:0007049', ('158', '168'))	('KDM5A', 'Gene', (53, 58))	('KDM5A', 'Gene', '5927', (53, 58))	('cell proliferation', 'biological_process', 'GO:0008283', ('79', '97'))	('inhibited', 'NegReg', (69, 78))	('silencing', 'Var', (59, 68))	('arrest', 'Reg', (148, 154))
72496	31160694	Histone methylation has been implicated as a good predictor for prognosis in various human cancers.	('Histone methylation', 'biological_process', 'GO:0016571', ('0', '19'))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('Histone', 'Protein', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('human', 'Species', '9606', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('methylation', 'Var', (8, 19))
72515	31160694	Notwithstanding, the molecular basis of altered LSD2 expression and its clinical implications in cancer progression are still unclear.	('LSD2', 'Gene', '221656', (48, 52))	('cancer', 'Disease', (97, 103))	('LSD2', 'Gene', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('altered', 'Var', (40, 47))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
72523	31160694	For that, the most significantly over-expressed HDMs (LSD2 and KDM5A) were targeted using gene-silencing strategy.	('KDM5A', 'Gene', '5927', (63, 68))	('gene-silencing', 'biological_process', 'GO:0016458', ('90', '104'))	('gene-silencing', 'Var', (90, 104))	('LSD2', 'Gene', '221656', (54, 58))	('over-expressed', 'PosReg', (33, 47))	('KDM5A', 'Gene', (63, 68))	('LSD2', 'Gene', (54, 58))
72529	31160694	Similarly, KDM5A knock-down in medulloblastoma and breast cancer suppressed cell proliferation with the induction of apoptotic genes expression.	('KDM5A', 'Gene', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('KDM5A', 'Gene', '5927', (11, 16))	('cell proliferation', 'biological_process', 'GO:0008283', ('76', '94'))	('medulloblastoma', 'Disease', 'MESH:D008527', (31, 46))	('knock-down', 'Var', (17, 27))	('cell proliferation', 'CPA', (76, 94))	('apoptotic genes', 'Gene', (117, 132))	('suppressed', 'NegReg', (65, 75))	('medulloblastoma', 'Phenotype', 'HP:0002885', (31, 46))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))	('medulloblastoma', 'Disease', (31, 46))
72550	31160694	For siRNA transfection studies, cells were allowed to grow at 60-80% confluency and transfected with 100 muM each of scrambled siRNA (EHUEGFP, esiRNAs, Sigma Aldrich) and siRNAs specifically targeting KDM5A (EHU0112051, esiRNAs, Sigma Aldrich) and LSD2 (EHU052581, esiRNAs, Sigma Aldrich) using 5 mul of lipofectamine 2000 (Invitrogen).	('LSD2', 'Gene', '221656', (248, 252))	('lipofectamine 2000', 'Chemical', 'MESH:C086724', (304, 322))	('EHU0112051', 'Var', (208, 218))	('EHU052581', 'Var', (254, 263))	('LSD2', 'Gene', (248, 252))	('KDM5A', 'Gene', (201, 206))	('KDM5A', 'Gene', '5927', (201, 206))
72591	30988818	The deregulation of miR-126 has also been identified in various types of cancer, where it regulates genes involved in the vascular endothelial growth factor and phosphatidylinositol 3-kinase pathways, and therefore serves an important role in processes including angiogenesis and cell cycle regulation.	('deregulation', 'Var', (4, 16))	('vascular endothelial growth factor', 'Gene', (122, 156))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('122', '156'))	('vascular endothelial growth factor', 'Gene', '7422', (122, 156))	('miR-126', 'Gene', '406913', (20, 27))	('serves', 'Reg', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('miR-126', 'Gene', (20, 27))	('regulates', 'Reg', (90, 99))	('genes', 'Gene', (100, 105))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('280', '301'))	('angiogenesis', 'biological_process', 'GO:0001525', ('263', '275'))
72629	30988818	Patients with low miR-126 expression also had shorter time to recurrence of disease, compared with that of patients with high miR-126 expression, 124.9+-17.9 and 155.4+-13.9 months, respectively (P=0.007; Fig.	('miR-126', 'Gene', '406913', (126, 133))	('miR-126', 'Gene', (126, 133))	('miR-126', 'Gene', '406913', (18, 25))	('Patients', 'Species', '9606', (0, 8))	('miR-126', 'Gene', (18, 25))	('shorter', 'NegReg', (46, 53))	('low', 'Var', (14, 17))	('patients', 'Species', '9606', (107, 115))
72639	30988818	However, no difference in the time to disease recurrence or disease-specific mortality were identified between patients with low or high miR-126 expression who had a primary tumor diameter <40 mm.	('miR-126', 'Gene', '406913', (137, 144))	('miR-126', 'Gene', (137, 144))	('primary tumor', 'Disease', (166, 179))	('primary tumor', 'Disease', 'MESH:D009369', (166, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('high', 'Var', (132, 136))	('patients', 'Species', '9606', (111, 119))
72660	30988818	An early event in the pathogenesis of RCC is the inactivation of the tumor suppressor Von Hippel-Lindau (VHL), which is a direct target gene of miR-21.	('Von Hippel-Lindau', 'Disease', (86, 103))	('RCC', 'Disease', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('VHL', 'Gene', (105, 108))	('miR-21', 'Gene', (144, 150))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('69', '85'))	('tumor', 'Disease', (69, 74))	('inactivation', 'Var', (49, 61))	('VHL', 'Gene', '7428', (105, 108))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('miR-21', 'Gene', '406991', (144, 150))	('pathogenesis', 'biological_process', 'GO:0009405', ('22', '34'))	('Von Hippel-Lindau', 'Disease', 'MESH:D006623', (86, 103))	('tumor suppressor', 'biological_process', 'GO:0051726', ('69', '85'))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
72661	30988818	As the downregulation of VHL may be caused by the upregulation of miR-21, the deregulation of miR-21 could constitute an early event in renal carcinogenesis.	('VHL', 'Gene', '7428', (25, 28))	('renal carcinogenesis', 'Disease', (136, 156))	('miR-21', 'Gene', (66, 72))	('upregulation', 'PosReg', (50, 62))	('renal carcinogenesis', 'Disease', 'MESH:D007674', (136, 156))	('downregulation', 'NegReg', (7, 21))	('miR-21', 'Gene', '406991', (66, 72))	('miR-21', 'Gene', (94, 100))	('VHL', 'Gene', (25, 28))	('deregulation', 'Var', (78, 90))	('miR-21', 'Gene', '406991', (94, 100))
72670	30988818	Patients with a high expression of miR-10b have previously been demonstrated to have longer progression-free and disease-free survival times.	('longer', 'PosReg', (85, 91))	('disease-free survival times', 'CPA', (113, 140))	('miR-10b', 'Gene', '406903', (35, 42))	('high', 'Var', (16, 20))	('Patients', 'Species', '9606', (0, 8))	('miR-10b', 'Gene', (35, 42))
72716	29991493	The transcriptional regulatory ability of FBP1 was first observed in clear cell renal cell carcinoma (ccRCC) tumors, in which FBP1 levels are uniformly decreased and FBP1 re-expression inhibits tumor progression by antagonizing glycolytic flux, thereby reducing the Warburg effect (Box 1).	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (69, 100))	('decreased', 'NegReg', (152, 161))	('FBP1', 'Gene', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', (194, 199))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('FBP1', 'Gene', '2203', (42, 46))	('glycolytic flux', 'MPA', (228, 243))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('reducing', 'NegReg', (253, 261))	('tumor', 'Disease', (109, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('Warburg effect', 'MPA', (266, 280))	('FBP1', 'Gene', '2203', (166, 170))	('FBP1', 'Gene', (42, 46))	('FBP1', 'Gene', '2203', (126, 130))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (80, 100))	('inhibits', 'NegReg', (185, 193))	('re-expression', 'Var', (171, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('clear cell renal cell carcinoma (ccRCC) tumors', 'Disease', 'MESH:C538614', (69, 115))	('antagonizing', 'NegReg', (215, 227))	('FBP1', 'Gene', (166, 170))
72718	29991493	Over 90% of ccRCC tumors harbor von Hippel-Lindau (VHL) mutations that stabilize hypoxia-inducible factors (HIFs) even under normoxia.	('ccRCC', 'Phenotype', 'HP:0006770', (12, 17))	('mutations', 'Var', (56, 65))	('ccRCC tumors harbor von Hippel-Lindau', 'Disease', 'MESH:D006623', (12, 49))	('ccRCC tumors harbor von Hippel-Lindau', 'Disease', (12, 49))	('hypoxia', 'Disease', (81, 88))	('hypoxia', 'Disease', 'MESH:D000860', (81, 88))	('VHL', 'Disease', (51, 54))	('VHL', 'Disease', 'MESH:D006623', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('stabilize', 'PosReg', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
72725	29991493	Unlike the constitutively active PKM1, the enzymatic activity of PKM2 is regulated by a variety of allosteric effectors, such as PEP, FBP, serine and SAICAR (Box 2), an intermediate in the biosynthesis of purines.	('FBP', 'Gene', (134, 137))	('biosynthesis', 'biological_process', 'GO:0009058', ('189', '201'))	('purines', 'Chemical', 'MESH:D011687', (205, 212))	('PKM', 'Gene', (65, 68))	('PKM', 'Gene', '5315', (65, 68))	('PKM2', 'Gene', (65, 69))	('PEP', 'Chemical', 'MESH:D010728', (129, 132))	('PKM2', 'Gene', '5315', (65, 69))	('PKM', 'Gene', '5315', (33, 36))	('serine', 'Chemical', 'MESH:D012694', (139, 145))	('enzymatic activity', 'MPA', (43, 61))	('serine', 'MPA', (139, 145))	('PKM', 'Gene', (33, 36))	('regulated', 'Reg', (73, 82))	('FBP', 'Gene', '2203', (134, 137))	('SAICAR', 'Chemical', 'MESH:C020635', (150, 156))	('PEP', 'Var', (129, 132))
72729	29991493	Strikingly, germline Pkm2 deletion causes spontaneous formation of hepatocellular carcinoma (HCC), suggesting that a systemic disruption of metabolic homeostasis by PKM2 loss is sufficient for tumor initiation in a non-cell-autonomous manner.	('HCC', 'Phenotype', 'HP:0001402', (93, 96))	('metabolic homeostasis', 'MPA', (140, 161))	('PKM2', 'Gene', (165, 169))	('Pkm2', 'Gene', '5315', (21, 25))	('PKM2', 'Gene', '5315', (165, 169))	('tumor initiation', 'Disease', 'MESH:D009369', (193, 209))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (67, 91))	('loss', 'NegReg', (170, 174))	('Pkm2', 'Gene', (21, 25))	('deletion', 'Var', (26, 34))	('hepatocellular carcinoma', 'Disease', (67, 91))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (67, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor initiation', 'Disease', (193, 209))	('homeostasis', 'biological_process', 'GO:0042592', ('150', '161'))	('formation', 'biological_process', 'GO:0009058', ('54', '63'))	('causes', 'Reg', (35, 41))
72743	29991493	Thus, dysregulation of MDH1 in p53-mediated cell cycle arrest and apoptosis upon glucose depletion may increase cellular susceptibility to oncogenic transformation.	('increase', 'PosReg', (103, 111))	('MDH1', 'Gene', (23, 27))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('44', '61'))	('arrest', 'Disease', (55, 61))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (44, 61))	('p53', 'Gene', '7157', (31, 34))	('oncogenic transformation', 'CPA', (139, 163))	('apoptosis', 'biological_process', 'GO:0097194', ('66', '75'))	('apoptosis', 'biological_process', 'GO:0006915', ('66', '75'))	('p53', 'Gene', (31, 34))	('cellular susceptibility', 'CPA', (112, 135))	('arrest', 'Disease', 'MESH:D006323', (55, 61))	('glucose', 'Chemical', 'MESH:D005947', (81, 88))	('apoptosis', 'CPA', (66, 75))	('MDH', 'molecular_function', 'GO:0018468', ('23', '26'))	('MDH1', 'Gene', '4190', (23, 27))	('dysregulation', 'Var', (6, 19))	('MDH', 'molecular_function', 'GO:0030060', ('23', '26'))	('MDH', 'molecular_function', 'GO:0033720', ('23', '26'))
72755	29991493	Moreover, forced MBP-1 expression results in impaired anchorage-independent growth in vitro and in vivo tumor formation in human breast carcinoma models, suggesting a tumor-suppressive role of MBP-1/ENO1.	('anchorage-independent growth', 'CPA', (54, 82))	('breast carcinoma', 'Disease', 'MESH:D001943', (129, 145))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('human', 'Species', '9606', (123, 128))	('expression', 'Var', (23, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('MBP-1', 'Gene', '2023', (193, 198))	('MBP-1', 'Gene', (193, 198))	('MBP-1', 'Gene', '2023', (17, 22))	('MBP-1', 'Gene', (17, 22))	('breast carcinoma', 'Phenotype', 'HP:0003002', (129, 145))	('breast carcinoma', 'Disease', (129, 145))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('ENO1', 'Gene', (199, 203))	('formation', 'biological_process', 'GO:0009058', ('110', '119'))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('impaired', 'NegReg', (45, 53))	('ENO1', 'Gene', '2023', (199, 203))
72797	29991493	H3T11 phosphorylation displaces HDAC3 from the promoters of CCND1 and MYC, promoting histone H3K9 acetylation and expression of c-Myc and cyclin D1, a regulator of the G1/S transition (Box 1).	('cyclin', 'molecular_function', 'GO:0016538', ('138', '144'))	('phosphorylation', 'biological_process', 'GO:0016310', ('6', '21'))	('CCND1', 'Gene', (60, 65))	('expression', 'MPA', (114, 124))	('MYC', 'Gene', '4609', (70, 73))	('H3T11', 'Var', (0, 5))	('HDAC3', 'Gene', '8841', (32, 37))	('c-Myc', 'Gene', (128, 133))	('promoting', 'PosReg', (75, 84))	('histone', 'MPA', (85, 92))	('c-Myc', 'Gene', '4609', (128, 133))	('CCND1', 'Gene', '595', (60, 65))	('cyclin D1', 'Gene', (138, 147))	('acetylation', 'MPA', (98, 109))	('MYC', 'Gene', (70, 73))	('acetyl', 'Chemical', 'MESH:D003545', (98, 104))	('HDAC3', 'Gene', (32, 37))	('histone H3K9 acetylation', 'biological_process', 'GO:0043970', ('85', '109'))	('cyclin D1', 'Gene', '595', (138, 147))
72805	29991493	Then, Set1-mediated H3K4me3 facilitates PKM2-mediated phosphorylation of H3T11.	('Set1', 'Gene', (6, 10))	('facilitates', 'PosReg', (28, 39))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('H3K4me3', 'Var', (20, 27))	('PKM2', 'Gene', (40, 44))	('H3T11', 'Protein', (73, 78))	('Set1', 'Gene', '9739', (6, 10))	('PKM2', 'Gene', '5315', (40, 44))
72838	29991493	First, it regulates the acetylation of specific histone lysine residues that are important for G1/S phase progression, such as H3K9 and H3K18.	('H3K9', 'Var', (127, 131))	('regulates', 'Reg', (10, 19))	('acetyl', 'Chemical', 'MESH:D003545', (24, 30))	('H3K18', 'Var', (136, 141))	('acetylation', 'MPA', (24, 35))	('histone', 'Protein', (48, 55))	('S phase', 'biological_process', 'GO:0051320', ('98', '105'))	('lysine', 'Chemical', 'MESH:D008239', (56, 62))
72850	29991493	Of note, although cytosolic ACLY levels remain constant, nuclear ACLY levels increase in S/G2 phase and decrease in G1, suggesting that ACLY may be available to supply acetyl-CoA during S/G2 phase when HR is preferred.	('ACLY', 'Gene', '47', (28, 32))	('G2 phase', 'biological_process', 'GO:0051319', ('91', '99'))	('ACLY', 'Gene', '47', (65, 69))	('ACLY', 'Gene', (28, 32))	('ACLY', 'Gene', (65, 69))	('S/G2', 'Var', (186, 190))	('S/G2', 'SUBSTITUTION', 'None', (186, 190))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (168, 178))	('decrease', 'NegReg', (104, 112))	('increase', 'PosReg', (77, 85))	('S/G2', 'Var', (89, 93))	('ACLY', 'Gene', '47', (136, 140))	('ACLY', 'Gene', (136, 140))	('G2 phase', 'biological_process', 'GO:0051319', ('188', '196'))	('S/G2', 'SUBSTITUTION', 'None', (89, 93))
72851	29991493	Phosphorylated ACLY increases acetyl-CoA production, which is essential for histone acetylation near DSBs, and the recruitment of BRCA1.	('Phosphorylated', 'Var', (0, 14))	('BRCA1', 'Gene', (130, 135))	('acetyl', 'Chemical', 'MESH:D003545', (84, 90))	('BRCA1', 'Gene', '672', (130, 135))	('DSBs', 'Chemical', '-', (101, 105))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (30, 40))	('histone acetylation', 'biological_process', 'GO:0016573', ('76', '95'))	('acetyl', 'Chemical', 'MESH:D003545', (30, 36))	('ACLY', 'Gene', '47', (15, 19))	('ACLY', 'Gene', (15, 19))	('acetyl-CoA production', 'MPA', (30, 51))	('increases', 'PosReg', (20, 29))
72866	29991493	The association between GAPDH and apoptosis was first established in neuronal cells, where the depletion of GAPDH completely blocks cytosine-arabinoside-induced apoptosis.	('apoptosis', 'biological_process', 'GO:0006915', ('34', '43'))	('apoptosis', 'biological_process', 'GO:0097194', ('161', '170'))	('depletion', 'Var', (95, 104))	('apoptosis', 'biological_process', 'GO:0006915', ('161', '170'))	('GAPDH', 'Gene', (108, 113))	('blocks', 'NegReg', (125, 131))	('cytosine-arabinoside', 'Chemical', 'MESH:D003561', (132, 152))	('apoptosis', 'biological_process', 'GO:0097194', ('34', '43'))	('cytosine-arabinoside-induced apoptosis', 'MPA', (132, 170))
72879	29991493	Moreover, mitochondrial HK2 inhibits apoptosis by regulating other PTP components, such as the adenine nucleotide translocator and cyclophilin D, and by limiting the production of reactive oxygen species (ROS).	('cyclophilin', 'molecular_function', 'GO:0004600', ('131', '142'))	('cyclophilin D', 'Gene', (131, 144))	('production of reactive oxygen species', 'MPA', (166, 203))	('mitochondrial', 'Var', (10, 23))	('adenine nucleotide', 'Chemical', 'MESH:D000227', (95, 113))	('inhibits', 'NegReg', (28, 36))	('apoptosis', 'CPA', (37, 46))	('apoptosis', 'biological_process', 'GO:0097194', ('37', '46'))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (180, 203))	('apoptosis', 'biological_process', 'GO:0006915', ('37', '46'))	('cyclophilin', 'molecular_function', 'GO:0016018', ('131', '142'))	('adenine nucleotide translocator', 'MPA', (95, 126))	('cyclophilin D', 'Gene', '10105', (131, 144))	('limiting', 'NegReg', (153, 161))	('HK2', 'molecular_function', 'GO:0008256', ('24', '27'))	('ROS', 'Chemical', 'MESH:D017382', (205, 208))	('HK2', 'Gene', '3099', (24, 27))	('HK2', 'Gene', (24, 27))
72881	29991493	In addition to its nuclear pro-apoptotic activity, mitochondrial GAPDH facilitates apoptosis by inducing mitochondrial membrane permeabilization (MOMP) and subsequent release of cytochrome c and AIF.	('inducing', 'PosReg', (96, 104))	('mitochondrial GAPDH', 'Var', (51, 70))	('AIF', 'Gene', (195, 198))	('cytochrome c', 'Gene', '54205', (178, 190))	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('mitochondrial membrane permeabilization', 'biological_process', 'GO:0035794', ('105', '144'))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('105', '127'))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('cytochrome c', 'molecular_function', 'GO:0045155', ('178', '190'))	('cytochrome c', 'Gene', (178, 190))	('apoptosis', 'CPA', (83, 92))	('cytochrome c', 'molecular_function', 'GO:0009461', ('178', '190'))	('MOMP', 'biological_process', 'GO:0097345', ('146', '150'))	('facilitates', 'PosReg', (71, 82))	('mitochondrial membrane permeabilization', 'MPA', (105, 144))	('AIF', 'Gene', '9131', (195, 198))
72888	29991493	The expression of Aco1p is controlled by many factors, including inhibitors such as glucose, and activators such as Huntingtin-associated protein (HAP2-5) and Rtg1p and Rtg3p.	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('glucose', 'Chemical', 'MESH:D005947', (84, 91))	('controlled', 'Reg', (27, 37))	('expression', 'MPA', (4, 14))	('HAP2-5', 'Gene', '9001;4801;4802', (147, 153))	('Rtg1p', 'Var', (159, 164))	('Aco1p', 'Gene', (18, 23))	('Rtg3p', 'Var', (169, 174))	('HAP2-5', 'Gene', (147, 153))
72890	29991493	In parallel, a study of patients with encephalomyopathy identified a mutation in SUCLA2, the gene encoding the beta-subunit of mitochondrial ADP-forming succinyl-CoA synthetase ligase (SCS-A).	('ADP', 'Chemical', 'MESH:D000244', (141, 144))	('SCS', 'molecular_function', 'GO:0004776', ('185', '188'))	('mutation', 'Var', (69, 77))	('encephalomyopathy', 'Disease', 'MESH:D017237', (38, 55))	('SUCLA2', 'Gene', '8803', (81, 87))	('patients', 'Species', '9606', (24, 32))	('CoA', 'Chemical', 'MESH:D003065', (162, 165))	('SUCLA2', 'Gene', (81, 87))	('encephalomyopathy', 'Disease', (38, 55))
72902	29991493	ACLY and ACSS2 inhibitors may suppress acetyl-CoA production in the nucleus, leading to decreased histone acetylation and gene transcription.	('ACSS2', 'Gene', (9, 14))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (39, 49))	('ACLY', 'Gene', (0, 4))	('acetyl', 'Chemical', 'MESH:D003545', (39, 45))	('transcription', 'biological_process', 'GO:0006351', ('127', '140'))	('acetyl-CoA production in the nucleus', 'MPA', (39, 75))	('histone acetylation', 'biological_process', 'GO:0016573', ('98', '117'))	('acetyl', 'Chemical', 'MESH:D003545', (106, 112))	('histone acetylation', 'MPA', (98, 117))	('decreased', 'NegReg', (88, 97))	('suppress', 'NegReg', (30, 38))	('inhibitors', 'Var', (15, 25))	('nucleus', 'cellular_component', 'GO:0005634', ('68', '75'))	('ACLY', 'Gene', '47', (0, 4))	('gene transcription', 'MPA', (122, 140))
72912	29991493	The small molecule TEPP-46 forces PKM2 to form tetramers, which decreases its recruitment to the nucleus and ultimately impairs H1299 human lung cancer cell xenograft growth.	('impairs H1299 human lung cancer', 'Disease', 'MESH:D008175', (120, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('recruitment to the nucleus', 'MPA', (78, 104))	('PKM2', 'Gene', (34, 38))	('nucleus', 'cellular_component', 'GO:0005634', ('97', '104'))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('PKM2', 'Gene', '5315', (34, 38))	('decreases', 'NegReg', (64, 73))	('impairs H1299 human lung cancer', 'Disease', (120, 151))	('TEPP-46', 'Var', (19, 26))
72920	33711272	Expression signatures for cancer cell subpopulations and immune evasion are associated with PBRM1 mutation and survival in primary and ICB-treated advanced RCC.	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('mutation', 'Var', (98, 106))	('ICB', 'Chemical', '-', (135, 138))	('cancer', 'Disease', (26, 32))	('PBRM1', 'Gene', '55193', (92, 97))	('RCC', 'Disease', (156, 159))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('immune evasion', 'biological_process', 'GO:0051842', ('57', '71'))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('immune evasion', 'biological_process', 'GO:0042783', ('57', '71'))	('PBRM1', 'Gene', (92, 97))
72921	33711272	Our findings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations critical for understanding response and resistance to ICB.	('ICB', 'Var', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('remodels', 'Reg', (34, 42))	('ICB', 'Chemical', '-', (30, 33))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('ICB', 'Chemical', '-', (192, 195))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('modifies', 'Reg', (72, 80))
72925	33711272	The most common RCC histologic subtype, clear cell RCC (ccRCC), frequently harbors characteristic second-hit loss-of-function mutations in VHL on a background of loss of chromosome 3p, where VHL resides.	('loss-of-function', 'NegReg', (109, 125))	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('VHL', 'Gene', (191, 194))	('VHL', 'Gene', (139, 142))	('loss', 'NegReg', (162, 166))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('RCC', 'Disease', (16, 19))	('VHL', 'Gene', '7428', (191, 194))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('VHL', 'Gene', '7428', (139, 142))	('chromosome', 'cellular_component', 'GO:0005694', ('170', '180'))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('mutations', 'Var', (126, 135))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
72926	33711272	These events result in decreased degradation of hypoxia-inducible factors (HIFs), causing mutant cells to shift to using glycolysis and secreting VEGF, which promotes angiogenesis.	('degradation', 'biological_process', 'GO:0009056', ('33', '44'))	('VEGF', 'Gene', (146, 150))	('using glycolysis', 'MPA', (115, 131))	('mutant', 'Var', (90, 96))	('HIFs', 'Disease', 'None', (75, 79))	('promotes', 'PosReg', (158, 166))	('angiogenesis', 'CPA', (167, 179))	('angiogenesis', 'biological_process', 'GO:0001525', ('167', '179'))	('degradation', 'MPA', (33, 44))	('VEGF', 'Gene', '7422', (146, 150))	('glycolysis', 'biological_process', 'GO:0006096', ('121', '131'))	('hypoxia', 'Disease', 'MESH:D000860', (48, 55))	('shift', 'PosReg', (106, 111))	('decreased', 'NegReg', (23, 32))	('hypoxia', 'Disease', (48, 55))	('HIFs', 'Disease', (75, 79))
72931	33711272	Observations of both intra- and intertumoral heterogeneity complicate mechanistic understanding, with multiple molecular subtypes of ccRCC defined by mutations in a set of chromatin remodelers that exhibit distinct patterns of evolution and metastasis.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('mutations', 'Var', (150, 159))	('chromatin', 'cellular_component', 'GO:0000785', ('172', '181'))
72938	33711272	Seven patients had ccRCC, while one tumor had a type 2 papillary RCC histology with PBRM1 and SETD2 mutations.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('mutations', 'Var', (100, 109))	('PBRM1', 'Gene', '55193', (84, 89))	('SETD2', 'Gene', (94, 99))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('SETD2', 'Gene', '29072', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('patients', 'Species', '9606', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('PBRM1', 'Gene', (84, 89))	('RCC', 'Disease', (21, 24))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('tumor', 'Disease', (36, 41))	('RCC', 'Disease', (65, 68))
72939	33711272	As expected, chromosome 3p loss was universally detected in ccRCC patients for whom genomic characterization was available, with additional second-hit mutations in VHL and/or genes encoding chromatin remodelers.	('chromosome', 'cellular_component', 'GO:0005694', ('13', '23'))	('VHL', 'Gene', '7428', (164, 167))	('VHL', 'Gene', (164, 167))	('chromatin', 'cellular_component', 'GO:0000785', ('190', '199'))	('loss', 'NegReg', (27, 31))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('mutations', 'Var', (151, 160))	('patients', 'Species', '9606', (66, 74))
72961	33711272	In melanoma models, polyfunctional progenitor exhausted CD8+ T cells differentiate to a more terminally exhausted phenotype during response to anti-PD1, and the latter population is primarily responsible for tumor killing despite being short lived.	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('anti-PD1', 'Var', (143, 151))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (208, 213))	('CD8', 'Gene', (56, 59))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('CD8', 'Gene', '925', (56, 59))
72962	33711272	Within 4-1BB-Lo cells from ICB-exposed patients in our cohort, we observed significant enrichment of the terminally exhausted gene signature in cells from responders compared with cells from non-responders (Figures 2G and S3E-S3G; Table S2).	('patients', 'Species', '9606', (39, 47))	('responders', 'Var', (155, 165))	('terminally exhausted gene signature', 'MPA', (105, 140))	('4-1BB', 'Gene', (7, 12))	('4-1BB', 'Gene', '3604', (7, 12))	('ICB', 'Chemical', '-', (27, 30))
72985	33711272	Much of this effect was driven by TAMs from patients with ICB response, which had further increases in expression levels of VSIR, VSIG4, PD-L2, and SIGLEC10 compared with cells from non-responders (all assessed post-ICB) (Figure 3G).	('TAMs', 'Chemical', '-', (34, 38))	('patients', 'Species', '9606', (44, 52))	('ICB', 'Var', (58, 61))	('expression levels', 'MPA', (103, 120))	('increases', 'PosReg', (90, 99))	('VSIG4', 'Gene', '11326', (130, 135))	('SIGLEC10', 'Gene', '89790', (148, 156))	('VSIR', 'Gene', (124, 128))	('ICB', 'Chemical', '-', (58, 61))	('SIGLEC10', 'Gene', (148, 156))	('PD-L2', 'Gene', (137, 142))	('PD-L2', 'Gene', '80380', (137, 142))	('ICB', 'Chemical', '-', (216, 219))	('VSIG4', 'Gene', (130, 135))
73008	33711272	In the Checkmate 025 cohort, we noted an increase in TP1 score in PBRM1 and KDM5C mutant tumors and an increase in TP2 score in tumors harboring 9p21.3 deletions, which were previously associated with ICB resistance (Figures 5C and 5D).	('tumors', 'Disease', (89, 95))	('increase', 'PosReg', (103, 111))	('KDM5C', 'Gene', '8242', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('PBRM1', 'Gene', (66, 71))	('tumors', 'Disease', (128, 134))	('mutant', 'Var', (82, 88))	('ICB', 'Chemical', '-', (201, 204))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('deletions', 'Var', (152, 161))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('PBRM1', 'Gene', '55193', (66, 71))	('KDM5C', 'Gene', (76, 81))	('increase', 'PosReg', (41, 49))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('TP1 score', 'MPA', (53, 62))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('TP2', 'MPA', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
73009	33711272	The association of TP1 score with PBRM1 mutations and TP2 score with 9p21.3 deletions was corroborated in the TCGA KIRC cohort (Figures S6E and S6F).	('mutations', 'Var', (40, 49))	('S6F', 'Mutation', 'p.S6F', (144, 147))	('PBRM1', 'Gene', (34, 39))	('PBRM1', 'Gene', '55193', (34, 39))
73018	33711272	Both cancer cell populations were inferred to signal to CD8+ T cells expressing CD44 via osteopontin (encoded by SPP1), an interaction that suppresses T cell activation in mouse models.	('SPP1', 'Gene', (113, 117))	('SPP1', 'Gene', '20750', (113, 117))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('mouse', 'Species', '10090', (172, 177))	('cancer', 'Disease', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('SPP', 'molecular_function', 'GO:0042499', ('113', '116'))	('osteopontin', 'Gene', '20750', (89, 100))	('osteopontin', 'Gene', (89, 100))	('CD8', 'Gene', (56, 59))	('T cell activation', 'biological_process', 'GO:0042110', ('151', '168'))	('CD8', 'Gene', '925', (56, 59))	('CD44', 'Var', (80, 84))
73055	33711272	Tumor tissue was were collected and transported in Medium 199 with Hank's salts (ThermoFisher Scientific #12350039) (samples P912, P913, P915, P916) or Medium 199 with Earle's salts (Sigma #M4530) (other samples) on ice.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('P912', 'Var', (125, 129))	("Hank's salts", 'Chemical', '-', (67, 79))	("Earle's salts", 'Chemical', '-', (168, 181))	('P916', 'Var', (143, 147))	('P913', 'Var', (131, 135))	('P915', 'Var', (137, 141))
73056	33711272	Enzymatic dissociation mix consisted of calcium- and magnesium-free Hank's Balanced Salt Solution (ThermoFisher Scientific #14170120) with 5 mM CaCl2 (Sigma #10043524), 100 mug/mL Collagenase Type 4 (Worthington Biochemical Corporation #LS004186), 0.75 u/mL Dispase (StemCell Technologies #7913), and 10 mug/mL DNAse I (StemCell Technologies #07900) for most samples (P906, P912, P913, P915, P916).	('P912', 'Var', (374, 378))	('P916', 'Var', (392, 396))	('P906', 'Var', (368, 372))	('P913', 'Var', (380, 384))	('calcium', 'Chemical', 'MESH:D002118', (40, 47))	('mug', 'molecular_function', 'GO:0043739', ('173', '176'))	('magnesium', 'Chemical', 'MESH:D008274', (53, 62))	('P915', 'Var', (386, 390))	('mug', 'molecular_function', 'GO:0043739', ('304', '307'))	('DNAse I', 'molecular_function', 'GO:0004530', ('311', '318'))
73095	33711272	In TCGA KIRC and Checkmate 025 cohorts, comparisons of signature scores between mutant and wild-type tumors, or between ICB response groups, were performed using a two-sided two-sided Wilcoxon rank-sum test with Benjamini-Hochberg FDR correction.	('mutant', 'Var', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('ICB', 'Chemical', '-', (120, 123))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
73112	29515108	The aberrant activation of NF-kappaB results in upregulation of anti-apoptotic and pro-tumorigenic genes and promotes survival and migration of cancer cells.	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('13', '36'))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('aberrant', 'Var', (4, 12))	('tumor', 'Disease', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('activation', 'PosReg', (13, 23))	('cancer', 'Disease', (144, 150))	('survival', 'CPA', (118, 126))	('NF-kappaB', 'Gene', '4790', (27, 36))	('NF-kappaB', 'Gene', (27, 36))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('promotes', 'PosReg', (109, 117))	('upregulation', 'PosReg', (48, 60))
73116	29515108	Activation of three types of ER stress sensors - protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1alpha) and activating transcription factor 6 (ATF6)- by dissociation from ER chaperone, GRP78, induces the UPR.	('transcription factor', 'molecular_function', 'GO:0000981', ('169', '189'))	('inositol-requiring enzyme 1', 'Gene', (114, 141))	('ATF6', 'Gene', '22926', (193, 197))	('IRE1alpha', 'Gene', (143, 152))	('IRE1alpha', 'Gene', '2081', (143, 152))	('dissociation', 'Var', (203, 215))	('PERK', 'Gene', (107, 111))	('inositol-requiring enzyme 1', 'Gene', '2081', (114, 141))	('activating transcription factor 6', 'Gene', '22926', (158, 191))	('activating transcription factor 6', 'Gene', (158, 191))	('PERK', 'Gene', '9451', (107, 111))	('GRP78', 'Gene', (235, 240))	('ATF6', 'Gene', (193, 197))	('GRP78', 'Gene', '3309', (235, 240))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('77', '98'))	('transcription', 'biological_process', 'GO:0006351', ('169', '182'))
73132	29515108	In addition to inhibition of angiogenesis, TKIs also exert a direct cytotoxic effect on tumor cells.	('TKIs', 'Var', (43, 47))	('inhibition', 'NegReg', (15, 25))	('angiogenesis', 'CPA', (29, 41))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('inhibition of angiogenesis', 'biological_process', 'GO:0016525', ('15', '41'))	('tumor', 'Disease', (88, 93))
73152	29515108	As expected, knockout of IKKbeta completely abolished sunitinib-induced NF-kappaB activation (Fig.	('IKKbeta', 'Gene', (25, 32))	('knockout', 'Var', (13, 21))	('IKKbeta', 'Gene', '3551', (25, 32))	('sunitinib', 'Chemical', 'MESH:D000077210', (54, 63))	('activation', 'PosReg', (82, 92))	('NF-kappaB', 'Gene', '4790', (72, 81))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('72', '92'))	('NF-kappaB', 'Gene', (72, 81))	('abolished', 'NegReg', (44, 53))
73154	29515108	In contrast, knockout of PERK had no effect on sunitinib-induced NF-kappaB activation (Fig.	('PERK', 'Gene', '9451', (25, 29))	('knockout', 'Var', (13, 21))	('activation', 'PosReg', (75, 85))	('NF-kappaB', 'Gene', '4790', (65, 74))	('NF-kappaB', 'Gene', (65, 74))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('65', '85'))	('sunitinib', 'Chemical', 'MESH:D000077210', (47, 56))	('PERK', 'Gene', (25, 29))
73163	29515108	Short hairpin RNA-mediated knockdown of IKKbeta or expression of dominant-negative (DN) IkappaBalpha reinstated sensitivity of 786-O cells to sunitinib-induced apoptosis (Fig.	('sensitivity', 'MPA', (112, 123))	('sunitinib', 'Chemical', 'MESH:D000077210', (142, 151))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('IkappaBalpha', 'Gene', '4792', (88, 100))	('dominant-negative', 'Var', (65, 82))	('RNA', 'cellular_component', 'GO:0005562', ('14', '17'))	('reinstated', 'PosReg', (101, 111))	('IKKbeta', 'Gene', (40, 47))	('IkappaBalpha', 'Gene', (88, 100))	('IKKbeta', 'Gene', '3551', (40, 47))
73168	29515108	The combined treatment with IKK-16 and sunitinib notably inhibited growth of PNX0010 tumors (Fig.	('IKK', 'molecular_function', 'GO:0008384', ('28', '31'))	('growth', 'MPA', (67, 73))	('inhibited', 'NegReg', (57, 66))	('IKK-16', 'Var', (28, 34))	('PNX0010 tumors', 'Disease', 'MESH:D009369', (77, 91))	('sunitinib', 'Chemical', 'MESH:D000077210', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('PNX0010 tumors', 'Disease', (77, 91))
73178	29515108	However, this possibility can be excluded based on our findings showing that knockout of PERK does not affect sunitinib-mediated NF-kappaB activation in 786-O cells (Fig.	('PERK', 'Gene', (89, 93))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('129', '149'))	('PERK', 'Gene', '9451', (89, 93))	('NF-kappaB', 'Gene', (129, 138))	('knockout', 'Var', (77, 85))	('sunitinib', 'Chemical', 'MESH:D000077210', (110, 119))	('NF-kappaB', 'Gene', '4790', (129, 138))
73182	29515108	Indeed, knockout of IRE1alpha dramatically affects NF-kappaB activity induced by sunitinib.	('IRE1alpha', 'Gene', (20, 29))	('IRE1alpha', 'Gene', '2081', (20, 29))	('knockout', 'Var', (8, 16))	('affects', 'Reg', (43, 50))	('NF-kappaB', 'Gene', '4790', (51, 60))	('activity', 'MPA', (61, 69))	('sunitinib', 'Chemical', 'MESH:D000077210', (81, 90))	('NF-kappaB', 'Gene', (51, 60))
73187	29515108	We therefore hypothesize that, in spite of the negative effect of sunitinib on IRE1alpha phosphorylation, sunitinib stabilizes its active conformation, thereby facilitating interaction with TRAF2 resulting in IKKbeta-dependent activation of NF-kappaB.	('TRAF2', 'Gene', (190, 195))	('IKKbeta', 'Gene', '3551', (209, 216))	('sunitinib', 'Chemical', 'MESH:D000077210', (66, 75))	('facilitating', 'PosReg', (160, 172))	('IRE1alpha', 'Gene', (79, 88))	('interaction', 'Interaction', (173, 184))	('NF-kappaB', 'Gene', '4790', (241, 250))	('IRE1alpha', 'Gene', '2081', (79, 88))	('active conformation', 'MPA', (131, 150))	('IKKbeta', 'Gene', (209, 216))	('activation', 'PosReg', (227, 237))	('sunitinib', 'Chemical', 'MESH:D000077210', (106, 115))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('227', '250'))	('TRAF2', 'Gene', '7186', (190, 195))	('NF-kappaB', 'Gene', (241, 250))	('phosphorylation', 'biological_process', 'GO:0016310', ('89', '104'))	('stabilizes', 'MPA', (116, 126))	('sunitinib', 'Var', (106, 115))
73192	29515108	However, treatment with a selective PERK inhibitor, GSK2656157, completely suppressed both thapsigargin- and sunitinib-mediated expression of IL-6, IL-8 and TNF-alpha.	('thapsigargin', 'Chemical', 'MESH:D019284', (91, 103))	('suppressed', 'NegReg', (75, 85))	('IL-6', 'Gene', '3569', (142, 146))	('IL-6', 'molecular_function', 'GO:0005138', ('142', '146'))	('GSK2656157', 'Chemical', 'MESH:C000597302', (52, 62))	('GSK2656157', 'Var', (52, 62))	('GSK', 'molecular_function', 'GO:0050321', ('52', '55'))	('PERK', 'Gene', (36, 40))	('IL-8', 'molecular_function', 'GO:0005153', ('148', '152'))	('IL-8', 'Gene', '3576', (148, 152))	('sunitinib-mediated expression', 'MPA', (109, 138))	('sunitinib', 'Chemical', 'MESH:D000077210', (109, 118))	('PERK', 'Gene', '9451', (36, 40))	('TNF-alpha', 'Gene', '7124', (157, 166))	('IL-8', 'Gene', (148, 152))	('TNF-alpha', 'Gene', (157, 166))	('IL-6', 'Gene', (142, 146))
73198	29515108	Indeed, pretreatment of 786-O cells with PERK inhibitor GSK2656157 failed to sensitize cells to sunitinib (data not shown).	('PERK', 'Gene', (41, 45))	('GSK2656157', 'Chemical', 'MESH:C000597302', (56, 66))	('PERK', 'Gene', '9451', (41, 45))	('sunitinib', 'Chemical', 'MESH:D000077210', (96, 105))	('GSK2656157', 'Var', (56, 66))	('GSK', 'molecular_function', 'GO:0050321', ('56', '59'))
73200	29515108	The authors reported that BiP/GRP78 depletion results in decreased PERK phosphorylation and suppression of activity of its downstream target, eIF2alpha.	('phosphorylation', 'biological_process', 'GO:0016310', ('72', '87'))	('BiP', 'Gene', (26, 29))	('activity', 'MPA', (107, 115))	('depletion', 'Var', (36, 45))	('eIF2alpha', 'Gene', (142, 151))	('eIF2', 'cellular_component', 'GO:0005850', ('142', '146'))	('BiP', 'Gene', '3309', (26, 29))	('PERK', 'Gene', '9451', (67, 71))	('eIF2alpha', 'Gene', '83939', (142, 151))	('suppression', 'NegReg', (92, 103))	('PERK', 'Gene', (67, 71))	('GRP78', 'Gene', '3309', (30, 35))	('GRP78', 'Gene', (30, 35))	('decreased', 'NegReg', (57, 66))
73204	29515108	The current study demonstrates for the first time that sunitinib induces two resistance-promoting signaling pathways, both of which originate from the ER stress response: a PERK-driven pathway that regulates the expression of IL-6, IL-8 and TNF-alpha cytokines, and a TRAF2-mediated NF-kappaB pro-survival pathway.	('ER stress response', 'biological_process', 'GO:0034976', ('151', '169'))	('pro-survival', 'biological_process', 'GO:0043066', ('293', '305'))	('PERK', 'Gene', (173, 177))	('IL-6', 'Gene', '3569', (226, 230))	('IL-8', 'Gene', (232, 236))	('IL-6', 'molecular_function', 'GO:0005138', ('226', '230'))	('sunitinib', 'Chemical', 'MESH:D000077210', (55, 64))	('IL-6', 'Gene', (226, 230))	('PERK', 'Gene', '9451', (173, 177))	('TRAF2', 'Gene', (268, 273))	('TNF-alpha', 'Gene', '7124', (241, 250))	('NF-kappaB', 'Gene', (283, 292))	('IL-8', 'molecular_function', 'GO:0005153', ('232', '236'))	('TNF-alpha', 'Gene', (241, 250))	('resistance-promoting signaling pathways', 'Pathway', (77, 116))	('TRAF2', 'Gene', '7186', (268, 273))	('NF-kappaB', 'Gene', '4790', (283, 292))	('IL-8', 'Gene', '3576', (232, 236))	('expression', 'MPA', (212, 222))	('induces', 'Reg', (65, 72))	('sunitinib', 'Var', (55, 64))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))
73210	29515108	Antibodies to Rel-A (#8242), phospho-Rel-A (S536) (#3033), NF-kappaB1 (p105/p50) (#13586), TRAF2 (#4712), IKKbeta (#8943), IRE1alpha (#3294), PERK (#5683), eIF2alpha (#5234), phospho-eIF2alpha (S51) (#9721) and ATF4 (#11815) were obtained from Cell Signaling Technology (Beverly, MA).	('ATF4', 'Gene', (211, 215))	('Rel-A', 'Gene', (37, 42))	('TRAF2', 'Gene', '7186', (91, 96))	('Signaling', 'biological_process', 'GO:0023052', ('249', '258'))	('IRE1alpha', 'Gene', (123, 132))	('eIF2', 'cellular_component', 'GO:0005850', ('156', '160'))	('PERK', 'Gene', '9451', (142, 146))	('#13586', 'Var', (82, 88))	('eIF2alpha', 'Gene', (183, 192))	('ATF4', 'Gene', '468', (211, 215))	('Rel-A', 'Gene', '5970', (14, 19))	('eIF2alpha', 'Gene', '83939', (183, 192))	('Rel-A', 'Gene', '5970', (37, 42))	('#11815', 'Var', (217, 223))	('IKKbeta', 'Gene', '3551', (106, 113))	('#8242', 'Var', (21, 26))	('eIF2alpha', 'Gene', (156, 165))	('#5683', 'Var', (148, 153))	('eIF2alpha', 'Gene', '83939', (156, 165))	('#8943', 'Var', (115, 120))	('#3294', 'Var', (134, 139))	('#3033', 'Var', (51, 56))	('p105', 'Gene', (71, 75))	('eIF2', 'cellular_component', 'GO:0005850', ('183', '187'))	('p50', 'Gene', '4790', (76, 79))	('IRE1alpha', 'Gene', '2081', (123, 132))	('#9721', 'Var', (200, 205))	('NF-kappaB', 'Gene', (59, 68))	('p50', 'Gene', (76, 79))	('IKKbeta', 'Gene', (106, 113))	('NF-kappaB', 'Gene', '4790', (59, 68))	('PERK', 'Gene', (142, 146))	('TRAF2', 'Gene', (91, 96))	('#4712', 'Var', (98, 103))	('#5234', 'Var', (167, 172))	('Rel-A', 'Gene', (14, 19))	('p105', 'Gene', '4790', (71, 75))
73213	29515108	IKK-16 (#S2882) and GSK2656157 (#S7033) were obtained from Selleckchem (Radnor, PA).	('#S2882', 'Var', (8, 14))	('#S7033', 'Var', (32, 38))	('GSK', 'molecular_function', 'GO:0050321', ('20', '23'))	('GSK2656157', 'Chemical', 'MESH:C000597302', (20, 30))	('IKK', 'molecular_function', 'GO:0008384', ('0', '3'))
73224	29515108	Open Reading Frame of DN IkappaBalpha (S32A/S36A) was amplified using pCMV-IkappaBalpha(S32A/S36A)-HA vector (a kind gift from N. Dulin, Ph.D., University of Chicago, IL) as a template and re-cloned into pLV-CMV-H4-puro lentiviral construct.	('IkappaBalpha', 'Gene', (25, 37))	('S32A', 'SUBSTITUTION', 'None', (88, 92))	('S36A', 'Mutation', 'p.S36A', (93, 97))	('IkappaBalpha', 'Gene', '4792', (75, 87))	('S32A', 'Var', (88, 92))	('S36A', 'Mutation', 'p.S36A', (44, 48))	('S32A', 'Var', (39, 43))	('IkappaBalpha', 'Gene', (75, 87))	('IkappaBalpha', 'Gene', '4792', (25, 37))	('S32A', 'SUBSTITUTION', 'None', (39, 43))
73225	29515108	IL-6, IL-8 and TNF-alpha protein levels in cell culture supernatants were determined by ELISA kits (#D6050, #D8000C and #DTA00C, respectively) (R&D Systems, Minneapolis, MN).	('IL-6', 'molecular_function', 'GO:0005138', ('0', '4'))	('#DTA00C', 'Var', (120, 127))	('#D6050', 'Var', (100, 106))	('IL-8', 'molecular_function', 'GO:0005153', ('6', '10'))	('IL-8', 'Gene', '3576', (6, 10))	('TNF-alpha', 'Gene', '7124', (15, 24))	('IL-6', 'Gene', (0, 4))	('IL-8', 'Gene', (6, 10))	('MN', 'CellLine', 'CVCL:U508', (170, 172))	('TNF-alpha', 'Gene', (15, 24))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('IL-6', 'Gene', '3569', (0, 4))
73343	31807164	A previous study has reported that renal tumors with high Fuhrman grades are more invasive, therefore, a more rigorous follow-up plan should be implemented after kidney preservation.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('high', 'Var', (53, 57))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('renal tumors', 'Phenotype', 'HP:0009726', (35, 47))	('Fuhrman', 'Gene', (58, 65))	('renal tumor', 'Phenotype', 'HP:0009726', (35, 46))	('invasive', 'CPA', (82, 90))	('renal tumors', 'Disease', 'MESH:D007680', (35, 47))	('renal tumors', 'Disease', (35, 47))
73361	31807164	The automatic exposure system was activated, with the tube currents of 130-180 milliampere-seconds (mAs) and 80-90 mAs, for 100 kVp and Sn 150 kVp, respectively.	('100 kVp', 'Var', (124, 131))	('mAs', 'cellular_component', 'GO:0034992', ('100', '103'))	('mAs', 'cellular_component', 'GO:0034992', ('115', '118'))	('Sn', 'Chemical', 'MESH:D014001', (136, 138))	('Sn 150 kVp', 'Var', (136, 146))
73388	31807164	The results showed that the NICA and NICC values for the arterial phase in the low-grade group were significantly higher than the high-grade group (P<0.01).	('NICA', 'Chemical', 'None', (28, 32))	('low-grade', 'Var', (79, 88))	('higher', 'PosReg', (114, 120))
73407	31807164	The findings of the present study indicated that for the 40-100 keV single-energy levels, significant differences were observed in the tumor CT value for the arterial phase between the low- and high-grade groups, while there was no significant difference in the CT value at the 120-160 single-energy levels.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('differences', 'Reg', (102, 113))	('40-100 keV', 'Var', (57, 67))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
73464	33053902	According to manufacturer's instructions, an event is classified as CTC or CEC when its morphological features are consistent with that of a cell and it exhibits the phenotype EpCAM+, CK+, DAPI+ and CD45- or CD146+, CD105+, DAPI+, and CD45-, respectively.	('EpCAM', 'Gene', (176, 181))	('CEC', 'Chemical', '-', (75, 78))	('CD105+', 'Var', (216, 222))	('CD45', 'Gene', '5788', (199, 203))	('CD45', 'Gene', (235, 239))	('DAPI+', 'Var', (189, 194))	('CD146', 'Gene', '4162', (208, 213))	('EpCAM', 'Gene', '4072', (176, 181))	('CD45', 'Gene', '5788', (235, 239))	('CD146', 'Gene', (208, 213))	('DAPI+', 'Var', (224, 229))	('CEC', 'Disease', (75, 78))	('CD45', 'Gene', (199, 203))	('CK', 'Gene', '51727', (184, 186))
73467	33053902	M30 is a neoepitope disclosed by caspase cleavage at cytokeratin 18 in early phases of apoptosis; results are expressed as the total number of CTC and M30-positive CTC per 7.5 mL PB.	('cytokeratin 18', 'Gene', (53, 67))	('M30-positive', 'Var', (151, 163))	('cytokeratin 18', 'Gene', '3875', (53, 67))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))
73469	33053902	We performed sequencing analysis for mutations in FH, MET, PETEN, SDHB and VHL genes.	('SDHB', 'Gene', (66, 70))	('VHL', 'Gene', (75, 78))	('VHL', 'Gene', '7428', (75, 78))	('mutations', 'Var', (37, 46))	('MET', 'Gene', '79811', (54, 57))	('SDHB', 'Gene', '6390', (66, 70))	('MET', 'Gene', (54, 57))	('PETEN', 'Gene', (59, 64))
73491	33053902	Moreover, Zhang T. and colleagues have already demonstrated that CTCs with c-MET amplification could be detected in patients with gastric, colorectal, and renal cancers.	('detected', 'Reg', (104, 112))	('renal cancers', 'Disease', 'MESH:D007680', (155, 168))	('c-MET', 'Gene', '4233', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('colorectal', 'Disease', (139, 149))	('renal cancers', 'Disease', (155, 168))	('patients', 'Species', '9606', (116, 124))	('renal cancer', 'Phenotype', 'HP:0009726', (155, 167))	('amplification', 'Var', (81, 94))	('c-MET', 'Gene', (75, 80))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('gastric', 'Disease', (130, 137))	('colorectal', 'Disease', 'MESH:D015179', (139, 149))
73561	33216824	For ccRCC the two highest-ranking m/z values were m/z = 723.5 and m/z = 704.5.	('m/z = 704.5', 'Var', (66, 77))	('m/z = 723.5', 'Var', (50, 61))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))
73562	33216824	The two highest values for RO were m/z = 806.5 and m/z = 1640.0 whereas the most influential signals for ChRCC comprised m/z = 1169.5 and m/z = 1039.5 (top 100 list of the features can be found in Supplementary Material 1).	('m/z = 1169.5', 'Var', (121, 133))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('RCC', 'Disease', (107, 110))	('m/z = 1640.0', 'Var', (51, 63))	('m/z = 1039.5', 'Var', (138, 150))	('m/z = 806.5', 'Var', (35, 46))
73594	33216824	Enriched protein functions comprised oxidative phosphorylation (hsa00190), citrate cycle (hsa00020), and fatty acid beta oxidation (GO:0006635).	('hsa00020', 'Var', (90, 98))	('citrate cycle', 'MPA', (75, 88))	('fatty acid beta oxidation', 'MPA', (105, 130))	('citrate', 'Chemical', 'MESH:D019343', (75, 82))	('fatty acid', 'Chemical', 'MESH:D005227', (105, 115))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('37', '62'))	('oxidative phosphorylation', 'MPA', (37, 62))	('hsa00190', 'Var', (64, 72))	('protein', 'cellular_component', 'GO:0003675', ('9', '16'))	('fatty acid beta oxidation', 'biological_process', 'GO:0006635', ('105', '130'))
73700	31116423	These genomic changes can serve as biomarkers of both response prediction (indicating tumor and patient outcome/response to a specific therapy) and a patient's prognosis (describing innate tumor aggressiveness, which aligns with patient survival regardless of treatment received).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (189, 194))	('patient', 'Species', '9606', (150, 157))	('tumor aggressiveness', 'Disease', (189, 209))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (86, 91))	('patient', 'Species', '9606', (96, 103))	('aggressiveness', 'Phenotype', 'HP:0000718', (195, 209))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('changes', 'Var', (14, 21))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (189, 209))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('patient', 'Species', '9606', (229, 236))
73710	31116423	Gene fusions commonly occur in epithelial cancers as a result of genomic rearrangements or abnormal mRNA processing.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('Gene fusions', 'Var', (0, 12))	('mRNA processing', 'CPA', (100, 115))	('epithelial cancers', 'Disease', 'MESH:D009369', (31, 49))	('mRNA processing', 'biological_process', 'GO:0006397', ('100', '115'))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('occur', 'Reg', (22, 27))	('epithelial cancers', 'Disease', (31, 49))	('genomic rearrangements', 'CPA', (65, 87))
73712	31116423	NGS is a high-throughput technique that rapidly examines and more broadly detects DNA mutations (often used for circulating tumor DNA), copy number variations (CNVs), and gene fusions (using an RNA sequencing panel) across the genome.	('mutations', 'Var', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('tumor', 'Disease', (124, 129))	('copy number variations', 'Var', (136, 158))	('pan', 'Gene', (209, 212))	('RNA', 'cellular_component', 'GO:0005562', ('194', '197'))	('gene fusions', 'Var', (171, 183))	('DNA', 'Gene', (82, 85))	('pan', 'Gene', '51816', (209, 212))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
73717	31116423	Any treating physician should know what, when, and how to test and how to make subsequent informed, patient-personalized treatment decisions.4, 5 Correct interpretation of profiling results is critical; many fear that overinterpretation or misinterpretation will lead to treatment of patients with ineffective but expensive therapies, negatively affecting not only patient lives but also the health care budget.	('lead to', 'Reg', (263, 270))	('patients', 'Species', '9606', (284, 292))	('misinterpretation', 'Var', (240, 257))	('patient', 'Species', '9606', (100, 107))	('overinterpretation', 'Var', (218, 236))	('patient', 'Species', '9606', (284, 291))	('patient', 'Species', '9606', (365, 372))
73724	31116423	Microsatellite instability (MSI) is the result of inactivation of the DNA mismatch repair (MMR) system and is characterized by a high frequency of frameshift mutations in microsatellite DNA.	('frameshift mutations', 'Var', (147, 167))	('MMR', 'biological_process', 'GO:0006298', ('91', '94'))	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('Microsatellite instability', 'Disease', (0, 26))	('microsatellite', 'Gene', (171, 185))	('inactivation', 'NegReg', (50, 62))	('DNA', 'Pathway', (70, 73))	('DNA', 'cellular_component', 'GO:0005574', ('186', '189'))	('mismatch repair', 'biological_process', 'GO:0006298', ('74', '89'))
73725	31116423	In a portion of tumors, MSI is caused by germline mutations in one of the MMR genes (MLH1, MSH2, MSH6, or PMS2), which results in hereditary Lynch syndrome.	('PMS2', 'Gene', '5395', (106, 110))	('MSH2', 'Gene', '4436', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', (16, 22))	('MLH1', 'Gene', (85, 89))	('hereditary Lynch syndrome', 'Disease', 'MESH:D061325', (130, 155))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('PMS2', 'Gene', (106, 110))	('MLH1', 'Gene', '4292', (85, 89))	('MMR', 'Gene', (74, 77))	('results in', 'Reg', (119, 129))	('MMR', 'biological_process', 'GO:0006298', ('74', '77'))	('caused by', 'Reg', (31, 40))	('MSH2', 'Gene', (91, 95))	('MSH6', 'Gene', (97, 101))	('hereditary Lynch syndrome', 'Disease', (130, 155))	('MSI', 'Disease', (24, 27))	('germline mutations', 'Var', (41, 59))	('MSH6', 'Gene', '2956', (97, 101))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))
73731	31116423	NTRK1, NTRK2, and NTRK3 fusions and the proteins they encode (neurotrophin receptor kinase A [TRKA], TRKB, and TRKC, respectively) are observed at an increased frequency in highly aggressive cancers such as glioblastoma multiforme, and recognition of their potential oncogenic activity led to the use of this fusion family as a predictive biomarker as well as a drug target.25  Larotrectinib is an oral and highly selective TRK inhibitor that was granted accelerated approval by the FDA on November 26, 2018, for the treatment of adult and pediatric patients with metastatic or unresectable solid tumors that have an NTRK fusion without a known acquired resistance mutation (NTRK kinase domain mutations, including solvent front mutations).	('glioblastoma multiforme', 'Disease', (207, 230))	('TRK', 'Gene', '4914', (111, 114))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (207, 230))	('NTRK2', 'Gene', (7, 12))	('TRK', 'Gene', '4914', (101, 104))	('TRK', 'Gene', (424, 427))	('fusion', 'Var', (622, 628))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('TRK', 'Gene', (19, 22))	('cancers', 'Disease', (191, 198))	('NTRK1', 'Gene', '4914', (0, 5))	('TRKB', 'Gene', (101, 105))	('solid tumors', 'Disease', (591, 603))	('TRK', 'Gene', (676, 679))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('TRK', 'Gene', (8, 11))	('NTRK1', 'Gene', (0, 5))	('TRK', 'Gene', (1, 4))	('TRK', 'Gene', '4914', (424, 427))	('TRK', 'Gene', (618, 621))	('TRK', 'Gene', '4914', (19, 22))	('TRK', 'Gene', '4914', (676, 679))	('TRKA', 'Gene', '4914', (94, 98))	('NTRK3', 'Gene', '4916', (18, 23))	('TRK', 'Gene', (94, 97))	('TRK', 'Gene', '4914', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (597, 602))	('NTRK2', 'Gene', '4915', (7, 12))	('TRK', 'Gene', (111, 114))	('patients', 'Species', '9606', (550, 558))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('solid tumors', 'Disease', 'MESH:D009369', (591, 603))	('tumors', 'Phenotype', 'HP:0002664', (597, 603))	('TRK', 'Gene', '4914', (1, 4))	('TRKB', 'Gene', '4915', (101, 105))	('glioblastoma', 'Phenotype', 'HP:0012174', (207, 219))	('NTRK3', 'Gene', (18, 23))	('TRK', 'Gene', '4914', (618, 621))	('TRKC', 'Gene', '4916', (111, 115))	('neurotrophin', 'molecular_function', 'GO:0005163', ('62', '74'))	('TRKC', 'Gene', (111, 115))	('TRKA', 'Gene', (94, 98))	('neurotrophin', 'molecular_function', 'GO:0005165', ('62', '74'))	('TRK', 'Gene', '4914', (94, 97))	('TRK', 'Gene', (101, 104))
73736	31116423	Tumor genetic (somatic) testing detects mutations that may actually be germline alterations, but germline alterations require confirmation in matched normal samples (eg, DNA extracted from white blood cells, buccal swabs, or cultured skin fibroblasts) from the tumor-bearing host.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('mutations', 'Var', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))
73739	31116423	This table indicates the cancer types for which germline testing should be carried out if the specified somatic mutations are found in a patient's tumor profile.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('patient', 'Species', '9606', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('mutations', 'Var', (112, 121))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancer', 'Disease', (25, 31))
73741	31116423	The first comprises common tumor mutations associated with rare germline alterations.	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (33, 42))
73742	31116423	For example, mutations in TP53 are found in greater than 60% of lung cancers.33 Although TP53 mutations can be inherited in the Li-Fraumeni syndrome, such familial syndromes are rare.	('TP53', 'Gene', (26, 30))	('TP53', 'Gene', '7157', (89, 93))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (128, 148))	('TP53', 'Gene', (89, 93))	('lung cancers', 'Disease', 'MESH:D008175', (64, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('mutations', 'Var', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('lung cancers', 'Phenotype', 'HP:0100526', (64, 76))	('Li-Fraumeni syndrome', 'Disease', (128, 148))	('inherited', 'Reg', (111, 120))	('TP53', 'Gene', '7157', (26, 30))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('lung cancers', 'Disease', (64, 76))
73743	31116423	For example, in colon cancer, dMMR is found by routine MSI or IHC testing in about 12% of tumors.34 Molecular germline testing demonstrates that about one-quarter of these dMMR alterations are inherited.	('alterations', 'Var', (177, 188))	('colon cancer', 'Disease', (16, 28))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('dMMR', 'Gene', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('colon cancer', 'Phenotype', 'HP:0003003', (16, 28))	('colon cancer', 'Disease', 'MESH:D015179', (16, 28))
73747	31116423	With routine molecular genetic tumor testing, BRCA1/BRCA2 mutations are being found in patients with other tumors where it is less expected.	('BRCA2', 'Gene', (52, 57))	('mutations', 'Var', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('found', 'Reg', (78, 83))	('BRCA1', 'Gene', '672', (46, 51))	('tumor', 'Disease', (31, 36))	('tumors', 'Disease', (107, 113))	('BRCA2', 'Gene', '675', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('BRCA1', 'Gene', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('patients', 'Species', '9606', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
73748	31116423	An analysis of 100 patients with pancreatic cancer found that 7 had mutations in BRCA2, 4 of which were in the germline.35 Finding BRCA1/BRCA2 mutations in the tumor may aid in choosing therapy but requires germline testing for confirmation and consideration of genetic counseling for the family.	('BRCA2', 'Gene', '675', (137, 142))	('patients', 'Species', '9606', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (33, 50))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('BRCA1', 'Gene', '672', (131, 136))	('BRCA2', 'Gene', (81, 86))	('BRCA2', 'Gene', '675', (81, 86))	('aid', 'Reg', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('pancreatic cancer', 'Disease', (33, 50))	('BRCA1', 'Gene', (131, 136))	('BRCA2', 'Gene', (137, 142))	('pancreatic cancer', 'Disease', 'MESH:D010190', (33, 50))	('tumor', 'Disease', (160, 165))	('mutations', 'Var', (143, 152))
73755	31116423	Patients with uncommon mutations of EGFR may also be treated with tyrosine kinase inhibitor therapy.	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('EGFR', 'Gene', '1956', (36, 40))	('mutations', 'Var', (23, 32))	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'Gene', (36, 40))	('tyrosine', 'Chemical', 'None', (66, 74))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('75', '91'))
73756	31116423	Other recommended markers of interest include EGFR insertion 20 mutations, RET rearrangements, and MET exon 14 mutations.	('mutations', 'Var', (111, 120))	('RET', 'Gene', (75, 78))	('rearrangements', 'Var', (79, 93))	('EGFR', 'Gene', '1956', (46, 50))	('insertion 20 mutations', 'Var', (51, 73))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('RET', 'Gene', '5979', (75, 78))	('EGFR', 'Gene', (46, 50))	('mutations', 'Var', (64, 73))
73761	31116423	Finally, guidelines now recommend universal MSI testing in all stages of CRC to determine whether patients have a germline mutation indicative of Lynch syndrome.41 If both the tumor DNA and the patient's germline DNA harbor an MMR defect, this indicates that the patient has Lynch syndrome.	('patient', 'Species', '9606', (263, 270))	('patient', 'Species', '9606', (194, 201))	('MMR', 'Gene', (227, 230))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('patient', 'Species', '9606', (98, 105))	('Lynch syndrome', 'Disease', 'MESH:D003123', (275, 289))	('Lynch syndrome', 'Disease', (146, 160))	('tumor', 'Disease', (176, 181))	('patients', 'Species', '9606', (98, 106))	('Lynch syndrome', 'Disease', 'MESH:D003123', (146, 160))	('defect', 'Var', (231, 237))	('DNA', 'cellular_component', 'GO:0005574', ('213', '216'))	('DNA', 'cellular_component', 'GO:0005574', ('182', '185'))	('MMR', 'biological_process', 'GO:0006298', ('227', '230'))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('Lynch syndrome', 'Disease', (275, 289))
73766	31116423	Mutations in or overexpression of additional genes that are predictive of outcomes include BRAF, HER2, KRAS, NRAS, NTRK, POLE, PIK3CA, PTEN, and RSP03.	('HER2', 'Gene', (97, 101))	('KRAS', 'Gene', (103, 107))	('KRAS', 'Gene', '3845', (103, 107))	('overexpression', 'PosReg', (16, 30))	('HER2', 'Gene', '2064', (97, 101))	('BRAF', 'Gene', '673', (91, 95))	('NRAS', 'Gene', (109, 113))	('PTEN', 'Gene', (135, 139))	('PIK3CA', 'Gene', (127, 133))	('TRK', 'Gene', (116, 119))	('BRAF', 'Gene', (91, 95))	('PTEN', 'Gene', '5728', (135, 139))	('PIK3CA', 'Gene', '5290', (127, 133))	('NRAS', 'Gene', '4893', (109, 113))	('TRK', 'Gene', '4914', (116, 119))	('Mutations in', 'Var', (0, 12))	('RSP03', 'Gene', (145, 150))
73770	31116423	BRAF mutational status is used as a strong predictor for overall survival (OS) at all stages of disease; patients with BRAF-mutated CRC have a generally poor prognosis.46, 47, 48, 49, 50, 51, 52 BRAF V600E is the best known mutation assessed using NGS.53 Compared with patients who have CRC with BRAF wild-type tumors, patients whose tumors manifest a BRAF mutation are generally older and more likely to be female.	('tumors', 'Disease', (311, 317))	('BRAF', 'Gene', (296, 300))	('BRAF', 'Gene', '673', (352, 356))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('BRAF', 'Gene', '673', (119, 123))	('V600E', 'Mutation', 'p.V600E', (200, 205))	('tumors', 'Disease', (334, 340))	('BRAF', 'Gene', (352, 356))	('BRAF', 'Gene', (119, 123))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('patients', 'Species', '9606', (269, 277))	('tumors', 'Disease', 'MESH:D009369', (311, 317))	('tumors', 'Disease', 'MESH:D009369', (334, 340))	('patients', 'Species', '9606', (105, 113))	('mutation', 'Var', (357, 365))	('BRAF', 'Gene', (195, 199))	('BRAF', 'Gene', '673', (195, 199))	('tumors', 'Phenotype', 'HP:0002664', (311, 317))	('tumors', 'Phenotype', 'HP:0002664', (334, 340))	('patients', 'Species', '9606', (319, 327))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('BRAF', 'Gene', '673', (296, 300))
73773	31116423	In The Cancer Genome Atlas extended 2017 study carried out by Robertson et al, findings from the complete cohort of 412 muscle-invasive bladder cancer cases revealed that mutations in the DNA repair genes ATM (n = 57; 14%) and ERCC2 (n = 40; 10%), and deletions in RAD51B (n = 10; 2%) were significant.55  It was found that all nonsilent somatic ERCC2 mutations were missense, and many could be mapped within the conserved helicase domain.	('RAD51B', 'Gene', (265, 271))	('mutations', 'Var', (352, 361))	('muscle-invasive bladder cancer', 'Disease', (120, 150))	('ATM', 'Gene', '472', (205, 208))	('Cancer', 'Disease', 'MESH:D009369', (7, 13))	('DNA repair', 'biological_process', 'GO:0006281', ('188', '198'))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('missense', 'Var', (367, 375))	('ATM', 'Gene', (205, 208))	('RAD51B', 'Gene', '5890', (265, 271))	('DNA', 'cellular_component', 'GO:0005574', ('188', '191'))	('invasive bladder', 'Phenotype', 'HP:0100645', (127, 143))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (120, 150))	('Cancer', 'Phenotype', 'HP:0002664', (7, 13))	('ERCC2', 'Gene', (346, 351))	('ERCC2', 'Gene', (227, 232))	('Cancer', 'Disease', (7, 13))	('ERCC2', 'Gene', '2068', (346, 351))	('RAD', 'biological_process', 'GO:1990116', ('265', '268'))	('ERCC2', 'Gene', '2068', (227, 232))
73774	31116423	Dominant negative effects on ERCC2 function were observed.56 Thus, bladder cancer missense mutations in ERCC2 were associated with improved response to cisplatin-based chemotherapy.	('ERCC2', 'Gene', '2068', (104, 109))	('ERCC2', 'Gene', '2068', (29, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (152, 161))	('bladder cancer', 'Disease', (67, 81))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('response to cisplatin-based chemotherapy', 'MPA', (140, 180))	('ERCC2', 'Gene', (104, 109))	('missense mutations', 'Var', (82, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('improved', 'PosReg', (131, 139))	('ERCC2', 'Gene', (29, 34))	('response to cisplatin', 'biological_process', 'GO:0072718', ('140', '161'))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
73776	31116423	Recently, Li et al reported developing a microscopy-based assay that measures the nucleotide excision repair function of clinically observed ERCC2 mutations.	('mutations', 'Var', (147, 156))	('ERCC2', 'Gene', '2068', (141, 146))	('ERCC2', 'Gene', (141, 146))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('82', '108'))	('nucleotide excision repair function', 'MPA', (82, 117))
73779	31116423	Current evidence presented here supports the idea that ERCC2 and ATM are potentially useful markers in muscle-invasive bladder cancer.55, 56, 57  It was recently reported that patients with metastatic castration-resistant prostate cancer (mCRPC) harboring germline mutations in BRCA1/BRCA2 and ATM have superior clinical outcomes after first-line treatment with abiraterone and enzalutamide (see Table 2.5).58 The authors suggested that this improved response is likely driven by mutations in BRCA1, BRCA2, and ATM.	('ATM', 'Gene', (511, 514))	('muscle-invasive bladder cancer', 'Disease', (103, 133))	('ATM', 'Gene', (65, 68))	('enzalutamide', 'Chemical', 'MESH:C540278', (378, 390))	('ATM', 'Gene', (294, 297))	('BRCA2', 'Gene', (500, 505))	('BRCA1', 'Gene', '672', (493, 498))	('abiraterone', 'Chemical', 'MESH:C089740', (362, 373))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('BRCA1', 'Gene', (493, 498))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('bladder cancer', 'Phenotype', 'HP:0009725', (119, 133))	('BRCA1', 'Gene', '672', (278, 283))	('BRCA2', 'Gene', (284, 289))	('BRCA1', 'Gene', (278, 283))	('ERCC2', 'Gene', (55, 60))	('invasive bladder', 'Phenotype', 'HP:0100645', (110, 126))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (103, 133))	('ATM', 'Gene', '472', (511, 514))	('prostate cancer', 'Disease', 'MESH:D011471', (222, 237))	('BRCA2', 'Gene', '675', (500, 505))	('ATM', 'Gene', '472', (65, 68))	('patients', 'Species', '9606', (176, 184))	('prostate cancer', 'Phenotype', 'HP:0012125', (222, 237))	('ERCC2', 'Gene', '2068', (55, 60))	('prostate cancer', 'Disease', (222, 237))	('mutations', 'Var', (480, 489))	('ATM', 'Gene', '472', (294, 297))	('BRCA2', 'Gene', '675', (284, 289))
73781	31116423	A separate, small, retrospective study found that all responders to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor therapy harbored BRCA2 mutations, whereas nonresponders did not.59 However, it was agreed that the functional relevance of mutations in DNA repair genes other than BRCA2 should be considered before committing to PARP inhibitor therapy.	('DNA repair', 'biological_process', 'GO:0006281', ('273', '283'))	('PARP', 'Gene', (349, 353))	('mutations', 'Var', (160, 169))	('PARP', 'Gene', '142', (121, 125))	('poly(adenosine diphosphate [ADP]-ribose)', 'Chemical', 'MESH:D011064', (68, 108))	('BRCA2', 'Gene', (301, 306))	('BRCA2', 'Gene', (154, 159))	('PARP', 'Gene', '142', (349, 353))	('DNA', 'cellular_component', 'GO:0005574', ('273', '276'))	('harbored', 'Reg', (145, 153))	('BRCA2', 'Gene', '675', (301, 306))	('BRCA2', 'Gene', '675', (154, 159))	('PARP', 'Gene', (121, 125))
73784	31116423	Of note, the response rate was numerically higher in patients with somatic BRCA1/BRCA2 or ATM mutations (12%), indicating that these could be predictive markers of response to checkpoint inhibitors.	('BRCA1', 'Gene', (75, 80))	('patients', 'Species', '9606', (53, 61))	('mutations', 'Var', (94, 103))	('higher', 'PosReg', (43, 49))	('ATM', 'Gene', '472', (90, 93))	('BRCA2', 'Gene', (81, 86))	('BRCA2', 'Gene', '675', (81, 86))	('response', 'MPA', (13, 21))	('BRCA1', 'Gene', '672', (75, 80))	('ATM', 'Gene', (90, 93))
73788	31116423	Abnormalities in MLH1 should prompt hypermethylation testing, as this can also cause tumors to be MSI-H in the absence of a germline mutation.	('Abnormalities', 'Var', (0, 13))	('MLH1', 'Gene', '4292', (17, 21))	('hype', 'Gene', '11153', (36, 40))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('MLH1', 'Gene', (17, 21))	('hype', 'Gene', (36, 40))	('cause', 'Reg', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
73789	31116423	The detection of a germline mutation affects subsequent screening for colon and ovarian cancer and prompts cascade testing to identify other affected family members.	('germline mutation', 'Var', (19, 36))	('affects', 'Reg', (37, 44))	('ovarian cancer', 'Phenotype', 'HP:0100615', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('colon and ovarian cancer', 'Disease', 'MESH:D010051', (70, 94))
73790	31116423	The presence of MSI-H because of either a germline mutation or hypermethylation provides an indication for pembrolizumab in the setting of recurrent uterine cancer, based on site-agnostic FDA approval granted in 2017.13 Women with POLE-aberrant endometrial cancers demonstrate a favorable prognosis and may require less aggressive therapy, although this remains theoretical at present.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('hype', 'Gene', (63, 67))	('uterine cancer', 'Phenotype', 'HP:0010784', (149, 163))	('POLE-aberrant endometrial cancers', 'Disease', (231, 264))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('Women', 'Species', '9606', (220, 225))	('hype', 'Gene', '11153', (63, 67))	('POLE-aberrant endometrial cancers', 'Disease', 'MESH:D016889', (231, 264))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('germline mutation', 'Var', (42, 59))	('MSI-H', 'Gene', (16, 21))	('cancer', 'Disease', (257, 263))
73791	31116423	Identification of hotspot mutations in genes such as BRAF, KRAS, PIK3CA, and PTEN may correlate with biological behavior but are not yet targetable.	('KRAS', 'Gene', '3845', (59, 63))	('PIK3CA', 'Gene', '5290', (65, 71))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))	('mutations', 'Var', (26, 35))	('PIK3CA', 'Gene', (65, 71))	('PTEN', 'Gene', (77, 81))	('PTEN', 'Gene', '5728', (77, 81))	('hotspot', 'PosReg', (18, 25))	('KRAS', 'Gene', (59, 63))
73792	31116423	Phase 2 data demonstrate activity of mTOR inhibitors in endometrioid carcinoma of the uterus, but these trials were not assay-directed to determine whether molecular testing can select for potential activity.64  The presence of pathogenic mutations in BRCA-related genes identify an important subset of high-grade serous epithelial ovarian cancers that have a specific biology, natural history, and susceptibility to platinum and PARP inhibitors.	('ovarian cancer', 'Phenotype', 'HP:0100615', (332, 346))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (56, 78))	('pathogenic', 'Reg', (228, 238))	('mutations', 'Var', (239, 248))	('mTOR', 'Gene', '2475', (37, 41))	('BRCA', 'Gene', '672', (252, 256))	('serous epithelial ovarian cancers', 'Disease', (314, 347))	('endometrioid carcinoma of the uterus', 'Disease', 'MESH:D018269', (56, 92))	('PARP', 'Gene', '142', (430, 434))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('BRCA', 'Gene', (252, 256))	('endometrioid carcinoma of the uterus', 'Disease', (56, 92))	('PARP', 'Gene', (430, 434))	('serous epithelial ovarian cancers', 'Disease', 'MESH:D010051', (314, 347))	('cancers', 'Phenotype', 'HP:0002664', (340, 347))	('platinum', 'Chemical', 'MESH:D010984', (417, 425))	('cancer', 'Phenotype', 'HP:0002664', (340, 346))	('ovarian cancers', 'Phenotype', 'HP:0100615', (332, 347))	('mTOR', 'Gene', (37, 41))	('presence', 'Var', (216, 224))
73793	31116423	The spectrum of mutations in this category includes those in BRCA1, BRCA2, RAD51C, RAD51D, BARD1, BRIP1, PALB2, MLH1, MSH2, MSH6, PMS2, and STK11 (see Table 2.7).65, 66, 67 Patients with these mutations have an improved prognosis with a higher likelihood of platinum sensitivity and long-term survival.	('BRCA1', 'Gene', (61, 66))	('STK11', 'Gene', (140, 145))	('PMS2', 'Gene', '5395', (130, 134))	('MLH1', 'Gene', '4292', (112, 116))	('PALB2', 'Gene', '79728', (105, 110))	('BRIP1', 'Gene', (98, 103))	('RAD51D', 'Gene', '5892', (83, 89))	('mutations', 'Var', (193, 202))	('higher', 'PosReg', (237, 243))	('long-term survival', 'CPA', (283, 301))	('STK11', 'molecular_function', 'GO:0033868', ('140', '145'))	('BRCA2', 'Gene', '675', (68, 73))	('MSH6', 'Gene', (124, 128))	('platinum sensitivity', 'CPA', (258, 278))	('MSH6', 'Gene', '2956', (124, 128))	('STK11', 'Gene', '6794', (140, 145))	('MSH2', 'Gene', (118, 122))	('RAD', 'biological_process', 'GO:1990116', ('83', '86'))	('PMS2', 'Gene', (130, 134))	('RAD51D', 'Gene', (83, 89))	('RAD51C', 'Gene', '5889', (75, 81))	('BRIP1', 'Gene', '83990', (98, 103))	('MSH2', 'Gene', '4436', (118, 122))	('Patients', 'Species', '9606', (173, 181))	('PALB2', 'Gene', (105, 110))	('BARD1', 'Gene', '580', (91, 96))	('MLH1', 'Gene', (112, 116))	('BARD1', 'Gene', (91, 96))	('RAD51C', 'Gene', (75, 81))	('BRCA2', 'Gene', (68, 73))	('BRCA1', 'Gene', '672', (61, 66))	('RAD', 'biological_process', 'GO:1990116', ('75', '78'))	('platinum', 'Chemical', 'MESH:D010984', (258, 266))
73795	31116423	Identification of these mutations directly affects therapy, as patients should be considered for treatment with PARP inhibitors immediately after upfront therapy with platinum and a taxane, based on the improved progression-free survival (PFS) observed in the SOLO-1 trial (Olaparib Maintenance Monotherapy in Patients With BRCA Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy; ClinicalTrials.gov identifier NCT01844986).68 This international superiority trial showed a 70% reduction in risk of ovarian cancer progression in women with BRCA germline or somatic mutations who received maintenance olaparib after primary therapy with paclitaxel and carboplatin.	('reduction', 'NegReg', (498, 507))	('paclitaxel', 'Chemical', 'MESH:D017239', (656, 666))	('BRCA', 'Gene', '672', (324, 328))	('women', 'Species', '9606', (549, 554))	('ovarian cancer', 'Disease', 'MESH:D010051', (519, 533))	('taxane', 'Chemical', 'MESH:C080625', (182, 188))	('Platinum', 'Chemical', 'MESH:D010984', (373, 381))	('BRCA', 'Gene', (560, 564))	('BRCA', 'Gene', (324, 328))	('platinum', 'Chemical', 'MESH:D010984', (167, 175))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (337, 351))	('mutations', 'Var', (585, 594))	('ovarian cancer', 'Disease', (519, 533))	('Patients', 'Species', '9606', (310, 318))	('PARP', 'Gene', '142', (112, 116))	('BRCA Mutated Ovarian Cancer', 'Disease', 'MESH:D010051', (324, 351))	('ovarian cancer', 'Phenotype', 'HP:0100615', (519, 533))	('BRCA Mutated Ovarian Cancer', 'Disease', (324, 351))	('PARP', 'Gene', (112, 116))	('patients', 'Species', '9606', (63, 71))	('carboplatin', 'Chemical', 'MESH:D016190', (671, 682))	('Cancer', 'Phenotype', 'HP:0002664', (345, 351))	('cancer', 'Phenotype', 'HP:0002664', (527, 533))	('BRCA', 'Gene', '672', (560, 564))
73796	31116423	Conversely, patients without BRCA-related mutations may be better served by antiangiogenic therapy with bevacizumab concurrent with upfront platinum and taxane therapy followed by maintenance bevacizumab therapy (Gynecologic Oncology Group study 0218 [GOG-7]).69, 70  In the recurrent setting, PARP inhibitors (olaparib and rucaparib) as monotherapy were first approved for ovarian cancer patients with BRCA1/BRCA2 mutations or HRD.	('BRCA', 'Gene', '672', (29, 33))	('BRCA', 'Gene', '672', (403, 407))	('BRCA', 'Gene', '672', (409, 413))	('patients', 'Species', '9606', (12, 20))	('ovarian cancer', 'Disease', 'MESH:D010051', (374, 388))	('HRD', 'Disease', (428, 431))	('GOG-7', 'Chemical', 'MESH:C520805', (252, 257))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('BRCA', 'Gene', (29, 33))	('BRCA', 'Gene', (403, 407))	('HRD', 'Disease', 'MESH:C537157', (428, 431))	('BRCA', 'Gene', (409, 413))	('PARP', 'Gene', '142', (294, 298))	('BRCA2', 'Gene', (409, 414))	('ovarian cancer', 'Disease', (374, 388))	('patients', 'Species', '9606', (389, 397))	('PARP', 'Gene', (294, 298))	('ovarian cancer', 'Phenotype', 'HP:0100615', (374, 388))	('Oncology', 'Phenotype', 'HP:0002664', (225, 233))	('taxane', 'Chemical', 'MESH:C080625', (153, 159))	('BRCA1', 'Gene', '672', (403, 408))	('platinum', 'Chemical', 'MESH:D010984', (140, 148))	('BRCA1', 'Gene', (403, 408))	('mutations', 'Var', (415, 424))	('BRCA2', 'Gene', '675', (409, 414))
73797	31116423	This indication has now been expanded to include olaparib, rucaparib, and niraparib as switch maintenance therapy for patients with platinum-sensitive ovarian cancer who have responded to platinum in the second-line or third-line setting.65, 66, 67, 71  The identification of BRCA-related gene mutations is also necessary to perform cascade testing on family members to identify affected family members who may be candidates for risk-reducing surgery and surveillance to prevent subsequent ovarian, tubal, peritoneal, and breast cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (151, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (522, 535))	('BRCA', 'Gene', (276, 280))	('ovarian', 'Disease', 'MESH:D010049', (151, 158))	('breast cancer', 'Disease', 'MESH:D001943', (522, 535))	('pan', 'Gene', '51816', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', (522, 535))	('niraparib', 'Chemical', 'MESH:C545685', (74, 83))	('ovarian', 'Disease', 'MESH:D010049', (490, 497))	('mutations', 'Var', (294, 303))	('pan', 'Gene', (31, 34))	('ovarian cancer', 'Disease', 'MESH:D010051', (151, 165))	('platinum', 'Chemical', 'MESH:D010984', (188, 196))	('peritoneal', 'Disease', (506, 516))	('ovarian', 'Disease', (151, 158))	('tubal', 'Disease', (499, 504))	('platinum', 'Chemical', 'MESH:D010984', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (529, 535))	('BRCA', 'Gene', '672', (276, 280))	('ovarian', 'Disease', (490, 497))	('patients', 'Species', '9606', (118, 126))	('ovarian cancer', 'Disease', (151, 165))
73807	31116423	The well-established biomarkers that drive treatment decisions for patients with breast cancers are estrogen receptor (ER) expression, progesterone receptor (PR) expression, and human epidermal growth factor receptor-2 (HER2) overexpression or amplification in the tumor (see Table 2.8).	('human', 'Species', '9606', (178, 183))	('overexpression', 'PosReg', (226, 240))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('PR', 'Gene', '5241', (158, 160))	('ER', 'Gene', '2099', (119, 121))	('estrogen receptor', 'Gene', (100, 117))	('tumor', 'Disease', (265, 270))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('ER', 'Gene', '2099', (221, 223))	('HER2', 'Gene', '2064', (220, 224))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('breast cancers', 'Disease', 'MESH:D001943', (81, 95))	('breast cancers', 'Disease', (81, 95))	('patients', 'Species', '9606', (67, 75))	('progesterone receptor', 'Gene', (135, 156))	('progesterone receptor', 'Gene', '5241', (135, 156))	('breast cancers', 'Phenotype', 'HP:0003002', (81, 95))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('epidermal growth factor receptor-2', 'Gene', (184, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('epidermal growth factor receptor-2', 'Gene', '2064', (184, 218))	('estrogen receptor', 'Gene', '2099', (100, 117))	('HER2', 'Gene', (220, 224))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('184', '207'))	('amplification', 'Var', (244, 257))
73811	31116423	Overexpression of AR occurs in a subset of triple-negative breast cancers (TNBC).72 Clinical trials of AR-targeted treatments have shown promising preliminary results in patients with metastatic, AR-positive TNBC.73 Mutations in ESR1 occur in the ligand-binding domain of the ER and can lead to a ligand-independent, constitutively active form of the ER.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Mutations', 'Var', (216, 225))	('ligand', 'molecular_function', 'GO:0005488', ('297', '303'))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('breast cancers', 'Disease', 'MESH:D001943', (59, 73))	('breast cancers', 'Disease', (59, 73))	('ER', 'Gene', '2099', (276, 278))	('AR', 'Gene', '367', (103, 105))	('patients', 'Species', '9606', (170, 178))	('AR', 'Gene', '367', (18, 20))	('breast cancers', 'Phenotype', 'HP:0003002', (59, 73))	('binding', 'molecular_function', 'GO:0005488', ('254', '261'))	('ER', 'Gene', '2099', (351, 353))	('lead to', 'Reg', (287, 294))	('ESR1', 'Gene', '2099', (229, 233))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('ligand', 'molecular_function', 'GO:0005488', ('247', '253'))	('ligand-independent', 'MPA', (297, 315))	('AR', 'Gene', '367', (196, 198))	('ESR1', 'Gene', (229, 233))
73812	31116423	De novo ESR1 mutations have been most commonly detected during or after treatment with aromatase inhibitors for hormone receptor-positive breast cancer.74 The treatment implication is to consider using selective ER downregulators that target ER directly in the setting of an ESR1 mutation.	('hormone receptor', 'Gene', '3164', (112, 128))	('mutation', 'Var', (280, 288))	('ER', 'Gene', '2099', (212, 214))	('ESR1', 'Gene', '2099', (8, 12))	('ESR1', 'Gene', (275, 279))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('ER', 'Gene', '2099', (242, 244))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('ESR1', 'Gene', (8, 12))	('breast cancer', 'Disease', (138, 151))	('ESR1', 'Gene', '2099', (275, 279))	('hormone receptor', 'Gene', (112, 128))
73826	31116423	It is encouraging that these drugs could be effective agents that allow us to replace chemotherapy entirely for pediatric glioma.86  Other central nervous system types for which molecular profiling has a role include ependymoma (RELA fusion), diffuse midline cerebellar gliomas (histone 3 mutations), medulloblastoma (WNT vs SHH activated), and ependymoma (C19MC amplification).	('glioma', 'Phenotype', 'HP:0009733', (270, 276))	('RELA', 'Gene', (229, 233))	('pediatric glioma', 'Disease', (112, 128))	('RELA', 'Gene', '5970', (229, 233))	('mutations', 'Var', (289, 298))	('SHH', 'Gene', '6469', (325, 328))	('midline cerebellar gliomas', 'Disease', 'MESH:D005910', (251, 277))	('medulloblastoma', 'Disease', (301, 316))	('gliomas', 'Phenotype', 'HP:0009733', (270, 277))	('ependymoma', 'Disease', (345, 355))	('cerebellar gliomas', 'Phenotype', 'HP:0010795', (259, 277))	('midline', 'cellular_component', 'GO:0031430', ('251', '258'))	('SHH', 'Gene', (325, 328))	('ependymoma', 'Disease', 'MESH:D004806', (217, 227))	('ependymoma', 'Disease', (217, 227))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('ependymoma', 'Phenotype', 'HP:0002888', (345, 355))	('ependymoma', 'Phenotype', 'HP:0002888', (217, 227))	('ependymoma', 'Disease', 'MESH:D004806', (345, 355))	('midline cerebellar gliomas', 'Disease', (251, 277))	('medulloblastoma', 'Disease', 'MESH:D008527', (301, 316))	('pediatric glioma', 'Disease', 'MESH:D005910', (112, 128))	('medulloblastoma', 'Phenotype', 'HP:0002885', (301, 316))
73829	31116423	Of other mutations tested, the epidermal growth factor gene EGFR variant vIII encodes a promising molecular target.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('31', '54'))	('vIII', 'Gene', '1351', (73, 77))	('EGFR', 'molecular_function', 'GO:0005006', ('60', '64'))	('EGFR', 'Gene', '1956', (60, 64))	('variant', 'Var', (65, 72))	('vIII', 'Gene', (73, 77))	('EGFR', 'Gene', (60, 64))
73834	31116423	It is assumed that this alteration constitutively activates the RAS/RAK/MEK/ERK kinase pathway.	('ERK', 'molecular_function', 'GO:0004707', ('76', '79'))	('activates', 'PosReg', (50, 59))	('RAK', 'Gene', '2444', (68, 71))	('RAK', 'Gene', (68, 71))	('ER', 'Gene', '2099', (76, 78))	('alteration', 'Var', (24, 34))	('MEK', 'Gene', (72, 75))	('MEK', 'Gene', '5609', (72, 75))
73839	31116423	There are several prominent exceptions to this diagnosis-only rule in gastrointestinal (GI) stromal tumors, in which mutations in KIT (particularly exon 11) and PDGFRA are notable biomarkers for therapeutic intervention with the tyrosine kinase inhibitors imatinib and sunitinib.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutations', 'Var', (117, 126))	('PDGFRA', 'Gene', (161, 167))	('tyrosine', 'Chemical', 'None', (229, 237))	('KIT', 'molecular_function', 'GO:0005020', ('130', '133'))	('PDGFRA', 'Gene', '5156', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('KIT', 'Gene', '3815', (130, 133))	('imatinib', 'Chemical', 'MESH:C097613', (256, 264))	('gastrointestinal (GI) stromal tumors', 'Disease', 'MESH:D046152', (70, 106))	('KIT', 'Gene', (130, 133))	('sunitinib', 'Chemical', 'MESH:C473478', (269, 278))
73850	31116423	It is important to be aware that selective inhibitors of BRAF encoded by mutant BRAF V600 can cause paradoxical activation of the MAPK pathway in cells that are BRAF V600 wild-type (particularly if they harbor a RAS mutation).	('BRAF', 'Gene', (80, 84))	('BRAF', 'Gene', '673', (57, 61))	('activation', 'PosReg', (112, 122))	('BRAF', 'Gene', (57, 61))	('BRAF', 'Gene', (161, 165))	('mutant', 'Var', (73, 79))	('BRAF', 'Gene', '673', (161, 165))	('MAPK', 'molecular_function', 'GO:0004707', ('130', '134'))	('MAPK pathway', 'Pathway', (130, 142))	('BRAF', 'Gene', '673', (80, 84))
73851	31116423	This effect occurs through RAF dimerization, leading to increased cell proliferation rather than inhibition.99 The combination of selective BRAF inhibitors with MEK1/MEK2 inhibitors is now FDA approved only for patients with BRAF V600-mutant melanoma.	('RAF', 'Gene', (27, 30))	('melanoma', 'Disease', 'MESH:D008545', (242, 250))	('MEK2', 'Gene', '5605', (166, 170))	('MEK2', 'Gene', (166, 170))	('patients', 'Species', '9606', (211, 219))	('RAF', 'Gene', '22882', (141, 144))	('V600-mutant', 'Var', (230, 241))	('MEK1', 'Gene', '5604', (161, 165))	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('melanoma', 'Disease', (242, 250))	('RAF', 'Gene', (141, 144))	('BRAF', 'Gene', '673', (140, 144))	('MEK2', 'molecular_function', 'GO:0004708', ('166', '170'))	('BRAF', 'Gene', (140, 144))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('MEK1', 'molecular_function', 'GO:0004708', ('161', '165'))	('RAF', 'Gene', '22882', (27, 30))	('RAF', 'Gene', '22882', (226, 229))	('BRAF', 'Gene', (225, 229))	('BRAF', 'Gene', '673', (225, 229))	('MEK1', 'Gene', (161, 165))	('RAF', 'Gene', (226, 229))
73852	31116423	In patients with resected, stage III, BRAF V600E/V600K-mutant melanoma, dabrafenib plus trametinib improves relapse-free survival by 53%.100 Similarly, dabrafenib plus trametinib and other BRAF/MEK inhibitor combinations have demonstrated objective response rates of up to 68% in patients with unresectable advanced BRAF V600E/K mutant melanoma.101  Other oncogenic driver mutations have been identified in melanomas for which targeted therapies have demonstrated clinical activity.	('melanoma', 'Phenotype', 'HP:0002861', (407, 415))	('melanoma', 'Disease', (407, 415))	('dabrafenib', 'Chemical', 'MESH:C561627', (72, 82))	('V600K', 'Var', (49, 54))	('dabrafenib', 'Chemical', 'MESH:C561627', (152, 162))	('melanomas', 'Disease', 'MESH:D008545', (407, 416))	('BRAF', 'Gene', '673', (38, 42))	('BRAF', 'Gene', (38, 42))	('BRAF', 'Gene', (189, 193))	('BRAF', 'Gene', '673', (189, 193))	('BRAF', 'Gene', '673', (316, 320))	('mutations', 'Var', (373, 382))	('MEK', 'Gene', '5609', (194, 197))	('melanoma', 'Disease', 'MESH:D008545', (336, 344))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('BRAF', 'Gene', (316, 320))	('melanomas', 'Disease', (407, 416))	('melanoma', 'Disease', (62, 70))	('patients', 'Species', '9606', (280, 288))	('melanoma', 'Disease', 'MESH:D008545', (407, 415))	('patients', 'Species', '9606', (3, 11))	('V600E', 'Var', (321, 326))	('MEK', 'Gene', (194, 197))	('trametinib', 'Chemical', 'MESH:C560077', (88, 98))	('V600E', 'Var', (43, 48))	('trametinib', 'Chemical', 'MESH:C560077', (168, 178))	('V600K', 'SUBSTITUTION', 'None', (49, 54))	('melanomas', 'Phenotype', 'HP:0002861', (407, 416))	('melanoma', 'Phenotype', 'HP:0002861', (336, 344))	('melanoma', 'Disease', (336, 344))	('V600E', 'SUBSTITUTION', 'None', (321, 326))	('V600E', 'SUBSTITUTION', 'None', (43, 48))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))
73853	31116423	KIT mutations (and amplifications) have been identified in up to 20% of patients with advanced melanoma, particular those with chronic sun-damaged, acral, or mucosal melanoma subtypes.102, 103 Of note, KIT mutations are often seen across multiple exons, and hotspot mutations are not typically observed.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('mutations', 'Var', (206, 215))	('melanoma', 'Disease', (166, 174))	('mucosal melanoma', 'Disease', (158, 174))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('KIT', 'molecular_function', 'GO:0005020', ('202', '205'))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('patients', 'Species', '9606', (72, 80))	('mucosal melanoma', 'Disease', 'MESH:D008545', (158, 174))	('melanoma', 'Disease', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('KIT', 'Gene', '3815', (0, 3))	('KIT', 'Gene', '3815', (202, 205))	('KIT', 'Gene', (0, 3))	('KIT', 'Gene', (202, 205))
73860	31116423	Improvement in PFS with the combination approach was best seen in patients whose tumors harbored a BRAF V600 mutation or had <1% PD-L1 staining (hazard ratios, 0.62 and 0.68, respectively).	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('PD-L1', 'Gene', (129, 134))	('V600', 'Var', (104, 108))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('PD-L1', 'Gene', '29126', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('PFS', 'MPA', (15, 18))	('Improvement', 'PosReg', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('patients', 'Species', '9606', (66, 74))
73876	31116423	The TAPUR study is an ongoing, nonrandomized, multicenter clinical trial that opened in 2016.115 This trial is testing the use of drugs already approved by the FDA that target a specific tumor mutation in individuals with advanced cancer outside of the drug's approved indication.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cancer', 'Disease', (231, 237))	('tumor', 'Disease', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('mutation', 'Var', (193, 201))
73885	31116423	There have been cross assay comparisons, particularly in NSCLC, for which the staining patterns were similar among the 28-8, 22C3, and SP142 antibodies.133, 134 However, SP142 staining of tumor cell membranes was shown to be weaker, resulting in fewer positive tumor cells than some other assays.	('tumor', 'Disease', (188, 193))	('NSCLC', 'Disease', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('SP142', 'Var', (170, 175))	('fewer', 'NegReg', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('positive', 'MPA', (252, 260))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
73891	31116423	Assays have been developed to test for PD-L1 expression, including the PD-L1 IHC assay with 28-8 Dako (developed for nivolumab), 22C3 Dako (developed for pembrolizumab), SP142 Ventana (atezolizumab), SP263 Ventana (durvalumab), and 73-10 Dako (avelumab).	('SP263 Ventana', 'Var', (200, 213))	('PD-L1', 'Gene', (39, 44))	('SP142', 'Var', (170, 175))	('PD-L1', 'Gene', (71, 76))	('PD-L1', 'Gene', '29126', (39, 44))	('PD-L1', 'Gene', '29126', (71, 76))	('22C3', 'Var', (129, 133))
73897	31116423	When microsatellites contain a clonal change in several repeated DNA nucleotide units, this results in MSI (tumors with such MSI are characterized as MSI-H, and this occurs when at least one of the MMR genes:MSH2, MLH1, MSH6, and PMS2:are inactivated, causing dMMR).10 Since MSI-H was established as a possible biomarker, the MSI status of a tumor has always required microdissection and PCR-based detection strategies.	('MSH2', 'Gene', (208, 212))	('MLH1', 'Gene', (214, 218))	('tumor', 'Disease', (108, 113))	('microsatellites', 'Var', (5, 20))	('MSH6', 'Gene', (220, 224))	('MLH1', 'Gene', '4292', (214, 218))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('MSH2', 'Gene', '4436', (208, 212))	('MSH6', 'Gene', '2956', (220, 224))	('PMS2', 'Gene', '5395', (230, 234))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Disease', (342, 347))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('tumors', 'Disease', (108, 114))	('PMS2', 'Gene', (230, 234))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('results', 'Reg', (92, 99))	('MMR', 'biological_process', 'GO:0006298', ('198', '201'))
73898	31116423	A sensitive and specific MSI assay by NGS has recently been developed that is comparable to the existing gold standard of PCR-based methods without requiring matched samples from tumor and normal tissues.10 MSI appears to be a generalized cancer phenotype in about 4% of all adult cancers in total.	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('cancer', 'Disease', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('cancer', 'Disease', (239, 245))	('tissues.10 MSI', 'Var', (196, 210))	('cancers', 'Disease', 'MESH:D009369', (281, 288))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('cancers', 'Disease', (281, 288))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('tumor', 'Disease', (179, 184))
73908	31116423	Immunogenicity is certainly associated with mutation load, suggesting that an increase in the number of somatic mutations present in tumor cells increases potential recognition by the immune system.135 Indeed, the presence of mutations in the tumor generates neoantigens (not expressed by normal cells), and the more mutations there are, the more the tumor is likely to be immunogenic.	('mutations', 'Var', (317, 326))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (351, 356))	('neoantigens', 'MPA', (259, 270))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('presence', 'Var', (214, 222))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Disease', (133, 138))	('mutations', 'Var', (226, 235))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
73911	31116423	This, of course, also shows that high TMB is in strong concordance with MSI-high in CRC.	('high', 'Var', (33, 37))	('CRC', 'Disease', (84, 87))	('TMB', 'Chemical', 'MESH:D014289', (38, 41))	('TMB', 'MPA', (38, 41))
73916	31116423	A population of tumors exhibiting MSI-H status but low TMB and no PD-L1 expression was identified.	('TMB', 'MPA', (55, 58))	('PD-L1', 'Gene', '29126', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('MSI-H status', 'Var', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('TMB', 'Chemical', 'MESH:D014289', (55, 58))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (16, 22))	('PD-L1', 'Gene', (66, 71))
73921	31116423	In the past, large-scale sequencing studies demonstrated that PBRM1 loss of function (LOF) alterations are present in a large portion (up to 41%) of ccRCC tumors.	('loss of function', 'NegReg', (68, 84))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('alterations', 'Var', (91, 102))	('PBRM1', 'Gene', (62, 67))	('ccRCC tumors', 'Disease', 'MESH:D009369', (149, 161))	('PBRM1', 'Gene', '55193', (62, 67))	('ccRCC tumors', 'Disease', (149, 161))
73924	31116423	HR is a complex DNA repair pathway involving multiple steps and has been reviewed extensively.143, 144 The BRCA1 and BRCA2 genes are critical for efficient double-strand DNA repair via HR and play an important role in the development and clinical progression of many cancers.145, 146 If a cell carries BRCA1/BRCA2 LOF mutations, it loses the ability to repair double-strand breaks by HR and is termed the HRD pathway.	('DNA repair', 'biological_process', 'GO:0006281', ('170', '180'))	('BRCA1', 'Gene', '672', (107, 112))	('mutations', 'Var', (318, 327))	('BRCA1', 'Gene', (107, 112))	('repair double-strand breaks', 'MPA', (353, 380))	('HRD', 'Disease', (405, 408))	('LOF', 'NegReg', (314, 317))	('DNA', 'cellular_component', 'GO:0005574', ('16', '19'))	('BRCA2', 'Gene', (308, 313))	('cancers', 'Disease', 'MESH:D009369', (267, 274))	('HRD', 'Disease', 'MESH:C537157', (405, 408))	('DNA repair', 'biological_process', 'GO:0006281', ('16', '26'))	('BRCA2', 'Gene', (117, 122))	('BRCA1', 'Gene', '672', (302, 307))	('ability', 'MPA', (342, 349))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('BRCA1', 'Gene', (302, 307))	('BRCA2', 'Gene', '675', (308, 313))	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))	('BRCA2', 'Gene', '675', (117, 122))	('cancers', 'Phenotype', 'HP:0002664', (267, 274))	('cancers', 'Disease', (267, 274))	('loses', 'NegReg', (332, 337))
73925	31116423	Such HRD cells are highly sensitive to DNA-damaging agents, such as platinum-based chemotherapies and other cytotoxic agents that can cause DNA strand breaks.147, 148 PARP plays a major role in DNA strand break repair.	('breaks.147', 'Var', (151, 161))	('PARP', 'Gene', (167, 171))	('HRD', 'Disease', 'MESH:C537157', (5, 8))	('DNA', 'cellular_component', 'GO:0005574', ('194', '197'))	('DNA strand break', 'MPA', (194, 210))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('HRD', 'Disease', (5, 8))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('PARP', 'Gene', '142', (167, 171))	('platinum', 'Chemical', 'MESH:D010984', (68, 76))
73929	31116423	Defects in HR repair can be because of epigenetic changes such as BRCA1 promoter methylation, somatic mutations in key HR-related genes, and frequent copy number alterations.149 In addition, mutations in other genes may result in HR-defective tumors and include but are not limited to PALB2, RAD51, CHEK2, and ATM.150, 151, 152, 153  The most common approach to test for HRD is genomic testing for alterations in BRCA1 and BRCA2 on the basis that BRCA1 and BRCA2 germline and somatic mutations are known to cause HRD.	('CHEK2', 'Gene', '11200', (299, 304))	('methylation', 'biological_process', 'GO:0032259', ('81', '92'))	('BRCA2', 'Gene', '675', (457, 462))	('ATM', 'Gene', '472', (310, 313))	('mutations', 'Var', (484, 493))	('PALB2', 'Gene', (285, 290))	('cause', 'Reg', (507, 512))	('BRCA1', 'Gene', '672', (447, 452))	('BRCA1', 'Gene', '672', (66, 71))	('BRCA2', 'Gene', '675', (423, 428))	('mutations', 'Var', (191, 200))	('BRCA1', 'Gene', (447, 452))	('BRCA1', 'Gene', (66, 71))	('HRD', 'Disease', (371, 374))	('alterations', 'Var', (398, 409))	('PALB2', 'Gene', '79728', (285, 290))	('ATM', 'Gene', (310, 313))	('HR-defective tumors', 'Disease', (230, 249))	('HRD', 'Disease', (513, 516))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('HRD', 'Disease', 'MESH:C537157', (371, 374))	('RAD51', 'Gene', (292, 297))	('RAD51', 'Gene', '5888', (292, 297))	('BRCA1', 'Gene', '672', (413, 418))	('HR-defective tumors', 'Disease', 'MESH:D009369', (230, 249))	('HRD', 'Disease', 'MESH:C537157', (513, 516))	('BRCA1', 'Gene', (413, 418))	('BRCA2', 'Gene', (457, 462))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('CHEK2', 'Gene', (299, 304))	('RAD', 'biological_process', 'GO:1990116', ('292', '295'))	('result in', 'Reg', (220, 229))	('BRCA2', 'Gene', (423, 428))
73931	31116423	A tumor can be characterized as HR-deficient or HR-nondeficient by combining the HRD score that it generates and its BRCA1/BRCA2 mutation status.	('HR-deficient or HR-nondeficient', 'Disease', 'MESH:D001919', (32, 63))	('BRCA2', 'Gene', '675', (123, 128))	('HRD', 'Disease', 'MESH:C537157', (81, 84))	('HR-deficient or HR-nondeficient', 'Disease', (32, 63))	('BRCA1', 'Gene', '672', (117, 122))	('mutation', 'Var', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('HRD', 'Disease', (81, 84))	('BRCA1', 'Gene', (117, 122))	('tumor', 'Disease', (2, 7))	('BRCA2', 'Gene', (123, 128))
73932	31116423	HRD is defined as an HRD score >=42 or the presence of a mutation in BRCA1/BRCA2.	('mutation', 'Var', (57, 65))	('BRCA1', 'Gene', '672', (69, 74))	('HRD', 'Disease', 'MESH:C537157', (21, 24))	('HRD', 'Disease', 'MESH:C537157', (0, 3))	('BRCA2', 'Gene', (75, 80))	('BRCA1', 'Gene', (69, 74))	('HRD', 'Disease', (21, 24))	('BRCA2', 'Gene', '675', (75, 80))	('HRD', 'Disease', (0, 3))	('presence', 'Reg', (43, 51))
73933	31116423	As an example of its accuracy, the myChoice HRD assay was seen to identify 100% of BRCA-mutated tumors and 57% of non-BRCA-mutated tumors that had HR deficiencies in patients with platinum-sensitive, high-grade, serous or BRCA-mutated, recurrent ovarian cancer.65  The FoundationFocus CDx BRCA (Foundation Medicine, Inc) assay was used to detect both germline and somatic BRCA1/BRCA2 mutation types associated with response to PARP inhibitor therapy.155, 156 This modified NGS-based assay determined the percentage of genomic loss of heterozygosity, mutations in BRCA1/BRCA2, and other HR genes in tumor tissue of patients with ovarian cancers taking part in the ARIEL PARP inhibitor rucaparib trial.	('BRCA', 'Gene', '672', (563, 567))	('BRCA2', 'Gene', '675', (569, 574))	('mutations', 'Var', (550, 559))	('BRCA2', 'Gene', '675', (378, 383))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('BRCA', 'Gene', '672', (118, 122))	('BRCA', 'Gene', (372, 376))	('tumor', 'Disease', (131, 136))	('PARP', 'Gene', '142', (427, 431))	('HR deficiencies', 'Disease', 'MESH:D001919', (147, 162))	('PARP', 'Gene', (427, 431))	('BRCA', 'Gene', (222, 226))	('AR', 'Gene', '367', (670, 672))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('BRCA', 'Gene', '672', (569, 573))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('BRCA', 'Gene', '672', (378, 382))	('BRCA', 'Gene', '672', (289, 293))	('BRCA', 'Gene', '672', (83, 87))	('BRCA', 'Gene', (563, 567))	('cancers', 'Phenotype', 'HP:0002664', (636, 643))	('ovarian cancers', 'Phenotype', 'HP:0100615', (628, 643))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('ovarian cancer', 'Disease', 'MESH:D010051', (628, 642))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('BRCA', 'Gene', (118, 122))	('tumor', 'Disease', (598, 603))	('cancer', 'Phenotype', 'HP:0002664', (636, 642))	('PARP', 'Gene', '142', (669, 673))	('ovarian cancer', 'Disease', 'MESH:D010051', (246, 260))	('loss', 'NegReg', (526, 530))	('tumor', 'Disease', 'MESH:D009369', (598, 603))	('BRCA', 'Gene', (569, 573))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('BRCA1', 'Gene', '672', (372, 377))	('BRCA', 'Gene', (378, 382))	('BRCA', 'Gene', (83, 87))	('BRCA', 'Gene', (289, 293))	('tumor', 'Disease', (96, 101))	('patients', 'Species', '9606', (614, 622))	('PARP', 'Gene', (669, 673))	('BRCA1', 'Gene', (372, 377))	('tumors', 'Disease', (131, 137))	('BRCA2', 'Gene', (569, 574))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('BRCA2', 'Gene', (378, 383))	('myChoice HRD', 'Disease', (35, 47))	('BRCA1', 'Gene', '672', (563, 568))	('myChoice HRD', 'Disease', 'MESH:C537157', (35, 47))	('BRCA1', 'Gene', (563, 568))	('ovarian cancer', 'Phenotype', 'HP:0100615', (628, 642))	('BRCA', 'Gene', '672', (372, 376))	('ovarian cancer', 'Disease', (246, 260))	('platinum', 'Chemical', 'MESH:D010984', (180, 188))	('ovarian cancers', 'Disease', (628, 643))	('AR', 'Gene', '367', (428, 430))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (598, 603))	('HR deficiencies', 'Disease', (147, 162))	('ovarian cancers', 'Disease', 'MESH:D010051', (628, 643))	('AR', 'Gene', '367', (663, 665))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('BRCA', 'Gene', '672', (222, 226))	('ovarian cancer', 'Phenotype', 'HP:0100615', (246, 260))	('patients', 'Species', '9606', (166, 174))
73936	31116423	Certain cancers, including ovarian, fallopian tube, breast, primary peritoneal, and GI (specifically a subgroup of pancreatic adenocarcinomas and gastric/esophageal cancers), have been shown to harbor aberrations in genes involved in the HRD pathway.	('HRD', 'Disease', (238, 241))	('HRD', 'Disease', 'MESH:C537157', (238, 241))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('ovarian', 'Disease', (27, 34))	('cancers', 'Disease', (8, 15))	('breast', 'Disease', (52, 58))	('fallopian tube', 'Disease', (36, 50))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('fallopian tube', 'Disease', 'MESH:D005184', (36, 50))	('pancreatic adenocarcinomas and gastric/esophageal cancers', 'Disease', 'MESH:D013274', (115, 172))	('fall', 'Phenotype', 'HP:0002527', (36, 40))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (115, 141))	('cancers', 'Disease', (165, 172))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('ovarian', 'Disease', 'MESH:D010049', (27, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('aberrations', 'Var', (201, 212))	('primary peritoneal', 'Disease', (60, 78))
73941	31116423	The primary outcome of the study will be the objective response rate to entrectinib.27   NTRK fusions may act as actionable targets in conjunction with other potentially targetable alterations, such as PD-L1-positive or MSI-H status, meaning that therapeutic combinations (TRK inhibitors plus immune checkpoint inhibitors, for example) are a promising strategy.159  The fibroblast growth factor receptor (FGFR) family comprises part of a tyrosine kinase signaling pathway that plays a role in oncogenesis through gene amplification, activating mutations, or translocation in several tumor types.	('tyrosine', 'Chemical', 'None', (438, 446))	('FGFR', 'Gene', (405, 409))	('PD-L1', 'Gene', '29126', (202, 207))	('tumor', 'Disease', (583, 588))	('FGFR', 'molecular_function', 'GO:0005007', ('405', '409'))	('TRK', 'Gene', (273, 276))	('gene amplification', 'Var', (513, 531))	('TRK', 'Gene', '4914', (273, 276))	('oncogenesis', 'biological_process', 'GO:0007048', ('493', '504'))	('translocation', 'Var', (558, 571))	('signaling pathway', 'biological_process', 'GO:0007165', ('454', '471'))	('activating', 'MPA', (533, 543))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('370', '394'))	('tumor', 'Disease', 'MESH:D009369', (583, 588))	('TRK', 'Gene', (90, 93))	('PD-L1', 'Gene', (202, 207))	('TRK', 'Gene', '4914', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (583, 588))
73943	31116423	Earlier this year, the FDA granted Breakthrough Therapy Designation for erdafitinib in the treatment of urothelial cancer, which is based on data from a multicenter phase 2 clinical trial focused on evaluating the efficacy and safety of erdafitinib in the treatment of adult patients with locally advanced or metastatic urothelial cancer harboring specific FGFR mutations.160 The overall response rate was 42% in 59 patients for whom data were available.160 Erdafitinib is also under investigation in the NCI-MATCH trial as a treatment for patients with tumors that have an FGFR mutation, fusion, or amplification (Table 7).	('patients', 'Species', '9606', (540, 548))	('amplification', 'Var', (600, 613))	('tumors', 'Phenotype', 'HP:0002664', (554, 560))	('patients', 'Species', '9606', (275, 283))	('tumor', 'Phenotype', 'HP:0002664', (554, 559))	('fusion', 'Var', (589, 595))	('tumors', 'Disease', (554, 560))	('FGFR', 'molecular_function', 'GO:0005007', ('574', '578'))	('urothelial cancer', 'Disease', 'MESH:D014523', (320, 337))	('mutation', 'Var', (579, 587))	('erdafitinib', 'Chemical', 'None', (72, 83))	('urothelial cancer', 'Disease', (320, 337))	('tumors', 'Disease', 'MESH:D009369', (554, 560))	('patients', 'Species', '9606', (416, 424))	('urothelial cancer', 'Disease', 'MESH:D014523', (104, 121))	('erdafitinib', 'Chemical', 'None', (237, 248))	('Erdafitinib', 'Chemical', 'None', (458, 469))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('urothelial cancer', 'Disease', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('FGFR', 'molecular_function', 'GO:0005007', ('357', '361'))	('FGFR', 'Gene', (574, 578))
73944	31116423	Also in the NCI-MATCH trial, 5 of 50 patients with an aberrant FGFR pathway had a partial response to AZD4547 (another FGFR tyrosine kinase inhibitor).161 Two of these patient's tumors had point mutations in FGFR2/FGFR3, and 2 others had FGFR3 fusions, suggesting that these particular types of mutation have increased sensitivity to the drug, which warrants further study in this patient subtype.	('FGFR3', 'Gene', (238, 243))	('FGFR3', 'Gene', (214, 219))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('FGFR', 'molecular_function', 'GO:0005007', ('238', '242'))	('patient', 'Species', '9606', (168, 175))	('FGFR', 'molecular_function', 'GO:0005007', ('119', '123'))	('point mutations', 'Var', (189, 204))	('FGFR3', 'Gene', '2261', (238, 243))	('FGFR3', 'Gene', '2261', (214, 219))	('sensitivity', 'MPA', (319, 330))	('FGFR', 'molecular_function', 'GO:0005007', ('214', '218'))	('patients', 'Species', '9606', (37, 45))	('FGFR', 'molecular_function', 'GO:0005007', ('208', '212'))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('patient', 'Species', '9606', (381, 388))	('FGFR2', 'Gene', (208, 213))	('AZD4547', 'Chemical', 'MESH:C572463', (102, 109))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('FGFR2', 'Gene', '2263', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('increased', 'PosReg', (309, 318))	('patient', 'Species', '9606', (37, 44))	('tumors', 'Disease', (178, 184))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('133', '149'))	('tyrosine', 'Chemical', 'None', (124, 132))
73945	31116423	Aberrant activation of MET receptor tyrosine kinase signaling occurs in various cancer types as result of various MET alterations, including amplification and an exon 14 mutation.	('amplification', 'Var', (141, 154))	('activation', 'PosReg', (9, 19))	('tyrosine', 'Chemical', 'None', (36, 44))	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('MET receptor tyrosine kinase signaling', 'MPA', (23, 61))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('exon 14 mutation', 'Var', (162, 178))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
73946	31116423	Crizotinib is an ALK/ROS1/MET inhibitor that is already FDA approved in ALK-positive or ROS1-positive NSCLC but also has proven clinical activity in cases of MET exon 14 alterations and MET amplification.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('ALK', 'Gene', '238', (17, 20))	('Crizotinib', 'Chemical', 'MESH:C551994', (0, 10))	('ROS1', 'Gene', '6098', (88, 92))	('ROS1', 'Gene', (21, 25))	('ALK', 'Gene', (17, 20))	('ALK', 'Gene', '238', (72, 75))	('ROS1', 'Gene', '6098', (21, 25))	('MET exon 14 alterations', 'Var', (158, 181))	('ROS1', 'Gene', (88, 92))	('MET amplification', 'Var', (186, 203))	('NSCLC', 'Disease', (102, 107))	('ALK', 'Gene', (72, 75))
73948	31116423	Crizotinib was generally well tolerated163 and is currently under study in the ASCO TAPUR trial for patients with tumors that have ALK, ROS1, or MET mutations and in the NCI-MATCH trial as a treatment for patients with tumors that have a MET amplification, MET exon 14 mutation, ALK translocation, or ROS1 translocation or inversion (Table 7).	('patients', 'Species', '9606', (205, 213))	('ROS1', 'Gene', (136, 140))	('patients', 'Species', '9606', (100, 108))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('MET amplification', 'Var', (238, 255))	('ROS1', 'Gene', (301, 305))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('ALK', 'Gene', '238', (131, 134))	('ALK', 'Gene', (131, 134))	('ALK', 'Gene', '238', (279, 282))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumors', 'Disease', (219, 225))	('ROS1', 'Gene', '6098', (136, 140))	('ALK', 'Gene', (279, 282))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('inversion', 'Var', (323, 332))	('Crizotinib', 'Chemical', 'MESH:C551994', (0, 10))	('ROS1', 'Gene', '6098', (301, 305))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (114, 120))	('MET exon 14 mutation', 'Var', (257, 277))
73951	31116423	Sapanisertib (TAK-228) demonstrated a reasonable safety profile as well as promising preliminary antitumor activity in a range of tumor types with aberrant MTOR.164 Tuberous sclerosis complex 1 and 2 (TSC1 and TSC2) mutations are also observed in certain tumor subtypes and may be targeted by sapanisertib.	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('sapanisertib', 'Chemical', 'None', (293, 305))	('tumor', 'Disease', (130, 135))	('Tuberous sclerosis complex', 'cellular_component', 'GO:0033596', ('165', '191'))	('TSC2', 'Gene', '7249', (210, 214))	('TSC1', 'Gene', (201, 205))	('Tuberous sclerosis', 'Disease', (165, 183))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('TSC1', 'Gene', '7248', (201, 205))	('Sapanisertib', 'Chemical', 'None', (0, 12))	('TSC2', 'Gene', (210, 214))	('tumor', 'Disease', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('MTOR', 'Gene', (156, 160))	('Tuberous sclerosis', 'Disease', 'MESH:D014402', (165, 183))	('tumor', 'Disease', (101, 106))	('MTOR', 'Gene', '2475', (156, 160))	('mutations', 'Var', (216, 225))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
73952	31116423	The agent is under investigation in the NCI-MATCH trial as a treatment for patients with tumors that have MTOR or TSC1/TSC2 mutations (Table 7).	('tumors', 'Disease', (89, 95))	('TSC1', 'Gene', '7248', (114, 118))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('mutations', 'Var', (124, 133))	('TSC1', 'Gene', (114, 118))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('patients', 'Species', '9606', (75, 83))	('MTOR', 'Gene', (106, 110))	('TSC2', 'Gene', '7249', (119, 123))	('MTOR', 'Gene', '2475', (106, 110))	('TSC2', 'Gene', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
73953	31116423	In the NCI-MATCH trial, 65 patients with a mutated phosphatidylinositol 3-kinase gene (PIK3CA) were treated with taselisib (a PIK3CA inhibitor) and, although there were no ORs to the drug, 24% of patients had prolonged stable disease for more than 6 months.	('PIK3CA', 'Gene', '5290', (87, 93))	('PIK3CA', 'Gene', (126, 132))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (51, 71))	('PIK3CA', 'Gene', '5290', (126, 132))	('patients', 'Species', '9606', (196, 204))	('patients', 'Species', '9606', (27, 35))	('PIK3CA', 'Gene', (87, 93))	('mutated', 'Var', (43, 50))
73955	31116423	Palbociclib, an inhibitor of aberrant CDK4/CDK6, is FDA approved for the treatment of hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women.166 Its effect on certain GI tumors is under investigation in the clinic.167 Palbociclib is also under investigation in the NCI-MATCH trial as a treatment for patients with tumors that have CDK4 or CDK6 amplification or CCND1, CCND2, or CCND3 amplification (and Rb expression/protein in both study arms).	('CDK6', 'Gene', (43, 47))	('CCND1', 'Gene', (487, 492))	('tumors', 'Disease', 'MESH:D009369', (440, 446))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('tumors', 'Disease', 'MESH:D009369', (296, 302))	('CCND3', 'Gene', (504, 509))	('patients', 'Species', '9606', (426, 434))	('CDK', 'molecular_function', 'GO:0004693', ('38', '41'))	('CDK4', 'Gene', '1019', (38, 42))	('CDK4', 'Gene', (457, 461))	('hormone receptor', 'Gene', (86, 102))	('HER2', 'Gene', (113, 117))	('CCND2', 'Gene', (494, 499))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('GI tumors', 'Disease', (293, 302))	('breast cancer', 'Disease', (151, 164))	('amplification', 'Var', (470, 483))	('CDK', 'molecular_function', 'GO:0004693', ('43', '46'))	('women', 'Species', '9606', (261, 266))	('CCND2', 'Gene', '894', (494, 499))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('CDK4', 'Gene', '1019', (457, 461))	('CDK6', 'Gene', '1021', (465, 469))	('protein', 'cellular_component', 'GO:0003675', ('543', '550'))	('tumors', 'Phenotype', 'HP:0002664', (296, 302))	('CCND3', 'Gene', '896', (504, 509))	('CDK', 'molecular_function', 'GO:0004693', ('465', '468'))	('tumors', 'Phenotype', 'HP:0002664', (440, 446))	('CDK6', 'Gene', (465, 469))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('CDK', 'molecular_function', 'GO:0004693', ('457', '460'))	('CDK6', 'Gene', '1021', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (440, 445))	('hormone receptor', 'Gene', '3164', (86, 102))	('GI tumors', 'Phenotype', 'HP:0007378', (293, 302))	('tumors', 'Disease', (440, 446))	('HER2', 'Gene', '2064', (113, 117))	('tumors', 'Disease', (296, 302))	('GI tumors', 'Disease', 'MESH:D046152', (293, 302))	('CCND1', 'Gene', '595', (487, 492))	('CDK4', 'Gene', (38, 42))
73956	31116423	The ASCO TAPUR trial is also investigating palbociclib in the treatment of patients with tumors that harbor CDKN2A, CDK4, or CDK6 amplifications (Table 7).	('amplifications', 'Var', (130, 144))	('tumors', 'Disease', (89, 95))	('CDKN2A', 'Gene', '1029', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('CDK', 'molecular_function', 'GO:0004693', ('116', '119'))	('patients', 'Species', '9606', (75, 83))	('CDK4', 'Gene', '1019', (116, 120))	('CDK4', 'Gene', (116, 120))	('CDK', 'molecular_function', 'GO:0004693', ('125', '128'))	('CDK6', 'Gene', (125, 129))	('CDKN2A', 'Gene', (108, 114))	('CDK6', 'Gene', '1021', (125, 129))
73958	31116423	DDR2 mutations are seen in several tumor types, including lung cancer, breast cancer, brain cancer, gynecologic cancer, and prostate cancer.168 The multikinase inhibitor dasatinib blocks DDR2 kinase activity to various degrees and is under investigation in the treatment of patients with tumors that possess a DDR2 S768R, I638F, or L239R mutation (NCI-MATCH).	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('S768R', 'Var', (315, 320))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('DDR2', 'Gene', '4921', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('brain cancer', 'Phenotype', 'HP:0030692', (86, 98))	('brain cancer', 'Disease', 'MESH:D001932', (86, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('kinase activity', 'molecular_function', 'GO:0016301', ('192', '207'))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('DDR2', 'Gene', '4921', (310, 314))	('I638F', 'Var', (322, 327))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('breast cancer', 'Disease', (71, 84))	('activity', 'MPA', (199, 207))	('L239R', 'SUBSTITUTION', 'None', (332, 337))	('patients', 'Species', '9606', (274, 282))	('tumor', 'Disease', (35, 40))	('dasatinib', 'Chemical', 'MESH:C488369', (170, 179))	('S768R', 'SUBSTITUTION', 'None', (315, 320))	('DDR2', 'Gene', (0, 4))	('DDR2', 'Gene', '4921', (187, 191))	('L239R', 'Var', (332, 337))	('cancer', 'Disease', (63, 69))	('tumor', 'Disease', (288, 293))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('DDR2', 'Gene', (310, 314))	('cancer', 'Disease', (92, 98))	('brain cancer', 'Disease', (86, 98))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (78, 84))	('lung cancer', 'Disease', (58, 69))	('cancer', 'Disease', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('DDR2', 'Gene', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (124, 139))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))	('prostate cancer', 'Phenotype', 'HP:0012125', (124, 139))	('blocks', 'NegReg', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('I638F', 'SUBSTITUTION', 'None', (322, 327))	('prostate cancer', 'Disease', (124, 139))	('tumors', 'Disease', (288, 294))
73959	31116423	The agent is also under investigation in the treatment of patients with tumors that harbor Bcr-abl, SRC, KIT, PDGFRB, EPHA2, FYN, LCK, or YES1 mutations (TAPUR trial) (Table 7).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('LCK', 'Gene', '3932', (130, 133))	('PDGFRB', 'Gene', (110, 116))	('tumors', 'Disease', (72, 78))	('PDGFRB', 'Gene', '5159', (110, 116))	('Bcr-abl', 'Gene', '25', (91, 98))	('EPHA2', 'Gene', (118, 123))	('FYN', 'Gene', (125, 128))	('KIT', 'Gene', (105, 108))	('YES1', 'Gene', '7525', (138, 142))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('SRC', 'Gene', '6714', (100, 103))	('Bcr-abl', 'Gene', (91, 98))	('mutations', 'Var', (143, 152))	('LCK', 'Gene', (130, 133))	('FYN', 'Gene', '2534', (125, 128))	('EPHA2', 'Gene', '1969', (118, 123))	('KIT', 'molecular_function', 'GO:0005020', ('105', '108'))	('patients', 'Species', '9606', (58, 66))	('SRC', 'Gene', (100, 103))	('KIT', 'Gene', '3815', (105, 108))	('YES1', 'Gene', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))
73972	31116423	An illustrated example of this was a recent patient's lung cancer demonstrating an actionable mutation in BRAF.	('lung cancer', 'Disease', (54, 65))	('patient', 'Species', '9606', (44, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('BRAF', 'Gene', '673', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('BRAF', 'Gene', (106, 110))	('mutation', 'Var', (94, 102))
73980	31116423	These fall into several categories, such as reimbursement issues, evaluating the tumor genomic data for potential germline testing, paring results to clinical trial opportunities, and collecting and collating the genomic data to clinical information and outcomes, as well as the incorporation of new opportunities such as sequencing cell-free DNA or routine pharmacogenetic testing.	('fall', 'Phenotype', 'HP:0002527', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('sequencing', 'Var', (322, 332))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('DNA', 'cellular_component', 'GO:0005574', ('343', '346'))	('tumor', 'Disease', (81, 86))
73989	31116423	Examples of major drivers for which there are currently no approved drugs include mutated beta-catenin, mutated P53, or mutated RAS, among others.	('mutated', 'Var', (104, 111))	('P53', 'Gene', (112, 115))	('RAS', 'Gene', (128, 131))	('beta-catenin', 'Gene', (90, 102))	('P53', 'Gene', '7157', (112, 115))	('mutated', 'Var', (82, 89))	('beta-catenin', 'Gene', '1499', (90, 102))	('mutated', 'Var', (120, 127))
73991	31116423	There are some exceptions with mutated EGFR, ALK, or BCR-ABL.	('ALK', 'Gene', '238', (45, 48))	('BCR-ABL', 'Gene', (53, 60))	('BCR-ABL', 'Gene', '25', (53, 60))	('ALK', 'Gene', (45, 48))	('EGFR', 'molecular_function', 'GO:0005006', ('39', '43'))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('mutated', 'Var', (31, 38))
73996	31116423	However, it is not unreasonable to expect that the many genomic changes representing the tail end of the curve of drivers may affect patient outcomes, especially if there are available drugs that target their pathways.	('patient', 'Species', '9606', (133, 140))	('changes', 'Var', (64, 71))	('affect', 'Reg', (126, 132))	('patient outcomes', 'MPA', (133, 149))
74011	31116423	Only patients with MSI-H, stage III colon cancer will be eligible for randomization, and the eligibility determination mandates genomic testing for defective MMR in patients with localized disease.	('MMR', 'biological_process', 'GO:0006298', ('158', '161'))	('patients', 'Species', '9606', (5, 13))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('colon cancer', 'Disease', 'MESH:D015179', (36, 48))	('localized disease', 'Disease', (179, 196))	('colon cancer', 'Disease', (36, 48))	('defective', 'Var', (148, 157))	('localized disease', 'Disease', 'MESH:D004828', (179, 196))	('patients', 'Species', '9606', (165, 173))	('MMR', 'Gene', (158, 161))	('MSI-H', 'Var', (19, 24))	('colon cancer', 'Phenotype', 'HP:0003003', (36, 48))
74029	29299115	In multivariate analysis, a high level of exo-miR-224 was a significant risk factor related to all prognoses investigated.	('high', 'Var', (28, 32))	('miR-224', 'Gene', '407009', (46, 53))	('miR-224', 'Gene', (46, 53))
74063	29299115	The high expression level exosomal miR-224 group had significantly shorter progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS) compared with the low level expression group (Figure 3A-3C, log-rank P < 0.0001, log-rank P = 0.0072, log-rank P = 0.0046, respectively).	('miR-224', 'Gene', '407009', (35, 42))	('high expression level', 'Var', (4, 25))	('cancer', 'Disease', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('shorter', 'NegReg', (67, 74))	('CSS', 'Chemical', '-', (134, 137))	('overall survival', 'CPA', (144, 160))	('miR-224', 'Gene', (35, 42))	('progression-free survival', 'CPA', (75, 100))
74065	29299115	High exosomal miR-224 expression was a significant independent risk factor related to PFS, CSS, and OS in multivariate analysis (HR = 11.0; P < 0.0001, HR = 1.6; P = 0.0140, HR = 9.1; P = 0.0043, respectively).	('PFS', 'Disease', (86, 89))	('High', 'Var', (0, 4))	('CSS', 'Disease', (91, 94))	('CSS', 'Chemical', '-', (91, 94))	('miR-224', 'Gene', (14, 21))	('expression', 'MPA', (22, 32))	('miR-224', 'Gene', '407009', (14, 21))
74069	29299115	After knock-down of intracellular miR-224 in Caki-1 cells using an miR-224 inhibitor, extracellular levels of miR-224 were also significantly decreased (Figure 4B).	('miR-224', 'Gene', '407009', (110, 117))	('miR-224', 'Gene', (67, 74))	('extracellular', 'cellular_component', 'GO:0005576', ('86', '99'))	('decreased', 'NegReg', (142, 151))	('miR-224', 'Gene', '407009', (67, 74))	('knock-down', 'Var', (6, 16))	('intracellular', 'cellular_component', 'GO:0005622', ('20', '33'))	('Caki-1', 'CellLine', 'CVCL:0234', (45, 51))	('miR-224', 'Gene', '407009', (34, 41))	('miR-224', 'Gene', (34, 41))	('miR-224', 'Gene', (110, 117))
74078	29299115	Under the similar condition, we next knocked down of miR-224 in Caki-1 cells and then exosomes are collected and the exosomes are added to the culture media of target cells such as 769-P and RPTEC (Figure 6C).	('Caki-1', 'CellLine', 'CVCL:0234', (64, 70))	('knocked', 'Var', (37, 44))	('miR-224', 'Gene', '407009', (53, 60))	('miR-224', 'Gene', (53, 60))
74081	29299115	RPTEC cells added exosomes of Caki-1 were significantly increased the ability to cell viability and invasion compared to RPTEC cells added exosomes of RPTEC (Supplementary Figure 3) Blood samples can contain several tumor components, including cell free tumor DNA, circulating tumor cells, and exosomes.	('tumor', 'Disease', (216, 221))	('DNA', 'cellular_component', 'GO:0005574', ('260', '263'))	('tumor', 'Disease', (254, 259))	('increased', 'PosReg', (56, 65))	('Caki-1', 'Gene', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('Caki-1', 'CellLine', 'CVCL:0234', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('invasion', 'CPA', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('exosomes', 'Var', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Disease', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('cell viability', 'CPA', (81, 95))
74100	29299115	miR-224 may be considered as a biomarker for prognosis and high miR-224 expression group patients may be candidates for careful follow-up after surgery.	('miR-224', 'Gene', (64, 71))	('high', 'Var', (59, 63))	('patients', 'Species', '9606', (89, 97))	('miR-224', 'Gene', (0, 7))	('miR-224', 'Gene', '407009', (64, 71))	('miR-224', 'Gene', '407009', (0, 7))
74109	29299115	Next, we found that exosomal miR-224 expression was associated with poor prognosis using the Kaplan-Meier survival curve.	('miR-224', 'Gene', (29, 36))	('miR-224', 'Gene', '407009', (29, 36))	('exosomal', 'Var', (20, 28))
74117	29299115	After knocking down miR-224 in renal cancer cell lines, extracellular miRNA-224 levels were also significantly decreased.	('renal cancer', 'Disease', (31, 43))	('miRNA-224', 'Gene', (70, 79))	('miRNA-224', 'Gene', '407009', (70, 79))	('decreased', 'NegReg', (111, 120))	('renal cancer', 'Disease', 'MESH:D007680', (31, 43))	('renal cancer', 'Phenotype', 'HP:0009726', (31, 43))	('extracellular', 'cellular_component', 'GO:0005576', ('56', '69'))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('miR-224', 'Gene', '407009', (20, 27))	('miR-224', 'Gene', (20, 27))	('knocking down', 'Var', (6, 19))
74174	31114381	Visfatin was detected in tumors or plasma of patients with variant types of cancers, which indicates its clinical importance in cancer progression.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('patients', 'Species', '9606', (45, 53))	('variant', 'Var', (59, 66))	('detected', 'Reg', (13, 21))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (128, 134))
74188	31114381	In addition, hepatocellular carcinoma patients with high serum visfatin levels had shorter overall survival times compared with those with low serum visfatin levels (p<0.001).	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('shorter', 'NegReg', (83, 90))	('overall survival times', 'CPA', (91, 113))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (13, 37))	('high', 'Var', (52, 56))	('patients', 'Species', '9606', (38, 46))	('hepatocellular carcinoma', 'Disease', (13, 37))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (13, 37))
74205	31114381	The visfatin inhibitor KPT-9274 was shown to interfere with the signaling pathway and resulted in a reduction of G2/M transit as well as an induction of apoptosis in several human RCC cell lines.	('reduction', 'NegReg', (100, 109))	('induction', 'Reg', (140, 149))	('KPT-9274', 'Var', (23, 31))	('human', 'Species', '9606', (174, 179))	('RCC', 'Disease', (180, 183))	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('KPT-9274', 'Chemical', 'MESH:C000622300', (23, 31))	('RCC', 'Phenotype', 'HP:0005584', (180, 183))	('signaling pathway', 'biological_process', 'GO:0007165', ('64', '81'))	('signaling pathway', 'Pathway', (64, 81))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('140', '162'))	('G2/M transit', 'MPA', (113, 125))	('interfere', 'NegReg', (45, 54))	('apoptosis', 'CPA', (153, 162))
74206	31114381	In addition, NAMPT gene silencing by specific siRNA decreased cell proliferation and increased apoptosis in multiple myeloma RPMI 8226 cells.	('gene silencing', 'Var', (19, 33))	('cell proliferation', 'biological_process', 'GO:0008283', ('62', '80'))	('multiple myeloma', 'Phenotype', 'HP:0006775', (108, 124))	('decreased', 'NegReg', (52, 61))	('apoptosis', 'CPA', (95, 104))	('apoptosis', 'biological_process', 'GO:0097194', ('95', '104'))	('multiple myeloma RPMI', 'Disease', (108, 129))	('cell proliferation', 'CPA', (62, 80))	('rat', 'Species', '10116', (74, 77))	('apoptosis', 'biological_process', 'GO:0006915', ('95', '104'))	('gene silencing', 'biological_process', 'GO:0016458', ('19', '33'))	('multiple myeloma RPMI', 'Disease', 'MESH:D009101', (108, 129))	('increased', 'PosReg', (85, 94))	('NAMPT', 'Gene', '10135', (13, 18))	('NAMPT', 'Gene', (13, 18))
74208	31114381	A similar inhibitory effect of FK866 was reported in a study of CRC progression.	('CRC', 'Disease', (64, 67))	('FK866', 'Var', (31, 36))	('CRC', 'Phenotype', 'HP:0003003', (64, 67))	('FK866', 'Chemical', 'MESH:C480543', (31, 36))
74209	31114381	FK866 addition blocked the NAMPT-mediated upregulation of the NAD(H) pool which protected cancer cells against detrimental oxidative stress.	('NAMPT', 'Gene', (27, 32))	('FK866', 'Chemical', 'MESH:C480543', (0, 5))	('oxidative stress', 'Phenotype', 'HP:0025464', (123, 139))	('NAD(H)', 'Chemical', 'MESH:D009243', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('FK866', 'Var', (0, 5))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('NAMPT', 'Gene', '10135', (27, 32))	('upregulation', 'PosReg', (42, 54))
74214	31114381	Visfatin promoted endothelial cell angiogenesis via IL-6, and its functions demonstrated by the tube formation, the rat aortic ring assay, and the mouse Matrigel plug assay were further eliminated by the inactivation of STAT3 signaling or the neutralization of IL-6 activity.	('rat', 'Species', '10116', (83, 86))	('mouse', 'Species', '10090', (147, 152))	('signaling', 'biological_process', 'GO:0023052', ('226', '235'))	('IL-6', 'molecular_function', 'GO:0005138', ('261', '265'))	('IL-6', 'molecular_function', 'GO:0005138', ('52', '56'))	('endothelial cell angiogenesis', 'CPA', (18, 47))	('tube formation', 'biological_process', 'GO:0035148', ('96', '110'))	('rat', 'Species', '10116', (116, 119))	('inactivation', 'Var', (204, 216))	('angiogenesis', 'biological_process', 'GO:0001525', ('35', '47'))	('IL-6', 'Gene', (52, 56))	('promoted', 'PosReg', (9, 17))
74219	31114381	The combination of GMX1777, which inhibits visfatin activity, with radiotherapy has been explored in head and neck cancer in vivo.	('neck', 'cellular_component', 'GO:0044326', ('110', '114'))	('cancer', 'Disease', (115, 121))	('GMX1777', 'Chemical', 'MESH:C541789', (19, 26))	('inhibits', 'NegReg', (34, 42))	('activity', 'MPA', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('GMX1777', 'Var', (19, 26))	('head and neck cancer', 'Phenotype', 'HP:0012288', (101, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('visfatin', 'Protein', (43, 51))
74220	31114381	Tumor microvessel density was estimated using the CD31 expression level, which was significantly reduced to 18% after GMX1777 treatment alone (p<0.01) and 4% when combined with radiotherapy (p<0.01) in FaDu tumors.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CD31', 'Gene', (50, 54))	('GMX1777', 'Var', (118, 125))	('CD31', 'Gene', '5175', (50, 54))	('reduced', 'NegReg', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('FaDu tumors', 'Disease', (202, 213))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('GMX1777', 'Chemical', 'MESH:C541789', (118, 125))	('FaDu tumors', 'Disease', 'MESH:D009369', (202, 213))
74233	31114381	On the contrary, visfatin knockdown in breast cancer cells revealed significant increase in metastatic activity as compared with the control shRNA-transduced cells.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('increase', 'PosReg', (80, 88))	('knockdown', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('metastatic activity', 'CPA', (92, 111))	('breast cancer', 'Disease', (39, 52))
74240	31114381	Visfatin silencing resulted in the elevation of drug sensitivity in CRC-resistant cells through transcriptional activation of multidrug resistance 1 (MDR1) via p65 activation and nuclear localization.	('transcriptional', 'MPA', (96, 111))	('drug resistance', 'Phenotype', 'HP:0020174', (131, 146))	('MDR', 'molecular_function', 'GO:0004745', ('150', '153'))	('Visfatin', 'Gene', (0, 8))	('drug sensitivity', 'Phenotype', 'HP:0020174', (48, 64))	('CRC', 'Phenotype', 'HP:0003003', (68, 71))	('drug sensitivity', 'MPA', (48, 64))	('multidrug resistance 1', 'Gene', (126, 148))	('activation', 'PosReg', (112, 122))	('MDR1', 'Gene', '5243', (150, 154))	('elevation', 'PosReg', (35, 44))	('multidrug resistance 1', 'Gene', '5243', (126, 148))	('nuclear localization', 'MPA', (179, 199))	('p65', 'Gene', (160, 163))	('silencing', 'Var', (9, 18))	('localization', 'biological_process', 'GO:0051179', ('187', '199'))	('MDR1', 'Gene', (150, 154))	('p65', 'Gene', '5970', (160, 163))	('activation', 'PosReg', (164, 174))
74241	31114381	The visfatin inhibitor GMX1778 further showed an enhancement in the efficacy of 177Lu-DOTATATE treatment for neuroendocrine tumors.	('enhancement', 'PosReg', (49, 60))	('neuroendocrine tumors', 'Disease', (109, 130))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('177Lu-DOTATATE', 'MPA', (80, 94))	('177Lu-DOTATATE', 'Chemical', 'MESH:C447941', (80, 94))	('efficacy', 'MPA', (68, 76))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('GMX1778', 'Chemical', 'MESH:C401312', (23, 30))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (109, 130))	('GMX1778', 'Var', (23, 30))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (109, 130))
74242	31114381	Moreover, pharmacological suppression of visfatin by the inhibitor FK866 decreased the NAD level and glycolytic activity, which led to an elevated antitumor capability of gemcitabine in orthotopic xenograft animal models and PDAC cells.	('inhibitor', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('gemcitabine', 'Chemical', 'MESH:C056507', (171, 182))	('PDAC', 'Phenotype', 'HP:0006725', (225, 229))	('decreased', 'NegReg', (73, 82))	('tumor', 'Disease', (151, 156))	('NAD', 'Chemical', 'MESH:D009243', (87, 90))	('FK866', 'Gene', (67, 72))	('suppression', 'NegReg', (26, 37))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('NAD level', 'MPA', (87, 96))	('FK866', 'Chemical', 'MESH:C480543', (67, 72))	('elevated', 'PosReg', (138, 146))	('glycolytic activity', 'MPA', (101, 120))
74243	31114381	Another study indicated that suppression of vistatin signaling by the inhibitors FK866 and CHS828 could sensitize glioblastoma to temozolomide treatment via activation of the ROS/JNK axis.	('CHS828', 'Chemical', 'MESH:C401312', (91, 97))	('sensitize', 'Reg', (104, 113))	('temozolomide', 'Chemical', 'MESH:D000077204', (130, 142))	('JNK', 'Gene', '5599', (179, 182))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('vistatin', 'Chemical', '-', (44, 52))	('JNK', 'molecular_function', 'GO:0004705', ('179', '182'))	('FK866', 'Var', (81, 86))	('suppression', 'NegReg', (29, 40))	('vistatin signaling', 'MPA', (44, 62))	('activation', 'PosReg', (157, 167))	('glioblastoma', 'Disease', (114, 126))	('glioblastoma', 'Disease', 'MESH:D005909', (114, 126))	('FK866', 'Chemical', 'MESH:C480543', (81, 86))	('JNK', 'Gene', (179, 182))	('ROS', 'Chemical', '-', (175, 178))	('CHS828', 'Gene', (91, 97))
74244	31114381	In myeloma, the combination of NAD+ depletion by FK866 and bortezomib activated caspase 8, caspase 9, caspase 3 and poly(ADP-ribose) polymerase, leading to synergistic effects in triggering cell death and increasing bortezomib sensitivity.	('activated', 'PosReg', (70, 79))	('caspase 9', 'Gene', (91, 100))	('myeloma', 'Disease', 'MESH:D009101', (3, 10))	('bortezomib', 'Chemical', 'MESH:D000069286', (216, 226))	('FK866', 'Var', (49, 54))	('increasing', 'PosReg', (205, 215))	('caspase 8', 'Gene', '841', (80, 89))	('FK866', 'Chemical', 'MESH:C480543', (49, 54))	('caspase 9', 'Gene', '842', (91, 100))	('myeloma', 'Disease', (3, 10))	('caspase 3', 'Gene', (102, 111))	('cell death', 'CPA', (190, 200))	('caspase 3', 'Gene', '836', (102, 111))	('bortezomib sensitivity', 'MPA', (216, 238))	('NAD+', 'Chemical', 'MESH:D009243', (31, 35))	('cell death', 'biological_process', 'GO:0008219', ('190', '200'))	('NAD+', 'MPA', (31, 35))	('caspase 8', 'Gene', (80, 89))	('bortezomib', 'Chemical', 'MESH:D000069286', (59, 69))	('poly(ADP-ribose) polymerase', 'Gene', '142', (116, 143))	('poly(ADP-ribose) polymerase', 'Gene', (116, 143))
74260	33299657	Patients with high T0 plasmatic levels of sPD-L1 had a shorter PFS (11.3 vs 22.5 months, p = .011) in the sunitinib group.	('PFS', 'MPA', (63, 66))	('sPD-L1', 'Var', (42, 48))	('shorter', 'NegReg', (55, 62))	('Patients', 'Species', '9606', (0, 8))	('sunitinib', 'Chemical', 'MESH:D000077210', (106, 115))
74262	33299657	mccRCC patients with high plasmatic levels of sPD-L1 or sPD-1 are poor responders to sunitinib.	('sPD-L1', 'Var', (46, 52))	('sPD-1', 'Gene', (56, 61))	('sPD-1', 'Gene', '3239', (56, 61))	('RCC', 'Disease', 'MESH:C538614', (3, 6))	('RCC', 'Disease', (3, 6))	('sunitinib', 'Chemical', 'MESH:D000077210', (85, 94))	('patients', 'Species', '9606', (7, 15))	('plasmatic levels', 'MPA', (26, 42))
74282	33299657	sPD-1 derived mainly from an alternative splicing of the pre-mRNA encoding the PD-1 Deltaex3 variant.	('splicing', 'biological_process', 'GO:0045292', ('41', '49'))	('sPD-1', 'Gene', '3239', (0, 5))	('PD-1', 'Gene', (79, 83))	('pre', 'molecular_function', 'GO:0003904', ('57', '60'))	('sPD-1', 'Gene', (0, 5))	('variant', 'Var', (93, 100))
74290	33299657	In these patients, sPD-L1 and sPD-1 are correlated with a poor prognosis, tumor size and tumor grade.	('patients', 'Species', '9606', (9, 17))	('sPD-L1', 'Var', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('sPD-1', 'Gene', '3239', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', (74, 79))	('sPD-1', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
74333	33299657	While high levels of sPD-L1 and sPD-1 are correlated to shorter PFS in the sunitinib group, they are not correlated to OS.	('sPD-1', 'Gene', '3239', (32, 37))	('PFS', 'MPA', (64, 67))	('shorter', 'NegReg', (56, 63))	('sPD-1', 'Gene', (32, 37))	('sPD-L1', 'Var', (21, 27))	('sunitinib', 'Chemical', 'MESH:D000077210', (75, 84))
74336	33299657	Our results clearly showed that patients with high levels of sPD-1 had a shorter PFS when treated with sunitinib.	('patients', 'Species', '9606', (32, 40))	('sunitinib', 'Chemical', 'MESH:D000077210', (103, 112))	('sPD-1', 'Gene', '3239', (61, 66))	('shorter', 'NegReg', (73, 80))	('high levels', 'Var', (46, 57))	('sPD-1', 'Gene', (61, 66))	('PFS', 'MPA', (81, 84))
74356	33402128	NCOA4 depletion can eliminate iron accumulation and thus weaken ferroptosis.	('NCOA4', 'Gene', (0, 5))	('weaken', 'NegReg', (57, 63))	('ferroptosis', 'Disease', (64, 75))	('NCOA4', 'Gene', '8031', (0, 5))	('iron accumulation', 'MPA', (30, 47))	('ferroptosis', 'biological_process', 'GO:0097707', ('64', '75'))	('depletion', 'Var', (6, 15))	('eliminate', 'NegReg', (20, 29))	('iron', 'Chemical', 'MESH:D007501', (30, 34))
74365	33402128	Univariate and multivariate analysis indicated the overall survival of ccRCC cases with low NCOA4 level is shorter than those of patients with high NCOA4 expression (p < 0.05).	('NCOA4', 'Gene', '8031', (92, 97))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('RCC', 'Disease', (73, 76))	('patients', 'Species', '9606', (129, 137))	('low', 'Var', (88, 91))	('NCOA4', 'Gene', (148, 153))	('shorter', 'NegReg', (107, 114))	('NCOA4', 'Gene', '8031', (148, 153))	('low NCOA4 level', 'Phenotype', 'HP:0032138', (88, 103))	('NCOA4', 'Gene', (92, 97))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
74367	33402128	ccRCC with NCOA4 deficiency presented the paucity of infiltrated immune cells and their matching marker sets, including CD8+ T cells.	('RCC', 'Disease', (2, 5))	('CD8', 'Gene', (120, 123))	('NCOA4', 'Gene', (11, 16))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('CD8', 'Gene', '925', (120, 123))	('deficiency', 'Var', (17, 27))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('NCOA4', 'Gene', '8031', (11, 16))
74368	33402128	Deficient NCOA4 expression was related to disease progression and poor prognosis, as well as impaired infiltration of immune cells in ccRCC.	('impaired', 'NegReg', (93, 101))	('Deficient', 'Var', (0, 9))	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('NCOA4', 'Gene', (10, 15))	('NCOA4', 'Gene', '8031', (10, 15))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('RCC', 'Disease', (136, 139))	('related', 'Reg', (31, 38))	('infiltration of immune cells', 'CPA', (102, 130))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('expression', 'MPA', (16, 26))
74378	33402128	NCOA4 was gradually considered as a key molecule promoting ferroptosis in various cancer cells and mounting studies displayed that NCOA4 depletion can inhibit ferroptosis by eliminating the accumulation of intracellular free iron, glutathione production and reactive oxygen species (ROS).	('ferroptosis', 'biological_process', 'GO:0097707', ('59', '70'))	('cancer', 'Disease', (82, 88))	('accumulation of intracellular free iron', 'MPA', (190, 229))	('inhibit', 'NegReg', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('NCOA4', 'Gene', (0, 5))	('depletion', 'Var', (137, 146))	('NCOA4', 'Gene', '8031', (0, 5))	('glutathione', 'Chemical', 'MESH:D005978', (231, 242))	('ferroptosis', 'Disease', (159, 170))	('reactive oxygen species', 'MPA', (258, 281))	('glutathione production', 'MPA', (231, 253))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('iron', 'Chemical', 'MESH:D007501', (225, 229))	('eliminating', 'NegReg', (174, 185))	('ROS', 'Chemical', 'MESH:D017382', (283, 286))	('intracellular', 'cellular_component', 'GO:0005622', ('206', '219'))	('NCOA4', 'Gene', (131, 136))	('ferroptosis', 'biological_process', 'GO:0097707', ('159', '170'))	('NCOA4', 'Gene', '8031', (131, 136))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (258, 281))
74381	33402128	Increased ferroptosis can also advance the anti-tumor effect of immunotherapy which pinpointed the positive feedback between ferroptosis and immunotherapy, cooperatively killing cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('ferroptosis', 'biological_process', 'GO:0097707', ('10', '21'))	('ferroptosis', 'biological_process', 'GO:0097707', ('125', '136'))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('advance', 'PosReg', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('ferroptosis', 'Var', (10, 21))
74387	33402128	Targeting NCOA4 may be a promising therapeutic strategy for ferroptosis-induction or/and with the combination of immunotherapy in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (130, 135))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('NCOA4', 'Gene', (10, 15))	('NCOA4', 'Gene', '8031', (10, 15))	('ferroptosis-induction', 'Disease', (60, 81))	('ferroptosis', 'biological_process', 'GO:0097707', ('60', '71'))	('Targeting', 'Var', (0, 9))
74429	33402128	NCOA4 depletion was reported to cause a cell disturbed ferroptosis process by eliminating the accumulation of intracellular free iron, glutathione and reactive oxygen species (ROS), and it was closely related to the tumorigenesis and progression of various cancers such as prostate cancer, ovarian cancer and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('ovarian cancer', 'Disease', 'MESH:D010051', (290, 304))	('breast cancer', 'Disease', 'MESH:D001943', (309, 322))	('reactive oxygen species', 'MPA', (151, 174))	('breast cancer', 'Disease', (309, 322))	('ROS', 'Chemical', 'MESH:D017382', (176, 179))	('prostate cancer', 'Disease', 'MESH:D011471', (273, 288))	('prostate cancer', 'Phenotype', 'HP:0012125', (273, 288))	('cause', 'Reg', (32, 37))	('tumor', 'Disease', (216, 221))	('NCOA4', 'Gene', (0, 5))	('NCOA4', 'Gene', '8031', (0, 5))	('prostate cancer', 'Disease', (273, 288))	('intracellular', 'cellular_component', 'GO:0005622', ('110', '123'))	('accumulation of intracellular free iron', 'MPA', (94, 133))	('ovarian cancer', 'Disease', (290, 304))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('cancers', 'Disease', 'MESH:D009369', (257, 264))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (151, 174))	('related', 'Reg', (201, 208))	('ovarian cancer', 'Phenotype', 'HP:0100615', (290, 304))	('glutathione', 'MPA', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('ferroptosis', 'biological_process', 'GO:0097707', ('55', '66'))	('iron', 'Chemical', 'MESH:D007501', (129, 133))	('glutathione', 'Chemical', 'MESH:D005978', (135, 146))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('breast cancer', 'Phenotype', 'HP:0003002', (309, 322))	('eliminating', 'NegReg', (78, 89))	('depletion', 'Var', (6, 15))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('cancers', 'Disease', (257, 264))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
74434	33402128	Expectedly, deficient NCOA4 was associated with the tumorigenesis and progression of ccRCC.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('deficient', 'Var', (12, 21))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('tumor', 'Disease', (52, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))	('progression', 'CPA', (70, 81))	('associated', 'Reg', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('NCOA4', 'Gene', (22, 27))	('NCOA4', 'Gene', '8031', (22, 27))
74438	33402128	These results indicated impaired ferroptosis resulting from NCOA4 deficiency may be the underlying mechanism for impaired NCOA4 as a negative predictor of ccRCC.	('NCOA4', 'Gene', (60, 65))	('NCOA4', 'Gene', (122, 127))	('impaired', 'Var', (113, 121))	('NCOA4', 'Gene', '8031', (60, 65))	('NCOA4', 'Gene', '8031', (122, 127))	('ferroptosis', 'biological_process', 'GO:0097707', ('33', '44'))	('deficiency', 'Var', (66, 76))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('ferroptosis', 'MPA', (33, 44))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', (157, 160))	('impaired', 'NegReg', (24, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (155, 160))
74451	33402128	Intriguingly, NCOA4 deficiency can impair the IFN-gamma receptor signaling, which is a major effector of activated T cells for inducing ferroptosis in immunotherapy.	('ferroptosis', 'biological_process', 'GO:0097707', ('136', '147'))	('deficiency', 'Var', (20, 30))	('NCOA4', 'Gene', (14, 19))	('IFN-gamma', 'Gene', (46, 55))	('IFN-gamma', 'Gene', '3458', (46, 55))	('NCOA4', 'Gene', '8031', (14, 19))	('impair', 'NegReg', (35, 41))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))
74465	31066170	Under harsh environmental conditions, genetic alterations conferring selective advantages may initiate the growth of tumor subclones, providing new opportunities for these tumors to grow.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('initiate', 'PosReg', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Disease', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('growth', 'CPA', (107, 113))	('tumor', 'Disease', (117, 122))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('iron', 'Chemical', 'MESH:D007501', (15, 19))	('genetic alterations', 'Var', (38, 57))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
74471	31066170	Therefore, loss of MYBBP1A increases adaptability spanning of tumors through metabolic switch.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('loss', 'Var', (11, 15))	('tumors', 'Disease', (62, 68))	('MYBBP1A', 'Gene', (19, 26))	('increases', 'PosReg', (27, 36))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('metabolic switch', 'CPA', (77, 93))
74482	31066170	Under these critical environmental conditions, genetic alterations that provide selective advantages may initiate the growth of tumor subclones, providing new opportunities for these tumors.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('iron', 'Chemical', 'MESH:D007501', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('initiate', 'PosReg', (105, 113))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Disease', (183, 188))	('genetic alterations', 'Var', (47, 66))	('tumor', 'Disease', (128, 133))	('tumors', 'Disease', (183, 189))
74488	31066170	Abnormal expression of PGC1alpha is associated with several chronic diseases, and in recent years, it has been shown to be a critical controller of cancer development.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('chronic diseases', 'Disease', (60, 76))	('PGC1alpha', 'Gene', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Abnormal', 'Var', (0, 8))	('associated', 'Reg', (36, 46))
74493	31066170	MYBBP1A binds to the leucine zipper motif in the NRD of c-MYB (Tavner et al., 1998).	('leucine zipper motif', 'Var', (21, 41))	('c-MYB', 'Gene', (56, 61))	('binds', 'Interaction', (8, 13))	('NRD', 'biological_process', 'GO:0070651', ('49', '52'))	('MYBBP1A', 'Gene', (0, 7))	('c-MYB', 'Gene', '4602', (56, 61))
74517	31066170	At 48 h, cells were seeded in 10-cm plates with media containing a selection drug (0.5-1 microg mL-1 puromycin, 50 microg mL-1 hygromycin B, and 400 microg mL-1 G418).	('L-1', 'Gene', (123, 126))	('L-1', 'Gene', (157, 160))	('puromycin', 'Chemical', 'MESH:D011691', (101, 110))	('0.5-1', 'Var', (83, 88))	('hygromycin B', 'Chemical', 'MESH:D006921', (127, 139))	('L-1', 'Gene', '3897', (97, 100))	('L-1', 'Gene', (97, 100))	('L-1', 'Gene', '3897', (123, 126))	('L-1', 'Gene', '3897', (157, 160))
74531	31066170	We used the following probes: beta-actin (Hs0160665_g1), MYBBP1A (Hs00959671_m1), MYB (Hs00920556_m1), PGC1alpha (Hs01016719_m1), SGLT1 (Hs01573790_m1), GLUT4 (Hs00168966_m1), HK2 (Hs00606086_m1), PFKM (Hs00175997_m1), GAPDH (Hs03929097_g1), PGK1 (Hs00943178_g1), PGAM1 (Hs01652468_g1), PKM (Hs00761782_g1), and LDHA (Hs01378790_g1).	('Hs01573790_m1', 'Var', (137, 150))	('Hs00959671_m1', 'Var', (66, 79))	('PGK1', 'Gene', (242, 246))	('PFKM', 'Gene', (197, 201))	('GAPDH', 'Gene', (219, 224))	('Hs00606086_m1', 'Var', (181, 194))	('beta-actin', 'Gene', (30, 40))	('Hs00168966_m1', 'Var', (160, 173))	('MYB', 'Gene', '4602', (82, 85))	('MYB', 'Gene', (82, 85))	('PKM', 'Gene', (287, 290))	('HK2', 'Gene', (176, 179))	('HK2', 'Gene', '3099', (176, 179))	('SGLT1', 'Gene', '6523', (130, 135))	('GLUT4', 'Gene', (153, 158))	('HK2', 'molecular_function', 'GO:0008256', ('176', '179'))	('Hs01016719_m1', 'Var', (114, 127))	('SGLT1', 'Gene', (130, 135))	('Hs00920556_m1', 'Var', (87, 100))	('MYB', 'Gene', '4602', (57, 60))	('MYB', 'Gene', (57, 60))	('PGAM1', 'Gene', (264, 269))	('PKM', 'Gene', '5315', (287, 290))	('LDHA', 'Gene', '3939', (312, 316))	('GLUT4', 'Gene', '6517', (153, 158))	('beta-actin', 'Gene', '728378', (30, 40))	('Hs03929097_g1', 'Var', (226, 239))	('PGK', 'molecular_function', 'GO:0004618', ('242', '245'))	('Hs01652468_g1', 'Var', (271, 284))	('Hs01378790_g1', 'Var', (318, 331))	('Hs00761782_g1', 'Var', (292, 305))	('Hs00175997_m1', 'Var', (203, 216))	('GAPDH', 'Gene', '2597', (219, 224))	('PGAM1', 'Gene', '5223', (264, 269))	('PFKM', 'Gene', '5213', (197, 201))	('Hs00943178_g1', 'Var', (248, 261))	('PGK1', 'Gene', '5230', (242, 246))	('LDHA', 'Gene', (312, 316))
74532	31066170	Membranes were incubated with the following primary antibodies: anti-MYBBP1A (Proteintech #14524-AP, Rosemont, IL, USA ), anti-PGC1alpha (Abcam #ab54481, Cambridge, UK), anti-SGLT1 (Abcam #ab14685), anti-p38 MAPK (Cell Signaling #9212, Danvers, MA, USA), and anti-phospho-p38 MAPK (T180/Y182) (Cell Signaling #9215).	('Signaling', 'biological_process', 'GO:0023052', ('299', '308'))	('p38', 'Gene', '1432', (204, 207))	('p38', 'Gene', (272, 275))	('SGLT1', 'Gene', '6523', (175, 180))	('Signaling', 'biological_process', 'GO:0023052', ('219', '228'))	('p38', 'Gene', (204, 207))	('anti-PGC1alpha', 'Var', (122, 136))	('T180/Y182', 'Var', (282, 291))	('p38', 'Gene', '1432', (272, 275))	('MAPK', 'molecular_function', 'GO:0004707', ('276', '280'))	('MAPK', 'molecular_function', 'GO:0004707', ('208', '212'))	('SGLT1', 'Gene', (175, 180))
74562	31066170	In addition, we previously reported that A498 MYBBP1A-downregulated cells metastasized in some host mice before the primary tumors reached large sizes while control cells did not, the MYBBP1A levels being lower in metastasis than in primary tumors from xenografted mice (Felipe-Abrio et al., 2019).	('primary tumors', 'Disease', (233, 247))	('cells metastasized', 'CPA', (68, 86))	('primary tumors', 'Disease', 'MESH:D009369', (116, 130))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('mice', 'Species', '10090', (100, 104))	('metastasis', 'CPA', (214, 224))	('primary tumors', 'Disease', 'MESH:D009369', (233, 247))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('primary tumors', 'Disease', (116, 130))	('mice', 'Species', '10090', (265, 269))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('lower', 'NegReg', (205, 210))	('A498', 'Var', (41, 45))	('MYBBP1A-downregulated', 'Gene', (46, 67))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
74566	31066170	Taken together, our data show that MYBBP1A downregulation induces PGC1alpha activation and that c-MYB plays a role in PGC1alpha modulation induced upon a loss of MYBBP1A.	('MYBBP1A', 'Gene', (162, 169))	('downregulation', 'NegReg', (43, 57))	('c-MYB', 'Gene', (96, 101))	('c-MYB', 'Gene', '4602', (96, 101))	('PGC1alpha', 'Gene', (66, 75))	('activation', 'PosReg', (76, 86))	('MYBBP1A', 'Gene', (35, 42))	('loss', 'Var', (154, 158))
74582	31066170	A498- and 786-O MYBBP1A-downregulated cells formed more colonies than control cells in both control and 2DG treatment conditions (Fig.	('MYBBP1A-downregulated', 'Gene', (16, 37))	('more', 'PosReg', (51, 55))	('colonies', 'CPA', (56, 64))	('2DG', 'Chemical', 'MESH:D003847', (104, 107))	('A498-', 'Var', (0, 5))
74595	31066170	However, at low-glucose or in glutamine-only media, the percentage of control V-YFP+ cells at the end of the experiment was greatly reduced in 786-O and A498 cells, indicating that the cells with low MYBBP1A were more competitive and grew better overcoming the control population in these restrictive conditions.	('low-glucose', 'Phenotype', 'HP:0001943', (12, 23))	('low-glucose', 'Chemical', '-', (12, 23))	('MYBBP1A', 'Gene', (200, 207))	('reduced', 'NegReg', (132, 139))	('more', 'PosReg', (213, 217))	('glutamine', 'Chemical', 'MESH:D005973', (30, 39))	('low', 'Var', (196, 199))	('grew', 'CPA', (234, 238))
74611	31066170	Alternatively, we studied the correlation between MYBBP1A and genes of the TCA, detecting a positive correlation between MYBBP1A and ACLY and a negative correlation with 15 other genes involved in the production and oxidation of acetyl-CoA by TCA (Fig.	('TCA', 'Chemical', 'MESH:D014238', (243, 246))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (229, 239))	('ACLY', 'Gene', '47', (133, 137))	('MYBBP1A', 'Var', (121, 128))	('ACLY', 'Gene', (133, 137))	('TCA', 'Chemical', 'MESH:D014238', (75, 78))
74626	31066170	Hence, loss of MYBBP1A may simultaneously activate PGC1alpha by alleviating direct repression (Fan et al., 2004) and increasing the PGC1alpha mRNA and protein levels through c-MYB.	('PGC1alpha', 'Gene', (132, 141))	('loss', 'Var', (7, 11))	('c-MYB', 'Gene', (174, 179))	('activate', 'PosReg', (42, 50))	('alleviating', 'NegReg', (64, 75))	('MYBBP1A', 'Gene', (15, 22))	('increasing', 'PosReg', (117, 127))	('direct repression', 'MPA', (76, 93))	('c-MYB', 'Gene', '4602', (174, 179))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))
74628	31066170	p38 activation is related to the CXCR4 pathway (Broussas et al., 2016; Zhan et al., 2016; Zuo et al., 2016), and since CXCR4 is a target gene of c-MYB (Quintana et al., 2011), activation of this transcription factor by loss of MYBBP1A (Felipe-Abrio et al., 2019) may lead to indirect activation of p38, therefore potentiating a loop leading to PGC1alpha activation.	('activation', 'PosReg', (354, 364))	('transcription', 'biological_process', 'GO:0006351', ('195', '208'))	('PGC1alpha', 'Gene', (344, 353))	('CXCR4', 'Gene', '7852', (119, 124))	('p38', 'Gene', '1432', (0, 3))	('p38', 'Gene', (298, 301))	('CXCR4', 'Gene', (119, 124))	('c-MYB', 'Gene', (145, 150))	('potentiating', 'PosReg', (313, 325))	('activation', 'PosReg', (176, 186))	('CXCR4', 'molecular_function', 'GO:0038147', ('33', '38'))	('CXCR4', 'molecular_function', 'GO:0038147', ('119', '124'))	('loss', 'Var', (219, 223))	('p38', 'Gene', '1432', (298, 301))	('p38', 'Gene', (0, 3))	('CXCR4', 'Gene', '7852', (33, 38))	('MYBBP1A', 'Gene', (227, 234))	('CXCR4', 'Gene', (33, 38))	('activation', 'PosReg', (284, 294))	('transcription factor', 'molecular_function', 'GO:0000981', ('195', '215'))	('c-MYB', 'Gene', '4602', (145, 150))
74632	31066170	We found that loss of MYBBP1A release PGC1alpha activity and transcription activation through c-MYB switching tumor bioenergetics, increasing glutaminolysis and sensitivity to oxidative channel inhibition.	('PGC1alpha', 'Enzyme', (38, 47))	('loss', 'Var', (14, 18))	('c-MYB', 'Gene', '4602', (94, 99))	('transcription', 'biological_process', 'GO:0006351', ('61', '74'))	('activity', 'MPA', (48, 56))	('MYBBP1A', 'Gene', (22, 29))	('tumor', 'Disease', (110, 115))	('glutaminolysis', 'MPA', (142, 156))	('activation', 'PosReg', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('release', 'PosReg', (30, 37))	('c-MYB', 'Gene', (94, 99))	('increasing', 'PosReg', (131, 141))	('sensitivity to oxidative channel inhibition', 'MPA', (161, 204))	('transcription', 'MPA', (61, 74))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
74637	31066170	Perhaps the group of renal carcinoma with low MYBBP1A better counteracts this antioxidative pressure executed by the HIF factors on PGC1alpha and give some ccRCC with more mitochondrial activity that possibly alters its tumor phenotype.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('more', 'PosReg', (167, 171))	('PGC1alpha', 'Gene', (132, 141))	('renal carcinoma', 'Disease', 'MESH:C538614', (21, 36))	('renal carcinoma', 'Phenotype', 'HP:0005584', (21, 36))	('MYBBP1A', 'Gene', (46, 53))	('tumor', 'Disease', (220, 225))	('alters', 'Reg', (209, 215))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('renal carcinoma', 'Disease', (21, 36))	('RCC', 'Disease', (158, 161))	('mitochondrial activity', 'MPA', (172, 194))	('low', 'Var', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
74647	31066170	In fact, tumor cells with low MYBBP1A are more sensitive to mitochondrial respiratory channel inhibition by rotenone, suggesting some degree of dependency of these cells from the oxidative metabolism.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('oxidative metabolism', 'biological_process', 'GO:0045333', ('179', '199'))	('low', 'Var', (26, 29))	('MYBBP1A', 'Gene', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mitochondrial respiratory channel inhibition', 'MPA', (60, 104))	('tumor', 'Disease', (9, 14))	('rotenone', 'Chemical', 'MESH:D012402', (108, 116))	('sensitive', 'Reg', (47, 56))
74660	28112366	Interference with Tim-3 expression using small interfering RNA exacerbated anoikis in 786-O and Caki-2 cells induced by poly-HEMA treatment.	('Caki-2', 'CellLine', 'CVCL:0235', (96, 102))	('exacerbated', 'PosReg', (63, 74))	('Tim-3', 'Gene', (18, 23))	('small interfering', 'Var', (41, 58))	('Tim-3', 'Gene', '84868', (18, 23))	('anoikis', 'Disease', (75, 82))	('poly-HEMA', 'Chemical', '-', (120, 129))	('RNA', 'cellular_component', 'GO:0005562', ('59', '62'))	('anoikis', 'biological_process', 'GO:0043276', ('75', '82'))
74661	28112366	E-cadherin upregulation, N-cadherin downregulation, and ECM detachment-induced reduction in invasion ability were all exacerbated by knockdown of Tim-3.	('downregulation', 'NegReg', (36, 50))	('cadherin', 'molecular_function', 'GO:0008014', ('27', '35'))	('Tim-3', 'Gene', (146, 151))	('exacerbated', 'PosReg', (118, 129))	('N-cadherin', 'Gene', (25, 35))	('Tim-3', 'Gene', '84868', (146, 151))	('knockdown', 'Var', (133, 142))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('N-cadherin', 'Gene', '1000', (25, 35))	('reduction', 'NegReg', (79, 88))	('E-cadherin', 'Gene', (0, 10))	('E-cadherin', 'Gene', '999', (0, 10))	('upregulation', 'PosReg', (11, 23))	('invasion ability', 'CPA', (92, 108))
74702	28112366	In Ho3342/PI staining, cells displaying blue nuclear fragmentation were interpreted as apoptotic cells, while cells with red were defined as necrotic.	('blue', 'Var', (40, 44))	('necrotic', 'Disease', (141, 149))	('necrotic', 'Disease', 'MESH:D009336', (141, 149))	('Ho3342', 'Chemical', '-', (3, 9))
74722	28112366	The Tim-3 transcription level decreased significantly in poly-HEMA treated 786-O and Caki-2 cells compared with control cells (P=0.038 and P=0.024, respectively; Fig.	('Tim-3', 'Gene', (4, 9))	('poly-HEMA', 'Chemical', '-', (57, 66))	('Tim-3', 'Gene', '84868', (4, 9))	('transcription', 'biological_process', 'GO:0006351', ('10', '23'))	('poly-HEMA', 'Var', (57, 66))	('Caki-2', 'CellLine', 'CVCL:0235', (85, 91))	('transcription level', 'MPA', (10, 29))	('decreased', 'NegReg', (30, 39))
74727	28112366	Knockdown of Tim-3 expression reduced activities further, with recorded OD570 nm values as follows: Poly-HEMA-treated + siRNA 786-O cells, 0.15+-0.015 P=0.021 vs. poly-HEMA treated cells; poly-HEMA treated + siRNA Caki-2 cells, 0.14+-0.021; P=0.038 vs. poly-HEMA treated cells (Fig.	('Tim-3', 'Gene', (13, 18))	('Knockdown', 'Var', (0, 9))	('Tim-3', 'Gene', '84868', (13, 18))	('poly-HEMA', 'Chemical', '-', (188, 197))	('Caki-2', 'CellLine', 'CVCL:0235', (214, 220))	('reduced', 'NegReg', (30, 37))	('poly-HEMA', 'Chemical', '-', (163, 172))	('Poly-HEMA', 'Chemical', '-', (100, 109))	('activities', 'MPA', (38, 48))	('poly-HEMA', 'Chemical', '-', (253, 262))
74728	28112366	Following Ho33342/PI double staining, control cells appeared blue with intact nuclei, while poly-HEMA treated cells demonstrated suspension and aggregation, with non-intact blue nuclei.	('Ho33342/PI', 'Var', (10, 20))	('poly-HEMA', 'Chemical', '-', (92, 101))	('aggregation', 'CPA', (144, 155))	('Ho33342', 'Chemical', 'MESH:C017807', (10, 17))
74732	28112366	Thus, detachment from the ECM induces anoikis, and knockdown of Tim-3 expression increased anoikis further.	('anoikis', 'CPA', (38, 45))	('Tim-3', 'Gene', (64, 69))	('Tim-3', 'Gene', '84868', (64, 69))	('anoikis', 'biological_process', 'GO:0043276', ('38', '45'))	('anoikis', 'biological_process', 'GO:0043276', ('91', '98'))	('increased', 'PosReg', (81, 90))	('induces', 'Reg', (30, 37))	('knockdown', 'Var', (51, 60))
74740	28112366	Tim-3 siRNA transfection enhanced these changes further in 786-O cells (P=0.023 vs. control group, P=0.004 vs. poly-HEMA treatment group; Fig.	('transfection', 'Var', (12, 24))	('poly-HEMA', 'Chemical', '-', (111, 120))	('Tim-3', 'Gene', '84868', (0, 5))	('Tim-3', 'Gene', (0, 5))
74742	28112366	Therefore, interference with Tim-3 expression enhanced the ECM detachment-induced E-cadherin upregulation and N-cadherin downregulation.	('upregulation', 'PosReg', (93, 105))	('cadherin', 'molecular_function', 'GO:0008014', ('112', '120'))	('cadherin', 'molecular_function', 'GO:0008014', ('84', '92'))	('E-cadherin', 'Gene', (82, 92))	('E-cadherin', 'Gene', '999', (82, 92))	('Tim-3', 'Gene', (29, 34))	('downregulation', 'NegReg', (121, 135))	('N-cadherin', 'Gene', (110, 120))	('enhanced', 'PosReg', (46, 54))	('interference', 'Var', (11, 23))	('ECM detachment-induced', 'CPA', (59, 81))	('Tim-3', 'Gene', '84868', (29, 34))	('N-cadherin', 'Gene', '1000', (110, 120))
74743	28112366	Poly-HEMA treated 786-O cells demonstrated significantly decreased invasive abilities compared with control cells, with 560 nm absorbance values of 0.113+-0.015 in poly-HEMA calls and 0.243+-0.04 in control cells (P=0.022; Fig.	('invasive abilities', 'CPA', (67, 85))	('poly-HEMA', 'Chemical', '-', (164, 173))	('Poly-HEMA', 'Chemical', '-', (0, 9))	('poly-HEMA calls', 'Var', (164, 179))	('decreased', 'NegReg', (57, 66))
74749	28112366	In addition, interference with Tim-3 expression attenuated the invasion of 786-O and Caki-2 cells, increased E-cadherin expression and decreased N-cadherin expression.	('expression', 'MPA', (120, 130))	('attenuated', 'NegReg', (48, 58))	('cadherin', 'molecular_function', 'GO:0008014', ('147', '155'))	('Tim-3', 'Gene', (31, 36))	('E-cadherin', 'Gene', (109, 119))	('E-cadherin', 'Gene', '999', (109, 119))	('interference', 'Var', (13, 25))	('N-cadherin', 'Gene', (145, 155))	('Tim-3', 'Gene', '84868', (31, 36))	('Caki-2', 'CellLine', 'CVCL:0235', (85, 91))	('decreased', 'NegReg', (135, 144))	('increased', 'PosReg', (99, 108))	('cadherin', 'molecular_function', 'GO:0008014', ('111', '119'))	('N-cadherin', 'Gene', '1000', (145, 155))
74764	28112366	The present study demonstrated morphological changes to cancer cells using Ho33342/PI double staining and acridine orange staining, assayed the apoptosis rate by flow cytometry analysis, and measured the rate of anoikis using the CytoSelect  24-well assay kit.	('apoptosis', 'biological_process', 'GO:0006915', ('144', '153'))	('acridine orange', 'Chemical', 'MESH:D000165', (106, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('144', '153'))	('Ho33342', 'Chemical', 'MESH:C017807', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Ho33342/PI', 'Var', (75, 85))	('apoptosis rate', 'CPA', (144, 158))	('anoikis', 'biological_process', 'GO:0043276', ('212', '219'))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
74765	28112366	It was revealed that knockdown of Tim-3 enhanced the rate of anoikis in 786-O and Caki-2 cells, indicating that Tim-3 is an anoikis inhibitory molecule.	('Tim-3', 'Gene', '84868', (112, 117))	('anoikis', 'CPA', (61, 68))	('Tim-3', 'Gene', '84868', (34, 39))	('anoikis', 'biological_process', 'GO:0043276', ('124', '131'))	('anoikis', 'biological_process', 'GO:0043276', ('61', '68'))	('Caki-2', 'CellLine', 'CVCL:0235', (82, 88))	('Tim-3', 'Gene', (112, 117))	('knockdown', 'Var', (21, 30))	('enhanced', 'PosReg', (40, 48))	('Tim-3', 'Gene', (34, 39))
74828	34012911	Finally, the effect of SMAD4 knockdown on SDCs was analyzed.	('SMAD4', 'Gene', (23, 28))	('SDCs', 'Chemical', '-', (42, 46))	('knockdown', 'Var', (29, 38))
74829	34012911	We demonstrated that SMAD4 is positively correlated with decreased disease specific survival (DSS) in RCC patients and clear cell RCC (ccRCC) subtype and associates with poor DSS in patients with RCC, especially in ccRCC as the most metastatic RCC subtype.	('RCC', 'Disease', (244, 247))	('DSS', 'Chemical', '-', (175, 178))	('DSS', 'Chemical', '-', (94, 97))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('patients', 'Species', '9606', (182, 190))	('RCC', 'Disease', 'MESH:C538614', (196, 199))	('RCC', 'Disease', 'MESH:C538614', (244, 247))	('RCC', 'Disease', (130, 133))	('RCC', 'Disease', (137, 140))	('RCC', 'Disease', (217, 220))	('SMAD4', 'Var', (21, 26))	('decreased disease', 'Disease', (57, 74))	('patients', 'Species', '9606', (106, 114))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('RCC', 'Disease', (102, 105))	('decreased disease', 'Disease', 'MESH:D002303', (57, 74))	('RCC', 'Disease', (196, 199))
74831	34012911	Inhibition of SMAD4 in PCs accelerated the dissociation of SDCs and decreased their clonogenicity, invasiveness, expression of mesenchymal markers and expression of SMAD4 and TGFbeta1 genes compared to SDCs before transfection.	('expression', 'MPA', (113, 123))	('decreased', 'NegReg', (68, 77))	('SDCs', 'Chemical', '-', (202, 206))	('SDCs', 'Chemical', '-', (59, 63))	('TGFbeta1', 'Gene', '7040', (175, 183))	('TGFbeta1', 'Gene', (175, 183))	('expression', 'MPA', (151, 161))	('dissociation', 'CPA', (43, 55))	('SMAD4', 'Gene', (165, 170))	('invasiveness', 'CPA', (99, 111))	('SMAD4', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('accelerated', 'PosReg', (27, 38))	('clonogenicity', 'CPA', (84, 97))
74832	34012911	We suggest that targeting SMAD4 may be useful against renal CSCs and may improve RCC prognosis.	('renal CSCs', 'Disease', (54, 64))	('targeting', 'Var', (16, 25))	('SMAD4', 'Gene', (26, 31))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('improve', 'PosReg', (73, 80))	('renal CSCs', 'Disease', 'MESH:D007674', (54, 64))
74854	34012911	In addition, we examined the following hypothesis: Silencing SMAD4 as an important mediator of TGF-beta pathway contributes to suppression of stem cell/mesenchymal cells and EMT characteristics in SDCs.	('SDCs', 'Chemical', '-', (197, 201))	('TGF-beta', 'Gene', '7039', (95, 103))	('Silencing', 'Var', (51, 60))	('SMAD4', 'Gene', (61, 66))	('EMT', 'biological_process', 'GO:0001837', ('174', '177'))	('TGF-beta', 'Gene', (95, 103))	('EMT characteristics', 'CPA', (174, 193))	('stem cell/mesenchymal cells', 'CPA', (142, 169))	('SDCs', 'Disease', (197, 201))	('suppression', 'NegReg', (127, 138))
74911	34012911	In addition, PCs, a significantly lower sphere forming ability than SDCs (P < 0.01) ( Figure 4A ).	('PCs', 'Var', (13, 16))	('lower', 'NegReg', (34, 39))	('sphere forming ability', 'CPA', (40, 62))	('SDCs', 'Chemical', '-', (68, 72))
74931	34012911	After confirming successful SiSMAD4 knock-down, we explored SMAD4 gene and protein expression by Western blot analysis in PCs and 2 SDCs populations.	('knock-down', 'Var', (36, 46))	('SMAD4', 'Gene', (60, 65))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('SDCs', 'Chemical', '-', (132, 136))
74934	34012911	In addition, SDCs generated a significantly lower sphere forming ability after transfection compared to before transfection (P < 0.01) ( Figure 4A ).	('lower', 'NegReg', (44, 49))	('transfection', 'Var', (79, 91))	('SDCs', 'Chemical', '-', (13, 17))	('sphere forming ability', 'CPA', (50, 72))
74936	34012911	Single cells of SDCs population formed smaller colonies and had lower colonization ability upon SMAD4 knockdown after transfection compared to the match cells before transfection (P < 0.05) ( Figures 4B-D  and  Supplementary Table S4 ).	('colonization ability', 'CPA', (70, 90))	('lower', 'NegReg', (64, 69))	('knockdown', 'Var', (102, 111))	('SMAD4', 'Gene', (96, 101))	('SDCs', 'Chemical', '-', (16, 20))	('smaller', 'NegReg', (39, 46))
74937	34012911	The cell invasion assay confirmed that invading cell numbers significantly decreased after SiSMAD4 transfection compared to the SDCs population (P <0.01) ( Figure 4C  and  Supplementary File, S1 ).	('invading cell numbers', 'CPA', (39, 60))	('SDCs', 'Chemical', '-', (128, 132))	('SiSMAD4 transfection', 'Var', (91, 111))	('decreased', 'NegReg', (75, 84))
74938	34012911	Flow cytometric analysis demonstrated that after transfection upon SMAD4 knockdown, single cells of SDCs population had a significant increase in the expression of the epithelial marker of CD24 (41.78%) and CD133 (1.69%) and presented decreased expression of CD44 (89.45%) and CD73 (76.59), as mesenchymal markers with the match cells before transfection ( Figure 6C ).	('CD44', 'Protein', (259, 263))	('expression', 'MPA', (150, 160))	('CD73', 'Gene', (277, 281))	('SMAD4', 'Gene', (67, 72))	('SDCs', 'Chemical', '-', (100, 104))	('CD133', 'Gene', (207, 212))	('decreased', 'NegReg', (235, 244))	('expression', 'MPA', (245, 255))	('increase', 'PosReg', (134, 142))	('CD24', 'Gene', (189, 193))	('SDCs', 'Gene', (100, 104))	('knockdown', 'Var', (73, 82))
74945	34012911	According to these evidences and to test whether SMAD4 silencing decreases the gene expression level of hsa-miR-204, as one of the most downregulated miRNAs in SDCs, we selected miR-204 and detected its expression by Taq Man miRNA assay.	('hsa-miR-204', 'Gene', '406987', (104, 115))	('miR-204', 'Gene', '406987', (178, 185))	('gene expression level', 'MPA', (79, 100))	('miR', 'Gene', '220972', (178, 181))	('miR', 'Gene', (108, 111))	('SDCs', 'Chemical', '-', (160, 164))	('miR', 'Gene', '220972', (225, 228))	('miR', 'Gene', (178, 181))	('silencing', 'Var', (55, 64))	('miR-204', 'Gene', (108, 115))	('miR', 'Gene', '220972', (150, 153))	('miR', 'Gene', (225, 228))	('decreases', 'NegReg', (65, 74))	('miR-204', 'Gene', (178, 185))	('hsa-miR-204', 'Gene', (104, 115))	('miR', 'Gene', (150, 153))	('gene expression', 'biological_process', 'GO:0010467', ('79', '94'))	('miR-204', 'Gene', '406987', (108, 115))	('miR', 'Gene', '220972', (108, 111))	('SMAD4', 'Gene', (49, 54))
74946	34012911	As expected, miR204 levels were more than 18-fold lower in SDCs than in the corresponding PCs and were significantly upregulated in SDCs after transfection (P <0.0001) ( Figure 9D ).	('lower', 'NegReg', (50, 55))	('SDCs', 'Disease', (59, 63))	('SDCs', 'Chemical', '-', (59, 63))	('transfection', 'Var', (143, 155))	('upregulated', 'PosReg', (117, 128))	('miR204', 'Gene', (13, 19))	('SDCs', 'Chemical', '-', (132, 136))	('miR204', 'Gene', '406987', (13, 19))
74947	34012911	To test whether SMAD4 silencing decreases the gene expression level of hsa-miR-204, as one of the most downregulated miRNAs in SDCs, we detected its expression by Taq Man miRNA assay.	('miR', 'Gene', '220972', (75, 78))	('miR', 'Gene', (75, 78))	('SDCs', 'Chemical', '-', (127, 131))	('SMAD4', 'Gene', (16, 21))	('hsa-miR-204', 'Gene', (71, 82))	('gene expression', 'biological_process', 'GO:0010467', ('46', '61'))	('miR', 'Gene', '220972', (171, 174))	('miR', 'Gene', (171, 174))	('hsa-miR-204', 'Gene', '406987', (71, 82))	('silencing', 'Var', (22, 31))	('miR', 'Gene', '220972', (117, 120))	('gene expression level', 'MPA', (46, 67))	('miR', 'Gene', (117, 120))	('decreases', 'NegReg', (32, 41))
74963	34012911	SMAD4 deletions or mutations have been widely observed in different cancer types, such as colorectal and pancreatic cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (105, 122))	('observed', 'Reg', (46, 54))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('deletions', 'Var', (6, 15))	('SMAD4', 'Gene', (0, 5))	('mutations', 'Var', (19, 28))	('colorectal and pancreatic cancers', 'Disease', 'MESH:D015179', (90, 123))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (105, 123))
74980	34012911	The discrepancy between these 2 studies may be due to different reagents, such as a primary anti-SMAD4 antibodies, and occurrence of cancer-related deaths in RCC patients.	('anti-SMAD4', 'Gene', (92, 102))	('anti-SMAD4', 'Var', (92, 102))	('patients', 'Species', '9606', (162, 170))	('deaths', 'Disease', (148, 154))	('deaths', 'Disease', 'MESH:D003643', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
74983	34012911	Furthermore, the inhibition of SMAD4 in PCs reduces the formation and/or stabilization of highly invasive SDCs with mesenchymal properties.	('SDCs', 'Chemical', '-', (106, 110))	('highly invasive SDCs with mesenchymal properties', 'CPA', (90, 138))	('stabilization', 'CPA', (73, 86))	('inhibition', 'Var', (17, 27))	('reduces', 'NegReg', (44, 51))	('formation', 'CPA', (56, 65))	('formation', 'biological_process', 'GO:0009058', ('56', '65'))	('SMAD4', 'Gene', (31, 36))
74991	34012911	Several researchers have revealed that knockdown or inhibition of stemness genes, including Lin28, results in reduction of CSC characteristics.	('reduction', 'NegReg', (110, 119))	('knockdown', 'Var', (39, 48))	('CSC characteristics', 'CPA', (123, 142))	('Lin28', 'Gene', (92, 97))	('Lin28', 'Gene', '79727', (92, 97))	('inhibition', 'NegReg', (52, 62))
74995	34012911	It has been shown that expression of Twist1 and Twist2 as mesenchymal genes has been accompanied with tumor progression in human solid tumors and the inhibition of snail1 in mesenchymal cells can lead to loss of self-renewal characteristics in vitro through downregulation of Nanog.	('Nanog', 'Gene', '79923', (276, 281))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('snail1', 'Gene', (164, 170))	('Nanog', 'Gene', (276, 281))	('human', 'Species', '9606', (123, 128))	('self-renewal characteristics', 'CPA', (212, 240))	('loss', 'NegReg', (204, 208))	('tumors', 'Disease', (135, 141))	('snail1', 'Gene', '6615', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('downregulation', 'NegReg', (258, 272))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('inhibition', 'Var', (150, 160))	('Twist2', 'Gene', (48, 54))	('tumor', 'Disease', (135, 140))	('Twist2', 'Gene', '117581', (48, 54))	('Twist1', 'Gene', (37, 43))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('Twist1', 'Gene', '7291', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('accompanied', 'Reg', (85, 96))
74996	34012911	Our previous research about the association of the cytoplasmic expression of Twist1, in worse progression-free survival of ccRCC, validates our in vitro finding about post transfection reduction of Twist1 in SDCs as one of the EMT targets and provides more evidences for the role of EMT in renal cancer pathogenesis.	('renal cancer', 'Disease', 'MESH:D007680', (290, 302))	('Twist1', 'Gene', '7291', (198, 204))	('Twist1', 'Gene', '7291', (77, 83))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('RCC', 'Disease', (125, 128))	('EMT', 'biological_process', 'GO:0001837', ('227', '230'))	('pathogenesis', 'biological_process', 'GO:0009405', ('303', '315'))	('Twist1', 'Gene', (198, 204))	('Twist1', 'Gene', (77, 83))	('renal cancer', 'Disease', (290, 302))	('reduction', 'NegReg', (185, 194))	('EMT', 'biological_process', 'GO:0001837', ('283', '286'))	('renal cancer', 'Phenotype', 'HP:0009726', (290, 302))	('cytoplasmic', 'Var', (51, 62))	('SDCs', 'Chemical', '-', (208, 212))
75001	34012911	A previous study found that CD105 expressing subpopulation in human RCC xenograft and patient samples have a greater capacity to form spheres in vitro and its knockdown can reduce sphere-forming ability and tumorigenicity.	('reduce', 'NegReg', (173, 179))	('sphere-forming ability', 'CPA', (180, 202))	('knockdown', 'Var', (159, 168))	('human', 'Species', '9606', (62, 67))	('CD105', 'Gene', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('CD105', 'Gene', '13805', (28, 33))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('patient', 'Species', '9606', (86, 93))	('RCC', 'Disease', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))
75004	34012911	In the present study, increased expression of mesenchymal markers and decreased expression of epithelial markers, such as CD34 and CD24, were observed in post transfection SDCs compared to SDCs before transfection.	('CD24', 'Gene', (131, 135))	('SDCs', 'Var', (172, 176))	('SDCs', 'Chemical', '-', (172, 176))	('SDCs', 'Chemical', '-', (189, 193))	('decreased', 'NegReg', (70, 79))	('CD34', 'Gene', (122, 126))	('increased', 'PosReg', (22, 31))	('expression', 'MPA', (80, 90))	('post transfection SDCs', 'Var', (154, 176))	('expression', 'MPA', (32, 42))
75005	34012911	In our study, some of the gene expressions and the surface markers were not in parallel with our hypothesis, indicating a decreased EMT-related property in transfected SDCs.	('EMT-related property', 'CPA', (132, 152))	('decreased EMT', 'Phenotype', 'HP:0032198', (122, 135))	('EMT', 'biological_process', 'GO:0001837', ('132', '135'))	('SDCs', 'Chemical', '-', (168, 172))	('transfected', 'Var', (156, 167))	('decreased', 'NegReg', (122, 131))
75009	34012911	This was mainly based on the exploring that the inhibition of SMAD4 simultaneously with the decreased TGFbeta1 reduces the formation of highly invasive cancer spheres in PCs, decreases clonogenicity, and invasiveness of cancer cells and leads to increase in EMT-related properties.	('EMT', 'biological_process', 'GO:0001837', ('258', '261'))	('clonogenicity', 'CPA', (185, 198))	('TGFbeta1', 'Gene', (102, 110))	('increase', 'PosReg', (246, 254))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('SMAD4', 'Gene', (62, 67))	('cancer', 'Disease', (152, 158))	('inhibition', 'Var', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('invasiveness of cancer', 'Disease', (204, 226))	('reduces', 'NegReg', (111, 118))	('decreased', 'NegReg', (92, 101))	('cancer', 'Disease', (220, 226))	('decreases', 'NegReg', (175, 184))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('TGFbeta1', 'Gene', '7040', (102, 110))	('invasiveness of cancer', 'Disease', 'MESH:D009362', (204, 226))	('EMT-related properties', 'CPA', (258, 280))	('formation', 'biological_process', 'GO:0009058', ('123', '132'))
75011	34012911	Our findings, for the first time, propose that targeting SMAD4 as a pivotal transducer of the TGF-beta-signaling pathway may be effective as a supplementary targeted therapy against renal CSCs and may improve the RCC prognosis, particularly the ccRCC subtype.	('renal CSCs', 'Disease', 'MESH:D007674', (182, 192))	('targeting', 'Var', (47, 56))	('SMAD4', 'Gene', (57, 62))	('signaling pathway', 'biological_process', 'GO:0007165', ('103', '120'))	('renal CSCs', 'Disease', (182, 192))	('TGF-beta', 'Gene', (94, 102))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('RCC', 'Disease', (213, 216))	('TGF-beta', 'Gene', '7039', (94, 102))	('RCC', 'Disease', 'MESH:C538614', (247, 250))	('RCC', 'Disease', (247, 250))	('improve', 'PosReg', (201, 208))
75014	28680592	HIF prolyl hydroxylase PHD3 regulates translational machinery and glucose metabolism in clear cell renal cell carcinoma A key feature of clear cell renal cell carcinoma (ccRCC) is the inactivation of the von Hippel-Lindau tumour suppressor protein (pVHL) that leads to the activation of hypoxia-inducible factor (HIF) pathway also in well-oxygenated conditions.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (148, 168))	('HIF', 'Gene', (0, 3))	('clear cell renal cell carcinoma', 'Disease', (88, 119))	('activation', 'PosReg', (273, 283))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (99, 119))	('clear cell renal cell carcinoma', 'Disease', (137, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('oxygen', 'Chemical', 'MESH:D010100', (339, 345))	('HIF', 'Gene', '405', (0, 3))	('hypoxia', 'Disease', (287, 294))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (88, 119))	('von Hippel-Lindau tumour', 'Disease', (204, 228))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (137, 168))	('glucose metabolism in clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (66, 119))	('hypoxia', 'Disease', 'MESH:D000860', (287, 294))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('protein', 'cellular_component', 'GO:0003675', ('240', '247'))	('pVHL', 'Gene', '7428', (249, 253))	('HIF', 'Gene', (313, 316))	('pVHL', 'Gene', (249, 253))	('inactivation', 'Var', (184, 196))	('tumour', 'Phenotype', 'HP:0002664', (222, 228))	('PHD', 'molecular_function', 'GO:0050175', ('23', '26'))	('glucose metabolism', 'biological_process', 'GO:0006006', ('66', '84'))	('PHD3', 'Gene', '112399', (23, 27))	('PHD3', 'Gene', (23, 27))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (88, 119))	('von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (204, 228))	('HIF', 'Gene', '405', (313, 316))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (137, 168))
75018	28680592	Our data reveals an intriguingly widespread effect of PHD3 knockdown with 91 significantly regulated proteins.	('knockdown', 'Var', (59, 68))	('PHD3', 'Gene', '112399', (54, 58))	('PHD3', 'Gene', (54, 58))	('PHD', 'molecular_function', 'GO:0050175', ('54', '57'))
75020	28680592	The main cellular functions regulated by PHD3 expression were glucose metabolism, protein translation and messenger RNA (mRNA) processing.	('glucose metabolism', 'MPA', (62, 80))	('expression', 'Var', (46, 56))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('protein translation', 'MPA', (82, 101))	('PHD3', 'Gene', '112399', (41, 45))	('mRNA) processing', 'biological_process', 'GO:0006397', ('121', '137'))	('PHD3', 'Gene', (41, 45))	('protein translation', 'biological_process', 'GO:0006412', ('82', '101'))	('glucose metabolism', 'biological_process', 'GO:0006006', ('62', '80'))	('PHD', 'molecular_function', 'GO:0050175', ('41', '44'))	('RNA', 'cellular_component', 'GO:0005562', ('116', '119'))	('glucose', 'Chemical', 'MESH:D005947', (62, 69))
75021	28680592	PHD3 silencing led to downregulation of most glycolytic enzymes from glucose transport to lactate production supported by the reduction in extracellular acidification and lactate production and increase in cellular oxygen consumption rate.	('glucose transport', 'MPA', (69, 86))	('glucose', 'Chemical', 'MESH:D005947', (69, 76))	('downregulation', 'NegReg', (22, 36))	('extracellular acidification', 'MPA', (139, 166))	('extracellular', 'cellular_component', 'GO:0005576', ('139', '152'))	('silencing', 'Var', (5, 14))	('cellular oxygen consumption rate', 'MPA', (206, 238))	('increase', 'PosReg', (194, 202))	('PHD3', 'Gene', '112399', (0, 4))	('lactate', 'Chemical', 'MESH:D019344', (171, 178))	('PHD3', 'Gene', (0, 4))	('acidification', 'biological_process', 'GO:0045851', ('153', '166'))	('lactate', 'Chemical', 'MESH:D019344', (90, 97))	('glycolytic enzymes', 'Enzyme', (45, 63))	('PHD', 'molecular_function', 'GO:0050175', ('0', '3'))	('lactate production', 'MPA', (171, 189))	('reduction', 'NegReg', (126, 135))	('glucose transport', 'biological_process', 'GO:1904659', ('69', '86'))	('oxygen', 'Chemical', 'MESH:D010100', (215, 221))
75025	28680592	Clear cell renal cell carcinoma (ccRCC), the most common subtype of human kidney carcinomas, is commonly associated with the inactivating mutations of VHL leading to a loss of function of the von Hippel-Lindau tumour suppressor protein (pVHL).	('human', 'Species', '9606', (68, 73))	('VHL', 'Gene', '7428', (238, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (192, 216))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('VHL', 'Gene', '7428', (151, 154))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('pVHL', 'Gene', '7428', (237, 241))	('protein', 'cellular_component', 'GO:0003675', ('228', '235'))	('pVHL', 'Gene', (237, 241))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('kidney carcinomas', 'Disease', 'MESH:C538614', (74, 91))	('loss of function', 'NegReg', (168, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('VHL', 'Gene', (238, 241))	('von Hippel-Lindau tumour', 'Disease', (192, 216))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('inactivating mutations', 'Var', (125, 147))	('VHL', 'Gene', (151, 154))	('associated', 'Reg', (105, 115))	('kidney carcinomas', 'Disease', (74, 91))
75044	28680592	Importantly, high PHD3 expression serves as a marker for poor prognosis in ccRCC patients as well as in other types of cancer.	('ccRCC', 'Disease', (75, 80))	('high', 'Var', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('patients', 'Species', '9606', (81, 89))	('cancer', 'Disease', (119, 125))	('PHD3', 'Gene', '112399', (18, 22))	('PHD', 'molecular_function', 'GO:0050175', ('18', '21'))	('PHD3', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('expression', 'MPA', (23, 33))
75047	28680592	As the protein-level data represents the functional level in cellular processes and signal transduction, we selected a discovery proteomics approach to gain an overall insight into the functions of high PHD3 expression in ccRCC cell line.	('protein', 'cellular_component', 'GO:0003675', ('7', '14'))	('PHD', 'molecular_function', 'GO:0050175', ('203', '206'))	('high', 'Var', (198, 202))	('ccRCC', 'Disease', (222, 227))	('signal transduction', 'biological_process', 'GO:0007165', ('84', '103'))	('PHD3', 'Gene', '112399', (203, 207))	('PHD3', 'Gene', (203, 207))
75048	28680592	Here, we show that PHD3 depletion significantly affects the essential cellular processes related to glucose metabolism, post-transcriptional modification and ribosomal subunits and translation regulation in ccRCC cells.	('PHD', 'molecular_function', 'GO:0050175', ('19', '22'))	('glucose', 'Chemical', 'MESH:D005947', (100, 107))	('ribosomal subunits', 'MPA', (158, 176))	('glucose metabolism', 'MPA', (100, 118))	('essential cellular processes', 'MPA', (60, 88))	('PHD3', 'Gene', (19, 23))	('PHD3', 'Gene', '112399', (19, 23))	('regulation', 'biological_process', 'GO:0065007', ('193', '203'))	('translation', 'biological_process', 'GO:0006412', ('181', '192'))	('depletion', 'Var', (24, 33))	('post-transcriptional modification', 'MPA', (120, 153))	('glucose metabolism', 'biological_process', 'GO:0006006', ('100', '118'))	('affects', 'Reg', (48, 55))	('translation regulation', 'MPA', (181, 203))
75049	28680592	This study provides novel insights into the role of PHD3 in ccRCC by revealing functional groups of proteins that respond to PHD3 knockdown.	('PHD3', 'Gene', (125, 129))	('ccRCC', 'Disease', (60, 65))	('knockdown', 'Var', (130, 139))	('PHD', 'molecular_function', 'GO:0050175', ('52', '55'))	('PHD3', 'Gene', '112399', (52, 56))	('PHD3', 'Gene', '112399', (125, 129))	('PHD3', 'Gene', (52, 56))	('PHD', 'molecular_function', 'GO:0050175', ('125', '128'))
75062	28680592	Western blot analyses with the following antibodies were performed: PHD3 (NB100-139, Novus Biologicals), CD70 (CD27 Ligand) (MAB2738, R&D Systems), Integrin beta1 (610468, BD Transduction Laboratories), LDHA (#3582, Cell Signaling Technologies), MDH2 (ab181873, Abcam), STAT1 (#9176, Cell Signaling Technologies), Fibronectin (F3648, Sigma), alpha-actinin 4 (ALX-210-356-C050, Enzo Life Sciences), GLUT1 (ab14683, Abcam), glyceraldehyde phosphate dehydrogenase (GAPDH) (5G4-6C5, HyTest), S6 ribosomal protein (#2217, Cell Signaling Technologies), pS6 ribosomal protein S235/236 (#2211, Cell Signaling Technologies), pS6 ribosomal protein S240/244 (#3564, Cell Signaling Technologies), p70 S6 kinase (#2708, Cell Signaling Technologies), p-p70 S6 kinase T389 (#9234, Cell Signaling Technologies), alpha-tubulin (sc-23948, Santa Cruz Biotechnology), beta-actin (AC-74, Sigma-Aldrich), anti-mouse-HRP (DAKO), and anti-rabbit HRP (DAKO).	('MDH2', 'Gene', (246, 250))	('ALX', 'Gene', (359, 362))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('620', '637'))	('PHD3', 'Gene', '112399', (68, 72))	('PHD3', 'Gene', (68, 72))	('GLUT1', 'Gene', '6513', (398, 403))	('GAPDH', 'Gene', '2597', (462, 467))	('mouse', 'Species', '10090', (888, 893))	('p70 S6 kinase', 'Gene', '6198', (685, 698))	('Fibronectin', 'Gene', '2335', (314, 325))	('glyceraldehyde phosphate dehydrogenase', 'Gene', '2597', (422, 460))	('Signaling', 'biological_process', 'GO:0023052', ('771', '780'))	('Integrin beta1', 'Gene', (148, 162))	('CD27 Ligand', 'Gene', '970', (111, 122))	('alpha-actinin 4', 'Gene', (342, 357))	('MDH', 'molecular_function', 'GO:0018468', ('246', '249'))	('Signaling', 'biological_process', 'GO:0023052', ('660', '669'))	('LDHA', 'Gene', '3939', (203, 207))	('rabbit', 'Species', '9986', (915, 921))	('p70 S6 kinase', 'Gene', (739, 752))	('beta-actin', 'Gene', '728378', (848, 858))	('Signaling', 'biological_process', 'GO:0023052', ('289', '298'))	('Signaling', 'biological_process', 'GO:0023052', ('221', '230'))	('GAPDH', 'Gene', (462, 467))	('CD27 Ligand', 'Gene', (111, 122))	('STAT1', 'Gene', (270, 275))	('ALX', 'Gene', '84941', (359, 362))	('Fibronectin', 'Gene', (314, 325))	('MDH2', 'Gene', '4191', (246, 250))	('Transduction', 'biological_process', 'GO:0009293', ('175', '187'))	('Signaling', 'biological_process', 'GO:0023052', ('591', '600'))	('MDH', 'molecular_function', 'GO:0030060', ('246', '249'))	('alpha-tubulin', 'Gene', '10376', (796, 809))	('Signaling', 'biological_process', 'GO:0023052', ('712', '721'))	('protein', 'cellular_component', 'GO:0003675', ('501', '508'))	('GLUT1', 'Gene', (398, 403))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('491', '508'))	('PHD', 'molecular_function', 'GO:0050175', ('68', '71'))	('protein', 'cellular_component', 'GO:0003675', ('630', '637'))	('p70 S6 kinase', 'Gene', '6198', (739, 752))	('MDH', 'molecular_function', 'GO:0033720', ('246', '249'))	('Signaling', 'biological_process', 'GO:0023052', ('522', '531'))	('alpha-actinin 4', 'Gene', '81', (342, 357))	('protein', 'cellular_component', 'GO:0003675', ('561', '568'))	('glyceraldehyde phosphate dehydrogenase', 'Gene', (422, 460))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('551', '568'))	('STAT1', 'Gene', '6772', (270, 275))	('LDHA', 'Gene', (203, 207))	('CD70', 'Gene', (105, 109))	('CD70', 'Gene', '970', (105, 109))	('and', 'Var', (906, 909))	('p70 S6 kinase', 'Gene', (685, 698))	('beta-actin', 'Gene', (848, 858))	('Integrin beta1', 'Gene', '3688', (148, 162))	('alpha-tubulin', 'Gene', (796, 809))
75100	28680592	In line with our LC-MS/MS results, in 786-O cells, PHD3 depletion in 786-O cells resulted in downregulation of lactate dehydrogenase A (LDHA), integrin beta1, CD70 (also known as CD27L) and upregulation of malate dehydrogenase (MDH2), signal transducer and activator of transcription 1 (STAT1), fibronectin, and alpha-actinin 4 with both siRNA sequences (Fig.	('MDH', 'molecular_function', 'GO:0033720', ('228', '231'))	('alpha-actinin 4', 'Gene', (312, 327))	('malate dehydrogenase', 'Gene', '10873', (206, 226))	('PHD3', 'Gene', '112399', (51, 55))	('PHD3', 'Gene', (51, 55))	('STAT1', 'Gene', (287, 292))	('integrin beta1', 'Gene', '3688', (143, 157))	('LDHA', 'Gene', (136, 140))	('MDH2', 'Gene', (228, 232))	('fibronectin', 'Gene', (295, 306))	('PHD', 'molecular_function', 'GO:0050175', ('51', '54'))	('CD70', 'Gene', (159, 163))	('CD27L', 'Gene', (179, 184))	('CD70', 'Gene', '970', (159, 163))	('upregulation', 'PosReg', (190, 202))	('malate dehydrogenase', 'Gene', (206, 226))	('CD27L', 'Gene', '970', (179, 184))	('transcription', 'biological_process', 'GO:0006351', ('270', '283'))	('downregulation', 'NegReg', (93, 107))	('STAT1', 'Gene', '6772', (287, 292))	('alpha-actinin 4', 'Gene', '81', (312, 327))	('fibronectin', 'Gene', '2335', (295, 306))	('lactate dehydrogenase A', 'Gene', '3939', (111, 134))	('integrin beta1', 'Gene', (143, 157))	('depletion', 'Var', (56, 65))	('MDH2', 'Gene', '4191', (228, 232))	('MDH', 'molecular_function', 'GO:0018468', ('228', '231'))	('LDHA', 'Gene', '3939', (136, 140))	('lactate dehydrogenase A', 'Gene', (111, 134))	('MDH', 'molecular_function', 'GO:0030060', ('228', '231'))	('signal transducer and activator of transcription 1', 'Gene', '6772', (235, 285))
75101	28680592	For integrin beta1, PHD3 depletion resulted in more pronounced downregulation of the mature form (upper band) as compared to the premature form (lower band).	('integrin beta1', 'Gene', '3688', (4, 18))	('PHD3', 'Gene', '112399', (20, 24))	('mature form', 'MPA', (85, 96))	('PHD3', 'Gene', (20, 24))	('PHD', 'molecular_function', 'GO:0050175', ('20', '23'))	('depletion', 'Var', (25, 34))	('integrin beta1', 'Gene', (4, 18))	('downregulation', 'NegReg', (63, 77))
75117	28680592	The key glycolytic enzymes PFKP, TPI1, ENO1, PGAM1 and LDHA, as well as GLUT1, were all found to be significantly downregulated by PHD3 knockdown in hypoxic condition.	('ENO1', 'Gene', '2023', (39, 43))	('downregulated', 'NegReg', (114, 127))	('GLUT1', 'Gene', '6513', (72, 77))	('PHD3', 'Gene', '112399', (131, 135))	('PHD3', 'Gene', (131, 135))	('PGAM1', 'Gene', (45, 50))	('LDHA', 'Gene', (55, 59))	('TPI1', 'Gene', '7167', (33, 37))	('PFKP', 'Gene', (27, 31))	('TPI1', 'Gene', (33, 37))	('hypoxic condition', 'Disease', 'MESH:D009135', (149, 166))	('hypoxic condition', 'Disease', (149, 166))	('PGAM1', 'Gene', '5223', (45, 50))	('GLUT1', 'Gene', (72, 77))	('knockdown', 'Var', (136, 145))	('PFKP', 'Gene', '5214', (27, 31))	('LDHA', 'Gene', '3939', (55, 59))	('ENO1', 'Gene', (39, 43))	('PHD', 'molecular_function', 'GO:0050175', ('131', '134'))
75121	28680592	ENO1 catalyzes the conversion of 2-phosphoglycerate (2-PG) into phosphoenolpyruvate (PEP) and thus the downregulation by PHD3 silencing leads to decreased levels of PEP and pyruvate.	('PHD', 'molecular_function', 'GO:0050175', ('121', '124'))	('pyruvate', 'Chemical', 'MESH:D019289', (75, 83))	('phosphoenolpyruvate', 'Chemical', 'MESH:D010728', (64, 83))	('PEP', 'Chemical', 'MESH:D010728', (165, 168))	('ENO1', 'Gene', (0, 4))	('PHD3', 'Gene', '112399', (121, 125))	('downregulation', 'NegReg', (103, 117))	('PEP', 'Chemical', 'MESH:D010728', (85, 88))	('decreased', 'NegReg', (145, 154))	('ENO1', 'Gene', '2023', (0, 4))	('pyruvate', 'Chemical', 'MESH:D019289', (173, 181))	('2-phosphoglycerate', 'Chemical', 'MESH:C008885', (33, 51))	('silencing', 'Var', (126, 135))	('PHD3', 'Gene', (121, 125))
75130	28680592	In line with the downregulated LDHA, extracellular lactate concentration was markedly reduced with PHD3 depletion in 786-O cells and even more pronounced effect was detected under hypoxic condition (normalized to cell count).	('extracellular lactate concentration', 'MPA', (37, 72))	('hypoxic condition', 'Disease', (180, 197))	('reduced', 'NegReg', (86, 93))	('PHD3', 'Gene', '112399', (99, 103))	('LDHA', 'Gene', (31, 35))	('extracellular', 'cellular_component', 'GO:0005576', ('37', '50'))	('PHD3', 'Gene', (99, 103))	('LDHA', 'Gene', '3939', (31, 35))	('lactate', 'Chemical', 'MESH:D019344', (51, 58))	('depletion', 'Var', (104, 113))	('PHD', 'molecular_function', 'GO:0050175', ('99', '102'))	('hypoxic condition', 'Disease', 'MESH:D009135', (180, 197))
75134	28680592	PHD3 silencing increased both basal OCR and maximal OCR measured after stimulating the cells with mitochondrial membrane uncoupling agent FCCP (carbonyl cyanide-4 trifluoromethoxy phenylhydrazone) that allows maximal electron flow through the electron transport chain and thus the maximal oxygen consumption at the mitochondria (Fig.	('electron transport chain', 'biological_process', 'GO:0022900', ('243', '267'))	('carbonyl cyanide-4 trifluoromethoxy phenylhydrazone', 'Chemical', 'MESH:C108897', (144, 195))	('PHD', 'molecular_function', 'GO:0050175', ('0', '3'))	('silencing', 'Var', (5, 14))	('increased', 'PosReg', (15, 24))	('oxygen', 'Chemical', 'MESH:D010100', (289, 295))	('PHD3', 'Gene', '112399', (0, 4))	('PHD3', 'Gene', (0, 4))	('OCR', 'Chemical', '-', (52, 55))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('98', '120'))	('mitochondria', 'cellular_component', 'GO:0005739', ('315', '327'))	('OCR', 'Chemical', '-', (36, 39))
75140	28680592	Within the group, a number of ribosomal protein subunits were significantly downregulated as response to PHD3 knockdown (Fig.	('knockdown', 'Var', (110, 119))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('30', '47'))	('ribosomal protein subunits', 'Protein', (30, 56))	('PHD3', 'Gene', '112399', (105, 109))	('PHD3', 'Gene', (105, 109))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('downregulated', 'NegReg', (76, 89))	('PHD', 'molecular_function', 'GO:0050175', ('105', '108'))
75145	28680592	Supporting the effect of PHD3 in protein production, another group that showed intriguing deregulation in response to PHD3 knockdown was the mRNA processing.	('PHD3', 'Gene', '112399', (118, 122))	('PHD3', 'Gene', (118, 122))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('deregulation', 'MPA', (90, 102))	('mRNA processing', 'MPA', (141, 156))	('PHD3', 'Gene', '112399', (25, 29))	('mRNA processing', 'biological_process', 'GO:0006397', ('141', '156'))	('PHD3', 'Gene', (25, 29))	('knockdown', 'Var', (123, 132))	('PHD', 'molecular_function', 'GO:0050175', ('25', '28'))	('PHD', 'molecular_function', 'GO:0050175', ('118', '121'))
75151	28680592	Next, we asked if the phosphorylation of p70 S6K and the downstream effector S6 ribosomal protein is affected by PHD3 depletion, as we saw the protein level of numerous translational machinery components downregulated in LC-MS/MS results.	('depletion', 'Var', (118, 127))	('PHD3', 'Gene', '112399', (113, 117))	('p70 S6K', 'Gene', (41, 48))	('PHD3', 'Gene', (113, 117))	('PHD', 'molecular_function', 'GO:0050175', ('113', '116'))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('LC-MS/MS', 'Disease', (221, 229))	('protein level', 'MPA', (143, 156))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('p70 S6K', 'Gene', '6198', (41, 48))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('80', '97'))	('downregulated', 'NegReg', (204, 217))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('affected', 'Reg', (101, 109))	('phosphorylation', 'MPA', (22, 37))
75154	28680592	In line, also, phosphorylation of S6 ribosomal protein (pS6 S235/236 and S240/244) was similarly downregulated by PHD3 depletion while total S6 ribosomal protein remained unaffected.	('S240/244', 'Var', (73, 81))	('S6 ribosomal protein', 'Protein', (34, 54))	('PHD3', 'Gene', (114, 118))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('37', '54'))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('144', '161'))	('downregulated', 'NegReg', (97, 110))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('phosphorylation', 'biological_process', 'GO:0016310', ('15', '30'))	('pS6 S235/236', 'Var', (56, 68))	('PHD', 'molecular_function', 'GO:0050175', ('114', '117'))	('PHD3', 'Gene', '112399', (114, 118))	('phosphorylation', 'MPA', (15, 30))
75159	28680592	In our previous studies, we have shown that PHD3 depletion causes cell cycle arrest at G1 in several carcinoma cell lines, including 786-O.	('PHD', 'molecular_function', 'GO:0050175', ('44', '47'))	('PHD3', 'Gene', '112399', (44, 48))	('carcinoma', 'Disease', 'MESH:D002277', (101, 110))	('PHD3', 'Gene', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('66', '83'))	('carcinoma', 'Disease', (101, 110))	('cell cycle arrest at G1', 'CPA', (66, 89))	('depletion', 'Var', (49, 58))
75161	28680592	In line with the previously published results on 786-O cell line, the FACS analysis showed that depleting PHD3 in RCC4 cell line causes G1 arrest both in normal oxygen pressure (21% O2) and in hypoxia (1% O2) (Additional file 3: Figure S3A), Additional file 4.	('hypoxia', 'Disease', (193, 200))	('PHD', 'molecular_function', 'GO:0050175', ('106', '109'))	('causes', 'Reg', (129, 135))	('depleting', 'Var', (96, 105))	('O2', 'Chemical', 'MESH:D010100', (205, 207))	('G1 arrest', 'CPA', (136, 145))	('oxygen', 'Chemical', 'MESH:D010100', (161, 167))	('PHD3', 'Gene', (106, 110))	('PHD3', 'Gene', '112399', (106, 110))	('RCC4', 'Gene', '84925', (114, 118))	('RCC4', 'Gene', (114, 118))	('hypoxia', 'Disease', 'MESH:D000860', (193, 200))	('O2', 'Chemical', 'MESH:D010100', (182, 184))
75162	28680592	We have previously shown that PHD3 depletion reduced proliferation in squamous cell carcinoma (SCC) cells measured by BrdU incorporation.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('reduced', 'NegReg', (45, 52))	('squamous cell carcinoma', 'Disease', (70, 93))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 93))	('PHD3', 'Gene', '112399', (30, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('BrdU incorporation', 'MPA', (118, 136))	('PHD3', 'Gene', (30, 34))	('proliferation', 'CPA', (53, 66))	('depletion', 'Var', (35, 44))	('PHD', 'molecular_function', 'GO:0050175', ('30', '33'))
75165	28680592	However, as we investigated the 3D colony growth of 786-O and RCC4 cells by using Matrigel  matrix, significant reduction in colony size with PHD3 silencing was seen in both cell lines (Fig.	('PHD', 'molecular_function', 'GO:0050175', ('142', '145'))	('RCC4', 'Gene', '84925', (62, 66))	('silencing', 'Var', (147, 156))	('RCC4', 'Gene', (62, 66))	('reduction', 'NegReg', (112, 121))	('PHD3', 'Gene', '112399', (142, 146))	('PHD3', 'Gene', (142, 146))	('colony size', 'CPA', (125, 136))
75172	28680592	The 786-O cells have inactivated pVHL and truncated HIF-1alpha.	('HIF-1alpha', 'Gene', (52, 62))	('inactivated', 'NegReg', (21, 32))	('truncated', 'Var', (42, 51))	('pVHL', 'Gene', '7428', (33, 37))	('HIF-1alpha', 'Gene', '3091', (52, 62))	('pVHL', 'Gene', (33, 37))
75180	28680592	Moreover, under hypoxia, the response to PHD3 knockdown was more widespread than under normoxic condition illustrated by both the number of regulated proteins and by the range of the quantified protein expression.	('hypoxia', 'Disease', 'MESH:D000860', (16, 23))	('knockdown', 'Var', (46, 55))	('PHD3', 'Gene', '112399', (41, 45))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('PHD3', 'Gene', (41, 45))	('PHD', 'molecular_function', 'GO:0050175', ('41', '44'))	('hypoxia', 'Disease', (16, 23))
75184	28680592	Interestingly, major proteome-level changes affected by PHD3 depletion were found in glucose metabolic pathway.	('PHD3', 'Gene', (56, 60))	('changes', 'Reg', (36, 43))	('proteome-level', 'MPA', (21, 35))	('depletion', 'Var', (61, 70))	('PHD3', 'Gene', '112399', (56, 60))	('PHD', 'molecular_function', 'GO:0050175', ('56', '59'))	('glucose', 'Chemical', 'MESH:D005947', (85, 92))	('glucose metabolic pathway', 'Pathway', (85, 110))
75185	28680592	Our findings imply that PHD3 silencing leads to suppression of glycolytic pathway as well as decreased conversion of pyruvate to lactate demonstrated by the regulation of nine glycolytic enzymes.	('PHD', 'molecular_function', 'GO:0050175', ('24', '27'))	('suppression', 'NegReg', (48, 59))	('silencing', 'Var', (29, 38))	('glycolytic pathway', 'Pathway', (63, 81))	('lactate', 'Chemical', 'MESH:D019344', (129, 136))	('decreased', 'NegReg', (93, 102))	('PHD3', 'Gene', '112399', (24, 28))	('conversion of pyruvate to lactate', 'MPA', (103, 136))	('pyruvate', 'Chemical', 'MESH:D019289', (117, 125))	('regulation', 'biological_process', 'GO:0065007', ('157', '167'))	('PHD3', 'Gene', (24, 28))
75189	28680592	Noticeably, the proteome-level data suggests decreased pyruvate to lactate conversion in response to PHD3 knockdown illustrated by LDHA downregulation under hypoxia and LDHB upregulation under normoxia.	('lactate', 'Chemical', 'MESH:D019344', (67, 74))	('pyruvate to lactate conversion', 'MPA', (55, 85))	('hypoxia', 'Disease', 'MESH:D000860', (157, 164))	('downregulation', 'NegReg', (136, 150))	('PHD', 'molecular_function', 'GO:0050175', ('101', '104'))	('decreased', 'NegReg', (45, 54))	('LDHA', 'Gene', (131, 135))	('hypoxia', 'Disease', (157, 164))	('knockdown', 'Var', (106, 115))	('pyruvate', 'Chemical', 'MESH:D019289', (55, 63))	('LDHB', 'Gene', (169, 173))	('upregulation', 'PosReg', (174, 186))	('LDHA', 'Gene', '3939', (131, 135))	('LDHB', 'Gene', '3945', (169, 173))	('PHD3', 'Gene', '112399', (101, 105))	('PHD3', 'Gene', (101, 105))
75192	28680592	In line with the proteome-level data, we found decreased extracellular lactate levels in response to PHD3 silencing in both cell lines and as previously shown by others in RCC4.	('extracellular', 'cellular_component', 'GO:0005576', ('57', '70'))	('lactate', 'Chemical', 'MESH:D019344', (71, 78))	('extracellular lactate levels', 'MPA', (57, 85))	('RCC4', 'Gene', (172, 176))	('RCC4', 'Gene', '84925', (172, 176))	('PHD', 'molecular_function', 'GO:0050175', ('101', '104'))	('silencing', 'Var', (106, 115))	('PHD3', 'Gene', '112399', (101, 105))	('PHD3', 'Gene', (101, 105))	('decreased', 'NegReg', (47, 56))
75201	28680592	This suggests an enhancement of TCA cycle by PHD3 knockdown while decreasing the flux towards lactate.	('TCA', 'Chemical', 'MESH:D014238', (32, 35))	('TCA cycle', 'MPA', (32, 41))	('knockdown', 'Var', (50, 59))	('TCA cycle', 'biological_process', 'GO:0006099', ('32', '41'))	('PHD', 'molecular_function', 'GO:0050175', ('45', '48'))	('flux towards lactate', 'MPA', (81, 101))	('PHD3', 'Gene', '112399', (45, 49))	('PHD3', 'Gene', (45, 49))	('enhancement', 'PosReg', (17, 28))	('decreasing', 'NegReg', (66, 76))	('lactate', 'Chemical', 'MESH:D019344', (94, 101))
75212	28680592	In line with RPL regulation, PHD3 knockdown mainly targeted the hnRNPs under hypoxia suggesting a specific role for PHD3 under restricted oxygen availability.	('PHD3', 'Gene', '112399', (29, 33))	('PHD3', 'Gene', (29, 33))	('hypoxia', 'Disease', (77, 84))	('PHD', 'molecular_function', 'GO:0050175', ('29', '32'))	('PHD', 'molecular_function', 'GO:0050175', ('116', '119'))	('targeted', 'Reg', (51, 59))	('PHD3', 'Gene', '112399', (116, 120))	('PHD3', 'Gene', (116, 120))	('hnRNPs', 'Protein', (64, 70))	('oxygen', 'Chemical', 'MESH:D010100', (138, 144))	('knockdown', 'Var', (34, 43))	('hypoxia', 'Disease', 'MESH:D000860', (77, 84))	('regulation', 'biological_process', 'GO:0065007', ('17', '27'))
75216	28680592	Phosphorylation of p70 S6K on T389 by mTORC1 and subsequent phosphorylation of S6 ribosomal protein have been shown to be responsible for the regulation of the TOP mRNA translation, a strictly regulated group of translational machinery components including all ribosomal proteins (reviewed in).	('p70 S6K', 'Gene', '6198', (19, 26))	('mTORC1', 'cellular_component', 'GO:0031931', ('38', '44'))	('TOP mRNA translation', 'MPA', (160, 180))	('regulation', 'biological_process', 'GO:0065007', ('142', '152'))	('mTORC1', 'Gene', '382056', (38, 44))	('T389', 'Var', (30, 34))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('82', '99'))	('phosphorylation', 'biological_process', 'GO:0016310', ('60', '75'))	('p70 S6K', 'Gene', (19, 26))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('translation', 'biological_process', 'GO:0006412', ('169', '180'))	('mTORC1', 'Gene', (38, 44))
75217	28680592	However, also, total p70 S6K protein expression was slightly decreased with PHD3 silencing, which could indicate a direct effect of PHD3 on p70 S6K, but further studies are needed to determine the detailed mechanism.	('PHD3', 'Gene', '112399', (132, 136))	('p70 S6K', 'Gene', '6198', (140, 147))	('p70 S6K', 'Gene', '6198', (21, 28))	('PHD', 'molecular_function', 'GO:0050175', ('132', '135'))	('silencing', 'Var', (81, 90))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('decreased', 'NegReg', (61, 70))	('p70 S6K', 'Gene', (140, 147))	('PHD3', 'Gene', '112399', (76, 80))	('p70 S6K', 'Gene', (21, 28))	('PHD3', 'Gene', (76, 80))	('PHD3', 'Gene', (132, 136))	('PHD', 'molecular_function', 'GO:0050175', ('76', '79'))
75220	28680592	Inhibition of mTOR signalling by small molecular inhibitor has been shown to reduce ccRCC cell clonogenicity and proliferation, but not affecting cell viability or apoptosis.	('mTOR', 'Gene', '2475', (14, 18))	('ccRCC', 'Disease', (84, 89))	('reduce', 'NegReg', (77, 83))	('Inhibition', 'Var', (0, 10))	('signalling', 'biological_process', 'GO:0023052', ('19', '29'))	('apoptosis', 'biological_process', 'GO:0097194', ('164', '173'))	('apoptosis', 'biological_process', 'GO:0006915', ('164', '173'))	('proliferation', 'CPA', (113, 126))	('mTOR', 'Gene', (14, 18))
75223	28680592	As PHD3 depletion reduces the activation of the key mTORC1 downstream effectors and has similar effects on cell growth than mTOR inhibition, it is plausible that PHD3 has a role in mTOR signalling pathway regulation.	('mTOR', 'Gene', (52, 56))	('cell growth', 'CPA', (107, 118))	('mTOR', 'Gene', '2475', (124, 128))	('mTORC1', 'Gene', '382056', (52, 58))	('PHD3', 'Gene', '112399', (162, 166))	('PHD3', 'Gene', (162, 166))	('activation', 'MPA', (30, 40))	('cell growth', 'biological_process', 'GO:0016049', ('107', '118'))	('mTOR', 'Gene', '2475', (52, 56))	('PHD', 'molecular_function', 'GO:0050175', ('162', '165'))	('reduces', 'NegReg', (18, 25))	('regulation', 'biological_process', 'GO:0065007', ('205', '215'))	('mTORC1', 'cellular_component', 'GO:0031931', ('52', '58'))	('PHD3', 'Gene', '112399', (3, 7))	('PHD3', 'Gene', (3, 7))	('signalling pathway', 'biological_process', 'GO:0007165', ('186', '204'))	('PHD', 'molecular_function', 'GO:0050175', ('3', '6'))	('mTOR', 'Gene', (181, 185))	('depletion', 'Var', (8, 17))	('mTOR', 'Gene', (124, 128))	('mTORC1', 'Gene', (52, 58))	('mTOR', 'Gene', '2475', (181, 185))
75228	28680592	To conclude, high PHD3 expression in ccRCC cells results in enhanced translation of the ribosomal proteins and other components of the protein synthesis machinery, thus protecting cancer cells from the cell cycle arrest caused by the environmental stress and enabling cells to overcome constrains of the hostile environment.	('translation', 'biological_process', 'GO:0006412', ('69', '80'))	('cell cycle arrest', 'CPA', (202, 219))	('high', 'Var', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('202', '219'))	('protein synthesis', 'biological_process', 'GO:0006412', ('135', '152'))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('enabling', 'PosReg', (259, 267))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('PHD3', 'Gene', '112399', (18, 22))	('protecting', 'PosReg', (169, 179))	('PHD3', 'Gene', (18, 22))	('PHD', 'molecular_function', 'GO:0050175', ('18', '21'))	('enhanced', 'PosReg', (60, 68))	('cancer', 'Disease', (180, 186))	('translation', 'MPA', (69, 80))
75229	28680592	In addition, high PHD3 expression would lead to enhanced glycolytic activity and increased lactate production, thus contributing to tumour progression.	('glycolytic activity', 'MPA', (57, 76))	('tumour', 'Disease', (132, 138))	('lactate', 'Chemical', 'MESH:D019344', (91, 98))	('high', 'Var', (13, 17))	('enhanced', 'PosReg', (48, 56))	('expression', 'MPA', (23, 33))	('lactate production', 'MPA', (91, 109))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('PHD3', 'Gene', '112399', (18, 22))	('PHD', 'molecular_function', 'GO:0050175', ('18', '21'))	('PHD3', 'Gene', (18, 22))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('increased', 'PosReg', (81, 90))	('contributing', 'Reg', (116, 128))
75235	28680592	Interestingly, under reduced oxygen availability, PHD3 knockdown illustrates more prominent and a greater number of protein identifications as compared to normoxia.	('PHD3', 'Gene', (50, 54))	('knockdown', 'Var', (55, 64))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('PHD', 'molecular_function', 'GO:0050175', ('50', '53'))	('oxygen', 'Chemical', 'MESH:D010100', (29, 35))	('protein identifications', 'MPA', (116, 139))	('PHD3', 'Gene', '112399', (50, 54))
75238	31765370	GPCRs show widespread differential mRNA expression and frequent mutation and copy number variation in solid tumors G protein-coupled receptors (GPCRs) are the most widely targeted gene family for Food and Drug Administration (FDA)-approved drugs.	('copy number variation', 'Var', (77, 98))	('solid tumors', 'Disease', (102, 114))	('GPCR', 'Gene', '148', (144, 148))	('GPCR', 'Gene', '148', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('GPCR', 'Gene', (144, 148))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('GPCR', 'Gene', (0, 4))	('solid tumors', 'Disease', 'MESH:D009369', (102, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
75246	31765370	Certain GPCRs are frequently mutated and appear to be hotspots, serving as bellwethers of accumulated genomic damage.	('GPCR', 'Gene', '148', (8, 12))	('mutated', 'Var', (29, 36))	('GPCR', 'Gene', (8, 12))
75251	31765370	Expression of certain GPCRs appears to have prognostic relevance, and many GPCRs undergo widespread mutation and copy number variation.	('GPCR', 'Gene', '148', (75, 79))	('copy number variation', 'Var', (113, 134))	('undergo', 'Reg', (81, 88))	('GPCR', 'Gene', (75, 79))	('GPCR', 'Gene', (22, 26))	('GPCR', 'Gene', '148', (22, 26))
75255	31765370	One reason for their limited use is the notion that GPCRs are rarely mutated in cancer :although mutations occur in heterotrimeric GTP binding (G) proteins that GPCRs activate :and that GPCRs regulate pathways, such as Wnt, mitogen-activated protein kinase (MAPK), and Phosphoinositide 3-Kinase (PI3K) signaling, with mutations in cancer.	('mutations', 'Var', (97, 106))	('Wnt', 'Pathway', (219, 222))	('mutations', 'Var', (318, 327))	('GTP', 'Chemical', 'MESH:D006160', (131, 134))	('cancer', 'Disease', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('GPCR', 'Gene', '148', (52, 56))	('MAPK', 'molecular_function', 'GO:0004707', ('258', '262'))	('GPCR', 'Gene', '148', (186, 190))	('PI3K', 'molecular_function', 'GO:0016303', ('296', '300'))	('Phosphoinositide 3-Kinase', 'Gene', '5293', (269, 294))	('GPCR', 'Gene', (52, 56))	('GPCR', 'Gene', '148', (161, 165))	('protein', 'cellular_component', 'GO:0003675', ('242', '249'))	('GPCR', 'Gene', (186, 190))	('regulate', 'Reg', (192, 200))	('GPCR', 'Gene', (161, 165))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Phosphoinositide 3-Kinase', 'Gene', (269, 294))	('cancer', 'Disease', (331, 337))	('GTP binding', 'molecular_function', 'GO:0005525', ('131', '142'))	('PI3K) signaling', 'biological_process', 'GO:0014065', ('296', '311'))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))
75257	31765370	To define the landscape of GPCRs in cancer, we undertook an integrated analysis of Differential Expression (DE), mutations, and copy number variation (CNV) of GPCRs, which are annotated by the Guide to Pharmacology database (GtoPdb), in 20 types of solid tumors (Table 1 and S1 and S2 Tables).	('GPCR', 'Gene', '148', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('cancer', 'Disease', (36, 42))	('solid tumors', 'Disease', 'MESH:D009369', (249, 261))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('GPCR', 'Gene', (27, 31))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('GPCR', 'Gene', '148', (159, 163))	('copy number variation', 'Var', (128, 149))	('solid tumors', 'Disease', (249, 261))	('GPCR', 'Gene', (159, 163))
75298	31765370	We compiled a list of GPCRs overexpressed in solid tumors with fold-changes and FDR along with expression in TPM (for median expression and within-group comparisons of different genes) and Counts Per Million (CPM; for intergroup comparisons of the same gene).	('TPM', 'Gene', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('overexpressed', 'PosReg', (28, 41))	('GPCR', 'Gene', (22, 26))	('solid tumors', 'Disease', (45, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('solid tumors', 'Disease', 'MESH:D009369', (45, 57))	('TPM', 'Chemical', '-', (109, 112))	('GPCR', 'Gene', '148', (22, 26))	('fold-changes', 'Var', (63, 75))
75349	31765370	EDNRB, which is highly overexpressed in SKCM, promotes migration and transformation of melanocytes and melanoma cells, and inhibition of EDNRB is pro-apoptotic.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('EDNRB', 'Gene', (0, 5))	('inhibition', 'Var', (123, 133))	('migration', 'CPA', (55, 64))	('EDNRB', 'Gene', (137, 142))	('transformation', 'CPA', (69, 83))	('transformation of melanocytes', 'Phenotype', 'HP:0002861', (69, 98))	('EDNRB', 'Gene', '1910', (0, 5))	('promotes', 'PosReg', (46, 54))	('EDNRB', 'Gene', '1910', (137, 142))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
75363	31765370	GPCR expression appears largely independent of driver mutations, such as in BRCA HR+ IDC tumors with either PI3KA or TP53 mutations (Fig 7A-7C); both groups have similar GPCR expression and DE of the same GPCRs compared to normal breast tissue.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('GPCR', 'Gene', '148', (0, 4))	('PI3KA', 'Gene', (108, 113))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('BRCA HR+ IDC tumors', 'Disease', 'MESH:D001919', (76, 95))	('BRCA', 'Phenotype', 'HP:0003002', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('GPCR', 'Gene', '148', (205, 209))	('GPCR', 'Gene', (0, 4))	('mutations', 'Var', (122, 131))	('BRCA HR+ IDC tumors', 'Disease', (76, 95))	('GPCR', 'Gene', '148', (170, 174))	('GPCR', 'Gene', (205, 209))	('GPCR', 'Gene', (170, 174))
75364	31765370	Similar results occur for lung adenocarcinoma (LUAD) and stomach adenocarcinoma (STAD) that have or lack TP53 mutations.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (26, 45))	('mutations', 'Var', (110, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('stomach adenocarcinoma', 'Disease', (57, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('TP53', 'Gene', '7157', (105, 109))	('lung adenocarcinoma', 'Disease', (26, 45))	('TP53', 'Gene', (105, 109))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (26, 45))	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (57, 79))
75388	31765370	In SKCM, which has the highest mutation burden among TCGA tumor types, the most highly overexpressed GPCRs (GPR143, EDNRB, and GPR56) are mutated in <2% of SKCM tumors, whereas frequently mutated GPCRs (e.g., GPR98, mutated in nearly 40% of tumors) typically have low expression.	('GPCR', 'Gene', '148', (196, 200))	('tumors', 'Disease', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('GPCR', 'Gene', (196, 200))	('GPCR', 'Gene', '148', (101, 105))	('GPR98', 'Gene', (209, 214))	('tumor', 'Disease', (161, 166))	('GPR56', 'Gene', (127, 132))	('GPCR', 'Gene', (101, 105))	('tumor', 'Disease', (58, 63))	('GPR143', 'Gene', (108, 114))	('tumor', 'Disease', (241, 246))	('SKCM tumors', 'Disease', (156, 167))	('SKCM tumors', 'Disease', 'MESH:D009369', (156, 167))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('EDNRB', 'Gene', '1910', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('EDNRB', 'Gene', (116, 121))	('GPR98', 'Gene', '84059', (209, 214))	('mutated', 'Var', (138, 145))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('overexpressed', 'PosReg', (87, 100))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('GPR56', 'Gene', '9289', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', (241, 247))	('GPR143', 'Gene', '4935', (108, 114))
75392	31765370	Furthermore, as discussed in the following sections on GPCR mutation, mutations to these GPCRs are predicted to have no functional impact and are not enriched significantly for mutations at specific sites; thus, overexpressed GPCRs in tumors are not expected to be altered in their function by mutations.	('GPCR', 'Gene', '148', (226, 230))	('mutations', 'Var', (70, 79))	('GPCR', 'Gene', '148', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('GPCR', 'Gene', (226, 230))	('GPCR', 'Gene', '148', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('GPCR', 'Gene', (89, 93))	('GPCR', 'Gene', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('tumors', 'Disease', (235, 241))	('overexpressed', 'PosReg', (212, 225))
75394	31765370	Tissues and tumors typically express >150 GPCRs (at detection thresholds >0.1 TPM) that couple to the major types of G proteins (Gs, Gi/o, Gq/11, G12/13), most frequently Gi/Go and Gq/G11 (S7A and S7B Fig).	('Gi/Go', 'Var', (171, 176))	('S7', 'Gene', '6264', (189, 191))	('TPM', 'Chemical', '-', (78, 81))	('GPCR', 'Gene', '148', (42, 46))	('S7', 'Gene', '6264', (197, 199))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('GPCR', 'Gene', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('couple', 'Reg', (88, 94))
75436	31765370	Analysis of 5,103 TCGA samples in 20 tumor types (S3 Table; 21 tumor types if one divides ESCA into esophageal adenocarcinoma and squamous cell carcinomas) revealed many GPCRs with frequent nonsilent mutations (Figs 11A and S8A), including a more frequently mutated subset (Fig 11A, inset).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('squamous cell carcinomas', 'Disease', (130, 154))	('mutations', 'Var', (200, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (100, 125))	('adenocarcinoma', 'Disease', 'MESH:D000230', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('GPCR', 'Gene', '148', (170, 174))	('GPCR', 'Gene', (170, 174))	('tumor', 'Disease', (63, 68))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (130, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (130, 154))	('adenocarcinoma', 'Disease', (111, 125))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
75439	31765370	SKCM has the highest frequency: approximately 40% of SKCM tumors have GPR98 mutations (Fig 11C and 11H).	('GPR98', 'Gene', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mutations', 'Var', (76, 85))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('SKCM tumors', 'Disease', (53, 64))	('SKCM tumors', 'Disease', 'MESH:D009369', (53, 64))	('GPR98', 'Gene', '84059', (70, 75))
75443	31765370	Frequently mutated GPCRs (e.g., GPR98, GPR112, and BAI3) are more likely to be mutated as Nmut increases (Fig 11E, SKCM as an example).	('BAI3', 'Gene', (51, 55))	('GPCR', 'Gene', (19, 23))	('mutated', 'Var', (79, 86))	('GPR112', 'Gene', '139378', (39, 45))	('GPR98', 'Gene', (32, 37))	('GPR112', 'Gene', (39, 45))	('GPCR', 'Gene', '148', (19, 23))	('GPR98', 'Gene', '84059', (32, 37))	('BAI3', 'Gene', '577', (51, 55))
75444	31765370	The relationship between Nmut and likelihood of GPR98 mutation is similar in SKCM and other cancers (Fig 11F); this is also observed for other frequently mutated GPCRs.	('mutation', 'Var', (54, 62))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('GPR98', 'Gene', '84059', (48, 53))	('GPCR', 'Gene', '148', (162, 166))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('SKCM', 'Disease', (77, 81))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('GPCR', 'Gene', (162, 166))	('GPR98', 'Gene', (48, 53))
75445	31765370	Hence, the likelihood of a GPCR being mutated appears to depend on the accumulation of genome damage and to be independent of the mechanisms for the mutations.	('GPCR', 'Gene', (27, 31))	('mutated', 'Var', (38, 45))	('GPCR', 'Gene', '148', (27, 31))
75447	31765370	Mutations of certain GPCRs, such as GPR98, may thus serve as a bellwether for genome-wide DNA damage.	('GPCR', 'Gene', '148', (21, 25))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('GPCR', 'Gene', (21, 25))	('Mutations', 'Var', (0, 9))	('GPR98', 'Gene', (36, 41))	('GPR98', 'Gene', '84059', (36, 41))
75448	31765370	Missense mutations and in-frame deletions are the most frequent nonsilent mutations in GPCR genes (S8C and S8D Fig and S5 Table).	('in-frame deletions', 'Var', (23, 41))	('GPCR', 'Gene', (87, 91))	('GPCR', 'Gene', '148', (87, 91))	('Missense mutations', 'Var', (0, 18))
75449	31765370	Mutations in frequently mutated GPCRs occur at many sites (S9A Fig), which contrasts with the smaller number of such sites in common oncogenes, e.g., KRAS.	('mutated', 'Var', (24, 31))	('GPCR', 'Gene', (32, 36))	('occur', 'Reg', (38, 43))	('Mutations', 'Var', (0, 9))	('GPCR', 'Gene', '148', (32, 36))	('KRAS', 'Gene', (150, 154))	('KRAS', 'Gene', '3845', (150, 154))
75450	31765370	Certain GPCR genes (e.g., GPR98) may be in genomic regions vulnerable to dysregulation of DNA damage and repair and belong to a subset of mutated genes; GPR98 mutations frequently occur alongside other frequently mutated genes such as TTN and MUC16 (S10A-S10G Fig).	('TTN', 'Gene', (235, 238))	('GPR98', 'Gene', '84059', (26, 31))	('GPCR', 'Gene', (8, 12))	('TTN', 'Gene', '7273', (235, 238))	('MUC16', 'Gene', '94025', (243, 248))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('mutations', 'Var', (159, 168))	('occur', 'Reg', (180, 185))	('GPR98', 'Gene', (153, 158))	('S10A', 'SUBSTITUTION', 'None', (250, 254))	('GPR98', 'Gene', (26, 31))	('GPR98', 'Gene', '84059', (153, 158))	('GPCR', 'Gene', '148', (8, 12))	('MUC16', 'Gene', (243, 248))	('S10G', 'Mutation', 'p.S10G', (255, 259))	('S10A', 'Var', (250, 254))
75456	31765370	Survival analysis of metastatic SKCM samples was performed in order to evaluate the impact on tumors of somatic nonsilent mutations to GPR98, GPR112, or other frequently mutated GPCRs.	('GPCR', 'Gene', '148', (178, 182))	('GPR112', 'Gene', '139378', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('GPR98', 'Gene', (135, 140))	('GPR112', 'Gene', (142, 148))	('mutations', 'Var', (122, 131))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('GPR98', 'Gene', '84059', (135, 140))	('GPCR', 'Gene', (178, 182))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
75459	31765370	We find the same result in other tumor types as well and thus conclude that somatic nonsilent mutations to GPCRs have no impact on patient survival.	('mutations', 'Var', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('GPCR', 'Gene', '148', (107, 111))	('tumor', 'Disease', (33, 38))	('patient', 'Species', '9606', (131, 138))	('GPCR', 'Gene', (107, 111))
75462	31765370	As cell-surface receptors, frequently mutated, well-expressed GPCRs may represent neo-antigens.	('mutated', 'Var', (38, 45))	('GPCR', 'Gene', '148', (62, 66))	('cell-surface', 'Protein', (3, 15))	('GPCR', 'Gene', (62, 66))	('cell-surface', 'cellular_component', 'GO:0009986', ('3', '15'))
75463	31765370	For SKCM, which has the most GPCR mutations among tumors types surveyed, DE analysis of primary melanomas and distant metastases that have or lack GPCR mutations (e.g., GPR98 and LPHN2) revealed little evidence that these mutations alter the tumor transcriptome, implying that such GPCR mutations are likely passenger, rather than driver, mutations (Figs 11H and S8C and S8D).	('LPHN2', 'Gene', '23266', (179, 184))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('mutations', 'Var', (287, 296))	('tumor', 'Disease', (242, 247))	('GPCR', 'Gene', '148', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('GPCR', 'Gene', '148', (147, 151))	('GPCR', 'Gene', (29, 33))	('alter', 'Reg', (232, 237))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('GPCR', 'Gene', '148', (282, 286))	('GPR98', 'Gene', (169, 174))	('GPCR', 'Gene', (147, 151))	('mutations', 'Var', (222, 231))	('GPCR', 'Gene', (282, 286))	('tumor', 'Disease', (50, 55))	('LPHN2', 'Gene', (179, 184))	('melanomas', 'Disease', 'MESH:D008545', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('melanomas', 'Disease', (96, 105))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('metastases', 'Disease', 'MESH:D009362', (118, 128))	('GPR98', 'Gene', '84059', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('metastases', 'Disease', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('tumors', 'Disease', (50, 56))
75464	31765370	Conversely, previous work has suggested that for known oncogenes (e.g., for TP53), there are often widespread transcriptomic changes associated with specific mutations.	('transcriptomic changes', 'MPA', (110, 132))	('mutations', 'Var', (158, 167))	('TP53', 'Gene', (76, 80))	('TP53', 'Gene', '7157', (76, 80))
75465	31765370	We found similar behavior for other tumors (e.g., BLCA) that have frequent GPCR mutations.	('GPCR', 'Gene', '148', (75, 79))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('mutations', 'Var', (80, 89))	('GPCR', 'Gene', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('BLCA', 'Phenotype', 'HP:0009725', (50, 54))
75466	31765370	As a further approach, we evaluated GPCR mutations, predicting the likelihood of functional consequences and site-specific enrichment of the mutations via MutSig 2CV version 3.1 (gdac.broadinstitute.org).	('GPCR', 'Gene', '148', (36, 40))	('GPCR', 'Gene', (36, 40))	('mutations', 'Var', (141, 150))
75467	31765370	The majority of GPCRs frequently mutated (Fig 11I, SKCM as example) show nonsilent mutations that are nonsignificant in terms of enrichment (compared to the background mutation rate of silent mutations over the same regions) for individual mutation sites.	('GPCR', 'Gene', '148', (16, 20))	('GPCR', 'Gene', (16, 20))	('mutated', 'Var', (33, 40))
75468	31765370	These mutations are not predicted to be functional (calculated from estimations of functional impact of mutations based on whether mutated regions are highly evolutionarily conserved) by MutSig 2CV, consistent with the idea that the frequent GPCR mutations are likely passenger and not driver mutations.	('mutations', 'Var', (247, 256))	('GPCR', 'Gene', '148', (242, 246))	('GPCR', 'Gene', (242, 246))
75474	31765370	Single-copy/heterozygous deletions of GPCRs are widespread, whereas homozygous deletions are rare (Fig 13A and 13D).	('GPCR', 'Gene', '148', (38, 42))	('Single-copy/heterozygous', 'Var', (0, 24))	('GPCR', 'Gene', (38, 42))
75484	31765370	However, tumors with amplification of GPR160 show a higher likelihood (approximately 33%, p = 0.003, Fig 13H) of expressing GPR160 at levels above the median for OV.	('GPR160', 'Gene', '26996', (124, 130))	('GPR160', 'Gene', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('OV', 'Phenotype', 'HP:0100615', (162, 164))	('GPR160', 'Gene', (38, 44))	('amplification', 'Var', (21, 34))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('GPR160', 'Gene', '26996', (38, 44))
75489	31765370	In this study, we identified mutations, CNVs, and alterations in mRNA expression of GPCRs in a range of solid tumors.	('GPCR', 'Gene', (84, 88))	('mutations', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('alterations', 'Reg', (50, 61))	('solid tumors', 'Disease', (104, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('mRNA expression', 'MPA', (65, 80))	('GPCR', 'Gene', '148', (84, 88))	('solid tumors', 'Disease', 'MESH:D009369', (104, 116))
75491	31765370	Mutations of certain GPCRs have been implicated in cancer, but a comprehensive analysis of GPCR amplification, expression, and DE has been lacking.	('GPCR', 'Gene', '148', (21, 25))	('implicated', 'Reg', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('GPCR', 'Gene', (21, 25))	('GPCR', 'Gene', (91, 95))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('GPCR', 'Gene', '148', (91, 95))
75495	31765370	Our analysis identified frequently mutated GPCRs (e.g., GPR98/ADGRV1 and GPR112/ADGRG4) in multiple cancers, especially melanoma (SKCM).	('mutated', 'Var', (35, 42))	('GPR98', 'Gene', (56, 61))	('GPCR', 'Gene', '148', (43, 47))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('ADGRG4', 'Gene', (80, 86))	('GPCR', 'Gene', (43, 47))	('GPR112', 'Gene', '139378', (73, 79))	('GPR98', 'Gene', '84059', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('GPR112', 'Gene', (73, 79))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('ADGRV1', 'Gene', '84059', (62, 68))	('ADGRG4', 'Gene', '139378', (80, 86))	('ADGRV1', 'Gene', (62, 68))	('cancers', 'Disease', (100, 107))
75496	31765370	GPCR mutations appear to reflect accumulation of DNA damage and mutations across the genome and may be tumor markers for this process.	('DNA damage', 'MPA', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('GPCR', 'Gene', '148', (0, 4))	('tumor', 'Disease', (103, 108))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('mutations', 'Var', (5, 14))	('GPCR', 'Gene', (0, 4))	('mutations', 'Var', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('accumulation', 'PosReg', (33, 45))
75502	31765370	Known driver mutations do not appear to influence GPCR expression in tumors, but we excluded rare mutations.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('GPCR', 'Gene', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('GPCR', 'Gene', '148', (50, 54))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('mutations', 'Var', (13, 22))
75534	31765370	GPCR mutations, CNV, and DE thus occur at a high frequency in solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('GPCR', 'Gene', '148', (0, 4))	('mutations', 'Var', (5, 14))	('GPCR', 'Gene', (0, 4))	('solid tumors', 'Disease', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('occur', 'Reg', (33, 38))	('solid tumors', 'Disease', 'MESH:D009369', (62, 74))
75551	31765370	The two methods yielded nearly identical results (S11C and S11D Fig).	('S11D', 'SUBSTITUTION', 'None', (59, 63))	('S11C', 'Var', (50, 54))	('S11C', 'SUBSTITUTION', 'None', (50, 54))	('S11D', 'Var', (59, 63))
75553	31765370	EBseq and edgeR yielded very similar results (S11A and S11B Fig), in particular for GPCRs, implying that assumptions implicit in the DE analysis via edgeR/TMM normalization do not skew or bias the results.	('GPCR', 'Gene', (84, 88))	('S11B', 'SUBSTITUTION', 'None', (55, 59))	('S11B', 'Var', (55, 59))	('S11A', 'Var', (46, 50))	('GPCR', 'Gene', '148', (84, 88))	('S11A', 'SUBSTITUTION', 'None', (46, 50))
75587	31765370	In general, DE of GPCRs is similar whether TCGA normal tissue or GTEx tissue is compared to TCGA tumor samples (e.g., S11E and S11F Fig), suggesting that such differences are unlikely to impact upon the general conclusions of this study.	('S11F', 'Mutation', 'p.S11F', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('S11F', 'Var', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('GPCR', 'Gene', '148', (18, 22))	('tumor', 'Disease', (97, 102))	('S11E', 'Mutation', 'p.S11E', (118, 122))	('GPCR', 'Gene', (18, 22))	('GTEx', 'Chemical', '-', (65, 69))
75598	31765370	This method was also used to evaluate the significance of associations between expression of GPCRs and presence of specific driver mutations (e.g., presence or absence of mutations to TP53 or KRAS) and association between GPCR mRNA expression and the thresholded GISTIC 2.0 CNV call.	('absence', 'NegReg', (160, 167))	('association', 'Interaction', (202, 213))	('GPCR', 'Gene', (222, 226))	('TP53', 'Gene', '7157', (184, 188))	('GPCR', 'Gene', '148', (93, 97))	('TP53', 'Gene', (184, 188))	('GPCR', 'Gene', '148', (222, 226))	('KRAS', 'Gene', (192, 196))	('mutations', 'Var', (171, 180))	('GPCR', 'Gene', (93, 97))	('KRAS', 'Gene', '3845', (192, 196))
75697	28347288	The predisposition indicated that stronger the ABCG2 expression, poorer the prognosis.	('prognosis', 'CPA', (76, 85))	('expression', 'Var', (53, 63))	('poorer', 'NegReg', (65, 71))	('stronger', 'PosReg', (34, 42))	('ABCG2', 'Gene', (47, 52))	('ABCG2', 'Gene', '9429', (47, 52))
75707	28347288	Till date, there is one report by Korenaga and colleagues indicating that the ABCG2 polymorphism (C421A) is a risk factor for developing non-papillary RCC.	('risk factor', 'Reg', (110, 121))	('C421A', 'Mutation', 'rs2231142', (98, 103))	('polymorphism (C421A', 'Var', (84, 103))	('ABCG2', 'Gene', (78, 83))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (151, 154))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('ABCG2', 'Gene', '9429', (78, 83))
75709	28347288	With the advent of efficient inhibitors of ABCG2, the combination strategies of targeted drugs and ABCG2 inhibitors might provide the promising therapeutic effect.	('inhibitors', 'Var', (29, 39))	('ABCG2', 'Gene', (43, 48))	('ABCG2', 'Gene', '9429', (99, 104))	('ABCG2', 'Gene', (99, 104))	('ABCG2', 'Gene', '9429', (43, 48))
75717	28347288	ABCG2 is a significant and independent prognostic marker of overall survival in patients with clear cell RCC managed by renal surgery, and its high expression is correlated with poor overall survival and increased metastasis.	('ABCG2', 'Gene', '9429', (0, 5))	('patients', 'Species', '9606', (80, 88))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('metastasis', 'CPA', (214, 224))	('overall', 'MPA', (183, 190))	('high', 'Var', (143, 147))	('RCC', 'Disease', (105, 108))	('increased', 'PosReg', (204, 213))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('poor', 'NegReg', (178, 182))	('ABCG2', 'Gene', (0, 5))
75819	29207627	We confirmed our previous findings that orellanine induces a pronounced increase in ROS (Figure 2A) and in addition, the alterations of ROS also correlated to disturbances in mitochondrial function (Figure 2B-2D).	('rat', 'Species', '10116', (125, 128))	('increase', 'PosReg', (72, 80))	('alterations', 'Var', (121, 132))	('correlated', 'Reg', (145, 155))	('mitochondrial function', 'MPA', (175, 197))	('ROS', 'Chemical', 'MESH:D017382', (136, 139))	('ROS', 'MPA', (84, 87))	('ROS', 'Gene', (136, 139))	('disturbances', 'Reg', (159, 171))	('ROS', 'Chemical', 'MESH:D017382', (84, 87))	('orellanine', 'Chemical', 'MESH:C030076', (40, 50))
75923	32986937	We and others reported candidate biomarkers, such as long non-coding RNAs, 9  gene expression signatures, 10 ,  11 ,  12 ,  13 ,  14 ,  15  epigenetics 16  for ccRCC progression and/or survival.	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('epigenetics 16', 'Var', (140, 154))	('gene expression', 'biological_process', 'GO:0010467', ('78', '93'))	('RCC', 'Disease', (162, 165))
75950	32986937	Cox regression models with nine genes, or clinical prognostic factors (tumor stage and grade) showed AUC of 0.731, 0.737 in TCGA (Figure 4A), 0.783, 0.716 in TCC data set (Figure 4B).	('0.716', 'Var', (149, 154))	('0.737', 'Var', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('TCC', 'cellular_component', 'GO:0005579', ('158', '161'))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('0.783', 'Var', (142, 147))	('tumor', 'Disease', (71, 76))	('0.731', 'Var', (108, 113))
76002	32986937	Dysregulation of gene expression in ccRCC could be caused by various genomic aberrations, such as methylation.	('RCC', 'Disease', (38, 41))	('gene expression', 'biological_process', 'GO:0010467', ('17', '32'))	('methylation', 'biological_process', 'GO:0032259', ('98', '109'))	('caused', 'Reg', (51, 57))	('methylation', 'Var', (98, 109))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
76008	32986937	Future studies are therefore required to validate our results, use immunohistochemistry to assay the corresponding protein expression, as well demonstrate that therapeutic targeting of the identified genes will result in inhibition of tumor growth.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('inhibition', 'NegReg', (221, 231))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', (235, 240))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('genes', 'Var', (200, 205))
76035	31901870	PLP2 was highly expressed in ccRCC tissues, and high PLP2 indicated an advanced tumour stage and grade and poor prognosis.	('tumour', 'Disease', (80, 86))	('PLP2', 'Gene', (53, 57))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('high', 'Var', (48, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('RCC', 'Disease', 'MESH:D002292', (31, 34))	('RCC', 'Disease', (31, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
76039	31901870	Alt-text: Unlabelled box Metabolic abnormalities are a characteristic of tumours, and dysfunction of lipid metabolism is one of the most important features of renal cell carcinoma (RCC), especially the clear cell type (ccRCC).	('RCC', 'Disease', 'MESH:D002292', (221, 224))	('clear cell type', 'Disease', (202, 217))	('RCC', 'Disease', 'MESH:D002292', (181, 184))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (159, 179))	('Alt', 'molecular_function', 'GO:0004021', ('0', '3'))	('Metabolic abnormalities', 'Disease', (25, 48))	('tumours', 'Disease', (73, 80))	('lipid metabolism', 'biological_process', 'GO:0006629', ('101', '117'))	('Metabolic abnormalities', 'Disease', 'MESH:D008659', (25, 48))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('renal cell carcinoma', 'Disease', (159, 179))	('tumours', 'Disease', 'MESH:D009369', (73, 80))	('lipid metabolism', 'MPA', (101, 117))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (159, 179))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('Metabolic abnormalities', 'Phenotype', 'HP:0001939', (25, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('RCC', 'Phenotype', 'HP:0005584', (221, 224))	('RCC', 'Disease', (221, 224))	('dysfunction', 'Var', (86, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (219, 224))	('RCC', 'Disease', (181, 184))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))
76101	31901870	Patients with high POU2F2 or PLP2 expression exhibited shorter OS and DFS times than those with low POU2F2 or PLP2 expression (Fig.	('DFS times', 'MPA', (70, 79))	('PLP2', 'Gene', (29, 33))	('POU2F2', 'Gene', (19, 25))	('expression', 'Var', (34, 44))	('shorter', 'NegReg', (55, 62))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))
76102	31901870	Univariate and multivariate survival analysis of OS and DFS indicated that high PLP2 expression but not high POU2F2 expression was a potential independent prognostic factor in ccRCC patients (Fig.	('expression', 'MPA', (85, 95))	('PLP2', 'Gene', (80, 84))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('high', 'Var', (75, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (176, 181))	('RCC', 'Disease', 'MESH:D002292', (178, 181))	('RCC', 'Disease', (178, 181))	('patients', 'Species', '9606', (182, 190))
76109	31901870	Patients with high PLP2 expression exhibited a higher risk of death and recurrence (Fig.	('recurrence', 'CPA', (72, 82))	('PLP2', 'Gene', (19, 23))	('expression', 'MPA', (24, 34))	('death', 'Disease', 'MESH:D003643', (62, 67))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('death', 'Disease', (62, 67))
76113	31901870	RCC is considered a metabolic disease, and GSEA demonstrated that high PLP2 expression was associated with fatty acid triacylglycerol metabolism, lipid catabolic processes and neutral lipid metabolic processes (Fig.	('fatty acid triacylglycerol', 'Chemical', 'MESH:D014280', (107, 133))	('metabolic disease', 'Disease', (20, 37))	('PLP2', 'Gene', (71, 75))	('metabolic disease', 'Disease', 'MESH:D008659', (20, 37))	('fatty acid triacylglycerol metabolism', 'MPA', (107, 144))	('RCC', 'Disease', 'MESH:D002292', (0, 3))	('high', 'Var', (66, 70))	('lipid catabolic processes', 'MPA', (146, 171))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('triacylglycerol metabolism', 'biological_process', 'GO:0006641', ('118', '144'))	('neutral lipid metabolic processes', 'MPA', (176, 209))	('RCC', 'Disease', (0, 3))	('associated', 'Reg', (91, 101))
76114	31901870	Silencing of PLP2 significantly promoted neutral lipid catabolic processes (involving triacylglycerol) (Fig.	('promoted', 'PosReg', (32, 40))	('neutral lipid catabolic processes', 'MPA', (41, 74))	('PLP2', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))	('triacylglycerol', 'Chemical', 'MESH:D014280', (86, 101))
76119	31901870	A luciferase reporter assay using wild-type (WT) or mutated (MUT) PLP2 in A498 and Caki-1 cells confirmed that miR-765 binds to the 3'-untranslated region (UTR) of PLP2 (Fig.	('binds', 'Interaction', (119, 124))	('PLP2', 'Gene', (66, 70))	('Caki-1', 'CellLine', 'CVCL:0234', (83, 89))	('mutated', 'Var', (52, 59))	('miR-765', 'Gene', '768220', (111, 118))	('miR-765', 'Gene', (111, 118))	('PLP2', 'Gene', (164, 168))
76130	31901870	In addition, PLP2 can reverse the angiogenesis-inhibiting effect with vascular endothelial growth factor A (VEGFA) and tumour metastasis ability by Ki67 of miR-765 (Fig.	('VEGFA', 'Gene', '7422', (108, 113))	('tumour metastasis', 'Disease', (119, 136))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('angiogenesis', 'biological_process', 'GO:0001525', ('34', '46'))	('vascular endothelial growth factor A', 'Gene', (70, 106))	('VEGFA', 'Gene', (108, 113))	('miR-765', 'Gene', '768220', (156, 163))	('Ki67', 'Var', (148, 152))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('70', '104'))	('tumour metastasis', 'Disease', 'MESH:D009362', (119, 136))	('angiogenesis-inhibiting', 'CPA', (34, 57))	('miR-765', 'Gene', (156, 163))	('vascular endothelial growth factor A', 'Gene', '7422', (70, 106))
76146	31901870	GSEA demonstrated that high PLP2 expression was significantly associated with EMT, the G2M checkpoint, fatty acid triacylglycerol metabolism, lipid catabolic processes and neutral lipid metabolic processes in ccRCC.	('triacylglycerol metabolism', 'biological_process', 'GO:0006641', ('114', '140'))	('high', 'Var', (23, 27))	('EMT', 'biological_process', 'GO:0001837', ('78', '81'))	('RCC', 'Disease', (211, 214))	('G2M checkpoint', 'MPA', (87, 101))	('associated', 'Reg', (62, 72))	('RCC', 'Phenotype', 'HP:0005584', (211, 214))	('ccRCC', 'Phenotype', 'HP:0006770', (209, 214))	('RCC', 'Disease', 'MESH:D002292', (211, 214))	('lipid catabolic processes', 'MPA', (142, 167))	('fatty acid triacylglycerol metabolism', 'MPA', (103, 140))	('G2M checkpoint', 'biological_process', 'GO:0000075', ('87', '101'))	('expression', 'MPA', (33, 43))	('neutral lipid metabolic processes', 'MPA', (172, 205))	('EMT', 'CPA', (78, 81))	('PLP2', 'Gene', (28, 32))	('fatty acid triacylglycerol', 'Chemical', 'MESH:D014280', (103, 129))
76147	31901870	Silencing of PLP2 impaired cell proliferation, migration and invasion, promoted neutral lipid catabolic processes and eliminated abnormal lipid accumulation in RCC cells.	('abnormal lipid accumulation', 'Phenotype', 'HP:0003119', (129, 156))	('promoted', 'PosReg', (71, 79))	('eliminated', 'NegReg', (118, 128))	('cell proliferation', 'CPA', (27, 45))	('RCC', 'Disease', 'MESH:D002292', (160, 163))	('RCC', 'Disease', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('invasion', 'CPA', (61, 69))	('migration', 'CPA', (47, 56))	('PLP2', 'Gene', (13, 17))	('neutral lipid catabolic processes', 'MPA', (80, 113))	('Silencing', 'Var', (0, 9))	('impaired', 'NegReg', (18, 26))	('abnormal lipid accumulation', 'MPA', (129, 156))	('cell proliferation', 'biological_process', 'GO:0008283', ('27', '45'))
76172	30995092	The American Urological Association guidelines for management of renal masses considers AS as a potential option for select patients with T1a (<= 4 cm) or T1b (> 4 and <= 7 cm) RCC, particularly those with comorbidities or limited life expectancy.	('As', 'Gene', '112935892', (24, 26))	('as', 'Gene', '112935892', (72, 74))	('AS', 'Gene', '112935892', (88, 90))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('RCC', 'Disease', (177, 180))	('RCC', 'Phenotype', 'HP:0005584', (177, 180))	('T1a (<= 4 cm', 'Var', (138, 150))	('as', 'Gene', '112935892', (91, 93))	('renal masses', 'Phenotype', 'HP:0009726', (65, 77))	('> 4', 'Var', (160, 163))	('patients', 'Species', '9606', (124, 132))
76250	30995092	Intratumoral areas of hypointense signal on shorter-TE opposed-phase images relative to longer-TE in-phase images are secondary to intracytoplasmic microscopic fat and are present in many ccRCCs.	('fat', 'Gene', (160, 163))	('as', 'Gene', '112935892', (103, 105))	('as', 'Gene', '112935892', (65, 67))	('fat', 'Gene', '2195', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('as', 'Gene', '112935892', (142, 144))	('RCC', 'Disease', (190, 193))	('RCC', 'Phenotype', 'HP:0005584', (190, 193))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('as', 'Gene', '112935892', (16, 18))	('tumor', 'Disease', (5, 10))	('hypointense', 'Var', (22, 33))
76258	30995092	found that the presence of SEI at mpMRI was an independent predictor for the diagnosis of oncocytoma (odds ratio = 16.21; 95% CI, 1.0-275.4), but the CI was wide (approaching 1) and the interobserver agreement was only moderate(kappa = 0.49).	('as', 'Gene', '112935892', (41, 43))	('oncocytoma', 'Disease', (90, 100))	('oncocytoma', 'Disease', 'MESH:D018249', (90, 100))	('presence', 'Var', (15, 23))	('as', 'Gene', '112935892', (211, 213))	('as', 'Gene', '112935892', (154, 156))	('mpMRI', 'Gene', (34, 39))
76259	30995092	reported SEI in both oncocytomas and chrRCCs, making the distinction between these two subtypes based on this imaging finding alone not reliable.	('SEI', 'Var', (9, 12))	('RCC', 'Disease', (40, 43))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('as', 'Gene', '112935892', (97, 99))	('oncocytomas', 'Disease', (21, 32))	('oncocytomas', 'Disease', 'MESH:D018249', (21, 32))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('as', 'Gene', '112935892', (30, 32))
76261	30995092	The hypointensity on T2-weighted imaging also is common with pRCC, but some differences exist that help in differentiation.	('pRCC', 'Gene', (61, 65))	('hypointensity', 'Var', (4, 17))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('pRCC', 'Gene', '5546', (61, 65))
76275	30995092	However, DWI may aid in the differentiation of some histologic subtypes, particularly when included in a comprehensive mpMRI assessment (discussed later), and may help in estimating tumor grade.	('help', 'Reg', (163, 167))	('as', 'Gene', '112935892', (125, 127))	('tumor', 'Disease', (182, 187))	('aid', 'Gene', (17, 20))	('DWI', 'Var', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('aid', 'Gene', '57379', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
76280	30995092	The first step in the algorithm by Kay and Pedrosa assesses the signal intensity on T2-weighted images and determines whether the lesion is hyper-, iso-, or hypointense relative to renal cortex.	('as', 'Gene', '112935892', (51, 53))	('signal intensity', 'MPA', (64, 80))	('hypointense', 'Var', (157, 168))	('hyper-', 'Var', (140, 146))	('iso-', 'Var', (148, 152))
76288	30995092	Among T2-isointense masses, ccRCC is suspected if the mass is heterogeneous or has microscopic fat, oncocytoma is suspected if SEI is present, chrRCC is suspected if moderately enhancing and homogeneous, and pRCC is suspected if there is mild progressive enhancement.	('fat', 'Gene', (95, 98))	('pRCC', 'Gene', '5546', (208, 212))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (209, 212))	('RCC', 'Disease', (209, 212))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('RCC', 'Disease', 'MESH:C538614', (209, 212))	('oncocytoma', 'Disease', (100, 110))	('pRCC', 'Gene', (208, 212))	('T2-isointense', 'Var', (6, 19))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('as', 'Gene', '112935892', (80, 82))	('as', 'Gene', '112935892', (55, 57))	('fat', 'Gene', '2195', (95, 98))	('RCC', 'Disease', (30, 33))	('heterogeneous', 'MPA', (62, 75))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('oncocytoma', 'Disease', 'MESH:D018249', (100, 110))	('as', 'Gene', '112935892', (21, 23))
76295	30995092	For example, a mass showing hyperintense signal on T2-weighted images, intense enhancement, and microscopic fat would receive a ccLS of 5 (highly likely ccRCC), whereas a mass showing hypointense signal on T2-weighted images and mild progressive enhancement would be designated a ccLS of 1 (very unlikely ccRCC).	('enhancement', 'PosReg', (79, 90))	('RCC', 'Disease', (155, 158))	('as', 'Gene', '112935892', (172, 174))	('RCC', 'Disease', 'MESH:C538614', (307, 310))	('ccLS', 'Chemical', '-', (128, 132))	('RCC', 'Disease', (307, 310))	('RCC', 'Phenotype', 'HP:0005584', (307, 310))	('as', 'Gene', '112935892', (166, 168))	('ccLS', 'Chemical', '-', (280, 284))	('as', 'Gene', '112935892', (16, 18))	('fat', 'Gene', (108, 111))	('ccLS', 'Var', (128, 132))	('fat', 'Gene', '2195', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('RCC', 'Disease', 'MESH:C538614', (155, 158))
76315	30995092	Incorporation of mpMRI into the workup of an indeterminate renal mass could reduce the number of biopsies, expedite treatment in high-risk patients, minimize complications, and potentially reduce the cost of care.	('as', 'Gene', '112935892', (66, 68))	('Incorporation', 'Var', (0, 13))	('patients', 'Species', '9606', (139, 147))	('reduce', 'NegReg', (76, 82))	('reduce', 'NegReg', (189, 195))	('mpMRI', 'Gene', (17, 22))
76384	30668544	MiR-223-3p overexpression significantly enhanced the proliferation of 786-O and Caki-1 cells (Figure 2E), while miR-223-3p knockdown significantly reduced their proliferation (Figure 2F).	('Caki-1', 'CellLine', 'CVCL:0234', (80, 86))	('reduced', 'NegReg', (147, 154))	('rat', 'Species', '10116', (60, 63))	('miR-223', 'Gene', '407008', (112, 119))	('MiR-223', 'Gene', '407008', (0, 7))	('proliferation', 'CPA', (53, 66))	('Caki-1 cells', 'CPA', (80, 92))	('rat', 'Species', '10116', (168, 171))	('knockdown', 'Var', (123, 132))	('MiR-223', 'Gene', (0, 7))	('enhanced', 'PosReg', (40, 48))	('miR-223', 'Gene', (112, 119))	('proliferation', 'CPA', (161, 174))
76397	30668544	Luciferase reporter constructs containing either wild-type or mutated SLC4A4 binding sequences upstream of the firefly luciferase gene were generated (Figure 4E).	('binding', 'molecular_function', 'GO:0005488', ('77', '84'))	('rat', 'Species', '10116', (144, 147))	('SLC4A4', 'Gene', (70, 76))	('mutated', 'Var', (62, 69))
76416	30668544	Furthermore, SLC4A4 vector transfection markedly inhibited the migration and invasion of Caki-1 cells in Transwell assays (Figure 6H and 6I).	('SLC4A4', 'Gene', (13, 19))	('transfection', 'Var', (27, 39))	('Caki-1', 'CellLine', 'CVCL:0234', (89, 95))	('rat', 'Species', '10116', (66, 69))	('inhibited', 'NegReg', (49, 58))
76423	30668544	Aberrant miRNA expression is known to be associated with cancer cell proliferation, invasion and metastasis, and miR-223-3p expression is dysregulated in many tumors.	('invasion', 'CPA', (84, 92))	('associated', 'Reg', (41, 51))	('cancer', 'Disease', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('metastasis', 'CPA', (97, 107))	('tumors', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('miR', 'Gene', '220972', (113, 116))	('Aberrant', 'Var', (0, 8))	('miR-223', 'Gene', '407008', (113, 120))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('miR', 'Gene', '220972', (9, 12))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('miR', 'Gene', (113, 116))	('miR', 'Gene', (9, 12))	('rat', 'Species', '10116', (76, 79))	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('miR-223', 'Gene', (113, 120))
76496	30895194	The molecular pathogenesis of carcinoma was complex, which was associated with inactivation and mutation of tumor suppressor genes and activation of oncogene.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('activation', 'PosReg', (135, 145))	('tumor suppressor', 'biological_process', 'GO:0051726', ('108', '124'))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('oncogene', 'Gene', (149, 157))	('inactivation', 'Var', (79, 91))	('pathogenesis', 'biological_process', 'GO:0009405', ('14', '26'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('108', '124'))	('mutation', 'Var', (96, 104))	('tumor', 'Disease', (108, 113))	('carcinoma', 'Disease', 'MESH:D002277', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('carcinoma', 'Disease', (30, 39))
76504	30895194	The platform for GDS505 and GDS2881 was GPL96, [HG-U133A] Affymetrix Human Genome U133A Array, and for GDS507 and GDS2880 was GPL97, [HG-U133B] Affymetrix Human Genome U133B Array.	('GDS', 'molecular_function', 'GO:0005085', ('103', '106'))	('GDS', 'molecular_function', 'GO:0005085', ('17', '20'))	('Human', 'Species', '9606', (69, 74))	('GDS507', 'Var', (103, 109))	('GDS', 'molecular_function', 'GO:0005085', ('28', '31'))	('GDS', 'molecular_function', 'GO:0005085', ('114', '117'))	('Human', 'Species', '9606', (155, 160))	('GDS2880', 'Var', (114, 121))	('GDS2881', 'Var', (28, 35))
76505	30895194	The data consisted of 38 ccRCC tissues (9 in GDS505, 9 in GDS507, 10 in GDS2880, and 10 in GDS2881) and 36 matched normal tissues (8 in GDS505, 8 in GDS507, 10 in GDS2880, and 10 in GDS2881).	('GDS', 'molecular_function', 'GO:0005085', ('91', '94'))	('GDS', 'molecular_function', 'GO:0005085', ('45', '48'))	('GDS', 'molecular_function', 'GO:0005085', ('182', '185'))	('GDS', 'molecular_function', 'GO:0005085', ('149', '152'))	('GDS', 'molecular_function', 'GO:0005085', ('136', '139'))	('GDS', 'molecular_function', 'GO:0005085', ('163', '166'))	('GDS505', 'Var', (45, 51))	('GDS', 'molecular_function', 'GO:0005085', ('72', '75'))	('ccRCC', 'Phenotype', 'HP:0006770', (25, 30))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('GDS', 'molecular_function', 'GO:0005085', ('58', '61'))
76512	30895194	Exclusion criteria were as follows: (1) abstract, comment, review, and meeting; (2) EGFR expression detected by Western blot, RT-PCR; (3) lack of sufficient information; (4) duplication.	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', (84, 88))	('duplication', 'Var', (174, 185))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))
76515	30895194	Four pathways associated with DEGs were enriched (Figure 4), HIF-1 signaling pathway, bile secretion, carbon metabolism, and fructose and mannose metabolism.	('carbon', 'Chemical', 'MESH:D002244', (102, 108))	('carbon metabolism', 'MPA', (102, 119))	('fructose', 'Chemical', 'MESH:D005632', (125, 133))	('secretion', 'biological_process', 'GO:0046903', ('91', '100'))	('HIF-1', 'Gene', '3091', (61, 66))	('DEGs', 'Var', (30, 34))	('mannose metabolism', 'biological_process', 'GO:0006013', ('138', '156'))	('bile secretion', 'MPA', (86, 100))	('mannose', 'Chemical', 'MESH:D008358', (138, 145))	('metabolism', 'biological_process', 'GO:0008152', ('109', '119'))	('HIF-1', 'Gene', (61, 66))	('signaling pathway', 'biological_process', 'GO:0007165', ('67', '84'))
76544	30895194	Amplification and mutations of EGFR have been shown to be driving events in many cancers, like non-small cell lung cancer, renal carcinoma, and basal-like breast cancers.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (95, 121))	('cancers', 'Disease', (162, 169))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('breast cancers', 'Disease', 'MESH:D001943', (155, 169))	('breast cancers', 'Disease', (155, 169))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (99, 121))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('EGFR', 'Gene', '1956', (31, 35))	('renal carcinoma', 'Disease', 'MESH:C538614', (123, 138))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (95, 121))	('breast cancers', 'Phenotype', 'HP:0003002', (155, 169))	('renal carcinoma', 'Disease', (123, 138))	('renal carcinoma', 'Phenotype', 'HP:0005584', (123, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('events', 'Reg', (66, 72))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('EGFR', 'molecular_function', 'GO:0005006', ('31', '35'))	('non-small cell lung cancer', 'Disease', (95, 121))	('Amplification', 'Var', (0, 13))	('EGFR', 'Gene', (31, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('mutations', 'Var', (18, 27))
76560	31959726	Moreover, patients with HHLA2/PD-L1 co-expression suffered the highest risk of disease progression and death by a significant margin.	('disease progression', 'CPA', (79, 98))	('co-expression', 'Var', (36, 49))	('HHLA2', 'Gene', '11148', (24, 29))	('HHLA2', 'Gene', (24, 29))	('patients', 'Species', '9606', (10, 18))
76586	31959726	HHLA2 was also reported to be overexpressed in RCC, compared with normal renal tissue, and the expression of HHLA2 was associated with poor prognosis of RCC.	('HHLA2', 'Gene', (109, 114))	('HHLA2', 'Gene', (0, 5))	('expression', 'Var', (95, 105))	('RCC', 'Disease', 'MESH:D002292', (153, 156))	('RCC', 'Disease', (153, 156))	('HHLA2', 'Gene', '11148', (0, 5))	('HHLA2', 'Gene', '11148', (109, 114))	('RCC', 'Disease', 'MESH:D002292', (47, 50))	('RCC', 'Disease', (47, 50))	('overexpressed', 'PosReg', (30, 43))	('associated', 'Reg', (119, 129))
76610	31959726	The HHLA2 positivity was significantly correlated with necrosis (p=0.001 for both cohorts), high Fuhrman grade (training cohort: p<0.001; validation cohort: p=0.032), and advanced TNM stage (training cohort: p<0.001; validation cohort: p=0.008) in both cohorts.	('necrosis', 'biological_process', 'GO:0008219', ('55', '63'))	('TNM', 'Gene', (180, 183))	('necrosis', 'biological_process', 'GO:0019835', ('55', '63'))	('necrosis', 'Disease', (55, 63))	('necrosis', 'biological_process', 'GO:0008220', ('55', '63'))	('HHLA2', 'Gene', (4, 9))	('correlated', 'Reg', (39, 49))	('high Fuhrman grade', 'CPA', (92, 110))	('necrosis', 'biological_process', 'GO:0001906', ('55', '63'))	('positivity', 'Var', (10, 20))	('TNM', 'Gene', '10178', (180, 183))	('necrosis', 'Disease', 'MESH:D009336', (55, 63))	('HHLA2', 'Gene', '11148', (4, 9))	('necrosis', 'biological_process', 'GO:0070265', ('55', '63'))
76611	31959726	Additionally, the HHLA2 positivity was associated with microvascular invasion (MVI) (p=0.035) in the training cohort, but not in the validation cohort.	('associated with', 'Reg', (39, 54))	('positivity', 'Var', (24, 34))	('HHLA2', 'Gene', (18, 23))	('microvascular', 'Disease', (55, 68))	('HHLA2', 'Gene', '11148', (18, 23))
76613	31959726	Similarly, in two cohorts, PD-L1 positivity was significantly associated with necrosis (p=0.041 and 0.001, respectively), high Fuhrman grade (p=0.002 and 0.003, respectively) and advanced TNM stage (p=0.003 and 0.002, respectively).	('TNM', 'Gene', '10178', (188, 191))	('necrosis', 'Disease', 'MESH:D009336', (78, 86))	('associated', 'Reg', (62, 72))	('TNM', 'Gene', (188, 191))	('high Fuhrman grade', 'CPA', (122, 140))	('necrosis', 'biological_process', 'GO:0070265', ('78', '86'))	('necrosis', 'biological_process', 'GO:0008219', ('78', '86'))	('necrosis', 'biological_process', 'GO:0019835', ('78', '86'))	('positivity', 'Var', (33, 43))	('necrosis', 'biological_process', 'GO:0008220', ('78', '86'))	('necrosis', 'Disease', (78, 86))	('PD-L1', 'Gene', (27, 32))	('necrosis', 'biological_process', 'GO:0001906', ('78', '86'))
76616	31959726	Kaplan-Meier analysis revealed that HHLA2 positivity was significantly associated with worse PFS and OS in the training cohort (training cohort, PFS: p<0.001; OS: p<0.001) and in the validation cohort (PFS: p<0.001, OS: p<0.001) (figure 2A).	('PFS', 'Disease', (93, 96))	('positivity', 'Var', (42, 52))	('HHLA2', 'Gene', '11148', (36, 41))	('HHLA2', 'Gene', (36, 41))
76634	31959726	Previous studies reported that high expression of HHLA2 was associated with poor prognosis in ccRCC; moreover, high HHLA2 expression was an independent risk factor for the prognosis of ccRCC.	('ccRCC', 'Disease', (94, 99))	('expression', 'MPA', (122, 132))	('ccRCC', 'Disease', 'MESH:D002292', (94, 99))	('HHLA2', 'Gene', (50, 55))	('HHLA2', 'Gene', (116, 121))	('HHLA2', 'Gene', '11148', (50, 55))	('ccRCC', 'Disease', (185, 190))	('HHLA2', 'Gene', '11148', (116, 121))	('ccRCC', 'Disease', 'MESH:D002292', (185, 190))	('high', 'Var', (111, 115))
76637	31959726	Furthermore, high expression of HHLA2 was an independent prognostic factor in both cohorts after adjusting for necrosis, MVI, Fuhrman grade, and TNM stage.	('HHLA2', 'Gene', (32, 37))	('necrosis', 'biological_process', 'GO:0001906', ('111', '119'))	('HHLA2', 'Gene', '11148', (32, 37))	('TNM', 'Gene', '10178', (145, 148))	('high expression', 'Var', (13, 28))	('necrosis', 'Disease', (111, 119))	('necrosis', 'biological_process', 'GO:0070265', ('111', '119'))	('necrosis', 'Disease', 'MESH:D009336', (111, 119))	('TNM', 'Gene', (145, 148))	('necrosis', 'biological_process', 'GO:0008219', ('111', '119'))	('necrosis', 'biological_process', 'GO:0019835', ('111', '119'))	('necrosis', 'biological_process', 'GO:0008220', ('111', '119'))
76642	31959726	We found that HHLA2/PD-L1 co-expression was significantly associated with the TNM stage, which acted as an independent prognostic factor for shorter PFS and OS.	('co-expression', 'Var', (26, 39))	('associated', 'Reg', (58, 68))	('TNM', 'Gene', (78, 81))	('HHLA2', 'Gene', (14, 19))	('HHLA2', 'Gene', '11148', (14, 19))	('TNM', 'Gene', '10178', (78, 81))
76680	32038982	These RNA modifications are reported to be several forms, such as N7-methyladenosine, 5-methylcytosine, N6-methyladenosine (m6A), and 2'-O-methylaion.	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('m6A', 'Gene', '56339', (124, 127))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (86, 102))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (104, 122))	('N7-methyladenosine', 'Chemical', 'MESH:C010223', (66, 84))	("2'-O-methylaion", 'Chemical', 'MESH:D013481', (134, 149))	('N7-methyladenosine', 'Var', (66, 84))	('N6-methyladenosine', 'Var', (104, 122))	('m6A', 'Gene', (124, 127))
76686	32038982	Accumulating evidences have suggested the fact that the dysregulated expression of m6A RNA methylation regulators are involved in the initiation and development of human cancers.	('m6A', 'Gene', (83, 86))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('RNA', 'cellular_component', 'GO:0005562', ('87', '90'))	('dysregulated', 'Var', (56, 68))	('cancers', 'Disease', (170, 177))	('human', 'Species', '9606', (164, 169))	('m6A', 'Gene', '56339', (83, 86))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('expression', 'MPA', (69, 79))	('involved', 'Reg', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('RNA methylation', 'biological_process', 'GO:0001510', ('87', '102'))
76688	32038982	High expression of YTHDF1 was found to be associated with advanced stages and unfavorable prognosis in hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (103, 127))	('High', 'Var', (0, 4))	('YTHDF1', 'Gene', '54915', (19, 25))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (103, 127))	('associated', 'Reg', (42, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('hepatocellular carcinoma', 'Disease', (103, 127))	('YTHDF1', 'Gene', (19, 25))
76690	32038982	Recently, a research focused on the mutations and copy number variants of 10 m6A regulatory genes in ccRCC and found copy number variants of these regulatory genes closely correlated with pathologic stage and prognosis of patients with ccRCC.	('ccRCC', 'Disease', 'MESH:D002292', (101, 106))	('RCC', 'Phenotype', 'HP:0005584', (238, 241))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (236, 241))	('ccRCC', 'Disease', (236, 241))	('patients', 'Species', '9606', (222, 230))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('copy number variants', 'Var', (117, 137))	('m6A', 'Gene', (77, 80))	('ccRCC', 'Disease', 'MESH:D002292', (236, 241))	('copy number variants', 'Var', (50, 70))	('m6A', 'Gene', '56339', (77, 80))	('correlated', 'Reg', (172, 182))	('ccRCC', 'Disease', (101, 106))
76702	32038982	Then, the differentially expressed m6A methylation regulators between tumor tissues and normal tissues were verified by two gene expression profiles (GSE14994 and GSE15641), which were downloaded from Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/).	('m6A', 'Gene', (35, 38))	('GSE15641', 'Var', (163, 171))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('m6A', 'Gene', '56339', (35, 38))	('Gene Expression', 'biological_process', 'GO:0010467', ('201', '216'))	('tumor', 'Disease', (70, 75))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('gene expression', 'biological_process', 'GO:0010467', ('124', '139'))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
76731	32038982	The results showed that ccRCC patients with high METTL14 expression had favorable prognosis (Figure 4D), while ccRCC patients with high METTL3 expression had bad prognosis (Figure 4E), which was in accordance with the LASSSO results and this partly strength the reliability of our findings.	('METTL3', 'Gene', '56339', (136, 142))	('high', 'Var', (44, 48))	('METTL3', 'Gene', (136, 142))	('ccRCC', 'Disease', 'MESH:D002292', (111, 116))	('METTL14', 'Gene', (49, 56))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('METTL14', 'Gene', '57721', (49, 56))	('ccRCC', 'Phenotype', 'HP:0006770', (24, 29))	('ccRCC', 'Disease', (24, 29))	('patients', 'Species', '9606', (30, 38))	('ccRCC', 'Disease', 'MESH:D002292', (24, 29))	('patients', 'Species', '9606', (117, 125))	('ccRCC', 'Disease', (111, 116))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))
76772	32038982	However, another research demonstrated that METTL14 functioned as an oncogene to promote tumorigenesis by mRNA m6A modification in leukemia.	('promote', 'PosReg', (81, 88))	('m6A', 'Gene', (111, 114))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('m6A', 'Gene', '56339', (111, 114))	('leukemia', 'Phenotype', 'HP:0001909', (131, 139))	('METTL14', 'Gene', '57721', (44, 51))	('leukemia', 'Disease', 'MESH:D007938', (131, 139))	('METTL14', 'Gene', (44, 51))	('leukemia', 'Disease', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('modification', 'Var', (115, 127))
76775	32038982	Then, the researchers also found that low level of METTL3 was associated with larger tumor size and higher histological grade in vivo study, and could promote RCC cell proliferation, migration and invasion function and induced G0/G1 arrest in vitro study.	('tumor', 'Disease', (85, 90))	('G0/G1 arrest', 'CPA', (227, 239))	('RCC', 'Disease', 'MESH:D002292', (159, 162))	('low level', 'Var', (38, 47))	('migration', 'CPA', (183, 192))	('METTL3', 'Gene', '56339', (51, 57))	('induced', 'Reg', (219, 226))	('METTL3', 'Gene', (51, 57))	('promote', 'PosReg', (151, 158))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cell proliferation', 'biological_process', 'GO:0008283', ('163', '181'))	('invasion function', 'CPA', (197, 214))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))
76780	32038982	In summary, dysregulation of m6A RNA methylation regulators were highly correlated with tumor progression and prognosis in ccRCC.	('correlated', 'Reg', (72, 82))	('dysregulation', 'Var', (12, 25))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('ccRCC', 'Disease', (123, 128))	('RNA methylation', 'biological_process', 'GO:0001510', ('33', '48'))	('m6A', 'Gene', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('ccRCC', 'Disease', 'MESH:D002292', (123, 128))	('m6A', 'Gene', '56339', (29, 32))	('tumor', 'Disease', (88, 93))	('RNA', 'cellular_component', 'GO:0005562', ('33', '36'))
76793	32038982	Additionally, the prognostic value of signature for low grade and high grade, early stage and later stage ccRCC was also noted.	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('low grade', 'Var', (52, 61))	('ccRCC', 'Disease', (106, 111))	('ccRCC', 'Disease', 'MESH:D002292', (106, 111))	('high grade', 'Var', (66, 76))
76823	29296184	Likewise the loss of E-cadherin induces an integrin alpha5 dependent spread of tumor cells in ovarian cancer.	('ovarian cancer', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('ovarian cancer', 'Disease', 'MESH:D010051', (94, 108))	('ovarian cancer', 'Phenotype', 'HP:0100615', (94, 108))	('E-cadherin', 'Gene', (21, 31))	('E-cadherin', 'Gene', '999', (21, 31))	('loss', 'Var', (13, 17))	('induces', 'Reg', (32, 39))	('cadherin', 'molecular_function', 'GO:0008014', ('23', '31'))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
76833	29296184	The correlation of the integrin alpha5 expression level in RCC tissue to several prognostic factors of the patients (Table 1) showed a significantly higher integrin alpha5 level in G3/G4 tumors than in G1/G2 tumors with a median of 2.11 and 1.71, respectively (p = 0.047, Figure 2).	('G2 tumors', 'Disease', (205, 214))	('G3/G4', 'Var', (181, 186))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('G2 tumors', 'Disease', 'MESH:C563949', (205, 214))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('higher', 'PosReg', (149, 155))	('integrin alpha5 level', 'MPA', (156, 177))	('patients', 'Species', '9606', (107, 115))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
76845	29296184	Integrin alpha5 blockade resulted in a decreased cell migration to 51% (p = 0.01) in Caki-1 and 30% (p < 0.001) in CCF-RC1 referred to untreated cells.	('cell migration', 'biological_process', 'GO:0016477', ('49', '63'))	('blockade', 'Var', (16, 24))	('Integrin alpha5', 'Gene', (0, 15))	('RC1', 'Gene', (119, 122))	('cell migration', 'CPA', (49, 63))	('Integrin alpha5', 'Gene', '3678', (0, 15))	('Caki-1', 'CellLine', 'CVCL:0234', (85, 91))	('decreased', 'NegReg', (39, 48))	('RC1', 'Gene', '57332', (119, 122))
76863	29296184	This observation is in good accordance with findings in other tumor entities like in esophageal squamous cell carcinoma where integrin alpha5 correlates with a worse overall survival and is associated with lymph node metastasis.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('integrin', 'Var', (126, 134))	('overall survival', 'MPA', (166, 182))	('esophageal squamous cell carcinoma', 'Disease', (85, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('tumor', 'Disease', (62, 67))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (85, 119))	('associated with', 'Reg', (190, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('worse', 'NegReg', (160, 165))
76871	29296184	In accordance with the situation in colon carcinoma cells, blocking of integrin alpha5 led to a decrease in cell adhesion of Caki-1 and CCF-RC1 cells and to a decrease of the chemotactic migration in direction to fibronectin.	('integrin alpha5', 'Protein', (71, 86))	('RC1', 'Gene', (140, 143))	('blocking', 'Var', (59, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('decrease', 'NegReg', (96, 104))	('fibronectin', 'Gene', '2335', (213, 224))	('chemotactic migration in direction', 'CPA', (175, 209))	('decrease', 'NegReg', (159, 167))	('cell adhesion', 'CPA', (108, 121))	('cell adhesion', 'biological_process', 'GO:0007155', ('108', '121'))	('colon carcinoma', 'Disease', 'MESH:D015179', (36, 51))	('Caki-1', 'CellLine', 'CVCL:0234', (125, 131))	('fibronectin', 'Gene', (213, 224))	('colon carcinoma', 'Disease', (36, 51))	('RC1', 'Gene', '57332', (140, 143))
76904	29296184	These two cell lines have a VHL deletion.	('VHL', 'Gene', (28, 31))	('deletion', 'Var', (32, 40))	('VHL', 'Gene', '7428', (28, 31))
76906	29296184	These tow cell lines have no VHL mutation or deletion.	('VHL', 'Gene', (29, 32))	('deletion', 'Var', (45, 53))	('mutation', 'Var', (33, 41))	('VHL', 'Gene', '7428', (29, 32))
76939	29296184	Cells of the intervention group were after 30 minutes treated with 10 mug/ml P1D6 anti-integrin alpha5 antibody and with 10 mug/ml fibronectin after one hour.	('mug', 'molecular_function', 'GO:0043739', ('70', '73'))	('mug', 'molecular_function', 'GO:0043739', ('124', '127'))	('antibody', 'cellular_component', 'GO:0042571', ('103', '111'))	('P1D6', 'Var', (77, 81))	('antibody', 'cellular_component', 'GO:0019815', ('103', '111'))	('fibronectin', 'Gene', (131, 142))	('antibody', 'cellular_component', 'GO:0019814', ('103', '111'))	('antibody', 'molecular_function', 'GO:0003823', ('103', '111'))	('fibronectin', 'Gene', '2335', (131, 142))
76956	27488395	This study was designed to elucidate the prognostic significance of DEF6, p53 and p16 immunoexpressions in different histology subtypes of ovarian carcinoma.	('ovarian carcinoma', 'Disease', 'MESH:D010051', (139, 156))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (139, 156))	('p16', 'Gene', (82, 85))	('ovarian carcinoma', 'Disease', (139, 156))	('p53', 'Gene', (74, 77))	('p16', 'Gene', '1029', (82, 85))	('DEF6', 'Var', (68, 72))	('p53', 'Gene', '7157', (74, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
76957	27488395	Immunohistochemistry results of DEF6, p53 and p16 on ovarian carcinoma were compared with histology subtypes, clinical data, overall survival (OS) and disease-free survival (DFS) by Cox regression and Kaplan-Meier analysis.	('p53', 'Gene', (38, 41))	('Cox', 'Gene', (182, 185))	('p53', 'Gene', '7157', (38, 41))	('Cox', 'Gene', '1351', (182, 185))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (53, 70))	('p16', 'Gene', '1029', (46, 49))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (53, 70))	('ovarian carcinoma', 'Disease', (53, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('DEF6', 'Var', (32, 36))	('p16', 'Gene', (46, 49))
76960	27488395	Aberrant p53 expression combined with positive DEF6 was associated with worst OS (P = 0.031) and DFS (P = 0.028).	('worst OS', 'Disease', (72, 80))	('Aberrant', 'Var', (0, 8))	('expression', 'MPA', (13, 23))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('DFS', 'Disease', (97, 100))
76962	27488395	Patients with aberrant p53 expression in high-grade serous carcinoma (P = 0.012) and patients with high DEF6 expression in clear cell carcinoma (P = 0.001) were also associated with shorter overall survival.	('serous carcinoma', 'Disease', (52, 68))	('serous carcinoma', 'Disease', 'MESH:D018284', (52, 68))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (123, 143))	('shorter', 'NegReg', (182, 189))	('clear cell carcinoma', 'Disease', (123, 143))	('expression', 'MPA', (27, 37))	('aberrant', 'Var', (14, 22))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('p53', 'Gene', (23, 26))	('overall', 'MPA', (190, 197))	('p53', 'Gene', '7157', (23, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))
76963	27488395	In univariate analysis, FIGO stage, DEF6 and p16 were associated with poor prognosis.	('FIGO', 'Disease', (24, 28))	('p16', 'Gene', '1029', (45, 48))	('p16', 'Gene', (45, 48))	('DEF6', 'Var', (36, 40))
76969	27488395	Loss of DEF6 in mice resulted in the development of systemic autoimmunity and developmental defects at the earliest stage of thymocyte differentiation.	('systemic autoimmunity', 'Disease', (52, 73))	('autoimmunity', 'Phenotype', 'HP:0002960', (61, 73))	('systemic autoimmunity', 'Disease', 'MESH:D001327', (52, 73))	('mice', 'Species', '10090', (16, 20))	('DEF6', 'Gene', (8, 12))	('thymocyte differentiation', 'biological_process', 'GO:0033077', ('125', '150'))	('Loss', 'Var', (0, 4))
76974	27488395	High levels of DEF6 were found to decrease cisplatin-induced growth suppression and apoptotic cell death, in association with decreased p53 activity and imbalanced expressions of the Bcl-2 family members.	('decreased', 'NegReg', (126, 135))	('Bcl-2', 'molecular_function', 'GO:0015283', ('183', '188'))	('growth suppression', 'CPA', (61, 79))	('apoptotic cell death', 'CPA', (84, 104))	('p53', 'Gene', '7157', (136, 139))	('Bcl-2', 'Gene', (183, 188))	('Bcl-2', 'Gene', '596', (183, 188))	('decrease', 'NegReg', (34, 42))	('DEF6', 'Var', (15, 19))	('cisplatin-induced', 'MPA', (43, 60))	('imbalanced expressions', 'MPA', (153, 175))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('84', '104'))	('activity', 'MPA', (140, 148))	('p53', 'Gene', (136, 139))
76977	27488395	Despite their potential close interaction in cell cycle progression, the roles of DEF6, p16 and p53 have not been fully elucidated in ovarian carcinomas.	('p16', 'Gene', (88, 91))	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (134, 152))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('p16', 'Gene', '1029', (88, 91))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (134, 152))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (134, 151))	('DEF6', 'Var', (82, 86))	('cell cycle', 'biological_process', 'GO:0007049', ('45', '55'))	('ovarian carcinomas', 'Disease', (134, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('interaction', 'Reg', (30, 41))
76979	27488395	Clinicopathological data and survival curves were compared between patients with different scores of DEF6 to explore the potential of DEF6 as a prognostic marker.	('DEF6', 'Gene', (101, 105))	('scores', 'Var', (91, 97))	('patients', 'Species', '9606', (67, 75))
76997	27488395	ES-2 (clear cell carcinoma), TOV-21G (clear cell carcinoma) and TOV-112D (endometrioid carcinoma) were obtained from ATCC bioresource center (Manassas, VA, USA).	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('clear cell carcinoma', 'Disease', (6, 26))	('TOV-112D', 'Var', (64, 72))	('clear cell carcinoma', 'Disease', (38, 58))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (6, 26))	('ES-2', 'Gene', '8220', (0, 4))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (74, 96))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (38, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (74, 96))	('ES-2', 'Gene', (0, 4))	('endometrioid carcinoma', 'Disease', (74, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
77009	27488395	As shown in Table 1, immunoexpressions of DEF6, p53 and p16 showed significant correlation with different histological subtypes of ovarian carcinoma.	('p53', 'Gene', (48, 51))	('DEF6', 'Var', (42, 46))	('correlation', 'Reg', (79, 90))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (131, 148))	('p16', 'Gene', '1029', (56, 59))	('p53', 'Gene', '7157', (48, 51))	('ovarian carcinoma', 'Disease', (131, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('p16', 'Gene', (56, 59))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (131, 148))
77012	27488395	Aberrant p53 expression was also observed in 82.7 % of high-grade serous carcinoma.	('serous carcinoma', 'Disease', (66, 82))	('serous carcinoma', 'Disease', 'MESH:D018284', (66, 82))	('Aberrant', 'Var', (0, 8))	('expression', 'MPA', (13, 23))	('observed', 'Reg', (33, 41))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
77016	27488395	In summary, high-grade serous carcinoma showed the highest frequencies of increased DEF6 and p16 expressions, as well as aberrant p53 expression.	('expression', 'MPA', (134, 144))	('p16', 'Gene', '1029', (93, 96))	('DEF6', 'Gene', (84, 88))	('increased', 'PosReg', (74, 83))	('serous carcinoma', 'Disease', (23, 39))	('aberrant', 'Var', (121, 129))	('p16', 'Gene', (93, 96))	('serous carcinoma', 'Disease', 'MESH:D018284', (23, 39))	('expressions', 'MPA', (97, 108))	('p53', 'Gene', (130, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('p53', 'Gene', '7157', (130, 133))
77020	27488395	The level of DEF6 in A2780 (unknown histology subtype) and TOV-21G (clear cell carcinoma) was comparatively low among the six cells, however, they revealed a double-band pattern on the DEF6 region as similar to the oral carcinoma cells.	('clear cell carcinoma', 'Disease', (68, 88))	('oral carcinoma', 'Disease', 'MESH:D020820', (215, 229))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (68, 88))	('revealed', 'Reg', (147, 155))	('A2780', 'Var', (21, 26))	('oral carcinoma', 'Disease', (215, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))
77021	27488395	We analyzed the prognostic significance of DEF6, p16 and p53 in the whole group of 180 cases of ovarian carcinoma.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (96, 113))	('ovarian carcinoma', 'Disease', (96, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('p16', 'Gene', (49, 52))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (96, 113))	('p53', 'Gene', (57, 60))	('DEF6', 'Var', (43, 47))	('p16', 'Gene', '1029', (49, 52))	('p53', 'Gene', '7157', (57, 60))
77023	27488395	The group with positive DEF6 and positive p16 expression was associated with the lowest OS (P = 0.027) and DFS (P = 0.023), whereas the DEF6 and p16 negative group had the highest OS and DFS.	('p16', 'Gene', '1029', (145, 148))	('p16', 'Gene', '1029', (42, 45))	('lowest', 'NegReg', (81, 87))	('DFS', 'CPA', (107, 110))	('p16', 'Gene', (42, 45))	('p16', 'Gene', (145, 148))	('positive', 'Var', (15, 23))	('DEF6', 'Gene', (24, 28))	('positive', 'Var', (33, 41))
77024	27488395	Similarly, the presence of aberrant p53 expression with concomitant DEF6 expression was statistically associated with worst prognosis, whereas the group negative for both had the best OS and DFS (P = 0.031 for OS and P = 0.028 for DFS, respectively).	('expression', 'MPA', (40, 50))	('aberrant', 'Var', (27, 35))	('p53', 'Gene', (36, 39))	('presence', 'Var', (15, 23))	('p53', 'Gene', '7157', (36, 39))	('expression', 'MPA', (73, 83))	('DEF6', 'Gene', (68, 72))
77025	27488395	Ovarian carcinoma patients with high DEF6 expression were associated with a poor overall survival compared with the patients with low DEF6 expression (P = 0.008; Fig.	('poor', 'NegReg', (76, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('patients', 'Species', '9606', (116, 124))	('Ovarian carcinoma', 'Phenotype', 'HP:0025318', (0, 17))	('Ovarian carcinoma', 'Disease', (0, 17))	('high DEF6 expression', 'Var', (32, 52))	('patients', 'Species', '9606', (18, 26))	('overall survival', 'MPA', (81, 97))	('Ovarian carcinoma', 'Disease', 'MESH:D010051', (0, 17))
77026	27488395	Also, ovarian carcinoma patients with high 16 expression had lower overall survival rate than those with low p16 expression, as determined using the Kaplan-Meier method (P = 0.022; Fig.	('lower', 'NegReg', (61, 66))	('p16', 'Gene', (109, 112))	('overall survival', 'MPA', (67, 83))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (6, 23))	('high 16 expression', 'Var', (38, 56))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (6, 23))	('p16', 'Gene', '1029', (109, 112))	('patients', 'Species', '9606', (24, 32))	('ovarian carcinoma', 'Disease', (6, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
77028	27488395	Patients with aberrant p53 expression had shorter survival rate than those with insignificant p53 expression in high-grade serous carcinoma (P = 0.012).	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('shorter', 'NegReg', (42, 49))	('survival', 'MPA', (50, 58))	('expression', 'MPA', (27, 37))	('serous carcinoma', 'Disease', (123, 139))	('aberrant', 'Var', (14, 22))	('Patients', 'Species', '9606', (0, 8))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('serous carcinoma', 'Disease', 'MESH:D018284', (123, 139))
77029	27488395	More importantly, in ovarian clear cell carcinoma, high expression of DEF6 was associated with shorter overall survival as compared to low DEF6 expression (P = 0.001, Fig.	('overall survival', 'MPA', (103, 119))	('DEF6', 'Gene', (70, 74))	('ovarian clear cell carcinoma', 'Disease', (21, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (21, 49))	('high expression', 'Var', (51, 66))	('shorter', 'NegReg', (95, 102))
77031	27488395	Univariate analysis identified FIGO stage (P = 0.023 for OS and P = 0.034 for DFS), DEF6 (P = 0.013 for OS and P = 0.009 for DFS) and p16 (P = 0.026 for OS and P = 0.031 for DFS) as prognostic factors.	('p16', 'Gene', '1029', (134, 137))	('p16', 'Gene', (134, 137))	('DEF6', 'Var', (84, 88))
77037	27488395	We compared the clinicopathological parameters and prognostic factors of DEF6, p16 and p53.	('DEF6', 'Var', (73, 77))	('p16', 'Gene', '1029', (79, 82))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('p16', 'Gene', (79, 82))
77042	27488395	In our study (Table 1), we found the highest percentage of score 3 p16 expression (74.7 %) in high-grade serous carcinoma, an ovarian carcinoma with notorious poor outcome, and similarly DEF6 (52 %).	('score 3', 'Var', (59, 66))	('p16', 'Gene', '1029', (67, 70))	('serous carcinoma', 'Disease', (105, 121))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (126, 143))	('serous carcinoma', 'Disease', 'MESH:D018284', (105, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (126, 143))	('p16', 'Gene', (67, 70))	('ovarian carcinoma', 'Disease', (126, 143))
77050	27488395	DEF6 is a novel p53 target gene and negatively regulated by p53, it can suppress cisplatin-mediated apoptosis of breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('DEF6', 'Var', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('cisplatin-mediated apoptosis', 'CPA', (81, 109))	('suppress', 'NegReg', (72, 80))	('breast cancer', 'Disease', (113, 126))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('p53', 'Gene', (16, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('p53', 'Gene', (60, 63))	('p53', 'Gene', '7157', (16, 19))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('p53', 'Gene', '7157', (60, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))
77051	27488395	In the present study, we found that strong DEF6 expression and aberrant p53 expression had the shortest survival, whereas co-expression of insignificant p53 expression and negative DEF6 displayed the longest survival rate, with the other two groups in between (P = 0.031 for OS and P = 0.028 for DFS, Table 3).	('DEF6 expression', 'Var', (43, 58))	('shortest', 'NegReg', (95, 103))	('p53', 'Gene', (72, 75))	('aberrant', 'Var', (63, 71))	('p53', 'Gene', '7157', (72, 75))	('survival', 'CPA', (104, 112))	('p53', 'Gene', (153, 156))	('expression', 'MPA', (76, 86))	('p53', 'Gene', '7157', (153, 156))
77052	27488395	Thus, the evaluation of the p53 status coupled with DEF6 might be important for risk stratification, which certainly awaits sequencing validation of the p53 status for further clarification.	('p53', 'Gene', (28, 31))	('DEF6', 'Var', (52, 56))	('p53', 'Gene', '7157', (28, 31))	('p53', 'Gene', '7157', (153, 156))	('p53', 'Gene', (153, 156))
77053	27488395	We further evaluated the overall survival rates of DEF6, p16 and p53 in all patients and four different histology subtypes of ovarian carcinoma by using Kaplan-Meier analysis.	('p53', 'Gene', (65, 68))	('DEF6', 'Var', (51, 55))	('patients', 'Species', '9606', (76, 84))	('p53', 'Gene', '7157', (65, 68))	('p16', 'Gene', (57, 60))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (126, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (126, 143))	('p16', 'Gene', '1029', (57, 60))	('ovarian carcinoma', 'Disease', (126, 143))
77054	27488395	Significantly shorter survival rates were seen in patients with high expressions of DEF6 (P = 0.008) and p16 (P = 0.022).	('p16', 'Gene', (105, 108))	('patients', 'Species', '9606', (50, 58))	('shorter', 'NegReg', (14, 21))	('p16', 'Gene', '1029', (105, 108))	('survival', 'MPA', (22, 30))	('DEF6', 'Var', (84, 88))
77055	27488395	Patients with aberrant p53 expression in high-grade serous carcinoma had shorter overall survival (P = 0.012).	('serous carcinoma', 'Disease', (52, 68))	('serous carcinoma', 'Disease', 'MESH:D018284', (52, 68))	('expression', 'MPA', (27, 37))	('aberrant', 'Var', (14, 22))	('shorter', 'NegReg', (73, 80))	('Patients', 'Species', '9606', (0, 8))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('overall survival', 'MPA', (81, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))
77056	27488395	Surprisingly, high expression of DEF6 in clear cell carcinoma was significantly correlated to shorter overall survival (P = 0.001).	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('clear cell carcinoma', 'Disease', (41, 61))	('DEF6', 'Gene', (33, 37))	('shorter', 'NegReg', (94, 101))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (41, 61))	('high', 'Var', (14, 18))	('overall', 'MPA', (102, 109))
77058	27488395	Therefore, our study suggests that patients of ovarian clear cell carcinoma with high DEF6 expression deserve a poor prognostic factor compared with other histological subtypes.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('DEF6', 'Gene', (86, 90))	('ovarian clear cell carcinoma', 'Disease', (47, 75))	('high', 'Var', (81, 85))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (47, 75))	('patients', 'Species', '9606', (35, 43))
77060	27488395	Univariate analysis showed that FIGO stage, DEF6 and p16 were associated with shorter survival (Table 3).	('p16', 'Gene', (53, 56))	('survival', 'MPA', (86, 94))	('FIGO', 'Disease', (32, 36))	('DEF6', 'Var', (44, 48))	('p16', 'Gene', '1029', (53, 56))	('shorter', 'NegReg', (78, 85))
77061	27488395	These findings suggest that DEF6 in ovarian carcinomas may facilitate tumor cell growth or proliferation, motility, invasion and metastasis, leading to high tumor stage and hence poor prognosis.	('tumor', 'Disease', (157, 162))	('motility', 'CPA', (106, 114))	('DEF6', 'Var', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (36, 54))	('tumor', 'Disease', (70, 75))	('facilitate', 'PosReg', (59, 69))	('invasion', 'CPA', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('cell growth', 'biological_process', 'GO:0016049', ('76', '87'))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (36, 53))	('ovarian carcinomas', 'Disease', (36, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (44, 54))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (36, 54))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
77068	29029447	Patients with high RSFA exhibited better progression-free survival than those with low RSFA in both univariable (HR: 0.240; 95% CI: 0.119-0.482; p < 0.001) and multivariable (HR: 0.432; 95% CI: 0.369-2.749; p = 0.027) analyses.	('RSFA', 'Chemical', '-', (19, 23))	('better', 'PosReg', (34, 40))	('progression-free survival', 'CPA', (41, 66))	('high RSFA', 'Var', (14, 23))	('Patients', 'Species', '9606', (0, 8))	('RSFA', 'Chemical', '-', (87, 91))
77070	29029447	These findings demonstrate that high RSFA is associated with better progression-free survival in non-metastatic ccRCC.	('high', 'Var', (32, 36))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('better', 'PosReg', (61, 67))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('RSFA', 'Chemical', '-', (37, 41))	('RSFA', 'Gene', (37, 41))
77086	29029447	Patients with high RSFA values also correlated with lower WHO/ISUP grade than those with low RSFA values (p = 0.007).	('RSFA', 'Chemical', '-', (19, 23))	('WHO/ISUP grade', 'MPA', (58, 72))	('lower', 'NegReg', (52, 57))	('RSFA', 'MPA', (19, 23))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('RSFA', 'Chemical', '-', (93, 97))
77092	29029447	In the univariable Cox analysis, high SFA, VFA, and RSFA values, lower Fuhrman and WHO/ISUP grades, lower AJCC stage, smaller tumor size, absence of sarcomatoid component and renal sinus invasion were associated with higher PFS.	('Cox', 'Gene', (19, 22))	('high', 'Var', (33, 37))	('RSFA', 'MPA', (52, 56))	('Fuhrman', 'CPA', (71, 78))	('lower', 'NegReg', (65, 70))	('lower', 'NegReg', (100, 105))	('SFA', 'Chemical', '-', (53, 56))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('SFA', 'MPA', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('AJCC', 'Disease', (106, 110))	('SFA', 'Chemical', '-', (38, 41))	('Cox', 'Gene', '1351', (19, 22))	('VFA', 'MPA', (43, 46))	('WHO/ISUP', 'CPA', (83, 91))	('RSFA', 'Chemical', '-', (52, 56))	('absence of sarcomatoid component and renal sinus invasion', 'Disease', 'MESH:C538614', (138, 195))	('tumor', 'Disease', (126, 131))
77093	29029447	However, multivariable analysis demonstrated that high RSFA, lower Fuhrman and WHO/ISUP grades, lower AJCC stage and absence of sarcomatoid component were associated with high PFS (Tables 2 and 3).	('AJCC stage', 'CPA', (102, 112))	('lower', 'NegReg', (61, 66))	('WHO/ISUP grades', 'CPA', (79, 94))	('Fuhrman', 'CPA', (67, 74))	('lower', 'NegReg', (96, 101))	('sarcomatoid component', 'Disease', (128, 149))	('RSFA', 'Chemical', '-', (55, 59))	('sarcomatoid component', 'Disease', 'MESH:C538614', (128, 149))	('high RSFA', 'Var', (50, 59))
77096	29029447	In matched cohorts, 20 patients experienced tumor progression with the 3-year PFS values for patients with low and high RSFA being 83.5% and 93.0%, respectively.	('patients', 'Species', '9606', (93, 101))	('patients', 'Species', '9606', (23, 31))	('RSFA', 'Chemical', '-', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('high RSFA', 'Var', (115, 124))	('tumor', 'Disease', (44, 49))	('low', 'Var', (107, 110))
77097	29029447	Further, survival analysis revealed that patients with larger RSFA value were associated with better PFS compared to patients with low RSFA (p = 0.028; Figure 1B).	('PFS', 'CPA', (101, 104))	('RSFA', 'Chemical', '-', (135, 139))	('patients', 'Species', '9606', (41, 49))	('better', 'PosReg', (94, 100))	('RSFA', 'Var', (62, 66))	('patients', 'Species', '9606', (117, 125))	('RSFA', 'Chemical', '-', (62, 66))
77106	29029447	Furthermore, Ladoire and colleagues suggested that high VFA was a predictive biomarker for lower survival in metastatic RCC patients that were given first-line anti-angiogenic drugs.	('lower', 'NegReg', (91, 96))	('survival', 'MPA', (97, 105))	('high', 'Var', (51, 55))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('patients', 'Species', '9606', (124, 132))
77114	29029447	PSM analysis also showed a strong relationship between high RSFA and better RCC survival.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('RSFA', 'Chemical', '-', (60, 64))	('better', 'PosReg', (69, 75))	('high', 'Var', (55, 59))
77142	29029447	In conclusion, our study demonstrates that high RSFA is associated with increased progression-free survival of ccRCC in Chinese patients.	('high RSFA', 'Var', (43, 52))	('increased', 'PosReg', (72, 81))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('patients', 'Species', '9606', (128, 136))	('RSFA', 'Chemical', '-', (48, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('progression-free survival', 'CPA', (82, 107))
77171	31788117	A total of 1,553 DElncRNAs were identified, and 5 candidate DElncRNAs (AC026992.2, AC245041.2, LINC00524, LINC01956 and LINC02080) were included in the nomogram.	('LINC01956', 'Var', (106, 115))	('LINC00524', 'Gene', '338002', (95, 104))	('LINC02080', 'Chemical', 'None', (120, 129))	('LINC00524', 'Gene', (95, 104))
77183	31788117	For instance, Ning et al demonstrated that lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) was overexpressed in ccRCC tissue, which was significantly associated with poor prognosis in patients with ccRCC and silencing of NEAT1 was able to inhibit ccRCC cell proliferation and invasion.	('inhibit', 'NegReg', (248, 255))	('ccRCC', 'Disease', (256, 261))	('ccRCC', 'Disease', 'MESH:D002292', (207, 212))	('associated', 'Reg', (159, 169))	('NEAT1', 'Gene', '283131', (93, 98))	('RCC', 'Phenotype', 'HP:0005584', (209, 212))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (258, 261))	('ccRCC', 'Disease', (207, 212))	('NEAT1', 'Gene', (230, 235))	('patients', 'Species', '9606', (193, 201))	('overexpressed', 'PosReg', (104, 117))	('NEAT1', 'Gene', (93, 98))	('invasion', 'CPA', (285, 293))	('silencing', 'Var', (217, 226))	('ccRCC', 'Disease', 'MESH:D002292', (121, 126))	('cell proliferation', 'biological_process', 'GO:0008283', ('262', '280'))	('NEAT1', 'Gene', '283131', (230, 235))	('ccRCC', 'Disease', 'MESH:D002292', (256, 261))	('ccRCC', 'Disease', (121, 126))
77201	31788117	A Kaplan-Meier plot and the log-rank test were used to construct survival curves and assess significant differences in OS between the low- and high-risk groups and the associations between the expression levels of candidate DElncRNAs and OS in patients with ccRCC.	('associations', 'Interaction', (168, 180))	('RCC', 'Phenotype', 'HP:0005584', (260, 263))	('DElncRNAs', 'Var', (224, 233))	('ccRCC', 'Disease', (258, 263))	('patients', 'Species', '9606', (244, 252))	('expression', 'MPA', (193, 203))	('ccRCC', 'Disease', 'MESH:D002292', (258, 263))
77207	31788117	A total of 5 candidate DElncRNAs (AC026992.2, AC245041.2, LINC00524, LINC01956 and LINC02080) were selected to develop a prognostic nomogram (Fig.	('LINC00524', 'Gene', (58, 67))	('LINC00524', 'Gene', '338002', (58, 67))	('LINC02080', 'Chemical', 'None', (83, 92))	('LINC02080', 'Var', (83, 92))	('AC245041.2', 'Var', (46, 56))	('LINC01956', 'Var', (69, 78))
77217	31788117	Furthermore, high expression of AC245041.2 (P<0.001), LINC00524 (P<0.001), LINC01956 (P<0.001) and LINC02080 (P<0.001), along with low expression level of AC026992.2 (P<0.001), was associated with a poor outcome for patients with ccRCC (Fig.	('RCC', 'Phenotype', 'HP:0005584', (232, 235))	('ccRCC', 'Disease', (230, 235))	('LINC00524', 'Gene', (54, 63))	('LINC00524', 'Gene', '338002', (54, 63))	('LINC01956', 'Var', (75, 84))	('patients', 'Species', '9606', (216, 224))	('AC245041.2', 'Var', (32, 42))	('ccRCC', 'Disease', 'MESH:D002292', (230, 235))	('LINC02080', 'Chemical', 'None', (99, 108))
77221	31788117	lncRNAs, a class of non-coding RNAs of >200 nt in length, have been demonstrated to have a significant role in transcriptional and post-transcriptional regulation, and deregulation of certain lncRNAs is involved in the initiation and progression of various cancer types.	('deregulation', 'Var', (168, 180))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('regulation', 'biological_process', 'GO:0065007', ('152', '162'))	('involved', 'Reg', (203, 211))	('lncRNAs', 'Gene', (192, 199))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cancer', 'Disease', (257, 263))
77225	31788117	Following screening by univariate regression analysis and LASSO regression analysis, the top 5 candidate DElncRNAs (AC026992.2, AC245041.2, LINC00524, LINC01956 and LINC02080) associated with survival were selected and used to develop a prognostic nomogram.	('LINC00524', 'Gene', '338002', (140, 149))	('LINC02080', 'Chemical', 'None', (165, 174))	('AC245041.2', 'Var', (128, 138))	('LINC02080', 'Var', (165, 174))	('associated', 'Reg', (176, 186))	('LASSO', 'Chemical', 'MESH:C000188', (58, 63))	('LINC00524', 'Gene', (140, 149))	('LINC01956', 'Var', (151, 160))
77226	31788117	Previously, Shi et al used 5 lncRNAs (ENSG00000229178, ENSG00000236453, ENSG00000245060, ENSG00000258789 and ENSG00000272558) for predicting 3-year OS of patients with ccRCC.	('ccRCC', 'Disease', 'MESH:D002292', (168, 173))	('ENSG00000272558', 'Var', (109, 124))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('patients', 'Species', '9606', (154, 162))	('ENSG00000258789', 'Var', (89, 104))	('ccRCC', 'Disease', (168, 173))	('ENSG00000245060', 'Var', (72, 87))	('ENSG00000229178', 'Var', (38, 53))	('ENSG00000236453', 'Var', (55, 70))
77227	31788117	In addition, Qu et al also built a prognostic lncRNA signature for predicting 5-year OS in localized ccRCC with 4 lncRNAs (ENSG00000255774, ENSG00000248323, ENSG00000260911 and ENSG00000231666).	('ccRCC', 'Disease', 'MESH:D002292', (101, 106))	('ENSG00000248323', 'Var', (140, 155))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('ENSG00000231666', 'Var', (177, 192))	('ENSG00000255774', 'Var', (123, 138))	('ENSG00000260911', 'Var', (157, 172))	('ccRCC', 'Disease', (101, 106))
77230	31788117	Furthermore, high expression levels of AC245041.2, LINC00524, LINC01956 and LINC02080 (P<0.001 for each) along with low expression levels of AC026992.2 (P<0.001) were highly negatively associated with OS of patients with ccRCC.	('ccRCC', 'Disease', 'MESH:D002292', (221, 226))	('patients', 'Species', '9606', (207, 215))	('associated', 'Reg', (185, 195))	('expression', 'MPA', (120, 130))	('LINC00524', 'Gene', (51, 60))	('expression levels', 'MPA', (18, 35))	('LINC00524', 'Gene', '338002', (51, 60))	('LINC02080', 'Chemical', 'None', (76, 85))	('RCC', 'Phenotype', 'HP:0005584', (223, 226))	('AC245041.2', 'Var', (39, 49))	('LINC02080', 'Var', (76, 85))	('negatively', 'NegReg', (174, 184))	('ccRCC', 'Disease', (221, 226))	('LINC01956', 'Var', (62, 71))
77235	31788117	Liu et al identified that inactivation of the mTOR signaling pathway inhibited apoptosis and promoted cell proliferation in ccRCC.	('ccRCC', 'Disease', 'MESH:D002292', (124, 129))	('inactivation', 'Var', (26, 38))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('mTOR', 'Gene', '2475', (46, 50))	('signaling pathway', 'biological_process', 'GO:0007165', ('51', '68'))	('mTOR', 'Gene', (46, 50))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('cell proliferation', 'biological_process', 'GO:0008283', ('102', '120'))	('apoptosis', 'CPA', (79, 88))	('inhibited', 'NegReg', (69, 78))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('promoted', 'PosReg', (93, 101))	('cell proliferation', 'CPA', (102, 120))	('ccRCC', 'Disease', (124, 129))
77246	31788117	In conclusion, 5 candidate DElncRNAs (AC026992.2, AC245041.2, LINC00524, LINC01956 and LINC02080) were identified in the present study, which were independent prognostic factors for patients with ccRCC, and exhibited potential utility as powerful molecular biomarkers for prognosis and risk assessment.	('LINC00524', 'Gene', (62, 71))	('LINC00524', 'Gene', '338002', (62, 71))	('LINC02080', 'Chemical', 'None', (87, 96))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('LINC02080', 'Var', (87, 96))	('patients', 'Species', '9606', (182, 190))	('ccRCC', 'Disease', (196, 201))	('AC245041.2', 'Var', (50, 60))	('ccRCC', 'Disease', 'MESH:D002292', (196, 201))	('AC026992.2', 'Var', (38, 48))	('LINC01956', 'Var', (73, 82))
77296	33573278	CACNA1D (Voltage-dependent L-type calcium channel subunit alpha-1D) is lowly expressed in RCC, and the expression level of CASP9 (Caspase-9) is altered in RCC by rs12124078 SNP, while CTSG (Cathepsin G) inhibition enhances apoptosis in human renal carcinoma (Caki) cells.	('RCC', 'Disease', (155, 158))	('CACNA1D', 'Gene', '776', (0, 7))	('CACNA1D', 'Gene', (0, 7))	('RCC', 'Disease', (90, 93))	('RCC', 'Disease', 'MESH:C538614', (155, 158))	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('expression level', 'MPA', (103, 119))	('altered', 'Reg', (144, 151))	('renal carcinoma', 'Phenotype', 'HP:0005584', (242, 257))	('human renal carcinoma', 'Disease', 'MESH:D001943', (236, 257))	('L-type calcium channel', 'molecular_function', 'GO:0008331', ('27', '49'))	('human renal carcinoma', 'Disease', (236, 257))	('inhibition', 'NegReg', (203, 213))	('CASP9', 'Gene', (123, 128))	('CTSG', 'Gene', (184, 188))	('Cathepsin G', 'Gene', (190, 201))	('Voltage-dependent L-type calcium channel subunit alpha-1D', 'Gene', '776', (9, 66))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('CASP9', 'Gene', '842', (123, 128))	('enhances', 'PosReg', (214, 222))	('Caspase-9', 'Gene', '842', (130, 139))	('rs12124078', 'Mutation', 'rs12124078', (162, 172))	('rs12124078 SNP', 'Var', (162, 176))	('Caspase-9', 'Gene', (130, 139))	('Cathepsin G', 'Gene', '1511', (190, 201))	('apoptosis', 'CPA', (223, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('apoptosis', 'biological_process', 'GO:0097194', ('223', '232'))	('CTSG', 'Gene', '1511', (184, 188))	('apoptosis', 'biological_process', 'GO:0006915', ('223', '232'))
77298	33573278	FGFR3 (fibroblast growth factor receptor 3) regulates cell proliferation, differentiation and apoptosis and it is frequently mutated in metastatic RCC and downregulated in ccRCC.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('apoptosis', 'CPA', (94, 103))	('fibroblast growth factor receptor 3', 'Gene', (7, 42))	('mutated', 'Var', (125, 132))	('regulates', 'Reg', (44, 53))	('differentiation', 'CPA', (74, 89))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('RCC', 'Disease', (174, 177))	('fibroblast growth factor receptor 3', 'Gene', '2261', (7, 42))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('7', '31'))	('apoptosis', 'biological_process', 'GO:0097194', ('94', '103'))	('apoptosis', 'biological_process', 'GO:0006915', ('94', '103'))	('cell proliferation', 'CPA', (54, 72))	('FGFR3', 'Gene', (0, 5))	('cell proliferation', 'biological_process', 'GO:0008283', ('54', '72'))	('downregulated', 'NegReg', (155, 168))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('FGFR3', 'Gene', '2261', (0, 5))
77299	33573278	High NFE2L3 (Nuclear factor erythroid 2-related factor 3) gene expression levels are associated with poor survival in ccRCC.	('NFE2L3', 'Gene', (5, 11))	('Nuclear factor erythroid 2-related factor 3', 'Gene', '9603', (13, 56))	('High', 'Var', (0, 4))	('NFE2L3', 'Gene', '9603', (5, 11))	('Nuclear factor erythroid 2-related factor 3', 'Gene', (13, 56))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('gene expression', 'biological_process', 'GO:0010467', ('58', '73'))
77317	33573278	SPINT2 is lowly expressed in ccRCC and may act as a tumor suppressor gene, since its knockdown induces increased invasiveness, migration and bone metastasis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('increased', 'PosReg', (103, 112))	('tumor', 'Disease', (52, 57))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('52', '68'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('52', '68'))	('invasiveness', 'CPA', (113, 125))	('knockdown', 'Var', (85, 94))	('SPINT2', 'Gene', '10653', (0, 6))	('bone metastasis', 'CPA', (141, 156))	('SPINT2', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('migration', 'CPA', (127, 136))	('RCC', 'Disease', (31, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
77337	32070431	Biometric analyses of the TCGA KIRC methylation data revealed candidate loci for age-dependent and tumor-specific DNA methylation within the last exon and in a genomic region corresponding to the 3'UTR TBR1 mRNA.	('tumor', 'Disease', (99, 104))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('DNA methylation', 'biological_process', 'GO:0006306', ('114', '129'))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('TBR1', 'Gene', (202, 206))	('DNA', 'MPA', (114, 117))	('KIRC', 'Disease', 'MESH:D002292', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('methylation', 'Var', (118, 129))	('KIRC', 'Disease', (31, 35))
77338	32070431	To evaluate whether methylation of TBR1 shows association with RCC carcinogenesis, we measured 15 tumor cell lines and 907 renal tissue samples including 355 normal tissues, 175 tissue pairs of normal tumor adjacent and corresponding tumor tissue as well 202 metastatic tissues samples of lung, bone, and brain metastases by the use of pyrosequencing.	('RCC', 'Disease', 'MESH:D002292', (63, 66))	('RCC', 'Disease', (63, 66))	('TBR1', 'Gene', (35, 39))	('tumor', 'Disease', (234, 239))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))	('association', 'Reg', (46, 57))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('metastases', 'Disease', (311, 321))	('tumor', 'Disease', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('methylation', 'Var', (20, 31))	('metastases', 'Disease', 'MESH:D009362', (311, 321))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Disease', (98, 103))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
77341	32070431	Our analyses provide statistical evidence of association between methylation of TBR1 and RCC development and disease progression.	('TBR1', 'Gene', (80, 84))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('disease progression', 'CPA', (109, 128))	('methylation', 'Var', (65, 76))	('RCC', 'Disease', 'MESH:D002292', (89, 92))	('methylation', 'biological_process', 'GO:0032259', ('65', '76'))
77347	32070431	Genes undergoing DNA methylation and epigenetic silencing of expression frequently show loss of function and can as a result match the classical mechanism of tumor suppressor inactivation due to genetic alterations.	('tumor', 'Disease', (158, 163))	('tumor suppressor', 'biological_process', 'GO:0051726', ('158', '174'))	('epigenetic silencing of', 'Var', (37, 60))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('158', '174'))	('DNA methylation', 'biological_process', 'GO:0006306', ('17', '32'))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('loss of function', 'NegReg', (88, 104))	('expression', 'MPA', (61, 71))
77348	32070431	DNA methylation in normal kidney tissues has been found often to be associated with age and other epidemiologic risk factors as well as renal cell cancer risk.	('associated', 'Reg', (68, 78))	('renal cell cancer', 'Phenotype', 'HP:0005584', (136, 153))	('renal cell cancer', 'Disease', 'MESH:D002292', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('methylation', 'Var', (4, 15))	('renal cell cancer', 'Disease', (136, 153))
77349	32070431	Moreover, studies found that DNA methylation can be linked to characteristics of RCC or ccRCC such as histology, clinical stage, histological grade, state of local or distant metastasis, prognosis of overall survival or time of disease recurrence as well as prediction of therapy response.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('linked', 'Reg', (52, 58))	('methylation', 'Var', (33, 44))	('RCC', 'Disease', 'MESH:D002292', (90, 93))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('DNA methylation', 'biological_process', 'GO:0006306', ('29', '44'))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:D002292', (81, 84))	('RCC', 'Disease', (81, 84))	('RCC', 'Disease', (90, 93))
77354	32070431	Neurological disorders have been attributed to homozygous as well heterozygous loss of TBR1 function due to mutations and chromosomal deletions.	('loss', 'NegReg', (79, 83))	('Neurological disorders', 'Disease', (0, 22))	('Neurological disorders', 'Disease', 'MESH:D009422', (0, 22))	('mutations', 'Var', (108, 117))	('chromosomal deletions', 'Var', (122, 143))	('TBR1', 'Gene', (87, 91))	('function', 'MPA', (92, 100))
77355	32070431	In contrast, only two studies describe at yet association of genetic alterations and malignant diseases.	('genetic alterations', 'Var', (61, 80))	('malignant diseases', 'Disease', 'None', (85, 103))	('association', 'Interaction', (46, 57))	('malignant diseases', 'Disease', (85, 103))
77358	32070431	To narrow down the group of candidates a review of literature for known or supposed associations between gene alterations and cancer was carried out revealing the TBR1 gene as a candidate gene.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('alterations', 'Var', (110, 121))	('TBR1', 'Gene', (163, 167))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))
77359	32070431	This section also includes microRNA response elements of the putatively cancer-related microRNAs miR-19, -375, -27ab, and -141/200a.	('miR-19', 'Var', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', (72, 78))
77362	32070431	Normal primary epithelial cells from kidney and prostate as well as the HB-CLS1 human bladder cancer cell line were detected with relative methylation values of 25-50%.	('bladder cancer', 'Disease', (86, 100))	('methylation', 'biological_process', 'GO:0032259', ('139', '150'))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('bladder cancer', 'Disease', 'MESH:D001749', (86, 100))	('methylation', 'Var', (139, 150))
77366	32070431	Paired tissue analysis revealed that by far the largest part of tumor tissues shows hypermethylation in tumor samples, a subset of corresponding tissue pairs did not exhibit higher methylation in tumors and a small part is characterized by hypo-methylated tumors, showing overall clear hypermethylation in tumor tissues (paired two-sided t test, P = 6.1 x 10-19).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', (306, 311))	('methylation', 'biological_process', 'GO:0032259', ('181', '192'))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumors', 'Disease', 'MESH:D009369', (256, 262))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('hypo-methylated tumors', 'Disease', 'MESH:D052456', (240, 262))	('tumor', 'Disease', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('tumors', 'Disease', (196, 202))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('hypermethylation', 'Var', (84, 100))	('tumors', 'Phenotype', 'HP:0002664', (256, 262))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumor', 'Disease', (64, 69))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('hypo-methylated tumors', 'Disease', (240, 262))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumors', 'Disease', (256, 262))
77373	32070431	In silico analysis using the TCGA KIRC data of 284 tumor patients then revealed that several CpG sites located in the gene body region upstream of the candidate locus show significant association with adverse clinic-pathological parameters as well as recurrence-free survival of patients (Fig.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('KIRC', 'Disease', (34, 38))	('recurrence-free survival', 'CPA', (251, 275))	('KIRC', 'Disease', 'MESH:D002292', (34, 38))	('CpG', 'Var', (93, 96))	('association', 'Interaction', (184, 195))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
77374	32070431	So, presumably one larger group of neighbored CpG sites located between exons 3 and 6 demonstrated comparatively higher odds ratios for association with state of distant metastasis, high-stage tumors, and loss of differentiation in tumors in bivariate logistic regression analyses including age as a covariate.	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('loss', 'Var', (205, 209))	('higher', 'PosReg', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (193, 199))	('high-stage', 'Disease', (182, 192))	('tumors', 'Disease', (232, 238))	('association', 'Interaction', (136, 147))
77377	32070431	Identification of new methylation marks associated with tumor risk and/or progression in specific human tissues may provide the base of molecular biomarkers for diagnosis and individualized therapy approaches as well as give reasonable starting points for functional analyses of kidney cancer tumor biology.	('methylation marks', 'Var', (22, 39))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('kidney cancer tumor', 'Disease', 'MESH:D009369', (279, 298))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('kidney cancer', 'Phenotype', 'HP:0009726', (279, 292))	('kidney cancer tumor', 'Disease', (279, 298))	('methylation', 'biological_process', 'GO:0032259', ('22', '33'))	('tumor', 'Disease', (293, 298))	('associated', 'Reg', (40, 50))
77378	32070431	80% of cancer-related methylated loci also show age-related methylation in normal tissues in silico analyses of genome-wide methylation databases such as the TCGA KIRC data for renal tissues could also be a rationale for the identification of new epigenetic marks with possible relevance for renal cell cancer.	('KIRC', 'Disease', 'MESH:D002292', (163, 167))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', (303, 309))	('methylation', 'biological_process', 'GO:0032259', ('124', '135'))	('renal cell cancer', 'Disease', (292, 309))	('methylation', 'Var', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('renal cell cancer', 'Phenotype', 'HP:0005584', (292, 309))	('renal cell cancer', 'Disease', 'MESH:D002292', (292, 309))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (303, 309))	('KIRC', 'Disease', (163, 167))
77381	32070431	From a technical point of view, therefore our results show that biometric analysis of the TCGA KIRC data may serve not only for statistical answering of tumor-related questions but is also suited in principal for the identification of normal tissue alteration such as age- and lifestyle-associated epigenetic marks.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('KIRC', 'Disease', (95, 99))	('epigenetic marks', 'Var', (298, 314))	('KIRC', 'Disease', 'MESH:D002292', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))
77385	32070431	These results are in line with a gradually enrichment of cells carrying TBR1 methylation during progression from normal to tumor tissues and tumor to metastatic tissues.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('methylation', 'biological_process', 'GO:0032259', ('77', '88'))	('methylation', 'Var', (77, 88))	('TBR1', 'Gene', (72, 76))	('tumor', 'Disease', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
77386	32070431	Therefore, our results statistically support the view that TBR1 methylation promotes the development both of tumor cells as well as of metastatic cells growing out of primary tumor tissues.	('tumor', 'Disease', (175, 180))	('methylation', 'Var', (64, 75))	('development', 'CPA', (89, 100))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('promotes', 'PosReg', (76, 84))	('TBR1', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('methylation', 'biological_process', 'GO:0032259', ('64', '75'))	('tumor', 'Disease', (109, 114))
77388	32070431	First, tumor heterogeneity for TBR1 epi-alterations could impede the detection of metastasis-positive tissues leading to a decreased statistical power, in particular when considering that only 16% of primary tumors were clinically classified as metastasis positive.	('TBR1', 'Gene', (31, 35))	('tumor', 'Disease', (7, 12))	('decreased', 'NegReg', (123, 132))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('epi-alterations', 'Var', (36, 51))	('primary tumors', 'Disease', (200, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Disease', (208, 213))	('statistical power', 'MPA', (133, 150))	('primary tumors', 'Disease', 'MESH:D001932', (200, 214))	('impede', 'NegReg', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
77390	32070431	Taking into account that our evaluation study using the TCGA KIRC data confirmed association of TBR1 methylation with disadvantageous clinical and survival parameters our study approach comparing renal tissues from normal towards full metastatic tissue nevertheless might provide an efficient way for identification of new genes relevant for tumor development and progression.	('association', 'Interaction', (81, 92))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('methylation', 'biological_process', 'GO:0032259', ('101', '112'))	('KIRC', 'Disease', 'MESH:D002292', (61, 65))	('KIRC', 'Disease', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('tumor', 'Disease', (342, 347))	('methylation', 'Var', (101, 112))	('TBR1', 'Gene', (96, 100))
77391	32070431	TBR1 alterations have been found primarily in neurological disorders thus far, while information about TBR1 alterations in human cancers is sparse.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('neurological disorders', 'Disease', 'MESH:D009422', (46, 68))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('neurological disorders', 'Disease', (46, 68))	('cancers', 'Disease', (129, 136))	('alterations', 'Var', (5, 16))	('found', 'Reg', (27, 32))	('TBR1', 'Gene', (0, 4))
77392	32070431	So, copy number variations for TBR1 have been reported for glioblastomas and mutation of the TBR1 gene was found in medulloblastomas, an embryonic cancer of the brain.	('TBR1', 'Gene', (31, 35))	('embryonic cancer', 'Disease', (137, 153))	('TBR1', 'Gene', (93, 97))	('medulloblastomas', 'Disease', 'MESH:D008527', (116, 132))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('medulloblastomas', 'Disease', (116, 132))	('mutation', 'Var', (77, 85))	('embryonic cancer', 'Disease', 'MESH:D009373', (137, 153))	('glioblastomas', 'Phenotype', 'HP:0012174', (59, 72))	('glioblastomas', 'Disease', 'MESH:D005909', (59, 72))	('reported', 'Reg', (46, 54))	('glioblastomas', 'Disease', (59, 72))	('embryonic cancer', 'Phenotype', 'HP:0002898', (137, 153))	('copy number variations', 'Var', (4, 26))	('found', 'Reg', (107, 112))
77394	32070431	Therefore, our results give additional evidence that TBR1 alterations play also a role in human cancers, in particular when considering that 11 out 12 cancer models representing the 3 urological tumor entities of kidney, urothelial, and prostate cancer show high TBR1 methylation.	('urothelial', 'Disease', (221, 231))	('methylation', 'biological_process', 'GO:0032259', ('268', '279'))	('tumor', 'Disease', (195, 200))	('methylation', 'MPA', (268, 279))	('TBR1', 'Gene', (263, 267))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancers', 'Disease', (96, 103))	('cancer', 'Disease', (96, 102))	('alterations', 'Var', (58, 69))	('cancer', 'Disease', (246, 252))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('kidney', 'Disease', (213, 219))	('cancer', 'Disease', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('prostate cancer', 'Disease', 'MESH:D011471', (237, 252))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('prostate cancer', 'Phenotype', 'HP:0012125', (237, 252))	('TBR1', 'Gene', (53, 57))	('prostate cancer', 'Disease', (237, 252))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
77395	32070431	As our study provided statistical evidence which is in line with a possible contribution of TBR1 alterations in the development and progression of RCC, functional studies are required to clarify the causal relevance of TBR1 alterations for renal cancers.	('renal cancers', 'Disease', (240, 253))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('TBR1', 'Gene', (92, 96))	('alterations', 'Var', (97, 108))	('renal cancer', 'Phenotype', 'HP:0009726', (240, 252))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('renal cancers', 'Disease', 'MESH:D007680', (240, 253))	('RCC', 'Disease', 'MESH:D002292', (147, 150))
77396	32070431	Taking into account that our analysis of KIRC data also revealed a significant tumor-specific reduction of TBR1 mRNA expression and biometrical data provided by the UCSC genome browser report the presence of microRNA response elements, from a theoretical point of view epigenetic alteration of both transcriptional as well as post-transcriptional control of TBR1 mRNA expression in RCC can be considered as possible starting points for functional analyses.	('transcriptional control', 'biological_process', 'GO:0006355', ('331', '354'))	('TBR1', 'Gene', (107, 111))	('TBR1', 'Gene', (358, 362))	('RCC', 'Phenotype', 'HP:0005584', (382, 385))	('tumor', 'Disease', (79, 84))	('reduction', 'NegReg', (94, 103))	('epigenetic alteration', 'Var', (269, 290))	('expression', 'MPA', (117, 127))	('RCC', 'Disease', (382, 385))	('RCC', 'Disease', 'MESH:D002292', (382, 385))	('KIRC', 'Disease', 'MESH:D002292', (41, 45))	('KIRC', 'Disease', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
77397	32070431	So tumor-specific hypermethylation and loss of mRNA expression are a characteristic of epigenetic silencing of gene expression while the presence of microRNA response elements of the miR-200 family point to a possible alteration in regulation of cellular response to hypoxia, representing one of the most important pathophysiological processes in RCC development.	('RCC', 'Disease', (347, 350))	('RCC', 'Phenotype', 'HP:0005584', (347, 350))	('gene expression', 'biological_process', 'GO:0010467', ('111', '126'))	('regulation of cellular response to hypoxia', 'biological_process', 'GO:1900037', ('232', '274'))	('tumor', 'Disease', (3, 8))	('hypermethylation', 'Var', (18, 34))	('hypoxia', 'Disease', 'MESH:D000860', (267, 274))	('RCC', 'Disease', 'MESH:D002292', (347, 350))	('regulation', 'MPA', (232, 242))	('alteration', 'Reg', (218, 228))	('hypoxia', 'Disease', (267, 274))	('mRNA expression', 'MPA', (47, 62))	('epigenetic silencing', 'Var', (87, 107))	('loss', 'NegReg', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
77398	32070431	Our study identified a new epigenetic methylation mark in normal kidney tissue showing accumulation with age and further enrichment in tumor as well as metastatic kidney tissues, thus providing statistical evidence of association between TBR1 DNA methylation and RCC development and disease progression.	('association', 'Interaction', (218, 229))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('TBR1', 'Gene', (238, 242))	('methylation', 'Var', (247, 258))	('RCC', 'Disease', (263, 266))	('tumor', 'Disease', (135, 140))	('RCC', 'Phenotype', 'HP:0005584', (263, 266))	('DNA methylation', 'biological_process', 'GO:0006306', ('243', '258'))	('RCC', 'Disease', 'MESH:D002292', (263, 266))	('DNA', 'Var', (243, 246))	('DNA', 'cellular_component', 'GO:0005574', ('243', '246'))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
77473	32071778	The accumulation of this protein is the consequence of the Von Hippel-Lindau (VHL) gene malfunction, a driver event in CCRCC.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('CCRCC', 'Disease', (119, 124))	('VHL', 'Disease', 'MESH:D006623', (78, 81))	('VHL', 'Disease', (78, 81))	('accumulation', 'PosReg', (4, 16))	('Von Hippel-Lindau', 'Gene', '7428', (59, 76))	('CCRCC', 'Phenotype', 'HP:0006770', (119, 124))	('CCRCC', 'Disease', 'MESH:D002292', (119, 124))	('Von Hippel-Lindau', 'Gene', (59, 76))	('malfunction', 'Var', (88, 99))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))
77532	29296589	The dysregulation of the oncoprotein, PKB/Akt has been linked with poor prognoses in human cancers.	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('dysregulation', 'Var', (4, 17))	('PKB/Akt', 'Gene', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('PKB/Akt', 'Gene', '207', (38, 45))	('human', 'Species', '9606', (85, 90))
77544	29296589	Truncal mutations in the Von Hippel-Lindau VHL tumour suppressor gene are the hallmark of this pathology, but therapies against this target have elicited, to date, only partial responses.	('Von Hippel-Lindau VHL tumour', 'Disease', (25, 53))	('Von Hippel-Lindau VHL tumour', 'Disease', 'MESH:D006623', (25, 53))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('Truncal mutations', 'Var', (0, 17))
77551	29296589	Upon the change in conformation of PKB, PDK1 phosphorylates threonine-308 to partially active it.	('conformation', 'Var', (19, 31))	('PDK1', 'Gene', (40, 44))	('PKB', 'Gene', (35, 38))	('PKB', 'Gene', '207', (35, 38))	('active', 'MPA', (87, 93))	('PDK1', 'molecular_function', 'GO:0004740', ('40', '44'))	('change', 'Reg', (9, 15))	('threonine', 'Chemical', 'MESH:D013912', (60, 69))	('PDK1', 'Gene', '5163', (40, 44))
77556	29296589	Alternatively, a mutation of PKB itself could cause dysregulation within this pathway.	('mutation', 'Var', (17, 25))	('PKB', 'Gene', '207', (29, 32))	('cause', 'Reg', (46, 51))	('dysregulation', 'MPA', (52, 65))	('PKB', 'Gene', (29, 32))
77632	31545453	However, little is known concerning the role of miR-205-5p in renal cell carcinoma (RCC).	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('RCC', 'Disease', 'MESH:D002292', (84, 87))	('RCC', 'Disease', (84, 87))	('renal cell carcinoma', 'Disease', (62, 82))	('miR-205-5p', 'Var', (48, 58))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (62, 82))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (62, 82))
77637	31545453	The expression of miR-205-5p was found to be downregulated in 25 RCC tissues compared to that noted in the adjacent normal tissues.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('miR-205-5p', 'Var', (18, 28))	('expression', 'MPA', (4, 14))	('downregulated', 'NegReg', (45, 58))	('RCC', 'Disease', 'MESH:D002292', (65, 68))	('RCC', 'Disease', (65, 68))
77638	31545453	Based on the results of the in vitro experiments, overexpression of miR-205-5p reduced RCC cell proliferation, invasion and migration.	('RCC', 'Disease', 'MESH:D002292', (87, 90))	('RCC', 'Disease', (87, 90))	('reduced', 'NegReg', (79, 86))	('overexpression', 'PosReg', (50, 64))	('migration', 'CPA', (124, 133))	('cell proliferation', 'biological_process', 'GO:0008283', ('91', '109'))	('miR-205-5p', 'Var', (68, 78))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
77639	31545453	Overexpression of miR-205-5p also promoted apoptosis and inhibited the EMT in RCC cells.	('miR-205-5p', 'Var', (18, 28))	('apoptosis', 'CPA', (43, 52))	('inhibited', 'NegReg', (57, 66))	('EMT', 'biological_process', 'GO:0001837', ('71', '74'))	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('promoted', 'PosReg', (34, 42))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('RCC', 'Disease', 'MESH:D002292', (78, 81))
77640	31545453	Moreover, the PI3K/Akt signaling pathway was found to be negatively regulated by miR-205-5p.	('Akt', 'Gene', '207', (19, 22))	('Akt signaling', 'biological_process', 'GO:0043491', ('19', '32'))	('Akt', 'Gene', (19, 22))	('negatively', 'NegReg', (57, 67))	('miR-205-5p', 'Var', (81, 91))	('PI3K', 'molecular_function', 'GO:0016303', ('14', '18'))	('signaling pathway', 'biological_process', 'GO:0007165', ('23', '40'))
77641	31545453	Bioinformatic analyses and luciferase reporter assays revealed that miR-205-5p directly targeted the 3'-UTR of vascular endothelial growth factor A (VEGFA).	('vascular endothelial growth factor A', 'Gene', '7422', (111, 147))	('VEGFA', 'Gene', (149, 154))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('111', '145'))	('vascular endothelial growth factor A', 'Gene', (111, 147))	('miR-205-5p', 'Var', (68, 78))	('VEGFA', 'Gene', '7422', (149, 154))
77642	31545453	Furthermore, miR-205-5p negatively regulated the expression of VEGFA in ccRCC cell lines.	('VEGFA', 'Gene', (63, 68))	('negatively', 'NegReg', (24, 34))	('expression', 'MPA', (49, 59))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('VEGFA', 'Gene', '7422', (63, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('miR-205-5p', 'Var', (13, 23))	('ccRCC', 'Disease', (72, 77))	('regulated', 'Reg', (35, 44))	('ccRCC', 'Disease', 'MESH:D002292', (72, 77))
77643	31545453	In ccRCC tissues, miR-205-5p expression was inversely correlated with VEGFA expression.	('miR-205-5p', 'Var', (18, 28))	('VEGFA', 'Gene', (70, 75))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('inversely', 'NegReg', (44, 53))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('VEGFA', 'Gene', '7422', (70, 75))	('ccRCC', 'Disease', (3, 8))	('correlated', 'Interaction', (54, 64))	('ccRCC', 'Disease', 'MESH:D002292', (3, 8))
77644	31545453	Moreover, overexpression of miR-205-5p inhibited RCC growth in vivo in a mouse xenograft model.	('RCC', 'Disease', 'MESH:D002292', (49, 52))	('RCC', 'Disease', (49, 52))	('inhibited', 'NegReg', (39, 48))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('mouse', 'Species', '10090', (73, 78))	('overexpression', 'PosReg', (10, 24))	('miR-205-5p', 'Var', (28, 38))
77645	31545453	Overall, miR-205-5p functions as a tumor suppressor in RCC by targeting VEGFA and the PI3K/Akt signaling pathway, providing a potential therapeutic target for the treatment of ccRCC.	('RCC', 'Disease', 'MESH:D002292', (55, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (176, 181))	('RCC', 'Disease', (178, 181))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('VEGFA', 'Gene', (72, 77))	('miR-205-5p', 'Var', (9, 19))	('Akt', 'Gene', (91, 94))	('tumor', 'Disease', (35, 40))	('RCC', 'Disease', 'MESH:D002292', (178, 181))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('Akt', 'Gene', '207', (91, 94))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))	('VEGFA', 'Gene', '7422', (72, 77))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('ccRCC', 'Disease', 'MESH:D002292', (176, 181))	('RCC', 'Disease', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('signaling pathway', 'biological_process', 'GO:0007165', ('95', '112'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('Akt signaling', 'biological_process', 'GO:0043491', ('91', '104'))	('targeting', 'Reg', (62, 71))	('PI3K', 'molecular_function', 'GO:0016303', ('86', '90'))	('ccRCC', 'Disease', (176, 181))
77652	31545453	Dysregulation of miRNAs has been shown to play vital roles in the tumorigenesis and development of various types of cancer, including ccRCC.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('roles', 'Reg', (53, 58))	('tumor', 'Disease', (66, 71))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (116, 122))	('miR', 'Gene', (17, 20))	('ccRCC', 'Disease', (134, 139))	('miR', 'Gene', '220972', (17, 20))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('ccRCC', 'Disease', 'MESH:D002292', (134, 139))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
77657	31545453	Recently, miR-205-5p has been reported to be involved in the tumorigenesis of various types of cancer, such as colon, prostate and hepatocellular carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('miR-205-5p', 'Var', (10, 20))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (131, 156))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (131, 155))	('cancer', 'Disease', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('involved', 'Reg', (45, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (131, 156))	('hepatocellular carcinomas', 'Disease', (131, 156))	('colon', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('prostate', 'Disease', (118, 126))	('tumor', 'Disease', (61, 66))
77658	31545453	For example, miR-205-5p has been reported to inhibit zinc finger E-box binding homeobox 1 (ZEB1), a transcription factor, in prostate cancer.	('transcription factor', 'molecular_function', 'GO:0000981', ('100', '120'))	('prostate cancer', 'Disease', 'MESH:D011471', (125, 140))	('prostate cancer', 'Phenotype', 'HP:0012125', (125, 140))	('ZEB1', 'Gene', '6935', (91, 95))	('zinc finger E-box binding homeobox 1', 'Gene', '6935', (53, 89))	('inhibit', 'NegReg', (45, 52))	('ZEB1', 'Gene', (91, 95))	('transcription', 'biological_process', 'GO:0006351', ('100', '113'))	('zinc finger E-box binding homeobox 1', 'Gene', (53, 89))	('prostate cancer', 'Disease', (125, 140))	('miR-205-5p', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('E-box binding', 'molecular_function', 'GO:0070888', ('65', '78'))
77659	31545453	Additionally, miR-205-5p was found to downregulate PTEN expression and thereby contribute to cisplatin resistance in ovarian cancer cells.	('miR-205-5p', 'Var', (14, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (117, 131))	('ovarian cancer', 'Disease', 'MESH:D010051', (117, 131))	('contribute', 'Reg', (79, 89))	('expression', 'MPA', (56, 66))	('downregulate', 'NegReg', (38, 50))	('cisplatin resistance', 'MPA', (93, 113))	('ovarian cancer', 'Disease', (117, 131))	('PTEN', 'Gene', (51, 55))	('PTEN', 'Gene', '5728', (51, 55))
77660	31545453	However, the expression and function of miR-205-5p in RCC remain elusive.	('miR-205-5p', 'Var', (40, 50))	('RCC', 'Disease', 'MESH:D002292', (54, 57))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))
77662	31545453	According to the results of the Kaplan-Meier analysis, low levels of miR-205-5p predicted a poor prognosis for patients with RCC.	('miR-205-5p', 'Var', (69, 79))	('RCC', 'Disease', 'MESH:D002292', (125, 128))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('low', 'Var', (55, 58))	('patients', 'Species', '9606', (111, 119))
77663	31545453	Overexpression of miR-205-5p inhibited the proliferation, migration, invasion and EMT of RCC cells.	('inhibited', 'NegReg', (29, 38))	('miR-205-5p', 'Var', (18, 28))	('EMT', 'biological_process', 'GO:0001837', ('82', '85'))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('invasion', 'CPA', (69, 77))	('RCC', 'Disease', 'MESH:D002292', (89, 92))	('migration', 'CPA', (58, 67))
77664	31545453	Bioinformatic analyses revealed that vascular endothelial growth factor A (VEGFA) is a direct downstream target of miR-205-5p.	('miR-205-5p', 'Var', (115, 125))	('VEGFA', 'Gene', '7422', (75, 80))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('37', '71'))	('vascular endothelial growth factor A', 'Gene', '7422', (37, 73))	('VEGFA', 'Gene', (75, 80))	('vascular endothelial growth factor A', 'Gene', (37, 73))
77666	31545453	Furthermore, the PI3K/Akt/mTOR signaling pathway was inhibited in cells overexpressing miR-205-5p.	('inhibited', 'NegReg', (53, 62))	('miR-205-5p', 'Var', (87, 97))	('signaling pathway', 'biological_process', 'GO:0007165', ('31', '48'))	('Akt', 'Gene', (22, 25))	('mTOR', 'Gene', (26, 30))	('mTOR', 'Gene', '2475', (26, 30))	('PI3K', 'molecular_function', 'GO:0016303', ('17', '21'))	('Akt', 'Gene', '207', (22, 25))
77667	31545453	In vivo experiments also confirmed that miR-205-5p inhibited the growth of xenograft tumors in mice.	('xenograft tumors', 'Disease', 'MESH:D009369', (75, 91))	('mice', 'Species', '10090', (95, 99))	('xenograft tumors', 'Disease', (75, 91))	('miR-205-5p', 'Var', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('inhibited', 'NegReg', (51, 60))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
77668	31545453	Based on our findings, miR-205-5p suppresses the tumorigenicity of RCC cells by targeting VEGFA and suppressing the PI3K/Akt/mTOR signaling pathway.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('PI3K', 'molecular_function', 'GO:0016303', ('116', '120'))	('Akt', 'Gene', (121, 124))	('mTOR', 'Gene', '2475', (125, 129))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('RCC', 'Disease', 'MESH:D002292', (67, 70))	('mTOR', 'Gene', (125, 129))	('suppresses', 'NegReg', (34, 44))	('VEGFA', 'Gene', (90, 95))	('RCC', 'Disease', (67, 70))	('tumor', 'Disease', (49, 54))	('VEGFA', 'Gene', '7422', (90, 95))	('signaling pathway', 'biological_process', 'GO:0007165', ('130', '147'))	('suppressing', 'NegReg', (100, 111))	('miR-205-5p', 'Var', (23, 33))	('Akt', 'Gene', '207', (121, 124))	('targeting', 'Reg', (80, 89))
77701	31545453	Sequences containing the wild-type (VEGFA-wt) or mutant (VEGFA-mut) seed region of VEGFA were synthesized and cloned into a luciferase reporter plasmid (pMIR-REPORT) (Promega Corporation, Madison, WI, USA).	('VEGFA', 'Gene', (83, 88))	('VEGFA', 'Gene', '7422', (57, 62))	('VEGFA', 'Gene', '7422', (36, 41))	('mutant', 'Var', (49, 55))	('VEGFA', 'Gene', '7422', (83, 88))	('VEGFA', 'Gene', (57, 62))	('VEGFA', 'Gene', (36, 41))
77714	31545453	We examined the endogenous expression of miR-205-5p in RCC tissues (n=25) and adjacent normal kidney tissues (n=25) to determine whether miR-205-5p is dysregulated in RCC.	('RCC', 'Disease', 'MESH:D002292', (55, 58))	('RCC', 'Disease', (55, 58))	('RCC', 'Disease', 'MESH:D002292', (167, 170))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('miR-205-5p', 'Var', (137, 147))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
77715	31545453	Significantly lower expression of miR-205-5p was detected in RCC tumor tissues than that observed in the normal tissues (P<0.01; Fig.	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('expression', 'MPA', (20, 30))	('tumor', 'Disease', (65, 70))	('lower', 'NegReg', (14, 19))	('miR-205-5p', 'Var', (34, 44))	('RCC', 'Disease', (61, 64))	('RCC', 'Disease', 'MESH:D002292', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
77716	31545453	In addition, we measured the expression of miR-205-5p in the cell line 293 and RCC cell lines 786-O, Caki-1 and ACHN.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('miR-205-5p', 'Var', (43, 53))	('RCC', 'Disease', 'MESH:D002292', (79, 82))	('RCC', 'Disease', (79, 82))
77717	31545453	Significantly lower expression of miR-205-5p was observed in RCC cell lines than in the 293 cells (Fig.	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('expression', 'MPA', (20, 30))	('lower', 'NegReg', (14, 19))	('miR-205-5p', 'Var', (34, 44))	('RCC', 'Disease', 'MESH:D002292', (61, 64))	('RCC', 'Disease', (61, 64))
77720	31545453	In addition, the Kaplan-Meier analysis revealed that downregulation of miR-205-5p was associated with a poor prognosis, indicating that miR-205-5p may serve as a promising candidate prognostic biomarker for patients with RCC (mean follow-up time of 42 months) (Fig.	('patients', 'Species', '9606', (207, 215))	('downregulation', 'NegReg', (53, 67))	('RCC', 'Phenotype', 'HP:0005584', (221, 224))	('RCC', 'Disease', 'MESH:D002292', (221, 224))	('RCC', 'Disease', (221, 224))	('miR-205-5p', 'Gene', (71, 81))	('miR-205-5p', 'Var', (136, 146))
77721	31545453	A univariate analysis using the Cox proportional hazard regression model revealed statistically significant correlations between the overall survival of patients with miR-205-5p expression (P=0.017) and tumor stage (P=0.023) (Table II).	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('patients', 'Species', '9606', (153, 161))	('miR-205-5p expression', 'Var', (167, 188))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('Cox', 'Gene', '1351', (32, 35))	('Cox', 'Gene', (32, 35))
77722	31545453	A multivariate analysis including miR-205-5p expression and the tumor stage showed that miR-205-5p (P=0.024) and tumor stage (P=0.034) were independent prognostic factors for the overall survival of patients with RCC (Table II).	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', (64, 69))	('miR-205-5p', 'Var', (88, 98))	('RCC', 'Disease', 'MESH:D002292', (213, 216))	('RCC', 'Disease', (213, 216))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	('patients', 'Species', '9606', (199, 207))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
77725	31545453	Thus, miR-205-5p suppressed the proliferation of RCC cells.	('RCC', 'Disease', 'MESH:D002292', (49, 52))	('RCC', 'Disease', (49, 52))	('miR-205-5p', 'Var', (6, 16))	('suppressed', 'NegReg', (17, 27))	('proliferation', 'CPA', (32, 45))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))
77726	31545453	Thus, miR-205-5p suppresses the migration of RCC cells.	('miR-205-5p', 'Var', (6, 16))	('suppresses', 'NegReg', (17, 27))	('RCC', 'Disease', 'MESH:D002292', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
77728	31545453	Meanwhile, the levels of invasion and migration marker proteins (MMP-7 and MMP-9) were also obviously decreased in cells overexpressing miR-205-5p (Fig.	('overexpressing', 'PosReg', (121, 135))	('MMP-9', 'molecular_function', 'GO:0004229', ('75', '80'))	('MMP-7', 'Gene', (65, 70))	('invasion', 'CPA', (25, 33))	('MMP-7', 'molecular_function', 'GO:0004235', ('65', '70'))	('miR-205-5p', 'Var', (136, 146))	('MMP-7', 'Gene', '4316', (65, 70))	('MMP-9', 'Gene', (75, 80))	('MMP-9', 'Gene', '4318', (75, 80))	('decreased', 'NegReg', (102, 111))	('levels of', 'MPA', (15, 24))
77729	31545453	Since epithelial-mesenchymal transition (EMT) is an indispensable process for tumor cell invasion and migration, we examined whether miR-205-5p affects EMT in RCC cells.	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('6', '39'))	('RCC', 'Disease', 'MESH:D002292', (159, 162))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('EMT', 'biological_process', 'GO:0001837', ('41', '44'))	('affects', 'Reg', (144, 151))	('EMT', 'biological_process', 'GO:0001837', ('152', '155'))	('tumor', 'Disease', (78, 83))	('miR-205-5p', 'Var', (133, 143))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))
77730	31545453	3B, overexpression of miR-205-5p significantly decreased the protein levels of N-cadherin, beta-catenin and Snail.	('N-cadherin', 'Gene', (79, 89))	('miR-205-5p', 'Var', (22, 32))	('beta-catenin', 'Gene', (91, 103))	('N-cadherin', 'Gene', '1000', (79, 89))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))	('Snail', 'Gene', '6615', (108, 113))	('Snail', 'Gene', (108, 113))	('beta-catenin', 'Gene', '1499', (91, 103))	('cadherin', 'molecular_function', 'GO:0008014', ('81', '89'))	('decreased', 'NegReg', (47, 56))
77731	31545453	Based on these data, miR-205-5p may inhibit the migration of RCC cells by suppressing the EMT.	('suppressing', 'NegReg', (74, 85))	('EMT', 'biological_process', 'GO:0001837', ('90', '93'))	('EMT', 'CPA', (90, 93))	('inhibit', 'NegReg', (36, 43))	('RCC', 'Disease', 'MESH:D002292', (61, 64))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('miR-205-5p', 'Var', (21, 31))
77732	31545453	3D, caspase-3, Bcl-2 and Bcl-xL levels were reduced in cells overexpressing miR-205-5p.	('miR-205-5p', 'Var', (76, 86))	('caspase-3', 'Gene', '836', (4, 13))	('Bcl-xL', 'Gene', '598', (25, 31))	('Bcl-2', 'molecular_function', 'GO:0015283', ('15', '20'))	('Bcl-2', 'Gene', (15, 20))	('Bcl-2', 'Gene', '596', (15, 20))	('Bcl-xL', 'Gene', (25, 31))	('reduced', 'NegReg', (44, 51))	('caspase-3', 'Gene', (4, 13))
77733	31545453	Therefore, miR-205-5p likely suppresses the proliferation of RCC cells by inducing apoptosis.	('suppresses', 'NegReg', (29, 39))	('miR-205-5p', 'Var', (11, 21))	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('RCC', 'Disease', 'MESH:D002292', (61, 64))	('RCC', 'Disease', (61, 64))	('apoptosis', 'CPA', (83, 92))	('inducing', 'Reg', (74, 82))	('proliferation', 'CPA', (44, 57))
77740	31545453	Notably, overexpression of miR-205-5p also increased the sensitivity of 786-O and ACHN to sunitinib (Fig.	('overexpression', 'PosReg', (9, 23))	('ACHN to sunitinib', 'MPA', (82, 99))	('increased', 'PosReg', (43, 52))	('sensitivity', 'MPA', (57, 68))	('sunitinib', 'Chemical', 'MESH:C473478', (90, 99))	('miR-205-5p', 'Var', (27, 37))
77741	31545453	Therefore, miR-205-5p is also involved in the response of RCC cells to chemotherapy.	('miR-205-5p', 'Var', (11, 21))	('involved', 'Reg', (30, 38))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:D002292', (58, 61))
77743	31545453	We, therefore, investigated the effects of miR-205-5p on the PI3K/Akt signaling pathway.	('Akt', 'Gene', (66, 69))	('PI3K', 'molecular_function', 'GO:0016303', ('61', '65'))	('signaling pathway', 'biological_process', 'GO:0007165', ('70', '87'))	('Akt signaling', 'biological_process', 'GO:0043491', ('66', '79'))	('Akt', 'Gene', '207', (66, 69))	('miR-205-5p', 'Var', (43, 53))	('investigated', 'Reg', (15, 27))
77744	31545453	5A, overexpression of miR-205-5p markedly decreased p-PI3K, p-Akt and p-mTOR levels.	('mTOR', 'Gene', '2475', (72, 76))	('decreased', 'NegReg', (42, 51))	('mTOR', 'Gene', (72, 76))	('Akt', 'Gene', '207', (62, 65))	('miR-205-5p', 'Var', (22, 32))	('PI3K', 'molecular_function', 'GO:0016303', ('54', '58'))	('p-PI3K', 'Pathway', (52, 58))	('Akt', 'Gene', (62, 65))
77745	31545453	Constitutively active Akt (myr-Akt) was overexpressed as described in a previous study to further elucidate the role of the PI3K/Akt pathway in the antitumor effects of miR-205-5p.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('PI3K', 'molecular_function', 'GO:0016303', ('124', '128'))	('Akt', 'Gene', (31, 34))	('Akt', 'Gene', '207', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('myr-Akt', 'Gene', '207', (27, 34))	('miR-205-5p', 'Var', (169, 179))	('tumor', 'Disease', (152, 157))	('Akt', 'Gene', (22, 25))	('Akt', 'Gene', '207', (31, 34))	('Akt', 'Gene', (129, 132))	('Akt', 'Gene', '207', (22, 25))	('myr-Akt', 'Gene', (27, 34))
77747	31545453	Myr-Akt also significantly suppressed miR-205-5p-induced apoptosis (Fig.	('Akt', 'Gene', (4, 7))	('apoptosis', 'biological_process', 'GO:0006915', ('57', '66'))	('Akt', 'Gene', '207', (4, 7))	('suppressed', 'NegReg', (27, 37))	('miR-205-5p-induced', 'Var', (38, 56))	('apoptosis', 'biological_process', 'GO:0097194', ('57', '66'))
77748	31545453	Based on these data, the tumor suppressor function of miR-205-5p in RCC is likely and at least partially mediated by its repression of the PI3K/Akt/mTOR pathway.	('Akt', 'Gene', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('25', '41'))	('mTOR', 'Gene', (148, 152))	('mTOR', 'Gene', '2475', (148, 152))	('tumor', 'Disease', (25, 30))	('miR-205-5p', 'Var', (54, 64))	('RCC', 'Disease', 'MESH:D002292', (68, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('Akt', 'Gene', '207', (144, 147))	('tumor suppressor', 'biological_process', 'GO:0051726', ('25', '41'))	('repression', 'NegReg', (121, 131))	('PI3K', 'molecular_function', 'GO:0016303', ('139', '143'))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
77749	31545453	According to bioinformatic analysis tools (TargetScan;  and miRanda; ), we speculated that VEGFA is a candidate target of miR-205-5p.	('miRanda', 'Disease', (60, 67))	('VEGFA', 'Gene', '7422', (91, 96))	('miR-205-5p', 'Var', (122, 132))	('VEGFA', 'Gene', (91, 96))	('miRanda', 'Disease', 'MESH:C537402', (60, 67))
77750	31545453	6A, the RT-qPCR analysis revealed significantly decreased levels of the VEGFA mRNA in 786-O and ACHN cells transfected with miR-205-5p.	('miR-205-5p', 'Var', (124, 134))	('VEGFA', 'Gene', (72, 77))	('decreased', 'NegReg', (48, 57))	('VEGFA', 'Gene', '7422', (72, 77))	('levels', 'MPA', (58, 64))
77751	31545453	Western blot analyses also showed decreased levels of the VEGFA protein in 786-O and ACHN cells transfected with the miR-205-5p mimic (Fig.	('VEGFA', 'Gene', (58, 63))	('decreased', 'NegReg', (34, 43))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('miR-205-5p mimic', 'Var', (117, 133))	('levels', 'MPA', (44, 50))	('VEGFA', 'Gene', '7422', (58, 63))
77752	31545453	We performed a Dual-Luciferase assay to further confirm that VEGFA is a target of miR-205-5p.	('VEGFA', 'Gene', '7422', (61, 66))	('VEGFA', 'Gene', (61, 66))	('miR-205-5p', 'Var', (82, 92))
77753	31545453	The wild-type (WT) and mutant (Mut) VEGFA 3-untranslated region (3'-UTR) constructs were subcloned into the pMIR reporter plasmid.	('VEGFA', 'Gene', (36, 41))	('VEGFA', 'Gene', '7422', (36, 41))	('mutant', 'Var', (23, 29))
77754	31545453	Overexpression of miR-205-5p decreased luciferase activity in both 786-O and ACHN cells transfected with the wild-type (WT) 3'-UTR of VEGFA, but not the mutant (Mut) 3'-UTR (Fig.	('miR-205-5p', 'Var', (18, 28))	('luciferase', 'Enzyme', (39, 49))	('VEGFA', 'Gene', '7422', (134, 139))	('luciferase activity', 'molecular_function', 'GO:0047077', ('39', '58'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('39', '58'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('39', '58'))	('activity', 'MPA', (50, 58))	('luciferase activity', 'molecular_function', 'GO:0047712', ('39', '58'))	('decreased', 'NegReg', (29, 38))	('VEGFA', 'Gene', (134, 139))	('luciferase activity', 'molecular_function', 'GO:0050248', ('39', '58'))
77755	31545453	Levels of the VEGFA mRNA in RCC and normal adjacent tissues were examined using qRT-PCR to elucidate the clinical relevance of miR-205-5p-mediated targeting of VEGFA in RCC.	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('VEGFA', 'Gene', '7422', (160, 165))	('VEGFA', 'Gene', (14, 19))	('RCC', 'Disease', 'MESH:D002292', (28, 31))	('RCC', 'Disease', 'MESH:D002292', (169, 172))	('RCC', 'Disease', (169, 172))	('miR-205-5p-mediated', 'Var', (127, 146))	('VEGFA', 'Gene', (160, 165))	('VEGFA', 'Gene', '7422', (14, 19))	('RCC', 'Disease', (28, 31))	('RCC', 'Phenotype', 'HP:0005584', (28, 31))
77757	31545453	Furthermore, an inverse correlation was observed between the expression of miR-205-5p and VEGFA expression in RCC tissues (r=-0.179) (Fig.	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('RCC', 'Disease', 'MESH:D002292', (110, 113))	('VEGFA', 'Gene', (90, 95))	('expression', 'MPA', (96, 106))	('miR-205-5p', 'Var', (75, 85))	('VEGFA', 'Gene', '7422', (90, 95))
77758	31545453	These results further confirmed that VEGFA expression is negatively regulated by miR-205-5p in RCC.	('VEGFA', 'Gene', '7422', (37, 42))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('RCC', 'Disease', 'MESH:D002292', (95, 98))	('RCC', 'Disease', (95, 98))	('VEGFA', 'Gene', (37, 42))	('miR-205-5p', 'Var', (81, 91))	('negatively', 'NegReg', (57, 67))	('expression', 'MPA', (43, 53))
77759	31545453	In summary, VEGFA is a target of miR-205-5p in RCC.	('VEGFA', 'Gene', '7422', (12, 17))	('miR-205-5p', 'Var', (33, 43))	('VEGFA', 'Gene', (12, 17))	('RCC', 'Disease', 'MESH:D002292', (47, 50))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))
77764	31545453	Based on these data, miR-205-5p also inhibits tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('inhibits', 'NegReg', (37, 45))	('miR-205-5p', 'Var', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
77765	31545453	In the present study, we identified a novel molecular mechanism by which miR-205-5p modulates renal cell carcinoma (RCC) through the suppression of VEGFA expression and the PI3K/Akt/mTOR signaling pathway.	('PI3K', 'molecular_function', 'GO:0016303', ('173', '177'))	('mTOR', 'Gene', '2475', (182, 186))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('RCC', 'Disease', (116, 119))	('suppression', 'NegReg', (133, 144))	('modulates', 'Reg', (84, 93))	('RCC', 'Disease', 'MESH:D002292', (116, 119))	('Akt', 'Gene', (178, 181))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (94, 114))	('signaling pathway', 'biological_process', 'GO:0007165', ('187', '204'))	('miR-205-5p', 'Var', (73, 83))	('Akt', 'Gene', '207', (178, 181))	('VEGFA', 'Gene', (148, 153))	('renal cell carcinoma', 'Disease', (94, 114))	('mTOR', 'Gene', (182, 186))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (94, 114))	('VEGFA', 'Gene', '7422', (148, 153))	('expression', 'MPA', (154, 164))
77773	31545453	Notably, miR-205-5p has been shown to be downregulated and function as a tumor suppressor in various types of cancer.	('cancer', 'Disease', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('miR-205-5p', 'Var', (9, 19))	('downregulated', 'NegReg', (41, 54))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor suppressor', 'biological_process', 'GO:0051726', ('73', '89'))	('tumor', 'Disease', (73, 78))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('73', '89'))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
77774	31545453	For example, miR-205-5p expression was found to be significantly decreased in prostate cancer tissues and to inhibit cancer cell aggressiveness by targeting HMGB3.	('HMGB3', 'Gene', '3149', (157, 162))	('decreased', 'NegReg', (65, 74))	('HMGB3', 'Gene', (157, 162))	('aggressiveness', 'Disease', (129, 143))	('expression', 'MPA', (24, 34))	('inhibit', 'NegReg', (109, 116))	('aggressiveness', 'Phenotype', 'HP:0000718', (129, 143))	('targeting', 'Reg', (147, 156))	('cancer', 'Disease', (117, 123))	('aggressiveness', 'Disease', 'MESH:D001523', (129, 143))	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('prostate cancer', 'Disease', 'MESH:D011471', (78, 93))	('prostate cancer', 'Phenotype', 'HP:0012125', (78, 93))	('prostate cancer', 'Disease', (78, 93))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('miR-205-5p', 'Var', (13, 23))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
77775	31545453	In a recent study, miR-205-5p significantly suppressed the migration and invasion of oral squamous carcinoma cells by inhibiting TIMP-2 expression.	('suppressed', 'NegReg', (44, 54))	('expression', 'MPA', (136, 146))	('TIMP-2', 'Gene', (129, 135))	('squamous carcinoma', 'Disease', 'MESH:D002294', (90, 108))	('TIMP-2', 'Gene', '7077', (129, 135))	('miR-205-5p', 'Var', (19, 29))	('squamous carcinoma', 'Disease', (90, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('invasion', 'CPA', (73, 81))	('inhibiting', 'NegReg', (118, 128))	('migration', 'CPA', (59, 68))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (90, 108))
77776	31545453	However, miR-205-5p expression is significantly increased in non-small cell lung cancer tissues, and it functions as an oncogene by downregulating erbB3 expression.	('erbB3', 'Gene', '2065', (147, 152))	('increased', 'PosReg', (48, 57))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (65, 87))	('expression', 'MPA', (20, 30))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (61, 87))	('miR-205-5p', 'Var', (9, 19))	('non-small cell lung cancer', 'Disease', (61, 87))	('erbB3', 'Gene', (147, 152))	('downregulating', 'NegReg', (132, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('expression', 'MPA', (153, 163))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (61, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
77777	31545453	Notably, overexpression of miR-205-5p increased the chemosensitivity of RCC cells to various agents, such as paclitaxel, 5-FU, oxaliplatin and sunitinib, in the present study.	('paclitaxel', 'Chemical', 'MESH:D017239', (109, 119))	('overexpression', 'PosReg', (9, 23))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('RCC', 'Disease', 'MESH:D002292', (72, 75))	('RCC', 'Disease', (72, 75))	('sunitinib', 'Chemical', 'MESH:C473478', (143, 152))	('5-FU', 'Chemical', 'MESH:D005472', (121, 125))	('oxaliplatin', 'Chemical', 'MESH:C030110', (127, 138))	('chemosensitivity', 'MPA', (52, 68))	('increased', 'PosReg', (38, 47))	('miR-205-5p', 'Var', (27, 37))
77778	31545453	Meanwhile, overexpression of miR-205-5p was found to mediate the resistance of hepatocellular carcinoma cells to 5-FU.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('hepatocellular carcinoma', 'Disease', (79, 103))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (79, 103))	('miR-205-5p', 'Var', (29, 39))	('5-FU', 'Chemical', 'MESH:D005472', (113, 117))	('mediate', 'Reg', (53, 60))	('overexpression', 'PosReg', (11, 25))	('resistance', 'MPA', (65, 75))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (79, 103))
77781	31545453	Overexpression of miR-205-5p inhibited the proliferation, migration and invasion of RCC cells.	('inhibited', 'NegReg', (29, 38))	('miR-205-5p', 'Var', (18, 28))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('RCC', 'Disease', 'MESH:D002292', (84, 87))	('RCC', 'Disease', (84, 87))	('proliferation', 'CPA', (43, 56))	('migration', 'CPA', (58, 67))
77782	31545453	Moreover, overexpression of miR-205-5p induced apoptosis, accompanied by the downregulation of caspase-3, Bcl-2 and Bcl-xL.	('downregulation', 'NegReg', (77, 91))	('caspase-3', 'Gene', '836', (95, 104))	('Bcl-xL', 'Gene', (116, 122))	('apoptosis', 'biological_process', 'GO:0097194', ('47', '56'))	('apoptosis', 'biological_process', 'GO:0006915', ('47', '56'))	('apoptosis', 'CPA', (47, 56))	('Bcl-xL', 'Gene', '598', (116, 122))	('caspase-3', 'Gene', (95, 104))	('Bcl-2', 'molecular_function', 'GO:0015283', ('106', '111'))	('overexpression', 'PosReg', (10, 24))	('Bcl-2', 'Gene', (106, 111))	('miR-205-5p', 'Var', (28, 38))	('Bcl-2', 'Gene', '596', (106, 111))
77784	31545453	Our data are consistent with a previous study showing that miR-205-5p modulated the levels of Bcl-2 proteins in melanoma.	('miR-205-5p', 'Var', (59, 69))	('modulated', 'Reg', (70, 79))	('Bcl-2', 'Gene', (94, 99))	('Bcl-2', 'Gene', '596', (94, 99))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('Bcl-2', 'molecular_function', 'GO:0015283', ('94', '99'))
77785	31545453	Thus, miR-205-5p may induce tumor cell apoptosis via the intrinsic pathway.	('miR-205-5p', 'Var', (6, 16))	('tumor', 'Disease', (28, 33))	('apoptosis', 'biological_process', 'GO:0097194', ('39', '48'))	('intrinsic pathway', 'Pathway', (57, 74))	('induce', 'PosReg', (21, 27))	('apoptosis', 'biological_process', 'GO:0006915', ('39', '48'))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
77791	31545453	Recently, overexpression of miR-205-5p was shown to inhibit EMT in colon cancer.	('inhibit', 'NegReg', (52, 59))	('colon cancer', 'Phenotype', 'HP:0003003', (67, 79))	('colon cancer', 'Disease', 'MESH:D015179', (67, 79))	('EMT in', 'CPA', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('colon cancer', 'Disease', (67, 79))	('overexpression', 'PosReg', (10, 24))	('EMT', 'biological_process', 'GO:0001837', ('60', '63'))	('miR-205-5p', 'Var', (28, 38))
77793	31545453	In the present study, miR-205-5p decreased the levels of mesenchymal marker proteins, such as N-cadherin, Snail and beta-catenin.	('Snail', 'Gene', '6615', (106, 111))	('Snail', 'Gene', (106, 111))	('beta-catenin', 'Gene', '1499', (116, 128))	('miR-205-5p', 'Var', (22, 32))	('N-cadherin', 'Gene', (94, 104))	('decreased', 'NegReg', (33, 42))	('cadherin', 'molecular_function', 'GO:0008014', ('96', '104'))	('beta-catenin', 'Gene', (116, 128))	('N-cadherin', 'Gene', '1000', (94, 104))	('levels of mesenchymal marker proteins', 'MPA', (47, 84))
77794	31545453	Therefore, miR-205-5p may suppress the invasion and migration of RCC cells by inhibiting EMT.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('miR-205-5p', 'Var', (11, 21))	('inhibiting', 'NegReg', (78, 88))	('suppress', 'NegReg', (26, 34))	('EMT', 'CPA', (89, 92))	('EMT', 'biological_process', 'GO:0001837', ('89', '92'))	('RCC', 'Disease', 'MESH:D002292', (65, 68))	('RCC', 'Disease', (65, 68))
77801	31545453	In the present study, we investigated the effects of miR-205-5p on the PI3K/Akt/mTOR pathway and observed decreased phosphorylation of proteins involved in the PI3K/Akt/mTOR pathway.	('decreased', 'NegReg', (106, 115))	('investigated', 'Reg', (25, 37))	('phosphorylation', 'MPA', (116, 131))	('mTOR', 'Gene', (80, 84))	('Akt', 'Gene', (76, 79))	('mTOR', 'Gene', '2475', (169, 173))	('mTOR', 'Gene', '2475', (80, 84))	('phosphorylation', 'biological_process', 'GO:0016310', ('116', '131'))	('proteins', 'Protein', (135, 143))	('miR-205-5p', 'Var', (53, 63))	('mTOR', 'Gene', (169, 173))	('Akt', 'Gene', '207', (165, 168))	('PI3K', 'molecular_function', 'GO:0016303', ('160', '164'))	('Akt', 'Gene', '207', (76, 79))	('Akt', 'Gene', (165, 168))	('PI3K', 'molecular_function', 'GO:0016303', ('71', '75'))
77802	31545453	Notably, forced expression of constitutively activated Akt decreased miR-205-5p-induced apoptosis, suggesting that miR-205-5p at least partially exerts its antitumor effects by inhibiting the PI3K/Akt/mTOR signaling pathway.	('Akt', 'Gene', (55, 58))	('inhibiting', 'NegReg', (177, 187))	('apoptosis', 'CPA', (88, 97))	('miR-205-5p', 'Var', (115, 125))	('Akt', 'Gene', '207', (197, 200))	('mTOR', 'Gene', (201, 205))	('apoptosis', 'biological_process', 'GO:0006915', ('88', '97'))	('decreased', 'NegReg', (59, 68))	('mTOR', 'Gene', '2475', (201, 205))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('Akt', 'Gene', (197, 200))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('PI3K', 'molecular_function', 'GO:0016303', ('192', '196'))	('Akt', 'Gene', '207', (55, 58))	('apoptosis', 'biological_process', 'GO:0097194', ('88', '97'))	('tumor', 'Disease', (160, 165))	('signaling pathway', 'biological_process', 'GO:0007165', ('206', '223'))
77805	31545453	In the present study, VEGFA expression was downregulated by miR-205-5p.	('downregulated', 'NegReg', (43, 56))	('VEGFA', 'Gene', '7422', (22, 27))	('expression', 'MPA', (28, 38))	('miR-205-5p', 'Var', (60, 70))	('VEGFA', 'Gene', (22, 27))
77807	31545453	Thus, we hypothesized that one mechanism by which miR-205-5p inactivated the PI3K/Akt pathway was through inhibition of VEGFA expression.	('PI3K', 'molecular_function', 'GO:0016303', ('77', '81'))	('VEGFA', 'Gene', '7422', (120, 125))	('Akt', 'Gene', '207', (82, 85))	('miR-205-5p', 'Var', (50, 60))	('VEGFA', 'Gene', (120, 125))	('Akt', 'Gene', (82, 85))	('inhibition', 'NegReg', (106, 116))	('inactivated', 'NegReg', (61, 72))
77808	31545453	We applied bioinformatics tools to identify the potential target genes of miR-205-5p and clarify the mechanisms by which miR-205-5p inhibited tumor growth.	('inhibited', 'NegReg', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('miR-205-5p', 'Gene', (74, 84))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('miR-205-5p', 'Var', (121, 131))
77811	31545453	Consistent with a previous study, the study also validated VEGFA as a target of miR-205-5p using a luciferase reporter assay.	('VEGFA', 'Gene', '7422', (59, 64))	('VEGFA', 'Gene', (59, 64))	('miR-205-5p', 'Var', (80, 90))
77812	31545453	Overexpression of miR-205-5p inhibited the expression of both the VEGFA mRNA and protein in 786-O and ACHN cells.	('inhibited', 'NegReg', (29, 38))	('miR-205-5p', 'Var', (18, 28))	('VEGFA', 'Gene', (66, 71))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('VEGFA', 'Gene', '7422', (66, 71))	('expression', 'MPA', (43, 53))	('protein', 'Protein', (81, 88))
77814	31545453	Based on these data, VEGFA is a direct target gene of miR-205-5p in RCC.	('VEGFA', 'Gene', (21, 26))	('miR-205-5p', 'Var', (54, 64))	('VEGFA', 'Gene', '7422', (21, 26))	('RCC', 'Disease', 'MESH:D002292', (68, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))
77818	31545453	Furthermore, inhibition of VEGFA could lead to a decrease in EMT markers in cancer stem cells.	('VEGFA', 'Gene', (27, 32))	('inhibition', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('decrease', 'NegReg', (49, 57))	('VEGFA', 'Gene', '7422', (27, 32))	('EMT', 'biological_process', 'GO:0001837', ('61', '64'))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
77822	31545453	Ectopic expression of miR-205-5p inhibited the proliferation, migration and invasion of RCC cells and promoted apoptosis.	('migration', 'CPA', (62, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('promoted', 'PosReg', (102, 110))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('RCC', 'Disease', 'MESH:D002292', (88, 91))	('RCC', 'Disease', (88, 91))	('miR-205-5p', 'Var', (22, 32))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('inhibited', 'NegReg', (33, 42))	('apoptosis', 'CPA', (111, 120))
77823	31545453	Overexpression of miR-205-5p repressed the PI3K/Akt/mTOR pathway.	('mTOR', 'Gene', (52, 56))	('Akt', 'Gene', (48, 51))	('miR-205-5p', 'Var', (18, 28))	('mTOR', 'Gene', '2475', (52, 56))	('PI3K', 'molecular_function', 'GO:0016303', ('43', '47'))	('Akt', 'Gene', '207', (48, 51))
77824	31545453	Moreover, miR-205-5p inhibited RCC growth in vivo in a mouse xenograft model.	('miR-205-5p', 'Var', (10, 20))	('mouse', 'Species', '10090', (55, 60))	('inhibited', 'NegReg', (21, 30))	('RCC', 'Disease', 'MESH:D002292', (31, 34))	('RCC', 'Disease', (31, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
77825	31545453	In addition, we identified VEGFA as a target of miR-205-5p in RCC.	('VEGFA', 'Gene', (27, 32))	('VEGFA', 'Gene', '7422', (27, 32))	('RCC', 'Disease', 'MESH:D002292', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('miR-205-5p', 'Var', (48, 58))
77848	33330027	Non-coding RNAs (ncRNAs) in plasma or serum, such as mircroRNA and long non-coding RNAs (lncRNAs), are considered as novel non-invasive biomarkers for cancers.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('long non-coding RNAs', 'Var', (67, 87))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('cancers', 'Disease', (151, 158))
77902	33330027	Real-Time PCR results confirmed that the expression level of plasma NR_038263 (SOCS2-AS1) showed a significant decrease in ccRCC patients (P = 0.004, Figure 3A).	('SOCS2-AS1', 'Gene', (79, 88))	('NR_038263', 'Var', (68, 77))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('patients', 'Species', '9606', (129, 137))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('SOCS2-AS1', 'Gene', '144481;8835;5729', (79, 88))	('decrease', 'NegReg', (111, 119))	('expression level', 'MPA', (41, 57))
77904	33330027	Expression of NR_038263 (SOCS2-AS1) was significantly lower in ccRCC tissues compared to that of the normal tissues (P < 0.0001, Figure 3B).	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('SOCS2-AS1', 'Gene', (25, 34))	('Expression', 'MPA', (0, 10))	('NR_038263', 'Var', (14, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('SOCS2-AS1', 'Gene', '144481;8835;5729', (25, 34))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('lower', 'NegReg', (54, 59))	('RCC', 'Disease', (65, 68))
77905	33330027	The expression of NR_038263 (SOCS2-AS1) was significantly lower in 786-O (P = 0.005) and ACHN (P= 0.045, Figure 3C) compared to that of the HK2 cells.	('HK2', 'molecular_function', 'GO:0008256', ('140', '143'))	('ACHN', 'Disease', (89, 93))	('lower', 'NegReg', (58, 63))	('expression', 'MPA', (4, 14))	('NR_038263', 'Var', (18, 27))	('SOCS2-AS1', 'Gene', (29, 38))	('786-O', 'CPA', (67, 72))	('SOCS2-AS1', 'Gene', '144481;8835;5729', (29, 38))
77907	33330027	NR_027011, NR_027471, uc.263-, and ENST00000442072 were highly expressed in the neoplasm and the plasma of ccRCC patients.	('patients', 'Species', '9606', (113, 121))	('NR_027011', 'Var', (0, 9))	('neoplasm', 'Disease', (80, 88))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('neoplasm', 'Disease', 'MESH:D009369', (80, 88))	('neoplasm', 'Phenotype', 'HP:0002664', (80, 88))	('NR_027471', 'Var', (11, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))
77908	33330027	NR_024256, ENST00000478814, and ENST00000436529 were down-regulated in the neoplasm and the plasma of ccRCC patients.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('NR_024256', 'Var', (0, 9))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('neoplasm', 'Disease', 'MESH:D009369', (75, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('ENST00000478814', 'Var', (11, 26))	('ENST00000436529', 'Var', (32, 47))	('patients', 'Species', '9606', (108, 116))	('neoplasm', 'Disease', (75, 83))	('neoplasm', 'Phenotype', 'HP:0002664', (75, 83))	('down-regulated', 'NegReg', (53, 67))	('RCC', 'Disease', (104, 107))
77909	33330027	The expression of H19, ENST00000413094, ENST00000439438, ENST00000443034, ENST00000448001, and NR_024054 was down-regulated in the E-MTAB-1830 and was up-regulated in our study.	('ENST00000448001', 'Var', (74, 89))	('down-regulated', 'NegReg', (109, 123))	('H19', 'Gene', '283120', (18, 21))	('H19', 'Gene', (18, 21))	('MTAB', 'molecular_function', 'GO:0047152', ('133', '137'))	('ENST00000443034', 'Var', (57, 72))	('NR_024054', 'Var', (95, 104))	('ENST00000413094', 'Var', (23, 38))	('ENST00000439438', 'Var', (40, 55))
77919	33330027	Irregular regulation of lncRNAs has been shown to be associated with the pathogenesis of several human cancers.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('regulation', 'biological_process', 'GO:0065007', ('10', '20'))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('human', 'Species', '9606', (97, 102))	('Irregular regulation', 'Var', (0, 20))	('associated', 'Reg', (53, 63))	('lncRNAs', 'Protein', (24, 31))	('pathogenesis', 'biological_process', 'GO:0009405', ('73', '85'))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
77931	33330027	In addition, the ccRCC patients with higher H19 expression were at a more advanced clinical stage with poorer prognosis than those with a low H19 level.	('higher', 'Var', (37, 43))	('age', 'Gene', '5973', (94, 97))	('patients', 'Species', '9606', (23, 31))	('H19', 'Gene', '283120', (142, 145))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('H19', 'Gene', (142, 145))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('ccRCC', 'Phenotype', 'HP:0006770', (17, 22))	('age', 'Gene', (94, 97))	('H19', 'Gene', '283120', (44, 47))	('H19', 'Gene', (44, 47))
77938	33330027	NEAT1 knock-down involved in the suppression of cell invasion and migration, as well as inhibition of the mRNA and protein expression of epithelial mesenchymal transition (EMT) related markers in ccRCC cell lines.	('NEAT1', 'Gene', (0, 5))	('NEAT1', 'Gene', '283131', (0, 5))	('inhibition', 'NegReg', (88, 98))	('cell invasion', 'CPA', (48, 61))	('knock-down', 'Var', (6, 16))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('ccRCC', 'Phenotype', 'HP:0006770', (196, 201))	('RCC', 'Disease', (198, 201))	('suppression', 'NegReg', (33, 44))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('EMT', 'biological_process', 'GO:0001837', ('172', '175'))	('epithelial mesenchymal transition', 'biological_process', 'GO:0001837', ('137', '170'))	('epithelial mesenchymal transition', 'CPA', (137, 170))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))
77943	33330027	AFAP1-AS1 silencing inhibited cell proliferation, EMT and metastasis through the PTEN-dependent signaling pathway.	('cell proliferation', 'CPA', (30, 48))	('EMT', 'biological_process', 'GO:0001837', ('50', '53'))	('AFAP1', 'Gene', (0, 5))	('AFAP1', 'Gene', '60312', (0, 5))	('inhibited', 'NegReg', (20, 29))	('PTEN', 'Gene', (81, 85))	('PTEN', 'Gene', '5728', (81, 85))	('AS1', 'Gene', '5729', (6, 9))	('AS1', 'Gene', (6, 9))	('signaling pathway', 'biological_process', 'GO:0007165', ('96', '113'))	('silencing', 'Var', (10, 19))	('cell proliferation', 'biological_process', 'GO:0008283', ('30', '48'))
77972	33330027	In addition, the expression of H19, ENST00000413094, ENST00000439438, ENST00000443034, ENST00000448001, and NR_024054 was down-regulated, while the E-MTAB-1830 was up-regulated.	('up-regulated', 'PosReg', (164, 176))	('down-regulated', 'NegReg', (122, 136))	('H19', 'Gene', '283120', (31, 34))	('NR_024054', 'Var', (108, 117))	('H19', 'Gene', (31, 34))	('expression', 'MPA', (17, 27))	('MTAB', 'molecular_function', 'GO:0047152', ('150', '154'))	('ENST00000443034', 'Var', (70, 85))	('ENST00000448001', 'Var', (87, 102))	('ENST00000413094', 'Var', (36, 51))	('ENST00000439438', 'Var', (53, 68))
77974	33330027	We speculated that the potential mechanisms were as follows: (a) the alteration of expression may contribute to the escape of cancer cells from the immune responses; (b) there might be degradation of some lncRNAs and mRNAs in the plasma; (c) the experimental bias may be partially responsible for this.	('escape', 'CPA', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('degradation', 'MPA', (185, 196))	('contribute', 'Reg', (98, 108))	('mRNAs', 'MPA', (217, 222))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('degradation', 'biological_process', 'GO:0009056', ('185', '196'))	('expression', 'MPA', (83, 93))	('alteration', 'Var', (69, 79))
77998	32111252	Compared to molecular subtypes reported by TCGA or other similar approaches, the subtypes generated by DeClust had higher correlations with cancer-intrinsic genomic alterations (e.g., somatic mutations and copy number variations) and lower correlations with tumor purity.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumor purity', 'Disease', (258, 270))	('correlations', 'Interaction', (122, 134))	('higher', 'PosReg', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('copy number variations', 'Var', (206, 228))	('tumor purity', 'Disease', 'MESH:D009369', (258, 270))
77999	32111252	While DeClust-identified subtypes were not more significantly associated with survival in general, DeClust identified a poor prognosis subtype of clear cell renal cancer, papillary renal cancer, and lung adenocarcinoma, all of which were characterized by CDKN2A deletions.	('renal cancer', 'Phenotype', 'HP:0009726', (157, 169))	('clear cell renal cancer', 'Phenotype', 'HP:0006770', (146, 169))	('renal cancer', 'Phenotype', 'HP:0009726', (181, 193))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (199, 218))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (199, 218))	('deletions', 'Var', (262, 271))	('papillary renal cancer', 'Disease', 'MESH:D007680', (171, 193))	('CDKN2A', 'Gene', (255, 261))	('clear cell renal cancer', 'Disease', (146, 169))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('papillary renal cancer', 'Disease', (171, 193))	('papillary renal cancer', 'Phenotype', 'HP:0006766', (171, 193))	('lung adenocarcinoma', 'Disease', (199, 218))	('CDKN2A', 'Gene', '1029', (255, 261))	('clear cell renal cancer', 'Disease', 'MESH:D002292', (146, 169))
78066	32111252	As a result, the expression profiles of SW780, BFTC950, and KU1919 cell lines in CCLE were chosen as the reference cancer cell profile for luminal, basal, and neuronal subtype, respectively.	('CCLE', 'Chemical', '-', (81, 85))	('cancer', 'Disease', (115, 121))	('SW780', 'CellLine', 'CVCL:1728', (40, 45))	('BFTC950', 'Var', (47, 54))	('KU1919', 'CellLine', 'CVCL:1344', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('SW780', 'Var', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
78084	32111252	For the pan-cancer dataset, we again focused on the accuracy of the primary outputs, but because ground truth in the pan-cancer dataset is not known, we examined how DeClust outputs compared to other approaches with regard to patient survival, known drive mutations, tumor purity, and cell compartment-specific gene expression (see Additional file 1: Figure S2 for an overview of our study workflow).	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('tumor purity', 'Disease', (267, 279))	('cancer', 'Disease', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('patient', 'Species', '9606', (226, 233))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('gene expression', 'biological_process', 'GO:0010467', ('311', '326'))	('tumor purity', 'Disease', 'MESH:D009369', (267, 279))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mutations', 'Var', (256, 265))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
78096	32111252	We subsequently confirmed the associations between DeClust estimates of stromal proportion and survival in independent datasets: GSE3538 for KIRC and GSE32894 for BLCA, respectively (Additional file 1: Figure S6, see the "Methods" section for details).	('GSE3538', 'Var', (129, 136))	('GSE3538', 'Chemical', '-', (129, 136))	('GSE32894', 'Var', (150, 158))	('GSE', 'Chemical', '-', (129, 132))	('BLCA', 'Chemical', '-', (163, 167))	('GSE', 'Chemical', '-', (150, 153))
78108	32111252	Cancer molecular subtypes driven by cancer cell-intrinsic properties as opposed to variations in non-cancer cell compartments are likely to be characterized by subtype-specific genomic alterations (somatic mutations or copy number alterations).	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (101, 107))	('copy number alterations', 'Var', (219, 242))	('cancer', 'Disease', (36, 42))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
78110	32111252	For example, FGFR3 mutations, one of the best characterized features of luminal-papillary bladder cancer, were present in 37% of the luminal-papillary subtype based on DeClust, versus 31% by TCGA (Fig.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('mutations', 'Var', (19, 28))	('luminal-papillary bladder cancer', 'Disease', (72, 104))	('luminal-papillary', 'Disease', (133, 150))	('FGFR3', 'Gene', (13, 18))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('luminal-papillary bladder cancer', 'Disease', 'MESH:D001749', (72, 104))	('FGFR3', 'Gene', '2261', (13, 18))
78111	32111252	Methylation is another common type of genomic alteration in cancer cells.	('Methylation', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
78113	32111252	A stronger subtype-specific association with genomic alterations is only an indirect indication that the subtypes are likely to be driven by cancer cell-intrinsic genomic alterations.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (141, 147))	('alterations', 'Var', (53, 64))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
78122	32111252	In summary, compared to TCGA subtypes, DeClust subtypes were more likely driven by cancer cell-intrinsic genetic alterations as opposed to non-cancer cell variations, in addition to having a stronger association with survival outcomes in certain tumor types.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('genetic alterations', 'Var', (105, 124))	('driven by', 'Reg', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Disease', (246, 251))	('cancer', 'Disease', (83, 89))
78130	32111252	Interestingly, all were enriched for CDKN2A deletions (Fig.	('deletions', 'Var', (44, 53))	('CDKN2A', 'Gene', '1029', (37, 43))	('CDKN2A', 'Gene', (37, 43))
78131	32111252	This is consistent with the previous discovery that samples with the same tumor suppressor gene inactivation in different cancer types tended to cluster together.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('inactivation', 'Var', (96, 108))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor suppressor', 'biological_process', 'GO:0051726', ('74', '90'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('74', '90'))	('tumor', 'Disease', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
78132	32111252	The associations of the worse survival and the outlier DeClust subtypes of KIRP, KIRC, and LUAD were replicated in independent datasets GSE2748, GSE3538, and GSE31210, respectively (Additional file 1: Figure S11).	('GSE', 'Chemical', '-', (136, 139))	('GSE', 'Chemical', '-', (145, 148))	('worse', 'NegReg', (24, 29))	('GSE3538', 'Var', (145, 152))	('GSE31210', 'Var', (158, 166))	('GSE2748', 'Var', (136, 143))	('GSE2748', 'Chemical', '-', (136, 143))	('GSE', 'Chemical', '-', (158, 161))	('GSE3538', 'Chemical', '-', (145, 152))
78169	32111252	Since identifying subtype-specific genetic alterations is an important strategy for identification of potential driver genes and associated therapeutic targets, DeClust could be a useful tool for such purposes, and helping to uncover genetic associations that are otherwise obscured by the non-cancer cell compartments.	('genetic alterations', 'Var', (35, 54))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancer', 'Disease', (294, 300))	('alterations', 'Var', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))
78171	32111252	DeClust identified poor prognosis subtypes in KIRC, KIRP, and LUAD, which were enriched for CDKN2A deletions, highlighting that for these cancer types, cancer cell-intrinsic molecular programs are key drivers of prognosis.	('cancer', 'Disease', (152, 158))	('CDKN2A', 'Gene', (92, 98))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('deletions', 'Var', (99, 108))	('CDKN2A', 'Gene', '1029', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
78198	32111252	The non-TCGA tumor expression datasets used in the study are available in GEO database: GSE2748, GSE3538, and GSE31210, GSE37614, GSE3538, GSE32894.	('tumor', 'Disease', (13, 18))	('GSE2748', 'Chemical', '-', (88, 95))	('GSE32894', 'Var', (139, 147))	('GSE3538', 'Chemical', '-', (97, 104))	('GSE', 'Chemical', '-', (110, 113))	('GSE', 'Chemical', '-', (97, 100))	('GSE3538', 'Chemical', '-', (130, 137))	('GSE', 'Chemical', '-', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('GSE37614', 'Var', (120, 128))	('GSE', 'Chemical', '-', (88, 91))	('GSE31210', 'Var', (110, 118))	('GSE', 'Chemical', '-', (120, 123))	('GSE3538', 'Var', (97, 104))	('GSE2748', 'Var', (88, 95))	('GSE', 'Chemical', '-', (130, 133))	('GSE3538', 'Var', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
78203	32046742	miR-124 and miR-203 synergistically inactivate EMT pathway via coregulation of ZEB2 in clear cell renal cell carcinoma (ccRCC) Clear cell renal cell carcinoma (ccRCC) is one of the most aggressive urological malignancies.	('miR-203', 'Gene', (12, 19))	('EMT', 'biological_process', 'GO:0001837', ('47', '50'))	('miR-124', 'Var', (0, 7))	('ccRCC', 'Disease', 'MESH:D002292', (160, 165))	('ccRCC', 'Disease', (120, 125))	('ZEB2', 'Gene', '9839', (79, 83))	('EMT pathway', 'Pathway', (47, 58))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (138, 158))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (127, 158))	('RCC', 'Phenotype', 'HP:0005584', (162, 165))	('inactivate', 'NegReg', (36, 46))	('miR-203', 'Gene', '406986', (12, 19))	('ccRCC', 'Phenotype', 'HP:0006770', (120, 125))	('ccRCC', 'Disease', (160, 165))	('Clear cell renal cell carcinoma', 'Disease', (127, 158))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (98, 118))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (87, 118))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('aggressive urological malignancies', 'Disease', (186, 220))	('coregulation', 'MPA', (63, 75))	('clear cell renal cell carcinoma', 'Disease', (87, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (160, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (127, 158))	('aggressive urological malignancies', 'Disease', 'MESH:D001523', (186, 220))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (87, 118))	('ccRCC', 'Disease', 'MESH:D002292', (120, 125))	('ZEB2', 'Gene', (79, 83))
78210	32046742	The inhibitory effects were abolished by ZEB2 knockdown.	('ZEB2', 'Gene', '9839', (41, 45))	('ZEB2', 'Gene', (41, 45))	('knockdown', 'Var', (46, 55))
78216	32046742	miRNAs are extensively implicated in fundamental biological processes and aberrant microRNA profiles have been reported in various cancers including RCC.	('RCC', 'Disease', (149, 152))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('N', 'Chemical', 'MESH:D009584', (89, 90))	('reported', 'Reg', (111, 119))	('RCC', 'Disease', 'MESH:D002292', (149, 152))	('microRNA profiles', 'MPA', (83, 100))	('aberrant', 'Var', (74, 82))
78221	32046742	We described a network-based procedure to identify tightly coregulating miRNAs, validated their expression, direct targets, function and evaluated their performance as binary classifiers in discriminating ccRCC from normal samples.	('ccRCC', 'Phenotype', 'HP:0006770', (205, 210))	('ccRCC', 'Disease', (205, 210))	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('ccRCC', 'Disease', 'MESH:D002292', (205, 210))	('miRNAs', 'Var', (72, 78))
78223	32046742	The data was derived from 34 specimens (17 RCC tumors and 17 corresponding non-tumor samples) based on platform GPL6480 and GPL8659.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('RCC', 'Disease', 'MESH:D002292', (43, 46))	('RCC', 'Disease', (43, 46))	('GPL6480', 'Var', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (47, 52))	('GPL8659', 'Var', (124, 131))
78235	32046742	The 786-O cell lines were inoculated in 24-well plates and cotransfected with miR-124 mimics, miR-203 mimics or scrambled mimics and WT/MT 3'UTR plasmids.	('miR-203', 'Gene', '406986', (94, 101))	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('WT', 'Disease', 'MESH:C536751', (133, 135))	('miR', 'Gene', '220972', (94, 97))	('miR', 'Gene', (94, 97))	('mimics', 'Var', (86, 92))	('miR-203', 'Gene', (94, 101))
78251	32046742	2c, a consistent reduction of luciferase activity upon either miR-124/miR-203 transfection suggested that both miRNAs repress ZEB2 directly.	('ZEB2', 'Gene', (126, 130))	('miR', 'Gene', (70, 73))	('luciferase activity', 'molecular_function', 'GO:0047077', ('30', '49'))	('transfection', 'Var', (78, 90))	('luciferase activity', 'molecular_function', 'GO:0045289', ('30', '49'))	('ZEB2', 'Gene', '9839', (126, 130))	('luciferase activity', 'molecular_function', 'GO:0047712', ('30', '49'))	('luciferase', 'Enzyme', (30, 40))	('luciferase activity', 'molecular_function', 'GO:0050397', ('30', '49'))	('miR', 'Gene', '220972', (62, 65))	('luciferase activity', 'molecular_function', 'GO:0050248', ('30', '49'))	('miR', 'Gene', '220972', (111, 114))	('miR-203', 'Gene', (70, 77))	('reduction', 'NegReg', (17, 26))	('miR', 'Gene', (62, 65))	('repress', 'NegReg', (118, 125))	('miR', 'Gene', '220972', (70, 73))	('miR-203', 'Gene', '406986', (70, 77))	('miR', 'Gene', (111, 114))	('activity', 'MPA', (41, 49))
78269	32046742	Both in RCC tissues and RCC cell lines where miR-124 and miR-203 were downregulated, we observed reduced expression of E-cadherin and beta-catenin (epithelial marker) as well as induced level of N-catenin and vimentin (mesenchymal markers), indicating that loss of both miRNAs significantly increased the migration and proliferation of ccRCC cells via regulating the key elements in EMT.	('RCC', 'Disease', 'MESH:D002292', (24, 27))	('RCC', 'Phenotype', 'HP:0005584', (338, 341))	('vimentin', 'cellular_component', 'GO:0045099', ('209', '217'))	('ccRCC', 'Phenotype', 'HP:0006770', (336, 341))	('N', 'Chemical', 'MESH:D009584', (195, 196))	('miR', 'Gene', (45, 48))	('increased', 'PosReg', (291, 300))	('vimentin', 'Gene', '7431', (209, 217))	('expression', 'MPA', (105, 115))	('vimentin', 'Gene', (209, 217))	('RCC', 'Disease', 'MESH:D002292', (338, 341))	('N', 'Chemical', 'MESH:D009584', (273, 274))	('cadherin', 'molecular_function', 'GO:0008014', ('121', '129'))	('EMT', 'biological_process', 'GO:0001837', ('383', '386'))	('reduced', 'NegReg', (97, 104))	('beta-catenin', 'Gene', (134, 146))	('loss', 'Var', (257, 261))	('miR', 'Gene', '220972', (270, 273))	('RCC', 'Disease', (8, 11))	('beta-catenin', 'Gene', '1499', (134, 146))	('miR', 'Gene', '220972', (57, 60))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('vimentin', 'cellular_component', 'GO:0045098', ('209', '217'))	('ccRCC', 'Disease', 'MESH:D002292', (336, 341))	('miR-203', 'Gene', (57, 64))	('downregulated', 'NegReg', (70, 83))	('migration', 'CPA', (305, 314))	('RCC', 'Phenotype', 'HP:0005584', (24, 27))	('regulating', 'Reg', (352, 362))	('RCC', 'Disease', (24, 27))	('miR', 'Gene', (270, 273))	('miR', 'Gene', (57, 60))	('RCC', 'Disease', 'MESH:D002292', (8, 11))	('ccRCC', 'Disease', (336, 341))	('E-cadherin', 'Gene', (119, 129))	('miR', 'Gene', '220972', (45, 48))	('E-cadherin', 'Gene', '999', (119, 129))	('miR-203', 'Gene', '406986', (57, 64))	('proliferation', 'CPA', (319, 332))	('RCC', 'Disease', (338, 341))
78270	32046742	Previous studies have confirmed that a large number of miRNAs was involved in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('involved', 'Reg', (66, 74))	('tumor', 'Disease', (78, 83))	('miRNAs', 'Var', (55, 61))
78274	32046742	Deregulation of miR-124 has been demonstrated in liver cancer, breast cancer, colorectal cancer, lung carcinoma and nasopharyngeal carcinoma.	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('breast cancer', 'Disease', (63, 76))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('lung carcinoma', 'Disease', 'MESH:D008175', (97, 111))	('liver cancer', 'Disease', 'MESH:D006528', (49, 61))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (116, 140))	('nasopharyngeal carcinoma', 'Disease', 'MESH:C538339', (116, 140))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('miR', 'Gene', '220972', (16, 19))	('colorectal cancer', 'Disease', (78, 95))	('liver cancer', 'Phenotype', 'HP:0002896', (49, 61))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('liver cancer', 'Disease', (49, 61))	('miR', 'Gene', (16, 19))	('nasopharyngeal carcinoma', 'Disease', (116, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('Deregulation', 'Var', (0, 12))	('lung carcinoma', 'Disease', (97, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))
78279	32046742	Methylation of miR-124 is more frequent in malignant ccRCC than in normal kidney tissues.	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('ccRCC', 'Disease', (53, 58))	('Methylation', 'Var', (0, 11))	('ccRCC', 'Disease', 'MESH:D002292', (53, 58))	('frequent', 'Reg', (31, 39))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('miR', 'Gene', '220972', (15, 18))	('miR', 'Gene', (15, 18))
78280	32046742	Hypermethylation of miR-124 is strongly associated with advanced RCC stage, differentiation grade and an increased risk of recurrence.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('Hypermethylation', 'Var', (0, 16))	('differentiation grade', 'CPA', (76, 97))	('miR', 'Gene', '220972', (20, 23))	('miR', 'Gene', (20, 23))	('associated', 'Reg', (40, 50))	('RCC', 'Disease', 'MESH:D002292', (65, 68))	('RCC', 'Disease', (65, 68))
78299	32046742	As previously shown and confirmed by our data, miR-124 and miR-203 transfection can also inhibit proliferation of renal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('transfection', 'Var', (67, 79))	('miR', 'Gene', '220972', (47, 50))	('renal cancer', 'Disease', (114, 126))	('miR', 'Gene', (47, 50))	('renal cancer', 'Phenotype', 'HP:0009726', (114, 126))	('miR', 'Gene', '220972', (59, 62))	('inhibit', 'NegReg', (89, 96))	('miR', 'Gene', (59, 62))	('renal cancer', 'Disease', 'MESH:D007680', (114, 126))	('miR-203', 'Gene', '406986', (59, 66))	('miR-203', 'Gene', (59, 66))
78307	32046742	However, in the process of tumor cell development, EMT will also cause the tumor cells to lose the properties of some epithelial cells to acquire the properties of some mesenchymal cells, and also enable the tumor cells to obtain stronger invasion and detachment ability.	('lose', 'NegReg', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cell development', 'biological_process', 'GO:0048468', ('33', '49'))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Disease', (27, 32))	('invasion', 'CPA', (239, 247))	('EMT', 'biological_process', 'GO:0001837', ('51', '54'))	('stronger', 'PosReg', (230, 238))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('enable', 'PosReg', (197, 203))	('properties', 'MPA', (99, 109))	('detachment ability', 'CPA', (252, 270))	('tumor', 'Disease', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('EMT', 'Var', (51, 54))	('tumor', 'Disease', (75, 80))
78309	32046742	Moreover, cancer cells can utilize EMT to acquire cancer stem cell characteristics through the modulation of miRNAs.	('modulation', 'Var', (95, 105))	('miRNAs', 'Protein', (109, 115))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('EMT', 'biological_process', 'GO:0001837', ('35', '38'))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', (10, 16))
78317	32046742	For example, in TGF, WNT and cytoskeletal remodeling pathway, TGF is considered to be the most critical factor in inducing EMT during developmental processes, carcinogenesis, and other pathological conditions.	('carcinogenesis', 'Disease', (159, 173))	('TGF', 'Var', (62, 65))	('inducing', 'PosReg', (114, 122))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('EMT', 'biological_process', 'GO:0001837', ('123', '126'))	('developmental processes', 'CPA', (134, 157))	('carcinogenesis', 'Disease', 'MESH:D063646', (159, 173))	('EMT', 'CPA', (123, 126))
78330	32046742	Therefore, activation of these genes can promote the development of EMT and initiate tumor growth and metastasis procedures.	('development of EMT', 'CPA', (53, 71))	('tumor', 'Disease', (85, 90))	('activation', 'Var', (11, 21))	('EMT', 'biological_process', 'GO:0001837', ('68', '71'))	('promote', 'PosReg', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('initiate', 'PosReg', (76, 84))
78338	32046742	SNG201905 and SYN201614) and Qinglan Project of Jiangsu Province.	('N', 'Chemical', 'MESH:D009584', (16, 17))	('SYN201614', 'Chemical', 'MESH:C000593256', (14, 23))	('SNG201905', 'Var', (0, 9))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('SYN201614', 'Var', (14, 23))
78346	32709062	Differential expression of PD-L1 on tumor samples could select a subset of patients who could benefit more in terms of PFS (those with higher levels; p-value for difference between subgroups: <0.0001) but it did not seem to impact in OS results (p-value for difference: 0.63).	('PFS', 'MPA', (119, 122))	('Differential', 'Var', (0, 12))	('benefit', 'PosReg', (94, 101))	('patients', 'Species', '9606', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('PD-L1', 'Gene', (27, 32))	('tumor', 'Disease', (36, 41))
78376	32709062	Selected studies have shown that either tumor cell or tumor-infiltrating immune cell PD-L1 overexpression is associated with deeper response rates with ICIs across different solid tumors, not only metastatic RCC.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('solid tumors', 'Disease', (174, 186))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('RCC', 'Phenotype', 'HP:0005584', (208, 211))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (54, 59))	('PD-L1', 'Gene', (85, 90))	('RCC', 'Disease', (208, 211))	('tumor', 'Disease', (180, 185))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('solid tumors', 'Disease', 'MESH:D009369', (174, 186))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('overexpression', 'Var', (91, 105))
78379	32709062	One theory is that the expression of PD-L2 modifies the response; current available tests do not assess this protein.	('response', 'MPA', (56, 64))	('PD-L2', 'Gene', (37, 42))	('modifies', 'Reg', (43, 51))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('PD-L2', 'Gene', '80380', (37, 42))	('expression', 'Var', (23, 33))
78382	32709062	However, the subgroup of patients with low-to-no PD-L1 expression (IC0) tended to have worse survival.	('low-to-no', 'Var', (39, 48))	('PD-L1 expression', 'Protein', (49, 65))	('worse', 'PosReg', (87, 92))	('patients', 'Species', '9606', (25, 33))
78403	32709062	Although further studies are necessary to confirm the findings, loss-of-function mutations in specific genes such as PBRM1 might predict clinical response to anti-PD-1 antibodies in metastatic RCC according to whole-exome sequencing studies in patients treated with nivolumab.	('RCC', 'Disease', (193, 196))	('RCC', 'Phenotype', 'HP:0005584', (193, 196))	('nivolumab', 'Chemical', 'MESH:D000077594', (266, 275))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('PBRM1', 'Gene', (117, 122))	('PBRM1', 'Gene', '55193', (117, 122))	('mutations', 'Var', (81, 90))	('PD-1', 'Gene', (163, 167))	('PD-1', 'Gene', '5133', (163, 167))	('patients', 'Species', '9606', (244, 252))	('loss-of-function', 'NegReg', (64, 80))
78408	32709062	The microbiome influences the processes of antitumor immunity, and the variations of some bacterial species have been associated with an increased likelihood of response.	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('influences', 'Reg', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('associated', 'Reg', (118, 128))	('tumor', 'Disease', (47, 52))	('variations', 'Var', (71, 81))
78432	32709062	The HR for PFS was improved in those patients treated with ICIs compared to standard of care (HR 0.82; 95% CI 0.73-0.92, p = 0.0006), as well as the HR for OS (HR 0.73; 95% CI 0.60-0.88, p = 0.0012).	('patients', 'Species', '9606', (37, 45))	('improved', 'PosReg', (19, 27))	('ICIs', 'Var', (59, 63))	('PFS', 'Disease', (11, 14))
78443	32709062	Therapy based on ICIs improved PFS compared to standard of care in PD-L1 positive patients but not in PD-L1 negative patients.	('improved', 'PosReg', (22, 30))	('patients', 'Species', '9606', (82, 90))	('PD-L1', 'Gene', (67, 72))	('PFS', 'MPA', (31, 34))	('positive', 'Var', (73, 81))	('patients', 'Species', '9606', (117, 125))
78447	32709062	On the other hand, as a consequence of their worse prognosis, PD-L1 positive patients could present shorter median PFS with TKIs compared to PD-L1 negative patients and this feature could explain the difference observed between these groups in terms of PFS but not OS; in this case the positive effect of immunotherapy would manifest earlier in the PD-L1 positive population.	('patients', 'Species', '9606', (156, 164))	('positive', 'Var', (68, 76))	('PFS', 'MPA', (115, 118))	('TKIs', 'MPA', (124, 128))	('shorter', 'NegReg', (100, 107))	('patients', 'Species', '9606', (77, 85))	('PD-L1', 'Gene', (62, 67))
78460	32709062	The combination of nivolumab with relatlimab (BMS-986016), an antibody directed against LAG3, has been shown to achieve an ORR of 16% in patients with advanced melanoma progressing after PD-1 or PD-L1 blockade; relatlimab is being tested in a phase III trial (ClinicalTrials.gov Identifier: NCT03470922).	('antibody', 'cellular_component', 'GO:0019814', ('62', '70'))	('PD-1 or PD-L1 blockade', 'Disease', (187, 209))	('LAG3', 'Gene', (88, 92))	('BMS-986016', 'Var', (46, 56))	('melanoma', 'Disease', (160, 168))	('LAG3', 'Gene', '3902', (88, 92))	('relatlimab', 'Chemical', '-', (211, 221))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('patients', 'Species', '9606', (137, 145))	('relatlimab', 'Chemical', '-', (34, 44))	('antibody', 'molecular_function', 'GO:0003823', ('62', '70'))	('PD-1 or PD-L1 blockade', 'Disease', 'MESH:D010300', (187, 209))	('antibody', 'cellular_component', 'GO:0042571', ('62', '70'))	('combination', 'Interaction', (4, 15))	('antibody', 'cellular_component', 'GO:0019815', ('62', '70'))	('nivolumab', 'Chemical', 'MESH:D000077594', (19, 28))
78468	32709062	OX40 agonists, such as PF-04518600 (in combination with axitinib or avelumab) are other types of molecules undergoing clinical development in RCC.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('OX40', 'Gene', '7293', (0, 4))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('PF-04518600', 'Chemical', '-', (23, 34))	('OX40', 'Gene', (0, 4))	('PF-04518600', 'Var', (23, 34))	('axitinib', 'Chemical', 'MESH:D000077784', (56, 64))	('avelumab', 'Chemical', 'MESH:C000609138', (68, 76))	('men', 'Species', '9606', (134, 137))
78498	28927098	Dysregulation of the Notch signaling pathway has been demonstrated to be associated with multiple types of human cancer, including CCRCC.	('Notch', 'Gene', '4851', (21, 26))	('Notch signaling pathway', 'biological_process', 'GO:0007219', ('21', '44'))	('Dysregulation', 'Var', (0, 13))	('human', 'Species', '9606', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('Notch', 'Gene', (21, 26))	('associated', 'Reg', (73, 83))	('cancer', 'Disease', (113, 119))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('CCRCC', 'Phenotype', 'HP:0006770', (131, 136))	('RCC', 'Disease', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
78518	28927098	The symbol - was considered as negative; + and ++ indicated low expression of Notch 1 protein, while +++ indicated high expression.	('expression', 'MPA', (64, 74))	('expression', 'MPA', (120, 130))	('low', 'NegReg', (60, 63))	('Notch 1', 'Gene', '4851', (78, 85))	('Notch 1', 'Gene', (78, 85))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('+++', 'Var', (101, 104))
78541	28927098	14702; dilution, 1:500; Cell Signaling Technology, Inc., Danvers, MA, USA), phosphorylated (p)-Akt (cat.	('cat', 'molecular_function', 'GO:0004096', ('100', '103'))	('Akt', 'Gene', '207', (95, 98))	('Akt', 'Gene', (95, 98))	('Signaling', 'biological_process', 'GO:0023052', ('29', '38'))	('phosphorylated', 'Var', (76, 90))
78562	28927098	Additional analysis indicated that high expression of Notch 1 protein was associated with TNM stage (chi2=6.267; P<0.05), Fuhrman grade (chi2=7.90; P<0.01) and tumor size (chi2=4.160; P<0.05), but not associated with sex (chi2=0.036; P>0.05) and age (chi2=0.054; P>0.05) (Table III).	('Fuhrman', 'Disease', (122, 129))	('protein', 'Protein', (62, 69))	('Notch 1', 'Gene', '4851', (54, 61))	('TNM', 'Disease', (90, 93))	('Notch 1', 'Gene', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))	('high', 'Var', (35, 39))	('associated', 'Reg', (74, 84))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
78574	28927098	Together, these findings indicated that inhibition of Notch 1 expression could inhibit cell proliferation and induce cell apoptosis in 786-O cells.	('inhibit', 'NegReg', (79, 86))	('inhibition', 'Var', (40, 50))	('Notch 1', 'Gene', '4851', (54, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('122', '131'))	('apoptosis', 'biological_process', 'GO:0006915', ('122', '131'))	('cell proliferation', 'biological_process', 'GO:0008283', ('87', '105'))	('Notch 1', 'Gene', (54, 61))	('cell proliferation', 'CPA', (87, 105))	('induce', 'Reg', (110, 116))	('cell apoptosis', 'CPA', (117, 131))	('expression', 'Protein', (62, 72))
78584	28927098	These findings demonstrated that inhibition of Notch 1 expression could suppress the activity of the Akt/mTOR signaling pathway in 786-O cells.	('inhibition', 'Var', (33, 43))	('Akt', 'Gene', '207', (101, 104))	('suppress', 'NegReg', (72, 80))	('Notch 1', 'Gene', '4851', (47, 54))	('Akt', 'Gene', (101, 104))	('expression', 'MPA', (55, 65))	('mTOR', 'Gene', (105, 109))	('mTOR', 'Gene', '2475', (105, 109))	('signaling pathway', 'biological_process', 'GO:0007165', ('110', '127'))	('Notch 1', 'Gene', (47, 54))	('activity', 'MPA', (85, 93))
78604	28927098	In the present study, Bcl-2 and procaspase-3 expression exhibited a marked dose-dependent decrease in 786-O cells following treatment with increasing concentrations of Notch 1-specific siRNA, which indicated that inhibition of Notch 1 by Notch 1 siRNA downregulated the Bcl-2 expression, resulting in the initiation of apoptotic process and the cleavage of procaspase-3, and ultimately leading to apoptosis in 786-O cells.	('Notch 1', 'Gene', (227, 234))	('apoptosis', 'biological_process', 'GO:0097194', ('397', '406'))	('apoptosis', 'biological_process', 'GO:0006915', ('397', '406'))	('Bcl-2', 'Gene', (22, 27))	('Bcl-2', 'Gene', '596', (270, 275))	('procaspase-3', 'Gene', (32, 44))	('Notch 1', 'Gene', (168, 175))	('cleavage', 'MPA', (345, 353))	('procaspase-3', 'Gene', (357, 369))	('Notch 1', 'Gene', (238, 245))	('Bcl-2', 'molecular_function', 'GO:0015283', ('270', '275'))	('Bcl-2', 'Gene', '596', (22, 27))	('apoptotic process', 'CPA', (319, 336))	('procaspase-3', 'Gene', '836', (32, 44))	('inhibition', 'Var', (213, 223))	('procaspase-3', 'Gene', '836', (357, 369))	('Notch 1', 'Gene', '4851', (227, 234))	('Bcl-2', 'molecular_function', 'GO:0015283', ('22', '27'))	('decrease', 'NegReg', (90, 98))	('expression', 'MPA', (276, 286))	('downregulated', 'NegReg', (252, 265))	('apoptotic process', 'biological_process', 'GO:0006915', ('319', '336'))	('leading to', 'Reg', (386, 396))	('Notch 1', 'Gene', '4851', (168, 175))	('expression', 'MPA', (45, 55))	('Bcl-2', 'Gene', (270, 275))	('Notch 1', 'Gene', '4851', (238, 245))
78612	28927098	It has been indicated that phosphorylated mTOR could induce cell cycle transition between the G1 and S phase to facilitate cell proliferation and control protein synthesis through the regulation of P70S6K.	('mTOR', 'Gene', '2475', (42, 46))	('cell cycle transition', 'biological_process', 'GO:0044771', ('60', '81'))	('P70S6K', 'Gene', '6198', (198, 204))	('S phase', 'biological_process', 'GO:0051320', ('101', '108'))	('mTOR', 'Gene', (42, 46))	('P70S6K', 'Gene', (198, 204))	('cell proliferation', 'CPA', (123, 141))	('protein synthesis', 'biological_process', 'GO:0006412', ('154', '171'))	('regulation', 'biological_process', 'GO:0065007', ('184', '194'))	('cell proliferation', 'biological_process', 'GO:0008283', ('123', '141'))	('control protein synthesis', 'MPA', (146, 171))	('cell cycle transition', 'biological_process', 'GO:0044770', ('60', '81'))	('induce', 'Reg', (53, 59))	('phosphorylated', 'Var', (27, 41))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('facilitate', 'PosReg', (112, 122))	('cell cycle transition', 'CPA', (60, 81))
78618	28927098	In addition, inhibition of Notch 1 expression inhibited cell proliferation and induced cell apoptosis in CCRCC 786-O cells, suggested that Notch 1 was involved in CCRCC development.	('Notch 1', 'Gene', (27, 34))	('Notch 1', 'Gene', (139, 146))	('cell proliferation', 'biological_process', 'GO:0008283', ('56', '74'))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('RCC', 'Disease', (107, 110))	('cell apoptosis', 'CPA', (87, 101))	('cell proliferation', 'CPA', (56, 74))	('CCRCC', 'Phenotype', 'HP:0006770', (163, 168))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('Notch 1', 'Gene', '4851', (27, 34))	('inhibited', 'NegReg', (46, 55))	('apoptosis', 'biological_process', 'GO:0097194', ('92', '101'))	('Notch 1', 'Gene', '4851', (139, 146))	('apoptosis', 'biological_process', 'GO:0006915', ('92', '101'))	('CCRCC', 'Phenotype', 'HP:0006770', (105, 110))	('inhibition', 'Var', (13, 23))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('RCC', 'Disease', (165, 168))
78625	27435027	However, 195,038 (41%) of all investigated CpG sites, including sites within pharmacogenes, were differentially methylated (adjusted P < 0.05) in five established RCC cell lines compared to primary tumors, resulting in altered transcriptional expression.	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('RCC', 'Disease', (163, 166))	('primary tumors', 'Disease', (190, 204))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('CpG', 'Gene', (43, 46))	('transcriptional expression', 'MPA', (227, 253))	('primary tumors', 'Disease', 'MESH:D009369', (190, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('methylated', 'Var', (112, 122))	('altered', 'Reg', (219, 226))
78626	27435027	Exemplarily, gene-specific analyses of DNA methylation, mRNA and protein expression demonstrate lack of expression of the clinically important drug transporter OCT2 (encoded by SLC22A2) in cell lines due to hypermethylation compared to tumors or metastases.	('DNA methylation', 'biological_process', 'GO:0006306', ('39', '54'))	('lack', 'NegReg', (96, 100))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('metastases', 'Disease', (246, 256))	('hypermethylation', 'Var', (207, 223))	('expression', 'MPA', (104, 114))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('OCT2', 'Gene', '6582', (160, 164))	('SLC22A2', 'Gene', (177, 184))	('metastases', 'Disease', 'MESH:D009362', (246, 256))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('tumors', 'Disease', (236, 242))	('SLC22A2', 'Gene', '6582', (177, 184))	('tumors', 'Disease', 'MESH:D009369', (236, 242))	('OCT2', 'Gene', (160, 164))
78627	27435027	Our findings provide evidence that RCC cell lines are of limited benefit for prediction of drug effects due to epigenetic alterations.	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('epigenetic alterations', 'Var', (111, 133))	('RCC', 'Disease', (35, 38))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
78638	27435027	For instance, genetic polymorphisms in ADME genes like the efflux transporter ABCB1 are associated with survival and toxicity in patients with metastatic RCC treated with sunitinib.	('ABCB1', 'Gene', (78, 83))	('ABCB1', 'Gene', '5243', (78, 83))	('patients', 'Species', '9606', (129, 137))	('toxicity', 'Disease', 'MESH:D064420', (117, 125))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('toxicity', 'Disease', (117, 125))	('RCC', 'Disease', (154, 157))	('genetic polymorphisms', 'Var', (14, 35))	('RCC', 'Phenotype', 'HP:0005584', (154, 157))	('efflux', 'biological_process', 'GO:0140115', ('59', '65'))	('sunitinib', 'Chemical', 'MESH:D000077210', (171, 180))	('associated with', 'Reg', (88, 103))	('efflux', 'biological_process', 'GO:0140352', ('59', '65'))
78643	27435027	This is of importance since epigenetic regulation through DNA methylation is crucial for cancer progression and metastases.	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('metastases', 'Disease', (112, 122))	('DNA methylation', 'biological_process', 'GO:0006306', ('58', '73'))	('cancer', 'Disease', (89, 95))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('regulation', 'biological_process', 'GO:0065007', ('39', '49'))	('DNA methylation', 'Var', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
78687	27435027	However, predominantly hypermethylation in CpG islands and related shores was observed in cell lines compared to primary tumors (Fig.	('primary tumors', 'Disease', 'MESH:D009369', (113, 127))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('observed', 'Reg', (78, 86))	('hypermethylation', 'Var', (23, 39))	('primary tumors', 'Disease', (113, 127))
78689	27435027	73.5% of CpG sites were significantly hypermethylated in the five investigated cell lines compared to primary ccRCC (Fig.	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('hypermethylated', 'Var', (38, 53))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))
78694	27435027	In summary, 1981 (41.7%) CpG sites within ADME genes and 1688 (39.3%) individual CpG sites within target gene regions were significantly (adjusted P < 0.05) differentially methylated between cell lines and primary ccRCC (see Volcano plot Fig.	('methylated', 'Var', (172, 182))	('differentially', 'Reg', (157, 171))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('ADME genes', 'Gene', (42, 52))	('RCC', 'Disease', (216, 219))	('RCC', 'Phenotype', 'HP:0005584', (216, 219))	('ccRCC', 'Phenotype', 'HP:0006770', (214, 219))
78695	27435027	Moreover, 399 (8.4%) of those CpG sites within ADME genes and 366 (8.5%) individual CpG sites within target gene regions were differentially methylated between cell lines and primary ccRCC with an adjusted P < 1E-05 (see Volcano plot Fig.	('RCC', 'Disease', (185, 188))	('ccRCC', 'Phenotype', 'HP:0006770', (183, 188))	('differentially', 'Reg', (126, 140))	('ADME genes', 'Gene', (47, 57))	('methylated', 'Var', (141, 151))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('RCC', 'Disease', 'MESH:C538614', (185, 188))
78696	27435027	Most of these significant sites in ADME (78.0%) and drug target genes (82.5%) were hypermethylated in cell lines compared to primary ccRCC tumors, which is comparable to the methylation alterations observed for other genes.	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('ccRCC tumors', 'Disease', (133, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('methylation', 'biological_process', 'GO:0032259', ('174', '185'))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('ADME', 'Gene', (35, 39))	('hypermethylated', 'Var', (83, 98))	('ccRCC tumors', 'Disease', 'MESH:D009369', (133, 145))
78703	27435027	Since aberrant methylation of pharmacogenes and drug targets might result in altered gene expression of the respective genes, we next investigated their transcriptional expression in cell lines as well as primary ccRCC and metastases samples using Affymetrix Human Transcriptome 2.0 microarrays.	('result', 'Reg', (67, 73))	('metastases', 'Disease', 'MESH:D009362', (223, 233))	('gene expression', 'biological_process', 'GO:0010467', ('85', '100'))	('gene expression', 'MPA', (85, 100))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('aberrant', 'Var', (6, 14))	('RCC', 'Disease', 'MESH:C538614', (215, 218))	('RCC', 'Disease', (215, 218))	('RCC', 'Phenotype', 'HP:0005584', (215, 218))	('ccRCC', 'Phenotype', 'HP:0006770', (213, 218))	('altered', 'Reg', (77, 84))	('methylation', 'MPA', (15, 26))	('Human', 'Species', '9606', (259, 264))	('metastases', 'Disease', (223, 233))
78728	27435027	In RCC cell lines, OCT2 protein expression is downregulated due to hypermethylation in the SLC22A2 promoter region compared to primary tumors or metastases.	('OCT2', 'Gene', (19, 23))	('metastases', 'Disease', (145, 155))	('primary tumors', 'Disease', (127, 141))	('protein', 'Protein', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('primary tumors', 'Disease', 'MESH:D009369', (127, 141))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('metastases', 'Disease', 'MESH:D009362', (145, 155))	('hypermethylation', 'Var', (67, 83))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('downregulated', 'NegReg', (46, 59))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('RCC', 'Disease', (3, 6))	('OCT2', 'Gene', '6582', (19, 23))	('expression', 'MPA', (32, 42))	('SLC22A2', 'Gene', '6582', (91, 98))	('RCC', 'Disease', 'MESH:C538614', (3, 6))	('SLC22A2', 'Gene', (91, 98))
78729	27435027	Therefore, detailed knowledge not only of the epigenetic alterations present in primary tumor tissue, but also in metastatic tissue is of great interest especially for the development of novel treatment strategies for patients with metastatic disease.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('patients', 'Species', '9606', (218, 226))	('epigenetic alterations', 'Var', (46, 68))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
78751	27435027	breast, prostate, colon) demonstrating CpG island hypermethylation in cancer cell lines compared to primary tumors.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('CpG', 'Protein', (39, 42))	('primary tumors', 'Disease', (100, 114))	('colon', 'Disease', (18, 23))	('hypermethylation', 'Var', (50, 66))	('primary tumors', 'Disease', 'MESH:D009369', (100, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('colon', 'Disease', 'MESH:D015179', (18, 23))
78753	27435027	the organic cation transporter OCT2/SLC22A2) were expressed at high levels in primary tumors and metastases, but seem to be downregulated in any of the investigated RCC cell lines due to hypermethylation.	('SLC22A2', 'Gene', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('organic cation transporter', 'MPA', (4, 30))	('metastases', 'Disease', (97, 107))	('primary tumors', 'Disease', 'MESH:D009369', (78, 92))	('SLC22A2', 'Gene', '6582', (36, 43))	('hypermethylation', 'Var', (187, 203))	('OCT2', 'Gene', '6582', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('downregulated', 'NegReg', (124, 137))	('primary tumors', 'Disease', (78, 92))	('metastases', 'Disease', 'MESH:D009362', (97, 107))	('OCT2', 'Gene', (31, 35))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('RCC', 'Disease', (165, 168))
78754	27435027	Interestingly, these cell lines differ in their basal phenotypes and genomes, such as the mutation status in the von Hippel-Lindau (VHL) gene.	('von Hippel-Lindau', 'Gene', '7428', (113, 130))	('VHL', 'Disease', (132, 135))	('VHL', 'Disease', 'MESH:D006623', (132, 135))	('mutation', 'Var', (90, 98))	('von Hippel-Lindau', 'Gene', (113, 130))
78799	30899419	SET-ing the stage for PI3Kbeta inhibitor sensitivity in clear cell renal cell carcinoma Genomic profiling of patients with clear cell renal cell carcinoma (ccRCC) has consistently shown that inactivation by mutation or methylation of the Von Hippel Lindau gene is a founder event in ccRCC carcinogenesis.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('patients', 'Species', '9606', (109, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (156, 161))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (67, 87))	('PI3Kbeta', 'Gene', (22, 30))	('Von Hippel Lindau', 'Disease', (238, 255))	('clear cell renal cell carcinoma', 'Disease', (56, 87))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (123, 154))	('methylation', 'Var', (219, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('PI3Kbeta', 'Gene', '5291', (22, 30))	('mutation', 'Var', (207, 215))	('ccRCC', 'Disease', (283, 288))	('Von Hippel Lindau', 'Disease', 'MESH:D006623', (238, 255))	('methylation', 'biological_process', 'GO:0032259', ('219', '230'))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (56, 87))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (123, 154))	('inactivation', 'Var', (191, 203))	('ccRCC', 'Phenotype', 'HP:0006770', (283, 288))	('clear cell renal cell carcinoma', 'Disease', (123, 154))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (134, 154))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (56, 87))
78800	30899419	In addition, loss of chromosome 3p-the chromosome on which VHL and other key drivers of ccRCC reside-is the most frequent chromosomal aberration seen in ccRCC.	('VHL', 'Gene', '7428', (59, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (153, 158))	('frequent chromosomal aberration', 'Phenotype', 'HP:0040012', (113, 144))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('ccRCC', 'Disease', (88, 93))	('loss', 'Var', (13, 17))	('chromosome', 'cellular_component', 'GO:0005694', ('21', '31'))	('chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))	('VHL', 'Gene', (59, 62))
78802	30899419	Other 3p genes including SWI/SNF complex gene PBRM1, the histone deubiquitinase BAP1, as well as the histone methyltransferase SETD2 are found to be mutated in 40-50%, 10-15%, and 10-15% ccRCC tumors, respectively and result in differential impact on RCC aggressiveness and prognosis.	('RCC tumors', 'Disease', (189, 199))	('mutated', 'Var', (149, 156))	('aggressiveness', 'Phenotype', 'HP:0000718', (255, 269))	('BAP1', 'Gene', '8314', (80, 84))	('RCC tumors', 'Disease', 'MESH:C538614', (189, 199))	('SETD2', 'Gene', '29072', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('65', '79'))	('RCC aggressiveness', 'Disease', (251, 269))	('PBRM1', 'Gene', (46, 51))	('SETD2', 'Gene', (127, 132))	('BAP1', 'Gene', (80, 84))	('impact', 'Reg', (241, 247))	('RCC aggressiveness', 'Disease', 'MESH:C538614', (251, 269))	('ccRCC', 'Phenotype', 'HP:0006770', (187, 192))	('PBRM1', 'Gene', '55193', (46, 51))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('25', '40'))
78805	30899419	In this current study, Terzo and Lim et al present preclinical data showing that SETD2 mutant RCC cells and xenograft RCC tumors display increased sensitivity, as evidenced by decreased cell viability and cellular proliferation, to PI3Kbeta-specific inhibition compared to SETD2 wildtype cells.	('RCC tumors', 'Disease', 'MESH:C538614', (118, 128))	('Lim', 'Gene', '10611', (33, 36))	('SETD2', 'Gene', '29072', (81, 86))	('sensitivity', 'MPA', (147, 158))	('Lim', 'Gene', (33, 36))	('SETD2', 'Gene', '29072', (273, 278))	('RCC tumors', 'Disease', (118, 128))	('SETD2', 'Gene', (273, 278))	('decreased', 'NegReg', (176, 185))	('cellular proliferation', 'CPA', (205, 227))	('SETD2', 'Gene', (81, 86))	('cell viability', 'CPA', (186, 200))	('mutant', 'Var', (87, 93))	('PI3Kbeta', 'Gene', '5291', (232, 240))	('increased', 'PosReg', (137, 146))	('PI3Kbeta', 'Gene', (232, 240))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
78806	30899419	Furthermore, PI3Kbeta and pan-PI3K, but not PI3Kalpha, inhibition leads to reduced cell viability and migration in a SETD2-loss dependent manner.	('pan-PI3K', 'Var', (26, 34))	('cell viability', 'CPA', (83, 97))	('reduced', 'NegReg', (75, 82))	('PI3Kbeta', 'Gene', '5291', (13, 21))	('SETD2', 'Gene', '29072', (117, 122))	('PI3K', 'molecular_function', 'GO:0016303', ('30', '34'))	('SETD2', 'Gene', (117, 122))	('PI3Kbeta', 'Gene', (13, 21))	('PI3Kalpha', 'Gene', '5290', (44, 53))	('PI3Kalpha', 'Gene', (44, 53))
78807	30899419	In addition, the AKT-specific inhibitor MK2206 led to similar anti-cancer activity and reduced pS6 phosphorylation levels only in SETD2-deficient cells, suggesting that AKT is a key effector linking SETD2 to PI3Kbeta.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('AKT', 'Gene', (17, 20))	('phosphorylation', 'biological_process', 'GO:0016310', ('99', '114'))	('cancer', 'Disease', (67, 73))	('SETD2', 'Gene', '29072', (130, 135))	('reduced', 'NegReg', (87, 94))	('AKT', 'Gene', (169, 172))	('PI3Kbeta', 'Gene', (208, 216))	('SETD2', 'Gene', '29072', (199, 204))	('MK2206', 'Var', (40, 46))	('SETD2', 'Gene', (130, 135))	('PI3Kbeta', 'Gene', '5291', (208, 216))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('SETD2', 'Gene', (199, 204))	('AKT', 'Gene', '207', (17, 20))	('MK2206', 'Chemical', 'MESH:C548887', (40, 46))	('pS6 phosphorylation levels', 'MPA', (95, 121))	('AKT', 'Gene', '207', (169, 172))
78810	30899419	For example, a phase 2 study of the AKT-inhibitor MK2206 in second-line setting for patients with metastatic ccRCC did not meet its primary efficacy endpoint and showed a high incidence of adverse events.	('MK2206', 'Var', (50, 56))	('patients', 'Species', '9606', (84, 92))	('AKT', 'Gene', '207', (36, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('metastatic ccRCC', 'Disease', (98, 114))	('AKT', 'Gene', (36, 39))	('MK2206', 'Chemical', 'MESH:C548887', (50, 56))
78821	32214151	Renal carcinoma CD105-/CD44- cells display stem-like properties in vitro and form aggressive tumors in vivo Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer.	('kidney cancer', 'Disease', 'MESH:D007680', (167, 180))	('Renal carcinoma', 'Disease', 'MESH:C538614', (0, 15))	('kidney cancer', 'Disease', (167, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (6, 15))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (108, 139))	('aggressive tumors', 'Disease', 'MESH:D001523', (82, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('CD105-/CD44- cells', 'Var', (16, 34))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (108, 139))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('aggressive tumors', 'Disease', (82, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (119, 139))	('Renal carcinoma', 'Disease', (0, 15))	('Clear cell renal cell carcinoma', 'Disease', (108, 139))	('Renal carcinoma', 'Phenotype', 'HP:0005584', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('kidney cancer', 'Phenotype', 'HP:0009726', (167, 180))
78826	32214151	Tumor growth was observed after implantation of CD105+, CD44+, CD44-, CD44-/CD105+ and CD44-/CD105- but not CD105- or CD44+/CD105+.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CD44+', 'Var', (56, 61))	('CD105', 'Gene', (48, 53))	('CD44-', 'Var', (63, 68))	('CD105', 'Gene', '13805', (48, 53))	('CD105', 'Gene', '13805', (93, 98))	('CD105', 'Gene', (93, 98))	('CD105', 'Gene', (124, 129))	('CD105', 'Gene', (108, 113))	('CD105', 'Gene', '13805', (76, 81))	('CD105', 'Gene', '13805', (124, 129))	('CD105', 'Gene', (76, 81))	('CD105', 'Gene', '13805', (108, 113))	('Tumor growth', 'CPA', (0, 12))
78836	32214151	As biomarkers of CSCs multiple surface proteins have been indicated including: CD105, CD133, CD44, or CXCR4; but the co-expression of multiple membrane markers on RCC-CSCs is not defined.	('CD133', 'Gene', (86, 91))	('CD133', 'Gene', '8842', (86, 91))	('CD105', 'Gene', '13805', (79, 84))	('CD105', 'Gene', (79, 84))	('CXCR4', 'molecular_function', 'GO:0038147', ('102', '107'))	('CD44', 'Var', (93, 97))	('membrane', 'cellular_component', 'GO:0016020', ('143', '151'))
78841	32214151	Additionally, our analysis revealed that CD105+ subpopulation of cells isolated from - metastatic papillary VHL wt - RCC ACHN cell line also express CD44, CD73, CD90, CD146 and alkaline phosphatase (AP).	('CD90', 'Gene', (161, 165))	('phosphatase', 'molecular_function', 'GO:0016791', ('186', '197'))	('CD73', 'Gene', '4907', (155, 159))	('CD105', 'Gene', (41, 46))	('VHL', 'Disease', (108, 111))	('alkaline phosphatase', 'MPA', (177, 197))	('VHL', 'Disease', 'MESH:D006623', (108, 111))	('CD90', 'Gene', '7070', (161, 165))	('CD105', 'Gene', '13805', (41, 46))	('CD146', 'Gene', (167, 172))	('CD44', 'Var', (149, 153))	('CD73', 'Gene', (155, 159))	('CD146', 'Gene', '4162', (167, 172))
78842	32214151	The others have shown that spheres derived from HEK293T, ACHN, Caki-1, and 786O renal cancer cell lines as well as CD105+ cells isolated from RCC specimens showed the presence of a CD44+ population with self-renewal properties, sphere formation capability and resistance to therapy.	('HEK293T', 'Var', (48, 55))	('sphere formation capability', 'CPA', (228, 255))	('HEK293T', 'CellLine', 'CVCL:0063;0.07577567894642183', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('self-renewal properties', 'CPA', (203, 226))	('CD44+ population', 'CPA', (181, 197))	('CD105', 'Gene', (115, 120))	('renal cancer', 'Disease', (80, 92))	('formation', 'biological_process', 'GO:0009058', ('235', '244'))	('CD105', 'Gene', '13805', (115, 120))	('renal cancer', 'Disease', 'MESH:D007680', (80, 92))	('renal cancer', 'Phenotype', 'HP:0009726', (80, 92))
78844	32214151	This cell line expressed four potential stem cell marker subpopulations (CD105, CD133, CD44 and CXCR4) as found in our flow cytometric analysis (Fig.	('CXCR4', 'molecular_function', 'GO:0038147', ('96', '101'))	('CD133', 'Gene', (80, 85))	('CD133', 'Gene', '8842', (80, 85))	('CD44', 'Var', (87, 91))	('CD105', 'Gene', (73, 78))	('CD105', 'Gene', '13805', (73, 78))
78845	32214151	The percentages of CD105, CD133, CD44, and CXCR4 positive cells were variable in Caki-1 cells.	('CD105', 'Gene', '13805', (19, 24))	('CD133', 'Gene', (26, 31))	('CD133', 'Gene', '8842', (26, 31))	('CXCR4', 'molecular_function', 'GO:0038147', ('43', '48'))	('CD44', 'Var', (33, 37))	('CD105', 'Gene', (19, 24))
78850	32214151	Spheres were enriched in cells expressing stem-like cell markers including membranous proteins CD105, CD133, CD44, and CXCR4.	('CD105', 'Gene', (95, 100))	('CD105', 'Gene', '13805', (95, 100))	('CD133', 'Gene', (102, 107))	('CD133', 'Gene', '8842', (102, 107))	('CD44', 'Var', (109, 113))	('CXCR4', 'molecular_function', 'GO:0038147', ('119', '124'))
78871	32214151	We have identified several lipid signals (mainly Lip13a and Lip09), choline compounds (Cho), creatine and phosphocreatine (Cr+PCr, tCr), glutamate (Glu) in all the tumors.	('phosphocreatine', 'Chemical', 'MESH:D010725', (106, 121))	('glutamate', 'MPA', (137, 146))	('Lip13a', 'MPA', (49, 55))	('creatine', 'Chemical', 'MESH:D003401', (113, 121))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('lipid', 'Chemical', 'MESH:D008055', (27, 32))	('tCr', 'cellular_component', 'GO:0042101', ('131', '134'))	('choline compounds', 'MPA', (68, 85))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('lipid signals', 'MPA', (27, 40))	('tCr', 'biological_process', 'GO:0006283', ('131', '134'))	('choline', 'Chemical', 'MESH:D002794', (68, 75))	('tumors', 'Disease', (164, 170))	('Cho', 'Chemical', '-', (87, 90))	('Glu', 'Chemical', 'MESH:D018698', (148, 151))	('tCr', 'Gene', (131, 134))	('tCr', 'Gene', '6962', (131, 134))	('glutamate', 'Chemical', 'MESH:D018698', (137, 146))	('Lip09', 'Var', (60, 65))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('creatine', 'Chemical', 'MESH:D003401', (93, 101))	('Cho', 'molecular_function', 'GO:0043848', ('87', '90'))
78880	32214151	Cells of CD44- xenografts overexpressed Nanog and Oct-4, while cells from CD44+ xenografts show very low expression of these stem-related markers (Fig.	('Oct-4', 'Gene', (50, 55))	('Nanog', 'Gene', '79923', (40, 45))	('Nanog', 'Gene', (40, 45))	('overexpressed', 'PosReg', (26, 39))	('Oct-4', 'Gene', '5460', (50, 55))	('CD44- xenografts', 'Var', (9, 25))
78886	32214151	xenograft model) identifies cells with stem cell properties and in the case of our subpopulations analyzed both CD105+, CD44+, as well as CD105-, CD44- and CD105-/CD44- gave rise to tumor growth in mice.	('gave rise', 'Reg', (169, 178))	('CD105', 'Gene', '13805', (156, 161))	('CD105', 'Gene', '13805', (112, 117))	('tumor', 'Disease', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('CD105', 'Gene', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('CD105', 'Gene', '13805', (138, 143))	('mice', 'Species', '10090', (198, 202))	('CD44-', 'Var', (146, 151))	('CD44+', 'Var', (120, 125))	('CD105', 'Gene', (156, 161))	('CD105', 'Gene', (112, 117))
78891	32214151	High CD105 mRNA expression was previously associated with RCC metastases and high tumor stage.	('CD105', 'Gene', '13805', (5, 10))	('High', 'Var', (0, 4))	('associated', 'Reg', (42, 52))	('metastases', 'Disease', 'MESH:D009362', (62, 72))	('CD105', 'Gene', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('mRNA expression', 'MPA', (11, 26))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('RCC', 'Disease', (58, 61))	('tumor', 'Disease', (82, 87))	('metastases', 'Disease', (62, 72))
78899	32214151	On the contrary, knockdown of CD105 by short hairpin RNA or CRISPR/cas9 reduced stemness markers expression (OCT, NANOG, SOX-2) and sphere-formation ability.	('reduced', 'NegReg', (72, 79))	('CD105', 'Gene', (30, 35))	('CD105', 'Gene', '13805', (30, 35))	('OCT', 'Gene', (109, 112))	('RNA', 'cellular_component', 'GO:0005562', ('53', '56'))	('SOX-2', 'Gene', '6657', (121, 126))	('stemness markers', 'CPA', (80, 96))	('formation', 'biological_process', 'GO:0009058', ('139', '148'))	('OCT', 'Gene', '5362', (109, 112))	('sphere-formation ability', 'CPA', (132, 156))	('SOX-2', 'Gene', (121, 126))	('knockdown', 'Var', (17, 26))	('NANOG', 'Gene', '79923', (114, 119))	('NANOG', 'Gene', (114, 119))	('cas', 'cellular_component', 'GO:0005650', ('67', '70'))
78900	32214151	CD105 silencing accelerate senescence in vitro and significantly decreased tumorigenicity and gemcitabine resistance.	('CD105', 'Gene', (0, 5))	('decreased', 'NegReg', (65, 74))	('CD105', 'Gene', '13805', (0, 5))	('gemcitabine', 'Chemical', 'MESH:C056507', (94, 105))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('senescence', 'biological_process', 'GO:0010149', ('27', '37'))	('gemcitabine resistance', 'MPA', (94, 116))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('silencing', 'Var', (6, 15))	('tumor', 'Disease', (75, 80))	('senescence', 'CPA', (27, 37))	('accelerate', 'PosReg', (16, 26))
78912	32214151	In breast cancer model it has been shown that HIF-1alpha as a regulator of CD44 that increased the number of CD44 molecules and the percentage of (variant exons v6 and v7/8) CD44 positive cells is higher in cancer cells in hypoxia, which might also be true for RCC that is known to harbor VHL mutations.	('HIF-1alpha', 'Gene', (46, 56))	('VHL', 'Disease', (289, 292))	('increased', 'PosReg', (85, 94))	('cancer', 'Disease', (10, 16))	('cancer', 'Disease', (207, 213))	('higher', 'PosReg', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('hypoxia', 'Disease', (223, 230))	('mutations', 'Var', (293, 302))	('v7/8', 'Var', (168, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('VHL', 'Disease', 'MESH:D006623', (289, 292))	('hypoxia', 'Disease', 'MESH:D000860', (223, 230))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('RCC', 'Disease', (261, 264))	('HIF-1alpha', 'Gene', '3091', (46, 56))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('CD44 molecules', 'MPA', (109, 123))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (3, 16))
78921	32214151	In particular in Caki-1 cell line subpopulation of CD44Low cells with co-expression of CD90 are less clonogenic, but this is not true for all CD44Low subpopulations.	('CD90', 'Gene', (87, 91))	('clonogenic', 'CPA', (101, 111))	('CD44Low', 'Var', (51, 58))	('less', 'NegReg', (96, 100))	('co-expression', 'Var', (70, 83))	('CD90', 'Gene', '7070', (87, 91))
78975	32214151	Cells were stained separately with fluorescent conjugated CD105, CD133, CXCR4 and CD44 according to the manufacturers' protocols along with the appropriate unstained controls.	('CD133', 'Gene', '8842', (65, 70))	('CD44', 'Var', (82, 86))	('CXCR4', 'molecular_function', 'GO:0038147', ('72', '77'))	('CD105', 'Gene', '13805', (58, 63))	('CD105', 'Gene', (58, 63))	('CD133', 'Gene', (65, 70))
78976	32214151	For co-expression experiments Caki-1 cells were prepared and labelled in a single tube with CD133 PercP, CD44-PE, CD105-FITC, CXCR4-APC in pairs.	('CD44-PE', 'Var', (105, 112))	('APC', 'cellular_component', 'GO:0005680', ('132', '135'))	('CXCR4', 'molecular_function', 'GO:0038147', ('126', '131'))	('FITC', 'Chemical', 'MESH:D016650', (120, 124))	('CD133', 'Gene', (92, 97))	('CD133', 'Gene', '8842', (92, 97))	('CD105', 'Gene', (114, 119))	('CD105', 'Gene', '13805', (114, 119))	('APC', 'Disease', 'MESH:D011125', (132, 135))	('APC', 'Disease', (132, 135))
78978	32214151	FITC anti-human CD105 Antibody (323204, BioLegend, California, USA), PE anti-CD133/2 (130-090-853, Miltenyi Biotec GmbH, Bergisch Gladbach, Germany), APC anti-human CD184 (CXCR4) Antibody (306509, BioLegend, California, USA), PE anti-CD44 antibody (130-095-180, Miltenyi Biotec GmbH, Bergisch Gladbach, Germany) were used.	('APC', 'Disease', 'MESH:D011125', (150, 153))	('APC', 'Disease', (150, 153))	('human', 'Species', '9606', (10, 15))	('130-095-180', 'Var', (249, 260))	('FITC', 'Chemical', 'MESH:D016650', (0, 4))	('306509', 'Var', (189, 195))	('CD184', 'Gene', (165, 170))	('antibody', 'cellular_component', 'GO:0019815', ('239', '247'))	('CD184', 'Gene', '7852', (165, 170))	('human', 'Species', '9606', (159, 164))	('CXCR4', 'molecular_function', 'GO:0038147', ('172', '177'))	('CD105', 'Gene', '13805', (16, 21))	('antibody', 'cellular_component', 'GO:0019814', ('239', '247'))	('APC', 'cellular_component', 'GO:0005680', ('150', '153'))	('CD133', 'Gene', (77, 82))	('CD133', 'Gene', '8842', (77, 82))	('antibody', 'molecular_function', 'GO:0003823', ('239', '247'))	('CD105', 'Gene', (16, 21))	('antibody', 'cellular_component', 'GO:0042571', ('239', '247'))
78981	32214151	Tumor spheres were incubated separately with diluted primary antibodies against CD105 (1:1000), CD133 (1:500), CD44 (1:1000) and CXCR4 (1:1000) at 4  C for 4 h; washed three times with PBS and incubated with Alexa Fluor 488 secondary goat anti-mouse antibody (1:400) for 1 h at room temperature.	('CD133', 'Gene', (96, 101))	('mouse', 'Species', '10090', (244, 249))	('CD133', 'Gene', '8842', (96, 101))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('antibody', 'molecular_function', 'GO:0003823', ('250', '258'))	('Alexa Fluor 488', 'Chemical', '-', (208, 223))	('CXCR4', 'molecular_function', 'GO:0038147', ('129', '134'))	('1:500', 'Var', (103, 108))	('PBS', 'Chemical', 'MESH:D007854', (185, 188))	('antibody', 'cellular_component', 'GO:0042571', ('250', '258'))	('goat', 'Species', '9925', (234, 238))	('CD44 (1:1000', 'Var', (111, 123))	('CD105', 'Gene', (80, 85))	('antibody', 'cellular_component', 'GO:0019815', ('250', '258'))	('antibody', 'cellular_component', 'GO:0019814', ('250', '258'))	('CD105', 'Gene', '13805', (80, 85))
79015	32219036	Moreover, several studies focused on m6A regulators in patients with ccRCC in recent years, for example, have reported the relationship between mutation and copy number variation (CNV) of m6A regulatory genes with ccRCC.	('copy number variation', 'Var', (157, 178))	('m6A', 'Gene', '56339', (188, 191))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('mutation', 'Var', (144, 152))	('m6A', 'Gene', (37, 40))	('m6A', 'Gene', (188, 191))	('patients', 'Species', '9606', (55, 63))	('m6A', 'Gene', '56339', (37, 40))	('RCC', 'Disease', (216, 219))	('RCC', 'Phenotype', 'HP:0005584', (216, 219))
79016	32219036	They found that the deletion of m6A "writer" genes was an independent prognostic factor for ccRCC patients, and copy number gain of m6A "eraser" genes could enhance the effect.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('m6A', 'Gene', (132, 135))	('m6A', 'Gene', (32, 35))	('m6A', 'Gene', '56339', (132, 135))	('patients', 'Species', '9606', (98, 106))	('deletion', 'Var', (20, 28))	('m6A', 'Gene', '56339', (32, 35))	('copy number gain', 'Var', (112, 128))
79017	32219036	In addition, ccRCC patients with any CNVs of m6A regulatory genes had worse OS and DFS than those with diploid genes.	('OS', 'Chemical', '-', (76, 78))	('m6A', 'Gene', '56339', (45, 48))	('DFS', 'CPA', (83, 86))	('patients', 'Species', '9606', (19, 27))	('worse', 'NegReg', (70, 75))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('RCC', 'Disease', (15, 18))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('CNVs', 'Var', (37, 41))	('m6A', 'Gene', (45, 48))
79035	32219036	Each factor with a p value < 0.05 in univariate analysis was then analyzed by multivariate cox regression, those with a p value < 0.05 and HR > 1 were viewed as independent prognostic factors.	('cox', 'Gene', '1351', (91, 94))	('p value < 0.05', 'Var', (120, 134))	('cox', 'Gene', (91, 94))
79048	32219036	The total RS was imputed as follows: (-0.413491830046862 x expression level of METTL14) + (0.0149601455134957 x expression level of HNRNPA2B1) + (0.0260335348056223 x expression level of METTL3).	('-0.413491830046862', 'Var', (38, 56))	('0.0260335348056223', 'Var', (146, 164))	('HNRNPA2B1', 'Gene', '3181', (132, 141))	('METTL14', 'Gene', (79, 86))	('METTL14', 'Gene', '57721', (79, 86))	('HNRNPA2B1', 'Gene', (132, 141))	('METTL3', 'Gene', '56339', (187, 193))	('METTL3', 'Gene', (187, 193))	('0.0149601455134957', 'Var', (91, 109))	('expression', 'MPA', (112, 122))
79063	32219036	Moreover, plenty of researches has disclosed the associations of m6A modification in former mentioned cancerous diseases or non-cancerous diseases such as type 2 diabetes mellitus, and infertility, thus, we decided to build an RS model found on m6A genes.	('type 2 diabetes mellitus', 'Disease', (155, 179))	('infertility', 'Disease', (185, 196))	('type 2 diabetes mellitus', 'Disease', 'MESH:D003924', (155, 179))	('m6A', 'Gene', '56339', (245, 248))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (162, 179))	('infertility', 'Disease', 'MESH:D007247', (185, 196))	('associations', 'Interaction', (49, 61))	('m6A', 'Gene', (245, 248))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancerous diseases', 'Disease', 'MESH:D009369', (128, 146))	('cancerous diseases', 'Disease', 'MESH:D009369', (102, 120))	('infertility', 'Phenotype', 'HP:0000789', (185, 196))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (155, 170))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('m6A', 'Gene', '56339', (65, 68))	('cancerous diseases', 'Disease', (128, 146))	('modification', 'Var', (69, 81))	('cancerous diseases', 'Disease', (102, 120))	('m6A', 'Gene', (65, 68))
79078	32110055	This study aimed to evaluate the contributions of hOGG1 rs1052133 genotypes to the RCC risk.	('RCC', 'Disease', 'MESH:D002292', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('rs1052133', 'Mutation', 'rs1052133', (56, 65))	('rs1052133', 'Var', (56, 65))	('hOGG1', 'Gene', (50, 55))	('hOGG1', 'Gene', '4968', (50, 55))
79080	32110055	The hOGG1 rs1052133 CC genotype was significantly associated with a decreased RCC risk compared with that of the GG genotype (odds ratio [OR] = 0.25, 95% confidence interval [CI] = 0.09-0.72, p = 0.0049).	('decreased', 'NegReg', (68, 77))	('hOGG1', 'Gene', (4, 9))	('RCC', 'Disease', (78, 81))	('rs1052133 CC', 'Var', (10, 22))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:D002292', (78, 81))	('rs1052133', 'Mutation', 'rs1052133', (10, 19))	('hOGG1', 'Gene', '4968', (4, 9))
79081	32110055	The frequency of the rs1052133 C allele was significantly low in the RCC group (22.5% vs 31.2%; OR = 0.64; 95% CI = 0.46-0.89, p = 0.0074).	('RCC', 'Disease', 'MESH:D002292', (69, 72))	('RCC', 'Disease', (69, 72))	('rs1052133', 'Mutation', 'rs1052133', (21, 30))	('rs1052133 C', 'Var', (21, 32))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
79082	32110055	Stratifying the analysis according to smoking, alcohol drinking, and diabetes status revealed no difference in the rs1052133 genotype distribution among these subgroups.	('diabetes status', 'Disease', 'MESH:D003920', (69, 84))	('alcohol drinking', 'Phenotype', 'HP:0030955', (47, 63))	('rs1052133', 'Mutation', 'rs1052133', (115, 124))	('rs1052133', 'Var', (115, 124))	('alcohol', 'Chemical', 'MESH:D000438', (47, 54))	('diabetes status', 'Disease', (69, 84))
79083	32110055	A significant differential distribution of rs1052133 genotypes was observed among subjects with hypertension.	('hypertension', 'Disease', 'MESH:D006973', (96, 108))	('hypertension', 'Disease', (96, 108))	('hypertension', 'Phenotype', 'HP:0000822', (96, 108))	('rs1052133', 'Mutation', 'rs1052133', (43, 52))	('rs1052133', 'Var', (43, 52))
79084	32110055	The CC genotype of rs1052133 may play a role in determining RCC susceptibility among Taiwanese people and may serve as a biomarker of RCC, particularly in patients with hypertension.	('hypertension', 'Disease', (169, 181))	('hypertension', 'Phenotype', 'HP:0000822', (169, 181))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (134, 137))	('rs1052133', 'Mutation', 'rs1052133', (19, 28))	('rs1052133', 'Var', (19, 28))	('RCC', 'Disease', (134, 137))	('people', 'Species', '9606', (95, 101))	('RCC', 'Disease', 'MESH:D002292', (60, 63))	('patients', 'Species', '9606', (155, 163))	('hypertension', 'Disease', 'MESH:D006973', (169, 181))	('RCC', 'Disease', 'MESH:D002292', (134, 137))
79097	32110055	Functional studies have shown that the genotype at rs1052133 (Ser326Cys) single nucleotide polymorphism (SNP) in exon 7 of hOGG1 may determine the glycosylase activity and serve as a genomic predictor of personal susceptibility to various cancer types.	('Ser326Cys', 'SUBSTITUTION', 'None', (62, 71))	('hOGG1', 'Gene', '4968', (123, 128))	('Ser', 'cellular_component', 'GO:0005790', ('62', '65'))	('glycosylase activity', 'MPA', (147, 167))	('rs1052133', 'Mutation', 'rs1052133', (51, 60))	('glycosylase', 'molecular_function', 'GO:0016798', ('147', '158'))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('single nucleotide polymorphism', 'Var', (73, 103))	('cancer', 'Disease', (239, 245))	('hOGG1', 'Gene', (123, 128))	('Ser326Cys', 'Var', (62, 71))	('determine', 'Reg', (133, 142))
79098	32110055	Therefore, in this study, we aimed to determine whether the hOGG1 rs1052133 polymorphism is associated with the RCC risk in Taiwan and to elucidate the interactions of this SNP with several clinical and behavioral factors.	('rs1052133', 'Mutation', 'rs1052133', (66, 75))	('rs1052133', 'Var', (66, 75))	('hOGG1', 'Gene', (60, 65))	('behavioral factors', 'Phenotype', 'HP:0000708', (203, 221))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('RCC', 'Disease', 'MESH:D002292', (112, 115))	('associated', 'Reg', (92, 102))	('hOGG1', 'Gene', '4968', (60, 65))
79111	32110055	The hOGG1 rs1052133 polymorphic site was genotyped as we previously described in 2013.	('hOGG1', 'Gene', (4, 9))	('rs1052133', 'Mutation', 'rs1052133', (10, 19))	('hOGG1', 'Gene', '4968', (4, 9))	('rs1052133', 'Var', (10, 19))
79113	32110055	The sequences of forward and reverse primers for hOGG1 rs1052133 genotyping were 5'-ACTGTCACTAGTCTCACCAG-3' and 5'-GGAAGGTGGGAAGGTG-3', respectively.	('hOGG1', 'Gene', (49, 54))	('hOGG1', 'Gene', '4968', (49, 54))	('rs1052133', 'Var', (55, 64))	('rs1052133', 'Mutation', 'rs1052133', (55, 64))
79118	32110055	For the C allele of hOGG1 rs1052133, the single 200 bp fragment was no longer digested.	('hOGG1', 'Gene', '4968', (20, 25))	('hOGG1', 'Gene', (20, 25))	('rs1052133', 'Mutation', 'rs1052133', (26, 35))	('rs1052133', 'Var', (26, 35))	('men', 'Species', '9606', (59, 62))
79120	32110055	Any result with both types of bands was identified as the heterovariant CG genotype of hOGG1 rs1052133.	('rs1052133', 'Mutation', 'rs1052133', (93, 102))	('hOGG1', 'Gene', '4968', (87, 92))	('rs1052133', 'Var', (93, 102))	('CG', 'Chemical', 'MESH:C028505', (72, 74))	('hOGG1', 'Gene', (87, 92))
79133	32110055	The observed genotypic and allelic frequencies of hOGG1 rs1052133 among RCC cases and controls and their associations with the risk of RCC are summarized in Table 2.	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('rs1052133', 'Mutation', 'rs1052133', (56, 65))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('rs1052133', 'Var', (56, 65))	('RCC', 'Disease', (72, 75))	('RCC', 'Disease', 'MESH:D002292', (72, 75))	('hOGG1', 'Gene', (50, 55))	('RCC', 'Disease', 'MESH:D002292', (135, 138))	('RCC', 'Disease', (135, 138))	('associations', 'Interaction', (105, 117))	('hOGG1', 'Gene', '4968', (50, 55))
79134	32110055	The hOGG1 rs1052133 genotypes among healthy controls were in a Hardy-Weinberg equilibrium (p = 0.0983).	('hOGG1', 'Gene', (4, 9))	('rs1052133', 'Mutation', 'rs1052133', (10, 19))	('hOGG1', 'Gene', '4968', (4, 9))	('rs1052133', 'Var', (10, 19))
79135	32110055	In the trend analysis, the distributions of hOGG1 rs1052133 genotypes significantly differed between the control and case groups (p = 0.0188).	('hOGG1', 'Gene', (44, 49))	('rs1052133', 'Mutation', 'rs1052133', (50, 59))	('rs1052133', 'Var', (50, 59))	('hOGG1', 'Gene', '4968', (44, 49))	('differed', 'Reg', (84, 92))
79136	32110055	In detail, the hOGG1 rs1052133 CG and CC variant genotypes were present at frequencies of 40.0% and 11.2% in the control group and 38.1% and 3.4% in the case group, respectively (Table 2, top panel).	('hOGG1', 'Gene', (15, 20))	('rs1052133', 'Mutation', 'rs1052133', (21, 30))	('CG', 'Chemical', 'MESH:C028505', (31, 33))	('rs1052133 CG', 'Var', (21, 33))	('hOGG1', 'Gene', '4968', (15, 20))
79137	32110055	In multivariate logistic regression analysis, after adjustments were made for age, gender, smoking, alcohol drinking, hypertension, diabetes, and family history status, the hOGG1 rs1052133 homovariant CC was associated with an altered RCC risk (OR = 0.31 and 0.78, 95% CI = 0.14-0.69 and 0.56-1.13, for hOGG1 rs1052133 CC homozygotes and CG heterozygotes, respectively; Table 2, top panel).	('hypertension', 'Phenotype', 'HP:0000822', (118, 130))	('RCC', 'Phenotype', 'HP:0005584', (235, 238))	('rs1052133 CC', 'Var', (309, 321))	('RCC', 'Disease', (235, 238))	('hOGG1', 'Gene', '4968', (173, 178))	('diabetes', 'Disease', 'MESH:D003920', (132, 140))	('hOGG1', 'Gene', (173, 178))	('RCC', 'Disease', 'MESH:D002292', (235, 238))	('alcohol drinking', 'Phenotype', 'HP:0030955', (100, 116))	('alcohol', 'Chemical', 'MESH:D000438', (100, 107))	('men', 'Species', '9606', (58, 61))	('rs1052133', 'Var', (179, 188))	('rs1052133', 'Mutation', 'rs1052133', (309, 318))	('diabetes', 'Disease', (132, 140))	('hypertension', 'Disease', 'MESH:D006973', (118, 130))	('hypertension', 'Disease', (118, 130))	('CG', 'Chemical', 'MESH:C028505', (338, 340))	('hOGG1', 'Gene', '4968', (303, 308))	('rs1052133', 'Mutation', 'rs1052133', (179, 188))	('hOGG1', 'Gene', (303, 308))
79138	32110055	The hOGG1 rs1052133 variant CG and CC genotypes were subsequently combined to construct a dominant genetic model, and our results revealed that the combined genotypes conferred a significantly reduced RCC risk (OR = 0.55, 95% CI = 0.47-0.88; Table 2; middle panel).	('RCC', 'Disease', 'MESH:D002292', (201, 204))	('RCC', 'Disease', (201, 204))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('hOGG1', 'Gene', (4, 9))	('CG', 'Chemical', 'MESH:C028505', (28, 30))	('reduced', 'NegReg', (193, 200))	('rs1052133', 'Mutation', 'rs1052133', (10, 19))	('hOGG1', 'Gene', '4968', (4, 9))	('rs1052133', 'Var', (10, 19))
79139	32110055	We examined the distributions of the allelic frequencies of hOGG1 rs1052133 among the cases and controls and found a significant association between the hOGG1 rs1052133 C allele and a decreased RCC risk in Taiwan (OR = 0.59, 95% CI = 0.43-0.83).	('rs1052133', 'Mutation', 'rs1052133', (66, 75))	('rs1052133', 'Var', (66, 75))	('hOGG1', 'Gene', (60, 65))	('rs1052133', 'Mutation', 'rs1052133', (159, 168))	('RCC', 'Disease', 'MESH:D002292', (194, 197))	('RCC', 'Disease', (194, 197))	('rs1052133 C', 'Var', (159, 170))	('RCC', 'Phenotype', 'HP:0005584', (194, 197))	('decreased', 'NegReg', (184, 193))	('hOGG1', 'Gene', '4968', (153, 158))	('hOGG1', 'Gene', '4968', (60, 65))	('hOGG1', 'Gene', (153, 158))
79141	32110055	We further performed stratification analysis to investigate the association between hOGG1 rs1052133 genotypes and the risk of RCC based on potential Taiwanese-specific personal behavioral and clinical factors, such as cigarette smoking, alcohol consumption, hypertension, and diabetes status, which are listed in Table 1.	('rs1052133', 'Mutation', 'rs1052133', (90, 99))	('hypertension', 'Disease', 'MESH:D006973', (258, 270))	('rs1052133', 'Var', (90, 99))	('alcohol', 'Chemical', 'MESH:D000438', (237, 244))	('diabetes status', 'Disease', 'MESH:D003920', (276, 291))	('RCC', 'Disease', (126, 129))	('hOGG1', 'Gene', '4968', (84, 89))	('RCC', 'Disease', 'MESH:D002292', (126, 129))	('hypertension', 'Disease', (258, 270))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('hypertension', 'Phenotype', 'HP:0000822', (258, 270))	('diabetes status', 'Disease', (276, 291))	('hOGG1', 'Gene', (84, 89))
79143	32110055	The adjusted ORs of the carriers with the CG and CC genotypes at hOGG1 rs1052133 were 0.81 and 0.38 for nonsmokers (95% CI = 0.44-1.37 and 0.14-1.22, respectively) and 0.81 and 0.24 for smokers (95% CI = 0.42-1.38 and 0.09-1.02, respectively; Figure 1), respectively.	('hOGG1', 'Gene', '4968', (65, 70))	('CG', 'Chemical', 'MESH:C028505', (42, 44))	('hOGG1', 'Gene', (65, 70))	('rs1052133', 'Mutation', 'rs1052133', (71, 80))	('rs1052133', 'Var', (71, 80))
79144	32110055	The results showed no obvious protective effect of hOGG1 rs1052133 genotype on the risk of RCC in nonsmokers or smokers (Figure 1).	('hOGG1', 'Gene', '4968', (51, 56))	('RCC', 'Disease', 'MESH:D002292', (91, 94))	('RCC', 'Disease', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('rs1052133', 'Mutation', 'rs1052133', (57, 66))	('rs1052133', 'Var', (57, 66))	('hOGG1', 'Gene', (51, 56))
79146	32110055	The adjusted ORs of the carriers with genotypes CG and CC at hOGG1 rs1052133 were 0.82 and 0.37 among nondrinkers (95% CI = 0.51-1.33 and 0.18-1.26, respectively) and 0.76 and 0.18 among alcohol drinkers (95% CI = 0.42-1.53 and 0.09-1.17, respectively; Figure 2), respectively.	('alcohol', 'Chemical', 'MESH:D000438', (187, 194))	('CG', 'Chemical', 'MESH:C028505', (48, 50))	('hOGG1', 'Gene', (61, 66))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (187, 203))	('rs1052133', 'Mutation', 'rs1052133', (67, 76))	('rs1052133', 'Var', (67, 76))	('hOGG1', 'Gene', '4968', (61, 66))
79147	32110055	The protective effects of hOGG1 rs1052133 genotypes on the risk of RCC appeared to be nonsignificant among nondrinkers and alcohol drinkers (Figure 2).	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('hOGG1', 'Gene', (26, 31))	('RCC', 'Disease', 'MESH:D002292', (67, 70))	('RCC', 'Disease', (67, 70))	('alcohol', 'Chemical', 'MESH:D000438', (123, 130))	('rs1052133', 'Mutation', 'rs1052133', (32, 41))	('rs1052133', 'Var', (32, 41))	('hOGG1', 'Gene', '4968', (26, 31))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (123, 139))
79149	32110055	The adjusted ORs of the carriers with CG and CC at hOGG1 rs1052133 were 0.80 and 0.67 among the subjects without hypertension (95% CI = 0.41-1.54 and 0.22-2.03, respectively) and 0.81 and 0.09 among the patients with hypertension (95% CI = 0.54-1.28 and 0.01-0.57, respectively; Figure 3).	('hypertension', 'Disease', (113, 125))	('CG', 'Chemical', 'MESH:C028505', (38, 40))	('hypertension', 'Phenotype', 'HP:0000822', (113, 125))	('hOGG1', 'Gene', '4968', (51, 56))	('hypertension', 'Disease', 'MESH:D006973', (217, 229))	('patients', 'Species', '9606', (203, 211))	('hypertension', 'Disease', (217, 229))	('rs1052133', 'Mutation', 'rs1052133', (57, 66))	('hypertension', 'Phenotype', 'HP:0000822', (217, 229))	('rs1052133', 'Var', (57, 66))	('hOGG1', 'Gene', (51, 56))	('hypertension', 'Disease', 'MESH:D006973', (113, 125))
79150	32110055	Notably, the protective effects of hOGG1 rs1052133 genotype on the risk of RCC were obvious among people with hypertension, and only the genotype of the homovariant CC was protective (Figure 3).	('rs1052133', 'Mutation', 'rs1052133', (41, 50))	('rs1052133', 'Var', (41, 50))	('hOGG1', 'Gene', '4968', (35, 40))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('hypertension', 'Disease', 'MESH:D006973', (110, 122))	('RCC', 'Disease', 'MESH:D002292', (75, 78))	('RCC', 'Disease', (75, 78))	('hypertension', 'Disease', (110, 122))	('hypertension', 'Phenotype', 'HP:0000822', (110, 122))	('people', 'Species', '9606', (98, 104))	('hOGG1', 'Gene', (35, 40))
79151	32110055	The distributions of hOGG1 rs1052133 genotype frequencies were not significantly different between the case and control groups among the subjects in the subpopulations without or with diabetes (Figure 4).	('hOGG1', 'Gene', '4968', (21, 26))	('rs1052133', 'Mutation', 'rs1052133', (27, 36))	('rs1052133', 'Var', (27, 36))	('diabetes', 'Disease', (184, 192))	('hOGG1', 'Gene', (21, 26))	('diabetes', 'Disease', 'MESH:D003920', (184, 192))
79152	32110055	The adjusted ORs of carriers with CG and CC at hOGG1 rs1052133 were 0.91 and 0.16 among the subjects without diabetes (95% CI = 0.61-1.33 and 0.18-1.07, respectively) and 0.66 and 0.31 among those with diabetes (95% CI = 0.24-1.19 and 0.07-1.36, respectively; Figure 4), respectively.	('CG', 'Chemical', 'MESH:C028505', (34, 36))	('diabetes', 'Disease', (202, 210))	('diabetes', 'Disease', 'MESH:D003920', (202, 210))	('hOGG1', 'Gene', (47, 52))	('rs1052133', 'Mutation', 'rs1052133', (53, 62))	('hOGG1', 'Gene', '4968', (47, 52))	('diabetes', 'Disease', (109, 117))	('rs1052133', 'Var', (53, 62))	('diabetes', 'Disease', 'MESH:D003920', (109, 117))
79153	32110055	The effect of hOGG1 rs1052133 genotype on the RCC risk appeared to be nonprotective regardless of the diabetes status (Figure 4).	('rs1052133', 'Mutation', 'rs1052133', (20, 29))	('rs1052133', 'Var', (20, 29))	('regardless of the diabetes status', 'Disease', 'MESH:D003920', (84, 117))	('RCC', 'Disease', (46, 49))	('hOGG1', 'Gene', '4968', (14, 19))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('RCC', 'Disease', 'MESH:D002292', (46, 49))	('regardless of the diabetes status', 'Disease', (84, 117))	('hOGG1', 'Gene', (14, 19))
79158	32110055	Then, hOGG1 cleaves 3' to the AP site, leaving 5'-phosphate, 3'-phospho-alpha, beta-unsaturated aldehyde, and an apurinic/apyrimidinic site for further actions of DNA polymerase beta and DNA ligases I and III.	('hOGG1', 'Gene', '4968', (6, 11))	('DNA polymerase beta', 'Gene', (163, 182))	('DNA', 'cellular_component', 'GO:0005574', ('187', '190'))	('DNA polymerase beta', 'Gene', '5423', (163, 182))	("5'-phosphate", 'MPA', (47, 59))	('hOGG1', 'Gene', (6, 11))	("5'-phosphate", 'Chemical', '-', (47, 59))	('leaving', 'Reg', (39, 46))	('DNA ligases I and III', 'Gene', '3980', (187, 208))	("3'-phospho-alpha, beta-unsaturated aldehyde", 'Chemical', '-', (61, 104))	('DNA polymerase beta', 'molecular_function', 'GO:0003887', ('163', '182'))	('cleaves', 'Var', (12, 19))	('DNA', 'cellular_component', 'GO:0005574', ('163', '166'))
79159	32110055	The most recognizable polymorphic site of hOGG1 is the well-known rs1052133 (Ser326Cys, C to G), and several genotype-phenotype studies have provided evidence that the glycosylase activity of the "G" variant of the hOGG1 enzyme is more sensitive to the inactivating influence of oxidizing agents than that of the "C" wild type; cells carrying "G" alleles can accumulate mutations more readily under the same challenges of oxidative stress.	('hOGG1', 'Gene', '4968', (42, 47))	('rs1052133', 'Mutation', 'rs1052133', (66, 75))	('oxidative stress', 'Phenotype', 'HP:0025464', (422, 438))	('hOGG1', 'Gene', (215, 220))	('Ser326Cys', 'Var', (77, 86))	('glycosylase', 'molecular_function', 'GO:0016798', ('168', '179'))	('Ser326Cys', 'SUBSTITUTION', 'None', (77, 86))	('hOGG1', 'Gene', (42, 47))	('Ser', 'cellular_component', 'GO:0005790', ('77', '80'))	('hOGG1', 'Gene', '4968', (215, 220))	('glycosylase', 'MPA', (168, 179))	('mutations', 'Var', (370, 379))
79160	32110055	To our knowledge, only one study has investigated the contribution of hOGG1 to RCC and focused on rs1052133 as we did.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('hOGG1', 'Gene', '4968', (70, 75))	('rs1052133', 'Mutation', 'rs1052133', (98, 107))	('rs1052133', 'Var', (98, 107))	('hOGG1', 'Gene', (70, 75))	('RCC', 'Disease', 'MESH:D002292', (79, 82))	('RCC', 'Disease', (79, 82))
79161	32110055	The G allele at hOGG1 rs1052133 is associated with a 1.4-fold increased risk of RCC in a Chinese population.	('hOGG1', 'Gene', (16, 21))	('hOGG1', 'Gene', '4968', (16, 21))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:D002292', (80, 83))	('rs1052133', 'Var', (22, 31))	('rs1052133', 'Mutation', 'rs1052133', (22, 31))
79162	32110055	This conclusion is consistent with our results that the CC genotype at hOGG1 rs1052133 was associated with a lower risk of RCC than that of the GG genotype (Table 2).	('lower', 'NegReg', (109, 114))	('hOGG1', 'Gene', (71, 76))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('rs1052133', 'Mutation', 'rs1052133', (77, 86))	('RCC', 'Disease', 'MESH:D002292', (123, 126))	('rs1052133', 'Var', (77, 86))	('hOGG1', 'Gene', '4968', (71, 76))
79163	32110055	In the current study, we further found that the determinant value of hOGG1 rs1052133 of the RCC risk was high among patients with hypertension.	('hypertension', 'Disease', 'MESH:D006973', (130, 142))	('hOGG1', 'Gene', '4968', (69, 74))	('patients', 'Species', '9606', (116, 124))	('hypertension', 'Disease', (130, 142))	('hypertension', 'Phenotype', 'HP:0000822', (130, 142))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('RCC', 'Disease', 'MESH:D002292', (92, 95))	('hOGG1', 'Gene', (69, 74))	('rs1052133', 'Mutation', 'rs1052133', (75, 84))	('rs1052133', 'Var', (75, 84))
79167	32110055	To the best of our knowledge, this study was the first to show an association between the hOGG1 rs1052133 polymorphism and the RCC risk in the Taiwanese population.	('rs1052133', 'Mutation', 'rs1052133', (96, 105))	('rs1052133', 'Var', (96, 105))	('hOGG1', 'Gene', '4968', (90, 95))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('hOGG1', 'Gene', (90, 95))	('RCC', 'Disease', (127, 130))	('RCC', 'Disease', 'MESH:D002292', (127, 130))
79171	32110055	In our stratified analyses, the association of rs1052133 with ccRCC was similar to the overall RCC, whereas the numbers of other non-ccRCC subtypes were too small for meaningful analysis.	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('RCC', 'Disease', 'MESH:D002292', (135, 138))	('RCC', 'Disease', (135, 138))	('RCC', 'Disease', 'MESH:D002292', (95, 98))	('RCC', 'Disease', (95, 98))	('rs1052133', 'Mutation', 'rs1052133', (47, 56))	('rs1052133', 'Var', (47, 56))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', 'MESH:D002292', (64, 67))	('RCC', 'Disease', (64, 67))
79172	32110055	CG and GG at hOGG1 rs1052133 are associated with an increased risk of various cancer types, including oral cancer, lung adenocarcinoma, breast cancer, laryngeal cancer, esophageal cancer, colorectal cancer, gallbladder cancer, prostate cancer, and leukemia.	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('breast cancer', 'Disease', (136, 149))	('leukemia', 'Disease', (248, 256))	('gallbladder cancer', 'Disease', 'MESH:D005706', (207, 225))	('leukemia', 'Disease', 'MESH:D007938', (248, 256))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('rs1052133', 'Mutation', 'rs1052133', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Disease', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (161, 167))	('hOGG1', 'Gene', '4968', (13, 18))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (115, 134))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('lung adenocarcinoma', 'Disease', (115, 134))	('hOGG1', 'Gene', (13, 18))	('colorectal cancer', 'Disease', 'MESH:D015179', (188, 205))	('cancer', 'Disease', (143, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (169, 186))	('cancer', 'Disease', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('colorectal cancer', 'Disease', (188, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('CG', 'Chemical', 'MESH:C028505', (0, 2))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (236, 242))	('gallbladder cancer', 'Disease', (207, 225))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('laryngeal cancer', 'Disease', 'MESH:D007822', (151, 167))	('esophageal cancer', 'Disease', (169, 186))	('rs1052133', 'Var', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (107, 113))	('laryngeal cancer', 'Disease', (151, 167))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (115, 134))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (151, 167))	('prostate cancer', 'Disease', 'MESH:D011471', (227, 242))	('prostate cancer', 'Phenotype', 'HP:0012125', (227, 242))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('leukemia', 'Phenotype', 'HP:0001909', (248, 256))	('associated', 'Reg', (33, 43))	('prostate cancer', 'Disease', (227, 242))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))
79173	32110055	Few negative findings have shown no association between hOGG1 rs1052133 genotypes and several cancer types.	('rs1052133', 'Mutation', 'rs1052133', (62, 71))	('rs1052133', 'Var', (62, 71))	('hOGG1', 'Gene', '4968', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('hOGG1', 'Gene', (56, 61))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
79174	32110055	Some reports have described controversial findings that the G allele may cause a reduced glycosylase hOGG1 activity, leading to an overall downregulation of the BER capacity.	('BER capacity', 'CPA', (161, 173))	('activity', 'MPA', (107, 115))	('BER', 'biological_process', 'GO:0006284', ('161', '164'))	('hOGG1', 'Gene', '4968', (101, 106))	('glycosylase', 'molecular_function', 'GO:0016798', ('89', '100'))	('reduced', 'NegReg', (81, 88))	('G allele', 'Var', (60, 68))	('hOGG1', 'Gene', (101, 106))	('downregulation', 'NegReg', (139, 153))
79177	32110055	In conclusion, our data suggested that hOGG1 rs1052133 genotype is associated with the RCC risk in Taiwan.	('RCC', 'Disease', 'MESH:D002292', (87, 90))	('RCC', 'Disease', (87, 90))	('hOGG1', 'Gene', (39, 44))	('rs1052133', 'Mutation', 'rs1052133', (45, 54))	('rs1052133', 'Var', (45, 54))	('hOGG1', 'Gene', '4968', (39, 44))	('associated', 'Reg', (67, 77))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
79245	29739622	Cabozantinib has shown excellent responses and is currently FDA approved for medullary thyroid cancer and advanced clear cell renal cell carcinoma (CCRC); cabozantinib was also recently shown to improve OS and PFS in previously treated hepatocellular carcinoma.	('cabozantinib', 'Chemical', 'MESH:C558660', (155, 167))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (115, 146))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (236, 260))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (236, 260))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (115, 146))	('thyroid cancer', 'Disease', (87, 101))	('PFS', 'Disease', (210, 213))	('cabozantinib', 'Var', (155, 167))	('improve', 'PosReg', (195, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('hepatocellular carcinoma', 'Disease', (236, 260))	('clear cell renal cell carcinoma', 'Disease', (115, 146))	('thyroid cancer', 'Disease', 'MESH:D013964', (87, 101))	('Cabozantinib', 'Chemical', 'MESH:C558660', (0, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (77, 101))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (126, 146))	('thyroid cancer', 'Phenotype', 'HP:0002890', (87, 101))
79246	29739622	Medullary thyroid cancer commonly exhibits RET mutations (in more than 50% of sporadic cases and in nearly all inherited cases of this disease) and increased coexpression of MET and its ligand HGF; these alterations may explain the increased activity of cabozantinib in this disease as both RET and MET tyrosine kinases are primary targets of cabozantinib.	('thyroid cancer', 'Phenotype', 'HP:0002890', (10, 24))	('thyroid cancer', 'Disease', (10, 24))	('RET', 'Gene', '5979', (291, 294))	('cabozantinib', 'Chemical', 'MESH:C558660', (254, 266))	('RET', 'Gene', (43, 46))	('Medullary thyroid cancer', 'Phenotype', 'HP:0002865', (0, 24))	('increased', 'PosReg', (148, 157))	('RET', 'Gene', '5979', (43, 46))	('RET', 'Gene', (291, 294))	('thyroid cancer', 'Disease', 'MESH:D013964', (10, 24))	('mutations', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('ligand', 'molecular_function', 'GO:0005488', ('186', '192'))	('cabozantinib', 'Chemical', 'MESH:C558660', (343, 355))	('HGF', 'Gene', (193, 196))	('HGF', 'Gene', '3082', (193, 196))
79251	29739622	Important differences between OCCC and CCRC such as the the prevalence of VHL mutations in CCRC as opposed to the absence of these mutations in OCCC, the increased incidence of abnormalities in the PI3K/mTOR/AKT pathway in OCCC (mutations/amplifications of PI3K pathway genes are observed in 33%-45% of OCCCs) and the increased incidence of ARID1A mutations in OCCC (observed in 46% of OCCCs) may explain the differences in treatment outcomes between the OCCC and CCRC.	('mTOR', 'Gene', (203, 207))	('AKT', 'Gene', '207', (208, 211))	('mutations', 'Var', (348, 357))	('ARID1A', 'Gene', '8289', (341, 347))	('ARID1A', 'Gene', (341, 347))	('mutations', 'Var', (78, 87))	('AKT', 'Gene', (208, 211))	('PI3K', 'molecular_function', 'GO:0016303', ('198', '202'))	('PI3K', 'molecular_function', 'GO:0016303', ('257', '261'))	('VHL', 'Disease', (74, 77))	('VHL', 'Disease', 'MESH:D006623', (74, 77))	('mTOR', 'Gene', '2475', (203, 207))
79294	33374569	Wavelet-based texture features were generated using eight different frequency band combinations, applying either a high- or low-pass filter in each of the three dimensions including high-high-high, high-high-low, high-low-low, high-low-high, low-high-low, low-high-high, low-low-high, and low-low-low.	('men', 'Species', '9606', (163, 166))	('high-high-high', 'Var', (182, 196))	('high-high-low', 'Var', (198, 211))	('low-low-low', 'Var', (289, 300))	('high-low-low', 'Var', (213, 225))	('low-high-high', 'Var', (256, 269))	('high-low-high', 'Var', (227, 240))	('low-high-low', 'Var', (242, 254))	('low-low-high', 'Var', (271, 283))
79315	33374569	A significant difference in the radiomics scores between low- and high-grade ccRCCs in all MDCT phases, with patients from the second group having higher values (Table 3), was observed.	('patients', 'Species', '9606', (109, 117))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('low-', 'Var', (57, 61))	('RCC', 'Disease', (79, 82))
79362	32628820	Comprehensive analysis of copy number variance and sensitivity to common targeted therapy in clear cell renal cell carcinoma: In silico analysis with in vitro validation Chromosomal rearrangements are common in clear cell renal cell carcinoma (ccRCC) and their roles in mediating sensitivity to tyrosine kinase inhibitors (TKIs) and mTOR inhibitors (mTORi) remain elusive.	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (93, 124))	('clear cell renal cell carcinoma', 'Disease', (93, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (93, 124))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (211, 242))	('clear cell renal cell carcinoma', 'Disease', (211, 242))	('ccRCC', 'Phenotype', 'HP:0006770', (244, 249))	('Chromosomal rearrangements', 'Var', (170, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (211, 242))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (222, 242))	('mTOR', 'Gene', '2475', (350, 354))	('mTOR', 'Gene', (333, 337))	('mTOR', 'Gene', (350, 354))	('mTOR', 'Gene', '2475', (333, 337))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (104, 124))
79363	32628820	We developed an in silico strategy by screening copy number variance (CNV) that was potentially related to TKI or mTORi sensitivity in ccRCC by reproducing the TCGA and GDSC datasets.	('mTOR', 'Gene', '2475', (114, 118))	('mTOR', 'Gene', (114, 118))	('copy number variance', 'Var', (48, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('ccRCC', 'Disease', (135, 140))
79368	32628820	Mutivariate analysis showed ADCYAP1, GNAS, and CCNE1 remained independently prognostic when adjusted for the rest.	('ADCYAP1', 'Var', (28, 35))	('CCNE1', 'Gene', '898', (47, 52))	('CCNE1', 'Gene', (47, 52))
79369	32628820	Here we show CNVs of several genes that are associated with sensitivity and resistance to commonly used TKIs and mTORi in ccRCC.	('associated', 'Reg', (44, 54))	('ccRCC', 'Phenotype', 'HP:0006770', (122, 127))	('ccRCC', 'Disease', (122, 127))	('mTOR', 'Gene', (113, 117))	('mTOR', 'Gene', '2475', (113, 117))	('CNVs', 'Var', (13, 17))
79374	32628820	It has come to a consensus that the inactivation of VHL gene, a suppressor gene relevant with cellular oxygen sensing, does business for the originality of tumor growth.	('VHL', 'Gene', '7428', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('oxygen', 'Chemical', 'MESH:D010100', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('inactivation', 'Var', (36, 48))	('VHL', 'Gene', (52, 55))
79375	32628820	VHL alteration could be found in various diseases not only retinal hemangioblastomas, pancreatic neuroendocrine tumors but also ccRCCs.	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (86, 118))	('pancreatic neuroendocrine tumors', 'Disease', (86, 118))	('ccRCCs', 'Disease', (128, 134))	('retinal hemangioblastomas', 'Phenotype', 'HP:0009711', (59, 84))	('alteration', 'Var', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('VHL', 'Gene', (0, 3))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (97, 118))	('VHL', 'Gene', '7428', (0, 3))	('found', 'Reg', (24, 29))	('retinal hemangioblastomas', 'Disease', (59, 84))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('retinal hemangioblastomas', 'Disease', 'MESH:D018325', (59, 84))
79377	32628820	3   Copy number variations (CNVs) are of great significance to the tumorigenesis, together with the gene mutation, transcription changes, translation adjusts, and epigenetic modification.	('translation', 'biological_process', 'GO:0006412', ('138', '149'))	('transcription', 'biological_process', 'GO:0006351', ('115', '128'))	('epigenetic', 'Var', (163, 173))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
79383	32628820	The GDSC dataset was used to select candidate focal deletion or amplifications that were associated with sensitivity to TKIs including cabozantinib, pazopanib, temsirolimus, axitinib, and sunitinib.	('associated', 'Reg', (89, 99))	('sunitinib', 'Chemical', 'MESH:D000077210', (188, 197))	('amplifications', 'Var', (64, 78))	('axitinib', 'Chemical', 'MESH:D000077784', (174, 182))	('temsirolimus', 'Chemical', 'MESH:C401859', (160, 172))	('cabozantinib', 'Chemical', 'MESH:C558660', (135, 147))	('pazopanib', 'Chemical', 'MESH:C516667', (149, 158))
79387	32628820	We used TRC (TRC, http://www.broadinstitute.org/rnai/public/) to construct shRNA targeting ADCYAP1 (TRCN0000371228), CTBP1 (TRCN0000273905), CDKN2A (TRCN0000255853), and LRP10 (TRCN0000063424).	('CDKN2A', 'Gene', '1029', (141, 147))	('ADCYAP1', 'Gene', (91, 98))	('rnai', 'biological_process', 'GO:0016246', ('48', '52'))	('TRCN0000273905', 'Var', (124, 138))	('CTBP1', 'Gene', (117, 122))	('LRP10', 'Gene', (170, 175))	('TRCN0000255853', 'Var', (149, 163))	('TRCN0000371228', 'Var', (100, 114))	('CDKN2A', 'Gene', (141, 147))	('LRP10', 'Gene', '26020', (170, 175))
79392	32628820	Primers were designed as per PrimerBank (https://pga.mgh.harvard.edu/cgi-bin/primerbank) as follows: ADCYAP1 (PrimerBank ID 153266791c1), GNAS (PrimerBank ID 4504047a2), ACRBP (PrimerBank ID 17999523c1), CTBP1 (PrimerBank ID 61743966c1), CCNE1 (PrimerBank ID 339275820c1).	('CCNE1', 'Gene', (238, 243))	('PrimerBank', 'Var', (245, 255))	('ACRBP', 'Gene', '84519', (170, 175))	('PrimerBank ID 153266791c1', 'Var', (110, 135))	('ACRBP', 'Gene', (170, 175))	('PrimerBank ID 17999523c1', 'Var', (177, 201))	('PrimerBank ID 61743966c1', 'Var', (211, 235))	('CCNE1', 'Gene', '898', (238, 243))	('PrimerBank ID 4504047a2', 'Var', (144, 167))
79423	32628820	Heterozygous loss of LRP10 occurred in 40% of ccRCC cases and was significantly associated with worsened overall survival (Figure 5B).	('LRP10', 'Gene', (21, 26))	('overall survival', 'MPA', (105, 121))	('LRP10', 'Gene', '26020', (21, 26))	('Heterozygous loss', 'Var', (0, 17))	('worsened', 'NegReg', (96, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('ccRCC', 'Disease', (46, 51))
79430	32628820	11  Shintani also put forward the significance of ADCYAP1 in psychomotor function and described the inhibition in jumping behavior seen in mice lacking PACAP (Adcyap1-/-).	('psychomotor function', 'Disease', 'MESH:D011596', (61, 81))	('jumping behavior', 'CPA', (114, 130))	('ADCYAP1', 'Var', (50, 57))	('Adcyap1', 'Gene', (159, 166))	('PACAP', 'Gene', (152, 157))	('Adcyap1', 'Gene', '11516', (159, 166))	('PACAP', 'Gene', '11516', (152, 157))	('mice', 'Species', '10090', (139, 143))	('psychomotor function', 'Disease', (61, 81))	('inhibition', 'NegReg', (100, 110))
79434	32628820	14  Based on the clinicopathology analysis and sequencing of oncogenes, mutations in GNAS along with Ras/Raf pathway tend to occur in invasive mucinous lung adenocarcinomas.	('mutations', 'Var', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (162, 172))	('invasive mucinous lung adenocarcinomas', 'Disease', 'MESH:D002288', (134, 172))	('GNAS', 'Gene', (85, 89))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (152, 172))	('occur', 'Reg', (125, 130))	('invasive mucinous lung adenocarcinomas', 'Disease', (134, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
79436	32628820	Sensitivity to Pazopanib was associated with ACRBP gain and CTBP1 loss.	('Pazopanib', 'Chemical', 'MESH:C516667', (15, 24))	('ACRBP', 'Gene', '84519', (45, 50))	('loss', 'NegReg', (66, 70))	('gain', 'PosReg', (51, 55))	('ACRBP', 'Gene', (45, 50))	('Sensitivity', 'Var', (0, 11))	('CTBP1', 'Gene', (60, 65))
79449	32628820	Although the metabolism of catecholamines and serotonin has been confirmed relevant to sulfoconjugation, a recent study focused on the single nucleotide polymorphisms of SULT1A3 gene and demonstrated the distinction of enzyme activities between them.	('SULT1A3', 'Gene', (170, 177))	('serotonin', 'Chemical', 'MESH:D012701', (46, 55))	('single nucleotide polymorphisms', 'Var', (135, 166))	('SULT1A3', 'Gene', '6818', (170, 177))	('metabolism', 'biological_process', 'GO:0008152', ('13', '23'))	('catecholamines', 'Chemical', 'MESH:D002395', (27, 41))	('focused', 'Reg', (120, 127))
79450	32628820	Whether their overexpression and copy number gain in tumor cells affects metabolism of compounds entering the cell remains unclear.	('metabolism', 'biological_process', 'GO:0008152', ('73', '83'))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('copy number gain', 'Var', (33, 49))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('metabolism of compounds entering the cell', 'MPA', (73, 114))	('affects', 'Reg', (65, 72))	('tumor', 'Disease', (53, 58))
79455	32628820	Loss of CDKN2A function by mutation or copy number loss is a major landmark in a variety of cancers.	('CDKN2A', 'Gene', (8, 14))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('CDKN2A', 'Gene', '1029', (8, 14))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('Loss', 'NegReg', (0, 4))	('copy number loss', 'Var', (39, 55))	('mutation', 'Var', (27, 35))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('function', 'MPA', (15, 23))
79460	32628820	It was reported that 14.8% of patients with ovarian clear cell carcinomas developed CCNE1 copy number gain, which in turns is correlated with poor overall survival and outcome.	('ovarian clear cell carcinomas', 'Disease', (44, 73))	('CCNE1', 'Gene', (84, 89))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (44, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('patients', 'Species', '9606', (30, 38))	('CCNE1', 'Gene', '898', (84, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('copy number gain', 'Var', (90, 106))
79533	31259150	In preclinical RCC models, endothelial cells chronically exposed to an anti-VEGF antibody proliferate in response to VEGF-C stimulation, whereas naive endothelial cells are unable to proliferate.	('VEGF-C', 'Gene', (117, 123))	('proliferate', 'PosReg', (90, 101))	('VEGF', 'Gene', (117, 121))	('VEGF', 'Gene', (76, 80))	('antibody', 'cellular_component', 'GO:0042571', ('81', '89'))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('RCC', 'Disease', (15, 18))	('antibody', 'cellular_component', 'GO:0019815', ('81', '89'))	('VEGF', 'Gene', '7422', (117, 121))	('VEGF', 'Gene', '7422', (76, 80))	('antibody', 'Var', (81, 89))	('VEGF-C', 'Gene', '7424', (117, 123))	('antibody', 'cellular_component', 'GO:0019814', ('81', '89'))	('antibody', 'molecular_function', 'GO:0003823', ('81', '89'))
79538	31259150	However, besides lymphatic networks, other factors like tumor-infiltrating lymphocytes (TILs) are also essential for recruitment of immune cells as the presence of TILs correlates with improved prognosis and therapy response to immunotherapy in several tumor types.	('improved', 'PosReg', (185, 193))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('presence', 'Var', (152, 160))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('prognosis', 'CPA', (194, 203))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('therapy response', 'CPA', (208, 224))	('tumor', 'Disease', (253, 258))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
79546	31259150	In addition, potential prognostic biomarkers were identified as, for example, a high CA-2 score (high frequencies of either M-11 or M-13 and low frequencies of M-5 macrophages) was associated with a worse clinical outcome.	('M-13', 'Var', (132, 136))	('M-11', 'Var', (124, 128))	('CA-2', 'Gene', (85, 89))	('CA-2', 'Gene', '760', (85, 89))
79550	31259150	In addition, DNA hypermethylation/CDKN2A alterations were associated with poor survival in all RCC subtypes.	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('13', '33'))	('associated', 'Reg', (58, 68))	('poor', 'NegReg', (74, 78))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('RCC', 'Disease', (95, 98))	('CDKN2A', 'Gene', (34, 40))	('CDKN2A', 'Gene', '1029', (34, 40))	('alterations', 'Var', (41, 52))
79577	31259150	These data are supported by an additional study demonstrating that VEGFR-1 knockdown leads to reduced macrophage infiltration in the tumor.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('reduced', 'NegReg', (94, 101))	('VEGFR-1', 'Gene', '2321', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('knockdown', 'Var', (75, 84))	('tumor', 'Disease', (133, 138))	('VEGFR-1', 'Gene', (67, 74))
79591	31259150	In the following section we will discuss individual key components of the TME in RCC that have implications for disease progression as therapeutic targets or have an impact on biological function:  Inhibition of angiogenesis can delay tumor growth, but on the other hand it can also promote metastasis through the existence of abnormal tumor vessels as blood vessel tortuosity in tumors impeded homing of immune cells [reviewed in ].	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('vessel tortuosity', 'Phenotype', 'HP:0004948', (359, 376))	('tumor', 'Phenotype', 'HP:0002664', (380, 385))	('tumor', 'Disease', (336, 341))	('abnormal tumor', 'Phenotype', 'HP:0002664', (327, 341))	('tumors', 'Disease', (380, 386))	('homing', 'CPA', (395, 401))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('metastasis', 'CPA', (291, 301))	('RCC', 'Disease', (81, 84))	('Inhibition of angiogenesis', 'biological_process', 'GO:0016525', ('198', '224'))	('Inhibition', 'Var', (198, 208))	('promote', 'PosReg', (283, 290))	('tumors', 'Disease', 'MESH:D009369', (380, 386))	('abnormal tumor', 'Disease', (327, 341))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('delay', 'NegReg', (229, 234))	('tumor', 'Disease', (380, 385))	('tumor', 'Disease', 'MESH:D009369', (380, 385))	('tumor', 'Disease', (235, 240))	('abnormal tumor', 'Disease', 'MESH:D009369', (327, 341))	('tumors', 'Phenotype', 'HP:0002664', (380, 386))
79616	31259150	The latest data from the Genitourinary ASCO meeting held in February 2019, simultaneously published in the New England Journal of Medicine, demonstrated that at a median follow-up of 12.8 months combination therapy was associated with a 47% reduction in the risk of death as compared to the comparator sunitinib.	('combination', 'Var', (195, 206))	('sunitinib', 'Chemical', 'MESH:D000077210', (302, 311))	('February 2019', 'Disease', (60, 73))	('February 2019', 'Disease', 'MESH:C000657245', (60, 73))	('reduction', 'NegReg', (241, 250))
79630	31259150	To the best of our knowledge two clinical studies are currently evaluating safety and antitumor activity of the RIG I agonist MK-4621 as a monotherapy and in combination with ICB (pembrolizumab) in patients with advanced/metastatic solid tumors (NCT03739138, NCT03065023) (https://clinicaltrials.gov).	('solid tumors', 'Disease', (232, 244))	('pembrolizumab', 'Chemical', 'MESH:C582435', (180, 193))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('patients', 'Species', '9606', (198, 206))	('solid tumors', 'Disease', 'MESH:D009369', (232, 244))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('NCT03739138', 'Var', (246, 257))	('MK-4621', 'Chemical', '-', (126, 133))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('tumor', 'Disease', (238, 243))	('RIG I', 'Gene', (112, 117))	('ICB', 'Chemical', '-', (175, 178))	('RIG I', 'Gene', '23586', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
79766	32111235	This method relies on a priori knowledge of tumor specific mutations and thus, for 29 DIAMOND patients, we carried out whole-exome sequencing (WES) of matched tumor tissue and buffy coat (Additional file 1: Fig.	('patients', 'Species', '9606', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mutations', 'Var', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', (44, 49))
79767	32111235	Patient-specific mutations of key RCC genes are listed in Additional file 1: Table S6.	('Patient', 'Species', '9606', (0, 7))	('mutations', 'Var', (17, 26))	('RCC', 'Disease', 'MESH:D002292', (34, 37))	('RCC', 'Disease', (34, 37))
79786	32111235	S11B), venous tumor thrombus invasion (Fig.	('S11B', 'Var', (0, 4))	('venous tumor', 'Phenotype', 'HP:0012721', (7, 19))	('venous tumor thrombus invasion', 'Disease', 'MESH:D013927', (7, 37))	('venous tumor thrombus', 'Phenotype', 'HP:0004936', (7, 28))	('S11B', 'SUBSTITUTION', 'None', (0, 4))	('venous tumor thrombus invasion', 'Disease', (7, 37))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
79787	32111235	S12A-C) or proliferation rate (Additional file 1: Fig.	('S12A', 'Var', (0, 4))	('S12A', 'SUBSTITUTION', 'None', (0, 4))	('proliferation rate', 'CPA', (11, 29))
79792	32111235	Based on existing data, one would expect a somatic mutation to be present in > 80% of metastatic ccRCC patients in at least one of these genes.	('patients', 'Species', '9606', (103, 111))	('RCC', 'Disease', 'MESH:D002292', (99, 102))	('mutation', 'Var', (51, 59))	('RCC', 'Disease', (99, 102))
79816	32111235	Of those, 6 patients (K18, K20, K23, K27, K39, K42) had mutations called at baseline (Fig.	('K23', 'Gene', (32, 35))	('patients', 'Species', '9606', (12, 20))	('K27', 'Gene', '342574', (37, 40))	('K18', 'Gene', (22, 25))	('K27', 'Gene', (37, 40))	('K20', 'Gene', (27, 30))	('K18', 'Gene', '3875', (22, 25))	('K39', 'Gene', '390792', (42, 45))	('K20', 'Gene', '54474', (27, 30))	('K42', 'Var', (47, 50))	('K39', 'Gene', (42, 45))	('K23', 'Gene', '25984', (32, 35))
79817	32111235	Due to low detection rates at baseline, we analyzed additional samples whose collection coincided with clinical progression and identified three further patients (K11, K21, K35) with detected ctDNA.	('clinical', 'Species', '191496', (103, 111))	('K11', 'Var', (163, 166))	('patients', 'Species', '9606', (153, 161))	('K35', 'Gene', '3886', (173, 176))	('K21', 'Var', (168, 171))	('K35', 'Gene', (173, 176))
79818	32111235	Moreover, ichorCNA was applied to available follow-up samples of 5 patients (K08, K13, K19, K40, K44) with detected ctDNA at baseline (Additional file 3: Table S8).	('K40', 'Gene', '125115', (92, 95))	('K13', 'Gene', (82, 85))	('patients', 'Species', '9606', (67, 75))	('K13', 'Gene', '3860', (82, 85))	('K40', 'Gene', (92, 95))	('K08', 'Var', (77, 80))	('K19', 'Gene', '3880', (87, 90))	('K19', 'Gene', (87, 90))	('K44', 'Var', (97, 100))
79832	32111235	The ctDNA mAF varied between plasma and urine (mean mAF of detected mutations = 2.2 x 10- 2 vs 1.2 x 10- 2 respectively), with differing representation of likely driver genes including VHL (ENST00000256474.2:c.333_340+1delCTACCGAGG) (Additional file 1: Fig.	('mAF', 'Gene', '17132', (52, 55))	('VHL', 'Disease', 'MESH:D006623', (185, 188))	('ENST00000256474.2:c.333_340+1delCTACCGAGG', 'DELETION', 'None', (190, 231))	('VHL', 'Disease', (185, 188))	('mAF', 'Gene', '17132', (10, 13))	('mAF', 'Gene', (10, 13))	('ENST00000256474.2:c.333_340+1delCTACCGAGG', 'Var', (190, 231))	('mutations', 'Var', (68, 77))	('mAF', 'Gene', (52, 55))
79859	32111235	Nevertheless, analysis of two well characterized DIAMOND patients revealed that mutations from the majority of sampled tumor regions were detected in plasma.	('tumor', 'Disease', (119, 124))	('mutations', 'Var', (80, 89))	('patients', 'Species', '9606', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
79868	32111235	Beyond this, assays that target multiple biomarkers, including proteins and methylated cfDNA, will improve sensitivity for detecting and interpreting tumor signal.	('improve', 'PosReg', (99, 106))	('cfDNA', 'Gene', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('sensitivity', 'MPA', (107, 118))	('methylated', 'Var', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
79872	32111235	ccRCC Clear cell RCC cfDNA Cell-free DNA chRCC Chromophobe RCC ctDNA Cell-free tumor DNA EDTA Ethylenediaminetetraacetic acid FF Fresh frozen FFPE Formalin fixed paraffin embedded gmAF Global mAF INVAR-TAPAS INtegration of VAriant Reads - TAilored PAnel Sequencing IR Informative reads mAF Mutant allele fraction mFAST-SeqS Modified Fast Aneuploidy Screening Test-Sequencing System OncoC Oncocytoma PCR Polymerase chain reaction pRCC Papillary RCC RCC Renal cell carcinoma RF Random forest SCNA Somatic copy number alteration SNV Single nucleotide variant sWGS Shallow whole-genome sequencing tMAD Trimmed median absolute deviation UCP Urine cell pellet UMI Unique molecular index USN Urine supernatant WES Whole-exome sequencing Supplementary information accompanies this paper at 10.1186/s13073-020-00723-8.	('Formalin', 'Chemical', 'MESH:D005557', (147, 155))	('OncoC Oncocytoma', 'Phenotype', 'HP:0011798', (382, 398))	('Aneuploidy', 'Disease', (338, 348))	('Mutant', 'Var', (290, 296))	('mAF', 'Gene', (181, 184))	('RCC', 'Disease', 'MESH:D002292', (444, 447))	('Aneuploidy', 'Disease', 'MESH:D000782', (338, 348))	('Renal cell carcinoma', 'Disease', (452, 472))	('RCC', 'Disease', (59, 62))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('RCC', 'Disease', (2, 5))	('Renal cell carcinoma', 'Disease', 'MESH:D002292', (452, 472))	('paraffin', 'Chemical', 'MESH:D010232', (162, 170))	('RCC', 'Disease', (448, 451))	('RCC', 'Disease', (43, 46))	('mAF', 'Gene', '17132', (192, 195))	('RCC', 'Disease', (17, 20))	('RCC', 'Disease', (430, 433))	('RCC', 'Disease', 'MESH:D002292', (59, 62))	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('Chromophobe RCC', 'Disease', 'MESH:D002292', (47, 62))	('tumor', 'Disease', (79, 84))	('mAF', 'Gene', (192, 195))	('Papillary RCC', 'Disease', (434, 447))	('RCC', 'Disease', 'MESH:D002292', (2, 5))	('Renal cell carcinoma', 'Phenotype', 'HP:0005584', (452, 472))	('Oncocytoma', 'Disease', (388, 398))	('RCC', 'Disease', 'MESH:D002292', (43, 46))	('RCC', 'Disease', 'MESH:D002292', (448, 451))	('RCC', 'Disease', 'MESH:D002292', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('RCC', 'Disease', 'MESH:D002292', (430, 433))	('tMAD', 'Chemical', '-', (593, 597))	('Ethylenediaminetetraacetic acid', 'Chemical', 'MESH:D004492', (94, 125))	('mAF', 'Gene', '17132', (286, 289))	('Oncocytoma', 'Disease', 'MESH:D018249', (388, 398))	('Chromophobe RCC', 'Disease', (47, 62))	('RCC', 'Disease', (444, 447))	('Papillary RCC', 'Disease', 'MESH:D002292', (434, 447))	('carcinoma', 'Phenotype', 'HP:0030731', (463, 472))	('mAF', 'Gene', (286, 289))	('mAF', 'Gene', '17132', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('EDTA', 'Chemical', 'MESH:D004492', (89, 93))
79881	32111235	The following sequencing raw data sets have been deposited at the European Genome-phenome Archive (EGA; http://www.ebi.ac.uk/ega/), which is hosted by the EBI, under the accession number EGAS00001003530: (1) sWGS data of DIAMOND cohort (tissue: EGAD00001005815, cfDNA from urine and plasma: EGAD00001005814), (2) sWGS data of the MonReC cohort (cfDNA from RCC patients: EGAD00001005804, non-cancer control: EGAD00001005805), (3) WES data of the DIAMOND cohort (EGAD00001005812), (4) INVAR-TAPAS data (mutation analysis of the DIAMOND cohort) (EGAD00001005813), (5) QIASeq data (mutation analysis of the MonReC cohort) (EGAD00001005806).	('cancer', 'Phenotype', 'HP:0002664', (391, 397))	('EGAD00001005812', 'Var', (461, 476))	('patients', 'Species', '9606', (360, 368))	('cancer', 'Disease', (391, 397))	('cancer', 'Disease', 'MESH:D009369', (391, 397))	('RCC', 'Disease', 'MESH:D002292', (356, 359))	('RCC', 'Disease', (356, 359))
80027	31865180	These results show that HIF1alpha increases the uptake and storage of dietary lipids in this early stage ccRCC model.	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (105, 110))	('RCC', 'Disease', (107, 110))	('uptake', 'biological_process', 'GO:0098739', ('48', '54'))	('storage', 'biological_process', 'GO:0051235', ('59', '66'))	('uptake', 'biological_process', 'GO:0098657', ('48', '54'))	('HIF1alpha', 'Var', (24, 33))	('storage of dietary lipids', 'MPA', (59, 84))	('uptake', 'MPA', (48, 54))	('lipids', 'Chemical', 'MESH:D008055', (78, 84))	('increases', 'PosReg', (34, 43))
80036	31865180	In early stage ccRCC, the expression levels of HIF1alpha are markedly enhanced by loss or inactivation of VHL tumor suppressor gene.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('VHL tumor', 'Disease', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('enhanced', 'PosReg', (70, 78))	('loss', 'NegReg', (82, 86))	('inactivation', 'Var', (90, 102))	('RCC', 'Disease', (17, 20))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('expression levels', 'MPA', (26, 43))	('VHL tumor', 'Disease', 'MESH:D006623', (106, 115))	('tumor suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('ccRCC', 'Phenotype', 'HP:0006770', (15, 20))
80037	31865180	Additional genomic events, such as loss of PBRM1, promote the malignant transformation of kidney lesions through activation of HIF1alpha transcriptional activity.	('PBRM1', 'Gene', (43, 48))	('kidney lesions', 'Disease', 'MESH:D007674', (90, 104))	('promote', 'PosReg', (50, 57))	('kidney lesions', 'Disease', (90, 104))	('loss', 'Var', (35, 39))	('PBRM1', 'Gene', '66923', (43, 48))	('activation', 'PosReg', (113, 123))	('HIF1alpha', 'Protein', (127, 136))	('malignant transformation of', 'CPA', (62, 89))
80038	31865180	To model early stage ccRCC in mice, we previously generated the TRACK (TRAnsgenic Cancer of the Kidney) transgenic mouse model with expression of a mutant, constitutively active HIF1alpha specifically in the proximal tubules of the kidneys.	('transgenic', 'Species', '10090', (104, 114))	('mice', 'Species', '10090', (30, 34))	('Cancer of the Kidney', 'Phenotype', 'HP:0009726', (82, 102))	('TRAnsgenic Cancer of the Kidney', 'Disease', 'MESH:D007680', (71, 102))	('HIF1alpha', 'Gene', (178, 187))	('TRAnsgenic Cancer of the Kidney', 'Disease', (71, 102))	('mouse', 'Species', '10090', (115, 120))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('mutant', 'Var', (148, 154))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (21, 26))
80039	31865180	These mutations in the oxygen-dependent degradation domain of the HIF1alpha found in TRACK kidneys preclude recognition by VHL, interfere with the proteasomal degradation of this HIF1alpha, and promote its transcriptional activity in the kidneys.	('interfere', 'NegReg', (128, 137))	('oxygen', 'Chemical', 'MESH:D010100', (23, 29))	('promote', 'PosReg', (194, 201))	('proteasomal degradation', 'MPA', (147, 170))	('preclude', 'NegReg', (99, 107))	('recognition', 'MPA', (108, 119))	('transcriptional activity', 'MPA', (206, 230))	('degradation', 'biological_process', 'GO:0009056', ('159', '170'))	('HIF1alpha', 'Gene', (66, 75))	('degradation', 'biological_process', 'GO:0009056', ('40', '51'))	('mutations', 'Var', (6, 15))
80043	31865180	Wild type (WT) C57BL/6 male mice and transgenic lines in the C57BL/6 background carrying constitutively active mutants of HIF1alpha (P402A, P564A, N803A, gamma-HIF1alphaM3) driven by a truncated gamma-glutamyl transpeptidase promoter, as previously characterized, were used for this study.	('P402A', 'Var', (133, 138))	('P402A', 'Mutation', 'p.P402A', (133, 138))	('HIF1alpha', 'Gene', (122, 131))	('transgenic', 'Species', '10090', (37, 47))	('P564A', 'Mutation', 'p.P564A', (140, 145))	('mice', 'Species', '10090', (28, 32))	('N803A', 'Var', (147, 152))	('P564A', 'Var', (140, 145))	('N803A', 'Mutation', 'p.N803A', (147, 152))
80118	31865180	We also compared the CD36 and FASN transcript levels in ccRCC patients with WT HIF1alpha versus a loss of the HIF1alpha locus.	('FASN', 'Gene', (30, 34))	('CD36', 'Species', '42374', (21, 25))	('FASN', 'Gene', '14104', (30, 34))	('compared', 'Reg', (8, 16))	('HIF1alpha', 'Var', (79, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('RCC', 'Disease', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('patients', 'Species', '9606', (62, 70))
80126	31865180	showed that the rate-limiting enzyme in mitochondrial FA import, carnitine palmitoyltransferase 1a (CPT1a), is directly repressed by HIF1alpha and HIF2alpha in human ccRCC cultures and that this repression results in a decrease in FA catabolism.	('HIF2alpha', 'Var', (147, 156))	('carnitine palmitoyltransferase 1a', 'Gene', '1374', (65, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (166, 171))	('CPT', 'molecular_function', 'GO:0004095', ('100', '103'))	('decrease', 'NegReg', (219, 227))	('FA catabolism', 'MPA', (231, 244))	('carnitine palmitoyltransferase 1a', 'Gene', (65, 98))	('CPT', 'molecular_function', 'GO:0004142', ('100', '103'))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('catabolism', 'biological_process', 'GO:0009056', ('234', '244'))	('RCC', 'Disease', (168, 171))	('CPT1a', 'Gene', (100, 105))	('CPT1a', 'Gene', '1374', (100, 105))	('human', 'Species', '9606', (160, 165))
80129	31865180	Human tumors were also found to be enriched for polyunsaturated, long-chain FAs.	('Human', 'Species', '9606', (0, 5))	('polyunsaturated', 'Var', (48, 63))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('FAs', 'Chemical', 'MESH:D005227', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
80134	31865180	These results suggest that HIF1alpha activation may not only lead to increased dietary FA uptake but that HIF1alpha may also enhance the enzymatic processing of FAs and cholesterol uptake.	('uptake', 'biological_process', 'GO:0098657', ('90', '96'))	('HIF1alpha', 'Var', (106, 115))	('FAs', 'Chemical', 'MESH:D005227', (161, 164))	('increased', 'PosReg', (69, 78))	('uptake', 'biological_process', 'GO:0098739', ('90', '96'))	('dietary FA uptake', 'MPA', (79, 96))	('cholesterol uptake', 'MPA', (169, 187))	('HIF1alpha', 'Gene', (27, 36))	('enhance', 'PosReg', (125, 132))	('enzymatic processing of FAs', 'MPA', (137, 164))	('cholesterol', 'Chemical', 'MESH:D002784', (169, 180))	('cholesterol uptake', 'biological_process', 'GO:0070508', ('169', '187'))
80155	28475899	Treatment with anti-PD-1 and anti-CTLA-4 antibodies can overcome T cell exhaustion in different cancer types, and clinical trials are investigating the effect of depletion of TAMs and the repolarization of pro-tumor TAMs into anti-tumor TAMs.	('TAMs', 'Chemical', '-', (216, 220))	('anti-CTLA-4', 'Var', (29, 40))	('depletion', 'MPA', (162, 171))	('TAMs', 'Chemical', '-', (175, 179))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('anti-CTLA-4', 'Gene', (29, 40))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('TAMs', 'Chemical', '-', (237, 241))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', (231, 236))	('T cell exhaustion', 'Phenotype', 'HP:0005435', (65, 82))	('anti-PD-1', 'Var', (15, 24))	('men', 'Species', '9606', (5, 8))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
80179	28475899	We observed highly similar phenotypes among CD4+ and CD8+ subsets including cells expressing CD127+, CD11b+, PD-1-/CD11b-, and CTLA-4+ (Figure 3D).	('CD8', 'Gene', (53, 56))	('CD8', 'Gene', '925', (53, 56))	('CD11b', 'Gene', (115, 120))	('CD11b', 'Gene', (101, 106))	('CD11b', 'Gene', '3684', (115, 120))	('CD11b', 'Gene', '3684', (101, 106))	('CD127+', 'Var', (93, 99))
80187	28475899	Except for T-16 and T-19, all clusters expressed CD38, a marker not previously associated with T cell exhaustion in cancer.	('T-19', 'Disease', 'MESH:C537198', (20, 24))	('CD38', 'Var', (49, 53))	('T-1', 'Gene', '921', (11, 14))	('T-1', 'Gene', '921', (20, 23))	('T-1', 'Gene', (11, 14))	('cancer', 'Disease', (116, 122))	('T-1', 'Gene', (20, 23))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('T cell exhaustion', 'Phenotype', 'HP:0005435', (95, 112))	('expressed', 'Reg', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('T-19', 'Disease', (20, 24))
80192	28475899	When cluster frequencies were analyzed based on tumor grade (Figures 3F and S4E), we observed that normal samples were positive for CD4+ central memory T cells (T-2), CD4+ and CD8+ effector memory cells (T-3, T-4), and CD8+/CD45RA+ T cells (T-14).	('CD8', 'Gene', '925', (176, 179))	('memory', 'biological_process', 'GO:0007613', ('145', '151'))	('T-3', 'Gene', (204, 207))	('T-1', 'Gene', (241, 244))	('T-2', 'Gene', (161, 164))	('tumor', 'Disease', (48, 53))	('T-1', 'Gene', '921', (241, 244))	('memory', 'biological_process', 'GO:0007613', ('190', '196'))	('CD8', 'Gene', (219, 222))	('T-2', 'Gene', '292', (161, 164))	('T-3', 'Gene', '292', (204, 207))	('CD4+', 'Var', (132, 136))	('CD8', 'Gene', (176, 179))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('CD8', 'Gene', '925', (219, 222))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
80224	28475899	This analysis suggests compositional patterns in that in samples with the highest amount of T-0 and T-1 PD-1+ cells, the T-4, T-5, and T-11 populations, which express little or no PD-1, were absent, suggesting that these T cell phenotypes might be mutually exclusive.	('T-1', 'Gene', (100, 103))	('T-1', 'Gene', '921', (100, 103))	('T-0', 'Var', (92, 95))	('T-1', 'Gene', '921', (135, 138))	('T-1', 'Gene', (135, 138))
80229	28475899	All pairs of CD4+ and CD8+ correlations qualitatively identified (Figure 3D) were present among the top 20 strongest correlations (Figure S7A; Table S5), consistent with the idea that CD4+ and CD8+ T cells in the TME are exposed to a similar milieu and tend to follow similar polarization schemes.	('CD8', 'Gene', '925', (193, 196))	('CD8', 'Gene', (193, 196))	('CD4+', 'Var', (184, 188))	('CD8', 'Gene', (22, 25))	('CD8', 'Gene', '925', (22, 25))
80251	28475899	The most important immune subpopulations for CA-2 are the pro-tumor macrophage subpopulations M-11, M-13, and M-5 (Figure 7B), in that patients with high CA-2 scores and poor progression-free survival times had high frequencies of either M-11 or M-13 and low frequencies of M-5 macrophages.	('patients', 'Species', '9606', (135, 143))	('M-5', 'Gene', (274, 277))	('M-1', 'Gene', (94, 97))	('CA-2', 'Gene', (45, 49))	('M-1', 'Gene', (100, 103))	('M-1', 'Gene', '100507027', (238, 241))	('M-1', 'Gene', '100507027', (246, 249))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('CA-2', 'Gene', '760', (154, 158))	('high', 'Var', (149, 153))	('M-1', 'Gene', '100507027', (94, 97))	('M-5', 'Gene', '213788', (110, 113))	('CA-2', 'Gene', (154, 158))	('M-1', 'Gene', '100507027', (100, 103))	('M-5', 'Gene', (110, 113))	('M-1', 'Gene', (238, 241))	('M-1', 'Gene', (246, 249))	('tumor', 'Disease', (62, 67))	('scores', 'Var', (159, 165))	('CA-2', 'Gene', '760', (45, 49))	('M-5', 'Gene', '213788', (274, 277))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
80272	28475899	Depletion or inhibition of CD38 slows progression of glioblastoma in animal models, and CD38-positive myeloid-derived suppressor cells suppress T cell activity and promote tumor growth in esophageal cancer models.	('esophageal cancer', 'Disease', 'MESH:D004938', (188, 205))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('glioblastoma', 'Disease', (53, 65))	('T cell activity', 'CPA', (144, 159))	('glioblastoma', 'Disease', 'MESH:D005909', (53, 65))	('tumor', 'Disease', (172, 177))	('suppress', 'NegReg', (135, 143))	('inhibition', 'Var', (13, 23))	('promote', 'PosReg', (164, 171))	('glioblastoma', 'Phenotype', 'HP:0012174', (53, 65))	('CD38-positive', 'Var', (88, 101))	('slows', 'NegReg', (32, 37))	('esophageal cancer', 'Disease', (188, 205))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('CD38', 'Gene', (27, 31))
80352	28475899	S.C. performed all experiments with help from D.S., L.A., M.A.S.J., and C.G.	('M.A.S.J.', 'Var', (58, 66))	('C.G', 'Var', (72, 75))	('men', 'Species', '9606', (25, 28))
80375	33836688	For example, studies have presented that about 90% of patients with sporadic ccRCC have mutations of VHL gene.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('VHL', 'Gene', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('VHL', 'Gene', '7428', (101, 104))	('patients', 'Species', '9606', (54, 62))	('mutations', 'Var', (88, 97))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
80376	33836688	When this gene is deleted, HIF-alpha accumulates, and genes such as VEGF, PDGF, TGF-alpha, and MMP are activated to participate in neovascularization formation, cell proliferation, infiltration and distant metastasis promote the development of tumors.	('cell proliferation', 'biological_process', 'GO:0008283', ('161', '179'))	('VEGF', 'Gene', (68, 72))	('TGF-alpha', 'Gene', (80, 89))	('MMP', 'molecular_function', 'GO:0004235', ('95', '98'))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('distant metastasis', 'CPA', (198, 216))	('cell proliferation', 'CPA', (161, 179))	('neovascularization formation', 'CPA', (131, 159))	('deleted', 'Var', (18, 25))	('PDGF', 'molecular_function', 'GO:0005161', ('74', '78'))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('infiltration', 'CPA', (181, 193))	('tumors', 'Disease', (244, 250))	('MMP', 'Gene', (95, 98))	('activated', 'PosReg', (103, 112))	('promote', 'PosReg', (217, 224))	('TGF-alpha', 'Gene', '7039', (80, 89))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('formation', 'biological_process', 'GO:0009058', ('150', '159'))	('PDGF', 'Gene', (74, 78))	('VEGF', 'Gene', '7422', (68, 72))
80434	33836688	found that overexpression of miR-145-5p and miR-141-3p could inhibit the migration and invasion of RCC cells by influencing the HS6ST2 expression.	('influencing', 'Reg', (112, 123))	('HS6ST2', 'Gene', '90161', (128, 134))	('-141-3p', 'Chemical', '-', (47, 54))	('miR-145', 'Gene', (29, 36))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('HS6ST2', 'Gene', (128, 134))	('inhibit', 'NegReg', (61, 68))	('miR-141-3p', 'Var', (44, 54))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('miR-145', 'Gene', '406937', (29, 36))	('expression', 'MPA', (135, 145))	('RCC', 'Disease', (99, 102))	('overexpression', 'PosReg', (11, 25))
80443	33836688	FBP1 overexpression inhibits the proliferation, migration, invasion and tumorigenesis of cholangiocarcinoma cells by inhibiting the Wnt/beta pathway.	('migration', 'CPA', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cholangiocarcinoma', 'Disease', (89, 107))	('FBP1', 'Gene', '2203', (0, 4))	('Wnt/beta pathway', 'Pathway', (132, 148))	('inhibits', 'NegReg', (20, 28))	('tumor', 'Disease', (72, 77))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (89, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (89, 107))	('inhibiting', 'NegReg', (117, 127))	('proliferation', 'CPA', (33, 46))	('FBP1', 'Gene', (0, 4))	('invasion', 'CPA', (59, 67))	('overexpression', 'Var', (5, 19))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
80444	33836688	FBP1 gene silencing could activate the MAPK pathway and then promote cell EMT, invasion and metastasis in prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('gene silencing', 'biological_process', 'GO:0016458', ('5', '19'))	('FBP1', 'Gene', '2203', (0, 4))	('EMT', 'biological_process', 'GO:0001837', ('74', '77'))	('activate', 'PosReg', (26, 34))	('gene silencing', 'Var', (5, 19))	('metastasis in prostate cancer', 'Disease', (92, 121))	('promote', 'PosReg', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('metastasis in prostate cancer', 'Disease', 'MESH:D011471', (92, 121))	('MAPK', 'molecular_function', 'GO:0004707', ('39', '43'))	('MAPK pathway', 'Pathway', (39, 51))	('FBP1', 'Gene', (0, 4))	('invasion', 'CPA', (79, 87))	('cell EMT', 'CPA', (69, 77))
80447	33836688	VCAN knockdown significantly reduced the proliferation of renal cancer cells and increased apoptosis, which is linked to the changes of several TNF signaling related genes such as TNFalpha, BID and BAK.	('knockdown', 'Var', (5, 14))	('TNF', 'Gene', '7124', (180, 183))	('VCAN', 'Gene', '1462', (0, 4))	('TNFalpha', 'Gene', '7124', (180, 188))	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('VCAN', 'Gene', (0, 4))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('BID', 'Gene', (190, 193))	('BAK', 'Gene', (198, 201))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('TNF', 'Gene', (144, 147))	('BAK', 'Gene', '578', (198, 201))	('BID', 'Gene', '637', (190, 193))	('renal cancer', 'Disease', (58, 70))	('apoptosis', 'CPA', (91, 100))	('renal cancer', 'Phenotype', 'HP:0009726', (58, 70))	('TNFalpha', 'Gene', (180, 188))	('increased', 'PosReg', (81, 90))	('proliferation', 'CPA', (41, 54))	('TNF', 'Gene', '7124', (144, 147))	('signaling', 'biological_process', 'GO:0023052', ('148', '157'))	('TNF', 'Gene', (180, 183))	('reduced', 'NegReg', (29, 36))	('renal cancer', 'Disease', 'MESH:D007680', (58, 70))
80457	33836688	Patients with high-risk scores had significantly lower OS compared to those with low-risk scores.	('Patients', 'Species', '9606', (0, 8))	('lower', 'NegReg', (49, 54))	('high-risk scores', 'Var', (14, 30))
80526	31839812	The survival curves were drawn to evaluate the association between three hub genes methylation levels and the prognosis of ccRCC, respectively.	('hub', 'Gene', (73, 76))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('methylation', 'biological_process', 'GO:0032259', ('83', '94'))	('hub', 'Gene', '1993', (73, 76))	('methylation', 'Var', (83, 94))	('association', 'Interaction', (47, 58))
80535	31839812	Also, the methylation of these hub genes was found negatively corelated with survival.	('survival', 'CPA', (77, 85))	('negatively', 'NegReg', (51, 61))	('hub', 'Gene', '1993', (31, 34))	('methylation', 'Var', (10, 21))	('hub', 'Gene', (31, 34))	('methylation', 'biological_process', 'GO:0032259', ('10', '21'))
80552	31839812	Also, the hyper-methylation of these hub genes was found negatively associated with survival (Figure 7).	('hub', 'Gene', '1993', (37, 40))	('associated', 'Reg', (68, 78))	('methylation', 'biological_process', 'GO:0032259', ('16', '27'))	('hub', 'Gene', (37, 40))	('negatively', 'NegReg', (57, 67))	('hyper-methylation', 'Var', (10, 27))	('survival', 'CPA', (84, 92))
80553	31839812	However, the hypo-methylated gene AGXT2 also showed a shorter OS, which will need further investigation In line with previous report, hyper-methylated and lower expressed genes showed worse prognosis.	('lower', 'NegReg', (155, 160))	('hyper-methylated', 'Var', (134, 150))	('AGXT2', 'Gene', '64902', (34, 39))	('AGXT2', 'Gene', (34, 39))
80563	31839812	And genes mutated in renal cancer are complicated in a quantity of disparate pathways regulating various aspects of cellular metabolism, such as iron sensing and/or oxygen, the tricarboxylic acid (TCA) cycle, tumor energetics and glutamine metabolism.	('glutamine', 'MPA', (230, 239))	('mutated', 'Var', (10, 17))	('TCA) cycle', 'biological_process', 'GO:0006099', ('197', '207'))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Disease', (209, 214))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (177, 195))	('renal cancer', 'Phenotype', 'HP:0009726', (21, 33))	('oxygen', 'Chemical', 'MESH:D010100', (165, 171))	('cellular metabolism', 'biological_process', 'GO:0044237', ('116', '135'))	('renal cancer', 'Disease', 'MESH:D007680', (21, 33))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('230', '250'))	('iron', 'Chemical', 'MESH:D007501', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('complicated', 'Reg', (38, 49))	('glutamine', 'Chemical', 'MESH:D005973', (230, 239))	('TCA', 'Chemical', 'MESH:D014233', (197, 200))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('renal cancer', 'Disease', (21, 33))
80610	31564221	A PCR quantification analysis of the SCARNA17 SNORD61, SNORD68, RNU6-2, and miRNAs such as miR-21-5p, miR-210-3p, miR-185-5p, miR-221-3p, and miR-145-5p was performed using the miScript SYBR Green PCR kit (Qiagen) with the miScript Primer assay Hs-SCARNA17 (#MS00014014), SNORD61 (#MS00033705), SNORD68 (#MS00033712), RNU6B-2 (#MS00033740), Hs-miR-21-5p (#MS00009079), Hs-miR-210-3p (#MS00003801), Hs-miR-185-5p (#MS00003647), Hs-miR-221-3p (#MS00003857), and Hs-miR-145-5p (#MS00003528; Qiagen).	('#MS00003857', 'Var', (442, 453))	('miR-145', 'Gene', '406937', (142, 149))	('SNORD68', 'Gene', '606500', (295, 302))	('#MS00014014', 'Var', (258, 269))	('SNORD68', 'Gene', (295, 302))	('miR-221', 'Gene', '407006', (430, 437))	('SNORD61', 'Gene', '26787', (46, 53))	('miR-210', 'Gene', (102, 109))	('SCARNA17', 'Gene', (248, 256))	('SNORD68', 'Gene', (55, 62))	('SNORD68', 'Gene', '606500', (55, 62))	('SNORD61', 'Gene', (272, 279))	('221-3p', 'Chemical', 'MESH:C560519', (130, 136))	('RNU6-2', 'Gene', '103625684', (64, 70))	('miR-145', 'Gene', (142, 149))	('miR-185', 'Gene', (401, 408))	('#MS00003528;', 'Var', (475, 487))	('miR-185', 'Gene', (114, 121))	('miR-145', 'Gene', '406937', (463, 470))	('miR-221', 'Gene', (126, 133))	('SCARNA17', 'Gene', '677769', (37, 45))	('#MS00033740', 'Var', (327, 338))	('SNORD61', 'Gene', (46, 53))	('miR-221', 'Gene', '407006', (126, 133))	('#MS00033712', 'Var', (304, 315))	('miR-145', 'Gene', (463, 470))	('RNU6B-2', 'Chemical', 'MESH:C459131', (318, 325))	('miR-21-5p', 'Gene', (91, 100))	('miR-21-5p', 'Gene', '406997', (91, 100))	('miR-185', 'Gene', '406961', (401, 408))	('SCARNA17', 'Gene', (37, 45))	('#MS00003647', 'Var', (413, 424))	('#MS00033705', 'Var', (281, 292))	('SNORD61', 'Gene', '26787', (272, 279))	('miR-185', 'Gene', '406961', (114, 121))	('miR-210', 'Gene', '406992', (372, 379))	('miR-21-5p', 'Gene', (344, 353))	('SCARNA17', 'Gene', '677769', (248, 256))	('miR-21-5p', 'Gene', '406997', (344, 353))	('221-3p', 'Chemical', 'MESH:C560519', (434, 440))	('miR-210', 'Gene', '406992', (102, 109))	('RNU6-2', 'Gene', (64, 70))	('miR-221', 'Gene', (430, 437))	('miR-210', 'Gene', (372, 379))
80740	32846785	KM and multivariate Cox regression analyses demonstrated that ccRCC patients with high-immune scores had significantly poor OS compared with those with low-immune scores.	('Cox', 'Gene', '1351', (20, 23))	('Cox', 'Gene', (20, 23))	('high-immune scores', 'Var', (82, 100))	('patients', 'Species', '9606', (68, 76))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('RCC', 'Disease', (64, 67))
80778	32846785	In respect of T stage or TNM stage, ccRCC patients in low-immune scores subgroup tended to be in the early stage.	('RCC', 'Disease', (38, 41))	('TNM', 'Gene', '10178', (25, 28))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('TNM', 'Gene', (25, 28))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('patients', 'Species', '9606', (42, 50))	('low-immune scores', 'Var', (54, 71))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
80779	32846785	In addition, patients in low-immune scores group tended to have low stromal scores compared with those in the high-immune scores group.	('patients', 'Species', '9606', (13, 21))	('low', 'NegReg', (64, 67))	('low-immune scores', 'Var', (25, 42))	('stromal', 'MPA', (68, 75))
80782	32846785	In the multivariate Cox regression analysis, high-immune scores were significantly associated with worse OS (HR: 1.41, 95%CI: 1.02-2.0) compared with low-immune scores.	('Cox', 'Gene', '1351', (20, 23))	('Cox', 'Gene', (20, 23))	('high-immune scores', 'Var', (45, 63))	('worse OS', 'Disease', (99, 107))
80783	32846785	Furthermore, ccRCC patients in the high-stromal scores group had significantly better OS (HR: 0.46, 95%CI: 0.30-0.70).	('high-stromal scores', 'Var', (35, 54))	('patients', 'Species', '9606', (19, 27))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('RCC', 'Disease', (15, 18))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('better', 'PosReg', (79, 85))
80790	32846785	Using Cox regression analyses and KM survival curves, we found that the OS time of patients with high-immune scores was significantly worse than that of patients with low-immune scores.	('patients', 'Species', '9606', (153, 161))	('Cox', 'Gene', '1351', (6, 9))	('Cox', 'Gene', (6, 9))	('patients', 'Species', '9606', (83, 91))	('worse', 'NegReg', (134, 139))	('high-immune scores', 'Var', (97, 115))
80800	32846785	In the present study, we discovered that high-immune scores were significantly related to poor OS time in patients with ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (120, 125))	('patients', 'Species', '9606', (106, 114))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('high-immune scores', 'Var', (41, 59))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('poor OS time', 'MPA', (90, 102))	('RCC', 'Disease', (122, 125))
80823	32846785	Our research shows that that high-immune scores are associated with worse OS in ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('high-immune', 'Var', (29, 40))	('worse OS', 'Disease', (68, 76))	('patients', 'Species', '9606', (86, 94))
80849	31299041	MicroRNAs (miRNAs) are composed of 21- to 25-nucleotide (nt) non-coding and single-stranded RNAs, which involve many biological processes or effects, including cell growth, cell-fate specification, cell apoptosis, and cell differentiation.	('cell differentiation', 'biological_process', 'GO:0030154', ('218', '238'))	('cell apoptosis', 'CPA', (198, 212))	('apoptosis', 'biological_process', 'GO:0006915', ('203', '212'))	('miR', 'Gene', '220972', (11, 14))	('single-stranded', 'Var', (76, 91))	('miR', 'Gene', (11, 14))	('cell-fate specification', 'biological_process', 'GO:0001708', ('173', '196'))	('cell differentiation', 'CPA', (218, 238))	('apoptosis', 'biological_process', 'GO:0097194', ('203', '212'))	('cell growth', 'biological_process', 'GO:0016049', ('160', '171'))
80854	31299041	miR-381 is increased glioma cell proliferation in vivo and in vitro, the actions of which were also related to reduced suppression of the AKT signaling pathway and the MEK/ERK signaling pathway.	('cell proliferation', 'biological_process', 'GO:0008283', ('28', '46'))	('MEK', 'Gene', (168, 171))	('increased', 'PosReg', (11, 20))	('MEK', 'Gene', '5609', (168, 171))	('glioma', 'Disease', 'MESH:D005910', (21, 27))	('ERK', 'molecular_function', 'GO:0004707', ('172', '175'))	('AKT', 'Gene', (138, 141))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('miR-381', 'Var', (0, 7))	('AKT signaling', 'biological_process', 'GO:0043491', ('138', '151'))	('ERK', 'Gene', '5594', (172, 175))	('glioma', 'Disease', (21, 27))	('reduced suppression', 'NegReg', (111, 130))	('signaling pathway', 'biological_process', 'GO:0007165', ('176', '193'))	('signaling pathway', 'biological_process', 'GO:0007165', ('142', '159'))	('AKT', 'Gene', '207', (138, 141))	('ERK', 'Gene', (172, 175))
80897	31299041	We assessed the effects of miR-381 expression on multi-drug resistance, showing that inhibition of miR-381 expression remarkably increased cell growth and chemoresistance as shown by MTT assay (Figure 4A, 4B).	('chemoresistance', 'CPA', (155, 170))	('cell growth', 'biological_process', 'GO:0016049', ('139', '150'))	('drug resistance', 'biological_process', 'GO:0042493', ('55', '70'))	('miR-381', 'Gene', (99, 106))	('drug resistance', 'Phenotype', 'HP:0020174', (55, 70))	('inhibition', 'Var', (85, 95))	('cell growth', 'CPA', (139, 150))	('increased', 'PosReg', (129, 138))	('expression', 'MPA', (107, 117))	('MTT', 'Chemical', 'MESH:C070243', (183, 186))	('drug resistance', 'biological_process', 'GO:0009315', ('55', '70'))
80904	31299041	Mice injected with miR-381 had tumors that were significantly lighter than in mice injected with NC (Figure 5C).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('lighter', 'NegReg', (62, 69))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('Mice', 'Species', '10090', (0, 4))	('mice', 'Species', '10090', (78, 82))	('miR-381', 'Var', (19, 26))
80907	31299041	miRNAs are derived from endogenous transcription, which is initiated by slicing of RNase III-associated enzymes.	('miR', 'Gene', (0, 3))	('slicing', 'Var', (72, 79))	('miR', 'Gene', '220972', (0, 3))	('transcription', 'biological_process', 'GO:0006351', ('35', '48'))
80913	31299041	Aberrant expression of miR-381 has been discovered in many cancers, such as liver cancer, breast cancer, lung cancer, and colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('liver cancer', 'Disease', 'MESH:D006528', (76, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Aberrant', 'Var', (0, 8))	('colon cancer', 'Disease', 'MESH:D015179', (122, 134))	('liver cancer', 'Phenotype', 'HP:0002896', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('liver cancer', 'Disease', (76, 88))	('miR-381', 'Gene', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('colon cancer', 'Disease', (122, 134))	('lung cancer', 'Disease', (105, 116))	('discovered', 'Reg', (40, 50))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('breast cancer', 'Disease', (90, 103))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))
80930	31299041	The effect of miR-381 expression on ccRCC cells was also evaluated both in vitro and in vivo, and the data showed that miR-381 enhanced the sensitivity of cells to Pa and Ci treatment.	('RCC', 'Disease', (38, 41))	('Ci', 'Chemical', 'MESH:D002945', (171, 173))	('enhanced', 'PosReg', (127, 135))	('miR-381', 'Var', (119, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('Pa', 'Chemical', 'MESH:D017239', (164, 166))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
80947	31462894	To date, several subtypes of RCC have been defined, of which clear cell RCC (ccRCC) is the most frequent (75-80%), followed by papillary RCC (pRCC; 15%) and chromophobe RCC (chRCC; 5%), and biallelic von-Hippel Lindau (VHL) gene defects occur in approximately 75% of sporadic ccRCC.	('RCC', 'Disease', 'MESH:C538614', (278, 281))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('von-Hippel Lindau', 'Gene', (200, 217))	('pRCC', 'Gene', '5546', (142, 146))	('RCC', 'Disease', (169, 172))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('VHL', 'Gene', (219, 222))	('RCC', 'Disease', (137, 140))	('chromophobe RCC', 'Disease', 'MESH:C538614', (157, 172))	('RCC', 'Disease', (176, 179))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('occur', 'Reg', (237, 242))	('defects', 'Var', (229, 236))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('von-Hippel Lindau', 'Gene', '7428', (200, 217))	('pRCC', 'Gene', (142, 146))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (143, 146))	('VHL', 'Gene', '7428', (219, 222))	('RCC', 'Disease', (79, 82))	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('RCC', 'Disease', (278, 281))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('papillary RCC', 'Disease', 'MESH:C538614', (127, 140))	('RCC', 'Disease', (72, 75))	('chromophobe RCC', 'Disease', (157, 172))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('papillary RCC', 'Disease', (127, 140))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', 'MESH:C538614', (79, 82))
80949	31462894	The key genetic inactivations or mutations for RCC include those in MET proto-oncogene (MET), polybromo 1 (PBRM1), transcription factor binding to IGHM enhancer 3 (TFE3), folliculin (FLCN), Tuberous Sclerosis Complex 1 (TSC1), fumarate hydratase (FH), succinate dehydrogenase complex subunit D (SDHD), phosphatase and tensin homolog (PTEN) and VHL, which leads to the accumulation of downstream oncogenic targets, such as HIFs.	('succinate dehydrogenase complex subunit D', 'Gene', '6392', (252, 293))	('TFE3', 'Gene', '7030', (164, 168))	('IGHM', 'Gene', '3507', (147, 151))	('transcription', 'biological_process', 'GO:0006351', ('115', '128'))	('Tuberous Sclerosis Complex', 'cellular_component', 'GO:0033596', ('190', '216'))	('accumulation', 'PosReg', (368, 380))	('mutations', 'Var', (33, 42))	('TSC1', 'Gene', '7248', (220, 224))	('Tuberous Sclerosis Complex 1', 'Gene', '7248', (190, 218))	('SDHD', 'Gene', '6392', (295, 299))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('fumarate hydratase', 'Gene', (227, 245))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('115', '143'))	('folliculin', 'Gene', (171, 181))	('SDHD', 'Gene', (295, 299))	('IGHM', 'Gene', (147, 151))	('folliculin', 'Gene', '201163', (171, 181))	('VHL', 'Gene', (344, 347))	('PTEN', 'Gene', (334, 338))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('succinate dehydrogenase complex subunit D', 'Gene', (252, 293))	('succinate dehydrogenase complex', 'cellular_component', 'GO:0045281', ('252', '283'))	('fumarate hydratase', 'Gene', '2271', (227, 245))	('FLCN', 'Gene', '201163', (183, 187))	('PBRM1', 'Gene', '55193', (107, 112))	('succinate dehydrogenase complex', 'cellular_component', 'GO:0045282', ('252', '283'))	('FH', 'Gene', '2271', (247, 249))	('VHL', 'Gene', '7428', (344, 347))	('PTEN', 'Gene', '5728', (334, 338))	('FLCN', 'Gene', (183, 187))	('Tuberous Sclerosis Complex 1', 'Gene', (190, 218))	('polybromo', 'Gene', (94, 103))	('TFE3', 'Gene', (164, 168))	('PBRM1', 'Gene', (107, 112))	('RCC', 'Disease', (47, 50))	('TSC1', 'Gene', (220, 224))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('302', '332'))	('phosphatase', 'molecular_function', 'GO:0016791', ('302', '313'))
80950	31462894	ccRCC develops resistance to apoptosis by diverse mechanisms, including VHL mutations.	('VHL', 'Gene', '7428', (72, 75))	('mutations', 'Var', (76, 85))	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('apoptosis', 'biological_process', 'GO:0097194', ('29', '38'))	('apoptosis', 'biological_process', 'GO:0006915', ('29', '38'))	('VHL', 'Gene', (72, 75))
80971	31462894	The tumor stroma expression of phosphorylated VEGFR2 (i.e., activated) might be taken as a predictive biomarker for clinical outcome in sunitinib-treated RCC patients.	('VEGFR2', 'Gene', (46, 52))	('tumor stroma', 'Disease', 'MESH:D009369', (4, 16))	('phosphorylated', 'Var', (31, 45))	('tumor stroma', 'Disease', (4, 16))	('RCC', 'Disease', (154, 157))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('RCC', 'Phenotype', 'HP:0005584', (154, 157))	('VEGFR2', 'Gene', '3791', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('patients', 'Species', '9606', (158, 166))	('sunitinib', 'Chemical', 'MESH:D000077210', (136, 145))
80975	31462894	For patients treated with inhibitors of VEGF or mTOR, molecular subgroups of PBRM1, BAP1, and KDM5C mutations might have predictive values for metastatic ccRCC.	('mutations', 'Var', (100, 109))	('mTOR', 'Gene', '2475', (48, 52))	('PBRM1', 'Gene', (77, 82))	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('mTOR', 'Gene', (48, 52))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('KDM5C', 'Gene', '8242', (94, 99))	('values', 'Reg', (132, 138))	('VEGF', 'Gene', (40, 44))	('RCC', 'Disease', (156, 159))	('PBRM1', 'Gene', '55193', (77, 82))	('BAP1', 'Gene', '8314', (84, 88))	('patients', 'Species', '9606', (4, 12))	('VEGF', 'Gene', '7422', (40, 44))	('BAP1', 'Gene', (84, 88))	('KDM5C', 'Gene', (94, 99))
80978	31462894	Five VEGFR1 genotyped SNPs (rs9582036, rs9554320, rs9554316, rs7993418 and rs9513070) were analyzed, and rs9582036 CC carriers had a poorer progression free survival (PFS) and overall survival (OS) compared to AC/AA carriers and thus could serve as potential predictive biomarkers for metastatic ccRCC patients receiving sunitinib treatment.	('poorer', 'NegReg', (133, 139))	('rs9582036', 'Mutation', 'rs9582036', (28, 37))	('RCC', 'Phenotype', 'HP:0005584', (298, 301))	('OS', 'Chemical', '-', (194, 196))	('rs9513070', 'Mutation', 'rs9513070', (75, 84))	('RCC', 'Disease', (298, 301))	('rs9554320', 'Mutation', 'rs9554320', (39, 48))	('RCC', 'Disease', 'MESH:C538614', (298, 301))	('rs9554320', 'Var', (39, 48))	('rs9582036 CC', 'Var', (105, 117))	('rs9582036', 'Mutation', 'rs9582036', (105, 114))	('progression free survival', 'CPA', (140, 165))	('rs7993418', 'Var', (61, 70))	('VEGFR1', 'Gene', '2321', (5, 11))	('VEGFR1', 'Gene', (5, 11))	('sunitinib', 'Chemical', 'MESH:D000077210', (321, 330))	('rs7993418', 'Mutation', 'rs7993418', (61, 70))	('overall survival', 'CPA', (176, 192))	('rs9554316', 'Mutation', 'rs9554316', (50, 59))	('rs9513070', 'Var', (75, 84))	('rs9554316', 'Var', (50, 59))	('rs9582036', 'Var', (28, 37))	('patients', 'Species', '9606', (302, 310))
80984	31462894	Targeted therapy can induce the death of most tumor cells, but a small heterogeneous subclone will survive and drive these cells to be resistant to therapeutic drugs.	('Targeted therapy', 'Var', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
81003	31462894	Preelevated TNF-alpha expression may make VHL-deficient cells more sensitive to cystine deprivation, which could induce necrosis.	('necrosis', 'Disease', (120, 128))	('Preelevated', 'Var', (0, 11))	('cystine deprivation', 'Disease', (80, 99))	('expression', 'Var', (22, 32))	('necrosis', 'biological_process', 'GO:0070265', ('120', '128'))	('necrosis', 'biological_process', 'GO:0008219', ('120', '128'))	('necrosis', 'Disease', 'MESH:D009336', (120, 128))	('necrosis', 'biological_process', 'GO:0019835', ('120', '128'))	('necrosis', 'biological_process', 'GO:0008220', ('120', '128'))	('TNF-alpha', 'Gene', '7124', (12, 21))	('necrosis', 'biological_process', 'GO:0001906', ('120', '128'))	('TNF-alpha', 'Gene', (12, 21))	('VHL-deficient', 'Disease', 'MESH:D006623', (42, 55))	('cystine deprivation', 'Disease', 'MESH:D003554', (80, 99))	('VHL-deficient', 'Disease', (42, 55))	('induce', 'Reg', (113, 119))
81024	31462894	The implication of translocation facor E3 and translocation facor EB in metabolic pathways and mTOR signaling are particularly intriguing in the processes of RCC tumorigenesis.	('facor EB', 'Gene', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('metabolic pathways', 'Pathway', (72, 90))	('tumor', 'Disease', (162, 167))	('translocation', 'Var', (46, 59))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('mTOR', 'Gene', (95, 99))	('mTOR', 'Gene', '2475', (95, 99))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
81030	31462894	STF-62247 induced autophagic cell death independent of HIF-1 in VHL-deficient cells, and its combination with radiation enhanced cell killing under oxic, hypoxic or physiological conditions.	('combination', 'Interaction', (93, 104))	('hypoxic', 'Disease', (154, 161))	('hypoxic', 'Disease', 'MESH:D000860', (154, 161))	('autophagic cell death', 'biological_process', 'GO:0048102', ('18', '39'))	('STF-62247', 'Var', (0, 9))	('enhanced', 'PosReg', (120, 128))	('autophagic cell death', 'CPA', (18, 39))	('HIF-1 in VHL-deficient', 'Disease', (55, 77))	('cell killing', 'biological_process', 'GO:0001906', ('129', '141'))	('HIF-1 in VHL-deficient', 'Disease', 'MESH:D006623', (55, 77))	('cell killing', 'CPA', (129, 141))
81037	31462894	The synthesis of GSH requires glutamine and cystine, and the inhibition of GSH synthesis by the deprivation of glutamine and cystine highly sensitized ccRCC cell growth in a MYC-dependent RCC mouse model.	('mouse', 'Species', '10090', (192, 197))	('sensitized', 'NegReg', (140, 150))	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('cell growth', 'biological_process', 'GO:0016049', ('157', '168'))	('GSH', 'Gene', (75, 78))	('inhibition', 'NegReg', (61, 71))	('cystine', 'Chemical', 'MESH:D003553', (125, 132))	('GSH', 'Chemical', 'MESH:D005978', (75, 78))	('cystine', 'Chemical', 'MESH:D003553', (44, 51))	('glutamine', 'Chemical', 'MESH:D005973', (111, 120))	('synthesis', 'biological_process', 'GO:0009058', ('79', '88'))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('synthesis', 'biological_process', 'GO:0009058', ('4', '13'))	('RCC', 'Disease', (153, 156))	('GSH', 'Chemical', 'MESH:D005978', (17, 20))	('deprivation', 'Var', (96, 107))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('RCC', 'Disease', (188, 191))	('glutamine', 'Chemical', 'MESH:D005973', (30, 39))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('glutamine', 'Protein', (111, 120))
81044	31462894	NF-kappaB-mediated MUC13 promoted the growth and survival of RCC cells, while silencing MUC13 increased the killing effect of sorafenib and sunitinib to RCC cells and reversed their acquired resistance to these targeted therapy drugs.	('MUC13', 'Gene', (19, 24))	('increased', 'PosReg', (94, 103))	('NF-kappaB', 'Gene', (0, 9))	('silencing', 'Var', (78, 87))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('acquired resistance', 'MPA', (182, 201))	('MUC13', 'Gene', '56667', (19, 24))	('NF-kappaB', 'Gene', '4790', (0, 9))	('reversed', 'Reg', (167, 175))	('MUC13', 'Gene', (88, 93))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('growth', 'CPA', (38, 44))	('sunitinib', 'Chemical', 'MESH:D000077210', (140, 149))	('MUC13', 'Gene', '56667', (88, 93))	('killing effect', 'CPA', (108, 122))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('RCC', 'Disease', (153, 156))	('survival', 'CPA', (49, 57))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('promoted', 'PosReg', (25, 33))	('sorafenib', 'Chemical', 'MESH:D000077157', (126, 135))
81047	31462894	Inhibitors of apoptosis protein inhibit apoptosis by restraining caspase 3/7/9.	('apoptosis', 'CPA', (40, 49))	('inhibit', 'NegReg', (32, 39))	('restraining', 'NegReg', (53, 64))	('apoptosis', 'biological_process', 'GO:0097194', ('40', '49'))	('Inhibitors', 'Var', (0, 10))	('apoptosis', 'biological_process', 'GO:0006915', ('40', '49'))	('caspase 3/7/9', 'Gene', (65, 78))	('apoptosis', 'biological_process', 'GO:0097194', ('14', '23'))	('caspase 3/7/9', 'Gene', '836;840;842', (65, 78))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('apoptosis', 'biological_process', 'GO:0006915', ('14', '23'))
81049	31462894	High expression of survivin was associated with a poor prognosis and strong clinicopathological features in patients with RCC and could be used as a biomarker for RCC management.	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('High', 'Var', (0, 4))	('RCC', 'Disease', (163, 166))	('survivin', 'Protein', (19, 27))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('patients', 'Species', '9606', (108, 116))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))
81050	31462894	An inhibitor of survivin, YM155, diminished and intercepted the transcription pathway of NF-kappaB and its target gene survivin, and a stimulator of NF-kappaB signaling, TNF-alpha, did not affect this type of inhibitory function.	('diminished', 'NegReg', (33, 43))	('NF-kappaB', 'Gene', (149, 158))	('NF-kappaB', 'Gene', '4790', (89, 98))	('TNF-alpha', 'Gene', '7124', (170, 179))	('NF-kappaB', 'Gene', (89, 98))	('TNF-alpha', 'Gene', (170, 179))	('YM155', 'Var', (26, 31))	('transcription', 'biological_process', 'GO:0006351', ('64', '77'))	('transcription pathway', 'Pathway', (64, 85))	('intercepted', 'Reg', (48, 59))	('signaling', 'biological_process', 'GO:0023052', ('159', '168'))	('NF-kappaB', 'Gene', '4790', (149, 158))
81062	31462894	As an important tumor suppressor, wild-type p53 regulates cell metabolism, cell cycle, cell senescence, apoptosis and drug resistance.	('metabolism', 'biological_process', 'GO:0008152', ('63', '73'))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('senescence', 'biological_process', 'GO:0010149', ('92', '102'))	('apoptosis', 'biological_process', 'GO:0097194', ('104', '113'))	('apoptosis', 'biological_process', 'GO:0006915', ('104', '113'))	('drug resistance', 'CPA', (118, 133))	('cell cycle', 'biological_process', 'GO:0007049', ('75', '85'))	('cell senescence', 'CPA', (87, 102))	('p53', 'Gene', '7157', (44, 47))	('tumor', 'Disease', (16, 21))	('regulates', 'Reg', (48, 57))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('16', '32'))	('wild-type', 'Var', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor suppressor', 'biological_process', 'GO:0051726', ('16', '32'))	('drug resistance', 'Phenotype', 'HP:0020174', (118, 133))	('p53', 'Gene', (44, 47))	('drug resistance', 'biological_process', 'GO:0009315', ('118', '133'))	('cell cycle', 'CPA', (75, 85))	('apoptosis', 'CPA', (104, 113))	('cell metabolism', 'CPA', (58, 73))	('drug resistance', 'biological_process', 'GO:0042493', ('118', '133'))
81063	31462894	Various mutations in p53 occur in tumors, and it is complicated to design effective targeted drugs specific to p53 mutations.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('p53', 'Gene', '7157', (21, 24))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))	('mutations', 'Var', (8, 17))	('occur', 'Reg', (25, 30))	('p53', 'Gene', (21, 24))
81064	31462894	Although wild-type p53 exists in most RCCs, its antitumor effects may be counteracted by variations in VHL, PBRM1, MDM2, MDM4, and HIF-1.	('RCC', 'Disease', (38, 41))	('tumor', 'Disease', (52, 57))	('MDM4', 'Gene', '4194', (121, 125))	('MDM4', 'Gene', (121, 125))	('p53', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('MDM2', 'Gene', (115, 119))	('RCC', 'Disease', 'MESH:C538614', (38, 41))	('variations', 'Var', (89, 99))	('VHL', 'Gene', '7428', (103, 106))	('MDM2', 'Gene', '4193', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('PBRM1', 'Gene', '55193', (108, 113))	('HIF-1', 'Gene', '3091', (131, 136))	('HIF-1', 'Gene', (131, 136))	('p53', 'Gene', '7157', (19, 22))	('PBRM1', 'Gene', (108, 113))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('VHL', 'Gene', (103, 106))
81067	31462894	Transglutaminase 2 (TGase 2) inhibition increases p53 stability, which synergizes with DNA-damaging drug (e.g., doxorubicin)-induced apoptosis, indicating that the combination of a TGase 2 inhibitor with a DNA-damaging agent may be a potential effective therapeutic approach for RCC.	('TGase 2', 'Gene', (181, 188))	('Transglutaminase 2', 'Gene', '7052', (0, 18))	('p53', 'Gene', (50, 53))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('TGase 2', 'Gene', '7052', (181, 188))	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('doxorubicin', 'Chemical', 'MESH:D004317', (112, 123))	('TGase 2', 'Gene', (20, 27))	('RCC', 'Disease', (279, 282))	('RCC', 'Phenotype', 'HP:0005584', (279, 282))	('TGase 2', 'Gene', '7052', (20, 27))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('stability', 'MPA', (54, 63))	('increases', 'PosReg', (40, 49))	('RCC', 'Disease', 'MESH:C538614', (279, 282))	('inhibition', 'Var', (29, 39))	('DNA', 'cellular_component', 'GO:0005574', ('206', '209'))	('p53', 'Gene', '7157', (50, 53))	('Transglutaminase 2', 'Gene', (0, 18))
81072	31462894	However, worse prognosis and low survival were displayed in patients with the MDM2 SNP309GG genotype, indicating that the polymorphism of MDM2 might be an independent poor prognostic factor for RCC.	('polymorphism', 'Var', (122, 134))	('MDM2', 'Gene', '4193', (78, 82))	('MDM2', 'Gene', (78, 82))	('patients', 'Species', '9606', (60, 68))	('RCC', 'Disease', 'MESH:C538614', (194, 197))	('RCC', 'Disease', (194, 197))	('RCC', 'Phenotype', 'HP:0005584', (194, 197))	('MDM2', 'Gene', '4193', (138, 142))	('MDM2', 'Gene', (138, 142))	('SNP309GG', 'Var', (83, 91))
81078	31462894	Caspase-8 is an important apoptosis regulator whose cell death-inducing activity is highly influenced by the insertion/deletion promoter polymorphism CASP8-652 6N ins/del (rs3834129), which may be correlated with the attenuation of the overall risk and metastasis risk of RCC.	('RCC', 'Disease', (272, 275))	('cell death-inducing activity', 'CPA', (52, 80))	('RCC', 'Phenotype', 'HP:0005584', (272, 275))	('CASP8-652', 'Gene', (150, 159))	('rs3834129', 'Var', (172, 181))	('apoptosis', 'biological_process', 'GO:0097194', ('26', '35'))	('influenced', 'Reg', (91, 101))	('RCC', 'Disease', 'MESH:C538614', (272, 275))	('apoptosis', 'biological_process', 'GO:0006915', ('26', '35'))	('cell death', 'biological_process', 'GO:0008219', ('52', '62'))	('Caspase-8', 'Gene', '841', (0, 9))	('6N ins/del (rs3834129', 'Var', (160, 181))	('rs3834129', 'Mutation', 'rs3834129', (172, 181))	('Caspase-8', 'Gene', (0, 9))
81079	31462894	The activation of caspase-8 lyses and inactivation of RIPK1 and RIPK3 form a complex with RIPK1 and FADD, triggering apoptosis, but the inhibition of caspase-8 derepresses RIPK1 and RIPK3, which interact with the RIP homology domain, and triggers necroptosis (Fig.	('RIP', 'Gene', (90, 93))	('RIPK1', 'Gene', (54, 59))	('inactivation', 'Var', (38, 50))	('RIPK1', 'Gene', (172, 177))	('RIP', 'Gene', '8737', (213, 216))	('RIP', 'Gene', '8737', (64, 67))	('RIP', 'Gene', '8737', (182, 185))	('RIPK1', 'Gene', '8737', (54, 59))	('necroptosis', 'Disease', (247, 258))	('RIPK1', 'Gene', '8737', (172, 177))	('caspase-8', 'Gene', '841', (150, 159))	('inhibition', 'Var', (136, 146))	('caspase-8', 'Gene', (18, 27))	('RIPK3', 'Gene', '11035', (64, 69))	('RIP', 'Gene', '8737', (54, 57))	('RIP', 'Gene', (213, 216))	('FADD', 'Gene', (100, 104))	('RIPK3', 'Gene', '11035', (182, 187))	('RIP', 'Gene', (64, 67))	('RIP', 'Gene', (182, 185))	('derepresses', 'NegReg', (160, 171))	('RIPK1', 'Gene', (90, 95))	('RIP', 'Gene', '8737', (172, 175))	('triggers', 'Reg', (238, 246))	('RIP', 'Gene', (54, 57))	('RIPK1', 'Gene', '8737', (90, 95))	('necroptosis', 'biological_process', 'GO:0070266', ('247', '258'))	('RIP', 'Gene', (172, 175))	('caspase-8', 'Gene', (150, 159))	('necroptosis', 'biological_process', 'GO:0097528', ('247', '258'))	('RIP', 'Gene', '8737', (90, 93))	('FADD', 'Gene', '8772', (100, 104))	('caspase-8', 'Gene', '841', (18, 27))	('apoptosis', 'biological_process', 'GO:0097194', ('117', '126'))	('apoptosis', 'biological_process', 'GO:0006915', ('117', '126'))	('RIPK3', 'Gene', (64, 69))	('RIPK3', 'Gene', (182, 187))
81081	31462894	Physapubescin, a predominant steroidal lactone, can decrease HIF-2alpha expression and cause death receptor 5 (DR5) upregulation, caspase-8 and -3 activation, and cleavage of poly (ADP-ribose) polymerase (PARP), which serves as a novel proapoptotic agent targeting VHL-null RCC cells.	('RCC', 'Disease', (274, 277))	('RCC', 'Phenotype', 'HP:0005584', (274, 277))	('HIF-2alpha', 'Gene', (61, 71))	('caspase-8 and -3', 'Gene', '841;836', (130, 146))	('cleavage', 'MPA', (163, 171))	('Physapubescin', 'Var', (0, 13))	('activation', 'PosReg', (147, 157))	('lactone', 'Chemical', 'MESH:D007783', (39, 46))	('Physapubescin', 'Chemical', 'MESH:C586239', (0, 13))	('expression', 'MPA', (72, 82))	('RCC', 'Disease', 'MESH:C538614', (274, 277))	('DR5', 'Gene', '8795', (111, 114))	('decrease', 'NegReg', (52, 60))	('VHL', 'Gene', (265, 268))	('DR5', 'Gene', (111, 114))	('death receptor 5', 'Gene', (93, 109))	('upregulation', 'PosReg', (116, 128))	('HIF-2alpha', 'Gene', '2034', (61, 71))	('death receptor 5', 'Gene', '8795', (93, 109))	('VHL', 'Gene', '7428', (265, 268))	('PARP', 'Gene', '142', (205, 209))	('poly (ADP-ribose) polymerase', 'Gene', '142', (175, 203))	('PARP', 'Gene', (205, 209))	('poly (ADP-ribose) polymerase', 'Gene', (175, 203))
81087	31462894	The combination of PD-1 and PD-L1 sends inhibitory signals to T and B cells by regulating the activation of effector T cells and ultimately weakens the antitumor immune response.	('weakens', 'NegReg', (140, 147))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('combination', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('inhibitory signals', 'MPA', (40, 58))	('tumor', 'Disease', (156, 161))	('activation', 'MPA', (94, 104))	('immune response', 'biological_process', 'GO:0006955', ('162', '177'))	('effector T cells', 'MPA', (108, 124))	('PD-L1', 'Gene', (28, 33))	('PD-1', 'Gene', (19, 23))
81091	31462894	In ccRCC, the VHL mutation was positively correlated with PD-L1 expression and may influence the response of ccRCC to anti-PD-L1/PD-1 immunotherapy.	('correlated', 'Interaction', (42, 52))	('expression', 'MPA', (64, 74))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('PD-L1', 'Gene', (58, 63))	('influence', 'Reg', (83, 92))	('mutation', 'Var', (18, 26))	('VHL', 'Gene', (14, 17))	('VHL', 'Gene', '7428', (14, 17))
81094	31462894	The loss of PBRM1 in ccRCC may alter overall tumor cell expression profiles and affect its responsiveness to immune checkpoint therapy.	('PBRM1', 'Gene', (12, 17))	('PBRM1', 'Gene', '55193', (12, 17))	('affect', 'Reg', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('responsiveness to immune checkpoint therapy', 'MPA', (91, 134))	('tumor', 'Disease', (45, 50))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('alter', 'Reg', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('loss', 'Var', (4, 8))
81109	31462894	The G allele of CTLA-4 rs231775 showed a significant association with improved OS in metastatic ccRCC patients treated with sunitinib and might be used as a potential prognostic biomarker.	('CTLA-4', 'Gene', '1493', (16, 22))	('OS', 'Chemical', '-', (79, 81))	('rs231775', 'Var', (23, 31))	('patients', 'Species', '9606', (102, 110))	('improved', 'PosReg', (70, 78))	('sunitinib', 'Chemical', 'MESH:D000077210', (124, 133))	('CTLA-4', 'Gene', (16, 22))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('rs231775', 'Mutation', 'rs231775', (23, 31))
81114	31462894	The loss of PTEN is associated with tumor progression, including the occurrence and metastasis of RCC, and synergizes with sorafenib in inhibiting RCC cells.	('sorafenib', 'Chemical', 'MESH:D000077157', (123, 132))	('inhibiting', 'NegReg', (136, 146))	('associated', 'Reg', (20, 30))	('metastasis', 'CPA', (84, 94))	('PTEN', 'Gene', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('RCC', 'Disease', (98, 101))	('PTEN', 'Gene', '5728', (12, 16))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('RCC', 'Disease', (147, 150))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('tumor', 'Disease', (36, 41))	('loss', 'Var', (4, 8))
81118	31462894	Until recently, a number of lncRNAs, including lncRP11-436H11.5, lncMALAT1, lncSARCC, lncRNA-HOTAIR, linc00152, and lncARSR, were also found to be associated with RCC progression or targeted therapy.	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('associated', 'Reg', (147, 157))	('RCC', 'Disease', (163, 166))	('HOTAIR', 'Gene', (93, 99))	('HOTAIR', 'Gene', '100124700', (93, 99))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('linc00152', 'Gene', (101, 110))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('lncMALAT1', 'Gene', (65, 74))	('linc00152', 'Gene', '112597', (101, 110))	('lncRP11-436H11.5', 'Var', (47, 63))
81186	33504936	Within SCRS literature, there are concerns for variations in cell cycle leading to increased heterogeneity or obscure subpopulations, however proliferation of CD8+ T cells is an important surrogate marker of antitumor immune response.	('cell cycle', 'biological_process', 'GO:0007049', ('61', '71'))	('SCRS', 'Species', '96451', (7, 11))	('immune response', 'biological_process', 'GO:0006955', ('218', '233'))	('CD8', 'Gene', (159, 162))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('heterogeneity', 'MPA', (93, 106))	('CD8', 'Gene', '925', (159, 162))	('variations', 'Var', (47, 57))	('tumor', 'Disease', (212, 217))
81191	33504936	These immune checkpoints were expressed at more moderate levels in both CD8_5 and CD8_6; however, CD8_6 exclusively expressed a number of proliferation markers, such as CDK1, MKI67, STMN1, and TOP2A (Fig.	('CDK1', 'Gene', (169, 173))	('CDK1', 'Gene', '983', (169, 173))	('MKI67', 'Gene', (175, 180))	('CD8_5', 'Gene', '353514', (72, 77))	('STMN1', 'Gene', '3925', (182, 187))	('STMN1', 'Gene', (182, 187))	('CD8_5', 'Gene', (72, 77))	('MKI67', 'Gene', '4288', (175, 180))	('TOP2A', 'Gene', '7153', (193, 198))	('CDK', 'molecular_function', 'GO:0004693', ('169', '172'))	('expressed', 'Reg', (116, 125))	('TOP2A', 'Gene', (193, 198))	('CD8_6', 'Var', (98, 103))
81251	33504936	Using mass cytometry data for T cells isolated from four healthy tissue samples, 68 ccRCC primary tumors, and four ccRCC metastasis, we identified a PD-1+ Ki-67Hi subset in 14.6% of a CD45+ CD3+ CD8+ T cells (Fig.	('ccRCC primary tumors', 'Disease', (84, 104))	('ccRCC primary tumors', 'Disease', 'MESH:D001932', (84, 104))	('PD-1+ Ki-67Hi', 'Var', (149, 162))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('CD45', 'Gene', (184, 188))	('CD3', 'Gene', '397455', (190, 193))	('CD8', 'Gene', (195, 198))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('CD8', 'Gene', '925', (195, 198))	('CD45', 'Gene', '5788', (184, 188))	('CD3', 'Gene', (190, 193))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))
81260	33504936	Similarly, therapeutic responses to anti-PD-1 therapy have been correlated with HLA heterozygosity in lung cancers and melanoma, which does not seem to be the case for ccRCC.	('lung cancers', 'Disease', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancers', 'Disease', 'MESH:D008175', (102, 114))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('ccRCC', 'Phenotype', 'HP:0006770', (168, 173))	('melanoma', 'Disease', (119, 127))	('lung cancers', 'Phenotype', 'HP:0100526', (102, 114))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('HLA heterozygosity', 'Var', (80, 98))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
81271	33504936	Other studies have found the ccRCC tumors polyclonal CD8+ T cells with an "immune-regulated" phenotype and lower cytotoxicity compared to tumors with oligoclonal CD8+ T cells.	('CD8', 'Gene', (53, 56))	('cytotoxicity', 'Disease', (113, 125))	('ccRCC tumors', 'Disease', (29, 41))	('lower', 'NegReg', (107, 112))	('cytotoxicity', 'Disease', 'MESH:D064420', (113, 125))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('CD8', 'Gene', (162, 165))	('ccRCC tumors', 'Disease', 'MESH:D009369', (29, 41))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('CD8', 'Gene', '925', (53, 56))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('polyclonal', 'Var', (42, 52))	('CD8', 'Gene', '925', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', (35, 41))
81492	32410064	In a preclinical study, sarcomatoid and carcinomatous tumors exhibited 42% somatic single-nucleotide variant (SSNV) concordance (Auvray et al.).	('sarcomatoid', 'Disease', (24, 35))	('carcinomatous tumors', 'Disease', 'MESH:D055756', (40, 60))	('carcinomatous tumors', 'Disease', (40, 60))	('single-nucleotide variant', 'Var', (83, 108))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('sarcomatoid', 'Disease', 'MESH:C538614', (24, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
81493	32410064	When compared with carcinomatous tumors, sarcomatoid tumors show a higher SSNV burden, a higher oncogene frequency of nonsynonymous SSNVs and a higher frequency of the loss of heterozygosity (LOH) (Bi et al.).	('higher', 'PosReg', (67, 73))	('loss', 'Var', (168, 172))	('SSNV', 'Disease', (74, 78))	('carcinomatous tumors', 'Disease', 'MESH:D055756', (19, 39))	('oncogene frequency', 'MPA', (96, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('carcinomatous tumors', 'Disease', (19, 39))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('higher', 'PosReg', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('sarcomatoid tumors', 'Disease', (41, 59))	('sarcomatoid tumors', 'Disease', 'MESH:C538614', (41, 59))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('sarcomatoid tumors', 'Phenotype', 'HP:0100242', (41, 59))
81510	32410064	Therefore, at every treatment continuation or modification, the oncologist must weigh in the overall burden of treatment, including the toxicity, time commitment and costs, and/or best supportive care, including the psychological and physical implications.	('toxicity', 'Disease', 'MESH:D064420', (136, 144))	('toxicity', 'Disease', (136, 144))	('modification', 'Var', (46, 58))
81535	32410064	A meta-analysis of phase III trials comparing zoledronic acid with denosumab in this setting concluded that denosumab was superior to zoledronic acid in reducing the risk of a first SRE by 17% and delaying the time to hypercalcemia of the malignancy (HR, 0.83; 95% CI, 0.76-0.90), although the OS and disease progression rates were not different between the treatments (Amadori et al.).	('hypercalcemia of the malignancy', 'Disease', 'MESH:D006934', (218, 249))	('hypercalcemia of the malignancy', 'Disease', (218, 249))	('denosumab', 'Chemical', 'MESH:D000069448', (67, 76))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (134, 149))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (46, 61))	('denosumab', 'Chemical', 'MESH:D000069448', (108, 117))	('hypercalcemia', 'Phenotype', 'HP:0003072', (218, 231))	('reducing', 'NegReg', (153, 161))	('denosumab', 'Var', (108, 117))	('delaying', 'NegReg', (197, 205))
81587	31233964	It was negative for vimentin and P504 (Fig.	('vimentin', 'Gene', (20, 28))	('vimentin', 'cellular_component', 'GO:0045098', ('20', '28'))	('vimentin', 'cellular_component', 'GO:0045099', ('20', '28'))	('P504', 'Var', (33, 37))	('vimentin', 'Gene', '7431', (20, 28))
81647	33725966	These alterations lead to high-frequency inactivation of the biallelic VHL.	('alterations', 'Var', (6, 17))	('VHL', 'Gene', (71, 74))	('VHL', 'Gene', '7428', (71, 74))	('lead to', 'Reg', (18, 25))	('high-frequency inactivation', 'MPA', (26, 53))
81648	33725966	Loss of VHL function stabilizes hypoxia-inducible factor 1alpha (HIF1alpha) and HIF2alpha, thereby enhancing expression of hypoxia-responsive genes, such as the vascular endothelial growth factor (VEGF) family and platelet-derived growth factor (PDGF) family that promote angiogenesis.	('VEGF', 'Gene', '7422', (197, 201))	('VHL', 'Gene', '7428', (8, 11))	('hypoxia', 'Disease', 'MESH:D000860', (123, 130))	('VEGF', 'Gene', (197, 201))	('HIF1alpha', 'Gene', '3091', (65, 74))	('promote', 'PosReg', (264, 271))	('HIF2alpha', 'Gene', '2034', (80, 89))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('214', '244'))	('angiogenesis', 'CPA', (272, 284))	('PDGF', 'molecular_function', 'GO:0005161', ('246', '250'))	('hypoxia', 'Disease', (32, 39))	('hypoxia-inducible factor 1alpha', 'Gene', (32, 63))	('HIF1alpha', 'Gene', (65, 74))	('hypoxia', 'Disease', 'MESH:D000860', (32, 39))	('vascular endothelial growth factor', 'Gene', '7422', (161, 195))	('Loss', 'Var', (0, 4))	('VHL', 'Gene', (8, 11))	('vascular endothelial growth factor', 'Gene', (161, 195))	('enhancing', 'PosReg', (99, 108))	('expression', 'MPA', (109, 119))	('HIF2alpha', 'Gene', (80, 89))	('angiogenesis', 'biological_process', 'GO:0001525', ('272', '284'))	('hypoxia', 'Disease', (123, 130))	('hypoxia-inducible factor 1alpha', 'Gene', '3091', (32, 63))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('161', '195'))
81650	33725966	In addition, genes involved in chromatin modification, including PBRM1, SETD2, KDM5C 9, KDM6A9, and BAP1, are also frequently mutated in ccRCC.	('BAP1', 'Gene', '8314', (100, 104))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('BAP1', 'Gene', (100, 104))	('chromatin modification', 'biological_process', 'GO:0006325', ('31', '53'))	('PBRM1', 'Gene', (65, 70))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('PBRM1', 'Gene', '55193', (65, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('KDM5C', 'Gene', (79, 84))	('chromatin', 'cellular_component', 'GO:0000785', ('31', '40'))	('KDM6A9', 'Gene', (88, 94))	('SETD2', 'Gene', '29072', (72, 77))	('chromatin modification', 'biological_process', 'GO:0016569', ('31', '53'))	('KDM5C', 'Gene', '8242', (79, 84))	('SETD2', 'Gene', (72, 77))	('mutated', 'Var', (126, 133))
81683	33725966	This analysis revealed that BAP1 mutations mainly occur in C1 (33.3%), followed by C2, C3, and C4.	('BAP1', 'Gene', '8314', (28, 32))	('occur', 'Reg', (50, 55))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
81686	33725966	In the C1 and C6 subtype, the mutation frequency of mTOR is the highest, and the mutation frequency of mTOR in the 2 groups is 16.7%.	('mTOR', 'Gene', (52, 56))	('mTOR', 'Gene', (103, 107))	('mTOR', 'Gene', '2475', (52, 56))	('highest', 'Reg', (64, 71))	('mutation', 'Var', (30, 38))	('mTOR', 'Gene', '2475', (103, 107))
81689	33725966	SETD2 mutations mainly affect C2 at a mutation frequency of 46.7%.	('SETD2', 'Gene', (0, 5))	('SETD2', 'Gene', '29072', (0, 5))	('affect', 'Reg', (23, 29))	('mutations', 'Var', (6, 15))
81690	33725966	TP53 mutations mainly affect C5 (50%) and C1 (33.3%).	('TP53', 'Gene', '7157', (0, 4))	('affect', 'Reg', (22, 28))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
81695	33725966	Next, we evaluated the total scores of homologous recombination repair defects (HRD), loss of heterozygosity (LOH), telomere allele imbalance (TAI), and large-scale state transition (LST) in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (191, 196))	('HRD', 'Disease', (80, 83))	('RCC', 'Disease', (193, 196))	('RCC', 'Phenotype', 'HP:0005584', (193, 196))	('loss', 'Var', (86, 90))	('imbalance', 'Phenotype', 'HP:0002172', (132, 141))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('homologous recombination', 'biological_process', 'GO:0035825', ('39', '63'))	('telomere', 'cellular_component', 'GO:0005696', ('116', '124'))	('HRD', 'Disease', 'None', (80, 83))	('telomere', 'cellular_component', 'GO:0000781', ('116', '124'))
81717	33725966	MICA (16.7%) and IDO1 (16.7%) were significantly mutated in C1, LAG3 was significantly mutated (6.7%) in C2, ARG1 (5.0%) had significant mutations in C4, and CD274 (16.7%) was significantly mutated in C6.	('MICA', 'Gene', '100507436', (0, 4))	('ARG1', 'Gene', '383', (109, 113))	('mutated', 'Var', (87, 94))	('CD274', 'Gene', '29126', (158, 163))	('LAG3', 'Gene', (64, 68))	('mutated', 'Reg', (49, 56))	('LAG3', 'Gene', '3902', (64, 68))	('IDO1', 'Gene', '3620', (17, 21))	('mutations', 'Var', (137, 146))	('IDO', 'molecular_function', 'GO:0033754', ('17', '20'))	('ARG1', 'Gene', (109, 113))	('CD274', 'Gene', (158, 163))	('IDO', 'molecular_function', 'GO:0047719', ('17', '20'))	('IDO1', 'Gene', (17, 21))	('MICA', 'Gene', (0, 4))
81719	33725966	Deletion rates for C10orf54, IL2RA, PRF1, and ENTPD1 were as high as 100% in C5.	('IL2RA', 'Gene', (29, 34))	('ENTPD1', 'Gene', (46, 52))	('ENTPD1', 'Gene', '953', (46, 52))	('C10orf54', 'Gene', (19, 27))	('PRF1', 'Gene', (36, 40))	('C10orf54', 'Gene', '64115', (19, 27))	('PRF1', 'Gene', '5551', (36, 40))	('IL2', 'molecular_function', 'GO:0005134', ('29', '32'))	('IL2RA', 'Gene', '3559', (29, 34))	('Deletion', 'Var', (0, 8))
81755	33725966	The mutation frequency of the VHL gene was lower in the C3 subtype than that of C2 and C6 subtypes.	('VHL', 'Gene', '7428', (30, 33))	('VHL', 'Gene', (30, 33))	('mutation', 'Var', (4, 12))	('lower', 'NegReg', (43, 48))
81756	33725966	The mutation frequency of the TP53 gene was lower in the C3 subtype than that of all other subtypes.	('lower', 'NegReg', (44, 49))	('TP53', 'Gene', '7157', (30, 34))	('TP53', 'Gene', (30, 34))	('mutation', 'Var', (4, 12))
81757	33725966	In the C3 subtype, the mutation frequency of the BAP gene was lower than that of C1 and C2 subtypes.	('BAP', 'Gene', (49, 52))	('lower', 'NegReg', (62, 67))	('BAP', 'Gene', '11331', (49, 52))	('mutation', 'Var', (23, 31))
81758	33725966	In the C3 subtype, the mutation frequency of PBRM1 gene was lower than that of C2 subtype.	('mutation', 'Var', (23, 31))	('PBRM1', 'Gene', '55193', (45, 50))	('PBRM1', 'Gene', (45, 50))	('lower', 'NegReg', (60, 65))
81760	33725966	The inactivation of VHL results in accumulation of hypoxia-inducible factors (HIFs) and overexpression of many genes, including those that promote angiogenesis and reprogramming of cellular metabolism.	('angiogenesis', 'biological_process', 'GO:0001525', ('147', '159'))	('inactivation', 'Var', (4, 16))	('promote', 'PosReg', (139, 146))	('overexpression', 'PosReg', (88, 102))	('HIFs', 'Disease', 'None', (78, 82))	('accumulation', 'PosReg', (35, 47))	('angiogenesis', 'CPA', (147, 159))	('VHL', 'Gene', (20, 23))	('cellular metabolism', 'biological_process', 'GO:0044237', ('181', '200'))	('hypoxia', 'Disease', (51, 58))	('HIFs', 'Disease', (78, 82))	('hypoxia', 'Disease', 'MESH:D000860', (51, 58))	('VHL', 'Gene', '7428', (20, 23))
81763	33725966	Therefore, the low frequency mutation of VHL, TP53, PBRM1, and BAP1 may be a potential mechanism for the better prognosis of the C3 subtype.	('mutation', 'Var', (29, 37))	('BAP1', 'Gene', (63, 67))	('TP53', 'Gene', '7157', (46, 50))	('PBRM1', 'Gene', (52, 57))	('TP53', 'Gene', (46, 50))	('VHL', 'Gene', (41, 44))	('PBRM1', 'Gene', '55193', (52, 57))	('VHL', 'Gene', '7428', (41, 44))	('BAP1', 'Gene', '8314', (63, 67))
81766	33725966	Infiltration of a large number of Treg cells into tumor tissues is usually associated with poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('Infiltration', 'Var', (0, 12))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))
81792	33725966	High-frequency mutation genes, homologous recombination repair defects, immune cell infiltration, immune regulatory genes, and enriched signaling pathways in ccRCC display wide heterogeneity in different ISs.	('defects', 'Var', (63, 70))	('homologous recombination', 'biological_process', 'GO:0035825', ('31', '55'))	('ccRCC', 'Phenotype', 'HP:0006770', (158, 163))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('RCC', 'Disease', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('signaling', 'biological_process', 'GO:0023052', ('136', '145'))
81881	32209138	Silencing RSK4 expression decreased their expression (Fig.	('expression', 'MPA', (42, 52))	('RSK4', 'Gene', '27330', (10, 14))	('Silencing', 'Var', (0, 9))	('decreased', 'NegReg', (26, 35))	('RSK4', 'Gene', (10, 14))
81898	32209138	The variant protein of CD44 could alter the biological behaviour of cells and promote cell invasion and metastasis by affecting the skeletal and signal transmission systems in cells.	('affecting', 'Reg', (118, 127))	('CD44', 'Gene', '960', (23, 27))	('protein', 'cellular_component', 'GO:0003675', ('12', '19'))	('promote', 'PosReg', (78, 85))	('metastasis', 'CPA', (104, 114))	('CD44', 'Gene', (23, 27))	('signal transmission', 'biological_process', 'GO:0023060', ('145', '164'))	('biological behaviour of cells', 'CPA', (44, 73))	('behaviour', 'biological_process', 'GO:0007610', ('55', '64'))	('protein', 'Protein', (12, 19))	('alter', 'Reg', (34, 39))	('cell invasion', 'CPA', (86, 99))	('variant', 'Var', (4, 11))
81914	32209138	The high expression of MMP-9 was correlated with poor prognosis.	('MMP-9', 'Gene', '4318', (23, 28))	('MMP-9', 'Gene', (23, 28))	('high', 'Var', (4, 8))	('MMP-9', 'molecular_function', 'GO:0004229', ('23', '28'))
81922	31016032	FAM129A acted as tumor promotor and miR-4521 acted as a suppressor in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('tumor', 'Disease', (17, 22))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('miR-4521', 'Gene', '100616406', (36, 44))	('RCC', 'Disease', (72, 75))	('miR-4521', 'Gene', (36, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('FAM129A', 'Var', (0, 7))
81923	31016032	As measured in surgical tumorous tissues from ccRCC patients, FAM129A overexpression and miR-4521 deficiency together contributed to ccRCC progression by promoting advances in patients' TNM stage and Fuhrman grade.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('si', 'Chemical', 'MESH:D012825', (146, 148))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('contributed', 'Reg', (118, 129))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	("patients' TNM stage", 'CPA', (176, 195))	('promoting advances', 'PosReg', (154, 172))	('Fuhrman grade', 'CPA', (200, 213))	('tumorous tissues', 'Disease', (24, 40))	('si', 'Chemical', 'MESH:D012825', (80, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('patients', 'Species', '9606', (52, 60))	('FAM129A', 'Var', (62, 69))	('deficiency', 'Var', (98, 108))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('miR-4521', 'Gene', (89, 97))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('patients', 'Species', '9606', (176, 184))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('RCC', 'Disease', (135, 138))	('tumorous tissues', 'Disease', 'MESH:D009369', (24, 40))	('miR-4521', 'Gene', '100616406', (89, 97))
81924	31016032	Both the FAM129A knockdown and miR-4521 overexpression could reduce the in vitro migration and invasion abilities of renal cancer cells 786-O and ACHN, through the TIMP-1/MMP2/MMP9 pathway and could decrease their proliferation by promoting their apoptosis through the MDM2/p53/Bcl2/Bax pathway.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('renal cancer', 'Disease', (117, 129))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('renal cancer', 'Phenotype', 'HP:0009726', (117, 129))	('proliferation', 'CPA', (214, 227))	('MDM2', 'Gene', '4193', (269, 273))	('MMP2', 'molecular_function', 'GO:0004228', ('171', '175'))	('reduce', 'NegReg', (61, 67))	('ACHN', 'Gene', (146, 150))	('apoptosis', 'biological_process', 'GO:0097194', ('247', '256'))	('MMP2', 'Gene', '4313', (171, 175))	('apoptosis', 'biological_process', 'GO:0006915', ('247', '256'))	('renal cancer', 'Disease', 'MESH:D007680', (117, 129))	('ACHN', 'Gene', '55323', (146, 150))	('TIMP-1', 'Gene', (164, 170))	('invasion abilities', 'CPA', (95, 113))	('TIMP-1', 'Gene', '7076', (164, 170))	('miR-4521', 'Gene', (31, 39))	('Bcl2', 'molecular_function', 'GO:0015283', ('278', '282'))	('promoting', 'PosReg', (231, 240))	('si', 'Chemical', 'MESH:D012825', (253, 255))	('MMP9', 'molecular_function', 'GO:0004229', ('176', '180'))	('p53', 'Gene', '7157', (274, 277))	('knockdown', 'Var', (17, 26))	('Bax', 'Gene', (283, 286))	('FAM129A knockdown', 'Var', (9, 26))	('Bcl2', 'Gene', (278, 282))	('apoptosis', 'CPA', (247, 256))	('p53', 'Gene', (274, 277))	('MMP9', 'Gene', (176, 180))	('decrease', 'NegReg', (199, 207))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('MMP9', 'Gene', '4318', (176, 180))	('miR-4521', 'Gene', '100616406', (31, 39))	('Bcl2', 'Gene', '596', (278, 282))	('Bax', 'Gene', '581', (283, 286))	('MMP2', 'Gene', (171, 175))	('MDM2', 'Gene', (269, 273))
81925	31016032	By directly targeting the 3'-UTR domain of FAM129A, miR-4521 was negatively correlated with FAM129A/FAM129A levels in ccRCC progression and renal cancer cell malignancies.	('si', 'Chemical', 'MESH:D012825', (131, 133))	('miR-4521', 'Gene', '100616406', (52, 60))	('renal cancer cell malignancies', 'Disease', 'MESH:C538614', (140, 170))	('negatively', 'NegReg', (65, 75))	('renal cancer', 'Phenotype', 'HP:0009726', (140, 152))	('renal cancer cell malignancies', 'Disease', (140, 170))	('miR-4521', 'Gene', (52, 60))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('FAM129A/FAM129A', 'Var', (92, 107))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('FAM129A', 'Var', (43, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))
81927	31016032	Micro-4521 deficiency leads to FAM129A/FAM129A upregulation, which synergistically enhances the migration and invasion of renal cancer cells due to the induced decrease of TIMP-1 and increases of MMP2 and MMP9, and increases their growth through escaping apoptosis by suppressing p53 by way of upregulation of induced MDM2.	('migration', 'CPA', (96, 105))	('si', 'Chemical', 'MESH:D012825', (114, 116))	('MMP9', 'Gene', (205, 209))	('upregulation', 'PosReg', (294, 306))	('MMP2', 'Gene', '4313', (196, 200))	('p53', 'Gene', (280, 283))	('MMP9', 'Gene', '4318', (205, 209))	('suppressing', 'NegReg', (268, 279))	('MMP9', 'molecular_function', 'GO:0004229', ('205', '209'))	('upregulation', 'PosReg', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('TIMP-1', 'Gene', '7076', (172, 178))	('si', 'Chemical', 'MESH:D012825', (261, 263))	('TIMP-1', 'Gene', (172, 178))	('renal cancer', 'Disease', (122, 134))	('apoptosis', 'biological_process', 'GO:0006915', ('255', '264'))	('apoptosis', 'biological_process', 'GO:0097194', ('255', '264'))	('renal cancer', 'Phenotype', 'HP:0009726', (122, 134))	('MDM2', 'Gene', (318, 322))	('deficiency', 'Var', (11, 21))	('Micro-4521', 'Gene', (0, 10))	('increases', 'PosReg', (183, 192))	('invasion', 'CPA', (110, 118))	('increases', 'PosReg', (215, 224))	('MMP2', 'Gene', (196, 200))	('FAM129A/FAM129A', 'Var', (31, 46))	('si', 'Chemical', 'MESH:D012825', (275, 277))	('escaping apoptosis', 'CPA', (246, 264))	('MDM2', 'Gene', '4193', (318, 322))	('decrease', 'NegReg', (160, 168))	('growth', 'MPA', (231, 237))	('MMP2', 'molecular_function', 'GO:0004228', ('196', '200'))	('renal cancer', 'Disease', 'MESH:D007680', (122, 134))	('p53', 'Gene', '7157', (280, 283))	('enhances', 'PosReg', (83, 91))
81941	31016032	Its deficiency negatively correlated with FAM129A upregulation and prompted clinical development and progression of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('RCC', 'Disease', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('upregulation', 'PosReg', (50, 62))	('clinical', 'Species', '191496', (76, 84))	('negatively', 'NegReg', (15, 25))	('deficiency', 'Var', (4, 14))	('FAM129A', 'Gene', (42, 49))	('prompted', 'PosReg', (67, 75))	('progression', 'CPA', (101, 112))	('clinical development', 'CPA', (76, 96))	('si', 'Chemical', 'MESH:D012825', (108, 110))
81943	31016032	The member A of family with sequence similarity 129 (FAM129A), also known as Niban, was originally identified in Eker rats with hereditary renal carcinoma induced by tuberous sclerosis 2 gene mutation (Tsc2).	('tuberous sclerosis 2', 'Disease', (166, 186))	('hereditary renal carcinoma', 'Disease', 'MESH:D007680', (128, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('hereditary renal carcinoma', 'Disease', (128, 154))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('renal carcinoma', 'Phenotype', 'HP:0005584', (139, 154))	('mutation', 'Var', (192, 200))	('tuberous sclerosis 2', 'Disease', 'MESH:C566021', (166, 186))	('induced by', 'Reg', (155, 165))	('si', 'Chemical', 'MESH:D012825', (181, 183))	('rats', 'Species', '10116', (118, 122))
81946	31016032	FAM129A was detected in sporadic RCCs including clear cell, granular cell and spindle cell carcinomas.	('spindle cell carcinomas', 'Disease', 'MESH:D002277', (78, 101))	('spindle cell carcinomas', 'Disease', (78, 101))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('detected', 'Reg', (12, 20))	('RCC', 'Disease', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('spindle', 'cellular_component', 'GO:0005819', ('78', '85'))	('clear cell', 'Disease', (48, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('granular cell', 'Disease', (60, 73))	('FAM129A', 'Var', (0, 7))
81948	31016032	FAM129A has been linked to renal interstitial fibrosis by increasing renal tubular cell apoptosis; however, its function and mechanism in ccRCC remain unclear.	('apoptosis', 'biological_process', 'GO:0006915', ('88', '97'))	('renal interstitial fibrosis', 'Phenotype', 'HP:0005576', (27, 54))	('apoptosis', 'biological_process', 'GO:0097194', ('88', '97'))	('renal interstitial fibrosis', 'Disease', 'MESH:D007674', (27, 54))	('renal interstitial fibrosis', 'Disease', (27, 54))	('linked', 'Reg', (17, 23))	('renal tubular', 'MPA', (69, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('increasing', 'PosReg', (58, 68))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('si', 'Chemical', 'MESH:D012825', (51, 53))	('si', 'Chemical', 'MESH:D012825', (94, 96))	('FAM129A', 'Var', (0, 7))
81949	31016032	Current work shows FAM129A is a promotor and miR-4521 is a suppressor in ccRCC.	('miR-4521', 'Gene', (45, 53))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('FAM129A', 'Var', (19, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))	('miR-4521', 'Gene', '100616406', (45, 53))
81950	31016032	FAM129A overexpression positively correlates with advances in TNM stage and Fuhrman grade of ccRCC patients.	('overexpression', 'PosReg', (8, 22))	('si', 'Chemical', 'MESH:D012825', (18, 20))	('advances', 'PosReg', (50, 58))	('FAM129A', 'Var', (0, 7))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('patients', 'Species', '9606', (99, 107))	('RCC', 'Disease', (95, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('si', 'Chemical', 'MESH:D012825', (25, 27))	('TNM stage', 'CPA', (62, 71))	('Fuhrman grade', 'CPA', (76, 89))
81951	31016032	miR-4521 deficiency contributed to enhanced TNM stage and Fuhrman grade of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('miR-4521', 'Gene', (0, 8))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('enhanced', 'PosReg', (35, 43))	('Fuhrman grade', 'CPA', (58, 71))	('TNM stage', 'CPA', (44, 53))	('deficiency', 'Var', (9, 19))	('miR-4521', 'Gene', '100616406', (0, 8))
81955	31016032	Among patients' clinicopathological parameters, miR-4521 deficiency was associated with patients' TNM stage (Fig.	('deficiency', 'Var', (57, 67))	('miR-4521', 'Gene', (48, 56))	('patients', 'Species', '9606', (88, 96))	('associated', 'Reg', (72, 82))	('patients', 'Species', '9606', (6, 14))	('TNM stage', 'Disease', (98, 107))	('miR-4521', 'Gene', '100616406', (48, 56))
81959	31016032	miR-4521 deficiency contributes to ccRCC development and progression.	('miR-4521', 'Gene', (0, 8))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('deficiency', 'Var', (9, 19))	('miR-4521', 'Gene', '100616406', (0, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (35, 40))	('progression', 'CPA', (57, 68))
81962	31016032	FAM129A levels in ccRCC patients with T2 and T3-4 stages increased by 12.1% and 157.9% more than T1 patients (Fig.	('patients', 'Species', '9606', (24, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (18, 23))	('patients', 'Species', '9606', (100, 108))	('increased', 'PosReg', (57, 66))	('RCC', 'Disease', (20, 23))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('FAM129A', 'Var', (0, 7))
81965	31016032	FAM129A was 70% (P = 0.0001) higher in tumorous tissues.	('higher', 'PosReg', (29, 35))	('tumorous tissues', 'Disease', 'MESH:D009369', (39, 55))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumorous tissues', 'Disease', (39, 55))	('FAM129A', 'Var', (0, 7))
81966	31016032	FAM129A-positive detection rates of tumorous tissues with ++ and +++ were 5 (10/2) and 18 (18/1) fold of those of nontumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumorous tissues', 'Disease', 'MESH:D009369', (36, 52))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('tumor', 'Disease', (117, 122))	('tumorous tissues', 'Disease', (36, 52))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('+++', 'Var', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', (36, 41))
81968	31016032	2f) showed, compared with paired paracancerous tissues, FAM129A was upregulated in 31 cases, unchanged in 3 cases, and decreased in 3 cases of the 37 available from 55 patients' tumorous tissues (Fig.	('paracancerous', 'Disease', (33, 46))	('decreased', 'NegReg', (119, 128))	('upregulated', 'PosReg', (68, 79))	('FAM129A', 'Var', (56, 63))	('tumorous tissues', 'Disease', 'MESH:D009369', (178, 194))	('paracancerous', 'Disease', 'None', (33, 46))	('patients', 'Species', '9606', (168, 176))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumorous tissues', 'Disease', (178, 194))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
81970	31016032	FAM129A/FAM129A overexpression contributes to ccRCC development and progression.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('overexpression contributes', 'PosReg', (16, 42))	('progression', 'CPA', (68, 79))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('FAM129A/FAM129A', 'Var', (0, 15))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
81971	31016032	FAM129A mRNA upregulation was detected in most cases (45/55) where patients' tumorous tissues were accompanied by miR-4521 downexpression (Fig.	('miR-4521', 'Gene', '100616406', (114, 122))	('patients', 'Species', '9606', (67, 75))	('mRNA', 'MPA', (8, 12))	('miR-4521', 'Gene', (114, 122))	('tumorous tissues', 'Disease', 'MESH:D009369', (77, 93))	('downexpression', 'NegReg', (123, 137))	('tumorous tissues', 'Disease', (77, 93))	('si', 'Chemical', 'MESH:D012825', (133, 135))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('upregulation', 'PosReg', (13, 25))	('FAM129A', 'Var', (0, 7))
81973	31016032	Consistent with this, FAM129A protein upregulation (Fig.	('si', 'Chemical', 'MESH:D012825', (3, 5))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('FAM129A', 'Var', (22, 29))	('protein', 'Protein', (30, 37))	('upregulation', 'PosReg', (38, 50))
81975	31016032	Hence, the correlation and regulation mechanism between FAM129A and miR-4521 was investigated and established.	('regulation', 'biological_process', 'GO:0065007', ('27', '37'))	('miR-4521', 'Gene', '100616406', (68, 76))	('FAM129A', 'Var', (56, 63))	('miR-4521', 'Gene', (68, 76))
81979	31016032	Thus 786-O and ACHN are appropriate cell models for investigating the function and regulation mechanism of miR-4521 and FAM129A in ccRCC.	('regulation', 'biological_process', 'GO:0065007', ('83', '93'))	('ACHN', 'Gene', (15, 19))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('miR-4521', 'Gene', (107, 115))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('ACHN', 'Gene', '55323', (15, 19))	('miR-4521', 'Gene', '100616406', (107, 115))	('FAM129A', 'Var', (120, 127))
81983	31016032	The plasmids of the 211 bp fragment of FAM129A 3'UTR containing wild-type (WT) and mutant (MUT, UCCUUAG mutated to CGCACAC) sequences were inserted into a psiCHECK 2.0 plasmid, named as wt-FAM129A-3'UTR and mut-FAM129A-3'UTR (Fig.	("mut-FAM129A-3'UTR", 'Var', (207, 224))	('FAM129A', 'Var', (39, 46))	('si', 'Chemical', 'MESH:D012825', (156, 158))	('mutant', 'Var', (83, 89))
81987	31016032	miR-4521 deregulation affected FAM129A expression.	('affected', 'Reg', (22, 30))	('miR-4521', 'Gene', (0, 8))	('FAM129A', 'Gene', (31, 38))	('deregulation', 'Var', (9, 21))	('miR-4521', 'Gene', '100616406', (0, 8))	('expression', 'MPA', (39, 49))	('si', 'Chemical', 'MESH:D012825', (45, 47))
81991	31016032	Its suppression contributes to elevated FAM129A in enhanced RCC malignancy.	('RCC malignancy', 'Disease', 'MESH:C538614', (60, 74))	('RCC malignancy', 'Disease', (60, 74))	('enhanced', 'PosReg', (51, 59))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('FAM129A', 'Var', (40, 47))	('elevated', 'PosReg', (31, 39))	('si', 'Chemical', 'MESH:D012825', (11, 13))
81992	31016032	Compared with the irrelevant siRNA (si-NC)-transfected cells, the mRNA and protein levels of FAM129A decreased by 37.6% (P = 0.0145) and 53.8% (P = 0.003, Fig.	('si', 'Chemical', 'MESH:D012825', (29, 31))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('FAM129A', 'Var', (93, 100))	('decreased', 'NegReg', (101, 110))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))
81994	31016032	FAM129A knockdown reduced their proliferation, migration and invasion capacities, and enhanced their apoptosis (Fig.	('knockdown', 'Var', (8, 17))	('reduced', 'NegReg', (18, 25))	('apoptosis', 'biological_process', 'GO:0006915', ('101', '110'))	('apoptosis', 'biological_process', 'GO:0097194', ('101', '110'))	('enhanced', 'PosReg', (86, 94))	('migration', 'CPA', (47, 56))	('invasion capacities', 'CPA', (61, 80))	('apoptosis', 'CPA', (101, 110))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('si', 'Chemical', 'MESH:D012825', (107, 109))	('FAM129A knockdown', 'Var', (0, 17))
81995	31016032	The proliferation rates of si-FAM129A-transfected 786-O and ACHN decreased by 19.0% (P = 0.008) and 12.6% (P = 0.01, Fig.	('si-FAM129A-transfected', 'Var', (27, 49))	('ACHN', 'Gene', '55323', (60, 64))	('decreased', 'NegReg', (65, 74))	('proliferation rates', 'CPA', (4, 23))	('ACHN', 'Gene', (60, 64))	('si', 'Chemical', 'MESH:D012825', (27, 29))
81996	31016032	5d) at 120 h. Compared with si-NC-transfected cells, the migration and invasion capacities of si-FAM129A-transfected 786-O were reduced by 48.8% (P = 0.0001) and 51.7% (P < 0.0001, Fig.	('si', 'Chemical', 'MESH:D012825', (28, 30))	('reduced', 'NegReg', (128, 135))	('si-FAM129A-transfected', 'Var', (94, 116))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('invasion capacities', 'CPA', (71, 90))	('si', 'Chemical', 'MESH:D012825', (94, 96))
81997	31016032	5e), and si-FAM129A-transfected ACHN were decreased by 46.2% (P = 0.0055) and 45.1% (P < 0.0001, Fig.	('ACHN', 'Gene', (32, 36))	('decreased', 'NegReg', (42, 51))	('si-FAM129A-transfected', 'Var', (9, 31))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('ACHN', 'Gene', '55323', (32, 36))
81998	31016032	Compared with the apoptotic percentages of si-NC-transfected cells, the apoptotic percentages of si-FAM129A-transfected 786-O and ACHN increased by 42.5% (P = 0.004) and 59.5% (P = 0.04) to 15.3 +- 0.5% and 20.5 +- 0.4%, respectively (Fig.	('apoptotic percentages', 'CPA', (72, 93))	('si-FAM129A-transfected', 'Var', (97, 119))	('si', 'Chemical', 'MESH:D012825', (97, 99))	('ACHN', 'Gene', '55323', (130, 134))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('increased', 'PosReg', (135, 144))	('ACHN', 'Gene', (130, 134))
81999	31016032	The fact that FAM129A knockdown antagonized malignant behaviors of RCC cells supported its overexpression in ccRCC clinical progression.	('si', 'Chemical', 'MESH:D012825', (131, 133))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (111, 114))	('RCC', 'Disease', (67, 70))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('clinical', 'Species', '191496', (115, 123))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('knockdown', 'Var', (22, 31))	('antagonized', 'NegReg', (32, 43))	('FAM129A knockdown', 'Var', (14, 31))
82000	31016032	miR-4521 overexpression retroregulated FAM129A, which synergically decreased the malignant properties of 786-O and ACHN cells.	('ACHN', 'Gene', (115, 119))	('miR-4521', 'Gene', (0, 8))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('miR-4521', 'Gene', '100616406', (0, 8))	('FAM129A', 'Var', (39, 46))	('decreased', 'NegReg', (67, 76))	('ACHN', 'Gene', '55323', (115, 119))
82010	31016032	Compared with si-NC-transfected cells, MMP2, MMP9, MDM2 and Bcl2 levels decreased by 42.4% (P = 0.004), 49.2% (P = 0.02), 53.1% (P = 0.04) and 45% (P = 0.03), and TIMP-1, p53 and Bax levels increased by 45.3% (P = 0.04), 81.1% (P = 0.03) and 37.8% (P = 0.04) in si-FAM129A-transfected 786-O cells (Fig.	('MMP2', 'Gene', '4313', (39, 43))	('Bax', 'Gene', '581', (179, 182))	('MDM2', 'Gene', (51, 55))	('Bcl2', 'Gene', (60, 64))	('MMP9', 'Gene', '4318', (45, 49))	('MMP9', 'Gene', (45, 49))	('Bcl2', 'Gene', '596', (60, 64))	('decreased', 'NegReg', (72, 81))	('MDM2', 'Gene', '4193', (51, 55))	('si-FAM129A-transfected', 'Var', (262, 284))	('si', 'Chemical', 'MESH:D012825', (262, 264))	('TIMP-1', 'Gene', (163, 169))	('TIMP-1', 'Gene', '7076', (163, 169))	('MMP2', 'molecular_function', 'GO:0004228', ('39', '43'))	('MMP9', 'molecular_function', 'GO:0004229', ('45', '49'))	('p53', 'Gene', '7157', (171, 174))	('MMP2', 'Gene', (39, 43))	('si', 'Chemical', 'MESH:D012825', (14, 16))	('Bcl2', 'molecular_function', 'GO:0015283', ('60', '64'))	('increased', 'PosReg', (190, 199))	('Bax', 'Gene', (179, 182))	('p53', 'Gene', (171, 174))
82011	31016032	FAM129A influences 786-O malignancy via TIMP-1/MMP2/MMP9 and MDM2/p53/Bcl2/Bax.	('Bcl2', 'molecular_function', 'GO:0015283', ('70', '74'))	('malignancy', 'Disease', (25, 35))	('MMP2', 'Gene', '4313', (47, 51))	('MMP2', 'molecular_function', 'GO:0004228', ('47', '51'))	('MDM2', 'Gene', (61, 65))	('Bcl2', 'Gene', (70, 74))	('TIMP-1', 'Gene', '7076', (40, 46))	('influences', 'Reg', (8, 18))	('TIMP-1', 'Gene', (40, 46))	('Bcl2', 'Gene', '596', (70, 74))	('MDM2', 'Gene', '4193', (61, 65))	('FAM129A', 'Var', (0, 7))	('MMP9', 'Gene', (52, 56))	('MMP9', 'Gene', '4318', (52, 56))	('MMP2', 'Gene', (47, 51))	('malignancy', 'Disease', 'MESH:D009369', (25, 35))	('Bax', 'Gene', (75, 78))	('p53', 'Gene', '7157', (66, 69))	('MMP9', 'molecular_function', 'GO:0004229', ('52', '56'))	('Bax', 'Gene', '581', (75, 78))	('p53', 'Gene', (66, 69))
82022	31016032	Its deficiency is a contributing factor in the development and progression of CLL and lung cancer.	('si', 'Chemical', 'MESH:D012825', (70, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('CLL', 'Disease', 'MESH:D015451', (78, 81))	('deficiency', 'Var', (4, 14))	('lung cancer', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('CLL', 'Phenotype', 'HP:0005550', (78, 81))	('CLL', 'Disease', (78, 81))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
82041	31016032	This work also showed miR-4521 level was negatively correlated with FAM129A level in ccRCC progression.	('miR-4521', 'Gene', (22, 30))	('negatively', 'NegReg', (41, 51))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('miR-4521', 'Gene', '100616406', (22, 30))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('FAM129A', 'Var', (68, 75))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
82042	31016032	FAM129A (Niban or Clorf24) is liked to thyroid cancer, HNSCC and sporadic renal carcinomas, acting in all as a tumor promoter.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('HNSCC', 'Phenotype', 'HP:0012288', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('HNSCC', 'Disease', (55, 60))	('thyroid cancer', 'Disease', (39, 53))	('thyroid cancer', 'Phenotype', 'HP:0002890', (39, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('renal carcinoma', 'Phenotype', 'HP:0005584', (74, 89))	('tumor', 'Disease', (111, 116))	('sporadic renal carcinomas', 'Disease', (65, 90))	('thyroid cancer', 'Disease', 'MESH:D013964', (39, 53))	('sporadic renal carcinomas', 'Disease', 'MESH:C538614', (65, 90))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('renal carcinomas', 'Phenotype', 'HP:0005584', (74, 90))	('FAM129A', 'Var', (0, 7))
82043	31016032	FAM129A, ITM1 and PVALB were the three earliest genes used for distinguishing benign thyroid nodules from malignant ones.	('PVALB', 'Gene', (18, 23))	('PVALB', 'Gene', '5816', (18, 23))	('benign thyroid nodules', 'Disease', (78, 100))	('ITM1', 'Gene', '3703', (9, 13))	('thyroid nodules', 'Phenotype', 'HP:0025388', (85, 100))	('FAM129A', 'Var', (0, 7))	('ITM1', 'Gene', (9, 13))
82044	31016032	FAM129A was absent in specimens from normal thyroid, benign follicular thyroid adenoma and thyroid hyperplasia, but was present and upregulated in papillary thyroid carcinoma and follicular thyroid carcinoma tissues.	('thyroid adenoma', 'Disease', 'MESH:D013964', (71, 86))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (190, 207))	('thyroid adenoma', 'Disease', (71, 86))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (157, 174))	('upregulated', 'PosReg', (132, 143))	('thyroid hyperplasia', 'Disease', (91, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('thyroid adenoma', 'Phenotype', 'HP:0000854', (71, 86))	('thyroid hyperplasia', 'Phenotype', 'HP:0008249', (91, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('thyroid hyperplasia', 'Disease', 'MESH:D013959', (91, 110))	('follicular thyroid adenoma', 'Phenotype', 'HP:0006731', (60, 86))	('FAM129A', 'Var', (0, 7))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (190, 207))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (147, 174))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (157, 174))	('follicular thyroid carcinoma', 'Phenotype', 'HP:0006731', (179, 207))	('thyroid carcinoma', 'Disease', (190, 207))	('papillary thyroid carcinoma', 'Disease', (147, 174))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (147, 174))
82046	31016032	FAM129A knockdown antagonized the in vitro proliferation, migration and invasion capacities of WRO and TPC1.	('si', 'Chemical', 'MESH:D012825', (76, 78))	('antagonized', 'NegReg', (18, 29))	('in vitro proliferation', 'CPA', (34, 56))	('knockdown', 'Var', (8, 17))	('invasion capacities of WRO', 'CPA', (72, 98))	('TPC1', 'Gene', (103, 107))	('TPC1', 'Gene', '53373', (103, 107))	('FAM129A knockdown', 'Var', (0, 17))	('migration', 'CPA', (58, 67))
82048	31016032	Compared with its absence in normal HNS epithelia, IHC assays indicated that FAM129A was positively detected in 42 out of 43 HNSCCs (97.6%) and 20 of 30 (66.6%) dysplastic lesions.	('HNSCCs', 'Disease', (125, 131))	('HNSCC', 'Phenotype', 'HP:0012288', (125, 130))	('dysplastic lesions', 'Disease', 'MESH:D021782', (161, 179))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('si', 'Chemical', 'MESH:D012825', (174, 176))	('dysplastic lesions', 'Disease', (161, 179))	('HNS epithelia', 'Disease', 'None', (36, 49))	('FAM129A', 'Var', (77, 84))	('HNS epithelia', 'Disease', (36, 49))	('detected', 'Reg', (100, 108))
82050	31016032	FAM129A expression was detected in Tsc1 and Tsc2 knockout mice, in sporadic human RCC including clear cell carcinomas, granular cell carcinomas and spindle cell carcinomas.	('clear cell carcinomas', 'Disease', (96, 117))	('carcinomas', 'Phenotype', 'HP:0030731', (161, 171))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (96, 117))	('granular cell carcinomas', 'Disease', 'MESH:D000230', (119, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('spindle cell carcinomas', 'Disease', 'MESH:D002277', (148, 171))	('FAM129A', 'Var', (0, 7))	('Tsc1', 'Gene', '64930', (35, 39))	('Tsc2', 'Gene', (44, 48))	('mice', 'Species', '10090', (58, 62))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('spindle', 'cellular_component', 'GO:0005819', ('148', '155'))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('Tsc1', 'Gene', (35, 39))	('si', 'Chemical', 'MESH:D012825', (14, 16))	('granular cell carcinomas', 'Disease', (119, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('human', 'Species', '9606', (76, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('spindle cell carcinomas', 'Disease', (148, 171))
82052	31016032	We propose that FAM129A acts in renal carcinoma by influencing tumor cell apoptosis based on its involvement in renal interstitial fibrosis via promoting renal tubular cells apoptosis.	('renal tubular cells apoptosis', 'CPA', (154, 183))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('renal interstitial fibrosis', 'Disease', (112, 139))	('si', 'Chemical', 'MESH:D012825', (80, 82))	('influencing', 'Reg', (51, 62))	('FAM129A', 'Var', (16, 23))	('renal interstitial fibrosis', 'Phenotype', 'HP:0005576', (112, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('si', 'Chemical', 'MESH:D012825', (180, 182))	('renal interstitial fibrosis', 'Disease', 'MESH:D007674', (112, 139))	('tumor', 'Disease', (63, 68))	('apoptosis', 'biological_process', 'GO:0097194', ('174', '183'))	('apoptosis', 'biological_process', 'GO:0006915', ('174', '183'))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('renal carcinoma', 'Disease', 'MESH:C538614', (32, 47))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('promoting', 'PosReg', (144, 153))	('renal carcinoma', 'Disease', (32, 47))	('renal carcinoma', 'Phenotype', 'HP:0005584', (32, 47))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
82053	31016032	This work revealed FAM129A as a promotor for ccRCC malignancy.	('FAM129A', 'Var', (19, 26))	('RCC malignancy', 'Disease', (47, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('RCC malignancy', 'Disease', 'MESH:C538614', (47, 61))
82056	31016032	Both IHC and WB assays indicated FAM129A protein expression level was increased in patients' tumorous tissues (Fig.	('tumorous tissues', 'Disease', 'MESH:D009369', (93, 109))	('tumorous tissues', 'Disease', (93, 109))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('increased', 'PosReg', (70, 79))	('FAM129A', 'Var', (33, 40))	('patients', 'Species', '9606', (83, 91))	('si', 'Chemical', 'MESH:D012825', (55, 57))
82057	31016032	The positive immunoreactivity against FAM129A was 70% higher, the positive detection rates of FAM129A with ++ and +++ degrees were 4-fold and 17-fold higher (Table 2), and the overall level determined by WB was 214.7% higher (Fig.	('higher', 'PosReg', (54, 60))	('FAM129A', 'Var', (38, 45))	('higher', 'PosReg', (150, 156))	('FAM129A', 'Var', (94, 101))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('positive immunoreactivity', 'MPA', (4, 29))	('si', 'Chemical', 'MESH:D012825', (6, 8))	('+++ degrees', 'Var', (114, 125))
82061	31016032	FAM129A was consistently more highly expressed in renal cancer cells, 786-O and ACHN, than in the normal renal cell, HK-2 (Fig.	('renal cancer', 'Disease', 'MESH:D007680', (50, 62))	('HK-2', 'molecular_function', 'GO:0008256', ('117', '121'))	('ACHN', 'Gene', (80, 84))	('HK-2', 'Gene', '3099', (117, 121))	('more highly', 'PosReg', (25, 36))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('HK-2', 'Gene', (117, 121))	('si', 'Chemical', 'MESH:D012825', (15, 17))	('renal cancer', 'Disease', (50, 62))	('ACHN', 'Gene', '55323', (80, 84))	('renal cancer', 'Phenotype', 'HP:0009726', (50, 62))	('FAM129A', 'Var', (0, 7))
82066	31016032	miR-4521 deficiency was both inversely correlated with upregulations of FAM129A mRNA and with protein (Fig.	('upregulations', 'PosReg', (55, 68))	('miR-4521', 'Gene', (0, 8))	('FAM129A', 'Gene', (72, 79))	('deficiency', 'Var', (9, 19))	('miR-4521', 'Gene', '100616406', (0, 8))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))
82068	31016032	miR-4521 reduction and FAM129A increase in 786-O and ACHN cells than HK-2 cells were also inversely associated (Fig.	('ACHN', 'Gene', '55323', (53, 57))	('HK-2', 'Gene', '3099', (69, 73))	('miR-4521', 'Gene', (0, 8))	('reduction', 'NegReg', (9, 18))	('HK-2', 'Gene', (69, 73))	('ACHN', 'Gene', (53, 57))	('miR-4521', 'Gene', '100616406', (0, 8))	('FAM129A', 'Var', (23, 30))	('HK-2', 'molecular_function', 'GO:0008256', ('69', '73'))	('increase', 'PosReg', (31, 39))
82070	31016032	Their direct interaction was validated by a dual-luciferase reporter assay combined with a mutation of the binding site UCCUUAG for FAM129A to CGCACAC (Fig.	('mutation', 'Var', (91, 99))	('si', 'Chemical', 'MESH:D012825', (115, 117))	('FAM129A', 'Var', (132, 139))	('CGCACAC', 'Gene', (143, 150))	('binding', 'molecular_function', 'GO:0005488', ('107', '114'))
82074	31016032	Its suppression is closely related to FAM129A upregulation, which might synergically enhance ccRCC cell's malignancy and patient's progression.	('suppression', 'NegReg', (4, 15))	('si', 'Chemical', 'MESH:D012825', (138, 140))	('upregulation', 'PosReg', (46, 58))	('FAM129A', 'Var', (38, 45))	('malignancy', 'Disease', (106, 116))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('RCC', 'Disease', (95, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('si', 'Chemical', 'MESH:D012825', (11, 13))	('patient', 'Species', '9606', (121, 128))	('malignancy', 'Disease', 'MESH:D009369', (106, 116))	('enhance', 'PosReg', (85, 92))
82076	31016032	We investigated changes in the levels of MMP2 and MMP9, two key metalloproteinases, and TIMP1, a key tissue inhibitor of metalloproteinase that regulates most MMPs, by following changes in the levels of FAM129A and miR-4521 in RCC cell lines.	('MMP', 'Gene', '4313;4318;79148;79148;79148', (50, 53))	('FAM129A', 'Var', (203, 210))	('TIMP1', 'Gene', '7076', (88, 93))	('MMP', 'Gene', '4313;4318;79148;79148;79148', (41, 44))	('MMP', 'Gene', '4313;4318;79148;79148;79148', (159, 162))	('RCC', 'Disease', (227, 230))	('RCC', 'Phenotype', 'HP:0005584', (227, 230))	('MMP2', 'Gene', (41, 45))	('miR-4521', 'Gene', (215, 223))	('MMP', 'Gene', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (227, 230))	('changes', 'Reg', (178, 185))	('MMP', 'Gene', (41, 44))	('MMP', 'Gene', (159, 162))	('MMP9', 'Gene', (50, 54))	('MMP2', 'Gene', '4313', (41, 45))	('MMP9', 'Gene', '4318', (50, 54))	('MMP2', 'molecular_function', 'GO:0004228', ('41', '45'))	('TIMP1', 'Gene', (88, 93))	('miR-4521', 'Gene', '100616406', (215, 223))	('MMP9', 'molecular_function', 'GO:0004229', ('50', '54'))
82077	31016032	TIMP-1 was upregulated by 45.3%, and MMP2 and MMP9 were downregulated by 42.4% and 49.2%, respectively, in 786-O cells following FAM129A knockdown (Fig.	('TIMP-1', 'Gene', (0, 6))	('MMP2', 'molecular_function', 'GO:0004228', ('37', '41'))	('TIMP-1', 'Gene', '7076', (0, 6))	('MMP2', 'Gene', '4313', (37, 41))	('upregulated', 'PosReg', (11, 22))	('MMP9', 'Gene', '4318', (46, 50))	('MMP9', 'molecular_function', 'GO:0004229', ('46', '50'))	('knockdown', 'Var', (137, 146))	('FAM129A knockdown', 'Var', (129, 146))	('MMP9', 'Gene', (46, 50))	('downregulated', 'NegReg', (56, 69))	('MMP2', 'Gene', (37, 41))
82084	31016032	8, the above results indicate FAM129A upregulation and/or miR-4521 deficiency contributed FAM129A upregulation affects ccRCC malignancy via the TIMP-1/MMP2/MMP pathway.	('FAM129A', 'Var', (90, 97))	('MMP', 'Gene', (156, 159))	('MMP2', 'molecular_function', 'GO:0004228', ('151', '155'))	('miR-4521', 'Gene', (58, 66))	('MMP', 'Gene', '4313;4318;79148;79148;79148', (151, 154))	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('MMP2', 'Gene', (151, 155))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('RCC malignancy', 'Disease', 'MESH:C538614', (121, 135))	('RCC malignancy', 'Disease', (121, 135))	('affects', 'Reg', (111, 118))	('MMP', 'molecular_function', 'GO:0004235', ('156', '159'))	('MMP', 'Gene', '4313;4318;79148;79148;79148', (156, 159))	('miR-4521', 'Gene', '100616406', (58, 66))	('MMP', 'Gene', (151, 154))	('MMP2', 'Gene', '4313', (151, 155))	('upregulation', 'PosReg', (98, 110))	('TIMP-1', 'Gene', (144, 150))	('TIMP-1', 'Gene', '7076', (144, 150))
82085	31016032	Interestingly, although FAM129A was more reduced in si-FAM129A-transfected 786-O and ACHN cells (Figs.	('reduced', 'NegReg', (41, 48))	('si-FAM129A-transfected', 'Var', (52, 74))	('ACHN', 'Gene', '55323', (85, 89))	('ACHN', 'Gene', (85, 89))	('si', 'Chemical', 'MESH:D012825', (52, 54))
82088	31016032	Except for its direct targeting with FAM129A, which has been established, the role of miR-4521 and its detailed action mechanism in ccRCC deserve more attention.	('miR-4521', 'Gene', '100616406', (86, 94))	('miR-4521', 'Gene', (86, 94))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('RCC', 'Disease', (134, 137))	('RCC', 'Phenotype', 'HP:0005584', (134, 137))	('FAM129A', 'Var', (37, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (132, 137))
82089	31016032	FAM129A upregulation and miR-4521 deficiency are inversely correlated and enhanced cancer cell invasiveness and ccRCC progression (Figs.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('upregulation', 'PosReg', (8, 20))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('deficiency', 'Var', (34, 44))	('miR-4521', 'Gene', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('FAM129A', 'Gene', (0, 7))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('cancer cell invasiveness', 'Disease', (83, 107))	('miR-4521', 'Gene', '100616406', (25, 33))	('cancer cell invasiveness', 'Disease', 'MESH:D009362', (83, 107))	('enhanced', 'PosReg', (74, 82))	('si', 'Chemical', 'MESH:D012825', (125, 127))
82090	31016032	FAM129A knockdown and miR-4521 overexpression reduced the proliferations and increased the apoptosis of 786-O and ACHN (Figs.	('miR-4521', 'Gene', (22, 30))	('ACHN', 'Gene', '55323', (114, 118))	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('si', 'Chemical', 'MESH:D012825', (97, 99))	('apoptosis', 'CPA', (91, 100))	('ACHN', 'Gene', (114, 118))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('miR-4521', 'Gene', '100616406', (22, 30))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('reduced', 'NegReg', (46, 53))	('increased', 'PosReg', (77, 86))	('FAM129A', 'Var', (0, 7))
82091	31016032	5 and 6), suggesting that FAM129A overexpression with miR-4521 deficiency might enhance ccRCC progression by promoting cancer cell growth by reducing apoptosis.	('apoptosis', 'CPA', (150, 159))	('miR-4521', 'Gene', '100616406', (54, 62))	('deficiency', 'Var', (63, 73))	('enhance', 'PosReg', (80, 87))	('FAM129A', 'Var', (26, 33))	('cell growth', 'biological_process', 'GO:0016049', ('126', '137'))	('promoting', 'PosReg', (109, 118))	('RCC', 'Disease', (90, 93))	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('overexpression', 'PosReg', (34, 48))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('miR-4521', 'Gene', (54, 62))	('reducing', 'NegReg', (141, 149))	('si', 'Chemical', 'MESH:D012825', (156, 158))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('apoptosis', 'biological_process', 'GO:0097194', ('150', '159'))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('apoptosis', 'biological_process', 'GO:0006915', ('150', '159'))
82094	31016032	The Bcl-2/Bax ratio is the critical indictor for apoptosis induced by imbalance of P53 and MDM2 .	('Bax', 'Gene', '581', (10, 13))	('imbalance', 'Phenotype', 'HP:0002172', (70, 79))	('MDM2', 'Gene', '4193', (91, 95))	('Bcl-2', 'molecular_function', 'GO:0015283', ('4', '9'))	('MDM2', 'Gene', (91, 95))	('Bcl-2', 'Gene', '596', (4, 9))	('Bax', 'Gene', (10, 13))	('P53', 'Gene', (83, 86))	('si', 'Chemical', 'MESH:D012825', (55, 57))	('apoptosis', 'biological_process', 'GO:0097194', ('49', '58'))	('P53', 'Gene', '7157', (83, 86))	('Bcl-2', 'Gene', (4, 9))	('apoptosis', 'biological_process', 'GO:0006915', ('49', '58'))	('imbalance', 'Var', (70, 79))
82095	31016032	This work showed that MDM2 and Bcl2 decreased and p53 and Bax increased in 786-O following FAM129A knockdown (Fig.	('increased', 'PosReg', (62, 71))	('Bcl2', 'molecular_function', 'GO:0015283', ('31', '35'))	('Bax', 'Gene', '581', (58, 61))	('MDM2', 'Gene', '4193', (22, 26))	('MDM2', 'Gene', (22, 26))	('Bcl2', 'Gene', (31, 35))	('Bax', 'Gene', (58, 61))	('p53', 'Gene', (50, 53))	('FAM129A knockdown', 'Var', (91, 108))	('knockdown', 'Var', (99, 108))	('p53', 'Gene', '7157', (50, 53))	('Bcl2', 'Gene', '596', (31, 35))	('decreased', 'NegReg', (36, 45))
82096	31016032	MDM2 suppression by FAM129A knockdown increased P53 causing Bcl2 reduction and Bax upregulation, which resulted in enhanced apoptosis and decreased proliferation of cancer cells (Figs.	('FAM129A', 'Var', (20, 27))	('P53', 'Gene', (48, 51))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('Bcl2', 'Gene', (60, 64))	('Bcl2', 'Gene', '596', (60, 64))	('proliferation', 'CPA', (148, 161))	('apoptosis', 'CPA', (124, 133))	('Bax', 'Gene', (79, 82))	('reduction', 'NegReg', (65, 74))	('si', 'Chemical', 'MESH:D012825', (55, 57))	('P53', 'Gene', '7157', (48, 51))	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('Bax', 'Gene', '581', (79, 82))	('suppression', 'NegReg', (5, 16))	('cancer', 'Disease', (165, 171))	('MDM2', 'Gene', (0, 4))	('upregulation', 'PosReg', (83, 95))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('si', 'Chemical', 'MESH:D012825', (12, 14))	('decreased', 'NegReg', (138, 147))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('Bcl2', 'molecular_function', 'GO:0015283', ('60', '64'))	('MDM2', 'Gene', '4193', (0, 4))	('enhanced', 'PosReg', (115, 123))	('increased', 'PosReg', (38, 47))
82097	31016032	8, FAM129A upregulation probably enhances ccRCC malignancy by increasing cancer cell growth through decreased apoptosis induced by p53 suppression.	('p53', 'Gene', (131, 134))	('ccRCC', 'Phenotype', 'HP:0006770', (42, 47))	('cell growth', 'biological_process', 'GO:0016049', ('80', '91'))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('increasing', 'PosReg', (62, 72))	('apoptosis', 'CPA', (110, 119))	('cancer', 'Disease', (73, 79))	('enhances', 'PosReg', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('suppression', 'NegReg', (135, 146))	('RCC malignancy', 'Disease', 'MESH:C538614', (44, 58))	('si', 'Chemical', 'MESH:D012825', (142, 144))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('RCC malignancy', 'Disease', (44, 58))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('apoptosis', 'biological_process', 'GO:0097194', ('110', '119'))	('p53', 'Gene', '7157', (131, 134))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('apoptosis', 'biological_process', 'GO:0006915', ('110', '119'))	('decreased', 'NegReg', (100, 109))	('upregulation', 'PosReg', (11, 23))	('FAM129A', 'Var', (3, 10))
82105	31016032	7) in si-FAM129A knockdown cells, their apoptotic rates were lower than miR-4521-mimic-transfected cells, 42.5% vs. 48.9% (Fig.	('miR-4521', 'Gene', '100616406', (72, 80))	('lower', 'NegReg', (61, 66))	('si-FAM129A knockdown', 'Var', (6, 26))	('miR-4521', 'Gene', (72, 80))	('knockdown', 'Var', (17, 26))	('si', 'Chemical', 'MESH:D012825', (6, 8))	('apoptotic rates', 'CPA', (40, 55))
82113	31016032	Collectively, FAM129A and miR-4521 act as a tumor promotor and suppressor in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('miR-4521', 'Gene', (26, 34))	('FAM129A', 'Var', (14, 21))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('miR-4521', 'Gene', '100616406', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
82114	31016032	Negatively correlated, FAM129A upregulation and miR-4521 deficiency contribute to ccRCC clinical progression with enhanced TNM stage and Fuhrman grade.	('deficiency', 'Var', (57, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('miR-4521', 'Gene', (48, 56))	('Fuhrman grade', 'CPA', (137, 150))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('enhanced', 'PosReg', (114, 122))	('clinical', 'Species', '191496', (88, 96))	('TNM stage', 'CPA', (123, 132))	('FAM129A', 'Var', (23, 30))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('miR-4521', 'Gene', '100616406', (48, 56))	('upregulation', 'PosReg', (31, 43))
82115	31016032	Binding to 3'UTR of FAM129A, miR-4521 retroregulates FAM129A/FAM129A in mediating ccRCC progression and renal cancer cell malignant properties.	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('miR-4521', 'Gene', '100616406', (29, 37))	('FAM129A/FAM129A', 'Var', (53, 68))	('renal cancer', 'Disease', (104, 116))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('renal cancer', 'Disease', 'MESH:D007680', (104, 116))	('RCC', 'Disease', (84, 87))	('renal cancer', 'Phenotype', 'HP:0009726', (104, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('mediating', 'Reg', (72, 81))	('miR-4521', 'Gene', (29, 37))
82116	31016032	FAM129A knockdown or miR-4521 upregulation decreases renal cancer cells' invasiveness via TIMP-1/MMP2/MMP9 and MDM2/p53/Bcl2/Bax.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('miR-4521', 'Gene', '100616406', (21, 29))	('MMP9', 'Gene', (102, 106))	('renal cancer', 'Phenotype', 'HP:0009726', (53, 65))	('MMP9', 'Gene', '4318', (102, 106))	('MMP2', 'molecular_function', 'GO:0004228', ('97', '101'))	('invasiveness', 'CPA', (73, 85))	('MMP9', 'molecular_function', 'GO:0004229', ('102', '106'))	('MMP2', 'Gene', (97, 101))	('FAM129A', 'Var', (0, 7))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('Bcl2', 'molecular_function', 'GO:0015283', ('120', '124'))	('decreases renal cancer', 'Disease', (43, 65))	('upregulation', 'PosReg', (30, 42))	('MDM2', 'Gene', (111, 115))	('Bcl2', 'Gene', (120, 124))	('p53', 'Gene', '7157', (116, 119))	('MMP2', 'Gene', '4313', (97, 101))	('TIMP-1', 'Gene', (90, 96))	('miR-4521', 'Gene', (21, 29))	('Bax', 'Gene', (125, 128))	('TIMP-1', 'Gene', '7076', (90, 96))	('decreases renal cancer', 'Disease', 'MESH:D007680', (43, 65))	('Bcl2', 'Gene', '596', (120, 124))	('Bax', 'Gene', '581', (125, 128))	('MDM2', 'Gene', '4193', (111, 115))	('p53', 'Gene', (116, 119))
82117	31016032	miR-4521 deficiency with its potential contribution to FAM129A upregulation might synergistically promote renal cancer cells' malignant behaviors by enhancing MMP2/MMP9 through suppressing TIMP-1 and increasing their growth by escaping apoptosis through suppressing p53 by way of upregulation of MDM2 via a decreased Bax/Bcl2 ratio.	('MMP2', 'Gene', '4313', (159, 163))	('si', 'Chemical', 'MESH:D012825', (184, 186))	('apoptosis', 'biological_process', 'GO:0097194', ('236', '245'))	('apoptosis', 'biological_process', 'GO:0006915', ('236', '245'))	('promote', 'PosReg', (98, 105))	('escaping apoptosis', 'CPA', (227, 245))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('growth', 'MPA', (217, 223))	('MDM2', 'Gene', (296, 300))	('enhancing', 'PosReg', (149, 158))	('si', 'Chemical', 'MESH:D012825', (206, 208))	('Bcl2', 'Gene', (321, 325))	('Bax', 'Gene', (317, 320))	('si', 'Chemical', 'MESH:D012825', (261, 263))	('TIMP-1', 'Gene', (189, 195))	('suppressing', 'NegReg', (177, 188))	('MMP9', 'Gene', (164, 168))	('renal cancer', 'Disease', (106, 118))	('TIMP-1', 'Gene', '7076', (189, 195))	('MMP9', 'Gene', '4318', (164, 168))	('miR-4521', 'Gene', (0, 8))	('Bcl2', 'Gene', '596', (321, 325))	('Bax', 'Gene', '581', (317, 320))	('renal cancer', 'Phenotype', 'HP:0009726', (106, 118))	('decreased', 'NegReg', (307, 316))	('MMP2', 'Gene', (159, 163))	('p53', 'Gene', '7157', (266, 269))	('MDM2', 'Gene', '4193', (296, 300))	('deficiency', 'Var', (9, 19))	('MMP2', 'molecular_function', 'GO:0004228', ('159', '163'))	('increasing', 'PosReg', (200, 210))	('si', 'Chemical', 'MESH:D012825', (242, 244))	('renal cancer', 'Disease', 'MESH:D007680', (106, 118))	('Bcl2', 'molecular_function', 'GO:0015283', ('321', '325'))	('upregulation', 'PosReg', (280, 292))	('suppressing', 'NegReg', (254, 265))	('p53', 'Gene', (266, 269))	('miR-4521', 'Gene', '100616406', (0, 8))	('MMP9', 'molecular_function', 'GO:0004229', ('164', '168'))
82142	31016032	Two milliliters of each group of 786-O and ACHN cell suspensions were separately distributed in the wells of six-well plate and incubated at 37  C with 5% CO2 for 24 h. Then 4 muL of each of the NC mimic, miR-4521 mimic, si-NC and si-FAM129A with concentration of 20 muM was separately mixed with 50 muL of RPMI-1640 medium, shaken gently and left for 5 min at RT.	('RPMI-1640 medium', 'Chemical', '-', (307, 323))	('muM', 'Gene', (267, 270))	('si-FAM129A', 'Var', (231, 241))	('ACHN', 'Gene', '55323', (43, 47))	('miR-4521', 'Gene', '100616406', (205, 213))	('si', 'Chemical', 'MESH:D012825', (221, 223))	('si', 'Chemical', 'MESH:D012825', (231, 233))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('muM', 'Gene', '56925', (267, 270))	('miR-4521', 'Gene', (205, 213))	('ACHN', 'Gene', (43, 47))	('si-NC', 'Var', (221, 226))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('CO2', 'Chemical', '-', (155, 158))
82161	31016032	The wild-type (WT) and mutant (MUT) binding site sequences in FAM129A 3'-UTR were amplified and cloned into psiCHECK 2.0 vectors.	('binding', 'molecular_function', 'GO:0005488', ('36', '43'))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('FAM129A', 'Gene', (62, 69))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('mutant', 'Var', (23, 29))
82165	31016032	The influences of changes in the levels of miR-4521 and FAM129A on 786-O and ACHN proliferation were determined by MTT assay.	('ACHN', 'Gene', '55323', (77, 81))	('miR-4521', 'Gene', '100616406', (43, 51))	('FAM129A', 'Var', (56, 63))	('ACHN', 'Gene', (77, 81))	('MTT', 'Chemical', 'MESH:C070243', (115, 118))	('miR-4521', 'Gene', (43, 51))
82190	30770793	In Brief, LXRalpha had the possibility to be a novel diagnostic and prognostic biomarker and therapeutic target in renal cell cancer and LXRalpha could regulate the metastasis of renal cell cancer via NLRP3 inflammamsome.	('metastasis of renal cell cancer', 'Disease', 'MESH:D009362', (165, 196))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('LXRalpha', 'Var', (137, 145))	('renal cell cancer', 'Disease', 'MESH:C538614', (115, 132))	('renal cell cancer', 'Phenotype', 'HP:0005584', (179, 196))	('renal cell cancer', 'Disease', (115, 132))	('metastasis of renal cell cancer', 'Disease', (165, 196))	('NLRP3', 'Gene', '114548', (201, 206))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('renal cell cancer', 'Phenotype', 'HP:0005584', (115, 132))	('renal cell cancer', 'Disease', 'MESH:C538614', (179, 196))	('regulate', 'Reg', (152, 160))	('NLRP3', 'Gene', (201, 206))
82206	30770793	Knockdown of NLRP3 could inhibit the proliferation and invasion of pancreatic cancer cells.	('Knockdown', 'Var', (0, 9))	('NLRP3', 'Gene', (13, 18))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (67, 84))	('invasion of', 'CPA', (55, 66))	('NLRP3', 'Gene', '114548', (13, 18))	('pancreatic cancer', 'Disease', 'MESH:D010190', (67, 84))	('pancreatic cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('inhibit', 'NegReg', (25, 32))
82214	30770793	Kaplan-Meier curves indicated that high expression of LXRalpha or LXRbeta predicted a poor prognosis in ccRCC patients, and the overexpression of LXRalpha in ccRCC patients who were T1+T2 stage (p = 0.0105) or G1+G2 stage (p = 0.0146) was also associated with a poor prognosis (Fig.	('overexpression', 'PosReg', (128, 142))	('LXRalpha', 'Gene', (54, 62))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('ccRCC', 'Phenotype', 'HP:0006770', (158, 163))	('RCC', 'Disease', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('LXRbeta', 'Gene', '7376', (66, 73))	('G1+G2', 'Var', (210, 215))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('RCC', 'Disease', (106, 109))	('LXRbeta', 'Gene', (66, 73))	('patients', 'Species', '9606', (164, 172))	('T1+T2', 'Var', (182, 187))	('patients', 'Species', '9606', (110, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))	('RCC', 'Disease', 'MESH:C538614', (106, 109))
82221	30770793	However, elevation degree of LXRalpha in ccRCC cancer tissue compared to normal kidney tissues was much higher than that of LXRbeta.	('LXRbeta', 'Gene', (124, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('LXRbeta', 'Gene', '7376', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('higher', 'PosReg', (104, 110))	('LXRalpha', 'Var', (29, 37))
82229	30770793	Similarly, wound healing assays revealed that the knockdown of LXRalpha could suppress the scratch healing capacity of ccRCC, while the overexpression of LXRalpha could enhance healing ability (Fig.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('wound healing', 'biological_process', 'GO:0042060', ('11', '24'))	('RCC', 'Disease', (121, 124))	('knockdown', 'Var', (50, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('scratch healing capacity of', 'CPA', (91, 118))	('healing ability', 'CPA', (177, 192))	('suppress', 'NegReg', (78, 86))	('enhance', 'PosReg', (169, 176))	('LXRalpha', 'Gene', (63, 71))
82230	30770793	In addition to transwell assays, apoptosis and cell cycle assays revealed that knockdown of LXRalpha had almost no effect on these processes in ccRCC cells (Fig.	('apoptosis', 'biological_process', 'GO:0097194', ('33', '42'))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('apoptosis', 'biological_process', 'GO:0006915', ('33', '42'))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('LXRalpha', 'Gene', (92, 100))	('cell cycle', 'biological_process', 'GO:0007049', ('47', '57'))	('knockdown', 'Var', (79, 88))
82236	30770793	According to the western blotting results, knockdown of LXRalpha could up-regulate the expression of NLRP3 in ccRCC cells, while LXRalpha overexpression could decrease the expression level of NLRP3 compared to corresponding normal control cells (Fig.	('NLRP3', 'Gene', '114548', (101, 106))	('NLRP3', 'Gene', (192, 197))	('knockdown', 'Var', (43, 52))	('NLRP3', 'Gene', '114548', (192, 197))	('expression', 'MPA', (172, 182))	('RCC', 'Disease', (112, 115))	('expression', 'MPA', (87, 97))	('decrease', 'NegReg', (159, 167))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('LXRalpha', 'Var', (56, 64))	('up-regulate', 'PosReg', (71, 82))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('NLRP3', 'Gene', (101, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))
82239	30770793	In accordance with expression level of NLRP3, knockdown of LXRalpha resulted in the up-regulation of CASP1 and IL-1beta expression and enhanced their cleavage products, CASP1 (p20) and IL-1beta (p15), compared with pro-CASP1 and pro-IL-1beta.	('p20', 'Gene', (176, 179))	('CASP1', 'Gene', '834', (219, 224))	('p15', 'Gene', '1030', (195, 198))	('NLRP3', 'Gene', '114548', (39, 44))	('LXRalpha', 'Gene', (59, 67))	('expression', 'MPA', (120, 130))	('CASP1', 'Gene', (169, 174))	('pro-IL-1beta', 'Gene', '3553', (229, 241))	('p20', 'Gene', '51673', (176, 179))	('cleavage products', 'MPA', (150, 167))	('IL-1', 'molecular_function', 'GO:0005149', ('185', '189'))	('enhanced', 'PosReg', (135, 143))	('IL-1beta', 'Gene', '3553', (185, 193))	('IL-1beta', 'Gene', '3553', (233, 241))	('CASP1', 'Gene', '834', (169, 174))	('regulation', 'biological_process', 'GO:0065007', ('87', '97'))	('IL-1', 'molecular_function', 'GO:0005149', ('111', '115'))	('IL-1beta', 'Gene', (233, 241))	('up-regulation', 'PosReg', (84, 97))	('IL-1beta', 'Gene', (185, 193))	('CASP1', 'Gene', (101, 106))	('IL-1beta', 'Gene', '3553', (111, 119))	('pro-IL-1beta', 'Gene', (229, 241))	('knockdown', 'Var', (46, 55))	('p15', 'Gene', (195, 198))	('CASP1', 'Gene', '834', (101, 106))	('IL-1beta', 'Gene', (111, 119))	('CASP1', 'Gene', (219, 224))	('IL-1', 'molecular_function', 'GO:0005149', ('233', '237'))	('NLRP3', 'Gene', (39, 44))
82242	30770793	In cells with stable LXRalpha-knockdown, si-NLRP3 transfection inhibited the up-regulation of CASP1 and IL-1beta that was caused by LXRalpha-knockdown (Figs.	('CASP1', 'Gene', (94, 99))	('regulation', 'biological_process', 'GO:0065007', ('80', '90'))	('si-NLRP3', 'Gene', (41, 49))	('si-NLRP3', 'Gene', '114548', (41, 49))	('IL-1beta', 'Gene', '3553', (104, 112))	('up-regulation', 'PosReg', (77, 90))	('IL-1beta', 'Gene', (104, 112))	('inhibited', 'NegReg', (63, 72))	('IL-1', 'molecular_function', 'GO:0005149', ('104', '108'))	('CASP1', 'Gene', '834', (94, 99))	('transfection', 'Var', (50, 62))
82245	30770793	To examine whether the knockdown of NLRP3 could interrupt the inhibitory effects on aggressiveness caused by LXRalpha knockdown in ccRCC cells, we performed rescue experiments by co-transfecting with sh-LXRalpha lentivirus (vs. the negative control) and si-NLRP3 (vs. the negative control) into ACHN and 786-O cells.	('aggressiveness', 'Phenotype', 'HP:0000718', (84, 98))	('NLRP3', 'Gene', (36, 41))	('ACHN', 'Gene', '55323', (295, 299))	('aggressiveness', 'Disease', 'MESH:D001523', (84, 98))	('sh-LXRalpha', 'Var', (200, 211))	('si-NLRP3', 'Gene', '114548', (254, 262))	('si-NLRP3', 'Gene', (254, 262))	('NLRP3', 'Gene', (257, 262))	('NLRP3', 'Gene', '114548', (36, 41))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('ACHN', 'Gene', (295, 299))	('inhibitory effects', 'MPA', (62, 80))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('aggressiveness', 'Disease', (84, 98))	('NLRP3', 'Gene', '114548', (257, 262))
82247	30770793	The wound healing assays verified that the weakening effect in cell migration induced by LXRalpha knockdown was effectively reversed by NLRP3 knockdown (Fig.	('NLRP3', 'Gene', (136, 141))	('knockdown', 'Var', (98, 107))	('cell migration', 'CPA', (63, 77))	('NLRP3', 'Gene', '114548', (136, 141))	('LXRalpha', 'Gene', (89, 97))	('cell migration', 'biological_process', 'GO:0016477', ('63', '77'))	('wound healing', 'biological_process', 'GO:0042060', ('4', '17'))	('knockdown', 'Var', (142, 151))
82248	30770793	Besides, according to the results of transwell migration and invasion assays in 786-O and ACHN that were cotransfection with sh-LXRalpha (vs. the negative control) and si-NLRP3 (vs. the negative control), we confirmed that knockdown of NLRP3 could reverse the inhibitory effect in ccRCC cell metastasis caused by knockdown of LXRalpha (Fig.	('NLRP3', 'Gene', (236, 241))	('ACHN', 'Gene', (90, 94))	('NLRP3', 'Gene', (171, 176))	('ccRCC', 'Phenotype', 'HP:0006770', (281, 286))	('RCC', 'Disease', (283, 286))	('LXRalpha', 'Gene', (326, 334))	('NLRP3', 'Gene', '114548', (171, 176))	('RCC', 'Phenotype', 'HP:0005584', (283, 286))	('si-NLRP3', 'Gene', (168, 176))	('NLRP3', 'Gene', '114548', (236, 241))	('RCC', 'Disease', 'MESH:C538614', (283, 286))	('ACHN', 'Gene', '55323', (90, 94))	('knockdown', 'Var', (223, 232))	('knockdown', 'Var', (313, 322))	('si-NLRP3', 'Gene', '114548', (168, 176))
82249	30770793	It was notable that knockdown of NLRP3 could promote the cell migration and invasion in ccRCC according to our wound healing, transwell migration and invasion assays.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('NLRP3', 'Gene', '114548', (33, 38))	('promote', 'PosReg', (45, 52))	('cell migration', 'biological_process', 'GO:0016477', ('57', '71'))	('wound healing', 'biological_process', 'GO:0042060', ('111', '124'))	('knockdown', 'Var', (20, 29))	('cell migration', 'CPA', (57, 71))	('NLRP3', 'Gene', (33, 38))	('invasion', 'CPA', (76, 84))	('RCC', 'Disease', (90, 93))
82253	30770793	After injection of 786-O cells, the fold change of mouse body weight in the LXRalpha knockdown group was significant higher than in the NC group, and the number of macroscopic metastases on the surface of the liver in the NC group was much more than that in the LXRalpha knockdown group (Fig.	('metastases', 'Disease', 'MESH:D009362', (176, 186))	('mouse', 'Species', '10090', (51, 56))	('knockdown', 'Var', (85, 94))	('higher', 'PosReg', (117, 123))	('LXRalpha knockdown', 'Var', (76, 94))	('metastases', 'Disease', (176, 186))	('mouse body weight', 'CPA', (51, 68))
82258	30770793	IHC of vimentin in this study also revealed that metastatic neoplasm numbers in the liver of LXRalpha knockdown groups were decreased compared to NC groups (Fig.	('neoplasm', 'Phenotype', 'HP:0002664', (60, 68))	('vimentin', 'Gene', (7, 15))	('knockdown', 'Var', (102, 111))	('decreased', 'NegReg', (124, 133))	('neoplasm', 'Disease', 'MESH:D009369', (60, 68))	('neoplasm', 'Disease', (60, 68))	('vimentin', 'cellular_component', 'GO:0045099', ('7', '15'))	('vimentin', 'cellular_component', 'GO:0045098', ('7', '15'))	('LXRalpha knockdown', 'Var', (93, 111))	('vimentin', 'Gene', '7431', (7, 15))
82262	30770793	According to our results, we demonstrated that LXRalpha functions as an important oncogene and could modulate the metastasis of renal cancer cells by down-regulate the NLRP3 inflammasome (Fig.	('metastasis of renal cancer', 'Disease', (114, 140))	('modulate', 'Reg', (101, 109))	('down-regulate', 'NegReg', (150, 163))	('LXRalpha', 'Var', (47, 55))	('metastasis of renal cancer', 'Disease', 'MESH:D009362', (114, 140))	('NLRP3', 'Gene', (168, 173))	('renal cancer', 'Phenotype', 'HP:0009726', (128, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('NLRP3', 'Gene', '114548', (168, 173))
82270	30770793	GW3965, a LXR agonist, dampen the cell proliferation in human T-cell acute lymphoblastic leukemia cells.	('leukemia', 'Phenotype', 'HP:0001909', (89, 97))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (69, 97))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (75, 97))	('GW3965', 'Var', (0, 6))	('human', 'Species', '9606', (56, 61))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (62, 97))	('dampen', 'NegReg', (23, 29))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (75, 97))	('GW3965', 'Chemical', 'MESH:C473027', (0, 6))	('cell proliferation', 'biological_process', 'GO:0008283', ('34', '52'))	('lymphoblastic leukemia', 'Disease', (75, 97))
82271	30770793	In lung cancer, LXRalpha is demonstrated to be an independent prognostic biomarker indicating a better survival.	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('LXRalpha', 'Var', (16, 24))
82272	30770793	Although the LXR agonists have been researched as anti-cancer drugs, SR9243 which is a LXR inverse agonist could inhibit the transcriptional activity of LXRs is proved to disrupt cancer cell growth.	('cell growth', 'biological_process', 'GO:0016049', ('186', '197'))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('inhibit', 'NegReg', (113, 120))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('transcriptional activity of LXRs', 'MPA', (125, 157))	('cancer', 'Disease', (179, 185))	('disrupt', 'NegReg', (171, 178))	('SR9243', 'Var', (69, 75))	('cancer', 'Disease', (55, 61))
82293	30770793	Besides, LXRalpha could promote the tumor metastasis by down-regulating the NLRP3 inflammasome in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('NLRP3', 'Gene', '114548', (76, 81))	('down-regulating', 'NegReg', (56, 71))	('LXRalpha', 'Var', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('promote', 'PosReg', (24, 31))	('NLRP3', 'Gene', (76, 81))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('tumor', 'Disease', (36, 41))
82334	29535842	Utilizing several xenograft models, we earlier reported that the enhanced antitumor activity of various chemotherapeutic agents by selenomethione and Se-methylselenocysteine in several human tumor xenografts is highly dose- and schedule-dependent.	('human', 'Species', '9606', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('enhanced', 'PosReg', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('selenomethione', 'Chemical', '-', (131, 145))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (78, 83))	('Se-methylselenocysteine', 'Var', (150, 173))	('selenomethione', 'Var', (131, 145))	('Se-methylselenocysteine', 'Chemical', '-', (150, 173))
82369	29535842	SLM is better absorbed than selenite, and plasma concentrations derived from SLM dosing are significantly higher than those derived from the other Se molecules, with no dose-dependent modulation of glutathione peroxidase or selenoprotein P1.	('SLM', 'Var', (77, 80))	('rat', 'Species', '10116', (56, 59))	('selenite', 'Chemical', 'MESH:D020887', (28, 36))	('Se', 'Chemical', 'MESH:D012643', (147, 149))	('higher', 'PosReg', (106, 112))	('plasma concentrations', 'MPA', (42, 63))
82374	29535842	For example, supplements with zinc which is needed for the maintenance of immune function, reportedly protect cells in the early steps of the apoptotic pathway.	('apoptotic pathway', 'Pathway', (142, 159))	('supplements', 'Var', (13, 24))	('men', 'Species', '9606', (19, 22))
82379	29535842	Studies in FaDu head and neck squamous cell carcinoma cells expressing hypoxia-inducible HIF1alpha confirmed that HIF is a Se target and its downregulation enhances drug effects.	('neck squamous cell carcinoma', 'Disease', (25, 53))	('enhances', 'PosReg', (156, 164))	('hypoxia', 'Disease', (71, 78))	('Se', 'Chemical', 'MESH:D012643', (123, 125))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (16, 53))	('HIF1alpha', 'Gene', (89, 98))	('FaDu', 'Chemical', '-', (11, 15))	('neck', 'cellular_component', 'GO:0044326', ('25', '29'))	('HIF1alpha', 'Gene', '3091', (89, 98))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (25, 53))	('downregulation', 'Var', (141, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (30, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('hypoxia', 'Disease', 'MESH:D000860', (71, 78))	('drug effects', 'MPA', (165, 177))
82455	29535842	Induction and maintenance of DNA double-strand break is generally associated with positive tumor response to therapy.	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('DNA double-strand break', 'Var', (29, 52))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
82468	29535842	Modulation of these markers by MSC results in an enhanced antitumor activity of chemo and radiation therapies in preclinical models.	('Modulation', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('enhanced', 'PosReg', (49, 57))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
82491	29535842	Blockade of HIF1alpha enhances myeloid derived suppressor cells (MDSC)-mediated T-cell activation.	('myeloid derived suppressor cells', 'CPA', (31, 63))	('HIF1alpha', 'Gene', '3091', (12, 21))	('enhances', 'PosReg', (22, 30))	('Blockade', 'Var', (0, 8))	('T-cell activation', 'biological_process', 'GO:0042110', ('80', '97'))	('HIF1alpha', 'Gene', (12, 21))
82493	29535842	Inhibition of PD-L1 leads to an improved treatment outcome.	('treatment outcome', 'CPA', (41, 58))	('men', 'Species', '9606', (46, 49))	('improved', 'PosReg', (32, 40))	('Inhibition', 'Var', (0, 10))	('PD-L1', 'Gene', (14, 19))
82494	29535842	PD-1 promotes ERK and mTOR pathways, and inhibition of the PD-1/PD-L1 axis leads to an enhanced antitumor activity of Docetaxel and Doxorubicin in an orthotopic metastatic mouse model.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Docetaxel', 'Chemical', 'MESH:D000077143', (118, 127))	('PD-1/PD-L1', 'Gene', (59, 69))	('PD-1', 'Gene', (0, 4))	('tumor', 'Disease', (100, 105))	('mouse', 'Species', '10090', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('ERK', 'molecular_function', 'GO:0004707', ('14', '17'))	('inhibition', 'Var', (41, 51))	('enhanced', 'PosReg', (87, 95))	('mTOR pathways', 'Pathway', (22, 35))	('promotes', 'PosReg', (5, 13))	('Doxorubicin', 'Chemical', 'MESH:D004317', (132, 143))
82501	29535842	Enhancement of antitumor activity of multiple anticancer drugs by MSC/SLM in several xenograft models have been found to be dependent on Se dose and schedule.	('Enhancement', 'PosReg', (0, 11))	('cancer', 'Disease', (50, 56))	('MSC/SLM', 'Var', (66, 73))	('Se', 'Chemical', 'MESH:D012643', (137, 139))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('men', 'Species', '9606', (7, 10))
82522	29535842	In six patients with advanced colorectal cancer treated with 2200 mug SLM in combination with 125 mg/m2 irinotecan, no grade 3 diarrhea was observed and one out of six patients developed grade 4 neutropenia with no grade 3 diarrhea.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('diarrhea', 'Disease', (127, 135))	('colorectal cancer', 'Disease', (30, 47))	('mug', 'molecular_function', 'GO:0043739', ('66', '69'))	('diarrhea', 'Disease', 'MESH:D003967', (127, 135))	('neutropenia', 'Phenotype', 'HP:0001875', (195, 206))	('neutropenia', 'Disease', 'MESH:D009503', (195, 206))	('colorectal cancer', 'Phenotype', 'HP:0003003', (30, 47))	('diarrhea', 'Phenotype', 'HP:0002014', (223, 231))	('diarrhea', 'Disease', 'MESH:D003967', (223, 231))	('colorectal cancer', 'Disease', 'MESH:D015179', (30, 47))	('diarrhea', 'Disease', (223, 231))	('2200 mug', 'Var', (61, 69))	('patients', 'Species', '9606', (168, 176))	('irinotecan', 'Chemical', 'MESH:D000077146', (104, 114))	('neutropenia', 'Disease', (195, 206))	('patients', 'Species', '9606', (7, 15))	('diarrhea', 'Phenotype', 'HP:0002014', (127, 135))
82531	29535842	Enhanced tumor accumulation of Se and SN38 results in an enhanced antitumor activity of irinotecan We have provided the rationale for use of a defined dose and schedule of SLM that can effectively enhance the therapeutic efficacy and selectivity of anticancer drugs, including axitinib, a tyrosine kinase inhibitor in ccRCC xenografts.	('irinotecan', 'Chemical', 'MESH:D000077146', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('298', '314'))	('SN38', 'Var', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('axitinib', 'Chemical', 'MESH:D000077784', (277, 285))	('Se', 'Chemical', 'MESH:D012643', (31, 33))	('cancer', 'Disease', (253, 259))	('tumor', 'Disease', (9, 14))	('rat', 'Species', '10116', (120, 123))	('enhance', 'PosReg', (197, 204))	('enhanced', 'PosReg', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
82546	29535842	Thus, the reported stable expression of HIFs in ccRCC tumors may be a consequence of VHL inactivation by miRNA-155 and or miRNA-210.	('inactivation', 'NegReg', (89, 101))	('VHL', 'Gene', (85, 88))	('miRNA-210', 'Var', (122, 131))	('ccRCC tumors', 'Disease', 'MESH:D009369', (48, 60))	('miRNA-155', 'Gene', '406947', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('VHL', 'Gene', '7428', (85, 88))	('ccRCC tumors', 'Disease', (48, 60))	('miRNA-155', 'Gene', (105, 114))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
82548	29535842	The unique profile of ccRCC tumors expressing mutant VHL stable expression of HIFs, and upregulated oncogenic miRNAs, and downregulated tumor suppressor miRNAs make it an excellent model for proof-of-concept that modulation of the expression levels and functions of these markers by therapeutically effective doses and schedules of Se may offer the potential to circumvent drug resistance, and may offer a new and novel clinical approach for the treatment of cancer	('tumor', 'Disease', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (459, 465))	('ccRCC tumors', 'Disease', (22, 34))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('ccRCC tumors', 'Disease', 'MESH:D009369', (22, 34))	('Se', 'Chemical', 'MESH:D012643', (332, 334))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('VHL', 'Gene', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', (136, 141))	('cancer', 'Disease', (459, 465))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('men', 'Species', '9606', (451, 454))	('mutant', 'Var', (46, 52))	('VHL', 'Gene', '7428', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (459, 465))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('136', '152'))	('drug resistance', 'biological_process', 'GO:0009315', ('373', '388'))	('drug resistance', 'Phenotype', 'HP:0020174', (373, 388))	('upregulated', 'PosReg', (88, 99))	('drug resistance', 'biological_process', 'GO:0042493', ('373', '388'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('136', '152'))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
82561	29702206	As newer technologies have become available to characterize tumor metabolism more broadly and specifically than ever before, many other examples of potentially clinically-actionable metabolic perturbations have become apparent, indicating that the propensity for enhanced glucose uptake is merely the tip of the iceberg.	('glucose', 'Chemical', 'MESH:D005947', (272, 279))	('al', 'Chemical', 'MESH:D000535', (102, 104))	('al', 'Chemical', 'MESH:D000535', (155, 157))	('metabolism', 'biological_process', 'GO:0008152', ('66', '76'))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('perturbations', 'Var', (192, 205))	('glucose uptake', 'MPA', (272, 286))	('glucose uptake', 'biological_process', 'GO:0046323', ('272', '286'))	('al', 'Chemical', 'MESH:D000535', (166, 168))	('tumor', 'Disease', (60, 65))	('enhanced', 'PosReg', (263, 271))
82570	29702206	Proton magnetic resonance spectroscopy (MRS) provides non-invasive detection of D-2-hydroxyglutarate (D-2HG) in gliomas with IDH1/2 mutations, and confirmed the previously observed profile of elevated choline and downregulated creatine and N-acetyl aspartate in gliomas compared to normal human brain.	('creatine', 'Chemical', 'MESH:D003401', (227, 235))	('gliomas', 'Disease', 'MESH:D005910', (262, 269))	('al', 'Chemical', 'MESH:D000535', (286, 288))	('IDH1/2', 'Gene', '3417;3418', (125, 131))	('gliomas', 'Phenotype', 'HP:0009733', (112, 119))	('human', 'Species', '9606', (289, 294))	('glioma', 'Phenotype', 'HP:0009733', (262, 268))	('IDH1/2', 'Gene', (125, 131))	('D-2-hydroxyglutarate', 'Gene', (80, 100))	('gliomas', 'Phenotype', 'HP:0009733', (262, 269))	('elevated', 'PosReg', (192, 200))	('N-acetyl aspartate', 'Chemical', 'MESH:C000179', (240, 258))	('downregulated', 'NegReg', (213, 226))	('gliomas', 'Disease', (112, 119))	('choline', 'Chemical', 'MESH:D002794', (201, 208))	('MRS', 'Disease', 'MESH:D008556', (40, 43))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('gliomas', 'Disease', (262, 269))	('MRS', 'Disease', (40, 43))	('mutations', 'Var', (132, 141))	('gliomas', 'Disease', 'MESH:D005910', (112, 119))	('D-2-hydroxyglutarate', 'Gene', '1734', (80, 100))	('elevated choline', 'Phenotype', 'HP:0012706', (192, 208))	('choline', 'MPA', (201, 208))
82582	29702206	We now appreciate that genomic or gene expression alterations in key enzymes of metabolic pathways support oncogenic transformation and/or enable tumor growth and progression.	('enable', 'PosReg', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('gene expression', 'biological_process', 'GO:0010467', ('34', '49'))	('support', 'PosReg', (99, 106))	('genomic', 'Var', (23, 30))	('tumor', 'Disease', (146, 151))	('oncogenic transformation', 'CPA', (107, 131))	('al', 'Chemical', 'MESH:D000535', (50, 52))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
82584	29702206	In a few important cases discussed in this section, mutations in metabolic enzymes result in the accumulation of metabolites that directly contribute to malignant transformation.	('mutations', 'Var', (52, 61))	('malignant transformation', 'CPA', (153, 177))	('metabolic', 'Enzyme', (65, 74))	('al', 'Chemical', 'MESH:D000535', (154, 156))	('result in', 'Reg', (83, 92))	('accumulation of metabolites', 'MPA', (97, 124))	('contribute', 'Reg', (139, 149))
82588	29702206	About 10 years ago, IDH1 and IDH2 mutations were identified in patients with low- and intermediate-grade gliomas and in glioblastomas arising from these initially less aggressive lesions.	('IDH1', 'Gene', '3417', (20, 24))	('IDH2', 'Gene', (29, 33))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('glioblastomas', 'Phenotype', 'HP:0012174', (120, 133))	('gliomas', 'Disease', 'MESH:D005910', (105, 112))	('IDH2', 'Gene', '3418', (29, 33))	('gliomas', 'Phenotype', 'HP:0009733', (105, 112))	('gliomas', 'Disease', (105, 112))	('glioblastomas', 'Disease', 'MESH:D005909', (120, 133))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('patients', 'Species', '9606', (63, 71))	('glioblastomas', 'Disease', (120, 133))	('IDH1', 'Gene', (20, 24))	('mutations', 'Var', (34, 43))	('al', 'Chemical', 'MESH:D000535', (158, 160))
82589	29702206	These mutations result in suppression of the canonical NADP+-dependent oxidative decarboxylation of alpha-KG.	('alpha-KG', 'Protein', (100, 108))	('al', 'Chemical', 'MESH:D000535', (52, 54))	('al', 'Chemical', 'MESH:D000535', (100, 102))	('suppression', 'NegReg', (26, 37))	('NADP+', 'Chemical', 'MESH:D009249', (55, 60))	('alpha-KG', 'Chemical', 'MESH:D007656', (100, 108))	('mutations', 'Var', (6, 15))
82590	29702206	However, the mutations are monoallelic and essentially always located in the same residues in the IDH1/IDH2 active site, suggesting a gain-of-function mechanism relevant to tumor initiation.	('IDH2', 'Gene', '3418', (103, 107))	('IDH1', 'Gene', '3417', (98, 102))	('tumor initiation', 'Disease', 'MESH:D009369', (173, 189))	('al', 'Chemical', 'MESH:D000535', (31, 33))	('al', 'Chemical', 'MESH:D000535', (55, 57))	('gain-of-function', 'PosReg', (134, 150))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor initiation', 'Disease', (173, 189))	('IDH1', 'Gene', (98, 102))	('al', 'Chemical', 'MESH:D000535', (50, 52))	('mutations', 'Var', (13, 22))	('IDH2', 'Gene', (103, 107))
82591	29702206	Metabolomics identified millimolar levels of D-2-hydroxyglutarate (D-2HG), a metabolite normally present at trace levels, in gliomas and cell lines expressing mutant IDH1.	('IDH1', 'Gene', (166, 170))	('gliomas', 'Disease', (125, 132))	('al', 'Chemical', 'MESH:D000535', (92, 94))	('D-2-hydroxyglutarate', 'Gene', '1734', (45, 65))	('gliomas', 'Disease', 'MESH:D005910', (125, 132))	('mutant', 'Var', (159, 165))	('IDH1', 'Gene', '3417', (166, 170))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('D-2-hydroxyglutarate', 'Gene', (45, 65))
82592	29702206	The R132 mutation in IDH1 confers a neomorphic activity resulting in NADPH-dependent generation of D-2HG from alpha-KG (Figure 1).	('neomorphic activity', 'MPA', (36, 55))	('NADPH-dependent generation of D-2HG from', 'MPA', (69, 109))	('NADPH', 'Chemical', 'MESH:D009249', (69, 74))	('alpha-KG', 'Chemical', 'MESH:D007656', (110, 118))	('IDH1', 'Gene', (21, 25))	('R132', 'Var', (4, 8))	('IDH1', 'Gene', '3417', (21, 25))
82593	29702206	Soon after this observation, mutations in IDH1 and IDH2 were identified in acute myeloid leukemia (AML), thyroid cancer, and in other tumor types.	('leukemia', 'Phenotype', 'HP:0001909', (89, 97))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (81, 97))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('IDH1', 'Gene', '3417', (42, 46))	('thyroid cancer', 'Disease', (105, 119))	('IDH2', 'Gene', (51, 55))	('IDH2', 'Gene', '3418', (51, 55))	('acute myeloid leukemia', 'Disease', (75, 97))	('mutations', 'Var', (29, 38))	('identified', 'Reg', (61, 71))	('tumor', 'Disease', (134, 139))	('thyroid cancer', 'Disease', 'MESH:D013964', (105, 119))	('AML', 'Disease', 'MESH:D015470', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (75, 97))	('thyroid cancer', 'Phenotype', 'HP:0002890', (105, 119))	('AML', 'Disease', (99, 102))	('IDH1', 'Gene', (42, 46))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (75, 97))
82594	29702206	Invariably, R132 mutations in IDH1 result in D-2HG accumulation, suggesting a critical role for D-2HG in driving tumorigenesis.	('tumor', 'Disease', (113, 118))	('IDH1', 'Gene', (30, 34))	('D-2HG accumulation', 'MPA', (45, 63))	('al', 'Chemical', 'MESH:D000535', (84, 86))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('result', 'Reg', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('R132 mutations', 'Var', (12, 26))	('IDH1', 'Gene', '3417', (30, 34))
82595	29702206	Orthogonal studies demonstrated that D-2HG functionally impairs alpha-KG dependent dioxygenases, such as histone and DNA demethylases and prolyl hydroxylases (Figure 1).	('al', 'Chemical', 'MESH:D000535', (64, 66))	('DNA demethylases', 'Enzyme', (117, 133))	('alpha-KG dependent dioxygenases', 'Enzyme', (64, 95))	('oxygen', 'Chemical', 'MESH:D010100', (85, 91))	('prolyl hydroxylases', 'Enzyme', (138, 157))	('alpha-KG', 'Chemical', 'MESH:D007656', (64, 72))	('al', 'Chemical', 'MESH:D000535', (51, 53))	('al', 'Chemical', 'MESH:D000535', (8, 10))	('histone', 'Enzyme', (105, 112))	('impairs', 'NegReg', (56, 63))	('N', 'Chemical', 'MESH:D009584', (118, 119))	('D-2HG', 'Var', (37, 42))	('DNA', 'cellular_component', 'GO:0005574', ('117', '120'))
82596	29702206	Small-molecules inhibiting mutant IDH1/2 were demonstrated to suppress D-2HG production, reduce tumor growth and/or induce differentiation of experimental models of glioma and leukemia, indicating the therapeutic potential of targeting these mutations.	('D-2HG production', 'MPA', (71, 87))	('suppress', 'NegReg', (62, 70))	('IDH1/2', 'Gene', '3417;3418', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('al', 'Chemical', 'MESH:D000535', (220, 222))	('mutant', 'Var', (27, 33))	('glioma and leukemia', 'Disease', 'MESH:D005910', (165, 184))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('tumor', 'Disease', (96, 101))	('IDH1/2', 'Gene', (34, 40))	('reduce', 'NegReg', (89, 95))	('al', 'Chemical', 'MESH:D000535', (152, 154))	('al', 'Chemical', 'MESH:D000535', (2, 4))	('leukemia', 'Phenotype', 'HP:0001909', (176, 184))	('induce', 'Reg', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('inhibiting', 'NegReg', (16, 26))	('differentiation', 'CPA', (123, 138))
82598	29702206	Mutations in the TCA cycle enzymes succinate dehydrogenase (SDH) and fumarate hydratase (FH) lead to familial cancer syndromes such as paraganglioma, pheochromocytoma and papillary renal cell carcinoma, indicating that these enzymes function as tumor suppressors.	('SDH', 'Gene', (60, 63))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (171, 201))	('familial cancer', 'Disease', 'MESH:D009369', (101, 116))	('succinate dehydrogenase', 'Gene', (35, 58))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('paraganglioma', 'Phenotype', 'HP:0002668', (135, 148))	('lead to', 'Reg', (93, 100))	('fumarate hydratase', 'Gene', (69, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (171, 201))	('Mutations', 'Var', (0, 9))	('familial cancer', 'Disease', (101, 116))	('succinate dehydrogenase', 'Gene', '1757', (35, 58))	('TCA', 'Gene', (17, 20))	('SDH', 'Gene', '1757', (60, 63))	('TCA', 'Chemical', 'MESH:D014238', (17, 20))	('papillary renal cell carcinoma', 'Disease', (171, 201))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('fumarate hydratase', 'Gene', '2271', (69, 87))	('pheochromocytoma', 'Disease', 'MESH:D010673', (150, 166))	('TCA cycle', 'biological_process', 'GO:0006099', ('17', '26'))	('tumor', 'Disease', (245, 250))	('FH', 'Gene', '2271', (89, 91))	('paraganglioma', 'Disease', (135, 148))	('paraganglioma', 'Disease', 'MESH:D010235', (135, 148))	('pheochromocytoma', 'Disease', (150, 166))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (150, 166))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (181, 201))
82599	29702206	Unlike IDH mutations, FH and SDH mutations result in the loss of enzymatic function, usually through the inheritance of one germline loss-of-function mutation followed by loss of the second allele in the tumor.	('IDH', 'Gene', (7, 10))	('loss-of-function', 'NegReg', (133, 149))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('IDH', 'Gene', '3417', (7, 10))	('enzymatic function', 'MPA', (65, 83))	('SDH', 'Gene', '1757', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('mutations', 'Var', (33, 42))	('al', 'Chemical', 'MESH:D000535', (190, 192))	('tumor', 'Disease', (204, 209))	('FH', 'Gene', '2271', (22, 24))	('loss', 'NegReg', (57, 61))	('al', 'Chemical', 'MESH:D000535', (88, 90))	('SDH', 'Gene', (29, 32))
82614	29702206	This pathway frequently becomes constitutively activated in cancer due to mutations/amplifications of key regulatory subunits and/or deletion of tumor suppressors.	('mutations/amplifications', 'Var', (74, 98))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('deletion', 'Var', (133, 141))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('activated', 'PosReg', (47, 56))	('cancer', 'Disease', (60, 66))	('tumor', 'Disease', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
82618	29702206	For instance, Epidermal Growth Factor Receptor (EGFR)-mutant lung adenocarcinoma cell lines require PI3K-AKT-mTOR signaling to maintain a growth-promoting metabolic program, and inhibition of the signaling pathway suppresses glycolysis.	('EGFR', 'Gene', '1956', (48, 52))	('AKT', 'Gene', '207', (105, 108))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (14, 46))	('inhibition', 'Var', (178, 188))	('signaling pathway', 'biological_process', 'GO:0007165', ('196', '213'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (61, 80))	('PI3K', 'molecular_function', 'GO:0016303', ('100', '104'))	('glycolysis', 'biological_process', 'GO:0006096', ('225', '235'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (61, 80))	('EGFR', 'molecular_function', 'GO:0005006', ('48', '52'))	('growth-promoting metabolic program', 'MPA', (138, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('al', 'Chemical', 'MESH:D000535', (118, 120))	('suppresses', 'NegReg', (214, 224))	('al', 'Chemical', 'MESH:D000535', (21, 23))	('Epidermal Growth Factor', 'molecular_function', 'GO:0005154', ('14', '37'))	('EGFR', 'Gene', (48, 52))	('AKT', 'Gene', (105, 108))	('mTOR', 'Gene', (109, 113))	('signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('glycolysis', 'MPA', (225, 235))	('al', 'Chemical', 'MESH:D000535', (200, 202))	('Epidermal Growth Factor Receptor', 'Gene', (14, 46))	('mTOR', 'Gene', '2475', (109, 113))	('lung adenocarcinoma', 'Disease', (61, 80))	('-mutant', 'Var', (53, 60))
82622	29702206	In these cases, signaling or transcriptional networks imposed by a mutation or combination of mutations can render cells exquisitely dependent on an activity that is dispensable in cells with different oncogenotypes.	('signaling', 'biological_process', 'GO:0023052', ('16', '25'))	('al', 'Chemical', 'MESH:D000535', (20, 22))	('signaling', 'MPA', (16, 25))	('mutation', 'Var', (67, 75))	('mutations', 'Var', (94, 103))	('al', 'Chemical', 'MESH:D000535', (42, 44))	('transcriptional networks', 'MPA', (29, 53))	('imposed', 'Reg', (54, 61))	('render', 'Reg', (108, 114))
82623	29702206	For example, in non-small cell lung cancer (NSCLC), metabolomics revealed marked differences between cells and tumors with concomitant mutations in the oncogene KRAS and tumor suppressor protein LKB1 compared to cells/tumors with mutant KRAS and wild-type LKB1.	('KRAS', 'Gene', (237, 241))	('differences', 'Reg', (81, 92))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', (218, 223))	('KRAS', 'Gene', '3845', (161, 165))	('LKB1', 'Gene', (195, 199))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (16, 42))	('LKB1', 'Gene', '6794', (256, 260))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('mutations', 'Var', (135, 144))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumor suppressor', 'biological_process', 'GO:0051726', ('170', '186'))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('al', 'Chemical', 'MESH:D000535', (22, 24))	('KRAS', 'Gene', (161, 165))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('al', 'Chemical', 'MESH:D000535', (69, 71))	('non-small cell lung cancer', 'Disease', (16, 42))	('tumor', 'Disease', (111, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('NSCLC', 'Disease', (44, 49))	('LKB1', 'Gene', (256, 260))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))	('tumors', 'Disease', (218, 224))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('170', '186'))	('KRAS', 'Gene', '3845', (237, 241))	('LKB1', 'Gene', '6794', (195, 199))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (20, 42))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (16, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
82624	29702206	Specifically, the co-mutants had broad alterations in pathways of nitrogen metabolism and expressed high levels of carbamoyl phosphate synthetase-1 (CPS1), the rate-limiting enzyme of urea cycle.	('urea', 'Chemical', 'MESH:D014508', (184, 188))	('CPS1', 'Gene', '1373', (149, 153))	('urea cycle', 'biological_process', 'GO:0000050', ('184', '194'))	('pathways of nitrogen metabolism', 'MPA', (54, 85))	('high levels of carbamoyl phosphate synthetase-1', 'Phenotype', 'HP:0003240', (100, 147))	('carbamoyl phosphate', 'Chemical', 'MESH:D002221', (115, 134))	('al', 'Chemical', 'MESH:D000535', (8, 10))	('al', 'Chemical', 'MESH:D000535', (39, 41))	('alterations', 'Reg', (39, 50))	('co-mutants', 'Var', (18, 28))	('nitrogen', 'Chemical', 'MESH:D009584', (66, 74))	('CPS1', 'Gene', (149, 153))	('metabolism', 'biological_process', 'GO:0008152', ('75', '85'))
82627	29702206	Suppressing CPS1 depletes the pyrimidine pool in co-mutant cells, resulting in DNA polymerase stalling, DNA damage, reduced tumor growth and increased sensitivity to cisplatin, whereas cells with wild-type LKB1 are resistant to CPS1 loss.	('pyrimidine', 'Chemical', 'MESH:C030986', (30, 40))	('sensitivity to cisplatin', 'MPA', (151, 175))	('al', 'Chemical', 'MESH:D000535', (96, 98))	('increased', 'PosReg', (141, 150))	('depletes', 'NegReg', (17, 25))	('DNA', 'MPA', (104, 107))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('CPS1', 'Gene', (228, 232))	('CPS1', 'Gene', '1373', (228, 232))	('reduced tumor', 'Disease', 'MESH:D015354', (116, 129))	('cisplatin', 'Chemical', 'MESH:D002945', (166, 175))	('LKB1', 'Gene', '6794', (206, 210))	('DNA', 'MPA', (79, 82))	('CPS1 loss', 'Disease', 'MESH:D015431', (228, 237))	('CPS1 loss', 'Disease', (228, 237))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))	('CPS1', 'Gene', (12, 16))	('Suppressing', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('CPS1', 'Gene', '1373', (12, 16))	('N', 'Chemical', 'MESH:D009584', (105, 106))	('N', 'Chemical', 'MESH:D009584', (80, 81))	('LKB1', 'Gene', (206, 210))	('reduced tumor', 'Disease', (116, 129))	('pyrimidine pool', 'MPA', (30, 45))	('stalling', 'NegReg', (94, 102))
82628	29702206	Similarly, high-grade KRASG12D/G12D-mutant lung cancer with TP53 null background exhibits elevated glycolysis and glucose-derived carbon flux into the TCA cycle and glutathione biosynthesis (Figure 2a, Right).	('TCA cycle', 'biological_process', 'GO:0006099', ('151', '160'))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('glycolysis', 'biological_process', 'GO:0006096', ('99', '109'))	('TP53', 'Gene', (60, 64))	('glutathione biosynthesis', 'MPA', (165, 189))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('glutathione biosynthesis', 'biological_process', 'GO:0006750', ('165', '189'))	('G12D', 'Mutation', 'rs121913529', (26, 30))	('carbon', 'Chemical', 'MESH:D002244', (130, 136))	('elevated', 'PosReg', (90, 98))	('glucose', 'Chemical', 'MESH:D005947', (114, 121))	('glycolysis', 'MPA', (99, 109))	('TP53', 'Gene', '7157', (60, 64))	('G12D', 'Mutation', 'rs121913529', (31, 35))	('lung cancer', 'Disease', (43, 54))	('glutathione', 'Chemical', 'MESH:D005978', (165, 176))	('derived', 'Chemical', '-', (122, 129))	('TCA', 'Chemical', 'MESH:D014238', (151, 154))	('glucose-derived carbon flux into the TCA cycle', 'MPA', (114, 160))	('KRASG12D/G12D-mutant', 'Var', (22, 42))
82630	29702206	More than 90% of pancreatic ductal adenocarcinoma (PDAC) contain the KRASG12D mutation.	('PDAC', 'Chemical', '-', (51, 55))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (17, 49))	('KRASG12D', 'Var', (69, 77))	('pancreatic ductal adenocarcinoma', 'Disease', (17, 49))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (17, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))
82631	29702206	Combined transcriptomics and metabolomics in KRASG12D-mutant PDAC revealed elevated glycolysis and increased fluxes into the hexosamine biosynthetic pathway (HBP) to maintain protein glycosylation and the non-oxidative pentose phosphate pathway (non-oxidative PPP) to generate DNA/RNA (Figure 2b).	('PDAC', 'Gene', (61, 65))	('fluxes', 'MPA', (109, 115))	('N', 'Chemical', 'MESH:D009584', (282, 283))	('hexosamine biosynthetic pathway', 'MPA', (125, 156))	('non-oxidative pentose phosphate pathway', 'Pathway', (205, 244))	('PDAC', 'Chemical', '-', (61, 65))	('glycolysis', 'biological_process', 'GO:0006096', ('84', '94'))	('RNA', 'cellular_component', 'GO:0005562', ('281', '284'))	('glycolysis', 'MPA', (84, 94))	('pentose phosphate', 'Chemical', 'MESH:D010428', (219, 236))	('elevated', 'PosReg', (75, 83))	('al', 'Chemical', 'MESH:D000535', (70, 72))	('increased', 'PosReg', (99, 108))	('KRASG12D-mutant', 'Var', (45, 60))	('protein', 'cellular_component', 'GO:0003675', ('175', '182'))	('N', 'Chemical', 'MESH:D009584', (278, 279))	('oxidative pentose phosphate pathway', 'biological_process', 'GO:0009051', ('209', '244'))	('DNA', 'cellular_component', 'GO:0005574', ('277', '280'))	('protein glycosylation', 'MPA', (175, 196))	('hexosamine', 'Chemical', 'MESH:D006595', (125, 135))	('protein glycosylation', 'biological_process', 'GO:0006486', ('175', '196'))	('maintain', 'PosReg', (166, 174))
82632	29702206	These KRASG12D tumors require MAPK signaling, but not the PI3K-AKT pathway, to maintain glucose flux through the HBP and the non-oxidative PPP.	('glucose flux', 'MPA', (88, 100))	('PI3K', 'molecular_function', 'GO:0016303', ('58', '62'))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('AKT', 'Gene', (63, 66))	('MAPK', 'molecular_function', 'GO:0004707', ('30', '34'))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('KRASG12D', 'Var', (6, 14))	('MAPK signaling', 'MPA', (30, 44))	('al', 'Chemical', 'MESH:D000535', (39, 41))	('glucose', 'Chemical', 'MESH:D005947', (88, 95))	('AKT', 'Gene', '207', (63, 66))	('MAPK signaling', 'biological_process', 'GO:0000165', ('30', '44'))	('tumors', 'Disease', (15, 21))
82640	29702206	Numerous studies have illustrated the impact of the BRAF V600E on metabolic phenotypes.	('metabolic', 'MPA', (66, 75))	('V600E', 'Mutation', 'rs113488022', (57, 62))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('V600E', 'Var', (57, 62))	('BRAF', 'Gene', '673', (52, 56))	('BRAF', 'Gene', (52, 56))
82642	29702206	HMGCL generates the ketone body acetoacetate, which physically binds to mutant BRAF protein to stabilize its interaction with Mitogen-Activated Protein Kinase Kinase 1 (MEK1), thus potentiating BRAF-dependent signals.	('ketone', 'Chemical', 'MESH:D007659', (20, 26))	('MEK1', 'Gene', (169, 173))	('BRAF', 'Gene', '673', (79, 83))	('Mitogen-Activated Protein Kinase Kinase 1', 'Gene', '5604', (126, 167))	('BRAF', 'Gene', (79, 83))	('interaction', 'Interaction', (109, 120))	('acetoacetate', 'Chemical', 'MESH:C016635', (32, 44))	('al', 'Chemical', 'MESH:D000535', (213, 215))	('mutant', 'Var', (72, 78))	('MEK1', 'Gene', '5604', (169, 173))	('MEK1', 'molecular_function', 'GO:0004708', ('169', '173'))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('HMGCL', 'Gene', '3155', (0, 5))	('protein', 'Protein', (84, 91))	('BRAF', 'Gene', '673', (194, 198))	('al', 'Chemical', 'MESH:D000535', (58, 60))	('BRAF', 'Gene', (194, 198))	('Mitogen-Activated Protein Kinase Kinase 1', 'Gene', (126, 167))	('HMGCL', 'Gene', (0, 5))	('ketone body', 'Phenotype', 'HP:0001946', (20, 31))	('potentiating', 'PosReg', (181, 193))
82657	29702206	Treating benign prostate epithelial cells with sarcosine or silencing the sarcosine-degrading enzyme sarcosine dehydrogenase (SARDH) enhanced invasive properties, while knockdown of the sarcosine-synthesizing enzyme glycine N-methyltransferase (GNMT) reduced invasion of prostate cancer cells.	('invasion', 'CPA', (259, 267))	('GNMT', 'Gene', '27232', (245, 249))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('GNMT', 'Gene', (245, 249))	('invasive properties', 'CPA', (142, 161))	('prostate cancer', 'Disease', 'MESH:D011471', (271, 286))	('prostate cancer', 'Phenotype', 'HP:0012125', (271, 286))	('glycine N-methyltransferase', 'Gene', (216, 243))	('prostate cancer', 'Disease', (271, 286))	('sarcosine', 'Chemical', 'MESH:D012521', (47, 56))	('enhanced', 'PosReg', (133, 141))	('knockdown', 'Var', (169, 178))	('sarcosine', 'Chemical', 'MESH:D012521', (101, 110))	('silencing', 'Var', (60, 69))	('glycine N-methyltransferase', 'Gene', '27232', (216, 243))	('reduced', 'NegReg', (251, 258))	('SARDH', 'Gene', '1757', (126, 131))	('SARDH', 'Gene', (126, 131))	('sarcosine', 'Chemical', 'MESH:D012521', (186, 195))	('al', 'Chemical', 'MESH:D000535', (33, 35))	('sarcosine', 'Chemical', 'MESH:D012521', (74, 83))	('GNMT', 'molecular_function', 'GO:0017174', ('245', '249'))
82660	29702206	We observed that inhibition of the hexosamine biosynthesis pathway (HBP) promotes castration-resistant prostate cancer (CRPC) (Figure 3).	('hexosamine', 'Chemical', 'MESH:D006595', (35, 45))	('biosynthesis', 'biological_process', 'GO:0009058', ('46', '58'))	('prostate cancer', 'Disease', 'MESH:D011471', (103, 118))	('inhibition', 'Var', (17, 27))	('prostate cancer', 'Phenotype', 'HP:0012125', (103, 118))	('promotes', 'PosReg', (73, 81))	('HBP', 'Gene', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('prostate cancer', 'Disease', (103, 118))
82691	29702206	TML abundance correlated with two distinct trimethylation marks on histone H3, H3K9me3 and H3K27me3.	('TML', 'Chemical', 'MESH:C003712', (0, 3))	('H3K27me3', 'Var', (91, 99))	('H3K9me3', 'Protein', (79, 86))	('trimethylation marks', 'MPA', (43, 63))	('histone H3', 'Protein', (67, 77))
82692	29702206	Erasing these marks by silencing or inhibiting the methyltransferases SET Domain Bifurcated 1 (SETDB1) and Enhancer Of Zeste Homolog 2 (EZH2) reduced free TML levels and decreased in vitro invasion and in vivo metastasis without impacting subcutaneous tumor growth.	('EZH2', 'Gene', (136, 140))	('inhibiting', 'NegReg', (36, 46))	('EZH2', 'Gene', '2146', (136, 140))	('reduced', 'NegReg', (142, 149))	('SET Domain Bifurcated 1', 'Gene', '9869', (70, 93))	('TML', 'Chemical', 'MESH:C003712', (155, 158))	('silencing', 'Var', (23, 32))	('subcutaneous tumor', 'Disease', (239, 257))	('SETDB1', 'Gene', '9869', (95, 101))	('free TML levels', 'MPA', (150, 165))	('decreased', 'NegReg', (170, 179))	('SET Domain Bifurcated 1', 'Gene', (70, 93))	('Enhancer Of Zeste Homolog 2', 'Gene', '2146', (107, 134))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (239, 257))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('subcutaneous tumor', 'Disease', 'MESH:D013352', (239, 257))	('SETDB1', 'Gene', (95, 101))	('Enhancer Of Zeste Homolog 2', 'Gene', (107, 134))
82717	29702206	Cancer originates from genomic alterations that rewire the landscape of transcriptome, proteome, and metabolome.	('alterations', 'Var', (31, 42))	('landscape', 'MPA', (59, 68))	('rewire', 'Reg', (48, 54))	('al', 'Chemical', 'MESH:D000535', (31, 33))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
82718	29702206	While changes in gene and protein expression have pleiotropic effects on the cell, changes in the metabolome often occur in the closest proximity to changes in cell biology; in other words, many changes in the cellular phenotype are most closely related to changes in metabolic activity downstream of altered transcription and protein function (Figure 4).	('metabolic activity', 'MPA', (268, 286))	('transcription', 'biological_process', 'GO:0006351', ('309', '322'))	('changes', 'Reg', (195, 202))	('changes', 'Var', (6, 13))	('changes', 'Reg', (257, 264))	('al', 'Chemical', 'MESH:D000535', (301, 303))	('protein', 'cellular_component', 'GO:0003675', ('327', '334'))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))
82763	29702206	Isotope tracing has been used extensively to characterize altered metabolic fluxes arising from mutations in tumor suppressors and oncogenes, or resulting from various metabolic stressors in cancer cells.	('metabolic fluxes', 'MPA', (66, 82))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('al', 'Chemical', 'MESH:D000535', (58, 60))	('tumor', 'Disease', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mutations', 'Var', (96, 105))	('altered', 'Reg', (58, 65))
82807	31710966	Furthermore, loss of DEPTOR confers resistance to second-generation mTOR kinase inhibitors through deregulated mTORC1 feedback to IRS-2/PI3K/Akt.	('IRS-2', 'Gene', '8660', (130, 135))	('DEPTOR', 'Gene', '64798', (21, 27))	('mTOR', 'Gene', '2475', (111, 115))	('IRS-2', 'Gene', (130, 135))	('mTOR', 'Gene', (111, 115))	('PI3K', 'molecular_function', 'GO:0016303', ('136', '140'))	('deregulated', 'NegReg', (99, 110))	('resistance', 'MPA', (36, 46))	('mTORC1', 'Gene', '382056', (111, 117))	('mTOR', 'Gene', '2475', (68, 72))	('mTORC1', 'cellular_component', 'GO:0031931', ('111', '117'))	('Akt', 'Gene', (141, 144))	('mTOR', 'Gene', (68, 72))	('Akt', 'Gene', '207', (141, 144))	('DEPTOR', 'Gene', (21, 27))	('loss', 'Var', (13, 17))	('mTORC1', 'Gene', (111, 117))
82808	31710966	This work reveals a hitherto unknown mechanism of resistance to mTOR kinase targeted therapy that is mediated by HIF-dependent reprograming of mTOR/DEPTOR networks and suggests that restoration of DEPTOR in ccRCC will confer sensitivity to mTOR kinase therapeutics.	('mTOR', 'Gene', '2475', (240, 244))	('DEPTOR', 'Gene', (148, 154))	('ccRCC', 'Disease', (207, 212))	('ccRCC', 'Phenotype', 'HP:0006770', (207, 212))	('DEPTOR', 'Gene', (197, 203))	('ccRCC', 'Disease', 'MESH:D002292', (207, 212))	('mTOR', 'Gene', (64, 68))	('restoration', 'Var', (182, 193))	('mTOR', 'Gene', '2475', (64, 68))	('DEPTOR', 'Gene', '64798', (148, 154))	('mTOR', 'Gene', '2475', (143, 147))	('HIF', 'Gene', '405', (113, 116))	('DEPTOR', 'Gene', '64798', (197, 203))	('sensitivity', 'MPA', (225, 236))	('mTOR', 'Gene', (143, 147))	('HIF', 'Gene', (113, 116))	('mTOR', 'Gene', (240, 244))
82816	31710966	Increased mTOR pathway activity is frequently observed in cancers with either mutations found in MTOR or components of the PI3K/Akt signaling pathway.	('mTOR', 'Gene', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('observed', 'Reg', (46, 54))	('Akt signaling', 'biological_process', 'GO:0043491', ('128', '141'))	('Akt', 'Gene', (128, 131))	('MTOR', 'Gene', '2475', (97, 101))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('mutations', 'Var', (78, 87))	('Increased', 'PosReg', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('activity', 'MPA', (23, 31))	('signaling pathway', 'biological_process', 'GO:0007165', ('132', '149'))	('Akt', 'Gene', '207', (128, 131))	('cancers', 'Disease', (58, 65))	('PI3K', 'molecular_function', 'GO:0016303', ('123', '127'))	('mTOR', 'Gene', '2475', (10, 14))	('MTOR', 'Gene', (97, 101))
82820	31710966	The majority of ccRCC tumors are characterized by inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL), which is part of an E3 ligase complex.	('von Hippel-Lindau tumor', 'Disease', 'MESH:D006623', (70, 93))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('von Hippel-Lindau tumor', 'Disease', (70, 93))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('ccRCC', 'Disease', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('ccRCC', 'Disease', 'MESH:D002292', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('pVHL', 'Gene', '7428', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (22, 27))	('pVHL', 'Gene', (114, 118))	('tumor suppressor', 'biological_process', 'GO:0051726', ('88', '104'))	('inactivation', 'Var', (50, 62))	('tumor', 'Disease', (88, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (16, 21))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('88', '104'))
82821	31710966	Defective pVHL leads to stabilization of hypoxia-inducible factors, HIF-1alpha and HIF-2alpha, that regulate transcription of numerous genes involved in cell proliferation, angiogenesis, and metabolism.	('HIF-2alpha', 'Gene', (83, 93))	('pVHL', 'Gene', '7428', (10, 14))	('metabolism', 'biological_process', 'GO:0008152', ('191', '201'))	('pVHL', 'Gene', (10, 14))	('transcription', 'biological_process', 'GO:0006351', ('109', '122'))	('HIF-1alpha', 'Gene', '3091', (68, 78))	('stabilization', 'MPA', (24, 37))	('regulate', 'Reg', (100, 108))	('hypoxia', 'Disease', (41, 48))	('hypoxia', 'Disease', 'MESH:D000860', (41, 48))	('HIF-2alpha', 'Gene', '2034', (83, 93))	('Defective', 'Var', (0, 9))	('angiogenesis', 'biological_process', 'GO:0001525', ('173', '185'))	('cell proliferation', 'biological_process', 'GO:0008283', ('153', '171'))	('HIF-1alpha', 'Gene', (68, 78))	('transcription', 'MPA', (109, 122))
82824	31710966	One puzzle in ccRCC is that neither mutations in components of PI3K/Akt/mTOR pathway nor current understanding of mTOR/HIF signaling can account for all of the elevated mTOR pathway activity found in ccRCC.	('ccRCC', 'Disease', (200, 205))	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('PI3K', 'molecular_function', 'GO:0016303', ('63', '67'))	('ccRCC', 'Phenotype', 'HP:0006770', (200, 205))	('ccRCC', 'Disease', 'MESH:D002292', (14, 19))	('HIF', 'Gene', '405', (119, 122))	('mTOR', 'Gene', (169, 173))	('mTOR', 'Gene', (114, 118))	('ccRCC', 'Disease', (14, 19))	('Akt', 'Gene', (68, 71))	('activity', 'MPA', (182, 190))	('elevated', 'PosReg', (160, 168))	('Akt', 'Gene', '207', (68, 71))	('mTOR', 'Gene', (72, 76))	('mTOR', 'Gene', '2475', (169, 173))	('mTOR', 'Gene', '2475', (114, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (14, 19))	('ccRCC', 'Disease', 'MESH:D002292', (200, 205))	('mTOR', 'Gene', '2475', (72, 76))	('mutations', 'Var', (36, 45))	('HIF', 'Gene', (119, 122))
82838	31710966	Genetic alterations in PI3K/Akt/mTOR pathway components are important contributors to mTOR activation in renal cancer.	('Genetic alterations', 'Var', (0, 19))	('Akt', 'Gene', (28, 31))	('mTOR', 'Gene', '2475', (86, 90))	('mTOR', 'Gene', '2475', (32, 36))	('mTOR', 'Gene', (86, 90))	('activation', 'PosReg', (91, 101))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mTOR', 'Gene', (32, 36))	('renal cancer', 'Disease', (105, 117))	('Akt', 'Gene', '207', (28, 31))	('renal cancer', 'Phenotype', 'HP:0009726', (105, 117))	('PI3K', 'molecular_function', 'GO:0016303', ('23', '27'))	('renal cancer', 'Disease', 'MESH:D007680', (105, 117))
82839	31710966	However, mutations in PI3K/Akt/mTOR proteins do not account for the widespread increase in mTOR pathway activity found in tumors.	('increase', 'PosReg', (79, 87))	('mTOR', 'Gene', (31, 35))	('mTOR', 'Gene', '2475', (31, 35))	('activity', 'MPA', (104, 112))	('mutations', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('Akt', 'Gene', '207', (27, 30))	('PI3K', 'molecular_function', 'GO:0016303', ('22', '26'))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mTOR', 'Gene', (91, 95))	('mTOR', 'Gene', '2475', (91, 95))	('Akt', 'Gene', (27, 30))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', (122, 127))
82845	31710966	As expected, AZD2014 decreased phosphorylation of mTORC1 and mTORC2 substrates, S6K1 and Akt respectively, in both VHL-deficient and VHL-competent cells.	('mTORC2', 'cellular_component', 'GO:0031932', ('61', '67'))	('AZD2014', 'Chemical', 'MESH:C585537', (13, 20))	('mTORC2', 'Gene', (61, 67))	('VHL-deficient and VHL-competent', 'Disease', 'MESH:D006623', (115, 146))	('decreased', 'NegReg', (21, 30))	('mTORC1', 'Gene', (50, 56))	('mTORC2', 'Gene', '74343', (61, 67))	('mTORC1', 'cellular_component', 'GO:0031931', ('50', '56'))	('phosphorylation', 'MPA', (31, 46))	('phospho', 'Chemical', 'MESH:C033601', (31, 38))	('AZD2014', 'Var', (13, 20))	('mTORC1', 'Gene', '382056', (50, 56))	('S6K1 and Akt', 'Gene', '6198;207', (80, 92))	('phosphorylation', 'biological_process', 'GO:0016310', ('31', '46'))
82846	31710966	mTOR kinase ablation increased DEPTOR protein accumulation in VHL-expressing cells only (786-O/VHL and RCC4/VHL), as previously shown in other cell types that are also VHL wild type, indicating that mTOR activity was not responsible for the low levels of DEPTOR observed in VHL-deficient cells (786-O and RCC4).	('ablation', 'Var', (12, 20))	('VHL', 'Gene', '7428', (95, 98))	('VHL', 'Gene', '7428', (62, 65))	('VHL', 'Gene', (108, 111))	('increased', 'PosReg', (21, 30))	('RCC4', 'Gene', (305, 309))	('VHL', 'Gene', (274, 277))	('DEPTOR', 'Gene', '64798', (255, 261))	('786-O', 'Chemical', 'MESH:C002925', (295, 300))	('786-O', 'Chemical', 'MESH:C002925', (89, 94))	('VHL-deficient', 'Disease', (274, 287))	('RCC4', 'Gene', '84925', (305, 309))	('mTOR', 'Gene', (0, 4))	('mTOR', 'Gene', (199, 203))	('VHL', 'Gene', '7428', (108, 111))	('DEPTOR', 'Gene', '64798', (31, 37))	('RCC4', 'Gene', (103, 107))	('VHL', 'Gene', (168, 171))	('VHL', 'Gene', '7428', (274, 277))	('DEPTOR', 'Gene', (255, 261))	('mTOR', 'Gene', '2475', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('mTOR', 'Gene', '2475', (199, 203))	('VHL', 'Gene', (95, 98))	('RCC4', 'Gene', '84925', (103, 107))	('VHL-deficient', 'Disease', 'MESH:D006623', (274, 287))	('VHL', 'Gene', (62, 65))	('VHL', 'Gene', '7428', (168, 171))	('DEPTOR', 'Gene', (31, 37))
82848	31710966	This was supported by results showing that addition of the proteasome inhibitor, MG132, had no effect on DEPTOR protein levels in VHL-deficient 786-O cells (Figure S1B), supporting the suggestion that DEPTOR is not suppressed by posttranslational mechanisms in VHL-deficient renal cells.	('DEPTOR', 'Gene', (201, 207))	('MG132', 'Var', (81, 86))	('VHL-deficient', 'Disease', 'MESH:D006623', (130, 143))	('DEPTOR', 'Gene', (105, 111))	('VHL-deficient', 'Disease', (130, 143))	('proteasome', 'molecular_function', 'GO:0004299', ('59', '69'))	('proteasome', 'cellular_component', 'GO:0000502', ('59', '69'))	('DEPTOR', 'Gene', '64798', (201, 207))	('VHL-deficient renal cells', 'Disease', 'MESH:D006623', (261, 286))	('786-O', 'Chemical', 'MESH:C002925', (144, 149))	('DEPTOR', 'Gene', '64798', (105, 111))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('VHL-deficient', 'Disease', (261, 274))	('VHL-deficient renal cells', 'Disease', (261, 286))	('VHL-deficient', 'Disease', 'MESH:D006623', (261, 274))	('MG132', 'Chemical', 'MESH:C072553', (81, 86))
82849	31710966	Loss of pVHL leads to stabilization of the transcription factors HIF-1alpha and HIF-2alpha, due to defective pVHL-mediated degradation of HIF-alpha subunits.	('degradation', 'biological_process', 'GO:0009056', ('123', '134'))	('defective', 'NegReg', (99, 108))	('HIF', 'Gene', '405', (65, 68))	('pVHL', 'Gene', '7428', (8, 12))	('pVHL', 'Gene', '7428', (109, 113))	('pVHL', 'Gene', (8, 12))	('pVHL', 'Gene', (109, 113))	('HIF', 'Gene', (80, 83))	('HIF-2alpha', 'Gene', '2034', (80, 90))	('transcription', 'biological_process', 'GO:0006351', ('43', '56'))	('degradation', 'MPA', (123, 134))	('HIF-1alpha', 'Gene', '3091', (65, 75))	('HIF', 'Gene', '405', (80, 83))	('stabilization', 'MPA', (22, 35))	('HIF', 'Gene', (138, 141))	('Loss', 'Var', (0, 4))	('HIF-2alpha', 'Gene', (80, 90))	('HIF-1alpha', 'Gene', (65, 75))	('HIF', 'Gene', (65, 68))	('HIF', 'Gene', '405', (138, 141))
82851	31710966	Inhibition of HIF-2 activity by PT2385 was confirmed by measurement of HIF-2 specific target genes, vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), and plasminogen activator inhibitor-1 (PAI-1), which were all significantly downregulated, demonstrating the expected effect of HIF-2 inhibition (Figure S1C).	('downregulated', 'NegReg', (240, 253))	('HIF', 'Gene', (292, 295))	('HIF', 'Gene', '405', (71, 74))	('HIF', 'Gene', '405', (292, 295))	('HIF', 'Gene', (14, 17))	('endothelin-1', 'Gene', '1906', (143, 155))	('vascular endothelial growth factor', 'Gene', '7422', (100, 134))	('PAI-1', 'Gene', '5054', (203, 208))	('plasminogen activator inhibitor-1', 'Gene', (168, 201))	('VEGF', 'Gene', '7422', (136, 140))	('endothelin-1', 'Gene', (143, 155))	('PAI-1', 'Gene', (203, 208))	('HIF', 'Gene', '405', (14, 17))	('vascular endothelial growth factor', 'Gene', (100, 134))	('plasminogen activator inhibitor-1', 'Gene', '5054', (168, 201))	('ET-1', 'Gene', '1906', (157, 161))	('VEGF', 'Gene', (136, 140))	('ET-1', 'Gene', (157, 161))	('activity', 'MPA', (20, 28))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('100', '134'))	('HIF', 'Gene', (71, 74))	('PT2385', 'Var', (32, 38))
82852	31710966	PT2385 treatment of both 786-O and RCC4 cells resulted in a marked increase in DEPTOR mRNA and protein (Figures 2B and 2C).	('PT2385', 'Var', (0, 6))	('DEPTOR', 'Gene', '64798', (79, 85))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('RCC4', 'Gene', (35, 39))	('increase', 'PosReg', (67, 75))	('RCC4', 'Gene', '84925', (35, 39))	('786-O', 'Chemical', 'MESH:C002925', (25, 30))	('DEPTOR', 'Gene', (79, 85))
82853	31710966	PT2385 also inhibited HIF-2alpha protein accumulation, which has been noted previously.	('inhibited', 'NegReg', (12, 21))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('PT2385', 'Var', (0, 6))	('HIF-2alpha', 'Gene', (22, 32))	('HIF-2alpha', 'Gene', '2034', (22, 32))
82856	31710966	Both HIF-1alpha and HIF-2alpha inhibition increased DEPTOR mRNA and protein, indicating that DEPTOR is suppressed by both HIFs in ccRCC (Figures 2D and 2E).	('ccRCC', 'Phenotype', 'HP:0006770', (130, 135))	('HIF', 'Gene', '405', (122, 125))	('HIF-1alpha', 'Gene', '3091', (5, 15))	('suppressed', 'NegReg', (103, 113))	('HIF-2alpha', 'Gene', (20, 30))	('DEPTOR', 'Gene', (52, 58))	('DEPTOR', 'Gene', (93, 99))	('HIF-1alpha', 'Gene', (5, 15))	('increased', 'PosReg', (42, 51))	('HIF', 'Gene', (5, 8))	('HIF', 'Gene', (20, 23))	('ccRCC', 'Disease', 'MESH:D002292', (130, 135))	('inhibition', 'Var', (31, 41))	('HIF', 'Gene', '405', (5, 8))	('HIF-2alpha', 'Gene', '2034', (20, 30))	('DEPTOR', 'Gene', '64798', (52, 58))	('HIF', 'Gene', (122, 125))	('HIF', 'Gene', '405', (20, 23))	('ccRCC', 'Disease', (130, 135))	('DEPTOR', 'Gene', '64798', (93, 99))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))
82872	31710966	Inhibition of BHLHe40 led to increased DEPTOR accumulation in 786-O and RCC4 VHL-deficient cells (Figure 3I).	('DEPTOR', 'Gene', (39, 45))	('RCC4', 'Gene', '84925', (72, 76))	('VHL-deficient', 'Disease', (77, 90))	('BHLHe40', 'Gene', '8553', (14, 21))	('increased', 'PosReg', (29, 38))	('VHL-deficient', 'Disease', 'MESH:D006623', (77, 90))	('DEPTOR', 'Gene', '64798', (39, 45))	('RCC4', 'Gene', (72, 76))	('Inhibition', 'Var', (0, 10))	('786-O', 'Chemical', 'MESH:C002925', (62, 67))	('BHLHe40', 'Gene', (14, 21))
82879	31710966	In line with our previous results, ablation of HIFs either by siRNAs or with PT2385 increased DEPTOR accumulation (Figures 4A-4C).	('HIF', 'Gene', (47, 50))	('DEPTOR', 'Gene', (94, 100))	('HIF', 'Gene', '405', (47, 50))	('DEPTOR', 'Gene', '64798', (94, 100))	('increased', 'PosReg', (84, 93))	('PT2385', 'Gene', (77, 83))	('ablation', 'Var', (35, 43))
82880	31710966	The most significant change upon inhibition of HIFs was mTOR phosphorylation directly at ser2448, which was notably attenuated.	('HIF', 'Gene', (47, 50))	('mTOR', 'Gene', (56, 60))	('HIF', 'Gene', '405', (47, 50))	('mTOR', 'Gene', '2475', (56, 60))	('ser2448', 'Var', (89, 96))	('inhibition', 'NegReg', (33, 43))	('phospho', 'Chemical', 'MESH:C033601', (61, 68))	('ser', 'cellular_component', 'GO:0005790', ('89', '92'))	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))
82881	31710966	By contrast, mTOR phosphorylation at ser2481 was unaffected.	('ser2481', 'Var', (37, 44))	('mTOR', 'Gene', (13, 17))	('ser', 'cellular_component', 'GO:0005790', ('37', '40'))	('mTOR', 'Gene', '2475', (13, 17))	('phospho', 'Chemical', 'MESH:C033601', (18, 25))	('phosphorylation', 'biological_process', 'GO:0016310', ('18', '33'))
82884	31710966	Loss of DEPTOR increased ser2448 phosphorylation in VHL-expressing cells (Figure 4D).	('VHL', 'Gene', '7428', (52, 55))	('ser2448', 'Protein', (25, 32))	('DEPTOR', 'Gene', (8, 14))	('ser', 'cellular_component', 'GO:0005790', ('25', '28'))	('phospho', 'Chemical', 'MESH:C033601', (33, 40))	('increased', 'PosReg', (15, 24))	('DEPTOR', 'Gene', '64798', (8, 14))	('phosphorylation', 'biological_process', 'GO:0016310', ('33', '48'))	('Loss', 'Var', (0, 4))	('VHL', 'Gene', (52, 55))
82885	31710966	Together, these results suggest that HIFs have divergent effects on mTOR signaling and that HIF-mediated downregulation of DEPTOR in ccRCC increases mTOR phosphorylation specifically at ser2448.	('mTOR', 'Gene', '2475', (149, 153))	('ccRCC', 'Disease', 'MESH:D002292', (133, 138))	('mTOR', 'Gene', '2475', (68, 72))	('ser', 'cellular_component', 'GO:0005790', ('186', '189'))	('increases', 'PosReg', (139, 148))	('ser2448', 'Var', (186, 193))	('ccRCC', 'Disease', (133, 138))	('signaling', 'biological_process', 'GO:0023052', ('73', '82'))	('DEPTOR', 'Gene', (123, 129))	('HIF', 'Gene', (37, 40))	('HIF', 'Gene', (92, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('phospho', 'Chemical', 'MESH:C033601', (154, 161))	('HIF', 'Gene', '405', (92, 95))	('HIF', 'Gene', '405', (37, 40))	('phosphorylation', 'biological_process', 'GO:0016310', ('154', '169'))	('downregulation', 'NegReg', (105, 119))	('mTOR', 'Gene', (149, 153))	('mTOR', 'Gene', (68, 72))	('DEPTOR', 'Gene', '64798', (123, 129))
82887	31710966	To test this, we restored DEPTOR expression in ccRCC cells and found that re-expression of DEPTOR inhibited ccRCC growth in a colony formation assay (Figures 5A-5C).	('ccRCC', 'Disease', (108, 113))	('ccRCC', 'Disease', 'MESH:D002292', (108, 113))	('formation', 'biological_process', 'GO:0009058', ('133', '142'))	('inhibited', 'NegReg', (98, 107))	('ccRCC', 'Disease', (47, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('re-expression', 'Var', (74, 87))	('DEPTOR', 'Gene', (26, 32))	('DEPTOR', 'Gene', (91, 97))	('ccRCC', 'Disease', 'MESH:D002292', (47, 52))	('DEPTOR', 'Gene', '64798', (91, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('DEPTOR', 'Gene', '64798', (26, 32))
82892	31710966	Specifically, the mTORC1 substrate, S6K1, phosphorylates IRS-1 at S636/639 to promote its degradation, which in turn, reduces PI3K/Akt signaling.	('degradation', 'MPA', (90, 101))	('mTORC1', 'Gene', (18, 24))	('promote', 'PosReg', (78, 85))	('Akt', 'Gene', (131, 134))	('mTORC1', 'cellular_component', 'GO:0031931', ('18', '24'))	('IRS-1', 'Gene', '3667', (57, 62))	('phospho', 'Chemical', 'MESH:C033601', (42, 49))	('reduces', 'NegReg', (118, 125))	('mTORC1', 'Gene', '382056', (18, 24))	('S636/639', 'Var', (66, 74))	('IRS-1', 'Gene', (57, 62))	('Akt signaling', 'biological_process', 'GO:0043491', ('131', '144'))	('PI3K', 'molecular_function', 'GO:0016303', ('126', '130'))	('degradation', 'biological_process', 'GO:0009056', ('90', '101'))	('S6K1', 'Gene', (36, 40))	('S6K1', 'Gene', '6198', (36, 40))	('Akt', 'Gene', '207', (131, 134))
82895	31710966	Conversely, knock down of DEPTOR reduces Akt phosphorylation as mTORC1 is active and negative feedback is predominant.	('mTORC1', 'Gene', '382056', (64, 70))	('DEPTOR', 'Gene', '64798', (26, 32))	('mTORC1', 'cellular_component', 'GO:0031931', ('64', '70'))	('DEPTOR', 'Gene', (26, 32))	('mTORC1', 'Gene', (64, 70))	('knock down', 'Var', (12, 22))	('Akt', 'Gene', '207', (41, 44))	('Akt', 'Gene', (41, 44))	('phospho', 'Chemical', 'MESH:C033601', (45, 52))	('reduces', 'NegReg', (33, 40))	('phosphorylation', 'biological_process', 'GO:0016310', ('45', '60'))
82906	31710966	Consistent with this assumption, reintroduction of DEPTOR in VHL-deficient ccRCC cells significantly enhanced the efficacy of the mTOR kinase inhibitor, AZD2014, to prevent cell proliferation (Figures 7A and 7B).	('kinase inhibitor', 'biological_process', 'GO:0033673', ('135', '151'))	('DEPTOR', 'Gene', (51, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('ccRCC', 'Disease', (75, 80))	('AZD2014', 'Chemical', 'MESH:C585537', (153, 160))	('cell proliferation', 'biological_process', 'GO:0008283', ('173', '191'))	('reintroduction', 'Var', (33, 47))	('VHL-deficient', 'Disease', 'MESH:D006623', (61, 74))	('DEPTOR', 'Gene', '64798', (51, 57))	('VHL-deficient', 'Disease', (61, 74))	('ccRCC', 'Disease', 'MESH:D002292', (75, 80))	('enhanced', 'PosReg', (101, 109))	('mTOR', 'Gene', (130, 134))	('mTOR', 'Gene', '2475', (130, 134))	('efficacy', 'MPA', (114, 122))	('cell proliferation', 'CPA', (173, 191))
82911	31710966	We further show that loss of DEPTOR leads to deregulated negative feedback to PI3K/Akt in ccRCC and resistance to second-generation mTOR kinase inhibitors that block both mTORC1 and mTORC2/Akt.	('mTOR', 'Gene', '2475', (182, 186))	('mTOR', 'Gene', '2475', (132, 136))	('DEPTOR', 'Gene', (29, 35))	('mTORC1', 'cellular_component', 'GO:0031931', ('171', '177'))	('resistance', 'MPA', (100, 110))	('mTOR', 'Gene', '2475', (171, 175))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('PI3K', 'molecular_function', 'GO:0016303', ('78', '82'))	('loss', 'Var', (21, 25))	('Akt', 'Gene', (189, 192))	('mTORC2', 'Gene', (182, 188))	('Akt', 'Gene', '207', (189, 192))	('mTORC2', 'cellular_component', 'GO:0031932', ('182', '188'))	('Akt', 'Gene', (83, 86))	('DEPTOR', 'Gene', '64798', (29, 35))	('mTORC2', 'Gene', '74343', (182, 188))	('Akt', 'Gene', '207', (83, 86))	('mTOR', 'Gene', (182, 186))	('ccRCC', 'Disease', 'MESH:D002292', (90, 95))	('deregulated negative feedback', 'MPA', (45, 74))	('mTOR', 'Gene', (132, 136))	('mTORC1', 'Gene', (171, 177))	('mTOR', 'Gene', (171, 175))	('ccRCC', 'Disease', (90, 95))	('mTORC1', 'Gene', '382056', (171, 177))
82926	31710966	In support of this notion, some activating mutations in mTOR in kidney cancer reduce binding to DEPTOR, further suggesting that DEPTOR is important in negatively regulating mTOR in ccRCC.	('mTOR', 'Gene', '2475', (173, 177))	('ccRCC', 'Disease', 'MESH:D002292', (181, 186))	('kidney cancer', 'Disease', 'MESH:D007680', (64, 77))	('activating', 'PosReg', (32, 42))	('binding', 'molecular_function', 'GO:0005488', ('85', '92'))	('reduce', 'NegReg', (78, 84))	('DEPTOR', 'Gene', '64798', (96, 102))	('ccRCC', 'Disease', (181, 186))	('DEPTOR', 'Gene', '64798', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('kidney cancer', 'Phenotype', 'HP:0009726', (64, 77))	('kidney cancer', 'Disease', (64, 77))	('mTOR', 'Gene', (56, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (181, 186))	('DEPTOR', 'Gene', (96, 102))	('DEPTOR', 'Gene', (128, 134))	('negatively', 'NegReg', (151, 161))	('mTOR', 'Gene', '2475', (56, 60))	('mutations', 'Var', (43, 52))	('mTOR', 'Gene', (173, 177))	('binding', 'Interaction', (85, 92))
82928	31710966	Our results are consistent with these reports, since we show that reintroduction of DEPTOR in ccRCC cells increases Akt activity and that loss of DEPTOR inhibits Akt signaling.	('ccRCC', 'Disease', (94, 99))	('ccRCC', 'Disease', 'MESH:D002292', (94, 99))	('loss', 'Var', (138, 142))	('DEPTOR', 'Gene', (84, 90))	('Akt', 'Gene', (162, 165))	('DEPTOR', 'Gene', (146, 152))	('Akt', 'Gene', '207', (116, 119))	('Akt signaling', 'biological_process', 'GO:0043491', ('162', '175'))	('DEPTOR', 'Gene', '64798', (84, 90))	('DEPTOR', 'Gene', '64798', (146, 152))	('reintroduction', 'Var', (66, 80))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('increases', 'PosReg', (106, 115))	('Akt', 'Gene', (116, 119))	('inhibits', 'NegReg', (153, 161))	('Akt', 'Gene', '207', (162, 165))
82935	31710966	We could show that reintroduction of DEPTOR in VHL-deficient cells significantly enhanced the efficacy of AZD2014, whereas DEPTOR had no effect on the efficacy of rapamycin.	('rapamycin', 'Chemical', 'MESH:D020123', (163, 172))	('efficacy', 'MPA', (94, 102))	('enhanced', 'PosReg', (81, 89))	('DEPTOR', 'Gene', (37, 43))	('VHL-deficient', 'Disease', 'MESH:D006623', (47, 60))	('VHL-deficient', 'Disease', (47, 60))	('DEPTOR', 'Gene', '64798', (37, 43))	('DEPTOR', 'Gene', (123, 129))	('AZD2014', 'Var', (106, 113))	('AZD2014', 'Chemical', 'MESH:C585537', (106, 113))	('DEPTOR', 'Gene', '64798', (123, 129))
82945	32281285	SNHG5 knockdown obviously suppressed the proliferative, migratory, and invasive capabilities of ccRCC cells, whereas SNHG5 overexpression induced the opposite effects.	('suppressed', 'NegReg', (26, 36))	('SNHG5', 'Gene', (0, 5))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('invasive capabilities of', 'CPA', (71, 95))	('rat', 'Species', '10116', (59, 62))	('proliferative', 'CPA', (41, 54))	('knockdown', 'Var', (6, 15))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('migratory', 'CPA', (56, 65))	('rat', 'Species', '10116', (48, 51))
82946	32281285	Mechanistically, SNHG5 activated the transcription of ZEB1, which exerts a pivotal role in modulation of epithelia-mesenchymal transition (EMT) and tumor metastasis.	('epithelia-mesenchymal transition', 'CPA', (105, 137))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('SNHG5', 'Var', (17, 22))	('activated', 'PosReg', (23, 32))	('tumor', 'Disease', (148, 153))	('ZEB1', 'Gene', (54, 58))	('ZEB1', 'Gene', '6935', (54, 58))	('transcription', 'biological_process', 'GO:0006351', ('37', '50'))	('EMT', 'biological_process', 'GO:0001837', ('139', '142'))	('transcription', 'MPA', (37, 50))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
82949	32281285	Additionally, in vivo assays further indicated that overexpression or silencing of SNHG5 in ccRCC cells promoted or suppressed the tumorigenesis and metastasis, respectively.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('metastasis', 'CPA', (149, 159))	('RCC', 'Disease', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('suppressed', 'NegReg', (116, 126))	('silencing', 'Var', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('SNHG5', 'Gene', (83, 88))	('promoted', 'PosReg', (104, 112))
82952	32281285	Overexpression of SNHG5 facilitates ccRCC progression, whereas knockdown of SNHG5 exerts the opposite effect.	('RCC', 'Disease', (38, 41))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('facilitates', 'PosReg', (24, 35))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('SNHG5', 'Gene', (18, 23))	('SNHG5', 'Gene', (76, 81))	('knockdown', 'Var', (63, 72))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
82960	32281285	It has been well documented that the dysregulation of long noncoding RNAs (lncRNAs) can contribute to the tumorigenesis and development of human carcinomas.	('dysregulation', 'Var', (37, 50))	('contribute', 'Reg', (88, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('carcinomas', 'Disease', 'MESH:D009369', (145, 155))	('carcinomas', 'Phenotype', 'HP:0030731', (145, 155))	('carcinomas', 'Disease', (145, 155))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('long noncoding RNAs', 'Protein', (54, 73))	('human', 'Species', '9606', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('development', 'CPA', (124, 135))	('tumor', 'Disease', (106, 111))
82961	32281285	LncRNAs play vital roles in the processes of transcriptional regulation, posttranscriptional modulation, and epigenetic modification and thus affect biological behaviors of human cancer cells.	('epigenetic modification', 'Var', (109, 132))	('affect', 'Reg', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('human', 'Species', '9606', (173, 178))	('regulation', 'biological_process', 'GO:0065007', ('61', '71'))	('cancer', 'Disease', (179, 185))
82964	32281285	6  The aberrant expression of HOTAIR was also confirmed to promote ccRCC malignancy by several groups.	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('aberrant expression', 'Var', (7, 26))	('ccRCC malignancy', 'Disease', (67, 83))	('HOTAIR', 'Gene', (30, 36))	('promote', 'PosReg', (59, 66))	('ccRCC malignancy', 'Disease', 'MESH:D009369', (67, 83))	('HOTAIR', 'Gene', '100124700', (30, 36))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
82971	32281285	Deregulation of SNHG5 was demonstrated to affect the miR-205-5p/ZEB1 signaling axis, which has been implicated in modulating the proliferation, migration, and invasion of ccRCC cells.	('affect', 'Reg', (42, 48))	('miR-205-5p', 'Chemical', '-', (53, 63))	('SNHG5', 'Gene', (16, 21))	('RCC', 'Disease', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('Deregulation', 'Var', (0, 12))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('ccRCC', 'Phenotype', 'HP:0006770', (171, 176))	('ZEB1', 'Gene', '6935', (64, 68))	('signaling', 'biological_process', 'GO:0023052', ('69', '78'))	('ZEB1', 'Gene', (64, 68))	('rat', 'Species', '10116', (33, 36))	('rat', 'Species', '10116', (147, 150))	('invasion', 'CPA', (159, 167))	('rat', 'Species', '10116', (136, 139))	('migration', 'CPA', (144, 153))
82988	32281285	The siRNA sequences were as below: si-SNHG5, 5'-AGUAAUAACAAAAAGGAACAU-3'; si-ZEB1, 5'-GGATAAAGAGATGGAAGAA-3'.	('ZEB1', 'Gene', '6935', (77, 81))	('ZEB1', 'Gene', (77, 81))	('si-SNHG5', 'Var', (35, 43))
82997	32281285	The antibodies against E-cadherin (#4065), vimentin (#3932), MMP2 (#4022), and GAPDH (D16H11) were procured from Cell Signaling Technology.	('vimentin', 'cellular_component', 'GO:0045098', ('43', '51'))	('MMP2', 'Gene', (61, 65))	('Signaling', 'biological_process', 'GO:0023052', ('118', '127'))	('#4065', 'Var', (35, 40))	('GAPDH', 'Gene', (79, 84))	('MMP2', 'Gene', '4313', (61, 65))	('E-cadherin', 'Gene', (23, 33))	('E-cadherin', 'Gene', '999', (23, 33))	('vimentin', 'Gene', '7431', (43, 51))	('vimentin', 'Gene', (43, 51))	('cadherin', 'molecular_function', 'GO:0008014', ('25', '33'))	('vimentin', 'cellular_component', 'GO:0045099', ('43', '51'))	('#4022', 'Var', (67, 72))	('MMP2', 'molecular_function', 'GO:0004228', ('61', '65'))	('#3932', 'Var', (53, 58))	('GAPDH', 'Gene', '2597', (79, 84))
83008	32281285	Synthetic fragments of SNHG5 sequence with the predicted binding sites of miR-205-5p or mutant type and ZEB1 3'-untranslated region (UTR) sequences with wild-type or mutant miR-205-5p-binding sites were cloned into pMIR-REPORT luciferase plasmids.	('SNHG5', 'Gene', (23, 28))	('miR-205-5p', 'Chemical', '-', (173, 183))	('binding', 'molecular_function', 'GO:0005488', ('184', '191'))	('miR-205-5p', 'Chemical', '-', (74, 84))	('miR-205-5p', 'Gene', (74, 84))	('mutant', 'Var', (166, 172))	('ZEB1', 'Gene', '6935', (104, 108))	('binding', 'molecular_function', 'GO:0005488', ('57', '64'))	('ZEB1', 'Gene', (104, 108))
83011	32281285	ACHN cells (4 x 106) stably expressing sh-SNHG5, sh-NC, pcDNA3.1/SNHG5, or pcDNA3.1/Con were implanted subcutaneously in female nude mice (aged 5 weeks, n = 5 in each group).	('nude mice', 'Species', '10090', (128, 137))	('sh-SNHG5', 'Gene', (39, 47))	('pcDNA3.1/SNHG5', 'Var', (56, 70))	('sh-NC', 'Gene', (49, 54))	('ACHN', 'Gene', '55323', (0, 4))	('ACHN', 'Gene', (0, 4))	('sh-SNHG5', 'Gene', '72655', (39, 47))
83023	32281285	In addition, SNHG5 was preferentially distributed within the ccRCC cell cytoplasm.	('RCC', 'Disease', (63, 66))	('SNHG5', 'Var', (13, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('preferentially', 'PosReg', (23, 37))	('cytoplasm', 'cellular_component', 'GO:0005737', ('72', '81'))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
83025	32281285	Together, these data may implicate the aberrant expression of SNHG5 in the tumorigenesis and progression of human ccRCC.	('aberrant', 'Var', (39, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('implicate', 'Reg', (25, 34))	('human', 'Species', '9606', (108, 113))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('SNHG5', 'Gene', (62, 67))	('RCC', 'Disease', (116, 119))	('progression', 'CPA', (93, 104))	('tumor', 'Disease', (75, 80))
83027	32281285	As presented in Figure 2A, SNHG5 expression was substantially reduced in the siRNA-mediated knockdown group compared to the scrambled negative control (si-Control) group of ACHN cells.	('ACHN', 'Gene', '55323', (173, 177))	('knockdown', 'Var', (92, 101))	('ACHN', 'Gene', (173, 177))	('SNHG5', 'Gene', (27, 32))	('expression', 'MPA', (33, 43))	('reduced', 'NegReg', (62, 69))
83028	32281285	The CCK-8 assay revealed that SNHG5 silencing markedly repressed the proliferation of ACHN cells, whereas the ectopic overexpression of SNHG5 promoted the proliferative ability of 786-O cells (Figure 2B,C).	('ACHN', 'Gene', (86, 90))	('rat', 'Species', '10116', (162, 165))	('proliferation', 'CPA', (69, 82))	('rat', 'Species', '10116', (76, 79))	('repressed', 'NegReg', (55, 64))	('SNHG5', 'Gene', (30, 35))	('SNHG5', 'Gene', (136, 141))	('proliferative ability', 'CPA', (155, 176))	('silencing', 'Var', (36, 45))	('promoted', 'PosReg', (142, 150))	('ACHN', 'Gene', '55323', (86, 90))
83029	32281285	Subsequently, wound-healing experiments indicated that the silencing of SNHG5 remarkably hampered the migration of ACHN cells, while SNHG5 overexpression enhanced the migratory abilities of 786-O cells (Figure 2D).	('hampered', 'NegReg', (89, 97))	('ACHN', 'Gene', (115, 119))	('wound-healing', 'biological_process', 'GO:0042060', ('14', '27'))	('enhanced', 'PosReg', (154, 162))	('rat', 'Species', '10116', (105, 108))	('rat', 'Species', '10116', (170, 173))	('ACHN', 'Gene', '55323', (115, 119))	('SNHG5', 'Gene', (72, 77))	('migratory abilities of 786-O cells', 'CPA', (167, 201))	('silencing', 'Var', (59, 68))	('SNHG5', 'Var', (133, 138))
83032	32281285	An EMT-like phenotype was induced by SNHG5 silencing in ACHN cells, whereas SNHG5 overexpression exerted the opposite effect on 786-O cells (Figure 2F).	('ACHN', 'Gene', (56, 60))	('EMT', 'biological_process', 'GO:0001837', ('3', '6'))	('silencing', 'NegReg', (43, 52))	('SNHG5', 'Var', (37, 42))	('ACHN', 'Gene', '55323', (56, 60))	('EMT-like phenotype', 'CPA', (3, 21))
83033	32281285	In the flat plate clone formation assay, knockdown of SNHG5 obviously inhibited the formation of ACHN cell colonies, whereas restoration of SNHG5 significantly facilitated the formation of 786-O cell colonies (Figure 2G).	('ACHN', 'Gene', (97, 101))	('facilitated', 'PosReg', (160, 171))	('formation', 'biological_process', 'GO:0009058', ('176', '185'))	('SNHG5', 'Gene', (54, 59))	('SNHG5', 'Gene', (140, 145))	('restoration', 'Var', (125, 136))	('formation of 786-O cell colonies', 'CPA', (176, 208))	('rat', 'Species', '10116', (130, 133))	('formation', 'biological_process', 'GO:0009058', ('84', '93'))	('inhibited', 'NegReg', (70, 79))	('ACHN', 'Gene', '55323', (97, 101))	('knockdown', 'Var', (41, 50))	('formation', 'biological_process', 'GO:0009058', ('24', '33'))
83035	32281285	Conversely, restoration of SNHG5 had the opposite effect on 786-O cells (Figure 2H).	('restoration', 'Var', (12, 23))	('SNHG5', 'Gene', (27, 32))	('rat', 'Species', '10116', (17, 20))
83036	32281285	These outcomes suggest that SNHG5 can promote ccRCC progression by affecting cell proliferation, migration, and invasion.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('affecting', 'Reg', (67, 76))	('SNHG5', 'Var', (28, 33))	('migration', 'CPA', (97, 106))	('cell proliferation', 'biological_process', 'GO:0008283', ('77', '95'))	('invasion', 'CPA', (112, 120))	('rat', 'Species', '10116', (89, 92))	('promote', 'PosReg', (38, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('rat', 'Species', '10116', (100, 103))	('cell proliferation', 'CPA', (77, 95))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
83038	32281285	SNHG5 silencing significantly suppressed tumor cell growth in vivo and exerted an obvious reduction in tumor volume and weight as compared with those of the control group (sh-NC); however, the transfection of ccRCC cells with pcDNA3.1/SNHG5 vector had an opposite effect when compared with the control group (Figure 3A-C).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('reduction', 'NegReg', (90, 99))	('RCC', 'Disease', (211, 214))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', (103, 108))	('SNHG5', 'Gene', (0, 5))	('suppressed', 'NegReg', (30, 40))	('RCC', 'Disease', 'MESH:C538614', (211, 214))	('RCC', 'Phenotype', 'HP:0005584', (211, 214))	('ccRCC', 'Phenotype', 'HP:0006770', (209, 214))	('cell growth', 'biological_process', 'GO:0016049', ('47', '58'))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('silencing', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
83042	32281285	A qRT-PCR assay was applied to validate the expression levels of candidate miRNAs in ccRCC cells transfected with si-SNHG5, si-NC, pcDNA3.1/SNHG5, or pcDNA3.1/Con.	('si-SNHG5', 'Var', (114, 122))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('pcDNA3.1/SNHG5', 'Var', (131, 145))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('si-NC', 'Var', (124, 129))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
83043	32281285	The results revealed that only miR-205-5p expression exhibited an obvious change in both transfected ccRCC cell lines (Figure 4A,B).	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('miR-205-5p', 'Var', (31, 41))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('miR-205-5p', 'Chemical', '-', (31, 41))
83046	32281285	Both SNHG5 and miR-205-5p were highly enriched in Ago2 immunoprecipitates compared to control IgG immunoprecipitates.	('Ago2', 'Gene', '27161', (50, 54))	('miR-205-5p', 'Var', (15, 25))	('Ago2', 'Gene', (50, 54))	('SNHG5', 'Var', (5, 10))	('miR-205-5p', 'Chemical', '-', (15, 25))
83047	32281285	Of note, low expression of miR-205-5p was observed in the four ccRCC-derived cell lines examined (ACHN, 786-O, A498, and SN12-PM6) than in HK-2 cells (Figure 4D).	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('expression', 'MPA', (13, 23))	('RCC', 'Disease', (65, 68))	('HK-2', 'CellLine', 'CVCL:0302', (139, 143))	('ACHN', 'Gene', '55323', (98, 102))	('HK-2', 'molecular_function', 'GO:0008256', ('139', '143'))	('ACHN', 'Gene', (98, 102))	('miR-205-5p', 'Chemical', '-', (27, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('miR-205-5p', 'Var', (27, 37))
83050	32281285	Interestingly, ZEB1 transcript was the only one among the analyzed candidates that were differentially expressed in miR-205-5p mimic-transfected ACHN cells or miR-205-5p inhibitor-transfected 786-O cells (Figure 4E,F).	('ZEB1', 'Gene', '6935', (15, 19))	('ACHN', 'Gene', (145, 149))	('ZEB1', 'Gene', (15, 19))	('miR-205-5p', 'Chemical', '-', (116, 126))	('miR-205-5p mimic-transfected', 'Var', (116, 144))	('miR-205-5p', 'Chemical', '-', (159, 169))	('ACHN', 'Gene', '55323', (145, 149))
83051	32281285	Furthermore, the expression of ZEB1 mRNA in ACHN cells was found to be obviously downregulated after knockdown of SNHG5 by siRNA, whereas the expression of ZEB1 mRNA in 786-O cells was remarkably upregulated by ectopic overexpression of SNHG5 (Figure 4G).	('ACHN', 'Gene', '55323', (44, 48))	('ZEB1', 'Gene', (156, 160))	('ZEB1', 'Gene', (31, 35))	('ZEB1', 'Gene', '6935', (156, 160))	('downregulated', 'NegReg', (81, 94))	('upregulated', 'PosReg', (196, 207))	('expression', 'MPA', (17, 27))	('ACHN', 'Gene', (44, 48))	('SNHG5', 'Var', (114, 119))	('ZEB1', 'Gene', '6935', (31, 35))
83052	32281285	Additionally, the restoration of miR-205-5p markedly reduced ZEB1 protein expression in ACHN cells.	('miR-205-5p', 'Chemical', '-', (33, 43))	('ACHN', 'Gene', '55323', (88, 92))	('restoration', 'Var', (18, 29))	('rat', 'Species', '10116', (23, 26))	('ACHN', 'Gene', (88, 92))	('miR-205-5p', 'Var', (33, 43))	('reduced', 'NegReg', (53, 60))	('ZEB1', 'Gene', '6935', (61, 65))	('ZEB1', 'Gene', (61, 65))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
83053	32281285	In contrast, the knockdown of miR-205-5p significantly increased the protein expression of ZEB1 in 786-O cells (Figure 4H).	('increased', 'PosReg', (55, 64))	('miR-205-5p', 'Chemical', '-', (30, 40))	('ZEB1', 'Gene', '6935', (91, 95))	('protein expression', 'MPA', (69, 87))	('miR-205-5p', 'Var', (30, 40))	('ZEB1', 'Gene', (91, 95))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))
83056	32281285	Compared to luciferase reporter activity in the control group, luciferase activity was markedly inhibited in ACHN cells cotransfected with SNHG5-wt plasmid and miR-205-5p mimic.	('luciferase activity', 'molecular_function', 'GO:0047077', ('63', '82'))	('ACHN', 'Gene', '55323', (109, 113))	('miR-205-5p', 'Chemical', '-', (160, 170))	('ACHN', 'Gene', (109, 113))	('luciferase activity', 'molecular_function', 'GO:0045289', ('63', '82'))	('miR-205-5p mimic', 'Var', (160, 176))	('luciferase activity', 'molecular_function', 'GO:0047712', ('63', '82'))	('activity', 'MPA', (74, 82))	('luciferase activity', 'molecular_function', 'GO:0050248', ('63', '82'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('63', '82'))	('inhibited', 'NegReg', (96, 105))	('luciferase', 'Enzyme', (63, 73))
83057	32281285	After the cotransfection of miR-205-5p inhibitor and SNHG5-wt plasmid into ACHN cells, luciferase activity in wild type group was dramatically enhanced compared to the control group.	('luciferase', 'Enzyme', (87, 97))	('ACHN', 'Gene', '55323', (75, 79))	('enhanced', 'PosReg', (143, 151))	('luciferase activity', 'molecular_function', 'GO:0045289', ('87', '106'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('87', '106'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('87', '106'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('87', '106'))	('miR-205-5p inhibitor', 'Var', (28, 48))	('miR-205-5p', 'Chemical', '-', (28, 38))	('ACHN', 'Gene', (75, 79))	('activity', 'MPA', (98, 106))	('luciferase activity', 'molecular_function', 'GO:0047077', ('87', '106'))
83058	32281285	Nevertheless, these effects were robustly reversed after mutating the putative binding sites of miR-205-5p (Figure 4J).	('binding', 'molecular_function', 'GO:0005488', ('79', '86'))	('binding', 'Interaction', (79, 86))	('mutating', 'Var', (57, 65))	('miR-205-5p', 'Chemical', '-', (96, 106))	('miR-205-5p', 'Gene', (96, 106))
83060	32281285	However, transfection with reporter vector harboring a mutant ZEB1 3'-UTR sequence (ZEB1-mut) in which putative miR-205-5p-targeted sites had been mutated abrogated the above effects (Figure 4K).	('ZEB1', 'Gene', '6935', (62, 66))	('abrogated', 'NegReg', (155, 164))	('ZEB1', 'Gene', (84, 88))	('miR-205-5p', 'Chemical', '-', (112, 122))	('ZEB1', 'Gene', '6935', (84, 88))	('mutant', 'Var', (55, 61))	('mutated', 'Var', (147, 154))	('ZEB1', 'Gene', (62, 66))
83071	32281285	Notably, we further confirmed the tumor-suppressive effect of miR-205-5p in ccRCC cells.	('miR-205-5p', 'Var', (62, 72))	('tumor', 'Disease', (34, 39))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('miR-205-5p', 'Chemical', '-', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
83072	32281285	Moreover, western blot analysis of the EMT-related marker ZEB1 indicated that the reduced protein level of ZEB1, induced by SNHG5 knockdown, was restored by the cotransfection with miR-205-5p inhibitor in ACHN cells (Figure 5H,I).	('ZEB1', 'Gene', '6935', (107, 111))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('ACHN', 'Gene', (205, 209))	('EMT', 'biological_process', 'GO:0001837', ('39', '42'))	('protein level', 'MPA', (90, 103))	('knockdown', 'Var', (130, 139))	('miR-205-5p', 'Chemical', '-', (181, 191))	('ACHN', 'Gene', '55323', (205, 209))	('reduced', 'NegReg', (82, 89))	('ZEB1', 'Gene', (58, 62))	('SNHG5', 'Gene', (124, 129))	('ZEB1', 'Gene', '6935', (58, 62))	('ZEB1', 'Gene', (107, 111))
83076	32281285	Restoration of SNHG5 enhanced the proliferation and colony formation of ccRCC cells and facilitated ccRCC cell migration and invasion; however, these promotive effects were attenuated by ZEB1 knockdown (Figure 6A-F).	('formation', 'biological_process', 'GO:0009058', ('59', '68'))	('Restoration', 'Var', (0, 11))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('ZEB1', 'Gene', (187, 191))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('colony formation', 'CPA', (52, 68))	('enhanced', 'PosReg', (21, 29))	('facilitated', 'PosReg', (88, 99))	('rat', 'Species', '10116', (5, 8))	('cell migration', 'biological_process', 'GO:0016477', ('106', '120'))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('SNHG5', 'Gene', (15, 20))	('proliferation', 'CPA', (34, 47))	('rat', 'Species', '10116', (114, 117))	('ZEB1', 'Gene', '6935', (187, 191))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('RCC', 'Disease', (102, 105))	('rat', 'Species', '10116', (41, 44))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('invasion', 'CPA', (125, 133))
83077	32281285	Consistent with the above results, the increased expression of ZEB1 in ccRCC cells, induced by the restoration of SNHG5, could also be reversed by cotransfection with si-ZEB1 (Figure 6G,H).	('ZEB1', 'Gene', (170, 174))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('RCC', 'Disease', (73, 76))	('ZEB1', 'Gene', '6935', (170, 174))	('expression', 'MPA', (49, 59))	('restoration', 'Var', (99, 110))	('increased', 'PosReg', (39, 48))	('ZEB1', 'Gene', (63, 67))	('ZEB1', 'Gene', '6935', (63, 67))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))	('SNHG5', 'Gene', (114, 119))	('rat', 'Species', '10116', (104, 107))
83085	32281285	14  Conversely, SNHG5 was shown to suppress gastric cancer (GC) cell proliferation and metastasis via interaction with MTA2.	('MTA2', 'Gene', '9219', (119, 123))	('GC', 'Phenotype', 'HP:0012126', (60, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('MTA2', 'Gene', (119, 123))	('rat', 'Species', '10116', (76, 79))	('metastasis', 'CPA', (87, 97))	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('gastric cancer', 'Disease', (44, 58))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('SNHG5', 'Var', (16, 21))	('suppress', 'NegReg', (35, 43))	('interaction', 'Interaction', (102, 113))
83098	32281285	27  Thus, in our study, we sought to determine whether SNHG5 may also serve as a ceRNA to modulate the tumorigenesis and progression of ccRCC.	('RCC', 'Disease', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('modulate', 'Reg', (90, 98))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('tumor', 'Disease', (103, 108))	('progression', 'CPA', (121, 132))	('SNHG5', 'Var', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
83100	32281285	As expected, SNHG5 was demonstrated to directly bind to miR-205-5p and attenuate the expression level of miR-205-5p in ccRCC cells.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('miR-205-5p', 'Var', (56, 66))	('bind', 'Interaction', (48, 52))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('miR-205-5p', 'Chemical', '-', (105, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('rat', 'Species', '10116', (30, 33))	('miR-205-5p', 'Chemical', '-', (56, 66))	('attenuate', 'NegReg', (71, 80))	('expression level', 'MPA', (85, 101))
83101	32281285	Recent reports have shown the tumor suppressive effect of miR-205-5p in several human tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('miR-205-5p', 'Chemical', '-', (58, 68))	('human', 'Species', '9606', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('miR-205-5p', 'Var', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (30, 35))
83103	32281285	Additionally, Pearson correlation analysis revealed that miR-205-5p was inversely associated with the abundance of SNHG5 in ccRCC samples.	('miR-205-5p', 'Chemical', '-', (57, 67))	('RCC', 'Disease', (126, 129))	('miR-205-5p', 'Var', (57, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (124, 129))	('inversely', 'NegReg', (72, 81))	('abundance', 'MPA', (102, 111))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('SNHG5', 'Gene', (115, 120))	('RCC', 'Disease', 'MESH:C538614', (126, 129))
83104	32281285	Importantly, SNHG5 and miR-205-5p in the Ago2-containing RNA-induced silencing complex (RISC) were also shown to be positively correlated by RIP analysis.	('SNHG5', 'Var', (13, 18))	('Ago2', 'Gene', (41, 45))	('miR-205-5p', 'Chemical', '-', (23, 33))	('RNA-induced silencing complex', 'cellular_component', 'GO:0016442', ('57', '86'))	('miR-205-5p', 'Var', (23, 33))	('Ago2', 'Gene', '27161', (41, 45))
83106	32281285	Moreover the biological function of SNHG5 in ccRCC cells is mediated by miR-205-5p, as shown by our rescue experiment.	('miR-205-5p', 'Var', (72, 82))	('SNHG5', 'Gene', (36, 41))	('mediated by', 'Reg', (60, 71))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('miR-205-5p', 'Chemical', '-', (72, 82))
83107	32281285	These results are consistent with our hypothesis and previous report 16  indicating that SNHG5 binds miR-205-5p and affects the expression and function of miR-205-5p in ccRCC.	('miR-205-5p', 'Chemical', '-', (101, 111))	('miR-205-5p', 'Var', (155, 165))	('function', 'MPA', (143, 151))	('SNHG5', 'Gene', (89, 94))	('affects', 'Reg', (116, 123))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('expression', 'MPA', (128, 138))	('miR-205-5p', 'Chemical', '-', (155, 165))	('RCC', 'Disease', (171, 174))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))
83115	32281285	34  Here, the present data showed that SNHG5 could increase the expression of ZEB1 by sequestering endogenous miR-205-5p in ccRCC cell lines.	('increase', 'PosReg', (51, 59))	('expression', 'MPA', (64, 74))	('sequestering endogenous miR-205-5p', 'MPA', (86, 120))	('sequestering', 'biological_process', 'GO:0051235', ('86', '98'))	('ZEB1', 'Gene', '6935', (78, 82))	('ZEB1', 'Gene', (78, 82))	('RCC', 'Disease', (126, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (124, 129))	('SNHG5', 'Var', (39, 44))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('miR-205-5p', 'Chemical', '-', (110, 120))
83116	32281285	Simultaneous correlation analysis indicated that ZEB1 mRNA level was inversely correlated with miR-205-5p but positively correlated with SNHG5 in ccRCC tissues.	('correlated', 'Interaction', (79, 89))	('RCC', 'Disease', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('miR-205-5p', 'Chemical', '-', (95, 105))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('correlated', 'Interaction', (121, 131))	('miR-205-5p', 'Var', (95, 105))	('inversely', 'NegReg', (69, 78))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('ZEB1', 'Gene', (49, 53))	('ZEB1', 'Gene', '6935', (49, 53))
83117	32281285	ZEB1 was eventually verified to be a direct target of miR-205-5p in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('miR-205-5p', 'Chemical', '-', (54, 64))	('miR-205-5p', 'Var', (54, 64))	('ZEB1', 'Gene', (0, 4))	('ZEB1', 'Gene', '6935', (0, 4))
83120	32281285	We therefore present a model that SNHG5 promotes the progression of EMT and tumor proliferation, migration, invasion and metastasis cascade by elevating ZEB1 expression through binding miR-205-5p in ccRCC (Figure 7).	('elevating', 'PosReg', (143, 152))	('tumor', 'Disease', (76, 81))	('miR-205-5p', 'Var', (185, 195))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('RCC', 'Disease', (201, 204))	('ZEB1', 'Gene', '6935', (153, 157))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('ccRCC', 'Phenotype', 'HP:0006770', (199, 204))	('EMT', 'biological_process', 'GO:0001837', ('68', '71'))	('SNHG5', 'Gene', (34, 39))	('binding', 'molecular_function', 'GO:0005488', ('177', '184'))	('binding', 'Interaction', (177, 184))	('rat', 'Species', '10116', (100, 103))	('progression', 'CPA', (53, 64))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('expression', 'MPA', (158, 168))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('miR-205-5p', 'Chemical', '-', (185, 195))	('promotes', 'PosReg', (40, 48))	('metastasis', 'CPA', (121, 131))	('migration', 'CPA', (97, 106))	('ZEB1', 'Gene', (153, 157))	('rat', 'Species', '10116', (89, 92))	('invasion', 'CPA', (108, 116))
83121	32281285	To conclude, this study provides promising evidence that high SNHG5 expression contributes to ccRCC progression.	('RCC', 'Disease', (96, 99))	('high', 'Var', (57, 61))	('contributes', 'Reg', (79, 90))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('SNHG5', 'Gene', (62, 67))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
83122	32281285	miR-205-5p was demonstrated to act as not only a direct target of SNHG5 but also a mediator of SNHG5 in ccRCC cells.	('miR-205-5p', 'Var', (0, 10))	('rat', 'Species', '10116', (22, 25))	('miR-205-5p', 'Chemical', '-', (0, 10))	('SNHG5', 'Gene', (66, 71))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))
83165	28052650	Target DNA (10 ng) was amplified by multiplex polymerase chain reaction (PCR) using fluorescent dyelinked primers for the 16 loci: 13 autosomal STR loci (CSF1PO, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, FGA, TH01, TPOX, and vWA); two additional STR loci, D2S1338 and D19S433, and the amelogenin locus.	('CSF1', 'molecular_function', 'GO:0005011', ('154', '158'))	('CSF1PO', 'Var', (154, 160))	('D16S539', 'Var', (205, 212))	('D2S1338', 'Var', (282, 289))	('D3S1358', 'Var', (162, 169))	('D5S818', 'Var', (171, 177))	('FGA', 'Gene', '2243', (230, 233))	('D13S317', 'Var', (196, 203))	('FGA', 'Gene', (230, 233))	('D19S433', 'Var', (294, 301))	('D8S1179', 'Var', (187, 194))	('D7S820', 'Var', (179, 185))	('DNA', 'cellular_component', 'GO:0005574', ('7', '10'))	('D18S51', 'Var', (214, 220))	('D21S11', 'Var', (222, 228))
83282	28596300	Mutation or hypermethylation-induced inactivation of the tumor suppressor gene Von-Hippel-Lindau (VHL) increases activity of the mitogen-activated protein kinase (MEK) protein.	('MEK', 'Gene', '5609', (163, 166))	('hypermethylation-induced inactivation', 'Var', (12, 49))	('mitogen-activated protein kinase', 'Gene', '5609', (129, 161))	('inactivation', 'Var', (37, 49))	('VHL', 'Disease', (98, 101))	('MEK', 'Gene', (163, 166))	('tumor', 'Disease', (57, 62))	('Von-Hippel-Lindau', 'Gene', '7428', (79, 96))	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('increases', 'PosReg', (103, 112))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('57', '73'))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('Von-Hippel-Lindau', 'Gene', (79, 96))	('mitogen-activated protein kinase', 'Gene', (129, 161))	('tumor suppressor', 'biological_process', 'GO:0051726', ('57', '73'))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))	('VHL', 'Disease', 'MESH:D006623', (98, 101))	('Mutation', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('activity', 'MPA', (113, 121))
83324	28596300	2016)), CDH1 (monoclonal mouse anti-E-cadherin, clone NHC-38, Dako, Agilent Technologies, Santa Clara, CA, USA, catalogue number: MA5-12547), MMP14 (monoclonal rabbit anti-MMP14, Abcam, Cambridge, UK, catalogue number: EP1264Y) and VIM (monoclonal mouse anti-vimentin, clone V9, Dako, Agilent Technologies, Santa Clara, CA, USA, catalogue number: M072529-2).	('EP1264Y', 'Var', (219, 226))	('mouse', 'Species', '10090', (25, 30))	('CDH1', 'Gene', (8, 12))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('MMP', 'molecular_function', 'GO:0004235', ('142', '145'))	('VIM', 'Gene', '7431', (232, 235))	('VIM', 'Gene', (232, 235))	('E-cadherin', 'Gene', (36, 46))	('E-cadherin', 'Gene', '999', (36, 46))	('MMP14', 'Gene', '4323', (172, 177))	('MMP14', 'Gene', (172, 177))	('vimentin', 'cellular_component', 'GO:0045098', ('259', '267'))	('MMP', 'molecular_function', 'GO:0004235', ('172', '175'))	('rabbit', 'Species', '9986', (160, 166))	('mouse', 'Species', '10090', (248, 253))	('vimentin', 'Gene', '7431', (259, 267))	('vimentin', 'cellular_component', 'GO:0045099', ('259', '267'))	('vimentin', 'Gene', (259, 267))	('MMP14', 'Gene', '4323', (142, 147))	('MMP14', 'Gene', (142, 147))	('CDH1', 'Gene', '999', (8, 12))
83325	28596300	Slides were incubated with the specified antibodies, such as AXL 1 mug/mL, CDH1 1:200 and VIM 1:1000, for 1 h at room temperature.	('CDH1', 'Gene', '999', (75, 79))	('VIM', 'Gene', (90, 93))	('AXL', 'Gene', '558', (61, 64))	('mug', 'molecular_function', 'GO:0043739', ('67', '70'))	('VIM', 'Gene', '7431', (90, 93))	('rat', 'Species', '10116', (123, 126))	('CDH1', 'Gene', (75, 79))	('AXL', 'Gene', (61, 64))	('1:200', 'Var', (80, 85))
83371	28596300	The classifier was successfully applied in renal allografts (classifier with 19 MARGS genes) and in solid human organ fibrosis (classifier with 10 of the 19 MARGS genes), (Rodder et al.	('human', 'Species', '9606', (106, 111))	('fibrosis', 'Disease', 'MESH:D005355', (118, 126))	('fibrosis', 'Disease', (118, 126))	('genes', 'Var', (86, 91))	('MARGS', 'Gene', (80, 85))
83431	27993167	It also demonstrates the survival prognostic importance of methylation alterations in KIRC tumors and points to the potential of epigenetic modulators in KIRC treatment.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('methylation alterations', 'Var', (59, 82))
83461	27993167	In this respect, we applied the same procedure as in the "extreme score stratification" approach, but we used a threshold of Z-score = 0 to stratify the patients (Z-score < 0 corresponds to lower than average; Z-score > 0 corresponds to higher than average).	('Z-score < 0', 'Var', (163, 174))	('Z-score', 'Var', (210, 217))	('patients', 'Species', '9606', (153, 161))	('lower', 'NegReg', (190, 195))
83498	27993167	While high expression of mir-10b is associated with worse outcomes in some types of cancer, high expression of mir-10b is associated with better outcomes in KIRC patients.	('patients', 'Species', '9606', (162, 170))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('mir-10b', 'Gene', '406903', (25, 32))	('cancer', 'Disease', (84, 90))	('mir-10b', 'Gene', (25, 32))	('high', 'Var', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mir-10b', 'Gene', (111, 118))	('mir-10b', 'Gene', '406903', (111, 118))
83503	27993167	Recent high-resolution methylome study of KIRC patients demonstrated that many kidney specific enhancers are targeted by aberrant hypermethylation and are prognostic for overall survival.	('aberrant hypermethylation', 'Var', (121, 146))	('hypermethylation', 'Var', (130, 146))	('patients', 'Species', '9606', (47, 55))	('prognostic', 'Reg', (155, 165))
83506	27993167	The three methylation markers selected by the single loci models in the three rounds are: cg26813907 (C19orf21), cg16419354 (FAM163A) and cg02812891 (ECEL1P2).	('ECEL1P2', 'Gene', '347694', (150, 157))	('cg16419354', 'Chemical', '-', (113, 123))	('cg16419354', 'Var', (113, 123))	('FAM163A', 'Gene', '148753', (125, 132))	('C19orf21', 'Gene', '126353', (102, 110))	('cg26813907', 'Var', (90, 100))	('cg26813907', 'Chemical', '-', (90, 100))	('cg02812891', 'Var', (138, 148))	('FAM163A', 'Gene', (125, 132))	('C19orf21', 'Gene', (102, 110))	('methylation', 'biological_process', 'GO:0032259', ('10', '21'))	('ECEL1P2', 'Gene', (150, 157))
83510	27993167	Since the abundance of mir-21 is highly predictive for survival as a standalone marker, we investigated whether the high expression of mir-21 in KIRC tumor samples is due to epigenetic changes in tumors or DNA sequence alteration.	('mir-21', 'Gene', (135, 141))	('due to', 'Reg', (167, 173))	('mir-21', 'Gene', '406991', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', (196, 201))	('epigenetic changes', 'Var', (174, 192))	('DNA', 'cellular_component', 'GO:0005574', ('206', '209'))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('expression', 'MPA', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('mir-21', 'Gene', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('mir-21', 'Gene', '406991', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
83523	27993167	The expression of IGF1R is inhibited by miRNA-223 and miRNA-let-7i that negatively associate with KIRC survival.	('miRNA-223', 'Gene', '407008', (40, 49))	('expression', 'MPA', (4, 14))	('miRNA-let-7i', 'Var', (54, 66))	('IGF1R', 'Gene', (18, 23))	('inhibited', 'NegReg', (27, 36))	('miRNA-223', 'Gene', (40, 49))	('IGF1R', 'Gene', '3480', (18, 23))
83524	27993167	However, another study has shown that VHL inactivation in KIRC cells likely leads to IGF1R upregulation and this contributes to renal tumorigenesis and it is associated to worse outcome.	('contributes', 'Reg', (113, 124))	('upregulation', 'PosReg', (91, 103))	('IGF1R', 'Gene', (85, 90))	('inactivation', 'Var', (42, 54))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('IGF1R', 'Gene', '3480', (85, 90))	('VHL', 'Gene', (38, 41))	('renal', 'Disease', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('VHL', 'Gene', '7428', (38, 41))	('tumor', 'Disease', (134, 139))
83533	27993167	Our analyses on KIRC patient cohort show that when molecular data alone are used for survival prediction, miRNA/mRNA/protein expression and methylation marks have statistically significant predictive powers compared to a random guess.	('patient', 'Species', '9606', (21, 28))	('methylation marks', 'Var', (140, 157))	('miRNA/mRNA/protein expression', 'MPA', (106, 135))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('methylation', 'biological_process', 'GO:0032259', ('140', '151'))
83555	27993167	7. pg 2: "The patients were assigned into three equally sized sets: n1 = 178, n2 = 178 and n3 = 177, such that no bias in terms of survival time and vital status was observed in each of the sets."	('pg 2', 'Gene', '8788', (3, 7))	('patients', 'Species', '9606', (14, 22))	('pg 2', 'Gene', (3, 7))	('n2 = 178', 'Var', (78, 86))
83593	33223511	According to the defined criteria, a local ccRCC and a metastatic ccRCC microarray Gene Expression Omnibus (GEO) dataset (GSE100186 and GSE137836) were enrolled in the study (Table 1).	('GSE100186', 'Var', (122, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('Gene Expression', 'biological_process', 'GO:0010467', ('83', '98'))	('GSE137836', 'Var', (136, 145))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
83594	33223511	After normalization of batch effect, in total, 961 circRNAs were differentially expressed between ccRCC and normal tissues in GSE100186 (Figure 2A), and 255 circRNAs were differentially expressed between metastatic ccRCC and primary tumor tissues in GSE137836 in total (Figure 2B).	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('ccRCC', 'Phenotype', 'HP:0006770', (215, 220))	('RCC', 'Disease', (217, 220))	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('GSE100186', 'Var', (126, 135))	('differentially', 'Reg', (171, 185))	('tumor', 'Disease', (233, 238))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('differentially', 'Reg', (65, 79))	('RCC', 'Phenotype', 'HP:0005584', (217, 220))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
83607	33223511	Specifically, high expression of TRIM2 predicted better survival, while XAF1 is negatively correlated with survival (Supplementary Figure 3B, 3D).	('TRIM2', 'Gene', (33, 38))	('XAF1', 'Gene', '54739', (72, 76))	('XAF1', 'Gene', (72, 76))	('high', 'Var', (14, 18))	('better', 'PosReg', (49, 55))	('TRIM2', 'Gene', '23321', (33, 38))	('survival', 'CPA', (56, 64))	('men', 'Species', '9606', (123, 126))
83620	33223511	The results revealed that the high expression of TRIM2 increased not only the resistance of ccRCC cell lines to paclitaxel, S-Trityl-L-cysteine, pyrimethamine, GW843682X and bortezomib (P < 0.05), but also the sensitivity of ccRCC cell lines to salubrinal, GNF-2, XMD8-85, PHA-665752 and BEZ235 (Supplementary Figure 5).	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('sensitivity', 'MPA', (210, 221))	('increased', 'PosReg', (55, 64))	('resistance', 'MPA', (78, 88))	('GW843682X', 'Var', (160, 169))	('TRIM2', 'Gene', (49, 54))	('pyrimethamine', 'Chemical', 'MESH:D011739', (145, 158))	('RCC', 'Disease', (227, 230))	('RCC', 'Phenotype', 'HP:0005584', (227, 230))	('GW843682X', 'Chemical', 'MESH:C524135', (160, 169))	('bortezomib', 'Chemical', 'MESH:D000069286', (174, 184))	('TRIM2', 'Gene', '23321', (49, 54))	('paclitaxel', 'Chemical', 'MESH:D017239', (112, 122))	('RCC', 'Disease', 'MESH:C538614', (227, 230))	('men', 'Species', '9606', (302, 305))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('high expression', 'Var', (30, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (225, 230))	('BEZ235', 'Chemical', 'MESH:C531198', (288, 294))	('S-Trityl-L-cysteine', 'Chemical', 'MESH:C003724', (124, 143))
83622	33223511	In tumor tissues, the relative mRNA expression levels of hsa_circ_0002286, hsa_circ_0000512 and TRIM2 were lower than those in normal tissues (P < 0.01), while the expression levels of hsa-mir-222-5p was significantly increased in tumor tissues (P < 0.01) (Figure 11A).	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('expression levels', 'MPA', (164, 181))	('tumor', 'Disease', (3, 8))	('hsa_circ_0002286', 'Var', (57, 73))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('lower', 'NegReg', (107, 112))	('TRIM2', 'Gene', '23321', (96, 101))	('increased', 'PosReg', (218, 227))	('tumor', 'Disease', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('TRIM2', 'Gene', (96, 101))	('mRNA expression levels', 'MPA', (31, 53))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
83623	33223511	Additionally, the relative mRNA expression levels of hsa_circ_0002286, hsa_circ_0000512, hsa_circ_0003596, hsa_circ_0035436, hsa-mir-222-5p and TRIM2 were markedly different between tumor cell lines and 293T cell line (P <0.05) (Figure 11B).	('TRIM2', 'Gene', '23321', (144, 149))	('different', 'Reg', (164, 173))	('tumor', 'Disease', (182, 187))	('293T', 'CellLine', 'CVCL:0063', (203, 207))	('TRIM2', 'Gene', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('mRNA expression levels', 'MPA', (27, 49))	('hsa_circ_0003596', 'Var', (89, 105))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
83638	33223511	Ultimately, a core tumor suppressor axis (circRNA_0002286 / miR-222-5p / TRIM2) was identified.	('tumor suppressor', 'biological_process', 'GO:0051726', ('19', '35'))	('circRNA_0002286', 'Var', (42, 57))	('core', 'cellular_component', 'GO:0019013', ('14', '18'))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('19', '35'))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('TRIM2', 'Gene', '23321', (73, 78))	('tumor', 'Disease', (19, 24))	('TRIM2', 'Gene', (73, 78))
83642	33223511	They confirmed that circ-AKT3 enhanced E-cadherin expression through competitive binding of mir-296-3p, thus inhibiting the metastasis of ccRCC.	('binding', 'molecular_function', 'GO:0005488', ('81', '88'))	('AKT3', 'Gene', '10000', (25, 29))	('inhibiting', 'NegReg', (109, 119))	('enhanced', 'PosReg', (30, 38))	('E-cadherin', 'Gene', (39, 49))	('metastasis', 'CPA', (124, 134))	('E-cadherin', 'Gene', '999', (39, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('mir-296-3p', 'Var', (92, 102))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('binding', 'Interaction', (81, 88))	('cadherin', 'molecular_function', 'GO:0008014', ('41', '49'))	('mir-296-3p', 'Chemical', '-', (92, 102))	('AKT3', 'Gene', (25, 29))
83645	33223511	MiRNAs, a kind of endogenous non coding RNA, affect the occurrence and development of various cancers by regulating the expression level of oncogenes and tumor suppressor genes.	('development', 'CPA', (71, 82))	('affect', 'Reg', (45, 51))	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('MiRNAs', 'Var', (0, 6))	('regulating', 'Reg', (105, 115))	('occurrence', 'CPA', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('154', '170'))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('154', '170'))	('expression level', 'MPA', (120, 136))	('men', 'Species', '9606', (78, 81))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('oncogenes', 'Protein', (140, 149))	('cancers', 'Disease', (94, 101))	('tumor', 'Disease', (154, 159))
83647	33223511	found that FGFR4 and EGFR were targets of mir-486-3p, and increased expression of mir-486-3p can induce apoptosis of hepatoma cells.	('hepatoma', 'Disease', (117, 125))	('mir-486-3p', 'Var', (82, 92))	('EGFR', 'Gene', (21, 25))	('EGFR', 'Gene', '1956', (21, 25))	('FGFR4', 'Gene', '2264', (11, 16))	('increased', 'PosReg', (58, 67))	('FGFR4', 'Gene', (11, 16))	('expression', 'MPA', (68, 78))	('hepatoma', 'Disease', 'MESH:D006528', (117, 125))	('induce', 'Reg', (97, 103))	('EGFR', 'molecular_function', 'GO:0005006', ('21', '25'))	('apoptosis', 'CPA', (104, 113))	('FGFR', 'molecular_function', 'GO:0005007', ('11', '15'))	('apoptosis', 'biological_process', 'GO:0097194', ('104', '113'))	('apoptosis', 'biological_process', 'GO:0006915', ('104', '113'))
83650	33223511	demonstrated that miR-584-5p functioned by targeting KCNE2 directly, and mediates the proliferation, migration and invasion of hepatocellular carcinoma (HCC) cells.	('KCNE2', 'Gene', (53, 58))	('targeting', 'Reg', (43, 52))	('migration', 'CPA', (101, 110))	('mediates', 'Reg', (73, 81))	('HCC', 'Phenotype', 'HP:0001402', (153, 156))	('proliferation', 'CPA', (86, 99))	('miR-584-5p', 'Var', (18, 28))	('invasion of hepatocellular carcinoma', 'Disease', 'MESH:D006528', (115, 151))	('KCNE2', 'Gene', '9992', (53, 58))	('invasion of hepatocellular carcinoma', 'Disease', (115, 151))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (127, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
83661	33223511	Therefore, the abnormal expression, mutation and unregulated activity of these enzymes are related to the development of cancer and chemotherapy resistance.	('related', 'Reg', (91, 98))	('expression', 'MPA', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('chemotherapy resistance', 'CPA', (132, 155))	('men', 'Species', '9606', (113, 116))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('mutation', 'Var', (36, 44))	('unregulated activity', 'MPA', (49, 69))
83674	33223511	We selected the GSE100186 and GSE137836 circRNA expression profiles, which were based on the same platform: GPL21825 074301 Arraystar Human CircRNA microarray V2.	('Human', 'Species', '9606', (134, 139))	('GSE137836', 'Var', (30, 39))	('GSE100186', 'Var', (16, 25))
83699	31011436	Representative tumor sections were immunostained with anti-B7-H3 and anti-B7-H1 antibodies.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('B7-H1', 'Gene', (74, 79))	('B7-H1', 'Gene', '29126', (74, 79))	('anti-B7-H3', 'Var', (54, 64))
83708	31011436	The immunologic treatment approach has always been in the focus of research and the co-stimulatory glycoprotein B7-H1 (PD-L1, CD 274) has been implicated as a potent inhibitor of T-cell-mediated antitumoral immunity and high expression levels were significantly associated with death in predominantly localized RCC.	('tumor', 'Disease', (199, 204))	('CD 274', 'Gene', (126, 132))	('CD 274', 'Gene', '29126', (126, 132))	('PD-L1', 'Gene', '29126', (119, 124))	('RCC', 'Disease', 'MESH:C538614', (311, 314))	('associated with', 'Reg', (262, 277))	('PD-L1', 'Gene', (119, 124))	('RCC', 'Disease', (311, 314))	('high', 'Var', (220, 224))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('death', 'Disease', 'MESH:D003643', (278, 283))	('death', 'Disease', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('B7-H1', 'Gene', (112, 117))	('B7-H1', 'Gene', '29126', (112, 117))
83711	31011436	In addition, PD-L1 expression was associated with aggressive features such as higher tumor-node-metastasis (TNM) stage, tumor size, or Fuhrman grade, and an increased risk of cancer-specific mortality in RCC patients.	('tumor', 'Disease', (85, 90))	('cancer', 'Disease', (175, 181))	('RCC', 'Disease', (204, 207))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('higher', 'PosReg', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', (120, 125))	('Fuhrman grade', 'CPA', (135, 148))	('expression', 'Var', (19, 29))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('tumor-node-metastasis', 'Disease', (85, 106))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor-node-metastasis', 'Disease', 'MESH:D009362', (85, 106))	('PD-L1', 'Gene', (13, 18))	('PD-L1', 'Gene', '29126', (13, 18))	('associated', 'Reg', (34, 44))	('patients', 'Species', '9606', (208, 216))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
83754	31011436	Although proportional hazards models of B7-H1 and B7-H3 expressions were not significantly associated with the patient's survival, an improved median OS and CSS was observed in patients with a B7-H3 expression <=16% (both: p = 0.02) [Figure 2; H/K].	('improved', 'PosReg', (134, 142))	('B7-H3', 'Var', (193, 198))	('patients', 'Species', '9606', (177, 185))	('median OS', 'CPA', (143, 152))	('OS', 'Chemical', '-', (150, 152))	('CSS', 'Chemical', '-', (157, 160))	('patient', 'Species', '9606', (111, 118))	('patient', 'Species', '9606', (177, 184))	('CSS', 'CPA', (157, 160))
83771	31011436	In contrast, RCC aberrantly expresses B7-H1 and binding to the T-cell PD-1 receptor results in impaired cytokine production or apoptosis of activated T cells that allows RCC to escape immune detection and destruction.	('B7-H1', 'Gene', (38, 43))	('cytokine production', 'biological_process', 'GO:0001816', ('104', '123'))	('binding', 'molecular_function', 'GO:0005488', ('48', '55'))	('B7-H1', 'Gene', '29126', (38, 43))	('RCC', 'Disease', (170, 173))	('impaired', 'NegReg', (95, 103))	('cytokine production', 'MPA', (104, 123))	('binding', 'Interaction', (48, 55))	('apoptosis', 'CPA', (127, 136))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', (13, 16))	('impaired cytokine production', 'Phenotype', 'HP:0031407', (95, 123))	('aberrantly', 'Var', (17, 27))	('apoptosis', 'biological_process', 'GO:0006915', ('127', '136'))	('apoptosis', 'biological_process', 'GO:0097194', ('127', '136'))
83773	31011436	Interestingly, we observed that a high B7-H1 expression was associated with metastasectomy and less metastases at the start of IFNT, but did not correlate with other parameters, survival or differ between SM mccRCC.	('metastases', 'Disease', (100, 110))	('metastasectomy', 'CPA', (76, 90))	('metastases', 'Disease', 'MESH:D009362', (100, 110))	('RCC', 'Disease', (211, 214))	('RCC', 'Disease', 'MESH:C538614', (211, 214))	('expression', 'MPA', (45, 55))	('high', 'Var', (34, 38))	('B7-H1', 'Gene', (39, 44))	('B7-H1', 'Gene', '29126', (39, 44))	('associated with', 'Reg', (60, 75))
83775	31011436	They observed that an aberrant tumor B7-H1 expression correlated with the development of metachronous mccRCC, but this may be in part due to the comparison of true localized cases with subsequently metastasized ones.	('aberrant', 'Var', (22, 30))	('correlated with', 'Reg', (54, 69))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('B7-H1', 'Gene', (37, 42))	('B7-H1', 'Gene', '29126', (37, 42))	('expression', 'MPA', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
83796	31011436	An interim analysis from a clinical trial with a specific anti-B7-H3 antibody indicates antitumor properties and an increased T-cell activity, with no dose-limiting toxicity and no severe immune-related side effects.	('T-cell activity', 'CPA', (126, 141))	('antibody', 'cellular_component', 'GO:0019815', ('69', '77'))	('anti-B7-H3', 'Var', (58, 68))	('antibody', 'cellular_component', 'GO:0019814', ('69', '77'))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('antibody', 'molecular_function', 'GO:0003823', ('69', '77'))	('tumor', 'Disease', (92, 97))	('toxicity', 'Disease', 'MESH:D064420', (165, 173))	('toxicity', 'Disease', (165, 173))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('antibody', 'cellular_component', 'GO:0042571', ('69', '77'))	('increased', 'PosReg', (116, 125))
83856	30993930	As shown in Table 2, AUC values were 0.731 for ADC, 0.752 for Ds, 0.567 for Df, 0.496 for f, 0.543 for DDC, 0.923 for alpha, 0.568 for MD, and 0.803 for MK.	('0.803', 'Var', (143, 148))	('0.543', 'Var', (93, 98))	('Ds', 'Chemical', '-', (62, 64))	('DDC', 'Gene', '1644', (103, 106))	('0.568', 'Var', (125, 130))	('DDC', 'Gene', (103, 106))	('0.567', 'Var', (66, 71))	('0.923', 'Var', (108, 113))	('0.496', 'Var', (80, 85))
83861	30993930	AUC values were 0.780 for ADC, 0.802 for Ds, 0.630 for Df, 0.663 for f, 0.707 for DDC, 0.712 for alpha, 0.568 for MD, and 0.823 for MK.	('DDC', 'Gene', '1644', (82, 85))	('DDC', 'Gene', (82, 85))	('0.712', 'Var', (87, 92))	('Ds', 'Chemical', '-', (41, 43))	('0.663', 'Var', (59, 64))	('0.568', 'Var', (104, 109))
83906	32368310	Since our previous study on the expression patterns of genome-wide lncRNAs in RCC based on microarray, increasing evidence has demonstrated that by acting as tumor suppressors or onco-lncRNAs, aberrant expression of lncRNAs plays a vital role in the development and evolution of many types of human carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (299, 308))	('tumor', 'Disease', (158, 163))	('carcinomas', 'Disease', 'MESH:D009369', (299, 309))	('carcinomas', 'Phenotype', 'HP:0030731', (299, 309))	('RCC', 'Disease', (78, 81))	('carcinomas', 'Disease', (299, 309))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('human', 'Species', '9606', (293, 298))	('aberrant', 'Var', (193, 201))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
83938	32368310	A risk-score formula was created based on the expression of these four lncRNAs for OS prediction, as follows: Risk score = (0.167*expression level of PVT1) + (0.149*expression level of MIR155HG) + (0.162* expression level of HAR1B)- (0.109*expression level of TCL6).	('0.167*', 'Var', (124, 130))	('expression', 'MPA', (130, 140))	('PVT1', 'Gene', (150, 154))	('MIR155HG', 'Gene', '114614', (185, 193))	('HAR1B', 'Gene', '768097', (225, 230))	('TCL6', 'Gene', '27004', (260, 264))	('MIR155HG', 'Gene', (185, 193))	('expression', 'MPA', (165, 175))	('PVT1', 'Gene', '5820', (150, 154))	('HAR1B', 'Gene', (225, 230))	('TCL6', 'Gene', (260, 264))	('expression level', 'MPA', (240, 256))
83941	32368310	The ccRCC patients in the high-score group experienced a significantly worse OS (HR: 2.57, 95%CI: 1.89-3.50, p < 0.001) than those in the low-score group (Figure 4F).	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('high-score', 'Var', (26, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (4, 9))	('patients', 'Species', '9606', (10, 18))	('worse', 'NegReg', (71, 76))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))
83968	32368310	Among all cancer types, renal clear cell carcinoma displays the strongest upregulation of PVT1, and its misregulation in ccRCC is largely associated with promoter hypomethylation.	('PVT1', 'Gene', '5820', (90, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (24, 50))	('renal clear cell carcinoma', 'Disease', (24, 50))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('upregulation', 'PosReg', (74, 86))	('associated', 'Reg', (138, 148))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('PVT1', 'Gene', (90, 94))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (121, 126))	('promoter hypomethylation', 'Var', (154, 178))	('cancer', 'Disease', (10, 16))
83970	32368310	also reported that high expression of PVT1 predicted an inferior prognosis in patients with gastric cancer.	('high', 'Var', (19, 23))	('gastric cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('PVT1', 'Gene', (38, 42))	('patients', 'Species', '9606', (78, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('PVT1', 'Gene', '5820', (38, 42))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('inferior', 'NegReg', (56, 64))
83979	32368310	investigated lncRNAs as prognostic biomarkers for papillary thyroid cancer, revealing that low HAR1A expression was associated with cancer recurrence and poor prognosis.	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (50, 74))	('cancer', 'Disease', (132, 138))	('HAR1A', 'Gene', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('low', 'Var', (91, 94))	('HAR1A', 'Gene', '768096', (95, 100))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (50, 74))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('thyroid cancer', 'Phenotype', 'HP:0002890', (60, 74))	('cancer', 'Disease', (68, 74))	('expression', 'MPA', (101, 111))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('papillary thyroid cancer', 'Disease', (50, 74))	('associated', 'Reg', (116, 126))
84012	31897192	A previous study demonstrated that TXNIP deficiency stimulates transforming growth factor-beta (TGF-beta)-induced epithelial-mesenchymal transition, indicating that TXNIP may suppress tumor progression.	('TXNIP', 'Gene', '10628', (35, 40))	('transforming growth factor-beta', 'Gene', (63, 94))	('TGF-beta', 'Gene', (96, 104))	('TXNIP', 'Gene', '10628', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('TXNIP', 'Gene', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('114', '147'))	('transforming growth factor-beta', 'molecular_function', 'GO:0005160', ('63', '94'))	('transforming growth factor-beta', 'Gene', '7040', (63, 94))	('deficiency', 'Var', (41, 51))	('epithelial-mesenchymal transition', 'CPA', (114, 147))	('stimulates', 'PosReg', (52, 62))	('tumor', 'Disease', (184, 189))	('TXNIP', 'Gene', (165, 170))	('TGF-beta', 'Gene', '7040', (96, 104))	('suppress', 'NegReg', (175, 183))
84054	31897192	TXNIP deficiency results in the high viability and estrogen-induced growth of breast tumors.	('high viability', 'CPA', (32, 46))	('breast tumors', 'Disease', (78, 91))	('deficiency', 'Var', (6, 16))	('estrogen-induced growth', 'CPA', (51, 74))	('breast tumors', 'Disease', 'MESH:D061325', (78, 91))	('estrogen', 'Chemical', 'MESH:D004967', (51, 59))	('TXNIP', 'Gene', (0, 5))	('TXNIP', 'Gene', '10628', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('breast tumors', 'Phenotype', 'HP:0100013', (78, 91))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
84114	28779136	EV005, RMH008, EV006, EV003 have the lower degree of intratumoral expression heterogeneity while EV001, EV007, RK26, RMH002, EV003, RMH004 has the higher degree of intratumoral expression heterogeneity (Fig.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('RK26', 'CellLine', 'CVCL:3155', (111, 115))	('EV001', 'Var', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('RK26', 'Var', (111, 115))	('EV007', 'Var', (104, 109))	('EV006', 'Var', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', (169, 174))	('RMH004', 'Var', (132, 138))
84116	28779136	3A) and the strong association of ccRCC mutation with CLEAR score was observed (ANOVA test, p = 1.18E-08).	('mutation', 'Var', (40, 48))	('RCC', 'Disease', (36, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (34, 39))	('RCC', 'Disease', 'MESH:C538614', (36, 39))
84169	32717723	Suppressing circDHX33 expression inhibits the proliferation and invasion of cultured cells, and suppresses tumor growth in vivo.	('Suppressing', 'Var', (0, 11))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('DHX33', 'Gene', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('DHX33', 'Gene', '56919', (16, 21))	('inhibits', 'NegReg', (33, 41))	('suppresses', 'NegReg', (96, 106))
84177	32717723	Ge et al reported that low circMTO1 expression leads to low proliferation and invasion in colorectal cancer through a mechanism that involves the Wnt/beta-catenin signaling pathway.	('beta-catenin', 'Gene', '1499', (150, 162))	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('invasion', 'CPA', (78, 86))	('low', 'Var', (23, 26))	('circMTO1', 'Gene', (27, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('signaling pathway', 'biological_process', 'GO:0007165', ('163', '180'))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('colorectal cancer', 'Disease', (90, 107))	('beta-catenin', 'Gene', (150, 162))	('low', 'NegReg', (56, 59))
84178	32717723	Shao et al have reported that hsa_circ_0075341 promotes cervical cancer by sponging miR-149-5p.	('miR-149', 'Gene', (84, 91))	('miR-149', 'Gene', '406941', (84, 91))	('hsa_circ_0075341', 'Var', (30, 46))	('promotes', 'PosReg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('sponging', 'Var', (75, 83))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
84182	32717723	This circRNA is formed by the splicing of DHX33 mRNA.	('DHX33', 'Gene', '56919', (42, 47))	('splicing', 'biological_process', 'GO:0045292', ('30', '38'))	('splicing', 'Var', (30, 38))	('DHX33', 'Gene', (42, 47))
84201	32717723	These findings suggested that circDHX33 silencing represses the proliferation and metastasis of RCC cells in vitro.	('RCC', 'Disease', (96, 99))	('represses', 'NegReg', (50, 59))	('proliferation', 'CPA', (64, 77))	('DHX33', 'Gene', '56919', (34, 39))	('silencing', 'Var', (40, 49))	('DHX33', 'Gene', (34, 39))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
84204	32717723	Pull-down assay revealed that miR-489-3p was strongly associated with the circDHX33 probe in both 786-O and A498 cells (Figure 4D-4E).	('miR-489-3p', 'Var', (30, 40))	('associated', 'Interaction', (54, 64))	('DHX33', 'Gene', (78, 83))	('A498', 'CellLine', 'CVCL:1056', (108, 112))	('DHX33', 'Gene', '56919', (78, 83))	('miR-489-3p', 'Chemical', '-', (30, 40))
84205	32717723	Figure 4F showed a schematic representation of miR-489-3p binding sites in circDHX33.	('miR-489-3p', 'Var', (47, 57))	('binding', 'molecular_function', 'GO:0005488', ('58', '65'))	('miR-489-3p', 'Chemical', '-', (47, 57))	('DHX33', 'Gene', '56919', (79, 84))	('DHX33', 'Gene', (79, 84))
84206	32717723	A luciferase assay revealed that the miR-489-3p mimics suppressed luciferase activity in circDHX33-WT group (Figure 4G).	('miR-489-3p mimics', 'Var', (37, 54))	('luciferase activity', 'molecular_function', 'GO:0047077', ('66', '85'))	('miR-489-3p', 'Chemical', '-', (37, 47))	('suppressed', 'NegReg', (55, 65))	('luciferase activity', 'molecular_function', 'GO:0045289', ('66', '85'))	('activity', 'MPA', (77, 85))	('luciferase activity', 'molecular_function', 'GO:0050248', ('66', '85'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('66', '85'))	('DHX33', 'Gene', (93, 98))	('luciferase activity', 'molecular_function', 'GO:0050397', ('66', '85'))	('DHX33', 'Gene', '56919', (93, 98))	('luciferase', 'Enzyme', (66, 76))
84207	32717723	The RIP assay confirmed an association between circDHX33 and miR-489-3p in RCC cells (Figure 4H).	('miR-489-3p', 'Var', (61, 71))	('DHX33', 'Gene', '56919', (51, 56))	('association', 'Interaction', (27, 38))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('miR-489-3p', 'Chemical', '-', (61, 71))	('RCC', 'Disease', (75, 78))	('DHX33', 'Gene', (51, 56))
84208	32717723	We next explored miR-489-3p expression in ccRCC using RT-qPCR analysis and discovered that it was downregulated in ccRCC tissues and cell lines (Figure 5A, 5B).	('downregulated', 'NegReg', (98, 111))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (42, 47))	('miR-489-3p', 'Var', (17, 27))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('miR-489-3p', 'Chemical', '-', (17, 27))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))
84212	32717723	Moreover, rescue experiments indicated that miR-489-3p inhibitors abolished the effects of circDHX33 silencing on786O cells proliferation and invasion abilities (Figure 5G, 5H).	('abolished', 'NegReg', (66, 75))	('silencing', 'Var', (101, 110))	('invasion abilities', 'CPA', (142, 160))	('miR-489-3p', 'Chemical', '-', (44, 54))	('DHX33', 'Gene', (95, 100))	('DHX33', 'Gene', '56919', (95, 100))
84213	32717723	Together, these findings suggest that circDHX33 sponges miR-489-3p in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('ccRCC', 'Phenotype', 'HP:0006770', (70, 75))	('miR-489-3p', 'Var', (56, 66))	('DHX33', 'Gene', (42, 47))	('DHX33', 'Gene', '56919', (42, 47))	('miR-489-3p', 'Chemical', '-', (56, 66))
84214	32717723	To explore the mechanism by which miR-489-3p functions in RCC, we searched TargetScan, Starbase, PITA, and RNA22 with the aim of identifying its target genes.	('miR-489-3p', 'Var', (34, 44))	('miR-489-3p', 'Chemical', '-', (34, 44))	('RNA', 'cellular_component', 'GO:0005562', ('107', '110'))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('RNA22', 'Gene', (107, 112))
84215	32717723	This analysis revealed MEK1 as a target of miR-489-3p with a specific binding site at the 3'-UTR (Figure 6A, 6B).	('MEK1', 'Gene', '5604', (23, 27))	('binding', 'Interaction', (70, 77))	('binding', 'molecular_function', 'GO:0005488', ('70', '77'))	('MEK1', 'molecular_function', 'GO:0004708', ('23', '27'))	('MEK1', 'Gene', (23, 27))	('miR-489-3p', 'Chemical', '-', (43, 53))	('miR-489-3p', 'Var', (43, 53))
84219	32717723	Additionally, a luciferase reporter assay revealed that miR-489-3p mimics significantly suppressed luciferase activity in the MEK1-Wt group but not in the MEK1-Mut group (Figure 6J).	('MEK1', 'Gene', (155, 159))	('luciferase activity', 'molecular_function', 'GO:0045289', ('99', '118'))	('activity', 'MPA', (110, 118))	('luciferase activity', 'molecular_function', 'GO:0047712', ('99', '118'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('99', '118'))	('MEK1', 'Gene', '5604', (126, 130))	('luciferase', 'Enzyme', (99, 109))	('luciferase activity', 'molecular_function', 'GO:0050397', ('99', '118'))	('MEK1', 'Gene', (126, 130))	('MEK1', 'Gene', '5604', (155, 159))	('suppressed', 'NegReg', (88, 98))	('MEK1', 'molecular_function', 'GO:0004708', ('155', '159'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('99', '118'))	('miR-489-3p', 'Chemical', '-', (56, 66))	('miR-489-3p mimics', 'Var', (56, 73))	('MEK1', 'molecular_function', 'GO:0004708', ('126', '130'))
84220	32717723	Moreover, correlation analysis showed that miR-489-3p expression negatively correlated with MEK1 expression in ccRCC tissues (Figure 6K).	('MEK1', 'molecular_function', 'GO:0004708', ('92', '96'))	('MEK1', 'Gene', '5604', (92, 96))	('negatively', 'NegReg', (65, 75))	('MEK1', 'Gene', (92, 96))	('miR-489-3p', 'Chemical', '-', (43, 53))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('expression', 'MPA', (97, 107))	('miR-489-3p', 'Var', (43, 53))
84221	32717723	Taken together, these findings indicate that MEK1 is downstream target of miR-489-3p in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('miR-489-3p', 'Var', (74, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('MEK1', 'Gene', '5604', (45, 49))	('miR-489-3p', 'Chemical', '-', (74, 84))	('MEK1', 'molecular_function', 'GO:0004708', ('45', '49'))	('MEK1', 'Gene', (45, 49))	('RCC', 'Disease', (90, 93))
84223	32717723	RT-qPCR showed that silencing circDHX33 decreased MEK1 expression in 786O cells and A498 cells, and that this effect was reversed by inhibitors of miR-489-3p (Figure 7A).	('MEK1', 'Gene', (50, 54))	('miR-489-3p', 'Chemical', '-', (147, 157))	('expression', 'MPA', (55, 65))	('decreased', 'NegReg', (40, 49))	('DHX33', 'Gene', '56919', (34, 39))	('DHX33', 'Gene', (34, 39))	('A498', 'CellLine', 'CVCL:1056', (84, 88))	('silencing', 'Var', (20, 29))	('MEK1', 'molecular_function', 'GO:0004708', ('50', '54'))	('MEK1', 'Gene', '5604', (50, 54))
84227	32717723	A significant inhibition of tumor growth was observed following circDHX33 knockdown (Figure 8A).	('tumor', 'Disease', (28, 33))	('knockdown', 'Var', (74, 83))	('DHX33', 'Gene', (68, 73))	('DHX33', 'Gene', '56919', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('inhibition', 'NegReg', (14, 24))
84228	32717723	Measurement of tumor volume and weight indicated they were markedly lower in the circDHX33 knockdown group relative to control group (Figure 8B, 8C).	('lower', 'NegReg', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('knockdown', 'Var', (91, 100))	('DHX33', 'Gene', '56919', (85, 90))	('tumor', 'Disease', (15, 20))	('DHX33', 'Gene', (85, 90))
84229	32717723	IHC analysis of Ki67 staining revealed that circDHX33 knockdown suppressed tumor cell proliferation in vivo (Figure 8D).	('knockdown', 'Var', (54, 63))	('Ki67', 'Gene', '17345', (16, 20))	('suppressed', 'NegReg', (64, 74))	('Ki67', 'Gene', (16, 20))	('cell proliferation', 'biological_process', 'GO:0008283', ('81', '99'))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('DHX33', 'Gene', (48, 53))	('DHX33', 'Gene', '56919', (48, 53))	('tumor', 'Disease', (75, 80))
84234	32717723	Huang et al showed that elevated levels of circRNA ABCB10 promoted the progression of cancer and predicted poor prognosis.	('progression of', 'CPA', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('circRNA', 'Var', (43, 50))	('promoted', 'PosReg', (58, 66))	('ABCB10', 'Gene', '23456', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('ABCB10', 'Gene', (51, 57))	('cancer', 'Disease', (86, 92))
84243	32717723	MiR-489-3p is a tumor suppressor in many types of cancers.	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('tumor suppressor', 'biological_process', 'GO:0051726', ('16', '32'))	('cancers', 'Disease', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('MiR-489-3p', 'Chemical', '-', (0, 10))	('tumor', 'Disease', (16, 21))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('16', '32'))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('MiR-489-3p', 'Var', (0, 10))
84244	32717723	Inhibition of miR-489-3p enhanced metastasis of osteosarcoma by stimulating PAX3-MET axis.	('PAX3', 'Gene', (76, 80))	('miR-489-3p', 'Chemical', '-', (14, 24))	('enhanced', 'PosReg', (25, 33))	('stimulating', 'PosReg', (64, 75))	('osteosarcoma', 'Phenotype', 'HP:0002669', (48, 60))	('osteosarcoma', 'Disease', (48, 60))	('osteosarcoma', 'Disease', 'MESH:D012516', (48, 60))	('metastasis', 'CPA', (34, 44))	('miR-489-3p', 'Gene', (14, 24))	('Inhibition', 'Var', (0, 10))	('PAX3', 'Gene', '5077', (76, 80))
84245	32717723	It was established that miR-489 inhibited the proliferative capacity and invasiveness of bladder cancer cells.	('proliferative capacity', 'CPA', (46, 68))	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('inhibited', 'NegReg', (32, 41))	('miR-489', 'Var', (24, 31))	('invasiveness of bladder cancer', 'Disease', (73, 103))	('invasiveness of bladder cancer', 'Disease', 'MESH:D001749', (73, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))
84247	32717723	Herein, we uncover that circDHX33 binds to miR-489-3p in ccRCC.	('binds', 'Interaction', (34, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('miR-489-3p', 'Chemical', '-', (43, 53))	('RCC', 'Disease', (59, 62))	('DHX33', 'Gene', (28, 33))	('DHX33', 'Gene', '56919', (28, 33))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('miR-489-3p', 'Var', (43, 53))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
84248	32717723	We also show that MiR-489-3p is reduced in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('MiR-489-3p', 'Var', (18, 28))	('MiR-489-3p', 'Chemical', '-', (18, 28))	('reduced', 'NegReg', (32, 39))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
84250	32717723	Together, these data suggest that circDHX33 exerts oncogenic effects by sponging miR-489-3p in ccRCC.	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('sponging', 'Var', (72, 80))	('miR-489-3p', 'Chemical', '-', (81, 91))	('DHX33', 'Gene', (38, 43))	('DHX33', 'Gene', '56919', (38, 43))	('oncogenic', 'MPA', (51, 60))
84253	32717723	Zhang et al demonstrated that circDLST promotes gastric cancer progression by modulating the miR-502-5p/NRAS/MEK1/ERK1/2 axis.	('gastric cancer', 'Disease', 'MESH:D013274', (48, 62))	('ERK1', 'molecular_function', 'GO:0004707', ('114', '118'))	('promotes', 'PosReg', (39, 47))	('NRAS', 'Gene', '4893', (104, 108))	('gastric cancer', 'Phenotype', 'HP:0012126', (48, 62))	('MEK1', 'Gene', (109, 113))	('ERK1/2', 'Gene', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('miR-502', 'Gene', '574504', (93, 100))	('ERK1/2', 'Gene', '5595;5594', (114, 120))	('MEK1', 'molecular_function', 'GO:0004708', ('109', '113'))	('MEK1', 'Gene', '5604', (109, 113))	('NRAS', 'Gene', (104, 108))	('gastric cancer', 'Disease', (48, 62))	('circDLST', 'Var', (30, 38))	('miR-502', 'Gene', (93, 100))	('modulating', 'Reg', (78, 88))
84255	32717723	We find that MEK1 is directly targeted by miR-489-3p and circDHX33 indirectly regulates MEK1 expression.	('regulates', 'Reg', (78, 87))	('MEK1', 'Gene', '5604', (88, 92))	('MEK1', 'Gene', (88, 92))	('MEK1', 'Gene', '5604', (13, 17))	('DHX33', 'Gene', (61, 66))	('MEK1', 'molecular_function', 'GO:0004708', ('13', '17'))	('DHX33', 'Gene', '56919', (61, 66))	('MEK1', 'Gene', (13, 17))	('miR-489-3p', 'Var', (42, 52))	('expression', 'MPA', (93, 103))	('miR-489-3p', 'Chemical', '-', (42, 52))	('MEK1', 'molecular_function', 'GO:0004708', ('88', '92'))
84278	32717723	Mutations on circDHX33 and the MEK1 3'UTR were induced by changing the conserved binding sites of miR-489-3p using a gene mutation kit (Takara).	('binding', 'molecular_function', 'GO:0005488', ('81', '88'))	('miR-489-3p', 'Chemical', '-', (98, 108))	('MEK1', 'molecular_function', 'GO:0004708', ('31', '35'))	('induced', 'Reg', (47, 54))	('Mutations', 'Var', (0, 9))	('DHX33', 'Gene', (17, 22))	('MEK1', 'Gene', '5604', (31, 35))	('DHX33', 'Gene', '56919', (17, 22))	('binding', 'Interaction', (81, 88))	('changing', 'Reg', (58, 66))	('MEK1', 'Gene', (31, 35))
84279	32717723	The mutated sequence or wild-type seed region were co-transfected with miR-489-3p mimics or miR-NC into RCC cells using Lipofectamine 2000.	('mutated', 'Var', (4, 11))	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (120, 138))	('miR-489-3p', 'Chemical', '-', (71, 81))	('RCC', 'Disease', (104, 107))
84286	32717723	Survival analysis for RCC patients with miR-489-3p expression was performed using the KM plot database (http://www.kmplot.com) and PROGgeneV2 (http://genomics.jefferson.edu/proggene/results.php).	('RCC', 'Disease', (22, 25))	('RCC', 'Phenotype', 'HP:0005584', (22, 25))	('RCC', 'Disease', 'MESH:C538614', (22, 25))	('patients', 'Species', '9606', (26, 34))	('miR-489-3p expression', 'Var', (40, 61))	('miR-489-3p', 'Chemical', '-', (40, 50))
84291	31801263	Changes in TRP channels' expression and function have been found to regulate cell proliferation and resistance or sensitivity of cancer cells to apoptotic-induced cell death, resulting in cancer-promoting effects or resistance to chemotherapy treatments.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cell proliferation', 'biological_process', 'GO:0008283', ('77', '95'))	('regulate', 'Reg', (68, 76))	('TRP channels', 'Gene', (11, 23))	('expression', 'MPA', (25, 35))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('resistance', 'CPA', (100, 110))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('rat', 'Species', '10116', (89, 92))	('cell death', 'biological_process', 'GO:0008219', ('163', '173'))	('Changes', 'Var', (0, 7))	('sensitivity', 'CPA', (114, 125))	('cancer', 'Disease', (188, 194))	('function', 'MPA', (40, 48))	('cell proliferation', 'CPA', (77, 95))
84303	31801263	Indeed, high TRPM8 expression is related to a worse OS in pancreatic cancer (PC) patients (p = 0.001); and increased TRPM7 expression represents an unfavorable factor in human bladder cancer (BCa) (p < 0.05).	('expression', 'MPA', (123, 133))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('bladder cancer', 'Phenotype', 'HP:0009725', (176, 190))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (58, 75))	('expression', 'MPA', (19, 29))	('high', 'Var', (8, 12))	('increased', 'PosReg', (107, 116))	('PC', 'Disease', 'MESH:D010190', (77, 79))	('BCa', 'Disease', (192, 195))	('pancreatic cancer', 'Disease', 'MESH:D010190', (58, 75))	('BCa', 'Disease', 'MESH:D001749', (192, 195))	('PC', 'Phenotype', 'HP:0002894', (77, 79))	('TRPM7', 'Gene', (117, 122))	('pancreatic cancer', 'Disease', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('patients', 'Species', '9606', (81, 89))	('human', 'Species', '9606', (170, 175))	('BCa', 'Phenotype', 'HP:0009725', (192, 195))	('TRPM8', 'Gene', (13, 18))	('bladder cancer', 'Disease', 'MESH:D001749', (176, 190))	('bladder cancer', 'Disease', (176, 190))
84305	31801263	Overexpression of TRPV3 correlates with tumor progression and short OS in non-small cell lung carcinoma (NSCLC) (p = 0.020); and loss or reduction of TRPML1 mRNA expression correlates with short survival in glioblastoma (GBM) patients (p < 0.0298).	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('short OS', 'Disease', (62, 70))	('short OS', 'Disease', 'MESH:C567932', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('TRPV3', 'Gene', (18, 23))	('TRPV3', 'Gene', '162514', (18, 23))	('short', 'Disease', (189, 194))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (74, 103))	('TRPML1', 'Gene', (150, 156))	('patients', 'Species', '9606', (226, 234))	('non-small cell lung carcinoma', 'Disease', (74, 103))	('glioblastoma', 'Disease', 'MESH:D005909', (207, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (78, 103))	('N', 'Chemical', 'MESH:D009584', (105, 106))	('GBM', 'Disease', (221, 224))	('loss', 'Var', (129, 133))	('TRPML1', 'Gene', '57192', (150, 156))	('glioblastoma', 'Disease', (207, 219))	('tumor', 'Disease', (40, 45))	('N', 'Chemical', 'MESH:D009584', (159, 160))	('GBM', 'Disease', 'MESH:D005909', (221, 224))	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (207, 219))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mRNA expression', 'MPA', (157, 172))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (74, 103))	('NSCLC', 'Disease', (105, 110))	('GBM', 'Phenotype', 'HP:0012174', (221, 224))
84306	31801263	In addition, in diffuse large B cell lymphoma, TRPM4 positivity confers worse OS (p = 0.004) and progression-free survival (p = 0.005) in rituximab-, cyclophosphamide-, doxorubicin-, vincristine-, and prednisone-treated lymphoma cells.	('lymphoma', 'Disease', (220, 228))	('B cell lymphoma', 'Disease', (30, 45))	('lymphoma', 'Disease', 'MESH:D008223', (220, 228))	('positivity', 'Var', (53, 63))	('lymphoma', 'Disease', (37, 45))	('TRPM4', 'Gene', (47, 52))	('lymphoma', 'Disease', 'MESH:D008223', (37, 45))	('B cell lymphoma', 'Disease', 'MESH:D016393', (30, 45))	('progression-free survival', 'CPA', (97, 122))	('prednisone', 'Chemical', 'MESH:D011241', (201, 211))	('lymphoma', 'Phenotype', 'HP:0002665', (220, 228))	('TRPM4', 'Gene', '54795', (47, 52))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (30, 45))	('lymphoma', 'Phenotype', 'HP:0002665', (37, 45))	('worse', 'NegReg', (72, 77))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (150, 166))	('large B cell', 'Phenotype', 'HP:0005404', (24, 36))	('vincristine', 'Chemical', 'MESH:D014750', (183, 194))	('doxorubicin', 'Chemical', 'MESH:D004317', (169, 180))
84315	31801263	Sustained treatment of glioma cells with the inhibitors SKF96365 (25 muM) and aminoethoxydiphenyl borate (2-APB) (100 muM) reduced cell proliferation, with an accumulation of glioma cells in the G2/M phase and impairment of cytokinesis.	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('rat', 'Species', '10116', (143, 146))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('cell proliferation', 'biological_process', 'GO:0008283', ('131', '149'))	('aminoethoxydiphenyl borate', 'Chemical', 'MESH:C109986', (78, 104))	('impairment of cytokinesis', 'Disease', (210, 235))	('accumulation', 'PosReg', (159, 171))	('glioma', 'Disease', (175, 181))	('SKF96365', 'Chemical', 'MESH:C063159', (56, 64))	('rat', 'Species', '10116', (100, 103))	('glioma', 'Disease', 'MESH:D005910', (175, 181))	('M phase', 'biological_process', 'GO:0000279', ('198', '205'))	('SKF96365', 'Var', (56, 64))	('muM', 'Gene', '56925', (118, 121))	('cytokinesis', 'biological_process', 'GO:0000910', ('224', '235'))	('muM', 'Gene', (118, 121))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))	('muM', 'Gene', '56925', (69, 72))	('muM', 'Gene', (69, 72))	('glioma', 'Disease', (23, 29))	('cell proliferation', 'CPA', (131, 149))	('impairment of cytokinesis', 'Disease', 'MESH:D008569', (210, 235))	('reduced', 'NegReg', (123, 130))
84316	31801263	However, 2-APB is not only a TRPC inhibitor, but it can also activate both TRPV2 and TRPV3 and, in addition, works as an inositol triphosphate (IP3)-induced Ca2+-release inhibitor.	('TRPV3', 'Gene', (85, 90))	('TRPV3', 'Gene', '162514', (85, 90))	('activate', 'PosReg', (61, 69))	('PC', 'Disease', 'MESH:D010190', (31, 33))	('Ca2+', 'Chemical', 'MESH:D002118', (157, 161))	('2-APB', 'Var', (9, 14))	('TRPV2', 'Protein', (75, 80))	('inositol triphosphate', 'Chemical', 'MESH:C092449', (121, 142))	('PC', 'Phenotype', 'HP:0002894', (31, 33))
84319	31801263	In this regard, in GBM cells, TRPC1 silencing or blockade using SKF96365 at 25 muM, 2-APB at 100 muM, or MRS1845 at 25 muM inhibits the chemotactic migration induced by EGF but not basal migration.	('EGF', 'molecular_function', 'GO:0005154', ('169', '172'))	('rat', 'Species', '10116', (151, 154))	('GBM', 'Disease', (19, 22))	('GBM', 'Disease', 'MESH:D005909', (19, 22))	('SKF96365', 'Chemical', 'MESH:C063159', (64, 72))	('PC', 'Phenotype', 'HP:0002894', (32, 34))	('rat', 'Species', '10116', (190, 193))	('muM', 'Gene', '56925', (97, 100))	('silencing', 'NegReg', (36, 45))	('muM', 'Gene', (97, 100))	('muM', 'Gene', '56925', (119, 122))	('inhibits', 'NegReg', (123, 131))	('SKF96365', 'Var', (64, 72))	('MRS1845', 'Var', (105, 112))	('muM', 'Gene', (119, 122))	('chemotactic migration induced by EGF', 'CPA', (136, 172))	('GBM', 'Phenotype', 'HP:0012174', (19, 22))	('TRPC1', 'Gene', (30, 35))	('muM', 'Gene', '56925', (79, 82))	('muM', 'Gene', (79, 82))	('TRPC1', 'Gene', '7220', (30, 35))
84321	31801263	The inhibition of TRPC1 using 2-APB or TRPC1 silencing reduces the adhesive and invasive capabilities of nasopharyngeal cancer cells, suggesting that TRPC1 can modulate metastasis spreading.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('silencing', 'Var', (45, 54))	('TRPC1', 'Gene', '7220', (39, 44))	('TRPC1', 'Gene', (39, 44))	('PC', 'Phenotype', 'HP:0002894', (152, 154))	('TRPC1', 'Gene', '7220', (150, 155))	('metastasis spreading', 'CPA', (169, 189))	('TRPC1', 'Gene', (150, 155))	('modulate', 'Reg', (160, 168))	('cancer', 'Disease', (120, 126))	('reduces', 'NegReg', (55, 62))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('TRPC1', 'Gene', '7220', (18, 23))	('TRPC1', 'Gene', (18, 23))	('PC', 'Phenotype', 'HP:0002894', (20, 22))	('PC', 'Phenotype', 'HP:0002894', (41, 43))	('inhibition', 'NegReg', (4, 14))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (105, 126))
84330	31801263	The BT-549 and Hs578T TNBC BC cell lines, which express high TRPC4 and TRPC1/C4 heterodimer levels, are more sensitive to EA than other TNBC cell lines.	('EA', 'Chemical', 'MESH:C534971', (122, 124))	('PC', 'Phenotype', 'HP:0002894', (73, 75))	('N', 'Chemical', 'MESH:D009584', (23, 24))	('TRPC1', 'Gene', '7220', (71, 76))	('TRPC1', 'Gene', (71, 76))	('high', 'PosReg', (56, 60))	('TRPC4', 'Gene', '7223', (61, 66))	('TRPC4', 'Gene', (61, 66))	('sensitive', 'MPA', (109, 118))	('N', 'Chemical', 'MESH:D009584', (137, 138))	('BT-549', 'CellLine', 'CVCL:1092', (4, 10))	('Hs578T', 'Var', (15, 21))	('heterodimer levels', 'MPA', (80, 98))	('TNBC', 'Gene', (22, 26))	('PC', 'Phenotype', 'HP:0002894', (63, 65))
84331	31801263	In Hs578T TNBC cells, EA induces Na+ and Ca2+ accumulation, whereas in BT-549 cells, it increases cytosolic Ca2+ levels and induces mitochondrial depolarization.	('cytosolic Ca2+ levels', 'MPA', (98, 119))	('Hs578T', 'Var', (3, 9))	('N', 'Chemical', 'MESH:D009584', (33, 34))	('mitochondrial depolarization', 'MPA', (132, 160))	('induces', 'Reg', (25, 32))	('Ca2+', 'Chemical', 'MESH:D002118', (41, 45))	('induces', 'Reg', (124, 131))	('Ca2+', 'Chemical', 'MESH:D002118', (108, 112))	('N', 'Chemical', 'MESH:D009584', (11, 12))	('increases', 'PosReg', (88, 97))	('mitochondrial depolarization', 'biological_process', 'GO:0051882', ('132', '160'))	('EA', 'Chemical', 'MESH:C534971', (22, 24))	('BT-549', 'CellLine', 'CVCL:1092', (71, 77))
84334	31801263	Ouabain (10 nM), an Na+/K+-ATPase inhibitor, increases EA-induced cytotoxicity; Na+ entry by the Na+ loading ionophore, gramicidin-A, causes cell death of SW982 cells, which are resistant to Pico145 (10 nM), suggesting that Na+ loading is itself cytotoxic even without TRPC1/C4 activation.	('cell death', 'biological_process', 'GO:0008219', ('141', '151'))	('cytotoxicity', 'Disease', 'MESH:D064420', (66, 78))	('causes', 'Reg', (134, 140))	('TRPC1', 'Gene', '7220', (269, 274))	('ATP', 'Chemical', 'MESH:D000255', (27, 30))	('EA', 'Chemical', 'MESH:C534971', (55, 57))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('ionophore', 'molecular_function', 'GO:0022809', ('109', '118'))	('N', 'Chemical', 'MESH:D009584', (80, 81))	('Na+', 'Var', (80, 83))	('PC', 'Phenotype', 'HP:0002894', (271, 273))	('cell death', 'CPA', (141, 151))	('cytotoxicity', 'Disease', (66, 78))	('N', 'Chemical', 'MESH:D009584', (224, 225))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('TRPC1', 'Gene', (269, 274))	('Ouabain', 'Chemical', 'MESH:D010042', (0, 7))	('SW982', 'CellLine', 'CVCL:1734', (155, 160))
84336	31801263	EA exerts a rapid cytotoxic effect on TRPC4-positive A498 RCCs and Hs578T TNBC.	('N', 'Chemical', 'MESH:D009584', (75, 76))	('EA', 'Chemical', 'MESH:C534971', (0, 2))	('PC', 'Phenotype', 'HP:0002894', (40, 42))	('TRPC4', 'Gene', '7223', (38, 43))	('TRPC4', 'Gene', (38, 43))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('Hs578T', 'Var', (67, 73))	('RCC', 'Disease', 'MESH:D002292', (58, 61))
84340	31801263	Indeed, inhibition of Na+/K+-ATPase by ouabain increases the EA-evoked cytotoxicity, suggesting that EA-mediated cancer cell cytotoxicity sustains Na+ entry through the heteromeric TRPC1/TRPC4 channels and EA cytotoxicity can be increased by Na+/K+-ATPase inhibition.	('N', 'Chemical', 'MESH:D009584', (22, 23))	('cytotoxicity', 'Disease', (209, 221))	('cancer', 'Disease', (113, 119))	('cytotoxicity', 'Disease', 'MESH:D064420', (209, 221))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('PC', 'Phenotype', 'HP:0002894', (183, 185))	('ATP', 'Chemical', 'MESH:D000255', (29, 32))	('TRPC4', 'Gene', (187, 192))	('N', 'Chemical', 'MESH:D009584', (242, 243))	('TRPC1', 'Gene', (181, 186))	('N', 'Chemical', 'MESH:D009584', (147, 148))	('inhibition', 'Var', (8, 18))	('TRPC4', 'Gene', '7223', (187, 192))	('ATP', 'Chemical', 'MESH:D000255', (249, 252))	('EA', 'Chemical', 'MESH:C534971', (206, 208))	('TRPC1', 'Gene', '7220', (181, 186))	('cytotoxicity', 'Disease', (71, 83))	('ouabain', 'Chemical', 'MESH:D010042', (39, 46))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cytotoxicity', 'Disease', 'MESH:D064420', (71, 83))	('cytotoxicity', 'Disease', (125, 137))	('PC', 'Phenotype', 'HP:0002894', (189, 191))	('EA', 'Chemical', 'MESH:C534971', (61, 63))	('heteromeric', 'MPA', (169, 180))	('cytotoxicity', 'Disease', 'MESH:D064420', (125, 137))	('Na+ entry', 'MPA', (147, 156))	('EA', 'Chemical', 'MESH:C534971', (101, 103))
84343	31801263	TZL enhances the intracellular Ca2+ and induces TRPC4 and TRPC5 overexpression and the assembly of TRPC1-TRPC4 and TRPC1-TRPC5 heterodimers in A498 RCC line, which are inhibited by Pico145.	('RCC', 'Disease', (148, 151))	('TRPC1', 'Gene', '7220', (99, 104))	('PC', 'Phenotype', 'HP:0002894', (50, 52))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('assembly', 'MPA', (87, 95))	('induces', 'PosReg', (40, 47))	('intracellular', 'cellular_component', 'GO:0005622', ('17', '30'))	('RCC', 'Disease', 'MESH:D002292', (148, 151))	('PC', 'Phenotype', 'HP:0002894', (117, 119))	('TRPC5', 'Gene', '7224', (58, 63))	('TRPC5', 'Gene', '7224', (121, 126))	('TRPC5', 'Gene', (58, 63))	('heterodimers', 'Protein', (127, 139))	('TRPC5', 'Gene', (121, 126))	('TRPC4', 'Gene', (105, 110))	('TRPC1', 'Gene', (115, 120))	('TRPC4', 'Gene', (48, 53))	('PC', 'Phenotype', 'HP:0002894', (107, 109))	('PC', 'Phenotype', 'HP:0002894', (101, 103))	('intracellular Ca2+', 'MPA', (17, 35))	('TRPC4', 'Gene', '7223', (105, 110))	('TRPC1', 'Gene', (99, 104))	('overexpression', 'PosReg', (64, 78))	('PC', 'Phenotype', 'HP:0002894', (60, 62))	('TRPC4', 'Gene', '7223', (48, 53))	('enhances', 'PosReg', (4, 12))	('Ca2+', 'Chemical', 'MESH:D002118', (31, 35))	('TZL', 'Var', (0, 3))	('TRPC1', 'Gene', '7220', (115, 120))
84346	31801263	AM237 also activates TRPC5 channels and potently inhibits EA-dependent activation.	('activates', 'PosReg', (11, 20))	('TRPC5', 'Gene', (21, 26))	('EA', 'Chemical', 'MESH:C534971', (58, 60))	('inhibits', 'NegReg', (49, 57))	('AM237', 'Var', (0, 5))	('PC', 'Phenotype', 'HP:0002894', (23, 25))	('TRPC5', 'Gene', '7224', (21, 26))	('EA-dependent activation', 'MPA', (58, 81))
84354	31801263	Treatment of A549 cells with GBM cells with SKF96365 (25 muM) and 2-APB (100 muM), all-trans retinoic acid (ATRA, 1 muM) for 96 h increased TRPC3, C4, and C6 expression and enhanced Ca2+ influx.	('muM', 'Gene', (116, 119))	('TRPC3', 'Gene', (140, 145))	('GBM', 'Phenotype', 'HP:0012174', (29, 32))	('increased', 'PosReg', (130, 139))	('muM', 'Gene', '56925', (57, 60))	('A549', 'CellLine', 'CVCL:0023', (13, 17))	('PC', 'Phenotype', 'HP:0002894', (142, 144))	('all-trans retinoic acid', 'Chemical', 'MESH:D014212', (83, 106))	('muM', 'Gene', (57, 60))	('expression', 'MPA', (158, 168))	('Ca2+ influx', 'MPA', (182, 193))	('muM', 'Gene', '56925', (77, 80))	('enhanced', 'PosReg', (173, 181))	('ATRA', 'Chemical', 'MESH:D014212', (108, 112))	('muM', 'Gene', (77, 80))	('SKF96365', 'Chemical', 'MESH:C063159', (44, 52))	('TRPC3', 'Gene', '7222', (140, 145))	('Ca2+', 'Chemical', 'MESH:D002118', (182, 186))	('GBM', 'Disease', (29, 32))	('SKF96365', 'Var', (44, 52))	('GBM', 'Disease', 'MESH:D005909', (29, 32))	('muM', 'Gene', '56925', (116, 119))
84362	31801263	Furthermore, nicotine upregulates hypoxia inducible factor 1alpha (HIF-1alpha) expression in A549 and NCI-H292 cells; silencing of HIF-1alpha stimulates an increase in TRPCs and Orai1 and decreases basal [Ca2+]i and SOCE.	('NCI-H292', 'CellLine', 'CVCL:0455', (102, 110))	('HIF-1alpha', 'Gene', '3091', (67, 77))	('PC', 'Phenotype', 'HP:0002894', (170, 172))	('OC', 'Disease', 'MESH:D010051', (217, 219))	('Orai1', 'Gene', (178, 183))	('decreases', 'NegReg', (188, 197))	('HIF-1alpha', 'Gene', (131, 141))	('increase', 'PosReg', (156, 164))	('HIF-1alpha', 'Gene', (67, 77))	('OC', 'Phenotype', 'HP:0100615', (217, 219))	('silencing', 'Var', (118, 127))	('Orai1', 'Gene', '84876', (178, 183))	('SOCE', 'biological_process', 'GO:0002115', ('216', '220'))	('hypoxia inducible factor 1alpha', 'Gene', (34, 65))	('A549', 'CellLine', 'CVCL:0023', (93, 97))	('SO', 'Chemical', 'MESH:C443440', (216, 218))	('[Ca2+]i', 'Chemical', 'MESH:D002118', (204, 211))	('PC', 'Disease', 'MESH:D010190', (170, 172))	('nicotine', 'Chemical', 'MESH:D009538', (13, 21))	('basal [Ca2+]i', 'MPA', (198, 211))	('HIF-1alpha', 'Gene', '3091', (131, 141))	('hypoxia inducible factor 1alpha', 'Gene', '3091', (34, 65))
84379	31801263	High expression of TRPC5 is associated with upregulation of glucose transporter 1 in CRCs, and an increase in glycolysis occurs in chemoresistance cells.	('CRC', 'Disease', 'MESH:D015179', (85, 88))	('High expression', 'Var', (0, 15))	('TRPC5', 'Gene', '7224', (19, 24))	('glycolysis', 'biological_process', 'GO:0006096', ('110', '120'))	('glucose', 'Chemical', 'MESH:D005947', (60, 67))	('glucose transporter 1', 'MPA', (60, 81))	('upregulation', 'PosReg', (44, 56))	('CRC', 'Disease', (85, 88))	('increase', 'PosReg', (98, 106))	('TRPC5', 'Gene', (19, 24))	('PC', 'Phenotype', 'HP:0002894', (21, 23))	('CRC', 'Phenotype', 'HP:0003003', (85, 88))	('glycolysis', 'MPA', (110, 120))
84387	31801263	In an HCC xenograft model, TRPC6 silencing resulted in slower growth and greater doxorubicin sensitivity with respect controls.	('TRPC6', 'Gene', (27, 32))	('PC', 'Phenotype', 'HP:0002894', (29, 31))	('greater', 'PosReg', (73, 80))	('doxorubicin', 'Chemical', 'MESH:D004317', (81, 92))	('silencing', 'Var', (33, 42))	('TRPC6', 'Gene', '7225', (27, 32))	('HCC', 'Disease', 'MESH:D006528', (6, 9))	('growth', 'MPA', (62, 68))	('HCC', 'Disease', (6, 9))	('slower', 'NegReg', (55, 61))	('HCC', 'Phenotype', 'HP:0001402', (6, 9))	('doxorubicin sensitivity', 'MPA', (81, 104))
84392	31801263	A previous report on TRPM2 modulators evaluated in Xenopus oocytes evidenced that H2O2, AMP, cyclic ADPR, dinucleotide phosphate, and nicotinic acid adenine dinucleotide do not affect TRPM2 channels in physiological conditions.	('nicotinic acid adenine dinucleotide', 'Chemical', 'MESH:C018348', (134, 169))	('TRPM2', 'Gene', (21, 26))	('dinucleotide phosphate', 'Chemical', 'MESH:C024376', (106, 128))	('H2O2', 'Chemical', 'MESH:D014867', (82, 86))	('TRPM2', 'Gene', '7226', (21, 26))	('AMP', 'Chemical', 'MESH:D000249', (88, 91))	('TRPM2', 'Gene', '7226', (184, 189))	('TRPM2', 'Gene', (184, 189))	('H2O2', 'Var', (82, 86))	('cyclic ADPR', 'Chemical', 'MESH:C082175', (93, 104))	('AMP', 'MPA', (88, 91))	('Xenopus', 'Species', '8355', (51, 58))
84405	31801263	Moreover, in ME and GaC patients, high TRPM5 mRNA expression correlates with poor OS rates.	('N', 'Chemical', 'MESH:D009584', (47, 48))	('GaC', 'Phenotype', 'HP:0012126', (20, 23))	('ME', 'Disease', 'MESH:D008545', (13, 15))	('rat', 'Species', '10116', (85, 88))	('GaC', 'Disease', (20, 23))	('high', 'Var', (34, 38))	('GaC', 'Disease', 'MESH:D013274', (20, 23))	('patients', 'Species', '9606', (24, 32))	('mRNA expression', 'MPA', (45, 60))	('poor', 'Disease', (77, 81))	('ME', 'Phenotype', 'HP:0002861', (13, 15))	('TRPM5', 'Gene', (39, 44))
84410	31801263	The inhibitory effects of WA on TRPM7 are strongly dependent on [Mg2+]i, indicating that this compound enhances Mg2+ blockade of the channels or that Mg2+ enhances the binding affinity of WA.	('WA', 'Chemical', 'MESH:C568854', (26, 28))	('Mg2+', 'Chemical', 'MESH:D008274', (112, 116))	('WA', 'Chemical', 'MESH:C568854', (188, 190))	('Mg2+', 'Var', (150, 154))	('TRPM7', 'Gene', (32, 37))	('Mg2+', 'Chemical', 'MESH:D008274', (150, 154))	('Mg2+', 'Chemical', 'MESH:D008274', (65, 69))	('Mg2+ blockade', 'MPA', (112, 125))	('enhances', 'PosReg', (155, 163))	('enhances', 'PosReg', (103, 111))	('binding affinity', 'Interaction', (168, 184))	('binding', 'molecular_function', 'GO:0005488', ('168', '175'))
84420	31801263	Recent findings in glioma have shown that vacquinol-1 (Vac) promotes cell death as a consequence of inefficient vacuole-lysosome fusion, which is reversed by exogenous ATP in GBM.	('promotes', 'PosReg', (60, 68))	('cell death', 'biological_process', 'GO:0008219', ('69', '79'))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))	('GBM', 'Disease', 'MESH:D005909', (175, 178))	('vacuole-lysosome fusion', 'CPA', (112, 135))	('ATP', 'Chemical', 'MESH:D000255', (168, 171))	('GBM', 'Phenotype', 'HP:0012174', (175, 178))	('glioma', 'Disease', (19, 25))	('vacquinol', 'Chemical', 'MESH:C000588923', (42, 51))	('cell death', 'CPA', (69, 79))	('lysosome', 'cellular_component', 'GO:0005764', ('120', '128'))	('vacquinol-1', 'Var', (42, 53))	('vacuole', 'cellular_component', 'GO:0005773', ('112', '119'))	('glioma', 'Disease', 'MESH:D005910', (19, 25))	('GBM', 'Disease', (175, 178))
84423	31801263	Overexpression of TRPM7 is responsible for Vac resistance in glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('glioma', 'Disease', (61, 67))	('responsible', 'Reg', (27, 38))	('Overexpression', 'Var', (0, 14))	('glioma', 'Disease', 'MESH:D005910', (61, 67))	('Vac resistance', 'MPA', (43, 57))	('TRPM7', 'Gene', (18, 23))
84425	31801263	Silencing TRPM7 in PC cells induces the replicative senescence program.	('PC', 'Phenotype', 'HP:0002894', (19, 21))	('induces', 'Reg', (28, 35))	('PC', 'Disease', 'MESH:D010190', (19, 21))	('Silencing', 'Var', (0, 9))	('replicative senescence program', 'CPA', (40, 70))	('replicative senescence', 'biological_process', 'GO:0090399', ('40', '62'))	('TRPM7', 'Gene', (10, 15))
84446	31801263	TRPM8 silencing reduces the effect of CBG on cell growth and on CHOP mRNA expression.	('CHOP', 'Gene', '1649', (64, 68))	('N', 'Chemical', 'MESH:D009584', (71, 72))	('CBG', 'Chemical', 'MESH:C037036', (38, 41))	('cell growth', 'CPA', (45, 56))	('CHOP', 'Gene', (64, 68))	('reduces', 'NegReg', (16, 23))	('cell growth', 'biological_process', 'GO:0016049', ('45', '56'))	('TRPM8', 'Gene', (0, 5))	('silencing', 'Var', (6, 15))
84451	31801263	Moreover, RQ-00203078, another TRPM8 antagonist, is used in HSC3 and HSC4 OSC cell lines.	('HSC', 'cellular_component', 'GO:0035301', ('60', '63'))	('HSC', 'cellular_component', 'GO:0035301', ('69', '72'))	('HSC3', 'Gene', (60, 64))	('OSC', 'Disease', 'MESH:D002294', (74, 77))	('OSC', 'Disease', (74, 77))	('RQ-00203078', 'Var', (10, 21))	('RQ-00203078', 'Chemical', 'MESH:C043461', (10, 21))	('HSC3', 'Gene', '150353', (60, 64))	('OSC', 'molecular_function', 'GO:0000250', ('74', '77'))
84452	31801263	RQ-00203078 (10 muM) completely abolishes menthol-induced TRPM8 whole-cell currents and SOCE in both cell lines.	('OC', 'Disease', 'MESH:D010051', (89, 91))	('OC', 'Phenotype', 'HP:0100615', (89, 91))	('SOCE', 'biological_process', 'GO:0002115', ('88', '92'))	('abolishes', 'NegReg', (32, 41))	('whole-cell currents', 'MPA', (64, 83))	('menthol', 'Chemical', 'MESH:D008610', (42, 49))	('RQ-00203078', 'Var', (0, 11))	('muM', 'Gene', '56925', (16, 19))	('SO', 'Chemical', 'MESH:C443440', (88, 90))	('RQ-00203078', 'Chemical', 'MESH:C043461', (0, 11))	('muM', 'Gene', (16, 19))	('TRPM8', 'Gene', (58, 63))
84453	31801263	Moreover, RQ-00203078 inhibits both menthol-induced basal cell proliferation as well as menthol-induced basal migration and invasion.	('rat', 'Species', '10116', (70, 73))	('RQ-00203078', 'Chemical', 'MESH:C043461', (10, 21))	('basal migration', 'CPA', (104, 119))	('rat', 'Species', '10116', (113, 116))	('basal cell proliferation', 'Phenotype', 'HP:0002671', (52, 76))	('basal cell proliferation', 'CPA', (52, 76))	('RQ-00203078', 'Var', (10, 21))	('inhibits', 'NegReg', (22, 30))	('invasion', 'CPA', (124, 132))	('menthol', 'Chemical', 'MESH:D008610', (36, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('58', '76'))	('menthol', 'Chemical', 'MESH:D008610', (88, 95))
84454	31801263	Menthol-induced MMP-9 activity is also suppressed by RQ-00203078.	('RQ-00203078', 'Chemical', 'MESH:C043461', (53, 64))	('MMP-9 activity', 'MPA', (16, 30))	('Menthol', 'Chemical', 'MESH:D008610', (0, 7))	('MMP-9', 'molecular_function', 'GO:0004229', ('16', '21'))	('suppressed', 'NegReg', (39, 49))	('RQ-00203078', 'Var', (53, 64))
84463	31801263	The mechanism of TRPM8 in gemcitabine-based chemotherapy is a consequence of the reduction in the expression and activity of multidrug resistance-associated proteins, such as P-gp in response to TRPM8 silencing.	('P-gp', 'Gene', '5243', (175, 179))	('silencing', 'Var', (201, 210))	('P-gp', 'Gene', (175, 179))	('reduction', 'NegReg', (81, 90))	('activity', 'MPA', (113, 121))	('TRPM8', 'Gene', (195, 200))	('gemcitabine', 'Chemical', 'MESH:C056507', (26, 37))	('drug resistance', 'Phenotype', 'HP:0020174', (130, 145))	('TRPM8', 'Gene', (17, 22))	('expression', 'MPA', (98, 108))
84464	31801263	Moreover, TRPM8 knockdown significantly increased human equilibrative nucleoside transporter 1 protein levels and the Bax/Bcl-2 pro-apoptotic ratio, while reducing ribonucleotide reductase M1 protein levels.	('Bax', 'Gene', (118, 121))	('ribonucleotide reductase M1 protein levels', 'MPA', (164, 206))	('reducing', 'NegReg', (155, 163))	('Bcl-2', 'molecular_function', 'GO:0015283', ('122', '127'))	('Bax', 'Gene', '581', (118, 121))	('knockdown', 'Var', (16, 25))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('nucleoside', 'Chemical', 'MESH:D009705', (70, 80))	('human', 'Species', '9606', (50, 55))	('ribonucleotide', 'Chemical', 'MESH:D012265', (164, 178))	('increased', 'PosReg', (40, 49))	('protein', 'cellular_component', 'GO:0003675', ('192', '199'))	('Bcl-2', 'Gene', (122, 127))	('Bcl-2', 'Gene', '596', (122, 127))	('rat', 'Species', '10116', (63, 66))	('TRPM8', 'Gene', (10, 15))	('rat', 'Species', '10116', (142, 145))
84465	31801263	Furthermore, in osteosarcoma cells, TRPM8 knockdown induces Ca2+imbalance, inhibition of protein kinase B (Akt)-Glycogen synthase kinase (GSK)-3beta, extracellular signal-regulated kinases (ERK)1/2 and FAK pathways, decreases proliferation, invasion, and migration, and improves apoptosis induced by epirubicin.	('migration', 'CPA', (255, 264))	('epirubicin', 'Chemical', 'MESH:D015251', (300, 310))	('TRPM8', 'Gene', (36, 41))	('osteosarcoma', 'Phenotype', 'HP:0002669', (16, 28))	('FAK', 'Gene', (202, 205))	('extracellular', 'cellular_component', 'GO:0005576', ('150', '163'))	('apoptosis', 'biological_process', 'GO:0097194', ('279', '288'))	('FAK', 'Gene', '5747', (202, 205))	('ERK)1', 'molecular_function', 'GO:0004707', ('190', '195'))	('apoptosis', 'biological_process', 'GO:0006915', ('279', '288'))	('invasion', 'CPA', (241, 249))	('proliferation', 'CPA', (226, 239))	('Ca2+imbalance', 'MPA', (60, 73))	('knockdown', 'Var', (42, 51))	('FAK', 'molecular_function', 'GO:0004717', ('202', '205'))	('decreases', 'NegReg', (216, 225))	('GSK', 'molecular_function', 'GO:0050321', ('138', '141'))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('Akt', 'Gene', (107, 110))	('inhibition', 'NegReg', (75, 85))	('osteosarcoma', 'Disease', (16, 28))	('rat', 'Species', '10116', (233, 236))	('induces', 'Reg', (52, 59))	('rat', 'Species', '10116', (258, 261))	('osteosarcoma', 'Disease', 'MESH:D012516', (16, 28))	('Akt', 'Gene', '207', (107, 110))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))	('improves', 'PosReg', (270, 278))	('apoptosis', 'CPA', (279, 288))	('extracellular signal-regulated kinases (ERK)1/2', 'Gene', '5595;5594', (150, 197))	('Ca2+', 'Chemical', 'MESH:D002118', (60, 64))
84475	31801263	Over 1000 different miRNAs are encoded by the human genome; approximately 20% to 30% of all genes are targeted by miRNAs, and a single miRNA may target up to 200 genes.	('miRNAs', 'Var', (114, 120))	('miRNAs', 'Chemical', 'MESH:D000596', (114, 120))	('human', 'Species', '9606', (46, 51))	('miRNAs', 'Chemical', 'MESH:D000596', (20, 26))	('target', 'Reg', (145, 151))
84476	31801263	In human cancers, specific miRNAs are expressed in different tissues, and changes in the control of gene expression have been associated with carcinogenesis.	('carcinogenesis', 'Disease', (142, 156))	('miRNAs', 'Chemical', 'MESH:D000596', (27, 33))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('associated', 'Reg', (126, 136))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('human', 'Species', '9606', (3, 8))	('gene expression', 'biological_process', 'GO:0010467', ('100', '115'))	('control of', 'MPA', (89, 99))	('changes', 'Var', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('carcinogenesis', 'Disease', 'MESH:D063646', (142, 156))
84478	31801263	The analysis of a possible correlation between the expression of selected miRNAs and the TRPM8 gene have shown an inverse correlation between high TRPM8 expression and low miR-26a expression.	('miR-26a', 'Gene', '407015', (172, 179))	('miR-26a', 'Gene', (172, 179))	('low', 'NegReg', (168, 171))	('expression', 'MPA', (180, 190))	('miRNAs', 'Chemical', 'MESH:D000596', (74, 80))	('expression', 'MPA', (153, 163))	('high', 'Var', (142, 146))	('TRPM8', 'Gene', (147, 152))	('TRPM8', 'Gene', (89, 94))
84483	31801263	TRPM3 expression is enhanced in human ccRCC with inactivated or deleted VHL.	('VHL', 'Gene', '7428', (72, 75))	('enhanced', 'PosReg', (20, 28))	('TRPM3', 'Gene', (0, 5))	('expression', 'MPA', (6, 16))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('VHL', 'Gene', (72, 75))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('ccRCC', 'Disease', (38, 43))	('ccRCC', 'Disease', 'MESH:D002292', (38, 43))	('human', 'Species', '9606', (32, 37))	('TRPM3', 'Gene', '80036', (0, 5))	('deleted', 'Var', (64, 71))
84484	31801263	Loss of VHL inhibits the expression of miR204, that in turn leads to an increase of the oncogenic autophagy in ccRCC, resulting in augmented TRPM3 expression, a direct target of miR204.	('increase', 'PosReg', (72, 80))	('VHL', 'Gene', '7428', (8, 11))	('ccRCC', 'Disease', 'MESH:D002292', (111, 116))	('expression', 'MPA', (147, 157))	('oncogenic autophagy', 'CPA', (88, 107))	('miR204', 'Gene', '406987', (39, 45))	('ccRCC', 'Disease', (111, 116))	('TRPM3', 'Gene', '80036', (141, 146))	('miR204', 'Gene', (39, 45))	('expression', 'MPA', (25, 35))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('inhibits', 'NegReg', (12, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('autophagy', 'biological_process', 'GO:0016236', ('98', '107'))	('Loss', 'Var', (0, 4))	('miR204', 'Gene', '406987', (178, 184))	('VHL', 'Gene', (8, 11))	('autophagy', 'biological_process', 'GO:0006914', ('98', '107'))	('augmented', 'PosReg', (131, 140))	('miR204', 'Gene', (178, 184))	('TRPM3', 'Gene', (141, 146))
84485	31801263	About 50% of the malignant ME show a somatic missense mutation at the amino acid residue V600 of the proto-oncogene B-raf (BRAF600).	('proto-oncogene B-raf', 'Gene', (101, 121))	('malignant ME', 'Disease', 'MESH:D008545', (17, 29))	('malignant ME', 'Disease', (17, 29))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('proto-oncogene B-raf', 'Gene', '673', (101, 121))	('missense mutation at', 'Var', (45, 65))	('ME', 'Phenotype', 'HP:0002861', (27, 29))
84489	31801263	Targeting BC cells with MRS1477, a dihydropyridine derivative acting as a positive allosteric modulator of TRPV1 channels, induces apoptotic cell death.	('apoptotic cell death', 'biological_process', 'GO:0006915', ('131', '151'))	('induces', 'Reg', (123, 130))	('MRS1477', 'Var', (24, 31))	('dihydropyridine', 'Chemical', 'MESH:C038806', (35, 50))	('TRPV1', 'Gene', (107, 112))	('TRPV1', 'Gene', '7442', (107, 112))	('apoptotic cell death', 'CPA', (131, 151))
84492	31801263	These effects are further increased when cells are incubated with MRS1477 alone or in combination with CPS.	('MRS1477', 'Var', (66, 73))	('increased', 'PosReg', (26, 35))	('CPS', 'Chemical', 'MESH:D002211', (103, 106))
84494	31801263	However, the tumor growth in MCF-7 tumor-bearing immunodeficient mice is not inhibited by MRS1477, suggesting that in vivo further studies are required.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', (13, 18))	('MRS1477', 'Var', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('mice', 'Species', '10090', (65, 69))	('tumor', 'Disease', (35, 40))	('MCF-7 tumor-bearing immunodeficient', 'Disease', (29, 64))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('MCF-7 tumor-bearing immunodeficient', 'Disease', 'MESH:C565129', (29, 64))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
84499	31801263	Moreover, CPS inhibits the DNA synthesis and increases the apoptotic bodies number.	('increases', 'PosReg', (45, 54))	('inhibits', 'NegReg', (14, 22))	('CPS', 'Chemical', 'MESH:D002211', (10, 13))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))	('N', 'Chemical', 'MESH:D009584', (28, 29))	('DNA synthesis', 'biological_process', 'GO:0071897', ('27', '40'))	('DNA synthesis', 'MPA', (27, 40))	('apoptotic bodies number', 'CPA', (59, 82))	('CPS', 'Var', (10, 13))
84502	31801263	CPS and CPZ further induce caspase-3 activation and reduce tumor growth in vivo.	('caspase-3', 'Gene', (27, 36))	('tumor', 'Disease', (59, 64))	('activation', 'PosReg', (37, 47))	('CPZ', 'Chemical', 'MESH:C071423', (8, 11))	('CPS', 'Chemical', 'MESH:D002211', (0, 3))	('caspase-3', 'Gene', '836', (27, 36))	('reduce', 'NegReg', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('CPS', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
84512	31801263	In BCa, the TRPV1 agonist CPS (80 muM) promotes Fas/CD95-mediated apoptosis.	('muM', 'Gene', '56925', (34, 37))	('apoptosis', 'biological_process', 'GO:0006915', ('66', '75'))	('BCa', 'Disease', (3, 6))	('promotes', 'PosReg', (39, 47))	('CD95', 'Gene', '355', (52, 56))	('BCa', 'Disease', 'MESH:D001749', (3, 6))	('TRPV1', 'Gene', (12, 17))	('muM', 'Gene', (34, 37))	('TRPV1', 'Gene', '7442', (12, 17))	('CPS', 'Var', (26, 29))	('apoptosis', 'biological_process', 'GO:0097194', ('66', '75'))	('CD95', 'Gene', (52, 56))	('BCa', 'Phenotype', 'HP:0009725', (3, 6))	('CPS', 'Chemical', 'MESH:D002211', (26, 29))
84513	31801263	CPS reduces in a dose-dependent manner the proliferation of the human well-differentiated low-grade papillary RT4 BCa cell line.	('human', 'Species', '9606', (64, 69))	('BCa', 'Phenotype', 'HP:0009725', (114, 117))	('reduces', 'NegReg', (4, 11))	('rat', 'Species', '10116', (50, 53))	('RT4 BCa', 'CellLine', 'CVCL:E025', (110, 117))	('CPS', 'Chemical', 'MESH:D002211', (0, 3))	('proliferation', 'CPA', (43, 56))	('CPS', 'Var', (0, 3))
84518	31801263	The agonist CPS evokes Ca2+influx in etoposide-resistant but not in etoposide-sensitive WERI-Rb1 retinoblastoma cells.	('Ca2+', 'Chemical', 'MESH:D002118', (23, 27))	('evokes', 'Reg', (16, 22))	('Rb1', 'Gene', (93, 96))	('CPS', 'Var', (12, 15))	('retinoblastoma', 'Disease', 'MESH:D012175', (97, 111))	('retinoblastoma', 'Disease', (97, 111))	('etoposide', 'Chemical', 'MESH:D005047', (37, 46))	('Rb1', 'Gene', '5925', (93, 96))	('etoposide', 'Chemical', 'MESH:D005047', (68, 77))	('CPS', 'Chemical', 'MESH:D002211', (12, 15))	('retinoblastoma', 'Phenotype', 'HP:0009919', (97, 111))	('Ca2+influx', 'MPA', (23, 33))
84528	31801263	Indeed, at the 50 nM concentration, CPZ sensitizes CRC cells to apoptosis stimulated by tumor necrosis factor (TNF)-related apoptosis-induced ligand.	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('88', '109'))	('apoptosis', 'CPA', (64, 73))	('CPZ', 'Var', (36, 39))	('necrosis', 'biological_process', 'GO:0008219', ('94', '102'))	('CRC', 'Disease', (51, 54))	('ligand', 'molecular_function', 'GO:0005488', ('142', '148'))	('CPZ', 'Chemical', 'MESH:C071423', (36, 39))	('CRC', 'Phenotype', 'HP:0003003', (51, 54))	('sensitizes', 'Reg', (40, 50))	('necrosis', 'biological_process', 'GO:0008220', ('94', '102'))	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('N', 'Chemical', 'MESH:D009584', (112, 113))	('CRC', 'Disease', 'MESH:D015179', (51, 54))	('tumor necrosis', 'Disease', 'MESH:D009336', (88, 102))	('necrosis', 'biological_process', 'GO:0070265', ('94', '102'))	('necrosis', 'biological_process', 'GO:0019835', ('94', '102'))	('tumor necrosis', 'Disease', (88, 102))	('rat', 'Species', '10116', (28, 31))	('necrosis', 'biological_process', 'GO:0001906', ('94', '102'))	('apoptosis', 'biological_process', 'GO:0097194', ('64', '73'))	('apoptosis', 'biological_process', 'GO:0006915', ('64', '73'))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
84538	31801263	Mutations of the TRPV2 pore completely inhibit CBD-induced chemoresistance.	('pore', 'cellular_component', 'GO:0046930', ('23', '27'))	('inhibit', 'NegReg', (39, 46))	('Mutations', 'Var', (0, 9))	('CBD', 'Chemical', 'MESH:D002185', (47, 50))	('CBD-induced chemoresistance', 'CPA', (47, 74))	('TRPV2', 'Gene', (17, 22))
84540	31801263	Furthermore, in MM cells, CBD induces TRPV2 upregulation and enhances the sensitivity to Bortezomib, improving cell growth inhibition, cell cycle arrest at the G1 phase, and mitochondrial and ROS-dependent necrosis, mainly in TRPV2-transfected RPMI8226 and U266 MM cells.	('improving', 'PosReg', (101, 110))	('necrosis', 'Disease', 'MESH:D009336', (206, 214))	('necrosis', 'biological_process', 'GO:0070265', ('206', '214'))	('necrosis', 'biological_process', 'GO:0019835', ('206', '214'))	('necrosis', 'biological_process', 'GO:0001906', ('206', '214'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('135', '152'))	('necrosis', 'Disease', (206, 214))	('cell growth', 'biological_process', 'GO:0016049', ('111', '122'))	('cell cycle arrest at the G1 phase', 'CPA', (135, 168))	('G1 phase', 'biological_process', 'GO:0051318', ('160', '168'))	('TRPV2', 'Gene', (38, 43))	('cell growth inhibition', 'CPA', (111, 133))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (135, 152))	('Bortezomib', 'Chemical', 'MESH:C400082', (89, 99))	('necrosis', 'biological_process', 'GO:0008219', ('206', '214'))	('upregulation', 'PosReg', (44, 56))	('CBD', 'Chemical', 'MESH:D002185', (26, 29))	('MM', 'Disease', 'MESH:D009101', (16, 18))	('CBD', 'Var', (26, 29))	('RPMI8226', 'CellLine', 'CVCL:0014', (244, 252))	('U266 MM', 'CellLine', 'CVCL:0566', (257, 264))	('enhances', 'PosReg', (61, 69))	('MM', 'Disease', 'MESH:D009101', (262, 264))	('sensitivity to Bortezomib', 'MPA', (74, 99))	('necrosis', 'biological_process', 'GO:0008220', ('206', '214'))
84542	31801263	Previous studies have found the presence of heterogeneous CD138+TRPV2+ and CD138+TRPV2- plasma cell subpopulations in MM patients.	('CD138+TRPV2-', 'Var', (75, 87))	('MM', 'Disease', 'MESH:D009101', (118, 120))	('patients', 'Species', '9606', (121, 129))	('CD138+TRPV2-', 'Gene', (75, 87))
84543	31801263	CBD, itself or in synergy with bortezomib, is able to inhibit growth, arrest cell cycle progression, and induce MM cell death by regulating the ERK, Akt, and NF-kappaB pathways with major effects in CD138+TRPV2+ MM cells.	('Akt', 'Gene', (149, 152))	('bortezomib', 'Chemical', 'MESH:C400082', (31, 41))	('cell cycle', 'biological_process', 'GO:0007049', ('77', '87'))	('MM', 'Disease', 'MESH:D009101', (212, 214))	('NF-kappaB pathways', 'Pathway', (158, 176))	('Akt', 'Gene', '207', (149, 152))	('induce', 'PosReg', (105, 111))	('cell death', 'biological_process', 'GO:0008219', ('115', '125'))	('inhibit', 'NegReg', (54, 61))	('arrest cell cycle progression', 'CPA', (70, 99))	('CD138+TRPV2+', 'Var', (199, 211))	('ERK', 'Gene', '5594', (144, 147))	('MM', 'Disease', 'MESH:D009101', (112, 114))	('growth', 'CPA', (62, 68))	('ERK', 'molecular_function', 'GO:0004707', ('144', '147'))	('ERK', 'Gene', (144, 147))	('regulating', 'Reg', (129, 139))	('N', 'Chemical', 'MESH:D009584', (158, 159))	('CBD', 'Chemical', 'MESH:D002185', (0, 3))
84555	31801263	Soricidin and its derivatives (SOR-C13, 14 nM; and SOR-C27, 65 nM) inhibit TRPV6-dependent Ca2+ uptake and bind TRPV6 with a high affinity in ovarian cancer (OC).	('bind', 'Interaction', (107, 111))	('TRPV6', 'Gene', (112, 117))	('ovarian cancer', 'Disease', (142, 156))	('ovarian cancer', 'Phenotype', 'HP:0100615', (142, 156))	('uptake', 'biological_process', 'GO:0098657', ('96', '102'))	('Ca2+', 'Chemical', 'MESH:D002118', (91, 95))	('SOR', 'molecular_function', 'GO:0033755', ('31', '34'))	('SOR-C27', 'Var', (51, 58))	('SOR', 'molecular_function', 'GO:0033755', ('51', '54'))	('TRPV6', 'Gene', '55503', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('uptake', 'biological_process', 'GO:0098739', ('96', '102'))	('SO', 'Chemical', 'MESH:C443440', (51, 53))	('inhibit', 'NegReg', (67, 74))	('OC', 'Disease', 'MESH:D010051', (158, 160))	('ovarian cancer', 'Disease', 'MESH:D010051', (142, 156))	('TRPV6', 'Gene', '55503', (112, 117))	('SOR', 'molecular_function', 'GO:0043826', ('31', '34'))	('TRPV6', 'Gene', (75, 80))	('SOR', 'molecular_function', 'GO:0043826', ('51', '54'))	('OC', 'Phenotype', 'HP:0100615', (158, 160))	('C13', 'Chemical', 'MESH:C513342', (35, 38))	('SO', 'Chemical', 'MESH:C443440', (31, 33))
84558	31801263	In addition, the side effects and best dose as well as safety/tolerability, pharmacokinetics, pharmacodynamics, and efficacy in treating patients with solid tumors, were evaluated in two different clinical trials (NCT03784677, NCT01578564, respectively).	('NCT03784677', 'Chemical', 'MESH:C079985', (214, 225))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('solid tumors', 'Disease', (151, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('patients', 'Species', '9606', (137, 145))	('NCT03784677', 'Var', (214, 225))	('N', 'Chemical', 'MESH:D009584', (227, 228))	('solid tumors', 'Disease', 'MESH:D009369', (151, 163))	('N', 'Chemical', 'MESH:D009584', (214, 215))
84560	31801263	These data show that the administration of SO-C13, up to 6.2 mg/kg, induces in 54.5% of patients (n = 22 patients) a stable disease, ranging from 2.8 to 12.5 months, and the best response was a 27% reduction in PC, with a 55% reduction in CA19-9 marker levels.	('SO-C13', 'Var', (43, 49))	('patients', 'Species', '9606', (105, 113))	('PC', 'Phenotype', 'HP:0002894', (211, 213))	('reduction', 'NegReg', (198, 207))	('patients', 'Species', '9606', (88, 96))	('SO', 'Chemical', 'MESH:C443440', (43, 45))	('rat', 'Species', '10116', (33, 36))	('reduction', 'NegReg', (226, 235))	('PC', 'Disease', 'MESH:D010190', (211, 213))	('CA19-9 marker levels', 'MPA', (239, 259))	('C13', 'Chemical', 'MESH:C513342', (46, 49))
84563	31801263	The mechanism involved in CPS-induced apoptosis of AGS cells depends on increased Ca2+ influx via TRPV6 channels; moreover, CPS induces apoptosis by stabilization of p53 through c-Jun N-terminal kinases activation.	('Ca2+', 'Chemical', 'MESH:D002118', (82, 86))	('p53', 'Gene', '7157', (166, 169))	('CPS', 'Chemical', 'MESH:D002211', (124, 127))	('apoptosis', 'biological_process', 'GO:0097194', ('38', '47'))	('apoptosis', 'biological_process', 'GO:0006915', ('38', '47'))	('Ca2+ influx', 'MPA', (82, 93))	('AGS', 'Disease', (51, 54))	('TRPV6', 'Gene', '55503', (98, 103))	('stabilization', 'MPA', (149, 162))	('N', 'Chemical', 'MESH:D009584', (184, 185))	('p53', 'Gene', (166, 169))	('AGS', 'Disease', 'MESH:C535607', (51, 54))	('CPS', 'Chemical', 'MESH:D002211', (26, 29))	('CPS', 'Var', (124, 127))	('increased', 'PosReg', (72, 81))	('TRPV6', 'Gene', (98, 103))	('apoptosis', 'CPA', (136, 145))	('c-Jun', 'Gene', '3725', (178, 183))	('apoptosis', 'biological_process', 'GO:0097194', ('136', '145'))	('apoptosis', 'biological_process', 'GO:0006915', ('136', '145'))	('activation', 'PosReg', (203, 213))	('c-Jun', 'Gene', (178, 183))
84571	31801263	The silencing of TRPV6 improves the pro-apoptotic activity of tamoxifen, suggesting that the increase of Ca2+influx, mediated by TRPV6 overexpression in BCs, is responsible for the reduced sensitivity to tamoxifen treatment.	('TRPV6', 'Gene', (129, 134))	('increase', 'PosReg', (93, 101))	('TRPV6', 'Gene', '55503', (17, 22))	('improves', 'PosReg', (23, 31))	('TRPV6', 'Gene', (17, 22))	('tamoxifen', 'Chemical', 'MESH:D013629', (62, 71))	('Ca2+', 'Chemical', 'MESH:D002118', (105, 109))	('pro-apoptotic activity of tamoxifen', 'MPA', (36, 71))	('tamoxifen', 'Chemical', 'MESH:D013629', (204, 213))	('Ca2+influx', 'MPA', (105, 115))	('TRPV6', 'Gene', '55503', (129, 134))	('silencing', 'Var', (4, 13))	('overexpression', 'PosReg', (135, 149))
84577	31801263	In addition to MCF-7 cell migration inhibition, TRPV6 silencing can inhibit MDA-MB-231 migration and invasion.	('TRPV6', 'Gene', '55503', (48, 53))	('silencing', 'Var', (54, 63))	('rat', 'Species', '10116', (29, 32))	('inhibit', 'NegReg', (68, 75))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (76, 86))	('MDA-MB-231', 'Gene', (76, 86))	('TRPV6', 'Gene', (48, 53))	('MCF-7', 'CellLine', 'CVCL:0031', (15, 20))	('cell migration', 'biological_process', 'GO:0016477', ('21', '35'))	('rat', 'Species', '10116', (90, 93))
84581	31801263	Experiments using mouse dorsal root ganglion neurons and human TRPA1-transfected HEK293 (hTRPA1-HEK293) cells as well as naive mice and TRPA1-knockout mice (1 mg/Kg/day) and B16-F10 melanoma cells treated with DBZ, demonstrated that DBZ directly activates TRPA1 and sensitizes it indirectly by generating oxidative stress products.	('HEK293', 'CellLine', 'CVCL:0045', (81, 87))	('activates', 'PosReg', (246, 255))	('HEK293', 'CellLine', 'CVCL:0045', (96, 102))	('human', 'Species', '9606', (57, 62))	('DBZ', 'Var', (233, 236))	('TRPA1', 'Gene', (256, 261))	('hTRPA1', 'Gene', (89, 95))	('oxidative stress products', 'MPA', (305, 330))	('rat', 'Species', '10116', (222, 225))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('melanoma', 'Disease', (182, 190))	('B16-F10', 'CellLine', 'CVCL:0159', (174, 181))	('rat', 'Species', '10116', (298, 301))	('hTRPA1', 'Gene', '8989', (89, 95))	('mice', 'Species', '10090', (127, 131))	('mice', 'Species', '10090', (151, 155))	('oxidative stress', 'Phenotype', 'HP:0025464', (305, 321))	('mouse', 'Species', '10090', (18, 23))	('DBZ', 'Chemical', 'MESH:D003606', (233, 236))	('DBZ', 'Chemical', 'MESH:D003606', (210, 213))	('generating', 'Reg', (294, 304))	('melanoma', 'Disease', 'MESH:D008545', (182, 190))
84582	31801263	Moreover, DBZ causes mechanical and cold allodynia in naive but not in TRPA1-knockout mice.	('DBZ', 'Var', (10, 13))	('mice', 'Species', '10090', (86, 90))	('allodynia', 'Disease', (41, 50))	('allodynia', 'Phenotype', 'HP:0012533', (41, 50))	('DBZ', 'Chemical', 'MESH:D003606', (10, 13))	('allodynia', 'Disease', 'MESH:D006930', (41, 50))
84586	31801263	Resveratrol induces activation of mutated TRPA1 in human PCa-associated fibroblasts.	('TRPA1', 'Protein', (42, 47))	('PC', 'Phenotype', 'HP:0002894', (57, 59))	('Resveratrol', 'Chemical', 'MESH:C059514', (0, 11))	('human', 'Species', '9606', (51, 56))	('PC', 'Disease', 'MESH:D010190', (57, 59))	('activation', 'PosReg', (20, 30))	('mutated', 'Var', (34, 41))
84588	31801263	Recently, it has been reported that resveratrol activates N-terminal-mutated TRPA1, leading to intracellular calcium increase, and increases HGF and VEGF expression and secretion, without inducing apoptosis in these cells.	('resveratrol', 'Chemical', 'MESH:C059514', (36, 47))	('increases', 'PosReg', (131, 140))	('VEGF', 'Gene', (149, 153))	('intracellular', 'cellular_component', 'GO:0005622', ('95', '108'))	('N-terminal-mutated', 'Var', (58, 76))	('apoptosis', 'biological_process', 'GO:0097194', ('197', '206'))	('apoptosis', 'biological_process', 'GO:0006915', ('197', '206'))	('increase', 'PosReg', (117, 125))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('intracellular calcium increase', 'Phenotype', 'HP:0003575', (95, 125))	('HGF', 'Gene', '3082', (141, 144))	('intracellular calcium', 'MPA', (95, 116))	('secretion', 'biological_process', 'GO:0046903', ('169', '178'))	('HGF', 'Gene', (141, 144))	('TRPA1', 'Gene', (77, 82))	('calcium', 'Chemical', 'MESH:D002118', (109, 116))	('VEGF', 'Gene', '7422', (149, 153))	('secretion', 'MPA', (169, 178))	('activates', 'PosReg', (48, 57))	('expression', 'MPA', (154, 164))
84599	31801263	Finally, blockade of TRPA1 by its antagonist HC-030031 prevents chemotherapy-induced peripheral neuropathy.	('HC-030031', 'Chemical', 'MESH:C552888', (45, 54))	('TRPA1', 'Protein', (21, 26))	('peripheral neuropathy', 'Disease', (85, 106))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (85, 106))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (85, 106))	('prevents', 'NegReg', (55, 63))	('blockade', 'Var', (9, 17))
84607	31801263	Moreover, recently, it has been reported that the endolysosomal TRPML1 channel, belonging to the mucolipin TRP channel family, is required for cancer cell proliferation bearing HRAS mutations and that TRPML1 expression was significantly elevated in HRAS-positive tumors and inversely correlated with poor prognosis.	('TRPML1', 'Gene', (201, 207))	('cell proliferation', 'biological_process', 'GO:0008283', ('150', '168'))	('expression', 'MPA', (208, 218))	('TRPML1', 'Gene', '57192', (201, 207))	('HRAS', 'Gene', '3265', (249, 253))	('TRPML1', 'Gene', (64, 70))	('cancer', 'Disease', (143, 149))	('HRAS', 'Gene', (249, 253))	('mutations', 'Var', (182, 191))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('HRAS', 'Gene', '3265', (177, 181))	('TRPML1', 'Gene', '57192', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('HRAS', 'Gene', (177, 181))	('HRAS-positive tumors', 'Disease', (249, 269))	('rat', 'Species', '10116', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('HRAS-positive tumors', 'Disease', 'MESH:D009369', (249, 269))	('elevated', 'PosReg', (237, 245))
84608	31801263	Mutations of KRAS and HRAS in cancer affect the efficacy of chemotherapy; changes in TRP channel expression could overcome drug resistance and increase the sensitivity of cancer cells to chemotherapy.	('drug resistance', 'biological_process', 'GO:0042493', ('123', '138'))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('affect', 'Reg', (37, 43))	('drug resistance', 'MPA', (123, 138))	('HRAS', 'Gene', '3265', (22, 26))	('HRAS', 'Gene', (22, 26))	('drug resistance', 'Phenotype', 'HP:0020174', (123, 138))	('Mutations', 'Var', (0, 9))	('expression', 'MPA', (97, 107))	('overcome', 'PosReg', (114, 122))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('KRAS', 'Gene', '3845', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('changes', 'Reg', (74, 81))	('TRP', 'Gene', (85, 88))	('sensitivity', 'MPA', (156, 167))	('efficacy of chemotherapy', 'CPA', (48, 72))	('KRAS', 'Gene', (13, 17))	('increase', 'PosReg', (143, 151))	('drug resistance', 'biological_process', 'GO:0009315', ('123', '138'))
84610	31801263	Furthermore, the role of changes in the epigenetics of TRP channels in cancers should also be considered.	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('changes', 'Reg', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('TRP channels', 'Protein', (55, 67))	('epigenetics', 'Var', (40, 51))
84611	31801263	It has been demonstrated that inactivation of TRP genes by aberrant methylation (hyper- and hypo-methylation) of GC-rich DNA regions, CpG islands, is suggested to be involved in tumor development and progression.	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('tumor', 'Disease', (178, 183))	('inactivation', 'Var', (30, 42))	('aberrant', 'Var', (59, 67))	('N', 'Chemical', 'MESH:D009584', (122, 123))	('rat', 'Species', '10116', (19, 22))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('methylation', 'biological_process', 'GO:0032259', ('97', '108'))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('methylation', 'MPA', (68, 79))	('involved', 'Reg', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('TRP genes', 'Gene', (46, 55))
84612	31801263	In this regard, hydrogen peroxide has been found to induce demethylation of the TRPM2 promoter region and increase the expression of TRPM2 in melanocytes; the TRPM6 and TRPM7 ion channels have been found to bind to the chromatin-remodeling complexes, induce histone phosphorylation, and decrease arginine methylation, resulting in changes in the transcription of hundreds of genes; transactivation of TRPA1 promoter by Notch1 receptor intracellular domain, which promotes TRPA1 expression in erytroleukemic cells, suppresses erythroid differentiation.	('transactivation', 'biological_process', 'GO:2000144', ('382', '397'))	('chromatin', 'cellular_component', 'GO:0000785', ('219', '228'))	('decrease arginine', 'Phenotype', 'HP:0005961', (287, 304))	('TRPM6', 'Gene', (159, 164))	('histone phosphorylation', 'biological_process', 'GO:0016572', ('258', '281'))	('demethylation', 'biological_process', 'GO:0070988', ('59', '72'))	('TRPM2', 'Gene', '7226', (80, 85))	('expression', 'MPA', (478, 488))	('transactivation', 'Var', (382, 397))	('TRPM2', 'Gene', '7226', (133, 138))	('arginine', 'Chemical', 'MESH:D001127', (296, 304))	('arginine methylation', 'MPA', (296, 316))	('changes', 'Reg', (331, 338))	('transcription', 'MPA', (346, 359))	('methylation', 'biological_process', 'GO:0032259', ('305', '316'))	('transcription', 'biological_process', 'GO:0006351', ('346', '359'))	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('219', '239'))	('promotes', 'PosReg', (463, 471))	('erythroid differentiation', 'CPA', (525, 550))	('TRPM2', 'Gene', (80, 85))	('TRPM2', 'Gene', (133, 138))	('TRPA1', 'Gene', (401, 406))	('ion channels', 'molecular_function', 'GO:0022831', ('175', '187'))	('decrease', 'NegReg', (287, 295))	('suppresses', 'NegReg', (514, 524))	('induce', 'PosReg', (251, 257))	('Notch1', 'Gene', (419, 425))	('Notch1', 'Gene', '4851', (419, 425))	('histone phosphorylation', 'MPA', (258, 281))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (16, 33))	('intracellular', 'cellular_component', 'GO:0005622', ('435', '448'))	('TRPA1', 'Gene', (472, 477))	('TRPM6', 'Gene', '140803', (159, 164))
84613	31801263	Moreover, regarding cancer chemoresistance, miR-320a is a mediator of the chemoresistance of BC cells by targeting TRPC5 and NFATc3 and the expression of miR320a is regulated by methylation of its promoter and the transcription factor, v-ets erythroblastosis virus E26 oncogene homolog 1.	('miR320a', 'Gene', (154, 161))	('NFATc3', 'Gene', '4775', (125, 131))	('transcription factor', 'molecular_function', 'GO:0000981', ('214', '234'))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('miR-320a', 'Gene', (44, 52))	('TRPC5', 'Gene', '7224', (115, 120))	('TRPC5', 'Gene', (115, 120))	('PC', 'Phenotype', 'HP:0002894', (117, 119))	('miR-320a', 'Gene', '407037', (44, 52))	('erythroblastosis', 'Disease', (242, 258))	('targeting', 'Reg', (105, 114))	('methylation', 'Var', (178, 189))	('cancer', 'Disease', (20, 26))	('erythroblastosis', 'Disease', 'MESH:D004899', (242, 258))	('methylation', 'biological_process', 'GO:0032259', ('178', '189'))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('NFATc3', 'Gene', (125, 131))	('miR320a', 'Gene', '407037', (154, 161))	('transcription', 'biological_process', 'GO:0006351', ('214', '227'))
84614	31801263	Aberrations in the expression of different splice variants, and their expression during tumor progression, may trigger a variety of Ca2+ signaling, which may contribute to the generation of more aggressive tumor clones.	('aggressive tumor', 'Disease', 'MESH:D001523', (195, 211))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('Ca2+ signaling', 'MPA', (132, 146))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('rat', 'Species', '10116', (180, 183))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('aggressive tumor', 'Disease', (195, 211))	('contribute to', 'Reg', (158, 171))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('signaling', 'biological_process', 'GO:0023052', ('137', '146'))	('Ca2+', 'Chemical', 'MESH:D002118', (132, 136))	('rat', 'Species', '10116', (4, 7))	('Aberrations', 'Var', (0, 11))	('tumor', 'Disease', (88, 93))	('trigger', 'Reg', (111, 118))
84617	31801263	Epigenetic changes of TRP channels could be the rationale to approach a personalized therapy in cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (96, 102))	('TRP channels', 'Protein', (22, 34))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('patients', 'Species', '9606', (103, 111))	('Epigenetic changes', 'Var', (0, 18))	('rat', 'Species', '10116', (48, 51))
84648	28187463	OS (P < 0.001) and CSS (P < 0.001) were worse in patients with low AGRs (<= 1.22) than in patients with high AGRs (> 1.22) prior to propensity score matching (PSM) (Figure 1A, 1B).	('OS', 'Chemical', '-', (0, 2))	('patients', 'Species', '9606', (90, 98))	('CSS', 'Chemical', '-', (19, 22))	('patients', 'Species', '9606', (49, 57))	('low', 'Var', (63, 66))	('CSS', 'CPA', (19, 22))	('worse', 'NegReg', (40, 45))
84672	28187463	Consequently, in addition to changes in the local tumor microenvironment, changes in levels of peripheral inflammatory factors, such as tumor necrosis factor (TNF), interleukin (IL)-1, -6, and -8, and vascular endothelial growth factor (VEGF), also promote tumor growth and metastasis.	('promote', 'PosReg', (249, 256))	('VEGF', 'Gene', (237, 241))	('tumor necrosis factor', 'Gene', '7124', (136, 157))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('201', '235'))	('necrosis', 'biological_process', 'GO:0008220', ('142', '150'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('136', '157'))	('TNF', 'Gene', (159, 162))	('tumor', 'Disease', (257, 262))	('necrosis', 'biological_process', 'GO:0070265', ('142', '150'))	('levels', 'MPA', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('necrosis', 'biological_process', 'GO:0019835', ('142', '150'))	('vascular endothelial growth factor', 'Gene', '7422', (201, 235))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', (50, 55))	('tumor necrosis factor', 'Gene', (136, 157))	('interleukin (IL)-1, -6, and -8', 'Gene', '3552;3569;3576', (165, 195))	('necrosis', 'biological_process', 'GO:0001906', ('142', '150'))	('IL)-1', 'molecular_function', 'GO:0005149', ('178', '183'))	('changes', 'Var', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('TNF', 'Gene', '7124', (159, 162))	('vascular endothelial growth factor', 'Gene', (201, 235))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('VEGF', 'Gene', '7422', (237, 241))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('necrosis', 'biological_process', 'GO:0008219', ('142', '150'))	('men', 'Species', '9606', (68, 71))
84701	28187463	mGPS was classified as follows: score 2 if serum CRP > 10 mg/L and albumin < 35 g/L; score 1 if serum CRP > 10 mg/L and albumin >= 35 g/L; score 0 if CRP <= 10 mg/L.	('albumin', 'MPA', (67, 74))	('< 35', 'Var', (75, 79))	('GPS', 'Disease', (1, 4))	('CRP', 'Gene', '1401', (49, 52))	('CRP', 'Gene', (150, 153))	('CRP', 'Gene', (102, 105))	('GPS', 'Disease', 'MESH:D055652', (1, 4))	('CRP', 'Gene', '1401', (150, 153))	('CRP', 'Gene', '1401', (102, 105))	('CRP', 'Gene', (49, 52))
84715	32051393	Moreover, a positive correlation between gankyrin and STAT3 or CCL24 expression in ccRCC specimens was observed, and improved accuracy for ccRCC patient prognosis was achieved by combining gankyrin and STAT3 or CCL24 expression with existing clinical prognostic indicators, including the TNM stage and SSIGN score.	('RCC', 'Disease', 'MESH:D002292', (141, 144))	('ccRCC', 'Phenotype', 'HP:0006770', (139, 144))	('CCL', 'molecular_function', 'GO:0044101', ('63', '66'))	('RCC', 'Disease', 'MESH:D002292', (85, 88))	('CCL24', 'Gene', (211, 216))	('CCL24', 'Gene', '6369', (211, 216))	('STAT3', 'Gene', (54, 59))	('TNM', 'Gene', '10178', (288, 291))	('TNM', 'Gene', (288, 291))	('improved', 'PosReg', (117, 125))	('STAT3', 'Gene', '6774', (54, 59))	('gankyrin', 'Var', (189, 197))	('CCL24', 'Gene', (63, 68))	('CCL24', 'Gene', '6369', (63, 68))	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('STAT3', 'Gene', (202, 207))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('patient', 'Species', '9606', (145, 152))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('combining', 'Interaction', (179, 188))	('RCC', 'Disease', (85, 88))	('STAT3', 'Gene', '6774', (202, 207))	('CCL', 'molecular_function', 'GO:0044101', ('211', '214'))
84723	32051393	In addition, gankyrin facilitates the proliferation, tumorigenicity, metastasis, and drug resistance of tumors through metabolic reprogramming and the mediation of signaling pathways such as the Wnt/beta-catenin pathway, NF-kappaB pathway, PI3K/AKT/HIF-1alpha/cyclin D1, RhoA/ROCK, and mTORC1 signaling.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumors', 'Disease', (104, 110))	('AKT', 'Gene', (245, 248))	('beta-catenin', 'Gene', (199, 211))	('mediation', 'Reg', (151, 160))	('proliferation', 'CPA', (38, 51))	('beta-catenin', 'Gene', '1499', (199, 211))	('HIF-1alpha', 'Gene', '3091', (249, 259))	('NF-kappaB pathway', 'Pathway', (221, 238))	('drug resistance', 'biological_process', 'GO:0009315', ('85', '100'))	('drug resistance', 'biological_process', 'GO:0042493', ('85', '100'))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('drug resistance', 'CPA', (85, 100))	('mTORC1', 'Gene', (286, 292))	('signaling', 'biological_process', 'GO:0023052', ('164', '173'))	('gankyrin', 'Var', (13, 21))	('metastasis', 'CPA', (69, 79))	('AKT', 'Gene', '207', (245, 248))	('mTORC1', 'cellular_component', 'GO:0031931', ('286', '292'))	('metabolic reprogramming', 'CPA', (119, 142))	('signaling pathways', 'Pathway', (164, 182))	('tumor', 'Disease', (104, 109))	('mTORC1', 'Gene', '382056', (286, 292))	('signaling', 'biological_process', 'GO:0023052', ('293', '302'))	('PI3K', 'molecular_function', 'GO:0016303', ('240', '244'))	('cyclin D1', 'Gene', (260, 269))	('HIF-1alpha', 'Gene', (249, 259))	('RhoA', 'Gene', (271, 275))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('cyclin D1', 'Gene', '595', (260, 269))	('cyclin', 'molecular_function', 'GO:0016538', ('260', '266'))	('facilitates', 'PosReg', (22, 33))	('tumor', 'Disease', (53, 58))	('drug resistance', 'Phenotype', 'HP:0020174', (85, 100))	('RhoA', 'Gene', '387', (271, 275))
84733	32051393	In this study, we mainly determined whether gankyrin facilitates the progression and targeted drug resistance of ccRCC, and examined whether the integration of gankyrin and STAT3 or CCL24 expression with established clinical indicators results in improved prediction of the prognosis of ccRCC patients.	('RCC', 'Disease', (289, 292))	('RCC', 'Phenotype', 'HP:0005584', (289, 292))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (287, 292))	('ccRCC', 'Phenotype', 'HP:0006770', (113, 118))	('RCC', 'Disease', (115, 118))	('STAT3', 'Gene', (173, 178))	('STAT3', 'Gene', '6774', (173, 178))	('RCC', 'Disease', 'MESH:D002292', (289, 292))	('drug resistance', 'biological_process', 'GO:0009315', ('94', '109'))	('RCC', 'Disease', 'MESH:D002292', (115, 118))	('drug resistance', 'biological_process', 'GO:0042493', ('94', '109'))	('CCL', 'molecular_function', 'GO:0044101', ('182', '185'))	('progression', 'CPA', (69, 80))	('gankyrin', 'Var', (44, 52))	('drug resistance', 'Phenotype', 'HP:0020174', (94, 109))	('CCL24', 'Gene', (182, 187))	('facilitates', 'PosReg', (53, 64))	('CCL24', 'Gene', '6369', (182, 187))	('patients', 'Species', '9606', (293, 301))	('improved', 'PosReg', (247, 255))	('targeted', 'CPA', (85, 93))
84747	32051393	Thirty-six hours after seeding, the noninvasive cells in the upper chamber were removed with a cotton swab, and the cells on the lower surface of the membrane were fixed with 4% paraformaldehyde fix solution (E672002, Sangon Biotech, Shanghai, China), stained with crystal violet (E607309, Sangon Biotech), and photographed at 200 x magnification.	('E607309', 'Var', (281, 288))	('membrane', 'cellular_component', 'GO:0016020', ('150', '158'))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (178, 194))	('crystal violet', 'Chemical', 'MESH:D005840', (265, 279))	('E672002', 'Var', (209, 216))
84749	32051393	The primary antibodies used in the this study were listed as follows: rabbit anti-gankyrin (ab182576), rabbit anti-STAT3 (ab32500), and rabbit anti-STAT3 (Phospho 727) (ab30647), rabbit anti-eotaxin-2 (CCL24) (ab203586), rabbit anti-CCR3 (ab32512) from Abcam (Cambridge, MA, USA) and rabbit anti-GAPDH (#2118S), rabbit anti-p44/42 MAPK (Erk1/2) (#4695), rabbit anti-p44/42 MAPK (Erk1/2) (Phospho Thr202/Tyr204) (#4370), rabbit anti-Akt (#9272), and rabbit anti-Akt (Phospho Ser473) (#9271) from Cell Signaling Technology (Danvers, MA, USA).	('Erk1/2', 'Gene', '5595;5594', (337, 343))	('GAPDH', 'Gene', '2597', (296, 301))	('Akt', 'Gene', (461, 464))	('CCR', 'molecular_function', 'GO:0043880', ('233', '236'))	('Akt', 'Gene', '207', (461, 464))	('eotaxin-2', 'Gene', '6369', (191, 200))	('Signaling', 'biological_process', 'GO:0023052', ('500', '509'))	('STAT3', 'Gene', (148, 153))	('MAPK', 'molecular_function', 'GO:0004707', ('331', '335'))	('GAPDH', 'Gene', (296, 301))	('CCL24', 'Gene', (202, 207))	('Erk1/2', 'Gene', (379, 385))	('CCL24', 'Gene', '6369', (202, 207))	('Akt', 'Gene', (432, 435))	('Erk1', 'molecular_function', 'GO:0004707', ('379', '383'))	('STAT3', 'Gene', '6774', (148, 153))	('Ser', 'cellular_component', 'GO:0005790', ('474', '477'))	('STAT3', 'Gene', (115, 120))	('p44', 'Gene', (366, 369))	('Erk1/2', 'Gene', (337, 343))	('eotaxin-2', 'Gene', (191, 200))	('Akt', 'Gene', '207', (432, 435))	('p44', 'Gene', '10561', (366, 369))	('#4370', 'Var', (412, 417))	('p44', 'Gene', (324, 327))	('STAT3', 'Gene', '6774', (115, 120))	('Erk1', 'molecular_function', 'GO:0004707', ('337', '341'))	('Erk1/2', 'Gene', '5595;5594', (379, 385))	('p44', 'Gene', '10561', (324, 327))	('MAPK', 'molecular_function', 'GO:0004707', ('373', '377'))	('CCL', 'molecular_function', 'GO:0044101', ('202', '205'))
84765	32051393	The STAT3-binding sites of the CCL24 promoter (sequence: CTGATGGAAA, -848 to -838 relative to the CCL24 transcription site) or its mutant sequence were cloned into a pGL3-basic luciferase reporter vector (Promega, USA).	('CCL24', 'Gene', (98, 103))	('CCL', 'molecular_function', 'GO:0044101', ('98', '101'))	('mutant', 'Var', (131, 137))	('pGL3', 'Gene', (166, 170))	('CCL24', 'Gene', '6369', (98, 103))	('pGL', 'molecular_function', 'GO:0004598', ('166', '169'))	('CCL', 'molecular_function', 'GO:0044101', ('31', '34'))	('transcription', 'biological_process', 'GO:0006351', ('104', '117'))	('pGL3', 'Gene', '6391', (166, 170))	('STAT3', 'Gene', '6774', (4, 9))	('CCL24', 'Gene', (31, 36))	('binding', 'molecular_function', 'GO:0005488', ('10', '17'))	('STAT3', 'Gene', (4, 9))	('CCL24', 'Gene', '6369', (31, 36))
84767	32051393	Cells were collected 48 h after transfection, and the CCL24 transcriptional activity was evaluated by measuring the luminescence using a Dual-Luciferase Assay Kit (E1910, Promega, Fitchburg, WI, USA).	('luminescence', 'MPA', (116, 128))	('E1910', 'Var', (164, 169))	('CCL24', 'Gene', '6369', (54, 59))	('CCL24', 'Gene', (54, 59))	('CCL', 'molecular_function', 'GO:0044101', ('54', '57'))
84786	32051393	Moreover, the effects of gankyrin overexpression on the invasion or migration abilities of ccRCC cells were examined through invasion or migration assays, respectively, and the results showed that the numbers of invaded and migrated ccRCC cells were higher in the gankyrin-overexpressing ccRCC cells compared with the control cells (Fig.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('higher', 'PosReg', (250, 256))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('RCC', 'Disease', 'MESH:D002292', (93, 96))	('RCC', 'Disease', (93, 96))	('gankyrin-overexpressing', 'Var', (264, 287))	('ccRCC', 'Phenotype', 'HP:0006770', (288, 293))	('RCC', 'Phenotype', 'HP:0005584', (290, 293))	('RCC', 'Phenotype', 'HP:0005584', (235, 238))	('RCC', 'Disease', 'MESH:D002292', (290, 293))	('RCC', 'Disease', (290, 293))	('RCC', 'Disease', 'MESH:D002292', (235, 238))	('RCC', 'Disease', (235, 238))	('ccRCC', 'Phenotype', 'HP:0006770', (233, 238))
84788	32051393	1e, f, pazopanib induced fewer apoptotic events and increased proliferation in the population of gankyrin-overexpressing 786-O cells compared with those found in the control ccRCC cells, as detected by flow cytometry and CCK-8 assays, respectively.	('RCC', 'Disease', (176, 179))	('increased', 'PosReg', (52, 61))	('fewer', 'NegReg', (25, 30))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('proliferation', 'CPA', (62, 75))	('pazopanib', 'Chemical', 'MESH:C516667', (7, 16))	('RCC', 'Disease', 'MESH:D002292', (176, 179))	('ccRCC', 'Phenotype', 'HP:0006770', (174, 179))	('apoptotic events', 'CPA', (31, 47))	('pazopanib', 'Var', (7, 16))
84795	32051393	Contrary to the above-mentioned results for gankyrin overexpression, pazopanib treatment resulted in more apoptotic events and decreased proliferation in the gankyrin-knockdown 786-O cells compared with those found in the control cells (Fig.	('decreased', 'NegReg', (127, 136))	('pazopanib', 'Chemical', 'MESH:C516667', (69, 78))	('apoptotic events', 'CPA', (106, 122))	('pazopanib', 'Var', (69, 78))	('proliferation', 'CPA', (137, 150))
84797	32051393	Furthermore, in vivo assays demonstrated that gankyrin knockdown decreased the growth and volume of 786-O cell-derived subcutaneous xenografts in the mouse model (Fig.	('decreased', 'NegReg', (65, 74))	('knockdown', 'Var', (55, 64))	('mouse', 'Species', '10090', (150, 155))
84798	32051393	In addition, immunohistochemistry (IHC) staining indicated that the gankyrin-knockdown 786-O cell-derived xenografts exhibited lower Ki-67 expression than the control 786-O-derived tumor specimens (Fig.	('gankyrin-knockdown', 'Var', (68, 86))	('tumor', 'Disease', (181, 186))	('Ki-67', 'Gene', '17345', (133, 138))	('lower', 'NegReg', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('expression', 'MPA', (139, 149))	('Ki-67', 'Gene', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
84808	32051393	Furthermore, in vivo assays showed that the neutralizing antibody against CCL24 abated the gankyrin-mediated increases in the growth and volume of 786-O cell-derived subcutaneous xenografts (Fig.	('CCL24', 'Gene', (74, 79))	('antibody', 'cellular_component', 'GO:0042571', ('57', '65'))	('antibody', 'cellular_component', 'GO:0019815', ('57', '65'))	('CCL24', 'Gene', '6369', (74, 79))	('antibody', 'cellular_component', 'GO:0019814', ('57', '65'))	('abated', 'NegReg', (80, 86))	('CCL', 'molecular_function', 'GO:0044101', ('74', '77'))	('antibody', 'molecular_function', 'GO:0003823', ('57', '65'))	('increases', 'PosReg', (109, 118))	('neutralizing antibody', 'Var', (44, 65))
84812	32051393	S3i), we next examined whether blocking CCR3 could alleviate the gankyrin/CCL24-increased growth and progression of ccRCC.	('CCL24', 'Gene', (74, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('RCC', 'Disease', 'MESH:D002292', (118, 121))	('RCC', 'Disease', (118, 121))	('CCL24', 'Gene', '6369', (74, 79))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('growth', 'CPA', (90, 96))	('CCR', 'molecular_function', 'GO:0043880', ('40', '43'))	('blocking', 'Var', (31, 39))	('CCL', 'molecular_function', 'GO:0044101', ('74', '77'))	('CCR3', 'Gene', (40, 44))	('alleviate', 'NegReg', (51, 60))	('progression', 'CPA', (101, 112))
84814	32051393	However, when CCL24 was knocked down in ccRCC cells, the increased expression of CCR3 was abated (Supplementary Fig.	('CCR3', 'Gene', (81, 85))	('RCC', 'Disease', 'MESH:D002292', (42, 45))	('abated', 'NegReg', (90, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('CCL', 'molecular_function', 'GO:0044101', ('14', '17'))	('knocked down', 'Var', (24, 36))	('CCL24', 'Gene', '6369', (14, 19))	('increased', 'PosReg', (57, 66))	('CCL24', 'Gene', (14, 19))	('CCR', 'molecular_function', 'GO:0043880', ('81', '84'))	('expression', 'MPA', (67, 77))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))
84818	32051393	Furthermore, knockdown of CCR3 by siRNA or SB328437 weakened the enhanced proliferation, invasion, migration, and tumorigenicity in ccRCC cells mediated by gankyrin and inhibited the gankyrin-mediated apoptosis of ccRCC cells (Fig.	('enhanced', 'PosReg', (65, 73))	('RCC', 'Disease', 'MESH:D002292', (134, 137))	('gankyrin-mediated apoptosis', 'CPA', (183, 210))	('CCR3', 'Gene', (26, 30))	('SB328437', 'Var', (43, 51))	('tumor', 'Disease', (114, 119))	('gankyrin', 'Protein', (156, 164))	('RCC', 'Disease', (216, 219))	('RCC', 'Phenotype', 'HP:0005584', (216, 219))	('inhibited', 'NegReg', (169, 178))	('ccRCC', 'Phenotype', 'HP:0006770', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('invasion', 'CPA', (89, 97))	('migration', 'CPA', (99, 108))	('RCC', 'Disease', 'MESH:D002292', (216, 219))	('weakened', 'NegReg', (52, 60))	('SB328437', 'Chemical', 'MESH:C417503', (43, 51))	('CCR', 'molecular_function', 'GO:0043880', ('26', '29'))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('apoptosis', 'biological_process', 'GO:0097194', ('201', '210'))	('apoptosis', 'biological_process', 'GO:0006915', ('201', '210'))	('RCC', 'Disease', (134, 137))	('RCC', 'Phenotype', 'HP:0005584', (134, 137))	('ccRCC', 'Phenotype', 'HP:0006770', (132, 137))
84822	32051393	Moreover, ccRCC cells with recombinant CCL24 exhibited less apoptosis and increased invasion and migration abilities relative to the naive ccRCC cells (Fig.	('RCC', 'Disease', 'MESH:D002292', (141, 144))	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('CCL24', 'Gene', (39, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (139, 144))	('CCL', 'molecular_function', 'GO:0044101', ('39', '42'))	('RCC', 'Phenotype', 'HP:0005584', (12, 15))	('CCL24', 'Gene', '6369', (39, 44))	('RCC', 'Disease', 'MESH:D002292', (12, 15))	('recombinant', 'Var', (27, 38))	('RCC', 'Disease', (12, 15))	('apoptosis', 'CPA', (60, 69))	('increased', 'PosReg', (74, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (10, 15))	('apoptosis', 'biological_process', 'GO:0097194', ('60', '69'))	('apoptosis', 'biological_process', 'GO:0006915', ('60', '69'))
84835	32051393	Taken together, these results suggest that high CCL24 expression predicts poor prognosis of ccRCC patients.	('expression', 'MPA', (54, 64))	('RCC', 'Disease', 'MESH:D002292', (94, 97))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('CCL', 'molecular_function', 'GO:0044101', ('48', '51'))	('high', 'Var', (43, 47))	('patients', 'Species', '9606', (98, 106))	('CCL24', 'Gene', (48, 53))	('CCL24', 'Gene', '6369', (48, 53))
84841	32051393	Then real-time PCR and ELISA assays were performed, the results of which indicated that STAT3 knockdown alleviated the gankyrin-mediated increase in CCL24 mRNA expression in ccRCC cells and CCL24 concentration in conditional medium of ccRCC cells (Figs.	('CCL24', 'Gene', (149, 154))	('knockdown', 'Var', (94, 103))	('alleviated', 'NegReg', (104, 114))	('CCL24', 'Gene', '6369', (149, 154))	('STAT3', 'Gene', '6774', (88, 93))	('CCL', 'molecular_function', 'GO:0044101', ('190', '193'))	('RCC', 'Disease', (176, 179))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('ccRCC', 'Phenotype', 'HP:0006770', (174, 179))	('increase', 'PosReg', (137, 145))	('RCC', 'Disease', (237, 240))	('RCC', 'Phenotype', 'HP:0005584', (237, 240))	('CCL24', 'Gene', (190, 195))	('ccRCC', 'Phenotype', 'HP:0006770', (235, 240))	('CCL24', 'Gene', '6369', (190, 195))	('RCC', 'Disease', 'MESH:D002292', (176, 179))	('CCL', 'molecular_function', 'GO:0044101', ('149', '152'))	('STAT3', 'Gene', (88, 93))	('mRNA expression', 'MPA', (155, 170))	('RCC', 'Disease', 'MESH:D002292', (237, 240))
84855	32051393	Based on the above findings, we next investigated whether blocking the regulatory loop by knocking down gankyrin or inhibiting CCR3 serves as an effective strategy for inhibiting the pazopanib resistance of ccRCC in vivo.	('inhibiting', 'NegReg', (116, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (207, 212))	('inhibiting', 'NegReg', (168, 178))	('knocking down', 'Var', (90, 103))	('gankyrin', 'Protein', (104, 112))	('RCC', 'Phenotype', 'HP:0005584', (209, 212))	('CCR', 'molecular_function', 'GO:0043880', ('127', '130'))	('pazopanib', 'Chemical', 'MESH:C516667', (183, 192))	('RCC', 'Disease', (209, 212))	('RCC', 'Disease', 'MESH:D002292', (209, 212))	('pazopanib resistance', 'MPA', (183, 203))	('CCR3', 'Gene', (127, 131))
84862	32051393	Therefore, blocking the positive regulatory loop consisting of gankyrin/STAT3/CCL24/CCR3 through gankyrin knockdown or treatment with the CCR3 inhibitor reverses the pazopanib resistance of ccRCC in vivo.	('pazopanib resistance', 'MPA', (166, 186))	('CCL24', 'Gene', (78, 83))	('blocking', 'NegReg', (11, 19))	('STAT3', 'Gene', (72, 77))	('RCC', 'Phenotype', 'HP:0005584', (192, 195))	('CCR', 'molecular_function', 'GO:0043880', ('84', '87'))	('positive regulatory loop', 'MPA', (24, 48))	('CCL24', 'Gene', '6369', (78, 83))	('CCL', 'molecular_function', 'GO:0044101', ('78', '81'))	('knockdown', 'Var', (106, 115))	('reverses', 'NegReg', (153, 161))	('RCC', 'Disease', (192, 195))	('RCC', 'Disease', 'MESH:D002292', (192, 195))	('pazopanib', 'Chemical', 'MESH:C516667', (166, 175))	('CCR', 'molecular_function', 'GO:0043880', ('138', '141'))	('ccRCC', 'Phenotype', 'HP:0006770', (190, 195))	('STAT3', 'Gene', '6774', (72, 77))
84886	32051393	Many studies have elucidated the intratumoral signaling pathways regulated by gankyrin, and among these, gankyrin activates STAT3 by mediating IL-6 signaling or binding to Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('STAT3', 'Gene', '6774', (124, 129))	('protein', 'cellular_component', 'GO:0003675', ('205', '212'))	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('binding', 'Interaction', (161, 168))	('activates', 'PosReg', (114, 123))	('STAT3', 'Gene', (124, 129))	('signaling', 'biological_process', 'GO:0023052', ('148', '157'))	('IL-6', 'Gene', (143, 147))	('phosphatase', 'molecular_function', 'GO:0016791', ('222', '233'))	('SHP-1', 'Gene', '5777', (237, 242))	('IL-6', 'Gene', '3569', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('SHP-1', 'Gene', (237, 242))	('IL-6', 'molecular_function', 'GO:0005138', ('143', '147'))	('binding', 'molecular_function', 'GO:0005488', ('161', '168'))	('gankyrin', 'Var', (105, 113))
84931	28449664	The positive staining of vimentin, CK, CK7, CK18, HMW-CK, CD34, AMACR, SMA, Bcl-2, HMB45 and melan A predominantly appeared in the tumor cell cytoplasm, whereas p53 and PAX8 mainly appeared in the nuclei.	('tumor', 'Disease', (131, 136))	('C', 'Chemical', 'MESH:D002244', (67, 68))	('C', 'Chemical', 'MESH:D002244', (44, 45))	('CK18', 'Gene', (44, 48))	('CD34', 'Gene', (58, 62))	('C', 'Chemical', 'MESH:D002244', (58, 59))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('Bcl-2', 'Gene', (76, 81))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('appeared', 'Reg', (115, 123))	('melan A', 'Gene', '2315', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('vimentin', 'cellular_component', 'GO:0045098', ('25', '33'))	('CK7', 'Var', (39, 42))	('C', 'Chemical', 'MESH:D002244', (39, 40))	('AMACR', 'Gene', (64, 69))	('cytoplasm', 'cellular_component', 'GO:0005737', ('142', '151'))	('melan A', 'Gene', (93, 100))	('Bcl-2', 'molecular_function', 'GO:0015283', ('76', '81'))	('C', 'Chemical', 'MESH:D002244', (54, 55))	('HMB45', 'Gene', (83, 88))	('vimentin', 'cellular_component', 'GO:0045099', ('25', '33'))
84947	28449664	The main expression panels of vimentin were C+/S+ (22/42) and C-/S+ (20/42).	('C-', 'Chemical', 'MESH:D002244', (62, 64))	('vimentin', 'cellular_component', 'GO:0045099', ('30', '38'))	('S', 'Chemical', 'MESH:D013455', (65, 66))	('vimentin', 'cellular_component', 'GO:0045098', ('30', '38'))	('C+', 'Chemical', 'MESH:D002244', (44, 46))	('C-/S+', 'Var', (62, 67))	('C+/S+', 'Var', (44, 49))	('S', 'Chemical', 'MESH:D013455', (47, 48))	('vimentin', 'Protein', (30, 38))
84949	28449664	The main expression panels of CK were C+/S+ (18/42) and C+/S- (16/42).	('S', 'Chemical', 'MESH:D013455', (41, 42))	('C', 'Chemical', 'MESH:D002244', (56, 57))	('C+', 'Chemical', 'MESH:D002244', (56, 58))	('C+/S-', 'Var', (56, 61))	('C+', 'Chemical', 'MESH:D002244', (38, 40))	('C', 'Chemical', 'MESH:D002244', (30, 31))	('C+/S+', 'Var', (38, 43))	('C', 'Chemical', 'MESH:D002244', (38, 39))	('S', 'Chemical', 'MESH:D013455', (59, 60))
84951	28449664	The expression panels of EMA were C+/S+ (21/42) and C+/S- (16/42).	('EMA', 'Gene', (25, 28))	('S', 'Chemical', 'MESH:D013455', (55, 56))	('C+/S-', 'Var', (52, 57))	('EMA', 'Gene', '4582', (25, 28))	('S', 'Chemical', 'MESH:D013455', (37, 38))	('C+', 'Chemical', 'MESH:D002244', (34, 36))	('C+', 'Chemical', 'MESH:D002244', (52, 54))	('C+/S+', 'Var', (34, 39))
84953	28449664	The expression panels of CK7 were C+/S- (11/42) and C-/S+ (5/42).	('C-', 'Chemical', 'MESH:D002244', (52, 54))	('C+/S-', 'Var', (34, 39))	('S', 'Chemical', 'MESH:D013455', (55, 56))	('C-/S+', 'Var', (52, 57))	('S', 'Chemical', 'MESH:D013455', (37, 38))	('C+', 'Chemical', 'MESH:D002244', (34, 36))	('CK7', 'Gene', (25, 28))
84955	28449664	The main expression panels of CK18 were C+/S+ (12/42) and C+/S- (13/42).	('CK18', 'Gene', (30, 34))	('C+/S-', 'Var', (58, 63))	('C+', 'Chemical', 'MESH:D002244', (40, 42))	('C+/S+', 'Var', (40, 45))	('S', 'Chemical', 'MESH:D013455', (43, 44))	('S', 'Chemical', 'MESH:D013455', (61, 62))	('C+', 'Chemical', 'MESH:D002244', (58, 60))
84958	28449664	The major expression panels of CAIXwere C+/S+ (20/42) and C-/S+ (12/42).	('C-/S+', 'Var', (58, 63))	('C+', 'Chemical', 'MESH:D002244', (40, 42))	('C+/S+', 'Var', (40, 45))	('S', 'Chemical', 'MESH:D013455', (43, 44))	('S', 'Chemical', 'MESH:D013455', (61, 62))	('C-', 'Chemical', 'MESH:D002244', (58, 60))
84961	28449664	The main expression panels of CD10 were C+/S+ (20/42) and C-/S+ (12/42).	('C-/S+', 'Var', (58, 63))	('C+', 'Chemical', 'MESH:D002244', (40, 42))	('CD10', 'molecular_function', 'GO:0004245', ('30', '34'))	('C+/S+', 'Var', (40, 45))	('S', 'Chemical', 'MESH:D013455', (43, 44))	('S', 'Chemical', 'MESH:D013455', (61, 62))	('CD10', 'Gene', (30, 34))	('C-', 'Chemical', 'MESH:D002244', (58, 60))
84963	28449664	The main expression panels of PAX8 were C+/S+ (24/42), and C+/S- (10/42).	('C+/S-', 'Var', (59, 64))	('PAX8', 'Gene', (30, 34))	('C+', 'Chemical', 'MESH:D002244', (40, 42))	('C+/S+', 'Var', (40, 45))	('S', 'Chemical', 'MESH:D013455', (43, 44))	('C+', 'Chemical', 'MESH:D002244', (59, 61))	('S', 'Chemical', 'MESH:D013455', (62, 63))
84964	28449664	2a, b, and c.  The expression panels of AMACR were C+/S+ (3/42), C+/S- (8/42), and C-/S+ (3/42).	('C+/S-', 'Var', (65, 70))	('S', 'Chemical', 'MESH:D013455', (86, 87))	('C-', 'Chemical', 'MESH:D002244', (83, 85))	('C+/S+', 'Var', (51, 56))	('AMACR', 'Gene', (40, 45))	('C-/S+', 'Var', (83, 88))	('S', 'Chemical', 'MESH:D013455', (54, 55))	('C+', 'Chemical', 'MESH:D002244', (51, 53))	('S', 'Chemical', 'MESH:D013455', (68, 69))	('C+', 'Chemical', 'MESH:D002244', (65, 67))
84969	28449664	Ten cases showed p53 expression in carcinoma cells and 20 cases showed p53 expression in sarcomatoid cells (P = 0.04).	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('sarcomatoid', 'Disease', 'MESH:C538614', (89, 100))	('carcinoma cells', 'Disease', 'MESH:C538614', (35, 50))	('carcinoma cells', 'Disease', (35, 50))	('p53', 'Var', (17, 20))	('sarcomatoid', 'Disease', (89, 100))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))
84970	28449664	The main expression panels of p53 were C+/S+ (8/42) and C-/S+ (12/42).	('C-', 'Chemical', 'MESH:D002244', (56, 58))	('C+', 'Chemical', 'MESH:D002244', (39, 41))	('C+/S+', 'Var', (39, 44))	('p53', 'Gene', (30, 33))	('C-/S+', 'Var', (56, 61))	('S', 'Chemical', 'MESH:D013455', (42, 43))	('S', 'Chemical', 'MESH:D013455', (59, 60))
84972	28449664	The expression panels of Bcl-2 were C+/S+ (9/42) and C+/S- (16/42).	('S', 'Chemical', 'MESH:D013455', (56, 57))	('Bcl-2', 'Gene', (25, 30))	('C+', 'Chemical', 'MESH:D002244', (53, 55))	('C+', 'Chemical', 'MESH:D002244', (36, 38))	('S', 'Chemical', 'MESH:D013455', (39, 40))	('C+/S+', 'Var', (36, 41))	('Bcl-2', 'molecular_function', 'GO:0015283', ('25', '30'))	('C+/S-', 'Var', (53, 58))
85015	28449664	Our study demonstrated that the expression rate of p53 was 48% in sarcomatoid cells, which is higher than that in carcinoma cells, suggesting that p53 might be involved in triggering the development of high malignant sarcomatoid tumors from renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('sarcomatoid tumors', 'Disease', 'MESH:C538614', (217, 235))	('p53', 'Var', (147, 150))	('carcinoma cells', 'Disease', (114, 129))	('sarcomatoid tumors', 'Phenotype', 'HP:0100242', (217, 235))	('renal cell carcinoma', 'Disease', (241, 261))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (241, 261))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('involved', 'Reg', (160, 168))	('sarcomatoid', 'Disease', (66, 77))	('sarcomatoid', 'Disease', (217, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('sarcomatoid tumors', 'Disease', (217, 235))	('carcinoma cells', 'Disease', 'MESH:C538614', (114, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (217, 224))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (241, 261))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomatoid', 'Disease', 'MESH:C538614', (217, 228))	('sarcomatoid', 'Disease', 'MESH:C538614', (66, 77))
85016	28449664	Furthermore, p53 could be a reliable marker for predicting the prognosis or treatment outcome of RCC with sarcomatoid differentiation.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('sarcomatoid differentiation', 'Disease', (106, 133))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('p53', 'Var', (13, 16))	('sarcomatoid differentiation', 'Disease', 'MESH:C538614', (106, 133))
85045	33163139	Through proteogenomic integration, they discerned the functional impact of genomic alterations in ccRCC and further characterized novel immune signatures in the tumor microenvironment.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('alterations', 'Var', (83, 94))	('ccRCC', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))
85074	27635226	However, pathologists have not yet adapted the old sampling protocols and seem not aware of a concerning paradox: The success of sophisticated devices and expensive platforms in detecting key tumor mutations depends on the selection rightness of tumor pieces which are (very often) made by residents.	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('mutations', 'Var', (198, 207))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
85086	33889499	Late metastasis of renal cell carcinoma cloaked in a non-healing foot ulcer: A very rare presentation A 67-year-old male who underwent right radical nephrectomy 15 years prior to current diagnosis for pT2bN0M0 ccRCC presented with an isolated purulent ulcer on left foot.	('purulent ulcer', 'Disease', 'MESH:D014456', (243, 257))	('foot ulcer', 'Disease', (65, 75))	('foot ulcer', 'Disease', 'MESH:D016523', (65, 75))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (19, 39))	('purulent ulcer', 'Disease', (243, 257))	('pT2bN0M0 ccRCC', 'Var', (201, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('metastasis of renal cell carcinoma', 'Disease', (5, 39))	('metastasis of renal cell carcinoma', 'Disease', 'MESH:C538614', (5, 39))
85114	33889499	Immunohistochemistry techniques demonstrate positivity for epithelial markers, keratin, epithelial membrane antigen (EMA), carcino-embryonic antigen (CEA), and vimentin.	('vimentin', 'cellular_component', 'GO:0045099', ('160', '168'))	('membrane', 'cellular_component', 'GO:0016020', ('99', '107'))	('vimentin', 'Gene', '7431', (160, 168))	('CEA', 'Gene', (150, 153))	('vimentin', 'Gene', (160, 168))	('carcino-embryonic antigen', 'Gene', '1084', (123, 148))	('CEA', 'Gene', '1084', (150, 153))	('vimentin', 'cellular_component', 'GO:0045098', ('160', '168'))	('carcino-embryonic antigen', 'Gene', (123, 148))	('positivity', 'Var', (44, 54))	('keratin', 'Protein', (79, 86))
85118	33889499	A single centimeter increase in initial tumor size at the time of nephrectomy is associated with a 7% increased risk of late distant metastasis, and patients with 2010 stage pT1b, pT2a, pT2b, or pT3-pT4 tumors are respectively 2.8, 4.5, 3.4 and 5.1 times more likely to develop significantly late distant metastases than are patients with stage pT1a.	('tumor', 'Disease', (203, 208))	('metastases', 'Disease', (305, 315))	('late distant metastasis', 'CPA', (120, 143))	('pT3', 'Gene', (195, 198))	('develop', 'PosReg', (270, 277))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('patients', 'Species', '9606', (149, 157))	('pT2a', 'Var', (180, 184))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('pT1b', 'Var', (174, 178))	('increase', 'PosReg', (20, 28))	('pT2b', 'Var', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('pT3', 'Gene', '7694', (195, 198))	('tumors', 'Disease', (203, 209))	('tumor', 'Disease', (40, 45))	('patients', 'Species', '9606', (325, 333))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('metastases', 'Disease', 'MESH:D009362', (305, 315))
85135	33602230	In vitro experiments showed that knockdown of TEK promoted the proliferation and migration of ccRCC cells, and we found that TEK promoted apoptosis by regulating the phosphorylation of AKT, thereby inhibiting cell proliferation.	('proliferation', 'CPA', (63, 76))	('cell proliferation', 'CPA', (209, 227))	('TEK', 'Gene', '7010', (125, 128))	('regulating', 'Reg', (151, 161))	('AKT', 'Gene', '207', (185, 188))	('apoptosis', 'CPA', (138, 147))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('phosphorylation', 'MPA', (166, 181))	('RCC', 'Disease', (96, 99))	('knockdown', 'Var', (33, 42))	('cell proliferation', 'biological_process', 'GO:0008283', ('209', '227'))	('TEK', 'Gene', (46, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('inhibiting', 'NegReg', (198, 208))	('AKT', 'Gene', (185, 188))	('promoted', 'PosReg', (50, 58))	('promoted', 'PosReg', (129, 137))	('apoptosis', 'biological_process', 'GO:0097194', ('138', '147'))	('TEK', 'Gene', '7010', (46, 49))	('apoptosis', 'biological_process', 'GO:0006915', ('138', '147'))	('TEK', 'Gene', (125, 128))	('migration', 'CPA', (81, 90))	('phosphorylation', 'biological_process', 'GO:0016310', ('166', '181'))
85147	33602230	Now there is increasing evidence that signaling pathways such as MAPK, PI3K and Wnt/beta-catenin in various types of cancer can impair immune function in the TME and thus resist immunotherapy.	('resist', 'NegReg', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('PI3K', 'Var', (71, 75))	('MAPK', 'Gene', (65, 69))	('impair immune function', 'Phenotype', 'HP:0002721', (128, 150))	('beta-catenin', 'Gene', (84, 96))	('impair', 'NegReg', (128, 134))	('immune function in the TME', 'CPA', (135, 161))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('MAPK', 'molecular_function', 'GO:0004707', ('65', '69'))	('cancer', 'Disease', (117, 123))	('signaling', 'biological_process', 'GO:0023052', ('38', '47'))	('beta-catenin', 'Gene', '1499', (84, 96))	('PI3K', 'molecular_function', 'GO:0016303', ('71', '75'))
85185	33602230	The primary antibodies were as follows: anti-Ki-67, 1:200 (Novus); anti-TEK, 1:200 (Abcam).	('anti-Ki-67', 'Var', (40, 50))	('TEK', 'Gene', (72, 75))	('TEK', 'Gene', '7010', (72, 75))
85206	33602230	low) had been proven to be an important predictor for patients with ccRCC (p < 0.05).	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('patients', 'Species', '9606', (54, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('low', 'Var', (0, 3))
85216	33602230	In addition, according to the GEPIA database, high expression of TEK significantly increases the survival rate of patients (Additional file 1: Fig.	('increases', 'PosReg', (83, 92))	('TEK', 'Gene', '7010', (65, 68))	('TEK', 'Gene', (65, 68))	('survival rate', 'CPA', (97, 110))	('patients', 'Species', '9606', (114, 122))	('high expression', 'Var', (46, 61))
85226	33602230	MTT assay showed that TEK knockdown significantly promoted the proliferation of ccRCC cells (Fig.	('promoted', 'PosReg', (50, 58))	('proliferation', 'CPA', (63, 76))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('TEK', 'Gene', '7010', (22, 25))	('RCC', 'Disease', (82, 85))	('knockdown', 'Var', (26, 35))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('TEK', 'Gene', (22, 25))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))
85227	33602230	The immunofluorescence staining of the proliferation marker Ki-67 also proved that the knockdown of TEK could increase the number of Ki-67 positive cells (Fig.	('TEK', 'Gene', (100, 103))	('increase', 'PosReg', (110, 118))	('TEK', 'Gene', '7010', (100, 103))	('knockdown', 'Var', (87, 96))
85228	33602230	In addition, the results of the cloning formation assay indicated that knockdown of TEK could increase the cloning ability of ccRCC cells (Fig.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('increase', 'PosReg', (94, 102))	('knockdown', 'Var', (71, 80))	('formation', 'biological_process', 'GO:0009058', ('40', '49'))	('TEK', 'Gene', '7010', (84, 87))	('TEK', 'Gene', (84, 87))	('cloning ability of', 'CPA', (107, 125))
85229	33602230	Transwell assay was then performed to evaluate the effect of TEK on cell migration, and the results showed that TEK knockdown significantly improved the migration of ccRCC cells compared with the control group (Fig.	('improved', 'PosReg', (140, 148))	('TEK', 'Gene', (61, 64))	('ccRCC', 'Phenotype', 'HP:0006770', (166, 171))	('migration', 'CPA', (153, 162))	('knockdown', 'Var', (116, 125))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('cell migration', 'biological_process', 'GO:0016477', ('68', '82'))	('RCC', 'Disease', (168, 171))	('TEK', 'Gene', '7010', (112, 115))	('TEK', 'Gene', (112, 115))	('TEK', 'Gene', '7010', (61, 64))
85230	33602230	In short, TEK knockdown could promote the proliferation and migration of ccRCC cells.	('TEK', 'Gene', '7010', (10, 13))	('promote', 'PosReg', (30, 37))	('TEK', 'Gene', (10, 13))	('proliferation', 'CPA', (42, 55))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('migration', 'CPA', (60, 69))	('knockdown', 'Var', (14, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))
85231	33602230	Next, we evaluated the effect of TEK on apoptosis of ccRCC cells by flow cytometry, and the results showed that TEK knockdown could effectively inhibit apoptosis (Fig.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('RCC', 'Disease', (55, 58))	('apoptosis', 'biological_process', 'GO:0097194', ('152', '161'))	('apoptosis', 'biological_process', 'GO:0006915', ('152', '161'))	('apoptosis', 'biological_process', 'GO:0097194', ('40', '49'))	('apoptosis', 'biological_process', 'GO:0006915', ('40', '49'))	('knockdown', 'Var', (116, 125))	('inhibit', 'NegReg', (144, 151))	('TEK', 'Gene', '7010', (33, 36))	('TEK', 'Gene', '7010', (112, 115))	('apoptosis', 'CPA', (152, 161))	('TEK', 'Gene', (33, 36))	('TEK', 'Gene', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
85232	33602230	qRT-PCR also confirmed the reduction of apoptosis-related genes in the TEK knockdown group (Fig.	('apoptosis-related genes', 'Gene', (40, 63))	('apoptosis', 'biological_process', 'GO:0097194', ('40', '49'))	('apoptosis', 'biological_process', 'GO:0006915', ('40', '49'))	('knockdown', 'Var', (75, 84))	('TEK', 'Gene', '7010', (71, 74))	('TEK', 'Gene', (71, 74))	('reduction', 'NegReg', (27, 36))
85233	33602230	In order to explain the changes in cell phenotypes caused by TEK knockdown, Western blot analysis was performed.	('knockdown', 'Var', (65, 74))	('TEK', 'Gene', (61, 64))	('TEK', 'Gene', '7010', (61, 64))
85234	33602230	First, we detected EMT-related proteins, and the results showed that TEK knockdown significantly increased the expression of N-cadherin, Vimentin, beta-catenin, and decreased the expression of E-cadherin (Fig.	('TEK', 'Gene', '7010', (69, 72))	('cadherin', 'molecular_function', 'GO:0008014', ('195', '203'))	('expression', 'MPA', (111, 121))	('knockdown', 'Var', (73, 82))	('decreased', 'NegReg', (165, 174))	('EMT', 'biological_process', 'GO:0001837', ('19', '22'))	('increased', 'PosReg', (97, 106))	('Vimentin', 'cellular_component', 'GO:0045099', ('137', '145'))	('E-cadherin', 'Gene', (193, 203))	('E-cadherin', 'Gene', '999', (193, 203))	('cadherin', 'molecular_function', 'GO:0008014', ('127', '135'))	('beta-catenin', 'Gene', (147, 159))	('Vimentin', 'Gene', '7431', (137, 145))	('beta-catenin', 'Gene', '1499', (147, 159))	('expression', 'MPA', (179, 189))	('TEK', 'Gene', (69, 72))	('N-cadherin', 'Gene', (125, 135))	('Vimentin', 'Gene', (137, 145))	('N-cadherin', 'Gene', '1000', (125, 135))	('Vimentin', 'cellular_component', 'GO:0045098', ('137', '145'))
85235	33602230	Consistent with flow cytometry analysis, Western blot results showed that TEK knockdown increased the expression of c-Myc, Bcl-2 and Bcl-xL.	('Bcl-2', 'Gene', (123, 128))	('Bcl-xL', 'Gene', '598', (133, 139))	('Bcl-2', 'molecular_function', 'GO:0015283', ('123', '128'))	('expression', 'MPA', (102, 112))	('knockdown', 'Var', (78, 87))	('Bcl-xL', 'Gene', (133, 139))	('increased', 'PosReg', (88, 97))	('c-Myc', 'Gene', '4609', (116, 121))	('TEK', 'Gene', '7010', (74, 77))	('TEK', 'Gene', (74, 77))	('Bcl-2', 'Gene', '596', (123, 128))	('c-Myc', 'Gene', (116, 121))
85248	33602230	Activation and phosphorylation of TEK lead to downstream signaling, promoting vascular maturation and endothelial cell survival.	('TEK', 'Gene', '7010', (34, 37))	('phosphorylation', 'Var', (15, 30))	('TEK', 'Gene', (34, 37))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('promoting', 'PosReg', (68, 77))	('endothelial cell survival', 'CPA', (102, 127))	('vascular maturation', 'CPA', (78, 97))	('phosphorylation', 'biological_process', 'GO:0016310', ('15', '30'))
85249	33602230	Angiopoietin-1/TEK signaling is important for vascular integrity, TEK knockout results in a significant increase in metastatic tumor cells in the lung.	('increase', 'PosReg', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('TEK', 'Gene', '7010', (66, 69))	('tumor', 'Disease', (127, 132))	('TEK', 'Gene', (66, 69))	('Angiopoietin-1', 'Gene', (0, 14))	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('TEK', 'Gene', '7010', (15, 18))	('TEK', 'Gene', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('knockout', 'Var', (70, 78))	('Angiopoietin-1', 'Gene', '284', (0, 14))
85250	33602230	Furthermore, TEK activation normalizes the structure and function of tumor vessels, thereby delaying tumor growth, slowing the metastatic process and enhancing the response to concomitant cytotoxic treatments.	('TEK', 'Gene', (13, 16))	('structure', 'MPA', (43, 52))	('metastatic process', 'CPA', (127, 145))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('enhancing', 'PosReg', (150, 159))	('delaying', 'NegReg', (92, 100))	('activation', 'Var', (17, 27))	('normalizes', 'Reg', (28, 38))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('response to concomitant cytotoxic treatments', 'MPA', (164, 208))	('slowing', 'NegReg', (115, 122))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('TEK', 'Gene', '7010', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
85251	33602230	Hence, we could speculate that the decrease of TEK expression in ccRCC might be the main reason for tumor hypoxia and subsequent invasion and metastasis, because the lack of TEK can cause the instability of blood vessels, resulting in impeded blood perfusion and increased permeability and leakage of blood vessels.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('leakage of blood vessels', 'CPA', (290, 314))	('RCC', 'Disease', (67, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('permeability', 'CPA', (273, 285))	('lack', 'Var', (166, 170))	('blood perfusion', 'CPA', (243, 258))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('decrease', 'NegReg', (35, 43))	('cause', 'Reg', (182, 187))	('tumor hypoxia', 'Disease', (100, 113))	('TEK', 'Gene', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('increased', 'PosReg', (263, 272))	('TEK', 'Gene', '7010', (174, 177))	('instability', 'MPA', (192, 203))	('TEK', 'Gene', (47, 50))	('impeded', 'NegReg', (235, 242))	('tumor hypoxia', 'Disease', 'MESH:D000860', (100, 113))	('TEK', 'Gene', '7010', (47, 50))
85253	33602230	According to the general concept, polarization towards the M1-like phenotype has anti-tumor effects, Tregs hinder defense against tumors.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('hinder', 'NegReg', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Disease', (130, 135))	('polarization', 'Var', (34, 46))
85258	33602230	In addition, in vitro experiments showed that TEK knockdown could promote the proliferation and migration of ccRCC cells, suggesting that TEK may be a good prognostic marker for ccRCC.	('migration', 'CPA', (96, 105))	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('RCC', 'Disease', (180, 183))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('knockdown', 'Var', (50, 59))	('TEK', 'Gene', '7010', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (180, 183))	('TEK', 'Gene', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('TEK', 'Gene', '7010', (46, 49))	('promote', 'PosReg', (66, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (178, 183))	('TEK', 'Gene', (46, 49))	('proliferation', 'CPA', (78, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))
85264	33602230	The above results indicated that TEK knockdown promoted the proliferation and migration of ccRCC cells, and affected cell apoptosis by regulating the phosphorylation of AKT.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('apoptosis', 'biological_process', 'GO:0097194', ('122', '131'))	('RCC', 'Disease', (93, 96))	('apoptosis', 'biological_process', 'GO:0006915', ('122', '131'))	('knockdown', 'Var', (37, 46))	('migration', 'CPA', (78, 87))	('phosphorylation', 'MPA', (150, 165))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('promoted', 'PosReg', (47, 55))	('proliferation', 'CPA', (60, 73))	('affected', 'Reg', (108, 116))	('TEK', 'Gene', (33, 36))	('AKT', 'Gene', (169, 172))	('cell apoptosis', 'CPA', (117, 131))	('TEK', 'Gene', '7010', (33, 36))	('phosphorylation', 'biological_process', 'GO:0016310', ('150', '165'))	('regulating', 'Reg', (135, 145))	('AKT', 'Gene', '207', (169, 172))
85280	32323803	The modifications of mRNAs, such as N1-methyladenosine, N6-methyladenosine (m6A), N7-methylguanosine, 5-methylcytosine and 2'-O-methylation, serve fundamental roles in the regulation of gene expression.	('regulation of gene expression', 'biological_process', 'GO:0010468', ('172', '201'))	('m6A', 'Gene', (76, 79))	("2'-O-methylation", 'MPA', (123, 139))	('N1-methyladenosine', 'Chemical', 'MESH:C002230', (36, 54))	('N7-methylguanosine', 'Chemical', 'MESH:C016578', (82, 100))	('m6A', 'Gene', '56339', (76, 79))	('methylation', 'biological_process', 'GO:0032259', ('128', '139'))	('N7-methylguanosine', 'Var', (82, 100))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (56, 74))	('5-methylcytosine', 'MPA', (102, 118))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (102, 118))
85289	32323803	Increasing evidence has suggested that dysregulated expression of m6A RNA methylation regulators affects the initiation and progression of cancers, such as glioblastoma, acute myeloid leukemia (AML), hepatocellular carcinoma and breast cancer.	('AML', 'Disease', 'MESH:D015470', (194, 197))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancers', 'Disease', (139, 146))	('AML', 'Disease', (194, 197))	('AML', 'Phenotype', 'HP:0004808', (194, 197))	('glioblastoma', 'Disease', (156, 168))	('RNA', 'cellular_component', 'GO:0005562', ('70', '73'))	('glioblastoma', 'Phenotype', 'HP:0012174', (156, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('hepatocellular carcinoma and breast cancer', 'Disease', 'MESH:D001943', (200, 242))	('acute myeloid leukemia', 'Disease', (170, 192))	('m6A', 'Gene', '56339', (66, 69))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (200, 224))	('progression', 'CPA', (124, 135))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('m6A', 'Gene', (66, 69))	('affects', 'Reg', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (170, 192))	('RNA methylation', 'biological_process', 'GO:0001510', ('70', '85'))	('dysregulated', 'Var', (39, 51))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (170, 192))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (176, 192))	('leukemia', 'Phenotype', 'HP:0001909', (184, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (229, 242))	('glioblastoma', 'Disease', 'MESH:D005909', (156, 168))
85290	32323803	Recently, m6A RNA methylation regulator expression levels were demonstrated to be effective biomarkers for discrimination among RCC subtypes, and genetic alterations of m6A RNA methylation regulators contributed to malignant progression and poor clinical characteristics in patients with clear cell renal cell carcinoma (ccRCC).	('malignant progression', 'CPA', (215, 236))	('m6A', 'Gene', '56339', (10, 13))	('ccRCC', 'Phenotype', 'HP:0006770', (321, 326))	('contributed', 'Reg', (200, 211))	('genetic alterations', 'Var', (146, 165))	('m6A', 'Gene', (169, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (310, 319))	('patients', 'Species', '9606', (274, 282))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (288, 319))	('RNA', 'cellular_component', 'GO:0005562', ('173', '176'))	('RNA methylation', 'biological_process', 'GO:0001510', ('14', '29'))	('RNA', 'cellular_component', 'GO:0005562', ('14', '17'))	('m6A', 'Gene', '56339', (169, 172))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (288, 319))	('clear cell renal cell carcinoma', 'Disease', (288, 319))	('m6A', 'Gene', (10, 13))	('RNA methylation', 'biological_process', 'GO:0001510', ('173', '188'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (299, 319))
85394	32323803	Among the m6A RNA methylation regulators, 'writers' are considered to be the main regulators of m6A in ccRCC, and Lobo et al reported that the mRNA deregulation of the 'writers' was associated with clinicopathological features and survival of patients with RCC.	('m6A', 'Gene', '56339', (10, 13))	('associated', 'Reg', (182, 192))	('m6A', 'Gene', '56339', (96, 99))	('patients', 'Species', '9606', (243, 251))	('RNA methylation', 'biological_process', 'GO:0001510', ('14', '29'))	('deregulation', 'Var', (148, 160))	('RNA', 'cellular_component', 'GO:0005562', ('14', '17'))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('mRNA', 'MPA', (143, 147))	('RCC', 'Disease', (257, 260))	('m6A', 'Gene', (10, 13))	('m6A', 'Gene', (96, 99))
85397	32323803	In a study by Tang et al, the expression of WTAP was also significantly upregulated in RCC cell lines and tissues, and high expression of WTAP was associated with poor OS in patients with ccRCC.	('expression', 'MPA', (30, 40))	('high expression', 'Var', (119, 134))	('WTAP', 'Gene', '9589', (138, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (188, 193))	('S', 'Chemical', 'MESH:D013455', (169, 170))	('WTAP', 'Gene', (138, 142))	('ccRCC', 'Disease', (188, 193))	('patients', 'Species', '9606', (174, 182))	('upregulated', 'PosReg', (72, 83))	('WTAP', 'Gene', '9589', (44, 48))	('WTAP', 'Gene', (44, 48))
85403	32323803	By contrast, METTL3 and METTL14 are regarded as suppressor genes in glioblastoma, and knockdown of METTL3 and METTL14 promotes the growth, self-renewal and tumorigenesis of human glioblastoma stem cells.	('knockdown', 'Var', (86, 95))	('glioblastoma', 'Disease', 'MESH:D005909', (68, 80))	('glioblastoma', 'Disease', 'MESH:D005909', (179, 191))	('tumor', 'Disease', (156, 161))	('glioblastoma', 'Disease', (68, 80))	('METTL3', 'Gene', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('glioblastoma', 'Disease', (179, 191))	('METTL14', 'Gene', '57721', (110, 117))	('METTL14', 'Gene', '57721', (24, 31))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('glioblastoma', 'Phenotype', 'HP:0012174', (179, 191))	('METTL3', 'Gene', '56339', (13, 19))	('METTL3', 'Gene', (99, 105))	('self-renewal', 'CPA', (139, 151))	('METTL14', 'Gene', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('METTL14', 'Gene', (110, 117))	('human', 'Species', '9606', (173, 178))	('METTL3', 'Gene', '56339', (99, 105))	('growth', 'CPA', (131, 137))	('promotes', 'PosReg', (118, 126))
85406	32323803	In hepatocellular carcinoma, downregulation of METTL14 can significantly promote tumor metastasis in vivo and in vitro.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('METTL14', 'Gene', '57721', (47, 54))	('tumor metastasis', 'Disease', 'MESH:D009362', (81, 97))	('tumor metastasis', 'Disease', (81, 97))	('downregulation', 'Var', (29, 43))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('promote', 'PosReg', (73, 80))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('METTL14', 'Gene', (47, 54))
85425	32323803	Due to the vital roles of RNA biology, p53 and VHL in the development of ccRCC, the dysregulated expression of the m6A RNA methylation regulators may result in abnormal RNA metabolism and alteration of p53 and VHL, which may affect the initiation and progression of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (266, 271))	('VHL', 'Gene', (47, 50))	('dysregulated', 'Var', (84, 96))	('alteration', 'Reg', (188, 198))	('ccRCC', 'Disease', (73, 78))	('RNA metabolism', 'MPA', (169, 183))	('p53', 'Gene', '7157', (39, 42))	('VHL', 'Gene', (210, 213))	('RNA metabolism', 'biological_process', 'GO:0016070', ('169', '183'))	('VHL', 'Gene', '7428', (47, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))	('RNA methylation', 'biological_process', 'GO:0001510', ('119', '134'))	('affect', 'Reg', (225, 231))	('p53', 'Gene', (39, 42))	('m6A', 'Gene', '56339', (115, 118))	('RNA', 'cellular_component', 'GO:0005562', ('26', '29'))	('VHL', 'Gene', '7428', (210, 213))	('p53', 'Gene', '7157', (202, 205))	('RNA', 'cellular_component', 'GO:0005562', ('169', '172'))	('ccRCC', 'Disease', (266, 271))	('m6A', 'Gene', (115, 118))	('result in', 'Reg', (150, 159))	('abnormal', 'Var', (160, 168))	('RNA', 'cellular_component', 'GO:0005562', ('119', '122'))	('p53', 'Gene', (202, 205))
85438	32323803	In conclusion, the present study systematically demonstrated the prevalent dysregulated expression, biological function and prognostic value of m6A RNA methylation regulators in ccRCC.	('m6A', 'Gene', '56339', (144, 147))	('RNA methylation', 'biological_process', 'GO:0001510', ('148', '163'))	('ccRCC', 'Phenotype', 'HP:0006770', (178, 183))	('ccRCC', 'Disease', (178, 183))	('RNA', 'cellular_component', 'GO:0005562', ('148', '151'))	('dysregulated', 'Var', (75, 87))	('m6A', 'Gene', (144, 147))	('expression', 'MPA', (88, 98))
85439	32323803	The dysregulated expression of the m6A RNA methylation regulators was associated with differential expression of genes enriched in RNA metabolism- and malignancy-related pathways.	('m6A', 'Gene', (35, 38))	('expression', 'MPA', (99, 109))	('RNA', 'cellular_component', 'GO:0005562', ('131', '134'))	('RNA methylation', 'biological_process', 'GO:0001510', ('39', '54'))	('RNA metabolism', 'biological_process', 'GO:0016070', ('131', '145'))	('m6A', 'Gene', '56339', (35, 38))	('expression', 'MPA', (17, 27))	('RNA', 'cellular_component', 'GO:0005562', ('39', '42'))	('dysregulated', 'Var', (4, 16))
85456	27809802	The ECM metagene was associated with poor prognosis in renal clear cell carcinoma and in lung adenocarcinoma but not in other cancers investigated.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (89, 108))	('ECM metagene', 'Var', (4, 16))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (55, 81))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('renal clear cell carcinoma', 'Disease', (55, 81))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('lung adenocarcinoma', 'Disease', (89, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (89, 108))
85557	27809802	Kidney renal clear cell carcinomas are frequently highly vascularized due to deletion or inactivation of the VHL suppressor gene which results in upregulation of hypoxia-inducible factors and angiogenic factors such as VEGF.	('VEGF', 'Gene', (219, 223))	('inactivation', 'Var', (89, 101))	('upregulation', 'PosReg', (146, 158))	('Kidney renal clear cell carcinomas', 'Disease', 'MESH:C538614', (0, 34))	('hypoxia', 'Disease', 'MESH:D000860', (162, 169))	('VHL', 'Gene', (109, 112))	('VEGF', 'Gene', '7422', (219, 223))	('deletion', 'Var', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('Kidney renal clear cell carcinomas', 'Disease', (0, 34))	('VHL', 'Gene', '7428', (109, 112))	('hypoxia', 'Disease', (162, 169))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))
85575	27809802	This may be somewhat counterintuitive given the vast number of reports that have linked beta-catenin/TCF with oncogenic effects following the discovery of Tcf as a component in the mediation of malignancy induced by APC deletion.	('APC', 'cellular_component', 'GO:0005680', ('216', '219'))	('APC', 'Disease', 'MESH:D011125', (216, 219))	('malignancy', 'Disease', 'MESH:D009369', (194, 204))	('TCF', 'Gene', (101, 104))	('APC', 'Disease', (216, 219))	('Tcf', 'Gene', (155, 158))	('beta-catenin', 'Gene', (88, 100))	('malignancy', 'Disease', (194, 204))	('deletion', 'Var', (220, 228))	('Tcf', 'Gene', '3172', (155, 158))	('TCF', 'Gene', '3172', (101, 104))	('beta-catenin', 'Gene', '1499', (88, 100))
85595	33593912	ZMYND8 preferentially binds phosphorylated EZH2 to promote a PRC2-dependent to -independent function switch in hypoxia-inducible factor-activated cancer The multiple-domain protein ZMYND8 is well known as a chromatin reader that recognizes methylated, acetylated, and/or mutated histones.	('hypoxia', 'Disease', (111, 118))	('EZH2', 'Gene', (43, 47))	('cancer', 'Disease', (146, 152))	('ZMYND8', 'Gene', (181, 187))	('ZMYND8', 'Gene', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('chromatin', 'cellular_component', 'GO:0000785', ('207', '216'))	('ZMYND8', 'Gene', '23613', (0, 6))	('ZMYND8', 'Gene', '23613', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('protein', 'cellular_component', 'GO:0003675', ('173', '180'))	('histones', 'Protein', (279, 287))	('hypoxia', 'Disease', 'MESH:D000860', (111, 118))	('EZH2', 'Gene', '2146', (43, 47))	('mutated', 'Var', (271, 278))
85603	33593912	ZMYND8 binds to EZH2, and their interaction is largely enhanced by CDK1 phosphorylation of EZH2 at T487.	('phosphorylation', 'biological_process', 'GO:0016310', ('72', '87'))	('EZH2', 'Gene', (91, 95))	('EZH2', 'Gene', (16, 20))	('ZMYND8', 'Gene', (0, 6))	('T487', 'Var', (99, 103))	('binds', 'Interaction', (7, 12))	('CDK1', 'Gene', '983', (67, 71))	('EZH2', 'Gene', '2146', (91, 95))	('CDK1', 'Gene', (67, 71))	('enhanced', 'PosReg', (55, 63))	('ZMYND8', 'Gene', '23613', (0, 6))	('CDK', 'molecular_function', 'GO:0004693', ('67', '70'))	('interaction', 'Interaction', (32, 43))	('EZH2', 'Gene', '2146', (16, 20))	('phosphorylation', 'Var', (72, 87))
85604	33593912	ZMYND8 depletion not only enhances Polycomb-dependent function of EZH2 in hypoxia-exposed breast cancer cells or von Hippel-Lindau (VHL)-deficient ccRCC cells, but also suppresses the FOXM1 transcription program.	('transcription', 'biological_process', 'GO:0006351', ('190', '203'))	('ZMYND8', 'Gene', (0, 6))	('FOXM1', 'Gene', '2305', (184, 189))	('hypoxia', 'Disease', (74, 81))	('EZH2', 'Gene', (66, 70))	('EZH2', 'Gene', '2146', (66, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (147, 152))	('suppresses', 'NegReg', (169, 179))	('hypoxia', 'Disease', 'MESH:D000860', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('ZMYND8', 'Gene', '23613', (0, 6))	('enhances', 'PosReg', (26, 34))	('von Hippel-Lindau (VHL)-deficient', 'Disease', 'MESH:D006623', (113, 146))	('FOXM1', 'Gene', (184, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('Polycomb-dependent function', 'MPA', (35, 62))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('breast cancer', 'Disease', (90, 103))	('depletion', 'Var', (7, 16))
85617	33593912	It has been shown that phosphorylation of EZH2 at serine 21 (S21) and threonine 487 (T487) by PKB/AKT and CDK1, respectively, results in the dissociation of EZH2 from the PRC2 complex.	('phosphorylation', 'biological_process', 'GO:0016310', ('23', '38'))	('dissociation', 'MPA', (141, 153))	('CDK', 'molecular_function', 'GO:0004693', ('106', '109'))	('PRC2 complex', 'cellular_component', 'GO:0035098', ('171', '183'))	('EZH2', 'Gene', '2146', (42, 46))	('AKT', 'Gene', '207', (98, 101))	('EZH2', 'Gene', (42, 46))	('T487', 'Var', (85, 89))	('threonine', 'Chemical', 'MESH:D013912', (70, 79))	('CDK1', 'Gene', (106, 110))	('CDK1', 'Gene', '983', (106, 110))	('serine', 'Chemical', 'MESH:D012694', (50, 56))	('EZH2', 'Gene', '2146', (157, 161))	('phosphorylation', 'MPA', (23, 38))	('EZH2', 'Gene', (157, 161))	('PKB', 'Gene', '207', (94, 97))	('results in', 'Reg', (126, 136))	('PKB', 'Gene', (94, 97))	('AKT', 'Gene', (98, 101))
85619	33593912	Most importantly, S21 phosphorylation of EZH2 not only switches off its gene repressor function, but also turns on its gene activator activity by enhancing EZH2 interaction with transcription factors such as androgen receptor, NFkappaB, and STAT3, stressing the importance of the noncanonical gene activator function of EZH2 in oncogenesis.	('EZH2', 'Gene', (41, 45))	('EZH2', 'Gene', '2146', (41, 45))	('S21', 'Var', (18, 21))	('transcription', 'biological_process', 'GO:0006351', ('178', '191'))	('EZH2', 'Gene', '2146', (320, 324))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('EZH2', 'Gene', (320, 324))	('turns', 'Reg', (106, 111))	('gene repressor function', 'MPA', (72, 95))	('switches off', 'NegReg', (55, 67))	('enhancing', 'PosReg', (146, 155))	('EZH2', 'Gene', '2146', (156, 160))	('EZH2', 'Gene', (156, 160))	('oncogenesis', 'biological_process', 'GO:0007048', ('328', '339'))	('STAT3', 'Gene', (241, 246))	('interaction', 'Interaction', (161, 172))	('androgen receptor', 'Gene', (208, 225))	('androgen receptor', 'Gene', '367', (208, 225))	('STAT3', 'Gene', '6774', (241, 246))	('gene activator activity', 'MPA', (119, 142))
85622	33593912	ZMYND8 acts as a dual reader of histone marks H3K4me1 and H3K14ac to inhibit expression of metastasis-linked genes.	('ZMYND8', 'Gene', (0, 6))	('expression', 'MPA', (77, 87))	('ZMYND8', 'Gene', '23613', (0, 6))	('H3K14ac', 'Var', (58, 65))	('metastasis-linked genes', 'Gene', (91, 114))	('inhibit', 'NegReg', (69, 76))
85627	33593912	We demonstrate that ZMYND8 interacts with T487-phosphorylated EZH2 and disrupts EZH2 binding with other PRC2 components in ccRCC cells.	('disrupts', 'NegReg', (71, 79))	('EZH2', 'Gene', '2146', (62, 66))	('ZMYND8', 'Gene', '23613', (20, 26))	('T487-phosphorylated', 'Var', (42, 61))	('interacts', 'Interaction', (27, 36))	('ccRCC', 'Disease', (123, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('EZH2', 'Gene', (62, 66))	('EZH2', 'Gene', (80, 84))	('ZMYND8', 'Gene', (20, 26))	('EZH2', 'Gene', '2146', (80, 84))	('binding', 'molecular_function', 'GO:0005488', ('85', '92'))	('binding', 'Interaction', (85, 92))
85629	33593912	In an attempt to define novel functions of ZMYND8 in cancer, we analyzed a published RNA-seq dataset derived from ZMYND8 wild-type (WT) and knockout (KO) MDA-MB-231 breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('ZMYND8', 'Gene', '23613', (43, 49))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (154, 164))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('cancer', 'Disease', (53, 59))	('ZMYND8', 'Gene', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('knockout', 'Var', (140, 148))	('RNA', 'cellular_component', 'GO:0005562', ('85', '88'))	('ZMYND8', 'Gene', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Disease', (172, 178))	('ZMYND8', 'Gene', '23613', (114, 120))
85635	33593912	The VHL gene is frequently deleted or mutated in ccRCC in patients and loss of VHL results in the stabilization of HIFalpha proteins, mimicking the role of hypoxia.	('hypoxia', 'Disease', (156, 163))	('hypoxia', 'Disease', 'MESH:D000860', (156, 163))	('VHL', 'Gene', '7428', (79, 82))	('VHL', 'Gene', '7428', (4, 7))	('stabilization', 'MPA', (98, 111))	('HIFalpha proteins', 'Protein', (115, 132))	('VHL', 'Gene', (4, 7))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('patients', 'Species', '9606', (58, 66))	('loss', 'Var', (71, 75))	('VHL', 'Gene', (79, 82))
85637	33593912	1H), knockdown of VHL resulted in up-regulation of HIF2alpha protein in MDA-MB-231 cells under normoxic conditions (Fig.	('HIF2alpha', 'Gene', (51, 60))	('VHL', 'Gene', '7428', (18, 21))	('regulation', 'biological_process', 'GO:0065007', ('37', '47'))	('knockdown', 'Var', (5, 14))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (72, 82))	('HIF2alpha', 'Gene', '2034', (51, 60))	('VHL', 'Gene', (18, 21))	('up-regulation', 'PosReg', (34, 47))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
85638	33593912	Similar to the results reported previously, we demonstrated that VHL knockdown or hypoxia exposure decreased the expression of PRC2 components SUZ12 and EED, consistent with the decreased level of H3K27me3 (Fig.	('EED', 'Gene', (153, 156))	('expression', 'MPA', (113, 123))	('decreased', 'NegReg', (99, 108))	('VHL', 'Gene', '7428', (65, 68))	('decreased', 'NegReg', (178, 187))	('SUZ12', 'Gene', '23512', (143, 148))	('SUZ12', 'Gene', (143, 148))	('hypoxia', 'Disease', (82, 89))	('hypoxia', 'Disease', 'MESH:D000860', (82, 89))	('knockdown', 'Var', (69, 78))	('VHL', 'Gene', (65, 68))	('PRC2', 'Gene', (127, 131))	('EED', 'Gene', '8726', (153, 156))
85643	33593912	To determine whether HIFalpha proteins play a critical role in ZMYND8 regulation of H3K27me3 levels in ccRCC cells, we knocked down HIF1alpha and HIF2alpha in hypoxia-treated or VHL-deficient cells.	('HIF1alpha', 'Gene', '3091', (132, 141))	('knocked down', 'Var', (119, 131))	('HIF2alpha', 'Gene', (146, 155))	('ZMYND8', 'Gene', (63, 69))	('regulation', 'biological_process', 'GO:0065007', ('70', '80'))	('HIF2alpha', 'Gene', '2034', (146, 155))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('VHL-deficient', 'Disease', (178, 191))	('ZMYND8', 'Gene', '23613', (63, 69))	('HIF1alpha', 'Gene', (132, 141))	('VHL-deficient', 'Disease', 'MESH:D006623', (178, 191))	('hypoxia', 'Disease', 'MESH:D000860', (159, 166))	('hypoxia', 'Disease', (159, 166))
85647	33593912	1 H and I), we chose to determine how ZMYND8 regulates PRC2 activities in ccRCC in which VHL is often deleted or mutated.	('ZMYND8', 'Gene', (38, 44))	('deleted', 'Var', (102, 109))	('PRC2', 'Gene', (55, 59))	('ccRCC', 'Disease', (74, 79))	('VHL', 'Gene', (89, 92))	('ZMYND8', 'Gene', '23613', (38, 44))	('VHL', 'Gene', '7428', (89, 92))	('mutated', 'Var', (113, 120))	('regulates', 'Reg', (45, 54))	('activities', 'MPA', (60, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))
85651	33593912	We found that in the VHL deletion/truncation group (238 patients), high levels of ZMYND8 mRNA were associated with poor overall survival (Fig.	('patients', 'Species', '9606', (56, 64))	('poor', 'NegReg', (115, 119))	('ZMYND8', 'Gene', '23613', (82, 88))	('VHL', 'Gene', (21, 24))	('overall survival', 'MPA', (120, 136))	('deletion/truncation', 'Var', (25, 44))	('VHL', 'Gene', '7428', (21, 24))	('ZMYND8', 'Gene', (82, 88))
85660	33593912	ZMYND8 depletion also failed to affect protein expression of other PRC2 components examined, such as SUZ12 and EED (Fig.	('ZMYND8', 'Gene', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('SUZ12', 'Gene', '23512', (101, 106))	('ZMYND8', 'Gene', '23613', (0, 6))	('SUZ12', 'Gene', (101, 106))	('depletion', 'Var', (7, 16))	('EED', 'Gene', '8726', (111, 114))	('protein expression', 'MPA', (39, 57))	('EED', 'Gene', (111, 114))
85661	33593912	While ZMYND8 depletion had little or no effect on the expression of total histone H3 protein, it largely increased H3K27me3 levels in both 786-O and A498 cells (Fig.	('ZMYND8', 'Gene', (6, 12))	('H3K27me3 levels', 'MPA', (115, 130))	('depletion', 'Var', (13, 22))	('histone H3 protein', 'Protein', (74, 92))	('ZMYND8', 'Gene', '23613', (6, 12))	('A498', 'CellLine', 'CVCL:1056', (149, 153))	('increased', 'PosReg', (105, 114))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
85670	33593912	Consistent with the finding that ZMYND depletion increased H3K27me3 levels in the promoter of PRC2 target gene RUNX2, it also increased occupancy of EZH2 and EED in the RUNX2 promoter in both cell lines (Fig.	('EED', 'Gene', '8726', (158, 161))	('occupancy', 'MPA', (136, 145))	('depletion', 'Var', (39, 48))	('RUNX2', 'Gene', '860', (111, 116))	('increased', 'PosReg', (49, 58))	('EED', 'Gene', (158, 161))	('RUNX2', 'Gene', '860', (169, 174))	('RUNX2', 'Gene', (111, 116))	('EZH2', 'Gene', '2146', (149, 153))	('RUNX2', 'Gene', (169, 174))	('H3K27me3 levels', 'MPA', (59, 74))	('EZH2', 'Gene', (149, 153))	('increased', 'PosReg', (126, 135))
85679	33593912	We first generated one N-terminal (DeltaPBP) and three C-terminal (DeltaC1, DeltaC2 and DeltaC3) truncation mutants from Flag-tagged ZMYND8 (SI Appendix, Fig.	('truncation mutants', 'Var', (97, 115))	('DeltaC1', 'Var', (67, 74))	('DeltaC3', 'Var', (88, 95))	('ZMYND8', 'Gene', '23613', (133, 139))	('DeltaC2', 'Var', (76, 83))	('DeltaC3', 'DELETION', 'None', (88, 95))	('DeltaC2', 'DELETION', 'None', (76, 83))	('DeltaC1', 'DELETION', 'None', (67, 74))	('ZMYND8', 'Gene', (133, 139))
85681	33593912	We demonstrated that FL Flag-ZMYND8, DeltaPBP, or DeltaC3 deletion mutants interacted with EZH2.	('EZH2', 'Gene', (91, 95))	('EZH2', 'Gene', '2146', (91, 95))	('DeltaC3', 'DELETION', 'None', (50, 57))	('interacted', 'Reg', (75, 85))	('ZMYND8', 'Gene', (29, 35))	('deletion mutants', 'Var', (58, 74))	('ZMYND8', 'Gene', '23613', (29, 35))	('DeltaC3', 'Var', (50, 57))
85682	33593912	In contrast, DeltaC1 or DeltaC2 mutant lacking the MYND domain failed to interact with EZH2 (SI Appendix, Fig.	('DeltaC2', 'Var', (24, 31))	('MYND domain', 'MPA', (51, 62))	('DeltaC1', 'DELETION', 'None', (13, 20))	('DeltaC2', 'DELETION', 'None', (24, 31))	('interact', 'Interaction', (73, 81))	('EZH2', 'Gene', '2146', (87, 91))	('EZH2', 'Gene', (87, 91))	('mutant', 'Var', (32, 38))	('DeltaC1', 'Var', (13, 20))	('lacking', 'NegReg', (39, 46))
85702	33593912	5C), we mutated those residues individually to alanine (A), including serine 21 (S21A) and threonine residues 345, 416, and 487 (T345A, T416A, and T487A).	('T345A', 'Mutation', 'rs765380980', (129, 134))	('T416A', 'Mutation', 'rs766047391', (136, 141))	('T487A', 'Mutation', 'rs770006533', (147, 152))	('T416A', 'Var', (136, 141))	('T487A', 'Var', (147, 152))	('S21A', 'Mutation', 'p.S21A', (81, 85))	('serine', 'Chemical', 'MESH:D012694', (70, 76))	('T345A', 'Var', (129, 134))	('threonine', 'Chemical', 'MESH:D013912', (91, 100))	('alanine', 'Chemical', 'MESH:D000409', (47, 54))
85703	33593912	WT EZH2 and the alanine mutants were transfected into 293T cells for co-IP assays.	('alanine mutants', 'Var', (16, 31))	('EZH2', 'Gene', (3, 7))	('EZH2', 'Gene', '2146', (3, 7))	('alanine', 'Chemical', 'MESH:D000409', (16, 23))	('293T', 'CellLine', 'CVCL:0063', (54, 58))
85704	33593912	We demonstrated that different from WT and S21A, T345A and T416A mutants, the binding of T487A mutant to ZMYND8 was largely reduced (Fig.	('binding', 'Interaction', (78, 85))	('T487A', 'Mutation', 'rs770006533', (89, 94))	('reduced', 'NegReg', (124, 131))	('T487A', 'Var', (89, 94))	('S21A', 'Mutation', 'p.S21A', (43, 47))	('ZMYND8', 'Gene', '23613', (105, 111))	('T416A', 'Mutation', 'rs766047391', (59, 64))	('binding', 'molecular_function', 'GO:0005488', ('78', '85'))	('ZMYND8', 'Gene', (105, 111))	('T345A', 'Mutation', 'rs765380980', (49, 54))
85705	33593912	Detection of a residual interaction between ZMYND8 and T487A-mutated EZH2 (Fig.	('interaction', 'Interaction', (24, 35))	('EZH2', 'Gene', '2146', (69, 73))	('ZMYND8', 'Gene', '23613', (44, 50))	('EZH2', 'Gene', (69, 73))	('T487A', 'Mutation', 'rs770006533', (55, 60))	('ZMYND8', 'Gene', (44, 50))	('T487A-mutated', 'Var', (55, 68))
85708	33593912	We further generated an EZH2 T487 phosphorylation-mimicking mutant (T487D) by converting T487 to aspartic acid (D).	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('T487D', 'Var', (68, 73))	('T487', 'Var', (89, 93))	('EZH2', 'Gene', '2146', (24, 28))	('EZH2', 'Gene', (24, 28))	('aspartic acid', 'Chemical', 'MESH:D001224', (97, 110))	('T487D', 'Mutation', 'p.T487D', (68, 73))
85709	33593912	We found that the T487D mutation substantially enhanced EZH2 interaction with ZMYND8 (Fig.	('enhanced', 'PosReg', (47, 55))	('T487D', 'Mutation', 'p.T487D', (18, 23))	('T487D', 'Var', (18, 23))	('ZMYND8', 'Gene', '23613', (78, 84))	('EZH2', 'Gene', '2146', (56, 60))	('ZMYND8', 'Gene', (78, 84))	('EZH2', 'Gene', (56, 60))	('interaction', 'Interaction', (61, 72))
85710	33593912	In addition, ZMYND8 depletion reduced the EZH2 phosphorylation level and increased EZH2 interactions with SUZ12 and EED (Fig.	('increased', 'PosReg', (73, 82))	('SUZ12', 'Gene', (106, 111))	('EED', 'Gene', '8726', (116, 119))	('EZH2', 'Gene', '2146', (83, 87))	('EZH2', 'Gene', '2146', (42, 46))	('EED', 'Gene', (116, 119))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('EZH2', 'Gene', (83, 87))	('ZMYND8', 'Gene', '23613', (13, 19))	('EZH2', 'Gene', (42, 46))	('depletion', 'Var', (20, 29))	('SUZ12', 'Gene', '23512', (106, 111))	('reduced', 'NegReg', (30, 37))	('ZMYND8', 'Gene', (13, 19))	('interactions', 'Interaction', (88, 100))
85713	33593912	These results also suggest that EZH2 T487 phosphorylation is important for ZMYND8-EZH2 interaction.	('EZH2', 'Gene', (82, 86))	('EZH2', 'Gene', '2146', (82, 86))	('ZMYND8', 'Gene', '23613', (75, 81))	('interaction', 'Interaction', (87, 98))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))	('EZH2', 'Gene', '2146', (32, 36))	('ZMYND8', 'Gene', (75, 81))	('EZH2', 'Gene', (32, 36))	('T487', 'Var', (37, 41))
85714	33593912	It has been reported that EZH2 T487 is phosphorylated by CDK1.	('EZH2', 'Gene', '2146', (26, 30))	('EZH2', 'Gene', (26, 30))	('CDK1', 'Gene', (57, 61))	('CDK1', 'Gene', '983', (57, 61))	('T487', 'Var', (31, 35))	('CDK', 'molecular_function', 'GO:0004693', ('57', '60'))
85718	33593912	In contrast, knockout of CDK1 by CRISPR/Cas9 in 786-O cells largely decreased EZH2 T487 phosphorylation level and the interaction between endogenous ZMYND8 and EZH2 proteins (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('88', '103'))	('decreased', 'NegReg', (68, 77))	('ZMYND8', 'Gene', (149, 155))	('Cas', 'cellular_component', 'GO:0005650', ('40', '43'))	('knockout', 'Var', (13, 21))	('CDK1', 'Gene', (25, 29))	('interaction', 'Interaction', (118, 129))	('CDK1', 'Gene', '983', (25, 29))	('EZH2', 'Gene', '2146', (160, 164))	('CDK', 'molecular_function', 'GO:0004693', ('25', '28'))	('EZH2', 'Gene', (160, 164))	('ZMYND8', 'Gene', '23613', (149, 155))	('EZH2', 'Gene', (78, 82))	('EZH2', 'Gene', '2146', (78, 82))
85720	33593912	Similar to the results obtained from the genetic manipulation, we found that pharmacologic inhibition by roscovitine, a pan inhibitor of CDK1, CDK2, and CDK5, or RO-3306, a CDK1-selective inhibitor, not only abolished EZH2 T487 phosphorylation, but also decreased ZMYND8-EZH2 interaction at the endogenous level in 786-O ccRCC cells (Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (321, 326))	('CDK', 'molecular_function', 'GO:0004693', ('143', '146'))	('CDK1', 'Gene', (173, 177))	('EZH2', 'Gene', '2146', (271, 275))	('CDK1', 'Gene', '983', (173, 177))	('EZH2', 'Gene', (271, 275))	('abolished', 'NegReg', (208, 217))	('CDK', 'molecular_function', 'GO:0004693', ('153', '156'))	('ZMYND8', 'Gene', '23613', (264, 270))	('RO-3306', 'Chemical', 'MESH:C512984', (162, 169))	('phosphorylation', 'biological_process', 'GO:0016310', ('228', '243'))	('CDK5', 'Gene', (153, 157))	('decreased', 'NegReg', (254, 263))	('CDK1', 'Gene', '983', (137, 141))	('CDK1', 'Gene', (137, 141))	('CDK2', 'Gene', '1017', (143, 147))	('CDK5', 'Gene', '1020', (153, 157))	('CDK', 'molecular_function', 'GO:0004693', ('137', '140'))	('RO-3306', 'Var', (162, 169))	('roscovitine', 'Chemical', 'MESH:D000077546', (105, 116))	('CDK2', 'Gene', (143, 147))	('ZMYND8', 'Gene', (264, 270))	('CDK', 'molecular_function', 'GO:0004693', ('173', '176'))	('EZH2', 'Gene', '2146', (218, 222))	('EZH2', 'Gene', (218, 222))
85721	33593912	Furthermore, we found that while ZMYND8 interaction with WT EZH2 was largely enhanced by CDK1 overexpression, the interaction between ZMYND8 and EZH2 nonphosphorylatable mutant T487A or T487D was unaffected (Fig.	('overexpression', 'PosReg', (94, 108))	('ZMYND8', 'Gene', '23613', (33, 39))	('EZH2', 'Gene', '2146', (145, 149))	('EZH2', 'Gene', (145, 149))	('CDK', 'molecular_function', 'GO:0004693', ('89', '92'))	('ZMYND8', 'Gene', '23613', (134, 140))	('T487A', 'Mutation', 'rs770006533', (177, 182))	('interaction', 'Interaction', (114, 125))	('ZMYND8', 'Gene', (33, 39))	('CDK1', 'Gene', (89, 93))	('CDK1', 'Gene', '983', (89, 93))	('EZH2', 'Gene', '2146', (60, 64))	('T487A', 'Var', (177, 182))	('EZH2', 'Gene', (60, 64))	('enhanced', 'PosReg', (77, 85))	('T487D', 'Mutation', 'p.T487D', (186, 191))	('T487D', 'Var', (186, 191))	('ZMYND8', 'Gene', (134, 140))	('interaction', 'Interaction', (40, 51))
85722	33593912	Together, these results suggest that CDK1 overexpression enhances EZH2 interaction with ZMYND8, and that this effect is specifically mediated through EZH2 T487 phosphorylation.	('CDK', 'molecular_function', 'GO:0004693', ('37', '40'))	('ZMYND8', 'Gene', '23613', (88, 94))	('EZH2', 'Gene', '2146', (150, 154))	('CDK1', 'Gene', (37, 41))	('overexpression enhances', 'PosReg', (42, 65))	('EZH2', 'Gene', (150, 154))	('CDK1', 'Gene', '983', (37, 41))	('ZMYND8', 'Gene', (88, 94))	('EZH2', 'Gene', (66, 70))	('EZH2', 'Gene', '2146', (66, 70))	('T487', 'Var', (155, 159))	('interaction', 'Interaction', (71, 82))	('phosphorylation', 'biological_process', 'GO:0016310', ('160', '175'))
85724	33593912	Meta-analysis of RNA-seq data from ZMYND8-proficient and -deficient MDA-MB-231 cells in hypoxic conditions indicated that ZMYND8 depletion inactivates the FOXM1 transcriptional program while activating the Polycomb function of EZH2 (Fig.	('FOXM1', 'Gene', (155, 160))	('Polycomb function', 'MPA', (206, 223))	('FOXM1', 'Gene', '2305', (155, 160))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (68, 78))	('ZMYND8', 'Gene', (35, 41))	('depletion', 'Var', (129, 138))	('RNA', 'cellular_component', 'GO:0005562', ('17', '20'))	('ZMYND8', 'Gene', '23613', (122, 128))	('inactivates', 'NegReg', (139, 150))	('EZH2', 'Gene', '2146', (227, 231))	('EZH2', 'Gene', (227, 231))	('ZMYND8', 'Gene', (122, 128))	('activating', 'PosReg', (191, 201))	('ZMYND8', 'Gene', '23613', (35, 41))
85733	33593912	We found that ZMYND8 depletion largely increased PRC2/EED occupancy but decreased FOXM1 binding at the MMP2 gene promoter, although no EZH2 binding change was detected in the promoter region (Fig.	('EED', 'Gene', '8726', (54, 57))	('EED', 'Gene', (54, 57))	('binding', 'molecular_function', 'GO:0005488', ('140', '147'))	('MMP2', 'Gene', (103, 107))	('ZMYND8', 'Gene', (14, 20))	('binding', 'molecular_function', 'GO:0005488', ('88', '95'))	('decreased', 'NegReg', (72, 81))	('FOXM1', 'Gene', (82, 87))	('MMP2', 'Gene', '4313', (103, 107))	('FOXM1', 'Gene', '2305', (82, 87))	('increased', 'PosReg', (39, 48))	('depletion', 'Var', (21, 30))	('EZH2', 'Gene', '2146', (135, 139))	('MMP2', 'molecular_function', 'GO:0004228', ('103', '107'))	('ZMYND8', 'Gene', '23613', (14, 20))	('EZH2', 'Gene', (135, 139))	('binding', 'Interaction', (88, 95))
85735	33593912	Additional co-IP experiments showed that apart from FL ZMYND8 and other deletion mutants (SI Appendix, Fig.	('ZMYND8', 'Gene', '23613', (55, 61))	('deletion mutants', 'Var', (72, 88))	('ZMYND8', 'Gene', (55, 61))
85737	33593912	6F), suggesting that a region between PWWP and MYND (amino acids 761 to 1002) in ZMYND8 is required for its interaction with FOXM1.	('FOXM1', 'Gene', (125, 130))	('ZMYND8', 'Gene', '23613', (81, 87))	('amino', 'Var', (53, 58))	('interaction', 'Interaction', (108, 119))	('ZMYND8', 'Gene', (81, 87))	('FOXM1', 'Gene', '2305', (125, 130))
85742	33593912	Furthermore, we found that CDK1 overexpression increased the FOXM1 association with WT EZH2, but not nonphosphorylatable mutants T487A and T487D (Fig.	('T487D', 'Mutation', 'p.T487D', (139, 144))	('EZH2', 'Gene', '2146', (87, 91))	('FOXM1', 'Gene', (61, 66))	('CDK1', 'Gene', '983', (27, 31))	('overexpression increased', 'PosReg', (32, 56))	('EZH2', 'Gene', (87, 91))	('FOXM1', 'Gene', '2305', (61, 66))	('CDK1', 'Gene', (27, 31))	('T487D', 'Var', (139, 144))	('CDK', 'molecular_function', 'GO:0004693', ('27', '30'))	('association', 'Interaction', (67, 78))	('T487A', 'Mutation', 'rs770006533', (129, 134))	('T487A', 'Var', (129, 134))
85753	33593912	ZMYND8 canonically functions as a chromatin reader that recognizes histone codes, such as methylation (H3K4me1, H3K4me3, and H3K36me2) and/or acetylation (H4K14ac and H4K16ac).	('ZMYND8', 'Gene', (0, 6))	('H4K14ac', 'Var', (155, 162))	('H3K4me1', 'Var', (103, 110))	('H3K4me3', 'Var', (112, 119))	('methylation', 'MPA', (90, 101))	('ZMYND8', 'Gene', '23613', (0, 6))	('methylation', 'biological_process', 'GO:0032259', ('90', '101'))	('H4K16ac', 'Var', (167, 174))	('chromatin', 'cellular_component', 'GO:0000785', ('34', '43'))	('H3K36me2', 'Var', (125, 133))	('acetylation', 'MPA', (142, 153))
85760	33593912	EZH2 canonically acts as a gene repressor in a PRC2-dependent manner by catalyzing H3K27me3 to mediate gene silencing.	('gene', 'MPA', (103, 107))	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('H3K27me3', 'Var', (83, 91))	('gene silencing', 'biological_process', 'GO:0016458', ('103', '117'))
85761	33593912	Notably, the PRC2 complex is disassembled due to EZH2 phosphorylation at different residues, such as S21 and T487, mediated by AKT and CDK1 kinases, respectively.	('CDK1', 'Gene', (135, 139))	('CDK', 'molecular_function', 'GO:0004693', ('135', '138'))	('CDK1', 'Gene', '983', (135, 139))	('EZH2', 'Gene', '2146', (49, 53))	('EZH2', 'Gene', (49, 53))	('S21', 'Var', (101, 104))	('AKT', 'Gene', '207', (127, 130))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('PRC2 complex', 'cellular_component', 'GO:0035098', ('13', '25'))	('T487', 'Var', (109, 113))	('AKT', 'Gene', (127, 130))	('phosphorylation', 'MPA', (54, 69))
85762	33593912	Further studies have shown that EZH2 phosphorylation at these sites not only abolishes its Polycomb-dependent repressor function, but also allows EZH2 to gain a Polycomb-independent gene activator function.	('gain', 'PosReg', (154, 158))	('abolishes', 'NegReg', (77, 86))	('phosphorylation', 'Var', (37, 52))	('Polycomb-independent gene activator function', 'MPA', (161, 205))	('EZH2', 'Gene', '2146', (146, 150))	('EZH2', 'Gene', (146, 150))	('Polycomb-dependent repressor function', 'MPA', (91, 128))	('EZH2', 'Gene', '2146', (32, 36))	('phosphorylation', 'biological_process', 'GO:0016310', ('37', '52'))	('EZH2', 'Gene', (32, 36))
85765	33593912	Additionally, it seems that ZMYND8 binding also protects and maintains EZH2 phosphorylation at T487, thereby tipping EZH2 function away from PRC2 and toward Polycomb-independent functions.	('T487', 'Var', (95, 99))	('EZH2', 'Gene', (71, 75))	('tipping', 'PosReg', (109, 116))	('phosphorylation', 'biological_process', 'GO:0016310', ('76', '91'))	('function', 'MPA', (122, 130))	('EZH2', 'Gene', (117, 121))	('EZH2', 'Gene', '2146', (117, 121))	('phosphorylation', 'MPA', (76, 91))	('ZMYND8', 'Gene', '23613', (28, 34))	('binding', 'molecular_function', 'GO:0005488', ('35', '42'))	('EZH2', 'Gene', '2146', (71, 75))	('ZMYND8', 'Gene', (28, 34))
85772	33593912	Our data suggest that EZH2 T487 phosphorylation is important for ZMYND8-EZH2 interaction, and that this interaction can be largely enhanced by CDK1 phosphorylation of EZH2.	('CDK', 'molecular_function', 'GO:0004693', ('143', '146'))	('EZH2', 'Gene', (167, 171))	('T487', 'Var', (27, 31))	('ZMYND8', 'Gene', (65, 71))	('EZH2', 'Gene', (22, 26))	('phosphorylation', 'biological_process', 'GO:0016310', ('32', '47'))	('CDK1', 'Gene', '983', (143, 147))	('interaction', 'Interaction', (104, 115))	('CDK1', 'Gene', (143, 147))	('phosphorylation', 'MPA', (32, 47))	('EZH2', 'Gene', '2146', (72, 76))	('EZH2', 'Gene', '2146', (22, 26))	('phosphorylation', 'biological_process', 'GO:0016310', ('148', '163'))	('EZH2', 'Gene', (72, 76))	('enhanced', 'PosReg', (131, 139))	('interaction', 'Interaction', (77, 88))	('ZMYND8', 'Gene', '23613', (65, 71))	('EZH2', 'Gene', '2146', (167, 171))
85785	29100303	In contrast, KRT8 knockdown suppressed ccRCC metastasis both in vitro and in vivo.	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('knockdown', 'Var', (18, 27))	('KRT8', 'Gene', (13, 17))	('suppressed', 'NegReg', (28, 38))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))
85797	29100303	Elevating KRT13 expression can directly drive metastasis to bone tissue, brain tissue and soft tissue in prostate cancer.	('drive', 'Reg', (40, 45))	('prostate cancer', 'Disease', (105, 120))	('metastasis to bone tissue', 'CPA', (46, 71))	('KRT13', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Elevating', 'Var', (0, 9))	('prostate cancer', 'Disease', 'MESH:D011471', (105, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (105, 120))	('expression', 'MPA', (16, 26))	('KRT13', 'Gene', '3860', (10, 15))
85812	29100303	A previous work showed that advanced-stage ccRCC tumors carry a high risk of venous invasion and that the presence of VTTs is strongly correlated with a poor prognosis in ccRCC patients.	('ccRCC tumors', 'Disease', 'MESH:D009369', (43, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('RCC', 'Disease', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('patients', 'Species', '9606', (177, 185))	('ccRCC', 'Phenotype', 'HP:0006770', (171, 176))	('ccRCC tumors', 'Disease', (43, 55))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('venous invasion', 'CPA', (77, 92))	('presence', 'Var', (106, 114))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
85823	29100303	The Cox proportional hazards regression analysis results indicated that KRT8 expression levels were an independent risk factor for PFS (hazard ratio [HR] 2.918, 95 % confidence interval [CI] 1.342-6.345, p=0.007) and OS (HR 3.512, 95 % CI 1.391-8.867, p=0.008) in patients with ccRCC after partial or radical nephrectomy (Table 2).	('expression levels', 'Var', (77, 94))	('PFS', 'Disease', (131, 134))	('RCC', 'Disease', 'MESH:C538614', (280, 283))	('RCC', 'Disease', (280, 283))	('RCC', 'Phenotype', 'HP:0005584', (280, 283))	('ccRCC', 'Phenotype', 'HP:0006770', (278, 283))	('KRT8', 'Gene', (72, 76))	('patients', 'Species', '9606', (264, 272))
85830	29100303	KRT8 knockdown or overexpression efficiency was confirmed by qRT-PCR and western blotting (Supplmentary Figure 2B-2D).	('Supplmentary Figure 2B-2D', 'Disease', (91, 116))	('knockdown', 'Var', (5, 14))	('KRT8', 'Gene', (0, 4))	('Supplmentary Figure 2B-2D', 'Disease', 'MESH:C563839', (91, 116))	('overexpression', 'PosReg', (18, 32))
85841	29100303	To explore the molecular mechanisms underlying KRT8-mediated increases in ccRCC metastasis, we first assessed whether KRT8 was involved in manipulating epithelial mesenchymal transition (EMT), which is thought to be a key process underlying cell metastasis.	('manipulating', 'Var', (139, 151))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('involved', 'Reg', (127, 135))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('epithelial mesenchymal transition', 'CPA', (152, 185))	('EMT', 'biological_process', 'GO:0001837', ('187', '190'))	('epithelial mesenchymal transition', 'biological_process', 'GO:0001837', ('152', '185'))	('KRT8', 'Gene', (118, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))
85846	29100303	To further validate the effects of KRT8 on IL-11/STAT3 signaling in vitro, we measured IL-11 mRNA and protein levels in different ACHN, Caki-1, and 786-O cell clones and found that KRT8 knockdown significantly decreased IL-11 mRNA and protein levels in ACHN-SH and Caki-1-SH cells.	('knockdown', 'Var', (186, 195))	('STAT3', 'Gene', (49, 54))	('IL-11', 'molecular_function', 'GO:0005142', ('220', '225'))	('ACHN', 'Gene', '55323', (130, 134))	('IL-11', 'molecular_function', 'GO:0005142', ('87', '92'))	('Caki-1-SH', 'CellLine', 'CVCL:0234', (265, 274))	('ACHN', 'Gene', '55323', (253, 257))	('KRT8', 'Gene', (181, 185))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('ACHN', 'Gene', (253, 257))	('decreased', 'NegReg', (210, 219))	('signaling', 'biological_process', 'GO:0023052', ('55', '64'))	('ACHN', 'Gene', (130, 134))	('protein', 'cellular_component', 'GO:0003675', ('235', '242'))	('STAT3', 'Gene', '6774', (49, 54))	('IL-11', 'molecular_function', 'GO:0005142', ('43', '48'))
85848	29100303	KRT8 knockdown significantly decreased IL-11 levels in the cell supernatants and STAT3 phosphorylation levels in ACHN-SH and Caki-1-SH cells, while KRT8 overexpression increased IL-11 levels in the cell supernatants and STAT3 phosphorylation levels in 786-O-KRT8 cells (Figure 5C and 5D).	('increased', 'PosReg', (168, 177))	('knockdown', 'Var', (5, 14))	('KRT8', 'Gene', (0, 4))	('STAT3', 'Gene', '6774', (81, 86))	('Caki-1-SH', 'CellLine', 'CVCL:0234', (125, 134))	('ACHN', 'Gene', (113, 117))	('STAT3', 'Gene', '6774', (220, 225))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))	('phosphorylation', 'biological_process', 'GO:0016310', ('226', '241'))	('STAT3', 'Gene', (81, 86))	('IL-11', 'molecular_function', 'GO:0005142', ('178', '183'))	('decreased', 'NegReg', (29, 38))	('IL-11 levels', 'MPA', (39, 51))	('IL-11', 'molecular_function', 'GO:0005142', ('39', '44'))	('IL-11', 'MPA', (178, 183))	('ACHN', 'Gene', '55323', (113, 117))	('STAT3', 'Gene', (220, 225))
85852	29100303	To further explore whether KRT8 promotes renal cancer cell migration and invasion through IL-11/STAT3, we overexpressed or knocked down IL-11 to conduct functional studies in renal cancer cells (Figure 6A).	('renal cancer', 'Disease', (175, 187))	('STAT3', 'Gene', (96, 101))	('IL-11', 'molecular_function', 'GO:0005142', ('136', '141'))	('IL-11', 'Gene', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('knocked down', 'Var', (123, 135))	('renal cancer', 'Disease', (41, 53))	('KRT8', 'Gene', (27, 31))	('renal cancer', 'Phenotype', 'HP:0009726', (175, 187))	('renal cancer', 'Disease', 'MESH:D007680', (41, 53))	('renal cancer', 'Disease', 'MESH:D007680', (175, 187))	('renal cancer', 'Phenotype', 'HP:0009726', (41, 53))	('IL-11', 'molecular_function', 'GO:0005142', ('90', '95'))	('invasion', 'CPA', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('promotes', 'PosReg', (32, 40))	('STAT3', 'Gene', '6774', (96, 101))	('cell migration', 'biological_process', 'GO:0016477', ('54', '68'))
85853	29100303	IL-11 overexpression attenuated the effects of KRT8 knockdown on renal cancer cell migration and invasion (Figure 6B).	('attenuated', 'NegReg', (21, 31))	('KRT8', 'Gene', (47, 51))	('renal cancer', 'Disease', (65, 77))	('renal cancer', 'Phenotype', 'HP:0009726', (65, 77))	('knockdown', 'Var', (52, 61))	('cell migration', 'biological_process', 'GO:0016477', ('78', '92'))	('renal cancer', 'Disease', 'MESH:D007680', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('IL-11', 'molecular_function', 'GO:0005142', ('0', '5'))	('invasion', 'CPA', (97, 105))
85854	29100303	Consistent with this finding, IL-11 knockdown abrogated the effects of KRT8 overexpression on renal cancer cell migration and invasion (Figure 6B).	('KRT8', 'Gene', (71, 75))	('IL-11', 'molecular_function', 'GO:0005142', ('30', '35'))	('IL-11', 'Gene', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('abrogated', 'NegReg', (46, 55))	('knockdown', 'Var', (36, 45))	('invasion', 'CPA', (126, 134))	('cell migration', 'biological_process', 'GO:0016477', ('107', '121'))	('renal cancer', 'Disease', (94, 106))	('renal cancer', 'Disease', 'MESH:D007680', (94, 106))	('renal cancer', 'Phenotype', 'HP:0009726', (94, 106))	('overexpression', 'PosReg', (76, 90))
85867	29100303	Prognostic analyses showed that patients with higher KRT8 expression levels had poorer PFS and OS than patients with lower KRT8 expression levels.	('KRT8 expression levels', 'Var', (53, 75))	('patients', 'Species', '9606', (103, 111))	('patients', 'Species', '9606', (32, 40))	('poorer', 'NegReg', (80, 86))
85876	29100303	We subsequently found that silencing KRT8 using specific shRNAs decreased renal cancer cell invasion and metastasis abilities, whereas KRT8 overexpression led to significant increases in ccRCC invasion and metastasis ability in vitro.	('increases', 'PosReg', (174, 183))	('metastasis ability', 'CPA', (206, 224))	('silencing', 'Var', (27, 36))	('metastasis abilities', 'CPA', (105, 125))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('decreased renal cancer', 'Disease', 'MESH:D007680', (64, 86))	('renal cancer', 'Phenotype', 'HP:0009726', (74, 86))	('decreased renal cancer', 'Disease', (64, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (187, 192))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('RCC', 'Disease', (189, 192))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))	('KRT8', 'Gene', (37, 41))
85882	29100303	The results of previous studies also showed that RCC cells can produce IL-11 in vitro and that high IL-11 expression is an independent predictor of a poor prognosis in ccRCC patients.	('RCC', 'Disease', (49, 52))	('IL-11', 'molecular_function', 'GO:0005142', ('100', '105'))	('RCC', 'Disease', (170, 173))	('expression', 'MPA', (106, 116))	('high', 'Var', (95, 99))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('patients', 'Species', '9606', (174, 182))	('IL-11', 'Gene', (100, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (168, 173))	('IL-11', 'molecular_function', 'GO:0005142', ('71', '76'))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
85896	29100303	High-level KRT8 expression may promote metastasis by activating IL-11/STAT3 signaling, however, the mechanism underlying KRT8 regulation in ccRCC awaits further investigation.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('expression', 'Var', (16, 26))	('IL-11', 'molecular_function', 'GO:0005142', ('64', '69'))	('STAT3', 'Gene', (70, 75))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('metastasis', 'CPA', (39, 49))	('regulation', 'biological_process', 'GO:0065007', ('126', '136'))	('KRT8', 'Gene', (11, 15))	('promote', 'PosReg', (31, 38))	('activating', 'Reg', (53, 63))	('STAT3', 'Gene', '6774', (70, 75))
85923	29100303	After incubating with antibodies specific for KRT8 (ab216022, ab215830; Abcam, CA, USA), IL-11 (ab187167; Abcam, CA, USA), STAT3 (ab119352; Abcam, CA, USA), P-STAT3 (ab76315; Abcam, CA, USA) and beta-actin (ab8226; Abcam, CA, USA), the blots were incubated with IRDye 800-conjugated goat anti-rabbit IgG and IRDye 700-conjugated goat anti-mouse IgG, and the bands were detected using an Odyssey infrared scanner (Li-Cor).	('STAT3', 'Gene', (123, 128))	('mouse', 'Species', '10090', (339, 344))	('goat', 'Species', '9925', (283, 287))	('STAT3', 'Gene', (159, 164))	('rabbit', 'Species', '9986', (293, 299))	('IL-11', 'molecular_function', 'GO:0005142', ('89', '94'))	('beta-actin', 'Gene', '728378', (195, 205))	('goat', 'Species', '9925', (329, 333))	('beta-actin', 'Gene', (195, 205))	('ab76315', 'Var', (166, 173))	('STAT3', 'Gene', '6774', (123, 128))	('ab216022', 'Var', (52, 60))	('ab119352', 'Var', (130, 138))	('STAT3', 'Gene', '6774', (159, 164))	('ab8226;', 'Var', (207, 214))
85992	31557788	A total of 185 samples were available in the RNASeq dataset with matching proteomics data (including 110 tumors), and 9884 genes with corresponding proteins in the proteomics data.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('9884', 'Var', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
86047	29723225	A survival advantage for patients undergoing NSS compared to radical nephrectomy (RN) could be reported in several non-randomized retrospective studies.	('NSS', 'Chemical', '-', (45, 48))	('survival', 'MPA', (2, 10))	('patients', 'Species', '9606', (25, 33))	('NSS', 'Var', (45, 48))
86109	29723225	Interestingly, they found a lower recurrence rate and cancer-specific mortality in the NSS group, but no significant difference in all-cause mortality.	('lower', 'NegReg', (28, 33))	('NSS', 'Var', (87, 90))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('recurrence rate', 'CPA', (34, 49))	('NSS', 'Chemical', '-', (87, 90))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
86111	29723225	But overall, we demonstrated a significant OS benefit after NSS (Fig 1).	('NSS', 'Chemical', '-', (60, 63))	('NSS', 'Var', (60, 63))	('OS', 'Chemical', '-', (43, 45))	('benefit', 'PosReg', (46, 53))
86179	33000227	There were more than 700 specimens obtained from the following GEO datasets: GSE4282, GSE46699, GSE53757, GSE15641, GSE68417, GSE14994, GSE40435, GSE71963 and GSE76351.	('GSE4282', 'Chemical', '-', (77, 84))	('GSE4282', 'Var', (77, 84))	('GSE68417', 'Var', (116, 124))	('GSE71963', 'Var', (146, 154))	('GSE53757', 'Var', (96, 104))	('GSE40435', 'Var', (136, 144))	('GSE46699', 'Var', (86, 94))	('GSE15641', 'Var', (106, 114))	('GSE14994', 'Var', (126, 134))	('GSE76351', 'Var', (159, 167))
86236	33000227	As shown in Table SI, the clinical characteristics (size, pathologic T, pathologic M and pathologic N) showed a significant difference between the high- and low-DEF6 expression groups in the TCGA database.	('DEF6', 'Gene', (161, 165))	('high-', 'Var', (147, 152))	('DEF6', 'Gene', '50619', (161, 165))
86237	33000227	Meanwhile, as shown in Table SII, the clinical characteristics (size) showed a significant difference between the high- and low-DEF6 expression groups in the present clinical database.	('high-', 'Var', (114, 119))	('DEF6', 'Gene', '50619', (128, 132))	('DEF6', 'Gene', (128, 132))
86242	33000227	The analysis contained 539 ccRCC samples in the TCGA database, 101 ccRCC samples in GSE40435 and 71 ccRCC samples in GSE53757.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('GSE40435', 'Var', (84, 92))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
86270	33000227	Univariate and multivariate Cox regression suggested that high DEF6 expression was significantly related to a poor prognosis for patients with ccRCC, which indicated that DEF6 may be an independent prognostic factor for ccRCC.	('DEF6', 'Gene', '50619', (63, 67))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('expression', 'MPA', (68, 78))	('patients', 'Species', '9606', (129, 137))	('RCC', 'Phenotype', 'HP:0005584', (222, 225))	('RCC', 'Disease', 'MESH:C538614', (222, 225))	('RCC', 'Disease', (222, 225))	('high', 'Var', (58, 62))	('DEF6', 'Gene', '50619', (171, 175))	('DEF6', 'Gene', (171, 175))	('DEF6', 'Gene', (63, 67))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))
86306	33000227	ccRCC clear cell renal cell carcinoma DEGs differentially expressed genes GEF guanine nucleotide exchange factor GEO Gene Expression Omnibus GO gene ontology GSEA gene set enrichment analysis KEGG Kyoto encyclopedia of genes and genomes OS overall survival PPI protein-protein interaction RCC renal cell carcinoma TCGA the Cancer Genome Atlas	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (6, 37))	('GEF', 'Gene', (74, 77))	('PPI', 'biological_process', 'GO:0060134', ('257', '260'))	('Cancer', 'Disease', (323, 329))	('GEF', 'Gene', '9181', (74, 77))	('RCC', 'Disease', (289, 292))	('RCC', 'Phenotype', 'HP:0005584', (289, 292))	('Gene Expression', 'biological_process', 'GO:0010467', ('117', '132'))	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (293, 313))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (17, 37))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (6, 37))	('Cancer', 'Disease', 'MESH:D009369', (323, 329))	('RCC', 'Disease', 'MESH:C538614', (289, 292))	('GEF', 'molecular_function', 'GO:0005085', ('74', '77'))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('protein', 'cellular_component', 'GO:0003675', ('269', '276'))	('PPI', 'Var', (257, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('GSEA', 'Chemical', '-', (158, 162))	('KEGG', 'Chemical', '-', (192, 196))	('clear cell renal cell carcinoma', 'Disease', (6, 37))	('renal cell carcinoma', 'Disease', (293, 313))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (293, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (304, 313))	('gene ontology', 'biological_process', 'GO:0003673', ('144', '157'))	('protein', 'cellular_component', 'GO:0003675', ('261', '268'))	('Cancer', 'Phenotype', 'HP:0002664', (323, 329))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (17, 37))
86363	30464630	The baseline variables with FDR-P <0.05 in univariable analysis and variables reported clinical relevant in prior studies were included into the multivariate Cox proportional hazards regression model.	('FDR-P', 'Var', (28, 33))	('Cox', 'Gene', (158, 161))	('Cox', 'Gene', '1351', (158, 161))
86379	30464630	The most common site of postoperative metastases for patients with cM0 were lung (N=5), bone (N=3), intra-abdominal (N=3) and ipsilateral local (N=4).	('cM0', 'Var', (67, 70))	('metastases', 'Disease', 'MESH:D009362', (38, 48))	('patients', 'Species', '9606', (53, 61))	('metastases', 'Disease', (38, 48))	('intra-abdominal', 'Disease', (100, 115))	('intra-abdominal', 'Disease', 'MESH:D059325', (100, 115))
86386	30464630	In contrast, the cohort of cM0 patients with Ki-67 index of SD >=30% and >=25% SD had significantly worse OS compared with Ki-67 index <30% and<25% SD (Figure 3A, B); however, in the cM1 setting, there was no observed difference (Figure 3C, D).	('SD', 'Chemical', '-', (148, 150))	('>=25% SD', 'Var', (73, 81))	('SD', 'Chemical', '-', (60, 62))	('index', 'Var', (51, 56))	('worse', 'NegReg', (100, 105))	('cM0', 'Var', (27, 30))	('patients', 'Species', '9606', (31, 39))	('Ki-67 index', 'Var', (45, 56))	('OS', 'Chemical', '-', (106, 108))	('SD', 'Chemical', '-', (79, 81))	('>=30%', 'Var', (63, 68))
86404	30464630	Recently, Wang et al have shown the poor prognostic value of high Ki-67 index in RCC by meta-analysis.	('Ki-67 index', 'Protein', (66, 77))	('high', 'Var', (61, 65))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))
86409	30464630	It has been reported that RCCs with <20% SD have partial response to targeted therapy, and those with higher amounts of SD are more likely to respond to cytotoxic chemotherapy consisting of doxorubicin and gemcitabine.	('partial', 'NegReg', (49, 56))	('doxorubicin', 'Chemical', 'MESH:D004317', (190, 201))	('SD', 'Chemical', '-', (120, 122))	('respond', 'MPA', (142, 149))	('<20% SD', 'Var', (36, 43))	('gemcitabine', 'Chemical', 'MESH:C056507', (206, 217))	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('SD', 'Chemical', '-', (41, 43))
86428	30456188	We will review the basic physics of MRI and demonstrate how hyperpolarized 13C MRI offers an innovative solution to early diagnosis as well as creates novel avenues for more targeted therapy.	('13C', 'Chemical', 'MESH:C000615229', (75, 78))	('hyperpolarized 13C', 'Var', (60, 78))	('MRI', 'Gene', (79, 82))
86453	30456188	Hereditary leiomyomatosis and renal cell cancer (HLRCC) is due to a mutation in the fumarate hydratase gene and causes type 2 papillary tumors.	('papillary tumors', 'Disease', (126, 142))	('causes', 'Reg', (112, 118))	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('renal cell cancer', 'Phenotype', 'HP:0005584', (30, 47))	('mutation', 'Var', (68, 76))	('papillary tumors', 'Phenotype', 'HP:0007482', (126, 142))	('due to', 'Reg', (59, 65))	('Hereditary leiomyomatosis and renal cell cancer', 'Disease', 'MESH:C535516', (0, 47))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('fumarate hydratase', 'Gene', '2271', (84, 102))	('fumarate hydratase', 'Gene', (84, 102))	('papillary tumors', 'Disease', 'MESH:D002291', (126, 142))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
86454	30456188	Mutation in the succinate dehydrogenase gene (SDH) causes chromophobe tumors as well as paragangliomas.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Mutation', 'Var', (0, 8))	('SDH', 'Gene', '6390', (46, 49))	('chromophobe tumors', 'Disease', 'MESH:D000238', (58, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('causes', 'Reg', (51, 57))	('chromophobe tumors', 'Disease', (58, 76))	('SDH', 'Gene', (46, 49))	('paragangliomas', 'Disease', (88, 102))	('paragangliomas', 'Phenotype', 'HP:0002668', (88, 102))	('paragangliomas', 'Disease', 'MESH:D010235', (88, 102))
86461	30456188	Von Hippel Lindau (VHL) syndromes causes ccRCC and is caused by dysfunction in the VHL gene leading to accumulation of hypoxia-induced factor (HIF) 1alpha which binds to vascular endothelial growth factor (VEGF) receptors, causing aberrant angiogenesis and tumorigenesis.	('angiogenesis', 'biological_process', 'GO:0001525', ('240', '252'))	('causing', 'Reg', (223, 230))	('VHL', 'Disease', (83, 86))	('Von Hippel Lindau', 'Gene', (0, 17))	('angiogenesis', 'CPA', (240, 252))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('170', '204'))	('hypoxia-induced factor (HIF) 1alpha', 'Gene', '3091', (119, 154))	('binds', 'Interaction', (161, 166))	('VHL', 'Disease', (19, 22))	('tumor', 'Disease', (257, 262))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('RCC', 'Disease', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('vascular endothelial growth factor', 'Gene', '7422', (170, 204))	('caused by', 'Reg', (54, 63))	('VEGF', 'Gene', '7422', (206, 210))	('vascular endothelial growth factor', 'Gene', (170, 204))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('accumulation', 'PosReg', (103, 115))	('VHL', 'Disease', 'MESH:D006623', (83, 86))	('VEGF', 'Gene', (206, 210))	('dysfunction', 'Var', (64, 75))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('VHL', 'Disease', 'MESH:D006623', (19, 22))	('causes', 'Reg', (34, 40))	('Von Hippel Lindau', 'Gene', '7428', (0, 17))
86462	30456188	VHL gene changes are seen in a large number of sporadic ccRCC as well.	('changes', 'Var', (9, 16))	('VHL', 'Disease', 'MESH:D006623', (0, 3))	('VHL', 'Disease', (0, 3))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
86474	30456188	Deprivation of arginine has been associated with prostate cancer cell death.	('arginine', 'Chemical', 'MESH:D001120', (15, 23))	('prostate cancer cell death', 'Disease', 'MESH:D011471', (49, 75))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Deprivation', 'Var', (0, 11))	('prostate cancer', 'Phenotype', 'HP:0012125', (49, 64))	('cell death', 'biological_process', 'GO:0008219', ('65', '75'))	('prostate cancer cell death', 'Disease', (49, 75))	('associated', 'Reg', (33, 43))
86518	30456188	In addition, they found that inhibition of MCT4 using 4,4'-diisothiocyanostilbene-2,2'disulfonic acid (DIDS) decreased the concentration of extracellular lactate, providing further evidence that this efflux is mediated by the MCT4 transporter.	('decreased', 'NegReg', (109, 118))	('MCT4', 'Gene', '9123', (226, 230))	('extracellular', 'cellular_component', 'GO:0005576', ('140', '153'))	('MCT', 'biological_process', 'GO:0120197', ('226', '229'))	('lactate', 'Chemical', 'MESH:D019344', (154, 161))	('MCT4', 'Gene', '9123', (43, 47))	('MCT4', 'Gene', (43, 47))	('MCT4', 'Gene', (226, 230))	('MCT', 'biological_process', 'GO:0120197', ('43', '46'))	('efflux', 'biological_process', 'GO:0140115', ('200', '206'))	('concentration of extracellular lactate', 'MPA', (123, 161))	('efflux', 'biological_process', 'GO:0140352', ('200', '206'))	('inhibition', 'Var', (29, 39))
86525	30456188	in 2013 at the University of California, San Francisco conducted the pilot clinical trial for hyperpolarized [1-13C]pyruvate MRS in human patients with prostate cancer.	('prostate cancer', 'Disease', (152, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('prostate cancer', 'Disease', 'MESH:D011471', (152, 167))	('prostate cancer', 'Phenotype', 'HP:0012125', (152, 167))	('[1-13C]pyruvate', 'Chemical', '-', (109, 124))	('human', 'Species', '9606', (132, 137))	('MRS', 'Gene', (125, 128))	('hyperpolarized', 'Var', (94, 108))	('MRS', 'Gene', '148398', (125, 128))	('patients', 'Species', '9606', (138, 146))
86569	30456188	While hyperpolarized MRI has already demonstrated a high potential to revolutionize the staging and treatment of GU tumors, further study is still needed before this can be widely disseminated as the first-line method.	('GU tumors', 'Disease', 'MESH:D009369', (113, 122))	('GU tumors', 'Disease', (113, 122))	('men', 'Species', '9606', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('hyperpolarized', 'Var', (6, 20))	('GU tumors', 'Phenotype', 'HP:0007379', (113, 122))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('GU tumor', 'Phenotype', 'HP:0007379', (113, 121))
86578	32041631	Furthermore, our results establish that inhibiting ABCB-1 with elacridar, in addition to sunitinib, has a positive impact on reverting sunitinib-resistance development in in vitro, ex vivo and in vivo models.	('sunitinib-resistance development', 'MPA', (135, 167))	('reverting', 'NegReg', (125, 134))	('sunitinib', 'Chemical', 'MESH:C473478', (89, 98))	('elacridar', 'Chemical', 'MESH:C083501', (63, 72))	('sunitinib', 'Chemical', 'MESH:C473478', (135, 144))	('inhibiting', 'Var', (40, 50))	('ABCB-1', 'Gene', (51, 57))
86605	32041631	The following reagents were purchased for this study: Sunitinib malate (Sutent, LC Laboratories, MA, USA); Elacridar (Toronto Research Chemicals, ON, CA); Mitomycin C and LY294002 (Sigma-Aldrich, MO, USA); AZD5363 and AZD8186 (Selleckchem, TX, USA); SL0101 (Calbiochem, CA, USA) and INK128 (Cayman Chemicals, MI, USA).	('INK128', 'Var', (283, 289))	('AZD5363', 'Var', (206, 213))	('Mitomycin C', 'Chemical', 'MESH:D016685', (155, 166))	('AZD8186', 'Chemical', 'MESH:C000595972', (218, 225))	('Sunitinib malate', 'Chemical', 'MESH:C473478', (54, 70))	('LY294002', 'Chemical', 'MESH:C085911', (171, 179))	('Elacridar', 'Chemical', 'MESH:C083501', (107, 116))	('SL0101', 'Var', (250, 256))	('AZD5363', 'Chemical', 'MESH:C575618', (206, 213))	('AZD8186', 'Var', (218, 225))	('LY294002', 'Var', (171, 179))
86648	32041631	Moreover, it is widely accepted that ccRCC tumors commonly have Von Hippel-Lindau (VHL) gene mutation.	('ccRCC tumors', 'Disease', (37, 49))	('VHL', 'Gene', '7428', (83, 86))	('Von Hippel-Lindau', 'Gene', '7428', (64, 81))	('Von Hippel-Lindau', 'Gene', (64, 81))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('ccRCC tumors', 'Disease', 'MESH:D009369', (37, 49))	('mutation', 'Var', (93, 101))	('VHL', 'Gene', (83, 86))
86649	32041631	However, our analysis from TCGA dataset shows that only ~ 50% of ccRCC patients have VHL mutation (Additional file 1: Figure S1).	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('VHL', 'Gene', (85, 88))	('patients', 'Species', '9606', (71, 79))	('mutation', 'Var', (89, 97))	('ccRCC', 'Disease', (65, 70))	('VHL', 'Gene', '7428', (85, 88))
86650	32041631	Therefore, we have conditioned both a VHL mutated 786-O (Additional file 1: Figure S1) and non-mutated Caki-1 ccRCC cell-lines.	('mutated', 'Var', (42, 49))	('786-O', 'Chemical', 'MESH:C002925', (50, 55))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('VHL', 'Gene', (38, 41))	('VHL', 'Gene', '7428', (38, 41))
86654	32041631	We have also found increased beta-catenin, SOX2 and GSK-3beta protein expression between Caki-1 DC and Caki-1WT, which could suggest cancer stem-cell-like (CSC) and epithelial-mesenchymal transition (EMT) characteristics in Caki-1 DC (Fig.	('GSK-3beta', 'Gene', '2931', (52, 61))	('GSK-3beta', 'Gene', (52, 61))	('GSK', 'molecular_function', 'GO:0050321', ('52', '55'))	('EMT', 'biological_process', 'GO:0001837', ('200', '203'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('165', '198'))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('Caki-1 DC', 'Var', (224, 233))	('cancer', 'Disease', (133, 139))	('beta-catenin', 'Gene', (29, 41))	('SOX2', 'Gene', (43, 47))	('increased', 'PosReg', (19, 28))	('expression', 'MPA', (70, 80))	('SOX2', 'Gene', '6657', (43, 47))	('beta-catenin', 'Gene', '1499', (29, 41))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
86664	32041631	Patients with clear-cell subtype were found to have decreased median time of survival with high YB-1 intensity (~ 65 months) compared to medium (~ 85 months) and low (NA) (Fig.	('high', 'Var', (91, 95))	('Patients', 'Species', '9606', (0, 8))	('decreased', 'NegReg', (52, 61))	('YB-1', 'Gene', (96, 100))
86666	32041631	The Kaplan-Meier analysis showed that mutation in both YBX1 and ABCB1 genes lead to poor prognosis in patients compared to no alteration in those genes.	('YBX1', 'Gene', (55, 59))	('ABCB1', 'Gene', (64, 69))	('patients', 'Species', '9606', (102, 110))	('ABCB1', 'Gene', '5243', (64, 69))	('YBX1', 'Gene', '4904', (55, 59))	('mutation', 'Var', (38, 46))
86677	32041631	Interestingly, the cell viability significantly decreased in Caki-1 DC when treated with a combination therapy of INK128 and 10 muM sunitinib compared to sunitinib monotherapy (Fig.	('combination', 'Interaction', (91, 102))	('muM', 'Gene', '56925', (128, 131))	('decreased', 'NegReg', (48, 57))	('sunitinib', 'Chemical', 'MESH:C473478', (154, 163))	('muM', 'Gene', (128, 131))	('INK128', 'Var', (114, 120))	('sunitinib', 'Chemical', 'MESH:C473478', (132, 141))	('cell viability', 'CPA', (19, 33))
86687	32041631	These observations were confirmed with Caki-1WT or Caki-1 DC engraftment in chicken embryo chorioallantoic membrane (CAM) ex vivo tumor model as well.	('membrane', 'cellular_component', 'GO:0016020', ('107', '115'))	('Caki-1', 'Var', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('chicken', 'Species', '9031', (76, 83))	('tumor', 'Disease', (130, 135))
86698	32041631	Immunohistochemical staining of the Caki-1WT and DC inoculated tumors for YB-1 and ABCB-1 shows increased protein levels in Caki-1 DC compared to WT (Fig.	('ABCB-1', 'Gene', (83, 89))	('increased', 'PosReg', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('inoculated tumors', 'Disease', 'MESH:D002372', (52, 69))	('YB-1', 'Gene', (74, 78))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('inoculated tumors', 'Disease', (52, 69))	('protein levels', 'MPA', (106, 120))	('Caki-1 DC', 'Var', (124, 133))
86706	32041631	We have also used another ccRCC cell-line, 786-O, that has VHL mutation.	('VHL', 'Gene', '7428', (59, 62))	('786-O', 'Chemical', 'MESH:C002925', (43, 48))	('mutation', 'Var', (63, 71))	('VHL', 'Gene', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (28, 31))
86713	32041631	The analysis showed a marked decrease in median overall survival time in ccRCC patients with high YB-1 gene intensity compare to medium and low gene intensities.	('overall survival time', 'MPA', (48, 69))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('YB-1', 'Gene', (98, 102))	('patients', 'Species', '9606', (79, 87))	('high', 'Var', (93, 97))	('decrease', 'NegReg', (29, 37))	('ccRCC', 'Disease', (73, 78))
86714	32041631	Moreover, in other cancer types, patients with mutations of YB-1 and ABCB-1 genes have decreased overall survival time.	('ABCB-1', 'Gene', (69, 75))	('overall survival time', 'CPA', (97, 118))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('patients', 'Species', '9606', (33, 41))	('YB-1', 'Gene', (60, 64))	('decreased', 'NegReg', (87, 96))	('cancer', 'Disease', (19, 25))	('mutations', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
86736	32041631	In this assay, tumors engrafted with Caki-1WT (sunitinib-sensitive) significantly decreased in size when treated with either sunitinib alone or sunitinib/elacridar combination therapy.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('sunitinib', 'Chemical', 'MESH:C473478', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('sunitinib', 'Chemical', 'MESH:C473478', (144, 153))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('elacridar', 'Chemical', 'MESH:C083501', (154, 163))	('Caki-1WT', 'Var', (37, 45))	('sunitinib', 'Chemical', 'MESH:C473478', (125, 134))	('decreased', 'NegReg', (82, 91))	('tumors', 'Disease', (15, 21))
86744	32041631	Overall, the current study demonstrates (i) the direct effect of sunitinib on mccRCC cells, (ii) this direct effect leads to several phenotypic changes in mccRCC, (iii) chronic sunitinib treatment develops acquired drug-resistance partly through YB-1/ABCB-1 mediated pathway and (iv) blocking ABCB-1 with elacridar has shown to overcome sunitinib-resistance in mccRCC samples.	('ABCB-1', 'Gene', (293, 299))	('sunitinib', 'Chemical', 'MESH:C473478', (177, 186))	('YB-1/ABCB-1', 'Pathway', (246, 257))	('drug-resistance', 'biological_process', 'GO:0009315', ('215', '230'))	('elacridar', 'Chemical', 'MESH:C083501', (305, 314))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('drug-resistance', 'biological_process', 'GO:0042493', ('215', '230'))	('drug-resistance', 'Phenotype', 'HP:0020174', (215, 230))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('sunitinib', 'Chemical', 'MESH:C473478', (65, 74))	('RCC', 'Phenotype', 'HP:0005584', (364, 367))	('sunitinib', 'Chemical', 'MESH:C473478', (337, 346))	('acquired drug-resistance', 'MPA', (206, 230))	('blocking', 'Var', (284, 292))
86782	31761620	After incubation at 37  C, 5% CO2 for 48 to 72 h, the cells were collected and stained with Propidium iodide (#P4864, Sigma-Aldrich, St. Louis, Missouri, United States) and Annexin V (#A35122, Life Technologies) for 15 min at room temperature.	('#A35122', 'Var', (184, 191))	('CO2', 'Chemical', 'MESH:D002245', (30, 33))	('Propidium iodide', 'Chemical', 'MESH:D011419', (92, 108))	('Annexin V', 'Gene', '308', (173, 182))	('#P4864', 'Var', (110, 116))	('Annexin V', 'Gene', (173, 182))
86798	31761620	Our analysis detected E542 and E545 pathogenic recurrent mutation hotspots in PIK3CA, but no known pathogenic recurrent hotspots in ARID1A (Suppl.	('PIK3CA', 'Gene', (78, 84))	('E542', 'Var', (22, 26))	('E545', 'Var', (31, 35))	('PIK3CA', 'Gene', '5290', (78, 84))	('ARID1A', 'Gene', '8289', (132, 138))	('pathogenic', 'Reg', (36, 46))	('ARID1A', 'Gene', (132, 138))
86800	31761620	There were only two recurrent mutations detected, R1461 and Q605 in ARID1A.	('ARID1A', 'Gene', (68, 74))	('R1461', 'Var', (50, 55))	('Q605', 'Var', (60, 64))	('ARID1A', 'Gene', '8289', (68, 74))
86801	31761620	Interestingly, there was no significant difference between EpiCC and MesCC in gene mutation and copy number aberration commonly associated with OCCC, except for ARID1B (Fisher exact test, p = 0 04).	('ARID1B', 'Gene', (161, 167))	('ARID1B', 'Gene', '57492', (161, 167))	('copy number aberration', 'Var', (96, 118))	('associated', 'Reg', (128, 138))	('OCCC', 'Disease', (144, 148))
86816	31761620	By scrutinizing the genetic, copy number and transcriptomic profiles of the EpiCC and MesCC subtypes, we have verified that both subtypes harbor OCCC-associated molecular footprints such as high rates of ARID1A, and PIK3CA mutations; low rates of TP53, BRCA1/2 mutations; high rates of ZNF217 amplification; and elevated OCCC gene expression signatures scores.	('mutations', 'Var', (261, 270))	('TP53', 'Gene', (247, 251))	('ZNF217', 'Gene', (286, 292))	('PIK3CA', 'Gene', (216, 222))	('BRCA1/2', 'Gene', (253, 260))	('OCCC gene expression signatures scores', 'MPA', (321, 359))	('elevated', 'PosReg', (312, 320))	('low', 'NegReg', (234, 237))	('ZNF217', 'Gene', '7764', (286, 292))	('gene expression', 'biological_process', 'GO:0010467', ('326', '341'))	('amplification', 'MPA', (293, 306))	('PIK3CA', 'Gene', '5290', (216, 222))	('TP53', 'Gene', '7157', (247, 251))	('ARID1A', 'Gene', (204, 210))	('mutations', 'Var', (223, 232))	('BRCA1/2', 'Gene', '672;675', (253, 260))	('ARID1A', 'Gene', '8289', (204, 210))
86826	32231741	Great efforts of high-throughput sequencing have revealed that SETD2 is mutated or its function is lost in a range of solid cancers, including renal cancer, gastrointestinal cancer, lung cancer, pancreatic cancer, osteosarcoma, and so on.	('osteosarcoma', 'Disease', 'MESH:D012516', (214, 226))	('lung cancer', 'Disease', (182, 193))	('renal cancer', 'Disease', 'MESH:D007680', (143, 155))	('pancreatic cancer', 'Disease', 'MESH:D010190', (195, 212))	('solid cancers', 'Disease', 'MESH:D009369', (118, 131))	('function', 'MPA', (87, 95))	('SETD2', 'Gene', (63, 68))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('pancreatic cancer', 'Disease', (195, 212))	('osteosarcoma', 'Phenotype', 'HP:0002669', (214, 226))	('solid cancers', 'Disease', (118, 131))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (157, 180))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('gastrointestinal cancer', 'Disease', (157, 180))	('SETD2', 'Gene', '29072', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (157, 180))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('renal cancer', 'Disease', (143, 155))	('mutated', 'Var', (72, 79))	('renal cancer', 'Phenotype', 'HP:0009726', (143, 155))	('lost', 'NegReg', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (195, 212))	('osteosarcoma', 'Disease', (214, 226))
86827	32231741	Mutation, or functional loss, of the SETD2 gene produces dysfunction in corresponding tumor tissue proteins, leading to tumorigenesis, progression, chemotherapy resistance, and unfavorable prognosis, suggesting that SETD2 possibly acts as a tumor suppressor.	('SETD2', 'Gene', '29072', (37, 42))	('dysfunction', 'MPA', (57, 68))	('SETD2', 'Gene', (216, 221))	('chemotherapy resistance', 'CPA', (148, 171))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (241, 246))	('SETD2', 'Gene', '29072', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('progression', 'CPA', (135, 146))	('tumor', 'Disease', (120, 125))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('241', '257'))	('leading to', 'Reg', (109, 119))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor suppressor', 'biological_process', 'GO:0051726', ('241', '257'))	('loss', 'NegReg', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('SETD2', 'Gene', (37, 42))	('tumor', 'Disease', (86, 91))	('Mutation', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('unfavorable prognosis', 'CPA', (177, 198))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
86830	32231741	Recent studies have revealed that histone methylation plays a crucial role in regulatory mechanism, histone lysine methyltransferases (KMTs) are associated with cell biosynthesis and its gene mutation or functional loss as well as subsequent downstream signaling pathways facilitates oncogenic processes.	('lysine', 'Chemical', 'MESH:D008239', (108, 114))	('histone methylation', 'biological_process', 'GO:0016571', ('34', '53'))	('signaling', 'biological_process', 'GO:0023052', ('253', '262'))	('mutation', 'Var', (192, 200))	('loss', 'NegReg', (215, 219))	('facilitates', 'PosReg', (272, 283))	('biosynthesis', 'biological_process', 'GO:0009058', ('166', '178'))	('oncogenic processes', 'CPA', (284, 303))
86832	32231741	Previous studies have reported that many other KMTs can catalyze H3K36 to generate monomethylated histone H3 (H3K36me1) or H3K36me2, such as ASH1L (absent small and homeotic disks protein 1 homolog), NSD1, NSD2, NSD3 (nuclear receptor-binding SET domain-containing proteins 1-3) and SMYD2 (SET and MYND domain containing 2).	('SMYD2', 'Gene', (283, 288))	('ASH1L', 'Gene', '55870', (141, 146))	('NSD3', 'Gene', '54904', (212, 216))	('NSD1', 'Gene', '64324', (200, 204))	('nuclear receptor-binding SET domain-containing proteins 1-3', 'Gene', '54904;64324', (218, 277))	('NSD2', 'Gene', (206, 210))	('H3K36', 'Var', (65, 70))	('monomethylated histone H3', 'Chemical', '-', (83, 108))	('SMYD2', 'Gene', '56950', (283, 288))	('NSD2', 'Gene', '7468', (206, 210))	('H3', 'Chemical', '-', (123, 125))	('NSD3', 'Gene', (212, 216))	('H3', 'Chemical', '-', (106, 108))	('H3', 'Chemical', '-', (65, 67))	('NSD1', 'Gene', (200, 204))	('ASH1L', 'Gene', (141, 146))	('SET and MYND domain containing 2', 'Gene', '56950', (290, 322))	('H3K36me2', 'Var', (123, 131))	('H3', 'Chemical', '-', (110, 112))	('nuclear receptor-binding', 'molecular_function', 'GO:0016922', ('218', '242'))	('protein', 'cellular_component', 'GO:0003675', ('180', '187'))
86834	32231741	SETD2 is mutated or its function is lost in various solid tumors, leading to imbalance in methylation, demethylation and epimutation, which eventually causes tumorigenesis.	('demethylation', 'biological_process', 'GO:0070988', ('103', '116'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', (58, 63))	('methylation', 'MPA', (90, 101))	('causes', 'Reg', (151, 157))	('solid tumors', 'Disease', (52, 64))	('SETD2', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('imbalance', 'MPA', (77, 86))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('SETD2', 'Gene', '29072', (0, 5))	('imbalance', 'Phenotype', 'HP:0002172', (77, 86))	('methylation', 'biological_process', 'GO:0032259', ('90', '101'))	('demethylation', 'MPA', (103, 116))	('epimutation', 'Var', (121, 132))	('solid tumors', 'Disease', 'MESH:D009369', (52, 64))	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('leading to', 'Reg', (66, 76))
86835	32231741	Loss of SETD2 affects the progress of the transcriptional elongation, resulting in failure of DNA damage repair.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('failure', 'NegReg', (83, 90))	('SETD2', 'Gene', (8, 13))	('transcriptional elongation', 'CPA', (42, 68))	('affects', 'Reg', (14, 21))	('Loss', 'Var', (0, 4))	('SETD2', 'Gene', '29072', (8, 13))
86836	32231741	SETD2 deficiency has also been linked to p53, downstream signaling pathway and non-histone protein process.	('p53', 'Gene', '7157', (41, 44))	('linked', 'Reg', (31, 37))	('SETD2', 'Gene', '29072', (0, 5))	('downstream signaling pathway', 'Pathway', (46, 74))	('deficiency', 'Var', (6, 16))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('SETD2', 'Gene', (0, 5))	('signaling pathway', 'biological_process', 'GO:0007165', ('57', '74'))	('non-histone protein process', 'Pathway', (79, 106))	('p53', 'Gene', (41, 44))
86837	32231741	All of these data suggest that mutation of SETD2 gene or its functional deficiency exists in tumors, and it may function as a tumor suppressor (Table 1).	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('126', '142'))	('SETD2', 'Gene', '29072', (43, 48))	('mutation', 'Var', (31, 39))	('tumor', 'Disease', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('SETD2', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumor suppressor', 'biological_process', 'GO:0051726', ('126', '142'))	('function', 'Reg', (112, 120))	('tumors', 'Disease', (93, 99))	('tumor', 'Disease', (126, 131))
86841	32231741	Mutation of SETD2 gene and dysfunction of downstream signaling pathways affect biological functions in many different ways, eventually causing tumorigenesis.	('SETD2', 'Gene', '29072', (12, 17))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('affect', 'Reg', (72, 78))	('tumor', 'Disease', (143, 148))	('SETD2', 'Gene', (12, 17))	('biological functions', 'MPA', (79, 99))	('Mutation', 'Var', (0, 8))	('causing', 'Reg', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
86842	32231741	The methyltransferase Set2 in yeast, which has homology similarity to human SETD2, is responsible for histone methylation, and both of Set2 and H3K36me3 are involved in transcription.	('SETD2', 'Gene', (76, 81))	('involved', 'Reg', (157, 165))	('yeast', 'Species', '4932', (30, 35))	('H3K36me3', 'Var', (144, 152))	('H3', 'Chemical', '-', (144, 146))	('histone methylation', 'MPA', (102, 121))	('human', 'Species', '9606', (70, 75))	('transcription', 'biological_process', 'GO:0006351', ('169', '182'))	('responsible', 'Reg', (86, 97))	('methyltransferase', 'Enzyme', (4, 21))	('SETD2', 'Gene', '29072', (76, 81))	('transcription', 'MPA', (169, 182))	('histone methylation', 'biological_process', 'GO:0016571', ('102', '121'))
86843	32231741	H3K36me3 can prevent initiation of spurious transcription by recruiting histone deacetylase complexes, and depletion of Set2 results in increased level of this adverse transcription.	('recruiting', 'PosReg', (61, 71))	('H3K36me3', 'Var', (0, 8))	('level of', 'MPA', (146, 154))	('H3', 'Chemical', '-', (0, 2))	('transcription', 'biological_process', 'GO:0006351', ('168', '181'))	('transcription', 'biological_process', 'GO:0006351', ('44', '57'))	('increased', 'PosReg', (136, 145))	('histone', 'Protein', (72, 79))	('depletion', 'Var', (107, 116))	('Set2', 'Gene', (120, 124))
86848	32231741	SETD2 and H3K36me3 are mainly related to human homologous recombination (HR), and the latter is a critical repair as well as tolerance pathway, which facilitates DNA DSB repair.	('DNA', 'cellular_component', 'GO:0005574', ('162', '165'))	('SETD2', 'Gene', '29072', (0, 5))	('H3K36me3', 'Var', (10, 18))	('human', 'Species', '9606', (41, 46))	('homologous recombination', 'biological_process', 'GO:0035825', ('47', '71'))	('SETD2', 'Gene', (0, 5))	('H3', 'Chemical', '-', (10, 12))	('facilitates', 'PosReg', (150, 161))
86850	32231741	In renal cancer, SETD2 mutation leads to unrepairable DNA damage, by which the key suppressor p53-mediated checkpoint can't be activated.	('unrepairable DNA damage', 'MPA', (41, 64))	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('mutation', 'Var', (23, 31))	('renal cancer', 'Disease', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('renal cancer', 'Phenotype', 'HP:0009726', (3, 15))	('SETD2', 'Gene', '29072', (17, 22))	('renal cancer', 'Disease', 'MESH:D007680', (3, 15))	('leads to', 'Reg', (32, 40))	('SETD2', 'Gene', (17, 22))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))
86852	32231741	Further studies have found that SETD2 and H3K36me3 neither physically modulate MMR nor alter the expression level or function of MMR gene.	('MMR', 'biological_process', 'GO:0006298', ('129', '132'))	('SETD2', 'Gene', '29072', (32, 37))	('modulate', 'Reg', (70, 78))	('SETD2', 'Gene', (32, 37))	('expression level', 'MPA', (97, 113))	('H3K36me3', 'Var', (42, 50))	('H3', 'Chemical', '-', (42, 44))	('function', 'MPA', (117, 125))	('MMR', 'biological_process', 'GO:0006298', ('79', '82'))	('alter', 'Reg', (87, 92))	('MMR', 'Gene', (79, 82))	('MMR gene', 'Gene', (129, 137))
86857	32231741	Besides, SETD2 and H3K36me3 are implicated in alternative splicing (AS), and this event is related to histone modification.	('SETD2', 'Gene', (9, 14))	('H3K36me3', 'Var', (19, 27))	('splicing', 'biological_process', 'GO:0045292', ('58', '66'))	('histone modification', 'biological_process', 'GO:0016570', ('102', '122'))	('H3', 'Chemical', '-', (19, 21))	('alternative splicing', 'MPA', (46, 66))	('implicated', 'Reg', (32, 42))	('SETD2', 'Gene', '29072', (9, 14))
86859	32231741	Studies have identified that 3P chromosome loss occurs in almost all cases of clear cell renal cell cancer (ccRCC), causing mutation of multifarious tumor suppressor genes either independently or simultaneously.	('causing', 'Reg', (116, 123))	('clear cell renal cell cancer', 'Disease', (78, 106))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('renal cell cancer', 'Phenotype', 'HP:0005584', (89, 106))	('clear cell renal cell cancer', 'Disease', 'MESH:C538614', (78, 106))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('149', '165'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('149', '165'))	('tumor', 'Disease', (149, 154))	('mutation', 'Var', (124, 132))	('loss', 'NegReg', (43, 47))	('clear cell renal cell cancer', 'Phenotype', 'HP:0006770', (78, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('chromosome', 'cellular_component', 'GO:0005694', ('32', '42'))
86860	32231741	SETD2 mutation fluently occurs in renal cancer, and the absence of SETD2 protein is more evident than deficiency of the SETD2 gene itself.	('renal cancer', 'Disease', (34, 46))	('SETD2', 'Gene', '29072', (67, 72))	('SETD2', 'Gene', '29072', (120, 125))	('protein', 'Protein', (73, 80))	('renal cancer', 'Phenotype', 'HP:0009726', (34, 46))	('occurs', 'Reg', (24, 30))	('SETD2', 'Gene', (67, 72))	('SETD2', 'Gene', (120, 125))	('mutation', 'Var', (6, 14))	('SETD2', 'Gene', '29072', (0, 5))	('renal cancer', 'Disease', 'MESH:D007680', (34, 46))	('SETD2', 'Gene', (0, 5))	('absence', 'NegReg', (56, 63))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
86861	32231741	The mutation of SETD2 gene in ccRCC has a proportion of 34.07%, with such a mutation being related to producing an aggressive cancer phenotype.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('SETD2', 'Gene', '29072', (16, 21))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('related', 'Reg', (91, 98))	('aggressive cancer', 'Disease', 'MESH:D009369', (115, 132))	('SETD2', 'Gene', (16, 21))	('ccRCC', 'Disease', (30, 35))	('mutation', 'Var', (4, 12))	('aggressive cancer', 'Disease', (115, 132))	('mutation', 'Var', (76, 84))
86862	32231741	The expression levels of SETD2 and H3K36me3 is associated with the tumor size, clinical stage and risk of carcinoma-related death, suggesting the worse prognosis in ccRCC patients with or without metastasis.	('carcinoma', 'Disease', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (165, 170))	('patients', 'Species', '9606', (171, 179))	('ccRCC', 'Disease', (165, 170))	('carcinoma', 'Disease', 'MESH:D002277', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('H3K36me3', 'Var', (35, 43))	('H3', 'Chemical', '-', (35, 37))	('SETD2', 'Gene', '29072', (25, 30))	('death', 'Disease', 'MESH:D003643', (124, 129))	('tumor', 'Disease', (67, 72))	('death', 'Disease', (124, 129))	('associated', 'Reg', (47, 57))	('SETD2', 'Gene', (25, 30))
86863	32231741	Besides, a comprehendsive evaluation of SETD2 and H3K36me3 expressions may be a factor in predicting preoperative risk stratification and guiding future treatment in patients with early-stage ccRCC.	('H3', 'Chemical', '-', (50, 52))	('SETD2', 'Gene', '29072', (40, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (192, 197))	('SETD2', 'Gene', (40, 45))	('ccRCC', 'Disease', (192, 197))	('H3K36me3', 'Var', (50, 58))	('patients', 'Species', '9606', (166, 174))
86866	32231741	SETD2 deficiency is associated with metabolism of three major substances, including carbohydrate, glycosaminoglycan and creatine, and SETD2-inactive cells are likely to enhance the PGC1alpha expression at the protein (PGC1alpha has been known as a stimulator in tumor of digestive system) level and undergo a higher level of tricarboxylic acid cycle process with released energy.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('PGC1alpha', 'Gene', '10891', (181, 190))	('higher', 'PosReg', (309, 315))	('glycosaminoglycan', 'Chemical', 'MESH:D006025', (98, 115))	('protein', 'cellular_component', 'GO:0003675', ('209', '216'))	('tumor of digestive system', 'Phenotype', 'HP:0007378', (262, 287))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (325, 343))	('deficiency', 'Var', (6, 16))	('SETD2', 'Gene', (0, 5))	('PGC1alpha', 'Gene', (181, 190))	('tricarboxylic acid cycle', 'biological_process', 'GO:0006099', ('325', '349'))	('creatine', 'Chemical', 'MESH:D003401', (120, 128))	('PGC1alpha', 'Gene', '10891', (218, 227))	('expression', 'MPA', (191, 201))	('tumor', 'Disease', (262, 267))	('SETD2', 'Gene', (134, 139))	('SETD2', 'Gene', '29072', (0, 5))	('undergo', 'Reg', (299, 306))	('enhance', 'PosReg', (169, 176))	('carbohydrate', 'Chemical', 'MESH:D002241', (84, 96))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('SETD2', 'Gene', '29072', (134, 139))	('metabolism', 'biological_process', 'GO:0008152', ('36', '46'))	('PGC1alpha', 'Gene', (218, 227))	('level', 'MPA', (316, 321))
86867	32231741	The dysfunction of SETD2-PGC1alpha metabolic pathway may act as a stimulating factor in ccRCC and provide a potential based on metabolomics of targeted treatment.	('SETD2', 'Gene', (19, 24))	('ccRCC', 'Disease', (88, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('PGC1alpha', 'Gene', '10891', (25, 34))	('dysfunction', 'Var', (4, 15))	('stimulating', 'Reg', (66, 77))	('PGC1alpha', 'Gene', (25, 34))	('SETD2', 'Gene', '29072', (19, 24))
86872	32231741	SETD2 mutation does exist in human prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (35, 50))	('SETD2', 'Gene', '29072', (0, 5))	('mutation', 'Var', (6, 14))	('prostate cancer', 'Phenotype', 'HP:0012125', (35, 50))	('SETD2', 'Gene', (0, 5))	('human', 'Species', '9606', (29, 34))	('prostate cancer', 'Disease', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
86874	32231741	Studies have identified that mutation of SETD2 gene or its functional loss also occurs in advanced GC.	('mutation', 'Var', (29, 37))	('advanced GC', 'Disease', (90, 101))	('loss', 'NegReg', (70, 74))	('functional', 'MPA', (59, 69))	('SETD2', 'Gene', '29072', (41, 46))	('SETD2', 'Gene', (41, 46))
86879	32231741	A univariate analysis has discovered that SETD2 mutation or its functional loss in GC patients in Singapore, especially in high-risk gastrointestinal stromal tumor (GIST).	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (133, 163))	('GIST', 'Phenotype', 'HP:0100723', (165, 169))	('gastrointestinal stromal tumor', 'Disease', (133, 163))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (133, 163))	('SETD2', 'Gene', '29072', (42, 47))	('mutation', 'Var', (48, 56))	('loss', 'NegReg', (75, 79))	('SETD2', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('patients', 'Species', '9606', (86, 94))
86886	32231741	Recently, SETD2 has been clarified to play a suppressive role in CRC, and inactivation of SETD2 induces tumor malignant potential and increases susceptibility to tumorigenesis.	('SETD2', 'Gene', (90, 95))	('induces', 'PosReg', (96, 103))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('SETD2', 'Gene', '29072', (10, 15))	('SETD2', 'Gene', (10, 15))	('increases', 'PosReg', (134, 143))	('CRC', 'Disease', (65, 68))	('SETD2', 'Gene', '29072', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('inactivation', 'Var', (74, 86))
86888	32231741	SETD2 deficiency may promote the expression of dishevelled segment polarity protein 2 (DVL2), resulting in increased stabilization and transcriptional activity of beta-catenin, leading to promoted oncogenesis, proliferation and metastasis.	('DVL2', 'Gene', '1856', (87, 91))	('expression', 'MPA', (33, 43))	('DVL2', 'Gene', (87, 91))	('promoted', 'PosReg', (188, 196))	('increased', 'PosReg', (107, 116))	('metastasis', 'CPA', (228, 238))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('deficiency', 'Var', (6, 16))	('SETD2', 'Gene', (0, 5))	('stabilization', 'MPA', (117, 130))	('beta-catenin', 'Gene', (163, 175))	('SETD2', 'Gene', '29072', (0, 5))	('oncogenesis', 'biological_process', 'GO:0007048', ('197', '208'))	('promote', 'PosReg', (21, 28))	('dishevelled segment polarity protein 2', 'Gene', '1856', (47, 85))	('beta-catenin', 'Gene', '1499', (163, 175))	('dishevelled segment polarity protein 2', 'Gene', (47, 85))	('proliferation', 'CPA', (210, 223))	('transcriptional activity', 'MPA', (135, 159))	('oncogenesis', 'CPA', (197, 208))
86889	32231741	In addition, functional loss of SETD2 disturbs SETD2-H3K36me3 expression and eventually affects AS in CRC, and such dysfunction is also linked to intestinal tumorigenesis.	('tumor', 'Disease', (157, 162))	('loss', 'Var', (24, 28))	('SETD2', 'Gene', '29072', (32, 37))	('H3', 'Chemical', '-', (53, 55))	('SETD2', 'Gene', '29072', (47, 52))	('affects', 'Reg', (88, 95))	('SETD2', 'Gene', (32, 37))	('SETD2', 'Gene', (47, 52))	('disturbs', 'NegReg', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('CRC', 'Disease', (102, 105))	('such dysfunction', 'Disease', 'MESH:D006331', (111, 127))	('such dysfunction', 'Disease', (111, 127))	('linked', 'Reg', (136, 142))
86890	32231741	Recent studies have found that epigenetic mechanisms also play a role in pancreatic cancer.	('role', 'Reg', (65, 69))	('epigenetic mechanisms', 'Var', (31, 52))	('pancreatic cancer', 'Disease', (73, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))
86891	32231741	SETD2 gene alters or mutates in around 10% patients with pancreatic cancer, and such data are consistent with TCGA.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('patients', 'Species', '9606', (43, 51))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (57, 74))	('SETD2', 'Gene', '29072', (0, 5))	('mutates', 'Var', (21, 28))	('SETD2', 'Gene', (0, 5))	('alters', 'Var', (11, 17))	('pancreatic cancer', 'Disease', (57, 74))	('pancreatic cancer', 'Disease', 'MESH:D010190', (57, 74))
86897	32231741	Mutation of SETD2 gene or its functional loss in lung cancer has a higher frequency in metastatic sites compared with primary sites, which is linked to poor prognosis.	('SETD2', 'Gene', '29072', (12, 17))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('SETD2', 'Gene', (12, 17))	('Mutation', 'Var', (0, 8))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('metastatic sites', 'CPA', (87, 103))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('loss', 'NegReg', (41, 45))
86899	32231741	Previous reports have identified that SETD2 deficiency is involved in resistance of chemotherapy drugs in solid tumors, and SETD2 also plays a key role in the treatment of lung cancer.	('SETD2', 'Gene', (124, 129))	('deficiency', 'Var', (44, 54))	('solid tumors', 'Disease', (106, 118))	('lung cancer', 'Disease', (172, 183))	('involved', 'Reg', (58, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('SETD2', 'Gene', '29072', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('SETD2', 'Gene', (38, 43))	('solid tumors', 'Disease', 'MESH:D009369', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('SETD2', 'Gene', '29072', (124, 129))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))	('resistance of chemotherapy drugs', 'MPA', (70, 102))
86900	32231741	Cisplatin constitutes a mainstay drug in combination chemotherapy regiments with other drugs in treatment of advanced non-small cell lung cancer (NSCLC), SETD2 mutation facilitates acquired cisplatin resistance due to decreased apoptosis of cancer cells, and such apoptosis occurs with abnormal H3K36me3 expression and ERK signaling pathway, finally contributing to worse relapse-free survival.	('cancer', 'Disease', (138, 144))	('signaling pathway', 'biological_process', 'GO:0007165', ('323', '340'))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('SETD2', 'Gene', (154, 159))	('acquired cisplatin resistance', 'MPA', (181, 210))	('ERK', 'Gene', '5594', (319, 322))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('apoptosis', 'biological_process', 'GO:0097194', ('228', '237'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (122, 144))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (118, 144))	('apoptosis', 'biological_process', 'GO:0006915', ('228', '237'))	('apoptosis', 'CPA', (228, 237))	('SETD2', 'Gene', '29072', (154, 159))	('apoptosis', 'biological_process', 'GO:0097194', ('264', '273'))	('facilitates', 'PosReg', (169, 180))	('cisplatin', 'Chemical', 'MESH:D002945', (190, 199))	('apoptosis', 'biological_process', 'GO:0006915', ('264', '273'))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('ERK', 'Gene', (319, 322))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('mutation', 'Var', (160, 168))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (118, 144))	('H3', 'Chemical', '-', (295, 297))	('NSCLC', 'Disease', (146, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (146, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('H3K36me3', 'Protein', (295, 303))	('non-small cell lung cancer', 'Disease', (118, 144))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('cancer', 'Disease', (241, 247))	('decreased', 'NegReg', (218, 227))	('ERK', 'molecular_function', 'GO:0004707', ('319', '322'))
86902	32231741	Previous research has shown that mutations of SETD2 gene frequently occur in high-grade gliomas and only occur in the area named cerebral hemispheres, and such situation is more common in children and adolescents than elderly populations.	('SETD2', 'Gene', (46, 51))	('occur', 'Reg', (68, 73))	('gliomas', 'Disease', (88, 95))	('mutations', 'Var', (33, 42))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('children', 'Species', '9606', (188, 196))	('SETD2', 'Gene', '29072', (46, 51))
86904	32231741	Interestingly, SETD2 mutation also occurs in central nervous system tumors, including low-grade gliomas and non-glial tumors, and this gene mutation also occurs in people over 55 years of age.	('people', 'Species', '9606', (164, 170))	('SETD2', 'Gene', '29072', (15, 20))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('SETD2', 'Gene', (15, 20))	('central nervous system tumors', 'Phenotype', 'HP:0100006', (45, 74))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('gliomas', 'Disease', 'MESH:D005910', (96, 103))	('mutation', 'Var', (21, 29))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('nervous system tumors', 'Phenotype', 'HP:0004375', (53, 74))	('central nervous system tumors', 'Disease', 'MESH:D016543', (45, 74))	('non-glial tumors', 'Disease', 'MESH:D005910', (108, 124))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('occurs', 'Reg', (35, 41))	('central nervous system tumors', 'Disease', (45, 74))	('gliomas', 'Disease', (96, 103))	('gliomas', 'Phenotype', 'HP:0009733', (96, 103))	('non-glial tumors', 'Disease', (108, 124))
86905	32231741	According to the TCGA and METABRIC databases, SETD2 is mutated in all subtypes of breast cancer with a proportion of 2.62%, and its incidence in triple-negative breast cancer is 1.2%.	('breast cancer', 'Disease', (82, 95))	('SETD2', 'Gene', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('mutated', 'Var', (55, 62))	('breast cancer', 'Disease', (161, 174))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('SETD2', 'Gene', '29072', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
86908	32231741	Such correlation also exists in the triple-negative breast cancer, and the difference is more obvious, indicating that SETD2 mutation is linked to poor prognosis.	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('SETD2', 'Gene', '29072', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('SETD2', 'Gene', (119, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('mutation', 'Var', (125, 133))
86913	32231741	SETD2 mutation in osteosarcoma can inhibit the growth of tumor cells.	('osteosarcoma', 'Phenotype', 'HP:0002669', (18, 30))	('osteosarcoma', 'Disease', (18, 30))	('mutation', 'Var', (6, 14))	('SETD2', 'Gene', '29072', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('osteosarcoma', 'Disease', 'MESH:D012516', (18, 30))	('SETD2', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('inhibit', 'NegReg', (35, 42))
86915	32231741	Malignant peritoneal mesothelioma is a rare tumor with limited treatment, gene sequencing of 13 patients with malignant mesothelioma has shown SETD2 mutation in malignant peritoneal mesothelioma, and it may be linked to PI3K-mTOR signaling pathway, which is expected to become a new target for the treatment of this type of tumor (Table 2).	('Malignant peritoneal mesothelioma', 'Disease', (0, 33))	('linked', 'Reg', (210, 216))	('mTOR', 'Gene', (225, 229))	('tumor', 'Disease', (44, 49))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (110, 132))	('mTOR', 'Gene', '2475', (225, 229))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('PI3K', 'molecular_function', 'GO:0016303', ('220', '224'))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (171, 194))	('mesothelioma', 'Disease', (120, 132))	('mesothelioma', 'Disease', (182, 194))	('malignant mesothelioma', 'Disease', (110, 132))	('mesothelioma', 'Disease', 'MESH:D008654', (120, 132))	('mesothelioma', 'Disease', 'MESH:D008654', (182, 194))	('SETD2', 'Gene', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('patients', 'Species', '9606', (96, 104))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (110, 132))	('signaling pathway', 'biological_process', 'GO:0007165', ('230', '247'))	('mesothelioma', 'Disease', (21, 33))	('Malignant peritoneal mesothelioma', 'Disease', 'MESH:C562839', (0, 33))	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (10, 33))	('tumor', 'Disease', (324, 329))	('SETD2', 'Gene', '29072', (143, 148))	('mesothelioma', 'Disease', 'MESH:D008654', (21, 33))	('malignant', 'Disease', (161, 170))	('mutation', 'Var', (149, 157))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
86916	32231741	In the present review, we summarized all recent findings on SETD2 mutation or its functional loss in a variety of solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('loss', 'NegReg', (93, 97))	('SETD2', 'Gene', '29072', (60, 65))	('SETD2', 'Gene', (60, 65))	('solid tumors', 'Disease', (114, 126))	('mutation', 'Var', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('solid tumors', 'Disease', 'MESH:D009369', (114, 126))
86919	32231741	Mutation of SETD2 gene or its functional loss causes dysfunction of downstream signaling pathways, including wnt signaling pathway, PGC1alpha metabolic pathway and PI3K-mTOR signaling pathway, and such dysfunction is related to tumor occurrence.	('SETD2', 'Gene', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('SETD2', 'Gene', '29072', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('mTOR', 'Gene', (169, 173))	('wnt signaling pathway', 'biological_process', 'GO:0016055', ('109', '130'))	('PGC1alpha', 'Gene', '10891', (132, 141))	('wnt signaling pathway', 'Pathway', (109, 130))	('dysfunction', 'MPA', (53, 64))	('loss', 'NegReg', (41, 45))	('mTOR', 'Gene', '2475', (169, 173))	('PI3K', 'molecular_function', 'GO:0016303', ('164', '168'))	('downstream signaling pathways', 'Pathway', (68, 97))	('signaling pathway', 'biological_process', 'GO:0007165', ('174', '191'))	('such dysfunction', 'Disease', (197, 213))	('PGC1alpha', 'Gene', (132, 141))	('Mutation', 'Var', (0, 8))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('tumor', 'Disease', (228, 233))	('such dysfunction', 'Disease', 'MESH:D006331', (197, 213))
86932	32345771	Our results suggest that expression of PTX3 can affect the immunoflogosis in the ccRCC microenvironment, by activating the classical pathway of CS (C1q) and releasing pro-angiogenic factors (C3a, C5a).	('C3a', 'Gene', (191, 194))	('C3a', 'Gene', '718', (191, 194))	('immunoflogosis', 'MPA', (59, 73))	('C1q', 'cellular_component', 'GO:0062167', ('148', '151'))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('classical pathway', 'Pathway', (123, 140))	('releasing', 'PosReg', (157, 166))	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('C1q', 'Gene', (148, 151))	('CS', 'Chemical', 'MESH:D002586', (144, 146))	('activating', 'PosReg', (108, 118))	('expression', 'Var', (25, 35))	('C1q', 'Gene', '712', (148, 151))	('affect', 'Reg', (48, 54))	('PTX3', 'Gene', (39, 43))	('PTX3', 'Gene', '5806', (39, 43))	('C5a', 'Gene', (196, 199))	('C5a', 'Gene', '728', (196, 199))
86988	32345771	ccRCC patients with baseline serum PTX3 levels <165.0 pg/ml showed significantly higher 10-year rate of overall survival, as compared with ccRCC patients with serum PTX3 levels >165.0 pg/ml (73.7% vs. 48.4%, p=0.002; Figure 6).	('overall survival', 'CPA', (104, 120))	('<165.0 pg/ml', 'Var', (47, 59))	('RCC', 'Disease', (141, 144))	('patients', 'Species', '9606', (145, 153))	('PTX3', 'Gene', '5806', (35, 39))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('ccRCC', 'Phenotype', 'HP:0006770', (139, 144))	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('higher', 'PosReg', (81, 87))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('PTX3', 'Gene', (165, 169))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('PTX3', 'Gene', '5806', (165, 169))	('patients', 'Species', '9606', (6, 14))	('PTX3', 'Gene', (35, 39))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
86991	32345771	Both CSS and PFS were significantly decreased in patients with high levels of PTX3.	('PTX3', 'Gene', (78, 82))	('high levels', 'Var', (63, 74))	('PFS', 'CPA', (13, 16))	('PTX3', 'Gene', '5806', (78, 82))	('CS', 'Chemical', 'MESH:D002586', (5, 7))	('patients', 'Species', '9606', (49, 57))	('CSS', 'CPA', (5, 8))	('decreased', 'NegReg', (36, 45))
87022	32345771	Data from the cancer genome atlas (TCGA) clear cell renal cell carcinoma patient cohort (KIRC), confirmed our findings showing a reduced survival in patients with high expression levels of PTX3 (Supplementary Figure 1).	('clear cell renal cell carcinoma', 'Disease', (41, 72))	('cancer', 'Disease', (14, 20))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (52, 72))	('patients', 'Species', '9606', (149, 157))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (41, 72))	('PTX3', 'Gene', '5806', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('PTX3', 'Gene', (189, 193))	('patient', 'Species', '9606', (73, 80))	('patient', 'Species', '9606', (149, 156))	('survival', 'MPA', (137, 145))	('reduced', 'NegReg', (129, 136))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('high expression', 'Var', (163, 178))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (41, 72))
87024	32345771	Moreover, high PTX3 levels were associated with advanced clinical stage and poor overall survival of patients with pancreatic carcinoma.	('poor', 'NegReg', (76, 80))	('PTX3', 'Gene', (15, 19))	('patients', 'Species', '9606', (101, 109))	('PTX3', 'Gene', '5806', (15, 19))	('pancreatic carcinoma', 'Disease', (115, 135))	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (115, 135))	('high', 'Var', (10, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))
87027	32345771	Taken together, our results suggest that expression of PTX3 can modulate the immunoflogosis in the ccRCC microenvironment, by activating the classical pathway of complement system (C1q) and releasing pro-angiogenic factors (C3a, C5a).	('C1q', 'Gene', (181, 184))	('expression', 'Var', (41, 51))	('C3a', 'Gene', '718', (224, 227))	('C5a', 'Gene', (229, 232))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('RCC', 'Disease', (101, 104))	('C5a', 'Gene', '728', (229, 232))	('modulate', 'Reg', (64, 72))	('PTX3', 'Gene', (55, 59))	('releasing', 'PosReg', (190, 199))	('C1q', 'cellular_component', 'GO:0062167', ('181', '184'))	('C3a', 'Gene', (224, 227))	('C1q', 'Gene', '712', (181, 184))	('PTX3', 'Gene', '5806', (55, 59))	('activating', 'PosReg', (126, 136))
87058	32571992	DNA damage repair pathway alterations in metastatic clear cell renal cell carcinoma and implications on systemic therapy Loss-of-function alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may determine benefit from immune-oncology (I/O) agents as shown in colon cancer.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (52, 83))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('DNA', 'cellular_component', 'GO:0005574', ('153', '156'))	('tumor', 'Disease', (209, 214))	('alterations', 'Var', (138, 149))	('colon cancer', 'Phenotype', 'HP:0003003', (295, 307))	('alterations', 'Var', (26, 37))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('DNA', 'Gene', (153, 156))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (52, 83))	('DDR', 'Gene', (172, 175))	('colon cancer', 'Disease', 'MESH:D015179', (295, 307))	('oncology', 'Phenotype', 'HP:0002664', (261, 269))	('Loss-of-function', 'NegReg', (121, 137))	('determine', 'Reg', (231, 240))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('clear cell renal cell carcinoma', 'Disease', (52, 83))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (63, 83))	('human', 'Species', '9606', (203, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('colon cancer', 'Disease', (295, 307))
87062	32571992	Patients were dichotomized according to underlying DDR gene alteration into (1) deleterious DDR gene alterations present (Del DDR); (2) wild-type (WT) and variants of unknown significance (VUS) DDR gene alterations present (WT/VUS DDR).	('alterations', 'Var', (101, 112))	('Patients', 'Species', '9606', (0, 8))	('DDR gene', 'Gene', (92, 100))
87068	32571992	Del DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort.	('alterations', 'Var', (8, 19))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('Del DDR alterations', 'Var', (0, 19))	('patients', 'Species', '9606', (52, 60))
87075	32571992	Since multiple key DDR genes have functional overlap, defects in DDR genes can be a source of genomic instability and may sensitize responses to I/O agents possibly through the production of tumor-associated neoantigen and/or the activation of the stimulator of interferon genes (STING) pathway.	('responses to I/O agents', 'MPA', (132, 155))	('DDR', 'Gene', (19, 22))	('source', 'Reg', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('defects', 'Var', (54, 61))	('genomic', 'MPA', (94, 101))	('DDR genes', 'Gene', (65, 74))	('sensitize', 'Reg', (122, 131))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))
87077	32571992	More recently, the presence of deleterious DDR gene alterations in bladder cancer was shown to be associated with improved clinical outcomes in patients treated with I/O agents.	('alterations', 'Var', (52, 63))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('bladder cancer', 'Disease', (67, 81))	('improved', 'PosReg', (114, 122))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('patients', 'Species', '9606', (144, 152))	('DDR gene', 'Gene', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
87078	32571992	Based on these observations, we retrospectively examined a cohort of 229 patients with metastatic ccRCC at the Memorial Sloan Kettering Cancer Center (MSKCC) who underwent targeted exon sequencing of tumor tissue by next generation sequencing (NGS) to define the frequency of DDR gene alterations.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('alterations', 'Var', (285, 296))	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('Cancer', 'Phenotype', 'HP:0002664', (136, 142))	('Cancer', 'Disease', (136, 142))	('tumor', 'Disease', (200, 205))	('Cancer', 'Disease', 'MESH:D009369', (136, 142))	('DDR', 'Gene', (276, 279))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('patients', 'Species', '9606', (73, 81))	('RCC', 'Disease', (100, 103))
87079	32571992	We then described the clinical phenotype of patients harboring deleterious DDR gene alterations in their tumors and studied their significance for clinical outcomes with standard systemic therapies (I/O agents and VEGF-TKI).	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('patients', 'Species', '9606', (44, 52))	('VEGF', 'Gene', (214, 218))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('alterations', 'Var', (84, 95))	('DDR gene', 'Gene', (75, 83))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('VEGF', 'Gene', '7422', (214, 218))
87088	32571992	Patients were dichotomized into two categories (1) deleterious DDR: including patients harboring deleterious DDR alterations at the somatic and/or germline level; (2) wild type/VUS DDR: including patients with tumors determined to be DDR wild type and those whose tumors contained VUS DDR gene alterations.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumors', 'Disease', (210, 216))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('patients', 'Species', '9606', (78, 86))	('patients', 'Species', '9606', (196, 204))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('tumors', 'Disease', (264, 270))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('alterations', 'Var', (113, 124))
87089	32571992	The following alterations were considered deleterious: truncating mutations (including frameshift insertion/deletion, nonsense, or splice site alterations) and functionally validated missense mutations per the annotation of the functionality in Catalogue of Somatic Mutations in Cancer (COSMIC) database using the FATHMM-MKL (Functional Analysis Through Hidden Markov Models- Multiple Kernel Learning) software (http://fathmm.biocompute.org.uk).	('Cancer', 'Disease', 'MESH:D009369', (279, 285))	('Cancer', 'Disease', (279, 285))	('frameshift insertion/deletion', 'Var', (87, 116))	('FA', 'Phenotype', 'HP:0001994', (314, 316))	('Cancer', 'Phenotype', 'HP:0002664', (279, 285))
87091	32571992	This method integrates a mutation's variant allelic frequency, tumor purity and base-specific ploidy and re-normalizes it to calculate the CCF estimates (range: 0-1), with values closer to 1 representing a higher likelihood of clonality.	('tumor', 'Disease', (63, 68))	('variant', 'Var', (36, 43))	('mutation', 'Var', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
87106	32571992	Across the 229 patients, 48 deleterious DDR gene alterations were identified in 43 patients (19% of the entire cohort), including 35 (73%) somatic and 13 (27%) germline deleterious DDR gene alterations (online supplementary table S2).	('patients', 'Species', '9606', (15, 23))	('alterations', 'Var', (49, 60))	('DDR gene', 'Gene', (40, 48))	('patients', 'Species', '9606', (83, 91))	('DDR gene', 'Gene', (181, 189))
87107	32571992	Five patients (2%) had concurrent deleterious DDR gene alterations in two genes (three patients had both somatic and germline mutations, two patients had two somatic mutations).	('alterations', 'Var', (55, 66))	('patients', 'Species', '9606', (5, 13))	('DDR gene', 'Gene', (46, 54))	('patients', 'Species', '9606', (87, 95))	('patients', 'Species', '9606', (141, 149))
87109	32571992	Clinical characteristics of patients harboring deleterious DDR alterations versus those whose tumors were DDR wild type/VUS are summarized in table 1.	('alterations', 'Var', (63, 74))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('DDR', 'Gene', (59, 62))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('patients', 'Species', '9606', (28, 36))
87110	32571992	The analysis failed in tumors of eight somatic DDR alterations and was not performed for the germline alterations.	('alterations', 'Var', (51, 62))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
87120	32571992	Median PFS was comparable for patients harboring deleterious DDR alterations and those whose tumors were DDR wild type/VUS (4.0 months; 95% CI: 2.7-NE; and 5.3 months; 95% CI: 4.1-9.8; respectively; log-rank p=0.930) (figure 3A).	('alterations', 'Var', (65, 76))	('DDR', 'Gene', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('patients', 'Species', '9606', (30, 38))	('tumors', 'Disease', (93, 99))
87128	32571992	Co-mutation plots in online supplementary figure S4A, B illustrate the distribution of the deleterious DDR gene alterations by the relevant genes and pathways with the radiographic responses for each patient in both the I/O and the TKI analyses.	('alterations', 'Var', (112, 123))	('patient', 'Species', '9606', (200, 207))	('DDR gene', 'Gene', (103, 111))
87132	32571992	The activity of I/O in this setting was first highlighted in the pivotal phase II study of pembrolizumab, which was conducted primarily in colon cancer and demonstrated that patients with deficient mismatch repair (dMMR) tumors had higher response rates compared with MMR-proficient tumors (40% vs 0%).	('mismatch repair', 'biological_process', 'GO:0006298', ('198', '213'))	('deficient mismatch', 'Var', (188, 206))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumors', 'Phenotype', 'HP:0002664', (283, 289))	('colon cancer', 'Disease', 'MESH:D015179', (139, 151))	('response', 'MPA', (239, 247))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('MMR', 'biological_process', 'GO:0006298', ('268', '271'))	('tumors', 'Disease', (221, 227))	('tumors', 'Disease', (283, 289))	('colon cancer', 'Disease', (139, 151))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumors', 'Disease', 'MESH:D009369', (283, 289))	('higher', 'PosReg', (232, 238))	('patients', 'Species', '9606', (174, 182))	('pembrolizumab', 'Chemical', 'MESH:C582435', (91, 104))	('colon cancer', 'Phenotype', 'HP:0003003', (139, 151))
87135	32571992	In a previously reported study of 60 patients with metastatic urothelial cancers enrolled in prospective trials who were treated with a variety of I/O-based regimens, the presence of deleterious DDR gene alterations across the same set of candidate genes tested here was associated with superior OS.	('alterations', 'Var', (204, 215))	('associated with', 'Reg', (271, 286))	('patients', 'Species', '9606', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('superior OS', 'Disease', (287, 298))	('urothelial cancers', 'Disease', 'MESH:D014523', (62, 80))	('presence', 'Var', (171, 179))	('urothelial cancers', 'Disease', (62, 80))	('DDR gene', 'Gene', (195, 203))
87136	32571992	Similarly, Wang et al recently demonstrated that the presence of concomitant mutations in HRR-MMR or HRR-BER pathways was associated with clinical benefit to I/O agents across several cancer types.	('cancer', 'Disease', (184, 190))	('HRR-MMR', 'Gene', (90, 97))	('HRR', 'biological_process', 'GO:0000724', ('90', '93'))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('HRR-BER', 'Gene', (101, 108))	('BER', 'biological_process', 'GO:0006284', ('105', '108'))	('mutations', 'Var', (77, 86))	('MMR', 'biological_process', 'GO:0006298', ('94', '97'))	('HRR', 'biological_process', 'GO:0000724', ('101', '104'))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('benefit', 'PosReg', (147, 154))
87142	32571992	In our cohort of >200 patients, we confirm that loss-of-function events in key DDR genes are common in the setting of advanced disease and report deleterious DDR gene alterations in 19% of patients, the majority deemed clonal per CCF estimates.	('patients', 'Species', '9606', (22, 30))	('DDR genes', 'Gene', (79, 88))	('loss-of-function', 'NegReg', (48, 64))	('alterations', 'Var', (167, 178))	('patients', 'Species', '9606', (189, 197))	('DDR gene', 'Gene', (158, 166))
87145	32571992	While there were no differences for PFS or ORR, longer median OS with I/O therapy was observed in patients whose tumors harbored deleterious DDR gene alterations versus those who were DDR WT/VUS (log-rank p=0.049).	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('DDR gene', 'Gene', (141, 149))	('patients', 'Species', '9606', (98, 106))	('alterations', 'Var', (150, 161))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
87176	29291011	Oxidative DNA damage can induce gene mutations, chromosomal remodeling and epigenetic instability that may contribute to carcinogenesis.	('induce', 'Reg', (25, 31))	('chromosomal remodeling', 'CPA', (48, 70))	('Oxidative', 'Var', (0, 9))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('epigenetic instability', 'CPA', (75, 97))	('contribute', 'Reg', (107, 117))	('carcinogenesis', 'Disease', 'MESH:D063646', (121, 135))	('gene mutations', 'CPA', (32, 46))	('carcinogenesis', 'Disease', (121, 135))
87225	29291011	Although a trend towards association between smoking, an adverse prognostic risk factor, and ccRCC tumor TfR1 H-score did not reach significance (p = 0.053), smoking was significantly associated with a higher ccRCC tumor TfR1 maximum staining intensity (MSI) (mean 1.3 for smoking history vs. mean 1.0 for no smoking history; p = 0.022).	('TfR1', 'Gene', (105, 109))	('RCC tumor', 'Disease', 'MESH:C538614', (95, 104))	('maximum staining intensity', 'MPA', (226, 252))	('RCC tumor', 'Disease', (211, 220))	('MSI', 'Disease', 'None', (254, 257))	('smoking', 'Var', (158, 165))	('RCC tumor', 'Disease', (95, 104))	('MSI', 'Disease', (254, 257))	('TfR1', 'Gene', '7037', (221, 225))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('higher', 'PosReg', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('RCC tumor', 'Disease', 'MESH:C538614', (211, 220))	('TfR1', 'Gene', '7037', (105, 109))	('TfR1', 'Gene', (221, 225))
87263	29291011	Alterations in iron uptake may play a unique role in RCC, since this cancer is often defined by a dysregulated VHL/HIF-alpha pathway that governs intracellular iron levels.	('VHL', 'Gene', (111, 114))	('Alterations', 'Var', (0, 11))	('VHL', 'Gene', '7428', (111, 114))	('iron uptake', 'MPA', (15, 26))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('iron', 'Chemical', 'MESH:D007501', (160, 164))	('intracellular', 'cellular_component', 'GO:0005622', ('146', '159'))	('iron', 'Chemical', 'MESH:D007501', (15, 19))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('uptake', 'biological_process', 'GO:0098739', ('20', '26'))	('cancer', 'Disease', (69, 75))	('uptake', 'biological_process', 'GO:0098657', ('20', '26'))
87268	29291011	Interestingly, polymorphisms have been identified within miRNA binding sites of the human TfR1 gene, TFRC, that increase the risk of RCC.	('miRNA binding', 'molecular_function', 'GO:0035198', ('57', '70'))	('TFRC', 'Gene', '7037', (101, 105))	('TfR1', 'Gene', '7037', (90, 94))	('TFRC', 'Gene', (101, 105))	('increase', 'PosReg', (112, 120))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('human', 'Species', '9606', (84, 89))	('TfR1', 'Gene', (90, 94))	('polymorphisms', 'Var', (15, 28))
87290	29291011	The requirement of iron to catalyze DNA repair might be critical for tumor progression, since ccRCC tumors are known to harbor recurrent mutations in several chromatin remodeling/DNA repair genes, and the requirement of efficient DNA repair in the setting of such mutations is well described.	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('DNA', 'cellular_component', 'GO:0005574', ('179', '182'))	('RCC tumors', 'Disease', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('RCC tumors', 'Disease', 'MESH:C538614', (96, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('DNA repair', 'biological_process', 'GO:0006281', ('179', '189'))	('iron', 'Chemical', 'MESH:D007501', (19, 23))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('chromatin', 'cellular_component', 'GO:0000785', ('158', '167'))	('DNA repair', 'biological_process', 'GO:0006281', ('36', '46'))	('tumor', 'Disease', (69, 74))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('158', '178'))	('DNA repair', 'biological_process', 'GO:0006281', ('230', '240'))	('mutations', 'Var', (137, 146))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('DNA', 'cellular_component', 'GO:0005574', ('230', '233'))
87328	29291011	We suspect that iron uptake has a unique role in RCC, given the presence of common alterations in the VHL/HIF-alpha pathway that regulates iron levels; in addition to compelling observations from rodent experiments and epidemiologic studies.	('RCC', 'Disease', (49, 52))	('alterations', 'Var', (83, 94))	('uptake', 'biological_process', 'GO:0098739', ('21', '27'))	('regulates iron levels', 'MPA', (129, 150))	('VHL', 'Gene', (102, 105))	('uptake', 'biological_process', 'GO:0098657', ('21', '27'))	('iron', 'Chemical', 'MESH:D007501', (139, 143))	('VHL', 'Gene', '7428', (102, 105))	('iron', 'Chemical', 'MESH:D007501', (16, 20))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
87330	29291011	Furthermore, alterations in TfR1 expression in the primary tumor and benign kidney correlate with RCC disease progression and patient mortality.	('RCC disease', 'Disease', 'MESH:C538614', (98, 109))	('primary tumor', 'Disease', (51, 64))	('alterations', 'Var', (13, 24))	('patient', 'Species', '9606', (126, 133))	('TfR1', 'Gene', '7037', (28, 32))	('primary tumor', 'Disease', 'MESH:D009369', (51, 64))	('RCC disease', 'Disease', (98, 109))	('TfR1', 'Gene', (28, 32))	('expression', 'MPA', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
87352	29291011	786-0, 769-P, A704 and RCC4 cell lines were derived from ccRCC primary renal tumors and harbor known VHL mutations.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('VHL', 'Gene', (101, 104))	('RCC4', 'CellLine', 'CVCL:0498', (23, 27))	('renal tumors', 'Disease', 'MESH:D007674', (71, 83))	('VHL', 'Gene', '7428', (101, 104))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('renal tumors', 'Disease', (71, 83))	('RCC', 'Disease', (23, 26))	('mutations', 'Var', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('renal tumor', 'Phenotype', 'HP:0009726', (71, 82))	('renal tumors', 'Phenotype', 'HP:0009726', (71, 83))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))
87355	29291011	All cell lines were maintained in vitro in DMEM media supplemented with L-glutamine (4 mM), sodium pyruvate (110mg/L), glucose (4.5g/L) (Corning Cellgro, Manassas, VA, USA), penicillin-streptomycin (100U) (Corning Cellgro) and 10% fetal bovine serum (Seradigm, Radnor, PA, USA).	('Rad', 'Gene', (261, 264))	('bovine', 'Species', '9913', (237, 243))	('L-glutamine', 'Chemical', 'MESH:D005973', (72, 83))	('penicillin', 'Chemical', 'MESH:D010406', (174, 184))	('rad', 'Gene', '6236', (253, 256))	('rad', 'Gene', (253, 256))	('glucose', 'Chemical', 'MESH:D005947', (119, 126))	('DMEM', 'Chemical', '-', (43, 47))	('sodium pyruvate', 'Chemical', '-', (92, 107))	('streptomycin', 'Chemical', 'MESH:D013307', (185, 197))	('110mg/L', 'Var', (109, 116))	('Rad', 'Gene', '6236', (261, 264))
87379	29291011	Univariable association between low vs. high TfR1 scores and survival outcomes was evaluated using Cox regression models and standard Kaplan-Meier methods, with comparisons made using a log-rank test.	('TfR1', 'Gene', '7037', (45, 49))	('TfR1', 'Gene', (45, 49))	('low', 'Var', (32, 35))	('scores', 'Var', (50, 56))
87380	29291011	Multivariable analyses of high vs. low TfR1 scores and survival outcomes were conducted using Cox regression models, adjusting for age (overall survival only), tumor stage, grade, and size.	('TfR1', 'Gene', (39, 43))	('scores', 'Var', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('rad', 'Gene', '6236', (174, 177))	('rad', 'Gene', (174, 177))	('tumor', 'Disease', (160, 165))	('TfR1', 'Gene', '7037', (39, 43))
87400	31297034	Furthermore, most sporadic RCCs in humans carry inactivating mutations in the VHL tumor suppressor gene, which leads to constitutive stabilization of the hypoxia inducible transcription factors HIF-1alpha and HIF-2alpha.	('HIF-2alpha', 'Gene', '2034', (209, 219))	('transcription', 'biological_process', 'GO:0006351', ('172', '185'))	('hypoxia', 'Disease', 'MESH:D000860', (154, 161))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('VHL tumor', 'Disease', (78, 87))	('HIF-1alpha', 'Gene', (194, 204))	('leads to', 'Reg', (111, 119))	('VHL tumor', 'Disease', 'MESH:D006623', (78, 87))	('HIF-2alpha', 'Gene', (209, 219))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('inactivating mutations', 'Var', (48, 70))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('82', '98'))	('humans', 'Species', '9606', (35, 41))	('hypoxia', 'Disease', (154, 161))	('tumor suppressor', 'biological_process', 'GO:0051726', ('82', '98'))	('HIF-1alpha', 'Gene', '3091', (194, 204))	('constitutive', 'MPA', (120, 132))
87454	31297034	High expression of MCT1 or MCT4 is well correlated with worse prognosis in patients with ccRCC.	('MCT4', 'Gene', '9123', (27, 31))	('High', 'Var', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('patients', 'Species', '9606', (75, 83))	('RCC', 'Disease', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (89, 94))	('correlated', 'Reg', (40, 50))	('MCT', 'biological_process', 'GO:0120197', ('27', '30'))	('MCT4', 'Gene', (27, 31))	('MCT', 'biological_process', 'GO:0120197', ('19', '22'))	('MCT1', 'Gene', (19, 23))	('MCT1', 'Gene', '6566', (19, 23))
87500	31297034	The complementation of 7ACC1 in the culture medium significantly slowed cell proliferation, migration, and invasion of 786-O cells in co-culturing conditions.	('ACC1', 'Gene', '597', (24, 28))	('cell proliferation', 'biological_process', 'GO:0008283', ('72', '90'))	('complementation', 'Var', (4, 19))	('ACC1', 'Gene', (24, 28))	('cell proliferation', 'CPA', (72, 90))	('migration', 'CPA', (92, 101))	('slowed', 'NegReg', (65, 71))	('invasion', 'CPA', (107, 115))
87533	32095654	Bioinformatics; Cancer research; Systems biology; PKM, Alternative splicing, Transcriptomics, Biomarker, Drug repositioning.	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('Cancer', 'Disease', (16, 22))	('Cancer', 'Disease', 'MESH:D009369', (16, 22))	('splicing', 'biological_process', 'GO:0045292', ('67', '75'))	('PKM', 'Gene', (50, 53))	('PKM', 'Gene', '5315', (50, 53))	('Alternative splicing', 'Var', (55, 75))
87540	32095654	Many studies have reported that different alternative splicing isoforms of PKM promote tumorigenesis, cell proliferation, metastasis and poor prognoses of patients in different cancers.	('poor prognoses', 'CPA', (137, 151))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('tumor', 'Disease', (87, 92))	('patients', 'Species', '9606', (155, 163))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('cell proliferation', 'biological_process', 'GO:0008283', ('102', '120'))	('promote', 'PosReg', (79, 86))	('splicing', 'biological_process', 'GO:0045292', ('54', '62'))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('PKM', 'Gene', (75, 78))	('metastasis', 'CPA', (122, 132))	('PKM', 'Gene', '5315', (75, 78))	('alternative splicing', 'Var', (42, 62))	('cell proliferation', 'CPA', (102, 120))
87543	32095654	We have observed that the expression level of four protein-coding transcripts of PKM, including ENST00000335181, which is encoding PKM2 and the most studied isoform of PKM, as well as ENST00000561609, ENST00000389093 and ENST00000568883 are highly associated with patients' prognoses.	('PKM', 'Gene', (168, 171))	('PKM', 'Gene', '5315', (168, 171))	('ENST00000335181', 'Gene', (96, 111))	('expression level', 'MPA', (26, 42))	('associated', 'Reg', (248, 258))	('ENST00000561609', 'Var', (184, 199))	('ENST00000568883', 'Var', (221, 236))	('PKM', 'Gene', (131, 134))	('patients', 'Species', '9606', (264, 272))	('PKM', 'Gene', '5315', (131, 134))	('PKM2', 'Gene', (131, 135))	('PKM', 'Gene', (81, 84))	('PKM', 'Gene', '5315', (81, 84))	('PKM2', 'Gene', '5315', (131, 135))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))	('ENST00000389093', 'Var', (201, 216))
87611	32095654	Inhibition of PIK3CB remarkably suppressed cell growth, migration and enhanced apoptosis in glioblastoma.	('glioblastoma', 'Disease', (92, 104))	('glioblastoma', 'Disease', 'MESH:D005909', (92, 104))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('glioblastoma', 'Phenotype', 'HP:0012174', (92, 104))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('cell growth', 'CPA', (43, 54))	('apoptosis', 'CPA', (79, 88))	('enhanced', 'PosReg', (70, 78))	('Inhibition', 'Var', (0, 10))	('PIK3CB', 'Gene', (14, 20))	('PIK3CB', 'Gene', '5291', (14, 20))	('cell growth', 'biological_process', 'GO:0016049', ('43', '54'))	('suppressed', 'NegReg', (32, 42))
87668	28561705	These metabolic changes can result from genetic aberrations in metabolic enzymes themselves, but can also be a downstream consequence of activating mutations in numerous growth factors and oncogenes, loss of tumor suppressor signaling, or epigenetic alterations, all of which we will discuss in more detail in later sections of this manuscript.	('mutations', 'Var', (148, 157))	('tumor suppressor', 'biological_process', 'GO:0051726', ('208', '224'))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('signaling', 'biological_process', 'GO:0023052', ('225', '234'))	('genetic aberrations', 'Disease', (40, 59))	('loss', 'NegReg', (200, 204))	('result', 'Reg', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('208', '224'))	('epigenetic alterations', 'Var', (239, 261))	('tumor', 'Disease', (208, 213))	('genetic aberrations', 'Disease', 'MESH:D030342', (40, 59))	('metabolic', 'MPA', (6, 15))
87672	28561705	Interestingly, although the overall mutational burden is relatively low in RCC in comparison to many other tumor types, the vast majority of mutations identified in these tumors are in some way involved in the cell's ability to sense or respond to nutrients, oxygen, iron, or energy, suggesting that metabolic pathway alterations are key drivers of proliferation in all subsets of RCC.	('involved', 'Reg', (194, 202))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('mutations', 'Var', (141, 150))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('oxygen', 'Chemical', 'MESH:D010100', (259, 265))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (171, 176))	('RCC', 'Disease', 'MESH:C538614', (381, 384))	('RCC', 'Disease', (381, 384))	('tumors', 'Disease', (171, 177))	('iron', 'Chemical', 'MESH:D007501', (267, 271))
87673	28561705	Mutations resulting in dysregulation of specific steps of glycolysis, the TCA cycle, and the ETC pathways have all been found in subtypes of RCC, illustrating the diversity of metabolic alterations that may contribute to tumorigenesis (Fig.	('RCC', 'Disease', (141, 144))	('ETC pathways', 'Pathway', (93, 105))	('dysregulation', 'Var', (23, 36))	('TCA', 'Chemical', 'MESH:D014238', (74, 77))	('contribute', 'Reg', (207, 217))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('found', 'Reg', (120, 125))	('glycolysis', 'biological_process', 'GO:0006096', ('58', '68'))	('Mutations', 'Var', (0, 9))	('glycolysis', 'MPA', (58, 68))	('TCA cycle', 'biological_process', 'GO:0006099', ('74', '83'))	('TCA cycle', 'MPA', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
87674	28561705	Here, we discuss three examples of mutations that alter different metabolic pathways in RCC.	('alter', 'Reg', (50, 55))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('metabolic pathways', 'Pathway', (66, 84))	('mutations', 'Var', (35, 44))
87675	28561705	Mutations in the von-Hippel-Lindau gene (VHL) are associated with a hereditary form of RCC found in patients with germline VHL Disease, but are also observed in nearly 90% of patients with sporadic clear cell kidney cancer (ccRCC).	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('VHL Disease', 'Disease', 'MESH:D006623', (123, 134))	('patients', 'Species', '9606', (100, 108))	('RCC', 'Disease', (226, 229))	('von-Hippel-Lindau', 'Disease', 'MESH:D006623', (17, 34))	('kidney cancer', 'Phenotype', 'HP:0009726', (209, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('sporadic clear cell kidney cancer', 'Disease', 'MESH:D008649', (189, 222))	('VHL', 'Gene', (123, 126))	('Mutations', 'Var', (0, 9))	('RCC', 'Disease', 'MESH:C538614', (226, 229))	('von-Hippel-Lindau', 'Disease', (17, 34))	('VHL Disease', 'Disease', (123, 134))	('VHL', 'Gene', '7428', (123, 126))	('VHL', 'Gene', (41, 44))	('RCC', 'Disease', (87, 90))	('patients', 'Species', '9606', (175, 183))	('sporadic clear cell kidney cancer', 'Disease', (189, 222))	('associated', 'Reg', (50, 60))	('VHL', 'Gene', '7428', (41, 44))
87677	28561705	In the majority of cases of ccRCC, inactivating mutations in VHL inhibit its ability to interact with the HIF proteins, and consequently the HIF proteins are stabilized, even during normoxic conditions.	('HIF proteins', 'Disease', 'MESH:D011488', (141, 153))	('inactivating mutations', 'Var', (35, 57))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('HIF proteins', 'Disease', (141, 153))	('RCC', 'Disease', (30, 33))	('VHL', 'Gene', (61, 64))	('interact', 'Interaction', (88, 96))	('VHL', 'Gene', '7428', (61, 64))	('inhibit', 'NegReg', (65, 72))	('HIF proteins', 'Disease', 'MESH:D011488', (106, 118))	('HIF proteins', 'Disease', (106, 118))	('ability', 'MPA', (77, 84))
87679	28561705	The aberrant activation of these proteins and growth factors is believed to contribute to tumor growth and proliferation downstream of inactivating mutations in VHL.	('proliferation', 'CPA', (107, 120))	('aberrant', 'Var', (4, 12))	('tumor growth', 'Disease', (90, 102))	('inactivating mutations', 'Var', (135, 157))	('tumor growth', 'Disease', 'MESH:D006130', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('activation', 'PosReg', (13, 23))	('VHL', 'Gene', (161, 164))	('VHL', 'Gene', '7428', (161, 164))	('contribute', 'Reg', (76, 86))
87692	28561705	Mutations in several TCA cycle enzymes have been observed in papillary renal cell carcinoma (pRCC).	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (61, 91))	('pRCC', 'Gene', '5546', (93, 97))	('papillary renal cell carcinoma', 'Disease', (61, 91))	('pRCC', 'Phenotype', 'HP:0006766', (93, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (71, 91))	('TCA', 'Chemical', 'MESH:D014238', (21, 24))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (61, 91))	('Mutations', 'Var', (0, 9))	('TCA cycle', 'biological_process', 'GO:0006099', ('21', '30'))	('pRCC', 'Gene', (93, 97))	('observed', 'Reg', (49, 57))	('TCA cycle', 'Gene', (21, 30))
87695	28561705	Likewise, germline mutations in fumarate hydratase (FH), the enzyme that catalyzes the conversion of fumarate to malate in the TCA cycle, have been found in patients with Herditary Leiomyomatosis Renal Cell Carcinoma (HLRCC) and very rarely, in sporadic cases of pRCC Since both SDH and FH mutations block normal TCA Cycle and ETC activity, cells from these tumors take up almost no oxygen, and rely primarily on glycolysis to supply energy and macromolecules needed for replication and growth.	('Carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('glycolysis', 'MPA', (413, 423))	('block', 'NegReg', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (358, 363))	('patients', 'Species', '9606', (157, 165))	('tumors', 'Disease', (358, 364))	('pRCC', 'Gene', '5546', (263, 267))	('ETC activity', 'MPA', (327, 339))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('fumarate hydratase', 'Gene', '2271', (32, 50))	('TCA Cycle', 'biological_process', 'GO:0006099', ('313', '322'))	('TCA Cycle', 'MPA', (313, 322))	('FH', 'Gene', '2271', (52, 54))	('SDH', 'Gene', (279, 282))	('tumors', 'Disease', 'MESH:D009369', (358, 364))	('pRCC', 'Phenotype', 'HP:0006766', (263, 267))	('TCA', 'Chemical', 'MESH:D014238', (313, 316))	('fumarate', 'Chemical', 'MESH:D005650', (101, 109))	('RCC', 'Disease', (264, 267))	('TCA cycle', 'biological_process', 'GO:0006099', ('127', '136'))	('pRCC', 'Gene', (263, 267))	('malate', 'Chemical', 'MESH:C030298', (113, 119))	('FH', 'Gene', '2271', (287, 289))	('oxygen', 'Chemical', 'MESH:D010100', (383, 389))	('Herditary Leiomyomatosis Renal Cell Carcinoma', 'Disease', 'MESH:C535516', (171, 216))	('RCC', 'Disease', 'MESH:C538614', (264, 267))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (196, 216))	('fumarate hydratase', 'Gene', (32, 50))	('TCA', 'Chemical', 'MESH:D014238', (127, 130))	('mutations', 'Var', (19, 28))	('Herditary Leiomyomatosis Renal Cell Carcinoma', 'Disease', (171, 216))	('tumors', 'Phenotype', 'HP:0002664', (358, 364))	('mutations', 'Var', (290, 299))	('glycolysis', 'biological_process', 'GO:0006096', ('413', '423'))	('fumarate', 'Chemical', 'MESH:D005650', (32, 40))	('RCC', 'Disease', (220, 223))	('SDH', 'Gene', '6390', (279, 282))
87703	28561705	FH mutations similarly result in the accumulation of both succinate and fumarate due to the malfunction of the FH enzyme in the TCA cycle.	('FH', 'Gene', '2271', (0, 2))	('malfunction', 'MPA', (92, 103))	('FH', 'Gene', '2271', (111, 113))	('fumarate', 'Chemical', 'MESH:D005650', (72, 80))	('succinate', 'MPA', (58, 67))	('TCA', 'Chemical', 'MESH:D014238', (128, 131))	('accumulation', 'PosReg', (37, 49))	('TCA cycle', 'biological_process', 'GO:0006099', ('128', '137'))	('mutations', 'Var', (3, 12))	('fumarate', 'MPA', (72, 80))	('succinate', 'Chemical', 'MESH:D019802', (58, 67))
87705	28561705	Similarly to SDH-mutant tumors, pRCC tumors with FH mutations have upregulated expression of the HIF target genes involved in proliferation, glycolysis, and angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('upregulated', 'PosReg', (67, 78))	('glycolysis', 'biological_process', 'GO:0006096', ('141', '151'))	('pRCC tumors', 'Disease', 'MESH:D009369', (32, 43))	('expression', 'MPA', (79, 89))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('pRCC', 'Phenotype', 'HP:0006766', (32, 36))	('angiogenesis', 'biological_process', 'GO:0001525', ('157', '169'))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('SDH', 'Gene', '6390', (13, 16))	('tumors', 'Disease', (37, 43))	('pRCC tumors', 'Disease', (32, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('mutations', 'Var', (52, 61))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('SDH', 'Gene', (13, 16))	('FH', 'Gene', '2271', (49, 51))
87708	28561705	The malfunctions of mitochondrial respiration and upregulation of glycolysis in these cells appear to be key factors in their proliferation, and thus investigation of these pathways may be important for improving outcome for patients with FH mutations.	('patients', 'Species', '9606', (225, 233))	('mitochondrial respiration', 'MPA', (20, 45))	('upregulation', 'PosReg', (50, 62))	('respiration', 'biological_process', 'GO:0045333', ('34', '45'))	('FH', 'Gene', '2271', (239, 241))	('malfunctions', 'Var', (4, 16))	('glycolysis', 'MPA', (66, 76))	('upregulation of glycolysis', 'biological_process', 'GO:0045821', ('50', '76'))	('respiration', 'biological_process', 'GO:0007585', ('34', '45'))
87714	28561705	Mitochondrial DNA sequencing has revealed that many chRCC tumors have mutations in genes involved in the ETC complex I, particularly in MT-ND5, and that these mitochondrial gene mutations also correlate with samples exhibiting an eosinophilic histological phenotype.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mutations', 'Var', (70, 79))	('MT-ND5', 'Gene', (136, 142))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('complex I', 'cellular_component', 'GO:0030964', ('109', '118'))	('RCC', 'Disease', (54, 57))	('Mitochondrial DNA', 'cellular_component', 'GO:0000262', ('0', '17'))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('MT-ND5', 'Gene', '4540', (136, 142))	('mutations', 'Var', (178, 187))
87719	28561705	A number of different kinds of genetic mutations have been associated with the dysregulation of metabolic pathways in various tumor types.	('genetic mutations', 'Var', (31, 48))	('metabolic pathways', 'Pathway', (96, 114))	('associated', 'Reg', (59, 69))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('dysregulation', 'MPA', (79, 92))	('tumor', 'Disease', (126, 131))
87724	28561705	While mutations in the MTOR gene itself can occur, it is more commonly activated downstream of gain-of-function mutations in the PI3K-AKT pathway or growth factors, or through inactivation of tumor suppressors such as PTEN.	('gain-of-function', 'PosReg', (95, 111))	('AKT', 'Gene', (134, 137))	('tumor', 'Disease', (192, 197))	('activated', 'PosReg', (71, 80))	('MTOR', 'Gene', (23, 27))	('PTEN', 'Gene', (218, 222))	('mutations', 'Var', (112, 121))	('PI3K', 'molecular_function', 'GO:0016303', ('129', '133'))	('PTEN', 'Gene', '5728', (218, 222))	('MTOR', 'Gene', '2475', (23, 27))	('inactivation', 'Var', (176, 188))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('AKT', 'Gene', '207', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
87733	28561705	However, resistance to these inhibitors appears to develop over time, possibly due to the accumulation of additional mutations in the mTOR pathway or through negative feedback of the pathway itself, as inhibiting mTOR signaling can also upregulate AKT signaling through insulin-like growth factor receptor 1 (IGF-1R).	('IGF-1R', 'Gene', (309, 315))	('mTOR', 'Gene', (213, 217))	('mutations', 'Var', (117, 126))	('AKT signaling', 'biological_process', 'GO:0043491', ('248', '261'))	('AKT', 'Gene', (248, 251))	('inhibiting', 'Var', (202, 212))	('signaling', 'biological_process', 'GO:0023052', ('218', '227'))	('upregulate', 'PosReg', (237, 247))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('270', '296'))	('mTOR', 'Gene', (134, 138))	('mTOR', 'Gene', '2475', (213, 217))	('mTOR', 'Gene', '2475', (134, 138))	('AKT', 'Gene', '207', (248, 251))	('IGF-1R', 'Gene', '3480', (309, 315))
87754	28561705	Therefore, mutations in IDH1 and 2 are believed to both alter cellular metabolism and potentially increase rates of DNA damage due to altered NADPH protection.	('mutations', 'Var', (11, 20))	('rates', 'MPA', (107, 112))	('IDH1 and 2', 'Gene', '3417;3418', (24, 34))	('cellular metabolism', 'MPA', (62, 81))	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('NADPH', 'Chemical', 'MESH:D009249', (142, 147))	('increase', 'PosReg', (98, 106))	('altered', 'Reg', (134, 141))	('alter', 'Reg', (56, 61))	('cellular metabolism', 'biological_process', 'GO:0044237', ('62', '81'))
87755	28561705	Mutations in IDH1 and 2 have been observed in several types of tumors, including leukemias, lymphomas, and gliomas.	('leukemias', 'Disease', 'MESH:D007938', (81, 90))	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('IDH1 and 2', 'Gene', '3417;3418', (13, 23))	('gliomas', 'Disease', (107, 114))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('lymphoma', 'Phenotype', 'HP:0002665', (92, 100))	('lymphomas', 'Disease', (92, 101))	('lymphomas', 'Disease', 'MESH:D008223', (92, 101))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('leukemias', 'Phenotype', 'HP:0001909', (81, 90))	('leukemias', 'Disease', (81, 90))	('observed', 'Reg', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('lymphomas', 'Phenotype', 'HP:0002665', (92, 101))
87756	28561705	The mutations identified in IDH1 and 2 in cancers appear to be gain-of-function point mutations that occur at specific arginine residues that presumably alter the structure of these proteins.	('cancers', 'Disease', (42, 49))	('proteins', 'Protein', (182, 190))	('arginine', 'Chemical', 'MESH:D001120', (119, 127))	('alter', 'Reg', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('IDH1 and 2', 'Gene', '3417;3418', (28, 38))	('gain-of-function', 'PosReg', (63, 79))	('structure', 'MPA', (163, 172))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('mutations', 'Var', (4, 13))	('cancers', 'Disease', 'MESH:D009369', (42, 49))
87758	28561705	High levels of D-2HG have been associated with increases in histone and DNA methylation, contributing to tumor progression.	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('DNA methylation', 'biological_process', 'GO:0006306', ('72', '87'))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('DNA methylation', 'MPA', (72, 87))	('increases', 'PosReg', (47, 56))	('histone', 'MPA', (60, 67))	('tumor', 'Disease', (105, 110))	('D-2HG', 'Var', (15, 20))
87759	28561705	It has also been shown that mutant IDH1 heterodimerizes with wild-type IDH1, inhibiting the activity of the wild-type enzyme and reducing levels of alpha-KG, which may play a role in the degradation of HIF proteins.	('HIF proteins', 'Disease', (202, 214))	('inhibiting', 'NegReg', (77, 87))	('mutant', 'Var', (28, 34))	('IDH1', 'Gene', (35, 39))	('alpha-KG', 'Chemical', 'MESH:D007656', (148, 156))	('HIF proteins', 'Disease', 'MESH:D011488', (202, 214))	('degradation', 'MPA', (187, 198))	('levels of alpha-KG', 'MPA', (138, 156))	('degradation', 'biological_process', 'GO:0009056', ('187', '198'))	('activity', 'MPA', (92, 100))	('reducing', 'NegReg', (129, 137))
87760	28561705	Thus, mutant IDH1 may also play a role in the stabilization of HIFs and increased activation of their transcription factors involved in tumorigenesis and angiogenesis.	('transcription', 'biological_process', 'GO:0006351', ('102', '115'))	('transcription', 'MPA', (102, 115))	('mutant', 'Var', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('IDH1', 'Gene', (13, 17))	('activation', 'PosReg', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('angiogenesis', 'biological_process', 'GO:0001525', ('154', '166'))
87761	28561705	Several targeted chemical inhibitors of the activity of specific IDH1 and IDH2 point mutants have been designed and have been shown to reduce D-2HG and growth in cells and mouse models .	('point mutants', 'Var', (79, 92))	('IDH2', 'Gene', (74, 78))	('mouse', 'Species', '10090', (172, 177))	('growth', 'CPA', (152, 158))	('D-2HG', 'MPA', (142, 147))	('IDH1', 'Gene', (65, 69))	('reduce', 'NegReg', (135, 141))
87771	28561705	Currently, several chemical inhibitors, as well as genetic ablation of FASN by RNAi, are being tested for effectiveness in reducing tumor cell growth and proliferation.	('reducing', 'NegReg', (123, 131))	('FASN', 'Gene', (71, 75))	('FASN', 'Gene', '2194', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cell growth', 'biological_process', 'GO:0016049', ('138', '149'))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('genetic ablation', 'Var', (51, 67))	('RNAi', 'biological_process', 'GO:0016246', ('79', '83'))	('tumor', 'Disease', (132, 137))
87776	28561705	Thus, epigenetic changes downstream of metabolic alterations can influence the expression levels of many genes in cancer cells, possibly giving them a survival and growth advantage.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('expression levels', 'MPA', (79, 96))	('giving', 'Reg', (137, 143))	('survival', 'CPA', (151, 159))	('epigenetic changes', 'Var', (6, 24))	('influence', 'Reg', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('growth advantage', 'CPA', (164, 180))	('cancer', 'Disease', (114, 120))
87779	28561705	Dysregulation of carbon metabolism pathways in cancer can alter the levels of SAM and methyl donors available, thus influencing the epigenetic modifications and expression of genes in these cells .	('carbon', 'Chemical', 'MESH:D002244', (17, 23))	('SAM', 'Chemical', 'MESH:D012436', (78, 81))	('influencing', 'Reg', (116, 127))	('expression of genes', 'MPA', (161, 180))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (47, 53))	('carbon', 'Enzyme', (17, 23))	('metabolism', 'biological_process', 'GO:0008152', ('24', '34'))	('alter', 'Reg', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('epigenetic modifications', 'MPA', (132, 156))	('donor', 'Species', '9606', (93, 98))
87780	28561705	Another mechanism by which metabolic pathways can effect epigenetics is through the TCA cycle metabolites.	('effect', 'Reg', (50, 56))	('TCA', 'Chemical', 'MESH:D014238', (84, 87))	('TCA cycle', 'biological_process', 'GO:0006099', ('84', '93'))	('epigenetics', 'Var', (57, 68))
87782	28561705	Likewise, D-2HG, the protein made from alpha-KG by cancer cells with IDH1/2 mutations (discussed above), inhibits the activity of alpha-KG-dependent demethylases.	('alpha-KG-dependent demethylases', 'Enzyme', (130, 161))	('mutations', 'Var', (76, 85))	('activity', 'MPA', (118, 126))	('alpha-KG', 'Chemical', 'MESH:D007656', (39, 47))	('IDH1/2', 'Gene', '3417;3418', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('alpha-KG', 'Chemical', 'MESH:D007656', (130, 138))	('inhibits', 'NegReg', (105, 113))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('IDH1/2', 'Gene', (69, 75))
87783	28561705	SDH and FH mutations which result in accumulation of succinate and fumarate in cancer cells can also act as competitive antagonists for inhibiting these alpha-KG-dependent demethylases.	('inhibiting', 'NegReg', (136, 146))	('mutations', 'Var', (11, 20))	('fumarate', 'Chemical', 'MESH:D005650', (67, 75))	('fumarate', 'MPA', (67, 75))	('succinate', 'MPA', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('alpha-KG', 'Chemical', 'MESH:D007656', (153, 161))	('SDH', 'Gene', (0, 3))	('FH', 'Gene', '2271', (8, 10))	('succinate', 'Chemical', 'MESH:D019802', (53, 62))	('alpha-KG-dependent demethylases', 'Enzyme', (153, 184))	('accumulation', 'PosReg', (37, 49))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('SDH', 'Gene', '6390', (0, 3))
87791	28561705	The mechanisms behind the metabolic reprogramming that takes place in most tumor cells are diverse, and include oncogenic activation, the repression of tumor suppressor signaling, epigenetic modifications, and mutations in metabolic enzymes themselves.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('mutations', 'Var', (210, 219))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor suppressor', 'biological_process', 'GO:0051726', ('152', '168'))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('152', '168'))	('signaling', 'biological_process', 'GO:0023052', ('169', '178'))	('epigenetic modifications', 'Var', (180, 204))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
87796	31782868	We first used qRT-PCR analysis to find dysregulated circRNAs in ccRCC.	('ccRCC', 'Disease', 'MESH:D002292', (64, 69))	('dysregulated', 'Var', (39, 51))	('ccRCC', 'Disease', (64, 69))	('circRNAs', 'MPA', (52, 60))
87798	31782868	However, the tumorigenic mechanism of hsa_circ_001895 on ccRCC is yet to be found.	('tumor', 'Disease', (13, 18))	('ccRCC', 'Disease', (57, 62))	('ccRCC', 'Disease', 'MESH:D002292', (57, 62))	('hsa_circ_001895', 'Var', (38, 53))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
87799	31782868	We first indicated that hsa_circ_001895 predicted a poor prognosis in ccRCC patients.	('patients', 'Species', '9606', (76, 84))	('ccRCC', 'Disease', (70, 75))	('hsa_circ_001895', 'Var', (24, 39))	('ccRCC', 'Disease', 'MESH:D002292', (70, 75))
87800	31782868	Additionally, overexpression of hsa_circ_001895 not only promoted cell proliferation, invasion and migration of ccRCC, but also inhibited cell apoptosis, whereas hsa_circ_001895 knockdown reversed the effect on ccRCC progression.	('cell apoptosis', 'CPA', (138, 152))	('hsa_circ_001895', 'Var', (32, 47))	('ccRCC', 'Disease', (211, 216))	('promoted', 'PosReg', (57, 65))	('invasion', 'CPA', (86, 94))	('ccRCC', 'Disease', (112, 117))	('cell proliferation', 'CPA', (66, 84))	('ccRCC', 'Disease', 'MESH:D002292', (211, 216))	('ccRCC', 'Disease', 'MESH:D002292', (112, 117))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('migration', 'CPA', (99, 108))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))	('overexpression', 'PosReg', (14, 28))	('inhibited', 'NegReg', (128, 137))
87801	31782868	In vivo s.c. xenotransplanted tumor model also showed that silencing hsa_circ_001895 could suppress in vivo ccRCC growth.	('ccRCC', 'Disease', (108, 113))	('ccRCC', 'Disease', 'MESH:D002292', (108, 113))	('hsa_circ_001895', 'Gene', (69, 84))	('suppress', 'NegReg', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('silencing', 'Var', (59, 68))	('tumor', 'Disease', (30, 35))
87803	31782868	Notably, the inhibitory effect of hsa_circ_001895 on ccRCC progression was reversed by miR-296-5p inhibitor.	('ccRCC', 'Disease', (53, 58))	('miR-296', 'Gene', (87, 94))	('ccRCC', 'Disease', 'MESH:D002292', (53, 58))	('hsa_circ_001895', 'Var', (34, 49))	('miR-296', 'Gene', '407022', (87, 94))
87804	31782868	In general, our findings indicated that hsa_circ_001895 may sponge miR-296-5p and promote SOX12 expression, which is the underlying mechanism of hsa_circ_001895-induced ccRCC progression.	('miR-296', 'Gene', '407022', (67, 74))	('SOX12', 'Gene', (90, 95))	('promote', 'PosReg', (82, 89))	('hsa_circ_001895', 'Var', (40, 55))	('ccRCC', 'Disease', 'MESH:D002292', (169, 174))	('expression', 'MPA', (96, 106))	('hsa_circ_001895-induced', 'Var', (145, 168))	('miR-296', 'Gene', (67, 74))	('SOX12', 'Gene', '6666', (90, 95))	('ccRCC', 'Disease', (169, 174))
87806	31782868	Hsa_circ_001895 promoted ccRCC proliferation.	('Hsa_circ_001895', 'Var', (0, 15))	('promoted', 'PosReg', (16, 24))	('ccRCC', 'Disease', (25, 30))	('ccRCC', 'Disease', 'MESH:D002292', (25, 30))
87809	31782868	Recently, research has found that circRNAs play an important role in growth and metastasis of various tumors.11 CircHIAT1 was downregulated in ccRCC, and inhibition of circHIAT1 promoted cell migration and invasion of ccRCC.12 As a result of the complicated pathogenesis of ccRCC, more circRNAs need to be discovered.	('cell migration', 'biological_process', 'GO:0016477', ('187', '201'))	('ccRCC', 'Disease', (218, 223))	('tumors', 'Disease', (102, 108))	('downregulated', 'NegReg', (126, 139))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('inhibition', 'Var', (154, 164))	('promoted', 'PosReg', (178, 186))	('ccRCC', 'Disease', (274, 279))	('ccRCC', 'Disease', 'MESH:D002292', (274, 279))	('ccRCC', 'Disease', 'MESH:D002292', (218, 223))	('invasion', 'CPA', (206, 214))	('ccRCC', 'Disease', (143, 148))	('cell migration', 'CPA', (187, 201))	('ccRCC', 'Disease', 'MESH:D002292', (143, 148))	('pathogenesis', 'biological_process', 'GO:0009405', ('258', '270'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
87829	31782868	For overexpression of hsa_circ_001895 and CTBP1, full length of hsa_circ_001895 and CTBP1 were constructed into pcDNA3.1 vector (Invitrogen).	('hsa_circ_001895', 'Var', (64, 79))	('CTBP1', 'Gene', '1487', (42, 47))	('CTBP1', 'Gene', (42, 47))	('CTBP1', 'Gene', '1487', (84, 89))	('CTBP1', 'Gene', (84, 89))
87830	31782868	786-O or A498 cells were transfected with pcDNA3.1-hsa_circ_001895 or pcDNA3.1-CTBP1 by Lipofectamine 2000 (Invitrogen).	('CTBP1', 'Gene', '1487', (79, 84))	('pcDNA3.1-hsa_circ_001895', 'Var', (42, 66))	('CTBP1', 'Gene', (79, 84))	('786-O', 'Chemical', 'MESH:C002925', (0, 5))	('A498', 'CellLine', 'CVCL:1056', (9, 13))
87845	31782868	Wild-type or mutant hsa_circ_001895 or 3'-UTR SOX12 was synthesized and then subcloned into pmirGLO (Promega).	('mutant', 'Var', (13, 19))	('SOX12', 'Gene', '6666', (46, 51))	('SOX12', 'Gene', (46, 51))
87846	31782868	miR-296-5p, miR-520h or miR-516a-5p containing the binding sites of hsa_circ_001895 were also subcloned into pmirGLO luciferase reporter vector.	('miR-296', 'Gene', (0, 7))	('binding', 'molecular_function', 'GO:0005488', ('51', '58'))	('miR-296', 'Gene', '407022', (0, 7))	('miR-516a-5p', 'Var', (24, 35))	('miR-520h', 'Gene', '574493', (12, 20))	('miR-520h', 'Gene', (12, 20))
87849	31782868	HEK293 cells were also transfected with pmirGLO-miR-296-5p, miR-520h, miR-516a-5p, NFIC, RNF44 or SOX12.	('NFIC', 'Gene', (83, 87))	('NFIC', 'Gene', '4782', (83, 87))	('miR-296', 'Gene', (48, 55))	('RNF44', 'Gene', (89, 94))	('SOX12', 'Gene', (98, 103))	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('RNF44', 'Gene', '22838', (89, 94))	('miR-520h', 'Gene', '574493', (60, 68))	('miR-516a-5p', 'Var', (70, 81))	('SOX12', 'Gene', '6666', (98, 103))	('miR-520h', 'Gene', (60, 68))	('miR-296', 'Gene', '407022', (48, 55))
87869	31782868	Additionally, hsa_circ_001895 was positively related to TNM stage of ccRCC by in situ hybridization (ISH; Figure 1C), suggesting that hsa_circ_001895 may contribute to the progression of ccRCC.	('ccRCC', 'Disease', (187, 192))	('ccRCC', 'Disease', 'MESH:D002292', (187, 192))	('hsa_circ_001895', 'Var', (134, 149))	('contribute', 'Reg', (154, 164))	('TNM', 'Gene', '10178', (56, 59))	('ccRCC', 'Disease', (69, 74))	('related', 'Reg', (45, 52))	('ccRCC', 'Disease', 'MESH:D002292', (69, 74))	('TNM', 'Gene', (56, 59))
87871	31782868	Kaplan-Meier survival analysis showed that high expression of hsa_circ_001895 showed shorter overall survival (OS) than patients with low expression of hsa_circ_001895 (P = .0406; Figure 1D).	('shorter', 'NegReg', (85, 92))	('high expression', 'Var', (43, 58))	('overall survival', 'MPA', (93, 109))	('patients', 'Species', '9606', (120, 128))	('hsa_circ_001895', 'Var', (62, 77))
87872	31782868	Further refinement analysis of correlation between hsa_circ_001895 expression and clinicopathological characteristics of ccRCC patients showed that among the 60 patients, high expression of hsa_circ_001895 was significantly related to TNM stage (P = .005), pT stage (P = .003) and pN stage (P = .001; Table 2).	('ccRCC', 'Disease', 'MESH:D002292', (121, 126))	('pT stage', 'Disease', (257, 265))	('TNM', 'Gene', (235, 238))	('hsa_circ_001895', 'Var', (190, 205))	('patients', 'Species', '9606', (127, 135))	('patients', 'Species', '9606', (161, 169))	('pN stage', 'Disease', (281, 289))	('TNM', 'Gene', '10178', (235, 238))	('related', 'Reg', (224, 231))	('ccRCC', 'Disease', (121, 126))
87876	31782868	RNase R that could digest linear RNAs was used to further verify the circular nature of hsa_circ_001895, and the result indicated that hsa_circ_001895 was resistant to RNase R digestion compared to linear CTBP1 (Figure 1F).	('CTBP1', 'Gene', (205, 210))	('hsa_circ_001895', 'Var', (135, 150))	('CTBP1', 'Gene', '1487', (205, 210))	('digestion', 'biological_process', 'GO:0007586', ('176', '185'))
87877	31782868	FISH also confirmed the cytoplasm localization of hsa_circ_001895 in ccRCC cells (Figure 2B).	('hsa_circ_001895', 'Var', (50, 65))	('localization', 'biological_process', 'GO:0051179', ('34', '46'))	('ccRCC', 'Disease', (69, 74))	('cytoplasm', 'cellular_component', 'GO:0005737', ('24', '33'))	('ccRCC', 'Disease', 'MESH:D002292', (69, 74))
87881	31782868	Second, CCK-8 (Figure 2D) showed that sh-hsa_circ_001895 decreased cell viability of ccRCC cells, whereas pcDNA-hsa_circ_001895 increased cell viability.	('ccRCC', 'Disease', (85, 90))	('sh-hsa_circ_001895', 'Var', (38, 56))	('ccRCC', 'Disease', 'MESH:D002292', (85, 90))	('cell viability', 'CPA', (67, 81))	('decreased', 'NegReg', (57, 66))
87883	31782868	As proteins involved in cell migration and invasion, E-cadherin was increased and N-cadherin was decreased by hsa_circ_001895 knockdown (Figure 3D).	('hsa_circ_001895', 'Gene', (110, 125))	('E-cadherin', 'Gene', (53, 63))	('N-cadherin', 'Gene', (82, 92))	('E-cadherin', 'Gene', '999', (53, 63))	('cadherin', 'molecular_function', 'GO:0008014', ('84', '92'))	('cell migration', 'biological_process', 'GO:0016477', ('24', '38'))	('N-cadherin', 'Gene', '1000', (82, 92))	('decreased', 'NegReg', (97, 106))	('cadherin', 'molecular_function', 'GO:0008014', ('55', '63'))	('knockdown', 'Var', (126, 135))	('increased', 'PosReg', (68, 77))
87884	31782868	Moreover, as proteins involved in cell apoptosis, Bcl-2 was decreased whereas Bax and Cleaved caspase 3 were increased by hsa_circ_001895 knockdown (Figure 3D).	('knockdown', 'Var', (138, 147))	('Cleaved caspase 3', 'MPA', (86, 103))	('decreased', 'NegReg', (60, 69))	('apoptosis', 'biological_process', 'GO:0097194', ('39', '48'))	('Bax', 'Gene', (78, 81))	('apoptosis', 'biological_process', 'GO:0006915', ('39', '48'))	('Bcl-2', 'Gene', (50, 55))	('Bcl-2', 'Gene', '596', (50, 55))	('hsa_circ_001895 knockdown', 'Var', (122, 147))	('Bcl-2', 'molecular_function', 'GO:0015283', ('50', '55'))	('increased', 'PosReg', (109, 118))	('Bax', 'Gene', '581', (78, 81))
87886	31782868	The potential binding targets of hsa_circ_001895 were predicted as miR-296-5p, miR-520h and miR-516a-5p through CircInteractome (circRNA interactome) and starBase (Figure 4A).	('miR-296', 'Gene', '407022', (67, 74))	('miR-520h', 'Gene', '574493', (79, 87))	('miR-516a-5p', 'Var', (92, 103))	('miR-296', 'Gene', (67, 74))	('miR-520h', 'Gene', (79, 87))	('hsa_circ_001895', 'Gene', (33, 48))	('binding', 'molecular_function', 'GO:0005488', ('14', '21'))
87887	31782868	Dual luciferase reporter assay indicated the highest relative intensity of miR-516a-5p, and higher relative intensity of miR-520h than miR-296-5p in HEK293 cells (Figure 4B).	('miR-516a-5p', 'Var', (75, 86))	('miR-296', 'Gene', '407022', (135, 142))	('miR-520h', 'Gene', '574493', (121, 129))	('miR-296', 'Gene', (135, 142))	('HEK293', 'CellLine', 'CVCL:0045', (149, 155))	('miR-520h', 'Gene', (121, 129))
87888	31782868	miR-296-5p was upregulated in 786-O and A498 cells transfected with sh-hsa_circ_001895, whereas miR-516a-5p and miR-520h were not affected by hsa_circ_001895 knockdown (Figure 4C).	('miR-520h', 'Gene', (112, 120))	('miR-296', 'Gene', (0, 7))	('upregulated', 'PosReg', (15, 26))	('786-O', 'Chemical', 'MESH:C002925', (30, 35))	('sh-hsa_circ_001895', 'Var', (68, 86))	('miR-296', 'Gene', '407022', (0, 7))	('A498', 'CellLine', 'CVCL:1056', (40, 44))	('miR-520h', 'Gene', '574493', (112, 120))
87893	31782868	Moreover, miR-296-5p was downregulated in ccRCC tissues (Figure 4H), and bivariate correlation analysis showed negative correlation between miR-296-5p and hsa_circ_001895 in ccRCC (Figure 4I).	('miR-296', 'Gene', (10, 17))	('ccRCC', 'Disease', (174, 179))	('downregulated', 'NegReg', (25, 38))	('miR-296', 'Gene', '407022', (140, 147))	('ccRCC', 'Disease', 'MESH:D002292', (174, 179))	('ccRCC', 'Disease', (42, 47))	('negative', 'NegReg', (111, 119))	('hsa_circ_001895', 'Var', (155, 170))	('ccRCC', 'Disease', 'MESH:D002292', (42, 47))	('miR-296', 'Gene', '407022', (10, 17))	('miR-296', 'Gene', (140, 147))
87894	31782868	Collectively, these results indicated that hsa_circ_001895 could directly bind to miR-296-5p and inhibit its expression.	('inhibit', 'NegReg', (97, 104))	('expression', 'MPA', (109, 119))	('hsa_circ_001895', 'Var', (43, 58))	('miR-296', 'Gene', '407022', (82, 89))	('bind', 'Interaction', (74, 78))	('miR-296', 'Gene', (82, 89))
87897	31782868	Both mRNA (Figure 5C) and protein (Figure 5D) expression of NFIC and SOX12 were downregulated in cells transfected with sh-hsa_circ_001895, whereas RNF44 was not affected by hsa_circ_001895 knockdown (Figure 5C,D).	('RNF44', 'Gene', '22838', (148, 153))	('SOX12', 'Gene', (69, 74))	('protein', 'MPA', (26, 33))	('mRNA', 'MPA', (5, 9))	('sh-hsa_circ_001895', 'Var', (120, 138))	('SOX12', 'Gene', '6666', (69, 74))	('NFIC', 'Gene', '4782', (60, 64))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('NFIC', 'Gene', (60, 64))	('downregulated', 'NegReg', (80, 93))	('RNF44', 'Gene', (148, 153))
87909	31782868	Moreover, cell cycle blocked by hsa_circ_001895 knockdown was promoted by additional transfection with miR-296-5p inhibitor (Figure 6D).	('cell cycle blocked', 'CPA', (10, 28))	('miR-296', 'Gene', (103, 110))	('hsa_circ_001895', 'Gene', (32, 47))	('cell cycle', 'biological_process', 'GO:0007049', ('10', '20'))	('promoted', 'PosReg', (62, 70))	('miR-296', 'Gene', '407022', (103, 110))	('knockdown', 'Var', (48, 57))
87913	31782868	These results showed that hsa_circ_001895 knockdown suppressed ccRCC progression by sponging miR-296-5p.	('miR-296', 'Gene', '407022', (93, 100))	('miR-296', 'Gene', (93, 100))	('ccRCC', 'Disease', (63, 68))	('suppressed', 'NegReg', (52, 62))	('ccRCC', 'Disease', 'MESH:D002292', (63, 68))	('knockdown', 'Var', (42, 51))
87917	31782868	Moreover, intratumoral injection of sh-hsa_circ_001895 inhibited tumor growth (Figure 8B), as shown by decreased tumor volume and weight (Figure 8C).	('tumor', 'Disease', (113, 118))	('sh-hsa_circ_001895', 'Var', (36, 54))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('decreased', 'NegReg', (103, 112))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('inhibited', 'NegReg', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
87921	31782868	Hsa_circ_001895 was positively associated with the TNM stage of ccRCC, and predicted a poor prognosis in ccRCC patients, suggesting the potential regulatory ability of hsa_circ_001895 on ccRCC progression.	('ccRCC', 'Disease', (187, 192))	('ccRCC', 'Disease', (105, 110))	('ccRCC', 'Disease', 'MESH:D002292', (187, 192))	('TNM', 'Gene', '10178', (51, 54))	('ccRCC', 'Disease', (64, 69))	('associated', 'Reg', (31, 41))	('ccRCC', 'Disease', 'MESH:D002292', (105, 110))	('ccRCC', 'Disease', 'MESH:D002292', (64, 69))	('Hsa_circ_001895', 'Var', (0, 15))	('TNM', 'Gene', (51, 54))	('patients', 'Species', '9606', (111, 119))
87922	31782868	However, due to the small sample size of our current clinical analysis (N = 60), significant relationship between high hsa_circ_001895 expression and other clinicopathological features of ccRCC patients may be not precise enough.	('ccRCC', 'Disease', (188, 193))	('high hsa_circ_001895 expression', 'Var', (114, 145))	('ccRCC', 'Disease', 'MESH:D002292', (188, 193))	('patients', 'Species', '9606', (194, 202))
87924	31782868	Circ-ABCB10 overexpression19 or hsa_circ_0001451 knockdown18 promoted ccRCC proliferation and induced cell apoptosis in vitro, revealing the relationship between potential markers and therapeutic targets of circRNAs in ccRCC.	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('overexpression19', 'PosReg', (12, 28))	('knockdown18', 'Var', (49, 60))	('ABCB10', 'Gene', '23456', (5, 11))	('cell apoptosis', 'CPA', (102, 116))	('ABCB10', 'Gene', (5, 11))	('promoted', 'PosReg', (61, 69))	('ccRCC', 'Disease', (219, 224))	('ccRCC', 'Disease', (70, 75))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))	('induced', 'Reg', (94, 101))	('ccRCC', 'Disease', 'MESH:D002292', (219, 224))	('ccRCC', 'Disease', 'MESH:D002292', (70, 75))
87926	31782868	Consistent with the clinical results of hsa_circ_001895 in ccRCC, in vitro functional assays showed that hsa_circ_001895 promoted ccRCC progression of ccRCC, as well as inhibition of cell apoptosis.	('ccRCC', 'Disease', 'MESH:D002292', (151, 156))	('hsa_circ_001895', 'Var', (105, 120))	('inhibition', 'NegReg', (169, 179))	('apoptosis', 'biological_process', 'GO:0097194', ('188', '197'))	('apoptosis', 'biological_process', 'GO:0006915', ('188', '197'))	('ccRCC', 'Disease', (130, 135))	('ccRCC', 'Disease', (59, 64))	('ccRCC', 'Disease', 'MESH:D002292', (130, 135))	('ccRCC', 'Disease', (151, 156))	('ccRCC', 'Disease', 'MESH:D002292', (59, 64))	('promoted', 'PosReg', (121, 129))	('cell apoptosis', 'CPA', (183, 197))
87927	31782868	Moreover, hsa_circ_001895 knockdown inhibited ccRCC progression, but induced cell apoptosis.	('ccRCC', 'Disease', 'MESH:D002292', (46, 51))	('inhibited', 'NegReg', (36, 45))	('cell apoptosis', 'CPA', (77, 91))	('apoptosis', 'biological_process', 'GO:0006915', ('82', '91'))	('knockdown', 'Var', (26, 35))	('apoptosis', 'biological_process', 'GO:0097194', ('82', '91'))	('induced', 'Reg', (69, 76))	('hsa_circ_001895', 'Gene', (10, 25))	('ccRCC', 'Disease', (46, 51))
87929	31782868	As the "oncogene" function of hsa_circ_001895 in ccRCC was found, we then determined the underlying mechanism.	('ccRCC', 'Disease', (49, 54))	('ccRCC', 'Disease', 'MESH:D002292', (49, 54))	('hsa_circ_001895', 'Var', (30, 45))
87930	31782868	First, the "oncogene" role of hsa_circ_001895 in ccRCC depends on the promotion of cell apoptosis through targeting Bcl-2, Bax and Cleaved caspase-3.	('Bax', 'Gene', '581', (123, 126))	('ccRCC', 'Disease', 'MESH:D002292', (49, 54))	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('114', '119'))	('Bcl-2', 'Gene', (116, 121))	('caspase-3', 'Gene', (139, 148))	('promotion', 'PosReg', (70, 79))	('hsa_circ_001895', 'Var', (30, 45))	('Bax', 'Gene', (123, 126))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('Cleaved', 'MPA', (131, 138))	('caspase-3', 'Gene', '836', (139, 148))	('cell apoptosis', 'CPA', (83, 97))	('ccRCC', 'Disease', (49, 54))	('Bcl-2', 'Gene', '596', (116, 121))	('targeting', 'NegReg', (106, 115))
87935	31782868	EMT is essential for the development of metastasis and contributes to the unfavorable prognosis in ccRCC.26, 27 EMT, as shown by downregulation of E-cadherin accompanied by upregulation of N-cadherin, could enhance metastasis of ccRCC.28 Both in vivo and in vitro results in the present study showed that hsa_circ_001895 knockdown could increase E-cadherin and decrease N-cadherin to inhibit EMT and metastasis of ccRCC.	('N-cadherin', 'Gene', (370, 380))	('ccRCC', 'Disease', 'MESH:D002292', (229, 234))	('E-cadherin', 'Gene', (346, 356))	('cadherin', 'molecular_function', 'GO:0008014', ('149', '157'))	('N-cadherin', 'Gene', '1000', (370, 380))	('N-cadherin', 'Gene', (189, 199))	('E-cadherin', 'Gene', '999', (346, 356))	('N-cadherin', 'Gene', '1000', (189, 199))	('ccRCC', 'Disease', (229, 234))	('cadherin', 'molecular_function', 'GO:0008014', ('372', '380'))	('knockdown', 'Var', (321, 330))	('E-cadherin', 'Gene', (147, 157))	('E-cadherin', 'Gene', '999', (147, 157))	('decrease', 'NegReg', (361, 369))	('increase', 'PosReg', (337, 345))	('EMT', 'biological_process', 'GO:0001837', ('0', '3'))	('hsa_circ_001895', 'Gene', (305, 320))	('inhibit', 'NegReg', (384, 391))	('ccRCC', 'Disease', 'MESH:D002292', (99, 104))	('EMT', 'biological_process', 'GO:0001837', ('112', '115'))	('EMT', 'biological_process', 'GO:0001837', ('392', '395'))	('ccRCC', 'Disease', 'MESH:D002292', (414, 419))	('ccRCC', 'Disease', (99, 104))	('cadherin', 'molecular_function', 'GO:0008014', ('348', '356'))	('cadherin', 'molecular_function', 'GO:0008014', ('191', '199'))	('ccRCC', 'Disease', (414, 419))
87938	31782868	miR-296-5p is a tumor suppressor in various tumors.31, 32, 33 The present study indicated that hsa_circ_001895 knockdown inhibited ccRCC progression but induced cell apoptosis through sponging miR-296-5p.	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('apoptosis', 'biological_process', 'GO:0097194', ('166', '175'))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('apoptosis', 'biological_process', 'GO:0006915', ('166', '175'))	('hsa_circ_001895', 'Gene', (95, 110))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('miR-296', 'Gene', (193, 200))	('cell apoptosis', 'CPA', (161, 175))	('inhibited', 'NegReg', (121, 130))	('ccRCC', 'Disease', 'MESH:D002292', (131, 136))	('miR-296', 'Gene', '407022', (193, 200))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (16, 21))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('16', '32'))	('ccRCC', 'Disease', (131, 136))	('tumors', 'Disease', (44, 50))	('miR-296', 'Gene', (0, 7))	('knockdown', 'Var', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor suppressor', 'biological_process', 'GO:0051726', ('16', '32'))	('induced', 'PosReg', (153, 160))	('miR-296', 'Gene', '407022', (0, 7))
87944	31782868	More recently, SOX12 was shown to be a predictive marker of prognosis in ccRCC patients.42 Our study showed that hsa_circ_001895 knockdown suppressed xenograft ccRCC tumor growth by SOX12, further confirming the important regulatory ability of SOX12 on ccRCC progression.	('ccRCC', 'Disease', 'MESH:D002292', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('SOX12', 'Gene', '6666', (182, 187))	('ccRCC', 'Disease', 'MESH:D002292', (253, 258))	('SOX12', 'Gene', '6666', (244, 249))	('ccRCC', 'Disease', 'MESH:D002292', (160, 165))	('ccRCC', 'Disease', (73, 78))	('xenograft', 'CPA', (150, 159))	('ccRCC', 'Disease', (253, 258))	('ccRCC', 'Disease', (160, 165))	('knockdown', 'Var', (129, 138))	('SOX12', 'Gene', (15, 20))	('tumor', 'Disease', (166, 171))	('suppressed', 'NegReg', (139, 149))	('SOX12', 'Gene', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('SOX12', 'Gene', (244, 249))	('patients', 'Species', '9606', (79, 87))	('hsa_circ_001895', 'Gene', (113, 128))	('SOX12', 'Gene', '6666', (15, 20))
87950	33922974	Many exploratory studies have identified epigenetic markers based on DNA methylation, histone modification, and ncRNA expression that epigenetically regulate gene expression in ccRCC.	('regulate', 'Reg', (149, 157))	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('ccRCC', 'Phenotype', 'HP:0006770', (177, 182))	('epigenetically', 'Var', (134, 148))	('ncRNA', 'Gene', (112, 117))	('gene expression', 'MPA', (158, 173))	('histone modification', 'biological_process', 'GO:0016570', ('86', '106'))	('ncRNA', 'Gene', '220202', (112, 117))	('DNA methylation', 'biological_process', 'GO:0006306', ('69', '84'))	('RCC', 'Phenotype', 'HP:0005584', (179, 182))	('gene expression', 'biological_process', 'GO:0010467', ('158', '173'))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('RCC', 'Disease', (179, 182))
87951	33922974	Additionally, epigenetic modifiers genes have been proposed as promising biomarkers for ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('epigenetic modifiers genes', 'Var', (14, 40))	('RCC', 'Disease', (90, 93))
87952	33922974	We review and discuss the current understanding of how epigenetic changes determine the main molecular pathways of ccRCC initiation and progression, and also its clinical implications.	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('ccRCC initiation', 'Disease', (115, 131))	('ccRCC initiation', 'Disease', 'MESH:D007319', (115, 131))	('epigenetic changes', 'Var', (55, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('determine', 'Reg', (74, 83))
87954	33922974	Interesting clinical trials on epigenetic treatments for ccRCC associated with well established antiangiogenic treatments and immune checkpoint inhibitors are revisited.	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('epigenetic treatments', 'Var', (31, 52))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
87980	33922974	Blockade of the PD1-PDL1 axis promotes T cell activation and immune killing of cancer cells.	('PDL1', 'Gene', '29126', (20, 24))	('promotes', 'PosReg', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Blockade', 'Var', (0, 8))	('T cell activation', 'biological_process', 'GO:0042110', ('39', '56'))	('PDL1', 'Gene', (20, 24))	('T cell activation', 'CPA', (39, 56))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
87986	33922974	Response rates are better in PDL1 positive tumors, but PDL1 negative ones also respond.	('PDL1', 'Gene', (29, 33))	('better', 'PosReg', (19, 25))	('Response', 'MPA', (0, 8))	('PDL1', 'Gene', '29126', (55, 59))	('positive', 'Var', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('PDL1', 'Gene', '29126', (29, 33))	('PDL1', 'Gene', (55, 59))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
87991	33922974	Abnormal epigenetic patterns will give new opportunities to develop novel therapies in RCC.	('epigenetic patterns', 'Var', (9, 28))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
87993	33922974	Maybe closer is the practical utility of epigenetic therapies to solve or delay therapy resistance in ccRCC, and also to identify the populations in which prolonged response to a certain therapy could be expected.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('delay', 'NegReg', (74, 79))	('epigenetic therapies', 'Var', (41, 61))	('solve', 'Reg', (65, 70))	('therapy resistance', 'MPA', (80, 98))	('RCC', 'Disease', (104, 107))
87995	33922974	As such, cancer epigenetics deals with the inheritable but reversible changes associated with gene expression dysregulation that manifest in a pre-malignant phenotype with the genomic sequence unaltered.	('cancer', 'Disease', (9, 15))	('pre', 'molecular_function', 'GO:0003904', ('143', '146'))	('gene expression', 'biological_process', 'GO:0010467', ('94', '109'))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('dysregulation', 'Var', (110, 123))
87996	33922974	Interest in epigenetic alterations associated with ccRCC provides an optimal scenario in the search for new tumor markers in this malignancy, and also to develop new treatment strategies facilitated by the reversibility of epigenetic modifications.	('malignancy', 'Disease', (130, 140))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('epigenetic alterations', 'Var', (12, 34))	('associated', 'Reg', (35, 45))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('tumor', 'Disease', (108, 113))	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('malignancy', 'Disease', 'MESH:D009369', (130, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))
87997	33922974	The main epigenetic mechanisms are DNA methylation, chromatin remodeling, post-translational histone modifications, short-noncoding RNAs, also known as microRNAs (miRNA), and long-noncoding RNAs (lncRNA).	('chromatin remodeling', 'CPA', (52, 72))	('ncRNA', 'Gene', (197, 202))	('methylation', 'Var', (39, 50))	('DNA methylation', 'biological_process', 'GO:0006306', ('35', '50'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('52', '72'))	('ncRNA', 'Gene', '220202', (197, 202))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('chromatin', 'cellular_component', 'GO:0000785', ('52', '61'))	('short-noncoding RNAs', 'Var', (116, 136))	('DNA', 'Var', (35, 38))	('long-noncoding RNAs', 'Var', (175, 194))
87998	33922974	These changes can be due to genetic alterations, linking genetics, and epigenetics in carcinogenesis.	('carcinogenesis', 'Disease', (86, 100))	('carcinogenesis', 'Disease', 'MESH:D063646', (86, 100))	('genetic alterations', 'Var', (28, 47))	('epigenetics', 'Var', (71, 82))
87999	33922974	Among the many epigenetic changes and signatures identified in RCC, aberrant promoter methylation of more than 200 genes have been reported and more than 120 miRNAs are deregulated.	('RCC', 'Disease', (63, 66))	('deregulated', 'Reg', (169, 180))	('methylation', 'biological_process', 'GO:0032259', ('86', '97'))	('reported', 'Reg', (131, 139))	('promoter methylation', 'MPA', (77, 97))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('aberrant', 'Var', (68, 76))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
88000	33922974	In addition, the selection of normal tissue for comparison with neoplasia can be problematic because aberrant promoter methylation is an early event in carcinogenesis allowing its detection in normal appearing tissue surrounding the tumor.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('carcinogenesis', 'Disease', (152, 166))	('tumor', 'Disease', (233, 238))	('neoplasia', 'Phenotype', 'HP:0002664', (64, 73))	('methylation', 'biological_process', 'GO:0032259', ('119', '130'))	('neoplasia', 'Disease', (64, 73))	('aberrant', 'Var', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('carcinogenesis', 'Disease', 'MESH:D063646', (152, 166))	('neoplasia', 'Disease', 'MESH:D009369', (64, 73))
88002	33922974	Firstly, epigenetic deregulation can lead precursor cells to proliferate and block their differentiation as seems to occur in germ cell malignancies.	('epigenetic deregulation', 'Var', (9, 32))	('lead', 'Reg', (37, 41))	('malignancies', 'Disease', 'MESH:D009369', (136, 148))	('malignancies', 'Disease', (136, 148))	('germ cell malignancies', 'Phenotype', 'HP:0100728', (126, 148))	('proliferate', 'CPA', (61, 72))	('block', 'NegReg', (77, 82))	('differentiation', 'CPA', (89, 104))
88004	33922974	Probably the most interesting epigenetic mechanism in ccRCC stands in common mutations in chromatin regulator genes that complement the inactivation of Von Hippel Lindau (VHL) tumor suppressor gene (TSG), and Hypoxia-inducible factors (HIF) pathway that allow tumor cell survival in a characteristic status of pseudo-hypoxia.	('Hypoxia', 'Disease', (209, 216))	('chromatin', 'cellular_component', 'GO:0000785', ('90', '99'))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('176', '192'))	('low tumor', 'Disease', 'MESH:D009800', (256, 265))	('tumor suppressor', 'biological_process', 'GO:0051726', ('176', '192'))	('tumor suppressor', 'Gene', '7248', (176, 192))	('VHL', 'Gene', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('hypoxia', 'Disease', (317, 324))	('low tumor', 'Disease', (256, 265))	('mutations', 'Var', (77, 86))	('VHL', 'Gene', '7428', (171, 174))	('hypoxia', 'Disease', 'MESH:D000860', (317, 324))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('Hypoxia', 'Disease', 'MESH:D000860', (209, 216))	('tumor suppressor', 'Gene', (176, 192))
88005	33922974	VHL gene is frequently inactivated in sporadic ccRCC by mutation, loss of heterozygosity, or promoter hypermethylation.	('RCC', 'Disease', (49, 52))	('promoter hypermethylation', 'Var', (93, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('VHL', 'Gene', (0, 3))	('loss of heterozygosity', 'Var', (66, 88))	('VHL', 'Gene', '7428', (0, 3))	('mutation', 'Var', (56, 64))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('inactivated', 'NegReg', (23, 34))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
88010	33922974	Recent genome-wide sequencing studies have revealed a number of mutations of genes coding for epigenome modifiers and chromatin remodelers, like PBRM1 (40%), SETD2 (10%), KDM5C (10%), KDM6A (1%), and BAP1 (10-15%).	('BAP1', 'Gene', (200, 204))	('KDM5C', 'Gene', (171, 176))	('BAP1', 'Gene', '8314', (200, 204))	('chromatin', 'cellular_component', 'GO:0000785', ('118', '127'))	('SETD2', 'Gene', '29072', (158, 163))	('KDM6A', 'Gene', (184, 189))	('KDM5C', 'Gene', '8242', (171, 176))	('mutations', 'Var', (64, 73))	('SETD2', 'Gene', (158, 163))	('PBRM1', 'Gene', (145, 150))	('KDM6A', 'Gene', '7403', (184, 189))
88011	33922974	Most of the mutations of histone modifier genes described in ccRCC are truncating and inactivating mutations producing loss of functions.	('inactivating', 'Var', (86, 98))	('RCC', 'Disease', (63, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('mutations', 'Var', (12, 21))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
88012	33922974	Apart from VHL mutations these are among the most common somatic genetic abnormalities encountered in renal tumors.	('renal tumors', 'Phenotype', 'HP:0009726', (102, 114))	('genetic abnormalities encountered in renal tumors', 'Disease', 'MESH:D030342', (65, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('genetic abnormalities encountered in renal tumors', 'Disease', (65, 114))	('mutations', 'Var', (15, 24))	('VHL', 'Gene', (11, 14))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('VHL', 'Gene', '7428', (11, 14))
88018	33922974	Liquid biopsy from direct washing of fresh biopsies can be an optimal method as well, to evaluate epigenetic changes that would facilitate accurate detection, tumor subtype determination, and evaluation of prognosis as well.	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('epigenetic changes', 'Var', (98, 116))
88021	33922974	The growing field of knowledge to determine the real impact of altered epigenetic patterns and their role in the diagnosis, monitoring, classification, prognosis, and treatment of kidney cancer is the main objective of this review.	('epigenetic patterns', 'Var', (71, 90))	('kidney cancer', 'Phenotype', 'HP:0009726', (180, 193))	('kidney cancer', 'Disease', 'MESH:D007680', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('kidney cancer', 'Disease', (180, 193))
88022	33922974	DNA methylation is the most widely studied epigenetic modification so far, and consists of the addition of a methyl group to the Cytosine within the CpG dinucleotide.	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('Cytosine', 'Chemical', 'MESH:D003596', (129, 137))	('CpG dinucleotide', 'Chemical', 'MESH:C015772', (149, 165))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('methylation', 'Var', (4, 15))	('DNA', 'Disease', (0, 3))	('methyl group', 'MPA', (109, 121))
88028	33922974	Two major changes occur in cancer affecting DNA methylation: global DNA hypomethylation of the genome and aberrant hypermethylation of the promoter region of TSGs.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('aberrant', 'Var', (106, 114))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('68', '87'))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('DNA methylation', 'biological_process', 'GO:0006306', ('44', '59'))
88030	33922974	In addition, the hypomethylation of CpG sites has been associated with the over-expression of oncogenes within cancer cells and with deregulation of proteins involved in the complex balance between methylation and the maintenance of the chromatin structure.	('hypomethylation', 'Var', (17, 32))	('oncogenes', 'Gene', (94, 103))	('CpG', 'Gene', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('associated', 'Reg', (55, 65))	('proteins', 'Protein', (149, 157))	('methylation', 'biological_process', 'GO:0032259', ('198', '209'))	('chromatin', 'cellular_component', 'GO:0000785', ('237', '246'))	('deregulation', 'Var', (133, 145))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('over-expression', 'PosReg', (75, 90))
88031	33922974	Hypermethylation of CpG islands located in the promoter regions of some TSGs prevents gene expression and, therefore, its protective role in the development of tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('gene expression', 'biological_process', 'GO:0010467', ('86', '101'))	('Hypermethylation', 'Var', (0, 16))	('prevents', 'NegReg', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('gene expression', 'MPA', (86, 101))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
88032	33922974	Gene silencing by promoter hypermethylation in cancer has been studied in depth and affects important functions for cell cycle, DNA repair, cell adhesion and invasion, apoptosis, miRNA expression, metabolism of carcinogens, and response to hormones.	('DNA repair', 'biological_process', 'GO:0006281', ('128', '138'))	('Gene silencing', 'biological_process', 'GO:0016458', ('0', '14'))	('apoptosis', 'biological_process', 'GO:0097194', ('168', '177'))	('apoptosis', 'biological_process', 'GO:0006915', ('168', '177'))	('miRNA expression', 'MPA', (179, 195))	('affects', 'Reg', (84, 91))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('DNA repair', 'MPA', (128, 138))	('cell adhesion', 'CPA', (140, 153))	('cell adhesion', 'biological_process', 'GO:0007155', ('140', '153'))	('cell cycle', 'biological_process', 'GO:0007049', ('116', '126'))	('functions', 'MPA', (102, 111))	('cell cycle', 'CPA', (116, 126))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('metabolism', 'biological_process', 'GO:0008152', ('197', '207'))	('metabolism', 'MPA', (197, 207))	('apoptosis', 'CPA', (168, 177))	('invasion', 'CPA', (158, 166))	('promoter hypermethylation', 'Var', (18, 43))
88036	33922974	Thirdly, methylation-specific PCR (MSP) derived methods enable a fast, simple method to detect methylated alleles of a certain gene in samples with low tumor content and even in biological fluids.	('low tumor', 'Disease', 'MESH:D009800', (148, 157))	('methylated', 'Var', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('low tumor', 'Disease', (148, 157))	('detect', 'Reg', (88, 94))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))
88037	33922974	However, among the limitations to generalize application of epigenetic markers in RCC is also cell type specificity and the aforementioned heterogeneity of this malignancy.	('malignancy', 'Disease', 'MESH:D009369', (161, 171))	('malignancy', 'Disease', (161, 171))	('epigenetic markers', 'Var', (60, 78))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))
88038	33922974	Aberrant DNA methylation is an early event in carcinogenesis, thus DNA methylation biomarkers has been implemented for the diagnosis of a wide range of malignancies including prostate, colorectal, and pulmonary neoplasia.	('pulmonary neoplasia', 'Disease', 'MESH:D009369', (201, 220))	('DNA methylation', 'biological_process', 'GO:0006306', ('67', '82'))	('carcinogenesis', 'Disease', 'MESH:D063646', (46, 60))	('Aberrant', 'Var', (0, 8))	('pulmonary neoplasia', 'Disease', (201, 220))	('carcinogenesis', 'Disease', (46, 60))	('pulmonary neoplasia', 'Phenotype', 'HP:0100526', (201, 220))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('prostate', 'Disease', (175, 183))	('malignancies', 'Disease', 'MESH:D009369', (152, 164))	('colorectal', 'Disease', (185, 195))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('neoplasia', 'Phenotype', 'HP:0002664', (211, 220))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('malignancies', 'Disease', (152, 164))
88045	33922974	RASSF1A and SPINT2 are more frequently methylated in pRCC while COL1A1 and IGFBP1 hypermethylation is more common in ccRCC.	('pRCC', 'Gene', (53, 57))	('SPINT2', 'Gene', (12, 18))	('COL1A1', 'Gene', (64, 70))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('methylated', 'Var', (39, 49))	('IGFBP1', 'Gene', (75, 81))	('common', 'Reg', (107, 113))	('SPINT2', 'Gene', '10653', (12, 18))	('IGFBP1', 'Gene', '3484', (75, 81))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RASSF1A', 'Gene', '11186', (0, 7))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('RCC', 'Disease', (119, 122))	('pRCC', 'Gene', '5546', (53, 57))	('RASSF1A', 'Gene', (0, 7))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('COL1A1', 'Gene', '1277', (64, 70))
88047	33922974	In fact, data from The Cancer Genome Atlas (TCGA) revealed that of all RCC subtypes, oncocytoma and chRCC are the most similar but, what is even more interesting, a signature of 30 hypermethylated genes distinguishes oncocytoma from chRCC involved, among others, in Wnt, MAPK, and TGFbeta signaling.	('Cancer', 'Disease', (23, 29))	('signaling', 'biological_process', 'GO:0023052', ('289', '298'))	('RCC', 'Phenotype', 'HP:0005584', (235, 238))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (235, 238))	('distinguishes', 'Reg', (203, 216))	('oncocytoma', 'Disease', 'MESH:D018249', (217, 227))	('Cancer', 'Disease', 'MESH:D009369', (23, 29))	('oncocytoma', 'Disease', (85, 95))	('RCC', 'Disease', 'MESH:C538614', (235, 238))	('MAPK', 'molecular_function', 'GO:0004707', ('271', '275'))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('oncocytoma', 'Disease', (217, 227))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('TGFbeta', 'Gene', (281, 288))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('RCC', 'Disease', (102, 105))	('hypermethylated genes', 'Var', (181, 202))	('oncocytoma', 'Disease', 'MESH:D018249', (85, 95))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('TGFbeta', 'Gene', '7039', (281, 288))
88059	33922974	Very recently some methylated genes with prognostic value in pRCC have also been described.	('methylated', 'Var', (19, 29))	('pRCC', 'Gene', (61, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('pRCC', 'Gene', '5546', (61, 65))
88062	33922974	Each of them, with the exception of MBD3, is capable of binding specifically to methylated DNA.	('MBD3', 'Gene', (36, 40))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('DNA', 'Protein', (91, 94))	('methylated', 'Var', (80, 90))	('binding', 'Interaction', (56, 63))	('binding', 'molecular_function', 'GO:0005488', ('56', '63'))	('MBD3', 'Gene', '53615', (36, 40))
88071	33922974	Similarly, it has been suggested that H3K9Ac and H3K18Ac levels could monitor patients with RCC after surgery, but as far as we know these likely markers have not been confirmed in prospective validations.	('patients', 'Species', '9606', (78, 86))	('H3K9Ac', 'MPA', (38, 44))	('H3K18Ac', 'Var', (49, 56))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (92, 95))
88073	33922974	Additionally, H3K27me1/-me2/-me3 staining is significantly more intense in pRCC than in ccRCC, and H3K27me3 levels are higher in oncocytoma than in RCC.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (148, 151))	('RCC', 'Disease', (76, 79))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('pRCC', 'Gene', (75, 79))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('oncocytoma', 'Disease', (129, 139))	('higher', 'PosReg', (119, 125))	('H3K27me3 levels', 'MPA', (99, 114))	('H3K27me1/-me2/-me3', 'Var', (14, 32))	('oncocytoma', 'Disease', 'MESH:D018249', (129, 139))	('pRCC', 'Gene', '5546', (75, 79))	('intense', 'PosReg', (64, 71))	('RCC', 'Disease', (90, 93))
88078	33922974	One of the mechanisms involved in the epigenetic-altered landscape in RCC related to hypoxic effect is the regulation of Jumonji domain containing histone demethylases by the mediator of hypoxic response HIFalpha.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('regulation', 'biological_process', 'GO:0065007', ('107', '117'))	('epigenetic-altered', 'Var', (38, 56))	('hypoxic', 'Disease', (187, 194))	('hypoxic', 'Disease', 'MESH:D000860', (187, 194))	('hypoxic', 'Disease', (85, 92))	('hypoxic', 'Disease', 'MESH:D000860', (85, 92))
88079	33922974	A number of genes that encode histone-modifying enzymes are mutated in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('RCC', 'Disease', (73, 76))	('mutated', 'Var', (60, 67))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
88080	33922974	Inactivating mutations described for SETD2 (H3K36 methyltransferase), KDM5C (H3K4 demethylase), KMD6A (H3K27 demethylase), MLL2 (H3K4 methyltransferase), Polybromo 1 (PBRM1), BRCA1 Associated Protein-1 (BAP1) remain among the most interesting epigenetic mechanisms for ccRCC progression.	('SETD2', 'Gene', '29072', (37, 42))	('KDM5C', 'Gene', (70, 75))	('MLL2', 'Gene', '8085', (123, 127))	('Polybromo 1', 'Gene', '55193', (154, 165))	('BAP1', 'Gene', '8314', (203, 207))	('PBRM1', 'Gene', (167, 172))	('ccRCC', 'Phenotype', 'HP:0006770', (269, 274))	('Polybromo 1', 'Gene', (154, 165))	('SETD2', 'Gene', (37, 42))	('BAP1', 'Gene', (203, 207))	('Inactivating mutations', 'Var', (0, 22))	('BRCA1 Associated Protein-1', 'Gene', '8314', (175, 201))	('MLL2', 'Gene', (123, 127))	('RCC', 'Disease', 'MESH:C538614', (271, 274))	('RCC', 'Disease', (271, 274))	('RCC', 'Phenotype', 'HP:0005584', (271, 274))	('BRCA1 Associated Protein-1', 'Gene', (175, 201))	('KDM5C', 'Gene', '8242', (70, 75))
88082	33922974	This gene is involved in genome stability as trimethylation of H3K36 by SETD2 is required for DNA repairing system through both homologous recombination repair and mismatch repair.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('mismatch', 'Var', (164, 172))	('mismatch repair', 'biological_process', 'GO:0006298', ('164', '179'))	('homologous recombination', 'biological_process', 'GO:0035825', ('128', '152'))	('H3K36', 'Protein', (63, 68))	('SETD2', 'Gene', '29072', (72, 77))	('SETD2', 'Gene', (72, 77))
88083	33922974	DNMT3B-mediated de novo DNA methylation occurs at the intron of genes marked with H3K36me3 but not those lacking H3K36me3.	('H3K36me3', 'Var', (82, 90))	('de novo DNA methylation', 'biological_process', 'GO:0043046', ('16', '39'))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('DNMT3B', 'Gene', '1789', (0, 6))	('DNMT3B', 'Gene', (0, 6))	('de novo DNA methylation', 'biological_process', 'GO:0043045', ('16', '39'))
88084	33922974	Mutations in the switching defective/sucrose nonfermenting (SWI/SNF) chromatin remodeling complex gene PBRM1 are identified in approximately 40% of ccRCC.	('chromatin remodeling', 'biological_process', 'GO:0006338', ('69', '89'))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('69', '97'))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('RCC', 'Disease', (150, 153))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('Mutations', 'Var', (0, 9))	('PBRM1', 'Gene', (103, 108))	('ccRCC', 'Phenotype', 'HP:0006770', (148, 153))	('identified', 'Reg', (113, 123))	('sucrose', 'Chemical', 'MESH:D013395', (37, 44))
88086	33922974	Thus, inactivation of the PBRM1 TSG amplifies the HIF-response of VHL negative ccRCC.	('PBRM1', 'Gene', (26, 31))	('inactivation', 'Var', (6, 18))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('VHL', 'Gene', (66, 69))	('HIF-response', 'MPA', (50, 62))	('VHL', 'Gene', '7428', (66, 69))	('amplifies', 'PosReg', (36, 45))
88092	33922974	KDM6A codifies a protein that demethylases lysine 27 in histone 3 (H3K27) and is mutated in only 1% of ccRCCs, while KDM5C encodes H3K4 demethylase and its mutation is present in approximately 10% of ccRCCs.	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('lysine', 'Chemical', 'MESH:D008239', (43, 49))	('KDM6A', 'Gene', '7403', (0, 5))	('mutated', 'Var', (81, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (200, 205))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('KDM5C', 'Gene', (117, 122))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('RCC', 'Disease', (202, 205))	('RCC', 'Phenotype', 'HP:0005584', (202, 205))	('KDM5C', 'Gene', '8242', (117, 122))	('KDM6A', 'Gene', (0, 5))
88094	33922974	Inhibition of EZH2 has been suggested as an effective therapeutic approach to KDM6A-mutated tumors.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('KDM6A', 'Gene', '7403', (78, 83))	('EZH2', 'Gene', (14, 18))	('EZH2', 'Gene', '2146', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Inhibition', 'Var', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('KDM6A', 'Gene', (78, 83))	('tumors', 'Disease', (92, 98))
88095	33922974	KDM5C acts as TSG and its deficiency results in genomic instability and aggressive forms of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('genomic instability', 'CPA', (48, 67))	('deficiency', 'Var', (26, 36))	('RCC', 'Disease', (94, 97))	('results in', 'Reg', (37, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('KDM5C', 'Gene', (0, 5))	('KDM5C', 'Gene', '8242', (0, 5))	('aggressive forms', 'CPA', (72, 88))
88096	33922974	Interestingly both KMD6A and KDM5C are considered escape from X-inactivation tumor suppressor or EXIT genes.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('77', '93'))	('KDM5C', 'Gene', (29, 34))	('tumor suppressor', 'Gene', (77, 93))	('KDM5C', 'Gene', '8242', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('KMD6A', 'Var', (19, 24))	('tumor suppressor', 'Gene', '7248', (77, 93))	('tumor suppressor', 'biological_process', 'GO:0051726', ('77', '93'))
88099	33922974	Lysine-specific histone Demethylase 1A (LSD1 or KDM1A) can demethylate both lysine 4 and lysine 9 of histone H3 (H3K4me and H3K9me), thereby acting as a co-activator or a co-repressor, depending on the context.	('KDM1A', 'Gene', (48, 53))	('Lysine-specific histone Demethylase 1A', 'Gene', (0, 38))	('lysine', 'Chemical', 'MESH:D008239', (76, 82))	('Lysine-specific histone Demethylase 1A', 'Gene', '23028', (0, 38))	('demethylate', 'Var', (59, 70))	('LSD1', 'Gene', '23028', (40, 44))	('LSD1', 'Gene', (40, 44))	('KDM1A', 'Gene', '23028', (48, 53))	('lysine', 'Chemical', 'MESH:D008239', (89, 95))	('H3K9me', 'Var', (124, 130))
88105	33922974	However, more recent evidence has confirmed high EZH2 expression correlates with poor overall survival in RCC, especially in advanced disease by promoting VEGF expression and cell proliferation while inhibiting apoptosis.	('EZH2', 'Gene', '2146', (49, 53))	('expression', 'Var', (54, 64))	('EZH2', 'Gene', (49, 53))	('VEGF', 'Gene', '7422', (155, 159))	('cell proliferation', 'biological_process', 'GO:0008283', ('175', '193'))	('overall survival', 'MPA', (86, 102))	('cell proliferation', 'CPA', (175, 193))	('VEGF', 'Gene', (155, 159))	('inhibiting', 'NegReg', (200, 210))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('expression', 'MPA', (160, 170))	('apoptosis', 'CPA', (211, 220))	('high', 'Var', (44, 48))	('promoting', 'PosReg', (145, 154))	('poor', 'NegReg', (81, 85))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('apoptosis', 'biological_process', 'GO:0097194', ('211', '220'))	('apoptosis', 'biological_process', 'GO:0006915', ('211', '220'))
88107	33922974	Mutations in SETD2 and KDM5C are mutually exclusive, as are mutations of PBRM1 and BAP1.	('KDM5C', 'Gene', (23, 28))	('BAP1', 'Gene', (83, 87))	('KDM5C', 'Gene', '8242', (23, 28))	('SETD2', 'Gene', '29072', (13, 18))	('Mutations', 'Var', (0, 9))	('SETD2', 'Gene', (13, 18))	('mutations', 'Var', (60, 69))	('PBRM1', 'Gene', (73, 78))	('BAP1', 'Gene', '8314', (83, 87))
88108	33922974	BAP1 or KDM5C mutations in ccRCC associate with aggressive disease, high Fuhrman grade, and metastatic at presentation (Figure 1), that imply worse prognosis and instantaneous activation of mTOR signaling.	('KDM5C', 'Gene', (8, 13))	('BAP1', 'Gene', (0, 4))	('mTOR', 'Gene', '2475', (190, 194))	('metastatic at presentation', 'CPA', (92, 118))	('KDM5C', 'Gene', '8242', (8, 13))	('associate', 'Reg', (33, 42))	('RCC', 'Disease', (29, 32))	('mTOR', 'Gene', (190, 194))	('BAP1', 'Gene', '8314', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('aggressive disease', 'Disease', 'MESH:D001523', (48, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (27, 32))	('signaling', 'biological_process', 'GO:0023052', ('195', '204'))	('high', 'Disease', (68, 72))	('aggressive disease', 'Disease', (48, 66))	('mutations', 'Var', (14, 23))
88109	33922974	However, mTOR activation in PBRM1 mutated tumors occurs after long latency periods.	('activation', 'PosReg', (14, 24))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mTOR', 'Gene', (9, 13))	('PBRM1', 'Gene', (28, 33))	('mTOR', 'Gene', '2475', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('mutated', 'Var', (34, 41))
88110	33922974	Additionally, the clinical significance of SETD2 and PBRM1 mutations is not well known.	('SETD2', 'Gene', (43, 48))	('SETD2', 'Gene', '29072', (43, 48))	('mutations', 'Var', (59, 68))	('PBRM1', 'Gene', (53, 58))
88111	33922974	miRNAs regulate a wide spectrum of cellular processes acting as oncogene or as tumor suppressors of the genes they regulate.	('cellular', 'CPA', (35, 43))	('tumor suppressor', 'Gene', '7248', (79, 95))	('regulate', 'Reg', (7, 15))	('tumor suppressor', 'Gene', (79, 95))	('miRNAs', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
88129	33922974	MiR-454 inhibition and MECP2 overexpression could both decrease the proliferative, migrative, and invasive abilities of RCC cells and also serve as an independent prognostic factor in RCC.	('MiR-454', 'Gene', (0, 7))	('overexpression', 'PosReg', (29, 43))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('RCC', 'Disease', (184, 187))	('MECP2', 'Gene', (23, 28))	('invasive abilities', 'CPA', (98, 116))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('decrease', 'NegReg', (55, 63))	('migrative', 'CPA', (83, 92))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('MiR-454', 'Gene', '768216', (0, 7))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('inhibition', 'Var', (8, 18))	('proliferative', 'CPA', (68, 81))	('MECP2', 'Gene', '4204', (23, 28))
88140	33922974	The cooperation between DMDRMR and IGF2BP3 regulates target genes in an m6A-dependent manner and may represent a potential diagnostic, prognostic, and likely therapeutic target in ccRCC.	('DMDRMR', 'Gene', (24, 30))	('regulates', 'Reg', (43, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('cooperation', 'Var', (4, 15))	('IGF2BP3', 'Gene', '10643', (35, 42))	('IGF2BP3', 'Gene', (35, 42))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('RCC', 'Disease', (182, 185))
88144	33922974	The N6-methyladenosine (m6A) RNA methylation is the most frequent, abundant, and conserved form of RNA methylation reported both in messenger RNAs and lncRNAs.	('ncRNA', 'Gene', '220202', (152, 157))	('RNA', 'cellular_component', 'GO:0005562', ('99', '102'))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (4, 22))	('RNA methylation', 'biological_process', 'GO:0001510', ('29', '44'))	('N6-methyladenosine', 'Var', (4, 22))	('RNA methylation', 'biological_process', 'GO:0001510', ('99', '114'))	('RNA', 'cellular_component', 'GO:0005562', ('29', '32'))	('ncRNA', 'Gene', (152, 157))
88145	33922974	Other well-characterized RNA modifications are 5-methylcytosine (m5C), N7-methylguanosine (m7G), and pseudo-uridine.	('N7-methylguanosine', 'Var', (71, 89))	('pseudo-uridine', 'Chemical', 'MESH:D011560', (101, 115))	('N7-methylguanosine', 'Chemical', 'MESH:C016578', (71, 89))	('RNA', 'cellular_component', 'GO:0005562', ('25', '28'))	('5-methylcytosine', 'MPA', (47, 63))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (47, 63))	('pseudo-uridine', 'Var', (101, 115))
88153	33922974	This group of proteins include the bromodomain-containing family of proteins that recognize acetylated lysine residues, the chromodomain-containing proteins that bind to methylated histones, and MBDs, mentioned previously, that bind to methylated DNA.	('bind', 'Interaction', (162, 166))	('MBDs', 'Disease', (195, 199))	('MBDs', 'Disease', 'None', (195, 199))	('bind', 'Interaction', (228, 232))	('DNA', 'cellular_component', 'GO:0005574', ('247', '250'))	('histones', 'Protein', (181, 189))	('methylated', 'Var', (236, 246))	('lysine', 'Chemical', 'MESH:D008239', (103, 109))
88162	33922974	So, DNMTi produce passive DNA demethylation and induce the expression of genes that have been silenced by promoter DNA methylation, thus reactivating silenced TSGs in cancer.	('DNA methylation', 'biological_process', 'GO:0006306', ('115', '130'))	('silenced TSGs', 'Disease', 'None', (150, 163))	('silenced TSGs', 'Disease', (150, 163))	('passive DNA demethylation', 'MPA', (18, 43))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('DNA demethylation', 'biological_process', 'GO:0080111', ('26', '43'))	('expression of', 'MPA', (59, 72))	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('induce', 'PosReg', (48, 54))	('cancer', 'Disease', (167, 173))	('DNMTi', 'Var', (4, 9))	('DNA', 'cellular_component', 'GO:0005574', ('115', '118'))	('reactivating', 'PosReg', (137, 149))	('DNMTi', 'Chemical', '-', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
88163	33922974	The exposure of different tumor cells to low doses of DNMTi cause apoptosis, reduced cell cycle activity, and decreased stem cell function.	('apoptosis', 'biological_process', 'GO:0006915', ('66', '75'))	('stem cell function', 'CPA', (120, 138))	('DNMTi', 'Var', (54, 59))	('cell cycle activity', 'CPA', (85, 104))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('cell cycle', 'biological_process', 'GO:0007049', ('85', '95'))	('decreased', 'NegReg', (110, 119))	('DNMTi', 'Chemical', '-', (54, 59))	('reduced', 'NegReg', (77, 84))	('apoptosis', 'CPA', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('apoptosis', 'biological_process', 'GO:0097194', ('66', '75'))
88168	33922974	Epigenetic therapy is a promising potential therapy for solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Epigenetic therapy', 'Var', (0, 18))	('tumors', 'Disease', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))
88169	33922974	Integrative expression and methylation data analysis of 63 cancer cell lines (breast, colorectal, and ovarian) after treatment with the DNMTi azacytidine demonstrated significant enrichment for immunomodulatory pathways.	('methylation', 'biological_process', 'GO:0032259', ('27', '38'))	('ovarian', 'Disease', 'MESH:D010049', (102, 109))	('immunomodulatory', 'Pathway', (194, 210))	('DNMTi', 'Var', (136, 141))	('azacytidine', 'Chemical', 'MESH:D001374', (142, 153))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('DNMTi', 'Chemical', '-', (136, 141))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('colorectal', 'Disease', (86, 96))	('ovarian', 'Disease', (102, 109))
88171	33922974	On the other hand, suppressed cell proliferation (>50% reduction in colony formation assay) with azacytidine therapy was detected, both in cell lines with VHL promoter methylation and also in some RCC cell lines without VHL TSG methylation, thus suggesting that multiple methylated TSGs might determine the response to demethylating therapies.	('VHL', 'Gene', '7428', (155, 158))	('methylation', 'biological_process', 'GO:0032259', ('168', '179'))	('cell proliferation', 'CPA', (30, 48))	('reduction', 'NegReg', (55, 64))	('suppressed', 'NegReg', (19, 29))	('RCC', 'Phenotype', 'HP:0005584', (197, 200))	('formation', 'biological_process', 'GO:0009058', ('75', '84'))	('azacytidine', 'Chemical', 'MESH:D001374', (97, 108))	('RCC', 'Disease', 'MESH:C538614', (197, 200))	('methylation', 'Var', (168, 179))	('RCC', 'Disease', (197, 200))	('VHL', 'Gene', (220, 223))	('VHL', 'Gene', '7428', (220, 223))	('methylation', 'biological_process', 'GO:0032259', ('228', '239'))	('determine', 'Reg', (293, 302))	('VHL', 'Gene', (155, 158))	('cell proliferation', 'biological_process', 'GO:0008283', ('30', '48'))
88180	33922974	Preclinical evidence with the DNMTi decitabine is abundant in renal cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('renal cancer', 'Disease', (62, 74))	('DNMTi', 'Var', (30, 35))	('renal cancer', 'Phenotype', 'HP:0009726', (62, 74))	('DNMTi', 'Chemical', '-', (30, 35))	('renal cancer', 'Disease', 'MESH:D007680', (62, 74))	('decitabine', 'Chemical', 'MESH:D000077209', (36, 46))
88191	33922974	Resistance of RCC to the apoptosis-inducing effects of IFNs was postulated to result from epigenetic silencing of genes by DNA methylation.	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('RCC', 'Disease', (14, 17))	('DNA', 'cellular_component', 'GO:0005574', ('123', '126'))	('epigenetic silencing', 'Var', (90, 110))	('apoptosis', 'biological_process', 'GO:0097194', ('25', '34'))	('apoptosis', 'biological_process', 'GO:0006915', ('25', '34'))	('DNA methylation', 'biological_process', 'GO:0006306', ('123', '138'))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
88193	33922974	The proapoptotic tumor suppressor RASSF1A was reactivated by DNMT1 inhibitors in the cell lines investigated and this was associated with demethylation of its promoter region.	('associated', 'Reg', (122, 132))	('inhibitors', 'Var', (67, 77))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('demethylation', 'biological_process', 'GO:0070988', ('138', '151'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('17', '33'))	('RASSF1A', 'Gene', (34, 41))	('DNMT1', 'Gene', (61, 66))	('tumor suppressor', 'Gene', (17, 33))	('reactivated', 'PosReg', (46, 57))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('17', '33'))	('RASSF1A', 'Gene', '11186', (34, 41))	('DNMT1', 'Gene', '1786', (61, 66))	('demethylation', 'MPA', (138, 151))	('tumor suppressor', 'Gene', '7248', (17, 33))
88194	33922974	The combination of anticancer agents and epigenetic drugs sustains a novel therapeutic strategy.	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('epigenetic drugs', 'Var', (41, 57))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))
88198	33922974	Another inhibitor of DNMT, the antisense oligodeoxynucleotide MG98 was intravenously administered at a dose of 360 mg/m2 twice weekly for three consecutive weeks out of four in 17 patients with advanced RCC receiving a median of two cycles with no objective responses.	('RCC', 'Phenotype', 'HP:0005584', (203, 206))	('MG98', 'Chemical', '-', (62, 66))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (41, 61))	('DNMT', 'Gene', '1786', (21, 25))	('MG98', 'Var', (62, 66))	('DNMT', 'Gene', (21, 25))	('RCC', 'Disease', 'MESH:C538614', (203, 206))	('RCC', 'Disease', (203, 206))	('patients', 'Species', '9606', (180, 188))
88201	33922974	Another phase-II trial explored two schedules of MG98 with IFNalpha2b and described frequent disease stabilization and partial response in one case.	('MG98', 'Chemical', '-', (49, 53))	('IFNalpha2b', 'Gene', '3440', (59, 69))	('IFNalpha2b', 'Gene', (59, 69))	('MG98', 'Var', (49, 53))	('disease stabilization', 'CPA', (93, 114))
88263	33922974	The strategies investigated include silence miRNAs that are overexpressed, such as, for example anti-mRNA oligonucleotides, miRNA-mask antisense oligonucleotides, and miRNA sponges to restore the expression of miRNAs that are downregulated.	('oligonucleotides', 'Chemical', 'MESH:D009841', (145, 161))	('expression', 'MPA', (196, 206))	('antisense', 'Var', (135, 144))	('oligonucleotides', 'Chemical', 'MESH:D009841', (106, 122))
88266	33922974	Oblimersen (G3139) is a phosphorothioate antisense oligonucleotide used for chronic lymphocytic leukemia and for advanced melanoma.	('G3139', 'Var', (12, 17))	('leukemia', 'Phenotype', 'HP:0001909', (96, 104))	('oligonucleotide', 'Chemical', 'MESH:D009841', (51, 66))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (76, 104))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (84, 104))	('lymphocytic leukemia', 'Disease', (84, 104))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('phosphorothioate', 'Chemical', '-', (24, 40))
88277	33922974	As a result, inhibitors of EZH2 and consequently H3K27 methylation remain a very interesting opportunity to develop future RCC therapies.	('H3K27', 'Protein', (49, 54))	('EZH2', 'Gene', (27, 31))	('EZH2', 'Gene', '2146', (27, 31))	('inhibitors', 'Var', (13, 23))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))
88278	33922974	For example, loss of SETD2 becomes synthetically lethal with loss of mitotic inhibitor protein kinase Wee1, loss of BAP1 is synthetically lethal with simultaneous inhibition of EZH2 or PRC2, and a third mechanism is loss of PBRM1, ARID1A, and some components of the SWI/SNF complex, together with inhibition of EZH2.	('SETD2', 'Gene', '29072', (21, 26))	('loss', 'NegReg', (61, 65))	('loss', 'Var', (13, 17))	('EZH2', 'Gene', '2146', (177, 181))	('EZH2', 'Gene', (177, 181))	('EZH2', 'Gene', '2146', (311, 315))	('EZH2', 'Gene', (311, 315))	('loss', 'Var', (108, 112))	('loss', 'NegReg', (216, 220))	('PBRM1', 'Gene', (224, 229))	('BAP1', 'Gene', '8314', (116, 120))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('ARID1A', 'Gene', (231, 237))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('266', '281'))	('ARID1A', 'Gene', '8289', (231, 237))	('Wee1', 'Gene', (102, 106))	('BAP1', 'Gene', (116, 120))	('SETD2', 'Gene', (21, 26))	('Wee1', 'Gene', '7465', (102, 106))
88281	33922974	Targeting the epigenome appears an attractive treatment option for RCC because the epigenetic dysregulation of this neoplasia is very extensive and affects many different signaling pathways and tumor hallmarks.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('signaling', 'biological_process', 'GO:0023052', ('171', '180'))	('RCC', 'Disease', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('neoplasia', 'Disease', (116, 125))	('tumor hallmarks', 'Disease', 'MESH:D009369', (194, 209))	('tumor hallmarks', 'Disease', (194, 209))	('epigenetic dysregulation', 'Var', (83, 107))	('neoplasia', 'Phenotype', 'HP:0002664', (116, 125))	('neoplasia', 'Disease', 'MESH:D009369', (116, 125))	('affects', 'Reg', (148, 155))
88282	33922974	The most important limitation is the lack of selectivity because epigenetic events are ubiquitously distributed across normal and cancer cells.	('cancer', 'Disease', (130, 136))	('epigenetic events', 'Var', (65, 82))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
88286	33922974	In fact, results of epigenetic therapy in hematologic malignancies are impressive, but not in solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('hematologic malignancies', 'Disease', (42, 66))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('epigenetic therapy', 'Var', (20, 38))	('hematologic malignancies', 'Disease', 'MESH:D019337', (42, 66))
88290	33922974	These findings suggest that new therapeutic strategies targeting gene dosage and epigenetic modification should be considered for improved personalized cancer medicine.	('epigenetic modification', 'Var', (81, 104))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
88294	33922974	It would be desirable that epigenetics-based treatments could re-sensitize the host immune response to immunotherapies and restore immunogenicity enforcing the expression of tumor associated antigens, checkpoint ligands in tumor cells, and antigen-processing machinery components.	('tumor', 'Disease', (174, 179))	('expression', 'MPA', (160, 170))	('immune response', 'biological_process', 'GO:0006955', ('84', '99'))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('restore', 'PosReg', (123, 130))	('antigen-processing', 'biological_process', 'GO:0019882', ('240', '258'))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('immunogenicity', 'MPA', (131, 145))	('epigenetics-based', 'Var', (27, 44))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
88296	33922974	PBRM1 deficient RenCa subcutaneous tumors in mice are more resistant to ICI, and a retrospective analysis of the IMmotion150 trial also suggests that PBRM1 mutation reduces benefit from immune checkpoint blockade.	('immune checkpoint blockade', 'MPA', (186, 212))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (22, 41))	('PBRM1', 'Gene', (150, 155))	('reduces', 'NegReg', (165, 172))	('deficient RenCa subcutaneous tumors', 'Disease', 'MESH:D013352', (6, 41))	('mice', 'Species', '10090', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('PBRM1', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('deficient RenCa subcutaneous tumors', 'Disease', (6, 41))	('mutation', 'Var', (156, 164))
88297	33922974	Nevertheless, the role of PBRM1 mutations in ccRCC in relation to the immune microenvironment is not totally clear.	('PBRM1', 'Gene', (26, 31))	('mutations', 'Var', (32, 41))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))
88299	33922974	Recent studies show truncating mutations in PBRM1 increase the clinical benefit of ICI therapy in patients with metastatic ccRCC.	('PBRM1', 'Gene', (44, 49))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('truncating mutations', 'Var', (20, 40))	('patients', 'Species', '9606', (98, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('increase', 'PosReg', (50, 58))	('clinical benefit', 'MPA', (63, 79))
88300	33922974	PBRM1 alterations have also been clinically validated as marker of ICI responsiveness in RCC but the effect on response and survival is modest and has been mainly observed in the subset of patients who received prior antiangiogenic therapy.	('alterations', 'Var', (6, 17))	('PBRM1', 'Gene', (0, 5))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('patients', 'Species', '9606', (189, 197))
88302	33922974	So, epigenetic treatments, via several signaling mechanisms involving both tumor cells and host immune cells, might enhance the efficacy of immune checkpoint therapy in RCC.	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('enhance', 'PosReg', (116, 123))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('RCC', 'Disease', (169, 172))	('epigenetic treatments', 'Var', (4, 25))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('signaling', 'biological_process', 'GO:0023052', ('39', '48'))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('efficacy', 'MPA', (128, 136))	('tumor', 'Disease', (75, 80))
88303	33922974	Additionally, genetic alterations in histone modifier genes in RCC could not only be responsible for the pathogenesis of the disease but also represent potential biomarkers of response to immunotherapies.	('RCC', 'Disease', (63, 66))	('genetic alterations', 'Var', (14, 33))	('responsible', 'Reg', (85, 96))	('pathogenesis', 'biological_process', 'GO:0009405', ('105', '117'))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
88304	33922974	In this sense, despite the initial failure of epigenetic treatments to reach the clinic, epigenetic therapy is currently a promising strategy for anticancer treatment and for development of new ccRCC tumor markers.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('new ccRCC tumor', 'Disease', 'MESH:C000657245', (190, 205))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('new ccRCC tumor', 'Disease', (190, 205))	('epigenetic therapy', 'Var', (89, 107))	('RCC', 'Phenotype', 'HP:0005584', (196, 199))	('ccRCC', 'Phenotype', 'HP:0006770', (194, 199))
88305	33922974	Epigenetic studies have provided a large body of evidence regarding hypermethylated genes, histone-modifying enzymes or miRNAs and new challenges at bench side of patients with RCC.	('patients', 'Species', '9606', (163, 171))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('RCC', 'Disease', (177, 180))	('RCC', 'Phenotype', 'HP:0005584', (177, 180))	('hypermethylated genes', 'Var', (68, 89))
88307	33922974	Additionally, early clinical trials have been conducted to evaluate epigenetic therapies for RCC, either alone or in combination with other therapies including IFN-alpha2b, IL-2, anti-VEGF, TKIs, and mTOR inhibitors.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Disease', (93, 96))	('mTOR', 'Gene', (200, 204))	('IFN-alpha2b', 'Gene', (160, 171))	('VEGF', 'Gene', (184, 188))	('mTOR', 'Gene', '2475', (200, 204))	('IL-2', 'molecular_function', 'GO:0005134', ('173', '177'))	('VEGF', 'Gene', '7422', (184, 188))	('IL-2', 'Gene', (173, 177))	('IL-2', 'Gene', '3558', (173, 177))	('epigenetic therapies', 'Var', (68, 88))	('IFN-alpha2b', 'Gene', '3440', (160, 171))
88330	32335374	However, more grade 3 and 4 AEs occurred in patients assigned combination therapy than those received monotherapy.	('combination', 'Var', (62, 73))	('patients', 'Species', '9606', (44, 52))	('grade 3', 'Disease', (14, 21))
88339	32335374	Alt-text: Unlabelled box Renal cell carcinoma (RCC) is the most common form of kidney cancer, in which clear cell RCC (ccRCC) accounts for 70-75% of all RCC cases, and associated with alterations in the von Hippel-Lindau (VHL) gene.	('associated', 'Reg', (168, 178))	('Renal cell carcinoma', 'Disease', 'MESH:C538614', (25, 45))	('VHL', 'Gene', (222, 225))	('Renal cell carcinoma', 'Phenotype', 'HP:0005584', (25, 45))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('kidney cancer', 'Disease', 'MESH:D007680', (79, 92))	('Alt', 'molecular_function', 'GO:0004021', ('0', '3'))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('von Hippel-Lindau', 'Gene', (203, 220))	('VHL', 'Gene', '7428', (222, 225))	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('kidney cancer', 'Phenotype', 'HP:0009726', (79, 92))	('RCC', 'Disease', (121, 124))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('alterations', 'Var', (184, 195))	('kidney cancer', 'Disease', (79, 92))	('RCC', 'Disease', (153, 156))	('von Hippel-Lindau', 'Gene', '7428', (203, 220))	('Renal cell carcinoma', 'Disease', (25, 45))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))
88341	32335374	The VHL inactivation and VEGF overexpression have been demonstrated to correlate with tumor aggressiveness and poor survival in RCC.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('RCC', 'Disease', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('tumor aggressiveness', 'Disease', (86, 106))	('aggressiveness', 'Phenotype', 'HP:0000718', (92, 106))	('VEGF', 'Gene', '7422', (25, 29))	('overexpression', 'PosReg', (30, 44))	('inactivation', 'Var', (8, 20))	('VHL', 'Gene', (4, 7))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (86, 106))	('VHL', 'Gene', '7428', (4, 7))	('VEGF', 'Gene', (25, 29))
88354	32335374	Intolerable toxicities were seen in several phase I studies evaluating combination of temsirolimus/everolimus and sunitinib or temsirolimus and sorafenib, respectively, while everolimus plus sorafenib showed favorable toxicity profile and preliminary antitumor activity.	('toxicity', 'Disease', (218, 226))	('temsirolimus', 'Var', (127, 139))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('combination', 'Interaction', (71, 82))	('tumor', 'Disease', (255, 260))	('temsirolimus', 'Chemical', 'MESH:C401859', (86, 98))	('toxicities', 'Disease', (12, 22))	('sorafenib', 'Chemical', 'MESH:D000077157', (191, 200))	('sunitinib', 'Chemical', 'MESH:D000077210', (114, 123))	('everolimus', 'Chemical', 'MESH:D000068338', (99, 109))	('everolimus', 'Chemical', 'MESH:D000068338', (175, 185))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('temsirolimus', 'Chemical', 'MESH:C401859', (127, 139))	('sorafenib', 'Chemical', 'MESH:D000077157', (144, 153))	('toxicity', 'Disease', 'MESH:D064420', (218, 226))	('toxicities', 'Disease', 'MESH:D064420', (12, 22))
88372	32335374	Additionally, eligible patients were required to have adequate hematologic, hepatic, and renal function (hemoglobin >=9.0 g/dL, ALT/AST <=1.5 x ULN or <=5 x ULN when having liver metastases, total bilirubin <=1.5 x ULN, and serum creatinine <=1.5 x ULN); and measurable disease according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1, and should not have received any chemotherapy, radiotherapy, biotherapy or endocrine therapy within 4 weeks before study treatment.	('liver', 'Disease', (173, 178))	('ALT', 'molecular_function', 'GO:0004021', ('128', '131'))	('Tumor', 'Phenotype', 'HP:0002664', (329, 334))	('creatinine', 'Chemical', 'MESH:D003404', (230, 240))	('patients', 'Species', '9606', (23, 31))	('hemoglobin', 'Var', (105, 115))	('AST', 'Gene', (132, 135))	('men', 'Species', '9606', (483, 486))	('metastases', 'Disease', (179, 189))	('AST', 'Gene', '26503', (132, 135))	('metastases', 'Disease', 'MESH:D009362', (179, 189))
88433	32335374	Since VHL mutations and the activation of VEGF and PDGF have been discovered, the treatment of advanced renal cell carcinoma (RCC) has undergone a major change with the development of potent angiogenesis inhibitors and targeted agents, including sorafenib, sunitinib, pazopanib, axitinib, everolimus, and tersirolimus.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (104, 124))	('VHL', 'Gene', (6, 9))	('angiogenesis', 'biological_process', 'GO:0001525', ('191', '203'))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('everolimus', 'Chemical', 'MESH:D000068338', (289, 299))	('men', 'Species', '9606', (176, 179))	('VEGF', 'Gene', '7422', (42, 46))	('VHL', 'Gene', '7428', (6, 9))	('PDGF', 'molecular_function', 'GO:0005161', ('51', '55'))	('renal cell carcinoma', 'Disease', (104, 124))	('VEGF', 'Gene', (42, 46))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (104, 124))	('tersirolimus', 'Chemical', '-', (305, 317))	('men', 'Species', '9606', (87, 90))	('axitinib', 'Chemical', 'MESH:D000077784', (279, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('sunitinib', 'Chemical', 'MESH:D000077210', (257, 266))	('pazopanib', 'Chemical', 'MESH:C516667', (268, 277))	('sorafenib', 'Chemical', 'MESH:D000077157', (246, 255))	('mutations', 'Var', (10, 19))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))
88464	32335374	Besides, we hypothesized that inhibition of TKI and downstream mTOR modulation may induce off-target effects, leading to the increased toxicity, which limited clinical application of combination of effective regimens.	('mTOR', 'Gene', (63, 67))	('increased', 'PosReg', (125, 134))	('inhibition', 'Var', (30, 40))	('induce', 'Reg', (83, 89))	('off-target effects', 'MPA', (90, 108))	('toxicity', 'Disease', 'MESH:D064420', (135, 143))	('toxicity', 'Disease', (135, 143))	('mTOR', 'Gene', '2475', (63, 67))	('TKI', 'Gene', (44, 47))	('men', 'Species', '9606', (212, 215))
88470	32335374	To balance the clinical benefit with the toxicity, antiangiogenic TKIs at safe dose in combination with low dose of everolimus were expected to enhance antitumor activity with tolerated toxicities.	('enhance', 'PosReg', (144, 151))	('toxicity', 'Disease', 'MESH:D064420', (41, 49))	('toxicity', 'Disease', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('antiangiogenic', 'Var', (51, 65))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tolerated toxicities', 'Disease', (176, 196))	('everolimus', 'Chemical', 'MESH:D000068338', (116, 126))	('tumor', 'Disease', (156, 161))	('tolerated toxicities', 'Disease', 'MESH:D018149', (176, 196))
88473	32335374	However, grade 3 and 4 AEs occurred in more patients allocated lenvatinib plus everolimus compared with those assigned single-agent everolimus (10 mg/day), with diarrhea, fatigue or asthenia, hypertension being the most common.	('diarrhea', 'Phenotype', 'HP:0002014', (161, 169))	('lenvatinib', 'Chemical', 'MESH:C531958', (63, 73))	('fatigue', 'Phenotype', 'HP:0012378', (171, 178))	('diarrhea', 'Disease', (161, 169))	('patients', 'Species', '9606', (44, 52))	('diarrhea', 'Disease', 'MESH:D003967', (161, 169))	('hypertension', 'Disease', (192, 204))	('everolimus', 'Chemical', 'MESH:D000068338', (132, 142))	('AEs', 'Disease', (23, 26))	('hypertension', 'Phenotype', 'HP:0000822', (192, 204))	('asthenia', 'Disease', 'MESH:D001247', (182, 190))	('lenvatinib', 'Var', (63, 73))	('fatigue', 'Disease', 'MESH:D005221', (171, 178))	('asthenia', 'Disease', (182, 190))	('everolimus', 'Chemical', 'MESH:D000068338', (79, 89))	('asthenia', 'Phenotype', 'HP:0025406', (182, 190))	('hypertension', 'Disease', 'MESH:D006973', (192, 204))	('fatigue', 'Disease', (171, 178))
88485	31043488	Expression of the receptor tyrosine kinase Ret was elevated in the kidneys of the TFE3-RCC mice, and treatment with RET inhibitor vandetanib significantly suppressed RCC growth.	('mice', 'Species', '10090', (91, 95))	('RCC growth', 'CPA', (166, 176))	('Ret', 'Gene', (43, 46))	('Ret', 'Gene', '19713', (43, 46))	('vandetanib', 'Chemical', 'MESH:C452423', (130, 140))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('Expression', 'MPA', (0, 10))	('suppressed', 'NegReg', (155, 165))	('elevated', 'PosReg', (51, 59))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))	('TFE3-RCC', 'Var', (82, 90))	('men', 'Species', '9606', (106, 109))
88486	31043488	Moreover, we found that Gpnmb (Glycoprotein nonmetastatic B) expression was notably elevated in the TFE3-RCC mouse kidneys as seen in human TFE3-RCC tumors, and confirmed that GPNMB is the direct transcriptional target of TFE3 fusions.	('TFE3-RCC tumors', 'Disease', (140, 155))	('human', 'Species', '9606', (134, 139))	('TFE3-RCC', 'Var', (100, 108))	('Gpnmb', 'Gene', (24, 29))	('elevated', 'PosReg', (84, 92))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('TFE3-RCC tumors', 'Disease', 'MESH:C538614', (140, 155))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('Glycoprotein nonmetastatic B', 'Gene', '93695', (31, 59))	('Glycoprotein nonmetastatic B', 'Gene', (31, 59))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('expression', 'MPA', (61, 71))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('mouse', 'Species', '10090', (109, 114))
88490	31043488	TFE3 Xp11.2 translocation RCC (TFE3-RCC) was defined as an independent subtype of RCC by WHO in 2004 and is characterized by distinctive morphological features and Xp11.2 rearrangements that create TFE3 gene fusions with a variety of partner genes (PRCC, SFPQ, ASPSCR, CLTC, NONO, RBM10, PARP14, LUC7L3, KHSRP etc.)	('CLTC', 'Gene', (269, 273))	('PARP14', 'Gene', '547253', (288, 294))	('PARP14', 'Gene', (288, 294))	('Xp11', 'Gene', '111712', (164, 168))	('RCC', 'Phenotype', 'HP:0005584', (250, 253))	('Xp11', 'Gene', (5, 9))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('Xp11', 'Gene', (164, 168))	('RBM10', 'Gene', (281, 286))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('RBM10', 'Gene', '236732', (281, 286))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('CLTC', 'Gene', '67300', (269, 273))	('KHSRP', 'Gene', '16549', (304, 309))	('TFE3', 'Gene', (198, 202))	('LUC7L3', 'Gene', '67684', (296, 302))	('fusions', 'Var', (208, 215))	('LUC7L3', 'Gene', (296, 302))	('men', 'Species', '9606', (180, 183))	('Xp11', 'Gene', '111712', (5, 9))	('KHSRP', 'Gene', (304, 309))
88498	31043488	We determined that GPNMB (glycoprotein nonmetastatic B) is directly transcribed and upregulated by chimeric TFE3 and performed GPNMB immunohistochemical staining in human TFE3-RCCs to investigate its potential in the diagnosis of this form of RCC.	('upregulated', 'PosReg', (84, 95))	('human', 'Species', '9606', (165, 170))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('RCC', 'Disease', (243, 246))	('chimeric', 'Var', (99, 107))	('RCC', 'Phenotype', 'HP:0005584', (243, 246))	('glycoprotein nonmetastatic B', 'Gene', '93695', (26, 54))	('TFE3', 'Gene', (108, 112))	('GPNMB', 'Gene', (19, 24))	('glycoprotein nonmetastatic B', 'Gene', (26, 54))
88521	31043488	UOK111, UOK115 and UOK140 are cell lines derived from ccRCC tumors with VHL gene mutations that were established in the UOB, NCI.	('VHL', 'Gene', '7428', (72, 75))	('ccRCC tumors', 'Disease', (54, 66))	('UOK115', 'CellLine', 'CVCL:B094', (8, 14))	('UOK111', 'CellLine', 'CVCL:B090', (0, 6))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mutations', 'Var', (81, 90))	('ccRCC tumors', 'Disease', 'MESH:D009369', (54, 66))	('VHL', 'Gene', (72, 75))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
88529	31043488	The Cancer Genome Atlas (TCGA) dataset was used to validate candidate transcriptional target genes of chimeric TFE3, which were identified by RNAseq analysis.	('TFE3', 'Gene', (111, 115))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('chimeric', 'Var', (102, 110))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
88547	31043488	If a yellow signal was observed in 30% or more of 100 counted cells, the tumor was defined as harboring SFPQ-TFE3.	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('SFPQ-TFE3', 'Var', (104, 113))
88596	31043488	We transfected reporter plasmids carrying wild type or mutant M-box motifs into doxycycline-inducible PRCC-TFE3 expressing HEK293 cells (Fig.3e).	('PRCC-TFE3', 'Gene', (102, 111))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('doxycycline', 'Chemical', 'MESH:D004318', (80, 91))	('HEK293', 'CellLine', 'CVCL:0045', (123, 129))	('M-box', 'Gene', (62, 67))	('mutant', 'Var', (55, 61))	('PRCC-TFE3', 'Gene', '94315;209446', (102, 111))
88598	31043488	Importantly, this PRCC-TFE3 dependent GPNMB promoter activity was attenuated in cells transfected with mutated M-box1 or M-box2 reporter plasmids.	('mutated', 'Var', (103, 110))	('GPNMB', 'Gene', (38, 43))	('PRCC-TFE3', 'Gene', '94315;209446', (18, 27))	('attenuated', 'NegReg', (66, 76))	('PRCC-TFE3', 'Gene', (18, 27))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))
88599	31043488	Furthermore, complete absence of PRCC-TFE3 dependent promoter activity was seen in cells transfected with a reporter plasmid in which both M-box1 and M-box2 were mutated (Fig.3f).	('absence', 'NegReg', (22, 29))	('mutated', 'Var', (162, 169))	('PRCC-TFE3', 'Gene', '94315;209446', (33, 42))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('PRCC-TFE3', 'Gene', (33, 42))
88609	31043488	4d, while GPNMB expression levels were statistically significantly higher (p<0.0001) in TFE3-RCC than in either papillary type 1 RCC, papillary type 2 RCC (p<0.0001) or total papillary RCC (p<0.0001), there were no statistically significant differences in Cathepsin K expression between TFE3-RCC and either papillary type 1 RCC, papillary type 2 RCC or total papillary RCC.	('papillary RCC', 'Disease', 'MESH:C538614', (175, 188))	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('papillary RCC', 'Disease', (175, 188))	('higher', 'PosReg', (67, 73))	('expression', 'MPA', (268, 278))	('papillary RCC', 'Disease', 'MESH:C538614', (359, 372))	('Cathepsin K', 'Gene', (256, 267))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('TFE3-RCC', 'Var', (88, 96))	('GPNMB expression levels', 'MPA', (10, 33))	('papillary RCC', 'Disease', (359, 372))	('Cathepsin K', 'Gene', '13038', (256, 267))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('RCC', 'Phenotype', 'HP:0005584', (292, 295))
88615	31043488	Interestingly, the 4 cases from a total of 76 clear cell and papillary RCC that were positive for GPNMB were also positive for nuclear TFE3 staining, which suggests that GPNMB positivity is the consequence of TFE3 activation by an unknown mechanism other than Xp11.2 translocation.	('Xp11', 'Gene', '111712', (260, 264))	('papillary RCC', 'Disease', (61, 74))	('activation', 'PosReg', (214, 224))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('positivity', 'Var', (176, 186))	('positive', 'Reg', (114, 122))	('TFE3', 'Gene', (209, 213))	('Xp11', 'Gene', (260, 264))	('GPNMB', 'Gene', (170, 175))	('papillary RCC', 'Disease', 'MESH:C538614', (61, 74))
88621	31043488	Results from the evaluation of our PRCC-TFE3-expressing mouse model have confirmed that chimeric PRCC-TFE3 is an oncogene which is responsible for RCC development in vivo.	('PRCC-TFE3', 'Gene', '94315;209446', (35, 44))	('PRCC-TFE3', 'Gene', '94315;209446', (97, 106))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('mouse', 'Species', '10090', (56, 61))	('chimeric', 'Var', (88, 96))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('PRCC-TFE3', 'Gene', (35, 44))	('RCC', 'Disease', (147, 150))	('PRCC-TFE3', 'Gene', (97, 106))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('men', 'Species', '9606', (158, 161))
88623	31043488	Indeed, overexpressed PRCC-TFE3 and SFPQ-TFE3 (data not shown) demonstrated predominant nuclear localization, while overexpressed wild-type TFE3 localized in the cytoplasm of HEK 293 cells.	('PRCC-TFE3', 'Gene', (22, 31))	('SFPQ-TFE3', 'Var', (36, 45))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('localization', 'biological_process', 'GO:0051179', ('96', '108'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('162', '171'))	('nuclear localization', 'MPA', (88, 108))	('PRCC-TFE3', 'Gene', '94315;209446', (22, 31))	('HEK 293', 'CellLine', 'CVCL:0045', (175, 182))
88631	31043488	It will be of great importance to clarify the details of the transcriptional network, including Nr4a1, perturbed by chimeric TFE3.	('TFE3', 'Gene', (125, 129))	('chimeric', 'Var', (116, 124))	('Nr4a1', 'Gene', (96, 101))	('Nr4a1', 'Gene', '15370', (96, 101))	('perturbed', 'Reg', (103, 112))
88645	31043488	Identification and characterization of additional TFE3-RCC driver gene mutations will contribute to a better understanding of the causes of TFE3-RCC heterogeneity and facilitate the development of effective targeted therapeutics.	('men', 'Species', '9606', (189, 192))	('mutations', 'Var', (71, 80))	('TFE3-RCC', 'Gene', (50, 58))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))
88646	31043488	This PRCC-TFE3 mouse model can be utilized in future studies to evaluate potential driver gene mutations by crossing with genetically engineered mice for selective gene deletion.	('PRCC-TFE3', 'Gene', '94315;209446', (5, 14))	('mouse', 'Species', '10090', (15, 20))	('mutations', 'Var', (95, 104))	('mice', 'Species', '10090', (145, 149))	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('PRCC-TFE3', 'Gene', (5, 14))
88647	31043488	Since the chimeric TFE3 proteins responsible for TFE3-RCC development act as oncogenic transcription factors, transcriptionally upregulated direct targets of chimeric TFE3 could be promising candidates for TFE3-RCC diagnostic markers.	('TFE3', 'Gene', (19, 23))	('men', 'Species', '9606', (65, 68))	('RCC', 'Phenotype', 'HP:0005584', (211, 214))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('chimeric', 'Var', (158, 166))	('transcription', 'biological_process', 'GO:0006351', ('87', '100'))
88692	33759378	We hypothesized that alterations in gene expression profiles during the evolutionary process of tumour metastasis affect the phenotype of metastatic cancer cells, resulting in the activation of distinct signalling pathways and drug resistance to specific treatments.	('tumour metastasis', 'Disease', 'MESH:D009362', (96, 113))	('phenotype', 'MPA', (125, 134))	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('signalling', 'biological_process', 'GO:0023052', ('203', '213'))	('drug resistance', 'CPA', (227, 242))	('drug resistance', 'Phenotype', 'HP:0020174', (227, 242))	('metastatic', 'CPA', (138, 148))	('affect', 'Reg', (114, 120))	('tumour metastasis', 'Disease', (96, 113))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('gene expression', 'biological_process', 'GO:0010467', ('36', '51'))	('drug resistance', 'biological_process', 'GO:0009315', ('227', '242'))	('signalling pathways', 'Pathway', (203, 222))	('drug resistance', 'biological_process', 'GO:0042493', ('227', '242'))	('alterations', 'Var', (21, 32))	('activation', 'PosReg', (180, 190))
88712	33759378	The TMAs were then incubated at room temperature with secondary antibodies (ab97080, goat anti-rabbit, 1:2000; ab97040, goat anti-mouse, 1:500; Abcam) for 20 minutes and horseradish peroxidase-labelled Streptase ovalbumin for 20 minutes, and DAB was used for colour development and counterstained with haematoxylin.	('horseradish', 'Species', '3704', (170, 181))	('ab97080', 'Var', (76, 83))	('ab97040', 'Var', (111, 118))	('haematoxylin', 'Chemical', 'MESH:D006416', (302, 314))	('DAB', 'Chemical', 'MESH:C000469', (242, 245))
88730	33759378	The dysregulation of these sub-dif markers may trigger cell cycle dysfunction and cell proliferation, differentiation and apoptosis pathways, thus inducing tumour cell metastasis, which is in accordance with another independent group's publication.	('inducing', 'Reg', (147, 155))	('apoptosis', 'biological_process', 'GO:0097194', ('122', '131'))	('cell cycle', 'biological_process', 'GO:0007049', ('55', '65'))	('cell cycle dysfunction', 'Phenotype', 'HP:0011018', (55, 77))	('cell proliferation', 'biological_process', 'GO:0008283', ('82', '100'))	('tumour', 'Disease', (156, 162))	('cell cycle dysfunction', 'CPA', (55, 77))	('dysregulation', 'Var', (4, 17))	('apoptosis', 'CPA', (122, 131))	('cell proliferation', 'CPA', (82, 100))	('apoptosis', 'biological_process', 'GO:0006915', ('122', '131'))	('trigger', 'Reg', (47, 54))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('differentiation', 'CPA', (102, 117))
88734	33759378	Specifically, 0.12% of the total patient series harboured only the IL6 amplification mutation, whereas 0.25% of the patients harboured the CASP3 deletion mutation (Figure 6).	('patient', 'Species', '9606', (33, 40))	('patient', 'Species', '9606', (116, 123))	('patients', 'Species', '9606', (116, 124))	('IL6', 'Gene', '3569', (67, 70))	('deletion mutation', 'Var', (145, 162))	('CASP3', 'Gene', '836', (139, 144))	('CASP3', 'Gene', (139, 144))	('IL6', 'molecular_function', 'GO:0005138', ('67', '70'))	('IL6', 'Gene', (67, 70))
88806	33681201	CPT1A can promote the proliferation of breast cancer cells by succinylation of enolase 1 and enhance metastasis of gastric cancer (GC) cells by succinylation of S100A10.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('CPT1A', 'Gene', (0, 5))	('succinyl', 'Chemical', '-', (144, 152))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('S100A10', 'Gene', '6281', (161, 168))	('enolase 1', 'Gene', '2023', (79, 88))	('promote', 'PosReg', (10, 17))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('enolase 1', 'Gene', (79, 88))	('breast cancer', 'Disease', (39, 52))	('succinyl', 'Chemical', '-', (62, 70))	('enhance', 'PosReg', (93, 100))	('CPT', 'molecular_function', 'GO:0004142', ('0', '3'))	('proliferation', 'CPA', (22, 35))	('GC', 'Phenotype', 'HP:0012126', (131, 133))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('succinylation', 'MPA', (62, 75))	('metastasis of gastric cancer', 'Disease', (101, 129))	('succinylation', 'Var', (144, 157))	('CPT1A', 'Gene', '1374', (0, 5))	('metastasis of gastric cancer', 'Disease', 'MESH:D013274', (101, 129))	('S100A10', 'Gene', (161, 168))	('CPT', 'molecular_function', 'GO:0004095', ('0', '3'))
88815	33681201	Compared to acetylation, succinylation can cause larger mass changes in substrate proteins due to the higher molecular weight of succinyl and can also have a greater effect on the charge of lysine residues from +1 to -1, resulting in more significant influences on the structure and function of target proteins.	('succinyl', 'Chemical', '-', (25, 33))	('lysine', 'Chemical', 'MESH:D008239', (190, 196))	('mass changes', 'MPA', (56, 68))	('influences', 'Reg', (251, 261))	('higher', 'PosReg', (102, 108))	('succinylation', 'Var', (25, 38))	('charge', 'MPA', (180, 186))	('effect', 'Reg', (166, 172))	('structure', 'MPA', (269, 278))	('molecular weight', 'MPA', (109, 125))	('function', 'MPA', (283, 291))	('succinyl', 'Chemical', '-', (129, 137))
88817	33681201	For example, succinylation of S100A10 or GLS can increase the stability of these proteins by antagonizing ubiquitination and proteasome-dependent degradation.	('ubiquitination', 'MPA', (106, 120))	('increase', 'PosReg', (49, 57))	('degradation', 'biological_process', 'GO:0009056', ('146', '157'))	('stability', 'MPA', (62, 71))	('S100A10', 'Gene', '6281', (30, 37))	('succinylation', 'Var', (13, 26))	('proteasome', 'molecular_function', 'GO:0004299', ('125', '135'))	('proteasome', 'cellular_component', 'GO:0000502', ('125', '135'))	('S100A10', 'Gene', (30, 37))	('GLS', 'Gene', '2744', (41, 44))	('antagonizing', 'NegReg', (93, 105))	('GLS', 'Gene', (41, 44))	('proteasome-dependent degradation', 'MPA', (125, 157))	('succinyl', 'Chemical', '-', (13, 21))
88854	33681201	However, univariate Cox regression analysis showed that the overall survival (OS) of patients with KIRC (also named ccRCC), but not other tumor types, was associated with all four regulators (P < 0.05) (Figure 1B and Supplementary Table S4).	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('RCC', 'Disease', (118, 121))	('tumor', 'Disease', (138, 143))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('Cox', 'Gene', '1351', (20, 23))	('Cox', 'Gene', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('patients', 'Species', '9606', (85, 93))	('associated', 'Interaction', (155, 165))	('KIRC', 'Var', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
88874	33681201	Interestingly, we found that most of the up-regulated pathways were related to immune regulation and part of the pathways overlapped between clusters 1 and 2, suggesting that succinylation regulators might promote the ccRCC by regulating immune pathways (Figures 4B,E).	('succinyl', 'Chemical', '-', (175, 183))	('ccRCC', 'Phenotype', 'HP:0006770', (218, 223))	('succinylation', 'Var', (175, 188))	('immune pathways', 'Pathway', (238, 253))	('regulation', 'biological_process', 'GO:0065007', ('86', '96'))	('regulating', 'Reg', (227, 237))	('promote', 'PosReg', (206, 213))	('RCC', 'Phenotype', 'HP:0005584', (220, 223))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('RCC', 'Disease', (220, 223))
88879	33681201	Kaplan-Meier analysis indicated that infiltration of Tregs was associated with the poor prognosis of OS (HR = 1.820, 95%CI = 1.140-2.906, P = 0.011) and infiltration of resting mast cells was associated with longer OS (HR = 0.462, 95%CI = 0.286-0.747, P = 0.001).	('longer OS', 'Disease', (208, 217))	('infiltration', 'Var', (37, 49))	('Tregs', 'Chemical', '-', (53, 58))	('infiltration', 'Var', (153, 165))
88892	33681201	N6-methyladenosine (m6A) methylation, one of the most common RNA-related modifications, is catalyzed by m6A regulators.	('RNA', 'cellular_component', 'GO:0005562', ('61', '64'))	('m6A', 'Gene', '56339', (20, 23))	('m6A', 'Gene', '56339', (104, 107))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('N6-methyladenosine', 'Var', (0, 18))	('methylation', 'biological_process', 'GO:0032259', ('25', '36'))	('m6A', 'Gene', (20, 23))	('m6A', 'Gene', (104, 107))
88906	33681201	From these data, we inferred that succinylation modification might promote malignant progression in ccRCC by regulating m6A regulators, at least partially by influencing protein expression levels.	('succinylation modification', 'Var', (34, 60))	('succinyl', 'Chemical', '-', (34, 42))	('protein expression levels', 'MPA', (170, 195))	('m6A', 'Gene', '56339', (120, 123))	('regulating', 'Reg', (109, 119))	('malignant progression', 'CPA', (75, 96))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('m6A', 'Gene', (120, 123))	('influencing', 'Reg', (158, 169))	('promote', 'PosReg', (67, 74))
88918	33681201	Further validation was performed in the ACHN cell line by Western blotting, showing that LRPPRC was down-regulated following the silencing of CPT1A while EIF3B was prominently up-regulated by the knockdown of SIRT5 (Figure 9C).	('SIRT5', 'Gene', (209, 214))	('LRPPRC', 'Gene', '10128', (89, 95))	('up-regulated', 'PosReg', (176, 188))	('EIF3', 'cellular_component', 'GO:0005852', ('154', '158'))	('SIRT5', 'Gene', '23408', (209, 214))	('EIF3B', 'Gene', (154, 159))	('silencing', 'Var', (129, 138))	('CPT1A', 'Gene', (142, 147))	('down-regulated', 'NegReg', (100, 114))	('LRPPRC', 'Gene', (89, 95))	('EIF3B', 'Gene', '8662', (154, 159))	('CPT', 'molecular_function', 'GO:0004142', ('142', '145'))	('CPT', 'molecular_function', 'GO:0004095', ('142', '145'))	('CPT1A', 'Gene', '1374', (142, 147))	('knockdown', 'Var', (196, 205))
88928	33681201	SIRT5 has been reported to desuccinylate SDHA to promote ccRCC tumorigenesis.	('SIRT5', 'Gene', (0, 5))	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('desuccinylate', 'Var', (27, 40))	('SDHA', 'Gene', (41, 45))	('SIRT5', 'Gene', '23408', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('promote', 'PosReg', (49, 56))	('succinyl', 'Chemical', '-', (29, 37))	('SDHA', 'Gene', '6389', (41, 45))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
88936	33681201	Furthermore, our pathway enrichment analyses of the three clusters suggested that succinylation regulators might play a role in the immune cell infiltration and m6A methylation in ccRCC.	('m6A', 'Gene', '56339', (161, 164))	('methylation', 'biological_process', 'GO:0032259', ('165', '176'))	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('play', 'Reg', (113, 117))	('methylation', 'Var', (165, 176))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('RCC', 'Disease', (182, 185))	('m6A', 'Gene', (161, 164))	('succinyl', 'Chemical', '-', (82, 90))
88946	33681201	Loss of SIRT5 promotes the transcription of IL-1beta in macrophages by increasing the succinylation level of PKM2 and forcing it to be translocated into the nucleus for the formation of the PKM2-HIF1alpha complex on the IL-1beta promoter.	('increasing', 'PosReg', (71, 81))	('HIF1alpha', 'Gene', (195, 204))	('promotes', 'PosReg', (14, 22))	('IL-1beta', 'Gene', (220, 228))	('PKM2', 'Gene', (109, 113))	('PKM2', 'Gene', (190, 194))	('PKM2', 'Gene', '5315', (190, 194))	('PKM2', 'Gene', '5315', (109, 113))	('IL-1', 'molecular_function', 'GO:0005149', ('220', '224'))	('IL-1beta', 'Gene', (44, 52))	('succinyl', 'Chemical', '-', (86, 94))	('transcription', 'biological_process', 'GO:0006351', ('27', '40'))	('forcing', 'Reg', (118, 125))	('IL-1beta', 'Gene', '3552', (220, 228))	('formation', 'biological_process', 'GO:0009058', ('173', '182'))	('nucleus', 'cellular_component', 'GO:0005634', ('157', '164'))	('Loss', 'Var', (0, 4))	('IL-1beta', 'Gene', '3552', (44, 52))	('HIF1alpha', 'Gene', '3091', (195, 204))	('IL-1', 'molecular_function', 'GO:0005149', ('44', '48'))	('transcription', 'MPA', (27, 40))	('succinylation level', 'MPA', (86, 105))	('SIRT5', 'Gene', (8, 13))	('SIRT5', 'Gene', '23408', (8, 13))
88966	33681201	For example, succinylation modification of GLS could inhibit ubiquitination via competition for same lysine residues leading to decrescent protein degradation and increscent protein stability.	('decrescent protein degradation', 'MPA', (128, 158))	('succinylation modification', 'Var', (13, 39))	('inhibit', 'NegReg', (53, 60))	('GLS', 'Gene', '2744', (43, 46))	('lysine', 'Chemical', 'MESH:D008239', (101, 107))	('GLS', 'Gene', (43, 46))	('increscent', 'NegReg', (163, 173))	('ubiquitination', 'MPA', (61, 75))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))	('protein degradation', 'biological_process', 'GO:0030163', ('139', '158'))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('succinyl', 'Chemical', '-', (13, 21))
88983	33375435	Genetic and epigenetic alterations are considered primary steps in cancer development, while posttranslational modifications (PTMs) play an important role in cancer progression and dissemination.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('epigenetic alterations', 'Var', (12, 34))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('Genetic', 'Var', (0, 7))	('cancer', 'Disease', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
88995	33375435	The presence of 3-NT was previously reported in some carcinomas, in ccRCC through immunohistochemically staining, in contrast nephropathy, as a biomarker for vascular involvement in Fabry disease, and in preeclampsia.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('Fabry disease', 'Disease', 'MESH:D000795', (182, 195))	('RCC', 'Disease', (70, 73))	('3-NT', 'Var', (16, 20))	('3-NT', 'Chemical', '-', (16, 20))	('nephropathy', 'Disease', (126, 137))	('preeclampsia', 'Phenotype', 'HP:0100602', (204, 216))	('nephropathy', 'Phenotype', 'HP:0000112', (126, 137))	('carcinomas', 'Disease', 'MESH:D009369', (53, 63))	('Fabry disease', 'Disease', (182, 195))	('reported', 'Reg', (36, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('carcinomas', 'Disease', (53, 63))	('nephropathy', 'Disease', 'MESH:D007674', (126, 137))	('preeclampsia', 'Disease', (204, 216))
89027	33375435	Many isoforms of pyruvate-kinases were identified L-PK (liver, kidney), R-PK (erythrocytes), M1-PK (muscles, brain), and M2-PK (liver, tumoral cells).	('tumoral', 'Disease', 'MESH:D009369', (135, 142))	('M2-PK', 'Var', (121, 126))	('pyruvate-kinases', 'Enzyme', (17, 33))	('pyruvate', 'Chemical', 'MESH:D019289', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('R-PK', 'Gene', (72, 76))	('L-PK', 'Var', (50, 54))	('R-PK', 'Gene', '5313', (72, 76))	('M1-PK', 'Var', (93, 98))	('tumoral', 'Disease', (135, 142))
89031	33375435	M2-PK acts as a protein kinase involved in gene transcription; it reprograms oxidative phosphorylation in aerobe glycolysis, promoting tumoral cells proliferation and migration.	('tumoral', 'Disease', 'MESH:D009369', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('77', '102'))	('transcription', 'biological_process', 'GO:0006351', ('48', '61'))	('protein', 'cellular_component', 'GO:0003675', ('16', '23'))	('promoting', 'PosReg', (125, 134))	('glycolysis', 'biological_process', 'GO:0006096', ('113', '123'))	('migration', 'CPA', (167, 176))	('oxidative phosphorylation', 'MPA', (77, 102))	('M2-PK', 'Var', (0, 5))	('tumoral', 'Disease', (135, 142))
89060	33375435	Recent studies have documented aberrant glycosylation in driving cancer progression to different stages across a variety of cancer types.	('cancer', 'Disease', (124, 130))	('aberrant', 'Var', (31, 39))	('glycosylation', 'MPA', (40, 53))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (31, 53))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('glycosylation', 'biological_process', 'GO:0070085', ('40', '53'))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
89065	33375435	One recent study developed a proteomic research, investigating the urinary N-glycoproteome of clear cell renal cell carcinoma at different evolution stages and showed an up-expression of P13P1, CD97, COCH and a down-expression of haptoglobin, fibronectin, ceruloplasmin, apolipoprotein B, phospholipids transfer protein, H factor of complement according to the RCC stage.	('apolipoprotein', 'molecular_function', 'GO:0005320', ('271', '285'))	('ceruloplasmin', 'Gene', '1356', (256, 269))	('CD97', 'Var', (194, 198))	('fibronectin', 'Gene', '2335', (243, 254))	('down-expression', 'NegReg', (211, 226))	('phospholipids', 'Protein', (289, 302))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (94, 125))	('N', 'Chemical', 'MESH:D009584', (75, 76))	('RCC', 'Disease', (361, 364))	('apolipoprotein B', 'Gene', (271, 287))	('phospholipids', 'Chemical', 'MESH:D010743', (289, 302))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (105, 125))	('haptoglobin', 'Gene', '3240', (230, 241))	('protein', 'cellular_component', 'GO:0003675', ('312', '319'))	('COCH', 'Gene', '1690', (200, 204))	('clear cell renal cell carcinoma', 'Disease', (94, 125))	('apolipoprotein', 'molecular_function', 'GO:0005319', ('271', '285'))	('RCC', 'Disease', 'MESH:C538614', (361, 364))	('up-expression', 'PosReg', (170, 183))	('P13P1', 'Var', (187, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('haptoglobin', 'Gene', (230, 241))	('fibronectin', 'Gene', (243, 254))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (94, 125))	('apolipoprotein B', 'Gene', '338', (271, 287))	('COCH', 'Gene', (200, 204))	('ceruloplasmin', 'Gene', (256, 269))
89102	33375435	A recent study showed that gastric cancer patients with high ADMA levels had poor prognosis and low survival rate.	('gastric cancer', 'Phenotype', 'HP:0012126', (27, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('ADMA', 'Chemical', 'MESH:C018524', (61, 65))	('high', 'Var', (56, 60))	('low', 'NegReg', (96, 99))	('ADMA levels', 'MPA', (61, 72))	('patients', 'Species', '9606', (42, 50))	('gastric cancer', 'Disease', (27, 41))	('gastric cancer', 'Disease', 'MESH:D013274', (27, 41))
89124	33375435	The variation of these markers was correlated with tumoral stage (T).	('correlated', 'Reg', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('variation', 'Var', (4, 13))	('tumoral', 'Disease', (51, 58))	('tumoral', 'Disease', 'MESH:D009369', (51, 58))
89125	33375435	The presence of tumoral necrosis was linked to high TuM2-PK and low TK-1.	('tumoral necrosis', 'Disease', (16, 32))	('tumoral necrosis', 'Phenotype', 'HP:0010885', (16, 32))	('tumoral necrosis', 'Disease', 'MESH:D009336', (16, 32))	('necrosis', 'biological_process', 'GO:0001906', ('24', '32'))	('low', 'NegReg', (64, 67))	('high', 'Var', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('necrosis', 'biological_process', 'GO:0008220', ('24', '32'))	('necrosis', 'biological_process', 'GO:0008219', ('24', '32'))	('TuM2', 'Chemical', '-', (52, 56))	('necrosis', 'biological_process', 'GO:0070265', ('24', '32'))	('TK-1', 'Gene', '7083', (68, 72))	('necrosis', 'biological_process', 'GO:0019835', ('24', '32'))	('TuM2-PK', 'Gene', (52, 59))	('TK-1', 'Gene', (68, 72))
89131	33375435	The present study showed no significant increase in quantitative determination of TuM2-PK in patients with T1N0Mo ccRCC compared with healthy subjects.	('T1N0Mo', 'Var', (107, 113))	('N', 'Chemical', 'MESH:D009584', (109, 110))	('increase', 'PosReg', (40, 48))	('TuM2', 'Chemical', '-', (82, 86))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))	('patients', 'Species', '9606', (93, 101))
89230	29544452	Drug resistance is associated with a transient increase in tumor vasculature and epigenetic changes in histone proteins in the chromatin, which contribute to tumor angiogenesis by inactivating the anti-angiogenic factors.	('Drug resistance', 'Phenotype', 'HP:0020174', (0, 15))	('inactivating', 'NegReg', (180, 192))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('epigenetic changes', 'Var', (81, 99))	('chromatin', 'cellular_component', 'GO:0000785', ('127', '136'))	('Drug resistance', 'Var', (0, 15))	('contribute', 'Reg', (144, 154))	('Drug resistance', 'biological_process', 'GO:0009315', ('0', '15'))	('angiogenesis', 'biological_process', 'GO:0001525', ('164', '176'))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('increase', 'PosReg', (47, 55))	('histone proteins', 'Protein', (103, 119))	('Drug resistance', 'biological_process', 'GO:0042493', ('0', '15'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('anti-angiogenic factors', 'CPA', (197, 220))
89344	29544452	Drug resistance is also associated with epigenetic changes in histone proteins in the chromatin, which may be reversible upon DE; thus, epigenetic therapies could be successful in ccRCC patients.	('Drug resistance', 'Disease', (0, 15))	('Drug resistance', 'Phenotype', 'HP:0020174', (0, 15))	('epigenetic changes', 'Var', (40, 58))	('chromatin', 'cellular_component', 'GO:0000785', ('86', '95'))	('Drug resistance', 'biological_process', 'GO:0042493', ('0', '15'))	('Drug resistance', 'biological_process', 'GO:0009315', ('0', '15'))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('RCC', 'Disease', (182, 185))	('histone proteins', 'Protein', (62, 78))	('patients', 'Species', '9606', (186, 194))
89360	33807297	Since cells are dependent on adaptive response machinery to cope with these insults, dysregulations in any of these stress-associated responsive programs have been implicated in many diseases such as cardiovascular diseases, neurodegenerative diseases, inflammatory diseases, and cancer.	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('cancer', 'Disease', (280, 286))	('neurodegenerative diseases', 'Disease', (225, 251))	('inflammatory diseases', 'Disease', (253, 274))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (225, 251))	('dysregulations', 'Var', (85, 99))	('cardiovascular diseases', 'Disease', (200, 223))	('implicated', 'Reg', (164, 174))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (200, 223))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (200, 223))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (225, 251))	('inflammatory diseases', 'Disease', 'MESH:D007249', (253, 274))
89378	33807297	In contrast, HSFY has been reported to be involved in germ cell development, whereby the deletion of HSFY results in male infertility.	('infertility', 'Phenotype', 'HP:0000789', (122, 133))	('HSFY', 'Gene', (101, 105))	('HSFY', 'Gene', '86614', (101, 105))	('HSFY', 'Gene', (13, 17))	('deletion', 'Var', (89, 97))	('HSFY', 'Gene', '86614', (13, 17))	('male infertility', 'Disease', 'MESH:D007248', (117, 133))	('results in', 'Reg', (106, 116))	('germ cell development', 'biological_process', 'GO:0007281', ('54', '75'))	('male infertility', 'Phenotype', 'HP:0003251', (117, 133))	('male infertility', 'Disease', (117, 133))
89393	33807297	Upon inspecting the UniProt and PhosphositePlus  databases, there were three phosphorylation sites (S298p, T471p, and S491p), two sumoylation sites (K287-sm and K293-sm), and one ubiquitylation site (K206-ub) reported for human HSF4 thus far (Figure 5).	('phosphorylation', 'MPA', (77, 92))	('sumoylation', 'biological_process', 'GO:0016925', ('130', '141'))	('T471p', 'Var', (107, 112))	('S298p', 'Var', (100, 105))	('K293', 'CellLine', 'CVCL:0045', (161, 165))	('S491p', 'Mutation', 'p.S491P', (118, 123))	('PhosphositePlus', 'Disease', 'None', (32, 47))	('PhosphositePlus', 'Disease', (32, 47))	('K287-sm', 'Var', (149, 156))	('T471p', 'Mutation', 'p.T471P', (107, 112))	('S298p', 'Mutation', 'p.S298P', (100, 105))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('human', 'Species', '9606', (222, 227))	('S491p', 'Var', (118, 123))	('K293-sm', 'Var', (161, 168))
89396	33807297	For instance, phosphorylation-mediated sumoylation of this HSF4b lysine residue reduced the expression of the crystallin gene, an important HSF4 downstream target that was involved in governing normal lens development and homeostasis.	('phosphorylation-mediated sumoylation', 'Var', (14, 50))	('lysine', 'Chemical', 'MESH:D008239', (65, 71))	('homeostasis', 'biological_process', 'GO:0042592', ('222', '233'))	('lens development', 'biological_process', 'GO:0002088', ('201', '217'))	('crystallin gene', 'Gene', (110, 125))	('HSF4b', 'Gene', (59, 64))	('sumoylation', 'biological_process', 'GO:0016925', ('39', '50'))	('reduced', 'NegReg', (80, 87))	('phosphorylation', 'biological_process', 'GO:0016310', ('14', '29'))	('sumoylation', 'Var', (39, 50))	('expression', 'MPA', (92, 102))
89398	33807297	The substitution of threonine to alanine at this residue caused HSF4b dissociation from the importin beta-1/Hsc70 complex, which consequently inhibited its translocation into the nucleus and subsequent transcription regulatory activities.	('Hsc', 'cellular_component', 'GO:0035301', ('108', '111'))	('HSF4b', 'Gene', (64, 69))	('dissociation', 'NegReg', (70, 82))	('alanine', 'Chemical', 'MESH:D000409', (33, 40))	('nucleus', 'cellular_component', 'GO:0005634', ('179', '186'))	('transcription', 'biological_process', 'GO:0006351', ('202', '215'))	('Hsc70', 'Gene', (108, 113))	('caused', 'Reg', (57, 63))	('importin', 'cellular_component', 'GO:0005646', ('92', '100'))	('substitution', 'Var', (4, 16))	('transcription regulatory activities', 'MPA', (202, 237))	('inhibited', 'NegReg', (142, 151))	('Hsc70', 'Gene', '3312', (108, 113))	('translocation into the nucleus', 'MPA', (156, 186))	('threonine', 'Chemical', 'MESH:D013912', (20, 29))
89402	33807297	In line with this, either BCAS2 depletion or the substitution of lysine to arginine at this position (K206R) reduced HSF4 ubiquitination that in turn increased HSF4 protein stability.	('lysine', 'Chemical', 'MESH:D008239', (65, 71))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('HSF4', 'Protein', (117, 121))	('arginine', 'Chemical', 'MESH:D001120', (75, 83))	('K206R', 'SUBSTITUTION', 'None', (102, 107))	('BCAS2', 'Gene', '10286', (26, 31))	('K206R', 'Var', (102, 107))	('HSF4 protein stability', 'MPA', (160, 182))	('BCAS2', 'Gene', (26, 31))	('increased HSF4 protein', 'Phenotype', 'HP:0032300', (150, 172))	('reduced', 'NegReg', (109, 116))	('increased', 'PosReg', (150, 159))	('ubiquitination', 'MPA', (122, 136))
89404	33807297	Moreover, due to HSF4 roles in regulating these important cellular processes, HSF4 genetic alterations or aberrant activities have also been implicated in diseases such as cataracts and cancer.	('cataracts', 'Disease', 'MESH:D002386', (172, 181))	('genetic alterations', 'Var', (83, 102))	('cataracts', 'Disease', (172, 181))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cataracts', 'Phenotype', 'HP:0000518', (172, 181))	('aberrant activities', 'Var', (106, 125))	('cataract', 'Phenotype', 'HP:0000518', (172, 180))	('HSF4', 'Gene', (78, 82))	('implicated', 'Reg', (141, 151))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
89410	33807297	However, unlike FGF1, FGF4, and FGF7, the expression of FGF2 did not get upregulated upon HSF4 inhibition in mice.	('FGF7', 'Gene', '14178', (32, 36))	('FGF4', 'Gene', (22, 26))	('FGF7', 'Gene', (32, 36))	('inhibition', 'Var', (95, 105))	('FGF1', 'Gene', (16, 20))	('FGF4', 'Gene', '14175', (22, 26))	('FGF2', 'Gene', '14173', (56, 60))	('FGF2', 'Gene', (56, 60))	('FGF1', 'Gene', '14164', (16, 20))	('mice', 'Species', '10090', (109, 113))
89419	33807297	Another prominent role of HSF4 is that HSF4 could protect lens cells from oxidative stress, DNA damage, and drug-induced apoptosis during lens development.	('age', 'Gene', (99, 102))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('age', 'Gene', '5973', (99, 102))	('apoptosis', 'biological_process', 'GO:0006915', ('121', '130'))	('HSF4', 'Var', (39, 43))	('protect', 'PosReg', (50, 57))	('apoptosis', 'biological_process', 'GO:0097194', ('121', '130'))	('lens development', 'biological_process', 'GO:0002088', ('138', '154'))	('oxidative stress', 'Phenotype', 'HP:0025464', (74, 90))
89428	33807297	Similar to the observations in the lens, HSF4 also antagonized HSF1 functions in the olfactory epithelium cell genesis by competing for binding at the leukemia inhibitory factor (LIF) heat shock elements.	('HSF4', 'Var', (41, 45))	('antagonized', 'NegReg', (51, 62))	('leukemia inhibitory factor', 'Gene', (151, 177))	('leukemia', 'Phenotype', 'HP:0001909', (151, 159))	('HSF1', 'Gene', (63, 67))	('competing', 'NegReg', (122, 131))	('binding', 'molecular_function', 'GO:0005488', ('136', '143'))	('leukemia inhibitory factor', 'Gene', '3976', (151, 177))	('shock', 'Phenotype', 'HP:0031273', (189, 194))	('leukemia inhibitory factor', 'molecular_function', 'GO:0005146', ('151', '177'))	('binding', 'Interaction', (136, 143))
89431	33807297	showed that loss of HSF1 in combination with either HSF2 or HSF4 aggravated the demyelination and astrogliosis of the murine central nervous system (CNS), highlighting the co-operation between HSF family members in maintaining CNS homeostasis.	('murine', 'Species', '10090', (118, 124))	('aggravated', 'PosReg', (65, 75))	('astrogliosis', 'Disease', 'None', (98, 110))	('HSF', 'Gene', (52, 55))	('HSF', 'Gene', (193, 196))	('demyelination', 'Phenotype', 'HP:0011096', (80, 93))	('HSF', 'Gene', '3569', (20, 23))	('loss', 'Var', (12, 16))	('homeostasis', 'biological_process', 'GO:0042592', ('231', '242'))	('astrogliosis', 'Disease', (98, 110))	('HSF', 'Gene', (60, 63))	('HSF', 'Gene', '3569', (52, 55))	('HSF', 'Gene', '3569', (193, 196))	('HSF', 'Gene', (20, 23))	('demyelination', 'Disease', 'MESH:D003711', (80, 93))	('demyelination', 'Disease', (80, 93))	('HSF', 'Gene', '3569', (60, 63))
89438	33807297	Since HSF4 is crucial in lens development, any dysregulations of HSF4 functions could hamper its function leading to a cataract.	('HSF4', 'Gene', (65, 69))	('hamper', 'NegReg', (86, 92))	('cataract', 'Disease', (119, 127))	('cataract', 'Disease', 'MESH:D002386', (119, 127))	('cataract', 'Phenotype', 'HP:0000518', (119, 127))	('dysregulations', 'Var', (47, 61))	('lens development', 'biological_process', 'GO:0002088', ('25', '41'))	('function', 'MPA', (97, 105))
89439	33807297	As discussed previously, knocking out HSF4 in mice resulted in abnormal lens development and the formation of early-onset cataract.	('lens development', 'biological_process', 'GO:0002088', ('72', '88'))	('resulted in', 'Reg', (51, 62))	('formation', 'biological_process', 'GO:0009058', ('97', '106'))	('lens development', 'CPA', (72, 88))	('cataract', 'Disease', 'MESH:D002386', (122, 130))	('cataract', 'Disease', (122, 130))	('cataract', 'Phenotype', 'HP:0000518', (122, 130))	('abnormal lens', 'Phenotype', 'HP:0000517', (63, 76))	('mice', 'Species', '10090', (46, 50))	('knocking out', 'Var', (25, 37))	('HSF4', 'Gene', (38, 42))
89440	33807297	In line with these observations, mutations in the HSF4 gene have been widely associated with the pathogenesis of human early-onset or congenital cataracts.	('congenital cataracts', 'Disease', 'MESH:D002386', (134, 154))	('cataract', 'Phenotype', 'HP:0000518', (145, 153))	('congenital cataract', 'Phenotype', 'HP:0000519', (134, 153))	('mutations', 'Var', (33, 42))	('HSF4', 'Gene', (50, 54))	('congenital cataracts', 'Phenotype', 'HP:0000519', (134, 154))	('cataracts', 'Phenotype', 'HP:0000518', (145, 154))	('pathogenesis', 'biological_process', 'GO:0009405', ('97', '109'))	('congenital cataracts', 'Disease', (134, 154))	('early-onset', 'Disease', (119, 130))	('human', 'Species', '9606', (113, 118))	('associated', 'Reg', (77, 87))
89441	33807297	An early study in a Chinese congenital cataract patient cohort revealed that this disease was linked to hereditary mutations in the HSF4 DBD.	('mutations', 'Var', (115, 124))	('HSF4 DBD', 'Gene', (132, 140))	('linked', 'Reg', (94, 100))	('cataract', 'Phenotype', 'HP:0000518', (39, 47))	('patient', 'Species', '9606', (48, 55))	('congenital cataract', 'Phenotype', 'HP:0000519', (28, 47))	('congenital cataract', 'Disease', (28, 47))	('congenital cataract', 'Disease', 'MESH:D002386', (28, 47))
89442	33807297	Mutation profiling in the HSF4 gene identified a T to C transition at the nucleotide 348 in all lamellar cataract-affected individuals that substituted the leucine to proline at the amino acid 115.	('cataract', 'Phenotype', 'HP:0000518', (105, 113))	('lamellar cataract', 'Disease', (96, 113))	('T to C', 'Var', (49, 55))	('lamellar cataract', 'Disease', 'MESH:C535342', (96, 113))	('leucine to proline at the amino acid 115', 'Mutation', 'rs1434767979', (156, 196))	('lamellar cataract', 'Phenotype', 'HP:0007971', (96, 113))	('HSF4', 'Gene', (26, 30))	('leucine', 'MPA', (156, 163))
89443	33807297	In addition, the same group also analyzed a Danish family whose members were affected with congenital cataracts, as well as in sporadic cataract diseases, and found other missense mutations at the HSF4 DBD.	('congenital cataracts', 'Phenotype', 'HP:0000519', (91, 111))	('cataract diseases', 'Disease', 'MESH:D002386', (136, 153))	('missense mutations', 'Var', (171, 189))	('cataracts', 'Phenotype', 'HP:0000518', (102, 111))	('affected', 'Reg', (77, 85))	('congenital cataract', 'Phenotype', 'HP:0000519', (91, 110))	('cataract', 'Phenotype', 'HP:0000518', (102, 110))	('congenital cataracts', 'Disease', (91, 111))	('HSF4 DBD', 'Gene', (197, 205))	('cataract', 'Phenotype', 'HP:0000518', (136, 144))	('congenital cataracts', 'Disease', 'MESH:D002386', (91, 111))	('cataract diseases', 'Disease', (136, 153))
89444	33807297	Interestingly, mutations at the HSF4 DBD were predominantly missense mutations that resulted in autosomal dominant disease.	('autosomal dominant disease', 'Disease', (96, 122))	('resulted in', 'Reg', (84, 95))	('autosomal dominant disease', 'Disease', 'MESH:D030342', (96, 122))	('HSF4', 'Gene', (32, 36))	('mutations', 'Var', (15, 24))
89446	33807297	In contrast, genetic alterations outside the HSF4 DBD were associated with autosomal recessive disease and composed of missense, frameshift, and nonsense mutations.	('autosomal recessive disease', 'Disease', (75, 102))	('nonsense mutations', 'Var', (145, 163))	('associated', 'Reg', (59, 69))	('frameshift', 'Var', (129, 139))	('missense', 'Var', (119, 127))	('genetic alterations', 'Var', (13, 32))	('HSF4', 'Gene', (45, 49))	('autosomal recessive disease', 'Disease', 'MESH:D030342', (75, 102))
89447	33807297	Functional and structural analyses on several of these reported mutations revealed that these mutations impaired the HSF4 DNA-binding and gene regulatory activity, which in turn would promote abnormal lens development and cataract formation.	('impaired', 'NegReg', (104, 112))	('HSF4', 'Protein', (117, 121))	('lens development', 'biological_process', 'GO:0002088', ('201', '217'))	('cataract', 'Disease', 'MESH:D002386', (222, 230))	('cataract', 'Disease', (222, 230))	('mutations', 'Var', (94, 103))	('cataract', 'Phenotype', 'HP:0000518', (222, 230))	('formation', 'biological_process', 'GO:0009058', ('231', '240'))	('abnormal lens', 'Phenotype', 'HP:0000517', (192, 205))	('lens development', 'CPA', (201, 217))	('gene regulatory activity', 'MPA', (138, 162))	('mutations', 'Var', (64, 73))	('DNA', 'cellular_component', 'GO:0005574', ('122', '125'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('122', '133'))	('promote', 'PosReg', (184, 191))
89448	33807297	There were five additional HSF4 mutations identified in a small fraction of age-related cataract patients.	('HSF4', 'Gene', (27, 31))	('cataract', 'Disease', 'MESH:D002386', (88, 96))	('cataract', 'Disease', (88, 96))	('age', 'Gene', '5973', (76, 79))	('cataract', 'Phenotype', 'HP:0000518', (88, 96))	('age-related cataract', 'Phenotype', 'HP:0011141', (76, 96))	('mutations', 'Var', (32, 41))	('age', 'Gene', (76, 79))	('patients', 'Species', '9606', (97, 105))
89449	33807297	Overall, the identification of these HSF4 genetic alterations and their associations with both congenital- and age-related cataracts further corroborated the HSF4 indispensable functions in governing normal lens development during eye organogenesis.	('congenital-', 'Disease', (95, 106))	('age-related cataracts', 'Phenotype', 'HP:0011141', (111, 132))	('age-related cataract', 'Phenotype', 'HP:0011141', (111, 131))	('lens development', 'biological_process', 'GO:0002088', ('207', '223'))	('organogenesis', 'biological_process', 'GO:0048513', ('235', '248'))	('age', 'Gene', '5973', (111, 114))	('cataract', 'Phenotype', 'HP:0000518', (123, 131))	('associations', 'Reg', (72, 84))	('cataracts', 'Phenotype', 'HP:0000518', (123, 132))	('HSF4', 'Gene', (37, 41))	('genetic alterations', 'Var', (42, 61))	('age', 'Gene', (111, 114))	('cataracts', 'Disease', 'MESH:D002386', (123, 132))	('cataracts', 'Disease', (123, 132))
89450	33807297	Analysis of TCGA PanCancer genomic data revealed that HSF4 was rarely targeted by mutations in cancers.	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('Cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Cancer', 'Disease', (20, 26))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('Cancer', 'Disease', 'MESH:D009369', (20, 26))	('mutations', 'Var', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
89451	33807297	Among the analyzed cancer types: bladder, uterine, esophagus, and stomach cancers had the highest frequency of HSF4 genetic alterations, which were about 3%-3.5% of all cases for each cancer type (Figure 6).	('cancer', 'Disease', (184, 190))	('stomach cancers', 'Phenotype', 'HP:0012126', (66, 81))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('HSF4', 'Gene', (111, 115))	('esophagus', 'Disease', (51, 60))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (19, 25))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('bladder', 'Disease', (33, 40))	('cancer', 'Disease', (74, 80))	('genetic alterations', 'Var', (116, 135))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('stomach cancers', 'Disease', 'MESH:D013274', (66, 81))	('stomach cancers', 'Disease', (66, 81))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('uterine', 'Disease', (42, 49))
89455	33807297	In line with this, ccRCC patients who had high expression of HSF4 had a worse prognosis as compared to patients expressing a low level of HSF4 (Figure 8a,b).	('ccRCC', 'Disease', (19, 24))	('high expression', 'Var', (42, 57))	('patients', 'Species', '9606', (25, 33))	('patients', 'Species', '9606', (103, 111))	('HSF4', 'Gene', (61, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (19, 24))
89458	33807297	Intriguingly, thyroid cancer patients who had high expression of HSF4 had a worse prognosis as compared to patients expressing a low level of HSF4 (Figure 8c,d).	('patients', 'Species', '9606', (29, 37))	('thyroid cancer', 'Phenotype', 'HP:0002890', (14, 28))	('thyroid cancer', 'Disease', (14, 28))	('HSF4', 'Gene', (65, 69))	('thyroid cancer', 'Disease', 'MESH:D013964', (14, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('patients', 'Species', '9606', (107, 115))	('high expression', 'Var', (46, 61))
89462	33807297	A recent study showed that HSF4 expression was significantly upregulated in hepatocellular carcinoma (HCC) tissues, whereby targeting HSF4 reduced HCC cell growth and metastasis-associated phenotypes both in-vitro and in-vivo.	('HSF4', 'Gene', (27, 31))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (76, 100))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (76, 100))	('hepatocellular carcinoma', 'Disease', (76, 100))	('HCC', 'Phenotype', 'HP:0001402', (147, 150))	('HCC', 'Disease', (147, 150))	('HSF4', 'Gene', (134, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('reduced', 'NegReg', (139, 146))	('HCC', 'Phenotype', 'HP:0001402', (102, 105))	('cell growth', 'biological_process', 'GO:0016049', ('151', '162'))	('targeting', 'Var', (124, 133))	('metastasis-associated', 'CPA', (167, 188))
89464	33807297	In fact, deregulations of the PI3K-AKT-mTOR signaling pathway have been widely implicated in cancer pathogenesis due to their central roles in promoting cell growth and regulating cellular metabolism and macromolecule biosynthesis.	('cell growth', 'CPA', (153, 164))	('promoting', 'PosReg', (143, 152))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('AKT', 'Gene', (35, 38))	('signaling pathway', 'biological_process', 'GO:0007165', ('44', '61'))	('macromolecule biosynthesis', 'biological_process', 'GO:0009059', ('204', '230'))	('deregulations', 'Var', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mTOR', 'Gene', (39, 43))	('cell growth', 'biological_process', 'GO:0016049', ('153', '164'))	('mTOR', 'Gene', '2475', (39, 43))	('macromolecule biosynthesis', 'MPA', (204, 230))	('PI3K', 'molecular_function', 'GO:0016303', ('30', '34'))	('AKT', 'Gene', '207', (35, 38))	('cellular metabolism', 'biological_process', 'GO:0044237', ('180', '199'))	('pathogenesis', 'biological_process', 'GO:0009405', ('100', '112'))
89468	33807297	Therefore, dysregulated expression of either molecule would, in turn, activate the hypoxia-responsive transcriptional programs, which have been widely implicated in promoting tumorigenesis.	('tumor', 'Disease', (175, 180))	('dysregulated', 'Var', (11, 23))	('hypoxia', 'Disease', 'MESH:D000860', (83, 90))	('expression', 'MPA', (24, 34))	('activate', 'PosReg', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('hypoxia', 'Disease', (83, 90))	('promoting', 'PosReg', (165, 174))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
89469	33807297	Moreover, HSF4 deletion in either p53 or Arf-deficient mice induced cellular senescence that in turn impaired cell growth and suppressed the formation of spontaneous tumor in these mice models.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('mice', 'Species', '10090', (181, 185))	('suppressed', 'NegReg', (126, 136))	('cellular senescence', 'CPA', (68, 87))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('impaired', 'NegReg', (101, 109))	('deletion', 'Var', (15, 23))	('formation', 'biological_process', 'GO:0009058', ('141', '150'))	('tumor', 'Disease', (166, 171))	('mice', 'Species', '10090', (55, 59))	('cell growth', 'biological_process', 'GO:0016049', ('110', '121'))	('cellular senescence', 'biological_process', 'GO:0090398', ('68', '87'))	('cell growth', 'CPA', (110, 121))	('HSF4', 'Gene', (10, 14))
89471	33807297	Concordantly, Hsp72 deletion inhibited Her2-induced mammary transformation due to the upregulation of p21 and subsequent induction of senescence-mediated cell growth inhibition.	('inhibited', 'NegReg', (29, 38))	('Hsp72', 'Gene', '3303', (14, 19))	('upregulation', 'PosReg', (86, 98))	('p21', 'Gene', '12575', (102, 105))	('cell growth', 'biological_process', 'GO:0016049', ('154', '165'))	('senescence-mediated cell growth inhibition', 'CPA', (134, 176))	('Her2', 'Gene', (39, 43))	('deletion', 'Var', (20, 28))	('Her2', 'Gene', '2064', (39, 43))	('p21', 'Gene', (102, 105))	('senescence', 'biological_process', 'GO:0010149', ('134', '144'))	('Hsp72', 'Gene', (14, 19))
89472	33807297	Therefore, any slight adjustments to HSF4 expression would impair the lens cell proliferation and differentiation that would result in the formation of cataracts.	('cataract', 'Phenotype', 'HP:0000518', (152, 160))	('result in', 'Reg', (125, 134))	('cataracts', 'Disease', 'MESH:D002386', (152, 161))	('adjustments', 'Var', (22, 33))	('cataracts', 'Disease', (152, 161))	('formation', 'biological_process', 'GO:0009058', ('139', '148'))	('impair', 'NegReg', (59, 65))	('HSF4', 'Gene', (37, 41))	('cataracts', 'Phenotype', 'HP:0000518', (152, 161))	('cell proliferation', 'biological_process', 'GO:0008283', ('75', '93'))	('lens cell proliferation', 'CPA', (70, 93))
89473	33807297	In fact, a myriad number of studies have reported that mutations in HSF4 were implicated in the formation of congenital or age-related cataracts.	('formation', 'biological_process', 'GO:0009058', ('96', '105'))	('age', 'Gene', (123, 126))	('mutations', 'Var', (55, 64))	('cataracts', 'Disease', 'MESH:D002386', (135, 144))	('cataracts', 'Disease', (135, 144))	('HSF4', 'Gene', (68, 72))	('age', 'Gene', '5973', (123, 126))	('implicated', 'Reg', (78, 88))	('age-related cataract', 'Phenotype', 'HP:0011141', (123, 143))	('age-related cataracts', 'Phenotype', 'HP:0011141', (123, 144))	('cataracts', 'Phenotype', 'HP:0000518', (135, 144))	('congenital', 'Disease', (109, 119))	('cataract', 'Phenotype', 'HP:0000518', (135, 143))
89474	33807297	For example, the emerging CRISPR-based genome editing tool can be used to systematically mutate the HSF4 gene to prioritize the dominant mutations leading to cataracts.	('HSF4', 'Gene', (100, 104))	('cataracts', 'Phenotype', 'HP:0000518', (158, 167))	('mutate', 'Var', (89, 95))	('cataract', 'Phenotype', 'HP:0000518', (158, 166))	('cataracts', 'Disease', 'MESH:D002386', (158, 167))	('cataracts', 'Disease', (158, 167))
89475	33807297	The mutations responsible for cataracts could then be reversed using a similar approach.	('cataracts', 'Phenotype', 'HP:0000518', (30, 39))	('cataract', 'Phenotype', 'HP:0000518', (30, 38))	('cataracts', 'Disease', (30, 39))	('mutations', 'Var', (4, 13))	('cataracts', 'Disease', 'MESH:D002386', (30, 39))
89476	33807297	For example, the CRISPR-Cas9 gene-editing tool is currently being utilized as a potential approach for restoring the inherited genetic mutations in the CEP290 gene that causes the blindness disorder Leber's congenital amaurosis 10 (LCA10).	("blindness disorder Leber's congenital amaurosis", 'Disease', (180, 227))	("blindness disorder Leber's congenital amaurosis", 'Disease', 'MESH:D057130', (180, 227))	('CEP290', 'Gene', (152, 158))	('CEP290', 'Gene', '80184', (152, 158))	('CEP', 'molecular_function', 'GO:0047849', ('152', '155'))	('mutations', 'Var', (135, 144))	('congenital amaurosis', 'Phenotype', 'HP:0007875', (207, 227))	('blindness', 'Phenotype', 'HP:0000618', (180, 189))	('Cas', 'cellular_component', 'GO:0005650', ('24', '27'))	('causes', 'Reg', (169, 175))
89478	33807297	The study showed that transactivation of photoreceptor-specific M-opsin (Opn1mw) resulted in prolonged retinal function and delayed retinal degradation in a mouse model.	('opsin', 'molecular_function', 'GO:0015053', ('66', '71'))	('degradation', 'biological_process', 'GO:0009056', ('140', '151'))	('retinal degradation', 'MPA', (132, 151))	('retinal', 'MPA', (103, 110))	('opsin', 'molecular_function', 'GO:0016918', ('66', '71'))	('opsin', 'molecular_function', 'GO:0046876', ('66', '71'))	('transactivation', 'biological_process', 'GO:2000144', ('22', '37'))	('opsin', 'biological_process', 'GO:0007602', ('66', '71'))	('delayed', 'NegReg', (124, 131))	('prolonged', 'PosReg', (93, 102))	('Opn1mw', 'Gene', '14539', (73, 79))	('Opn1mw', 'Gene', (73, 79))	('mouse', 'Species', '10090', (157, 162))	('transactivation', 'Var', (22, 37))	('opsin', 'molecular_function', 'GO:0009881', ('66', '71'))
89479	33807297	Hence, a similar approach could be used in the case of HSF4 to reverse the defective mutations or to activate HSF4 expression to prevent cataracts.	('cataracts', 'Phenotype', 'HP:0000518', (137, 146))	('HSF4', 'Gene', (110, 114))	('cataract', 'Phenotype', 'HP:0000518', (137, 145))	('mutations', 'Var', (85, 94))	('cataracts', 'Disease', (137, 146))	('activate', 'PosReg', (101, 109))	('expression', 'MPA', (115, 125))	('cataracts', 'Disease', 'MESH:D002386', (137, 146))
89484	33807297	Whilst the association between HSF4 mutations and cataract formation has been comprehensively elucidated, there are also emerging reports implicating the association between HSF4 and cancer pathogenesis.	('cataract', 'Disease', 'MESH:D002386', (50, 58))	('cataract', 'Disease', (50, 58))	('HSF4', 'Gene', (31, 35))	('cataract', 'Phenotype', 'HP:0000518', (50, 58))	('cancer', 'Disease', (183, 189))	('pathogenesis', 'biological_process', 'GO:0009405', ('190', '202'))	('formation', 'biological_process', 'GO:0009058', ('59', '68'))	('mutations', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
89486	33807297	Meanwhile, HSF4 upregulation was found to be associated with poor prognosis in colorectal, liver, and kidney cancers, whereby targeting HSF4 in liver cancer cells impaired the cell growth both in-vitro and in-vivo.	('kidney cancers', 'Disease', 'MESH:D007680', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('liver', 'Disease', (91, 96))	('liver cancer', 'Phenotype', 'HP:0002896', (144, 156))	('liver cancer', 'Disease', 'MESH:D006528', (144, 156))	('impaired', 'NegReg', (163, 171))	('cell growth', 'CPA', (176, 187))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('targeting', 'Var', (126, 135))	('liver cancer', 'Disease', (144, 156))	('kidney cancer', 'Phenotype', 'HP:0009726', (102, 115))	('cell growth', 'biological_process', 'GO:0016049', ('176', '187'))	('colorectal', 'Disease', (79, 89))	('HSF4', 'Gene', (136, 140))	('kidney cancers', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('kidney cancers', 'Phenotype', 'HP:0009726', (102, 116))
89492	33807297	VHL biallelic inactivation and the resultant pro-oncogenic HIFa accumulation contribute to 90% of all sporadic ccRCC cases, making the VHL-HIFa axis the hallmark gatekeeper of kidney tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('VHL', 'Gene', (0, 3))	('VHL-HIFa axis the hallmark gatekeeper of kidney tumorigenesis', 'Disease', 'MESH:D006623', (135, 196))	('HIFa accumulation', 'Disease', (59, 76))	('HIFa accumulation', 'Disease', 'MESH:C579880', (59, 76))	('ccRCC', 'Disease', (111, 116))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('biallelic inactivation', 'Var', (4, 26))
89511	33488680	Ribosomal diseases caused by ribosomal protein and rRNA biogenic factor defects, such as Diamond-Blackfan anemia and Shwachman-Diamond syndrome, affect the same tissues and exhibit similar pathology precisely because RBPs bind to the same type of RNA.	('defects', 'Var', (72, 79))	('Shwachman-Diamond syndrome', 'Disease', (117, 143))	('anemia', 'Phenotype', 'HP:0001903', (106, 112))	('RNA', 'cellular_component', 'GO:0005562', ('247', '250'))	('affect', 'Reg', (145, 151))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('Ribosomal diseases', 'Disease', (0, 18))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('29', '46'))	('anemia', 'Disease', (106, 112))	('bind', 'Interaction', (222, 226))	('ribosomal protein', 'Protein', (29, 46))	('anemia', 'Disease', 'MESH:D000740', (106, 112))	('Shwachman-Diamond syndrome', 'Disease', 'MESH:D000081003', (117, 143))
89512	33488680	Mutations in mRBPs or their targets in neurons lead to abnormal aggregation of proteins or RNA, resulting in a variety of neurodegenerative and neuromuscular diseases.	('proteins', 'Protein', (79, 87))	('mRBPs', 'Gene', (13, 18))	('aggregation of', 'MPA', (64, 78))	('lead to', 'Reg', (47, 54))	('resulting in', 'Reg', (96, 108))	('RNA', 'MPA', (91, 94))	('abnormal aggregation', 'Phenotype', 'HP:0030402', (55, 75))	('Mutations', 'Var', (0, 9))	('neurodegenerative and neuromuscular diseases', 'Disease', 'MESH:D019636', (122, 166))	('RNA', 'cellular_component', 'GO:0005562', ('91', '94'))
89541	33488680	The biological processes analysis showed that these RBPs were significantly enriched in RNA catabolic process, posttranscriptional regulation of gene expression, translational initiation, regulation of cellular amide metabolic process, protein localization to endoplasmic reticulum, meiotic cell cycle, gene silencing, cellular process involved in reproduction in multicellular organism, transposition, and regulation of mRNA metabolic process.	('cellular process involved in reproduction in multicellular organism', 'biological_process', 'GO:0022412', ('319', '386'))	('RNA catabolic process', 'biological_process', 'GO:0006401', ('88', '109'))	('gene silencing', 'biological_process', 'GO:0016458', ('303', '317'))	('regulation of cellular amide metabolic process', 'biological_process', 'GO:0034248', ('188', '234'))	('protein localization to endoplasmic reticulum', 'biological_process', 'GO:0070972', ('236', '281'))	('regulation of mRNA metabolic process', 'biological_process', 'GO:1903311', ('407', '443'))	('translational initiation', 'biological_process', 'GO:0006413', ('162', '186'))	('amide', 'Chemical', 'MESH:D000577', (211, 216))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('260', '281'))	('posttranscriptional regulation of gene expression', 'biological_process', 'GO:0010608', ('111', '160'))	('transposition', 'biological_process', 'GO:0032196', ('388', '401'))	('RNA', 'cellular_component', 'GO:0005562', ('88', '91'))	('meiotic cell cycle', 'biological_process', 'GO:0051321', ('283', '301'))	('protein', 'cellular_component', 'GO:0003675', ('236', '243'))	('RNA catabolic', 'Disease', (88, 101))	('gene silencing', 'Var', (303, 317))	('cellular process', 'cellular_component', 'GO:0042995', ('319', '335'))
89604	33488680	These results suggest that RBPs may influence the occurrence and progression of tumors by regulating multiple biological processes including RNA processing, RNA metabolism, RNA transport, translation regulation and mRNA surveillance pathway.	('translation', 'biological_process', 'GO:0006412', ('188', '199'))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('RNA processing', 'biological_process', 'GO:0006396', ('141', '155'))	('tumors', 'Disease', (80, 86))	('RNA metabolism', 'biological_process', 'GO:0016070', ('157', '171'))	('RNA', 'cellular_component', 'GO:0005562', ('157', '160'))	('mRNA surveillance pathway', 'Pathway', (215, 240))	('RNA processing', 'MPA', (141, 155))	('RNA transport', 'biological_process', 'GO:0050658', ('173', '186'))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('translation regulation', 'MPA', (188, 210))	('RNA transport', 'MPA', (173, 186))	('RBPs', 'Var', (27, 31))	('RNA', 'cellular_component', 'GO:0005562', ('173', '176'))	('regulating', 'Reg', (90, 100))	('regulation', 'biological_process', 'GO:0065007', ('200', '210'))	('influence', 'Reg', (36, 45))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('RNA metabolism', 'MPA', (157, 171))	('RNA', 'cellular_component', 'GO:0005562', ('141', '144'))
89607	33488680	found that this family is the source of somatic mutations in tumor cells that drive tumor evolution and may be associated with tumor cell recurrence, metastasis, and treatment resistance.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (61, 66))	('drive', 'Reg', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('associated', 'Reg', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('metastasis', 'CPA', (150, 160))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('mutations', 'Var', (48, 57))
89609	33488680	The DAZL mutation was found to be associated with testicular cancer.	('mutation', 'Var', (9, 17))	('associated', 'Reg', (34, 44))	('testicular cancer', 'Phenotype', 'HP:0010788', (50, 67))	('DAZL', 'Gene', '1618', (4, 8))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('DAZL', 'Gene', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
89620	33488680	also found that high expression of RPL36A was associated with the tumorigenesis of glioblastoma multiform.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('glioblastoma', 'Disease', 'MESH:D005909', (83, 95))	('glioblastoma', 'Phenotype', 'HP:0012174', (83, 95))	('tumor', 'Disease', (66, 71))	('high', 'Var', (16, 20))	('glioblastoma', 'Disease', (83, 95))	('associated', 'Reg', (46, 56))	('RPL36A', 'Gene', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('RPL36A', 'Gene', '6173', (35, 41))
89638	29748390	The Clinical Activity of PD-1/PD-L1 Inhibitors in Metastatic Non-Clear Cell Renal Cell Carcinoma Programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors have shown activity in metastatic clear cell renal cell carcinoma (ccRCC).	('Metastatic Non-Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538445', (50, 96))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (76, 96))	('activity', 'MPA', (169, 177))	('clear cell renal cell carcinoma', 'Disease', (192, 223))	('-Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (64, 96))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (203, 223))	('RCC', 'Disease', (227, 230))	('RCC', 'Phenotype', 'HP:0005584', (227, 230))	('PD-1', 'Gene', (25, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('PD-1', 'Gene', '5133', (25, 29))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (192, 223))	('RCC', 'Disease', 'MESH:C538614', (227, 230))	('PD-L1', 'Gene', (30, 35))	('PD-L1', 'Gene', (140, 145))	('PD-L1', 'Gene', '29126', (140, 145))	('PD-L1', 'Gene', '29126', (30, 35))	('ligand', 'molecular_function', 'GO:0005488', ('130', '136'))	('Metastatic Non-Clear Cell Renal Cell Carcinoma', 'Disease', (50, 96))	('inhibitors', 'Var', (147, 157))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (192, 223))	('PD-1', 'Gene', (117, 121))	('Carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('PD-1', 'Gene', '5133', (117, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (225, 230))
89644	29748390	Responses were observed in patients with ccRCC with sarcomatoid and/or rhabdoid differentiation (n = 3/7, 43%), translocation RCC (n = 1/3, 33%), and papillary RCC (n = 4/14, 29%).	('papillary RCC', 'Disease', 'MESH:C538614', (150, 163))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('papillary RCC', 'Disease', (150, 163))	('rhabdoid', 'Disease', 'MESH:D018335', (71, 79))	('sarcomatoid', 'Disease', (52, 63))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('RCC', 'Disease', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('rhabdoid', 'Disease', (71, 79))	('RCC', 'Disease', (43, 46))	('patients', 'Species', '9606', (27, 35))	('sarcomatoid', 'Disease', 'MESH:C538614', (52, 63))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('translocation', 'Var', (112, 125))	('RCC', 'Disease', 'MESH:C538614', (126, 129))
89651	29748390	Unlike ccRCC, where the initiating oncogenic event has been attributed to VHL gene inactivation, driver mutation events of distinct nccRCC entities are heterogeneous.	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('VHL', 'Gene', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (9, 12))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (9, 12))	('inactivation', 'Var', (83, 95))	('RCC', 'Disease', (135, 138))	('VHL', 'Gene', '7428', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (9, 12))	('ccRCC', 'Phenotype', 'HP:0006770', (7, 12))
89675	29748390	Eight patients underwent next-generation sequencing utilizing the Dana-Farber Cancer Institute Oncopanel test, a hybrid-capture and parallel sequencing assay that surveys exonic DNA of 400 cancer genes.	('Cancer', 'Disease', (78, 84))	('DNA', 'cellular_component', 'GO:0005574', ('178', '181'))	('Cancer', 'Disease', 'MESH:D009369', (78, 84))	('Cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('exonic DNA', 'Var', (171, 181))	('patients', 'Species', '9606', (6, 14))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
89704	29748390	In the overall cohort, patients with IMDC favorable risk disease had the longest TTF (6.0 months; 95% CI, 0.7-not reached), whereas the TTF for patients with intermediate- and poor-risk disease was 4.0 months (95% CI, 2.8-6.7) and 1.9 months (95% CI, 0.5-4.0), respectively (log-rank P = 0.15; Table 2, Fig.	('patients', 'Species', '9606', (23, 31))	('patients', 'Species', '9606', (144, 152))	('IMDC', 'Var', (37, 41))	('TTF', 'MPA', (81, 84))
89707	29748390	We identified recurrent mutations in BAP1 (n = 5, 23.3%) and SETD2 (n = 3, 15.8%) in our cohort.	('SETD2', 'Gene', '29072', (61, 66))	('SETD2', 'Gene', (61, 66))	('BAP1', 'Gene', '8314', (37, 41))	('mutations', 'Var', (24, 33))	('BAP1', 'Gene', (37, 41))
89708	29748390	Additionally, aberrations in DNA repair genes, including BRCA2 (n = 1), ATM (n = 1), FANCA (n = 1), FANCG (n = 1), and POLQ (n = 1), were identified in 4 patients (21.1%).	('DNA repair genes', 'Gene', (29, 45))	('aberrations', 'Var', (14, 25))	('DNA repair', 'biological_process', 'GO:0006281', ('29', '39'))	('FANCG', 'Gene', (100, 105))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('ATM', 'Gene', '472', (72, 75))	('BRCA2', 'Gene', (57, 62))	('FANCA', 'Gene', '2175', (85, 90))	('patients', 'Species', '9606', (154, 162))	('POLQ', 'Gene', (119, 123))	('BRCA2', 'Gene', '675', (57, 62))	('FANCA', 'Gene', (85, 90))	('FANCG', 'Gene', '2189', (100, 105))	('ATM', 'Gene', (72, 75))	('POLQ', 'Gene', '10721', (119, 123))
89732	29748390	Additionally, an integrative analysis using whole-exome sequencing, RNA sequencing, and DNA methylation profiling identified a cluster of ccRCC with sarcomatoid differentiation enriched for aberrations in genes regulating T-cell receptor signaling and adaptive immunity, suggesting potential sensitivity to immune checkpoint inhibitors.	('signaling', 'biological_process', 'GO:0023052', ('238', '247'))	('sarcomatoid', 'Disease', (149, 160))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('DNA methylation', 'biological_process', 'GO:0006306', ('88', '103'))	('DNA', 'cellular_component', 'GO:0005574', ('88', '91'))	('aberrations', 'Var', (190, 201))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('sarcomatoid', 'Disease', 'MESH:C538614', (149, 160))	('RNA', 'cellular_component', 'GO:0005562', ('68', '71'))
89738	29748390	Additional studies are investigating nivolumab (NCT02596035) and pembrolizumab (NCT02853344), a humanized monoclonal antibody to PD-1, in nccRCC patients.	('patients', 'Species', '9606', (145, 153))	('RCC', 'Disease', (141, 144))	('nivolumab', 'Chemical', 'MESH:D000077594', (37, 46))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('NCT02596035', 'Var', (48, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (139, 144))	('NCT02853344', 'Var', (80, 91))	('antibody', 'cellular_component', 'GO:0042571', ('117', '125'))	('antibody', 'cellular_component', 'GO:0019815', ('117', '125'))	('human', 'Species', '9606', (96, 101))	('RCC', 'Disease', 'MESH:C538614', (141, 144))	('antibody', 'cellular_component', 'GO:0019814', ('117', '125'))	('pembrolizumab', 'Chemical', 'MESH:C582435', (65, 78))	('antibody', 'molecular_function', 'GO:0003823', ('117', '125'))	('PD-1', 'Gene', (129, 133))	('PD-1', 'Gene', '5133', (129, 133))
89739	29748390	Our next-generation sequencing analysis revealed that 1 patient in the objective response cohort had a POLQ nonsense mutation in the DNA-binding domain, which could affect microhomology-mediated end-joining (MMEJ).	('nonsense mutation in', 'Var', (108, 128))	('POLQ', 'Gene', (103, 107))	('affect', 'Reg', (165, 171))	('POLQ', 'Gene', '10721', (103, 107))	('MMEJ', 'biological_process', 'GO:0097681', ('208', '212'))	('patient', 'Species', '9606', (56, 63))	('microhomology-mediated end-joining', 'MPA', (172, 206))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('133', '144'))
89748	29748390	Currently, two randomized studies compare sunitinib to selective or non-selective MET inhibitors in patients with advanced papillary RCC, where MET is known to be altered (NCT02761057 and NCT03091192).	('papillary RCC', 'Disease', 'MESH:C538614', (123, 136))	('sunitinib', 'Chemical', 'MESH:D000077210', (42, 51))	('altered', 'Reg', (163, 170))	('papillary RCC', 'Disease', (123, 136))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('patients', 'Species', '9606', (100, 108))	('NCT03091192', 'Var', (188, 199))	('NCT02761057', 'Var', (172, 183))
89762	29662646	Renal cell carcinoma (RCC) is a heterogeneous tumor caused by alterations in different genes.	('Renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('RCC', 'Disease', (22, 25))	('RCC', 'Phenotype', 'HP:0005584', (22, 25))	('caused by', 'Reg', (52, 61))	('tumor', 'Disease', (46, 51))	('RCC', 'Disease', 'MESH:C538614', (22, 25))	('Renal cell carcinoma', 'Phenotype', 'HP:0005584', (0, 20))	('alterations', 'Var', (62, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('Renal cell carcinoma', 'Disease', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
89769	29662646	The pRCC is associated with germline mutations of MET proto-oncogene, and these mutations activate MET signaling to promote tumor and cell motility.	('cell motility', 'biological_process', 'GO:0048870', ('134', '147'))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('mutations', 'Var', (80, 89))	('pRCC', 'Gene', (4, 8))	('MET', 'MPA', (99, 102))	('tumor', 'Disease', (124, 129))	('promote', 'PosReg', (116, 123))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('signaling', 'biological_process', 'GO:0023052', ('103', '112'))	('activate', 'PosReg', (90, 98))	('associated', 'Reg', (12, 22))	('germline mutations', 'Var', (28, 46))	('MET proto-oncogene', 'Gene', (50, 68))	('pRCC', 'Gene', '5546', (4, 8))
89771	29662646	In ccRCC, common genetic aberrations are LOH, hypermethylation, or mutation or deletions in the 3p chromosome region.	('mutation', 'Var', (67, 75))	('deletions', 'Var', (79, 88))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('RCC', 'Disease', (5, 8))	('LOH', 'Disease', (41, 44))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('hypermethylation', 'Var', (46, 62))	('chromosome region', 'cellular_component', 'GO:0098687', ('99', '116'))
89772	29662646	Frequent aberrations of chromosome 3p region cause inactivation of von Hippel-Lindau (VHL) gene in ccRCC.	('von Hippel-Lindau', 'Gene', '7428', (67, 84))	('inactivation', 'NegReg', (51, 63))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('chromosome', 'cellular_component', 'GO:0005694', ('24', '34'))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('RCC', 'Disease', (101, 104))	('aberrations', 'Var', (9, 20))	('VHL', 'Gene', (86, 89))	('von Hippel-Lindau', 'Gene', (67, 84))	('VHL', 'Gene', '7428', (86, 89))
89776	29662646	The pVHL mediates both K48- and K63-linked poly-ubiquitination, which is involved in protein degradation, protein trafficking, and post-translational modification respectively.	('pVHL', 'Gene', (4, 8))	('pVHL', 'Gene', '7428', (4, 8))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('post-translational modification', 'biological_process', 'GO:0043687', ('131', '162'))	('protein degradation', 'biological_process', 'GO:0030163', ('85', '104'))	('K48-', 'Var', (23, 27))	('K63-linked', 'Var', (32, 42))	('involved', 'Reg', (73, 81))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
89782	29662646	In canonical signaling, TGF-beta ligand binds to a constitutively active TGF-beta type II receptor (TbetaRII); TBRII thereafter recruits and activates TGF-beta type I receptor (TBRI or ALK5 or ALK5-Full Length; ALK5-FL) by phosphorylation in its serine/glycine-rich sequence called the GS domain.	('ALK5', 'Gene', '7046', (193, 197))	('GS', 'Disease', 'MESH:D011125', (286, 288))	('TbetaRII', 'Gene', (100, 108))	('TGF-beta', 'Gene', '7040', (73, 81))	('activates', 'PosReg', (141, 150))	('ALK5', 'Gene', (211, 215))	('TBRI', 'Chemical', '-', (177, 181))	('ALK5', 'Gene', '7046', (185, 189))	('TGF-beta', 'Gene', '7040', (151, 159))	('phosphorylation', 'Var', (223, 238))	('TBRI', 'Chemical', '-', (111, 115))	('TGF-beta type II receptor', 'Gene', '7048', (73, 98))	('TGF-beta', 'Gene', '7040', (24, 32))	('ALK5', 'Gene', (193, 197))	('TGF-beta', 'Gene', (73, 81))	('signaling', 'biological_process', 'GO:0023052', ('13', '22'))	('ligand', 'molecular_function', 'GO:0005488', ('33', '39'))	('TGF-beta type I receptor', 'Gene', (151, 175))	('glycine', 'Chemical', 'MESH:D005998', (253, 260))	('ALK5', 'Gene', (185, 189))	('TbetaRII', 'Gene', '7048', (100, 108))	('phosphorylation', 'biological_process', 'GO:0016310', ('223', '238'))	('recruits', 'PosReg', (128, 136))	('serine', 'Chemical', 'MESH:D012694', (246, 252))	('TGF-beta type II receptor', 'Gene', (73, 98))	('TGF-beta', 'Gene', (151, 159))	('TGF-beta', 'Gene', (24, 32))	('TGF-beta type I receptor', 'Gene', '7046', (151, 175))	('ALK5', 'Gene', '7046', (211, 215))
89811	29662646	In ACHN cells, cells treated with vehicle control (siRNA control) showed no expression of the PAI-1 protein, but knockdown of VHL by siRNA showed expression of the PAI-1 protein.	('VHL', 'Gene', '7428', (126, 129))	('PAI-1', 'Gene', '5054', (94, 99))	('PAI-1', 'Gene', (164, 169))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('VHL', 'Gene', (126, 129))	('knockdown', 'Var', (113, 122))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('PAI-1', 'Gene', (94, 99))	('expression', 'MPA', (146, 156))	('PAI-1', 'Gene', '5054', (164, 169))
89812	29662646	Further, knockdown of VHL by siRNA and overexpression of ALK5, followed by TGF-beta treatment for 6 hours, enhanced the expression of PAI-1 protein level (Figure 3D, n=3 independent experiments).	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('ALK5', 'Gene', '7046', (57, 61))	('VHL', 'Gene', (22, 25))	('knockdown', 'Var', (9, 18))	('expression', 'MPA', (120, 130))	('PAI-1', 'Gene', (134, 139))	('ALK5', 'Gene', (57, 61))	('VHL', 'Gene', '7428', (22, 25))	('enhanced', 'PosReg', (107, 115))	('TGF-beta', 'Gene', '7040', (75, 83))	('PAI-1', 'Gene', '5054', (134, 139))	('TGF-beta', 'Gene', (75, 83))
89820	29662646	These results revealed that the presence of wild-type VHL reduced the invasiveness induced by TGF-beta, while overexpression of ALK5 and treatment with TGF-beta increased the invasiveness.	('VHL reduced the invasiveness', 'Disease', (54, 82))	('TGF-beta', 'Gene', '7040', (152, 160))	('TGF-beta', 'Gene', '7040', (94, 102))	('presence', 'Var', (32, 40))	('TGF-beta', 'Gene', (152, 160))	('TGF-beta', 'Gene', (94, 102))	('VHL reduced the invasiveness', 'Disease', 'MESH:D006623', (54, 82))	('ALK5', 'Gene', '7046', (128, 132))	('ALK5', 'Gene', (128, 132))
89821	29662646	Importantly, knockdown of VHL through siRNA followed by TGF-beta stimulation, significantly increased the invasiveness of cell.	('TGF-beta', 'Gene', '7040', (56, 64))	('VHL', 'Gene', (26, 29))	('TGF-beta', 'Gene', (56, 64))	('VHL', 'Gene', '7428', (26, 29))	('increased', 'PosReg', (92, 101))	('knockdown', 'Var', (13, 22))	('invasiveness of cell', 'CPA', (106, 126))
89822	29662646	This result indicated that knockdown of VHL alone is sufficient to sensitize ACHN cells to TGF-beta stimulation (Figure 3F, n=3 independent experiments).	('knockdown', 'Var', (27, 36))	('VHL', 'Gene', (40, 43))	('TGF-beta', 'Gene', '7040', (91, 99))	('VHL', 'Gene', '7428', (40, 43))	('sensitize', 'Reg', (67, 76))	('TGF-beta', 'Gene', (91, 99))
89832	29662646	MG132, a well-known proteasomal inhibitor, inhibited proteasomal activity and increased the stability of ALK5 protein compared with the MG132 untreated cells (Figure 4E and 4F).	('MG132', 'Var', (0, 5))	('MG132', 'Chemical', 'MESH:C072553', (136, 141))	('ALK5', 'Gene', '7046', (105, 109))	('MG132', 'Chemical', 'MESH:C072553', (0, 5))	('ALK5', 'Gene', (105, 109))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('inhibited', 'NegReg', (43, 52))	('increased', 'PosReg', (78, 87))	('stability', 'MPA', (92, 101))	('proteasomal activity', 'MPA', (53, 73))
89838	29662646	Further, the introduction of VHL along with ALK5-HA in A498 (VHL-/-) cells showed a strong PLA signal (K48 and HA) (Figure 4H).	('VHL', 'Gene', (29, 32))	('A498', 'CellLine', 'CVCL:1056', (55, 59))	('PLA signal', 'MPA', (91, 101))	('K48', 'Var', (103, 106))	('VHL', 'Gene', '7428', (29, 32))	('ALK5-HA', 'Gene', '7046', (44, 51))	('VHL', 'Gene', (61, 64))	('ALK5-HA', 'Gene', (44, 51))	('VHL', 'Gene', '7428', (61, 64))
89841	29662646	Knock-down of VHL by siRNA reduced the K48-linked poly-ubiquitination of transiently over-expressed ALK5-HA, which confirmed pVHL dependent K48-linked ubiquitination of ALK5 (Figure 4I, Supplementary Figure 4B).	('reduced', 'NegReg', (27, 34))	('ALK5-HA', 'Gene', '7046', (100, 107))	('ALK5', 'Gene', (169, 173))	('ALK5-HA', 'Gene', (100, 107))	('Knock-down', 'Var', (0, 10))	('pVHL', 'Gene', '7428', (125, 129))	('pVHL', 'Gene', (125, 129))	('ALK5', 'Gene', '7046', (100, 104))	('VHL', 'Gene', (126, 129))	('VHL', 'Gene', (14, 17))	('VHL', 'Gene', '7428', (126, 129))	('ALK5', 'Gene', (100, 104))	('K48-linked poly-ubiquitination', 'MPA', (39, 69))	('ALK5', 'Gene', '7046', (169, 173))	('VHL', 'Gene', '7428', (14, 17))
89843	29662646	Cells transfected with ALK5-HA showed significantly higher PLA signals (proximity of K48 and HA) than the control cells (Figure 4J).	('HA', 'Var', (93, 95))	('ALK5-HA', 'Gene', '7046', (23, 30))	('higher', 'PosReg', (52, 58))	('PLA signals', 'MPA', (59, 70))	('ALK5-HA', 'Gene', (23, 30))	('K48', 'Var', (85, 88))
89850	29662646	Although the mutation or deletion of VHL, is a promoting factor in the ccRCC type, VHL alone is not sufficient for tumor progression in RCCs.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('VHL', 'Gene', '7428', (83, 86))	('RCC', 'Disease', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('VHL', 'Gene', (37, 40))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('mutation', 'Var', (13, 21))	('tumor', 'Disease', (115, 120))	('VHL', 'Gene', '7428', (37, 40))	('deletion', 'Var', (25, 33))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))	('VHL', 'Gene', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
89861	29662646	Most of the patients with ccRCC are affected by treatment of targeting agents, while the effects of treatment on other RCCs and also non-ccRCCs are diminished.	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('patients', 'Species', '9606', (12, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (26, 31))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('targeting agents', 'Var', (61, 77))	('RCC', 'Phenotype', 'HP:0005584', (28, 31))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RCC', 'Disease', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))	('RCC', 'Disease', (28, 31))	('affected', 'Reg', (36, 44))
89872	29662646	By overexpression versus knock-down of VHL, the expression of endogenous pVHL was observed to affect TGF-beta signaling as well as invasive properties of ccRCC cells.	('TGF-beta', 'Gene', '7040', (101, 109))	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('VHL', 'Gene', (74, 77))	('RCC', 'Disease', (156, 159))	('affect', 'Reg', (94, 100))	('VHL', 'Gene', (39, 42))	('pVHL', 'Gene', (73, 77))	('TGF-beta', 'Gene', (101, 109))	('VHL', 'Gene', '7428', (74, 77))	('pVHL', 'Gene', '7428', (73, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (154, 159))	('VHL', 'Gene', '7428', (39, 42))	('signaling', 'biological_process', 'GO:0023052', ('110', '119'))	('expression', 'Var', (48, 58))	('invasive properties of', 'CPA', (131, 153))
89874	29662646	The in-vitro experiment data presented in this study showed that the knocking down of VHL induced the downstream targets of TGF-beta pathway such as PAI-1, and the presence of intact wild-type VHL inhibited the PAI-1 expression driven by TGF-beta stimulation.	('VHL', 'Gene', (193, 196))	('knocking down', 'Var', (69, 82))	('inhibited', 'NegReg', (197, 206))	('TGF-beta', 'Gene', '7040', (238, 246))	('PAI-1', 'Gene', '5054', (149, 154))	('VHL', 'Gene', '7428', (193, 196))	('TGF-beta', 'Gene', (238, 246))	('TGF-beta', 'Gene', (124, 132))	('expression', 'MPA', (217, 227))	('PAI-1', 'Gene', '5054', (211, 216))	('TGF-beta', 'Gene', '7040', (124, 132))	('VHL', 'Gene', (86, 89))	('PAI-1', 'Gene', (149, 154))	('PAI-1', 'Gene', (211, 216))	('VHL', 'Gene', '7428', (86, 89))
89876	29662646	In-vitro studies, performed in ccRCC cell lines, also showed that the pVHL interacted with ALK5, indicating that pVHL thereby might regulate the protein stability of ALK5, consequently controlling the TGF-beta signaling through proteasomal degradation of ALK5 by K48-linked poly-ubiquitination.	('TGF-beta', 'Gene', '7040', (201, 209))	('protein stability', 'MPA', (145, 162))	('controlling', 'Reg', (185, 196))	('regulate', 'Reg', (132, 140))	('signaling', 'biological_process', 'GO:0023052', ('210', '219'))	('pVHL', 'Gene', '7428', (70, 74))	('ALK5', 'Gene', '7046', (91, 95))	('pVHL', 'Gene', (70, 74))	('TGF-beta', 'Gene', (201, 209))	('ALK5', 'Gene', '7046', (255, 259))	('proteasomal degradation', 'MPA', (228, 251))	('ALK5', 'Gene', (91, 95))	('RCC', 'Disease', (33, 36))	('pVHL', 'Gene', '7428', (113, 117))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('ALK5', 'Gene', (255, 259))	('ccRCC', 'Phenotype', 'HP:0006770', (31, 36))	('pVHL', 'Gene', (113, 117))	('ALK5', 'Gene', '7046', (166, 170))	('K48-linked', 'Var', (263, 273))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('degradation', 'biological_process', 'GO:0009056', ('240', '251'))	('ALK5', 'Gene', (166, 170))
89901	29662646	The membranes were incubated overnight at 4 C with gentle agitation with the indicated primary antibodies; TGF-betaRI (or ALK5, V-22) (sc-398, Santa Cruz Biotechnology, Santa Cruz, CA, USA), which identifies ALK5-FL and ALK5-ICD, as previously reported, HA (CST #2367 and CST #3724, Cell Signaling Technology, Danvers, MA, USA), HA (12CA5, Roche, Basel, Switzerland), phospho-SMAD2 (CST #3108, Cell Signaling Technology), PAI-1/Serpine1 (NBP1-19773, Novus Biologicals, Littleton, CO, USA), VHL (VHL40 (in vitro studies), Santa Cruz Biotechnology), VHL (NB100-485 (Human clinical sample), Novus Biologicals), K48-linkage Specific (CST #4289, Cell Signaling Technology), K48-linkage Specific (ab140601, Abcam, Cambridge, United Kingdom), P4D1 Ubiquitin (CST #3936, Cell Signaling Technology) and beta-actin (A5316, Sigma-Aldrich, St. Louis, MO, USA).	('Ubiquitin', 'molecular_function', 'GO:0031386', ('741', '750'))	('Signaling', 'biological_process', 'GO:0023052', ('288', '297'))	('Serpine1', 'Gene', (428, 436))	('PAI-1', 'Gene', (422, 427))	('San', 'Gene', '80218', (169, 172))	('VHL', 'Gene', (490, 493))	('SMAD2', 'Gene', (376, 381))	('Human', 'Species', '9606', (564, 569))	('San', 'Gene', (143, 146))	('ALK5', 'Gene', (220, 224))	('VHL', 'Gene', '7428', (548, 551))	('Signaling', 'biological_process', 'GO:0023052', ('399', '408'))	('P4D1 Ubiquitin', 'Protein', (736, 750))	('TGF-beta', 'Gene', (107, 115))	('ALK5', 'Gene', '7046', (122, 126))	('VHL', 'Gene', '7428', (490, 493))	('NBP1', 'Gene', (438, 442))	('VHL', 'Gene', (495, 498))	('beta-actin', 'Protein', (794, 804))	('agitation', 'Phenotype', 'HP:0000713', (58, 67))	('clinical', 'Species', '191496', (570, 578))	('San', 'Gene', '80218', (143, 146))	('agitation', 'Disease', 'MESH:D011595', (58, 67))	('agitation', 'Disease', (58, 67))	('ALK5', 'Gene', '7046', (208, 212))	('NBP1', 'Gene', '4682', (438, 442))	('CST', 'Var', (752, 755))	('ALK5', 'Gene', (122, 126))	('Signaling', 'biological_process', 'GO:0023052', ('768', '777'))	('San', 'Gene', (521, 524))	('VHL', 'Gene', '7428', (495, 498))	('Serpine1', 'Gene', '5054', (428, 436))	('San', 'Gene', (169, 172))	('ALK5', 'Gene', (208, 212))	('SMAD2', 'Gene', '4087', (376, 381))	('VHL', 'Gene', (548, 551))	('Signaling', 'biological_process', 'GO:0023052', ('646', '655'))	('ALK5', 'Gene', '7046', (220, 224))	('PAI-1', 'Gene', '5054', (422, 427))	('San', 'Gene', '80218', (521, 524))	('TGF-beta', 'Gene', '7040', (107, 115))
89907	29662646	A498 and ACHN cells were treated with TGF-beta1 (R&D system, UK) (10 ng/ml) for 1h, 2h, 3h, and 6h.	('TGF-beta1', 'Gene', '7040', (38, 47))	('TGF-beta1', 'Gene', (38, 47))	('6h', 'Chemical', '-', (96, 98))	('A498', 'CellLine', 'CVCL:1056', (0, 4))	('2h', 'Chemical', 'MESH:D003903', (84, 86))	('1h', 'Chemical', '-', (80, 82))	(') (10', 'Var', (63, 68))	('3h', 'Chemical', 'MESH:D014316', (88, 90))
89947	32082158	Similarly, another study has also shown that exosomes derived from proximal renal tubular cells treated with fenoldopam (a dopamine receptor agonist) could be transferred to distal renal tubule and collecting duct, and further modulated production of reactive oxygen species (ROS) in the cells lining these tubular segments.	('ROS', 'Chemical', 'MESH:D017382', (276, 279))	('fenoldopam', 'Chemical', 'MESH:D018818', (109, 119))	('fenoldopam', 'Var', (109, 119))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (251, 274))	('modulated', 'Reg', (227, 236))
89983	32082158	Also, transferring insulin growth factor-1 (IGF-1) receptor to cisplatin-treated renal tubular cells and co-incubation of these injured cells with soluble IGF-1 and exosomes derived from bone marrow MSCs significantly increased cell proliferation.	('IGF-1', 'Gene', (155, 160))	('transferring', 'Var', (6, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('insulin', 'molecular_function', 'GO:0016088', ('19', '26'))	('insulin growth factor-1', 'Gene', (19, 42))	('insulin growth factor-1', 'Gene', '3479', (19, 42))	('IGF-1', 'Gene', '3479', (44, 49))	('increased', 'PosReg', (218, 227))	('IGF-1', 'Gene', (44, 49))	('cell proliferation', 'biological_process', 'GO:0008283', ('228', '246'))	('soluble', 'cellular_component', 'GO:0005625', ('147', '154'))	('cell proliferation', 'CPA', (228, 246))	('MSCs', 'molecular_function', 'GO:0043854', ('199', '203'))	('rat', 'Species', '10116', (240, 243))	('IGF-1', 'Gene', '3479', (155, 160))
89988	32082158	High-glucose also enhanced secretion of exosomes from macrophages, which then caused mesangial proliferation and activated inflammatory cascade in the renal tissue.	('High-glucose', 'Var', (0, 12))	('High-glucose', 'Phenotype', 'HP:0003074', (0, 12))	('enhanced', 'PosReg', (18, 26))	('activated', 'PosReg', (113, 122))	('High-glucose', 'Chemical', '-', (0, 12))	('rat', 'Species', '10116', (102, 105))	('secretion of exosomes from macrophages', 'MPA', (27, 65))	('mesangial proliferation', 'CPA', (85, 108))	('inflammatory', 'CPA', (123, 135))	('mesangial proliferation', 'Phenotype', 'HP:0012574', (85, 108))	('caused', 'Reg', (78, 84))	('secretion', 'biological_process', 'GO:0046903', ('27', '36'))
89989	32082158	Knockdown of TGF-beta1 significantly reduced such effects of exosomes indicating that TGF-beta1 serves as an important mediator for interactions or cross talks between macrophages and renal cells.	('TGF-beta1', 'Gene', '7040', (13, 22))	('TGF-beta1', 'Gene', (13, 22))	('effects of exosomes', 'MPA', (50, 69))	('Knockdown', 'Var', (0, 9))	('TGF-beta1', 'Gene', '7040', (86, 95))	('TGF-beta1', 'Gene', (86, 95))	('interactions', 'Interaction', (132, 144))	('reduced', 'NegReg', (37, 44))
90015	32082158	Comparing to those derived from healthy individuals, urinary exosomes derived from autosomal dominant PKD (ADPKD) patients with PKD1 gene mutation had decreased levels of polycystin-1 and polycystin-2, but increase of transmembrane protein 2.	('polycystin-1', 'Gene', (171, 183))	('polycystin-2', 'Gene', (188, 200))	('polycystin-1', 'Gene', '5310', (171, 183))	('transmembrane', 'cellular_component', 'GO:0044214', ('218', '231'))	('polycystin', 'molecular_function', 'GO:0005227', ('171', '181'))	('transmembrane protein 2', 'Gene', '23670', (218, 241))	('PKD1', 'Gene', (128, 132))	('protein', 'cellular_component', 'GO:0003675', ('232', '239'))	('mutation', 'Var', (138, 146))	('PKD', 'Disease', (128, 131))	('polycystin-2', 'Gene', '5311', (188, 200))	('PKD', 'Disease', 'MESH:D007690', (109, 112))	('ADPKD', 'Disease', (107, 112))	('PKD', 'Disease', 'MESH:D007690', (102, 105))	('patients', 'Species', '9606', (114, 122))	('PKD1', 'Gene', '5310', (128, 132))	('PKD', 'Disease', (109, 112))	('PKD', 'Disease', (102, 105))	('decreased', 'NegReg', (151, 160))	('decreased levels of polycystin', 'Phenotype', 'HP:0500152', (151, 181))	('transmembrane protein 2', 'Gene', (218, 241))	('transmembrane', 'cellular_component', 'GO:0016021', ('218', '231'))	('polycystin', 'molecular_function', 'GO:0005227', ('188', '198'))	('ADPKD', 'Disease', 'MESH:D007690', (107, 112))	('PKD', 'Disease', 'MESH:D007690', (128, 131))	('increase', 'PosReg', (206, 214))
90039	32082158	Similarly, other more recent studies have reported that urinary exosomal miR-30c-5p and miR-204-5p might serve as the diagnostic markers for early-stage ccRCC (in a human study) and Xp11.2 translocation RCC (in a murine model), respectively.	('miR', 'Gene', (88, 91))	('RCC', 'Disease', (155, 158))	('ccRCC', 'Disease', (153, 158))	('RCC', 'Disease', 'MESH:D002292', (155, 158))	('ccRCC', 'Disease', 'MESH:D002292', (153, 158))	('human', 'Species', '9606', (165, 170))	('RCC', 'Phenotype', 'HP:0005584', (203, 206))	('murine', 'Species', '10090', (213, 219))	('miR', 'Gene', '220972', (73, 76))	('miR', 'Gene', (73, 76))	('RCC', 'Disease', 'MESH:D002292', (203, 206))	('RCC', 'Disease', (203, 206))	('Xp11.2 translocation', 'Var', (182, 202))	('miR', 'Gene', '220972', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))
90062	32082158	Interestingly, knockdown of expression of vimentin (one of the significantly increased proteins in exosomes derived from the COM-exposed macrophages identified by proteomics approach) by small-interfering RNA (siRNA) could abolish the effects of exosomes derived from the COM-exposed macrophages on monocytic and T-cell migration and phagocytic activity of macrophages.	('vimentin', 'Gene', '7431', (42, 50))	('small-interfering', 'Var', (187, 204))	('rat', 'Species', '10116', (323, 326))	('knockdown', 'Var', (15, 24))	('vimentin', 'Gene', (42, 50))	('abolish', 'NegReg', (223, 230))	('vimentin', 'cellular_component', 'GO:0045099', ('42', '50'))	('RNA', 'cellular_component', 'GO:0005562', ('205', '208'))	('T-cell migration', 'biological_process', 'GO:0072678', ('313', '329'))	('vimentin', 'cellular_component', 'GO:0045098', ('42', '50'))
90074	32082158	Finally, genetic manipulation of specific transcript or protein compositions of the exosome would yield better understanding of the mechanisms for exosomal involvement in kidney stone disease.	('genetic manipulation', 'Var', (9, 29))	('kidney stone disease', 'Disease', (171, 191))	('kidney stone', 'Phenotype', 'HP:0000787', (171, 183))	('exosome', 'cellular_component', 'GO:0070062', ('84', '91'))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('kidney stone disease', 'Disease', 'MESH:D007669', (171, 191))
90083	28522811	A multivariate analysis identified positive PD-L1 expression was an independent adverse prognostic factor for both progression free survival (hazard ratio: 3.7, P = 0.018) and overall survival (hazard ratio: 4.5, P = 0.034).	('positive', 'Var', (35, 43))	('PD-L1', 'Gene', '29126', (44, 49))	('PD-L1', 'Gene', (44, 49))
90092	28522811	However, previous studies indicate that Xp11.2 RCC presents at an advanced stage with a rapid clinical course.	('Xp11.2', 'Var', (40, 46))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))
90100	28522811	Representative images of the TFE3 break-apart FISH assay show the classical TFE3 rearrangement associated with Xp11.2 translocation (Fig.	('TFE3', 'Gene', (29, 33))	('TFE3', 'Gene', (76, 80))	('TFE3', 'Gene', '7030', (76, 80))	('TFE3', 'Gene', '7030', (29, 33))	('associated', 'Reg', (95, 105))	('rearrangement', 'Var', (81, 94))
90103	28522811	At the last follow-up, 11 patients (31%) had died of Xp11.2 RCC and 11 (31%) patients had progressive disease.	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('patients', 'Species', '9606', (26, 34))	('patients', 'Species', '9606', (77, 85))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('Xp11.2', 'Var', (53, 59))
90111	28522811	The PFS was shorter for patients who had tumors with positive PD-L1 expression (median time to disease progression, 7 months) than for those with for tumors with negative PD-L1 expression (median time to disease progression, 30 months; P = 0.01; Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('PD-L1', 'Gene', '29126', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('PD-L1', 'Gene', '29126', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('PFS', 'MPA', (4, 7))	('PD-L1', 'Gene', (171, 176))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('shorter', 'NegReg', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('patients', 'Species', '9606', (24, 32))	('PD-L1', 'Gene', (62, 67))	('positive', 'Var', (53, 61))
90112	28522811	Positive tumor PD-L1 expression was significantly associated with shorter OS (P = 0.001): 78% (7/9) of patients with positive tumor PD-L1 expression had a median OS of 17 months (95% CI, 12.1-21.9), whereas only 15% (4/27) of those with negative tumor PD-L1 expression died of the disease within the study period (median OS, not reached; Fig.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('PD-L1', 'Gene', (132, 137))	('PD-L1', 'Gene', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('PD-L1', 'Gene', (252, 257))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('positive', 'Var', (117, 125))	('tumor', 'Disease', (9, 14))	('PD-L1', 'Gene', '29126', (132, 137))	('patients', 'Species', '9606', (103, 111))	('PD-L1', 'Gene', '29126', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('PD-L1', 'Gene', '29126', (252, 257))	('tumor', 'Disease', (246, 251))	('tumor', 'Disease', (126, 131))
90116	28522811	Advanced tumor T stage (HR: 7.3, P = 0.007), regional lymph node metastasis (HR: 10.6, P = 0.003), distant metastasis (HR: 17.2, P < 0.001), ISUP grade (HR: 0.2, P = 0.030) and positive PD-L1 expression (HR: 6.7, P = 0.003) were associated with shorter OS.	('Advanced tumor T', 'Disease', 'MESH:D020178', (0, 16))	('PD-L1', 'Gene', (186, 191))	('regional lymph node metastasis', 'CPA', (45, 75))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('PD-L1', 'Gene', '29126', (186, 191))	('Advanced tumor T', 'Disease', (0, 16))	('distant metastasis', 'CPA', (99, 117))	('ISUP grade', 'CPA', (141, 151))	('positive', 'Var', (177, 185))	('shorter', 'Disease', (245, 252))
90126	28522811	High survivin expression combined with PD-L1 positivity was significantly associated with a high risk of death for ccRCC patients in both univariate (risk ratio, 12.82; 95% CI, 7.50-21.92; P < 0.001) and multivariate (risk ratio, 2.81; 95% CI, 1.56-5.04; P < 0.001) analyses.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('PD-L1', 'Gene', (39, 44))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('High', 'Var', (0, 4))	('PD-L1', 'Gene', '29126', (39, 44))	('expression', 'MPA', (14, 24))	('survivin', 'Protein', (5, 13))	('patients', 'Species', '9606', (121, 129))	('associated', 'Reg', (74, 84))
90159	28522811	In conclusion, positive PD-L1 expression is independently associated with tumor progression and predicts an adverse prognosis for Xp11.2 RCC patients.	('expression', 'MPA', (30, 40))	('associated', 'Reg', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('PD-L1', 'Gene', (24, 29))	('tumor', 'Disease', (74, 79))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))	('positive', 'Var', (15, 23))	('patients', 'Species', '9606', (141, 149))	('PD-L1', 'Gene', '29126', (24, 29))
90179	27465101	Microsatellite alteration and immunohistochemical expression profile of chromosome 9p21 in patients with sporadic renal cell carcinoma following surgical resection Long-term prognostic significance of loss of heterozygosity on chromosome 9p21 for localized renal cell carcinoma following surgery remains unreported.	('p21', 'Gene', '644914', (239, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('patients', 'Species', '9606', (91, 99))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (114, 134))	('chromosome', 'cellular_component', 'GO:0005694', ('227', '237'))	('chromosome', 'cellular_component', 'GO:0005694', ('72', '82'))	('sporadic renal cell carcinoma', 'Disease', (105, 134))	('sporadic renal cell carcinoma', 'Disease', 'MESH:C538614', (105, 134))	('p21', 'Gene', (84, 87))	('localized renal cell carcinoma', 'Disease', 'MESH:C538614', (247, 277))	('p21', 'Gene', (239, 242))	('localized renal cell carcinoma', 'Disease', (247, 277))	('loss of heterozygosity', 'Var', (201, 223))	('p21', 'Gene', '644914', (84, 87))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (257, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))
90180	27465101	The study assessed the frequency of deletions of different loci of chromosome 9p along with immunohistochemical profile of proteins in surgically resected renal cancer tissue and correlated this with long-term outcomes.	('chromosome', 'cellular_component', 'GO:0005694', ('67', '77'))	('deletions', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('renal cancer', 'Disease', (155, 167))	('renal cancer', 'Phenotype', 'HP:0009726', (155, 167))	('renal cancer', 'Disease', 'MESH:D007680', (155, 167))
90183	27465101	Only 5 of the markers showed LOH (D9S1814, D9S916, D9S974, D9S942, and D9S171).	('D9S916', 'Var', (43, 49))	('D9S974', 'Var', (51, 57))	('D9S942', 'Var', (59, 65))	('D9S974', 'CellLine', 'CVCL:U295', (51, 57))	('D9S1814', 'Var', (34, 41))	('S916', 'CellLine', 'CVCL:8863', (45, 49))	('D9S171', 'Var', (71, 77))
90185	27465101	Loss of heterozygosity for microsatellite analysis was correlated with tumour characteristics, recurrence free, cancer specific, and overall survival, including significance of immunohistochemical profile of protein expressions.	('tumour', 'Disease', (71, 77))	('microsatellite', 'Var', (27, 41))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('Loss', 'NegReg', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('protein', 'cellular_component', 'GO:0003675', ('208', '215'))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
90188	27465101	Most commonly observed LOH in the 3 markers: D9S916, D9S974, and D9S942 were associated with poor survival, and were statistically significant on multivariate analysis.	('D9S942', 'Var', (65, 71))	('D9S974', 'Var', (53, 59))	('S916', 'CellLine', 'CVCL:8863', (47, 51))	('D9S916', 'Var', (45, 51))	('D9S974', 'CellLine', 'CVCL:U295', (53, 59))	('poor', 'NegReg', (93, 97))
90191	27465101	Microsatellite alterations in tumor DNA relative to normal are potential genetic prognostic markers for RCC.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('Microsatellite alterations', 'Var', (0, 26))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('tumor', 'Disease', (30, 35))	('RCC', 'Disease', (104, 107))
90193	27465101	Loss of heterozygosity (LOH) at chromosome 3p and inactivation of the von Hippel-Lindau tumor suppressor (VHL) genes are known to have association with ccRCC.	('von Hippel-Lindau tumor', 'Disease', 'MESH:D006623', (70, 93))	('von Hippel-Lindau tumor', 'Disease', (70, 93))	('Loss of heterozygosity', 'Var', (0, 22))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('RCC', 'Disease', (154, 157))	('VHL', 'Gene', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor suppressor', 'biological_process', 'GO:0051726', ('88', '104'))	('VHL', 'Gene', '7428', (106, 109))	('inactivation', 'Var', (50, 62))	('association', 'Interaction', (135, 146))	('chromosome', 'cellular_component', 'GO:0005694', ('32', '42'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('88', '104'))
90195	27465101	Investigators previously used microsatellite markers to identify loss of various loci on 9p chromosome in renal cell cancer with various frequencies of microdeletions.	('loss', 'NegReg', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('renal cell cancer', 'Phenotype', 'HP:0005584', (106, 123))	('microdeletions', 'Var', (152, 166))	('chromosome', 'cellular_component', 'GO:0005694', ('92', '102'))	('renal cell cancer', 'Disease', 'MESH:C538614', (106, 123))	('renal cell cancer', 'Disease', (106, 123))
90196	27465101	Fluorescent in situ hybridization studies have shown loss of chromosome 9p in renal cancer carries a poor prognosis, but mapping studies on 9p are only a few and none with long-term outcomes.	('renal cancer', 'Disease', 'MESH:D007680', (78, 90))	('renal cancer', 'Phenotype', 'HP:0009726', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('loss', 'Var', (53, 57))	('chromosome', 'cellular_component', 'GO:0005694', ('61', '71'))	('renal cancer', 'Disease', (78, 90))
90201	27465101	In the present study, we report microsatellite alterations (LOH) on chromosomes 9p using different markers along with comprehensive immunohistochemical analysis and correlate this with the long-term outcomes of patients with ccRCC after surgical excision with curative intent.	('RCC', 'Disease', (227, 230))	('RCC', 'Phenotype', 'HP:0005584', (227, 230))	('patients', 'Species', '9606', (211, 219))	('RCC', 'Disease', 'MESH:C538614', (227, 230))	('microsatellite alterations', 'Var', (32, 58))
90221	27465101	The level of interobserver agreement upon validity of scoring and deletion status per represented block of tumour was assessed using Kappa statistical analysis.	('deletion status', 'Var', (66, 81))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('tumour', 'Disease', (107, 113))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))
90228	27465101	Most allelic deletions were detected, telomeric to CDKN2A region at D9S916, with 11 out of 52 informative tumours (21 %) displaying LOH.	('CDKN2A', 'Gene', '1029', (51, 57))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('S916', 'CellLine', 'CVCL:8863', (70, 74))	('tumours', 'Phenotype', 'HP:0002664', (106, 113))	('D9S916', 'Var', (68, 74))	('tumours', 'Disease', 'MESH:D009369', (106, 113))	('tumours', 'Disease', (106, 113))	('CDKN2A', 'Gene', (51, 57))
90229	27465101	For the 2 microsatellites within CDKN2A coding region, ten out of 58 informative cases (17 %) and 9 out of 62 informative cases (14.5 %) displayed LOH at D9S974 and D9S942 respectively.	('D9S942', 'Var', (165, 171))	('D9S974', 'CellLine', 'CVCL:U295', (154, 160))	('CDKN2A', 'Gene', (33, 39))	('CDKN2A', 'Gene', '1029', (33, 39))	('D9S974', 'Var', (154, 160))
90230	27465101	In contrast, centromeric to CDKN2A coding region, D9S1814 showed LOH in 3 out of 38 cases (7.8 %), which was the lowest rate of LOH as well as informative cases out of the 5 primers.	('CDKN2A', 'Gene', '1029', (28, 34))	('CDKN2A', 'Gene', (28, 34))	('D9S1814', 'Var', (50, 57))
90231	27465101	D9S171 (9p13) showed allelic deletion in 11 out of 57 informative tumours (19 %).	('allelic deletion', 'Var', (21, 37))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('tumours', 'Disease', 'MESH:D009369', (66, 73))	('D9S171', 'Gene', (0, 6))	('tumours', 'Disease', (66, 73))
90237	27465101	Cases displaying LOH at least in one marker on 9p21 were highly significantly associated with higher risk of RCC-specific death compared to cases with no allelic deletion (Fig.	('LOH', 'Var', (17, 20))	('p21', 'Gene', (48, 51))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('p21', 'Gene', '644914', (48, 51))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))
90238	27465101	This was mostly observed with LOH in the 3 markers within this region with the highest number of informative cases: D9S916, D9S974, and D9S942.	('D9S916', 'Var', (116, 122))	('D9S974', 'Var', (124, 130))	('D9S974', 'CellLine', 'CVCL:U295', (124, 130))	('S916', 'CellLine', 'CVCL:8863', (118, 122))	('D9S942', 'Var', (136, 142))
90244	27465101	4) tumours and the mean ADFP expression in 9p-deleted tumours was significantly lower compared to tumours with normal 9p status (1.87 and 2.25 respectively; p = 0.015).	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('9p-deleted', 'Var', (43, 53))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('tumours', 'Disease', (54, 61))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('ADFP', 'Gene', (24, 28))	('tumours', 'Disease', 'MESH:D009369', (98, 105))	('tumours', 'Disease', (98, 105))	('ADFP', 'Gene', '123', (24, 28))	('lower', 'NegReg', (80, 85))	('tumours', 'Disease', 'MESH:D009369', (3, 10))	('tumours', 'Disease', (3, 10))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))
90247	27465101	This study investigated the association between loss of heterozygosity (LOH) in the region of chromosome 9p21, immunohistochemical expression of a number of proteins associated with the region, staging (lower vs. higher) of renal cancers and long-term outcome following resection of clinically localized renal cancer.	('renal cancer', 'Phenotype', 'HP:0009726', (304, 316))	('renal cancers', 'Disease', (224, 237))	('loss', 'Var', (48, 52))	('localized renal cancer', 'Disease', (294, 316))	('p21', 'Gene', '644914', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('renal cancer', 'Phenotype', 'HP:0009726', (224, 236))	('chromosome', 'cellular_component', 'GO:0005694', ('94', '104'))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('localized renal cancer', 'Disease', 'MESH:D007680', (294, 316))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('renal cancers', 'Disease', 'MESH:D007680', (224, 237))	('p21', 'Gene', (106, 109))
90248	27465101	The main allelic deletion was detected at loci telomeric to CDKN2A region at D9S916, with 11 out of 52 informative cases (21 %) displaying LOH.	('S916', 'CellLine', 'CVCL:8863', (79, 83))	('D9S916', 'Var', (77, 83))	('CDKN2A', 'Gene', '1029', (60, 66))	('CDKN2A', 'Gene', (60, 66))
90249	27465101	The frequency of LOH was directly linked to the stage (p = 0.005) and metastases (p = 0.006) of the tumours, indicating a higher frequency of LOH is associated with a more aggressive renal cell cancer.	('tumours', 'Disease', (100, 107))	('metastases', 'Disease', 'MESH:D009362', (70, 80))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('aggressive renal cell cancer', 'Disease', 'MESH:C538614', (172, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('renal cell cancer', 'Phenotype', 'HP:0005584', (183, 200))	('LOH', 'Var', (142, 145))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('tumours', 'Disease', 'MESH:D009369', (100, 107))	('metastases', 'Disease', (70, 80))	('aggressive renal cell cancer', 'Disease', (172, 200))
90250	27465101	There was a significantly higher risk of cancer related death in patients showing LOH in at least one marker on 9p21 in comparison to those patients with no allelic deletion.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('LOH', 'Var', (82, 85))	('patients', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (140, 148))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('p21', 'Gene', (113, 116))	('p21', 'Gene', '644914', (113, 116))
90256	27465101	In a similar study, with larger numbers of SNP markers were shown to rapidly detect allelic imbalances; the results were validated by comparing them with analysis of the same tumours using the microsatellite allelotype method.	('allelic', 'Var', (84, 91))	('imbalance', 'Phenotype', 'HP:0002172', (92, 101))	('tumours', 'Phenotype', 'HP:0002664', (175, 182))	('tumours', 'Disease', 'MESH:D009369', (175, 182))	('detect', 'Reg', (77, 83))	('tumours', 'Disease', (175, 182))	('SNP', 'Var', (43, 46))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('imbalances', 'Phenotype', 'HP:0002172', (92, 102))
90258	27465101	confirmed that SNP array analysis is an important method of detecting novel microdeletions and may be involved in the progression of cc-RCC, as well as confirming larger chromosomal imbalances.	('imbalance', 'Phenotype', 'HP:0002172', (182, 191))	('involved', 'Reg', (102, 110))	('imbalances', 'Phenotype', 'HP:0002172', (182, 192))	('microdeletions', 'Var', (76, 90))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))
90260	27465101	Allelic loss using polymorphic microsatellites have been used to determine the progression of papillary renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('loss', 'NegReg', (8, 12))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (94, 124))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (94, 124))	('Allelic', 'Var', (0, 7))	('papillary renal cell carcinoma', 'Disease', (94, 124))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (104, 124))
90261	27465101	It is suggestive that LOH at chromosomes 8p12-21.1, 9p21, and 14q24.2-qter regions directly corresponds to higher tumour grade and pathological progression.	('tumour', 'Disease', (114, 120))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('pathological progression', 'CPA', (131, 155))	('p21', 'Gene', (53, 56))	('LOH', 'Var', (22, 25))	('p21', 'Gene', '644914', (53, 56))	('tumour', 'Disease', 'MESH:D009369', (114, 120))
90271	27465101	Patients were followed up for a median of 95 months and it was found that 9p deletion was an indicator of higher risk recurrence (P = 0.008) and RCC-related death (P = 0.001).	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('Patients', 'Species', '9606', (0, 8))	('9p deletion', 'Var', (74, 85))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))
90274	27465101	Deletion in 9p can be commonly seen in a number of epithelial tumours.	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('epithelial tumours', 'Disease', 'MESH:D000077216', (51, 69))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('epithelial tumours', 'Disease', (51, 69))	('Deletion', 'Var', (0, 8))
90279	27465101	There is often co-deletion of these loci in most of cancers in human.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('human', 'Species', '9606', (63, 68))	('co-deletion', 'Var', (15, 26))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
90282	27465101	Our observation and previously published study confirms the expression of p16 protein is absent or low in renal cell cancer samples, suggesting that loss of the p16 gene may be key event involved in renal cell cancer.	('p16', 'Gene', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('low', 'NegReg', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('p16', 'Gene', (161, 164))	('renal cell cancer', 'Phenotype', 'HP:0005584', (199, 216))	('renal cell cancer', 'Phenotype', 'HP:0005584', (106, 123))	('loss', 'Var', (149, 153))	('p16', 'Gene', '1029', (74, 77))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('renal cell cancer', 'Disease', 'MESH:C538614', (106, 123))	('p16', 'Gene', '1029', (161, 164))	('renal cell cancer', 'Disease', 'MESH:C538614', (199, 216))	('protein', 'Protein', (78, 85))	('renal cell cancer', 'Disease', (106, 123))	('renal cell cancer', 'Disease', (199, 216))
90287	27465101	From the published literature, it is reasonable to assume that the cellular response to hypoxia, a common feature in renal cancers involves reversible cell cycle arrest characterized by dephosphorylated Rb, loss of CDK activity, and decreased cyclin synthesis.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('CDK', 'Protein', (215, 218))	('cell cycle arrest', 'CPA', (151, 168))	('cyclin synthesis', 'MPA', (243, 259))	('decreased', 'NegReg', (233, 242))	('renal cancer', 'Phenotype', 'HP:0009726', (117, 129))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('151', '168'))	('renal cancers', 'Disease', 'MESH:D007680', (117, 130))	('hypoxia', 'Disease', (88, 95))	('hypoxia', 'Disease', 'MESH:D000860', (88, 95))	('loss', 'NegReg', (207, 211))	('CDK activity', 'molecular_function', 'GO:0004693', ('215', '227'))	('dephosphorylated', 'Var', (186, 202))	('cyclin', 'molecular_function', 'GO:0016538', ('243', '249'))	('cellular response to hypoxia', 'biological_process', 'GO:0071456', ('67', '95'))	('activity', 'MPA', (219, 227))	('renal cancers', 'Disease', (117, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('synthesis', 'biological_process', 'GO:0009058', ('250', '259'))
90292	27465101	In conclusions, the study has confirmed previous findings that p21 region harbours one of the tumour suppressor genes and the loss of heterozygosity in this region is associated with aggressive tumours and predicted poor clinical outcomes on long-term.	('tumour', 'Disease', (94, 100))	('tumours', 'Phenotype', 'HP:0002664', (194, 201))	('loss of heterozygosity', 'Var', (126, 148))	('associated with', 'Reg', (167, 182))	('tumour', 'Disease', (194, 200))	('p21', 'Gene', (63, 66))	('p21', 'Gene', '644914', (63, 66))	('aggressive tumours', 'Disease', 'MESH:D001523', (183, 201))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('aggressive tumours', 'Disease', (183, 201))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('tumour', 'Disease', 'MESH:D009369', (194, 200))	('tumour', 'Disease', 'MESH:D009369', (94, 100))
90298	33022986	Thus, we discuss here at length how changes in PGC-1alpha function impact the states of renal cancer, acute kidney injury (AKI) and chronic kidney disease (CKD), as well as emerging data that illuminate pivotal roles for PGC-1alpha during renal development.	('impact', 'Reg', (67, 73))	('illuminate', 'Chemical', '-', (192, 202))	('acute kidney injury', 'Disease', 'MESH:D058186', (102, 121))	('renal cancer', 'Disease', 'MESH:D007680', (88, 100))	('chronic kidney disease', 'Disease', (132, 154))	('kidney disease', 'Phenotype', 'HP:0000112', (140, 154))	('PGC-1alpha', 'Gene', (47, 57))	('changes', 'Var', (36, 43))	('acute kidney injury', 'Disease', (102, 121))	('chronic kidney disease', 'Disease', 'MESH:D051436', (132, 154))	('CKD', 'Disease', (156, 159))	('CKD', 'Disease', 'MESH:D012080', (156, 159))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (132, 154))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('acute kidney', 'Phenotype', 'HP:0001919', (102, 114))	('renal cancer', 'Disease', (88, 100))	('renal cancer', 'Phenotype', 'HP:0009726', (88, 100))
90299	33022986	We survey a new intriguing association of PGC-1alpha function with ciliogenesis and polycystic kidney disease (PKD), where recent animal studies revealed that embryonic renal cyst formation can occur in the context of PGC-1alpha deficiency.	('deficiency', 'Var', (229, 239))	('ciliogenesis', 'biological_process', 'GO:0060271', ('67', '79'))	('embryonic renal cyst', 'Disease', (159, 179))	('PGC-1alpha', 'Gene', (218, 228))	('polycystic kidney disease', 'Disease', 'MESH:D007690', (84, 109))	('kidney disease', 'Phenotype', 'HP:0000112', (95, 109))	('polycystic kidney', 'Phenotype', 'HP:0000113', (84, 101))	('formation', 'biological_process', 'GO:0009058', ('180', '189'))	('PGC-1alpha', 'Gene', (42, 52))	('PKD', 'Disease', (111, 114))	('renal cyst', 'Phenotype', 'HP:0000107', (169, 179))	('polycystic kidney disease', 'Disease', (84, 109))	('PKD', 'Disease', 'MESH:C537180', (111, 114))	('ciliogenesis', 'Disease', (67, 79))	('embryonic renal cyst', 'Disease', 'MESH:D007674', (159, 179))
90333	33022986	Additionally, PGC-1alpha is highly upregulated in the retina during postnatal development in mice, especially from P5-P17.	('P5-P17', 'Var', (115, 121))	('upregulated', 'PosReg', (35, 46))	('mice', 'Species', '10090', (93, 97))	('PGC-1alpha', 'Gene', (14, 24))
90334	33022986	Consequently, mice deficient in PGC-1alpha have signs of reduced retinal angiogenesis in both early developmental stages and adulthood.	('retinal angiogenesis', 'CPA', (65, 85))	('mice', 'Species', '10090', (14, 18))	('angiogenesis', 'biological_process', 'GO:0001525', ('73', '85'))	('reduced', 'NegReg', (57, 64))	('PGC-1alpha', 'Gene', (32, 42))	('deficient', 'Var', (19, 28))
90336	33022986	Mice deficient in one factor develop relatively normally; however, when both factors are knocked out, the compound mutant mice develop a number of heart defects and perish shortly after birth.	('mice', 'Species', '10090', (122, 126))	('heart defects', 'Disease', (147, 160))	('mutant', 'Var', (115, 121))	('heart defects', 'Phenotype', 'HP:0030680', (147, 160))	('Mice', 'Species', '10090', (0, 4))	('heart defects', 'Disease', 'MESH:D006330', (147, 160))
90338	33022986	Additionally, loss of PGC-1alpha results in cardiomyopathy following transverse aortic constriction.	('loss', 'Var', (14, 18))	('cardiomyopathy', 'Disease', (44, 58))	('results in', 'Reg', (33, 43))	('PGC-1alpha', 'Protein', (22, 32))	('constriction', 'cellular_component', 'GO:0005702', ('87', '99'))	('cardiomyopathy following transverse aortic constriction', 'Phenotype', 'HP:0005152', (44, 99))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (44, 58))	('cardiomyopathy', 'Disease', 'MESH:D009202', (44, 58))
90364	33022986	Subjects deficient in PGC-1alpha experience deleterious outcomes after suffering from acute kidney injury (AKI) as they progressively undergo renal fibrosis and suffer from chronic kidney disease (CKD).	('acute kidney', 'Phenotype', 'HP:0001919', (86, 98))	('PGC-1alpha', 'Gene', (22, 32))	('chronic kidney disease', 'Disease', (173, 195))	('acute kidney injury', 'Disease', (86, 105))	('acute kidney injury', 'Disease', 'MESH:D058186', (86, 105))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (173, 195))	('renal fibrosis', 'Disease', 'MESH:D005355', (142, 156))	('undergo', 'PosReg', (134, 141))	('kidney disease', 'Phenotype', 'HP:0000112', (181, 195))	('renal fibrosis', 'Disease', (142, 156))	('CKD', 'Disease', (197, 200))	('suffer', 'Reg', (161, 167))	('CKD', 'Disease', 'MESH:D012080', (197, 200))	('renal fibrosis', 'Phenotype', 'HP:0030760', (142, 156))	('chronic kidney disease', 'Disease', 'MESH:D051436', (173, 195))	('deficient', 'Var', (9, 18))
90365	33022986	When basal expression of PGC-1alpha is disrupted in the kidney, the risk of cancer increases.	('increases', 'PosReg', (83, 92))	('PGC-1alpha', 'Gene', (25, 35))	('disrupted', 'Var', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
90369	33022986	Inactivation of PGC-1alpha in cancer cells rescued hyperplastic phenotypes in FLCN-null kidneys.	('PGC-1alpha', 'Gene', (16, 26))	('rescued', 'PosReg', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('Inactivation', 'Var', (0, 12))	('hyperplastic phenotypes', 'MPA', (51, 74))
90372	33022986	The most common genetic driver of ccRCC is the tumor suppressor Von Hippel-Lindau (Vhl), which, when mutated, promotes constitutive expression of HIF-a and promotes metastasis, invasion, angiogenesis, and metabolism.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('47', '63'))	('metastasis', 'CPA', (165, 175))	('tumor', 'Disease', (47, 52))	('invasion', 'CPA', (177, 185))	('angiogenesis', 'biological_process', 'GO:0001525', ('187', '199'))	('mutated', 'Var', (101, 108))	('constitutive', 'MPA', (119, 131))	('tumor suppressor', 'biological_process', 'GO:0051726', ('47', '63'))	('ccRCC', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('metabolism', 'CPA', (205, 215))	('promotes', 'PosReg', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('metabolism', 'biological_process', 'GO:0008152', ('205', '215'))	('HIF-a', 'Protein', (146, 151))	('angiogenesis', 'CPA', (187, 199))	('promotes', 'PosReg', (156, 164))
90424	33022986	Furthermore, stimulating PGC-1alpha expression in diabetic kidneys via AICAR treatment rescued superoxide production in kidneys in addition to a number of clinical outputs.	('stimulating', 'Var', (13, 24))	('superoxide production', 'MPA', (95, 116))	('PGC-1alpha', 'Gene', (25, 35))	('superoxide', 'Chemical', 'MESH:D013481', (95, 105))	('diabetic kidneys', 'Disease', (50, 66))	('rescued', 'PosReg', (87, 94))	('diabetic kidneys', 'Disease', 'MESH:D003920', (50, 66))
90428	33022986	Using an inducible nephron-specific PGC-1alpha overexpression line, the authors found excess PGC-1alpha causes collapsing glomerulopathy including albuminuria and renal failure/glomerulosclerosis.	('glomerulosclerosis', 'Disease', 'MESH:D005921', (177, 195))	('glomerulopathy', 'Disease', (122, 136))	('glomerulopathy', 'Disease', 'MESH:D007674', (122, 136))	('albuminuria and renal failure', 'Disease', 'MESH:D051437', (147, 176))	('renal failure', 'Phenotype', 'HP:0000083', (163, 176))	('glomerulosclerosis', 'Disease', (177, 195))	('causes', 'Reg', (104, 110))	('excess', 'Var', (86, 92))	('glomerulosclerosis', 'Phenotype', 'HP:0000096', (177, 195))	('glomerulopathy', 'Phenotype', 'HP:0100820', (122, 136))	('PGC-1alpha', 'Gene', (93, 103))	('albuminuria', 'Phenotype', 'HP:0012592', (147, 158))
90455	33022986	The authors were able to rescue superoxide production by supplementing PKD1 mutant cells with MitoQuinone, a mitochondrion antioxidant.	('PKD1', 'Gene', (71, 75))	('rescue', 'PosReg', (25, 31))	('superoxide production', 'MPA', (32, 53))	('MitoQuinone', 'Chemical', 'MESH:C429014', (94, 105))	('superoxide', 'Chemical', 'MESH:D013481', (32, 42))	('mutant', 'Var', (76, 82))	('mitochondrion', 'cellular_component', 'GO:0005739', ('109', '122'))
90461	33022986	While studies of PGC-1alpha knockouts in mice do not result in cystogenesis, there are a number of reasons to continue investigations.	('mice', 'Species', '10090', (41, 45))	('knockouts', 'Var', (28, 37))	('PGC-1alpha', 'Gene', (17, 27))
90462	33022986	Some of these reasons include: the possibility of PGC-1beta compensation, the unending connections of PGC-1alpha pathway components and their relationship to PKD etiology and progression and compelling data from recent studies using zebrafish pronephros where loss of PGC-1alpha induces cystogenesis in the kidney.	('zebrafish', 'Species', '7955', (233, 242))	('PKD', 'Disease', 'MESH:C537180', (158, 161))	('PKD', 'Disease', (158, 161))	('induces', 'Reg', (279, 286))	('cystogenesis in the', 'CPA', (287, 306))	('PGC-1alpha', 'Gene', (268, 278))	('loss', 'Var', (260, 264))
90469	33022986	This variety of transcript variants could result in compensation in knockout murine models, which have historically targeted exons 3-5, although there are a number of PGC-1alpha transcript variants that do not include these exons.	('variants', 'Var', (27, 35))	('PGC-1alpha', 'Gene', (167, 177))	('variants', 'Var', (189, 197))	('murine', 'Species', '10090', (77, 83))	('result', 'Reg', (42, 48))
90471	33022986	The dynamic expression and roles of PGC-1alpha and the associated transcript variants give reason to question if PGC-1alpha may be involved in an even greater number of processes in mammalian physiology.	('PGC-1alpha', 'Gene', (36, 46))	('variants', 'Var', (77, 85))	('involved', 'Reg', (131, 139))	('mammalian', 'Species', '9606', (182, 191))
90473	33022986	It does not appear that this compensation exists in all vertebrates as PGC-1alpha deficient zebrafish exhibit more severe phenotypes than their mammalian counterparts.	('zebrafish', 'Species', '7955', (92, 101))	('mammalian', 'Species', '9606', (144, 153))	('deficient', 'Var', (82, 91))	('PGC-1alpha', 'Gene', (71, 81))
90475	33022986	Specifically, loss of PGC-1alpha results in a decrease of expression in the transporter Slc12a3 (NCCT) in zebrafish and mice.	('zebrafish', 'Species', '7955', (106, 115))	('PGC-1alpha', 'Gene', (22, 32))	('loss', 'Var', (14, 18))	('transporter', 'MPA', (76, 87))	('mice', 'Species', '10090', (120, 124))	('expression', 'MPA', (58, 68))	('decrease', 'NegReg', (46, 54))
90480	32029730	Our analysis reveals that a mutational signature associated with aristolochic acid (AA) exposure is widespread in Chinese ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('aristolochic acid', 'Chemical', 'MESH:D034341', (65, 82))	('aristolochic acid', 'Var', (65, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (122, 127))	('ccRCC', 'Disease', (122, 127))	('ccRCC', 'Disease', 'MESH:D002292', (122, 127))
90481	32029730	Tumors from patients with ccRCC-TT show a higher mutational burden and genomic instability; in addition, mutations in BAP1 and SETD2 are highly enriched in patients with ccRCC-TT.	('ccRCC', 'Disease', (26, 31))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (105, 114))	('RCC', 'Phenotype', 'HP:0005584', (28, 31))	('patients', 'Species', '9606', (156, 164))	('patients', 'Species', '9606', (12, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (26, 31))	('TT', 'Disease', 'MESH:D013927', (176, 178))	('BAP1', 'Gene', '8314', (118, 122))	('Tumors', 'Disease', (0, 6))	('ccRCC', 'Disease', 'MESH:D002292', (170, 175))	('mutational burden', 'MPA', (49, 66))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('SETD2', 'Gene', (127, 132))	('BAP1', 'Gene', (118, 122))	('TT', 'Disease', 'MESH:D013927', (32, 34))	('ccRCC', 'Disease', (170, 175))	('ccRCC', 'Disease', 'MESH:D002292', (26, 31))	('SETD2', 'Gene', '29072', (127, 132))	('genomic instability', 'CPA', (71, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (170, 175))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))
90485	32029730	Here, the authors analyse a cohort of Chinese ccRCC cases revealing a mutational signature associated with aristolochic acid exposure, and higher mutational burden and enrichment for BAP1 and SETD2 mutations in ccRCC cases associated with tumor thrombus.	('ccRCC', 'Disease', 'MESH:D002292', (46, 51))	('ccRCC', 'Phenotype', 'HP:0006770', (211, 216))	('associated', 'Reg', (223, 233))	('BAP1', 'Gene', (183, 187))	('ccRCC', 'Disease', (46, 51))	('aristolochic acid', 'MPA', (107, 124))	('mutations', 'Var', (198, 207))	('SETD2', 'Gene', (192, 197))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('mutational burden', 'MPA', (146, 163))	('higher', 'PosReg', (139, 145))	('tumor thrombus', 'Disease', 'MESH:D013927', (239, 253))	('ccRCC', 'Disease', 'MESH:D002292', (211, 216))	('SETD2', 'Gene', '29072', (192, 197))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	('tumor thrombus', 'Disease', (239, 253))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('associated', 'Reg', (91, 101))	('BAP1', 'Gene', '8314', (183, 187))	('ccRCC', 'Disease', (211, 216))	('aristolochic acid', 'Chemical', 'MESH:D034341', (107, 124))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))
90489	32029730	In the Caucasian population, ccRCC is featured by ubiquitous biallelic inactivation of VHL, which can be caused by chromosome 3p loss, concomitant VHL mutation, or promoter methylation.	('promoter methylation', 'Var', (164, 184))	('ccRCC', 'Disease', (29, 34))	('ccRCC', 'Disease', 'MESH:D002292', (29, 34))	('VHL', 'Disease', 'MESH:D006623', (147, 150))	('methylation', 'biological_process', 'GO:0032259', ('173', '184'))	('VHL', 'Disease', (147, 150))	('loss', 'NegReg', (129, 133))	('mutation', 'Var', (151, 159))	('chromosome', 'cellular_component', 'GO:0005694', ('115', '125'))	('VHL', 'Disease', 'MESH:D006623', (87, 90))	('VHL', 'Disease', (87, 90))	('caused', 'Reg', (105, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
90490	32029730	Other frequent genomic alterations of ccRCC include mutations in chromatin and histone modifier genes such as PBRM1, BAP1, and SETD2 (refs.).	('mutations', 'Var', (52, 61))	('BAP1', 'Gene', '8314', (117, 121))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('SETD2', 'Gene', '29072', (127, 132))	('chromatin', 'cellular_component', 'GO:0000785', ('65', '74'))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('BAP1', 'Gene', (117, 121))	('ccRCC', 'Disease', (38, 43))	('ccRCC', 'Disease', 'MESH:D002292', (38, 43))	('SETD2', 'Gene', (127, 132))	('PBRM1', 'Gene', (110, 115))	('PBRM1', 'Gene', '55193', (110, 115))
90502	32029730	Importantly, we find that inactivation of one of the chromatin remodeling genes BAP1 and SETD2 is significantly more common in ccRCC patients with TT.	('common', 'Reg', (117, 123))	('inactivation', 'Var', (26, 38))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('53', '73'))	('SETD2', 'Gene', '29072', (89, 94))	('BAP1', 'Gene', '8314', (80, 84))	('patients', 'Species', '9606', (133, 141))	('TT', 'Disease', 'MESH:D013927', (147, 149))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('SETD2', 'Gene', (89, 94))	('ccRCC', 'Disease', (127, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('ccRCC', 'Disease', 'MESH:D002292', (127, 132))	('chromatin', 'cellular_component', 'GO:0000785', ('53', '62'))	('BAP1', 'Gene', (80, 84))
90505	32029730	A total of 12,534 somatic changes were identified, including 12,012 single-nucleotide variants (SNVs) and 522 insertions or deletions (InDels).	('single-nucleotide variants', 'Var', (68, 94))	('deletions', 'Var', (124, 133))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('insertions', 'Var', (110, 120))
90509	32029730	Notably, VHL mutation was the most prominent variation (58%), followed by PBRM1 (29%), CSMD3 (11%), BAP1 (11%), SETD2 (11%), and KDM5C (11%).	('BAP1', 'Gene', '8314', (100, 104))	('CSMD3', 'Gene', (87, 92))	('CSMD3', 'Gene', '114788', (87, 92))	('KDM5C', 'Gene', (129, 134))	('PBRM1', 'Gene', '55193', (74, 79))	('SETD2', 'Gene', '29072', (112, 117))	('mutation', 'Var', (13, 21))	('BAP1', 'Gene', (100, 104))	('KDM5C', 'Gene', '8242', (129, 134))	('SETD2', 'Gene', (112, 117))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('VHL', 'Disease', 'MESH:D006623', (9, 12))	('VHL', 'Disease', (9, 12))	('PBRM1', 'Gene', (74, 79))
90511	32029730	However, the Chinese cohort had significantly higher mutation frequencies in CSMD3 (11% vs. 3%, Fisher's exact test, p = 5.99e-04) and TMPRSS13 (7% vs. 0.2%, Fisher's exact test, p = 1.25e-05) in comparison with those of the TCGA cohort (Fig.	('TMPRSS13', 'Gene', '84000', (135, 143))	('TMPRSS13', 'Gene', (135, 143))	('mutation', 'Var', (53, 61))	('higher', 'PosReg', (46, 52))	('CSMD3', 'Gene', (77, 82))	('CSMD3', 'Gene', '114788', (77, 82))
90513	32029730	Moreover, recent studies showed that loss of CSMD3 could increase the proliferation of airway epithelial cells and is involved in the tumorigenesis of lung cancer.	('CSMD3', 'Gene', (45, 50))	('CSMD3', 'Gene', '114788', (45, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('proliferation of airway epithelial cells', 'CPA', (70, 110))	('lung cancer', 'Disease', (151, 162))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('involved', 'Reg', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('increase', 'PosReg', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('loss', 'Var', (37, 41))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))	('tumor', 'Disease', (134, 139))
90517	32029730	Some new recurrent SCNA regions were identified in Chinese ccRCC, including 7q11.22 gain, 11q14.1 gain, 12q24.32 gain, and 6q24.3 loss (Fig.	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('ccRCC', 'Disease', 'MESH:D002292', (59, 64))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('ccRCC', 'Disease', (59, 64))	('6q24.3', 'Var', (123, 129))	('12q24.32', 'Var', (104, 112))	('gain', 'PosReg', (113, 117))	('loss', 'NegReg', (130, 134))	('N', 'Chemical', 'MESH:D009584', (21, 22))	('gain', 'PosReg', (98, 102))	('gain', 'PosReg', (84, 88))
90520	32029730	Signatures MS2 and MS3 correspond to Catalog of Somatic Mutations in Cancer (COSMIC; https://cancer.sanger.ac.uk/cosmic/signatures/) Signature SBS5 and SBS40, respectively.	('MS3', 'Gene', (19, 22))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('MS2', 'Gene', (11, 14))	('SBS40', 'Var', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('MS3', 'Gene', '100271695', (19, 22))	('MS2', 'Gene', '100271694', (11, 14))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))
90521	32029730	SBS5 exhibits transcriptional strand bias for T > C substitutions in the ApTpN context, is found in most cancers and is correlated with age.	('T > C substitutions', 'Var', (46, 65))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('N', 'Chemical', 'MESH:D009584', (77, 78))	('found', 'Reg', (91, 96))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ApTpN', 'Gene', (73, 78))
90522	32029730	In addition, the etiology of SBS40 is unknown, but the number of mutations attributed to SBS40 is correlated with patient age for some types of human cancer.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('SBS40', 'Gene', (89, 94))	('human', 'Species', '9606', (144, 149))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('patient', 'Species', '9606', (114, 121))	('mutations', 'Var', (65, 74))
90529	32029730	It is worth noting that AA patients had significantly higher mutation frequencies in CSMD3 (22.5% vs. 6.25%, Fisher's exact test, p = 0.01273, Fig.	('higher', 'PosReg', (54, 60))	('mutation', 'Var', (61, 69))	('patients', 'Species', '9606', (27, 35))	('CSMD3', 'Gene', (85, 90))	('CSMD3', 'Gene', '114788', (85, 90))
90533	32029730	Moreover, we observed that BAP1, CSMD3, TP53, SETD2, PTEN, PCLO, PIK3CA, and VHL were mutated at a higher frequency in ccRCC-TT patients (Fig.	('mutated', 'Var', (86, 93))	('TP53', 'Gene', '7157', (40, 44))	('PTEN', 'Gene', (53, 57))	('ccRCC', 'Disease', 'MESH:D002292', (119, 124))	('VHL', 'Disease', 'MESH:D006623', (77, 80))	('PIK3CA', 'Gene', '5290', (65, 71))	('ccRCC', 'Disease', (119, 124))	('PCLO', 'Chemical', 'MESH:C498630', (59, 63))	('PTEN', 'Gene', '5728', (53, 57))	('BAP1', 'Gene', '8314', (27, 31))	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('SETD2', 'Gene', (46, 51))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('CSMD3', 'Gene', '114788', (33, 38))	('PIK3CA', 'Gene', (65, 71))	('TP53', 'Gene', (40, 44))	('patients', 'Species', '9606', (128, 136))	('SETD2', 'Gene', '29072', (46, 51))	('VHL', 'Disease', (77, 80))	('BAP1', 'Gene', (27, 31))	('CSMD3', 'Gene', (33, 38))	('TT', 'Disease', 'MESH:D013927', (125, 127))
90534	32029730	Specifically, mutations in BAP1, an important gene that is involved in chromatin dynamics, is associated with a high risk for metastasis in uveal melanoma and is known as a tumor suppressor in ccRCC, occurred more frequently in ccRCC-TT patients in comparison with ccRCC patients (24% vs. 5%, Fisher's exact test, p = 0.002186, Fig.	('ccRCC', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('RCC', 'Phenotype', 'HP:0005584', (267, 270))	('ccRCC', 'Phenotype', 'HP:0006770', (265, 270))	('RCC', 'Phenotype', 'HP:0005584', (195, 198))	('uveal melanoma', 'Phenotype', 'HP:0007716', (140, 154))	('patients', 'Species', '9606', (237, 245))	('ccRCC', 'Phenotype', 'HP:0006770', (193, 198))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('ccRCC', 'Disease', 'MESH:D002292', (228, 233))	('occurred', 'Reg', (200, 208))	('TT', 'Disease', 'MESH:D013927', (234, 236))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('associated', 'Reg', (94, 104))	('mutations', 'Var', (14, 23))	('BAP1', 'Gene', '8314', (27, 31))	('ccRCC', 'Disease', (228, 233))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('173', '189'))	('patients', 'Species', '9606', (271, 279))	('RCC', 'Phenotype', 'HP:0005584', (230, 233))	('ccRCC', 'Disease', 'MESH:D002292', (265, 270))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('ccRCC', 'Phenotype', 'HP:0006770', (228, 233))	('melanoma', 'Disease', (146, 154))	('BAP1', 'Gene', (27, 31))	('tumor suppressor', 'biological_process', 'GO:0051726', ('173', '189'))	('ccRCC', 'Disease', 'MESH:D002292', (193, 198))	('tumor', 'Disease', (173, 178))	('chromatin', 'cellular_component', 'GO:0000785', ('71', '80'))	('ccRCC', 'Disease', (265, 270))
90535	32029730	In addition, Chinese ccRCC-TT patients had a higher mutation frequency of SETD2 (19% vs. 7%, Fisher's exact test, p = 0.04278, Fig.	('SETD2', 'Gene', '29072', (74, 79))	('SETD2', 'Gene', (74, 79))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (21, 26))	('ccRCC', 'Disease', (21, 26))	('patients', 'Species', '9606', (30, 38))	('TT', 'Disease', 'MESH:D013927', (27, 29))	('mutation', 'Var', (52, 60))	('higher', 'PosReg', (45, 51))	('ccRCC', 'Disease', 'MESH:D002292', (21, 26))
90536	32029730	3b), a H3K36 methyltransferase whose inactivation promoted renal cancer branched evolution and whose overexpression in gastric cancer cell lines significantly inhibited cell proliferation, migration, and invasion.	('renal cancer', 'Disease', (59, 71))	('invasion', 'CPA', (204, 212))	('overexpression', 'PosReg', (101, 115))	('promoted', 'PosReg', (50, 58))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('renal cancer', 'Phenotype', 'HP:0009726', (59, 71))	('cell proliferation', 'biological_process', 'GO:0008283', ('169', '187'))	('gastric cancer', 'Disease', (119, 133))	('renal cancer', 'Disease', 'MESH:D007680', (59, 71))	('H3K36 methyltransferase', 'Enzyme', (7, 30))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('cell proliferation', 'CPA', (169, 187))	('inactivation', 'Var', (37, 49))	('inhibited', 'NegReg', (159, 168))
90538	32029730	Consistently, BAP1 and/or SETD2 mutations were highly enriched in ccRCC-TT patients (40% vs. 8%, Fisher's exact test, p = 0.04379), which was in agreement with a previous study (Supplementary Fig.	('BAP1', 'Gene', '8314', (14, 18))	('SETD2', 'Gene', '29072', (26, 31))	('BAP1', 'Gene', (14, 18))	('patients', 'Species', '9606', (75, 83))	('SETD2', 'Gene', (26, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('mutations', 'Var', (32, 41))	('TT', 'Disease', 'MESH:D013927', (72, 74))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('ccRCC', 'Disease', (66, 71))	('ccRCC', 'Disease', 'MESH:D002292', (66, 71))
90539	32029730	Permutation tests showed that BAP1 mutations were mutually exclusive with SETD2 mutations (Fig.	('SETD2', 'Gene', '29072', (74, 79))	('BAP1', 'Gene', (30, 34))	('mutations', 'Var', (80, 89))	('SETD2', 'Gene', (74, 79))	('BAP1', 'Gene', '8314', (30, 34))	('mutations', 'Var', (35, 44))
90540	32029730	We also observed mutual exclusivity between BAP1 mutation and SETD2 mutation in the TCGA data, and survival analysis of BAP1/SETD2 status showed different outcomes for the two types of events, with cases with BAP1 or SETD2 mutation exhibiting worse overall survival (OS) in comparison with wild-type individuals (median OS 31.2 vs. 37.9 months, p = 0.0016, log-rank test, Supplementary Fig.	('BAP1', 'Gene', (209, 213))	('BAP1', 'Gene', (44, 48))	('SETD2', 'Gene', '29072', (217, 222))	('mutation', 'Var', (223, 231))	('SETD2', 'Gene', '29072', (62, 67))	('BAP1', 'Gene', '8314', (44, 48))	('BAP1', 'Gene', '8314', (120, 124))	('SETD2', 'Gene', '29072', (125, 130))	('SETD2', 'Gene', (217, 222))	('SETD2', 'Gene', (62, 67))	('BAP1', 'Gene', '8314', (209, 213))	('SETD2', 'Gene', (125, 130))	('BAP1', 'Gene', (120, 124))
90541	32029730	In addition, DNA replication and base excision repair pathways were highly enriched in tumors with BAP1 or SETD2 mutations in comparison with tumors lacking these mutations (Supplementary Fig.	('BAP1', 'Gene', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('enriched', 'PosReg', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('mutations', 'Var', (113, 122))	('SETD2', 'Gene', '29072', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('base excision repair', 'biological_process', 'GO:0006284', ('33', '53'))	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('BAP1', 'Gene', '8314', (99, 103))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('base excision repair pathways', 'Pathway', (33, 62))	('N', 'Chemical', 'MESH:D009584', (14, 15))	('DNA replication', 'biological_process', 'GO:0006260', ('13', '28'))	('SETD2', 'Gene', (107, 112))
90543	32029730	These results highlighted that ccRCC patients with BAP1 or SETD2 mutations in the primary tumor are more prone to develop a thrombus.	('thrombus', 'Disease', (124, 132))	('BAP1', 'Gene', '8314', (51, 55))	('BAP1', 'Gene', (51, 55))	('patients', 'Species', '9606', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('SETD2', 'Gene', '29072', (59, 64))	('thrombus', 'Disease', 'MESH:D013927', (124, 132))	('develop', 'PosReg', (114, 121))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('prone', 'Reg', (105, 110))	('SETD2', 'Gene', (59, 64))	('ccRCC', 'Phenotype', 'HP:0006770', (31, 36))	('ccRCC', 'Disease', (31, 36))	('mutations', 'Var', (65, 74))	('ccRCC', 'Disease', 'MESH:D002292', (31, 36))
90547	32029730	Taken together, these results suggested that dysfunction of the chromatin remodeling pathway is critical for the occurrence of a thrombus in ccRCC patients.	('ccRCC', 'Disease', 'MESH:D002292', (141, 146))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('64', '84'))	('dysfunction', 'Var', (45, 56))	('thrombus', 'Disease', (129, 137))	('chromatin remodeling pathway', 'Pathway', (64, 92))	('chromatin', 'cellular_component', 'GO:0000785', ('64', '73'))	('patients', 'Species', '9606', (147, 155))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('ccRCC', 'Phenotype', 'HP:0006770', (141, 146))	('ccRCC', 'Disease', (141, 146))	('thrombus', 'Disease', 'MESH:D013927', (129, 137))
90549	32029730	Mutations were classified as shared mutations if they occurred in both the primary tumor and thrombus, and specific if they were only detected in either sample.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('Mutations', 'Var', (0, 9))	('thrombus', 'Disease', 'MESH:D013927', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('thrombus', 'Disease', (93, 101))
90550	32029730	The percentage of specific mutations in each ccRCC-TT case ranged from 3.9% to 100%, with an average of 43.44%, demonstrating a variable extent of genomic heterogeneity between the primary tumor and thrombus (Fig.	('mutations', 'Var', (27, 36))	('tumor', 'Disease', (189, 194))	('thrombus', 'Disease', 'MESH:D013927', (199, 207))	('TT', 'Disease', 'MESH:D013927', (51, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('thrombus', 'Disease', (199, 207))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('ccRCC', 'Disease', (45, 50))	('ccRCC', 'Disease', 'MESH:D002292', (45, 50))
90551	32029730	Although some primary tumors and thrombi displayed ongoing evolution leading to specific mutations, most putative driver mutations, such as those in VHL, BAP1, and SETD2, were shared by two regions (Fig.	('leading', 'Reg', (69, 76))	('BAP1', 'Gene', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('VHL', 'Disease', (149, 152))	('SETD2', 'Gene', '29072', (164, 169))	('VHL', 'Disease', 'MESH:D006623', (149, 152))	('mutations', 'Var', (89, 98))	('tumors and thrombi', 'Disease', 'MESH:D009369', (22, 40))	('SETD2', 'Gene', (164, 169))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('BAP1', 'Gene', '8314', (154, 158))
90552	32029730	Interestingly, there was no shared mutation between the primary tumor and thrombus in patients C032 and C042, which was indicative of multi-clonal origin.	('tumor', 'Disease', (64, 69))	('C032', 'Var', (95, 99))	('thrombus', 'Disease', (74, 82))	('C042', 'Var', (104, 108))	('C042', 'Chemical', 'MESH:C572522', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('thrombus', 'Disease', 'MESH:D013927', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('patients', 'Species', '9606', (86, 94))
90565	32029730	The m1 cluster showed upregulation of the autophagy pathway and higher frequencies of CSMD3 mutations (42.9% in m1 vs. 8.3% in others, Fisher's exact test, p = 0.003); this cluster also harbored a greater number of ARID1A mutations (14.3% vs. 1.2%, Fisher's exact test, p = 0.053) and PIK3CA mutations (14.3% vs. 2.4%, Fisher's exact test, p = 0.097).	('ARID1A', 'Gene', (215, 221))	('mutations', 'Var', (292, 301))	('CSMD3', 'Gene', '114788', (86, 91))	('autophagy', 'biological_process', 'GO:0006914', ('42', '51'))	('CSMD3', 'Gene', (86, 91))	('mutations', 'Var', (92, 101))	('autophagy pathway', 'CPA', (42, 59))	('PIK3CA', 'Gene', (285, 291))	('mutations', 'Var', (222, 231))	('upregulation', 'PosReg', (22, 34))	('PIK3CA', 'Gene', '5290', (285, 291))	('ARID1A', 'Gene', '8289', (215, 221))	('autophagy', 'biological_process', 'GO:0016236', ('42', '51'))
90566	32029730	Some genes associated with DNA repair were upregulated in cluster m2, and BAP1 mutations were more frequent in this cluster (31.3% vs. 7.3%, Fisher's exact test, p = 0.016); however, this group also harbored more SETD2 mutations (19% vs 12%, Fisher's exact test, p = 0.24).	('upregulated', 'PosReg', (43, 54))	('SETD2', 'Gene', '29072', (213, 218))	('BAP1', 'Gene', '8314', (74, 78))	('N', 'Chemical', 'MESH:D009584', (28, 29))	('SETD2', 'Gene', (213, 218))	('mutations', 'Var', (219, 228))	('BAP1', 'Gene', (74, 78))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))	('mutations', 'Var', (79, 88))	('DNA repair', 'biological_process', 'GO:0006281', ('27', '37'))
90567	32029730	Deletion of CDKN2A (50% vs 20.3%, Fisher's exact test, p = 0.008) and amplification of MDM4 (54.1% vs. 23.0%, Fisher's exact test, p = 0.009) were more frequent in Cluster m3 (Fig.	('frequent', 'Reg', (152, 160))	('MDM4', 'Gene', '4194', (87, 91))	('CDKN2A', 'Gene', (12, 18))	('CDKN2A', 'Gene', '1029', (12, 18))	('MDM4', 'Gene', (87, 91))	('Cluster m3', 'Disease', (164, 174))	('amplification', 'Var', (70, 83))	('Deletion', 'Var', (0, 8))
90570	32029730	Significant concordance was observed between our cluster m3 and the TCGA T3 subtype, and both two subtypes were characterized by a higher frequency of CDKN2A deletion (Fig.	('CDKN2A', 'Gene', '1029', (151, 157))	('CDKN2A', 'Gene', (151, 157))	('deletion', 'Var', (158, 166))
90571	32029730	Our Cluster m4 showed similarity to the TCGA T1 subtype, but PBRM1 mutations, which are common in the TCGA T1 subtypes were not enriched in cluster m4 (Supplementary Table 2).	('PBRM1', 'Gene', '55193', (61, 66))	('PBRM1', 'Gene', (61, 66))	('mutations', 'Var', (67, 76))
90576	32029730	Compared with the TCGA cohort, we found a higher prevalence of CSMD3 (11%) and TMPRSS13 (7%) mutations in Chinese patients.	('CSMD3', 'Gene', (63, 68))	('CSMD3', 'Gene', '114788', (63, 68))	('mutations', 'Var', (93, 102))	('TMPRSS13', 'Gene', (79, 87))	('patients', 'Species', '9606', (114, 122))	('TMPRSS13', 'Gene', '84000', (79, 87))
90583	32029730	In the current study, we found that patients with TT harbored significantly higher frequencies of mutations in BAP1 or SETD2.	('TT', 'Disease', 'MESH:D013927', (50, 52))	('patients', 'Species', '9606', (36, 44))	('BAP1', 'Gene', '8314', (111, 115))	('SETD2', 'Gene', '29072', (119, 124))	('mutations', 'Var', (98, 107))	('BAP1', 'Gene', (111, 115))	('SETD2', 'Gene', (119, 124))	('higher', 'PosReg', (76, 82))
90584	32029730	Interestingly, BAP1 and SETD2 mutations were mutually exclusive in our cohort, possibly because these two genes are functionally similar; both genes are involved in the chromatin remodeling pathway.	('BAP1', 'Gene', (15, 19))	('chromatin', 'cellular_component', 'GO:0000785', ('169', '178'))	('SETD2', 'Gene', '29072', (24, 29))	('BAP1', 'Gene', '8314', (15, 19))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('169', '189'))	('mutations', 'Var', (30, 39))	('SETD2', 'Gene', (24, 29))	('chromatin', 'Pathway', (169, 178))	('involved', 'Reg', (153, 161))
90585	32029730	described a multiple clonal drivers-subtype that sometimes involves BAP1 and SETD2 mutations in the same patient, but they also claimed that they generally observed mutual exclusivity between BAP1 and SETD2 mutations at the clonal level.	('mutations', 'Var', (83, 92))	('patient', 'Species', '9606', (105, 112))	('SETD2', 'Gene', '29072', (77, 82))	('BAP1', 'Gene', (192, 196))	('SETD2', 'Gene', (201, 206))	('SETD2', 'Gene', (77, 82))	('BAP1', 'Gene', '8314', (68, 72))	('BAP1', 'Gene', '8314', (192, 196))	('BAP1', 'Gene', (68, 72))	('SETD2', 'Gene', '29072', (201, 206))
90586	32029730	Moreover, BAP1 and SETD2 mutations were uniformly observed as shared mutations in both primary tumors and thrombi, indicating that mutations in these two genes occur relatively early during tumorigenesis.	('mutations', 'Var', (25, 34))	('SETD2', 'Gene', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('BAP1', 'Gene', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (190, 195))	('BAP1', 'Gene', '8314', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors and thrombi', 'Disease', 'MESH:D009369', (95, 113))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('SETD2', 'Gene', '29072', (19, 24))	('tumor', 'Disease', (95, 100))
90587	32029730	This finding suggests that the thrombosis process is a predetermined event that may be associated with BAP1 or SETD2 mutations in primary tumors.	('BAP1', 'Gene', '8314', (103, 107))	('mutations', 'Var', (117, 126))	('thrombosis', 'Disease', (31, 41))	('BAP1', 'Gene', (103, 107))	('associated', 'Reg', (87, 97))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('thrombosis', 'Disease', 'MESH:D013927', (31, 41))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('SETD2', 'Gene', '29072', (111, 116))	('SETD2', 'Gene', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
90588	32029730	Previous studies reported that mutations in BAP1 or SETD2 were associated with worse survival for ccRCC patients.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('mutations', 'Var', (31, 40))	('worse', 'NegReg', (79, 84))	('ccRCC', 'Disease', (98, 103))	('associated', 'Reg', (63, 73))	('ccRCC', 'Disease', 'MESH:D002292', (98, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('BAP1', 'Gene', '8314', (44, 48))	('SETD2', 'Gene', '29072', (52, 57))	('patients', 'Species', '9606', (104, 112))	('SETD2', 'Gene', (52, 57))	('BAP1', 'Gene', (44, 48))
90589	32029730	Our results reveal that mutations in BAP1 or SETD2 were highly enriched in patients with TT, which may indicate that the poor prognosis associated with BAP1 or SETD2 mutations is owing to the formation of a TT.	('SETD2', 'Gene', (45, 50))	('SETD2', 'Gene', '29072', (160, 165))	('mutations', 'Var', (166, 175))	('SETD2', 'Gene', (160, 165))	('TT', 'Disease', 'MESH:D013927', (89, 91))	('SETD2', 'Gene', '29072', (45, 50))	('BAP1', 'Gene', '8314', (152, 156))	('patients', 'Species', '9606', (75, 83))	('BAP1', 'Gene', '8314', (37, 41))	('formation', 'biological_process', 'GO:0009058', ('192', '201'))	('BAP1', 'Gene', (152, 156))	('mutations', 'Var', (24, 33))	('BAP1', 'Gene', (37, 41))	('TT', 'Disease', 'MESH:D013927', (207, 209))
90611	32029730	Next, realignment of all insertions and deletions (INDELs) and base quality recalibration were carried out using the Genome Analysis Toolkit (GATK 2.1-8).	('kit', 'Gene', (137, 140))	('kit', 'Gene', '3815', (137, 140))	('deletions', 'Var', (40, 49))	('insertions', 'Var', (25, 35))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('N', 'Chemical', 'MESH:D009584', (52, 53))
90622	32029730	Furthermore, we defined potential driver mutations if one of the following conditions was met: (1) mutations were documented by the COSMIC database (ccRCC-associated or related to another type of cancer; (2) mutations in the gene were identified by recent large-cohort ccRCC sequencing studies; (3) mutations in the gene were present in the KEGG (Kyoto Encyclopedia of Genes and Genomes) cancer pathways.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('present', 'Reg', (326, 333))	('ccRCC', 'Disease', 'MESH:D002292', (269, 274))	('cancer', 'Phenotype', 'HP:0002664', (388, 394))	('ccRCC', 'Phenotype', 'HP:0006770', (269, 274))	('ccRCC', 'Disease', 'MESH:D002292', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (388, 394))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', (388, 394))	('mutations', 'Var', (299, 308))	('RCC', 'Phenotype', 'HP:0005584', (271, 274))	('ccRCC', 'Phenotype', 'HP:0006770', (149, 154))	('ccRCC', 'Disease', (149, 154))	('ccRCC', 'Disease', (269, 274))
90629	32029730	To examine the correlations between BAP1 and SETD2 mutations and survival for the TCGA data, 417 patient samples were separated into gene-mutated and wild-type subsets.	('SETD2', 'Gene', (45, 50))	('mutations', 'Var', (51, 60))	('BAP1', 'Gene', '8314', (36, 40))	('patient', 'Species', '9606', (97, 104))	('BAP1', 'Gene', (36, 40))	('SETD2', 'Gene', '29072', (45, 50))
90692	31326335	We further observed that in clear cell RCC, lower BMI and male gender were associated with decreased survival, but this was not the case for chromophobe renal cell carcinoma.	('lower BMI', 'Phenotype', 'HP:0045082', (44, 53))	('lower BMI', 'Var', (44, 53))	('survival', 'MPA', (101, 109))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (153, 173))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('chromophobe renal cell carcinoma', 'Disease', (141, 173))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (141, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('clear cell RCC', 'Disease', (28, 42))	('decreased', 'NegReg', (91, 100))
90709	28875953	On the contrary, 14q LOH was a rare genomic alternation in advanced-staged ccRCC without PIS.	('14q LOH', 'Var', (17, 24))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('PIS', 'Chemical', '-', (89, 92))
90711	28875953	The results imply that the disruption of a 14q gene(s) might result in not only the inflammatory manifestations in the tumor host but also the poor survival rate as well.	('tumor', 'Disease', (119, 124))	('poor survival rate', 'CPA', (143, 161))	('result in', 'Reg', (61, 70))	('disruption', 'Var', (27, 37))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('inflammatory manifestations', 'CPA', (84, 111))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
90744	28875953	LOH was scored when the intensity ratio equaled either <0.70 (tumor allele 1 LOH) or >1.4 (tumor allele 2 LOH).	('<0.70', 'Var', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
90766	28875953	Until now, at least three different tumor suppressor genes seem to be involved in ccRCC tumorigenesis; (1) 3p12-14, which includes the breakpoint of the familial t(3;8) constitutional translocation and a recently cloned, putative tumor suppressor gene, the fragile histidine triad gene, is involved in hereditary RCC development; (2) 3p21.2-21.3, a common region of deletion in many cancers including lung cancer; and (3) 3p25-26, which contains tumor suppressor gene of von Hippel-Lindau disease.	('tumor suppressor', 'biological_process', 'GO:0051726', ('230', '246'))	('cancers', 'Disease', (383, 390))	('lung cancer', 'Phenotype', 'HP:0100526', (401, 412))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('446', '462'))	('deletion', 'Var', (366, 374))	('cancer', 'Phenotype', 'HP:0002664', (383, 389))	('RCC', 'Disease', (84, 87))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', (446, 451))	('RCC', 'Disease', (313, 316))	('RCC', 'Phenotype', 'HP:0005584', (313, 316))	('tumor suppressor', 'biological_process', 'GO:0051726', ('446', '462'))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (471, 496))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('36', '52'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (446, 451))	('cancer', 'Phenotype', 'HP:0002664', (406, 412))	('tumor', 'Disease', (88, 93))	('cancers', 'Disease', 'MESH:D009369', (383, 390))	('tumor', 'Disease', (230, 235))	('von Hippel-Lindau disease', 'Disease', (471, 496))	('RCC', 'Disease', 'MESH:C538614', (313, 316))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor suppressor', 'biological_process', 'GO:0051726', ('36', '52'))	('lung cancer', 'Disease', (401, 412))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('involved', 'Reg', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (446, 451))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('230', '246'))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('lung cancer', 'Disease', 'MESH:D008175', (401, 412))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('cancers', 'Phenotype', 'HP:0002664', (383, 390))	('triad', 'cellular_component', 'GO:0030315', ('275', '280'))
90767	28875953	No significant difference in LOH frequency was detected among the six different 3p markers between Groups A and B, indicating that chromosomal deletion on 3p is a common lesion in ccRCC regardless of the presence of PIS.	('PIS', 'Chemical', '-', (216, 219))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('chromosomal deletion on 3p', 'Var', (131, 157))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('RCC', 'Disease', (182, 185))
90770	28875953	LOH at 8p, 9p, and 14q has been reportedly associated with advanced-stage ccRCC.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('LOH at 8p', 'Var', (0, 9))	('associated', 'Reg', (43, 53))
90771	28875953	In agreement with the previous reports, we identified high frequencies of 8p, 9p, and 14q LOH in the advanced-stage ccRCC samples (data not shown).	('14q LOH', 'Var', (86, 93))	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('RCC', 'Disease', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))
90772	28875953	demonstrated that 14q loss in ccRCC was correlated with poor patient outcome.	('14q', 'Var', (18, 21))	('patient', 'Species', '9606', (61, 68))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('loss', 'NegReg', (22, 26))
90773	28875953	Among all the chromosome arms we investigated, only 14q loss was specifically observed more frequent in ccRCC with PIS than ccRCC without PIS.	('loss', 'NegReg', (56, 60))	('PIS', 'Chemical', '-', (138, 141))	('14q', 'Var', (52, 55))	('PIS', 'Chemical', '-', (115, 118))	('chromosome', 'cellular_component', 'GO:0005694', ('14', '24'))	('PIS', 'Disease', (115, 118))	('RCC', 'Disease', (106, 109))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('RCC', 'Disease', 'MESH:C538614', (126, 129))
90776	28875953	The present results imply that disruption of 14q gene(s) might result in not only aggressive tumor growth but also in the development of inflammatory syndromes.	('inflammatory syndromes', 'Disease', (137, 159))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('aggressive tumor', 'Disease', (82, 98))	('14q gene', 'Gene', (45, 53))	('disruption', 'Var', (31, 41))	('result in', 'Reg', (63, 72))	('aggressive tumor', 'Disease', 'MESH:D001523', (82, 98))
90779	28875953	It is intriguing to speculate that the putative tumor-derived factors might be attributing to 14q LOH in RCC with PIS.	('PIS', 'Chemical', '-', (114, 117))	('tumor', 'Disease', (48, 53))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('14q LOH', 'Var', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
90781	28875953	The results imply that the disruption of a 14q gene(s) might result in not only aggressive tumor growth but also inflammatory manifestations in the tumor host as well.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('result in', 'Reg', (61, 70))	('disruption', 'Var', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('aggressive tumor', 'Disease', 'MESH:D001523', (80, 96))	('aggressive tumor', 'Disease', (80, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('inflammatory manifestations', 'CPA', (113, 140))
90796	27705920	Currently, some molecular characteristics of ccRCC have been uncovered, such as recurrent mutations of von Hippel-Lindau (VHL), PBRM1, BAP1 and SETD2, and loss of chromosome 3p.	('chromosome', 'cellular_component', 'GO:0005694', ('163', '173'))	('PBRM1', 'Gene', '55193', (128, 133))	('mutations', 'Var', (90, 99))	('VHL', 'Disease', 'MESH:D006623', (122, 125))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('BAP1', 'Gene', '8314', (135, 139))	('von Hippel-Lindau', 'Gene', (103, 120))	('VHL', 'Disease', (122, 125))	('SETD2', 'Gene', '29072', (144, 149))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('BAP1', 'Gene', (135, 139))	('RCC', 'Disease', (47, 50))	('SETD2', 'Gene', (144, 149))	('von Hippel-Lindau', 'Gene', '7428', (103, 120))	('PBRM1', 'Gene', (128, 133))
90797	27705920	These genomic aberrations can potentially change the landscape of tumor transcriptomes by altering expression of global gene sets.	('expression of global gene sets', 'MPA', (99, 129))	('aberrations', 'Var', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('change', 'Reg', (42, 48))	('altering', 'Reg', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('landscape', 'MPA', (53, 62))
90798	27705920	For example, VHL mutations lead to imbalances of hypoxia inducible factors (HIF-1alpha and HIF-2alpha, or HIF1A and EPAS1) and then dysregulation of cellular metabolism.	('EPAS1', 'Gene', '2034', (116, 121))	('VHL', 'Disease', (13, 16))	('HIF1A', 'Gene', (106, 111))	('dysregulation', 'MPA', (132, 145))	('EPAS1', 'Gene', (116, 121))	('imbalances', 'MPA', (35, 45))	('HIF1A', 'Gene', '3091', (106, 111))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (76, 101))	('VHL', 'Disease', 'MESH:D006623', (13, 16))	('imbalances', 'Phenotype', 'HP:0002172', (35, 45))	('cellular metabolism', 'MPA', (149, 168))	('hypoxia', 'Disease', 'MESH:D000860', (49, 56))	('lead to', 'Reg', (27, 34))	('hypoxia', 'Disease', (49, 56))	('cellular metabolism', 'biological_process', 'GO:0044237', ('149', '168'))	('mutations', 'Var', (17, 26))
90799	27705920	Mutations in chromatin remodeling genes, including PBRM1, BAP1 and SETD2, may affect additional functional pathways through chromatin remodeling/histone methylation.	('SETD2', 'Gene', '29072', (67, 72))	('BAP1', 'Gene', (58, 62))	('SETD2', 'Gene', (67, 72))	('functional', 'MPA', (96, 106))	('histone methylation', 'biological_process', 'GO:0016571', ('145', '164'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('13', '33'))	('Mutations', 'Var', (0, 9))	('affect', 'Reg', (78, 84))	('PBRM1', 'Gene', (51, 56))	('chromatin', 'cellular_component', 'GO:0000785', ('124', '133'))	('chromatin', 'cellular_component', 'GO:0000785', ('13', '22'))	('chromatin remodeling/histone', 'MPA', (124, 152))	('PBRM1', 'Gene', '55193', (51, 56))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('124', '144'))	('BAP1', 'Gene', '8314', (58, 62))
90831	27705920	For example, mutations of VHL and PBRM1 frequently occur in clusters R1, R2, R3 and R4 but scarcely in R5.	('VHL', 'Disease', (26, 29))	('PBRM1', 'Gene', (34, 39))	('PBRM1', 'Gene', '55193', (34, 39))	('occur', 'Reg', (51, 56))	('mutations', 'Var', (13, 22))	('VHL', 'Disease', 'MESH:D006623', (26, 29))
90832	27705920	BAP1 mutations are abundant in R2 (20.83%) and R3 (17.95%) compared to R1 (1.01%) and R4 (4.71%) (p=5.86e-7, Fisher's exact test), whereas the PBRM1 gene is mutated more frequently in R1 (44.44%) and R4 (40.00%) compared to R2 (26.67%) and R3 (24.36%) (p=1.65e-4) (Figure 4A and Supplementary Table S5).	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('PBRM1', 'Gene', (143, 148))	('PBRM1', 'Gene', '55193', (143, 148))	('BAP1', 'Gene', '8314', (0, 4))
90833	27705920	The well-known frequent somatic alterations in ccRCC, such as losses of chromosome 3p and gene mutations of VHL, PBRM1 and BAP1, rarely occur in R5 (Supplementary Table S5).	('BAP1', 'Gene', (123, 127))	('RCC', 'Disease', (49, 52))	('chromosome', 'cellular_component', 'GO:0005694', ('72', '82'))	('PBRM1', 'Gene', (113, 118))	('gene mutations', 'Var', (90, 104))	('PBRM1', 'Gene', '55193', (113, 118))	('VHL', 'Disease', (108, 111))	('VHL', 'Disease', 'MESH:D006623', (108, 111))	('BAP1', 'Gene', '8314', (123, 127))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('losses', 'NegReg', (62, 68))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
90854	27705920	Notably, among the 10 prognosis modules (Figure 7A), the functions of M5 (blood vessel morphogenesis), M6 (carboxylic acid metabolism) and M10 (mitotic cell cycle) have been reported to be critical in ccRCC.	('blood vessel morphogenesis', 'biological_process', 'GO:0048514', ('74', '100'))	('M10', 'Var', (139, 142))	('mitotic cell cycle', 'biological_process', 'GO:0000278', ('144', '162'))	('carboxylic acid metabolism', 'biological_process', 'GO:0019752', ('107', '133'))	('RCC', 'Disease', 'MESH:C538614', (203, 206))	('carboxylic acid', 'Chemical', 'MESH:D002264', (107, 122))	('RCC', 'Disease', (203, 206))	('RCC', 'Phenotype', 'HP:0005584', (203, 206))
90855	27705920	Other prognosis modules such as M4 (mitochondrion translation), M7 (histone lysine methylation), M17 (extracellular matrix organization) and M18 (positive regulation of autophagy) may also exert important functions in tumorigenesis of ccRCC although they are less well-studied for the moment.	('translation', 'biological_process', 'GO:0006412', ('50', '61'))	('M17', 'Var', (97, 100))	('histone lysine methylation', 'biological_process', 'GO:0034968', ('68', '94'))	('histone lysine', 'Chemical', '-', (68, 82))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('102', '122'))	('M18', 'Var', (141, 144))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('positive regulation of autophagy', 'biological_process', 'GO:0010508', ('146', '178'))	('exert', 'Reg', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('mitochondrion', 'cellular_component', 'GO:0005739', ('36', '49'))	('extracellular matrix organization', 'biological_process', 'GO:0030198', ('102', '135'))	('RCC', 'Disease', (237, 240))	('RCC', 'Phenotype', 'HP:0005584', (237, 240))	('tumor', 'Disease', (218, 223))	('functions', 'Reg', (205, 214))	('RCC', 'Disease', 'MESH:C538614', (237, 240))
90856	27705920	This result also shows that low expression of M6 (carboxylic acid metabolism) and M18 (positive regulation of autophagy) and high expression of M10 (mitotic cell cycle), M17 (extracellular matrix organization) and M28 (lymphocyte activation) may be associated with poor prognosis in ccRCC (absolute Pearson's correlation coefficient > 0.5 in R2).	('RCC', 'Phenotype', 'HP:0005584', (285, 288))	('carboxylic acid metabolism', 'biological_process', 'GO:0019752', ('50', '76'))	('M10', 'Gene', (144, 147))	('positive regulation of autophagy', 'biological_process', 'GO:0010508', ('87', '119'))	('carboxylic acid', 'Chemical', 'MESH:D002264', (50, 65))	('M17', 'Var', (170, 173))	('lymphocyte activation', 'biological_process', 'GO:0046649', ('219', '240'))	('M28', 'Var', (214, 217))	('extracellular matrix organization', 'biological_process', 'GO:0030198', ('175', '208'))	('low', 'NegReg', (28, 31))	('mitotic cell cycle', 'biological_process', 'GO:0000278', ('149', '167'))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('175', '195'))	('M18', 'Gene', (82, 85))	('RCC', 'Disease', 'MESH:C538614', (285, 288))	('RCC', 'Disease', (285, 288))
90894	31840081	In the present article we utilized two entirely different approaches: targeting mammalian target of rapamycin (mTOR) pathway that is known to be involved in VEGF synthesis, and disruption of VEGF/Neuroplin-1 (NRP1) axis that is known to activate proangiogenic and pro-tumorigenic signaling in endothelial and tumor cells, respectively.	('mammalian target of rapamycin', 'Gene', (80, 109))	('NRP', 'biological_process', 'GO:0085015', ('209', '212'))	('tumor', 'Disease', (309, 314))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('disruption', 'Var', (177, 187))	('synthesis', 'biological_process', 'GO:0009058', ('162', '171'))	('signaling', 'biological_process', 'GO:0023052', ('280', '289'))	('activate', 'PosReg', (237, 245))	('tumor', 'Disease', (268, 273))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('proangiogenic', 'CPA', (246, 259))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('tumor', 'Disease', 'MESH:D009369', (268, 273))	('mammalian target of rapamycin', 'Gene', '2475', (80, 109))
90897	31840081	The TTP-liposomes encapsulating both Everolimus and EG00229 (EG-L) demonstrated higher in vitro and in vivo growth retardation than the single drug-loaded liposomes (E-L and G-L) in two different ccRCC models and led to a noticeable reduction in lung metastasis in vivo.	('growth retardation', 'Disease', (108, 126))	('EG00229', 'Chemical', '-', (52, 59))	('TTP', 'Gene', (4, 7))	('lung metastasis', 'CPA', (246, 261))	('growth retardation', 'Phenotype', 'HP:0001510', (108, 126))	('Everolimus', 'Chemical', 'MESH:D000068338', (37, 47))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('ccRCC', 'Phenotype', 'HP:0006770', (196, 201))	('RCC', 'Disease', (198, 201))	('EG00229', 'Var', (52, 59))	('reduction', 'NegReg', (233, 242))	('growth retardation', 'Disease', 'MESH:D006130', (108, 126))	('higher', 'PosReg', (80, 86))	('TTP', 'Gene', '22695', (4, 7))
90898	31840081	In addition, EG-L displayed remarkable inhibition of tumor growth in a highly aggressive syngeneic immune-competent mouse model of ccRCC developed in Balb/c mice.	('mice', 'Species', '10090', (157, 161))	('EG-L', 'Var', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('inhibition', 'NegReg', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('tumor', 'Disease', (53, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('mouse', 'Species', '10090', (116, 121))
90902	31840081	This VHL gene inactivation and high VEGF expression in RCC have been correlated with tumor aggressiveness and poor survival.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('correlated', 'Reg', (69, 79))	('tumor aggressiveness', 'Disease', (85, 105))	('RCC', 'Disease', (55, 58))	('expression', 'MPA', (41, 51))	('VHL', 'Gene', (5, 8))	('aggressiveness', 'Phenotype', 'HP:0000718', (91, 105))	('inactivation', 'Var', (14, 26))	('VHL', 'Gene', '22346', (5, 8))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (85, 105))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
90914	31840081	For instance, mTOR inhibitors have been shown to inhibit hypoxia- or growth factor-induced endothelial cell proliferation, migration, and tube formation in in vitro studies.	('tube formation', 'biological_process', 'GO:0035148', ('138', '152'))	('endothelial cell proliferation', 'biological_process', 'GO:0001935', ('91', '121'))	('tube formation', 'CPA', (138, 152))	('hypoxia', 'Disease', (57, 64))	('hypoxia', 'Disease', 'MESH:D000860', (57, 64))	('inhibitors', 'Var', (19, 29))	('migration', 'CPA', (123, 132))	('inhibit', 'NegReg', (49, 56))	('mTOR', 'Gene', (14, 18))
90916	31840081	Inhibition of mTOR induces apoptosis in tumor-associated endothelial cells that ultimately leads to significant reductions in microvessel density and tumor growth.	('microvessel density', 'CPA', (126, 145))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('reductions', 'NegReg', (112, 122))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('apoptosis', 'biological_process', 'GO:0097194', ('27', '36'))	('tumor', 'Disease', (150, 155))	('apoptosis', 'biological_process', 'GO:0006915', ('27', '36'))	('mTOR', 'Gene', (14, 18))
90918	31840081	Moreover, mTOR contributes in the hypoxic tumor response by stabilizing hypoxia-inducible factor-1alpha (HIF-1 alpha), hence it is not surprising that mTOR inhibitors can reduce VEGF expression and act as antiangiogenic agents.	('inhibitors', 'Var', (156, 166))	('VEGF', 'Protein', (178, 182))	('reduce', 'NegReg', (171, 177))	('HIF-1 alpha', 'Gene', '15251', (105, 116))	('hypoxia-inducible factor-1alpha', 'Gene', '15251', (72, 103))	('HIF-1 alpha', 'Gene', (105, 116))	('hypoxia-inducible factor-1alpha', 'Gene', (72, 103))	('expression', 'MPA', (183, 193))	('stabilizing', 'MPA', (60, 71))	('hypoxic tumor', 'Disease', (34, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('hypoxic tumor', 'Disease', 'MESH:D009369', (34, 47))
90920	31840081	Among them, one small-molecule inhibitor, EG00229, demonstrated remarkable growth inhibition in glioma and lung cancer via combined antiangiogenic and antitumor activity.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('growth inhibition', 'CPA', (75, 92))	('tumor', 'Disease', (155, 160))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('EG00229', 'Var', (42, 49))	('lung cancer', 'Disease', (107, 118))	('EG00229', 'Chemical', '-', (42, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('antiangiogenic', 'CPA', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('glioma', 'Disease', (96, 102))
90921	31840081	In addition, EG00229 has been shown to elicit immune-modulatory activity by blocking the M2 shift in microglial cells.	('M2 shift in microglial', 'MPA', (89, 111))	('EG00229', 'Var', (13, 20))	('elicit immune-modulatory activity', 'MPA', (39, 72))	('blocking', 'NegReg', (76, 84))	('EG00229', 'Chemical', '-', (13, 20))
90922	31840081	Based on our previous work showing that the VEGF/NRP1 axis can be a great target for ccRCC, we sought to examine whether EG00229 would have similar antitumor efficacy in RCC, either alone or in combination with other drugs.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('RCC', 'Disease', (170, 173))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('tumor', 'Disease', (152, 157))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('NRP', 'biological_process', 'GO:0085015', ('49', '52'))	('EG00229', 'Var', (121, 128))	('EG00229', 'Chemical', '-', (121, 128))
90926	31840081	Another added advantage of our liposomal formulation is that we have tagged a proprietary tumor-targeting peptide (TTP) to the surface of the liposomes to enhance the tumor-specific delivery of the drugs and reduce any toxicity arising from the treatment of Everolimus as well as systemic inhibition of NRP1.	('tagged', 'Var', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('enhance', 'PosReg', (155, 162))	('toxicity', 'Disease', 'MESH:D064420', (219, 227))	('toxicity', 'Disease', (219, 227))	('TTP', 'Gene', (115, 118))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('TTP', 'Gene', '22695', (115, 118))	('men', 'Species', '9606', (250, 253))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('NRP', 'biological_process', 'GO:0085015', ('303', '306'))	('NRP1', 'Protein', (303, 307))	('Everolimus', 'Chemical', 'MESH:D000068338', (258, 268))	('tumor', 'Disease', (167, 172))	('reduce', 'NegReg', (208, 214))
90935	31840081	The average hydrodynamic size, polydispersity index (PDI), and zeta potential of empty liposomes (L) as well as liposomes containing Everolimus (E-L), EG00229 (G-L), and a combination of both (EG-L) are consolidated in Table 2.	('EG00229', 'Var', (151, 158))	('Everolimus', 'Chemical', 'MESH:D000068338', (133, 143))	('zeta potential', 'MPA', (63, 77))	('EG00229', 'Chemical', '-', (151, 158))	('polydispersity index', 'MPA', (31, 51))
90954	31840081	Similar to the in vitro studies, EG-L was better than E-L or G-L in impeding tumor growth in both 786-O and A498 xenografts (Fig.	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('impeding', 'NegReg', (68, 76))	('tumor', 'Disease', (77, 82))	('EG-L', 'Var', (33, 37))
90976	31840081	Interestingly, the H&E-stained whole-lung sections displayed metastatic nodules in the control mouse or mice treated with L or E-L, whereas G-L and EG-L treated mice lung sections exhibited no detectable nodules (Fig.	('mice', 'Species', '10090', (161, 165))	('mice', 'Species', '10090', (104, 108))	('with', 'Var', (117, 121))	('displayed metastatic', 'CPA', (51, 71))	('H&E', 'Chemical', '-', (19, 22))	('mouse', 'Species', '10090', (95, 100))
90977	31840081	Our results suggest that both G-L and EG-L were capable of reducing the lung metastases in ccRCC, which might have significant clinical relevance.	('lung metastases', 'Disease', (72, 87))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('lung metastases', 'Disease', 'MESH:D009362', (72, 87))	('RCC', 'Disease', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('reducing', 'NegReg', (59, 67))	('EG-L', 'Var', (38, 42))
91007	31840081	EG00229 has been shown to bind to the b1 domain of NRP1 leading to the disruption of VEGF-NRP1 binding.	('NRP', 'biological_process', 'GO:0085015', ('51', '54'))	('NRP', 'biological_process', 'GO:0085015', ('90', '93'))	('EG00229', 'Var', (0, 7))	('disruption', 'NegReg', (71, 81))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))	('VEGF-NRP1', 'Protein', (85, 94))	('NRP1', 'Gene', (51, 55))	('EG00229', 'Chemical', '-', (0, 7))	('binding', 'Interaction', (95, 102))
91009	31840081	In addition, disruption of VEGF-NRP1 axis inhibits the tumor cell autocrine signaling via regulating the expression and function of various downstream effector molecules including Ras and beta-catenin.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('function', 'MPA', (120, 128))	('inhibits', 'NegReg', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('beta-catenin', 'Gene', '12387', (188, 200))	('autocrine signaling', 'biological_process', 'GO:0035425', ('66', '85'))	('NRP', 'biological_process', 'GO:0085015', ('32', '35'))	('disruption', 'Var', (13, 23))	('tumor', 'Disease', (55, 60))	('regulating', 'Reg', (90, 100))	('VEGF-NRP1 axis', 'Gene', (27, 41))	('beta-catenin', 'Gene', (188, 200))	('expression', 'MPA', (105, 115))
91012	31840081	Hence, in the present work, we hypothesized that targeting the VEGF signaling in ccRCC via a bifurcated approach by combining Everolimus and EG00229 in a tumor-targeted liposomal formulation will be beneficial.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('VEGF signaling', 'biological_process', 'GO:0038084', ('63', '77'))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('EG00229', 'Var', (141, 148))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('Everolimus', 'Chemical', 'MESH:D000068338', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('EG00229', 'Chemical', '-', (141, 148))	('tumor', 'Disease', (154, 159))
91014	31840081	At the same time, EG00229 will disrupt VEGF-NRP1 axis leading to the inhibition of VEGF/VEGFR2/NRP1-mediated proangiogenic signaling pathways in endothelial cells and VEGF/NRP1/Ras-mediated autocrine activation of tumor cell growth.	('VEGF-NRP1 axis', 'Gene', (39, 53))	('EG00229', 'Chemical', '-', (18, 25))	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('disrupt', 'NegReg', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('VEGFR2', 'Gene', '16542', (88, 94))	('cell growth', 'biological_process', 'GO:0016049', ('220', '231'))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('EG00229', 'Var', (18, 25))	('NRP', 'biological_process', 'GO:0085015', ('95', '98'))	('tumor', 'Disease', (214, 219))	('NRP', 'biological_process', 'GO:0085015', ('172', '175'))	('VEGFR2', 'Gene', (88, 94))	('inhibition', 'NegReg', (69, 79))	('NRP', 'biological_process', 'GO:0085015', ('44', '47'))
91017	31840081	On the contrary, EG00229 binds to the b1 domain of NRP1 and disrupts the angiogenic signaling in tumor-endothelial cells as well as autocrine signaling in tumor cells as mentioned above.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('autocrine signaling', 'biological_process', 'GO:0035425', ('132', '151'))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('autocrine signaling', 'MPA', (132, 151))	('angiogenic signaling', 'MPA', (73, 93))	('binds', 'Interaction', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('EG00229', 'Var', (17, 24))	('NRP', 'biological_process', 'GO:0085015', ('51', '54'))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', (97, 102))	('EG00229', 'Chemical', '-', (17, 24))	('men', 'Species', '9606', (170, 173))	('NRP1', 'Gene', (51, 55))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('disrupts', 'NegReg', (60, 68))
91018	31840081	In addition, immune-modulatory effect of EG00229 may act against the immune-suppressive function of Everolimus, thus promoting antitumor immunity.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('promoting', 'PosReg', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('EG00229', 'Var', (41, 48))	('tumor', 'Disease', (131, 136))	('EG00229', 'Chemical', '-', (41, 48))	('Everolimus', 'Chemical', 'MESH:D000068338', (100, 110))
91020	31840081	We further postulated that the tumor-targeted delivery will require lower doses of Everolimus and EG00229.	('Everolimus', 'Chemical', 'MESH:D000068338', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('EG00229', 'Var', (98, 105))	('tumor', 'Disease', (31, 36))	('EG00229', 'Chemical', '-', (98, 105))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
91026	31840081	CXCR3-associated chemokine ligands CXCL9, CXCL10, and CXCL11 demonstrate pleotropic roles in immunity and angiogenesis and correlate with poor prognosis in patients with ccRCC.	('patients', 'Species', '9606', (156, 164))	('angiogenesis', 'biological_process', 'GO:0001525', ('106', '118'))	('CXCL11', 'Var', (54, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (170, 175))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('RCC', 'Disease', (172, 175))
91067	31840081	Empty liposome (L), liposome containing Everolimus (E-L), EG00229 (G-L), and a combination thereof (EG-L) were intravenously administered three times a week into mice bearing ~300-500 mm3 tumors.	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('EG00229', 'Var', (58, 65))	('mice', 'Species', '10090', (162, 166))	('Everolimus', 'Chemical', 'MESH:D000068338', (40, 50))	('EG00229', 'Chemical', '-', (58, 65))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))
91112	29801658	To link phenotypes with intratumour gene features, radiomics studies, which decode tumour phenotypes into mineable quantitative image features, have successfully interlinked non-invasive imaging features and key cancer genetic mutations in ccRCC.	('tumour', 'Disease', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('tumour', 'Disease', (29, 35))	('RCC', 'Phenotype', 'HP:0005584', (242, 245))	('ccRCC', 'Phenotype', 'HP:0006770', (240, 245))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', (212, 218))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('ccRCC', 'Disease', (240, 245))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('mutations', 'Var', (227, 236))
91123	29801658	Clinical parameters, X4   R23x6, included TNM stage, tumour Fuhrman grade, and whole tumour size.	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('Clinical', 'Species', '191496', (0, 8))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('tumour', 'Disease', (53, 59))	('tumour', 'Disease', (85, 91))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('X4   R23x6', 'Var', (21, 31))
91133	29801658	In this step, the low-dimensional latent components of SPLS from the above step were as the new dataset of radiomics features, X1   R23x4, which was associated with mRNA X2, microvascular density X3, clinical parameters X4 and molecular subtypes X5.	('X1   R23x4', 'Var', (127, 137))	('PLS', 'Disease', 'MESH:D010214', (56, 59))	('PLS', 'Disease', (56, 59))	('clinical', 'Species', '191496', (200, 208))
91140	29801658	2 shows that all 23 specimens were projected to four latent components T= [rf1, rf2, rf3, rf4] and displayed in a three-dimensional MDS plot.	('MDS', 'Disease', (132, 135))	('MDS', 'Disease', 'MESH:D009190', (132, 135))	('rf3', 'Var', (85, 88))
91162	29801658	So, in multi-omic analysis, using the low-dimensional latent components of SPLS as the new dataset of radiomics features, X1   R23x4, the best CCR of 95.65% was obtained (permutation test, p < 10-4).	('PLS', 'Disease', 'MESH:D010214', (76, 79))	('CCR', 'molecular_function', 'GO:0043880', ('143', '146'))	('X1   R23x4', 'Var', (122, 132))	('PLS', 'Disease', (76, 79))
91179	32251515	Analysis of transcriptomic data demonstrates extensive epigenetic gene silencing of the transcription factor PRDM16 in renal cancer.	('renal cancer', 'Phenotype', 'HP:0009726', (119, 131))	('transcription factor', 'molecular_function', 'GO:0000981', ('88', '108'))	('gene silencing', 'biological_process', 'GO:0016458', ('66', '80'))	('renal cancer', 'Disease', 'MESH:D007680', (119, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('epigenetic gene silencing', 'Var', (55, 80))	('PRDM16', 'Gene', (109, 115))	('renal cancer', 'Disease', (119, 131))	('transcription', 'biological_process', 'GO:0006351', ('88', '101'))
91180	32251515	We show that restoration of PRDM16 in RCC cells suppresses in vivo tumor growth.	('RCC', 'Disease', (38, 41))	('PRDM16', 'Gene', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('suppresses', 'NegReg', (48, 58))	('tumor', 'Disease', (67, 72))	('restoration', 'Var', (13, 24))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
91184	32251515	Finally, we show that reconstitution of RCC cells with a PRDM16 mutant unable to bind CtBPs nullifies PRDM16's effects on both SEMA5B repression and tumor growth suppression.	('tumor growth suppression', 'Disease', 'MESH:D006130', (149, 173))	('PRDM16', 'Gene', (102, 108))	('nullifies', 'NegReg', (92, 101))	('CtBPs', 'Chemical', '-', (86, 91))	('RCC', 'Disease', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('SEMA5B', 'Gene', '54437', (127, 133))	('PRDM16', 'Gene', (57, 63))	('SEMA5B', 'Gene', (127, 133))	('mutant', 'Var', (64, 70))	('tumor growth suppression', 'Disease', (149, 173))
91188	32251515	The most common tumor-initiating event in this malignancy is alteration of the von Hippel-Lindau (VHL) gene, which encodes an E3 ubiquitin ligase.	('von Hippel-Lindau', 'Gene', (79, 96))	('alteration', 'Var', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('ubiquitin', 'molecular_function', 'GO:0031386', ('129', '138'))	('VHL', 'Gene', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('von Hippel-Lindau', 'Gene', '7428', (79, 96))	('VHL', 'Gene', '7428', (98, 101))	('tumor', 'Disease', (16, 21))	('malignancy', 'Disease', 'MESH:D009369', (47, 57))	('malignancy', 'Disease', (47, 57))
91191	32251515	VHL loss, silencing, or mutation can result in the aberrant stabilization of HIFs.	('VHL loss', 'Disease', 'MESH:D006623', (0, 8))	('VHL loss', 'Disease', (0, 8))	('HIFs', 'Disease', 'None', (77, 81))	('result in', 'Reg', (37, 46))	('HIFs', 'Disease', (77, 81))	('mutation', 'Var', (24, 32))	('silencing', 'Var', (10, 19))
91197	32251515	Recent studies indicate a role for epigenetics in the modulation of HIF signaling in RCC.	('epigenetics', 'Var', (35, 46))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', (85, 88))	('HIF signaling', 'MPA', (68, 81))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))
91198	32251515	Here, we identify epigenetic silencing of the transcription factor PR (PRD1-BF1-RIZ1 homologous) domain-containing 16 (PRDM16) in RCC.	('transcription', 'biological_process', 'GO:0006351', ('46', '59'))	('transcription factor', 'molecular_function', 'GO:0000981', ('46', '66'))	('epigenetic silencing', 'Var', (18, 38))	('PR', 'Gene', '140738', (67, 69))	('PR', 'Gene', '140738', (71, 73))	('RCC', 'Disease', (130, 133))	('PR', 'Gene', '140738', (119, 121))	('RCC', 'Disease', 'MESH:C538614', (130, 133))
91199	32251515	Loss of PRDM16 leads to the enhanced expression of the HIF-responsive gene semaphorin 5B (SEMA5B), which supports RCC growth in vivo.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('SEMA5B', 'Gene', (90, 96))	('RCC', 'Disease', (114, 117))	('semaphorin 5B', 'Gene', (75, 88))	('enhanced', 'PosReg', (28, 36))	('PRDM16', 'Gene', (8, 14))	('semaphorin 5B', 'Gene', '54437', (75, 88))	('expression', 'MPA', (37, 47))	('Loss', 'Var', (0, 4))	('SEMA5B', 'Gene', '54437', (90, 96))
91220	32251515	The most common tumor-initiating event in ccRCC is alteration of the VHL gene.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('RCC', 'Disease', (44, 47))	('tumor', 'Disease', (16, 21))	('alteration', 'Var', (51, 61))	('VHL', 'Gene', (69, 72))	('VHL', 'Gene', '7428', (69, 72))
91222	32251515	Analysis of TCGA data demonstrates that PRDM16 is silenced in both VHL mutant and WT ccRCC relative to normal kidney (Fig.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('VHL', 'Gene', '7428', (67, 70))	('silenced', 'NegReg', (50, 58))	('mutant', 'Var', (71, 77))	('PRDM16', 'Gene', (40, 46))	('VHL', 'Gene', (67, 70))
91223	32251515	Prior studies indicate that PRDM family members may be a subject to epigenetic regulation in cancer.	('PR', 'Gene', '140738', (28, 30))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('epigenetic', 'Var', (68, 78))	('regulation', 'biological_process', 'GO:0065007', ('79', '89'))
91228	32251515	We found significant enrichment of 5mC within the region encompassing cg01514538 in RCC cell lines RXF-393 and RCC4 (Fig.	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('cg01514538', 'Var', (70, 80))	('RCC4', 'Gene', '84925', (111, 115))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('RCC4', 'Gene', (111, 115))	('men', 'Species', '9606', (27, 30))	('5mC', 'Chemical', '-', (35, 38))
91229	32251515	Moreover, 5mC levels were higher in multiple regions encompassing CpG sites within this island (cg05346286, cg03969902, and cg01514538) in tumor relative to normal kidney in multiple patient-matched samples (Fig.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('higher', 'PosReg', (26, 32))	('5mC levels', 'MPA', (10, 20))	('cg05346286', 'Var', (96, 106))	('cg01514538', 'Var', (124, 134))	('cg05346286', 'Chemical', '-', (96, 106))	('cg03969902', 'Chemical', '-', (108, 118))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('patient', 'Species', '9606', (183, 190))	('cg03969902', 'Var', (108, 118))	('5mC', 'Chemical', '-', (10, 13))
91247	32251515	In both OSRC-2 and Caki-1 cells, restoration of PRDM16 expression significantly suppressed RCC xenograft growth (Fig.	('PRDM16', 'Gene', (48, 54))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))	('expression', 'MPA', (55, 65))	('Caki-1', 'CellLine', 'CVCL:0234', (19, 25))	('restoration', 'Var', (33, 44))	('OSRC', 'Gene', (8, 12))	('suppressed', 'NegReg', (80, 90))	('OSRC', 'Gene', '5925', (8, 12))
91258	32251515	Additionally, this finding was validated in vivo as SEMA5B mRNA expression was lower in PRDM16 expressing xenograft tumors relative to control tumors (Fig.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (143, 149))	('lower', 'NegReg', (79, 84))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('xenograft', 'Var', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('PRDM16', 'Gene', (88, 94))	('SEMA5B', 'Gene', '54437', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('SEMA5B', 'Gene', (52, 58))
91261	32251515	VHL mutant lines had variable expression (Fig.	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', (0, 3))	('expression', 'MPA', (30, 40))	('mutant', 'Var', (4, 10))
91264	32251515	As VHL is known to promote the degradation of HIF, reconstitution of VHL led to an expected reduction in the expression of the HIF target gene GLUT1 in both RCC4 and 786-O cells (Fig.	('reconstitution', 'Var', (51, 65))	('RCC4', 'Gene', (157, 161))	('RCC4', 'Gene', '84925', (157, 161))	('expression', 'MPA', (109, 119))	('GLUT1', 'Gene', (143, 148))	('reduction', 'NegReg', (92, 101))	('degradation', 'biological_process', 'GO:0009056', ('31', '42'))	('GLUT1', 'Gene', '6513', (143, 148))	('VHL', 'Gene', (3, 6))	('VHL', 'Gene', (69, 72))	('VHL', 'Gene', '7428', (3, 6))	('VHL', 'Gene', '7428', (69, 72))
91268	32251515	Consistent with VHL's role in HIF regulation, restoration of VHL in OSRC-2 cells led to reduced HIF-1alpha and HIF-2alpha protein (Fig.	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('HIF-1alpha', 'Gene', (96, 106))	('HIF-2alpha', 'Gene', (111, 121))	('VHL', 'Gene', (16, 19))	('OSRC', 'Gene', '5925', (68, 72))	('VHL', 'Gene', '7428', (16, 19))	('HIF-2alpha', 'Gene', '2034', (111, 121))	('VHL', 'Gene', (61, 64))	('restoration', 'Var', (46, 57))	('HIF-1alpha', 'Gene', '3091', (96, 106))	('VHL', 'Gene', '7428', (61, 64))	('reduced', 'NegReg', (88, 95))	('regulation', 'biological_process', 'GO:0065007', ('34', '44'))	('OSRC', 'Gene', (68, 72))
91269	32251515	In concert with our transcript data, VHL restoration also led to reduced SEMA5B protein (Figs.	('restoration', 'Var', (41, 52))	('SEMA5B', 'Gene', '54437', (73, 79))	('reduced', 'NegReg', (65, 72))	('VHL', 'Gene', (37, 40))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('SEMA5B', 'Gene', (73, 79))	('VHL', 'Gene', '7428', (37, 40))
91280	32251515	However, the expression of PRDM16 blunted the ability of DMOG to induce SEMA5B (Fig.	('SEMA5B', 'Gene', (72, 78))	('PRDM16', 'Gene', (27, 33))	('SEMA5B', 'Gene', '54437', (72, 78))	('DMOG', 'Chemical', 'MESH:C040947', (57, 61))	('expression', 'Var', (13, 23))	('blunted', 'NegReg', (34, 41))	('ability', 'MPA', (46, 53))
91291	32251515	Notably, we found that SEMA5B knockdown significantly reduced OSRC-2 xenograft growth (Fig.	('SEMA5B', 'Gene', '54437', (23, 29))	('OSRC', 'Gene', (62, 66))	('reduced', 'NegReg', (54, 61))	('OSRC', 'Gene', '5925', (62, 66))	('SEMA5B', 'Gene', (23, 29))	('knockdown', 'Var', (30, 39))
91304	32251515	Mutation of this motif to PLASS disrupts PRDM16/CtBP interaction in adipocytes.	('CtBP', 'Chemical', '-', (48, 52))	('PRDM16/CtBP', 'Gene', (41, 52))	('Mutation', 'Var', (0, 8))	('interaction', 'Interaction', (53, 64))	('disrupts', 'NegReg', (32, 40))
91305	32251515	In agreement with these data, mutation of this motif in PRDM16 disrupts CtBP interaction (Fig.	('CtBP', 'Protein', (72, 76))	('CtBP', 'Chemical', '-', (72, 76))	('mutation', 'Var', (30, 38))	('PRDM16', 'Gene', (56, 62))	('disrupts', 'NegReg', (63, 71))	('men', 'Species', '9606', (8, 11))
91308	32251515	We next examined the ability of WT and mutant PRDM16 to suppress SEMA5B mRNA and protein expression (Fig.	('SEMA5B', 'Gene', (65, 71))	('suppress', 'NegReg', (56, 64))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('PRDM16', 'Gene', (46, 52))	('mutant', 'Var', (39, 45))	('SEMA5B', 'Gene', '54437', (65, 71))
91309	32251515	Consistent with prior data, WT PRDM16 significantly reduced SEMA5B expression, whereas mutant PRDM16 had no effect on SEMA5B.	('SEMA5B', 'Gene', (118, 124))	('SEMA5B', 'Gene', '54437', (118, 124))	('reduced', 'NegReg', (52, 59))	('PRDM16', 'Gene', (94, 100))	('mutant', 'Var', (87, 93))	('SEMA5B', 'Gene', (60, 66))	('SEMA5B', 'Gene', '54437', (60, 66))
91312	32251515	In contrast, CtBP binding to this region was significantly reduced in RCC cells expressing mutant PRDM16 as compared with WT PRDM16 (Fig.	('binding', 'molecular_function', 'GO:0005488', ('18', '25'))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('reduced', 'NegReg', (59, 66))	('RCC', 'Disease', (70, 73))	('binding', 'Interaction', (18, 25))	('CtBP', 'Protein', (13, 17))	('CtBP', 'Chemical', '-', (13, 17))	('mutant', 'Var', (91, 97))	('PRDM16', 'Gene', (98, 104))
91315	32251515	Whereas WT PRDM16 transduced RCC cells demonstrated reduced proliferation compared with control cells, RCC cells transduced with mutant PRDM16 failed to demonstrate any decrease in proliferation (Fig.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('reduced', 'NegReg', (52, 59))	('RCC', 'Disease', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('proliferation', 'CPA', (60, 73))	('PRDM16', 'Gene', (136, 142))	('mutant', 'Var', (129, 135))
91316	32251515	Furthermore, PRDM16 mutant transduced cells readily grew in vivo in contrast with WT PRDM16-expressing cells, which demonstrated markedly reduced tumor growth (Fig.	('PRDM16', 'Gene', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('reduced', 'NegReg', (138, 145))	('tumor', 'Disease', (146, 151))	('mutant', 'Var', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
91329	32251515	7, our data have relevance to both VHL WT tumors, which are hypoxic, and VHL mutant tumors, which are pseudohypoxic.	('VHL', 'Gene', '7428', (73, 76))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('VHL WT tumors', 'Disease', (35, 48))	('hypoxic', 'Disease', 'MESH:D000860', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('hypoxic', 'Disease', (108, 115))	('tumors', 'Disease', (84, 90))	('VHL', 'Gene', (35, 38))	('hypoxic', 'Disease', 'MESH:D000860', (60, 67))	('hypoxic', 'Disease', (60, 67))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('mutant', 'Var', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('VHL', 'Gene', '7428', (35, 38))	('VHL', 'Gene', (73, 76))	('tumors', 'Disease', (42, 48))	('VHL WT tumors', 'Disease', 'MESH:D006623', (35, 48))
91335	32251515	In leukemia, gene arrangements of PRDM16 result in loss of the PR domain, which is associated with methyltransferase activity.	('PR', 'Gene', '140738', (63, 65))	('gene arrangements', 'Var', (13, 30))	('leukemia', 'Phenotype', 'HP:0001909', (3, 11))	('leukemia', 'Disease', 'MESH:D007938', (3, 11))	('methyltransferase activity', 'molecular_function', 'GO:0008168', ('99', '125'))	('leukemia', 'Disease', (3, 11))	('loss', 'NegReg', (51, 55))	('PR', 'Gene', '140738', (34, 36))	('men', 'Species', '9606', (25, 28))
91338	32251515	These data suggest that PRDM16 methylation, and therefore its silencing, in cancer is not simply a random occurrence.	('PRDM16', 'Gene', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('methylation', 'Var', (31, 42))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('silencing', 'NegReg', (62, 71))
91347	32251515	3 D) would argue against a compensatory effect upon SEMA5B knockdown.	('knockdown', 'Var', (59, 68))	('SEMA5B', 'Gene', '54437', (52, 58))	('SEMA5B', 'Gene', (52, 58))
91354	32251515	Mutations of VHL are highly prevalent in ccRCC.	('VHL', 'Gene', (13, 16))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('Mutations', 'Var', (0, 9))	('RCC', 'Disease', (43, 46))	('VHL', 'Gene', '7428', (13, 16))	('prevalent', 'Reg', (28, 37))
91355	32251515	Our data add to the growing body of evidence of the role of epigenetics in the amplification of HIF signaling in RCC.	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('amplification of HIF signaling', 'MPA', (79, 109))	('epigenetics', 'Var', (60, 71))
91358	32251515	Recent studies indicate that alteration of PBRM1 promotes the expression of HIF-responsive genes.	('PBRM1', 'Gene', (43, 48))	('PBRM1', 'Gene', '55193', (43, 48))	('expression', 'MPA', (62, 72))	('promotes', 'PosReg', (49, 57))	('alteration', 'Var', (29, 39))
91360	32251515	Experimental studies of RCC by demonstrate that DNA demethylation promotes the expression of the HIF target gene CYTIP in an in vivo model of ccRCC lung colonization.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('RCC', 'Disease', (24, 27))	('DNA demethylation', 'Var', (48, 65))	('expression', 'MPA', (79, 89))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('CYTIP', 'Gene', '9595', (113, 118))	('promotes', 'PosReg', (66, 74))	('DNA demethylation', 'biological_process', 'GO:0080111', ('48', '65'))	('CYTIP', 'Gene', (113, 118))	('RCC', 'Disease', (144, 147))	('men', 'Species', '9606', (6, 9))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
91361	32251515	Our studies support a novel mechanism for the promotion of HIF signaling through DNA hypermethylation of the PRDM16 gene, which results in enhanced expression of the HIF target SEMA5B gene.	('signaling', 'biological_process', 'GO:0023052', ('63', '72'))	('SEMA5B', 'Gene', '54437', (177, 183))	('DNA hypermethylation', 'Var', (81, 101))	('SEMA5B', 'Gene', (177, 183))	('promotion', 'PosReg', (46, 55))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('HIF signaling', 'MPA', (59, 72))	('PRDM16', 'Gene', (109, 115))	('expression', 'MPA', (148, 158))	('enhanced', 'PosReg', (139, 147))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('81', '101'))
91366	32251515	Our findings herein, as well as previously published data, indicate that epigenetic alterations can amplify HIF signaling in RCC.	('epigenetic alterations', 'Var', (73, 95))	('HIF signaling', 'MPA', (108, 121))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('amplify', 'PosReg', (100, 107))	('signaling', 'biological_process', 'GO:0023052', ('112', '121'))
91375	32251515	These data provide novel insight into the contribution of epigenetics in regulating HIF signaling in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('signaling', 'biological_process', 'GO:0023052', ('88', '97'))	('epigenetics', 'Var', (58, 69))	('HIF signaling', 'MPA', (84, 97))
91387	32251515	shRNA constructs (from Sigma-Aldrich) are as follows: pLKO.1-shControl (SHC002), pLKO.1-shSEMA5B1 (TRCN0000060474), and pLKO.1-shSEMA5B2 (TRCN0000060473).	('SEMA5B', 'Gene', (90, 96))	('TRCN0000060473', 'Var', (138, 152))	('SEMA5B', 'Gene', '54437', (129, 135))	('TRCN0000060474', 'Var', (99, 113))	('SEMA5B', 'Gene', (129, 135))	('SEMA5B', 'Gene', '54437', (90, 96))
91388	32251515	Sources of antibodies used in this study are as follows: PRDM16 from Thermo Fisher Scientific (720206); CtBP-1/2 from Active Motif (61261); Flag (for immunoblotting and immunoprecipitation; F1804) SEMA5B (HPA066548) from Sigma-Aldrich; Flag (for ChIP; 14793), HA (3724), and HIF-1alpha (14179) from Cell Signaling Technology; HIF-2alpha (GTX632015) from GeneTex; normal IgG (12-371) from Millipore; and beta-actin (ab49900) from Abcam.	('HIF-1alpha', 'Gene', (275, 285))	('SEMA5B', 'Gene', (197, 203))	('SEMA5B', 'Gene', '54437', (197, 203))	('CtBP-1/2', 'Gene', (104, 112))	('HIF-2alpha', 'Gene', (326, 336))	('F1804', 'Var', (190, 195))	('HIF-1alpha', 'Gene', '3091', (275, 285))	('HIF-2alpha', 'Gene', '2034', (326, 336))	('CtBP-1/2', 'Gene', '1487;1488', (104, 112))	('Signaling', 'biological_process', 'GO:0023052', ('304', '313'))
91408	32251515	Indicated Taqman primers were predesigned from Applied Biosystems as follows: PRDM16 (Hs00922682_m1), SEMA5B (Hs00400720_m1), PPARGC1A (Hs00173304_m1), ESRRG (Hs00976243_m1), UCP1 (Hs01084772_m1), GLUT1 (Hs00892681_m1), PDK1 (Hs01561847_m1), RPLPO1 (Hs99999902_m1), and TBP (Hs00427620_m1).	('Hs00400720_m1', 'Var', (110, 123))	('GLUT1', 'Gene', (197, 202))	('PPARGC1A', 'Gene', '10891', (126, 134))	('Hs00892681_m1', 'Var', (204, 217))	('PDK1', 'Gene', (220, 224))	('Hs99999902_m1', 'Var', (250, 263))	('Hs00976243_m1', 'Var', (159, 172))	('SEMA5B', 'Gene', (102, 108))	('TBP', 'Gene', '6908', (270, 273))	('ESRRG', 'Gene', '2104', (152, 157))	('Hs00173304_m1', 'Var', (136, 149))	('GLUT1', 'Gene', '6513', (197, 202))	('PDK1', 'Gene', '5163', (220, 224))	('ESRRG', 'Gene', (152, 157))	('SEMA5B', 'Gene', '54437', (102, 108))	('PDK1', 'molecular_function', 'GO:0004740', ('220', '224'))	('UCP1', 'Gene', '7350', (175, 179))	('Hs01084772_m1', 'Var', (181, 194))	('Hs01561847_m1', 'Var', (226, 239))	('Hs00427620_m1', 'Var', (275, 288))	('UCP1', 'Gene', (175, 179))	('PPARGC1A', 'Gene', (126, 134))	('Hs00922682_m1', 'Var', (86, 99))	('TBP', 'Gene', (270, 273))
91409	32251515	All immunoprecipitation steps were performed at 4 C. Cells expressing Flag-tagged PRDM16 WT or PRDM16 mutant were lysed in buffer X (50 mM Hepes, pH 7.5, 150 mM NaCl, 0.1% NP-40, and 1 mM EDTA) containing 1x protease/phosphatase inhibitor (Thermo Fisher Scientific).	('PRDM16', 'Gene', (82, 88))	('mutant', 'Var', (102, 108))	('Hepes', 'Chemical', 'MESH:D006531', (139, 144))	('NP-40', 'Chemical', 'MESH:C010615', (172, 177))	('NaCl', 'Chemical', 'MESH:D012965', (161, 165))	('phosphatase', 'molecular_function', 'GO:0016791', ('217', '228'))	('EDTA', 'Chemical', 'MESH:D004492', (188, 192))	('PRDM16', 'Gene', (95, 101))
91415	32251515	To study PRDM16-CtBP binding site near the SEMA5B transcription start site, stably transfected OS-RC-2 cells expressing either Flag-PRDM16 WT or Flag-PRDM16 mutant were cultured in 150 mm tissue culture dishes to 90% confluency (~6 x 106 cells per plate).	('Flag-PRDM16', 'Gene', (127, 138))	('mutant', 'Var', (157, 163))	('SEMA5B', 'Gene', (43, 49))	('SEMA5B', 'Gene', '54437', (43, 49))	('Flag-PRDM16', 'Gene', (145, 156))	('OS-RC-2', 'CellLine', 'CVCL:1626', (95, 102))	('transcription', 'biological_process', 'GO:0006351', ('50', '63'))	('CtBP', 'Chemical', '-', (16, 20))	('binding', 'molecular_function', 'GO:0005488', ('21', '28'))
91443	29702530	We further confirmed that polyubiquitylated p62 form large complex than unmodified p62 by electro-microscopy and dynamic light scattering analysis.	('polyubiquitylated', 'Var', (26, 43))	('p62', 'Gene', '8878', (83, 86))	('p62', 'Gene', (83, 86))	('complex', 'Interaction', (59, 66))	('p62', 'Gene', '8878', (44, 47))	('p62', 'Gene', (44, 47))
91446	29702530	Multiple Lys (K) residues in p62 were mapped as the sites for this E2-supported ubiquitylation, which include K420 in the UBA domain of p62.	('UBA', 'Chemical', '-', (122, 125))	('p62', 'Gene', '8878', (136, 139))	('p62', 'Gene', (136, 139))	('K420', 'Var', (110, 114))	('Lys', 'Chemical', 'MESH:D008239', (9, 12))	('ubiquitylation', 'MPA', (80, 94))	('p62', 'Gene', (29, 32))	('p62', 'Gene', '8878', (29, 32))
91447	29702530	As previously reported, UBA domains in p62 formed stable dimers, which would prevent p62 from binding to polyUb chain in autophagy cargos; our in vitro polyUb-binding data showed that polyubiquitylated p62 in the presence of the E2s bind to polyUb chains much more efficiently than unmodified p62.	('polyubiquitylated', 'Var', (184, 201))	('bind', 'Interaction', (233, 237))	('p62', 'Gene', (85, 88))	('p62', 'Gene', '8878', (202, 205))	('binding', 'molecular_function', 'GO:0005488', ('94', '101'))	('autophagy', 'biological_process', 'GO:0016236', ('121', '130'))	('p62', 'Gene', (202, 205))	('UBA', 'Chemical', '-', (24, 27))	('autophagy', 'biological_process', 'GO:0006914', ('121', '130'))	('binding', 'molecular_function', 'GO:0005488', ('159', '166'))	('p62', 'Gene', '8878', (293, 296))	('p62', 'Gene', (293, 296))	('polyUb chains', 'Protein', (241, 254))	('p62', 'Gene', '8878', (39, 42))	('p62', 'Gene', '8878', (85, 88))	('p62', 'Gene', (39, 42))
91448	29702530	Consistently, electro-microscopy and dynamic light scattering analyses indicated that polyubiquitylated p62 might predominantly form large complex with polyUb chains (~ two fold lager in diameter) than unmodified p62, suggesting that p62 might have indeed adopted an open conformation upon E2-supported polyubiquitylation.	('p62', 'Gene', (213, 216))	('complex', 'Interaction', (139, 146))	('p62', 'Gene', '8878', (234, 237))	('p62', 'Gene', '8878', (104, 107))	('p62', 'Gene', (234, 237))	('p62', 'Gene', '8878', (213, 216))	('p62', 'Gene', (104, 107))	('polyUb', 'Protein', (152, 158))	('polyubiquitylated', 'Var', (86, 103))	('adopted', 'Reg', (256, 263))
91449	29702530	Conclusion: By discovering E2-supported ubiquitylation of p62 as a novel mechanism for activating its autophagy receptor function under Ub+ stress conditions, our work has thus revealed a unique "sensor" function of p62 in modulating autophagy as part of the cellular responses to prolonged proteasomal inhibition, heat shock or Ub overexpression.	('autophagy', 'CPA', (234, 243))	('p62', 'Gene', (58, 61))	('p62', 'Gene', '8878', (216, 219))	('p62', 'Gene', '8878', (58, 61))	('modulating', 'Reg', (223, 233))	('shock', 'Disease', (320, 325))	('p62', 'Gene', (216, 219))	('shock', 'Phenotype', 'HP:0031273', (320, 325))	('activating', 'PosReg', (87, 97))	('ubiquitylation', 'Var', (40, 54))	('autophagy', 'biological_process', 'GO:0016236', ('102', '111'))	('autophagy', 'biological_process', 'GO:0016236', ('232', '241'))	('autophagy', 'biological_process', 'GO:0006914', ('102', '111'))	('shock', 'Disease', 'MESH:D012769', (320, 325))	('autophagy', 'biological_process', 'GO:0006914', ('232', '241'))
91456	29702530	Results: In recent years, our team have conducted a series of studies on HIC1 and found that hyper methylation of HIC1 promoters in a variety of solid tumor tissues (including prostate cancer, breast cancer, lung cancer, etc.)	('breast cancer', 'Disease', (193, 206))	('solid tumor', 'Disease', 'MESH:D009369', (145, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (208, 219))	('hyper methylation', 'Var', (93, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('methylation', 'biological_process', 'GO:0032259', ('99', '110'))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('prostate cancer', 'Disease', 'MESH:D011471', (176, 191))	('lung cancer', 'Disease', 'MESH:D008175', (208, 219))	('HIC1', 'Gene', (114, 118))	('prostate cancer', 'Phenotype', 'HP:0012125', (176, 191))	('solid tumor', 'Disease', (145, 156))	('breast cancer', 'Disease', 'MESH:D001943', (193, 206))	('lung cancer', 'Disease', (208, 219))	('prostate cancer', 'Disease', (176, 191))
91458	29702530	In vitro and in vivo experiments show that the recovery of HIC1 expression could significantly reduce the tumor proliferation, invasion, and metastasis.	('expression', 'MPA', (64, 74))	('reduce', 'NegReg', (95, 101))	('HIC1', 'Gene', (59, 63))	('invasion', 'CPA', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('recovery', 'Var', (47, 55))	('tumor', 'Disease', (106, 111))
91464	29702530	By contrast, Mdm2 mutant mice demonstrate attenuated MCD induction and increased lipid accumulation in the liver.	('lipid', 'Chemical', 'MESH:D008055', (81, 86))	('Mdm2', 'Var', (13, 17))	('mice', 'Species', '10090', (25, 29))	('attenuated', 'NegReg', (42, 52))	('increased lipid', 'Phenotype', 'HP:0003077', (71, 86))	('increased', 'PosReg', (71, 80))	('lipid accumulation', 'MPA', (81, 99))	('MCD', 'Disease', 'MESH:D012514', (53, 56))	('MCD', 'Disease', (53, 56))
91465	29702530	Furthermore, to test whether RP-Mdm2-p53 pathway involved in the tumor suppressive function of p53, we crossed Mdm2C305F mouse with Emu-myc mouse, and found that interruption of RP-MDM2 interaction strikingly accelerates oncogenic Myc-induced lymphomagenesis.	('mouse', 'Species', '10090', (140, 145))	('myc', 'Gene', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('myc', 'Gene', '17869', (136, 139))	('MDM2', 'Gene', (181, 185))	('accelerates', 'PosReg', (209, 220))	('interruption', 'Var', (162, 174))	('mouse', 'Species', '10090', (121, 126))	('interaction', 'Interaction', (186, 197))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Myc', 'Gene', (231, 234))	('MDM2', 'Gene', '17246', (181, 185))	('Myc', 'Gene', '17869', (231, 234))
91470	29702530	The goal of this study is to determine the regulatory role of miR-1207-5p and the mechanism underlying in oral cancer metastasis.	('oral cancer metastasis', 'Disease', 'MESH:D009362', (106, 128))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('oral cancer metastasis', 'Disease', (106, 128))	('miR-1207-5p', 'Var', (62, 73))
91473	29702530	Results: The miR-1207-5p was significantly up-regulated in oral local carcinoma and distal metastasis carcinoma tissues, while tryptase-alpha-1 (TPSAB1) was dramatically up-regulated in oral local carcinoma tissues.	('carcinoma', 'Disease', 'MESH:D002277', (70, 79))	('TPSAB1', 'Gene', (145, 151))	('carcinoma', 'Disease', 'MESH:D002277', (197, 206))	('metastasis carcinoma', 'Disease', (91, 111))	('distal', 'Disease', (84, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('TPSAB1', 'Gene', '7177', (145, 151))	('tryptase-alpha-1', 'Gene', (127, 143))	('carcinoma', 'Disease', (102, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('tryptase-alpha-1', 'Gene', '7177', (127, 143))	('carcinoma', 'Disease', (70, 79))	('up-regulated', 'PosReg', (170, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('carcinoma', 'Disease', (197, 206))	('up-regulated', 'PosReg', (43, 55))	('metastasis carcinoma', 'Disease', 'MESH:D009362', (91, 111))	('miR-1207-5p', 'Var', (13, 24))	('carcinoma', 'Disease', 'MESH:D002277', (102, 111))
91474	29702530	By prediction analysis and reciprocally expression of both miR-1207-5p and its target TPSAB1 in oral tumor tissue, TPSAB1 was further confirmed as a target of miR-1207-5p.	('TPSAB1', 'Gene', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('miR-1207-5p', 'Var', (59, 70))	('oral tumor', 'Disease', 'MESH:D020820', (96, 106))	('TPSAB1', 'Gene', '7177', (86, 92))	('oral tumor', 'Phenotype', 'HP:0100649', (96, 106))	('TPSAB1', 'Gene', '7177', (115, 121))	('miR-1207-5p', 'Var', (159, 170))	('TPSAB1', 'Gene', (86, 92))	('oral tumor', 'Disease', (96, 106))
91475	29702530	Conclusion: The data above indicate that miR-1207-5p may be potential biomarker or target of oral cancer metastasis and induce oral cancer metastasis by targeted Tryptase alpha-1.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('induce', 'PosReg', (120, 126))	('oral cancer metastasis', 'Disease', 'MESH:D009362', (93, 115))	('oral cancer metastasis', 'Disease', (127, 149))	('oral cancer metastasis', 'Disease', (93, 115))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Tryptase alpha-1', 'Gene', '7177', (162, 178))	('miR-1207-5p', 'Var', (41, 52))	('Tryptase alpha-1', 'Gene', (162, 178))	('oral cancer metastasis', 'Disease', 'MESH:D009362', (127, 149))
91493	29702530	Moreover, overexpressed Tid1-S represses aerobic glycolysis while mitochondrial respiration was enhanced, which indicates a switch of Warburg effect.	('enhanced', 'PosReg', (96, 104))	('represses', 'NegReg', (31, 40))	('respiration', 'biological_process', 'GO:0007585', ('80', '91'))	('Tid1', 'Gene', (24, 28))	('respiration', 'biological_process', 'GO:0045333', ('80', '91'))	('mitochondrial respiration', 'MPA', (66, 91))	('aerobic glycolysis', 'MPA', (41, 59))	('Tid1', 'Gene', '9093', (24, 28))	('glycolysis', 'biological_process', 'GO:0006096', ('49', '59'))	('overexpressed', 'Var', (10, 23))
91511	29702530	Furthermore, we demonstrated that MST1 deacetylation promoted the interaction of MST1 with HSC70 in the cells, resulting in a lysosome-dependent degradation of MST1 via chaperone-mediated autophagy (CMA).	('HSC70', 'Gene', '3312', (91, 96))	('MST1', 'Gene', (34, 38))	('promoted', 'PosReg', (53, 61))	('degradation', 'biological_process', 'GO:0009056', ('145', '156'))	('interaction', 'Interaction', (66, 77))	('lysosome', 'cellular_component', 'GO:0005764', ('126', '134'))	('HSC70', 'Gene', (91, 96))	('chaperone-mediated autophagy', 'biological_process', 'GO:0061684', ('169', '197'))	('CMA', 'biological_process', 'GO:0061684', ('199', '202'))	('MST1', 'Gene', (160, 164))	('deacetylation', 'Var', (39, 52))	('HSC', 'cellular_component', 'GO:0035301', ('91', '94'))	('chaperone-mediated autophagy', 'CPA', (169, 197))	('MST1', 'Gene', (81, 85))	('lysosome-dependent degradation', 'MPA', (126, 156))
91520	29702530	The overexpression of miR-21 in PANC-1 cannot lead to the variation of TGFbeta; the inhibition of miR-21 can cause the highly expression of TGFbeta.	('miR-21', 'Gene', (98, 104))	('TGFbeta', 'Gene', '7040', (140, 147))	('TGFbeta', 'Gene', (71, 78))	('cause', 'Reg', (109, 114))	('miR-21', 'Gene', '406991', (22, 28))	('TGFbeta', 'Gene', (140, 147))	('PANC-1', 'CellLine', 'CVCL:0480', (32, 38))	('TGFbeta', 'Gene', '7040', (71, 78))	('miR-21', 'Gene', '406991', (98, 104))	('miR-21', 'Gene', (22, 28))	('inhibition', 'Var', (84, 94))
91539	29702530	The most study of FMRP is focused on nerve diseases such as FXS caused by FMRP dysfunction, while how does it affect cancer progression is still unknown.	('FMRP', 'Gene', '2332', (74, 78))	('caused', 'Reg', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('FMRP', 'Gene', (74, 78))	('dysfunction', 'Var', (79, 90))	('FMRP', 'Gene', '2332', (18, 22))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('FXS', 'Disease', (60, 63))	('cancer', 'Disease', (117, 123))	('FMRP', 'Gene', (18, 22))	('FXS', 'Disease', 'MESH:D005600', (60, 63))
91549	29702530	FMRP knock down decrease the HCCLM3 metastasis, and the FMRP protein level is elevated in Hepatocellular Carcinoma tissue, suggesting that FMRP may affect the Hepatocellular Carcinoma Metastasis though regulating expression of STAT3.	('decrease', 'NegReg', (16, 24))	('Carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('Hepatocellular Carcinoma Metastasis', 'Disease', 'MESH:D009362', (159, 194))	('Hepatocellular Carcinoma', 'Disease', 'MESH:D006528', (159, 183))	('Hepatocellular Carcinoma', 'Phenotype', 'HP:0001402', (90, 114))	('Hepatocellular Carcinoma Metastasis', 'Disease', (159, 194))	('affect', 'Reg', (148, 154))	('FMRP', 'Gene', '2332', (0, 4))	('FMRP', 'Gene', '2332', (56, 60))	('HCCLM3', 'Chemical', '-', (29, 35))	('HCCLM3 metastasis', 'MPA', (29, 46))	('Hepatocellular Carcinoma', 'Phenotype', 'HP:0001402', (159, 183))	('STAT3', 'Gene', (227, 232))	('FMRP', 'Gene', (139, 143))	('expression', 'MPA', (213, 223))	('regulating', 'Reg', (202, 212))	('knock down', 'Var', (5, 15))	('STAT3', 'Gene', '6774', (227, 232))	('Hepatocellular Carcinoma', 'Disease', (90, 114))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))	('Carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('elevated', 'PosReg', (78, 86))	('FMRP', 'Gene', (0, 4))	('Hepatocellular Carcinoma', 'Disease', 'MESH:D006528', (90, 114))	('FMRP', 'Gene', '2332', (139, 143))	('FMRP', 'Gene', (56, 60))
91568	29702530	Result: Our results showed that 18A4 successfully suppressed B16F10 melanoma pulmonary lung metastasis in C57/Bl6 mice and suppressed tumor growth in NSCLC models.	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('suppressed', 'NegReg', (50, 60))	('18A4', 'Var', (32, 36))	('suppressed', 'NegReg', (123, 133))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma pulmonary lung metastasis', 'Disease', 'MESH:D009362', (68, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('mice', 'Species', '10090', (114, 118))	('melanoma pulmonary lung metastasis', 'Disease', (68, 102))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('NSCLC', 'Disease', (150, 155))	('tumor', 'Disease', (134, 139))
91585	29702530	Brusatol is deemed as a unique inhibitor of the Nrf2 pathway, through previous researches we found out brusatol inhibits growth and induces apoptosis in pancreatic cancer cells and meantime restrain NF-kappaB pathways.	('growth', 'CPA', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (153, 170))	('NF-kappaB', 'Gene', '4790', (199, 208))	('apoptosis', 'CPA', (140, 149))	('restrain', 'NegReg', (190, 198))	('Nrf2', 'Gene', '4780', (48, 52))	('brusatol', 'Chemical', 'MESH:C020237', (103, 111))	('induces', 'PosReg', (132, 139))	('pancreatic cancer', 'Disease', (153, 170))	('brusatol', 'Var', (103, 111))	('apoptosis', 'biological_process', 'GO:0097194', ('140', '149'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (153, 170))	('NF-kappaB', 'Gene', (199, 208))	('Nrf2', 'Gene', (48, 52))	('inhibits', 'NegReg', (112, 120))	('apoptosis', 'biological_process', 'GO:0006915', ('140', '149'))	('Brusatol', 'Chemical', 'MESH:C020237', (0, 8))
91624	29702530	Knocked down STAT3 in HCCLM3, resulting in decreased amount of its expression in mitochondria and prevents HCC cells proliferation, ATP production, and cell migration and invasion.	('Knocked down', 'Var', (0, 12))	('mitochondria', 'cellular_component', 'GO:0005739', ('81', '93'))	('HCCLM3', 'Gene', (22, 28))	('HCCLM3', 'Chemical', '-', (22, 28))	('invasion', 'CPA', (171, 179))	('HCC cells proliferation', 'CPA', (107, 130))	('expression in mitochondria', 'MPA', (67, 93))	('prevents', 'NegReg', (98, 106))	('cell migration', 'biological_process', 'GO:0016477', ('152', '166'))	('amount', 'MPA', (53, 59))	('ATP', 'Gene', (132, 135))	('ATP', 'Gene', '51761', (132, 135))	('STAT3', 'Gene', '6774', (13, 18))	('decreased', 'NegReg', (43, 52))	('STAT3', 'Gene', (13, 18))
91633	29702530	Results: The results of PCR showed that circHIPK3 is upregulated in pancreatic cancer cell lines and silencing of circHIPK3 inhibits pancreatic cancer cells proliferation and promotes apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('promotes', 'PosReg', (175, 183))	('silencing', 'Var', (101, 110))	('inhibits', 'NegReg', (124, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (133, 150))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('circHIPK3', 'Gene', (114, 123))	('apoptosis', 'biological_process', 'GO:0097194', ('184', '193'))	('apoptosis', 'biological_process', 'GO:0006915', ('184', '193'))	('pancreatic cancer', 'Disease', (133, 150))	('pancreatic cancer', 'Disease', 'MESH:D010190', (133, 150))	('pancreatic cancer', 'Disease', (68, 85))	('pancreatic cancer', 'Disease', 'MESH:D010190', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('apoptosis', 'CPA', (184, 193))
91634	29702530	In addition, invasion and EMT related markers between si-circHIPK3 and NC groups were compared using RT-PCR and Western blotting assays, which indicates that circHIPK3 promoted invasion and EMT in pancreatic carcinoma cell lines.	('EMT', 'biological_process', 'GO:0001837', ('190', '193'))	('invasion', 'CPA', (177, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('EMT', 'biological_process', 'GO:0001837', ('26', '29'))	('circHIPK3', 'Var', (158, 167))	('pancreatic carcinoma', 'Disease', (197, 217))	('EMT', 'CPA', (190, 193))	('promoted', 'PosReg', (168, 176))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (197, 217))
91635	29702530	Interestingly, in agreement with the data of RT-PCR and Western blotting, the fluorescence intensity results and transwell assay indicated that downregulation of circHIPK3 observably decreased invasive and migration capacity of pancreatic cancer cells by contrast with NC groups.	('circHIPK3', 'Gene', (162, 171))	('downregulation', 'Var', (144, 158))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (228, 245))	('decreased', 'NegReg', (183, 192))	('pancreatic cancer', 'Disease', (228, 245))	('pancreatic cancer', 'Disease', 'MESH:D010190', (228, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
91636	29702530	Moreover, according to the growth rate of xenograft tumors and IHC (ki67 and MMPs) between si-circHIPK3 and NC groups,we found that intratumoral silencing of circHIPK3 suppresses pancreatic cancer growth and metastasis in vivo.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('pancreatic cancer', 'Disease', 'MESH:D010190', (179, 196))	('tumor', 'Disease', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('silencing', 'Var', (145, 154))	('tumor', 'Disease', (52, 57))	('tumors', 'Disease', (52, 58))	('xenograft tumor', 'Disease', (42, 57))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('suppresses', 'NegReg', (168, 178))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (179, 196))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('circHIPK3', 'Gene', (158, 167))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('xenograft tumor', 'Disease', 'MESH:D009369', (42, 57))	('pancreatic cancer', 'Disease', (179, 196))
91637	29702530	Conclusion: Silencing of circHIPK3 could suppress cell proliferation, migration and invasion, reverse EMT as well as inhibit tumor growth and metastasis in vitro and in vivo, suggesting that circHIPK3 would be a promising target of diagnosis and therapy in pancreatic cancer.	('circHIPK3', 'Gene', (25, 34))	('EMT', 'biological_process', 'GO:0001837', ('102', '105'))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('invasion', 'CPA', (84, 92))	('pancreatic cancer', 'Disease', (257, 274))	('migration', 'CPA', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('pancreatic cancer', 'Disease', 'MESH:D010190', (257, 274))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('Silencing', 'Var', (12, 21))	('tumor', 'Disease', (125, 130))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('suppress', 'NegReg', (41, 49))	('reverse EMT', 'CPA', (94, 105))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (257, 274))	('inhibit', 'NegReg', (117, 124))	('cell proliferation', 'CPA', (50, 68))
91639	29702530	MicroRNAs are ideal regulators of mRNA translation since their activity can be easily reversed by modulating the RNA silencing complex (RISC), that uses them as guide for RNA recognition.	('RISC', 'Gene', '59342', (136, 140))	('RNA', 'cellular_component', 'GO:0005562', ('171', '174'))	('translation', 'biological_process', 'GO:0006412', ('39', '50'))	('modulating', 'Var', (98, 108))	('RNA', 'cellular_component', 'GO:0005562', ('113', '116'))	('RISC', 'Gene', (136, 140))
91641	29702530	We will use as model the STAT3 mRNA and the miRNAs miR-17 which is known for regulating STAT3 translation.	('STAT3', 'Gene', (25, 30))	('miR-17', 'Gene', (51, 57))	('STAT3', 'Gene', '6774', (88, 93))	('miR-17', 'Gene', '406952', (51, 57))	('STAT3', 'Gene', (88, 93))	('miRNAs', 'Var', (44, 50))	('translation', 'biological_process', 'GO:0006412', ('94', '105'))	('STAT3', 'Gene', '6774', (25, 30))
91644	29702530	We anticipate that deregulated STAT3 expression as a consequence of lack of miRNA regulation will affect cell migration.	('cell migration', 'biological_process', 'GO:0016477', ('105', '119'))	('deregulated', 'Var', (19, 30))	('STAT3', 'Gene', (31, 36))	('miRNA regulation', 'MPA', (76, 92))	('regulation', 'biological_process', 'GO:0065007', ('82', '92'))	('lack', 'NegReg', (68, 72))	('affect', 'Reg', (98, 104))	('cell migration', 'CPA', (105, 119))	('STAT3', 'Gene', '6774', (31, 36))
91660	29702530	Alteration of these genes are associated with changes in central glucose metabolism particularly aerobic glycolysis, the Warburg effect, which is the main theme of cancer metabolism.	('changes', 'Reg', (46, 53))	('glucose metabolism', 'biological_process', 'GO:0006006', ('65', '83'))	('aerobic glycolysis', 'MPA', (97, 115))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('metabolism', 'biological_process', 'GO:0008152', ('171', '181'))	('Alteration', 'Var', (0, 10))	('central glucose metabolism', 'MPA', (57, 83))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('Warburg effect', 'Disease', (121, 135))	('glycolysis', 'biological_process', 'GO:0006096', ('105', '115'))	('glucose', 'Chemical', 'MESH:D005947', (65, 72))
91666	29702530	Background: Deuterium, the heavy non-radiating isotope of hydrogen, blocks mitochondrial energy production by damaging ATP synthase and thus induces molecular crowding and the Warburg effect.	('ATP synthase', 'molecular_function', 'GO:0016467', ('119', '131'))	('ATP', 'Gene', (119, 122))	('ATP', 'Gene', '51761', (119, 122))	('blocks', 'NegReg', (68, 74))	('Deuterium', 'Var', (12, 21))	('induces', 'Reg', (141, 148))	('molecular crowding', 'CPA', (149, 167))	('Deuterium', 'Chemical', 'MESH:D003903', (12, 21))	('hydrogen', 'Chemical', 'MESH:D006859', (58, 66))	('Warburg effect', 'CPA', (176, 190))	('damaging', 'NegReg', (110, 118))	('mitochondrial energy production', 'MPA', (75, 106))	('ATP synthase', 'molecular_function', 'GO:0016468', ('119', '131'))
91673	29702530	Conclusion: Deuterium depletion by natural low deuterium ketogenic substrate oxidation is essential to produce deuterium depleted matrix water for mitochondrial health as deuterium free rotations of the ATP synthase nanomotor protein increases substrate intake and TCA cycle turnover to prevent molecular crowding to treat cancer.	('TCA cycle', 'biological_process', 'GO:0006099', ('265', '274'))	('ATP synthase', 'molecular_function', 'GO:0016467', ('203', '215'))	('deuterium', 'Chemical', 'MESH:D003903', (111, 120))	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('deuterium', 'Chemical', 'MESH:D003903', (47, 56))	('ATP', 'Gene', '51761', (203, 206))	('substrate intake', 'MPA', (244, 260))	('Deuterium', 'Chemical', 'MESH:D003903', (12, 21))	('water', 'Chemical', 'MESH:D014867', (137, 142))	('TCA', 'Chemical', 'MESH:D014238', (265, 268))	('deuterium', 'Chemical', 'MESH:D003903', (171, 180))	('TCA cycle', 'Enzyme', (265, 274))	('ATP synthase', 'molecular_function', 'GO:0016468', ('203', '215'))	('deuterium', 'Var', (171, 180))	('protein', 'cellular_component', 'GO:0003675', ('226', '233'))	('cancer', 'Disease', (323, 329))	('ATP', 'Gene', (203, 206))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('increases', 'PosReg', (234, 243))
91679	32029792	Our in vitro experiments demonstrated that GPNCA silencing inhibited tumor growth via inhibiting its nearby gene GSK3B.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('silencing', 'Var', (49, 58))	('tumor', 'Disease', (69, 74))	('GSK3B', 'Gene', (113, 118))	('inhibited', 'NegReg', (59, 68))	('GSK3B', 'Gene', '2932', (113, 118))	('inhibiting', 'NegReg', (86, 96))	('GPNCA', 'Gene', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('GSK', 'molecular_function', 'GO:0050321', ('113', '116'))
91690	32029792	Finally, we confirmed that GPNCA silencing could inhibit HepG2 and HCT116 tumor cell growth via regulating its nearby gene GSK3B.	('GPNCA', 'Gene', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('silencing', 'Var', (33, 42))	('HepG2', 'CellLine', 'CVCL:0027', (57, 62))	('GSK3B', 'Gene', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('regulating', 'Reg', (96, 106))	('GSK3B', 'Gene', '2932', (123, 128))	('cell growth', 'biological_process', 'GO:0016049', ('80', '91'))	('tumor', 'Disease', (74, 79))	('inhibit', 'NegReg', (49, 56))	('HCT116', 'CellLine', 'CVCL:0291', (67, 73))	('GSK', 'molecular_function', 'GO:0050321', ('123', '126'))
91694	32029792	Here, we termed LncRNA GPNCA whose gene Ensembl ID was ENSG00000242622.1 and was upregulated in the Chr3q13.33 (120094895-120136783) region next to GSK3B.	('120094895-120136783', 'Var', (112, 131))	('upregulated', 'PosReg', (81, 92))	('GSK3B', 'Gene', '2932', (148, 153))	('GSK3B', 'Gene', (148, 153))	('GSK', 'molecular_function', 'GO:0050321', ('148', '151'))
91712	32029792	The results from liver cancer patients showed that those with GPNCA expression (FPKM value) > 0.295 were of high-risk and had poor survival (HR = 1.890, 95% CI, 1.278-2.795, P = 0.0012), (Fig.	('liver cancer', 'Phenotype', 'HP:0002896', (17, 29))	('liver cancer', 'Disease', 'MESH:D006528', (17, 29))	('survival', 'MPA', (131, 139))	('liver cancer', 'Disease', (17, 29))	('patients', 'Species', '9606', (30, 38))	('poor', 'NegReg', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('> 0.295', 'Var', (92, 99))
91713	32029792	S1B); whilst renal clear cell cancer patients with GPNCA expression (FPKM value) > 0.421 were of high-risk resulting in poor OS (AUC value > 0.5, HR = 2.166, 95% CI, 1.269-3.698, P = 0.0002)(Fig.	('renal clear cell cancer', 'Disease', (13, 36))	('renal clear cell cancer', 'Disease', 'MESH:D002292', (13, 36))	('clear cell cancer', 'Phenotype', 'HP:0006770', (19, 36))	('patients', 'Species', '9606', (37, 45))	('> 0.421', 'Var', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
91714	32029792	The results of breast cancer patients with GPNCA expression (FPKM value) >= 0.417 were of high-risk leading to poor OS (HR = 1.392, 95% CI, 1.032-1.959, P = 0.0324) (Fig.	('patients', 'Species', '9606', (29, 37))	('GPNCA', 'Var', (43, 48))	('>= 0.417', 'Var', (73, 81))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancer', 'Disease', (15, 28))	('poor OS', 'MPA', (111, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
91715	32029792	These data suggested that high GPNCA expression was indeed associated with poor OS in several cancers but not enough sensitive to be an independent clinical biomarker for prognosis.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('high', 'Var', (26, 30))	('GPNCA expression', 'Protein', (31, 47))	('associated', 'Reg', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('poor OS', 'Disease', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
91727	32029792	In intro ChIP (Chromatin immunoprecipitation) assays revealed that H3k27ac enrichment was markedly higher in HepG2 cells (liver cancer cells) compared to LO2 cells (normal liver cells) on the GPNCA promoter region (Fig.	('liver cancer', 'Phenotype', 'HP:0002896', (122, 134))	('liver cancer', 'Disease', 'MESH:D006528', (122, 134))	('liver cancer', 'Disease', (122, 134))	('higher', 'PosReg', (99, 105))	('H3k27ac', 'Protein', (67, 74))	('HepG2', 'Var', (109, 114))	('HepG2', 'CellLine', 'CVCL:0027', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('Chromatin', 'cellular_component', 'GO:0000785', ('15', '24'))	('LO2', 'CellLine', 'CVCL:6926', (154, 157))	('enrichment', 'MPA', (75, 85))
91743	32029792	The results showed that GPNCA silencing inhibited cell proliferation both in HepG2 and HCT116 cells (Fig.	('inhibited', 'NegReg', (40, 49))	('HepG2', 'CellLine', 'CVCL:0027', (77, 82))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('HCT116', 'CellLine', 'CVCL:0291', (87, 93))	('GPNCA', 'Protein', (24, 29))	('silencing', 'Var', (30, 39))	('cell proliferation', 'CPA', (50, 68))
91745	32029792	Taken together, these data demonstrate that GPNCA silencing inhibits tumor cell growth.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('silencing', 'Var', (50, 59))	('inhibits', 'NegReg', (60, 68))	('cell growth', 'biological_process', 'GO:0016049', ('75', '86'))	('GPNCA', 'Gene', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
91759	32029792	However, the expressions of GPNCA were not influenced by GSK3B knockdown both in HCT116 and HepG2 cells (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (81, 87))	('GSK3B', 'Gene', '2932', (57, 62))	('HepG2', 'CellLine', 'CVCL:0027', (92, 97))	('GSK3B', 'Gene', (57, 62))	('GSK', 'molecular_function', 'GO:0050321', ('57', '60'))	('knockdown', 'Var', (63, 72))
91767	32029792	Furthermore, we found that the upregulation of GPNCA was associated with the high enrichment of H3k27ac on the GPNCA promoter region via EP300 and GCN5, implicating GPNCA as an oncogene.	('GPNCA', 'Disease', (47, 52))	('H3k27ac', 'Var', (96, 103))	('EP300', 'Gene', (137, 142))	('EP300', 'Gene', '2033', (137, 142))	('GCN5', 'Gene', (147, 151))	('GCN5', 'Gene', '2648', (147, 151))	('upregulation', 'PosReg', (31, 43))
91783	32029792	In vitro experiments revealed that GPNCA silencing markedly inhibits tumor cell proliferation via regulation of GSK3B, suggesting that drugs targeted to GPNCA may hold potential considerable value for anti-cancer therapy.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('GSK3B', 'Gene', '2932', (112, 117))	('silencing', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('GSK3B', 'Gene', (112, 117))	('tumor', 'Disease', (69, 74))	('GPNCA', 'Gene', (35, 40))	('regulation', 'MPA', (98, 108))	('regulation of GSK', 'biological_process', 'GO:1902947', ('98', '115'))	('cell proliferation', 'biological_process', 'GO:0008283', ('75', '93'))	('inhibits', 'NegReg', (60, 68))	('GSK', 'molecular_function', 'GO:0050321', ('112', '115'))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
91799	32029792	Primary antibodies were showed as follows: EP300 (Abcam, ab14984), KAT2A/GCN5 (Abcam, ab208097), H3k27ac (Abcam, ab177178), beta-actin (Proteintech, 60008-1-lg), Lamin B1 (CST, #13435) and Histone 3 (Abcam, ab1791).	('GCN5', 'Gene', '2648', (73, 77))	('beta-actin', 'Gene', (124, 134))	('Lamin B1', 'Gene', (162, 170))	('EP300', 'Gene', (43, 48))	('KAT2A', 'Gene', '2648', (67, 72))	('Lamin B1', 'Gene', '4001', (162, 170))	('Histone 3', 'Protein', (189, 198))	('H3k27ac', 'Var', (97, 104))	('KAT2A', 'Gene', (67, 72))	('GCN5', 'Gene', (73, 77))	('KAT', 'molecular_function', 'GO:0003988', ('67', '70'))	('beta-actin', 'Gene', '728378', (124, 134))	('EP300', 'Gene', '2033', (43, 48))
91813	31477750	HSP60 silencing significantly attenuated growth of OC cells in both cells and mice xenografts.	('mice', 'Species', '10090', (78, 82))	('HSP60', 'Protein', (0, 5))	('OC', 'Phenotype', 'HP:0100615', (51, 53))	('growth of OC cells', 'CPA', (41, 59))	('silencing', 'Var', (6, 15))	('attenuated', 'NegReg', (30, 40))
91814	31477750	Metabolomic analysis revealed that HSP60 silencing resulted in a more than 100-fold increase in cellular adenine levels, leading to increased adenosine monophosphate and an activated AMPK pathway, and consequently reduced mTORC1-mediated S6K and 4EBP1 phosphorylation to inhibit protein synthesis that suppressed the proliferation of OC cells.	('silencing', 'Var', (41, 50))	('protein synthesis', 'biological_process', 'GO:0006412', ('279', '296'))	('EBP1', 'Gene', '4790', (247, 251))	('suppressed', 'NegReg', (302, 312))	('phosphorylation', 'biological_process', 'GO:0016310', ('252', '267'))	('AMPK', 'molecular_function', 'GO:0004691', ('183', '187'))	('protein', 'cellular_component', 'GO:0003675', ('279', '286'))	('adenosine monophosphate', 'Chemical', 'MESH:D000249', (142, 165))	('increased', 'PosReg', (132, 141))	('increase', 'PosReg', (84, 92))	('AMPK', 'Gene', (183, 187))	('phosphorylation', 'MPA', (252, 267))	('AMPK', 'molecular_function', 'GO:0047322', ('183', '187'))	('adenosine monophosphate', 'MPA', (142, 165))	('mTORC1', 'Gene', (222, 228))	('adenine', 'Chemical', 'MESH:D000225', (105, 112))	('reduced', 'NegReg', (214, 221))	('inhibit', 'NegReg', (271, 278))	('mTORC1', 'Gene', '382056', (222, 228))	('HSP60', 'Protein', (35, 40))	('protein synthesis', 'MPA', (279, 296))	('OC', 'Phenotype', 'HP:0100615', (334, 336))	('EBP1', 'Gene', (247, 251))	('cellular adenine levels', 'MPA', (96, 119))	('mTORC1', 'cellular_component', 'GO:0031931', ('222', '228'))	('AMPK', 'molecular_function', 'GO:0050405', ('183', '187'))	('AMPK', 'Gene', '5562', (183, 187))
91815	31477750	These results suggest that HSP60 knockdown breaks mitochondrial proteostasis, and inactivates the mTOR pathway to inhibit OC progression, suggesting that HSP60 is a potential therapeutic target for OC treatment.	('breaks', 'NegReg', (43, 49))	('inhibit', 'NegReg', (114, 121))	('OC', 'Phenotype', 'HP:0100615', (122, 124))	('knockdown', 'Var', (33, 42))	('mitochondrial proteostasis', 'MPA', (50, 76))	('OC', 'Phenotype', 'HP:0100615', (198, 200))	('mTOR', 'Gene', '2475', (98, 102))	('HSP60', 'Protein', (27, 32))	('inactivates', 'NegReg', (82, 93))	('mTOR', 'Gene', (98, 102))
91830	31477750	Our earlier studies demonstrated that HSP60 knockdown interrupted the integrity of respiratory complex I, leading to reactive oxygen species (ROS) overproduction to activate the AMPK pathway, which drove cell growth of clear cell renal cell carcinoma (ccRCC).	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (219, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('interrupted', 'NegReg', (54, 65))	('activate', 'PosReg', (165, 173))	('integrity', 'MPA', (70, 79))	('HSP60', 'Protein', (38, 43))	('respiratory complex', 'MPA', (83, 102))	('drove', 'PosReg', (198, 203))	('AMPK', 'molecular_function', 'GO:0050405', ('178', '182'))	('overproduction', 'PosReg', (147, 161))	('ROS', 'Chemical', 'MESH:D017382', (142, 145))	('knockdown', 'Var', (44, 53))	('AMPK', 'Gene', (178, 182))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (117, 140))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (219, 250))	('AMPK', 'molecular_function', 'GO:0004691', ('178', '182'))	('cell growth', 'biological_process', 'GO:0016049', ('204', '215'))	('clear cell renal cell carcinoma', 'Disease', (219, 250))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (230, 250))	('ccRCC', 'Phenotype', 'HP:0006770', (252, 257))	('AMPK', 'molecular_function', 'GO:0047322', ('178', '182'))	('AMPK', 'Gene', '5562', (178, 182))	('complex I', 'cellular_component', 'GO:0030964', ('95', '104'))
91836	31477750	We found that HSP60 was highly expressed in ovarian tumors, and knockdown of HSP60 significantly impeded cell proliferation by disrupting mitochondrial proteostasis and activating the adenine-dependent AMPK pathway, indicating that HSP60 is a potential target for OC therapy.	('AMPK', 'molecular_function', 'GO:0047322', ('202', '206'))	('mitochondrial proteostasis', 'MPA', (138, 164))	('AMPK', 'Gene', (202, 206))	('ovarian tumors', 'Disease', (44, 58))	('impeded', 'NegReg', (97, 104))	('cell proliferation', 'CPA', (105, 123))	('ovarian tumors', 'Disease', 'MESH:D010051', (44, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('disrupting', 'NegReg', (127, 137))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('AMPK', 'molecular_function', 'GO:0050405', ('202', '206'))	('AMPK', 'Gene', '5562', (202, 206))	('HSP60', 'Gene', (77, 82))	('ovarian tumor', 'Phenotype', 'HP:0100615', (44, 57))	('ovarian tumors', 'Phenotype', 'HP:0100615', (44, 58))	('OC', 'Phenotype', 'HP:0100615', (264, 266))	('cell proliferation', 'biological_process', 'GO:0008283', ('105', '123'))	('AMPK', 'molecular_function', 'GO:0004691', ('202', '206'))	('adenine', 'Chemical', 'MESH:D000225', (184, 191))	('activating', 'PosReg', (169, 179))	('knockdown', 'Var', (64, 73))
91856	31477750	Western blotting was used to analyze HSP60 silencing efficacy in A2780 cells, demonstrating that HSP60 expression was decreased by more than 50% in HSP60-KD1 cells and 70% in HSP60-KD2 cells (Fig.	('A2780', 'CellLine', 'CVCL:0134', (65, 70))	('expression', 'MPA', (103, 113))	('HSP60-KD1', 'Var', (148, 157))	('decreased', 'NegReg', (118, 127))	('HSP60', 'Protein', (97, 102))
91857	31477750	Further analysis by CCK-8 assays showed that HSP60 knockdown in A2780 cells resulted in a marked decrease in the proliferation rate (Fig.	('decrease', 'NegReg', (97, 105))	('HSP60', 'Protein', (45, 50))	('A2780', 'CellLine', 'CVCL:0134', (64, 69))	('proliferation rate', 'CPA', (113, 131))	('knockdown', 'Var', (51, 60))
91860	31477750	The xenograft experiments revealed that HSP60 knockdown significantly slowed tumor growth.	('knockdown', 'Var', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('HSP60', 'Protein', (40, 45))	('slowed', 'NegReg', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
91861	31477750	Furthermore, we found that HSP60 inhibition by mizoribine decreased the growth of A2780 and HSP60-KD A2780 cells (Fig.	('growth', 'CPA', (72, 78))	('decreased', 'NegReg', (58, 67))	('inhibition', 'NegReg', (33, 43))	('A2780', 'CellLine', 'CVCL:0134', (101, 106))	('HSP60-KD A2780', 'Var', (92, 106))	('A2780', 'CellLine', 'CVCL:0134', (82, 87))	('mizoribine', 'Chemical', 'MESH:C010052', (47, 57))	('HSP60', 'Protein', (27, 32))
91862	31477750	Importantly, A2780 cells were more susceptible to mizoribine treatment than HSP60-KD cells.	('A2780', 'CellLine', 'CVCL:0134', (13, 18))	('susceptible', 'MPA', (35, 46))	('A2780', 'Var', (13, 18))	('mizoribine', 'Chemical', 'MESH:C010052', (50, 60))
91863	31477750	These results demonstrated that high HSP60 expression is important to promote tumor progression of OC, which is a potential therapeutic target for OC treatment.	('high', 'Var', (32, 36))	('HSP60', 'Protein', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('OC', 'Phenotype', 'HP:0100615', (99, 101))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('promote', 'PosReg', (70, 77))	('OC', 'Phenotype', 'HP:0100615', (147, 149))	('tumor', 'Disease', (78, 83))	('expression', 'MPA', (43, 53))
91864	31477750	Depending on the average reporter ion ratios in TMT quantitative analysis, 343 proteins were significantly downregulated (ratio < 0.67, p-value < 0.05), while 102 proteins were upregulated (ratio > 1.5, p-value < 0.05) in HSP60-KD1 cells compared with control cells (Supplementary Tables S3 and S4).	('upregulated', 'PosReg', (177, 188))	('proteins', 'Protein', (79, 87))	('TMT', 'Gene', (48, 51))	('proteins', 'Protein', (163, 171))	('downregulated', 'NegReg', (107, 120))	('TMT', 'molecular_function', 'GO:0018708', ('48', '51'))	('TMT', 'Gene', '25823', (48, 51))	('HSP60-KD1', 'Var', (222, 231))
91865	31477750	IPA showed that 21 cancer-related pathways were mostly inhibited (with the largest absolute values of z-score and p-values < 0.05) in HSP60-KD1 A2780 cells (Fig.	('A2780', 'CellLine', 'CVCL:0134', (144, 149))	('HSP60-KD1 A2780 cells', 'Var', (134, 155))	('IPA', 'Chemical', '-', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('inhibited', 'NegReg', (55, 64))
91866	31477750	Suppression of OSPHOS implied mitochondrial dysfunction in HSP60-KD A2780 cells, while decreased tRNA charging, p70S6K, and mTOR signaling pathways revealed that HSP60 silencing inhibited protein synthesis.	('silencing', 'Var', (168, 177))	('mTOR', 'Gene', '2475', (124, 128))	('p70S6K', 'Gene', (112, 118))	('mitochondrial dysfunction', 'Disease', (30, 55))	('protein synthesis', 'biological_process', 'GO:0006412', ('188', '205'))	('protein synthesis', 'MPA', (188, 205))	('Suppression', 'NegReg', (0, 11))	('OSPHOS', 'Protein', (15, 21))	('decreased', 'NegReg', (87, 96))	('inhibited', 'NegReg', (178, 187))	('HSP60', 'Protein', (162, 167))	('tRNA', 'molecular_function', 'GO:0030533', ('97', '101'))	('p70S6K', 'Gene', '6198', (112, 118))	('tRNA charging', 'biological_process', 'GO:0006418', ('97', '110'))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (30, 55))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('mTOR', 'Gene', (124, 128))	('tRNA charging', 'MPA', (97, 110))	('signaling', 'biological_process', 'GO:0023052', ('129', '138'))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (30, 55))	('tRNA charging', 'biological_process', 'GO:0043039', ('97', '110'))	('A2780', 'CellLine', 'CVCL:0134', (68, 73))
91867	31477750	Other pathways, including inositol phosphate and phosphoinositide metabolism, IGF-1 signaling, ErbB4 signaling, endothelin-1 signaling, and neuregulin signaling, were all inactivated in HSP60-KD cells.	('ErbB4', 'Gene', (95, 100))	('endothelin-1', 'Gene', (112, 124))	('ErbB4', 'Gene', '2066', (95, 100))	('inactivated', 'NegReg', (171, 182))	('phosphoinositide metabolism', 'biological_process', 'GO:0046488', ('49', '76'))	('HSP60-KD', 'Var', (186, 194))	('IGF-1', 'Gene', '3479', (78, 83))	('phosphoinositide', 'Chemical', 'MESH:D010716', (49, 65))	('IGF-1', 'Gene', (78, 83))	('neuregulin signaling', 'MPA', (140, 160))	('endothelin-1', 'Gene', '1906', (112, 124))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('inositol phosphate', 'Chemical', 'MESH:D007295', (26, 44))	('signaling', 'biological_process', 'GO:0023052', ('151', '160'))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))
91872	31477750	These results indicated that HSP60 knockdown disrupted mitochondrial integrity and suppressed OXPHOS in A2780 cells.	('knockdown', 'Var', (35, 44))	('HSP60', 'Protein', (29, 34))	('OXPHOS', 'biological_process', 'GO:0002082', ('94', '100'))	('A2780', 'CellLine', 'CVCL:0134', (104, 109))	('OXPHOS', 'MPA', (94, 100))	('mitochondrial integrity', 'MPA', (55, 78))	('disrupted', 'NegReg', (45, 54))	('suppressed', 'NegReg', (83, 93))
91873	31477750	Furthermore, HSP60 knockdown upregulated expression of S-methyl-5'-thioadenosine phosphorylase (MTAP) and cytosolic purine 5'-nucleotidase (NT5C2) (Supplementary Tables S3 and S4).	('MTAP', 'Gene', '4507', (96, 100))	("cytosolic purine 5'-nucleotidase", 'Gene', (106, 138))	("cytosolic purine 5'-nucleotidase", 'Gene', '22978', (106, 138))	('upregulated', 'PosReg', (29, 40))	('expression', 'MPA', (41, 51))	("S-methyl-5'-thioadenosine phosphorylase", 'Gene', (55, 94))	('knockdown', 'Var', (19, 28))	('HSP60', 'Protein', (13, 18))	("S-methyl-5'-thioadenosine phosphorylase", 'Gene', '4507', (55, 94))	('NT5C2', 'Gene', (140, 145))	('MTAP', 'Gene', (96, 100))	('NT5C2', 'Gene', '22978', (140, 145))
91874	31477750	We found that HSP60 silencing increased adenine levels by 104-fold among 259 altered metabolites in HSP60-KD1 cells (Fig.	('HSP60', 'Protein', (14, 19))	('adenine', 'Chemical', 'MESH:D000225', (40, 47))	('increased', 'PosReg', (30, 39))	('adenine levels', 'MPA', (40, 54))	('silencing', 'Var', (20, 29))	('metabolites', 'MPA', (85, 96))
91876	31477750	IPA analysis of the significantly changed metabolites demonstrated that purine nucleotide de novo biosynthesis II and AMPK signaling pathways were the most activated (with the largest z-scores and p-values < 0.05) canonical pathways in HSP60 KD cells (Supplementary Tables S9 and S10).	('activated', 'PosReg', (156, 165))	('IPA', 'Chemical', '-', (0, 3))	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('AMPK', 'Gene', '5562', (118, 122))	('AMPK', 'Gene', (118, 122))	('HSP60 KD', 'Var', (236, 244))	('AMPK', 'molecular_function', 'GO:0050405', ('118', '122'))	('AMPK', 'molecular_function', 'GO:0004691', ('118', '122'))	('purine nucleotide', 'Pathway', (72, 89))	('AMPK', 'molecular_function', 'GO:0047322', ('118', '122'))	('purine', 'Chemical', 'MESH:C030985', (72, 78))	('biosynthesis', 'biological_process', 'GO:0009058', ('98', '110'))
91878	31477750	We found that adenine precursor 5'-methylthioadenosine (MTA) was decreased by 30% and 64% in HSP60-KD1 and KD2 cells, respectively (Fig.	('decreased', 'NegReg', (65, 74))	('adenine', 'Chemical', 'MESH:D000225', (14, 21))	('HSP60-KD1', 'Var', (93, 102))	("adenine precursor 5'-methylthioadenosine", 'MPA', (14, 54))	('MTA', 'Chemical', 'MESH:C008500', (56, 59))	("5'-methylthioadenosine", 'Chemical', 'MESH:C008500', (32, 54))
91879	31477750	Conversion of MTA to adenine is catalyzed by MTA phosphorylase (MTAP), which was upregulated in HSP60-KD A2780 cells based on proteomics and western blot results (Fig.	('MTA', 'Chemical', 'MESH:C008500', (64, 67))	('upregulated', 'PosReg', (81, 92))	('MTA', 'Chemical', 'MESH:C008500', (45, 48))	('MTAP', 'Gene', (64, 68))	('MTA phosphorylase', 'Gene', '4507', (45, 62))	('MTA', 'Chemical', 'MESH:C008500', (14, 17))	('A2780', 'CellLine', 'CVCL:0134', (105, 110))	('MTA phosphorylase', 'Gene', (45, 62))	('MTAP', 'Gene', '4507', (64, 68))	('adenine', 'Chemical', 'MESH:D000225', (21, 28))	('HSP60-KD A2780', 'Var', (96, 110))
91883	31477750	Western blotting showed that phosphorylation of AMPKalpha-T172 was significantly increased in HSP60-KD cells (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('29', '44'))	('HSP60-KD cells', 'Var', (94, 108))	('AMPK', 'Gene', '5562', (48, 52))	('AMPK', 'Gene', (48, 52))	('increased', 'PosReg', (81, 90))	('phosphorylation', 'MPA', (29, 44))
91890	31477750	Then we treated HSP60-KD A2780 cells with MTAP inhibitor MT-DADMe-ImmA (MTDIA) and demonstrated that inhibition of production of adenine in cells by MTDIA could rescue the mTOR pathway of HSP60-KD1 and KD2 cells in a dose-dependent manner (Fig.	('rescue', 'PosReg', (161, 167))	('mTOR', 'Gene', (172, 176))	('MTAP', 'Gene', '4507', (42, 46))	('inhibition', 'Var', (101, 111))	('A2780', 'CellLine', 'CVCL:0134', (25, 30))	('DADMe', 'Chemical', '-', (60, 65))	('adenine', 'Chemical', 'MESH:D000225', (129, 136))	('MTAP', 'Gene', (42, 46))	('mTOR', 'Gene', '2475', (172, 176))
91902	31477750	In the present study, we proved that HSP60 was upregulated in OC tissues compared with normal tissues, and HSP60 knockdown reduced the proliferation of ovarian cancer cells.	('HSP60', 'Gene', (107, 112))	('ovarian cancer', 'Disease', 'MESH:D010051', (152, 166))	('ovarian cancer', 'Disease', (152, 166))	('HSP60', 'Protein', (37, 42))	('upregulated', 'PosReg', (47, 58))	('proliferation', 'CPA', (135, 148))	('OC', 'Phenotype', 'HP:0100615', (62, 64))	('knockdown', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('ovarian cancer', 'Phenotype', 'HP:0100615', (152, 166))	('reduced', 'NegReg', (123, 130))
91905	31477750	Our previous study showed that HSP60 silencing activated the AMPK pathway.	('activated', 'PosReg', (47, 56))	('AMPK', 'Gene', '5562', (61, 65))	('silencing', 'Var', (37, 46))	('AMPK', 'Gene', (61, 65))	('AMPK', 'molecular_function', 'GO:0050405', ('61', '65'))	('AMPK', 'molecular_function', 'GO:0004691', ('61', '65'))	('HSP60', 'Protein', (31, 36))	('AMPK', 'molecular_function', 'GO:0047322', ('61', '65'))
91910	31477750	It has been reported that MTAP is downregulated in solid tumors and hematological malignancies because of MTAP deletion or methylation at the MTAP promoter region.	('MTAP', 'Gene', (142, 146))	('methylation', 'biological_process', 'GO:0032259', ('123', '134'))	('downregulated', 'NegReg', (34, 47))	('hematological malignancies', 'Disease', (68, 94))	('MTAP', 'Gene', '4507', (142, 146))	('hematological malignancies', 'Disease', 'MESH:D019337', (68, 94))	('MTAP', 'Gene', '4507', (106, 110))	('methylation', 'Var', (123, 134))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('solid tumors', 'Disease', (51, 63))	('MTAP', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('MTAP', 'Gene', (106, 110))	('hematological malignancies', 'Phenotype', 'HP:0004377', (68, 94))	('solid tumors', 'Disease', 'MESH:D009369', (51, 63))	('MTAP', 'Gene', '4507', (26, 30))	('deletion', 'Var', (111, 119))
91914	31477750	In our metabolomic study, methionine was decreased significantly in HSP60-KD A2780 cells.	('methionine', 'Chemical', 'MESH:D008715', (26, 36))	('decreased', 'NegReg', (41, 50))	('HSP60-KD', 'Var', (68, 76))	('methionine', 'MPA', (26, 36))	('A2780', 'CellLine', 'CVCL:0134', (77, 82))
91916	31477750	We found that SAM was decreased in HSP60-KD A2780 cells, which might reduce methylation of the MTAP promoter, inducing MTAP expression.	('HSP60-KD A2780', 'Var', (35, 49))	('methylation', 'MPA', (76, 87))	('MTAP', 'Gene', (119, 123))	('inducing', 'Reg', (110, 118))	('SAM', 'Chemical', 'MESH:D012436', (14, 17))	('expression', 'MPA', (124, 134))	('MTAP', 'Gene', (95, 99))	('methylation', 'biological_process', 'GO:0032259', ('76', '87'))	('reduce', 'NegReg', (69, 75))	('A2780', 'CellLine', 'CVCL:0134', (44, 49))	('MTAP', 'Gene', '4507', (119, 123))	('MTAP', 'Gene', '4507', (95, 99))
91917	31477750	Further analysis revealed that HSP60 silencing increased the AMP level by 8-fold, leading to the increased AMP/ATP ratio and AMPK activation.	('increased', 'PosReg', (97, 106))	('AMP', 'Chemical', 'MESH:D000249', (107, 110))	('AMP', 'Chemical', 'MESH:D000249', (125, 128))	('AMP/ATP ratio', 'MPA', (107, 120))	('silencing', 'Var', (37, 46))	('increased', 'PosReg', (47, 56))	('AMPK', 'molecular_function', 'GO:0004691', ('125', '129'))	('AMPK', 'molecular_function', 'GO:0050405', ('125', '129'))	('AMP level', 'MPA', (61, 70))	('ATP', 'Chemical', 'MESH:D000255', (111, 114))	('AMP', 'Chemical', 'MESH:D000249', (61, 64))	('HSP60', 'Protein', (31, 36))	('AMPK', 'Gene', '5562', (125, 129))	('AMPK', 'Gene', (125, 129))	('AMPK', 'molecular_function', 'GO:0047322', ('125', '129'))
91918	31477750	Indeed, HSP60 silencing significantly increased AMPK T172 phosphorylation.	('silencing', 'Var', (14, 23))	('HSP60', 'Protein', (8, 13))	('AMPK', 'molecular_function', 'GO:0004691', ('48', '52'))	('AMPK', 'molecular_function', 'GO:0047322', ('48', '52'))	('AMPK', 'Gene', '5562', (48, 52))	('phosphorylation', 'biological_process', 'GO:0016310', ('58', '73'))	('AMPK', 'Gene', (48, 52))	('increased', 'PosReg', (38, 47))	('AMPK', 'molecular_function', 'GO:0050405', ('48', '52'))
91920	31477750	Our results showed that HSP60 knockdown activated AMPKalpha and inhibited mTOR and its downstream targets p70S6 kinase and 4EBP1 in A2780 cells.	('AMPK', 'Gene', '5562', (50, 54))	('p70S6 kinase', 'MPA', (106, 118))	('AMPK', 'Gene', (50, 54))	('activated', 'PosReg', (40, 49))	('inhibited', 'NegReg', (64, 73))	('mTOR', 'Gene', (74, 78))	('mTOR', 'Gene', '2475', (74, 78))	('A2780', 'CellLine', 'CVCL:0134', (132, 137))	('HSP60', 'Protein', (24, 29))	('knockdown', 'Var', (30, 39))	('EBP1', 'Gene', (124, 128))	('EBP1', 'Gene', '4790', (124, 128))
91921	31477750	These results demonstrate that HSP60 silencing activates adenine/AMPK pathways to inhibit protein synthesis in OC cells (Fig.	('OC', 'Phenotype', 'HP:0100615', (111, 113))	('protein synthesis', 'MPA', (90, 107))	('adenine', 'Chemical', 'MESH:D000225', (57, 64))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('AMPK', 'Gene', (65, 69))	('inhibit', 'NegReg', (82, 89))	('activates', 'PosReg', (47, 56))	('silencing', 'Var', (37, 46))	('AMPK', 'molecular_function', 'GO:0050405', ('65', '69'))	('AMPK', 'molecular_function', 'GO:0004691', ('65', '69'))	('AMPK', 'Gene', '5562', (65, 69))	('HSP60', 'Protein', (31, 36))	('AMPK', 'molecular_function', 'GO:0047322', ('65', '69'))	('protein synthesis', 'biological_process', 'GO:0006412', ('90', '107'))
91924	31477750	HSP60 knockdown interrupted the integrity of the respiratory chain and downregulated proteins involved in translation, led to accumulation of adenine and activation of the AMPK pathway, thereby inhibiting the mTOR pathway, which shut down protein synthesis and suppressed cell growth.	('integrity', 'MPA', (32, 41))	('adenine', 'MPA', (142, 149))	('AMPK', 'molecular_function', 'GO:0047322', ('172', '176'))	('adenine', 'Chemical', 'MESH:D000225', (142, 149))	('activation', 'PosReg', (154, 164))	('respiratory chain', 'MPA', (49, 66))	('mTOR', 'Gene', (209, 213))	('protein synthesis', 'biological_process', 'GO:0006412', ('239', '256'))	('inhibiting', 'NegReg', (194, 204))	('AMPK', 'Gene', (172, 176))	('cell growth', 'CPA', (272, 283))	('proteins', 'Protein', (85, 93))	('cell growth', 'biological_process', 'GO:0016049', ('272', '283'))	('translation', 'MPA', (106, 117))	('suppressed', 'NegReg', (261, 271))	('translation', 'biological_process', 'GO:0006412', ('106', '117'))	('mTOR', 'Gene', '2475', (209, 213))	('downregulated', 'NegReg', (71, 84))	('AMPK', 'molecular_function', 'GO:0050405', ('172', '176'))	('AMPK', 'Gene', '5562', (172, 176))	('interrupted', 'NegReg', (16, 27))	('accumulation', 'PosReg', (126, 138))	('AMPK', 'molecular_function', 'GO:0004691', ('172', '176'))	('protein synthesis', 'MPA', (239, 256))	('respiratory chain', 'cellular_component', 'GO:0070469', ('49', '66'))	('HSP60', 'Protein', (0, 5))	('knockdown', 'Var', (6, 15))	('shut down', 'NegReg', (229, 238))	('protein', 'cellular_component', 'GO:0003675', ('239', '246'))
91941	31477750	mTOR, phosphor-mTOR (Ser2448), p70s6k, phosphor-p70S6K (Thr389) antibodies were obtained from Sigma (St Louis, MO).	('Ser', 'cellular_component', 'GO:0005790', ('21', '24'))	('p70s6k', 'Gene', (31, 37))	('Ser2448', 'Var', (21, 28))	('mTOR', 'Gene', (15, 19))	('Thr389', 'Chemical', '-', (56, 62))	('mTOR', 'Gene', '2475', (15, 19))	('p70S6K', 'Gene', '6198', (48, 54))	('p70S6K', 'Gene', (48, 54))	('Ser2448', 'Chemical', '-', (21, 28))	('mTOR', 'Gene', '2475', (0, 4))	('p70s6k', 'Gene', '6198', (31, 37))	('mTOR', 'Gene', (0, 4))
91953	31477750	For xenograft experiments, 6 x 106 HSP60-KD1, HSP60-KD2 A2780 and the control cells were harvested, washed, resuspended in 150 muL PBS and injected subcutaneously into 5-week-old nude mice (Vital River Company, China).	('PBS', 'Disease', 'MESH:D011535', (131, 134))	('A2780', 'CellLine', 'CVCL:0134', (56, 61))	('PBS', 'Disease', (131, 134))	('HSP60-KD1', 'Var', (35, 44))	('nude mice', 'Species', '10090', (179, 188))	('HSP60-KD2 A2780', 'Var', (46, 61))
91955	31477750	A2780 cells were grown in light SILAC medium containing arginine 12C6 14N4 and lysine 12C6 14N2, the shRNA targeting HSP60 and control shRNA were transfected transiently into A2780 cells respectively, and cultured for 48 h, then the medium was changed to the heavy SILAC medium containing stable isotope-enriched amino acids arginine 13C6 15N4 and lysine 13C6 14N2, after 6 h of incubation, cells were lysed, and proteins were digested with trypsin, and labeled with TMT reagents.	('lysine 13C6 14N2', 'Var', (348, 364))	('TMT', 'molecular_function', 'GO:0018708', ('467', '470'))	('arginine', 'Var', (56, 64))	('TMT', 'Gene', '25823', (467, 470))	('A2780', 'CellLine', 'CVCL:0134', (175, 180))	('A2780', 'CellLine', 'CVCL:0134', (0, 5))	('TMT', 'Gene', (467, 470))
91963	32384474	A nonsense mutation in PKD2 (p.Arg742X), which is well known as a pathogenic variant in ADPKD, was identified in the paired triple set.	('PKD2', 'Gene', (23, 27))	('ADPKD', 'Disease', 'MESH:D007690', (88, 93))	('ADPKD', 'Disease', (88, 93))	('p.Arg742X', 'Var', (29, 38))	('p.Arg742X', 'Mutation', 'rs121918040', (29, 38))	('PKD2', 'Gene', '5311', (23, 27))
91964	32384474	In the tumor sample, a somatic missense mutation of VHL (p.S65L) was found, which is known as a pathogenic mutation in Von Hippel-Lindau syndrome and RCC.	('Von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (119, 145))	('VHL', 'Gene', '7428', (52, 55))	('tumor', 'Disease', (7, 12))	('p.S65L', 'Mutation', 'rs5030826', (57, 63))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('RCC', 'Disease', (150, 153))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('VHL', 'Gene', (52, 55))	('p.S65L', 'Var', (57, 63))	('Von Hippel-Lindau syndrome', 'Disease', (119, 145))
91974	32384474	Meanwhile, many reports have described genetic alterations in RCC.	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('genetic alterations', 'Var', (39, 58))
91975	32384474	In roughly 95% of ccRCC cases, the short arm of chromosome 3 (3p) is lost; therefore, loss of 3p is the most frequent genetic alteration linked to ccRCC development.	('RCC', 'Disease', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('loss of 3p', 'Var', (86, 96))	('RCC', 'Disease', 'MESH:C538614', (149, 152))	('chromosome', 'cellular_component', 'GO:0005694', ('48', '58'))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('short arm', 'Phenotype', 'HP:0009824', (35, 44))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('RCC', 'Disease', (20, 23))	('linked', 'Reg', (137, 143))
91976	32384474	Gain of 5q (occurring in 69% of cases), partial loss of 14q (occurring in 42% of cases), gain of 7q (occurring in 20% of cases), loss of 8p (occurring in 32% of cases), and deletion of 9p (occurring in 29% of cases) are less frequent in ccRCC than loss of 3p, but are nonetheless important genetic alterations in ccRCC.	('loss', 'NegReg', (48, 52))	('loss of 8p', 'Var', (129, 139))	('Gain', 'PosReg', (0, 4))	('RCC', 'Disease', (239, 242))	('RCC', 'Disease', 'MESH:C538614', (315, 318))	('RCC', 'Disease', (315, 318))	('RCC', 'Phenotype', 'HP:0005584', (315, 318))	('RCC', 'Phenotype', 'HP:0005584', (239, 242))	('RCC', 'Disease', 'MESH:C538614', (239, 242))	('gain of 7q', 'Var', (89, 99))	('deletion of 9p', 'Var', (173, 187))
91982	32384474	That study suggested that disruption of this signaling pathway may be the link between RCC and polycystic kidney disease.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('polycystic kidney', 'Phenotype', 'HP:0000113', (95, 112))	('kidney disease', 'Phenotype', 'HP:0000112', (106, 120))	('disruption', 'Var', (26, 36))	('polycystic kidney disease', 'Disease', 'MESH:D007690', (95, 120))	('signaling pathway', 'biological_process', 'GO:0007165', ('45', '62'))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))	('polycystic kidney disease', 'Disease', (95, 120))
91993	32384474	To identify mutations at the transcriptome level, RNA sequencing reads were mapped to hg19 with STAR v2.4.0f1.	('STAR', 'Gene', '6770', (96, 100))	('mutations', 'Var', (12, 21))	('STAR', 'Gene', (96, 100))	('hg19', 'Gene', (86, 90))	('RNA', 'cellular_component', 'GO:0005562', ('50', '53'))
91995	32384474	To diagnose ADPKD, we examined the sequences of PKD1 and PKD2 from the blood samples, and detected a nonsense PKD2 mutation, R742X, which is well known as a definitely pathogenic variant in ADPKD.	('ADPKD', 'Disease', (12, 17))	('ADPKD', 'Disease', (190, 195))	('ADPKD', 'Disease', 'MESH:D007690', (190, 195))	('ADPKD', 'Disease', 'MESH:D007690', (12, 17))	('PKD2', 'Gene', '5311', (110, 114))	('PKD1', 'Gene', (48, 52))	('PKD2', 'Gene', (110, 114))	('PKD2', 'Gene', '5311', (57, 61))	('R742X', 'Var', (125, 130))	('PKD2', 'Gene', (57, 61))	('pathogenic', 'Reg', (168, 178))	('PKD1', 'Gene', '5310', (48, 52))	('R742X', 'Mutation', 'rs121918040', (125, 130))
91996	32384474	In a functional study, it was found that this nonsense PKD2 mutation results in an absence of the C-terminal region containing the coiled-coil domain, which causes failure to create the polycystin-1 and polycystin-2 complex that regulates Ca2+, Na+, and K+ concentration as a Ca2+-regulated non-selective cation channel in renal epithelial cells.	('mutation', 'Var', (60, 68))	('polycystin-1', 'Gene', '5310', (186, 198))	('polycystin-2', 'Gene', '5311', (203, 215))	('PKD2', 'Gene', (55, 59))	('polycystin', 'molecular_function', 'GO:0005227', ('203', '213'))	('Ca2+', 'Chemical', 'MESH:D000069285', (276, 280))	('polycystin-2', 'Gene', (203, 215))	('failure', 'NegReg', (164, 171))	('absence', 'NegReg', (83, 90))	('Ca2+', 'Chemical', 'MESH:D000069285', (239, 243))	('polycystin', 'molecular_function', 'GO:0005227', ('186', '196'))	('polycystin-1', 'Gene', (186, 198))	('PKD2', 'Gene', '5311', (55, 59))
91998	32384474	First, we found several germline and somatic mutations in genes including DNAH5, KMT5A, CCDC175, and TPSAB1 from the blood, tumor, and cyst of the patient (Table 1).	('KMT5A', 'Gene', (81, 86))	('mutations', 'Var', (45, 54))	('CCDC175', 'Gene', '729665', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('CCDC175', 'Gene', (88, 95))	('KMT5A', 'Gene', '387893', (81, 86))	('patient', 'Species', '9606', (147, 154))	('tumor', 'Disease', (124, 129))	('TPSAB1', 'Gene', (101, 107))	('DNAH5', 'Gene', (74, 79))	('DNAH5', 'Gene', '1767', (74, 79))	('TPSAB1', 'Gene', '7177', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
92000	32384474	In particular, eight of 19 genes (VHL, PBRM1, SETD2, KDM5C, PTEN, BAP1, MTOR, and TP53) were found to be extremely significantly mutated (FDR < 0.1 and q < 0.00001) in RCC in a previous study.	('BAP1', 'Gene', (66, 70))	('PTEN', 'Gene', (60, 64))	('PBRM1', 'Gene', '55193', (39, 44))	('KDM5C', 'Gene', (53, 58))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('PTEN', 'Gene', '5728', (60, 64))	('RCC', 'Disease', (168, 171))	('PBRM1', 'Gene', (39, 44))	('TP53', 'Gene', (82, 86))	('SETD2', 'Gene', (46, 51))	('MTOR', 'Gene', (72, 76))	('MTOR', 'Gene', '2475', (72, 76))	('mutated', 'Var', (129, 136))	('VHL', 'Gene', (34, 37))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('SETD2', 'Gene', '29072', (46, 51))	('BAP1', 'Gene', '8314', (66, 70))	('KDM5C', 'Gene', '8242', (53, 58))	('TP53', 'Gene', '7157', (82, 86))	('VHL', 'Gene', '7428', (34, 37))
92001	32384474	In this case, a missense VHL mutation, S65L, which has been reported to lead to tumorigenesis by disrupting the dynamic organization of pVHL and HIF-1alpha for ubiquitin-dependent degradation, was only detected in tumor tissue, not blood or cyst samples (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('ubiquitin', 'molecular_function', 'GO:0031386', ('160', '169'))	('HIF-1alpha', 'Gene', '3091', (145, 155))	('pVHL', 'Gene', '7428', (136, 140))	('disrupting', 'NegReg', (97, 107))	('dynamic organization', 'MPA', (112, 132))	('S65L', 'Mutation', 'rs5030826', (39, 43))	('ubiquitin-dependent degradation', 'MPA', (160, 191))	('HIF-1alpha', 'Gene', (145, 155))	('VHL', 'Gene', (137, 140))	('tumor', 'Disease', (80, 85))	('VHL', 'Gene', (25, 28))	('tumor', 'Disease', (214, 219))	('lead to', 'Reg', (72, 79))	('S65L', 'Var', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('degradation', 'biological_process', 'GO:0009056', ('180', '191'))	('VHL', 'Gene', '7428', (25, 28))	('VHL', 'Gene', '7428', (137, 140))	('pVHL', 'Gene', (136, 140))
92002	32384474	Furthermore, a novel missense SMARCA4 mutation (K981T) was also detected.	('K981T', 'Var', (48, 53))	('SMARCA4', 'Gene', (30, 37))	('SMARCA4', 'Gene', '6597', (30, 37))	('K981T', 'Mutation', 'p.K981T', (48, 53))
92005	32384474	Frequent patterns of SCNAs in RCC were found to include loss of chromosome 3p and 14q or gain of chromosome 5q at the arm level, as well as gain of 5q35, 8q24, 3q26, and 1q32 or loss of 14q24, 9p21.3, 6q26, 8p11, 10q23, 1p36, 4q35, 13q21, 15q21, and 2q37 at the focal level.	('gain', 'PosReg', (140, 144))	('gain', 'PosReg', (89, 93))	('loss', 'NegReg', (56, 60))	('4q35', 'Var', (226, 230))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('chromosome', 'cellular_component', 'GO:0005694', ('97', '107'))	('RCC', 'Disease', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('chromosome', 'cellular_component', 'GO:0005694', ('64', '74'))	('1p36', 'Var', (220, 224))	('9p21.3', 'Var', (193, 199))	('loss', 'NegReg', (178, 182))
92007	32384474	First, loss of chromosome 3p, which is the most commonly involved pattern (frequency: 95% in ccRCC) at the arm level, was detected.	('loss', 'Var', (7, 11))	('chromosome', 'cellular_component', 'GO:0005694', ('15', '25'))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('RCC', 'Disease', (95, 98))
92008	32384474	This region contains VHL, where a missense mutation, S65L, was detected in this patient's tumor, as well as PBRM1, BAP1, SETD2, and CADM2, which are known to be the most frequently mutated genes in RCC, as described above, and are putative tumor suppressor genes.	('S65L', 'Var', (53, 57))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('VHL', 'Gene', (21, 24))	('SETD2', 'Gene', (121, 126))	('tumor', 'Disease', (240, 245))	('tumor', 'Disease', (90, 95))	('SETD2', 'Gene', '29072', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('VHL', 'Gene', '7428', (21, 24))	('patient', 'Species', '9606', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('S65L', 'Mutation', 'rs5030826', (53, 57))	('BAP1', 'Gene', '8314', (115, 119))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('240', '256'))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('PBRM1', 'Gene', '55193', (108, 113))	('tumor suppressor', 'biological_process', 'GO:0051726', ('240', '256'))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('RCC', 'Disease', (198, 201))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('BAP1', 'Gene', (115, 119))	('PBRM1', 'Gene', (108, 113))	('CADM2', 'Gene', '253559', (132, 137))	('CADM2', 'Gene', (132, 137))
92009	32384474	Next, gain of 1q21-23.1, 7p22.2-22.3, 13q14.11, and 13q34 at the focal level, which is not a known pattern in RCC, was detected (Table 2).	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('gain', 'PosReg', (6, 10))	('13q34', 'Var', (52, 57))
92010	32384474	Taken together, we found that double somatic mutations:the missense mutation S65L and the loss of chromosome 3p:occurred at VHL, a tumor suppressor gene, in the tumor tissue of the ADPKD patient.	('missense mutation', 'Var', (59, 76))	('S65L', 'Gene', (77, 81))	('VHL', 'Gene', '7428', (124, 127))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('S65L', 'Mutation', 'rs5030826', (77, 81))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('131', '147'))	('chromosome', 'cellular_component', 'GO:0005694', ('98', '108'))	('VHL', 'Gene', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('ADPKD', 'Disease', (181, 186))	('ADPKD', 'Disease', 'MESH:D007690', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor suppressor', 'biological_process', 'GO:0051726', ('131', '147'))	('patient', 'Species', '9606', (187, 194))	('tumor', 'Disease', (161, 166))
92013	32384474	The loss-of-heterozygosity of the VHL mutation was called as a heterozygous variant with 45% VAF, which was normalized to 100% VAF with the loss of chromosome 3p, where VHL is located.	('VHL', 'Gene', '7428', (169, 172))	('VHL', 'Gene', (34, 37))	('mutation', 'Var', (38, 46))	('chromosome', 'cellular_component', 'GO:0005694', ('148', '158'))	('VHL', 'Gene', '7428', (34, 37))	('VHL', 'Gene', (169, 172))	('loss-of-heterozygosity', 'NegReg', (4, 26))
92016	32384474	Specifically, angiogenesis in tumors seemed to be upregulated through the VEGF signaling pathway resulting from the loss of VHL.	('VEGF', 'Gene', '7422', (74, 78))	('tumors', 'Disease', (30, 36))	('upregulated', 'PosReg', (50, 61))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('VHL', 'Gene', '7428', (124, 127))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('signaling pathway', 'biological_process', 'GO:0007165', ('79', '96'))	('VEGF', 'Gene', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('angiogenesis', 'biological_process', 'GO:0001525', ('14', '26'))	('angiogenesis', 'CPA', (14, 26))	('VEGF signaling', 'biological_process', 'GO:0038084', ('74', '88'))	('loss', 'Var', (116, 120))	('VHL', 'Gene', (124, 127))
92018	32384474	In the present study, we found loss of function of the VHL gene, including 3p deletion combined with a missense mutation in RCC, in a patient with ADPKD, not VHL syndrome.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('VHL', 'Gene', '7428', (158, 161))	('missense mutation', 'Var', (103, 120))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('VHL syndrome', 'Disease', 'MESH:D006623', (158, 170))	('loss of function', 'NegReg', (31, 47))	('ADPKD', 'Disease', (147, 152))	('VHL', 'Gene', (158, 161))	('ADPKD', 'Disease', 'MESH:D007690', (147, 152))	('VHL', 'Gene', (55, 58))	('VHL syndrome', 'Disease', (158, 170))	('VHL', 'Gene', '7428', (55, 58))	('patient', 'Species', '9606', (134, 141))
92025	32384474	VEGF expression in cancer is elevated in response to tissue hypoxia, as a result of mutations of the VHL gene.	('VHL', 'Gene', (101, 104))	('expression', 'MPA', (5, 15))	('hypoxia', 'Disease', (60, 67))	('elevated', 'PosReg', (29, 37))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('VHL', 'Gene', '7428', (101, 104))	('hypoxia', 'Disease', 'MESH:D000860', (60, 67))	('VEGF', 'Gene', '7422', (0, 4))	('cancer', 'Disease', (19, 25))	('mutations', 'Var', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('VEGF', 'Gene', (0, 4))
92045	32384474	In this study, we investigated a Korean ADPKD patient with RCC and found some somatic mutations in tumor suppressor genes and oncogenes using whole exome sequencing.	('mutations', 'Var', (86, 95))	('tumor', 'Disease', (99, 104))	('patient', 'Species', '9606', (46, 53))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('99', '115'))	('ADPKD', 'Disease', (40, 45))	('ADPKD', 'Disease', 'MESH:D007690', (40, 45))	('tumor suppressor', 'biological_process', 'GO:0051726', ('99', '115'))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
92059	29527128	Approximately 60-80% of ccRCC cases exhibit the most frequent genetic feature, the loss of von Hippel-Lindau (VHL), which increases the expression of hypoxia-inducible factors (HIFs), their targets, and cell survival.	('expression', 'MPA', (136, 146))	('hypoxia', 'Disease', (150, 157))	('cell survival', 'CPA', (203, 216))	('loss', 'Var', (83, 87))	('hypoxia', 'Disease', 'MESH:D000860', (150, 157))	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('VHL', 'Disease', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('VHL', 'Disease', 'MESH:D006623', (110, 113))	('increases', 'PosReg', (122, 131))
92078	29527128	VEGF and VEGFR polymorphisms affected outcomes in sunitinib-treated mRCC patients, especially VEGFR1 polymorphisms.	('RCC', 'Disease', (69, 72))	('VEGF', 'Gene', (94, 98))	('VEGFR', 'Gene', '3791', (94, 99))	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('VEGFR', 'Gene', (94, 99))	('VEGFR1', 'Gene', '2321', (94, 100))	('outcomes', 'MPA', (38, 46))	('VEGFR1', 'Gene', (94, 100))	('VEGF', 'Gene', '7422', (9, 13))	('polymorphisms', 'Var', (15, 28))	('affected', 'Reg', (29, 37))	('VEGF', 'Gene', '7422', (0, 4))	('VEGF', 'Gene', (9, 13))	('VEGFR', 'Gene', '3791', (9, 14))	('sunitinib', 'Chemical', 'MESH:D000077210', (50, 59))	('polymorphisms', 'Var', (101, 114))	('patients', 'Species', '9606', (73, 81))	('VEGF', 'Gene', (0, 4))	('VEGFR', 'Gene', (9, 14))	('VEGF', 'Gene', '7422', (94, 98))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
92108	29527128	However, the inhibition of mTORC1 produces a loss of negative feedback loops, which upregulates the downstream effectors of the PI3K/AKT/mTOR pathway and activates of HIFs (an activator of angiogenesis).	('HIFs', 'CPA', (167, 171))	('angiogenesis', 'biological_process', 'GO:0001525', ('189', '201'))	('mTOR', 'Gene', (137, 141))	('PI3', 'Gene', '5266', (128, 131))	('mTORC1', 'Gene', (27, 33))	('AKT', 'Gene', (133, 136))	('mTOR', 'Gene', '2475', (27, 31))	('mTORC1', 'Gene', '382056', (27, 33))	('PI3K', 'molecular_function', 'GO:0016303', ('128', '132'))	('mTOR', 'Gene', '2475', (137, 141))	('PI3', 'Gene', (128, 131))	('AKT', 'Gene', '207', (133, 136))	('activates', 'PosReg', (154, 163))	('negative feedback loops', 'MPA', (53, 76))	('mTORC1', 'cellular_component', 'GO:0031931', ('27', '33'))	('inhibition', 'Var', (13, 23))	('upregulates', 'PosReg', (84, 95))	('loss', 'NegReg', (45, 49))	('mTOR', 'Gene', (27, 31))
92113	29527128	Combined treatment with everolimus and a Toll-like receptor 9 agonist immune modulatory oligonucleotide effectively interfered with tumour growth and angiogenesis in VHL wild-type and mutant models of RCC.	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('Toll-like receptor 9', 'Gene', '54106', (41, 61))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('Toll-like receptor 9', 'Gene', (41, 61))	('VHL', 'Disease', (166, 169))	('mutant', 'Var', (184, 190))	('angiogenesis', 'CPA', (150, 162))	('oligonucleotide', 'Chemical', 'MESH:D009841', (88, 103))	('everolimus', 'Chemical', 'MESH:D000068338', (24, 34))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour growth', 'Disease', (132, 145))	('VHL', 'Disease', 'MESH:D006623', (166, 169))	('angiogenesis', 'biological_process', 'GO:0001525', ('150', '162'))	('interfered', 'NegReg', (116, 126))	('tumour growth', 'Disease', 'MESH:D006130', (132, 145))
92119	29527128	The first generation of EGFR-TKIs such as erlotinib or gefitinib, exhibit resistance after several months of treatment in patients with EGFR-activating mutations, especially in NSCLC patients.	('EGFR', 'Gene', '1956', (24, 28))	('mutations', 'Var', (152, 161))	('EGFR', 'Gene', (24, 28))	('EGFR', 'molecular_function', 'GO:0005006', ('24', '28'))	('gefitinib', 'Chemical', 'MESH:D000077156', (55, 64))	('patients', 'Species', '9606', (122, 130))	('NSCLC', 'Disease', (177, 182))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'molecular_function', 'GO:0005006', ('136', '140'))	('EGFR', 'Gene', (136, 140))	('patients', 'Species', '9606', (183, 191))	('erlotinib', 'Chemical', 'MESH:D000069347', (42, 51))
92120	29527128	The EGFR T790M mutation confers resistance to gefitinib via blockade of drug binding.	('T790M', 'Var', (9, 14))	('EGFR', 'Gene', (4, 8))	('resistance', 'MPA', (32, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('4', '8'))	('gefitinib', 'Chemical', 'MESH:D000077156', (46, 55))	('blockade', 'NegReg', (60, 68))	('drug binding', 'molecular_function', 'GO:0008144', ('72', '84'))	('T790M', 'Mutation', 'rs121434569', (9, 14))	('drug binding', 'Interaction', (72, 84))	('EGFR', 'Gene', '1956', (4, 8))
92123	29527128	Second-generation drugs inhibit EGFR T790M, but these agents also inhibit wild-type EGFR.	('T790M', 'Mutation', 'rs121434569', (37, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('T790M', 'Var', (37, 42))	('EGFR', 'Gene', '1956', (32, 36))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'molecular_function', 'GO:0005006', ('32', '36'))	('inhibit', 'NegReg', (66, 73))	('EGFR', 'Gene', (32, 36))	('EGFR', 'Gene', (84, 88))	('inhibit', 'NegReg', (24, 31))
92126	29527128	Compensatory TK signalling is observed in EGFR-TKI therapy, and KRAS, anaplastic lymphoma kinase (ALK), c-MET and BRAF mutations are also associated with poor responses to anti-EGFR therapy in some cancers.	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('c-MET', 'Gene', '4233', (104, 109))	('signalling', 'biological_process', 'GO:0023052', ('16', '26'))	('EGFR', 'molecular_function', 'GO:0005006', ('177', '181'))	('c-MET', 'Gene', (104, 109))	('EGFR', 'Gene', (42, 46))	('lymphoma', 'Phenotype', 'HP:0002665', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('KRAS', 'Gene', '3845', (64, 68))	('ALK', 'Gene', '238', (98, 101))	('mutations', 'Var', (119, 128))	('EGFR', 'Gene', (177, 181))	('ALK', 'Gene', (98, 101))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('cancers', 'Disease', (198, 205))	('KRAS', 'Gene', (64, 68))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (70, 89))	('EGFR', 'Gene', '1956', (42, 46))	('anaplastic lymphoma kinase', 'Gene', '238', (70, 96))	('EGFR', 'Gene', '1956', (177, 181))	('anaplastic lymphoma kinase', 'Gene', (70, 96))
92131	29527128	AEE788 is another potent inhibitor of EGFR and VEGFR TKs at the isolated enzyme level and in cellular systems, AEE788 profoundly reduce RCC cells growth in vitro.	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))	('EGFR', 'Gene', '1956', (48, 52))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('AEE788', 'Var', (111, 117))	('EGFR', 'Gene', (38, 42))	('reduce', 'NegReg', (129, 135))	('VEGFR', 'Gene', (47, 52))	('AEE788', 'Chemical', 'MESH:C489254', (0, 6))	('EGFR', 'Gene', (48, 52))	('AEE788', 'Chemical', 'MESH:C489254', (111, 117))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('VEGFR', 'Gene', '3791', (47, 52))	('RCC', 'Disease', (136, 139))
92139	29527128	MET mutations are frequently found in Papillary RCC (pRCC).	('pRCC', 'Gene', (53, 57))	('found', 'Reg', (29, 34))	('Papillary RCC', 'Gene', '5546', (38, 51))	('MET mutations', 'Var', (0, 13))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('Papillary RCC', 'Gene', (38, 51))	('pRCC', 'Gene', '5546', (53, 57))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
92151	29527128	A bi-functional antibody-receptor domain fusion protein that targeted IGF-IR and VEGF for degradation, bi-AbCap, exhibited superior inhibition of tumour growth in RCC, colon cancer, and pancreatic cancer compared to a combination of anti-IGF-IR and anti-VEGF therapies.	('colon cancer', 'Disease', (168, 180))	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (186, 203))	('RCC', 'Disease', (163, 166))	('tumour growth', 'Disease', 'MESH:D006130', (146, 159))	('IGF-IR', 'Gene', (238, 244))	('antibody', 'molecular_function', 'GO:0003823', ('16', '24'))	('IGF-IR', 'Gene', '3480', (238, 244))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('colon cancer', 'Phenotype', 'HP:0003003', (168, 180))	('antibody', 'cellular_component', 'GO:0042571', ('16', '24'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (186, 203))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('degradation', 'biological_process', 'GO:0009056', ('90', '101'))	('IGF-IR', 'Gene', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('IGF-IR', 'Gene', '3480', (70, 76))	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('VEGF', 'Gene', '7422', (81, 85))	('inhibition', 'NegReg', (132, 142))	('VEGF', 'Gene', '7422', (254, 258))	('pancreatic cancer', 'Disease', (186, 203))	('tumour growth', 'Disease', (146, 159))	('VEGF', 'Gene', (81, 85))	('colon cancer', 'Disease', 'MESH:D015179', (168, 180))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('antibody', 'cellular_component', 'GO:0019815', ('16', '24'))	('VEGF', 'Gene', (254, 258))	('bi-AbCap', 'Var', (103, 111))	('antibody', 'cellular_component', 'GO:0019814', ('16', '24'))
92157	29527128	TrkB silencing improved the anticancer efficiency of sorafenib in anoikis-resistant ACHN (a renal cancer cell line derived from metastatic site) RCC cells via inactivation of PI3K/Akt and MEK/ERK pathways.	('MEK', 'Gene', '5609', (188, 191))	('ERK', 'Gene', '5594', (192, 195))	('sorafenib', 'Chemical', 'MESH:D000077157', (53, 62))	('cancer', 'Disease', (98, 104))	('renal cancer', 'Disease', (92, 104))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('renal cancer', 'Phenotype', 'HP:0009726', (92, 104))	('RCC', 'Disease', (145, 148))	('MEK', 'Gene', (188, 191))	('cancer', 'Disease', (32, 38))	('inactivation', 'NegReg', (159, 171))	('PI3', 'Gene', '5266', (175, 178))	('Akt', 'Gene', (180, 183))	('silencing', 'Var', (5, 14))	('anoikis-resistant ACHN', 'Disease', (66, 88))	('anoikis', 'biological_process', 'GO:0043276', ('66', '73'))	('TrkB', 'Gene', '4915', (0, 4))	('ERK', 'molecular_function', 'GO:0004707', ('192', '195'))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('improved', 'PosReg', (15, 23))	('ERK', 'Gene', (192, 195))	('Akt', 'Gene', '207', (180, 183))	('renal cancer', 'Disease', 'MESH:D007680', (92, 104))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('PI3', 'Gene', (175, 178))	('TrkB', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('PI3K', 'molecular_function', 'GO:0016303', ('175', '179'))
92158	29527128	System treatment using multi-target drugs, immune checkpoint inhibitors or drugs combinations may be a promising approach to RCC therapy in the future because of the emergence of drug resistance to VEGFR-TKI, which may facilitate tumour invasiveness and metastasis.	('facilitate', 'PosReg', (219, 229))	('VEGFR', 'Gene', (198, 203))	('tumour invasiveness', 'Disease', (230, 249))	('tumour invasiveness', 'Disease', 'MESH:D009361', (230, 249))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('drug resistance', 'Phenotype', 'HP:0020174', (179, 194))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('drug resistance', 'biological_process', 'GO:0009315', ('179', '194'))	('drug resistance', 'biological_process', 'GO:0042493', ('179', '194'))	('drug resistance', 'Var', (179, 194))	('VEGFR', 'Gene', '3791', (198, 203))
92166	29527128	Recent preclinical and clinical data on ccRCC indicate that PT2385 and PT2399 effectively inhibit cancer cell growth, proliferation, and tumour angiogenesis characteristic.	('inhibit', 'NegReg', (90, 97))	('PT2385', 'Chemical', 'MESH:C000614279', (60, 66))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cell growth', 'biological_process', 'GO:0016049', ('105', '116'))	('PT2399', 'Var', (71, 77))	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('tumour', 'Disease', (137, 143))	('angiogenesis', 'biological_process', 'GO:0001525', ('144', '156'))	('cancer', 'Disease', (98, 104))	('PT2385', 'Var', (60, 66))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
92169	29250163	miR-502-mediated histone methyltransferase SET8 expression is associated with clear cell renal cell carcinoma risk Genetic variants may affect the interactions between microRNAs (miRNAs/miRs) and their target genes by modulating their binding affinity or by creating, or destroying a miRNA-binding site.	('interactions', 'Interaction', (147, 159))	('miR-502', 'Gene', '574504', (0, 7))	('binding affinity', 'Interaction', (235, 251))	('miRNA-binding', 'molecular_function', 'GO:0035198', ('284', '297'))	('SET8', 'Gene', '387893', (43, 47))	('binding', 'molecular_function', 'GO:0005488', ('235', '242'))	('associated', 'Reg', (62, 72))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (78, 109))	('miRNA-binding site', 'MPA', (284, 302))	('miR-502', 'Gene', (0, 7))	('SET8', 'Gene', (43, 47))	('clear cell renal cell carcinoma', 'Disease', (78, 109))	('affect', 'Reg', (136, 142))	('destroying', 'NegReg', (271, 281))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (89, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('modulating', 'Reg', (218, 228))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (78, 109))	('variants', 'Var', (123, 131))
92171	29250163	In the present study, the rs16917496 polymorphism within the miR-502 binding site of the SET8 mRNA 3' untranslated region (3'UTR) in patients with clear cell renal cell carcinoma (ccRCC) and healthy controls was genotyped.	('SET8', 'Gene', (89, 93))	('SET8', 'Gene', '387893', (89, 93))	('miR-502', 'Gene', '574504', (61, 68))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (147, 178))	('binding', 'molecular_function', 'GO:0005488', ('69', '76'))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('patients', 'Species', '9606', (133, 141))	('miR-502', 'Gene', (61, 68))	('rs16917496', 'Mutation', 'rs16917496', (26, 36))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (158, 178))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (147, 178))	('RCC', 'Disease', (182, 185))	('clear cell renal cell carcinoma', 'Disease', (147, 178))	('rs16917496', 'Var', (26, 36))
92174	29250163	Low SET8 protein levels were negatively associated with tumor-node-metastasis staging in patients with ccRCC according to the size of tumor and lymph node metastases.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('Low', 'Var', (0, 3))	('tumor', 'Disease', (56, 61))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('metastases', 'Disease', 'MESH:D009362', (155, 165))	('RCC', 'Disease', (105, 108))	('negatively', 'NegReg', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('patients', 'Species', '9606', (89, 97))	('protein', 'cellular_component', 'GO:0003675', ('9', '16'))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('SET8', 'Gene', (4, 8))	('SET8', 'Gene', '387893', (4, 8))	('tumor', 'Disease', (134, 139))	('metastases', 'Disease', (155, 165))
92186	29250163	Thus, single nucleotide polymorphisms (SNPs) in the 3'UTR may impede existing binding sites or create novel binding sites, resulting in the misregulation of target genes, which may affect the tumor risk of an individual.	('tumor', 'Disease', (192, 197))	('single nucleotide polymorphisms', 'Var', (6, 37))	('binding sites', 'Interaction', (108, 121))	('binding', 'molecular_function', 'GO:0005488', ('78', '85'))	('binding', 'molecular_function', 'GO:0005488', ('108', '115'))	('binding sites', 'Interaction', (78, 91))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('impede', 'NegReg', (62, 68))	('misregulation', 'MPA', (140, 153))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('affect', 'Reg', (181, 187))
92192	29250163	Furthermore, SET8 expression levels were identified to be associated with the rs16917496 SNP in the SET8 3'UTR.	('SET8', 'Gene', '387893', (100, 104))	('rs16917496', 'Mutation', 'rs16917496', (78, 88))	('associated', 'Reg', (58, 68))	('expression levels', 'MPA', (18, 35))	('rs16917496 SNP', 'Var', (78, 92))	('SET8', 'Gene', (13, 17))	('SET8', 'Gene', '387893', (13, 17))	('SET8', 'Gene', (100, 104))
92193	29250163	In the present study, the rs16917496 SNP in patients with ccRCC in a case-control study was genotyped to assess its association with the risk of cancer.	('cancer', 'Disease', (145, 151))	('association', 'Interaction', (116, 127))	('patients', 'Species', '9606', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('RCC', 'Disease', (60, 63))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('rs16917496', 'Mutation', 'rs16917496', (26, 36))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('rs16917496', 'Var', (26, 36))
92198	29250163	The primers for amplification were 5'-CCTGGTCAGTGGTCAGCAAAT-3' (sense) and 5'-CTGGGAAACACGCTCAAAATC-3' (antisense) for rs16917496 in the 3'UTR of SET8 (National Center for Biotechnology Information database: ).	('SET8', 'Gene', (146, 150))	("and 5'-CTGGGAAACACGCTCAAAATC-", 'Chemical', '-', (71, 100))	('SET8', 'Gene', '387893', (146, 150))	('rs16917496', 'Mutation', 'rs16917496', (119, 129))	("5'-CCTGGTCAGTGGTCAGCAAAT-3", 'Chemical', '-', (35, 61))	('rs16917496', 'Var', (119, 129))
92230	29250163	A total of 140 patients with ccRCC and 130 controls were genotyped for the rs16917496 SNP.	('rs16917496 SNP', 'Var', (75, 89))	('patients', 'Species', '9606', (15, 23))	('rs16917496', 'Mutation', 'rs16917496', (75, 85))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))
92233	29250163	The overall frequencies and genotype distributions of the rs16917496 polymorphism in patients with ccRCC and controls are presented in Table II.	('rs16917496', 'Var', (58, 68))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Disease', (101, 104))	('patients', 'Species', '9606', (85, 93))	('rs16917496', 'Mutation', 'rs16917496', (58, 68))
92234	29250163	The C allele frequencies of rs16917496 in patients with ccRCC (26.79%) were significantly lower compared with that in controls (35.38%) (P=0.031), and the presence of the C allele significantly decreased the risk of developing ccRCC (OR=0.668; 95% CI, 0.463-0.964).	('rs16917496', 'Var', (28, 38))	('RCC', 'Disease', 'MESH:C538614', (229, 232))	('RCC', 'Disease', (229, 232))	('lower', 'NegReg', (90, 95))	('RCC', 'Disease', (58, 61))	('decreased', 'NegReg', (194, 203))	('patients', 'Species', '9606', (42, 50))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('rs16917496', 'Mutation', 'rs16917496', (28, 38))
92236	29250163	To identify the association between the rs16917496 SNP and SET8 expression, SET8 expression was measured by immunostaining in 140 ccRCC tissues.	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('rs16917496 SNP', 'Var', (40, 54))	('RCC', 'Disease', (132, 135))	('SET8', 'Gene', (76, 80))	('SET8', 'Gene', '387893', (76, 80))	('rs16917496', 'Mutation', 'rs16917496', (40, 50))	('SET8', 'Gene', (59, 63))	('SET8', 'Gene', '387893', (59, 63))
92242	29250163	Notably, low SET8 protein expression was negatively associated with ccRCC Tumor-Node-Metastasis (TNM) staging (P=0.002), tumor size (P=0.039) and lymph node metastasis (P=0.014).	('expression', 'MPA', (26, 36))	('low', 'Var', (9, 12))	('lymph node metastasis', 'CPA', (146, 167))	('negatively', 'NegReg', (41, 51))	('RCC', 'Disease', (70, 73))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('Tumor-Node-Metastasis', 'CPA', (74, 95))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('protein', 'Protein', (18, 25))	('tumor', 'Disease', (121, 126))	('Tumor', 'Phenotype', 'HP:0002664', (74, 79))	('SET8', 'Gene', (13, 17))	('SET8', 'Gene', '387893', (13, 17))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
92251	29250163	Compared with the psi-H1-transfected cells and blank control cells, the proliferation rate of renal carcinoma 786-O cells was significantly decreased between 36 and 72 h following SET8 siRNA-2 transfection (P<0.05; Fig.	('decreased', 'NegReg', (140, 149))	('renal carcinoma', 'Phenotype', 'HP:0005584', (94, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('proliferation rate', 'CPA', (72, 90))	('SET8', 'Gene', (180, 184))	('SET8', 'Gene', '387893', (180, 184))	('renal carcinoma', 'Disease', 'MESH:C538614', (94, 109))	('renal carcinoma', 'Disease', (94, 109))	('transfection', 'Var', (193, 205))
92255	29250163	Compared with cells transfected with empty psi-H1, c-Myc mRNA levels significantly decreased upon SET8 knockdown (Fig.	('c-Myc', 'Gene', '4609', (51, 56))	('decreased', 'NegReg', (83, 92))	('c-Myc', 'Gene', (51, 56))	('SET8', 'Gene', (98, 102))	('SET8', 'Gene', '387893', (98, 102))	('knockdown', 'Var', (103, 112))
92265	29250163	In the present study, the association between the rs16917496 SNP in the miR-502 binding site of the SET8 3'UTR and SET8 expression was assessed, and its implications in ccRCC development were investigated.	('SET8', 'Gene', '387893', (100, 104))	('miR-502', 'Gene', '574504', (72, 79))	('rs16917496 SNP', 'Var', (50, 64))	('binding', 'molecular_function', 'GO:0005488', ('80', '87'))	('SET8', 'Gene', (115, 119))	('rs16917496', 'Mutation', 'rs16917496', (50, 60))	('SET8', 'Gene', '387893', (115, 119))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('RCC', 'Disease', (171, 174))	('miR-502', 'Gene', (72, 79))	('SET8', 'Gene', (100, 104))
92266	29250163	Logistic regression analysis revealed that the rs16917496 SNP was associated with ccRCC risk.	('associated', 'Reg', (66, 76))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('rs16917496', 'Mutation', 'rs16917496', (47, 57))	('RCC', 'Disease', (84, 87))	('rs16917496', 'Var', (47, 57))
92267	29250163	Therefore, the association between the rs16917496 SNP and SET8 expression was examined.	('rs16917496', 'Mutation', 'rs16917496', (39, 49))	('rs16917496 SNP', 'Var', (39, 53))	('SET8', 'Gene', (58, 62))	('SET8', 'Gene', '387893', (58, 62))
92271	29250163	The present data suggested that altering SET8 expression, at least partially by the rs16917496 SNP in the miR-502 binding site of the SET8 3'UTR, was associated with ccRCC development and progression.	('miR-502', 'Gene', '574504', (106, 113))	('progression', 'CPA', (188, 199))	('rs16917496', 'Mutation', 'rs16917496', (84, 94))	('binding', 'molecular_function', 'GO:0005488', ('114', '121'))	('miR-502', 'Gene', (106, 113))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('RCC', 'Disease', (168, 171))	('SET8', 'Gene', (134, 138))	('SET8', 'Gene', '387893', (134, 138))	('SET8', 'Gene', '387893', (41, 45))	('rs16917496 SNP', 'Var', (84, 98))	('SET8', 'Gene', (41, 45))	('associated with', 'Reg', (150, 165))
92273	29250163	Accumulating evidence has suggested that polymorphisms within miRNA-binding sites may affect miRNA regulation of target gene expression and consequently modify cancer risk and outcome.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('affect', 'Reg', (86, 92))	('modify', 'Reg', (153, 159))	('cancer', 'Disease', (160, 166))	('polymorphisms', 'Var', (41, 54))	('miRNA regulation of target gene expression', 'MPA', (93, 135))	('gene expression', 'biological_process', 'GO:0010467', ('120', '135'))	('miRNA-binding', 'Protein', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('regulation', 'biological_process', 'GO:0065007', ('99', '109'))	('miRNA-binding', 'molecular_function', 'GO:0035198', ('62', '75'))
92274	29250163	The rs16917496 SNP in the miR-502 binding site of SET8 has been associated with the risk of several tumor types, including hepatocellular carcinoma, small cell lung cancer and non-Hodgkin's lymphoma.	('rs16917496', 'Mutation', 'rs16917496', (4, 14))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (180, 198))	('tumor', 'Disease', (100, 105))	('SET8', 'Gene', '387893', (50, 54))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (123, 147))	("non-Hodgkin's lymphoma", 'Disease', (176, 198))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('associated', 'Reg', (64, 74))	('small cell lung cancer', 'Disease', 'MESH:D055752', (149, 171))	('miR-502', 'Gene', (26, 33))	('small cell lung cancer', 'Disease', (149, 171))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (123, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))	('binding', 'molecular_function', 'GO:0005488', ('34', '41'))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('lymphoma', 'Phenotype', 'HP:0002665', (190, 198))	('SET8', 'Gene', (50, 54))	('rs16917496 SNP', 'Var', (4, 18))	('hepatocellular carcinoma', 'Disease', (123, 147))	('miR-502', 'Gene', '574504', (26, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (149, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (176, 198))
92277	29250163	These data demonstrated that the rs16917496 SNP in the miR-502 binding site of SET8 mediated SET8 expression and consequently modified ccRCC cancer risk.	('miR-502', 'Gene', (55, 62))	('SET8', 'Gene', (79, 83))	('rs16917496 SNP', 'Var', (33, 47))	('mediated', 'Reg', (84, 92))	('SET8', 'Gene', '387893', (79, 83))	('SET8', 'Gene', (93, 97))	('SET8', 'Gene', '387893', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('miR-502', 'Gene', '574504', (55, 62))	('rs16917496', 'Mutation', 'rs16917496', (33, 43))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('RCC', 'Disease', (137, 140))	('modified', 'Reg', (126, 134))	('cancer', 'Disease', (141, 147))	('binding', 'molecular_function', 'GO:0005488', ('63', '70'))	('expression', 'MPA', (98, 108))
92284	29250163	The present results indicated that SNPs of a miRNA binding site were associated with ccRCC risk, but the results require validation in other populations and in laboratory-based functional studies.	('SNPs', 'Var', (35, 39))	('miRNA', 'Protein', (45, 50))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('miRNA binding', 'molecular_function', 'GO:0035198', ('45', '58'))	('associated', 'Reg', (69, 79))
92293	33553151	Weighted gene co-expression network analysis with functional enrichment analysis indicated that m6A RNA methylation might affect clinical prognosis through regulating immune functions in patients with ccRCC.	('regulating', 'Reg', (156, 166))	('patients', 'Species', '9606', (187, 195))	('ccRCC', 'Phenotype', 'HP:0006770', (201, 206))	('immune functions', 'MPA', (167, 183))	('clinical', 'MPA', (129, 137))	('RNA methylation', 'biological_process', 'GO:0001510', ('100', '115'))	('m6A', 'Gene', '56339', (96, 99))	('affect', 'Reg', (122, 128))	('methylation', 'Var', (104, 115))	('RNA', 'cellular_component', 'GO:0005562', ('100', '103'))	('RCC', 'Disease', 'MESH:C538614', (203, 206))	('RCC', 'Disease', (203, 206))	('RCC', 'Phenotype', 'HP:0005584', (203, 206))	('m6A', 'Gene', (96, 99))
92302	33553151	Taking into account the heterogeneity in ccRCC, several potential biomarkers for diagnosis and survival prediction have been reported in recent years, such as carbonic anhydrase 9 (Genega et al.,), PBRM1, and BAP1 mutation (Varela et al.,).	('PBRM1', 'Gene', (198, 203))	('PBRM1', 'Gene', '55193', (198, 203))	('mutation', 'Var', (214, 222))	('BAP1', 'Gene', (209, 213))	('carbonic anhydrase 9', 'Gene', '768', (159, 179))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('carbonic anhydrase 9', 'Gene', (159, 179))	('BAP1', 'Gene', '8314', (209, 213))
92303	33553151	The modification and epigenetic alteration of RNA have recently been primarily identified, including N6-methyladenosine (m6A) (Roundtree et al.,; Boccaletto et al.,).	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (101, 119))	('RNA', 'Gene', (46, 49))	('m6A', 'Gene', (121, 124))	('m6A', 'Gene', '56339', (121, 124))	('RNA', 'cellular_component', 'GO:0005562', ('46', '49'))	('epigenetic alteration', 'Var', (21, 42))
92311	33553151	Five GEO datasets, including GSE46699 (Eckel-Passow et al.,), GSE53757 (von Roemeling et al.,), GSE22541 (Wuttig et al.,), GSE17895 (Dalgliesh et al.,), and GSE40435 (Wozniak et al.,), were finally selected and downloaded with gene expression data and clinical data.	('GSE17895', 'Var', (123, 131))	('GSE22541', 'Var', (96, 104))	('GSE53757', 'Var', (62, 70))	('GSE40435', 'Var', (157, 165))	('gene expression', 'biological_process', 'GO:0010467', ('227', '242'))	('von Roemeling', 'Disease', 'MESH:D006623', (72, 85))	('von Roemeling', 'Disease', (72, 85))
92312	33553151	Four datasets (GSE46699, GSE53757, GSE22541, and GSE17895) with microarray data were detected based on the Affymetrix Human Genome U133 Plus 2.0 Array.	('GSE22541', 'Var', (35, 43))	('GSE17895', 'Var', (49, 57))	('GSE53757', 'Var', (25, 33))	('Human', 'Species', '9606', (118, 123))	('GSE46699', 'Var', (15, 23))
92320	33553151	We performed a LASSO Cox regression analysis to identified survival-related m6A RNA methylation genes and calculated their coefficients in the TCGA training cohort.	('m6A', 'Gene', (76, 79))	('methylation', 'Var', (84, 95))	('m6A', 'Gene', '56339', (76, 79))	('RNA methylation', 'biological_process', 'GO:0001510', ('80', '95'))	('RNA', 'cellular_component', 'GO:0005562', ('80', '83'))
92324	33553151	The significantly differentially expressed genes (DEGs) were firstly identified between the ccRCC tissue and the normal renal tissue from GSE40435, GSE53757, and GSE46699.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('GSE46699', 'Var', (162, 170))	('differentially', 'Reg', (18, 32))	('GSE53757', 'Var', (148, 156))	('GSE40435', 'Var', (138, 146))
92357	33553151	And then, these modifications could be recognized by readers, resulting in downregulating tumor suppressor or upregulating oncogene expression (Wang et al.,).	('tumor suppressor', 'biological_process', 'GO:0051726', ('90', '106'))	('oncogene', 'Protein', (123, 131))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('90', '106'))	('upregulating', 'PosReg', (110, 122))	('modifications', 'Var', (16, 29))	('downregulating', 'NegReg', (75, 89))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
92360	33553151	The important role of m6A modification in immune cell-related pathogenesis through the m6A mediated degradation of Naive T cell had been recently identified (Li H. B. et al.,).	('degradation', 'biological_process', 'GO:0009056', ('100', '111'))	('m6A', 'Gene', (87, 90))	('m6A', 'Gene', (22, 25))	('modification', 'Var', (26, 38))	('m6A', 'Gene', '56339', (87, 90))	('pathogenesis', 'biological_process', 'GO:0009405', ('62', '74'))	('m6A', 'Gene', '56339', (22, 25))	('degradation', 'MPA', (100, 111))
92368	31810328	D-loop Mutations in Renal Cell Carcinoma Improve Predictive Accuracy for Cancer-Related Death by Integrating with Mutations in the NADH Dehydrogenase Subunit 1 Gene Renal cell carcinoma (RCC) is associated with various genetic alterations.	('RCC', 'Disease', (187, 190))	('RCC', 'Phenotype', 'HP:0005584', (187, 190))	('Improve', 'PosReg', (41, 48))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (20, 40))	('Carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('Renal cell carcinoma', 'Disease', (165, 185))	('Mutations', 'Var', (114, 123))	('RCC', 'Disease', 'MESH:D002292', (187, 190))	('Renal cell carcinoma', 'Disease', 'MESH:D002292', (165, 185))	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Renal Cell Carcinoma', 'Disease', (20, 40))	('Renal cell carcinoma', 'Phenotype', 'HP:0005584', (165, 185))	('Mutations', 'Var', (7, 16))	('Death', 'Disease', 'MESH:D003643', (88, 93))	('NADH Dehydrogenase Subunit 1', 'Gene', '4535', (131, 159))	('Death', 'Disease', (88, 93))	('Renal Cell Carcinoma', 'Disease', 'MESH:D002292', (20, 40))	('NADH Dehydrogenase Subunit 1', 'Gene', (131, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
92369	31810328	Although whole-genome/exome sequencing analysis has revealed that nuclear genome alterations are associated with clinical outcomes, the association between nucleotide alterations in the mitochondrial genome and RCC clinical outcomes remains unclear.	('nuclear genome', 'MPA', (66, 80))	('RCC', 'Disease', (211, 214))	('RCC', 'Phenotype', 'HP:0005584', (211, 214))	('RCC', 'Disease', 'MESH:D002292', (211, 214))	('mitochondrial genome', 'cellular_component', 'GO:0000262', ('186', '206'))	('alterations', 'Var', (81, 92))	('associated', 'Reg', (97, 107))
92371	31810328	Moreover, we analyzed the relationship between D-loop mutations and NADH dehydrogenase subunit 1 (MT-ND1) mutations, which we previously found to be associated with clinical outcomes in localized RCC.	('NADH dehydrogenase subunit 1', 'Gene', (68, 96))	('MT-ND1', 'Gene', '4535', (98, 104))	('MT-ND1', 'Gene', (98, 104))	('NADH dehydrogenase subunit 1', 'Gene', '4535', (68, 96))	('associated', 'Reg', (149, 159))	('mutations', 'Var', (106, 115))	('RCC', 'Disease', 'MESH:D002292', (196, 199))	('RCC', 'Disease', (196, 199))	('RCC', 'Phenotype', 'HP:0005584', (196, 199))
92372	31810328	Among the 61 localized RCCs, 34 patients (55.7%) had at least one mitochondrial D-loop mutation.	('patients', 'Species', '9606', (32, 40))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('mitochondrial D-loop', 'Gene', (66, 86))	('RCC', 'Disease', (23, 26))	('RCC', 'Disease', 'MESH:D002292', (23, 26))	('mutation', 'Var', (87, 95))
92374	31810328	Moreover, patients with D-loop mutations showed no differences in cancer-specific survival when compared with patients without D-loop mutations.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('patients', 'Species', '9606', (10, 18))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('D-loop mutations', 'Var', (24, 40))	('patients', 'Species', '9606', (110, 118))	('cancer', 'Disease', (66, 72))
92375	31810328	However, the co-occurrence of D-loop and MT-ND1 mutations improved the predictive accuracy of cancer-related deaths among our cohort, increasing the concordance index (C-index) from 0.757 to 0.810.	('MT-ND1', 'Gene', '4535', (41, 47))	('improved', 'PosReg', (58, 66))	('increasing', 'PosReg', (134, 144))	('death', 'Disease', 'MESH:D003643', (109, 114))	('death', 'Disease', (109, 114))	('MT-ND1', 'Gene', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('concordance', 'MPA', (149, 160))	('D-loop', 'Gene', (30, 36))	('mutations', 'Var', (48, 57))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
92376	31810328	Thus, we found that D-loop mutations are associated with adverse pathological features in localized RCC and may improve predictive accuracy for cancer-specific deaths when combined with MT-ND1 mutations.	('improve', 'PosReg', (112, 119))	('death', 'Disease', 'MESH:D003643', (160, 165))	('death', 'Disease', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('MT-ND1', 'Gene', '4535', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('MT-ND1', 'Gene', (186, 192))	('cancer', 'Disease', (144, 150))	('RCC', 'Disease', 'MESH:D002292', (100, 103))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('D-loop mutations', 'Var', (20, 36))
92378	31810328	Mutations in the von Hippel-Lindau gene have been extensively studied in clear cell RCC (ccRCC) and have been shown to play a critical role in the initiation and progression of this disease.	('von Hippel-Lindau', 'Disease', (17, 34))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (17, 34))	('RCC', 'Disease', 'MESH:D002292', (91, 94))	('RCC', 'Disease', (91, 94))	('role', 'Reg', (135, 139))	('RCC', 'Disease', 'MESH:D002292', (84, 87))	('RCC', 'Disease', (84, 87))	('Mutations', 'Var', (0, 9))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))
92379	31810328	Papillary RCC is the second most common histological subtype of RCC and is characterized genetically by trisomy and tetrasomy of chromosome 7, trisomy of chromosome 17, and loss of the Y chromosome.	('RCC', 'Disease', 'MESH:D002292', (10, 13))	('Y chromosome', 'cellular_component', 'GO:0000806', ('185', '197'))	('tetrasomy', 'Var', (116, 125))	('chromosome', 'cellular_component', 'GO:0005694', ('154', '164'))	('trisomy', 'Var', (104, 111))	('RCC', 'Disease', (64, 67))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('Y chromosome', 'CPA', (185, 197))	('loss', 'Var', (173, 177))	('trisomy of chromosome', 'Var', (143, 164))	('RCC', 'Disease', 'MESH:D002292', (64, 67))	('RCC', 'Disease', (10, 13))	('RCC', 'Phenotype', 'HP:0005584', (10, 13))	('chromosome', 'cellular_component', 'GO:0005694', ('129', '139'))
92381	31810328	Gene mutations in RCC do not only affect the tumor histological phenotype but also alter clinical behaviors or outcomes.	('RCC', 'Disease', (18, 21))	('RCC', 'Phenotype', 'HP:0005584', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('mutations', 'Var', (5, 14))	('alter', 'Reg', (83, 88))	('outcomes', 'CPA', (111, 119))	('clinical behaviors', 'CPA', (89, 107))	('affect', 'Reg', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('RCC', 'Disease', 'MESH:D002292', (18, 21))
92382	31810328	Recent large-scale whole-exome and targeted sequencing studies have revealed frequent recurrent mutations in ccRCC and have reported that specific gene mutations, such as BAP1 or SETD2 mutations, are associated with shorter overall survival and higher relapse rates.	('BAP1', 'Gene', (171, 175))	('higher', 'PosReg', (245, 251))	('overall', 'MPA', (224, 231))	('mutations', 'Var', (152, 161))	('shorter', 'NegReg', (216, 223))	('RCC', 'Disease', 'MESH:D002292', (111, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('SETD2', 'Gene', '29072', (179, 184))	('SETD2', 'Gene', (179, 184))	('relapse rates', 'CPA', (252, 265))	('BAP1', 'Gene', '8314', (171, 175))	('mutations', 'Var', (185, 194))	('mutations', 'Var', (96, 105))
92383	31810328	A comprehensive genome analysis of RCC is currently underway to assess nuclear DNA (nDNA) mutations in RCC; however, the mutational profiles of mitochondrial DNA (mtDNA) in patients with RCC have not been sufficiently elucidated, and the associations of mtDNA mutations with clinicopathological features and prognoses among patients with localized RCC are poorly understood.	('RCC', 'Disease', 'MESH:D002292', (103, 106))	('mutations', 'Var', (90, 99))	('RCC', 'Disease', (187, 190))	('RCC', 'Phenotype', 'HP:0005584', (187, 190))	('mtDNA', 'cellular_component', 'GO:0000262', ('254', '259'))	('RCC', 'Disease', 'MESH:D002292', (348, 351))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('RCC', 'Disease', (35, 38))	('patients', 'Species', '9606', (324, 332))	('patients', 'Species', '9606', (173, 181))	('RCC', 'Disease', 'MESH:D002292', (187, 190))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))	('RCC', 'Disease', 'MESH:D002292', (35, 38))	('mtDNA', 'cellular_component', 'GO:0000262', ('163', '168'))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (348, 351))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('144', '161'))	('RCC', 'Disease', (348, 351))
92386	31810328	In a previous study, we analyzed mutations in the mitochondrial NADH dehydrogenase subunit 1 (MT-ND1) gene to determine their associations with clinicopathological parameters and postoperative recurrence of RCC in 62 Japanese patients.	('associations', 'Reg', (126, 138))	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('MT-ND1', 'Gene', '4535', (94, 100))	('RCC', 'Disease', 'MESH:D002292', (207, 210))	('RCC', 'Disease', (207, 210))	('mutations', 'Var', (33, 42))	('NADH dehydrogenase subunit 1', 'Gene', '4535', (64, 92))	('patients', 'Species', '9606', (226, 234))	('MT-ND1', 'Gene', (94, 100))	('NADH dehydrogenase subunit 1', 'Gene', (64, 92))
92387	31810328	Our previous results suggested a significant association between the presence of MT-ND1 mutations and the postoperative recurrence of localized RCC.	('MT-ND1', 'Gene', (81, 87))	('RCC', 'Disease', 'MESH:D002292', (144, 147))	('presence', 'Var', (69, 77))	('mutations', 'Var', (88, 97))	('MT-ND1', 'Gene', '4535', (81, 87))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))
92389	31810328	In addition, mutations in the D-loop region in cancer tissues are predictive of clinical outcome.	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (13, 22))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))
92391	31810328	Moreover, in RCC, a previous study reported a relationship between single nucleotide polymorphisms in the D-loop region and survival rates.	('survival rates', 'CPA', (124, 138))	('RCC', 'Disease', 'MESH:D002292', (13, 16))	('single nucleotide polymorphisms', 'Var', (67, 98))	('RCC', 'Disease', (13, 16))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))
92392	31810328	However, no studies have reported the association between somatic mutations in the D-loop region and cancer-specific survival (CSS).	('cancer', 'Disease', (101, 107))	('somatic mutations in', 'Var', (58, 78))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
92394	31810328	Overall, we found that D-loop mutations are associated with adverse pathological features in localized RCC, which may improve the prediction of cancer-specific deaths when used in combination with MT-ND1 mutations.	('RCC', 'Disease', 'MESH:D002292', (103, 106))	('RCC', 'Disease', (103, 106))	('death', 'Disease', 'MESH:D003643', (160, 165))	('death', 'Disease', (160, 165))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('D-loop mutations', 'Var', (23, 39))	('MT-ND1', 'Gene', '4535', (197, 203))	('improve', 'PosReg', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('MT-ND1', 'Gene', (197, 203))
92403	31810328	Total mtDNA was amplified by PCR with the following primer sets, which were designed to cover the entire 1120-bp mtDNA D-loop region: HUMmt-148F, 5'-ATCCCATTATTTATCGCACCT-3'; homoR1, 5'-AAATAATAGGATGAGGCAGGAATCAAAGA-3'; Homo_mt_Gap_3F, 5'-TCGGAGGACAACCAGTAAGC-3'; Homo_mt_Gap_3R, 5'-GCACTCTTGTGCGGGATATT-3'; homoF2, 5'-GCACTCTTGTGCGGGATATT-3'; F376, 5'-TAACACCAGCCTAACCAGATTTC-3'; R505, 5'-TGTGTGTGCTGGGTAGGATGG-3'; F320, 5'-GCTTCTGGCCACAGCACTTAAAC-3'; R465, 5'-GATGAGATTAGTAGTATGGGAGTGGG-3'; F16137, 5'-CCATAAATACTTGACCACCTGTAG-3'; R16269, 5'-AGGTTTGTTGGTATCCTAGTGGGTGA-3'; F16137, 5'-CCATAAATACTTGACCACCTGTAG-3'; and R16231, 5'-GAGTTGCAGTTGATGTGTGATAGTTG-3'.	('mtDNA', 'cellular_component', 'GO:0000262', ('113', '118'))	('mtDNA', 'cellular_component', 'GO:0000262', ('6', '11'))	('R16269', 'Var', (533, 539))	('F16137', 'Chemical', 'MESH:D005461', (493, 499))	("5'-TCGGAGGACAACCAGTAAGC", 'Chemical', 'MESH:C068492', (236, 259))	('F16137', 'Var', (575, 581))	('R16231', 'Var', (619, 625))	('F16137', 'Var', (493, 499))	('F16137', 'Chemical', 'MESH:D005461', (575, 581))
92411	31810328	Seven variables were binarized as follows: age (<= 62 years versus > 62 years), sex (women versus men), tumor diameter (<= 32 mm versus > 32 mm), histology type (ccRCC versus non-ccRCC), pT stage (<= pT2 versus >= pT3), International Society of Urological Pathology (ISUP) grade (1/2 versus 3/4), and microvascular invasion (MVI) (absence or presence).	('microvascular invasion', 'CPA', (301, 323))	('pT3', 'Gene', (214, 217))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('men', 'Species', '9606', (87, 90))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))	('tumor', 'Disease', (104, 109))	('women', 'Species', '9606', (85, 90))	('<= 32', 'Var', (120, 125))	('RCC', 'Disease', 'MESH:D002292', (164, 167))	('RCC', 'Disease', (164, 167))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))	('men', 'Species', '9606', (98, 101))	('RCC', 'Disease', 'MESH:D002292', (181, 184))	('RCC', 'Disease', (181, 184))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('pT3', 'Gene', '7694', (214, 217))
92413	31810328	We also evaluated the association of CSS with D-loop mutations with or without MT-ND1 mutations identified in our previous study.	('CSS', 'Disease', (37, 40))	('MT-ND1', 'Gene', '4535', (79, 85))	('MT-ND1', 'Gene', (79, 85))	('D-loop mutations', 'Var', (46, 62))
92414	31810328	The C-index was calculated to discriminate the predictive accuracy for CSS between a model, including only MT-ND1 mutations and D-loop mutations added to the MT-ND1 model.	('MT-ND1', 'Gene', '4535', (107, 113))	('MT-ND1', 'Gene', (158, 164))	('mutations', 'Var', (114, 123))	('D-loop', 'Var', (128, 134))	('MT-ND1', 'Gene', (107, 113))	('MT-ND1', 'Gene', '4535', (158, 164))
92425	31810328	Specifically, patients hk370 and hk407 contained eight mutations in the D-loop region, which accounted for the highest number of mutations per patient.	('contained', 'Reg', (39, 48))	('patient', 'Species', '9606', (143, 150))	('hk407', 'Var', (33, 38))	('patient', 'Species', '9606', (14, 21))	('patients', 'Species', '9606', (14, 22))	('hk370', 'Var', (23, 28))
92427	31810328	The D-loop mutation rate was 1.295 (79 mutations/61 patients), and the ND1 mutation rate, as determined in our previous study, was 0.475 (29 mutations/61 patients).	('ND1', 'Gene', '4535', (71, 74))	('patients', 'Species', '9606', (154, 162))	('ND1', 'Gene', (71, 74))	('D-loop mutation', 'Var', (4, 19))	('mutations/61', 'Var', (39, 51))	('patients', 'Species', '9606', (52, 60))
92428	31810328	The D-loop mutation rate was approximately 2.7 times higher than the MT-ND1 mutation rate.	('MT-ND1', 'Gene', (69, 75))	('MT-ND1', 'Gene', '4535', (69, 75))	('D-loop mutation', 'Var', (4, 19))
92429	31810328	The number of mutation sites per patient was associated with age (> 62 years), histological subtype (non-clear subtype), tumor diameter (> 32 mm), and ISUP grade (grades 3 and 4), as shown in Table 3.	('patient', 'Species', '9606', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('associated', 'Reg', (45, 55))	('mutation', 'Var', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
92431	31810328	Mutation at position 16295 was found in seven patients (hk362, 377, 379, 384, 407, 415, and 416), at position 249 in five patients (hk384, 388, 404, 413, and 418), and at position 310 in three patients (hk376, 400, and 403).	('hk384', 'Var', (132, 137))	('hk376', 'Var', (203, 208))	('patients', 'Species', '9606', (193, 201))	('patients', 'Species', '9606', (46, 54))	('hk362', 'Var', (56, 61))	('patients', 'Species', '9606', (122, 130))
92432	31810328	After the integration of mutation data for the D-loop region and MT-ND1 gene, 41 patients were found to have mutations in the D-loop region and/or MT-ND1 gene.	('MT-ND1', 'Gene', '4535', (65, 71))	('MT-ND1', 'Gene', (147, 153))	('patients', 'Species', '9606', (81, 89))	('D-loop region', 'Gene', (126, 139))	('MT-ND1', 'Gene', (65, 71))	('mutations', 'Var', (109, 118))	('MT-ND1', 'Gene', '4535', (147, 153))
92433	31810328	Of these 41 patients, 11 patients had mutations in both the D-loop region and the MT-ND1 gene, 23 patients had mutations only in the D-loop region, and seven patients had mutations only in the MT-ND1 gene, whereas 20 patients did not have mutations in either the D-loop region or the MT-ND1 gene.	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (217, 225))	('MT-ND1', 'Gene', (82, 88))	('MT-ND1', 'Gene', '4535', (193, 199))	('patients', 'Species', '9606', (98, 106))	('MT-ND1', 'Gene', (193, 199))	('patients', 'Species', '9606', (25, 33))	('patients', 'Species', '9606', (158, 166))	('MT-ND1', 'Gene', '4535', (284, 290))	('mutations', 'Var', (38, 47))	('MT-ND1', 'Gene', '4535', (82, 88))	('MT-ND1', 'Gene', (284, 290))
92434	31810328	Log-rank tests further showed that CSS was worse in patients with both D-loop and MT-ND1 mutations (Figure 1b).	('CSS', 'CPA', (35, 38))	('MT-ND1', 'Gene', (82, 88))	('mutations', 'Var', (89, 98))	('D-loop', 'Var', (71, 77))	('worse', 'Reg', (43, 48))	('MT-ND1', 'Gene', '4535', (82, 88))	('patients', 'Species', '9606', (52, 60))
92435	31810328	After integrating the data for D-loop mutations and MT-ND1 mutations, we found that the concordance index (C-index) increased from 0.757 to 0.810 (Table 4).	('concordance index', 'MPA', (88, 105))	('MT-ND1', 'Gene', '4535', (52, 58))	('MT-ND1', 'Gene', (52, 58))	('mutations', 'Var', (59, 68))	('increased', 'PosReg', (116, 125))	('mutations', 'Var', (38, 47))
92436	31810328	We focused on mutation sites from five patients (hk385, hk392, hk394, hk400, and hk403) who had died from RCC.	('patients', 'Species', '9606', (39, 47))	('hk403', 'Var', (81, 86))	('hk392', 'Var', (56, 61))	('hk394', 'Var', (63, 68))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('hk400', 'Var', (70, 75))	('RCC', 'Disease', 'MESH:D002292', (106, 109))	('hk385', 'Var', (49, 54))
92437	31810328	Among these patients, three (hk385, hk392, and hk403) had mutations in both the D-loop region and MT-ND1.	('mutations', 'Var', (58, 67))	('patients', 'Species', '9606', (12, 20))	('MT-ND1', 'Gene', (98, 104))	('hk385', 'Var', (29, 34))	('hk403', 'Var', (47, 52))	('hk392', 'Var', (36, 41))	('MT-ND1', 'Gene', '4535', (98, 104))
92438	31810328	In addition, we found that patient hk394 had mutations only in the MT-ND1 gene, whereas patient hk400 had mutations only in the D-loop region.	('patient', 'Species', '9606', (88, 95))	('mutations', 'Var', (45, 54))	('patient', 'Species', '9606', (27, 34))	('MT-ND1', 'Gene', '4535', (67, 73))	('MT-ND1', 'Gene', (67, 73))
92440	31810328	We found that previous reports had described associations of mutations in the D-loop region with esophageal cancer, nasopharyngeal carcinoma, breast cancer, and ovarian cancer.	('D-loop region', 'Gene', (78, 91))	('nasopharyngeal carcinoma', 'Disease', (116, 140))	('associations', 'Interaction', (45, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (116, 140))	('nasopharyngeal carcinoma', 'Disease', 'MESH:C538339', (116, 140))	('ovarian cancer', 'Phenotype', 'HP:0100615', (161, 175))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('esophageal cancer', 'Disease', (97, 114))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancer', 'Disease', (142, 155))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ovarian cancer', 'Disease', 'MESH:D010051', (161, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('ovarian cancer', 'Disease', (161, 175))
92441	31810328	Additional reports described associations between mutations in the MT-ND1 gene and thyroid tumors, ovarian carcinoma, colorectal cancer, and prostate cancer.	('ovarian carcinoma', 'Disease', 'MESH:D010051', (99, 116))	('colorectal cancer', 'Phenotype', 'HP:0003003', (118, 135))	('ovarian carcinoma', 'Disease', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('thyroid tumors', 'Disease', (83, 97))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('prostate cancer', 'Disease', 'MESH:D011471', (141, 156))	('colorectal cancer', 'Disease', 'MESH:D015179', (118, 135))	('prostate cancer', 'Phenotype', 'HP:0012125', (141, 156))	('thyroid tumors', 'Disease', 'MESH:D013966', (83, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('MT-ND1', 'Gene', (67, 73))	('colorectal cancer', 'Disease', (118, 135))	('prostate cancer', 'Disease', (141, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('mutations', 'Var', (50, 59))	('associations', 'Interaction', (29, 41))	('MT-ND1', 'Gene', '4535', (67, 73))
92442	31810328	In the current study, we identified somatic D-loop mutations among 55.7% of patients with localized RCC.	('patients', 'Species', '9606', (76, 84))	('D-loop mutations', 'Var', (44, 60))	('RCC', 'Disease', 'MESH:D002292', (100, 103))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
92443	31810328	The mutation number per patient in the D-loop region was approximately 2.7-fold higher than that in the MT-ND1 gene, as determined in our previous study.	('patient', 'Species', '9606', (24, 31))	('MT-ND1', 'Gene', '4535', (104, 110))	('MT-ND1', 'Gene', (104, 110))	('mutation', 'Var', (4, 12))
92446	31810328	To the best of our knowledge, this is the first study demonstrating a high mutation rate in the D-loop region in Japanese patients with localized RCC.	('RCC', 'Disease', 'MESH:D002292', (146, 149))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('mutation', 'Var', (75, 83))	('patients', 'Species', '9606', (122, 130))
92447	31810328	In our RCC cohort, larger tumor diameter (>32 mm) and higher ISUP grade (>=grade 3) were associated with larger numbers of D-loop mutations.	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('RCC', 'Disease', 'MESH:D002292', (7, 10))	('D-loop mutations', 'Var', (123, 139))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('RCC', 'Disease', (7, 10))	('RCC', 'Phenotype', 'HP:0005584', (7, 10))
92449	31810328	These results suggested that the accumulation of mutations in the D-loop region may be related to an aggressive cancer phenotype.	('mutations', 'Var', (49, 58))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('related', 'Reg', (87, 94))	('D-loop region', 'Gene', (66, 79))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
92452	31810328	A recent study analyzing somatic mutations in the D-loop region of 120 patients with oral squamous cell carcinoma showed that the 5-year survival rate in patients with somatic mutations was significantly higher than that in patients without mutations.	('mutations', 'Var', (176, 185))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('oral squamous cell carcinoma', 'Disease', (85, 113))	('patients', 'Species', '9606', (71, 79))	('patients', 'Species', '9606', (154, 162))	('patients', 'Species', '9606', (224, 232))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (85, 113))	('higher', 'PosReg', (204, 210))
92453	31810328	Alternatively, the esophageal squamous cell carcinoma survival rate of patients with D310 mutations was lower than that in patients without this mutation.	('D310 mutations', 'Var', (85, 99))	('esophageal squamous cell carcinoma', 'Disease', (19, 53))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (19, 53))	('patients', 'Species', '9606', (71, 79))	('patients', 'Species', '9606', (123, 131))	('lower', 'NegReg', (104, 109))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (30, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))
92454	31810328	In our RCC cohort, the presence of D-loop mutations was not significantly associated with CSS when considered alone; however, when integrating mutations in the MT-ND1 gene and D-loop region, there was a clear separation of the CSS curve.	('MT-ND1', 'Gene', '4535', (160, 166))	('RCC', 'Disease', 'MESH:D002292', (7, 10))	('RCC', 'Disease', (7, 10))	('RCC', 'Phenotype', 'HP:0005584', (7, 10))	('MT-ND1', 'Gene', (160, 166))	('mutations', 'Var', (143, 152))
92455	31810328	Indeed, 11 patients with both MT-ND1 and D-loop mutations showed worse CSS, and the 5-year CSS was 81.8%.	('MT-ND1', 'Gene', (30, 36))	('CSS', 'Disease', (71, 74))	('MT-ND1', 'Gene', '4535', (30, 36))	('patients', 'Species', '9606', (11, 19))	('D-loop mutations', 'Var', (41, 57))
92457	31810328	This result indicates that patients without any mutations in the MT-ND1 gene and D-loop region may have a favorable prognosis.	('patients', 'Species', '9606', (27, 35))	('mutations', 'Var', (48, 57))	('MT-ND1', 'Gene', (65, 71))	('MT-ND1', 'Gene', '4535', (65, 71))
92459	31810328	The results showed that the C-index for predicting CSS improved from 0.757 to 0.810 by integrating MT-ND1 mutations and D-loop mutations.	('MT-ND1', 'Gene', (99, 105))	('MT-ND1', 'Gene', '4535', (99, 105))	('mutations', 'Var', (106, 115))	('CSS', 'Disease', (51, 54))
92460	31810328	To the best of our knowledge, only a few studies have previously reported the ability of mtDNA mutations to predict clinical outcome in patients with RCC.	('RCC', 'Disease', 'MESH:D002292', (150, 153))	('RCC', 'Disease', (150, 153))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('patients', 'Species', '9606', (136, 144))	('mutations', 'Var', (95, 104))	('mtDNA', 'cellular_component', 'GO:0000262', ('89', '94'))	('mtDNA', 'Gene', (89, 94))
92461	31810328	Moreover, this is the first study to report the ability of D-loop mutations to improve the prediction accuracy for CSS in localized RCC.	('CSS', 'Disease', (115, 118))	('RCC', 'Disease', 'MESH:D002292', (132, 135))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('improve', 'PosReg', (79, 86))	('D-loop mutations', 'Var', (59, 75))
92464	31810328	Indeed, patients with mutations in both regions showed a higher risk of recurrence or death, and three patients (hk385, hk392, and hk403), who had both of these mutations, died during our study.	('recurrence', 'MPA', (72, 82))	('death', 'Disease', 'MESH:D003643', (86, 91))	('death', 'Disease', (86, 91))	('mutations', 'Var', (22, 31))	('patients', 'Species', '9606', (103, 111))	('patients', 'Species', '9606', (8, 16))
92467	31810328	Nevertheless, we showed that there were high mutation rates in the mitochondrial D-loop region and that accumulation of D-loop mutations was associated with adverse pathological tumor features in localized RCC.	('tumor', 'Disease', (178, 183))	('accumulation', 'PosReg', (104, 116))	('associated', 'Reg', (141, 151))	('mutation', 'Var', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('RCC', 'Phenotype', 'HP:0005584', (206, 209))	('D-loop', 'Gene', (120, 126))	('mutations', 'Var', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('RCC', 'Disease', 'MESH:D002292', (206, 209))	('RCC', 'Disease', (206, 209))
92468	31810328	Furthermore, we found that patients with RCC with both D-loop and MT-ND1 mutations exhibited more advanced CSS than patients with either D-loop mutations or MT-ND1 mutations.	('MT-ND1', 'Gene', '4535', (157, 163))	('MT-ND1', 'Gene', '4535', (66, 72))	('MT-ND1', 'Gene', (157, 163))	('D-loop', 'Var', (55, 61))	('patients', 'Species', '9606', (116, 124))	('MT-ND1', 'Gene', (66, 72))	('patients', 'Species', '9606', (27, 35))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('RCC', 'Disease', 'MESH:D002292', (41, 44))	('RCC', 'Disease', (41, 44))	('mutations', 'Var', (73, 82))
92469	31810328	The C-index improved following the inclusion of D-loop mutations in the ND1 risk model.	('ND1', 'Gene', '4535', (72, 75))	('C-index', 'MPA', (4, 11))	('ND1', 'Gene', (72, 75))	('improved', 'PosReg', (12, 20))	('D-loop mutations', 'Var', (48, 64))
92473	29602399	While classical concepts in cancer research in general had led to the concept that cancer is a disease resulting from mutations in the control of growth-regulating pathways, reinforced by the discovery of oncogenes, more contemporary research particularly in kidney cancer has uncovered changes in metabolic pathways mediated by those same genes which control tumor energetics and biosynthesis.	('changes', 'Reg', (287, 294))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('metabolic pathways', 'Pathway', (298, 316))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('tumor', 'Disease', (360, 365))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (360, 365))	('mutations', 'Var', (118, 127))	('kidney cancer', 'Disease', 'MESH:D007680', (259, 272))	('cancer', 'Disease', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', (266, 272))	('kidney cancer', 'Phenotype', 'HP:0009726', (259, 272))	('biosynthesis', 'biological_process', 'GO:0009058', ('381', '393'))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('kidney cancer', 'Disease', (259, 272))	('cancer', 'Disease', (83, 89))
92475	29602399	For example, in the case of kidney cancer there exists near universal presence of pVHL inactivation in the most common form, clear cell RCC (ccRCC), leading to activation of hypoxia-relevant and other metabolic pathways.	('ccRCC', 'Phenotype', 'HP:0006770', (141, 146))	('kidney cancer', 'Phenotype', 'HP:0009726', (28, 41))	('kidney cancer', 'Disease', 'MESH:D007680', (28, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('hypoxia', 'Disease', (174, 181))	('activation', 'PosReg', (160, 170))	('hypoxia', 'Disease', 'MESH:D000860', (174, 181))	('inactivation', 'Var', (87, 99))	('kidney cancer', 'Disease', (28, 41))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('pVHL', 'Gene', '7428', (82, 86))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('RCC', 'Disease', (143, 146))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('pVHL', 'Gene', (82, 86))	('RCC', 'Disease', (136, 139))
92482	29602399	Many of these metabolic derangements, especially in cancer of the kidney, have now been linked directly to oncogenic mutations (Table 1, permission obtained from ).	('cancer of the kidney', 'Disease', (52, 72))	('mutations', 'Var', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('metabolic derangements', 'Phenotype', 'HP:0001939', (14, 36))	('cancer of the kidney', 'Disease', 'MESH:D007680', (52, 72))	('linked', 'Reg', (88, 94))	('cancer of the kidney', 'Phenotype', 'HP:0009726', (52, 72))
92483	29602399	This research has led to the concept that the evolution of altered metabolism, so-called metabolic reprogramming, is associated with a kidney cancer that is most likely to thrive within the body.	('altered', 'Var', (59, 66))	('associated', 'Reg', (117, 127))	('metabolism', 'biological_process', 'GO:0008152', ('67', '77'))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('metabolism', 'MPA', (67, 77))	('kidney cancer', 'Disease', 'MESH:D007680', (135, 148))	('kidney cancer', 'Phenotype', 'HP:0009726', (135, 148))	('evolution', 'Var', (46, 55))	('kidney cancer', 'Disease', (135, 148))
92491	29602399	Such unexpected aberrations of metabolism in RCC have provided new opportunities for both imaging and for the development of new targets for therapeutic intervention.	('metabolism', 'MPA', (31, 41))	('metabolism', 'biological_process', 'GO:0008152', ('31', '41'))	('aberrations', 'Var', (16, 27))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
92493	29602399	The most studied gene abnormality is in VHL, the mutation of which results in upregulation of several key hypoxia pathways; this results in the abundant angiogenesis, as a result of vascular endothelial growth factor (VEGF), and accounts for many of the paraneoplastic effects, for example increased erythropoietin, seen in this disease.	('erythropoietin', 'Gene', '2056', (300, 314))	('paraneoplastic', 'Disease', 'MESH:D010257', (254, 268))	('hypoxia', 'Disease', (106, 113))	('VHL', 'Gene', '7428', (40, 43))	('vascular endothelial growth factor', 'Gene', '7422', (182, 216))	('VEGF', 'Gene', '7422', (218, 222))	('angiogenesis', 'CPA', (153, 165))	('vascular endothelial growth factor', 'Gene', (182, 216))	('hypoxia', 'Disease', 'MESH:D000860', (106, 113))	('mutation', 'Var', (49, 57))	('upregulation', 'PosReg', (78, 90))	('VEGF', 'Gene', (218, 222))	('paraneoplastic', 'Disease', (254, 268))	('erythropoietin', 'molecular_function', 'GO:0005128', ('300', '314'))	('increased', 'PosReg', (290, 299))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('182', '216'))	('VHL', 'Gene', (40, 43))	('angiogenesis', 'biological_process', 'GO:0001525', ('153', '165'))	('erythropoietin', 'Gene', (300, 314))
92502	29602399	This technique has revolutionized imaging for some malignancies, yet is problematic in RCC due to variable tumour uptake of 18F-FDG and its secretion into the urinary system, so is not commonly used for routine staging of kidney tumors.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('kidney tumors', 'Disease', 'MESH:D007674', (222, 235))	('18F-FDG', 'Var', (124, 131))	('kidney tumors', 'Phenotype', 'HP:0009726', (222, 235))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('uptake', 'biological_process', 'GO:0098657', ('114', '120'))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('tumour', 'Disease', (107, 113))	('uptake', 'biological_process', 'GO:0098739', ('114', '120'))	('secretion', 'biological_process', 'GO:0046903', ('140', '149'))	('kidney tumors', 'Disease', (222, 235))	('secretion', 'MPA', (140, 149))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))	('RCC', 'Disease', (87, 90))	('malignancies', 'Disease', 'MESH:D009369', (51, 63))	('malignancies', 'Disease', (51, 63))	('18F-FDG', 'Chemical', 'MESH:D019788', (124, 131))
92511	29602399	Recent studies targeting HIFalpha using PT2385 resulted in inhibition of tumor growth in the different RCC cell lines and now is being tested in clinical trials.	('inhibition', 'NegReg', (59, 69))	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('PT2385', 'Var', (40, 46))
92513	29602399	Consistent with this finding, inhibitors of fatty acids oxidation such as the Peroxisome proliferator-activated receptor (PPAR) alpha antagonist GW6471 was tested in several ccRCC models and shown to inhibit xenograft ccRCC tumor growth.	('ccRCC', 'Phenotype', 'HP:0006770', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('inhibit', 'NegReg', (200, 207))	('PPAR', 'Gene', '5465', (122, 126))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('Peroxisome proliferator-activated receptor', 'Gene', '5465', (78, 120))	('GW6471', 'Var', (145, 151))	('RCC', 'Disease', (176, 179))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('GW6471', 'Chemical', 'MESH:C449302', (145, 151))	('tumor', 'Disease', (224, 229))	('ccRCC', 'Phenotype', 'HP:0006770', (174, 179))	('PPAR', 'Gene', (122, 126))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('Peroxisome proliferator-activated receptor', 'Gene', (78, 120))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('RCC', 'Phenotype', 'HP:0005584', (220, 223))	('fatty acids', 'Chemical', 'MESH:D005227', (44, 55))	('Peroxisome', 'cellular_component', 'GO:0005777', ('78', '88'))	('xenograft', 'CPA', (208, 217))	('RCC', 'Disease', (220, 223))
92515	29602399	Inhibition of FASN by cerulin or its derivative C75 induced a rapid increase in malonyl-coA with a marked reduction in lipogenesis in multiple cancer models, including RCC cells.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cerulin', 'Chemical', '-', (22, 29))	('malonyl-coA', 'MPA', (80, 91))	('lipogenesis', 'MPA', (119, 130))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('FASN', 'Gene', (14, 18))	('lipogenesis', 'biological_process', 'GO:0008610', ('119', '130'))	('reduction', 'NegReg', (106, 115))	('FASN', 'Gene', '2194', (14, 18))	('malonyl-coA', 'Chemical', 'MESH:D008316', (80, 91))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('increase', 'PosReg', (68, 76))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('RCC', 'Disease', (168, 171))
92520	29602399	Consequently, inhibition of IDO prevents the purported immunosuppressive effect and enables T-cell activation in a murine immune-competent RCC model.	('prevents', 'NegReg', (32, 40))	('IDO', 'molecular_function', 'GO:0033754', ('28', '31'))	('T-cell activation', 'biological_process', 'GO:0042110', ('92', '109'))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('IDO', 'molecular_function', 'GO:0047719', ('28', '31'))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('T-cell activation', 'CPA', (92, 109))	('IDO', 'Gene', (28, 31))	('enables', 'PosReg', (84, 91))	('inhibition', 'Var', (14, 24))	('murine', 'Species', '10090', (115, 121))
92523	29602399	Two combination IDO inhibitor and checkpoint inhibitor antibody studies (clinicaltrials.gov NCT02178722, NCT02318277), a combination IDO inhibitor and JAK inhibitor study in advanced solid tumors (NCT02559492), and an IDO inhibitor alone study on refractory solid tumors (NCT02048709) are all recruiting.	('solid tumors', 'Disease', 'MESH:D009369', (183, 195))	('antibody', 'cellular_component', 'GO:0042571', ('55', '63'))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('NCT02318277', 'Var', (105, 116))	('IDO', 'molecular_function', 'GO:0047719', ('218', '221'))	('solid tumors', 'Disease', (258, 270))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('antibody', 'cellular_component', 'GO:0019815', ('55', '63'))	('IDO', 'molecular_function', 'GO:0047719', ('16', '19'))	('IDO', 'molecular_function', 'GO:0033754', ('218', '221'))	('IDO', 'molecular_function', 'GO:0033754', ('133', '136'))	('solid tumors', 'Disease', (183, 195))	('antibody', 'cellular_component', 'GO:0019814', ('55', '63'))	('solid tumors', 'Disease', 'MESH:D009369', (258, 270))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('IDO', 'molecular_function', 'GO:0047719', ('133', '136'))	('JAK', 'molecular_function', 'GO:0004713', ('151', '154'))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('antibody', 'molecular_function', 'GO:0003823', ('55', '63'))	('IDO', 'molecular_function', 'GO:0033754', ('16', '19'))
92529	29602399	Furthermore Inhibitors of NADPH synthesis such as KPT-9274 have showed decreased tumor burden in RCC mouse model.	('NADPH', 'Gene', (26, 31))	('NADPH', 'Chemical', 'MESH:D009249', (26, 31))	('KPT-9274', 'Var', (50, 58))	('RCC', 'Disease', (97, 100))	('KPT-9274', 'Chemical', 'MESH:C000622300', (50, 58))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('mouse', 'Species', '10090', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('synthesis', 'biological_process', 'GO:0009058', ('32', '41'))	('decreased', 'NegReg', (71, 80))	('tumor', 'Disease', (81, 86))
92555	32140311	According to their biogenesis, circRNAs can be categorized as exonic (ecircRNAs), circular intronic (ciRNAs), retained-intron or exon-intron (EIciRNAs), and intergenic.	('circ', 'Chemical', '-', (71, 75))	('circ', 'Chemical', '-', (82, 86))	('exon-intron', 'Var', (129, 140))	('circ', 'Chemical', '-', (31, 35))	('exonic', 'Disease', (62, 68))
92562	32140311	circ-0000523 can interact with miR-31 and inhibit the Wnt/ beta-catenin signaling pathway, and thus, it can regulate the growth of colorectal cancer cells.	('growth', 'CPA', (121, 127))	('miR-31', 'Gene', (31, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('beta-catenin', 'Gene', '1499', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('signaling pathway', 'biological_process', 'GO:0007165', ('72', '89'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('circ-0000523', 'Chemical', '-', (0, 12))	('miR-31', 'Gene', '407035', (31, 37))	('regulate', 'Reg', (108, 116))	('inhibit', 'NegReg', (42, 49))	('colorectal cancer', 'Disease', (131, 148))	('circ-0000523', 'Var', (0, 12))	('interact', 'Interaction', (17, 25))	('beta-catenin', 'Gene', (59, 71))
92580	32140311	Modulating MBL levels significantly affects the biosynthesis of circ-Mbl.	('Modulating', 'Var', (0, 10))	('biosynthesis', 'biological_process', 'GO:0009058', ('48', '60'))	('affects', 'Reg', (36, 43))	('circ', 'Chemical', '-', (64, 68))	('biosynthesis of', 'MPA', (48, 63))
92582	32140311	More concretely, aberrant circ-Foxo3 expression represses cell cycle progression by binding to the cell cycle proteins cyclin-dependent kinase 2 (CDK2) and cyclin-dependent kinase inhibitor 1 (P21), which results in the formation of a ternary complex and subsequently blocks cell cycle progression.	('aberrant', 'Var', (17, 25))	('circ', 'Chemical', '-', (26, 30))	('cell cycle', 'biological_process', 'GO:0007049', ('58', '68'))	('CDK2', 'Gene', (146, 150))	('binding', 'Interaction', (84, 91))	('blocks', 'NegReg', (268, 274))	('P21', 'Gene', '1026', (193, 196))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('173', '189'))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('156', '189'))	('cell cycle', 'biological_process', 'GO:0007049', ('99', '109'))	('Foxo3', 'Gene', '2309', (31, 36))	('cell cycle progression', 'CPA', (275, 297))	('cyclin', 'molecular_function', 'GO:0016538', ('119', '125'))	('P21', 'Gene', (193, 196))	('cell cycle', 'biological_process', 'GO:0007049', ('275', '285'))	('cyclin-dependent kinase inhibitor 1', 'Gene', '1026', (156, 191))	('cell cycle progression', 'CPA', (58, 80))	('binding', 'molecular_function', 'GO:0005488', ('84', '91'))	('cyclin-dependent kinase 2', 'Gene', '1017', (119, 144))	('represses', 'NegReg', (48, 57))	('results in', 'Reg', (205, 215))	('formation', 'biological_process', 'GO:0009058', ('220', '229'))	('ternary complex', 'MPA', (235, 250))	('CDK', 'molecular_function', 'GO:0004693', ('146', '149'))	('cyclin-dependent kinase 2', 'Gene', (119, 144))	('CDK2', 'Gene', '1017', (146, 150))	('Foxo3', 'Gene', (31, 36))	('cyclin-dependent kinase inhibitor 1', 'Gene', (156, 191))
92595	32140311	Silencing circ-HIPK3 can significantly inhibit the growth of human cells by directly binding to and inhibiting miR-124 activity.	('HIPK3', 'Gene', (15, 20))	('binding to', 'Interaction', (85, 95))	('growth of human cells', 'CPA', (51, 72))	('inhibit', 'NegReg', (39, 46))	('circ', 'Chemical', '-', (10, 14))	('inhibiting', 'NegReg', (100, 110))	('miR-124', 'Protein', (111, 118))	('activity', 'MPA', (119, 127))	('Silencing', 'Var', (0, 9))	('binding', 'molecular_function', 'GO:0005488', ('85', '92'))	('human', 'Species', '9606', (61, 66))	('HIPK3', 'Gene', '10114', (15, 20))
92596	32140311	Dysregulated circ-HIPK3 expression correlates with the occurrence and progression of human diseases and circ-HIPK3 functions differ among diseases.	('circ', 'Chemical', '-', (13, 17))	('HIPK3', 'Gene', '10114', (109, 114))	('HIPK3', 'Gene', (109, 114))	('circ', 'Chemical', '-', (104, 108))	('HIPK3', 'Gene', '10114', (18, 23))	('Dysregulated', 'Var', (0, 12))	('HIPK3', 'Gene', (18, 23))	('human diseases', 'Disease', (85, 99))	('human', 'Species', '9606', (85, 90))
92601	32140311	reported that circ-000285 derived from HIPK3 inhibits BC.	('HIPK3', 'Gene', '10114', (39, 44))	('HIPK3', 'Gene', (39, 44))	('inhibits', 'NegReg', (45, 53))	('BC', 'Disease', 'MESH:D001749', (54, 56))	('BC', 'Phenotype', 'HP:0009725', (54, 56))	('circ-000285', 'Chemical', '-', (14, 25))	('circ-000285', 'Var', (14, 25))
92604	32140311	Additionally, circ-0000285 is associated with tumor size, differentiation, lymph node metastasis, distant metastasis, and TNM stage.	('differentiation', 'CPA', (58, 73))	('associated', 'Reg', (30, 40))	('TNM', 'Gene', '10178', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('lymph node metastasis', 'CPA', (75, 96))	('tumor', 'Disease', (46, 51))	('distant metastasis', 'CPA', (98, 116))	('TNM', 'Gene', (122, 125))	('circ', 'Chemical', '-', (14, 18))	('circ-0000285', 'Var', (14, 26))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
92633	32140311	Functionally, circ-BPTF knockdown reduces tumor progression in vitro and in vivo.	('tumor', 'Disease', (42, 47))	('BPTF', 'Gene', (19, 23))	('BPTF', 'Gene', '2186', (19, 23))	('reduces', 'NegReg', (34, 41))	('circ', 'Chemical', '-', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('knockdown', 'Var', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
92636	32140311	Therefore, attenuating circ-BPTF expression might be a promising direction to pursue as a strategy for treating BC.	('circ', 'Chemical', '-', (23, 27))	('BC', 'Disease', 'MESH:D001749', (112, 114))	('BC', 'Phenotype', 'HP:0009725', (112, 114))	('attenuating', 'Var', (11, 22))	('BPTF', 'Gene', (28, 32))	('BPTF', 'Gene', '2186', (28, 32))
92638	32140311	Functionally, silencing circ-VANGL1 significantly attenuates BC cell proliferation, cell cycle, migration, and invasion in vitro and suppresses tumor growth in vivo.	('silencing', 'Var', (14, 23))	('tumor', 'Disease', (144, 149))	('migration', 'CPA', (96, 105))	('BC', 'Disease', 'MESH:D001749', (61, 63))	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('circ', 'Chemical', '-', (24, 28))	('BC', 'Phenotype', 'HP:0009725', (61, 63))	('suppresses', 'NegReg', (133, 143))	('cell cycle', 'biological_process', 'GO:0007049', ('84', '94'))	('cell cycle', 'CPA', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('VANGL1', 'Gene', (29, 35))	('VANGL1', 'Gene', '81839', (29, 35))	('attenuates', 'NegReg', (50, 60))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('invasion', 'CPA', (111, 119))
92641	32140311	reported that circ-0058063 is upregulated in BC tissues, and that silencing circ-0058063 attenuates the migration capacity of cancer cells, increases cell apoptosis rates, and arrests cells at the G0/G1 phase in vitro, thereby suppressing tumor growth in vivo.	('increases', 'PosReg', (140, 149))	('cell apoptosis rates', 'CPA', (150, 170))	('arrest', 'Disease', 'MESH:D006323', (176, 182))	('suppressing', 'NegReg', (227, 238))	('BC', 'Disease', 'MESH:D001749', (45, 47))	('cancer', 'Disease', (126, 132))	('circ', 'Chemical', '-', (14, 18))	('tumor', 'Disease', (239, 244))	('attenuates', 'NegReg', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('arrest', 'Disease', (176, 182))	('G1 phase', 'biological_process', 'GO:0051318', ('200', '208'))	('circ', 'Chemical', '-', (76, 80))	('BC', 'Phenotype', 'HP:0009725', (45, 47))	('apoptosis', 'biological_process', 'GO:0097194', ('155', '164'))	('cells at the G0/G1 phase', 'CPA', (184, 208))	('apoptosis', 'biological_process', 'GO:0006915', ('155', '164'))	('circ-0058063', 'Var', (76, 88))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('silencing circ-0058063', 'Var', (66, 88))
92642	32140311	Mechanistically, circ-0058063 can negatively modulate miR-145-5p as a sponge, and elevate CDK6 expression to promote BC progression.	('expression', 'MPA', (95, 105))	('CDK', 'molecular_function', 'GO:0004693', ('90', '93'))	('promote', 'PosReg', (109, 116))	('miR-145', 'Gene', (54, 61))	('circ', 'Chemical', '-', (17, 21))	('miR-145', 'Gene', '406937', (54, 61))	('BC', 'Disease', 'MESH:D001749', (117, 119))	('circ-0058063', 'Var', (17, 29))	('BC', 'Phenotype', 'HP:0009725', (117, 119))	('CDK6', 'Gene', (90, 94))	('elevate', 'PosReg', (82, 89))	('CDK6', 'Gene', '1021', (90, 94))
92649	32140311	identified circ-0000144 as a novel oncogene in BC, because its expression is significantly upregulated in BC, compared with adjacent non-tumor tissues, and high levels of circ-0000144 expression are associated with a poor prognosis.	('upregulated', 'PosReg', (91, 102))	('tumor', 'Disease', (137, 142))	('circ', 'Chemical', '-', (171, 175))	('BC', 'Disease', 'MESH:D001749', (47, 49))	('expression', 'MPA', (63, 73))	('circ-0000144', 'Var', (171, 183))	('BC', 'Disease', 'MESH:D001749', (106, 108))	('BC', 'Phenotype', 'HP:0009725', (106, 108))	('circ', 'Chemical', '-', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('BC', 'Phenotype', 'HP:0009725', (47, 49))	('circ-0000144', 'Gene', (11, 23))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
92650	32140311	Functionally, circ-0000144 knockdown attenuates BC cell proliferation and invasion in vitro, and reduces tumor volumes in vivo.	('knockdown', 'Var', (27, 36))	('cell proliferation', 'biological_process', 'GO:0008283', ('51', '69'))	('invasion', 'CPA', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('circ', 'Chemical', '-', (14, 18))	('circ-0000144', 'Gene', (14, 26))	('attenuates', 'NegReg', (37, 47))	('reduces', 'NegReg', (97, 104))	('BC', 'Disease', 'MESH:D001749', (48, 50))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('BC', 'Phenotype', 'HP:0009725', (48, 50))
92651	32140311	Mechanistically, circ-0000144 is a sponge for miR-217, and RUNX2 is a target of miR-217.	('RUNX2', 'Gene', (59, 64))	('circ', 'Chemical', '-', (17, 21))	('miR-217', 'Gene', '406999', (80, 87))	('miR-217', 'Gene', (46, 53))	('circ-0000144', 'Var', (17, 29))	('miR-217', 'Gene', (80, 87))	('miR-217', 'Gene', '406999', (46, 53))	('RUNX2', 'Gene', '860', (59, 64))
92655	32140311	Functionally, silencing circ-UVRAG suppresses tumor formation and metastasis.	('formation', 'biological_process', 'GO:0009058', ('52', '61'))	('UVRAG', 'Gene', (29, 34))	('silencing', 'Var', (14, 23))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('circ', 'Chemical', '-', (24, 28))	('suppresses', 'NegReg', (35, 45))	('UVRAG', 'Gene', '7405', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
92668	32140311	Functional experiments have confirmed that circ-0001451 knockdown promotes the proliferation of ccRCC cell lines and inhibits apoptosis in vitro, indicating its potential as novel diagnostic biomarker of ccRCC and a potential target for ccRCC treatment.	('proliferation', 'CPA', (79, 92))	('apoptosis', 'CPA', (126, 135))	('circ-0001451 knockdown', 'Var', (43, 65))	('men', 'Species', '9606', (17, 20))	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('men', 'Species', '9606', (248, 251))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('inhibits', 'NegReg', (117, 125))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('RCC', 'Disease', (239, 242))	('RCC', 'Phenotype', 'HP:0005584', (239, 242))	('promotes', 'PosReg', (66, 74))	('RCC', 'Disease', 'MESH:D002292', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (206, 209))	('RCC', 'Disease', (206, 209))	('knockdown', 'Var', (56, 65))	('circ', 'Chemical', '-', (43, 47))	('RCC', 'Disease', 'MESH:D002292', (239, 242))	('RCC', 'Disease', 'MESH:D002292', (206, 209))
92672	32140311	Mechanistically, ER beta represses circ-ATP2B1 expression by inhibiting its host gene ATP2B1 and directly binding to the ERE (-1765 to -1760 nt) on the 5'-promoter of ATP2B1.	('ER beta', 'Gene', (17, 24))	('inhibiting', 'NegReg', (61, 71))	('ATP2B1', 'Gene', '490', (86, 92))	('binding', 'molecular_function', 'GO:0005488', ('106', '113'))	('binding', 'Interaction', (106, 113))	('ATP2B1', 'Gene', (167, 173))	('ATP2B1', 'Gene', (40, 46))	('ATP2B1', 'Gene', '490', (167, 173))	('ER beta', 'Gene', '2099', (17, 24))	('ATP2B1', 'Gene', '490', (40, 46))	('-1765 to -1760 nt', 'Var', (126, 143))	('circ', 'Chemical', '-', (35, 39))	('expression', 'MPA', (47, 57))	('ATP2B1', 'Gene', (86, 92))
92685	32140311	Notably, miR-145 is a tumor suppressor in cancer, found using microarray analysis that miR-145 overexpression promotes the expression of circRNA-101981, circRNA-008068, and circRNA-406557, and suppresses that of circRNA-101996 and circRNA-091420 in PCa LNCaP cells.	('miR-145', 'Gene', '406937', (87, 94))	('circ', 'Chemical', '-', (231, 235))	('expression', 'MPA', (123, 133))	('miR-145', 'Gene', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('circRNA-008068', 'Var', (153, 167))	('miR-145', 'Gene', (87, 94))	('overexpression promotes', 'PosReg', (95, 118))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('22', '38'))	('suppresses', 'NegReg', (193, 203))	('PCa', 'Phenotype', 'HP:0012125', (249, 252))	('circ', 'Chemical', '-', (212, 216))	('circRNA-406557', 'Var', (173, 187))	('circRNA-101981', 'Var', (137, 151))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('tumor suppressor', 'biological_process', 'GO:0051726', ('22', '38'))	('circ', 'Chemical', '-', (173, 177))	('circ', 'Chemical', '-', (137, 141))	('PCa LNCaP', 'CellLine', 'CVCL:0395', (249, 258))	('miR-145', 'Gene', '406937', (9, 16))	('cancer', 'Disease', (42, 48))	('tumor', 'Disease', (22, 27))	('circ', 'Chemical', '-', (153, 157))
92692	32140311	Functional experiments have shown that silencing circ-SMARCA5 in PCa cells suppresses proliferation, increases the amount of cells in G1 phase, decreases that in S phase, and elevates apoptosis rates.	('suppresses', 'NegReg', (75, 85))	('silencing', 'Var', (39, 48))	('SMARCA5', 'Gene', '8467', (54, 61))	('apoptosis rates', 'CPA', (184, 199))	('men', 'Species', '9606', (17, 20))	('proliferation', 'CPA', (86, 99))	('PCa', 'Disease', 'MESH:D011471', (65, 68))	('PCa', 'Phenotype', 'HP:0012125', (65, 68))	('elevates', 'PosReg', (175, 183))	('PCa', 'Disease', (65, 68))	('S phase', 'biological_process', 'GO:0051320', ('162', '169'))	('G1 phase', 'biological_process', 'GO:0051318', ('134', '142'))	('SMARCA5', 'Gene', (54, 61))	('decreases', 'NegReg', (144, 153))	('increases', 'PosReg', (101, 110))	('apoptosis', 'biological_process', 'GO:0097194', ('184', '193'))	('apoptosis', 'biological_process', 'GO:0006915', ('184', '193'))	('circ', 'Chemical', '-', (49, 53))	('S phase', 'MPA', (162, 169))
92697	32140311	Dysregulated circRNA expression is inextricably associated with cancer development.	('circ', 'Chemical', '-', (13, 17))	('associated', 'Reg', (48, 58))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('Dysregulated', 'Var', (0, 12))	('men', 'Species', '9606', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
92731	30732138	Neither serum nor CSF was positive for paraneoplastic-associated antibodies such as anti-Hu, anti-Yo, anti-Ri anti-Ma2, anti-CV2, or anti-Amphiphysin, which rules out a diagnosis of paraneoplastic neurologic syndromes.	('paraneoplastic', 'Disease', (39, 53))	('anti-CV2', 'Var', (120, 128))	('paraneoplastic neurologic syndromes', 'Disease', 'MESH:D020361', (182, 217))	('paraneoplastic', 'Disease', 'MESH:D010257', (182, 196))	('paraneoplastic neurologic syndromes', 'Disease', (182, 217))	('paraneoplastic', 'Disease', (182, 196))	('paraneoplastic', 'Disease', 'MESH:D010257', (39, 53))	('anti-Amphiphysin', 'Var', (133, 149))	('anti-Yo', 'Var', (93, 100))	('anti-Ri anti-Ma2', 'Var', (102, 118))	('anti-Hu', 'Var', (84, 91))
92761	30732138	Our case demonstrates an interesting association between positive AQP4 in CSF of a patient with both NMOSD and renal clear cell carcinoma.	('positive', 'Var', (57, 65))	('CSF', 'Disease', (74, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (111, 137))	('renal clear cell carcinoma', 'Disease', (111, 137))	('AQP4', 'Gene', (66, 70))	('AQP4', 'Gene', '361', (66, 70))	('patient', 'Species', '9606', (83, 90))
92768	29088883	We performed this meta-analysis to evaluate the pathologic and prognostic impacts of high c-Met expression in patients with RCC.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('c-Met', 'Gene', (90, 95))	('high', 'Var', (85, 89))	('c-Met', 'Gene', '4233', (90, 95))	('patients', 'Species', '9606', (110, 118))
92772	29088883	In conclusion, this meta-analysis demonstrates that high c-Met expression correlate with significantly worse pathological features and overall survival, indicating c-Met overexpression is a potential adverse prognostic marker for patients with RCC.	('c-Met', 'Gene', '4233', (164, 169))	('RCC', 'Disease', (244, 247))	('RCC', 'Phenotype', 'HP:0005584', (244, 247))	('worse', 'NegReg', (103, 108))	('expression', 'MPA', (63, 73))	('patients', 'Species', '9606', (230, 238))	('pathological features', 'CPA', (109, 130))	('c-Met', 'Gene', (57, 62))	('high', 'Var', (52, 56))	('c-Met', 'Gene', '4233', (57, 62))	('c-Met', 'Gene', (164, 169))	('RCC', 'Disease', 'MESH:C538614', (244, 247))
92783	29088883	Thus, dysregulation of c-Met and HGF has been implicated in the pathogenesis of cancers.	('HGF', 'Gene', (33, 36))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('HGF', 'Gene', '3082', (33, 36))	('implicated', 'Reg', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('dysregulation', 'Var', (6, 19))	('c-Met', 'Gene', (23, 28))	('c-Met', 'Gene', '4233', (23, 28))	('pathogenesis', 'biological_process', 'GO:0009405', ('64', '76'))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
92786	29088883	Several meta-analyses in common tumors indicated that high c-Met expression was associated with a poor prognosis.	('c-Met', 'Gene', '4233', (59, 64))	('high', 'Var', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('expression', 'MPA', (65, 75))	('tumors', 'Disease', (32, 38))	('c-Met', 'Gene', (59, 64))
92788	29088883	High c-Met expression has been associated with poor pathologic features and prognosis in many studies.	('c-Met', 'Gene', (5, 10))	('expression', 'MPA', (11, 21))	('c-Met', 'Gene', '4233', (5, 10))	('High', 'Var', (0, 4))
92808	29088883	The results show that high c-Met expression is associated with significantly worse pathological features and prognosis.	('c-Met', 'Gene', (27, 32))	('high', 'Var', (22, 26))	('expression', 'MPA', (33, 43))	('c-Met', 'Gene', '4233', (27, 32))
92812	29088883	In addition, VHL mutation and/or loss of heterozygosity have been associated with c-Met expression in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('VHL', 'Disease', (13, 16))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('VHL', 'Disease', 'MESH:D006623', (13, 16))	('mutation', 'Var', (17, 25))	('associated', 'Reg', (66, 76))	('c-Met', 'Gene', (82, 87))	('c-Met', 'Gene', '4233', (82, 87))	('loss of heterozygosity', 'Var', (33, 55))	('expression', 'MPA', (88, 98))	('RCC', 'Disease', (104, 107))
92814	29088883	In RCC, many studies have suggested that c-Met expression is associated with significantly inferior clinicopathological features, such as tumor grade, primary tumor stage, lymphatic invasion, metastases, and worse progression-free survival or OS.	('metastases', 'Disease', 'MESH:D009362', (192, 202))	('inferior', 'NegReg', (91, 99))	('tumor', 'Disease', (138, 143))	('c-Met', 'Gene', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('c-Met', 'Gene', '4233', (41, 46))	('expression', 'Var', (47, 57))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('tumor', 'Disease', (159, 164))	('metastases', 'Disease', (192, 202))	('OS', 'Chemical', 'MESH:D009992', (243, 245))	('RCC', 'Disease', (3, 6))	('progression-free survival', 'CPA', (214, 239))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('RCC', 'Disease', 'MESH:C538614', (3, 6))	('lymphatic invasion', 'CPA', (172, 190))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
92818	29088883	evaluated c-Met expression as a prognostic marker in 317 patients with RCC and found that high c-Met expression was an independent predictor of survival (multivariate HR = 1.013 [95% CI: 1.002-1.023], P = 0.015).	('c-Met', 'Gene', (10, 15))	('c-Met', 'Gene', '4233', (10, 15))	('patients', 'Species', '9606', (57, 65))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('high', 'Var', (90, 94))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('c-Met', 'Gene', (95, 100))	('expression', 'MPA', (101, 111))	('c-Met', 'Gene', '4233', (95, 100))
92819	29088883	assessed c-Met expression and MET copy number in 572 patients with ccRCC.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('patients', 'Species', '9606', (53, 61))	('c-Met', 'Gene', (9, 14))	('c-Met', 'Gene', '4233', (9, 14))	('MET copy number', 'Var', (30, 45))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
92820	29088883	Patients with high c-Met expression showed significantly worse OS than those with c-Met-low tumor (HR = 1.49 [95% CI: 1.11-2.0], P = 0.008) in univariate analysis.	('OS', 'Chemical', 'MESH:D009992', (63, 65))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('c-Met', 'Gene', (19, 24))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('c-Met', 'Gene', '4233', (82, 87))	('c-Met', 'Gene', (82, 87))	('c-Met', 'Gene', '4233', (19, 24))	('tumor', 'Disease', (92, 97))
92828	29088883	Our findings indicate that high c-Met expression represent a potential adverse prognostic marker for patients with RCC.	('patients', 'Species', '9606', (101, 109))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('high', 'Var', (27, 31))	('c-Met', 'Gene', (32, 37))	('c-Met', 'Gene', '4233', (32, 37))
92831	29088883	Several meta-analyses in other cancers have also demonstrated that high c-Met expression is an adverse prognostic marker for survival.	('expression', 'MPA', (78, 88))	('high', 'Var', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('c-Met', 'Gene', (72, 77))	('c-Met', 'Gene', '4233', (72, 77))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('cancers', 'Disease', (31, 38))	('cancers', 'Disease', 'MESH:D009369', (31, 38))
92838	29088883	In a phase II study with RCC, interestingly, therapeutic response of foretinib (a multi-kinase inhibitor targeting c-Met, VEGF, RON, AXL, and TIE-2 receptors) was closely associated with the germline MET mutations.	('RON', 'Gene', (128, 131))	('VEGF', 'Gene', '7422', (122, 126))	('foretinib', 'Chemical', 'MESH:C544831', (69, 78))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('88', '104'))	('therapeutic', 'MPA', (45, 56))	('AXL', 'Gene', '558', (133, 136))	('c-Met', 'Gene', (115, 120))	('RON', 'Gene', '4486', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('c-Met', 'Gene', '4233', (115, 120))	('AXL', 'Gene', (133, 136))	('VEGF', 'Gene', (122, 126))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('foretinib', 'Gene', (69, 78))	('germline MET mutations', 'Var', (191, 213))	('associated', 'Reg', (171, 181))	('RCC', 'Disease', (25, 28))
92839	29088883	In addition, the efficacy of c-Met-targeting agents has been associated with high c-Met expression in non-small-cell lung cancer and hepatocellular carcinoma.	('high', 'Var', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('lung cancer', 'Disease', (117, 128))	('c-Met', 'Gene', (29, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('c-Met', 'Gene', (82, 87))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (133, 157))	('c-Met', 'Gene', '4233', (82, 87))	('hepatocellular carcinoma', 'Disease', (133, 157))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (133, 157))	('expression', 'MPA', (88, 98))	('c-Met', 'Gene', '4233', (29, 34))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))
92844	29088883	c-Met upregulation by anti-VEGF therapy may explain the reason why patients with high c-Met expression achieved less survival benefit from sunitinib.	('survival', 'MPA', (117, 125))	('c-Met', 'Gene', '4233', (0, 5))	('c-Met', 'Gene', (86, 91))	('patients', 'Species', '9606', (67, 75))	('VEGF', 'Gene', '7422', (27, 31))	('high', 'Var', (81, 85))	('less', 'NegReg', (112, 116))	('c-Met', 'Gene', '4233', (86, 91))	('sunitinib', 'Chemical', 'MESH:D000077210', (139, 148))	('upregulation', 'PosReg', (6, 18))	('VEGF', 'Gene', (27, 31))	('c-Met', 'Gene', (0, 5))
92856	29088883	These findings indicate that high c-Met expression is a potential adverse prognostic marker for patients with RCC.	('RCC', 'Disease', (110, 113))	('high', 'Var', (29, 33))	('c-Met', 'Gene', '4233', (34, 39))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('patients', 'Species', '9606', (96, 104))	('c-Met', 'Gene', (34, 39))
92865	31575051	Circular RNAs in Clear Cell Renal Cell Carcinoma: Their Microarray-Based Identification, Analytical Validation, and Potential Use in a Clinico-Genomic Model to Improve Prognostic Accuracy Circular RNAs (circRNAs) may act as novel cancer biomarkers.	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (17, 48))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('Clear Cell Renal Cell Carcinoma', 'Disease', (17, 48))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (28, 48))	('cancer', 'Disease', (230, 236))	('Circular', 'Var', (188, 196))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:D002292', (17, 48))	('Carcinoma', 'Phenotype', 'HP:0030731', (39, 48))
92880	31575051	In ccRCC, 85% of the detected circRNAs derived from exonic gene sequences (Figure 2B) corresponding to data found in other human tissues.	('human', 'Species', '9606', (123, 128))	('derived', 'Reg', (39, 46))	('exonic gene sequences', 'Var', (52, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))
92917	31575051	Four of these 20 circRNAs are identical with four of the 17 top differentially expressed circRNAs, including the circEGLN3, listed in Table 2 (circBase ID: circ_0025135, circ_00331594, circ_0029340, and circ_0101692).	('circ_0025135', 'Var', (156, 168))	('circ_00331594', 'Var', (170, 183))	('EGLN3', 'Gene', '112399', (117, 122))	('circ_0101692', 'Var', (203, 215))	('EGLN3', 'Gene', (117, 122))	('circBase ID', 'Disease', 'MESH:C537985', (143, 154))	('circ_0029340', 'Var', (185, 197))	('circBase ID', 'Disease', (143, 154))
92926	31575051	In contrast, over-expression of circRNAs can also be protective against tumor progression as shown by the example of circSLCA1, which promotes the tumor suppressor PTEN via miR-130b/miR-494 sponging in bladder cancer.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('circSLCA1', 'Var', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('bladder cancer', 'Phenotype', 'HP:0009725', (202, 216))	('promotes', 'PosReg', (134, 142))	('PTEN', 'Gene', (164, 168))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('147', '163'))	('PTEN', 'Gene', '5728', (164, 168))	('tumor', 'Disease', (72, 77))	('sponging in bladder', 'Phenotype', 'HP:0100645', (190, 209))	('tumor suppressor', 'biological_process', 'GO:0051726', ('147', '163'))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('miR-494', 'Gene', '574452', (182, 189))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('miR-494', 'Gene', (182, 189))	('miR-130b', 'Gene', '406920', (173, 181))	('miR-130b', 'Gene', (173, 181))	('bladder cancer', 'Disease', 'MESH:D001749', (202, 216))	('bladder cancer', 'Disease', (202, 216))
92930	31575051	The up-regulation of both circEGLN3 and linRNA of EGLN3 in ccRCC and the predicted interaction via miR-31-5p and miR-1205 could reflect a self-sustaining mechanism of the oncogene EGLN3.	('miR-31-5p', 'Var', (99, 108))	('EGLN3', 'Gene', (30, 35))	('EGLN3', 'Gene', (50, 55))	('interaction', 'Interaction', (83, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('ccRCC', 'Disease', (59, 64))	('EGLN3', 'Gene', '112399', (180, 185))	('miR-1205', 'Gene', (113, 121))	('EGLN3', 'Gene', (180, 185))	('up-regulation', 'PosReg', (4, 17))	('regulation', 'biological_process', 'GO:0065007', ('7', '17'))	('miR-1205', 'Gene', '100302161', (113, 121))	('EGLN3', 'Gene', '112399', (30, 35))	('EGLN3', 'Gene', '112399', (50, 55))
92931	31575051	This hypothesis is supported by new reports that miRNA-31-5p acts as tumor suppressor and is down-regulated in renal cell carcinoma.	('miRNA-31-5p', 'Var', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (111, 131))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (111, 131))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('69', '85'))	('tumor', 'Disease', (69, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('down-regulated', 'NegReg', (93, 107))	('tumor suppressor', 'biological_process', 'GO:0051726', ('69', '85'))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('renal cell carcinoma', 'Disease', (111, 131))
92967	29777398	These alterations result in broad transcriptional changes, including in tumor suppressor genes.	('alterations', 'Var', (6, 17))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor suppressor', 'biological_process', 'GO:0051726', ('72', '88'))	('tumor', 'Disease', (72, 77))	('transcriptional changes', 'MPA', (34, 57))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('72', '88'))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
92969	29777398	In this review we examine the role of DNA methylation in renal cell carcinoma disease etiology and progression, the preclinical use of DNA methylation alterations as diagnostic, prognostic and predictive biomarkers, and the potential for DNA methylation-directed therapies.	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('DNA methylation', 'biological_process', 'GO:0006306', ('238', '253'))	('renal cell carcinoma disease', 'Disease', 'MESH:C538614', (57, 85))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (57, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('DNA methylation', 'biological_process', 'GO:0006306', ('38', '53'))	('DNA', 'cellular_component', 'GO:0005574', ('238', '241'))	('alterations', 'Var', (151, 162))	('DNA methylation', 'biological_process', 'GO:0006306', ('135', '150'))	('renal cell carcinoma disease', 'Disease', (57, 85))
92982	29777398	Deletions of the 3p chromosome arm and somatic von Hippel-Lindau (VHL) tumor suppressor gene mutations lead to loss of VHL protein expression in a majority of ccRCC cases.	('tumor suppressor', 'biological_process', 'GO:0051726', ('71', '87'))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('loss', 'NegReg', (111, 115))	('mutations', 'Var', (93, 102))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('71', '87'))	('VHL protein', 'Protein', (119, 130))	('expression', 'MPA', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('RCC', 'Disease', (161, 164))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (47, 76))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('chromosome', 'cellular_component', 'GO:0005694', ('20', '30'))	('Deletions', 'Var', (0, 9))
92983	29777398	Likewise, germline mutations of the VHL gene produce a highly penetrant inherited syndrome (von Hippel-Lindau disease) in which multifocal ccRCC is a prominent feature.	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('VHL', 'Gene', (36, 39))	('RCC', 'Disease', 'MESH:C538614', (141, 144))	('inherited syndrome', 'Disease', (72, 90))	('germline mutations', 'Var', (10, 28))	('von Hippel-Lindau disease', 'Disease', (92, 117))	('inherited syndrome', 'Disease', 'None', (72, 90))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (92, 117))	('produce', 'Reg', (45, 52))
92984	29777398	Despite being a driver of development and progression, VHL disruption is not sufficient to cause ccRCC in mice.	('mice', 'Species', '10090', (106, 110))	('cause', 'Reg', (91, 96))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('disruption', 'Var', (59, 69))	('VHL', 'Gene', (55, 58))
92985	29777398	Whole genome sequencing studies have indicated mutations in the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex and epigenome modifiers (i.e.	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('105', '133'))	('SWI/SNF', 'Gene', (96, 103))	('mutations', 'Var', (47, 56))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('105', '125'))	('sucrose', 'Chemical', 'MESH:D013395', (71, 78))
92987	29777398	In fact, chromatin remodeling pathway gene mutations were detected in 69.3% of ccRCC, 53.0% of pRCC, and 14.9% of chRCC tissues in The Cancer Genome Atlas (TCGA) data set, demonstrating common molecular pathways disrupted across RCC subtypes.	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (135, 154))	('RCC', 'Disease', 'MESH:C538614', (229, 232))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('RCC', 'Disease', (116, 119))	('Cancer Genome Atlas', 'Disease', (135, 154))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', (81, 84))	('chromatin', 'Pathway', (9, 18))	('pRCC', 'Gene', '5546', (95, 99))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('Cancer', 'Phenotype', 'HP:0002664', (135, 141))	('RCC', 'Disease', (96, 99))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('9', '29'))	('detected', 'Reg', (58, 66))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('pRCC', 'Gene', (95, 99))	('RCC', 'Disease', (229, 232))	('RCC', 'Phenotype', 'HP:0005584', (229, 232))	('chromatin', 'cellular_component', 'GO:0000785', ('9', '18'))	('mutations', 'Var', (43, 52))
92994	29777398	These changes in methylation can result in significant changes in gene expression that include the activation of oncogenes and silencing of tumor suppressor genes .	('methylation', 'MPA', (17, 28))	('tumor suppressor', 'biological_process', 'GO:0051726', ('140', '156'))	('oncogenes', 'Gene', (113, 122))	('changes', 'Var', (6, 13))	('activation', 'PosReg', (99, 109))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('gene expression', 'biological_process', 'GO:0010467', ('66', '81'))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('gene expression', 'MPA', (66, 81))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('140', '156'))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('silencing', 'NegReg', (127, 136))	('changes', 'Reg', (55, 62))	('tumor', 'Disease', (140, 145))
92998	29777398	Hypermethylation of CpG islands that silences expression of tumor suppressor genes has been studied in ccRCC for more than 20 years.	('silences', 'NegReg', (37, 45))	('tumor', 'Disease', (60, 65))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('60', '76'))	('Hypermethylation', 'Var', (0, 16))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('RCC', 'Disease', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('expression', 'MPA', (46, 56))	('tumor suppressor', 'biological_process', 'GO:0051726', ('60', '76'))
93000	29777398	More recently, TCGA confirmed these findings by demonstrating 7% of ccRCC cases showed epigenetic silencing at VHL.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('VHL', 'Gene', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('epigenetic silencing', 'Var', (87, 107))
93002	29777398	This underscores observations that VHL inactivation through promoter methylation (or mutation and deletion) often occurs during, and contributes to, RCC carcinogenesis yet is not sufficient to drive malignant progression.	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('contributes', 'Reg', (133, 144))	('methylation', 'biological_process', 'GO:0032259', ('69', '80'))	('deletion', 'Var', (98, 106))	('mutation', 'Var', (85, 93))	('promoter', 'MPA', (60, 68))	('RCC carcinogenesis', 'Disease', (149, 167))	('RCC carcinogenesis', 'Disease', 'MESH:C538614', (149, 167))	('VHL', 'Gene', (35, 38))	('inactivation', 'NegReg', (39, 51))
93003	29777398	Since deletions at 3p often encompass the entire chromosomal arm, DNA methylation of genes in that chromosomal segment have been investigated as possible contributors to ccRCC genesis and progression.	('DNA methylation', 'biological_process', 'GO:0006306', ('66', '81'))	('deletions', 'Var', (6, 15))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('RCC', 'Disease', (172, 175))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))
93005	29777398	RASSF1A promoter methylation was described in 32 of 138 primary ccRCC tumors and 12 of 27 primary papillary RCC tumors (the second most common histologic subtype of RCC).	('RCC tumors', 'Disease', (66, 76))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('RCC tumors', 'Disease', 'MESH:C538614', (66, 76))	('papillary RCC tumors', 'Disease', (98, 118))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('RASSF1A', 'Gene', '11186', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('RASSF1A', 'Gene', (0, 7))	('methylation', 'Var', (17, 28))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('RCC tumors', 'Disease', 'MESH:C538614', (108, 118))	('papillary RCC tumors', 'Disease', 'MESH:C538614', (98, 118))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('RCC', 'Disease', (165, 168))
93007	29777398	Additionally, two meta analyses identified significant association between RASSF1A hypermethylation and RCC risk (OR=19.35, 95% confidence intervals, CI=9.57- 39.13; and OR=4.14, 95% CI=1.06-16.1), as well as between RASSF1A promoter methylation and tumor grade (OR=3.32, 95% CI=1.55-7.12).	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RASSF1A', 'Gene', (217, 224))	('RASSF1A', 'Gene', '11186', (75, 82))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('hypermethylation', 'Var', (83, 99))	('RASSF1A', 'Gene', '11186', (217, 224))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('methylation', 'biological_process', 'GO:0032259', ('234', '245'))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('RASSF1A', 'Gene', (75, 82))	('tumor', 'Disease', (250, 255))	('RCC', 'Disease', (104, 107))
93008	29777398	Early ex vivo and in vitro studies also show that DNA methylation may be involved in metastasis to bone through TIMP metallopeptidase inhibitor 2 (TIMP2) regulation .	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('methylation', 'Var', (54, 65))	('TIMP2', 'Gene', (147, 152))	('DNA methylation', 'biological_process', 'GO:0006306', ('50', '65'))	('TIMP metallopeptidase inhibitor 2', 'Gene', '7077', (112, 145))	('TIMP metallopeptidase inhibitor 2', 'Gene', (112, 145))	('involved', 'Reg', (73, 81))	('TIMP2', 'Gene', '7077', (147, 152))	('metastasis to bone', 'CPA', (85, 103))	('regulation', 'biological_process', 'GO:0065007', ('154', '164'))
93009	29777398	While many other tumor suppressor genes have been shown to undergo epigenetic silencing in RCC, it remains to be seen which may be driving cancer etiology and progression and which are passenger effects of genome-wide remodeling.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('tumor suppressor', 'biological_process', 'GO:0051726', ('17', '33'))	('tumor', 'Disease', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))	('driving', 'Reg', (131, 138))	('epigenetic silencing', 'Var', (67, 87))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('17', '33'))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('cancer', 'Disease', (139, 145))
93016	29777398	Kidney cancer tissues have also been shown to have widespread DNA hypermethylation in gene bodies and kidney-specific enhancer regions, and that these alterations are linked to dysregulated hypoxia signaling pathways and RCC-cell sensitivity to decitabine, a hypomethylating chemotherapeutic that acts by inhibiting DNA methyltransferase.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('signaling', 'biological_process', 'GO:0023052', ('198', '207'))	('RCC', 'Phenotype', 'HP:0005584', (221, 224))	('hypermethylation', 'Var', (66, 82))	('dysregulated hypoxia', 'Disease', (177, 197))	('DNA', 'cellular_component', 'GO:0005574', ('316', '319'))	('RCC', 'Disease', 'MESH:C538614', (221, 224))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('RCC', 'Disease', (221, 224))	('Kidney cancer', 'Disease', 'MESH:D007680', (0, 13))	('decitabine', 'Chemical', 'MESH:D000077209', (245, 255))	('dysregulated hypoxia', 'Disease', 'MESH:D000860', (177, 197))	('Kidney cancer', 'Phenotype', 'HP:0009726', (0, 13))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('62', '82'))	('linked', 'Reg', (167, 173))	('Kidney cancer', 'Disease', (0, 13))
93017	29777398	The underlying mechanisms of altered DNA methylation in RCC are unknown, particularly the causes of de novo hypermethylation in discrete regions of the genome.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('DNA methylation', 'biological_process', 'GO:0006306', ('37', '52'))	('altered', 'Var', (29, 36))
93020	29777398	Additionally, oxidative stress can induce epigenetic reprogramming, including DNA hypermethylation, and thereby drive malignant transformation, and regional hypoxia and differences in activation of hypoxia signaling pathways in RCC can influence the oxidative state of kidney cancer cells.	('DNA hypermethylation', 'MPA', (78, 98))	('RCC', 'Disease', 'MESH:C538614', (228, 231))	('induce', 'Reg', (35, 41))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))	('drive', 'PosReg', (112, 117))	('oxidative stress', 'Phenotype', 'HP:0025464', (14, 30))	('epigenetic reprogramming', 'MPA', (42, 66))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('78', '98'))	('hypoxia', 'Disease', (198, 205))	('influence', 'Reg', (236, 245))	('kidney cancer', 'Disease', 'MESH:D007680', (269, 282))	('hypoxia', 'Disease', (157, 164))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('oxidative state', 'MPA', (250, 265))	('signaling', 'biological_process', 'GO:0023052', ('206', '215'))	('hypoxia', 'Disease', 'MESH:D000860', (198, 205))	('RCC', 'Disease', (228, 231))	('malignant transformation', 'CPA', (118, 142))	('hypoxia', 'Disease', 'MESH:D000860', (157, 164))	('RCC', 'Phenotype', 'HP:0005584', (228, 231))	('differences', 'Var', (169, 180))	('kidney cancer', 'Phenotype', 'HP:0009726', (269, 282))	('kidney cancer', 'Disease', (269, 282))
93021	29777398	TCGA analysis of ccRCC identified an association between SETD2 (a histone methyltransferase) mutations and global DNA hypomethylation outside of gene promoter regions, supporting the premise that histone H3K36 trimethylation might help maintain heterochromatin.	('SETD2', 'Gene', '29072', (57, 62))	('mutations', 'Var', (93, 102))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('114', '133'))	('heterochromatin', 'cellular_component', 'GO:0000792', ('245', '260'))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('histone H3K36 trimethylation', 'biological_process', 'GO:0097198', ('196', '224'))	('SETD2', 'Gene', (57, 62))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('global DNA hypomethylation', 'MPA', (107, 133))
93022	29777398	Furthermore, in RCC cell lines, SETD2 loss-of-function mutations disrupt both the epigenome and transcriptome through redistribution of histone H3K36 trimethylation, resulting in genome-wide DNA hypermethylation.	('SETD2', 'Gene', '29072', (32, 37))	('DNA', 'cellular_component', 'GO:0005574', ('191', '194'))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('trimethylation', 'MPA', (150, 164))	('RCC', 'Disease', (16, 19))	('disrupt', 'NegReg', (65, 72))	('mutations', 'Var', (55, 64))	('loss-of-function', 'NegReg', (38, 54))	('SETD2', 'Gene', (32, 37))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('transcriptome', 'MPA', (96, 109))	('histone H3K36 trimethylation', 'biological_process', 'GO:0097198', ('136', '164'))	('redistribution', 'MPA', (118, 132))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('191', '211'))	('histone H3K36', 'Protein', (136, 149))	('DNA hypermethylation', 'MPA', (191, 211))
93023	29777398	Thus, through DNA mutation SETD2 disruption could drive genome-wide changes that result in de-differentiation and cancer progression.	('disruption', 'Var', (33, 43))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('result', 'Reg', (81, 87))	('de-differentiation', 'CPA', (91, 109))	('SETD2', 'Gene', '29072', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('SETD2', 'Gene', (27, 32))	('DNA', 'cellular_component', 'GO:0005574', ('14', '17'))	('cancer', 'Disease', (114, 120))
93026	29777398	Interestingly, truncating PBRM1 mutations, a very common event in ccRCC that also affects chromatin structure, may also drive DNA methylation events and cancer progression.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('drive', 'Reg', (120, 125))	('DNA methylation', 'biological_process', 'GO:0006306', ('126', '141'))	('cancer', 'Disease', (153, 159))	('PBRM1', 'Gene', (26, 31))	('chromatin', 'cellular_component', 'GO:0000785', ('90', '99'))	('affects', 'Reg', (82, 89))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('chromatin structure', 'MPA', (90, 109))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('DNA methylation events', 'MPA', (126, 148))	('RCC', 'Disease', (68, 71))	('mutations', 'Var', (32, 41))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('truncating', 'Var', (15, 25))
93027	29777398	A recent report suggests both gene expression and DNA methylation changes associated with mutations in chromatin modifier genes are present in clear cell and papillary RCC TCGA tumors and are predictive of worse outcome.	('DNA methylation', 'MPA', (50, 65))	('papillary RCC TCGA tumors', 'Disease', (158, 183))	('mutations', 'Var', (90, 99))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('chromatin', 'cellular_component', 'GO:0000785', ('103', '112'))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('DNA methylation', 'biological_process', 'GO:0006306', ('50', '65'))	('clear cell', 'Disease', (143, 153))	('papillary RCC TCGA tumors', 'Disease', 'MESH:C538614', (158, 183))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('changes', 'Reg', (66, 73))	('chromatin modifier genes', 'Gene', (103, 127))	('gene expression', 'biological_process', 'GO:0010467', ('30', '45'))
93030	29777398	For example, DNA methylation was shown to lead to transcriptional silencing of the microRNA miR-10b in 9 ccRCC patient tumors and 5 RCC cell lines, and miR-10b has been shown to act functionally as a tumor suppressor.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('RCC', 'Disease', (107, 110))	('tumors', 'Disease', (119, 125))	('miR-10b', 'Gene', (92, 99))	('tumor', 'Disease', (200, 205))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('200', '216'))	('patient', 'Species', '9606', (111, 118))	('DNA methylation', 'biological_process', 'GO:0006306', ('13', '28'))	('silencing', 'NegReg', (66, 75))	('miR-10b', 'Gene', '406903', (92, 99))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumor suppressor', 'biological_process', 'GO:0051726', ('200', '216'))	('miR-10b', 'Gene', (152, 159))	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('miR-10b', 'Gene', '406903', (152, 159))	('transcriptional', 'MPA', (50, 65))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('DNA methylation', 'Var', (13, 28))
93031	29777398	TCGA also reported DNA methylation silencing of miR-10b expression, as well as silencing of miR-21 and miR- 30a.	('silencing', 'NegReg', (35, 44))	('silencing', 'MPA', (79, 88))	('methylation', 'Var', (23, 34))	('miR- 30a', 'Gene', '407029', (103, 111))	('miR- 30a', 'Gene', (103, 111))	('miR-21', 'Gene', '406991', (92, 98))	('miR-10b', 'Gene', '406903', (48, 55))	('expression', 'MPA', (56, 66))	('DNA methylation', 'biological_process', 'GO:0006306', ('19', '34'))	('miR-21', 'Gene', (92, 98))	('miR-10b', 'Gene', (48, 55))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
93032	29777398	DNA methylation silencing of both miR-9-1 and miR-9-3 (p<0.001) has been reported in 74 ccRCC tumor samples compared to paired normal tissues from 32 of these cases and with reduced recurrence-free survival (p=0.034 and p=0.007, respectively).	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('miR-9-3', 'Gene', (46, 53))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('miR-9-3', 'Gene', '407051', (46, 53))	('miR-9-1', 'Gene', '407046', (34, 41))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('methylation', 'Var', (4, 15))	('miR-9-1', 'Gene', (34, 41))	('silencing', 'NegReg', (16, 25))	('tumor', 'Disease', (94, 99))	('recurrence-free survival', 'CPA', (182, 206))	('reduced', 'NegReg', (174, 181))	('RCC', 'Disease', (90, 93))
93039	29777398	RCC DNA methylation changes are a promising source of candidate diagnostic biomarkers because they are found early during carcinogenesis, including in precancerous lesions.	('carcinogenesis', 'Disease', 'MESH:D063646', (122, 136))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))	('carcinogenesis', 'Disease', (122, 136))	('DNA methylation', 'biological_process', 'GO:0006306', ('4', '19'))	('precancerous lesions', 'Disease', 'MESH:D011230', (151, 171))	('methylation changes', 'Var', (8, 27))	('precancerous lesions', 'Disease', (151, 171))	('changes', 'Var', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('RCC', 'Disease', (0, 3))
93043	29777398	For example, methylated DNA was detected in at least one of six loci in preoperative urine sediment in 88% of 50 RCC patients compared to none of the normal controls (specificity 100%).	('methylated', 'Var', (13, 23))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('detected', 'Reg', (32, 40))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('patients', 'Species', '9606', (117, 125))
93046	29777398	Detection of CpG island methylation of VHL (area under the receiver operating characteristic curve, AUC ROC = 0.705) and RASSF1A (AUC ROC=0.694) were discriminative of RCC from benign disease.	('benign disease', 'Disease', (177, 191))	('benign disease', 'Disease', 'MESH:D009369', (177, 191))	('VHL', 'Gene', (39, 42))	('methylation', 'Var', (24, 35))	('RASSF1A', 'Gene', (121, 128))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('RCC', 'Disease', (168, 171))	('RASSF1A', 'Gene', '11186', (121, 128))
93054	29777398	While methylation can be used as a diagnostic tool to distinguish normal from malignant renal lesions, it could also help with classification of histological subtypes of RCC.	('malignant renal lesions', 'Disease', 'MESH:D007674', (78, 101))	('RCC', 'Disease', (170, 173))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('malignant renal lesions', 'Disease', (78, 101))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('methylation', 'Var', (6, 17))	('malignant renal lesions', 'Phenotype', 'HP:0009726', (78, 101))	('help', 'Reg', (117, 121))
93060	29777398	Panels of prognostic biomarkers have also been described, including GREM1, LAD1, NEFH, and NEURL, and methylation at each site alone or in combination was predictive of patient prognosis in three independent patient cohorts (HR=3.64 and 95% CI=1.02-13.00, HR=7.54 and 95% CI=2.68-21.19, and HR=3.60 and 95% CI=2.02-6.40).	('NEURL', 'Gene', '9148', (91, 96))	('methylation', 'biological_process', 'GO:0032259', ('102', '113'))	('patient', 'Species', '9606', (208, 215))	('GREM1', 'Gene', '26585', (68, 73))	('NEURL', 'Gene', (91, 96))	('methylation', 'Var', (102, 113))	('NEFH', 'Gene', (81, 85))	('LAD1', 'Gene', (75, 79))	('NEFH', 'Gene', '4744', (81, 85))	('GREM1', 'Gene', (68, 73))	('patient', 'Species', '9606', (169, 176))	('LAD1', 'Gene', '3898', (75, 79))
93064	29777398	Because defects in the spindle checkpoint pathway have been associated with CIMP in ccRCC tumors, this subset of patients may benefit from spindle checkpoint-targeting therapies.	('RCC tumors', 'Disease', (86, 96))	('spindle checkpoint pathway', 'Pathway', (23, 49))	('CIMP', 'Chemical', '-', (76, 80))	('defects', 'Var', (8, 15))	('spindle', 'cellular_component', 'GO:0005819', ('139', '146'))	('patients', 'Species', '9606', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('RCC tumors', 'Disease', 'MESH:C538614', (86, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('spindle checkpoint', 'biological_process', 'GO:0031577', ('23', '41'))	('spindle checkpoint', 'biological_process', 'GO:0031577', ('139', '157'))	('CIMP', 'Disease', (76, 80))	('spindle', 'cellular_component', 'GO:0005819', ('23', '30'))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('associated', 'Reg', (60, 70))
93070	29777398	Increased hypermethylation in all three of these RCC histologic subtypes was associated with decreased patient survival (p<0.0001).	('hypermethylation', 'Var', (10, 26))	('RCC', 'Disease', (49, 52))	('patient survival', 'CPA', (103, 119))	('decreased', 'NegReg', (93, 102))	('patient', 'Species', '9606', (103, 110))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
93073	29777398	While most studies have focused on promoter DNA methylation, examining DNA methylation patterns outside of the promoter region has demonstrated that many kidney-specific enhancers (regions associated with H3K4Me1 marks), as well as sites enriched for anti-AP2 alpha antibody (AP2a), aryl hydrocarbon receptor precursor (AHR), aryl hydrocarbon receptor nuclear translocator (ARNT), HAIRY, and HIF1 transcription factor binding, are also hypermethylated and associated with patient prognosis.	('binding', 'Interaction', (418, 425))	('aryl hydrocarbon receptor', 'Gene', (283, 308))	('DNA methylation', 'biological_process', 'GO:0006306', ('71', '86'))	('ARNT', 'Gene', (374, 378))	('associated with', 'Reg', (456, 471))	('AP2a', 'Gene', '160', (276, 280))	('antibody', 'cellular_component', 'GO:0019815', ('266', '274'))	('enhancers', 'PosReg', (170, 179))	('aryl hydrocarbon receptor', 'Gene', '196', (283, 308))	('antibody', 'cellular_component', 'GO:0019814', ('266', '274'))	('AP2', 'cellular_component', 'GO:0005908', ('276', '279'))	('AHR', 'Gene', (320, 323))	('aryl hydrocarbon receptor nuclear translocator', 'Gene', (326, 372))	('aryl hydrocarbon receptor nuclear translocator', 'Gene', '405', (326, 372))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('AP2a', 'Gene', (276, 280))	('antibody', 'molecular_function', 'GO:0003823', ('266', '274'))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('antibody', 'cellular_component', 'GO:0042571', ('266', '274'))	('transcription', 'biological_process', 'GO:0006351', ('397', '410'))	('HIF1', 'Gene', '29072', (392, 396))	('hypermethylated', 'Var', (436, 451))	('patient', 'Species', '9606', (472, 479))	('HIF1', 'Gene', (392, 396))	('DNA methylation', 'biological_process', 'GO:0006306', ('44', '59'))	('aryl hydrocarbon receptor', 'Gene', '196', (326, 351))	('AHR', 'Gene', '196', (320, 323))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('397', '425'))	('AP2', 'cellular_component', 'GO:0005908', ('256', '259'))	('ARNT', 'Gene', '405', (374, 378))
93074	29777398	Interestingly, profiling both 5-methylcytosine and 5- hydroxymethylcytosine (oxidized 5-methylcytosine) in patient tumors and RCC cell lines suggests that gene body hypermethylation may actually be linked to loss of 5-hydroxymethylcytosine through IDH1 down regulation, and that loss is both prognostic (p<0.0001) and a marker of DNA methylation pattern remodeling.	('5-methylcytosine', 'Chemical', 'MESH:D044503', (30, 46))	('regulation', 'biological_process', 'GO:0065007', ('258', '268'))	('5-hydroxymethylcytosine', 'MPA', (216, 239))	('5- hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (51, 75))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('IDH1', 'Gene', '3417', (248, 252))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('hypermethylation', 'Var', (165, 181))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (86, 102))	('loss', 'NegReg', (208, 212))	('tumors', 'Disease', (115, 121))	('DNA', 'cellular_component', 'GO:0005574', ('330', '333'))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('RCC', 'Disease', (126, 129))	('down regulation', 'NegReg', (253, 268))	('patient', 'Species', '9606', (107, 114))	('DNA methylation', 'biological_process', 'GO:0006306', ('330', '345'))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (216, 239))	('IDH1', 'Gene', (248, 252))
93078	29777398	The PI3K pathway is regulated by miR-21 and GRB10, and hypomethylation of miR-21 and hypermethylation of GRB10 increase PI3K signaling and are associated with worse outcomes.	('hypermethylation', 'Var', (85, 101))	('GRB10', 'Gene', (105, 110))	('GRB10', 'Gene', (44, 49))	('increase', 'PosReg', (111, 119))	('associated', 'Reg', (143, 153))	('miR-21', 'Gene', '406991', (33, 39))	('GRB10', 'Gene', '2887', (44, 49))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('PI3K', 'molecular_function', 'GO:0016303', ('120', '124'))	('hypomethylation', 'Var', (55, 70))	('PI3K signaling', 'biological_process', 'GO:0014065', ('120', '134'))	('miR-21', 'Gene', '406991', (74, 80))	('PI3K pathway', 'Pathway', (4, 16))	('miR-21', 'Gene', (33, 39))	('GRB10', 'Gene', '2887', (105, 110))	('miR-21', 'Gene', (74, 80))	('PI3K signaling', 'Pathway', (120, 134))
93084	29777398	Hypermethylation of neurofilament heavy (NEFH), cystatin 6 (CST6), and ladinin 1 (LAD1) have been associated with poor prognosis and poor response to several antiangiogenic therapies in advanced RCC.	('neurofilament heavy', 'Gene', '4744', (20, 39))	('Hypermethylation', 'Var', (0, 16))	('cystatin 6', 'Gene', '1474', (48, 58))	('RCC', 'Phenotype', 'HP:0005584', (195, 198))	('RCC', 'Disease', (195, 198))	('LAD1', 'Gene', (82, 86))	('NEFH', 'Gene', '4744', (41, 45))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('ladinin 1', 'Gene', (71, 80))	('cystatin 6', 'Gene', (48, 58))	('NEFH', 'Gene', (41, 45))	('CST6', 'Gene', (60, 64))	('associated', 'Reg', (98, 108))	('neurofilament', 'cellular_component', 'GO:0005883', ('20', '33'))	('neurofilament heavy', 'Gene', (20, 39))	('CST6', 'Gene', '1474', (60, 64))	('LAD1', 'Gene', '3898', (82, 86))	('cystatin', 'molecular_function', 'GO:0004869', ('48', '56'))	('ladinin 1', 'Gene', '3898', (71, 80))
93090	29777398	For example, 5-aza-2'-deoxycytidine increases the susceptibility of RCC cells to paclitaxel (a tubulin-targeting drug) in vitro, putatively by activating the PI3K/Akt-LEF1/ss-catenin pathway.	('activating', 'Reg', (143, 153))	('Akt', 'Gene', (163, 166))	('LEF1', 'Gene', '51176', (167, 171))	('LEF1', 'Gene', (167, 171))	('PI3K', 'molecular_function', 'GO:0016303', ('158', '162'))	('paclitaxel', 'Chemical', 'MESH:D017239', (81, 91))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('susceptibility', 'MPA', (50, 64))	('Akt', 'Gene', '207', (163, 166))	('increases', 'PosReg', (36, 45))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (13, 35))	("5-aza-2'-deoxycytidine", 'Var', (13, 35))
93091	29777398	Similarly, organic cation transporter 2 (OCT2) is commonly suppressed in RCC through promoter hypermethylation, and treatment with 5-aza-2'-deoxycytidine induces demethylation and re-expression of OCT2 which sensitizes RCC cells and xenografts to oxaliplatin, a platinum-based antineoplastic.	('OCT2', 'Gene', '6582', (41, 45))	('OCT2', 'Gene', (197, 201))	('RCC', 'Disease', (219, 222))	('RCC', 'Phenotype', 'HP:0005584', (219, 222))	('demethylation', 'MPA', (162, 175))	('OCT2', 'Gene', (41, 45))	('re-expression', 'MPA', (180, 193))	('RCC', 'Disease', 'MESH:C538614', (219, 222))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))	('platinum', 'Chemical', 'MESH:D010984', (262, 270))	('RCC', 'Disease', (73, 76))	('demethylation', 'biological_process', 'GO:0070988', ('162', '175'))	('promoter', 'Var', (85, 93))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (247, 258))	('OCT2', 'Gene', '6582', (197, 201))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('organic cation transporter 2', 'Gene', (11, 39))	('organic cation transporter 2', 'Gene', '6582', (11, 39))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (131, 153))	('suppressed', 'NegReg', (59, 69))
93096	29777398	For example, gene expression profiling of RCC cell lines showed that 5-aza-2'-deoxycytidine suppresses cell growth through G2/M cell cycle arrest and the p38-NF-KB signaling pathway, suggesting this pathway could be exploited therapeutically.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('p38', 'Gene', '1432', (154, 157))	('suppresses', 'NegReg', (92, 102))	("5-aza-2'-deoxycytidine", 'Var', (69, 91))	('arrest', 'Disease', 'MESH:D006323', (139, 145))	('cell growth', 'CPA', (103, 114))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (69, 91))	('gene expression', 'biological_process', 'GO:0010467', ('13', '28'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('128', '145'))	('cell growth', 'biological_process', 'GO:0016049', ('103', '114'))	('signaling pathway', 'biological_process', 'GO:0007165', ('164', '181'))	('arrest', 'Disease', (139, 145))	('p38', 'Gene', (154, 157))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (128, 145))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))
93097	29777398	Clear cell RCC tumors with Notch pathway activation due to DNA methylation and copy number variation alterations appear to be clinically distinct and show better overall survival, highlighting the possibility of targeting Notch signaling with or without DNMT inhibitors.	('DNA methylation', 'Var', (59, 74))	('DNA methylation', 'biological_process', 'GO:0006306', ('59', '74'))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('alterations', 'Var', (101, 112))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('Notch pathway', 'Pathway', (27, 40))	('Clear cell RCC tumors', 'Disease', 'MESH:C538614', (0, 21))	('copy number variation alterations', 'Var', (79, 112))	('better', 'PosReg', (155, 161))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('activation', 'PosReg', (41, 51))	('DNMT', 'Gene', '1786', (254, 258))	('signaling', 'biological_process', 'GO:0023052', ('228', '237'))	('Clear cell RCC tumors', 'Disease', (0, 21))	('DNMT', 'Gene', (254, 258))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
93098	29777398	Recent studies have also highlighted that 16% of RCC cases have loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) through mutation, deletion, or promoter hypermethylation and that this tumor suppressor and cell cycle regulator may be targetable by cyclin-dependent kinase (CDK) 4 and 6 inhibitors.	('CDKN2A', 'Gene', '1029', (110, 116))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('210', '230'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('189', '205'))	('deletion', 'Var', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (72, 108))	('cyclin-dependent kinase (CDK) 4', 'Gene', '1019', (252, 283))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (72, 108))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('RCC', 'Disease', (49, 52))	('promoter hypermethylation', 'Var', (149, 174))	('loss', 'NegReg', (64, 68))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('89', '105'))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('210', '230'))	('CDK', 'molecular_function', 'GO:0004693', ('277', '280'))	('RCC', 'Disease', 'MESH:C538614', (49, 52))	('CDKN2A', 'Gene', (110, 116))	('tumor', 'Disease', (189, 194))	('mutation', 'Var', (126, 134))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('72', '105'))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('cyclin', 'molecular_function', 'GO:0016538', ('252', '258'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('189', '205'))
93100	29777398	In addition, treatment with 5-aza-2'-deoxycytidine can induce expression of the cancer testis antigens (CTA) MAGE-1, -2, -3, and -4, GAGE1-6, and NY-ESO-1 for which there are targeted immunotherapies.	('cancer testis', 'Phenotype', 'HP:0010788', (80, 93))	('cancer testis', 'Disease', 'MESH:D013736', (80, 93))	('NY-ESO-1', 'Gene', '246100', (146, 154))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('GAGE1-6', 'Gene', (133, 140))	('NY-ESO-1', 'Gene', (146, 154))	('expression', 'MPA', (62, 72))	('CTA', 'Gene', (104, 107))	('GAGE1-6', 'Gene', '2543;645037;2575;2576;2577;2578', (133, 140))	('induce', 'PosReg', (55, 61))	('cancer testis', 'Disease', (80, 93))	("5-aza-2'-deoxycytidine", 'Var', (28, 50))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (28, 50))	('MAGE-1, -2, -3, and -4', 'Gene', '4100;266740;4102;4103', (109, 131))
93103	29777398	Given the success of immunotherapy for treating advanced RCC, the possibility of improving responses though modulation of DNA methylation is an exciting future area of preclinical and clinical investigation.	('DNA methylation', 'biological_process', 'GO:0006306', ('122', '137'))	('modulation', 'Var', (108, 118))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('DNA', 'cellular_component', 'GO:0005574', ('122', '125'))
93104	29777398	Of particular interest, a recent exome sequencing study of 35 metastatic ccRCC patients found that patients with inactivating mutations in PBRM1 were more responsive to anti-PD-1 monotherapy (p=0.012), as were ccRCC patients in a validation cohort (p=0.0071, n=63).	('responsive to anti-PD-1 monotherapy', 'MPA', (155, 190))	('more', 'PosReg', (150, 154))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('patients', 'Species', '9606', (216, 224))	('patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (79, 87))	('RCC', 'Disease', (212, 215))	('RCC', 'Phenotype', 'HP:0005584', (212, 215))	('inactivating mutations', 'Var', (113, 135))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('PBRM1', 'Gene', (139, 144))
93106	29777398	Widespread and reproducible methylation changes demonstrate an important role for methylation alterations in renal cell carcinoma.	('changes', 'Var', (40, 47))	('renal cell carcinoma', 'Disease', (109, 129))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (109, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('methylation changes', 'Var', (28, 47))	('methylation', 'biological_process', 'GO:0032259', ('82', '93'))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (109, 129))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))
93107	29777398	However, much work needs to be done to identify which of the methylation changes are causative in RCC development and progression, and which changes are passengers.	('methylation changes', 'Var', (61, 80))	('causative', 'Reg', (85, 94))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('changes', 'Var', (73, 80))
93110	29777398	Growing evidence suggests that DNA methylation changes are a promising source of disease biomarkers that could be used for diagnosis, prognosis, therapeutic monitoring or prediction of response to therapies, perhaps even across RCC subtypes.	('RCC', 'Disease', 'MESH:C538614', (228, 231))	('RCC', 'Disease', (228, 231))	('RCC', 'Phenotype', 'HP:0005584', (228, 231))	('changes', 'Var', (47, 54))	('DNA methylation', 'biological_process', 'GO:0006306', ('31', '46'))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))
93120	29777398	In addition, promising work documenting the role of DNA methylation in modulating drug resistance could lead to novel combination approaches that render cytotoxic and/or targeted therapies effective in previously refractory cancers.	('drug resistance', 'Phenotype', 'HP:0020174', (82, 97))	('drug resistance', 'biological_process', 'GO:0009315', ('82', '97'))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('DNA methylation', 'biological_process', 'GO:0006306', ('52', '67'))	('lead', 'Reg', (104, 108))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('methylation', 'Var', (56, 67))	('cancers', 'Disease', (224, 231))	('drug resistance', 'biological_process', 'GO:0042493', ('82', '97'))
93151	29348897	The median body mass index (BMI) was 24.55 +- 3.73 and the BMI was stratified as follows: less than 18.5 (underweight), 18.5 to 24.99 (normal), 25 to 27.99 (overweight), 28 to 31.99 (obese) and more than 32 (morbidly obese).	('less than 18.5', 'Var', (90, 104))	('obese', 'Disease', (183, 188))	('median body', 'cellular_component', 'GO:0097568', ('4', '15'))	('obese', 'Disease', 'MESH:D009765', (217, 222))	('overweight', 'Phenotype', 'HP:0025502', (157, 167))	('obese', 'Disease', 'MESH:D009765', (183, 188))	('obese', 'Disease', (217, 222))
93174	29348897	Recently, a study discovered that structurally modified curcumin could promote the apoptosis of human renal cell carcinoma by inhibiting STAT phosphorylation.	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('curcumin', 'Protein', (56, 64))	('promote', 'PosReg', (71, 78))	('inhibiting', 'NegReg', (126, 136))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('human', 'Species', '9606', (96, 101))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (102, 122))	('STAT phosphorylation', 'MPA', (137, 157))	('phosphorylation', 'biological_process', 'GO:0016310', ('142', '157'))	('renal cell carcinoma', 'Disease', (102, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (102, 122))	('apoptosis', 'CPA', (83, 92))	('structurally modified', 'Var', (34, 55))	('curcumin', 'Chemical', 'MESH:D003474', (56, 64))
93212	33173535	Long Non-coding RNA LINC01094 Promotes the Development of Clear Cell Renal Cell Carcinoma by Upregulating SLC2A3 via MicroRNA-184 Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (141, 161))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (130, 161))	('SLC2A3', 'Gene', (106, 112))	('Upregulating', 'PosReg', (93, 105))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (58, 89))	('SLC2A3', 'Gene', '6515', (106, 112))	('LINC01094', 'Gene', '100505702', (20, 29))	('Promotes', 'PosReg', (30, 38))	('RCC', 'Disease', (200, 203))	('Clear Cell Renal Cell Carcinoma', 'Disease', (58, 89))	('MicroRNA-184', 'Var', (117, 129))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (130, 161))	('LINC01094', 'Gene', (20, 29))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (58, 89))	('Clear cell renal cell carcinoma', 'Disease', (130, 161))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (69, 89))	('RCC', 'Disease', 'MESH:C538614', (200, 203))	('Carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('RNA', 'cellular_component', 'GO:0005562', ('16', '19'))	('ccRCC', 'Phenotype', 'HP:0006770', (163, 168))	('RCC', 'Disease', (165, 168))
93221	33173535	Silencing LINC01094, up-regulating miR-184, or reducing SLC2A3 inhibited the growth, migration, and invasion of ccRCC cells.	('reducing', 'NegReg', (47, 55))	('miR-184', 'Gene', (35, 42))	('LINC01094', 'Gene', (10, 19))	('RCC', 'Disease', (114, 117))	('growth', 'CPA', (77, 83))	('SLC2A3', 'MPA', (56, 62))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('LINC01094', 'Gene', '100505702', (10, 19))	('invasion', 'CPA', (100, 108))	('inhibited', 'NegReg', (63, 72))	('up-regulating', 'PosReg', (21, 34))	('Silencing', 'Var', (0, 9))
93222	33173535	Tumor growth was suppressed by silenced LINC01215 via reducing the expression of SLC2A3 via miR-184.	('LINC01215', 'Gene', (40, 49))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('miR-184', 'Var', (92, 99))	('SLC2A3', 'Gene', (81, 87))	('suppressed', 'NegReg', (17, 27))	('Tumor growth', 'CPA', (0, 12))	('expression', 'MPA', (67, 77))	('LINC01215', 'Gene', '101929623', (40, 49))	('reducing', 'NegReg', (54, 62))
93223	33173535	Taken together, silencing LINC01094 inhibited SLC2A3 expression by up-regulating miR-184, thereby inhibiting the development of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('LINC01094', 'Gene', '100505702', (26, 35))	('inhibited', 'NegReg', (36, 45))	('development', 'CPA', (113, 124))	('SLC2A3', 'Gene', (46, 52))	('up-regulating', 'PosReg', (67, 80))	('miR-184', 'Gene', (81, 88))	('silencing', 'Var', (16, 25))	('LINC01094', 'Gene', (26, 35))	('RCC', 'Disease', (130, 133))	('expression', 'MPA', (53, 63))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('inhibiting', 'NegReg', (98, 108))
93228	33173535	Notably, long non-coding RNAs (lncRNAs) have been shown to play crucial roles in cancer biology.	('long non-coding RNAs', 'Var', (9, 29))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
93231	33173535	LncRNA NONHSAT123350 participates in the pathogenesis of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('pathogenesis', 'biological_process', 'GO:0009405', ('41', '53'))	('participates', 'Reg', (21, 33))	('NONHSAT123350', 'Var', (7, 20))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))
93237	33173535	It has also been suggested that aberrantly expressed miRNAs are related to the occurrence and development of ccRCC through participating in critical biological processes.	('aberrantly expressed', 'Var', (32, 52))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('participating', 'Reg', (123, 136))	('RCC', 'Disease', (111, 114))	('related', 'Reg', (64, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('miRNAs', 'Protein', (53, 59))
93242	33173535	The ccRCC-related microarray data were obtained from the Gene Expression Omnibus (GEO) database1, and differential analysis was performed on the retrieved datasets of GSE53757 (miRNA) and GSE53757 (gene).	('GSE53757', 'Var', (188, 196))	('GSE53757', 'Var', (167, 175))	('ccRCC', 'Phenotype', 'HP:0006770', (4, 9))	('Gene Expression', 'biological_process', 'GO:0010467', ('57', '72'))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))
93269	33173535	The 3'-untranslated regions (3'-UTR) of LINC01094 or SLC2A3 mRNA containing wild type (WT) or mutant (MUT) binding site was artificially synthesized and inserted into the pmiR-RB-REPORTTM plasmid (RiboBio, Co., Ltd., Guangzhou, China) using restriction endonuclease.	('LINC01094', 'Gene', '100505702', (40, 49))	('SLC2A3', 'Gene', (53, 59))	('mutant', 'Var', (94, 100))	('LINC01094', 'Gene', (40, 49))	('binding', 'molecular_function', 'GO:0005488', ('107', '114'))
93270	33173535	The correctly sequenced luciferase reporter plasmids WT and MUT were co-transformed with NC mimic or miR-184 mimic into HEK293T cells, respectively.	('HEK293T', 'CellLine', 'CVCL:0063', (120, 127))	('miR-184', 'Var', (101, 108))	('luciferase', 'Enzyme', (24, 34))
93277	33173535	The antibody used in the RIP assay was rabbit anti-Ago2 (ab186733, 1: 50, Abcam) which was mixed at room temperature for 30 min, and rabbit anti-IgG (ab109489, 1: 100, Abcam) was used as NC.	('antibody', 'cellular_component', 'GO:0042571', ('4', '12'))	('Ago2', 'Gene', (51, 55))	('antibody', 'cellular_component', 'GO:0019815', ('4', '12'))	('antibody', 'cellular_component', 'GO:0019814', ('4', '12'))	('antibody', 'molecular_function', 'GO:0003823', ('4', '12'))	('ab186733', 'Var', (57, 65))	('Ago2', 'Gene', '27161', (51, 55))
93314	33173535	It was found that overexpression of LINC01094 promoted the growth of 786-O cells, but silencing LINC01094 inhibited it (both p < 0.05; Figure 2C).	('promoted', 'PosReg', (46, 54))	('silencing', 'Var', (86, 95))	('LINC01094', 'Gene', (96, 105))	('LINC01094', 'Gene', '100505702', (36, 45))	('inhibited', 'NegReg', (106, 115))	('LINC01094', 'Gene', '100505702', (96, 105))	('LINC01094', 'Gene', (36, 45))	('growth', 'MPA', (59, 65))
93316	33173535	According to the flow cytometry, the transfection of oe-LINC01094 could decrease the apoptosis rate of 786-O cells while sh-LINC01094 significantly increased the cell apoptosis rate (all p < 0.05; Figure 2F).	('LINC01094', 'Gene', (56, 65))	('increased', 'PosReg', (148, 157))	('LINC01094', 'Gene', (124, 133))	('apoptosis rate', 'CPA', (85, 99))	('apoptosis', 'biological_process', 'GO:0097194', ('167', '176'))	('LINC01094', 'Gene', '100505702', (56, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('167', '176'))	('LINC01094', 'Gene', '100505702', (124, 133))	('apoptosis', 'biological_process', 'GO:0097194', ('85', '94'))	('decrease', 'NegReg', (72, 80))	('apoptosis', 'biological_process', 'GO:0006915', ('85', '94'))	('transfection', 'Var', (37, 49))
93324	33173535	Compared with the cells transfected with NC mimic, the luciferase activity of the cells co-transfected with both miR-184 mimic and WT-LINC01094 was lower than that of the cells treated with NC, whereas, cells co-transfected with miR-184 mimic and MUT-LINC01094 did not change significantly (Figure 3D).	('LINC01094', 'Gene', (251, 260))	('luciferase activity', 'molecular_function', 'GO:0047077', ('55', '74'))	('LINC01094', 'Gene', '100505702', (134, 143))	('activity', 'MPA', (66, 74))	('miR-184', 'Var', (113, 120))	('lower', 'NegReg', (148, 153))	('luciferase activity', 'molecular_function', 'GO:0045289', ('55', '74'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('55', '74'))	('LINC01094', 'Gene', '100505702', (251, 260))	('luciferase activity', 'molecular_function', 'GO:0050248', ('55', '74'))	('LINC01094', 'Gene', (134, 143))	('luciferase', 'Enzyme', (55, 65))	('luciferase activity', 'molecular_function', 'GO:0050397', ('55', '74'))
93328	33173535	Then, RT-qPCR was performed to measure the miR-184 expression on the collected ccRCC tissues and the adjacent normal tissues, which showed that the expression of miR-184 in ccRCC tissues was much lower than that in adjacent normal tissues (p < 0.05; Figure 3H).	('ccRCC', 'Phenotype', 'HP:0006770', (173, 178))	('lower', 'NegReg', (196, 201))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('RCC', 'Disease', (175, 178))	('expression', 'MPA', (148, 158))	('RCC', 'Disease', 'MESH:C538614', (175, 178))	('miR-184', 'Var', (162, 169))
93333	33173535	Whilst compared with the NC mimic, the transfection of miR-184 mimic decreased the levels of LINC01094, but the levels of LINC01094 were increased by the treatment of miR-184 inhibitor compared with the NC inhibitor (all p < 0.05; Figure 3K).	('miR-184 inhibitor', 'Var', (167, 184))	('LINC01094', 'Gene', '100505702', (122, 131))	('LINC01094', 'Gene', (93, 102))	('decreased', 'NegReg', (69, 78))	('increased', 'PosReg', (137, 146))	('levels', 'MPA', (112, 118))	('LINC01094', 'Gene', (122, 131))	('LINC01094', 'Gene', '100505702', (93, 102))
93354	33173535	When compared with oe-S-NC, the transfection with oe-SLC2A3 increased the expression of SLC2A3, while sh-SLC2A3 led to the opposite tendency of SLC2A3 expression in comparison to sh-S-NC (all p < 0.05; Figures 5I,J).	('expression', 'MPA', (74, 84))	('SLC2A3', 'Gene', (88, 94))	('sh-S', 'Gene', '10084', (102, 106))	('sh-S', 'Gene', (102, 106))	('expression', 'MPA', (151, 161))	('sh-S', 'Gene', '10084', (179, 183))	('sh-SLC2A3', 'Gene', '6515', (102, 111))	('sh-S', 'Gene', (179, 183))	('SLC2A3', 'Gene', (144, 150))	('sh-SLC2A3', 'Gene', (102, 111))	('oe-SLC2A3', 'Var', (50, 59))	('increased', 'PosReg', (60, 69))
93356	33173535	The above-described results indicated that overexpressed SLC2A3 promoted the proliferation, migration, and invasion of ccRCC cells, but inhibited the cell apoptosis.	('promoted', 'PosReg', (64, 72))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('apoptosis', 'biological_process', 'GO:0006915', ('155', '164'))	('SLC2A3', 'Gene', (57, 63))	('cell apoptosis', 'CPA', (150, 164))	('inhibited', 'NegReg', (136, 145))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('migration', 'CPA', (92, 101))	('overexpressed', 'Var', (43, 56))	('invasion', 'CPA', (107, 115))	('apoptosis', 'biological_process', 'GO:0097194', ('155', '164'))	('proliferation', 'CPA', (77, 90))
93358	33173535	The above-described results suggested that overexpressed miR-184 could inhibit the expression of SLC2A3, thereby inhibiting the proliferation, migration, and invasion of ccRCC cells but promoting cell apoptosis.	('SLC2A3', 'Gene', (97, 103))	('inhibit', 'NegReg', (71, 78))	('inhibiting', 'NegReg', (113, 123))	('promoting', 'PosReg', (186, 195))	('ccRCC', 'Phenotype', 'HP:0006770', (170, 175))	('miR-184', 'Var', (57, 64))	('proliferation', 'CPA', (128, 141))	('invasion', 'CPA', (158, 166))	('migration', 'CPA', (143, 152))	('expression', 'MPA', (83, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('201', '210'))	('apoptosis', 'biological_process', 'GO:0006915', ('201', '210'))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('overexpressed', 'PosReg', (43, 56))	('RCC', 'Disease', (172, 175))
93364	33173535	However, silencing LINC01094 caused the opposite effects.	('LINC01094', 'Gene', (19, 28))	('silencing', 'Var', (9, 18))	('LINC01094', 'Gene', '100505702', (19, 28))
93368	33173535	In the present study, we aimed to find a novel therapy for ccRCC and verified that down-regulating LINC01094 could increase miR-184 expression and inhibit SLC2A3 expression, thereby curtailing the development of ccRCC.	('SLC2A3 expression', 'MPA', (155, 172))	('miR-184', 'Gene', (124, 131))	('down-regulating', 'Var', (83, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (212, 217))	('LINC01094', 'Gene', '100505702', (99, 108))	('increase', 'PosReg', (115, 123))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('curtailing', 'NegReg', (182, 192))	('RCC', 'Disease', (214, 217))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', 'MESH:C538614', (214, 217))	('RCC', 'Disease', (61, 64))	('inhibit', 'NegReg', (147, 154))	('expression', 'MPA', (132, 142))	('LINC01094', 'Gene', (99, 108))
93373	33173535	Accordingly, the present study attempted to further investigate the role of LINC01094 in promoting the development of ccRCC by up-regulating the SLC2A3 via miR-184.	('miR-184', 'Var', (156, 163))	('LINC01094', 'Gene', (76, 85))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('LINC01094', 'Gene', '100505702', (76, 85))	('RCC', 'Disease', (120, 123))	('up-regulating', 'PosReg', (127, 140))	('promoting', 'PosReg', (89, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))	('development', 'CPA', (103, 114))	('SLC2A3', 'Gene', (145, 151))
93374	33173535	Besides, we demonstrated that miR-184 was a target of LINC01094, and silencing LINC01094 could increase the expression of miR-184 in ccRCC cells.	('LINC01094', 'Gene', (79, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('increase', 'PosReg', (95, 103))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('LINC01094', 'Gene', (54, 63))	('RCC', 'Disease', (135, 138))	('LINC01094', 'Gene', '100505702', (79, 88))	('expression', 'MPA', (108, 118))	('miR-184', 'Gene', (122, 129))	('LINC01094', 'Gene', '100505702', (54, 63))	('silencing', 'Var', (69, 78))
93381	33173535	Moreover, miR-184 functions as a tumor suppressor in renal cell carcinoma where it suppresses cell proliferation and induces renal cancer cell apoptosis.	('renal cell carcinoma', 'Disease', (53, 73))	('renal cancer', 'Disease', (125, 137))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (53, 73))	('renal cancer', 'Phenotype', 'HP:0009726', (125, 137))	('suppresses', 'NegReg', (83, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('tumor', 'Disease', (33, 38))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('33', '49'))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))	('renal cancer', 'Disease', 'MESH:D007680', (125, 137))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('induces', 'PosReg', (117, 124))	('tumor suppressor', 'biological_process', 'GO:0051726', ('33', '49'))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (53, 73))	('cell proliferation', 'CPA', (94, 112))	('miR-184', 'Var', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cell proliferation', 'biological_process', 'GO:0008283', ('94', '112'))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))
93389	33173535	Hence, on the basis of the above findings, our study proved that silencing LINC01094 inhibited the SLC2A3 expression by up-regulating miR-184, which further inhibited the proliferation, migration, and invasion of 786-O cells and tumor growth but promoted apoptosis.	('inhibited', 'NegReg', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('promoted', 'PosReg', (246, 254))	('expression', 'MPA', (106, 116))	('up-regulating', 'PosReg', (120, 133))	('proliferation', 'CPA', (171, 184))	('apoptosis', 'biological_process', 'GO:0097194', ('255', '264'))	('apoptosis', 'biological_process', 'GO:0006915', ('255', '264'))	('invasion of 786-O cells', 'CPA', (201, 224))	('LINC01094', 'Gene', '100505702', (75, 84))	('migration', 'CPA', (186, 195))	('tumor', 'Disease', (229, 234))	('miR-184', 'Gene', (134, 141))	('silencing', 'Var', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('inhibited', 'NegReg', (157, 166))	('SLC2A3', 'Gene', (99, 105))	('apoptosis', 'CPA', (255, 264))	('LINC01094', 'Gene', (75, 84))
93392	33173535	The ccRCC-related microarray data were obtained from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/), GSE53757 (miRNA), and GSE53757 (gene).	('GSE53757', 'Var', (133, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (4, 9))	('Gene Expression', 'biological_process', 'GO:0010467', ('57', '72'))	('GSE53757', 'Var', (155, 163))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))
93406	32498409	The loss or inactivation of pVHL function in ccRCC leads to a state of "pseudohypoxia" where stabilized HIF-1alpha and HIF-2alpha induce the transcription of hypoxia responsive genes, resulting in alterations such as increased glucose and ribose metabolism, pH deregulation, cell proliferation, and angiogenesis, giving ccRCC a high metastatic potential.	('induce', 'PosReg', (130, 136))	('RCC', 'Phenotype', 'HP:0005584', (322, 325))	('RCC', 'Disease', (322, 325))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('inactivation', 'Var', (12, 24))	('ccRCC', 'Phenotype', 'HP:0006770', (320, 325))	('loss', 'NegReg', (4, 8))	('increased glucose', 'Phenotype', 'HP:0003074', (217, 234))	('hypoxia', 'Disease', (158, 165))	('RCC', 'Disease', 'MESH:C538614', (322, 325))	('transcription', 'MPA', (141, 154))	('HIF-1alpha', 'Gene', '3091', (104, 114))	('metabolism', 'biological_process', 'GO:0008152', ('244', '254'))	('HIF-2alpha', 'Gene', '2034', (119, 129))	('increased', 'PosReg', (217, 226))	('glucose', 'Chemical', 'MESH:D005947', (227, 234))	('cell proliferation', 'biological_process', 'GO:0008283', ('273', '291'))	('hypoxia', 'Disease', (78, 85))	('pVHL', 'Gene', '7428', (28, 32))	('ribose', 'Chemical', 'MESH:D012266', (239, 245))	('pVHL', 'Gene', (28, 32))	('hypoxia', 'Disease', 'MESH:D000860', (158, 165))	('pH deregulation', 'MPA', (258, 273))	('angiogenesis', 'biological_process', 'GO:0001525', ('297', '309'))	('angiogenesis', 'CPA', (299, 311))	('hypoxia', 'Disease', 'MESH:D000860', (78, 85))	('HIF-1alpha', 'Gene', (104, 114))	('transcription', 'biological_process', 'GO:0006351', ('139', '152'))	('cell proliferation', 'CPA', (275, 293))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('HIF-2alpha', 'Gene', (119, 129))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))
93429	32498409	In addition to that, hsa-miR-210-3p presented a tendency for being upregulated (p = 0.053) and hsa-miR-1246 presented a tendency for being downregulated (p = 0.053), both in the metastatic samples, when compared with the follow-up group (Figure 2D,F).	('hsa-miR-1246', 'Gene', (95, 107))	('hsa-miR-1246', 'Gene', '100302142', (95, 107))	('hsa-miR-210-3p', 'Var', (21, 35))	('downregulated', 'NegReg', (139, 152))	('upregulated', 'PosReg', (67, 78))
93436	32498409	Patients with a high or low expression level had a lower overall survival compared to patients with intermediate levels of hsa-miR-200c-3p (log rank Mantel Cox test, p = 0.025) (Figure 3C).	('hsa-miR-200c', 'Gene', '406985', (123, 135))	('hsa-miR-200c', 'Gene', (123, 135))	('lower', 'NegReg', (51, 56))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (57, 73))	('low', 'Var', (24, 27))	('patients', 'Species', '9606', (86, 94))
93437	32498409	In addition to that, patients with lower levels of has-miR-25-3p presented a tendency for a lower overall survival (log rank Mantel Cox test, p = 0.054) (Figure 3A).	('has-miR-25-3p', 'Var', (51, 64))	('miR-25-3p', 'Chemical', '-', (55, 64))	('patients', 'Species', '9606', (21, 29))	('overall survival', 'MPA', (98, 114))	('lower', 'NegReg', (92, 97))
93448	32498409	In fact, hsa-miR-25-3p, hsa-miR-126-5p, hsa-miR-200c-3p, and hsa-miR-301a-3p have already been reported in EVs, with an impact on cell proliferation, pre-metastatic niche formation, invasion, and metastization in other tumor models.	('hsa-miR-200c', 'Gene', (40, 52))	('cell proliferation', 'biological_process', 'GO:0008283', ('130', '148'))	('hsa-miR-25', 'Gene', '407014', (9, 19))	('tumor', 'Disease', (219, 224))	('pre-metastatic niche formation', 'CPA', (150, 180))	('metastization', 'CPA', (196, 209))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('impact', 'Reg', (120, 126))	('EVs', 'Disease', (107, 110))	('hsa-miR-126', 'Gene', '406913', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('hsa-miR-25', 'Gene', (9, 19))	('hsa-miR-200c', 'Gene', '406985', (40, 52))	('miR-25-3p', 'Chemical', '-', (13, 22))	('hsa-miR-126', 'Gene', (24, 35))	('hsa-miR-301a-3p', 'Var', (61, 76))	('formation', 'biological_process', 'GO:0009058', ('171', '180'))	('pre', 'molecular_function', 'GO:0003904', ('150', '153'))	('invasion', 'CPA', (182, 190))	('cell proliferation', 'CPA', (130, 148))
93449	32498409	When we looked into the validated target genes of the four miRNAs that decreased after tumor removal, we observed that PTEN was the most common target, being regulated by hsa-miR-25-3p, hsa-miR-200c-3p and miR-301a-3p.	('miR-25-3p', 'Chemical', '-', (175, 184))	('tumor removal', 'Disease', (87, 100))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('regulated', 'Reg', (158, 167))	('PTEN', 'Gene', (119, 123))	('hsa-miR-25', 'Gene', '407014', (171, 181))	('miR-301a-3p', 'Var', (206, 217))	('tumor removal', 'Disease', 'MESH:D009369', (87, 100))	('PTEN', 'Gene', '5728', (119, 123))	('hsa-miR-25', 'Gene', (171, 181))	('hsa-miR-200c', 'Gene', '406985', (186, 198))	('hsa-miR-200c', 'Gene', (186, 198))
93454	32498409	This epigenetic silencing of PTEN in metastatic cells leads to CCL2 secretion and myeloid cell recruitment, which promoted metastatic cell expansion through reduced apoptosis and enhanced proliferation through PI3K/Akt pathway activation.	('myeloid cell recruitment', 'CPA', (82, 106))	('apoptosis', 'biological_process', 'GO:0097194', ('165', '174'))	('apoptosis', 'biological_process', 'GO:0006915', ('165', '174'))	('CCL', 'molecular_function', 'GO:0044101', ('63', '66'))	('PTEN', 'Gene', (29, 33))	('apoptosis', 'CPA', (165, 174))	('CCL2', 'Gene', '6347', (63, 67))	('proliferation', 'CPA', (188, 201))	('PI3K', 'molecular_function', 'GO:0016303', ('210', '214'))	('cell expansion', 'biological_process', 'GO:0016049', ('134', '148'))	('PTEN', 'Gene', '5728', (29, 33))	('epigenetic silencing', 'Var', (5, 25))	('metastatic cell expansion', 'CPA', (123, 148))	('promoted', 'PosReg', (114, 122))	('reduced', 'NegReg', (157, 164))	('CCL2', 'Gene', (63, 67))	('enhanced', 'PosReg', (179, 187))	('secretion', 'MPA', (68, 77))	('Akt', 'Gene', (215, 218))	('CCL2 secretion', 'biological_process', 'GO:0035926', ('63', '77'))	('activation', 'PosReg', (227, 237))	('Akt', 'Gene', '207', (215, 218))
93460	32498409	To support this hypothesis, a study performed by Wang and colleagues showed that, under a hypoxic microenvironment, pancreatic cancer cells generate EVs enriched in hsa-miR-301a-3p that induce M2 macrophages polarization through the PTEN/PI3K/Akt signalling pathway and promote metastization.	('iron', 'Chemical', 'MESH:D007501', (106, 110))	('PTEN', 'Gene', '5728', (233, 237))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('promote', 'PosReg', (270, 277))	('Akt', 'Gene', '207', (243, 246))	('PI3K', 'molecular_function', 'GO:0016303', ('238', '242'))	('hypoxic', 'Disease', (90, 97))	('hypoxic', 'Disease', 'MESH:D000860', (90, 97))	('Akt', 'Gene', (243, 246))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('hsa-miR-301a-3p', 'Var', (165, 180))	('metastization', 'CPA', (278, 291))	('induce', 'PosReg', (186, 192))	('M2 macrophages polarization', 'CPA', (193, 220))	('pancreatic cancer', 'Disease', (116, 133))	('signalling pathway', 'biological_process', 'GO:0007165', ('247', '265'))	('PTEN', 'Gene', (233, 237))	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))
93466	32498409	Although based on a limited number of cases, our results may highlight the importance of a balance in EV-derived miRNA abundance and how disruption of that balance can have an impact on the patients' prognosis.	('patients', 'Species', '9606', (190, 198))	('impact', 'Reg', (176, 182))	('EV-derived miRNA abundance', 'MPA', (102, 128))	('disruption', 'Var', (137, 147))
93479	32498409	The plasma fraction was then centrifuged 3 additional times at increasing speeds (300x g, 2100x g and 10,000x g) for a period of 15 min each in order to obtain platelet-free-plasma (PFP).	('PFP', 'Chemical', '-', (182, 185))	('2100x g', 'Var', (90, 97))	('300x g', 'Var', (82, 88))
93483	32498409	The A60-Micro-Plus machine is equipped with three spatially separated lasers (488 nm - Position C, 405 nm - Position A and 638 nm-Position B), 7 fluorescence color detectors (525/50, LWP590, 530/30, 574/26, 590/40, 695/40, 676/36), and 3 light scatter detectors (SALS, MALS and LALS).	('MALS', 'Gene', '259197', (269, 273))	('525/50', 'Var', (175, 181))	('MALS', 'Gene', (269, 273))	('LWP590', 'Var', (183, 189))
93488	32498409	Taken together, these results suggest that EVs content varies depending on the presence or absence of the disease and an increase of EVs enriched in hsa-miR-301a-3p, and decrease of EVs enriched in hsa-miR-1293, may be potential biomarkers of metastatic disease in ccRCC patients.	('increase', 'PosReg', (121, 129))	('metastatic disease', 'Disease', (243, 261))	('hsa-miR-1293', 'Gene', '100302220', (198, 210))	('RCC', 'Disease', 'MESH:C538614', (267, 270))	('decrease', 'NegReg', (170, 178))	('RCC', 'Disease', (267, 270))	('RCC', 'Phenotype', 'HP:0005584', (267, 270))	('decrease of EV', 'Phenotype', 'HP:0000762', (170, 184))	('absence of the disease', 'Disease', (91, 113))	('ccRCC', 'Phenotype', 'HP:0006770', (265, 270))	('patients', 'Species', '9606', (271, 279))	('hsa-miR-1293', 'Gene', (198, 210))	('hsa-miR-301a-3p', 'Var', (149, 164))	('absence of the disease', 'Disease', 'MESH:D004832', (91, 113))
93491	29896907	Modulating ATP binding cassette transporters in papillary renal cell carcinoma type 2 enhances its response to targeted molecular therapy Papillary renal cell carcinoma (PRCC) is the most common nonclear cell RCCs and is known to comprise two histological subtypes.	('Modulating', 'Var', (0, 10))	('papillary renal cell carcinoma type 2', 'Phenotype', 'HP:0006732', (48, 85))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (58, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('papillary renal cell carcinoma type 2', 'Disease', (48, 85))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (148, 168))	('Papillary renal cell carcinoma', 'Disease', (138, 168))	('PRCC', 'Gene', '5546', (170, 174))	('papillary renal cell carcinoma type 2', 'Disease', 'MESH:C538614', (48, 85))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (48, 78))	('Papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (138, 168))	('PRCC', 'Gene', (170, 174))	('ATP binding', 'molecular_function', 'GO:0005524', ('11', '22'))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('Papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (138, 168))
93499	29896907	ABCC2 blockage resulted in higher sunitinib uptake, both in vitro (P = 0.0016) and in vivo (P = 0.0031).	('sunitinib', 'Chemical', 'MESH:D000077210', (34, 43))	('ABCC2', 'Gene', (0, 5))	('uptake', 'biological_process', 'GO:0098657', ('44', '50'))	('uptake', 'biological_process', 'GO:0098739', ('44', '50'))	('sunitinib uptake', 'MPA', (34, 50))	('higher', 'PosReg', (27, 33))	('blockage', 'Var', (6, 14))
93501	29896907	Our results demonstrate that combined targeted therapy with sunitinib and ABCC2 blocker in PRCC2 has therapeutic potential.	('PRCC', 'Gene', (91, 95))	('blocker', 'Var', (80, 87))	('ABCC2', 'Gene', (74, 79))	('sunitinib', 'Chemical', 'MESH:D000077210', (60, 69))	('PRCC', 'Gene', '5546', (91, 95))
93527	29896907	Blockage of ABCC2 in addition to the standard first-line therapies of metastatic RCCs might be of added benefit to the tumor treatment.	('metastatic RCCs', 'Disease', (70, 85))	('ABCC2', 'Gene', (12, 17))	('tumor', 'Disease', (119, 124))	('Blockage', 'Var', (0, 8))	('benefit', 'PosReg', (104, 111))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
93579	29896907	The group of cells treated with MK571 only also showed a considerable reduction in cell viability.	('MK571', 'Var', (32, 37))	('cell viability', 'CPA', (83, 97))	('MK571', 'Chemical', 'MESH:C059141', (32, 37))	('reduction', 'NegReg', (70, 79))
93586	29896907	MK571-treated cells showed considerable dye uptake (indicating dye retention), whereas untreated cells failed to stain indicating an active export of the Hoescht dye by ABCC2.	('dye uptake', 'MPA', (40, 50))	('export', 'MPA', (140, 146))	('uptake', 'biological_process', 'GO:0098657', ('44', '50'))	('uptake', 'biological_process', 'GO:0098739', ('44', '50'))	('MK571-treated', 'Var', (0, 13))	('MK571', 'Chemical', 'MESH:C059141', (0, 5))	('retention', 'biological_process', 'GO:0051235', ('67', '76'))
93589	29896907	The results show a near doubling of the uptake of sunitinib after the addition of MK571, from 28 044 median fluorescence intensity (MFI) to 54 421 MFI (Fig.	('uptake', 'MPA', (40, 46))	('MK571', 'Var', (82, 87))	('sunitinib', 'Chemical', 'MESH:D000077210', (50, 59))	('MK571', 'Chemical', 'MESH:C059141', (82, 87))	('uptake', 'biological_process', 'GO:0098657', ('40', '46'))	('uptake', 'biological_process', 'GO:0098739', ('40', '46'))
93597	29896907	Similar to what was observed in vitro, the best tumor response (final tumor size and tumor rate of growth) was observed in the group that was exposed to the sunitinib and MK571 treatment (Fig.	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('MK571', 'Var', (171, 176))	('MK571', 'Chemical', 'MESH:C059141', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('sunitinib', 'Chemical', 'MESH:D000077210', (157, 166))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
93602	29896907	The sunitinib + MK571 group showed the highest level of apoptosis (mean 43.125%), which was significantly higher (P = 0.0045) compared to other treatment groups (Fig.	('sunitinib', 'Chemical', 'MESH:D000077210', (4, 13))	('higher', 'PosReg', (106, 112))	('MK571', 'Var', (16, 21))	('MK571', 'Chemical', 'MESH:C059141', (16, 21))	('apoptosis', 'biological_process', 'GO:0097194', ('56', '65'))	('apoptosis', 'CPA', (56, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('56', '65'))
93625	29896907	We hypothesized that blocking ABCC2 would enhance the cancer response to the current first-line therapy (VEGF TKI, e.g., sunitinib) (Tivnan et al., 2015).	('ABCC2', 'Gene', (30, 35))	('enhance', 'PosReg', (42, 49))	('blocking', 'Var', (21, 29))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('sunitinib', 'Chemical', 'MESH:D000077210', (121, 130))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
93637	29896907	Contrarily ABCC2-low RCC cell lines (CAL-54) did not show an increase in sunitinib uptake upon ABCC2 blockage.	('ABCC2', 'Gene', (95, 100))	('sunitinib', 'Chemical', 'MESH:D000077210', (73, 82))	('blockage', 'Var', (101, 109))	('uptake', 'biological_process', 'GO:0098739', ('83', '89'))	('sunitinib uptake', 'MPA', (73, 89))	('uptake', 'biological_process', 'GO:0098657', ('83', '89'))
93638	29896907	The results ascertain what was shown in other studies regarding an increase in drug uptake upon ABC transporter blockage, especially in cancer with a high level of transporters (S. Shukla et al., 2011).	('ABC', 'Gene', (96, 99))	('ABC transporter', 'molecular_function', 'GO:0140359', ('96', '111'))	('drug uptake', 'MPA', (79, 90))	('ABC', 'Gene', '10058', (96, 99))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('increase', 'PosReg', (67, 75))	('cancer', 'Disease', (136, 142))	('blockage', 'Var', (112, 120))	('uptake', 'biological_process', 'GO:0098739', ('84', '90'))	('uptake', 'biological_process', 'GO:0098657', ('84', '90'))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
93645	29896907	Interestingly, ABCC2 blockage alone by MK571 also affected the PRCC2 cell line growth both in vitro and in vivo, in keeping with emerging evidence suggesting that ABC transporters contribute to tumor growth in ways beyond drug efflux (Fletcher et al., 2010; Nozaki et al., 2010).	('PRCC', 'Gene', '5546', (63, 67))	('ABC', 'Gene', (163, 166))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('ABC', 'Gene', '10058', (15, 18))	('PRCC', 'Gene', (63, 67))	('MK571', 'Var', (39, 44))	('MK571', 'Chemical', 'MESH:C059141', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('efflux', 'biological_process', 'GO:0140115', ('227', '233'))	('ABC', 'Gene', (15, 18))	('blockage', 'NegReg', (21, 29))	('tumor', 'Disease', (194, 199))	('ABC', 'Gene', '10058', (163, 166))	('efflux', 'biological_process', 'GO:0140352', ('227', '233'))	('contribute', 'Reg', (180, 190))	('affected', 'Reg', (50, 58))
93657	29896907	in the SUPAP trial assessing the effect of sunitinib treatment only on the two PRCC subtypes found slightly superior benefit with type 1 versus the type 2 (better partial response, longer stable disease, and overall survival).	('PRCC', 'Gene', '5546', (79, 83))	('partial', 'NegReg', (163, 170))	('PRCC', 'Gene', (79, 83))	('sunitinib', 'Chemical', 'MESH:D000077210', (43, 52))	('type', 'Var', (130, 134))
93673	29396852	Mechanism dissection revealed that miR-32-5p could suppress TR4 protein expression levels via direct binding to the 3'UTR of TR4 mRNA, and TR4 might then alter the HGF/Met signaling at the transcriptional regulation via direct binding to the TR4-response-elements (TR4RE) on the HGF promoter.	('TR4', 'Protein', (60, 63))	('suppress', 'NegReg', (51, 59))	('-32-5p', 'Chemical', '-', (38, 44))	('signaling', 'biological_process', 'GO:0023052', ('172', '181'))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('binding', 'molecular_function', 'GO:0005488', ('227', '234'))	('alter', 'Reg', (154, 159))	('regulation', 'biological_process', 'GO:0065007', ('205', '215'))	('HGF/Met signaling', 'MPA', (164, 181))	('binding', 'Interaction', (227, 234))	('miR-32-5p', 'Var', (35, 44))	('binding', 'Interaction', (101, 108))	('binding', 'molecular_function', 'GO:0005488', ('101', '108'))	('TR4', 'Var', (139, 142))
93674	29396852	Then the in vitro data also demonstrated the efficacy of Sunitinib, a currently used drug to treat ccRCC, could be increased after targeting this newly identified miR-32-5p/TR4/HGF/Met signaling.	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('increased', 'PosReg', (115, 124))	('Sunitinib', 'Chemical', 'MESH:D000077210', (57, 66))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('RCC', 'Disease', (101, 104))	('signaling', 'biological_process', 'GO:0023052', ('185', '194'))	('efficacy', 'MPA', (45, 53))	('-32-5p', 'Chemical', '-', (166, 172))	('miR-32-5p/TR4/HGF/Met', 'Var', (163, 184))
93687	29396852	We also demonstrated miR-32-5p might suppress ccRCC metastasis via suppressing the TR4/HGF/Met signaling.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('-32-5p', 'Chemical', '-', (24, 30))	('TR4/HGF/Met signaling', 'MPA', (83, 104))	('miR-32-5p', 'Var', (21, 30))	('suppress', 'NegReg', (37, 45))	('signaling', 'biological_process', 'GO:0023052', ('95', '104'))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('suppressing', 'NegReg', (67, 78))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
93701	29396852	), Bi-Phospho-MET/HGFR (Y1234/Y1235) (AM1000a, One World Lab.	('HGFR', 'Gene', (18, 22))	('HGFR', 'Gene', '4233', (18, 22))	('Y1234/Y1235) (AM1000a', 'Var', (24, 45))
93705	29396852	959 bp fragments of TR4 3'UTR containing wild type or mutant miRNA-responsive elements were cloned into the psiCHECK -2 vector construct (Promega) downstream of the Renilla luciferase ORF.	('TR4', 'Gene', (20, 23))	('Renilla luciferase ORF', 'Disease', (165, 187))	('mutant', 'Var', (54, 60))	('Renilla luciferase ORF', 'Disease', 'None', (165, 187))
93708	29396852	OSRC-2 cells expressing Luciferase and expressing pLKO.1-shTR4, pLKO.1-scramble, or pLVTHM-miR-32-5p (2X106) were injected into the left renal capsule of 6-week-old male athymic nude mice (NCI) (n = 8 mice per group).	('OSRC-2', 'CellLine', 'CVCL:1901', (0, 6))	('pLKO.1-shTR4', 'Var', (50, 62))	('mice', 'Species', '10090', (183, 187))	('-32-5p', 'Chemical', '-', (94, 100))	('mice', 'Species', '10090', (201, 205))	('nude mice', 'Species', '10090', (178, 187))	('capsule', 'cellular_component', 'GO:0042603', ('143', '150'))	('pLKO.1-scramble', 'Var', (64, 79))
93725	29396852	The results revealed that adding TR4-cDNA led to significantly increase the invasion capacity of the ACHN cells that have lower endogenous TR4 (Fig.	('TR4-cDNA', 'Var', (33, 41))	('increase', 'PosReg', (63, 71))	('ACHN', 'Gene', (101, 105))	('ACHN', 'Gene', '55323', (101, 105))
93726	29396852	2A), and knocking-down TR4 could significantly decrease the invasion capacity of the OSRC-2 cells that have higher endogenous TR4 (Fig.	('knocking-down', 'Var', (9, 22))	('TR4', 'Gene', (23, 26))	('endogenous', 'MPA', (115, 125))	('decrease', 'NegReg', (47, 55))	('OSRC-2', 'CellLine', 'CVCL:1901', (85, 91))	('higher', 'PosReg', (108, 114))	('invasion capacity of the OSRC-2 cells', 'CPA', (60, 97))
93728	29396852	We also replaced the Matrigel-coated Transwell invasion assay with the 3D invasion assay to confirm the above findings and results revealed that adding TR4-cDNA increased the cell invasion in ACHN cells (Fig.	('TR4-cDNA', 'Var', (152, 160))	('increased', 'PosReg', (161, 170))	('ACHN', 'Gene', (192, 196))	('ACHN', 'Gene', '55323', (192, 196))
93729	29396852	2C) and knocking-down TR4 with TR4-shRNA decreased the cell invasion in OSRC-2 cells (Fig.	('cell invasion in OSRC-2 cells', 'CPA', (55, 84))	('knocking-down', 'Var', (8, 21))	('decreased', 'NegReg', (41, 50))	('TR4', 'Gene', (22, 25))	('OSRC-2', 'CellLine', 'CVCL:1901', (72, 78))
93730	29396852	Finally, results from wound healing assays also indicated that adding TR4-cDNA increased the cell migration in ACHN cells (Fig.	('ACHN', 'Gene', (111, 115))	('increased', 'PosReg', (79, 88))	('wound healing', 'biological_process', 'GO:0042060', ('22', '35'))	('ACHN', 'Gene', '55323', (111, 115))	('cell migration', 'biological_process', 'GO:0016477', ('93', '107'))	('TR4-cDNA', 'Var', (70, 78))
93731	29396852	2E), and knocking-down TR4 decreased the cell migration in OSRC-2 and SW839 cells (Fig.	('OSRC-2', 'CellLine', 'CVCL:1901', (59, 65))	('knocking-down', 'Var', (9, 22))	('decreased', 'NegReg', (27, 36))	('cell migration', 'biological_process', 'GO:0016477', ('41', '55'))	('SW839', 'CellLine', 'CVCL:3604', (70, 75))	('cell migration in OSRC-2', 'CPA', (41, 65))	('TR4', 'Gene', (23, 26))
93736	29396852	We then confirmed the above results at the protein level showing adding TR4-cDNA led to increase the expression of HGF and phospho-Met with unchanged total-Met expression in ACHN cells (Fig.	('TR4-cDNA', 'Var', (72, 80))	('ACHN', 'Gene', '55323', (174, 178))	('total-Met expression', 'MPA', (150, 170))	('increase', 'PosReg', (88, 96))	('ACHN', 'Gene', (174, 178))	('HGF', 'Protein', (115, 118))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('expression', 'MPA', (101, 111))	('phospho-Met', 'MPA', (123, 134))
93737	29396852	In contrast, knocking-down TR4 with TR4-shRNA led to significantly decreased HGF and phospho-Met with unchanged total-Met expression in OSRC-2 cells (Fig.	('TR4', 'Gene', (27, 30))	('decreased', 'NegReg', (67, 76))	('HGF', 'MPA', (77, 80))	('total-Met expression', 'MPA', (112, 132))	('OSRC-2', 'CellLine', 'CVCL:1901', (136, 142))	('phospho-Met', 'MPA', (85, 96))	('knocking-down', 'Var', (13, 26))	('TR4-shRNA', 'Var', (36, 45))
93738	29396852	As early studies indicated that HGF/Met signaling might promote cancer cell migration and invasion via elevating MMP2/MMP9 expression, we also assayed these potential downstream signals, and results revealed that adding TR4-cDNA led to increase the expression of MMP2 and MMP9 in ACHN cells and knocking-down TR4 with TR4-shRNA suppressed the expression of MMP2 and MMP9 in OSRC-2 cells (Fig.	('expression', 'MPA', (123, 133))	('ACHN', 'Gene', (280, 284))	('OSRC-2', 'CellLine', 'CVCL:1901', (374, 380))	('MMP2', 'Gene', (113, 117))	('expression', 'MPA', (249, 259))	('MMP2', 'molecular_function', 'GO:0004228', ('357', '361'))	('cancer', 'Disease', (64, 70))	('MMP9', 'Gene', (118, 122))	('increase', 'PosReg', (236, 244))	('TR4-cDNA', 'Var', (220, 228))	('MMP2', 'Gene', (263, 267))	('promote', 'PosReg', (56, 63))	('MMP9', 'Gene', '4318', (118, 122))	('MMP2', 'Gene', (357, 361))	('invasion', 'CPA', (90, 98))	('ACHN', 'Gene', '55323', (280, 284))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('MMP2', 'Gene', '4313', (113, 117))	('MMP9', 'molecular_function', 'GO:0004229', ('366', '370'))	('signaling', 'biological_process', 'GO:0023052', ('40', '49'))	('knocking-down', 'Var', (295, 308))	('cell migration', 'biological_process', 'GO:0016477', ('71', '85'))	('MMP9', 'molecular_function', 'GO:0004229', ('272', '276'))	('elevating', 'PosReg', (103, 112))	('MMP9', 'Gene', (272, 276))	('MMP2', 'Gene', '4313', (263, 267))	('MMP9', 'Gene', '4318', (272, 276))	('MMP9', 'molecular_function', 'GO:0004229', ('118', '122'))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('MMP2', 'Gene', '4313', (357, 361))	('MMP2', 'molecular_function', 'GO:0004228', ('113', '117'))	('MMP2', 'molecular_function', 'GO:0004228', ('263', '267'))	('MMP9', 'Gene', '4318', (366, 370))	('MMP9', 'Gene', (366, 370))
93739	29396852	Similar results were also obtained in SW839 cells showing knocking-down TR4 suppressed HGF/Met/MMP2-MMP9 signaling (Supplementary Fig.	('MMP9', 'molecular_function', 'GO:0004229', ('100', '104'))	('SW839', 'CellLine', 'CVCL:3604', (38, 43))	('MMP2-MMP9', 'Gene', (95, 104))	('MMP2-MMP9', 'Gene', '4313;4318', (95, 104))	('suppressed', 'NegReg', (76, 86))	('TR4', 'Gene', (72, 75))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('MMP2', 'molecular_function', 'GO:0004228', ('95', '99'))	('knocking-down', 'Var', (58, 71))
93743	29396852	We then constructed the HGF promoter luciferase reporter by inserting a 1 kb 5' promoter region of HGF containing either wild-type or mutated TR4RE into the pGL3 luciferase backbone (Fig.	('pGL3', 'Gene', '6391', (157, 161))	('mutated', 'Var', (134, 141))	('TR4RE', 'Gene', (142, 147))	('pGL3', 'Gene', (157, 161))	('pGL', 'molecular_function', 'GO:0004598', ('157', '160'))
93744	29396852	3I), and results revealed that adding TR4-cDNA significantly increased luciferase activity in ACHN and OSRC-2 cells with wild type and not mutated TR4RE (Fig.	('OSRC-2', 'CellLine', 'CVCL:1901', (103, 109))	('luciferase activity', 'molecular_function', 'GO:0047077', ('71', '90'))	('ACHN', 'Gene', (94, 98))	('luciferase', 'Enzyme', (71, 81))	('luciferase activity', 'molecular_function', 'GO:0045289', ('71', '90'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('71', '90'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('71', '90'))	('increased', 'PosReg', (61, 70))	('activity', 'MPA', (82, 90))	('luciferase activity', 'molecular_function', 'GO:0050397', ('71', '90'))	('ACHN', 'Gene', '55323', (94, 98))	('TR4-cDNA', 'Var', (38, 46))
93746	29396852	We then focused on 6 miRNAs whose expression were down-regulated in patients with distant metastasis based on the data from Wotschofsky Z', s microarray, and results from these miRNAs effects on TR4 expression found altering the miR-32-5p led to decrease TR4 expression in both ccRCC cell lines (Fig.	('miR-32-5p', 'Var', (229, 238))	('decrease', 'NegReg', (246, 254))	('TR4', 'Gene', (255, 258))	('RCC', 'Disease', 'MESH:C538614', (280, 283))	('RCC', 'Disease', (280, 283))	('RCC', 'Phenotype', 'HP:0005584', (280, 283))	('patients', 'Species', '9606', (68, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (278, 283))	('-32-5p', 'Chemical', '-', (232, 238))	('expression', 'MPA', (259, 269))	('down-regulated', 'NegReg', (50, 64))
93747	29396852	Importantly, treating with mir-32-5p inhibitor (5 nmol/L, MIN0000090, Qiagen) resulted in an increase of TR4 mRNA in ACHN cells and a decreased TR4 mRNA expression after adding the miR-32-5p in OSRC-2 and SW839 cells (Supplementary Fig.	('decreased', 'NegReg', (134, 143))	('mir-32', 'Gene', (27, 33))	('ACHN', 'Gene', (117, 121))	('OSRC-2', 'CellLine', 'CVCL:1901', (194, 200))	('increase', 'PosReg', (93, 101))	('-32-5p', 'Chemical', '-', (184, 190))	('TR4 mRNA expression', 'MPA', (144, 163))	('mir-32', 'Gene', '407036', (27, 33))	('ACHN', 'Gene', '55323', (117, 121))	('SW839', 'CellLine', 'CVCL:3604', (205, 210))	('MIN0000090', 'Var', (58, 68))	('-32-5p', 'Chemical', '-', (30, 36))
93748	29396852	Results from a clinical sample survey also revealed a significant negative correlation (r=-0.5521, p=0.0142), using the Pearson correlation coefficient, between the expression of miR-32-5p and TR4 in 19 ccRCC patient specimens (Fig.	('-32-5p', 'Chemical', '-', (182, 188))	('patient', 'Species', '9606', (209, 216))	('RCC', 'Disease', (205, 208))	('RCC', 'Phenotype', 'HP:0005584', (205, 208))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('miR-32-5p', 'Var', (179, 188))	('TR4', 'Gene', (193, 196))	('ccRCC', 'Phenotype', 'HP:0006770', (203, 208))	('negative', 'NegReg', (66, 74))
93750	29396852	Similar results also occurred showing a negative correlation between miR-32-5p and TR4 expression in multiple ccRCC cell lines (Fig.	('-32-5p', 'Chemical', '-', (72, 78))	('TR4', 'Gene', (83, 86))	('miR-32-5p', 'Var', (69, 78))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))	('negative', 'NegReg', (40, 48))
93754	29396852	We also applied the Matrigel-coated Transwell invasion assay to confirm the consequence of miR-32-5p expression, and results revealed that knocking-down miR-32-5p significantly promoted ACHN cells invasion (Fig.	('promoted', 'PosReg', (177, 185))	('knocking-down', 'Var', (139, 152))	('ACHN', 'Gene', (186, 190))	('miR-32-5p', 'Gene', (153, 162))	('-32-5p', 'Chemical', '-', (94, 100))	('-32-5p', 'Chemical', '-', (156, 162))	('ACHN', 'Gene', '55323', (186, 190))
93757	29396852	Wound healing assays also indicated that knocking-down miR-32-5p promoted cell invasion in ACHN cells (Fig.	('miR-32-5p', 'Gene', (55, 64))	('-32-5p', 'Chemical', '-', (58, 64))	('ACHN', 'Gene', '55323', (91, 95))	('Wound healing', 'biological_process', 'GO:0042060', ('0', '13'))	('promoted', 'PosReg', (65, 73))	('ACHN', 'Gene', (91, 95))	('knocking-down', 'Var', (41, 54))
93758	29396852	4I) and adding miR-32-5p decreased cell migration in OSRC-2 (Fig.	('miR-32-5p', 'Var', (15, 24))	('OSRC-2', 'Disease', (53, 59))	('decreased', 'NegReg', (25, 34))	('OSRC-2', 'CellLine', 'CVCL:1901', (53, 59))	('-32-5p', 'Chemical', '-', (18, 24))	('cell migration in', 'CPA', (35, 52))	('cell migration', 'biological_process', 'GO:0016477', ('35', '49'))
93761	29396852	To further link the miR-32-5p-suppressed TR4 to the TR4/ HGF/Met/MMP2-MMP9 signaling for altering the ccRCC metastasis, we first confirmed that knocking-down miR-32-5p increased the expression of TR4, HGF, and phosphorylated-Met (phospho-Met) expression with little impact on the total-Met expression in ACHN cells (Fig.	('-32-5p', 'Chemical', '-', (23, 29))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('ACHN', 'Gene', (304, 308))	('MMP9', 'molecular_function', 'GO:0004229', ('70', '74'))	('MMP2', 'molecular_function', 'GO:0004228', ('65', '69'))	('RCC', 'Disease', (104, 107))	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('ACHN', 'Gene', '55323', (304, 308))	('TR4', 'Gene', (196, 199))	('-32-5p', 'Chemical', '-', (161, 167))	('expression', 'MPA', (182, 192))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('MMP2-MMP9', 'Gene', '4313;4318', (65, 74))	('knocking-down', 'Var', (144, 157))	('increased', 'PosReg', (168, 177))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('MMP2-MMP9', 'Gene', (65, 74))	('HGF', 'Protein', (201, 204))	('miR-32-5p', 'Gene', (158, 167))
93764	29396852	As expected, altering the miR-32-5p expression also led to regulate the gene expression of MMP2 and MMP9, the downstream targets of the TR4/HGF/Met axis (Fig.	('MMP2', 'Gene', (91, 95))	('MMP9', 'Gene', (100, 104))	('MMP9', 'molecular_function', 'GO:0004229', ('100', '104'))	('MMP9', 'Gene', '4318', (100, 104))	('MMP2', 'Gene', '4313', (91, 95))	('-32-5p', 'Chemical', '-', (29, 35))	('miR-32-5p', 'Protein', (26, 35))	('MMP2', 'molecular_function', 'GO:0004228', ('91', '95'))	('regulate', 'Reg', (59, 67))	('gene expression', 'MPA', (72, 87))	('gene expression', 'biological_process', 'GO:0010467', ('72', '87'))	('altering', 'Var', (13, 21))
93765	29396852	Importantly, using the rescue assay, we found knocking-down TR4 could partially block the cell invasion induced by miR-32-5p inhibitor in ACHN cells and adding TR4-cDNA could partially reverse the miR-32-5p-suppressed cell invasion in OSRC-2 cells (Fig.	('ACHN', 'Gene', (138, 142))	('cell invasion in OSRC-2', 'CPA', (218, 241))	('knocking-down', 'Var', (46, 59))	('-32-5p', 'Chemical', '-', (200, 206))	('cell invasion', 'CPA', (90, 103))	('block', 'NegReg', (80, 85))	('OSRC-2', 'CellLine', 'CVCL:1901', (235, 241))	('-32-5p', 'Chemical', '-', (118, 124))	('TR4', 'Gene', (60, 63))	('ACHN', 'Gene', '55323', (138, 142))
93766	29396852	Knocking down TR4 could also partially block the HGF and phospho-Met expression induced by miR-32-5p inhibitor in ACHN cells (Fig.	('ACHN', 'Gene', '55323', (114, 118))	('Knocking down', 'Var', (0, 13))	('TR4', 'Gene', (14, 17))	('phospho-Met expression', 'MPA', (57, 79))	('ACHN', 'Gene', (114, 118))	('-32-5p', 'Chemical', '-', (94, 100))	('block', 'NegReg', (39, 44))	('HGF', 'MPA', (49, 52))
93767	29396852	5C) and adding TR4 could partially revers the miR-32-5p-suppressed HGF and phospho-Met expression in OSRC-2 cells, with little influence on the total Met expression in both cells (Fig.	('phospho-Met expression', 'MPA', (75, 97))	('OSRC-2', 'CellLine', 'CVCL:1901', (101, 107))	('-32-5p', 'Chemical', '-', (49, 55))	('revers', 'NegReg', (35, 41))	('miR-32-5p-suppressed', 'Var', (46, 66))	('HGF', 'MPA', (67, 70))
93768	29396852	S6A suggest that miR-32-5p suppressed ccRCC cells invasion via altering the TR4/, HGF/Met/MMP2-MMP9 signaling.	('-32-5p', 'Chemical', '-', (20, 26))	('RCC', 'Disease', (40, 43))	('altering', 'Reg', (63, 71))	('suppressed', 'NegReg', (27, 37))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('MMP2', 'molecular_function', 'GO:0004228', ('90', '94'))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('miR-32-5p', 'Var', (17, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('MMP9', 'molecular_function', 'GO:0004229', ('95', '99'))	('MMP2-MMP9', 'Gene', (90, 99))	('MMP2-MMP9', 'Gene', '4313;4318', (90, 99))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))
93773	29396852	5F), and adding miR-32-5p markedly decreased luciferase activity in OSRC-2 cells transfected with wild type TR4 3'UTR, but not the mutant TR4 3'UTR (Fig.	('miR-32-5p', 'Var', (16, 25))	('luciferase activity', 'molecular_function', 'GO:0047077', ('45', '64'))	('activity', 'MPA', (56, 64))	('luciferase activity', 'molecular_function', 'GO:0045289', ('45', '64'))	('decreased', 'NegReg', (35, 44))	('luciferase activity', 'molecular_function', 'GO:0047712', ('45', '64'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('45', '64'))	('OSRC-2', 'CellLine', 'CVCL:1901', (68, 74))	('-32-5p', 'Chemical', '-', (19, 25))	('luciferase activity', 'molecular_function', 'GO:0050397', ('45', '64'))	('luciferase', 'Enzyme', (45, 55))
93776	29396852	To confirm all above in vitro cell lines data in the in vivo mouse model, we prepared orthotopic xenografts of OSRC-2 cells with luciferase expression and with/without shTR4 or miR-32-5p.	('miR-32-5p', 'Var', (177, 186))	('-32-5p', 'Chemical', '-', (180, 186))	('luciferase', 'Enzyme', (129, 139))	('mouse', 'Species', '10090', (61, 66))	('OSRC-2', 'CellLine', 'CVCL:1901', (111, 117))
93780	29396852	Importantly, our IHC staining from these ccRCC xenografts also demonstrated that OSCR-2-Luc-miR-32-5p tumors had a lower TR4 expression compared to tumors from the OSCR-2-Luc control group and the tumors from the OSCR-2-Luc miR-32-5p group.	('-32-5p', 'Chemical', '-', (227, 233))	('lower', 'NegReg', (115, 120))	('OSCR-2-Luc-miR-32-5p', 'Var', (81, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('RCC', 'Disease', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('tumors', 'Disease', (197, 203))	('tumors', 'Disease', (102, 108))	('expression', 'MPA', (125, 135))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('TR4', 'Protein', (121, 124))	('tumors', 'Disease', (148, 154))	('-32-5p', 'Chemical', '-', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (148, 154))
93782	29396852	6A-F) demonstrate that targeting this newly identified miR-32-5p/TR4/HGF/Met signaling with small molecules including the TR4-shRNA or miR-32-5p can suppress ccRCC metastasis.	('-32-5p', 'Chemical', '-', (58, 64))	('suppress', 'NegReg', (149, 157))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('ccRCC', 'Phenotype', 'HP:0006770', (158, 163))	('RCC', 'Disease', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('-32-5p', 'Chemical', '-', (138, 144))	('miR-32-5p', 'Var', (135, 144))	('signaling', 'biological_process', 'GO:0023052', ('77', '86'))
93783	29396852	Interestingly, we found this newly identified miR-32-5p/TR4/HGF/Met signaling might also impact the current Sunitinib-chemotherapy to suppress the ccRCC.	('RCC', 'Disease', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('impact', 'NegReg', (89, 95))	('-32-5p', 'Chemical', '-', (49, 55))	('RCC', 'Disease', 'MESH:C538614', (149, 152))	('ccRCC', 'Phenotype', 'HP:0006770', (147, 152))	('suppress', 'NegReg', (134, 142))	('miR-32-5p/TR4/HGF/Met', 'Var', (46, 67))	('Sunitinib', 'Chemical', 'MESH:D000077210', (108, 117))	('signaling', 'biological_process', 'GO:0023052', ('68', '77'))
93790	29396852	We provided the first preclinical evidence showing targeting the newly identified miR-32-5p/TR4/HGF/Met signaling with small molecules including miR-32-5p or TR4-shRNA could further suppress the ccRCC metastasis.	('miR-32-5p/TR4/HGF/Met', 'Var', (82, 103))	('RCC', 'Phenotype', 'HP:0005584', (197, 200))	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))	('RCC', 'Disease', 'MESH:C538614', (197, 200))	('ccRCC', 'Phenotype', 'HP:0006770', (195, 200))	('RCC', 'Disease', (197, 200))	('-32-5p', 'Chemical', '-', (148, 154))	('suppress', 'NegReg', (182, 190))	('-32-5p', 'Chemical', '-', (85, 91))	('TR4-shRNA', 'Var', (158, 167))	('miR-32-5p', 'Var', (145, 154))
93795	29396852	While our results from ccRCC cell lines suggest that the HGF/Met signaling may function through autocrine signaling to promote ccRCC cell invasion/migration, it is possible that upon activation via phosphorylation or gene amplification of Met, the HGF/Met signaling can also function through a paracrine axis involving cancer-associated fibroblasts and endothelium to influence the ccRCC metastasis.	('autocrine signaling', 'biological_process', 'GO:0035425', ('96', '115'))	('RCC', 'Disease', (384, 387))	('cancer', 'Disease', (319, 325))	('RCC', 'Phenotype', 'HP:0005584', (384, 387))	('ccRCC', 'Phenotype', 'HP:0006770', (382, 387))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('promote', 'PosReg', (119, 126))	('RCC', 'Disease', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('RCC', 'Disease', 'MESH:C538614', (384, 387))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('RCC', 'Disease', (25, 28))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))	('ccRCC', 'Phenotype', 'HP:0006770', (23, 28))	('activation', 'PosReg', (183, 193))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('influence', 'Reg', (368, 377))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('gene amplification', 'Var', (217, 235))	('phosphorylation', 'biological_process', 'GO:0016310', ('198', '213'))	('signaling', 'biological_process', 'GO:0023052', ('256', '265'))	('Met', 'Gene', (239, 242))
93799	29396852	Our finding that miR-32-5p might function as an metastasis suppressor in ccRCC via directly targeting the 3'UTR of TR4 to suppress the TR4-HGF/Met signaling is interesting since earlier studies suggested miR-32 could also function as an oncogene to promote PCa and colorectal carcinoma progression.	('-32-5p', 'Chemical', '-', (20, 26))	('promote', 'PosReg', (249, 256))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (265, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('PCa', 'Disease', (257, 260))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('TR4-HGF/Met signaling', 'MPA', (135, 156))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('signaling', 'biological_process', 'GO:0023052', ('147', '156'))	('PCa', 'Phenotype', 'HP:0012125', (257, 260))	('TR4', 'Gene', (115, 118))	('miR-32', 'Var', (204, 210))	('suppress', 'NegReg', (122, 130))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))	('colorectal carcinoma', 'Disease', (265, 285))
93800	29396852	In summary, TR4 may up-regulate HGF/Met signaling to promote ccRCC metastasis and miR-32-5p may target TR4/HGF/Met signaling to suppress ccRCC metastasis.	('miR-32-5p', 'Var', (82, 91))	('RCC', 'Disease', (63, 66))	('HGF/Met signaling', 'MPA', (32, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('up-regulate', 'PosReg', (20, 31))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('RCC', 'Disease', (139, 142))	('promote', 'PosReg', (53, 60))	('signaling', 'biological_process', 'GO:0023052', ('40', '49'))	('signaling', 'biological_process', 'GO:0023052', ('115', '124'))	('target', 'Reg', (96, 102))	('TR4', 'Gene', (12, 15))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('-32-5p', 'Chemical', '-', (85, 91))	('suppress', 'NegReg', (128, 136))
93801	29396852	Using small molecules including TR4-shRNA or miR-32-5p may help to potentially develop new therapies to better suppress the ccRCC metastasis.	('suppress', 'NegReg', (111, 119))	('-32-5p', 'Chemical', '-', (48, 54))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (124, 129))	('RCC', 'Disease', (126, 129))	('miR-32-5p', 'Var', (45, 54))	('RCC', 'Disease', 'MESH:C538614', (126, 129))
93804	29396852	Finally, we demonstrated that targeting this newly identified signaling with small molecules including miR-32-5p or TR4-shRNA can further suppress ccRCC metastasis, as well as alter the Sunitinib-chemotherapy efficacy to suppress the ccRCC metastasis.	('RCC', 'Disease', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('suppress', 'NegReg', (138, 146))	('TR4-shRNA', 'Var', (116, 125))	('Sunitinib', 'Chemical', 'MESH:D000077210', (186, 195))	('RCC', 'Disease', (236, 239))	('suppress', 'NegReg', (221, 229))	('RCC', 'Phenotype', 'HP:0005584', (236, 239))	('RCC', 'Disease', 'MESH:C538614', (236, 239))	('ccRCC', 'Phenotype', 'HP:0006770', (234, 239))	('signaling', 'biological_process', 'GO:0023052', ('62', '71'))	('miR-32-5p', 'Var', (103, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (147, 152))	('alter', 'Reg', (176, 181))	('RCC', 'Disease', 'MESH:C538614', (149, 152))	('-32-5p', 'Chemical', '-', (106, 112))
93808	31863007	Notably, mutations on key residues of BD4 disrupt recognition of p53 K382Ac.	('BD4', 'Gene', (38, 41))	('disrupt', 'NegReg', (42, 49))	('p53 K382Ac', 'Var', (65, 75))	('mutations', 'Var', (9, 18))	('K382Ac', 'Chemical', '-', (69, 75))	('recognition', 'MPA', (50, 61))	('BD4', 'Chemical', '-', (38, 41))
93809	31863007	The mutation in BD4 also reduces p53 binding to promoters of target genes such as CDKN1A (p21).	('binding', 'Interaction', (37, 44))	('p53 binding', 'molecular_function', 'GO:0002039', ('33', '44'))	('reduces', 'NegReg', (25, 32))	('p53', 'Protein', (33, 36))	('BD4', 'Chemical', '-', (16, 19))	('CDKN1A', 'Gene', (82, 88))	('mutation', 'Var', (4, 12))	('BD4', 'Gene', (16, 19))	('CDKN1A', 'Gene', '1026', (82, 88))
93810	31863007	Consequently, the PBRM1 BD4 mutant fails to fully support p53 transcriptional activity and is defective as a tumor suppressor.	('tumor suppressor', 'biological_process', 'GO:0051726', ('109', '125'))	('mutant', 'Var', (28, 34))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('109', '125'))	('PBRM1 BD4', 'Gene', (18, 27))	('fails', 'NegReg', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('p53', 'Protein', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))	('BD4', 'Chemical', '-', (24, 27))
93814	31863007	Here, the authors show that PBRM1 is a reader protein for p53's C-terminal domain acetylation on lysine 382 through its bromodomain 4 and that mutations in this domain leads to compromised tumour suppressive function and renal tumour growth.	('tumour', 'Phenotype', 'HP:0002664', (227, 233))	('lysine', 'Chemical', 'MESH:D008239', (97, 103))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('acetylation on lysine 382', 'MPA', (82, 107))	('renal tumour', 'Phenotype', 'HP:0009726', (221, 233))	('mutations in', 'Var', (143, 155))	('compromised', 'NegReg', (177, 188))	('tumour suppressive function and renal tumour', 'Disease', 'MESH:D007680', (189, 233))
93817	31863007	p53 acetylation can be divided into two groups: acetylation on two lysine residues in p53's DNA-binding domain (K120 and K164), which directly affects its binding to DNA and acetylation on six lysine residues in p53's C-terminal domain (CTD) (K370, K372, K373, K381, K382, and K386), which regulates its transcriptional activity through interactions with other proteins, also known as acetylation 'readers'.	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('binding', 'Interaction', (155, 162))	('K164', 'Var', (121, 125))	('interactions', 'Interaction', (337, 349))	('K373', 'Var', (255, 259))	('K386', 'Var', (277, 281))	('K382', 'Chemical', '-', (267, 271))	('K372', 'Var', (249, 253))	('regulates', 'Reg', (290, 299))	('lysine', 'Chemical', 'MESH:D008239', (67, 73))	('transcriptional activity', 'MPA', (304, 328))	('p53', 'Gene', (86, 89))	('DNA', 'cellular_component', 'GO:0005574', ('166', '169'))	('K370', 'Var', (243, 247))	('binding', 'molecular_function', 'GO:0005488', ('155', '162'))	('K120', 'Var', (112, 116))	('lysine', 'Chemical', 'MESH:D008239', (193, 199))	('K381', 'Var', (261, 265))	('K382', 'Var', (267, 271))	('affects', 'Reg', (143, 150))	('DNA-binding', 'molecular_function', 'GO:0003677', ('92', '103'))
93820	31863007	In agreement with it being a pivotal TSG, around half of human tumors harbor mutations in TP53.	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('TP53', 'Gene', (90, 94))	('tumors', 'Disease', (63, 69))	('mutations', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('human', 'Species', '9606', (57, 62))
93821	31863007	Interestingly, clear cell Renal Cell Carcinoma (ccRCC), the most common subtype of kidney cancer, seems to be an exception: only a small subset of tumors harbor mutations in TP53 (~3%).	('Carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('kidney cancer', 'Disease', 'MESH:D007680', (83, 96))	('TP53', 'Gene', (174, 178))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('clear cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (15, 46))	('kidney cancer', 'Phenotype', 'HP:0009726', (83, 96))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('kidney cancer', 'Disease', (83, 96))	('clear cell Renal Cell Carcinoma', 'Disease', (15, 46))	('clear cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (15, 46))	('mutations', 'Var', (161, 170))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (26, 46))
93822	31863007	This suggests the possibility that p53 tumor suppressor function may be compromised by mutations of other genes in ccRCC tumors.	('p53', 'Gene', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('39', '55'))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor suppressor', 'biological_process', 'GO:0051726', ('39', '55'))	('ccRCC tumors', 'Disease', 'MESH:D009369', (115, 127))	('tumor', 'Disease', (39, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('mutations', 'Var', (87, 96))	('ccRCC tumors', 'Disease', (115, 127))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
93823	31863007	We investigated whether mutations in the Polybromo-1 gene (PBRM1) in ccRCC impaired the p53 pathway indirectly.	('ccRCC impaired', 'Disease', 'MESH:D060825', (69, 83))	('ccRCC impaired', 'Disease', (69, 83))	('Polybromo-1', 'Gene', (41, 52))	('PBRM1', 'Gene', (59, 64))	('Polybromo-1', 'Gene', '55193', (41, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (69, 74))	('p53 pathway', 'Pathway', (88, 99))	('mutations', 'Var', (24, 33))
93824	31863007	PBRM1 is mutated in approximately 40% of ccRCC tumors.	('ccRCC tumors', 'Disease', 'MESH:D009369', (41, 53))	('mutated', 'Var', (9, 16))	('PBRM1', 'Gene', (0, 5))	('ccRCC tumors', 'Disease', (41, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
93826	31863007	Its mutation amplifies the HIF-response and collaborates with Vhl mutation to generate ccRCC in mouse models.	('HIF-response', 'CPA', (27, 39))	('Vhl', 'Gene', '22346', (62, 65))	('mouse', 'Species', '10090', (96, 101))	('amplifies', 'PosReg', (13, 22))	('mutation', 'Var', (4, 12))	('Vhl', 'Gene', (62, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('ccRCC', 'Disease', (87, 92))
93827	31863007	A recent paper reported that the components of SWI/SNF complexes had an overall 20% mutation rate in cancer, which is the second most highly mutated entity next to p53.	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutation', 'Var', (84, 92))
93828	31863007	SWI/SNF mutations are also mutually exclusive with TP53 mutations in many cancer types.	('SWI/SNF', 'Gene', (0, 7))	('TP53', 'Gene', (51, 55))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('mutations', 'Var', (8, 17))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
93831	31863007	We find that BD4 of PBRM1 is critical for recognition of K382Ac on p53 and this is critical for PBRM1's tumor suppressor function.	('tumor suppressor', 'biological_process', 'GO:0051726', ('104', '120'))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('PBRM1', 'Gene', (20, 25))	('K382Ac', 'Var', (57, 63))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('104', '120'))	('K382Ac', 'Chemical', '-', (57, 63))	('tumor', 'Disease', (104, 109))	('p53', 'Gene', (67, 70))	('BD4', 'Chemical', '-', (13, 16))	('PBRM1', 'Gene', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
93839	31863007	Since p53's CTD contains several lysines that are acetylated upon DNA damage and BDs are putative acetylation readers, we reasoned that lysine acetylation may significantly boost the PBRM1-p53 interaction.	('lysine', 'Var', (136, 142))	('boost', 'PosReg', (173, 178))	('lysine', 'Chemical', 'MESH:D008239', (33, 39))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('interaction', 'Interaction', (193, 204))	('lysines', 'Chemical', 'MESH:D008239', (33, 40))	('lysine', 'Chemical', 'MESH:D008239', (136, 142))	('PBRM1-p53', 'Protein', (183, 192))
93846	31863007	K382Ac seems to be naturally occurring without the treatment of DNA damaging agents as it can be detected in the nucleus of cancer cells in human ccRCC tumors (Supplementary Fig.	('human', 'Species', '9606', (140, 145))	('cancer', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('nucleus', 'cellular_component', 'GO:0005634', ('113', '120'))	('ccRCC tumors', 'Disease', 'MESH:D009369', (146, 158))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('K382Ac', 'Var', (0, 6))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('K382Ac', 'Chemical', '-', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('ccRCC tumors', 'Disease', (146, 158))
93847	31863007	Moreover, a p53 6KR mutant, in which lysine residues 370, 372, 373, 381, 382 and 386 were mutated to arginine, failed to increase binding to PBRM1 in presence of p300 co-expression, despite similar basal binding to PBRM1 as wild-type p53 (Fig.	('binding', 'molecular_function', 'GO:0005488', ('130', '137'))	('increase', 'PosReg', (121, 129))	('p300', 'Gene', '2033', (162, 166))	('lysine', 'Chemical', 'MESH:D008239', (37, 43))	('binding', 'molecular_function', 'GO:0005488', ('204', '211'))	('p300', 'Gene', (162, 166))	('binding', 'Interaction', (204, 211))	('PBRM1', 'Gene', (141, 146))	('expression', 'Species', '29278', (170, 180))	('arginine', 'Chemical', 'MESH:D001120', (101, 109))	('failed', 'NegReg', (111, 117))	('binding', 'Interaction', (130, 137))	('lysine residues', 'Var', (37, 52))
93853	31863007	In both cases the p53 peptide with K382Ac showed higher affinity to PBRM1 than the non-acetylated peptide (Fig.	('affinity', 'Interaction', (56, 64))	('PBRM1', 'Gene', (68, 73))	('K382Ac', 'Var', (35, 41))	('higher', 'PosReg', (49, 55))	('K382Ac', 'Chemical', '-', (35, 41))
93854	31863007	2g, lane 7 vs. lane 2), suggesting that the bromodomians alone were sufficient for the enhanced binding to the p53 K382Ac peptide.	('binding', 'molecular_function', 'GO:0005488', ('96', '103'))	('binding', 'Interaction', (96, 103))	('p53 K382Ac', 'Var', (111, 121))	('enhanced', 'PosReg', (87, 95))	('K382Ac', 'Chemical', '-', (115, 121))
93855	31863007	Similarly, in two doubly acetylated peptides K372Ac/K382Ac and K373Ac/K382Ac, only K372Ac/K382Ac showed higher affinity to PBRM1 than the non-acetylated peptide and even the K382Ac peptide (Fig.	('affinity', 'Interaction', (111, 119))	('K373Ac', 'Chemical', '-', (63, 69))	('PBRM1', 'Gene', (123, 128))	('K382Ac', 'Chemical', '-', (174, 180))	('K372Ac/K382Ac', 'Var', (83, 96))	('K372Ac', 'Chemical', '-', (45, 51))	('K372Ac/K382Ac', 'Var', (45, 58))	('peptides', 'Chemical', 'MESH:D010455', (36, 44))	('K372Ac', 'Chemical', '-', (83, 89))	('K382Ac', 'Chemical', '-', (52, 58))	('higher', 'PosReg', (104, 110))	('K373Ac/K382Ac', 'Var', (63, 76))	('K382Ac', 'Chemical', '-', (70, 76))	('K382Ac', 'Chemical', '-', (90, 96))
93856	31863007	Moreover, although the basal bindings were similar, the p53 K382R mutant did not show a p300-dependent increase in binding to PBRM1 as did the wild-type p53 (Fig.	('p300', 'Gene', '2033', (88, 92))	('PBRM1', 'Gene', (126, 131))	('K382R', 'Mutation', 'p.K382R', (60, 65))	('binding', 'Interaction', (115, 122))	('p53 K382R', 'Var', (56, 65))	('p300', 'Gene', (88, 92))	('binding', 'molecular_function', 'GO:0005488', ('115', '122'))
93857	31863007	Altogether, these data suggest PBRM1 may recognize particular p53 acetylation pattern/code(s) containing K382Ac.	('K382Ac', 'Chemical', '-', (105, 111))	('acetylation', 'MPA', (66, 77))	('p53', 'Gene', (62, 65))	('K382Ac', 'Var', (105, 111))
93858	31863007	3a) and found that deletion up to and including BD4 significantly reduced the interaction between PBRM1 and p53 but not with other SWI/SNF complex components BRG1, BRD7, and BAF57 (Fig.	('PBRM1', 'Gene', (98, 103))	('reduced', 'NegReg', (66, 73))	('BRD7', 'Gene', '29117', (164, 168))	('BD4', 'Chemical', '-', (48, 51))	('BD4', 'Gene', (48, 51))	('p53', 'Gene', (108, 111))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('131', '146'))	('deletion', 'Var', (19, 27))	('BRG1', 'Gene', '6597', (158, 162))	('BAF57', 'Gene', '6605', (174, 179))	('BRG1', 'Gene', (158, 162))	('BRD7', 'Gene', (164, 168))	('interaction', 'Interaction', (78, 89))	('BAF57', 'Gene', (174, 179))
93860	31863007	On PBRM1, only BD2 has been identified as a reader of histone 3 lysine 14 acetylation (H3K14Ac), and it is not known which BD may be responsible for the recognition of K382Ac on p53.	('PBRM1', 'Gene', (3, 8))	('BD2', 'Gene', (15, 18))	('BD2', 'Gene', '1673', (15, 18))	('K382Ac', 'Var', (168, 174))	('lysine', 'Chemical', 'MESH:D008239', (64, 70))	('H3K14Ac', 'Chemical', '-', (87, 94))	('K382Ac', 'Chemical', '-', (168, 174))
93862	31863007	BD4 alone bound p53 CTD peptides but did not show selective affinity to the K382Ac peptide, whereas the five other individual BDs failed to bind the peptides (Supplementary Fig.	('p53', 'Var', (16, 19))	('peptides', 'Chemical', 'MESH:D010455', (24, 32))	('bound', 'Interaction', (10, 15))	('peptides', 'Chemical', 'MESH:D010455', (149, 157))	('K382Ac', 'Var', (76, 82))	('BD4', 'Chemical', '-', (0, 3))	('K382Ac', 'Chemical', '-', (76, 82))
93863	31863007	We postulated that adjacent BD(s) may assist BD4 in recognizing p53 acetylated at K382 since additional BDs assist BD2 in recognizing H3K14Ac, as reported in two recent papers.	('H3K14Ac', 'Chemical', '-', (134, 141))	('K382', 'Chemical', '-', (82, 86))	('H3K14Ac', 'Var', (134, 141))	('p53', 'Var', (64, 67))	('K382', 'Var', (82, 86))	('BD2', 'Gene', (115, 118))	('BD2', 'Gene', '1673', (115, 118))	('BD4', 'Chemical', '-', (45, 48))
93864	31863007	The combination of bromodomains 4 and 5 (BD45) showed enhanced binding to the K382Ac peptide compared to the non-acetylated control (Fig.	('K382Ac', 'Var', (78, 84))	('binding', 'Interaction', (63, 70))	('K382Ac', 'Chemical', '-', (78, 84))	('BD4', 'Chemical', '-', (41, 44))	('enhanced', 'PosReg', (54, 62))	('binding', 'molecular_function', 'GO:0005488', ('63', '70'))
93865	31863007	To determine which BD is critical for recognition of p53 acetylation, we mutated critical YN residues, previously reported to be required to form a hydrogen bond with the target acetyl-lysine, to alanines to disrupt bromodomain 4 (BD4*) and 5 (BD5*) (Fig.	('mutated', 'Var', (73, 80))	('BD4', 'Chemical', '-', (231, 234))	('alanines', 'Chemical', 'MESH:D000409', (196, 204))	('acetyl-lysine', 'Chemical', '-', (178, 191))	('hydrogen', 'Chemical', 'MESH:D006859', (148, 156))	('BD5', 'Gene', (244, 247))	('BD5', 'Gene', '245908', (244, 247))
93866	31863007	The BD4* mutation in BD45 abolished the enhanced binding to the K382Ac peptide whereas the BD5* mutation did not (Fig.	('K382Ac', 'Var', (64, 70))	('binding', 'Interaction', (49, 56))	('BD5', 'Gene', (91, 94))	('BD45', 'Gene', (21, 25))	('BD5', 'Gene', '245908', (91, 94))	('K382Ac', 'Chemical', '-', (64, 70))	('BD4', 'Chemical', '-', (21, 24))	('abolished', 'NegReg', (26, 35))	('enhanced', 'PosReg', (40, 48))	('BD4* mutation', 'Var', (4, 17))	('binding', 'molecular_function', 'GO:0005488', ('49', '56'))	('BD4', 'Chemical', '-', (4, 7))
93867	31863007	This suggests that BD4, not BD5, is the critical BD of PBRM1 for enhanced binding to K382 acetylated p53.	('BD5', 'Gene', (28, 31))	('BD5', 'Gene', '245908', (28, 31))	('p53', 'Protein', (101, 104))	('K382', 'Chemical', '-', (85, 89))	('enhanced', 'PosReg', (65, 73))	('binding', 'molecular_function', 'GO:0005488', ('74', '81'))	('BD4', 'Chemical', '-', (19, 22))	('PBRM1', 'Gene', (55, 60))	('K382 acetylated', 'Var', (85, 100))	('binding', 'Interaction', (74, 81))
93868	31863007	In vitro, a purified GST-BD2345 protein preferentially bound the K382Ac peptide (Supplementary Fig.	('BD2', 'Gene', (25, 28))	('BD2', 'Gene', '1673', (25, 28))	('bound', 'Interaction', (55, 60))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('preferentially', 'PosReg', (40, 54))	('K382Ac', 'Var', (65, 71))	('K382Ac', 'Chemical', '-', (65, 71))
93871	31863007	We identified two BD4 tumor-derived mutations from cBioPortal (N601K and E602K, Fig.	('BD4', 'Chemical', '-', (18, 21))	('BD4', 'Gene', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('N601K', 'Var', (63, 68))	('N601K', 'Mutation', 'p.N601K', (63, 68))	('E602K', 'Mutation', 'p.E602K', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('E602K', 'Var', (73, 78))	('tumor', 'Disease', (22, 27))
93872	31863007	3d), and found that they also abolished the increased affinity to the K382Ac peptide (Fig.	('K382Ac', 'Chemical', '-', (70, 76))	('affinity', 'MPA', (54, 62))	('abolished', 'NegReg', (30, 39))	('K382Ac', 'Var', (70, 76))
93873	31863007	In full-length PBRM1, as expected, the BD4* mutation did not affect its affinity to H3K14Ac, a putative substrate of BD2, but specifically abolished its recognition of p53 K382Ac (Fig.	('H3K14Ac', 'Chemical', '-', (84, 91))	('p53 K382Ac', 'Var', (168, 178))	('BD4*', 'Var', (39, 43))	('BD2', 'Gene', (117, 120))	('BD2', 'Gene', '1673', (117, 120))	('recognition', 'MPA', (153, 164))	('abolished', 'NegReg', (139, 148))	('K382Ac', 'Chemical', '-', (172, 178))	('BD4', 'Chemical', '-', (39, 42))
93874	31863007	Moreover, the interaction between the full-length PBRM1 BD4* mutant and p53 was not enhanced by p300 co-expression (Fig.	('PBRM1', 'Gene', (50, 55))	('interaction', 'Interaction', (14, 25))	('BD4', 'Chemical', '-', (56, 59))	('p300', 'Gene', (96, 100))	('BD4* mutant', 'Var', (56, 67))	('expression', 'Species', '29278', (104, 114))	('p300', 'Gene', '2033', (96, 100))
93875	31863007	These data clearly suggest that BD4 of PBRM1 is critical for recognition of K382Ac on p53.	('p53', 'Gene', (86, 89))	('BD4', 'Chemical', '-', (32, 35))	('K382Ac', 'Var', (76, 82))	('K382Ac', 'Chemical', '-', (76, 82))	('PBRM1', 'Gene', (39, 44))
93876	31863007	To assess PBRM1's role in p53 function, we knocked out PBRM1 in H1299 cells and found the induction of putative p53 downstream target p21 (encoded by CDKN1A) was significantly reduced upon p53 transfection (Fig.	('reduced', 'NegReg', (176, 183))	('CDKN1A', 'Gene', (150, 156))	('CDKN1A', 'Gene', '1026', (150, 156))	('knocked out', 'Var', (43, 54))	('p53 transfection', 'Var', (189, 205))	('PBRM1', 'Gene', (55, 60))	('induction', 'MPA', (90, 99))	('H1299', 'CellLine', 'CVCL:0060', (64, 69))	('transfection', 'Var', (193, 205))
93877	31863007	A PCR array was performed to examine the expression of most known p53 downstream targets in the parental and PBRM1 knockout (KO) H1299 cells after transfection of p53.	('transfection', 'Var', (147, 159))	('expression', 'Species', '29278', (41, 51))	('PBRM1', 'Gene', (109, 114))	('H1299', 'CellLine', 'CVCL:0060', (129, 134))
93883	31863007	To examine whether recognition of K382Ac by PBRM1 is critical to PBRM1's role in facilitating p53 transcription, we restored expression of wild-type PBRM1 and the BD4* mutant in H1299 PBRM1 KO cells (Supplementary Fig.	('restored', 'PosReg', (116, 124))	('BD4', 'Chemical', '-', (163, 166))	('expression', 'Species', '29278', (125, 135))	('K382Ac', 'Chemical', '-', (34, 40))	('expression', 'MPA', (125, 135))	('K382Ac', 'Var', (34, 40))	('H1299', 'CellLine', 'CVCL:0060', (178, 183))	('BD4*', 'Var', (163, 167))	('transcription', 'biological_process', 'GO:0006351', ('98', '111'))	('PBRM1', 'Gene', (149, 154))
93884	31863007	Only wild-type PBRM1 restored the expression of p21 driven by p53 while the BD4* mutant did not (Fig.	('expression', 'MPA', (34, 44))	('p21', 'Protein', (48, 51))	('BD4', 'Chemical', '-', (76, 79))	('p53', 'Var', (62, 65))	('expression', 'Species', '29278', (34, 44))
93886	31863007	Knockdown of PBRM1 by short hairpin RNAs (shRNAs) significantly reduced p21 induction, and MDM2 induction in most cases, by p53 upon DNA damage in kidney cancer cell lines ACHN (Fig.	('damage in kidney', 'Phenotype', 'HP:0000112', (137, 153))	('ACHN', 'Gene', (172, 176))	('damage in kidney cancer', 'Disease', (137, 160))	('kidney cancer', 'Phenotype', 'HP:0009726', (147, 160))	('PBRM1', 'Gene', (13, 18))	('MDM2', 'Gene', '4193', (91, 95))	('MDM2', 'Gene', (91, 95))	('p21', 'Gene', (72, 75))	('ACHN', 'Gene', '55323', (172, 176))	('damage in kidney cancer', 'Disease', 'MESH:D007680', (137, 160))	('reduced', 'NegReg', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('p53', 'Var', (124, 127))
93891	31863007	We found that p21 induction by p53 was also reduced by PBRM1 knockdown in ACHN cells (Fig.	('p53', 'Gene', (31, 34))	('ACHN', 'Gene', '55323', (74, 78))	('p21', 'Gene', (14, 17))	('ACHN', 'Gene', (74, 78))	('knockdown', 'Var', (61, 70))	('reduced', 'NegReg', (44, 51))	('PBRM1', 'Gene', (55, 60))
93894	31863007	In agreement with the results in H1299 PBRM1 KO cells, in RCC4 cells, the PBRM1 BD4* mutant failed to enhance p21 expression after p53 activation, either by DNA damage (Fig.	('enhance', 'PosReg', (102, 109))	('p21', 'Protein', (110, 113))	('RCC4', 'Gene', (58, 62))	('RCC4', 'Gene', '84925', (58, 62))	('BD4', 'Chemical', '-', (80, 83))	('H1299', 'CellLine', 'CVCL:0060', (33, 38))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('expression', 'Species', '29278', (114, 124))	('BD4*', 'Var', (80, 84))	('expression', 'MPA', (114, 124))	('PBRM1', 'Gene', (74, 79))
93896	31863007	Similarly, the N601K and E602K PBRM1 mutants also failed to enhance p21 expression after DNA damage (Fig.	('E602K', 'Mutation', 'p.E602K', (25, 30))	('expression', 'Species', '29278', (72, 82))	('E602K', 'Var', (25, 30))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('PBRM1', 'Gene', (31, 36))	('p21', 'Protein', (68, 71))	('enhance', 'PosReg', (60, 67))	('N601K', 'Var', (15, 20))	('N601K', 'Mutation', 'p.N601K', (15, 20))
93898	31863007	We further investigated several p53 downstream target genes in RCC4 cells, and found their expression was up-regulated by restoration of PBRM1 but not PBRM1 BD4* (Fig.	('expression', 'MPA', (91, 101))	('RCC4', 'Gene', (63, 67))	('RCC4', 'Gene', '84925', (63, 67))	('PBRM1', 'Gene', (137, 142))	('BD4', 'Chemical', '-', (157, 160))	('restoration', 'Var', (122, 133))	('up-regulated', 'PosReg', (106, 118))	('expression', 'Species', '29278', (91, 101))
93899	31863007	ChIP experiments also showed that p53 binding to the RE1 region on the CDKN1A promoter was significantly enhanced by wild-type but not BD4* mutant PBRM1, whereas p53 binding to the TSS region on CDKN1A was weak and showed no significant change after PBRM1 expression in RCC4 cells (Fig.	('CDKN1A', 'Gene', (71, 77))	('BD4', 'Var', (135, 138))	('CDKN1A', 'Gene', '1026', (71, 77))	('binding', 'Interaction', (38, 45))	('CDKN1A', 'Gene', (195, 201))	('BD4', 'Chemical', '-', (135, 138))	('p53 binding', 'molecular_function', 'GO:0002039', ('34', '45'))	('PBRM1', 'Gene', (147, 152))	('CDKN1A', 'Gene', '1026', (195, 201))	('RCC4', 'Gene', '84925', (270, 274))	('expression', 'Species', '29278', (256, 266))	('p53 binding', 'molecular_function', 'GO:0002039', ('162', '173'))	('RCC4', 'Gene', (270, 274))	('p53', 'Protein', (34, 37))	('enhanced', 'PosReg', (105, 113))	('mutant', 'Var', (140, 146))
93901	31863007	In ACHN cells, PBRM1 knockdown by two different shRNAs significantly decreased the proportion of G1 phase cells and increased the proportion of S phase cells after DNA damage (Fig.	('knockdown', 'Var', (21, 30))	('decreased', 'NegReg', (69, 78))	('S phase', 'biological_process', 'GO:0051320', ('144', '151'))	('ACHN', 'Gene', '55323', (3, 7))	('increased', 'PosReg', (116, 125))	('DNA', 'cellular_component', 'GO:0005574', ('164', '167'))	('G1 phase cells', 'CPA', (97, 111))	('PBRM1', 'Gene', (15, 20))	('ACHN', 'Gene', (3, 7))	('G1 phase', 'biological_process', 'GO:0051318', ('97', '105'))
93905	31863007	We restored wild-type or BD4* mutant PBRM1 expression in Ren-01 PBRM1 KO cells and found the expression of p53 downstream targets was rescued by wild-type but not BD4* mutant PBRM1 after DNA damage (Fig.	('Ren', 'Gene', (57, 60))	('PBRM1', 'Gene', (37, 42))	('rescued', 'PosReg', (134, 141))	('Ren', 'Gene', '5972', (57, 60))	('BD4', 'Chemical', '-', (163, 166))	('BD4* mutant', 'Var', (163, 174))	('DNA', 'cellular_component', 'GO:0005574', ('187', '190'))	('PBRM1', 'Gene', (175, 180))	('expression', 'Species', '29278', (93, 103))	('expression', 'MPA', (93, 103))	('expression', 'Species', '29278', (43, 53))	('expression', 'MPA', (43, 53))	('BD4', 'Chemical', '-', (25, 28))	('BD4* mutant', 'Var', (25, 36))
93907	31863007	Thus BD4 mutation on PBRM1 abolishes its ability to assist p53 to induce a subset of its downstream targets.	('mutation', 'Var', (9, 17))	('PBRM1', 'Gene', (21, 26))	('induce a subset of its downstream targets', 'MPA', (66, 107))	('ability', 'MPA', (41, 48))	('BD4', 'Chemical', '-', (5, 8))	('abolishes', 'NegReg', (27, 36))
93908	31863007	In a nude mouse xenograft model, restoration of wild-type PBRM1 in Ren-01 PBRM1 KO cells suppressed tumor growth when compared with cells expressing either GFP or the BD4* PBRM1 mutant (Fig.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mouse', 'Species', '10090', (10, 15))	('tumor', 'Disease', (100, 105))	('suppressed', 'NegReg', (89, 99))	('Ren', 'Gene', (67, 70))	('PBRM1', 'Gene', (58, 63))	('Ren', 'Gene', '5972', (67, 70))	('restoration', 'Var', (33, 44))	('BD4', 'Chemical', '-', (167, 170))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
93921	31863007	K382 acetylation on p53, which may be modified by p300 and CBP after DNA damage, acts as a binding signal for the BDs of PBRM1.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('p300', 'Gene', '2033', (50, 54))	('CBP', 'Gene', (59, 62))	('modified', 'Reg', (38, 46))	('acetylation', 'MPA', (5, 16))	('CBP', 'Gene', '1387', (59, 62))	('K382', 'Chemical', '-', (0, 4))	('K382', 'Var', (0, 4))	('binding', 'molecular_function', 'GO:0005488', ('91', '98'))	('p300', 'Gene', (50, 54))	('binding', 'Interaction', (91, 98))	('CBP', 'molecular_function', 'GO:0008140', ('59', '62'))
93922	31863007	The backbone of p53 peptide might already bind PBRM1, and K382Ac enhances this interaction.	('bind', 'Interaction', (42, 46))	('K382Ac', 'Chemical', '-', (58, 64))	('PBRM1', 'Protein', (47, 52))	('K382Ac', 'Var', (58, 64))	('enhances', 'PosReg', (65, 73))
93923	31863007	We identified BD4 of PBRM1 as the cognate binding partner of K382Ac on p53 (Fig.	('BD4', 'Chemical', '-', (14, 17))	('K382Ac', 'Var', (61, 67))	('K382Ac', 'Chemical', '-', (61, 67))	('PBRM1', 'Gene', (21, 26))	('binding', 'molecular_function', 'GO:0005488', ('42', '49'))
93924	31863007	Suppression of PBRM1 reduces the induction of many p53 transcriptional targets, and the BD4* PBRM1 mutant that fails to recognize K382Ac on p53 was defective in tumor suppression and regulation of p53 targets (Figs.	('BD4*', 'Var', (88, 92))	('PBRM1', 'Gene', (15, 20))	('regulation', 'MPA', (183, 193))	('K382Ac', 'Chemical', '-', (130, 136))	('Suppression', 'Var', (0, 11))	('mutant', 'Var', (99, 105))	('BD4', 'Chemical', '-', (88, 91))	('tumor suppression', 'Disease', 'MESH:D009369', (161, 178))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('PBRM1', 'Gene', (93, 98))	('p53 transcriptional targets', 'MPA', (51, 78))	('regulation', 'biological_process', 'GO:0065007', ('183', '193'))	('defective', 'NegReg', (148, 157))	('tumor suppression', 'Disease', (161, 178))	('induction', 'MPA', (33, 42))	('reduces', 'NegReg', (21, 28))
93926	31863007	Thus we hypothesize that DNA damage increases p53 abundance and the K382Ac level, which not only dissociates SET from p53 to relieve the suppression of p53 transcriptional activity, but it also provides a binding signal to PBRM1 for enhanced transcription.	('p53 transcriptional activity', 'MPA', (152, 180))	('binding', 'molecular_function', 'GO:0005488', ('205', '212'))	('suppression', 'MPA', (137, 148))	('enhanced', 'PosReg', (233, 241))	('transcription', 'biological_process', 'GO:0006351', ('242', '255'))	('K382Ac', 'Chemical', '-', (68, 74))	('p53 abundance', 'MPA', (46, 59))	('PBRM1', 'Gene', (223, 228))	('K382Ac', 'Var', (68, 74))	('increases', 'PosReg', (36, 45))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))	('transcription', 'MPA', (242, 255))	('binding', 'Interaction', (205, 212))
93927	31863007	PBRM1 binds to both H3K14Ac and K382Ac on p53, and these interactions may retain p53 much longer at its target promoters to promote full transcriptional activation of its targets (Fig.	('K382Ac', 'Var', (32, 38))	('K382Ac', 'Chemical', '-', (32, 38))	('PBRM1', 'Gene', (0, 5))	('full transcriptional activation', 'MPA', (132, 163))	('H3K14Ac', 'Chemical', '-', (20, 27))	('promote', 'PosReg', (124, 131))	('H3K14Ac', 'Var', (20, 27))	('binds', 'Interaction', (6, 11))
93932	31863007	In this study, we report that acetylation on p53 lysine 382 enhanced the interaction between PBRM1 and p53 via recognition by PBRM1 BD4.	('lysine', 'Chemical', 'MESH:D008239', (49, 55))	('p53', 'Gene', (103, 106))	('interaction', 'Interaction', (73, 84))	('BD4', 'Chemical', '-', (132, 135))	('acetylation', 'MPA', (30, 41))	('PBRM1', 'Gene', (93, 98))	('p53 lysine 382', 'Var', (45, 59))	('enhanced', 'PosReg', (60, 68))
93933	31863007	A previous report showed that the BDs of PBRM1 did not bind to a p53 K382Ac peptide.	('bind', 'Interaction', (55, 59))	('not', 'NegReg', (51, 54))	('p53 K382Ac', 'Var', (65, 75))	('PBRM1', 'Gene', (41, 46))	('K382Ac', 'Chemical', '-', (69, 75))
93935	31863007	Nevertheless, two shorter peptides lacking K370, K372 and K373 (374-393, 20 residues) failed to interact with PBRM1 (Fig.	('peptides', 'Chemical', 'MESH:D010455', (26, 34))	('K370', 'Var', (43, 47))	('K373', 'Var', (58, 62))	('PBRM1', 'Gene', (110, 115))	('K372', 'Var', (49, 53))	('interact', 'Interaction', (96, 104))
93936	31863007	This suggests that those amino acid residues (368-373), though approximately 10 residues away from the recognition site (K382Ac), were still critical for PBRM1 binding.	('binding', 'molecular_function', 'GO:0005488', ('160', '167'))	('PBRM1', 'Gene', (154, 159))	('K382Ac', 'Chemical', '-', (121, 127))	('binding', 'Interaction', (160, 167))	('K382Ac', 'Var', (121, 127))
93938	31863007	Two recent papers have shown cooperation between BDs of PBRM1 in recognition of H3K14Ac.	('H3K14Ac', 'Var', (80, 87))	('PBRM1', 'Gene', (56, 61))	('H3K14Ac', 'Chemical', '-', (80, 87))
93941	31863007	Interestingly, the K382Q mutation on p53 failed to mimic K382Ac to enhance binding to PBRM1 (Supplementary Fig.	('K382Ac', 'Var', (57, 63))	('K382Q', 'Var', (19, 24))	('K382Ac', 'Chemical', '-', (57, 63))	('binding', 'molecular_function', 'GO:0005488', ('75', '82'))	('PBRM1', 'Gene', (86, 91))	('K382Q', 'Mutation', 'p.K382Q', (19, 24))	('enhance', 'PosReg', (67, 74))	('binding', 'Interaction', (75, 82))
93942	31863007	We conclude that although the K382Q mutation abolishes the positive charge of K382, it failed to fully recapitulate the characteristics of acetylated K382 on p53.	('K382', 'Chemical', '-', (150, 154))	('K382', 'Chemical', '-', (30, 34))	('K382Q', 'Var', (30, 35))	('K382Q', 'Mutation', 'p.K382Q', (30, 35))	('positive charge', 'MPA', (59, 74))	('abolishes', 'NegReg', (45, 54))	('K382', 'Chemical', '-', (78, 82))
93943	31863007	An interesting finding here was that K372Ac/K382Ac double acetylation significantly enhanced the interaction between PBRM1 and p53 whereas K373Ac/K382Ac did not enhance, and possibly even reduced, the interaction.	('K372Ac', 'Chemical', '-', (37, 43))	('K372Ac/K382Ac', 'Var', (37, 50))	('K382Ac', 'Chemical', '-', (146, 152))	('K373Ac', 'Chemical', '-', (139, 145))	('K373Ac/K382Ac', 'Var', (139, 152))	('reduced', 'NegReg', (188, 195))	('K382Ac', 'Chemical', '-', (44, 50))	('interaction', 'Interaction', (201, 212))	('interaction', 'Interaction', (97, 108))	('p53', 'Protein', (127, 130))	('enhanced', 'PosReg', (84, 92))	('PBRM1', 'Protein', (117, 122))
93947	31863007	In future studies, we will investigate whether different combinations of post-translational modifications, such as acetylation and methylation, interfere with PBRM1's recognition of K382Ac.	('acetylation', 'MPA', (115, 126))	('methylation', 'biological_process', 'GO:0032259', ('131', '142'))	('K382Ac', 'Var', (182, 188))	('interfere', 'NegReg', (144, 153))	('methylation', 'MPA', (131, 142))	('recognition', 'MPA', (167, 178))	('K382Ac', 'Chemical', '-', (182, 188))	('PBRM1', 'Gene', (159, 164))
93950	31863007	Unexpectedly, the PBRM1 BD4* mutant, which failed to recognize p53 K382Ac but recognized H3K14Ac (Fig.	('H3K14Ac', 'Chemical', '-', (89, 96))	('K382Ac', 'Chemical', '-', (67, 73))	('p53 K382Ac', 'Var', (63, 73))	('BD4*', 'Var', (24, 28))	('PBRM1', 'Gene', (18, 23))	('H3K14Ac', 'Var', (89, 96))	('BD4', 'Chemical', '-', (24, 27))
93954	31863007	Nevertheless, the acetylation-dependent interaction between PBRM1 and p53 is critical for increased p53 binding at the CDKN1A promoter since the BD4* mutant failed to enhance p53 binding to RE1 (Figs.	('BD4', 'Chemical', '-', (145, 148))	('increased', 'PosReg', (90, 99))	('CDKN1A', 'Gene', (119, 125))	('p53 binding', 'molecular_function', 'GO:0002039', ('100', '111'))	('binding', 'Interaction', (104, 111))	('CDKN1A', 'Gene', '1026', (119, 125))	('p53 binding', 'molecular_function', 'GO:0002039', ('175', '186'))	('BD4*', 'Var', (145, 149))	('interaction', 'Interaction', (40, 51))	('p53', 'Protein', (100, 103))	('acetylation-dependent', 'MPA', (18, 39))
93955	31863007	Our in vitro and in vivo results, including kidney tumor patient samples, showed loss of PBRM1 in ccRCC dampened p53 function and especially p21 expression, which is key for cell cycle arrest and senescence.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('senescence', 'biological_process', 'GO:0010149', ('196', '206'))	('p21 expression', 'MPA', (141, 155))	('arrest', 'Disease', 'MESH:D006323', (185, 191))	('kidney tumor', 'Disease', 'MESH:D007680', (44, 56))	('patient', 'Species', '9606', (57, 64))	('PBRM1', 'Gene', (89, 94))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('174', '191'))	('kidney tumor', 'Phenotype', 'HP:0009726', (44, 56))	('expression', 'Species', '29278', (145, 155))	('function', 'MPA', (117, 125))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (174, 191))	('kidney tumor', 'Disease', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('arrest', 'Disease', (185, 191))	('ccRCC', 'Disease', (98, 103))	('p53', 'Protein', (113, 116))	('dampened', 'NegReg', (104, 112))	('loss', 'Var', (81, 85))
93956	31863007	This is also consistent with previous reports showing that PBRM1 knockout in mouse kidneys permits continued cell proliferation through inhibition of replication stress.	('cell proliferation', 'CPA', (109, 127))	('PBRM1', 'Gene', (59, 64))	('inhibition', 'NegReg', (136, 146))	('mouse', 'Species', '10090', (77, 82))	('cell proliferation', 'biological_process', 'GO:0008283', ('109', '127'))	('knockout', 'Var', (65, 73))	('replication stress', 'CPA', (150, 168))
93959	31863007	This may be attributed to the tissue-specificity of PBRM1 function and may explain why most PBRM1 mutations are found in renal cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('found', 'Reg', (112, 117))	('renal cancer', 'Disease', (121, 133))	('mutations', 'Var', (98, 107))	('renal cancer', 'Disease', 'MESH:D007680', (121, 133))	('renal cancer', 'Phenotype', 'HP:0009726', (121, 133))	('PBRM1', 'Gene', (92, 97))
93961	31863007	The PBRM1 BD4* mutant, which is highly specific in its inability to support the p53 pathway but being able to recognize H3K14Ac, compromised the tumor suppressive function of PBRM1 (Fig.	('BD4* mutant', 'Var', (10, 21))	('compromised', 'NegReg', (129, 140))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('PBRM1', 'Gene', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('p53 pathway', 'Pathway', (80, 91))	('H3K14Ac', 'Chemical', '-', (120, 127))	('tumor', 'Disease', (145, 150))	('BD4', 'Chemical', '-', (10, 13))
93963	31863007	p21 in combination with other p53 targets may channel this tumor suppressor function.	('tumor', 'Disease', (59, 64))	('p21', 'Var', (0, 3))	('channel', 'PosReg', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor suppressor', 'biological_process', 'GO:0051726', ('59', '75'))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('59', '75'))
93970	31863007	Puromycin (P-7255), G418 (A1720), Doxycycline (D9891), and Nicotinamide (NAM, 72340) were purchased from Millipore Sigma.	('P-7255', 'Var', (11, 17))	('G418', 'Chemical', 'MESH:C010680', (20, 24))	('NAM', 'Chemical', 'MESH:D009536', (73, 76))	('Puromycin', 'Chemical', 'MESH:D011691', (0, 9))	('Nicotinamide', 'Chemical', 'MESH:D009536', (59, 71))	('P-7255', 'Chemical', '-', (11, 17))	('D9891', 'Chemical', '-', (47, 52))	('G418', 'Var', (20, 24))	('Doxycycline', 'Chemical', 'MESH:D004318', (34, 45))	('A1720', 'Chemical', '-', (26, 31))
93971	31863007	Antibodies for vinculin (sc-73614), actin (sc-8432), p53 (FL-393, sc-6243 and DO-1, sc-126) and p21 (sc-6246) were purchased from Santa Cruz Biotechnology.	('sc-73614', 'Var', (25, 33))	('sc-73614', 'Chemical', '-', (25, 33))	('vinculin', 'Gene', '7414', (15, 23))	('vinculin', 'Gene', (15, 23))
93972	31863007	Antibodies for GST (#2625), p21 (#2947), PUMA (#12450) and Myc (#2040) were purchased from Cell Signaling Technology.	('Myc', 'Gene', '4609', (59, 62))	('PUMA', 'Gene', '27113', (41, 45))	('Myc', 'Gene', (59, 62))	('#12450', 'Var', (47, 53))	('Signaling', 'biological_process', 'GO:0023052', ('96', '105'))	('PUMA', 'Gene', (41, 45))	('#2625', 'Var', (20, 25))
93973	31863007	Anti-PBRM1 (A301-591A), -BRD7 (A302-304A) and -BAF57 antibodies (A300-810A) were purchased from Bethyl Laboratories.	('A301-591A', 'Var', (12, 21))	('Anti-PBRM1', 'Gene', (0, 10))	('BAF57', 'Gene', '6605', (47, 52))	('A300-810A', 'Var', (65, 74))	('BRD7', 'Gene', (25, 29))	('BAF57', 'Gene', (47, 52))	('A302-304A', 'Var', (31, 40))	('BRD7', 'Gene', '29117', (25, 29))
93974	31863007	Antibodies for Flag (M2, F3165), MDM2 (OP145) and gammaH2Ax (05-636) were purchased from Millipore Sigma.	('MDM2', 'Gene', (33, 37))	('OP145', 'CellLine', 'CVCL:4398', (39, 44))	('MDM2', 'Gene', '4193', (33, 37))	('F3165', 'Var', (25, 30))
93990	31863007	To establish clones with knockout of PBRM1 or p53 or inducible expression of PBRM1, cell lines were transfected with pX335 constructs plus a linear puromycin marker (631626, Clontech), p53 Double Nickase Plasmid (h) (sc-416469-NIC, Santa Cruz Biotechnology), or pTetOne construct plus linear puromycin marker using Lipofectamine  2000 (11668019, Thermo Scientific) or X-tremeGENE  HP DNA Transfection Reagent (6366546001, Sigma-Aldrich).	('pTetOne', 'Chemical', '-', (262, 269))	('PBRM1', 'Gene', (37, 42))	('puromycin', 'Chemical', 'MESH:D011691', (292, 301))	('PBRM1', 'Gene', (77, 82))	('puromycin', 'Chemical', 'MESH:D011691', (148, 157))	('expression', 'Species', '29278', (63, 73))	('DNA', 'cellular_component', 'GO:0005574', ('384', '387'))	('knockout', 'Var', (25, 33))
94030	31863007	Primary immunostaining was performed using antibodies against p21 (Cell-Signaling, cat#:#2947, 1:25), anti-p53 K382Ac antibody (GTX62061, 1:250), and PBRM1 (Bethyl labs, Cat# A301-591A, 1:50), Antibodies were incubated at room temperature for 30 min.	('PBRM1', 'Gene', (150, 155))	('antibody', 'cellular_component', 'GO:0042571', ('118', '126'))	('cat', 'molecular_function', 'GO:0004096', ('83', '86'))	('Signaling', 'biological_process', 'GO:0023052', ('72', '81'))	('antibody', 'cellular_component', 'GO:0019815', ('118', '126'))	('K382Ac', 'Var', (111, 117))	('antibody', 'cellular_component', 'GO:0019814', ('118', '126'))	('Cat', 'molecular_function', 'GO:0004096', ('170', '173'))	('K382Ac', 'Chemical', '-', (111, 117))	('antibody', 'molecular_function', 'GO:0003823', ('118', '126'))	('p21', 'Gene', (62, 65))
94040	30171816	Mechanism analysis revealed that ERbeta can promote RCC cell invasion via an increase in transforming growth factor beta1 (TGF-beta1)/SMAD3 signals, and interrupting TGF-beta1/SMAD3 signals with a TGFbetaR1 inhibitor can reverse/block ERbeta-increased RCC cell migration.	('transforming growth factor beta1', 'Gene', '7040', (89, 121))	('TGFbeta', 'Gene', '7040;21803', (197, 204))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('promote', 'PosReg', (44, 51))	('TGFbetaR', 'molecular_function', 'GO:0005024', ('197', '205'))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Phenotype', 'HP:0005584', (252, 255))	('RCC', 'Disease', (52, 55))	('RCC', 'Disease', 'MESH:C538614', (252, 255))	('RCC', 'Disease', (252, 255))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('89', '120'))	('cell migration', 'biological_process', 'GO:0016477', ('256', '270'))	('increase', 'PosReg', (77, 85))	('transforming growth factor beta1', 'Gene', (89, 121))	('interrupting', 'Var', (153, 165))	('TGFbeta', 'Gene', (197, 204))
94106	30171816	Importantly, we found that 18% (nine of 49) pT1 stage RCC tumors vs. 57% (18 of 31) of pT2-3 stage RCC tumors had a stronger ERbeta staining (P = 0.0005) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('stronger', 'PosReg', (116, 124))	('RCC tumors', 'Disease', 'MESH:C538614', (99, 109))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC tumors', 'Disease', (54, 64))	('RCC tumors', 'Disease', (99, 109))	('ERbeta', 'Protein', (125, 131))	('pT1', 'Var', (44, 47))	('RCC tumors', 'Disease', 'MESH:C538614', (54, 64))
94112	30171816	1D) and was significantly higher in the T3/T4 stage compared to the T1/T2 stage, and the metastasis patients had significantly higher ERbeta expression compared to patients with non-metastasis (Fig.	('metastasis', 'Var', (89, 99))	('higher', 'PosReg', (26, 32))	('T3/T4', 'Disease', (40, 45))	('ERbeta', 'Protein', (134, 140))	('patients', 'Species', '9606', (100, 108))	('higher', 'PosReg', (127, 133))	('patients', 'Species', '9606', (164, 172))
94120	30171816	In addition, knocking down ERbeta with ERbeta-shRNA suppressed RCC cell growth in RCC 786-O cells (Fig.	('RCC', 'Disease', (63, 66))	('knocking down', 'Var', (13, 26))	('RCC', 'Disease', 'MESH:C538614', (63, 66))	('cell growth', 'biological_process', 'GO:0016049', ('67', '78'))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('suppressed', 'NegReg', (52, 62))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('ERbeta', 'Gene', (27, 33))
94121	30171816	2D) and increasing ERbeta with ectopic ERbeta-cDNA expression increased RCC cell growth in A498 cells (Fig.	('increased', 'PosReg', (62, 71))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('cell growth', 'biological_process', 'GO:0016049', ('76', '87'))	('ectopic', 'Var', (31, 38))	('ERbeta-cDNA', 'Gene', (39, 50))	('ERbeta', 'MPA', (19, 25))
94125	30171816	3A, knocking down ERbeta suppressed RCC 786-O cell migration.	('knocking down', 'Var', (4, 17))	('ERbeta', 'Gene', (18, 24))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('suppressed', 'NegReg', (25, 35))	('cell migration', 'biological_process', 'GO:0016477', ('46', '60'))
94130	30171816	As expected, increased ERbeta led to increased N-cadherin expression when comparing the 786-O sh-Luc vs. 786-O sh-ERbeta and A498 ERbeta vs. A498 Vec control (Fig.	('A498', 'Var', (125, 129))	('N-cadherin', 'Gene', '1000', (47, 57))	('cadherin', 'molecular_function', 'GO:0008014', ('49', '57'))	('increased ERbeta', 'Phenotype', 'HP:0003141', (13, 29))	('N-cadherin', 'Gene', (47, 57))	('increased', 'PosReg', (37, 46))	('increased', 'PosReg', (13, 22))	('ERbeta', 'CPA', (23, 29))
94145	30171816	Similarly, when implanted in female mice, those RCC cells with higher ERbeta grew bigger tumors than those RCC cells with lower ERbeta expression (Fig.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('tumors', 'Disease', (89, 95))	('ERbeta', 'Var', (70, 76))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('RCC', 'Disease', (107, 110))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('mice', 'Species', '10090', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
94150	30171816	Data showed that four out of five mice with orthotopically renal implanted A498-ERbeta cells formed diaphragm, liver, lung and mesentery metastasis and one of six mice had metastasis in A498-vector control group (with lower ERbeta) (Fig.	('liver', 'CPA', (111, 116))	('mice', 'Species', '10090', (34, 38))	('A498-ERbeta', 'Var', (75, 86))	('mice', 'Species', '10090', (163, 167))	('diaphragm', 'CPA', (100, 109))
94157	30171816	However, if we only compared ERbeta expression within the male or female groups, RCC cell grafts with higher ERbeta developed more distal metastatic tumors.	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('higher', 'PosReg', (102, 108))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('ERbeta', 'Var', (109, 115))
94172	30171816	The results show that anti-estrogen treated mice had higher body weights than control mice.	('higher', 'PosReg', (53, 59))	('body weights', 'CPA', (60, 72))	('mice', 'Species', '10090', (86, 90))	('anti-estrogen', 'Var', (22, 35))	('mice', 'Species', '10090', (44, 48))
94251	29371934	These lncRNAs epigenetically regulate gene expression through binding to PRC2 in various biological processes, especially during cancer, such as HOTAIR, TUG1, MALAT1, PINT etc.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('MALAT1', 'Gene', '378938', (159, 165))	('PRC2', 'Gene', (73, 77))	('binding', 'Interaction', (62, 69))	('TUG1', 'Gene', '55000', (153, 157))	('HOTAIR', 'Gene', '100124700', (145, 151))	('PINT', 'Gene', '378805', (167, 171))	('cancer', 'Disease', (129, 135))	('gene expression', 'MPA', (38, 53))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('gene expression', 'biological_process', 'GO:0010467', ('38', '53'))	('TUG1', 'Gene', (153, 157))	('MALAT1', 'Gene', (159, 165))	('PINT', 'Gene', (167, 171))	('epigenetically', 'Var', (14, 28))	('regulate', 'Reg', (29, 37))	('binding', 'molecular_function', 'GO:0005488', ('62', '69'))	('HOTAIR', 'Gene', (145, 151))
94258	29371934	We also found that Lucat1 is capable of facilitating cell growth, migration and invasion through epigenetically suppressing p57 in renal cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('invasion', 'CPA', (80, 88))	('Lucat1', 'Gene', (19, 25))	('migration', 'CPA', (66, 75))	('cell growth', 'CPA', (53, 64))	('epigenetically suppressing', 'Var', (97, 123))	('facilitating', 'PosReg', (40, 52))	('p57', 'Gene', '1028', (124, 127))	('renal cancer', 'Disease', (131, 143))	('cell growth', 'biological_process', 'GO:0016049', ('53', '64'))	('p57', 'Gene', (124, 127))	('renal cancer', 'Phenotype', 'HP:0009726', (131, 143))	('Lucat1', 'Gene', '100505994', (19, 25))	('renal cancer', 'Disease', 'MESH:D007680', (131, 143))
94266	29371934	Additionally, multivariate cox regression analysis revealed that high Lucat1 expression, age, TNM stage, grade, metastasis are independent predictors of OS in ccRCC patients (Table 2).	('expression', 'MPA', (77, 87))	('Lucat1', 'Gene', '100505994', (70, 76))	('TNM', 'Gene', '10178', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (159, 164))	('Lucat1', 'Gene', (70, 76))	('high', 'Var', (65, 69))	('RCC', 'Disease', (161, 164))	('patients', 'Species', '9606', (165, 173))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('TNM', 'Gene', (94, 97))
94267	29371934	Kaplan-Meier analysis indicated that high Lucat1 expression was related to a poorer overall survival (log-rank test, P <0.001, Figure 1G) and disease free survival (log-rank test, P <0.001, Figure 1H).	('high', 'Var', (37, 41))	('disease free survival', 'CPA', (142, 163))	('Lucat1', 'Gene', '100505994', (42, 48))	('expression', 'MPA', (49, 59))	('Lucat1', 'Gene', (42, 48))	('overall survival', 'CPA', (84, 100))	('poorer', 'NegReg', (77, 83))
94268	29371934	Taken together, these results confirmed that high Lucat1 expression was related to poor prognosis, and upregulated expression of Lucat1 might be crucial in ccRCC tumorigenesis and progression.	('expression', 'MPA', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Lucat1', 'Gene', (50, 56))	('Lucat1', 'Gene', (129, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (156, 161))	('tumor', 'Disease', (162, 167))	('high', 'Var', (45, 49))	('expression', 'MPA', (115, 125))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('Lucat1', 'Gene', '100505994', (50, 56))	('Lucat1', 'Gene', '100505994', (129, 135))	('upregulated', 'PosReg', (103, 114))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
94270	29371934	MTS (Figure 2B, 2C) assay and Colony formation assay (Figure 2D, 2E) showed that knockdown Lucat1 inhibited cell proliferation in ACHN, 786-O and OS-RC-2 cells.	('Lucat1', 'Gene', (91, 97))	('OS-RC-2', 'CellLine', 'CVCL:1626', (146, 153))	('ACHN', 'Gene', '55323', (130, 134))	('inhibited', 'NegReg', (98, 107))	('formation', 'biological_process', 'GO:0009058', ('37', '46'))	('knockdown', 'Var', (81, 90))	('ACHN', 'Gene', (130, 134))	('Lucat1', 'Gene', '100505994', (91, 97))	('cell proliferation', 'CPA', (108, 126))	('cell proliferation', 'biological_process', 'GO:0008283', ('108', '126'))
94271	29371934	Further assay of transwell showed that knockdown Lucat1 suppressed renal cancer cell migration and invasion (Figure 2F, 2G, 2H and 2I).	('renal cancer', 'Phenotype', 'HP:0009726', (67, 79))	('renal cancer', 'Disease', 'MESH:D007680', (67, 79))	('Lucat1', 'Gene', '100505994', (49, 55))	('knockdown', 'Var', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('suppressed', 'NegReg', (56, 66))	('invasion', 'CPA', (99, 107))	('Lucat1', 'Gene', (49, 55))	('cell migration', 'biological_process', 'GO:0016477', ('80', '94'))	('renal cancer', 'Disease', (67, 79))
94272	29371934	Moreover, knockdown Lucat1 expression resulted in an accumulation of ACHN and 786-O cells in the G1 phase of the cell cycle (Figure 2J, 2K).	('Lucat1', 'Gene', '100505994', (20, 26))	('cell cycle', 'biological_process', 'GO:0007049', ('113', '123'))	('ACHN', 'Gene', (69, 73))	('Lucat1', 'Gene', (20, 26))	('ACHN', 'Gene', '55323', (69, 73))	('expression', 'Var', (27, 37))	('knockdown', 'Var', (10, 19))	('G1 phase', 'biological_process', 'GO:0051318', ('97', '105'))	('accumulation', 'PosReg', (53, 65))
94285	29371934	ChIP assays demonstrated that knockdown of Lucat1 decreased the binding of EZH2 and H3K27me3 levels across the p57 promoters (Figure 3G, 3H).	('binding', 'Interaction', (64, 71))	('Lucat1', 'Gene', (43, 49))	('H3K27me3', 'Protein', (84, 92))	('EZH2', 'Gene', (75, 79))	('binding', 'molecular_function', 'GO:0005488', ('64', '71'))	('EZH2', 'Gene', '2146', (75, 79))	('decreased', 'NegReg', (50, 59))	('Lucat1', 'Gene', '100505994', (43, 49))	('knockdown', 'Var', (30, 39))	('p57', 'Gene', '1028', (111, 114))	('p57', 'Gene', (111, 114))
94287	29371934	The results disclosed that Lucat1 knockdown increased the expression of p57 at the mRNA and protein levels (Figure 3I, 3J).	('Lucat1', 'Gene', '100505994', (27, 33))	('expression', 'MPA', (58, 68))	('increased', 'PosReg', (44, 53))	('Lucat1', 'Gene', (27, 33))	('p57', 'Gene', '1028', (72, 75))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('p57', 'Gene', (72, 75))	('knockdown', 'Var', (34, 43))
94292	29371934	Colony formation assay and MTS demonstrated that the knockdown of Lucat1 inhibited cell growth was partly reversed by sh-p57 treatment (Figure 4E, 4F, 4G, 4H and Supplementary Figure 3).	('cell growth', 'biological_process', 'GO:0016049', ('83', '94'))	('knockdown', 'Var', (53, 62))	('p57', 'Gene', '1028', (121, 124))	('Lucat1', 'Gene', '100505994', (66, 72))	('p57', 'Gene', (121, 124))	('inhibited', 'NegReg', (73, 82))	('formation', 'biological_process', 'GO:0009058', ('7', '16'))	('Lucat1', 'Gene', (66, 72))	('cell growth', 'CPA', (83, 94))
94293	29371934	Further study showed that knockdown of Lucat1 lead G0-1 cycle arrest was partly reversed by down-regulation of p57 (Figure 4I and 4J).	('regulation', 'biological_process', 'GO:0065007', ('97', '107'))	('G0-1 cycle arrest', 'CPA', (51, 68))	('Lucat1', 'Gene', '100505994', (39, 45))	('down-regulation', 'NegReg', (92, 107))	('knockdown', 'Var', (26, 35))	('p57', 'Gene', '1028', (111, 114))	('p57', 'Gene', (111, 114))	('Lucat1', 'Gene', (39, 45))
94297	29371934	We applied the efficient CRISPR/Cas genome editing system targeting exon 2 of EZH2 to knock out this gene in 786-O cells.	('Cas', 'cellular_component', 'GO:0005650', ('32', '35'))	('knock', 'Var', (86, 91))	('EZH2', 'Gene', (78, 82))	('EZH2', 'Gene', '2146', (78, 82))
94315	29371934	What's more, silencing Lucat1 also impaired cell proliferation, migration and invasion, and cell cycle arrest in vitro, and inhibited tumorigenesis of ccRCC cells in vivo.	('cell proliferation', 'CPA', (44, 62))	('Lucat1', 'Gene', (23, 29))	('invasion', 'CPA', (78, 86))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('silencing', 'Var', (13, 22))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('92', '109'))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('RCC', 'Disease', (153, 156))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('ccRCC', 'Phenotype', 'HP:0006770', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cell cycle arrest', 'CPA', (92, 109))	('Lucat1', 'Gene', '100505994', (23, 29))	('inhibited', 'NegReg', (124, 133))	('impaired', 'NegReg', (35, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('44', '62'))	('tumor', 'Disease', (134, 139))
94320	29371934	In addition, we also found that knockdown of Lucat1 increased the expression of p57 in ccRCC cells.	('increased', 'PosReg', (52, 61))	('Lucat1', 'Gene', '100505994', (45, 51))	('knockdown', 'Var', (32, 41))	('expression', 'MPA', (66, 76))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('Lucat1', 'Gene', (45, 51))	('p57', 'Gene', '1028', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('p57', 'Gene', (80, 83))
94321	29371934	Furthermore, we found that knockdown of Lucat1 inhibited cell proliferation, migration and invasion, and cell cycle arrest, while knockdown of p57 reversed the negative role of cell proliferation, and cell cycle arrest in ACHN and 786-O cell lines, which indicated p57 was a novel Lucat1 target, and Lucat1 could function as oncogene through suppressing p57 expression in ccRCC cells.	('Lucat1', 'Gene', (281, 287))	('ACHN', 'Gene', '55323', (222, 226))	('p57', 'Gene', '1028', (354, 357))	('cell proliferation', 'biological_process', 'GO:0008283', ('57', '75'))	('Lucat1', 'Gene', '100505994', (40, 46))	('cell proliferation', 'CPA', (57, 75))	('p57', 'Gene', (143, 146))	('p57', 'Gene', '1028', (265, 268))	('Lucat1', 'Gene', '100505994', (300, 306))	('expression', 'MPA', (358, 368))	('ccRCC', 'Phenotype', 'HP:0006770', (372, 377))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('201', '218'))	('knockdown', 'Var', (27, 36))	('cell proliferation', 'biological_process', 'GO:0008283', ('177', '195'))	('Lucat1', 'Gene', (40, 46))	('p57', 'Gene', (354, 357))	('cell cycle arrest', 'CPA', (105, 122))	('Lucat1', 'Gene', (300, 306))	('ACHN', 'Gene', (222, 226))	('Lucat1', 'Gene', '100505994', (281, 287))	('RCC', 'Phenotype', 'HP:0005584', (374, 377))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('105', '122'))	('RCC', 'Disease', (374, 377))	('inhibited', 'NegReg', (47, 56))	('p57', 'Gene', '1028', (143, 146))	('suppressing', 'NegReg', (342, 353))	('p57', 'Gene', (265, 268))	('RCC', 'Disease', 'MESH:C538614', (374, 377))
94323	29371934	We applied the efficient CRISPR/Cas genome editing system targeting exon 2 of EZH2 to knock out this gene in 786-O cells and found a higher expression of p57 in the EZH2-knockout cell lines.	('Cas', 'cellular_component', 'GO:0005650', ('32', '35'))	('EZH2', 'Gene', (165, 169))	('expression', 'MPA', (140, 150))	('EZH2', 'Gene', '2146', (165, 169))	('higher', 'PosReg', (133, 139))	('knock', 'Var', (86, 91))	('p57', 'Gene', '1028', (154, 157))	('EZH2', 'Gene', (78, 82))	('EZH2', 'Gene', '2146', (78, 82))	('p57', 'Gene', (154, 157))
94325	29371934	We have tried to detect the genes that can regulate the expression of Lucat1 in ccRCC, and found that the PTEN mutant group exhibited a higher expression of Lucat1 than the PTEN wide-type group from TCGA (supplementary Figure 4).	('Lucat1', 'Gene', '100505994', (157, 163))	('expression', 'MPA', (143, 153))	('Lucat1', 'Gene', '100505994', (70, 76))	('mutant', 'Var', (111, 117))	('higher', 'PosReg', (136, 142))	('Lucat1', 'Gene', (157, 163))	('PTEN', 'Gene', (173, 177))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('Lucat1', 'Gene', (70, 76))	('RCC', 'Disease', (82, 85))	('PTEN', 'Gene', (106, 110))	('PTEN', 'Gene', '5728', (173, 177))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('PTEN', 'Gene', '5728', (106, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))
94344	28902136	Dual Strands of Pre-miR-149 Inhibit Cancer Cell Migration and Invasion through Targeting FOXM1 in Renal Cell Carcinoma Our recent studies revealed that dual strands of certain pre-microRNAs, e.g., pre-miR-144, pre-miR-145, and pre-miR-150, act as antitumor microRNAs (miRNAs) in several cancers.	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Disease', (251, 256))	('miR', 'Gene', (214, 217))	('miR', 'Gene', '220972', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('FOXM1', 'Gene', '2305', (89, 94))	('miR-145', 'Gene', '406937', (214, 221))	('miR', 'Gene', '220972', (201, 204))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('miR-149', 'Gene', '406941', (20, 27))	('miR', 'Gene', (268, 271))	('Cell Migration', 'biological_process', 'GO:0016477', ('43', '57'))	('pre', 'molecular_function', 'GO:0003904', ('176', '179'))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (98, 118))	('pre', 'molecular_function', 'GO:0003904', ('227', '230'))	('Carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('miR-150', 'Gene', '406942', (231, 238))	('miR-145', 'Gene', (214, 221))	('pre', 'molecular_function', 'GO:0003904', ('197', '200'))	('cancers', 'Phenotype', 'HP:0002664', (287, 294))	('miR', 'Gene', (20, 23))	('Inhibit', 'NegReg', (28, 35))	('cancers', 'Disease', (287, 294))	('miR', 'Gene', (201, 204))	('miR-144', 'Gene', (201, 208))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('pre', 'molecular_function', 'GO:0003904', ('210', '213'))	('miR', 'Gene', '220972', (231, 234))	('FOXM1', 'Gene', (89, 94))	('Pre', 'molecular_function', 'GO:0003904', ('16', '19'))	('miR-150', 'Gene', (231, 238))	('miR', 'Gene', (231, 234))	('miR', 'Gene', '220972', (214, 217))	('Renal Cell Carcinoma', 'Disease', (98, 118))	('miR-149', 'Gene', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (287, 294))	('Invasion', 'CPA', (62, 70))	('miR', 'Gene', '220972', (268, 271))	('Cancer Cell Migration', 'CPA', (36, 57))	('miR-144', 'Gene', '406936', (201, 208))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (98, 118))	('Targeting', 'Var', (79, 88))
94350	28902136	Knockdown studies using si-FOXM1 showed that the expression of FOXM1 enhanced RCC cell aggressiveness.	('FOXM1', 'Gene', '2305', (27, 32))	('FOXM1', 'Gene', (27, 32))	('RCC cell aggressiveness', 'Disease', 'MESH:C538614', (78, 101))	('enhanced', 'PosReg', (69, 77))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('aggressiveness', 'Phenotype', 'HP:0000718', (87, 101))	('RCC cell aggressiveness', 'Disease', (78, 101))	('FOXM1', 'Gene', '2305', (63, 68))	('FOXM1', 'Gene', (63, 68))	('expression', 'Var', (49, 59))
94351	28902136	Interestingly, the analysis of a large number of patients in the The Cancer Genome Atlas (TCGA) database (n = 260) demonstrated that patients with high FOXM1 expression had significantly shorter survival than did those with low FOXM1 expression (p = 1.5 x 10-6).	('FOXM1', 'Gene', (152, 157))	('FOXM1', 'Gene', '2305', (152, 157))	('FOXM1', 'Gene', (228, 233))	('patients', 'Species', '9606', (133, 141))	('FOXM1', 'Gene', '2305', (228, 233))	('high', 'Var', (147, 151))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('patients', 'Species', '9606', (49, 57))	('shorter', 'NegReg', (187, 194))	('Cancer Genome Atlas', 'Disease', (69, 88))	('survival', 'MPA', (195, 203))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (69, 88))
94361	28902136	Overexpression of oncogenic miRNAs and dysfunction of antitumor miRNAs are associated with human cancer pathogenesis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('pathogenesis', 'biological_process', 'GO:0009405', ('104', '116'))	('cancer', 'Disease', (97, 103))	('miR', 'Gene', '220972', (64, 67))	('miR', 'Gene', (64, 67))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))	('associated', 'Reg', (75, 85))	('dysfunction', 'Var', (39, 50))	('human', 'Species', '9606', (91, 96))
94363	28902136	Therefore, aberrantly expressed miRNAs can disrupt regulatory miRNA-mRNA networks in cancer cells.	('miR', 'Gene', (32, 35))	('miR', 'Gene', '220972', (62, 65))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('miR', 'Gene', (62, 65))	('cancer', 'Disease', (85, 91))	('aberrantly expressed', 'Var', (11, 31))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('disrupt', 'NegReg', (43, 50))	('miR', 'Gene', '220972', (32, 35))
94402	28902136	The Kaplan-Meier curves for OS rates showed that the group with high expression of FOXM1 had a significantly shorter survival than the low expression group in ccRCC (p = 1.5 x 10-6, Figure 5A).	('OS', 'Chemical', '-', (28, 30))	('high expression', 'Var', (64, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (159, 164))	('RCC', 'Disease', (161, 164))	('survival', 'CPA', (117, 125))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('FOXM1', 'Gene', (83, 88))	('shorter', 'NegReg', (109, 116))	('FOXM1', 'Gene', '2305', (83, 88))
94406	28902136	The target prediction databases indicated that both miR-149-5p and miR-149-3p had one putative target site in the 3'-UTR of FOXM1 for miR-149-5p (position 909-915) and miR-149-3p (positions 588-594) (Figure 6C).	('miR-149', 'Gene', '406941', (52, 59))	('miR-149', 'Gene', (134, 141))	('miR-149', 'Gene', '406941', (67, 74))	('miR-149', 'Gene', '406941', (134, 141))	('5p', 'Chemical', '-', (142, 144))	('FOXM1', 'Gene', '2305', (124, 129))	('position 909-915', 'Var', (146, 162))	('FOXM1', 'Gene', (124, 129))	('miR-149', 'Gene', (168, 175))	('5p', 'Chemical', '-', (60, 62))	('miR-149', 'Gene', '406941', (168, 175))	('miR-149', 'Gene', (52, 59))	('miR-149', 'Gene', (67, 74))	('positions 588-594', 'Var', (180, 197))
94407	28902136	The TargetScan database identified one putative target site in the 3'-UTR of FOXM1 for miR-149-5p (position 909-915) and miR-149-3p (positions 588-594).	('5p', 'Chemical', '-', (95, 97))	('position 909-915', 'Var', (99, 115))	('FOXM1', 'Gene', (77, 82))	('FOXM1', 'Gene', '2305', (77, 82))	('miR-149', 'Gene', (87, 94))	('miR-149', 'Gene', (121, 128))	('miR-149', 'Gene', '406941', (87, 94))	('miR-149', 'Gene', '406941', (121, 128))
94411	28902136	Our present data showed that si-FOXM1 transfection effectively downregulated FOXM1 expression in A498 and 786-O cells (Figure 7A,B).	('FOXM1', 'Gene', '2305', (32, 37))	('FOXM1', 'Gene', (32, 37))	('FOXM1', 'Gene', (77, 82))	('transfection', 'Var', (38, 50))	('downregulated', 'NegReg', (63, 76))	('FOXM1', 'Gene', '2305', (77, 82))	('expression', 'MPA', (83, 93))
94412	28902136	Functional assays demonstrated that cell proliferation, migration, and invasion were all inhibited in si-FOXM1 transfectants compared with mock- or miR control-transfected cells (p < 0.0001, Figure 7C-E).	('migration', 'CPA', (56, 65))	('inhibited', 'NegReg', (89, 98))	('invasion', 'CPA', (71, 79))	('cell proliferation', 'biological_process', 'GO:0008283', ('36', '54'))	('FOXM1', 'Gene', (105, 110))	('FOXM1', 'Gene', '2305', (105, 110))	('transfectants', 'Var', (111, 124))	('miR', 'Gene', '220972', (148, 151))	('miR', 'Gene', (148, 151))	('cell proliferation', 'CPA', (36, 54))
94425	28902136	In breast cancer, miR-149-5p was downregulated by the hyper-methylation of its promoter region and was found to be involved in Adriamycin-resistant breast cancer cells targeting GlcNAc N-deacetylase/N-sulfotransferase-1 (NDST1).	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('Adriamycin', 'Chemical', 'MESH:D004317', (127, 137))	('hyper-methylation', 'Var', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('NDST1', 'Gene', (221, 226))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('5p', 'Chemical', '-', (26, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('breast cancer', 'Disease', (148, 161))	('involved', 'Reg', (115, 123))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('miR-149', 'Gene', (18, 25))	('miR-149', 'Gene', '406941', (18, 25))	('NDST1', 'Gene', '3340', (221, 226))	('downregulated', 'NegReg', (33, 46))
94428	28902136	In colorectal carcinoma, the expression of miR-149-5p regulated cell growth, migration, and invasion through its targeting of the EPH receptor B3 gene (EphB3), and the knockdown of EphB3 inhibited tumor growth by in vivo assays.	('miR-149', 'Gene', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('invasion', 'CPA', (92, 100))	('inhibited', 'NegReg', (187, 196))	('EphB3', 'Gene', (152, 157))	('EphB3', 'Gene', '2049', (181, 186))	('miR-149', 'Gene', '406941', (43, 50))	('migration', 'CPA', (77, 86))	('colorectal carcinoma', 'Disease', (3, 23))	('cell growth', 'CPA', (64, 75))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('5p', 'Chemical', '-', (51, 53))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (3, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('regulated', 'Reg', (54, 63))	('cell growth', 'biological_process', 'GO:0016049', ('64', '75'))	('EPH receptor B3', 'Gene', '2049', (130, 145))	('knockdown', 'Var', (168, 177))	('EphB3', 'Gene', (181, 186))	('EPH receptor B3', 'Gene', (130, 145))	('EphB3', 'Gene', '2049', (152, 157))	('tumor', 'Disease', (197, 202))
94450	28902136	Our present data demonstrated that the knockdown of FOXM1 in tumor cells by RNAi reduced cell proliferation, migration, and invasion, suggesting that FOXM1 acts as an oncogene in RCC cells.	('FOXM1', 'Gene', (52, 57))	('RCC', 'Phenotype', 'HP:0005584', (179, 182))	('cell proliferation', 'CPA', (89, 107))	('knockdown', 'Var', (39, 48))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('FOXM1', 'Gene', '2305', (150, 155))	('migration', 'CPA', (109, 118))	('cell proliferation', 'biological_process', 'GO:0008283', ('89', '107'))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('FOXM1', 'Gene', (150, 155))	('reduced', 'NegReg', (81, 88))	('RNAi', 'biological_process', 'GO:0016246', ('76', '80'))	('invasion', 'CPA', (124, 132))	('tumor', 'Disease', (61, 66))	('FOXM1', 'Gene', '2305', (52, 57))	('RCC', 'Disease', (179, 182))
94451	28902136	Moreover, recent meta-analyses have indicated that high expression of FOXM1 was significantly associated with poor overall survival in most solid tumors.	('FOXM1', 'Gene', '2305', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('overall survival', 'MPA', (115, 131))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('solid tumors', 'Disease', (140, 152))	('associated', 'Reg', (94, 104))	('poor', 'NegReg', (110, 114))	('high expression', 'Var', (51, 66))	('solid tumors', 'Disease', 'MESH:D009369', (140, 152))	('FOXM1', 'Gene', (70, 75))
94459	28902136	Stem-loop RT-PCR (TaqMan MicroRNA Assays; product ID: 002255 for miR-149-5p and 002164 for miR-149-3p; Applied Biosystems, Foster City, CA, USA) was used for these assays.	('5p', 'Chemical', '-', (73, 75))	('miR-149', 'Gene', '406941', (91, 98))	('002164', 'Var', (80, 86))	('miR-149', 'Gene', (65, 72))	('miR-149', 'Gene', '406941', (65, 72))	('miR-149', 'Gene', (91, 98))
94477	28902136	The aberrant expression of FOXM1 enhanced cancer cell aggressiveness, and high expression of FOXM1 was significantly associated with a poor prognosis of this disease.	('FOXM1', 'Gene', (93, 98))	('FOXM1', 'Gene', '2305', (27, 32))	('expression', 'MPA', (79, 89))	('associated', 'Reg', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer cell aggressiveness', 'Disease', (42, 68))	('aggressiveness', 'Phenotype', 'HP:0000718', (54, 68))	('aberrant expression', 'Var', (4, 23))	('cancer cell aggressiveness', 'Disease', 'MESH:C538614', (42, 68))	('FOXM1', 'Gene', (27, 32))	('FOXM1', 'Gene', '2305', (93, 98))	('enhanced', 'PosReg', (33, 41))
94486	33581726	Kaplan-Meier survival analysis indicated that KIRC patients with BAG1 high expression have a longer survival time than those with BAG1 low expression (p < 0.000).	('BAG1', 'Gene', (130, 134))	('BAG1', 'Gene', '573', (130, 134))	('survival time', 'CPA', (100, 113))	('patients', 'Species', '9606', (51, 59))	('high expression', 'Var', (70, 85))	('BAG1', 'Gene', (65, 69))	('longer', 'PosReg', (93, 99))	('BAG1', 'Gene', '573', (65, 69))
94488	33581726	GSEA indicated that the signaling pathways including fatty acid metabolism and oxidative phosphorylation were differentially enriched in high BAG1 expression phenotype.	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('79', '104'))	('oxidative phosphorylation', 'MPA', (79, 104))	('fatty acid metabolism', 'MPA', (53, 74))	('fatty acid', 'Chemical', 'MESH:D005227', (53, 63))	('high', 'Var', (137, 141))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('53', '74'))	('BAG1', 'Gene', '573', (142, 146))	('BAG1', 'Gene', (142, 146))	('GSEA', 'Chemical', '-', (0, 4))	('signaling', 'biological_process', 'GO:0023052', ('24', '33'))
94531	33581726	1c and d, KIRC patients with higher BAG1 expression experienced significantly favorable overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p < 0.001) than those with lower BAG1 expression through GEPIA tool.	('BAG1', 'Gene', (36, 40))	('patients', 'Species', '9606', (15, 23))	('BAG1', 'Gene', '573', (36, 40))	('disease-free survival', 'CPA', (126, 147))	('BAG1', 'Gene', '573', (188, 192))	('BAG1', 'Gene', (188, 192))	('overall survival', 'CPA', (88, 104))	('expression', 'Var', (41, 51))
94532	33581726	Table 3a showed that the univariate analysis using Cox regression indicated that high BAG1 expression correlated significantly with a good OS (hazard ratio [HR]: 2.11; 95% confidence interval [CI]:1.5-2.97; p < 0.001).	('BAG1', 'Gene', (86, 90))	('expression', 'MPA', (91, 101))	('high', 'Var', (81, 85))	('good', 'Disease', (134, 138))	('BAG1', 'Gene', '573', (86, 90))
94543	33581726	Overexpression of BAG-1 has closely related to cell differentiation and TNM stage in esophageal cancer and its downregulation inhibits the proliferation and invasion of human esophageal carcinoma cells.	('related', 'Reg', (36, 43))	('cell differentiation', 'biological_process', 'GO:0030154', ('47', '67'))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (175, 195))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('downregulation inhibits', 'NegReg', (111, 134))	('BAG-1', 'Gene', (18, 23))	('carcinoma', 'Disease', (186, 195))	('human', 'Species', '9606', (169, 174))	('BAG-1', 'Gene', '573', (18, 23))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('carcinoma', 'Disease', 'MESH:D009369', (186, 195))
94548	33581726	In this study, KIRC patients with higher BAG1 expression have a significantly better overall survival (OS) and disease-free survival (DFS) than those with lower BAG1 expression (Fig.	('better', 'PosReg', (78, 84))	('expression', 'Var', (46, 56))	('higher', 'Var', (34, 40))	('BAG1', 'Gene', '573', (41, 45))	('BAG1', 'Gene', '573', (161, 165))	('BAG1', 'Gene', (41, 45))	('BAG1', 'Gene', (161, 165))	('patients', 'Species', '9606', (20, 28))	('disease-free survival', 'CPA', (111, 132))	('overall survival', 'CPA', (85, 101))
94599	29884728	However, a recent study reported that RCCs have the highest number of indel mutations on a pan-cancer basis, which may yield a disproportionately higher amount of neoantigens and elicit robust adaptive immune responses.	('higher', 'PosReg', (146, 152))	('RCC', 'Disease', (38, 41))	('neoantigens', 'MPA', (163, 174))	('yield', 'Reg', (119, 124))	('indel mutations', 'Var', (70, 85))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('elicit', 'Reg', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('adaptive immune responses', 'CPA', (193, 218))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
94604	29884728	eTME-IS patients have abundant tumor infiltration of Tregs, NK cells, Th1 cells, neutrophils, macrophages, B cells, and CD8+ T cells, and are enriched for clear-cell tumors with BAP1 mutations and papillary tumors of type 2 histology.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('eTME-IS', 'Chemical', '-', (0, 7))	('BAP1', 'Gene', (178, 182))	('CD8', 'Gene', '925', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('papillary tumors', 'Phenotype', 'HP:0007482', (197, 213))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('clear-cell tumors', 'Disease', (155, 172))	('mutations', 'Var', (183, 192))	('papillary tumors', 'Disease', (197, 213))	('papillary tumors', 'Disease', 'MESH:D002291', (197, 213))	('clear-cell tumors', 'Disease', 'MESH:D008649', (155, 172))	('CD8', 'Gene', (120, 123))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', (207, 212))	('patients', 'Species', '9606', (8, 16))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
94614	29884728	As only the human tumor cells carry these somatic mutations, these data are consistent with the notion that only the tumor cell population expands in mice and that the stroma is replaced by the host.	('mice', 'Species', '10090', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (18, 23))	('mutations', 'Var', (50, 59))	('tumor', 'Disease', (117, 122))	('human', 'Species', '9606', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
94622	29884728	However, it is worth noting that the drift applied almost exclusively to tumors having undergone genome duplication, which is a rare event in RCC.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('genome duplication', 'Var', (97, 115))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
94623	29884728	We also show the whole genome CNVs in the primary tumor and tumorgraft of XP166 (11th passage) and XP243 (1st passage).	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('XP243', 'Var', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (50, 55))
94691	29884728	We found that IS was enriched for mutations in BAP1 (p=7.7x10-5), a tumor suppressor associated with high grade cancers.	('tumor', 'Disease', (68, 73))	('tumor suppressor', 'biological_process', 'GO:0051726', ('68', '84'))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('68', '84'))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cancers', 'Disease', (112, 119))	('IS', 'Chemical', '-', (14, 16))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (34, 43))	('BAP1', 'Gene', (47, 51))
94692	29884728	In contrast, PBRM1 mutations were more homogeneously distributed across both subtypes, though enriched in NIS.	('NIS', 'Chemical', 'MESH:D009532', (106, 109))	('PBRM1', 'Gene', (13, 18))	('NIS', 'Disease', (106, 109))	('mutations', 'Var', (19, 28))	('PBRM1', 'Gene', '55193', (13, 18))
94695	29884728	As in the TCGA ccRCC cohort, in the KCP cohort, eTME-IS ccRCC patients were associated with enriched BAP1 mutations, although statistical significance was not achieved (p=0.21, N=70).	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('associated', 'Reg', (76, 86))	('BAP1', 'Gene', (101, 105))	('RCC', 'Disease', (58, 61))	('mutations', 'Var', (106, 115))	('RCC', 'Disease', (17, 20))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('eTME-IS', 'Chemical', '-', (48, 55))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('patients', 'Species', '9606', (62, 70))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))
94697	29884728	In this cohort, we found 9 patients with BAP1 mutations out of all 95 available patients.	('patients', 'Species', '9606', (27, 35))	('BAP1', 'Gene', (41, 45))	('patients', 'Species', '9606', (80, 88))	('mutations', 'Var', (46, 55))
94700	29884728	We observed more CD4 and CD8 T cell infiltration in Bap1-mutated mice than in Pbrm1-mutated mice, suggesting a causal relationship may exist between BAP1 mutations and the eTME-IS phenotype (Sup.	('more', 'PosReg', (12, 16))	('Pbrm1', 'Gene', (78, 83))	('Pbrm1', 'Gene', '66923', (78, 83))	('Bap1', 'Gene', '104416', (52, 56))	('CD4', 'CPA', (17, 20))	('CD8', 'Gene', (25, 28))	('mice', 'Species', '10090', (65, 69))	('eTME-IS', 'Chemical', '-', (172, 179))	('Bap1', 'Gene', (52, 56))	('CD8', 'Gene', '925', (25, 28))	('BAP1', 'Gene', (149, 153))	('mutations', 'Var', (154, 163))	('eTME-IS phenotype', 'Disease', (172, 189))	('mice', 'Species', '10090', (92, 96))
94718	29884728	), which showed that eTME-IS samples are associated with more necrosis than eTME-NIS samples (Fig.	('eTME-IS', 'Var', (21, 28))	('necrosis', 'Disease', (62, 70))	('eTME-IS', 'Chemical', '-', (21, 28))	('necrosis', 'biological_process', 'GO:0070265', ('62', '70'))	('necrosis', 'biological_process', 'GO:0008219', ('62', '70'))	('necrosis', 'biological_process', 'GO:0019835', ('62', '70'))	('necrosis', 'Disease', 'MESH:D009336', (62, 70))	('necrosis', 'biological_process', 'GO:0001906', ('62', '70'))	('eTME-NIS', 'Chemical', '-', (76, 84))	('necrosis', 'biological_process', 'GO:0008220', ('62', '70'))
94723	29884728	Comparing eTME-IS and eTME-NIS tumors, we showed that eTME-IS tumors have a higher level of neutrophils than eTME-NIS tumors (p=0.021), and they also elicit higher levels of neutrophils in the mouse (p=0.031).	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('eTME-NIS tumors', 'Disease', 'MESH:D009369', (22, 37))	('levels of neutrophils', 'MPA', (164, 185))	('eTME-NIS tumors', 'Disease', 'MESH:D009369', (109, 124))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('eTME-IS', 'Chemical', '-', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (31, 37))	('tumors', 'Disease', (62, 68))	('eTME-NIS tumors', 'Disease', (22, 37))	('eTME-NIS tumors', 'Disease', (109, 124))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('higher', 'PosReg', (157, 163))	('tumors', 'Disease', (118, 124))	('higher', 'PosReg', (76, 82))	('level of neutrophils', 'MPA', (83, 103))	('elicit', 'Reg', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('eTME-IS', 'Var', (54, 61))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('eTME-IS', 'Chemical', '-', (10, 17))	('mouse', 'Species', '10090', (193, 198))
94743	29884728	In all the TCGA RCC patients combined, higher proportions of eTME-IS patients had elevated platelet counts (p=0.039) and low hemoglobin levels (p=0.019) compared with eTME-NIS patients (Fig.	('patients', 'Species', '9606', (176, 184))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('eTME-IS', 'Chemical', '-', (61, 68))	('RCC', 'Disease', (16, 19))	('eTME-NIS', 'Chemical', '-', (167, 175))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('elevated platelet', 'Phenotype', 'HP:0001894', (82, 99))	('hemoglobin levels', 'MPA', (125, 142))	('elevated', 'PosReg', (82, 90))	('patients', 'Species', '9606', (20, 28))	('platelet counts', 'MPA', (91, 106))	('patients', 'Species', '9606', (69, 77))	('low', 'NegReg', (121, 124))	('low hemoglobin', 'Phenotype', 'HP:0001903', (121, 135))	('eTME-IS', 'Var', (61, 68))	('TCGA', 'Gene', (11, 15))
94744	29884728	Overall, these data show that tumors with eTME-IS are associated with thrombocytosis and anemia, which may represent systemic manifestations of tumor-induced inflammation.	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('anemia', 'Disease', (89, 95))	('inflammation', 'Disease', (158, 170))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('eTME-IS', 'Var', (42, 49))	('thrombocytosis', 'Disease', (70, 84))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('thrombocytosis', 'Phenotype', 'HP:0001894', (70, 84))	('associated', 'Reg', (54, 64))	('tumors', 'Disease', (30, 36))	('tumor', 'Disease', (144, 149))	('inflammation', 'biological_process', 'GO:0006954', ('158', '170'))	('anemia', 'Disease', 'MESH:D000740', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('eTME-IS', 'Chemical', '-', (42, 49))	('inflammation', 'Disease', 'MESH:D007249', (158, 170))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', (30, 35))	('anemia', 'Phenotype', 'HP:0001903', (89, 95))	('thrombocytosis', 'Disease', 'MESH:D013922', (70, 84))
94748	29884728	Our results show that eTME-IS patients seem to have lower sodium levels as well (p=0.014) (Sup.	('eTME-IS', 'Chemical', '-', (22, 29))	('lower', 'NegReg', (52, 57))	('sodium', 'Chemical', 'MESH:D012964', (58, 64))	('patients', 'Species', '9606', (30, 38))	('sodium levels', 'MPA', (58, 71))	('eTME-IS', 'Var', (22, 29))	('lower sodium', 'Phenotype', 'HP:0002902', (52, 64))
94750	29884728	Our Kaplan-Meier analyses showed that eTME-IS patients had significantly worse overall survival across all three patient cohorts analyzed (Fig.	('patient', 'Species', '9606', (46, 53))	('patient', 'Species', '9606', (113, 120))	('patients', 'Species', '9606', (46, 54))	('eTME-IS', 'Var', (38, 45))	('worse', 'NegReg', (73, 78))	('eTME-IS', 'Chemical', '-', (38, 45))	('overall survival', 'MPA', (79, 95))
94751	29884728	6c) (HR=1.8 (95% CI=1.3-2.5) and p=1.4x10-4 in the TCGA ccRCC cohort, HR=11.9 (4.1-34.5) and p=4.6x10-6 in the UTSW cohort, and HR=2.3 (1.2-4.5) and p=0.014 in the TCGA nccRCC cohort).	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('p=1.4x10-4', 'Var', (33, 43))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('RCC', 'Disease', (172, 175))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))
94767	29884728	Furthermore, as reported by the authors, their findings are largely relegated to tumors that experience genome duplication, which is rare in RCC.	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('genome duplication', 'Var', (104, 122))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
94771	29884728	In their study, the authors identified a ccRCC "immune-regulated" subtype of patients, characterized by inflammation, CD4+ICOS+ cells with a Treg phenotype, and high risk of disease progression, which likely corresponds to the eTME-IS phenotype.	('inflammation', 'Disease', (104, 116))	('CD4+ICOS+', 'Var', (118, 127))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('eTME-IS', 'Chemical', '-', (227, 234))	('patients', 'Species', '9606', (77, 85))	('RCC', 'Disease', (43, 46))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('inflammation', 'Disease', 'MESH:D007249', (104, 116))	('inflammation', 'biological_process', 'GO:0006954', ('102', '114'))
94778	29884728	Interestingly, BAP1 deficiency has been associated with a peritoneal inflammatory response upon exposure to asbestos fibers in mice, and with an inflammatory phenotype in primary uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (179, 193))	('BAP1', 'Gene', (15, 19))	('peritoneal inflammatory response', 'MPA', (58, 90))	('mice', 'Species', '10090', (127, 131))	('deficiency', 'Var', (20, 30))	('inflammatory response', 'biological_process', 'GO:0006954', ('69', '90'))	('asbestos fibers', 'Disease', 'MESH:D001195', (108, 123))	('uveal melanoma', 'Phenotype', 'HP:0007716', (179, 193))	('uveal melanoma', 'Disease', (179, 193))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('asbestos fibers', 'Disease', (108, 123))	('associated', 'Reg', (40, 50))
94838	28599476	In the present study, in order to achieve an improved understanding of ccRCC, early metastatic and non-metastatic ccRCC samples were used to screen DEGs associated with metastatic ccRCC.	('DEGs', 'Var', (148, 152))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('RCC', 'Disease', (73, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('associated', 'Reg', (153, 163))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('RCC', 'Disease', (182, 185))	('RCC', 'Disease', (116, 119))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
94875	28599476	Furthermore, the loss of NR4A1 may enhance macrophage-mediated kidney injury and diseases due to a large increase in immune cell infiltration (predominantly macrophages, and to a lesser extent T cells and B cells).	('NR4A1', 'Gene', (25, 30))	('NR4A1', 'Gene', '3164', (25, 30))	('enhance', 'PosReg', (35, 42))	('increase', 'PosReg', (105, 113))	('kidney injury and diseases', 'Disease', 'MESH:D007674', (63, 89))	('loss', 'Var', (17, 21))	('immune cell infiltration', 'CPA', (117, 141))
94896	30816499	BHLHE41 knockdown significantly reduced cell proliferation and migration of A498 and CAKI-1 cells.	('BHLHE41', 'Gene', (0, 7))	('CAKI-1', 'CellLine', 'CVCL:0234', (85, 91))	('knockdown', 'Var', (8, 17))	('reduced', 'NegReg', (32, 39))	('cell proliferation', 'biological_process', 'GO:0008283', ('40', '58'))	('cell proliferation', 'CPA', (40, 58))
94916	30816499	A498 cells are Von Hippel-Lindau tumor suppressor (VHL) mutant cells and CAKI cells are VHL wild-type cells.	('mutant', 'Var', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('VHL', 'Disease', (51, 54))	('VHL', 'Disease', 'MESH:D006623', (51, 54))	('tumor suppressor', 'biological_process', 'GO:0051726', ('33', '49'))	('Von Hippel-Lindau tumor suppressor', 'Gene', (15, 49))	('A498', 'Var', (0, 4))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('33', '49'))	('Von Hippel-Lindau tumor suppressor', 'Gene', '7428', (15, 49))	('VHL', 'Disease', (88, 91))	('VHL', 'Disease', 'MESH:D006623', (88, 91))
94968	30816499	Using WST-1 assays, it was observed that the knockdown of BHLHE41 in A498 and CAKI-1 cells significantly suppressed cell proliferation at 48, 72 and 96 h detection time points (Fig.	('suppressed', 'NegReg', (105, 115))	('cell proliferation', 'biological_process', 'GO:0008283', ('116', '134'))	('BHLHE41', 'Gene', (58, 65))	('CAKI-1', 'CellLine', 'CVCL:0234', (78, 84))	('cell proliferation', 'CPA', (116, 134))	('knockdown', 'Var', (45, 54))
94974	30816499	p70S6K activity was significantly reduced in BHLHE41 knockdown A498 and CAKI-1 cells.	('activity', 'MPA', (7, 15))	('reduced', 'NegReg', (34, 41))	('knockdown', 'Var', (53, 62))	('BHLHE41', 'Gene', (45, 52))	('p70S6K', 'Gene', (0, 6))	('CAKI-1', 'CellLine', 'CVCL:0234', (72, 78))	('p70S6K', 'Gene', '6198', (0, 6))
94975	30816499	p-AKT levels were incomparable between the BHLHE41 knockdown and control cells.	('BHLHE41', 'Gene', (43, 50))	('AKT', 'Gene', (2, 5))	('AKT', 'Gene', '207', (2, 5))	('knockdown', 'Var', (51, 60))
94984	30816499	Disruption of circadian rhythms results in sleep disturbance and the progression of cancer.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('sleep disturbance', 'Disease', (43, 60))	('sleep', 'biological_process', 'GO:0030431', ('43', '48'))	('results in', 'Reg', (32, 42))	('cancer', 'Disease', (84, 90))	('sleep disturbance', 'Disease', 'MESH:D012893', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('sleep disturbance', 'Phenotype', 'HP:0002360', (43, 60))	('progression', 'CPA', (69, 80))	('Disruption', 'Var', (0, 10))
94993	30816499	Bigot et al reported an association for a single-nucleotide polymorphism rs7132434 and the risk for ccRCC.	('rs7132434', 'Mutation', 'rs7132434', (73, 82))	('association', 'Interaction', (24, 35))	('rs7132434', 'Var', (73, 82))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('single-nucleotide polymorphism rs7132434', 'Var', (42, 82))
94994	30816499	The rs7132434 polymorphism influences BHLHE41 expression.	('BHLHE41', 'Gene', (38, 45))	('influences', 'Reg', (27, 37))	('rs7132434', 'Var', (4, 13))	('expression', 'MPA', (46, 56))	('rs7132434', 'Mutation', 'rs7132434', (4, 13))
94995	30816499	Overexpressing BHLHE41 produce a larger mouse xenograft tumor, but no significant differences in ACHN cell growth rate or cell migration were observed in in vitro experiments.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('larger', 'PosReg', (33, 39))	('tumor', 'Disease', (56, 61))	('Overexpressing', 'Var', (0, 14))	('cell migration', 'biological_process', 'GO:0016477', ('122', '136'))	('cell growth', 'biological_process', 'GO:0016049', ('102', '113'))	('mouse', 'Species', '10090', (40, 45))	('BHLHE41', 'Gene', (15, 22))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
94996	30816499	In the present study, BHLHE41 knockdown was determined to significantly inhibit cell proliferation and migration in A498 and CAKI-1 ccRCC cells.	('cell proliferation', 'CPA', (80, 98))	('cell proliferation', 'biological_process', 'GO:0008283', ('80', '98'))	('RCC', 'Disease', (134, 137))	('CAKI-1', 'CellLine', 'CVCL:0234', (125, 131))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('knockdown', 'Var', (30, 39))	('inhibit', 'NegReg', (72, 79))	('RCC', 'Phenotype', 'HP:0005584', (134, 137))	('ccRCC', 'Phenotype', 'HP:0006770', (132, 137))	('BHLHE41', 'Gene', (22, 29))
95002	30816499	3'UTR hypermethylation interferes p15INK4b gene expression in primary lymphomas.	('gene expression', 'biological_process', 'GO:0010467', ('43', '58'))	('lymphomas', 'Disease', (70, 79))	('hypermethylation', 'Var', (6, 22))	('p15INK4b', 'Gene', '1030', (34, 42))	('lymphomas', 'Disease', 'MESH:D008223', (70, 79))	('expression', 'MPA', (48, 58))	('lymphomas', 'Phenotype', 'HP:0002665', (70, 79))	('p15INK4b', 'Gene', (34, 42))	('interferes', 'NegReg', (23, 33))
95004	30816499	These studies demonstrated that the methylation of the 3'UTR can affect the occurrence of tumors by regulating the level of RNA and/or protein.	('affect', 'Reg', (65, 71))	('level of RNA and/or', 'MPA', (115, 134))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('methylation', 'Var', (36, 47))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('regulating', 'Reg', (100, 110))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('RNA', 'cellular_component', 'GO:0005562', ('124', '127'))	("3'UTR", 'Protein', (55, 60))
95006	30816499	BHLHE41 knockdown reduced cell proliferation and migration of ccRCC cells.	('BHLHE41', 'Gene', (0, 7))	('knockdown', 'Var', (8, 17))	('cell proliferation', 'biological_process', 'GO:0008283', ('26', '44'))	('reduced', 'NegReg', (18, 25))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('RCC', 'Disease', (64, 67))	('cell proliferation', 'CPA', (26, 44))
95021	30538545	These results showed that TRIM2 acted as an antitumor gene and a specifi prognostic indicator for patients with ccRCC, which indicated that positive modulation of TRIM2 might be a novel treatment strategy for ccRCC.	('TRIM2', 'Gene', (163, 168))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('tumor', 'Disease', (48, 53))	('RCC', 'Disease', (211, 214))	('TRIM2', 'Gene', (26, 31))	('RCC', 'Disease', 'MESH:C538614', (211, 214))	('patients', 'Species', '9606', (98, 106))	('TRIM2', 'Gene', '23321', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('positive modulation', 'Var', (140, 159))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('TRIM2', 'Gene', '23321', (26, 31))
95068	30538545	Significantly lower TRIM2 expression was found in T stage IV and III, when contrasted to T stage I and II (Figure 1C); furthermore, lower TRIM2 expression was found in T stage IV or III compared with T stage I or II, and the same result was showed in T stage IV compared with T stage III (Figure 1D).	('expression', 'MPA', (26, 36))	('TRIM2', 'Gene', '23321', (20, 25))	('III', 'Var', (182, 185))	('TRIM2', 'Gene', '23321', (138, 143))	('lower', 'NegReg', (14, 19))	('expression', 'MPA', (144, 154))	('TRIM2', 'Gene', (20, 25))	('TRIM2', 'Gene', (138, 143))	('lower', 'NegReg', (132, 137))
95079	30538545	TRIM2 could sufficiently discriminate ccRCC with the AUC of 0.9537 (95% CI: 0.9318-0.9757; P<0.0001) from normal tissues (Figure 3A), and it could effectively distinguish ccRCC with the AUC of 0.9632 (95% CI: 0.9273-0.9991; P<0.0001) from paired normal tissues (Figure 3B).	('TRIM2', 'Gene', '23321', (0, 5))	('RCC', 'Disease', (173, 176))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('0.9537', 'Var', (60, 66))	('RCC', 'Disease', (40, 43))	('TRIM2', 'Gene', (0, 5))	('RCC', 'Disease', 'MESH:C538614', (40, 43))
95085	30538545	Patients with low TRIM2 expression exhibited shorter OS time (Figure 4A, P<0.0001).	('TRIM2', 'Gene', '23321', (18, 23))	('expression', 'MPA', (24, 34))	('shorter', 'NegReg', (45, 52))	('Patients', 'Species', '9606', (0, 8))	('OS time', 'MPA', (53, 60))	('TRIM2', 'Gene', (18, 23))	('low', 'Var', (14, 17))
95090	30538545	Univariate Cox proportion HR analysis showed the following the results: age >60 years (HR, 1.803; P<0.001), T stage (T III + VI) (HR, 3.120; P<0.001), N stage (N1) (HR, 3.823; P<0.001), M stage (M1) (HR, 4.346; P<0.001), G grade (G3 + G4) (HR, 2.639; P<0.001), and low TRIM2 expression status (HR, 1.951; P<0.001).	('N stage', 'CPA', (151, 158))	('TRIM2', 'Gene', (269, 274))	('G grade', 'CPA', (221, 228))	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('M stage', 'CPA', (186, 193))	('expression', 'MPA', (275, 285))	('TRIM2', 'Gene', '23321', (269, 274))	('T stage', 'CPA', (108, 115))	('low', 'Var', (265, 268))
95105	30538545	Overexpression of TRIM2 significantly repressed the migration and invasion abilities by transwell assays when compared with NC group (Figure 7C and D), and furthermore, the proliferation of 786-O and ACHN cells was markedly inhibited in transfection with TRIM2 compared to NC group (Figure 7E and F).	('TRIM2', 'Gene', '23321', (18, 23))	('TRIM2', 'Gene', '23321', (255, 260))	('inhibited', 'NegReg', (224, 233))	('transfection', 'Var', (237, 249))	('TRIM2', 'Gene', (18, 23))	('proliferation', 'CPA', (173, 186))	('repressed', 'NegReg', (38, 47))	('TRIM2', 'Gene', (255, 260))
95118	30538545	The dysfunction of TRIM2 may be one of the factors involved in the occurrence and development of ccRCC to a certain extent, and the association between TRIM2 and renal cancer has not been reported.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('TRIM2', 'Gene', (19, 24))	('dysfunction', 'Var', (4, 15))	('TRIM2', 'Gene', '23321', (152, 157))	('renal cancer', 'Disease', (162, 174))	('involved', 'Reg', (51, 59))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('renal cancer', 'Disease', 'MESH:D007680', (162, 174))	('TRIM2', 'Gene', '23321', (19, 24))	('renal cancer', 'Phenotype', 'HP:0009726', (162, 174))	('TRIM2', 'Gene', (152, 157))
95132	30538545	Further in vitro experiment verified that overexpressing TRIM2 inhibited ccRCC cells' proliferation and malignant.	('TRIM2', 'Gene', (57, 62))	('malignant', 'CPA', (104, 113))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('inhibited', 'NegReg', (63, 72))	('overexpressing', 'Var', (42, 56))	('TRIM2', 'Gene', '23321', (57, 62))
95159	28775935	Certain subtypes of RCC, such as those that are dependent on aerobic glycolysis due to dysfunction in one of their Krebs cycle enzymes [e.g., hereditary leiomyomatosis and renal cell cancer (HLRCC)-associated papillary type II RCC or succinate dehydrogenase (SDH)-associated RCC], may be especially well suited to imaging with PET/CT.	('SDH', 'Gene', (259, 262))	('Krebs cycle', 'biological_process', 'GO:0006099', ('115', '126'))	('succinate dehydrogenase', 'Gene', (234, 257))	('papillary type II RCC', 'Disease', (209, 230))	('Krebs', 'Chemical', '-', (115, 120))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('RCC', 'Disease', (20, 23))	('RCC', 'Disease', (227, 230))	('RCC', 'Disease', 'MESH:C538614', (275, 278))	('RCC', 'Phenotype', 'HP:0005584', (227, 230))	('RCC', 'Disease', (193, 196))	('RCC', 'Phenotype', 'HP:0005584', (193, 196))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('hereditary leiomyomatosis and renal cell cancer', 'Disease', 'MESH:C535516', (142, 189))	('RCC', 'Disease', 'MESH:C538614', (227, 230))	('succinate dehydrogenase', 'Gene', '6390', (234, 257))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('SDH', 'Gene', '6390', (259, 262))	('papillary type II RCC', 'Disease', 'MESH:C538614', (209, 230))	('papillary type', 'Phenotype', 'HP:0007482', (209, 223))	('dysfunction', 'Var', (87, 98))	('renal cell cancer', 'Phenotype', 'HP:0005584', (172, 189))	('RCC', 'Disease', (275, 278))	('RCC', 'Phenotype', 'HP:0005584', (275, 278))	('glycolysis', 'biological_process', 'GO:0006096', ('69', '79'))
95164	28775935	This study was the first clinical validation of 124I-cG250 PET as a biomarker for RCC.	('cG250', 'Chemical', 'MESH:C106533', (53, 58))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('124I-cG250 PET', 'Var', (48, 62))
95165	28775935	The chief disadvantage of using the monoclonal antibody 124I-cG250 is that its half-life is several days, requiring prolonged waiting times after injection before tumor to background ratios are adequate.	('124I-cG250', 'Var', (56, 66))	('antibody', 'cellular_component', 'GO:0042571', ('47', '55'))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('cG250', 'Chemical', 'MESH:C106533', (61, 66))	('antibody', 'cellular_component', 'GO:0019814', ('47', '55'))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('antibody', 'cellular_component', 'GO:0019815', ('47', '55'))	('tumor', 'Disease', (163, 168))	('antibody', 'molecular_function', 'GO:0003823', ('47', '55'))
95192	28775935	of diffusion-weighted imaging (DWI) studies in the characterization of renal masses showed moderate accuracy for distinguishing between benign vs. malignant lesions (86% sensitivity and 78% specificity) and low-vs. high-grade ccRCC (AUC of 0.83).	('RCC', 'Disease', 'MESH:C538614', (228, 231))	('ccRCC', 'Phenotype', 'HP:0006770', (226, 231))	('RCC', 'Disease', (228, 231))	('RCC', 'Phenotype', 'HP:0005584', (228, 231))	('renal masses', 'Phenotype', 'HP:0009726', (71, 83))	('low-vs. high-grade', 'Var', (207, 225))
95224	28775935	In patients treated with pazopanib, low levels of IL-8, HGF, osteopontin and TIMP-1 were all associated with significantly longer PFS.	('IL-8', 'Gene', (50, 54))	('low levels', 'Var', (36, 46))	('longer', 'PosReg', (123, 129))	('osteopontin', 'Gene', '6696', (61, 72))	('IL-8', 'molecular_function', 'GO:0005153', ('50', '54'))	('TIMP-1', 'Gene', (77, 83))	('patients', 'Species', '9606', (3, 11))	('pazopanib', 'Chemical', 'MESH:C516667', (25, 34))	('TIMP-1', 'Gene', '7076', (77, 83))	('osteopontin', 'Gene', (61, 72))	('HGF', 'Gene', (56, 59))	('IL-8', 'Gene', '3576', (50, 54))	('HGF', 'Gene', '3082', (56, 59))
95232	28775935	High serum LDH is an established poor prognostic factor in RCC and is part of the MSKCC risk score.	('High', 'Var', (0, 4))	('LDH', 'Protein', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
95265	28775935	performed targeted gene sequencing on four tumor specimens from patients with locally advanced or mRCC to identify known RCC mutations.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('mutations', 'Var', (125, 134))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('patients', 'Species', '9606', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('RCC', 'Disease', (99, 102))	('tumor', 'Disease', (43, 48))
95297	28775935	Due to its role in MITF transcription, it also shows positivity in translocation RCCs, as translocation RCCs involves the TFE3 or TFEB genes, which are members of the MITF family.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('MITF', 'Gene', '4286', (19, 23))	('MITF', 'Gene', (167, 171))	('MITF', 'Gene', (19, 23))	('TFEB', 'Gene', '7942', (130, 134))	('TFEB', 'Gene', (130, 134))	('TFE3', 'Gene', (122, 126))	('MITF', 'Gene', '4286', (167, 171))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('positivity', 'Var', (53, 63))	('TFE3', 'Gene', '7030', (122, 126))	('transcription', 'biological_process', 'GO:0006351', ('24', '37'))	('RCC', 'Disease', (104, 107))
95311	28775935	CD10 is also positive for Xp11.2 translocation RCC but negative for all other RCC histologies.	('CD10', 'Gene', '4311', (0, 4))	('positive', 'Reg', (13, 21))	('RCC', 'Disease', (78, 81))	('Xp11.2 translocation', 'Var', (26, 46))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('CD10', 'Gene', (0, 4))	('CD10', 'molecular_function', 'GO:0004245', ('0', '4'))
95317	28775935	Other RCC associated mutations include PBRM1, SETD2, KDM5C, PTEN, BAP1, MTOR, and TP53.	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('TP53', 'Gene', (82, 86))	('mutations', 'Var', (21, 30))	('SETD2', 'Gene', (46, 51))	('KDM5C', 'Gene', (53, 58))	('MTOR', 'Gene', (72, 76))	('PBRM1', 'Gene', '55193', (39, 44))	('BAP1', 'Gene', '8314', (66, 70))	('KDM5C', 'Gene', '8242', (53, 58))	('MTOR', 'Gene', '2475', (72, 76))	('BAP1', 'Gene', (66, 70))	('PTEN', 'Gene', (60, 64))	('PTEN', 'Gene', '5728', (60, 64))	('TP53', 'Gene', '7157', (82, 86))	('SETD2', 'Gene', '29072', (46, 51))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))	('PBRM1', 'Gene', (39, 44))
95318	28775935	By cytogenetics, VHL tumors commonly show loss of heterozygosity (LOH) of chromosome 3p, and biallelic inactivation of VHLgene (3p25), as well as gain of 5q22, loss of 6q, 8p, 9p and 14q.	('VHL', 'Disease', 'MESH:D006623', (119, 122))	('VHL', 'Disease', (119, 122))	('VHL tumors', 'Disease', (17, 27))	('VHL', 'Disease', (17, 20))	('VHL tumors', 'Disease', 'MESH:D006623', (17, 27))	('VHL', 'Disease', 'MESH:D006623', (17, 20))	('biallelic inactivation', 'Var', (93, 115))	('loss', 'Var', (160, 164))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('gain', 'PosReg', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('chromosome', 'cellular_component', 'GO:0005694', ('74', '84'))	('loss', 'NegReg', (42, 46))
95319	28775935	A more recent entity, multilocular cystic renal neoplasm of low malignant potential has also been found to be associated with 3p deletion and in some cases, VHL mutations.	('VHL', 'Disease', 'MESH:D006623', (157, 160))	('multilocular cystic renal neoplasm', 'Disease', 'MESH:D052177', (22, 56))	('cystic renal neoplasm', 'Phenotype', 'HP:0000800', (35, 56))	('VHL', 'Disease', (157, 160))	('neoplasm', 'Phenotype', 'HP:0002664', (48, 56))	('associated', 'Reg', (110, 120))	('mutations', 'Var', (161, 170))	('renal neoplasm', 'Phenotype', 'HP:0009726', (42, 56))	('multilocular cystic renal neoplasm', 'Disease', (22, 56))
95321	28775935	Papillary type II is more heterogeneous and may be associated with silencing of CDKN2A, mutations in SETD2 and NRF2-ARE pathways, TFE3 fusions, as well as some CpG island methylator phenotypes.	('SETD2', 'Gene', (101, 106))	('CDKN2A', 'Gene', '1029', (80, 86))	('Papillary type II', 'Disease', (0, 17))	('NRF2', 'Gene', '4780', (111, 115))	('SETD2', 'Gene', '29072', (101, 106))	('silencing', 'NegReg', (67, 76))	('TFE3', 'Gene', (130, 134))	('mutations', 'Var', (88, 97))	('Papillary type II', 'Disease', 'MESH:D002291', (0, 17))	('NRF2', 'Gene', (111, 115))	('associated', 'Reg', (51, 61))	('TFE3', 'Gene', '7030', (130, 134))	('CDKN2A', 'Gene', (80, 86))	('Papillary type', 'Phenotype', 'HP:0007482', (0, 14))
95322	28775935	Patients with hereditary papillary renal cancer (HPRC) develop bilateral multifocal type I tumors, while those with HLRCC, which is caused by a germline mutation of the fumarate hydratase gene, develop papillary type II tumors that characteristically have eosinophilic cytoplasm and large inclusion-like nucleoli.	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('caused by', 'Reg', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('papillary type II tumors', 'Disease', 'MESH:D002291', (202, 226))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('renal cancer', 'Phenotype', 'HP:0009726', (35, 47))	('Patients', 'Species', '9606', (0, 8))	('bilateral multifocal type I tumors', 'Disease', (63, 97))	('fumarate hydratase', 'Gene', (169, 187))	('mutation', 'Var', (153, 161))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('papillary type II tumors', 'Disease', (202, 226))	('hereditary papillary renal cancer', 'Disease', (14, 47))	('papillary renal cancer', 'Phenotype', 'HP:0006766', (25, 47))	('RCC', 'Disease', (118, 121))	('bilateral multifocal type I tumors', 'Disease', 'MESH:D009369', (63, 97))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('hereditary papillary renal cancer', 'Disease', 'MESH:D007681', (14, 47))	('papillary type', 'Phenotype', 'HP:0007482', (202, 216))	('fumarate hydratase', 'Gene', '2271', (169, 187))	('develop', 'PosReg', (194, 201))	('cytoplasm', 'cellular_component', 'GO:0005737', ('269', '278'))
95325	28775935	TFE3 and TFEB of the MiT family transcriptions factors are associated with Xp11.2 and t(6;11)(p21;q12) translocation RCCs, respectively.	('Xp11.2', 'Disease', (75, 81))	('TFEB', 'Gene', (9, 13))	('RCC', 'Disease', (117, 120))	('TFE3', 'Gene', '7030', (0, 4))	('t(6;11)(p21;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (86, 102))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('t(6;11)(p21;q12', 'Var', (86, 101))	('associated', 'Reg', (59, 69))	('TFE3', 'Gene', (0, 4))	('TFEB', 'Gene', '7942', (9, 13))
95328	28775935	Significant mutations have been found in TP53 and PTEN.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('mutations', 'Var', (12, 21))	('PTEN', 'Gene', (50, 54))	('PTEN', 'Gene', '5728', (50, 54))
95330	28775935	Oncocytoma is frequently associated with CCND1 mutations, and most commonly shows complete or partial loss of chromosome 1.	('associated', 'Reg', (25, 35))	('CCND1', 'Gene', '595', (41, 46))	('mutations', 'Var', (47, 56))	('Oncocytoma', 'Disease', 'MESH:D018249', (0, 10))	('chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('loss', 'NegReg', (102, 106))	('Oncocytoma', 'Disease', (0, 10))	('CCND1', 'Gene', (41, 46))
95332	28775935	Multiple chRCCs, oncocytomas, hybrid tumors and/or oncocytosis are seen in Birt-Hogg-Dube (BHD) syndrome, caused by a mutation in the folliculin gene.	('folliculin', 'Gene', '201163', (134, 144))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('Birt-Hogg-Dube (BHD) syndrome', 'Disease', 'MESH:D058249', (75, 104))	('folliculin', 'Gene', (134, 144))	('oncocytomas', 'Disease', (17, 28))	('oncocytosis', 'Disease', (51, 62))	('oncocytomas', 'Disease', 'MESH:D018249', (17, 28))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('caused by', 'Reg', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('mutation', 'Var', (118, 126))	('tumors', 'Disease', (37, 43))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
95352	31842336	Abnormalities in their expression or function contribute to the development of multiple disorders, including cancer.	('function', 'MPA', (37, 45))	('contribute to', 'Reg', (46, 59))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Abnormalities', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('multiple disorders', 'Disease', 'MESH:D009105', (79, 97))	('cancer', 'Disease', (109, 115))	('men', 'Species', '9606', (71, 74))	('multiple disorders', 'Disease', (79, 97))	('expression', 'MPA', (23, 33))
95371	31842336	The key molecular alteration in ccRCC is von Hippel-Lindau (VHL) gene mutation, which leads to uncontrolled hypoxia-induced factor (HIF) expression, followed by the activation of several growth factor pathways, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and others.	('PDGF', 'molecular_function', 'GO:0005161', ('296', '300'))	('VEGF', 'Gene', '7422', (257, 261))	('VEGF', 'Gene', (257, 261))	('vascular endothelial growth factor', 'Gene', (221, 255))	('VHL', 'Gene', (60, 63))	('rat', 'Species', '10116', (22, 25))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('221', '255'))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('264', '294'))	('RCC', 'Disease', (34, 37))	('von Hippel-Lindau', 'Gene', (41, 58))	('growth factor pathways', 'Pathway', (187, 209))	('VHL', 'Gene', '7428', (60, 63))	('hypoxia', 'Disease', (108, 115))	('RCC', 'Disease', 'MESH:D002292', (34, 37))	('von Hippel-Lindau', 'Gene', '7428', (41, 58))	('mutation', 'Var', (70, 78))	('uncontrolled', 'MPA', (95, 107))	('hypoxia', 'Disease', 'MESH:D000860', (108, 115))	('vascular endothelial growth factor', 'Gene', '7422', (221, 255))	('activation', 'PosReg', (165, 175))
95448	31842336	In patients with a good response (PSA level after 7 months of ADT <0.2 ng/mL), it is 75 months while in patients with a poor response (PSA > 4.0 ng/mL), it is 13 months.	('PSA', 'Gene', (34, 37))	('PSA', 'Gene', '354', (34, 37))	('ADT', 'cellular_component', 'GO:0030956', ('62', '65'))	('<0.2 ng/mL', 'Var', (66, 76))	('PSA', 'Gene', (135, 138))	('patients', 'Species', '9606', (3, 11))	('PSA', 'Gene', '354', (135, 138))	('patients', 'Species', '9606', (104, 112))
95460	31842336	The relieved domain is translocated to the nucleus where it interacts with various molecules and activates multiple signaling pathways, including these involving Ras, RHOA (Ras homolog family member A), PI3K (phosphoinositide 3-kinase), PP2A (protein phosphatase 2A), MAPK (mitogen-activated protein kinase), TAKI1 (TGF-beta-activated kinase), ERK1/2 (extracellular signal-regulated kinase 1/2), and JNK (c-Jun N-terminal kinase).	('c-Jun N-terminal kinase', 'Gene', (405, 428))	('PI3K', 'Var', (203, 207))	('ERK1/2', 'Gene', (344, 350))	('ERK1/2', 'Gene', '5595;5594', (344, 350))	('ERK1', 'molecular_function', 'GO:0004707', ('344', '348'))	('extracellular signal-regulated kinase 1/2', 'Gene', '5595', (352, 393))	('TGF-beta-activated kinase', 'Gene', (316, 341))	('protein phosphatase 2A', 'molecular_function', 'GO:0050115', ('243', '265'))	('protein', 'cellular_component', 'GO:0003675', ('292', '299'))	('MAPK', 'molecular_function', 'GO:0004707', ('268', '272'))	('nucleus', 'cellular_component', 'GO:0005634', ('43', '50'))	('protein', 'cellular_component', 'GO:0003675', ('243', '250'))	('PP2A', 'Gene', '5524', (237, 241))	('RHOA', 'Gene', '387', (167, 171))	('extracellular', 'cellular_component', 'GO:0005576', ('352', '365'))	('PI3K', 'molecular_function', 'GO:0016303', ('203', '207'))	('extracellular signal-regulated kinase 1/2', 'Gene', (352, 393))	('RHOA', 'Gene', (167, 171))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))	('activates', 'PosReg', (97, 106))	('JNK', 'Gene', (400, 403))	('TGF-beta-activated kinase', 'Gene', '56911', (316, 341))	('c-Jun N-terminal kinase', 'Gene', '5599', (405, 428))	('MAPK', 'Gene', (268, 272))	('JNK', 'molecular_function', 'GO:0004705', ('400', '403'))	('JNK', 'Gene', '5599', (400, 403))	('PP2A', 'Gene', (237, 241))
95465	31842336	It appears that as tumors progress, cancer cells tend to acquire resistance to TGF-beta growth inhibitory effects due to mutations and/or functional inactivation of TGF-beta pathway elements.	('TGF-beta', 'Gene', (165, 173))	('TGF-beta', 'Gene', (79, 87))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('mutations', 'Var', (121, 130))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('men', 'Species', '9606', (185, 188))	('growth inhibitory effects', 'MPA', (88, 113))	('cancer', 'Disease', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('resistance', 'MPA', (65, 75))
95466	31842336	The most commonly mutated genes of the TGF-beta signaling pathway include TGFBR1, TGFBR2, SMAD4, and SMAD2.	('mutated', 'Var', (18, 25))	('signaling pathway', 'biological_process', 'GO:0007165', ('48', '65'))	('TGFBR2', 'Gene', '7048', (82, 88))	('TGFBR1', 'Gene', (74, 80))	('TGFBR2', 'Gene', (82, 88))
95470	31842336	The same study also showed that miRNAs contribute to the transcriptional activity of the TGF-beta pathway, indicating functional links between short-non-coding RNAs and transforming growth factor effects in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('links', 'Interaction', (129, 134))	('cancer', 'Disease', (207, 213))	('N', 'Chemical', 'MESH:D009584', (161, 162))	('TGF-beta pathway', 'Pathway', (89, 105))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('N', 'Chemical', 'MESH:D009584', (35, 36))	('short-non-coding RNAs', 'Var', (143, 164))	('transcriptional activity', 'MPA', (57, 81))
95473	31842336	Activin A and TGFB2 are involved in the formation of the ureteric bud while TGFB2 knock-out results in kidney agenesis in mice.	('mice', 'Species', '10090', (122, 126))	('knock-out', 'Var', (82, 91))	('results in', 'Reg', (92, 102))	('TGFB2', 'Gene', '21808', (14, 19))	('kidney agenesis', 'Phenotype', 'HP:0000104', (103, 118))	('TGFB2', 'Gene', (14, 19))	('kidney agenesis', 'Disease', 'MESH:D007674', (103, 118))	('formation', 'biological_process', 'GO:0009058', ('40', '49'))	('Activin', 'molecular_function', 'GO:0005160', ('0', '7'))	('kidney agenesis', 'Disease', (103, 118))	('TGFB2', 'Gene', (76, 81))	('Activin', 'molecular_function', 'GO:0016915', ('0', '7'))	('TGFB2', 'Gene', '21808', (76, 81))
95486	31842336	Moreover, an analysis of 151 cases of urinary system cancers provided evidence that an intronic variant of TGFBR1, Int7G24A (rs334354), was associated with a higher risk of RCC development.	('TGFBR1', 'Gene', (107, 113))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('associated with', 'Reg', (140, 155))	('RCC', 'Disease', (173, 176))	('cancers', 'Disease', (53, 60))	('rs334354', 'Mutation', 'rs334354', (125, 133))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('RCC', 'Disease', 'MESH:D002292', (173, 176))	('rs334354', 'Var', (125, 133))	('men', 'Species', '9606', (184, 187))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
95493	31842336	Recently, downregulation of TGFBR3 expression in advanced ccRCC tumor samples was confirmed by an independent study in which the loss of this receptor led to the stimulation of cell migration and formation of lung metastasis.	('Re', 'Chemical', 'MESH:D012211', (0, 2))	('tumor', 'Disease', (64, 69))	('TGFBR3', 'Gene', (28, 34))	('RCC', 'Disease', (60, 63))	('lung metastasis', 'CPA', (209, 224))	('loss', 'Var', (129, 133))	('stimulation of cell migration', 'biological_process', 'GO:0030335', ('162', '191'))	('RCC', 'Disease', 'MESH:D002292', (60, 63))	('cell migration', 'CPA', (177, 191))	('downregulation', 'NegReg', (10, 24))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('stimulation', 'PosReg', (162, 173))	('rat', 'Species', '10116', (185, 188))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('formation', 'biological_process', 'GO:0009058', ('196', '205'))
95499	31842336	VHL inactivation is the key molecular aberration associated with ccRCC and several studies demonstrated regulation of TGF-beta signaling by VHL status.	('inactivation', 'Var', (4, 16))	('signaling', 'biological_process', 'GO:0023052', ('127', '136'))	('RCC', 'Disease', 'MESH:D002292', (67, 70))	('TGF-beta signaling', 'MPA', (118, 136))	('RCC', 'Disease', (67, 70))	('rat', 'Species', '10116', (98, 101))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', (140, 143))	('regulation', 'biological_process', 'GO:0065007', ('104', '114'))	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', '7428', (140, 143))	('rat', 'Species', '10116', (42, 45))
95502	31842336	Pro-cancerous TGF-beta effects were confirmed by antibody-mediated neutralization of TGF-beta1, which led to tumor regression and inhibition of angiogenesis in a xenograft athymic mouse model.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('antibody', 'cellular_component', 'GO:0042571', ('49', '57'))	('neutralization', 'Var', (67, 81))	('mouse', 'Species', '10090', (180, 185))	('inhibition', 'NegReg', (130, 140))	('cancer', 'Disease', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('antibody', 'molecular_function', 'GO:0003823', ('49', '57'))	('angiogenesis', 'CPA', (144, 156))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('antibody-mediated neutralization', 'biological_process', 'GO:0097282', ('49', '81'))	('antibody', 'cellular_component', 'GO:0019815', ('49', '57'))	('TGF-beta1', 'Gene', (85, 94))	('antibody', 'cellular_component', 'GO:0019814', ('49', '57'))	('tumor', 'Disease', (109, 114))	('inhibition of angiogenesis', 'biological_process', 'GO:0016525', ('130', '156'))
95519	31842336	The silencing of FAK and PINCH1 inhibited cooperation between TGF-beta1 and RGD.	('PINCH1', 'Gene', (25, 31))	('inhibited', 'NegReg', (32, 41))	('rat', 'Species', '10116', (47, 50))	('FAK', 'Gene', (17, 20))	('FAK', 'Gene', '5747', (17, 20))	('FAK', 'molecular_function', 'GO:0004717', ('17', '20'))	('cooperation', 'Interaction', (42, 53))	('silencing', 'Var', (4, 13))	('PINCH1', 'Gene', '3987', (25, 31))
95524	31842336	Inhibition of TGF-beta1 signaling attenuates tumor growth and osteolysis in mice with ccRCC xenografts.	('attenuates', 'NegReg', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('TGF-beta1', 'Gene', (14, 23))	('osteolysis', 'Disease', 'MESH:D010014', (62, 72))	('tumor', 'Disease', (45, 50))	('RCC', 'Disease', 'MESH:D002292', (88, 91))	('RCC', 'Disease', (88, 91))	('osteolysis', 'Phenotype', 'HP:0002797', (62, 72))	('mice', 'Species', '10090', (76, 80))	('Inhibition', 'Var', (0, 10))	('osteolysis', 'Disease', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('signaling', 'biological_process', 'GO:0023052', ('24', '33'))
95530	31842336	These alterations included multiple copy number losses or gains (e.g., of TGFB1, TGFB3, TGFBR2, BMPR1B, ACVR2B, SMAD4, SMAD2, SMAD1, SMAD7, PITX2) as well as mutations of TGFRB2 (R522X, S320X, S320X).	('TGFBR2', 'Gene', '7048', (88, 94))	('SMAD7', 'Gene', '4092', (133, 138))	('PITX2', 'Gene', '5308', (140, 145))	('ACVR2B', 'Gene', (104, 110))	('S320X', 'Var', (186, 191))	('SMAD1', 'Gene', '4086', (126, 131))	('BMPR1B', 'Gene', '658', (96, 102))	('S320X', 'Mutation', 'p.S320X', (186, 191))	('TGFRB2', 'Gene', (171, 177))	('TGFBR2', 'Gene', (88, 94))	('TGFB1', 'Gene', '7040', (74, 79))	('mutations', 'Var', (158, 167))	('TGFB1', 'Gene', (74, 79))	('S320X', 'Var', (193, 198))	('losses', 'NegReg', (48, 54))	('R522X', 'Var', (179, 184))	('S320X', 'Mutation', 'p.S320X', (193, 198))	('TGFB3', 'Gene', '7043', (81, 86))	('gains', 'PosReg', (58, 63))	('PITX2', 'Gene', (140, 145))	('SMAD7', 'Gene', (133, 138))	('BMPR1B', 'Gene', (96, 102))	('ACVR2B', 'Gene', '93', (104, 110))	('TGFB3', 'Gene', (81, 86))	('SMAD1', 'Gene', (126, 131))	('rat', 'Species', '10116', (10, 13))	('R522X', 'Mutation', 'rs863223852', (179, 184))
95531	31842336	The functional significance of these alterations, as well as their influence on penile cancer progression, await future analyses.	('penile cancer', 'Disease', 'MESH:D009369', (80, 93))	('penile cancer', 'Disease', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('rat', 'Species', '10116', (41, 44))	('alterations', 'Var', (37, 48))
95536	31842336	In fetal testis, TGF-beta attenuates proliferation, indicating that aberrances of the TGF-beta pathway may lead to tumor development.	('lead to', 'Reg', (107, 114))	('TGF-beta', 'Gene', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('men', 'Species', '9606', (128, 131))	('tumor', 'Disease', (115, 120))	('rat', 'Species', '10116', (44, 47))	('proliferation', 'CPA', (37, 50))	('attenuates', 'NegReg', (26, 36))	('aberrances', 'Var', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
95537	31842336	Indeed, alpha-inhibin acts as a tumor suppressor and its knock-out results in the development of mixed or incompletely differentiated gonadal tumors, including intratubular, focally invasive gonadal stromal tumors in testis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('gonadal tumors', 'Phenotype', 'HP:0010785', (134, 148))	('tumor suppressor', 'biological_process', 'GO:0051726', ('32', '48'))	('results in', 'Reg', (67, 77))	('alpha-inhibin', 'Protein', (8, 21))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('intratubular', 'Disease', (160, 172))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('men', 'Species', '9606', (89, 92))	('inhibin', 'molecular_function', 'GO:0016916', ('14', '21'))	('knock-out', 'Var', (57, 66))	('inhibin', 'molecular_function', 'GO:0005160', ('14', '21'))	('invasive gonadal stromal tumors', 'Disease', 'MESH:D018312', (182, 213))	('gonadal tumors', 'Disease', 'MESH:D006058', (134, 148))	('gonadal tumors', 'Disease', (134, 148))	('rat', 'Species', '10116', (163, 166))	('mixed', 'Disease', (97, 102))	('tumor', 'Disease', (142, 147))	('invasive gonadal stromal tumors', 'Disease', (182, 213))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('32', '48'))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))
95544	31842336	In a study involving 577 tumor cases and > 700 controls, the TGFB1 Ex5-73C > T variant was positively associated with TGCT risk while Ex1-282G and 509C > T variants were linked with increased risks of seminoma and non-seminoma, respectively (Purdue at al., 2007).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('509C > T', 'Mutation', 'rs1800469', (147, 155))	('associated', 'Reg', (102, 112))	('Ex1', 'Gene', (134, 137))	('Ex1', 'Gene', '122786', (134, 137))	('tumor', 'Disease', (25, 30))	('seminoma and non-seminoma', 'Disease', 'MESH:D018239', (201, 226))	('Ex5-73C > T', 'Var', (67, 78))	('TGFB1', 'Gene', '7040', (61, 66))	('TGCT', 'Disease', (118, 122))	('Ex5-73C > T', 'Mutation', 'rs1800472', (67, 78))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('TGFB1', 'Gene', (61, 66))
95545	31842336	In the TGF-beta1 protein sequence, the Ex5-73C > T (rs1800472) variant results in a substitution of threonine with isoleucine (T263I) while Ex1-282G > C (rs1800471) changes the arginine to proline (P25R).	('Ex5-73C > T', 'Mutation', 'rs1800472', (39, 50))	('TGF-beta1', 'Gene', (7, 16))	('arginine', 'Chemical', 'MESH:D001127', (177, 185))	('P25R', 'Mutation', 'rs1800471', (198, 202))	('rs1800472', 'Mutation', 'rs1800472', (52, 61))	('results in', 'Reg', (71, 81))	('proline', 'Chemical', 'MESH:C489032', (189, 196))	('T263I', 'Mutation', 'rs1800472', (127, 132))	('changes', 'Reg', (165, 172))	('isoleucine', 'Chemical', 'MESH:C043801', (115, 125))	('threonine', 'Chemical', 'MESH:C061951', (100, 109))	('Ex1-282G > C (rs1800471', 'Var', (140, 163))	('arginine to proline', 'MPA', (177, 196))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('Ex5-73C > T', 'Var', (39, 50))	('rs1800471', 'Mutation', 'rs1800471', (154, 163))
95546	31842336	The functional consequences of these alterations are unknown, although it was suggested they could influence TGF-beta expression, with Ex5-73T causing a decrease, and Ex1-282G > C resulting in an increase of TGF-beta protein levels.	('Ex5-73T', 'Var', (135, 142))	('TGF-beta protein levels', 'MPA', (208, 231))	('increase', 'PosReg', (196, 204))	('influence', 'Reg', (99, 108))	('protein', 'cellular_component', 'GO:0003675', ('217', '224'))	('Ex1-282G > C', 'Var', (167, 179))	('TGF-beta', 'Gene', (109, 117))	('rat', 'Species', '10116', (41, 44))	('expression', 'MPA', (118, 128))	('decrease', 'NegReg', (153, 161))
95547	31842336	The -509C > T (rs1800469) variant does not change the TGF-beta1 amino acid sequence; however, it was linked with elevated plasma concentrations of TGF-beta1.	('plasma concentrations', 'MPA', (122, 143))	('-509C > T', 'Mutation', 'rs1800469', (4, 13))	('elevated', 'PosReg', (113, 121))	('elevated plasma concentrations', 'Phenotype', 'HP:0020170', (113, 143))	('rat', 'Species', '10116', (136, 139))	('rs1800469', 'Mutation', 'rs1800469', (15, 24))	('rs1800469', 'Var', (15, 24))
95548	31842336	The exact mechanism by which altered TGF-beta functioning could affect the development of TGCT is currently unknown.	('development', 'CPA', (75, 86))	('TGCT', 'Disease', (90, 94))	('altered', 'Var', (29, 36))	('affect', 'Reg', (64, 70))	('men', 'Species', '9606', (82, 85))	('TGF-beta', 'Protein', (37, 45))
95554	31842336	The associations between bladder cancer's clinical course and genetic variants of TGF-beta1 and its receptors has been confirmed by several studies.	('associations', 'Interaction', (4, 16))	('bladder cancer', 'Phenotype', 'HP:0009725', (25, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('genetic variants', 'Var', (62, 78))	('TGF-beta1', 'Gene', (82, 91))	('bladder cancer', 'Disease', 'MESH:D001749', (25, 39))	('bladder cancer', 'Disease', (25, 39))
95555	31842336	TGFB1 c.29C > T substitution (rs1800470) correlates with an increased risk of bladder cancer.	('c.29C > T', 'Mutation', 'rs1800470', (6, 15))	('TGFB1', 'Gene', (0, 5))	('bladder cancer', 'Phenotype', 'HP:0009725', (78, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('bladder cancer', 'Disease', 'MESH:D001749', (78, 92))	('bladder cancer', 'Disease', (78, 92))	('c.29C > T', 'Var', (6, 15))	('rs1800470', 'Mutation', 'rs1800470', (30, 39))	('rs1800470', 'Var', (30, 39))	('TGFB1', 'Gene', '7040', (0, 5))
95556	31842336	This SNP (Single Nucleotide Polymorphism) is located in a region encoding the hydrophobic core of the TGF-beta1 signal peptide and results in a substitution of proline with leucine in the 10th position of the amino acid sequence.	('results in a', 'Reg', (131, 143))	('leucine', 'Chemical', 'MESH:C038361', (173, 180))	('core', 'cellular_component', 'GO:0019013', ('90', '94'))	('N', 'Chemical', 'MESH:D009584', (6, 7))	('proline', 'MPA', (160, 167))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('leucine', 'MPA', (173, 180))	('substitution', 'Var', (144, 156))	('proline', 'Chemical', 'MESH:C489032', (160, 167))
95557	31842336	found Int7G24A (rs334354) intronic variant of the TGFBR1 gene frequently associates with transitional cell carcinoma (TCC) of the bladder as well as renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('cell carcinoma', 'Disease', 'MESH:D002292', (102, 116))	('renal cell carcinoma', 'Disease', (149, 169))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (149, 169))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (149, 169))	('cell carcinoma', 'Disease', (102, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('TC', 'Disease', 'MESH:D013736', (118, 120))	('rs334354', 'Mutation', 'rs334354', (16, 24))	('rs334354', 'Var', (16, 24))	('TGFBR1', 'Gene', (50, 56))	('cell carcinoma', 'Disease', 'MESH:D002292', (155, 169))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (89, 116))	('associates with', 'Reg', (73, 88))	('TCC', 'cellular_component', 'GO:0005579', ('118', '121'))
95560	31842336	Interestingly, the Int7G24A SNP is also associated with increased risks of osteosarcoma, colorectal, and breast cancer, suggestive of its general involvement in cancer predisposition.	('osteosarcoma', 'Disease', (75, 87))	('Int7G24A', 'Var', (19, 27))	('osteosarcoma', 'Disease', 'MESH:D012516', (75, 87))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('colorectal', 'Disease', 'MESH:D015179', (89, 99))	('colorectal', 'Disease', (89, 99))	('men', 'Species', '9606', (153, 156))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Disease', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('osteosarcoma', 'Phenotype', 'HP:0002669', (75, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
95565	31842336	However, it was also shown that a loss of TGFBR1 expression correlates with poor prognoses of bladder cancer patients while loss of TGFBR1 and TGFBR2 correlated with increased bladder tumor grades, which agrees with the decreased TGFBR2 expression in invasive tumors compared with superficial transitional cell carcinomas.	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (293, 320))	('patients', 'Species', '9606', (109, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (311, 320))	('cell carcinoma', 'Disease', 'MESH:D002292', (306, 320))	('invasive tumors', 'Disease', (251, 266))	('carcinomas', 'Phenotype', 'HP:0030731', (311, 321))	('carcinomas', 'Disease', 'MESH:D002277', (311, 321))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('bladder tumor', 'Phenotype', 'HP:0009725', (176, 189))	('loss', 'Var', (124, 128))	('TGFBR2', 'Gene', '7048', (143, 149))	('TGFBR2', 'Gene', '7048', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('loss', 'NegReg', (34, 38))	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('bladder cancer', 'Disease', (94, 108))	('TGFBR1', 'Gene', (132, 138))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('bladder tumor', 'Disease', (176, 189))	('carcinomas', 'Disease', (311, 321))	('transitional cell carcinomas', 'Phenotype', 'HP:0006740', (293, 321))	('TGFBR1', 'Gene', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('TGFBR2', 'Gene', (143, 149))	('TGFBR2', 'Gene', (230, 236))	('bladder tumor', 'Disease', 'MESH:D001749', (176, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('increased', 'PosReg', (166, 175))	('cell carcinoma', 'Disease', (306, 320))	('invasive tumors', 'Disease', 'MESH:D009361', (251, 266))
95580	31842336	Loss of the IQGAP1 tumor suppressor leads to increased expression of TGFBR2 and activated the TGF-beta1 signaling pathway, thereby stimulating growth of human bladder cancer cells.	('tumor suppressor', 'biological_process', 'GO:0051726', ('19', '35'))	('IQGAP1', 'Gene', (12, 18))	('TGFBR2', 'Gene', (69, 75))	('human', 'Species', '9606', (153, 158))	('tumor', 'Disease', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('bladder cancer', 'Disease', 'MESH:D001749', (159, 173))	('bladder cancer', 'Disease', (159, 173))	('increased', 'PosReg', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('bladder cancer', 'Phenotype', 'HP:0009725', (159, 173))	('growth', 'CPA', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('expression', 'MPA', (55, 65))	('IQGAP1', 'Gene', '8826', (12, 18))	('TGFBR2', 'Gene', '7048', (69, 75))	('Loss', 'Var', (0, 4))	('TGF-beta1 signaling pathway', 'Pathway', (94, 121))	('activated', 'PosReg', (80, 89))	('stimulating', 'PosReg', (131, 142))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('19', '35'))	('signaling pathway', 'biological_process', 'GO:0007165', ('104', '121'))
95585	31842336	Blockade of Shh activity inhibits TGF-beta1-induced migration, invasion, and clonogenic growth of bladder cancer cells.	('clonogenic growth', 'CPA', (77, 94))	('Shh', 'Gene', (12, 15))	('TGF-beta1-induced', 'Gene', (34, 51))	('inhibits', 'NegReg', (25, 33))	('Blockade', 'Var', (0, 8))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('bladder cancer', 'Disease', (98, 112))	('invasion', 'CPA', (63, 71))	('Shh', 'Gene', '6469', (12, 15))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('rat', 'Species', '10116', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
95589	31842336	These effects are mediated by TGFBR1, as silencing of this receptor attenuates the migration and invasiveness of T24 cells, with concomitant downregulation of pro-invasive MMP9, as well as integrins alpha2, alpha3, and beta1.	('attenuates', 'NegReg', (68, 78))	('MMP9', 'molecular_function', 'GO:0004229', ('172', '176'))	('silencing', 'Var', (41, 50))	('MMP9', 'Gene', '4318', (172, 176))	('MMP9', 'Gene', (172, 176))	('alpha2, alpha3, and beta1', 'Gene', '170589;28883;28881', (199, 224))	('pro-invasive', 'CPA', (159, 171))	('invasiveness of T24 cells', 'CPA', (97, 122))	('downregulation', 'NegReg', (141, 155))	('TGFBR1', 'Gene', (30, 36))	('rat', 'Species', '10116', (86, 89))
95597	31842336	Loss of PPM1A promotes TGF-beta1-induced EMT in vitro and correlates with bladder cancer progression and poor prognosis for patients.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TGF-beta1-induced', 'Protein', (23, 40))	('bladder cancer', 'Phenotype', 'HP:0009725', (74, 88))	('PPM1A', 'Gene', (8, 13))	('bladder cancer', 'Disease', 'MESH:D001749', (74, 88))	('promotes', 'PosReg', (14, 22))	('PPM1A', 'Gene', '5494', (8, 13))	('EMT', 'biological_process', 'GO:0001837', ('41', '44'))	('bladder cancer', 'Disease', (74, 88))	('Loss', 'Var', (0, 4))	('patients', 'Species', '9606', (124, 132))
95601	31842336	Silencing of Malat1 attenuates TGF-beta1-induced migration and invasion of bladder cancer cells and inhibits progression of tumor xenografts in mice.	('attenuates', 'NegReg', (20, 30))	('rat', 'Species', '10116', (52, 55))	('inhibits', 'NegReg', (100, 108))	('invasion of bladder cancer', 'Disease', (63, 89))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('Malat1', 'Gene', (13, 19))	('mice', 'Species', '10090', (144, 148))	('migration', 'CPA', (49, 58))	('invasion of bladder cancer', 'Disease', 'MESH:D001749', (63, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', (124, 129))	('TGF-beta1-induced', 'Gene', (31, 48))	('Silencing', 'Var', (0, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
95613	31842336	COL6A3 silencing resulted in reduced expression of TGF-beta as well as phosphorylation of SMAD2 and SMAD3.	('phosphorylation', 'MPA', (71, 86))	('COL6A3', 'Gene', (0, 6))	('TGF-beta', 'Protein', (51, 59))	('SMAD3', 'Gene', '4088', (100, 105))	('COL6A3', 'Gene', '1293', (0, 6))	('phosphorylation', 'biological_process', 'GO:0016310', ('71', '86'))	('reduced', 'NegReg', (29, 36))	('SMAD3', 'Gene', (100, 105))	('SMAD2', 'Protein', (90, 95))	('expression', 'MPA', (37, 47))	('silencing', 'Var', (7, 16))
95615	31842336	Silencing of Trim59 attenuates migration and invasion of bladder cancer cells while the presence of TGF-beta1 relieves the suppressive effect of Trim59 knock-out.	('attenuates', 'NegReg', (20, 30))	('Trim59', 'Gene', '286827', (145, 151))	('Trim59', 'Gene', '286827', (13, 19))	('invasion of bladder cancer', 'Disease', (45, 71))	('TGF-beta1', 'Gene', (100, 109))	('Trim59', 'Gene', (13, 19))	('invasion of bladder cancer', 'Disease', 'MESH:D001749', (45, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('rat', 'Species', '10116', (34, 37))	('Silencing', 'Var', (0, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (57, 71))	('Trim59', 'Gene', (145, 151))
95619	31842336	It is thus difficult to conclude to what extent the silencing of both genes contributed to the attenuation of MSC tumor growth stimulatory effects.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('silencing', 'Var', (52, 61))	('attenuation', 'NegReg', (95, 106))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('MSC', 'Disease', (110, 113))	('tumor', 'Disease', (114, 119))
95629	31842336	The importance of TGF-beta receptors in bladder cancer is underscored by studies that demonstrated that Tgfbr2 knock-out or Tgfbr1 inhibition attenuates growth and progression of chemically-induced bladder tumors in mice while TGFBR3 knock-down in a human T24 bladder cancer cell line results in reduced viability, colony formation, migration, and invasion.	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('formation', 'biological_process', 'GO:0009058', ('322', '331'))	('Tgfbr1', 'Gene', (124, 130))	('bladder tumors', 'Disease', (198, 212))	('migration', 'CPA', (333, 342))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('bladder tumors', 'Phenotype', 'HP:0009725', (198, 212))	('bladder cancer', 'Disease', 'MESH:D001749', (40, 54))	('bladder cancer', 'Disease', (40, 54))	('colony formation', 'CPA', (315, 331))	('knock-out', 'Var', (111, 120))	('rat', 'Species', '10116', (93, 96))	('bladder cancer', 'Phenotype', 'HP:0009725', (40, 54))	('progression', 'CPA', (164, 175))	('mice', 'Species', '10090', (216, 220))	('bladder tumor', 'Phenotype', 'HP:0009725', (198, 211))	('bladder cancer', 'Disease', 'MESH:D001749', (260, 274))	('bladder cancer', 'Disease', (260, 274))	('invasion', 'CPA', (348, 356))	('Tgfbr1', 'Gene', '21812', (124, 130))	('bladder tumors', 'Disease', 'MESH:D001749', (198, 212))	('Tgfbr2', 'Gene', (104, 110))	('bladder cancer', 'Phenotype', 'HP:0009725', (260, 274))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('rat', 'Species', '10116', (336, 339))	('human', 'Species', '9606', (250, 255))	('inhibition attenuates', 'NegReg', (131, 152))
95630	31842336	Deletion of Tgfbr2 decreased the population of cancer stem cells, attenuated proliferation, and induced apoptosis of bladder cancer cells in vivo.	('attenuated', 'NegReg', (66, 76))	('induced', 'Reg', (96, 103))	('apoptosis', 'biological_process', 'GO:0097194', ('104', '113'))	('apoptosis', 'biological_process', 'GO:0006915', ('104', '113'))	('apoptosis', 'CPA', (104, 113))	('cancer', 'Disease', (47, 53))	('bladder cancer', 'Disease', 'MESH:D001749', (117, 131))	('cancer', 'Disease', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('proliferation', 'CPA', (77, 90))	('bladder cancer', 'Disease', (117, 131))	('Deletion', 'Var', (0, 8))	('rat', 'Species', '10116', (84, 87))	('Tgfbr2', 'Gene', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (117, 131))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('decreased', 'NegReg', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
95631	31842336	Furthermore, conditional knock-out of Tgfbr2 decreased EMT as indicated by lowered expression of mesenchymal markers, including vimentin, Slug, Snai1, Twist, and Zeb1, with concomitant upregulation of epithelial E-cadherin.	('lowered', 'NegReg', (75, 82))	('EMT', 'CPA', (55, 58))	('vimentin', 'cellular_component', 'GO:0045098', ('128', '136'))	('decreased EMT', 'Phenotype', 'HP:0032198', (45, 58))	('E-cadherin', 'Gene', (212, 222))	('expression', 'MPA', (83, 93))	('E-cadherin', 'Gene', '999', (212, 222))	('Tgfbr2', 'Gene', (38, 44))	('vimentin', 'Gene', '7431', (128, 136))	('vimentin', 'Gene', (128, 136))	('Twist', 'Gene', '7291', (151, 156))	('Zeb1', 'Gene', '6935', (162, 166))	('vimentin', 'cellular_component', 'GO:0045099', ('128', '136'))	('knock-out', 'Var', (25, 34))	('Zeb1', 'Gene', (162, 166))	('cadherin', 'molecular_function', 'GO:0008014', ('214', '222'))	('Snai1', 'Gene', '6615', (144, 149))	('Snai1', 'Gene', (144, 149))	('decreased', 'NegReg', (45, 54))	('Twist', 'Gene', (151, 156))	('upregulation', 'PosReg', (185, 197))	('EMT', 'biological_process', 'GO:0001837', ('55', '58'))
95632	31842336	Notably, TGFBR2 mutations are frequently found in bladder cancer patients.	('found', 'Reg', (41, 46))	('bladder cancer', 'Phenotype', 'HP:0009725', (50, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('bladder cancer', 'Disease', 'MESH:D001749', (50, 64))	('mutations', 'Var', (16, 25))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('TGFBR2', 'Gene', (9, 15))	('bladder cancer', 'Disease', (50, 64))	('patients', 'Species', '9606', (65, 73))	('TGFBR2', 'Gene', '7048', (9, 15))
95633	31842336	Glu269 to Lys mutation (G A) facilitates TGF-beta1-induced invasion of bladder cancer cells.	('invasion of bladder cancer', 'Disease', 'MESH:D001749', (59, 85))	('TGF-beta1-induced', 'Gene', (41, 58))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Glu269 to Lys', 'Mutation', 'p.E269K', (0, 13))	('Glu269 to Lys mutation', 'Var', (0, 22))	('facilitates', 'PosReg', (29, 40))	('bladder cancer', 'Phenotype', 'HP:0009725', (71, 85))	('invasion of bladder cancer', 'Disease', (59, 85))
95642	31842336	Specifically, ectopic expression of GDF-9 in bladder cancer cell lines attenuated cell growth, and reduced migration and adhesion.	('rat', 'Species', '10116', (110, 113))	('GDF-9', 'Gene', '2661', (36, 41))	('cell growth', 'biological_process', 'GO:0016049', ('82', '93'))	('bladder cancer', 'Phenotype', 'HP:0009725', (45, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('attenuated', 'NegReg', (71, 81))	('reduced', 'NegReg', (99, 106))	('cell growth', 'CPA', (82, 93))	('GDF-9', 'Gene', (36, 41))	('ectopic expression', 'Var', (14, 32))	('bladder cancer', 'Disease', 'MESH:D001749', (45, 59))	('bladder cancer', 'Disease', (45, 59))
95645	31842336	Remarkably, GDF-15 knock-out resulted in reverse effects.	('GDF-15', 'Gene', '9518', (12, 18))	('GDF-15', 'Gene', (12, 18))	('Re', 'Chemical', 'MESH:D012211', (0, 2))	('knock-out', 'Var', (19, 28))
95647	31842336	The GDF-15 evaluation in bladder cancer cell lines suggested that its expression could be reduced in bladder tumors, possibly due to DNA hypermethylation as well p53 inactivation in bladder cancer cells.	('reduced', 'NegReg', (90, 97))	('p53', 'Gene', (162, 165))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('bladder cancer', 'Disease', 'MESH:D001749', (25, 39))	('bladder cancer', 'Disease', (25, 39))	('bladder tumors', 'Disease', 'MESH:D001749', (101, 115))	('bladder cancer', 'Phenotype', 'HP:0009725', (25, 39))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('bladder cancer', 'Disease', 'MESH:D001749', (182, 196))	('bladder cancer', 'Disease', (182, 196))	('GDF-15', 'Gene', '9518', (4, 10))	('bladder cancer', 'Phenotype', 'HP:0009725', (182, 196))	('bladder tumors', 'Disease', (101, 115))	('expression', 'MPA', (70, 80))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('133', '153'))	('bladder tumors', 'Phenotype', 'HP:0009725', (101, 115))	('GDF-15', 'Gene', (4, 10))	('bladder tumor', 'Phenotype', 'HP:0009725', (101, 114))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('p53', 'Gene', '7157', (162, 165))	('inactivation', 'Var', (166, 178))	('hypermethylation', 'Var', (137, 153))
95657	31842336	Contrarily, earlier research reported a lack of promoter methylation and mutations in the TGFBR2 gene.	('TGFBR2', 'Gene', '7048', (90, 96))	('TGFBR2', 'Gene', (90, 96))	('methylation', 'biological_process', 'GO:0032259', ('57', '68'))	('mutations', 'Var', (73, 82))
95664	31842336	Furthermore, the expression of TGFBR2 is suppressed by DHT, which attenuates the binding of Sp1 to its promoter.	('binding', 'molecular_function', 'GO:0005488', ('81', '88'))	('TGFBR2', 'Gene', (31, 37))	('expression', 'MPA', (17, 27))	('suppressed', 'NegReg', (41, 51))	('TGFBR2', 'Gene', '7048', (31, 37))	('DHT', 'Var', (55, 58))	('binding', 'Interaction', (81, 88))	('DHT', 'Chemical', 'MESH:D013196', (55, 58))
95666	31842336	AR mutations or loss, which lead to androgen resistance in differentiated prostate cancers, contribute to TGF-beta overexpression, stimulation of growth, viability, and aggressiveness of prostate cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('prostate cancer', 'Phenotype', 'HP:0012125', (74, 89))	('androgen resistance', 'MPA', (36, 55))	('overexpression', 'PosReg', (115, 129))	('aggressiveness of prostate cancer', 'Disease', (169, 202))	('prostate cancers', 'Phenotype', 'HP:0012125', (74, 90))	('aggressiveness', 'Phenotype', 'HP:0000718', (169, 183))	('prostate cancers', 'Disease', (74, 90))	('aggressiveness of prostate cancer', 'Disease', 'MESH:D011471', (169, 202))	('androgen resistance', 'Phenotype', 'HP:0008226', (36, 55))	('TGF-beta', 'Gene', (106, 114))	('growth', 'MPA', (146, 152))	('AR', 'Gene', '367', (0, 2))	('stimulation of growth', 'biological_process', 'GO:0045927', ('131', '152'))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('viability', 'CPA', (154, 163))	('androgen', 'Chemical', 'MESH:D000728', (36, 44))	('loss', 'NegReg', (16, 20))	('prostate cancer', 'Phenotype', 'HP:0012125', (187, 202))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('prostate cancers', 'Disease', 'MESH:D011471', (74, 90))	('mutations', 'Var', (3, 12))	('stimulation', 'PosReg', (131, 142))
95677	31842336	Specifically, PI3K/AKT inhibition attenuates TGF-beta-induced expression of vimentin, downregulation of keratin, and increased cell motility.	('attenuates', 'NegReg', (34, 44))	('vimentin', 'Gene', '7431', (76, 84))	('TGF-beta-induced', 'Gene', (45, 61))	('increased', 'PosReg', (117, 126))	('inhibition', 'Var', (23, 33))	('rat', 'Species', '10116', (106, 109))	('expression', 'MPA', (62, 72))	('AKT', 'Gene', '207', (19, 22))	('vimentin', 'cellular_component', 'GO:0045099', ('76', '84'))	('vimentin', 'Gene', (76, 84))	('cell motility', 'CPA', (127, 140))	('vimentin', 'cellular_component', 'GO:0045098', ('76', '84'))	('downregulation', 'NegReg', (86, 100))	('AKT', 'Gene', (19, 22))	('cell motility', 'biological_process', 'GO:0048870', ('127', '140'))	('PI3K', 'molecular_function', 'GO:0016303', ('14', '18'))	('keratin', 'Protein', (104, 111))
95680	31842336	Inhibition of either TGF-beta or NF-kappabeta suppressed the invasion of cancer cells and the EMT process.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('EMT', 'biological_process', 'GO:0001837', ('94', '97'))	('TGF-beta', 'Protein', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('NF-kappabeta', 'Gene', (33, 45))	('EMT process', 'CPA', (94, 105))	('NF-kappabeta', 'Gene', '4790', (33, 45))	('Inhibition', 'Var', (0, 10))	('suppressed', 'NegReg', (46, 56))
95687	31842336	It was therefore suggested that blocking of TGF-beta signaling in the prostate tumor microenvironment could inhibit cancer progression.	('prostate tumor', 'Phenotype', 'HP:0100787', (70, 84))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('cancer', 'Disease', (116, 122))	('men', 'Species', '9606', (97, 100))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('inhibit', 'NegReg', (108, 115))	('prostate tumor', 'Disease', 'MESH:D011471', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('TGF-beta', 'Protein', (44, 52))	('blocking', 'Var', (32, 40))	('prostate tumor', 'Disease', (70, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
95694	31842336	Remarkably, PMEAP1 knock-out induces TGF-beta signaling and the formation of bone metastases, indicating negative feedback regulation between the two genes.	('bone metastases', 'Disease', (77, 92))	('PMEAP1', 'Gene', (12, 18))	('Re', 'Chemical', 'MESH:D012211', (0, 2))	('knock-out', 'Var', (19, 28))	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('TGF-beta signaling', 'MPA', (37, 55))	('regulation', 'biological_process', 'GO:0065007', ('123', '133'))	('formation', 'biological_process', 'GO:0009058', ('64', '73'))	('induces', 'PosReg', (29, 36))	('bone metastases', 'Disease', 'MESH:D009362', (77, 92))
95716	31842336	Inhibition of miR-629 results in suppression of TGF-beta-dependent induction of SMAD2/3 and SMAD4 through upregulation of TRIM33 expression.	('miR-629', 'Gene', '693214', (14, 21))	('induction', 'MPA', (67, 76))	('expression', 'MPA', (129, 139))	('SMAD4', 'Gene', (92, 97))	('SMAD2/3', 'Gene', (80, 87))	('miR-629', 'Gene', (14, 21))	('suppression', 'NegReg', (33, 44))	('TGF-beta-dependent', 'Protein', (48, 66))	('Inhibition', 'Var', (0, 10))	('upregulation', 'PosReg', (106, 118))	('TRIM33', 'Gene', '51592', (122, 128))	('TRIM33', 'Gene', (122, 128))
95721	31842336	Remarkably, induced expression of TAK1 leads to stimulation of tumor growth, which can be inhibited by overexpression of miR-486-5p.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('Re', 'Chemical', 'MESH:D012211', (0, 2))	('TAK1', 'Gene', (34, 38))	('expression', 'Var', (20, 30))	('stimulation', 'PosReg', (48, 59))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('miR', 'Gene', '220972', (121, 124))	('miR', 'Gene', (121, 124))	('TAK1', 'Gene', '6885', (34, 38))
95722	31842336	miRNAs can also interfere with TGF-beta-induced signaling in renal cancer cells.	('renal cancer', 'Phenotype', 'HP:0009726', (61, 73))	('interfere', 'NegReg', (16, 25))	('renal cancer', 'Disease', 'MESH:D007680', (61, 73))	('TGF-beta-induced signaling', 'MPA', (31, 57))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('miRNAs', 'Var', (0, 6))	('renal cancer', 'Disease', (61, 73))
95732	31842336	Inhibition of miR-25-3p potentiates the TGF-beta1-stimulatory effect on the expression of adhesion proteins, indicating its interference with the cellular effects of transforming growth factor.	('adhesion proteins', 'Protein', (90, 107))	('expression', 'MPA', (76, 86))	('Inhibition', 'Var', (0, 10))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('TGF-beta1-stimulatory', 'Gene', (40, 61))	('potentiates', 'PosReg', (24, 35))
95742	31842336	The global analysis of 782 miRNAs in germ-cell tumors revealed that TGF-beta signaling was one of the two predicted pathways most highly targeted by miRNAs that were differentially expressed in yolk sack tumors (YSTs) compared with germinomatous tumors (GERs).	('germinomatous tumors', 'Disease', (232, 252))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('signaling', 'biological_process', 'GO:0023052', ('77', '86'))	('TGF-beta', 'Gene', (68, 76))	('tumors', 'Disease', (246, 252))	('tumors', 'Disease', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('yolk sack tumors', 'Disease', (194, 210))	('tumors', 'Disease', (204, 210))	('GERs', 'Disease', (254, 258))	('yolk sack tumors', 'Disease', 'MESH:D018240', (194, 210))	('yolk', 'cellular_component', 'GO:0060417', ('194', '198'))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('miRNAs', 'Var', (149, 155))	('GERs', 'Disease', 'MESH:D009369', (254, 258))	('germinomatous tumors', 'Disease', 'MESH:D009369', (232, 252))	('germinomatous tumors', 'Phenotype', 'HP:0100620', (232, 252))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('YSTs', 'Disease', (212, 216))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('YSTs', 'Disease', 'MESH:D018240', (212, 216))
95743	31842336	The expressions of 34 genes of the TGF-beta/BMP signaling pathway (including ligands, receptors, SMAD proteins, key target genes) were altered in YST compared with GER.	('BMP', 'Gene', '649;650;2658', (44, 47))	('expressions', 'MPA', (4, 15))	('BMP signaling pathway', 'biological_process', 'GO:0030509', ('44', '65'))	('altered', 'Reg', (135, 142))	('BMP', 'Gene', (44, 47))	('YST', 'Var', (146, 149))
95752	31842336	Induced ZEB1-AS1 expression inhibits apoptosis, promotes the cell cycle, and activates proliferation, as well as stimulates the growth of bladder cancer xenografts in mice.	('bladder cancer', 'Disease', 'MESH:D001749', (138, 152))	('bladder cancer', 'Disease', (138, 152))	('proliferation', 'CPA', (87, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (138, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cell cycle', 'biological_process', 'GO:0007049', ('61', '71'))	('rat', 'Species', '10116', (94, 97))	('apoptosis', 'CPA', (37, 46))	('ZEB1-AS1', 'Gene', (8, 16))	('stimulates', 'PosReg', (113, 123))	('growth', 'CPA', (128, 134))	('activates', 'PosReg', (77, 86))	('inhibits', 'NegReg', (28, 36))	('apoptosis', 'biological_process', 'GO:0097194', ('37', '46'))	('apoptosis', 'biological_process', 'GO:0006915', ('37', '46'))	('expression', 'Var', (17, 27))	('cell cycle', 'CPA', (61, 71))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (8, 16))	('mice', 'Species', '10090', (167, 171))	('promotes', 'PosReg', (48, 56))
95753	31842336	According to another study, miR-200b targets and inhibits the expression of MMP16.	('MMP', 'molecular_function', 'GO:0004235', ('76', '79'))	('inhibits', 'NegReg', (49, 57))	('expression', 'MPA', (62, 72))	('MMP16', 'Gene', (76, 81))	('miR-200b', 'Var', (28, 36))	('MMP16', 'Gene', '4325', (76, 81))
95754	31842336	TGF-beta1-mediated repression miR-200b leads to activation of MMP16 expression and stimulation of the migration of bladder cancer cells.	('bladder cancer', 'Disease', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('expression', 'MPA', (68, 78))	('rat', 'Species', '10116', (105, 108))	('MMP16', 'Gene', (62, 67))	('miR-200b', 'Var', (30, 38))	('bladder cancer', 'Phenotype', 'HP:0009725', (115, 129))	('activation', 'PosReg', (48, 58))	('stimulation', 'PosReg', (83, 94))	('migration', 'CPA', (102, 111))	('MMP16', 'Gene', '4325', (62, 67))	('MMP', 'molecular_function', 'GO:0004235', ('62', '65'))	('bladder cancer', 'Disease', 'MESH:D001749', (115, 129))
95758	31842336	The miRNA-TGF-beta interference also contributes to the chemoresistance of bladder cancer cells (further discussed in Chapter 6).	('miRNA-TGF-beta interference', 'Var', (4, 31))	('contributes', 'Reg', (37, 48))	('chemoresistance', 'CPA', (56, 71))	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('bladder cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))
95767	31842336	Inoculation of mice with prostate cancer cells overexpressing both miR-373-3p and TR4 results in the development of metastases, suggesting that silencing of miR-373-3p and/or TR4 might be used in prostate cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('miR', 'Gene', (157, 160))	('miR', 'Gene', (67, 70))	('men', 'Species', '9606', (217, 220))	('prostate cancer', 'Disease', 'MESH:D011471', (25, 40))	('prostate cancer', 'Phenotype', 'HP:0012125', (25, 40))	('prostate cancer', 'Disease', (25, 40))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('metastases', 'Disease', 'MESH:D009362', (116, 126))	('development', 'CPA', (101, 112))	('prostate cancer', 'Disease', 'MESH:D011471', (196, 211))	('prostate cancer', 'Phenotype', 'HP:0012125', (196, 211))	('miR', 'Gene', '220972', (157, 160))	('men', 'Species', '9606', (108, 111))	('prostate cancer', 'Disease', (196, 211))	('metastases', 'Disease', (116, 126))	('silencing', 'Var', (144, 153))	('mice', 'Species', '10090', (15, 19))	('miR', 'Gene', '220972', (67, 70))	('TR4', 'Gene', (82, 85))
95771	31842336	Transfection of prostate cancer cell lines with miR-93 mimics stimulates their proliferation, migration, and invasion.	('proliferation', 'CPA', (79, 92))	('invasion', 'CPA', (109, 117))	('rat', 'Species', '10116', (97, 100))	('miR-93', 'Gene', '407051', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('miR-93', 'Gene', (48, 54))	('migration', 'CPA', (94, 103))	('Transfection of prostate cancer', 'Disease', 'MESH:D011471', (0, 31))	('prostate cancer', 'Phenotype', 'HP:0012125', (16, 31))	('mimics', 'Var', (55, 61))	('Transfection of prostate cancer', 'Disease', (0, 31))	('stimulates', 'PosReg', (62, 72))	('rat', 'Species', '10116', (86, 89))
95787	31842336	Re-introduction of miR-539 into prostate cancer cells inhibits expression of DLX1, leading to attenuation of TGF-beta signaling, inhibition of proliferation, migration, and invasion, as well as growth of prostate cancer xenografts in mice.	('invasion', 'CPA', (173, 181))	('rat', 'Species', '10116', (150, 153))	('TGF-beta signaling', 'MPA', (109, 127))	('inhibits', 'NegReg', (54, 62))	('signaling', 'biological_process', 'GO:0023052', ('118', '127'))	('migration', 'CPA', (158, 167))	('Re', 'Chemical', 'MESH:D012211', (0, 2))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mice', 'Species', '10090', (234, 238))	('prostate cancer', 'Disease', 'MESH:D011471', (32, 47))	('prostate cancer', 'Phenotype', 'HP:0012125', (32, 47))	('prostate cancer', 'Disease', (32, 47))	('miR-539', 'Var', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('prostate cancer', 'Disease', 'MESH:D011471', (204, 219))	('expression', 'MPA', (63, 73))	('prostate cancer', 'Phenotype', 'HP:0012125', (204, 219))	('prostate cancer', 'Disease', (204, 219))	('DLX1', 'Gene', (77, 81))	('growth', 'CPA', (194, 200))	('inhibition', 'NegReg', (129, 139))	('rat', 'Species', '10116', (161, 164))	('attenuation', 'NegReg', (94, 105))	('proliferation', 'CPA', (143, 156))
95805	31842336	Loss of miR-15 and miR-16 in prostate cancer cells potentiates TGF-beta signaling by upregulating USP9X (a gene encoding an enzyme deubiquitinating SMAD4), as well as activin RIIA, an activin receptor, contributing to the survival of cancer cells in bone marrow and the formation of bone metastasis.	('contributing', 'Reg', (202, 214))	('TGF-beta signaling', 'MPA', (63, 81))	('prostate cancer', 'Disease', (29, 44))	('miR-1', 'Gene', '79187', (19, 24))	('upregulating', 'PosReg', (85, 97))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('activin', 'molecular_function', 'GO:0016915', ('167', '174'))	('miR-1', 'Gene', (8, 13))	('survival', 'CPA', (222, 230))	('USP', 'molecular_function', 'GO:0051748', ('98', '101'))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (38, 44))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))	('activin', 'Gene', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('miR-1', 'Gene', '79187', (8, 13))	('activin', 'molecular_function', 'GO:0005160', ('184', '191'))	('activin', 'Gene', (167, 174))	('USP9X', 'Gene', '8239', (98, 103))	('miR-1', 'Gene', (19, 24))	('Loss', 'Var', (0, 4))	('potentiates', 'PosReg', (51, 62))	('USP9X', 'Gene', (98, 103))	('activin', 'molecular_function', 'GO:0005160', ('167', '174'))	('activin', 'molecular_function', 'GO:0016915', ('184', '191'))	('activin', 'Gene', '83729', (184, 191))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('formation', 'biological_process', 'GO:0009058', ('270', '279'))	('prostate cancer', 'Disease', 'MESH:D011471', (29, 44))	('prostate cancer', 'Phenotype', 'HP:0012125', (29, 44))	('cancer', 'Disease', (234, 240))	('activin', 'Gene', '83729', (167, 174))
95821	31842336	In that study, antisense oligonucleotides attenuated TGF-beta secretion by bladder cancer cells, reduced colony growth in soft agar, and inhibited the growth of tumors inoculated in mice.	('attenuated', 'NegReg', (42, 52))	('inhibited', 'NegReg', (137, 146))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('bladder cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mice', 'Species', '10090', (182, 186))	('reduced', 'NegReg', (97, 104))	('secretion', 'MPA', (62, 71))	('TGF-beta secretion', 'biological_process', 'GO:0038044', ('53', '71'))	('antisense oligonucleotides', 'Var', (15, 41))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumors inoculated', 'Disease', (161, 178))	('tumors inoculated', 'Disease', 'MESH:D002372', (161, 178))	('TGF-beta', 'Protein', (53, 61))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))	('colony growth in', 'CPA', (105, 121))
95824	31842336	An example of such an approach is M7824, a bi-functional fusion protein consisting of avemulab, a monoclonal antibody directed against PD-L1 (programmed death-ligand 1) and the extracellular domain of TGFBR2.	('PD-L1', 'Gene', (135, 140))	('antibody', 'cellular_component', 'GO:0019815', ('109', '117'))	('TGFBR2', 'Gene', '7048', (201, 207))	('programmed death-ligand 1', 'Gene', (142, 167))	('programmed death-ligand 1', 'Gene', '29126', (142, 167))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('antibody', 'cellular_component', 'GO:0019814', ('109', '117'))	('antibody', 'molecular_function', 'GO:0003823', ('109', '117'))	('ligand', 'molecular_function', 'GO:0005488', ('159', '165'))	('TGFBR2', 'Gene', (201, 207))	('M7824', 'Var', (34, 39))	('antibody', 'cellular_component', 'GO:0042571', ('109', '117'))	('extracellular', 'cellular_component', 'GO:0005576', ('177', '190'))
95827	31842336	The study demonstrated that the TGFBR2 component of M7824 increased the sensitivity of urothelial transitional cell carcinoma cells towards TRAIL-mediated lysis.	('TRAIL', 'Gene', (140, 145))	('increased', 'PosReg', (58, 67))	('TGFBR2', 'Gene', '7048', (32, 38))	('urothelial transitional cell carcinoma', 'Disease', (87, 125))	('lysis', 'biological_process', 'GO:0019835', ('155', '160'))	('urothelial transitional cell carcinoma', 'Disease', 'MESH:D002295', (87, 125))	('sensitivity', 'MPA', (72, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (98, 125))	('rat', 'Species', '10116', (17, 20))	('TGFBR2', 'Gene', (32, 38))	('TRAIL', 'Gene', '8743', (140, 145))	('M7824', 'Var', (52, 57))
95828	31842336	Compared to the sole PD-L1 blockade, M7824 also stimulated antigen-specific CD8+-mediated tumor cell lysis.	('M7824', 'Var', (37, 42))	('antigen-specific CD8+-mediated', 'MPA', (59, 89))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('lysis', 'biological_process', 'GO:0019835', ('101', '106'))	('stimulated', 'PosReg', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
95829	31842336	Mechanistically, treatment of bladder cancer cells with M7824 altered the expression of genes involved in the angiogenesis process, remodeling of the extracellular matrix, EMT, as well as extracellular markers involved in immunogenic modulation.	('expression', 'MPA', (74, 84))	('altered', 'Reg', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('angiogenesis', 'biological_process', 'GO:0001525', ('110', '122'))	('bladder cancer', 'Disease', 'MESH:D001749', (30, 44))	('bladder cancer', 'Disease', (30, 44))	('men', 'Species', '9606', (22, 25))	('extracellular', 'cellular_component', 'GO:0005576', ('188', '201'))	('EMT', 'biological_process', 'GO:0001837', ('172', '175'))	('M7824', 'Var', (56, 61))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('150', '170'))	('angiogenesis', 'CPA', (110, 122))	('bladder cancer', 'Phenotype', 'HP:0009725', (30, 44))
95831	31842336	TGF-beta +C28.>T polymorphism (in other studies described as c.-1347C > T, -509C > T, and rs1800469) was linked with patients' outcome to BCG (Bacillus Calmette-Guerin) immunotherapy.	('linked with', 'Reg', (105, 116))	('rs1800469', 'Mutation', 'rs1800469', (90, 99))	('c.-1347C > T', 'Var', (61, 73))	('c.-1347C > T', 'Mutation', 'rs1800469', (61, 73))	('-509C > T', 'Mutation', 'rs1800469', (75, 84))	('rs1800469', 'Var', (90, 99))	('patients', 'Species', '9606', (117, 125))	('Bacillus Calmette-Guerin', 'Species', '33892', (143, 167))	('BCG', 'Species', '33892', (138, 141))	('TGF-beta +C28.', 'Gene', (0, 14))
95833	31842336	Interestingly, this genotype is associated with increased TGF-beta expression when compared with CC homozygotes, and individuals with T substitution have twice higher TGF-beta1 plasma concentrations when compared with CC carriers.	('increased', 'PosReg', (48, 57))	('higher', 'PosReg', (160, 166))	('rat', 'Species', '10116', (191, 194))	('T substitution', 'Var', (134, 148))	('TGF-beta', 'Protein', (58, 66))	('expression', 'MPA', (67, 77))	('increased TGF-beta', 'Phenotype', 'HP:0030269', (48, 66))	('TGF-beta1 plasma concentrations', 'MPA', (167, 198))
95878	31723226	Tailoring treatments to specific groups of patients becomes very popular in recent years due to the confirmation that the fundamental biology of each patient is unique, such as DNA, RNA, protein and methylation.	('patient', 'Species', '9606', (150, 157))	('patient', 'Species', '9606', (43, 50))	('patients', 'Species', '9606', (43, 51))	('RNA', 'cellular_component', 'GO:0005562', ('182', '185'))	('DNA', 'cellular_component', 'GO:0005574', ('177', '180'))	('methylation', 'Var', (199, 210))	('methylation', 'biological_process', 'GO:0032259', ('199', '210'))	('RNA', 'Disease', (182, 185))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))	('DNA', 'Disease', (177, 180))
95897	31723226	However, most of these studies focused on genetics variants discovery or identifying biomarkers for subtypes of RCC.	('RCC', 'Disease', (112, 115))	('variants', 'Var', (51, 59))	('RCC', 'Disease', 'MESH:D002292', (112, 115))
96012	28465356	MicroRNA-497 suppresses renal cell carcinoma by targeting VEGFR-2 in ACHN cells Abnormal expression of miRNAs contributed to cancers through regulation of proliferation, apoptosis and drug resistance of cancer cells.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('contributed', 'Reg', (110, 121))	('ACHN', 'Gene', '55323', (69, 73))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('drug resistance', 'biological_process', 'GO:0009315', ('184', '199'))	('drug resistance', 'CPA', (184, 199))	('VEGFR-2', 'Gene', '3791', (58, 65))	('drug resistance', 'biological_process', 'GO:0042493', ('184', '199'))	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (24, 44))	('expression', 'MPA', (89, 99))	('regulation', 'Reg', (141, 151))	('miRNAs', 'Var', (103, 109))	('cancer', 'Disease', (125, 131))	('apoptosis', 'biological_process', 'GO:0097194', ('170', '179'))	('apoptosis', 'biological_process', 'GO:0006915', ('170', '179'))	('apoptosis', 'CPA', (170, 179))	('regulation', 'biological_process', 'GO:0065007', ('141', '151'))	('VEGFR-2', 'Gene', (58, 65))	('proliferation', 'CPA', (155, 168))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (203, 209))	('renal cell carcinoma', 'Disease', (24, 44))	('drug resistance', 'Phenotype', 'HP:0020174', (184, 199))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (24, 44))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('ACHN', 'Gene', (69, 73))	('cancers', 'Disease', (125, 132))	('suppresses', 'NegReg', (13, 23))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
96075	28465356	miR-497 mimics also increased relative caspase-3 protein level.	('increased', 'PosReg', (20, 29))	('caspase-3', 'Gene', (39, 48))	('miR-497', 'Gene', (0, 7))	('miR-497', 'Gene', '574456', (0, 7))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('mimics', 'Var', (8, 14))	('caspase-3', 'Gene', '836', (39, 48))
96078	28465356	We found that VEGFR-2 was significantly decreased after transfection of miR-497 mimics (Figure 5A, P<0.01).	('VEGFR-2', 'Gene', '3791', (14, 21))	('miR-497', 'Gene', '574456', (72, 79))	('VEGFR-2', 'Gene', (14, 21))	('miR-497', 'Gene', (72, 79))	('transfection', 'Var', (56, 68))	('decreased', 'NegReg', (40, 49))
96097	28465356	miR-497 mimics significantly reduced cell viability and increased the apoptosis in ACHN cells.	('increased', 'PosReg', (56, 65))	('apoptosis', 'biological_process', 'GO:0097194', ('70', '79'))	('miR-497', 'Gene', (0, 7))	('miR-497', 'Gene', '574456', (0, 7))	('mimics', 'Var', (8, 14))	('reduced', 'NegReg', (29, 36))	('ACHN', 'Gene', '55323', (83, 87))	('apoptosis', 'biological_process', 'GO:0006915', ('70', '79'))	('cell viability', 'CPA', (37, 51))	('ACHN', 'Gene', (83, 87))
96099	28465356	For the behaviour examination, miR-497 mimics also decreased cell migration and invasion compared with control group; while their inhibitors did not increase the invasion and migration of ACHN cells.	('invasion', 'CPA', (80, 88))	('ACHN', 'Gene', '55323', (188, 192))	('behaviour', 'biological_process', 'GO:0007610', ('8', '17'))	('miR-497', 'Gene', (31, 38))	('decreased', 'NegReg', (51, 60))	('miR-497', 'Gene', '574456', (31, 38))	('cell migration', 'biological_process', 'GO:0016477', ('61', '75'))	('ACHN', 'Gene', (188, 192))	('cell migration', 'CPA', (61, 75))	('mimics', 'Var', (39, 45))
96112	28465356	We found that miR-497 mimics significantly increased p38 signalling pathway, however, miR-497 mimics inhibited the activation of MEK.	('p38', 'Gene', '5594', (53, 56))	('mimics', 'Var', (22, 28))	('miR-497', 'Gene', (86, 93))	('miR-497', 'Gene', '574456', (86, 93))	('signalling pathway', 'biological_process', 'GO:0007165', ('57', '75'))	('miR-497', 'Gene', (14, 21))	('p38', 'Gene', (53, 56))	('increased', 'PosReg', (43, 52))	('miR-497', 'Gene', '574456', (14, 21))	('inhibited', 'NegReg', (101, 110))	('MEK', 'Gene', (129, 132))	('MEK', 'Gene', '5609', (129, 132))
96150	32494157	A defect in one allele of the VHL gene is inherited in patients with VHL syndrome and a defect in the other allele is acquired in the affected organ.	('VHL', 'Gene', (30, 33))	('defect', 'Var', (2, 8))	('VHL syndrome', 'Disease', 'MESH:D006623', (69, 81))	('VHL', 'Gene', '7428', (30, 33))	('VHL', 'Gene', (69, 72))	('patients', 'Species', '9606', (55, 63))	('VHL', 'Gene', '7428', (69, 72))	('VHL syndrome', 'Disease', (69, 81))
96152	32494157	Alterations in the VHL tumor suppressor gene on chromosome 3 can be seen in 90% of cases of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('VHL tumor', 'Disease', (19, 28))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('23', '39'))	('Alterations', 'Var', (0, 11))	('VHL tumor', 'Disease', 'MESH:D006623', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor suppressor', 'biological_process', 'GO:0051726', ('23', '39'))	('chromosome', 'cellular_component', 'GO:0005694', ('48', '58'))
96175	32494157	Alteration in the VHL tumor suppressor gene on chromosome 3 can be seen in 90% of cases of ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('22', '38'))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Disease', (93, 96))	('VHL tumor', 'Disease', 'MESH:D006623', (18, 27))	('Alteration', 'Var', (0, 10))	('chromosome', 'cellular_component', 'GO:0005694', ('47', '57'))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('VHL tumor', 'Disease', (18, 27))	('tumor suppressor', 'biological_process', 'GO:0051726', ('22', '38'))
96186	32494157	However, the safety and quality-of-life profiles favored pazopanib in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or palmar-plantar erythrodysesthesia.	('fatigue', 'Disease', 'MESH:D005221', (149, 156))	('pazopanib', 'Var', (57, 66))	('palmar-plantar erythrodysesthesia', 'Disease', (160, 193))	('plantar erythrodysesthesia', 'Phenotype', 'HP:0100870', (167, 193))	('fatigue', 'Disease', (149, 156))	('palmar-plantar erythrodysesthesia', 'Disease', 'MESH:C536338', (160, 193))	('fatigue', 'Phenotype', 'HP:0012378', (149, 156))	('pazopanib', 'Chemical', 'MESH:C516667', (57, 66))
96187	32494157	At the same time, sunitinib was more commonly associated with thrombocytopenia but less frequently with transaminitis compared to pazopanib.	('thrombocytopenia', 'Disease', 'MESH:D013921', (62, 78))	('pazopanib', 'Chemical', 'MESH:C516667', (130, 139))	('sunitinib', 'Var', (18, 27))	('sunitinib', 'Chemical', 'MESH:D000077210', (18, 27))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (62, 78))	('thrombocytopenia', 'Disease', (62, 78))	('associated', 'Reg', (46, 56))
96199	32494157	The mTOR pathway can be activated by cancer cells via different mechanisms, including loss of p53, mutations in upstream components of PI3K (Figure 2), and paracrine growth factor production, or via mTOR complexes such as TSC1/2, PTEN, Lkb1, and Nf1.	('PTEN', 'Gene', '5728', (230, 234))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('paracrine growth factor production', 'MPA', (156, 190))	('mTOR', 'Gene', '2475', (4, 8))	('p53', 'Gene', '7157', (94, 97))	('loss', 'Var', (86, 90))	('Nf1', 'Gene', '4763', (246, 249))	('PI3K', 'Gene', (135, 139))	('mTOR', 'Gene', (199, 203))	('p53', 'Gene', (94, 97))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('PI3K', 'molecular_function', 'GO:0016303', ('135', '139'))	('mTOR', 'Gene', '2475', (199, 203))	('PTEN', 'Gene', (230, 234))	('Lkb1', 'Gene', (236, 240))	('mutations', 'Var', (99, 108))	('Nf1', 'Gene', (246, 249))	('mTOR', 'Gene', (4, 8))	('Lkb1', 'Gene', '6794', (236, 240))
96206	32494157	The concept of immunosurveillance and acquisition of somatic mutations over an individual's lifetime has been foundational to understanding tumorigenesis and, therefore, the exploration of mechanisms to potentiate mutant clone clearance via reinvigoration of immune surveillance has been a cornerstone of cancer drug development in recent years.	('cancer', 'Disease', (305, 311))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('potentiate', 'PosReg', (203, 213))	('mutant', 'Var', (214, 220))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('tumor', 'Disease', (140, 145))
96219	32494157	A more recent trial for patients with mRCC utilizing high-dose IL-2 resulted in an ORR of 25%, including 7.5% CRs, and a median response duration of 20.6 months.	('high-dose', 'Var', (53, 62))	('IL-2', 'Gene', (63, 67))	('IL-2', 'Gene', '3558', (63, 67))	('IL-2', 'molecular_function', 'GO:0005134', ('63', '67'))	('CRs', 'Disease', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('patients', 'Species', '9606', (24, 32))
96220	32494157	However, high-dose IL-2 was associated with serious toxicities such as capillary leak syndrome, hypotension, and fatal end-organ failure, thereby necessitating the judicious use of high-dose IL-2 in carefully selected patients with good performance status and preserved organ function.	('toxicities', 'Disease', (52, 62))	('capillary leak syndrome', 'Disease', 'MESH:D019559', (71, 94))	('patients', 'Species', '9606', (218, 226))	('capillary leak', 'Phenotype', 'HP:0030005', (71, 85))	('hypotension', 'Phenotype', 'HP:0002615', (96, 107))	('capillary leak syndrome', 'Disease', (71, 94))	('IL-2', 'Gene', '3558', (191, 195))	('toxicities', 'Disease', 'MESH:D064420', (52, 62))	('hypotension', 'Disease', 'MESH:D007022', (96, 107))	('IL-2', 'Gene', (191, 195))	('IL-2', 'Gene', (19, 23))	('IL-2', 'Gene', '3558', (19, 23))	('end-organ failure', 'Disease', 'MESH:D007676', (119, 136))	('IL-2', 'molecular_function', 'GO:0005134', ('19', '23'))	('IL-2', 'molecular_function', 'GO:0005134', ('191', '195'))	('high-dose', 'Var', (9, 18))	('end-organ failure', 'Disease', (119, 136))	('hypotension', 'Disease', (96, 107))
96393	31814765	Glucose consumption of 786-O cells was significantly increased after transfection by siPKM2.	('Glucose', 'Chemical', 'MESH:D005947', (0, 7))	('PKM2', 'Gene', (87, 91))	('increased', 'PosReg', (53, 62))	('transfection', 'Var', (69, 81))	('PKM2', 'Gene', '5315', (87, 91))	('Glucose consumption', 'MPA', (0, 19))
96400	31814765	An abundant and conserved microRNA (miRNA), miR-122-5p plays an important role in maintaining liver function, and its abnormal expression may contribute to the occurrence and development of various liver diseases by affecting hepatitis C virus RNA, liver metabolism and drug resistance and so on.	('miR-122-5p', 'Gene', '100188847', (44, 54))	('liver function', 'MPA', (94, 108))	('drug resistance', 'CPA', (270, 285))	('abnormal expression', 'Var', (118, 137))	('metabolism', 'biological_process', 'GO:0008152', ('255', '265'))	('liver diseases', 'Phenotype', 'HP:0001392', (198, 212))	('drug resistance', 'biological_process', 'GO:0009315', ('270', '285'))	('RNA', 'cellular_component', 'GO:0005562', ('244', '247'))	('drug resistance', 'biological_process', 'GO:0042493', ('270', '285'))	('affecting', 'Reg', (216, 225))	('hepatitis C virus', 'Species', '11103', (226, 243))	('drug resistance', 'Phenotype', 'HP:0020174', (270, 285))	('hepatitis', 'Phenotype', 'HP:0012115', (226, 235))	('liver diseases', 'Disease', 'MESH:D008107', (198, 212))	('maintaining liver function', 'Phenotype', 'HP:0001410', (82, 108))	('liver metabolism', 'MPA', (249, 265))	('hepatitis', 'MPA', (226, 235))	('miR-122-5p', 'Gene', (44, 54))	('liver diseases', 'Disease', (198, 212))	('contribute', 'Reg', (142, 152))
96428	31814765	For the lactate production assay, lactate standard was plated into 96-well plates as 0, 0.031, 0.063, 0.125, 0.25, 0.5, 1 and 2 mumol/mL.	('lactate', 'Chemical', 'MESH:D019344', (8, 15))	('0.125', 'Var', (102, 107))	('0.25', 'Var', (109, 113))	('lactate production', 'MPA', (8, 26))	('0.063', 'Var', (95, 100))	('lactate', 'Chemical', 'MESH:D019344', (34, 41))	('0.031', 'Var', (88, 93))
96448	31814765	The results showed that the expression levels of PI3K, AKT3, mTOR and PKM2 in all renal cancer cells were higher than in HK2 cells.	('expression levels', 'MPA', (28, 45))	('AKT3', 'Gene', (55, 59))	('renal cancer', 'Disease', 'MESH:D007680', (82, 94))	('PI3K', 'Var', (49, 53))	('AKT3', 'Gene', '10000', (55, 59))	('HK2', 'CellLine', 'CVCL:0302', (121, 124))	('renal cancer', 'Phenotype', 'HP:0009726', (82, 94))	('HK2', 'molecular_function', 'GO:0008256', ('121', '124'))	('PKM2', 'Gene', (70, 74))	('higher', 'PosReg', (106, 112))	('PI3K', 'molecular_function', 'GO:0016303', ('49', '53'))	('PKM2', 'Gene', '5315', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mTOR', 'Gene', (61, 65))	('renal cancer', 'Disease', (82, 94))	('mTOR', 'Gene', '2475', (61, 65))
96449	31814765	There were significant differences in the expression levels of PI3K, AKT3, mTOR and PKM2 among different renal cancer cells (Figure 2A).	('PKM2', 'Gene', '5315', (84, 88))	('renal cancer', 'Phenotype', 'HP:0009726', (105, 117))	('expression levels', 'MPA', (42, 59))	('AKT3', 'Gene', (69, 73))	('PI3K', 'molecular_function', 'GO:0016303', ('63', '67'))	('PI3K', 'Var', (63, 67))	('differences', 'Reg', (23, 34))	('AKT3', 'Gene', '10000', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('renal cancer', 'Disease', (105, 117))	('mTOR', 'Gene', (75, 79))	('mTOR', 'Gene', '2475', (75, 79))	('PKM2', 'Gene', (84, 88))	('renal cancer', 'Disease', 'MESH:D007680', (105, 117))
96466	31814765	After transfection by siPKM2, the G1 phase of 786-O cells was significantly blocked, and the S phase was significantly increased.	('blocked', 'NegReg', (76, 83))	('PKM2', 'Gene', (24, 28))	('transfection', 'Var', (6, 18))	('G1 phase', 'biological_process', 'GO:0051318', ('34', '42'))	('S phase', 'biological_process', 'GO:0051320', ('93', '100'))	('S phase', 'CPA', (93, 100))	('PKM2', 'Gene', '5315', (24, 28))	('G1 phase of 786-O cells', 'CPA', (34, 57))	('increased', 'PosReg', (119, 128))
96469	31814765	Therefore, knockdown of miR-122-5p or PKM2 could affect cell cycle progression in renal cancer cells.	('miR-122-5p', 'Gene', (24, 34))	('affect', 'Reg', (49, 55))	('renal cancer', 'Disease', 'MESH:D007680', (82, 94))	('renal cancer', 'Phenotype', 'HP:0009726', (82, 94))	('PKM2', 'Gene', (38, 42))	('cell cycle progression', 'CPA', (56, 78))	('PKM2', 'Gene', '5315', (38, 42))	('cell cycle', 'biological_process', 'GO:0007049', ('56', '66'))	('miR-122-5p', 'Gene', '100188847', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('renal cancer', 'Disease', (82, 94))	('knockdown', 'Var', (11, 20))
96472	31814765	Thus, knockdown of miR-122-5p or PKM2 could promote renal cancer cell apoptosis.	('PKM2', 'Gene', '5315', (33, 37))	('promote', 'PosReg', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('miR-122-5p', 'Gene', '100188847', (19, 29))	('apoptosis', 'biological_process', 'GO:0097194', ('70', '79'))	('renal cancer', 'Disease', (52, 64))	('apoptosis', 'biological_process', 'GO:0006915', ('70', '79'))	('renal cancer', 'Phenotype', 'HP:0009726', (52, 64))	('PKM2', 'Gene', (33, 37))	('knockdown', 'Var', (6, 15))	('renal cancer', 'Disease', 'MESH:D007680', (52, 64))	('miR-122-5p', 'Gene', (19, 29))
96498	31814765	After knockdown of miR-122-5p, the S phase of 786-O cells was significantly increased, and the G1 and G2 phases were significantly shortened.	('miR-122-5p', 'Gene', '100188847', (19, 29))	('increased', 'PosReg', (76, 85))	('S phase of 786-O cells', 'CPA', (35, 57))	('shortened', 'NegReg', (131, 140))	('G2 phases', 'CPA', (102, 111))	('knockdown', 'Var', (6, 15))	('miR-122-5p', 'Gene', (19, 29))	('S phase', 'biological_process', 'GO:0051320', ('35', '42'))
96501	31814765	Therefore, knockdown of miR-122-5p inhibited cell viability.	('miR-122-5p', 'Gene', (24, 34))	('cell viability', 'CPA', (45, 59))	('miR-122-5p', 'Gene', '100188847', (24, 34))	('inhibited', 'NegReg', (35, 44))	('knockdown', 'Var', (11, 20))
96503	31814765	It has been confirmed that its dysregulation is related to poor prognosis in renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('renal cell carcinoma', 'Disease', (77, 97))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (77, 97))	('dysregulation', 'Var', (31, 44))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (77, 97))
96507	31814765	After knockdown of PKM2, the proliferation and migration abilities of renal cancer cells were significantly decreased.	('abilities of renal cancer', 'Disease', 'MESH:D007680', (57, 82))	('PKM2', 'Gene', '5315', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('decreased', 'NegReg', (108, 117))	('renal cancer', 'Phenotype', 'HP:0009726', (70, 82))	('knockdown', 'Var', (6, 15))	('PKM2', 'Gene', (19, 23))	('abilities of renal cancer', 'Disease', (57, 82))
96508	31814765	Furthermore, we found that apoptosis and autophagy were both significantly increased after inhibiting PKM2.	('PKM2', 'Gene', (102, 106))	('autophagy', 'CPA', (41, 50))	('PKM2', 'Gene', '5315', (102, 106))	('autophagy', 'biological_process', 'GO:0016236', ('41', '50'))	('autophagy', 'biological_process', 'GO:0006914', ('41', '50'))	('apoptosis', 'CPA', (27, 36))	('inhibiting', 'Var', (91, 101))	('increased', 'PosReg', (75, 84))	('apoptosis', 'biological_process', 'GO:0097194', ('27', '36'))	('apoptosis', 'biological_process', 'GO:0006915', ('27', '36'))
96512	31814765	Because, after miR-122-5p knockdown, the expression level of PKM2 was significantly increased in 786-O cells.	('PKM2', 'Gene', (61, 65))	('PKM2', 'Gene', '5315', (61, 65))	('miR-122-5p', 'Gene', (15, 25))	('knockdown', 'Var', (26, 35))	('increased', 'PosReg', (84, 93))	('expression level', 'MPA', (41, 57))	('miR-122-5p', 'Gene', '100188847', (15, 25))
96518	31814765	Furthermore, knockdown of PKM2 contributed to metabolic reprogramming.	('PKM2', 'Gene', '5315', (26, 30))	('knockdown', 'Var', (13, 22))	('metabolic reprogramming', 'CPA', (46, 69))	('PKM2', 'Gene', (26, 30))
96524	30122945	Quantitative real-time polymerase chain reaction (PCR) was performed to demonstrate that CRPAT4 was differentially expressed between ccRCC and the normal controls and that high CRPAT4 expression significantly associated with advanced Fuhrman nuclear grades.	('associated with', 'Reg', (209, 224))	('CRPAT4', 'Gene', (177, 183))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))	('advanced Fuhrman nuclear grades', 'CPA', (225, 256))	('CRPAT4', 'Gene', (89, 95))	('high', 'Var', (172, 176))	('expression', 'MPA', (184, 194))
96525	30122945	Functional studies indicated that CRPAT4 was an HIF-1alpha regulated gene, and CRPAT4 knockdown significantly inhibited cell migration and proliferation in the absence of HIF-1alpha.	('HIF-1alpha', 'Gene', (48, 58))	('knockdown', 'Var', (86, 95))	('HIF-1alpha', 'Gene', '3091', (171, 181))	('cell migration', 'biological_process', 'GO:0016477', ('120', '134'))	('CRPAT4', 'Gene', (34, 40))	('inhibited', 'NegReg', (110, 119))	('HIF-1alpha', 'Gene', '3091', (48, 58))	('HIF-1alpha', 'Gene', (171, 181))	('CRPAT4', 'Gene', (79, 85))
96542	30122945	Survival analysis indicated that the high expression of CRPAT4 was significantly associated with bad prognosis in ccRCC patients.	('RCC', 'Disease', (116, 119))	('high', 'Var', (37, 41))	('CRPAT4', 'Protein', (56, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('patients', 'Species', '9606', (120, 128))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('associated', 'Reg', (81, 91))
96543	30122945	Functional studies revealed that CRPAT4 is regulated by HIF-1alpha, and its knockdown significantly inhibited cell proliferation and migration by inhibiting the migration-associated gene AVL9.	('CRPAT4', 'Gene', (33, 39))	('knockdown', 'Var', (76, 85))	('HIF-1alpha', 'Gene', (56, 66))	('cell proliferation', 'biological_process', 'GO:0008283', ('110', '128'))	('HIF-1alpha', 'Gene', '3091', (56, 66))	('inhibited', 'NegReg', (100, 109))	('inhibiting', 'NegReg', (146, 156))	('AVL9', 'Gene', (187, 191))
96545	30122945	Thus, our study first validated the novel lncRNA CRPAT4 in ccRCC, which has the potential to be a prognostic marker as well as a novel therapeutic target.	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('lncRNA', 'Var', (42, 48))	('CRPAT4', 'Gene', (49, 55))
96561	30122945	The primary antibodies used were anti-HIF1alpha (1:500; Cell Signaling Technology, Danvers, MA, USA), anti-HIF2alpha (1:500; R&D Systems, Minneapolis, MN, USA), anti-AVL9 (1:100; abcam, Cambridge, MA, USA), and anti-GAPDH (1:1,000; Cell Signaling Technology).	('and', 'Var', (207, 210))	('HIF2alpha', 'Gene', (107, 116))	('MN', 'CellLine', 'CVCL:U508', (151, 153))	('HIF1alpha', 'Gene', (38, 47))	('1:500;', 'Var', (118, 124))	('HIF2alpha', 'Gene', '2034', (107, 116))	('HIF1alpha', 'Gene', '3091', (38, 47))	('Signaling', 'biological_process', 'GO:0023052', ('61', '70'))	('Signaling', 'biological_process', 'GO:0023052', ('237', '246'))
96562	30122945	In brief, 24 h after transfection, uniform wounds were created across the confluent cell monolayer using sterile 200 muL pipette tips.	('pipette tips', 'Disease', 'MESH:D060725', (121, 133))	('transfection', 'Var', (21, 33))	('pipette tips', 'Disease', (121, 133))
96577	30122945	Analysis of the CRPAT4 expression in 30 ccRCC surgical specimens revealed that CRPAT4 was significantly highly expressed in the advanced Fuhrman nuclear grade tumors (G3+ G4, n=11) compared to in the low-grade tumors (G1+G2, n=19) (Figure 1D, P=0.0357).	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('highly expressed', 'PosReg', (104, 120))	('tumors', 'Disease', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('G3+ G4', 'Var', (167, 173))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('men', 'Species', '9606', (60, 63))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('CRPAT4', 'Gene', (79, 85))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))
96590	30122945	Cell counting on seven consecutive days showed that the cell proliferation was significantly inhibited in 786-O cells treated with CRPAT4 siRNAs compared with the control siRNA group, while only modest inhibitory effect on cell proliferation was observed in Caki-1 cells treated with CRPAT4 siRNAs compared with the control siRNA group (Figure 4B).	('CRPAT4 siRNAs', 'Var', (131, 144))	('cell proliferation', 'CPA', (56, 74))	('cell proliferation', 'biological_process', 'GO:0008283', ('223', '241'))	('Caki-1', 'CellLine', 'CVCL:0234', (258, 264))	('inhibited', 'NegReg', (93, 102))	('cell proliferation', 'biological_process', 'GO:0008283', ('56', '74'))
96593	30122945	Furthermore, no significant changes of the AVL9 mRNA expression were observed following CRPAT4 knockdown in both 786-O and Caki-1 cells (Figure 4E).	('Caki-1', 'CellLine', 'CVCL:0234', (123, 129))	('knockdown', 'Var', (95, 104))	('CRPAT4', 'Gene', (88, 94))	('AVL9 mRNA expression', 'MPA', (43, 63))
96604	30122945	In addition, the expression of CRPAT4 was found to be significantly increased in the more advanced tumors (Fuhrman nuclear grade G3-G4) compared with the less-advanced tumors (Fuhrman nuclear grade G1-G2).	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('Fuhrman nuclear grade G3-G4', 'Var', (107, 134))	('expression', 'MPA', (17, 27))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('CRPAT4', 'Gene', (31, 37))	('increased', 'PosReg', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumors', 'Disease', (99, 105))
96609	30122945	It is reported that the inactivating mutation of vhl was found in >80% of sporadic ccRCC cases.	('vhl', 'Gene', (49, 52))	('inactivating mutation', 'Var', (24, 45))	('found', 'Reg', (57, 62))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('RCC', 'Disease', (85, 88))	('vhl', 'Gene', '7428', (49, 52))
96610	30122945	Inactive mutation of the vhl gene, either genetic or epigenetic, leads to vhl protein deficiency, and further leads to the accumulation of HIF as well as the abnormal activation of the hypoxia pathway.	('accumulation', 'PosReg', (123, 135))	('vhl', 'Gene', '7428', (74, 77))	('vhl', 'Gene', (25, 28))	('protein deficiency', 'Disease', (78, 96))	('leads to', 'Reg', (65, 73))	('leads to', 'Reg', (110, 118))	('epigenetic', 'Var', (53, 63))	('activation', 'PosReg', (167, 177))	('vhl', 'Gene', '7428', (25, 28))	('hypoxia', 'Disease', (185, 192))	('protein deficiency', 'Disease', 'MESH:D011488', (78, 96))	('hypoxia', 'Disease', 'MESH:D000860', (185, 192))	('HIF', 'MPA', (139, 142))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('vhl', 'Gene', (74, 77))
96611	30122945	To investigate the potential regulatory effect of the hypoxia pathway on the CRPAT4 expression, we examined the CRPAT4 expression in the vhl mutant cell line 786-O and vhl wild-type cell line Caki-1 under hypoxic treatment.	('vhl', 'Gene', (168, 171))	('hypoxia', 'Disease', (54, 61))	('hypoxia', 'Disease', 'MESH:D000860', (54, 61))	('mutant', 'Var', (141, 147))	('CRPAT4', 'Gene', (112, 118))	('vhl', 'Gene', '7428', (137, 140))	('vhl', 'Gene', '7428', (168, 171))	('Caki-1', 'CellLine', 'CVCL:0234', (192, 198))	('men', 'Species', '9606', (218, 221))	('vhl', 'Gene', (137, 140))
96612	30122945	The 786-O cells constitutively and exclusively expressed HIF-2alpha but not HIF-1alpha due to the HIF-1alpha gene mutation, while Caki-1 cells expressed inducible HIF-1alpha and HIF-2alpha under hypoxic treatment.	('HIF-1alpha', 'Gene', '3091', (98, 108))	('HIF-1alpha', 'Gene', '3091', (76, 86))	('HIF-2alpha', 'Gene', '2034', (178, 188))	('HIF-1alpha', 'Gene', (76, 86))	('HIF-1alpha', 'Gene', (163, 173))	('HIF-2alpha', 'Gene', (57, 67))	('Caki-1', 'CellLine', 'CVCL:0234', (130, 136))	('men', 'Species', '9606', (208, 211))	('HIF-1alpha', 'Gene', (98, 108))	('HIF-2alpha', 'Gene', (178, 188))	('HIF-2alpha', 'Gene', '2034', (57, 67))	('mutation', 'Var', (114, 122))	('HIF-1alpha', 'Gene', '3091', (163, 173))
96615	30122945	Interestingly, a functional study revealed that CRPAT4 knockdown could significantly inhibit cell proliferation and migration only in vhl mut 786-O cells, but the effect remained modest in vhl wild-type Caki-1 cells.	('knockdown', 'Var', (55, 64))	('vhl', 'Gene', (134, 137))	('vhl', 'Gene', (189, 192))	('vhl', 'Gene', '7428', (134, 137))	('inhibit', 'NegReg', (85, 92))	('cell proliferation', 'CPA', (93, 111))	('cell proliferation', 'biological_process', 'GO:0008283', ('93', '111'))	('vhl', 'Gene', '7428', (189, 192))	('CRPAT4', 'Gene', (48, 54))	('Caki-1', 'CellLine', 'CVCL:0234', (203, 209))
96622	30122945	Notably, AVL9 knockdown significantly inhibited the human adenocarcinomic alveolar basal epithelial cell A549 migration.	('adenocarcinomic alveolar basal epithelial cell A549 migration', 'Disease', 'MESH:D002280', (58, 119))	('human', 'Species', '9606', (52, 57))	('inhibited', 'NegReg', (38, 47))	('knockdown', 'Var', (14, 23))	('AVL9', 'Gene', (9, 13))
96625	30122945	In conclusion, our study first demonstrated a novel lncRNA CRPAT4 as a potential prognostic marker as well as a risk stratification factor in ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('patients', 'Species', '9606', (148, 156))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('lncRNA', 'Var', (52, 58))
96669	33608777	Five cases of SR-B1 positivity and 4 cases of CD10 positivity in CCOC showed shoe-nail-like cells.	('positivity', 'Var', (20, 30))	('CD10', 'Gene', (46, 50))	('shoe-nail-like cells', 'CPA', (77, 97))	('SR-B1', 'Gene', '949', (14, 19))	('CD10', 'Gene', '4311', (46, 50))	('SR-B1', 'Gene', (14, 19))	('CD10', 'molecular_function', 'GO:0004245', ('46', '50'))
96670	33608777	Two cases of CD10 positivity in CCOC were clear cells.	('CD10', 'molecular_function', 'GO:0004245', ('13', '17'))	('CD10', 'Gene', (13, 17))	('positivity', 'Var', (18, 28))	('CD10', 'Gene', '4311', (13, 17))
96674	33608777	SR-B1 positivity supported the diagnosis of ccRCC with a sensitivity of 74.4% and a specificity of 83.9%.	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('SR-B1', 'Gene', '949', (0, 5))	('positivity', 'Var', (6, 16))	('ccRCC', 'Disease', (44, 49))	('SR-B1', 'Gene', (0, 5))
96675	33608777	CD10 positivity supported the diagnosis of CCOC with a sensitivity of 93.3% and a specificity of 80.6% (Table 3).	('CD10', 'Gene', '4311', (0, 4))	('positivity', 'Var', (5, 15))	('CCOC', 'Disease', (43, 47))	('CD10', 'Gene', (0, 4))	('CD10', 'molecular_function', 'GO:0004245', ('0', '4'))
96678	33608777	In addition to ccRCC and CCOC, other common cytoplasmic tumors include Perivascular epithelioid cell tumor (PEComa), MiT family translocation renal cell carcinoma, fetal adenocarcinoma of the lung, hemangioblastoma, clear cell malignant mesothelioma, and serous carcinoma of the ovary.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('PEComa', 'Disease', 'MESH:D054973', (108, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('tumors', 'Disease', (56, 62))	('Perivascular epithelioid cell tumor', 'Disease', 'MESH:D054973', (71, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('hemangioblastoma', 'Disease', 'MESH:D018325', (198, 214))	('PEComa', 'Disease', (108, 114))	('adenocarcinoma of the lung', 'Disease', (170, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (142, 162))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('serous carcinoma of the ovary', 'Disease', 'MESH:D010051', (255, 284))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (227, 249))	('ccRCC', 'Phenotype', 'HP:0006770', (15, 20))	('MiT family translocation', 'Var', (117, 141))	('Perivascular epithelioid cell tumor', 'Disease', (71, 106))	('hemangioblastoma', 'Disease', (198, 214))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (198, 214))	('malignant mesothelioma', 'Disease', (227, 249))	('renal cell carcinoma', 'Disease', (142, 162))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (170, 196))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (142, 162))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (227, 249))	('epithelioid cell tumor', 'Phenotype', 'HP:0032060', (84, 106))	('serous carcinoma of the ovary', 'Disease', (255, 284))
96679	33608777	2), such as melanin labeling S-100 and HMB45 positivity in PEComa (Fletcher et al.	('PEComa', 'Disease', (59, 65))	('positivity', 'Var', (45, 55))	('HMB45', 'Gene', (39, 44))	('PEComa', 'Disease', 'MESH:D054973', (59, 65))
96680	33608777	), TFE3 or TFEB positivity in MiT family translocation renal cell carcinoma (Moch et al.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('TFE3', 'Gene', '7030', (3, 7))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (55, 75))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (55, 75))	('TFE3', 'Gene', (3, 7))	('TFEB', 'Gene', '7942', (11, 15))	('TFEB', 'Gene', (11, 15))	('positivity', 'Var', (16, 26))	('renal cell carcinoma', 'Disease', (55, 75))
96681	33608777	), TTF-1 and NapsinA positivity in fetal adenocarcinoma of the lung (Huang and Chen), Inhibin A positivity and PAX8/PAX2 negativity in hemangioblastoma (Carney et al.	('PAX2', 'Gene', '5076', (116, 120))	('Inhibin A', 'Gene', (86, 95))	('hemangioblastoma', 'Disease', 'MESH:D018325', (135, 151))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (41, 67))	('NapsinA', 'Gene', (13, 20))	('positivity', 'Var', (21, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('TTF-1', 'Gene', '7270', (3, 8))	('PAX2', 'Gene', (116, 120))	('hemangioblastoma', 'Disease', (135, 151))	('NapsinA', 'Gene', '9476', (13, 20))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (135, 151))	('adenocarcinoma of the lung', 'Disease', (41, 67))	('PAX8', 'Gene', (111, 115))	('TTF-1', 'Gene', (3, 8))	('positivity', 'Var', (96, 106))	('PAX8', 'Gene', '7849', (111, 115))	('Inhibin', 'molecular_function', 'GO:0005160', ('86', '93'))	('Inhibin', 'molecular_function', 'GO:0016916', ('86', '93'))
96701	32047561	Genome-wide Analysis of the Alternative Splicing Profiles Revealed Novel Prognostic Index for Kidney Renal Cell Clear Cell Carcinoma Alternative splicing (AS) is a major mechanism that greatly enhanced the diversity of proteome.	('Carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('splicing', 'biological_process', 'GO:0045292', ('145', '153'))	('Alternative splicing', 'Var', (133, 153))	('Kidney Renal Cell Clear Cell Carcinoma', 'Disease', 'MESH:D002292', (94, 132))	('enhanced', 'PosReg', (193, 201))	('diversity', 'MPA', (206, 215))	('Renal Cell Clear Cell Carcinoma', 'Phenotype', 'HP:0006770', (101, 132))	('Splicing', 'biological_process', 'GO:0045292', ('40', '48'))	('Kidney Renal Cell Clear Cell Carcinoma', 'Disease', (94, 132))
96702	32047561	Mounting evidence demonstrated that aberration of AS are important steps for the initiation and progression of human cancers.	('aberration', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('human', 'Species', '9606', (111, 116))	('cancers', 'Disease', (117, 124))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))
96715	32047561	A growing body of researches suggested that aberration of AS are important steps for the initiation and progression of human cancers.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('aberration', 'Var', (44, 54))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('human', 'Species', '9606', (119, 124))
96725	32047561	For all major subtypes of RCC, exon skip (ES) was the predominant splicing type with the highest number of AS events.	('RCC', 'Disease', (26, 29))	('exon skip', 'Var', (31, 40))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('RCC', 'Disease', 'MESH:D002292', (26, 29))	('splicing', 'biological_process', 'GO:0045292', ('66', '74'))
96757	32047561	Indeed most of the prognosis-related splicing isoforms of PLAGL1 in the present study indicated worse clinical outcome (HR>1).	('PLAGL1', 'Gene', (58, 64))	('worse', 'Reg', (96, 101))	('PLAGL1', 'Gene', '5325', (58, 64))	('splicing', 'Var', (37, 45))	('splicing', 'biological_process', 'GO:0045292', ('37', '45'))	('clinical outcome', 'MPA', (102, 118))
96760	32047561	Albeit the reported tumor suppressive role of NDRG2 in KIRC, the vast majority of splice variants stemmed from NDRG2 were negatively associated with the OS of KIRC.	('splice variants', 'Var', (82, 97))	('NDRG2', 'Gene', '57447', (46, 51))	('in KIRC', 'Disease', (52, 59))	('NDRG2', 'Gene', (111, 116))	('in KIRC', 'Disease', 'MESH:D002292', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('NDRG2', 'Gene', (46, 51))	('KIRC', 'Disease', (55, 59))	('KIRC', 'Disease', 'MESH:D002292', (55, 59))	('negatively', 'NegReg', (122, 132))	('KIRC', 'Disease', 'MESH:D002292', (159, 163))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('KIRC', 'Disease', (159, 163))	('NDRG2', 'Gene', '57447', (111, 116))	('tumor', 'Disease', (20, 25))
96781	32047561	AS profiles of RCC patients were generated using SpliceSeq, a java program that provides a clear view of the splicing patterns through accurate alignment of reads and exon-inclusion or skipping splice junction.	('patients', 'Species', '9606', (19, 27))	('RCC', 'Disease', 'MESH:D002292', (15, 18))	('RCC', 'Disease', (15, 18))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('splicing', 'biological_process', 'GO:0045292', ('109', '117'))	('skipping splice junction', 'Var', (185, 209))	('exon-inclusion', 'Var', (167, 181))
96807	27806328	Patients with high NUCB2 mRNA transcription level (P = 0.005) and protein expression level (P = 0.024 and P < 0.001, respectively) had shorter cancer-specific survival in Kaplan-Meier survival curve.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mRNA transcription level', 'MPA', (25, 49))	('NUCB2', 'Gene', '4925', (19, 24))	('protein expression level', 'MPA', (66, 90))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('NUCB2', 'Gene', (19, 24))	('shorter', 'NegReg', (135, 142))	('mRNA transcription', 'biological_process', 'GO:0009299', ('25', '43'))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
96817	27806328	Additionally, the 5-year CSS rate was 91% for T1N0M0 patients which comprised the largest group of non-metastatic ccRCC patients while no specific prognostic algorithm was developed to distinct those patients with poor prognosis.	('CSS', 'CPA', (25, 28))	('patients', 'Species', '9606', (200, 208))	('patients', 'Species', '9606', (53, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('T1N0M0', 'Var', (46, 52))	('patients', 'Species', '9606', (120, 128))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('CSS', 'Chemical', '-', (25, 28))	('RCC', 'Disease', (116, 119))
96847	27806328	Furthermore, NUCB2 high expression was correlated with worse ECOG PS score (P = 0.004) and presence of necrosis (P < 0.001) in the validation set.	('ECOG', 'MPA', (61, 65))	('high', 'Var', (19, 23))	('NUCB2', 'Gene', (13, 18))	('necrosis', 'biological_process', 'GO:0070265', ('103', '111'))	('necrosis', 'Disease', (103, 111))	('necrosis', 'biological_process', 'GO:0008219', ('103', '111'))	('necrosis', 'biological_process', 'GO:0019835', ('103', '111'))	('necrosis', 'biological_process', 'GO:0008220', ('103', '111'))	('worse', 'NegReg', (55, 60))	('necrosis', 'biological_process', 'GO:0001906', ('103', '111'))	('NUCB2', 'Gene', '4925', (13, 18))	('necrosis', 'Disease', 'MESH:D009336', (103, 111))
96850	27806328	In the TCGA KIRC cohort, patients with high mRNA transcription showed worse clinical outcome (P < 0.001).	('mRNA transcription', 'MPA', (44, 62))	('patients', 'Species', '9606', (25, 33))	('high', 'Var', (39, 43))	('mRNA transcription', 'biological_process', 'GO:0009299', ('44', '62'))
96851	27806328	Also, NUCB2 expression was associated with unfavorable prognosis both in the training and validation cohort (P = 0.024 and P < 0.001, respectively).	('expression', 'Var', (12, 22))	('NUCB2', 'Gene', '4925', (6, 11))	('NUCB2', 'Gene', (6, 11))
96873	27806328	In this study, Qi et al analyzed a cohort with 188 ccRCC patients and reported that high NUCB2 expression was statistically significantly correlated to pT stage and metastasis.	('metastasis', 'CPA', (165, 175))	('high', 'Var', (84, 88))	('NUCB2', 'Gene', (89, 94))	('correlated', 'Reg', (138, 148))	('patients', 'Species', '9606', (57, 65))	('NUCB2', 'Gene', '4925', (89, 94))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('pT stage', 'Disease', (152, 160))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))	('expression', 'MPA', (95, 105))
96875	27806328	Multivariate Cox proportional analysis identified that high expression level of NUCB2 remain an independent unfavorable prognostic factor for OS in their relatively small cohort.	('NUCB2', 'Gene', '4925', (80, 85))	('Cox', 'Gene', (13, 16))	('NUCB2', 'Gene', (80, 85))	('high', 'Var', (55, 59))	('Cox', 'Gene', '1351', (13, 16))
96876	27806328	In this large validation study that included 616 patients with non-metastasis ccRCC from two distinctive medical institutions, we were able to clarify that a high NUCB2 expression level was an independent negative prognostic indicator for CSS.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('NUCB2', 'Gene', '4925', (163, 168))	('CSS', 'Disease', (239, 242))	('expression level', 'MPA', (169, 185))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('high', 'Var', (158, 162))	('CSS', 'Chemical', '-', (239, 242))	('NUCB2', 'Gene', (163, 168))	('patients', 'Species', '9606', (49, 57))	('negative', 'NegReg', (205, 213))
96893	27806328	Takagi et al reported the NUCB2 expression was positively associated with Ki67 expression, and knockdown of NUCB2 significantly impaired tumor cell proliferation and migration in endometrial carcinoma.	('NUCB2', 'Gene', '4925', (108, 113))	('NUCB2', 'Gene', (26, 31))	('endometrial carcinoma', 'Disease', (179, 200))	('associated', 'Reg', (58, 68))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (179, 200))	('impaired tumor', 'Disease', (128, 142))	('migration', 'CPA', (166, 175))	('NUCB2', 'Gene', '4925', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('NUCB2', 'Gene', (108, 113))	('knockdown', 'Var', (95, 104))	('cell proliferation', 'biological_process', 'GO:0008283', ('143', '161'))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (179, 200))	('impaired tumor', 'Disease', 'MESH:D015417', (128, 142))
96898	27806328	Nonetheless, even considering these limitations, we clearly identified that high NUCB2 expression level is an independent prognostic indicator for CSS in non-metastatic ccRCC patients.	('NUCB2', 'Gene', (81, 86))	('expression level', 'MPA', (87, 103))	('RCC', 'Disease', (171, 174))	('NUCB2', 'Gene', '4925', (81, 86))	('CSS', 'Chemical', '-', (147, 150))	('patients', 'Species', '9606', (175, 183))	('CSS', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('high', 'Var', (76, 80))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))
96899	27806328	In conclusion, we demonstrated that high expression level of NUCB2 was significantly associated with poor clinical outcome of patient with ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (139, 144))	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('RCC', 'Disease', 'MESH:C538614', (141, 144))	('patient', 'Species', '9606', (126, 133))	('NUCB2', 'Gene', '4925', (61, 66))	('expression level', 'MPA', (41, 57))	('high', 'Var', (36, 40))	('associated', 'Reg', (85, 95))	('NUCB2', 'Gene', (61, 66))
96907	32390008	Widespread dysregulation of the KP is common in RCC and is likely to contribute to tumour immune evasion, carrying implications for effective therapeutic targeting of this critical pathway Renal cancer is one of the ten most common adult cancers, accounting for over 100,000 deaths worldwide each year.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('Renal cancer', 'Phenotype', 'HP:0009726', (189, 201))	('contribute', 'Reg', (69, 79))	('cancers', 'Phenotype', 'HP:0002664', (238, 245))	('Renal cancer', 'Disease', (189, 201))	('deaths', 'Disease', (275, 281))	('adult cancers', 'Disease', 'MESH:D009369', (232, 245))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('dysregulation', 'Var', (11, 24))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('tumour', 'Disease', (83, 89))	('deaths', 'Disease', 'MESH:D003643', (275, 281))	('adult cancers', 'Disease', (232, 245))	('immune evasion', 'biological_process', 'GO:0042783', ('90', '104'))	('immune evasion', 'biological_process', 'GO:0051842', ('90', '104'))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('Renal cancer', 'Disease', 'MESH:D007680', (189, 201))
96918	32390008	More recently, alteration in the metabolism of the essential amino acid tryptophan in cancer, through the kynurenine pathway, has come to wide attention as a mechanism by which tumours may escape immune control and promote disease progression.	('immune control', 'CPA', (196, 210))	('tumours', 'Disease', 'MESH:D009369', (177, 184))	('tryptophan', 'Chemical', 'MESH:D014364', (72, 82))	('tumours', 'Disease', (177, 184))	('promote', 'PosReg', (215, 222))	('metabolism', 'biological_process', 'GO:0008152', ('33', '43'))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('kynurenine', 'Enzyme', (106, 116))	('escape', 'PosReg', (189, 195))	('metabolism', 'MPA', (33, 43))	('kynurenine', 'Chemical', 'MESH:D007737', (106, 116))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Disease', (86, 92))	('essential amino acid', 'Chemical', 'MESH:D000601', (51, 71))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('tumours', 'Phenotype', 'HP:0002664', (177, 184))	('alteration', 'Var', (15, 25))	('disease progression', 'CPA', (223, 242))
96922	32390008	The harnessing of this phenomenon by tumours has led to the development of inhibitors of IDO1 that have progressed to clinical trials in combination with CPI.	('IDO1', 'Gene', (89, 93))	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('inhibitors', 'Var', (75, 85))	('tumours', 'Disease', 'MESH:D009369', (37, 44))	('tumours', 'Disease', (37, 44))	('IDO', 'molecular_function', 'GO:0033754', ('89', '92'))	('IDO1', 'Gene', '3620', (89, 93))	('CPI', 'Chemical', '-', (154, 157))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('IDO', 'molecular_function', 'GO:0047719', ('89', '92'))
96927	32390008	HPA056942 and HPA031115), KYNU (cat.	('KYNU', 'Gene', '8942', (26, 30))	('HPA031115', 'Var', (14, 23))	('HPA056942', 'Var', (0, 9))	('KYNU', 'Gene', (26, 30))	('cat', 'molecular_function', 'GO:0004096', ('32', '35'))
96978	32390008	Taken together, these results indicate that loss of QPRT is a common event in ccRCC although regulation by VHL in vitro is cell line dependent.	('regulation', 'biological_process', 'GO:0065007', ('93', '103'))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('QPRT', 'Gene', (52, 56))	('loss', 'Var', (44, 48))
96980	32390008	The reaction catalysed by QPRT is a rate-limiting step in this pathway, therefore loss of QPRT may lead to an increase in the level of QUIN.	('loss', 'Var', (82, 86))	('increase', 'PosReg', (110, 118))	('QUIN', 'Chemical', 'MESH:D017378', (135, 139))	('QPRT', 'Gene', (90, 94))
96986	32390008	In the data set for the seven matched pairs of chromophobe RCC versus normal kidney, very similar results as for ccRCC were obtained, with expression of QPRT, KMO and HAAO being below the level of detection in tumours (with one exception).	('HAAO', 'Gene', '23498', (167, 171))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('chromophobe RCC versus normal kidney', 'Disease', (47, 83))	('RCC', 'Disease', (115, 118))	('chromophobe RCC versus normal kidney', 'Disease', 'MESH:C538614', (47, 83))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('KMO', 'Var', (159, 162))	('tumours', 'Phenotype', 'HP:0002664', (210, 217))	('HAAO', 'Gene', (167, 171))	('tumours', 'Disease', 'MESH:D009369', (210, 217))	('QPRT', 'Var', (153, 157))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('tumours', 'Disease', (210, 217))
97003	32390008	This study provides the first comprehensive demonstration of a wide and coordinate dysregulation of the kynurenine pathway in RCC and that this is a common, unifying event, highlighting its importance in the pathogenesis of these cancers and potentially providing insights of relevance to therapeutic targeting.	('kynurenine pathway', 'Pathway', (104, 122))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancers', 'Disease', 'MESH:D009369', (230, 237))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('dysregulation', 'Var', (83, 96))	('kynurenine', 'Chemical', 'MESH:D007737', (104, 114))	('cancers', 'Disease', (230, 237))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('pathogenesis', 'biological_process', 'GO:0009405', ('208', '220'))	('RCC', 'Disease', 'MESH:C538614', (126, 129))
97005	32390008	Dysregulation of the pathway was initially highlighted in neuropsychiatric disorders but has now been implicated more widely and increasingly in tumorigenesis and immune evasion.	('tumorigenesis', 'CPA', (145, 158))	('neuropsychiatric disorders', 'Disease', 'MESH:D001523', (58, 84))	('immune evasion', 'biological_process', 'GO:0042783', ('163', '177'))	('Dysregulation', 'Var', (0, 13))	('implicated', 'Reg', (102, 112))	('immune evasion', 'biological_process', 'GO:0051842', ('163', '177'))	('immune', 'MPA', (163, 169))	('neuropsychiatric disorders', 'Disease', (58, 84))
97011	32390008	However, it is apparent that this is not mainly VHL dependent and may be an indirect effect, since this was not seen in other VHL-transfectant cell line models and changes in QPRT expression were subsequently shown to occur in ccRCC independent of VHL mutation status and in chromophobe and papillary RCC tissues where VHL is not involved.	('QPRT', 'Gene', (175, 179))	('mutation', 'Var', (252, 260))	('RCC', 'Disease', 'MESH:C538614', (229, 232))	('RCC', 'Disease', (301, 304))	('RCC', 'Disease', (229, 232))	('RCC', 'Phenotype', 'HP:0005584', (229, 232))	('RCC', 'Phenotype', 'HP:0005584', (301, 304))	('expression', 'MPA', (180, 190))	('changes', 'Var', (164, 171))	('RCC', 'Disease', 'MESH:C538614', (301, 304))	('VHL', 'Gene', (248, 251))	('occur', 'Reg', (218, 223))
97012	32390008	We subsequently learnt that the 786-pRC cell line we employed also contains a p53 mutation (personal communication from WG Kaelin to R Craven), although we do not believe this to be implicated either, since p53 mutations are rarely seen in RCC.	('mutation', 'Var', (82, 90))	('p53', 'Gene', (207, 210))	('p53', 'Gene', '7157', (207, 210))	('p53', 'Gene', (78, 81))	('p53', 'Gene', '7157', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (240, 243))	('RCC', 'Disease', (240, 243))	('RCC', 'Phenotype', 'HP:0005584', (240, 243))
97014	32390008	As predicted, we found that that loss of QPRT was associated with increased QUIN in tumour tissue, and metabolomic studies of urine and tissue samples from RCC patients reported higher concentrations of quinolinate compared with healthy controls or normal tissue.	('tumour', 'Disease', (84, 90))	('patients', 'Species', '9606', (160, 168))	('increased', 'PosReg', (66, 75))	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('RCC', 'Disease', (156, 159))	('QPRT', 'Gene', (41, 45))	('higher', 'PosReg', (178, 184))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('loss', 'Var', (33, 37))	('concentrations', 'MPA', (185, 199))	('QUIN in', 'MPA', (76, 83))	('QUIN', 'Chemical', 'MESH:D017378', (76, 80))	('tumour', 'Disease', 'MESH:D009369', (84, 90))	('quinolinate', 'Chemical', 'MESH:D017378', (203, 214))
97019	32390008	In a microenvironment deficient in tryptophan, QUIN was found to inhibit proliferation of both lymphocytes and natural killer (NK) cells.	('QUIN', 'Chemical', 'MESH:D017378', (47, 51))	('proliferation', 'CPA', (73, 86))	('tryptophan', 'Chemical', 'MESH:D014364', (35, 45))	('inhibit', 'NegReg', (65, 72))	('QUIN', 'Var', (47, 51))
97025	32390008	Critically, one can expect that loss of KMO, alongside an increase in IDO expression, will lead to the accumulation in tumour tissue of kynurenine.	('Critically', 'Disease', (0, 10))	('expression', 'MPA', (74, 84))	('increase', 'PosReg', (58, 66))	('kynurenine', 'Chemical', 'MESH:D007737', (136, 146))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('loss', 'NegReg', (32, 36))	('IDO', 'molecular_function', 'GO:0047719', ('70', '73'))	('kynurenine', 'Var', (136, 146))	('accumulation', 'PosReg', (103, 115))	('tumour', 'Disease', (119, 125))	('IDO', 'Gene', '3620', (70, 73))	('Critically', 'Disease', 'MESH:D016638', (0, 10))	('IDO', 'Gene', (70, 73))	('IDO', 'molecular_function', 'GO:0033754', ('70', '73'))	('KMO', 'Gene', (40, 43))
97028	32390008	The immune-suppressive properties of kynurenine are well described, and it has been shown to inhibit T cell and NK cell proliferation and promote immune suppression via the aryl hydrocarbon receptor.	('inhibit', 'NegReg', (93, 100))	('kynurenine', 'Var', (37, 47))	('NK cell proliferation', 'biological_process', 'GO:0001787', ('112', '133'))	('immune suppression', 'CPA', (146, 164))	('promote', 'PosReg', (138, 145))	('kynurenine', 'Chemical', 'MESH:D007737', (37, 47))	('aryl hydrocarbon receptor', 'Gene', '196', (173, 198))	('immune-suppressive', 'CPA', (4, 22))	('aryl hydrocarbon receptor', 'Gene', (173, 198))
97041	32390008	Furthermore, since the 786-0 cell line is known to contain a phosphatase and tensin homologue (PTEN) mutation (although rarely observed in ccRCC tissues), it would be of interest to examine how deficiency of PTEN and/or dysregulation of the phosphoinositide-3 kinase/AKT/mammalian target of rapamycin signalling pathway impacts QPRT expression.	('target of rapamycin signalling pathway', 'biological_process', 'GO:0031929', ('281', '319'))	('PTEN', 'Gene', '5728', (95, 99))	('impacts', 'Reg', (320, 327))	('deficiency of PTEN', 'Disease', (194, 212))	('phosphatase', 'molecular_function', 'GO:0016791', ('61', '72'))	('deficiency of PTEN', 'Disease', 'MESH:D006223', (194, 212))	('AKT', 'Gene', (267, 270))	('QPRT', 'Gene', (328, 332))	('PTEN', 'Gene', (208, 212))	('mammalian target of rapamycin', 'Gene', '2475', (271, 300))	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('AKT', 'Gene', '207', (267, 270))	('dysregulation', 'Var', (220, 233))	('PTEN', 'Gene', '5728', (208, 212))	('mammalian target of rapamycin', 'Gene', (271, 300))	('PTEN', 'Gene', (95, 99))	('phosphatase and tensin homologue', 'Gene', '5728', (61, 93))	('mutation', 'Var', (101, 109))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
97042	32390008	We have also not examined how dysregulation of the kynurenine pathway in RCC correlates with patient outcomes.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('kynurenine pathway', 'Pathway', (51, 69))	('RCC', 'Disease', (73, 76))	('dysregulation', 'Var', (30, 43))	('patient', 'Species', '9606', (93, 100))	('kynurenine', 'Chemical', 'MESH:D007737', (51, 61))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
97083	30972888	Receiver operating characteristic curve analysis was undertaken to determine the area under the curve, and the optimal cut-off value was taken as the farthest point from the diagonal line of the curve.4 Cases in which the PD-1-positive TIIC score, PD-L1-positive TIIC score, or PD-L1-positive tumor score was higher than the cut-off values were defined as high cases, and those with percentages lower than the cut-off values were defined as low cases.	('PD-1', 'Gene', '5133', (222, 226))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('PD-L1-positive', 'Var', (248, 262))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('tumor', 'Disease', (293, 298))	('higher', 'PosReg', (309, 315))	('PD-1', 'Gene', (222, 226))
97100	30972888	Patients with ccRCC harboring a high PD-1-positive TIIC score at the tumor nest had significantly shorter progression-free and overall survival rates than those with tumors with a low PD-1-positive TIIC-positive score (P = 0.007 and P < 0.001) (Fig.	('high', 'Var', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('overall survival rates', 'CPA', (127, 149))	('Patients', 'Species', '9606', (0, 8))	('PD-1', 'Gene', (184, 188))	('PD-1', 'Gene', '5133', (184, 188))	('tumors', 'Disease', (166, 172))	('shorter', 'NegReg', (98, 105))	('RCC', 'Disease', (16, 19))	('ccRCC', 'Phenotype', 'HP:0006770', (14, 19))	('tumor', 'Disease', (166, 171))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('PD-1', 'Gene', (37, 41))	('PD-1', 'Gene', '5133', (37, 41))
97104	30972888	2E), but patients with a high PD-L1-positive TIIC score at tumor nest had a significantly shorter overall survival than those with tumors harboring low PD-L1-positive TIIC score (P < 0.001) (Fig.	('patients', 'Species', '9606', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('shorter', 'NegReg', (90, 97))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Disease', (131, 136))	('PD-L1-positive', 'Var', (30, 44))	('tumors', 'Disease', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('high PD-L1-positive', 'Var', (25, 44))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('overall survival', 'MPA', (98, 114))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
97106	30972888	Patients with ccRCC harboring a high PD-L1-positive tumor score had a slightly shorter progression-free survival and overall survival than those with a low PD-L1-positive tumor score (P = 0.015 and P = 0.007, respectively) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('RCC', 'Disease', (16, 19))	('high PD-L1-positive', 'Var', (32, 51))	('tumor', 'Disease', (52, 57))	('overall survival', 'CPA', (117, 133))	('shorter', 'NegReg', (79, 86))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('PD-L1-positive', 'Var', (37, 51))	('progression-free survival', 'CPA', (87, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (14, 19))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
97162	28753786	Xenograft tumors and their original tumors showed high fidelity in regard to histology, mutation status, copy number change, and targeted therapy response.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('original tumors', 'Disease', 'MESH:D009369', (27, 42))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('original tumors', 'Disease', (27, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('copy number change', 'Var', (105, 123))
97174	28753786	Treatment for patients with cancer has recently shifted to a more personalized or so-called precision medicine approach, and mutations of clear cell renal cell carcinoma (ccRCC) could be predictive of treatment response to targeted therapy.	('mutations', 'Var', (125, 134))	('RCC', 'Disease', (173, 176))	('clear cell renal cell carcinoma', 'Disease', (138, 169))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (149, 169))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (138, 169))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (138, 169))	('patients', 'Species', '9606', (14, 22))
97225	28753786	We also detected comparable chromosomal copy number alterations between matched tumor samples (Fig.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('chromosomal copy number', 'Var', (28, 51))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (80, 85))
97226	28753786	One noted difference is an MAGI2 deletion that is present in the primary tumor but absent in the corresponding xenograft tumor.	('MAGI2', 'Gene', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('deletion', 'Var', (33, 41))	('MAGI2', 'Gene', '9863', (27, 32))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
97246	28753786	These metastatic tumors may include important driver mutations and possibly mutations that could predict response or resistance to targeted therapies.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('mutations', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
97262	28852123	The overall survival (OS) was shorter for ccRCC patients with high COL23A1 expression (P = 0.002).	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (42, 47))	('RCC', 'Disease', (44, 47))	('overall survival', 'MPA', (4, 20))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('patients', 'Species', '9606', (48, 56))	('OS', 'Chemical', '-', (22, 24))	('COL23A1', 'Gene', (67, 74))	('high', 'Var', (62, 66))	('shorter', 'NegReg', (30, 37))	('expression', 'MPA', (75, 85))
97263	28852123	In multivariate analysis, high COL23A1 expression was an independent prognostic factor of OS (HR: 3.024, P = 0.017).	('COL23A1', 'Gene', (31, 38))	('OS', 'Chemical', '-', (90, 92))	('high', 'Var', (26, 30))	('expression', 'MPA', (39, 49))
97265	28852123	Cell adhesion and migration capacity was also downregulated by knockdown of COL23A1.	('Cell adhesion', 'biological_process', 'GO:0007155', ('0', '13'))	('rat', 'Species', '10116', (21, 24))	('Cell adhesion', 'CPA', (0, 13))	('downregulated', 'NegReg', (46, 59))	('migration capacity', 'CPA', (18, 36))	('COL23A1', 'Gene', (76, 83))	('knockdown', 'Var', (63, 72))
97289	28852123	There was a significant correlation between high COL23A1 expression and larger tumor size (P = 0.017).	('expression', 'MPA', (57, 67))	('high', 'Var', (44, 48))	('tumor', 'Disease', (79, 84))	('COL23A1', 'Gene', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
97293	28852123	Patients with high COL23A1 expression had significantly worse OS (P = 0.002; Fig.	('OS', 'Chemical', '-', (62, 64))	('expression', 'MPA', (27, 37))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('COL23A1', 'Gene', (19, 26))
97306	28852123	Next, a fluorescence-activated cell sorting assay was employed to investigate whether the inhibition of ccRCC cell proliferation upon knockdown of COL23A1 is associated with cell cycle arrest.	('inhibition', 'NegReg', (90, 100))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('174', '191'))	('COL23A1', 'Gene', (147, 154))	('cell proliferation', 'biological_process', 'GO:0008283', ('110', '128'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (174, 191))	('knockdown', 'Var', (134, 143))	('rat', 'Species', '10116', (122, 125))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))
97307	28852123	Flow cytometry results indicated that COL23A1 knockdown ccRCC cells had a larger G0/G1 population and a decreased S phase population compared with the siNC group for both cell lines (Fig.	('S phase population', 'CPA', (114, 132))	('knockdown', 'Var', (46, 55))	('decreased', 'NegReg', (104, 113))	('G0/G1 population', 'CPA', (81, 97))	('COL23A1', 'Gene', (38, 45))	('larger', 'PosReg', (74, 80))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('S phase', 'biological_process', 'GO:0051320', ('114', '121'))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
97318	28852123	Moreover, we demonstrated that knockdown of COL23A1 inhibited ccRCC cell proliferation, which was correlated with inhibition of cell cycle progression, and also attenuated the cell adhesion and migration capability of ccRCC cells.	('ccRCC', 'Phenotype', 'HP:0006770', (218, 223))	('RCC', 'Disease', (220, 223))	('inhibited', 'NegReg', (52, 61))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('attenuated', 'NegReg', (161, 171))	('rat', 'Species', '10116', (197, 200))	('rat', 'Species', '10116', (80, 83))	('cell adhesion', 'biological_process', 'GO:0007155', ('176', '189'))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('RCC', 'Disease', (64, 67))	('rat', 'Species', '10116', (20, 23))	('inhibition', 'NegReg', (114, 124))	('cell cycle', 'biological_process', 'GO:0007049', ('128', '138'))	('cell cycle progression', 'CPA', (128, 150))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Phenotype', 'HP:0005584', (220, 223))	('cell proliferation', 'biological_process', 'GO:0008283', ('68', '86'))	('COL23A1', 'Gene', (44, 51))	('knockdown', 'Var', (31, 40))
97331	28852123	In addition to validation by western blot analysis at the protein level, IHC results demonstrated that high protein expression of COL23A1 was significantly correlated with poor prognosis of patients with ccRCC (P = 0.002).	('patients', 'Species', '9606', (190, 198))	('rat', 'Species', '10116', (92, 95))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('RCC', 'Phenotype', 'HP:0005584', (206, 209))	('high', 'Var', (103, 107))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('RCC', 'Disease', 'MESH:C538614', (206, 209))	('COL23A1', 'Gene', (130, 137))	('RCC', 'Disease', (206, 209))	('ccRCC', 'Phenotype', 'HP:0006770', (204, 209))
97333	28852123	Exogenously expressed recombinant COL23A1 competed with corneal epithelial cell surface COL23A1 for binding to collagen IV and Matrigel, and COL23A1 directly interacted with integrin alpha2beta1 and sufficiently induced integrin alpha2beta1-dependent attachment and spreading of keratinocytes, corroborating the results of Spivey et al., who reported that COL23A1 played a role in cancer cell adhesion, anchorage-independent growth, and metastasis.	('collagen', 'molecular_function', 'GO:0005202', ('111', '119'))	('COL23A1', 'Var', (141, 148))	('induced', 'PosReg', (212, 219))	('spreading', 'CPA', (266, 275))	('cancer', 'Phenotype', 'HP:0002664', (381, 387))	('cell adhesion', 'biological_process', 'GO:0007155', ('388', '401'))	('attachment', 'CPA', (251, 261))	('rat', 'Species', '10116', (301, 304))	('metastasis', 'CPA', (437, 447))	('COL23A1', 'Gene', (34, 41))	('binding', 'Interaction', (100, 107))	('cancer', 'Disease', 'MESH:D009369', (381, 387))	('binding', 'molecular_function', 'GO:0005488', ('100', '107'))	('rat', 'Species', '10116', (281, 284))	('cancer', 'Disease', (381, 387))	('interacted', 'Interaction', (158, 168))	('cell surface', 'cellular_component', 'GO:0009986', ('75', '87'))	('anchorage-independent growth', 'CPA', (403, 431))
97334	28852123	Our research demonstrated that knockdown of COL23A1 attenuated ccRCC cell adhesion and migration in vitro.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('rat', 'Species', '10116', (90, 93))	('cell adhesion', 'biological_process', 'GO:0007155', ('69', '82'))	('attenuated', 'NegReg', (52, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('rat', 'Species', '10116', (20, 23))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('COL23A1', 'Gene', (44, 51))	('knockdown', 'Var', (31, 40))	('RCC', 'Disease', (65, 68))
97336	28852123	Three days after silencing of COL23A1, the proliferation of 786-O and A-498 cells was significantly inhibited compared with cells in control groups.	('inhibited', 'NegReg', (100, 109))	('rat', 'Species', '10116', (50, 53))	('A-498', 'CellLine', 'CVCL:1056', (70, 75))	('proliferation', 'CPA', (43, 56))	('silencing', 'Var', (17, 26))	('COL23A1', 'Gene', (30, 37))
97337	28852123	Furthermore, knockdown of COL23A1 induced cell cycle arrest in G0/G1 phase, which may partially account for the inhibitory effect on the proliferation of ccRCC cells.	('cell cycle arrest', 'CPA', (42, 59))	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('ccRCC', 'Phenotype', 'HP:0006770', (154, 159))	('RCC', 'Disease', (156, 159))	('G1 phase', 'biological_process', 'GO:0051318', ('66', '74'))	('knockdown', 'Var', (13, 22))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('42', '59'))	('COL23A1', 'Gene', (26, 33))	('rat', 'Species', '10116', (144, 147))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (42, 59))
97388	29492220	RNA-Seq data showed changes in 11.6% and 41.8% of the global transcriptome of Caki-1 cells overexpressing wild-type MCPIP1 or its D141N mutant, respectively.	('MCPIP1', 'Gene', '80149', (116, 122))	('global transcriptome', 'MPA', (54, 74))	('Caki-1', 'CellLine', 'CVCL:0234', (78, 84))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('MCPIP1', 'Gene', (116, 122))	('D141N', 'Var', (130, 135))	('D141N', 'Mutation', 'rs756978216', (130, 135))
97395	29492220	Deletion of the short arm of chromosome 3 that includes the von Hippel Lindau tumor suppressor (VHL) gene correlates with increased expression and activity of HIF-1alpha and HIF-2alpha in 90% of the ccRCC patient samples.	('von Hippel Lindau tumor suppressor', 'Gene', (60, 94))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('patient', 'Species', '9606', (205, 212))	('short arm', 'Phenotype', 'HP:0009824', (16, 25))	('ccRCC', 'Phenotype', 'HP:0006770', (199, 204))	('chromosome', 'cellular_component', 'GO:0005694', ('29', '39'))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (159, 184))	('tumor suppressor', 'biological_process', 'GO:0051726', ('78', '94'))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('von Hippel Lindau tumor suppressor', 'Gene', '7428', (60, 94))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('78', '94'))	('VHL', 'Gene', (96, 99))	('increased', 'PosReg', (122, 131))	('expression', 'MPA', (132, 142))	('VHL', 'Gene', '7428', (96, 99))	('activity', 'MPA', (147, 155))	('Deletion', 'Var', (0, 8))
97410	29492220	To characterize global transcriptome changes upon MCPIP1 overexpression, we generated Caki-1 cell lines expressing doxycycline-inducible wild-type (MCPIP1) or mutant MCPIP1 (inactivated PIN domain; D141N) using lentiviral vectors.	('MCPIP1', 'Gene', '80149', (148, 154))	('MCPIP1', 'Gene', '80149', (166, 172))	('MCPIP1', 'Gene', '80149', (50, 56))	('doxycycline', 'Chemical', 'MESH:D004318', (115, 126))	('mutant', 'Var', (159, 165))	('MCPIP1', 'Gene', (148, 154))	('D141N', 'Mutation', 'rs756978216', (198, 203))	('Caki-1', 'CellLine', 'CVCL:0234', (86, 92))	('MCPIP1', 'Gene', (166, 172))	('MCPIP1', 'Gene', (50, 56))
97412	29492220	We performed RNA-Seq analysis of RNA isolated from MCPIP1, D141N and PURO cells, which were grown in media containing puromycin for 10 days.	('D141N', 'Mutation', 'rs756978216', (59, 64))	('D141N', 'Var', (59, 64))	('puromycin', 'Chemical', 'MESH:D011691', (118, 127))	('MCPIP1', 'Gene', (51, 57))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('MCPIP1', 'Gene', '80149', (51, 57))	('RNA', 'cellular_component', 'GO:0005562', ('33', '36'))
97413	29492220	We performed pairwise comparison of gene expression in MCPIP1 and D141N samples against PURO (adj.	('D141N', 'Var', (66, 71))	('D141N', 'Mutation', 'rs756978216', (66, 71))	('MCPIP1', 'Gene', (55, 61))	('MCPIP1', 'Gene', '80149', (55, 61))	('gene expression', 'biological_process', 'GO:0010467', ('36', '51'))
97415	29492220	This accounts for 11.6% and 41.8% of the global transcriptome for MCPIP1 and D141N, respectively, because the AmpliSeq-based RNA-Seq covers 20812 human transcripts.	('RNA', 'cellular_component', 'GO:0005562', ('125', '128'))	('MCPIP1', 'Gene', (66, 72))	('human', 'Species', '9606', (146, 151))	('D141N', 'Mutation', 'rs756978216', (77, 82))	('MCPIP1', 'Gene', '80149', (66, 72))	('D141N', 'Var', (77, 82))
97416	29492220	We performed Gene Ontology (GO) and KEGG enrichment analysis on the differentially expressed genes in the MCPIP1 vs. PURO and D141N vs. PURO groups.	('D141N', 'Var', (126, 131))	('MCPIP1', 'Gene', (106, 112))	('MCPIP1', 'Gene', '80149', (106, 112))	('Gene Ontology', 'biological_process', 'GO:0003673', ('13', '26'))	('D141N', 'Mutation', 'rs756978216', (126, 131))
97418	29492220	The upregulated genes in the D141N vs. PURO group belonged to 40 BP, 10 MF and 17 CC categories (p-adj.	('upregulated', 'PosReg', (4, 15))	('D141N', 'Var', (29, 34))	('D141N', 'Mutation', 'rs756978216', (29, 34))
97419	29492220	The downregulated genes in the MCPIP1 vs. PURO group were enriched in 10 BP, 9 MF, and 7 CC functional categories, whereas the downregulated genes in the D141N vs. PURO group were enriched in 13 BP, 4 MF and 10 CC categories (p-adj.	('D141N', 'Var', (154, 159))	('downregulated', 'NegReg', (4, 17))	('MCPIP1', 'Gene', (31, 37))	('MCPIP1', 'Gene', '80149', (31, 37))	('D141N', 'Mutation', 'rs756978216', (154, 159))
97420	29492220	The biological processes upregulated in MCPIP1 and D141N cells (p-adj.	('MCPIP1', 'Gene', (40, 46))	('D141N', 'Mutation', 'rs756978216', (51, 56))	('MCPIP1', 'Gene', '80149', (40, 46))	('D141N', 'Var', (51, 56))	('upregulated', 'PosReg', (25, 36))	('biological processes', 'CPA', (4, 24))
97421	29492220	< 0.01) were distinct in MCPIP1 and D141N cells, and were involved in endoplasmic reticulum stress and nucleotide metabolism, respectively.	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('70', '91'))	('MCPIP1', 'Gene', (25, 31))	('involved', 'Reg', (58, 66))	('MCPIP1', 'Gene', '80149', (25, 31))	('nucleotide metabolism', 'biological_process', 'GO:0009117', ('103', '124'))	('D141N', 'Mutation', 'rs756978216', (36, 41))	('D141N', 'Var', (36, 41))
97422	29492220	Moreover, transcripts associated with lysosomes were downregulated in both MCPIP1 and D141N cells.	('MCPIP1', 'Gene', '80149', (75, 81))	('transcripts', 'MPA', (10, 21))	('D141N', 'Var', (86, 91))	('D141N', 'Mutation', 'rs756978216', (86, 91))	('MCPIP1', 'Gene', (75, 81))	('downregulated', 'NegReg', (53, 66))
97424	29492220	Cell cycle was the top upregulated KEGG pathway, whereas lysosomal regulation was the most downregulated KEGG pathway in MCPIP1 and D141N cells.	('downregulated', 'NegReg', (91, 104))	('upregulated', 'PosReg', (23, 34))	('KEGG pathway', 'Pathway', (105, 117))	('MCPIP1', 'Gene', (121, 127))	('D141N', 'Var', (132, 137))	('KEGG pathway', 'Pathway', (35, 47))	('MCPIP1', 'Gene', '80149', (121, 127))	('D141N', 'Mutation', 'rs756978216', (132, 137))	('regulation', 'biological_process', 'GO:0065007', ('67', '77'))	('lysosomal regulation', 'MPA', (57, 77))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('Cell', 'CPA', (0, 4))
97425	29492220	We additionally analyzed the differentially expressed genes between MCPIP1 and D141N overexpressing cells.	('D141N', 'Var', (79, 84))	('D141N', 'Mutation', 'rs756978216', (79, 84))	('MCPIP1', 'Gene', (68, 74))	('MCPIP1', 'Gene', '80149', (68, 74))
97430	29492220	The functional analysis with GO and KEGG databases demonstrated overlapping and distinct cellular processes for cell lines overexpressing wild type and mutated MCPIP1 protein.	('protein', 'Protein', (167, 174))	('MCPIP1', 'Gene', '80149', (160, 166))	('protein', 'cellular_component', 'GO:0003675', ('167', '174'))	('mutated', 'Var', (152, 159))	('MCPIP1', 'Gene', (160, 166))
97433	29492220	< 0.05), whereas, the remaining 36 were upregulated in D141N cells (fold change > 1.5 and p-adj.	('D141N', 'Var', (55, 60))	('D141N', 'Mutation', 'rs756978216', (55, 60))	('upregulated', 'PosReg', (40, 51))
97448	29492220	DDB1 knockdown upregulates both p21 protein and mRNA levels, thereby suggesting that regulation of p21 is complex.	('regulation', 'biological_process', 'GO:0065007', ('85', '95'))	('mRNA levels', 'MPA', (48, 59))	('upregulates', 'PosReg', (15, 26))	('DDB1', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('p21', 'Gene', '1026', (32, 35))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('p21', 'Gene', '1026', (99, 102))	('p21', 'Gene', (32, 35))	('p21', 'Gene', (99, 102))
97452	29492220	This suggests that MCPIP1 overexpression inhibits cell cycling and growth by upregulating the p21Cip1 cell cycle inhibitor in cells.	('upregulating', 'PosReg', (77, 89))	('inhibits', 'NegReg', (41, 49))	('p21Cip1', 'Gene', (94, 101))	('MCPIP1', 'Gene', '80149', (19, 25))	('cell cycling', 'CPA', (50, 62))	('p21Cip1', 'Gene', '1026', (94, 101))	('growth', 'CPA', (67, 73))	('cell cycle', 'biological_process', 'GO:0007049', ('102', '112'))	('overexpression', 'Var', (26, 40))	('MCPIP1', 'Gene', (19, 25))
97463	29492220	Here, we postulate that low MCPIP1 levels promotes growth and progression of ccRCC cells by upregulating factors such as HSPA5 and AGR2, which are involved in protein folding and secretion in the ER.	('secretion', 'biological_process', 'GO:0046903', ('179', '188'))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('growth', 'CPA', (51, 57))	('HSPA5', 'Gene', '3309', (121, 126))	('MCPIP1', 'Gene', (28, 34))	('protein folding', 'biological_process', 'GO:0006457', ('159', '174'))	('AGR2', 'Gene', '10551', (131, 135))	('progression', 'CPA', (62, 73))	('upregulating', 'PosReg', (92, 104))	('HSPA5', 'Gene', (121, 126))	('promotes', 'PosReg', (42, 50))	('MCPIP1', 'Gene', '80149', (28, 34))	('low', 'Var', (24, 27))	('AGR2', 'Gene', (131, 135))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
97471	29492220	SPHK1 catalyzes phosphorylation of sphingosine to sphingosine-1-phosphate (S1P), which promotes proliferation; meanwhile, sphingosine induces cell growth arrest and apoptosis (reviewed in).	('arrest', 'Disease', (154, 160))	('sphingosine', 'Chemical', 'MESH:D013110', (122, 133))	('apoptosis', 'biological_process', 'GO:0097194', ('165', '174'))	('SPHK1', 'Gene', (0, 5))	('apoptosis', 'biological_process', 'GO:0006915', ('165', '174'))	('growth arrest', 'Phenotype', 'HP:0001510', (147, 160))	('proliferation', 'CPA', (96, 109))	('apoptosis', 'CPA', (165, 174))	('sphingosine', 'Chemical', 'MESH:D013110', (35, 46))	('phosphorylation', 'biological_process', 'GO:0016310', ('16', '31'))	('SPHK1', 'Gene', '8877', (0, 5))	('arrest', 'Disease', 'MESH:D006323', (154, 160))	('sphingosine', 'Chemical', 'MESH:D013110', (50, 61))	('induces', 'Reg', (134, 141))	('promotes', 'PosReg', (87, 95))	('cell growth', 'biological_process', 'GO:0016049', ('142', '153'))	('sphingosine-1-phosphate', 'Chemical', 'MESH:C060506', (50, 73))	('sphingosine', 'Var', (122, 133))
97475	29492220	Therefore, we postulate that low MCPIP1 expression in ccRCC cells increase S1P levels by enhancing SPHK1, which results in higher proliferation rates.	('increase', 'PosReg', (66, 74))	('RCC', 'Disease', (56, 59))	('enhancing', 'PosReg', (89, 98))	('S1P levels', 'MPA', (75, 85))	('SPHK1', 'Gene', (99, 104))	('low', 'Var', (29, 32))	('higher', 'PosReg', (123, 129))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('SPHK1', 'Gene', '8877', (99, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('MCPIP1', 'Gene', (33, 39))	('proliferation rates', 'CPA', (130, 149))	('MCPIP1', 'Gene', '80149', (33, 39))
97480	29492220	Moreover, LPA induces HIF1alpha expression in colon cancer cells at the transcriptional level.	('LPA', 'Chemical', 'MESH:C032881', (10, 13))	('HIF1alpha', 'Gene', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('colon cancer', 'Disease', (46, 58))	('LPA', 'Var', (10, 13))	('HIF1alpha', 'Gene', '3091', (22, 31))	('induces', 'Reg', (14, 21))	('expression', 'MPA', (32, 42))	('colon cancer', 'Phenotype', 'HP:0003003', (46, 58))	('colon cancer', 'Disease', 'MESH:D015179', (46, 58))
97482	29492220	Since VEGF-A and LPA is a are both proangiogenic factors, our findings suggest that MCPIP1 overexpression inhibits angiogenesis in Caki-1 cells by downregulating VEGFA and ENPP2.	('downregulating', 'NegReg', (147, 161))	('inhibits', 'NegReg', (106, 114))	('MCPIP1', 'Gene', '80149', (84, 90))	('Caki-1', 'CellLine', 'CVCL:0234', (131, 137))	('VEGFA', 'Gene', (162, 167))	('MCPIP1', 'Gene', (84, 90))	('angiogenesis', 'CPA', (115, 127))	('VEGF-A', 'Gene', '7422', (6, 12))	('VEGF-A', 'Gene', (6, 12))	('ENPP2', 'Gene', '5168', (172, 177))	('angiogenesis', 'biological_process', 'GO:0001525', ('115', '127'))	('ENPP2', 'Gene', (172, 177))	('LPA', 'Chemical', 'MESH:C032881', (17, 20))	('overexpression', 'Var', (91, 105))	('VEGFA', 'Gene', '7422', (162, 167))
97490	29492220	showed that high MMP-2 expression was associated with poor prognosis and rapid progression of RCC.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (94, 97))	('high', 'Var', (12, 16))	('MMP-2', 'Gene', (17, 22))	('MMP-2', 'molecular_function', 'GO:0004228', ('17', '22'))	('MMP-2', 'Gene', '4313', (17, 22))	('expression', 'MPA', (23, 33))
97496	29492220	High NDRG1 expression has shown potential as a prognostic biomarker in many types of cancers, including ccRCC.	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('NDRG1', 'Gene', (5, 10))	('cancers', 'Disease', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('RCC', 'Disease', (106, 109))	('NDRG1', 'Gene', '10397', (5, 10))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))
97503	29492220	NGEF gene polymorphism is associated with obesity and adipose tissue content.	('adipose tissue content', 'MPA', (54, 76))	('polymorphism', 'Var', (10, 22))	('obesity', 'Phenotype', 'HP:0001513', (42, 49))	('NGEF', 'Gene', '25791', (0, 4))	('obesity', 'Disease', 'MESH:D009765', (42, 49))	('NGEF', 'Gene', (0, 4))	('obesity', 'Disease', (42, 49))	('associated', 'Reg', (26, 36))
97507	29492220	We postulate that changes in NGEF mRNA levels may impact lipid storage in Caki-1 cells.	('changes', 'Var', (18, 25))	('NGEF', 'Gene', (29, 33))	('lipid storage', 'biological_process', 'GO:0019915', ('57', '70'))	('impact', 'Reg', (50, 56))	('lipid storage', 'MPA', (57, 70))	('NGEF', 'Gene', '25791', (29, 33))	('Caki-1', 'CellLine', 'CVCL:0234', (74, 80))	('lipid', 'Chemical', 'MESH:D008055', (57, 62))
97524	29492220	As shown in Figure 6, MCPIP1 overexpression leads to large scale changes in transcript levels, especially those involved in protein folding, cell cycle progression, hypoxia response, angiogenesis and cell signaling.	('transcript levels', 'MPA', (76, 93))	('angiogenesis', 'CPA', (183, 195))	('MCPIP1', 'Gene', '80149', (22, 28))	('signaling', 'biological_process', 'GO:0023052', ('205', '214'))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('hypoxia', 'Disease', 'MESH:D000860', (165, 172))	('cell cycle', 'CPA', (141, 151))	('overexpression', 'Var', (29, 43))	('changes', 'Reg', (65, 72))	('cell cycle', 'biological_process', 'GO:0007049', ('141', '151'))	('protein folding', 'biological_process', 'GO:0006457', ('124', '139'))	('protein folding', 'MPA', (124, 139))	('hypoxia', 'Disease', (165, 172))	('angiogenesis', 'biological_process', 'GO:0001525', ('183', '195'))	('MCPIP1', 'Gene', (22, 28))
97526	29492220	We used the doxycycline-dependent TetON overexpression system for stable expression of wild type MCPIP1 and mutant form of MCPIP1 with inactivated PIN domain (D141N) (pLIX MCPIP1, pLIX D141N).	('D141N', 'Mutation', 'rs756978216', (185, 190))	('MCPIP1', 'Gene', (123, 129))	('TetON', 'Chemical', '-', (34, 39))	('doxycycline', 'Chemical', 'MESH:D004318', (12, 23))	('MCPIP1', 'Gene', (172, 178))	('D141N', 'Var', (159, 164))	('MCPIP1', 'Gene', '80149', (123, 129))	('mutant', 'Var', (108, 114))	('D141N', 'Mutation', 'rs756978216', (159, 164))	('MCPIP1', 'Gene', '80149', (172, 178))	('MCPIP1', 'Gene', (97, 103))	('MCPIP1', 'Gene', '80149', (97, 103))
97546	29100286	The pVHL172 isoform is not a tumor suppressor and up-regulates a subset of pro-tumorigenic genes including TGFB1 and MMP13 The von Hippel-Lindau (VHL) tumor suppressor gene is often deleted or mutated in ccRCC (clear cell renal cell carcinoma) producing a non-functional protein.	('protein', 'cellular_component', 'GO:0003675', ('271', '278'))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('MMP13', 'molecular_function', 'GO:0030404', ('117', '122'))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (211, 242))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (127, 156))	('MMP13', 'Gene', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('TGFB1', 'Gene', '7040', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('TGFB1', 'Gene', (107, 112))	('up-regulates', 'PosReg', (50, 62))	('ccRCC', 'Disease', (204, 209))	('tumor', 'Disease', (79, 84))	('mutated', 'Var', (193, 200))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (211, 242))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('151', '167'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('29', '45'))	('non-functional protein', 'MPA', (256, 278))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor suppressor', 'biological_process', 'GO:0051726', ('151', '167'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('29', '45'))	('tumor', 'Disease', (151, 156))	('clear cell renal cell carcinoma', 'Disease', (211, 242))	('tumor', 'Disease', (29, 34))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (222, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
97563	29100286	Inactivation of pVHL stabilizes HIF-alpha that heterodimerizes with HIF-beta and translocates in the nucleus to activate the transcription of many genes involved in the hypoxic response and other pro-tumorigenic processes.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('HIF-beta', 'Disease', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('HIF-beta', 'Disease', 'MESH:D012497', (68, 76))	('tumor', 'Disease', (200, 205))	('genes', 'Gene', (147, 152))	('transcription', 'MPA', (125, 138))	('transcription', 'biological_process', 'GO:0006351', ('125', '138'))	('heterodimerizes', 'Interaction', (47, 62))	('pVHL', 'Gene', '7428', (16, 20))	('Inactivation', 'Var', (0, 12))	('pVHL', 'Gene', (16, 20))	('nucleus', 'cellular_component', 'GO:0005634', ('101', '108'))	('activate', 'PosReg', (112, 120))
97566	29100286	Loss of VHL function by deletion, mutation or promoter hypermethylation contributes to ccRCC initiation by promoting HIF-dependent overproduction of proangiogenic factors, including VEGF and PDGF.	('VHL', 'Gene', '7428', (8, 11))	('promoter hypermethylation', 'Var', (46, 71))	('VHL', 'Gene', (8, 11))	('promoting', 'PosReg', (107, 116))	('VEGF', 'Gene', '7422', (182, 186))	('mutation', 'Var', (34, 42))	('PDGF', 'molecular_function', 'GO:0005161', ('191', '195'))	('overproduction', 'MPA', (131, 145))	('Loss', 'NegReg', (0, 4))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('ccRCC', 'Disease', (87, 92))	('deletion', 'Var', (24, 32))	('VEGF', 'Gene', (182, 186))
97569	29100286	Loss of pVHL in ccRCC has also been associated with modulation of TGFB1 expression and poor prognosis.	('ccRCC', 'Disease', (16, 21))	('TGFB1', 'Gene', '7040', (66, 71))	('TGFB1', 'Gene', (66, 71))	('modulation', 'MPA', (52, 62))	('expression', 'MPA', (72, 82))	('pVHL', 'Gene', '7428', (8, 12))	('pVHL', 'Gene', (8, 12))	('Loss', 'Var', (0, 4))	('ccRCC', 'Phenotype', 'HP:0006770', (16, 21))
97574	29100286	Importantly, it has been reported that some VHL mutations may favor the expression of VHL variant 2 in ccRCC.	('favor', 'PosReg', (62, 67))	('VHL', 'Gene', (44, 47))	('expression', 'MPA', (72, 82))	('VHL', 'Gene', '7428', (44, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('ccRCC', 'Disease', (103, 108))	('VHL', 'Gene', (86, 89))	('mutations', 'Var', (48, 57))	('VHL', 'Gene', '7428', (86, 89))
97599	29100286	Interestingly, the expression of pVHL172 in cells induced spheroids formation which size was significantly larger (Figure 2A, right panel; p-value=3.805 10-5).	('spheroids formation', 'CPA', (58, 77))	('expression', 'Var', (19, 29))	('pVHL', 'Gene', '7428', (33, 37))	('formation', 'biological_process', 'GO:0009058', ('68', '77'))	('pVHL', 'Gene', (33, 37))	('larger', 'PosReg', (107, 113))
97612	29100286	Thus pVHL172 expression slightly delayed tumor growth induction, but then increased tumor growth speed.	('delayed', 'NegReg', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('increased', 'PosReg', (74, 83))	('expression', 'Var', (13, 23))	('tumor', 'Disease', (84, 89))	('pVHL', 'Gene', '7428', (5, 9))	('pVHL', 'Gene', (5, 9))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
97621	29100286	In summary to these observations, we concluded that the expression of pVHL172 rather promoted a higher percentage of the sarcomatoid phenotype in tumors that is correlated to a poor prognostic factor in kidney cancer.	('sarcomatoid', 'Disease', (121, 132))	('kidney cancer', 'Phenotype', 'HP:0009726', (203, 216))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('kidney cancer', 'Disease', 'MESH:D007680', (203, 216))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('pVHL', 'Gene', '7428', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('kidney cancer', 'Disease', (203, 216))	('pVHL', 'Gene', (70, 74))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('promoted', 'PosReg', (85, 93))	('rat', 'Species', '10116', (78, 81))	('sarcomatoid', 'Disease', 'MESH:C538614', (121, 132))	('tumors', 'Disease', (146, 152))	('expression', 'Var', (56, 66))
97622	29100286	Collectively, all the results indicated that expression of pVHL172 exacerbates molecular pathways previously observed in tumoral VHL null cells (i.e.	('pVHL', 'Gene', '7428', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('pVHL', 'Gene', (59, 63))	('exacerbates', 'PosReg', (67, 78))	('tumoral VHL', 'Disease', (121, 132))	('molecular pathways', 'Pathway', (79, 97))	('expression', 'Var', (45, 55))	('tumoral VHL', 'Disease', 'MESH:D006623', (121, 132))
97637	29100286	To confirm that MMP13 upregulation was pVHL172-dependent, pVHL172 was knocked down in 786-O-pVHL172 cells by using a specific VHL172 siRNA (SiVHL).	('MMP13', 'Gene', (16, 21))	('MMP13', 'molecular_function', 'GO:0030404', ('16', '21'))	('VHL', 'Gene', '7428', (40, 43))	('pVHL', 'Gene', '7428', (39, 43))	('VHL', 'Gene', (126, 129))	('knocked', 'Var', (70, 77))	('pVHL', 'Gene', (39, 43))	('VHL', 'Gene', (93, 96))	('VHL', 'Gene', '7428', (142, 145))	('MMP13', 'Gene', '4322', (16, 21))	('pVHL', 'Gene', '7428', (92, 96))	('pVHL', 'Gene', (92, 96))	('VHL', 'Gene', '7428', (126, 129))	('VHL', 'Gene', (59, 62))	('VHL', 'Gene', '7428', (93, 96))	('upregulation', 'PosReg', (22, 34))	('VHL', 'Gene', '7428', (59, 62))	('pVHL', 'Gene', '7428', (58, 62))	('VHL', 'Gene', (40, 43))	('pVHL', 'Gene', (58, 62))	('VHL', 'Gene', (142, 145))
97638	29100286	Upon SiVHL transfection, pVHL172 expression was reduced by 82% compared with non-transfected cells and cells transfected with control siRNA (SiC) (Figure 3D).	('pVHL', 'Gene', '7428', (25, 29))	('pVHL', 'Gene', (25, 29))	('VHL', 'Gene', (26, 29))	('reduced', 'NegReg', (48, 55))	('VHL', 'Gene', '7428', (26, 29))	('transfection', 'Var', (11, 23))	('expression', 'MPA', (33, 43))	('VHL', 'Gene', (7, 10))	('VHL', 'Gene', '7428', (7, 10))
97648	29100286	HIF-2alpha is stabilized by hypoxia or mutations of pVHL.	('pVHL', 'Gene', '7428', (52, 56))	('HIF-2alpha', 'Gene', '2034', (0, 10))	('pVHL', 'Gene', (52, 56))	('mutations', 'Var', (39, 48))	('hypoxia', 'Disease', (28, 35))	('hypoxia', 'Disease', 'MESH:D000860', (28, 35))	('HIF-2alpha', 'Gene', (0, 10))
97672	29100286	Loss of the VHL gene plays an important role in the development of sporadic or hereditary ccRCC in some patients with VHL disease.	('VHL', 'Gene', (12, 15))	('VHL', 'Gene', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('sporadic', 'Disease', (67, 75))	('VHL', 'Gene', '7428', (12, 15))	('VHL', 'Gene', '7428', (118, 121))	('VHL disease', 'Disease', (118, 129))	('hereditary ccRCC', 'Disease', (79, 95))	('VHL disease', 'Disease', 'MESH:D006623', (118, 129))	('Loss', 'Var', (0, 4))	('patients', 'Species', '9606', (104, 112))
97684	29100286	Our study also evidences that pVHL172 expression correlates with a higher proportion of sarcomatoid areas in tumor sections.	('pVHL', 'Gene', (30, 34))	('sarcomatoid', 'Disease', 'MESH:C538614', (88, 99))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('expression', 'Var', (38, 48))	('sarcomatoid', 'Disease', (88, 99))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))	('pVHL', 'Gene', '7428', (30, 34))
97699	29100286	also reported that high MMP-13 expression correlated significantly with adverse overall survival, while MMP-1 independently did not show any significant correlation with survival.	('MMP-13', 'Gene', (24, 30))	('high', 'Var', (19, 23))	('MMP-1', 'Gene', '4312', (24, 29))	('MMP-1', 'Gene', (24, 29))	('MMP-1', 'Gene', '4312', (104, 109))	('MMP-13', 'molecular_function', 'GO:0030404', ('24', '30'))	('expression', 'MPA', (31, 41))	('MMP-1', 'Gene', (104, 109))	('MMP-13', 'Gene', '4322', (24, 30))	('MMP-1', 'molecular_function', 'GO:0004232', ('104', '109'))
97705	29100286	Previous proteomic analysis reported SETBD1and TCF25 as interactors for pVHL (Delta114-154).	('Delta114-154', 'Var', (78, 90))	('SETBD1and', 'Gene', (37, 46))	('TCF25', 'Gene', '22980', (47, 52))	('pVHL', 'Gene', '7428', (72, 76))	('pVHL', 'Gene', (72, 76))	('interactors', 'Interaction', (56, 67))	('TCF25', 'Gene', (47, 52))
97713	29100286	Our data support that the presence of pVHL172 in cells may provide a growth advantage to affect the tumor progression and the physiological impact of the balance of expression of pVHL213 and /or pVHL172 remain to be explored.	('pVHL', 'Gene', (179, 183))	('pVHL', 'Gene', '7428', (195, 199))	('pVHL', 'Gene', (38, 42))	('pVHL', 'Gene', '7428', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('pVHL', 'Gene', (195, 199))	('tumor', 'Disease', (100, 105))	('affect', 'Reg', (89, 95))	('presence', 'Var', (26, 34))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('growth advantage', 'CPA', (69, 85))	('pVHL', 'Gene', '7428', (38, 42))
97718	29100286	VHL knockdown experiments were performed by transfecting 75 nM siRNA against VHL variant 2 or a control siRNA using JetPRIME for 72 hours.	('VHL', 'Gene', (77, 80))	('VHL', 'Gene', '7428', (77, 80))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('variant 2', 'Var', (81, 90))
97740	32560659	HnRNP A1 - mediated alternative splicing of CCDC50 contributes to cancer progression of clear cell renal cell carcinoma via ZNF395 Aberrant alternative splicing events play critical roles in carcinogenesis and progression of many cancers, while sparse studies regarding to alternative splicing are available for clear cell renal cell carcinoma (ccRCC).	('RCC', 'Disease', (347, 350))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (323, 343))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('clear cell renal cell carcinoma', 'Disease', (88, 119))	('splicing', 'biological_process', 'GO:0045292', ('285', '293'))	('contributes', 'Reg', (51, 62))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (99, 119))	('clear cell renal cell carcinoma', 'Disease', (312, 343))	('carcinoma', 'Phenotype', 'HP:0030731', (334, 343))	('RCC', 'Disease', 'MESH:C538614', (347, 350))	('HnRNP', 'cellular_component', 'GO:0030530', ('0', '5'))	('HnRNP', 'molecular_function', 'GO:0008436', ('0', '5'))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (88, 119))	('cancers', 'Disease', (230, 237))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('CCDC50', 'Gene', '152137', (44, 50))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (312, 343))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('roles', 'Reg', (182, 187))	('splicing', 'biological_process', 'GO:0045292', ('32', '40'))	('CCDC50', 'Gene', (44, 50))	('splicing', 'biological_process', 'GO:0045292', ('152', '160'))	('carcinogenesis', 'Disease', (191, 205))	('HnRNP A1', 'Gene', (0, 8))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (88, 119))	('cancers', 'Disease', 'MESH:D009369', (230, 237))	('Aberrant', 'Var', (131, 139))	('HnRNP A1', 'Gene', '3178', (0, 8))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (312, 343))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('ZNF395', 'Gene', (124, 130))	('carcinogenesis', 'Disease', 'MESH:D063646', (191, 205))	('cancer', 'Disease', (66, 72))
97742	32560659	Bioinformatic algorithm was utilized to identify significant exon skipping events in ccRCC via exon sequencing data from The Cancer Genome Atlas.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('Cancer', 'Disease', (125, 131))	('exon skipping', 'Var', (61, 74))	('Cancer', 'Disease', 'MESH:D009369', (125, 131))	('Cancer', 'Phenotype', 'HP:0002664', (125, 131))
97749	32560659	Higher percent spliced-in index was associated with better survival in ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('spliced-in index', 'Var', (15, 31))	('better', 'PosReg', (52, 58))	('patients', 'Species', '9606', (77, 85))
97751	32560659	Besides, we identified that heterogeneous nuclear ribonucleoprotein A1 (HnRNP A1) could promote the skipping of exon 6, which resulted in higher portion of CCDC50-S and oncogenic transformation.	('heterogeneous nuclear ribonucleoprotein', 'cellular_component', 'GO:0030530', ('28', '67'))	('skipping', 'Var', (100, 108))	('heterogeneous nuclear ribonucleoprotein A1', 'Gene', (28, 70))	('heterogeneous nuclear ribonucleoprotein A1', 'Gene', '3178', (28, 70))	('promote', 'PosReg', (88, 95))	('heterogeneous nuclear ribonucleoprotein', 'molecular_function', 'GO:0008436', ('28', '67'))	('oncogenic transformation', 'CPA', (169, 193))	('CCDC50', 'Gene', '152137', (156, 162))	('HnRNP A1', 'Gene', (72, 80))	('CCDC50', 'Gene', (156, 162))	('HnRNP', 'molecular_function', 'GO:0008436', ('72', '77'))	('higher', 'PosReg', (138, 144))	('HnRNP', 'cellular_component', 'GO:0030530', ('72', '77'))	('HnRNP A1', 'Gene', '3178', (72, 80))
97752	32560659	Moreover, zinc finger protein 395 (ZNF395) was identified as a downstream protein of CCDC50-S, and the interaction initiated oncogenic pathways which were involved in ccRCC progression.	('zinc finger protein 395', 'Gene', '55893', (10, 33))	('zinc finger protein 395', 'Gene', (10, 33))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('ZNF395', 'Gene', '55893', (35, 41))	('RCC', 'Disease', (169, 172))	('interaction', 'Var', (103, 114))	('ZNF395', 'Gene', (35, 41))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('initiated', 'Reg', (115, 124))	('oncogenic pathways', 'Pathway', (125, 143))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('CCDC50', 'Gene', '152137', (85, 91))	('CCDC50', 'Gene', (85, 91))
97753	32560659	Aberrant alternative splicing of CCDC50 is regulated by HnRNP A1 in ccRCC.	('HnRNP A1', 'Gene', '3178', (56, 64))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('Aberrant', 'Var', (0, 8))	('regulated', 'Reg', (43, 52))	('splicing', 'biological_process', 'GO:0045292', ('21', '29'))	('HnRNP A1', 'Gene', (56, 64))	('CCDC50', 'Gene', '152137', (33, 39))	('CCDC50', 'Gene', (33, 39))	('HnRNP', 'molecular_function', 'GO:0008436', ('56', '61'))	('HnRNP', 'cellular_component', 'GO:0030530', ('56', '61'))
97758	32560659	Previous studies have identified the somatic von Hippel-Lindau (VHL) mutations and downstream hypoxia-inducible factors (HIFs) - related pathways in the carcinogenesis of ccRCC, while recent high-throughput sequencing also identifies aberrant changes in epigenetic regulatory genes or precursor mRNA (pre-mRNA) splicing.	('carcinogenesis of ccRCC', 'Disease', 'MESH:D063646', (153, 176))	('mutations', 'Var', (69, 78))	('von Hippel-Lindau', 'Gene', (45, 62))	('HIFs', 'Disease', (121, 125))	('pre', 'molecular_function', 'GO:0003904', ('301', '304'))	('VHL', 'Gene', (64, 67))	('von Hippel-Lindau', 'Gene', '7428', (45, 62))	('hypoxia', 'Disease', (94, 101))	('hypoxia', 'Disease', 'MESH:D000860', (94, 101))	('VHL', 'Gene', '7428', (64, 67))	('epigenetic regulatory', 'MPA', (254, 275))	('carcinogenesis of ccRCC', 'Disease', (153, 176))	('HIFs', 'Disease', 'None', (121, 125))	('pre-mRNA) splicing', 'biological_process', 'GO:0000398', ('301', '319'))
97762	32560659	In fact, alternative splicing has been demonstrated to play roles in plenty of key biological processes and human diseases, including several cancers.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', (142, 149))	('alternative splicing', 'Var', (9, 29))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('splicing', 'biological_process', 'GO:0045292', ('21', '29'))	('human', 'Species', '9606', (108, 113))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('play roles', 'Reg', (55, 65))
97763	32560659	Mutations in cis-acting splicing elements and alterations of several splicing factors can dramatically change the splicing patterns of cancer-involved genes, contributing to tumorigenesis and cancer progression.	('tumor', 'Disease', (174, 179))	('splicing patterns', 'MPA', (114, 131))	('cancer', 'Disease', (135, 141))	('contributing', 'Reg', (158, 170))	('splicing', 'biological_process', 'GO:0045292', ('69', '77'))	('change', 'Reg', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (192, 198))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('splicing', 'biological_process', 'GO:0045292', ('24', '32'))	('splicing', 'biological_process', 'GO:0045292', ('114', '122'))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
97766	32560659	These studies imply that specific alternative splicing pattern may remarkably contribute to more reliable definition of molecular biomarkers for cancer early diagnosis and prognosis, and may translate into effective therapeutic targets.	('cancer', 'Disease', (145, 151))	('translate', 'Reg', (191, 200))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('splicing', 'biological_process', 'GO:0045292', ('46', '54'))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('alternative splicing pattern', 'Var', (34, 62))
97771	32560659	Upon epidermal growth factor (EGF) stimulation, the truncated CCDC50 protein could be phosphorylated at tyrosine 145 and 146, and then functioned as an inhibitor for the ligand - induced downregulation of epidermal growth factor receptor (EGFR).	('CCDC50', 'Gene', '152137', (62, 68))	('EGF', 'Gene', (239, 242))	('epidermal growth factor receptor', 'Gene', (205, 237))	('EGF', 'Gene', (30, 33))	('CCDC50', 'Gene', (62, 68))	('epidermal growth factor receptor', 'Gene', '1956', (205, 237))	('EGF', 'molecular_function', 'GO:0005154', ('30', '33'))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('EGFR', 'Gene', (239, 243))	('downregulation', 'NegReg', (187, 201))	('ligand', 'molecular_function', 'GO:0005488', ('170', '176'))	('protein', 'Protein', (69, 76))	('EGF', 'Gene', '1950', (239, 242))	('epidermal growth factor', 'Gene', '1950', (205, 228))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('5', '28'))	('tyrosine', 'Chemical', 'MESH:D014443', (104, 112))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('205', '228'))	('truncated', 'Var', (52, 61))	('EGF', 'Gene', '1950', (30, 33))	('EGFR', 'molecular_function', 'GO:0005006', ('239', '243'))	('EGFR', 'Gene', '1956', (239, 243))	('epidermal growth factor', 'Gene', (5, 28))	('epidermal growth factor', 'Gene', '1950', (5, 28))
97772	32560659	Furthermore, the truncated CCDC50 was proved to be phosphorylated on tyrosine residues by Src family kinases, acting as a negative regulator for the nuclear factor-kappa B (NF-kappaB) - mediated apoptotic pathway.	('tyrosine', 'Chemical', 'MESH:D014443', (69, 77))	('NF-kappaB', 'Gene', (173, 182))	('CCDC50', 'Gene', '152137', (27, 33))	('truncated', 'Var', (17, 26))	('negative', 'NegReg', (122, 130))	('CCDC50', 'Gene', (27, 33))	('nuclear factor-kappa B', 'Gene', (149, 171))	('nuclear factor-kappa B', 'Gene', '4790', (149, 171))	('NF-kappaB', 'Gene', '4790', (173, 182))
97775	32560659	CCDC50 gene is comprised of 12 exons and the inclusion or skipping of exon 6 can generate full-length or short transcript, respectively.	('short transcript', 'MPA', (105, 121))	('skipping', 'Var', (58, 66))	('CCDC50', 'Gene', (0, 6))	('CCDC50', 'Gene', '152137', (0, 6))	('inclusion', 'Var', (45, 54))
97779	32560659	In this study, we firstly validated the bioinformatic result of aberrant CCDC50 splicing in our renal cancer samples.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('renal cancer', 'Disease', (96, 108))	('renal cancer', 'Phenotype', 'HP:0009726', (96, 108))	('CCDC50', 'Gene', '152137', (73, 79))	('renal cancer', 'Disease', 'MESH:D007680', (96, 108))	('CCDC50', 'Gene', (73, 79))	('splicing', 'biological_process', 'GO:0045292', ('80', '88'))	('aberrant', 'Var', (64, 72))
97783	32560659	Overall, our findings suggested that HnRNP A1 - regulated aberrant alternative splicing of CCDC50 could contribute to the carcinogenesis and progression of ccRCC by modulating ZNF395.	('aberrant alternative splicing', 'Var', (58, 87))	('contribute', 'Reg', (104, 114))	('splicing', 'biological_process', 'GO:0045292', ('79', '87'))	('carcinogenesis', 'Disease', 'MESH:D063646', (122, 136))	('HnRNP', 'cellular_component', 'GO:0030530', ('37', '42'))	('modulating', 'Reg', (165, 175))	('HnRNP A1', 'Gene', '3178', (37, 45))	('HnRNP', 'molecular_function', 'GO:0008436', ('37', '42'))	('ZNF395', 'Gene', '55893', (176, 182))	('carcinogenesis', 'Disease', (122, 136))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))	('ZNF395', 'Gene', (176, 182))	('CCDC50', 'Gene', '152137', (91, 97))	('CCDC50', 'Gene', (91, 97))	('HnRNP A1', 'Gene', (37, 45))
97803	32560659	The dysregulation of alternative RNA splicing plays a critical role in tumor development and progression.	('dysregulation', 'Var', (4, 17))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('RNA splicing', 'biological_process', 'GO:0008380', ('33', '45'))	('alternative RNA splicing', 'MPA', (21, 45))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('RNA', 'cellular_component', 'GO:0005562', ('33', '36'))
97810	32560659	Dysregulated CCDC50 exon splicing was identified as a candidate splicing event after our analysis.	('CCDC50', 'Gene', (13, 19))	('splicing', 'biological_process', 'GO:0045292', ('64', '72'))	('Dysregulated', 'Var', (0, 12))	('splicing', 'biological_process', 'GO:0045292', ('25', '33'))	('CCDC50', 'Gene', '152137', (13, 19))
97811	32560659	The mean PSI in 72 tumors and all 533 tumors was 0.081 +- 0.049 and 0.124 +- 0.142, while the mean PSI in 72 paired normal tissues was 0.468 +- 0.146 (p < 0.01) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (19, 25))	('0.124', 'Var', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
97818	32560659	Exon 6 (528 bp) can be regulated by alternative splicing, and skipping and inclusion of exon 6 can generate the truncated (CCDC50-S) or full-length transcript (CCDC50-FL), respectively.	('CCDC50', 'Gene', (123, 129))	('skipping', 'Var', (62, 70))	('splicing', 'biological_process', 'GO:0045292', ('48', '56'))	('CCDC50', 'Gene', '152137', (160, 166))	('FL', 'Chemical', 'MESH:D005459', (167, 169))	('CCDC50', 'Gene', (160, 166))	('CCDC50', 'Gene', '152137', (123, 129))
97834	32560659	Furthermore, the silence of CCDC50 transcripts obviously inhibited cell migration and invasion (Fig.	('silence', 'Var', (17, 24))	('CCDC50', 'Gene', '152137', (28, 34))	('CCDC50', 'Gene', (28, 34))	('inhibited', 'NegReg', (57, 66))	('cell migration', 'biological_process', 'GO:0016477', ('67', '81'))	('cell migration', 'CPA', (67, 81))	('invasion', 'CPA', (86, 94))
97854	32560659	4Db) both demonstrated that HnRNP A1 overexpression decreased the full-length transcript while knockdown of HnRNP A1 increased the relative expression of full-length transcript.	('HnRNP', 'molecular_function', 'GO:0008436', ('108', '113'))	('HnRNP A1', 'Gene', '3178', (108, 116))	('overexpression', 'PosReg', (37, 51))	('HnRNP', 'cellular_component', 'GO:0030530', ('28', '33'))	('HnRNP', 'cellular_component', 'GO:0030530', ('108', '113'))	('increased', 'PosReg', (117, 126))	('decreased', 'NegReg', (52, 61))	('HnRNP A1', 'Gene', (108, 116))	('HnRNP A1', 'Gene', (28, 36))	('knockdown', 'Var', (95, 104))	('full-length transcript', 'MPA', (66, 88))	('HnRNP A1', 'Gene', '3178', (28, 36))	('HnRNP', 'molecular_function', 'GO:0008436', ('28', '33'))
97864	32560659	5a-c, knockdown of HnRNP A1 significantly reduced the proliferative ability of 786-O and OS-RC-2 cells, while ectopic expression of HnRNP A1 increased these capacities of renal cancer cells.	('reduced', 'NegReg', (42, 49))	('HnRNP A1', 'Gene', '3178', (132, 140))	('renal cancer', 'Phenotype', 'HP:0009726', (171, 183))	('HnRNP', 'molecular_function', 'GO:0008436', ('19', '24'))	('HnRNP', 'cellular_component', 'GO:0030530', ('19', '24'))	('increased', 'PosReg', (141, 150))	('proliferative ability of 786-O', 'CPA', (54, 84))	('HnRNP A1', 'Gene', '3178', (19, 27))	('renal cancer', 'Disease', 'MESH:D007680', (171, 183))	('HnRNP', 'molecular_function', 'GO:0008436', ('132', '137'))	('HnRNP A1', 'Gene', (132, 140))	('OS-RC-2', 'CellLine', 'CVCL:1626', (89, 96))	('HnRNP', 'cellular_component', 'GO:0030530', ('132', '137'))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('knockdown', 'Var', (6, 15))	('HnRNP A1', 'Gene', (19, 27))	('renal cancer', 'Disease', (171, 183))
97870	32560659	Through digging from TCGA data and the RNAseq data from previous article about CCDC50, we found that ZNF395, PFKFB4, SLC2A3, LAMP1, BNIP3L and TP53I3 were among the most affected proteins after CCDC50 knockdown.	('LAMP1', 'Gene', (125, 130))	('knockdown', 'Var', (201, 210))	('ZNF395', 'Gene', (101, 107))	('PFKFB4', 'Gene', '5210', (109, 115))	('TP53I3', 'Gene', '9540', (143, 149))	('CCDC50', 'Gene', '152137', (79, 85))	('LAMP1', 'Gene', '3916', (125, 130))	('PFKFB4', 'Gene', (109, 115))	('CCDC50', 'Gene', (79, 85))	('SLC2A3', 'Gene', '6515', (117, 123))	('ZNF395', 'Gene', '55893', (101, 107))	('CCDC50', 'Gene', '152137', (194, 200))	('CCDC50', 'Gene', (194, 200))	('affected', 'Reg', (170, 178))	('BNIP3L', 'Gene', '665', (132, 138))	('SLC2A3', 'Gene', (117, 123))	('BNIP3L', 'Gene', (132, 138))	('TP53I3', 'Gene', (143, 149))
97871	32560659	Because CCDC50-S was the main transcript and CCDC50-FL was hard to detect in renal cancer tissues and cell lines, we used CCDC50 knockdown plasmid to represent the knockdown of CCDC50-S. Our RT-qPCR and western blot results validated that the mRNA and protein expression levels of ZNF395 were attenuated after CCDC50 knockdown in vitro, and the tendency was reversed after ectopic expression of CCDC50-S (Fig.	('ZNF395', 'Gene', (281, 287))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CCDC50', 'Gene', (310, 316))	('protein', 'cellular_component', 'GO:0003675', ('252', '259'))	('CCDC50', 'Gene', (8, 14))	('renal cancer', 'Disease', (77, 89))	('CCDC50', 'Gene', '152137', (395, 401))	('CCDC50', 'Gene', '152137', (45, 51))	('renal cancer', 'Phenotype', 'HP:0009726', (77, 89))	('ZNF395', 'Gene', '55893', (281, 287))	('CCDC50', 'Gene', '152137', (122, 128))	('renal cancer', 'Disease', 'MESH:D007680', (77, 89))	('CCDC50', 'Gene', (395, 401))	('CCDC50', 'Gene', (45, 51))	('CCDC50', 'Gene', '152137', (177, 183))	('attenuated', 'NegReg', (293, 303))	('knockdown', 'Var', (317, 326))	('CCDC50', 'Gene', (122, 128))	('FL', 'Chemical', 'MESH:D005459', (52, 54))	('CCDC50', 'Gene', '152137', (8, 14))	('CCDC50', 'Gene', '152137', (310, 316))	('CCDC50', 'Gene', (177, 183))
97877	32560659	After the RCC cell lines stably overexpressing ZNF395 or silencing ZNF395 with shRNA was constructed and validated (Additional file 2, Supplementary Figure 9), we made an inquiry for the specific roles of ZNF395 in renal cancer.	('ZNF395', 'Gene', (67, 73))	('renal cancer', 'Disease', 'MESH:D007680', (215, 227))	('ZNF395', 'Gene', (205, 211))	('ZNF395', 'Gene', (47, 53))	('ZNF395', 'Gene', '55893', (67, 73))	('silencing', 'Var', (57, 66))	('ZNF395', 'Gene', '55893', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('ZNF395', 'Gene', '55893', (47, 53))	('renal cancer', 'Disease', (215, 227))	('RCC', 'Disease', (10, 13))	('renal cancer', 'Phenotype', 'HP:0009726', (215, 227))	('RCC', 'Disease', 'MESH:C538614', (10, 13))
97882	32560659	This study firstly sketched the aberrant exon skipping profiling in ccRCC with TCGA dataset, and proved the reliability of this profiling by validating the aberrant splicing of CCDC50 exon 6 in independent ccRCC cohort.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('splicing', 'biological_process', 'GO:0045292', ('165', '173'))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('RCC', 'Disease', (208, 211))	('CCDC50', 'Gene', '152137', (177, 183))	('CCDC50', 'Gene', (177, 183))	('aberrant splicing', 'Var', (156, 173))
97883	32560659	We also observed that splicing factor HnRNP A1 could exert it carcinogenic functions in ccRCC via promoting the skipping of exon 6 of CCDC50 pre-mRNA and increasing the proportion of oncogenic truncated transcript of CCDC50.	('oncogenic truncated transcript', 'MPA', (183, 213))	('HnRNP A1', 'Gene', (38, 46))	('carcinogenic', 'Disease', 'MESH:D063646', (62, 74))	('HnRNP A1', 'Gene', '3178', (38, 46))	('splicing', 'biological_process', 'GO:0045292', ('22', '30'))	('pre', 'molecular_function', 'GO:0003904', ('141', '144'))	('CCDC50', 'Gene', (134, 140))	('RCC', 'Disease', (90, 93))	('proportion', 'MPA', (169, 179))	('promoting', 'PosReg', (98, 107))	('CCDC50', 'Gene', '152137', (217, 223))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('increasing', 'PosReg', (154, 164))	('HnRNP', 'cellular_component', 'GO:0030530', ('38', '43'))	('CCDC50', 'Gene', (217, 223))	('HnRNP', 'molecular_function', 'GO:0008436', ('38', '43'))	('skipping', 'Var', (112, 120))	('carcinogenic', 'Disease', (62, 74))	('CCDC50', 'Gene', '152137', (134, 140))
97886	32560659	Our findings not only identified a common and important splicing event in ccRCC, but also provided integrated regulatory network which elucidated the mechanism of exon skipping involving in renal cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('exon skipping', 'Var', (163, 176))	('splicing', 'biological_process', 'GO:0045292', ('56', '64'))	('renal cancer', 'Disease', (190, 202))	('renal cancer', 'Disease', 'MESH:D007680', (190, 202))	('renal cancer', 'Phenotype', 'HP:0009726', (190, 202))
97888	32560659	Additionally, mutation of CCDC50 gene or de novo deletion of 3q29 which compromised CCDC50 gene was shown to cause progressive hearing loss in several studies, underlining the critical functions of CCDC50 in human.	('hearing', 'biological_process', 'GO:0007605', ('127', '134'))	('progressive hearing loss', 'Phenotype', 'HP:0001730', (115, 139))	('hearing loss', 'Phenotype', 'HP:0000365', (127, 139))	('CCDC50', 'Gene', (84, 90))	('CCDC50', 'Gene', '152137', (198, 204))	('CCDC50', 'Gene', '152137', (84, 90))	('mutation', 'Var', (14, 22))	('hearing loss', 'Disease', (127, 139))	('deletion', 'Var', (49, 57))	('CCDC50', 'Gene', '152137', (26, 32))	('CCDC50', 'Gene', (198, 204))	('CCDC50', 'Gene', (26, 32))	('hearing loss', 'Disease', 'MESH:D034381', (127, 139))	('human', 'Species', '9606', (208, 213))
97891	32560659	identified that copy number gain of CCDC50 was more common in cyclin D1-negative pleomorphic mantle cell lymphoma, but the significance of this finding was still elusive.	('cyclin D1', 'Gene', (62, 71))	('lymphoma', 'Phenotype', 'HP:0002665', (105, 113))	('copy number gain', 'Var', (16, 32))	('pleomorphic mantle cell lymphoma', 'Disease', (81, 113))	('pleomorphic mantle cell lymphoma', 'Disease', 'MESH:D020522', (81, 113))	('cell lymphoma', 'Phenotype', 'HP:0012191', (100, 113))	('cyclin', 'molecular_function', 'GO:0016538', ('62', '68'))	('CCDC50', 'Gene', '152137', (36, 42))	('CCDC50', 'Gene', (36, 42))	('cyclin D1', 'Gene', '595', (62, 71))	('common', 'Reg', (52, 58))
97897	32560659	We found that CCDC50 was upregulated in ccRCC and the predominant CCDC50 transcript exerted an oncogenic function in ccRCC, which was consistent with the pro-survival function shown by Fartsing et al.. Like the majority of human genes, CCDC50 locus could generate diverse mRNA transcripts through the alternative splicing of pre-mRNA.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('CCDC50', 'Gene', '152137', (66, 72))	('alternative splicing', 'Var', (301, 321))	('CCDC50', 'Gene', '152137', (14, 20))	('human', 'Species', '9606', (223, 228))	('pre', 'molecular_function', 'GO:0003904', ('325', '328'))	('pro-survival', 'biological_process', 'GO:0043066', ('154', '166'))	('CCDC50', 'Gene', (66, 72))	('CCDC50', 'Gene', (14, 20))	('CCDC50', 'Gene', (236, 242))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('CCDC50', 'Gene', '152137', (236, 242))	('RCC', 'Disease', (119, 122))	('splicing', 'biological_process', 'GO:0045292', ('313', '321'))	('mRNA', 'MPA', (272, 276))	('RCC', 'Disease', (42, 45))
97900	32560659	Our results were conformed with previous findings, and we further elucidated that dysregulation of alternative splicing of CCDC50 was a normal phenomenon in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('dysregulation', 'Var', (82, 95))	('CCDC50', 'Gene', (123, 129))	('alternative splicing', 'MPA', (99, 119))	('splicing', 'biological_process', 'GO:0045292', ('111', '119'))	('CCDC50', 'Gene', '152137', (123, 129))	('RCC', 'Disease', (159, 162))
97901	32560659	Furthermore, we provided reliable evidence that truncated or full-length CCDC50 could promote or inhibit the proliferation, migration, invasion, and tumor growth of renal cancer, respectively.	('inhibit', 'NegReg', (97, 104))	('migration', 'CPA', (124, 133))	('truncated', 'Var', (48, 57))	('tumor growth of renal cancer', 'Disease', (149, 177))	('renal cancer', 'Phenotype', 'HP:0009726', (165, 177))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('CCDC50', 'Gene', '152137', (73, 79))	('promote', 'PosReg', (86, 93))	('CCDC50', 'Gene', (73, 79))	('tumor growth of renal cancer', 'Disease', 'MESH:D007680', (149, 177))	('proliferation', 'CPA', (109, 122))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('invasion', 'CPA', (135, 143))
97903	32560659	An increasing body of literature shows that dysregulation of pre-mRNA splicing contributes to tumorigenesis and turns into potent drivers of malignant phenotypes, our results indicated that CCDC50 could also be regarded as an outstanding example because the splicing pattern of CCDC50 could predict survival of ccRCC patients.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('RCC', 'Disease', 'MESH:C538614', (313, 316))	('dysregulation', 'Var', (44, 57))	('CCDC50', 'Gene', '152137', (278, 284))	('patients', 'Species', '9606', (317, 325))	('CCDC50', 'Gene', (278, 284))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('61', '78'))	('pre', 'molecular_function', 'GO:0003904', ('61', '64'))	('contributes', 'Reg', (79, 90))	('tumor', 'Disease', (94, 99))	('CCDC50', 'Gene', '152137', (190, 196))	('CCDC50', 'Gene', (190, 196))	('splicing', 'biological_process', 'GO:0045292', ('258', '266'))	('pre-mRNA splicing', 'MPA', (61, 78))	('predict', 'Reg', (291, 298))	('RCC', 'Disease', (313, 316))
97905	32560659	HnRNPs are a set of ~ 20 abundant proteins which involve in several post-translational modifications such as splicing of introns, 5'-end capping, and polyadenylation.	('HnRNP', 'Gene', '3183', (0, 5))	('splicing', 'MPA', (109, 117))	('polyadenylation', 'Var', (150, 165))	("5'-end capping", 'biological_process', 'GO:0006370', ('130', '144'))	("5'-end capping", 'MPA', (130, 144))	('splicing', 'biological_process', 'GO:0045292', ('109', '117'))	('HnRNP', 'Gene', (0, 5))	('involve', 'Reg', (49, 56))
97910	32560659	For example, HnRNP A1 could bind to sequences flanking pyruvate kinase exon 9 and cause the exon 10 inclusion, increasing the PKM2/PKM1 ratio and promoting aerobic glycolysis in brain tumors.	('HnRNP A1', 'Gene', (13, 21))	('bind', 'Interaction', (28, 32))	('inclusion', 'Reg', (100, 109))	('HnRNP A1', 'Gene', '3178', (13, 21))	('brain tumors', 'Disease', (178, 190))	('HnRNP', 'molecular_function', 'GO:0008436', ('13', '18'))	('HnRNP', 'cellular_component', 'GO:0030530', ('13', '18'))	('PKM2', 'Gene', (126, 130))	('promoting', 'PosReg', (146, 155))	('PKM2', 'Gene', '5315', (126, 130))	('exon', 'Var', (92, 96))	('aerobic glycolysis', 'MPA', (156, 174))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('cause', 'Reg', (82, 87))	('glycolysis', 'biological_process', 'GO:0006096', ('164', '174'))	('brain tumors', 'Disease', 'MESH:D001932', (178, 190))	('brain tumors', 'Phenotype', 'HP:0030692', (178, 190))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('increasing', 'PosReg', (111, 121))
97912	32560659	These data shed light on how splicing factor HnRNP A1 contributed to the tumor progression.	('HnRNP', 'molecular_function', 'GO:0008436', ('45', '50'))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('HnRNP A1', 'Gene', (45, 53))	('tumor', 'Disease', (73, 78))	('splicing factor', 'Var', (29, 44))	('contributed', 'Reg', (54, 65))	('splicing', 'biological_process', 'GO:0045292', ('29', '37'))	('HnRNP A1', 'Gene', '3178', (45, 53))	('HnRNP', 'cellular_component', 'GO:0030530', ('45', '50'))
97918	32560659	VHL inactivation stabilized HIF-2alpha - HIF-1beta heterodimer binding at the enhancers, and further activated the transcription of ZNF395 by recruiting histone acetyltransferase p300 on ZNF395 promoter.	('transcription', 'biological_process', 'GO:0006351', ('115', '128'))	('VHL', 'Gene', '7428', (0, 3))	('HIF-2alpha', 'Gene', (28, 38))	('inactivation', 'Var', (4, 16))	('ZNF395', 'Gene', '55893', (132, 138))	('ZNF395', 'Gene', '55893', (187, 193))	('HIF-1beta', 'Gene', (41, 50))	('transcription', 'MPA', (115, 128))	('activated', 'PosReg', (101, 110))	('p300', 'Gene', (179, 183))	('HIF-2alpha', 'Gene', '2034', (28, 38))	('binding', 'Interaction', (63, 70))	('heterodimer', 'Protein', (51, 62))	('VHL', 'Gene', (0, 3))	('p300', 'Gene', '2033', (179, 183))	('recruiting', 'PosReg', (142, 152))	('HIF-1beta', 'Gene', '3091', (41, 50))	('ZNF395', 'Gene', (187, 193))	('binding', 'molecular_function', 'GO:0005488', ('63', '70'))	('ZNF395', 'Gene', (132, 138))
97923	32560659	Besides, HIF-2alpha accumulation under hypoxic microenvironment could promote EGFR mRNA translation and diminish the necessity for EGFR mutations, the mutual promotion of EGFR and HIF-2alpha - p300 - ZNF395 pathway turned out to be significant driver of tumorigenic progression of ccRCC.	('EGFR', 'Gene', (171, 175))	('HIF-2alpha', 'Gene', (180, 190))	('RCC', 'Disease', (283, 286))	('HIF-2alpha', 'Gene', '2034', (9, 19))	('EGFR', 'Gene', (131, 135))	('mutations', 'Var', (136, 145))	('EGFR', 'Gene', '1956', (78, 82))	('ZNF395', 'Gene', (200, 206))	('hypoxic', 'Disease', (39, 46))	('hypoxic', 'Disease', 'MESH:D000860', (39, 46))	('RCC', 'Disease', 'MESH:C538614', (283, 286))	('promote', 'PosReg', (70, 77))	('EGFR', 'molecular_function', 'GO:0005006', ('78', '82'))	('EGFR', 'Gene', '1956', (171, 175))	('promotion', 'PosReg', (158, 167))	('diminish', 'NegReg', (104, 112))	('tumor', 'Disease', (254, 259))	('HIF-2alpha', 'Gene', (9, 19))	('ZNF395', 'Gene', '55893', (200, 206))	('HIF-2alpha', 'Gene', '2034', (180, 190))	('translation', 'biological_process', 'GO:0006412', ('88', '99'))	('EGFR', 'Gene', '1956', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('EGFR', 'Gene', (78, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('171', '175'))	('p300', 'Gene', (193, 197))	('EGFR', 'molecular_function', 'GO:0005006', ('131', '135'))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('p300', 'Gene', '2033', (193, 197))
97929	32560659	In summary, this study validates the aberrant splicing pattern of CCDC50 exon 6 initially identified by bioinformatic methods, and identifies oncogenic splicing factor HnRNP A1 as a regulator of CCDC50 exon 6 skipping in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (223, 226))	('RCC', 'Disease', (223, 226))	('skipping', 'Var', (209, 217))	('CCDC50', 'Gene', '152137', (66, 72))	('splicing', 'biological_process', 'GO:0045292', ('152', '160'))	('HnRNP A1', 'Gene', (168, 176))	('CCDC50', 'Gene', (66, 72))	('HnRNP', 'cellular_component', 'GO:0030530', ('168', '173'))	('HnRNP', 'molecular_function', 'GO:0008436', ('168', '173'))	('splicing', 'biological_process', 'GO:0045292', ('46', '54'))	('HnRNP A1', 'Gene', '3178', (168, 176))	('CCDC50', 'Gene', '152137', (195, 201))	('CCDC50', 'Gene', (195, 201))
97952	33488669	Defective DDR can lead to accumulated DNA lesions and genome instability, which contribute to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('accumulated', 'PosReg', (26, 37))	('genome instability', 'CPA', (54, 72))	('tumor', 'Disease', (94, 99))	('DDR', 'Gene', (10, 13))	('Defective', 'Var', (0, 9))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('lead', 'Reg', (18, 22))	('contribute', 'Reg', (80, 90))	('DNA lesions', 'MPA', (38, 49))
97953	33488669	It has been reported that germline mutations in exonuclease 5 can impair DNA repair ability and cause androgen-related prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (119, 134))	('exonuclease 5', 'Gene', (48, 61))	('germline mutations', 'Var', (26, 44))	('cause', 'Reg', (96, 101))	('impair', 'NegReg', (66, 72))	('prostate cancer', 'Disease', (119, 134))	('exonuclease 5', 'Gene', '64789', (48, 61))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('DNA repair', 'MPA', (73, 83))	('prostate cancer', 'Disease', 'MESH:D011471', (119, 134))	('DNA repair', 'biological_process', 'GO:0006281', ('73', '83'))
97956	33488669	High TTK protein kinase (TTK) expression in breast cancer is associated with efficient repair through homologous recombination and low radiation sensitivity.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('High', 'Var', (0, 4))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('TTK', 'Gene', '7272', (25, 28))	('breast cancer', 'Disease', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('protein', 'cellular_component', 'GO:0003675', ('9', '16'))	('TTK', 'Gene', (5, 8))	('homologous recombination', 'biological_process', 'GO:0035825', ('102', '126'))	('TTK', 'molecular_function', 'GO:0050321', ('25', '28'))	('TTK', 'Gene', '7272', (5, 8))	('TTK', 'molecular_function', 'GO:0050321', ('5', '8'))	('TTK', 'Gene', (25, 28))	('TTK protein kinase', 'Gene', '7272', (5, 23))	('TTK protein kinase', 'Gene', (5, 23))
97959	33488669	Many studies reported the prognostic and biological significance of the cancer-driven genetic alterations including von Hippel-Lindau, TP53 as well as PTEN mutations in RCC.	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('RCC', 'Disease', (169, 172))	('mutations', 'Var', (156, 165))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (116, 133))	('TP53', 'Gene', '7157', (135, 139))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('TP53', 'Gene', (135, 139))	('von Hippel-Lindau', 'Disease', (116, 133))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('PTEN', 'Gene', '5728', (151, 155))	('PTEN', 'Gene', (151, 155))	('cancer', 'Disease', (72, 78))
97995	33488669	Small cell lung cancer patients with high SLFN1 expression might benefit from PARP inhibition.	('Small cell lung cancer', 'Disease', (0, 22))	('PARP', 'Gene', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('high', 'Var', (37, 41))	('patients', 'Species', '9606', (23, 31))	('SLFN1', 'Gene', (42, 47))	('expression', 'MPA', (48, 58))	('PARP', 'Gene', '142', (78, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('Small cell lung cancer', 'Disease', 'MESH:D055752', (0, 22))	('benefit', 'Reg', (65, 72))	('Small cell lung cancer', 'Phenotype', 'HP:0030357', (0, 22))
98000	33488669	A group led by Sato has shown that genotoxic stress such as irradiation or PARP inhibition can upregulate the expression of PD-L1 through the ATM-ATR/CHK1 pathway.	('PD-L1', 'Gene', (124, 129))	('CHK1', 'Gene', (150, 154))	('ATM', 'Gene', '472', (142, 145))	('genotoxic stress', 'Disease', 'MESH:D000079225', (35, 51))	('ATR', 'Gene', '545', (146, 149))	('PARP', 'Gene', (75, 79))	('upregulate', 'PosReg', (95, 105))	('genotoxic stress', 'Disease', (35, 51))	('PD-L1', 'Gene', '29126', (124, 129))	('expression', 'MPA', (110, 120))	('PARP', 'Gene', '142', (75, 79))	('CHK1', 'Gene', '1111', (150, 154))	('inhibition', 'Var', (80, 90))	('ATM', 'Gene', (142, 145))	('ATR', 'Gene', (146, 149))
98001	33488669	found that PARP inhibitors can upregulate PD-L1 and promote immune suppression.	('PD-L1', 'Gene', '29126', (42, 47))	('PARP', 'Gene', '142', (11, 15))	('inhibitors', 'Var', (16, 26))	('PARP', 'Gene', (11, 15))	('PD-L1', 'Gene', (42, 47))	('immune suppression', 'CPA', (60, 78))	('upregulate', 'PosReg', (31, 41))	('promote', 'PosReg', (52, 59))
98002	33488669	The association of mutations in DNA repair genes and immune regulatory genes with bladder cancer has also been documented.	('bladder cancer', 'Phenotype', 'HP:0009725', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('association', 'Interaction', (4, 15))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('mutations', 'Var', (19, 28))	('bladder cancer', 'Disease', 'MESH:D001749', (82, 96))	('bladder cancer', 'Disease', (82, 96))	('DNA repair genes', 'Gene', (32, 48))	('DNA repair', 'biological_process', 'GO:0006281', ('32', '42'))
98003	33488669	Moreover, it has been reported that alterations in DDR genes which cause loss of function are frequent in metastatic ccRCC, which may certainly affect the effectiveness of immunotherapy.	('frequent', 'Reg', (94, 102))	('alterations', 'Var', (36, 47))	('DDR genes', 'Gene', (51, 60))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))	('affect', 'Reg', (144, 150))
98005	33488669	As it has been reported that antibodies against immune evasion genes could restore responses of tumor-associated T cells to tumor related antigens, and higher PD-L1 expression on tumor cells and/or immune cells was shown to be associated with better efficacy of anti-PD1/PD-L1 immunotherapies, we speculated that patients with high risk might benefit from immunotherapy.	('higher', 'PosReg', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('responses', 'MPA', (83, 92))	('tumor', 'Disease', (124, 129))	('immune evasion', 'biological_process', 'GO:0042783', ('48', '62'))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('PD-L1', 'Gene', (271, 276))	('immune evasion', 'biological_process', 'GO:0051842', ('48', '62'))	('PD-L1', 'Gene', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('PD-L1', 'Gene', '29126', (271, 276))	('PD-L1', 'Gene', '29126', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('restore', 'PosReg', (75, 82))	('patients', 'Species', '9606', (313, 321))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('antibodies', 'Var', (29, 39))	('expression', 'MPA', (165, 175))	('tumor', 'Disease', (179, 184))
98060	33178820	These DEGs might worsen the symptoms of patients and finally curtail survival time.	('curtail', 'NegReg', (61, 68))	('worsen', 'Reg', (17, 23))	('patients', 'Species', '9606', (40, 48))	('survival time', 'CPA', (69, 82))	('DEGs', 'Var', (6, 10))	('symptoms', 'CPA', (28, 36))
98070	33178820	Luckily, when patients were divided to highly or lowly expressed ID1 groups at a standardized cut-off value (1.079) and the overall survival time between two groups was studied (Figure 3(d)), the data indicated that lowly expressed ID1 was associated with poor overall survival in clear cell renal cell carcinoma (P = 0.015).	('ID1', 'Gene', '3397', (232, 235))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (292, 312))	('ID1', 'Gene', (65, 68))	('poor', 'NegReg', (256, 260))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (281, 312))	('clear cell renal cell carcinoma', 'Disease', (281, 312))	('ID1', 'Gene', (232, 235))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (281, 312))	('ID1', 'Gene', '3397', (65, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('lowly expressed', 'Var', (216, 231))	('patients', 'Species', '9606', (14, 22))
98076	33178820	The results displayed that lowly expressed ID1 was associated with high serum calcium and high probability of metastasis (Table 3).	('ID1', 'Gene', '3397', (43, 46))	('metastasis', 'CPA', (110, 120))	('calcium', 'Chemical', 'MESH:D002118', (78, 85))	('high serum calcium', 'Phenotype', 'HP:0003072', (67, 85))	('high serum calcium', 'MPA', (67, 85))	('ID1', 'Gene', (43, 46))	('lowly expressed', 'Var', (27, 42))
98084	33178820	Based on the outcome that lowly expressed ID1 might promote cancer cell metastasis and thereby influence patient's survival time, we supposed that ID1 probably affect immune system.	('ID1', 'Gene', (147, 150))	('patient', 'Species', '9606', (105, 112))	('ID1', 'Gene', (42, 45))	('influence', 'Reg', (95, 104))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('affect', 'Reg', (160, 166))	('cancer', 'Disease', (60, 66))	('lowly expressed', 'Var', (26, 41))	('ID1', 'Gene', '3397', (147, 150))	('ID1', 'Gene', '3397', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('promote', 'PosReg', (52, 59))
98107	33178820	It reviewed that lowly expressed ID1 is associated with high serum calcium and high probability of metastasis (Figure 4).	('high serum calcium', 'MPA', (56, 74))	('calcium', 'Chemical', 'MESH:D002118', (67, 74))	('high serum calcium', 'Phenotype', 'HP:0003072', (56, 74))	('ID1', 'Gene', '3397', (33, 36))	('ID1', 'Gene', (33, 36))	('metastasis', 'CPA', (99, 109))	('lowly expressed', 'Var', (17, 32))
98135	30008851	ROC curves revealed that the diagnostic accuracy (area under the curve) of tissue miR-210, miR-224, the ratio of miR-210/miR-141 (miR210/141), miR-224/miR-141 (miR224/141) and miR-210x miR-224/miR-141 (miR210x224/141) in ccRCC was 0.8329, 0.8511, 0.9412, 0.9898 and 0.9771, respectively.	('RCC', 'Disease', 'MESH:C538614', (223, 226))	('miR-141', 'Gene', '406933', (193, 200))	('miR210', 'Gene', (130, 136))	('miR-141', 'Gene', (193, 200))	('miR-224', 'Gene', '407009', (91, 98))	('miR-224', 'Gene', (91, 98))	('miR-141', 'Gene', '406933', (121, 128))	('miR210', 'Gene', (202, 208))	('miR-210', 'Gene', '406992', (113, 120))	('0.9412', 'Var', (247, 253))	('miR-210', 'Gene', '406992', (82, 89))	('ccRCC', 'Phenotype', 'HP:0006770', (221, 226))	('miR-141', 'Gene', '406933', (151, 158))	('miR224/141', 'Gene', (160, 170))	('miR-141', 'Gene', (121, 128))	('miR-210', 'Gene', '406992', (176, 183))	('miR-210', 'Gene', (113, 120))	('miR210/141', 'Gene', '406992;406933', (130, 140))	('miR-210', 'Gene', (82, 89))	('miR-224', 'Gene', (185, 192))	('miR-141', 'Gene', (151, 158))	('miR-224', 'Gene', '407009', (185, 192))	('RCC', 'Phenotype', 'HP:0005584', (223, 226))	('miR-210', 'Gene', (176, 183))	('RCC', 'Disease', (223, 226))	('miR210', 'Gene', '406992', (130, 136))	('miR224/141', 'Gene', '407009;406933', (160, 170))	('miR210/141', 'Gene', (130, 140))	('miR-224', 'Gene', '407009', (143, 150))	('miR-224', 'Gene', (143, 150))	('miR210', 'Gene', '406992', (202, 208))
98138	30008851	The diagnostic accuracy of plasma miR-210 and miR-224 were 0.6775 (89.55% sensitivity and 48.48% specificity) and 0.6056 (88.06% sensitivity and 40.91% specificity), respectively.	('miR-210', 'Gene', '406992', (34, 41))	('miR-224', 'Gene', '407009', (46, 53))	('miR-224', 'Gene', (46, 53))	('0.6056', 'Var', (114, 120))	('miR-210', 'Gene', (34, 41))	('0.6775', 'Var', (59, 65))
98179	30008851	This revealed that the miR-210/miR-224 ratio served as a useful biomarker for discriminating ccRCC from normal tissues, with an AUC of 0.8329 (95% confidence intervals (CI), 0.7594-0.9065; P<0.0001) and 0.8511 (95% CI, 0.7885-0.9137; P<0.0001), respectively (Fig.	('0.8511', 'Var', (203, 209))	('miR-210', 'Gene', (23, 30))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('RCC', 'Disease', (95, 98))	('miR-210', 'Gene', '406992', (23, 30))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('miR-224', 'Gene', '407009', (31, 38))	('miR-224', 'Gene', (31, 38))
98180	30008851	At a threshold of 0.005373 for relative miR-210 expression, the sensitivity was 82.35% and the specificity was 79.41% (Fig.	('miR-210', 'Gene', (40, 47))	('0.005373', 'Var', (18, 26))	('expression', 'MPA', (48, 58))	('miR-210', 'Gene', '406992', (40, 47))
98186	30008851	ROC curve analyses demonstrated that the diagnostic accuracy of miR210/141, miR224/141 and miR(210x224)/141 with AUCs of 0.9412, 0.9898 and 0.9771, respectively, were increased compared with that of miR-141 (AUC=0.93).	('miR', 'Gene', (91, 94))	('diagnostic', 'MPA', (41, 51))	('0.9898', 'Var', (129, 135))	('miR-141', 'Gene', (199, 206))	('miR224/141', 'Gene', '407009;406933', (76, 86))	('miR', 'Gene', '220972', (64, 67))	('miR', 'Gene', (64, 67))	('miR-141', 'Gene', '406933', (199, 206))	('miR224/141', 'Gene', (76, 86))	('increased', 'PosReg', (167, 176))	('miR', 'Gene', (199, 202))	('miR', 'Gene', '220972', (199, 202))	('miR210/141', 'Gene', '406992;406933', (64, 74))	('miR210/141', 'Gene', (64, 74))	('miR', 'Gene', '220972', (76, 79))	('0.9771', 'Var', (140, 146))	('miR', 'Gene', (76, 79))	('miR', 'Gene', '220972', (91, 94))
98277	29805829	Immunohistochemical stains showed that the neoplastic cells were positive for Pax-8, p53, CK7, HMWK 903, and INI-1 and focally positive for p504s (AMACR).	('AMACR', 'Gene', '23600', (147, 152))	('CK7', 'Gene', '3855', (90, 93))	('Pax-8', 'Gene', (78, 83))	('positive', 'Reg', (65, 73))	('p53', 'Gene', '7157', (85, 88))	('Pax-8', 'Gene', '7849', (78, 83))	('p504s', 'Var', (140, 145))	('p53', 'Gene', (85, 88))	('HMWK', 'Gene', '3827', (95, 99))	('HMWK', 'Gene', (95, 99))	('AMACR', 'Gene', (147, 152))	('INI-1', 'Gene', '6598', (109, 114))	('CK7', 'Gene', (90, 93))	('INI-1', 'Gene', (109, 114))
98298	29805829	Immunohistochemical stains showed that the neoplastic cells were positive for Pax-8 (Figure 5), p53 (Figure 6), CK7 (Figure 7), HMWK 903 (Figure 8), and INI-1 (Figure 9) and focally positive for p504s (AMACR) (Figure 10).	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('HMWK', 'Gene', (128, 132))	('HMWK', 'Gene', '3827', (128, 132))	('Pax-8', 'Gene', (78, 83))	('INI-1', 'Gene', '6598', (153, 158))	('positive', 'Reg', (65, 73))	('CK7', 'Gene', (112, 115))	('p504s', 'Var', (195, 200))	('CK7', 'Gene', '3855', (112, 115))	('INI-1', 'Gene', (153, 158))	('Pax-8', 'Gene', '7849', (78, 83))	('AMACR', 'Gene', '23600', (202, 207))	('AMACR', 'Gene', (202, 207))
98300	29805829	ALK immunostain was performed to rule out an ALK rearrangement-associated Renal Cell Carcinoma and was negative.	('ALK', 'Gene', '238', (45, 48))	('Renal Cell Carcinoma', 'Disease', (74, 94))	('Carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('rearrangement-associated', 'Var', (49, 73))	('ALK', 'Gene', (45, 48))	('ALK', 'Gene', (0, 3))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (74, 94))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (74, 94))	('ALK', 'Gene', '238', (0, 3))
98316	29805829	Hereditary Leiomyomatosis and Renal Cell Carcinoma-associated Renal Cell Carcinoma is a rare subtype of the familial RCCs that follows an autosomal dominant pattern of germline fumarate hydratase mutations and usually affects the renal cortex and medulla.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('fumarate hydratase', 'Gene', (177, 195))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('Hereditary Leiomyomatosis and Renal Cell Carcinoma-associated Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (0, 82))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (62, 82))	('Carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('Carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('fumarate hydratase', 'Gene', '2271', (177, 195))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (30, 50))	('mutations', 'Var', (196, 205))
98318	29805829	ALK rearrangement-associated Renal Cell Carcinomas are extremely rare entities, with less than ten cases reported in the literature, which tend to occur in pediatric patients with sickle cell trait.	('Carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('Renal Cell Carcinomas', 'Phenotype', 'HP:0005584', (29, 50))	('sickle cell trait', 'Disease', (180, 197))	('Renal Cell Carcinomas', 'Disease', (29, 50))	('ALK', 'Gene', (0, 3))	('rearrangement-associated', 'Var', (4, 28))	('Carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (29, 49))	('Renal Cell Carcinomas', 'Disease', 'MESH:C538614', (29, 50))	('patients', 'Species', '9606', (166, 174))	('ALK', 'Gene', '238', (0, 3))
98322	29805829	The succinate dehydratase genes (SDH) are usually lost in a double-hit inactivation, resulting in a loss of SDHB immunohistochemical staining.	('SDH', 'Gene', (33, 36))	('SDHB', 'Gene', (108, 112))	('SDHB', 'Gene', '6390', (108, 112))	('lost', 'NegReg', (50, 54))	('inactivation', 'Var', (71, 83))	('loss', 'NegReg', (100, 104))
98336	28569782	Stable overexpression of miR-30a-5p in 769-P cells was sufficient to prevent cellular proliferation and invasion in vitro and in vivo.	('expression', 'Species', '29278', (11, 21))	('cellular proliferation', 'CPA', (77, 99))	('overexpression', 'PosReg', (7, 21))	('miR-30a-5p', 'Var', (25, 35))	('prevent', 'NegReg', (69, 76))	('invasion', 'CPA', (104, 112))
98337	28569782	Upon further examination, it was found that miR-30a-5p directly targeted the 3'-UTR of ZEB2 and suppressed ccRCC cell epithelial-mesenchymal transition.	('miR-30a-5p', 'Var', (44, 54))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('118', '151'))	('ZEB2', 'Gene', '9839', (87, 91))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('suppressed', 'NegReg', (96, 106))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('ZEB2', 'Gene', (87, 91))
98339	28569782	Taken together, these data reveal an important role for miR-30a-5p in the regulation of ccRCC proliferation and invasion, and indicate the potential for miR-30a-5p in applications furthering ccRCC prognostics and therapeutics.	('miR-30a-5p', 'Var', (153, 163))	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('RCC', 'Disease', (193, 196))	('RCC', 'Phenotype', 'HP:0005584', (193, 196))	('ccRCC', 'Phenotype', 'HP:0006770', (191, 196))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('invasion', 'CPA', (112, 120))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('regulation', 'biological_process', 'GO:0065007', ('74', '84'))	('RCC', 'Disease', (90, 93))
98347	28569782	Furthermore, several miRNAs, for example, miR-215, miR-200 s, miR-708, miR-205, miR-204, miR-199a and miR-141, have been reported to regulate ccRCC cell growth, apoptosis, migration and/or invasion, suggesting miRNA dysfunction may be associated with renal carcinogenesis.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('apoptosis', 'biological_process', 'GO:0097194', ('161', '170'))	('regulate', 'Reg', (133, 141))	('miR-141', 'Var', (102, 109))	('apoptosis', 'biological_process', 'GO:0006915', ('161', '170'))	('miR-200 s', 'Var', (51, 60))	('miR-204', 'Var', (80, 87))	('miR-215', 'Var', (42, 49))	('renal carcinogenesis', 'Disease', (251, 271))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('miR-205', 'Var', (71, 78))	('migration', 'CPA', (172, 181))	('miR-708', 'Var', (62, 69))	('cell growth', 'biological_process', 'GO:0016049', ('148', '159'))	('renal carcinogenesis', 'Disease', 'MESH:D007674', (251, 271))	('apoptosis', 'CPA', (161, 170))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('associated', 'Reg', (235, 245))	('miR-199a', 'Var', (89, 97))	('invasion', 'CPA', (189, 197))
98350	28569782	One such downregulated miRNA identified was miR-30a-5p, which was one of the most influential in ccRCC pathogenesis.	('miR-30a-5p', 'Var', (44, 54))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('pathogenesis', 'biological_process', 'GO:0009405', ('103', '115'))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('downregulated', 'NegReg', (9, 22))
98352	28569782	In addition, miR-30a-5p has been demonstrated to suppress tumor growth in colon carcinomas, decrease cellular proliferation and invasion of Ewing tumors, inhibit cancer cell proliferation and induce apoptosis in liver cancers.	('cell proliferation', 'biological_process', 'GO:0008283', ('169', '187'))	('cancer', 'Disease', (162, 168))	('liver cancers', 'Disease', (212, 225))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('tumor', 'Disease', (146, 151))	('colon carcinomas', 'Disease', (74, 90))	('apoptosis', 'biological_process', 'GO:0097194', ('199', '208'))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Ewing tumors', 'Phenotype', 'HP:0012254', (140, 152))	('apoptosis', 'biological_process', 'GO:0006915', ('199', '208'))	('colon carcinomas', 'Disease', 'MESH:D015179', (74, 90))	('suppress', 'NegReg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor', 'Disease', (58, 63))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cellular proliferation', 'CPA', (101, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('decrease', 'NegReg', (92, 100))	('induce', 'Reg', (192, 198))	('miR-30a-5p', 'Var', (13, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('Ewing tumors', 'Disease', 'MESH:C563168', (140, 152))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('invasion', 'CPA', (128, 136))	('liver cancers', 'Disease', 'MESH:D006528', (212, 225))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('inhibit', 'NegReg', (154, 161))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('Ewing tumors', 'Disease', (140, 152))	('liver cancers', 'Phenotype', 'HP:0002896', (212, 225))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('cancer', 'Disease', (218, 224))	('apoptosis', 'CPA', (199, 208))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))
98353	28569782	Altogether, these data indicate a potential tumor suppressive function for miR-30a-5p.	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (44, 49))	('miR-30a-5p', 'Var', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
98356	28569782	Ectopic overexpression of miR-30a-5p in ccRCC cells was sufficient to inhibit cell invasion and metastasis both in vitro and in vivo.	('overexpression', 'PosReg', (8, 22))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('miR-30a-5p', 'Var', (26, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('expression', 'Species', '29278', (12, 22))	('inhibit', 'NegReg', (70, 77))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))
98357	28569782	More importantly, this study provides the first evidence that miR-30a-5p directly targets the zinc-finger E-box binding homeobox 2 (ZEB2) mRNA.	('E-box binding', 'molecular_function', 'GO:0070888', ('106', '119'))	('ZEB2', 'Gene', '9839', (132, 136))	('targets', 'Reg', (82, 89))	('miR-30a-5p', 'Var', (62, 72))	('ZEB2', 'Gene', (132, 136))
98358	28569782	In addition, miR-30a-5p appeared to play a crucial role in regulating epithelial-mesenchymal transition (EMT) activity and thereby inhibited ccRCC cell invasiveness and metastasis.	('ccRCC', 'Phenotype', 'HP:0006770', (141, 146))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('70', '103'))	('miR-30a-5p', 'Var', (13, 23))	('epithelial-mesenchymal transition', 'CPA', (70, 103))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('EMT', 'biological_process', 'GO:0001837', ('105', '108'))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('inhibited', 'NegReg', (131, 140))	('RCC', 'Disease', (143, 146))
98371	28569782	To determine whether ZEB2 is a direct target of miR-30a-5p, the 3'-UTR of ZEB2, as well as two sequences with mutations in the miR-30a-5p binding site, were subcloned downstream of a luciferase reporter.	('mutations', 'Var', (110, 119))	('ZEB2', 'Gene', (74, 78))	('ZEB2', 'Gene', '9839', (21, 25))	('ZEB2', 'Gene', (21, 25))	('binding', 'molecular_function', 'GO:0005488', ('138', '145'))	('ZEB2', 'Gene', '9839', (74, 78))
98375	28569782	Collectively, these data support the bioinformatic prediction suggesting the 3'-UTR of ZEB2 is a direct target of miR-30a-5p.	('miR-30a-5p', 'Var', (114, 124))	('ZEB2', 'Gene', '9839', (87, 91))	('ZEB2', 'Gene', (87, 91))
98376	28569782	Next, the biological functions of miR-30a-5p in ccRCC tumorigenesis and progression were explored.	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('miR-30a-5p', 'Var', (34, 44))	('RCC', 'Disease', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('tumor', 'Disease', (54, 59))
98379	28569782	The CCK8 assay revealed that miR-30a-5p overexpression significantly decreased cell viability (Figure 3c).	('decreased', 'NegReg', (69, 78))	('miR-30a-5p', 'Var', (29, 39))	('expression', 'Species', '29278', (44, 54))	('cell viability', 'CPA', (79, 93))
98380	28569782	In colony formation assay, miR-30a-5p-transfected cells created notably fewer and smaller colonies than the miR-control-transfected and wild-type cells (Figure 3d), indicating a role for miR-30a-5p in inhibiting growth of ccRCC cells.	('RCC', 'Disease', (224, 227))	('miR-30a-5p', 'Var', (187, 197))	('growth', 'CPA', (212, 218))	('smaller', 'NegReg', (82, 89))	('RCC', 'Phenotype', 'HP:0005584', (224, 227))	('fewer', 'NegReg', (72, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (222, 227))	('formation', 'biological_process', 'GO:0009058', ('10', '19'))	('colonies', 'CPA', (90, 98))	('inhibiting', 'NegReg', (201, 211))	('miR-30a-5p-transfected', 'Var', (27, 49))	('RCC', 'Disease', 'MESH:C538614', (224, 227))
98382	28569782	Overexpression of miR-30a-5p was found to suppress 769-P cell migration in the wound healing assay (Figure 3e) and invasion in the Matrigel assay (Figure 3f).	('suppress', 'NegReg', (42, 50))	('invasion in the Matrigel assay', 'CPA', (115, 145))	('wound healing', 'biological_process', 'GO:0042060', ('79', '92'))	('expression', 'Species', '29278', (4, 14))	('cell migration', 'biological_process', 'GO:0016477', ('57', '71'))	('miR-30a-5p', 'Var', (18, 28))	('769-P cell migration in the wound healing assay', 'CPA', (51, 98))
98384	28569782	Therefore, to investigate the effect of miR-30a-5p on cancer cell proliferation, wild-type, miR-control-transfected and miR-30a-5p-transfected 769-P cells were introduced into a nude mouse xenograft model.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('mouse', 'Species', '10090', (183, 188))	('miR-30a-5p-transfected', 'Var', (120, 142))	('cancer', 'Disease', (54, 60))	('cell proliferation', 'biological_process', 'GO:0008283', ('61', '79'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
98385	28569782	Forty-two days post injection of the cells, the volume and weight of tumors in mice injected with cells transfected with miR-30a-5p were markedly lower than in the other cohorts (P<0.01 in tumor volume and weight comparisons) (Figures 4a-c).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (69, 74))	('mice', 'Species', '10090', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('lower', 'NegReg', (146, 151))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('miR-30a-5p', 'Var', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
98388	28569782	As shown in Figure 4d, the mice injected with the miR-30a-5p overexpressing 769-P cells had fewer nodes per lung than the mice in the other groups (P<0.01).	('mice', 'Species', '10090', (122, 126))	('miR-30a-5p', 'Var', (50, 60))	('nodes per lung', 'CPA', (98, 112))	('mice', 'Species', '10090', (27, 31))	('fewer', 'NegReg', (92, 97))
98394	28569782	Upon miR-30a-5p overexpression, it was found E-cadherin expression increased, while the mesenchymal marker Vimentin decreased in 769-P cells (Figure 5a).	('E-cadherin', 'Protein', (45, 55))	('overexpression', 'PosReg', (16, 30))	('Vimentin', 'Gene', (107, 115))	('Vimentin', 'cellular_component', 'GO:0045099', ('107', '115'))	('miR-30a-5p', 'Var', (5, 15))	('expression', 'Species', '29278', (56, 66))	('Vimentin', 'Gene', '7431', (107, 115))	('expression', 'MPA', (56, 66))	('increased', 'PosReg', (67, 76))	('cadherin', 'molecular_function', 'GO:0008014', ('47', '55'))	('decreased', 'NegReg', (116, 125))	('Vimentin', 'cellular_component', 'GO:0045098', ('107', '115'))	('expression', 'Species', '29278', (20, 30))
98395	28569782	It was then examined if ZEB2 was capable of counteracting the miR-30a-5p-mediated suppression of EMT.	('miR-30a-5p-mediated', 'Var', (62, 81))	('EMT', 'biological_process', 'GO:0001837', ('97', '100'))	('ZEB2', 'Gene', '9839', (24, 28))	('EMT', 'CPA', (97, 100))	('ZEB2', 'Gene', (24, 28))
98397	28569782	As expected, ZEB2 overexpression in miR-30a-5p 769-P cells nullified the miR-30a-5p reversal of EMT (Figure 5b).	('nullified', 'NegReg', (59, 68))	('ZEB2', 'Gene', '9839', (13, 17))	('ZEB2', 'Gene', (13, 17))	('EMT', 'biological_process', 'GO:0001837', ('96', '99'))	('expression', 'Species', '29278', (22, 32))	('miR-30a-5p', 'Var', (73, 83))	('overexpression', 'PosReg', (18, 32))
98404	28569782	Therefore, wild-type and mutant DLEU2 sequence constructs were subcloned into the pMIR luciferase reporter and then co-transfected into 769-P cells with miR-30a-5p or the miR-control.	('miR-30a-5p', 'Var', (153, 163))	('DLEU2', 'Gene', '8847', (32, 37))	('mutant', 'Var', (25, 31))	('DLEU2', 'Gene', (32, 37))
98405	28569782	The luciferase activity of cells pMIR-DLEU2 was significantly decreased upon co-transfection with miR-30a-5p, while the luciferase activity in cells in the other treatment cohorts was unaffected (Figure 6c).	('luciferase activity', 'molecular_function', 'GO:0050248', ('120', '139'))	('miR-30a-5p', 'Var', (98, 108))	('luciferase activity', 'molecular_function', 'GO:0045289', ('120', '139'))	('decreased', 'NegReg', (62, 71))	('DLEU2', 'Gene', (38, 43))	('luciferase activity', 'molecular_function', 'GO:0047077', ('4', '23'))	('activity', 'MPA', (15, 23))	('luciferase activity', 'molecular_function', 'GO:0045289', ('4', '23'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('120', '139'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('4', '23'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('120', '139'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('120', '139'))	('luciferase', 'Enzyme', (4, 14))	('luciferase activity', 'molecular_function', 'GO:0050248', ('4', '23'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('4', '23'))	('DLEU2', 'Gene', '8847', (38, 43))
98411	28569782	As stated above, miR-30a-5p expression is associated with a favorable prognosis in ccRCC patients.	('expression', 'Species', '29278', (28, 38))	('miR-30a-5p expression', 'Var', (17, 38))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('patients', 'Species', '9606', (89, 97))	('RCC', 'Disease', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))
98416	28569782	In functional studies, proliferation, colony formation, migration and invasion of ccRCC cells in vitro, and tumor growth and metastasis in vivo were dramatically suppressed upon reintroduction of miR-30a-5p.	('migration', 'CPA', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('tumor', 'Disease', (108, 113))	('miR-30a-5p', 'Var', (196, 206))	('RCC', 'Disease', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('proliferation', 'CPA', (23, 36))	('colony formation', 'CPA', (38, 54))	('suppressed', 'NegReg', (162, 172))	('formation', 'biological_process', 'GO:0009058', ('45', '54'))	('invasion', 'CPA', (70, 78))
98417	28569782	These results suggest that miR-30a-5p plays a crucial role in the growth, invasiveness and metastatic potential of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('growth', 'CPA', (66, 72))	('metastatic potential', 'CPA', (91, 111))	('miR-30a-5p', 'Var', (27, 37))	('invasiveness', 'CPA', (74, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))
98421	28569782	Therefore, it was determined whether ZEB2 is a potential functional target of miR-30a-5p, as ZEB2 has been shown to have an important role in the EMT.	('ZEB2', 'Gene', '9839', (37, 41))	('EMT', 'CPA', (146, 149))	('ZEB2', 'Gene', (37, 41))	('miR-30a-5p', 'Var', (78, 88))	('EMT', 'biological_process', 'GO:0001837', ('146', '149'))	('ZEB2', 'Gene', '9839', (93, 97))	('ZEB2', 'Gene', (93, 97))
98422	28569782	In this study, it was shown that miR-30a-5p binds to a complementary site, which is conserved among most vertebrates on the 3'-UTR of ZEB2, resulting in a marked decrease in ZEB2 expression.	('expression', 'Species', '29278', (179, 189))	('expression', 'MPA', (179, 189))	('ZEB2', 'Gene', '9839', (134, 138))	('ZEB2', 'Gene', '9839', (174, 178))	('ZEB2', 'Gene', (134, 138))	('ZEB2', 'Gene', (174, 178))	('decrease', 'NegReg', (162, 170))	('miR-30a-5p', 'Var', (33, 43))
98424	28569782	To the authors' knowledge, these observations provide the first evidence that miR-30a-5p mechanistically acts through the regulation of ZEB2.	('regulation', 'biological_process', 'GO:0065007', ('122', '132'))	('ZEB2', 'Gene', '9839', (136, 140))	('miR-30a-5p', 'Var', (78, 88))	('ZEB2', 'Gene', (136, 140))	('acts', 'Reg', (105, 109))
98428	28569782	In ccRCC cells, it appears miR-30a-5p modulates tumor cell migration and invasion through regulation of ZEB2.	('tumor', 'Disease', (48, 53))	('modulates', 'Reg', (38, 47))	('regulation', 'Reg', (90, 100))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('RCC', 'Disease', (5, 8))	('ZEB2', 'Gene', '9839', (104, 108))	('miR-30a-5p', 'Var', (27, 37))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('regulation', 'biological_process', 'GO:0065007', ('90', '100'))	('invasion', 'CPA', (73, 81))	('ZEB2', 'Gene', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('cell migration', 'biological_process', 'GO:0016477', ('54', '68'))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
98429	28569782	As shown by the enhanced expression of the epithelial marker E-cadherin and decreased expression of the mesenchymal marker Vimentin, the reintroduction of miR-30a-5p into 769-P cells reversed EMT by acting through ZEB2.	('cadherin', 'molecular_function', 'GO:0008014', ('63', '71'))	('EMT', 'biological_process', 'GO:0001837', ('192', '195'))	('expression', 'Species', '29278', (25, 35))	('ZEB2', 'Gene', (214, 218))	('expression', 'MPA', (25, 35))	('expression', 'Species', '29278', (86, 96))	('Vimentin', 'cellular_component', 'GO:0045098', ('123', '131'))	('decreased', 'NegReg', (76, 85))	('E-cadherin', 'Protein', (61, 71))	('expression', 'MPA', (86, 96))	('Vimentin', 'Gene', (123, 131))	('Vimentin', 'cellular_component', 'GO:0045099', ('123', '131'))	('miR-30a-5p', 'Var', (155, 165))	('EMT', 'CPA', (192, 195))	('enhanced', 'PosReg', (16, 24))	('Vimentin', 'Gene', '7431', (123, 131))	('ZEB2', 'Gene', '9839', (214, 218))
98433	28569782	The distinct functions of DLEU2 in different tumors may be a result of the different DLEU2 transcripts generated by alternative splicing.	('DLEU2', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('DLEU2', 'Gene', (85, 90))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('alternative splicing', 'Var', (116, 136))	('splicing', 'biological_process', 'GO:0045292', ('128', '136'))	('DLEU2', 'Gene', '8847', (26, 31))	('DLEU2', 'Gene', '8847', (85, 90))
98434	28569782	A DLEU2-induced reduction in miR-30a-5p may result in a derepression of the mRNA targets of miR-30a-5p, such as ZEB2, and facilitate the malignant progression of ccRCC cells through a competing endogenous RNA mechanism.	('miR-30a-5p', 'Var', (92, 102))	('ZEB2', 'Gene', '9839', (112, 116))	('DLEU2', 'Gene', (2, 7))	('ZEB2', 'Gene', (112, 116))	('reduction', 'NegReg', (16, 25))	('malignant progression', 'CPA', (137, 158))	('derepression', 'MPA', (56, 68))	('RNA', 'cellular_component', 'GO:0005562', ('205', '208'))	('DLEU2', 'Gene', '8847', (2, 7))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('ccRCC', 'Phenotype', 'HP:0006770', (162, 167))	('RCC', 'Disease', (164, 167))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))	('miR-30a-5p', 'Gene', (29, 39))	('facilitate', 'PosReg', (122, 132))	('mRNA targets', 'MPA', (76, 88))
98436	28569782	In summary, we investigated the potential functions and mechanisms of action of miR-30a-5p in ccRCC proliferation and aggressiveness.	('RCC', 'Disease', (96, 99))	('aggressiveness', 'Phenotype', 'HP:0000718', (118, 132))	('aggressiveness', 'Disease', 'MESH:D001523', (118, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('miR-30a-5p', 'Var', (80, 90))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('aggressiveness', 'Disease', (118, 132))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
98440	28569782	Importantly, miR-30a-5p has potential as a new prognostic marker for and/or an effective therapeutic target against ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('RCC', 'Disease', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('miR-30a-5p', 'Var', (13, 23))
98473	28569782	Finally, qRT-PCR was performed to detect miR-30a-5p and DLEU2 in the precipitates.	('miR-30a-5p', 'Var', (41, 51))	('DLEU2', 'Gene', (56, 61))	('DLEU2', 'Gene', '8847', (56, 61))
98481	31865909	Cancer is caused by somatic mutations in a single founder cell that lead to the unrestrained proliferation of the descendants of that cell.	('lead to', 'Reg', (68, 75))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('caused by', 'Reg', (10, 19))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (28, 37))	('unrestrained proliferation of the descendants', 'CPA', (80, 125))
98482	31865909	According to the clonal theory of cancer, descendants of the founder cell will continue to acquire new somatic mutations that may drive disease progression.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('mutations', 'Var', (111, 120))	('drive', 'Reg', (130, 135))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))
98483	31865909	Since different descendants acquire distinct mutations, the history of a tumor can be described as a type of phylogenetic tree.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('mutations', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (73, 78))
98497	31865909	In particular, these methods use the infinite sites assumption (ISA), which states that any locus in the genome mutates at most once during the history of tumor, a simplification that makes the underlying computational problem more tractable.	('mutates', 'Var', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))
98505	31865909	A clonal treeT (or tumor phylogeny) is a rooted tree on n nodes with each node labeled by a distinct mutation.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mutation', 'Var', (101, 109))	('tumor', 'Disease', (19, 24))
98506	31865909	Each node represents a tumor cell population that contains all mutations along its root-node path.	('mutations', 'Var', (63, 72))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))
98543	31865909	Of the 11 patients we analyzed, only the 100000x coverage targeted sequencing data for CLL006 and CLL077 admitted E-VAFFP solutions.	('E-VAFFP', 'Chemical', '-', (114, 121))	('CLL077', 'Var', (98, 104))	('CLL', 'Phenotype', 'HP:0005550', (87, 90))	('patients', 'Species', '9606', (10, 18))	('CLL', 'Phenotype', 'HP:0005550', (98, 101))	('CLL006', 'Gene', (87, 93))
98549	31865909	The trees we found in this way for patients EV003, EV005, EV006, EV007, RMH002, RMH008, and RK26 display strong agreement with those found by LICHeE.	('EV006', 'Var', (58, 63))	('RMH002', 'Var', (72, 78))	('EV007', 'Var', (65, 70))	('LICHeE', 'Disease', (142, 148))	('LICHeE', 'Disease', 'None', (142, 148))	('EV005', 'Var', (51, 56))	('patients', 'Species', '9606', (35, 43))	('EV003', 'Var', (44, 49))
98562	31865909	(E-)VAFFP (Enumeration) variant allele frequency factorization problem A-D ancestor-descendant ccRCC Clear cell renal cell carcinoma CLL Chronic lymphocytic leukemia DAG Directed acyclic graph ISA Infinite sites assumption PTR Partial transitive reduction SNV Single nucleotide variant VAF Variant allele frequency WGS Whole genome sequencing Supplementary information accompanies this paper at 10.1186/s12920-019-0626-0.	('Clear cell renal cell carcinoma', 'Disease', (101, 132))	('leukemia', 'Phenotype', 'HP:0001909', (157, 165))	('PTR', 'molecular_function', 'GO:0008975', ('223', '226'))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('Chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (137, 165))	('DAG', 'Gene', (166, 169))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (101, 132))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (112, 132))	('Variant', 'Var', (290, 297))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (101, 132))	('CLL', 'Phenotype', 'HP:0005550', (133, 136))	('Chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (137, 165))	('VAF', 'Gene', (286, 289))	('Chronic lymphocytic leukemia', 'Disease', (137, 165))	('DAG', 'Gene', '1605', (166, 169))	('Single nucleotide variant', 'Var', (260, 285))
98563	31627266	Current Concepts of Non-Coding RNAs in the Pathogenesis of Non-Clear Cell Renal Cell Carcinoma Renal cell carcinoma (RCC) is a relatively rare malignancy of the urinary tract system.	('malignancy', 'Disease', 'MESH:D009369', (143, 153))	('-Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (62, 94))	('RCC', 'Disease', 'MESH:D002292', (117, 120))	('RCC', 'Disease', (117, 120))	('Non-Clear Cell Renal Cell Carcinoma', 'Disease', (59, 94))	('malignancy', 'Disease', (143, 153))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('Renal cell carcinoma', 'Disease', 'MESH:D002292', (95, 115))	('Carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('Renal cell carcinoma', 'Disease', (95, 115))	('malignancy of the urinary tract', 'Phenotype', 'HP:0010786', (143, 174))	('Non-Coding RNAs', 'Var', (20, 35))	('Non-Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:D002292', (59, 94))	('Pathogenesis', 'biological_process', 'GO:0009405', ('43', '55'))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (74, 94))
98569	31627266	Additionally, a growing body of evidence supports the role of long non-coding RNAs (lncRNAs) in cancer development and progression.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('progression', 'CPA', (119, 130))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('long non-coding RNAs', 'Var', (62, 82))
98570	31627266	Most studies on non-coding RNAs in RCC focus on clear-cell histology, and there is a relatively limited number of studies on non-ccRCC subtypes.	('RCC', 'Disease', 'MESH:D002292', (35, 38))	('RCC', 'Disease', (35, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (129, 134))	('ccRCC', 'Disease', (129, 134))	('non-coding RNAs', 'Var', (16, 31))	('RCC', 'Disease', 'MESH:D002292', (131, 134))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('ccRCC', 'Disease', 'MESH:D002292', (129, 134))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))
98571	31627266	The aim of this review is to give an overview of the current knowledge regarding the role of non-coding RNAs (including short and long non-coding RNAs) in non-ccRCC and to highlight possible implications as diagnostic, prognostic and predictive biomarkers.	('short and long non-coding RNAs', 'Var', (120, 150))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('ccRCC', 'Phenotype', 'HP:0006770', (159, 164))	('ccRCC', 'Disease', (159, 164))	('ccRCC', 'Disease', 'MESH:D002292', (159, 164))
98596	31627266	The present review aims to summarize the current literature of non-coding RNA research in five non-clear cell RCC histologies and to focus on their potential clinical implementations in diagnosis, prognosis and therapy.	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('non-coding', 'Var', (63, 73))	('RCC', 'Disease', 'MESH:D002292', (110, 113))	('RNA', 'cellular_component', 'GO:0005562', ('74', '77'))
98598	31627266	Studies that investigated non-coding RNAs in at least one non-clear cell RCC subtype were included in this review.	('non-coding', 'Var', (26, 36))	('RCC', 'Disease', 'MESH:D002292', (73, 76))	('RCC', 'Disease', (73, 76))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
98601	31627266	In addition, MET mutations are common in type 1 tumors.	('common', 'Reg', (31, 37))	('MET mutations', 'Var', (13, 26))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
98602	31627266	In type 2, CDKN2A alterations, either by mutations or by hypermethylation, occur frequently.	('mutations', 'Var', (41, 50))	('alterations', 'Reg', (18, 29))	('CDKN2A', 'Gene', (11, 17))	('hypermethylation', 'Var', (57, 73))	('CDKN2A', 'Gene', '1029', (11, 17))
98609	31627266	In addition, in pRCC, increased miR-21 expression (gene locus 17q23.1) is linked to copy number changes of the genome, since pRCC cells feature a high frequency of trisomy 17 and, therefore, an increase of the related gene products.	('pRCC', 'Gene', (16, 20))	('pRCC', 'Gene', '5546', (125, 129))	('miR-21', 'Gene', '406991', (32, 38))	('increase', 'PosReg', (194, 202))	('increased', 'PosReg', (22, 31))	('trisomy 17', 'Var', (164, 174))	('pRCC', 'Gene', (125, 129))	('miR-21', 'Gene', (32, 38))	('pRCC', 'Gene', '5546', (16, 20))	('expression', 'MPA', (39, 49))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))
98610	31627266	As mentioned earlier, numerical chromosomal alterations are more frequently associated with type 1 pRCC.	('numerical chromosomal alterations', 'Var', (22, 55))	('pRCC', 'Gene', (99, 103))	('associated', 'Reg', (76, 86))	('pRCC', 'Gene', '5546', (99, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
98625	31627266	In the first step, the miRNAs used to distinguish between healthy and tumor tissue were miR-145, miR-200c, miR-210 and mi-R502-3p.	('miR', 'Gene', (88, 91))	('miR-200c', 'Gene', (97, 105))	('miR', 'Gene', '220972', (23, 26))	('miR-200c', 'Gene', '406985', (97, 105))	('miR', 'Gene', (23, 26))	('miR-210', 'Gene', (107, 114))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('miR-210', 'Gene', '406992', (107, 114))	('tumor', 'Disease', (70, 75))	('mi-R502-3p', 'Var', (119, 129))	('miR-145', 'Gene', (88, 95))	('miR-145', 'Gene', '406937', (88, 95))	('miR', 'Gene', '220972', (107, 110))	('miR', 'Gene', (107, 110))	('miR', 'Gene', '220972', (97, 100))	('miR', 'Gene', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('miR', 'Gene', '220972', (88, 91))
98630	31627266	Nonetheless, higher HIF1alpha levels and, consequently, elevated miR-210 expression may also occur in non-hypoxic states due to mutations of the Von Hippel Lindau (VHL) gene, which leads to insufficient HIF1alpha-degradation.	('miR-210', 'Gene', '406992', (65, 72))	('elevated', 'PosReg', (56, 64))	('hypoxic', 'Disease', (106, 113))	('VHL', 'Disease', (164, 167))	('hypoxic', 'Disease', 'MESH:D000860', (106, 113))	('mutations', 'Var', (128, 137))	('Von Hippel Lindau', 'Gene', (145, 162))	('HIF1alpha', 'Gene', (20, 29))	('VHL', 'Disease', 'MESH:D006623', (164, 167))	('degradation', 'biological_process', 'GO:0009056', ('213', '224'))	('HIF1alpha', 'Gene', (203, 212))	('higher', 'PosReg', (13, 19))	('Von Hippel Lindau', 'Gene', '7428', (145, 162))	('expression', 'MPA', (73, 83))	('HIF1alpha', 'Gene', '3091', (203, 212))	('HIF1alpha', 'Gene', '3091', (20, 29))	('miR-210', 'Gene', (65, 72))
98725	31627266	Xp11 translocation RCC is the most common renal neoplasm in children.	('Xp11 translocation', 'Var', (0, 18))	('neoplasm', 'Phenotype', 'HP:0002664', (48, 56))	('RCC', 'Disease', 'MESH:D002292', (19, 22))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('children', 'Species', '9606', (60, 68))	('renal neoplasm', 'Disease', (42, 56))	('renal neoplasm', 'Disease', 'MESH:D007680', (42, 56))	('renal neoplasm', 'Phenotype', 'HP:0009726', (42, 56))
98726	31627266	Xp11 RCCs show characteristic chromosomal translocations at a breaking point:the locus Xp11.2:resulting in a distinctive gene fusion including the TFE3 transcription factor gene.	('TFE3 transcription factor gene', 'Gene', (147, 177))	('RCC', 'Disease', 'MESH:D002292', (5, 8))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('locus', 'Var', (81, 86))	('breaking point', 'Phenotype', 'HP:0001061', (62, 76))	('transcription', 'biological_process', 'GO:0006351', ('152', '165'))	('gene fusion', 'MPA', (121, 132))	('transcription factor', 'molecular_function', 'GO:0000981', ('152', '172'))
98731	31627266	Mutations of the putative promoter region of the lncRNA NEAT1 (nuclear-enriched abundant transcript 1) were found in 17% of pRCC.	('found', 'Reg', (108, 113))	('pRCC', 'Gene', '5546', (124, 128))	('nuclear-enriched abundant transcript 1', 'Gene', '283131', (63, 101))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('NEAT1', 'Gene', '283131', (56, 61))	('pRCC', 'Gene', (124, 128))	('Mutations', 'Var', (0, 9))	('NEAT1', 'Gene', (56, 61))	('nuclear-enriched abundant transcript 1', 'Gene', (63, 101))
98740	31627266	Furthermore, high levels of lncRNAs AC003092.1, RP6-191P20.4, RP11-401P9.4 and RP11-496D24.2 correlated with worse prognosis.	('RP11', 'Gene', (62, 66))	('AC003092.1', 'Var', (36, 46))	('RP6-191P20.4', 'Var', (48, 60))	('RP11', 'Gene', '26121', (62, 66))	('RP11', 'Gene', '26121', (79, 83))	('RP11', 'Gene', (79, 83))
98751	31627266	The lncRNAs included in the signature are AC003092.1, AC079160.1, COL18A1-AS1, LINC00520, LINC02154 and SLC7A11-AS1.	('AC079160.1', 'Var', (54, 64))	('COL18A1-AS1', 'Gene', '378832', (66, 77))	('COL18A1-AS1', 'Gene', (66, 77))	('SLC7A11-AS1', 'Gene', '641364', (104, 115))	('AC003092.1', 'Var', (42, 52))	('LINC02154', 'Var', (90, 99))	('LINC00520', 'Gene', '645687', (79, 88))	('LINC02154', 'Chemical', 'None', (90, 99))	('LINC00520', 'Gene', (79, 88))	('SLC7A11-AS1', 'Gene', (104, 115))
98805	28928816	Following the analysis of GSE53757 and GSE46699, which contained paired ccRCC cancer and normal adjacent tissue samples, 32 differentially expressed lncRNAs (adjusted P<0.01) in ccRCC were identified.	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('RCC', 'Disease', (180, 183))	('GSE53757', 'Var', (26, 34))	('cancer', 'Disease', (78, 84))	('RCC', 'Disease', (74, 77))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('GSE46699', 'Var', (39, 47))
98810	28928816	The lncRNA ENSG00000244020 was decreased in ccRCC and metastatic ccRCC, suggesting that silencing of ENSG00000244020 may be important in ccRCC development.	('lncRNA', 'MPA', (4, 10))	('RCC', 'Disease', (46, 49))	('ENSG00000244020', 'Gene', (101, 116))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('decreased', 'NegReg', (31, 40))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('silencing', 'Var', (88, 97))	('metastatic', 'CPA', (54, 64))
98815	28928816	The comprehensive biological process of the molecular mechanism of ccRCC may involve in stepwise accumulation of genomic instability, epigenetic changes, gene mutations and deviant expression of protein-coding genes and noncodings.	('deviant', 'Var', (173, 180))	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('expression', 'MPA', (181, 191))	('epigenetic', 'MPA', (134, 144))	('genomic instability', 'CPA', (113, 132))	('gene mutations', 'Var', (154, 168))	('biological process', 'biological_process', 'GO:0008150', ('18', '36'))	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))
98816	28928816	The genome-wide association researches have found several mutations conferring risk of ccRCC, including von Hippel-Lindau gene (VHL), which codes for a tumor suppressor gene.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('mutations', 'Var', (58, 67))	('VHL', 'Gene', '7428', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('von Hippel-Lindau', 'Disease', (104, 121))	('tumor suppressor', 'biological_process', 'GO:0051726', ('152', '168'))	('tumor', 'Disease', (152, 157))	('RCC', 'Disease', (89, 92))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('152', '168'))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (104, 121))	('VHL', 'Gene', (128, 131))
98817	28928816	Various causes, such as mutation, loss of heterozygosity, allelic deletion and promoter hypermethylation, makes VHL inactivation on chromosome 3p as a high frequent genetic event in ccRCC.	('inactivation', 'Var', (116, 128))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('RCC', 'Disease', (184, 187))	('VHL', 'Gene', (112, 115))	('VHL', 'Gene', '7428', (112, 115))	('chromosome', 'cellular_component', 'GO:0005694', ('132', '142'))
98819	28928816	Moreover, some genes, such as KDM5C [lysine (K)-specific demethylase 5C], PBRM1 (polybromo-1), BAP1 (BRCA1 associated protein-1), KDM6A [lysine (K)-specific demethylase 6A] and SETD2 (SET domain containing 2), are involved in chromatin modification in primary human renal cell carcinoma (RCC) and their mutations will profoundly change their chromatin organization and their transcriptional program.	('mutations', 'Var', (303, 312))	('renal cell carcinoma', 'Disease', (266, 286))	('chromatin organization', 'MPA', (342, 364))	('BRCA1 associated protein-1', 'Gene', '8314', (101, 127))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (266, 286))	('lysine', 'Chemical', 'MESH:D008239', (37, 43))	('BAP1', 'Gene', '8314', (95, 99))	('chromatin modification', 'biological_process', 'GO:0016569', ('226', '248'))	('polybromo-1', 'Gene', (81, 92))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))	('chromatin organization', 'biological_process', 'GO:0006325', ('342', '364'))	('SETD2', 'Gene', (177, 182))	('RCC', 'Disease', (288, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('transcriptional program', 'CPA', (375, 398))	('involved', 'Reg', (214, 222))	('change', 'Reg', (329, 335))	('KDM5C', 'Var', (30, 35))	('SETD2', 'Gene', '29072', (177, 182))	('BAP1', 'Gene', (95, 99))	('chromatin modification', 'biological_process', 'GO:0006325', ('226', '248'))	('RCC', 'Disease', 'MESH:C538614', (288, 291))	('BRCA1 associated protein-1', 'Gene', (101, 127))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (266, 286))	('lysine', 'Chemical', 'MESH:D008239', (137, 143))	('human', 'Species', '9606', (260, 265))	('PBRM1', 'Gene', '55193', (74, 79))	('chromatin', 'cellular_component', 'GO:0000785', ('226', '235'))	('polybromo-1', 'Gene', '55193', (81, 92))	('PBRM1', 'Gene', (74, 79))	('KDM6A', 'Gene', (130, 135))	('chromatin', 'cellular_component', 'GO:0000785', ('342', '351'))
98820	28928816	On the other side, the non-coding RNA transcripts also showed significant difference in ccRCC, such as overexpression of miRNA-210 and downregulation of miR-141 and miR-200c.	('miR-141', 'Gene', (153, 160))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('RNA', 'cellular_component', 'GO:0005562', ('34', '37'))	('miR-141', 'Gene', '406933', (153, 160))	('downregulation', 'NegReg', (135, 149))	('overexpression', 'PosReg', (103, 117))	('miR-200c', 'Gene', (165, 173))	('miR-200c', 'Gene', '406985', (165, 173))	('miRNA-210', 'Var', (121, 130))	('RCC', 'Disease', (90, 93))
98824	28928816	Three data sets of human exon arrays, GSE53757, GSE46699 and GSE47352, were downloaded from GEO.	('GSE53757', 'Var', (38, 46))	('human', 'Species', '9606', (19, 24))	('GSE47352', 'Var', (61, 69))	('GSE46699', 'Var', (48, 56))
98832	28928816	Among them, NR_24418 and TCL6 have been reported to be associated with ccRCC (Table I).	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('associated', 'Reg', (55, 65))	('NR_24418', 'Var', (12, 20))	('TCL6', 'Gene', (25, 29))	('TCL6', 'Gene', '27004', (25, 29))
98835	28928816	Among them, CRNDE showed higher expression in both ccRCC and metastatic samples compared to normal tissue and non-metastatic ones, while ENSG00000244020 is lower expressed.	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('ENSG00000244020', 'Var', (137, 152))	('higher', 'PosReg', (25, 31))	('expression', 'MPA', (32, 42))	('CRNDE', 'Protein', (12, 17))
98839	28928816	Previous studies have reported some lncRNAs in human cancers, including ENSG00000177133, NR_024418, TCL6, GAS5, DLEU2, CRNDE and MIR155HG, while recent studies have reported NR_24418 and TCL6 associated with ccRCC.	('NR_024418', 'Var', (89, 98))	('associated', 'Reg', (192, 202))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('GAS5', 'Gene', (106, 110))	('RCC', 'Disease', (210, 213))	('TCL6', 'Gene', '27004', (100, 104))	('TCL6', 'Gene', (100, 104))	('MIR155HG', 'Gene', (129, 137))	('MIR155HG', 'Gene', '114614', (129, 137))	('TCL6', 'Gene', (187, 191))	('TCL6', 'Gene', '27004', (187, 191))	('DLEU2', 'Gene', '8847', (112, 117))	('human', 'Species', '9606', (47, 52))	('GAS', 'molecular_function', 'GO:0034005', ('106', '109'))	('RCC', 'Disease', 'MESH:C538614', (210, 213))	('DLEU2', 'Gene', (112, 117))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('GAS5', 'Gene', '60674', (106, 110))	('NR_24418', 'Var', (174, 182))
98845	28928816	However, the fold change (FC) of TCL6 in RCC showed an increased expression (FC=1.96), which is opposite to our results (logFC=-2.20 in GSE53757 and logFC=-1.19 in GSE46699, P<0.01).	('fold', 'MPA', (13, 17))	('TCL6', 'Gene', (33, 37))	('TCL6', 'Gene', '27004', (33, 37))	('increased', 'PosReg', (55, 64))	('GSE53757', 'Var', (136, 144))	('expression', 'MPA', (65, 75))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))
98847	28928816	We found NR_024418 is decreased in ccRCC in two arrays (logFC=-2.51 in GSE53757 and logFC=-1.28 in GSE46699, P<0.01), which is consistent with the results (logFC=-4.16) published in 2012.	('GSE53757', 'Var', (71, 79))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('NR_024418', 'Var', (9, 18))	('decreased', 'NegReg', (22, 31))
98853	28928816	GAS5 transcripts are subject to complex post-transcriptional processing and some, but not all, GAS5 transcripts sensitize mammalian cells to apoptosis inducers.	('GAS', 'molecular_function', 'GO:0034005', ('95', '98'))	('apoptosis', 'biological_process', 'GO:0097194', ('141', '150'))	('GAS5', 'Gene', '60674', (0, 4))	('apoptosis', 'biological_process', 'GO:0006915', ('141', '150'))	('GAS5', 'Gene', (95, 99))	('sensitize', 'Reg', (112, 121))	('transcripts', 'Var', (100, 111))	('GAS5', 'Gene', (0, 4))	('mammalian', 'Species', '9606', (122, 131))	('GAS', 'molecular_function', 'GO:0034005', ('0', '3'))	('apoptosis', 'CPA', (141, 150))	('GAS5', 'Gene', '60674', (95, 99))
98855	28928816	However, in our study, we found GAS5 upregulated in ccRCC in both arrays (logFC=1.10 in GSE53757 and logFC=1.03 in GSE46699, P<0.01).	('GAS5', 'Gene', (32, 36))	('upregulated', 'PosReg', (37, 48))	('RCC', 'Disease', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('GAS5', 'Gene', '60674', (32, 36))	('GSE46699', 'Var', (115, 123))	('GAS', 'molecular_function', 'GO:0034005', ('32', '35'))	('GSE53757', 'Var', (88, 96))
98861	28928816	Specifically, at the locus for mouse CRNDE, the promoter was bound by select pluripotency-related transcription factors, including c-Myc and n-Myc, while knockdown of CRNDE was associated with decreased levels of a different suite of critical pluripotency markers: Sox2, Klf4, Nanog, and Oct4.	('Klf4', 'Gene', (271, 275))	('pluripotency', 'Disease', (243, 255))	('pluripotency', 'Disease', (77, 89))	('Nanog', 'Gene', (277, 282))	('Oct4', 'Gene', (288, 292))	('decreased', 'NegReg', (193, 202))	('transcription', 'biological_process', 'GO:0006351', ('98', '111'))	('Sox2', 'Gene', '20674', (265, 269))	('mouse', 'Species', '10090', (31, 36))	('CRNDE', 'Gene', (167, 172))	('knockdown', 'Var', (154, 163))	('levels', 'MPA', (203, 209))	('Oct4', 'Gene', '100846986', (288, 292))	('pluripotency', 'Disease', 'None', (243, 255))	('pluripotency', 'Disease', 'None', (77, 89))	('Nanog', 'Gene', '71950', (277, 282))	('n-Myc', 'Gene', '18109', (141, 146))	('critical pluripotency', 'Disease', 'MESH:D016638', (234, 255))	('Klf4', 'Gene', '16600', (271, 275))	('n-Myc', 'Gene', (141, 146))	('Sox2', 'Gene', (265, 269))	('critical pluripotency', 'Disease', (234, 255))
98863	28928816	However, studies about the other genes, such as ENSG00000177133, DLEU2, MIR155HG, ENSG00000214145 and ENSG00000244020 are really rare.	('ENSG00000177133', 'Var', (48, 63))	('DLEU2', 'Gene', (65, 70))	('ENSG00000244020', 'Var', (102, 117))	('MIR155HG', 'Gene', '114614', (72, 80))	('MIR155HG', 'Gene', (72, 80))	('ENSG00000214145', 'Var', (82, 97))	('DLEU2', 'Gene', '8847', (65, 70))
98880	32022527	This test specifically genotyped single nucleotide polymorphisms (SNPs) that were relevant to: (a) pharmaceutical drug response (b) genetic diseases and (c) complex diseases.	('genetic diseases', 'Disease', (132, 148))	('single nucleotide polymorphisms', 'Var', (33, 64))	('genetic diseases', 'Disease', 'MESH:D030342', (132, 148))
98886	32022527	The other two (rs8065832 y rs2018781) are located near splicing sites, which makes them clinically relevant but still unknown.	('rs8065832', 'Mutation', 'rs8065832', (15, 24))	('rs2018781', 'Mutation', 'rs2018781', (27, 36))	('rs2018781', 'Var', (27, 36))	('splicing', 'biological_process', 'GO:0045292', ('55', '63'))	('rs8065832', 'Var', (15, 24))
98889	32022527	The in silico analyses (Table-3) predicted that the variant rs2018781 most likely has probably no impact on splicing.	('rs2018781', 'Var', (60, 69))	('splicing', 'MPA', (108, 116))	('rs2018781', 'Mutation', 'rs2018781', (60, 69))	('splicing', 'biological_process', 'GO:0045292', ('108', '116'))
98890	32022527	However, for the variant rs8065832, two of the algorithms predicted a higher score than the natural splicing site score (> 10%).	('splicing', 'biological_process', 'GO:0045292', ('100', '108'))	('rs8065832', 'Var', (25, 34))	('higher', 'PosReg', (70, 76))	('score', 'MPA', (77, 82))	('rs8065832', 'Mutation', 'rs8065832', (25, 34))
98895	32022527	The patient was classified as having right clear cell carcinoma (T1aN0M0) and left papillary-type renal carcinoma (T1aN0M0).	('left papillary-type renal carcinoma', 'Disease', (78, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('papillary-type renal carcinoma', 'Phenotype', 'HP:0006766', (83, 113))	('right clear cell carcinoma', 'Disease', 'MESH:C538614', (37, 63))	('T1aN0M0', 'Var', (65, 72))	('right clear cell carcinoma', 'Disease', (37, 63))	('patient', 'Species', '9606', (4, 11))	('renal carcinoma', 'Phenotype', 'HP:0005584', (98, 113))	('T1aN0M0', 'Var', (115, 122))	('left papillary-type renal carcinoma', 'Disease', 'MESH:C538614', (78, 113))
98899	32022527	The only exception was a variant in the FLCN gene, c.1062+6C>T (rs8065832).	('c.1062+6C>T', 'Mutation', 'rs8065832', (51, 62))	('FLCN', 'Gene', '201163', (40, 44))	('c.1062+6C>T', 'Var', (51, 62))	('FLCN', 'Gene', (40, 44))	('rs8065832', 'Mutation', 'rs8065832', (64, 73))
98914	32022527	As previously mentioned, mutations in VHL, MET, FH, and FLCN genes have been associated with von Hippel-Lindau (VHL)-mediated ccRCC, hereditary type I pRCC, hereditary leiomyomatosis, type II pRCC and BHD.	('MET', 'Gene', (43, 46))	('FLCN', 'Gene', (56, 60))	('von Hippel-Lindau', 'Gene', (93, 110))	('VHL', 'Gene', '7428', (112, 115))	('VHL', 'Gene', (38, 41))	('mutations', 'Var', (25, 34))	('RCC', 'Disease', (193, 196))	('RCC', 'Phenotype', 'HP:0005584', (193, 196))	('hereditary type I pRCC, hereditary leiomyomatosis, type II pRCC', 'Disease', 'MESH:C535516', (133, 196))	('von Hippel-Lindau', 'Gene', '7428', (93, 110))	('VHL', 'Gene', '7428', (38, 41))	('associated', 'Reg', (77, 87))	('RCC', 'Disease', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('RCC', 'Disease', (152, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('BHD', 'Disease', 'MESH:C564185', (201, 204))	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('VHL', 'Gene', (112, 115))	('BHD', 'Disease', (201, 204))	('FLCN', 'Gene', '201163', (56, 60))
98915	32022527	The most common form of sporadic ccRCC showed that VHL is affected by loss of heterozygosity at chromosome 3p in 90% of cases.	('RCC', 'Disease', (35, 38))	('VHL', 'Gene', '7428', (51, 54))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('loss of heterozygosity', 'Var', (70, 92))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('VHL', 'Gene', (51, 54))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
98916	32022527	However, somatic mutations or epigenetic silencing have been reported in >80% of these tumors, which is not surprising considering that this gene is a major driver of ccRCC pathogenesis.	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('RCC', 'Disease', (169, 172))	('pathogenesis', 'biological_process', 'GO:0009405', ('173', '185'))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('epigenetic silencing', 'Var', (30, 50))	('reported', 'Reg', (61, 69))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
98919	32022527	In our patient, we have found an intronic variant (rs8065832) that potentially affects the splicing of the FLCN gene, which has been associated with BHD syndrome.	('rs8065832', 'Mutation', 'rs8065832', (51, 60))	('splicing', 'MPA', (91, 99))	('BHD syndrome', 'Disease', (149, 161))	('patient', 'Species', '9606', (7, 14))	('splicing', 'biological_process', 'GO:0045292', ('91', '99'))	('FLCN', 'Gene', (107, 111))	('rs8065832', 'Var', (51, 60))	('affects', 'Reg', (79, 86))	('FLCN', 'Gene', '201163', (107, 111))	('BHD syndrome', 'Disease', 'MESH:C564185', (149, 161))	('associated', 'Reg', (133, 143))
98922	32022527	They also found this variant had a higher frequency among CRC cases compared to control patients (p=0.055), which suggests that this variant is in linkage disequilibrium with other pathogenic variants.	('CRC', 'Phenotype', 'HP:0003003', (58, 61))	('CRC', 'Disease', 'MESH:D015179', (58, 61))	('patients', 'Species', '9606', (88, 96))	('variant', 'Var', (133, 140))	('CRC', 'Disease', (58, 61))
98923	32022527	In this patient, the FLCN gene variant was not associated with other clinical symptoms usually related with FLCN mutation and BHD syndrome.	('FLCN', 'Gene', (21, 25))	('BHD syndrome', 'Disease', 'MESH:C564185', (126, 138))	('FLCN', 'Gene', (108, 112))	('FLCN', 'Gene', '201163', (21, 25))	('BHD syndrome', 'Disease', (126, 138))	('patient', 'Species', '9606', (8, 15))	('FLCN', 'Gene', '201163', (108, 112))	('variant', 'Var', (31, 38))
98925	32022527	have investigated the mutation in the tumor suppressor gene FLCN that is associated with renal cancer, but additional functional and biochemical validation are required to guide further research regarding the role of FCLN in RCC development.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('renal cancer', 'Disease', (89, 101))	('FLCN', 'Gene', '201163', (60, 64))	('mutation', 'Var', (22, 30))	('FCLN', 'Chemical', '-', (217, 221))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('38', '54'))	('RCC', 'Disease', (225, 228))	('renal cancer', 'Phenotype', 'HP:0009726', (89, 101))	('RCC', 'Phenotype', 'HP:0005584', (225, 228))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('renal cancer', 'Disease', 'MESH:D007680', (89, 101))	('associated', 'Reg', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('FLCN', 'Gene', (60, 64))	('tumor suppressor', 'biological_process', 'GO:0051726', ('38', '54'))
98927	32022527	We found that variant rs6983267 and the G/G genotype found in the patient is associated with higher risk of not only colorectal cancer, but an increased risk of thyroid, prostate, lung and renal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (117, 134))	('rs6983267', 'Mutation', 'rs6983267', (22, 31))	('thyroid', 'Disease', (161, 168))	('renal cancer', 'Disease', (189, 201))	('colorectal cancer', 'Phenotype', 'HP:0003003', (117, 134))	('lung', 'Disease', (180, 184))	('renal cancer', 'Phenotype', 'HP:0009726', (189, 201))	('patient', 'Species', '9606', (66, 73))	('colorectal cancer', 'Disease', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('renal cancer', 'Disease', 'MESH:D007680', (189, 201))	('variant rs6983267', 'Var', (14, 31))	('prostate', 'Disease', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
98930	32022527	Since variant has a high frequency in some populations, it is possible that this variant might be a low-penetrance cancer susceptibility allele.	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('variant', 'Var', (6, 13))
98931	32022527	The patient has the G/G genotype for rs6983267, which has been associated a higher risk for developing CRC and renal cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('patient', 'Species', '9606', (4, 11))	('renal cancer', 'Disease', (111, 123))	('rs6983267', 'Var', (37, 46))	('CRC', 'Disease', 'MESH:D015179', (103, 106))	('CRC', 'Phenotype', 'HP:0003003', (103, 106))	('renal cancer', 'Phenotype', 'HP:0009726', (111, 123))	('renal cancer', 'Disease', 'MESH:D007680', (111, 123))	('CRC', 'Disease', (103, 106))	('rs6983267', 'Mutation', 'rs6983267', (37, 46))
98932	32022527	To our knowledge, these polymorphisms (rs8065832 and rs6983267) have not been described previously in the context of ccRCC or pRCC.	('rs8065832', 'Var', (39, 48))	('rs6983267', 'Mutation', 'rs6983267', (53, 62))	('pRCC', 'Gene', (126, 130))	('rs8065832', 'Mutation', 'rs8065832', (39, 48))	('rs6983267', 'Var', (53, 62))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('pRCC', 'Gene', '5546', (126, 130))
98934	32022527	Although these results are promising, future research is necessary to establish the role of FLCN variants rs8065832, and rs6983267 in regard to increasing susceptibility to renal cancer.	('variants rs8065832', 'Var', (97, 115))	('renal cancer', 'Disease', 'MESH:D007680', (173, 185))	('rs6983267', 'Var', (121, 130))	('FLCN', 'Gene', '201163', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('rs8065832', 'Var', (106, 115))	('rs6983267', 'Mutation', 'rs6983267', (121, 130))	('rs8065832', 'Mutation', 'rs8065832', (106, 115))	('FLCN', 'Gene', (92, 96))	('renal cancer', 'Disease', (173, 185))	('renal cancer', 'Phenotype', 'HP:0009726', (173, 185))
98949	30072739	Emerging biomarkers for anti-PD-1 response include the expression level of its ligand PD-L1 , mutation burden or mismatch-repair deficiency , and tumor-infiltrating lymphocytes .	('PD-1', 'Gene', '5133', (29, 33))	('deficiency', 'Disease', 'MESH:D007153', (129, 139))	('expression level', 'MPA', (55, 71))	('ligand', 'molecular_function', 'GO:0005488', ('79', '85'))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mismatch-repair', 'biological_process', 'GO:0006298', ('113', '128'))	('PD-L1', 'Gene', '29126', (86, 91))	('tumor', 'Disease', (146, 151))	('mismatch-repair', 'MPA', (113, 128))	('mutation burden', 'Var', (94, 109))	('deficiency', 'Disease', (129, 139))	('PD-L1', 'Gene', (86, 91))	('PD-1', 'Gene', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
98954	30072739	Several other types of non-coding RNAs, such as long-noncoding RNAs (lncRNAs) , enhancer RNAs  and circular RNAs  have also been implicated in various cancer types .	('circular RNAs', 'Var', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('enhancer', 'PosReg', (80, 88))	('implicated', 'Reg', (129, 139))	('cancer', 'Disease', (151, 157))	('long-noncoding', 'Var', (48, 62))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
98964	30072739	Here we performed a pan-cancer analysis of ~22 nt size-selected small RNA-seq (smRNA-seq) datasets from TCGA, exploring the expression of small RNAs mapping to annotated human snoRNAs in 10,262 patient samples across 32 cancer types.	('patient', 'Species', '9606', (194, 201))	('small', 'Var', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('snoRNA', 'Gene', '85390', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('human', 'Species', '9606', (170, 175))	('cancer', 'Disease', (220, 226))	('snoRNA', 'Gene', (176, 182))	('RNA', 'cellular_component', 'GO:0005562', ('70', '73'))
98978	30072739	This pan-cancer sdRNA transcriptome is derived from several subtypes of snoRNAs with distinct structures and motifs, such as canonical C/D box snoRNAs, H/ACA box snoRNAs, C/D box small Cajal body RNAs (scaRNAs), H/ACA box scaRNAs, hybrid snoRNAs, and several other subtypes (Figure 1b, Table S1, Table S2).	('snoRNA', 'Gene', '85390', (143, 149))	('cancer', 'Disease', (9, 15))	('snoRNA', 'Gene', (162, 168))	('snoRNA', 'Gene', '85390', (72, 78))	('Cajal body', 'cellular_component', 'GO:0015030', ('185', '195'))	('snoRNA', 'Gene', '85390', (162, 168))	('snoRNA', 'Gene', '85390', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('snoRNA', 'Gene', (143, 149))	('C/D box', 'Var', (171, 178))	('snoRNA', 'Gene', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('snoRNA', 'Gene', (238, 244))
98983	30072739	In the case of C/D snoRNAs, these analyses revealed three classes of read distributions, corresponding to 5' sdRNAs, 3' sdRNAs, or mixed sdRNAs (Figure 1c).	('D snoRNAs', 'Phenotype', 'HP:0025267', (17, 26))	('C/D', 'Var', (15, 18))	('snoRNA', 'Gene', (19, 25))	('mixed', 'Disease', (131, 136))	('snoRNA', 'Gene', '85390', (19, 25))	('D snoRNA', 'Phenotype', 'HP:0025267', (17, 25))
98993	30072739	The sdRNA transcriptome exhibited a wide dynamic range of expression across all cancers (Figure S5a), such that 300.13 +- 4.21 (mean +- s.e.m.)	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('sdRNA', 'Gene', (4, 9))	('300.13 +- 4.21', 'Var', (112, 126))
99075	30072739	For instance, high expression of sdRNAs derived from SNORA116, an H/ACA snoRNA, was connected to poorer survival in three independent cohorts: lower grade gliomas (LGG), liver hepatocellular carcinoma (LIHC), and uterine corpus endometrial carcinoma (UCEC) (Figure 7b).	('snoRNA', 'cellular_component', 'GO:0005733', ('72', '78'))	('liver hepatocellular carcinoma', 'Disease', (170, 200))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (228, 249))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))	('expression', 'MPA', (19, 29))	('corpus endometrial carcinoma', 'Disease', (221, 249))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (221, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (176, 200))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (170, 200))	('SNORA116', 'Var', (53, 61))	('poorer', 'NegReg', (97, 103))	('snoRNA', 'Gene', '85390', (72, 78))	('ACA snoRNA', 'Phenotype', 'HP:0025267', (68, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('snoRNA', 'Gene', (72, 78))	('gliomas', 'Disease', (155, 162))
99076	30072739	As another example, high levels of sdRNAs from SNORD145, a CD snoRNA, were associated with shorter survival times in kidney clear cell carcinoma (KIRC), sarcoma (SARC), and uterine corpus endometrial carcinoma (UCEC) (Figure 7c).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (188, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('snoRNA', 'Gene', (62, 68))	('shorter', 'NegReg', (91, 98))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (117, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('snoRNA', 'cellular_component', 'GO:0005733', ('62', '68'))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (181, 209))	('corpus endometrial carcinoma', 'Disease', (181, 209))	('SARC', 'Phenotype', 'HP:0100242', (162, 166))	('snoRNA', 'Gene', '85390', (62, 68))	('sarcoma', 'Disease', 'MESH:D012509', (153, 160))	('sarcoma', 'Disease', (153, 160))	('SNORD145', 'Var', (47, 55))	('sdRNAs', 'MPA', (35, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('D snoRNA', 'Phenotype', 'HP:0025267', (60, 68))	('survival times', 'CPA', (99, 113))	('kidney clear cell carcinoma', 'Disease', (117, 144))
99077	30072739	SdRNAs from SNORA116 and SNORD145 thus appear to be indicators of cancers with a more aggressive course.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('SNORA116', 'Var', (12, 20))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('SNORD145', 'Var', (25, 33))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
99095	30072739	Because the ImmuneSurv score analyses were conducted in a cancer type-specific manner, we then sought a global assessment of sdRNAs and their relationships to cancer immunity regardless of cancer type (PANCAN32), by compiling all sdRNAs that were found to be significant in any of the 5 categories: PD-L1, CD8+ T cell abundance, GZMA, survival, or copy number variation (supplemental results, Figure S9) in any cancer type.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (411, 417))	('cancer immunity regardless of cancer', 'Disease', 'MESH:D009369', (159, 195))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('CD8', 'Gene', (306, 309))	('GZMA', 'Gene', '3001', (329, 333))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('GZMA', 'Gene', (329, 333))	('PD-L1', 'Gene', (299, 304))	('PD-L1', 'Gene', '29126', (299, 304))	('cancer', 'Disease', (411, 417))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('CD8', 'Gene', '925', (306, 309))	('copy number variation', 'Var', (348, 369))	('cancer', 'Disease', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (411, 417))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer immunity regardless of cancer', 'Disease', (159, 195))	('cancer', 'Disease', (58, 64))
99106	30072739	Of note, SNORD115 has been demonstrated to act as a regulator of alternative splicing , and its deletion is sufficient to cause Prader-Willi syndrome.	('SNORD115', 'Gene', '692218', (9, 17))	('cause', 'Reg', (122, 127))	('deletion', 'Var', (96, 104))	('Prader-Willi syndrome', 'Disease', 'MESH:D011218', (128, 149))	('Prader-Willi syndrome', 'Disease', (128, 149))	('alternative splicing', 'MPA', (65, 85))	('SNORD115', 'Gene', (9, 17))	('splicing', 'biological_process', 'GO:0045292', ('77', '85'))
99133	30072739	GISTIC 2.0 copy number variation calls were obtained from the GDAC Firehose (http://gdac.broadinstitute.org/) on September 2017.	('copy number variation', 'Var', (11, 32))	('DAC', 'Gene', (63, 66))	('DAC', 'Gene', '6468', (63, 66))
99135	30072739	Raw fastq files for independent smRNA-seq datasets (GSE33858, GSE46622, E-MTAB-3494) were accessed by NCBI GEO (https://www.ncbi.nlm.nih.gov/geo/) or EBI (https://www.ebi.ac.uk/).	('EBI', 'Gene', (150, 153))	('GSE46622', 'Var', (62, 70))	('EBI', 'Gene', '6907', (150, 153))	('GSE33858', 'Var', (52, 60))	('MTAB', 'molecular_function', 'GO:0047152', ('74', '78'))	('ebi', 'Gene', '6907', (167, 170))	('ebi', 'Gene', (167, 170))
99161	30072739	As these tables report the precise genomic coordinates in which the amplification or deletion was identified, we utilized a q < 0.05 threshold and subsequently intersected the coordinates with the snoRNA annotations .	('deletion', 'Var', (85, 93))	('snoRNA', 'cellular_component', 'GO:0005733', ('197', '203'))	('snoRNA', 'Gene', (197, 203))	('snoRNA', 'Gene', '85390', (197, 203))
99162	30072739	Amplification and deletion calls for individual snoRNAs were then compiled into separate tables.	('deletion', 'Var', (18, 26))	('snoRNA', 'Gene', (48, 54))	('snoRNA', 'Gene', '85390', (48, 54))
99165	30072739	For pan-cancer analysis, we considered all sdRNAs that were found to be significant in at least one cancer type across the following 5 analyses: CD274 correlation, GMZA correlation, CD8+ T cell abundance, copy number variation, and survival.	('cancer', 'Disease', (8, 14))	('CD8', 'Gene', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('CD8', 'Gene', '925', (182, 185))	('CD274', 'Gene', '29126', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('copy number variation', 'Var', (205, 226))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('CD274', 'Gene', (145, 150))
99171	30072739	Thus, for the example above (NNSNSN), sdRNAs from snoRNA X were found to be significantly associated with survival and significant for CNV in cancer type Y.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('snoRNA', 'cellular_component', 'GO:0005733', ('50', '56'))	('snoRNA', 'Gene', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('associated with', 'Reg', (90, 105))	('sdRNAs', 'Var', (38, 44))	('snoRNA', 'Gene', '85390', (50, 56))	('cancer', 'Disease', (142, 148))
99282	30144808	Clear cell renal cell carcinoma (ccRCC) comprises about 3% of adult cancer cases and is an aggressive tumor characterized in most cases by the inactivation of the tumor -suppressor gene VHL.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', (163, 168))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('tumor -suppressor', 'molecular_function', 'GO:0008181', ('163', '180'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('aggressive tumor', 'Disease', (91, 107))	('RCC', 'Disease', (35, 38))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('tumor -suppressor', 'biological_process', 'GO:0051726', ('163', '180'))	('VHL', 'Gene', (186, 189))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('tumor', 'Disease', (102, 107))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('inactivation', 'Var', (143, 155))	('VHL', 'Gene', '7428', (186, 189))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Disease', (68, 74))	('aggressive tumor', 'Disease', 'MESH:D001523', (91, 107))
99283	30144808	The Von Hippel-Lindau protein (pVHL) regulates the hypoxia-inducible factor (HIF), and the loss of the pVHL function causes constitutive stabilization of HIF-1alpha and HIF-2alpha, resulting in the induction of HIF-transcriptional targets.	('stabilization', 'MPA', (137, 150))	('pVHL', 'Gene', '7428', (103, 107))	('pVHL', 'Gene', '7428', (31, 35))	('pVHL', 'Gene', (103, 107))	('pVHL', 'Gene', (31, 35))	('Von Hippel-Lindau', 'Disease', 'MESH:D006623', (4, 21))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('hypoxia', 'Disease', (51, 58))	('Von Hippel-Lindau', 'Disease', (4, 21))	('induction', 'Reg', (198, 207))	('hypoxia', 'Disease', 'MESH:D000860', (51, 58))	('loss', 'Var', (91, 95))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (154, 179))	('HIF-transcriptional targets', 'MPA', (211, 238))
99290	30144808	The blockage of programmed cell death 1 (PD-1) and its interference with its ligand, programmed death ligand 1 (PD-L1) reorganizes the T-cell activity in the tumor microenvironment and facilitates critical antitumor responses.	('tumor', 'Disease', (158, 163))	('ligand', 'molecular_function', 'GO:0005488', ('77', '83'))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('PD-1', 'Gene', (41, 45))	('facilitates', 'PosReg', (185, 196))	('T-cell activity', 'CPA', (135, 150))	('tumor', 'Disease', (210, 215))	('PD-1', 'Gene', '5133', (41, 45))	('ligand', 'molecular_function', 'GO:0005488', ('102', '108'))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('programmed cell death', 'biological_process', 'GO:0012501', ('16', '37'))	('blockage', 'Var', (4, 12))	('reorganizes', 'Reg', (119, 130))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
99299	30144808	Although the VHL function loss is a critical factor in the RCC progression, some recent studies have identified the correlation between the VHL mutation and the immune checkpoint molecules.	('VHL function loss', 'Disease', (13, 30))	('VHL function loss', 'Disease', 'MESH:D006623', (13, 30))	('VHL', 'Gene', (13, 16))	('mutation', 'Var', (144, 152))	('VHL', 'Gene', (140, 143))	('VHL', 'Gene', '7428', (13, 16))	('VHL', 'Gene', '7428', (140, 143))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))
99300	30144808	However, only a few studies have established a strong correlation between the VHL mutation and PD-L1 expression.	('mutation', 'Var', (82, 90))	('PD-L1', 'Gene', (95, 100))	('VHL', 'Gene', '7428', (78, 81))	('VHL', 'Gene', (78, 81))
99301	30144808	In addition, studies with cell culture experiments have reported that HIF-2alpha stabilization, induced by the VHL mutation, together with impaired pVHL increased the PD-L1 expression, suggesting that PD-L1 is a HIF-2alpha target, which is upregulated in pVHL-deficient ccRCC.	('RCC', 'Disease', (272, 275))	('pVHL', 'Gene', (255, 259))	('VHL', 'Gene', '7428', (149, 152))	('VHL', 'Gene', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (270, 275))	('pVHL', 'Gene', '7428', (148, 152))	('PD-L1', 'Gene', (167, 172))	('VHL', 'Gene', '7428', (111, 114))	('pVHL', 'Gene', (148, 152))	('VHL', 'Gene', (256, 259))	('increased', 'PosReg', (153, 162))	('VHL', 'Gene', '7428', (256, 259))	('expression', 'MPA', (173, 183))	('mutation', 'Var', (115, 123))	('VHL', 'Gene', (149, 152))	('pVHL', 'Gene', '7428', (255, 259))	('RCC', 'Disease', 'MESH:C538614', (272, 275))
99323	30144808	Likewise, samples with scores of 0-2 for PD1, CD4, and CD8 were encoded as "none or mild," whereas scores of 3-4 were encoded as "dense" lymphocytic infiltration in the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('CD4', 'Var', (46, 49))	('CD8', 'Gene', (55, 58))	('tumor', 'Disease', (169, 174))	('CD8', 'Gene', '925', (55, 58))	('PD1', 'Gene', '5133', (41, 44))	('PD1', 'Gene', (41, 44))
99337	30144808	In addition, most studies have suggested that patients with intratumoral high PD-L1 expression exhibited aggressive tumors and have increased risk of death from RCC.	('patients', 'Species', '9606', (46, 54))	('aggressive tumors', 'Disease', 'MESH:D001523', (105, 122))	('tumor', 'Disease', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('PD-L1', 'Gene', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('aggressive tumors', 'Disease', (105, 122))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('RCC', 'Disease', (161, 164))	('exhibited', 'Reg', (95, 104))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('high', 'Var', (73, 77))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('tumor', 'Disease', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
99338	30144808	One of the most extensive meta-analysis investigating 1863 patients from 10 studies reported that the PD-L1 expression is correlated with poor overall survival in ccRCC and non-ccRCC.	('expression', 'Var', (108, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (177, 182))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('ccRCC', 'Phenotype', 'HP:0006770', (163, 168))	('PD-L1', 'Gene', (102, 107))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('overall survival', 'MPA', (143, 159))	('patients', 'Species', '9606', (59, 67))	('RCC', 'Disease', (179, 182))	('poor', 'NegReg', (138, 142))	('RCC', 'Disease', (165, 168))
99348	30144808	Furthermore, ccRCCs harboring the PD-L1 expression significantly correlated with PD-1-, CD4-, and CD8-positive dense inflammatory response.	('CD8', 'Gene', (98, 101))	('inflammatory response', 'biological_process', 'GO:0006954', ('117', '138'))	('PD-1', 'Gene', (81, 85))	('expression', 'Var', (40, 50))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('PD-1', 'Gene', '5133', (81, 85))	('RCC', 'Disease', (15, 18))	('CD8', 'Gene', '925', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('PD-L1', 'Gene', (34, 39))	('correlated', 'Reg', (65, 75))
99360	30144808	In contrast, the knockdown of HIF-2alpha, but not of HIF-1alpha, decreased PD-L1 protein levels in ccRCC cell lines.	('decreased', 'NegReg', (65, 74))	('HIF-2alpha', 'Var', (30, 40))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('RCC', 'Disease', (101, 104))	('decreased PD', 'Phenotype', 'HP:0032198', (65, 77))	('PD-L1 protein levels', 'MPA', (75, 95))	('knockdown', 'Var', (17, 26))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))
99364	30144808	have found PD-L1 expression to be associated in particular with non-inactivated wild-type VHL tumors.	('associated', 'Reg', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('VHL tumors', 'Disease', (90, 100))	('expression', 'Var', (17, 27))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('VHL tumors', 'Disease', 'MESH:D006623', (90, 100))	('PD-L1', 'Gene', (11, 16))
99365	30144808	have reported PD-L1 expression and fewer VHL gene mutations in ccRCC4 tumors.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mutations', 'Var', (50, 59))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('VHL', 'Gene', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('PD-L1', 'Gene', (14, 19))	('VHL', 'Gene', '7428', (41, 44))	('RCC', 'Disease', (65, 68))
99380	30144808	The blockade of PD-L1 under hypoxia enhances T-cell activation.	('enhances', 'PosReg', (36, 44))	('PD-L1', 'Gene', (16, 21))	('blockade', 'Var', (4, 12))	('T-cell activation', 'biological_process', 'GO:0042110', ('45', '62'))	('hypoxia', 'Disease', (28, 35))	('hypoxia', 'Disease', 'MESH:D000860', (28, 35))	('T-cell activation', 'CPA', (45, 62))
99383	30144808	In our study, PD-L1 tumor cell expression was 13.8% of the ccRCC cases with SP263 clone and it was correlated with higher levels of PD-1, CD4, and CD8.	('CD8', 'Gene', (147, 150))	('PD-L1 tumor', 'Disease', 'MESH:D010300', (14, 25))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('PD-1', 'Gene', (132, 136))	('levels', 'MPA', (122, 128))	('CD8', 'Gene', '925', (147, 150))	('CD4', 'MPA', (138, 141))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('PD-1', 'Gene', '5133', (132, 136))	('RCC', 'Disease', (61, 64))	('SP263 clone', 'Var', (76, 87))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('higher', 'PosReg', (115, 121))	('PD-L1 tumor', 'Disease', (14, 25))
99394	32109249	The analyses showed that chromophobe renal tumors are a homogeneous group characterized by an overexpression of miR 1229, miR 10a, miR 182, miR 1208, miR 222, miR 221, miR 891b, miR 629-5p and miR 221-5p.	('overexpression', 'PosReg', (94, 108))	('miR 1208', 'Gene', '100302281', (140, 148))	('miR 221', 'Gene', '407006', (193, 200))	('miR 222', 'Gene', '407007', (150, 157))	('miR 1229', 'Gene', '100302156', (112, 120))	('miR 891b', 'Gene', '100126304', (168, 176))	('miR 10a', 'Gene', '406902', (122, 129))	('miR 221', 'Gene', '407006', (159, 166))	('miR 182', 'Gene', '406958', (131, 138))	('miR 629-5p', 'Var', (178, 188))	('miR 221', 'Gene', (193, 200))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('renal tumors', 'Phenotype', 'HP:0009726', (37, 49))	('miR 222', 'Gene', (150, 157))	('miR 221', 'Gene', (159, 166))	('miR 182', 'Gene', (131, 138))	('miR 10a', 'Gene', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('miR 1229', 'Gene', (112, 120))	('chromophobe renal tumors', 'Disease', 'MESH:D002292', (25, 49))	('renal tumor', 'Phenotype', 'HP:0009726', (37, 48))	('miR 1208', 'Gene', (140, 148))	('chromophobe renal tumors', 'Disease', (25, 49))	('miR 891b', 'Gene', (168, 176))
99429	32109249	SAM showed that chromophobe tumors are a very homogeneous molecular group with a higher expression of miR 1229, miR 10a, miR 182, miR 1208, miR 222, miR 221, miR 891b, miR 629-5p and miR 221-5p (Fig 1).	('miR 222', 'Gene', (140, 147))	('miR 891b', 'Gene', (158, 166))	('expression', 'MPA', (88, 98))	('miR 1208', 'Gene', '100302281', (130, 138))	('miR 221', 'Gene', '407006', (183, 190))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('miR 1229', 'Gene', '100302156', (102, 110))	('miR 10a', 'Gene', '406902', (112, 119))	('miR 891b', 'Gene', '100126304', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('miR 221', 'Gene', '407006', (149, 156))	('miR 182', 'Gene', '406958', (121, 128))	('miR 221', 'Gene', (183, 190))	('chromophobe tumors', 'Disease', (16, 34))	('miR 629-5p', 'Var', (168, 178))	('miR 222', 'Gene', '407007', (140, 147))	('miR 221', 'Gene', (149, 156))	('miR 10a', 'Gene', (112, 119))	('miR 182', 'Gene', (121, 128))	('higher', 'PosReg', (81, 87))	('chromophobe tumors', 'Disease', 'MESH:D000238', (16, 34))	('miR 1229', 'Gene', (102, 110))	('miR 1208', 'Gene', (130, 138))
99483	32349455	Scientific evidence has demonstrated that the alterations in the volatile part of exometabolome (VOCs and volatile carbonyl compounds (VCCs) profiles) reflect the genetic mutations, adaptations and modifications in biochemical pathways of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('alterations', 'Reg', (46, 57))	('volatile carbonyl compounds', 'MPA', (106, 133))	('volatile part of exometabolome', 'MPA', (65, 95))	('modifications', 'Reg', (198, 211))	('biochemical pathways', 'Pathway', (215, 235))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Disease', (239, 244))	('mutations', 'Var', (171, 180))
99506	32349455	2-Ethoxy-2-methylpropane, 2,4-dimethyl-1-heptene and 4-methylbenzaldehyde were consumed by all cell lines but at a lower extent in 769-P and 786-O compared with HK-2 (Table 1).	('769-P', 'Var', (131, 136))	('HK-2', 'Gene', (161, 165))	('HK-2', 'molecular_function', 'GO:0008256', ('161', '165'))	('2,4-dimethyl-1-heptene', 'Chemical', '-', (26, 48))	('lower', 'NegReg', (115, 120))	('4-methylbenzaldehyde', 'Chemical', 'MESH:C020627', (53, 73))	('2-Ethoxy-2-methylpropane', 'Chemical', 'MESH:C098546', (0, 24))	('HK-2', 'Gene', '3099', (161, 165))	('786-O', 'Var', (141, 146))
99545	32349455	Moreover, acetaldehyde can lead to activation of proto-oncogenes, inactivation of tumor suppressor genes in replicating cells and inhibition of many important enzymes of DNA synthesis pathways, playing an important role in carcinogenesis.	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('carcinogenesis', 'Disease', 'MESH:D063646', (223, 237))	('inactivation', 'NegReg', (66, 78))	('tumor suppressor', 'biological_process', 'GO:0051726', ('82', '98'))	('inhibition', 'NegReg', (130, 140))	('acetaldehyde', 'Chemical', 'MESH:D000079', (10, 22))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('proto-oncogenes', 'Gene', (49, 64))	('carcinogenesis', 'Disease', (223, 237))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('82', '98'))	('acetaldehyde', 'Var', (10, 22))	('tumor', 'Disease', (82, 87))	('DNA synthesis', 'biological_process', 'GO:0071897', ('170', '183'))	('activation', 'PosReg', (35, 45))
99564	32349455	Nevertheless, our findings support the hypothesis that altered energy production in RCC cells enables them to survive under oxidative stress conditions and to migrate to other tissues and form metastases.	('energy production', 'MPA', (63, 80))	('migrate', 'CPA', (159, 166))	('metastases', 'Disease', (193, 203))	('altered', 'Var', (55, 62))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('oxidative stress', 'Phenotype', 'HP:0025464', (124, 140))	('metastases', 'Disease', 'MESH:D009362', (193, 203))
99572	32349455	Thus, 769-P and 786-O are recognized as primary ccRCC while Caki-1 is a metastatic ccRCC cell line.	('786-O', 'Var', (16, 21))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('RCC', 'Disease', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('RCC', 'Disease', (85, 88))
99584	32349455	The results showed that alterations in the volatile profile are capable of discriminating RCC from non-tumorigenic renal cells.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('alterations', 'Var', (24, 35))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('volatile profile', 'MPA', (43, 59))	('RCC', 'Disease', (90, 93))
99598	33311452	In-depth mechanistic exploring discovered that the Cys2-His2 zinc finger (C2H2-ZnF) domain of SORBS2 directly bound to the 3' untranslated region (3'UTR) of MTUS1 mRNA, which increased MTUS1 mRNA stability.	('MTUS1', 'Gene', (185, 190))	('2-His', 'molecular_function', 'GO:0033770', ('54', '59'))	('MTUS1', 'Gene', '57509', (157, 162))	('Cys2-His2', 'Var', (51, 60))	('bound', 'Interaction', (110, 115))	('MTUS1', 'Gene', '57509', (185, 190))	('His', 'Chemical', 'MESH:D006639', (56, 59))	('SORBS2', 'Gene', '8470', (94, 100))	('increased', 'PosReg', (175, 184))	('MTUS1', 'Gene', (157, 162))	('SORBS2', 'Gene', (94, 100))	('Cys', 'Chemical', 'MESH:D003545', (51, 54))
99607	33311452	As a result, RBP malfunction almost influences each step during the development and progression of cancer, including sustaining cell proliferation, resisting apoptosis, avoiding immune surveillance, inducing angiogenesis, and activating invasion and metastasis.	('RBP', 'Gene', (13, 16))	('angiogenesis', 'biological_process', 'GO:0001525', ('208', '220'))	('apoptosis', 'CPA', (158, 167))	('inducing', 'Reg', (199, 207))	('angiogenesis', 'CPA', (208, 220))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('immune surveillance', 'MPA', (178, 197))	('cell proliferation', 'CPA', (128, 146))	('RBP', 'Gene', '57794', (13, 16))	('resisting', 'NegReg', (148, 157))	('malfunction', 'Var', (17, 28))	('influences', 'Reg', (36, 46))	('cell proliferation', 'biological_process', 'GO:0008283', ('128', '146'))	('sustaining', 'PosReg', (117, 127))	('avoiding', 'NegReg', (169, 177))	('activating', 'PosReg', (226, 236))	('cancer', 'Disease', (99, 105))	('apoptosis', 'biological_process', 'GO:0097194', ('158', '167'))	('apoptosis', 'biological_process', 'GO:0006915', ('158', '167'))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
99627	33311452	Denatured proteins were separated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, transferred to a polyvinylidene difluoride membrane (Millipore), blocked with skim milk, and then incubated with the indicated primary antibody overnight at 4  C and probed with secondary antibody at room temperature for 2 h. The primary antibodies were listed as follows: SORBS2 (SAB4200183, MilliporeSigma), E-cadherin (ab1416, Abcam), N-cadherin (ab18203, Abcam), Vimentin (ab92547, Abcam), MTUS1 (ab198176, Abcam), acetylated-tubulin (T6793, MilliporeSigma), beta-tubulin (T4026, MilliporeSigma), KIF2C (sc-81305, Santa Cruz Biotechnology), and GAPDH (sc-32233, Santa Cruz Biotechnology).	('E-cadherin', 'Gene', (409, 419))	('antibody', 'molecular_function', 'GO:0003823', ('287', '295'))	('antibody', 'cellular_component', 'GO:0019815', ('234', '242'))	('E-cadherin', 'Gene', '999', (409, 419))	('cadherin', 'molecular_function', 'GO:0008014', ('439', '447'))	('antibody', 'cellular_component', 'GO:0042571', ('287', '295'))	('SORBS2', 'Gene', (372, 378))	('Vimentin', 'cellular_component', 'GO:0045099', ('466', '474'))	('MTUS1', 'Gene', (493, 498))	('SORBS2', 'Gene', '8470', (372, 378))	('antibody', 'cellular_component', 'GO:0019814', ('234', '242'))	('T6793', 'Var', (538, 543))	('Vimentin', 'Gene', '7431', (466, 474))	('MTUS1', 'Gene', '57509', (493, 498))	('cadherin', 'molecular_function', 'GO:0008014', ('411', '419'))	('T4026', 'Var', (576, 581))	('antibody', 'cellular_component', 'GO:0019815', ('287', '295'))	('acetylated-tubulin', 'Protein', (518, 536))	('KIF2C', 'Gene', '11004', (600, 605))	('Vimentin', 'Gene', (466, 474))	('GAPDH', 'Gene', '2597', (648, 653))	('Vimentin', 'cellular_component', 'GO:0045098', ('466', '474'))	('antibody', 'molecular_function', 'GO:0003823', ('234', '242'))	('N-cadherin', 'Gene', (437, 447))	('KIF2C', 'Gene', (600, 605))	('N-cadherin', 'Gene', '1000', (437, 447))	('antibody', 'cellular_component', 'GO:0042571', ('234', '242'))	('antibody', 'cellular_component', 'GO:0019814', ('287', '295'))	('membrane', 'cellular_component', 'GO:0016020', ('142', '150'))	('beta-tubulin', 'Protein', (562, 574))	('GAPDH', 'Gene', (648, 653))
99628	33311452	For detection of KIF2CS192 phosphorylation (p-S192), autoradiograph was performed.	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('p-S192', 'Var', (44, 50))	('KIF2C', 'Gene', (17, 22))	('phosphorylation', 'MPA', (27, 42))	('KIF2C', 'Gene', '11004', (17, 22))
99646	33311452	The full-length SORBS2 and point mutated SORBS2 was synthesized and cloned into pcDNA3.1 plasmid (Sangon Biotech, Shanghai).	('SORBS2', 'Gene', (16, 22))	('point mutated', 'Var', (27, 40))	('SORBS2', 'Gene', '8470', (41, 47))	('SORBS2', 'Gene', (41, 47))	('SORBS2', 'Gene', '8470', (16, 22))
99679	33311452	We observed that deletion of the 300-500 bp of MTUS1 mRNA 3'UTR significantly decreased the luciferase activity (Fig.	('luciferase activity', 'molecular_function', 'GO:0047077', ('92', '111'))	('activity', 'MPA', (103, 111))	('luciferase', 'Enzyme', (92, 102))	('MTUS1', 'Gene', '57509', (47, 52))	('luciferase activity', 'molecular_function', 'GO:0045289', ('92', '111'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('92', '111'))	('deletion', 'Var', (17, 25))	('luciferase activity', 'molecular_function', 'GO:0050397', ('92', '111'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('92', '111'))	('MTUS1', 'Gene', (47, 52))	('decreased', 'NegReg', (78, 87))
99682	33311452	Figure 4E demonstrated that transfection of full-length SORBS2 notably increased luciferase activity, whereas transfection of mutated SORBS2 profoundly reduced luciferase activity.	('luciferase activity', 'molecular_function', 'GO:0047712', ('81', '100'))	('luciferase', 'Enzyme', (160, 170))	('SORBS2', 'Gene', (134, 140))	('SORBS2', 'Gene', '8470', (56, 62))	('mutated', 'Var', (126, 133))	('luciferase activity', 'molecular_function', 'GO:0050248', ('81', '100'))	('SORBS2', 'Gene', '8470', (134, 140))	('luciferase activity', 'molecular_function', 'GO:0050397', ('81', '100'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('160', '179'))	('reduced', 'NegReg', (152, 159))	('luciferase activity', 'molecular_function', 'GO:0047712', ('160', '179'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('160', '179'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('160', '179'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('160', '179'))	('activity', 'MPA', (92, 100))	('activity', 'MPA', (171, 179))	('luciferase', 'Enzyme', (81, 91))	('luciferase activity', 'molecular_function', 'GO:0047077', ('81', '100'))	('increased', 'PosReg', (71, 80))	('SORBS2', 'Gene', (56, 62))	('luciferase activity', 'molecular_function', 'GO:0045289', ('81', '100'))
99686	33311452	Figure 5A, B indicated significant knockdown of MTUS1 by si-MTUS1 in mRNA and protein levels.	('knockdown', 'Var', (35, 44))	('MTUS1', 'Gene', (48, 53))	('MTUS1', 'Gene', '57509', (60, 65))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('MTUS1', 'Gene', '57509', (48, 53))	('MTUS1', 'Gene', (60, 65))
99688	33311452	Figure 5C, D demonstrated that MTUS1 knockdown dramatically increased the migratory and invasive ability of Caki-1 and ACHN cell lines and partially alleviated SORBS2-overexpression-induced metastasis suppression.	('SORBS2', 'Gene', (160, 166))	('metastasis suppression', 'Disease', 'MESH:D009362', (190, 212))	('MTUS1', 'Gene', (31, 36))	('alleviated', 'NegReg', (149, 159))	('knockdown', 'Var', (37, 46))	('metastasis suppression', 'Disease', (190, 212))	('SORBS2', 'Gene', '8470', (160, 166))	('MTUS1', 'Gene', '57509', (31, 36))	('increased', 'PosReg', (60, 69))	('invasive ability of Caki-1', 'CPA', (88, 114))
99690	33311452	We detected a marked decrease of acetylated tubulin, a marker of stabilized microtubules, upon MTUS1 knockdown (Fig.	('acetylated tubulin', 'MPA', (33, 51))	('decrease', 'NegReg', (21, 29))	('MTUS1', 'Gene', '57509', (95, 100))	('MTUS1', 'Gene', (95, 100))	('knockdown', 'Var', (101, 110))
99691	33311452	Immunofluorescent staining of tubulin demonstrated that MTUS1 knockdown led to reduced microtubule extension and halo-like distribution of microtubule that indicated destabilized microtubule network (Fig.	('destabilized', 'NegReg', (166, 178))	('microtubule', 'cellular_component', 'GO:0005874', ('179', '190'))	('microtubule extension', 'MPA', (87, 108))	('microtubule', 'cellular_component', 'GO:0005874', ('87', '98'))	('reduced', 'NegReg', (79, 86))	('MTUS1', 'Gene', (56, 61))	('halo', 'cellular_component', 'GO:1990038', ('113', '117'))	('microtubule network', 'MPA', (179, 198))	('halo-like distribution of microtubule', 'MPA', (113, 150))	('MTUS1', 'Gene', '57509', (56, 61))	('microtubule', 'cellular_component', 'GO:0005874', ('139', '150'))	('knockdown', 'Var', (62, 71))
99697	33311452	Autoradiograph image indicated that Aurora B kinase mainly phosphorylated the S192 site of KIF2C (Fig.	('S192', 'Var', (78, 82))	('KIF2C', 'Gene', '11004', (91, 96))	('Aurora B', 'Gene', '9212', (36, 44))	('KIF2C', 'Gene', (91, 96))	('Aurora B', 'Gene', (36, 44))
99699	33311452	Phosphorylation of S192 site could lead to the inhibition of KIF2C depolymerase activity and reduced directional migration and invasion of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('KIF2C', 'Gene', '11004', (61, 66))	('Phosphorylation', 'Var', (0, 15))	('inhibition', 'NegReg', (47, 57))	('reduced', 'NegReg', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('S192 site', 'Var', (19, 28))	('tumor', 'Disease', (139, 144))	('activity', 'MPA', (80, 88))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('KIF2C', 'Gene', (61, 66))	('depolymerase', 'Enzyme', (67, 79))
99706	33311452	Loss of SORBS2 reduced the mRNA stability of MTUS1, which could lead to microtubule destabilization in ccRCC cells.	('MTUS1', 'Gene', (45, 50))	('microtubule destabilization', 'biological_process', 'GO:0031117', ('72', '99'))	('lead to', 'Reg', (64, 71))	('mRNA stability', 'MPA', (27, 41))	('microtubule', 'cellular_component', 'GO:0005874', ('72', '83'))	('reduced', 'NegReg', (15, 22))	('microtubule destabilization', 'MPA', (72, 99))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('SORBS2', 'Gene', '8470', (8, 14))	('Loss', 'Var', (0, 4))	('MTUS1', 'Gene', '57509', (45, 50))	('SORBS2', 'Gene', (8, 14))
99709	33311452	The SoHo domain is implicated in binding to the lipid raft protein flotillin and the three SH3 domains are known to interact with poly-proline motifs of c-Arg and c-Abl kinases.	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('c-Abl', 'Gene', (163, 168))	('lipid', 'Chemical', 'MESH:D008055', (48, 53))	('c-Abl', 'Gene', '25', (163, 168))	('lipid raft', 'cellular_component', 'GO:0045121', ('48', '58'))	('binding', 'Interaction', (33, 40))	('interact', 'Interaction', (116, 124))	('poly-proline', 'Chemical', 'MESH:C011083', (130, 142))	('poly-proline motifs', 'Var', (130, 149))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
99751	31409759	Exploration of functional pseudogenes associated with renal cell carcinoma and their corresponding ceRNA mechanism may provide novel insights for diagnosis, therapy and prognosis of renal cell carcinoma in the future.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (182, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('associated', 'Reg', (38, 48))	('renal cell carcinoma', 'Disease', (54, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (54, 74))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (54, 74))	('renal cell carcinoma', 'Disease', (182, 202))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (182, 202))	('pseudogenes', 'Var', (26, 37))
99752	31409759	In this study, we first screened differentially expressed pseudogenes in RCC by analyzing dreamBase and GEPIA.	('pseudogenes', 'Var', (58, 69))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
99755	31409759	Therefore, differentially expressed pseudogenes in ccRCC was first obtained to explore the functional pseudogenes and excavate their potential mechanisms of action in RCC using human pseudogene database, namely dreamBase.	('pseudogenes', 'Var', (102, 113))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('human', 'Species', '9606', (177, 182))
99758	31409759	Next, we determined the prognostic values of 47 potential pseudogenes in human ccRCC based on TCGA data using GEPIA database.	('pseudogenes', 'Var', (58, 69))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('human', 'Species', '9606', (73, 78))	('RCC', 'Disease', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))
99760	31409759	Among the 47 potential pseudogenes, only high expression of three upregulated pseudogenes (AC007326.9, DUXAP8 and DUXAP9) and four downregulated pseudogenes (NUDT4P2, RP11-255H23.2, AF186192.5 and SLC2A3P1) indicated poorer and better OS and RFS in patients with ccRCC, respectively (Supplementary Table 3).	('NUDT4P2', 'Gene', (158, 165))	('RFS', 'Disease', 'MESH:D005198', (242, 245))	('NUDT4P2', 'Gene', '170688', (158, 165))	('RP11', 'Gene', '26121', (167, 171))	('SLC2A3P1', 'Gene', (197, 205))	('ccRCC', 'Phenotype', 'HP:0006770', (263, 268))	('RCC', 'Disease', (265, 268))	('RCC', 'Phenotype', 'HP:0005584', (265, 268))	('poorer', 'NegReg', (217, 223))	('SLC2A3P1', 'Gene', '100128062', (197, 205))	('upregulated', 'PosReg', (66, 77))	('RFS', 'Disease', (242, 245))	('RCC', 'Disease', 'MESH:C538614', (265, 268))	('AF186192.5', 'Var', (182, 192))	('DUXAP9', 'Gene', '503638', (114, 120))	('patients', 'Species', '9606', (249, 257))	('RP11', 'Gene', (167, 171))	('DUXAP9', 'Gene', (114, 120))	('DUXAP8', 'Gene', (103, 109))	('DUXAP8', 'Gene', '503637', (103, 109))	('better', 'PosReg', (228, 234))
99771	31409759	In the next step, we determined the expression and prognostic values of the three miRNAs (miR-29c-3p, miR-92b-3p and miR-500a-3p) in ccRCC.	('miR-500a-3p', 'Var', (117, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))	('miR-92b-3p', 'Var', (102, 112))	('miR-29c', 'Gene', '407026', (90, 97))	('miR-29c', 'Gene', (90, 97))
99774	31409759	We also found that miR-500a-3p expression in cancer tissues was significantly lower than that in normal tissues (Figure 4C).	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('miR-500a-3p', 'Var', (19, 30))	('expression', 'MPA', (31, 41))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('lower', 'NegReg', (78, 83))
99775	31409759	Survival analysis for the three miRNAs demonstrated that ccRCC patients with higher expression of miR-29c-3p and miR-92b-3p had better and worse prognosis as presented in Figure 4D and Figure 4E, respectively.	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('higher', 'PosReg', (77, 83))	('miR-92b-3p', 'Var', (113, 123))	('miR-29c', 'Gene', '407026', (98, 105))	('miR-29c', 'Gene', (98, 105))	('patients', 'Species', '9606', (63, 71))	('expression', 'MPA', (84, 94))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
99789	31409759	As shown in Table 4, high expression of GAPDH, COL1A1 and COL1A2 indicated a poor prognosis in patients with ccRCC.	('COL1A2', 'Gene', (58, 64))	('patients', 'Species', '9606', (95, 103))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('high', 'Var', (21, 25))	('COL1A1', 'Gene', (47, 53))	('GAPDH', 'Gene', '2597', (40, 45))	('GAPDH', 'Gene', (40, 45))
99805	31409759	Subsequently, we employed siRNAs of DUXAP8/ DUXAP9 to knockdown DUXAP8/DUXAP9 and used mimic of miR-29c-3p to upregulate miR-29c-3p.	('miR-29c', 'Gene', '407026', (121, 128))	('DUXAP9', 'Gene', (44, 50))	('DUXAP8', 'Gene', '503637', (64, 70))	('knockdown', 'Var', (54, 63))	('miR-29c', 'Gene', (121, 128))	('DUXAP9', 'Gene', (71, 77))	('DUXAP9', 'Gene', '503638', (71, 77))	('DUXAP9', 'Gene', '503638', (44, 50))	('miR-29c', 'Gene', '407026', (96, 103))	('DUXAP8', 'Gene', (36, 42))	('miR-29c', 'Gene', (96, 103))	('DUXAP8', 'Gene', '503637', (36, 42))	('DUXAP8', 'Gene', (64, 70))	('upregulate', 'PosReg', (110, 120))
99807	31409759	As shown in Figure 7L, knockdown of DUXAP8 or DUXAP9 could significantly suppress cell growth and overexpression of miR-29c-3p also inhibited cell growth.	('cell growth', 'CPA', (142, 153))	('inhibited', 'NegReg', (132, 141))	('suppress', 'NegReg', (73, 81))	('DUXAP8', 'Gene', (36, 42))	('cell growth', 'biological_process', 'GO:0016049', ('82', '93'))	('knockdown', 'Var', (23, 32))	('DUXAP9', 'Gene', (46, 52))	('DUXAP9', 'Gene', '503638', (46, 52))	('miR-29c', 'Gene', '407026', (116, 123))	('miR-29c', 'Gene', (116, 123))	('cell growth', 'CPA', (82, 93))	('cell growth', 'biological_process', 'GO:0016049', ('142', '153'))	('DUXAP8', 'Gene', '503637', (36, 42))
99808	31409759	Moreover, we found that cells with knockdown of DUXA8/DUXAP9 and overexpression of miR-29c-3p grew the slowest.	('knockdown', 'Var', (35, 44))	('DUXAP9', 'Gene', (54, 60))	('DUXAP9', 'Gene', '503638', (54, 60))	('slowest', 'NegReg', (103, 110))	('miR-29c', 'Gene', (83, 90))	('miR-29c', 'Gene', '407026', (83, 90))
99810	31409759	Taken together, amplification of pseudogenes DUXAP8 and DUXAP9 may lead to increase expression of COL1A1 and COL1A2 by competitively binding to miR-29c-3p, resulting in uncontrolled cell proliferation in renal cell carcinoma (Figure 8).	('DUXAP9', 'Gene', (56, 62))	('renal cell carcinoma', 'Disease', (204, 224))	('uncontrolled cell proliferation', 'CPA', (169, 200))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (204, 224))	('COL1A2', 'Gene', (109, 115))	('miR-29c', 'Gene', (144, 151))	('DUXAP8', 'Gene', (45, 51))	('DUXAP8', 'Gene', '503637', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (204, 224))	('binding', 'molecular_function', 'GO:0005488', ('133', '140'))	('increase', 'PosReg', (75, 83))	('expression', 'MPA', (84, 94))	('DUXAP9', 'Gene', '503638', (56, 62))	('cell proliferation', 'biological_process', 'GO:0008283', ('182', '200'))	('amplification', 'Var', (16, 29))	('COL1A1', 'Gene', (98, 104))	('miR-29c', 'Gene', '407026', (144, 151))	('pseudogenes', 'Var', (33, 44))	('binding', 'Interaction', (133, 140))
99814	31409759	In this study, we first screened several differentially expressed pseudogenes in ccRCC using the dreamBase database, after which expression levels of these pseudogenes were further validated using another database (GEPIA).	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('pseudogenes', 'Var', (66, 77))
99819	31409759	All these reports together with the previous analytic results suggest that pseudogene DUXAP8 and DUXAP9 may serve as two promising therapeutic targets ad prognostic biomarkers for RCC.	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('RCC', 'Disease', (180, 183))	('RCC', 'Phenotype', 'HP:0005584', (180, 183))	('DUXAP9', 'Gene', (97, 103))	('DUXAP8', 'Gene', (86, 92))	('DUXAP9', 'Gene', '503638', (97, 103))	('DUXAP8', 'Gene', '503637', (86, 92))	('pseudogene', 'Var', (75, 85))
99835	31409759	The group of Li J also supposed that COL1A1 and COL1A2 might predict poor clinical outcomes in gastric cancer patients.	('COL1A2', 'Gene', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('COL1A1', 'Var', (37, 43))	('gastric cancer', 'Disease', 'MESH:D013274', (95, 109))	('gastric cancer', 'Disease', (95, 109))	('clinical', 'Species', '191496', (74, 82))	('patients', 'Species', '9606', (110, 118))	('gastric cancer', 'Phenotype', 'HP:0012126', (95, 109))
99849	31409759	StarBase (version 3) (http://starbase.sysu.edu.cn/) was also utilized to perform correlation analysis between pseudogene and miRNA in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('pseudogene', 'Var', (110, 120))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))
99859	31409759	The cells were maintained in minimal essential medium (MEM) supplemented with 10% FBS, penicillin (100 U/ml) and streptomycin (100ug/ml).	('FBS', 'Disease', 'MESH:D005198', (82, 85))	('100ug/ml', 'Var', (127, 135))	('streptomycin', 'Chemical', 'MESH:D013307', (113, 125))	('penicillin', 'Chemical', 'MESH:D010406', (87, 97))	('FBS', 'Disease', (82, 85))	('essential medium', 'Chemical', '-', (37, 53))
99862	31409759	The expression level of DUXAP8, DUXAP9, miR- 29c-3p, COL1A1 and COL1A2 was analyzed by quantitative real-time PCR as we previously described.	('DUXAP8', 'Gene', (24, 30))	('DUXAP8', 'Gene', '503637', (24, 30))	('COL1A1', 'Gene', (53, 59))	('DUXAP9', 'Gene', (32, 38))	('DUXAP9', 'Gene', '503638', (32, 38))	('miR- 29c-3p', 'Var', (40, 51))	('COL1A2', 'Gene', (64, 70))
99868	31409759	To sum up, this study for the first time comprehensively and systematically explored the function and ceRNA regulatory mechanism of pseudogenes in renal cell carcinoma.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (147, 167))	('pseudogenes', 'Var', (132, 143))	('renal cell carcinoma', 'Disease', (147, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (147, 167))
99888	30254456	HOXA-AS2 promotes breast cancer proliferation and invasion by manipulating miR-520c-3p expression.	('HOXA-AS2', 'Gene', '285943', (0, 8))	('miR', 'Gene', '220972', (75, 78))	('invasion', 'CPA', (50, 58))	('miR', 'Gene', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('breast cancer', 'Disease', (18, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('HOXA-AS2', 'Gene', (0, 8))	('manipulating', 'Var', (62, 74))	('promotes', 'PosReg', (9, 17))
99943	30254456	In the clinical classification, DHRS4-AS1 levels in T1+T2 subjects were lower than those of T3+T4 subjects (Figure 1C and D).	('clinical', 'Species', '191496', (7, 15))	('lower', 'NegReg', (72, 77))	('DHRS4-AS1', 'Gene', '55449;10901;5729', (32, 41))	('DHRS4-AS1', 'Gene', (32, 41))	('T1+T2', 'Var', (52, 57))
99974	30254456	As shown in Figure 6A, DHRS4-AS1 overexpression significantly inhibited 786-O and 769-P cells' motility as measured by a wound-healing assay (Figure 6B).	('wound-healing', 'biological_process', 'GO:0042060', ('121', '134'))	('inhibited', 'NegReg', (62, 71))	('overexpression', 'Var', (33, 47))	('DHRS4-AS1', 'Gene', '55449;10901;5729', (23, 32))	('DHRS4-AS1', 'Gene', (23, 32))
99998	30254456	Then we tried to guess the reason which resulted in the downregulation of DHRS4-AS1, as methylation is the most common cause of gene silencing, so we browsed the UCSC data base and found there is methylation island in the promoter region of DHRS4-AS1 (Figure S1A).	('DHRS4-AS1', 'Gene', '55449;10901;5729', (241, 250))	('DHRS4-AS1', 'Gene', (241, 250))	('gene silencing', 'biological_process', 'GO:0016458', ('128', '142'))	('methylation', 'Var', (196, 207))	('methylation', 'biological_process', 'GO:0032259', ('196', '207'))	('downregulation', 'NegReg', (56, 70))	('DHRS4-AS1', 'Gene', (74, 83))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('DHRS4-AS1', 'Gene', '55449;10901;5729', (74, 83))
100000	30254456	After 72 h, the cells were harvested, then qRT-PCR was executed to estimate the expression of DHRS4-AS1, as shown in Figure S1B the expression of DHRS4-AS1 was significantly downregulated in 5-azacytidine treatment group compare with the control group.	('DHRS4-AS1', 'Gene', (146, 155))	('downregulated', 'NegReg', (174, 187))	('DHRS4-AS1', 'Gene', '55449;10901;5729', (146, 155))	('DHRS4-AS1', 'Gene', '55449;10901;5729', (94, 103))	('DHRS4-AS1', 'Gene', (94, 103))	('5-azacytidine', 'Chemical', 'MESH:D001374', (191, 204))	('expression', 'MPA', (132, 142))	('5-azacytidine', 'Var', (191, 204))
100034	33923219	This VHL mutation course is the main pathway of ccRCC.	('mutation', 'Var', (9, 17))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('VHL', 'Gene', (5, 8))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('VHL', 'Gene', '7428', (5, 8))
100035	33923219	Modifications of various genes similarly manifest as other types of RCC.	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('Modifications', 'Var', (0, 13))
100037	33923219	Chromophobe RCC is associated with mutations of TP53 and PTEN, while translocation RCC is associated with fusions of TFE3 or TFEB genes.	('associated', 'Reg', (19, 29))	('RCC', 'Phenotype', 'HP:0005584', (12, 15))	('RCC', 'Disease', (12, 15))	('TFEB', 'Gene', (125, 129))	('Chromophobe RCC', 'Disease', 'MESH:C538614', (0, 15))	('RCC', 'Disease', (83, 86))	('TP53', 'Gene', '7157', (48, 52))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('TFEB', 'Gene', '7942', (125, 129))	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('PTEN', 'Gene', (57, 61))	('Chromophobe RCC', 'Disease', (0, 15))	('TFE3', 'Gene', (117, 121))	('TFE3', 'Gene', '7030', (117, 121))	('TP53', 'Gene', (48, 52))	('associated', 'Reg', (90, 100))	('PTEN', 'Gene', '5728', (57, 61))	('mutations', 'Var', (35, 44))
100089	33923219	Moreover, high-dose IL-2 was related to severe cardiovascular toxicity due to increased vascular permeability, with treatment-related death occurring in 4% of patients.	('cardiovascular toxicity', 'Disease', 'MESH:D002318', (47, 70))	('vascular permeability', 'MPA', (88, 109))	('IL-2', 'Gene', (20, 24))	('cardiovascular toxicity', 'Disease', (47, 70))	('high-dose', 'Var', (10, 19))	('increased', 'PosReg', (78, 87))	('patients', 'Species', '9606', (159, 167))	('IL-2', 'molecular_function', 'GO:0005134', ('20', '24'))	('IL-2', 'Gene', '3558', (20, 24))
100107	33923219	Blockades of immune checkpoint components such as PD-1/PD-L1 and CTLA-4 have shown considerable oncological benefit and have shifted treatment strategies targeted at RCC.	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('RCC', 'Disease', (166, 169))	('CTLA-4', 'Gene', (65, 71))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('oncological benefit', 'CPA', (96, 115))	('CTLA-4', 'Gene', '1493', (65, 71))	('PD-1/PD-L1', 'Disease', 'MESH:D010300', (50, 60))	('Blockades', 'Var', (0, 9))	('PD-1/PD-L1', 'Disease', (50, 60))
100118	33923219	The ORR was superior in the combination group compared to the sunitinib group a 42% versus 27% (p < 0.001).	('ORR', 'MPA', (4, 7))	('sunitinib', 'Chemical', 'MESH:D000077210', (62, 71))	('combination', 'Var', (28, 39))
100122	33923219	ORR was lower in the combination arm than the sunitinib arm (29% vs. 52%; p < 0.001).	('lower', 'NegReg', (8, 13))	('ORR', 'MPA', (0, 3))	('combination', 'Var', (21, 32))	('sunitinib', 'Chemical', 'MESH:D000077210', (46, 55))
100128	33923219	However, median OS was comparable in both PD-L1 positive (HR 0.84; 95% CI 0.62-1.15; p = 0.286) and in ITT patients (HR 0.93; 95% CI 0.76-1.14; p = 0.475) in the second interim analysis.	('patients', 'Species', '9606', (107, 115))	('PD-L1', 'Gene', '29126', (42, 47))	('positive', 'Var', (48, 56))	('PD-L1', 'Gene', (42, 47))
100138	33923219	TRAEs appeared in 99.5% of patients who received avelumab plus axitinib, but in 99.3% of patients who received sunitinib.	('sunitinib', 'Chemical', 'MESH:D000077210', (111, 120))	('avelumab', 'Chemical', 'MESH:C000609138', (49, 57))	('avelumab', 'Var', (49, 57))	('patients', 'Species', '9606', (27, 35))	('axitinib', 'Chemical', 'MESH:D000077784', (63, 71))	('patients', 'Species', '9606', (89, 97))	('TRAEs', 'Disease', (0, 5))
100148	33923219	Notably, the rate of grade 3 or higher TRAEs was higher in the pembrolizumab-axitinib arm than the sunitinib arm (62.9% vs. 58.1%).	('pembrolizumab-axitinib', 'Var', (63, 85))	('axitinib', 'Chemical', 'MESH:D000077784', (77, 85))	('TRAEs', 'Disease', (39, 44))	('sunitinib', 'Chemical', 'MESH:D000077210', (99, 108))	('pembrolizumab', 'Chemical', 'MESH:C582435', (63, 76))
100174	33923219	TKI inhibits the process in which mutations of the VHL gene induces HIF to accelerate VEGF for neovasculation and tumor development.	('accelerate', 'PosReg', (75, 85))	('VHL', 'Gene', '7428', (51, 54))	('induces', 'Reg', (60, 67))	('neovasculation and tumor', 'Disease', 'MESH:D009369', (95, 119))	('VEGF', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('HIF', 'CPA', (68, 71))	('VEGF', 'Gene', '7422', (86, 90))	('VHL', 'Gene', (51, 54))	('mutations', 'Var', (34, 43))
100194	33578925	Fusion of the androgen receptor (AR) target gene TMPRSS2 to the ETS (E26 transcription-specific) gene family (ERG, ETV1, and ETV4), particularly the TMPRSS2-ERG, commonly occurs in PC and plays important role in PC initiation and progression.	('ERG', 'Gene', (157, 160))	('TMPRSS2', 'Gene', '7113', (149, 156))	('ERG', 'Gene', '2078', (110, 113))	('transcription', 'biological_process', 'GO:0006351', ('73', '86'))	('TMPRSS2', 'Gene', (149, 156))	('ETV1', 'Gene', (115, 119))	('ERG', 'Gene', '2078', (157, 160))	('androgen receptor', 'Gene', (14, 31))	('AR', 'Gene', '367', (33, 35))	('role', 'Reg', (204, 208))	('androgen receptor', 'Gene', '367', (14, 31))	('ETV4', 'Gene', (125, 129))	('ETV1', 'Gene', '2115', (115, 119))	('occurs', 'Reg', (171, 177))	('TMPRSS2', 'Gene', '7113', (49, 56))	('ETV4', 'Gene', '2118', (125, 129))	('Fusion', 'Var', (0, 6))	('PC', 'Gene', '5091', (212, 214))	('PC', 'Phenotype', 'HP:0012125', (212, 214))	('PC', 'Gene', '5091', (181, 183))	('PC', 'Phenotype', 'HP:0012125', (181, 183))	('ERG', 'Gene', (110, 113))	('TMPRSS2', 'Gene', (49, 56))
100208	33578925	Ectopic expression of CNTN1 in LNCaP cells enhances cell proliferation.	('CNTN1', 'Gene', (22, 27))	('cell proliferation', 'biological_process', 'GO:0008283', ('52', '70'))	('cell proliferation', 'CPA', (52, 70))	('enhances', 'PosReg', (43, 51))	('Ectopic expression', 'Var', (0, 18))	('LNCaP', 'CellLine', 'CVCL:0395', (31, 36))
100210	33578925	The 10 leading-edge genes of this enrichment are novel to PC; they display differential expression in PC compared to normal prostate tissue, PCs with TMPRSS2-ERG fusion compared to those without the fusion, and mPCs compared to primary PC.	('PC', 'Gene', '5091', (102, 104))	('PC', 'Phenotype', 'HP:0012125', (102, 104))	('PC', 'Gene', '5091', (212, 214))	('PC', 'Phenotype', 'HP:0012125', (212, 214))	('PC', 'Gene', '5091', (141, 143))	('PC', 'Gene', '5091', (58, 60))	('PC', 'Phenotype', 'HP:0012125', (236, 238))	('PC', 'Phenotype', 'HP:0012125', (58, 60))	('PC', 'Phenotype', 'HP:0012125', (141, 143))	('TMPRSS2', 'Gene', '7113', (150, 157))	('men', 'Species', '9606', (40, 43))	('PC', 'Gene', '5091', (236, 238))	('fusion', 'Var', (162, 168))	('ERG', 'Gene', '2078', (158, 161))	('expression', 'MPA', (88, 98))	('ERG', 'Gene', (158, 161))	('TMPRSS2', 'Gene', (150, 157))
100243	33578925	In comparison to LNCaP EV cells, LNCaP CNTN1 cells display increases in cell proliferation (Figure 1B) and colony formation (Figure 1C,D), supporting CNTN1 enhancing LNCaP cell proliferation.	('formation', 'biological_process', 'GO:0009058', ('114', '123'))	('colony formation', 'CPA', (107, 123))	('LNCaP', 'CellLine', 'CVCL:0395', (33, 38))	('cell proliferation', 'biological_process', 'GO:0008283', ('172', '190'))	('cell proliferation', 'biological_process', 'GO:0008283', ('72', '90'))	('CNTN1', 'Var', (150, 155))	('LNCaP cell proliferation', 'CPA', (166, 190))	('cell proliferation', 'CPA', (72, 90))	('LNCaP', 'CellLine', 'CVCL:0395', (166, 171))	('LNCaP', 'CellLine', 'CVCL:0395', (17, 22))	('enhancing', 'PosReg', (156, 165))	('LNCaP CNTN1', 'CellLine', 'CVCL:0395', (33, 44))	('increases', 'PosReg', (59, 68))
100260	33578925	PCs within iCluster 1 are featured with ETV1 and ETV4 fusion, SHOP mutations, FOXA1 mutations, and CHD1 deletion, but lack ERG fusion.	('fusion', 'Var', (54, 60))	('ERG', 'Gene', (123, 126))	('ETV1', 'Gene', '2115', (40, 44))	('PC', 'Gene', '5091', (0, 2))	('CHD1', 'Gene', (99, 103))	('FOXA1', 'Gene', '3169', (78, 83))	('PC', 'Phenotype', 'HP:0012125', (0, 2))	('CHD1', 'Gene', '1105', (99, 103))	('ETV4', 'Gene', (49, 53))	('lack ERG', 'Phenotype', 'HP:0000550', (118, 126))	('FOXA1', 'Gene', (78, 83))	('mutations', 'Var', (67, 76))	('mutations', 'Var', (84, 93))	('ERG', 'Gene', '2078', (123, 126))	('ETV4', 'Gene', '2118', (49, 53))	('ETV1', 'Gene', (40, 44))	('deletion', 'Var', (104, 112))
100261	33578925	iCluster 2 PCs are enriched with ERG fusion and PTEN deletion.	('PTEN', 'Gene', (48, 52))	('PTEN', 'Gene', '5728', (48, 52))	('PC', 'Gene', '5091', (11, 13))	('deletion', 'Var', (53, 61))	('PC', 'Phenotype', 'HP:0012125', (11, 13))	('ERG', 'Gene', '2078', (33, 36))	('ERG', 'Gene', (33, 36))
100263	33578925	TP53 hetero-deficiency and RB1 deletion occur more frequently in iCluster 1 and iCluster 2 PCs.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('RB1', 'Gene', '5925', (27, 30))	('hetero-deficiency', 'Disease', (5, 22))	('deletion', 'Var', (31, 39))	('PC', 'Gene', '5091', (91, 93))	('hetero-deficiency', 'Disease', 'MESH:D007153', (5, 22))	('PC', 'Phenotype', 'HP:0012125', (91, 93))	('RB1', 'Gene', (27, 30))
100270	33578925	Trends (p < 0.1) of differential expression in PCs with TMPRSS2-ERG fusion compared to those without the fusion also occur in NANS, C1orf106, FBOX6, and SRD5A3 (Figure 4).	('ERG', 'Gene', (64, 67))	('PC', 'Gene', '5091', (47, 49))	('C1orf106', 'Gene', '55765', (132, 140))	('PC', 'Phenotype', 'HP:0012125', (47, 49))	('fusion', 'Var', (68, 74))	('TMPRSS2', 'Gene', '7113', (56, 63))	('TMPRSS2', 'Gene', (56, 63))	('expression', 'MPA', (33, 43))	('C1orf106', 'Gene', (132, 140))	('ERG', 'Gene', '2078', (64, 67))
100287	33578925	While tumors within the group marked with high expression of either TMEM45B or FBXO6 are at higher risks of relapse, the reverse patterns are observed for NANS and ARFGEF3 (Figure 8).	('ARFGEF3', 'Gene', (164, 171))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('TMEM45B', 'Gene', (68, 75))	('ARFGEF3', 'Gene', '57221', (164, 171))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('high', 'Var', (42, 46))	('relapse', 'CPA', (108, 115))	('FBXO6', 'Gene', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
100308	33578925	Furthermore, LE gene panel score remains a risk factor of ccRCC death after adjusting for age at diagnosis, sex, tumor stage, and tumor grade (Table 3).	('ccRCC death', 'Disease', (58, 69))	('tumor', 'Disease', (113, 118))	('ccRCC death', 'Disease', 'MESH:D003643', (58, 69))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('LE gene panel score', 'Var', (13, 32))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('risk factor', 'Reg', (43, 54))	('tumor', 'Disease', (130, 135))
100341	33578925	Collectively, we provide a comprehensive set of evidence supporting the LE gene panel as a novel prognostic biomarker for multiple cancer types.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('LE gene panel', 'Var', (72, 85))
100352	33578925	FBXO6 can induce Chk1 degradation.	('Chk1', 'Gene', (17, 21))	('degradation', 'biological_process', 'GO:0009056', ('22', '33'))	('FBXO6', 'Var', (0, 5))	('Chk1', 'Gene', '1111', (17, 21))
100373	33578925	Consistent with ARFGEF2 protein expression being detected in a subclass of bone metastatic CRPCs, we observed its differential expression in PCs with TMPRSS2-ERG fusion vs. those without the fusion (Figure 4), mPCs vs. primary PCs (Figure 3B), as well as CRPC vs. androgen-sensitive PCs (Figure 6).	('PC', 'Gene', '5091', (257, 259))	('PC', 'Phenotype', 'HP:0012125', (257, 259))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('fusion', 'Var', (162, 168))	('expression', 'MPA', (127, 137))	('PC', 'Gene', '5091', (141, 143))	('PC', 'Phenotype', 'HP:0012125', (141, 143))	('PC', 'Gene', '5091', (283, 285))	('ERG', 'Gene', (158, 161))	('ARFGEF2', 'Gene', (16, 23))	('PC', 'Gene', '5091', (227, 229))	('PC', 'Phenotype', 'HP:0012125', (227, 229))	('TMPRSS2', 'Gene', '7113', (150, 157))	('PC', 'Gene', '5091', (93, 95))	('PC', 'Gene', '5091', (211, 213))	('PC', 'Phenotype', 'HP:0012125', (93, 95))	('PC', 'Phenotype', 'HP:0012125', (211, 213))	('ERG', 'Gene', '2078', (158, 161))	('TMPRSS2', 'Gene', (150, 157))
100387	31446433	Genetic mutation of PLOD1/2/3 was present in ~3% of ccRCC patients and was associated with significantly poorer prognosis compared with expression of wild-type PLOD1/2/3 (p<0.001).	('Genetic mutation', 'Var', (0, 16))	('PLOD1/2/3', 'Gene', '5351;5352;8985', (20, 29))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('PLOD1/2/3', 'Gene', (20, 29))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('PLOD1/2/3', 'Gene', '5351;5352;8985', (160, 169))	('patients', 'Species', '9606', (58, 66))	('poorer', 'NegReg', (105, 111))	('PLOD1/2/3', 'Gene', (160, 169))
100388	31446433	This study thus identifies tumor expression of wild-type or mutated PLOD1/2/3 mRNA as a potential predictive biomarker for ccRCC patients and sheds light on the underlying molecular pathogenesis of ccRCC.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (198, 203))	('PLOD1/2/3', 'Gene', '5351;5352;8985', (68, 77))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (200, 203))	('RCC', 'Disease', (125, 128))	('PLOD1/2/3', 'Gene', (68, 77))	('tumor', 'Disease', (27, 32))	('patients', 'Species', '9606', (129, 137))	('RCC', 'Disease', 'MESH:C538614', (200, 203))	('RCC', 'Phenotype', 'HP:0005584', (200, 203))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('pathogenesis', 'biological_process', 'GO:0009405', ('182', '194'))	('mutated', 'Var', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
100395	31446433	Thus, it is not surprising that mutations in collagen and/or defects in its synthesis, processing, and assembly may contribute to the development and progression of cancer.	('collagen', 'molecular_function', 'GO:0005202', ('45', '53'))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('contribute', 'Reg', (116, 126))	('synthesis', 'biological_process', 'GO:0009058', ('76', '85'))	('collagen', 'Protein', (45, 53))	('defects', 'NegReg', (61, 68))	('synthesis', 'MPA', (76, 85))	('mutations', 'Var', (32, 41))	('assembly', 'MPA', (103, 111))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('processing', 'MPA', (87, 97))
100400	31446433	Previous studies have implicated mutation or overexpression of PLODs in many human diseases, including neoplasms such as breast, colorectal, and lung carcinomas and Ehlers-Danlos syndrome, an autosomal recessive disorder characterized by joint and skin abnormalities.	('neoplasms', 'Disease', 'MESH:D009369', (103, 112))	('lung carcinomas', 'Disease', (145, 160))	('colorectal', 'Disease', (129, 139))	('overexpression', 'PosReg', (45, 59))	('neoplasms', 'Disease', (103, 112))	('Ehlers-Danlos syndrome', 'Disease', 'MESH:D004535', (165, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('carcinomas', 'Phenotype', 'HP:0030731', (150, 160))	('skin abnormalities', 'Disease', 'MESH:D012868', (248, 266))	('mutation', 'Var', (33, 41))	('breast', 'Disease', (121, 127))	('skin abnormalities', 'Disease', (248, 266))	('PLOD', 'Gene', '5351', (63, 67))	('neoplasms', 'Phenotype', 'HP:0002664', (103, 112))	('human', 'Species', '9606', (77, 82))	('PLOD', 'Gene', (63, 67))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (192, 220))	('Ehlers-Danlos syndrome', 'Disease', (165, 187))	('autosomal recessive disorder', 'Disease', (192, 220))	('lung carcinomas', 'Disease', 'MESH:D008175', (145, 160))	('skin abnormalities', 'Phenotype', 'HP:0000951', (248, 266))
100406	31446433	We also assessed the genetic mutation rate of the three isoforms and determined the prognostic value of wild-type and mutated PLOD1/2/3 in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (139, 144))	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('PLOD1/2/3', 'Gene', '5351;5352;8985', (126, 135))	('mutated', 'Var', (118, 125))	('PLOD1/2/3', 'Gene', (126, 135))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
100437	31446433	As shown in Figure 6, the overall total mutation rate (missense mutations, truncations, amplifications, and deletions) of PLOD1/2/3 in ccRCC patients was 3.1%, with individual rates for PLOD1, PLOD2, and PLOD3 of 0.4%, 1.2%, and 1.5%, respectively (Figure 6A).	('PLOD1', 'Gene', (186, 191))	('mutation', 'Var', (40, 48))	('PLOD1/2/3', 'Gene', '5351;5352;8985', (122, 131))	('PLOD1', 'Gene', '5351', (186, 191))	('PLOD3', 'Gene', (204, 209))	('PLOD3', 'Gene', '8985', (204, 209))	('PLOD1/2/3', 'Gene', (122, 131))	('PLOD1', 'Gene', (122, 127))	('PLOD1', 'Gene', '5351', (122, 127))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('RCC', 'Disease', (137, 140))	('patients', 'Species', '9606', (141, 149))
100438	31446433	Kaplan-Meier analysis of the survival of ccRCC patients with or without PLOD1/2/3 mutations demonstrated that both OS (Figure 6B) and PFS (Figure 6C) were significantly shorter for patients expressing mutated compared with wild-type PLOD1/2/3.	('PLOD1/2/3', 'Gene', '5351;5352;8985', (233, 242))	('PFS', 'MPA', (134, 137))	('mutated', 'Var', (201, 208))	('patients', 'Species', '9606', (47, 55))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('PLOD1/2/3', 'Gene', '5351;5352;8985', (72, 81))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('PLOD1/2/3', 'Gene', (233, 242))	('PLOD1/2/3', 'Gene', (72, 81))	('RCC', 'Disease', (43, 46))	('shorter', 'NegReg', (169, 176))	('patients', 'Species', '9606', (181, 189))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))
100447	31446433	Genetic alterations and abnormal epigenetic regulation are known to affect the development and progression of RCC.	('RCC', 'Disease', (110, 113))	('progression', 'CPA', (95, 106))	('Genetic alterations', 'Var', (0, 19))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('epigenetic regulation', 'Var', (33, 54))	('development', 'CPA', (79, 90))	('regulation', 'biological_process', 'GO:0065007', ('44', '54'))	('affect', 'Reg', (68, 74))
100451	31446433	More than 30 genetic alterations in the PLOD1 gene have been found to cause Ehlers-Danlos syndrome, a group of disorders that affect the connective tissues that support the skin, bones, blood vessels, and many other organs and tissues.	('Ehlers-Danlos syndrome', 'Disease', 'MESH:D004535', (76, 98))	('PLOD1', 'Gene', (40, 45))	('PLOD1', 'Gene', '5351', (40, 45))	('Ehlers-Danlos syndrome', 'Disease', (76, 98))	('cause', 'Reg', (70, 75))	('genetic alterations', 'Var', (13, 32))
100460	31446433	PLOD2 and PLOD3 were among 54 glycoproteins found to be upregulated in colorectal cancer compared with normal tissue.	('PLOD3', 'Gene', (10, 15))	('PLOD3', 'Gene', '8985', (10, 15))	('colorectal cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('PLOD2', 'Var', (0, 5))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('upregulated', 'PosReg', (56, 67))
100461	31446433	PLOD2 and another collagen cross-linking enzyme, lysyl oxidase homolog-2, were shown to be epigenetically regulated by the tumor-suppressive microRNAs miR-26a and miR-26b and to promote metastasis in RCC.	('miR-26b', 'Gene', (163, 170))	('miR-26a', 'Gene', '407015', (151, 158))	('tumor', 'Disease', (123, 128))	('epigenetically', 'Var', (91, 105))	('lysyl oxidase homolog-2', 'Gene', '4017', (49, 72))	('RCC', 'Disease', (200, 203))	('miR-26b', 'Gene', '407017', (163, 170))	('RCC', 'Phenotype', 'HP:0005584', (200, 203))	('metastasis', 'CPA', (186, 196))	('promote', 'PosReg', (178, 185))	('miR-26a', 'Gene', (151, 158))	('RCC', 'Disease', 'MESH:C538614', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('collagen', 'molecular_function', 'GO:0005202', ('18', '26'))	('lysyl oxidase homolog-2', 'Gene', (49, 72))
100464	31446433	In cervical carcinoma, hypoxia- and TGF-beta-induced PLOD2 expression increases the proliferative, adhesive, and invasive capabilities of cells by promoting the epithelial-mesenchymal transition and formation of focal adhesions.	('hypoxia', 'Disease', 'MESH:D000860', (23, 30))	('adhesive', 'CPA', (99, 107))	('epithelial-mesenchymal transition', 'CPA', (161, 194))	('promoting', 'PosReg', (147, 156))	('TGF-beta', 'Gene', '7040', (36, 44))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('161', '194'))	('cervical carcinoma', 'Disease', (3, 21))	('hypoxia', 'Disease', (23, 30))	('increases', 'PosReg', (70, 79))	('proliferative', 'CPA', (84, 97))	('cervical carcinoma', 'Disease', 'MESH:D002575', (3, 21))	('PLOD2', 'Gene', (53, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('TGF-beta', 'Gene', (36, 44))	('formation', 'biological_process', 'GO:0009058', ('199', '208'))	('expression', 'Var', (59, 69))	('invasive capabilities of cells', 'CPA', (113, 143))
100473	31446433	Interestingly, we also showed that genetic mutation of PLOD1/2/3, which is present in ~3% of ccRCC patients, was associated with significantly poorer prognosis compared with wild-type PLOD1/2/3.	('poorer', 'NegReg', (143, 149))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('patients', 'Species', '9606', (99, 107))	('RCC', 'Disease', (95, 98))	('PLOD1/2/3', 'Gene', '5351;5352;8985', (55, 64))	('PLOD1/2/3', 'Gene', '5351;5352;8985', (184, 193))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('PLOD1/2/3', 'Gene', (55, 64))	('PLOD1/2/3', 'Gene', (184, 193))	('genetic mutation', 'Var', (35, 51))
100487	31446433	We analyzed the genomic profiles of PLOD1/2/3 for mutations and putative copy-number alterations (GISTIC) and mRNA expression z-scores (RNASeq V2 RSEM) with a threshold of +-1.8.	('mutations', 'Var', (50, 59))	('PLOD1/2/3', 'Gene', '5351;5352;8985', (36, 45))	('copy-number alterations', 'Var', (73, 96))	('PLOD1/2/3', 'Gene', (36, 45))
100529	31380284	PSMs have been recognized as an adverse prognostic sign for disease prognosis or local recurrence, and thus, NSS may theoretically decrease the probability of complete tumor resection.	('tumor', 'Disease', (168, 173))	('PSMs', 'Disease', (0, 4))	('NSS', 'Var', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('decrease', 'NegReg', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
100557	30655922	Sel-ADC value of a <= 1.405 mm2/s has a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy value of 78.6, 72.2, 73.87, 77.13, and 75.4, respectively, to differentiate high-grade from low-grade ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (235, 240))	('mm2', 'Gene', '10687', (28, 31))	('mm2', 'Gene', (28, 31))	('high-grade', 'Disease', (209, 219))	('RCC', 'Disease', (237, 240))	('<= 1.405', 'Var', (19, 27))	('RCC', 'Disease', 'MESH:C538614', (237, 240))
100606	30655922	The mean Sel-ADC value was significantly lower in Fuhrman grade 3 than Fuhrman grade 1 ccRCCs (p = 0.004) (Table 2).	('Fuhrman grade 3', 'Var', (50, 65))	('Sel-ADC value', 'MPA', (9, 22))	('lower', 'NegReg', (41, 46))	('RCC', 'Disease', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))
100609	30655922	A Sel-ADC value of a <= 1.405 mm2/s has a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy value of 78.6, 72.2, 73.87, 77.13, and 75.4, respectively, to differentiate high-grade ccRCC from low-grade ccRCC.	('RCC', 'Disease', (224, 227))	('RCC', 'Disease', 'MESH:C538614', (224, 227))	('ccRCC', 'Phenotype', 'HP:0006770', (222, 227))	('RCC', 'Disease', (245, 248))	('RCC', 'Disease', 'MESH:C538614', (245, 248))	('ccRCC', 'Phenotype', 'HP:0006770', (243, 248))	('mm2', 'Gene', '10687', (30, 33))	('mm2', 'Gene', (30, 33))	('<= 1.405', 'Var', (21, 29))
100654	27530247	Characterization of VHL missense mutations in sporadic clear cell renal cell carcinoma: hotspots, affected binding domains, functional impact on pVHL and therapeutic relevance The VHL protein (pVHL) is a multiadaptor protein that interacts with more than 30 different binding partners involved in many oncogenic processes.	('protein', 'cellular_component', 'GO:0003675', ('184', '191'))	('missense mutations', 'Var', (24, 42))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (66, 86))	('binding', 'molecular_function', 'GO:0005488', ('107', '114'))	('VHL', 'Gene', (180, 183))	('protein', 'cellular_component', 'GO:0003675', ('217', '224'))	('interacts', 'Interaction', (230, 239))	('VHL', 'Gene', (20, 23))	('renal cell carcinoma', 'Disease', (66, 86))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (66, 86))	('VHL', 'Gene', (146, 149))	('VHL', 'Gene', '7428', (180, 183))	('VHL', 'Gene', (194, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('pVHL', 'Gene', '7428', (193, 197))	('pVHL', 'Gene', (193, 197))	('VHL', 'Gene', '7428', (20, 23))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (55, 86))	('VHL', 'Gene', '7428', (146, 149))	('pVHL', 'Gene', '7428', (145, 149))	('binding', 'molecular_function', 'GO:0005488', ('268', '275'))	('VHL', 'Gene', '7428', (194, 197))	('pVHL', 'Gene', (145, 149))
100655	27530247	About 70 % of clear cell renal cell carcinoma (ccRCC) have VHL mutations with varying impact on pVHL function.	('mutations', 'Var', (63, 72))	('RCC', 'Disease', (49, 52))	('clear cell renal cell carcinoma', 'Disease', (14, 45))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (14, 45))	('VHL', 'Gene', '7428', (97, 100))	('pVHL', 'Gene', '7428', (96, 100))	('VHL', 'Gene', '7428', (59, 62))	('pVHL', 'Gene', (96, 100))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (14, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (25, 45))	('VHL', 'Gene', (59, 62))	('VHL', 'Gene', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
100657	27530247	In contrast to nonsense and frameshift mutations that highly likely nullify pVHL multipurpose functions, missense mutations may rather specifically influence the binding capability of pVHL to its partners.	('missense mutations', 'Var', (105, 123))	('binding', 'molecular_function', 'GO:0005488', ('162', '169'))	('pVHL', 'Gene', '7428', (76, 80))	('pVHL', 'Gene', (76, 80))	('pVHL', 'Gene', '7428', (184, 188))	('pVHL', 'Gene', (184, 188))	('binding', 'Interaction', (162, 169))	('influence', 'Reg', (148, 157))	('nullify', 'NegReg', (68, 75))
100658	27530247	In this study we focused on the VHL missense mutation pattern in ccRCC, and studied their potential effects on pVHL protein stability and binding partners and discussed treatment options.	('VHL', 'Gene', (32, 35))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('VHL', 'Gene', '7428', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('pVHL', 'Gene', '7428', (111, 115))	('VHL', 'Gene', (112, 115))	('pVHL', 'Gene', (111, 115))	('VHL', 'Gene', '7428', (112, 115))	('missense mutation', 'Var', (36, 53))	('binding', 'molecular_function', 'GO:0005488', ('138', '145'))
100659	27530247	We sequenced VHL in 360 sporadic ccRCC FFPE samples and compared observed and expected frequency of missense mutations in 32 different binding domains.	('RCC', 'Disease', (35, 38))	('VHL', 'Gene', (13, 16))	('binding', 'molecular_function', 'GO:0005488', ('135', '142'))	('VHL', 'Gene', '7428', (13, 16))	('missense mutations', 'Var', (100, 118))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
100660	27530247	The response to HIF-related, anti-angiogenic treatment of 30 patients with known VHL mutation status was also investigated.	('patients', 'Species', '9606', (61, 69))	('VHL', 'Gene', '7428', (81, 84))	('VHL', 'Gene', (81, 84))	('mutation', 'Var', (85, 93))
100661	27530247	We identified 254 VHL mutations (68.3 % of the cases) including 89 missense mutations (35 %).	('VHL', 'Gene', '7428', (18, 21))	('VHL', 'Gene', (18, 21))	('mutations', 'Var', (22, 31))	('missense mutations', 'Var', (67, 85))
100662	27530247	Codons Ser65, Asn78, Ser80, Trp117 and Leu184 represented hotspots and missense mutations in Trp117 and Leu 184 were predicted to highly destabilize pVHL.	('missense mutations', 'Var', (71, 89))	('Ser65', 'Chemical', '-', (7, 12))	('Trp117', 'Chemical', '-', (93, 99))	('Leu', 'Chemical', 'MESH:D007930', (104, 107))	('Ser', 'cellular_component', 'GO:0005790', ('21', '24'))	('Asn78', 'Chemical', '-', (14, 19))	('Ser80', 'Chemical', '-', (21, 26))	('destabilize', 'NegReg', (137, 148))	('Leu 184', 'Var', (104, 111))	('Ser', 'cellular_component', 'GO:0005790', ('7', '10'))	('Leu184', 'Chemical', '-', (39, 45))	('Ser80', 'Var', (21, 26))	('pVHL', 'Gene', '7428', (149, 153))	('Trp117', 'Gene', (93, 99))	('pVHL', 'Gene', (149, 153))	('Leu', 'Chemical', 'MESH:D007930', (39, 42))	('Trp117', 'Chemical', '-', (28, 34))	('Leu184', 'Var', (39, 45))
100663	27530247	About 40 % of VHL missense mutations were predicted to cause severe protein malfunction.	('protein malfunction', 'MPA', (68, 87))	('VHL', 'Gene', (14, 17))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('cause', 'Reg', (55, 60))	('missense mutations', 'Var', (18, 36))	('VHL', 'Gene', '7428', (14, 17))
100666	27530247	VHL missense mutations may exert mild, moderate or strong impact on pVHL stability.	('missense mutations', 'Var', (4, 22))	('impact', 'Reg', (58, 64))	('VHL', 'Gene', (0, 3))	('pVHL', 'Gene', '7428', (68, 72))	('VHL', 'Gene', (69, 72))	('VHL', 'Gene', '7428', (0, 3))	('pVHL', 'Gene', (68, 72))	('VHL', 'Gene', '7428', (69, 72))
100667	27530247	Besides the HIF binding domain, other pVHL binding sites seem to be non-randomly altered by missense mutations.	('pVHL', 'Gene', (38, 42))	('binding', 'molecular_function', 'GO:0005488', ('16', '23'))	('binding', 'molecular_function', 'GO:0005488', ('43', '50'))	('pVHL', 'Gene', '7428', (38, 42))	('missense mutations', 'Var', (92, 110))	('altered', 'Reg', (81, 88))
100668	27530247	In contrast to LOF mutations that affect all the different pathways normally controlled by pVHL, missense mutations may be rather appropriate for designing tailor-made treatment strategies for ccRCC.	('RCC', 'Disease', (195, 198))	('pVHL', 'Gene', '7428', (91, 95))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('pVHL', 'Gene', (91, 95))	('missense mutations', 'Var', (97, 115))
100670	27530247	There are three main RCC subtypes that are determined by their histologic features: papillary RCC, chromophobe RCC and clear cell RCC (ccRCC), the latter is known to be closely related with mutation of the Von Hippel-Lindau gene (VHL).	('mutation', 'Var', (190, 198))	('related', 'Reg', (177, 184))	('RCC', 'Disease', (94, 97))	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('chromophobe RCC', 'Disease', (99, 114))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('Von Hippel-Lindau', 'Gene', '7428', (206, 223))	('RCC', 'Disease', (130, 133))	('Von Hippel-Lindau', 'Gene', (206, 223))	('VHL', 'Gene', (230, 233))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('RCC', 'Disease', (21, 24))	('chromophobe RCC', 'Disease', 'MESH:C538614', (99, 114))	('VHL', 'Gene', '7428', (230, 233))
100678	27530247	VHL has been shown to be affected in more than 80 % of the ccRCC cases, either by allelic deletion, promoter methylation (19 %), or mutations (70-80 %).	('mutations', 'Var', (132, 141))	('affected', 'Reg', (25, 33))	('methylation', 'biological_process', 'GO:0032259', ('109', '120'))	('VHL', 'Gene', (0, 3))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('VHL', 'Gene', '7428', (0, 3))	('promoter methylation', 'Var', (100, 120))
100679	27530247	Given the multiple functions of pVHL the inactivation of VHL is a critical point in the initiation of tumor formation in the context of ccRCC.	('RCC', 'Disease', (138, 141))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('VHL', 'Gene', (33, 36))	('inactivation', 'Var', (41, 53))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('VHL', 'Gene', (57, 60))	('pVHL', 'Gene', '7428', (32, 36))	('VHL', 'Gene', '7428', (33, 36))	('formation', 'biological_process', 'GO:0009058', ('108', '117'))	('pVHL', 'Gene', (32, 36))	('VHL', 'Gene', '7428', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
100680	27530247	To date, controversial data exist about correlations between VHL mutations and pathological parameters, overall and disease-free survival.	('VHL', 'Gene', '7428', (61, 64))	('VHL', 'Gene', (61, 64))	('mutations', 'Var', (65, 74))
100681	27530247	Whereas frameshift and nonsense mutations highly likely abrogate pVHL function, the effects on pVHL stability and binding ability of missense mutations occurring in about 25 % of ccRCC patients are rather unclear.	('pVHL', 'Gene', '7428', (65, 69))	('abrogate', 'NegReg', (56, 64))	('pVHL', 'Gene', (65, 69))	('frameshift', 'Var', (8, 18))	('pVHL', 'Gene', '7428', (95, 99))	('binding', 'molecular_function', 'GO:0005488', ('114', '121'))	('nonsense mutations', 'Var', (23, 41))	('patients', 'Species', '9606', (185, 193))	('missense', 'Var', (133, 141))	('RCC', 'Disease', 'MESH:C538614', (181, 184))	('RCC', 'Disease', (181, 184))	('pVHL', 'Gene', (95, 99))
100682	27530247	Such mutations may not, partly or fully affect interacting functions of pVHL, which subsequently influence differently biological pathways involved in tumor carcinogenesis.	('biological pathways', 'Pathway', (119, 138))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor carcinogenesis', 'Disease', (151, 171))	('tumor carcinogenesis', 'Disease', 'MESH:D063646', (151, 171))	('pVHL', 'Gene', '7428', (72, 76))	('mutations', 'Var', (5, 14))	('pVHL', 'Gene', (72, 76))	('affect', 'Reg', (40, 46))	('influence', 'Reg', (97, 106))
100683	27530247	Evidence of mutant VHL expression at the RNA level as well as at the protein level was described in other studies.	('RNA', 'cellular_component', 'GO:0005562', ('41', '44'))	('VHL', 'Gene', (19, 22))	('mutant', 'Var', (12, 18))	('VHL', 'Gene', '7428', (19, 22))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))
100684	27530247	Although pVHL mutant forms tend to rapidly degrade, they still may exhibit partial function.	('mutant', 'Var', (14, 20))	('pVHL', 'Gene', (9, 13))	('pVHL', 'Gene', '7428', (9, 13))	('degrade', 'NegReg', (43, 50))
100685	27530247	We therefore hypothesize that missense mutations exert different impact on the binding capability of pVHL targets and its pathways which may lead to diverse tumor aggressiveness and response to treatment.	('tumor aggressiveness', 'Disease', (157, 177))	('aggressiveness', 'Phenotype', 'HP:0000718', (163, 177))	('pVHL', 'Gene', '7428', (101, 105))	('pathways', 'Pathway', (122, 130))	('missense mutations', 'Var', (30, 48))	('pVHL', 'Gene', (101, 105))	('binding', 'molecular_function', 'GO:0005488', ('79', '86'))	('binding', 'Interaction', (79, 86))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (157, 177))	('lead to', 'Reg', (141, 148))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('impact', 'Reg', (65, 71))
100686	27530247	As treatments currently used in clinics for the metastatic disease are mostly anti-angiogenic tyrosine-kinase inhibitors targeting VEGFR and PDGFR to counter the upregulation of HIF caused by inactivation of VHL, it is of considerable interest to improve our knowledge on the additional HIF non-related pathways affected by VHL mutations.	('inactivation', 'Var', (192, 204))	('VHL', 'Gene', '7428', (324, 327))	('VHL', 'Gene', (208, 211))	('PDGFR', 'Gene', (141, 146))	('upregulation', 'PosReg', (162, 174))	('PDGFR', 'Gene', '5159', (141, 146))	('VEGFR', 'Gene', '3791', (131, 136))	('VHL', 'Gene', '7428', (208, 211))	('VHL', 'Gene', (324, 327))	('VEGFR', 'Gene', (131, 136))
100688	27530247	We particularly focused on missense mutations and their potential biological effects on the pathways regulated by pVHL's interactors as well as their impact on anti-angiogenic treatment response.	('pathways', 'Pathway', (92, 100))	('impact', 'Reg', (150, 156))	('missense mutations', 'Var', (27, 45))	('effects', 'Reg', (77, 84))	('pVHL', 'Gene', '7428', (114, 118))	('pVHL', 'Gene', (114, 118))
100689	27530247	The identification of ccRCC based on the pathways potentially affected by VHL missense mutations may be important for selecting appropriate targeted therapies.	('RCC', 'Disease', (24, 27))	('missense mutations', 'Var', (78, 96))	('VHL', 'Gene', (74, 77))	('VHL', 'Gene', '7428', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
100701	27530247	All VHL mutations were validated by a second independent PCR and sequence analysis.	('VHL', 'Gene', '7428', (4, 7))	('VHL', 'Gene', (4, 7))	('mutations', 'Var', (8, 17))
100702	27530247	ddG < -2.0: highly destabilizing and disease-associated -2.0 <= ddG < - 1.0: destabilizing -1.0 <= ddG < -0.5: slightly destabilizing -0.5 <= ddG <= 0.5: neutral 0.5 < ddG <= 1: slightly stabilizing 1.0 < ddG <= 2: stabilizing ddG > 2.0: highly stabilizing and disease-associated The effect of missense mutation on the stability of pVHL and its potential association to the disease were predicted in silico using the program Site Directed Mutator (SDM).	('pVHL', 'Gene', (332, 336))	('pVHL', 'Gene', '7428', (332, 336))	('missense mutation', 'Var', (294, 311))
100703	27530247	The crystal structure of pVHL was isolated from VCB complex 1 lm8.pdb crystal structure (Piccolo database) and uploaded into the program to calculate the thermodynamic change (ddG) occurring after modification of one amino acid according to the main chain conformation, solvent accessibility and hydrogen bonding class.	('pVHL', 'Gene', '7428', (25, 29))	('modification', 'Var', (197, 209))	('pVHL', 'Gene', (25, 29))	('lm8.pdb', 'Gene', (62, 69))	('hydrogen', 'Chemical', 'MESH:D006859', (296, 304))	('VCB complex', 'cellular_component', 'GO:0030891', ('48', '59'))
100705	27530247	Preferentially mutated codons of VHL were determined by calculating observed and expected frequencies of 88 out of 89 missense mutations.	('VHL', 'Gene', '7428', (33, 36))	('VHL', 'Gene', (33, 36))	('missense', 'Var', (118, 126))
100706	27530247	Two hundred forty-six of 360 (68.3 %) sequenced ccRCC were mutated.	('RCC', 'Disease', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('mutated', 'Var', (59, 66))
100709	27530247	Since deletions, insertions, splice site mutations and nonsense mutations most likely abrogate most if not all pVHL functions, they were referred to as loss of function (LOF) mutations.	('abrogate', 'NegReg', (86, 94))	('nonsense mutations', 'Var', (55, 73))	('deletions', 'Var', (6, 15))	('insertions', 'Var', (17, 27))	('pVHL', 'Gene', '7428', (111, 115))	('pVHL', 'Gene', (111, 115))	('loss of function', 'NegReg', (152, 168))	('splice site mutations', 'Var', (29, 50))
100710	27530247	An overview of VHL LOF and missense mutation sites in the pVHL sequence and the affected binding domains of pVHL's interactors are shown in Fig.	('VHL', 'Gene', '7428', (59, 62))	('binding', 'molecular_function', 'GO:0005488', ('89', '96'))	('pVHL', 'Gene', '7428', (108, 112))	('pVHL', 'Gene', '7428', (58, 62))	('VHL', 'Gene', (15, 18))	('missense mutation sites', 'Var', (27, 50))	('pVHL', 'Gene', (108, 112))	('pVHL', 'Gene', (58, 62))	('LOF', 'NegReg', (19, 22))	('VHL', 'Gene', (109, 112))	('VHL', 'Gene', '7428', (15, 18))	('VHL', 'Gene', '7428', (109, 112))	('VHL', 'Gene', (59, 62))
100713	27530247	Fourteen mutations (5.5 %) were located at Ser65, nine (3.5 %) at Trp117, 8 (3.1 %) at Phe76, 7 (2.8 % each) at Asn78, Ser80, Leu135, and Arg161, 6 (2.4 %) at His115, and 5 mutations were at Gly114 and Leu184 (2 % each).	('His115', 'Chemical', '-', (159, 165))	('Ser80', 'Chemical', '-', (119, 124))	('Ser80', 'Var', (119, 124))	('Leu135', 'Var', (126, 132))	('Arg161', 'Var', (138, 144))	('Gly114', 'Chemical', '-', (191, 197))	('Ser', 'cellular_component', 'GO:0005790', ('43', '46'))	('Leu184', 'Var', (202, 208))	('Ser65', 'Var', (43, 48))	('Arg161', 'Chemical', '-', (138, 144))	('Phe76', 'Chemical', '-', (87, 92))	('Leu184', 'Chemical', '-', (202, 208))	('Ser65', 'Chemical', '-', (43, 48))	('Gly114', 'Var', (191, 197))	('Asn78', 'Chemical', '-', (112, 117))	('Leu135', 'Chemical', '-', (126, 132))	('Trp117', 'Chemical', '-', (66, 72))	('Ser', 'cellular_component', 'GO:0005790', ('119', '122'))
100714	27530247	The codons that were most often affected by missense mutations were Ser65, Asn78, Ser80 (six mutations each, 6.7 %), Trp117 and Leu184 (five mutations each, 5.6 %).	('Ser', 'cellular_component', 'GO:0005790', ('82', '85'))	('Asn78', 'Gene', (75, 80))	('Leu184', 'Chemical', '-', (128, 134))	('Trp117', 'Gene', (117, 123))	('missense mutations', 'Var', (44, 62))	('Ser80', 'Gene', (82, 87))	('Leu184', 'Var', (128, 134))	('Ser65', 'Gene', (68, 73))	('Trp117', 'Chemical', '-', (117, 123))	('Ser80', 'Chemical', '-', (82, 87))	('Ser65', 'Chemical', '-', (68, 73))	('Ser', 'cellular_component', 'GO:0005790', ('68', '71'))	('Asn78', 'Chemical', '-', (75, 80))
100715	27530247	Codons Phe76 and Leu135 showed only LOF mutations.	('Leu135', 'Chemical', '-', (17, 23))	('Phe76', 'Var', (7, 12))	('LOF', 'NegReg', (36, 39))	('Leu135', 'Var', (17, 23))	('Phe76', 'Chemical', '-', (7, 12))
100716	27530247	We next assigned 88 of 89 missense mutations to the putative binding domains of 32 pVHL interactors.	('missense mutations', 'Var', (26, 44))	('pVHL', 'Gene', (83, 87))	('binding', 'molecular_function', 'GO:0005488', ('61', '68'))	('pVHL', 'Gene', '7428', (83, 87))
100717	27530247	As expected, large binding domains of interacting partners covering more than 60 amino acids of pVHL showed relative high frequencies of mutations.	('pVHL', 'Gene', '7428', (96, 100))	('pVHL', 'Gene', (96, 100))	('mutations', 'Var', (137, 146))	('binding', 'molecular_function', 'GO:0005488', ('19', '26'))	('binding', 'Interaction', (19, 26))
100718	27530247	Between 44 and 100 % of the missense mutations were located in the VHLAK (100 %), HIF1AN (77.3 %), BCL2L11 (70.5 %), RPB1 (60.2 %), and RPB7 (44.3 %) binding domains.	('VHLAK', 'Gene', (67, 72))	('RPB1', 'Gene', '5430', (117, 121))	('RPB7', 'Gene', (136, 140))	('RPB1', 'Gene', (117, 121))	('HIF1AN', 'Gene', (82, 88))	('BCL2', 'molecular_function', 'GO:0015283', ('99', '103'))	('HIF1AN', 'Gene', '55662', (82, 88))	('VHLAK', 'Gene', '10168', (67, 72))	('missense mutations', 'Var', (28, 46))	('BCL2L11', 'Gene', '10018', (99, 106))	('binding', 'molecular_function', 'GO:0005488', ('150', '157'))	('BCL2L11', 'Gene', (99, 106))	('RPB7', 'Gene', '5436', (136, 140))
100719	27530247	Notably, about half of the missense mutations (45/88, 51.1 %) resided in the HIF1alpha and HIF2alpha (EPAS1) binding domain comprising 51 amino acids.	('EPAS1', 'Gene', '2034', (102, 107))	('HIF2alpha', 'Gene', '2034', (91, 100))	('EPAS1', 'Gene', (102, 107))	('binding', 'molecular_function', 'GO:0005488', ('109', '116'))	('HIF1alpha', 'Gene', '3091', (77, 86))	('missense mutations', 'Var', (27, 45))	('HIF2alpha', 'Gene', (91, 100))	('HIF1alpha', 'Gene', (77, 86))
100720	27530247	Between 20 and 35 % of the missense mutations were located in the binding domains of PRKCD, VDU1/2, PRKCZ, EEF1A1, Nur77 and CARD9 (25-60 amino acids).	('binding', 'molecular_function', 'GO:0005488', ('66', '73'))	('PRKCZ', 'Gene', (100, 105))	('VDU1/2', 'Gene', '23032;10868', (92, 98))	('VDU1/2', 'Gene', (92, 98))	('PRKCZ', 'Gene', '5590', (100, 105))	('PRKCD', 'Gene', (85, 90))	('missense mutations', 'Var', (27, 45))	('PRKCD', 'Gene', '5580', (85, 90))	('Nur77', 'Gene', (115, 120))	('EEF1A1', 'Gene', (107, 113))	('CARD9', 'Gene', (125, 130))	('CARD9', 'Gene', '64170', (125, 130))	('EEF1A1', 'Gene', '1915', (107, 113))	('Nur77', 'Gene', '3164', (115, 120))
100721	27530247	The frequencies of missense mutations found in the smaller binding domains (9-28 amino acids) of JADE1, SP1, KIF3A, TUBA4A, HuR, aPKC-lambda/iota, TBP1, CCT-zeta-2, EloC and p53 ranged between 8 and 23 %.	('HuR', 'Gene', '1994', (124, 127))	('TBP1', 'Gene', '100874116', (147, 151))	('CCT-zeta-2', 'Gene', '10693', (153, 163))	('aPKC-lambda/iota', 'Gene', (129, 145))	('CCT-zeta-2', 'Gene', (153, 163))	('TBP1', 'Gene', (147, 151))	('KIF3A', 'Gene', '11127', (109, 114))	('p53', 'Gene', '7157', (174, 177))	('binding', 'molecular_function', 'GO:0005488', ('59', '66'))	('binding', 'Interaction', (59, 66))	('p53', 'Gene', (174, 177))	('SP1', 'Gene', (104, 107))	('TUBA4A', 'Gene', '7277', (116, 122))	('JADE1', 'Gene', (97, 102))	('KIF3A', 'Gene', (109, 114))	('TUBA4A', 'Gene', (116, 122))	('missense mutations', 'Var', (19, 37))	('EloC', 'Gene', '6921', (165, 169))	('HuR', 'Gene', (124, 127))	('JADE1', 'Gene', '79960', (97, 102))	('EloC', 'Gene', (165, 169))	('aPKC-lambda/iota', 'Gene', '5584', (129, 145))
100722	27530247	As the first 54 amino acids of pVHL were not covered by Sanger sequencing, the expected number of missense mutation per codon was 0.55.	('pVHL', 'Gene', (31, 35))	('missense', 'Var', (98, 106))	('pVHL', 'Gene', '7428', (31, 35))
100723	27530247	We found that the binding domains showing significantly higher rates of missense mutations were for pVHL interactors HIF1AN, BCL2L11, HIF1alpha, HIF2alpha, RPB1, PRKCZ, aPKC-lambda/iota, EEF1A1, CCT-zeta-2, and Cullin2.	('PRKCZ', 'Gene', (162, 167))	('EEF1A1', 'Gene', '1915', (187, 193))	('aPKC-lambda/iota', 'Gene', (169, 185))	('RPB1', 'Gene', '5430', (156, 160))	('PRKCZ', 'Gene', '5590', (162, 167))	('BCL2L11', 'Gene', '10018', (125, 132))	('BCL2', 'molecular_function', 'GO:0015283', ('125', '129'))	('HIF1AN', 'Gene', (117, 123))	('missense mutations', 'Var', (72, 90))	('Cullin2', 'Gene', '8453', (211, 218))	('pVHL', 'Gene', '7428', (100, 104))	('EEF1A1', 'Gene', (187, 193))	('pVHL', 'Gene', (100, 104))	('BCL2L11', 'Gene', (125, 132))	('RPB1', 'Gene', (156, 160))	('HIF1AN', 'Gene', '55662', (117, 123))	('binding', 'molecular_function', 'GO:0005488', ('18', '25'))	('HIF2alpha', 'Gene', (145, 154))	('Cullin2', 'Gene', (211, 218))	('HIF1alpha', 'Gene', '3091', (134, 143))	('CCT-zeta-2', 'Gene', '10693', (195, 205))	('HIF1alpha', 'Gene', (134, 143))	('CCT-zeta-2', 'Gene', (195, 205))	('aPKC-lambda/iota', 'Gene', '5584', (169, 185))	('higher', 'PosReg', (56, 62))	('HIF2alpha', 'Gene', '2034', (145, 154))
100724	27530247	pVHL binding partners with involved pathways and the ratio of observed versus expected frequency of missense mutations are shown in Table 2.	('pVHL', 'Gene', '7428', (0, 4))	('pVHL', 'Gene', (0, 4))	('missense', 'Var', (100, 108))	('binding', 'molecular_function', 'GO:0005488', ('5', '12'))	('binding', 'Interaction', (5, 12))
100726	27530247	In this context, ddG is an indicator of pVHL stability and suggests whether or not a missense mutation causes deleterious functional impact and is associated with disease.	('associated', 'Reg', (147, 157))	('disease', 'Disease', (163, 170))	('pVHL', 'Gene', '7428', (40, 44))	('pVHL', 'Gene', (40, 44))	('missense mutation', 'Var', (85, 102))
100727	27530247	A large proportion of the VHL missense mutations (60/88, 68 %) were predicted to destabilize the resulting protein (ddG < -0.5), eleven mutations (11/88, 12.5 %) had a neutral effect (-0.5 < ddG < 0.5), and 17 had a stabilizing effect (17/88, 19.3 %) on pVHL.	('pVHL', 'Gene', '7428', (254, 258))	('pVHL', 'Gene', (254, 258))	('VHL', 'Gene', (26, 29))	('destabilize', 'NegReg', (81, 92))	('missense mutations', 'Var', (30, 48))	('VHL', 'Gene', '7428', (26, 29))	('protein', 'Protein', (107, 114))	('VHL', 'Gene', (255, 258))	('VHL', 'Gene', '7428', (255, 258))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
100728	27530247	Thirty-three of 88 (37.5 %) missense mutations were highly destabilizing and only 2 (2.3 %), were highly stabilizing, suggesting that about 40 % of VHL missense mutations were predicted to cause protein malfunction (ddG < -2 and ddG > 2 respectively).	('VHL', 'Gene', (148, 151))	('missense mutations', 'Var', (152, 170))	('VHL', 'Gene', '7428', (148, 151))	('protein malfunction', 'MPA', (195, 214))	('cause', 'Reg', (189, 194))	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))
100729	27530247	VHL missense mutations and their predicted effects on pVHL stability and association with disease are listed in Additional file 5: Table S3.	('missense mutations', 'Var', (4, 22))	('VHL', 'Gene', (0, 3))	('pVHL', 'Gene', '7428', (54, 58))	('VHL', 'Gene', (55, 58))	('VHL', 'Gene', '7428', (0, 3))	('pVHL', 'Gene', (54, 58))	('VHL', 'Gene', '7428', (55, 58))
100730	27530247	Notably, all of the hotspot missense mutations found in codons Trp117 and Leu184 were destabilizing and 3 out of 5 and 5 out of 5 mutations, respectively, were predicted to cause protein malfunction.	('protein malfunction', 'MPA', (179, 198))	('Leu184', 'Var', (74, 80))	('missense', 'Var', (28, 36))	('Trp117', 'Gene', (63, 69))	('Leu184', 'Chemical', '-', (74, 80))	('cause', 'Reg', (173, 178))	('Trp117', 'Chemical', '-', (63, 69))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))
100731	27530247	In addition, all missense mutations in codon Ser80 destabilize pVHL, codon Ser65 had 3 destabilizing and 3 stabilizing mutations, and codon Ser65 had 2 destabilizing and 4 stabilizing mutations.	('Ser', 'cellular_component', 'GO:0005790', ('75', '78'))	('pVHL', 'Gene', '7428', (63, 67))	('Ser', 'cellular_component', 'GO:0005790', ('45', '48'))	('pVHL', 'Gene', (63, 67))	('Ser', 'cellular_component', 'GO:0005790', ('140', '143'))	('missense mutations', 'Var', (17, 35))	('Ser80', 'Chemical', '-', (45, 50))	('codon Ser80', 'Gene', (39, 50))	('codon Ser65', 'Gene', (69, 80))	('destabilize', 'NegReg', (51, 62))	('Ser65', 'Chemical', '-', (75, 80))	('Ser65', 'Chemical', '-', (140, 145))
100734	27530247	Treatment administered, response, VHL mutation status, tumor stage and grade are listed in Table 3.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('VHL', 'Gene', (34, 37))	('mutation', 'Var', (38, 46))	('VHL', 'Gene', '7428', (34, 37))
100735	27530247	The proportion of responders (stable + regressive disease) was 52.6 % for the LOF (10/19), 33.3 % for the missense mutations (2/6), and 40 % for the wild-type VHL (2/5).	('missense mutations', 'Var', (106, 124))	('regressive disease', 'Disease', 'MESH:C537770', (39, 57))	('regressive disease', 'Disease', (39, 57))	('VHL', 'Gene', (159, 162))	('VHL', 'Gene', '7428', (159, 162))
100737	27530247	It is widely accepted that in almost all ccRCC both VHL alleles are inactivated by chromosome 3p loss, mutation and hypermethylation.	('VHL', 'Gene', '7428', (52, 55))	('loss', 'NegReg', (97, 101))	('chromosome', 'cellular_component', 'GO:0005694', ('83', '93'))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('mutation', 'Var', (103, 111))	('hypermethylation', 'Var', (116, 132))	('VHL', 'Gene', (52, 55))
100738	27530247	In contrast to frameshifts, nonsense codons and alteration of splice sites, which highly likely cause loss of function of pVHL in about 50 % of these tumors, the consequences of VHL missense mutations present in 25 % may significantly vary.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('VHL', 'Gene', (123, 126))	('missense mutations', 'Var', (182, 200))	('VHL', 'Gene', (178, 181))	('VHL', 'Gene', '7428', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('pVHL', 'Gene', '7428', (122, 126))	('VHL', 'Gene', '7428', (178, 181))	('pVHL', 'Gene', (122, 126))
100742	27530247	The high mutation rate in our ccRCC cohort confirmed previous results showing that VHL alteration is rather independent of heterogeneity and ubiquitously present in ccRCC.	('VHL', 'Gene', '7428', (83, 86))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('RCC', 'Disease', (167, 170))	('alteration', 'Var', (87, 97))	('VHL', 'Gene', (83, 86))
100743	27530247	In cases with intratumoral heterogeneity related to VHL, own studies have shown the presence of de novo VHL mutations.	('VHL', 'Gene', '7428', (104, 107))	('VHL', 'Gene', '7428', (52, 55))	('mutations', 'Var', (108, 117))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('VHL', 'Gene', (104, 107))	('VHL', 'Gene', (52, 55))
100744	27530247	Minor populations of tumor cells with VHL mutations are extremely rare.	('tumor', 'Disease', (21, 26))	('VHL', 'Gene', '7428', (38, 41))	('VHL', 'Gene', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('mutations', 'Var', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
100748	27530247	The frequency of VHL mutations found in about 70 % of the patients was comparable to previously published data.	('patients', 'Species', '9606', (58, 66))	('VHL', 'Gene', '7428', (17, 20))	('VHL', 'Gene', (17, 20))	('mutations', 'Var', (21, 30))
100750	27530247	Although most of the VHL mutations were private, we found several hotspot mutations in our cohort.	('mutations', 'Var', (25, 34))	('VHL', 'Gene', '7428', (21, 24))	('VHL', 'Gene', (21, 24))
100751	27530247	Between 5 and 14 mutations affected codons Ser65, Phe76, Asn78, Ser80, Gly114, His115, Trp117, Leu135, Arg161 and Leu184.	('Ser80', 'Gene', (64, 69))	('His115', 'Var', (79, 85))	('Leu135', 'Chemical', '-', (95, 101))	('Asn78', 'Chemical', '-', (57, 62))	('Arg161', 'Var', (103, 109))	('Trp117', 'Chemical', '-', (87, 93))	('Asn78', 'Gene', (57, 62))	('Phe76', 'Chemical', '-', (50, 55))	('Leu184', 'Chemical', '-', (114, 120))	('Arg161', 'Chemical', '-', (103, 109))	('Trp117', 'Var', (87, 93))	('Ser65', 'Var', (43, 48))	('Leu135', 'Var', (95, 101))	('Ser', 'cellular_component', 'GO:0005790', ('64', '67'))	('Gly114', 'Chemical', '-', (71, 77))	('Ser', 'cellular_component', 'GO:0005790', ('43', '46'))	('affected', 'Reg', (27, 35))	('His115', 'Chemical', '-', (79, 85))	('Gly114', 'Var', (71, 77))	('Leu184', 'Var', (114, 120))	('Ser80', 'Chemical', '-', (64, 69))	('Ser65', 'Chemical', '-', (43, 48))	('Phe76', 'Var', (50, 55))
100752	27530247	Interestingly, approximately one third of the 88 missense mutations occurred at codons Ser65, Asn78, Ser80, Trp117 and Leu184 (5-6 mutations per codon).	('Ser', 'cellular_component', 'GO:0005790', ('101', '104'))	('missense', 'Var', (49, 57))	('Ser65', 'Chemical', '-', (87, 92))	('Leu184', 'Var', (119, 125))	('occurred', 'Reg', (68, 76))	('Asn78', 'Chemical', '-', (94, 99))	('Ser80', 'Chemical', '-', (101, 106))	('Trp117', 'Gene', (108, 114))	('Ser80', 'Var', (101, 106))	('Leu184', 'Chemical', '-', (119, 125))	('Trp117', 'Chemical', '-', (108, 114))	('Ser', 'cellular_component', 'GO:0005790', ('87', '90'))	('Asn78', 'Gene', (94, 99))
100753	27530247	Those missense mutations have already been described in the VHL mutations database-UMD and in the COSMIC database for ccRCC where they represent about 10 % of all VHL mutations.	('VHL', 'Gene', '7428', (163, 166))	('VHL', 'Gene', (60, 63))	('missense mutations', 'Var', (6, 24))	('VHL', 'Gene', '7428', (60, 63))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('VHL', 'Gene', (163, 166))
100755	27530247	In addition to the hotspot missense mutations, we also noticed considerable discrepancies between the expected and observed number of missense mutations which particularly affected the binding domains of 10 of 32 pVHL targets.	('pVHL', 'Gene', '7428', (213, 217))	('missense mutations', 'Var', (134, 152))	('pVHL', 'Gene', (213, 217))	('binding', 'Interaction', (185, 192))	('binding', 'molecular_function', 'GO:0005488', ('185', '192'))	('affected', 'Reg', (172, 180))
100756	27530247	Significant more missense mutations than expected were seen in binding domains specific for HIF1AN, BCL2L11, HIF1alpha, HIF2alpha, RPB1, PRKCZ, aPKC-lambda/iota, EEF1A1, CCT-zeta-2, and Cullin2.	('HIF2alpha', 'Gene', '2034', (120, 129))	('HIF1alpha', 'Gene', (109, 118))	('BCL2L11', 'Gene', '10018', (100, 107))	('missense mutations', 'Var', (17, 35))	('CCT-zeta-2', 'Gene', '10693', (170, 180))	('BCL2', 'molecular_function', 'GO:0015283', ('100', '104'))	('CCT-zeta-2', 'Gene', (170, 180))	('HIF1AN', 'Gene', (92, 98))	('EEF1A1', 'Gene', '1915', (162, 168))	('BCL2L11', 'Gene', (100, 107))	('aPKC-lambda/iota', 'Gene', '5584', (144, 160))	('RPB1', 'Gene', '5430', (131, 135))	('Cullin2', 'Gene', '8453', (186, 193))	('PRKCZ', 'Gene', (137, 142))	('aPKC-lambda/iota', 'Gene', (144, 160))	('EEF1A1', 'Gene', (162, 168))	('PRKCZ', 'Gene', '5590', (137, 142))	('HIF1AN', 'Gene', '55662', (92, 98))	('RPB1', 'Gene', (131, 135))	('HIF2alpha', 'Gene', (120, 129))	('binding', 'Interaction', (63, 70))	('Cullin2', 'Gene', (186, 193))	('HIF1alpha', 'Gene', '3091', (109, 118))	('binding', 'molecular_function', 'GO:0005488', ('63', '70'))
100758	27530247	This was recently shown with the mutants Phe81Ser and Arg167Gln which cause partial abrogation of VBC complex interactions and fail to downregulate HIF1/2alpha.	('downregulate', 'NegReg', (135, 147))	('Arg167Gln', 'Var', (54, 63))	('Phe81Ser', 'SUBSTITUTION', 'None', (41, 49))	('Phe81Ser', 'Var', (41, 49))	('interactions', 'Interaction', (110, 122))	('abrogation', 'NegReg', (84, 94))	('Arg167Gln', 'SUBSTITUTION', 'None', (54, 63))	('Ser', 'cellular_component', 'GO:0005790', ('46', '49'))	('VBC complex', 'cellular_component', 'GO:0031462', ('98', '109'))	('VBC complex', 'Protein', (98, 109))
100760	27530247	For example, disruption of pVHL binding leads to subsequent ubiquitination of aPKC-lambda/iota, which in turn deregulates JunB expression and promotes tumor progression in VHL disease-related pheochromocytoma.	('ubiquitination', 'MPA', (60, 74))	('VHL disease', 'Disease', 'MESH:D006623', (172, 183))	('VHL disease', 'Disease', (172, 183))	('deregulates', 'Reg', (110, 121))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('disruption', 'Var', (13, 23))	('JunB', 'Gene', (122, 126))	('pheochromocytoma', 'Disease', 'MESH:D010673', (192, 208))	('pVHL', 'Gene', '7428', (27, 31))	('aPKC-lambda/iota', 'Gene', '5584', (78, 94))	('pVHL', 'Gene', (27, 31))	('JunB', 'Gene', '3726', (122, 126))	('expression', 'MPA', (127, 137))	('pheochromocytoma', 'Disease', (192, 208))	('binding', 'molecular_function', 'GO:0005488', ('32', '39'))	('aPKC-lambda/iota', 'Gene', (78, 94))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (192, 208))	('binding', 'Interaction', (32, 39))	('tumor', 'Disease', (151, 156))	('promotes', 'PosReg', (142, 150))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
100762	27530247	Moreover, VHL mutations were shown to impair the interaction with pVHL and CCT-zeta-2 which, consequently, caused improper folding of the VBC complex.	('VHL', 'Gene', '7428', (10, 13))	('mutations', 'Var', (14, 23))	('caused', 'Reg', (107, 113))	('pVHL', 'Gene', '7428', (66, 70))	('VHL', 'Gene', '7428', (67, 70))	('impair', 'NegReg', (38, 44))	('pVHL', 'Gene', (66, 70))	('interaction', 'Interaction', (49, 60))	('CCT-zeta-2', 'Gene', '10693', (75, 85))	('VHL', 'Gene', (10, 13))	('VBC complex', 'cellular_component', 'GO:0031462', ('138', '149'))	('folding', 'MPA', (123, 130))	('CCT-zeta-2', 'Gene', (75, 85))	('improper', 'NegReg', (114, 122))	('VHL', 'Gene', (67, 70))
100766	27530247	The strikingly low frequency of mutations (15 times lower than expected) in this region of VHL may reflect the importance of sustaining accurate pVHL trafficking in ccRCC.	('VHL', 'Gene', (146, 149))	('VHL', 'Gene', '7428', (146, 149))	('VHL', 'Gene', (91, 94))	('pVHL', 'Gene', '7428', (145, 149))	('VHL', 'Gene', '7428', (91, 94))	('mutations', 'Var', (32, 41))	('pVHL', 'Gene', (145, 149))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('RCC', 'Disease', (167, 170))
100768	27530247	The tool for determining protein stability was proven powerful with mutations predicted to be highly destabilizing leading to both faster degradation of pVHL and stabilization of HIF1/2alpha.	('degradation', 'MPA', (138, 149))	('faster', 'PosReg', (131, 137))	('HIF1/2alpha', 'Protein', (179, 190))	('pVHL', 'Gene', '7428', (153, 157))	('degradation', 'biological_process', 'GO:0009056', ('138', '149'))	('pVHL', 'Gene', (153, 157))	('mutations', 'Var', (68, 77))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('stabilization', 'MPA', (162, 175))
100769	27530247	Based on this observation it is conceivable that those mutations are critical for most if not all binding partners of pVHL.	('binding', 'molecular_function', 'GO:0005488', ('98', '105'))	('pVHL', 'Gene', (118, 122))	('pVHL', 'Gene', '7428', (118, 122))	('mutations', 'Var', (55, 64))
100770	27530247	In addition to their potential influence on pVHL function we also attempted to further characterize the 88 missense mutations with regard to their tumorigenic potential.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('pVHL', 'Gene', '7428', (44, 48))	('missense mutations', 'Var', (107, 125))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('pVHL', 'Gene', (44, 48))
100771	27530247	We used the Symphony classification system that allows subclassifying VHL missense mutations in VHL disease patients according to their risk of developing ccRCC.	('VHL', 'Gene', (70, 73))	('VHL disease', 'Disease', (96, 107))	('VHL', 'Gene', '7428', (70, 73))	('missense mutations', 'Var', (74, 92))	('VHL disease', 'Disease', 'MESH:D006623', (96, 107))	('VHL', 'Gene', (96, 99))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('patients', 'Species', '9606', (108, 116))	('RCC', 'Disease', (157, 160))	('VHL', 'Gene', '7428', (96, 99))
100772	27530247	Among the 88 missense mutations, 61 (80 %) were classified by Symphony as high risk of developing ccRCC.	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('missense mutations', 'Var', (13, 31))
100773	27530247	We conclude that most of the missense mutations, even those with neutral or mild impact on pVHL stability as predicted by SDM, may have strong tumorigenic potential.	('tumor', 'Disease', (143, 148))	('pVHL', 'Gene', '7428', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('missense mutations', 'Var', (29, 47))	('pVHL', 'Gene', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
100774	27530247	Notably, only two of the remaining 17 missense mutations were highly destabilizing mutations (Ile151Ser and His115Leu) and classified as low risk of ccRCC.	('His115Leu', 'Var', (108, 117))	('Ile151Ser', 'Mutation', 'rs869025655', (94, 103))	('His115Leu', 'Mutation', 'p.H115L', (108, 117))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (151, 154))	('destabilizing', 'NegReg', (69, 82))	('Ile151Ser', 'Var', (94, 103))	('Ser', 'cellular_component', 'GO:0005790', ('100', '103'))
100780	27530247	Fifty-three percent of the patients with LOF, 33 % with missense mutations, and 40 % wild-type responded to the treatment (regressive or stable disease).	('patients', 'Species', '9606', (27, 35))	('missense mutations', 'Var', (56, 74))	('stable disease', 'Disease', 'MESH:D060050', (137, 151))	('stable disease', 'Disease', (137, 151))
100781	27530247	No significant association was seen between VHL mutation status and response to treatment in our cohort, although a higher response rate in patients with LOF compared to wild-type or missense mutations has been described in a larger study.	('higher', 'PosReg', (116, 122))	('VHL', 'Gene', (44, 47))	('response', 'MPA', (123, 131))	('VHL', 'Gene', '7428', (44, 47))	('mutation', 'Var', (48, 56))	('patients', 'Species', '9606', (140, 148))
100784	27530247	Mutations in the two latter genes seem to be linked to enhanced cell proliferation, tumor aggressiveness and patient outcome.	('patient', 'Species', '9606', (109, 116))	('cell proliferation', 'CPA', (64, 82))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (84, 104))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('enhanced', 'PosReg', (55, 63))	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('Mutations', 'Var', (0, 9))	('tumor aggressiveness', 'Disease', (84, 104))	('aggressiveness', 'Phenotype', 'HP:0000718', (90, 104))
100785	27530247	Twenty percent of ccRCC have mutations in MTOR, TSC1, PIK3CA, and PTEN and indicates that deregulated mTOR pathways may also be critical in this tumor subtype.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('PTEN', 'Gene', (66, 70))	('PIK3CA', 'Gene', (54, 60))	('TSC1', 'Gene', (48, 52))	('PTEN', 'Gene', '5728', (66, 70))	('PIK3CA', 'Gene', '5290', (54, 60))	('MTOR', 'Gene', '2475', (42, 46))	('mutations', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('mTOR', 'Gene', (102, 106))	('TSC1', 'Gene', '7248', (48, 52))	('MTOR', 'Gene', (42, 46))	('mTOR', 'Gene', '2475', (102, 106))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('RCC', 'Disease', (20, 23))
100786	27530247	Interestingly, up to 5 % of ccRCC with intact VHL are characterized by loss of heterozygosity of 8q21 and mutations in TCEB1, which is located in this chromosomal region.	('chromosomal region', 'cellular_component', 'GO:0098687', ('151', '169'))	('TCEB1', 'Gene', '6921', (119, 124))	('VHL', 'Gene', (46, 49))	('TCEB1', 'Gene', (119, 124))	('VHL', 'Gene', '7428', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('RCC', 'Disease', (30, 33))	('loss', 'NegReg', (71, 75))	('mutations', 'Var', (106, 115))
100788	27530247	The new 2016 WHO classification has not yet recognized RCC with TCEB1 mutations as own tumor entity, but included such tumors in the category of emerging entities.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('RCC', 'Disease', (55, 58))	('tumor', 'Disease', (119, 124))	('mutations', 'Var', (70, 79))	('TCEB1', 'Gene', '6921', (64, 69))	('TCEB1', 'Gene', (64, 69))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
100792	27530247	In summary, our VHL sequence analysis of 360 ccRCC revealed pVHL binding sites which are preferentially altered by missense mutations.	('VHL', 'Gene', (16, 19))	('binding sites', 'Interaction', (65, 78))	('altered', 'Reg', (104, 111))	('VHL', 'Gene', '7428', (16, 19))	('VHL', 'Gene', (61, 64))	('binding', 'molecular_function', 'GO:0005488', ('65', '72'))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('pVHL', 'Gene', '7428', (60, 64))	('VHL', 'Gene', '7428', (61, 64))	('missense mutations', 'Var', (115, 133))	('pVHL', 'Gene', (60, 64))
100793	27530247	In contrast to LOF mutations which probably influence most of the pVHL regulated pathways, missense mutations may rather deregulate only single or few of those pathways.	('pVHL', 'Gene', (66, 70))	('missense mutations', 'Var', (91, 109))	('pVHL', 'Gene', '7428', (66, 70))	('deregulate', 'Reg', (121, 131))
100794	27530247	Moreover, about 15 % of ccRCC patients having missense mutations with no, mild or only moderate impact on pVHL function even may have fully or at least partially functional pVHL.	('missense mutations', 'Var', (46, 64))	('RCC', 'Disease', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('patients', 'Species', '9606', (30, 38))	('pVHL', 'Gene', '7428', (173, 177))	('pVHL', 'Gene', (173, 177))	('pVHL', 'Gene', '7428', (106, 110))	('pVHL', 'Gene', (106, 110))
100796	27530247	We therefore hypothesize that the relatively low response rate to anti-angiogenic drugs may be explained by the multipurpose nature of pVHL and the manifold effects on pathways caused by the different mutation types.	('pVHL', 'Gene', '7428', (135, 139))	('mutation', 'Var', (201, 209))	('effects', 'Reg', (157, 164))	('pVHL', 'Gene', (135, 139))
100797	27530247	Patients with VHL missense mutation may rather benefit from targeted therapies than patients with LOF mutations (Fig.	('benefit', 'PosReg', (47, 54))	('patients', 'Species', '9606', (84, 92))	('missense mutation', 'Var', (18, 35))	('Patients', 'Species', '9606', (0, 8))	('VHL', 'Gene', (14, 17))	('VHL', 'Gene', '7428', (14, 17))
100801	30130544	We evaluated the patterns of relapse and potential implications for post-nephrectomy surveillance for patients with non-ccRCC enrolled in the largest randomized trial of adjuvant anti-angiogenic therapy for high-risk RCC (E2805).	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('RCC', 'Disease', (217, 220))	('patients', 'Species', '9606', (102, 110))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))	('E2805', 'Var', (222, 227))
100819	30130544	Importantly, E2805 is the only reported phase III trial of adjuvant anti-angiogenic systemic therapy to include patients with non-ccRCC histologies.	('E2805', 'Var', (13, 18))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('patients', 'Species', '9606', (112, 120))	('RCC', 'Disease', (132, 135))
100827	30130544	Overall, 403 patients with non-ccRCC were enrolled in E2805 and included for analysis (N = 135 sunitinib, N = 130 sorafenib, N = 138 placebo).	('E2805', 'Var', (54, 59))	('patients', 'Species', '9606', (13, 21))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('sorafenib', 'Chemical', 'MESH:D000077157', (114, 123))	('sunitinib', 'Chemical', 'MESH:D000077210', (95, 104))
100865	30130544	The E2805 study included a relatively high risk cohort of completely resected RCC patients, and therefore these findings may not be generalizable to resected non-ccRCC patients with estimated lower recurrence rates.	('E2805', 'Var', (4, 9))	('patients', 'Species', '9606', (82, 90))	('RCC', 'Disease', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('RCC', 'Disease', (164, 167))	('patients', 'Species', '9606', (168, 176))
100870	29732003	Clear cell renal cell carcinomas frequently bear a mutated Von Hippel-Lindau (VHL) gene.	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('Clear cell renal cell carcinomas', 'Disease', (0, 32))	('Von Hippel-Lindau', 'Gene', '7428', (59, 76))	('VHL', 'Gene', (78, 81))	('Von Hippel-Lindau', 'Gene', (59, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('Clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (0, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (11, 32))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('Clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (0, 32))	('mutated', 'Var', (51, 58))
100873	29732003	57/57 CCC and 104/125 CRC-UMF from the 25 patients with VHL-mutated tumor carried the same VHL mutation detected in the tumor.	('tumor', 'Disease', (68, 73))	('VHL', 'Gene', (91, 94))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('CCC', 'cellular_component', 'GO:0030896', ('6', '9'))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('patients', 'Species', '9606', (42, 50))	('tumor', 'Disease', (120, 125))	('mutation', 'Var', (95, 103))
100875	29732003	All the CCC and 83,2% (104/125) of the CRC-UMF were found to carry the same VHL mutation identified in the corresponding tumorous tissue, validating cytopathological identification of CCC in patients with clear cell renal cell carcinoma.	('VHL', 'Gene', (76, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('patients', 'Species', '9606', (191, 199))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumorous', 'Disease', 'MESH:D009369', (121, 129))	('tumorous', 'Disease', (121, 129))	('clear cell renal cell carcinoma', 'Disease', (205, 236))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (205, 236))	('CCC', 'cellular_component', 'GO:0030896', ('184', '187'))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (205, 236))	('CCC', 'cellular_component', 'GO:0030896', ('8', '11'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (216, 236))	('mutation', 'Var', (80, 88))
100884	29732003	The classification of sarcoma, previously based on the site of the tumor (bone or soft tissue), currently also relies, in selected cases, on mutations associated with specific histological subtypes.	('mutations', 'Var', (141, 150))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('sarcoma', 'Disease', 'MESH:D012509', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('sarcoma', 'Disease', (22, 29))	('tumor', 'Disease', (67, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (22, 29))
100885	29732003	Clear cell renal cell carcinoma (ccRCC), which accounts for approximately 75% of cases of renal cell carcinoma (RCC), is characterized in up to 83% of cases by mutations of the Von Hippel-Lindau (VHL) gene.	('mutations', 'Var', (160, 169))	('VHL', 'Gene', (196, 199))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('renal cell carcinoma', 'Disease', (90, 110))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (90, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('RCC', 'Disease', (35, 38))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('Von Hippel-Lindau', 'Gene', '7428', (177, 194))	('Von Hippel-Lindau', 'Gene', (177, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (11, 31))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (90, 110))	('RCC', 'Disease', 'MESH:C538614', (112, 115))
100886	29732003	Together with inactivating epigenetic alterations and loss of heterozygosity (LOH), VHL gene mutations contribute to more than 90% of patients exhibiting loss of function (LOF) of the VHL protein (pVHL).	('VHL gene', 'Gene', (84, 92))	('mutations', 'Var', (93, 102))	('loss of function', 'NegReg', (154, 170))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('patients', 'Species', '9606', (134, 142))	('pVHL', 'Gene', '7428', (197, 201))	('pVHL', 'Gene', (197, 201))
100889	29732003	Our results show that all the CCC have been found to carry the same VHL mutation detected in the tumorous tissue.	('tumorous', 'Disease', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumorous', 'Disease', 'MESH:D009369', (97, 105))	('CCC', 'cellular_component', 'GO:0030896', ('30', '33'))	('VHL', 'Gene', (68, 71))	('mutation', 'Var', (72, 80))
100891	29732003	Tumor tissue DNA analyses from the 30 patients included in this study revealed that four patients (13.3%) had no detectable VHL mutations in their tumor samples (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('mutations', 'Var', (128, 137))	('patients', 'Species', '9606', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('patients', 'Species', '9606', (38, 46))	('VHL', 'Gene', (124, 127))
100892	29732003	At genetic level, 25 of 30 tumor samples (83.3%) were characterized by mutations in the VHL coding sequence.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('VHL', 'Gene', (88, 91))	('mutations', 'Var', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
100893	29732003	Interestingly, three patients (10%) harboured two simultaneous VHL mutations in their primary tumor sample, each located on a different exon of the VHL gene (Table 2).	('VHL', 'Gene', (148, 151))	('harboured', 'Reg', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('mutations', 'Var', (67, 76))	('patients', 'Species', '9606', (21, 29))	('VHL', 'Gene', (63, 66))
100894	29732003	The rest of the cohort presented single VHL mutations located either on exon one (33.4% of patients), exon two (13.3% of patients) or exon three (30% of patients) of the VHL gene.	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (153, 161))	('VHL', 'Gene', (170, 173))	('VHL', 'Gene', (40, 43))	('mutations', 'Var', (44, 53))	('patients', 'Species', '9606', (121, 129))
100895	29732003	Genetic analysis of tumor DNA samples revealed that 38.9% of patients had deletions inducing frameshifts, 44.4% presented transversions and 16.7% harboured transitions.	('deletions', 'Var', (74, 83))	('transversions', 'Var', (122, 135))	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('frameshifts', 'Var', (93, 104))	('patients', 'Species', '9606', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
100896	29732003	All VHL mutations found were investigated to determine their phenotypic impact on pVHL functions by searching four distinct databases (see Methods and Table 1).	('pVHL', 'Gene', '7428', (82, 86))	('pVHL', 'Gene', (82, 86))	('VHL', 'Gene', (4, 7))	('mutations', 'Var', (8, 17))
100898	29732003	It is important to note that the 85% sensitivity and 44% specificity of PolyPhen predictions for loss-of-function mutations may explain the discrepancies between the reported impact of a missense mutation found in the literature and the PolyPhen prediction obtained for the same mutation (see Table 1).	('mutations', 'Var', (114, 123))	('PolyPhen', 'Chemical', '-', (72, 80))	('PolyPhen', 'Chemical', '-', (237, 245))	('loss-of-function', 'NegReg', (97, 113))
100906	29732003	Our molecular results showed a complete correlation of absence of VHL mutation in the tumor and in the corresponding CCC and CRC-UMF.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('CCC', 'Disease', (117, 120))	('tumor', 'Disease', (86, 91))	('CCC', 'cellular_component', 'GO:0030896', ('117', '120'))	('CRC-UMF', 'Disease', (125, 132))	('absence', 'NegReg', (55, 62))	('VHL', 'Gene', (66, 69))	('mutation', 'Var', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
100908	29732003	Remarkably, the type of VHL mutation detected in the 57 validated CCC, as well as in 104 CRC-UMF, correlated exactly with that detected in the corresponding tumor samples, strongly suggesting the neoplastic nature of at least some cells classified as CRC-UMF by the cytopathologists.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('mutation', 'Var', (28, 36))	('VHL', 'Gene', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('CCC', 'cellular_component', 'GO:0030896', ('66', '69'))
100909	29732003	We also found 21 CRC-UMF derived from 11 patients which exhibited a distinct VHL mutation from that found in the corresponding tumor tissue, raising the issue of their possible pre-tumor nature and/or origin from a minority tumor cell clone.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', (127, 132))	('VHL', 'Gene', (77, 80))	('mutation', 'Var', (81, 89))	('tumor', 'Disease', (224, 229))	('pre', 'molecular_function', 'GO:0003904', ('177', '180'))	('patients', 'Species', '9606', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
100910	29732003	One hundred and sixty-one CRC (CCC and CRC-UMF) isolated from the blood of these 25 patients showed mutations of the VHL gene identical to and 21 CRC-UMF displayed mutations of the VHL gene different from those detected in the corresponding tumor tissue.	('mutations', 'Var', (100, 109))	('CCC', 'cellular_component', 'GO:0030896', ('31', '34'))	('patients', 'Species', '9606', (84, 92))	('tumor', 'Disease', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('VHL', 'Gene', (117, 120))
100911	29732003	In these 182 CRC detected in 25 patients, we found 18 different VHL mutations affecting the three exons of the VHL gene: seven are missense mutations that induce an amino acid change within the VHL protein in eight patients (26.7%), one is a silent mutation with no effect at protein level found in a single patient, seven are deletions causing frameshifts and three are nonsense mutations that generate premature stop codons and result in a truncated VHL protein for 16 patients (Table 1).	('patient', 'Species', '9606', (308, 315))	('patients', 'Species', '9606', (215, 223))	('patients', 'Species', '9606', (32, 40))	('affecting', 'Reg', (78, 87))	('amino acid change', 'MPA', (165, 182))	('protein', 'cellular_component', 'GO:0003675', ('276', '283'))	('VHL protein', 'Protein', (452, 463))	('patients', 'Species', '9606', (471, 479))	('protein', 'cellular_component', 'GO:0003675', ('456', '463'))	('patient', 'Species', '9606', (471, 478))	('VHL', 'Gene', (64, 67))	('induce', 'Reg', (155, 161))	('protein', 'cellular_component', 'GO:0003675', ('198', '205'))	('frameshifts', 'Var', (345, 356))	('mutations', 'Var', (68, 77))	('patient', 'Species', '9606', (32, 39))	('truncated', 'MPA', (442, 451))	('patient', 'Species', '9606', (215, 222))
100915	29732003	Interestingly, double mutations were found in 19 of the 205 CRC analysed (9.3%), all belonging to three patients bearing the same double mutations in their tumor tissues (Table 2).	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('found', 'Reg', (37, 42))	('CRC', 'Disease', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('double mutations', 'Var', (15, 31))	('patients', 'Species', '9606', (104, 112))
100916	29732003	by allele drop out (ADO).	('ADO', 'Disease', 'None', (20, 23))	('drop out', 'NegReg', (10, 18))	('ADO', 'Disease', (20, 23))	('allele', 'Var', (3, 9))
100918	29732003	Still, we found concordance of genetic profiles identified in all 64 validated CCC and in 120 CRC-UMF, concerning both homozygous and heterozygous VHL mutations, as compared to corresponding tumor samples.	('CCC', 'Disease', (79, 82))	('CCC', 'cellular_component', 'GO:0030896', ('79', '82'))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('CRC-UMF', 'Disease', (94, 101))	('VHL', 'Gene', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('mutations', 'Var', (151, 160))
100926	29732003	We tested 30 patients with ccRCC, as this particular cancer is characterized by VHL mutations in up to 83% of cases, and included, as control samples, the corresponding tumorous tissues, and corresponding individual leukocytes.	('VHL', 'Gene', (80, 83))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('patients', 'Species', '9606', (13, 21))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('tested', 'Reg', (3, 9))	('tumorous', 'Disease', 'MESH:D009369', (169, 177))	('mutations', 'Var', (84, 93))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumorous', 'Disease', (169, 177))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('ccRCC', 'Phenotype', 'HP:0006770', (27, 32))
100928	29732003	However, 25 (83.3%) of the 30 patients harboured a mutated VHL gene in the primary tumor and allowed the comparison based on genetic data.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('patients', 'Species', '9606', (30, 38))	('VHL', 'Gene', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('mutated', 'Var', (51, 58))
100930	29732003	Twenty-one CRC-UMF derived from 11 of these patients were found to bear VHL mutations different from those of the primary tumor.	('mutations', 'Var', (76, 85))	('patients', 'Species', '9606', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))	('VHL', 'Gene', (72, 75))
100931	29732003	Interestingly, no CCC nor CRC-UMF lacking a VHL mutation were found in the blood of the 25 patients with a VHL-mutated tumor.	('tumor', 'Disease', (119, 124))	('CCC', 'cellular_component', 'GO:0030896', ('18', '21'))	('patients', 'Species', '9606', (91, 99))	('VHL', 'Gene', (44, 47))	('mutation', 'Var', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
100939	29732003	VHL mutations can be used as a genetic proof of the cellular tumor nature.	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('VHL', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mutations', 'Var', (4, 13))	('tumor', 'Disease', (61, 66))
100941	29732003	Furthermore, in patients diagnosed with ccRCC, several reports have shown that genetic alterations of the VHL locus are the only ubiquitous drivers found in the tumor, including when comparing multiple metastatic sites to the primary tumor.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('tumor', 'Disease', (234, 239))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('patients', 'Species', '9606', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('VHL', 'Gene', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor', 'Disease', (161, 166))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('genetic alterations', 'Var', (79, 98))
100942	29732003	Such observations prompted us to use VHL mutations as a marker of tumor nature in patients with ccRCC and a VHL mutated gene in the tumor tissue.	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('VHL', 'Gene', (37, 40))	('tumor', 'Disease', (66, 71))	('patients', 'Species', '9606', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('tumor', 'Disease', (132, 137))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('VHL', 'Gene', (108, 111))
100945	29732003	In fact, promoter hypermethylation of VHL with silencing effect, histone modifications affecting transcription and mutations leading to aberrant splicing of mRNA precursors could lead to truncated and/or abnormal VHL protein, thereby contributing to pVHL LOF.	('mutations', 'Var', (115, 124))	('promoter hypermethylation', 'Var', (9, 34))	('modifications', 'Var', (73, 86))	('VHL protein', 'Protein', (213, 224))	('protein', 'cellular_component', 'GO:0003675', ('217', '224'))	('silencing', 'NegReg', (47, 56))	('splicing', 'biological_process', 'GO:0045292', ('145', '153'))	('VHL', 'Gene', (38, 41))	('LOF', 'NegReg', (255, 258))	('pVHL', 'Gene', '7428', (250, 254))	('transcription', 'biological_process', 'GO:0006351', ('97', '110'))	('pVHL', 'Gene', (250, 254))	('truncated', 'MPA', (187, 196))
100947	29732003	As detailed in Table 3, complete loss of functional pVHL due to truncating homozygous VHL mutations was found in 13 patients (43.3%) of our cohort.	('mutations', 'Var', (90, 99))	('pVHL', 'Gene', '7428', (52, 56))	('functional', 'MPA', (41, 51))	('loss', 'NegReg', (33, 37))	('pVHL', 'Gene', (52, 56))	('patients', 'Species', '9606', (116, 124))	('truncating', 'MPA', (64, 74))	('VHL', 'Gene', (86, 89))
100948	29732003	These mutations, based on the literature, are a full genetic hallmark of tumor phenotype.	('genetic hallmark of tumor', 'Disease', (53, 78))	('genetic hallmark of tumor', 'Disease', 'MESH:D030342', (53, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mutations', 'Var', (6, 15))
100950	29732003	In another group of 10 patients (33%) we found heterozygous VHL mutations in the tumor tissue and in the corresponding CRC (Table 3).	('patients', 'Species', '9606', (23, 31))	('VHL', 'Gene', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('mutations', 'Var', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
100951	29732003	In these patients, the pVHL LOF could be related to concomitant epigenetic alterations or undetected monoallelic large deletions.	('patients', 'Species', '9606', (9, 17))	('epigenetic alterations', 'Var', (64, 86))	('pVHL', 'Gene', '7428', (23, 27))	('pVHL', 'Gene', (23, 27))	('LOF', 'NegReg', (28, 31))
100952	29732003	However, two of these 11 patients harboured double missense VHL mutations in the tumor tissue that were found identical in the corresponding CRC (including seven CCC and seven CRC-UMF) and could presumably be located on the two VHL alleles, leading to pVHL LOF.	('VHL', 'Gene', (60, 63))	('CCC', 'cellular_component', 'GO:0030896', ('162', '165'))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('patients', 'Species', '9606', (25, 33))	('mutations', 'Var', (64, 73))	('LOF', 'NegReg', (257, 260))	('pVHL', 'Gene', '7428', (252, 256))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('pVHL', 'Gene', (252, 256))	('tumor', 'Disease', (81, 86))
100954	29732003	Furthermore, other VHL-neighboring tumor suppressor genes such as PBRM1, BAP1 and SETD2, located on chromosome 3p21, can be targeted by LOH but could not be analysed in the present study.	('SETD2', 'Gene', '29072', (82, 87))	('BAP1', 'Gene', '8314', (73, 77))	('LOH', 'Var', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('SETD2', 'Gene', (82, 87))	('VHL-neighboring tumor', 'Disease', (19, 40))	('BAP1', 'Gene', (73, 77))	('VHL-neighboring tumor', 'Disease', 'MESH:D006623', (19, 40))	('tumor suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('PBRM1', 'Gene', (66, 71))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))	('PBRM1', 'Gene', '55193', (66, 71))	('chromosome', 'cellular_component', 'GO:0005694', ('100', '110'))
100962	29732003	Strikingly, in our study performed blindly, all the 57 CRC defined as CCC by "reference" cytopathological criteria were carrying the same VHL mutation found in the corresponding tumorous tissue, which was always absent in the corresponding leukocytes used as controls.	('CCC', 'Disease', (70, 73))	('CCC', 'cellular_component', 'GO:0030896', ('70', '73'))	('tumorous', 'Disease', 'MESH:D009369', (178, 186))	('mutation', 'Var', (142, 150))	('tumorous', 'Disease', (178, 186))	('VHL', 'Gene', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
100963	29732003	In addition to this, 104 single cells classified as CRC-UMF by morphological examination were also found to carry the same VHL mutation detected in the corresponding tumorous tissue and could be considered as tumor cells.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumorous', 'Disease', 'MESH:D009369', (166, 174))	('mutation', 'Var', (127, 135))	('tumorous', 'Disease', (166, 174))	('VHL', 'Gene', (123, 126))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
100970	29732003	We did not find any unusual clinical characteristics in the four patients without VHL mutations, none of the four was a metastatic patient.	('mutations', 'Var', (86, 95))	('VHL', 'Gene', (82, 85))	('patient', 'Species', '9606', (65, 72))	('patients', 'Species', '9606', (65, 73))	('patient', 'Species', '9606', (131, 138))
100990	29732003	At single-cell level, PCR analyses may be affected by allele drop out (ADO) due to the loss of signal from one allele.	('loss', 'NegReg', (87, 91))	('signal', 'MPA', (95, 101))	('allele', 'Var', (54, 60))	('drop out', 'NegReg', (61, 69))	('affected', 'Reg', (42, 50))	('ADO', 'Disease', (71, 74))	('ADO', 'Disease', 'None', (71, 74))
100998	29732003	It is important to note that the 85% sensitivity and 44% specificity of PolyPhen predictions for loss-of-function mutations warrant caution when interpreting PolyPhen scores.	('mutations', 'Var', (114, 123))	('PolyPhen', 'Chemical', '-', (72, 80))	('PolyPhen', 'Chemical', '-', (158, 166))	('loss-of-function', 'NegReg', (97, 113))
101001	28951115	Characterization and Impact of TERT Promoter Region Mutations on Clinical Outcome in Renal Cell Carcinoma Mutations in the promoter region of the TERT gene have been detected in a variety of cancers.	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (85, 105))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('detected', 'Reg', (166, 174))	('cancers', 'Disease', (191, 198))	('Mutations', 'Var', (106, 115))	('Renal Cell Carcinoma', 'Disease', (85, 105))	('Carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('TERT', 'Gene', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('TERT', 'Gene', (146, 150))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (85, 105))	('TERT', 'Gene', '7015', (146, 150))	('TERT', 'Gene', '7015', (31, 35))
101002	28951115	To determine the role and relevance of TERT promoter region mutations in both clear cell (ccRCC) and non-clear cell (nccRCC) renal cell carcinoma using ultra-deep and whole-genome sequencing methods on primary tumor samples.	('TERT', 'Gene', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('renal cell carcinoma', 'Disease', (125, 145))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (125, 145))	('clear cell', 'Disease', (78, 88))	('TERT', 'Gene', '7015', (39, 43))	('tumor', 'Disease', (210, 215))	('RCC', 'Disease', (92, 95))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (125, 145))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
101006	28951115	In >80% of the cases, mutations were located at C228T and were found to co- occur only rarely with other relevant RCC driver genes.	('C228T', 'Var', (48, 53))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('C228T', 'Mutation', 'rs750893877', (48, 53))	('mutations', 'Var', (22, 31))
101012	28951115	We show a previously unrecognized frequency of TERT promoter mutations in both clear cell and non-clear cell renal cell carcinoma.	('TERT', 'Gene', (47, 51))	('-clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (97, 129))	('TERT', 'Gene', '7015', (47, 51))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (109, 129))	('clear cell', 'Disease', (79, 89))	('mutations', 'Var', (61, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (98, 129))	('clear cell renal cell carcinoma', 'Disease', (98, 129))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (98, 129))
101020	28951115	The TERT enzyme is responsible for addition of telomeric repeats to chromosomal ends.	('telomeric repeats', 'Var', (47, 64))	('TERT', 'Gene', (4, 8))	('TERT', 'Gene', '7015', (4, 8))
101023	28951115	Cancer-specific TERT transcription is putatively caused by mutations upstream of the translational start site of TERT, in the TERT promoter region.	('TERT', 'Gene', (16, 20))	('caused by', 'Reg', (49, 58))	('TERT', 'Gene', '7015', (113, 117))	('TERT', 'Gene', '7015', (16, 20))	('TERT', 'Gene', (126, 130))	('transcription', 'biological_process', 'GO:0006351', ('21', '34'))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('TERT', 'Gene', '7015', (126, 130))	('mutations', 'Var', (59, 68))	('TERT', 'Gene', (113, 117))
101024	28951115	Mutations in this crucial regulatory element allow TERT expression, leading to the creation of a novel binding site for the ETS family of transcription factors, which ultimately increases TERT transcriptional activity.	('TERT', 'Gene', (188, 192))	('TERT', 'Gene', '7015', (188, 192))	('TERT', 'Gene', (51, 55))	('binding', 'Interaction', (103, 110))	('binding', 'molecular_function', 'GO:0005488', ('103', '110'))	('Mutations', 'Var', (0, 9))	('TERT', 'Gene', '7015', (51, 55))	('transcription', 'biological_process', 'GO:0006351', ('138', '151'))	('increases', 'PosReg', (178, 187))
101025	28951115	Overexpression of the TERT gene, and consequently high TERT activity, has been described in many cancers including melanoma, glioblastoma, and thyroid and urothelial tumors, and TERT promoter region mutations have been associated with advanced disease course and poor outcome.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('glioblastoma', 'Disease', (125, 137))	('mutations', 'Var', (199, 208))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('TERT', 'Gene', (22, 26))	('thyroid', 'Disease', (143, 150))	('cancers', 'Disease', (97, 104))	('glioblastoma', 'Phenotype', 'HP:0012174', (125, 137))	('TERT', 'Gene', '7015', (22, 26))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('urothelial tumors', 'Disease', (155, 172))	('associated', 'Reg', (219, 229))	('TERT', 'Gene', (178, 182))	('TERT', 'Gene', '7015', (178, 182))	('described', 'Reg', (79, 88))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('TERT', 'Gene', (55, 59))	('urothelial tumors', 'Disease', 'MESH:D001749', (155, 172))	('TERT', 'Gene', '7015', (55, 59))	('glioblastoma', 'Disease', 'MESH:D005909', (125, 137))
101030	28951115	While TERT promoter mutations were detected in <5% of the cases analyzed, a wide range of breakpoints were observed within the TERT promoter region and were associated with TERT upregulation; however, the association with clinical outcomes was not established.	('TERT', 'Gene', (173, 177))	('associated', 'Reg', (157, 167))	('TERT', 'Gene', '7015', (173, 177))	('TERT', 'Gene', (127, 131))	('TERT', 'Gene', '7015', (127, 131))	('TERT', 'Gene', (6, 10))	('TERT', 'Gene', '7015', (6, 10))	('breakpoints', 'Var', (90, 101))	('mutations', 'Var', (20, 29))
101041	28951115	A panel of nine genes (VHL, PBRM1, BAP1, SETD2, TERT, KDM5C, TP53, mTOR, PTEN) was selected a priori for analysis on the basis of previously published data for known driver mutations in RCC.	('VHL', 'Gene', (23, 26))	('mTOR', 'Gene', (67, 71))	('BAP1', 'Gene', (35, 39))	('TP53', 'Gene', (61, 65))	('KDM5C', 'Gene', (54, 59))	('RCC', 'Disease', (186, 189))	('mTOR', 'Gene', '2475', (67, 71))	('VHL', 'Gene', '7428', (23, 26))	('SETD2', 'Gene', (41, 46))	('PTEN', 'Gene', (73, 77))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('mutations', 'Var', (173, 182))	('PBRM1', 'Gene', '55193', (28, 33))	('SETD2', 'Gene', '29072', (41, 46))	('TP53', 'Gene', '7157', (61, 65))	('PTEN', 'Gene', '5728', (73, 77))	('BAP1', 'Gene', '8314', (35, 39))	('PBRM1', 'Gene', (28, 33))	('TERT', 'Gene', (48, 52))	('KDM5C', 'Gene', '8242', (54, 59))	('TERT', 'Gene', '7015', (48, 52))
101060	28951115	Of these alterations, the promoter region was affected in 17/18 (94.4%) ccRCC and 13/14 (92.8%) nccRCC patients.	('RCC', 'Disease', (74, 77))	('alterations', 'Var', (9, 20))	('promoter region', 'MPA', (26, 41))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('RCC', 'Disease', (99, 102))	('patients', 'Species', '9606', (103, 111))	('affected', 'Reg', (46, 54))
101061	28951115	The genes most commonly mutated in the 147 ccRCC patients were located on chromosome 3p: VHL (81.0%), PBRM1 (42.9%), SETD2 (27.9%), and BAP1 (20.4%).	('mutated', 'Var', (24, 31))	('BAP1', 'Gene', (136, 140))	('PBRM1', 'Gene', (102, 107))	('VHL', 'Gene', (89, 92))	('PBRM1', 'Gene', '55193', (102, 107))	('chromosome', 'cellular_component', 'GO:0005694', ('74', '84'))	('SETD2', 'Gene', '29072', (117, 122))	('VHL', 'Gene', '7428', (89, 92))	('patients', 'Species', '9606', (49, 57))	('SETD2', 'Gene', (117, 122))	('BAP1', 'Gene', '8314', (136, 140))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))
101063	28951115	Among those, 17 patients (94.4%) had alterations detected in the promoter region, and one (5.6%) was diagnosed with a TERT gene mutation and was excluded from further association analyses.	('TERT', 'Gene', '7015', (118, 122))	('patients', 'Species', '9606', (16, 24))	('alterations', 'Var', (37, 48))	('TERT', 'Gene', (118, 122))
101064	28951115	TERT promoter alterations were mutually exclusive in all cases: 13 (76.5%) were at site C228T, two (11.8%) at C250T, and two (11.8%) at C898T.	('C228T', 'Mutation', 'rs750893877', (88, 93))	('C250T', 'Mutation', 'rs774673756', (110, 115))	('C228T', 'Var', (88, 93))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('C898T', 'Mutation', 'c.898C>T', (136, 141))
101065	28951115	VHL mutations co-occurred in 70.6% of the cases with TERT promoter mutations.	('TERT', 'Gene', (53, 57))	('TERT', 'Gene', '7015', (53, 57))	('VHL', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('VHL', 'Gene', '7428', (0, 3))
101066	28951115	Among patients with TERT promoter mutations, 88.2% were wild-type for PBRM1 (p = 0.008).	('TERT', 'Gene', (20, 24))	('TERT', 'Gene', '7015', (20, 24))	('PBRM1', 'Gene', (70, 75))	('patients', 'Species', '9606', (6, 14))	('PBRM1', 'Gene', '55193', (70, 75))	('mutations', 'Var', (34, 43))
101067	28951115	TERT promoter mutations were not significantly associated with any of the other mutations studied (Fig.	('TERT', 'Gene', '7015', (0, 4))	('mutations', 'Var', (14, 23))	('TERT', 'Gene', (0, 4))
101075	28951115	Analysis of associations between other mutations and CSS and RFS revealed that BAP1 mutations were associated with a higher risk of cancer-specific death, whereas SETD2 mutations were associated with a risk of tumor recurrence (Table 3).	('SETD2', 'Gene', (163, 168))	('cancer', 'Disease', (132, 138))	('BAP1', 'Gene', '8314', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('RFS', 'Chemical', '-', (61, 64))	('tumor', 'Disease', (210, 215))	('BAP1', 'Gene', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutations', 'Var', (84, 93))	('death', 'Disease', 'MESH:D003643', (148, 153))	('associated', 'Reg', (184, 194))	('death', 'Disease', (148, 153))	('CSS', 'Chemical', '-', (53, 56))	('SETD2', 'Gene', '29072', (163, 168))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
101076	28951115	Multivariable Cox regression models were adjusted for SSIGN score to assess the association between mutations and CSS and RFS (Supplementary Table 2).	('mutations', 'Var', (100, 109))	('CSS', 'Gene', (114, 117))	('CSS', 'Chemical', '-', (114, 117))	('RFS', 'Chemical', '-', (122, 125))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('association', 'Interaction', (80, 91))	('RFS', 'Gene', (122, 125))
101077	28951115	TERT promoter (HR 3.55, 95% CI 1.37-9.20; p = 0.009) and BAP1 mutations (HR 2.93, 95% CI 1.28-6.71; p = 0.011) were significantly associated with higher risk of cancer-specific death.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('death', 'Disease', (177, 182))	('death', 'Disease', 'MESH:D003643', (177, 182))	('TERT', 'Gene', (0, 4))	('BAP1', 'Gene', '8314', (57, 61))	('TERT', 'Gene', '7015', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('BAP1', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
101078	28951115	Only TP53 mutations were significantly associated with higher risk of recurrence (HR 2.17, 95% CI 1.07-4.41; p = 0.033).	('mutations', 'Var', (10, 19))	('TP53', 'Gene', '7157', (5, 9))	('TP53', 'Gene', (5, 9))
101080	28951115	The genes most frequently mutated among those evaluated for analysis were TP53 (25.4%), TERT (10.4%), PTEN (8.2%), and mTOR (6.7%; (Fig.	('TERT', 'Gene', '7015', (88, 92))	('mTOR', 'Gene', '2475', (119, 123))	('TP53', 'Gene', '7157', (74, 78))	('mutated', 'Var', (26, 33))	('mTOR', 'Gene', (119, 123))	('PTEN', 'Gene', (102, 106))	('TP53', 'Gene', (74, 78))	('PTEN', 'Gene', '5728', (102, 106))	('TERT', 'Gene', (88, 92))
101081	28951115	A TERT gene mutation was observed for one patient (E441del).	('TERT', 'Gene', (2, 6))	('TERT', 'Gene', '7015', (2, 6))	('E441del', 'Var', (51, 58))	('patient', 'Species', '9606', (42, 49))	('E441del', 'Mutation', 'p.441delE', (51, 58))
101082	28951115	All 13 non-exonic alterations affected the promoter region, of which 11 alterations involved hotspot C228T (84.6%).	('affected', 'Reg', (30, 38))	('non-exonic', 'Var', (7, 17))	('promoter region', 'MPA', (43, 58))	('C228T', 'Mutation', 'rs750893877', (101, 106))	('involved', 'Reg', (84, 92))
101083	28951115	TERT promoter mutations showed no association with the incidence of mutations in the other genes evaluated.	('TERT', 'Gene', '7015', (0, 4))	('mutations', 'Var', (14, 23))	('TERT', 'Gene', (0, 4))
101091	28951115	Survival analysis for patients with and without TERT promoter mutations revealed a wild-type TERT advantage for CSS, but statistical significance was not reached (Fig.	('CSS', 'Disease', (112, 115))	('patients', 'Species', '9606', (22, 30))	('TERT', 'Gene', (48, 52))	('CSS', 'Chemical', '-', (112, 115))	('TERT', 'Gene', (93, 97))	('TERT', 'Gene', '7015', (48, 52))	('TERT', 'Gene', '7015', (93, 97))	('mutations', 'Var', (62, 71))
101095	28951115	As previously described, TERT promoter mutations were commonly detected in chromophobe RCC, but they also occurred in other nccRCC subtypes (papillary, unclassified and TFE3 translocation RCC).	('chromophobe RCC', 'Disease', (75, 90))	('detected', 'Reg', (63, 71))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('TFE3', 'Gene', (169, 173))	('RCC', 'Disease', (87, 90))	('TERT', 'Gene', (25, 29))	('RCC', 'Disease', (127, 130))	('TFE3', 'Gene', '7030', (169, 173))	('mutations', 'Var', (39, 48))	('TERT', 'Gene', '7015', (25, 29))	('chromophobe RCC', 'Disease', 'MESH:C538614', (75, 90))	('RCC', 'Disease', (188, 191))	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('occurred', 'Reg', (106, 114))
101099	28951115	Previous studies have shown that these hotspot mutations lead to higher TERT expression and subsequent telomerase activity, which is ultimately associated with cancer progression and poor prognosis.	('telomerase', 'Enzyme', (103, 113))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('telomerase activity', 'molecular_function', 'GO:0003720', ('103', '122'))	('activity', 'MPA', (114, 122))	('associated', 'Reg', (144, 154))	('cancer', 'Disease', (160, 166))	('mutations', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('higher', 'PosReg', (65, 71))	('TERT', 'Gene', (72, 76))	('TERT', 'Gene', '7015', (72, 76))
101100	28951115	TERT promoter mutations allow the creation of ETS1 binding sites, leading to TERT transcription.	('binding', 'molecular_function', 'GO:0005488', ('51', '58'))	('TERT', 'Gene', (77, 81))	('binding', 'Interaction', (51, 58))	('TERT', 'Gene', '7015', (77, 81))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('transcription', 'biological_process', 'GO:0006351', ('82', '95'))	('leading to', 'Reg', (66, 76))	('ETS1', 'Gene', '2113', (46, 50))	('ETS1', 'Gene', (46, 50))	('mutations', 'Var', (14, 23))
101103	28951115	This supports the observation that TERT expression is enhanced in cases of concomitant VHL gene inactivation and TERT promoter mutation.	('VHL', 'Gene', '7428', (87, 90))	('TERT', 'Gene', '7015', (113, 117))	('inactivation', 'Var', (96, 108))	('TERT', 'Gene', (35, 39))	('VHL', 'Gene', (87, 90))	('enhanced', 'PosReg', (54, 62))	('TERT', 'Gene', '7015', (35, 39))	('TERT', 'Gene', (113, 117))
101104	28951115	In our ccRCC cohort, we found that VHL mutations occurred in approximately 70% of patients carrying TERT promoter mutations.	('patients', 'Species', '9606', (82, 90))	('RCC', 'Disease', 'MESH:C538614', (9, 12))	('RCC', 'Disease', (9, 12))	('TERT', 'Gene', (100, 104))	('mutations', 'Var', (39, 48))	('VHL', 'Gene', (35, 38))	('TERT', 'Gene', '7015', (100, 104))	('VHL', 'Gene', '7428', (35, 38))	('occurred', 'Reg', (49, 57))
101109	28951115	We therefore believe that identifying TERT promoter alterations, as one of the most commonly mutated sites in kidney cancer, may reveal a valuable actionable target, in particular for patients lacking other alterations.	('alterations', 'Var', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('patients', 'Species', '9606', (184, 192))	('TERT', 'Gene', (38, 42))	('kidney cancer', 'Disease', 'MESH:D007680', (110, 123))	('kidney cancer', 'Phenotype', 'HP:0009726', (110, 123))	('TERT', 'Gene', '7015', (38, 42))	('kidney cancer', 'Disease', (110, 123))
101112	28951115	Larger validation studies with longer follow-up are needed to evaluate the impact of TERT promoter mutations in kidney cancer.	('TERT', 'Gene', (85, 89))	('kidney cancer', 'Disease', (112, 125))	('TERT', 'Gene', '7015', (85, 89))	('mutations', 'Var', (99, 108))	('kidney cancer', 'Phenotype', 'HP:0009726', (112, 125))	('kidney cancer', 'Disease', 'MESH:D007680', (112, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
101114	28951115	Therefore, future analyses of multiple regions from primary tumors and matched metastatic sites are necessary to determine the relevance of TERT promoter mutations in RCC.	('TERT', 'Gene', (140, 144))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('TERT', 'Gene', '7015', (140, 144))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('RCC', 'Disease', (167, 170))	('mutations', 'Var', (154, 163))	('tumors', 'Disease', (60, 66))
101117	28951115	Our work has highlighted a previously unrecognized frequency of TERT promoter mutations in both clear cell and non-clear cell RCC.	('TERT', 'Gene', (64, 68))	('TERT', 'Gene', '7015', (64, 68))	('mutations', 'Var', (78, 87))	('RCC', 'Disease', (126, 129))	('RCC', 'Disease', 'MESH:C538614', (126, 129))
101140	27911274	Alterations in the expression and/or glycosylation of mucins are associated with cellular growth, differentiation, transformation, adhesion, invasion and immune surveillance.	('invasion', 'CPA', (141, 149))	('cellular growth', 'CPA', (81, 96))	('expression', 'MPA', (19, 29))	('glycosylation', 'MPA', (37, 50))	('cellular growth', 'biological_process', 'GO:0016049', ('81', '96'))	('mucin', 'Gene', (54, 59))	('transformation', 'CPA', (115, 129))	('Alterations', 'Var', (0, 11))	('adhesion', 'CPA', (131, 139))	('associated', 'Reg', (65, 75))	('glycosylation', 'biological_process', 'GO:0070085', ('37', '50'))	('mucin', 'Gene', '100508689', (54, 59))	('differentiation', 'CPA', (98, 113))	('immune surveillance', 'CPA', (154, 173))
101141	27911274	The aberrant expression of mucins may have correlation with cancer biology.	('mucin', 'Gene', '100508689', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('aberrant', 'Var', (4, 12))	('cancer', 'Disease', (60, 66))	('mucin', 'Gene', (27, 32))	('correlation', 'Reg', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
101148	27911274	High expression of MUC13 also predicts an inferior outcome of patients with colorectal cancer, esophageal squamous cell carcinoma and pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (134, 151))	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('esophageal squamous cell carcinoma', 'Disease', (95, 129))	('High', 'Var', (0, 4))	('MUC13', 'Gene', (19, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (134, 151))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('colorectal cancer', 'Disease', (76, 93))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (95, 129))	('patients', 'Species', '9606', (62, 70))	('pancreatic cancer', 'Disease', (134, 151))
101166	27911274	According to the Supplementary Table S1, we observed that high MUC13 expression significantly correlated with reduced RFS and worse OS (HR, 2.952; 95% CI, 1.588 to 5.488, p < 0.001 and HR, 2.890; 95% CI, 1.614 to 5.172, p < 0.001, respectively).	('reduced', 'NegReg', (110, 117))	('RFS', 'CPA', (118, 121))	('OS', 'Chemical', '-', (132, 134))	('worse OS', 'CPA', (126, 134))	('high', 'Var', (58, 62))	('MUC13', 'Gene', (63, 68))
101169	27911274	PT stage, Fuhrman grade, LVI and necrosis, high MUC13 expression (HR, 2.082; 95% CI, 1.115 to 3.889, p = 0.021) were independent predictors of RFS.	('expression', 'MPA', (54, 64))	('necrosis', 'Disease', 'MESH:D009336', (33, 41))	('necrosis', 'biological_process', 'GO:0008220', ('33', '41'))	('RFS', 'Disease', (143, 146))	('high', 'Var', (43, 47))	('necrosis', 'biological_process', 'GO:0001906', ('33', '41'))	('necrosis', 'Disease', (33, 41))	('necrosis', 'biological_process', 'GO:0070265', ('33', '41'))	('necrosis', 'biological_process', 'GO:0008219', ('33', '41'))	('necrosis', 'biological_process', 'GO:0019835', ('33', '41'))
101172	27911274	The C-index of the SSIGN was 0.7440 for OS and 0.7336 for RFS, and improved to 0.7933 for OS (p = 0.009) and 0.7836 for RFS (p = 0.006) when MUC13 expression was added.	('OS', 'Chemical', '-', (90, 92))	('improved', 'PosReg', (67, 75))	('OS', 'Chemical', '-', (40, 42))	('0.7836', 'Var', (109, 115))
101175	27911274	As far as we know, this study was the first investigation illustrating the correlation between high MUC13 expression and unfavorable prognosis of postoperative non-metastatic ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('RCC', 'Disease', (177, 180))	('high', 'Var', (95, 99))	('expression', 'MPA', (106, 116))	('ccRCC', 'Phenotype', 'HP:0006770', (175, 180))	('patients', 'Species', '9606', (181, 189))	('MUC13', 'Protein', (100, 105))
101183	27911274	One of these studies illustrated that exogenous MUC13 expression correlated with remarkable reduction in cell-cell adhesion and significantly (p < 0.05) increases cell motility, proliferation, and tumorigenesis in a xenograft mouse model system with ovarian cancer.	('cell-cell adhesion', 'CPA', (105, 123))	('MUC13', 'Gene', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('proliferation', 'CPA', (178, 191))	('ovarian cancer', 'Disease', 'MESH:D010051', (250, 264))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('cell motility', 'biological_process', 'GO:0048870', ('163', '176'))	('ovarian cancer', 'Disease', (250, 264))	('reduction', 'NegReg', (92, 101))	('increases', 'PosReg', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('cell motility', 'CPA', (163, 176))	('tumor', 'Disease', (197, 202))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('105', '123'))	('exogenous', 'Var', (38, 47))	('ovarian cancer', 'Phenotype', 'HP:0100615', (250, 264))	('mouse', 'Species', '10090', (226, 231))
101193	27911274	Previous study demonstrated that blockage of MUC13 decreased sensitivity of esophageal squamous cell carcinoma cell lines to paclitaxel.	('MUC13', 'Protein', (45, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('paclitaxel', 'Chemical', 'MESH:D017239', (125, 135))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (76, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('decreased', 'NegReg', (51, 60))	('blockage', 'Var', (33, 41))	('esophageal squamous cell carcinoma', 'Disease', (76, 110))	('sensitivity', 'MPA', (61, 72))
101196	27911274	Silencing MUC13 can improve the sensitivity of colorectal cancer cells to chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('colorectal cancer', 'Disease', (47, 64))	('improve', 'PosReg', (20, 27))	('colorectal cancer', 'Disease', 'MESH:D015179', (47, 64))	('sensitivity', 'MPA', (32, 43))	('Silencing', 'Var', (0, 9))	('colorectal cancer', 'Phenotype', 'HP:0003003', (47, 64))	('MUC13', 'Gene', (10, 15))
101200	27911274	High expression of MUC13 is regard as an independent prognostic indicator of early-staged gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('High', 'Var', (0, 4))	('MUC13', 'Gene', (19, 24))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('gastric cancer', 'Disease', (90, 104))
101209	27911274	In conclusion, our observations revealed that high MUC13 expression can independently predicts unfavorable postoperative RFS and OS for ccRCC patients.	('RCC', 'Disease', (138, 141))	('expression', 'MPA', (57, 67))	('MUC13', 'Protein', (51, 56))	('predicts', 'Reg', (86, 94))	('high', 'Var', (46, 50))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('OS', 'Chemical', '-', (129, 131))	('patients', 'Species', '9606', (142, 150))
101240	31424551	However, current studies build phylogenies based on knowledge from only one type of somatic mutation, such as single nucleotide variants (SNVs) and copy number alteration.	('copy number alteration', 'Var', (148, 170))	('single nucleotide variants', 'Var', (110, 136))	('N', 'Chemical', 'MESH:D009584', (139, 140))
101256	31424551	1E-G) and additionally for patients P90, P17, EV001, and EV002 (supplementary figs.	('P90', 'Gene', '83987', (36, 39))	('P17', 'Gene', (41, 44))	('EV002', 'Var', (57, 62))	('patients', 'Species', '9606', (27, 35))	('P17', 'Gene', '653820', (41, 44))	('P90', 'Gene', (36, 39))
101259	31424551	To first validate the use of this method on longitudinal, spatial, and temporal cohorts, we created simulated data sets, A and B, to represent cancer patient profiles through introducing controlled mutational events (fig.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('patient', 'Species', '9606', (150, 157))	('mutational', 'Var', (198, 208))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
101270	31424551	We use these as a basis for comparison, aware that bias will have been introduced as only reads which uniquely aligned to the reference genome have been considered and the variant callers used could only identify SNVs and small indels but not larger aberrations.	('small indels', 'Var', (222, 234))	('SNVs', 'Var', (213, 217))	('N', 'Chemical', 'MESH:D009584', (214, 215))
101291	31424551	This approach allows for the inclusion of all information regardless of whether it would align to a reference genome preventing bias to pipeline specific information and allowing the inclusion of larger insertions and deletions or chromosomal rearrangements which would be difficult to align.	('deletions', 'Var', (218, 227))	('ran', 'Gene', (247, 250))	('bias', 'MPA', (128, 132))	('ran', 'Gene', '5901', (247, 250))
101296	31424551	In both cases, clear similarities could be seen when comparing the results of alignment-free analysis to the trees produced using alignment-based approaches, deduced from changes in SNVs and small indels, however, clear and possibly fundamental differences could be seen.	('SNVs', 'Gene', (182, 186))	('changes', 'Var', (171, 178))	('N', 'Chemical', 'MESH:D009584', (183, 184))
101297	31424551	This may be a result of unassessed gene fusion events, larger indels or chromosomal rearrangements which are also contributing to the tumors mutational landscape and therefore affecting the evolutionary pathway of these cancer patients.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('evolutionary pathway', 'Pathway', (190, 210))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('contributing', 'Reg', (114, 126))	('affecting', 'Reg', (176, 185))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('larger indels', 'Var', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Disease', (220, 226))	('ran', 'Gene', (88, 91))	('patients', 'Species', '9606', (227, 235))	('ran', 'Gene', '5901', (88, 91))
101306	31424551	Both the glioma and the ccRCC cohort were preprocessed using the same steps prior to applying our algorithm: SAMTOOLs was used to revert files for patient's P17, EV001, EV002, and RMH004 from bam to fastq files to allow us to work with the raw reads obtained from sequencing.	('glioma', 'Disease', (9, 15))	('EV002', 'Var', (169, 174))	('patient', 'Species', '9606', (147, 154))	('P17', 'Gene', (157, 160))	('EV001', 'Var', (162, 167))	('ccRCC', 'Phenotype', 'HP:0006770', (24, 29))	('ccRCC', 'Disease', (24, 29))	('P17', 'Gene', '653820', (157, 160))	('glioma', 'Disease', 'MESH:D005910', (9, 15))	('ccRCC', 'Disease', 'MESH:D002292', (24, 29))	('glioma', 'Phenotype', 'HP:0009733', (9, 15))	('RMH004', 'Var', (180, 186))
101416	30340515	Von-Hippel Lindau (VHL) is an autosomal dominant hereditary cancer predisposition syndrome characterized by abberations in the VHL tumor supressor gene at chromosome location 3p25.3.	('VHL tumor', 'Disease', 'MESH:D006623', (127, 136))	('chromosome', 'cellular_component', 'GO:0005694', ('155', '165'))	('autosomal dominant hereditary cancer', 'Disease', 'MESH:D009386', (30, 66))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('VHL', 'Gene', (19, 22))	('VHL tumor', 'Disease', (127, 136))	('VHL', 'Gene', (127, 130))	('VHL', 'Gene', '7428', (19, 22))	('Von-Hippel Lindau', 'Gene', (0, 17))	('abberations', 'Var', (108, 119))	('VHL', 'Gene', '7428', (127, 130))	('autosomal dominant hereditary cancer', 'Disease', (30, 66))	('Von-Hippel Lindau', 'Gene', '7428', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
101473	30340515	In addition, it has been shown that gain-of-function CTNNB1 mutant protein promotes increased expression of PAX-8 mRNA in mice.	('gain-of-function', 'PosReg', (36, 52))	('mice', 'Species', '10090', (122, 126))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('PAX-8 mRNA', 'Protein', (108, 118))	('increased', 'PosReg', (84, 93))	('protein', 'Protein', (67, 74))	('expression', 'MPA', (94, 104))	('mutant', 'Var', (60, 66))	('CTNNB1', 'Gene', (53, 59))
101477	30340515	Mutant VHL or normal VHL under hypoxic conditions facilitates HIF-1alpha binding to HIF1-beta and HIF-1 protein complex formation which causes downstream transcription of hypoxia-inducible genes such as CA-9.	('HIF-1alpha', 'Gene', (62, 72))	('causes', 'Reg', (136, 142))	('hypoxia', 'Disease', 'MESH:D000860', (171, 178))	('VHL', 'Gene', (21, 24))	('VHL', 'Gene', '7428', (7, 10))	('binding', 'molecular_function', 'GO:0005488', ('73', '80'))	('HIF1-beta', 'Gene', (84, 93))	('protein complex formation', 'biological_process', 'GO:0065003', ('104', '129'))	('protein complex', 'cellular_component', 'GO:0032991', ('104', '119'))	('hypoxic conditions', 'Disease', 'MESH:D009135', (31, 49))	('facilitates', 'PosReg', (50, 61))	('VHL', 'Gene', '7428', (21, 24))	('transcription', 'biological_process', 'GO:0006351', ('154', '167'))	('HIF-1', 'Gene', '3091', (62, 67))	('HIF-1', 'Gene', (62, 67))	('binding', 'Interaction', (73, 80))	('HIF-1alpha', 'Gene', '3091', (62, 72))	('Mutant', 'Var', (0, 6))	('downstream transcription', 'MPA', (143, 167))	('HIF1-beta', 'Gene', '405', (84, 93))	('CA-9', 'Gene', (203, 207))	('HIF-1', 'Gene', '3091', (98, 103))	('hypoxic conditions', 'Disease', (31, 49))	('hypoxia', 'Disease', (171, 178))	('HIF-1', 'Gene', (98, 103))	('VHL', 'Gene', (7, 10))
101480	30340515	Furthermore, both syndromic and sporadic ELSTs have been shown to harbor mutations in the VHL gene; however, to the best of our knowledge molecular profiling of ELST has not yet been attempted.	('VHL', 'Gene', '7428', (90, 93))	('syndromic', 'Disease', (18, 27))	('syndromic', 'Disease', 'MESH:D013577', (18, 27))	('VHL', 'Gene', (90, 93))	('mutations', 'Var', (73, 82))
101482	30340515	Loss of 9q is also frequently seen in ccRCC, where it, along with 14q deletions, denote a poorer prognosis.	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('Loss', 'Var', (0, 4))	('RCC', 'Disease', (40, 43))
101483	30340515	In our cohort, only one ELST patient had combined 3p/9q/14q losses but no tumor recurrence after 1.6 years of follow-up (Case 16).	('patient', 'Species', '9606', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('3p/9q/14q losses', 'Var', (50, 66))
101512	28060746	In keeping with this wide involvement in cellular function, mitochondria can accelerate tumor growth, as shown in studies using mitochondrial DNA (mtDNA)-deficient rho0 cells in mouse xenograft models.	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('128', '145'))	('mouse', 'Species', '10090', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('mitochondria', 'cellular_component', 'GO:0005739', ('60', '72'))	('mitochondria', 'Var', (60, 72))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('mtDNA', 'cellular_component', 'GO:0000262', ('147', '152'))	('tumor', 'Disease', (88, 93))	('accelerate', 'PosReg', (77, 87))
101513	28060746	In clinical studies, single nucleotide variants in mtDNA have been observed to be associated with cancer prognosis.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mtDNA', 'Gene', (51, 56))	('associated', 'Reg', (82, 92))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('mtDNA', 'cellular_component', 'GO:0000262', ('51', '56'))	('single nucleotide variants', 'Var', (21, 47))
101514	28060746	However, reduced or absent mitochondrial function, resulting from mtDNA mutations or low copy number, or reduced mitochondrial content, have been observed in many cancers types, including thyroid, pancreatic, kidney and colon cancer.	('mutations', 'Var', (72, 81))	('absent', 'NegReg', (20, 26))	('cancers', 'Disease', (163, 170))	('mtDNA', 'Gene', (66, 71))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('mtDNA', 'cellular_component', 'GO:0000262', ('66', '71'))	('low copy number', 'Var', (85, 100))	('colon cancer', 'Phenotype', 'HP:0003003', (220, 232))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('reduced', 'NegReg', (9, 16))	('mitochondrial function', 'MPA', (27, 49))	('reduced', 'NegReg', (105, 112))	('pancreatic, kidney and colon cancer', 'Disease', 'MESH:D010190', (197, 232))	('mitochondrial content', 'MPA', (113, 134))	('reduced mitochondrial content', 'Phenotype', 'HP:0040013', (105, 134))	('thyroid', 'Disease', (188, 195))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
101516	28060746	In this study, we investigated how deficiency of mitochondrial function affects tumor phenotype in xenograft models.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('deficiency of mitochondrial function', 'Phenotype', 'HP:0003287', (35, 71))	('tumor', 'Disease', (80, 85))	('deficiency', 'Var', (35, 45))	('affects', 'Reg', (72, 79))
101520	28060746	Finally, using rho0 and its derivative cells, we found that mtDNA deficiency resulted in impaired HIF-1 transactivation during hypoxia.	('transactivation', 'biological_process', 'GO:2000144', ('104', '119'))	('hypoxia', 'Disease', (127, 134))	('hypoxia', 'Disease', 'MESH:D000860', (127, 134))	('impaired HIF-1', 'Disease', (89, 103))	('deficiency', 'Var', (66, 76))	('impaired HIF-1', 'Disease', 'MESH:D009422', (89, 103))	('mtDNA', 'cellular_component', 'GO:0000262', ('60', '65'))	('mtDNA', 'Gene', (60, 65))
101536	28060746	GSEA of HT-29 rho0x and the original rho0n cells, both in culture, showed that several hypoxia-related signature gene sets were highly enriched in HT-29 rho0x cells.	('HT-29', 'CellLine', 'CVCL:0320', (8, 13))	('HT-29 rho0x', 'Var', (147, 158))	('hypoxia', 'Disease', (87, 94))	('hypoxia', 'Disease', 'MESH:D000860', (87, 94))	('HT-29', 'CellLine', 'CVCL:0320', (147, 152))	('GSEA', 'Chemical', '-', (0, 4))
101537	28060746	Furthermore, HIF-1alpha protein was constitutively expressed at higher levels in HT-29 rho0x than in rho0n cells (Figure 3b).	('higher', 'PosReg', (64, 70))	('rho0x', 'Var', (87, 92))	('HT-29', 'CellLine', 'CVCL:0320', (81, 86))	('HIF-1alpha', 'Gene', '3091', (13, 23))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('HT-29 rho0x', 'Var', (81, 92))	('HIF-1alpha', 'Gene', (13, 23))
101538	28060746	Consistent with these findings, for the same amount of nuclear protein, HIF-1 DNA binding activity was twofold higher in HT-29 rho0x cells than in HT-29 rho0n cells (Figure 3c).	('HT-29', 'Var', (121, 126))	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('HIF-1', 'Gene', (72, 77))	('activity', 'MPA', (90, 98))	('DNA binding', 'molecular_function', 'GO:0003677', ('78', '89'))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))	('higher', 'PosReg', (111, 117))	('HT-29', 'CellLine', 'CVCL:0320', (147, 152))	('HT-29', 'CellLine', 'CVCL:0320', (121, 126))	('HIF-1', 'Gene', '3091', (72, 77))
101539	28060746	HIF-1 transcriptional activity was also five times higher in HT-29 rho0x cells than in HT-29 rho0n cells, as determined by HIF-1 reporter assay (Figure 3d).	('HIF-1', 'Gene', (0, 5))	('transcriptional activity', 'MPA', (6, 30))	('HIF-1', 'Gene', (123, 128))	('HT-29', 'CellLine', 'CVCL:0320', (61, 66))	('HT-29', 'CellLine', 'CVCL:0320', (87, 92))	('HIF-1', 'Gene', '3091', (0, 5))	('HIF-1', 'Gene', '3091', (123, 128))	('higher', 'PosReg', (51, 57))	('HT-29 rho0x', 'Var', (61, 72))
101543	28060746	4EBP1 phosphorylation was comparable in HT-29 rho0x and HT-29 rho0n cells; however, levels of phosphorylated p70 S6K and S6 were slightly higher in HT-29 rho0x cells than in HT-29 rho0n cells (Figure 3b).	('4EBP1', 'Gene', (0, 5))	('p70 S6K', 'Gene', '6198', (109, 116))	('phosphorylated', 'MPA', (94, 108))	('levels', 'MPA', (84, 90))	('HT-29', 'CellLine', 'CVCL:0320', (40, 45))	('HT-29 rho0x', 'Var', (148, 159))	('phosphorylation', 'biological_process', 'GO:0016310', ('6', '21'))	('p70 S6K', 'Gene', (109, 116))	('HT-29', 'CellLine', 'CVCL:0320', (174, 179))	('4EBP1', 'Gene', '1978', (0, 5))	('HT-29', 'CellLine', 'CVCL:0320', (56, 61))	('higher', 'PosReg', (138, 144))	('HT-29', 'CellLine', 'CVCL:0320', (148, 153))
101578	28060746	In agreement with our present study, a previous study showed that mtDNA depletion retarded growth of human glioblastoma DBTRG-O5MG and human breast cancer MCF-7 cell tumors in mouse xenograft models.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('mtDNA', 'cellular_component', 'GO:0000262', ('66', '71'))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('glioblastoma', 'Disease', 'MESH:D005909', (107, 119))	('breast cancer MCF-7 cell tumors', 'Disease', 'MESH:D001943', (141, 172))	('human', 'Species', '9606', (135, 140))	('glioblastoma', 'Disease', (107, 119))	('retarded growth', 'Phenotype', 'HP:0001510', (82, 97))	('glioblastoma', 'Phenotype', 'HP:0012174', (107, 119))	('human', 'Species', '9606', (101, 106))	('depletion', 'Var', (72, 81))	('breast cancer MCF-7 cell tumors', 'Disease', (141, 172))	('retarded', 'Disease', (82, 90))	('mtDNA', 'Gene', (66, 71))	('retarded', 'Disease', 'MESH:D008607', (82, 90))	('mouse', 'Species', '10090', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('growth', 'CPA', (91, 97))
101582	28060746	It should be noted that in clinical settings, clear cell renal cell carcinoma (ccRCC) is known to exhibit significant loss of mitochondrial proteins and often shows somatic VHL mutation, resulting in constitutive HIF-alpha subunit stabilization.	('VHL', 'Gene', (173, 176))	('mutation', 'Var', (177, 185))	('HIF-alpha subunit stabilization', 'MPA', (213, 244))	('VHL', 'Gene', '7428', (173, 176))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (46, 77))	('clear cell renal cell carcinoma', 'Disease', (46, 77))	('loss', 'NegReg', (118, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('constitutive', 'MPA', (200, 212))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (46, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (57, 77))	('mitochondrial proteins', 'Protein', (126, 148))
101584	28060746	In ccRCC, development of xenografts with mutated pVHL has been shown to require HIF-alpha activity, and HIF-1 pathway upregulation suppressed biosynthesis of mitochondria.	('biosynthesis of mitochondria', 'MPA', (142, 170))	('mutated', 'Var', (41, 48))	('pVHL', 'Gene', '7428', (49, 53))	('upregulation', 'PosReg', (118, 130))	('pVHL', 'Gene', (49, 53))	('HIF-1', 'Gene', (104, 109))	('mitochondria', 'cellular_component', 'GO:0005739', ('158', '170'))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('ccRCC', 'Disease', (3, 8))	('suppressed', 'NegReg', (131, 141))	('biosynthesis', 'biological_process', 'GO:0009058', ('142', '154'))	('HIF-1', 'Gene', '3091', (104, 109))
101651	32371459	CCR5 blockade prolonged the survival of tumor-bearing mice, resulting in enhanced cytotoxicity of T cells and antigen presentation of dendritic cells but repressed immune checkpoint expression.	('blockade', 'Var', (5, 13))	('CCR5', 'Gene', (0, 4))	('mice', 'Species', '10090', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('prolonged', 'PosReg', (14, 23))	('cytotoxicity of T', 'Disease', 'MESH:D064420', (82, 99))	('survival', 'CPA', (28, 36))	('antigen presentation', 'biological_process', 'GO:0019882', ('110', '130'))	('cytotoxicity of T', 'Disease', (82, 99))	('enhanced', 'PosReg', (73, 81))	('antigen presentation', 'MPA', (110, 130))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('CCR', 'molecular_function', 'GO:0043880', ('0', '3'))
101657	32371459	Genomics studies have revealed that multiple genes with significant mutations, including the von Hippel-Lindau (VHL) gene, polybromo-1 (PBRM1) gene and BRCA1-associated protein 1 (BAP1) gene, are present in ccRCC and are capable of driving tumor development and progression.	('polybromo-1', 'Gene', (123, 134))	('BRCA1-associated protein 1', 'Gene', (152, 178))	('PBRM1', 'Gene', '55193', (136, 141))	('von Hippel-Lindau', 'Gene', (93, 110))	('RCC', 'Phenotype', 'HP:0005584', (209, 212))	('VHL', 'Gene', '7428', (112, 115))	('RCC', 'Disease', (209, 212))	('PBRM1', 'Gene', (136, 141))	('tumor', 'Disease', (240, 245))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('RCC', 'Disease', 'MESH:C538614', (209, 212))	('von Hippel-Lindau', 'Gene', '7428', (93, 110))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('driving', 'PosReg', (232, 239))	('ccRCC', 'Phenotype', 'HP:0006770', (207, 212))	('BRCA1-associated protein 1', 'Gene', '8314', (152, 178))	('BAP1', 'Gene', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('polybromo-1', 'Gene', '55193', (123, 134))	('VHL', 'Gene', (112, 115))	('mutations', 'Var', (68, 77))
101658	32371459	Existing studies indicate that the mechanism of ccRCC development first involves VHL gene mutation on chromosome 3 associated with short-arm deletion of homologous chromosomes; then, the tumor progresses in one of two directions, PBRM1 gene mutation or BAP1 gene mutation.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('VHL', 'Gene', (81, 84))	('PBRM1', 'Gene', (230, 235))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('PBRM1', 'Gene', '55193', (230, 235))	('VHL', 'Gene', '7428', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('RCC', 'Disease', (50, 53))	('short-arm deletion', 'Disease', (131, 149))	('tumor', 'Disease', (187, 192))	('short-arm', 'Phenotype', 'HP:0009824', (131, 140))	('chromosome', 'cellular_component', 'GO:0005694', ('102', '112'))	('mutation', 'Var', (90, 98))	('BAP1', 'Gene', (253, 257))
101659	32371459	Patients with ccRCC with BAP1 mutation are often with higher grade, metastasis development and worse prognosis.	('BAP1', 'Gene', (25, 29))	('higher', 'PosReg', (54, 60))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('RCC', 'Disease', (16, 19))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('mutation', 'Var', (30, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (14, 19))	('Patients', 'Species', '9606', (0, 8))	('metastasis development', 'CPA', (68, 90))
101662	32371459	Several clinical trials have investigated the therapeutic effect of programmed cell death 1 (PD-1) inhibitors in advanced kidney cancer, some of which obtained positive feedback.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('programmed cell death 1', 'Gene', (68, 91))	('kidney cancer', 'Disease', (122, 135))	('inhibitors', 'Var', (99, 109))	('programmed cell death', 'biological_process', 'GO:0012501', ('68', '89'))	('PD-1', 'Gene', (93, 97))	('PD-1', 'Gene', '5133', (93, 97))	('kidney cancer', 'Phenotype', 'HP:0009726', (122, 135))	('kidney cancer', 'Disease', 'MESH:D007680', (122, 135))	('programmed cell death 1', 'Gene', '5133', (68, 91))
101663	32371459	Previous study has demonstrated relatively high immune activity in BAP1-mutant ccRCC (online supplementary figure 1a).	('BAP1-mutant', 'Var', (67, 78))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('immune activity', 'MPA', (48, 63))
101664	32371459	However, whether BAP1-mutant ccRCC is sensitive to ICIs has rarely been documented.	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('BAP1-mutant', 'Var', (17, 28))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
101672	32371459	We found that CCR5 blockade might serve as a novel cancer-immunotherapy strategy to induce a robust immune response and improve clinical outcomes.	('blockade', 'Var', (19, 27))	('improve', 'PosReg', (120, 127))	('CCR', 'molecular_function', 'GO:0043880', ('14', '17'))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('CCR5', 'Protein', (14, 18))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('immune response', 'biological_process', 'GO:0006955', ('100', '115'))
101686	32371459	The mutation rate of BAP1 in ccRCC was 14%-15%.	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('BAP1', 'Gene', (21, 25))	('mutation', 'Var', (4, 12))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
101687	32371459	Genome sequencing in the TCGA cohort identified 40 BAP1-mutant patients with 42 mutations, about 24% (10/42) of which was frameshift mutation, 26% (11/42) of which was nonsense mutation, 12% (5/42) of which splice mutation, 7% (3/42) of which was translation start site mutation.	('translation', 'biological_process', 'GO:0006412', ('247', '258'))	('mutations', 'Var', (80, 89))	('BAP1-mutant', 'Gene', (51, 62))	('patients', 'Species', '9606', (63, 71))	('BAP1-mutant', 'Var', (51, 62))	('frameshift mutation', 'Var', (122, 141))
101688	32371459	Another cohort found that nearly 90% (22/25) BAP1-negative patients with ccRCC measured by immunohistochemistry (IHC) had BAP1 mutation.	('BAP1', 'Gene', (122, 126))	('mutation', 'Var', (127, 135))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('patients', 'Species', '9606', (59, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))
101690	32371459	Consistent with previous reports, we found that BAP1 mutation was typically associated with loss of the protein and indicated poor prognosis for patients with renal cell carcinoma (online supplementary figure 2a-c and online supplementary table 2).	('patients', 'Species', '9606', (145, 153))	('the protein', 'Protein', (100, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('mutation', 'Var', (53, 61))	('protein', 'Protein', (104, 111))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (159, 179))	('BAP1', 'Gene', (48, 52))	('loss', 'NegReg', (92, 96))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('renal cell carcinoma', 'Disease', (159, 179))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (159, 179))
101697	32371459	In BAP1-knockdown subcutaneous tumor-bearing mouse model, tumor volume was significantly reduced after treating with an anti-CCR5 antibody (figure 2B).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('antibody', 'molecular_function', 'GO:0003823', ('130', '138'))	('CCR', 'molecular_function', 'GO:0043880', ('125', '128'))	('tumor', 'Disease', (31, 36))	('mouse', 'Species', '10090', (45, 50))	('antibody', 'cellular_component', 'GO:0042571', ('130', '138'))	('anti-CCR5', 'Var', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('antibody', 'cellular_component', 'GO:0019815', ('130', '138'))	('reduced', 'NegReg', (89, 96))	('antibody', 'cellular_component', 'GO:0019814', ('130', '138'))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (18, 36))
101699	32371459	Moreover, we found that the use of anti-CCR5 antibody caused extensive necrosis of tumor cells (figure 2D) and a similar result was observed by flow cytometry analysis.	('necrosis', 'biological_process', 'GO:0008220', ('71', '79'))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('antibody', 'cellular_component', 'GO:0019815', ('45', '53'))	('necrosis of tumor', 'Disease', 'MESH:D009336', (71, 88))	('CCR', 'molecular_function', 'GO:0043880', ('40', '43'))	('antibody', 'cellular_component', 'GO:0019814', ('45', '53'))	('antibody', 'molecular_function', 'GO:0003823', ('45', '53'))	('necrosis', 'biological_process', 'GO:0070265', ('71', '79'))	('necrosis', 'biological_process', 'GO:0008219', ('71', '79'))	('necrosis of tumor', 'Disease', (71, 88))	('necrosis', 'biological_process', 'GO:0019835', ('71', '79'))	('antibody', 'cellular_component', 'GO:0042571', ('45', '53'))	('anti-CCR5', 'Var', (35, 44))	('necrosis', 'biological_process', 'GO:0001906', ('71', '79'))
101705	32371459	These findings suggested that blockade of CCR5 could effectively inhibit the progression of BAP1-mutant ccRCC.	('progression', 'CPA', (77, 88))	('blockade', 'Var', (30, 38))	('CCR5', 'Gene', (42, 46))	('BAP1-mutant', 'Gene', (92, 103))	('CCR', 'molecular_function', 'GO:0043880', ('42', '45'))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('inhibit', 'NegReg', (65, 72))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))
101706	32371459	After observing a large number of immune cells around the necrotic foci of renal tumor cells treated with the anti-CCR5 antibody, we postulated that blockade of CCR5 could enhance the antitumor immune response.	('tumor', 'Disease', (188, 193))	('CCR5', 'Gene', (161, 165))	('necrotic foci of renal tumor', 'Disease', (58, 86))	('immune response', 'biological_process', 'GO:0006955', ('194', '209'))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('antibody', 'molecular_function', 'GO:0003823', ('120', '128'))	('CCR', 'molecular_function', 'GO:0043880', ('161', '164'))	('enhance', 'PosReg', (172, 179))	('antibody', 'cellular_component', 'GO:0042571', ('120', '128'))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', (81, 86))	('necrotic foci of renal tumor', 'Disease', 'MESH:D007681', (58, 86))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('antibody', 'cellular_component', 'GO:0019815', ('120', '128'))	('renal tumor', 'Phenotype', 'HP:0009726', (75, 86))	('CCR', 'molecular_function', 'GO:0043880', ('115', '118'))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('blockade', 'Var', (149, 157))	('antibody', 'cellular_component', 'GO:0019814', ('120', '128'))
101708	32371459	We found that the proportions of tumor-infiltrating CD8+ T cells and dendritic cells (DCs) were increased in mice treated with anti-CCR5 antibody and the corresponding proportions of interferon (IFN)-gamma+, GZMB+, PRF1+, CD80+ and CD86+ cells were also increased, indicating enhanced cell cytotoxicity and antigen presentation (figure 3A).	('PRF1', 'Gene', '18646', (215, 219))	('antibody', 'Var', (137, 145))	('mice', 'Species', '10090', (109, 113))	('CD8', 'Gene', (52, 55))	('CD8', 'Gene', (232, 235))	('interferon (IFN)-gamma', 'Gene', (183, 205))	('GZMB+', 'CPA', (208, 213))	('interferon (IFN)-gamma', 'Gene', '15978', (183, 205))	('antibody', 'molecular_function', 'GO:0003823', ('137', '145'))	('CD8', 'Gene', '925', (222, 225))	('antibody', 'cellular_component', 'GO:0042571', ('137', '145'))	('tumor', 'Disease', (33, 38))	('enhanced', 'PosReg', (276, 284))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('anti-CCR5 antibody', 'Var', (127, 145))	('antigen presentation', 'biological_process', 'GO:0019882', ('307', '327'))	('antigen presentation', 'MPA', (307, 327))	('antibody', 'cellular_component', 'GO:0019815', ('137', '145'))	('CD8', 'Gene', '925', (52, 55))	('cytotoxicity', 'Disease', (290, 302))	('increased', 'PosReg', (254, 263))	('increased', 'PosReg', (96, 105))	('CD8', 'Gene', '925', (232, 235))	('CD8', 'Gene', (222, 225))	('CCR', 'molecular_function', 'GO:0043880', ('132', '135'))	('cytotoxicity', 'Disease', 'MESH:D064420', (290, 302))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('PRF1', 'Gene', (215, 219))	('antibody', 'cellular_component', 'GO:0019814', ('137', '145'))
101716	32371459	We next explored the specific mechanism by which blockade of CCR5 activated the antitumor immunity.	('CCR5', 'Gene', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('blockade', 'Var', (49, 57))	('activated', 'PosReg', (66, 75))	('CCR', 'molecular_function', 'GO:0043880', ('61', '64'))
101718	32371459	A previous study indicated that CCR5 was partially expressed on the surface of Tregs and blockade of CCR5 affected the recruitment of Tregs.	('recruitment', 'CPA', (119, 130))	('Tregs', 'Chemical', '-', (134, 139))	('affected', 'Reg', (106, 114))	('blockade', 'Var', (89, 97))	('Tregs', 'Chemical', '-', (79, 84))	('CCR5', 'Gene', (101, 105))	('CCR', 'molecular_function', 'GO:0043880', ('32', '35'))	('CCR', 'molecular_function', 'GO:0043880', ('101', '104'))
101720	32371459	In addition, we found that total CD8+ T cells increased and CD4+ T cells and macrophages decreased slightly after CCR5 blockade, but there was no significantly difference in total number of CD8+ T cells, CD4+ T cells and macrophages or corresponding CCR5+ or CCR5- immune cell subtypes between the two groups (online supplementary figure 4a).	('CD8', 'Gene', '925', (190, 193))	('CD8', 'Gene', (33, 36))	('CD8', 'Gene', '925', (33, 36))	('increased', 'PosReg', (46, 55))	('blockade', 'Var', (119, 127))	('T cells increased', 'Phenotype', 'HP:0100828', (38, 55))	('CCR', 'molecular_function', 'GO:0043880', ('250', '253'))	('CCR', 'molecular_function', 'GO:0043880', ('114', '117'))	('CD4', 'Gene', (204, 207))	('CD4', 'Gene', (60, 63))	('CD4', 'Gene', '920', (204, 207))	('CCR', 'molecular_function', 'GO:0043880', ('259', '262'))	('CCR5', 'Gene', (114, 118))	('CD8', 'Gene', (190, 193))	('CD4', 'Gene', '920', (60, 63))
101725	32371459	Given that research has shown positive PD-L1 expression in tumor cells and that our study revealed a decreased number of tumor-infiltrating PD-L1+ cells after treatment with the CCR5-blocking antibody (figure 3A), we analyzed the distribution of PD-L1 in BAP1-mutant tumor tissues and found that tumor cells had a significantly higher proportion of PD-L1+ cells than non-tumor cells (figure 5A).	('tumor', 'Disease', (371, 376))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('antibody', 'cellular_component', 'GO:0019815', ('192', '200'))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('BAP1-mutant', 'Var', (255, 266))	('PD-L1', 'Gene', (39, 44))	('PD-L1', 'Gene', (246, 251))	('tumor', 'Disease', (296, 301))	('tumor', 'Disease', (121, 126))	('PD-L1', 'Gene', '29126', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('PD-L1', 'Gene', '29126', (246, 251))	('PD-L1', 'Gene', (349, 354))	('antibody', 'cellular_component', 'GO:0019814', ('192', '200'))	('CCR', 'molecular_function', 'GO:0043880', ('178', '181'))	('PD-L1', 'Gene', '29126', (349, 354))	('tumor', 'Disease', 'MESH:D009369', (296, 301))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('PD-L1', 'Gene', (140, 145))	('PD-L1', 'Gene', '29126', (140, 145))	('antibody', 'molecular_function', 'GO:0003823', ('192', '200'))	('antibody', 'cellular_component', 'GO:0042571', ('192', '200'))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('higher', 'PosReg', (328, 334))	('tumor', 'Disease', (267, 272))	('BAP1-mutant', 'Gene', (255, 266))
101730	32371459	Moreover, blockade of CCR5 caused PD-L1 expression to decrease without addition of exogenous chemokines.	('expression', 'MPA', (40, 50))	('CCR5', 'Gene', (22, 26))	('decrease', 'NegReg', (54, 62))	('CCR', 'molecular_function', 'GO:0043880', ('22', '25'))	('blockade', 'Var', (10, 18))	('PD-L1', 'Gene', (34, 39))	('PD-L1', 'Gene', '29126', (34, 39))
101732	32371459	The concentration of CCL2-5 was significantly higher in BAP1-mutant ccRCC (figure 5E).	('BAP1-mutant', 'Var', (56, 67))	('concentration', 'MPA', (4, 17))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('CCL', 'molecular_function', 'GO:0044101', ('21', '24'))	('higher', 'PosReg', (46, 52))	('CCL2', 'Gene', (21, 25))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('CCL2', 'Gene', '6347', (21, 25))
101733	32371459	BAP1 is known to interact with BRCA1 and possess deubiquitinating enzyme activity and thus BAP1 can prevent further degradation of the protein.	('BAP1', 'Var', (91, 95))	('BAP1', 'Gene', (0, 4))	('enzyme activity', 'molecular_function', 'GO:0003824', ('66', '81'))	('BRCA1', 'Gene', '672', (31, 36))	('BRCA1', 'Gene', (31, 36))	('deubiquitinating enzyme', 'molecular_function', 'GO:0004843', ('49', '72'))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('prevent', 'NegReg', (100, 107))	('degradation', 'MPA', (116, 127))	('degradation', 'biological_process', 'GO:0009056', ('116', '127'))	('deubiquitinating enzyme activity', 'MPA', (49, 81))	('interact', 'Interaction', (17, 25))
101734	32371459	In the present study, we found BAP1 gene mutation in approximately 10% of patients from TCGA database.	('mutation', 'Var', (41, 49))	('patients', 'Species', '9606', (74, 82))	('BAP1', 'Gene', (31, 35))
101737	32371459	Therefore, BAP1 mutation induces a decrease in target protein expression, which is likely to affect tumor development and progression through downstream pathways.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutation', 'Var', (16, 24))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('affect', 'Reg', (93, 99))	('tumor', 'Disease', (100, 105))	('decrease', 'NegReg', (35, 43))	('BAP1', 'Gene', (11, 15))	('target protein expression', 'MPA', (47, 72))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
101746	32371459	We further explored the specific mechanisms by which CCR5 blockade enhanced the antitumor immunity.	('CCR5', 'Gene', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('CCR', 'molecular_function', 'GO:0043880', ('53', '56'))	('tumor', 'Disease', (84, 89))	('blockade', 'Var', (58, 66))	('enhanced', 'PosReg', (67, 75))
101753	32371459	Intriguingly, we observed stronger immunosuppressive capacity in CCR5+ Tregs than in CCR5- Tregs.	('CCR', 'molecular_function', 'GO:0043880', ('65', '68'))	('CCR5+ Tregs', 'Var', (65, 76))	('Tregs', 'Chemical', '-', (71, 76))	('Tregs', 'Chemical', '-', (91, 96))	('stronger', 'PosReg', (26, 34))	('CCR', 'molecular_function', 'GO:0043880', ('85', '88'))	('immunosuppressive capacity', 'MPA', (35, 61))
101755	32371459	In addition, enhanced infiltration and more IL-10 secreted by CCR5+ Tregs than CCR5- Tregs in lymphoid and central nervous system tissues retarded encephalitis progression in mice model.	('mice', 'Species', '10090', (175, 179))	('enhanced', 'PosReg', (13, 21))	('more', 'PosReg', (39, 43))	('IL-10', 'Protein', (44, 49))	('encephalitis', 'Phenotype', 'HP:0002383', (147, 159))	('Tregs', 'Chemical', '-', (68, 73))	('Tregs', 'Chemical', '-', (85, 90))	('CCR5+', 'Var', (62, 67))	('CCR', 'molecular_function', 'GO:0043880', ('79', '82'))	('infiltration', 'CPA', (22, 34))	('lymphoid and central nervous system tissues retarded encephalitis', 'Disease', 'MESH:D002493', (94, 159))	('IL-10', 'molecular_function', 'GO:0005141', ('44', '49'))	('CCR', 'molecular_function', 'GO:0043880', ('62', '65'))
101757	32371459	Besides recruiting CCR5+ Tregs, we also found that BAP1-mutant tumor cells generated CCL2, CCL3 and CCL5, which bound to CCR5 on the cell surface and induced PD-L1 expression.	('CCR', 'molecular_function', 'GO:0043880', ('121', '124'))	('induced', 'PosReg', (150, 157))	('CCL3', 'Gene', (91, 95))	('CCL', 'molecular_function', 'GO:0044101', ('100', '103'))	('CCL2', 'Gene', (85, 89))	('cell surface', 'cellular_component', 'GO:0009986', ('133', '145'))	('PD-L1', 'Gene', (158, 163))	('Tregs', 'Chemical', '-', (25, 30))	('PD-L1', 'Gene', '29126', (158, 163))	('tumor', 'Disease', (63, 68))	('CCL5', 'Gene', '6352', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('CCR', 'molecular_function', 'GO:0043880', ('19', '22'))	('CCL2', 'Gene', '6347', (85, 89))	('CCL', 'molecular_function', 'GO:0044101', ('91', '94'))	('BAP1-mutant', 'Gene', (51, 62))	('expression', 'MPA', (164, 174))	('CCL3', 'Gene', '6348', (91, 95))	('CCL', 'molecular_function', 'GO:0044101', ('85', '88'))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('bound', 'Interaction', (112, 117))	('BAP1-mutant', 'Var', (51, 62))	('CCL5', 'Gene', (100, 104))
101763	32371459	We demonstrated that BAP1 mutation led to increased expression of CCR5 on Tregs and tumor cells.	('increased', 'PosReg', (42, 51))	('Tregs', 'Chemical', '-', (74, 79))	('CCR', 'molecular_function', 'GO:0043880', ('66', '69'))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('mutation', 'Var', (26, 34))	('BAP1', 'Gene', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('CCR5', 'Gene', (66, 70))	('expression', 'MPA', (52, 62))	('tumor', 'Disease', (84, 89))
101764	32371459	Application of anti-CCR5 antibody induced the antitumor immune response and effectively inhibited tumor growth.	('inhibited', 'NegReg', (88, 97))	('anti-CCR5', 'Var', (15, 24))	('induced', 'PosReg', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('antibody', 'cellular_component', 'GO:0019815', ('25', '33'))	('CCR', 'molecular_function', 'GO:0043880', ('20', '23'))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('antibody', 'cellular_component', 'GO:0019814', ('25', '33'))	('antibody', 'molecular_function', 'GO:0003823', ('25', '33'))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (98, 103))	('immune response', 'biological_process', 'GO:0006955', ('56', '71'))	('tumor', 'Disease', (50, 55))	('antibody', 'cellular_component', 'GO:0042571', ('25', '33'))
101782	31875150	The importance of the GRAM domain was indicated by the mutations disrupting its phosphatase activity leading to X-linked myotubular myopathy in case of myotubularin.	('myotubularin', 'Gene', (152, 164))	('X-linked myotubular myopathy', 'Disease', (112, 140))	('mutations', 'Var', (55, 64))	('leading to', 'Reg', (101, 111))	('myotubularin', 'Gene', '4534', (152, 164))	('X-linked myotubular myopathy', 'Disease', 'MESH:D020914', (112, 140))	('disrupting', 'NegReg', (65, 75))	('phosphatase', 'Enzyme', (80, 91))	('myopathy', 'Phenotype', 'HP:0003198', (132, 140))	('phosphatase activity', 'molecular_function', 'GO:0016791', ('80', '100'))	('activity', 'MPA', (92, 100))
101784	31875150	For instance, recently some reports implicated that GRAMD1B was responsible for chemo-resistance of the ovarian cancer patients, while the isolation of this gene resulted in anti-tumor effect in combination with paclitaxel synergistically.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('ovarian cancer', 'Disease', (104, 118))	('GRAMD1B', 'Gene', (52, 59))	('isolation', 'Var', (139, 148))	('responsible', 'Reg', (64, 75))	('patients', 'Species', '9606', (119, 127))	('ovarian cancer', 'Phenotype', 'HP:0100615', (104, 118))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('GRAMD1B', 'Gene', '57476', (52, 59))	('chemo-resistance', 'MPA', (80, 96))	('ovarian cancer', 'Disease', 'MESH:D010051', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('paclitaxel', 'Chemical', 'MESH:D017239', (212, 222))	('tumor', 'Disease', (179, 184))
101803	31875150	This study carried out the GSEA to elucidate the significant difference in survival rates observed between the low and high GRAMD1C groups after initially generating a sequential list of all genes according to their correlation to GRAMD1C expressions.	('low', 'Var', (111, 114))	('GRAMD1C', 'Gene', (124, 131))	('GRAMD1C', 'Gene', '54762', (231, 238))	('high', 'Var', (119, 123))	('GRAMD1C', 'Gene', (231, 238))	('GSEA', 'Chemical', '-', (27, 31))	('GRAMD1C', 'Gene', '54762', (124, 131))
101823	31875150	Among them, T cells CD4 memory resting (p = 0.034), monocytes (p = 0.004), dendritic cells resting (p < 0.001) and mast cells resting (p < 0.001) are apparently increased in high expression group relative to low expression group.	('CD4', 'Gene', (20, 23))	('CD4', 'Gene', '920', (20, 23))	('monocytes', 'CPA', (52, 61))	('high expression', 'Var', (174, 189))	('mast cells', 'CPA', (115, 125))	('increased', 'PosReg', (161, 170))	('dendritic cells', 'CPA', (75, 90))	('memory', 'biological_process', 'GO:0007613', ('24', '30'))
101824	31875150	In contrast, the proportions of plasma cells (p = 0.017), T cells follicular helper (p = 0.049), T cells regulatory (Tregs) (p < 0.001), macrophages M0 (p < 0.001) are lower in high expression group.	('T cells follicular helper', 'CPA', (58, 83))	('lower', 'NegReg', (168, 173))	('T cells regulatory', 'CPA', (97, 115))	('macrophages M0', 'CPA', (137, 151))	('Tregs', 'Chemical', '-', (117, 122))	('plasma cells', 'CPA', (32, 44))	('high expression', 'Var', (177, 192))
101833	31875150	In the enrichment analysis of MSigDB Collection (c2.cp.biocarta and c2.cp.kegg), significant differences caused by GRAMD1C were revealed in the GSEA (p-value  < 0.05).	('GRAMD1C', 'Gene', '54762', (115, 122))	('c2.cp.kegg', 'Var', (68, 78))	('GRAMD1C', 'Gene', (115, 122))	('GSEA', 'Chemical', '-', (144, 148))	('differences', 'Reg', (93, 104))
101843	31875150	To further investigate the functions of GRAMD1C in KIRC, we performed immune-related analysis using CIBERSORT, which showed that the GRAMD1C expression significantly effects the leukocyte fraction in tumor microenvirenment of KIRC.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('leukocyte', 'MPA', (178, 187))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('GRAMD1C', 'Gene', '54762', (40, 47))	('effects', 'Reg', (166, 173))	('tumor', 'Disease', (200, 205))	('GRAMD1C', 'Gene', (40, 47))	('GRAMD1C', 'Gene', '54762', (133, 140))	('GRAMD1C', 'Gene', (133, 140))	('expression', 'Var', (141, 151))
101862	31875150	The reinvigorate dysfunctional or 'exhausted' cytotoxic CD8+ T cells can be enabled to attack the cancer cells and counter the immunosuppression by anticancer immunotherapy with immune checkpoint inhibitors (ICIs); anti-PD-L1 monoclonal antibodies (mAbs), anti-PD-1 and anti-CTLA-4, have shown remarkable clinical efficacy across a range of different cancers, with advanced-stage disease patients.	('advanced-stage disease', 'Disease', 'MESH:D006223', (365, 387))	('CTLA-4', 'Gene', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (351, 357))	('cancer', 'Disease', (98, 104))	('patients', 'Species', '9606', (388, 396))	('CD8', 'Gene', '925', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (351, 358))	('cancer', 'Disease', (152, 158))	('cancers', 'Disease', (351, 358))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (351, 357))	('anti-PD-1', 'Var', (256, 265))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('anti-PD-L1', 'Var', (215, 225))	('CD8', 'Gene', (56, 59))	('advanced-stage disease', 'Disease', (365, 387))	('cancers', 'Disease', 'MESH:D009369', (351, 358))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('CTLA-4', 'Gene', '1493', (275, 281))	('cancer', 'Disease', (351, 357))
101880	31137694	Patients with combined CTLA-4 expression and PD-1-expression are at highest risk in OS and CSS.	('PD-1-expression', 'Var', (45, 60))	('CSS', 'Disease', (91, 94))	('Patients', 'Species', '9606', (0, 8))	('CSS', 'Chemical', '-', (91, 94))	('OS', 'Chemical', '-', (84, 86))	('CTLA-4', 'Gene', (23, 29))
101881	31137694	In RCC patients, PD-1 expression in TIMC and CTLA-4 expression in TIMC are associated with a worse OS and CSS.	('associated with', 'Reg', (75, 90))	('PD-1', 'Gene', (17, 21))	('TIMC', 'Chemical', '-', (66, 70))	('expression', 'Var', (22, 32))	('worse OS', 'Disease', (93, 101))	('CSS', 'Disease', (106, 109))	('TIMC', 'Chemical', '-', (36, 40))	('RCC', 'Disease', (3, 6))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('OS', 'Chemical', '-', (99, 101))	('CSS', 'Chemical', '-', (106, 109))	('RCC', 'Disease', 'MESH:C538614', (3, 6))	('patients', 'Species', '9606', (7, 15))	('CTLA-4', 'Gene', (45, 51))
101895	31137694	The expression of PD-L1 in TIMC in RCC is associated with a worse prognosis in ccRCC, but the relevance of PD-L1 expression in TIMC in other histological subtypes remains unknown.	('RCC', 'Disease', (35, 38))	('associated', 'Reg', (42, 52))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('TIMC', 'Chemical', '-', (127, 131))	('expression', 'Var', (4, 14))	('PD-L1', 'Gene', (18, 23))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('TIMC', 'Chemical', '-', (27, 31))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
101900	31137694	Polymorphisms in the CTLA-4 gene are associated with a higher risk for high-stage ccRCC and are associated with better OS in metastatic patients treated with TKI.	('CTLA-4', 'Gene', (21, 27))	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('Polymorphisms', 'Var', (0, 13))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('patients', 'Species', '9606', (136, 144))	('OS', 'Chemical', '-', (119, 121))
101914	31137694	The secondary reaction was performed using a Ventana ultraView Universal DAB Detection Kit (Ventana Medical Systems, Tucson, AZ, USA) for anti-PD1 and anti-CD3 and a Ventana OptiView DAB IHC Detection Kit (Ventana Medical Systems, Tucson, AZ, USA) for anti PD-L1.	('anti-CD3', 'Var', (151, 159))	('DAB', 'Chemical', 'MESH:C000469', (73, 76))	('PD1', 'Gene', '5133', (143, 146))	('DAB', 'Chemical', 'MESH:C000469', (183, 186))	('PD1', 'Gene', (143, 146))
101939	31137694	A small subgroup of patients with a positive PD-1 expression in TIMC and a positive CTLA-4 expression in TIMC are at high risk in their estimated mean OS (29.8 vs. 108.8 months, p < 0.001) (Figure 6) and CSS (39.3 vs. 142.4 months, p < 0.001) (Figure 7).	('OS', 'Chemical', '-', (151, 153))	('PD-1', 'Gene', (45, 49))	('CTLA-4', 'Gene', (84, 90))	('expression', 'Var', (50, 60))	('TIMC', 'Chemical', '-', (105, 109))	('CSS', 'Chemical', '-', (204, 207))	('TIMC', 'Chemical', '-', (64, 68))	('patients', 'Species', '9606', (20, 28))
101941	31137694	Though PD-1 expression in TIMC is not associated with an estimated mean OS (65.9 vs. 116.2 months, p = 0.058) and CSS (92.4 vs. 148.0 months, p = 0.329) in primary non-metastatic patients, CTLA-4 expression in TIMC (OS 94.9 vs. 114.8 months, p = 0.041; CSS 125.3 vs. 146.8 months, p = 0.001), and the combination of PD-1 expression in TIMC and CTLA-4 expression in TIMC are significantly associated with a worse estimated mean OS (32.0 vs. 116.2 months, p = 0.001) and CSS (32.0 vs. 148.7 months, p = 0.001) (Table 5).	('TIMC', 'Chemical', '-', (335, 339))	('TIMC', 'Chemical', '-', (210, 214))	('OS', 'Chemical', '-', (216, 218))	('associated', 'Reg', (388, 398))	('OS', 'Chemical', '-', (72, 74))	('CSS', 'Chemical', '-', (114, 117))	('CTLA-4', 'Gene', (344, 350))	('CSS', 'MPA', (469, 472))	('TIMC', 'Chemical', '-', (365, 369))	('CSS', 'Chemical', '-', (469, 472))	('OS', 'Chemical', '-', (427, 429))	('CSS', 'Chemical', '-', (253, 256))	('combination', 'Var', (301, 312))	('patients', 'Species', '9606', (179, 187))	('PD-1', 'Gene', (316, 320))	('TIMC', 'Chemical', '-', (26, 30))
101945	31137694	As shown in the log rank test, PD-1 expression in TIMC (HR = 2.5, p = 0.003) and CTLA-4 expression in TIMC (HR = 2.4, p = 0.017) are significantly associated with a worse OS.	('worse OS', 'Disease', (165, 173))	('associated with', 'Reg', (147, 162))	('expression', 'Var', (36, 46))	('TIMC', 'Chemical', '-', (50, 54))	('PD-1', 'Gene', (31, 35))	('CTLA-4', 'Gene', (81, 87))	('TIMC', 'Chemical', '-', (102, 106))	('OS', 'Chemical', '-', (171, 173))
101947	31137694	The PD-1 and CTLA-4 double positive subgroup is again associated with a worse OS (HR = 4.3, p = 0.002) and a worse CSS (HR = 6.3, p = 0.003) (Table S1).	('CSS', 'MPA', (115, 118))	('CSS', 'Chemical', '-', (115, 118))	('PD-1', 'Gene', (4, 8))	('double positive', 'Var', (20, 35))	('OS', 'Chemical', '-', (78, 80))	('CTLA-4', 'Gene', (13, 19))
101948	31137694	In primary non metastatic patients, only a high tumor grade (G3, HR = 4.4, p = 0.001), CTLA-4 expression (HR = 2.5, p = 0.005), and the combination of PD-1 and CTLA-4 expression (HR = 16.3, p < 0.001) are significantly associated with a worse CSS (Table S2).	('associated with', 'Reg', (219, 234))	('PD-1', 'Gene', (151, 155))	('CSS', 'Disease', (243, 246))	('CTLA-4', 'Gene', (160, 166))	('patients', 'Species', '9606', (26, 34))	('high tumor', 'Disease', (43, 53))	('CSS', 'Chemical', '-', (243, 246))	('high tumor', 'Disease', 'MESH:D009369', (43, 53))	('combination', 'Var', (136, 147))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
101962	31137694	Antibodies to CTLA-4 were the first checkpoint inhibitors with anti-tumor activity.	('tumor', 'Disease', (68, 73))	('Antibodies', 'Var', (0, 10))	('CTLA-4', 'Gene', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
101975	31137694	Large scale trials on adjuvant CI therapies in RCC with antibodies targeting PD-1 and CTLA-4 (NCT03138512; NCT03142334; NCT03288532; NCT03024996) are initiated or ongoing.	('CTLA-4', 'Gene', (86, 92))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('NCT03138512; NCT03142334; NCT03288532; NCT03024996', 'Var', (94, 144))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('PD-1', 'Gene', (77, 81))
102008	31783776	reported that low sLAG3 was associated with advanced stage in non-small-cell lung cancer (NSCLC).	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('LAG3', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('LAG3', 'Gene', '3902', (19, 23))	('associated', 'Reg', (28, 38))	('non-small-cell lung cancer', 'Disease', (62, 88))	('NSCLC', 'Disease', (90, 95))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (62, 88))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('low', 'Var', (14, 17))
102048	31783776	Unconditional logistic regression analysis indicated that high level of sLAG3 (OR, 3.36, 95%CI 1.55-7.27, P = 0.002) were significantly associated with increased risk of advanced disease (Table 2).	('associated', 'Reg', (136, 146))	('LAG3', 'Gene', (73, 77))	('advanced disease', 'Disease', (170, 186))	('LAG3', 'Gene', '3902', (73, 77))	('high level', 'Var', (58, 68))
102049	31783776	Multivariate Cox proportional hazard analysis showed that patients with high level of sPD-L2 had significantly increased risk of recurrence (HR, 2.51, 95%CI 1.46-4.34, P = 9.33E-04), compare to low-level patients.	('PD-L2', 'Gene', '80380', (87, 92))	('patients', 'Species', '9606', (204, 212))	('high level', 'Var', (72, 82))	('recurrence', 'CPA', (129, 139))	('patients', 'Species', '9606', (58, 66))	('PD-L2', 'Gene', (87, 92))
102052	31783776	The most significant biomarker is sBTLA, patients with high sBTLA level had 6-fold increased death risk compare to patients with low sBTLA (95%CI 2.00-18.10, P = 1.4E-03).	('patients', 'Species', '9606', (115, 123))	('BTLA', 'Gene', (61, 65))	('BTLA', 'Gene', '151888', (61, 65))	('BTLA', 'Gene', '151888', (134, 138))	('BTLA', 'Gene', (134, 138))	('death', 'Disease', 'MESH:D003643', (93, 98))	('patients', 'Species', '9606', (41, 49))	('high', 'Var', (55, 59))	('death', 'Disease', (93, 98))	('BTLA', 'Gene', '151888', (35, 39))	('BTLA', 'Gene', (35, 39))
102076	31783776	This finding is partially supported by one previous study suggesting that high PD-L2 expression in tumor is associated with reduced cancer free survival in RCC patients.	('tumor', 'Disease', (99, 104))	('cancer', 'Disease', (132, 138))	('patients', 'Species', '9606', (160, 168))	('reduced', 'NegReg', (124, 131))	('high', 'Var', (74, 78))	('RCC', 'Disease', 'MESH:D002292', (156, 159))	('RCC', 'Disease', (156, 159))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('PD-L2', 'Gene', (79, 84))	('PD-L2', 'Gene', '80380', (79, 84))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
102080	31783776	Our results indicated that high level of sLAG3 is associated with advanced tumor stage in ccRCC patients.	('high level', 'Var', (27, 37))	('ccRCC', 'Disease', 'MESH:D002292', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('ccRCC', 'Disease', (90, 95))	('LAG3', 'Gene', (42, 46))	('patients', 'Species', '9606', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('LAG3', 'Gene', '3902', (42, 46))	('associated', 'Reg', (50, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('tumor', 'Disease', (75, 80))
102083	31783776	However, another study of breast cancer showed that sLAG3 could serve as "Th1" (type I T helper cell) marker and that high level of sLAG3 predicted better OS.	('breast cancer', 'Disease', (26, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('LAG3', 'Gene', (133, 137))	('LAG3', 'Gene', (53, 57))	('Th1', 'Gene', '51497', (74, 77))	('LAG3', 'Gene', '3902', (133, 137))	('LAG3', 'Gene', '3902', (53, 57))	('high level', 'Var', (118, 128))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Th1', 'Gene', (74, 77))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))
102130	33339852	HIF-1alpha is constitutively degraded by the action of prolyl-hydroxylases, which hydroxylate HIF-1alpha on P402 and P564, allowing recognition by the tumor suppressor protein von Hippel Lindau (VHL), an ubiquitin ligase that targets HIF-1alpha for proteasome-mediated degradation.	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('proteasome', 'molecular_function', 'GO:0004299', ('249', '259'))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor suppressor', 'biological_process', 'GO:0051726', ('151', '167'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('204', '213'))	('tumor', 'Disease', (151, 156))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('151', '167'))	('P564', 'Var', (117, 121))	('VHL', 'Gene', '22346', (195, 198))	('VHL', 'Gene', (195, 198))	('P402', 'Var', (108, 112))	('degradation', 'biological_process', 'GO:0009056', ('269', '280'))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('proteasome', 'cellular_component', 'GO:0000502', ('249', '259'))
102136	33339852	However, our reported findings indicate that hypoxia stimulates Rab5 GTP-loading, without any fluctuations in total Rab5 expression, and that these events appear to be adaptative and sustained in time, since re-oxygenation did not diminish elevated Rab5-GTP levels, and RNAi-mediated knockdown of HIF-1alpha decreased hypoxia-driven Rab5 activation.	('Rab5', 'Gene', '5868', (116, 120))	('Rab5', 'Gene', (64, 68))	('Rab5', 'Gene', (116, 120))	('Rab5', 'Gene', '5868', (333, 337))	('hypoxia', 'Disease', (318, 325))	('hypoxia', 'Disease', 'MESH:D000860', (318, 325))	('knockdown', 'Var', (284, 293))	('GTP', 'Chemical', 'MESH:D006160', (254, 257))	('Rab5', 'Gene', (333, 337))	('RNAi', 'biological_process', 'GO:0016246', ('270', '274'))	('GTP', 'Chemical', 'MESH:D006160', (69, 72))	('hypoxia', 'Disease', (45, 52))	('decreased', 'NegReg', (308, 317))	('hypoxia', 'Disease', 'MESH:D000860', (45, 52))	('Rab5', 'Gene', '5868', (249, 253))	('Rab5', 'Gene', '5868', (64, 68))	('Rab5', 'Gene', (249, 253))	('oxygen', 'Chemical', 'MESH:D010100', (211, 217))
102148	33339852	Monoclonal anti-Rab5 (sc46692) and anti-RhoA (sc-418) were from Santa Cruz Biotechnologies.	('Rab5', 'Gene', '5868', (16, 20))	('Rab5', 'Gene', (16, 20))	('RhoA', 'Gene', (40, 44))	('RhoA', 'Gene', '11848', (40, 44))	('sc46692', 'Var', (22, 29))
102154	33339852	Transfections were performed with Optimem (#31985088, Gibco), the Lipofectamine 2000 (#11668027) and the Lipofectamine RNAiMAX (13778075), both from Invitrogen.	('#31985088', 'Var', (43, 52))	('Lipofectamine', 'Chemical', 'MESH:C086724', (105, 118))	('13778075', 'Var', (128, 136))	('#11668027', 'Var', (86, 95))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (66, 84))	('Lipofectamine', 'Chemical', 'MESH:C086724', (66, 79))	('Optimem', 'Chemical', '-', (34, 41))
102189	33339852	As expected, HIF-1alphaP564A/P402A accumulated notably upon transfection, whereas HIF-1alphaWT was increased minimally, when compared with endogenous HIF-1alpha (Fig.	('transfection', 'Var', (60, 72))	('accumulated', 'PosReg', (35, 46))	('P402A', 'Mutation', 'p.P402A', (29, 34))	('HIF-1alphaP564A/P402A', 'Var', (13, 34))
102190	33339852	Remarkably, neither the expression of wild type nor of the stabilized HIF-1alpha mutant altered total Rab5 levels (Fig.	('Rab5', 'Gene', '5868', (102, 106))	('HIF-1alpha', 'Gene', (70, 80))	('Rab5', 'Gene', (102, 106))	('mutant', 'Var', (81, 87))
102192	33339852	Most importantly, expression of HIF-1alphaP564A/P402A, but not HIF-1alphaWT, induced a significant increase of Rab5-GTP levels (Fig.	('Rab5-GTP levels', 'MPA', (111, 126))	('increase', 'PosReg', (99, 107))	('HIF-1alphaP564A/P402A', 'Var', (32, 53))	('P402A', 'Mutation', 'p.P402A', (48, 53))
102194	33339852	These observations were further supported in a cell model of endogenous stabilization of HIF-1alpha, RCC4 clear cell renal cell carcinoma (CCRCC), which harbor an inactivating mutation in VHL, thereby preventing degradation of endogenous HIF-1alpha in normoxic conditions.	('RCC', 'Disease', (141, 144))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (117, 137))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (106, 137))	('RCC4 clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (101, 137))	('preventing', 'NegReg', (201, 211))	('RCC4 clear cell renal cell carcinoma', 'Disease', (101, 137))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Disease', (101, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('degradation', 'biological_process', 'GO:0009056', ('212', '223'))	('VHL', 'Gene', (188, 191))	('VHL', 'Gene', '22346', (188, 191))	('inactivating mutation', 'Var', (163, 184))	('CCRCC', 'Phenotype', 'HP:0006770', (139, 144))	('degradation', 'MPA', (212, 223))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
102195	33339852	As expected, RCC4 had increased levels of endogenous HIF-1alpha, when compared with VHL-reconstituted cells (RCC4+VHL), and these events were not associated with fluctuations in total Rab5 levels (Fig.	('endogenous', 'MPA', (42, 52))	('VHL', 'Gene', '22346', (114, 117))	('VHL', 'Gene', (84, 87))	('VHL', 'Gene', '22346', (84, 87))	('levels', 'MPA', (32, 38))	('increased', 'PosReg', (22, 31))	('Rab5', 'Gene', '5868', (184, 188))	('RCC4', 'Var', (13, 17))	('Rab5', 'Gene', (184, 188))	('VHL', 'Gene', (114, 117))
102198	33339852	As anticipated, C26H29NO2 decreased the expression of HIF-1alpha target genes in hypoxia, including RhoA and VEGFA (Fig.	('expression', 'MPA', (40, 50))	('VEGFA', 'Gene', '22339', (109, 114))	('RhoA', 'Gene', '11848', (100, 104))	('hypoxia', 'Disease', (81, 88))	('RhoA', 'Gene', (100, 104))	('hypoxia', 'Disease', 'MESH:D000860', (81, 88))	('decreased', 'NegReg', (26, 35))	('O2', 'Chemical', 'MESH:D010100', (23, 25))	('VEGFA', 'Gene', (109, 114))	('C26H29NO2', 'Var', (16, 25))
102200	33339852	Intriguingly, C26H29NO2 reduced the amount of Rab5-GTP in hypoxia, to levels that were even below those observed in normoxic conditions (Fig.	('C26H29NO2', 'Var', (14, 23))	('reduced', 'NegReg', (24, 31))	('hypoxia', 'Disease', (58, 65))	('hypoxia', 'Disease', 'MESH:D000860', (58, 65))	('O2', 'Chemical', 'MESH:D010100', (21, 23))
102210	33339852	To validate these observations, we analyzed the expression of these Rab5-GEFs in the RCC4 model of endogenous HIF-1alpha stabilization, and observed that ALS2, but neither RIN2 or RIN3, increased significantly (Fig.	('Rab5', 'Gene', (68, 72))	('Rab5', 'Gene', '5868', (68, 72))	('RIN3', 'Gene', '217835', (180, 184))	('increased', 'PosReg', (186, 195))	('RIN2', 'Gene', '74030', (172, 176))	('RIN3', 'Gene', (180, 184))	('ALS2', 'Var', (154, 158))	('RIN2', 'Gene', (172, 176))
102212	33339852	2C), among which the HRE located at - 792 bp from the TSS was confirmed as the most likely candidate, based on bioinformatics analysis (UCSC Genome Browser Database) indicating the presence of well-known parameters associated with transcription, including enrichment of histone acetylation (H3K27Ac) and hypersensitivity to DNaseI (Fig.	('hypersensitivity', 'biological_process', 'GO:0002524', ('304', '320'))	('histone acetylation', 'biological_process', 'GO:0016573', ('270', '289'))	('transcription', 'biological_process', 'GO:0006351', ('231', '244'))	('H3K27Ac', 'Var', (291, 298))	('hypersensitivity', 'Disease', 'MESH:D004342', (304, 320))	('DNaseI', 'Gene', (324, 330))	('DNaseI', 'Gene', '13419', (324, 330))	('hypersensitivity', 'Disease', (304, 320))
102218	33339852	2E), whereas an almost sixfold increase in ALS2 was detected in RCC4, when compared with RCC4+VHL cells (Fig.	('VHL', 'Gene', '22346', (94, 97))	('ALS2', 'MPA', (43, 47))	('RCC4', 'Var', (64, 68))	('VHL', 'Gene', (94, 97))	('increase', 'PosReg', (31, 39))
102220	33339852	As expected, targeting of endogenous HIF-1alpha abrogated its stabilization in hypoxia and, most importantly, ALS2 induction in hypoxia was prevented by siRNA-mediated downregulation of HIF-1alpha (Fig.	('abrogated', 'NegReg', (48, 57))	('prevented', 'NegReg', (140, 149))	('HIF-1alpha', 'Gene', (186, 196))	('HIF-1alpha', 'Gene', (37, 47))	('targeting', 'Var', (13, 22))	('downregulation', 'NegReg', (168, 182))	('hypoxia', 'Disease', (79, 86))	('hypoxia', 'Disease', 'MESH:D000860', (79, 86))	('hypoxia', 'Disease', 'MESH:D000860', (128, 135))	('hypoxia', 'Disease', (128, 135))	('ALS2', 'Gene', (110, 114))
102226	33339852	Most importantly, siRNA-mediated targeting of endogenous ALS2 prevented Rab5-GTP loading induced by hypoxia (Fig.	('targeting', 'Var', (33, 42))	('Rab5-GTP loading induced', 'MPA', (72, 96))	('prevented', 'NegReg', (62, 71))	('ALS2', 'Gene', (57, 61))	('hypoxia', 'Disease', 'MESH:D000860', (100, 107))	('hypoxia', 'Disease', (100, 107))
102229	33339852	Alternatively, transfection of RCC+VHL cells with GFP-ALS2, but not GFP alone, resulted in partial recovery of cell migration in this model (Fig.	('cell migration', 'biological_process', 'GO:0016477', ('111', '125'))	('RCC+VHL', 'Disease', (31, 38))	('cell migration in this model', 'CPA', (111, 139))	('RCC+VHL', 'Disease', 'MESH:C538614', (31, 38))	('GFP-ALS2', 'Var', (50, 58))	('transfection', 'Var', (15, 27))
102230	33339852	To determine whether the effects of ALS2 on cell migration induced by hypoxia and HIF-1alpha were due to its GEF activity towards Rab5, we used a VPS-deficient mutant of ALS2 (GFP-ALS2DeltaVPS), previously shown to lack Rab5-GEF activity.	('GFP-ALS2DeltaVPS', 'Gene', '74018', (176, 192))	('GFP-ALS2DeltaVPS', 'Gene', (176, 192))	('effects', 'Reg', (25, 32))	('Rab5', 'Gene', '5868', (130, 134))	('GEF', 'molecular_function', 'GO:0005085', ('109', '112'))	('Rab5', 'Gene', (130, 134))	('GEF', 'molecular_function', 'GO:0005085', ('225', '228'))	('ALS2', 'Gene', (170, 174))	('Rab5', 'Gene', '5868', (220, 224))	('hypoxia', 'Disease', 'MESH:D000860', (70, 77))	('Rab5', 'Gene', (220, 224))	('cell migration', 'biological_process', 'GO:0016477', ('44', '58'))	('mutant', 'Var', (160, 166))	('VPS-deficient', 'Disease', 'MESH:D007153', (146, 159))	('hypoxia', 'Disease', (70, 77))	('cell migration', 'CPA', (44, 58))	('VPS-deficient', 'Disease', (146, 159))
102242	33339852	In accordance with our previous observations, hypoxia augmented the extent of lung colonization in siRNA-control cells; however, knockdown of endogenous ALS2 resulted in a significant decrease in hypoxia-induced lung colonization (Fig.	('decrease', 'NegReg', (184, 192))	('hypoxia', 'Disease', (46, 53))	('hypoxia', 'Disease', 'MESH:D000860', (46, 53))	('hypoxia augmented', 'Disease', 'MESH:D000860', (46, 63))	('ALS2', 'Gene', (153, 157))	('lung colonization', 'CPA', (78, 95))	('knockdown', 'Var', (129, 138))	('hypoxia', 'Disease', (196, 203))	('hypoxia', 'Disease', 'MESH:D000860', (196, 203))	('hypoxia augmented', 'Disease', (46, 63))
102245	33339852	To evaluate the relevance of this association in cancer, we assessed the expression of ALS2 in clear cell renal cell carcinoma (CCRCC) biopsies, since this type of cancer is associated with mutations in VHL.	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (95, 126))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('ALS2', 'Gene', (87, 91))	('cancer', 'Disease', (49, 55))	('associated', 'Reg', (174, 184))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('mutations', 'Var', (190, 199))	('clear cell renal cell carcinoma', 'Disease', (95, 126))	('RCC', 'Disease', (130, 133))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (106, 126))	('VHL', 'Gene', (203, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('VHL', 'Gene', '22346', (203, 206))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (95, 126))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('CCRCC', 'Phenotype', 'HP:0006770', (128, 133))
102260	33339852	Specifically, using COS-7 and HeLa cells, ALS2 was shown to promote Rab5 activation at macropinosomes, whereas mutant ALS2 failed to localize to macropinosomes and was associated with defective autophagy/endolysosomal dynamics in HeLa cells and in ALS2-deficient primary cultured neurons.	('activation', 'PosReg', (73, 83))	('Rab5', 'Gene', (68, 72))	('autophagy', 'biological_process', 'GO:0016236', ('194', '203'))	('mutant', 'Var', (111, 117))	('Rab5', 'Gene', '5868', (68, 72))	('ALS2', 'Gene', (118, 122))	('autophagy', 'biological_process', 'GO:0006914', ('194', '203'))	('HeLa', 'CellLine', 'CVCL:0030', (30, 34))	('HeLa', 'CellLine', 'CVCL:0030', (230, 234))	('autophagy/endolysosomal dynamics', 'CPA', (194, 226))	('defective', 'NegReg', (184, 193))
102270	33339852	However, our data obtained in B16-F10 melanoma cells indicate that neither ALS2 knockdown nor 24 h hypoxia affected cell viability.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('knockdown', 'Var', (80, 89))	('hypoxia', 'Disease', 'MESH:D000860', (99, 106))	('B16-F10', 'CellLine', 'CVCL:0159', (30, 37))	('hypoxia', 'Disease', (99, 106))	('ALS2', 'Gene', (75, 79))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))
102281	30556455	Postoperative pathological analysis showed Fuhrman grade I ccRCC, T1bN0M0.	('man', 'Species', '9606', (47, 50))	('T1bN0M0', 'Var', (66, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('Fuhrman', 'Disease', (43, 50))
102295	30556455	Postoperative pathological analysis showed that the tumor was T1bN0M0 stage ccRCC that infiltrated the renal capsule (Figure 1a).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('T1bN0M0', 'Var', (62, 69))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('capsule', 'cellular_component', 'GO:0042603', ('109', '116'))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))
102334	32751108	Molecular studies have clearly shown that CCRCC is universally initiated by Von Hippel Lindau (VHL) gene dysregulation, followed by different types of additional genetic events involving epigenetic regulatory genes, dictating disease progression, aggressiveness, and differential response to treatments.	('Von Hippel Lindau', 'Gene', (76, 93))	('aggressiveness', 'Disease', 'MESH:D001523', (247, 261))	('VHL', 'Gene', (95, 98))	('aggressiveness', 'Disease', (247, 261))	('initiated by', 'Reg', (63, 75))	('VHL', 'Gene', '7428', (95, 98))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('Von Hippel Lindau', 'Gene', '7428', (76, 93))	('RCC', 'Disease', (44, 47))	('men', 'Species', '9606', (297, 300))	('aggressiveness', 'Phenotype', 'HP:0000718', (247, 261))	('dictating', 'Reg', (216, 225))	('gene dysregulation', 'Var', (100, 118))	('dysregulation', 'Var', (105, 118))
102350	32751108	Many autosomal dominant hereditary RCC syndromes have been reported and included those in which germline pathogenic mutations at the level of VHL, MET, FH, SDH A/B/C/D, FLCN, TSC1/TSC2, BAP1, CDC73, and MiTF are involved.	('CDC73', 'Gene', '79577', (192, 197))	('TSC2', 'Gene', '7249', (180, 184))	('SDH A/B/C/D', 'Gene', '6389;6390;6391;6392', (156, 167))	('MET', 'Gene', '79811', (147, 150))	('VHL', 'Gene', '7428', (142, 145))	('autosomal dominant hereditary RCC syndromes', 'Disease', (5, 48))	('TSC2', 'Gene', (180, 184))	('SDH A/B/C/D', 'Gene', (156, 167))	('BAP1', 'Gene', '8314', (186, 190))	('autosomal dominant hereditary RCC syndromes', 'Disease', 'MESH:C538614', (5, 48))	('mutations', 'Var', (116, 125))	('TSC1', 'Gene', (175, 179))	('MiTF', 'Gene', '4286', (203, 207))	('MET', 'Gene', (147, 150))	('TSC1', 'Gene', '7248', (175, 179))	('MiTF', 'Gene', (203, 207))	('FH', 'Gene', '2271', (152, 154))	('FLCN', 'Gene', (169, 173))	('BAP1', 'Gene', (186, 190))	('CDC73', 'Gene', (192, 197))	('VHL', 'Gene', (142, 145))
102351	32751108	FH and BAP1 germline RCCs are associated with more aggressive disease.	('FH', 'Gene', '2271', (0, 2))	('aggressive disease', 'Disease', (51, 69))	('BAP1', 'Gene', (7, 11))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('aggressive disease', 'Disease', 'MESH:D001523', (51, 69))	('RCC', 'Disease', (21, 24))	('germline', 'Var', (12, 20))	('BAP1', 'Gene', '8314', (7, 11))	('associated with', 'Reg', (30, 45))
102355	32751108	The prevalence of germline mutations in known predisposition genes and other genes associated with cancer development was explored in 254 patients with advanced RCC; about 16% carried pathogenic or seemingly pathogenic germline variants at the level of 17 different cancer-predisposition genes: 5.5% of these patients carried mutations at the level of RCC-associated genes, such as FH, BAP1, VHL, MET, SDHA, and SDHB; 10.5% of these patients carried mutations in genes not clearly associated with RCC, including the CHEK2 gene.	('mutations', 'Var', (326, 335))	('RCC', 'Disease', (497, 500))	('men', 'Species', '9606', (113, 116))	('MET', 'Gene', (397, 400))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('RCC', 'Disease', (352, 355))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('BAP1', 'Gene', '8314', (386, 390))	('RCC', 'Disease', 'MESH:C538614', (497, 500))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('RCC', 'Disease', (161, 164))	('patients', 'Species', '9606', (433, 441))	('mutations', 'Var', (450, 459))	('SDHB', 'Gene', (412, 416))	('patients', 'Species', '9606', (138, 146))	('VHL', 'Gene', (392, 395))	('RCC', 'Disease', 'MESH:C538614', (352, 355))	('MET', 'Gene', '79811', (397, 400))	('CHEK2', 'Gene', (516, 521))	('BAP1', 'Gene', (386, 390))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('CHEK2', 'Gene', '11200', (516, 521))	('cancer', 'Disease', (266, 272))	('SDHA', 'Gene', (402, 406))	('VHL', 'Gene', '7428', (392, 395))	('cancer', 'Disease', (99, 105))	('FH', 'Gene', '2271', (382, 384))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('patients', 'Species', '9606', (309, 317))	('variants', 'Var', (228, 236))	('SDHA', 'Gene', '6389', (402, 406))
102360	32751108	Germline VHL gene mutations predispose affected subjects to the development of benign and malignant tumors located at the central nervous system and visceral organs.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('VHL', 'Gene', (9, 12))	('VHL', 'Gene', '7428', (9, 12))	('men', 'Species', '9606', (71, 74))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('malignant tumors', 'Disease', (90, 106))	('tumors located at the central nervous system', 'Phenotype', 'HP:0100006', (100, 144))	('malignant tumors', 'Disease', 'MESH:D009369', (90, 106))	('predispose', 'Reg', (28, 38))	('mutations', 'Var', (18, 27))
102363	32751108	The genotype correlates with the type of tumor risk observed in VHL syndrome: truncating or missense mutations are associated with type 1 and missense mutations with type 2.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('VHL syndrome', 'Disease', (64, 76))	('associated', 'Reg', (115, 125))	('VHL syndrome', 'Disease', 'MESH:D006623', (64, 76))	('truncating', 'MPA', (78, 88))	('missense mutations', 'Var', (142, 160))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('missense mutations', 'Var', (92, 110))
102364	32751108	Recent studies have explored the relationship between genotype and phenotype in VHL syndrome: G239T mutation was linked with VHL type 2B, associated with renal cell carcinoma, pheochromocytoma, and cerebellar hemangioma; A232T mutation was related to VHL type I, associated with renal cell carcinoma alone; G500A mutation was associated with VHL type II, characterized by pheochromocytoma and cerebellar, retina and spinal cord hemangioblastoma; A293G mutation was associated with pheochromocytoma and thus with type IIC VHL.	('pheochromocytoma', 'Disease', (372, 388))	('G500A', 'Var', (307, 312))	('VHL', 'Gene', (80, 83))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (279, 299))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (372, 388))	('G239T', 'Var', (94, 99))	('spinal cord hemangioblastoma', 'Disease', (416, 444))	('renal cell carcinoma', 'Disease', (154, 174))	('A293G', 'SUBSTITUTION', 'None', (446, 451))	('VHL', 'Gene', '7428', (342, 345))	('A293G', 'Var', (446, 451))	('VHL', 'Gene', (251, 254))	('G500A', 'SUBSTITUTION', 'None', (307, 312))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (154, 174))	('VHL syndrome', 'Disease', 'MESH:D006623', (80, 92))	('cerebellar hemangioma', 'Disease', (198, 219))	('VHL', 'Gene', (125, 128))	('pheochromocytoma', 'Disease', 'MESH:D010673', (481, 497))	('VHL', 'Gene', '7428', (80, 83))	('cerebellar hemangioma', 'Phenotype', 'HP:0006880', (198, 219))	('VHL', 'Gene', (521, 524))	('spinal cord hemangioblastoma', 'Phenotype', 'HP:0009713', (416, 444))	('A232T', 'Var', (221, 226))	('spinal cord hemangioblastoma', 'Disease', 'MESH:D018325', (416, 444))	('VHL', 'Gene', '7428', (251, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('renal cell carcinoma', 'Disease', (279, 299))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (279, 299))	('pheochromocytoma', 'Disease', (481, 497))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (481, 497))	('pheochromocytoma', 'Disease', 'MESH:D010673', (176, 192))	('VHL', 'Gene', '7428', (125, 128))	('VHL', 'Gene', '7428', (521, 524))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (428, 444))	('A232T', 'SUBSTITUTION', 'None', (221, 226))	('cerebellar hemangioma', 'Disease', 'MESH:D006391', (198, 219))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (154, 174))	('pheochromocytoma', 'Disease', (176, 192))	('G239T', 'SUBSTITUTION', 'None', (94, 99))	('associated', 'Reg', (465, 475))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (176, 192))	('pheochromocytoma', 'Disease', 'MESH:D010673', (372, 388))	('VHL syndrome', 'Disease', (80, 92))	('VHL', 'Gene', (342, 345))	('hemangioma', 'Phenotype', 'HP:0001028', (209, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))
102365	32751108	The role of different types of germline VHL mutations classified as missense or truncating mutations and two subgroups of missense mutations subdivided according to mutations affecting the HIF-alpha binding site (HM) and mutations not affecting the HIF-alpha binding site (nHM) was also investigated.	('binding', 'molecular_function', 'GO:0005488', ('259', '266'))	('VHL', 'Gene', (40, 43))	('VHL', 'Gene', '7428', (40, 43))	('mutations', 'Var', (44, 53))	('mutations', 'Var', (165, 174))	('binding', 'molecular_function', 'GO:0005488', ('199', '206'))
102367	32751108	The results of this study showed that: (i) Missense mutations are associated with an increased risk of pheochromocytoma, but a lower risk of renal cancer than truncating mutations; among missense mutations, HM mutations conferred a higher risk than nHM mutations of developing renal cancer.	('pheochromocytoma', 'Disease', 'MESH:D010673', (103, 119))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (103, 119))	('renal cancer', 'Disease', 'MESH:D007680', (277, 289))	('mutations', 'Var', (210, 219))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('renal cancer', 'Phenotype', 'HP:0009726', (277, 289))	('renal cancer', 'Disease', (141, 153))	('Missense mutations', 'Var', (43, 61))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('renal cancer', 'Disease', 'MESH:D007680', (141, 153))	('renal cancer', 'Phenotype', 'HP:0009726', (141, 153))	('pheochromocytoma', 'Disease', (103, 119))	('renal cancer', 'Disease', (277, 289))
102369	32751108	Patients with VHL disease and asymptomatic family members carriers of the VHL mutation are annually screened for asymptomatic tumors and starting from the age of 16 years are controlled for RCC by magnetic resonance imaging, thus these patients undergo RCC removal when the tumor mass reaches 3 cm of diameter.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Disease', 'MESH:C538614', (253, 256))	('VHL disease', 'Disease', 'MESH:D006623', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('VHL', 'Gene', (14, 17))	('tumor', 'Disease', (274, 279))	('VHL disease', 'Disease', (14, 25))	('tumors', 'Disease', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('patients', 'Species', '9606', (236, 244))	('Patients', 'Species', '9606', (0, 8))	('undergo', 'Reg', (245, 252))	('VHL', 'Gene', '7428', (14, 17))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('VHL', 'Gene', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (126, 131))	('mutation', 'Var', (78, 86))	('RCC', 'Disease', (190, 193))	('RCC', 'Disease', (253, 256))	('VHL', 'Gene', '7428', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (126, 131))
102371	32751108	Both in CCRCC with germline VHL mutation and in sporadic CCRCC, the most relevant copy number alterations occurred at the level of 3p deletion involving the VHL gene, p9 deletion involving CDKN2A and CDKN2B genes, and of 8q amplification involving the MYC gene amplification.	('CDKN2B', 'Gene', '1030', (200, 206))	('MYC', 'Gene', '4609', (252, 255))	('VHL', 'Gene', (157, 160))	('CDKN2A', 'Gene', '1029', (189, 195))	('RCC', 'Disease', (59, 62))	('VHL', 'Gene', '7428', (157, 160))	('amp', 'Chemical', 'MESH:D000249', (224, 227))	('VHL', 'Gene', (28, 31))	('RCC', 'Disease', (10, 13))	('mutation', 'Var', (32, 40))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('copy number', 'MPA', (82, 93))	('p9 deletion', 'Var', (167, 178))	('MYC', 'Gene', (252, 255))	('amp', 'Chemical', 'MESH:D000249', (261, 264))	('VHL', 'Gene', '7428', (28, 31))	('CDKN2B', 'Gene', (200, 206))	('RCC', 'Disease', 'MESH:C538614', (10, 13))	('CDKN2A', 'Gene', (189, 195))	('germline', 'Var', (19, 27))	('alterations', 'Reg', (94, 105))
102372	32751108	Several studies have explored the evolution at clonal level of RCCs developing in individuals with germline VHL mutations.	('RCC', 'Disease', (63, 66))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('VHL', 'Gene', '7428', (108, 111))	('mutations', 'Var', (112, 121))	('VHL', 'Gene', (108, 111))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
102373	32751108	The genomic analysis on multi-focal RCCs developing in an individual with germline VHL mutation showed that tumors arising in this multifocal context are clonally independent and harbor distinct secondary events, such as loss of chromosome 3p; despite this heterogeneity, the genetic alterations converge upon PI3K-AKT-mTOR signaling pathway; the tumors display only a minimal intratumoral heterogeneity.	('RCC', 'Disease', (36, 39))	('tumors', 'Phenotype', 'HP:0002664', (347, 353))	('tumor', 'Disease', (108, 113))	('AKT', 'Gene', (315, 318))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('tumor', 'Disease', (382, 387))	('tumors', 'Disease', (347, 353))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('mTOR', 'Gene', (319, 323))	('signaling pathway', 'biological_process', 'GO:0007165', ('324', '341'))	('tumor', 'Disease', 'MESH:D009369', (382, 387))	('VHL', 'Gene', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (347, 353))	('AKT', 'Gene', '207', (315, 318))	('chromosome', 'cellular_component', 'GO:0005694', ('229', '239'))	('tumors', 'Disease', (108, 114))	('converge', 'Reg', (296, 304))	('PI3K', 'molecular_function', 'GO:0016303', ('310', '314'))	('mutation', 'Var', (87, 95))	('mTOR', 'Gene', '2475', (319, 323))	('tumor', 'Phenotype', 'HP:0002664', (382, 387))	('VHL', 'Gene', '7428', (83, 86))	('tumor', 'Disease', (347, 352))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (347, 352))
102374	32751108	These observations suggested the development of RCC from germline VHL mutation, follow the evolutionary principles of complementary contingency and convergence.	('germline', 'Var', (57, 65))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('men', 'Species', '9606', (124, 127))	('men', 'Species', '9606', (40, 43))	('VHL', 'Gene', (66, 69))	('VHL', 'Gene', '7428', (66, 69))	('RCC', 'Disease', (48, 51))
102376	32751108	The pattern of nucleotide substitution and the number and type of copy number alterations follow an individual pattern, thus suggesting that the genetic background and the environment plays a significant role in the types of secondary genetic alterations occurring during the development of RCCs with germline VHL mutations.	('men', 'Species', '9606', (179, 182))	('VHL', 'Gene', (310, 313))	('mutations', 'Var', (314, 323))	('VHL', 'Gene', '7428', (310, 313))	('RCC', 'Disease', (291, 294))	('men', 'Species', '9606', (283, 286))	('RCC', 'Disease', 'MESH:C538614', (291, 294))
102377	32751108	Studies based on the analysis of early renal cancers derived from nephrectomies performed in VHL disease patients provided evidence that biallelic inactivation of VHL is observed in preneoplastic renal lesions, in association with HIF activation.	('VHL', 'Gene', '7428', (163, 166))	('renal cancer', 'Phenotype', 'HP:0009726', (39, 51))	('patients', 'Species', '9606', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('VHL', 'Gene', '7428', (93, 96))	('preneoplastic renal lesions', 'Disease', 'MESH:D007674', (182, 209))	('VHL disease', 'Disease', (93, 104))	('biallelic', 'Var', (137, 146))	('renal cancers', 'Disease', 'MESH:D007680', (39, 52))	('renal cancers', 'Disease', (39, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('preneoplastic renal lesions', 'Disease', (182, 209))	('VHL disease', 'Disease', 'MESH:D006623', (93, 104))	('VHL', 'Gene', (93, 96))	('VHL', 'Gene', (163, 166))	('preneoplastic renal lesions', 'Phenotype', 'HP:0009726', (182, 209))	('S', 'Chemical', 'MESH:D013455', (0, 1))
102379	32751108	Biallelic VHL inactivation is also required for the development of sporadic renal cancer, but requires a longer time than in VHL disease since the two VHL alleles must be inactivated.	('sporadic renal cancer', 'Disease', (67, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('VHL', 'Gene', (125, 128))	('renal cancer', 'Phenotype', 'HP:0009726', (76, 88))	('VHL', 'Gene', '7428', (125, 128))	('VHL disease', 'Disease', (125, 136))	('inactivation', 'Var', (14, 26))	('VHL', 'Gene', (151, 154))	('VHL disease', 'Disease', 'MESH:D006623', (125, 136))	('VHL', 'Gene', (10, 13))	('sporadic renal cancer', 'Disease', 'MESH:D007680', (67, 88))	('VHL', 'Gene', '7428', (151, 154))	('VHL', 'Gene', '7428', (10, 13))	('men', 'Species', '9606', (59, 62))
102380	32751108	Sporadic CCRCC displays loss of the short arm of chromosome 3 (observed in >=90% of patients), with a deletion region encompassing four tumor suppressor genes that are also frequent targets for inactivating point mutations on the other chromosomal allele: VHL (with point mutations in 60-70% of cases and epigenetic silencing in about 5-10% of patients), PBRM1 (40%), BAP1 (10%), and SETD2 (10%).	('SETD2', 'Gene', (384, 389))	('RCC', 'Disease', (11, 14))	('point mutations', 'Var', (266, 281))	('patients', 'Species', '9606', (84, 92))	('short arm', 'Phenotype', 'HP:0009824', (36, 45))	('chromosome', 'cellular_component', 'GO:0005694', ('49', '59'))	('SETD2', 'Gene', '29072', (384, 389))	('S', 'Chemical', 'MESH:D013455', (384, 385))	('epigenetic silencing', 'Var', (305, 325))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('tumor', 'Disease', (136, 141))	('patients', 'Species', '9606', (344, 352))	('PBRM1', 'Gene', '55193', (355, 360))	('BAP1', 'Gene', '8314', (368, 372))	('VHL', 'Gene', (256, 259))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('PBRM1', 'Gene', (355, 360))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('136', '152'))	('loss', 'NegReg', (24, 28))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('tumor suppressor', 'biological_process', 'GO:0051726', ('136', '152'))	('BAP1', 'Gene', (368, 372))	('VHL', 'Gene', '7428', (256, 259))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
102383	32751108	In VHL disease, one allele is altered through germline mutations and this explains the high penetrance and the accelerated RCC development observed in these patients.	('accelerated', 'PosReg', (111, 122))	('germline mutations', 'Var', (46, 64))	('VHL disease', 'Disease', 'MESH:D006623', (3, 14))	('patients', 'Species', '9606', (157, 165))	('RCC', 'Disease', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('VHL disease', 'Disease', (3, 14))	('men', 'Species', '9606', (134, 137))
102384	32751108	The retrospective study analysis of the natural history of RCC developing in VHL disease showed that: (i) The mean age of onset was 38.8 years, with a mean initial tumor size of 3.1 cm; (ii) the mean tumor growth rate was 0.49 cm/year; (iii) some factors, such as later age of onset, larger initial tumor size, missense mutation, mutations located at the level of exon 3, were associated with faster tumor growth; (iv) bilateral tumors, large initial tumors, fast tumor growth, and presence of metastases are high-risk factors for poor prognosis in germline VHL-related RCCs.	('tumor', 'Disease', (464, 469))	('VHL disease', 'Disease', 'MESH:D006623', (77, 88))	('tumor', 'Disease', (164, 169))	('tumors', 'Disease', (429, 435))	('VHL', 'Gene', (77, 80))	('tumor', 'Disease', (400, 405))	('VHL disease', 'Disease', (77, 88))	('tumor', 'Disease', 'MESH:D009369', (464, 469))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('RCC', 'Disease', 'MESH:C538614', (570, 573))	('tumors', 'Phenotype', 'HP:0002664', (451, 457))	('metastases', 'Disease', 'MESH:D009362', (494, 504))	('RCC', 'Disease', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('tumor', 'Disease', 'MESH:D009369', (400, 405))	('tumors', 'Disease', 'MESH:D009369', (429, 435))	('tumor', 'Disease', (200, 205))	('VHL', 'Gene', '7428', (77, 80))	('metastases', 'Disease', (494, 504))	('tumors', 'Disease', (451, 457))	('VHL', 'Gene', (558, 561))	('missense mutation', 'Var', (311, 328))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Disease', (429, 434))	('tumor', 'Phenotype', 'HP:0002664', (400, 405))	('tumor', 'Disease', (451, 456))	('tumor', 'Disease', 'MESH:D009369', (429, 434))	('tumors', 'Disease', 'MESH:D009369', (451, 457))	('VHL', 'Gene', '7428', (558, 561))	('tumor', 'Disease', 'MESH:D009369', (451, 456))	('tumors', 'Phenotype', 'HP:0002664', (429, 435))	('mutations', 'Var', (330, 339))	('tumor', 'Disease', (299, 304))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('bilateral', 'Disease', (419, 428))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('RCC', 'Disease', (570, 573))	('tumor', 'Phenotype', 'HP:0002664', (429, 434))
102386	32751108	Germline mutations located at the level of the tyrosine kinase domain of the hepatocyte growth factor receptor, c-Met, are responsible for hereditary papillary renal cell cancer (HPRCC) type I, a very rare form of familial kidney cancer.	('hepatocyte growth factor receptor', 'Gene', (77, 110))	('familial kidney cancer', 'Disease', 'MESH:D007680', (214, 236))	('responsible for', 'Reg', (123, 138))	('papillary renal cell cancer', 'Phenotype', 'HP:0006766', (150, 177))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('PRCC', 'Gene', '5546', (180, 184))	('familial kidney cancer', 'Disease', (214, 236))	('kidney cancer', 'Phenotype', 'HP:0009726', (223, 236))	('hereditary papillary renal cell cancer', 'Disease', 'MESH:C538614', (139, 177))	('Germline', 'Var', (0, 8))	('c-Met', 'Gene', (112, 117))	('hereditary papillary renal cell cancer', 'Disease', (139, 177))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('77', '101'))	('c-Met', 'Gene', '4233', (112, 117))	('hepatocyte growth factor receptor', 'Gene', '4233', (77, 110))	('PRCC', 'Gene', (180, 184))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('renal cell cancer', 'Phenotype', 'HP:0005584', (160, 177))
102387	32751108	The mutants c-Met observed in these patients in suitable cellular and animal models display enhanced and dysregulated kinase activity and induce cell transformation and tumorigenicity.	('kinase activity', 'molecular_function', 'GO:0016301', ('118', '133'))	('cell transformation', 'CPA', (145, 164))	('mutants', 'Var', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('patients', 'Species', '9606', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('induce', 'Reg', (138, 144))	('c-Met', 'Gene', (12, 17))	('tumor', 'Disease', (169, 174))	('c-Met', 'Gene', '4233', (12, 17))	('dysregulated kinase activity', 'MPA', (105, 133))	('enhanced', 'PosReg', (92, 100))
102388	32751108	A fundamental study by Schmidt and coworkers in 1997 led to the identification of missense mutations located in the tyrosine kinase domain of the MET gene in the germline of affected members of HPRCC families, as well as in a subset of sporadic PRCCs.	('PRCC', 'Gene', '5546', (195, 199))	('missense mutations located in', 'Var', (82, 111))	('PRCC', 'Gene', (195, 199))	('MET', 'Gene', '79811', (146, 149))	('PRCC', 'Gene', '5546', (245, 249))	('S', 'Chemical', 'MESH:D013455', (23, 24))	('MET', 'Gene', (146, 149))	('men', 'Species', '9606', (7, 10))	('PRCC', 'Gene', (245, 249))
102389	32751108	The same authors in a study on PRCCs identified 13% of cases with c-MET mutations: half of these patients were found to harbor germline c-MET and the rest only somatic c-MET mutations.	('mutations', 'Var', (72, 81))	('c-MET', 'Gene', '4233', (136, 141))	('c-MET', 'Gene', (66, 71))	('PRCC', 'Gene', '5546', (31, 35))	('c-MET', 'Gene', '4233', (168, 173))	('c-MET', 'Gene', '4233', (66, 71))	('PRCC', 'Gene', (31, 35))	('c-MET', 'Gene', (136, 141))	('c-MET', 'Gene', (168, 173))	('patients', 'Species', '9606', (97, 105))
102391	32751108	MET mutations cause constitutive activation of the cytoplasmic domain of the receptor, stimulate cell growth, and represent the main pathogenetic event in the development of HPRCC.	('MET', 'Gene', '79811', (0, 3))	('cell growth', 'CPA', (97, 108))	('activation', 'PosReg', (33, 43))	('PRCC', 'Gene', (175, 179))	('cell growth', 'biological_process', 'GO:0016049', ('97', '108'))	('MET', 'Gene', (0, 3))	('cytoplasmic domain', 'MPA', (51, 69))	('men', 'Species', '9606', (166, 169))	('stimulate', 'PosReg', (87, 96))	('mutations', 'Var', (4, 13))	('PRCC', 'Gene', '5546', (175, 179))
102392	32751108	Direct DNA diagnosis in HPRCC is based on the identification of mutations at the level of MET exons 15-21, encoding the cytoplasmic domain of the receptor.	('PRCC', 'Gene', '5546', (25, 29))	('PRCC', 'Gene', (25, 29))	('MET', 'Gene', '79811', (90, 93))	('MET', 'Gene', (90, 93))	('mutations', 'Var', (64, 73))	('DNA', 'cellular_component', 'GO:0005574', ('7', '10'))
102394	32751108	Papillary renal neoplasms from both patients with hereditary or somatic c-MET mutations share the same histologic features typical of chromophil basophilic type I PRCC, including macrophages and psammoma bodies; a papillary and/or tubulopapillary architecture is observed in all these tumors; clear cells were commonly detected in variable proportions in all c-MET-mutated PRCCs.	('PRCC', 'Gene', (373, 377))	('Papillary renal neoplasms', 'Disease', 'MESH:D007681', (0, 25))	('PRCC', 'Gene', '5546', (373, 377))	('c-MET', 'Gene', (72, 77))	('c-MET', 'Gene', (359, 364))	('patients', 'Species', '9606', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('neoplasms', 'Phenotype', 'HP:0002664', (16, 25))	('mutations', 'Var', (78, 87))	('PRCC', 'Gene', '5546', (163, 167))	('tumors', 'Disease', (285, 291))	('Papillary renal neoplasms', 'Disease', (0, 25))	('tumors', 'Disease', 'MESH:D009369', (285, 291))	('c-MET', 'Gene', '4233', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('renal neoplasms', 'Phenotype', 'HP:0009726', (10, 25))	('c-MET', 'Gene', '4233', (359, 364))	('PRCC', 'Gene', (163, 167))
102396	32751108	Interestingly, a case of a family with HPRCC was reported with a novel germline missense mutation of c-MET with a histological pattern consisting in multiple adenomas and papillary renal cell carcinomas with focal clear cells and a mixture of type I and type II pattern.	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (171, 202))	('c-MET', 'Gene', (101, 106))	('papillary renal cell carcinomas', 'Disease', (171, 202))	('PRCC', 'Gene', '5546', (40, 44))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (181, 202))	('missense mutation', 'Var', (80, 97))	('adenomas', 'Disease', 'MESH:D000236', (158, 166))	('c-MET', 'Gene', '4233', (101, 106))	('papillary renal cell carcinomas', 'Disease', 'MESH:C538614', (171, 202))	('carcinomas', 'Phenotype', 'HP:0030731', (192, 202))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (181, 201))	('PRCC', 'Gene', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('adenomas', 'Disease', (158, 166))
102398	32751108	Thus, foretinib, a pan-kinase inhibitor of MET, VEGFR2, RON, and AXL, was evaluated in patients with PRCC, showing 50% of partial responses among patients with HPRCC and 20% in PRCC patients with somatic c-MET mutations.	('MET', 'Gene', (43, 46))	('mutations', 'Var', (210, 219))	('patients', 'Species', '9606', (182, 190))	('partial responses', 'MPA', (122, 139))	('PRCC', 'Gene', '5546', (177, 181))	('PRCC', 'Gene', (101, 105))	('RON', 'Gene', (56, 59))	('MET', 'Gene', (206, 209))	('VEGFR2', 'Gene', (48, 54))	('RON', 'Gene', '4486', (56, 59))	('AXL', 'Gene', '558', (65, 68))	('MET', 'Gene', '79811', (43, 46))	('c-MET', 'Gene', '4233', (204, 209))	('patients', 'Species', '9606', (146, 154))	('VEGFR2', 'Gene', '3791', (48, 54))	('c-MET', 'Gene', (204, 209))	('PRCC', 'Gene', (161, 165))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('23', '39'))	('PRCC', 'Gene', '5546', (101, 105))	('foretinib', 'Chemical', 'MESH:C544831', (6, 15))	('PRCC', 'Gene', (177, 181))	('MET', 'Gene', '79811', (206, 209))	('AXL', 'Gene', (65, 68))	('patients', 'Species', '9606', (87, 95))	('PRCC', 'Gene', '5546', (161, 165))
102400	32751108	The majority of patients with this syndrome were found to have germline mutations in PTEN.	('PTEN', 'Gene', '5728', (85, 89))	('germline mutations', 'Var', (63, 81))	('patients', 'Species', '9606', (16, 24))	('PTEN', 'Gene', (85, 89))
102406	32751108	A recent study reported an atypical presentation of Cowden syndrome in a subject with heterozygous mutation C1003T in the PTEN gene, who developed four primary onset carcinomas (one melanoma, two CCRCC, and a follicular variant of papillary thyroid carcinoma).	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('carcinomas', 'Disease', (166, 176))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (231, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('papillary thyroid carcinoma', 'Disease', (231, 258))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (231, 258))	('Cowden syndrome', 'Disease', 'MESH:D006223', (52, 67))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('PTEN', 'Gene', (122, 126))	('melanoma', 'Disease', (182, 190))	('carcinomas', 'Disease', 'MESH:D009369', (166, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (166, 176))	('C1003T', 'Var', (108, 114))	('PTEN', 'Gene', '5728', (122, 126))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (241, 258))	('Cowden syndrome', 'Disease', (52, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('C1003T', 'SUBSTITUTION', 'None', (108, 114))	('RCC', 'Disease', (198, 201))	('melanoma', 'Disease', 'MESH:D008545', (182, 190))
102407	32751108	Interestingly, the analysis of family's genetic background identified deleterious variants in two candidate modifier genes: CECAM1 and MIB2; CECAM1 is a tumor suppressor gene which presents loss of expression in RCC.	('variants', 'Var', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('MIB2', 'Gene', '142678', (135, 139))	('tumor suppressor', 'biological_process', 'GO:0051726', ('153', '169'))	('loss', 'NegReg', (190, 194))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('153', '169'))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('MIB2', 'Gene', (135, 139))	('RCC', 'Disease', (212, 215))	('expression', 'MPA', (198, 208))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('CECAM1', 'Gene', (124, 130))	('CECAM1', 'Gene', (141, 147))
102408	32751108	The BRCA1-associated protein1 (BAP1) syndrome is a tumor predisposition syndrome dependent on the presence of germline pathogenic variants at the level of the tumor suppressor gene BAP1 that predisposes to the development of various types of tumors including uveal melanoma, mesothelioma, cutaneous melanoma, and RCC.	('uveal melanoma', 'Phenotype', 'HP:0007716', (259, 273))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('predisposes to', 'Reg', (191, 205))	('BRCA1-associated protein1', 'Gene', '8314', (4, 29))	('tumor', 'Disease', (242, 247))	('BRCA1-associated protein1', 'Gene', (4, 29))	('BAP1', 'Gene', '8314', (181, 185))	('melanoma', 'Disease', 'MESH:D008545', (265, 273))	('RCC', 'Disease', (313, 316))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('variants', 'Var', (130, 138))	('men', 'Species', '9606', (217, 220))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('BAP1', 'Gene', '8314', (31, 35))	('tumor', 'Disease', (51, 56))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('159', '175'))	('melanoma', 'Phenotype', 'HP:0002861', (299, 307))	('melanoma', 'Disease', (299, 307))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor suppressor', 'biological_process', 'GO:0051726', ('159', '175'))	('RCC', 'Disease', 'MESH:C538614', (313, 316))	('BAP1', 'Gene', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Disease', (159, 164))	('BAP1', 'Gene', (31, 35))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('melanoma', 'Disease', (265, 273))	('tumors', 'Disease', (242, 248))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mesothelioma', 'Disease', (275, 287))	('cutaneous melanoma', 'Disease', (289, 307))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (289, 307))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (289, 307))	('mesothelioma', 'Disease', 'MESH:D008654', (275, 287))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('melanoma', 'Disease', 'MESH:D008545', (299, 307))
102413	32751108	The three most frequently observed missense mutations in these patients are H94R, L100P, and T173C.	('T173C', 'SUBSTITUTION', 'None', (93, 98))	('L100P', 'Var', (82, 87))	('L100P', 'SUBSTITUTION', 'None', (82, 87))	('H94R', 'SUBSTITUTION', 'None', (76, 80))	('T173C', 'Var', (93, 98))	('patients', 'Species', '9606', (63, 71))	('H94R', 'Var', (76, 80))
102414	32751108	identified in a family prone to RCC a germline mutation of BAP1 gene (277A>G; Thr93Ala); furthermore, these authors screened 11 families that included individuals carrying germline deleterious BAP1 mutations and 6 of these families presented with RCC-affected individuals.	('277A>G', 'SUBSTITUTION', 'None', (70, 76))	('RCC', 'Disease', (247, 250))	('BAP1', 'Gene', (59, 63))	('BAP1', 'Gene', '8314', (193, 197))	('BAP1', 'Gene', '8314', (59, 63))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('mutations', 'Var', (198, 207))	('BAP1', 'Gene', (193, 197))	('Thr93Ala', 'Chemical', '-', (78, 86))	('RCC', 'Disease', 'MESH:C538614', (247, 250))	('277A>G', 'Var', (70, 76))
102415	32751108	reported a family with a BAP1 germline variant (41T>A; L14H), disrupting a highly conserved residue in the catalytic domain: 22% of the individuals of this family display RCC, mostly multifocal and of the clear cell type.	('L14H', 'SUBSTITUTION', 'None', (55, 59))	('BAP1', 'Gene', (25, 29))	('L14H', 'Var', (55, 59))	('41T>A', 'SUBSTITUTION', 'None', (48, 53))	('variant', 'Var', (39, 46))	('41T>A', 'Var', (48, 53))	('disrupting', 'NegReg', (62, 72))	('highly conserved residue in the catalytic domain', 'MPA', (75, 123))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('RCC', 'Disease', (171, 174))	('BAP1', 'Gene', '8314', (25, 29))
102418	32751108	Germline mutations of the genes encoding the SDH subunits result in hereditary syndromes associated with the development of paraganglioma-pheochromocytoma, gastrointestinal stromal tumors, and RCC.	('Germline mutations', 'Var', (0, 18))	('associated', 'Reg', (89, 99))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (138, 154))	('RCC', 'Disease', (193, 196))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('hereditary syndromes', 'Disease', 'MESH:D061325', (68, 88))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('paraganglioma', 'Phenotype', 'HP:0002668', (124, 137))	('paraganglioma-pheochromocytoma', 'Disease', (124, 154))	('SDH', 'Gene', (45, 48))	('gastrointestinal stromal tumors', 'Disease', (156, 187))	('paraganglioma-pheochromocytoma', 'Disease', 'MESH:D010673', (124, 154))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (156, 187))	('result in', 'Reg', (58, 67))	('men', 'Species', '9606', (116, 119))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (156, 187))	('hereditary syndromes', 'Disease', (68, 88))
102420	32751108	Most of the renal tumors developing in individuals with SDH deficiency, particularly those associated with germline SDHB mutations, exhibit a distinctive morphology consisting in tumors composed by cuboidal cells with bubbly eosinophilic cytoplasm, arranged in solid nests or in tubules surrounding central spaces.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('mutations', 'Var', (121, 130))	('tumors', 'Disease', (179, 185))	('renal tumors', 'Disease', (12, 24))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('renal tumor', 'Phenotype', 'HP:0009726', (12, 23))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('SDHB', 'Gene', (116, 120))	('SDH deficiency', 'Disease', (56, 70))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('renal tumors', 'Phenotype', 'HP:0009726', (12, 24))	('cytoplasm', 'cellular_component', 'GO:0005737', ('238', '247'))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('SDH deficiency', 'Disease', 'MESH:D007153', (56, 70))	('renal tumors', 'Disease', 'MESH:D007674', (12, 24))
102421	32751108	have reported SDH-deficient renal carcinomas from 27 patients and estimated that 0.05%-0.2% of all carcinomas are SDH deficient; 94% of these tumors displayed the typical morphology of SDH-deficient renal cancers; all the patients performing a genetic evaluation displayed germline SDHB mutations (only in one patient SDHA mutations were detected); a part of these patients had a metastatic disease, associated with high-grade nuclear atypia or coagulative necrosis.	('patients', 'Species', '9606', (365, 373))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('SDH-deficient renal cancers', 'Disease', 'MESH:D007680', (185, 212))	('patients', 'Species', '9606', (222, 230))	('mutations', 'Var', (287, 296))	('necrosis', 'biological_process', 'GO:0008220', ('457', '465'))	('coagulative necrosis', 'Disease', (445, 465))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('SDHA', 'Gene', (318, 322))	('renal carcinomas', 'Phenotype', 'HP:0005584', (28, 44))	('patients', 'Species', '9606', (53, 61))	('SDH-deficient renal carcinomas', 'Disease', 'MESH:C538614', (14, 44))	('SDHA', 'Gene', '6389', (318, 322))	('necrosis', 'biological_process', 'GO:0070265', ('457', '465'))	('necrosis', 'biological_process', 'GO:0019835', ('457', '465'))	('tumors', 'Disease', (142, 148))	('necrosis', 'biological_process', 'GO:0001906', ('457', '465'))	('patient', 'Species', '9606', (310, 317))	('carcinomas', 'Disease', (34, 44))	('patient', 'Species', '9606', (53, 60))	('patient', 'Species', '9606', (365, 372))	('carcinomas', 'Disease', (99, 109))	('renal carcinoma', 'Phenotype', 'HP:0005584', (28, 43))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('patient', 'Species', '9606', (222, 229))	('metastatic disease', 'Disease', (380, 398))	('carcinomas', 'Phenotype', 'HP:0030731', (34, 44))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('SDHB', 'Gene', (282, 286))	('coagulative necrosis', 'Disease', 'MESH:D001778', (445, 465))	('SDH-deficient renal carcinomas', 'Disease', (14, 44))	('renal cancer', 'Phenotype', 'HP:0009726', (199, 211))	('necrosis', 'biological_process', 'GO:0008219', ('457', '465'))	('coagulative necrosis', 'Phenotype', 'HP:0010885', (445, 465))	('carcinomas', 'Disease', 'MESH:D009369', (34, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinomas', 'Disease', 'MESH:D009369', (99, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('SDH-deficient renal cancers', 'Disease', (185, 212))
102422	32751108	reported the characterization of 11 SDH-deficient RCC and observed the common presence of intratumoral mast cells; the majority of patients with SDHB gene mutations exhibited also loss of the second allele.	('patients', 'Species', '9606', (131, 139))	('mutations', 'Var', (155, 164))	('SDHB', 'Gene', (145, 149))	('SDH-deficient RCC', 'Disease', (36, 53))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('SDH-deficient RCC', 'Disease', 'MESH:C538614', (36, 53))	('tumor', 'Disease', (95, 100))
102425	32751108	In some rare patients, SDH mutations may co-occur with Xp11 translocation RCC, characterized by TFE3 chromosomal translocations involving break points in the TFE3 gene; renal cell carcinomas with translocations make part of MiT family translocation renal cell carcinoma and are composed by eosinophilic cells, with cytoplasmic inclusions and prominent nucleoli.	('mutations', 'Var', (27, 36))	('patients', 'Species', '9606', (13, 21))	('TFE3', 'Gene', (96, 100))	('TFE3', 'Gene', '7030', (96, 100))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (169, 189))	('renal cell carcinoma', 'Disease', (249, 269))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (249, 269))	('RCC', 'Disease', (74, 77))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (169, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('renal cell carcinomas', 'Disease', (169, 190))	('TFE3', 'Gene', (158, 162))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('translocations', 'Var', (196, 210))	('TFE3', 'Gene', '7030', (158, 162))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (169, 190))	('SDH', 'Gene', (23, 26))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (169, 189))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (249, 269))
102428	32751108	The most commonly mutated gene was SDHB (with 137G>A being the most frequent mutation) and less frequently SDHC (380A>G being the most frequent mutation) and SDHA.	('380A>G', 'SUBSTITUTION', 'None', (113, 119))	('SDHA', 'Gene', (158, 162))	('137G>A', 'Var', (46, 52))	('SDHB', 'Gene', (35, 39))	('SDHC', 'Gene', (107, 111))	('SDHC', 'Gene', '6391', (107, 111))	('SDHA', 'Gene', '6389', (158, 162))	('137G>A', 'SUBSTITUTION', 'None', (46, 52))	('380A>G', 'Var', (113, 119))
102429	32751108	Rare cases of SDH-deficient renal cell cancers are related to alterations of the SDHA gene: Yakirevich et al.	('SDHA', 'Gene', (81, 85))	('SDH-deficient renal cell cancers', 'Disease', (14, 46))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('SDH-deficient renal cell cancers', 'Disease', 'MESH:C538614', (14, 46))	('renal cell cancer', 'Phenotype', 'HP:0005584', (28, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('SDHA', 'Gene', '6389', (81, 85))	('related', 'Reg', (51, 58))	('alterations', 'Var', (62, 73))
102430	32751108	reported a case of SDH-deficiency RCC, characterized by homozygous deletion of the SDHA gene (9 of the SDHA gene exons were deleted): at immunohistochemical level, the expression of both SDHA and SDHB was lost.	('SDH-deficiency RCC', 'Disease', (19, 37))	('SDHA', 'Gene', '6389', (187, 191))	('SDHA', 'Gene', '6389', (83, 87))	('SDH-deficiency RCC', 'Disease', 'MESH:C538614', (19, 37))	('expression', 'MPA', (168, 178))	('SDHA', 'Gene', (83, 87))	('SDHA', 'Gene', (103, 107))	('SDHA', 'Gene', (187, 191))	('deletion', 'Var', (67, 75))	('lost', 'NegReg', (205, 209))	('SDHB', 'Gene', (196, 200))	('SDHA', 'Gene', '6389', (103, 107))
102431	32751108	The characterization of an SDHB-deficient RCC cell line isolated from young patient carrying the SDHBR46Q mutation was used as a tool to elucidate the alterations of metabolism caused by SDH deficiency.	('SDH deficiency', 'Disease', (187, 201))	('SDH deficiency', 'Disease', 'MESH:D007153', (187, 201))	('mutation', 'Var', (106, 114))	('metabolism', 'biological_process', 'GO:0008152', ('166', '176'))	('SDHBR46Q', 'Gene', (97, 105))	('SDHB-deficient RCC', 'Disease', 'MESH:C538614', (27, 45))	('patient', 'Species', '9606', (76, 83))	('SDHB-deficient RCC', 'Disease', (27, 45))
102433	32751108	The SDH function and molecular organization require two conserved L(I)YR motifs present in SDHB; the SDHBR46Q mutation impairs one of these two L(I)YR motifs, by changing IYR to IYQ and thus determining an incapacity of SDHB to incorporate Fe-S cluster, with its consequent unstability.	('incapacity', 'NegReg', (206, 216))	('impairs', 'NegReg', (119, 126))	('changing', 'Reg', (162, 170))	('IYR', 'MPA', (171, 174))	('mutation', 'Var', (110, 118))	('SDHBR46Q', 'Gene', (101, 109))	('incorporate', 'MPA', (228, 239))	('Fe-S', 'Chemical', '-', (240, 244))
102435	32751108	As a consequence of SDHB degradation, SDHB-mutant cells displayed markedly decreased oxygen consumption, increased succinate levels, and pronounced use of glutamine as the main source of TCA cycle metabolites via reductive carboxylation (reduction of glutamine-derived alpha-ketoglutarate into citrate).	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (269, 288))	('succinate', 'Chemical', 'MESH:D019802', (115, 124))	('glutamine', 'Chemical', 'MESH:D005973', (251, 260))	('oxygen', 'Chemical', 'MESH:D010100', (85, 91))	('glutamine', 'Chemical', 'MESH:D005973', (155, 164))	('TCA cycle', 'biological_process', 'GO:0006099', ('187', '196'))	('degradation', 'biological_process', 'GO:0009056', ('25', '36'))	('degradation', 'Var', (25, 36))	('succinate levels', 'MPA', (115, 131))	('oxygen consumption', 'MPA', (85, 103))	('reductive carboxylation', 'MPA', (213, 236))	('increased', 'PosReg', (105, 114))	('SDHB-mutant', 'Gene', (38, 49))	('citrate', 'Chemical', 'MESH:D019343', (294, 301))	('TCA', 'Chemical', 'MESH:D014238', (187, 190))	('increased succinate levels', 'Phenotype', 'HP:0020149', (105, 131))	('SDHB', 'Gene', (20, 24))	('decreased', 'NegReg', (75, 84))
102437	32751108	Through the study of SDHB-ablated kidney mouse cells it was shown that lack of SDH activity induces the commitment of the cells to consume extracellular pyruvate, inducing Warburg-like bioenergetic features; pyruvate carboxylation shifts glucose-derived carbons into aspartate biosynthesis and, through this mechanism, sustains tumor cell growth.	('ablated kidney', 'Phenotype', 'HP:0000104', (26, 40))	('mouse', 'Species', '10090', (41, 46))	('tumor', 'Disease', (328, 333))	('glucose-derived carbons', 'MPA', (238, 261))	('lack', 'Var', (71, 75))	('carbons', 'Chemical', 'MESH:D002244', (254, 261))	('extracellular', 'cellular_component', 'GO:0005576', ('139', '152'))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('Warburg-like bioenergetic features', 'MPA', (172, 206))	('pyruvate', 'Chemical', 'MESH:D019289', (153, 161))	('pyruvate', 'Chemical', 'MESH:D019289', (208, 216))	('men', 'Species', '9606', (110, 113))	('sustains', 'PosReg', (319, 327))	('SDH', 'Gene', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('cell growth', 'biological_process', 'GO:0016049', ('334', '345'))	('glucose', 'Chemical', 'MESH:D005947', (238, 245))	('aspartate', 'Chemical', 'MESH:D001224', (267, 276))	('aspartate biosynthesis', 'biological_process', 'GO:0006532', ('267', '289'))	('inducing', 'Reg', (163, 171))
102438	32751108	SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite.	('inactivation', 'Var', (4, 16))	('SDH', 'Gene', (0, 3))	('succinate', 'MPA', (52, 61))	('accumulation', 'PosReg', (36, 48))	('succinate', 'Chemical', 'MESH:D019802', (52, 61))
102441	32751108	A pulsed proton magnetic resonance spectroscopy (1)H-MRS sequence was developed, optimized, and applied to imaging of patients with paraganglioma: a succinate peak was detected at 2.44 ppm in all paraganglioma patients carrying an SDHx gene mutation, but not in patients exempt of SDHx mutation.	('SDHx', 'Gene', (231, 235))	('paraganglioma', 'Disease', 'MESH:D010235', (196, 209))	('paraganglioma', 'Disease', (132, 145))	('S', 'Chemical', 'MESH:D013455', (55, 56))	('succinate', 'Chemical', 'MESH:D019802', (149, 158))	('S', 'Chemical', 'MESH:D013455', (231, 232))	('paraganglioma', 'Phenotype', 'HP:0002668', (132, 145))	('paraganglioma', 'Disease', 'MESH:D010235', (132, 145))	('paraganglioma', 'Phenotype', 'HP:0002668', (196, 209))	('paraganglioma', 'Disease', (196, 209))	('mutation', 'Var', (241, 249))	('S', 'Chemical', 'MESH:D013455', (281, 282))	('patients', 'Species', '9606', (210, 218))	('patients', 'Species', '9606', (262, 270))	('patients', 'Species', '9606', (118, 126))
102443	32751108	Succinate accumulated in individuals with germline SDHx mutations acts as an oncometabolite and is responsible at a large extent for the oncogenic effect mediated by SDH mutational deficiency.	('deficiency', 'Disease', (181, 191))	('mutations', 'Var', (56, 65))	('deficiency', 'Disease', 'MESH:D007153', (181, 191))	('Succinate', 'Chemical', 'MESH:D019802', (0, 9))	('mutational', 'Var', (170, 180))	('oncometabolite', 'MPA', (77, 91))	('SDHx', 'Gene', (51, 55))	('SDH', 'Gene', (166, 169))
102449	32751108	Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata, and aggressive papillary renal cancer; according to these observations, it was proposed that FH acts as a tumor suppressor.	('Germline mutations', 'Var', (0, 18))	('FH', 'Gene', '2271', (22, 24))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('202', '218'))	('aggressive papillary renal cancer', 'Disease', (100, 133))	('skin leiomyomata', 'Disease', (78, 94))	('FH', 'Gene', '2271', (189, 191))	('tumor', 'Disease', (202, 207))	('tumor suppressor', 'biological_process', 'GO:0051726', ('202', '218'))	('skin leiomyomata', 'Phenotype', 'HP:0007620', (78, 94))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('dominantly inherited uterine fibroids', 'Disease', (39, 76))	('predispose', 'Reg', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('aggressive papillary renal cancer', 'Disease', 'MESH:D007680', (100, 133))	('FH acts', 'Disease', 'MESH:D006938', (189, 196))	('uterine fibroids', 'Phenotype', 'HP:0000131', (60, 76))	('renal cancer', 'Phenotype', 'HP:0009726', (121, 133))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('skin leiomyomata', 'Disease', 'MESH:C535516', (78, 94))	('papillary renal cancer', 'Phenotype', 'HP:0006766', (111, 133))	('FH acts', 'Disease', (189, 196))
102452	32751108	have investigated 13 patients with FH-deficient renal cancers and observed absent expression in 12/13 cases, germline FH mutations in seven cases, and somatic mutations of FH gene in the remaining four cases.	('FH-deficient renal cancers', 'Disease', 'MESH:D007680', (35, 61))	('FH', 'Gene', '2271', (35, 37))	('mutations', 'Var', (121, 130))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('expression', 'MPA', (82, 92))	('FH-deficient renal cancers', 'Disease', (35, 61))	('FH', 'Gene', '2271', (118, 120))	('patients', 'Species', '9606', (21, 29))	('renal cancer', 'Phenotype', 'HP:0009726', (48, 60))	('absent', 'NegReg', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('FH', 'Gene', '2271', (172, 174))
102456	32751108	These four cases were FH-negative and 2SC-positive at immunohistochemical level and in 3/4 cases harbored germline FH mutations and in 1/4 somatic FH mutations.	('FH', 'Gene', '2271', (147, 149))	('mutations', 'Var', (118, 127))	('FH', 'Gene', '2271', (115, 117))	('S', 'Chemical', 'MESH:D013455', (39, 40))	('FH', 'Gene', '2271', (22, 24))	('harbored', 'Reg', (97, 105))
102457	32751108	Germline FH mutations are observed in about 90% of families with HLRCC.	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('mutations', 'Var', (12, 21))	('FH', 'Gene', '2271', (9, 11))	('RCC', 'Disease', (67, 70))
102459	32751108	In cases positive for FH mutations, the most frequent mutations located along the entire length of the coding region were represented by missense and frameshifts, and more rarely, by non-sense and splice site mutations.	('mutations', 'Var', (25, 34))	('FH', 'Gene', '2271', (22, 24))	('non-sense', 'Var', (183, 192))	('frameshifts', 'Var', (150, 161))	('missense', 'Var', (137, 145))
102460	32751108	In a large series of HLRCC patients, 68 different germline mutations of the FHG gene were identified: 18 truncating or frameshift mutations, 37 missense mutations, 9 splice-site, and 4 large deletions.	('missense mutations', 'Var', (144, 162))	('FH', 'Gene', '2271', (76, 78))	('truncating', 'MPA', (105, 115))	('splice-site', 'Var', (166, 177))	('patients', 'Species', '9606', (27, 35))	('RCC', 'Disease', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('frameshift mutations', 'Var', (119, 139))
102461	32751108	have explored the occurrence of FH gene mutations in a group of patients with phenotypic manifestations consistent with HLRCC reporting in the 13 families explored, 11 complete FH gene deletions, and 2 partial FH gene deletion; kidney cancer was diagnosed in 32% of these patients and in 54% of families possessing either complete or partial FH deletions.	('diagnosed', 'Reg', (246, 255))	('FH', 'Gene', '2271', (210, 212))	('patients', 'Species', '9606', (64, 72))	('kidney cancer', 'Disease', 'MESH:D007680', (228, 241))	('mutations', 'Var', (40, 49))	('FH', 'Gene', '2271', (177, 179))	('kidney cancer', 'Phenotype', 'HP:0009726', (228, 241))	('patients', 'Species', '9606', (272, 280))	('FH', 'Gene', '2271', (32, 34))	('FH', 'Gene', '2271', (342, 344))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('RCC', 'Disease', (122, 125))	('kidney cancer', 'Disease', (228, 241))
102462	32751108	These observations clearly indicate that FH gene deletions, as well as gene mutations are associated with the development of RCCs.	('mutations', 'Var', (76, 85))	('FH', 'Gene', '2271', (41, 43))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('men', 'Species', '9606', (117, 120))	('associated', 'Reg', (90, 100))	('deletions', 'Var', (49, 58))
102476	32751108	The glycolytic shift induced by fumarate deficiency induced several consequences at the level of the AMP-activated pathway (AMPK): (i) AMPK levels were decreased with consequent lowered expression of the iron transported DNMT1; (ii) in turn, reduced DNMT1 levels induced a condition of cytosolic iron deficiency, activating the iron regulatory proteins, IRP1 and IRP2, and increasing the expression of HIF-1alpha; (iii) activation of AMPK or silencing of HIF-1alpha decreases the invasive properties of FH-deficient renal cancer cells.	('AMPK', 'Gene', (434, 438))	('DNMT1', 'Gene', (221, 226))	('AMPK', 'molecular_function', 'GO:0004691', ('434', '438'))	('increasing', 'PosReg', (373, 383))	('DNMT1', 'Gene', '1786', (250, 255))	('decreases', 'NegReg', (466, 475))	('AMPK', 'molecular_function', 'GO:0047322', ('124', '128'))	('AMPK', 'Gene', '5562', (135, 139))	('iron deficiency', 'Disease', 'MESH:C562385', (296, 311))	('HIF-1alpha', 'Gene', (402, 412))	('AMPK', 'molecular_function', 'GO:0050405', ('135', '139'))	('HIF-1alpha', 'Gene', '3091', (455, 465))	('IRP2', 'Gene', (363, 367))	('deficiency', 'Disease', 'MESH:D007153', (41, 51))	('iron deficiency', 'Disease', (296, 311))	('silencing', 'Var', (442, 451))	('AMPK', 'molecular_function', 'GO:0047322', ('434', '438'))	('IRP2', 'Gene', '3658', (363, 367))	('FH-deficient renal cancer', 'Disease', 'MESH:D007680', (503, 528))	('iron', 'Chemical', 'MESH:D007501', (204, 208))	('AMPK', 'Gene', '5562', (124, 128))	('deficiency', 'Disease', 'MESH:D007153', (301, 311))	('AMPK', 'Gene', '5562', (434, 438))	('cancer', 'Phenotype', 'HP:0002664', (522, 528))	('deficiency', 'Disease', (41, 51))	('AMPK', 'molecular_function', 'GO:0004691', ('135', '139'))	('expression', 'MPA', (388, 398))	('DNMT1', 'Gene', '1786', (221, 226))	('DNMT1', 'Gene', (250, 255))	('FH-deficient renal cancer', 'Disease', (503, 528))	('HIF-1alpha', 'Gene', (455, 465))	('AMPK', 'molecular_function', 'GO:0050405', ('124', '128'))	('deficiency', 'Disease', (301, 311))	('iron', 'Chemical', 'MESH:D007501', (328, 332))	('AMPK', 'Gene', (135, 139))	('AMPK', 'molecular_function', 'GO:0050405', ('434', '438'))	('IRP1', 'Gene', (354, 358))	('iron', 'Chemical', 'MESH:D007501', (296, 300))	('IRP1', 'Gene', '48', (354, 358))	('AMPK', 'molecular_function', 'GO:0004691', ('124', '128'))	('AMPK', 'molecular_function', 'GO:0047322', ('135', '139'))	('renal cancer', 'Phenotype', 'HP:0009726', (516, 528))	('HIF-1alpha', 'Gene', '3091', (402, 412))	('activating', 'PosReg', (313, 323))	('fumarate', 'Chemical', 'MESH:D005650', (32, 40))	('AMPK', 'Gene', (124, 128))
102486	32751108	Through the study of numerous families inheriting the mutated gene responsible for BHD syndrome it is estimated an increased risk of developing RCC for BHD-affected family members of about 7-fold in comparison with unaffected individuals.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('BHD', 'Disease', 'MESH:C564185', (152, 155))	('BHD syndrome', 'Disease', 'MESH:C564185', (83, 95))	('BHD', 'Disease', (83, 86))	('mutated gene', 'Var', (54, 66))	('BHD', 'Disease', (152, 155))	('RCC', 'Disease', (144, 147))	('BHD syndrome', 'Disease', (83, 95))	('BHD', 'Disease', 'MESH:C564185', (83, 86))
102492	32751108	The majority of FLCN mutations identified in the germline of BHD patients are frameshift mutations (insertion/deletion), nonsense mutations that are predicted to truncate and to inactivate the FLCN protein.	('BHD', 'Disease', (61, 64))	('BHD', 'Disease', 'MESH:C564185', (61, 64))	('inactivate', 'NegReg', (178, 188))	('frameshift mutations', 'Var', (78, 98))	('FLCN protein', 'Protein', (193, 205))	('patients', 'Species', '9606', (65, 73))	('protein', 'cellular_component', 'GO:0003675', ('198', '205'))	('FLCN', 'Gene', (16, 20))	('protein', 'Protein', (198, 205))	('mutations', 'Var', (21, 30))
102494	32751108	These conclusions were supported by a study carried out by Vocke and coworkers on 77 renal tumors derived from 12 patients with germline FLCN mutations to identify somatic mutations in the second copy of BHD, showing FLCN somatic mutations in 53% of cases and loss-of-heterozygosity at the BHD locus in 17% of cases.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (172, 181))	('BHD', 'Disease', (290, 293))	('mutations', 'Var', (142, 151))	('renal tumors', 'Phenotype', 'HP:0009726', (85, 97))	('BHD', 'Disease', 'MESH:C564185', (290, 293))	('BHD', 'Disease', 'MESH:C564185', (204, 207))	('renal tumors', 'Disease', (85, 97))	('renal tumors', 'Disease', 'MESH:D007674', (85, 97))	('mutations', 'Var', (230, 239))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('FLCN', 'Gene', (137, 141))	('loss-of-heterozygosity', 'NegReg', (260, 282))	('patients', 'Species', '9606', (114, 122))	('BHD', 'Disease', (204, 207))	('renal tumor', 'Phenotype', 'HP:0009726', (85, 96))
102496	32751108	The study of some germline missense mutations in the folliculin gene, such as H255Y and K508R, observed in BHD patients with renal carcinomas has directly supported their pathogenic role: the FLCN H255Y mutant protein displayed a loss of its tumor suppressive function inducing kidney cell proliferation and the clinical manifestations of BHD, the FLCN K508R mutant protein exerted a dominant negative effect on the function of WT FLCN in the regulation of kidney cell proliferation.	('clinical manifestations', 'CPA', (312, 335))	('renal carcinomas', 'Disease', (125, 141))	('H255Y', 'SUBSTITUTION', 'None', (197, 202))	('renal carcinomas', 'Phenotype', 'HP:0005584', (125, 141))	('cell proliferation', 'biological_process', 'GO:0008283', ('464', '482'))	('K508R', 'Var', (353, 358))	('tumor', 'Disease', (242, 247))	('folliculin', 'Gene', (53, 63))	('protein', 'cellular_component', 'GO:0003675', ('210', '217'))	('K508R', 'Var', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('BHD', 'Disease', 'MESH:C564185', (339, 342))	('H255Y', 'Var', (78, 83))	('folliculin', 'Gene', '201163', (53, 63))	('K508R', 'SUBSTITUTION', 'None', (353, 358))	('FLCN', 'Gene', (348, 352))	('negative', 'NegReg', (393, 401))	('protein', 'cellular_component', 'GO:0003675', ('366', '373'))	('BHD', 'Disease', (339, 342))	('cell proliferation', 'biological_process', 'GO:0008283', ('285', '303'))	('H255Y', 'Var', (197, 202))	('K508R', 'SUBSTITUTION', 'None', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('renal carcinomas', 'Disease', 'MESH:C538614', (125, 141))	('BHD', 'Disease', 'MESH:C564185', (107, 110))	('loss', 'NegReg', (230, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('regulation', 'biological_process', 'GO:0065007', ('443', '453'))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('H255Y', 'SUBSTITUTION', 'None', (78, 83))	('BHD', 'Disease', (107, 110))	('kidney cell proliferation', 'CPA', (278, 303))	('renal carcinoma', 'Phenotype', 'HP:0005584', (125, 140))	('patients', 'Species', '9606', (111, 119))
102500	32751108	All patients displayed FLCN germline mutations; somatic FLCN mutations were observed in 25 out of the 29 kidney tumors: 20 tumors displayed frameshift/nonsense mutations or loss of heterozygosity at the level of the allele not affected by the germline mutation.	('kidney tumors', 'Phenotype', 'HP:0009726', (105, 118))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('kidney tumor', 'Phenotype', 'HP:0009726', (105, 117))	('FLCN', 'Gene', (56, 60))	('loss of', 'NegReg', (173, 180))	('mutations', 'Var', (61, 70))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('kidney tumors', 'Disease', (105, 118))	('patients', 'Species', '9606', (4, 12))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('kidney tumors', 'Disease', 'MESH:D007680', (105, 118))	('frameshift/nonsense mutations', 'Var', (140, 169))	('tumors', 'Disease', (112, 118))
102502	32751108	The number of somatic variants was similar in the various histological subtypes of BHD-associated kidney tumors; the frequency of gene mutations was usually low in these tumors, with variants in chromatin remodeling genes being frequently observed (59% of cases); furthermore, variants in genes associated with the mitochondrial pathway, lipid metabolism, and glycolytic pathway were observed in 28%, 24%, and 7% of cases, respectively.	('tumors', 'Disease', (105, 111))	('BHD-associated kidney tumors', 'Disease', 'MESH:C564185', (83, 111))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('195', '215'))	('lipid', 'Chemical', 'MESH:D008055', (338, 343))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('BHD-associated kidney tumors', 'Disease', (83, 111))	('kidney tumors', 'Phenotype', 'HP:0009726', (98, 111))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('low', 'NegReg', (157, 160))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('chromatin', 'cellular_component', 'GO:0000785', ('195', '204'))	('variants', 'Var', (277, 285))	('kidney tumor', 'Phenotype', 'HP:0009726', (98, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('observed', 'Reg', (384, 392))	('tumors', 'Disease', (170, 176))	('lipid metabolism', 'biological_process', 'GO:0006629', ('338', '354'))
102504	32751108	It is of interest to note that at molecular level BHD-related hybrid oncocytic/chromophobe tumors can be differentiated from the sporadic counterpart of these tumors in that these last tumors have copy number losses in chromosomes 1 and XY, but lacks recurrent mutations.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('BHD', 'Disease', 'MESH:C564185', (50, 53))	('copy number losses', 'Var', (197, 215))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('chromophobe tumors', 'Disease', (79, 97))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('BHD', 'Disease', (50, 53))	('chromophobe tumors', 'Disease', 'MESH:D000238', (79, 97))
102506	32751108	The protein folliculin is involved in numerous biological processes, such as membrane trafficking, energy and nutrient homeostasis, and lysosomal biogenesis, and the mutations affecting this protein generate different phenotypes, in relation with their cellular context.	('membrane', 'cellular_component', 'GO:0016020', ('77', '85'))	('mutations', 'Var', (166, 175))	('protein', 'cellular_component', 'GO:0003675', ('191', '198'))	('homeostasis', 'biological_process', 'GO:0042592', ('119', '130'))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))	('folliculin', 'Gene', '201163', (12, 22))	('folliculin', 'Gene', (12, 22))
102510	32751108	Thus, functional studies have shown that FNIP1 and FNIP2 act as tumor suppressors since mice deficient in FNIP1 and FNIP2 tumors display tumors developing at the level of several organs.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (137, 142))	('tumors display tumors', 'Disease', 'MESH:D009369', (122, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('FNIP2', 'Gene', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('FNIP1', 'Gene', (106, 111))	('deficient', 'Var', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mice', 'Species', '10090', (88, 92))	('tumor', 'Disease', (122, 127))	('tumors display tumors', 'Disease', (122, 143))
102514	32751108	Studies in mice with the kidney-targeted FLCN inactivation develop polycystic kidneys and cystic tumors, exhibiting activation of mTORC1.	('cystic tumors', 'Disease', (90, 103))	('FLCN', 'Gene', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cystic tumors', 'Disease', 'MESH:D052177', (90, 103))	('mTORC1', 'Gene', (130, 136))	('polycystic kidneys', 'Disease', 'MESH:D007690', (67, 85))	('develop', 'Reg', (59, 66))	('mice', 'Species', '10090', (11, 15))	('mTORC1', 'cellular_component', 'GO:0031931', ('130', '136'))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('inactivation', 'Var', (46, 58))	('mTORC1', 'Gene', '382056', (130, 136))	('polycystic kidneys', 'Disease', (67, 85))	('polycystic kidneys', 'Phenotype', 'HP:0000113', (67, 85))	('S', 'Chemical', 'MESH:D013455', (0, 1))
102515	32751108	Homozygous deletion of FLCN in mice resulted in early embryonic lethality; FLCN heterozygous knockout (FLCN+/-) mice appeared normal at birth, but developed kidney cysts and solid tumors, as they aged, of different histologic types (oncocytic hybrid, oncocytoma, and clear cell carcinoma with concomitant loss of heterozygosity of FLCN); these tumors displayed increased mTORC1 and TORC2 activity.	('mTORC1', 'Gene', '382056', (371, 377))	('TORC2', 'Gene', '74343', (382, 387))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('mice', 'Species', '10090', (31, 35))	('solid tumors', 'Disease', 'MESH:D009369', (174, 186))	('TORC2', 'Gene', (382, 387))	('FLCN', 'Gene', (23, 27))	('tumors', 'Disease', 'MESH:D009369', (344, 350))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('embryonic lethality', 'Disease', (54, 73))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (267, 287))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('kidney cysts', 'Disease', 'MESH:D007674', (157, 169))	('increased', 'PosReg', (361, 370))	('tumors', 'Disease', (180, 186))	('oncocytoma', 'Disease', (251, 261))	('TORC2', 'cellular_component', 'GO:0031932', ('382', '387'))	('embryonic lethality', 'Disease', 'MESH:D020964', (54, 73))	('kidney cysts', 'Phenotype', 'HP:0000107', (157, 169))	('kidney cysts', 'Disease', (157, 169))	('tumors', 'Phenotype', 'HP:0002664', (344, 350))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('mice', 'Species', '10090', (112, 116))	('solid tumors', 'Disease', (174, 186))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('tumors', 'Disease', (344, 350))	('mTORC1', 'Gene', (371, 377))	('deletion', 'Var', (11, 19))	('oncocytoma', 'Disease', 'MESH:D018249', (251, 261))	('clear cell carcinoma', 'Disease', (267, 287))	('mTORC1', 'cellular_component', 'GO:0031931', ('371', '377'))
102516	32751108	The investigation of other mouse models further supported a role for FLCN as a positive regulator of TORC1 and provided evidence that inappropriate mTORC1 levels can be associated with renal cancerogenesis.	('mTORC1', 'Gene', (148, 154))	('TORC1', 'cellular_component', 'GO:0031931', ('101', '106'))	('inappropriate', 'Var', (134, 147))	('mouse', 'Species', '10090', (27, 32))	('renal cancerogenesis', 'Disease', 'MESH:D007674', (185, 205))	('renal cancer', 'Phenotype', 'HP:0009726', (185, 197))	('TORC1', 'Gene', (101, 106))	('mTORC1', 'cellular_component', 'GO:0031931', ('148', '154'))	('mTORC1', 'Gene', '382056', (148, 154))	('associated', 'Reg', (169, 179))	('renal cancerogenesis', 'Disease', (185, 205))	('TORC1', 'Gene', '382056', (101, 106))	('TORC1', 'Gene', '382056', (149, 154))	('TORC1', 'Gene', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
102521	32751108	Furthermore, various studies have shown that FLCN deficiency triggers AMPK activation; furthermore, FNIP1 mutations are associated with high AMPK activity.	('FNIP1', 'Gene', (100, 105))	('AMPK', 'Gene', (141, 145))	('associated', 'Reg', (120, 130))	('FLCN deficiency', 'Disease', (45, 60))	('FLCN deficiency', 'Disease', 'MESH:D007153', (45, 60))	('AMPK activity', 'molecular_function', 'GO:0004679', ('141', '154'))	('AMPK', 'molecular_function', 'GO:0050405', ('70', '74'))	('AMPK', 'molecular_function', 'GO:0004691', ('70', '74'))	('AMPK', 'molecular_function', 'GO:0047322', ('70', '74'))	('mutations', 'Var', (106, 115))	('AMPK', 'Gene', '5562', (141, 145))	('AMPK', 'Gene', '5562', (70, 74))	('AMPK', 'Gene', (70, 74))
102529	32751108	Subjects carrying a germline pathogenic variant of MITF have a more than five-fold increased risk of developing melanoma and renal cancer, as compared to the individuals not bearing these variants.	('melanoma and renal cancer', 'Disease', 'MESH:D007680', (112, 137))	('variant', 'Var', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('MITF', 'Gene', (51, 55))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('renal cancer', 'Phenotype', 'HP:0009726', (125, 137))	('MITF', 'Gene', '4286', (51, 55))	('S', 'Chemical', 'MESH:D013455', (0, 1))
102530	32751108	The molecular characterization of these MITF oncogenic variants showed a mutation at the level of codon 318 (E318K), located at the level of a small-ubiquitin-like modifier (SUMO) consensus site (psiKXE), determining a strong impairment of SUMOylation of MITF.	('S', 'Chemical', 'MESH:D013455', (174, 175))	('E318K', 'SUBSTITUTION', 'None', (109, 114))	('impairment', 'NegReg', (226, 236))	('MITF', 'Gene', (40, 44))	('MITF', 'Gene', '4286', (40, 44))	('SUMOylation', 'biological_process', 'GO:0016925', ('240', '251'))	('psiKXE', 'Disease', (196, 202))	('E318K', 'Var', (109, 114))	('psiKXE', 'Disease', 'None', (196, 202))	('men', 'Species', '9606', (232, 235))	('MITF', 'Gene', '4286', (255, 259))	('MITF', 'Gene', (255, 259))	('SUMOylation', 'MPA', (240, 251))	('ubiquitin', 'molecular_function', 'GO:0031386', ('149', '158'))	('S', 'Chemical', 'MESH:D013455', (240, 241))
102531	32751108	The E318K mutation increased the binding to the HIF1alpha promoter and increased its transcriptional activity.	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('E318K', 'SUBSTITUTION', 'None', (4, 9))	('transcriptional activity', 'MPA', (85, 109))	('E318K', 'Var', (4, 9))	('HIF1alpha', 'Gene', (48, 57))	('increased', 'PosReg', (19, 28))	('HIF1alpha', 'Gene', '3091', (48, 57))	('increased', 'PosReg', (71, 80))	('binding', 'Interaction', (33, 40))
102532	32751108	However, the MITF E318K mutation does not seem to be involved in sporadic RCC: in fact, in a screening based on the analysis of 403 sporadic RCCs only one MITF E318K mutation was detected.	('RCC', 'Disease', (141, 144))	('E318K', 'Var', (160, 165))	('MITF', 'Gene', '4286', (13, 17))	('MITF', 'Gene', (13, 17))	('RCC', 'Disease', (74, 77))	('E318K', 'SUBSTITUTION', 'None', (18, 23))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('E318K', 'Var', (18, 23))	('MITF', 'Gene', (155, 159))	('MITF', 'Gene', '4286', (155, 159))	('E318K', 'SUBSTITUTION', 'None', (160, 165))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
102546	32751108	In addition to these typical chromosomal losses, CHRCCs display also copy number gains that were detected in chromosomes 4, 7, 11, 12, 14q, and 18q.	('gains', 'PosReg', (81, 86))	('CHRCCs', 'Disease', 'None', (49, 55))	('CHRCCs', 'Disease', (49, 55))	('copy number', 'Var', (69, 80))
102548	32751108	The analysis of gene copy number by next generation sequencing showed the occurrence of multiple abnormalities in CHRCC; this analysis showed that the two most frequent deletions involved the tumor suppressor genes RB1 and ERBB4.	('tumor', 'Disease', (192, 197))	('multiple abnormalities', 'Disease', (88, 110))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('multiple abnormalities', 'Disease', 'MESH:D000015', (88, 110))	('ERBB4', 'Gene', '2066', (223, 228))	('RB1', 'Gene', (215, 218))	('tumor suppressor', 'biological_process', 'GO:0051726', ('192', '208'))	('ERBB4', 'Gene', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('192', '208'))	('CHRCC', 'Disease', (114, 119))	('RB1', 'Gene', '5925', (215, 218))	('deletions', 'Var', (169, 178))	('CHRCC', 'Disease', 'None', (114, 119))
102551	32751108	The results of this study showed: (i) The typical and frequent chromosome losses described in other studies, observed in all cases corresponding to the classic variant and in about 53% of cases corresponding to the eosinophilic variant; (ii) TP53 (32% of cases) and PTEN (9% of cases) were the only two genes frequently mutated in these tumors, while mutations of other cancer-relevant genes (such as MTOR, NRAS) were found at lower frequencies; (iii) the gene expression profile showed a high index of mRNA expression correlation for CHRCC with distal regions of the nephron; (iv) the analysis of mitochondrial DNA showed mutations at the level of genes involved in respiration and oxidative phosphorylation; (v) whole genome sequencing analysis showed the occurrence of kataegis (a mutational phenomenon involving highly localized substitution mutations, C > T or C > G), occurring at the level of some chromosome regions involved in rearrangements, involving also rearrangements occurring within the TERT promoter gene region (observed in 12% of cases) and associated with elevated TERT expression.	('elevated', 'PosReg', (1076, 1084))	('PTEN', 'Gene', (266, 270))	('TERT', 'Gene', (1085, 1089))	('cancer', 'Disease', 'MESH:D009369', (370, 376))	('TERT', 'Gene', '7015', (1085, 1089))	('rearrangements', 'Var', (967, 981))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('683', '708'))	('men', 'Species', '9606', (945, 948))	('NRAS', 'Gene', (407, 411))	('PTEN', 'Gene', '5728', (266, 270))	('tumors', 'Phenotype', 'HP:0002664', (337, 343))	('gene expression', 'biological_process', 'GO:0010467', ('456', '471'))	('kataegis', 'Disease', (772, 780))	('chromosome loss', 'Disease', (63, 78))	('TERT', 'Gene', (1003, 1007))	('TP53', 'Gene', (242, 246))	('TERT', 'Gene', '7015', (1003, 1007))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('CHRCC', 'Disease', (535, 540))	('CHRCC', 'Disease', 'None', (535, 540))	('men', 'Species', '9606', (976, 979))	('C > T or C > G', 'Var', (857, 871))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('598', '615'))	('tumors', 'Disease', (337, 343))	('cancer', 'Disease', (370, 376))	('chromosome loss', 'Disease', 'MESH:D025063', (63, 78))	('respiration', 'biological_process', 'GO:0007585', ('667', '678'))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))	('men', 'Species', '9606', (800, 803))	('respiration', 'biological_process', 'GO:0045333', ('667', '678'))	('tumors', 'Disease', 'MESH:D009369', (337, 343))	('NRAS', 'Gene', '4893', (407, 411))	('chromosome', 'cellular_component', 'GO:0005694', ('905', '915'))	('MTOR', 'Gene', (401, 405))	('TP53', 'Gene', '7157', (242, 246))	('MTOR', 'Gene', '2475', (401, 405))
102554	32751108	Some of these mutations may play a relevant role in the pathogenesis of CHRCC.	('role', 'Reg', (44, 48))	('CHRCC', 'Disease', (72, 77))	('CHRCC', 'Disease', 'None', (72, 77))	('pathogenesis', 'biological_process', 'GO:0009405', ('56', '68'))	('play', 'Reg', (28, 32))	('mutations', 'Var', (14, 23))	('S', 'Chemical', 'MESH:D013455', (0, 1))
102555	32751108	Thus, the PDHB gene encodes the E1beta subunit of the pyruvate dehydrogenase complex (PDHc), catalyzing the conversion of pyruvate to acetyl-CoA, thus providing a link between glycolysis and the TCA cycle; the two mutations observed in CHRCC are reminiscent of those observed in a neurological condition associated with germline mutations of this gene and causing lactic acidosis.	('PDHB', 'Gene', '5162', (10, 14))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (134, 144))	('TCA cycle', 'biological_process', 'GO:0006099', ('195', '204'))	('lactic acidosis', 'Disease', 'MESH:D000140', (364, 379))	('pyruvate dehydrogenase complex', 'cellular_component', 'GO:0045254', ('54', '84'))	('causing', 'Reg', (356, 363))	('CHRCC', 'Disease', (236, 241))	('pyruvate', 'Chemical', 'MESH:D019289', (122, 130))	('CHRCC', 'Disease', 'None', (236, 241))	('mutations', 'Var', (214, 223))	('lactic acidosis', 'Disease', (364, 379))	('TCA', 'Chemical', 'MESH:D014238', (195, 198))	('acidosis', 'Phenotype', 'HP:0001941', (371, 379))	('glycolysis', 'biological_process', 'GO:0006096', ('176', '186'))	('neurological condition', 'Phenotype', 'HP:0000707', (281, 303))	('pyruvate', 'Chemical', 'MESH:D019289', (54, 62))	('PDHB', 'Gene', (10, 14))	('lactic acidosis', 'Phenotype', 'HP:0003128', (364, 379))	('E1beta subunit', 'Gene', (32, 46))	('E1beta subunit', 'Gene', '594', (32, 46))
102556	32751108	PRKAG2 encodes one of the three gamma subunits of AMPK, a key sensor of cellular metabolism; the mutations of this gene, observed at the level of the inhibitory pseudosubstrate sequence within AMPK gamma subunit, may lead to constitutive AMPK activation.	('mutations', 'Var', (97, 106))	('PRKAG2', 'Gene', (0, 6))	('AMPK', 'molecular_function', 'GO:0047322', ('193', '197'))	('AMPK', 'molecular_function', 'GO:0050405', ('50', '54'))	('AMPK', 'Gene', (193, 197))	('PRKAG2', 'Gene', '51422', (0, 6))	('AMPK', 'Gene', (50, 54))	('AMPK', 'Gene', '5562', (238, 242))	('lead to', 'Reg', (217, 224))	('AMPK', 'molecular_function', 'GO:0050405', ('238', '242'))	('AMPK', 'molecular_function', 'GO:0050405', ('193', '197'))	('AMPK', 'molecular_function', 'GO:0004691', ('50', '54'))	('AMPK', 'molecular_function', 'GO:0004691', ('238', '242'))	('AMPK', 'Gene', '5562', (193, 197))	('AMPK', 'Gene', '5562', (50, 54))	('AMPK', 'molecular_function', 'GO:0047322', ('50', '54'))	('AMPK', 'Gene', (238, 242))	('AMPK', 'molecular_function', 'GO:0004691', ('193', '197'))	('cellular metabolism', 'biological_process', 'GO:0044237', ('72', '91'))	('AMPK', 'molecular_function', 'GO:0047322', ('238', '242'))
102559	32751108	Some recurrent mutations have a prognostic impact in CHRCC patients: PTEN mutations correlated with decreased survival; CDKN2A alterations (including loss of the region of chromosome 9p encoding CDKN2A and promoter hypermethylation) correlated with a decreased survival.	('S', 'Chemical', 'MESH:D013455', (0, 1))	('PTEN', 'Gene', '5728', (69, 73))	('survival', 'MPA', (110, 118))	('CHRCC', 'Disease', 'None', (53, 58))	('PTEN', 'Gene', (69, 73))	('CDKN2A', 'Gene', (195, 201))	('CDKN2A', 'Gene', (120, 126))	('mutations', 'Var', (74, 83))	('decreased', 'NegReg', (251, 260))	('CDKN2A', 'Gene', '1029', (195, 201))	('decreased', 'NegReg', (100, 109))	('CDKN2A', 'Gene', '1029', (120, 126))	('patients', 'Species', '9606', (59, 67))	('chromosome', 'cellular_component', 'GO:0005694', ('172', '182'))	('alterations', 'Var', (127, 138))	('CHRCC', 'Disease', (53, 58))	('survival', 'MPA', (261, 269))
102564	32751108	This hyperdiploid pattern is due to either loss of the CHRCC-7 set-chromosomes, associated with duplication of the remaining genome or duplication of multiple chromosomes excluding the CHRCC-7 set-chromosomes: this condition was defined as imbalanced chromosome duplication (ICD).	('duplication', 'Var', (135, 146))	('hyperdiploid', 'Disease', (5, 17))	('CHRCC', 'Disease', (185, 190))	('CHRCC', 'Disease', 'None', (185, 190))	('imbalanced chromosome duplication', 'Disease', (240, 273))	('hyperdiploid', 'Disease', 'MESH:D054198', (5, 17))	('duplication', 'Var', (96, 107))	('loss', 'NegReg', (43, 47))	('CHRCC', 'Disease', (55, 60))	('chromosome', 'cellular_component', 'GO:0005694', ('251', '261'))	('CHRCC', 'Disease', 'None', (55, 60))
102565	32751108	The comparative analysis of metastatic and non-metastatic CHRCC showed among metastatic tumors increased frequencies of TP53 mutations, PTEN mutations, and ICD (observed at frequency of 55%, 27%, and 43%, respectively) compared with those observed in nonmetastatic CHRCC (25%, 7%, and 10%, respectively).	('mutations', 'Var', (125, 134))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('mutations', 'Var', (141, 150))	('ICD', 'Disease', (156, 159))	('CHRCC', 'Disease', (58, 63))	('PTEN', 'Gene', '5728', (136, 140))	('CHRCC', 'Disease', (265, 270))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('CHRCC', 'Disease', 'None', (58, 63))	('PTEN', 'Gene', (136, 140))	('CHRCC', 'Disease', 'None', (265, 270))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
102566	32751108	Phylogenetic studies of paired-primary-metastatic samples allowed to propose a tumor progression process, involving the nearly universal loss of CHRCC-7 set-chromosomes as the only driver event in the pathogenesis of CHRCC, followed by TP53 mutations that were detected in 82% of metastatic samples and then by ICD and PTEN mutations that were detected in 82% of metastatic samples and then by ICD and PTEN mutation, occurring in a mutually exclusive manner.	('PTEN', 'Gene', '5728', (319, 323))	('amp', 'Chemical', 'MESH:D000249', (51, 54))	('amp', 'Chemical', 'MESH:D000249', (375, 378))	('TP53', 'Gene', (236, 240))	('PTEN', 'Gene', (402, 406))	('pathogenesis', 'biological_process', 'GO:0009405', ('201', '213'))	('loss', 'NegReg', (137, 141))	('tumor', 'Disease', (79, 84))	('PTEN', 'Gene', '5728', (402, 406))	('CHRCC', 'Disease', (217, 222))	('CHRCC', 'Disease', 'None', (217, 222))	('amp', 'Chemical', 'MESH:D000249', (292, 295))	('CHRCC', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('TP53', 'Gene', '7157', (236, 240))	('PTEN', 'Gene', (319, 323))	('CHRCC', 'Disease', 'None', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('mutations', 'Var', (241, 250))
102590	32751108	Whole exome sequencing performed in 157 PRCCs identified several somatic mutations, occurring with a significant frequency, at the level of tumor-related genes, such as MET, SETD2, NF2, KDM6A, SMARCB1, FAT1, BAP1, PBRM1, STAG2, NFE2L2, and TP53.	('TP53', 'Gene', '7157', (240, 244))	('STAG2', 'Gene', '10735', (221, 226))	('PRCC', 'Gene', '5546', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('FAT1', 'Gene', (202, 206))	('BAP1', 'Gene', (208, 212))	('NFE2L2', 'Gene', (228, 234))	('SMARCB1', 'Gene', '6598', (193, 200))	('PBRM1', 'Gene', '55193', (214, 219))	('STAG2', 'Gene', (221, 226))	('SMARCB1', 'Gene', (193, 200))	('MET', 'Gene', '79811', (169, 172))	('NF2', 'Gene', '4771', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('PBRM1', 'Gene', (214, 219))	('KDM6A', 'Gene', '7403', (186, 191))	('NF2', 'Gene', (181, 184))	('TP53', 'Gene', (240, 244))	('FAT1', 'Gene', '2195', (202, 206))	('SETD2', 'Gene', (174, 179))	('PRCC', 'Gene', (40, 44))	('BAP1', 'Gene', '8314', (208, 212))	('SETD2', 'Gene', '29072', (174, 179))	('KDM6A', 'Gene', (186, 191))	('MET', 'Gene', (169, 172))	('NFE2L2', 'Gene', '4780', (228, 234))	('mutations', 'Var', (73, 82))	('tumor', 'Disease', (140, 145))
102592	32751108	However, some genetic alterations are specific to types of PRCCs: (1) MET mutations are much more frequent in type 1 than type 2 PRCCs (17% vs. 1.6%, respectively) and were observed in 11% of unclassified PRCCs; levels of MET mRNA and MET protein phosphorylation were higher in type 1 than type 2 tumors.	('type 2 tumors', 'Disease', (290, 303))	('MET', 'Gene', '79811', (70, 73))	('MET', 'Gene', '79811', (235, 238))	('type 2 tumors', 'Disease', 'MESH:C000657245', (290, 303))	('PRCC', 'Gene', (59, 63))	('PRCC', 'Gene', '5546', (205, 209))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))	('PRCC', 'Gene', (129, 133))	('higher', 'PosReg', (268, 274))	('protein phosphorylation', 'biological_process', 'GO:0006468', ('239', '262'))	('MET', 'Gene', (222, 225))	('observed', 'Reg', (173, 181))	('MET', 'Gene', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('PRCC', 'Gene', '5546', (59, 63))	('MET', 'Gene', (235, 238))	('mutations', 'Var', (74, 83))	('PRCC', 'Gene', '5546', (129, 133))	('MET', 'Gene', '79811', (222, 225))	('PRCC', 'Gene', (205, 209))	('protein', 'cellular_component', 'GO:0003675', ('239', '246'))
102593	32751108	(2) 8% type 2 PRCCs displayed 9p21 chromosomal focal loss with loss of CDKN2A locus; other type 2 PRCCs exhibited CDKN2A mutations or promoter hypermethylation, resulting in a total of 13% of tumors with CDKN2A alterations; CDKN2A loss was associated with low overall survival.	('mutations', 'Var', (121, 130))	('CDKN2A', 'Gene', '1029', (204, 210))	('tumors', 'Disease', (192, 198))	('PRCC', 'Gene', (14, 18))	('loss', 'NegReg', (53, 57))	('CDKN2A', 'Gene', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('promoter hypermethylation', 'Var', (134, 159))	('9p21', 'Gene', (30, 34))	('CDKN2A', 'Gene', (224, 230))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('PRCC', 'Gene', '5546', (14, 18))	('PRCC', 'Gene', (98, 102))	('CDKN2A', 'Gene', '1029', (114, 120))	('CDKN2A', 'Gene', (71, 77))	('chromosomal focal loss', 'Phenotype', 'HP:0040012', (35, 57))	('loss', 'NegReg', (63, 67))	('CDKN2A', 'Gene', (204, 210))	('CDKN2A', 'Gene', '1029', (224, 230))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('CDKN2A', 'Gene', '1029', (71, 77))	('PRCC', 'Gene', '5546', (98, 102))
102594	32751108	(3) Type 2 PRCCs are associated with mutations in chromatin-modifying genes SETD2 (19.4%), BAP1 (10.4%), and PBRM1 (11.9%) which are frequently mutated in CCRCCs; mutations of BAP1 and PBRM1 were mutually exclusive, whereas SETD2 mutations co-occurred with PBMR1 mutations in most cases.	('SETD2', 'Gene', (76, 81))	('BAP1', 'Gene', (91, 95))	('PRCC', 'Gene', '5546', (11, 15))	('PBRM1', 'Gene', (185, 190))	('RCC', 'Disease', (12, 15))	('BAP1', 'Gene', (176, 180))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('SETD2', 'Gene', '29072', (76, 81))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('chromatin', 'cellular_component', 'GO:0000785', ('50', '59'))	('SETD2', 'Gene', (224, 229))	('associated', 'Reg', (21, 31))	('PRCC', 'Gene', (11, 15))	('PBRM1', 'Gene', '55193', (109, 114))	('PBMR1', 'Gene', (257, 262))	('mutations', 'Var', (37, 46))	('SETD2', 'Gene', '29072', (224, 229))	('BAP1', 'Gene', '8314', (91, 95))	('mutations', 'Var', (163, 172))	('PBRM1', 'Gene', (109, 114))	('BAP1', 'Gene', '8314', (176, 180))	('PBRM1', 'Gene', '55193', (185, 190))	('RCC', 'Disease', (157, 160))
102595	32751108	(4) Another feature of type 2 PRCCs consists in the increased expression of NRF2-associated response element (ARE) pathway; these findings were in line with other studies showing increased activation of the NRF2-ARE pathway in type 2 PRCCs and mutations in NRF2-ARE pathway genes NFE2L2, CUL3, KEAP1, and SRT1.	('NRF2', 'Gene', '4780', (76, 80))	('CUL3', 'Gene', (288, 292))	('NRF2', 'Gene', (257, 261))	('NRF2', 'Gene', '4780', (207, 211))	('PRCC', 'Gene', (30, 34))	('PRCC', 'Gene', (234, 238))	('men', 'Species', '9606', (104, 107))	('NRF2', 'Gene', (76, 80))	('S', 'Chemical', 'MESH:D013455', (305, 306))	('mutations', 'Var', (244, 253))	('NFE2L2', 'Gene', '4780', (280, 286))	('KEAP1', 'Gene', '9817', (294, 299))	('KEAP1', 'Gene', (294, 299))	('NRF2', 'Gene', (207, 211))	('type', 'Disease', (227, 231))	('PRCC', 'Gene', '5546', (30, 34))	('PRCC', 'Gene', '5546', (234, 238))	('CUL3', 'Gene', '8452', (288, 292))	('NFE2L2', 'Gene', (280, 286))	('activation', 'PosReg', (189, 199))	('NRF2', 'Gene', '4780', (257, 261))
102596	32751108	(5) A CpG island methylator phenotype (CIMP) was observed in a subgroup of type 2 PRCCs characterized by mutations of FH gene and poor survival.	('PRCC', 'Gene', (82, 86))	('FH', 'Gene', '2271', (118, 120))	('mutations', 'Var', (105, 114))	('observed', 'Reg', (49, 57))	('PRCC', 'Gene', '5546', (82, 86))
102597	32751108	Finally, from this study it emerges that unclassified PRCCs display molecular properties hybrid between type 1 and type 2 PRCCs; the frequency of chromosomal 7 gain in these tumors is intermediate (26%) between type 1 (85%) and type 2 (18%).	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('PRCC', 'Gene', (122, 126))	('gain', 'PosReg', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('chromosomal 7', 'Var', (146, 159))	('PRCC', 'Gene', '5546', (54, 58))	('PRCC', 'Gene', '5546', (122, 126))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('PRCC', 'Gene', (54, 58))
102598	32751108	in their study of molecular characterization of non-clear RCCs reported a detailed analysis of MET mutations occurring in PRCCs; particularly, they observed MET mutations in 15% of the PRCC samples: all these mutations, with just a single exception, affected the kinase domain of MET, all displaying elevated phosphorylation, suggesting their constitutive activation.	('PRCC', 'Gene', '5546', (185, 189))	('RCC', 'Disease', (123, 126))	('RCC', 'Disease', (58, 61))	('MET', 'Gene', (95, 98))	('phosphorylation', 'MPA', (309, 324))	('RCC', 'Disease', (186, 189))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('MET', 'Gene', '79811', (280, 283))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('amp', 'Chemical', 'MESH:D000249', (191, 194))	('MET', 'Gene', (157, 160))	('PRCC', 'Gene', (122, 126))	('PRCC', 'Gene', (185, 189))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('kinase domain', 'MPA', (263, 276))	('MET', 'Gene', '79811', (95, 98))	('affected', 'Reg', (250, 258))	('mutations', 'Var', (209, 218))	('phosphorylation', 'biological_process', 'GO:0016310', ('309', '324'))	('PRCC', 'Gene', '5546', (122, 126))	('MET', 'Gene', (280, 283))	('MET', 'Gene', '79811', (157, 160))	('elevated', 'PosReg', (300, 308))
102600	32751108	Particularly, in patients with type 1 PRCC the most commonly altered genes were MET (33%), TERT (30%), CDKN2A/B (18%), and EGFR (8%); in patients with type 2 PRCC the most recurrent gene mutations were CDKN2A/B (18%), TERT (18%), NF2 (13%), FH (13%), and MET (7%).	('EGFR', 'Gene', (123, 127))	('PRCC', 'Gene', (158, 162))	('MET', 'Gene', (255, 258))	('NF2', 'Gene', '4771', (230, 233))	('PRCC', 'Gene', (38, 42))	('CDKN2A/B', 'Gene', '1029;1030', (202, 210))	('NF2', 'Gene', (230, 233))	('CDKN2A/B', 'Gene', (103, 111))	('EGFR', 'Gene', '1956', (123, 127))	('TERT', 'Gene', (218, 222))	('MET', 'Gene', (80, 83))	('PRCC', 'Gene', '5546', (158, 162))	('MET', 'Gene', '79811', (255, 258))	('FH', 'Gene', '2271', (241, 243))	('PRCC', 'Gene', '5546', (38, 42))	('TERT', 'Gene', (91, 95))	('TERT', 'Gene', '7015', (218, 222))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('patients', 'Species', '9606', (137, 145))	('TERT', 'Gene', '7015', (91, 95))	('patients', 'Species', '9606', (17, 25))	('CDKN2A/B', 'Gene', '1029;1030', (103, 111))	('CDKN2A/B', 'Gene', (202, 210))	('mutations', 'Var', (187, 196))	('MET', 'Gene', '79811', (80, 83))
102604	32751108	Li and coworkers using this approach discovered mutations at the level of an intron of MET gene, connected to an oncogenically relevant splicing event; furthermore, in other cases a methylation dysregulation on nearby, leading to a cryptic promoter activation of the MET gene was identified.	('splicing', 'biological_process', 'GO:0045292', ('136', '144'))	('MET', 'Gene', '79811', (87, 90))	('methylation dysregulation', 'Var', (182, 207))	('methylation', 'biological_process', 'GO:0032259', ('182', '193'))	('MET', 'Gene', (87, 90))	('MET', 'Gene', '79811', (267, 270))	('mutations', 'Var', (48, 57))	('MET', 'Gene', (267, 270))
102605	32751108	Furthermore, it was identified the recurrent mutation of the long noncoding RNA NEAT1 and these mutations are associated with increased NEAT1 expression and negative outcome.	('NEAT1', 'Gene', (136, 141))	('RNA', 'cellular_component', 'GO:0005562', ('76', '79'))	('NEAT1', 'Gene', '283131', (80, 85))	('mutation', 'Var', (45, 53))	('expression', 'MPA', (142, 152))	('NEAT1', 'Gene', (80, 85))	('increased', 'PosReg', (126, 135))	('NEAT1', 'Gene', '283131', (136, 141))
102607	32751108	Through the analysis of 29 patients at the level of various tumor regions (center and periphery of each tumor) the authors reached the important conclusion that, at variance with previous studies in CCRCC, in PRCC driver gene mutations and most arm-level somatic copy number alterations are clonal.	('PRCC', 'Gene', '5546', (209, 213))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('PRCC', 'Gene', (209, 213))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('patients', 'Species', '9606', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mutations', 'Var', (226, 235))	('RCC', 'Disease', (210, 213))	('tumor', 'Disease', (60, 65))	('RCC', 'Disease', 'MESH:C538614', (210, 213))
102622	32751108	The most frequent and typical genetic alteration of CCRCC is represented by biallelic inactivation on the VHL gene determined by allelic deletion or loss of heterogeneity on chromosome 3p (observed in >90% of cases), together with gene mutation (observed in about 50% of cases) or promoter hypermethylation (observed in 5-10% of cases).	('biallelic', 'Var', (76, 85))	('RCC', 'Disease', (54, 57))	('chromosome', 'cellular_component', 'GO:0005694', ('174', '184'))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('VHL', 'Gene', (106, 109))	('VHL', 'Gene', '7428', (106, 109))
102623	32751108	Other frequent genetic alterations are represented by mutations in genes involved in chromatin modification, such as PBRM1, SETD2, KDM5C, KDM6A, and BAP1.	('SETD2', 'Gene', (124, 129))	('KDM5C', 'Gene', '8242', (131, 136))	('chromatin modification', 'biological_process', 'GO:0016569', ('85', '107'))	('KDM6A', 'Gene', (138, 143))	('BAP1', 'Gene', '8314', (149, 153))	('mutations', 'Var', (54, 63))	('PBRM1', 'Gene', (117, 122))	('KDM6A', 'Gene', '7403', (138, 143))	('PBRM1', 'Gene', '55193', (117, 122))	('BAP1', 'Gene', (149, 153))	('chromatin', 'cellular_component', 'GO:0000785', ('85', '94'))	('chromatin modification', 'biological_process', 'GO:0006325', ('85', '107'))	('SETD2', 'Gene', '29072', (124, 129))	('KDM5C', 'Gene', (131, 136))
102626	32751108	Almost all cases exhibiting PBMR1, SETD2, and BAP1 mutations occurred in CCRCC cases displaying VHL inactivation.	('mutations', 'Var', (51, 60))	('BAP1', 'Gene', '8314', (46, 50))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('PBMR1', 'Gene', (28, 33))	('occurred', 'Reg', (61, 69))	('BAP1', 'Gene', (46, 50))	('VHL', 'Gene', (96, 99))	('SETD2', 'Gene', '29072', (35, 40))	('VHL', 'Gene', '7428', (96, 99))	('SETD2', 'Gene', (35, 40))
102627	32751108	Importantly, SETD2 and BAP1 mutations displayed lower allelic burdens than coexisting VHL mutations, suggesting that these mutations are acquired at later times during tumor development.	('BAP1', 'Gene', (23, 27))	('allelic burdens', 'MPA', (54, 69))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('lower', 'NegReg', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('SETD2', 'Gene', '29072', (13, 18))	('BAP1', 'Gene', '8314', (23, 27))	('VHL', 'Gene', '7428', (86, 89))	('SETD2', 'Gene', (13, 18))	('VHL', 'Gene', (86, 89))	('mutations', 'Var', (28, 37))	('men', 'Species', '9606', (181, 184))
102628	32751108	PBRM1 mutations had no significant impact on overall survival, whereas BAP1 mutations, mutually exclusive with PBRM1 mutations, were associated with a shorter overall survival; finally, SETD2 mutations displayed a high relapse rate.	('SETD2', 'Gene', (186, 191))	('mutations', 'Var', (192, 201))	('mutations', 'Var', (76, 85))	('overall survival', 'MPA', (159, 175))	('shorter', 'NegReg', (151, 158))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('BAP1', 'Gene', '8314', (71, 75))	('PBRM1', 'Gene', (111, 116))	('PBRM1', 'Gene', '55193', (111, 116))	('BAP1', 'Gene', (71, 75))	('SETD2', 'Gene', '29072', (186, 191))
102629	32751108	Interestingly, 5% of CCRCC patients displayed TCEB1 mutations, not associated with VHL gene alterations, but constantly associated with loss of chromosome 8; TCEB1 encodes a protein involved in the formation of the RNA polymerase II elongation factor complex but also involved in the VHL complex formation.	('mutations', 'Var', (52, 61))	('VHL complex', 'cellular_component', 'GO:0030891', ('284', '295'))	('VHL', 'Gene', '7428', (83, 86))	('VHL', 'Gene', (284, 287))	('TCEB1', 'Gene', '6921', (158, 163))	('chromosome', 'cellular_component', 'GO:0005694', ('144', '154'))	('TCEB1', 'Gene', (158, 163))	('VHL', 'Gene', '7428', (284, 287))	('RNA', 'cellular_component', 'GO:0005562', ('215', '218'))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('patients', 'Species', '9606', (27, 35))	('RCC', 'Disease', (23, 26))	('TCEB1', 'Gene', '6921', (46, 51))	('formation', 'biological_process', 'GO:0009058', ('296', '305'))	('TCEB1', 'Gene', (46, 51))	('formation', 'biological_process', 'GO:0009058', ('198', '207'))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))	('VHL', 'Gene', (83, 86))
102631	32751108	Therefore, CCRCC with VHL loss or with TCEB1 mutations accounts for 95.4% of the cases.	('TCEB1', 'Gene', (39, 44))	('mutations', 'Var', (45, 54))	('VHL loss', 'Disease', 'MESH:D006623', (22, 30))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', (13, 16))	('TCEB1', 'Gene', '6921', (39, 44))	('VHL loss', 'Disease', (22, 30))
102632	32751108	Other genes recurrently mutated in CCRCC included TET2, KEAP1, and MTOR: TET2 mutations and deletions occurred in 16% of cases; mutually exclusive mutations in KEAP1, NRF2, and CUL3 occurred in 6.6% of cases; MTOR mutations were observed in 5.7% of cases.	('mutations', 'Var', (147, 156))	('CUL3', 'Gene', '8452', (177, 181))	('MTOR', 'Gene', (67, 71))	('MTOR', 'Gene', (209, 213))	('RCC', 'Disease', (37, 40))	('MTOR', 'Gene', '2475', (67, 71))	('MTOR', 'Gene', '2475', (209, 213))	('KEAP1', 'Gene', '9817', (56, 61))	('TET2', 'Gene', (50, 54))	('mutations', 'Var', (78, 87))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('NRF2', 'Gene', '4780', (167, 171))	('KEAP1', 'Gene', (56, 61))	('KEAP1', 'Gene', '9817', (160, 165))	('TET2', 'Gene', (73, 77))	('KEAP1', 'Gene', (160, 165))	('CUL3', 'Gene', (177, 181))	('NRF2', 'Gene', (167, 171))	('TET2', 'Gene', '54790', (50, 54))	('TET2', 'Gene', '54790', (73, 77))	('deletions', 'Var', (92, 101))
102637	32751108	reported among the CNAs the loss of 8p with or without loss of 8q (20% of cases), an abnormality frequently associated with TCEB1 mutations.	('TCEB1', 'Gene', '6921', (124, 129))	('mutations', 'Var', (130, 139))	('TCEB1', 'Gene', (124, 129))	('loss', 'NegReg', (28, 32))
102638	32751108	Integrative data analysis showed that the most frequently mutated network involved VHL and numerous interacting partners, leading to activation of the transcription factor program mediated by HIF1A/ARNT; the second most mutated network included PBRM1, ARID1A, and SMARCA4, key genes at the level of chromatin remodeling complex; the mutations of the chromatin regulators PBRM1, STD2, and BAP1 induce different patterns of altered gene expression in the context of a background caused by VHL loss; mutually exclusive alterations targeting multiple complexes of the PI3K/AKT/MTOR pathway occur in about 28% of the cases and suggest a potential therapeutic targeting.	('transcription factor', 'molecular_function', 'GO:0000981', ('151', '171'))	('ARNT', 'Gene', '405', (198, 202))	('HIF1A', 'Gene', (192, 197))	('SMARCA4', 'Gene', (264, 271))	('transcription', 'biological_process', 'GO:0006351', ('151', '164'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('299', '319'))	('AKT', 'Gene', (569, 572))	('ARNT', 'Gene', (198, 202))	('S', 'Chemical', 'MESH:D013455', (378, 379))	('BAP1', 'Gene', '8314', (388, 392))	('PBRM1', 'Gene', '55193', (245, 250))	('MTOR', 'Gene', (573, 577))	('mutations', 'Var', (333, 342))	('VHL', 'Gene', (83, 86))	('PBRM1', 'Gene', (245, 250))	('VHL loss', 'Disease', (487, 495))	('S', 'Chemical', 'MESH:D013455', (264, 265))	('MTOR', 'Gene', '2475', (573, 577))	('BAP1', 'Gene', (388, 392))	('HIF1A', 'Gene', '3091', (192, 197))	('VHL', 'Gene', (487, 490))	('PBRM1', 'Gene', '55193', (371, 376))	('AKT', 'Gene', '207', (569, 572))	('gene expression', 'biological_process', 'GO:0010467', ('430', '445'))	('VHL loss', 'Disease', 'MESH:D006623', (487, 495))	('SMARCA4', 'Gene', '6597', (264, 271))	('ARID1A', 'Gene', (252, 258))	('VHL', 'Gene', '7428', (83, 86))	('PBRM1', 'Gene', (371, 376))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('299', '327'))	('VHL', 'Gene', '7428', (487, 490))	('PI3K', 'molecular_function', 'GO:0016303', ('564', '568'))	('chromatin', 'cellular_component', 'GO:0000785', ('350', '359'))	('ARID1A', 'Gene', '8289', (252, 258))
102640	32751108	evaluated all genetic alterations occurring in CCRCCC-inducing activation of PI3K signaling and estimated a frequency of 76% of cases exhibiting PI3K activation; furthermore, they reported also the frequent (40%) activation of p53 signaling.	('RCC', 'Disease', (49, 52))	('PI3K', 'molecular_function', 'GO:0016303', ('77', '81'))	('p53', 'Gene', (227, 230))	('genetic alterations', 'Var', (14, 33))	('p53', 'Gene', '7157', (227, 230))	('signaling', 'biological_process', 'GO:0023052', ('231', '240'))	('activation', 'PosReg', (213, 223))	('PI3K', 'MPA', (77, 81))	('PI3K signaling', 'biological_process', 'GO:0014065', ('77', '91'))	('PI3K', 'molecular_function', 'GO:0016303', ('145', '149'))	('activation', 'PosReg', (63, 73))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
102643	32751108	Copy number gains of chromosome 5q occurring in CCRCC drive overexpression of the gene SQSTM1; the p62 SQSMT1 protein is involved in activation of NRF2, and through this mechanism, in promotion of resistance to redox stress and in stimulation of renal cancer cell growth in vitro and in vivo.	('promotion', 'PosReg', (184, 193))	('Copy number', 'Var', (0, 11))	('SQSTM1', 'Gene', (87, 93))	('NRF2', 'Gene', (147, 151))	('stimulation', 'PosReg', (231, 242))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('overexpression', 'PosReg', (60, 74))	('protein', 'Protein', (110, 117))	('RCC', 'Disease', (50, 53))	('p62', 'Var', (99, 102))	('resistance to redox stress', 'MPA', (197, 223))	('SQSTM1', 'Gene', '8878', (87, 93))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('renal cancer', 'Disease', (246, 258))	('S', 'Chemical', 'MESH:D013455', (105, 106))	('SQSMT1', 'Gene', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('renal cancer', 'Phenotype', 'HP:0009726', (246, 258))	('S', 'Chemical', 'MESH:D013455', (89, 90))	('S', 'Chemical', 'MESH:D013455', (103, 104))	('cell growth', 'biological_process', 'GO:0016049', ('259', '270'))	('S', 'Chemical', 'MESH:D013455', (87, 88))	('activation', 'PosReg', (133, 143))	('chromosome', 'cellular_component', 'GO:0005694', ('21', '31'))	('NRF2', 'Gene', '4780', (147, 151))	('renal cancer', 'Disease', 'MESH:D007680', (246, 258))
102646	32751108	refined the analysis of molecular abnormalities of CCRCC performed by TCGA and showed that in these tumors: TP53 and BAP1 mutations and CDKN2A alterations were associated with decreased survival; at mRNA expression level an increased expression of the vasculature development signature, due to the activation of the VHL/HIF pathway, increased the immune response signature compared to other RCC types and increased ribose metabolism pathway, associated with poor survival.	('TP53', 'Gene', (108, 112))	('expression', 'MPA', (234, 244))	('ribose metabolism pathway', 'Pathway', (415, 440))	('decreased', 'NegReg', (176, 185))	('RCC', 'Disease', (53, 56))	('activation', 'PosReg', (298, 308))	('VHL', 'Gene', '7428', (316, 319))	('men', 'Species', '9606', (271, 274))	('BAP1', 'Gene', '8314', (117, 121))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('CDKN2A', 'Gene', (136, 142))	('ribose', 'Chemical', 'MESH:D012266', (415, 421))	('RCC', 'Disease', (391, 394))	('increased', 'PosReg', (224, 233))	('vasculature development', 'biological_process', 'GO:0001944', ('252', '275'))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('TP53', 'Gene', '7157', (108, 112))	('tumors', 'Disease', (100, 106))	('CDKN2A', 'Gene', '1029', (136, 142))	('BAP1', 'Gene', (117, 121))	('RCC', 'Disease', 'MESH:C538614', (391, 394))	('alterations', 'Var', (143, 154))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('immune', 'MPA', (347, 353))	('mutations', 'Var', (122, 131))	('VHL', 'Gene', (316, 319))	('immune response', 'biological_process', 'GO:0006955', ('347', '362'))	('increased', 'PosReg', (333, 342))	('metabolism', 'biological_process', 'GO:0008152', ('422', '432'))
102654	32751108	The results of these two studies provided some fundamental data about intratumor heterogeneity of CCRCC: only a small fraction of genetic alterations display a clonal distribution, such as VHL loss and chromosome arm 3p loss, whereas other genes recurrently mutated such as SETD2 and BAP1 have a subclonal pattern of distribution within the tumor.	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('men', 'Species', '9606', (52, 55))	('VHL loss', 'Disease', (189, 197))	('BAP1', 'Gene', '8314', (284, 288))	('SETD2', 'Gene', (274, 279))	('chromosome', 'cellular_component', 'GO:0005694', ('202', '212'))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('tumor', 'Disease', (75, 80))	('VHL loss', 'Disease', 'MESH:D006623', (189, 197))	('SETD2', 'Gene', '29072', (274, 279))	('alterations', 'Var', (138, 149))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('BAP1', 'Gene', (284, 288))	('chromosome', 'Var', (202, 212))	('tumor', 'Disease', (341, 346))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (341, 346))	('RCC', 'Disease', (100, 103))	('loss', 'NegReg', (220, 224))
102655	32751108	It is of interest to note that the multi-region sequencing allowed the identification of a higher frequency of gene mutations and copy number alterations than by single tumor sampling.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('gene mutations', 'Var', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('copy number alterations', 'Var', (130, 153))	('amp', 'Chemical', 'MESH:D000249', (176, 179))
102661	32751108	Huang and coworkers have analyzed the clonal architectures of 473 CCRCC patients and showed that the evolution patterns of CCRCC have consistent inter-patient heterogeneity, with del(3p) being considered as the common earliest molecular event, followed by three most recurrent patterns of clonal evolution dictated by different molecular events: (i) VHL and PBRM1 mutations; (ii) del(14q); (iii) amp(7), del(1p), del(6q), amp(7q), del(3q).	('RCC', 'Disease', (125, 128))	('amp(7', 'Var', (396, 401))	('patient', 'Species', '9606', (72, 79))	('RCC', 'Disease', (68, 71))	('amp(7q', 'Var', (422, 428))	('VHL', 'Gene', '7428', (350, 353))	('del(1p', 'Gene', '10085', (404, 410))	('PBRM1', 'Gene', '55193', (358, 363))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('patient', 'Species', '9606', (151, 158))	('amp', 'Chemical', 'MESH:D000249', (422, 425))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('mutations', 'Var', (364, 373))	('PBRM1', 'Gene', (358, 363))	('del(14q)', 'Var', (380, 388))	('del(3q', 'Var', (431, 437))	('del(6q', 'Var', (413, 419))	('amp', 'Chemical', 'MESH:D000249', (396, 399))	('VHL', 'Gene', (350, 353))	('patients', 'Species', '9606', (72, 80))
102662	32751108	The analysis of these patients allowed to identify three prognostic subtypes of CCRCC with different clonal architectures and immune infiltrates: patients with a long-life expectancy are enriched with VHL, but depleted of BAP1 mutations, and have high levels of Th17 and CD8+T lymphocytes, while patients with a short survival are characterized by high burden of CNAs (frequent del(14q)), high levels of Tregs and Th2 cells.	('VHL', 'Gene', (201, 204))	('VHL', 'Gene', '7428', (201, 204))	('CD8', 'Gene', (271, 274))	('patients', 'Species', '9606', (22, 30))	('Th17', 'MPA', (262, 266))	('CD8', 'Gene', '925', (271, 274))	('depleted', 'NegReg', (210, 218))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('BAP1', 'Gene', '8314', (222, 226))	('RCC', 'Disease', (82, 85))	('del(14q', 'Var', (378, 385))	('patients', 'Species', '9606', (296, 304))	('patients', 'Species', '9606', (146, 154))	('BAP1', 'Gene', (222, 226))
102664	32751108	At arm level, 3p loss (93%) was the most frequent CNA, followed by 5q gain (54%), chromosome 14q loss (42%), chromosome 7 gain (34%), and chromosome 9 loss (21%); furthermore, about 13% of tumors displayed extensive copy number variations along all chromosomes, thus indicating a high degree of genomic instability.	('loss', 'NegReg', (97, 101))	('chromosome', 'cellular_component', 'GO:0005694', ('82', '92'))	('3p loss', 'Var', (14, 21))	('chromosome', 'cellular_component', 'GO:0005694', ('138', '148'))	('gain', 'PosReg', (70, 74))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))	('loss', 'NegReg', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('gain', 'PosReg', (122, 126))	('copy number variations', 'Var', (216, 238))
102665	32751108	This analysis showed also that 61% of CCRCC cases displayed one or more translocations, mainly involving the chromosome 3p locus and chromosome 5 (20%).	('translocations', 'Var', (72, 86))	('RCC', 'Disease', (40, 43))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))	('chromosome', 'cellular_component', 'GO:0005694', ('133', '143'))
102666	32751108	This study confirmed the data on the frequency of most recurrence gene mutations and provided evidence that all the genetic alterations, including VHL, PBMR1, BAP1, KDM5C, and SETD2 are related to genetic events resulting in reduced expression of both mRNA and protein, thus indicating loss-of-function and supporting the classification of these genes as tumor suppressors.	('BAP1', 'Gene', '8314', (159, 163))	('expression', 'MPA', (233, 243))	('alterations', 'Var', (124, 135))	('reduced', 'NegReg', (225, 232))	('KDM5C', 'Gene', (165, 170))	('SETD2', 'Gene', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('protein', 'Protein', (261, 268))	('VHL', 'Gene', (147, 150))	('mutations', 'Var', (71, 80))	('SETD2', 'Gene', '29072', (176, 181))	('BAP1', 'Gene', (159, 163))	('mRNA and', 'MPA', (252, 260))	('loss-of-function', 'NegReg', (286, 302))	('VHL', 'Gene', '7428', (147, 150))	('KDM5C', 'Gene', '8242', (165, 170))	('PBMR1', 'Gene', (152, 157))	('tumor', 'Disease', (355, 360))	('protein', 'cellular_component', 'GO:0003675', ('261', '268'))	('tumor', 'Disease', 'MESH:D009369', (355, 360))
102669	32751108	The proteomic analysis allowed the subdivision of CCRCC into three groups: CCRCC1 associated with higher tumor grade and stage and characterized by elevated adaptive immune response, N-linked glycosylation, OXPHOS protein expression and fatty acid metabolism and high frequency of BAP1 mutations and CIMP+ status; CCRCC2 and CCRCC3 were associated with lower tumor grade and stage: tumors in CCRCC2 were associated with tumor immunity, whereas tumors in CCRCC3 with glycolysis, mTOR signaling, and hypoxia and display higher frequency of PBRM1 mutations.	('BAP1', 'Gene', (281, 285))	('tumor', 'Phenotype', 'HP:0002664', (420, 425))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (444, 449))	('tumors', 'Disease', (382, 388))	('OXPHOS', 'biological_process', 'GO:0002082', ('207', '213'))	('tumors', 'Disease', (444, 450))	('RCC', 'Disease', 'MESH:C538614', (394, 397))	('RCC', 'Disease', (456, 459))	('S', 'Chemical', 'MESH:D013455', (212, 213))	('glycosylation', 'biological_process', 'GO:0070085', ('192', '205'))	('mTOR', 'Gene', (478, 482))	('RCC', 'Disease', (52, 55))	('PBRM1', 'Gene', '55193', (538, 543))	('glycolysis', 'MPA', (466, 476))	('tumor', 'Disease', (382, 387))	('signaling', 'biological_process', 'GO:0023052', ('483', '492'))	('tumor', 'Disease', (359, 364))	('tumors', 'Disease', 'MESH:D009369', (444, 450))	('RCC', 'Disease', 'MESH:C538614', (456, 459))	('tumor', 'Disease', (105, 110))	('associated', 'Reg', (404, 414))	('tumor', 'Disease', 'MESH:D009369', (382, 387))	('tumors', 'Disease', 'MESH:D009369', (382, 388))	('adaptive immune response', 'biological_process', 'GO:0002250', ('157', '181'))	('PBRM1', 'Gene', (538, 543))	('tumor', 'Disease', 'MESH:D009369', (359, 364))	('mTOR', 'Gene', '2475', (478, 482))	('RCC', 'Disease', (327, 330))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', (420, 425))	('hypoxia', 'Disease', (498, 505))	('tumor', 'Disease', (444, 449))	('BAP1', 'Gene', '8314', (281, 285))	('RCC', 'Disease', (316, 319))	('tumor', 'Disease', 'MESH:D009369', (420, 425))	('tumor', 'Phenotype', 'HP:0002664', (382, 387))	('tumor', 'Disease', 'MESH:D009369', (444, 449))	('tumor', 'Phenotype', 'HP:0002664', (359, 364))	('mutations', 'Var', (544, 553))	('RCC', 'Disease', 'MESH:C538614', (327, 330))	('RCC', 'Disease', (77, 80))	('RCC', 'Disease', (394, 397))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('protein', 'cellular_component', 'GO:0003675', ('214', '221'))	('tumors', 'Phenotype', 'HP:0002664', (382, 388))	('glycolysis', 'biological_process', 'GO:0006096', ('466', '476'))	('tumors', 'Phenotype', 'HP:0002664', (444, 450))	('hypoxia', 'Disease', 'MESH:D000860', (498, 505))	('RCC', 'Disease', 'MESH:C538614', (316, 319))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('237', '258'))
102679	32751108	62% of these patients displayed VHL mutations and 44% PBMR1 mutations; angiogenesis-related gene expression signature was higher in VHL-mutated and PBRM1-mutated CCRCCs; within treatment evaluation showed that PBRM1 mutations were associated with improved PFS in the sunitinib arm; in the PBRM1-mutated patients atezolizumab+bevacizumab showed improved PFS compared to atezolizumab alone.	('PBRM1', 'Gene', '55193', (289, 294))	('PBRM1', 'Gene', '55193', (210, 215))	('S', 'Chemical', 'MESH:D013455', (355, 356))	('VHL', 'Gene', '7428', (32, 35))	('patients', 'Species', '9606', (13, 21))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('PBRM1', 'Gene', (210, 215))	('PBRM1', 'Gene', (289, 294))	('VHL', 'Gene', (132, 135))	('S', 'Chemical', 'MESH:D013455', (258, 259))	('angiogenesis', 'biological_process', 'GO:0001525', ('71', '83'))	('improved', 'PosReg', (247, 255))	('sunitinib', 'Chemical', 'MESH:D000077210', (267, 276))	('men', 'Species', '9606', (182, 185))	('PBRM1', 'Gene', '55193', (148, 153))	('VHL', 'Gene', '7428', (132, 135))	('PFS', 'Disease', (256, 259))	('PBRM1', 'Gene', (148, 153))	('patients', 'Species', '9606', (303, 311))	('VHL', 'Gene', (32, 35))	('gene expression', 'biological_process', 'GO:0010467', ('92', '107'))	('bevacizumab', 'Chemical', 'MESH:D000068258', (325, 336))	('RCC', 'Disease', (164, 167))	('mutations', 'Var', (216, 225))	('atezolizumab', 'Chemical', 'MESH:C000594389', (369, 381))	('atezolizumab', 'Chemical', 'MESH:C000594389', (312, 324))
102680	32751108	Whole genome sequencing studies performed in 35 metastatic CCRCC patients undergoing treatment with an anti-PD-1 blocking agent showed that clinical benefit to this treatment was significantly associated with mutations in the PBMR1 gene.	('men', 'Species', '9606', (90, 93))	('PBMR1', 'Gene', (226, 231))	('men', 'Species', '9606', (170, 173))	('PD-1', 'Gene', (108, 112))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('mutations', 'Var', (209, 218))	('RCC', 'Disease', (61, 64))	('PD-1', 'Gene', '5133', (108, 112))	('patients', 'Species', '9606', (65, 73))	('associated', 'Reg', (193, 203))
102686	32751108	Loss of SMARCB1 (also known as INI1) is a key diagnostic feature of these tumors: Calderaro et al.	('SMARCB1', 'Gene', '6598', (8, 15))	('SMARCB1', 'Gene', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('INI1', 'Gene', (31, 35))	('INI1', 'Gene', '6598', (31, 35))	('Loss', 'Var', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
102689	32751108	reported novel balanced translocations disrupting SMARCB1 in 4 of 5 cases studied; all these 4 cases occurred in patients with sickle cell trait or disease, whereas the remaining case displayed a homozygous deletion of SMARCB1 and presented in a patient with normal hemoglobin.	('patient', 'Species', '9606', (246, 253))	('balanced translocations', 'Var', (15, 38))	('patient', 'Species', '9606', (113, 120))	('sickle cell trait', 'Disease', (127, 144))	('SMARCB1', 'Gene', '6598', (50, 57))	('occurred', 'Reg', (101, 109))	('patients', 'Species', '9606', (113, 121))	('SMARCB1', 'Gene', (50, 57))	('SMARCB1', 'Gene', '6598', (219, 226))	('SMARCB1', 'Gene', (219, 226))	('disrupting', 'NegReg', (39, 49))
102693	32751108	Tumors pertaining to the three subsets associated with different FISH findings displayed comparable clinicopathologic features; the only peculiarity was related to the cases with homozygous SMARCB1 deletion being associated with the solid growth pattern, whereas tumor-bearing SMARCB1 translocations were more associated with reticular/cribiform growth.	('reticular/cribiform growth', 'Disease', (326, 352))	('associated', 'Reg', (310, 320))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('growth pattern', 'biological_process', 'GO:0007150', ('239', '253'))	('associated', 'Reg', (213, 223))	('deletion', 'Var', (198, 206))	('Tumors', 'Disease', (0, 6))	('S', 'Chemical', 'MESH:D013455', (67, 68))	('tumor', 'Disease', (263, 268))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('growth pattern', 'biological_process', 'GO:0040007', ('239', '253'))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('SMARCB1', 'Gene', (190, 197))	('SMARCB1', 'Gene', '6598', (190, 197))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('S', 'Chemical', 'MESH:D013455', (190, 191))	('SMARCB1', 'Gene', '6598', (277, 284))	('solid growth pattern', 'CPA', (233, 253))	('S', 'Chemical', 'MESH:D013455', (277, 278))	('SMARCB1', 'Gene', (277, 284))
102702	32751108	performed miRNA expression analysis and targeted next-generation sequencing mutational profiling on 13 cases of TCRCC: the expression profile of some miRs, such as miR-155 and miR-34a, that were downregulated was clearly different from that observed in PRCC; the gene sequencing showed recurrent mutations of ABL1 and PDGFRA genes, both genes being only rarely mutated in other RCC types.	('miR-34a', 'Gene', '407040', (176, 183))	('ABL1', 'Gene', '25', (309, 313))	('PRCC', 'Gene', (253, 257))	('RCC', 'Disease', (114, 117))	('RCC', 'Disease', 'MESH:C538614', (378, 381))	('miR-155', 'Gene', (164, 171))	('ABL1', 'Gene', (309, 313))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('miR-34a', 'Gene', (176, 183))	('PDGFRA', 'Gene', '5156', (318, 324))	('PDGFRA', 'Gene', (318, 324))	('PRCC', 'Gene', '5546', (253, 257))	('miR-155', 'Gene', '406947', (164, 171))	('RCC', 'Disease', (378, 381))	('RCC', 'Disease', 'MESH:C538614', (254, 257))	('mutations', 'Var', (296, 305))	('RCC', 'Disease', (254, 257))
102709	32751108	Initial studies have shown genetic abnormalities of WT1 gene, Wnt-activating mutations of CTNNB1 and WTX, abnormalities of 11p15 copy number, and methylation.	('11p15', 'Protein', (123, 128))	('CTNNB1', 'Gene', '1499', (90, 96))	('genetic abnormalities of WT1', 'Disease', (27, 55))	('WTX', 'Gene', '139285', (101, 104))	('genetic abnormalities of WT1', 'Disease', 'MESH:D030342', (27, 55))	('mutations', 'Var', (77, 86))	('abnormalities', 'Var', (106, 119))	('CTNNB1', 'Gene', (90, 96))	('methylation', 'Var', (146, 157))	('WTX', 'Gene', (101, 104))	('methylation', 'biological_process', 'GO:0032259', ('146', '157'))
102710	32751108	Subsequent genetic studies of large cohorts of WT patients have identified new mutations: recurrent mutations of the miRNA-processing gene DROSHA (observed in about 12% of cases) and non-recurrent mutations in other genes of this pathway (DICER1, DGCR8, XPO5, and TARBP2), associated with the downregulation of miRNA expression in a subset of WTs.	('XPO5', 'Gene', '57510', (254, 258))	('mutations', 'Var', (100, 109))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('DGCR8', 'Gene', '54487', (247, 252))	('S', 'Chemical', 'MESH:D013455', (142, 143))	('patients', 'Species', '9606', (50, 58))	('TARBP2', 'Gene', '6895', (264, 270))	('TARBP2', 'Gene', (264, 270))	('DGCR8', 'Gene', (247, 252))	('miRNA-processing', 'biological_process', 'GO:0035196', ('117', '133'))	('miRNA expression', 'MPA', (311, 327))	('DROSHA', 'Gene', '29102', (139, 145))	('DROSHA', 'Gene', (139, 145))	('downregulation', 'NegReg', (293, 307))	('XPO5', 'Gene', (254, 258))	('DICER1', 'Gene', (239, 245))	('DICER1', 'Gene', '23405', (239, 245))	('mutations', 'Var', (79, 88))
102711	32751108	Recurrent mutations at the level of the homeodomain of SIX1 and SIX2 genes involved in the control of renal development, particularly frequent in WTs with blastemal histology (18% of cases), as well as DROSHA mutations (18% of cases); mutations of MYCN, SMARCA4, and ARID1A.	('MYCN', 'Gene', (248, 252))	('SMARCA4', 'Gene', (254, 261))	('SIX2', 'Gene', (64, 68))	('mutations', 'Var', (235, 244))	('men', 'Species', '9606', (115, 118))	('SMARCA4', 'Gene', '6597', (254, 261))	('DROSHA', 'Gene', (202, 208))	('MYCN', 'Gene', '4613', (248, 252))	('SIX2', 'Gene', '10736', (64, 68))	('DROSHA', 'Gene', '29102', (202, 208))	('SIX1', 'Gene', (55, 59))	('SIX1', 'Gene', '6495', (55, 59))	('mutations', 'Var', (10, 19))	('ARID1A', 'Gene', '8289', (267, 273))	('ARID1A', 'Gene', (267, 273))
102712	32751108	The most recurrent gene mutations occurring in high-risk subgroups of WT patients subdivided into those exhibiting a favorable histology (FHWT) that subsequently relapsed and those with diffuse anaplasia (DAWT) were defined: recurrent DROSHA, DGCR8, and SIX1/2 homeodomain genes were observed in FHWT; recurrent TP53 alterations are observed in DAWT, with 48% of cases showing TP53 mutations, 11% copy loss without mutation: patients with stage III/IV DAWTs had lower relapse and death rates than those with TP53 abnormalities.	('mutations', 'Var', (382, 391))	('DROSHA', 'Gene', '29102', (235, 241))	('TP53', 'Gene', (377, 381))	('death', 'Disease', 'MESH:D003643', (480, 485))	('TP53', 'Gene', '7157', (508, 512))	('DROSHA', 'Gene', (235, 241))	('DGCR8', 'Gene', (243, 248))	('SIX1/2', 'Gene', (254, 260))	('patients', 'Species', '9606', (425, 433))	('DGCR8', 'Gene', '54487', (243, 248))	('lower', 'NegReg', (462, 467))	('TP53', 'Gene', (312, 316))	('FH', 'Gene', '2271', (296, 298))	('FH', 'Gene', '2271', (138, 140))	('patients', 'Species', '9606', (73, 81))	('TP53', 'Gene', '7157', (377, 381))	('death', 'Disease', (480, 485))	('TP53', 'Gene', (508, 512))	('SIX1/2', 'Gene', '6495;10736', (254, 260))	('TP53', 'Gene', '7157', (312, 316))
102713	32751108	Another study showed the frequent occurrence of insertion/deletion MLTT1 (a gene known to be involved in transcriptional elongation during early development) mutations, associated with altered binding to acetylated histone tails: these tumors show an increase in MYC gene expression and HOX genes dysregulation.	('binding', 'molecular_function', 'GO:0005488', ('193', '200'))	('MYC', 'Gene', '4609', (263, 266))	('dysregulation', 'MPA', (297, 310))	('expression', 'MPA', (272, 282))	('HOX genes', 'Gene', (287, 296))	('men', 'Species', '9606', (152, 155))	('tumors', 'Disease', (236, 242))	('insertion/deletion', 'Var', (48, 66))	('gene expression', 'biological_process', 'GO:0010467', ('267', '282'))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('MYC', 'Gene', (263, 266))	('increase', 'PosReg', (251, 259))	('mutations', 'Var', (158, 167))	('MLTT1', 'Gene', (67, 72))	('tumors', 'Disease', 'MESH:D009369', (236, 242))
102715	32751108	In addition to genes previously found to be mutated in WTs (WT1, CTNNB1, AMER1, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), this study discovered as frequently mutated in WTs also BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A genes.	('WT1', 'Gene', (60, 63))	('BCORL1', 'Gene', (207, 213))	('ARID1A', 'Gene', '8289', (253, 259))	('BCOR', 'Gene', (201, 205))	('AMER1', 'Gene', (73, 78))	('MYCN', 'Gene', '4613', (128, 132))	('ASXL1', 'Gene', '171023', (234, 239))	('BCOR', 'Gene', '54880', (207, 211))	('XPO5', 'Gene', (95, 99))	('DICER1', 'Gene', '23405', (101, 107))	('WT1', 'Gene', '7490', (60, 63))	('mutated', 'Var', (181, 188))	('MAP3K', 'molecular_function', 'GO:0004709', ('241', '246'))	('SIX2', 'Gene', (115, 119))	('CTNNB1', 'Gene', '1499', (65, 71))	('COL6A3', 'Gene', (226, 232))	('BCOR', 'Gene', (207, 211))	('COL6A3', 'Gene', '1293', (226, 232))	('MAP3K4', 'Gene', '4216', (241, 247))	('NONO', 'Gene', (215, 219))	('TP53', 'Gene', (138, 142))	('MLLT1', 'Gene', '4298', (121, 126))	('DICER1', 'Gene', (101, 107))	('AMER1', 'Gene', '139285', (73, 78))	('ASXL1', 'Gene', (234, 239))	('DGCR8', 'Gene', (88, 93))	('SIX1', 'Gene', '6495', (109, 113))	('MAP3K4', 'Gene', (241, 247))	('MYCN', 'Gene', (128, 132))	('DGCR8', 'Gene', '54487', (88, 93))	('MAX', 'Gene', (221, 224))	('XPO5', 'Gene', '57510', (95, 99))	('DROSHA', 'Gene', '29102', (80, 86))	('CTNNB1', 'Gene', (65, 71))	('DROSHA', 'Gene', (80, 86))	('SIX1', 'Gene', (109, 113))	('ARID1A', 'Gene', (253, 259))	('TP53', 'Gene', '7157', (138, 142))	('SIX2', 'Gene', '10736', (115, 119))	('NONO', 'Gene', '4841', (215, 219))	('BCOR', 'Gene', '54880', (201, 205))	('MLLT1', 'Gene', (121, 126))	('BCORL1', 'Gene', '63035', (207, 213))
102716	32751108	TP53 was the most frequently mutated gene in the discovery set, enriched in DAWT histology; importantly, mutations in TP53 were significantly associated with DAWT histology (56/118 DAWT and 9/533 FHWT); frequently, TP53 mutations display a lower allelic fraction, consistent with the role of TP53 as a secondary mutation in WTs.	('TP53', 'Gene', '7157', (0, 4))	('FH', 'Gene', '2271', (196, 198))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (292, 296))	('TP53', 'Gene', (292, 296))	('lower', 'NegReg', (240, 245))	('allelic fraction', 'MPA', (246, 262))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', '7157', (215, 219))	('mutations', 'Var', (105, 114))	('associated', 'Reg', (142, 152))	('TP53', 'Gene', (118, 122))	('TP53', 'Gene', (215, 219))	('mutations', 'Var', (220, 229))
102717	32751108	CTNNB1 was the most frequently mutated gene with global frequency of 13.5%; CTNNB1 mutations were much more frequent among FHWT (16%) than among DWAT (1.7%); analysis of co-occurrence mutations showed a significant co-occurrence of CTNNB1 mutations WT1 (about 39% of tumors with CTNNB1 mutations also had WT1 mutations and about 74% of tumors with WT1 mutations also had CTNNB1 mutations).	('WT1', 'Gene', (305, 308))	('CTNNB1', 'Gene', (371, 377))	('tumors', 'Disease', (336, 342))	('CTNNB1', 'Gene', '1499', (232, 238))	('CTNNB1', 'Gene', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('WT1', 'Gene', '7490', (305, 308))	('CTNNB1', 'Gene', '1499', (279, 285))	('WT1', 'Gene', (249, 252))	('mutations', 'Var', (286, 295))	('tumors', 'Disease', 'MESH:D009369', (336, 342))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('FH', 'Gene', '2271', (123, 125))	('tumors', 'Disease', (267, 273))	('CTNNB1', 'Gene', (232, 238))	('WT1', 'Gene', '7490', (249, 252))	('CTNNB1', 'Gene', '1499', (0, 6))	('CTNNB1', 'Gene', (279, 285))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('CTNNB1', 'Gene', '1499', (371, 377))	('tumors', 'Disease', 'MESH:D009369', (267, 273))	('WT1', 'Gene', (348, 351))	('CTNNB1', 'Gene', '1499', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (336, 342))	('CTNNB1', 'Gene', (0, 6))	('WT1', 'Gene', '7490', (348, 351))
102718	32751108	A significant co-occurrence was also observed between DROSHA and SIX1/SIX2 mutations (15% of tumors with DROSHA mutations also had mutations in SIX1 or SIX2, and 23% tumors with SIX1 or SIX2 mutations also had DROSHA mutations).	('DROSHA', 'Gene', '29102', (54, 60))	('SIX2', 'Gene', '10736', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('DROSHA', 'Gene', (54, 60))	('mutations', 'Var', (112, 121))	('SIX1', 'Gene', '6495', (178, 182))	('SIX1', 'Gene', '6495', (65, 69))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('SIX2', 'Gene', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('SIX1', 'Gene', (65, 69))	('SIX1', 'Gene', '6495', (144, 148))	('DROSHA', 'Gene', '29102', (210, 216))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('SIX1', 'Gene', (178, 182))	('DROSHA', 'Gene', (210, 216))	('tumors', 'Disease', (166, 172))	('DROSHA', 'Gene', '29102', (105, 111))	('SIX2', 'Gene', (152, 156))	('DROSHA', 'Gene', (105, 111))	('SIX2', 'Gene', '10736', (70, 74))	('SIX1', 'Gene', (144, 148))	('tumors', 'Disease', (93, 99))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('mutations', 'Var', (131, 140))	('SIX2', 'Gene', '10736', (186, 190))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('SIX2', 'Gene', (70, 74))
102719	32751108	At the level of CNAs, WTs are characterized by gains and losses of entire chromosomes or chromosomal arms, such as gains of 1q, 6, and 12 and loss of 4q, 16q, 17p, 14, 11, and 22; gain of 1q was shown in about 48% of cases; gain of 1q was not concurrent with any recurrent mutation, suggesting a possible role as a secondary event; amplification of 2p24 including MYCN locus, was found in 11.5% of FHWTs and 25.5% DAWTs; loss of 17p correlated with TP53 mutations, as well as loss of 4q and 14q.	('loss of 17p', 'Var', (421, 432))	('FHWTs', 'Disease', 'None', (398, 403))	('MYCN', 'Gene', (364, 368))	('MYCN', 'Gene', '4613', (364, 368))	('FHWTs', 'Disease', (398, 403))	('TP53', 'Gene', '7157', (449, 453))	('amp', 'Chemical', 'MESH:D000249', (332, 335))	('loss', 'Var', (476, 480))	('TP53', 'Gene', (449, 453))	('mutations', 'Var', (454, 463))
102721	32751108	Chromosomal loss at 9q22 caused recurrent loss of MIRLET7A gene family: MIRLET7A1 (5%), MIRLET7A2 (18%), MIRLET7A3 (/21%).	('Chromosomal loss', 'Var', (0, 16))	('MIRLET7A3', 'Gene', (105, 114))	('MIRLET7A2', 'Gene', '406882', (88, 97))	('MIRLET7A1', 'Gene', (72, 81))	('MIRLET7A gene family', 'Gene', (50, 70))	('MIRLET7A3', 'Gene', '406883', (105, 114))	('MIRLET7A1', 'Gene', '406881', (72, 81))	('MIRLET7A2', 'Gene', (88, 97))	('loss', 'NegReg', (42, 46))
102723	32751108	This study showed that WTs: (i) Derive from the cooperation of multiple genetic events; (ii) display different genetic alterations, associated with differential gene expression profiles; (iii) have multiple driver genes, the majority being altered in <5% of tumors; (iv) display mutations at the level of genes with common functions, mainly represented by genes involved in early renal development or epigenetic regulation.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('mutations', 'Var', (279, 288))	('regulation', 'biological_process', 'GO:0065007', ('412', '422'))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumors', 'Disease', (258, 264))	('men', 'Species', '9606', (393, 396))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('gene expression', 'biological_process', 'GO:0010467', ('161', '176'))
102726	32751108	Using human and mouse cellular models, evidence was provided that ENL mutants induce gene expression changes that promote a premalignant condition and in nephrogenesis models induce the formation of undifferentiated cellular structures resembling those observed in WTs.	('premalignant condition', 'Disease', (124, 146))	('induce', 'Reg', (175, 181))	('human', 'Species', '9606', (6, 11))	('gene expression', 'biological_process', 'GO:0010467', ('85', '100'))	('mutants', 'Var', (70, 77))	('formation', 'biological_process', 'GO:0009058', ('186', '195'))	('nephrogenesis', 'biological_process', 'GO:0072006', ('154', '167'))	('nephrogenesis', 'biological_process', 'GO:0001822', ('154', '167'))	('ENL', 'Gene', (66, 69))	('formation', 'CPA', (186, 195))	('mouse', 'Species', '10090', (16, 21))	('gene expression changes', 'MPA', (85, 108))	('nephrogenesis', 'Disease', (154, 167))	('nephrogenesis', 'Disease', 'None', (154, 167))	('promote', 'PosReg', (114, 121))
102727	32751108	At mechanistic level, these ENL mutations exhibit a function similar to their normal counterpart, occupying similar target genomic loci, but with a clearly increased occupancy, leading to a pronounced increase in the recruitment and activity of transcription elongation machinery, thus enforcing the rate and the level of gene transcription of these target genes.	('men', 'Species', '9606', (224, 227))	('activity', 'MPA', (233, 241))	('transcription', 'biological_process', 'GO:0006351', ('245', '258'))	('increase', 'PosReg', (201, 209))	('transcription', 'biological_process', 'GO:0006351', ('327', '340'))	('transcription elongation', 'CPA', (245, 269))	('increased', 'PosReg', (156, 165))	('mutations', 'Var', (32, 41))	('ENL', 'Gene', (28, 31))	('recruitment', 'MPA', (217, 228))
102731	32751108	To perform this analysis, these investigators initially investigated some children with unilateral WTs and sampled tumor, blood and normal kidney tissue specimens from the same individuals: in two of the three cases analyzed, mosaic mutations in normal kidneys that were present in the corresponding tumor, but absent from blood were observed.	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mosaic mutations', 'Var', (226, 242))	('tumor', 'Disease', (300, 305))	('tumor', 'Disease', (115, 120))	('children', 'Species', '9606', (74, 82))	('mutations', 'Var', (233, 242))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('amp', 'Chemical', 'MESH:D000249', (108, 111))	('men', 'Species', '9606', (158, 161))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
102736	32751108	sRCC is not a distinct RCC subtype, but represents a shift in the epithelial differentiation to mesenchymal differentiation in the context of pre-existing RCC; this conclusion is supported by two lines of observations: both an epithelial and a mesenchymal component is present in these tumors; both the epithelial and sarcomatoid components share the large majority of gene mutations, copy number alterations, and X-chromosome inactivation patterns.	('RCC', 'Disease', (155, 158))	('sarcomatoid', 'Disease', 'MESH:C538614', (318, 329))	('copy number alterations', 'Var', (385, 408))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('pre', 'molecular_function', 'GO:0003904', ('142', '145'))	('RCC', 'Disease', 'MESH:C538614', (1, 4))	('gene mutations', 'Var', (369, 383))	('tumors', 'Disease', (286, 292))	('RCC', 'Disease', (1, 4))	('tumors', 'Disease', 'MESH:D009369', (286, 292))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('RCC', 'Disease', (23, 26))	('sarcomatoid', 'Disease', (318, 329))	('X-chromosome', 'cellular_component', 'GO:0000805', ('414', '426'))	('X-chromosome inactivation', 'biological_process', 'GO:0009048', ('414', '439'))	('RCC', 'Disease', 'MESH:C538614', (155, 158))
102740	32751108	The most recurrent mutations in these patients involved VHL (72%), chromatin remodeling genes SETD2 (40%), PBMR1 (34%) and BAP1 (26%), TERT promoter (18%), PTEN (14%), TSC2 (12%), and Hippo pathway members NF2 (10%) and FAT1 (10%).	('VHL', 'Gene', (56, 59))	('TERT', 'Gene', '7015', (135, 139))	('PTEN', 'Gene', (156, 160))	('TSC2', 'Gene', (168, 172))	('chromatin', 'cellular_component', 'GO:0000785', ('67', '76'))	('NF2', 'Gene', '4771', (206, 209))	('patients', 'Species', '9606', (38, 46))	('NF2', 'Gene', (206, 209))	('VHL', 'Gene', '7428', (56, 59))	('PTEN', 'Gene', '5728', (156, 160))	('PBMR1', 'Gene', (107, 112))	('BAP1', 'Gene', '8314', (123, 127))	('FAT1', 'Gene', '2195', (220, 224))	('FAT1', 'Gene', (220, 224))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('67', '87'))	('BAP1', 'Gene', (123, 127))	('TSC2', 'Gene', '7249', (168, 172))	('SETD2', 'Gene', (94, 99))	('mutations', 'Var', (19, 28))	('SETD2', 'Gene', '29072', (94, 99))	('TERT', 'Gene', (135, 139))
102742	32751108	It is of interest to note that concerning the chromatin remodeling genes, in addition to SETD2, PBRM1, and BAP1 mutations, were observed also mutations of ARID1A and ARID1B genes and of several genes acting as epigenetic regulators.	('mutations', 'Var', (142, 151))	('BAP1', 'Gene', '8314', (107, 111))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('46', '66'))	('SETD2', 'Gene', '29072', (89, 94))	('BAP1', 'Gene', (107, 111))	('ARID1B', 'Gene', (166, 172))	('mutations', 'Var', (112, 121))	('SETD2', 'Gene', (89, 94))	('ARID1A', 'Gene', '8289', (155, 161))	('PBRM1', 'Gene', (96, 101))	('ARID1A', 'Gene', (155, 161))	('PBRM1', 'Gene', '55193', (96, 101))	('chromatin', 'cellular_component', 'GO:0000785', ('46', '55'))	('ARID1B', 'Gene', '57492', (166, 172))
102743	32751108	In 23 patients the genomic profiles of paired epithelial and mesenchymal components were compared, showing that: SETD2 and TERT alterations markedly differed between the two components; one tumor harbored NF2 and CDKN2A mutations exclusively in the mesenchymal component; two tumors harbored TP53 mutations exclusively in the mesenchymal component.	('TP53', 'Gene', (292, 296))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('patients', 'Species', '9606', (6, 14))	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('NF2', 'Gene', '4771', (205, 208))	('TERT', 'Gene', (123, 127))	('TERT', 'Gene', '7015', (123, 127))	('SETD2', 'Gene', (113, 118))	('NF2', 'Gene', (205, 208))	('mutations', 'Var', (220, 229))	('tumors', 'Disease', (276, 282))	('TP53', 'Gene', '7157', (292, 296))	('SETD2', 'Gene', '29072', (113, 118))	('CDKN2A', 'Gene', (213, 219))	('tumor', 'Disease', (276, 281))	('tumor', 'Disease', (190, 195))	('tumors', 'Disease', 'MESH:D009369', (276, 282))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('CDKN2A', 'Gene', '1029', (213, 219))
102745	32751108	Hippo-mutant sRCCs showed YAP/TAZ upregulation, thus showing that Hippo pathway is activated in these tumors; furthermore, Hippo pathway inhibition or restoration of normal NF2 expression inhibited the proliferation and invasiveness of sRCC.	('TAZ', 'Gene', '6901', (30, 33))	('RCC', 'Disease', (14, 17))	('TAZ', 'Gene', (30, 33))	('inhibited', 'NegReg', (188, 197))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('expression', 'MPA', (177, 187))	('NF2', 'Gene', '4771', (173, 176))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('NF2', 'Gene', (173, 176))	('Hippo pathway', 'Pathway', (123, 136))	('tumors', 'Disease', (102, 108))	('YAP', 'Gene', '55249', (26, 29))	('RCC', 'Disease', (237, 240))	('YAP', 'Gene', (26, 29))	('proliferation', 'CPA', (202, 215))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('Hippo-mutant', 'Var', (0, 12))	('inhibition', 'NegReg', (137, 147))	('RCC', 'Disease', 'MESH:C538614', (237, 240))	('upregulation', 'PosReg', (34, 46))
102746	32751108	Ito and coworkers reported a detailed analysis on CNAs occurring in 17 sRCCs, showing that these tumors are associated with a high rate of chromosomal abnormalities involving losses of 9q, 15q, 18p/q, and 22q and gains of 1q and 8q occurring at significantly higher frequencies compared to the corresponding non-sarcomatoid RCCs.	('RCC', 'Disease', 'MESH:C538614', (324, 327))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (139, 164))	('RCC', 'Disease', (72, 75))	('non-sarcomatoid', 'Disease', 'MESH:C538614', (308, 323))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('18p/q', 'Var', (194, 199))	('RCC', 'Disease', (324, 327))	('gains', 'PosReg', (213, 218))	('sarcomatoid RCCs', 'Disease', 'MESH:C538614', (312, 328))	('tumors', 'Disease', (97, 103))	('chromosomal abnormalities', 'Disease', (139, 164))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('losses', 'Var', (175, 181))	('sarcomatoid RCCs', 'Disease', (312, 328))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('non-sarcomatoid', 'Disease', (308, 323))	('15q', 'Var', (189, 192))
102749	32751108	reported the extensive molecular characterization of 62 primary high-grade uRCCs: sequencing analysis showed recurrent mutations at the level of 29 genes, the most frequent being NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%), MTOR (8%), PTEN (7%), and TSC1 (7%); integrated molecular analyses showed the existence of a subset (26% of uRCCs) characterized by NF2 loss, dysregulated Hippo-YAP pathway and poor survival and of another subset (21% of uRCCs), characterized by recurrent mutations of MTOR, TSC1, TSC2, or PTEN, hyperactive MT OR signaling and a better clinical outcome.	('RCC', 'Disease', 'MESH:C538614', (450, 453))	('mutations', 'Var', (484, 493))	('RCC', 'Disease', (337, 340))	('RCC', 'Disease', (76, 79))	('TSC1', 'Gene', (503, 507))	('PTEN', 'Gene', (518, 522))	('SETD2', 'Gene', (190, 195))	('BAP1', 'Gene', '8314', (203, 207))	('RCC', 'Disease', 'MESH:C538614', (337, 340))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('TSC2', 'Gene', '7249', (509, 513))	('TSC1', 'Gene', '7248', (503, 507))	('dysregulated', 'Reg', (370, 382))	('KMT2C', 'Gene', (215, 220))	('KMT2C', 'Gene', '58508', (215, 220))	('poor', 'NegReg', (405, 409))	('NF2', 'Gene', '4771', (179, 182))	('PTEN', 'Gene', '5728', (518, 522))	('PTEN', 'Gene', (239, 243))	('TSC1', 'Gene', (254, 258))	('YAP', 'Gene', '55249', (389, 392))	('SETD2', 'Gene', '29072', (190, 195))	('NF2', 'Gene', (179, 182))	('TSC2', 'Gene', (509, 513))	('YAP', 'Gene', (389, 392))	('BAP1', 'Gene', (203, 207))	('MTOR', 'Gene', (228, 232))	('hyperactive MT', 'Disease', (524, 538))	('hyperactive MT', 'Disease', 'MESH:D006948', (524, 538))	('MTOR', 'Gene', (497, 501))	('TSC1', 'Gene', '7248', (254, 258))	('MTOR', 'Gene', '2475', (228, 232))	('NF2', 'Gene', '4771', (360, 363))	('signaling', 'biological_process', 'GO:0023052', ('542', '551'))	('MTOR', 'Gene', '2475', (497, 501))	('PTEN', 'Gene', '5728', (239, 243))	('RCC', 'Disease', (450, 453))	('loss', 'NegReg', (364, 368))	('NF2', 'Gene', (360, 363))
102750	32751108	The frequent NF2 abnormalities and the consequent dysregulation of the Hippo pathway represent a common feature of both sRCC and uRCC and support the targeting of this pathway for the therapy of a subset of these aggressive RCCs.	('RCC', 'Disease', (224, 227))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('NF2', 'Gene', '4771', (13, 16))	('RCC', 'Disease', (121, 124))	('Hippo pathway', 'Pathway', (71, 84))	('aggressive RCCs', 'Disease', (213, 228))	('aggressive RCCs', 'Disease', 'MESH:D001523', (213, 228))	('RCC', 'Disease', (130, 133))	('abnormalities', 'Var', (17, 30))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('NF2', 'Gene', (13, 16))	('dysregulation', 'Reg', (50, 63))	('RCC', 'Disease', 'MESH:C538614', (224, 227))
102761	32751108	These various types of RCC have been defined on the basis of their histological appearance, the presence of distinct driver mutations, varying clinical course, and different responses to therapy.	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('mutations', 'Var', (124, 133))
102766	32751108	Thus, molecular studies in CCRCC have defined the dysregulation of the VHL gene as an almost universal initial, founding event, followed by different types of additional genetic events involving PBRM1, KDM5C, SETD2, or BAP1 that differentially dictate disease progression and aggressiveness.	('aggressiveness', 'Disease', (276, 290))	('KDM5C', 'Gene', '8242', (202, 207))	('aggressiveness', 'Phenotype', 'HP:0000718', (276, 290))	('VHL', 'Gene', (71, 74))	('BAP1', 'Gene', (219, 223))	('SETD2', 'Gene', '29072', (209, 214))	('PBRM1', 'Gene', (195, 200))	('RCC', 'Disease', (29, 32))	('PBRM1', 'Gene', '55193', (195, 200))	('VHL', 'Gene', '7428', (71, 74))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('SETD2', 'Gene', (209, 214))	('aggressiveness', 'Disease', 'MESH:D001523', (276, 290))	('dictate', 'Reg', (244, 251))	('dysregulation', 'Var', (50, 63))	('KDM5C', 'Gene', (202, 207))	('BAP1', 'Gene', '8314', (219, 223))
102767	32751108	CCRCC tumors with PBRM1 mutations respond to targeted therapy differently than tumors with BAP1 mutations.	('BAP1', 'Gene', (91, 95))	('CCRCC tumors', 'Disease', 'MESH:D009369', (0, 12))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('CCRCC tumors', 'Disease', (0, 12))	('PBRM1', 'Gene', (18, 23))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('BAP1', 'Gene', '8314', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('PBRM1', 'Gene', '55193', (18, 23))	('mutations', 'Var', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
102776	32751108	The rationale for their use was related to the very frequent VHL alterations observed in RCCs and responsible for activation of hypoxia signaling pathway in these tumors.	('activation', 'PosReg', (114, 124))	('alterations', 'Var', (65, 76))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('RCC', 'Disease', (89, 92))	('tumors', 'Disease', (163, 169))	('VHL', 'Gene', (61, 64))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('VHL', 'Gene', '7428', (61, 64))	('hypoxia', 'Disease', 'MESH:D000860', (128, 135))	('signaling pathway', 'biological_process', 'GO:0007165', ('136', '153'))	('hypoxia', 'Disease', (128, 135))
102793	32751108	showed the preliminary results of a phase II study (NCT 03401788) involving the treatment of 61 patients with germline VHL mutant, localized/nonmetastatic CCRCC, common lesions outside the kidney (non-RCC tumors such as hemangioblastomas (80%) and pancreatic lesions (50%)); about 28% of the patients displayed objective responses and about 87% of patients showed decrease in the size of target lesions.	('patients', 'Species', '9606', (348, 356))	('RCC tumors', 'Disease', (201, 211))	('VHL', 'Gene', '7428', (119, 122))	('decrease', 'NegReg', (364, 372))	('RCC tumors', 'Disease', 'MESH:C538614', (201, 211))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('patients', 'Species', '9606', (292, 300))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('RCC', 'Disease', (201, 204))	('hemangioblastomas', 'Disease', (220, 237))	('pancreatic lesions', 'Disease', (248, 266))	('germline', 'Var', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('hemangioblastomas', 'Disease', 'MESH:D018325', (220, 237))	('pancreatic lesions', 'Disease', 'MESH:D010195', (248, 266))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('men', 'Species', '9606', (85, 88))	('patients', 'Species', '9606', (96, 104))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (220, 236))	('VHL', 'Gene', (119, 122))	('RCC', 'Disease', (157, 160))	('mutant', 'Var', (123, 129))
102906	29854314	Foretinib (GSK1363089) induces p53-dependent apoptosis in endometrial cancer Foretinib (GSK1363089 or XL880), which is an oral multikinase inhibitor developed to primarily target the hepatocyte growth factor (HGF)/Met signaling pathway, has shown anti-tumor effects against some cancers in preclinical and clinical studies.	('GSK', 'molecular_function', 'GO:0050321', ('88', '91'))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('cancers', 'Phenotype', 'HP:0002664', (279, 286))	('XL880', 'Chemical', 'MESH:C544831', (102, 107))	('cancers', 'Disease', (279, 286))	('p53', 'Gene', '7157', (31, 34))	('factor ', 'Gene', '7422', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('Foretinib', 'Chemical', 'MESH:C544831', (0, 9))	('Met signaling pathway', 'biological_process', 'GO:0048012', ('214', '235'))	('p53', 'Gene', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('GSK', 'molecular_function', 'GO:0050321', ('11', '14'))	('GSK1363089', 'Chemical', 'MESH:C544831', (11, 21))	('endometrial cancer', 'Phenotype', 'HP:0012114', (58, 76))	('GSK1363089', 'Chemical', 'MESH:C544831', (88, 98))	('factor ', 'Gene', (201, 208))	('cancers', 'Disease', 'MESH:D009369', (279, 286))	('endometrial cancer', 'Disease', (58, 76))	('GSK1363089', 'Var', (11, 21))	('endometrial cancer', 'Disease', 'MESH:D016889', (58, 76))	('Foretinib', 'Chemical', 'MESH:C544831', (77, 86))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('tumor', 'Disease', (252, 257))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('183', '207'))
102910	29854314	p53 mutations were observed in 37 (10.8%) of 344 endometrial cancer specimens.	('p53', 'Gene', (0, 3))	('endometrial cancer', 'Disease', (49, 67))	('observed', 'Reg', (19, 27))	('endometrial cancer', 'Phenotype', 'HP:0012114', (49, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('endometrial cancer', 'Disease', 'MESH:D016889', (49, 67))	('mutations', 'Var', (4, 13))
102912	29854314	Foretinib induces an anti-cancer effect through the anti-phosphorylation of Met, which results in the induction of p53-dependent apoptosis; foretinib was found to exert greater anti-cancer activity in endometrial cancer specimens with wild-type p53 than in specimens with p53 mutations.	('cancer', 'Disease', (26, 32))	('anti-phosphorylation', 'MPA', (52, 72))	('foretinib', 'Gene', (140, 149))	('endometrial cancer', 'Disease', 'MESH:D016889', (201, 219))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('nde', 'Gene', '54820', (123, 126))	('ter', 'Gene', '9524', (173, 176))	('wild-type', 'Var', (235, 244))	('nde', 'Gene', (123, 126))	('Foretinib', 'Chemical', 'MESH:C544831', (0, 9))	('cancer', 'Disease', (182, 188))	('cancer', 'Disease', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('ter', 'Gene', (173, 176))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('endometrial cancer', 'Phenotype', 'HP:0012114', (201, 219))	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('endometrial cancer', 'Disease', (201, 219))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('phosphorylation', 'biological_process', 'GO:0016310', ('57', '72'))	('foretinib', 'Chemical', 'MESH:C544831', (140, 149))
102928	29854314	In several epithelial and mesenchymal cancers, the high expression of the Met protein has been reported to be an independent predictor of an adverse outcome, and Met was reported to activate cancer cell dissemination.	('high expression', 'MPA', (51, 66))	('mesenchymal cancers', 'Disease', (26, 45))	('activate', 'PosReg', (182, 190))	('epithelial', 'Disease', (11, 21))	('mesenchymal cancers', 'Disease', 'MESH:C535700', (26, 45))	('cancer', 'Disease', (191, 197))	('nde', 'Gene', '54820', (114, 117))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Disease', (38, 44))	('protein', 'Protein', (78, 85))	('nde', 'Gene', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('nde', 'Gene', '54820', (119, 122))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('Met', 'Gene', (74, 77))	('Met', 'Var', (162, 165))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('nde', 'Gene', (119, 122))	('cancer', 'Disease', 'MESH:D009369', (38, 44))
102946	29854314	It has been well documented that the activation of PI3K signaling increases the translocation of the mouse double minute 2 homolog (MDM2) from the cytoplasm to the nucleus, allowing p53 to be degraded by proteasomes.	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('PI3K', 'Var', (51, 55))	('increases', 'PosReg', (66, 75))	('mouse', 'Species', '10090', (101, 106))	('nucleus', 'cellular_component', 'GO:0005634', ('164', '171'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('147', '156'))	('homolog (MDM2', 'Gene', '17246', (123, 136))	('translocation', 'MPA', (80, 93))	('PI3K signaling', 'biological_process', 'GO:0014065', ('51', '65'))	('p53', 'Protein', (182, 185))	('degraded', 'MPA', (192, 200))
102955	29854314	Figure 3D shows that the anti-proliferation effect of foretinib was reduced in p53 siRNA-transfected cells.	('foretinib', 'Gene', (54, 63))	('foretinib', 'Chemical', 'MESH:C544831', (54, 63))	('anti-proliferation effect', 'CPA', (25, 50))	('p53', 'Var', (79, 82))	('reduced', 'NegReg', (68, 75))
102958	29854314	As shown in Figure 5A, the HGF siRNA-transfected EC cells showed significant growth inhibition, which occurred in a time-dependent manner, in comparison to the scrambled siRNA-transfected cells.	('growth inhibition', 'CPA', (77, 94))	('HGF siRNA-transfected', 'Var', (27, 48))	('nde', 'Gene', '54820', (125, 128))	('nde', 'Gene', (125, 128))
102959	29854314	Moreover, HGF siRNA transfection induced a significantly greater level of apoptosis in comparison to the scrambled siRNA-transfected cells (Figure 5B and 5C).	('apoptosis', 'MPA', (74, 83))	('HGF siRNA transfection', 'Var', (10, 32))	('transfection', 'Var', (20, 32))	('ter', 'Gene', '9524', (61, 64))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('ter', 'Gene', (61, 64))
102960	29854314	In order to assess whether the p53-dependent apoptosis was induced via the inhibition of autocrine HGF/Met signaling, we examined the expression of p-Akt, p-MDM2, p53 and PUMA in HGF siRNA-transfected EC cells by Western blotting.	('ste', 'Gene', (215, 218))	('signaling', 'biological_process', 'GO:0023052', ('107', '116'))	('ste', 'Gene', '6783', (215, 218))	('nde', 'Gene', (39, 42))	('ter', 'Gene', '9524', (216, 219))	('p-MDM2', 'Var', (155, 161))	('nde', 'Gene', '54820', (39, 42))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('ter', 'Gene', (216, 219))
102962	29854314	These data suggest that autocrine HGF/Met signaling interferes with the p53 activity in EC cells, and that inhibiting autocrine HGF/Met signaling restores the p53 function.	('ter', 'Gene', '9524', (54, 57))	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('p53', 'Protein', (72, 75))	('activity', 'MPA', (76, 84))	('inhibiting', 'Var', (107, 117))	('p53 function', 'MPA', (159, 171))	('ter', 'Gene', (54, 57))	('signaling', 'biological_process', 'GO:0023052', ('136', '145'))	('restores', 'PosReg', (146, 154))
102975	29854314	Table 2 shows the association between the malignant potential of the tumor and the p53 status (determined by immunochemical staining).	('ter', 'Gene', '9524', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('ter', 'Gene', (97, 100))	('tumor', 'Disease', (69, 74))	('association', 'Interaction', (18, 29))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('p53 status', 'Var', (83, 93))
102977	29854314	Thirty-seven (10.8%) patients were positive for p53 and 307 (89.2%) were negative for p53.	('patients', 'Species', '9606', (21, 29))	('positive', 'Reg', (35, 43))	('p53', 'Var', (48, 51))
102978	29854314	The rate of p53 positivity in the high-grade tumor group (24.0%) was significantly higher than that in the low-grade tumor group (6.0%).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('p53', 'Protein', (12, 15))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('positivity', 'Var', (16, 26))	('higher', 'PosReg', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
102981	29854314	Foretinib was found to induce anti-cancer effects by the anti-phosphorylation of Met, which results in the induction of p53-dependent apoptosis; foretinib had more anti-cancer activity in endometrial cancer specimens with wild-type p53 than in specimens with p53 mutations.	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('wild-type', 'Var', (222, 231))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('endometrial cancer', 'Phenotype', 'HP:0012114', (188, 206))	('foretinib', 'Chemical', 'MESH:C544831', (145, 154))	('Foretinib', 'Chemical', 'MESH:C544831', (0, 9))	('endometrial cancer', 'Disease', (188, 206))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('more', 'PosReg', (159, 163))	('foretinib', 'Gene', (145, 154))	('nde', 'Gene', '54820', (128, 131))	('endometrial cancer', 'Disease', 'MESH:D016889', (188, 206))	('nde', 'Gene', (128, 131))	('apoptosis', 'biological_process', 'GO:0097194', ('134', '143'))	('apoptosis', 'biological_process', 'GO:0006915', ('134', '143'))	('cancer', 'Disease', (35, 41))	('cancer', 'Disease', (200, 206))	('phosphorylation', 'biological_process', 'GO:0016310', ('62', '77'))
102987	29854314	Although the full spectrum of activity is still being uncovered, mutant p53 has been found in various cancers and involvement in the development and progression of cancer has been clarified.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('mutant', 'Var', (65, 71))	('p53', 'Gene', (72, 75))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', (164, 170))	('found', 'Reg', (85, 90))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))
102988	29854314	Mutant p53 has been found in approximately 10-20% of uterine endometrioid carcinomas and >90% of uterine serous or clear cell carcinomas.	('ter', 'Gene', '9524', (54, 57))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (61, 83))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (61, 84))	('clear cell carcinomas', 'Disease', (115, 136))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('ter', 'Gene', '9524', (98, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('ter', 'Gene', (54, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (115, 136))	('found', 'Reg', (20, 25))	('ter', 'Gene', (98, 101))	('Mutant', 'Var', (0, 6))	('endometrioid carcinomas', 'Disease', (61, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (61, 84))	('p53', 'Gene', (7, 10))
102989	29854314	In addition, there is a trend toward a higher frequency of p53 mutations with increasing histopathological grades in uterine endometrioid carcinomas.	('mutations', 'Var', (63, 72))	('p53', 'Gene', (59, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('ter', 'Gene', (118, 121))	('endometrioid carcinomas', 'Disease', (125, 148))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (125, 148))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (125, 147))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (125, 148))	('ter', 'Gene', '9524', (118, 121))
102990	29854314	reported that mutant p53 was found in 43% of Grade 3 uterine endometrioid carcinomas, while it was not detected in Grade 1 endometrioid carcinomas.	('ter', 'Gene', '9524', (54, 57))	('endometrioid carcinomas', 'Disease', (123, 146))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (61, 84))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (123, 146))	('found', 'Reg', (29, 34))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (61, 83))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (123, 145))	('mutant', 'Var', (14, 20))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (123, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('ter', 'Gene', (54, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('endometrioid carcinomas', 'Disease', (61, 84))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (61, 84))	('p53', 'Gene', (21, 24))
102991	29854314	It also reported that p53 mutations are detected in 24-36% of clear cell carcinomas.	('p53', 'Gene', (22, 25))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (62, 83))	('detected', 'Reg', (40, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('mutations', 'Var', (26, 35))	('clear cell carcinomas', 'Disease', (62, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
102992	29854314	Mutations in p53 are not a simple phenomenon because some tumors harbor mutations in p53 that allow the protein to retain its functions.	('mutations', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('protein', 'Protein', (104, 111))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('p53', 'Gene', (85, 88))	('functions', 'MPA', (126, 135))
102999	29854314	This also suggests that foretinib would be effective for treating high-grade endometrial cancer, which causes p53 mutations.	('p53', 'Gene', (110, 113))	('endometrial cancer', 'Disease', 'MESH:D016889', (77, 95))	('mutations', 'Var', (114, 123))	('endometrial cancer', 'Disease', (77, 95))	('foretinib', 'Chemical', 'MESH:C544831', (24, 33))	('endometrial cancer', 'Phenotype', 'HP:0012114', (77, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
103081	33469315	For example, high expression of lncRNA PANDAR is related to high TNM stage, lymph node metastasis and distant metastasis of ccRCC patients, and silencing of PANDAR induces cell cycle arrest and apoptosis of ccRCC cells.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (172, 189))	('RCC', 'Phenotype', 'HP:0005584', (209, 212))	('RCC', 'Disease', (209, 212))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('induces', 'Reg', (164, 171))	('arrest', 'Disease', 'MESH:D006323', (183, 189))	('distant metastasis', 'CPA', (102, 120))	('expression', 'MPA', (18, 28))	('PANDAR', 'Gene', '101154753', (39, 45))	('RCC', 'Disease', 'MESH:C538614', (209, 212))	('PANDAR', 'Gene', (39, 45))	('apoptosis', 'biological_process', 'GO:0097194', ('194', '203'))	('apoptosis', 'CPA', (194, 203))	('ccRCC', 'Phenotype', 'HP:0006770', (207, 212))	('apoptosis', 'biological_process', 'GO:0006915', ('194', '203'))	('TNM', 'Gene', '10178', (65, 68))	('arrest', 'Disease', (183, 189))	('RCC', 'Disease', (126, 129))	('patients', 'Species', '9606', (130, 138))	('related', 'Reg', (49, 56))	('TNM', 'Gene', (65, 68))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('172', '189'))	('lymph node metastasis', 'CPA', (76, 97))	('PANDAR', 'Gene', '101154753', (157, 163))	('PANDAR', 'Gene', (157, 163))	('silencing', 'Var', (144, 153))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (124, 129))
103084	33469315	Aberrantly expressed miRNAs participate in the growth and metastasis of ccRCC.	('Aberrantly', 'Var', (0, 10))	('RCC', 'Disease', (74, 77))	('miRNAs', 'Protein', (21, 27))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('growth', 'CPA', (47, 53))	('metastasis', 'CPA', (58, 68))
103086	33469315	Additionally, in ccRCC, miR-124 and miR-203 participate in the activation of the epithelial-mesenchymal transition (EMT) pathway by regulating ZEB2.	('ZEB2', 'Gene', '9839', (143, 147))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('81', '114'))	('EMT', 'biological_process', 'GO:0001837', ('116', '119'))	('ZEB2', 'Gene', (143, 147))	('miR-203', 'Gene', '406986', (36, 43))	('miR-203', 'Gene', (36, 43))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('ccRCC', 'Phenotype', 'HP:0006770', (17, 22))	('miR-124', 'Var', (24, 31))	('regulating', 'Reg', (132, 142))	('activation', 'PosReg', (63, 73))
103089	33469315	It was further found that silencing of PCED1B-AS1 suppressed the proliferation, migration and epithelial-mesenchymal transition (EMT) of ccRCC cells.	('PCED1B-AS1', 'Gene', '100233209', (39, 49))	('suppressed', 'NegReg', (50, 60))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('94', '127'))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('migration', 'CPA', (80, 89))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('RCC', 'Disease', (139, 142))	('EMT', 'biological_process', 'GO:0001837', ('129', '132'))	('silencing', 'Var', (26, 35))	('PCED1B-AS1', 'Gene', (39, 49))	('epithelial-mesenchymal transition', 'CPA', (94, 127))
103111	33469315	HEK-293 cells were inoculated into 24-well plates, and miR-484 mimics or NC mimics and pmirGLO plasmids containing wild-type or mutant sequence of PCED1B-AS1 or 3'-UTR of ZEB1 were co-transfected into HEK-293 cells by LipofectamineTM 3000 reagent (Invitrogen, Carlsbad, CA, USA).	('PCED1B-AS1', 'Gene', (147, 157))	('HEK-293', 'CellLine', 'CVCL:0045', (201, 208))	('PCED1B-AS1', 'Gene', '100233209', (147, 157))	('mutant', 'Var', (128, 134))	('miR-484', 'Gene', '619553', (55, 62))	('ZEB1', 'Gene', (171, 175))	('LipofectamineTM 3000', 'Chemical', '-', (218, 238))	('ZEB1', 'Gene', '6935', (171, 175))	('HEK-293', 'CellLine', 'CVCL:0045', (0, 7))	('miR-484', 'Gene', (55, 62))
103114	33469315	Cell extracts were then incubated with magnetic beads, which were coupled with anti-Ago2 antibody or control IgG (Millipore, Billerica, MA, USA).	('antibody', 'cellular_component', 'GO:0019815', ('89', '97'))	('coupled', 'Interaction', (66, 73))	('antibody', 'cellular_component', 'GO:0019814', ('89', '97'))	('antibody', 'molecular_function', 'GO:0003823', ('89', '97'))	('Ago2', 'Gene', '27161', (84, 88))	('antibody', 'Var', (89, 97))	('Ago2', 'Gene', (84, 88))	('antibody', 'cellular_component', 'GO:0042571', ('89', '97'))
103118	33469315	The information of primary antibody is as follows: anti-ZEB1 (1:1000, Abcam, ab203829), anti-N-cadherin (1:1000, Abcam, ab202030), anti-E-cadherin (1:1000, Abcam, ab40772), anti-beta-actin (1:2000, Abcam, Ab8226).	('antibody', 'cellular_component', 'GO:0042571', ('27', '35'))	('ZEB1', 'Gene', (56, 60))	('cadherin', 'molecular_function', 'GO:0008014', ('138', '146'))	('ZEB1', 'Gene', '6935', (56, 60))	('1:1000', 'Var', (105, 111))	('1:1000', 'Var', (148, 154))	('E-cadherin', 'Gene', (136, 146))	('E-cadherin', 'Gene', '999', (136, 146))	('antibody', 'cellular_component', 'GO:0019815', ('27', '35'))	('beta-actin', 'Gene', '728378', (178, 188))	('N-cadherin', 'Gene', (93, 103))	('antibody', 'cellular_component', 'GO:0019814', ('27', '35'))	('antibody', 'molecular_function', 'GO:0003823', ('27', '35'))	('beta-actin', 'Gene', (178, 188))	('cadherin', 'molecular_function', 'GO:0008014', ('95', '103'))	('N-cadherin', 'Gene', '1000', (93, 103))
103122	33469315	The overall survival time (OS) of ccRCC patients with high expression of PCED1B-AS1 was significantly shorter than those with low expression of PCED1B-AS1 (Figure 1B).	('shorter', 'NegReg', (102, 109))	('PCED1B-AS1', 'Gene', (144, 154))	('high expression', 'Var', (54, 69))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('survival', 'MPA', (12, 20))	('patients', 'Species', '9606', (40, 48))	('PCED1B-AS1', 'Gene', '100233209', (144, 154))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (34, 39))	('PCED1B-AS1', 'Gene', (73, 83))	('PCED1B-AS1', 'Gene', '100233209', (73, 83))
103127	33469315	The results showed that high expression of PCED1B-AS1 was associated with high tumor stage and high Fuhrman grade, but not related to age, gender, tumor diameter, and lymph node metastasis.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', (79, 84))	('associated', 'Reg', (58, 68))	('high Fuhrman grade', 'CPA', (95, 113))	('PCED1B-AS1', 'Gene', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('high', 'Var', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('expression', 'MPA', (29, 39))	('PCED1B-AS1', 'Gene', '100233209', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
103129	33469315	To probe the function of PCED1B-AS1 in ccRCC, we investigated its biological function in A498 and Caki-1 cells by knocking down PCED1B-AS1 expression using siRNA (Figure 2A).	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('PCED1B-AS1', 'Gene', (25, 35))	('knocking', 'Var', (114, 122))	('PCED1B-AS1', 'Gene', '100233209', (25, 35))	('PCED1B-AS1', 'Gene', (128, 138))	('Caki-1', 'CellLine', 'CVCL:0234', (98, 104))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('PCED1B-AS1', 'Gene', '100233209', (128, 138))	('RCC', 'Disease', (41, 44))
103131	33469315	The results showed that PCED1B-AS1 knockdown markedly suppressed the proliferation of A498 and Caki-1 cells (Figure 2B and C).	('PCED1B-AS1', 'Gene', (24, 34))	('knockdown', 'Var', (35, 44))	('proliferation', 'CPA', (69, 82))	('suppressed', 'NegReg', (54, 64))	('Caki-1', 'CellLine', 'CVCL:0234', (95, 101))	('PCED1B-AS1', 'Gene', '100233209', (24, 34))
103132	33469315	Wound healing experiments were used to examine the effect of PCED1B-AS1 on cell migration, the results of which demonstrated that the migration ccRCC cells with PCED1B-AS1 silenced was significantly inhibited (Figure 2D).	('PCED1B-AS1', 'Gene', '100233209', (61, 71))	('PCED1B-AS1', 'Gene', (161, 171))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('silenced', 'Var', (172, 180))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('PCED1B-AS1', 'Gene', '100233209', (161, 171))	('inhibited', 'NegReg', (199, 208))	('Wound healing', 'biological_process', 'GO:0042060', ('0', '13'))	('cell migration', 'biological_process', 'GO:0016477', ('75', '89'))	('PCED1B-AS1', 'Gene', (61, 71))
103133	33469315	Western blotting was used to detect the expression of EMT-related proteins, and the data demonstrated that silencing of PCED1B-AS1 significantly increased E-cadherin expression and decreased N-cadherin expression in ccRCC cells (Figure 2E).	('E-cadherin', 'Gene', '999', (155, 165))	('cadherin', 'molecular_function', 'GO:0008014', ('193', '201'))	('silencing', 'Var', (107, 116))	('N-cadherin', 'Gene', '1000', (191, 201))	('PCED1B-AS1', 'Gene', '100233209', (120, 130))	('ccRCC', 'Phenotype', 'HP:0006770', (216, 221))	('increased', 'PosReg', (145, 154))	('cadherin', 'molecular_function', 'GO:0008014', ('157', '165'))	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('RCC', 'Disease', (218, 221))	('E-cadherin', 'Gene', (155, 165))	('RCC', 'Phenotype', 'HP:0005584', (218, 221))	('expression', 'MPA', (166, 176))	('N-cadherin', 'Gene', (191, 201))	('PCED1B-AS1', 'Gene', (120, 130))	('EMT', 'biological_process', 'GO:0001837', ('54', '57'))	('decreased', 'NegReg', (181, 190))
103149	33469315	The dual-luciferase reporter experiment revealed that transfection of miR-484 mimics reduced luciferase activity of ZEB1-WT reporter, but had no significant effect on the luciferase activity in ZEB1-MUT group (Figure 5B).	('activity', 'MPA', (104, 112))	('ZEB1', 'Gene', '6935', (194, 198))	('luciferase activity', 'molecular_function', 'GO:0047077', ('93', '112'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('93', '112'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('93', '112'))	('ZEB1', 'Gene', (116, 120))	('luciferase', 'Enzyme', (93, 103))	('luciferase activity', 'molecular_function', 'GO:0050397', ('93', '112'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('171', '190'))	('ZEB1', 'Gene', (194, 198))	('luciferase activity', 'molecular_function', 'GO:0050248', ('93', '112'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('171', '190'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('171', '190'))	('reduced', 'NegReg', (85, 92))	('mimics', 'Var', (78, 84))	('miR-484', 'Gene', '619553', (70, 77))	('ZEB1', 'Gene', '6935', (116, 120))	('miR-484', 'Gene', (70, 77))	('luciferase activity', 'molecular_function', 'GO:0050248', ('171', '190'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('171', '190'))
103154	33469315	qRT-PCR revealed that silencing PCED1B-AS1 increased the expression of miR-484, and the transfection of miR-484 inhibitors remarkably inhibited miR-484 expression (Figure 6A).	('expression', 'MPA', (57, 67))	('miR-484', 'Gene', (71, 78))	('miR-484', 'Gene', '619553', (144, 151))	('inhibited', 'NegReg', (134, 143))	('miR-484', 'Gene', '619553', (104, 111))	('silencing', 'Var', (22, 31))	('miR-484', 'Gene', '619553', (71, 78))	('miR-484', 'Gene', (144, 151))	('increased', 'PosReg', (43, 52))	('PCED1B-AS1', 'Gene', (32, 42))	('miR-484', 'Gene', (104, 111))	('expression', 'MPA', (152, 162))	('PCED1B-AS1', 'Gene', '100233209', (32, 42))
103155	33469315	Western blotting revealed that inhibiting PCED1B-AS1 significantly inhibited the expression of ZEB1, and transfection of miR-484 inhibitors partially restored ZEB1 protein expression (Figure 6B).	('miR-484', 'Gene', (121, 128))	('ZEB1', 'Gene', (159, 163))	('PCED1B-AS1', 'Gene', (42, 52))	('inhibited', 'NegReg', (67, 76))	('ZEB1', 'Gene', '6935', (159, 163))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('inhibiting', 'Var', (31, 41))	('PCED1B-AS1', 'Gene', '100233209', (42, 52))	('ZEB1', 'Gene', (95, 99))	('ZEB1', 'Gene', '6935', (95, 99))	('miR-484', 'Gene', '619553', (121, 128))	('expression', 'MPA', (81, 91))
103156	33469315	Functional experiments showed that inhibition of miR-484 counteracted the effects of PCED1B-AS1 knockdown on the proliferation, migration, and EMT of A498 and Caki-1 cells (Figure 6C-F).	('PCED1B-AS1', 'Gene', (85, 95))	('knockdown', 'Var', (96, 105))	('miR-484', 'Gene', (49, 56))	('EMT', 'biological_process', 'GO:0001837', ('143', '146'))	('miR-484', 'Gene', '619553', (49, 56))	('PCED1B-AS1', 'Gene', '100233209', (85, 95))	('migration', 'CPA', (128, 137))	('Caki-1', 'CellLine', 'CVCL:0234', (159, 165))	('EMT', 'CPA', (143, 146))
103163	33469315	Another study reports that lncRNA SNHG5 is up-regulated in ccRCC tissues, and inhibition of SNHG5 reduces the proliferation and invasion of ccRCC cell and promoted apoptosis.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('SNHG5', 'Gene', (92, 97))	('SNHG5', 'Gene', '387066', (34, 39))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('reduces', 'NegReg', (98, 105))	('proliferation', 'CPA', (110, 123))	('apoptosis', 'CPA', (164, 173))	('SNHG5', 'Gene', (34, 39))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('promoted', 'PosReg', (155, 163))	('apoptosis', 'biological_process', 'GO:0097194', ('164', '173'))	('apoptosis', 'biological_process', 'GO:0006915', ('164', '173'))	('invasion', 'CPA', (128, 136))	('up-regulated', 'PosReg', (43, 55))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('SNHG5', 'Gene', '387066', (92, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('inhibition', 'Var', (78, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))
103169	33469315	We found that PCED1B-AS1 was up-regulated in ccRCC, and the knockdown of PCED1B-AS1 inhibited cell proliferation, migration, and EMT process, indicating that PCED1B-AS1 functioned as a cancer-promoting factor in ccRCC.	('EMT', 'biological_process', 'GO:0001837', ('129', '132'))	('RCC', 'Disease', 'MESH:C538614', (214, 217))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('cancer', 'Disease', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('PCED1B-AS1', 'Gene', (73, 83))	('up-regulated', 'PosReg', (29, 41))	('knockdown', 'Var', (60, 69))	('PCED1B-AS1', 'Gene', '100233209', (73, 83))	('PCED1B-AS1', 'Gene', (158, 168))	('ccRCC', 'Phenotype', 'HP:0006770', (212, 217))	('EMT process', 'CPA', (129, 140))	('PCED1B-AS1', 'Gene', '100233209', (158, 168))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cell proliferation', 'CPA', (94, 112))	('PCED1B-AS1', 'Gene', (14, 24))	('migration', 'CPA', (114, 123))	('cell proliferation', 'biological_process', 'GO:0008283', ('94', '112'))	('RCC', 'Disease', (214, 217))	('RCC', 'Phenotype', 'HP:0005584', (214, 217))	('PCED1B-AS1', 'Gene', '100233209', (14, 24))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('inhibited', 'NegReg', (84, 93))
103181	33469315	"Rescue" experiments showed that transfection with miR-484 inhibitor not only partially restored ZEB1 expression but also significantly weakened the inhibition of PCED1B-AS1 knockdown on ccRCC cell proliferation, migration, and EMT process.	('weakened', 'NegReg', (136, 144))	('EMT', 'biological_process', 'GO:0001837', ('226', '229'))	('restored', 'PosReg', (88, 96))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('migration', 'CPA', (213, 222))	('inhibition', 'NegReg', (149, 159))	('ZEB1', 'Gene', '6935', (97, 101))	('miR-484', 'Gene', '619553', (51, 58))	('miR-484', 'Gene', (51, 58))	('ZEB1', 'Gene', (97, 101))	('expression', 'MPA', (102, 112))	('PCED1B-AS1', 'Gene', (163, 173))	('knockdown', 'Var', (174, 183))	('PCED1B-AS1', 'Gene', '100233209', (163, 173))	('EMT process', 'CPA', (228, 239))	('ccRCC', 'Phenotype', 'HP:0006770', (187, 192))	('RCC', 'Disease', (189, 192))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))	('cell proliferation', 'biological_process', 'GO:0008283', ('191', '209'))
103192	32555180	In contrast to previous studies of ccRCC, in pRCC, driver gene mutations and most arm-level somatic copy number alterations (SCNAs) are clonal.	('mutations', 'Var', (63, 72))	('RCC', 'Disease', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('pRCC', 'Gene', (45, 49))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('pRCC', 'Gene', '5546', (45, 49))
103215	32555180	The average SNV and indel rates across tumors were 1.21/Mb and 0.18/Mb, respectively: on average, 1.00/Mb and 0.18/Mb for pRCC1; 1.46/Mb and 0.21/Mb for pRCC2.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('pRCC', 'Gene', (122, 126))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('pRCC', 'Gene', '5546', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('SNV', 'Var', (12, 15))	('pRCC', 'Gene', (153, 157))	('tumors', 'Disease', (39, 45))	('pRCC', 'Gene', '5546', (122, 126))
103221	32555180	In pRCC2 tumors, we observed a SMARCB1 driver mutation in one pRCC2; TERT promoter in two pRCC2; SETD2, PBRM1 and NF2 in one pRCC2 tumor each.	('pRCC', 'Gene', '5546', (3, 7))	('pRCC', 'Gene', '5546', (90, 94))	('tumor', 'Disease', (131, 136))	('TERT', 'Gene', (69, 73))	('TERT', 'Gene', '7015', (69, 73))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('PBRM1', 'Gene', '55193', (104, 109))	('SETD2', 'Gene', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumors', 'Disease', (9, 15))	('pRCC', 'Gene', (3, 7))	('tumor', 'Disease', (9, 14))	('PBRM1', 'Gene', (104, 109))	('pRCC', 'Gene', (90, 94))	('SETD2', 'Gene', '29072', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('pRCC', 'Gene', '5546', (62, 66))	('pRCC', 'Gene', '5546', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('NF2', 'Gene', '4771', (114, 117))	('SMARCB1', 'Gene', '6598', (31, 38))	('mutation', 'Var', (46, 54))	('SMARCB1', 'Gene', (31, 38))	('NF2', 'Gene', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('pRCC', 'Gene', (125, 129))	('pRCC', 'Gene', (62, 66))
103222	32555180	We also found clonal indels in NF2 in two tumors (cdRCC and mixRCC), and MET (mixRCC), SMARCB1 (pRCC1) and ROS1 (pRCC2) indels in one tumor each.	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('NF2', 'Gene', '4771', (31, 34))	('ROS1', 'Gene', '6098', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('pRCC', 'Gene', (113, 117))	('RCC', 'Disease', (114, 117))	('tumor', 'Disease', (42, 47))	('NF2', 'Gene', (31, 34))	('RCC', 'Disease', (52, 55))	('RCC', 'Disease', (81, 84))	('pRCC', 'Gene', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (97, 100))	('pRCC', 'Gene', '5546', (96, 100))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ROS1', 'Gene', (107, 111))	('indels', 'Var', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('SMARCB1', 'Gene', '6598', (87, 94))	('tumor', 'Disease', (134, 139))	('RCC', 'Disease', (63, 66))	('SMARCB1', 'Gene', (87, 94))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('tumors', 'Disease', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('pRCC', 'Gene', '5546', (113, 117))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
103223	32555180	We found no mutations in TP53, mutated in a high proportion of cases across cancer types, and no mutations in the 5'UTR region of TERT, which has been reported as mutated in a sizeable fraction of ccRCC (Fig.	('TP53', 'Gene', (25, 29))	('TERT', 'Gene', (130, 134))	('TERT', 'Gene', '7015', (130, 134))	('mutations', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('TP53', 'Gene', '7157', (25, 29))	('RCC', 'Disease', (199, 202))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('RCC', 'Disease', 'MESH:C538614', (199, 202))
103227	32555180	In these tumors, SNVs in other genes or other genomic alterations yet to be defined are the likely driver events.	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('SNVs', 'Var', (17, 21))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
103228	32555180	An analysis of the germline sequencing data provided evidence of rare, potentially deleterious, germline variants in known cancer susceptibility genes ("Methods" section).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('variants', 'Var', (105, 113))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))
103229	32555180	These include two different variants in POLE in two different tumors; two different variants in CHEK2 in two different tumors; one variant in BRIP1 and PTCH1 both in a single tumor; and additional rare variants, one per tumor (e.g., TP53, MET, EGFR, among others, Supplementary Data 6).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', (220, 225))	('BRIP1', 'Gene', '83990', (142, 147))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('EGFR', 'Gene', '1956', (244, 248))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', (62, 68))	('MET', 'Var', (239, 242))	('BRIP1', 'Gene', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (175, 180))	('PTCH1', 'Gene', '5727', (152, 157))	('TP53', 'Gene', (233, 237))	('CHEK2', 'Gene', (96, 101))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', (119, 124))	('EGFR', 'Gene', (244, 248))	('CHEK2', 'Gene', '11200', (96, 101))	('tumor', 'Disease', (62, 67))	('PTCH1', 'Gene', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('244', '248'))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('TP53', 'Gene', '7157', (233, 237))
103230	32555180	This is consistent with a report on the relatively high frequency of germline mutations in cancer susceptibility genes in non-clear cell renal cell carcinomas.	('non-clear cell renal cell carcinomas', 'Disease', (122, 158))	('non-clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (122, 158))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (137, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (126, 158))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (137, 157))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (126, 157))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('germline mutations', 'Var', (69, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
103243	32555180	1c and 2), which most likely originated in the primary tumor region T02 or T10, share the same driver mutations in PBRM1 and SMARCB1.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('SMARCB1', 'Gene', '6598', (125, 132))	('SMARCB1', 'Gene', (125, 132))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('mutations', 'Var', (102, 111))	('PBRM1', 'Gene', (115, 120))	('PBRM1', 'Gene', '55193', (115, 120))
103255	32555180	In both of our metastatic cases (stage 4 at diagnosis), pRCC2_1824_13 and rSRC_1697_10, intermixing of subclones has extended to metastatic sites, pointing to the occurrence of polyclonal seeding as previously observed in metastatic prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (233, 248))	('prostate cancer', 'Phenotype', 'HP:0012125', (233, 248))	('pRCC', 'Gene', '5546', (56, 60))	('rSRC_1697_10', 'Var', (74, 86))	('pRCC', 'Gene', (56, 60))	('prostate cancer', 'Disease', (233, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
103268	32555180	Metastatic lesions shared most SCNAs with their primary tumors, but also displayed metastasis-specific SCNAs (e.g., hemizygous deletion loss of heterozygosity in 4q of pRCC2_1824_13, Fig.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('pRCC', 'Gene', '5546', (168, 172))	('metastasis-specific SCNAs', 'Disease', (83, 108))	('deletion', 'Var', (127, 135))	('tumors', 'Disease', (56, 62))	('pRCC', 'Gene', (168, 172))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('loss of', 'NegReg', (136, 143))
103269	32555180	Among the rarer subtypes, both rSRC and cdRCC had clonal focal homozygous deletions of CDKN2A at 9p21.3 (Fig.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('deletions', 'Var', (74, 83))	('CDKN2A', 'Gene', '1029', (87, 93))	('RCC', 'Disease', (42, 45))	('CDKN2A', 'Gene', (87, 93))
103270	32555180	For example, the SMARCB1 p.R373T mutation occurred earlier than the 22q LOH in pRCC2_1824_13_T08, and the truncated mutation KMT2C p.S789* occurred later than the chr7 amplification in pRCC2_1494.	('KMT2C', 'Gene', '58508', (125, 130))	('p.S789*', 'Var', (131, 138))	('p.R373T', 'Mutation', 'p.R373T', (25, 32))	('pRCC', 'Gene', (79, 83))	('pRCC', 'Gene', (185, 189))	('p.R373T', 'Var', (25, 32))	('SMARCB1', 'Gene', (17, 24))	('p.S789*', 'Mutation', 'p.S789*', (131, 138))	('SMARCB1', 'Gene', '6598', (17, 24))	('KMT2C', 'Gene', (125, 130))	('pRCC', 'Gene', '5546', (79, 83))	('pRCC', 'Gene', '5546', (185, 189))
103274	32555180	1c), including a deletion within MET in one pRCC2, and several fusions involving genes previously reported in renal cancer or other tumors.	('pRCC', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('renal cancer', 'Disease', (110, 122))	('renal cancer', 'Disease', 'MESH:D007680', (110, 122))	('renal cancer', 'Phenotype', 'HP:0009726', (110, 122))	('deletion', 'Var', (17, 25))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('pRCC', 'Gene', '5546', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('MET', 'Gene', (33, 36))	('fusions', 'Reg', (63, 70))
103286	32555180	At least three transposon insertions could have potentially affected the expression of proteins involved in chromatin regulation and chromosome structural maintenance and, in turn, the maintenance of genome integrity in this tumor (Supplementary Method).	('insertions', 'Var', (26, 36))	('affected', 'Reg', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('chromatin', 'cellular_component', 'GO:0000785', ('108', '117'))	('proteins', 'Protein', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('regulation', 'biological_process', 'GO:0065007', ('118', '128'))	('chromosome structural', 'CPA', (133, 154))	('transposon', 'Gene', (15, 25))	('tumor', 'Disease', (225, 230))	('maintenance of genome integrity', 'biological_process', 'GO:0051276', ('185', '216'))	('expression', 'MPA', (73, 83))	('chromosome', 'cellular_component', 'GO:0005694', ('133', '143'))
103294	32555180	We also observed a small proportion of mutations attributed to the clock-like mutational signature 1(3.5% of total SNVs) and signature 8 (1.4%), which has unknown etiology.	('clock', 'Gene', '9575', (67, 72))	('clock', 'Gene', (67, 72))	('mutations', 'Var', (39, 48))
103304	32555180	Multi-region whole-genome sequencing demonstrates that papillary renal cell carcinomas and rarer renal cancer subtypes generally have much less driver gene mutation and copy number alteration intra-tumor heterogeneity than clear cell renal cell carcinomas.	('less', 'NegReg', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (234, 254))	('intra-tumor', 'Disease', (192, 203))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (223, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('carcinomas', 'Phenotype', 'HP:0030731', (245, 255))	('copy number alteration', 'Var', (169, 191))	('clear cell renal cell carcinomas', 'Disease', (223, 255))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (234, 255))	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (55, 86))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (65, 85))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (223, 254))	('renal cancer', 'Disease', (97, 109))	('driver gene', 'MPA', (144, 155))	('intra-tumor', 'Disease', 'MESH:D009369', (192, 203))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (65, 86))	('renal cancer', 'Phenotype', 'HP:0009726', (97, 109))	('papillary renal cell carcinomas', 'Disease', (55, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('papillary renal cell carcinomas', 'Disease', 'MESH:C538614', (55, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (55, 85))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (223, 255))	('renal cancer', 'Disease', 'MESH:D007680', (97, 109))
103306	32555180	Large-scale copy number aberrations, often associated with inter-chromosomal translocations, were frequently clonal across all samples from a tumor.	('tumor', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('copy number aberrations', 'Var', (12, 35))
103307	32555180	In support of this hypothesis, bulk- and single-cell based copy number and sequencing studies of breast and prostate cancers have suggested that complex aneuploid copy number changes may occur in only a few cell divisions at the earliest stages of tumor progression, leading to punctuated evolution.	('copy number changes', 'Var', (163, 182))	('aneuploid', 'Disease', (153, 162))	('tumor', 'Disease', (248, 253))	('breast and prostate cancers', 'Disease', 'MESH:D001943', (97, 124))	('leading to', 'Reg', (267, 277))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('prostate cancer', 'Phenotype', 'HP:0012125', (108, 123))	('punctuated evolution', 'MPA', (278, 298))	('aneuploid', 'Disease', 'MESH:D000782', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('prostate cancers', 'Phenotype', 'HP:0012125', (108, 124))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
103309	32555180	Thus, our data indicate that papillary renal cell carcinomas initiate through a combination of large clonal SCNAs and mutations in different driver genes, while tumor progression is further promoted by additional SNVs, small scale SCNAs and SVs.	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (39, 60))	('papillary renal cell carcinomas', 'Disease', (29, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('mutations', 'Var', (118, 127))	('papillary renal cell carcinomas', 'Disease', 'MESH:C538614', (29, 60))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (39, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (29, 59))	('tumor', 'Disease', (161, 166))	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (29, 60))
103314	32555180	Signatures SBS5 and SBS40 accounted for 92.5% of all somatic mutations observed in pRCC.	('pRCC', 'Gene', '5546', (83, 87))	('SBS40', 'Var', (20, 25))	('pRCC', 'Gene', (83, 87))
103315	32555180	High frequency of signature SBS40 has been found in kidney cancer in previous studies, possibly due to the organ's cells constant contact with mutagens during the blood filtration process.	('kidney cancer', 'Phenotype', 'HP:0009726', (52, 65))	('signature SBS40', 'Var', (18, 33))	('kidney cancer', 'Disease', 'MESH:D007680', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('kidney cancer', 'Disease', (52, 65))
103322	32555180	Although based on a limited number of tumors, the observed clonal patterns of both large scale SCNAs and SNVs/indels in driver genes suggest a single tumor biopsy would be sufficient to characterize these changes.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('SNVs/indels', 'Var', (105, 116))	('tumor', 'Disease', (150, 155))
103325	32555180	Further therapeutic challenges for the renal cell tumors we studied are provided by the subclonal nature of SVs as well as the low mutation burden and the notable lack of TP53 mutations, both of which may hinder response to immune checkpoint inhibitors.	('TP53', 'Gene', (171, 175))	('mutations', 'Var', (176, 185))	('renal cell tumors', 'Disease', 'MESH:C538614', (39, 56))	('response to', 'MPA', (212, 223))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('hinder', 'NegReg', (205, 211))	('renal cell tumors', 'Disease', (39, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('TP53', 'Gene', '7157', (171, 175))
103333	32555180	For example, trisomies 7 and 17 are frequent in pRCC1 but can be also found, less frequently, in pRCC2.	('pRCC', 'Gene', '5546', (48, 52))	('pRCC', 'Gene', '5546', (97, 101))	('trisomies', 'Var', (13, 22))	('pRCC', 'Gene', (48, 52))	('pRCC', 'Gene', (97, 101))
103355	32555180	Putative driver mutations were defined if they met one of the following requirements: (i) if the variant was predicted to be deleterious, including stop-gain, frameshift and splicing mutation, and had a SIFT score < 0.05 or a PolyPhen score >0.995 or a CCAD score >0.99; or (ii) If the variant was identified as a recurrent hotspot (statistically significant, http://cancerhotspots.org) or a 3D clustered hotspot (http://3dhotspots.org) in a population-scale cohort of tumor samples of various cancer types using a previously described methodology.	('variant', 'Var', (97, 104))	('frameshift', 'Var', (159, 169))	('tumor', 'Disease', 'MESH:D009369', (469, 474))	('cancer', 'Disease', 'MESH:D009369', (494, 500))	('cancer', 'Disease', 'MESH:D009369', (367, 373))	('cancer', 'Disease', (494, 500))	('cancer', 'Disease', (367, 373))	('tumor', 'Phenotype', 'HP:0002664', (469, 474))	('tumor', 'Disease', (469, 474))	('splicing', 'biological_process', 'GO:0045292', ('174', '182'))	('cancer', 'Phenotype', 'HP:0002664', (494, 500))	('cancer', 'Phenotype', 'HP:0002664', (367, 373))
103372	32555180	The MALAT-TFEB and EWSR1-PATZ1 fusions were validated and confirmed by Sanger sequencing.	('TFEB', 'Gene', '7942', (10, 14))	('PATZ1', 'Gene', (25, 30))	('TFEB', 'Gene', (10, 14))	('EWSR1', 'Gene', (19, 24))	('PATZ1', 'Gene', '23598', (25, 30))	('EWSR1', 'Gene', '2130', (19, 24))	('fusions', 'Var', (31, 38))
103390	28423523	A series of in vivo and in vitro assays were performed to confirm the effect of miR-106b-5p on ccRCC stemness phenotype.	('miR-106b-5p', 'Var', (80, 91))	('RCC', 'Disease', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))
103391	28423523	ccRCC cells and tissues expressed more miR-106b-5p than normal controls.	('RCC', 'Disease', (2, 5))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('miR-106b-5p', 'Var', (39, 50))
103392	28423523	Gain- and loss-of-function studies demonstrated that overexpression of miR-106b-5p in ccRCC cells increased the spheres formation ability and the proportion of side population cells.	('spheres formation ability', 'CPA', (112, 137))	('overexpression', 'PosReg', (53, 67))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('increased', 'PosReg', (98, 107))	('miR-106b-5p', 'Var', (71, 82))	('formation', 'biological_process', 'GO:0009058', ('120', '129'))
103393	28423523	Ectopic expression of miR-106b-5p in ccRCC cells increased tumour growth rates and the number of metastatic colonies in the lungs by using an orthotopic kidney cancer model and a tail vein injection model, respectively.	('increased', 'PosReg', (49, 58))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('kidney cancer', 'Disease', 'MESH:D007680', (153, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('kidney cancer', 'Phenotype', 'HP:0009726', (153, 166))	('miR-106b-5p', 'Var', (22, 33))	('tumour', 'Disease', (59, 65))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('kidney cancer', 'Disease', (153, 166))
103394	28423523	Mechanistic studies revealed that, miR-106b-5p has an activating effect on Wnt/beta-catenin signalling.	('beta-catenin', 'Gene', '1499', (79, 91))	('miR-106b-5p', 'Var', (35, 46))	('signalling', 'biological_process', 'GO:0023052', ('92', '102'))	('activating', 'MPA', (54, 64))	('beta-catenin', 'Gene', (79, 91))
103395	28423523	miR-106p-5p overexpression simultaneously targets multiple negative regulators of the Wnt/beta-catenin pathway, namely, LZTFL1, SFRP1 and DKK2.	('overexpression', 'PosReg', (12, 26))	('LZTFL1', 'Gene', (120, 126))	('beta-catenin', 'Gene', (90, 102))	('LZTFL1', 'Gene', '54585', (120, 126))	('DKK2', 'Gene', (138, 142))	('DKK2', 'Gene', '27123', (138, 142))	('beta-catenin', 'Gene', '1499', (90, 102))	('SFRP1', 'Gene', (128, 133))	('miR-106p-5p', 'Var', (0, 11))
103396	28423523	In addition, we also confirmed that miR-106b-5p and its targets expression correlates with the overall-survival of ccRCC patients from TCGA.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('patients', 'Species', '9606', (121, 129))	('miR-106b-5p', 'Var', (36, 47))
103397	28423523	These findings suggest that miR-106b-5p mediates the constitutive activation of Wnt/beta-catenin signalling, likely serving as a potential therapeutic target for ccRCC.	('miR-106b-5p', 'Var', (28, 39))	('beta-catenin', 'Gene', (84, 96))	('signalling', 'biological_process', 'GO:0023052', ('97', '107'))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('RCC', 'Disease', (164, 167))	('beta-catenin', 'Gene', '1499', (84, 96))	('activation', 'PosReg', (66, 76))
103404	28423523	Methylation of CpG nucleotides or genes mutation are associated with Wnt signalling activation and ccRCC malignancy.	('mutation', 'Var', (40, 48))	('signalling', 'biological_process', 'GO:0023052', ('73', '83'))	('activation', 'PosReg', (84, 94))	('Methylation', 'Var', (0, 11))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Disease', (101, 104))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('associated', 'Reg', (53, 63))	('malignancy', 'Disease', 'MESH:D009369', (105, 115))	('malignancy', 'Disease', (105, 115))	('Wnt signalling', 'Pathway', (69, 83))
103406	28423523	The knockdown of several Wnt signalling antagonists, like WIF1, Dkk, SFRP1, SOSTDC1 and IGFBP4 have been reported to play important roles in the aberrant Wnt signaling in ccRCC.	('roles', 'Reg', (132, 137))	('RCC', 'Disease', (173, 176))	('signaling', 'biological_process', 'GO:0023052', ('158', '167'))	('WIF1', 'Gene', (58, 62))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('WIF1', 'Gene', '11197', (58, 62))	('signalling', 'biological_process', 'GO:0023052', ('29', '39'))	('SFRP1', 'Gene', (69, 74))	('IGFBP4', 'Gene', '3487', (88, 94))	('Dkk', 'Gene', (64, 67))	('SOSTDC1', 'Gene', '25928', (76, 83))	('SOSTDC1', 'Gene', (76, 83))	('knockdown', 'Var', (4, 13))	('IGFBP4', 'Gene', (88, 94))	('aberrant', 'MPA', (145, 153))
103410	28423523	miR-106b-5p belongs to the microRNA precursor miR-17 family, and there have been a number of studies based on its roles in tumor proliferation and metastasis.	('tumor', 'Disease', (123, 128))	('miR-106b-5p', 'Var', (0, 11))	('miR-17', 'Gene', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('miR-17', 'Gene', '406952', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
103412	28423523	In this study, we found that miR-106b-5p overexpression promotes ccRCC cells stemness both in vitro and in vivo.	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('miR-106b-5p', 'Var', (29, 40))	('RCC', 'Disease', (67, 70))	('promotes', 'PosReg', (56, 64))
103413	28423523	miR-106b-5p plays important role in the down regulation of Wnt antagonists in ccRCC by simultaneously targets LZTFL1, SFRP1 and DKK2.	('RCC', 'Disease', (80, 83))	('miR-106b-5p', 'Var', (0, 11))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('LZTFL1', 'Gene', (110, 116))	('regulation', 'biological_process', 'GO:0065007', ('45', '55'))	('DKK2', 'Gene', (128, 132))	('DKK2', 'Gene', '27123', (128, 132))	('down regulation', 'NegReg', (40, 55))	('targets', 'Reg', (102, 109))	('SFRP1', 'Gene', (118, 123))	('LZTFL1', 'Gene', '54585', (110, 116))
103414	28423523	Furthermore, miR-106b-5p and its targets are closely associated with ccRCC patient survival by analysing TCGA data.	('miR-106b-5p', 'Var', (13, 24))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('associated', 'Reg', (53, 63))	('patient', 'Species', '9606', (75, 82))
103415	28423523	Our data show miR-106b-5p plays important roles in the sustainment of ccRCC cells stemness.	('RCC', 'Disease', (72, 75))	('miR-106b-5p', 'Var', (14, 25))	('sustainment', 'CPA', (55, 66))	('RCC', 'Disease', 'MESH:C538614', (72, 75))
103418	28423523	In addition, the metastatic ccRCC cell line Caki-1 showed the highest levels of miR-106b-5p (Figure 1A).	('miR-106b-5p', 'Var', (80, 91))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('Caki-1', 'CellLine', 'CVCL:0234', (44, 50))	('RCC', 'Disease', (30, 33))
103420	28423523	We next silenced miR-106b-5p in Caki-1 cells and overexpressed miR-106b-5p in HK2 and A498 cells.	('HK2', 'molecular_function', 'GO:0008256', ('78', '81'))	('silenced', 'NegReg', (8, 16))	('miR-106b-5p', 'Gene', (17, 28))	('Caki-1', 'CellLine', 'CVCL:0234', (32, 38))	('miR-106b-5p', 'Var', (63, 74))
103421	28423523	In addition, miR-106b-5p-sponge transduction significantly decreased the miR-106b-5p levels in Caki-1 cells (p < 0.0001, paired t-test).	('miR-106b-5p levels', 'MPA', (73, 91))	('transduction', 'biological_process', 'GO:0009293', ('32', '44'))	('decreased', 'NegReg', (59, 68))	('Caki-1', 'CellLine', 'CVCL:0234', (95, 101))	('miR-106b-5p-sponge', 'Var', (13, 31))
103423	28423523	We can see that the size and numbers of spheres increased in miR-106b-5p overexpression A498 cells and decreased in miR-106b-5p knockdown Caki-1 cells (Figure 2A).	('increased', 'PosReg', (48, 57))	('miR-106b-5p', 'Var', (116, 127))	('decreased', 'NegReg', (103, 112))	('miR-106b-5p', 'Var', (61, 72))	('Caki-1', 'CellLine', 'CVCL:0234', (138, 144))
103424	28423523	In addition, more side population (SP) cells were seen in miR-106b-5p-transduced- A498 cells than vector control cells, whereas fewer SP cells were seen in miR-106b-5p-silenced Caki-1 cells compared with control cells (Figure 2B).	('more', 'PosReg', (13, 17))	('miR-106b-5p-transduced- A498', 'Var', (58, 86))	('Caki-1', 'CellLine', 'CVCL:0234', (177, 183))
103425	28423523	Notably, overexpression of miR-106b-5p in A498 and HK-2 cells leads to upregulation of ccRCC stemness associated markers like Sox2, Oct4, ABCC2, CXCR4 and CD105, and the results were opposite in miR-106b-5p-silenced cells (Figure 2C).	('Sox2', 'Gene', (126, 130))	('overexpression', 'PosReg', (9, 23))	('CXCR4', 'Gene', (145, 150))	('miR-106b-5p', 'Var', (27, 38))	('HK-2', 'Gene', (51, 55))	('CXCR4', 'molecular_function', 'GO:0038147', ('145', '150'))	('Oct4', 'Gene', (132, 136))	('CD105', 'MPA', (155, 160))	('ABCC2', 'Gene', (138, 143))	('RCC', 'Disease', (89, 92))	('ABCC2', 'Gene', '1244', (138, 143))	('Sox2', 'Gene', '6657', (126, 130))	('upregulation', 'PosReg', (71, 83))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('CXCR4', 'Gene', '7852', (145, 150))	('Oct4', 'Gene', '5460', (132, 136))	('HK-2', 'molecular_function', 'GO:0008256', ('51', '55'))	('HK-2', 'Gene', '3099', (51, 55))
103426	28423523	Our data indicate that miR-106b-5p promotes ccRCC cells stemness in vitro.	('miR-106b-5p', 'Var', (23, 34))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('promotes', 'PosReg', (35, 43))	('RCC', 'Disease', (46, 49))
103427	28423523	We further studied the in vivo impact of miR-106b-5p on ccRCC cell growth and metastasis by injecting A498 cells containing either a control or miR-106b-5p-overexpression vector into BALB/c nude mice, either orthotopically or via the tail vein.	('nude mice', 'Species', '10090', (190, 199))	('RCC', 'Disease', (58, 61))	('cell growth', 'biological_process', 'GO:0016049', ('62', '73'))	('miR-106b-5p-overexpression', 'Var', (144, 170))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
103428	28423523	To assess the role of miR-106b-5p in ccRCC cells tumorigenicity, different doses (3 x 106, 3 x 105 and 3 x 104) of miR-106b-5p transduced cells and control cells were orthotopically implanted into renal capsules of the mice.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mice', 'Species', '10090', (219, 223))	('tumor', 'Disease', (49, 54))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('miR-106b-5p', 'Var', (115, 126))
103429	28423523	As shown in Figure 3A-3C, miR-106-5p overexpression in ccRCC cells promoted tumorigenesis and increased tumour growth rate.	('overexpression', 'PosReg', (37, 51))	('promoted', 'PosReg', (67, 75))	('increased', 'PosReg', (94, 103))	('tumor', 'Disease', (76, 81))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('tumour', 'Disease', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('miR-106-5p', 'Var', (26, 36))
103430	28423523	In the mouse metastasis model, the numbers of metastatic colonies in the lungs were dramatically increased in mice injected with miR-106b-5p-overexpressing cells, compared to control cells (Figure 3D, 3E).	('increased', 'PosReg', (97, 106))	('mouse', 'Species', '10090', (7, 12))	('metastatic colonies in the lungs', 'CPA', (46, 78))	('mice', 'Species', '10090', (110, 114))	('miR-106b-5p-overexpressing', 'Var', (129, 155))
103432	28423523	miR-106b-5p overexpression in A498 cells significantly increased the mRNA expression levels of seven well-known genes relevant to Wnt/beta-catenin pathway (Figure 4A).	('beta-catenin', 'Gene', '1499', (134, 146))	('overexpression', 'PosReg', (12, 26))	('increased', 'PosReg', (55, 64))	('miR-106b-5p', 'Var', (0, 11))	('mRNA expression levels of seven', 'MPA', (69, 100))	('beta-catenin', 'Gene', (134, 146))
103433	28423523	miR-106b-5p overexpression in ccRCC cells enhanced the nucleus translocation of beta-catenin as determined by western blotting analysis of cellular fractionation, and the results were reverse in miR-106b-5p knockdown Caki-1 cells (Figure 4B).	('miR-106b-5p', 'Var', (195, 206))	('miR-106b-5p', 'Var', (0, 11))	('enhanced', 'PosReg', (42, 50))	('RCC', 'Disease', (32, 35))	('beta-catenin', 'Gene', (80, 92))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('beta-catenin', 'Gene', '1499', (80, 92))	('Caki-1', 'CellLine', 'CVCL:0234', (217, 223))	('nucleus', 'cellular_component', 'GO:0005634', ('55', '62'))
103434	28423523	Meanwhile, immunofluorescence analysis showed that overexpression of miR-106b-5p in A498 cells increased nuclear accumulation of beta-catenin (Figure 4C).	('beta-catenin', 'Gene', '1499', (129, 141))	('miR-106b-5p', 'Var', (69, 80))	('beta-catenin', 'Gene', (129, 141))	('nuclear accumulation', 'MPA', (105, 125))	('increased', 'PosReg', (95, 104))	('overexpression', 'PosReg', (51, 65))
103435	28423523	We then evaluated the elimination of Wnt signalling on miR-106b-5p mediated cancer cell stemness.	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('miR-106b-5p', 'Var', (55, 66))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('signalling', 'biological_process', 'GO:0023052', ('41', '51'))
103436	28423523	As we shown in Figure 4D-4F, beta-catenin or TCF4 knockdown by siRNA transfection directly repressed Wnt signalling, eliminated the enhancement of miR-106b-5p overexpression on ccRCC cells stemness as determined by spheres formation assay and in vivo assay.	('TCF4', 'Gene', (45, 49))	('TCF4', 'Gene', '6925', (45, 49))	('formation', 'biological_process', 'GO:0009058', ('223', '232'))	('enhancement', 'PosReg', (132, 143))	('knockdown', 'Var', (50, 59))	('miR-106b-5p', 'Var', (147, 158))	('signalling', 'biological_process', 'GO:0023052', ('105', '115'))	('beta-catenin', 'Gene', (29, 41))	('eliminated', 'NegReg', (117, 127))	('beta-catenin', 'Gene', '1499', (29, 41))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('RCC', 'Disease', (179, 182))
103437	28423523	These results indicate that miR-106b-5p promote stemness and tumorigenesis in ccRCC cells is dependent on the activating of Wnt signalling.	('promote', 'PosReg', (40, 47))	('RCC', 'Disease', (80, 83))	('miR-106b-5p', 'Var', (28, 39))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('signalling', 'biological_process', 'GO:0023052', ('128', '138'))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('stemness', 'CPA', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
103438	28423523	To explore the potential mechanisms underlying miR-106b-5p activating Wnt signalling in ccRCC cells, we first used miRanda and TargetScan databases to mine miRNA targets.	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('activating', 'PosReg', (59, 69))	('Wnt signalling', 'MPA', (70, 84))	('signalling', 'biological_process', 'GO:0023052', ('74', '84'))	('miR-106b-5p', 'Var', (47, 58))	('RCC', 'Disease', (90, 93))
103439	28423523	We then found three well-known Wnt signalling antagonists, LZTFL1, SFRP1 and DKK2, which may be inhibited by miR-106b-5p (Figure 5A).	('signalling', 'biological_process', 'GO:0023052', ('35', '45'))	('inhibited', 'NegReg', (96, 105))	('LZTFL1', 'Gene', (59, 65))	('miR-106b-5p', 'Var', (109, 120))	('LZTFL1', 'Gene', '54585', (59, 65))	('DKK2', 'Gene', (77, 81))	('SFRP1', 'Gene', (67, 72))	('DKK2', 'Gene', '27123', (77, 81))
103440	28423523	Furthermore, the mRNA and protein levels of LZTFL1, SFRP1 and DKK2 were significantly down-regulated in miR-106b-5p overexpression ccRCC cells but up-regulated in miR-106b-5p-silenced cells as determined by qPCR and western blotting, respectively (Figure 5B, 5C).	('LZTFL1', 'Gene', (44, 50))	('LZTFL1', 'Gene', '54585', (44, 50))	('DKK2', 'Gene', (62, 66))	('SFRP1', 'Gene', (52, 57))	('DKK2', 'Gene', '27123', (62, 66))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('RCC', 'Disease', (133, 136))	('down-regulated', 'NegReg', (86, 100))	('overexpression', 'Var', (116, 130))	('up-regulated', 'PosReg', (147, 159))	('miR-106b-5p overexpression', 'Var', (104, 130))
103441	28423523	Subsequently, luciferase reporter assay was used to confirm the targeting of miR-106b-5p to the 3' untranslated regions (3'-UTRs) of LZTFL1, SFRP1 and DKK2.	('LZTFL1', 'Gene', (133, 139))	('DKK2', 'Gene', (151, 155))	('DKK2', 'Gene', '27123', (151, 155))	('LZTFL1', 'Gene', '54585', (133, 139))	('SFRP1', 'Gene', (141, 146))	('miR-106b-5p', 'Var', (77, 88))
103442	28423523	As shown in Figure 5D, the luciferase activity was reduced in miR-106b-5p overexpression HK-2 and A498 cells.	('luciferase activity', 'molecular_function', 'GO:0047712', ('27', '46'))	('activity', 'MPA', (38, 46))	('reduced', 'NegReg', (51, 58))	('luciferase activity', 'molecular_function', 'GO:0050397', ('27', '46'))	('HK-2', 'Gene', (89, 93))	('luciferase activity', 'molecular_function', 'GO:0050248', ('27', '46'))	('miR-106b-5p overexpression', 'Var', (62, 88))	('luciferase', 'Enzyme', (27, 37))	('luciferase activity', 'molecular_function', 'GO:0047077', ('27', '46'))	('HK-2', 'Gene', '3099', (89, 93))	('HK-2', 'molecular_function', 'GO:0008256', ('89', '93'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('27', '46'))
103444	28423523	These data suggest that miR-106b-5p simultaneous suppressed LZTFL1, SFRP1 and DKK2 by binding to there 3'-UTRs.	('DKK2', 'Gene', (78, 82))	('DKK2', 'Gene', '27123', (78, 82))	('LZTFL1', 'Gene', (60, 66))	('SFRP1', 'Gene', (68, 73))	('miR-106b-5p', 'Var', (24, 35))	('LZTFL1', 'Gene', '54585', (60, 66))	('binding', 'Interaction', (86, 93))	('suppressed', 'NegReg', (49, 59))	('binding', 'molecular_function', 'GO:0005488', ('86', '93'))
103447	28423523	As we shown in Figure 6A, high expression of miR-106b-5p predicts poor overall survival (OS) in ccRCC patients by Kaplan-Meier survival analysis (log-rank test, P = 0.0049).	('patients', 'Species', '9606', (102, 110))	('miR-106b-5p', 'Var', (45, 56))	('RCC', 'Disease', (98, 101))	('overall survival', 'MPA', (71, 87))	('OS', 'Chemical', '-', (89, 91))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('poor', 'NegReg', (66, 70))
103451	28423523	Our data suggest that miR-106b-5p overexpression activates Wnt signalling in ccRCC through suppressing three Wnt antagonists and promotes ccRCC aggressiveness and stem-cell-like phenotype.	('suppressing', 'NegReg', (91, 102))	('promotes', 'PosReg', (129, 137))	('activates', 'PosReg', (49, 58))	('aggressiveness', 'Disease', (144, 158))	('overexpression', 'PosReg', (34, 48))	('signalling', 'biological_process', 'GO:0023052', ('63', '73'))	('aggressiveness', 'Phenotype', 'HP:0000718', (144, 158))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('three Wnt antagonists', 'MPA', (103, 124))	('miR-106b-5p', 'Var', (22, 33))	('RCC', 'Disease', (140, 143))	('Wnt signalling', 'Pathway', (59, 73))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('stem-cell-like phenotype', 'CPA', (163, 187))	('aggressiveness', 'Disease', 'MESH:D001523', (144, 158))	('RCC', 'Disease', (79, 82))
103454	28423523	Dysregulation of Wnt signalling and changes x of TCF4 binding are reported to be related to ccRCC progression.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (94, 97))	('binding', 'molecular_function', 'GO:0005488', ('54', '61'))	('Dysregulation', 'Var', (0, 13))	('changes', 'Var', (36, 43))	('TCF4', 'Gene', (49, 53))	('related', 'Reg', (81, 88))	('TCF4', 'Gene', '6925', (49, 53))	('Wnt signalling', 'Pathway', (17, 31))	('signalling', 'biological_process', 'GO:0023052', ('21', '31'))	('binding', 'Interaction', (54, 61))
103455	28423523	In accordance with this observation, we found that beta-catenin or TCF4 knockdown by siRNA transfection directly repressed Wnt/beta-catenin signalling, eliminated the enhancement of miR-106b-5p overexpression on ccRCC cells stemness and tumorigenesis.	('tumor', 'Disease', (237, 242))	('overexpression', 'PosReg', (194, 208))	('miR-106b-5p', 'Var', (182, 193))	('signalling', 'biological_process', 'GO:0023052', ('140', '150'))	('beta-catenin', 'Gene', '1499', (51, 63))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('RCC', 'Disease', (214, 217))	('RCC', 'Disease', 'MESH:C538614', (214, 217))	('beta-catenin', 'Gene', (51, 63))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('enhancement', 'PosReg', (167, 178))	('TCF4', 'Gene', '6925', (67, 71))	('TCF4', 'Gene', (67, 71))	('beta-catenin', 'Gene', (127, 139))	('knockdown', 'Var', (72, 81))	('eliminated', 'NegReg', (152, 162))	('beta-catenin', 'Gene', '1499', (127, 139))
103456	28423523	Our results suggested that miR-106b-5p mediated activation of Wnt/beta-catenin/TCF signalling contribute to the development of ccRCC.	('TCF', 'Gene', (79, 82))	('TCF', 'Gene', '3172', (79, 82))	('beta-catenin', 'Gene', (66, 78))	('miR-106b-5p', 'Var', (27, 38))	('beta-catenin', 'Gene', '1499', (66, 78))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('RCC', 'Disease', (129, 132))	('signalling', 'biological_process', 'GO:0023052', ('83', '93'))	('activation', 'PosReg', (48, 58))
103461	28423523	Our data shown LZTFL1, SFRP1 and DKK2 were simultaneously suppressed by miR-106b-5p, which might be help to the explanation of the loss-of-function of Wnt antagonists in ccRCC.	('SFRP1', 'Gene', (23, 28))	('LZTFL1', 'Gene', (15, 21))	('LZTFL1', 'Gene', '54585', (15, 21))	('miR-106b-5p', 'Var', (72, 83))	('suppressed', 'NegReg', (58, 68))	('DKK2', 'Gene', (33, 37))	('DKK2', 'Gene', '27123', (33, 37))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('RCC', 'Disease', (172, 175))
103465	28423523	In our study, the role of miR-106b-5p in promoting stem cell-like properties of ccRCC cells was focused.	('promoting', 'PosReg', (41, 50))	('stem cell-like properties of', 'CPA', (51, 79))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('miR-106b-5p', 'Var', (26, 37))
103468	28423523	In our study, silencing of miR-106b-5p leaded to Wnt signalling inactivation and significantly inhibited renal CSCs and tumorigenesis.	('signalling', 'biological_process', 'GO:0023052', ('53', '63'))	('silencing', 'Var', (14, 23))	('renal CSCs', 'Disease', (105, 115))	('miR-106b-5p', 'Gene', (27, 38))	('inhibited', 'NegReg', (95, 104))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('Wnt signalling', 'Pathway', (49, 63))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('inactivation', 'NegReg', (64, 76))	('tumor', 'Disease', (120, 125))
103469	28423523	These results demonstrate that miR-106b-5p might be a potential therapeutic target for Wnt signalling in ccRCC to suppress tumorigenesis.	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('tumor', 'Disease', (123, 128))	('suppress', 'NegReg', (114, 122))	('RCC', 'Disease', (107, 110))	('miR-106b-5p', 'Var', (31, 42))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('signalling', 'biological_process', 'GO:0023052', ('91', '101'))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
103470	28423523	Our current study suggested that overexpression of miR-106b-5p in ccRCC cells activates Wnt signalling by simultaneous suppression of LZTFL1, SFRP1, and DKK2 and constitutive promoting CSCs and tumorigenesis in ccRCC.	('activates', 'PosReg', (78, 87))	('SFRP1', 'Gene', (142, 147))	('RCC', 'Disease', (68, 71))	('tumor', 'Disease', (194, 199))	('suppression', 'NegReg', (119, 130))	('Wnt signalling', 'MPA', (88, 102))	('LZTFL1', 'Gene', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('miR-106b-5p', 'Var', (51, 62))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('signalling', 'biological_process', 'GO:0023052', ('92', '102'))	('overexpression', 'PosReg', (33, 47))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('RCC', 'Disease', (213, 216))	('DKK2', 'Gene', (153, 157))	('DKK2', 'Gene', '27123', (153, 157))	('promoting', 'PosReg', (175, 184))	('LZTFL1', 'Gene', '54585', (134, 140))	('RCC', 'Disease', 'MESH:C538614', (213, 216))
103499	28423523	In the tumour metastasis analysis, ten 4-week-old BALB/c nude mice in each experimental group were injected with A498-miR-106b-5p or A498-vector cells, respectively.	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('nude mice', 'Species', '10090', (57, 66))	('tumour metastasis', 'Disease', (7, 24))	('A498-miR-106b-5p', 'Var', (113, 129))	('tumour metastasis', 'Disease', 'MESH:D009362', (7, 24))
103547	27842541	Heterogeneous responses were more frequent in patients treated with pazopanib (7/8 = 88%) than sunitinib (8/19 = 44%) (p = 0.03), but did not differ in patients who had dose reductions due to toxicities (5/9 = 56%) compared to those who did not (10/18 = 56%).	('patients', 'Species', '9606', (46, 54))	('pazopanib', 'Chemical', 'MESH:C516667', (68, 77))	('toxicities', 'Disease', 'MESH:D064420', (192, 202))	('Heterogeneous responses', 'MPA', (0, 23))	('pazopanib', 'Var', (68, 77))	('sunitinib', 'Chemical', 'MESH:D000077210', (95, 104))	('toxicities', 'Disease', (192, 202))	('patients', 'Species', '9606', (152, 160))
103627	31661010	Thirty-nine of 41 patients had a genetically confirmed VHL mutation; 2 of 41 had a clinical diagnosis of VHL.	('VHL', 'Disease', 'MESH:D006623', (55, 58))	('VHL', 'Disease', (55, 58))	('mutation', 'Var', (59, 67))	('patients', 'Species', '9606', (18, 26))	('VHL', 'Disease', 'MESH:D006623', (105, 108))	('VHL', 'Disease', (105, 108))
103642	31661010	There was no significant difference between the RGRs of the different germline VHL mutations and those of the entire cohort.	('mutations', 'Var', (83, 92))	('VHL', 'Disease', 'MESH:D006623', (79, 82))	('VHL', 'Disease', (79, 82))
103697	29656894	The molecular landscape of ccRCC was elucidated by a number of next-generation sequencing studies that revealed frequent inactivation of the VHL tumor suppressor gene, alterations in the SWI/SNF complex, histone-modifying genes, and the PI3K/AKT/mTOR pathway.	('histone-modifying', 'Protein', (204, 221))	('AKT', 'Gene', '207', (242, 245))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('145', '161'))	('VHL tumor', 'Disease', 'MESH:D006623', (141, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('187', '202'))	('SWI/SNF complex', 'Gene', (187, 202))	('RCC', 'Disease', (29, 32))	('inactivation', 'NegReg', (121, 133))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('mTOR', 'Gene', (246, 250))	('AKT', 'Gene', (242, 245))	('mTOR', 'Gene', '2475', (246, 250))	('PI3K', 'molecular_function', 'GO:0016303', ('237', '241'))	('VHL tumor', 'Disease', (141, 150))	('tumor suppressor', 'biological_process', 'GO:0051726', ('145', '161'))	('alterations', 'Var', (168, 179))
103698	29656894	We previously reported significant mutational and somatic copy number alteration (SCNA) intratumor heterogeneity (ITH) in ten cases of advanced ccRCC, showing that single-biopsy analyses may miss important genetic events or misclassify them as clonal due to the "illusion of clonality," thus hindering our understanding of tumor evolution.	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('mutational', 'Var', (35, 45))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (323, 328))	('tumor', 'Disease', (93, 98))	('miss', 'NegReg', (191, 195))	('tumor', 'Disease', 'MESH:D009369', (323, 328))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
103699	29656894	To date, attempts to molecularly classify ccRCC have included single biopsy analyses of mutations or gene expression and methylation.	('methylation', 'biological_process', 'GO:0032259', ('121', '132'))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('RCC', 'Disease', (44, 47))	('methylation', 'Var', (121, 132))	('gene expression', 'biological_process', 'GO:0010467', ('101', '116'))
103705	29656894	Single nucleotide variants (SNVs), dinucleotides variants (DNVs), small insertion and deletions (INDELs), and SCNAs were successfully derived from 1,206 tumor regions across 106 primary tumors (median 7 [range, 3-75] regions per tumor) from 101 patients, as five patients donated pairs of primary tumors.	('primary tumors', 'Disease', (178, 192))	('patients', 'Species', '9606', (245, 253))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (186, 191))	('primary tumors', 'Disease', (289, 303))	('tumor', 'Disease', (297, 302))	('DNV', 'Chemical', '-', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('primary tumors', 'Disease', 'MESH:D009369', (178, 192))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Disease', (153, 158))	('Single nucleotide variants', 'Var', (0, 26))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))	('primary tumors', 'Disease', 'MESH:D009369', (289, 303))	('dinucleotides variants', 'Var', (35, 57))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('patients', 'Species', '9606', (263, 271))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))
103708	29656894	We identified a total of 740 somatic mutations including 538 SNVs (440 non-synonymous SNVs), 7 DNVs, and 195 INDELs (Table S2).	('DNVs', 'Var', (95, 99))	('DNV', 'Chemical', '-', (95, 98))	('SNVs', 'Var', (61, 65))
103711	29656894	VHL mutations were the only consistently clonal event, present in 77/106 tumors (Figure 1A).	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('VHL', 'Gene', (0, 3))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('mutations', 'Var', (4, 13))
103712	29656894	VHL was methylated in 17 additional tumors (Figure 1A and Data S1).	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('VHL', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('methylated', 'Var', (8, 18))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
103714	29656894	4/11 VHL wild type tumors (K206, K228, K427, and K446) (Figure 1A) had evidence of sarcomatoid differentiation (Table S1), a feature reported to be associated with a lower frequency of VHL mutations.	('K228', 'Var', (33, 37))	('sarcomatoid', 'Disease', (83, 94))	('K206', 'Var', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('VHL wild type tumors', 'Disease', 'MESH:D006623', (5, 25))	('VHL wild type tumors', 'Disease', (5, 25))	('sarcomatoid', 'Disease', 'MESH:C538614', (83, 94))	('K427', 'Var', (39, 43))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('K446', 'Var', (49, 53))
103715	29656894	K255, another VHL wild-type tumor, had evidence of both clear cell and papillary histology, and we observed SCNAs specific to both subtypes, including gains of 5q and 16 (Data S2).	('tumor', 'Disease', (28, 33))	('papillary histology', 'Phenotype', 'HP:0007482', (71, 90))	('gains', 'Var', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('K255', 'Var', (0, 4))
103722	29656894	Loss of chromosome 3p, which is pathognomonic with ccRCC and encompasses four commonly mutated genes (VHL, PBRM1, SETD2, and BAP1), was observed in all but five tumors (K021, K375, K354, K255, K114R) (Figure 1A).	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('K375', 'Var', (175, 179))	('SETD2', 'Gene', (114, 119))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('K255', 'Var', (187, 191))	('K021', 'Var', (169, 173))	('K114R', 'Var', (193, 198))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('BAP1', 'Gene', (125, 129))	('Loss', 'NegReg', (0, 4))	('K114R', 'Mutation', 'p.K114R', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('PBRM1', 'Gene', (107, 112))	('K354', 'Var', (181, 185))	('SETD2', 'Gene', '29072', (114, 119))
103723	29656894	Of the five, three tumors had clonal 3p copy neutral allelic imbalance (CNAI) (STAR Methods) (K021, K375, K354) (Data S3), one was a mixture of clear cell and papillary histology with no mutations in 3p genes (K255; Figure 1A), and one harbored a mutation in TCEB1 with 8q loss (K114R; Figure 1A).	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('K114R', 'Mutation', 'p.K114R', (279, 284))	('papillary histology', 'Phenotype', 'HP:0007482', (159, 178))	('mutation', 'Var', (247, 255))	('K021', 'Var', (94, 98))	('STAR', 'Gene', '6770', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('loss', 'NegReg', (273, 277))	('STAR', 'Gene', (79, 83))	('imbalance', 'Phenotype', 'HP:0002172', (61, 70))	('TCEB1', 'Gene', '6921', (259, 264))	('K354', 'Var', (106, 110))	('TCEB1', 'Gene', (259, 264))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
103724	29656894	3p loss was subclonal in five tumors: one harboring a VHL mutation (K252) (Figure 1A), one VHL methylation (K070) (Figure 1A), one tumor that was VHL wild-type but SETD2 muttant (K427) (Figure 1A), and two with no mutations in any of the 3p genes (K169, K446) (Figure 1A).	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('VHL', 'Gene', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('mutation', 'Var', (58, 66))	('tumor', 'Disease', (131, 136))	('SETD2', 'Gene', '29072', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('methylation', 'biological_process', 'GO:0032259', ('95', '106'))	('SETD2', 'Gene', (164, 169))	('tumor', 'Disease', (30, 35))	('loss', 'NegReg', (3, 7))
103732	29656894	We profiled three patients with synchronous bilateral ccRCCs and two patients with multifocal ccRCCs, with no family history of ccRCC, or germline mutations in the known ccRCC predisposition genes (Table S1).	('RCC', 'Disease', (96, 99))	('mutations', 'Var', (147, 156))	('RCC', 'Disease', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('RCC', 'Disease', (130, 133))	('patients', 'Species', '9606', (18, 26))	('patients', 'Species', '9606', (69, 77))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('RCC', 'Disease', (172, 175))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
103734	29656894	K265, K352, and K334 harbored distinct mutations in VHL and 3p loss events in each of the tumors (Figure 1A and Data S3).	('K352', 'Var', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('K265', 'Var', (0, 4))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('loss', 'NegReg', (63, 67))	('VHL', 'Gene', (52, 55))	('K334', 'Var', (16, 20))
103735	29656894	The right-sided K097 tumor harbored a VHL mutation and VHL was methylated in the left tumor (Figures 1A and Data S1).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', (86, 91))	('harbored', 'Reg', (27, 35))	('left tumor', 'Disease', (81, 91))	('mutation', 'Var', (42, 50))	('VHL', 'Gene', (38, 41))	('left tumor', 'Disease', 'MESH:D009369', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
103736	29656894	Left K114 tumor harbored a VHL mutation and 3p loss, while in the right tumor we detected a clonal TCEB1 mutation with the loss of 8q21.11, encompassing the TCEB1 locus (Figure 1A).	('TCEB1', 'Gene', '6921', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('TCEB1', 'Gene', (157, 162))	('TCEB1', 'Gene', (99, 104))	('mutation', 'Var', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Left K114 tumor', 'Disease', 'MESH:D009369', (0, 15))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', (72, 77))	('mutation', 'Var', (31, 39))	('Left K114 tumor', 'Disease', (0, 15))	('loss', 'NegReg', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('TCEB1', 'Gene', '6921', (157, 162))
103738	29656894	However, the two tumors had distinct VHL mutations (Data S1) implying a case of bilateral metachronous ccRCCs.	('mutations', 'Var', (41, 50))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('VHL', 'Gene', (37, 40))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
103740	29656894	We and others have reported parallel evolution of mutations in the same genes or pathways within distinct tumor subclones in ccRCCs.	('mutations', 'Var', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('tumor', 'Disease', (106, 111))
103742	29656894	Certain tumors were notable for the number of parallel events they harbored (e.g., K243 had 10 distinct SETD2 mutations) (Figure 3).	('SETD2', 'Gene', (104, 109))	('mutations', 'Var', (110, 119))	('K243', 'Var', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('SETD2', 'Gene', '29072', (104, 109))
103743	29656894	In tumor K448, we observed 5 distinct BAP1 mutations and 3 SETD2 mutations, but BAP1 and SETD2 mutations never co-occurred within the same clone.	('tumor', 'Disease', (3, 8))	('BAP1', 'Gene', (38, 42))	('SETD2', 'Gene', '29072', (89, 94))	('SETD2', 'Gene', '29072', (59, 64))	('SETD2', 'Gene', (89, 94))	('mutations', 'Var', (43, 52))	('SETD2', 'Gene', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
103749	29656894	In our analyses of event co-occurrences at the clone level (STAR Methods), we observe an enrichment for mutual exclusivity between BAP1 and SETD2/PBRM1 mutations (Figure 4A).	('STAR', 'Gene', (60, 64))	('mutations', 'Var', (152, 161))	('SETD2', 'Gene', '29072', (140, 145))	('SETD2', 'Gene', (140, 145))	('BAP1', 'Gene', (131, 135))	('STAR', 'Gene', '6770', (60, 64))
103751	29656894	BAP1 had a propensity for being a lone additional mutational driver event in VHL-mutant clones, whereas PBRM1 and SETD2 were enriched for mutual clonal co-occurrence.	('SETD2', 'Gene', (114, 119))	('BAP1', 'Gene', (0, 4))	('VHL-mutant', 'Gene', (77, 87))	('SETD2', 'Gene', '29072', (114, 119))	('VHL-mutant', 'Var', (77, 87))
103755	29656894	In our previous report of ten ccRCC tumors, mutations in VHL and loss of 3p were consistently clonal, and PBRM1 was an additional clonal driver mutation in three cases.	('loss', 'Gene', (65, 69))	('PBRM1', 'Gene', (106, 111))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('VHL', 'Gene', (57, 60))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
103759	29656894	Assessment of proliferation by multiregional Ki67 immunohistochemistry (IHC) staining (STAR Methods) showed elevated proliferation index in cases with additional clonal driver mutations (p = 0.034, Figure 4D; Table S3), consistent with the simulation.	('mutations', 'Var', (176, 185))	('proliferation index', 'CPA', (117, 136))	('Ki67', 'Gene', '17345', (45, 49))	('STAR', 'Gene', '6770', (87, 91))	('STAR', 'Gene', (87, 91))	('Ki67', 'Gene', (45, 49))	('elevated', 'PosReg', (108, 116))
103760	29656894	The order in which driver events are acquired can have prognostic and therapeutic implications, as shown by with respect to the order of JAK2 and TET2 mutations in myeloproliferative neoplasms.	('JAK', 'molecular_function', 'GO:0004713', ('137', '140'))	('neoplasms', 'Phenotype', 'HP:0002664', (183, 192))	('JAK2', 'Gene', '3717', (137, 141))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (164, 192))	('TET2', 'Gene', (146, 150))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (164, 192))	('JAK2', 'Gene', (137, 141))	('myeloproliferative neoplasms', 'Disease', (164, 192))	('TET2', 'Gene', '54790', (146, 150))	('mutations', 'Var', (151, 160))
103762	29656894	In order to reduce the burden of multiple testing, we limited further analyses to those trajectories containing the most frequent ccRCC driver events: VHL, PBRM1, SETD2, BAP1, PI3K/AKT/mTOR pathway mutations, or driver SCNAs (Figure 1B).	('mTOR', 'Gene', (185, 189))	('SETD2', 'Gene', (163, 168))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('RCC', 'Disease', (132, 135))	('AKT', 'Gene', (181, 184))	('PI3K', 'molecular_function', 'GO:0016303', ('176', '180'))	('mutations', 'Var', (198, 207))	('BAP1', 'Gene', (170, 174))	('VHL', 'Gene', (151, 154))	('AKT', 'Gene', '207', (181, 184))	('SETD2', 'Gene', '29072', (163, 168))	('mTOR', 'Gene', '2475', (185, 189))	('PBRM1', 'Gene', (156, 161))
103764	29656894	In addition, PBRM1 mutations were found to consistently precede PI3K pathway mutations, SETD2 mutations, and driver SCNA events (Figure 4E).	('driver SCNA', 'Disease', (109, 120))	('PI3K', 'molecular_function', 'GO:0016303', ('64', '68'))	('SETD2', 'Gene', '29072', (88, 93))	('mutations', 'Var', (94, 103))	('PBRM1', 'Gene', (13, 18))	('SETD2', 'Gene', (88, 93))	('mutations', 'Var', (19, 28))	('PI3K pathway', 'Pathway', (64, 76))	('mutations', 'Var', (77, 86))
103771	29656894	This pattern would be consistent with sufficient selective fitness being achieved within the dominant clone through fixation of multiple driver mutations and SCNAs causing a clonal sweep during tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('fixation', 'Var', (116, 124))	('tumor', 'Disease', (194, 199))	('mutations', 'Var', (144, 153))
103773	29656894	Where the tumors harbored other driver mutations, they were never found in the same subclone as the BAP1 mutation (K448, K252, K153, K136) (Figure 1 and Data S2).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('K153', 'Var', (127, 131))	('K252', 'Var', (121, 125))	('BAP1', 'Gene', (100, 104))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('K136', 'Var', (133, 137))	('K448', 'Var', (115, 119))
103777	29656894	This pattern would be consistent with the notion of slower branched growth with early PBRM1 mutations followed by strong and repeated selection for SETD2 mutations.	('SETD2', 'Gene', (148, 153))	('mutations', 'Var', (92, 101))	('slower', 'NegReg', (52, 58))	('PBRM1', 'Gene', (86, 91))	('SETD2', 'Gene', '29072', (148, 153))
103780	29656894	The fifth and sixth subtypes were "PBRM1   PI3K" and "PBRM1  SCNA," characterized by early PBRM1 mutation followed by mutational activation of the PI3K/AKT/mTOR pathway or subclonal SCNAs, respectively, and enriched for lower grade tumors.	('PBRM1', 'Gene', (91, 96))	('AKT', 'Gene', '207', (152, 155))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('mutational', 'Var', (118, 128))	('mTOR', 'Gene', (156, 160))	('mTOR', 'Gene', '2475', (156, 160))	('activation', 'PosReg', (129, 139))	('AKT', 'Gene', (152, 155))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('mutation', 'Var', (97, 105))	('tumors', 'Disease', (232, 238))
103783	29656894	We note that the only <=4 cm tumor that was upstaged due to the presence of renal vein invasion (K021) was in the "multiple clonal driver" category, consistent with this evolutionary path enhancing vascular invasion independent of tumor size.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('renal vein invasion', 'Disease', 'MESH:D007674', (76, 95))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('K021', 'Var', (97, 101))	('tumor', 'Disease', (231, 236))	('tumor', 'Disease', (29, 34))	('renal vein invasion', 'Disease', (76, 95))
103797	29656894	We therefore assessed whether patients whose tumors had high ITH index (>median value) had significantly reduced progression free survival (PFS), compared to those with low ITH index.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('high ITH index', 'Var', (56, 70))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('patients', 'Species', '9606', (30, 38))	('reduced', 'NegReg', (105, 112))	('progression free survival', 'CPA', (113, 138))
103799	29656894	Patients in our cohort whose tumors had high wGII (>median value) had a non-significant trend towards shorter PFS compared to those with low wGII (p = 0.0717 log-rank HR = 1.9 [0.9-4.0], p = 0.9400 adjusted) (Figure 7A).	('shorter', 'NegReg', (102, 109))	('tumors', 'Disease', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('high wGII', 'Var', (40, 49))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('PFS', 'MPA', (110, 113))	('tumors', 'Disease', 'MESH:D009369', (29, 35))
103811	29656894	The majority of these tumors had no other detectable mutational drivers, suggesting that BAP1 mutations combined with SCNAs drive a robust clonal expansion.	('BAP1', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', (22, 28))
103812	29656894	Accordingly, in a recently published mouse model of ccRCC, co-targeting of VHL and BAP1 resulted in high grade tumors with short latency.	('VHL', 'Gene', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('BAP1', 'Gene', (83, 87))	('RCC', 'Disease', (54, 57))	('co-targeting', 'Var', (59, 71))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('mouse', 'Species', '10090', (37, 42))
103814	29656894	The conserved ordering of SETD2 and PBRM1 mutations and the strong repeated selection of SETD2 mutant subclones that induce a limited clonal expansion raise interesting biological questions.	('PBRM1', 'Gene', (36, 41))	('SETD2', 'Gene', '29072', (26, 31))	('SETD2', 'Gene', '29072', (89, 94))	('SETD2', 'Gene', (26, 31))	('SETD2', 'Gene', (89, 94))	('mutant', 'Var', (95, 101))	('mutations', 'Var', (42, 51))
103816	29656894	The spatial clustering of parallel SETD2 mutations suggests a potential role for niche-specific selection, or even niche construction by the SETD2 mutant subclones.	('mutations', 'Var', (41, 50))	('mutant', 'Var', (147, 153))	('SETD2', 'Gene', (35, 40))	('SETD2', 'Gene', '29072', (141, 146))	('SETD2', 'Gene', '29072', (35, 40))	('SETD2', 'Gene', (141, 146))
103817	29656894	PBRM1 mutations are highly enriched as an early event in ccRCC, evidenced by their being clonal in 74% of cases, but also by the "PBRM1   PI3K" and "PBRM1   SCNA" evolutionary subtypes.	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('PBRM1', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('RCC', 'Disease', (59, 62))
103818	29656894	In a mouse model of ccRCC, co-targeting of VHL and PBRM1 led to low grade ccRCC tumors that arose late, while an aggressive phenotype was triggered by the additional disruption of TSC1, a component of the PI3K pathway.	('TSC1', 'Gene', (180, 184))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('VHL', 'Gene', (43, 46))	('RCC', 'Disease', (22, 25))	('co-targeting', 'Var', (27, 39))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('RCC', 'Disease', 'MESH:C538614', (22, 25))	('PBRM1', 'Gene', (51, 56))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('mouse', 'Species', '10090', (5, 10))	('low', 'Disease', (64, 67))	('PI3K', 'molecular_function', 'GO:0016303', ('205', '209'))	('disruption', 'Var', (166, 176))
103833	29656894	For clinical parameter correlation and outcome analyses for cases with multiple tumours (K114, K324, K354, K097, k265) we used the higher stage (or if stage was equal, then the larger of the two tumours, namely: K114_L, K334_R, K352_1, K097_L, K265_1.	('K352_1', 'Var', (228, 234))	('tumours', 'Disease', 'MESH:D009369', (80, 87))	('tumours', 'Disease', (80, 87))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('K114_L', 'Var', (212, 218))	('K334_R', 'Mutation', 'p.K334R', (220, 226))	('K097_L', 'Mutation', 'p.K097L', (236, 242))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumours', 'Disease', 'MESH:D009369', (195, 202))	('K097_L', 'Var', (236, 242))	('K265_1', 'Var', (244, 250))	('tumours', 'Disease', (195, 202))	('K334_R', 'Var', (220, 226))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
103836	29656894	(ThermoFisher Scientific) Validation of the patient VHL mutations was carried using PCR followed by Big Dye Terminator Sanger sequencing on the ABI 3700.	('mutations', 'Var', (56, 65))	('VHL', 'Gene', (52, 55))	('patient', 'Species', '9606', (44, 51))
103839	29656894	See Data S1 for Oligonucleotide sequences Methylation of the VHL promoter was detected after bisulphite treatment of 500ng of patient DNA using the EZ DNA Methylation-Direct kit (Zymo Research).	('bisulphite', 'Chemical', 'MESH:C042345', (93, 103))	('DNA Methylation', 'biological_process', 'GO:0006306', ('151', '166'))	('Methylation', 'Var', (42, 53))	('Oligonucleotide', 'Chemical', 'MESH:D009841', (16, 31))	('patient', 'Species', '9606', (126, 133))	('VHL', 'Gene', (61, 64))	('Methylation', 'biological_process', 'GO:0032259', ('42', '53'))	('detected', 'Reg', (78, 86))	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))
62952	29656894	Primary antibody used was rabbit anti-Ki67 (AB16667, Abcam, Cambridge, UK) and secondary antibody was Discovery Omnimap anti-rabbit HRP RUO (760-4311, Roche, Rotkreuz, Switzerland).	('antibody', 'cellular_component', 'GO:0019815', ('8', '16'))	('Ki67', 'Gene', '17345', (38, 42))	('antibody', 'cellular_component', 'GO:0019814', ('8', '16'))	('antibody', 'cellular_component', 'GO:0019815', ('89', '97'))	('antibody', 'molecular_function', 'GO:0003823', ('8', '16'))	('antibody', 'cellular_component', 'GO:0019814', ('89', '97'))	('rabbit', 'Species', '9986', (26, 32))	('antibody', 'molecular_function', 'GO:0003823', ('89', '97'))	('antibody', 'cellular_component', 'GO:0042571', ('8', '16'))	('Ki67', 'Gene', (38, 42))	('antibody', 'cellular_component', 'GO:0042571', ('89', '97'))	('760-4311', 'Var', (141, 149))	('rabbit', 'Species', '9986', (125, 131))
62974	29656894	Single Nucleotide Variant (SNV) calling was performed using Mutect v1.1.7 and small scale insetion/deletions (INDELs) were called running VarScan v2.4.1 in somatic mode with a minimum variant frequency (--min-var-freq) of 0.005, a tumour purity estimate (--tumor-purity) of 0.75 and then validated using Scalpel v0.5.3 (scalpel-discovery in - -somatic mode) (intersection between two callers taken).	('tumor', 'Disease', (257, 262))	('tumour', 'Phenotype', 'HP:0002664', (231, 237))	('tumour purity', 'Disease', (231, 244))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('a minimum variant', 'Species', '181476', (174, 191))	('tumour purity', 'Disease', 'MESH:D009369', (231, 244))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('insetion/deletions', 'Var', (90, 108))
62979	29656894	Deleterious mutations were defined if two out of three algorithms - SIFT, PolyPhen2 and MutationTaster - predicted the mutation as deleterious.	('mutation', 'Var', (119, 127))	('algorithms - SIFT', 'Disease', (55, 72))	('algorithms - SIFT', 'Disease', 'None', (55, 72))
103852	29656894	Mutations detected in high-confidence driver genes (VHL, PBRM1, SETD2, PIK3CA, MTOR, PTEN, KDM5C, CSMD3, BAP1, TP53, TSC1, TSC2, ARID1A, TCEB1) were defined as driver mutations.	('KDM5C', 'Gene', '8242', (91, 96))	('PTEN', 'Gene', (85, 89))	('TSC2', 'Gene', '7249', (123, 127))	('PBRM1', 'Gene', (57, 62))	('PIK3CA', 'Gene', '5290', (71, 77))	('ARID1A', 'Gene', (129, 135))	('TP53', 'Gene', '7157', (111, 115))	('CSMD3', 'Gene', '114788', (98, 103))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', '5728', (85, 89))	('MTOR', 'Gene', (79, 83))	('TSC2', 'Gene', (123, 127))	('VHL', 'Gene', (52, 55))	('ARID1A', 'Gene', '8289', (129, 135))	('TCEB1', 'Gene', (137, 142))	('KDM5C', 'Gene', (91, 96))	('MTOR', 'Gene', '2475', (79, 83))	('SETD2', 'Gene', (64, 69))	('CSMD3', 'Gene', (98, 103))	('PIK3CA', 'Gene', (71, 77))	('SETD2', 'Gene', '29072', (64, 69))	('TCEB1', 'Gene', '6921', (137, 142))	('TP53', 'Gene', (111, 115))	('TSC1', 'Gene', (117, 121))	('BAP1', 'Gene', (105, 109))
103857	29656894	Cancer cell fraction for INDELs were calculated using method described in STAR Methods: Subclonal deconstruction of mutations.	('STAR', 'Gene', (74, 78))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (116, 125))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cell fraction', 'cellular_component', 'GO:0000267', ('7', '20'))	('STAR', 'Gene', '6770', (74, 78))
62998	29656894	To estimate the clonality of a mutation in a region, we used the following formula:where  is the variant allele frequency at the mutation base;  is estimated tumour purity;  and  are the tumour locus specific copy number and the normal locus specific copy number which was assumed to be 2 for autosomal chromosomes; and  is the fraction of tumour cells carrying the mutation.	('variant', 'Var', (97, 104))	('tumour', 'Disease', (187, 193))	('tumour', 'Disease', 'MESH:D009369', (187, 193))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumour', 'Phenotype', 'HP:0002664', (340, 346))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('tumour purity', 'Disease', 'MESH:D009369', (158, 171))	('mutation', 'Var', (31, 39))	('tumour', 'Disease', 'MESH:D009369', (340, 346))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('tumour', 'Disease', (158, 164))	('tumour', 'Disease', (340, 346))	('tumour purity', 'Disease', (158, 171))
103859	29656894	As a consequence some tumour clones are based on only a limited number of genomic markers, however three contingency measures are in place to mitigate against phylogenetic misconstruction: i) ultra-deep 500x sequencing coverage, which ensures stably derived cancer cell fraction estimates, ii) a bespoke gene panel which is enriched for driver events, increasing the likelihood that mutational markers are driving genuine clonal expansion, iii) cross-capture validation with tree structures in >10 cases confirmed using exome sequencing data (Table S5).	('tumour', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('tumour', 'Disease', (22, 28))	('mutational', 'Var', (383, 393))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Disease', (258, 264))	('cell fraction', 'cellular_component', 'GO:0000267', ('265', '278'))
103865	29656894	SNPs used must be called in all regions of the tumour and have a B-allele frequency (BAF, total variant base / total reference bases at a position) of between 0.35 and 0.65 in the germline sample.	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('tumour', 'Disease', (47, 53))	('BAF', 'Gene', '8815', (85, 88))	('variant', 'Var', (96, 103))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('BAF', 'Gene', (85, 88))
103883	29656894	Analysis was conducted on the most frequent driver mutational events (BAP1, PBRM1, SETD2, VHL, Figure 1B), the most frequent SCNAs (3p loss, 5q gain) and SCNA events with established clinically prognostic value (loss 4q, loss 9p, loss 14q and gain 8q).	('PBRM1', 'Gene', (76, 81))	('gain', 'PosReg', (144, 148))	('loss', 'NegReg', (135, 139))	('loss 9p', 'Var', (221, 228))	('SETD2', 'Gene', '29072', (83, 88))	('loss 14q', 'Var', (230, 238))	('BAP1', 'Gene', (70, 74))	('loss 4q', 'Var', (212, 219))	('SETD2', 'Gene', (83, 88))	('gain', 'PosReg', (243, 247))	('VHL', 'Gene', (90, 93))
103893	29656894	To reduce risk of multiple testing we limited further analyses to those trajectories containing the most frequent ("core") ccRCC driver events: VHL, PBRM1, BAP1, SETD2, PI3K/AKT/mTOR pathway mutations or driver SCNAs.	('SETD2', 'Gene', (162, 167))	('AKT', 'Gene', (174, 177))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('mutations', 'Var', (191, 200))	('SETD2', 'Gene', '29072', (162, 167))	('AKT', 'Gene', '207', (174, 177))	('core', 'cellular_component', 'GO:0019013', ('115', '119'))	('VHL', 'Gene', (144, 147))	('PI3K', 'molecular_function', 'GO:0016303', ('167', '171'))	('BAP1', 'Gene', (156, 160))	('PBRM1', 'Gene', (149, 154))	('mTOR', 'Gene', (178, 182))	('mTOR', 'Gene', '2475', (178, 182))
103894	29656894	in the case of K243 where a single PBRM1 mutation precedes 10 SETD2 mutations, this is counted only once) and PI3K/AKT/mTOR pathway mutations interacting with SCNAs were not considered due to the nonspecific many-to-many relationship.	('AKT', 'Gene', '207', (115, 118))	('PI3K', 'molecular_function', 'GO:0016303', ('110', '114'))	('AKT', 'Gene', (115, 118))	('mutation', 'Var', (41, 49))	('SETD2', 'Gene', '29072', (62, 67))	('mTOR', 'Gene', (119, 123))	('PBRM1', 'Gene', (35, 40))	('mutations', 'Var', (68, 77))	('SETD2', 'Gene', (62, 67))	('mTOR', 'Gene', '2475', (119, 123))
103895	29656894	Cases were assigned to groups based on the following series of rules (applied in a hierarchical manner in the order listed): i) presence of >= 2 BAP1, PBRM1, SETD2 or PTEN clonal mutational events meant assignment to "multiple clonal driver" group (the selection of these four genes is based on the timing results observed in Figure 4B) , ii) presence of a tumour clone/subclone with a BAP1 mutational driver event, and no other "core" mutational driver events aside from VHL in that same clone/subclone, meant assignment to the "BAP1 driven" group, iii) presence of a tumour clone/subclone with PBRM1 mutation followed by a SETD2 mutation, meant assignment to the "PBRM1->SETD2" group, iv) presence of a tumour clone/subclone with PBRM1 mutation followed by a PI3K pathway mutation, meant assignment to the "PBRM1->PI3K" group, v) presence of a tumour clone/subclone with PBRM1 mutation followed by a driver SCNA event, meant assignment to the "PBRM1->SCNA" group, vi) absence of VHL mutation or methylation meant assignment to "VHL wildtype" group, vii) presence of VHL as the only "core" mutational driver event meant assignment to the "VHL monodriver" group.	('tumour', 'Phenotype', 'HP:0002664', (569, 575))	('mutation', 'Var', (631, 639))	('tumour', 'Disease', 'MESH:D009369', (569, 575))	('tumour', 'Disease', (569, 575))	('tumour', 'Phenotype', 'HP:0002664', (846, 852))	('tumour', 'Disease', 'MESH:D009369', (846, 852))	('tumour', 'Disease', (846, 852))	('PBRM1', 'Gene', (596, 601))	('PTEN', 'Gene', (167, 171))	('SETD2', 'Gene', (625, 630))	('SETD2', 'Gene', (673, 678))	('SETD2', 'Gene', (158, 163))	('mutation', 'Var', (602, 610))	('tumour', 'Phenotype', 'HP:0002664', (357, 363))	('tumour', 'Phenotype', 'HP:0002664', (705, 711))	('SETD2', 'Gene', '29072', (625, 630))	('SETD2', 'Gene', '29072', (673, 678))	('SETD2', 'Gene', '29072', (158, 163))	('tumour', 'Disease', 'MESH:D009369', (357, 363))	('tumour', 'Disease', (357, 363))	('tumour', 'Disease', 'MESH:D009369', (705, 711))	('PTEN', 'Gene', '5728', (167, 171))	('tumour', 'Disease', (705, 711))
103900	29656894	Empirical error rates were determined by exhaustive consideration of all pairs of biopsies from a given tumour sample and, for each pair, comparing the number of variants detected in one or more of the full set of biopsies not found in either member of that pair ("False negative") or determined to be subclonal in the full set but detected in both samples in that pair ("illusion of clonality").	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('variants', 'Var', (162, 170))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('tumour', 'Disease', (104, 110))
103902	29656894	We acknowledge that, despite dense sampling, the variant set found across all biopsies per tumour clearly may also be missing very rare low frequency driver events itself.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('variant', 'Var', (49, 56))	('tumour', 'Disease', (91, 97))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
103938	31819484	Short hairpin (sh)RNAs against human TNIP1 (NM_006058.4, Shanghai Sunbio, Shanghai, China), was used to knockdown TNIP1.	('TNIP1', 'Gene', (37, 42))	('human', 'Species', '9606', (31, 36))	('TNIP1', 'Gene', (114, 119))	('knockdown', 'Var', (104, 113))
103967	31819484	Malignancy decreased with differentiation, low >medium > high; Fuhrman stage, III-IV > I-II; tumor stage, T3+T4 > T1+T2; lymphatic metastasis, yes > no; and postoperative recurrence: yes > no.	('III-IV', 'Chemical', 'MESH:C412893', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('Malignancy', 'CPA', (0, 10))	('T3+T4 > T1+T2', 'Var', (106, 119))	('lymphatic metastasis', 'CPA', (121, 141))	('decreased', 'NegReg', (11, 20))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
103975	31819484	Western blotting confirmed the decrease of Bcl-2 expression and the increase of both Bax and cleaved-caspase-3 expression in cells overexpressing TNIP1 compared with the control cells (P < 0.05).	('cleaved-caspase-3 expression', 'MPA', (93, 121))	('overexpressing', 'Var', (131, 145))	('decrease', 'NegReg', (31, 39))	('expression', 'MPA', (49, 59))	('Bax', 'Gene', (85, 88))	('increase', 'PosReg', (68, 76))	('Bcl-2', 'Gene', (43, 48))	('Bcl-2', 'Gene', '596', (43, 48))	('TNIP1', 'Gene', (146, 151))	('Bax', 'Gene', '581', (85, 88))	('Bcl-2', 'molecular_function', 'GO:0015283', ('43', '48'))
103976	31819484	Flow cytometry with Annexin V-FITC/PI staining and Western blotting found that apoptosis of 786-O cells was increased, Bcl-2 expression was decreased, and Bax and cleaved-caspase-3 expression were increased more with TNIP1-shRNA+C/EBPbeta-siRNA transfection than with C/EBPbeta-siRNAs transfection (P < 0.05).	('decreased', 'NegReg', (140, 149))	('TNIP1-shRNA+C/EBPbeta-siRNA transfection', 'Var', (217, 257))	('cleaved-caspase-3 expression', 'MPA', (163, 191))	('Annexin V', 'Gene', '308', (20, 29))	('Annexin V', 'Gene', (20, 29))	('Bcl-2', 'molecular_function', 'GO:0015283', ('119', '124'))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('Bax', 'Gene', '581', (155, 158))	('increased', 'PosReg', (108, 117))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('expression', 'MPA', (125, 135))	('increased', 'PosReg', (197, 206))	('apoptosis', 'MPA', (79, 88))	('Bcl-2', 'Gene', (119, 124))	('Bcl-2', 'Gene', '596', (119, 124))	('Bax', 'Gene', (155, 158))
103977	31819484	Apoptosis was decreased, Bcl-2 was increased, and Bax and cleaved-caspase-3 expression were lower with TNIP1-shRNA+C/EBPbeta-siRNA than with TNIP1-shRNA transfection (P < 0.05).	('increased', 'PosReg', (35, 44))	('Bax', 'Gene', (50, 53))	('Bcl-2', 'Gene', (25, 30))	('decreased', 'NegReg', (14, 23))	('Bcl-2', 'Gene', '596', (25, 30))	('TNIP1-shRNA+C/EBPbeta-siRNA', 'Var', (103, 130))	('Apoptosis', 'CPA', (0, 9))	('cleaved-caspase-3 expression', 'MPA', (58, 86))	('Bax', 'Gene', '581', (50, 53))	('Bcl-2', 'molecular_function', 'GO:0015283', ('25', '30'))	('lower', 'NegReg', (92, 97))
103978	31819484	Apoptosis and Bax and cleaved-caspase-3 expression were increased and Bcl-2 expression was decreased, more with C/EBPbeta-siRNA transfection than with TNIP1-shRNA transfection (Figure 6C and D).	('Bcl-2', 'Gene', (70, 75))	('increased', 'PosReg', (56, 65))	('Bcl-2', 'Gene', '596', (70, 75))	('C/EBPbeta-siRNA transfection', 'Var', (112, 140))	('cleaved-caspase-3 expression', 'MPA', (22, 50))	('Bax', 'Gene', '581', (14, 17))	('Bcl-2', 'molecular_function', 'GO:0015283', ('70', '75'))	('expression', 'MPA', (76, 86))	('Apoptosis', 'CPA', (0, 9))	('transfection', 'Var', (128, 140))	('Bax', 'Gene', (14, 17))	('decreased', 'NegReg', (91, 100))
103990	31819484	Downregulation of TNIP1 increased C/EBPbeta expression; overexpression of TNIP1 decreased C/EBPbeta expression in HaCaT cell, which are spontaneously immortalized human keratinocytes.	('TNIP1', 'Gene', (74, 79))	('Downregulation', 'Var', (0, 14))	('C/EBPbeta', 'MPA', (34, 43))	('expression', 'MPA', (100, 110))	('decreased', 'NegReg', (80, 89))	('human', 'Species', '9606', (163, 168))	('TNIP1', 'Gene', (18, 23))	('HaCaT', 'CellLine', 'CVCL:0038', (114, 119))
103992	31819484	This study is the first to find that C/EBPbeta was overexpressed in human ccRCC tissues, and was negatively regulated by TNIP1, leading to increased cell proliferation, entry into the cell cycle, and inhibition of apoptosis.	('C/EBPbeta', 'Var', (37, 46))	('entry', 'CPA', (169, 174))	('apoptosis', 'CPA', (214, 223))	('inhibition', 'NegReg', (200, 210))	('ccRCC', 'Disease', (74, 79))	('human', 'Species', '9606', (68, 73))	('inhibition of apoptosis', 'biological_process', 'GO:0043066', ('200', '223'))	('ccRCC', 'Disease', 'MESH:D002292', (74, 79))	('cell proliferation', 'biological_process', 'GO:0008283', ('149', '167'))	('increased', 'PosReg', (139, 148))	('negatively', 'NegReg', (97, 107))	('cell cycle', 'biological_process', 'GO:0007049', ('184', '194'))	('cell proliferation', 'CPA', (149, 167))	('TNIP1', 'Gene', (121, 126))
104006	28534535	Developing in vitro and in vivo model systems that accurately reflect both the genetic diversity and the lineage specificity of cancer is crucial in order to understand the role of cancer-specific genetic alterations in tumorigenesis, tumour maintenance, and therapeutic sensitivity.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('tumour', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('alterations', 'Var', (205, 216))	('tumour', 'Disease', (235, 241))	('genetic alterations', 'Var', (197, 216))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('tumour', 'Phenotype', 'HP:0002664', (235, 241))	('cancer', 'Disease', (128, 134))
104010	28534535	For example, translocations in ETS family transcription factors ERG, FLI1, ETV1, and ETV4 are observed in half of all prostate cancers but not in other urological malignancies.	('ETV4', 'Gene', (85, 89))	('ETV1', 'Gene', (75, 79))	('FLI1', 'Gene', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('observed', 'Reg', (94, 102))	('FLI1', 'Gene', '2313', (69, 73))	('ETV1', 'Gene', '2115', (75, 79))	('prostate cancers', 'Disease', 'MESH:D011471', (118, 134))	('transcription', 'biological_process', 'GO:0006351', ('42', '55'))	('ETV4', 'Gene', '2118', (85, 89))	('malignancies', 'Disease', 'MESH:D009369', (163, 175))	('prostate cancer', 'Phenotype', 'HP:0012125', (118, 133))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('prostate cancers', 'Phenotype', 'HP:0012125', (118, 134))	('translocations', 'Var', (13, 27))	('malignancies', 'Disease', (163, 175))	('prostate cancers', 'Disease', (118, 134))
104011	28534535	Among prostate cancers that lack ETS translocations, the most common genetic alterations are mutations in the E3-ligase SPOP and the pioneer transcription factor FOXA1, which are also two highly prostate-specific events.	('transcription factor', 'molecular_function', 'GO:0000981', ('141', '161'))	('mutations', 'Var', (93, 102))	('prostate cancers', 'Disease', 'MESH:D011471', (6, 22))	('common', 'Reg', (62, 68))	('prostate cancer', 'Phenotype', 'HP:0012125', (6, 21))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('FOXA1', 'Gene', (162, 167))	('alterations', 'Var', (77, 88))	('FOXA1', 'Gene', '3169', (162, 167))	('prostate cancers', 'Phenotype', 'HP:0012125', (6, 22))	('transcription', 'biological_process', 'GO:0006351', ('141', '154'))	('E3-ligase', 'Protein', (110, 119))	('SPOP', 'Gene', '8405', (120, 124))	('prostate cancers', 'Disease', (6, 22))	('SPOP', 'Gene', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
104012	28534535	However, ccRCC is characterized by mutations involving von Hippel-Lindau (VHL) and chromatin modifiers including SETD2, BAP1, PBRM1, ARID1A, and SMARCA4.	('ARID1A', 'Gene', '8289', (133, 139))	('von Hippel-Lindau', 'Gene', (55, 72))	('mutations', 'Var', (35, 44))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('RCC', 'Disease', (11, 14))	('VHL', 'Disease', (74, 77))	('BAP1', 'Gene', (120, 124))	('SETD2', 'Gene', (113, 118))	('PBRM1', 'Gene', '55193', (126, 131))	('SMARCA4', 'Gene', '6597', (145, 152))	('von Hippel-Lindau', 'Gene', '7428', (55, 72))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('PBRM1', 'Gene', (126, 131))	('SETD2', 'Gene', '29072', (113, 118))	('VHL', 'Disease', 'MESH:D006623', (74, 77))	('ARID1A', 'Gene', (133, 139))	('SMARCA4', 'Gene', (145, 152))	('BAP1', 'Gene', '8314', (120, 124))	('chromatin', 'cellular_component', 'GO:0000785', ('83', '92'))
104015	28534535	For example, cell lines have been instrumental in the discovery of biomarkers of therapeutic response, highlighting the role of BRAF mutations in sensitivity to dual specificity mitogen-activated protein kinase kinase (MEK) inhibitors or BRCA1/2 mutations in sensitivity to poly [ADP-ribose] polymerase 1 (PARP) inhibitors.	('poly [ADP-ribose] polymerase 1', 'Gene', '142', (274, 304))	('BRAF', 'Gene', '673', (128, 132))	('mitogen-activated protein kinase kinase', 'Gene', '5609', (178, 217))	('PARP', 'Gene', '142', (306, 310))	('mitogen-activated protein kinase kinase', 'Gene', (178, 217))	('BRCA1/2', 'Gene', (238, 245))	('MEK', 'Gene', (219, 222))	('MEK', 'Gene', '5609', (219, 222))	('mutations', 'Var', (246, 255))	('poly [ADP-ribose] polymerase 1', 'Gene', (274, 304))	('mutations', 'Var', (133, 142))	('PARP', 'Gene', (306, 310))	('men', 'Species', '9606', (40, 43))	('BRCA1/2', 'Gene', '672;675', (238, 245))	('BRAF', 'Gene', (128, 132))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))
104019	28534535	Genetically engineered mouse models are genetically well-defined and can be used to delineate the minimal set of genetic alterations that can cause tumorigenesis and affect therapeutic sensitivity.	('alterations', 'Var', (121, 132))	('affect', 'Reg', (166, 172))	('therapeutic sensitivity', 'MPA', (173, 196))	('mouse', 'Species', '10090', (23, 28))	('cause', 'Reg', (142, 147))	('tumorigenesis', 'CPA', (148, 161))
104026	28534535	Independently, building on work showing that treatment with Rho-associated protein kinase (ROCK) inhibitors can induce immortality in primary keratinocytes growing on fibroblast feeders, Liu and colleagues demonstrated that the combination of a ROCK inhibitor (Y-27632) and feeder fibroblast culture conditions enables the indefinite growth of multiple primary human epithelial cell types.	('immortality', 'CPA', (119, 130))	('Y-27632', 'Chemical', 'MESH:C108830', (261, 268))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('men', 'Species', '9606', (50, 53))	('human', 'Species', '9606', (361, 366))	('induce', 'Reg', (112, 118))	('inhibitors', 'Var', (97, 107))
104044	28534535	Germline mutations in SMAD4 and BMPR1A have been discovered in some subsets of patients with juvenile polyposis, indicating a role for the BMP pathway in the pathogenesis of this disease.	('BMP', 'Gene', '649', (32, 35))	('juvenile polyposis', 'Disease', (93, 111))	('BMPR1A', 'Gene', '657', (32, 38))	('SMAD4', 'Gene', (22, 27))	('pathogenesis', 'biological_process', 'GO:0009405', ('158', '170'))	('BMP', 'Gene', '649', (139, 142))	('Germline', 'Var', (0, 8))	('BMP', 'Gene', (32, 35))	('BMP', 'Gene', (139, 142))	('juvenile polyposis', 'Disease', 'MESH:C537702', (93, 111))	('patients', 'Species', '9606', (79, 87))	('BMPR1A', 'Gene', (32, 38))	('discovered', 'Reg', (49, 59))	('juvenile polyposis', 'Phenotype', 'HP:0004784', (93, 111))
104057	28534535	These patient-derived organoids recapitulated the molecular diversity of prostate cancer subtypes, such as TMPRSS2-ERG fusion, SPOP mutation, SPINK1 overexpression, and CHD1 loss.	('prostate cancer', 'Disease', (73, 88))	('SPOP', 'Gene', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TMPRSS2', 'Gene', '7113', (107, 114))	('patient', 'Species', '9606', (6, 13))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('CHD1 loss', 'Disease', 'MESH:D015431', (169, 178))	('CHD1 loss', 'Disease', (169, 178))	('SPINK1', 'Gene', (142, 148))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('TMPRSS2', 'Gene', (107, 114))	('SPINK1', 'Gene', '6690', (142, 148))	('SPOP', 'Gene', '8405', (127, 131))	('mutation', 'Var', (132, 140))	('overexpression', 'PosReg', (149, 163))
104060	28534535	Moreover, Lobo and colleagues established patient-matched malignant and nonmalignant primary cell cultures from sample from patients with ccRCC with VHL mutations.	('mutations', 'Var', (153, 162))	('VHL', 'Disease', (149, 152))	('patient', 'Species', '9606', (42, 49))	('VHL', 'Disease', 'MESH:D006623', (149, 152))	('patient', 'Species', '9606', (124, 131))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('patients', 'Species', '9606', (124, 132))
104061	28534535	Surprisingly, the unselected tumour cell lines derived from primary ccRCC samples failed to show the VHL mutations that matching their parental tumour samples, which means that these cell lines are not cancer cells.	('parental tumour', 'Disease', (135, 150))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('tumour', 'Disease', (29, 35))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('parental tumour', 'Disease', 'MESH:D063129', (135, 150))	('mutations', 'Var', (105, 114))	('tumour', 'Disease', (144, 150))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Disease', (202, 208))	('VHL', 'Disease', 'MESH:D006623', (101, 104))	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('VHL', 'Disease', (101, 104))
104104	28534535	Large-scale screens of human cancer cell lines : including gene expression profiling, chromosomal copy number profiling, genomic sequencing data, and pharmacological sensitivity profiling : indicate that genetic information can predict a response to treatment and could guide future precision medicine regimens.	('cancer', 'Disease', (29, 35))	('men', 'Species', '9606', (306, 309))	('predict', 'Reg', (228, 235))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('gene expression', 'biological_process', 'GO:0010467', ('59', '74'))	('human', 'Species', '9606', (23, 28))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('response', 'CPA', (238, 246))	('men', 'Species', '9606', (255, 258))	('genetic', 'Var', (204, 211))
104107	28534535	However, as an example, only seven prostate cancer cell lines are currently established, and many do not harbour the recurrent genetic lesions commonly observed in patients with this disease (such as TMPRSS2-ERG interstitial deletion, SPOP mutation, FOXA1 mutation, and CHD1 loss).	('prostate cancer', 'Disease', 'MESH:D011471', (35, 50))	('mutation', 'Var', (256, 264))	('TMPRSS2', 'Gene', '7113', (200, 207))	('FOXA1', 'Gene', '3169', (250, 255))	('SPOP', 'Gene', '8405', (235, 239))	('prostate cancer', 'Phenotype', 'HP:0012125', (35, 50))	('mutation', 'Var', (240, 248))	('patients', 'Species', '9606', (164, 172))	('CHD1 loss', 'Disease', 'MESH:D015431', (270, 279))	('CHD1 loss', 'Disease', (270, 279))	('SPOP', 'Gene', (235, 239))	('FOXA1', 'Gene', (250, 255))	('prostate cancer', 'Disease', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('TMPRSS2', 'Gene', (200, 207))
104112	28534535	The organoids harboured recurrent disease-specific genomic alterations, such as ETS translocations, SPOP mutations, FOXA1 mutations, and CHD1 loss.	('ETS', 'Disease', (80, 83))	('SPOP', 'Gene', (100, 104))	('FOXA1', 'Gene', '3169', (116, 121))	('translocations', 'Var', (84, 98))	('CHD1 loss', 'Disease', (137, 146))	('mutations', 'Var', (105, 114))	('mutations', 'Var', (122, 131))	('CHD1 loss', 'Disease', 'MESH:D015431', (137, 146))	('SPOP', 'Gene', '8405', (100, 104))	('FOXA1', 'Gene', (116, 121))
104115	28534535	One of the seven lines : MSK-PCa2, which harbours an AR amplification, PTEN loss, and PIK3R1 mutation : demonstrated sensitivity to enzalutamide with an IC50 of 50 nM and to the PI3-kinase inhibitors, which strengthens the conclusion that molecular subtyping is essential for targeting therapy.	('loss', 'NegReg', (76, 80))	('sensitivity', 'MPA', (117, 128))	('PIK3R1', 'Gene', '5295', (86, 92))	('PCa2', 'Gene', (29, 33))	('PIK3R1', 'Gene', (86, 92))	('mutation ', 'Var', (93, 102))	('enzalutamide', 'Chemical', 'MESH:C540278', (132, 144))	('PTEN', 'Gene', (71, 75))	('PCa2', 'Gene', '103164619', (29, 33))	('PTEN', 'Gene', '5728', (71, 75))
104121	28534535	Using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Target (MSK-IMPACT) DNA sequencing analysis, the researchers showed that the generated organoid lines have similar mutational profiles to those of tumour samples, and can provide a platform for personalized drug-response assays in urothelial cancers.	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumour', 'Disease', 'MESH:D009369', (229, 235))	('tumour', 'Disease', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('Mutation', 'Var', (42, 50))	('urothelial cancers', 'Disease', 'MESH:D014523', (313, 331))	('urothelial cancers', 'Disease', (313, 331))	('tumour', 'Phenotype', 'HP:0002664', (229, 235))	('cancers', 'Phenotype', 'HP:0002664', (324, 331))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))
104122	28534535	For individual patients, 3D organoid systems are the first step toward achieving precision medicine that identifies therapeutic targets that will confer maximum benefit based on genetic changes that are specific to an individual's cancer.	('genetic changes', 'Var', (178, 193))	('patients', 'Species', '9606', (15, 23))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Disease', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
104134	28534535	Oncogenic transformation of basal cells can initiate prostate tumorigenesis, which suggests a basal cell origin for mouse and human prostate cancer.	('prostate cancer', 'Disease', (132, 147))	('human', 'Species', '9606', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('prostate tumorigenesis', 'Disease', (53, 75))	('prostate cancer', 'Disease', 'MESH:D011471', (132, 147))	('prostate cancer', 'Phenotype', 'HP:0012125', (132, 147))	('mouse', 'Species', '10090', (116, 121))	('Oncogenic transformation', 'Var', (0, 24))
104142	28534535	Deletion of Pten in CARNs resulted in high-grade PIN and carcinoma after androgen-mediated regeneration, suggesting that CARNs in the regressed prostate can act as a cell of origin.	('resulted in', 'Reg', (26, 37))	('Pten', 'Gene', (12, 16))	('CARNs', 'Gene', (20, 25))	('carcinoma', 'Disease', 'MESH:D002277', (57, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('regeneration', 'biological_process', 'GO:0031099', ('91', '103'))	('high-grade PIN and', 'CPA', (38, 56))	('carcinoma', 'Disease', (57, 66))	('Deletion', 'Var', (0, 8))
104169	28534535	Thus, osteoblasts proliferate in response to FGF9 produced by PDXs and FGFR1 is overexpressed in response to FGF9, aberrant FGF signalling could, therefore, promote prostate cancer progression and metastasis.	('FGF', 'Gene', (71, 74))	('osteoblasts proliferate', 'CPA', (6, 29))	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('FGF', 'Gene', '2253;2254;2255', (109, 112))	('FGF', 'Gene', '2253;2254;2255', (45, 48))	('FGF', 'Gene', '2253;2254;2255', (124, 127))	('FGFR1', 'Gene', (71, 76))	('FGF', 'Gene', (109, 112))	('metastasis', 'CPA', (197, 207))	('FGF', 'Gene', (45, 48))	('FGF9', 'Gene', (109, 113))	('FGF9', 'Gene', '2254', (109, 113))	('FGF', 'Gene', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('FGF9', 'Gene', (45, 49))	('FGF9', 'Gene', '2254', (45, 49))	('promote', 'PosReg', (157, 164))	('prostate cancer', 'Disease', 'MESH:D011471', (165, 180))	('FGF', 'Gene', '2253;2254;2255', (71, 74))	('prostate cancer', 'Phenotype', 'HP:0012125', (165, 180))	('FGFR1', 'Gene', '2260', (71, 76))	('signalling', 'biological_process', 'GO:0023052', ('128', '138'))	('prostate cancer', 'Disease', (165, 180))	('aberrant', 'Var', (115, 123))
104173	28534535	Disruption of proteins that are associated with tumorigenesis using small-molecule inhibitors was found to perturb interactions between the tumours and cancer-associated cells.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('proteins', 'Protein', (14, 22))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('perturb', 'NegReg', (107, 114))	('interactions', 'Interaction', (115, 127))	('tumours', 'Disease', 'MESH:D009369', (140, 147))	('tumours', 'Disease', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('Disruption', 'Var', (0, 10))
104174	28534535	For example, focal adhesion kinase (FAK) inhibitors (Y11 and PF-573228) affected both the tumour and the stroma, constraining tumour growth and the dissemination of stromal cells.	('FAK', 'Gene', (36, 39))	('affected', 'Reg', (72, 80))	('Y11', 'Var', (53, 56))	('tumour growth', 'Disease', (126, 139))	('FAK', 'Gene', '5747', (36, 39))	('PF-573228', 'Var', (61, 70))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('focal adhesion kinase', 'Gene', '5747', (13, 34))	('tumour', 'Disease', (90, 96))	('focal adhesion', 'cellular_component', 'GO:0005925', ('13', '27'))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('dissemination of stromal cells', 'CPA', (148, 178))	('focal adhesion kinase', 'Gene', (13, 34))	('tumour growth', 'Disease', 'MESH:D006130', (126, 139))	('FAK', 'molecular_function', 'GO:0004717', ('36', '39'))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('constraining', 'NegReg', (113, 125))	('tumour', 'Disease', (126, 132))
104175	28534535	Y11 and PF-573228, which both target the same phosphorylation site of FAK, have therapeutic potential in vitro without notable cytotoxicity.	('phosphorylation', 'biological_process', 'GO:0016310', ('46', '61'))	('FAK', 'molecular_function', 'GO:0004717', ('70', '73'))	('cytotoxicity', 'Disease', (127, 139))	('PF-573228', 'Var', (8, 17))	('FAK', 'Gene', (70, 73))	('cytotoxicity', 'Disease', 'MESH:D064420', (127, 139))	('FAK', 'Gene', '5747', (70, 73))
104181	28534535	However, truly nonmalignant cells do not propagate in traditional tissue culture media, therefore, these experiments use immortalized cells, generated either spontaneously through acquisition of mutations in TP53 or CDKN2A, or by use of viral oncogenes that inactivate tumour suppressors such as p53 and retinoblastoma-associated protein and are subject to the Hayflick limit.	('p53', 'Gene', (296, 299))	('p53', 'Gene', '7157', (296, 299))	('retinoblastoma', 'Phenotype', 'HP:0009919', (304, 318))	('retinoblastoma-associated protein', 'Gene', (304, 337))	('Hayflick limit', 'Phenotype', 'HP:0003193', (361, 375))	('men', 'Species', '9606', (111, 114))	('retinoblastoma-associated protein', 'Gene', '5925', (304, 337))	('protein', 'cellular_component', 'GO:0003675', ('330', '337'))	('tumour', 'Phenotype', 'HP:0002664', (269, 275))	('inactivate', 'NegReg', (258, 268))	('tumour', 'Disease', 'MESH:D009369', (269, 275))	('CDKN2A', 'Gene', (216, 222))	('mutations', 'Var', (195, 204))	('TP53', 'Gene', (208, 212))	('CDKN2A', 'Gene', '1029', (216, 222))	('tumour', 'Disease', (269, 275))
104183	28534535	Genetically engineered mouse models could be used to investigate cell types of origin by introducing oncogenic lesions in different epithelial lineages in vivo, followed by lineage-tracing to study their progeny and potential transformation.	('lesions', 'Var', (111, 118))	('mouse', 'Species', '10090', (23, 28))	('introducing', 'Reg', (89, 100))
104188	28534535	Organoids generated from human normal colonic tissue were engineered to express mutations in the tumour suppressor genes APC, SMAD4, and TP53, and in the oncogenes KRAS and PIK3CA.	('tumour', 'Disease', (97, 103))	('PIK3CA', 'Gene', '5290', (173, 179))	('APC', 'cellular_component', 'GO:0005680', ('121', '124'))	('colonic', 'Disease', 'MESH:D015179', (38, 45))	('mutations', 'Var', (80, 89))	('colonic', 'Disease', (38, 45))	('human', 'Species', '9606', (25, 30))	('SMAD4', 'Gene', (126, 131))	('APC', 'Disease', 'MESH:D011125', (121, 124))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumour', 'Disease', 'MESH:D009369', (97, 103))	('APC', 'Disease', (121, 124))	('PIK3CA', 'Gene', (173, 179))	('TP53', 'Gene', (137, 141))
104191	28534535	Mice injected with organoids containing KRAS, APC, and TP53 mutations developed adenoma nodules, whereas mice injected with organoids containing KRAS, APC, TP53, and SMAD4 mutations had more invasive carcinomas at 8 weeks after injection.	('mice', 'Species', '10090', (105, 109))	('APC', 'cellular_component', 'GO:0005680', ('46', '49'))	('APC', 'Disease', (46, 49))	('TP53', 'Gene', (55, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('carcinomas', 'Phenotype', 'HP:0030731', (200, 210))	('APC', 'Disease', 'MESH:D011125', (151, 154))	('APC', 'Disease', (151, 154))	('invasive carcinomas', 'Disease', (191, 210))	('Mice', 'Species', '10090', (0, 4))	('invasive carcinomas', 'Disease', 'MESH:D009361', (191, 210))	('mutations', 'Var', (60, 69))	('APC', 'Disease', 'MESH:D011125', (46, 49))	('adenoma nodules', 'Disease', 'MESH:D000236', (80, 95))	('APC', 'cellular_component', 'GO:0005680', ('151', '154'))	('adenoma nodules', 'Disease', (80, 95))
104192	28534535	These results demonstrate that the introduction of oncogenic mutations enables nonmalignant human colonic or intestinal stem cell organoids to develop into tumours in vivo, this technique could be useful for organoids derived from urological tissue.	('colonic', 'Disease', (98, 105))	('tumours', 'Disease', 'MESH:D009369', (156, 163))	('tumours', 'Disease', (156, 163))	('mutations', 'Var', (61, 70))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('colonic', 'Disease', 'MESH:D015179', (98, 105))	('human', 'Species', '9606', (92, 97))	('tumours', 'Phenotype', 'HP:0002664', (156, 163))
104193	28534535	In prostate cancer, silencing of Pten expression with short hairpin (sh)RNA in prostate organoids derived from PBCre Rosa26LSL-ERG mice caused organoids to display hyperplastic phenotypes ex vivo and generate hyperplastic prostate glandular structures in a urogenital sinus mesenchyme recombination assay, which is consistent with PtenloxP/loxP-Rosa26LSL-ERG grafts.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('Pten', 'Gene', (33, 37))	('prostate cancer', 'Disease', (3, 18))	('RNA', 'cellular_component', 'GO:0005562', ('72', '75'))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mice', 'Species', '10090', (131, 135))	('silencing', 'Var', (20, 29))	('generate hyperplastic', 'PosReg', (200, 221))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
104194	28534535	In kidney cancer, Freedman and colleagues applied the CRISPR-Cas9 technique to introduce biallelic, truncating mutations into PKD1 or PKD2 in human pluripotent stem cells cultured in organoid systems to model polycystic kidney disease.	('Cas', 'cellular_component', 'GO:0005650', ('61', '64'))	('mutations', 'Var', (111, 120))	('kidney cancer', 'Phenotype', 'HP:0009726', (3, 16))	('polycystic kidney disease', 'Disease', (209, 234))	('PKD2', 'Gene', (134, 138))	('PKD1', 'Gene', (126, 130))	('kidney cancer', 'Disease', 'MESH:D007680', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('kidney cancer', 'Disease', (3, 16))	('polycystic kidney', 'Phenotype', 'HP:0000113', (209, 226))	('truncating', 'NegReg', (100, 110))	('human', 'Species', '9606', (142, 147))	('polycystic kidney disease', 'Disease', 'MESH:D007690', (209, 234))	('kidney disease', 'Phenotype', 'HP:0000112', (220, 234))	('PKD1', 'Gene', '5310', (126, 130))	('PKD2', 'Gene', '5311', (134, 138))
104197	28534535	For example, prostate organoids derived from PBCre Rosa26LSL-ERG mice showed no signs of neoplasia in vitro, consistent with in vivo data, but Pten deletion and Erg overexpression induced a hyperplastic phenotype in these organoids with protrusion into the Matrigel matrix, suggesting aggressive behaviour.	('induced', 'Reg', (180, 187))	('deletion', 'Var', (148, 156))	('protrusion into the Matrigel matrix', 'CPA', (237, 272))	('neoplasia', 'Phenotype', 'HP:0002664', (89, 98))	('aggressive behaviour', 'CPA', (285, 305))	('Pten', 'Gene', (143, 147))	('mice', 'Species', '10090', (65, 69))	('neoplasia', 'Disease', (89, 98))	('hyperplastic phenotype', 'CPA', (190, 212))	('overexpression', 'PosReg', (165, 179))	('aggressive behaviour', 'Phenotype', 'HP:0000718', (285, 305))	('behaviour', 'biological_process', 'GO:0007610', ('296', '305'))	('neoplasia', 'Disease', 'MESH:D009369', (89, 98))	('Erg', 'Gene', (161, 164))
104203	28534535	In a mouse model of tyrosinaemia type I liver disease induced by a fumarylacetoacetate hydrolase (Fah-/-) mutation, organoids clonally expanded from single Lgr5-positive liver stem cells, which expressed Fah, were integrated into damaged livers by intrasplenical injection.	('induced by', 'Reg', (54, 64))	('fumarylacetoacetate hydrolase', 'Gene', (67, 96))	('mutation', 'Var', (106, 114))	('liver disease', 'Phenotype', 'HP:0001392', (40, 53))	('mouse', 'Species', '10090', (5, 10))	('tyrosinaemia type I liver disease', 'Disease', 'MESH:D008107', (20, 53))	('tyrosinaemia type I liver disease', 'Disease', (20, 53))	('Fah-/-', 'Gene', (98, 104))	('fumarylacetoacetate hydrolase', 'Gene', '14085', (67, 96))	('Fah-/-', 'Gene', '14085', (98, 104))
104213	28534535	Correction of the most common cystic fibrosis transmembrane conductor receptor (CFTR) mutation, CTFR F508del, was achieved using CRISPR-Cas9 genome editing technology in organoids derived from intestinal stem cells from two patients with cystic fibrosis, using a homologous recombination approach.	('F508del', 'Var', (101, 108))	('transmembrane', 'cellular_component', 'GO:0044214', ('46', '59'))	('CFTR', 'Gene', '1080', (80, 84))	('transmembrane', 'cellular_component', 'GO:0016021', ('46', '59'))	('Cas', 'cellular_component', 'GO:0005650', ('136', '139'))	('cystic fibrosis', 'Disease', 'MESH:D003550', (238, 253))	('cystic fibrosis transmembrane conductor receptor', 'Gene', '1080', (30, 78))	('CTFR', 'Gene', (96, 100))	('cystic fibrosis transmembrane conductor receptor', 'Gene', (30, 78))	('homologous recombination', 'biological_process', 'GO:0035825', ('263', '287'))	('patients', 'Species', '9606', (224, 232))	('CFTR', 'Gene', (80, 84))	('cystic fibrosis', 'Disease', 'MESH:D003550', (30, 45))	('cystic fibrosis', 'Disease', (238, 253))	('F508del', 'DELETION', 'None', (101, 108))
104318	28033421	So, the identification of alterations that may influence tumor behavior and clinical outcome in primary tumors and metastases is needed to improve the management of these patients.	('metastases', 'Disease', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('primary tumors', 'Disease', (96, 110))	('influence', 'Reg', (47, 56))	('metastases', 'Disease', 'MESH:D009362', (115, 125))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('alterations', 'Var', (26, 37))	('primary tumors', 'Disease', 'MESH:D009369', (96, 110))	('patients', 'Species', '9606', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
104381	33678805	For example, a very small number of CD44+CD24- (~100 cells) breast CSCs showed tumorigenicity in mouse xenotransplantation assays, whereas tens of thousands of cells with alternate phenotypes were not.	('tumor', 'Disease', (79, 84))	('CD44+CD24-', 'Var', (36, 46))	('mouse', 'Species', '10090', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
104386	33678805	It is now clear that tumors are heterogeneous, and that the heterogeneity of cancer arises from the genetic or epigenetic differences between the cancer cells themselves and diverse cell types initially recruited to the tumor.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (21, 26))	('epigenetic differences', 'Var', (111, 133))	('cancer', 'Disease', (77, 83))	('tumors', 'Disease', (21, 27))	('tumor', 'Disease', (220, 225))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
104388	33678805	The clonal evolution model demonstrates that successive mutations accumulating in a given cell produce dominant clone populations, which thrive under the selection of microenvironmental pressure, and ultimately determine the tumor phenotype.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('mutations', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', (225, 230))	('determine', 'Reg', (211, 220))
104394	33678805	Nevertheless, studies have demonstrated that many cell surface markers can be used to isolate CSCs-rich subtypes in various types of solid tumors and hematological malignancy, including CD133, CD44, CD90, CD34, ALDH1, EpCAM, etc.	('cell surface', 'cellular_component', 'GO:0009986', ('50', '62'))	('ALDH1', 'Gene', (211, 216))	('CD44', 'Var', (193, 197))	('CD9', 'Gene', '928', (199, 202))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('CD34', 'Var', (205, 209))	('ALDH', 'molecular_function', 'GO:0004030', ('211', '215'))	('hematological malignancy', 'Disease', (150, 174))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('hematological malignancy', 'Disease', 'MESH:D019337', (150, 174))	('ALDH1', 'Gene', '216', (211, 216))	('hematological malignancy', 'Phenotype', 'HP:0004377', (150, 174))	('CD133', 'Gene', (186, 191))	('CD133', 'Gene', '8842', (186, 191))	('EpCAM', 'Gene', (218, 223))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('CD9', 'Gene', (199, 202))	('EpCAM', 'Gene', '4072', (218, 223))
104395	33678805	For example, the combination of CD34, CD38, and IL3Ralpha can achieve the prospective separation of leukemia stem cells.	('CD34', 'Protein', (32, 36))	('CD38', 'Var', (38, 42))	('leukemia', 'Disease', 'MESH:D007938', (100, 108))	('IL3Ralpha', 'Gene', '3563', (48, 57))	('leukemia', 'Disease', (100, 108))	('leukemia', 'Phenotype', 'HP:0001909', (100, 108))	('IL3', 'molecular_function', 'GO:0005135', ('48', '51'))	('IL3Ralpha', 'Gene', (48, 57))
104402	33678805	The combination of CD44+CD24- and ALDH1+ has been widely used to isolate a variety of solid CSCs, especially for the enrichment of breast CSCs and oral squamous cell carcinoma stem cells.	('breast CSCs and oral squamous cell carcinoma', 'Disease', 'MESH:D001943', (131, 175))	('ALDH1', 'Gene', '216', (34, 39))	('ALDH', 'molecular_function', 'GO:0004030', ('34', '38'))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('CD44+CD24-', 'Var', (19, 29))	('ALDH1', 'Gene', (34, 39))
104416	33678805	In addition, it is readily to detect tumorigenic CD44+CD24-/low CSCs in pleural fluid and bone marrow in metastatic breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('CD44+CD24-/low CSCs', 'Var', (49, 68))	('breast cancer', 'Disease', (116, 129))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('pleural fluid', 'Phenotype', 'HP:0002202', (72, 85))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))
104431	33678805	Subsequently, phosphorylated ERK activates myosin light chain kinase (MLCK).	('myosin light chain kinase', 'Gene', (43, 68))	('ERK', 'Gene', '5594', (29, 32))	('myosin light chain kinase', 'molecular_function', 'GO:0004687', ('43', '68'))	('MLCK', 'molecular_function', 'GO:0004687', ('70', '74'))	('myosin light chain kinase', 'Gene', '4638', (43, 68))	('activates', 'PosReg', (33, 42))	('MLCK', 'Gene', '4638', (70, 74))	('ERK', 'Gene', (29, 32))	('ERK', 'molecular_function', 'GO:0004707', ('29', '32'))	('phosphorylated', 'Var', (14, 28))	('MLCK', 'Gene', (70, 74))
104436	33678805	In addition, exosomes also carry high concentrations of tetraspanins proteins (CD9, CD63, CD81, and CD82), signal receptors, and integrins, which are involved in antigen presentation, cell adhesion, immune regulation, and the pathophysiology of target cells.	('cell adhesion', 'biological_process', 'GO:0007155', ('184', '197'))	('tetraspanins proteins', 'Protein', (56, 77))	('CD8', 'Gene', (100, 103))	('CD8', 'Gene', (90, 93))	('CD8', 'Gene', '925', (100, 103))	('CD9', 'Gene', '928', (79, 82))	('antigen presentation', 'biological_process', 'GO:0019882', ('162', '182'))	('CD9', 'Gene', (79, 82))	('CD63', 'Var', (84, 88))	('regulation', 'biological_process', 'GO:0065007', ('206', '216'))	('integrins', 'Protein', (129, 138))	('CD8', 'Gene', '925', (90, 93))
104442	33678805	For example, studies have shown that EVs-mediated communication between different GSCs subpopulations leads to the generation of cancer cell subpopulations with intermediate phenotypes.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('GSCs', 'Chemical', '-', (82, 86))	('EVs-mediated communication', 'Var', (37, 63))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('leads to', 'Reg', (102, 110))
104474	33678805	showed that exosomes containing CD44v6 and Tspan8 derived from PaCIC promoted a shift toward stem cell features in CD44v6 knockdown and Tspan8 knockdown non-PaCIC.	('Tspan8', 'Gene', (43, 49))	('Tspan8', 'Gene', '7103', (43, 49))	('-PaCIC', 'Phenotype', 'HP:0006699', (156, 162))	('CD44v6 knockdown', 'Var', (115, 131))	('knockdown', 'Var', (122, 131))	('Tspan8', 'Gene', (136, 142))	('Tspan8', 'Gene', '7103', (136, 142))	('stem cell features', 'CPA', (93, 111))
104475	33678805	Exosomal CD44v6 and Tspan8 act as a hub, initiated by CD44v6-dependent RTK, GPCR, and integrin activation.	('CD44v6-dependent', 'Var', (54, 70))	('Tspan8', 'Gene', (20, 26))	('Tspan8', 'Gene', '7103', (20, 26))	('integrin activation', 'biological_process', 'GO:0033622', ('86', '105'))
104483	33678805	Mechanistically, exosomal cicRNA-ABCC1 activated the Wnt/beta-catenin pathway to promote the progression of colorectal cancer.	('ABCC1', 'Gene', '4363', (33, 38))	('activated', 'PosReg', (39, 48))	('promote', 'PosReg', (81, 88))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('exosomal', 'Var', (17, 25))	('colorectal cancer', 'Disease', (108, 125))	('beta-catenin', 'Gene', (57, 69))	('ABCC1', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('beta-catenin', 'Gene', '1499', (57, 69))
104492	33678805	The study demonstrated that CCRCC stem cells-derived exosomal miR-19b-3p strongly promoted tumor cell EMT through targeting PTEN signaling pathway.	('EMT', 'biological_process', 'GO:0001837', ('102', '105'))	('PTEN', 'Gene', (124, 128))	('PTEN', 'Gene', '5728', (124, 128))	('promoted', 'PosReg', (82, 90))	('miR-19b-3p', 'Var', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('CCRCC', 'Phenotype', 'HP:0006770', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('miR-19b-3p', 'Chemical', '-', (62, 72))	('signaling pathway', 'biological_process', 'GO:0007165', ('129', '146'))
104525	33678805	Patients with a high proportion of CD105+ renal CSCs often show tumor metastatic disease.	('tumor', 'Disease', (64, 69))	('renal CSCs', 'Disease', (42, 52))	('Patients', 'Species', '9606', (0, 8))	('CD105+', 'Var', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
104526	33678805	It was reported that MVs released by CD105+ renal CSCs enhanced tumor angiogenesis.	('tumor', 'Disease', (64, 69))	('enhanced', 'PosReg', (55, 63))	('angiogenesis', 'biological_process', 'GO:0001525', ('70', '82'))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('CD105+', 'Var', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
104564	33678805	Patients with abundant exosomal miR-146a expression in serum exhibited higher CSCs traits and showed increased tumor-infiltrating CD66+ neutrophils, as well as decreased tumor-infiltrating CD8+ T cells, suggesting the production of an immunosuppressive microenvironment (Fig.	('higher', 'PosReg', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('increased', 'PosReg', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('miR-146a', 'Gene', '406938', (32, 40))	('CD8', 'Gene', (189, 192))	('CSCs traits', 'CPA', (78, 89))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (170, 175))	('exosomal', 'Var', (23, 31))	('Patients', 'Species', '9606', (0, 8))	('CD8', 'Gene', '925', (189, 192))	('decreased', 'NegReg', (160, 169))	('miR-146a', 'Gene', (32, 40))
104566	33678805	showed that exosomal miR-19b-3p derived from CCRCC stem cells initiated the EMT program of tumor cells and promoted metastasis.	('miR-19b-3p', 'Chemical', '-', (21, 31))	('exosomal', 'Var', (12, 20))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('initiated', 'PosReg', (62, 71))	('EMT', 'biological_process', 'GO:0001837', ('76', '79'))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('CCRCC', 'Phenotype', 'HP:0006770', (45, 50))	('metastasis', 'CPA', (116, 126))	('promoted', 'PosReg', (107, 115))	('tumor', 'Disease', (91, 96))
104567	33678805	However, specific contributions of non-CSCs-derived exosomes miR-19b-3p in tumor progression have yet to be established.	('miR-19b-3p', 'Chemical', '-', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('miR-19b-3p', 'Var', (61, 71))	('tumor', 'Disease', (75, 80))
104568	33678805	It is worth noting that a study reported that tubular epithelial cells-derived exosomal miR-19b-3p promoted the activation of M1 macrophage, driving the occurrence of tubular interstitial inflammation.	('miR-19b-3p', 'Chemical', '-', (88, 98))	('activation', 'PosReg', (112, 122))	('promoted', 'PosReg', (99, 107))	('inflammation', 'Disease', 'MESH:D007249', (188, 200))	('inflammation', 'biological_process', 'GO:0006954', ('188', '200'))	('miR-19b-3p', 'Var', (88, 98))	('inflammation', 'Disease', (188, 200))
104569	33678805	Therefore, further research should consider the unique role of CSCs exosomal miR-19b-3p, which may be developed as a new target for the treatment of cancer.	('cancer', 'Disease', (149, 155))	('miR-19b-3p', 'Chemical', '-', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('miR-19b-3p', 'Var', (77, 87))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
104577	33678805	Consistently, PaCIC secreted exosomes transferred CD44v6 protein (a biomarker of pancreatic CSC) to non-PaCIC and promoted their apoptosis-resistance, EMT, motility, and tumor progression.	('EMT', 'biological_process', 'GO:0001837', ('151', '154'))	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('CD44v6', 'Var', (50, 56))	('pancreatic CSC', 'Disease', 'MESH:D010195', (81, 95))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('apoptosis-resistance', 'CPA', (129, 149))	('motility', 'CPA', (156, 164))	('pancreatic CSC', 'Disease', (81, 95))	('tumor', 'Disease', (170, 175))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('promoted', 'PosReg', (114, 122))	('EMT', 'CPA', (151, 154))	('-PaCIC', 'Phenotype', 'HP:0006699', (103, 109))	('protein', 'Protein', (57, 64))
104599	33678805	Conceivably, anti-CD44 antibody-coated EVs could directly target CSCs and subsequently induce their death.	('antibody', 'cellular_component', 'GO:0042571', ('23', '31'))	('anti-CD44', 'Var', (13, 22))	('induce', 'Reg', (87, 93))	('antibody', 'cellular_component', 'GO:0019815', ('23', '31'))	('death', 'Disease', 'MESH:D003643', (100, 105))	('death', 'Disease', (100, 105))	('antibody', 'cellular_component', 'GO:0019814', ('23', '31'))	('antibody', 'molecular_function', 'GO:0003823', ('23', '31'))	('CSCs', 'CPA', (65, 69))
104609	33678805	Therefore, it can be seen from the current discussion that many biological characteristics of cancer cells are determined by non-genetic mechanisms, and epigenetics also plays an important role in cancer progression.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('epigenetics', 'Var', (153, 164))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
104614	31575731	HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species Inactivation of the VHL tumor suppressor gene is the signature initiating event in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, and causes the accumulation of hypoxia-inducible factor 2alpha (HIF-2alpha).	('CDK4/6', 'Gene', '1019;1021', (44, 50))	('hypoxia-inducible factor 2alpha', 'Gene', (284, 315))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('114', '130'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('114', '130'))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (173, 204))	('Inactivation', 'Var', (90, 102))	('hypoxia-inducible factor 2alpha', 'Gene', '2034', (284, 315))	('kidney cancer', 'Disease', 'MESH:D007680', (238, 251))	('VHL tumor', 'Disease', (110, 119))	('CDK', 'molecular_function', 'GO:0004693', ('44', '47'))	('VHL tumor', 'Disease', 'MESH:D006623', (110, 119))	('clear cell renal cell carcinoma', 'Disease', (173, 204))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (184, 204))	('CDK4/6', 'Gene', (44, 50))	('VHL loss', 'Disease', (66, 74))	('kidney cancer', 'Phenotype', 'HP:0009726', (238, 251))	('ccRCC', 'Phenotype', 'HP:0006770', (206, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('kidney cancer', 'Disease', (238, 251))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('VHL loss', 'Disease', 'MESH:D006623', (66, 74))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (173, 204))	('accumulation', 'PosReg', (268, 280))
104627	31575731	Patients who do not respond to these therapies are sometimes treated with inhibitors of mammalian target of rapamycin (mTOR), which are also palliative and not curative in this setting.	('mammalian target of rapamycin', 'Gene', '2475', (88, 117))	('mammalian target of rapamycin', 'Gene', (88, 117))	('inhibitors', 'Var', (74, 84))	('Patients', 'Species', '9606', (0, 8))	('mTOR', 'Gene', (119, 123))	('mTOR', 'Gene', '2475', (119, 123))
104631	31575731	Applying synthetic lethality to identify therapeutic targets is particularly attractive for cancer because it leverages mutations that are cancer specific, thereby creating a potential therapeutic window between cancer cells and normal host cells.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (139, 145))
104634	31575731	These screens reidentified inactivation of CDK4/6 as synthetic lethal with loss of VHL, suggesting that this interaction is highly robust.	('inactivation', 'Var', (27, 39))	('CDK4/6', 'Gene', (43, 49))	('VHL', 'Gene', (83, 86))	('CDK', 'molecular_function', 'GO:0004693', ('43', '46'))	('loss', 'NegReg', (75, 79))	('CDK4/6', 'Gene', '1019;1021', (43, 49))
104635	31575731	Inhibiting CDK4/6 suppressed the proliferation of pVHL-defective ccRCCs both ex vivo and in vivo, including pVHL-defective ccRCCs that are HIF-2alpha independent.	('Inhibiting', 'Var', (0, 10))	('pVHL', 'Gene', '7428', (108, 112))	('pVHL', 'Gene', (108, 112))	('pVHL', 'Gene', '7428', (50, 54))	('CDK', 'molecular_function', 'GO:0004693', ('11', '14'))	('CDK4/6', 'Gene', '1019;1021', (11, 17))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('pVHL', 'Gene', (50, 54))	('proliferation', 'CPA', (33, 46))	('suppressed', 'NegReg', (18, 28))	('CDK4/6', 'Gene', (11, 17))
104640	31575731	Using single-cell cloning, we generated an S2R+ derivative that had a vhl frameshift mutation (hereafter referred to as vhl-null S2R+ cells) and confirmed that this derivative accumulated high amounts of hypoxia-inducible mRNAs (such as LDH and CG11652) driven by sima, which is the Drosophila ortholog of the human genes encoding HIF-1alpha and HIF-2alpha (Fig.	('Drosophila', 'Species', '7227', (283, 293))	('hypoxia', 'Disease', (204, 211))	('hypoxia', 'Disease', 'MESH:D000860', (204, 211))	('HIF-1alpha', 'Gene', '3091', (331, 341))	('frameshift mutation', 'Var', (74, 93))	('human', 'Species', '9606', (310, 315))	('HIF-1alpha', 'Gene', (331, 341))	('vhl', 'Gene', (70, 73))	('CG11652', 'Gene', (245, 252))
104666	31575731	VHL expression in the absence of palbociclib had minimal effects on the fitness of the 786-O, UMRC-2, and 769-P cells for the duration of the competition assays and conferred a fitness disadvantage to the A498 cells (fig.	('fitness', 'Disease', (177, 184))	('expression', 'Species', '29278', (4, 14))	('A498', 'CellLine', 'CVCL:1056', (205, 209))	('UMRC-2', 'CellLine', 'CVCL:2739', (94, 100))	('fitness', 'Disease', 'MESH:D012640', (177, 184))	('VHL', 'Gene', (0, 3))	('expression', 'Var', (4, 14))	('palbociclib', 'Chemical', 'MESH:C500026', (33, 44))	('fitness', 'Disease', (72, 79))	('fitness', 'Disease', 'MESH:D012640', (72, 79))
104669	31575731	In a complementary set of experiments, we introduced a palbociclib-resistant CDK6 variant (D104S) into 786-O cells (Fig.	('D104S', 'Var', (91, 96))	('CDK6', 'Gene', (77, 81))	('D104S', 'Mutation', 'p.D104S', (91, 96))	('palbociclib', 'Chemical', 'MESH:C500026', (55, 66))	('CDK', 'molecular_function', 'GO:0004693', ('77', '80'))
104670	31575731	First, we confirmed that CDK6 (D104S) attenuated the pharmacodynamic effects of palbociclib on the abundance of phosphorylated pRb relative to cells expressing wild-type CDK6 (Fig.	('CDK6 (D104S', 'Var', (25, 36))	('attenuated', 'NegReg', (38, 48))	('pharmacodynamic effects', 'MPA', (53, 76))	('CDK', 'molecular_function', 'GO:0004693', ('170', '173'))	('palbociclib', 'Chemical', 'MESH:C500026', (80, 91))	('abundance of phosphorylated', 'MPA', (99, 126))	('pRb', 'Gene', (127, 130))	('CDK', 'molecular_function', 'GO:0004693', ('25', '28'))	('pRb', 'Gene', '5925', (127, 130))	('D104S', 'Mutation', 'p.D104S', (31, 36))
104671	31575731	The cells expressing CDK6(D104S) were then infected to stably express either VHL and Tdtomato (VHL-Tdtomato) or GFP alone (EV-GFP) and used in our competition assays.	('infected', 'Disease', (43, 51))	('VHL', 'Gene', (77, 80))	('D104S', 'Mutation', 'p.D104S', (26, 31))	('CDK', 'molecular_function', 'GO:0004693', ('21', '24'))	('EV', 'Chemical', '-', (123, 125))	('tomato', 'Species', '4081', (87, 93))	('infected', 'Disease', 'MESH:D007239', (43, 51))	('CDK6(D104S', 'Var', (21, 31))	('tomato', 'Species', '4081', (101, 107))
104672	31575731	The presence of the D104S variant, like the loss of pRb, rendered the VHL-Tdtomato and EV-GFP equally sensitive to palbociclib (Fig.	('EV', 'Chemical', '-', (87, 89))	('pRb', 'Gene', '5925', (52, 55))	('D104S', 'Var', (20, 25))	('pRb', 'Gene', (52, 55))	('D104S', 'Mutation', 'p.D104S', (20, 25))	('palbociclib', 'Chemical', 'MESH:C500026', (115, 126))	('tomato', 'Species', '4081', (76, 82))	('sensitive to palbociclib', 'MPA', (102, 126))
104676	31575731	The observed rescue by CDK6(D104S) indicated that inhibition of CDK6 is necessary for the antifitness effects of palbociclib in VHL-/- ccRCC cells but did not address whether inhibition of CDK6 would also be sufficient for such effects.	('fitness', 'Disease', (94, 101))	('fitness', 'Disease', 'MESH:D012640', (94, 101))	('CDK6', 'Gene', (64, 68))	('inhibition', 'Var', (50, 60))	('CDK', 'molecular_function', 'GO:0004693', ('64', '67'))	('CDK', 'molecular_function', 'GO:0004693', ('189', '192'))	('D104S', 'Mutation', 'p.D104S', (28, 33))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('CDK', 'molecular_function', 'GO:0004693', ('23', '26'))	('palbociclib', 'Chemical', 'MESH:C500026', (113, 124))
104682	31575731	To begin to understand the basis of the synthetic lethal relationship between CDK4/6 and VHL, we next created a pVHL variant in which the beta domain of pVHL, which is responsible for substrate recognition, is deleted (pVHLDeltaB) (fig.	('pVHL', 'Gene', (112, 116))	('CDK4/6', 'Gene', '1019;1021', (78, 84))	('pVHL', 'Gene', '7428', (219, 223))	('pVHL', 'Gene', (219, 223))	('pVHL', 'Gene', '7428', (153, 157))	('CDK4/6', 'Gene', (78, 84))	('pVHL', 'Gene', '7428', (112, 116))	('pVHL', 'Gene', (153, 157))	('CDK', 'molecular_function', 'GO:0004693', ('78', '81'))	('variant', 'Var', (117, 124))
104687	31575731	HIF-2alpha acts as an oncogenic driver in most ccRCC, and many ccRCC cell lines, including 786-O cells, express HIF-2alpha but not HIF-1alpha.	('HIF-2alpha', 'Var', (112, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('HIF-1alpha', 'Gene', (131, 141))	('ccRCC', 'Disease', (47, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('HIF-1alpha', 'Gene', '3091', (131, 141))
104692	31575731	In a complimentary set of experiments, we first treated the 786-O VHL-Tdtomato cells with increasing amounts of the prolyl hydroxylase inhibitor FG4592 and determined that 100 muM or more FG4592 induced an increase in HIF-2alpha abundance to an amount that was comparable to that in EV-GFP cells (Fig.	('HIF-2alpha', 'Protein', (218, 228))	('EV', 'Chemical', '-', (283, 285))	('FG4592', 'Var', (188, 194))	('muM', 'Gene', '56925', (176, 179))	('abundance', 'MPA', (229, 238))	('tomato', 'Species', '4081', (72, 78))	('muM', 'Gene', (176, 179))	('increase', 'PosReg', (206, 214))
104698	31575731	We observed a synergistic increase in the ratio of VHL-Tdtomato:EV-GFP cells that had been treated with both palbociclib and PT2399, as compared to cells treated with palbociclib alone in the HIF-2alpha-dependent 786-O and A498 cell lines.	('PT2399', 'Chemical', 'MESH:C000614278', (125, 131))	('increase', 'PosReg', (26, 34))	('A498', 'CellLine', 'CVCL:1056', (223, 227))	('EV', 'Chemical', '-', (64, 66))	('palbociclib', 'Chemical', 'MESH:C500026', (109, 120))	('tomato', 'Species', '4081', (57, 63))	('PT2399', 'Var', (125, 131))	('palbociclib', 'Chemical', 'MESH:C500026', (167, 178))
104699	31575731	Note that PT2399 monotherapy did not cause a statistically significant increase in the VHL-Tdtomato:EV-GFP ratio, consistent with earlier studies showing that 786-O cells tolerate the loss of HIF-2alpha in short-term cultures under high serum conditions.	('PT2399', 'Chemical', 'MESH:C000614278', (10, 16))	('HIF-2alpha', 'Protein', (192, 202))	('loss', 'Var', (184, 188))	('VHL-Tdtomato', 'MPA', (87, 99))	('tomato', 'Species', '4081', (93, 99))	('PT2399', 'Var', (10, 16))	('EV', 'Chemical', '-', (100, 102))
104701	31575731	As expected, PT2399 also decreased basal cyclin D1 mRNA and protein abundance in 786-O cells.	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('decreased', 'NegReg', (25, 34))	('cyclin', 'molecular_function', 'GO:0016538', ('41', '47'))	('PT2399', 'Var', (13, 19))	('PT2399', 'Chemical', 'MESH:C000614278', (13, 19))
104702	31575731	However, for reasons that remain to be investigated, PT2399 had variable effects on basal cyclin D1 mRNA and protein abundance in the A498 cells [Fig.	('PT2399', 'Var', (53, 59))	('A498', 'CellLine', 'CVCL:1056', (134, 138))	('effects', 'Reg', (73, 80))	('cyclin', 'molecular_function', 'GO:0016538', ('90', '96'))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('PT2399', 'Chemical', 'MESH:C000614278', (53, 59))
104704	31575731	4B), PT2399 enhances palbociclib's antifitness effects on HIF-2alpha-dependent ccRCC cell lines and does not antagonize its effects on HIF-2alpha-independent ccRCC lines.	('palbociclib', 'Chemical', 'MESH:C500026', (21, 32))	('PT2399', 'Var', (5, 11))	('ccRCC', 'Phenotype', 'HP:0006770', (158, 163))	('fitness', 'Disease', (39, 46))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('fitness', 'Disease', 'MESH:D012640', (39, 46))	('PT2399', 'Chemical', 'MESH:C000614278', (5, 11))	('palbociclib', 'Gene', (21, 32))	('enhances', 'PosReg', (12, 20))
104711	31575731	As expected, PT2399 decreased cyclin D1 abundance, and both agents, singly and in combination, decreased both phospho-pRb and Ki-67 staining (fig.	('decreased', 'NegReg', (95, 104))	('cyclin', 'MPA', (30, 36))	('pRb', 'Gene', (118, 121))	('decreased', 'NegReg', (20, 29))	('cyclin', 'molecular_function', 'GO:0016538', ('30', '36'))	('pRb', 'Gene', '5925', (118, 121))	('PT2399', 'Var', (13, 19))	('PT2399', 'Chemical', 'MESH:C000614278', (13, 19))
104722	31575731	Palbociclib and PT2399 each individually prolonged the survival of the 786-O cell tumor-bearing mice, with a trend toward enhanced survival in the combination treatment arm (Fig.	('enhanced', 'PosReg', (122, 130))	('mice', 'Species', '10090', (96, 100))	('Palbociclib', 'Chemical', 'MESH:C500026', (0, 11))	('PT2399', 'Var', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('survival', 'CPA', (55, 63))	('prolonged', 'PosReg', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('PT2399', 'Chemical', 'MESH:C000614278', (16, 22))	('tumor', 'Disease', (82, 87))
104726	31575731	Consistent with our cell culture studies, however, the activity of palbociclib in the UMRC-2 model was not enhanced by PT2399 (Fig.	('activity', 'MPA', (55, 63))	('PT2399', 'Var', (119, 125))	('UMRC-2', 'CellLine', 'CVCL:2739', (86, 92))	('palbociclib', 'Chemical', 'MESH:C500026', (67, 78))	('PT2399', 'Chemical', 'MESH:C000614278', (119, 125))
104727	31575731	We show that inactivation of the VHL tumor suppressor gene is synthetic lethal with loss of CDK4/6 activity.	('VHL tumor', 'Disease', (33, 42))	('inactivation', 'Var', (13, 25))	('CDK4/6', 'Gene', (92, 98))	('CDK', 'molecular_function', 'GO:0004693', ('92', '95'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('37', '53'))	('loss', 'NegReg', (84, 88))	('VHL tumor', 'Disease', 'MESH:D006623', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('37', '53'))	('CDK4/6', 'Gene', '1019;1021', (92, 98))	('activity', 'MPA', (99, 107))
104728	31575731	This relationship is robust because it can be detected in both Drosophila cells and a variety of human cancer cell lines and with both genetic CDK4/6 inhibitors and pharmacological CDK4/6 inhibitors.	('CDK', 'molecular_function', 'GO:0004693', ('143', '146'))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('CDK4/6', 'Gene', '1019;1021', (181, 187))	('CDK4/6', 'Gene', '1019;1021', (143, 149))	('inhibitors', 'Var', (150, 160))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('human', 'Species', '9606', (97, 102))	('CDK4/6', 'Gene', (143, 149))	('cancer', 'Disease', (103, 109))	('CDK4/6', 'Gene', (181, 187))	('Drosophila', 'Species', '7227', (63, 73))	('CDK', 'molecular_function', 'GO:0004693', ('181', '184'))
104729	31575731	The antiproliferative effects of the pharmacological inhibitors were on-target because they were observed with two structurally distinct inhibitors and were rescued with a drug-resistant CDK6 point mutant or by eliminating pRb.	('pRb', 'Gene', '5925', (223, 226))	('pRb', 'Gene', (223, 226))	('CDK', 'molecular_function', 'GO:0004693', ('187', '190'))	('eliminating', 'NegReg', (211, 222))	('CDK6', 'Gene', (187, 191))	('point mutant', 'Var', (192, 204))	('antiproliferative', 'CPA', (4, 21))
104737	31575731	Exploiting synthetic lethal relationships potentially addresses two vexing problems in cancer drug discovery: (i) how to pharmacologically tackle loss-of-function mutations and (ii) how to achieve a therapeutic window between normal cells and tumor cells.	('cancer', 'Disease', (87, 93))	('mutations', 'Var', (163, 172))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('loss-of-function', 'NegReg', (146, 162))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
104739	31575731	The VHL tumor suppressor gene is mutated in >90% of ccRCC cases, usually as the initiating or "truncal" event, and is thus an ideal target for the development of synthetic lethality-based therapy that will selectively kill ccRCC cells.	('tumor suppressor', 'biological_process', 'GO:0051726', ('8', '24'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('8', '24'))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('mutated', 'Var', (33, 40))	('VHL tumor', 'Disease', (4, 13))	('ccRCC', 'Phenotype', 'HP:0006770', (223, 228))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('ccRCC', 'Disease', (52, 57))	('VHL tumor', 'Disease', 'MESH:D006623', (4, 13))
104744	31575731	We observed synergistic suppression of cancer cell growth ex vivo when using a CDK4/6 inhibitor in combination with a HIF-2alpha inhibitor in cell lines in which inhibition of HIF-2alpha decreases cyclin D1.	('CDK', 'molecular_function', 'GO:0004693', ('79', '82'))	('suppression', 'NegReg', (24, 35))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cyclin', 'molecular_function', 'GO:0016538', ('197', '203'))	('cyclin D1', 'MPA', (197, 206))	('CDK4/6', 'Gene', '1019;1021', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('inhibition', 'Var', (162, 172))	('cell growth', 'biological_process', 'GO:0016049', ('46', '57'))	('decreases', 'NegReg', (187, 196))	('CDK4/6', 'Gene', (79, 85))
104762	31575731	Several studies have demonstrated that inhibiting CDK4/6 increases the immunogenicity of cancer cells and their removal by T cells.	('removal', 'CPA', (112, 119))	('CDK4/6', 'Gene', (50, 56))	('CDK', 'molecular_function', 'GO:0004693', ('50', '53'))	('immunogenicity of', 'CPA', (71, 88))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('inhibiting', 'Var', (39, 49))	('cancer', 'Disease', (89, 95))	('increases', 'PosReg', (57, 66))	('CDK4/6', 'Gene', '1019;1021', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
104763	31575731	It is therefore possible that the antitumor effects we observed with CDK4/6 inhibitors would have been greater in immunocompetent hosts, including people.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('CDK', 'molecular_function', 'GO:0004693', ('69', '72'))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('CDK4/6', 'Gene', '1019;1021', (69, 75))	('inhibitors', 'Var', (76, 86))	('people', 'Species', '9606', (147, 153))	('CDK4/6', 'Gene', (69, 75))
104798	31575731	The pLenti-CDK6-D104S lentiviral vector was made by Gateway cloning the pDONR223-CDK6-D104S entry clone (a gift from N. Persky, Broad Institute) into the pLenti-EF1alpha-gate-3HA-PGK-Puromycin destination vector (a gift from G. Lu, Kaelin Laboratory alumnus) as described above.	('pDONR223-CDK6-D104S', 'Var', (72, 91))	('3HA-PGK-Puromycin', 'Chemical', '-', (175, 192))	('D104S', 'Mutation', 'p.D104S', (16, 21))	('EF1alpha', 'Gene', '1917', (161, 169))	('CDK', 'molecular_function', 'GO:0004693', ('11', '14'))	('CDK', 'molecular_function', 'GO:0004693', ('81', '84'))	('PGK', 'molecular_function', 'GO:0004618', ('179', '182'))	('EF1alpha', 'Gene', (161, 169))	('D104S', 'Mutation', 'p.D104S', (86, 91))
104844	31575731	Cells were infected with a pLX304-EV-IRES-GFP (EV-GFP), pLX304-VHL-IRES-Tdtomato (VHL-Tdtomato), or pLX304-VHLDeltaB-IRES-Tdtomato (VHLDeltaB-Tdtomato) lentivirus as indicated, followed by selection for antibiotic resistance with blasticidin (10 mug/ml).	('pLX304-VHLDeltaB-IRES-Tdtomato', 'Var', (100, 130))	('tomato', 'Species', '4081', (74, 80))	('tomato', 'Species', '4081', (144, 150))	('mug', 'molecular_function', 'GO:0043739', ('246', '249'))	('infected', 'Disease', 'MESH:D007239', (11, 19))	('blasticidin', 'Chemical', 'MESH:C004500', (230, 241))	('EV', 'Chemical', '-', (47, 49))	('EV', 'Chemical', '-', (34, 36))	('pLX304-VHL-IRES-Tdtomato', 'Var', (56, 80))	('tomato', 'Species', '4081', (124, 130))	('infected', 'Disease', (11, 19))	('tomato', 'Species', '4081', (88, 94))
104874	31575731	Once the tumors showed at least two consecutive weeks of growth, the mice were randomized to receive abemaciclib (60 mg/kg), palbociclib (65 mg/kg), PT2399 (20 mg/kg), the combination of palbociclib (65 mg/kg) and PT2399 (20 mg/kg), or the corresponding vehicle(s), all by oral gavage daily for 28 days.	('PT2399', 'Var', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('PT2399', 'Chemical', 'MESH:C000614278', (149, 155))	('palbociclib', 'Chemical', 'MESH:C500026', (187, 198))	('PT2399', 'Chemical', 'MESH:C000614278', (214, 220))	('mice', 'Species', '10090', (69, 73))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('palbociclib', 'Chemical', 'MESH:C500026', (125, 136))	('abemaciclib', 'Chemical', 'MESH:C000590451', (101, 112))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
104920	29209141	In order to explore the potential mechanism of how module genes impact correlative clinical feature, we uploaded all genes in blue module into the DAVID database and performed GO functional enrichment analysis.	('genes', 'Var', (58, 63))	('clinical', 'Species', '191496', (83, 91))	('impact', 'Reg', (64, 70))
104982	28435451	Meanwhile, knockdown of AHNAK2 impaired the cell oncologic-metabolism by inhibiting lipid synthesis.	('AHNAK2', 'Gene', (24, 30))	('metabolism', 'biological_process', 'GO:0008152', ('59', '69'))	('lipid synthesis', 'biological_process', 'GO:0008610', ('84', '99'))	('lipid synthesis', 'MPA', (84, 99))	('cell oncologic-metabolism', 'MPA', (44, 69))	('inhibiting', 'NegReg', (73, 83))	('impaired', 'NegReg', (31, 39))	('lipid', 'Chemical', 'MESH:D008055', (84, 89))	('knockdown', 'Var', (11, 20))
104990	28435451	In most ccRCCs, loss of von Hippel-Lindau and dysregulated hypoxia signaling leads to the activation of a wide variety of genes.	('activation', 'PosReg', (90, 100))	('dysregulated hypoxia', 'Disease', (46, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (8, 13))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (24, 41))	('loss', 'Var', (16, 20))	('dysregulated hypoxia', 'Disease', 'MESH:D000860', (46, 66))	('RCC', 'Disease', (10, 13))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))	('von Hippel-Lindau', 'Disease', (24, 41))	('RCC', 'Disease', 'MESH:C538614', (10, 13))
105008	28435451	Human AHNAK2 promoter (from -2131bp to +88bp) was generated by polymerase chain reaction and cloned into pGL4.17 vector.	('Human', 'Species', '9606', (0, 5))	('pGL4', 'Gene', '6390', (105, 109))	('from -2131bp', 'Var', (23, 35))	('pGL4', 'Gene', (105, 109))	('pGL', 'molecular_function', 'GO:0004598', ('105', '108'))
105016	28435451	The following antibodies were used for immunofluorescence: antibodies against AHNAK2 (1:200, SIGMA, HPA000878), and HIF1alpha (1:100, GeneTex, GTX127309).	('HIF1alpha', 'Gene', '3091', (116, 125))	('AHNAK2', 'Gene', (78, 84))	('HIF1alpha', 'Gene', (116, 125))	('1:200', 'Var', (86, 91))
105035	28435451	Gene set enrichment analysis (GSEA; http://www.broad.mit.edu/gsea) was performed to identify gene sets changed by high AHNAK2 expression vs. low AHNAK2 expression from the public TCGA dataset.	('GSEA', 'Chemical', '-', (30, 34))	('high', 'Var', (114, 118))	('expression', 'MPA', (126, 136))	('AHNAK2', 'Gene', (119, 125))
105056	28435451	Cell proliferation was suppressed significantly by knockdown of AHNAK2 in CAKI-1 cells (p < 0.001; Figure 3C).	('AHNAK2', 'Gene', (64, 70))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('CAKI-1', 'CellLine', 'CVCL:0234', (74, 80))	('suppressed', 'NegReg', (23, 33))	('Cell proliferation', 'CPA', (0, 18))	('knockdown', 'Var', (51, 60))
105057	28435451	Moreover, CAKI-1 cells stably expressing AHNAK2 shRNA had a marked lower number of colonies compared to control shRNA-transfected cells (Figure 3D).	('CAKI-1', 'CellLine', 'CVCL:0234', (10, 16))	('lower', 'NegReg', (67, 72))	('AHNAK2', 'Var', (41, 47))
105059	28435451	These in vitro data were consistent with our finding that increased AHNAK2 is associated with a higher occurrence of human ccRCC metastasis in patients.	('human', 'Species', '9606', (117, 122))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('AHNAK2', 'Gene', (68, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('patients', 'Species', '9606', (143, 151))	('increased', 'Var', (58, 67))
105061	28435451	We found that knockdown of AHNAK2 significantly inhibited tumor growth in nude mice (Figure 3H).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('nude mice', 'Species', '10090', (74, 83))	('AHNAK2', 'Gene', (27, 33))	('inhibited', 'NegReg', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('knockdown', 'Var', (14, 23))
105062	28435451	Tumor volume and tumor weight were significantly decreased in the xenografts derived from AHNAK2 knockdown cells compared to the control cells (Figure 3I, 3J).	('Tumor volume', 'CPA', (0, 12))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('knockdown', 'Var', (97, 106))	('tumor', 'Disease', (17, 22))	('decreased', 'NegReg', (49, 58))	('AHNAK2', 'Gene', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
105071	28435451	A smaller quantity of lipid droplets were detected in CAKI-1 cells with AHNAK2 knockdown than in control cells, as measured by quantitative Oil-Red O staining (Figure 4E, 4F).	('CAKI-1', 'CellLine', 'CVCL:0234', (54, 60))	('Oil-Red O', 'Chemical', 'MESH:C011049', (140, 149))	('AHNAK2', 'Gene', (72, 78))	('knockdown', 'Var', (79, 88))	('lipid', 'Chemical', 'MESH:D008055', (22, 27))
105072	28435451	These data suggest that AHNAK2 knockdown impairs cell oncologic-metabolism by inhibiting the lipid synthesis.	('lipid synthesis', 'MPA', (93, 108))	('cell oncologic-metabolism', 'MPA', (49, 74))	('lipid synthesis', 'biological_process', 'GO:0008610', ('93', '108'))	('AHNAK2', 'Gene', (24, 30))	('inhibiting', 'NegReg', (78, 88))	('lipid', 'Chemical', 'MESH:D008055', (93, 98))	('impairs', 'NegReg', (41, 48))	('metabolism', 'biological_process', 'GO:0008152', ('64', '74'))	('knockdown', 'Var', (31, 40))
105081	28435451	In contrast, knockdown of HIF1alpha decreased significantly hypoxia-induced expression of AHNAK2 at both the mRNA and protein levels (Figure 5C, 5E), while knockdown of HIF2alpha cannot (Figure 5D).	('HIF1alpha', 'Gene', (26, 35))	('hypoxia', 'Disease', (60, 67))	('HIF2alpha', 'Gene', (169, 178))	('hypoxia', 'Disease', 'MESH:D000860', (60, 67))	('HIF1alpha', 'Gene', '3091', (26, 35))	('AHNAK2', 'Gene', (90, 96))	('HIF2alpha', 'Gene', '2034', (169, 178))	('knockdown', 'Var', (13, 22))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))	('decreased', 'NegReg', (36, 45))
105088	28435451	Deletion of HRE1 area (the AP20 vs. the AP18) nearly abolished the transactivation of AHNAK2 promoter by hypoxia (Figure 6E).	('AHNAK2 promoter', 'Gene', (86, 101))	('transactivation', 'biological_process', 'GO:2000144', ('67', '82'))	('hypoxia', 'Disease', (105, 112))	('hypoxia', 'Disease', 'MESH:D000860', (105, 112))	('HRE1 area', 'Gene', (12, 21))	('transactivation', 'MPA', (67, 82))	('abolished', 'NegReg', (53, 62))	('Deletion', 'Var', (0, 8))
105093	28435451	To understand the role of AHNAK2 in hypoxia-induced EMT, we knocked down AHNAK2 in HIF1alpha overexpressing CAKI-1 cells.	('hypoxia', 'Disease', 'MESH:D000860', (36, 43))	('knocked down', 'Var', (60, 72))	('hypoxia', 'Disease', (36, 43))	('HIF1alpha', 'Gene', (83, 92))	('EMT', 'biological_process', 'GO:0001837', ('52', '55'))	('AHNAK2', 'Gene', (73, 79))	('HIF1alpha', 'Gene', '3091', (83, 92))	('CAKI-1', 'CellLine', 'CVCL:0234', (108, 114))
105094	28435451	AHNAK2 knockdown at least partially reversed the transition to a dispersed, fusiform morphology induced by HIF1alpha under hypoxia (Figure 7B).	('hypoxia', 'Disease', 'MESH:D000860', (123, 130))	('AHNAK2', 'Gene', (0, 6))	('hypoxia', 'Disease', (123, 130))	('HIF1alpha', 'Gene', (107, 116))	('knockdown', 'Var', (7, 16))	('HIF1alpha', 'Gene', '3091', (107, 116))
105095	28435451	Meanwhile, AHNAK2 knockdown inhibited the upregulation of the EMT markers vimentin, beta-catenin, and the stem cell markers OCT-4, and Nanog by HIF1alpha (Figure 7C, 7D).	('Nanog', 'Gene', (135, 140))	('vimentin', 'Gene', '7431', (74, 82))	('inhibited', 'NegReg', (28, 37))	('vimentin', 'cellular_component', 'GO:0045098', ('74', '82'))	('vimentin', 'Gene', (74, 82))	('OCT-4', 'Gene', '5460', (124, 129))	('stem cell', 'CPA', (106, 115))	('EMT', 'biological_process', 'GO:0001837', ('62', '65'))	('AHNAK2', 'Gene', (11, 17))	('HIF1alpha', 'Gene', '3091', (144, 153))	('knockdown', 'Var', (18, 27))	('OCT-4', 'Gene', (124, 129))	('HIF1alpha', 'Gene', (144, 153))	('vimentin', 'cellular_component', 'GO:0045099', ('74', '82'))	('beta-catenin', 'Gene', (84, 96))	('beta-catenin', 'Gene', '1499', (84, 96))	('EMT', 'CPA', (62, 65))	('Nanog', 'Gene', '79923', (135, 140))	('upregulation', 'PosReg', (42, 54))
105096	28435451	Furthermore, we found that AHNAK2 knockdown reversed the stimulative effect of hypoxia on CAKI-1 cells migration, a phenotype of EMT (p < 0.001; Figure 7E, 7F).	('CAKI-1 cells migration', 'CPA', (90, 112))	('AHNAK2', 'Gene', (27, 33))	('EMT', 'biological_process', 'GO:0001837', ('129', '132'))	('hypoxia', 'Disease', 'MESH:D000860', (79, 86))	('hypoxia', 'Disease', (79, 86))	('knockdown', 'Var', (34, 43))	('CAKI-1', 'CellLine', 'CVCL:0234', (90, 96))
105105	28435451	Further, knockdown of AHNAK2 can inhibits the fatty acid and lipid synthesis, the processes vital for cancer energy maintenance and cellular nutrient, suggesting that the oncogenic effects of AHNAK2 might be achieved by changing cell oncologic-metabolism.	('AHNAK2', 'Gene', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('knockdown', 'Var', (9, 18))	('fatty acid', 'Chemical', 'MESH:D005227', (46, 56))	('lipid synthesis', 'biological_process', 'GO:0008610', ('61', '76'))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('inhibits', 'NegReg', (33, 41))	('metabolism', 'biological_process', 'GO:0008152', ('244', '254'))	('lipid', 'Chemical', 'MESH:D008055', (61, 66))
105113	28435451	HIF1alpha regulates AHNAK2 promoter activity based on loss-of-function analysis by knockdown of HIF1alpha or deletion of hypoxia response elements of the AHNAK2 promoter.	('AHNAK2 promoter', 'Gene', (20, 35))	('deletion', 'Var', (109, 117))	('HIF1alpha', 'Gene', (0, 9))	('hypoxia', 'Disease', 'MESH:D000860', (121, 128))	('activity', 'MPA', (36, 44))	('HIF1alpha', 'Gene', '3091', (0, 9))	('HIF1alpha', 'Gene', (96, 105))	('HIF1alpha', 'Gene', '3091', (96, 105))	('loss-of-function', 'NegReg', (54, 70))	('hypoxia', 'Disease', (121, 128))
105114	28435451	Third, the motifs of HIF1alpha, MUT2 (-1920 bp, -1915 bp) and MUT3 (-1894 bp, -1889 bp), appear to be responsible for the transcriptional activity of AHNAK2 based on site-directed mutagenesis analysis.	('transcriptional activity', 'MPA', (122, 146))	('-1894 bp', 'Var', (68, 76))	('AHNAK2', 'Gene', (150, 156))	('MUT3', 'Gene', (62, 66))	('HIF1alpha', 'Gene', (21, 30))	('responsible', 'Reg', (102, 113))	('HIF1alpha', 'Gene', '3091', (21, 30))	('mutagenesis', 'biological_process', 'GO:0006280', ('180', '191'))	('-1920 bp', 'Var', (38, 46))
105128	28435451	Our observations that knockdown of AHNAK2 partially reverses the EMT phenotype including EMT gene expression, cell morphology and stem cell properties support the notion that AHNAK2 acts downstream of the hypoxia and HIF1alpha axis, affecting hypoxia-induced EMT and stem cell properties.	('AHNAK2', 'Gene', (175, 181))	('hypoxia', 'Disease', (243, 250))	('hypoxia', 'Disease', 'MESH:D000860', (243, 250))	('gene expression', 'biological_process', 'GO:0010467', ('93', '108'))	('reverses', 'NegReg', (52, 60))	('affecting', 'Reg', (233, 242))	('HIF1alpha', 'Gene', (217, 226))	('knockdown', 'Var', (22, 31))	('hypoxia', 'Disease', 'MESH:D000860', (205, 212))	('HIF1alpha', 'Gene', '3091', (217, 226))	('AHNAK2', 'Gene', (35, 41))	('EMT gene', 'Gene', (89, 97))	('EMT', 'biological_process', 'GO:0001837', ('259', '262'))	('EMT', 'biological_process', 'GO:0001837', ('65', '68'))	('EMT', 'biological_process', 'GO:0001837', ('89', '92'))	('hypoxia', 'Disease', (205, 212))
105137	27732931	Multivariate Cox proportional hazards regression analyses showed that positive Dicer expression was an independent favorable factor for prognosis of ccRCC patients (hazard ratio (HR) = 0.709, P = 0.025 for 5-year overall survival; HR = 0.655, P = 0.008 for disease specific survival).	('Cox', 'Gene', (13, 16))	('positive', 'Var', (70, 78))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('patients', 'Species', '9606', (155, 163))	('RCC', 'Disease', (151, 154))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('Dicer', 'Gene', '23405', (79, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (149, 154))	('Dicer', 'Gene', (79, 84))	('Cox', 'Gene', '1351', (13, 16))
105139	27732931	Tumor metastasis model in vivo showed much more metastatic nodules of lung in the Dicer knockdown group than the control group via increased MMP-2 expression.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('more', 'PosReg', (43, 47))	('MMP-2', 'Gene', (141, 146))	('knockdown', 'Var', (88, 97))	('Dicer', 'Gene', '23405', (82, 87))	('MMP-2', 'molecular_function', 'GO:0004228', ('141', '146'))	('Dicer', 'Gene', (82, 87))	('metastatic nodules of lung', 'CPA', (48, 74))	('MMP-2', 'Gene', '4313', (141, 146))
105163	27732931	Our results demonstrated that ccRCC patients with positive Dicer expression had more favorable 5-year overall survival and disease specific survival than the ones with negative Dicer expression (P = 0.020 and P = 0.004, respectively; Figure 1D-1E).	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('patients', 'Species', '9606', (36, 44))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('Dicer', 'Gene', '23405', (177, 182))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('disease specific survival', 'CPA', (123, 148))	('Dicer', 'Gene', (177, 182))	('Dicer', 'Gene', '23405', (59, 64))	('overall survival', 'CPA', (102, 118))	('Dicer', 'Gene', (59, 64))	('positive', 'Var', (50, 58))
105166	27732931	The multivariate COX regression analysis further showed that positive Dicer expression was an independent favorable prognostic factor for 5-year overall survival and disease specific survival of ccRCC patients after adjusting with classical factors, such as age, tumor size and TNM stage (HR = 0.709, 95% CI = 0.525 to 0.957, P = 0.025 for 5-year overall survival; HR = 0.655, 95% CI = 0.479 to 0.896, P = 0.008 for disease-free survival; Table 3).	('patients', 'Species', '9606', (201, 209))	('Dicer', 'Gene', '23405', (70, 75))	('Dicer', 'Gene', (70, 75))	('COX', 'Gene', (17, 20))	('positive', 'Var', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('TNM', 'Gene', '10178', (278, 281))	('RCC', 'Phenotype', 'HP:0005584', (197, 200))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('RCC', 'Disease', 'MESH:C538614', (197, 200))	('ccRCC', 'Phenotype', 'HP:0006770', (195, 200))	('RCC', 'Disease', (197, 200))	('tumor', 'Disease', (263, 268))	('TNM', 'Gene', (278, 281))	('COX', 'Gene', '1351', (17, 20))
105173	27732931	The growths of HUVECs were significantly accelerated in the conditioned medium from Dicer knocked down 786-O and ACHN cells while significantly slowed in the conditioned medium form Dicer over-expression 786-O and ACHN cells compared with the corresponding controls (Figure 4A).	('ACHN', 'Gene', '55323', (214, 218))	('Dicer', 'Gene', '23405', (84, 89))	('Dicer', 'Gene', (84, 89))	('slowed', 'NegReg', (144, 150))	('ACHN', 'Gene', (113, 117))	('ACHN', 'Gene', (214, 218))	('ACHN', 'Gene', '55323', (113, 117))	('growths of HUVECs', 'CPA', (4, 21))	('accelerated', 'PosReg', (41, 52))	('knocked down', 'Var', (90, 102))	('Dicer', 'Gene', '23405', (182, 187))	('Dicer', 'Gene', (182, 187))
105174	27732931	Moreover, the average number of complete tubular structures formed by HUVECs was significantly increased in conditioned medium from Dicer knocked down 786-O and ACHN cells but decreased in that from Dicer over-expression 786-O and ACHN cells when compared with the corresponding controls, respectively (Figure 4B-4C).	('ACHN', 'Gene', '55323', (231, 235))	('ACHN', 'Gene', (231, 235))	('Dicer', 'Gene', '23405', (132, 137))	('Dicer', 'Gene', (132, 137))	('decreased', 'NegReg', (176, 185))	('ACHN', 'Gene', '55323', (161, 165))	('ACHN', 'Gene', (161, 165))	('Dicer', 'Gene', '23405', (199, 204))	('Dicer', 'Gene', (199, 204))	('knocked', 'Var', (138, 145))	('increased', 'PosReg', (95, 104))
105177	27732931	The transwell assays showed that the increased abilities of cell migration and invasion in Dicer knockdown 786-O and ACHN cells could be significantly inhibited by Dicer over-expression (Figure 5B-5D).	('cell migration', 'CPA', (60, 74))	('knockdown', 'Var', (97, 106))	('ACHN', 'Gene', (117, 121))	('cell migration', 'biological_process', 'GO:0016477', ('60', '74'))	('Dicer', 'Gene', '23405', (91, 96))	('Dicer', 'Gene', (91, 96))	('inhibited', 'NegReg', (151, 160))	('over-expression', 'PosReg', (170, 185))	('increased', 'PosReg', (37, 46))	('ACHN', 'Gene', '55323', (117, 121))	('invasion', 'CPA', (79, 87))	('Dicer', 'Gene', '23405', (164, 169))	('Dicer', 'Gene', (164, 169))
105178	27732931	Moreover, the elevated tubular structure formations in the conditioned medium collected from Dicer knockdown 786-O and ACHN cells were significantly abrogated in that form Dicer over-expression (Figure 5E-5F).	('Dicer', 'Gene', (172, 177))	('over-expression', 'PosReg', (178, 193))	('Dicer', 'Gene', (93, 98))	('ACHN', 'Gene', '55323', (119, 123))	('abrogated', 'NegReg', (149, 158))	('knockdown', 'Var', (99, 108))	('ACHN', 'Gene', (119, 123))	('tubular structure formations', 'CPA', (23, 51))	('elevated', 'PosReg', (14, 22))	('Dicer', 'Gene', '23405', (93, 98))	('Dicer', 'Gene', '23405', (172, 177))
105181	27732931	Our data showed that Dicer knockdown significantly stimulated while Dicer over-expression significantly suppressed MMP-2 protein expression, but not the expressions of MMP-9, TIMP-1 and TIMP-2 in 786-O and ACHN cells compared with the respective controls (Figure 6A-6B).	('suppressed', 'NegReg', (104, 114))	('MMP-9', 'molecular_function', 'GO:0004229', ('168', '173'))	('MMP-2', 'Gene', '4313', (115, 120))	('over-expression', 'PosReg', (74, 89))	('Dicer', 'Gene', '23405', (21, 26))	('ACHN', 'Gene', (206, 210))	('stimulated', 'PosReg', (51, 61))	('Dicer', 'Gene', (21, 26))	('TIMP-2', 'Gene', '7077', (186, 192))	('knockdown', 'Var', (27, 36))	('MMP-2', 'Gene', (115, 120))	('TIMP-2', 'Gene', (186, 192))	('Dicer', 'Gene', '23405', (68, 73))	('Dicer', 'Gene', (68, 73))	('MMP-9', 'Gene', '4318', (168, 173))	('MMP-2', 'molecular_function', 'GO:0004228', ('115', '120'))	('MMP-9', 'Gene', (168, 173))	('ACHN', 'Gene', '55323', (206, 210))	('TIMP-1', 'Gene', (175, 181))	('TIMP-1', 'Gene', '7076', (175, 181))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))
105183	27732931	Our results indicated that MMP-2 activity was significantly increased by Dicer knockdown in 786-O and ACHN cells compared with the respective controls (Figure 6C-6D).	('ACHN', 'Gene', '55323', (102, 106))	('MMP-2', 'Gene', (27, 32))	('Dicer', 'Gene', '23405', (73, 78))	('Dicer', 'Gene', (73, 78))	('MMP-2', 'Gene', '4313', (27, 32))	('activity', 'MPA', (33, 41))	('MMP-2', 'molecular_function', 'GO:0004228', ('27', '32'))	('ACHN', 'Gene', (102, 106))	('knockdown', 'Var', (79, 88))	('increased', 'PosReg', (60, 69))
105192	27732931	Our data exhibited that tumor cells mainly metastasized into lungs and the Fluc activity in Dicer knockdown group appeared significantly higher than the control group (Figure 8A-8B).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('Fluc activity', 'MPA', (75, 88))	('knockdown', 'Var', (98, 107))	('higher', 'PosReg', (137, 143))	('Dicer', 'Gene', '23405', (92, 97))	('Dicer', 'Gene', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
105194	27732931	Our data showed that lungs were infiltrated with the poorly differentiated neoplastic cells, and the number of micrometastases in the Dicer knockdown group was much more than the control (Figure 8C-8D).	('more', 'PosReg', (165, 169))	('metastases', 'Disease', (116, 126))	('Dicer', 'Gene', '23405', (134, 139))	('Dicer', 'Gene', (134, 139))	('metastases', 'Disease', 'MESH:D009362', (116, 126))	('knockdown', 'Var', (140, 149))
105196	27732931	The results revealed that Dicer expressions were significantly reduced, whereas MMP-2 expressions were significantly up-regulated in the knockdown group when compared with the controls (Figure 8E-8F).	('MMP-2', 'Gene', '4313', (80, 85))	('reduced', 'NegReg', (63, 70))	('up-regulated', 'PosReg', (117, 129))	('MMP-2', 'molecular_function', 'GO:0004228', ('80', '85'))	('Dicer', 'Gene', '23405', (26, 31))	('expressions', 'MPA', (86, 97))	('knockdown', 'Var', (137, 146))	('MMP-2', 'Gene', (80, 85))	('Dicer', 'Gene', (26, 31))
105201	27732931	Furthermore, ccRCC patients with positive Dicer expression had a favorable survival, and Cox proportional hazards regression analyses showed that positive Dicer expression was an independent protective factor for prognosis of ccRCC patients.	('Cox', 'Gene', '1351', (89, 92))	('Cox', 'Gene', (89, 92))	('Dicer', 'Gene', '23405', (155, 160))	('patients', 'Species', '9606', (19, 27))	('Dicer', 'Gene', (155, 160))	('RCC', 'Disease', 'MESH:C538614', (228, 231))	('patients', 'Species', '9606', (232, 240))	('RCC', 'Disease', (228, 231))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('RCC', 'Phenotype', 'HP:0005584', (228, 231))	('RCC', 'Disease', (15, 18))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (226, 231))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('positive', 'Var', (146, 154))	('Dicer', 'Gene', '23405', (42, 47))	('Dicer', 'Gene', (42, 47))	('positive', 'Var', (33, 41))
105240	27732931	1 x 106 stable Dicer knockdown and control ccRCC cells suspended by 2 ml fresh serum-free medium were cultured in 60-mm plates for 24 hours, and then conditioned medium was collected.	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('Dicer', 'Gene', '23405', (15, 20))	('Dicer', 'Gene', (15, 20))	('knockdown', 'Var', (21, 30))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
105242	27732931	1 x 106 stable Dicer knockdown and control ccRCC cells were seeded in 60-mm plate for 24 hours, and 2 ml conditioned medium was collected and concentrated with Amicon Ultra-4-30k centrifugal filters (Millipore, USA) at 4 C. Then, the standard protocol was used as described previously.	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('Dicer', 'Gene', '23405', (15, 20))	('Dicer', 'Gene', (15, 20))	('knockdown', 'Var', (21, 30))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
105243	27732931	1 x 106 stable Dicer knockdown and control ccRCC cells were seeded in 60-mm plate for 24 hours, and 2ml conditioned medium was collected.	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('Dicer', 'Gene', '23405', (15, 20))	('Dicer', 'Gene', (15, 20))	('knockdown', 'Var', (21, 30))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
105259	30836712	In addition, a significant correlation between ghrelin and Aurora A expression level in 15 ccRCC cell line was confirmed by variant probes.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('RCC', 'Disease', (93, 96))	('Aurora A', 'Gene', '6790', (59, 67))	('ghrelin', 'Protein', (47, 54))	('Aurora A', 'Gene', (59, 67))	('ghrelin', 'Chemical', 'MESH:D054439', (47, 54))	('variant', 'Var', (124, 131))
105260	30836712	ccRCC patients with high ghrelin and Aurora A status were clinically associated with poor outcome.	('Aurora A', 'Gene', (37, 45))	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('ghrelin', 'Protein', (25, 32))	('high', 'Var', (20, 24))	('patients', 'Species', '9606', (6, 14))	('Aurora A', 'Gene', '6790', (37, 45))	('ghrelin', 'Chemical', 'MESH:D054439', (25, 32))
105271	30836712	In addition, ghrelin expression in RCC patients was associated with poor outcomes and with lymph node and distant metastasis.	('RCC', 'Disease', (35, 38))	('patients', 'Species', '9606', (39, 47))	('poor outcomes', 'CPA', (68, 81))	('associated', 'Reg', (52, 62))	('ghrelin', 'Protein', (13, 20))	('expression', 'Var', (21, 31))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('ghrelin', 'Chemical', 'MESH:D054439', (13, 20))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
105289	30836712	The results revealed the association of high ghrelin expression with cancer and cellular movement (ranked top 1, Figure 1B,C).	('high', 'Var', (40, 44))	('ghrelin', 'Chemical', 'MESH:D054439', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ghrelin', 'Protein', (45, 52))	('cellular movement', 'CPA', (80, 97))	('expression', 'MPA', (53, 63))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
105290	30836712	Furthermore, Aurora A was one of upregulated targets identified in high ghrelin group.	('upregulated', 'PosReg', (33, 44))	('high', 'Var', (67, 71))	('Aurora A', 'Gene', (13, 21))	('Aurora A', 'Gene', '6790', (13, 21))	('ghrelin', 'Chemical', 'MESH:D054439', (72, 79))
105293	30836712	In addition, Aurora A's interactive network had also been explored based on clinical data that MMP2 and VEGF were also increased in high ghrelin group (Figure 1D), indicating the potential value of studying ghrelin-Aurora A axis in RCC.	('MMP2', 'Gene', (95, 99))	('Aurora A', 'Gene', (215, 223))	('VEGF', 'Gene', (104, 108))	('RCC', 'Phenotype', 'HP:0005584', (232, 235))	('RCC', 'Disease', 'MESH:C538614', (232, 235))	('VEGF', 'Gene', '7422', (104, 108))	('RCC', 'Disease', (232, 235))	('Aurora A', 'Gene', (13, 21))	('ghrelin', 'Chemical', 'MESH:D054439', (207, 214))	('MMP2', 'Gene', '4313', (95, 99))	('Aurora A', 'Gene', '6790', (215, 223))	('MMP2', 'molecular_function', 'GO:0004228', ('95', '99'))	('ghrelin', 'Chemical', 'MESH:D054439', (137, 144))	('Aurora A', 'Gene', '6790', (13, 21))	('increased', 'PosReg', (119, 128))	('high ghrelin', 'Var', (132, 144))
105295	30836712	The Kaplan-Meier plot showed the correlation of high Aurora A expression with poor overall survival (p = 0.001, Figure 2A).	('Aurora A', 'Gene', '6790', (53, 61))	('high', 'Var', (48, 52))	('overall survival', 'CPA', (83, 99))	('Aurora A', 'Gene', (53, 61))
105302	30836712	Among ccRCC cell lines in CCLE dataset, the analysis was performed using variant Aurora A probes, and a positive correlation with rho = 0.715 and 0.784 was observed respectively by each Aurora A probe (Figure 3A,B).	('Aurora A', 'Gene', (186, 194))	('RCC', 'Disease', (8, 11))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('CCLE', 'Chemical', '-', (26, 30))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('Aurora A', 'Gene', (81, 89))	('ccRCC', 'Phenotype', 'HP:0006770', (6, 11))	('Aurora A', 'Gene', '6790', (186, 194))	('variant', 'Var', (73, 80))	('Aurora A', 'Gene', '6790', (81, 89))
105306	30836712	In the results, ghrelin ectopic overexpression elicited Aurora A upregulation at RNA level, respectively in clone 1 and clone 2 (Figure 4A) and ACHN cells (Figure 4B).	('ghrelin', 'Chemical', 'MESH:D054439', (16, 23))	('Aurora A', 'Gene', '6790', (56, 64))	('ACHN', 'Chemical', '-', (144, 148))	('ectopic', 'Var', (24, 31))	('upregulation', 'PosReg', (65, 77))	('ghrelin', 'Protein', (16, 23))	('Aurora A', 'Gene', (56, 64))	('RNA', 'cellular_component', 'GO:0005562', ('81', '84'))
105312	30836712	Aurora A silencing resulted in the reduction of cell invasion compared with the ghrelin treatment (Figure 5C).	('Aurora A', 'Gene', '6790', (0, 8))	('silencing', 'Var', (9, 18))	('ghrelin', 'Chemical', 'MESH:D054439', (80, 87))	('cell invasion', 'CPA', (48, 61))	('Aurora A', 'Gene', (0, 8))	('reduction', 'NegReg', (35, 44))
105319	30836712	The high level of MMP10 in renal cancer patients was found to be associated with poor survival (p = 0.000284, Figure 6A).	('renal cancer', 'Disease', (27, 39))	('high level', 'Var', (4, 14))	('MMP10', 'molecular_function', 'GO:0030303', ('18', '23'))	('renal cancer', 'Phenotype', 'HP:0009726', (27, 39))	('patients', 'Species', '9606', (40, 48))	('renal cancer', 'Disease', 'MESH:D007680', (27, 39))	('poor', 'NegReg', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('MMP10', 'Gene', (18, 23))	('MMP10', 'Gene', '4319', (18, 23))
105320	30836712	In addition, MMP10 upregulation was reduced after Aurora A silencing in ACHN cells (Figure 6B).	('Aurora A', 'Gene', (50, 58))	('MMP10', 'Gene', (13, 18))	('upregulation', 'PosReg', (19, 31))	('MMP10', 'Gene', '4319', (13, 18))	('reduced', 'NegReg', (36, 43))	('MMP10', 'molecular_function', 'GO:0030303', ('13', '18'))	('Aurora A', 'Gene', '6790', (50, 58))	('silencing', 'Var', (59, 68))	('ACHN', 'Chemical', '-', (72, 76))
105322	30836712	The ghrelin receptor, GHS-R1a, was relatively silenced by specific shRNAs (clone sh2 and sh3), and knockdown of GHS-R1a blocked the signaling axis elicited by ghrelin overexpression (Figure 6D).	('ghrelin receptor', 'Gene', '2693', (4, 20))	('ghrelin', 'Chemical', 'MESH:D054439', (4, 11))	('GHS-R', 'Gene', (22, 27))	('ghrelin', 'Chemical', 'MESH:D054439', (159, 166))	('GHS-R', 'Gene', (112, 117))	('GHS-R', 'Gene', '2693', (22, 27))	('GHS-R', 'Gene', '2693', (112, 117))	('ghrelin receptor', 'Gene', (4, 20))	('blocked', 'NegReg', (120, 127))	('signaling axis', 'MPA', (132, 146))	('signaling', 'biological_process', 'GO:0023052', ('132', '141'))	('knockdown', 'Var', (99, 108))
105345	30836712	The BORA level was also increased in high ghrelin group suggesting a potential role of ghrelin in activating Aurora A in RCC.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('ghrelin', 'Chemical', 'MESH:D054439', (42, 49))	('Aurora A', 'Gene', (109, 117))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('ghrelin', 'Chemical', 'MESH:D054439', (87, 94))	('high ghrelin', 'Var', (37, 49))	('BORA', 'Gene', (4, 8))	('Aurora A', 'Gene', '6790', (109, 117))	('activating', 'MPA', (98, 108))	('increased', 'PosReg', (24, 33))	('BORA', 'Gene', '79866', (4, 8))
105352	30836712	A study in colorectal cancer revealed that the pretreatment of antagonist D(Lys-3)-GHRP-6 inhibited ghrelin-mediated ghrelin receptor function and cell migration ability.	('rat', 'Species', '10116', (155, 158))	('colorectal cancer', 'Disease', 'MESH:D015179', (11, 28))	('ghrelin receptor', 'Gene', '2693', (117, 133))	('function', 'MPA', (134, 142))	('ghrelin', 'Chemical', 'MESH:D054439', (117, 124))	('Lys-3)-GHRP', 'Chemical', '-', (76, 87))	('ghrelin', 'Chemical', 'MESH:D054439', (100, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (11, 28))	('ghrelin receptor', 'Gene', (117, 133))	('colorectal cancer', 'Disease', (11, 28))	('ghrelin-mediated', 'Protein', (100, 116))	('cell migration ability', 'CPA', (147, 169))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('inhibited', 'NegReg', (90, 99))	('cell migration', 'biological_process', 'GO:0016477', ('147', '161'))	('D(Lys-3)-GHRP-6', 'Var', (74, 89))
105390	30836712	In addition, patients with high ghrelin and Aurora A status have poor outcomes.	('ghrelin', 'Protein', (32, 39))	('Aurora A', 'Gene', (44, 52))	('patients', 'Species', '9606', (13, 21))	('high', 'Var', (27, 31))	('ghrelin', 'Chemical', 'MESH:D054439', (32, 39))	('Aurora A', 'Gene', '6790', (44, 52))
105395	28222071	Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma: a multicentre, single-arm phase I/II clinical trial Class II histone deacetylase (HDAC) inhibitors induce hypoxia-inducible factor-1 and -2alpha degradation and have antitumour effects in combination with vascular endothelial growth factor (VEGF) inhibitors.	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (94, 125))	('patients', 'Species', '9606', (80, 88))	('vascular endothelial growth factor', 'Gene', '7422', (332, 366))	('histone deacetylase', 'Gene', (19, 38))	('induce', 'PosReg', (226, 232))	('VEGF', 'Gene', '7422', (368, 372))	('tumour', 'Phenotype', 'HP:0002664', (297, 303))	('HDAC', 'Gene', (209, 213))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('332', '366'))	('vascular endothelial growth factor', 'Gene', (332, 366))	('tumour', 'Disease', 'MESH:D009369', (297, 303))	('histone deacetylase', 'Gene', '9734', (188, 207))	('clear-cell renal cell carcinoma', 'Disease', (94, 125))	('VEGF', 'Gene', (368, 372))	('tumour', 'Disease', (297, 303))	('inhibitors', 'Var', (215, 225))	('vorinostat', 'Chemical', 'MESH:D000077337', (49, 59))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (105, 125))	('degradation', 'biological_process', 'GO:0009056', ('272', '283'))	('hypoxia-inducible factor-1 and -2alpha', 'Gene', '2034', (233, 271))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (94, 125))	('histone deacetylase', 'Gene', (188, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('histone deacetylase', 'Gene', '9734', (19, 38))	('bevacizumab', 'Chemical', 'MESH:D000068258', (65, 76))	('HDAC', 'Gene', '9734', (209, 213))
105406	28222071	The genetic and epigenetic silencing of the Von Hippel-Lindau gene and consequent stabilisation of the hypoxia-inducible factor-1 and -2alpha (HIF-1alpha and HIF-2alpha) are associated with the distinctive sensitivity of ccRCC to VEGF signalling pathway inhibitors.	('RCC', 'Disease', 'MESH:C538614', (223, 226))	('associated', 'Reg', (174, 184))	('RCC', 'Disease', (223, 226))	('VEGF', 'Gene', '7422', (230, 234))	('hypoxia-inducible factor-1 and -2alpha', 'Gene', '2034', (103, 141))	('Von Hippel-Lindau', 'Disease', 'MESH:D006623', (44, 61))	('signalling pathway', 'biological_process', 'GO:0007165', ('235', '253'))	('Von Hippel-Lindau', 'Disease', (44, 61))	('epigenetic silencing', 'Var', (16, 36))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (143, 168))	('VEGF', 'Gene', (230, 234))	('ccRCC', 'Phenotype', 'HP:0006770', (221, 226))
105411	28222071	Histone deacetylase (HDAC) inhibitors have been reported to have pleiotropic antiangiogenesis activity, including inhibition of HIFs.	('HDAC', 'Gene', '9734', (21, 25))	('inhibition', 'NegReg', (114, 124))	('Histone deacetylase', 'Gene', '9734', (0, 19))	('inhibitors', 'Var', (27, 37))	('Histone deacetylase', 'Gene', (0, 19))	('HIFs', 'CPA', (128, 132))	('antiangiogenesis activity', 'CPA', (77, 102))	('HDAC', 'Gene', (21, 25))
105435	28222071	Normal organ and marrow function was required, including leukocyte count >3000/mm3, absolute neutrophil count >1500/mm3, platelets >100 000/mm3, total bilirubin <1.5 x laboratory upper limit of normal, AST/ALT <=2.5 x laboratory upper limit of normal, creatinine <1.5 x laboratory upper limit of normal, or measured creatinine clearance of >50 ml min-1 per 1.73 m2, PT/INR <1.5, and urine protein <1+.	('ALT', 'molecular_function', 'GO:0004021', ('206', '209'))	('urine protein', 'MPA', (383, 396))	('AST', 'Gene', (202, 205))	('bilirubin', 'Chemical', 'MESH:D001663', (151, 160))	('AST', 'Gene', '26503', (202, 205))	('creatinine clearance', 'MPA', (316, 336))	('creatinine', 'Chemical', 'MESH:D003404', (316, 326))	('urine protein', 'Phenotype', 'HP:0000093', (383, 396))	('creatinine', 'MPA', (252, 262))	('protein', 'cellular_component', 'GO:0003675', ('389', '396'))	('>100 000/mm3', 'Var', (131, 143))	('creatinine', 'Chemical', 'MESH:D003404', (252, 262))
105534	28222071	The approval of axitinib has confirmed retrospective studies, suggesting that sequencing of TKIs can still induce disease control despite progression following front-line therapies with anti-VEGF therapies.	('VEGF', 'Gene', (191, 195))	('axitinib', 'Chemical', 'MESH:D000077784', (16, 24))	('induce', 'Reg', (107, 113))	('TKIs', 'Gene', (92, 96))	('VEGF', 'Gene', '7422', (191, 195))	('disease control', 'Disease', (114, 129))	('sequencing', 'Var', (78, 88))
105549	28222071	Our correlative studies suggest that modulation of chemokines may be associated with response to treatments targeting the HIF/VEGF axis.	('modulation', 'Var', (37, 47))	('VEGF', 'Gene', '7422', (126, 130))	('associated', 'Reg', (69, 79))	('VEGF', 'Gene', (126, 130))
105557	28222071	Recurrent mutations in histone methyltransferases and demethylases suggest that epigenetic changes driven by specific genetic alterations may represent new targets for therapeutic intervention in ccRCC.	('histone methyltransferases', 'Enzyme', (23, 49))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('ccRCC', 'Phenotype', 'HP:0006770', (196, 201))	('RCC', 'Disease', (198, 201))	('demethylases', 'Enzyme', (54, 66))	('mutations', 'Var', (10, 19))
105569	28222071	In our analysis, despite the small sample size, modulation of specific circulating microRNAs was associated with tumour response.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('modulation', 'Var', (48, 58))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('tumour', 'Disease', (113, 119))	('associated', 'Reg', (97, 107))
105577	28222071	Interestingly, miR-605 has been reported to cross-talk with p53, and phase I trial with vorinostat plus pazopanib has reported clinical benfit in patients with mutated p53 colon carcinoma and sarcoma.	('p53', 'Gene', '7157', (168, 171))	('mutated', 'Var', (160, 167))	('p53', 'Gene', (60, 63))	('colon carcinoma and sarcoma', 'Disease', 'MESH:D015179', (172, 199))	('vorinostat', 'Chemical', 'MESH:D000077337', (88, 98))	('pazopanib', 'Chemical', 'MESH:C516667', (104, 113))	('miR-605', 'Gene', (15, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('p53', 'Gene', '7157', (60, 63))	('miR-605', 'Gene', '693190', (15, 22))	('patients', 'Species', '9606', (146, 154))	('p53', 'Gene', (168, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (192, 199))
105581	28222071	Further analysis of patients responding to epigenetic therapies in the context of VEGF inhibition will identify the subset of ccRCC patients who may benefit from this combination therapeutic strategy.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('VEGF', 'Gene', (82, 86))	('epigenetic therapies', 'Var', (43, 63))	('patients', 'Species', '9606', (20, 28))	('patients', 'Species', '9606', (132, 140))	('VEGF', 'Gene', '7422', (82, 86))
105590	30819726	The Kaplan-Meier survival curve indicated that high Kif11 expression, nuclear grade and TNM stage were independent factors to predict poor prognosis in patients with CCRCC.	('Kif11', 'Gene', (52, 57))	('TNM', 'Gene', (88, 91))	('high', 'Var', (47, 51))	('CCRCC', 'Disease', (166, 171))	('CCRCC', 'Phenotype', 'HP:0006770', (166, 171))	('TNM', 'Gene', '10178', (88, 91))	('patients', 'Species', '9606', (152, 160))
105591	30819726	In addition, inhibition of Kif11 expression by SB743921 suppressed cell proliferation, migration and the EMT process with increased apoptosis rate.	('migration', 'CPA', (87, 96))	('Kif11', 'Gene', (27, 32))	('apoptosis', 'biological_process', 'GO:0097194', ('132', '141'))	('apoptosis rate', 'CPA', (132, 146))	('apoptosis', 'biological_process', 'GO:0006915', ('132', '141'))	('suppressed', 'NegReg', (56, 66))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('SB743921', 'Var', (47, 55))	('inhibition', 'NegReg', (13, 23))	('S', 'Chemical', 'MESH:D013455', (47, 48))	('increased', 'PosReg', (122, 131))	('cell proliferation', 'CPA', (67, 85))	('EMT', 'biological_process', 'GO:0001837', ('105', '108'))	('EMT process', 'CPA', (105, 116))
105600	30819726	In genetics, mutation of the von Hippel-Lindau disease tumour suppressor gene (VHL) was thought to be associated with a more favourable prognosis.	('von Hippel-Lindau disease tumour', 'Disease', 'MESH:D006623', (29, 61))	('associated', 'Reg', (102, 112))	('von Hippel-Lindau disease tumour', 'Disease', (29, 61))	('mutation', 'Var', (13, 21))	('VHL', 'Disease', 'MESH:D006623', (79, 82))	('VHL', 'Disease', (79, 82))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))
105631	30819726	Human kidney cancer cells (786-O) were cultured in RPMI 1640 medium (22400089, Invitrogen, China) containing 10% fetal bovine serum (FBS; 10099141, Invitrogen) and 100 U/mL penicilin/strapmycin antibotic (P/S, 15070063, Invitrogen) at 37 C in a cell incubator with a humidified atmosphere containing 5% CO2.	('CO2', 'Chemical', '-', (303, 306))	('bovine', 'Species', '9913', (119, 125))	('Human', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('kidney cancer', 'Phenotype', 'HP:0009726', (6, 19))	('FBS', 'Disease', 'MESH:D005198', (133, 136))	('S', 'Chemical', 'MESH:D013455', (135, 136))	('S', 'Chemical', 'MESH:D013455', (207, 208))	('kidney cancer', 'Disease', (6, 19))	('kidney cancer', 'Disease', 'MESH:D007680', (6, 19))	('22400089', 'Var', (69, 77))	('P', 'Chemical', 'MESH:D010758', (52, 53))	('FBS', 'Disease', (133, 136))	('strapmycin', 'Chemical', '-', (183, 193))	('P', 'Chemical', 'MESH:D010758', (205, 206))	('penicilin', 'Chemical', '-', (173, 182))	('P/S', 'Var', (205, 208))
105632	30819726	To evaluate the essential role of Kif11 in kidney cancer development, 786-O cells were treated with 0, 1.0 or 5.0 nM of a small compound inhibitor against Kif11 (SB743921; Selleck, S2182).	('kidney cancer', 'Disease', (43, 56))	('S', 'Chemical', 'MESH:D013455', (172, 173))	('SB743921', 'Var', (162, 170))	('S', 'Chemical', 'MESH:D013455', (162, 163))	('Kif11', 'Gene', (155, 160))	('kidney cancer', 'Disease', 'MESH:D007680', (43, 56))	('S', 'Chemical', 'MESH:D013455', (181, 182))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('kidney cancer', 'Phenotype', 'HP:0009726', (43, 56))
105661	30819726	With the Kaplan-Meier analysis, high Kif11 expression (HR=2.782, p=0.022), nuclear grade (HR=2.432, p<0.001) and TNM stage (HR=2.320, p=0.001) were all independent prognostic markers of poor 5-year overall survival (table 2).	('high', 'Var', (32, 36))	('poor', 'NegReg', (186, 190))	('TNM', 'Gene', (113, 116))	('TNM', 'Gene', '10178', (113, 116))	('Kif11', 'Gene', (37, 42))	('expression', 'MPA', (43, 53))
105662	30819726	Patients with CCRCC with high expression of Kif11 protein had significantly shorter overall survival compared with those with low or no Kif11 expression (figure 3).	('CCRCC', 'Disease', (14, 19))	('CCRCC', 'Phenotype', 'HP:0006770', (14, 19))	('high expression', 'Var', (25, 40))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('overall survival', 'MPA', (84, 100))	('Patients', 'Species', '9606', (0, 8))	('protein', 'Protein', (50, 57))	('Kif11', 'Gene', (44, 49))	('shorter', 'NegReg', (76, 83))
105667	30819726	After 72 hours of incubation with SB743921, the results of qRT-PCR showed that the EMT process significantly decreased in a dose-dependent manner with SB743921 treatments (figure 5).	('decreased', 'NegReg', (109, 118))	('P', 'Chemical', 'MESH:D010758', (63, 64))	('EMT process', 'CPA', (83, 94))	('EMT', 'biological_process', 'GO:0001837', ('83', '86'))	('SB743921', 'Var', (34, 42))	('SB743921', 'Var', (151, 159))	('S', 'Chemical', 'MESH:D013455', (34, 35))	('S', 'Chemical', 'MESH:D013455', (151, 152))
105670	30819726	High expression of Kif11 confers a survival disadvantage to patients with ACC (log rank p=2.8e-06, HR (high)=5.30), patients with BLCA (log rank p=0.045, HR (high)=1.40), patients with KICH (log rank p=0.02, HR (high)=5.20), patients with KIRP (log rank p=0.00028, HR (high)=3.00), patients with SARC (log rank p=0.00057, HR (high)=1.90), patients with LIHC (log rank p=0.00024, HR (high)=1.80), patients with AAD (log rank p=0.043, HR (high)=1.60), patients with LGG (log rank p=0.0087, HR (high)=1.50) and patients with UVM (log rank p=0.014, HR (high)=3.30) (figure 6).	('patients', 'Species', '9606', (396, 404))	('ACC', 'Phenotype', 'HP:0006744', (74, 77))	('patients', 'Species', '9606', (450, 458))	('LIHC', 'Disease', 'None', (353, 357))	('P', 'Chemical', 'MESH:D010758', (242, 243))	('High expression', 'Var', (0, 15))	('patients', 'Species', '9606', (60, 68))	('patients', 'Species', '9606', (116, 124))	('Kif11', 'Gene', (19, 24))	('patients', 'Species', '9606', (171, 179))	('patients', 'Species', '9606', (339, 347))	('UVM', 'Phenotype', 'HP:0007716', (522, 525))	('KICH', 'Disease', 'None', (185, 189))	('disadvantage', 'NegReg', (44, 56))	('patients', 'Species', '9606', (282, 290))	('patients', 'Species', '9606', (225, 233))	('S', 'Chemical', 'MESH:D013455', (296, 297))	('survival', 'CPA', (35, 43))	('SARC', 'Phenotype', 'HP:0100242', (296, 300))	('KICH', 'Disease', (185, 189))	('LIHC', 'Disease', (353, 357))	('patients', 'Species', '9606', (508, 516))
105677	30819726	In Alzheimer's disease, the inhibition of Kif11 by amyloid beta (Abeta) could block neuronal function and cause neuronal dysfunction with the mechanism of reduced transport of neurotrophin and neurotransmitter receptors to the cell surface.	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (3, 22))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (3, 22))	('cell surface', 'cellular_component', 'GO:0009986', ('227', '239'))	('neurotrophin', 'Gene', (176, 188))	('reduced', 'NegReg', (155, 162))	('cause', 'Reg', (106, 111))	("Alzheimer's disease", 'Disease', (3, 22))	('neurotrophin', 'molecular_function', 'GO:0005163', ('176', '188'))	('neuronal function', 'CPA', (84, 101))	('inhibition', 'Var', (28, 38))	('neurotrophin', 'Gene', '627', (176, 188))	('transport', 'biological_process', 'GO:0006810', ('163', '172'))	('block', 'NegReg', (78, 83))	('neuronal dysfunction', 'Disease', 'MESH:D009410', (112, 132))	('neuronal dysfunction', 'Disease', (112, 132))	('neurotrophin', 'molecular_function', 'GO:0005165', ('176', '188'))	('Kif11', 'Gene', (42, 47))
105680	30819726	The loss of Kif11 activity by mutation, immunodepletion, inhibition or by RNA interference could result in spindle assembly defects, cell cycle arrest and apoptosis, which leads to cell death.	('cell death', 'biological_process', 'GO:0008219', ('181', '191'))	('activity', 'MPA', (18, 26))	('mutation', 'Var', (30, 38))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('133', '150'))	('cell', 'CPA', (181, 185))	('RNA interference', 'MPA', (74, 90))	('spindle assembly', 'biological_process', 'GO:0051225', ('107', '123'))	('arrest', 'Disease', 'MESH:D006323', (144, 150))	('loss', 'NegReg', (4, 8))	('result', 'Reg', (97, 103))	('spindle assembly defects', 'CPA', (107, 131))	('Kif11', 'Gene', (12, 17))	('RNA interference', 'biological_process', 'GO:0016246', ('74', '90'))	('apoptosis', 'CPA', (155, 164))	('spindle', 'cellular_component', 'GO:0005819', ('107', '114'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (133, 150))	('apoptosis', 'biological_process', 'GO:0097194', ('155', '164'))	('arrest', 'Disease', (144, 150))	('apoptosis', 'biological_process', 'GO:0006915', ('155', '164'))	('inhibition', 'NegReg', (57, 67))	('RNA', 'cellular_component', 'GO:0005562', ('74', '77'))
105681	30819726	Moreover, transgenic mice with overexpressed Kif11 expression exhibited high tendencies to develop different malignancies.	('malignancies', 'Disease', 'MESH:D009369', (109, 121))	('Kif11', 'Gene', (45, 50))	('malignancies', 'Disease', (109, 121))	('overexpressed', 'PosReg', (31, 44))	('develop', 'PosReg', (91, 98))	('transgenic mice', 'Species', '10090', (10, 25))	('expression', 'Var', (51, 61))
105684	30819726	In our study, high Kif11 protein levels were associated with poor overall survival in patients with CCRCC, which indicates that the Kif11 protein level may be used as an independent clinical marker in predicting unfavourable prognosis.	('overall survival', 'MPA', (66, 82))	('CCRCC', 'Disease', (100, 105))	('Kif11', 'Gene', (19, 24))	('high', 'Var', (14, 18))	('CCRCC', 'Phenotype', 'HP:0006770', (100, 105))	('poor', 'NegReg', (61, 65))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('patients', 'Species', '9606', (86, 94))
105688	30819726	In our study, SB743921 was selected as a Kif11 inhibitor with the inhibition of the ATPase activities of Kif11.	('ATPase activities', 'Protein', (84, 101))	('P', 'Chemical', 'MESH:D010758', (86, 87))	('SB743921', 'Var', (14, 22))	('inhibition', 'NegReg', (66, 76))	('S', 'Chemical', 'MESH:D013455', (14, 15))
105689	30819726	Our results showed that SB743921 decreased the proliferation of 786-O cells with subsequent apoptosis and inhibition of the EMT process.	('SB743921', 'Var', (24, 32))	('apoptosis', 'biological_process', 'GO:0097194', ('92', '101'))	('apoptosis', 'biological_process', 'GO:0006915', ('92', '101'))	('apoptosis', 'CPA', (92, 101))	('EMT', 'biological_process', 'GO:0001837', ('124', '127'))	('EMT process', 'CPA', (124, 135))	('decreased', 'NegReg', (33, 42))	('inhibition', 'NegReg', (106, 116))	('S', 'Chemical', 'MESH:D013455', (24, 25))
105693	30819726	Inhibition of Kif11 expression in 786-O cells by SB743921 suppressed cell proliferation, migration and the epithelial to mesenchymal transition process with increased apoptosis rate.	('SB743921', 'Var', (49, 57))	('Inhibition', 'NegReg', (0, 10))	('apoptosis rate', 'CPA', (167, 181))	('S', 'Chemical', 'MESH:D013455', (49, 50))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('107', '143'))	('suppressed', 'NegReg', (58, 68))	('cell proliferation', 'CPA', (69, 87))	('epithelial to mesenchymal transition process', 'CPA', (107, 151))	('apoptosis', 'biological_process', 'GO:0097194', ('167', '176'))	('increased', 'PosReg', (157, 166))	('apoptosis', 'biological_process', 'GO:0006915', ('167', '176'))	('cell proliferation', 'biological_process', 'GO:0008283', ('69', '87'))	('migration', 'CPA', (89, 98))	('Kif11', 'Gene', (14, 19))
105702	30459299	MTHFD1 transfection of human CCRCC Caki-1 cells in vitro inhibited cell proliferation and promoted apoptosis, associated with reduced expression of cyclin D1, reduced Akt phosphorylation, and increased expression of Bax/Bcl-2 and p53.	('phosphorylation', 'biological_process', 'GO:0016310', ('171', '186'))	('Akt', 'Gene', '207', (167, 170))	('expression', 'MPA', (202, 212))	('Bax', 'Gene', (216, 219))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('CCRCC', 'Phenotype', 'HP:0006770', (29, 34))	('Bcl-2', 'Gene', (220, 225))	('cell proliferation', 'CPA', (67, 85))	('Bax', 'Gene', '581', (216, 219))	('reduced', 'NegReg', (159, 166))	('MTHFD1', 'Gene', (0, 6))	('transfection', 'Var', (7, 19))	('human', 'Species', '9606', (23, 28))	('MTHFD1', 'Gene', '4522', (0, 6))	('p53', 'Gene', (230, 233))	('Bcl-2', 'Gene', '596', (220, 225))	('expression', 'MPA', (134, 144))	('cyclin D1', 'Gene', (148, 157))	('inhibited', 'NegReg', (57, 66))	('Bcl-2', 'molecular_function', 'GO:0015283', ('220', '225'))	('apoptosis', 'CPA', (99, 108))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('cyclin', 'molecular_function', 'GO:0016538', ('148', '154'))	('RCC', 'Disease', (31, 34))	('reduced', 'NegReg', (126, 133))	('increased', 'PosReg', (192, 201))	('Caki-1', 'CellLine', 'CVCL:0234', (35, 41))	('cyclin D1', 'Gene', '595', (148, 157))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))	('phosphorylation', 'MPA', (171, 186))	('promoted', 'PosReg', (90, 98))	('Akt', 'Gene', (167, 170))	('RCC', 'Disease', 'MESH:C538614', (31, 34))
105716	30459299	Similarly, MTHFD2 mRNA and protein have been shown to be overexpressed in human cancer, including breast cancer and is associated with poor survival in breast cancer.	('cancer', 'Disease', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (80, 86))	('associated', 'Reg', (119, 129))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('MTHFD2', 'Gene', '10797', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('overexpressed', 'PosReg', (57, 70))	('MTHFD2', 'Gene', (11, 17))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('mRNA', 'Var', (18, 22))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('poor', 'NegReg', (135, 139))	('breast cancer', 'Disease', (98, 111))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Disease', (152, 165))	('human', 'Species', '9606', (74, 79))
105718	30459299	Previous studies have reported that polymorphisms of MTHFD1 are associated with impaired DNA synthesis, cell division and development, and oncogenesis, but the findings of these studies have been inconsistent.	('oncogenesis', 'CPA', (139, 150))	('associated', 'Reg', (64, 74))	('polymorphisms', 'Var', (36, 49))	('impaired', 'NegReg', (80, 88))	('MTHFD1', 'Gene', '4522', (53, 59))	('cell division', 'biological_process', 'GO:0051301', ('104', '117'))	('oncogenesis', 'biological_process', 'GO:0007048', ('139', '150'))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('MTHFD1', 'Gene', (53, 59))	('DNA synthesis', 'biological_process', 'GO:0071897', ('89', '102'))
105719	30459299	The MTHFD1 polymorphic 1958AA variant has been shown to significantly increase the risk of developing gastric cancer, when compared with the 1958GG or 1958AG genotypes.	('increase', 'PosReg', (70, 78))	('gastric cancer', 'Disease', (102, 116))	('variant', 'Var', (30, 37))	('MTHFD1', 'Gene', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))	('MTHFD1', 'Gene', '4522', (4, 10))
105720	30459299	showed that the expression of the MTHFD1 1958AA polymorphism was associated with a reduced risk of developing colon cancer, and also showed a significant difference between MTHFD1 1958G>A genotypes in patients with cancer compared with normal subjects.	('patients', 'Species', '9606', (201, 209))	('colon cancer', 'Disease', (110, 122))	('1958G>A', 'Var', (180, 187))	('cancer', 'Disease', (215, 221))	('MTHFD1', 'Gene', (34, 40))	('reduced', 'NegReg', (83, 90))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('1958G>A', 'Mutation', 'rs2236225', (180, 187))	('MTHFD1', 'Gene', '4522', (173, 179))	('MTHFD1', 'Gene', '4522', (34, 40))	('colon cancer', 'Disease', 'MESH:D015179', (110, 122))	('colon cancer', 'Phenotype', 'HP:0003003', (110, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('MTHFD1', 'Gene', (173, 179))
105737	30459299	Proteins incubated with primary antibodies, including: rabbit anti-Bcl-2 (ab32124) (1: 1000) (Abcam, Cambridge, MA, USA), anti-Bax (ab32503) (1: 1500) (Abcam, Cambridge, MA, USA), anti-MTHFD1(ab103698) (1: 1000) (Abcam, Cambridge, MA, USA), anti-p53 (ab32049) (1: 1000) (Abcam, Cambridge, MA, USA), anti-cyclin D1 (ab134175) (1: 1000) (Abcam, Cambridge, MA, USA), anti-GAPDH (ab8245) (1: 1000) (Abcam, Cambridge, MA, USA), anti-p-Akt (ab38449) (1: 1000) (Abcam, Cambridge, MA, USA), washed with TBST, and then incubated with HRP-conjugated goat anti-rabbit IgG secondary antibodies (Proteintech, Rosemont, IL, USA).	('cyclin D1', 'Gene', '595', (304, 313))	('MTHFD1', 'Gene', (185, 191))	('GAPDH', 'Gene', (369, 374))	('ab38449', 'Var', (435, 442))	('MTHFD1', 'Gene', '4522', (185, 191))	('rabbit', 'Species', '9986', (550, 556))	('Bax', 'Gene', (127, 130))	('Bcl-2', 'Gene', (67, 72))	('goat', 'Species', '9925', (540, 544))	('TBS', 'Chemical', '-', (495, 498))	('Bax', 'Gene', '581', (127, 130))	('Bcl-2', 'Gene', '596', (67, 72))	('Akt', 'Gene', (430, 433))	('rabbit', 'Species', '9986', (55, 61))	('Bcl-2', 'molecular_function', 'GO:0015283', ('67', '72'))	('cyclin D1', 'Gene', (304, 313))	('Akt', 'Gene', '207', (430, 433))	('GAPDH', 'Gene', '2597', (369, 374))	('cyclin', 'molecular_function', 'GO:0016538', ('304', '310'))
105762	30459299	The results of flow cytometry analysis to assess cell cycle showed that the G2-phase of the cell cycle was significantly reduced in the Caki-1 cells that were transfected with MTHFD1, compared with the control group or the EV group (12.53% vs. 23.41% vs. 21.01%, respectively) (P<0.05) (Figure 3D).	('MTHFD1', 'Gene', '4522', (176, 182))	('G2-phase', 'biological_process', 'GO:0051319', ('76', '84'))	('transfected', 'Var', (159, 170))	('reduced', 'NegReg', (121, 128))	('MTHFD1', 'Gene', (176, 182))	('Caki-1', 'CellLine', 'CVCL:0234', (136, 142))	('G2-phase of the cell cycle', 'CPA', (76, 102))	('cell cycle', 'biological_process', 'GO:0007049', ('49', '59'))	('cell cycle', 'biological_process', 'GO:0007049', ('92', '102'))	('EV', 'Chemical', '-', (223, 225))
105766	30459299	As shown in Figure 4, compared with the control group or the EV group, MTHFD1 transfection significantly increased the expression of Bax both in mRNA and protein levels (protein, P<0.05; mRNA, P<0.01) (Figure 4A, 4C, 4D).	('expression', 'MPA', (119, 129))	('transfection', 'Var', (78, 90))	('Bax', 'Gene', (133, 136))	('MTHFD1', 'Gene', '4522', (71, 77))	('EV', 'Chemical', '-', (61, 63))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('increased', 'PosReg', (105, 114))	('Bax', 'Gene', '581', (133, 136))	('MTHFD1', 'Gene', (71, 77))
105769	30459299	The results showed that tumor the suppressor p53 was significantly upregulated in Caki-1 cells compared with the control group or EV group of Caki-1 cells at both the mRNA and protein levels (P<0.01) (Figure 5A, 5C, 5D).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('p53', 'Gene', (45, 48))	('Caki-1', 'CellLine', 'CVCL:0234', (142, 148))	('tumor', 'Disease', (24, 29))	('EV', 'Chemical', '-', (130, 132))	('Caki-1', 'CellLine', 'CVCL:0234', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('upregulated', 'PosReg', (67, 78))	('Caki-1', 'Var', (82, 88))	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))
105775	30459299	The MTHFD1 gene has several potentially single nucleotide polymorphisms including T401C (R134K) and G1958A (R653Q), which are associated with methotrexate sensitivity in acute lymphoblastic leukemia (ALL), congenital heart disease, neural tube defect, and an increased risk of breast cancer and colorectal cancer.	('T401C (R134K', 'Var', (82, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('methotrexate', 'Chemical', 'MESH:D008727', (142, 154))	('R134K', 'Mutation', 'rs1950902', (89, 94))	('colorectal cancer', 'Disease', 'MESH:D015179', (295, 312))	('neural tube defect', 'Disease', 'MESH:D009436', (232, 250))	('leukemia', 'Phenotype', 'HP:0001909', (190, 198))	('T401C', 'Mutation', 'rs1950902', (82, 87))	('ALL', 'Phenotype', 'HP:0006721', (200, 203))	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('associated', 'Reg', (126, 136))	('colorectal cancer', 'Disease', (295, 312))	('R653Q', 'Var', (108, 113))	('breast cancer', 'Disease', (277, 290))	('congenital heart disease', 'Disease', 'MESH:D006331', (206, 230))	('neural tube defect', 'Phenotype', 'HP:0045005', (232, 250))	('R653Q', 'Mutation', 'rs2236225', (108, 113))	('acute lymphoblastic leukemia', 'Disease', (170, 198))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (170, 198))	('neural tube defect', 'Disease', (232, 250))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (170, 198))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('G1958A', 'Mutation', 'rs2236225', (100, 106))	('congenital heart disease', 'Disease', (206, 230))	('colorectal cancer', 'Phenotype', 'HP:0003003', (295, 312))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (176, 198))	('congenital heart disease', 'Phenotype', 'HP:0001627', (206, 230))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('MTHFD1', 'Gene', (4, 10))	('G1958A (R653Q', 'Var', (100, 113))	('MTHFD1', 'Gene', '4522', (4, 10))
105796	30459299	MTHFD1 transfection of Caki-1 cells inhibited cell proliferation, promoted cell apoptosis, and induced cell cycle arrest.	('cell apoptosis', 'CPA', (75, 89))	('inhibited', 'NegReg', (36, 45))	('promoted', 'PosReg', (66, 74))	('cell cycle arrest', 'CPA', (103, 120))	('induced', 'Reg', (95, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('MTHFD1', 'Gene', (0, 6))	('Caki-1', 'CellLine', 'CVCL:0234', (23, 29))	('transfection', 'Var', (7, 19))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('103', '120'))	('MTHFD1', 'Gene', '4522', (0, 6))	('cell proliferation', 'CPA', (46, 64))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (103, 120))	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))
105799	29724720	SETD2 Haploinsufficiency for Microtubule Methylation is an Early Driver of Genomic Instability in Renal Cell Carcinoma Loss of the short arm of chromosome 3 (3p) occurs early in >95% of clear cell renal cell carcinoma (ccRCC).	('Microtubule', 'cellular_component', 'GO:0005874', ('29', '40'))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (98, 118))	('Carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('clear cell renal cell carcinoma', 'Disease', (186, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('Haploinsufficiency for Microtubule', 'Disease', 'MESH:D058495', (6, 40))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (197, 217))	('SETD2', 'Gene', '29072', (0, 5))	('Renal Cell Carcinoma', 'Disease', (98, 118))	('chromosome', 'cellular_component', 'GO:0005694', ('144', '154'))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (186, 217))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (98, 118))	('SETD2', 'Gene', (0, 5))	('Loss', 'Var', (119, 123))	('Methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('Haploinsufficiency for Microtubule', 'Disease', (6, 40))	('short arm', 'Phenotype', 'HP:0009824', (131, 140))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (186, 217))
105803	29724720	In SETD2-inactivated human kidney cells, rescue with a pathogenic SETD2 mutant deficient for microtubule (alphaTubK40me3) but not histone (H3K36me3) methylation replicated this phenotype.	('methylation', 'biological_process', 'GO:0032259', ('149', '160'))	('histone (H3K36me', 'biological_process', 'GO:0010452', ('130', '146'))	('mutant', 'Var', (72, 78))	('deficient', 'NegReg', (79, 88))	('human', 'Species', '9606', (21, 26))	('H3K36me3', 'Gene', '126961', (139, 147))	('H3K36me3', 'Gene', (139, 147))	('microtubule', 'MPA', (93, 104))	('SETD2', 'Gene', (66, 71))	('microtubule', 'cellular_component', 'GO:0005874', ('93', '104'))
105806	29724720	Many cancer types are characterized by large scale, characteristic alterations of chromosomal copy number.	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Disease', (5, 11))	('alterations', 'Reg', (67, 78))	('chromosomal copy number', 'Var', (82, 105))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
105807	29724720	Clear cell renal cell carcinoma (ccRCC) is characterized by frequent inactivating mutations of the Von Hippel-Lindau (VHL) tumor suppressor gene, with accompanying loss of heterozygosity provided by a large deletion of chromosome 3p.	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('inactivating mutations', 'Var', (69, 91))	('tumor suppressor', 'Gene', (123, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('chromosome', 'cellular_component', 'GO:0005694', ('219', '229'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('123', '139'))	('VHL', 'Disease', (118, 121))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('VHL', 'Disease', 'MESH:D006623', (118, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('123', '139'))	('tumor suppressor', 'Gene', '7248', (123, 139))	('loss', 'NegReg', (164, 168))
105811	29724720	Bi-allelic deficiency of SETD2 via deletions and inactivating mutations occur in up to 20% of primary human RCC tumors and it is associated with more advanced disease and the metastatic phenotype, typically lethal within 1-5 years.	('RCC tumors', 'Disease', (108, 118))	('Bi-allelic deficiency', 'Disease', 'MESH:C566065', (0, 21))	('associated with', 'Reg', (129, 144))	('Bi-allelic deficiency', 'Disease', (0, 21))	('inactivating mutations', 'Var', (49, 71))	('occur', 'Reg', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('RCC tumors', 'Disease', 'MESH:C538614', (108, 118))	('deletions', 'Var', (35, 44))	('human', 'Species', '9606', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('SETD2', 'Gene', (25, 30))
105813	29724720	Examination of H3K36me3 status in ccRCC cells of metastatic tumor specimens suggest that SETD2 mutations may occur in over 50% of metastatic lesions.	('occur', 'Reg', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('SETD2', 'Gene', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('H3K36me3', 'Gene', '126961', (15, 23))	('mutations', 'Var', (95, 104))	('tumor', 'Disease', (60, 65))	('H3K36me3', 'Gene', (15, 23))
105814	29724720	Furthermore, a study of ccRCC intratumoral heterogeneity identified distinct SETD2 mutations across subsections of an individual tumor, suggesting a selection bias for SETD2 mutation in the course of ccRCC development.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('mutations', 'Var', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('SETD2', 'Gene', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))
105815	29724720	Mutations in this domain are common in ccRCC, suggesting loss of catalytic activity is a critical event in tumor development.	('ccRCC', 'Disease', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('common', 'Reg', (29, 35))	('catalytic activity', 'molecular_function', 'GO:0003824', ('65', '83'))	('Mutations in', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
105819	29724720	This mutation preserves the H3 trimethylation catalytic activity of SETD2, suggesting SETD2 may have other key functions in addition to its to the well-characterized role as a histone methyltransferase.	('H3', 'Gene', '126961', (28, 30))	('SETD2', 'Gene', (68, 73))	('catalytic activity', 'molecular_function', 'GO:0003824', ('46', '64'))	('mutation', 'Var', (5, 13))	('SETD2', 'Gene', (86, 91))
105820	29724720	SETD2 trimethylates alpha-tubulin on lysine 40 (alphaTubK40me3) of microtubules and loss of this mark results in genomic instability.	('alpha-tubulin', 'Gene', (20, 33))	('trimethylates', 'Chemical', '-', (6, 19))	('alpha-tubulin', 'Gene', '10376', (20, 33))	('lysine', 'Chemical', 'MESH:D008239', (37, 43))	('SETD2', 'Gene', (0, 5))	('results in', 'Reg', (102, 112))	('genomic instability', 'CPA', (113, 132))	('loss', 'Var', (84, 88))
105822	29724720	These mitotic alterations caused by loss of alphaTubK40me3 can lead to chromosomal abnormalities and genomic instability, hallmarks of tumorigenesis, and are thought to be an important source of genetic diversity and development of cell clones during tumor progression.	('tumor', 'Disease', (251, 256))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (71, 96))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('genomic instability', 'CPA', (101, 120))	('loss', 'Var', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('alphaTubK40me3', 'Protein', (44, 58))	('lead to', 'Reg', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('mitotic alterations', 'CPA', (6, 25))	('chromosomal abnormalities', 'Disease', (71, 96))
105824	29724720	The presence of micronuclei is a reliable cytological indicator of chromosome instability, and micronuclei are a common feature of many solid tumors and pre-neoplastic lesions, but have not been studied in any detail in ccRCC to date.	('neoplastic lesions', 'Phenotype', 'HP:0002664', (157, 175))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('chromosome', 'cellular_component', 'GO:0005694', ('67', '77'))	('solid tumors', 'Disease', (136, 148))	('micronuclei', 'Var', (16, 27))	('micronuclei', 'Var', (95, 106))	('solid tumors', 'Disease', 'MESH:D009369', (136, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('pre', 'molecular_function', 'GO:0003904', ('153', '156'))	('chromosome instability', 'Phenotype', 'HP:0040012', (67, 89))
105829	29724720	Comparing different SETD2 mutations, we also found that the SRI-domain mutation, which rescues H3K36me3, but not alphaTubK40me3, fails to rescue micronuclei formation and mitotic defects in SETD2-deleted cells compared to WT SETD2.	('mitotic defects', 'CPA', (171, 186))	('micronuclei formation', 'CPA', (145, 166))	('formation', 'biological_process', 'GO:0009058', ('157', '166'))	('mutations', 'Var', (26, 35))	('rescues', 'PosReg', (87, 94))	('SETD2', 'Gene', (20, 25))	('H3K36me3', 'Gene', '126961', (95, 103))	('H3K36me3', 'Gene', (95, 103))
105830	29724720	Importantly, micronuclei were also a common feature of 3p deleted ccRCC cell lines and were seen in a significant fraction of tumor cells from all patients with ccRCC.	('3p deleted', 'Var', (55, 65))	('micronuclei', 'Var', (13, 24))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('patients', 'Species', '9606', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('ccRCC', 'Disease', (66, 71))	('tumor', 'Disease', (126, 131))
105832	29724720	Moreover, our results shed light on a new mechanism by which mono-allelic inactivation of SETD2 or 3p loss can drive tumorigenesis in other cancers, and points to microtubule methylation as a key tumor suppressive activity of SETD2.	('SETD2', 'Gene', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (196, 201))	('microtubule', 'cellular_component', 'GO:0005874', ('163', '174'))	('tumor', 'Disease', (117, 122))	('methylation', 'biological_process', 'GO:0032259', ('175', '186'))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('mono-allelic inactivation', 'Var', (61, 86))	('loss', 'NegReg', (102, 106))	('drive', 'PosReg', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
105837	29724720	For Setd2w/f and Setd2f/f mouse embryonic fibroblasts, cells were maintained in phenol-red free media (DMEM, high glucose, HEPES, no phenol red) supplemented with Sodium Pyruvate and GlutaMAX (ThermoFisher Scientific), to prevent any spontaneous activation of the Cre recombinase by estrogenic compounds found in phenol red containing media.	('Setd2w/f', 'Var', (4, 12))	('phenol red', 'Chemical', 'MESH:D010637', (313, 323))	('Sodium Pyruvate', 'Chemical', '-', (163, 178))	('DMEM', 'Chemical', '-', (103, 107))	('glucose', 'Chemical', 'MESH:D005947', (114, 121))	('HEPES', 'Chemical', 'MESH:D006531', (123, 128))	('GlutaMAX', 'Chemical', 'MESH:D005973', (183, 191))	('Setd2f/f', 'Var', (17, 25))	('Cre recombinase', 'Enzyme', (264, 279))	('phenol red', 'Chemical', 'MESH:D010637', (133, 143))	('high glucose', 'Phenotype', 'HP:0003074', (109, 121))	('phenol-red', 'Chemical', 'MESH:D010637', (80, 90))	('mouse', 'Species', '10090', (26, 31))
105841	29724720	embryos of Setd2w/f or Setd2f/f mice, respectively.	('Setd2w/f', 'Var', (11, 19))	('mice', 'Species', '10090', (32, 36))	('Setd2f/f', 'Var', (23, 31))
105844	29724720	The phenotype of Setd2w/f MEFs is similar to that observed with bi-allelic loss (Setd2f/f), for which micronuclei were counted after two days of tamoxifen treatment, while the Setd2w/f MEFs remain viable as a culture for several passages.	('bi-allelic loss', 'Var', (64, 79))	('tamoxifen', 'Chemical', 'MESH:D013629', (145, 154))	('Setd2w/f', 'Var', (17, 25))
105857	29724720	For SETD2 knockdown HKC cells, lysates were separated on a 4-15% SDS-PAGE gel and the proteins were subsequently transferred to a PVDF membrane.	('PVDF', 'Chemical', 'MESH:C024865', (130, 134))	('membrane', 'cellular_component', 'GO:0016020', ('135', '143'))	('SETD2', 'Gene', (4, 9))	('SDS', 'Chemical', 'MESH:D012967', (65, 68))	('knockdown', 'Var', (10, 19))
105868	29724720	Setd2 knockout was induced in MEFs (as described above), then fixed in 3.7% formaldehyde solution for 15 minutes, permeabilized in Triton-X 100 for 20 minutes and incubated for an hour in blocking buffer containing 3% bovine serum albumin (BSA) in 1XPBS at room temperature (RT).	('formaldehyde', 'Chemical', 'MESH:D005557', (76, 88))	('knockout', 'Var', (6, 14))	('1XPBS', 'Chemical', '-', (248, 253))	('bovine', 'Species', '9913', (218, 224))	('Setd2', 'Gene', (0, 5))	('Triton-X 100', 'Chemical', 'MESH:D017830', (131, 143))
105886	29724720	Densitometry analyses using ImageStudio Ver2.0 were performed on immunoblots of H3K36me3 and alphaTubK40me3 normalized to H3 and alphaTubulin, respectively.	('H3K36me3', 'Gene', '126961', (80, 88))	('H3', 'Gene', '126961', (80, 82))	('alphaTubK40me3', 'Var', (93, 107))	('H3K36me3', 'Gene', (80, 88))	('H3', 'Gene', '126961', (122, 124))
105887	29724720	Previous studies have linked SETD2 inactivation to genomic instability in RCC utilizing tumor-derived analysis.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('SETD2', 'Gene', (29, 34))	('inactivation', 'Var', (35, 47))	('RCC', 'Disease', (74, 77))	('genomic instability', 'MPA', (51, 70))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
105888	29724720	We first asked if loss of this tumor suppressor alone was sufficient to promote genomic instability in non-tumor kidney epithelial cells.	('tumor suppressor', 'biological_process', 'GO:0051726', ('31', '47'))	('tumor suppressor', 'Gene', '7248', (31, 47))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('loss', 'Var', (18, 22))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (31, 36))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('31', '47'))	('promote', 'PosReg', (72, 79))	('tumor suppressor', 'Gene', (31, 47))	('tumor kidney', 'Phenotype', 'HP:0009726', (107, 119))	('genomic', 'MPA', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
105890	29724720	This panel included lines rescued with a fully functional wild-type N-terminal truncated SETD2 (tSETD2), a tSETD2 catalytically-dead SET domain-mutant (R1625C), and a tSETD2 SRI domain-mutant (R2510H).	('R1625C', 'Var', (152, 158))	('R2510H', 'Var', (193, 199))	('R2510H', 'Mutation', 'p.R2510H', (193, 199))	('R1625C', 'Mutation', 'p.R1625C', (152, 158))
105891	29724720	Genomic instability was a prominent feature of SETD2 -/- HKC cells expressing empty vector (GFP), catalytically-dead SET domain mutant tSETD2 R1625C, or the SRI domain mutant tSETD2 R2510H (Fig.	('Genomic instability', 'CPA', (0, 19))	('tSETD2', 'Gene', (175, 181))	('R2510H', 'Var', (182, 188))	('R1625C', 'Mutation', 'p.R1625C', (142, 148))	('R2510H', 'Mutation', 'p.R2510H', (182, 188))	('R1625C', 'Var', (142, 148))	('tSETD2', 'Gene', (135, 141))
105894	29724720	Neither empty vector (GFP), catalytically-dead SET domain R1625C, nor SRI domain R2510H SETD2 mutants rescued the increase in micronuclei observed in SETD2 -/- HKC.	('R2510H', 'Mutation', 'p.R2510H', (81, 87))	('increase', 'PosReg', (114, 122))	('R1625C', 'Mutation', 'p.R1625C', (58, 64))	('mutants', 'Var', (94, 101))	('SETD2', 'Gene', (88, 93))	('micronuclei', 'CPA', (126, 137))
105896	29724720	This was also the case in SETD2 -/- HKC cells reconstituted with catalytically-dead SET domain (R1625C) and SRI domain (R2510H) tSETD2 mutants (Fig.	('tSETD2', 'Gene', (128, 134))	('R1625C', 'Mutation', 'p.R1625C', (96, 102))	('R2510H', 'Mutation', 'p.R2510H', (120, 126))	('R2510H', 'Var', (120, 126))	('R1625C', 'Var', (96, 102))
105898	29724720	One question that arises is whether the cells that have experienced genomic instability as a result of SETD2 depletion remain in the population and perpetuate these genomic changes as potential clonal features furthering the process of tumorigenesis.	('depletion', 'Var', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('SETD2', 'Gene', (103, 108))	('tumor', 'Disease', (236, 241))
105900	29724720	To determine the impact of reduced SETD2 dosage (mono-allelic loss) on microtubule vs. histone methylation, we employed tamoxifen-inducible ER-Cre wild-type Setd2 (w/w), heterozygous (w/f) and homozygous (f/f) Setd2 mutant mouse embryonic fibroblasts (MEFs).	('mouse', 'Species', '10090', (223, 228))	('mutant', 'Var', (216, 222))	('tamoxifen', 'Chemical', 'MESH:D013629', (120, 129))	('histone methylation', 'biological_process', 'GO:0016571', ('87', '106'))	('Setd2', 'Gene', (210, 215))	('microtubule', 'cellular_component', 'GO:0005874', ('71', '82'))
105901	29724720	These cells lack the genetic diversity found in cancer cell lines, thus allowing for Setd2 alterations to be examined in isolation from other genetic aberrations, and for drawing causal associations between mono- and bi-allelic Setd2 loss and genomic stability.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('genomic stability', 'CPA', (243, 260))	('Setd2', 'Gene', (228, 233))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('bi-allelic', 'Var', (217, 227))	('Setd2', 'Gene', (85, 90))	('loss', 'NegReg', (234, 238))
105906	29724720	Micronuclei of Setd2f/f and Setd2w/f MEFs stained with Hoechst, CENPB and CREST also exhibited both CREST (+) whole chromosome and CREST (-) acentric chromosome staining (Fig.	('Setd2w/f', 'Var', (28, 36))	('chromosome', 'cellular_component', 'GO:0005694', ('150', '160'))	('CENPB', 'Gene', (64, 69))	('CREST', 'Gene', (100, 105))	('CREST', 'Gene', (131, 136))	('CREST', 'Gene', '26039', (100, 105))	('exhibited', 'Reg', (85, 94))	('CREST', 'Gene', '26039', (131, 136))	('CENPB', 'Gene', '1059', (64, 69))	('CREST', 'Gene', '26039', (74, 79))	('chromosome', 'cellular_component', 'GO:0005694', ('116', '126'))	('CREST', 'Gene', (74, 79))	('Hoechst', 'Chemical', '-', (55, 62))
105907	29724720	Both Setd2f/f and Setd2w/f MEFs showed increased total micronuclei number, but homozygous Setd2 MEFs (Setd2f/f) showed a more dramatic increase in Hoechst (+) CENPB/CREST (-) micronuclei, containing acentric chromosome fragments, compared to Setd2w/f MEFs (Fig.	('CENPB', 'Gene', '1059', (159, 164))	('Setd2', 'Var', (90, 95))	('CREST', 'Gene', (165, 170))	('increase', 'PosReg', (135, 143))	('CREST', 'Gene', '26039', (165, 170))	('Hoechst', 'Chemical', '-', (147, 154))	('micronuclei number', 'CPA', (55, 73))	('CENPB', 'Gene', (159, 164))	('chromosome', 'cellular_component', 'GO:0005694', ('208', '218'))
105913	29724720	The frequency of micronuclei in tumor cells ranged from 1.1% to 30%.	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('micronuclei', 'Var', (17, 28))
105917	29724720	Additionally, sequencing available tissue from the ccRCC tumor samples identified none with deleterious SETD2 mutations (Supplementary Fig.	('SETD2', 'Gene', (104, 109))	('mutations', 'Var', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('ccRCC', 'Disease', (51, 56))
105920	29724720	Thus, ccRCC cell lines and ccRCC patient-derived tumor cells exhibit both the genomic instability (micronuclei) associated with mono-allelic SETD2 deletion, as a consequence of chromosome 3p loss, as well as the dependence on the SRI domain for nonhistone methylating SETD2 function.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('chromosome', 'cellular_component', 'GO:0005694', ('177', '187'))	('patient', 'Species', '9606', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('loss', 'NegReg', (191, 195))	('tumor', 'Disease', (49, 54))	('deletion', 'Var', (147, 155))	('genomic instability', 'CPA', (78, 97))	('SETD2', 'Gene', (141, 146))
105924	29724720	First, with the loss of 3p and haploinsufficiency for SETD2 as an early event contributing to genomic instability, and upon bi-allelic inactivation, the additional loss of H3K36 trimethylating activity (Fig.	('trimethylating activity', 'MPA', (178, 201))	('haploinsufficiency', 'Disease', (31, 49))	('H3', 'Gene', '126961', (172, 174))	('SETD2', 'Gene', (54, 59))	('loss', 'NegReg', (16, 20))	('haploinsufficiency', 'Disease', 'MESH:D058495', (31, 49))	('inactivation', 'Var', (135, 147))	('contributing', 'Reg', (78, 90))	('genomic instability', 'MPA', (94, 113))	('loss', 'NegReg', (164, 168))
105925	29724720	SETD2 is mutated or lost in a growing list of tumors, and notably mutations in SETD2 are enriched in chemotherapy refractory pediatric acute lymphocytic leukemia.	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('lymphocytic leukemia', 'Disease', (141, 161))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (135, 161))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (141, 161))	('SETD2', 'Gene', (79, 84))	('tumors', 'Disease', (46, 52))	('leukemia', 'Phenotype', 'HP:0001909', (153, 161))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
105930	29724720	Beyond loss of genomic stability, bi-allelic SETD2 inactivation may contribute to tumorigenesis in several ways, in particularly in mediating DNA repair.	('mediating', 'Reg', (132, 141))	('SETD2', 'Gene', (45, 50))	('DNA repair', 'MPA', (142, 152))	('DNA', 'cellular_component', 'GO:0005574', ('142', '145'))	('DNA repair', 'biological_process', 'GO:0006281', ('142', '152'))	('inactivation', 'Var', (51, 63))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('contribute', 'Reg', (68, 78))	('bi-allelic', 'Var', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
105937	29724720	Importantly, micronuclei have also been documented in primary cancers, although ccRCC has not been well characterized in this regard.	('ccRCC', 'Disease', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('micronuclei', 'Var', (13, 24))	('documented', 'Reg', (40, 50))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))
105942	29724720	In this regard, the shared genomic instability phenotype seen with SETD2 haploinsufficiency and SRI-domain defects that abrogate microtubule but not histone methylation argues that maintenance of genomic stability by SETD2 is linked to its function as a microtubule methyltransferase.	('microtubule', 'cellular_component', 'GO:0005874', ('254', '265'))	('microtubule', 'cellular_component', 'GO:0005874', ('129', '140'))	('haploinsufficiency', 'Disease', (73, 91))	('microtubule', 'MPA', (129, 140))	('defects', 'Var', (107, 114))	('SETD2', 'Gene', (67, 72))	('histone methylation', 'biological_process', 'GO:0016571', ('149', '168'))	('haploinsufficiency', 'Disease', 'MESH:D058495', (73, 91))	('abrogate', 'NegReg', (120, 128))	('SETD2', 'Gene', (217, 222))	('histone methylation', 'MPA', (149, 168))
105946	29724720	It is now well accepted that the main drivers of cancer are not limited to highly penetrant dominant and recessive mutations, but also include heterozygous losses giving rise to haploinsufficiency states.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('rise to haploinsufficiency', 'Disease', (170, 196))	('rise to haploinsufficiency', 'Disease', 'MESH:D058495', (170, 196))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))	('heterozygous losses', 'Var', (143, 162))
105948	29724720	Another example of haploinsufficiency in cancer progression is PERK, an endoplasmic reticulum transmembrane protein kinase, displaying pro-tumorigenic activity in melanomas harboring activated BrafV600E mutation.	('melanomas', 'Disease', 'MESH:D008545', (163, 172))	('haploinsufficiency', 'Disease', (19, 37))	('PERK', 'Gene', '9451', (63, 67))	('transmembrane', 'cellular_component', 'GO:0016021', ('94', '107'))	('tumor', 'Disease', (139, 144))	('melanomas', 'Disease', (163, 172))	('cancer', 'Disease', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('transmembrane', 'cellular_component', 'GO:0044214', ('94', '107'))	('melanomas', 'Phenotype', 'HP:0002861', (163, 172))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('72', '93'))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('BrafV600E mutation', 'Var', (193, 211))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('PERK', 'Gene', (63, 67))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('BrafV600E', 'Mutation', 'rs113488022', (193, 202))	('haploinsufficiency', 'Disease', 'MESH:D058495', (19, 37))
105949	29724720	However, deletion of one allele of PERK is permissive for BrafV600E-dependent transformation, while excision of both alleles did not cooperate with BrafV600E in melanoma tumorigenicity.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('deletion', 'Var', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('PERK', 'Gene', (35, 39))	('tumor', 'Disease', (170, 175))	('PERK', 'Gene', '9451', (35, 39))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', (161, 169))	('BrafV600E', 'Mutation', 'rs113488022', (58, 67))	('BrafV600E', 'Mutation', 'rs113488022', (148, 157))
105950	29724720	Interestingly, PERK mutations decreasing its activity are seen at a 7% frequency.	('activity', 'MPA', (45, 53))	('decreasing', 'NegReg', (30, 40))	('PERK', 'Gene', (15, 19))	('PERK', 'Gene', '9451', (15, 19))	('mutations', 'Var', (20, 29))
105969	30271502	The established mechanisms that explain how cigarette-smoking leads to carcinogenesis include as follows: (1) exposure to smoking-related carcinogens, (2) formation of DNA adducts between carcinogens and DNA, and (3) mutations induced in critical oncogenes or tumor suppressor genes.	('tumor', 'Disease', (260, 265))	('DNA', 'cellular_component', 'GO:0005574', ('204', '207'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('260', '276'))	('formation', 'biological_process', 'GO:0009058', ('155', '164'))	('carcinogenesis', 'Disease', (71, 85))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('adducts', 'Interaction', (172, 179))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('260', '276'))	('DNA', 'cellular_component', 'GO:0005574', ('168', '171'))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('mutations', 'Var', (217, 226))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))
105976	30271502	And dose-response associations with F2RL3 methylation were demonstrated for both current and long-term tobacco exposure.	('F2RL3', 'Gene', (36, 41))	('methylation', 'biological_process', 'GO:0032259', ('42', '53'))	('tobacco', 'Species', '4097', (103, 110))	('methylation', 'Var', (42, 53))	('F2RL3', 'Gene', '9002', (36, 41))
106003	30271502	We also found that the mean value of F2RL3 mRNA expression was higher in patients with stage III-IV and grade 3-4, compared with participants with stage I-II and grade 1-2, respectively (all p<0.05, Fig.	('participants', 'Species', '9606', (129, 141))	('F2RL3', 'Gene', (37, 42))	('mRNA expression', 'MPA', (43, 58))	('patients', 'Species', '9606', (73, 81))	('F2RL3', 'Gene', '9002', (37, 42))	('grade 3-4', 'Var', (104, 113))	('stage III-IV', 'Disease', (87, 99))	('higher', 'PosReg', (63, 69))
106009	30271502	Interestingly, high expression of F2RL3 mRNA and protein remained an independently prognostic factor for PFS (p<0.001 and =0.002, respectively) and OS (p<0.001 and =0.004, respectively) in multivariate Cox regression model (Table 2-3).	('high', 'Var', (15, 19))	('F2RL3', 'Gene', '9002', (34, 39))	('Cox', 'Gene', '1351', (202, 205))	('Cox', 'Gene', (202, 205))	('PFS', 'Disease', (105, 108))	('F2RL3', 'Gene', (34, 39))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))
106014	30271502	Non-significant differences between population with low and middle F2RL3 mRNA expression were found for PFS and OS.	('F2RL3', 'Gene', (67, 72))	('F2RL3', 'Gene', '9002', (67, 72))	('PFS', 'Disease', (104, 107))	('low', 'Var', (52, 55))
106015	30271502	However, it was interestingly noted that a trend of significant difference in OS between the groups of low and middle F2RL3 expression was observed after follow-up of 70 months (Fig.	('low', 'Var', (103, 106))	('F2RL3', 'Gene', '9002', (118, 123))	('expression', 'MPA', (124, 134))	('F2RL3', 'Gene', (118, 123))
106016	30271502	For the association of patients' prognosis with F2RL3 protein expression, we found that the PFS and OS in the patents with positive F2RL3 protein expression were significantly shorten than in negative F2RL3 protein expression, respectively (p=0.002 and =0.008, respectively, Fig.	('positive', 'Var', (123, 131))	('protein', 'cellular_component', 'GO:0003675', ('207', '214'))	('F2RL3', 'Gene', (201, 206))	('PFS', 'CPA', (92, 95))	('F2RL3', 'Gene', (132, 137))	('F2RL3', 'Gene', '9002', (48, 53))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('F2RL3', 'Gene', '9002', (201, 206))	('patients', 'Species', '9606', (23, 31))	('protein', 'Protein', (138, 145))	('F2RL3', 'Gene', '9002', (132, 137))	('F2RL3', 'Gene', (48, 53))	('shorten', 'NegReg', (176, 183))	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))
106017	30271502	In addition, the median PFS in the cohort of patients with low, middle and high F2RL3 expression were 90, 74 and 37 months, respectively.	('F2RL3', 'Gene', (80, 85))	('high', 'Var', (75, 79))	('patients', 'Species', '9606', (45, 53))	('F2RL3', 'Gene', '9002', (80, 85))
106029	30271502	In addition, a study conducted by Zhang et al indicated that F2RL3 methylation is a strong predictor of cancer mortality and pathways associated with F2RL3 methylation may regulate harmful effects of smoking.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('F2RL3', 'Gene', (61, 66))	('methylation', 'biological_process', 'GO:0032259', ('67', '78'))	('F2RL3', 'Gene', (150, 155))	('cancer', 'Disease', (104, 110))	('F2RL3', 'Gene', '9002', (61, 66))	('F2RL3', 'Gene', '9002', (150, 155))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('methylation', 'biological_process', 'GO:0032259', ('156', '167'))	('methylation', 'Var', (67, 78))
106034	30271502	In the current study, we observed that high mRNA expression of F2RL3 present in patients with T3-4, N1, M1, or ISUP grade 3-4.	('F2RL3', 'Gene', '9002', (63, 68))	('patients', 'Species', '9606', (80, 88))	('mRNA expression', 'MPA', (44, 59))	('F2RL3', 'Gene', (63, 68))	('T3-4', 'Var', (94, 98))
106036	30271502	This supports that high F2RL3 expression associated with advanced TNM stage or ISUP grade is an adverse prognostic factor for ccRCC.	('F2RL3', 'Gene', '9002', (24, 29))	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('high', 'Var', (19, 23))	('RCC', 'Disease', (128, 131))	('expression', 'MPA', (30, 40))	('TNM', 'Gene', '10178', (66, 69))	('F2RL3', 'Gene', (24, 29))	('TNM', 'Gene', (66, 69))
106097	33475752	Most patients received VEGF targeted therapy in the first line (88%; 8895 patients).	('targeted therapy', 'Var', (28, 44))	('patients', 'Species', '9606', (5, 13))	('patients', 'Species', '9606', (74, 82))	('VEGF', 'Gene', (23, 27))	('VEGF', 'Gene', '7422', (23, 27))
106151	33475752	This finding may in part be explained by the previously demonstrated tendency of localized nonclear cell histologic variants to have a lower risk of recurrence and/or death following surgical resection, resulting in skewed proportions in our cohort consisting exclusively of patients with metastatic disease.	('variants', 'Var', (116, 124))	('death', 'Disease', 'MESH:D003643', (167, 172))	('death', 'Disease', (167, 172))	('lower', 'NegReg', (135, 140))	('patients', 'Species', '9606', (275, 283))
106169	31636445	Their discovery has led us to revisit the original, dispelled Warburg hypothesis, first postulated in the 1950s, of aberrant metabolism as an aetiological determinant of cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('metabolism', 'biological_process', 'GO:0008152', ('125', '135'))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('aberrant', 'Var', (116, 124))
106180	31636445	Loss of chromosome 3p, a pathognomonic feature of ccRCC occurring in >90% of patients, was typically found to be the initiating driver event in sporadic ccRCC, arising as early as childhood in as little as a few hundred cells, preceding cancer diagnosis by up to 3-5 decades.	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('RCC', 'Disease', (155, 158))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('RCC', 'Disease', (52, 55))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('patients', 'Species', '9606', (77, 85))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (237, 243))	('Loss', 'Var', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (155, 158))
106183	31636445	As genomic technology advances, the genetic perturbations implicated in ccRCC continue to expand and include somatic mutations in TERT, PTEN, MYC, and mTOR signalling pathways as well as other numerous metabolic pathways, which will be discussed further in this review alongside subtype-specific genetic perturbations such as mutations in fumarate hydratase (FH) in type 2 pRCC.	('signalling', 'biological_process', 'GO:0023052', ('156', '166'))	('mutations', 'Var', (326, 335))	('fumarate hydratase', 'Gene', (339, 357))	('PTEN', 'Gene', '5728', (136, 140))	('pRCC', 'Gene', '5546', (373, 377))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('mTOR', 'Gene', (151, 155))	('mutations', 'Var', (117, 126))	('TERT', 'Gene', (130, 134))	('MYC', 'Gene', (142, 145))	('pRCC', 'Gene', (373, 377))	('TERT', 'Gene', '7015', (130, 134))	('fumarate hydratase', 'Gene', '2271', (339, 357))	('FH', 'Gene', '2271', (359, 361))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('PTEN', 'Gene', (136, 140))	('RCC', 'Phenotype', 'HP:0005584', (374, 377))	('mTOR', 'Gene', '2475', (151, 155))	('RCC', 'Disease', (374, 377))	('MYC', 'Gene', '4609', (142, 145))	('RCC', 'Disease', 'MESH:C538614', (374, 377))
106186	31636445	One classic example in RCC is the ability of VHL inactivation to rewire the normal metabolic adaptation response to oxygen deprivation.	('VHL', 'Gene', '7428', (45, 48))	('rewire', 'Reg', (65, 71))	('inactivation', 'Var', (49, 61))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('VHL', 'Gene', (45, 48))	('oxygen', 'Chemical', 'MESH:D010100', (116, 122))
106187	31636445	Inactivation of VHL in ccRCC leads to the aberrant accumulation of the transcription factors hypoxia-inducible factor (HIF)1alpha and HIF2alpha despite normoxia, with resultant upregulation of pathways involved in glycolysis, fatty acid, and glycogen synthesis.	('HIF2alpha', 'Gene', '2034', (134, 143))	('VHL', 'Gene', (16, 19))	('RCC', 'Disease', (25, 28))	('VHL', 'Gene', '7428', (16, 19))	('hypoxia-inducible factor (HIF)1alpha', 'Gene', '3091', (93, 129))	('upregulation', 'PosReg', (177, 189))	('accumulation', 'PosReg', (51, 63))	('fatty acid', 'Chemical', 'MESH:D005227', (226, 236))	('glycogen', 'Chemical', 'MESH:D006003', (242, 250))	('glycolysis', 'biological_process', 'GO:0006096', ('214', '224'))	('pathways involved', 'Pathway', (193, 210))	('HIF2alpha', 'Gene', (134, 143))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('transcription', 'biological_process', 'GO:0006351', ('71', '84'))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('Inactivation', 'Var', (0, 12))	('glycogen synthesis', 'biological_process', 'GO:0005978', ('242', '260'))
106203	31636445	However, the identification of key genetic mutations in cancer cells encoding for enzymes in mitochondrial metabolism such as FH and SDH paved the way for the next chapter of cancer metabolism, the discovery and evolution of the oncometabolite paradigm.	('SDH', 'Gene', (133, 136))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (43, 52))	('FH', 'Gene', '2271', (126, 128))	('metabolism', 'biological_process', 'GO:0008152', ('182', '192'))	('metabolism', 'biological_process', 'GO:0008152', ('107', '117'))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
106204	31636445	By definition, oncometabolites are conventional metabolites that when aberrantly accumulated have pro-oncogenic capabilities that can contribute to tumorigenesis, especially via epigenetic dysregulation, as well as influence tumour phenotype and progression.	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('progression', 'CPA', (246, 257))	('tumour', 'Disease', (225, 231))	('epigenetic dysregulation', 'Var', (178, 202))	('influence', 'Reg', (215, 224))	('contribute', 'Reg', (134, 144))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('tumorigenesis', 'CPA', (148, 161))
106219	31636445	In Dang et al's study, abnormally elevated D2HG levels (up to tens of mumol per gram of tissue)were expressed by>100-fold greater in patients with malignant gliomas harbouring a single mutant copy of the isocitrate dehydrogenase (IDH) 1 gene compared to malignant gliomas with wildtype IDH genes.	('single mutant', 'Var', (178, 191))	('greater', 'PosReg', (122, 129))	('gliomas', 'Phenotype', 'HP:0009733', (264, 271))	('abnormally elevated D2HG', 'Phenotype', 'HP:0003115', (23, 47))	('malignant gliomas', 'Disease', (254, 271))	('D2HG levels', 'MPA', (43, 54))	('malignant gliomas', 'Disease', 'MESH:D005910', (147, 164))	('malignant gliomas', 'Disease', 'MESH:D005910', (254, 271))	('isocitrate dehydrogenase (IDH) 1', 'Gene', '3417', (204, 236))	('patients', 'Species', '9606', (133, 141))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('glioma', 'Phenotype', 'HP:0009733', (264, 270))	('elevated', 'PosReg', (34, 42))	('D2HG', 'Chemical', '-', (43, 47))	('gliomas', 'Phenotype', 'HP:0009733', (157, 164))	('malignant gliomas', 'Disease', (147, 164))
106221	31636445	Mutation of the IDH1 gene confers a gain-of-function neomorphic activity of the IDH enzyme that catalyses the reduction of alphaKG to D2HG, leading to its accumulation.	('gain-of-function', 'PosReg', (36, 52))	('reduction', 'NegReg', (110, 119))	('accumulation', 'PosReg', (155, 167))	('Mutation', 'Var', (0, 8))	('IDH', 'Gene', (80, 83))	('IDH1', 'Gene', (16, 20))	('neomorphic activity', 'MPA', (53, 72))	('D2HG', 'Chemical', '-', (134, 138))
106225	31636445	Identification of loss-of-function mutations in genes encoding the key TCA cycle enzymes SDH and FH, which lead to the accumulation of succinate and fumarate respectively, as well as a gain-of-function mutation in IDH, which leads to the accumulation of D2HG, has led to appreciation of how these genetic perturbations act as tumour suppressor genes and oncogenes.	('fumarate', 'MPA', (149, 157))	('mutation', 'Var', (202, 210))	('TCA cycle', 'biological_process', 'GO:0006099', ('71', '80'))	('SDH', 'Gene', (89, 92))	('succinate', 'Chemical', 'MESH:D019802', (135, 144))	('loss-of-function', 'NegReg', (18, 34))	('IDH', 'Gene', (214, 217))	('accumulation', 'PosReg', (238, 250))	('fumarate', 'Chemical', 'MESH:D005650', (149, 157))	('D2HG', 'Chemical', '-', (254, 258))	('accumulation', 'PosReg', (119, 131))	('TCA', 'Chemical', 'MESH:D014233', (71, 74))	('succinate', 'MPA', (135, 144))	('gain-of-function', 'PosReg', (185, 201))	('tumour', 'Phenotype', 'HP:0002664', (326, 332))	('D2HG', 'MPA', (254, 258))	('tumour', 'Disease', 'MESH:D009369', (326, 332))	('FH', 'Gene', '2271', (97, 99))	('tumour', 'Disease', (326, 332))	('mutations', 'Var', (35, 44))
106226	31636445	Both FH and SDH mutations in tumours follow the Knudson's 'two hit' hypothesis of tumorigenesis.	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('tumour', 'Disease', (29, 35))	('mutations', 'Var', (16, 25))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('SDH', 'Gene', (12, 15))	('FH', 'Gene', '2271', (5, 7))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))
106227	31636445	In patients with heterozygous germline mutations for SDH or FH i.e.	('patients', 'Species', '9606', (3, 11))	('SDH', 'Gene', (53, 56))	('FH', 'Gene', '2271', (60, 62))	('germline mutations', 'Var', (30, 48))
106228	31636445	loss of the remaining wildtype allele, seems to be the clinching factor in tumorigenesis and in both cases, converge on the predisposition to the development of PGL/ phaeochromocytomas (PCC).	('loss', 'Var', (0, 4))	('phaeochromocytomas', 'Disease', 'MESH:D010673', (166, 184))	('PCC', 'Disease', (186, 189))	('PGL', 'Phenotype', 'HP:0002668', (161, 164))	('tumorigenesis', 'CPA', (75, 88))	('PCC', 'Disease', 'MESH:D010673', (186, 189))	('PCC', 'cellular_component', 'GO:0120205', ('186', '189'))	('PGL', 'molecular_function', 'GO:0004598', ('161', '164'))	('PGL', 'Disease', (161, 164))	('phaeochromocytomas', 'Disease', (166, 184))	('PGL', 'Disease', 'MESH:D010235', (161, 164))
106230	31636445	Loss of heterozygosity in multiple subunits of SDH predisposes to a variety of cancers including SDH-deficient RCC, a very rare and aggressive disease, whereas LOH in patients with heterozygous FH germline mutations predisposes to HLRCC, an autosomal dominant hereditary cancer syndrome characterised by cutaneous and uterine leiomyomas and a highly aggressive form (type 2) of pRCC.	('aggressive disease', 'Disease', (132, 150))	('RCC', 'Disease', 'MESH:C538614', (379, 382))	('HLRCC', 'Disease', 'MESH:C535516', (231, 236))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('pRCC', 'Gene', (378, 382))	('RCC', 'Phenotype', 'HP:0005584', (233, 236))	('aggressive disease', 'Disease', 'MESH:D001523', (132, 150))	('RCC', 'Disease', (233, 236))	('SDH-deficient', 'Gene', (97, 110))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('autosomal dominant hereditary cancer syndrome', 'Disease', 'MESH:D009386', (241, 286))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('RCC', 'Disease', 'MESH:C538614', (233, 236))	('mutations', 'Var', (206, 215))	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('autosomal dominant hereditary cancer syndrome', 'Disease', (241, 286))	('leiomyomas', 'Disease', (326, 336))	('FH', 'Gene', '2271', (194, 196))	('Loss', 'Var', (0, 4))	('pRCC', 'Gene', '5546', (378, 382))	('RCC', 'Disease', (379, 382))	('RCC', 'Phenotype', 'HP:0005584', (379, 382))	('SDH', 'Gene', (47, 50))	('RCC', 'Disease', (111, 114))	('leiomyomas', 'Disease', 'MESH:D007889', (326, 336))	('patients', 'Species', '9606', (167, 175))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('uterine leiomyomas', 'Phenotype', 'HP:0000131', (318, 336))	('HLRCC', 'Disease', (231, 236))	('predisposes', 'Reg', (51, 62))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
106233	31636445	This divergence in the clinical phenotypes observed suggest that the 'two-hit' mutational timing and tissue-specific nature of mutations may be crucial to cancer predisposition.	('mutations', 'Var', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
106237	31636445	Current hypotheses have been recently discussed, and, building upon this insight, we postulate a concept of 'LOH tolerance' in 'permissive' tissues that propagate tumourigenesis due to their capability to be more flexible (such as the ability to metabolically adapt and/or compensate as a result of these genetic perturbations e.g.	('genetic perturbations', 'Var', (305, 326))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('perturbations', 'Var', (313, 326))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('tumour', 'Disease', (163, 169))
106242	31636445	More recently, D2HG accumulation as a result of loss-of-function mutations in D2HGDH has been observed in a small subset of large B-cell lymphoma, implicating both the synthesis and conversion of D2HG in its accumulation in cancer.	('lymphoma', 'Disease', (137, 145))	('synthesis', 'biological_process', 'GO:0009058', ('168', '177'))	('accumulation', 'PosReg', (20, 32))	('D2HGDH', 'Gene', '728294', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('lymphoma', 'Disease', 'MESH:D008223', (137, 145))	('lymphoma', 'Phenotype', 'HP:0002665', (137, 145))	('D2HG', 'Chemical', '-', (15, 19))	('loss-of-function', 'NegReg', (48, 64))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (130, 145))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('D2HG', 'Chemical', '-', (78, 82))	('D2HG', 'Chemical', '-', (196, 200))	('cancer', 'Disease', (224, 230))	('mutations', 'Var', (65, 74))	('D2HGDH', 'Gene', (78, 84))
106243	31636445	Using the cBioPortal Database, <1% of IDH1/2 mutations are found in large-scale cancer genomic studies of RCC such as the TCGA dataset.	('mutations', 'Var', (45, 54))	('IDH1/2', 'Gene', '3417;3418', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('IDH1/2', 'Gene', (38, 44))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('RCC', 'Disease', (106, 109))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('cancer', 'Disease', (80, 86))
106247	31636445	Furthermore, loss of L2HGDH conferred a worse prognosis in patients with ccRCC compared to those with L2HGDH, with preliminary metabolomic profiling suggesting that increasing levels of L2HG are associated with RCC tumour progression, further corroborating its role as an oncometabolite.	('associated', 'Reg', (195, 205))	('tumour', 'Disease', 'MESH:D009369', (215, 221))	('L2HGDH', 'Gene', (102, 108))	('RCC', 'Disease', (211, 214))	('tumour', 'Disease', (215, 221))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('L2HG', 'Protein', (186, 190))	('L2HGDH', 'Gene', (21, 27))	('RCC', 'Disease', 'MESH:C538614', (211, 214))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Phenotype', 'HP:0005584', (211, 214))	('RCC', 'Disease', (75, 78))	('L2HGDH', 'Gene', '79944', (102, 108))	('increasing', 'PosReg', (165, 175))	('patients', 'Species', '9606', (59, 67))	('L2HGDH', 'Gene', '79944', (21, 27))	('tumour', 'Phenotype', 'HP:0002664', (215, 221))	('loss', 'Var', (13, 17))
106248	31636445	More recently, mutations in several genes, alphaKG dehydrogenase (alphaKGDH), lipoic acid synthase (LIAS)  and lipoyltransferase-1 (LIPT1) have also been implicated in 2HG accumulation.	('2HG', 'Disease', (168, 171))	('LIAS', 'Gene', (100, 104))	('LIPT1', 'Gene', (132, 137))	('alphaKGDH', 'Gene', '4967', (66, 75))	('lipoic acid synthase', 'Gene', '11019', (78, 98))	('mutations', 'Var', (15, 24))	('LIAS', 'Gene', '11019', (100, 104))	('implicated', 'Reg', (154, 164))	('lipoyltransferase-1', 'Gene', (111, 130))	('lipoic acid synthase', 'Gene', (78, 98))	('lipoyltransferase-1', 'Gene', '51601', (111, 130))	('lipoic acid synthase', 'molecular_function', 'GO:0016992', ('78', '98'))	('LIPT1', 'Gene', '51601', (132, 137))	('alphaKGDH', 'Gene', (66, 75))
106250	31636445	The truncated TCA cycle due to these mutations promoted the production of L2HG from accumulated alphaKG, with evidence of downstream oncometabolite activity inhibiting PHDs leading to HIF stabilisation and HIF1-targeted gene activation including VEGF and GLUT1.	('production', 'MPA', (60, 70))	('HIF1', 'Gene', '3091', (206, 210))	('promoted', 'PosReg', (47, 55))	('activation', 'PosReg', (225, 235))	('TCA', 'Chemical', 'MESH:D014233', (14, 17))	('mutations', 'Var', (37, 46))	('VEGF', 'Gene', (246, 250))	('GLUT1', 'Gene', (255, 260))	('HIF1', 'Gene', (206, 210))	('PHDs', 'Chemical', 'MESH:D013929', (168, 172))	('GLUT1', 'Gene', '6513', (255, 260))	('TCA cycle', 'biological_process', 'GO:0006099', ('14', '23'))	('VEGF', 'Gene', '7422', (246, 250))
106253	31636445	Characterisation of heterozygous germline mutations in this setting may provide additional insight for the tumorigenic role of L2HG accumulation in alphaKGDH/LIAS mutations.	('alphaKGDH', 'Gene', (148, 157))	('LIAS', 'Gene', '11019', (158, 162))	('mutations', 'Var', (163, 172))	('LIAS', 'Gene', (158, 162))	('alphaKGDH', 'Gene', '4967', (148, 157))	('accumulation', 'PosReg', (132, 144))	('L2HG', 'Gene', (127, 131))
106254	31636445	Table 1. highlights the genetic mutations in oncometabolite-associated RCC subtypes, the clinical features and potential therapeutic strategies which will be discussed further in this review.	('mutations', 'Var', (32, 41))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))
106265	31636445	HIF-dependent expression of micro-RNA210 (miR-210) in lung adenocarcinoma cells in vitro was demonstrated to target the SDHD subunit and impair SDH function, and the ensuing succinate accumulation in turn leads to HIF stabilisation through inhibition of PHDs perpetuating this hypoxic phenotype.	('inhibition', 'NegReg', (240, 250))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (54, 73))	('RNA', 'cellular_component', 'GO:0005562', ('34', '37'))	('impair', 'NegReg', (137, 143))	('HIF stabilisation', 'MPA', (214, 231))	('target', 'Reg', (109, 115))	('SDHD', 'Gene', '6392', (120, 124))	('PHDs', 'Chemical', 'MESH:D013929', (254, 258))	('function', 'MPA', (148, 156))	('leads to', 'Reg', (205, 213))	('succinate accumulation', 'MPA', (174, 196))	('SDHD', 'Gene', (120, 124))	('lung adenocarcinoma', 'Disease', (54, 73))	('SDH', 'Protein', (144, 147))	('succinate', 'Chemical', 'MESH:D019802', (174, 183))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (54, 73))	('micro-RNA210', 'Var', (28, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))
106279	31636445	Interestingly, HIF1alpha/2alpha inactivation in SDHB-deficient osteosarcoma cells significantly impaired tumour growth in a mouse xenograft model whereas HIF1alpha/2alpha inactivation in a FH-deficient mouse model of renal cyst disease exacerbated or failed to ameliorate this phenotype respectively.	('SDHB-deficient osteosarcoma cells significantly impaired tumour growth', 'Disease', 'MESH:D006130', (48, 118))	('renal cyst', 'Phenotype', 'HP:0000107', (217, 227))	('FH', 'Gene', '2271', (189, 191))	('renal cyst disease', 'Disease', (217, 235))	('mouse', 'Species', '10090', (202, 207))	('osteosarcoma', 'Phenotype', 'HP:0002669', (63, 75))	('mouse', 'Species', '10090', (124, 129))	('inactivation', 'Var', (32, 44))	('renal cyst disease', 'Disease', 'MESH:D007674', (217, 235))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
106281	31636445	Whilst L2HG has also been shown to inactivate PHDs and aberrantly stabilise HIF1alpha, the activity of D2HG on PHD remains contentious.	('D2HG', 'Chemical', '-', (103, 107))	('stabilise', 'Reg', (66, 75))	('PHDs', 'Protein', (46, 50))	('PHD', 'molecular_function', 'GO:0050175', ('111', '114'))	('inactivate', 'NegReg', (35, 45))	('HIF1alpha', 'Protein', (76, 85))	('L2HG', 'Var', (7, 11))	('aberrantly', 'Var', (55, 65))	('PHDs', 'Chemical', 'MESH:D013929', (46, 50))
106284	31636445	DNA methylation at 'CpG islands' (clusters of dinucleotide sequence of a cytosine followed by a guanosine nucleotide in the 5'-3' direction, often found in promoter regions upstream of transcription sites) usually represses downstream gene transcription.	('guanosine nucleotide', 'Chemical', '-', (96, 116))	('transcription', 'biological_process', 'GO:0006351', ('185', '198'))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('methylation', 'Var', (4, 15))	('transcription', 'biological_process', 'GO:0006351', ('240', '253'))	('dinucleotide', 'Chemical', 'MESH:D015226', (46, 58))	('represses', 'NegReg', (214, 223))	('cytosine', 'Chemical', 'MESH:D003596', (73, 81))
106287	31636445	In general, global DNA hypomethylation, leading to inappropriate transcriptional activity and chromosomal instability, coupled with specific patterns of hypermethylated CpG promoter islands, especially upstream of tumour suppressor genes resulting in repressed expression, is characteristic of many tumour types.	('hypermethylated', 'Var', (153, 168))	('inappropriate transcriptional activity', 'MPA', (51, 89))	('tumour', 'Disease', (214, 220))	('tumour', 'Phenotype', 'HP:0002664', (299, 305))	('expression', 'MPA', (261, 271))	('chromosomal instability', 'Phenotype', 'HP:0040012', (94, 117))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('19', '38'))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('tumour', 'Disease', 'MESH:D009369', (299, 305))	('tumour', 'Disease', 'MESH:D009369', (214, 220))	('tumour', 'Disease', (299, 305))	('chromosomal instability', 'CPA', (94, 117))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
106290	31636445	In addition, succinate accumulation in SDHB-knockout chromaffin cells and SDHB-knockdown murine ovarian cancer cells, as well as 2HG accumulation in IDH1 mutant cells, demonstrated KDM and TET inhibition with characteristic hypermethylation phenotypes associated with suppression of cellular differentiation and activation of EMT, through up- or downregulation of positive and negative EMT regulator genes respectively.	('negative', 'NegReg', (377, 385))	('downregulation', 'NegReg', (346, 360))	('EMT regulator genes', 'Gene', (386, 405))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ovarian cancer', 'Disease', 'MESH:D010051', (96, 110))	('activation', 'PosReg', (312, 322))	('EMT', 'Gene', (326, 329))	('SDHB-knockdown', 'Gene', (74, 88))	('suppression', 'NegReg', (268, 279))	('IDH1', 'Gene', (149, 153))	('EMT', 'biological_process', 'GO:0001837', ('386', '389'))	('TET', 'Chemical', '-', (189, 192))	('EMT', 'biological_process', 'GO:0001837', ('326', '329'))	('succinate', 'Chemical', 'MESH:D019802', (13, 22))	('cellular differentiation', 'CPA', (283, 307))	('ovarian cancer', 'Disease', (96, 110))	('up-', 'PosReg', (339, 342))	('ovarian cancer', 'Phenotype', 'HP:0100615', (96, 110))	('murine', 'Species', '10090', (89, 95))	('inhibition', 'NegReg', (193, 203))	('mutant', 'Var', (154, 160))
106291	31636445	HLRCC-derived FH-deficient cells also elicited an EMT signature in keeping with SDH-deficient cells, via fumarate-induced TET-mediated epigenetic suppression of miR-200, a short RNA molecule with tumour suppressive effects on EMT gene expression by modulating mRNA translation.	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('EMT', 'biological_process', 'GO:0001837', ('50', '53'))	('HLRCC', 'Disease', (0, 5))	('tumour', 'Disease', 'MESH:D009369', (196, 202))	('TET', 'Chemical', '-', (122, 125))	('HLRCC', 'Disease', 'MESH:C535516', (0, 5))	('EMT', 'biological_process', 'GO:0001837', ('226', '229'))	('tumour', 'Disease', (196, 202))	('modulating', 'Reg', (249, 259))	('translation', 'biological_process', 'GO:0006412', ('265', '276'))	('elicited', 'Reg', (38, 46))	('FH', 'Gene', '2271', (14, 16))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('RNA', 'cellular_component', 'GO:0005562', ('178', '181'))	('gene expression', 'biological_process', 'GO:0010467', ('230', '245'))	('epigenetic', 'Var', (135, 145))	('fumarate', 'Chemical', 'MESH:D005650', (105, 113))	('miR-200', 'Gene', (161, 168))	('suppression', 'NegReg', (146, 157))	('mRNA translation', 'MPA', (260, 276))
106292	31636445	This EMT phenotypic switch induced by oncometabolite accumulation in FH- and SDH-mutant RCC tumours is no doubt a contributing factor to their clinically aggressive behaviour.	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('behaviour', 'biological_process', 'GO:0007610', ('165', '174'))	('tumour', 'Disease', (92, 98))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('FH', 'Gene', '2271', (69, 71))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('aggressive behaviour', 'Phenotype', 'HP:0000718', (154, 174))	('SDH-mutant', 'Var', (77, 87))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('EMT', 'biological_process', 'GO:0001837', ('5', '8'))
106294	31636445	DNA hypermethylation linking to repression of specific-lineage differentiation has also been observed in patients with IDH1/2 mutant chondrosarcoma and acute myeloid leukaemia.	('patients', 'Species', '9606', (105, 113))	('IDH1/2', 'Gene', '3417;3418', (119, 125))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (133, 147))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('0', '20'))	('IDH1/2', 'Gene', (119, 125))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (152, 175))	('acute myeloid leukaemia', 'Disease', (152, 175))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (152, 175))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (158, 175))	('chondrosarcoma', 'Disease', (133, 147))	('chondrosarcoma', 'Disease', 'MESH:D002813', (133, 147))	('mutant', 'Var', (126, 132))	('observed', 'Reg', (93, 101))
106295	31636445	Furthermore, accumulations of D2HG resulted in increased DNA methylation (5mc) with concurrent decreased DNA hydroxymethylation, indicating TET inhibition, was observed in human IDH1 glioma tissue and in ectopic expression of IDH1/2 mutations in various cell types, which blocked cellular differentiation.	('DNA methylation', 'MPA', (57, 72))	('decreased', 'NegReg', (95, 104))	('IDH1 glioma', 'Disease', (178, 189))	('IDH1/2', 'Gene', '3417;3418', (226, 232))	('IDH1 glioma', 'Disease', 'MESH:D005910', (178, 189))	('5mc', 'Chemical', 'MESH:D044503', (74, 77))	('DNA methylation', 'biological_process', 'GO:0006306', ('57', '72'))	('human', 'Species', '9606', (172, 177))	('TET', 'Chemical', '-', (140, 143))	('increased', 'PosReg', (47, 56))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('IDH1/2', 'Gene', (226, 232))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('mutations', 'Var', (233, 242))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('D2HG', 'Chemical', '-', (30, 34))	('D2HG', 'Var', (30, 34))	('DNA hydroxymethylation', 'MPA', (105, 127))
106296	31636445	Identification of specific DNA hypermethylation patterns within a subset of colorectal cancers gave rise to the CpG island methylator phenotype (CIMP)-associated cancer subtypes, characterised by their extensive epigenomic aberrations and distinct biology, which has been increasingly recognised in other malignancies including gliomas (G-CIMP)  and more recently, in a subset of type 2 papillary RCC (CIMP-RCC).	('cancer', 'Disease', (162, 168))	('malignancies', 'Disease', (305, 317))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('27', '47'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('RCC', 'Disease', (407, 410))	('RCC', 'Phenotype', 'HP:0005584', (407, 410))	('gliomas', 'Disease', (328, 335))	('colorectal cancers', 'Disease', (76, 94))	('CIMP', 'Chemical', '-', (339, 343))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))	('CIMP', 'Chemical', '-', (402, 406))	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('RCC', 'Phenotype', 'HP:0005584', (397, 400))	('G-CIMP', 'Chemical', '-', (337, 343))	('RCC', 'Disease', (397, 400))	('RCC', 'Disease', 'MESH:C538614', (407, 410))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('CpG island', 'Gene', (112, 122))	('gliomas', 'Disease', 'MESH:D005910', (328, 335))	('hypermethylation patterns', 'Var', (31, 56))	('CIMP', 'Chemical', '-', (145, 149))	('RCC', 'Disease', 'MESH:C538614', (397, 400))	('glioma', 'Phenotype', 'HP:0009733', (328, 334))	('colorectal cancers', 'Disease', 'MESH:D015179', (76, 94))	('gliomas', 'Phenotype', 'HP:0009733', (328, 335))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('malignancies', 'Disease', 'MESH:D009369', (305, 317))
106297	31636445	Interestingly, G-CIMP tumours are tightly associated with IDH1 mutations and introduction of mutant-IDH1 into human primary astrocytes leads to an accumulation of D2HG, inhibition of TET and reproduced a DNA hypermethylation profile that mirrored the changes observed in G-CIMP.	('G-CIMP', 'Chemical', '-', (271, 277))	('tumour', 'Disease', 'MESH:D009369', (22, 28))	('accumulation', 'PosReg', (147, 159))	('tumour', 'Disease', (22, 28))	('D2HG', 'Chemical', '-', (163, 167))	('TET', 'Chemical', '-', (183, 186))	('mutant-IDH1', 'Var', (93, 104))	('mutations', 'Var', (63, 72))	('D2HG', 'Protein', (163, 167))	('G-CIMP', 'Chemical', '-', (15, 21))	('human', 'Species', '9606', (110, 115))	('DNA hypermethylation profile', 'MPA', (204, 232))	('G-CIMP', 'Disease', (15, 21))	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('inhibition', 'NegReg', (169, 179))	('DNA', 'cellular_component', 'GO:0005574', ('204', '207'))	('associated', 'Reg', (42, 52))	('TET', 'MPA', (183, 186))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('204', '224'))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('IDH1', 'Gene', (58, 62))
106305	31636445	Furthermore, inhibition of TBK1/p65 axis in FH-deficient RCC cells blocked HIF1alpha expression and reduced cellular invasion in vitro, suggesting a novel target for treatment in FH-deficient RCC.	('blocked', 'NegReg', (67, 74))	('RCC', 'Disease', (192, 195))	('RCC', 'Phenotype', 'HP:0005584', (192, 195))	('FH', 'Gene', '2271', (44, 46))	('p65', 'Gene', (32, 35))	('FH', 'Gene', '2271', (179, 181))	('RCC', 'Disease', (57, 60))	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('TBK1', 'Gene', '29110', (27, 31))	('expression', 'MPA', (85, 95))	('TBK1', 'molecular_function', 'GO:0008384', ('27', '31'))	('TBK1', 'Gene', (27, 31))	('HIF1alpha', 'Protein', (75, 84))	('inhibition', 'Var', (13, 23))	('reduced', 'NegReg', (100, 107))	('p65', 'Gene', '5970', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('cellular invasion', 'CPA', (108, 125))
106307	31636445	In a similar fashion, silencing HIF1alpha in HLRCC-derived (FH-deficient) RCC cell lines diminished the invasive properties of these cells.	('invasive properties of these cells', 'CPA', (104, 138))	('HIF1alpha', 'Protein', (32, 41))	('diminished', 'NegReg', (89, 99))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('HLRCC', 'Disease', (45, 50))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('silencing', 'Var', (22, 31))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('FH', 'Gene', '2271', (60, 62))	('HLRCC', 'Disease', 'MESH:C535516', (45, 50))
106308	31636445	Potentially contradicting this theory, the genetic inactivation of HIF1alpha/2alpha in Fh1 (murine FH)-deficient mice was shown to exacerbate, or failed to ameliorate, the renal cyst phenotype respectively, suggesting alternate mechanisms for oncogenesis in FH-deficient cells.	('HIF1alpha/2alpha', 'Gene', (67, 83))	('FH', 'Gene', '2271', (258, 260))	('Fh1', 'Gene', (87, 90))	('murine', 'Species', '10090', (92, 98))	('genetic inactivation', 'Var', (43, 63))	('renal cyst', 'Phenotype', 'HP:0000107', (172, 182))	('oncogenesis', 'biological_process', 'GO:0007048', ('243', '254'))	('exacerbate', 'PosReg', (131, 141))	('renal cyst', 'Disease', 'MESH:D007674', (172, 182))	('renal cyst', 'Disease', (172, 182))	('FH', 'Gene', '2271', (99, 101))	('mice', 'Species', '10090', (113, 117))	('Fh1', 'Gene', '14194', (87, 90))
106315	31636445	On the contrary, succination of the antioxidant glutathione in FH-deficient RCC cells, depletes the antioxidant capacity of these cells, rendering them susceptible to endogenous accumulation of ROS with subsequent stabilisation of HIF1alpha and induction of cellular senescence.	('depletes', 'NegReg', (87, 95))	('stabilisation', 'MPA', (214, 227))	('HIF1alpha', 'Protein', (231, 240))	('RCC', 'Disease', (76, 79))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('FH', 'Gene', '2271', (63, 65))	('succination', 'Var', (17, 28))	('cellular senescence', 'biological_process', 'GO:0090398', ('258', '277'))	('glutathione', 'Chemical', 'MESH:D005978', (48, 59))	('rendering', 'Reg', (137, 146))	('cellular senescence', 'CPA', (258, 277))	('antioxidant capacity', 'MPA', (100, 120))	('ROS', 'Chemical', '-', (194, 197))	('ROS', 'Protein', (194, 197))	('accumulation', 'PosReg', (178, 190))
106317	31636445	Ablation of a key mediator of senescence, p21, in Fh1-deficient mice induced the transformation of benign renal cysts into hyperplastic lesions suggesting that this fumarate-induced senescent event needs to be overcome for renal tumorigenesis to proceed.	('benign renal cysts', 'Disease', (99, 117))	('renal cyst', 'Phenotype', 'HP:0000107', (106, 116))	('transformation', 'MPA', (81, 95))	('benign renal cysts', 'Disease', 'MESH:D007674', (99, 117))	('Fh1', 'Gene', '14194', (50, 53))	('Ablation', 'Var', (0, 8))	('Fh1', 'Gene', (50, 53))	('p21', 'Gene', (42, 45))	('p21', 'Gene', '12575', (42, 45))	('fumarate', 'Chemical', 'MESH:D005650', (165, 173))	('renal cysts', 'Phenotype', 'HP:0000107', (106, 117))	('senescence', 'biological_process', 'GO:0010149', ('30', '40'))	('induced', 'Reg', (69, 76))	('mice', 'Species', '10090', (64, 68))
106318	31636445	Although ROS in itself can activate the Nrf2 signalling pathway through KEAP1 inhibition, fumarate-dependent succination of KEAP1 seems to be the predominant mechanism for Nrf2 activation in these FH-deficient cells.	('fumarate-dependent succination', 'MPA', (90, 120))	('KEAP1', 'Gene', '9817', (72, 77))	('activate', 'PosReg', (27, 35))	('activation', 'PosReg', (177, 187))	('KEAP1', 'Gene', '9817', (124, 129))	('Nrf2 signalling pathway', 'Pathway', (40, 63))	('inhibition', 'Var', (78, 88))	('signalling pathway', 'biological_process', 'GO:0007165', ('45', '63'))	('FH', 'Gene', '2271', (197, 199))	('KEAP1', 'Gene', (72, 77))	('ROS', 'Chemical', '-', (9, 12))	('KEAP1', 'Gene', (124, 129))	('fumarate', 'Chemical', 'MESH:D005650', (90, 98))
106334	31636445	In addition, the loss of FH leads to a complex metabolic rewiring pattern involving the diversion of increased glutamine uptake into the haem synthesis/degradation pathway, which critically sustains mitochondrial NADH levels and mitochondrial membrane potential.	('glutamine uptake', 'MPA', (111, 127))	('glutamine', 'Chemical', 'MESH:D005973', (111, 120))	('mitochondrial', 'MPA', (229, 242))	('FH', 'Gene', '2271', (25, 27))	('increased', 'PosReg', (101, 110))	('increased glutamine', 'Phenotype', 'HP:0003217', (101, 120))	('NADH', 'Chemical', 'MESH:D009243', (213, 217))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('229', '251'))	('mitochondrial NADH levels', 'MPA', (199, 224))	('synthesis', 'biological_process', 'GO:0009058', ('142', '151'))	('degradation', 'biological_process', 'GO:0009056', ('152', '163'))	('metabolic', 'MPA', (47, 56))	('uptake', 'biological_process', 'GO:0098739', ('121', '127'))	('haem', 'Chemical', 'MESH:D006418', (137, 141))	('loss', 'Var', (17, 21))	('uptake', 'biological_process', 'GO:0098657', ('121', '127'))
106337	31636445	Perhaps unsurprisingly in RCC, given the multitude of ways in which fumarate lives up to its deserving oncometabolite status, an increased gene expression of FH is correlated with better survival outcomes, and correspondingly, FH gene suppression correlates with very poor prognosis.	('gene expression', 'MPA', (139, 154))	('FH', 'Gene', '2271', (227, 229))	('fumarate', 'Chemical', 'MESH:D005650', (68, 76))	('gene', 'Var', (230, 234))	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('increased', 'PosReg', (129, 138))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('better', 'PosReg', (180, 186))	('survival', 'CPA', (187, 195))	('gene expression', 'biological_process', 'GO:0010467', ('139', '154'))	('FH', 'Gene', '2271', (158, 160))
106348	31636445	Interestingly, the accumulation of D2HG competitively inhibits SDH activity in IDH1-mutant fibrosarcoma cells, causing a hypersuccinylated phenotype and apoptosis resistance, two established hallmarks of cancer.	('fibrosarcoma', 'Disease', (91, 103))	('IDH1-mutant', 'Gene', (79, 90))	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (91, 103))	('SDH activity', 'MPA', (63, 75))	('D2HG', 'Protein', (35, 39))	('D2HG', 'Chemical', '-', (35, 39))	('fibrosarcoma', 'Disease', 'MESH:D005354', (91, 103))	('causing', 'Reg', (111, 118))	('hypersuccinylated phenotype', 'MPA', (121, 148))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('IDH1-mutant', 'Var', (79, 90))	('inhibits', 'NegReg', (54, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('153', '162'))	('apoptosis', 'biological_process', 'GO:0006915', ('153', '162'))	('accumulation', 'PosReg', (19, 31))	('apoptosis resistance', 'CPA', (153, 173))
106349	31636445	Re-expression of the desuccinylase SIRT5, as well as glycine supplementation led to reversal of this hypersuccinylated phenotype and slowed oncogenic growth in vitro.	('oncogenic growth in vitro', 'CPA', (140, 165))	('SIRT5', 'Gene', (35, 40))	('slowed', 'NegReg', (133, 139))	('Re-expression', 'Var', (0, 13))	('glycine', 'Chemical', 'MESH:D005998', (53, 60))	('SIRT5', 'Gene', '23408', (35, 40))	('hypersuccinylated phenotype', 'MPA', (101, 128))
106354	31636445	Furthermore, silencing PC expression attenuated SDH-deficient tumour growth in vivo in a mouse model.	('PC expression', 'Protein', (23, 36))	('SDH-deficient', 'Gene', (48, 61))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('tumour growth', 'Disease', (62, 75))	('tumour growth', 'Disease', 'MESH:D006130', (62, 75))	('attenuated', 'NegReg', (37, 47))	('mouse', 'Species', '10090', (89, 94))	('silencing', 'Var', (13, 22))
106356	31636445	As highlighted earlier, although SDH-deficient renal tumours represent a rare (0.2% of all RCCs) and recently recognised distinct RCC subtype (WHO 2016 Classification), overall it is a highly aggressive tumour with a younger onset of disease (mean age 37- 46years) with the majority of tumours likely to harbour SDHB mutations (82%), although mutations in all four subunits and the assembly factor SDHAF2 have been implicated as tumour suppressor genes in the pathogenesis of RCC.	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('tumour', 'Disease', (53, 59))	('RCC', 'Disease', (91, 94))	('tumour', 'Disease', 'MESH:D009369', (203, 209))	('aggressive tumour', 'Disease', 'MESH:D001523', (192, 209))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('tumour', 'Disease', (203, 209))	('SDHAF2', 'Gene', (398, 404))	('mutations', 'Var', (317, 326))	('SDHAF2', 'Gene', '54949', (398, 404))	('SDH-deficient', 'Gene', (33, 46))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('tumour', 'Phenotype', 'HP:0002664', (429, 435))	('RCC', 'Disease', (476, 479))	('tumour', 'Disease', 'MESH:D009369', (429, 435))	('RCC', 'Phenotype', 'HP:0005584', (476, 479))	('tumour', 'Phenotype', 'HP:0002664', (286, 292))	('pathogenesis', 'biological_process', 'GO:0009405', ('460', '472'))	('tumour', 'Disease', 'MESH:D009369', (286, 292))	('tumour', 'Disease', (429, 435))	('aggressive tumour', 'Disease', (192, 209))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('tumour', 'Disease', (286, 292))	('tumours', 'Phenotype', 'HP:0002664', (286, 293))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))	('RCC', 'Disease', 'MESH:C538614', (476, 479))	('SDHB', 'Gene', (312, 316))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (53, 59))
106362	31636445	In multiple IDH-wildtype leukaemic cell lines, dose-dependent inhibition of cell proliferation and viability were demonstrated upon addition of D2HG.	('viability', 'CPA', (99, 108))	('D2HG', 'Chemical', '-', (144, 148))	('D2HG', 'Var', (144, 148))	('cell proliferation', 'CPA', (76, 94))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('62', '94'))	('inhibition', 'NegReg', (62, 72))
106364	31636445	However, in support of an anti-tumoural effect, D2HG accumulation (either exogenous addition or endogenously through IDH mutation) demonstrated attenuated progression of the disease and increased survival in an in vivo xenograft model of leukaemia.	('attenuated', 'NegReg', (144, 154))	('leukaemia', 'Disease', 'MESH:D007938', (238, 247))	('survival', 'CPA', (196, 204))	('D2HG', 'Chemical', '-', (48, 52))	('D2HG', 'Var', (48, 52))	('IDH', 'Gene', (117, 120))	('increased', 'PosReg', (186, 195))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('leukaemia', 'Disease', (238, 247))	('progression', 'CPA', (155, 166))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('tumour', 'Disease', (31, 37))
106365	31636445	Mechanistically, D2HG competitively inhibits the fat mass and obesity-associated protein (FTO), the first identified mRNA demethylase and member of the alphaKGDD family, which in turn downmodulates the expression of targeted genes, such as MYC, RARA and ASB2, normally involved in promoting cell growth and transformation.	('D2HG', 'Var', (17, 21))	('obesity', 'Phenotype', 'HP:0001513', (62, 69))	('MYC', 'Gene', (240, 243))	('FTO', 'Gene', '79068', (90, 93))	('ASB2', 'Gene', '51676', (254, 258))	('fat mass and obesity-associated protein', 'Gene', '79068', (49, 88))	('expression', 'MPA', (202, 212))	('RARA', 'Gene', '5914', (245, 249))	('cell growth', 'biological_process', 'GO:0016049', ('291', '302'))	('downmodulates', 'NegReg', (184, 197))	('inhibits', 'NegReg', (36, 44))	('ASB2', 'Gene', (254, 258))	('D2HG', 'Chemical', '-', (17, 21))	('MYC', 'Gene', '4609', (240, 243))	('RARA', 'Gene', (245, 249))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('FTO', 'Gene', (90, 93))
106367	31636445	Furthermore, direct inhibition of ATP synthase and subsequent downregulation of mTOR signalling by D2HG accumulation in IDH1-mutant glioma cells in vitro and in vivo suggest growth suppressive functions of D2HG and further corroborates the anti-tumoural effects of D2HG.	('tumour', 'Disease', 'MESH:D009369', (245, 251))	('glioma', 'Disease', (132, 138))	('tumour', 'Disease', (245, 251))	('IDH1-mutant', 'Var', (120, 131))	('downregulation', 'NegReg', (62, 76))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('D2HG', 'Chemical', '-', (99, 103))	('growth suppressive functions', 'CPA', (174, 202))	('D2HG', 'Chemical', '-', (265, 269))	('accumulation', 'PosReg', (104, 116))	('signalling', 'biological_process', 'GO:0023052', ('85', '95'))	('inhibition', 'NegReg', (20, 30))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('ATP synthase', 'molecular_function', 'GO:0016467', ('34', '46'))	('D2HG', 'Chemical', '-', (206, 210))	('mTOR', 'Gene', (80, 84))	('ATP synthase', 'Enzyme', (34, 46))	('mTOR', 'Gene', '2475', (80, 84))	('D2HG', 'Gene', (99, 103))	('ATP synthase', 'molecular_function', 'GO:0016468', ('34', '46'))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))	('IDH1-mutant', 'Gene', (120, 131))
106371	31636445	Supporting this notion, accumulations of D2HG and L2HG were observed in colorectal cell lines in the absence of IDH or D-/L2HGDH mutations.	('L2HGDH', 'Gene', (122, 128))	('D2HG', 'Chemical', '-', (41, 45))	('mutations', 'Var', (129, 138))	('L2HGDH', 'Gene', '79944', (122, 128))	('accumulations', 'PosReg', (24, 37))
106372	31636445	Dissecting their individual roles in this setting revealed that D2HG, but not L2HG, was found to have pro-tumoural roles in EMT gene upregulation through KDM inhibition and subsequent histone hypermethylation, as well as in the acquisition of invasive and migratory phenotypes in these cells.	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('KDM', 'MPA', (154, 157))	('upregulation', 'PosReg', (133, 145))	('histone', 'MPA', (184, 191))	('EMT', 'biological_process', 'GO:0001837', ('124', '127'))	('tumour', 'Disease', (106, 112))	('D2HG', 'Chemical', '-', (64, 68))	('inhibition', 'NegReg', (158, 168))	('D2HG', 'Var', (64, 68))	('hypermethylation', 'Var', (192, 208))	('EMT gene', 'Gene', (124, 132))
106377	31636445	Unravelling the oncogenic identity of a small group of seemingly innocuous metabolites has given rise to the oncometabolite paradigm, whereby aberrant accumulations of member metabolites have demonstrated potent pro-oncogenic capabilities that impact on tumorigenesis, tumour phenotypes and progression.	('progression', 'CPA', (291, 302))	('aberrant', 'Var', (142, 150))	('tumour', 'Phenotype', 'HP:0002664', (269, 275))	('tumour', 'Disease', 'MESH:D009369', (269, 275))	('tumorigenesis', 'CPA', (254, 267))	('accumulations', 'PosReg', (151, 164))	('pro-oncogenic capabilities', 'CPA', (212, 238))	('impact', 'Reg', (244, 250))	('tumour', 'Disease', (269, 275))
106388	31636445	As highlighted, L2HG is significantly accumulated in human ccRCC tissues, partly attributable to the LOH of the L2HGDH gene as well as the promiscuous activity of MDH2 on predominantly glutamine-derived alphaKG.	('glutamine', 'Chemical', 'MESH:D005973', (185, 194))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('L2HGDH', 'Gene', '79944', (112, 118))	('MDH', 'molecular_function', 'GO:0030060', ('163', '166'))	('MDH2', 'Gene', '4191', (163, 167))	('MDH', 'molecular_function', 'GO:0018468', ('163', '166'))	('human', 'Species', '9606', (53, 58))	('MDH2', 'Gene', (163, 167))	('LOH', 'Var', (101, 104))	('RCC', 'Disease', (61, 64))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('MDH', 'molecular_function', 'GO:0033720', ('163', '166'))	('L2HGDH', 'Gene', (112, 118))
106393	31636445	Although it is highly unlikely that the effects of glutaminase inhibition in RCC are purely mediated through L2HG (as not all RCC tumours accumulate L2HG), given that the loss of L2HGDH and accumulation of L2HG confers a worse prognosis in patients with ccRCC and concurrently, upregulation of the glutamine transporter correlates with aggressive ccRCC and worse prognosis, it would be of immense value to ascertain whether there is crossover talk, given the ability of L2HG to significantly modulate the epigenetic cell state, as well as determine whether glutaminase inhibition has a more profound effect in L2HG-associated RCC tumours given the oncometabolite gamut of capabilities.	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('RCC', 'Disease', 'MESH:C538614', (626, 629))	('L2HGDH', 'Gene', (179, 185))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('glutaminase', 'Gene', (51, 62))	('glutamine', 'Chemical', 'MESH:D005973', (298, 307))	('L2HGDH', 'Gene', '79944', (179, 185))	('glutaminase', 'Gene', (557, 568))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('tumours', 'Phenotype', 'HP:0002664', (630, 637))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('tumour', 'Disease', (130, 136))	('RCC', 'Disease', (256, 259))	('RCC', 'Phenotype', 'HP:0005584', (256, 259))	('inhibition', 'NegReg', (569, 579))	('tumour', 'Phenotype', 'HP:0002664', (630, 636))	('tumour', 'Disease', 'MESH:D009369', (630, 636))	('loss', 'Var', (171, 175))	('glutaminase', 'Gene', '2744', (51, 62))	('tumour', 'Disease', (630, 636))	('RCC', 'Disease', 'MESH:C538614', (256, 259))	('RCC', 'Disease', (349, 352))	('RCC', 'Phenotype', 'HP:0005584', (349, 352))	('patients', 'Species', '9606', (240, 248))	('modulate', 'Reg', (492, 500))	('RCC', 'Phenotype', 'HP:0005584', (626, 629))	('RCC', 'Disease', (626, 629))	('RCC', 'Disease', (77, 80))	('glutaminase', 'Gene', '2744', (557, 568))	('RCC', 'Disease', 'MESH:C538614', (349, 352))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))
106394	31636445	In addition to glutamine/MDH2 axis inhibition, genetic restoration of L2HGDH also demonstrated suppression of tumour growth in vivo.	('MDH2', 'Gene', '4191', (25, 29))	('MDH', 'molecular_function', 'GO:0033720', ('25', '28'))	('MDH2', 'Gene', (25, 29))	('glutamine', 'Chemical', 'MESH:D005973', (15, 24))	('MDH', 'molecular_function', 'GO:0030060', ('25', '28'))	('genetic restoration', 'Var', (47, 66))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('L2HGDH', 'Gene', (70, 76))	('tumour growth', 'Disease', (110, 123))	('suppression', 'NegReg', (95, 106))	('MDH', 'molecular_function', 'GO:0018468', ('25', '28'))	('L2HGDH', 'Gene', '79944', (70, 76))	('tumour growth', 'Disease', 'MESH:D006130', (110, 123))
106404	31636445	As epigenetic dysregulation and pseudohypoxia drive are strongly implicated in the pathogenesis and progression of RCC, broad targeting of alphaKGDD combating both these elements, warrants further investigation in this setting.	('pathogenesis', 'biological_process', 'GO:0009405', ('83', '95'))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('pseudohypoxia', 'Disease', (32, 45))	('pseudohypoxia', 'Disease', '-', (32, 45))	('epigenetic', 'Var', (3, 13))	('implicated', 'Reg', (65, 75))
106406	31636445	Attenuation of tumour growth upon HIF2alpha inhibition was demonstrated in vitro and in multiple RCC tumourgraft models.	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('inhibition', 'Var', (44, 54))	('HIF2alpha', 'Gene', '2034', (34, 43))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('Attenuation', 'NegReg', (0, 11))	('tumour', 'Disease', (101, 107))	('tumour', 'Disease', (15, 21))	('HIF2alpha', 'Gene', (34, 43))	('tumour growth', 'Disease', (15, 28))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('tumour growth', 'Disease', 'MESH:D006130', (15, 28))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))
106412	31636445	Furthermore, decitabine (a derivative of 5-azacitidine) demonstrated tumour growth suppression in IDH1-mutant glioma cells in vivo.	('glioma', 'Disease', (110, 116))	('tumour growth suppression', 'Disease', 'MESH:D006130', (69, 94))	('IDH1-mutant', 'Var', (98, 109))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('decitabine', 'Chemical', 'MESH:D000077209', (13, 23))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('IDH1-mutant', 'Gene', (98, 109))	('tumour growth suppression', 'Disease', (69, 94))	('5-azacitidine', 'Chemical', 'MESH:D001374', (41, 54))
106417	31636445	Furthermore, knockdown of KDM6A, a known H3K27 demethylase, in L2HGDH-wildtype RCC phenocopied the enhanced migratory properties of elevated L2HG-RCC cells, implicating KDM6A as a specific target for L2HG in RCC.	('enhanced', 'PosReg', (99, 107))	('KDM6A', 'Gene', (169, 174))	('KDM6A', 'Gene', (26, 31))	('knockdown', 'Var', (13, 22))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('migratory properties', 'CPA', (108, 128))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (208, 211))	('RCC', 'Disease', (208, 211))	('L2HGDH', 'Gene', (63, 69))	('L2HGDH', 'Gene', '79944', (63, 69))	('RCC', 'Disease', (79, 82))	('KDM6A', 'Gene', '7403', (169, 174))	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('KDM6A', 'Gene', '7403', (26, 31))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('HG-RCC', 'CellLine', 'CVCL:2174;-0.03627339336219138', (143, 149))	('RCC', 'Disease', 'MESH:C538614', (79, 82))
106418	31636445	Interestingly, mutations, predominantly somatic, in KDM6A (also referred to as UTX) have been identified in renal cancer , suggesting that chromatin remodelling via oncometabolites may recapitulate the effects of other epigenetic modifiers mutated in RCC.	('chromatin remodelling', 'biological_process', 'GO:0006338', ('139', '160'))	('renal cancer', 'Disease', (108, 120))	('KDM6A', 'Gene', (52, 57))	('identified', 'Reg', (94, 104))	('mutations', 'Var', (15, 24))	('UTX', 'Gene', '7403', (79, 82))	('renal cancer', 'Phenotype', 'HP:0009726', (108, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('renal cancer', 'Disease', 'MESH:D007680', (108, 120))	('RCC', 'Disease', (251, 254))	('RCC', 'Phenotype', 'HP:0005584', (251, 254))	('KDM6A', 'Gene', '7403', (52, 57))	('RCC', 'Disease', 'MESH:C538614', (251, 254))	('UTX', 'Gene', (79, 82))	('chromatin', 'cellular_component', 'GO:0000785', ('139', '148'))
106419	31636445	Due to the identification of mutations in epigenetic regulators, such as KDM6A/UTX in renal cancer, several studies have investigated the effects of DNMT inhibitors in renal cancer with encouraging results demonstrating growth inhibition in VHL-mutant and -wildtype RCC cell lines.	('DNMT', 'Gene', '1786', (149, 153))	('UTX', 'Gene', '7403', (79, 82))	('DNMT', 'Gene', (149, 153))	('RCC', 'Disease', (266, 269))	('renal cancer', 'Disease', (86, 98))	('RCC', 'Phenotype', 'HP:0005584', (266, 269))	('renal cancer', 'Disease', 'MESH:D007680', (168, 180))	('renal cancer', 'Phenotype', 'HP:0009726', (86, 98))	('growth', 'MPA', (220, 226))	('UTX', 'Gene', (79, 82))	('RCC', 'Disease', 'MESH:C538614', (266, 269))	('KDM6A', 'Gene', (73, 78))	('VHL', 'Gene', (241, 244))	('renal cancer', 'Disease', 'MESH:D007680', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('mutations', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('VHL', 'Gene', '7428', (241, 244))	('renal cancer', 'Disease', (168, 180))	('renal cancer', 'Phenotype', 'HP:0009726', (168, 180))	('KDM6A', 'Gene', '7403', (73, 78))
106422	31636445	Overall, these studies demonstrate that targeting epigenetic modifiers in RCC has evidence of anti-tumoural effects that may also potentiate and synergise with other adjunctive therapies such as interferon therapy.	('potentiate', 'PosReg', (130, 140))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', (99, 105))	('epigenetic modifiers', 'Var', (50, 70))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
106435	31636445	L2HG is associated with poorer patient prognosis and tumour progression.	('tumour', 'Disease', (53, 59))	('L2HG', 'Var', (0, 4))	('patient', 'Species', '9606', (31, 38))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (53, 59))
106450	31636445	In addition, metabolomic analyses of urine from Fh1-deficient mice and growth media of FH-deficient cells revealed consistently elevated levels of argininosuccinate as a result of fumarate-induced reversal of ASL activity, raising its potential as a urinary biomarker for the early detection of FH-deficient renal cancer.	('Fh1', 'Gene', (48, 51))	('renal cancer', 'Disease', (308, 320))	('levels of argininosuccinate', 'MPA', (137, 164))	('renal cancer', 'Disease', 'MESH:D007680', (308, 320))	('FH', 'Gene', '2271', (87, 89))	('FH', 'Gene', '2271', (295, 297))	('mice', 'Species', '10090', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('ASL activity', 'MPA', (209, 221))	('fumarate', 'Chemical', 'MESH:D005650', (180, 188))	('reversal', 'NegReg', (197, 205))	('fumarate-induced', 'Var', (180, 196))	('elevated', 'PosReg', (128, 136))	('argininosuccinate', 'Chemical', 'MESH:D001125', (147, 164))	('Fh1', 'Gene', '14194', (48, 51))	('renal cancer', 'Phenotype', 'HP:0009726', (308, 320))
106456	31636445	Oncometabolites are aberrantly accumulated metabolites that possess pro-oncogenic capabilities that contribute to tumorigenesis via epigenetic dysregulation and can influence tumour progression through phenotypic switches such as EMT.	('tumorigenesis', 'CPA', (114, 127))	('epigenetic', 'Var', (132, 142))	('tumour', 'Disease', 'MESH:D009369', (175, 181))	('influence', 'Reg', (165, 174))	('tumour', 'Disease', (175, 181))	('EMT', 'Disease', (230, 233))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('EMT', 'biological_process', 'GO:0001837', ('230', '233'))
106461	31861116	We investigated the the prognostic significance of GSTO1 (rs4925) and GSTO2 (rs156697 and rs2297235) polymorphisms in clear cell renal cell carcinoma (ccRCC) patients.	('ccRCC', 'Disease', 'MESH:D002292', (151, 156))	('rs156697', 'Mutation', 'rs156697', (77, 85))	('rs2297235', 'Var', (90, 99))	('clear cell renal cell carcinoma', 'Disease', (118, 149))	('rs4925', 'Var', (58, 64))	('rs156697', 'Var', (77, 85))	('GSTO1', 'Gene', (51, 56))	('rs4925', 'Mutation', 'rs4925', (58, 64))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (129, 149))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (118, 149))	('rs2297235', 'Mutation', 'rs2297235', (90, 99))	('ccRCC', 'Disease', (151, 156))	('patients', 'Species', '9606', (158, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('GSTO2', 'Gene', (70, 75))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (118, 149))
106464	31861116	GSTO1*C/C genotype independently predicted higher risk of overall mortality among male ccRCC patients (p = 0.037).	('GSTO1*C/C', 'Var', (0, 9))	('higher', 'PosReg', (43, 49))	('overall mortality', 'MPA', (58, 75))	('ccRCC', 'Disease', (87, 92))	('ccRCC', 'Disease', 'MESH:D002292', (87, 92))	('patients', 'Species', '9606', (93, 101))
106467	31861116	This study demonstrated significant prognostic role of GSTO1 polymorphism in ccRCC.	('GSTO1', 'Gene', (55, 60))	('polymorphism', 'Var', (61, 73))	('ccRCC', 'Disease', (77, 82))	('ccRCC', 'Disease', 'MESH:D002292', (77, 82))
106471	31861116	Indeed, among genetic factors that contribute to RCC risk, the most investigated is mutation of VHL gene, underlying the abnormal accumulation of hypoxia-inducible factor alpha (HIFalpha) proteins in normoxia.	('RCC', 'Disease', 'MESH:D002292', (49, 52))	('RCC', 'Disease', (49, 52))	('hypoxia', 'Disease', 'MESH:D000860', (146, 153))	('accumulation', 'PosReg', (130, 142))	('VHL', 'Gene', (96, 99))	('VHL', 'Gene', '7428', (96, 99))	('hypoxia', 'Disease', (146, 153))	('mutation', 'Var', (84, 92))
106480	31861116	This may not come as a surprise, since most of the genes encoding for members of GST enzyme superfamily are highly polymorphic, therefore, altering the individual susceptibility to environmental and oxidative stress.	('oxidative stress', 'Phenotype', 'HP:0025464', (199, 215))	('genes', 'Var', (51, 56))	('altering', 'Reg', (139, 147))	('men', 'Species', '9606', (188, 191))
106492	31861116	Additionally, they demonstrated that GSTO1-1 knockdown blocks cancer stem cell enrichment, tumor initiation and metastasis.	('GSTO1-1', 'Gene', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('metastasis', 'CPA', (112, 122))	('tumor initiation', 'Disease', 'MESH:D009369', (91, 107))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('cancer', 'Disease', (62, 68))	('GSTO1-1', 'Gene', '9446', (37, 44))	('men', 'Species', '9606', (85, 88))	('blocks', 'NegReg', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumor initiation', 'Disease', (91, 107))	('knockdown', 'Var', (45, 54))
106495	31861116	Based on the association between structure and function, three GSTO polymorphisms seem to be of greatest importance: one transition polymorphism in the position 183 at 5' untranslated region (5' UTR) of GSTO2 gene (GSTO2*A183G, rs2297235), as well as two single nucleotide polymorphisms GSTO1*C419A (rs4925) and GSTO2*A424G (rs156697).	('A183G', 'Mutation', 'rs2297235', (221, 226))	('rs2297235', 'Var', (228, 237))	('A424G', 'Mutation', 'rs156697', (318, 323))	('GSTO2', 'Gene', (312, 317))	('rs4925', 'Var', (300, 306))	('rs4925', 'Mutation', 'rs4925', (300, 306))	('C419A', 'Mutation', 'rs4925', (293, 298))	('rs2297235', 'Mutation', 'rs2297235', (228, 237))	('GSTO2', 'Gene', (203, 208))	('GSTO2*A183G', 'Var', (215, 226))	('rs156697', 'Mutation', 'rs156697', (325, 333))
106496	31861116	GSTO1 rs4925 polymorphism, causing alanine to aspartate substitution in amino acid 140 (*Ala140Asp), results in a change in its deglutathionylase activity.	('GSTO1', 'Gene', (0, 5))	('polymorphism', 'Var', (13, 25))	('deglutathionylase activity', 'MPA', (128, 154))	('alanine to aspartate', 'MPA', (35, 55))	('rs4925 polymorphism', 'Var', (6, 25))	('causing', 'Reg', (27, 34))	('alanine to aspartate substitution in amino acid 140', 'Mutation', 'rs4925', (35, 86))	('change', 'Reg', (114, 120))	('rs4925', 'Mutation', 'rs4925', (6, 12))
106497	31861116	Regarding GSTO2 rs156697 polymorphism, which causes an asparagine to aspartate substitution in amino acid 142 (* Asn142Asp), a strong association between variant GSTO2*G allele and lower GSTO2 gene expression has been shown.	('GSTO2*', 'Gene', (162, 168))	('Asn142Asp', 'Var', (113, 122))	('Asn142Asp', 'SUBSTITUTION', 'None', (113, 122))	('rs156697', 'Mutation', 'rs156697', (16, 24))	('GSTO2', 'Gene', (187, 192))	('rs156697', 'Var', (16, 24))	('lower', 'NegReg', (181, 186))	('causes', 'Reg', (45, 51))	('variant', 'Var', (154, 161))	('asparagine to aspartate substitution in amino acid 142', 'Mutation', 'rs156697', (55, 109))	('GSTO2', 'Gene', (10, 15))	('expression', 'MPA', (198, 208))	('gene expression', 'biological_process', 'GO:0010467', ('193', '208'))
106498	31861116	These GSTO polymorphisms were independent predictors of a higher risk of death among patients with muscle invasive bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('muscle invasive bladder cancer', 'Disease', (99, 129))	('invasive bladder', 'Phenotype', 'HP:0100645', (106, 122))	('GSTO', 'Gene', (6, 10))	('patients', 'Species', '9606', (85, 93))	('polymorphisms', 'Var', (11, 24))	('bladder cancer', 'Phenotype', 'HP:0009725', (115, 129))	('death', 'Disease', 'MESH:D003643', (73, 78))	('death', 'Disease', (73, 78))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (99, 129))
106499	31861116	Regarding GST omega class polymorphisms in ccRCC, haplotype comprised of all three variant alleles (GSTO1*A (rs4925), GSTO2*G (rs156697) and GSTO2*G (rs2297235)) showed significantly higher risk of disease development compared to haplotype consisting of all three referent alleles.	('rs4925', 'Var', (109, 115))	('higher', 'PosReg', (183, 189))	('disease development', 'CPA', (198, 217))	('rs4925', 'Mutation', 'rs4925', (109, 115))	('ccRCC', 'Disease', (43, 48))	('GSTO1*A (rs4925', 'Var', (100, 115))	('rs156697', 'Var', (127, 135))	('ccRCC', 'Disease', 'MESH:D002292', (43, 48))	('rs156697', 'Mutation', 'rs156697', (127, 135))	('men', 'Species', '9606', (213, 216))	('rs2297235', 'Mutation', 'rs2297235', (150, 159))
106501	31861116	Therefore, we aimed to evaluate the effect of specific GSTO gene variants on the postoperative prognosis in patients with ccRCC.	('GSTO gene', 'Gene', (55, 64))	('variants', 'Var', (65, 73))	('ccRCC', 'Disease', (122, 127))	('ccRCC', 'Disease', 'MESH:D002292', (122, 127))	('patients', 'Species', '9606', (108, 116))
106510	31861116	Kaplan-Meier survival analysis did not show statistically significant effect of either GSTO1 (rs4925) or GSTO2 (rs156697 and rs2297235) polymorphisms on overall survival among ccRCC patients (Figure 1a).	('rs2297235', 'Var', (125, 134))	('rs4925', 'Mutation', 'rs4925', (94, 100))	('GSTO1', 'Gene', (87, 92))	('rs156697', 'Mutation', 'rs156697', (112, 120))	('rs156697', 'Var', (112, 120))	('GSTO2', 'Gene', (105, 110))	('rs2297235', 'Mutation', 'rs2297235', (125, 134))	('patients', 'Species', '9606', (182, 190))	('rs4925', 'Var', (94, 100))	('ccRCC', 'Disease', (176, 181))	('ccRCC', 'Disease', 'MESH:D002292', (176, 181))
106513	31861116	However, GSTO2 rs156697 and rs2297235 polymorphisms did not show effect on overall survival among male ccRCC patients (Figure 1b).	('GSTO2', 'Gene', (9, 14))	('rs2297235', 'Mutation', 'rs2297235', (28, 37))	('patients', 'Species', '9606', (109, 117))	('ccRCC', 'Disease', 'MESH:D002292', (103, 108))	('ccRCC', 'Disease', (103, 108))	('rs156697', 'Mutation', 'rs156697', (15, 23))	('rs156697', 'Var', (15, 23))	('rs2297235', 'Var', (28, 37))
106514	31861116	Furthermore, our results did not exhibit effect of either GSTO1 (rs4925) or GSTO2 (rs156697 and rs2297235) polymorphisms on overall survival among female ccRCC patients (Figure 1c).	('rs2297235', 'Var', (96, 105))	('GSTO2', 'Gene', (76, 81))	('patients', 'Species', '9606', (160, 168))	('ccRCC', 'Disease', (154, 159))	('rs4925', 'Var', (65, 71))	('rs2297235', 'Mutation', 'rs2297235', (96, 105))	('rs156697', 'Mutation', 'rs156697', (83, 91))	('rs156697', 'Var', (83, 91))	('ccRCC', 'Disease', 'MESH:D002292', (154, 159))	('rs4925', 'Mutation', 'rs4925', (65, 71))
106515	31861116	The multivariate Cox regression analysis did not show statistically significant association between either GSTO1 (rs1495) or GSTO2 (rs156697 and rs2297235) genotypes and overall mortality, adjusted by recognized prognostic factors, Fuhrman nuclear grade and pT stage, among ccRCC patients (Table 2).	('rs1495', 'Var', (114, 120))	('patients', 'Species', '9606', (280, 288))	('Cox', 'Gene', '1351', (17, 20))	('GSTO1', 'Gene', (107, 112))	('ccRCC', 'Disease', (274, 279))	('Cox', 'Gene', (17, 20))	('rs2297235', 'Var', (145, 154))	('ccRCC', 'Disease', 'MESH:D002292', (274, 279))	('rs1495', 'Mutation', 'rs1495', (114, 120))	('rs2297235', 'Mutation', 'rs2297235', (145, 154))	('rs156697', 'Mutation', 'rs156697', (132, 140))	('GSTO2', 'Gene', (125, 130))	('rs156697', 'Var', (132, 140))
106516	31861116	However, when we analyzed this association among male patients, the multivariate Cox regression analysis confirmed GSTO1*CC genotype as an independent predictor of higher risk for overall mortality in those patients.	('patients', 'Species', '9606', (207, 215))	('patients', 'Species', '9606', (54, 62))	('Cox', 'Gene', '1351', (81, 84))	('Cox', 'Gene', (81, 84))	('GSTO1*CC', 'Var', (115, 123))
106517	31861116	Regarding both investigated GSTO2 polymorphisms (rs156697 and rs2297235), the results did not reach statistical significance (p > 0.05, Table 3).	('rs2297235', 'Var', (62, 71))	('rs2297235', 'Mutation', 'rs2297235', (62, 71))	('rs156697', 'Mutation', 'rs156697', (49, 57))	('rs156697', 'Var', (49, 57))	('GSTO2', 'Gene', (28, 33))
106532	31861116	Increased expression of RSK1p90 phospho-S380 (p = 0.010), Akt1 phospho-S473 (p = 0.026) and ERK1/2 phospho-Y204/197 (p = 0.015) in tumor ccRCC compared to respective non-tumor tissue has been shown (Figure 3, Figure S1, Table S1).	('Akt1', 'Gene', (58, 62))	('non-tumor', 'Disease', (166, 175))	('ccRCC', 'Disease', (137, 142))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', (170, 175))	('ERK1', 'molecular_function', 'GO:0004707', ('92', '96'))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('expression', 'MPA', (10, 20))	('phospho-S380', 'Var', (32, 44))	('Akt1', 'Gene', '207', (58, 62))	('RSK1p', 'Gene', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('non-tumor', 'Disease', 'MESH:C580335', (166, 175))	('Increased', 'PosReg', (0, 9))	('ERK1/2', 'Gene', (92, 98))	('RSK1p', 'Gene', '6195', (24, 29))	('ERK1/2', 'Gene', '5595;5594', (92, 98))	('phospho-S473', 'Var', (63, 75))	('ccRCC', 'Disease', 'MESH:D002292', (137, 142))
106534	31861116	Western blot analysis, following protein immunoprecipitation of ccRCC tissue samples by anti-GSTO1 antibody, showed association of GSTO1 with RPS6 phospho-S235/236 and Akt phospho-S473, downstream effectors of PI3K/Akt/mTOR pathway (Figure 4, Figure S1).	('mTOR', 'Gene', (219, 223))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('S235', 'Chemical', 'MESH:C056056', (155, 159))	('ccRCC', 'Disease', 'MESH:D002292', (64, 69))	('RPS6 phospho-S235/236', 'Var', (142, 163))	('mTOR', 'Gene', '2475', (219, 223))	('antibody', 'cellular_component', 'GO:0019814', ('99', '107'))	('PI3K', 'molecular_function', 'GO:0016303', ('210', '214'))	('ccRCC', 'Disease', (64, 69))	('phospho-S235/236', 'Var', (147, 163))	('association', 'Interaction', (116, 127))	('antibody', 'molecular_function', 'GO:0003823', ('99', '107'))	('antibody', 'cellular_component', 'GO:0042571', ('99', '107'))	('GSTO1', 'Gene', (131, 136))	('Akt', 'Gene', (168, 171))	('Akt', 'Gene', '207', (168, 171))	('Akt', 'Gene', (215, 218))	('antibody', 'cellular_component', 'GO:0019815', ('99', '107'))	('Akt', 'Gene', '207', (215, 218))
106536	31861116	Although increased expression of ERK1/2 phospho-Y204/197 was found in tumor ccRCC tissue (Figure 3), the association of this protein with GSTO1 was not observed.	('ccRCC', 'Disease', 'MESH:D002292', (76, 81))	('expression', 'MPA', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (70, 75))	('increased', 'PosReg', (9, 18))	('ERK1/2', 'Gene', (33, 39))	('ERK1/2', 'Gene', '5595;5594', (33, 39))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('ERK1', 'molecular_function', 'GO:0004707', ('33', '37'))	('ccRCC', 'Disease', (76, 81))	('phospho-Y204/197', 'Var', (40, 56))
106539	31861116	In addition, GSTO1*C/C genotype independently predicted higher risk of overall mortality among male ccRCC patients when the association between different gene variants and overall mortality, adjusted by established prognostic factors, was analyzed.	('GSTO1*C/C', 'Var', (13, 22))	('overall mortality', 'MPA', (71, 88))	('patients', 'Species', '9606', (106, 114))	('higher', 'PosReg', (56, 62))	('ccRCC', 'Disease', (100, 105))	('ccRCC', 'Disease', 'MESH:D002292', (100, 105))
106548	31861116	Our results on different prognostic significance of GSTO1 polymorphism in male and female patients with ccRCC is a further proof of gender-specific molecular patterns in ccRCC.	('ccRCC', 'Disease', 'MESH:D002292', (104, 109))	('ccRCC', 'Disease', (170, 175))	('ccRCC', 'Disease', 'MESH:D002292', (170, 175))	('polymorphism', 'Var', (58, 70))	('GSTO1', 'Gene', (52, 57))	('patients', 'Species', '9606', (90, 98))	('ccRCC', 'Disease', (104, 109))
106550	31861116	Possible underlying mechanism of prognostic significance of GSTO1 polymorphism in male ccRCC might be the role of GSTO1 in IL-1beta posttranslational processing.	('IL-1beta', 'Gene', '3552', (123, 131))	('IL-1', 'molecular_function', 'GO:0005149', ('123', '127'))	('IL-1beta', 'Gene', (123, 131))	('polymorphism', 'Var', (66, 78))	('ccRCC', 'Disease', (87, 92))	('ccRCC', 'Disease', 'MESH:D002292', (87, 92))	('GSTO1', 'Gene', (60, 65))
106551	31861116	Petrella and Vincenti elucidated that previously established association between high levels of IL-1beta and RCC progression might be explained by the stimulation of tumor cell invasion.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('IL-1', 'molecular_function', 'GO:0005149', ('96', '100'))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('IL-1beta', 'Gene', '3552', (96, 104))	('stimulation', 'PosReg', (151, 162))	('high', 'Var', (81, 85))	('tumor', 'Disease', (166, 171))	('RCC', 'Disease', 'MESH:D002292', (109, 112))	('RCC', 'Disease', (109, 112))	('IL-1beta', 'Gene', (96, 104))
106553	31861116	Considering that GSTO1-1 activity is affected by GSTO1 allelic variant, it seems plausible that GSTO1 polymorphism might also influence activation of IL-1beta.	('polymorphism', 'Var', (102, 114))	('affected', 'Reg', (37, 45))	('IL-1', 'molecular_function', 'GO:0005149', ('150', '154'))	('IL-1beta', 'Gene', '3552', (150, 158))	('GSTO1', 'Gene', (96, 101))	('activation', 'MPA', (136, 146))	('IL-1beta', 'Gene', (150, 158))	('GSTO1-1', 'Gene', (17, 24))	('GSTO1', 'Gene', (49, 54))	('influence', 'Reg', (126, 135))	('GSTO1-1', 'Gene', '9446', (17, 24))	('activity', 'MPA', (25, 33))
106575	31861116	It has been shown that the phosphorylation of Akt at S473 (Akt1 pS473), either by mTOR or by DNA-dependent protein kinase, promotes complete enzymatic activity of Akt.	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('Akt', 'Gene', '207', (46, 49))	('Akt1', 'Gene', (59, 63))	('Akt', 'Gene', (59, 62))	('promotes', 'PosReg', (123, 131))	('Akt', 'Gene', (163, 166))	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('at S473', 'Var', (50, 57))	('enzymatic activity', 'MPA', (141, 159))	('Akt', 'Gene', (46, 49))	('phosphorylation', 'MPA', (27, 42))	('Akt1', 'Gene', '207', (59, 63))	('Akt', 'Gene', '207', (59, 62))	('mTOR', 'Gene', (82, 86))	('mTOR', 'Gene', '2475', (82, 86))	('Akt', 'Gene', '207', (163, 166))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
106591	31861116	Namely, KT53 initiated a significant increase in cisplatin-induced cell death in the human breast cancer cell line.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('death', 'Disease', 'MESH:D003643', (72, 77))	('KT53', 'Var', (8, 12))	('increase', 'PosReg', (37, 45))	('death', 'Disease', (72, 77))	('cell death', 'biological_process', 'GO:0008219', ('67', '77'))	('cisplatin-induced', 'MPA', (49, 66))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('human', 'Species', '9606', (85, 90))
106596	31861116	Beside the results on the effect of GSTO polymorphisms on overall survival, it would be beneficial to investigate its potential association with cancer specific survival in a larger cohort.	('cancer', 'Disease', (145, 151))	('polymorphisms', 'Var', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('GSTO', 'Gene', (36, 40))
106605	31861116	Genotyping of GSTO1*C419A (rs4925), GSTO2*A424G (rs156697) and GSTO2*A183G (rs2297235) polymorphisms was achieved by quantitative polymerase chain reaction (qPCR) on Mastercycler ep realplex (Eppendorf, Hamburg, Germany) using TaqMan SNP Genotyping assays (Thermo Fisher Scientific, Waltham, MA, USA, assay ID: C_11309430_30, C_3223136_1, C_3223142_1, respectively).	('rs2297235', 'Var', (76, 85))	('C_3223136_1', 'Var', (326, 337))	('C_3223142_1', 'Var', (339, 350))	('rs4925', 'Mutation', 'rs4925', (27, 33))	('rs156697', 'Mutation', 'rs156697', (49, 57))	('rs2297235', 'Mutation', 'rs2297235', (76, 85))	('A424G', 'Mutation', 'rs156697', (42, 47))	('GSTO2', 'Gene', (63, 68))	('C_11309430_30', 'Var', (311, 324))	('A183G', 'Mutation', 'rs2297235', (69, 74))	('C419A', 'Mutation', 'rs4925', (20, 25))
106608	31861116	Akt/MAPK Signaling Pathway Antibody Cocktail was used for simultaneous detection of phosphorylated 90kDa ribosomal protein S6 kinase 1 (RSK1p90) phospho-S380, protein kinase B (Akt) phospho-S473, extracellular-signal-regulated kinase (ERK1 phospho-Y204)/ERK2 phospho-Y187) and ribosomal protein S6 (RPS6) phospho-S235/236 (rabbit, Abcam, UK).	('rabbit', 'Species', '9986', (323, 329))	('Signaling Pathway', 'biological_process', 'GO:0007165', ('9', '26'))	('extracellular', 'cellular_component', 'GO:0005576', ('196', '209'))	('ERK', 'Gene', (235, 238))	('Akt', 'Gene', '207', (0, 3))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('ERK2', 'molecular_function', 'GO:0004707', ('254', '258'))	('MAPK Signaling', 'biological_process', 'GO:0000165', ('4', '18'))	('phospho-S380', 'Var', (145, 157))	('ERK', 'Gene', '5594', (254, 257))	('protein', 'cellular_component', 'GO:0003675', ('287', '294'))	('RSK1p', 'Gene', (136, 141))	('ERK1', 'molecular_function', 'GO:0004707', ('235', '239'))	('RSK1p', 'Gene', '6195', (136, 141))	('Akt', 'Gene', (177, 180))	('protein kinase B', 'Gene', '2185', (159, 175))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('105', '122'))	('MAPK', 'molecular_function', 'GO:0004707', ('4', '8'))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('277', '294'))	('Akt', 'Gene', '207', (177, 180))	('protein kinase B', 'Gene', (159, 175))	('ERK', 'Gene', (254, 257))	('phospho-S473', 'Var', (182, 194))	('ERK', 'Gene', '5594', (235, 238))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('Akt', 'Gene', (0, 3))	('S235', 'Chemical', 'MESH:C056056', (313, 317))
106620	31861116	This study demonstrated a significant prognostic role of GSTO1 polymorphism in ccRCC.	('ccRCC', 'Disease', (79, 84))	('ccRCC', 'Disease', 'MESH:D002292', (79, 84))	('GSTO1', 'Gene', (57, 62))	('polymorphism', 'Var', (63, 75))
106628	29141220	The casein kinase-1 delta (CK1delta) phosphorylates T362 in the catalytic domain of PP5, which activates and enhances phosphatase activity independent of Hsp90.	('enhances', 'PosReg', (109, 117))	('Hsp90', 'Gene', '3320', (154, 159))	('PP5', 'Gene', '5536', (84, 87))	('T362', 'Chemical', '-', (52, 56))	('T362', 'Var', (52, 56))	('phosphatase activity', 'molecular_function', 'GO:0016791', ('118', '138'))	('phosphatase activity', 'MPA', (118, 138))	('CK1delta', 'Gene', (27, 35))	('activates', 'PosReg', (95, 104))	('Hsp90', 'Gene', (154, 159))	('CK1delta', 'Gene', '1453', (27, 35))	('PP5', 'Gene', (84, 87))
106634	29141220	Kidney cancer cells with mutations and inactivation of VHL have elevated PP5.	('PP5', 'Gene', '5536', (73, 76))	('mutations', 'Var', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('elevated', 'PosReg', (64, 72))	('Kidney cancer', 'Disease', 'MESH:D007680', (0, 13))	('PP5', 'Gene', (73, 76))	('Kidney cancer', 'Phenotype', 'HP:0009726', (0, 13))	('VHL', 'Gene', (55, 58))	('inactivation', 'Var', (39, 51))	('VHL', 'Gene', '7428', (55, 58))	('Kidney cancer', 'Disease', (0, 13))
106648	29141220	In this study we identified CK1delta to phosphorylate T362 in the catalytic domain of PP5, which is involved in its activation and hyperactivity, independent of Hsp90 binding.	('Hsp90', 'Gene', '3320', (161, 166))	('hyperactivity', 'Disease', (131, 144))	('CK1delta', 'Gene', '1453', (28, 36))	('hyperactivity', 'Phenotype', 'HP:0000752', (131, 144))	('Hsp90 binding', 'molecular_function', 'GO:0051879', ('161', '174'))	('PP5', 'Gene', (86, 89))	('activation', 'PosReg', (116, 126))	('CK1delta', 'Gene', (28, 36))	('T362', 'Chemical', '-', (54, 58))	('PP5', 'Gene', '5536', (86, 89))	('hyperactivity', 'Disease', 'MESH:D006948', (131, 144))	('Hsp90', 'Gene', (161, 166))	('T362', 'Var', (54, 58))
106649	29141220	We have also identified the tumor suppressor von Hippel-Lindau protein (VHL) to target K185/K199 for ubiquitination and proteasomal degradation of PP5 in a hypoxia independent manner.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('hypoxia', 'Disease', (156, 163))	('hypoxia', 'Disease', 'MESH:D000860', (156, 163))	('tumor', 'Disease', (28, 33))	('PP5', 'Gene', (147, 150))	('VHL', 'Gene', '7428', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('von Hippel-Lindau protein', 'Gene', (45, 70))	('PP5', 'Gene', '5536', (147, 150))	('degradation', 'biological_process', 'GO:0009056', ('132', '143'))	('ubiquitination', 'MPA', (101, 115))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('von Hippel-Lindau protein', 'Gene', '7428', (45, 70))	('tumor suppressor', 'biological_process', 'GO:0051726', ('28', '44'))	('proteasomal degradation', 'MPA', (120, 143))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('28', '44'))	('K185/K199', 'Var', (87, 96))	('VHL', 'Gene', (72, 75))
106650	29141220	Mutation and inactivation of VHL has been associated with clear cell renal cell carcinoma (ccRCC).	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (58, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (69, 89))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('inactivation', 'Var', (13, 25))	('VHL', 'Gene', (29, 32))	('associated', 'Reg', (42, 52))	('Mutation', 'Var', (0, 8))	('VHL', 'Gene', '7428', (29, 32))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (58, 89))	('clear cell renal cell carcinoma', 'Disease', (58, 89))
106652	29141220	Small interfering RNA (siRNA) mediated silencing of PP5 induced apoptosis in VHL-null ccRCC, suggesting a prosurvival role for PP5 in these cells.	('PP5', 'Gene', (127, 130))	('RNA', 'cellular_component', 'GO:0005562', ('18', '21'))	('VHL', 'Gene', (77, 80))	('apoptosis', 'CPA', (64, 73))	('PP5', 'Gene', '5536', (127, 130))	('PP5', 'Gene', (52, 55))	('VHL', 'Gene', '7428', (77, 80))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('silencing', 'Var', (39, 48))	('apoptosis', 'biological_process', 'GO:0006915', ('64', '73'))	('apoptosis', 'biological_process', 'GO:0097194', ('64', '73'))	('PP5', 'Gene', '5536', (52, 55))
106656	29141220	Threonine and serine phosphorylation of Ppt1-His6 was detectable by immunoblotting using pan-anti-phosphothreonine-P6623 and anti-phosphoserine-P5754 (Sigma-Aldrich) antibodies (Figure S1A).	('serine', 'Chemical', 'MESH:D012694', (137, 143))	('phosphoserine', 'Chemical', 'MESH:D010768', (130, 143))	('His6', 'Chemical', 'MESH:C471213', (45, 49))	('phosphothreonine', 'Chemical', 'MESH:D010769', (98, 114))	('Ppt1-His6', 'Gene', (40, 49))	('Ppt', 'molecular_function', 'GO:0043751', ('40', '43'))	('anti-phosphoserine-P5754', 'Var', (125, 149))	('detectable', 'Reg', (54, 64))	('Threonine', 'Chemical', 'MESH:D013912', (0, 9))	('serine', 'Chemical', 'MESH:D012694', (14, 20))	('Ppt', 'molecular_function', 'GO:0015121', ('40', '43'))	('phosphorylation', 'biological_process', 'GO:0016310', ('21', '36'))
106677	29141220	We identified five threonine residues within this CK1 consensus site (Figure 1D); T33, T121, T171, T238 and T362.	('T171', 'Var', (93, 97))	('T33', 'Var', (82, 85))	('T238', 'Chemical', '-', (99, 103))	('T362', 'Chemical', '-', (108, 112))	('T362', 'Var', (108, 112))	('T238', 'Var', (99, 103))	('threonine', 'Chemical', 'MESH:D013912', (19, 28))	('T121', 'Var', (87, 91))	('CK1', 'Species', '2498238', (50, 53))
106679	29141220	These sites were individually mutated to non-phosphorylatable alanine in the PP5-FLAG construct and transiently co-expressed with or without CK1delta-cMyc in HEK293 cells.	('alanine', 'Chemical', 'MESH:D000409', (62, 69))	('CK1delta', 'Gene', '1453', (141, 149))	('HEK293', 'CellLine', 'CVCL:0045', (158, 164))	('PP5-FLAG', 'Gene', (77, 85))	('mutated', 'Var', (30, 37))	('PP5-FLAG', 'Gene', '5536', (77, 85))	('CK1delta', 'Gene', (141, 149))
106681	29141220	Overexpression of CK1delta-cMyc increased threonine phosphorylation of wild-type PP5-FLAG and the non-phosphorylatable threonine mutants except for T362A-PP5-FLAG (Figures 1F and S1D).	('threonine', 'Chemical', 'MESH:D013912', (119, 128))	('PP5-FLAG', 'Gene', '5536', (81, 89))	('threonine', 'Chemical', 'MESH:D013912', (42, 51))	('PP5-FLAG', 'Gene', (81, 89))	('PP5-FLAG', 'Gene', (154, 162))	('increased threonine', 'Phenotype', 'HP:0003354', (32, 51))	('phosphorylation', 'biological_process', 'GO:0016310', ('52', '67'))	('increased', 'PosReg', (32, 41))	('T362A', 'Var', (148, 153))	('CK1delta', 'Gene', (18, 26))	('threonine phosphorylation', 'MPA', (42, 67))	('PP5-FLAG', 'Gene', '5536', (154, 162))	('T362A', 'SUBSTITUTION', 'None', (148, 153))	('CK1delta', 'Gene', '1453', (18, 26))
106682	29141220	The threonine phosphorylation of this mutant was significantly lower, even with overexpression of CK1delta-cMyc (Figures 1F and S1D), suggesting that T362 is phosphorylated by CK1delta.	('CK1delta', 'Gene', '1453', (176, 184))	('lower', 'NegReg', (63, 68))	('T362', 'Var', (150, 154))	('CK1delta', 'Gene', (98, 106))	('threonine', 'Chemical', 'MESH:D013912', (4, 13))	('CK1delta', 'Gene', '1453', (98, 106))	('phosphorylation', 'biological_process', 'GO:0016310', ('14', '29'))	('threonine phosphorylation', 'MPA', (4, 29))	('CK1delta', 'Gene', (176, 184))	('T362', 'Chemical', '-', (150, 154))
106683	29141220	We obtained further evidence by carrying out an in vitro kinase assay with bacterially expressed and purified wild-type PP5-His6 and the non-phosphorylatable mutant T362A-PP5-His6.	('PP5', 'Gene', (120, 123))	('PP5', 'Gene', (171, 174))	('His6', 'Chemical', 'MESH:C471213', (124, 128))	('T362A', 'Var', (165, 170))	('T362A', 'SUBSTITUTION', 'None', (165, 170))	('PP5', 'Gene', '5536', (120, 123))	('PP5', 'Gene', '5536', (171, 174))	('His6', 'Chemical', 'MESH:C471213', (175, 179))
106684	29141220	We were unable to detect the threonine phosphorylation of this mutant by immunoblotting (Figure 1G) therefore confirming CK1delta targets and phosphorylates only T362 in PP5.	('PP5', 'Gene', '5536', (170, 173))	('T362', 'Chemical', '-', (162, 166))	('phosphorylation', 'biological_process', 'GO:0016310', ('39', '54'))	('T362', 'Var', (162, 166))	('threonine', 'Chemical', 'MESH:D013912', (29, 38))	('CK1delta', 'Gene', (121, 129))	('PP5', 'Gene', (170, 173))	('CK1delta', 'Gene', '1453', (121, 129))
106688	29141220	We repeated the same experiments instead using the non-phosphorylating T362A-PP5-His6.	('PP5', 'Gene', '5536', (77, 80))	('T362A', 'SUBSTITUTION', 'None', (71, 76))	('T362A', 'Var', (71, 76))	('PP5', 'Gene', (77, 80))	('His6', 'Chemical', 'MESH:C471213', (81, 85))
106690	29141220	However, addition of Hsp90alpha or CK1delta (attempting to phosphorylate T362A-PP5-His6 in vitro) did not stimulate the phosphatase activity (Figures S2A and S2B).	('Hsp90alpha', 'Gene', '3320', (21, 31))	('T362A', 'SUBSTITUTION', 'None', (73, 78))	('Hsp90alpha', 'Gene', (21, 31))	('phosphatase activity', 'molecular_function', 'GO:0016791', ('120', '140'))	('PP5', 'Gene', (79, 82))	('His6', 'Chemical', 'MESH:C471213', (83, 87))	('T362A', 'Var', (73, 78))	('CK1delta', 'Gene', '1453', (35, 43))	('CK1delta', 'Gene', (35, 43))	('PP5', 'Gene', '5536', (79, 82))	('phosphatase', 'MPA', (120, 131))
106703	29141220	To obtain further evidence for this observation we overexpressed wild-type PP5-FLAG and the phospho-mutants T362A and T362E in HEK293 cells.	('T362A', 'SUBSTITUTION', 'None', (108, 113))	('T362E', 'Var', (118, 123))	('PP5-FLAG', 'Gene', (75, 83))	('HEK293', 'CellLine', 'CVCL:0045', (127, 133))	('T362E', 'Mutation', 'p.T362E', (118, 123))	('PP5-FLAG', 'Gene', '5536', (75, 83))	('T362A', 'Var', (108, 113))
106706	29141220	This effect was enhanced with overexpression of the phosphomimetic T362E-PP5-FLAG and unaffected (similar to the empty vector control) with T362A-PP5-FLAG, which is consistent with our in vitro data (Figure 2G).	('PP5-FLAG', 'Gene', (146, 154))	('T362A', 'Var', (140, 145))	('PP5-FLAG', 'Gene', '5536', (73, 81))	('PP5-FLAG', 'Gene', '5536', (146, 154))	('T362A', 'SUBSTITUTION', 'None', (140, 145))	('T362E', 'Mutation', 'p.T362E', (67, 72))	('enhanced', 'PosReg', (16, 24))	('PP5-FLAG', 'Gene', (73, 81))
106707	29141220	Finally, we confirmed that the interaction of the phospho-T362 mutants with Hsp90, Cdc37 and GR were not affected, and therefore our observation is not due to lack of interaction of PP5 mutants with the substrates (Figure 2H).	('PP5', 'Gene', (182, 185))	('T362', 'Chemical', '-', (58, 62))	('mutants', 'Var', (63, 70))	('interaction', 'Interaction', (31, 42))	('Cdc37', 'Gene', '11140', (83, 88))	('Hsp90', 'Gene', (76, 81))	('GR', 'Gene', '2908', (93, 95))	('Cdc37', 'Gene', (83, 88))	('Hsp90', 'Gene', '3320', (76, 81))	('PP5', 'Gene', '5536', (182, 185))
106724	29141220	Overexpression of these genes did not affect the endogenous PP5 protein levels, but as expected markedly reduced HIF1alpha levels (Figure 3E).	('HIF1alpha', 'Gene', (113, 122))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('HIF1alpha', 'Gene', '3091', (113, 122))	('PP5', 'Gene', '5536', (60, 63))	('genes', 'Var', (24, 29))	('reduced', 'NegReg', (105, 112))	('PP5', 'Gene', (60, 63))
106736	29141220	Based on the data available on PhosphoSitePlus  (www.phosphosite.org), which is an online systems biology resource providing comprehensive information on PTMs of human proteins, we identified five ubiquitinated lysine sites (K32, K40, K185, K199 and K320) on PP5 (Figure 4A).	('K199', 'Var', (241, 245))	('PP5', 'Gene', '5536', (259, 262))	('K320', 'Var', (250, 254))	('lysine', 'Chemical', 'MESH:D008239', (211, 217))	('K40', 'Var', (230, 233))	('human', 'Species', '9606', (162, 167))	('PP5', 'Gene', (259, 262))	('K185', 'Var', (235, 239))	('K32', 'Var', (225, 228))
106740	29141220	However, ubiquitination of PP5 was significantly reduced in the K185R and K199R mutants (Figure 4C).	('K199R', 'Mutation', 'p.K199R', (74, 79))	('PP5', 'Gene', (27, 30))	('K185R', 'Var', (64, 69))	('reduced', 'NegReg', (49, 56))	('K199R', 'Var', (74, 79))	('ubiquitination', 'MPA', (9, 23))	('PP5', 'Gene', '5536', (27, 30))	('K185R', 'Mutation', 'p.K185R', (64, 69))
106741	29141220	Our data also showed that K185R and K199R-PP5-FLAG mutants were slightly more stable than the wild-type PP5-FLAG expressed in HEK293 cells (Figure S4B), whereas these mutants were expressed at the same levels as the wild-type PP5-FLAG in the VHL-null 786-O cells (Figure S4C).	('PP5-FLAG', 'Gene', (104, 112))	('PP5-FLAG', 'Gene', '5536', (104, 112))	('K185R', 'Var', (26, 31))	('VHL', 'Gene', (242, 245))	('HEK293', 'CellLine', 'CVCL:0045', (126, 132))	('VHL', 'Gene', '7428', (242, 245))	('K199R', 'Mutation', 'p.K199R', (36, 41))	('K185R', 'Mutation', 'p.K185R', (26, 31))	('PP5-FLAG', 'Gene', (226, 234))	('PP5-FLAG', 'Gene', '5536', (226, 234))	('PP5-FLAG', 'Gene', (42, 50))	('PP5-FLAG', 'Gene', '5536', (42, 50))
106742	29141220	We next created a K185R/K199R-PP5-FLAG double mutant and transiently expressed it in HEK293 cells.	('HEK293', 'CellLine', 'CVCL:0045', (85, 91))	('K185R', 'Var', (18, 23))	('K199R', 'Mutation', 'p.K199R', (24, 29))	('PP5-FLAG', 'Gene', (30, 38))	('PP5-FLAG', 'Gene', '5536', (30, 38))	('K185R', 'SUBSTITUTION', 'None', (18, 23))
106745	29141220	Next, bacterially expressed and purified wild-type PP5-His6 and K185R/K199R-PP5-His6 double mutant were used in our in vitro ubiquitination assay.	('PP5', 'Gene', '5536', (76, 79))	('K185R', 'Var', (64, 69))	('PP5', 'Gene', (51, 54))	('His6', 'Chemical', 'MESH:C471213', (55, 59))	('PP5', 'Gene', (76, 79))	('His6', 'Chemical', 'MESH:C471213', (80, 84))	('K185R', 'SUBSTITUTION', 'None', (64, 69))	('K199R', 'Mutation', 'p.K199R', (70, 75))	('PP5', 'Gene', '5536', (51, 54))
106746	29141220	Our data show that the recombinant wild-type PP5-His6 but not the K185R/K199R-PP5-His6 mutant were subject to ubiquitination.	('PP5', 'Gene', (78, 81))	('PP5', 'Gene', '5536', (45, 48))	('PP5', 'Gene', (45, 48))	('His6', 'Chemical', 'MESH:C471213', (49, 53))	('K185R', 'Var', (66, 71))	('PP5', 'Gene', '5536', (78, 81))	('ubiquitination', 'MPA', (110, 124))	('subject', 'Reg', (99, 106))	('K199R', 'Mutation', 'p.K199R', (72, 77))	('His6', 'Chemical', 'MESH:C471213', (82, 86))	('K185R', 'SUBSTITUTION', 'None', (66, 71))
106748	29141220	To gain further evidence of VHL-mediated ubiquitination of K185/K199-PP5 in cells, we transiently co-expressed the wild-type PP5-FLAG or K185R/K199R-PP5-FLAG with VHL30-His6 for 16 hr in VHL-null 786-O cells, then treated them with 50nM BZ for 2 hr.	('PP5-FLAG', 'Gene', (125, 133))	('PP5', 'Gene', '5536', (125, 128))	('PP5-FLAG', 'Gene', (149, 157))	('PP5', 'Gene', (149, 152))	('VHL', 'Gene', (163, 166))	('VHL', 'Gene', (187, 190))	('K185R', 'Var', (137, 142))	('PP5', 'Gene', (69, 72))	('PP5-FLAG', 'Gene', '5536', (125, 133))	('PP5-FLAG', 'Gene', '5536', (149, 157))	('PP5', 'Gene', (125, 128))	('VHL', 'Gene', (28, 31))	('VHL', 'Gene', '7428', (163, 166))	('VHL', 'Gene', '7428', (187, 190))	('His6', 'Chemical', 'MESH:C471213', (169, 173))	('K199R', 'Mutation', 'p.K199R', (143, 148))	('PP5', 'Gene', '5536', (149, 152))	('VHL', 'Gene', '7428', (28, 31))	('BZ', 'Chemical', 'MESH:D000069286', (237, 239))	('K185R', 'SUBSTITUTION', 'None', (137, 142))	('PP5', 'Gene', '5536', (69, 72))
106749	29141220	We were only able to detect the ubiquitination of the wild-type PP5 but not the K185R/K199R-PP5 double mutant (Figure 4F).	('PP5', 'Gene', (64, 67))	('PP5', 'Gene', (92, 95))	('K185R', 'SUBSTITUTION', 'None', (80, 85))	('PP5', 'Gene', '5536', (92, 95))	('PP5', 'Gene', '5536', (64, 67))	('K185R', 'Var', (80, 85))	('ubiquitination', 'MPA', (32, 46))	('K199R', 'Mutation', 'p.K199R', (86, 91))	('detect', 'Reg', (21, 27))
106750	29141220	The K185R-, K199R-PP5 single or double mutants interacted with the same affinity as the wild-type PP5 to VHL30 (Figure 4G).	('PP5', 'Gene', (98, 101))	('K199R', 'Mutation', 'p.K199R', (12, 17))	('VHL', 'Gene', (105, 108))	('PP5', 'Gene', (18, 21))	('K185R-', 'Var', (4, 10))	('PP5', 'Gene', '5536', (98, 101))	('VHL', 'Gene', '7428', (105, 108))	('K185R', 'Mutation', 'p.K185R', (4, 9))	('PP5', 'Gene', '5536', (18, 21))
106751	29141220	Therefore the reduced ubiquitination of these mutants could not be due to their inability to bind to VHL30.	('ubiquitination', 'MPA', (22, 36))	('VHL', 'Gene', (101, 104))	('reduced', 'NegReg', (14, 21))	('bind', 'Interaction', (93, 97))	('VHL', 'Gene', '7428', (101, 104))	('mutants', 'Var', (46, 53))
106752	29141220	Taken together, our data show that VHL E3 ligase ubiquitinates K185 and K199 residues in PP5.	('PP5', 'Gene', (89, 92))	('K199 residues', 'Var', (72, 85))	('PP5', 'Gene', '5536', (89, 92))	('K185', 'Var', (63, 67))	('VHL', 'Gene', (35, 38))	('VHL', 'Gene', '7428', (35, 38))
106763	29141220	We also showed that silencing of PP5 in 786-O cells did not affect the CK1delta protein levels (Figure S5B).	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('PP5', 'Gene', '5536', (33, 36))	('CK1delta', 'Gene', (71, 79))	('CK1delta', 'Gene', '1453', (71, 79))	('PP5', 'Gene', (33, 36))	('silencing', 'Var', (20, 29))
106767	29141220	786-O cells treated or untreated with 2 microM IC261 16 hr and PP5 was immunoprecipitated and as expected, IC261 treatment led to a marked reduction of PP5 threonine phosphorylation but not serine phosphorylation (Figure 5G).	('PP5', 'Gene', '5536', (152, 155))	('reduction', 'NegReg', (139, 148))	('threonine', 'Chemical', 'MESH:D013912', (156, 165))	('PP5', 'Gene', (63, 66))	('phosphorylation', 'biological_process', 'GO:0016310', ('197', '212'))	('IC261', 'Var', (107, 112))	('PP5', 'Gene', (152, 155))	('phosphorylation', 'biological_process', 'GO:0016310', ('166', '181'))	('serine', 'Chemical', 'MESH:D012694', (190, 196))	('PP5', 'Gene', '5536', (63, 66))
106773	29141220	Increasing amounts of IC261 correlated with increased induction of the pro-apoptotic markers cleaved caspase-3 and cleaved-PARP only in A498 and 786-O (VHL-null) cells (Figure 6A).	('PARP', 'Gene', (123, 127))	('VHL', 'Gene', (152, 155))	('cleaved caspase-3', 'MPA', (93, 110))	('VHL', 'Gene', '7428', (152, 155))	('PARP', 'Gene', '142', (123, 127))	('induction', 'PosReg', (54, 63))	('IC261', 'Var', (22, 27))
106779	29141220	Our data revealed that 2.0microM IC261 significantly inhibited the proliferation of A498, 786-O cells compared to Caki-1 cells (Figure 6C).	('Caki-1', 'CellLine', 'CVCL:0234', (114, 120))	('proliferation', 'CPA', (67, 80))	('inhibited', 'NegReg', (53, 62))	('IC261', 'Var', (33, 38))
106783	29141220	We addressed this question by transiently expressing wild-type PP5-FLAG and its phospho-PP5 mutants T362A and T362E in 786-O cells.	('PP5-FLAG', 'Gene', '5536', (63, 71))	('T362E', 'Var', (110, 115))	('PP5', 'Gene', (63, 66))	('T362E', 'Mutation', 'p.T362E', (110, 115))	('PP5', 'Gene', '5536', (88, 91))	('T362A', 'Var', (100, 105))	('PP5', 'Gene', (88, 91))	('T362A', 'SUBSTITUTION', 'None', (100, 105))	('PP5-FLAG', 'Gene', (63, 71))	('PP5', 'Gene', '5536', (63, 66))
106784	29141220	Treating the cells expressing empty vector (EV) or non-phosphorylatable T362A-PP5-FLAG mutant with 2.0microM IC261 led to induction of the pro-apoptotic markers cleaved caspase-3 and cleaved-PARP.	('PARP', 'Gene', '142', (191, 195))	('PP5-FLAG', 'Gene', '5536', (78, 86))	('PP5-FLAG', 'Gene', (78, 86))	('T362A', 'Var', (72, 77))	('cleaved', 'MPA', (161, 168))	('PARP', 'Gene', (191, 195))	('T362A', 'SUBSTITUTION', 'None', (72, 77))
106787	29141220	Our data showed that treating the 786-O cells transiently expressing EV or non-phosphorylatable T362A-PP5-FLAG mutant with 2.0microM IC261 caused a marked reduction in cell proliferation where as this effect was not observed in 786-O cells expressing wild-type PP5-FLAG and phospho-mutant T362E-PP5 mutants treated with 2.0microM IC261 (Figure 6F and S6C).	('PP5-FLAG', 'Gene', '5536', (261, 269))	('cell proliferation', 'CPA', (168, 186))	('PP5', 'Gene', (102, 105))	('PP5', 'Gene', (261, 264))	('T362E', 'Mutation', 'p.T362E', (289, 294))	('cell proliferation', 'biological_process', 'GO:0008283', ('168', '186'))	('PP5-FLAG', 'Gene', (102, 110))	('PP5', 'Gene', '5536', (102, 105))	('T362A', 'Var', (96, 101))	('PP5', 'Gene', '5536', (295, 298))	('PP5-FLAG', 'Gene', '5536', (102, 110))	('PP5', 'Gene', '5536', (261, 264))	('T362A', 'SUBSTITUTION', 'None', (96, 101))	('PP5-FLAG', 'Gene', (261, 269))	('IC261', 'Var', (133, 138))	('reduction', 'NegReg', (155, 164))	('PP5', 'Gene', (295, 298))
106792	29141220	Our data showed that the serine/threonine kinase CK1delta interacts with and phosphorylates T362 on PP5.	('PP5', 'Gene', (100, 103))	('phosphorylates', 'MPA', (77, 91))	('serine', 'Chemical', 'MESH:D012694', (25, 31))	('CK1delta', 'Gene', (49, 57))	('T362', 'Chemical', '-', (92, 96))	('PP5', 'Gene', '5536', (100, 103))	('interacts', 'Interaction', (58, 67))	('threonine', 'Chemical', 'MESH:D013912', (32, 41))	('T362', 'Var', (92, 96))	('CK1delta', 'Gene', '1453', (49, 57))
106796	29141220	Our cell-based assays have demonstrated that expression of the non-phosphorylating T362A-PP5 did not dephosphorylate PP5 substrates such as GR and Cdc37, whereas over-expression of the phosphomimetic T362E-PP5 had the opposite effect on those two substrates.	('PP5', 'Gene', (89, 92))	('PP5', 'Gene', (206, 209))	('Cdc37', 'Gene', '11140', (147, 152))	('GR', 'Gene', '2908', (140, 142))	('PP5', 'Gene', (117, 120))	('T362A', 'Var', (83, 88))	('PP5', 'Gene', '5536', (89, 92))	('T362E', 'Mutation', 'p.T362E', (200, 205))	('Cdc37', 'Gene', (147, 152))	('PP5', 'Gene', '5536', (206, 209))	('T362A', 'SUBSTITUTION', 'None', (83, 88))	('dephosphorylate', 'MPA', (101, 116))	('PP5', 'Gene', '5536', (117, 120))
106797	29141220	Our findings clearly demonstrate that although phosphorylation of T362-PP5 does not affect the binding of PP5 to its substrates or even Hsp90, the phosphatase activity of PP5 is influenced by T362 phosphorylation (Figure 7).	('phosphatase activity', 'MPA', (147, 167))	('PP5', 'Gene', (171, 174))	('Hsp90', 'Gene', '3320', (136, 141))	('phosphatase activity', 'molecular_function', 'GO:0016791', ('147', '167'))	('PP5', 'Gene', (106, 109))	('T362 phosphorylation', 'Var', (192, 212))	('PP5', 'Gene', '5536', (71, 74))	('T362', 'Chemical', '-', (66, 70))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('phosphorylation', 'biological_process', 'GO:0016310', ('197', '212'))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))	('PP5', 'Gene', '5536', (106, 109))	('PP5', 'Gene', '5536', (171, 174))	('influenced', 'Reg', (178, 188))	('PP5', 'Gene', (71, 74))	('Hsp90', 'Gene', (136, 141))	('T362', 'Chemical', '-', (192, 196))
106800	29141220	T362 is also at the center of an acidic patch located between D365, D364, and E416, E417.	('E416', 'Var', (78, 82))	('T362', 'Var', (0, 4))	('E417', 'Var', (84, 88))	('D364', 'Var', (68, 72))	('D365', 'Var', (62, 66))	('T362', 'Chemical', '-', (0, 4))
106801	29141220	Therefore, it is conceivable that phosphorylation or phosphomimetic mutation of T362 could either destabilize the domain as a whole or cause some local unfolding, possibly allosterically 'opening' the active site, therefore increasing the rate of phosphatase activity.	('local unfolding', 'MPA', (146, 161))	('rate', 'MPA', (239, 243))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('phosphatase activity', 'MPA', (247, 267))	('mutation', 'Var', (68, 76))	('destabilize', 'NegReg', (98, 109))	('T362', 'Chemical', '-', (80, 84))	('phosphatase activity', 'molecular_function', 'GO:0016791', ('247', '267'))	('T362', 'Gene', (80, 84))	("'opening", 'PosReg', (187, 195))	('domain', 'MPA', (114, 120))	('increasing', 'PosReg', (224, 234))	('phosphorylation', 'Var', (34, 49))	('cause', 'Reg', (135, 140))
106807	29141220	Mutation and inactivation of VHL is associated with the most common type of kidney cancer, known as ccRCC.	('inactivation', 'Var', (13, 25))	('VHL', 'Gene', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('kidney cancer', 'Phenotype', 'HP:0009726', (76, 89))	('Mutation', 'Var', (0, 8))	('kidney cancer', 'Disease', 'MESH:D007680', (76, 89))	('VHL', 'Gene', '7428', (29, 32))	('ccRCC', 'Disease', (100, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('kidney cancer', 'Disease', (76, 89))	('associated', 'Reg', (36, 46))
106808	29141220	We further demonstrated that inactivation of VHL in tumors or established cell lines leads to increased PP5 protein levels.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('increased', 'PosReg', (94, 103))	('PP5', 'Gene', (104, 107))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('VHL in tumors', 'Disease', (45, 58))	('PP5', 'Gene', '5536', (104, 107))	('VHL in tumors', 'Disease', 'MESH:D006623', (45, 58))	('inactivation', 'Var', (29, 41))
106816	29141220	It is worth noting that IC261 is also a potent inhibitor of CK1epsilon, however CK1epsilon does not phosphorylate PP5.	('IC261', 'Var', (24, 29))	('PP5', 'Gene', (114, 117))	('CK1', 'Species', '2498238', (80, 83))	('CK1', 'Species', '2498238', (60, 63))	('PP5', 'Gene', '5536', (114, 117))
106818	29141220	Based on previous studies, there is circumstantial evidence suggesting that aberrant expression of PP5 may aid tumor development and progression.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('PP5', 'Gene', '5536', (99, 102))	('aberrant expression', 'Var', (76, 95))	('aid', 'PosReg', (107, 110))	('PP5', 'Gene', (99, 102))
106841	29141220	Casein kinase-1 delta (CK1delta) phosphorylates T362 in the catalytic domain of PP5.	('PP5', 'Gene', '5536', (80, 83))	('T362', 'Chemical', '-', (48, 52))	('CK1delta', 'Gene', '1453', (23, 31))	('CK1delta', 'Gene', (23, 31))	('T362', 'Var', (48, 52))	('PP5', 'Gene', (80, 83))
106843	29141220	Von Hippel-Lindau protein (VHL) multi-monoubiquitinates PP5 on K185 and K199.	('PP5', 'Gene', '5536', (56, 59))	('Von Hippel-Lindau protein', 'Gene', '7428', (0, 25))	('K185', 'Var', (63, 67))	('Von Hippel-Lindau protein', 'Gene', (0, 25))	('PP5', 'Gene', (56, 59))	('VHL', 'Gene', (27, 30))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))	('VHL', 'Gene', '7428', (27, 30))	('K199', 'Var', (72, 76))
106853	31379814	Through plotting survival curve in Kaplan-Meier Plotter, it was found that hypomethylation of HHLA2 DNA was a favorable prognostic factor for KIRC patients.	('HHLA2', 'Gene', '11148', (94, 99))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('patients', 'Species', '9606', (147, 155))	('HHLA2', 'Gene', (94, 99))	('KIRC', 'Disease', (142, 146))	('hypomethylation', 'Var', (75, 90))
106854	31379814	Yet, the copy number variant of HHLA2 was not significantly correlated with the overall survival of KIRC patients.	('HHLA2', 'Gene', (32, 37))	('patients', 'Species', '9606', (105, 113))	('copy number', 'Var', (9, 20))	('HHLA2', 'Gene', '11148', (32, 37))	('correlated', 'Reg', (60, 70))
106872	31379814	To contribute to the understanding of these discrepancies, we investigated the expression profiling and prognostic value of HHLA2 in human cancer according to multiple public databases and investigated what transcription factor may be associated with the dysregulation of HHLA2 in KIRC, our finding may be helpful for the further study on HHLA2.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('transcription', 'biological_process', 'GO:0006351', ('207', '220'))	('HHLA2', 'Gene', '11148', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('HHLA2', 'Gene', (272, 277))	('HHLA2', 'Gene', (339, 344))	('dysregulation', 'Var', (255, 268))	('HHLA2', 'Gene', '11148', (272, 277))	('HHLA2', 'Gene', '11148', (339, 344))	('human', 'Species', '9606', (133, 138))	('transcription factor', 'molecular_function', 'GO:0000981', ('207', '227'))	('HHLA2', 'Gene', (124, 129))	('cancer', 'Disease', (139, 145))
106878	31379814	UCSC Xena browser was used for evaluating the correlation between expression level of HHLA2 mRNA, methylation status, copy number variant of HHLA2 DNA and the overall survival time in kidney clear cell carcinoma.	('HHLA2', 'Gene', '11148', (141, 146))	('kidney clear cell carcinoma', 'Disease', (184, 211))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (184, 211))	('copy number variant', 'Var', (118, 137))	('DNA', 'cellular_component', 'GO:0005574', ('147', '150'))	('HHLA2', 'Gene', (141, 146))	('HHLA2', 'Gene', (86, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('mRNA, methylation', 'biological_process', 'GO:0080009', ('92', '109'))	('HHLA2', 'Gene', '11148', (86, 91))
106882	31379814	After detailed and careful searching, two independent clinical cohorts (GSE40435, GSE22541) containing tumor staging information were used for validation.	('GSE22541', 'Var', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('GSE40435', 'Var', (72, 80))
106906	31379814	The previous studies showed that copy number variant of HHLA2 DNA may be involved in the dysregulation of HHLA2 expression level in breast cancer.	('HHLA2', 'Gene', '11148', (56, 61))	('dysregulation', 'MPA', (89, 102))	('HHLA2', 'Gene', (106, 111))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('copy number variant', 'Var', (33, 52))	('HHLA2', 'Gene', (56, 61))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('HHLA2', 'Gene', '11148', (106, 111))	('involved', 'Reg', (73, 81))	('expression level', 'MPA', (112, 128))	('breast cancer', 'Disease', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))
106907	31379814	So, we will investigate whether DNA variant of HHLA2 have a similar effect on KIRC patients.	('HHLA2', 'Gene', (47, 52))	('variant', 'Var', (36, 43))	('KIRC', 'Disease', (78, 82))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('HHLA2', 'Gene', '11148', (47, 52))	('patients', 'Species', '9606', (83, 91))
106909	31379814	Survival analysis showed that the hypomethylation of HHLA2 DNA and overexpression of HHLA2 mRNA were favorable prognostic factors for KIRC patients.	('HHLA2', 'Gene', (53, 58))	('patients', 'Species', '9606', (139, 147))	('overexpression', 'PosReg', (67, 81))	('HHLA2', 'Gene', (85, 90))	('HHLA2', 'Gene', '11148', (53, 58))	('KIRC', 'Disease', (134, 138))	('HHLA2', 'Gene', '11148', (85, 90))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('hypomethylation', 'Var', (34, 49))
106910	31379814	However, there was no significant correlation between HHLA2 copy number variant and patient prognosis (Figures 5B-D).	('HHLA2', 'Gene', (54, 59))	('HHLA2', 'Gene', '11148', (54, 59))	('patient', 'Species', '9606', (84, 91))	('copy number variant', 'Var', (60, 79))
106931	31379814	In a further study with KIRC as a case, we found that overexpressed or hypomethylation of HHLA2 is a favorable prognostic factor for KIRC, however, there was no significant correlation between copy number variant of HHLA2 and the prognosis of KIRC patients.	('copy number', 'Var', (193, 204))	('HHLA2', 'Gene', '11148', (90, 95))	('KIRC', 'Disease', (133, 137))	('patients', 'Species', '9606', (248, 256))	('HHLA2', 'Gene', (216, 221))	('overexpressed', 'PosReg', (54, 67))	('HHLA2', 'Gene', '11148', (216, 221))	('hypomethylation', 'Var', (71, 86))	('HHLA2', 'Gene', (90, 95))
106932	31379814	Our finding was not consistent with previous report that elevated expression of HHLA2 may be associated with abnormal copy-number variant of HHLA2 DNA in basal breast cancer.	('copy-number variant', 'Var', (118, 137))	('HHLA2', 'Gene', '11148', (141, 146))	('HHLA2', 'Gene', '11148', (80, 85))	('elevated', 'PosReg', (57, 65))	('DNA', 'cellular_component', 'GO:0005574', ('147', '150'))	('expression', 'MPA', (66, 76))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('HHLA2', 'Gene', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('HHLA2', 'Gene', (80, 85))
106942	31379814	In addition to the function of HHLA2 in KIRC, the potential mechanism involved in dysregulated expression of HHLA2 is also noteworthy, our result provided a possible explanation for this question, inconsistent with the previous report on breast cancer, the epigenetic modification but not copy number variant may be responsible for the dysregulated expression of HHLA2 in KIRC.	('HHLA2', 'Gene', '11148', (31, 36))	('HHLA2', 'Gene', (363, 368))	('expression', 'MPA', (349, 359))	('dysregulated', 'MPA', (336, 348))	('HHLA2', 'Gene', (109, 114))	('HHLA2', 'Gene', '11148', (363, 368))	('epigenetic modification', 'Var', (257, 280))	('HHLA2', 'Gene', (31, 36))	('breast cancer', 'Disease', 'MESH:D001943', (238, 251))	('HHLA2', 'Gene', '11148', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('breast cancer', 'Disease', (238, 251))	('breast cancer', 'Phenotype', 'HP:0003002', (238, 251))
106950	30816681	We found a significant difference in overall survival (OS) between groups, with high syntaxin 6 expression correlating with decreased survival.	('expression', 'MPA', (96, 106))	('decreased', 'NegReg', (124, 133))	('syntaxin 6', 'Gene', (85, 95))	('survival', 'MPA', (134, 142))	('high', 'Var', (80, 84))	('syntaxin 6', 'Gene', '10228', (85, 95))
106956	30816681	Silencing of syntaxin 6 in ACHN cells significantly decreased the cell viability (p < 0.001).	('cell viability', 'CPA', (66, 80))	('decreased', 'NegReg', (52, 61))	('ACHN', 'Gene', '55323', (27, 31))	('syntaxin 6', 'Gene', (13, 23))	('Silencing', 'Var', (0, 9))	('ACHN', 'Gene', (27, 31))	('syntaxin 6', 'Gene', '10228', (13, 23))
106957	30816681	Overall, syntaxin 6 could be a prognostic biomarker for patients with papillary RCC and syntaxin 6 inhibitors hold promise as a novel therapy against RCC.	('patients', 'Species', '9606', (56, 64))	('syntaxin 6', 'Gene', (88, 98))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('inhibitors', 'Var', (99, 109))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('RCC', 'Disease', (150, 153))	('syntaxin 6', 'Gene', '10228', (9, 19))	('syntaxin 6', 'Gene', '10228', (88, 98))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('syntaxin 6', 'Gene', (9, 19))
106963	30816681	Classically, mutations in the von Hippel-Lindau (VHL) gene prevents ubiquitination and degradation of hypoxia-inducible factors (HIF) such as HIF-1alpha.	('ubiquitination', 'MPA', (68, 82))	('degradation', 'MPA', (87, 98))	('hypoxia', 'Disease', 'MESH:D000860', (102, 109))	('HIF-1alpha', 'Gene', (142, 152))	('von Hippel-Lindau', 'Gene', '7428', (30, 47))	('VHL', 'Disease', 'MESH:D006623', (49, 52))	('degradation', 'biological_process', 'GO:0009056', ('87', '98'))	('VHL', 'Disease', (49, 52))	('hypoxia', 'Disease', (102, 109))	('prevents', 'NegReg', (59, 67))	('mutations', 'Var', (13, 22))	('HIF-1alpha', 'Gene', '3091', (142, 152))	('von Hippel-Lindau', 'Gene', (30, 47))
106985	30816681	Those patients with high syntaxin 6 expression had a median overall survival of 5.844 years.	('syntaxin 6', 'Gene', '10228', (25, 35))	('high', 'Var', (20, 24))	('patients', 'Species', '9606', (6, 14))	('syntaxin 6', 'Gene', (25, 35))	('expression', 'MPA', (36, 46))
106988	30816681	Median overall survival for ccRCC tumors with high syntaxin 6 expression was 6.140 years.	('high', 'Var', (46, 50))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('syntaxin 6', 'Gene', '10228', (51, 61))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('RCC', 'Disease', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('syntaxin 6', 'Gene', (51, 61))
106990	30816681	Similarly, median overall survival for pRCC tumors with high syntaxin 6 expression (5.844 years) was significantly lower than survival for those tumors with low/medium syntaxin 6 expression (p < 0.0001) (Fig.	('tumors', 'Disease', (44, 50))	('pRCC', 'Gene', (39, 43))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('syntaxin 6', 'Gene', '10228', (168, 178))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('syntaxin 6', 'Gene', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('lower', 'NegReg', (115, 120))	('syntaxin 6', 'Gene', (168, 178))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('pRCC', 'Gene', '5546', (39, 43))	('syntaxin 6', 'Gene', '10228', (61, 71))	('high', 'Var', (56, 60))
107020	30816681	Interestingly, high co-expression of syntaxin 6 with VEGFR2, PDGF-beta, TP53 and VEGF all predicted significantly worse survival in those patients with pRCC (Fig.	('pRCC', 'Gene', '5546', (152, 156))	('VEGF', 'Gene', (53, 57))	('syntaxin 6', 'Gene', '10228', (37, 47))	('high', 'Var', (15, 19))	('syntaxin 6', 'Gene', (37, 47))	('TP53', 'Gene', '7157', (72, 76))	('pRCC', 'Gene', (152, 156))	('survival', 'MPA', (120, 128))	('patients', 'Species', '9606', (138, 146))	('PDGF-beta', 'Gene', '5155', (61, 70))	('VEGF', 'Gene', '7422', (81, 85))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('worse', 'NegReg', (114, 119))	('VEGF', 'Gene', (81, 85))	('VEGFR2', 'Gene', (53, 59))	('PDGF-beta', 'Gene', (61, 70))	('TP53', 'Gene', (72, 76))	('VEGFR2', 'Gene', '3791', (53, 59))	('VEGF', 'Gene', '7422', (53, 57))	('PDGF', 'molecular_function', 'GO:0005161', ('61', '65'))
107025	30816681	Syntaxin 6 knock-down was confirmed by real time-PCR (Fig.	('Syntaxin 6', 'Gene', (0, 10))	('Syntaxin 6', 'Gene', '10228', (0, 10))	('knock-down', 'Var', (11, 21))
107032	30816681	With c-met mutations known to be common in pRCC, MET inhibitors such as capozantanib and foretinib have been developed and are in clinical trials.	('mutations', 'Var', (11, 20))	('pRCC', 'Gene', (43, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('pRCC', 'Gene', '5546', (43, 47))	('c-met', 'Gene', (5, 10))	('foretinib', 'Chemical', 'MESH:C544831', (89, 98))	('capozantanib', 'Chemical', '-', (72, 84))	('c-met', 'Gene', '4233', (5, 10))
107033	30816681	Nevertheless, c-met mutations are specific to Type 1 pRCC, not the more aggressive Type 2 tumors.	('c-met', 'Gene', (14, 19))	('pRCC', 'Gene', (53, 57))	('c-met', 'Gene', '4233', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('aggressive Type 2 tumors', 'Disease', 'MESH:D001523', (72, 96))	('pRCC', 'Gene', '5546', (53, 57))	('mutations', 'Var', (20, 29))	('aggressive Type 2 tumors', 'Disease', (72, 96))
107039	30816681	The relationship between high syntaxin 6 expression and aggressive disease appears to be more strongly associated with type 2 pRCC tumors.	('aggressive disease', 'Disease', (56, 74))	('associated', 'Reg', (103, 113))	('expression', 'MPA', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('pRCC', 'Gene', (126, 130))	('syntaxin 6', 'Gene', (30, 40))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('high', 'Var', (25, 29))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('aggressive disease', 'Disease', 'MESH:D001523', (56, 74))	('syntaxin 6', 'Gene', '10228', (30, 40))	('pRCC', 'Gene', '5546', (126, 130))
107046	30816681	The exact mechanism through which high syntaxin 6 is promoting survival in pRCC cell lines is unclear.	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('pRCC', 'Gene', (75, 79))	('syntaxin 6', 'Gene', (39, 49))	('survival', 'CPA', (63, 71))	('promoting', 'PosReg', (53, 62))	('high', 'Var', (34, 38))	('syntaxin 6', 'Gene', '10228', (39, 49))	('pRCC', 'Gene', '5546', (75, 79))
107049	30816681	They found that inhibition of syntaxin 6 function led to targeting of Golgi-localized VEGFR2 for degradation in lysosomes.	('Golgi', 'cellular_component', 'GO:0005794', ('70', '75'))	('VEGFR2', 'Gene', '3791', (86, 92))	('syntaxin 6', 'Gene', (30, 40))	('VEGFR2', 'Gene', (86, 92))	('degradation', 'biological_process', 'GO:0009056', ('97', '108'))	('degradation in lysosomes', 'MPA', (97, 121))	('syntaxin 6', 'Gene', '10228', (30, 40))	('targeting', 'MPA', (57, 66))	('inhibition', 'Var', (16, 26))
107055	30816681	Although these proangiogenic growth factors are known to play critical roles in the development of vascular ccRCC through VHL mutations, it is surprising to note their relatively high expression in pRCC, where VHL mutations rarely occur.	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('pRCC', 'Gene', (198, 202))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('VHL', 'Disease', 'MESH:D006623', (122, 125))	('VHL', 'Disease', 'MESH:D006623', (210, 213))	('VHL', 'Disease', (122, 125))	('VHL', 'Disease', (210, 213))	('pRCC', 'Gene', '5546', (198, 202))	('mutations', 'Var', (126, 135))	('RCC', 'Disease', (199, 202))	('RCC', 'Phenotype', 'HP:0005584', (199, 202))	('RCC', 'Disease', 'MESH:C538614', (199, 202))
107087	30816681	ACHN cells (2 x 103 cells/well) were plated in 96 well plates and transfected with syntaxin 6 siRNA as described above.	('transfected', 'Var', (66, 77))	('syntaxin 6', 'Gene', (83, 93))	('syntaxin 6', 'Gene', '10228', (83, 93))	('ACHN', 'Gene', '55323', (0, 4))	('ACHN', 'Gene', (0, 4))
107104	29996914	In a phase II trial, DPV-001 alone or with granulocyte-macrophage colony-stimulating factor (GM-CSF) or imiquimod for adjuvant treatment of stage III NSCLC was tolerable and induced or boosted IgG antibodies to TAAs (tumour-associated antigens).	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('DPV-001', 'Var', (21, 28))	('boosted', 'PosReg', (185, 192))	('granulocyte-macrophage colony-stimulating factor', 'Gene', '1437', (43, 91))	('tumour', 'Disease', 'MESH:D009369', (217, 223))	('TAAs', 'Protein', (211, 215))	('DPV', 'Chemical', '-', (21, 24))	('tumour', 'Disease', (217, 223))	('IgG antibodies', 'MPA', (193, 207))	('granulocyte-macrophage colony-stimulating factor', 'Gene', (43, 91))	('IgG antibodies', 'Phenotype', 'HP:0003237', (193, 207))	('NSCLC', 'Disease', (150, 155))	('GM-CSF', 'Gene', '1437', (93, 99))	('GM-CSF', 'Gene', (93, 99))	('granulocyte-macrophage colony-stimulating factor', 'molecular_function', 'GO:0005129', ('43', '91'))
107105	29996914	DPV-001 also expanded populations of T cells with increases in CD4 T cells similar to those observed in patients receiving anti-CTLA-4 ipilimumab.	('CD4', 'Gene', (63, 66))	('DPV-001', 'Var', (0, 7))	('DPV', 'Chemical', '-', (0, 3))	('CTLA-4', 'Gene', (128, 134))	('ipilimumab', 'Chemical', 'MESH:D000074324', (135, 145))	('CD4', 'Gene', '920', (63, 66))	('increases', 'PosReg', (50, 59))	('patients', 'Species', '9606', (104, 112))	('CTLA-4', 'Gene', '1493', (128, 134))
107115	29996914	Tumour-associated antigens (TAAs) are self-derived proteins rendered immunogenic in tumours by aberrant expression.	('aberrant expression', 'Var', (95, 114))	('tumours', 'Disease', 'MESH:D009369', (84, 91))	('tumours', 'Disease', (84, 91))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))
107129	29996914	A related EU-supported project is HEPAMUT, the primary aim of which is the identification and immunological validation of mutated neoantigens specific to HCC (www.hepamut.eu).	('HCC', 'Gene', (154, 157))	('mutated', 'Var', (122, 129))	('HCC', 'Gene', '619501', (154, 157))
107132	29996914	Mutated peptides may represent non-self neoantigens that are exclusively presented on tumour cells and are not affected by central T cell tolerance.	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('peptides', 'Protein', (8, 16))	('tumour', 'Disease', (86, 92))	('Mutated', 'Var', (0, 7))
107134	29996914	Data suggest that the neoepitopes in patients with strong clinical benefit from CTLA-4 blockade may resemble epitopes from pathogens that T cells are likely to recognise.	('patients', 'Species', '9606', (37, 45))	('blockade', 'Var', (87, 95))	('CTLA-4', 'Gene', (80, 86))	('CTLA-4', 'Gene', '1493', (80, 86))
107135	29996914	Thus, patients with neoantigens similar to pathogen antigens are more likely to respond to treatment.	('neoantigens', 'Var', (20, 31))	('respond to treatment', 'MPA', (80, 100))	('patients', 'Species', '9606', (6, 14))
107136	29996914	Anti-PD-1 antibodies represent a potent therapy of melanoma and other solid tumours.	('solid tumours', 'Disease', (70, 83))	('melanoma', 'Disease', (51, 59))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('Anti-PD-1', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('solid tumours', 'Disease', 'MESH:D009369', (70, 83))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
107139	29996914	Dual Tim-3 and PD-1 expression is associated with enhanced tumour antigen-specific CD8+ T cell dysfunction in melanoma patients.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('Dual', 'Var', (0, 4))	('patients', 'Species', '9606', (119, 127))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('CD8', 'Gene', '925', (83, 86))	('CD8', 'Gene', (83, 86))	('T cell dysfunction', 'Phenotype', 'HP:0005435', (88, 106))	('Tim-3', 'Gene', (5, 10))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('enhanced', 'PosReg', (50, 58))	('tumour', 'Disease', (59, 65))	('PD-1', 'Gene', (15, 19))	('Tim-3', 'Gene', '84868', (5, 10))
107142	29996914	TIGIT ligands are highly expressed in metastatic melanoma and TIGIT and PD-1 blockade increases the proliferation, cytokine production, and degranulation of both tumour antigen-specific CD8+ T cells and CD8+ TILs in the presence of TIGIT ligand-expressing cells.	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('tumour', 'Disease', (162, 168))	('CD8', 'Gene', '925', (186, 189))	('degranulation', 'MPA', (140, 153))	('blockade', 'Var', (77, 85))	('cytokine production', 'biological_process', 'GO:0001816', ('115', '134'))	('increases', 'PosReg', (86, 95))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('CD8', 'Gene', (203, 206))	('CD8', 'Gene', '925', (203, 206))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('cytokine production', 'MPA', (115, 134))	('PD-1', 'Gene', (72, 76))	('ligand', 'molecular_function', 'GO:0005488', ('238', '244'))	('CD8', 'Gene', (186, 189))	('tumour', 'Disease', 'MESH:D009369', (162, 168))	('melanoma', 'Disease', (49, 57))	('rat', 'Species', '10116', (107, 110))
107146	29996914	Similarly, the anti-TIGIT antibody BMS 9862017 is being investigated in a phase I/IIa first-in-human study alone and in combination with anti-PD-1 nivolumab in advanced solid tumours (NCT02913313).	('human', 'Species', '9606', (95, 100))	('antibody', 'cellular_component', 'GO:0019815', ('26', '34'))	('advanced solid tumours', 'Disease', (160, 182))	('antibody', 'cellular_component', 'GO:0019814', ('26', '34'))	('antibody', 'molecular_function', 'GO:0003823', ('26', '34'))	('tumours', 'Phenotype', 'HP:0002664', (175, 182))	('nivolumab', 'Chemical', 'MESH:D000077594', (147, 156))	('antibody', 'cellular_component', 'GO:0042571', ('26', '34'))	('BMS 9862017', 'Var', (35, 46))	('advanced solid tumours', 'Disease', 'MESH:D006223', (160, 182))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))
107151	29996914	PD-1/PD-L1 expression, cytolytic activity, and mutational load are positive and interdependent prognostic features in melanoma and other tumours.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('mutational load', 'Var', (47, 62))	('melanoma and other tumours', 'Disease', 'MESH:D008545', (118, 144))	('PD-L1', 'Gene', (5, 10))	('cytolytic', 'MPA', (23, 32))	('expression', 'MPA', (11, 21))	('tumours', 'Phenotype', 'HP:0002664', (137, 144))	('PD-L1', 'Gene', '29126', (5, 10))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
107155	29996914	Circulating tumour DNA (ctDNA) isolated from plasma has been shown to reflect the mutational status of glioblastoma, and extracellular vesicles containing ctDNA, microRNA and proteins act as reservoirs for biomarkers such as typical DNA mutations, regulatory microRNAs and oncoproteins.	('DNA', 'cellular_component', 'GO:0005574', ('233', '236'))	('tumour', 'Disease', (12, 18))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))	('extracellular', 'cellular_component', 'GO:0005576', ('121', '134'))	('glioblastoma', 'Disease', (103, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (103, 115))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('mutations', 'Var', (237, 246))	('tumour', 'Disease', 'MESH:D009369', (12, 18))	('glioblastoma', 'Phenotype', 'HP:0012174', (103, 115))
107156	29996914	At Massachusetts General Hospital, serial ctDNA BRAF mutation has been shown to correlate with response/progression in patients treated with anti-BRAF vemurafenib and high-dose interleukin (IL)-2.	('BRAF', 'Gene', (146, 150))	('mutation', 'Var', (53, 61))	('vemurafenib', 'Chemical', 'MESH:D000077484', (151, 162))	('patients', 'Species', '9606', (119, 127))	('BRAF', 'Gene', '673', (146, 150))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('IL)-2', 'molecular_function', 'GO:0005134', ('190', '195'))
107157	29996914	Also, serial ctDNA mutation correlates with response/progression in patients treated with immune checkpoint inhibitors.	('patients', 'Species', '9606', (68, 76))	('response/progression', 'Disease', (44, 64))	('mutation', 'Var', (19, 27))	('ctDNA', 'Gene', (13, 18))
107159	29996914	Mutational load and possibly copy number alterations also predict response to immunotherapy; analysis of mutational load and copy number gains/losses is feasible from ctDNA.	('mutational load', 'Var', (105, 120))	('copy number gains/losses', 'Var', (125, 149))	('rat', 'Species', '10116', (45, 48))
107168	29996914	However, in patients with a high TMB, response rate was higher with nivolumab and median PFS was prolonged (9.7 vs. 5.8 months; hazard ratio [HR] for disease progression or death, 0.62; 95% CI: 0.38-1.00).	('patients', 'Species', '9606', (12, 20))	('rat', 'Species', '10116', (135, 138))	('nivolumab', 'Chemical', 'MESH:D000077594', (68, 77))	('rat', 'Species', '10116', (47, 50))	('prolonged', 'PosReg', (97, 106))	('higher', 'PosReg', (56, 62))	('response', 'MPA', (38, 46))	('high', 'Var', (28, 32))	('TMB', 'Chemical', '-', (33, 36))	('nivolumab', 'Var', (68, 77))
107169	29996914	There was no significant association between TMB and PD-L1 tumour expression level but the highest response rate was seen in patients with both high TMB and PD-L1 expression >=50%.	('rat', 'Species', '10116', (108, 111))	('PD-L1', 'Gene', (53, 58))	('PD-L1 tumour', 'Disease', (53, 65))	('PD-L1 tumour', 'Disease', 'MESH:D010300', (53, 65))	('TMB', 'Chemical', '-', (45, 48))	('TMB', 'Chemical', '-', (149, 152))	('PD-L1', 'Gene', (157, 162))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('PD-L1', 'Gene', '29126', (53, 58))	('high', 'Var', (144, 148))	('PD-L1', 'Gene', '29126', (157, 162))	('patients', 'Species', '9606', (125, 133))
107173	29996914	Tumours with nonsense mutations, indels, or homozygous deletions in the FANCE or MLH1 genes have significantly higher TMB.	('nonsense mutations', 'Var', (13, 31))	('indels', 'Var', (33, 39))	('TMB', 'CPA', (118, 121))	('MLH1', 'Gene', '4292', (81, 85))	('MLH1', 'Gene', (81, 85))	('FANCE', 'Gene', '2178', (72, 77))	('homozygous deletions', 'Var', (44, 64))	('TMB', 'Chemical', '-', (118, 121))	('higher', 'PosReg', (111, 117))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('FANCE', 'Gene', (72, 77))
107188	29996914	When patients were stratified according to their PD-L1 expression level, OS was 59% greater among patients in the highest tertile of PD-L1 expression with atezolizumab compared with docetaxel (p<0.0001).	('expression', 'Var', (139, 149))	('patients', 'Species', '9606', (5, 13))	('PD-L1', 'Gene', '29126', (49, 54))	('docetaxel', 'Chemical', 'MESH:D000077143', (182, 191))	('PD-L1', 'Gene', (133, 138))	('OS', 'Chemical', '-', (73, 75))	('patients', 'Species', '9606', (98, 106))	('atezolizumab', 'Chemical', 'MESH:C000594389', (155, 167))	('PD-L1', 'Gene', '29126', (133, 138))	('rat', 'Species', '10116', (21, 24))	('greater', 'PosReg', (84, 91))	('PD-L1', 'Gene', (49, 54))
107217	29996914	Response rates in melanoma with single agent anti-PD1 inhibitors are higher than those seen in RCC.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('rat', 'Species', '10116', (9, 12))	('inhibitors', 'Var', (54, 64))	('PD1', 'Gene', '5133', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('RCC', 'Disease', (95, 98))	('PD1', 'Gene', (50, 53))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('higher', 'PosReg', (69, 75))	('melanoma', 'Disease', (18, 26))
107254	29996914	PD-1 blockade with nivolumab may boost host immunity against HCC and improve clinical outcomes.	('blockade', 'Var', (5, 13))	('host immunity', 'CPA', (39, 52))	('PD-1', 'Gene', (0, 4))	('HCC', 'Gene', (61, 64))	('clinical outcomes', 'CPA', (77, 94))	('boost', 'PosReg', (33, 38))	('HCC', 'Gene', '619501', (61, 64))	('improve', 'PosReg', (69, 76))	('nivolumab', 'Chemical', 'MESH:D000077594', (19, 28))
107266	29996914	NK cells can also be recruited by AdV-transduced DC via IL-8 and IFN-gamma-inducible protein-10 (IP-10), and show cytotoxic activity.	('cytotoxic activity', 'CPA', (114, 132))	('AdV-transduced', 'Var', (34, 48))	('IFN-gamma-inducible protein-10', 'Gene', '3627', (65, 95))	('IL-8', 'molecular_function', 'GO:0005153', ('56', '60'))	('IP-10', 'Gene', (97, 102))	('IFN-gamma-inducible protein-10', 'Gene', (65, 95))	('NK cells', 'CPA', (0, 8))	('IL-8', 'Gene', '3576', (56, 60))	('recruited', 'PosReg', (21, 30))	('IL-8', 'Gene', (56, 60))	('IP-10', 'Gene', '3627', (97, 102))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
107268	29996914	ICOSL, OX40L) with AdVTMM2 DC compared to healthy donors, while both melanoma patients and healthy donors had increased expression of co-inhibitory molecules (TIM3L, PD-L1, PD-L2, CTLA-4) in matured compared with immature DC [unpublished data].	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('PD-L2', 'Gene', (173, 178))	('ICOSL', 'Gene', '23308', (0, 5))	('increased', 'PosReg', (110, 119))	('patients', 'Species', '9606', (78, 86))	('OX40L', 'Gene', '7292', (7, 12))	('donor', 'Species', '9606', (99, 104))	('PD-L1', 'Gene', (166, 171))	('TIM3L', 'Gene', (159, 164))	('ICOSL', 'Gene', (0, 5))	('expression', 'MPA', (120, 130))	('PD-L1', 'Gene', '29126', (166, 171))	('donor', 'Species', '9606', (50, 55))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))	('AdVTMM2', 'Var', (19, 26))	('CTLA-4', 'Gene', '1493', (180, 186))	('OX40L', 'Gene', (7, 12))	('PD-L2', 'Gene', '80380', (173, 178))	('CTLA-4', 'Gene', (180, 186))
107297	29996914	Across clinical trials, there has been an association between T cell expansion and persistence and tumour regression in patients with hematologic and solid cancers receiving ACT.	('hematologic', 'Disease', (134, 145))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('T cell expansion', 'Var', (62, 78))	('persistence', 'CPA', (83, 94))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('solid cancers', 'Disease', (150, 163))	('tumour', 'Disease', (99, 105))	('solid cancers', 'Disease', 'MESH:D009369', (150, 163))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('patients', 'Species', '9606', (120, 128))	('cell expansion', 'biological_process', 'GO:0016049', ('64', '78'))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
107303	29996914	Overexpression of a Fas death domain variant prevents Fas crosslinking.	('Fas', 'Chemical', 'MESH:C038178', (54, 57))	('Fas', 'Disease', (54, 57))	('variant', 'Var', (37, 44))	('prevents', 'NegReg', (45, 53))	('Fas', 'Chemical', 'MESH:C038178', (20, 23))
107304	29996914	T cells engineered with Fas mutants are expressed 5-10-fold higher compared with wild-type Fas, preventing FasL-induced apoptosis in a dominant negative fashion.	('Fas', 'Chemical', 'MESH:C038178', (107, 110))	('preventing', 'NegReg', (96, 106))	('mutants', 'Var', (28, 35))	('Fas', 'Chemical', 'MESH:C038178', (91, 94))	('FasL', 'Gene', (107, 111))	('apoptosis', 'biological_process', 'GO:0097194', ('120', '129'))	('FasL', 'Gene', '356', (107, 111))	('apoptosis', 'biological_process', 'GO:0006915', ('120', '129'))	('Fas', 'Chemical', 'MESH:C038178', (24, 27))
107316	29996914	CD28 but not ICOS induces IL-2 and combining CD28 and ICOS augments the effector function of murine T cells.	('IL-2', 'Gene', (26, 30))	('murine', 'Species', '10090', (93, 99))	('CD28', 'Var', (0, 4))	('CD28', 'Var', (45, 49))	('IL-2', 'molecular_function', 'GO:0005134', ('26', '30'))	('effector function of murine T cells', 'CPA', (72, 107))	('augments', 'PosReg', (59, 67))	('IL-2', 'Gene', '16183', (26, 30))
107329	29996914	However, despite the high response rates after CART19 immunotherapy, a subset of patients still relapses and, in particular in B-ALL, the majority of the relapses are caused by the loss of CD19 on leukemic cells.	('CAR', 'Gene', (47, 50))	('leukemic', 'Disease', 'MESH:D007938', (197, 205))	('patients', 'Species', '9606', (81, 89))	('caused by', 'Reg', (167, 176))	('CD19', 'Gene', (189, 193))	('CAR', 'Gene', '653108', (47, 50))	('rat', 'Species', '10116', (35, 38))	('loss', 'Var', (181, 185))	('CD19', 'Gene', '930', (189, 193))	('leukemic', 'Disease', (197, 205))
107330	29996914	Several mechanisms of CD19-targeted therapy resistance have been described, including convergence of acquired mutations of the CD19 gene, alternative CD19 splicing and others.	('splicing', 'biological_process', 'GO:0045292', ('155', '163'))	('mutations', 'Var', (110, 119))	('alternative', 'Var', (138, 149))	('CD19', 'Gene', (22, 26))	('CD19', 'Gene', (127, 131))	('CD19', 'Gene', (150, 154))	('CD19', 'Gene', '930', (22, 26))	('CD19', 'Gene', '930', (127, 131))	('CD19', 'Gene', '930', (150, 154))
107348	29996914	Tumours with a pathological response had higher densities of immune cells (CD3, CD8, CD20) and patients who responded to neoadjuvant treatment had higher densities of immune cells (CD3, CD8, CD20, CD45RO, FOXP3).	('CD20', 'Gene', (85, 89))	('CD4', 'Gene', (197, 200))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('CD8', 'Gene', (186, 189))	('FOXP3', 'Gene', '50943', (205, 210))	('CD20', 'Gene', '54474', (85, 89))	('CD8', 'Gene', '925', (80, 83))	('CD20', 'Gene', (191, 195))	('densities', 'MPA', (154, 163))	('CD20', 'Gene', '54474', (191, 195))	('higher', 'PosReg', (147, 153))	('CD8', 'Gene', (80, 83))	('CD8', 'Gene', '925', (186, 189))	('patients', 'Species', '9606', (95, 103))	('FOXP3', 'Gene', (205, 210))	('higher', 'PosReg', (41, 47))	('densities', 'MPA', (48, 57))	('CD4', 'Gene', '920', (197, 200))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('CD3', 'Var', (181, 184))
107448	30442117	We transfected FABP7- siRNA into SKRC10 cells to knock down the expression of FABP7.	('expression', 'MPA', (64, 74))	('SKRC10', 'CellLine', 'CVCL:6175', (33, 39))	('FABP7', 'Gene', '2173', (15, 20))	('FABP7', 'Gene', '2173', (78, 83))	('FABP7', 'Gene', (15, 20))	('knock', 'Var', (49, 54))	('FABP7', 'Gene', (78, 83))
107449	30442117	Interestingly, FABP7 knockdown reduced the expression of Stat3 (Fig.	('reduced', 'NegReg', (31, 38))	('Stat3', 'Gene', '6774', (57, 62))	('FABP7', 'Gene', '2173', (15, 20))	('Stat3', 'Gene', (57, 62))	('FABP7', 'Gene', (15, 20))	('knockdown', 'Var', (21, 30))	('expression', 'MPA', (43, 53))
107457	30442117	5b), while combined knock down of FABP7 and FABP6 did not inhibit the cell growth more than knock down of FABP6 alone.	('FABP6', 'Gene', '2172', (44, 49))	('FABP6', 'Gene', '2172', (106, 111))	('FABP7', 'Gene', (34, 39))	('cell growth', 'CPA', (70, 81))	('FABP6', 'Gene', (44, 49))	('FABP6', 'Gene', (106, 111))	('FABP7', 'Gene', '2173', (34, 39))	('knock down', 'Var', (20, 30))	('cell growth', 'biological_process', 'GO:0016049', ('70', '81'))
107473	30442117	They supposed that inhibition of lipid storage may reduce the ability in protecting the cancer cells from toxicity by reactive oxygen and decrease the survival of the cancer cells under the condition of hypoxia-reoxygenation.	('cancer', 'Disease', (88, 94))	('toxicity', 'Disease', 'MESH:D064420', (106, 114))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('inhibition', 'Var', (19, 29))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('reactive oxygen', 'Chemical', '-', (118, 133))	('survival', 'CPA', (151, 159))	('toxicity', 'Disease', (106, 114))	('cancer', 'Disease', (167, 173))	('hypoxia', 'Disease', 'MESH:D000860', (203, 210))	('reduce', 'NegReg', (51, 57))	('decrease', 'NegReg', (138, 146))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('lipid', 'Chemical', 'MESH:D008055', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('hypoxia', 'Disease', (203, 210))	('lipid storage', 'biological_process', 'GO:0019915', ('33', '46'))
107479	30442117	In our study, it was also confirmed that the knockdown of FABP7 reduced Stat3 expression, which may result in growth inhibition and reduction of the invasive potential.	('Stat3', 'Gene', (72, 77))	('growth inhibition', 'CPA', (110, 127))	('FABP7', 'Gene', (58, 63))	('reduction', 'NegReg', (132, 141))	('FABP7', 'Gene', '2173', (58, 63))	('invasive potential', 'CPA', (149, 167))	('reduced', 'NegReg', (64, 71))	('Stat3', 'Gene', '6774', (72, 77))	('knockdown', 'Var', (45, 54))
107487	30442117	Our study showed that FABP6 can complement FABP7 in a cell type-dependent manner and indicates that a knockdown of FABP7 and/or FABP6 can reduce viability and invasive potential of ccRCC cells.	('men', 'Species', '9606', (38, 41))	('FABP6', 'Gene', (128, 133))	('FABP7', 'Gene', '2173', (115, 120))	('FABP6', 'Gene', (22, 27))	('knockdown', 'Var', (102, 111))	('ccRCC', 'Disease', (181, 186))	('FABP7', 'Gene', (115, 120))	('invasive potential', 'CPA', (159, 177))	('FABP7', 'Gene', '2173', (43, 48))	('viability', 'CPA', (145, 154))	('FABP7', 'Gene', (43, 48))	('reduce', 'NegReg', (138, 144))	('FABP6', 'Gene', '2172', (22, 27))	('FABP6', 'Gene', '2172', (128, 133))
107530	30258932	For example, in breast cancer, overexpression of NEAT1 promotes EMT and invasion in vitro as well as dissemination and metastasis in vivo.	('breast cancer', 'Disease', (16, 29))	('overexpression', 'Var', (31, 45))	('promotes', 'PosReg', (55, 63))	('NEAT1', 'Gene', '283131', (49, 54))	('EMT', 'biological_process', 'GO:0001837', ('64', '67'))	('NEAT1', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('dissemination', 'CPA', (101, 114))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
107531	30258932	Exogenous modulation of NEAT1 modulates gemcitabine sensitivity in cholangiocarcinoma.	('modulates', 'Reg', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('modulation', 'Var', (10, 20))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('gemcitabine sensitivity', 'MPA', (40, 63))	('NEAT1', 'Gene', '283131', (24, 29))	('NEAT1', 'Gene', (24, 29))	('cholangiocarcinoma', 'Disease', (67, 85))	('gemcitabine', 'Chemical', 'MESH:C056507', (40, 51))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))
107533	30258932	Moreover, in breast cancer, hepatocellular carcinoma, and papillary kidney cancer, whole-genome analysis indicates NEAT1 carries specific mutations that affect their expression levels.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (28, 52))	('kidney cancer', 'Phenotype', 'HP:0009726', (68, 81))	('hepatocellular carcinoma', 'Disease', (28, 52))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('papillary kidney cancer', 'Disease', (58, 81))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (28, 52))	('affect', 'Reg', (153, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('expression levels', 'MPA', (166, 183))	('breast cancer', 'Disease', (13, 26))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('papillary kidney cancer', 'Phenotype', 'HP:0006766', (58, 81))	('NEAT1', 'Gene', (115, 120))	('NEAT1', 'Gene', '283131', (115, 120))	('papillary kidney cancer', 'Disease', 'MESH:D007681', (58, 81))	('mutations', 'Var', (138, 147))
107534	30258932	rs512715 of NEAT1 is also associated with an increased risk of cervical cancer.	('rs512715', 'Mutation', 'rs512715', (0, 8))	('NEAT1', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cervical cancer', 'Disease', 'MESH:D002583', (63, 78))	('rs512715', 'Var', (0, 8))	('cervical cancer', 'Disease', (63, 78))	('NEAT1', 'Gene', '283131', (12, 17))	('associated', 'Reg', (26, 36))
107557	30258932	However, a recent study indicated that in breast invasive cancer, from TCGA datasets, NEAT1 was focally deleted in ~8% of breast cancers and its promoters carried various mutations, and three out of the four mutations they validated reproducibly decreased NEAT1 expression compared with the wild type sequence.	('NEAT1', 'Gene', '283131', (256, 261))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancers', 'Disease', 'MESH:D001943', (122, 136))	('breast cancers', 'Disease', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('NEAT1', 'Gene', (256, 261))	('deleted', 'NegReg', (104, 111))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('expression', 'MPA', (262, 272))	('breast invasive cancer', 'Disease', (42, 64))	('mutations', 'Var', (208, 217))	('NEAT1', 'Gene', '283131', (86, 91))	('breast invasive cancer', 'Disease', 'MESH:D001943', (42, 64))	('NEAT1', 'Gene', (86, 91))	('breast cancers', 'Phenotype', 'HP:0003002', (122, 136))	('mutations', 'Var', (171, 180))	('decreased', 'NegReg', (246, 255))
107570	30258932	In lung cancer, NEAT1 is up-regulated by the direct binding of Oct4, since knockdown of NEAT1 abolishes Oct4-mediated lung cancer cell growth and motility.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('Oct4', 'Gene', '5460', (63, 67))	('lung cancer', 'Disease', (118, 129))	('cell growth', 'biological_process', 'GO:0016049', ('130', '141'))	('abolishes', 'NegReg', (94, 103))	('NEAT1', 'Gene', (88, 93))	('Oct4', 'Gene', (104, 108))	('knockdown', 'Var', (75, 84))	('binding', 'Interaction', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('NEAT1', 'Gene', (16, 21))	('lung cancer', 'Disease', (3, 14))	('Oct4', 'Gene', (63, 67))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('NEAT1', 'Gene', '283131', (88, 93))	('up-regulated', 'PosReg', (25, 37))	('binding', 'molecular_function', 'GO:0005488', ('52', '59'))	('motility', 'CPA', (146, 154))	('NEAT1', 'Gene', '283131', (16, 21))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('Oct4', 'Gene', '5460', (104, 108))
107582	30258932	The aberrant expression of NEAT1 in certain types of cancer may be resulted from the cooperation and antagonism between different transcription factors.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('expression', 'MPA', (13, 23))	('aberrant', 'Var', (4, 12))	('NEAT1', 'Gene', '283131', (27, 32))	('transcription', 'biological_process', 'GO:0006351', ('130', '143'))	('NEAT1', 'Gene', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('resulted from', 'Reg', (67, 80))
107589	30258932	In laryngeal squamous cell cancer, high expression of NEAT1 decreases miR-107 expression, thus regulating CDK6 level and exerting an oncogenic effect.	('decreases', 'NegReg', (60, 69))	('regulating', 'Reg', (95, 105))	('laryngeal squamous cell cancer', 'Disease', (3, 33))	('NEAT1', 'Gene', (54, 59))	('expression', 'MPA', (78, 88))	('NEAT1', 'Gene', '283131', (54, 59))	('laryngeal squamous cell cancer', 'Disease', 'MESH:D002294', (3, 33))	('CDK6', 'Gene', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('CDK', 'molecular_function', 'GO:0004693', ('106', '109'))	('CDK6', 'Gene', '1021', (106, 110))	('oncogenic effect', 'CPA', (133, 149))	('high expression', 'Var', (35, 50))	('miR-107', 'Gene', '406901', (70, 77))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (13, 33))	('miR-107', 'Gene', (70, 77))
107608	30258932	Recently, several studies have revealed the mutations and polymorphisms of NEAT1 are also closely correlated with the prognosis of cancers, which has added complexity to NEAT1-associated signaling and function.	('NEAT1', 'Gene', '283131', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('NEAT1', 'Gene', (75, 80))	('signaling', 'biological_process', 'GO:0023052', ('187', '196'))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('polymorphisms', 'Var', (58, 71))	('correlated', 'Reg', (98, 108))	('mutations', 'Var', (44, 53))	('NEAT1', 'Gene', '283131', (170, 175))	('NEAT1', 'Gene', (170, 175))
107609	30258932	Moreover, since the two major isoforms of NEAT1 produced from alternative transcription have been reported to have different cellular location and tumor regulation properties, it is necessary to distinguish the exact expression and function of these two isoforms.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('regulation', 'biological_process', 'GO:0065007', ('153', '163'))	('NEAT1', 'Gene', '283131', (42, 47))	('alternative transcription', 'Var', (62, 87))	('NEAT1', 'Gene', (42, 47))	('transcription', 'biological_process', 'GO:0006351', ('74', '87'))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
107619	33377624	XCR1 knockdown by small interfering RNA (siRNA) significantly increased ccRCC cell proliferation and migration, and decreased cell apoptosis.	('increased', 'PosReg', (62, 71))	('cell proliferation', 'biological_process', 'GO:0008283', ('78', '96'))	('migration', 'CPA', (101, 110))	('knockdown', 'Var', (5, 14))	('XCR1', 'Gene', (0, 4))	('RNA', 'cellular_component', 'GO:0005562', ('36', '39'))	('apoptosis', 'biological_process', 'GO:0097194', ('131', '140'))	('RCC', 'Disease', (74, 77))	('cell apoptosis', 'CPA', (126, 140))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('apoptosis', 'biological_process', 'GO:0006915', ('131', '140'))	('XCR1', 'Gene', '2829', (0, 4))	('decreased', 'NegReg', (116, 125))
107621	33377624	XCR1 knockdown significantly increased RCC cells proliferation and migration, and decreased apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('92', '101'))	('apoptosis', 'biological_process', 'GO:0006915', ('92', '101'))	('apoptosis', 'CPA', (92, 101))	('knockdown', 'Var', (5, 14))	('XCR1', 'Gene', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('increased', 'PosReg', (29, 38))	('RCC', 'Disease', (39, 42))	('migration', 'CPA', (67, 76))	('XCR1', 'Gene', '2829', (0, 4))	('decreased', 'NegReg', (82, 91))
107635	33377624	XCR1 overexpression could inhibit liver cancer cells' proliferation, and promote tumor migration (Kim et al., 2012).	('liver cancer', 'Phenotype', 'HP:0002896', (34, 46))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('XCR1', 'Gene', (0, 4))	('inhibit', 'NegReg', (26, 33))	('overexpression', 'Var', (5, 19))	('cancer', 'Disease', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('XCR1', 'Gene', '2829', (0, 4))	('promote', 'PosReg', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Disease', (81, 86))
107688	33377624	Additionally, CCK8 and Transwell migration results showed that, after knockdown of XCR1, the RCC cells proliferation and migration were shown to be significantly increased (Figure 5b,c).	('migration', 'CPA', (121, 130))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('knockdown', 'Var', (70, 79))	('RCC', 'Disease', (93, 96))	('increased', 'PosReg', (162, 171))	('XCR1', 'Gene', (83, 87))	('XCR1', 'Gene', '2829', (83, 87))
107712	33377624	On the one hand, the blockade of STAT interrupts the transmission of signals arriving at the cell nucleus, which would cause genetic disorders and tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('genetic disorders', 'Disease', (125, 142))	('STAT', 'Gene', (33, 37))	('cause', 'Reg', (119, 124))	('interrupts', 'NegReg', (38, 48))	('blockade', 'Var', (21, 29))	('genetic disorders', 'Disease', 'MESH:D030342', (125, 142))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cell nucleus', 'cellular_component', 'GO:0005634', ('93', '105'))
107713	33377624	O n the other hand, large amounts of target genes are transcribed as a result of abnormal STAT activation, which could also cause tumorigenesis (Yamazaki et al., 2010; Yang et al., 2017).	('STAT', 'Gene', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('activation', 'PosReg', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cause', 'Reg', (124, 129))	('tumor', 'Disease', (130, 135))	('abnormal', 'Var', (81, 89))
107714	33377624	It is reported that the abnormal activation of STAT3 promotes in tumor formation, while STAT1's abnormal activation in tumors triggers the body's anti-tumor mechanism (Yanru et al., 2018).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('abnormal', 'Var', (24, 32))	('STAT3', 'Gene', (47, 52))	('STAT1', 'Gene', (88, 93))	('formation', 'biological_process', 'GO:0009058', ('71', '80'))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('promotes', 'PosReg', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('activation', 'PosReg', (33, 43))	('tumors', 'Disease', (119, 125))	('tumor', 'Disease', (65, 70))	('STAT3', 'Gene', '6774', (47, 52))	('activation', 'PosReg', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('STAT1', 'Gene', '6772', (88, 93))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('triggers', 'Reg', (126, 134))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
107718	33377624	After knockdown of XCR1, cell proliferation and migration increased notably, while the apoptosis rate decreased significantly.	('increased', 'PosReg', (58, 67))	('XCR1', 'Gene', '2829', (19, 23))	('cell proliferation', 'biological_process', 'GO:0008283', ('25', '43'))	('cell proliferation', 'CPA', (25, 43))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('apoptosis rate', 'CPA', (87, 101))	('knockdown', 'Var', (6, 15))	('XCR1', 'Gene', (19, 23))	('decreased', 'NegReg', (102, 111))
107721	33377624	Downregulation of XCR1 promoted ccRCC cell proliferation and migration, and might decrease RCC cell apoptosis.	('XCR1', 'Gene', '2829', (18, 22))	('promoted', 'PosReg', (23, 31))	('decrease', 'NegReg', (82, 90))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('Downregulation', 'Var', (0, 14))	('RCC', 'Disease', (91, 94))	('migration', 'CPA', (61, 70))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('XCR1', 'Gene', (18, 22))	('cell proliferation', 'biological_process', 'GO:0008283', ('38', '56'))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('RCC', 'Disease', (34, 37))
107726	31371982	Additionally, high-resolution mass spectrometry was used to analyze kidney-derived cells and tissues, and the eukaryotic expression vectors that led to the mutations of lysine were constructed and transfected into HEK293T cells.	('lysine', 'Gene', (169, 175))	('mutations', 'Var', (156, 165))	('lysine', 'Chemical', 'MESH:D008239', (169, 175))	('HEK293T cells', 'CellLine', 'CVCL:0063', (214, 227))	('expression vectors', 'Species', '29278', (121, 139))
107730	31371982	Inhibition of the Lys-trimethylation in LDHA increased the LDH activity of HEK293T cells and upregulated their proliferation.	('HEK293T cells', 'CellLine', 'CVCL:0063', (75, 88))	('Lys', 'Chemical', 'MESH:D008239', (18, 21))	('increased', 'PosReg', (45, 54))	('proliferation', 'CPA', (111, 124))	('LDHA', 'Gene', (40, 44))	('Inhibition', 'Var', (0, 10))	('Lys-trimethylation', 'Var', (18, 36))	('LDH activity', 'CPA', (59, 71))	('upregulated', 'PosReg', (93, 104))	('LDHA', 'Gene', '3939', (40, 44))
107731	31371982	Conclusion: We suggested that LDHA affects the metabolism and proliferation of cells via a Lys-trimethylation-mediated mechanism; Lys-trimethylation might be a potential target for therapeutic research or used as a prognostic and treatment biomarker of several diseases.	('LDHA', 'Gene', (30, 34))	('LDHA', 'Gene', '3939', (30, 34))	('Lys-trimethylation', 'Var', (130, 148))	('metabolism', 'biological_process', 'GO:0008152', ('47', '57'))	('Lys', 'Chemical', 'MESH:D008239', (91, 94))	('metabolism', 'MPA', (47, 57))	('men', 'Species', '9606', (235, 238))	('affects', 'Reg', (35, 42))	('Lys', 'Chemical', 'MESH:D008239', (130, 133))
107734	31371982	Monomethylation may have marginal effects on alpha-amino nitrogen nucleophilicity and basicity; however, trimethylation (or dimethylation in case of proline) can result in the abolishment of nucleophilicity and a permanent positive charge on the N-terminal amino group; hence, the molecular biological functions of monomethylation may be different from those of trimethylation.	('nitrogen', 'Chemical', 'MESH:D009584', (57, 65))	('men', 'Species', '9606', (183, 186))	('trimethylation', 'Var', (105, 119))	('proline', 'Chemical', 'MESH:D011392', (149, 156))	('nucleophilicity', 'MPA', (191, 206))	('abolishment', 'NegReg', (176, 187))
107737	31371982	Trimethylation at different lysine sites has different effects on the physical functions of cells.	('Trimethylation', 'Var', (0, 14))	('physical functions of cells', 'CPA', (70, 97))	('effects', 'Reg', (55, 62))	('lysine', 'Chemical', 'MESH:D008239', (28, 34))
107738	31371982	Trimethylation of histone H3 at lysine 4 (H3K4me3) represents the active chromatin that counters the repressive chromatin milieu suppressed by the methylation of H3K9 and H3K27 in higher eukaryotes.	('chromatin', 'cellular_component', 'GO:0000785', ('112', '121'))	('lysine', 'Chemical', 'MESH:D008239', (32, 38))	('H3K27', 'Protein', (171, 176))	('methylation', 'Var', (147, 158))	('H3K9', 'Protein', (162, 166))	('repressive chromatin milieu', 'MPA', (101, 128))	('methylation', 'biological_process', 'GO:0032259', ('147', '158'))	('chromatin', 'cellular_component', 'GO:0000785', ('73', '82'))
107741	31371982	Waldmann T et al have focused mainly on post-translational histone modifications since they are one of the major epigenetic mechanisms regulating gene expression, and their imbalance can result in cancer.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('expression', 'Species', '29278', (151, 161))	('result in', 'Reg', (187, 196))	('cancer', 'Disease', (197, 203))	('imbalance', 'Var', (173, 182))	('gene expression', 'biological_process', 'GO:0010467', ('146', '161'))	('imbalance', 'Phenotype', 'HP:0002172', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))
107749	31371982	Characterization of trimethylation may be important for the interpretation of results from previous biological studies and could reinforce our ability to treat renal diseases.	('trimethylation', 'Var', (20, 34))	('renal diseases', 'Disease', (160, 174))	('renal diseases', 'Disease', 'MESH:D007674', (160, 174))
107779	31371982	Lysine (K5) on the N-terminal of the lactate dehydrogenase A (LDHA) protein sequence was mutated to arginine (R) in the purified plasmid DNA, which was abbreviated as LDHA@K5R.	('LDHA', 'Gene', '3939', (167, 171))	('K5', 'Gene', '3852', (8, 10))	('LDHA', 'Gene', '3939', (62, 66))	('LDHA', 'Gene', (62, 66))	('K5R', 'Chemical', '-', (172, 175))	('lactate dehydrogenase A', 'Gene', (37, 60))	('arginine', 'Chemical', 'MESH:D001120', (100, 108))	('lactate dehydrogenase A', 'Gene', '3939', (37, 60))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('mutated', 'Var', (89, 96))	('DNA', 'cellular_component', 'GO:0005574', ('137', '140'))	('K5', 'Gene', '3852', (172, 174))	('LDHA', 'Gene', (167, 171))
107790	31371982	After anti-LDHA antibodies and Protein A+G Agarose were added to the protein extracts of the H293T cells, immunoprecipitation was performed; additionally, Western blotting was performed using anti-trimethyl lysine (1:3,000; immunechem, Canada, Catalog # ICP0601) and anti-LDHA antibodies (1:500; abcam, USA, Catalog # ab84716) as the primary antibodies.	('LDHA', 'Gene', (272, 276))	('LDHA', 'Gene', (11, 15))	('trimethyl lysine', 'Chemical', 'MESH:C003712', (197, 213))	('LDHA', 'Gene', '3939', (272, 276))	('LDHA', 'Gene', '3939', (11, 15))	('H293T', 'SUBSTITUTION', 'None', (93, 98))	('Agarose', 'Chemical', 'MESH:D012685', (43, 50))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('H293T', 'Var', (93, 98))
107808	31371982	Although the MASCOT and SEQUEST analyses showed that several proteins were Lys-trimethylated, only L-lactate dehydrogenase A chain (LDHA) was found to conform to all the above requirements simultaneously, because of the limitations of our experimental operations.	('men', 'Species', '9606', (183, 186))	('LDHA', 'Gene', (132, 136))	('Lys-trimethylated', 'Var', (75, 92))	('L-lactate dehydrogenase A chain', 'Gene', '3939', (99, 130))	('men', 'Species', '9606', (245, 248))	('Lys', 'Chemical', 'MESH:D008239', (75, 78))	('L-lactate dehydrogenase A chain', 'Gene', (99, 130))	('LDHA', 'Gene', '3939', (132, 136))	('proteins', 'Protein', (61, 69))
107814	31371982	Lysine (K5) on the N-terminal of LDHA protein sequence was mutated to arginine (R) in the purified plasmid DNA, which was abbreviated as LDHA@K5R, and lysine (K5) on the N-terminal of the LDHA protein sequence was mutated to glutamine (Q) in the purified plasmid DNA, which was abbreviated as LDHA@K5Q.	('LDHA', 'Gene', '3939', (188, 192))	('glutamine', 'Chemical', 'MESH:D005973', (225, 234))	('K5', 'Gene', '3852', (142, 144))	('LDHA', 'Gene', (33, 37))	('mutated', 'Var', (214, 221))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))	('LDHA', 'Gene', (293, 297))	('K5R', 'Chemical', '-', (142, 145))	('K5', 'Gene', '3852', (298, 300))	('LDHA', 'Gene', (188, 192))	('LDHA', 'Gene', '3939', (137, 141))	('mutated', 'Var', (59, 66))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('DNA', 'cellular_component', 'GO:0005574', ('263', '266'))	('LDHA', 'Gene', '3939', (33, 37))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))	('K5', 'Gene', '3852', (159, 161))	('K5', 'Gene', '3852', (8, 10))	('LDHA', 'Gene', '3939', (293, 297))	('arginine', 'Chemical', 'MESH:D001120', (70, 78))	('lysine', 'Chemical', 'MESH:D008239', (151, 157))	('LDHA', 'Gene', (137, 141))
107816	31371982	Both arginine and lysine are alkaline amino acids, and glutamine is a hydrophilic amino acid; thus, when the eukaryotic expression vectors were transfected into HEK293T cells, it was assumed that if LDHA was Lys-trimethylated on the K5, the mutation of lysine (K5) will lead to the reduction or disappearance of trimethylation in LDHA, but the expression of LDHA remained unchanged.	('lysine', 'Gene', (253, 259))	('LDHA', 'Gene', (358, 362))	('LDHA', 'Gene', '3939', (330, 334))	('lysine', 'Chemical', 'MESH:D008239', (253, 259))	('reduction', 'NegReg', (282, 291))	('HEK293T cells', 'CellLine', 'CVCL:0063', (161, 174))	('alkaline amino acid', 'Chemical', '-', (29, 48))	('LDHA', 'Gene', (199, 203))	('Lys', 'Chemical', 'MESH:D008239', (208, 211))	('mutation', 'Var', (241, 249))	('K5', 'Gene', '3852', (233, 235))	('LDHA', 'Gene', (330, 334))	('disappearance', 'NegReg', (295, 308))	('expression vectors', 'Species', '29278', (120, 138))	('LDHA', 'Gene', '3939', (358, 362))	('expression', 'Species', '29278', (344, 354))	('expression', 'Species', '29278', (120, 130))	('glutamine', 'Chemical', 'MESH:D005973', (55, 64))	('trimethylation', 'MPA', (312, 326))	('lysine', 'Chemical', 'MESH:D008239', (18, 24))	('LDHA', 'Gene', '3939', (199, 203))	('arginine', 'Chemical', 'MESH:D001120', (5, 13))	('K5', 'Gene', '3852', (261, 263))
107827	31371982	Once again, we verified that LDHA was Lys-trimethylated on the K5 of its protein sequence by constructing eukaryotic expression vectors that led to the mutations of lysine (K5) on LDHA.	('Lys', 'Chemical', 'MESH:D008239', (38, 41))	('mutations', 'Var', (152, 161))	('K5', 'Gene', '3852', (173, 175))	('lysine', 'Chemical', 'MESH:D008239', (165, 171))	('LDHA', 'Gene', (180, 184))	('LDHA', 'Gene', (29, 33))	('LDHA', 'Gene', '3939', (180, 184))	('expression vectors', 'Species', '29278', (117, 135))	('LDHA', 'Gene', '3939', (29, 33))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('K5', 'Gene', '3852', (63, 65))
107828	31371982	The results of the Western blotting analysis showed that the mutation of lysine (K5) decreased the level of trimethylation in LDHA, while the expression of LDHA remained unchanged.	('decreased', 'NegReg', (85, 94))	('LDHA', 'Gene', '3939', (156, 160))	('LDHA', 'Gene', (126, 130))	('LDHA', 'Gene', '3939', (126, 130))	('lysine', 'Chemical', 'MESH:D008239', (73, 79))	('mutation', 'Var', (61, 69))	('K5', 'Gene', '3852', (81, 83))	('LDHA', 'Gene', (156, 160))	('expression', 'Species', '29278', (142, 152))	('level of trimethylation', 'MPA', (99, 122))
107837	31371982	The ratio of HEK293T cells showing EdU and Hoechst fluorescent signals was 0.22+-0.03 without and 0.41+-0.06 with Lys-trimethylation inhibition (Figure 4B), and the inhibition of Lys-trimethylation in LDHA upregulated the proliferation of HEK293T cells by 1.87-fold (p<0.01, n=3).	('Lys', 'Chemical', 'MESH:D008239', (179, 182))	('HEK293T cells', 'CellLine', 'CVCL:0063', (13, 26))	('Lys', 'Chemical', 'MESH:D008239', (114, 117))	('HEK293T cells', 'CPA', (239, 252))	('Lys-trimethylation', 'Var', (179, 197))	('LDHA', 'Gene', (201, 205))	('Hoechst', 'Chemical', '-', (43, 50))	('upregulated', 'PosReg', (206, 217))	('LDHA', 'Gene', '3939', (201, 205))	('inhibition', 'Var', (165, 175))	('EdU', 'Chemical', 'MESH:C031086', (35, 38))	('proliferation', 'CPA', (222, 235))	('HEK293T cells', 'CellLine', 'CVCL:0063', (239, 252))
107842	31371982	We detected the LDH activity of HEK293T cells following Lys-trimethylation inhibition by using the LDH Activity Assay Kit, and the results showed that when the expression of Lys-trimethylation in LDHA was suppressed, the LDH activity increased accordingly, while the LDHA expression remained unchanged.	('suppressed', 'NegReg', (205, 215))	('expression', 'MPA', (160, 170))	('increased', 'PosReg', (234, 243))	('expression', 'Species', '29278', (272, 282))	('LDHA', 'Gene', '3939', (196, 200))	('Lys', 'Chemical', 'MESH:D008239', (56, 59))	('Lys-trimethylation', 'Var', (174, 192))	('LDHA', 'Gene', (267, 271))	('LDH activity', 'MPA', (221, 233))	('Lys', 'Chemical', 'MESH:D008239', (174, 177))	('expression', 'Species', '29278', (160, 170))	('LDHA', 'Gene', '3939', (267, 271))	('HEK293T cells', 'CellLine', 'CVCL:0063', (32, 45))	('LDHA', 'Gene', (196, 200))
107843	31371982	We measured the proliferation of HEK293T cells following Lys-trimethylation inhibition by using EdU and Western blotting analyses, and found that the inhibition of Lys-trimethylation in LDHA upregulated the proliferation of HEK293T cells.	('upregulated', 'PosReg', (191, 202))	('HEK293T cells', 'CellLine', 'CVCL:0063', (224, 237))	('inhibition', 'Var', (150, 160))	('Lys-trimethylation', 'Var', (164, 182))	('LDHA', 'Gene', (186, 190))	('proliferation', 'CPA', (207, 220))	('EdU', 'Chemical', 'MESH:C031086', (96, 99))	('Lys', 'Chemical', 'MESH:D008239', (57, 60))	('LDHA', 'Gene', '3939', (186, 190))	('Lys', 'Chemical', 'MESH:D008239', (164, 167))	('HEK293T cells', 'CellLine', 'CVCL:0063', (33, 46))
107848	31371982	LDHA activation mediated by phosphorylation promotes tumor cell invasion and tumor metastasis.	('phosphorylation', 'Var', (28, 43))	('promotes', 'PosReg', (44, 52))	('LDHA', 'Gene', (0, 4))	('tumor metastasis', 'Disease', 'MESH:D009362', (77, 93))	('tumor metastasis', 'Disease', (77, 93))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('LDHA', 'Gene', '3939', (0, 4))	('activation', 'PosReg', (5, 15))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (77, 82))	('phosphorylation', 'biological_process', 'GO:0016310', ('28', '43'))
107849	31371982	In lung cancer cells and leukemia cells harboring dysregulated fibroblast growth factor receptor 1 (FGFR1), the phosphorylation of LDHA at tyrosine has been shown to promote tumor cell metabolism and the growth of tumors by regulating NADH/NAD+ redox homeostasis.	('leukemia', 'Disease', (25, 33))	('leukemia', 'Disease', 'MESH:D007938', (25, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('fibroblast growth factor receptor 1', 'Gene', '2260', (63, 98))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('NAD+', 'Chemical', 'MESH:D009243', (240, 244))	('tumors', 'Disease', (214, 220))	('NADH', 'Chemical', 'MESH:D009243', (235, 239))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('FGFR1', 'Gene', '2260', (100, 105))	('fibroblast growth factor receptor 1', 'Gene', (63, 98))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('63', '87'))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('dysregulated', 'Var', (50, 62))	('LDHA', 'Gene', '3939', (131, 135))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('promote', 'PosReg', (166, 173))	('FGFR', 'molecular_function', 'GO:0005007', ('100', '104'))	('lung cancer', 'Disease', (3, 14))	('metabolism', 'biological_process', 'GO:0008152', ('185', '195'))	('growth', 'CPA', (204, 210))	('FGFR1', 'Gene', (100, 105))	('tyrosine', 'Chemical', 'MESH:D014443', (139, 147))	('phosphorylation', 'Var', (112, 127))	('tumor', 'Disease', (214, 219))	('phosphorylation', 'biological_process', 'GO:0016310', ('112', '127'))	('tumor', 'Disease', (174, 179))	('leukemia', 'Phenotype', 'HP:0001909', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('NADH/NAD+ redox homeostasis', 'MPA', (235, 262))	('LDHA', 'Gene', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('regulating', 'Reg', (224, 234))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('homeostasis', 'biological_process', 'GO:0042592', ('251', '262'))
107850	31371982	LDHA K5 may be also acetylated and succinylated, and the LDHA K5 substitutions will similarly affect all other potential lysine modifications at this residue.	('LDHA', 'Gene', '3939', (57, 61))	('substitutions', 'Var', (65, 78))	('lysine', 'Chemical', 'MESH:D008239', (121, 127))	('LDHA', 'Gene', (0, 4))	('LDHA', 'Gene', '3939', (0, 4))	('affect', 'Reg', (94, 100))	('lysine modifications', 'MPA', (121, 141))	('K5', 'Gene', '3852', (5, 7))	('acetylated', 'MPA', (20, 30))	('LDHA', 'Gene', (57, 61))	('K5', 'Gene', '3852', (62, 64))
107854	31371982	Lys-trimethylation in LDHA plays an important role in the metabolism and proliferation of cells and may be useful as a potential target for therapy or a prognostic and treatment biomarker of several diseases.	('metabolism', 'CPA', (58, 68))	('LDHA', 'Gene', '3939', (22, 26))	('plays', 'Reg', (27, 32))	('Lys-trimethylation', 'Var', (0, 18))	('role', 'Reg', (46, 50))	('metabolism', 'biological_process', 'GO:0008152', ('58', '68'))	('men', 'Species', '9606', (173, 176))	('LDHA', 'Gene', (22, 26))	('Lys', 'Chemical', 'MESH:D008239', (0, 3))
107856	32815150	Due to inactivation of the von Hippel-Lindau tumour suppressor, the hypoxia-inducible transcription factors (HIFs) are constitutively activated in these tumours, resulting in a pseudo-hypoxic phenotype.	('tumours', 'Disease', 'MESH:D009369', (153, 160))	('tumours', 'Disease', (153, 160))	('von Hippel-Lindau tumour', 'Disease', (27, 51))	('hypoxic', 'Disease', 'MESH:D000860', (184, 191))	('HIFs', 'Disease', 'None', (109, 113))	('transcription', 'biological_process', 'GO:0006351', ('86', '99'))	('hypoxia', 'Disease', (68, 75))	('inactivation', 'Var', (7, 19))	('hypoxia', 'Disease', 'MESH:D000860', (68, 75))	('activated', 'PosReg', (134, 143))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('HIFs', 'Disease', (109, 113))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (27, 51))	('tumours', 'Phenotype', 'HP:0002664', (153, 160))	('hypoxic', 'Disease', (184, 191))
107862	32815150	We found that the eosinophilic phenotype displayed a higher proliferative drive and lower differentiation, and we confirmed a correlation to tumours of higher stage.	('tumours', 'Disease', (141, 148))	('differentiation', 'CPA', (90, 105))	('proliferative drive', 'CPA', (60, 79))	('higher', 'PosReg', (53, 59))	('eosinophilic', 'Var', (18, 30))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('tumours', 'Phenotype', 'HP:0002664', (141, 148))	('lower', 'NegReg', (84, 89))	('tumours', 'Disease', 'MESH:D009369', (141, 148))	('eosin', 'Chemical', 'MESH:D004801', (18, 23))
107863	32815150	We further identified mutations of the tumour suppressor p53 (TP53) exclusively in the eosinophilic ccRCC component, where mTORC1 activity was also elevated.	('elevated', 'PosReg', (148, 156))	('TP53', 'Gene', '7157', (62, 66))	('eosinophilic ccRCC component', 'Disease', (87, 115))	('mTORC1', 'Gene', '382056', (123, 129))	('eosinophilic ccRCC component', 'Disease', 'MESH:C565165', (87, 115))	('tumour suppressor p53', 'Gene', (39, 60))	('TP53', 'Gene', (62, 66))	('mTORC1', 'cellular_component', 'GO:0031931', ('123', '129'))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('mTORC1', 'Gene', (123, 129))	('mutations', 'Var', (22, 31))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour suppressor p53', 'Gene', '7157', (39, 60))
107872	32815150	In ccRCC, loss of VHL results in constitutive HIF activation, rendering ccRCC cells a pseudo-hypoxic phenotype, resulting in the distinctive appearance.	('loss', 'Var', (10, 14))	('VHL', 'Gene', '7428', (18, 21))	('hypoxic', 'Disease', (93, 100))	('activation', 'PosReg', (50, 60))	('hypoxic', 'Disease', 'MESH:D000860', (93, 100))	('HIF', 'MPA', (46, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('VHL', 'Gene', (18, 21))
107915	32815150	Quantification of Ki67 positivity in the validation cohort further verified this observation (Figure 3C).	('Ki67', 'Chemical', '-', (18, 22))	('Ki67', 'Gene', (18, 22))	('positivity', 'Var', (23, 33))
107937	32815150	Immunohistochemical staining of biphasic ccRCC showed no difference in phosphorylation of mTOR at S2481 (data not shown), associated with active mTORC2.	('phosphorylation', 'MPA', (71, 86))	('mTORC2', 'Gene', '74343', (145, 151))	('mTORC2', 'cellular_component', 'GO:0031932', ('145', '151'))	('mTOR', 'Gene', (90, 94))	('mTOR', 'Gene', '2475', (90, 94))	('mTOR', 'Gene', (145, 149))	('at S2481', 'Var', (95, 103))	('mTOR', 'Gene', '2475', (145, 149))	('phosphorylation', 'biological_process', 'GO:0016310', ('71', '86'))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('mTORC2', 'Gene', (145, 151))
107943	32815150	The TCGA report from 2018 [1] reported TP53 mutations in 2.6% of ccRCCs.	('ccRCCs', 'Disease', (65, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))
107944	32815150	By performing mutation calling analysis on the RNA-sequencing data, we identified missense mutations in TP53 in three of four eosinophilic samples.	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('missense mutations', 'Var', (82, 100))	('RNA', 'cellular_component', 'GO:0005562', ('47', '50'))	('eosin', 'Chemical', 'MESH:D004801', (126, 131))
107945	32815150	The mutations were all within the DNA binding domain of TP53 and are reported to result in loss of function (Figure 5E) (https://cancer.sanger.ac.uk/cosmic).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('function', 'MPA', (99, 107))	('TP53', 'Gene', '7157', (56, 60))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('TP53', 'Gene', (56, 60))	('loss', 'NegReg', (91, 95))	('mutations', 'Var', (4, 13))	('DNA binding', 'molecular_function', 'GO:0003677', ('34', '45'))
107946	32815150	Variations in TP53 were not found in any other sample, either in the corresponding clear cell tissue from biphasic tumours or in the other ccRCCs or normal kidney samples.	('ccRCC', 'Phenotype', 'HP:0006770', (139, 144))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('Variations', 'Var', (0, 10))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('biphasic tumours', 'Disease', 'MESH:D009369', (106, 122))	('biphasic tumours', 'Disease', (106, 122))
107947	32815150	Nuclear p53 positivity is considered a sign of mutated protein, as mutations tend to stabilize the protein, resulting in nuclear accumulation [27].	('nuclear accumulation', 'MPA', (121, 141))	('p53', 'Gene', (8, 11))	('p53', 'Gene', '7157', (8, 11))	('mutations', 'Var', (67, 76))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('stabilize', 'MPA', (85, 94))
107948	32815150	Nuclear p53 was confirmed in the eosinophilic samples carrying missense mutations (supplementary material, Figure S4).	('missense mutations', 'Var', (63, 81))	('p53', 'Gene', '7157', (8, 11))	('p53', 'Gene', (8, 11))	('eosin', 'Chemical', 'MESH:D004801', (33, 38))
107952	32815150	These results suggest that mutated TP53 is associated with the eosinophilic phenotype.	('eosin', 'Chemical', 'MESH:D004801', (63, 68))	('mutated', 'Var', (27, 34))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('eosinophilic phenotype', 'Disease', (63, 85))	('associated', 'Reg', (43, 53))
107974	32815150	In addition, PPARG expression was strongly reduced in ccRCC_Beo samples (Figure 6C), and the GO term 'PPAR signalling pathway' was significantly downregulated (Figure 2D), suggesting that lipid content is reduced in eosinophilic tissue through transcriptional regulation of lipogenesis.	('downregulated', 'NegReg', (145, 158))	('expression', 'MPA', (19, 29))	('signalling pathway', 'biological_process', 'GO:0007165', ('107', '125'))	('PPAR', 'Gene', '5465', (13, 17))	('PPAR', 'Gene', '5465', (102, 106))	('lipid', 'Chemical', 'MESH:D008055', (188, 193))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('reduced', 'NegReg', (205, 212))	('reduced', 'NegReg', (43, 50))	('PPARG', 'Gene', '5468', (13, 18))	('eosin', 'Chemical', 'MESH:D004801', (216, 221))	('PPAR', 'Gene', (13, 17))	('PPAR', 'Gene', (102, 106))	('lipid content', 'MPA', (188, 201))	('PPARG', 'Gene', (13, 18))	('ccRCC_Beo', 'Var', (54, 63))	('regulation of lipogenesis', 'biological_process', 'GO:0046890', ('260', '285'))
108001	32815150	This is interesting in light of a recent publication where elevated phosphorylation of mTOR at S2448 was found in metastatic RCC [21].	('mTOR', 'Gene', '2475', (87, 91))	('at S2448', 'Var', (92, 100))	('phosphorylation', 'MPA', (68, 83))	('phosphorylation', 'biological_process', 'GO:0016310', ('68', '83'))	('elevated', 'PosReg', (59, 67))	('metastatic RCC [21]', 'Disease', (114, 133))	('mTOR', 'Gene', (87, 91))
108006	32815150	TP53 mutations are considered rare in ccRCC but are more frequently found in other subtypes of RCC, including papillary and chromophobe.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('chromophobe', 'Disease', (124, 135))	('papillary', 'Disease', (110, 119))	('mutations', 'Var', (5, 14))	('found', 'Reg', (68, 73))	('ccRCC', 'Disease', (38, 43))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))
108008	32815150	Gerlinger et al detected TP53 mutations in 6% of ccRCC cases when analysing single biopsies, while multiregional sequencing showed mutations in 40% [49].	('TP53', 'Gene', (25, 29))	('mutations', 'Var', (30, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('ccRCC', 'Disease', (49, 54))	('TP53', 'Gene', '7157', (25, 29))
108009	32815150	This indicates the presence of focal areas with mutated TP53, easily missed when analysing single biopsies.	('TP53', 'Gene', '7157', (56, 60))	('TP53', 'Gene', (56, 60))	('mutated', 'Var', (48, 55))
108010	32815150	We found TP53 mutations in three of four eosinophilic samples, and nuclear p53 staining in eight of ten analysed eosinophilic cores.	('eosin', 'Chemical', 'MESH:D004801', (41, 46))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('eosin', 'Chemical', 'MESH:D004801', (113, 118))	('mutations', 'Var', (14, 23))
108011	32815150	Together, these results suggest that mutated TP53 is associated with the eosinophilic phenotype and that it is focally more prevalent in ccRCC than previously appreciated, probably underestimated due to intratumor heterogeneity.	('prevalent', 'Reg', (124, 133))	('TP53', 'Gene', (45, 49))	('eosinophilic phenotype', 'MPA', (73, 95))	('eosin', 'Chemical', 'MESH:D004801', (73, 78))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('ccRCC', 'Disease', (137, 142))	('associated', 'Reg', (53, 63))	('mutated', 'Var', (37, 44))	('TP53', 'Gene', '7157', (45, 49))
108013	32815150	Indeed, EM imaging showed that lipid content was reduced in eosinophilic compared with clear cell tissue.	('reduced', 'NegReg', (49, 56))	('lipid content', 'MPA', (31, 44))	('lipid', 'Chemical', 'MESH:D008055', (31, 36))	('eosinophilic', 'Var', (60, 72))	('eosin', 'Chemical', 'MESH:D004801', (60, 65))
108022	32815150	It might also be a sign of increased formation of neoantigens, since eosinophilic tissue areas associate with TP53 mutations.	('eosin', 'Chemical', 'MESH:D004801', (69, 74))	('mutations', 'Var', (115, 124))	('TP53', 'Gene', '7157', (110, 114))	('TP53', 'Gene', (110, 114))	('formation', 'biological_process', 'GO:0009058', ('37', '46'))
108030	32472114	Our analysis revealed that infiltrated tumors are depleted of favorable PBRM1 mutations and enriched for unfavorable chromosomal losses of 9p21.3 when compared to non-infiltrated tumors, demonstrating how the potential interplay of immunophenotypes with somatic alterations impacts therapeutic efficacy.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumors', 'Disease', (179, 185))	('chromosomal loss', 'Disease', 'MESH:D025063', (117, 133))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('impacts', 'Reg', (274, 281))	('mutations', 'Var', (78, 87))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('PBRM1', 'Gene', (72, 77))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('chromosomal loss', 'Disease', (117, 133))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('PBRM1', 'Gene', '55193', (72, 77))	('tumors', 'Disease', (39, 45))	('therapeutic efficacy', 'CPA', (282, 302))
108040	32472114	This analysis uncovered the landscape of somatic alterations in advanced ccRCC, and defined novel copy number changes associated with both the patterns of immune infiltration in ccRCC and the clinical outcome to PD-1 blockade.	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('RCC', 'Disease', (180, 183))	('ccRCC', 'Phenotype', 'HP:0006770', (178, 183))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('copy number changes', 'Var', (98, 117))	('associated', 'Reg', (118, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))
108046	32472114	1), WES data were available from 454 patients (261 patients treated with anti-PD1, 193 patients treated with mTOR inhibition; Supplementary Table 2).	('patients', 'Species', '9606', (37, 45))	('mTOR', 'Gene', '2475', (109, 113))	('anti-PD1', 'Gene', (73, 81))	('mTOR', 'Gene', (109, 113))	('patients', 'Species', '9606', (51, 59))	('anti-PD1', 'Var', (73, 81))	('patients', 'Species', '9606', (87, 95))
108050	32472114	We also identified frequent somatic single nucleotide variants (sSNVs) in the PI(3)K-AKT-mTOR pathway, including MTOR (9%), PTEN (6%), TSC1 (3%) and PIK3CA (3%) mutations.	('mTOR', 'Gene', '2475', (89, 93))	('PTEN', 'Gene', (124, 128))	('TSC1', 'Gene', (135, 139))	('PTEN', 'Gene', '5728', (124, 128))	('MTOR', 'Gene', (113, 117))	('AKT', 'Gene', '207', (85, 88))	('PIK3CA', 'Gene', (149, 155))	('mutations', 'Var', (161, 170))	('single nucleotide variants', 'Var', (36, 62))	('MTOR', 'Gene', '2475', (113, 117))	('AKT', 'Gene', (85, 88))	('PI(3)K', 'molecular_function', 'GO:0016303', ('78', '84'))	('PIK3CA', 'Gene', '5290', (149, 155))	('mTOR', 'Gene', (89, 93))	('TSC1', 'Gene', '7248', (135, 139))
108053	32472114	To determine whether advanced ccRCC (stage IV) is enriched for particular somatic alterations compared to earlier (stage I-III) disease, we compared the data generated from the CheckMate cohorts (where all patients had advanced disease at the time of trial enrollment) with TCGA ccRCC data (n=366 with mutation data; n=501 with copy number data), of which fewer than 20% of patients had stage IV disease (Fig.	('stage IV disease', 'Disease', (387, 403))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('stage IV disease', 'Disease', 'MESH:D058625', (387, 403))	('patients', 'Species', '9606', (206, 214))	('RCC', 'Disease', 'MESH:C538614', (281, 284))	('patients', 'Species', '9606', (374, 382))	('RCC', 'Disease', (281, 284))	('ccRCC', 'Phenotype', 'HP:0006770', (279, 284))	('mutation', 'Var', (302, 310))
108055	32472114	Earlier stage disease had recurrent mutations in members of the mammalian SWI/SNF chromatin remodeling complexes (ARID1A and SMARCA4) and in the DNA damage repair pathway (ATM).	('DNA', 'cellular_component', 'GO:0005574', ('145', '148'))	('mammalian', 'Species', '9606', (64, 73))	('DNA damage repair pathway', 'Pathway', (145, 170))	('mutations', 'Var', (36, 45))	('chromatin', 'cellular_component', 'GO:0000785', ('82', '91'))	('SMARCA4', 'Gene', '6597', (125, 132))	('Earlier stage disease', 'Disease', (0, 21))	('SMARCA4', 'Gene', (125, 132))	('ATM', 'Gene', (172, 175))	('ARID1A', 'Gene', (114, 120))	('SWI/SNF', 'Gene', (74, 81))	('ARID1A', 'Gene', '8289', (114, 120))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('82', '102'))	('ATM', 'Gene', '472', (172, 175))
108056	32472114	In contrast, in advanced disease we identified recurrent mutations in the PI(3)K-AKT-mTOR pathway member TSC1, and in NF2, a tumor suppressor that encodes a member of the Hippo signaling pathway.	('TSC1', 'Gene', '7248', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('TSC1', 'Gene', (105, 109))	('AKT', 'Gene', '207', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('171', '194'))	('NF2', 'Gene', (118, 121))	('tumor suppressor', 'biological_process', 'GO:0051726', ('125', '141'))	('tumor', 'Disease', (125, 130))	('PI(3)K', 'molecular_function', 'GO:0016303', ('74', '80'))	('mutations', 'Var', (57, 66))	('AKT', 'Gene', (81, 84))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('125', '141'))	('mTOR', 'Gene', '2475', (85, 89))	('mTOR', 'Gene', (85, 89))	('NF2', 'Gene', '4771', (118, 121))
108057	32472114	NF2 mutations have previously been described in other aggressive kidney cancer histologies, including unclassified RCC, collecting duct cacinoma, sarcomatoid histology, and type 2 papillary RCC.	('cacinoma', 'Disease', 'None', (136, 144))	('NF2', 'Gene', (0, 3))	('kidney cancer', 'Phenotype', 'HP:0009726', (65, 78))	('sarcomatoid', 'Disease', (146, 157))	('described', 'Reg', (35, 44))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (190, 193))	('RCC', 'Disease', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('NF2', 'Gene', '4771', (0, 3))	('sarcomatoid histology', 'Phenotype', 'HP:0100242', (146, 167))	('aggressive kidney cancer', 'Disease', (54, 78))	('cacinoma', 'Disease', (136, 144))	('sarcomatoid', 'Disease', 'MESH:C538614', (146, 157))	('mutations', 'Var', (4, 13))	('aggressive kidney cancer', 'Disease', 'MESH:D007680', (54, 78))
108058	32472114	Here, we found NF2 mutations to associate with a worse overall survival (OS) in all stages of ccRCC, though this appeared to be abrogated by PD-1 blockade (Fig.	('RCC', 'Disease', (96, 99))	('overall survival', 'MPA', (55, 71))	('worse', 'NegReg', (49, 54))	('mutations', 'Var', (19, 28))	('NF2', 'Gene', (15, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('NF2', 'Gene', '4771', (15, 18))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
108061	32472114	We also identified loss of 9q34.3 as a frequent event in advanced RCC.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('RCC', 'Disease', (66, 69))	('loss', 'Var', (19, 23))
108067	32472114	Although ccRCC has a modest total mutation burden, it has a relatively high proportion of frameshift insertions and deletions (indels), which can potentially generate novel open reading frames (neoORFs) and consequently, may provide a rich source of neoantigens.	('neoORFs', 'Disease', (194, 201))	('frameshift insertions', 'Var', (90, 111))	('neoORFs', 'Disease', 'None', (194, 201))	('deletions', 'Var', (116, 125))	('ccRCC', 'Phenotype', 'HP:0006770', (9, 14))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('generate', 'Reg', (158, 166))	('open reading frames', 'MPA', (173, 192))	('RCC', 'Disease', (11, 14))
108077	32472114	We systematically evaluated whether any individual mutations or copy number alterations were associated with response or resistance to PD-1 blockade by determining if any (i) were significantly recurrent (using MutSig2CV for mutations, and GISTIC2 for copy number alterations), and further, (ii) had a significant effect on survival (PFS and OS) with PD-1 blockade but not with mTOR inhibition.	('mTOR', 'Gene', (378, 382))	('mutations', 'Var', (51, 60))	('FS', 'Disease', 'MESH:D018223', (335, 337))	('effect', 'Reg', (314, 320))	('associated', 'Reg', (93, 103))	('PD-1', 'Gene', (351, 355))	('survival', 'CPA', (324, 332))	('mTOR', 'Gene', '2475', (378, 382))
108078	32472114	Within the CM-009 cohort, truncating mutations in PBRM1 were previously associated with improved survival following PD-1 blockade in previously treated (anti-angiogenic-refractory) patients, which was then validated using the CM-025 cohort.	('truncating mutations', 'Var', (26, 46))	('PBRM1', 'Gene', (50, 55))	('survival', 'MPA', (97, 105))	('PBRM1', 'Gene', '55193', (50, 55))	('patients', 'Species', '9606', (181, 189))	('improved', 'PosReg', (88, 96))	('CM-025', 'Chemical', '-', (226, 232))
108079	32472114	Our pooled analysis of all three cohorts (consisting mostly of previously treated, anti-angiogenic-refractory patients) again demonstrated the association of truncating mutations in PBRM1 with improved response and survival (p < 0.001 for OS).	('truncating mutations', 'Var', (158, 178))	('PBRM1', 'Gene', (182, 187))	('improved', 'PosReg', (193, 201))	('PBRM1', 'Gene', '55193', (182, 187))	('response', 'MPA', (202, 210))	('patients', 'Species', '9606', (110, 118))	('survival', 'CPA', (215, 223))
108080	32472114	We found that PBRM1 alterations were associated with higher angiogenesis gene expression (p < 0.001, Wilcoxon rank-sum test for angiogenesis signature), but lower IL6-JAK-STAT3 signaling (p = 0.01 for ssGSEA scores).	('alterations', 'Var', (20, 31))	('GSEA', 'Chemical', '-', (203, 207))	('signaling', 'biological_process', 'GO:0023052', ('177', '186'))	('higher', 'PosReg', (53, 59))	('IL6', 'molecular_function', 'GO:0005138', ('163', '166'))	('angiogenesis', 'MPA', (60, 72))	('PBRM1', 'Gene', (14, 19))	('STAT3', 'Gene', '6774', (171, 176))	('IL6', 'Gene', '3569', (163, 166))	('angiogenesis', 'biological_process', 'GO:0001525', ('60', '72'))	('angiogenesis', 'biological_process', 'GO:0001525', ('128', '140'))	('STAT3', 'Gene', (171, 176))	('PBRM1', 'Gene', '55193', (14, 19))	('gene expression', 'biological_process', 'GO:0010467', ('73', '88'))	('IL6', 'Gene', (163, 166))	('JAK', 'molecular_function', 'GO:0004713', ('167', '170'))	('lower', 'NegReg', (157, 162))
108082	32472114	Among the significantly recurrent somatic copy number alterations (sCNAs), only focal loss of 10q23.31 (in 35% of tumors) was associated with improved PFS and OS following PD-1 blockade, but not mTOR inhibition (Fig.	('10q23.31', 'Gene', (94, 102))	('loss', 'Var', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('improved', 'PosReg', (142, 150))	('FS', 'Disease', 'MESH:D018223', (152, 154))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('mTOR', 'Gene', '2475', (195, 199))	('mTOR', 'Gene', (195, 199))
108085	32472114	By gene set enrichment analysis (GSEA) using the 50 Hallmark genes sets from the Molecular Signatures Database, ccRCC tumors with del(10q23.31) did not reveal an increase in mTOR pathway activity, arguing against a functional role for PTEN loss in these patients.	('ccRCC tumors', 'Disease', 'MESH:D009369', (112, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('del(10q23.31', 'Var', (130, 142))	('ccRCC tumors', 'Disease', (112, 124))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('activity', 'MPA', (187, 195))	('GSEA', 'Chemical', '-', (33, 37))	('PTEN', 'Gene', (235, 239))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('PTEN', 'Gene', '5728', (235, 239))	('mTOR', 'Gene', (174, 178))	('patients', 'Species', '9606', (254, 262))	('mTOR', 'Gene', '2475', (174, 178))
108104	32472114	Of the recurrent sSNVs and sIndels, only truncating mutations in PBRM1 were enriched in non-infiltrated tumors, and no mutations were enriched in infiltrated tumors (Extended Data Fig.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('PBRM1', 'Gene', (65, 70))	('PBRM1', 'Gene', '55193', (65, 70))	('tumors', 'Disease', (104, 110))	('truncating mutations', 'Var', (41, 61))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('non-infiltrated', 'Disease', (88, 103))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
108105	32472114	Consistent with this finding, tumors with PBRM1 mutations had a lower total CD8+ T cell infiltration by IF (p = 0.013, Wilcoxon rank-sum test).	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('lower', 'NegReg', (64, 69))	('PBRM1', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('PBRM1', 'Gene', '55193', (42, 47))	('CD8', 'Gene', (76, 79))	('CD8', 'Gene', '925', (76, 79))	('mutations', 'Var', (48, 57))
108106	32472114	PBRM1 mutations, which we found to be associated with improved response, PFS, and OS with PD-1 blockade (Fig.	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('improved', 'PosReg', (54, 62))	('response', 'MPA', (63, 71))	('FS', 'Disease', 'MESH:D018223', (74, 76))	('mutations', 'Var', (6, 15))
108109	32472114	As for sCNAs, none were enriched in non-infiltrated tumors, but multiple focal chromosomal losses or gains were detected more frequently in infiltrated tumors (e.g amplifications of 12q24.32, 20q13.33, and 8q24.3; and deletions of 9p21.3, 9q34.3, 6p22.2, and 6p21.32; all q < 0.05, Fig.	('deletions', 'Var', (218, 227))	('chromosomal loss', 'Disease', 'MESH:D025063', (79, 95))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('8q24.3', 'Var', (206, 212))	('gains', 'PosReg', (101, 106))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('amplifications', 'Var', (164, 178))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('tumors', 'Disease', (52, 58))	('20q13.33', 'Var', (192, 200))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('focal chromosomal losses', 'Phenotype', 'HP:0040012', (73, 97))	('chromosomal loss', 'Disease', (79, 95))	('12q24.32', 'Var', (182, 190))	('tumors', 'Disease', (152, 158))	('infiltrated', 'Disease', (140, 151))
108113	32472114	Among chromosomal losses, only del(9p21.3) was enriched in infiltrated tumors, and also associated with worse PFS and OS in infiltrated tumors with PD-1 blockade, but not with mTOR inhibition (Fig.	('tumors', 'Disease', (136, 142))	('infiltrated', 'Disease', (59, 70))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('mTOR', 'Gene', '2475', (176, 180))	('del(9p21.3', 'Var', (31, 41))	('mTOR', 'Gene', (176, 180))	('FS', 'Disease', 'MESH:D018223', (111, 113))	('tumors', 'Disease', (71, 77))	('chromosomal loss', 'Disease', (6, 22))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('PD-1', 'Gene', (148, 152))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('associated', 'Reg', (88, 98))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('chromosomal loss', 'Disease', 'MESH:D025063', (6, 22))
108114	32472114	Tumors with del(9p21.3) had a higher total CD8+ T cell infiltration as compared to wildtype (p = 0.002, Wilcoxon rank-sum test).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CD8', 'Gene', (43, 46))	('CD8', 'Gene', '925', (43, 46))	('higher', 'PosReg', (30, 36))	('del(9p21.3', 'Var', (12, 22))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
108121	32472114	Through a comprehensive immunogenomic characterization of advanced ccRCC treated with PD-1 blockade, we identified numerous copy number alterations in advanced ccRCC, including deletions of 9q34.3, and loss of the regions of 6p containing components of antigen presenting machinery and HLA class II molecules.	('HLA', 'Gene', (286, 289))	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('9q34.3', 'Gene', (190, 196))	('deletions', 'Var', (177, 186))	('RCC', 'Disease', (162, 165))	('ccRCC', 'Phenotype', 'HP:0006770', (160, 165))	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('HLA', 'Gene', '3117', (286, 289))	('loss', 'NegReg', (202, 206))
108127	32472114	We identified that CD8+ T cell infiltrated tumors are relatively depleted for PBRM1 mutations (which are associated with response), and are enriched for chromosomal losses of 9p21.3 (which is associated with resistance to PD-1 blockade in infiltrated tumors).	('CD8', 'Gene', (19, 22))	('chromosomal loss', 'Disease', (153, 169))	('CD8', 'Gene', '925', (19, 22))	('PBRM1', 'Gene', '55193', (78, 83))	('tumors', 'Disease', (251, 257))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('depleted', 'NegReg', (65, 73))	('mutations', 'Var', (84, 93))	('chromosomal loss', 'Disease', 'MESH:D025063', (153, 169))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('PBRM1', 'Gene', (78, 83))
108128	32472114	Overall then, although infiltrated tumors are immunogenically "hot" (and therefore, should conceptually be primed to respond better to PD-1 blockade), they are relatively depleted of PBRM1 mutations (which are correlated with improved survival with anti-PD-1 therapy), and are enriched for 9p21.3 deletions (which are associated with worse outcomes with PD-1 blockade) (Fig.	('deletions', 'Var', (297, 306))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumors', 'Disease', (35, 41))	('mutations', 'Var', (189, 198))	('PBRM1', 'Gene', (183, 188))	('PBRM1', 'Gene', '55193', (183, 188))
108130	32472114	Given the limited number of samples for which immunofluorescence and WES data were available, this potential interplay between CD8+ T cell infiltration and del(9p21.3) will need to be confirmed in future studies of anti-PD-1 monotherapy in ccRCC.	('CD8', 'Gene', (127, 130))	('RCC', 'Disease', 'MESH:C538614', (242, 245))	('RCC', 'Disease', (242, 245))	('ccRCC', 'Phenotype', 'HP:0006770', (240, 245))	('CD8', 'Gene', '925', (127, 130))	('del', 'Var', (156, 159))
108133	32472114	With respect to the therapeutic setting, these clinical studies were performed in the previously treated, anti-angiogenic refractory setting, and prior studies of front-line anti-PD-L1:based-therapy did not demonstrate a benefit from PBRM1 mutations in the first-line setting.	('mutations', 'Var', (240, 249))	('PBRM1', 'Gene', (234, 239))	('PD-L1', 'Gene', (179, 184))	('PBRM1', 'Gene', '55193', (234, 239))	('PD-L1', 'Gene', '29126', (179, 184))
108134	32472114	Further, the exact mechanism by which PBRM1 alterations could alter response to PD-1 blockade remains largely undefined.	('response to PD-1 blockade', 'MPA', (68, 93))	('PBRM1', 'Gene', (38, 43))	('alterations', 'Var', (44, 55))	('PBRM1', 'Gene', '55193', (38, 43))	('alter', 'Reg', (62, 67))
108135	32472114	In agreement with prior studies, PBRM1 alterations were associated with higher angiogenesis gene expression; however, in contrast to past reports, we found PBRM1 alterations were associated with lower IL6-JAK-STAT3 signaling, potentially attributable to differences in cohorts (including differences in immune infiltration), or to limitations in transcriptomic analysis from FFPE tissue.	('PBRM1', 'Gene', '55193', (33, 38))	('JAK', 'molecular_function', 'GO:0004713', ('205', '208'))	('angiogenesis gene', 'Gene', (79, 96))	('alterations', 'Var', (162, 173))	('lower', 'NegReg', (195, 200))	('PBRM1', 'Gene', '55193', (156, 161))	('IL6', 'molecular_function', 'GO:0005138', ('201', '204'))	('signaling', 'biological_process', 'GO:0023052', ('215', '224'))	('gene expression', 'biological_process', 'GO:0010467', ('92', '107'))	('angiogenesis', 'biological_process', 'GO:0001525', ('79', '91'))	('STAT3', 'Gene', '6774', (209, 214))	('IL6', 'Gene', '3569', (201, 204))	('alterations', 'Var', (39, 50))	('IL6', 'Gene', (201, 204))	('STAT3', 'Gene', (209, 214))	('PBRM1', 'Gene', (33, 38))	('PBRM1', 'Gene', (156, 161))
108143	32472114	Patient data from three prospective clinical trials of the anti-PD-1 antibody nivolumab in advanced clear cell renal cell carcinoma (ccRCC) were used in this study - CheckMate 009 (CM-009; NCT01358721), CheckMate 010 (CM-010; NCT01354431) and CheckMate 025 (CM-025; NCT01668784).	('CM-025', 'Chemical', '-', (258, 264))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (100, 131))	('antibody', 'molecular_function', 'GO:0003823', ('69', '77'))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('antibody', 'cellular_component', 'GO:0042571', ('69', '77'))	('nivolumab', 'Chemical', 'MESH:D000077594', (78, 87))	('CM-010', 'Chemical', '-', (218, 224))	('CM-010; NCT01354431', 'Var', (218, 237))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (100, 131))	('antibody', 'cellular_component', 'GO:0019815', ('69', '77'))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('CM-009; NCT01358721', 'Var', (181, 200))	('clear cell renal cell carcinoma', 'Disease', (100, 131))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (111, 131))	('antibody', 'cellular_component', 'GO:0019814', ('69', '77'))	('CM-025', 'Var', (258, 264))	('RCC', 'Disease', (135, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('Patient', 'Species', '9606', (0, 7))
108169	32472114	Similarly, the FrameShift indels metric (FS) was calculated as the sum of all frameshift mutations (frameshift insertions and frameshift deletions) per sample.	('FS', 'Disease', 'MESH:D018223', (41, 43))	('frameshift insertions', 'Var', (100, 121))	('frameshift deletions', 'Var', (126, 146))
108171	32472114	Polysolver was used to computationally infer alleles and mutations in class I HLA genes (HLA-A/B/C).	('HLA', 'Gene', '3117', (78, 81))	('HLA', 'Gene', '3117', (89, 92))	('HLA-A/B/C', 'Gene', (89, 98))	('HLA', 'Gene', (78, 81))	('HLA', 'Gene', (89, 92))	('HLA-A/B/C', 'Gene', '3105;3106;3107', (89, 98))	('mutations', 'Var', (57, 66))
108174	32472114	Samples were excluded if they had an interquartile range of log2(TPM+1) < 0.5 (indicating low dynamic range), had less than 15,000 genes detected (indicating low library complexity), had an End 2 Sense Rate<0.90, or End 1 Sense Rate>0.10 (as defined by RNA-seqQC2, indicating strand bias).	('End 1', 'Gene', (216, 221))	('log2', 'Var', (60, 64))	('End 1', 'Gene', '55823', (216, 221))	('End 2 Sense', 'MPA', (190, 201))	('RNA', 'cellular_component', 'GO:0005562', ('253', '256'))
108201	32472114	Specifically, anti-CD8 antibody (C8/144B, mouse monoclonal antibody, Agilent - 1:10000 in CM-010 and 1:5000 in CM-025) was detected using the Opal 520 fluorophore (1:50 in CM-010 and 1:150 in CM-025, FITC); slides were then counterstained with Spectral DAPI (PerkinElmer) and manually coverslipped.	('CD8', 'Gene', (19, 22))	('antibody', 'cellular_component', 'GO:0042571', ('23', '31'))	('CM-025', 'Chemical', '-', (111, 117))	('C8/144B', 'Var', (33, 40))	('CD8', 'Gene', '925', (19, 22))	('FITC', 'Chemical', 'MESH:D016650', (200, 204))	('antibody', 'cellular_component', 'GO:0019815', ('59', '67'))	('antibody', 'cellular_component', 'GO:0019814', ('59', '67'))	('antibody', 'molecular_function', 'GO:0003823', ('59', '67'))	('antibody', 'cellular_component', 'GO:0019815', ('23', '31'))	('CM-010', 'Chemical', '-', (172, 178))	('antibody', 'cellular_component', 'GO:0019814', ('23', '31'))	('antibody', 'molecular_function', 'GO:0003823', ('23', '31'))	('antibody', 'cellular_component', 'GO:0042571', ('59', '67'))	('DAPI', 'Chemical', 'MESH:C007293', (253, 257))	('CM-010', 'Chemical', '-', (90, 96))	('CM-025', 'Chemical', '-', (192, 198))
108223	32472114	Kaplan-Meier analysis and univariable Cox regression analysis (coxph function) were done using the R packages survival and survminer to evaluate the association between progression-free and overall survival times and genomic alterations (amplification, deletion, truncating mutation, HLA heterozygosity or infiltration).	('truncating', 'MPA', (263, 273))	('amplification', 'Var', (238, 251))	('HLA', 'Gene', (284, 287))	('deletion', 'Var', (253, 261))	('HLA', 'Gene', '3117', (284, 287))	('infiltration', 'Var', (306, 318))
108225	32472114	Additional multivariable analysis including MSKCC risk group, lines of therapy (<=1 or >=2), or timing of sample collection (days before beginning trial therapy) as covariates confirmed the significant association of truncating mutations in PBRM1, del(10q23.31), and del(9p21.3) within infiltrated tumors as significantly associated with altered PFS and OS.	('tumors', 'Phenotype', 'HP:0002664', (298, 304))	('FS', 'Disease', 'MESH:D018223', (347, 349))	('tumors', 'Disease', (298, 304))	('tumors', 'Disease', 'MESH:D009369', (298, 304))	('PBRM1', 'Gene', '55193', (241, 246))	('del(10q23.31', 'Var', (248, 260))	('PBRM1', 'Gene', (241, 246))	('truncating mutations', 'Var', (217, 237))	('del(9p21.3', 'Var', (267, 277))	('associated', 'Reg', (322, 332))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))
108228	32472114	WES data from patients who consented to deposition have been submitted to the European Genome-phenome Archive (Accession numbers EGAS00001004290, EGAS00001004291, EGAS00001004290).	('EGAS00001004291', 'Var', (146, 161))	('patients', 'Species', '9606', (14, 22))	('EGAS00001004290', 'Var', (163, 178))
108233	31862408	Furthermore, HOTAIRM1 transcripts are downregulated by hypoxia-mimetic stress and knockdown of the cytoplasmic HM1-3 isoform in normoxic cells post-transcriptionally induces Hypoxia-Inducible Factor 1alpha (HIF1alpha) protein, a key activator of ANGPTL4.	('ANGPTL4', 'Gene', '51129', (246, 253))	('HIF1alpha', 'Gene', '3091', (207, 216))	('hypoxia-mimetic stress', 'Disease', (55, 77))	('Hypoxia-Inducible Factor 1alpha', 'Gene', (174, 205))	('knockdown', 'Var', (82, 91))	('downregulated', 'NegReg', (38, 51))	('induces', 'PosReg', (166, 173))	('protein', 'cellular_component', 'GO:0003675', ('218', '225'))	('HOTAIRM1 transcripts', 'Gene', (13, 33))	('Hypoxia-Inducible Factor 1alpha', 'Gene', '3091', (174, 205))	('ANGPTL4', 'Gene', (246, 253))	('hypoxia-mimetic stress', 'Disease', 'MESH:D000860', (55, 77))	('HIF1alpha', 'Gene', (207, 216))
108234	31862408	Our results demonstrate the pervasive downregulation of the specific HOTAIRM1 cytoplasmic isoform HM1-3 in ccRCC and suggest possible roles of HOTAIRM1 in kidney differentiation and suppression of HIF1-dependent angiogenic pathways.	('HIF1', 'Gene', (197, 201))	('kidney differentiation', 'CPA', (155, 177))	('downregulation', 'NegReg', (38, 52))	('HOTAIRM1', 'Var', (143, 151))	('RCC', 'Disease', (109, 112))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('HIF1', 'Gene', '3091', (197, 201))	('suppression', 'NegReg', (182, 193))
108250	31862408	Using a model kidney proximal tubule ccRCC cell line (CAKI-1) that is VHL-positive and expresses all HOTAIRM1 isoforms, we demonstrate that the cytoplasmic isoform HM1-3 suppresses HIF1alpha protein levels and attenuates hypoxia-responsive target genes under normoxic conditions.	('VHL', 'Gene', (70, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('suppresses', 'NegReg', (170, 180))	('VHL', 'Gene', '7428', (70, 73))	('HM1-3', 'Var', (164, 169))	('HIF1alpha', 'Gene', (181, 190))	('attenuates', 'NegReg', (210, 220))	('CAKI-1', 'CellLine', 'CVCL:0234', (54, 60))	('protein', 'cellular_component', 'GO:0003675', ('191', '198'))	('HIF1alpha', 'Gene', '3091', (181, 190))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('hypoxia-responsive', 'Disease', 'MESH:D000860', (221, 239))	('hypoxia-responsive', 'Disease', (221, 239))
108302	31862408	Evaluation of HOTAIRM1 FPKM tumor/normal ratios, using 50 matched pair samples contained within these datasets, confirmed the above qPCR results showing that HM1-3 is the only significantly downregulated HOTAIRM1 transcript, as determined by Wilcoxon signed ranked test (Figure 1E).	('P', 'Chemical', 'MESH:D010758', (133, 134))	('HM1-3', 'Var', (158, 163))	('HOTAIRM1', 'Gene', (204, 212))	('P', 'Chemical', 'MESH:D010758', (24, 25))	('transcript', 'MPA', (213, 223))	('FPKM tumor', 'Disease', (23, 33))	('FPKM tumor', 'Disease', 'MESH:D009369', (23, 33))	('downregulated', 'NegReg', (190, 203))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
108310	31862408	Several human renal proximal tubule epithelial cell lines were investigated for their HOTAIRM1 expression by RT-qPCR, including normal immortalized cells (HK-2) and two ccRCC cell lines (ACHN and CAKI-1).	('P', 'Chemical', 'MESH:D010758', (113, 114))	('HK-2', 'molecular_function', 'GO:0008256', ('155', '159'))	('RT-qPCR', 'Var', (109, 116))	('CAKI-1', 'CellLine', 'CVCL:0234', (196, 202))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('RCC', 'Disease', (171, 174))	('human', 'Species', '9606', (8, 13))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))	('HOTAIRM1', 'Gene', (86, 94))
108329	31862408	We confirmed that the upregulation of both ANGPTL4 and DDAH1 mRNAs in HOTAIRM1 knockdown CAKI-1 cells could be partially rescued by overexpression of the HM1-3 isoform (Figure 3D; Supplemental Figure 6).	('HOTAIRM1', 'Gene', (70, 78))	('ANGPTL4', 'Gene', (43, 50))	('ANGPTL4', 'Gene', '51129', (43, 50))	('CAKI-1', 'CellLine', 'CVCL:0234', (89, 95))	('DDAH1', 'Gene', '23576', (55, 60))	('DDAH1', 'Gene', (55, 60))	('upregulation', 'PosReg', (22, 34))	('knockdown', 'Var', (79, 88))
108331	31862408	Interestingly, this regulation is probably at the transcriptional level for ANGPTL4, since knockdown of HM1-3 and HM1-2-3 (with either siRNA #2 or #3) also increased the levels of the ANGPTL4 pre-mRNA (Figure 3E, see also below).	('pre', 'molecular_function', 'GO:0003904', ('192', '195'))	('regulation', 'biological_process', 'GO:0065007', ('20', '30'))	('increased', 'PosReg', (156, 165))	('knockdown', 'Var', (91, 100))	('HM1-3', 'Gene', (104, 109))	('HM1-2-3', 'Gene', '81502', (114, 121))	('HM1-2-3', 'Gene', (114, 121))	('levels of', 'MPA', (170, 179))	('ANGPTL4', 'Gene', (184, 191))	('ANGPTL4', 'Gene', '51129', (76, 83))	('ANGPTL4', 'Gene', (76, 83))	('ANGPTL4', 'Gene', '51129', (184, 191))
108337	31862408	Notably, Hotairm1 knockdown increased the expression of Angptl4 and reduced Ddah1 mRNA levels, concomitant with a modest induction of the pluripotency gene Sox2 (Supplemental Figure 7B).	('increased', 'PosReg', (28, 37))	('Hotairm1', 'Gene', (9, 17))	('knockdown', 'Var', (18, 27))	('Sox2', 'Gene', '6657', (156, 160))	('expression', 'MPA', (42, 52))	('Sox2', 'Gene', (156, 160))	('Ddah1', 'Gene', '23576', (76, 81))	('Angptl4', 'Gene', (56, 63))	('mRNA levels', 'MPA', (82, 93))	('reduced', 'NegReg', (68, 75))	('Ddah1', 'Gene', (76, 81))
108340	31862408	However, as seen above with CAKI-1 cells and ES-derived neural lineage cells, Hotairm1 knockdown also induced Angptl4 expression in these renal progenitor cells (Figure 3H).	('Hotairm1', 'Gene', (78, 86))	('induced', 'Reg', (102, 109))	('CAKI-1', 'CellLine', 'CVCL:0234', (28, 34))	('Angptl4', 'Gene', (110, 117))	('expression', 'MPA', (118, 128))	('knockdown', 'Var', (87, 96))
108351	31862408	Note also that the knockdown of HOTAIRM1 transcripts did not affect VHL protein expression (Figure 4B).	('HOTAIRM1', 'Gene', (32, 40))	('knockdown', 'Var', (19, 28))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('VHL', 'Gene', (68, 71))	('VHL', 'Gene', '7428', (68, 71))	('expression', 'MPA', (80, 90))
108353	31862408	Under these conditions knockdown of HOTAIRM1 failed to induce ANGPTL4 (Figure 4C), indicating a requirement for HIF1 signaling.	('HOTAIRM1', 'Gene', (36, 44))	('ANGPTL4', 'Gene', (62, 69))	('HIF1', 'Gene', (112, 116))	('knockdown', 'Var', (23, 32))	('ANGPTL4', 'Gene', '51129', (62, 69))	('HIF1', 'Gene', '3091', (112, 116))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))
108359	31862408	HOTAIRM1 is downregulated by hypoxia-mimetic stress and knockdown of its cytoplasmic isoforms in normoxic CAKI-1 cells leads to increased HIF1alpha protein levels and upregulation of hypoxia-responsive genes, including the angiogenic ANGPTL4 gene.	('hypoxia-mimetic stress', 'Disease', 'MESH:D000860', (29, 51))	('downregulated', 'NegReg', (12, 25))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('increased', 'PosReg', (128, 137))	('hypoxia-mimetic stress', 'Disease', (29, 51))	('ANGPTL4', 'Gene', (234, 241))	('CAKI-1', 'CellLine', 'CVCL:0234', (106, 112))	('HIF1alpha', 'Gene', (138, 147))	('HOTAIRM1', 'Gene', (0, 8))	('ANGPTL4', 'Gene', '51129', (234, 241))	('HIF1alpha', 'Gene', '3091', (138, 147))	('upregulation', 'PosReg', (167, 179))	('hypoxia-responsive', 'Disease', 'MESH:D000860', (183, 201))	('hypoxia-responsive', 'Disease', (183, 201))	('knockdown', 'Var', (56, 65))
108363	31862408	Additionally, HOTAIRM1 appeared to be necessary to maintain the kidney progenitor state, as knockdown of HOTAIRM1 reduced expression of the kidney lineage differentiation markers, OSR1, GDNF and PAX2.	('expression', 'MPA', (122, 132))	('HOTAIRM1', 'Gene', (105, 113))	('OSR1', 'Gene', '130497', (180, 184))	('reduced', 'NegReg', (114, 121))	('knockdown', 'Var', (92, 101))	('PAX2', 'Gene', '5076', (195, 199))	('GDNF', 'Gene', (186, 190))	('OSR1', 'Gene', (180, 184))	('PAX2', 'Gene', (195, 199))
108378	32038722	Genomic CNVs were identified at the single-cell level, and the tumor cells showed widespread amplification and deletion across the whole genome.	('amplification', 'Var', (93, 106))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('deletion', 'Var', (111, 119))
108380	32038722	Besides, receptor protein tyrosine kinase (RTK) genes also showed widespread copy number variations in cancer cells.	('RTK) genes', 'Gene', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('copy number variations', 'Var', (77, 99))	('tyrosine', 'Chemical', 'None', (26, 34))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))
108381	32038722	Our studies indicated that the genomic CNVs in RTK genes and downstream signaling transduction pathways may be involved in VHL/PBRM1-negative ccRCC pathogenesis and progression, and highlighted the role of the comprehensive investigation of genomic CNVs at the single-cell level in both clarifying pathogenic mechanism and identifying potential therapeutic targets in cancers.	('cancers', 'Disease', (368, 375))	('VHL', 'Disease', (123, 126))	('cancers', 'Disease', 'MESH:D009369', (368, 375))	('VHL', 'Disease', 'MESH:D006623', (123, 126))	('RTK genes', 'Gene', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (368, 374))	('CNVs', 'Var', (39, 43))	('involved', 'Reg', (111, 119))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('transduction', 'biological_process', 'GO:0009293', ('82', '94'))	('cancers', 'Phenotype', 'HP:0002664', (368, 375))	('pathogenesis', 'biological_process', 'GO:0009405', ('148', '160'))	('ccRCC', 'Disease', (142, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('ccRCC', 'Disease', 'MESH:D002292', (142, 147))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))
108384	32038722	Increasing studies have shown that the development of ccRCC seems to be shaped by chromosomal lesions and a number of somatic mutations.	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('chromosomal lesions', 'Var', (82, 101))	('ccRCC', 'Disease', (54, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('ccRCC', 'Disease', 'MESH:D002292', (54, 59))
108386	32038722	Nearly 90% of ccRCCs undertake the deletion on chromosome 3p, leading to a very high frequency of VHL inactivation.	('VHL', 'Disease', 'MESH:D006623', (98, 101))	('VHL', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('ccRCC', 'Phenotype', 'HP:0006770', (14, 19))	('chromosome', 'cellular_component', 'GO:0005694', ('47', '57'))	('ccRCC', 'Disease', (14, 19))	('deletion', 'Var', (35, 43))	('ccRCC', 'Disease', 'MESH:D002292', (14, 19))
108387	32038722	Moreover, VHL and PBRM1 are mutated in about 50 and 41% of sporadic ccRCC, respectively.	('mutated', 'Var', (28, 35))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('VHL', 'Disease', (10, 13))	('VHL', 'Disease', 'MESH:D006623', (10, 13))	('PBRM1', 'Gene', (18, 23))	('ccRCC', 'Disease', (68, 73))	('ccRCC', 'Disease', 'MESH:D002292', (68, 73))
108389	32038722	Based on the next-generation sequencing technology, previous studies identified many driver mutations in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (105, 110))	('ccRCC', 'Disease', (105, 110))	('ccRCC', 'Disease', 'MESH:D002292', (105, 110))	('mutations', 'Var', (92, 101))
108396	32038722	performed a single-cell exome sequencing to elucidate the genetic mechanisms of the ccRCC by identifying the single nucleotide variants (SNVs).	('ccRCC', 'Disease', (84, 89))	('ccRCC', 'Disease', 'MESH:D002292', (84, 89))	('single nucleotide variants', 'Var', (109, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))
108403	32038722	The comparison between cancer and normal cells revealed widespread amplification and deletion across the whole genome in tumor cells (Figure 1A).	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('amplification', 'Var', (67, 80))	('tumor', 'Disease', (121, 126))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('deletion', 'Var', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
108407	32038722	What's more, single-cell sequencing data revealed the amplification of copy number showed a high degree of consistency, which suggests the amplification may play an important role in the progression of ccRCC.	('amplification', 'Var', (139, 152))	('RCC', 'Phenotype', 'HP:0005584', (204, 207))	('play', 'Reg', (157, 161))	('ccRCC', 'Phenotype', 'HP:0006770', (202, 207))	('role', 'Reg', (175, 179))	('ccRCC', 'Disease', (202, 207))	('ccRCC', 'Disease', 'MESH:D002292', (202, 207))
108408	32038722	On the contrary, the deletion showed higher intratumor heterogeneity in the cancer cells.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('higher', 'PosReg', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('deletion', 'Var', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
108416	32038722	The results indicated that copy numbers in the significant CNV loci have a high degree of consistency across all the cancer cells.	('cancer', 'Disease', (117, 123))	('copy numbers', 'Var', (27, 39))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))
108421	32038722	FGFR4 gene belongs to the fibroblast growth factor receptor family, and the activation of FGFR4 can promote cell growth and angiogenesis in cancer.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR4', 'Gene', (90, 95))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('activation', 'Var', (76, 86))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('26', '50'))	('cell growth', 'biological_process', 'GO:0016049', ('108', '119'))	('angiogenesis', 'biological_process', 'GO:0001525', ('124', '136'))	('promote', 'PosReg', (100, 107))	('FGFR4', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('FGFR', 'molecular_function', 'GO:0005007', ('90', '94'))
108422	32038722	CDK2 gene is commonly excessive activation in human cancers, and dysfunction of CDK2 can lead to uncontrolled cell growth.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('lead to', 'Reg', (89, 96))	('dysfunction', 'Var', (65, 76))	('CDK', 'molecular_function', 'GO:0004693', ('80', '83'))	('uncontrolled', 'MPA', (97, 109))	('CDK', 'molecular_function', 'GO:0004693', ('0', '3'))	('CDK2', 'Gene', (80, 84))	('cell growth', 'biological_process', 'GO:0016049', ('110', '121'))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('CDK2 gene', 'Gene', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
108424	32038722	While the top significantly deleted loci (Figure 4, Supplementary Table S2B) (1q21.3, 1p35.2, 16q24.3, 3p14.1, etc.	('1p35.2', 'Var', (86, 92))	('1q21.3', 'Var', (78, 84))	('p35', 'cellular_component', 'GO:0070745', ('87', '90'))	('p35', 'cellular_component', 'GO:0043514', ('87', '90'))	('S2B', 'Chemical', 'MESH:D013455', (72, 75))	('16q24.3', 'Var', (94, 101))
108427	32038722	PARP1 gene played an important role in DNA repair and cell apoptosis, the cell with PARP1 deficiency show resistance to DNA damage-induced programmed cell death and increased cancer risk.	('apoptosis', 'biological_process', 'GO:0097194', ('59', '68'))	('apoptosis', 'biological_process', 'GO:0006915', ('59', '68'))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('programmed cell death', 'biological_process', 'GO:0012501', ('139', '160'))	('cancer', 'Disease', (175, 181))	('resistance', 'CPA', (106, 116))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('PARP1', 'Gene', (84, 89))	('deficiency', 'Var', (90, 100))	('DNA', 'cellular_component', 'GO:0005574', ('120', '123'))	('death', 'Disease', 'MESH:D003643', (155, 160))	('DNA repair', 'biological_process', 'GO:0006281', ('39', '49'))	('death', 'Disease', (155, 160))	('increased', 'PosReg', (165, 174))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
108432	32038722	The inactivation of these genes leads to uncontrolled tumor growth, which may contribute to the VHL/PBRM1-negative ccRCC pathogenesis and progression To better understand the potential biological and functional characteristics of the significantly amplified and deleted genes in cancer cells, biological function pathways in ccRCC had been further investigated.	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('ccRCC', 'Disease', 'MESH:D002292', (325, 330))	('pathogenesis', 'biological_process', 'GO:0009405', ('121', '133'))	('leads to', 'Reg', (32, 40))	('cancer', 'Disease', (279, 285))	('inactivation', 'Var', (4, 16))	('ccRCC', 'Disease', (325, 330))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('VHL', 'Disease', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('ccRCC', 'Disease', 'MESH:D002292', (115, 120))	('RCC', 'Phenotype', 'HP:0005584', (327, 330))	('ccRCC', 'Phenotype', 'HP:0006770', (325, 330))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('ccRCC', 'Disease', (115, 120))	('uncontrolled', 'MPA', (41, 53))	('VHL', 'Disease', 'MESH:D006623', (96, 99))	('tumor', 'Disease', (54, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))
108439	32038722	The single cancer cells show widespread amplification and deletion on multiple RTKs compared with the normal cells, the NC and NCinCT groups show similar RTK gene profile.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('amplification', 'Var', (40, 53))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('deletion', 'Var', (58, 66))	('cancer', 'Disease', (11, 17))
108441	32038722	On the contrary, EPHB2, ERBB4, FGFR1, PDGFRA, KDR, and FLT1 genes showed deletion in cancer cells (Figure 6).	('FLT1', 'Gene', (55, 59))	('PDGFRA', 'Gene', (38, 44))	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('ERBB4', 'Gene', (24, 29))	('KDR', 'Gene', (46, 49))	('EPHB2', 'Gene', (17, 22))	('FGFR1', 'Gene', (31, 36))	('deletion', 'Var', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
108446	32038722	We reclassified all the single cells and identified pathological mutations in VHL/PBRM1-negative ccRCC cells.	('VHL', 'Disease', 'MESH:D006623', (78, 81))	('ccRCC', 'Disease', 'MESH:D002292', (97, 102))	('VHL', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('ccRCC', 'Disease', (97, 102))	('mutations', 'Var', (65, 74))
108447	32038722	Similar to the genomic CNVs in other cancers, the pathogenesis in VHL/PBRM1-negative ccRCC seems to be shaped by the accumulation of amplification in driver genes (IGFBP4, ERBB2, ERBB3, FGFR4, CDK2, and FLT4), the loss of function in tumor suppressor genes (Chmp1A, CADM2) and autophagy genes (PRAP1, ULK1).	('tumor', 'Disease', (234, 239))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('234', '250'))	('CADM2', 'Gene', (266, 271))	('FGFR4', 'Gene', (186, 191))	('VHL', 'Disease', (66, 69))	('ULK1', 'Gene', (301, 305))	('CDK2', 'Gene', (193, 197))	('Chmp1A', 'Gene', (258, 264))	('autophagy', 'CPA', (277, 286))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('FGFR', 'molecular_function', 'GO:0005007', ('186', '190'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('234', '250'))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('ccRCC', 'Disease', 'MESH:D002292', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('CDK', 'molecular_function', 'GO:0004693', ('193', '196'))	('autophagy', 'biological_process', 'GO:0016236', ('277', '286'))	('ccRCC', 'Disease', (85, 90))	('IGFBP4', 'Gene', (164, 170))	('VHL', 'Disease', 'MESH:D006623', (66, 69))	('pathogenesis', 'biological_process', 'GO:0009405', ('50', '62'))	('FLT4', 'Gene', (203, 207))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('ERBB2', 'Gene', (172, 177))	('loss of function', 'NegReg', (214, 230))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))	('ERBB3', 'Gene', (179, 184))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('accumulation', 'PosReg', (117, 129))	('cancers', 'Disease', (37, 44))	('amplification', 'Var', (133, 146))	('autophagy', 'biological_process', 'GO:0006914', ('277', '286'))	('PRAP1', 'Gene', (294, 299))
108448	32038722	At the same time, RTK genes showed widespread copy number variations in cancer cells specifically.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('copy number variations', 'Var', (46, 68))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('RTK genes', 'Gene', (18, 27))	('cancer', 'Disease', (72, 78))
108449	32038722	Mutations on RTKs may take part in the overactivity of downstream signaling transduction pathways, leading to the uncontrolled growth of ccRCC cells.	('RTKs', 'Gene', (13, 17))	('signaling', 'biological_process', 'GO:0023052', ('66', '75'))	('transduction', 'biological_process', 'GO:0009293', ('76', '88'))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('ccRCC', 'Disease', (137, 142))	('leading to', 'Reg', (99, 109))	('Mutations', 'Var', (0, 9))	('overactivity', 'PosReg', (39, 51))	('uncontrolled growth', 'MPA', (114, 133))	('downstream signaling transduction pathways', 'Pathway', (55, 97))	('take part', 'Reg', (22, 31))	('ccRCC', 'Disease', 'MESH:D002292', (137, 142))
108469	31692936	NSD2 (also known as WHSC1 and MMSET) was initially found to be deleted in Wolf-Hirschhorn syndrome (WHS) and rearranged with the immunoglobulin locus in 15%~20% multiple myeloma (MM) cases.	('Wolf-Hirschhorn syndrome', 'Disease', (74, 98))	('MM', 'Disease', 'MESH:D009101', (30, 32))	('multiple myeloma', 'Disease', (161, 177))	('MMSET', 'Gene', (30, 35))	('NSD2', 'Gene', (0, 4))	('WHS', 'Disease', 'MESH:D054877', (20, 23))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('129', '143'))	('MMSET', 'Gene', '7468', (30, 35))	('NSD2', 'Gene', '7468', (0, 4))	('WHSC1', 'Gene', (20, 25))	('Wolf-Hirschhorn syndrome', 'Disease', 'MESH:D054877', (74, 98))	('MM', 'Disease', 'MESH:D009101', (179, 181))	('WHS', 'Disease', (100, 103))	('multiple myeloma', 'Phenotype', 'HP:0006775', (161, 177))	('rearranged', 'Var', (109, 119))	('WHS', 'Disease', (20, 23))	('multiple myeloma', 'Disease', 'MESH:D009101', (161, 177))	('WHS', 'Disease', 'MESH:D054877', (100, 103))	('WHSC1', 'Gene', '7468', (20, 25))
108472	31692936	Over-expression of NSD2 could promote EMT process and invasive properties of prostate cancer.	('promote', 'PosReg', (30, 37))	('invasive properties', 'CPA', (54, 73))	('prostate cancer', 'Disease', (77, 92))	('EMT process', 'CPA', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('NSD2', 'Gene', '7468', (19, 23))	('prostate cancer', 'Disease', 'MESH:D011471', (77, 92))	('Over-expression', 'Var', (0, 15))	('EMT', 'biological_process', 'GO:0001837', ('38', '41'))	('prostate cancer', 'Phenotype', 'HP:0012125', (77, 92))	('NSD2', 'Gene', (19, 23))
108473	31692936	Contrarily, suppression of NSD2 by miRNAs would obviously attenuate cell growth and motility via impairing EMT process in gastric cancer and endometrial cancer.	('endometrial cancer', 'Disease', (141, 159))	('NSD2', 'Gene', '7468', (27, 31))	('cell growth', 'biological_process', 'GO:0016049', ('68', '79'))	('attenuate', 'NegReg', (58, 67))	('impairing', 'NegReg', (97, 106))	('NSD2', 'Gene', (27, 31))	('gastric cancer', 'Disease', (122, 136))	('suppression', 'NegReg', (12, 23))	('cell growth', 'CPA', (68, 79))	('endometrial cancer', 'Disease', 'MESH:D016889', (141, 159))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('endometrial cancer', 'Phenotype', 'HP:0012114', (141, 159))	('EMT process', 'CPA', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('miRNAs', 'Var', (35, 41))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))	('EMT', 'biological_process', 'GO:0001837', ('107', '110'))
108477	31692936	In addition, depletion of NSD2 would greatly inhibit cell migration and invasion through repressing EMT process in RCC.	('NSD2', 'Gene', (26, 30))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:D002292', (115, 118))	('RCC', 'Disease', (115, 118))	('depletion', 'Var', (13, 22))	('cell migration', 'biological_process', 'GO:0016477', ('53', '67'))	('EMT', 'biological_process', 'GO:0001837', ('100', '103'))	('repressing', 'NegReg', (89, 99))	('cell migration', 'CPA', (53, 67))	('inhibit', 'NegReg', (45, 52))	('invasion', 'CPA', (72, 80))	('NSD2', 'Gene', '7468', (26, 30))
108478	31692936	Altogether, NSD2 may play an important role in RCC metastasis and targeting NSD2 may be a promising therapeutic approach for mRCC patients.	('RCC', 'Disease', 'MESH:D002292', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('NSD2', 'Gene', '7468', (76, 80))	('patients', 'Species', '9606', (130, 138))	('targeting', 'Var', (66, 75))	('NSD2', 'Gene', '7468', (12, 16))	('RCC', 'Disease', (47, 50))	('RCC', 'Disease', 'MESH:D002292', (47, 50))	('RCC', 'Disease', (126, 129))	('NSD2', 'Gene', (76, 80))	('NSD2', 'Gene', (12, 16))
108504	31692936	Moreover, the RNA sequencing data from ccRCC databases (GSE66270 and GSE66271) was also reanalyzed.	('GSE66270', 'Var', (56, 64))	('RNA', 'cellular_component', 'GO:0005562', ('14', '17'))	('GSE66271', 'Var', (69, 77))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('RCC', 'Disease', 'MESH:D002292', (41, 44))	('RCC', 'Disease', (41, 44))
108505	31692936	GSE66270 included 14 primary ccRCC tissues and 14 paired adjacent normal tissues, and GSE66271 included 13 metastatic ccRCC tissues and 13 paired adjacent normal tissues.	('GSE66271', 'Var', (86, 94))	('RCC', 'Disease', 'MESH:D002292', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('GSE66270', 'Var', (0, 8))	('RCC', 'Disease', 'MESH:D002292', (31, 34))	('RCC', 'Disease', (31, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
108524	31692936	Consequently, this study illustrated that knockdown of NSD2 could inhibit cell migration and invasion, indicating that NSD2 may be a vital regulator in the metastatic process in RCC.	('NSD2', 'Gene', (119, 123))	('NSD2', 'Gene', '7468', (55, 59))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('cell migration', 'biological_process', 'GO:0016477', ('74', '88'))	('NSD2', 'Gene', (55, 59))	('inhibit', 'NegReg', (66, 73))	('RCC', 'Disease', (178, 181))	('RCC', 'Disease', 'MESH:D002292', (178, 181))	('invasion', 'CPA', (93, 101))	('NSD2', 'Gene', '7468', (119, 123))	('knockdown', 'Var', (42, 51))
108527	31692936	After inhibition of NSD2, E-cadherin protein expression was increased in 786-O and ACHN cells, whereas the expressions of N-cadherin and Vimentin were decreased at protein level (all P < 0.05, Figure 5).	('NSD2', 'Gene', '7468', (20, 24))	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('N-cadherin', 'Gene', (122, 132))	('cadherin', 'molecular_function', 'GO:0008014', ('124', '132'))	('Vimentin', 'cellular_component', 'GO:0045099', ('137', '145'))	('E-cadherin', 'Gene', (26, 36))	('NSD2', 'Gene', (20, 24))	('N-cadherin', 'Gene', '1000', (122, 132))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('decreased', 'NegReg', (151, 160))	('E-cadherin', 'Gene', '999', (26, 36))	('Vimentin', 'Gene', (137, 145))	('inhibition', 'Var', (6, 16))	('Vimentin', 'cellular_component', 'GO:0045098', ('137', '145'))	('increased', 'PosReg', (60, 69))	('Vimentin', 'Gene', '7431', (137, 145))	('cadherin', 'molecular_function', 'GO:0008014', ('28', '36'))
108532	31692936	Strikingly, metastatic RCC harbored higher rates of NSD1 inactivation and SETD2 mutation, compared with localized RCC.	('NSD1', 'Gene', '64324', (52, 56))	('SETD2', 'Gene', '29072', (74, 79))	('higher', 'PosReg', (36, 42))	('RCC', 'Disease', (114, 117))	('RCC', 'Disease', 'MESH:D002292', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('SETD2', 'Gene', (74, 79))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('NSD1', 'Gene', (52, 56))	('RCC', 'Disease', 'MESH:D002292', (23, 26))	('RCC', 'Disease', (23, 26))	('inactivation', 'NegReg', (57, 69))	('mutation', 'Var', (80, 88))
108536	31692936	The family members have been confirmed to involve in carcinogenesis through mono- or di-methylating lysine 36 of histone H3 (H3K36).	('di-methylating', 'Var', (85, 99))	('carcinogenesis', 'Disease', (53, 67))	('H3K36', 'Gene', (125, 130))	('lysine', 'Chemical', 'MESH:C114808', (100, 106))	('mono-', 'Var', (76, 81))	('involve', 'Reg', (42, 49))
108537	31692936	NSD2 preferentially catalyzed di-methylation of H3K36 (H3K36me2), which activates gene transcription and promotes tumorigenesis.	('activates', 'PosReg', (72, 81))	('promotes', 'PosReg', (105, 113))	('tumorigenesis', 'CPA', (114, 127))	('NSD2', 'Gene', '7468', (0, 4))	('methylation', 'biological_process', 'GO:0032259', ('33', '44'))	('gene transcription', 'MPA', (82, 100))	('NSD2', 'Gene', (0, 4))	('H3K36', 'Protein', (48, 53))	('di-methylation', 'Var', (30, 44))	('transcription', 'biological_process', 'GO:0006351', ('87', '100'))
108539	31692936	Besides, over-expression of NSD2 may induce cervical carcinogenesis by activating the AKT/MMP-2 signaling pathway.	('cervical carcinogenesis', 'Disease', (44, 67))	('over-expression', 'Var', (9, 24))	('MMP-2', 'Gene', '4313', (90, 95))	('AKT', 'Gene', (86, 89))	('NSD2', 'Gene', '7468', (28, 32))	('NSD2', 'Gene', (28, 32))	('MMP-2', 'Gene', (90, 95))	('AKT', 'Gene', '207', (86, 89))	('induce', 'PosReg', (37, 43))	('MMP-2', 'molecular_function', 'GO:0004228', ('90', '95'))	('activating', 'PosReg', (71, 81))	('signaling pathway', 'biological_process', 'GO:0007165', ('96', '113'))
108544	31692936	Previous studies have manifested that aberrant expression of NSD2 would regulate EMT in diverse cancers.	('NSD2', 'Gene', '7468', (61, 65))	('NSD2', 'Gene', (61, 65))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancers', 'Disease', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('aberrant', 'Var', (38, 46))	('EMT in diverse', 'CPA', (81, 95))	('EMT', 'biological_process', 'GO:0001837', ('81', '84'))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('regulate', 'Reg', (72, 80))	('expression', 'MPA', (47, 57))
108547	31692936	Here, we discovered that knockdown of NSD2 would remarkably repress migration and invasion in RCC cells.	('RCC', 'Disease', 'MESH:D002292', (94, 97))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('NSD2', 'Gene', '7468', (38, 42))	('NSD2', 'Gene', (38, 42))	('repress', 'NegReg', (60, 67))	('knockdown', 'Var', (25, 34))
108549	31692936	Taken together, these findings demonstrated that silencing of NSD2 could potently suppress cell metastasis through inhibiting EMT in RCC.	('silencing', 'Var', (49, 58))	('NSD2', 'Gene', '7468', (62, 66))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('EMT', 'biological_process', 'GO:0001837', ('126', '129'))	('NSD2', 'Gene', (62, 66))	('inhibiting', 'NegReg', (115, 125))	('cell metastasis', 'CPA', (91, 106))	('RCC', 'Disease', (133, 136))	('suppress', 'NegReg', (82, 90))	('RCC', 'Disease', 'MESH:D002292', (133, 136))
108633	33976979	The feature of kidney cancer is to participate in the target genes' mutation of metabolic pathways .	('metabolic pathways', 'Pathway', (80, 98))	('mutation', 'Var', (68, 76))	('kidney cancer', 'Phenotype', 'HP:0009726', (15, 28))	('kidney cancer', 'Disease', 'MESH:D007680', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('kidney cancer', 'Disease', (15, 28))	('participate', 'Reg', (35, 46))
108665	33408523	Circ_101341 Deteriorates the Progression of Clear Cell Renal Cell Carcinoma Through the miR- 411/EGLN3 Axis Clear cell renal cell carcinoma (ccRCC) is one of the main subtypes of renal cell carcinoma, with intense aggressiveness.	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (108, 139))	('renal cell carcinoma', 'Disease', (179, 199))	('miR- 411', 'Gene', (88, 96))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (44, 75))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (179, 199))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (119, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('EGLN3', 'Gene', '112399', (97, 102))	('EGLN3', 'Gene', (97, 102))	('aggressiveness', 'Disease', (214, 228))	('miR- 411', 'Gene', '693121', (88, 96))	('Clear Cell Renal Cell Carcinoma', 'Disease', (44, 75))	('aggressiveness', 'Phenotype', 'HP:0000718', (214, 228))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (55, 75))	('Deteriorates', 'NegReg', (12, 24))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (108, 139))	('Carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('aggressiveness', 'Disease', 'MESH:D001523', (214, 228))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (119, 139))	('ccRCC', 'Phenotype', 'HP:0006770', (141, 146))	('Clear cell renal cell carcinoma', 'Disease', (108, 139))	('RCC', 'Disease', (143, 146))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (44, 75))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (179, 199))	('Progression', 'CPA', (29, 40))	('Circ_101341', 'Var', (0, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('RCC', 'Disease', 'MESH:C538614', (143, 146))
108667	33408523	The intention of this study was to investigate the expression of circ_101341 and explore its function in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (105, 110))	('RCC', 'Disease', (107, 110))	('circ_101341', 'Var', (65, 76))	('circ_101341', 'Chemical', '-', (65, 76))
108674	33408523	Circ_101341 directly targeted miR-411, and miR-411 inhibition revised the inhibitory effects of circ_101341 knockdown on proliferation, migration and invasion in ccRCC cells.	('inhibition', 'NegReg', (51, 61))	('knockdown', 'Var', (108, 117))	('miR-411', 'Gene', (30, 37))	('miR-411', 'Gene', (43, 50))	('proliferation', 'CPA', (121, 134))	('circ_101341', 'Gene', (96, 107))	('inhibitory', 'MPA', (74, 84))	('invasion', 'CPA', (150, 158))	('circ_101341', 'Chemical', '-', (96, 107))	('miR-411', 'Gene', '693121', (30, 37))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('miR-411', 'Gene', '693121', (43, 50))	('RCC', 'Disease', (164, 167))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))	('migration', 'CPA', (136, 145))	('ccRCC', 'Phenotype', 'HP:0006770', (162, 167))
108675	33408523	Moreover, miR-411 directly bound to EGLN3, and EGLN3 overexpression also rescued the effects of circ_101341 knockdown.	('effects', 'MPA', (85, 92))	('knockdown', 'Var', (108, 117))	('miR-411', 'Gene', '693121', (10, 17))	('EGLN3', 'Gene', (36, 41))	('EGLN3', 'Gene', (47, 52))	('bound', 'Interaction', (27, 32))	('EGLN3', 'Gene', '112399', (36, 41))	('circ_101341', 'Chemical', '-', (96, 107))	('miR-411', 'Gene', (10, 17))	('rescued', 'PosReg', (73, 80))	('EGLN3', 'Gene', '112399', (47, 52))
108676	33408523	Circ_101341 functioned as a tumor promoter to strengthen proliferation, migration and invasion by regulating EGLN3 via sponging miR-411, indicating that circ_101341 was a potential diagnostic and therapeutic biomarker of ccRCC.	('EGLN3', 'Gene', '112399', (109, 114))	('regulating', 'Reg', (98, 108))	('RCC', 'Disease', 'MESH:C538614', (223, 226))	('tumor', 'Disease', (28, 33))	('migration', 'CPA', (72, 81))	('EGLN3', 'Gene', (109, 114))	('RCC', 'Disease', (223, 226))	('ccRCC', 'Phenotype', 'HP:0006770', (221, 226))	('miR-411', 'Gene', '693121', (128, 135))	('circ_101341', 'Var', (153, 164))	('circ_101341', 'Chemical', '-', (153, 164))	('proliferation', 'CPA', (57, 70))	('miR-411', 'Gene', (128, 135))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('invasion', 'CPA', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('strengthen', 'PosReg', (46, 56))	('RCC', 'Phenotype', 'HP:0005584', (223, 226))
108690	33408523	Herein, bioinformatic analysis displayed that miR-411 was a potential target of circ_101341.	('miR-411', 'Gene', (46, 53))	('circ_101341', 'Chemical', '-', (80, 91))	('circ_101341', 'Var', (80, 91))	('miR-411', 'Gene', '693121', (46, 53))
108696	33408523	In the present study, we mainly determined the expression of circ_101341 in ccRCC tissues and cells and investigated its functions in ccRCC development.	('circ_101341', 'Chemical', '-', (61, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('RCC', 'Disease', (136, 139))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('circ_101341', 'Var', (61, 72))
108697	33408523	Besides, the relationship between miR-411 and circ_101341 or EGLN3 was established to reveal a potential regulatory mechanism of circ_101341 in ccRCC.	('miR-411', 'Gene', '693121', (34, 41))	('circ_101341', 'Chemical', '-', (129, 140))	('EGLN3', 'Gene', (61, 66))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('miR-411', 'Gene', (34, 41))	('circ_101341', 'Chemical', '-', (46, 57))	('circ_101341', 'Var', (129, 140))	('EGLN3', 'Gene', '112399', (61, 66))
108724	33408523	A498 cells infected with sh-circ_101341 were subcutaneously implanted in the flanks of mice (n=4), and sh-NC acted as the control (n=4).	('sh-circ_101341', 'Var', (25, 39))	('infected', 'Disease', 'MESH:D007239', (11, 19))	('mice', 'Species', '10090', (87, 91))	('circ_101341', 'Chemical', '-', (28, 39))	('infected', 'Disease', (11, 19))
108727	33408523	Generally, SW839 and A498 cells after corresponding transfection were resuspended in serum-free medium and then added into the top of chambers coated with or without Matrigel (BD Biosciences) for invasion assay or migration assay.	('invasion assay', 'CPA', (196, 210))	('SW839', 'CellLine', 'CVCL:3604', (11, 16))	('migration assay', 'CPA', (214, 229))	('transfection', 'Var', (52, 64))
108732	33408523	USA), anti-N-cad (ab76011, Abcam), anti-MMP9 (ab137867, Abcam), anti-EGLN3 (anti-PHD3; ab30782, Abcam), anti-GAPDH (ab181602, Abcam) and Goat-anti-Rabbit horseradish peroxidase (HRP; ab205718, Abcam).	('GAPDH', 'Gene', (109, 114))	('horseradish peroxidase (HRP', 'molecular_function', 'GO:0004601', ('154', '181'))	('EGLN3', 'Gene', '112399', (69, 74))	('PHD3', 'Gene', '112399', (81, 85))	('PHD', 'molecular_function', 'GO:0050175', ('81', '84'))	('PHD3', 'Gene', (81, 85))	('MMP9', 'molecular_function', 'GO:0004229', ('40', '44'))	('EGLN3', 'Gene', (69, 74))	('MMP9', 'Gene', (40, 44))	('ab137867', 'Var', (46, 54))	('horseradish', 'Species', '3704', (154, 165))	('N-cad', 'Gene', '1000', (11, 16))	('ab76011', 'Var', (18, 25))	('MMP9', 'Gene', '4318', (40, 44))	('N-cad', 'Gene', (11, 16))	('GAPDH', 'Gene', '2597', (109, 114))
108736	33408523	The pGL4-based luciferase reporter plasmids containing wild-type circ_101341 (circ_101341-WT) or mutant-type circ_101341 (circ_101341-MUT, mutated at the putative miR-411 binding site) were designed and assembled by Ribobio.	('circ_101341', 'Chemical', '-', (78, 89))	('circ_101341', 'Chemical', '-', (109, 120))	('binding', 'molecular_function', 'GO:0005488', ('171', '178'))	('circ_101341', 'Chemical', '-', (122, 133))	('mutant-type', 'Var', (97, 108))	('miR-411', 'Gene', '693121', (163, 170))	('pGL', 'molecular_function', 'GO:0004598', ('4', '7'))	('circ_101341', 'Chemical', '-', (65, 76))	('miR-411', 'Gene', (163, 170))	('circ_101341', 'Var', (109, 120))
108738	33408523	A498 and SW839 cells were cotransfected with miR-411 and circ_101341-WT, circ_101341-MUT, EGLN3-WT or EGLN3-MUT, and miR-NC transfection acted as the control.	('miR-411', 'Gene', '693121', (45, 52))	('EGLN3', 'Gene', '112399', (102, 107))	('EGLN3', 'Gene', (102, 107))	('circ_101341-MUT', 'Var', (73, 88))	('SW839', 'CellLine', 'CVCL:3604', (9, 14))	('miR-411', 'Gene', (45, 52))	('EGLN3', 'Gene', '112399', (90, 95))	('circ_101341', 'Chemical', '-', (73, 84))	('circ_101341-WT', 'Var', (57, 71))	('EGLN3', 'Gene', (90, 95))	('circ_101341', 'Chemical', '-', (57, 68))
108742	33408523	Analysis of the ccRCC dataset GSE100186, downloaded from the Gene Expression Omnibus (GEO) repository (https://www.ncbi.nlm.nih.gov/gds/), presented dozens of differentially expressed circRNAs.	('RCC', 'Disease', (18, 21))	('RCC', 'Phenotype', 'HP:0005584', (18, 21))	('GSE100186', 'Var', (30, 39))	('gds', 'molecular_function', 'GO:0005085', ('132', '135'))	('RCC', 'Disease', 'MESH:C538614', (18, 21))	('Gene Expression', 'biological_process', 'GO:0010467', ('61', '76'))	('ccRCC', 'Phenotype', 'HP:0006770', (16, 21))
108743	33408523	The schematic diagram showed that circ_101341 was derived from precursor EGLN3 mRNA exon2 and exon3 (Figure 1B).	('EGLN3', 'Gene', (73, 78))	('EGLN3', 'Gene', '112399', (73, 78))	('circ_101341', 'Var', (34, 45))	('circ_101341', 'Chemical', '-', (34, 45))
108744	33408523	In the data from GSE100186 dataset, circ_101341 was significantly upregulated in ccRCC tissues (n=4) compared with normal tissues (n=4) (Figure 1C).	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('upregulated', 'PosReg', (66, 77))	('circ_101341', 'Chemical', '-', (36, 47))	('circ_101341', 'Var', (36, 47))
108745	33408523	Next, the expression of circ_101341 was verified in clinical ccRCC tissues, and the data showed that the expression of circ_101341 was notably enhanced in ccRCC tissues (n=60) relative to normal tissues (n=60) (Figure 1D).	('RCC', 'Disease', (63, 66))	('circ_101341', 'Var', (119, 130))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('circ_101341', 'Chemical', '-', (119, 130))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (155, 160))	('enhanced', 'PosReg', (143, 151))	('circ_101341', 'Chemical', '-', (24, 35))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', (157, 160))	('expression', 'MPA', (105, 115))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
108746	33408523	Moreover, Kaplan-Meier survival curve revealed that the overall survival of ccRCC patients with high circ_101341 expression was always lower than with low circ_101341 expression (Figure 1E).	('patients', 'Species', '9606', (82, 90))	('survival', 'MPA', (64, 72))	('RCC', 'Disease', (78, 81))	('high circ_101341 expression', 'Var', (96, 123))	('lower', 'NegReg', (135, 140))	('circ_101341', 'Chemical', '-', (155, 166))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('circ_101341', 'Chemical', '-', (101, 112))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))
108748	33408523	Obviously, the expression of circ_101341 in SW839 and A498 cells was relatively higher than that in Caki-1 and 786-O cells.	('SW839', 'CellLine', 'CVCL:3604', (44, 49))	('circ_101341', 'Chemical', '-', (29, 40))	('expression', 'MPA', (15, 25))	('circ_101341', 'Var', (29, 40))	('Caki-1', 'CellLine', 'CVCL:0234', (100, 106))	('higher', 'PosReg', (80, 86))
108750	33408523	Moreover, we noticed that RNase R treatment hardly affected the expression of circ_101341 but significantly diminished the RNA expression of its linear mRNA (EGLN3) (Figure 1G), suggesting that circ_101341 harbored a circular structure and stably expressed in A498 and SW839 cells.	('circ_101341', 'Chemical', '-', (78, 89))	('EGLN3', 'Gene', '112399', (158, 163))	('diminished', 'NegReg', (108, 118))	('EGLN3', 'Gene', (158, 163))	('RNA expression', 'MPA', (123, 137))	('SW839', 'CellLine', 'CVCL:3604', (269, 274))	('RNA', 'cellular_component', 'GO:0005562', ('123', '126'))	('circ_101341', 'Var', (194, 205))	('circ_101341', 'Gene', (78, 89))	('circ_101341', 'Chemical', '-', (194, 205))
108751	33408523	These data suggested that circ_101341 was highly expressed in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('RCC', 'Disease', (64, 67))	('circ_101341', 'Var', (26, 37))	('circ_101341', 'Chemical', '-', (26, 37))
108753	33408523	The data from qRT-PCR displayed that the expression of circ_101341 dwindled most in A498 and SW839 cells transfected with sh-circ#2 relative to #1 and #3 (Figure 2A and B).	('expression', 'MPA', (41, 51))	('SW839', 'CellLine', 'CVCL:3604', (93, 98))	('circ_101341', 'Var', (55, 66))	('circ_101341', 'Chemical', '-', (55, 66))	('dwindled', 'Reg', (67, 75))	('sh-circ', 'Var', (122, 129))
108755	33408523	The analysis of CCK-8 exhibited that circ_101341 knockdown prominently inhibited the proliferation of A498 and SW839 cells (Figure 2C and D).	('knockdown', 'Var', (49, 58))	('circ_101341 knockdown', 'Var', (37, 58))	('circ_101341', 'Chemical', '-', (37, 48))	('inhibited', 'NegReg', (71, 80))	('SW839', 'CellLine', 'CVCL:3604', (111, 116))	('proliferation', 'CPA', (85, 98))
108756	33408523	Likewise, colony formation assay presented that circ_101341 knockdown pronouncedly diminished the number of colonies of A498 and SW839 cells (Figure 2E).	('circ_101341', 'Gene', (48, 59))	('formation', 'biological_process', 'GO:0009058', ('17', '26'))	('knockdown', 'Var', (60, 69))	('circ_101341', 'Chemical', '-', (48, 59))	('SW839', 'CellLine', 'CVCL:3604', (129, 134))	('diminished', 'NegReg', (83, 93))
108758	33408523	As shown in Figure 2F and G, the stable knockdown of circ_101341 weakened both tumor volume and tumor weight, leading to decreased tumor size.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('decreased tumor', 'Disease', (121, 136))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (96, 101))	('decreased tumor', 'Disease', 'MESH:D002303', (121, 136))	('tumor', 'Disease', (131, 136))	('circ_101341', 'Var', (53, 64))	('weakened', 'NegReg', (65, 73))	('circ_101341', 'Chemical', '-', (53, 64))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
108759	33408523	These data manifested that circ_101341 knockdown limited the development of ccRCC in vitro and in vivo.	('circ_101341', 'Gene', (27, 38))	('development of', 'CPA', (61, 75))	('knockdown', 'Var', (39, 48))	('limited', 'NegReg', (49, 56))	('circ_101341', 'Chemical', '-', (27, 38))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))
108761	33408523	Noticeably, the number of migrated and invaded cells was substantially declined in A498 and SW839 cells with the transfection of sh-circ_101341#2 compared with sh-NC (Figure 3A and B).	('transfection', 'Var', (113, 125))	('sh-circ_101341#2', 'Var', (129, 145))	('declined', 'NegReg', (71, 79))	('circ_101341', 'Chemical', '-', (132, 143))	('SW839', 'CellLine', 'CVCL:3604', (92, 97))
108762	33408523	The expression levels of EMT indicators were examined by Western blot, and the result showed that the expression of E-cad was significantly reinforced with the knockdown of circ_101341, while the expression of N-cad and MMP9 was reduced with the knockdown of circ_101341 in A498 and SW839 cells (Figure 3C and D).	('MMP9', 'Gene', (220, 224))	('E-cad', 'Gene', '999', (116, 121))	('MMP9', 'molecular_function', 'GO:0004229', ('220', '224'))	('knockdown', 'Var', (160, 169))	('expression', 'MPA', (102, 112))	('MMP9', 'Gene', '4318', (220, 224))	('E-cad', 'Gene', (116, 121))	('circ_101341', 'Gene', (173, 184))	('circ_101341', 'Chemical', '-', (259, 270))	('SW839', 'CellLine', 'CVCL:3604', (283, 288))	('N-cad', 'Gene', (210, 215))	('circ_101341', 'Chemical', '-', (173, 184))	('reinforced', 'PosReg', (140, 150))	('N-cad', 'Gene', '1000', (210, 215))	('EMT', 'biological_process', 'GO:0001837', ('25', '28'))
108763	33408523	These observations illustrated that circ_101341 knockdown sequestered cell migration, invasion and EMT.	('cell migration', 'biological_process', 'GO:0016477', ('70', '84'))	('cell migration', 'CPA', (70, 84))	('circ_101341', 'Gene', (36, 47))	('EMT', 'CPA', (99, 102))	('sequestered', 'NegReg', (58, 69))	('circ_101341', 'Chemical', '-', (36, 47))	('invasion', 'CPA', (86, 94))	('EMT', 'biological_process', 'GO:0001837', ('99', '102'))	('knockdown', 'Var', (48, 57))
108767	33408523	Pull-down assay showed that miR-411 could be abundantly enriched by circ_101341 probe compared to oligo probe (Figure S1).	('miR-411', 'Gene', (28, 35))	('circ_101341', 'Chemical', '-', (68, 79))	('circ_101341 probe', 'Var', (68, 85))	('miR-411', 'Gene', '693121', (28, 35))
108768	33408523	Circinteractome presented that there was a specific binding site between circ_101341 and miR-411 (Figure 4B).	('miR-411', 'Gene', (89, 96))	('binding', 'molecular_function', 'GO:0005488', ('52', '59'))	('circ_101341', 'Var', (73, 84))	('binding', 'Interaction', (52, 59))	('circ_101341', 'Chemical', '-', (73, 84))	('miR-411', 'Gene', '693121', (89, 96))
108769	33408523	Next, the fusion plasmids circ_101341-WT and circ_101341-MUT were constructed to perform dual-luciferase reporter assay, and the result showed that the reintroduction of miR-411 markedly reduced the luciferase activity in A498 and SW839 cells transfected with circ_101341-WT but not circ_101341-MUT (Figure 4C).	('luciferase activity', 'molecular_function', 'GO:0050248', ('199', '218'))	('activity', 'MPA', (210, 218))	('circ_101341', 'Chemical', '-', (260, 271))	('luciferase activity', 'molecular_function', 'GO:0050397', ('199', '218'))	('miR-411', 'Gene', '693121', (170, 177))	('circ_101341', 'Chemical', '-', (283, 294))	('luciferase', 'Enzyme', (199, 209))	('circ_101341', 'Chemical', '-', (45, 56))	('reduced', 'NegReg', (187, 194))	('luciferase activity', 'molecular_function', 'GO:0047077', ('199', '218'))	('circ_101341-WT', 'Var', (260, 274))	('SW839', 'CellLine', 'CVCL:3604', (231, 236))	('circ_101341', 'Chemical', '-', (26, 37))	('luciferase activity', 'molecular_function', 'GO:0045289', ('199', '218'))	('miR-411', 'Gene', (170, 177))	('luciferase activity', 'molecular_function', 'GO:0047712', ('199', '218'))
108770	33408523	Besides, RIP assay showed that both circ_101341 and miR-411 were remarkably enriched in the anti-Ago2 group compared with that in the anti-IgG group (Figure 4D).	('Ago2', 'Gene', '27161', (97, 101))	('miR-411', 'Gene', '693121', (52, 59))	('Ago2', 'Gene', (97, 101))	('miR-411', 'Gene', (52, 59))	('circ_101341', 'Chemical', '-', (36, 47))	('circ_101341', 'Var', (36, 47))
108771	33408523	In addition, RNA pull-down assay was conducted using Bio-miR-411 in A498 and SW839 cell lysates, and the result demonstrated that circ_101341 was significantly enriched in Bio-miR-411 relative to Bio-NC (Figure 4E).	('SW839', 'CellLine', 'CVCL:3604', (77, 82))	('miR-411', 'Gene', '693121', (176, 183))	('miR-411', 'Gene', (57, 64))	('miR-411', 'Gene', '693121', (57, 64))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('miR-411', 'Gene', (176, 183))	('circ_101341', 'Var', (130, 141))	('circ_101341', 'Chemical', '-', (130, 141))
108772	33408523	Moreover, the expression of miR-411 was markedly strengthened by circ_101341 knockdown in A498 and SW839 cells (Figure 4F).	('SW839', 'CellLine', 'CVCL:3604', (99, 104))	('strengthened', 'PosReg', (49, 61))	('miR-411', 'Gene', '693121', (28, 35))	('circ_101341', 'Gene', (65, 76))	('knockdown', 'Var', (77, 86))	('circ_101341', 'Chemical', '-', (65, 76))	('miR-411', 'Gene', (28, 35))	('expression', 'MPA', (14, 24))
108773	33408523	All data maintained that circ_101341 directly targeted miR-411.	('miR-411', 'Gene', '693121', (55, 62))	('circ_101341', 'Var', (25, 36))	('circ_101341', 'Chemical', '-', (25, 36))	('targeted', 'Reg', (46, 54))	('miR-411', 'Gene', (55, 62))
108774	33408523	Subsequently, the effects of the interaction between circ_101341 and miR-411 were observed in A498 and SW839 cells.	('miR-411', 'Gene', '693121', (69, 76))	('SW839', 'CellLine', 'CVCL:3604', (103, 108))	('circ_101341', 'Chemical', '-', (53, 64))	('miR-411', 'Gene', (69, 76))	('circ_101341', 'Var', (53, 64))	('interaction', 'Interaction', (33, 44))
108777	33408523	The number of migrated and invaded cells was promoted in A498 and SW839 cells with the transfection of sh-circ#2+anti-miR-411 relative to sh-circ#2+anti-NC (Figure 5D and E).	('miR-411', 'Gene', '693121', (118, 125))	('SW839', 'CellLine', 'CVCL:3604', (66, 71))	('promoted', 'PosReg', (45, 53))	('transfection', 'Var', (87, 99))	('miR-411', 'Gene', (118, 125))
108778	33408523	Furthermore, the levels of E-cad were depleted in A498 and SW839 cells with the transfection of sh-circ#2+anti-miR-411 relative to sh-circ#2+anti-NC, while the levels of N-cad and MMP9 were opposite to that of E-cad (Figure 5F and G).	('N-cad', 'Gene', '1000', (170, 175))	('SW839', 'CellLine', 'CVCL:3604', (59, 64))	('miR-411', 'Gene', '693121', (111, 118))	('MMP9', 'Gene', (180, 184))	('E-cad', 'Gene', '999', (27, 32))	('depleted', 'NegReg', (38, 46))	('MMP9', 'Gene', '4318', (180, 184))	('E-cad', 'Gene', (27, 32))	('E-cad', 'Gene', '999', (210, 215))	('MMP9', 'molecular_function', 'GO:0004229', ('180', '184'))	('levels', 'MPA', (17, 23))	('transfection', 'Var', (80, 92))	('miR-411', 'Gene', (111, 118))	('E-cad', 'Gene', (210, 215))	('N-cad', 'Gene', (170, 175))
108779	33408523	These results concluded that the anti-tumor role of circ_101341 knockdown was abolished by miR-411 absence.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('miR-411', 'Gene', (91, 98))	('absence', 'NegReg', (99, 106))	('circ_101341', 'Gene', (52, 63))	('miR-411', 'Gene', '693121', (91, 98))	('circ_101341', 'Chemical', '-', (52, 63))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('knockdown', 'Var', (64, 73))	('abolished', 'NegReg', (78, 87))
108797	33408523	Current studies suggested that the dysregulation of circRNAs is closely associated with tumorigenesis and progression.	('circRNAs', 'Gene', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('associated', 'Reg', (72, 82))	('progression', 'CPA', (106, 117))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('dysregulation', 'Var', (35, 48))	('tumor', 'Disease', (88, 93))
108798	33408523	Interestingly, the dataset GSE100186 presented that circ_101341 was a significantly upregulated circRNA in ccRCC tissues compared with normal tissues.	('upregulated', 'PosReg', (84, 95))	('circRNA', 'MPA', (96, 103))	('circ_101341', 'Var', (52, 63))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('circ_101341', 'Chemical', '-', (52, 63))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))
108799	33408523	Hence, we speculated that circ_101341 might implicate in ccRCC progression.	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('implicate', 'Reg', (44, 53))	('RCC', 'Disease', (59, 62))	('circ_101341', 'Var', (26, 37))	('circ_101341', 'Chemical', '-', (26, 37))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
108800	33408523	Molecular experiments discovered that the expression of circ_101341 was aberrantly enhanced in ccRCC tissues and cells, and circ_101341 knockdown functionally suppressed cell proliferation, migration and invasion in vitro and limited tumor growth in vivo.	('tumor', 'Disease', (234, 239))	('invasion', 'CPA', (204, 212))	('expression', 'MPA', (42, 52))	('circ_101341', 'Chemical', '-', (56, 67))	('suppressed', 'NegReg', (159, 169))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('circ_101341', 'Gene', (56, 67))	('circ_101341', 'Chemical', '-', (124, 135))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('limited', 'NegReg', (226, 233))	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('knockdown', 'Var', (136, 145))	('circ_101341 knockdown', 'Var', (124, 145))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('enhanced', 'PosReg', (83, 91))	('cell proliferation', 'biological_process', 'GO:0008283', ('170', '188'))	('cell proliferation', 'CPA', (170, 188))
108801	33408523	These findings manifested that circ_101341 served as a tumor promoter in ccRCC progression.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('circ_101341', 'Var', (31, 42))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('tumor', 'Disease', (55, 60))	('RCC', 'Disease', (75, 78))	('circ_101341', 'Chemical', '-', (31, 42))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))
108802	33408523	For example, circ_0039569 contributed to the formation and metastasis of RCC by adsorbing miR-34a-5p.	('metastasis', 'CPA', (59, 69))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('circ_0039569', 'Var', (13, 25))	('formation', 'CPA', (45, 54))	('adsorbing', 'MPA', (80, 89))	('formation', 'biological_process', 'GO:0009058', ('45', '54'))	('miR-34a-5p', 'Protein', (90, 100))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
108803	33408523	Circ_001895 promoted ccRCC progression in vitro and in vivo via targeting miR-296-5p.	('promoted', 'PosReg', (12, 20))	('Circ_001895', 'Var', (0, 11))	('targeting', 'Reg', (64, 73))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('miR-296', 'Gene', '407022', (74, 81))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (21, 26))	('RCC', 'Disease', (23, 26))	('miR-296', 'Gene', (74, 81))
108807	33408523	Zhang et al concluded that miR-411 was targeted by circ_000926, and miR-411 depletion abolished the anti-tumor role of circ_000926 downregulation in RCC progression.	('circ_000926', 'Var', (119, 130))	('RCC', 'Disease', (149, 152))	('depletion', 'MPA', (76, 85))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('miR-411', 'Gene', '693121', (27, 34))	('miR-411', 'Gene', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('miR-411', 'Gene', (27, 34))	('abolished', 'NegReg', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('miR-411', 'Gene', '693121', (68, 75))	('downregulation', 'NegReg', (131, 145))	('tumor', 'Disease', (105, 110))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
108810	33408523	Therefore, it could be concluded that circ_101341 triggered ccRCC progression by inhibiting the expression of miR-411.	('circ_101341', 'Var', (38, 49))	('miR-411', 'Gene', '693121', (110, 117))	('inhibiting', 'NegReg', (81, 91))	('triggered', 'PosReg', (50, 59))	('circ_101341', 'Chemical', '-', (38, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('expression', 'MPA', (96, 106))	('miR-411', 'Gene', (110, 117))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))
108818	33408523	Circ_101341 was strikingly upregulated in ccRCC tissues and cells.	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (42, 47))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('Circ_101341', 'Var', (0, 11))	('upregulated', 'PosReg', (27, 38))
108819	33408523	Circ_101341 knockdown inhibited proliferation, migration and invasion of ccRCC cells, and inhibited tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('inhibited', 'NegReg', (22, 31))	('tumor', 'Disease', (100, 105))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('knockdown', 'Var', (12, 21))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('invasion', 'CPA', (61, 69))	('RCC', 'Disease', (75, 78))	('migration', 'CPA', (47, 56))	('Circ_101341', 'Gene', (0, 11))	('proliferation', 'CPA', (32, 45))	('inhibited', 'NegReg', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))
108820	33408523	Mechanically, circ_101341 aggravated the progression of ccRCC via the miR-411/EGLN3 pathway, hinting that circ_101341 might be a promising biomarker for diagnosis and therapy of ccRCC.	('miR-411', 'Gene', '693121', (70, 77))	('EGLN3', 'Gene', '112399', (78, 83))	('circ_101341', 'Var', (106, 117))	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('RCC', 'Disease', (180, 183))	('circ_101341', 'Chemical', '-', (106, 117))	('circ_101341', 'Var', (14, 25))	('RCC', 'Phenotype', 'HP:0005584', (180, 183))	('ccRCC', 'Phenotype', 'HP:0006770', (178, 183))	('circ_101341', 'Chemical', '-', (14, 25))	('aggravated', 'PosReg', (26, 36))	('miR-411', 'Gene', (70, 77))	('progression', 'CPA', (41, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('EGLN3', 'Gene', (78, 83))
108826	32012804	The EVI1 rs1344555 genetic variant is associated with poorer survival and greater progression of metastatic ccRCC patients treated with everolimus.	('ccRCC', 'Disease', (108, 113))	('poorer', 'NegReg', (54, 60))	('ccRCC', 'Disease', 'MESH:C538614', (108, 113))	('rs1344555', 'Mutation', 'rs1344555', (9, 18))	('rs1344555', 'Var', (9, 18))	('EVI1', 'Gene', (4, 8))	('survival', 'MPA', (61, 69))	('everolimus', 'Chemical', 'MESH:D000068338', (136, 146))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('patients', 'Species', '9606', (114, 122))
108827	32012804	This study leads us to propose that evaluation of EVI1 protein or gene expression, and of EVI1 genetic variants may help improve estimates of prognosis and the benefit of everolimus-based therapy in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (199, 204))	('variants', 'Var', (103, 111))	('ccRCC', 'Disease', (199, 204))	('gene expression', 'biological_process', 'GO:0010467', ('66', '81'))	('ccRCC', 'Disease', 'MESH:C538614', (199, 204))	('everolimus', 'Chemical', 'MESH:D000068338', (171, 181))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('EVI1', 'Gene', (90, 94))
108837	32012804	Furthermore, oncogenic EVI1 frequently enhances PI3K-AKT-mTOR signaling, as by repression of PTEN in leukemogenesis.	('PTEN', 'Gene', (93, 97))	('PTEN', 'Gene', '5728', (93, 97))	('EVI1', 'Gene', (23, 27))	('enhances', 'PosReg', (39, 47))	('AKT', 'Gene', '207', (53, 56))	('oncogenic', 'Var', (13, 22))	('signaling', 'biological_process', 'GO:0023052', ('62', '71'))	('repression', 'NegReg', (79, 89))	('PI3K', 'molecular_function', 'GO:0016303', ('48', '52'))	('mTOR', 'Gene', (57, 61))	('leukemogenesis', 'Disease', (101, 115))	('mTOR', 'Gene', '2475', (57, 61))	('AKT', 'Gene', (53, 56))
108838	32012804	In intestinal epithelial cells, oncogenic EVI1 overactivates PI3K-AKT signaling in response to TGFbeta-mediated and taxol-mediated apoptosis.	('oncogenic', 'Var', (32, 41))	('AKT signaling', 'biological_process', 'GO:0043491', ('66', '79'))	('PI3K', 'molecular_function', 'GO:0016303', ('61', '65'))	('AKT', 'Gene', (66, 69))	('TGFbeta', 'Gene', (95, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('131', '140'))	('EVI1', 'Gene', (42, 46))	('TGFbeta', 'Gene', '7039', (95, 102))	('taxol', 'Chemical', 'MESH:D017239', (116, 121))	('apoptosis', 'biological_process', 'GO:0006915', ('131', '140'))	('response', 'MPA', (83, 91))	('AKT', 'Gene', '207', (66, 69))	('overactivates', 'PosReg', (47, 60))
108841	32012804	The depicted associations between oncogenic EVI1 and abnormally enhanced mTOR activity raise the possibility that EVI1 influences cancer prognosis and therapeutic response in a clinical setting where this kinase plays a central role, that of ccRCC.	('mTOR', 'Gene', '2475', (73, 77))	('influences', 'Reg', (119, 129))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('EVI1', 'Gene', (44, 48))	('mTOR', 'Gene', (73, 77))	('ccRCC', 'Disease', (242, 247))	('ccRCC', 'Disease', 'MESH:C538614', (242, 247))	('cancer', 'Disease', (130, 136))	('oncogenic', 'Var', (34, 43))	('ccRCC', 'Phenotype', 'HP:0006770', (242, 247))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('enhanced', 'PosReg', (64, 72))
108842	32012804	This is the most frequent type of kidney cancer in adults, which is commonly caused by genetic alterations that hamper proper cellular response to hypoxia and, in turn, demand enhanced mTOR signaling.	('mTOR', 'Gene', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('kidney cancer', 'Phenotype', 'HP:0009726', (34, 47))	('genetic alterations', 'Var', (87, 106))	('signaling', 'biological_process', 'GO:0023052', ('190', '199'))	('cellular response to hypoxia', 'biological_process', 'GO:0071456', ('126', '154'))	('hypoxia', 'Disease', (147, 154))	('kidney cancer', 'Disease', (34, 47))	('hypoxia', 'Disease', 'MESH:D000860', (147, 154))	('hamper', 'NegReg', (112, 118))	('alterations', 'Var', (95, 106))	('enhanced', 'PosReg', (176, 184))	('caused', 'Reg', (77, 83))	('mTOR', 'Gene', '2475', (185, 189))	('kidney cancer', 'Disease', 'MESH:D007680', (34, 47))
108851	32012804	Combined analysis of the immunohistochemistry results from the tumors and venous tumor thrombi showed a significant association between EVI1 positivity and poorer patient outcome: multivariate Cox regression (including age and gender) overall survival (OS) EVI1 positivity hazard ratio (HR) = 2.94, 95% CI = 1.13-7.63, p = 0.027 (Figure 1C).	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('venous tumor thrombi', 'Disease', 'MESH:D020246', (74, 94))	('EVI1', 'Gene', (136, 140))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('positivity', 'Var', (141, 151))	('venous tumor thrombi', 'Phenotype', 'HP:0004936', (74, 94))	('tumors', 'Disease', (63, 69))	('patient', 'Species', '9606', (163, 170))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('venous tumor', 'Phenotype', 'HP:0012721', (74, 86))	('Cox', 'Gene', '1351', (193, 196))	('Cox', 'Gene', (193, 196))	('venous tumor thrombi', 'Disease', (74, 94))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
108863	32012804	While the full-length isoform did not show any significant effects, all three cell lines were considerably less sensitive to everolimus when GFP-EVI1Del190-515 was overexpressed relative to GFP alone, with >25-fold differences in the half-maximal inhibitory concentration (IC50) observed (Figure 3A).	('less', 'NegReg', (107, 111))	('everolimus', 'Chemical', 'MESH:D000068338', (125, 135))	('half-maximal', 'MPA', (234, 246))	('EVI1Del190', 'Chemical', '-', (145, 155))	('GFP-EVI1Del190-515', 'Var', (141, 159))	('sensitive to everolimus', 'MPA', (112, 135))
108864	32012804	Rapalogs are primarily cytostatic instead of cytotoxic and, at the highest everolimus concentration (100 microM) tested for 72 hours, the percentages of cell viability were for the GFP alone and GFP-EVI1Del190-515 conditions, respectively: 786-O, 26% and 21%; A498, 24% and 52%; and ACHN, 26% and 60%.	('ACHN', 'Chemical', '-', (283, 287))	('EVI1Del190', 'Chemical', '-', (199, 209))	('GFP-EVI1Del190-515', 'Var', (195, 213))	('A498', 'Chemical', '-', (260, 264))	('everolimus', 'Chemical', 'MESH:D000068338', (75, 85))	('cell viability', 'CPA', (153, 167))	('786-O', 'Var', (240, 245))
108865	32012804	Molecular analyses showed that overexpression of GFP-EVI1Del190-515 causes a robust increase of basal phospho-Ser235/236-ribosomal S6 protein (pS6) in two of the cell lines (786-O and ACHN; Figure 3B, left panels).	('ACHN', 'Chemical', '-', (184, 188))	('Ser', 'cellular_component', 'GO:0005790', ('110', '113'))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('increase', 'PosReg', (84, 92))	('GFP-EVI1Del190-515', 'Var', (49, 67))	('EVI1Del190', 'Chemical', '-', (53, 63))	('Ser235', 'Chemical', '-', (110, 116))	('overexpression', 'PosReg', (31, 45))
108867	32012804	Therefore, oncogenic EVI1 may be linked to enhanced mTOR signaling in some RCC cell models, which in turn might influence sensitivity to everolimus.	('enhanced', 'PosReg', (43, 51))	('mTOR', 'Gene', (52, 56))	('sensitivity to everolimus', 'MPA', (122, 147))	('mTOR', 'Gene', '2475', (52, 56))	('influence', 'Reg', (112, 121))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('oncogenic', 'Var', (11, 20))	('EVI1', 'Gene', (21, 25))	('everolimus', 'Chemical', 'MESH:D000068338', (137, 147))
108869	32012804	Variant forms at this locus have been associated with lung and kidney function, and cancer risk, including breast and lung cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('associated', 'Reg', (38, 48))	('cancer', 'Disease', (84, 90))	('Variant forms', 'Var', (0, 13))	('breast and lung cancer', 'Disease', 'MESH:D001943', (107, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (123, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('lung', 'Disease', (54, 58))
108870	32012804	Therefore, we analyzed leading variants from these studies (rs1344555, rs16853722, and rs75316749, respectively) to establish their association with progression of metastatic ccRCC treated with everolimus (Supplementary Table S3).	('association', 'Reg', (132, 143))	('rs75316749', 'Mutation', 'rs75316749', (87, 97))	('rs75316749', 'Var', (87, 97))	('everolimus', 'Chemical', 'MESH:D000068338', (194, 204))	('ccRCC', 'Phenotype', 'HP:0006770', (175, 180))	('ccRCC', 'Disease', (175, 180))	('rs1344555', 'Mutation', 'rs1344555', (60, 69))	('rs1344555', 'Var', (60, 69))	('rs16853722', 'Mutation', 'rs16853722', (71, 81))	('ccRCC', 'Disease', 'MESH:C538614', (175, 180))	('rs16853722', 'Var', (71, 81))	('men', 'Species', '9606', (212, 215))
108871	32012804	The rs1344555 variant was significantly associated with progression-free survival (PFS) and OS of everolimus-treated metastatic ccRCC: CC versus CT/TT genotypes PFS, hazard ratio (HR) = 1.96, 95% CI = 1.01-3.81, p = 0.047; and OS HR = 2.09, 95% CI = 1.08-4.08, p = 0.029 (Figure 4A).	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('ccRCC', 'Disease', (128, 133))	('ccRCC', 'Disease', 'MESH:C538614', (128, 133))	('rs1344555', 'Var', (4, 13))	('everolimus', 'Chemical', 'MESH:D000068338', (98, 108))	('rs1344555', 'Mutation', 'rs1344555', (4, 13))	('associated', 'Reg', (40, 50))	('progression-free', 'Disease', (56, 72))
108872	32012804	In this setting, the T allele was associated with a higher probability of disease progression and patient death and, in the original lung study, was associated with inferior organ function.	('patient', 'Species', '9606', (98, 105))	('death', 'Disease', 'MESH:D003643', (106, 111))	('death', 'Disease', (106, 111))	('inferior', 'NegReg', (165, 173))	('T allele', 'Var', (21, 29))	('disease progression', 'CPA', (74, 93))	('organ function', 'CPA', (174, 188))
108873	32012804	A significant association between the genotypes of rs1344555 and the percentage of AKT1-positive metastatic ccRCC cells was revealed (Kruskal-Wallis test p = 0.018; Figure 4B).	('ccRCC', 'Disease', (108, 113))	('ccRCC', 'Disease', 'MESH:C538614', (108, 113))	('AKT1', 'Gene', '207', (83, 87))	('AKT1', 'Gene', (83, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('rs1344555', 'Mutation', 'rs1344555', (51, 60))	('rs1344555', 'Var', (51, 60))
108874	32012804	Notably, a TCGA-genotyped variant correlated with rs1344555, rs11718241 (r2 = 0.94 in European populations), proved to be an expression quantitative locus (eQTL) for EVI1 in the total KIRC cohort and in the CC-e.3 subtype (Figure 4C).	('rs11718241', 'Var', (61, 71))	('rs1344555', 'Var', (50, 59))	('rs11718241', 'Mutation', 'rs11718241', (61, 71))	('rs1344555', 'Mutation', 'rs1344555', (50, 59))
108875	32012804	Based on 1000 Genome Project data, the minor alleles of both variants (T) were correlated, and therefore one increased the risk of progression (rs1344555-T, Figure 4A) while the other was associated with a relatively higher level of expression of EVI1 (rs11718241-T, Figure 4C).	('rs11718241', 'Mutation', 'rs11718241', (253, 263))	('progression', 'MPA', (131, 142))	('expression', 'MPA', (233, 243))	('higher', 'PosReg', (217, 223))	('rs11718241-T', 'Var', (253, 265))	('rs1344555', 'Mutation', 'rs1344555', (144, 153))	('EVI1', 'Protein', (247, 251))	('increased', 'PosReg', (109, 118))	('rs1344555-T', 'Var', (144, 155))
108876	32012804	The rs16853722 variant did not show significant associations, while analyses of rs75316749 raised the possibility of associations with metastatic ccRCC OS, although the number of informative cases was too small for them to be statistically significant.	('ccRCC', 'Disease', 'MESH:C538614', (146, 151))	('rs75316749', 'Var', (80, 90))	('rs16853722', 'Var', (4, 14))	('rs75316749', 'Mutation', 'rs75316749', (80, 90))	('associations', 'Interaction', (117, 129))	('rs16853722', 'Mutation', 'rs16853722', (4, 14))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('ccRCC', 'Disease', (146, 151))
108877	32012804	Five rs75316749 heterozygous (AG) individuals were identified in the metastatic ccRCC cohort, with an estimated HR of 0.30 (log-rank p = 0.039; Figure 4C).	('ccRCC', 'Disease', (80, 85))	('ccRCC', 'Disease', 'MESH:C538614', (80, 85))	('rs75316749', 'Var', (5, 15))	('rs75316749', 'Mutation', 'rs75316749', (5, 15))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))
108878	32012804	In this setting, the minor allele G, which has previously been linked to increased lung and breast cancer risk, may be associated with a lower probability of death.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('lung', 'Disease', (83, 87))	('lower', 'NegReg', (137, 142))	('death', 'Disease', 'MESH:D003643', (158, 163))	('death', 'Disease', (158, 163))	('minor', 'Var', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
108879	32012804	This study proposes that evaluation of EVI1 protein or gene expression, and of specific EVI1 genetic variants, may help improve estimates of prognosis and of benefit from everolimus-based therapy in ccRCC.	('EVI1', 'Gene', (88, 92))	('gene expression', 'biological_process', 'GO:0010467', ('55', '70'))	('ccRCC', 'Phenotype', 'HP:0006770', (199, 204))	('ccRCC', 'Disease', (199, 204))	('variants', 'Var', (101, 109))	('everolimus', 'Chemical', 'MESH:D000068338', (171, 181))	('ccRCC', 'Disease', 'MESH:C538614', (199, 204))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('benefit', 'PosReg', (158, 165))
108883	32012804	The influence of common genetic variation on everolimus-based therapy is based on the results of variants previously associated with lung function and with pleiotropy, including cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('associated', 'Reg', (117, 127))	('lung function', 'Disease', (133, 146))	('variants', 'Var', (97, 105))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('everolimus', 'Chemical', 'MESH:D000068338', (45, 55))
108884	32012804	Thus, the depicted genetic variants could also be relevant for predicting progression and/or therapeutic response in other cancer settings.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('variants', 'Var', (27, 35))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))
108888	32012804	We may speculate that oncogenic EVI1 in ccRCC is linked to the acquisition of stem cell-like and/or EMT features, as described in other cancer types.	('EVI1', 'Gene', (32, 36))	('oncogenic', 'Var', (22, 31))	('EMT', 'Gene', (100, 103))	('EMT', 'Gene', '3702', (100, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('ccRCC', 'Disease', (40, 45))	('stem cell-like and/or', 'CPA', (78, 99))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('ccRCC', 'Disease', 'MESH:C538614', (40, 45))	('cancer', 'Disease', (136, 142))	('EMT', 'biological_process', 'GO:0001837', ('100', '103'))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
108891	32012804	Collectively, the prognostic and therapeutic predictive associations indicate that targeting EVI1 could improve the cure of advanced ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('ccRCC', 'Disease', (133, 138))	('cure', 'CPA', (116, 120))	('ccRCC', 'Disease', 'MESH:C538614', (133, 138))	('improve', 'PosReg', (104, 111))	('targeting', 'Var', (83, 92))	('EVI1', 'Gene', (93, 97))
108900	32012804	The cohort of patients genotyped for selected genetic variants corresponded to a prospective, single-arm phase II study of metastatic RCC (93.1% ccRCC) treated with everolimus (Supplementary Table S3).	('ccRCC', 'Disease', 'MESH:C538614', (145, 150))	('patients', 'Species', '9606', (14, 22))	('men', 'Species', '9606', (183, 186))	('ccRCC', 'Phenotype', 'HP:0006770', (145, 150))	('RCC', 'Disease', (147, 150))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('RCC', 'Disease', (134, 137))	('variants', 'Var', (54, 62))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('ccRCC', 'Disease', (145, 150))	('everolimus', 'Chemical', 'MESH:D000068338', (165, 175))
108921	32012804	The antibodies were anti-total and anti-phospho-Ser473 AKT1 (#9272 and #9271, respectively, Cell Signaling Technology, Danvers, MA, USA), anti-total and anti-phospho-Ser235/236-ribosomal S6 protein (#SC-74459, Santa Cruz Biotechnology, Dallas, TX, USA; and #4858, Cell Signaling Technology, respectively), and anti-VCL (V9131, Sigma-Aldrich).	('Ser235', 'Chemical', '-', (166, 172))	('Ser', 'cellular_component', 'GO:0005790', ('48', '51'))	('AKT1', 'Gene', '207', (55, 59))	('anti-phospho-Ser473', 'Var', (35, 54))	('anti-total', 'Var', (138, 148))	('protein', 'cellular_component', 'GO:0003675', ('190', '197'))	('V9131', 'CellLine', 'CVCL:U048;-0.08620743054117545', (320, 325))	('Signaling', 'biological_process', 'GO:0023052', ('269', '278'))	('AKT1', 'Gene', (55, 59))	('VCL', 'Gene', (315, 318))	('anti-phospho-Ser235/236-ribosomal', 'Var', (153, 186))	('VCL', 'Gene', '7414', (315, 318))	('Ser', 'cellular_component', 'GO:0005790', ('166', '169'))	('Ser473', 'Chemical', '-', (48, 54))	('Signaling', 'biological_process', 'GO:0023052', ('97', '106'))
108924	32012804	Determination of EVI1 protein or gene expression, and of defined EVI1 genetic variants could improve estimates of ccRCC patient outcome and benefit from everolimus in the clinical scenario.	('ccRCC', 'Disease', (114, 119))	('benefit', 'PosReg', (140, 147))	('ccRCC', 'Disease', 'MESH:C538614', (114, 119))	('everolimus', 'Chemical', 'MESH:D000068338', (153, 163))	('patient', 'Species', '9606', (120, 127))	('gene expression', 'biological_process', 'GO:0010467', ('33', '48'))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('EVI1', 'Gene', (65, 69))	('improve', 'PosReg', (93, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('variants', 'Var', (78, 86))
108981	28594929	Anti-CD31 (ab28364, Abcam, Cambridge, UK) and anti-Ki67 (ab15580, Abcam, Cambridge, UK) rabbit polyclonal antibodies were used following the manufacturer's protocol.	('ab28364', 'Var', (11, 18))	('rabbit', 'Species', '9986', (88, 94))	('Ki67', 'Gene', (51, 55))	('Ki67', 'Gene', '17345', (51, 55))
108983	28594929	Six fields from each sample avoiding necrotic areas at x20 magnification for CD31+ and x40 magnification for the Ki67 were used for the analysis.	('necrotic', 'Disease', 'MESH:D009336', (37, 45))	('CD31+', 'Var', (77, 82))	('Ki67', 'Gene', (113, 117))	('x40 magnification', 'Var', (87, 104))	('Ki67', 'Gene', '17345', (113, 117))	('necrotic', 'Disease', (37, 45))
109043	32280238	Artificial modulation of PCK1 (down- and upregulation) in two ccRCC cell lines was performed to explore the role of PCK1 in the glycolytic phenotype and in tumor growth and metastasis in vitro and in vivo.	('modulation', 'Var', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('RCC', 'Disease', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('PCK1', 'Gene', (25, 29))	('tumor', 'Disease', (156, 161))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('upregulation', 'PosReg', (41, 53))
109049	32280238	Clinically, low levels of PCK1 expression were associated with poor prognosis in patients with ccRCC.	('RCC', 'Disease', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('PCK1', 'Gene', (26, 30))	('patients', 'Species', '9606', (81, 89))	('expression', 'MPA', (31, 41))	('low levels', 'Var', (12, 22))
109051	32280238	We also demonstrated that PCK1 reduces the stability of LDHA through posttranslational regulation.	('reduces', 'NegReg', (31, 38))	('LDHA', 'Gene', (56, 60))	('LDHA', 'Gene', '3939', (56, 60))	('PCK1', 'Var', (26, 30))	('regulation', 'biological_process', 'GO:0065007', ('87', '97'))	('stability', 'MPA', (43, 52))
109071	32280238	Furthermore, low levels of PCK1 expression are associated with poor prognosis in patients with HCC.	('low levels', 'Var', (13, 23))	('HCC', 'Disease', (95, 98))	('HCC', 'Phenotype', 'HP:0001402', (95, 98))	('patients', 'Species', '9606', (81, 89))	('PCK1', 'Gene', (27, 31))	('expression', 'MPA', (32, 42))
109077	32280238	The dysregulation of LDHA is found in many types of cancer, including gastric cancer, ccRCC, colorectal cancer, non-small-cell lung cancer, and breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('LDHA', 'Gene', '3939', (21, 25))	('breast cancer', 'Disease', (144, 157))	('dysregulation', 'Var', (4, 17))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('non-small-cell lung cancer', 'Disease', (112, 138))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (112, 138))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('gastric cancer', 'Disease', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (151, 157))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (116, 138))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('LDHA', 'Gene', (21, 25))	('gastric cancer', 'Disease', 'MESH:D013274', (70, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (78, 84))	('RCC', 'Disease', (88, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('colorectal cancer', 'Disease', (93, 110))	('cancer', 'Disease', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (112, 138))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('found', 'Reg', (29, 34))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('gastric cancer', 'Phenotype', 'HP:0012126', (70, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
109079	32280238	Genetic and pharmacological inhibition of LDHA has been shown to cause cancer cell death and significantly suppress tumor metastasis.	('suppress', 'NegReg', (107, 115))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('LDHA', 'Gene', (42, 46))	('LDHA', 'Gene', '3939', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('inhibition', 'Var', (28, 38))	('death', 'Disease', 'MESH:D003643', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cause', 'PosReg', (65, 70))	('death', 'Disease', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cell death', 'biological_process', 'GO:0008219', ('78', '88'))	('tumor', 'Disease', (116, 121))
109087	32280238	Our data indicate that PCK1 is detrimental to ccRCC cells and suggest that activating PCK1 expression is a potential treatment strategy for patients with ccRCC.	('PCK1', 'Gene', (86, 90))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('ccRCC', 'Phenotype', 'HP:0006770', (154, 159))	('RCC', 'Disease', (156, 159))	('patients', 'Species', '9606', (140, 148))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('activating', 'Var', (75, 85))	('RCC', 'Disease', (48, 51))
109091	32280238	The shRNA-mediated knockdown of PCK1, LDHA and LAMP2A in ccRCC cells was accomplished using the targeted sequences provided in Supplementary Table 1.	('LDHA', 'Gene', (38, 42))	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('PCK1', 'Gene', (32, 36))	('LDHA', 'Gene', '3939', (38, 42))	('knockdown', 'Var', (19, 28))	('LAMP2A', 'Gene', (47, 53))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))
109096	32280238	To analyze endogenous protein-protein interactions, whole lysates were incubated with antibodies against PCK1 or LDHA and 15 muL of protein A/G agarose (Pierce, USA) overnight at 4 C. Then, the resulting samples were washed with IP buffer three times and analyzed by Western blotting.	('PCK1', 'Gene', (105, 109))	('LDHA', 'Gene', (113, 117))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('agarose', 'Chemical', 'MESH:D012685', (144, 151))	('muL', 'Gene', '4591', (125, 128))	('antibodies', 'Var', (86, 96))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('LDHA', 'Gene', '3939', (113, 117))	('muL', 'Gene', (125, 128))
109124	32280238	The final scores for PCK1 or LDHA in those ccRCC tissues were on a scale from 0 to 9, in which a score <=3 was defined as representing a low expression level and a score >3 represented a high expression level.	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('to 9', 'Species', '1214577', (80, 84))	('expression level', 'MPA', (141, 157))	('score <=3', 'Var', (97, 106))	('LDHA', 'Gene', (29, 33))	('PCK1', 'Gene', (21, 25))	('LDHA', 'Gene', '3939', (29, 33))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))
109134	32280238	To investigate the functional significance of PCK1 in ccRCC progression, we stably knocked down PCK1 in two ccRCC cell lines, 769-P and Caki-1 (Figure 1A).	('RCC', 'Disease', (110, 113))	('RCC', 'Disease', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('Caki-1', 'CellLine', 'CVCL:0234', (136, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('PCK1', 'Gene', (96, 100))	('knocked', 'Var', (83, 90))
109142	32280238	We observed that glucose uptake was apparently upregulated in the absence of PCK1 but significantly downregulated when PCK1 was overexpressed in 769-P and Caki-1 cells (Figure 2B).	('Caki-1', 'CellLine', 'CVCL:0234', (155, 161))	('glucose uptake', 'CPA', (17, 31))	('glucose uptake', 'biological_process', 'GO:0046323', ('17', '31'))	('upregulated', 'PosReg', (47, 58))	('PCK1', 'Gene', (77, 81))	('PCK1', 'Gene', (119, 123))	('overexpressed', 'PosReg', (128, 141))	('downregulated', 'NegReg', (100, 113))	('absence', 'Var', (66, 73))	('glucose', 'Chemical', 'MESH:D005947', (17, 24))
109144	32280238	We found that lactate production was increased by the stable knockdown of PCK1 in both ccRCC cell lines.	('lactate production', 'MPA', (14, 32))	('PCK1', 'Gene', (74, 78))	('RCC', 'Disease', (89, 92))	('knockdown', 'Var', (61, 70))	('increased', 'PosReg', (37, 46))	('lactate', 'Chemical', 'MESH:D019344', (14, 21))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))
109147	32280238	Compared with the control ccRCC cells, the shPCK1 cells demonstrated an increased ECAR and decreased OCR, and these findings were supported by the results of overexpressing PCK1 (Supplementary Figure 3 and Figure 2D-F).	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('increased', 'PosReg', (72, 81))	('OCR', 'MPA', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (26, 31))	('PCK1', 'Gene', (173, 177))	('RCC', 'Disease', (28, 31))	('ECAR', 'MPA', (82, 86))	('overexpressing', 'Var', (158, 172))	('decreased', 'NegReg', (91, 100))
109150	32280238	The proportion of 6-14CO2 in the total CO2 released was reduced in 769-P and Caki-1 cells with stably silenced PCK1 but increased in the ccRCC cells overexpressing PCK1 (Figure 2G).	('PCK1', 'Gene', (111, 115))	('CO2 released', 'MPA', (39, 51))	('proportion', 'MPA', (4, 14))	('CO2', 'Chemical', 'MESH:D002245', (39, 42))	('reduced', 'NegReg', (56, 63))	('Caki-1', 'CellLine', 'CVCL:0234', (77, 83))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('RCC', 'Disease', (139, 142))	('PCK1', 'Var', (164, 168))	('increased', 'PosReg', (120, 129))	('14CO2', 'Chemical', '-', (20, 25))	('CO2', 'Chemical', 'MESH:D002245', (22, 25))
109151	32280238	Altogether, these results provide evidence that PCK1 shunts glucose from glycolysis to oxidative phosphorylation metabolism, which is the opposite of what occurs in the Warburg effect.	('metabolism', 'biological_process', 'GO:0008152', ('113', '123'))	('oxidative phosphorylation metabolism', 'MPA', (87, 123))	('glycolysis', 'MPA', (73, 83))	('glucose', 'MPA', (60, 67))	('glucose', 'Chemical', 'MESH:D005947', (60, 67))	('shunts', 'Reg', (53, 59))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('87', '112'))	('glycolysis', 'biological_process', 'GO:0006096', ('73', '83'))	('PCK1', 'Var', (48, 52))
109157	32280238	However, when PCK1 was re-expressed in shPCK1 Caki-1 cells, the growth advantage was eliminated (Figure 3C-E).	('Caki-1', 'CellLine', 'CVCL:0234', (46, 52))	('eliminated', 'NegReg', (85, 95))	('growth advantage', 'CPA', (64, 80))	('PCK1', 'Gene', (14, 18))	('re-expressed', 'Var', (23, 35))	('shPCK1', 'Gene', (39, 45))
109158	32280238	Lactate production analysis of the tumor masses further confirmed that PCK1 knockdown increased lactate production (Figure 3F).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('lactate production', 'MPA', (96, 114))	('increased', 'PosReg', (86, 95))	('knockdown', 'Var', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('Lactate', 'Chemical', 'MESH:D019344', (0, 7))	('PCK1', 'Gene', (71, 75))	('tumor', 'Disease', (35, 40))	('lactate', 'Chemical', 'MESH:D019344', (96, 103))	('increased lactate production', 'Phenotype', 'HP:0003128', (86, 114))
109161	32280238	Together, these results indicate that silencing PCK1 in ccRCC cell lines promotes glycolysis and tumor growth both in vivo and in vitro.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('glycolysis', 'MPA', (82, 92))	('PCK1', 'Gene', (48, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('RCC', 'Disease', (58, 61))	('glycolysis', 'biological_process', 'GO:0006096', ('82', '92'))	('promotes', 'PosReg', (73, 81))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('silencing', 'Var', (38, 47))
109175	32280238	PCK1 knockdown stably increased LDHA protein levels (Figure 5A).	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('knockdown', 'Var', (5, 14))	('increased', 'PosReg', (22, 31))	('LDHA', 'Gene', (32, 36))	('PCK1', 'Gene', (0, 4))	('LDHA', 'Gene', '3939', (32, 36))
109176	32280238	Although the abundance of LDHA proteins can be regulated by multiple mechanisms, including transcriptional and posttranslational modifications, the effect of PCK1 overexpression on LDHA levels likely occurred through a posttranscriptional mechanism because there was no increase in LDHA mRNA level after PCK1 knockdown (Figure 5B).	('LDHA', 'Gene', (181, 185))	('LDHA', 'Gene', '3939', (181, 185))	('PCK1', 'Gene', (304, 308))	('LDHA', 'Gene', (282, 286))	('LDHA', 'Gene', '3939', (282, 286))	('LDHA', 'Gene', (26, 30))	('knockdown', 'Var', (309, 318))	('LDHA', 'Gene', '3939', (26, 30))
109178	32280238	However, PCK1 had no effect on the mRNA levels of LDHA (Figure 5C and D, and Supplementary Figure 5A and B).	('mRNA levels', 'MPA', (35, 46))	('PCK1', 'Var', (9, 13))	('LDHA', 'Gene', '3939', (50, 54))	('LDHA', 'Gene', (50, 54))
109182	32280238	We treated cells with leupeptin, a lysosomal protease inhibitor that can block lysosome-dependent protein degradation, and found that leupeptin caused a significant accumulation of LDH-A proteins, confirming the involvement of lysosomes in LDHA degradation in Caki-1 cells (Figure 5G).	('protein degradation', 'biological_process', 'GO:0030163', ('98', '117'))	('leupeptin', 'Var', (134, 143))	('LDHA', 'Gene', (240, 244))	('leupeptin', 'Chemical', 'MESH:C032854', (22, 31))	('leupeptin', 'Chemical', 'MESH:C032854', (134, 143))	('accumulation', 'PosReg', (165, 177))	('degradation', 'biological_process', 'GO:0009056', ('245', '256'))	('LDHA', 'Gene', '3939', (240, 244))	('Caki-1', 'CellLine', 'CVCL:0234', (260, 266))	('lysosome', 'cellular_component', 'GO:0005764', ('79', '87'))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('LDH-A', 'Gene', '3939', (181, 186))	('LDH-A', 'Gene', (181, 186))
109183	32280238	We found that silencing LAMP2A significantly increased the LDHA protein level (Figure 5H).	('silencing', 'Var', (14, 23))	('LDHA', 'Gene', (59, 63))	('LDHA', 'Gene', '3939', (59, 63))	('increased', 'PosReg', (45, 54))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('LAMP2A', 'Gene', (24, 30))
109184	32280238	Moreover, silencing LAMP2A also blocked the reduction in the LDHA protein level caused by PCK1 overexpression (Figure 5H).	('LDHA', 'Gene', '3939', (61, 65))	('blocked', 'NegReg', (32, 39))	('overexpression', 'PosReg', (95, 109))	('reduction', 'NegReg', (44, 53))	('LAMP2A', 'Gene', (20, 26))	('silencing', 'Var', (10, 19))	('LDHA', 'Gene', (61, 65))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('PCK1', 'Gene', (90, 94))
109188	32280238	LDHA activity is essential to maintaining a high glycolysis rate by regenerating NAD+, which is required in the early steps of glycolysis.	('LDHA', 'Gene', (0, 4))	('glycolysis', 'biological_process', 'GO:0006096', ('127', '137'))	('NAD+', 'Chemical', 'MESH:D009243', (81, 85))	('LDHA', 'Gene', '3939', (0, 4))	('regenerating', 'Var', (68, 80))	('glycolysis', 'biological_process', 'GO:0006096', ('49', '59'))	('glycolysis rate', 'MPA', (49, 64))	('NAD+', 'MPA', (81, 85))
109196	32280238	Furthermore, LDHA knockdown abolished the ability of PCK1 to regulate cancer cell proliferation, migration, and invasion (Figure 6H-K).	('knockdown', 'Var', (18, 27))	('LDHA', 'Gene', '3939', (13, 17))	('cell proliferation', 'biological_process', 'GO:0008283', ('77', '95'))	('migration', 'CPA', (97, 106))	('abolished', 'NegReg', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('PCK1', 'Gene', (53, 57))	('invasion', 'CPA', (112, 120))	('LDHA', 'Gene', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (70, 76))
109242	31652459	Its aberrant expression generally correlates with clinicopathological characterization of patients.	('patients', 'Species', '9606', (90, 98))	('aberrant', 'Var', (4, 12))	('correlates', 'Reg', (34, 44))
109248	31652459	Moreover, 1762450 new cancer cases and 606880 cancer deaths are expected in 2019 in the United States.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('1762450', 'Var', (10, 17))	('cancer', 'Disease', (46, 52))	('cancer deaths', 'Disease', 'MESH:D003643', (46, 59))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer deaths', 'Disease', (46, 59))
109263	31652459	TP73-AS1 was found to be down-regulated in oligodendroglioma; its low levels were related to an 1p/19q co-deletion and to tumor location.	('oligodendroglioma', 'Disease', 'MESH:D009837', (43, 60))	('TP73-AS1', 'Gene', '57212', (0, 8))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('down-regulated', 'NegReg', (25, 39))	('1p/19q co-deletion', 'Var', (96, 114))	('oligodendroglioma', 'Disease', (43, 60))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('TP73-AS1', 'Gene', (0, 8))	('tumor', 'Disease', (122, 127))
109264	31652459	This implies that both the loss of chromosome 1p and epigenetic modifications were the main mechanisms leading to TP73-AS1 down-regulation.	('regulation', 'biological_process', 'GO:0065007', ('128', '138'))	('TP73-AS1', 'Gene', (114, 122))	('chromosome', 'cellular_component', 'GO:0005694', ('35', '45'))	('down-regulation', 'NegReg', (123, 138))	('epigenetic modifications', 'Var', (53, 77))	('TP73-AS1', 'Gene', '57212', (114, 122))
109266	31652459	showed that the expression of TP73-AS1 was up-regulated in glioma tissue samples and that knocking down TP73-AS1 could suppress glioma cell proliferation and invasion.	('TP73-AS1', 'Gene', '57212', (104, 112))	('glioma', 'Disease', (59, 65))	('glioma', 'Disease', (128, 134))	('cell proliferation', 'biological_process', 'GO:0008283', ('135', '153'))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('knocking down', 'Var', (90, 103))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('TP73-AS1', 'Gene', (30, 38))	('TP73-AS1', 'Gene', '57212', (30, 38))	('suppress', 'NegReg', (119, 127))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('invasion', 'CPA', (158, 166))	('glioma cell proliferation', 'Disease', 'MESH:D005910', (128, 153))	('up-regulated', 'PosReg', (43, 55))	('TP73-AS1', 'Gene', (104, 112))	('expression', 'MPA', (16, 26))	('glioma cell proliferation', 'Disease', (128, 153))
109269	31652459	Silencing of TP73-AS1 inhibited glioma cell proliferation, invasion and high mobility group box 1 protein (HMGB1) protein expression.	('glioma cell proliferation', 'Disease', 'MESH:D005910', (32, 57))	('inhibited', 'NegReg', (22, 31))	('glioma cell proliferation', 'Disease', (32, 57))	('TP73-AS1', 'Gene', (13, 21))	('protein', 'Protein', (114, 121))	('HMGB1', 'Gene', (107, 112))	('HMGB1', 'Gene', '3146', (107, 112))	('TP73-AS1', 'Gene', '57212', (13, 21))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('invasion', 'CPA', (59, 67))	('high mobility group box 1', 'Gene', (72, 97))	('Silencing', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (32, 38))	('high mobility group box 1', 'Gene', '3146', (72, 97))
109273	31652459	Silencing of TP73-AS1 induced ESCC apoptosis and inhibited proliferation, whereas overexpression of BDH2 could reverse this process via the caspase-3 pathway.	('BDH2', 'Gene', (100, 104))	('proliferation', 'CPA', (59, 72))	('BDH2', 'Gene', '56898', (100, 104))	('caspase-3', 'Gene', '836', (140, 149))	('apoptosis', 'biological_process', 'GO:0097194', ('35', '44'))	('apoptosis', 'biological_process', 'GO:0006915', ('35', '44'))	('TP73-AS1', 'Gene', (13, 21))	('TP73-AS1', 'Gene', '57212', (13, 21))	('ESCC', 'Disease', (30, 34))	('caspase-3', 'Gene', (140, 149))	('Silencing', 'Var', (0, 9))	('inhibited', 'NegReg', (49, 58))	('ESCC', 'Disease', 'MESH:C562729', (30, 34))
109274	31652459	Moreover, it was confirmed that silencing of TP73-AS1 reduced the average tumor size in mice.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('silencing', 'Var', (32, 41))	('TP73-AS1', 'Gene', (45, 53))	('reduced', 'NegReg', (54, 61))	('tumor', 'Disease', (74, 79))	('TP73-AS1', 'Gene', '57212', (45, 53))	('mice', 'Species', '10090', (88, 92))
109275	31652459	In addition, knocking down TP73-AS1 or BDH2 increased the chemosensitivity of ESCC to cisplatin and 5-FU.	('knocking down', 'Var', (13, 26))	('ESCC', 'Disease', (78, 82))	('5-FU', 'Chemical', 'MESH:D005472', (100, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('ESCC', 'Disease', 'MESH:C562729', (78, 82))	('BDH2', 'Gene', (39, 43))	('TP73-AS1', 'Gene', (27, 35))	('TP73-AS1', 'Gene', '57212', (27, 35))	('BDH2', 'Gene', '56898', (39, 43))	('increased', 'PosReg', (44, 53))	('chemosensitivity', 'MPA', (58, 74))
109278	31652459	Additionally, silencing of TP73-AS1 inhibited HCC cell proliferation.	('silencing', 'Var', (14, 23))	('HCC', 'Disease', (46, 49))	('inhibited', 'NegReg', (36, 45))	('HCC', 'Phenotype', 'HP:0001402', (46, 49))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('TP73-AS1', 'Gene', '57212', (27, 35))	('TP73-AS1', 'Gene', (27, 35))	('HCC', 'Disease', 'MESH:D006528', (46, 49))
109282	31652459	Furthermore, knocking down TP73-AS1 markedly depresses CRC cell proliferation, migration, and invasion in vitro as well as tumor growth in vivo.	('invasion', 'CPA', (94, 102))	('knocking down', 'Var', (13, 26))	('migration', 'CPA', (79, 88))	('tumor', 'Disease', (123, 128))	('CRC', 'Phenotype', 'HP:0003003', (55, 58))	('CRC', 'Disease', 'MESH:D015179', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('depresses', 'NegReg', (45, 54))	('TP73-AS1', 'Gene', (27, 35))	('TP73-AS1', 'Gene', '57212', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('CRC', 'Disease', (55, 58))
109289	31652459	Moreover, a knockdown mutation of TP73-AS1 suppressed cell survival, migration, and invasion, inducing cell cycle arrest in osteosarcoma in vitro.	('invasion', 'CPA', (84, 92))	('mutation', 'Var', (22, 30))	('cell cycle arrest', 'CPA', (103, 120))	('osteosarcoma', 'Disease', (124, 136))	('osteosarcoma', 'Phenotype', 'HP:0002669', (124, 136))	('osteosarcoma', 'Disease', 'MESH:D012516', (124, 136))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('103', '120'))	('inducing', 'Reg', (94, 102))	('TP73-AS1', 'Gene', '57212', (34, 42))	('cell survival', 'CPA', (54, 67))	('TP73-AS1', 'Gene', (34, 42))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (103, 120))	('migration', 'CPA', (69, 78))	('suppressed', 'NegReg', (43, 53))
109290	31652459	Mechanistically, TP73-AS1 silencing depressed osteosarcoma tumor growth in vivo as well as cell proliferation and invasion in vitro via regulating the miR-142/Ras-related C3 toxin substrate 1 (Rac1) pathway.	('Rac1', 'Gene', (193, 197))	('miR-142', 'Gene', (151, 158))	('regulating', 'Reg', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('depressed osteosarcoma tumor', 'Disease', (36, 64))	('TP73-AS1', 'Gene', (17, 25))	('TP73-AS1', 'Gene', '57212', (17, 25))	('depressed osteosarcoma tumor', 'Disease', 'MESH:D003866', (36, 64))	('Rac1', 'Gene', '5879', (193, 197))	('osteosarcoma', 'Phenotype', 'HP:0002669', (46, 58))	('silencing', 'Var', (26, 35))	('cell proliferation', 'biological_process', 'GO:0008283', ('91', '109'))	('invasion', 'CPA', (114, 122))	('cell proliferation', 'CPA', (91, 109))	('miR-142', 'Gene', '406934', (151, 158))
109298	31652459	Moreover, a TP73-AS1 knockdown suppressed cell proliferation and invasion, and facilitated apoptosis, whereas overexpression of TP73-AS1 reversed this progression.	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('TP73-AS1', 'Gene', (12, 20))	('TP73-AS1', 'Gene', '57212', (128, 136))	('apoptosis', 'CPA', (91, 100))	('TP73-AS1', 'Gene', '57212', (12, 20))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('cell proliferation', 'CPA', (42, 60))	('cell proliferation', 'biological_process', 'GO:0008283', ('42', '60'))	('suppressed', 'NegReg', (31, 41))	('invasion', 'CPA', (65, 73))	('knockdown', 'Var', (21, 30))	('facilitated', 'PosReg', (79, 90))	('TP73-AS1', 'Gene', (128, 136))
109301	31652459	Both in breast cancer (BC) tissue samples and cell lines, TP73-AS1 has been found to be up-regulated and this overexpression has been related to several BC clinicopathologic characterizations, such as TNM stage, tumor size, lymph node metastasis, and oOS In contrast, TP73-AS1 silencing suppressed vasculogenic mimicry, invasion, migration, and inhibited BC cell proliferation.	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('BC', 'Disease', 'MESH:D001943', (153, 155))	('suppressed', 'NegReg', (287, 297))	('silencing', 'Var', (277, 286))	('cell proliferation', 'biological_process', 'GO:0008283', ('358', '376'))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('vasculogenic mimicry', 'CPA', (298, 318))	('TP73-AS1', 'Gene', '57212', (58, 66))	('breast cancer', 'Disease', (8, 21))	('inhibited', 'NegReg', (345, 354))	('BC', 'Phenotype', 'HP:0003002', (153, 155))	('invasion', 'CPA', (320, 328))	('TP73-AS1', 'Gene', (58, 66))	('BC', 'Disease', 'MESH:D001943', (355, 357))	('migration', 'CPA', (330, 339))	('BC', 'Disease', 'MESH:D001943', (23, 25))	('BC', 'Phenotype', 'HP:0003002', (355, 357))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Disease', (212, 217))	('TP73-AS1', 'Gene', '57212', (268, 276))	('BC', 'Phenotype', 'HP:0003002', (23, 25))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('up-regulated', 'PosReg', (88, 100))	('TP73-AS1', 'Gene', (268, 276))
109302	31652459	Mechanistically, it was shown that several pathways participate in those biological functions altered after the knockdown of TP73-AS1.	('TP73-AS1', 'Gene', '57212', (125, 133))	('knockdown', 'Var', (112, 121))	('TP73-AS1', 'Gene', (125, 133))
109310	31652459	Silencing of TP73-AS1 inhibited cell proliferation, migration, and invasion, while overexpression stimulated progression in vitro.	('cell proliferation', 'biological_process', 'GO:0008283', ('32', '50'))	('inhibited', 'NegReg', (22, 31))	('migration', 'CPA', (52, 61))	('invasion', 'CPA', (67, 75))	('TP73-AS1', 'Gene', (13, 21))	('TP73-AS1', 'Gene', '57212', (13, 21))	('Silencing', 'Var', (0, 9))	('cell proliferation', 'CPA', (32, 50))
109311	31652459	Furthermore, the knockdown of the TP73-AS1 gene depressed tumor growth in mice.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('depressed tumor', 'Disease', (48, 63))	('TP73-AS1', 'Gene', '57212', (34, 42))	('knockdown', 'Var', (17, 26))	('TP73-AS1', 'Gene', (34, 42))	('mice', 'Species', '10090', (74, 78))	('depressed tumor', 'Disease', 'MESH:D003866', (48, 63))
109315	31652459	Meanwhile, a knockdown mutation of the TP73-AS1 gene inhibited tumor growth both in vitro and in vivo.	('tumor', 'Disease', (63, 68))	('knockdown mutation', 'Var', (13, 31))	('inhibited', 'NegReg', (53, 62))	('TP73-AS1', 'Gene', (39, 47))	('TP73-AS1', 'Gene', '57212', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
109316	31652459	In addition, knocking down TP73-AS1 promoted apoptosis through the activation of the caspase-3 and caspase-9 pathways.	('knocking down', 'Var', (13, 26))	('caspase-9', 'Gene', '842', (99, 108))	('caspase-3', 'Gene', (85, 94))	('TP73-AS1', 'Gene', (27, 35))	('caspase-9', 'Gene', (99, 108))	('TP73-AS1', 'Gene', '57212', (27, 35))	('apoptosis', 'CPA', (45, 54))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('promoted', 'PosReg', (36, 44))	('caspase-3', 'Gene', '836', (85, 94))
109323	31652459	Moreover, silencing TP73-AS1 depressed LAD tumor growth and metastasis in vivo.	('LAD', 'Phenotype', 'HP:0030078', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('depressed', 'NegReg', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('LAD', 'Disease', (39, 42))	('TP73-AS1', 'Gene', '57212', (20, 28))	('TP73-AS1', 'Gene', (20, 28))	('tumor', 'Disease', (43, 48))	('LAD', 'Disease', 'MESH:C538231', (39, 42))	('silencing', 'Var', (10, 19))
109324	31652459	Mechanistically, the molecular pathway TP73-AS1/miR-449a/enhancer of zeste homolog 2 (EZH2) promotes NSCLC tumorigenesis via epigenetic modulation, whereas TP73-AS1 promotes the progression of LAD through the activation of the PI3K/AKT signaling pathway.	('AKT', 'Gene', '207', (232, 235))	('TP73-AS1', 'Gene', (156, 164))	('LAD', 'Phenotype', 'HP:0030078', (193, 196))	('tumor', 'Disease', (107, 112))	('AKT signaling', 'biological_process', 'GO:0043491', ('232', '245'))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('PI3K', 'molecular_function', 'GO:0016303', ('227', '231'))	('promotes', 'PosReg', (92, 100))	('NSCLC', 'Disease', (101, 106))	('LAD', 'Disease', (193, 196))	('LAD', 'Disease', 'MESH:C538231', (193, 196))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('miR-449a', 'Gene', (48, 56))	('TP73-AS1', 'Gene', '57212', (39, 47))	('AKT', 'Gene', (232, 235))	('EZH2', 'Gene', '2146', (86, 90))	('EZH2', 'Gene', (86, 90))	('signaling pathway', 'biological_process', 'GO:0007165', ('236', '253'))	('TP73-AS1', 'Gene', '57212', (156, 164))	('epigenetic modulation', 'Var', (125, 146))	('TP73-AS1', 'Gene', (39, 47))	('miR-449a', 'Gene', '554213', (48, 56))
109327	31652459	Silencing of TP73-AS1 suppresses pancreatic cancer migration and invasion.	('suppresses', 'NegReg', (22, 32))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (33, 50))	('TP73-AS1', 'Gene', (13, 21))	('TP73-AS1', 'Gene', '57212', (13, 21))	('pancreatic cancer', 'Disease', (33, 50))	('invasion', 'CPA', (65, 73))	('pancreatic cancer', 'Disease', 'MESH:D010190', (33, 50))	('Silencing', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
109332	31652459	Its abnormal expression is statistically correlated with clinicopathological characteristics of cancer, such as TNM stage, tumor size, lymph node metastasis, and prognosis.	('TNM stage', 'Disease', (112, 121))	('tumor', 'Disease', (123, 128))	('abnormal', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('correlated', 'Reg', (41, 51))	('lymph node', 'Disease', (135, 145))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
109337	31652459	In addition, methylated TP73-AS1 is frequently detected in cancer cell lines of multiple myeloma, but this methylation does not have a significant correlation with tumor pathogenesis and progression.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('methylated', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('multiple myeloma', 'Phenotype', 'HP:0006775', (80, 96))	('multiple myeloma', 'Disease', 'MESH:D009101', (80, 96))	('methylation', 'biological_process', 'GO:0032259', ('107', '118'))	('pathogenesis', 'biological_process', 'GO:0009405', ('170', '182'))	('multiple myeloma', 'Disease', (80, 96))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('detected', 'Reg', (47, 55))	('TP73-AS1', 'Gene', '57212', (24, 32))	('cancer', 'Disease', (59, 65))	('TP73-AS1', 'Gene', (24, 32))
109353	30949398	Moreover, Kaplan-Meier curves associated high VNN3 expression with poor prognoses (TCGA, p < .0001; ICGC, p = .00076), confirming that ccRCC prognosis can be predicted via VNN3 expression patterns.	('high', 'Var', (41, 45))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('expression', 'MPA', (51, 61))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('VNN3', 'Gene', (46, 50))	('RCC', 'Disease', (137, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))
109381	30949398	Notably, patients with low VNN3 expression showed a higher survival rate than those with high VNN3 expression in TCGA (p < .0001; Figure 2(A)) and ICGC (p = .00076; Figure 2(D)).	('patients', 'Species', '9606', (9, 17))	('low', 'Var', (23, 26))	('survival rate', 'CPA', (59, 72))	('expression', 'Var', (32, 42))	('VNN3', 'Gene', (27, 31))	('higher', 'PosReg', (52, 58))
109403	30949398	In this study, we found that high VNN3 expression correlated to a bad ccRCC prognosis based on the mRNA expression database.	('high', 'Var', (29, 33))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('VNN3', 'Gene', (34, 38))	('RCC', 'Disease', (72, 75))	('ccRCC', 'Phenotype', 'HP:0006770', (70, 75))	('expression', 'MPA', (39, 49))
109414	30104738	HIF2A is activated in clear cell renal cell carcinoma (ccRCC) through mutations in the von Hippel-Lindau tumour suppressor gene (VHL), which under normal conditions targets HIF2A for proteosomal degradation.	('HIF2A', 'Gene', '2034', (0, 5))	('VHL', 'Disease', (129, 132))	('mutations', 'Var', (70, 79))	('degradation', 'biological_process', 'GO:0009056', ('195', '206'))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (22, 53))	('HIF2A', 'Gene', (173, 178))	('von Hippel-Lindau tumour', 'Disease', (87, 111))	('clear cell renal cell carcinoma', 'Disease', (22, 53))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (33, 53))	('HIF2A', 'Gene', (0, 5))	('HIF2A', 'Gene', '2034', (173, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (22, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('VHL', 'Disease', 'MESH:D006623', (129, 132))	('von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (87, 111))
109423	30104738	Given that VHL mutations are remarkably specific for ccRCC, this suggested the possibility that high HIF2A mRNA expression levels in ccRCC may modulate the potential at which VHL loss promotes tumorigenesis.	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('ccRCC', 'Disease', (53, 58))	('tumorigenesis', 'CPA', (193, 206))	('HIF2A', 'Gene', (101, 106))	('VHL', 'Disease', (175, 178))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('VHL', 'Disease', 'MESH:D006623', (175, 178))	('VHL', 'Disease', 'MESH:D006623', (11, 14))	('mutations', 'Var', (15, 24))	('VHL', 'Disease', (11, 14))	('HIF2A', 'Gene', '2034', (101, 106))	('mRNA expression levels', 'MPA', (107, 129))	('modulate', 'Reg', (143, 151))	('high', 'PosReg', (96, 100))	('loss', 'NegReg', (179, 183))	('promotes', 'PosReg', (184, 192))
109443	30104738	This confirmed that decreasing levels of mCherry fluorescence selected for an increasing fraction of EGFP positive cells in iHIF2A-1 and iHIF2A-2 transduced cells whereas no changes were observed in cells transduced with the non-targeting sgRNA or iHIF2A-3 (Fig.	('HIF2A', 'Gene', (125, 130))	('HIF2A', 'Gene', (249, 254))	('mCherry fluorescence', 'MPA', (41, 61))	('HIF2A', 'Gene', '2034', (138, 143))	('HIF2A', 'Gene', '2034', (125, 130))	('HIF2A', 'Gene', '2034', (249, 254))	('HIF2A', 'Gene', (138, 143))	('EGFP', 'Gene', (101, 105))	('transduced', 'Var', (146, 156))
109459	30104738	Additionally, varying sensitivity of ccRCC cells to HIF2A inhibition has been attributed to different levels of HIF2A expression as well as acquired mutations in the HIF2A complex.	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('mutations', 'Var', (149, 158))	('HIF2A', 'Gene', (112, 117))	('HIF2A', 'Gene', '2034', (52, 57))	('HIF2A', 'Gene', '2034', (166, 171))	('HIF2A', 'Gene', '2034', (112, 117))	('HIF2A', 'Gene', (166, 171))	('HIF2A', 'Gene', (52, 57))
109465	30104738	ccRCCs often carry mutations in the histone methyltransferase SETD2, which promotes homologous repair.	('ccRCCs', 'Disease', (0, 6))	('promotes', 'PosReg', (75, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('mutations', 'Var', (19, 28))	('SETD2', 'Gene', '29072', (62, 67))	('homologous', 'MPA', (84, 94))	('SETD2', 'Gene', (62, 67))
109472	30104738	The identity of the UOK101 cells has been confirmed by Sanger sequencing-based detection of a previously identified homozygous VHL mutation in June 2018, and STR analysis confirmed that the UOK101 cells had not been cross-contaminated with other commonly used cell lines.	('UOK101', 'CellLine', 'CVCL:B076', (20, 26))	('VHL', 'Disease', 'MESH:D006623', (127, 130))	('VHL', 'Disease', (127, 130))	('UOK101', 'CellLine', 'CVCL:B076', (190, 196))	('mutation', 'Var', (131, 139))
109480	30104738	Lenti-Cas9-EGFP (adapted from Addgene #52962) was used for HIF2A mutagenesis.	('Cas', 'cellular_component', 'GO:0005650', ('6', '9'))	('mutagenesis', 'biological_process', 'GO:0006280', ('65', '76'))	('HIF2A', 'Gene', '2034', (59, 64))	('mutagenesis', 'Var', (65, 76))	('HIF2A', 'Gene', (59, 64))
109482	30104738	qRT-PCR was performed using the StepOnePlus instrument (Thermo) with pre-designed TaqMan gene expression assays (Thermo): EPAS1 (Hs01026149_m1), CXCR4 (Hs00607978_s1), VHL (Hs03046964_s1) and TBP (Hs00427620_m1).	('gene expression', 'biological_process', 'GO:0010467', ('89', '104'))	('TBP', 'Gene', (192, 195))	('EPAS1', 'Gene', '2034', (122, 127))	('TBP', 'Gene', '6908', (192, 195))	('CXCR4', 'Gene', (145, 150))	('VHL', 'Disease', 'MESH:D006623', (168, 171))	('EPAS1', 'Gene', (122, 127))	('VHL', 'Disease', (168, 171))	('CXCR4', 'molecular_function', 'GO:0038147', ('145', '150'))	('pre', 'molecular_function', 'GO:0003904', ('69', '72'))	('Hs01026149_m1', 'Var', (129, 142))	('Hs00607978_s1', 'Var', (152, 165))	('CXCR4', 'Gene', '7852', (145, 150))	('Hs00427620_m1', 'Var', (197, 210))	('Hs03046964_s1', 'Var', (173, 186))
109485	30104738	Primary antibodies for HIF2A (Novus Biologicals NB100-122), FLAG (Sigma #F3165), VHL (BD Biosciences #564183) and beta-actin (Sigma #A1978) were used.	('beta-actin', 'Gene', '728378', (114, 124))	('VHL', 'Disease', (81, 84))	('Sigma', 'Var', (126, 131))	('beta-actin', 'Gene', (114, 124))	('HIF2A', 'Gene', (23, 28))	('HIF2A', 'Gene', '2034', (23, 28))	('VHL', 'Disease', 'MESH:D006623', (81, 84))
109505	31727869	In this study, 10 candidate lncRNAs with diagnostic and prognostic values in ccRCC were identified: IGFL2-AS1, AC023043.1, AP000439.2, AC124854.1, AL355102.4, TMEM246-AS1, AL133467.3, ZNF582-AS1, LINC01510 and PSMG3-AS1.	('AL355102.4', 'Var', (147, 157))	('PSMG3', 'Gene', '84262', (210, 215))	('AS1', 'Gene', '5729', (106, 109))	('AS1', 'Gene', '5729', (216, 219))	('ZNF582', 'Gene', (184, 190))	('AC023043.1', 'Var', (111, 121))	('AS1', 'Gene', '5729', (191, 194))	('ccRCC', 'Disease', 'MESH:D002292', (77, 82))	('AS1', 'Gene', '5729', (167, 170))	('AC124854.1', 'Var', (135, 145))	('ccRCC', 'Disease', (77, 82))	('ZNF582', 'Gene', '147948', (184, 190))	('AS1', 'Gene', (106, 109))	('AS1', 'Gene', (216, 219))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('AP000439.2', 'Var', (123, 133))	('AS1', 'Gene', (191, 194))	('AL133467.3', 'Var', (172, 182))	('PSMG3', 'Gene', (210, 215))	('AS1', 'Gene', (167, 170))
109511	31727869	It is characterized by inactivating mutations in the VHL gene and is associated with a high risk of metastasis and poor response to chemotherapy.	('VHL', 'Disease', (53, 56))	('VHL', 'Disease', 'MESH:D006623', (53, 56))	('associated', 'Reg', (69, 79))	('inactivating mutations', 'Var', (23, 45))	('metastasis', 'CPA', (100, 110))
109518	31727869	Apart from functional effects on tumor progression, lncRNAs also exhibit various modulatory roles through different mechanisms, including translation of protein-coding genes, epigenetic transcriptional modulation, remodeling of and interactions with chromatin, genome defense or RNA turnover.	('interactions', 'Interaction', (232, 244))	('RNA', 'cellular_component', 'GO:0005562', ('279', '282'))	('nov', 'Gene', (286, 289))	('translation', 'biological_process', 'GO:0006412', ('138', '149'))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('protein', 'cellular_component', 'GO:0003675', ('153', '160'))	('epigenetic transcriptional modulation', 'Var', (175, 212))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('nov', 'Gene', '4856', (286, 289))	('tumor', 'Disease', (33, 38))	('chromatin', 'cellular_component', 'GO:0000785', ('250', '259'))	('translation', 'MPA', (138, 149))
109519	31727869	Based on these findings, dysregulated expression patterns of lncRNAs in cancer development indicate that these lncRNAs may act as potential molecular biomarkers.	('cancer', 'Disease', (72, 78))	('men', 'Species', '9606', (86, 89))	('expression', 'MPA', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('dysregulated', 'Var', (25, 37))
109542	31727869	AC023043.1, AL355102.4 and AL355075.4 were risk factors with a hazard ratio (HR) >1 (Supplementary Tables 7, 13, 15), while AP000439.2, AC124854.1, TMEM246-AS1, AL133467.3, ZNF582-AS1, LINC01510 and PSMG3-AS1 were protective factors with an HR <1 (Supplementary Tables 9, 11, 17, 19, 21, 23, 25).	('AC023043.1', 'Var', (0, 10))	('AS1', 'Gene', '5729', (180, 183))	('AS1', 'Gene', (205, 208))	('PSMG3', 'Gene', (199, 204))	('AS1', 'Gene', (180, 183))	('AS1', 'Gene', (156, 159))	('AC124854.1', 'Var', (136, 146))	('AL355075.4', 'Var', (27, 37))	('ZNF582', 'Gene', (173, 179))	('AS1', 'Gene', '5729', (156, 159))	('AS1', 'Gene', '5729', (205, 208))	('PSMG3', 'Gene', '84262', (199, 204))	('men', 'Species', '9606', (254, 257))	('men', 'Species', '9606', (91, 94))	('ZNF582', 'Gene', '147948', (173, 179))	('AL355102.4', 'Var', (12, 22))	('AP000439.2', 'Var', (124, 134))
109543	31727869	N, M, grade and stage, which were used for primary diagnosis, all exhibited poor prognosis with advanced levels (N1, M1, G3+G4 and S3+S4).	('N1', 'Var', (113, 115))	('S3+S4', 'Var', (131, 136))	('G3+G4', 'Var', (121, 126))	('S3+S4', 'Chemical', 'MESH:D013455', (131, 136))
109546	31727869	Still, IGFL2-AS1, AC023043.1, AL355102.4 and AL355075.4 were identified as risk factors with an HR >1 (Supplementary Tables 6, 8, 14, 16), while AC124854.1, AL133467.3, ZNF582-AS1, LINC01510 and PSMG3-AS1 were identified as protective factors with an HR <1 (Supplementary Tables 12, 20, 22, 24, 26).	('AS1', 'Gene', '5729', (176, 179))	('AS1', 'Gene', (201, 204))	('AS1', 'Gene', (176, 179))	('AL355102.4', 'Var', (30, 40))	('AS1', 'Gene', '5729', (201, 204))	('ZNF582', 'Gene', (169, 175))	('PSMG3', 'Gene', '84262', (195, 200))	('men', 'Species', '9606', (264, 267))	('PSMG3', 'Gene', (195, 200))	('AC023043.1', 'Var', (18, 28))	('AL355075.4', 'Var', (45, 55))	('AS1', 'Gene', '5729', (13, 16))	('AS1', 'Gene', (13, 16))	('men', 'Species', '9606', (109, 112))	('ZNF582', 'Gene', '147948', (169, 175))
109547	31727869	AP000439.2 and TMEM246-AS1, together with age, N, M, grade and stage, constituted prognostic factors in ccRCC, among which AP000439.2 and TMEM246-AS1 exhibited protective values (Supplementary Tables 10, 18).	('ccRCC', 'Disease', 'MESH:D002292', (104, 109))	('men', 'Species', '9606', (185, 188))	('AS1', 'Gene', '5729', (146, 149))	('AS1', 'Gene', (146, 149))	('AP000439.2', 'Var', (123, 133))	('AS1', 'Gene', '5729', (23, 26))	('AS1', 'Gene', (23, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))	('ccRCC', 'Disease', (104, 109))
109550	31727869	As shown in Figures 1C, 1D, 2A, 2B and 2E-2F, and Supplementary Tables 5-8, the IGFL2-AS1 and AC023043.1 genes were upregulated in kidney cancer samples and indicated poor prognosis when highly expressed, which revealed that IGFL2-AS1 and AC023043.1 tended to be risk factors with higher gene expression for Cox HR >1.	('AS1', 'Gene', (231, 234))	('kidney cancer', 'Disease', (131, 144))	('2B', 'Chemical', 'MESH:C023970', (32, 34))	('kidney cancer', 'Disease', 'MESH:D007680', (131, 144))	('AS1', 'Gene', '5729', (231, 234))	('upregulated', 'PosReg', (116, 127))	('Cox HR >1', 'Disease', (308, 317))	('men', 'Species', '9606', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('kidney cancer', 'Phenotype', 'HP:0009726', (131, 144))	('gene expression', 'biological_process', 'GO:0010467', ('288', '303'))	('AC023043.1', 'Gene', (94, 104))	('AS1', 'Gene', '5729', (86, 89))	('AS1', 'Gene', (86, 89))	('AC023043.1', 'Var', (239, 249))
109551	31727869	However, in Figures 1E, 1F, 2C, 2D and 2G-2H, and Supplementary Tables 9-12, the AP000439.2 and AC124854.1 genes were upregulated in kidney cancer samples and indicated good prognosis when highly expressed, which revealed that AP000439.2 and AC124854.1 tended to be protective factors with higher gene expression for a Cox HR <1.	('gene expression', 'biological_process', 'GO:0010467', ('297', '312'))	('kidney cancer', 'Disease', (133, 146))	('higher', 'PosReg', (290, 296))	('AC124854.1', 'Gene', (96, 106))	('men', 'Species', '9606', (56, 59))	('AP000439.2', 'Gene', (81, 91))	('AP000439.2', 'Var', (227, 237))	('kidney cancer', 'Disease', 'MESH:D007680', (133, 146))	('upregulated', 'PosReg', (118, 129))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('kidney cancer', 'Phenotype', 'HP:0009726', (133, 146))	('AC124854.1', 'Var', (242, 252))
109553	31727869	In Figure 1G, 1H, 2I-J and 2P-Q, and Supplementary Tables 13-16, the AL355102.4 and AL355075.4 genes were downregulated in kidney cancer samples and indicated good prognosis when lowly expressed, which revealed that AL355102.4 and AL355075.4 tended to be risk factors with higher gene expression for a Cox HR >1.	('Cox HR >1', 'Disease', (302, 311))	('gene expression', 'biological_process', 'GO:0010467', ('280', '295'))	('higher', 'PosReg', (273, 279))	('kidney cancer', 'Phenotype', 'HP:0009726', (123, 136))	('downregulated', 'NegReg', (106, 119))	('AL355102.4', 'Gene', (69, 79))	('kidney cancer', 'Disease', (123, 136))	('AL355102.4', 'Var', (216, 226))	('men', 'Species', '9606', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('AL355075.4', 'Gene', (84, 94))	('AL355075.4', 'Var', (231, 241))	('kidney cancer', 'Disease', 'MESH:D007680', (123, 136))
109554	31727869	Nevertheless, in Figures 1I-1M, 2K-2O and 2R-2V, and Supplementary Tables 17-26, the TMEM246-AS1, AL133467.3, ZNF582-AS1, LINC01510 and PSMG3-AS1 genes were downregulated in kidney cancer samples and indicated poor prognosis when lowly expressed, which revealed that TMEM246-AS1, AL133467.3, ZNF582-AS1, LINC01510 and PSMG3-AS1 tended to be protective factors with higher gene expression for a Cox HR <1.	('AS1', 'Gene', (142, 145))	('PSMG3', 'Gene', (136, 141))	('AS1', 'Gene', (324, 327))	('ZNF582', 'Gene', '147948', (292, 298))	('ZNF582', 'Gene', '147948', (110, 116))	('AS1', 'Gene', (275, 278))	('gene expression', 'MPA', (372, 387))	('PSMG3', 'Gene', '84262', (318, 323))	('AS1', 'Gene', (299, 302))	('AS1', 'Gene', (117, 120))	('AS1', 'Gene', (93, 96))	('PSMG3', 'Gene', '84262', (136, 141))	('AL133467.3', 'Var', (280, 290))	('gene expression', 'biological_process', 'GO:0010467', ('372', '387'))	('LINC01510', 'Gene', (122, 131))	('AS1', 'Gene', '5729', (142, 145))	('LINC01510', 'Var', (304, 313))	('kidney cancer', 'Disease', 'MESH:D007680', (174, 187))	('AS1', 'Gene', '5729', (324, 327))	('downregulated', 'NegReg', (157, 170))	('ZNF582', 'Gene', (292, 298))	('AS1', 'Gene', '5729', (299, 302))	('2K-2O', 'Chemical', 'MESH:D011188', (32, 37))	('AS1', 'Gene', '5729', (117, 120))	('AS1', 'Gene', '5729', (275, 278))	('kidney cancer', 'Phenotype', 'HP:0009726', (174, 187))	('AS1', 'Gene', '5729', (93, 96))	('ZNF582', 'Gene', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('kidney cancer', 'Disease', (174, 187))	('PSMG3', 'Gene', (318, 323))	('higher', 'PosReg', (365, 371))	('men', 'Species', '9606', (59, 62))
109557	31727869	To visualize and clarify these relationships, we divided patient samples into two subgroups, according to corresponding characteristics (age <=60 vs age >60, female vs male, T1+T2 vs T3+T4, N0 vs N1, M0 vs M1, G1+G2 vs G3+G4, S1+S2 vs S3+S4), which exhibited statistical differences with respect to each lncRNA expression after Pearson's chi 2 test.	('patient', 'Species', '9606', (57, 64))	('S1', 'Chemical', 'MESH:D013455', (226, 228))	('N0 vs N1', 'Var', (190, 198))	('T1+T2 vs T3+T4', 'Var', (174, 188))	('M0 vs M1', 'Var', (200, 208))	('S3+S4', 'Chemical', 'MESH:D013455', (235, 240))	('G1+G2 vs G3+G4', 'Var', (210, 224))	('S1+S2', 'Var', (226, 231))
109571	31727869	That is, in tumor samples with advanced T, N, M, grade, stage and relatively older age, lncRNAs in higher expression levels indicated poor prognosis for ccRCC patients.	('ccRCC', 'Phenotype', 'HP:0006770', (153, 158))	('ccRCC', 'Disease', (153, 158))	('ccRCC', 'Disease', 'MESH:D002292', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('lncRNAs', 'Var', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('patients', 'Species', '9606', (159, 167))
109573	31727869	Among these, AP000439.2 (AUC=0.9169, P<0.0001), AL355102.4 (AUC=0.9318, P<0.0001), ZNF582-AS1 (AUC=0.942, P<0.0001) and PSMG3-AS1 (AUC=0.9181, P<0.0001) exhibited the strongest diagnostic values.	('PSMG3', 'Gene', '84262', (120, 125))	('PSMG3', 'Gene', (120, 125))	('AS1', 'Gene', '5729', (90, 93))	('AL355102.4', 'Var', (48, 58))	('AP000439.2', 'Var', (13, 23))	('AS1', 'Gene', '5729', (126, 129))	('AS1', 'Gene', (126, 129))	('ZNF582', 'Gene', '147948', (83, 89))	('AS1', 'Gene', (90, 93))	('ZNF582', 'Gene', (83, 89))
109574	31727869	To obtain more detailed information about the 10 candidate lncRNAs, DFS and OS analysis of the ccRCC subgroups was performed in relation to clinicopathological characteristics such as G1+G2, M0, N0, T1+T2 and S1+S2.	('S1', 'Chemical', 'MESH:D013455', (209, 211))	('S1+S2', 'Var', (209, 214))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('ccRCC', 'Disease', (95, 100))	('ccRCC', 'Disease', 'MESH:D002292', (95, 100))	('T1+T2', 'Var', (199, 204))	('G1+G2', 'Var', (184, 189))
109575	31727869	In addition, ROC curves were used to distinguish between the G1+G2 and G3+G4, M0 and M1, N0 and N1, T1+T2 and T3+T4, and S1+S2 and S3+S4 patient samples (Supplementary Figure 7-16).	('S3+S4', 'Var', (131, 136))	('T3+T4', 'Var', (110, 115))	('patient', 'Species', '9606', (137, 144))	('G3+G4', 'Var', (71, 76))	('S1', 'Chemical', 'MESH:D013455', (121, 123))	('S1+S2', 'Var', (121, 126))	('S3+S4', 'Chemical', 'MESH:D013455', (131, 136))	('men', 'Species', '9606', (160, 163))	('G1+G2', 'Var', (61, 66))	('T1+T2', 'Var', (100, 105))
109576	31727869	Two lncRNAs, AC023043.1 and AL133467.3, exhibited statistically significant differences for both DFS and OS in the G1+G2, M0, N0, T1+T2 and S1+S2 subgroups.	('S1', 'Chemical', 'MESH:D013455', (140, 142))	('T1+T2', 'Var', (130, 135))	('AL133467.3', 'Var', (28, 38))	('G1+G2', 'Var', (115, 120))	('differences', 'Reg', (76, 87))
109577	31727869	Furthermore, AC023043.1 and AL133467.3 could also distinguish between the G1+G2 and G3+G4, M0 and M1, N0 and N1, T1+T2 and T3+T4, and S1+S2 and S3+S4 kidney cancer patient subgroups (Supplementary Figure 8, 13).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('kidney cancer', 'Phenotype', 'HP:0009726', (150, 163))	('men', 'Species', '9606', (189, 192))	('S3+S4 kidney cancer', 'Disease', 'MESH:D007680', (144, 163))	('patient', 'Species', '9606', (164, 171))	('S3+S4 kidney cancer', 'Disease', (144, 163))	('AL133467.3', 'Var', (28, 38))	('T1+T2', 'Var', (113, 118))	('T3+T4', 'Var', (123, 128))	('G1+G2', 'Var', (74, 79))	('S1', 'Chemical', 'MESH:D013455', (134, 136))	('G3+G4', 'Var', (84, 89))	('S1+S2', 'Var', (134, 139))
109578	31727869	Overall, 10 candidate lncRNAs (IGFL2-AS1, AC023043.1, AP000439.2, AC124854.1, AL355102.4, TMEM246-AS1, AL133467.3, ZNF582-AS1, LINC01510 and PSMG3-AS1) were selected as diagnostic and prognostic biomarkers for ccRCC, as they exhibited a strong correlation with clinicopathological characteristics.	('AC023043.1', 'Var', (42, 52))	('ZNF582', 'Gene', (115, 121))	('AC124854.1', 'Var', (66, 76))	('AS1', 'Gene', '5729', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (210, 215))	('AS1', 'Gene', '5729', (122, 125))	('AS1', 'Gene', (37, 40))	('AL133467.3', 'Var', (103, 113))	('PSMG3', 'Gene', (141, 146))	('ZNF582', 'Gene', '147948', (115, 121))	('AS1', 'Gene', (147, 150))	('AP000439.2', 'Var', (54, 64))	('AS1', 'Gene', (98, 101))	('PSMG3', 'Gene', '84262', (141, 146))	('AS1', 'Gene', (122, 125))	('ccRCC', 'Disease', 'MESH:D002292', (210, 215))	('AL355102.4', 'Var', (78, 88))	('AS1', 'Gene', '5729', (37, 40))	('AS1', 'Gene', '5729', (147, 150))	('ccRCC', 'Disease', (210, 215))
109580	31727869	Considering highest diagnostic value of AP000439.2 among four upregulated lncRNAs, 11 previously reported RCC biomarkers were selected and undertaken multivariate COX analysis with AP000439.2 (Supplementary Figure 17A).	('men', 'Species', '9606', (199, 202))	('RCC', 'Disease', 'MESH:D002292', (106, 109))	('AP000439.2', 'Var', (40, 50))	('RCC', 'Disease', (106, 109))
109581	31727869	As shown in Figure 4K-4R, compared with single-gene diagnosis, AP000439.2 significantly improved diagnostic value of 8 reported RCC biomarkers, which indicated strong diagnostic efficacy of AP000439.2.	('RCC', 'Disease', 'MESH:D002292', (128, 131))	('diagnostic value', 'MPA', (97, 113))	('RCC', 'Disease', (128, 131))	('AP000439.2', 'Var', (63, 73))	('improved', 'PosReg', (88, 96))
109585	31727869	As shown by the results, IGFL2-AS1, AC023043.1, AP000439.2 and AC124854.1 were upregulated in tumor cells and tissues, while AL355102.4, TMEM246-AS1, AL133467.3, ZNF582-AS1, LINC01510 and PSMG3-AS1 were downregulated in KIRC cell lines and tumors.	('AS1', 'Gene', '5729', (145, 148))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('AS1', 'Gene', '5729', (169, 172))	('AS1', 'Gene', '5729', (194, 197))	('tumors', 'Disease', (240, 246))	('AP000439.2', 'Var', (48, 58))	('tumor', 'Disease', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('ZNF582', 'Gene', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('AS1', 'Gene', '5729', (31, 34))	('AS1', 'Gene', (145, 148))	('PSMG3', 'Gene', (188, 193))	('AS1', 'Gene', (169, 172))	('AS1', 'Gene', (194, 197))	('AL355102.4', 'Var', (125, 135))	('AC124854.1', 'Var', (63, 73))	('ZNF582', 'Gene', '147948', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('PSMG3', 'Gene', '84262', (188, 193))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('tumor', 'Disease', (94, 99))	('AC023043.1', 'Var', (36, 46))	('upregulated', 'PosReg', (79, 90))	('AS1', 'Gene', (31, 34))
109586	31727869	The corresponding lncRNAs were LINC01510 (Figure 5C), AP000439.2 (Figure 5D), TMEM246-AS1 (Figure 5E) and AC124854.1 (Figure 5F), respectively.	('AS1', 'Gene', '5729', (86, 89))	('AS1', 'Gene', (86, 89))	('AC124854.1', 'Var', (106, 116))
109589	31727869	IGFL2-AS1 was enriched in cytokine-cytokine receptor interaction, the p53 and JAK-STAT signaling pathways (Supplementary Figure 20A), while AC023043.1 possibly participated in alpha-linolenic acid metabolism and the cytosolic DNA sensing pathway (Supplementary Figure 20B).	('JAK-STAT signaling pathways', 'Pathway', (78, 105))	('cytosolic DNA sensing pathway', 'Pathway', (216, 245))	('alpha-linolenic acid', 'Chemical', 'MESH:D017962', (176, 196))	('signaling', 'biological_process', 'GO:0023052', ('87', '96'))	('cytokine-cytokine', 'MPA', (26, 43))	('alpha-linolenic acid metabolism', 'biological_process', 'GO:0036109', ('176', '207'))	('JAK', 'molecular_function', 'GO:0004713', ('78', '81'))	('DNA', 'cellular_component', 'GO:0005574', ('226', '229'))	('men', 'Species', '9606', (113, 116))	('AC023043.1', 'Var', (140, 150))	('men', 'Species', '9606', (253, 256))	('participated', 'Reg', (160, 172))	('AS1', 'Gene', '5729', (6, 9))	('AS1', 'Gene', (6, 9))
109590	31727869	AP000439.2 was found to involve renal cell carcinoma, fatty acid, tryptophan, histidine and glycerolipid metabolism, and the mTOR signaling pathway (Supplementary Figure 20C), while AC124854.1 might participate in the adipocytokine signaling pathway, renal cell carcinoma, histidine metabolism, mTOR signaling pathway and glycolysis gluconeogenesis (Supplementary Figure 21A).	('histidine', 'Chemical', 'MESH:C115717', (273, 282))	('gluconeogenesis', 'biological_process', 'GO:0006094', ('333', '348'))	('glycolysis gluconeogenesis', 'Disease', (322, 348))	('glycerolipid metabolism', 'Disease', (92, 115))	('mTOR signaling pathway', 'Pathway', (125, 147))	('glycolysis', 'biological_process', 'GO:0006096', ('322', '332'))	('adipocytokine signaling pathway', 'biological_process', 'GO:0033210', ('218', '249'))	('adipocytokine signaling pathway', 'Pathway', (218, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (32, 52))	('signaling pathway', 'biological_process', 'GO:0007165', ('130', '147'))	('AP000439.2', 'Var', (0, 10))	('glycerolipid metabolism', 'biological_process', 'GO:0046486', ('92', '115'))	('histidine metabolism', 'Pathway', (273, 293))	('glycolysis gluconeogenesis', 'Phenotype', 'HP:0005959', (322, 348))	('histidine', 'Chemical', 'MESH:C115717', (78, 87))	('adipocytokine signaling pathway', 'biological_process', 'GO:0033209', ('218', '249'))	('participate', 'Reg', (199, 210))	('adipocytokine signaling pathway', 'biological_process', 'GO:0033211', ('218', '249'))	('renal cell carcinoma', 'Disease', (32, 52))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (32, 52))	('AC124854.1', 'Var', (182, 192))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (251, 271))	('mTOR signaling pathway', 'Pathway', (295, 317))	('involve', 'Reg', (24, 31))	('tryptophan', 'Chemical', 'None', (66, 76))	('men', 'Species', '9606', (356, 359))	('histidine metabolism', 'biological_process', 'GO:0006547', ('273', '293'))	('men', 'Species', '9606', (155, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('glycolysis gluconeogenesis', 'Disease', 'MESH:C564972', (322, 348))	('fatty acid', 'Chemical', 'MESH:D005227', (54, 64))	('renal cell carcinoma', 'Disease', (251, 271))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (251, 271))	('glycerolipid metabolism', 'Disease', 'MESH:D008659', (92, 115))	('signaling pathway', 'biological_process', 'GO:0007165', ('300', '317'))
109591	31727869	AL355102.4 was enriched in histidine, tryptophan, beta alanine, fatty acid and arginine-proline metabolism (Supplementary Figure 21B), while ZNF582-AS1 possibly participated in pentose and glucuronate interconversions, the pentose phosphate pathway, alanine aspartate-glutamate metabolism and the p53 signaling pathway (Supplementary Figure 22A).	('pentose', 'Chemical', 'MESH:D010429', (223, 230))	('men', 'Species', '9606', (114, 117))	('ZNF582', 'Gene', '147948', (141, 147))	('histidine', 'Chemical', 'MESH:C115717', (27, 36))	('tryptophan', 'Chemical', 'None', (38, 48))	('beta alanine', 'Chemical', 'MESH:D015091', (50, 62))	('fatty acid', 'MPA', (64, 74))	('participated', 'Reg', (161, 173))	('AS1', 'Gene', (148, 151))	('proline metabolism', 'biological_process', 'GO:0006560', ('88', '106'))	('pentose phosphate pathway', 'Pathway', (223, 248))	('men', 'Species', '9606', (326, 329))	('p53 signaling pathway', 'Pathway', (297, 318))	('histidine', 'MPA', (27, 36))	('glutamate metabolism', 'biological_process', 'GO:0006536', ('268', '288'))	('AL355102.4', 'Var', (0, 10))	('alanine', 'MPA', (250, 257))	('pentose', 'Chemical', 'MESH:D010429', (177, 184))	('tryptophan', 'MPA', (38, 48))	('fatty acid', 'Chemical', 'MESH:D005227', (64, 74))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('223', '248'))	('glucuronate', 'Chemical', 'MESH:D005965', (189, 200))	('ZNF582', 'Gene', (141, 147))	('beta alanine', 'MPA', (50, 62))	('alanine aspartate-glutamate', 'Chemical', 'None', (250, 277))	('AS1', 'Gene', '5729', (148, 151))	('pentose phosphate', 'Chemical', 'MESH:D010429', (223, 240))	('p53 signaling pathway', 'biological_process', 'GO:0030330', ('297', '318'))	('arginine-proline', 'Chemical', 'MESH:C020924', (79, 95))	('arginine-proline metabolism', 'MPA', (79, 106))
109592	31727869	LINC01510 was involved in the p53 and Wnt signaling pathways, and cell cycle (Supplementary Figure 22B).	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('cell cycle', 'CPA', (66, 76))	('LINC01510', 'Var', (0, 9))	('cell cycle', 'biological_process', 'GO:0007049', ('66', '76'))	('involved', 'Reg', (14, 22))	('men', 'Species', '9606', (84, 87))	('2B', 'Chemical', 'MESH:C023970', (100, 102))
109597	31727869	As shown in Supplementary Figure 23A-23J, high enrichment of H3K27Ac, H3K4Me1 and H3K4Me3 were found at the promoter regions of AC023043.1, AL133467.3, PSMG3-AS1, ZNF582-AS1 and AL355102.4.	('ZNF582', 'Gene', (163, 169))	('AS1', 'Gene', '5729', (170, 173))	('AL355102.4', 'Var', (178, 188))	('H3K27Ac', 'Protein', (61, 68))	('PSMG3', 'Gene', '84262', (152, 157))	('H3K27Ac', 'Chemical', 'MESH:C024755', (61, 68))	('AC023043.1', 'Var', (128, 138))	('men', 'Species', '9606', (18, 21))	('H3K4Me1', 'Chemical', 'MESH:C024755', (70, 77))	('AS1', 'Gene', '5729', (158, 161))	('ZNF582', 'Gene', '147948', (163, 169))	('AS1', 'Gene', (170, 173))	('H3K4Me1', 'Var', (70, 77))	('AL133467.3', 'Var', (140, 150))	('PSMG3', 'Gene', (152, 157))	('AS1', 'Gene', (158, 161))	('men', 'Species', '9606', (53, 56))	('H3K4Me3', 'Var', (82, 89))	('H3K4Me3', 'Chemical', 'MESH:C024755', (82, 89))
109619	31727869	Among the 10 candidate lncRNAs, AC023043.1, AC124854.1, AL355102.4, TMEM246-AS1, AL133467.3 and PSMG3-AS1 had not been previously reported.	('AS1', 'Gene', '5729', (76, 79))	('AS1', 'Gene', (76, 79))	('AL133467.3', 'Var', (81, 91))	('AC124854.1', 'Var', (44, 54))	('PSMG3', 'Gene', '84262', (96, 101))	('AS1', 'Gene', '5729', (102, 105))	('AC023043.1', 'Var', (32, 42))	('PSMG3', 'Gene', (96, 101))	('AL355102.4', 'Var', (56, 66))	('AS1', 'Gene', (102, 105))
109621	31727869	AP000439.2 was found to be associated with non-small cell lung cancer by pathway analysis method based on global influence (PAGI).	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (43, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('associated', 'Reg', (27, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('AP000439.2', 'Var', (0, 10))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (47, 69))	('non-small cell lung cancer', 'Disease', (43, 69))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (43, 69))
109624	31727869	In addition, LINC01510 was also associated with poor prognosis and promoted malignant progression in non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', (101, 127))	('promoted', 'PosReg', (67, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (105, 127))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (101, 127))	('LINC01510', 'Var', (13, 22))	('malignant progression', 'CPA', (76, 97))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (101, 127))
109631	31727869	A previous study has also reported that miR-34c might be upregulated in lung formation, but was inversely downregulated during bronchial tumorigenesis.	('miR-34c', 'Var', (40, 47))	('tumor', 'Disease', (137, 142))	('downregulated', 'NegReg', (106, 119))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('lung formation', 'biological_process', 'GO:0060431', ('72', '86'))	('lung formation', 'CPA', (72, 86))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('upregulated', 'PosReg', (57, 68))
109647	31727869	In addition, a recent study has found that phospholipase C-like 1/uncoupling protein 1 mediating lipid browning could promote kidney cancer cell "slimming" and consume abnormal lipid accumulation, which represses the progression of ccRCC.	('kidney cancer', 'Disease', 'MESH:D007680', (126, 139))	('represses', 'NegReg', (203, 212))	('ccRCC', 'Disease', (232, 237))	('ccRCC', 'Phenotype', 'HP:0006770', (232, 237))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('kidney cancer', 'Disease', (126, 139))	('abnormal lipid accumulation', 'Phenotype', 'HP:0003119', (168, 195))	('ccRCC', 'Disease', 'MESH:D002292', (232, 237))	('consume', 'MPA', (160, 167))	('promote', 'PosReg', (118, 125))	('lipid', 'Var', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('kidney cancer', 'Phenotype', 'HP:0009726', (126, 139))
109673	29562667	Clear cell carcinoma of renal cancer (ccRCC) makes up approximately 70% of all renal malignancies and harbors up to 92% of Von Hippel-Lindau (VHL) inactivation.	('VHL', 'Gene', '7428', (142, 145))	('inactivation', 'Var', (147, 159))	('renal malignancies', 'Disease', 'MESH:D007674', (79, 97))	('carcinoma of renal cancer', 'Disease', 'MESH:D007680', (11, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('renal cancer', 'Phenotype', 'HP:0009726', (24, 36))	('carcinoma of renal cancer', 'Disease', (11, 36))	('Von Hippel-Lindau', 'Gene', (123, 140))	('carcinoma of renal cancer', 'Phenotype', 'HP:0005584', (11, 36))	('Von Hippel-Lindau', 'Gene', '7428', (123, 140))	('Clear cell carcinoma of renal cancer', 'Phenotype', 'HP:0006770', (0, 36))	('renal malignancies', 'Phenotype', 'HP:0009726', (79, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('renal malignancies', 'Disease', (79, 97))	('VHL', 'Gene', (142, 145))
109678	29562667	Therefore, the loss of VHL leads to HIFalpha accumulation and translocation into the nucleus, which subsequently activates the transcription of HIF target genes that are involved in critical oncogenic pathways, including angiogenesis (e.g.,Vascular endothelial growth factor ((VEGF)), glycolysis and glucose transport (e.g., Glucose transporter type I (GLUT1)), and erythropoiesis (e.g., Erythropoietin (EPO)).	('glucose', 'Chemical', 'MESH:D005947', (300, 307))	('glucose transport', 'MPA', (300, 317))	('Glucose transporter type I', 'MPA', (325, 351))	('VHL', 'Gene', (23, 26))	('loss', 'Var', (15, 19))	('Vascular endothelial growth factor', 'Gene', (240, 274))	('angiogenesis', 'biological_process', 'GO:0001525', ('221', '233'))	('glycolysis', 'MPA', (285, 295))	('Erythropoietin', 'Gene', (388, 402))	('transcription', 'MPA', (127, 140))	('GLUT1', 'Gene', (353, 358))	('erythropoiesis', 'biological_process', 'GO:0030218', ('366', '380'))	('glycolysis', 'biological_process', 'GO:0006096', ('285', '295'))	('Vascular endothelial growth factor', 'Gene', '7422', (240, 274))	('VHL', 'Gene', '7428', (23, 26))	('Erythropoietin', 'Gene', '2056', (388, 402))	('nucleus', 'cellular_component', 'GO:0005634', ('85', '92'))	('angiogenesis', 'CPA', (221, 233))	('transcription', 'biological_process', 'GO:0006351', ('127', '140'))	('Erythropoietin', 'molecular_function', 'GO:0005128', ('388', '402'))	('VEGF', 'Gene', '7422', (277, 281))	('EPO', 'Gene', '2056', (404, 407))	('EPO', 'Gene', (404, 407))	('accumulation', 'PosReg', (45, 57))	('GLUT1', 'Gene', '6513', (353, 358))	('Vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('240', '274'))	('activates', 'PosReg', (113, 122))	('VEGF', 'Gene', (277, 281))	('translocation', 'MPA', (62, 75))	('glucose transport', 'biological_process', 'GO:1904659', ('300', '317'))
109689	29562667	This study identified NDRG3 as the hypoxia-inducible lactate sensor that provides crucial hypoxia signaling of oxygen-dependent regulation in an HIF-independent manner; therefore, a combinatorial targeting of both HIF and NDRG3 might be a highly effective therapy in cancer.	('regulation', 'biological_process', 'GO:0065007', ('128', '138'))	('combinatorial', 'Var', (182, 195))	('lactate', 'Chemical', 'MESH:D019344', (53, 60))	('cancer', 'Disease', (267, 273))	('NDRG3', 'Gene', '57446', (222, 227))	('NDRG3', 'Gene', (222, 227))	('NDRG3', 'Gene', (22, 27))	('crucial hypoxia', 'Disease', (82, 97))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('crucial hypoxia', 'Disease', 'MESH:D000860', (82, 97))	('oxygen', 'Chemical', 'MESH:D010100', (111, 117))	('hypoxia', 'Disease', 'MESH:D000860', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('hypoxia', 'Disease', (90, 97))	('hypoxia', 'Disease', 'MESH:D000860', (90, 97))	('hypoxia', 'Disease', (35, 42))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('NDRG3', 'Gene', '57446', (22, 27))
109696	29562667	AKT phosphorylation at Thr308 and Ser473 increases its kinase activity to stimulate its downstream mTORC1 activation, leading to an increase in the activity of various anabolic, biosynthetic pathways for cell growth and proliferation.	('AKT', 'Gene', (0, 3))	('Thr308', 'Chemical', '-', (23, 29))	('Ser', 'cellular_component', 'GO:0005790', ('34', '37'))	('Ser473', 'Var', (34, 40))	('mTORC1', 'Gene', (99, 105))	('biosynthetic pathways', 'Pathway', (178, 199))	('Ser473', 'Chemical', '-', (34, 40))	('proliferation', 'CPA', (220, 233))	('mTORC1', 'Gene', '382056', (99, 105))	('increase', 'PosReg', (132, 140))	('kinase activity', 'molecular_function', 'GO:0016301', ('55', '70'))	('AKT', 'Gene', '207', (0, 3))	('activation', 'PosReg', (106, 116))	('mTORC1', 'cellular_component', 'GO:0031931', ('99', '105'))	('increases', 'PosReg', (41, 50))	('activity', 'MPA', (148, 156))	('cell growth', 'biological_process', 'GO:0016049', ('204', '215'))	('Thr308', 'Var', (23, 29))	('anabolic', 'Pathway', (168, 176))	('stimulate', 'PosReg', (74, 83))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('kinase activity', 'MPA', (55, 70))
109699	29562667	Phosphorylated, active AKT is recruited to mitochondria under hypoxic conditions, whereby PDK1 is phosphorylated at T346, which switches tumor metabolism to glycolysis and maintains the redox balance needed for tumor cell survival and proliferation.	('glycolysis', 'biological_process', 'GO:0006096', ('157', '167'))	('switches', 'PosReg', (128, 136))	('T346', 'Var', (116, 120))	('AKT', 'Gene', (23, 26))	('tumor', 'Disease', (211, 216))	('PDK1', 'molecular_function', 'GO:0004740', ('90', '94'))	('PDK1', 'Gene', '5163', (90, 94))	('mitochondria', 'cellular_component', 'GO:0005739', ('43', '55'))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('hypoxic conditions', 'Disease', 'MESH:D009135', (62, 80))	('glycolysis', 'MPA', (157, 167))	('redox balance', 'MPA', (186, 199))	('maintains', 'Reg', (172, 181))	('tumor', 'Disease', (137, 142))	('AKT', 'Gene', '207', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('metabolism', 'biological_process', 'GO:0008152', ('143', '153'))	('PDK1', 'Gene', (90, 94))	('hypoxic conditions', 'Disease', (62, 80))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
109703	29562667	revealed a pan-cancer proteogenomic atlas for PI3K/AKT/mTOR changes across over 10,000 human cancers, supporting the notion that VHL mutations are associated with highly active AKT/mTOR signaling.	('AKT', 'Gene', '207', (177, 180))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('human', 'Species', '9606', (87, 92))	('mutations', 'Var', (133, 142))	('PI3K', 'molecular_function', 'GO:0016303', ('46', '50'))	('mTOR', 'Gene', (55, 59))	('cancer', 'Disease', (15, 21))	('AKT', 'Gene', (51, 54))	('VHL', 'Gene', (129, 132))	('AKT', 'Gene', (177, 180))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('mTOR', 'Gene', (181, 185))	('cancers', 'Disease', (93, 100))	('cancer', 'Disease', (93, 99))	('mTOR', 'Gene', '2475', (55, 59))	('signaling', 'biological_process', 'GO:0023052', ('186', '195'))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('VHL', 'Gene', '7428', (129, 132))	('mTOR', 'Gene', '2475', (181, 185))	('AKT', 'Gene', '207', (51, 54))
109710	29562667	More direct, aberrant protein expression also activates the NF-kappaB pathway (e.g., VHL loss).	('VHL loss', 'Disease', 'MESH:D006623', (85, 93))	('NF-kappaB', 'Gene', '4790', (60, 69))	('VHL loss', 'Disease', (85, 93))	('activates', 'PosReg', (46, 55))	('NF-kappaB', 'Gene', (60, 69))	('protein', 'Protein', (22, 29))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('aberrant', 'Var', (13, 21))
109712	29562667	NF-kappaB hyper-activation can promote resistance to chemotherapy or cytokine treatments and correlates with a worse outcome in ccRCC.	('ccRCC', 'Disease', (128, 133))	('NF-kappaB', 'Gene', '4790', (0, 9))	('NF-kappaB', 'Gene', (0, 9))	('hyper-activation', 'Var', (10, 26))	('promote', 'PosReg', (31, 38))	('resistance to chemotherapy', 'MPA', (39, 65))
109715	29562667	ccRCC cells with VHL inactivation are resistant to TNF cytotoxicity, and their sensitivity to TNF can be restored by reconstituted wild-type VHL in these cells, at least partially through suppressing the NF-kappaB-dependent anti-apoptotic pathway.	('NF-kappaB', 'Gene', (204, 213))	('VHL', 'Gene', '7428', (141, 144))	('inactivation', 'Var', (21, 33))	('suppressing', 'NegReg', (188, 199))	('TNF', 'Gene', (51, 54))	('TNF', 'Gene', (94, 97))	('TNF', 'Gene', '7124', (51, 54))	('cytotoxicity', 'Disease', (55, 67))	('VHL', 'Gene', (17, 20))	('NF-kappaB', 'Gene', '4790', (204, 213))	('TNF', 'Gene', '7124', (94, 97))	('VHL', 'Gene', '7428', (17, 20))	('VHL', 'Gene', (141, 144))	('cytotoxicity', 'Disease', 'MESH:D064420', (55, 67))
109732	29562667	The authors showed that B-Myb depletion increases tumor growth by regulating different downstream genes from HIF and can antagonize HIF-dependent tumorigenesis in an HIF-independent manner.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('depletion', 'Var', (30, 39))	('B-Myb', 'Gene', '4605', (24, 29))	('tumor', 'Disease', (146, 151))	('B-Myb', 'Gene', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('regulating', 'Reg', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('increases', 'PosReg', (40, 49))	('antagonize', 'NegReg', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
109738	29562667	Although previous research suggested that ccRCC cell lines display constitutive active Notch signaling that is independent of VHL/HIF signaling, a very recent study demonstrated that VHL mutations affect vessel branching and maturation via Notch, though the underlying mechanism remains unknown.	('VHL', 'Gene', '7428', (183, 186))	('Notch signaling', 'MPA', (87, 102))	('signaling', 'biological_process', 'GO:0023052', ('134', '143'))	('vessel branching', 'CPA', (204, 220))	('signaling', 'biological_process', 'GO:0023052', ('93', '102'))	('mutations', 'Var', (187, 196))	('affect', 'Reg', (197, 203))	('VHL', 'Gene', (126, 129))	('VHL', 'Gene', '7428', (126, 129))	('VHL', 'Gene', (183, 186))	('Notch', 'MPA', (240, 245))
109743	29562667	used paired primary patient tumor and normal samples, ccRCC cell lines, and normal kidney cell lines, followed by an extensive profiling of histone markers including H3K27Ac (marks active enhancer), H3K4me3 (marks active transcription in proximity to promoters), and H3K4me (marks enhancers) in ccRCC.	('H3K27Ac', 'Var', (166, 173))	('tumor', 'Disease', (28, 33))	('H3K4me', 'Var', (267, 273))	('ccRCC', 'Disease', (295, 300))	('H3K4me3', 'Var', (199, 206))	('patient', 'Species', '9606', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('transcription', 'biological_process', 'GO:0006351', ('221', '234'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
109744	29562667	It is worth mentioning that they confirmed that 90% of tumors carried VHL loss-of-function mutations.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('VHL loss', 'Disease', 'MESH:D006623', (70, 78))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('mutations', 'Var', (91, 100))	('tumors', 'Disease', (55, 61))	('VHL loss', 'Disease', (70, 78))	('tumors', 'Disease', 'MESH:D009369', (55, 61))
109764	29562667	In summary, this paper showed that hypoxia, by regulating G9a protein levels and through the H3K9 dimethylation of key tumor suppressor promoters, contributes to an increased breast tumorigenesis.	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', (182, 187))	('regulating', 'Reg', (47, 57))	('tumor suppressor', 'biological_process', 'GO:0051726', ('119', '135'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('119', '135'))	('hypoxia', 'Disease', 'MESH:D000860', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('G9a', 'Gene', (58, 61))	('G9a', 'Gene', '10919', (58, 61))	('H3K9', 'Var', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('hypoxia', 'Disease', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('increased', 'PosReg', (165, 174))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
109767	29562667	It is worth noting that the loss of VHL was reported to induce DNA replication stress and cause the accumulation of DNA damage that constrains cell proliferation and oncogeneic transformation.	('oncogeneic transformation', 'CPA', (166, 191))	('loss', 'Var', (28, 32))	('constrains', 'NegReg', (132, 142))	('VHL', 'Gene', (36, 39))	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('cell proliferation', 'CPA', (143, 161))	('VHL', 'Gene', '7428', (36, 39))	('induce', 'Reg', (56, 62))	('accumulation', 'MPA', (100, 112))	('DNA damage', 'MPA', (116, 126))	('DNA replication', 'biological_process', 'GO:0006260', ('63', '78'))	('DNA replication stress', 'MPA', (63, 85))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('cell proliferation', 'biological_process', 'GO:0008283', ('143', '161'))
109776	29562667	PT2399 selectively inhibits HIF2alpha (but not HIF1alpha) binding with ARNT, an essential co-factor for the transactivation of downstream target genes by HIF2alpha for oncogenesis.	('HIF1alpha', 'Gene', (47, 56))	('PT2399', 'Chemical', 'MESH:C000614278', (0, 6))	('binding', 'Interaction', (58, 65))	('transactivation', 'biological_process', 'GO:2000144', ('108', '123'))	('oncogenesis', 'biological_process', 'GO:0007048', ('168', '179'))	('ARNT', 'Gene', '405', (71, 75))	('HIF1alpha', 'Gene', '3091', (47, 56))	('binding', 'molecular_function', 'GO:0005488', ('58', '65'))	('inhibits', 'NegReg', (19, 27))	('HIF2alpha', 'Protein', (28, 37))	('PT2399', 'Var', (0, 6))	('ARNT', 'Gene', (71, 75))
109777	29562667	As a result, PT2399 efficiently blocked ccRCC cell proliferation in a 3-D culture, tumor growth, and metastatic potential in vivo.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('blocked', 'NegReg', (32, 39))	('metastatic potential', 'CPA', (101, 121))	('tumor', 'Disease', (83, 88))	('ccRCC', 'Disease', (40, 45))	('PT2399', 'Var', (13, 19))	('PT2399', 'Chemical', 'MESH:C000614278', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))
109778	29562667	More importantly, PT2399 displayed superior efficacy and better tolerability compared to current standard ccRCC therapy, such as sunitinib.	('PT2399', 'Var', (18, 24))	('efficacy', 'MPA', (44, 52))	('PT2399', 'Chemical', 'MESH:C000614278', (18, 24))	('ccRCC', 'Disease', (106, 111))	('sunitinib', 'Chemical', 'MESH:D000077210', (129, 138))
109781	29562667	It has also been shown that p53 mutations may be associated with an acquired resistance to PT2399 treatment.	('p53', 'Gene', (28, 31))	('p53', 'Gene', '7157', (28, 31))	('associated', 'Reg', (49, 59))	('mutations', 'Var', (32, 41))	('PT2399', 'Chemical', 'MESH:C000614278', (91, 97))	('acquired resistance to', 'MPA', (68, 90))
109783	29562667	It is possible to identify second-site targets that, when combined with a tumor specific mutation, cause a specific cancer cell death without affecting normal cells.	('death', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('cancer', 'Disease', (116, 122))	('mutation', 'Var', (89, 97))	('cause', 'Reg', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('cell death', 'biological_process', 'GO:0008219', ('123', '133'))	('tumor', 'Disease', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('death', 'Disease', 'MESH:D003643', (128, 133))
109785	29562667	Tumor-specific genetic alterations (such as VHL loss) reveal not only the biological changes that drive tumor progression but also vulnerabilities that can be exploited therapeutically.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('alterations', 'Var', (23, 34))	('VHL loss', 'Disease', 'MESH:D006623', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('VHL loss', 'Disease', (44, 52))
109788	29562667	Mechanistically, they identified that STF-62247 induces cell toxicity through autophagy and HIF-independent signaling.	('toxicity', 'Disease', 'MESH:D064420', (61, 69))	('autophagy', 'biological_process', 'GO:0016236', ('78', '87'))	('toxicity', 'Disease', (61, 69))	('STF-62247', 'Var', (38, 47))	('autophagy', 'biological_process', 'GO:0006914', ('78', '87'))	('autophagy', 'CPA', (78, 87))	('induces', 'Reg', (48, 55))	('signaling', 'biological_process', 'GO:0023052', ('108', '117'))	('HIF-independent signaling', 'CPA', (92, 117))
109794	29562667	The latest research on the selective toxicity of EZH1 inhibitors on VHL-null ccRCC cells also showed their dependency on HIF signaling.	('toxicity', 'Disease', (37, 45))	('inhibitors', 'Var', (54, 64))	('EZH1', 'Gene', (49, 53))	('VHL', 'Gene', (68, 71))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('VHL', 'Gene', '7428', (68, 71))	('EZH1', 'Gene', '2145', (49, 53))	('toxicity', 'Disease', 'MESH:D064420', (37, 45))
109796	29562667	For example, a focused shRNA library screening identified that CDK6, MET, or MEK1 shRNAs may be selectively toxic to VHL-deficient ccRCC cells, but the effect is mediated in an HIF-independent fashion.	('MEK1', 'Gene', '5604', (77, 81))	('MET', 'Var', (69, 72))	('MEK1', 'Gene', (77, 81))	('MEK1', 'molecular_function', 'GO:0004708', ('77', '81'))	('CDK6', 'Gene', (63, 67))	('CDK6', 'Gene', '1021', (63, 67))	('CDK', 'molecular_function', 'GO:0004693', ('63', '66'))	('VHL-deficient', 'Disease', 'MESH:D006623', (117, 130))	('ccRCC', 'Disease', (131, 136))	('VHL-deficient', 'Disease', (117, 130))
109821	33723286	The overexpression or amplification of HER2 is present in approximately 25% of breast cancer cases .	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('HER2', 'Gene', (39, 43))	('amplification', 'Var', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('HER2', 'Gene', '2064', (39, 43))	('overexpression', 'PosReg', (4, 18))
109842	33723286	These include MET (proportion of patient samples with a mutation in kidney renal papillary carcinomas: 24%), MUC16 (20%), KMT2C (19%), SETD2 (17%) and FAT1 (15%).	('SETD2', 'Gene', (135, 140))	('patient', 'Species', '9606', (33, 40))	('kidney renal papillary carcinomas', 'Disease', 'MESH:D007681', (68, 101))	('MUC16', 'Gene', '94025', (109, 114))	('renal papillary carcinomas', 'Phenotype', 'HP:0006766', (75, 101))	('MET', 'Gene', '79811', (14, 17))	('KMT2C', 'Gene', '58508', (122, 127))	('KMT2C', 'Gene', (122, 127))	('MUC16', 'Gene', (109, 114))	('MET', 'Gene', (14, 17))	('mutation', 'Var', (56, 64))	('FAT1', 'Gene', '2195', (151, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('FAT1', 'Gene', (151, 155))	('kidney renal papillary carcinomas', 'Disease', (68, 101))	('SETD2', 'Gene', '29072', (135, 140))
109865	33723286	In renal papillary carcinoma, the high expression CDK1 was associated with the enrichment of apoptosis genes (p = 0.025).	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))	('CDK1', 'Gene', (50, 54))	('CDK', 'molecular_function', 'GO:0004693', ('50', '53'))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('high expression', 'Var', (34, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('associated', 'Reg', (59, 69))	('apoptosis genes', 'Gene', (93, 108))	('renal papillary carcinoma', 'Disease', 'MESH:C538614', (3, 28))	('renal papillary carcinoma', 'Disease', (3, 28))	('CDK1', 'Gene', '983', (50, 54))
109882	33723286	c-MYC was the first characterized oncogene that is activated by chromosome translocation in human Burkitt's lymphomas .	("Burkitt's lymphomas", 'Disease', (98, 117))	('c-MYC', 'Gene', '4609', (0, 5))	("Burkitt's lymphomas", 'Disease', 'MESH:D002051', (98, 117))	('chromosome', 'cellular_component', 'GO:0005694', ('64', '74'))	('lymphomas', 'Phenotype', 'HP:0002665', (108, 117))	('c-MYC', 'Gene', (0, 5))	('human', 'Species', '9606', (92, 97))	('chromosome translocation', 'Var', (64, 88))
109886	33723286	This pathway is mutated in more than 85% of colorectal cancers .	('colorectal cancers', 'Disease', 'MESH:D015179', (44, 62))	('colorectal cancers', 'Disease', (44, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mutated', 'Var', (16, 23))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('colorectal cancer', 'Phenotype', 'HP:0003003', (44, 61))
109888	33723286	In addition, high expression of CTNNB1 is associated with shorter survival in colorectal cancer .	('shorter', 'NegReg', (58, 65))	('survival', 'MPA', (66, 74))	('high', 'Var', (13, 17))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('CTNNB1', 'Gene', '1499', (32, 38))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('CTNNB1', 'Gene', (32, 38))	('colorectal cancer', 'Disease', (78, 95))
109895	33723286	Among these, high signature expression was associated with poor survival in low grade glioma, liver cancer, kidney papillary cancer, lung adenocarcinoma and sarcoma.	('glioma', 'Disease', (86, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('high', 'Var', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (133, 152))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (86, 92))	('glioma', 'Disease', 'MESH:D005910', (86, 92))	('sarcoma', 'Disease', 'MESH:D012509', (157, 164))	('liver cancer', 'Phenotype', 'HP:0002896', (94, 106))	('liver cancer', 'Disease', 'MESH:D006528', (94, 106))	('kidney papillary cancer', 'Disease', (108, 131))	('lung adenocarcinoma', 'Disease', (133, 152))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (133, 152))	('liver cancer', 'Disease', (94, 106))	('kidney papillary cancer', 'Disease', 'MESH:D007680', (108, 131))	('sarcoma', 'Disease', (157, 164))
109920	33723286	For each sample, the preprocessed and annotated Mutation Annotation Format (MAF) data files that were generated by using MuTect2 for variant detection were used to compute the tumor mutation burden.	('tumor', 'Disease', (176, 181))	('variant', 'Var', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))
109931	30581339	VHL Dependent Expression of REDD1 and PDK3 Proteins in Clear-cell Renal Cell Carcinoma Sporadic clear-cell renal cell carcinoma (ccRCC) is associated with mutations in the VHL gene, upregulated mammalian target of rapamycin (mTOR) activity and glycolytic metabolism.	('ccRCC', 'Phenotype', 'HP:0006770', (129, 134))	('Sporadic clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (87, 127))	('PDK3', 'molecular_function', 'GO:0004740', ('38', '42'))	('mTOR', 'Gene', (225, 229))	('activity', 'MPA', (231, 239))	('VHL', 'Gene', (172, 175))	('VHL', 'Gene', '7428', (0, 3))	('Carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (107, 127))	('mTOR', 'Gene', '2475', (225, 229))	('metabolism', 'biological_process', 'GO:0008152', ('255', '265'))	('glycolytic metabolism', 'MPA', (244, 265))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (66, 86))	('VHL', 'Gene', '7428', (172, 175))	('mammalian target of rapamycin', 'Gene', '2475', (194, 223))	('Clear-cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (55, 86))	('Clear-cell Renal Cell Carcinoma', 'Disease', (55, 86))	('PDK3', 'Gene', '5165', (38, 42))	('REDD1', 'Gene', (28, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (96, 127))	('REDD1', 'Gene', '54541', (28, 33))	('mammalian target of rapamycin', 'Gene', (194, 223))	('mutations', 'Var', (155, 164))	('PDK3', 'Gene', (38, 42))	('upregulated', 'PosReg', (182, 193))	('Sporadic clear-cell renal cell carcinoma', 'Disease', (87, 127))	('VHL', 'Gene', (0, 3))	('Clear-cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (55, 86))
109933	30581339	Total proteins were isolated from 21 tumorous samples with biallelic inactivation, 10 with monoallelic inactivation and 6 tumors with a wild-type VHL (wtVHL) gene obtained from patients who underwent total nephrectomy.	('tumors', 'Disease', (122, 128))	('VHL', 'Gene', (146, 149))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('VHL', 'Gene', (153, 156))	('biallelic inactivation', 'Var', (59, 81))	('VHL', 'Gene', '7428', (146, 149))	('patients', 'Species', '9606', (177, 185))	('VHL', 'Gene', '7428', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumorous', 'Disease', 'MESH:D009369', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumorous', 'Disease', (37, 45))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
109935	30581339	Tumors with monoallelic inactivation of VHL underexpressed REDD1 in comparison to wtVHL tumors (P = 0.042), tumors with biallelic VHL inactivation (P < 0.005) and control tissue (P = 0.004).	('wtVHL tumors', 'Disease', 'MESH:D009369', (82, 94))	('monoallelic inactivation', 'Var', (12, 36))	('VHL', 'Gene', '7428', (40, 43))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('VHL', 'Gene', (84, 87))	('Tumors', 'Disease', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('wtVHL tumors', 'Disease', (82, 94))	('REDD1', 'Gene', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('VHL', 'Gene', '7428', (84, 87))	('VHL', 'Gene', (130, 133))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumors', 'Disease', (108, 114))	('REDD1', 'Gene', '54541', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('VHL', 'Gene', (40, 43))	('underexpressed', 'NegReg', (44, 58))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('VHL', 'Gene', '7428', (130, 133))	('tumors', 'Disease', (88, 94))
109936	30581339	Additionally, REDD1 expression was higher in tumors with VHL biallelic inactivation than in control tissue (P = 0.008).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('expression', 'MPA', (20, 30))	('REDD1', 'Gene', (14, 19))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('VHL', 'Gene', (57, 60))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('VHL', 'Gene', '7428', (57, 60))	('biallelic inactivation', 'Var', (61, 83))	('higher', 'PosReg', (35, 41))	('REDD1', 'Gene', '54541', (14, 19))
109939	30581339	We have shown for the first time VHL dependent expression of PDK3 and we provide additional evidence that VHL mutational status affects REDD1 expression in sporadic ccRCC.	('REDD1', 'Gene', (136, 141))	('PDK3', 'Gene', '5165', (61, 65))	('PDK3', 'Gene', (61, 65))	('mutational', 'Var', (110, 120))	('VHL', 'Gene', (33, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (165, 170))	('ccRCC', 'Disease', (165, 170))	('VHL', 'Gene', '7428', (33, 36))	('VHL', 'Gene', (106, 109))	('REDD1', 'Gene', '54541', (136, 141))	('expression', 'MPA', (142, 152))	('VHL', 'Gene', '7428', (106, 109))	('PDK3', 'molecular_function', 'GO:0004740', ('61', '65'))	('affects', 'Reg', (128, 135))
109941	30581339	Inactivation of the VHL gene contributes to early phases of renal tumorigenesis by accummulation of hypoxia inducible factors (HIFs) and deregulation of processes important for renal epithelial cell morphology.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('deregulation', 'Reg', (137, 149))	('processes', 'CPA', (153, 162))	('VHL', 'Gene', (20, 23))	('hypoxia', 'Disease', 'MESH:D000860', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('VHL', 'Gene', '7428', (20, 23))	('hypoxia', 'Disease', (100, 107))	('contributes', 'Reg', (29, 40))	('Inactivation', 'Var', (0, 12))	('accummulation', 'PosReg', (83, 96))
109943	30581339	It is well known that mTORC1 controls cellular growth, proliferation and metabolism via its effector molecules p70S6K1 (Ribosomal protein S6 kinase beta-1) and eIF4E-BP1 (Eukaryotic Translation Initiation Factor 4E Binding Protein 1) and that it is under the control of AMPK (5' adenosine monophosphate-activated protein kinase) and REDD1 (Regulated in Development and DNA Damage Response 1).	('cellular growth', 'biological_process', 'GO:0016049', ('38', '53'))	('Eukaryotic Translation Initiation Factor 4E Binding Protein 1', 'Gene', '1978', (171, 232))	('AMPK', 'Gene', '5563', (270, 274))	('controls', 'Reg', (29, 37))	('eIF4E-BP1', 'Gene', '1978', (160, 169))	('DNA Damage Response', 'biological_process', 'GO:0006974', ('369', '388'))	('AMPK', 'molecular_function', 'GO:0047322', ('270', '274'))	('REDD1', 'Gene', (333, 338))	('metabolism', 'CPA', (73, 83))	('cellular growth', 'CPA', (38, 53))	('proliferation', 'CPA', (55, 68))	('REDD1', 'Gene', '54541', (333, 338))	('Regulated in Development and DNA Damage Response 1', 'Gene', '54541', (340, 390))	('AMPK', 'Gene', (270, 274))	('p70S6K1', 'Var', (111, 118))	('metabolism', 'biological_process', 'GO:0008152', ('73', '83'))	('Translation Initiation', 'biological_process', 'GO:0006413', ('182', '204'))	('AMPK', 'molecular_function', 'GO:0050405', ('270', '274'))	('DNA', 'cellular_component', 'GO:0005574', ('369', '372'))	('eIF4', 'cellular_component', 'GO:0008304', ('160', '164'))	('eIF4E-BP1', 'Gene', (160, 169))	('protein', 'cellular_component', 'GO:0003675', ('313', '320'))	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('mTORC1', 'Gene', (22, 28))	('mTORC1', 'cellular_component', 'GO:0031931', ('22', '28'))	('Ribosomal protein', 'molecular_function', 'GO:0003735', ('120', '137'))	('AMPK', 'molecular_function', 'GO:0004691', ('270', '274'))	('Ribosomal protein S6 kinase beta-1', 'Gene', (120, 154))	('Ribosomal protein S6 kinase beta-1', 'Gene', '6198', (120, 154))	('mTORC1', 'Gene', '382056', (22, 28))
109961	30581339	We used tumor samples with known mutational status in the VHL gene previously reported by our group.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('mutational status', 'Var', (33, 50))	('VHL', 'Gene', (58, 61))	('tumor', 'Disease', (8, 13))	('VHL', 'Gene', '7428', (58, 61))
109962	30581339	Among 37 samples of ccRCCs, in 21 (56.8%) tumors biallelic inactivation of VHL gene was detected (intragenic mutation plus loss of heterozygosity on 3p locus), 10 (27.0%) tumors have shown monoallelic inactivation of VHL (mutation or LOH on 3p locus) and in 6 (16.2%) tumors no alterations in VHL were found (wt VHL).	('VHL', 'Gene', (293, 296))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('biallelic', 'Var', (49, 58))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('VHL', 'Gene', (75, 78))	('VHL', 'Gene', '7428', (293, 296))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('VHL', 'Gene', '7428', (75, 78))	('VHL', 'Gene', (312, 315))	('tumors', 'Disease', (268, 274))	('VHL', 'Gene', (217, 220))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('mutation', 'Var', (109, 117))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumors', 'Disease', (42, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (20, 25))	('VHL', 'Gene', '7428', (312, 315))	('tumors', 'Disease', 'MESH:D009369', (268, 274))	('VHL', 'Gene', '7428', (217, 220))
109966	30581339	Only tumors with biallelic inactivation demonstrated lower mTOR and higher eIF4EBP1 expression in comparison to control tissue (P = 0.002 for both).	('eIF4', 'cellular_component', 'GO:0008304', ('75', '79'))	('biallelic inactivation', 'Var', (17, 39))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('higher', 'PosReg', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('eIF4EBP1', 'Gene', (75, 83))	('expression', 'MPA', (84, 94))	('mTOR', 'Gene', '2475', (59, 63))	('lower', 'NegReg', (53, 58))	('eIF4EBP1', 'Gene', '1978', (75, 83))	('mTOR', 'Gene', (59, 63))
109968	30581339	Tumors with monoallelic inactivation of VHL underexpressed REDD1 in comparison to both wt tumors (P = 0.042) and tumors with biallelic gene inactivation (P < 0.005) as well as to control tissue (P = 0.004).	('REDD1', 'Gene', (59, 64))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('VHL', 'Gene', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('monoallelic inactivation', 'Var', (12, 36))	('VHL', 'Gene', '7428', (40, 43))	('Tumors', 'Disease', (0, 6))	('tumors', 'Disease', (90, 96))	('underexpressed', 'NegReg', (44, 58))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('REDD1', 'Gene', '54541', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
109969	30581339	On the contrary, REDD1 expression in tumorous tissue with biallelic inactivation of VHL was higher than in control tissue (P = 0.008) (Figure 4).	('higher', 'PosReg', (92, 98))	('biallelic inactivation', 'Var', (58, 80))	('VHL', 'Gene', (84, 87))	('REDD1', 'Gene', (17, 22))	('VHL', 'Gene', '7428', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumorous', 'Disease', 'MESH:D009369', (37, 45))	('tumorous', 'Disease', (37, 45))	('REDD1', 'Gene', '54541', (17, 22))	('expression', 'MPA', (23, 33))
109973	30581339	Tumors with biallelic VHL gene inactivation exhibited higher expression levels of REDD1 than those with monoallelic VHL inactivation and corresponding control tissues.	('VHL', 'Gene', (22, 25))	('higher', 'PosReg', (54, 60))	('biallelic', 'Var', (12, 21))	('VHL', 'Gene', '7428', (22, 25))	('REDD1', 'Gene', '54541', (82, 87))	('VHL', 'Gene', (116, 119))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('VHL', 'Gene', '7428', (116, 119))	('REDD1', 'Gene', (82, 87))	('expression levels', 'MPA', (61, 78))
109974	30581339	While mTOR expression was similar among tumor tissues, it was lower in tissues with biallelic inactivation than in controls.	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('biallelic inactivation', 'Var', (84, 106))	('lower', 'NegReg', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('mTOR', 'Gene', '2475', (6, 10))	('mTOR', 'Gene', (6, 10))
109982	30581339	Similar expression levels of REDD1 in wt VHL and tumors with biallelic inactivation of VHL may indicate functional inactivation of pVHL rendered by hypoxia.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('inactivation', 'NegReg', (115, 127))	('tumors', 'Disease', (49, 55))	('expression levels', 'MPA', (8, 25))	('VHL', 'Gene', '7428', (87, 90))	('VHL', 'Gene', (132, 135))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('REDD1', 'Gene', (29, 34))	('VHL', 'Gene', '7428', (132, 135))	('REDD1', 'Gene', '54541', (29, 34))	('biallelic', 'Var', (61, 70))	('pVHL', 'Gene', '7428', (131, 135))	('pVHL', 'Gene', (131, 135))	('VHL', 'Gene', (41, 44))	('hypoxia', 'Disease', (148, 155))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('VHL', 'Gene', (87, 90))	('hypoxia', 'Disease', 'MESH:D000860', (148, 155))	('VHL', 'Gene', '7428', (41, 44))
109986	30581339	Possible explanations for the depletion of REDD1 could be the presence of Redd1 mutations, which are apparently rare.	('Redd1', 'Gene', (74, 79))	('mutations', 'Var', (80, 89))	('depletion', 'MPA', (30, 39))	('REDD1', 'Gene', '54541', (43, 48))	('Redd1', 'Gene', '54541', (74, 79))	('REDD1', 'Gene', (43, 48))
109991	30581339	Results of our study also implicate that the meta bolic profile of ccRCCs depends on the VHL mutational status.	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('mutational', 'Var', (93, 103))	('depends', 'Reg', (74, 81))	('VHL', 'Gene', (89, 92))	('VHL', 'Gene', '7428', (89, 92))	('ccRCCs', 'Disease', (67, 73))	('meta bolic profile', 'MPA', (45, 63))
109996	30581339	Although small sample size was a limitation of the present study, significant differences in the expression profile of wtVHL and tumors with biallelic inactivation of VHL may provide advantages in the therapy of ccRCC and should be considered for further investigation.	('VHL', 'Gene', '7428', (121, 124))	('advantages', 'PosReg', (183, 193))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (212, 217))	('biallelic inactivation', 'Var', (141, 163))	('ccRCC', 'Disease', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('VHL', 'Gene', (167, 170))	('therapy', 'CPA', (201, 208))	('VHL', 'Gene', '7428', (167, 170))	('VHL', 'Gene', (121, 124))	('expression', 'MPA', (97, 107))
109998	30581339	Our study provides additional evidence that VHL mutational status affects REDD1 expression in these tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutational status', 'Var', (48, 65))	('VHL', 'Gene', (44, 47))	('REDD1', 'Gene', '54541', (74, 79))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('REDD1', 'Gene', (74, 79))	('VHL', 'Gene', '7428', (44, 47))	('affects', 'Reg', (66, 73))	('expression', 'MPA', (80, 90))
110000	30581339	C control renal tissue; M/LOH VHL-mutated or loss of heterozygosity of 3p locus; M+LOH VHL-mutated and loss of heterozygosity of 3p locus; WT wild-type VHL.	('VHL', 'Gene', '7428', (87, 90))	('VHL', 'Gene', (152, 155))	('VHL', 'Gene', '7428', (152, 155))	('loss of heterozygosity', 'NegReg', (45, 67))	('VHL', 'Gene', (30, 33))	('VHL', 'Gene', '7428', (30, 33))	('M+LOH', 'Var', (81, 86))	('VHL', 'Gene', (87, 90))	('loss', 'NegReg', (103, 107))
110014	28946910	The diagnosis was molecularly confirmed with EWSR1 gene rearrangement.	('gene rearrangement', 'Var', (51, 69))	('EWSR1', 'Gene', (45, 50))	('EWSR1', 'Gene', '2130', (45, 50))
110080	31781328	Moreover, oxidation of H2S reduces the FAD prosthetic group, which uses ubiquinone (Q) as an electron acceptor, in electron transport chain which has a role in ATP production (Figure 1).	('reduces', 'NegReg', (27, 34))	('H2S', 'Gene', '110798', (23, 26))	('FAD', 'Chemical', 'MESH:D005182', (39, 42))	('ubiquinone', 'Chemical', 'MESH:D014451', (72, 82))	('oxidation', 'Var', (10, 19))	('FAD prosthetic group', 'Enzyme', (39, 59))	('H2S', 'Gene', (23, 26))	('ATP', 'Chemical', 'MESH:D000255', (160, 163))	('electron transport chain', 'biological_process', 'GO:0022900', ('115', '139'))
110092	31781328	It is reported that endogenous H2S can have procancerous effects and help the survival of tumors by stimulating angiogenesis along with promoting cell proliferation, metastasis, and drug resistance.	('help', 'PosReg', (69, 73))	('H2S', 'Gene', (31, 34))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('rat', 'Species', '10116', (158, 161))	('cell proliferation', 'CPA', (146, 164))	('H2S', 'Gene', '110798', (31, 34))	('drug resistance', 'CPA', (182, 197))	('survival', 'CPA', (78, 86))	('drug resistance', 'biological_process', 'GO:0009315', ('182', '197'))	('drug resistance', 'biological_process', 'GO:0042493', ('182', '197'))	('metastasis', 'CPA', (166, 176))	('angiogenesis', 'CPA', (112, 124))	('stimulating', 'PosReg', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cell proliferation', 'biological_process', 'GO:0008283', ('146', '164'))	('cancerous', 'Disease', 'MESH:D009369', (47, 56))	('angiogenesis', 'biological_process', 'GO:0001525', ('112', '124'))	('endogenous', 'Var', (20, 30))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('promoting', 'PosReg', (136, 145))	('drug resistance', 'Phenotype', 'HP:0020174', (182, 197))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('cancerous', 'Disease', (47, 56))	('tumors', 'Disease', (90, 96))
110114	31781328	Various reports suggest that alterations in H2S synthesis pathways may increase the risk of bladder cancer, suggesting that the modification of these pathways may lead to the development of novel diagnostic and therapeutic approaches for urological cancers.	('synthesis', 'biological_process', 'GO:0009058', ('48', '57'))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('bladder cancer', 'Disease', (92, 106))	('bladder cancer', 'Disease', 'MESH:D001749', (92, 106))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancers', 'Disease', (249, 256))	('alterations', 'Var', (29, 40))	('H2S', 'Gene', '110798', (44, 47))	('rat', 'Species', '10116', (33, 36))	('increase', 'PosReg', (71, 79))	('bladder cancer', 'Phenotype', 'HP:0009725', (92, 106))	('lead to', 'Reg', (163, 170))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('men', 'Species', '9606', (182, 185))	('H2S', 'Gene', (44, 47))
110140	31781328	Inactivation of the Von Hippel-Lindau (VHL) tumor suppressor, which is responsible for the degradation of hypoxia-inducible factor alpha subunits (HIF-1/2alpha) during normoxia, occurs in 90% of ccRCC cases.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('44', '60'))	('HIF-1/2alpha', 'Gene', (147, 159))	('RCC', 'Phenotype', 'HP:0005584', (197, 200))	('ccRCC', 'Phenotype', 'HP:0006770', (195, 200))	('hypoxia', 'Disease', 'MESH:D000860', (106, 113))	('ccRCC', 'Disease', (195, 200))	('hypoxia', 'Disease', (106, 113))	('HIF-1/2alpha', 'Gene', '3091;2034', (147, 159))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('degradation', 'biological_process', 'GO:0009056', ('91', '102'))	('ccRCC', 'Disease', 'MESH:D002292', (195, 200))	('tumor suppressor', 'biological_process', 'GO:0051726', ('44', '60'))	('Inactivation', 'Var', (0, 12))	('Von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (20, 49))
110157	31781328	also showed that, upon induction of apoptosis, the expression of these enzymes was upregulated in the RCC4 cell line (human RCC cell line) and silencing of CBS and CSE expression made the cells resistant to apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('207', '216'))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('apoptosis', 'biological_process', 'GO:0006915', ('207', '216'))	('CBS', 'Gene', (156, 159))	('human RCC', 'CellLine', 'CVCL:3285', (118, 127))	('RCC4', 'CellLine', 'CVCL:0498', (102, 106))	('resistant to apoptosis', 'CPA', (194, 216))	('CSE', 'Gene', (164, 167))	('expression', 'MPA', (51, 61))	('upregulated', 'PosReg', (83, 94))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('23', '45'))	('silencing', 'Var', (143, 152))
110158	31781328	It is possible that endogenous H2S induces apoptosis in ccRCC as it was previously reported with exogenous administration.	('rat', 'Species', '10116', (115, 118))	('apoptosis', 'CPA', (43, 52))	('H2S', 'Gene', (31, 34))	('endogenous', 'Var', (20, 30))	('induces', 'Reg', (35, 42))	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('ccRCC', 'Disease', 'MESH:D002292', (56, 61))	('ccRCC', 'Disease', (56, 61))	('H2S', 'Gene', '110798', (31, 34))
110159	31781328	The mechanisms behind RCC progression are not well understood, but it is suggested that knocking down of heat shock protein 60 (HSP60) increases the epithelial to mesenchymal transition and enhances invasion and also disturbs the respiratory complex 1 and triggers reactive oxygen molecules and then DNA methylation for further tumorigenesis.	('RCC', 'Disease', 'MESH:D002292', (22, 25))	('heat shock protein 60', 'Gene', '3329', (105, 126))	('knocking down', 'Var', (88, 101))	('epithelial to mesenchymal transition', 'CPA', (149, 185))	('tumor', 'Disease', (328, 333))	('DNA methylation', 'biological_process', 'GO:0006306', ('300', '315'))	('disturbs', 'Reg', (217, 225))	('HSP60', 'Gene', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('DNA methylation', 'MPA', (300, 315))	('oxygen', 'Chemical', 'MESH:D010100', (274, 280))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('reactive oxygen molecules', 'MPA', (265, 290))	('enhances', 'PosReg', (190, 198))	('shock', 'Phenotype', 'HP:0031273', (110, 115))	('triggers', 'Reg', (256, 264))	('rat', 'Species', '10116', (235, 238))	('increases', 'PosReg', (135, 144))	('invasion', 'CPA', (199, 207))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('149', '185'))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('DNA', 'cellular_component', 'GO:0005574', ('300', '303'))	('RCC', 'Disease', (22, 25))	('RCC', 'Phenotype', 'HP:0005584', (22, 25))	('heat shock protein 60', 'Gene', (105, 126))	('respiratory', 'Enzyme', (230, 241))	('HSP60', 'Gene', '3329', (128, 133))
110194	31781328	Moreover, pharmacological modulation of H2S synthetic pathways and exogenous administration of donor molecules may one day provide us with additional therapeutic avenues in treating patients with urological malignancies.	('urological malignancies', 'Disease', (196, 219))	('urological malignancies', 'Disease', 'MESH:D014571', (196, 219))	('H2S', 'Gene', '110798', (40, 43))	('rat', 'Species', '10116', (85, 88))	('donor', 'Species', '9606', (95, 100))	('patients', 'Species', '9606', (182, 190))	('modulation', 'Var', (26, 36))	('H2S', 'Gene', (40, 43))
110196	32487203	Because aberrant microRNA (miR) promoter methylation contributes to cancer development, we investigated whether altered miR-30a-5p expression associates with DNA promoter methylation and evaluated the usefulness as clear cell RCC (ccRCC) diagnostic and prognostic markers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('miR-30a-5p', 'Gene', (120, 130))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('DNA', 'cellular_component', 'GO:0005574', ('158', '161'))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('RCC', 'Disease', 'MESH:C538614', (233, 236))	('aberrant', 'Var', (8, 16))	('cancer', 'Disease', (68, 74))	('RCC', 'Disease', (226, 229))	('miR-30a-5p', 'Chemical', '-', (120, 130))	('altered', 'Var', (112, 119))	('contributes', 'Reg', (53, 64))	('RCC', 'Disease', (233, 236))	('men', 'Species', '9606', (82, 85))	('RCC', 'Disease', 'MESH:C538614', (226, 229))	('methylation', 'biological_process', 'GO:0032259', ('171', '182'))
110201	32487203	MiR-30a-5pme in ccRCC tissues was confirmed in an independent patient's cohort of IPOPorto and associated with shorter time to relapse.	('RCC', 'Disease', (18, 21))	('patient', 'Species', '9606', (62, 69))	('-30a-5pme', 'Chemical', '-', (3, 12))	('IPOPorto', 'Chemical', '-', (82, 90))	('MiR-30a-5p', 'Chemical', '-', (0, 10))	('MiR-30a-5pme', 'Var', (0, 12))	('RCC', 'Disease', 'MESH:C538614', (18, 21))
110202	32487203	In urine samples, miR-30a-5pme levels identified cancer both in testing and validation cohorts, with 83% sensitivity/53% specificity and 63% sensitivity/67% specificity, respectively.	('identified', 'Reg', (38, 48))	('-30a-5pme', 'Chemical', '-', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('miR-30a-5pme levels', 'Var', (18, 37))	('miR-30a-5p', 'Chemical', '-', (18, 28))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
110216	32487203	MiRs' deregulation has been shown to participate in tumorigenesis, affecting differentiation, invasion, migration and apoptosis and has been implicated in urological tumors.	('invasion', 'CPA', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('migration', 'CPA', (104, 113))	('tumor', 'Disease', (52, 57))	('apoptosis', 'biological_process', 'GO:0097194', ('118', '127'))	('apoptosis', 'biological_process', 'GO:0006915', ('118', '127'))	('MiRs', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('apoptosis', 'CPA', (118, 127))	('deregulation', 'Var', (6, 18))	('tumors', 'Disease', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('affecting', 'Reg', (67, 76))	('tumor', 'Disease', (166, 171))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('implicated', 'Reg', (141, 151))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('participate', 'Reg', (37, 48))	('differentiation', 'CPA', (77, 92))
110217	32487203	Several studies have associated microRNAs (miRs) deregulation with ccRCC clinicopathological features, suggesting a role in tumor initiation and progression.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('tumor initiation', 'Disease', 'MESH:D009369', (124, 140))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('microRNAs', 'MPA', (32, 41))	('deregulation', 'Var', (49, 61))	('tumor initiation', 'Disease', (124, 140))
110219	32487203	In ccRCC, an onco-suppressor function was proposed for miR-30a-5p, since its downregulation was associated with metastasis development.	('downregulation', 'NegReg', (77, 91))	('miR-30a-5p', 'Chemical', '-', (55, 65))	('metastasis development', 'CPA', (112, 134))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('RCC', 'Disease', (5, 8))	('miR-30a-5p', 'Var', (55, 65))	('men', 'Species', '9606', (130, 133))
110220	32487203	Moreover, miR-30a-5p was found to inhibit autophagy, by targeting BECN1, the gene encoding for beclin-1, a key protein for autophagosome formation.	('BECN1', 'Gene', '8678', (66, 71))	('autophagosome', 'cellular_component', 'GO:0005776', ('123', '136'))	('autophagy', 'biological_process', 'GO:0006914', ('42', '51'))	('autophagy', 'CPA', (42, 51))	('inhibit', 'NegReg', (34, 41))	('miR-30a-5p', 'Chemical', '-', (10, 20))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('beclin-1', 'Gene', (95, 103))	('BECN1', 'Gene', (66, 71))	('miR-30a-5p', 'Var', (10, 20))	('targeting', 'Reg', (56, 65))	('beclin-1', 'Gene', '8678', (95, 103))	('autophagosome formation', 'biological_process', 'GO:0000045', ('123', '146'))	('autophagy', 'biological_process', 'GO:0016236', ('42', '51'))
110221	32487203	In addition, miR-30a-5p was shown to decrease tumor microvessel density, by targeting endothelial DLL4, which is enrolled in tumor angiogenesis.	('decrease', 'NegReg', (37, 45))	('DLL4', 'Gene', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('angiogenesis', 'biological_process', 'GO:0001525', ('131', '143'))	('miR-30a-5p', 'Var', (13, 23))	('endothelial', 'Protein', (86, 97))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (125, 130))	('DLL4', 'Gene', '54567', (98, 102))	('targeting', 'Reg', (76, 85))	('miR-30a-5p', 'Chemical', '-', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
110223	32487203	Similarly to protein coding genes, miRs' downregulation might be associated with aberrant promoter methylation, a common feature of urological tumors.	('aberrant', 'Var', (81, 89))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('methylation', 'biological_process', 'GO:0032259', ('99', '110'))	('tumors', 'Disease', (143, 149))	('promoter', 'MPA', (90, 98))	('miRs', 'Gene', (35, 39))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('downregulation', 'NegReg', (41, 55))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
110259	32487203	In univariable analysis, both miR-30a-5p expression and promoter methylation independently predicted worse overall survival (OS) and shorter recurrence-free survival (RFS).	('shorter', 'NegReg', (133, 140))	('RFS', 'Disease', (167, 170))	('miR-30a-5p', 'Var', (30, 40))	('overall survival', 'MPA', (107, 123))	('RFS', 'Disease', 'MESH:D005198', (167, 170))	('worse', 'NegReg', (101, 106))	('recurrence-free survival', 'CPA', (141, 165))	('methylation', 'biological_process', 'GO:0032259', ('65', '76'))	('miR-30a-5p', 'Chemical', '-', (30, 40))
110260	32487203	Of note, miR-30a-5pme also remained an independent predictor of shorter RFS in this model, as well as when tumor grade was included (Supplementary Table 1).	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('miR-30a-5pme', 'Var', (9, 21))	('miR-30a-5p', 'Chemical', '-', (9, 19))	('men', 'Species', '9606', (139, 142))	('RFS', 'Disease', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('-30a-5pme', 'Chemical', '-', (12, 21))	('RFS', 'Disease', 'MESH:D005198', (72, 75))	('shorter', 'NegReg', (64, 71))
110266	32487203	Conversely, no significant association was found between miR-30a-5pme levels and classical clinical indexes, namely synchronous metastatic dissemination (p = 0.545), recurrence (p = 0.128), Fuhrman Grade (p = 0.165), stage (p = 0.816), tumor size (p = 0.161) and age (p = 0.305).	('-30a-5pme', 'Chemical', '-', (60, 69))	('synchronous metastatic dissemination', 'CPA', (116, 152))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('miR-30a-5pme', 'Var', (57, 69))	('miR-30a-5p', 'Chemical', '-', (57, 67))	('Fuhrman Grade', 'CPA', (190, 203))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Disease', (236, 241))
110273	32487203	In multivariable analysis, only pathological stage, nuclear grade and miR-30a-5pme levels (20th percentile) retained independent prognostic value for DSS (Table 2; Supplementary Table 4 and 5).	('miR-30a-5pme', 'Var', (70, 82))	('miR-30a-5p', 'Chemical', '-', (70, 80))	('DSS', 'Gene', (150, 153))	('-30a-5pme', 'Chemical', '-', (73, 82))	('DSS', 'Gene', '5376', (150, 153))	('men', 'Species', '9606', (170, 173))
110276	32487203	Moreover, miR-30a-5pme levels identified malignancy with 83% sensitivity and 53% specificity, providing an overall accuracy of 67% [AUC of 0.6837, (P = 0.0009) (Fig.	('miR-30a-5pme', 'Var', (10, 22))	('malignancy', 'Disease', 'MESH:D009369', (41, 51))	('malignancy', 'Disease', (41, 51))	('miR-30a-5p', 'Chemical', '-', (10, 20))	('-30a-5pme', 'Chemical', '-', (13, 22))
110279	32487203	However, no further associations were found between miR-30a-5pme levels and other variables, namely age and tumor size (P = 0.294 and P = 0.224, respectively).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('miR-30a-5pme', 'Var', (52, 64))	('miR-30a-5p', 'Chemical', '-', (52, 62))	('tumor', 'Disease', (108, 113))	('-30a-5pme', 'Chemical', '-', (55, 64))
110283	32487203	Remarkably, higher miR-30a-5pme (above 70th percentile) also associated with shorter MFS and worse DSS [P = 0.003 and P = 0.001, respectively; Fig.	('MFS', 'Disease', 'MESH:D008382', (85, 88))	('DSS', 'Gene', (99, 102))	('DSS', 'Gene', '5376', (99, 102))	('miR-30a-5pme', 'Var', (19, 31))	('MFS', 'Disease', (85, 88))	('shorter', 'NegReg', (77, 84))	('miR-30a-5p', 'Chemical', '-', (19, 29))	('-30a-5pme', 'Chemical', '-', (22, 31))
110290	32487203	Moreover, miR-30a-5pme did not significantly associate with either age or tumor size (p = 0.280 and p = 0.460, respectively.	('associate', 'Reg', (45, 54))	('miR-30a-5pme', 'Var', (10, 22))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('miR-30a-5p', 'Chemical', '-', (10, 20))	('-30a-5pme', 'Chemical', '-', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))
110295	32487203	This being said, we aimed to determine whether (a) miR-30a-5p expression silencing was due to aberrant promoter methylation and (b) miR-30a-5pme levels might not only accurately detect ccRCC in tissue and urine samples, but also identify patients at increased risk to develop metastatic disease independently of standard clinicopathological parameters.	('methylation', 'biological_process', 'GO:0032259', ('112', '123'))	('metastatic disease', 'Disease', (276, 294))	('RCC', 'Disease', (187, 190))	('miR-30a-5pme', 'Var', (132, 144))	('miR-30a-5p', 'Chemical', '-', (51, 61))	('aid', 'Gene', '57379', (12, 15))	('promoter methylation', 'MPA', (103, 123))	('develop', 'PosReg', (268, 275))	('RCC', 'Disease', 'MESH:C538614', (187, 190))	('expression', 'MPA', (62, 72))	('miR-30a-5p', 'Gene', (51, 61))	('miR-30a-5p', 'Chemical', '-', (132, 142))	('-30a-5pme', 'Chemical', '-', (135, 144))	('aid', 'Gene', (12, 15))	('patients', 'Species', '9606', (238, 246))	('silencing', 'NegReg', (73, 82))
110299	32487203	Thus, our results add miR-30a-5p to the growing list of epigenetically-deregulated microRNAs in urologic malignancies, reinforcing the contribution of epigenetic alterations to renal carcinogenesis.	('renal carcinogenesis', 'Disease', 'MESH:D063646', (177, 197))	('malignancies', 'Disease', (105, 117))	('miR-30a-5p', 'Var', (22, 32))	('miR-30a-5p', 'Chemical', '-', (22, 32))	('malignancies', 'Disease', 'MESH:D009369', (105, 117))	('renal carcinogenesis', 'Disease', (177, 197))
110300	32487203	Notwithstanding the mechanism underlying miR-30a-5p downregulation in ccRCC, our study firstly demonstrated that miR-30a-5pme levels might be a specific biomarker for this cancer type.	('miR-30a-5p', 'Chemical', '-', (41, 51))	('-30a-5pme', 'Chemical', '-', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('miR-30a-5pme', 'Var', (113, 125))	('downregulation', 'NegReg', (52, 66))	('cancer', 'Disease', (172, 178))	('miR-30a-5p', 'Chemical', '-', (113, 123))
110308	32487203	Although miR-30a-5pme biomarker performance in Cohort #3 was not impressive, it should be highlighted that miR-30a-5pme levels were able to identify six out of each ten ccRCC in urine samples and, notably, correctly classified seven out of each ten suspects.	('miR-30a-5pme', 'Var', (107, 119))	('miR-30a-5p', 'Chemical', '-', (107, 117))	('miR-30a-5p', 'Chemical', '-', (9, 19))	('-30a-5pme', 'Chemical', '-', (110, 119))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('RCC', 'Disease', (171, 174))	('-30a-5pme', 'Chemical', '-', (12, 21))
110314	32487203	Importantly, miR-30a-5pme levels might aid for diagnostic and prognostic purposes, helping to identify patients at higher risk for disease progression and metastization, although additional markers should be included to improve its overall performance as diagnostic/prognostic biomarker.	('aid', 'Gene', (39, 42))	('aid', 'Gene', '57379', (39, 42))	('miR-30a-5p', 'Chemical', '-', (13, 23))	('patients', 'Species', '9606', (103, 111))	('metastization', 'CPA', (155, 168))	('miR-30a-5pme', 'Var', (13, 25))	('-30a-5pme', 'Chemical', '-', (16, 25))
110330	32313718	Moreover, RASSF10, CD68 or CD163, TNM stage, and SSIGN score were identified as independent risk factors in predicting ccRCC patients' prognosis.	('CD68', 'Var', (19, 23))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('CD163', 'Var', (27, 32))	('RASSF10', 'Var', (10, 17))	('patients', 'Species', '9606', (125, 133))
110331	32313718	Time-dependent c-index analyses revealed that the combination of RASSF10 and TAMs resulted in a higher index than that resulting from each alone in the postoperative prognosis of ccRCC patients, and the integration of RASSF10 and TAMs with the TNM stage or SSIGN score achieved the best accuracy in assessing the prognosis of ccRCC patients.	('ccRCC', 'Phenotype', 'HP:0006770', (326, 331))	('TAMs', 'Chemical', '-', (230, 234))	('ccRCC', 'Phenotype', 'HP:0006770', (179, 184))	('index', 'MPA', (103, 108))	('RASSF10', 'Var', (65, 72))	('TAMs', 'Chemical', '-', (77, 81))	('patients', 'Species', '9606', (332, 340))	('RCC', 'Disease', 'MESH:C538614', (328, 331))	('RCC', 'Disease', (328, 331))	('patients', 'Species', '9606', (185, 193))	('higher', 'PosReg', (96, 102))	('RCC', 'Disease', 'MESH:C538614', (181, 184))	('RCC', 'Disease', (181, 184))	('RASSF10', 'Var', (218, 225))
110346	32313718	Furthermore, CD163+ TAMs are useful for assessing the clinical prognosis of patients with ccRCC.	('patients', 'Species', '9606', (76, 84))	('TAMs', 'Chemical', '-', (20, 24))	('CD163+', 'Var', (13, 19))	('RCC', 'Disease', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))
110351	32313718	Moreover, recent studies have demonstrated that RASSF10 methylation is a potential docetaxel-resistant marker for human breast cancer and hepatocellular carcinoma, suggesting that RASSF10 is also a potential therapeutic target.	('docetaxel', 'Chemical', 'MESH:D000077143', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (138, 162))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (138, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('hepatocellular carcinoma', 'Disease', (138, 162))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('RASSF10', 'Gene', (48, 55))	('human', 'Species', '9606', (114, 119))	('methylation', 'Var', (56, 67))
110353	32313718	The epigenetic silencing of RASSF10 is usually observed in tumors, and its hypermethylation serves as an independent prognostic factor in patients.	('epigenetic silencing', 'Var', (4, 24))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('observed', 'Reg', (47, 55))	('RASSF10', 'Gene', (28, 35))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('hypermethylation', 'MPA', (75, 91))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('patients', 'Species', '9606', (138, 146))
110373	32313718	The primary antibodies used were rabbit anti-RASSF10 antibody (PA5-48377, Thermo Fisher) and rabbit anti-GAPDH antibody (2118S, Cell Signaling Technology).	('PA5-48377', 'Var', (63, 72))	('antibody', 'cellular_component', 'GO:0019815', ('111', '119'))	('antibody', 'molecular_function', 'GO:0003823', ('53', '61'))	('antibody', 'cellular_component', 'GO:0019814', ('111', '119'))	('antibody', 'molecular_function', 'GO:0003823', ('111', '119'))	('GAPDH', 'Gene', '2597', (105, 110))	('antibody', 'cellular_component', 'GO:0042571', ('53', '61'))	('antibody', 'cellular_component', 'GO:0019815', ('53', '61'))	('Signaling', 'biological_process', 'GO:0023052', ('133', '142'))	('antibody', 'cellular_component', 'GO:0042571', ('111', '119'))	('GAPDH', 'Gene', (105, 110))	('antibody', 'cellular_component', 'GO:0019814', ('53', '61'))
110406	32313718	As shown in Supplementary Table S7 and Supplementary Figure S2i-j, low expression levels of RASSF10 predicted a higher WHO/ISUP grading (p = .003), TNM stage (p = .011), SSIGN score (p = .01), and worse OS (p < .001) and PFS (p < .001) of ccRCC patients in the training cohort than their counterparts, which was also confirmed in the validation cohort (Supplementary Table S8; Supplementary Figure S2k-l).	('PFS', 'CPA', (221, 224))	('low', 'Var', (67, 70))	('RASSF10', 'Gene', (92, 99))	('TNM stage', 'CPA', (148, 157))	('higher', 'PosReg', (112, 118))	('patients', 'Species', '9606', (245, 253))	('SSIGN score', 'CPA', (170, 181))	('WHO/ISUP grading', 'CPA', (119, 135))	('RCC', 'Disease', 'MESH:C538614', (241, 244))	('RCC', 'Disease', (241, 244))	('expression levels', 'MPA', (71, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (239, 244))
110414	32313718	Then, cohort 1 of ccRCC patients was divided into four groups: RASSF10highCD68low, RASSF10lowCD68low, RASSF10highCD68high, and RASSF10lowCD68high (Table 2).	('RASSF10highCD68high', 'Var', (102, 121))	('RASSF10lowCD68high', 'Var', (127, 145))	('RASSF10highCD68low', 'Var', (63, 81))	('patients', 'Species', '9606', (24, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (18, 23))	('RCC', 'Disease', (20, 23))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('RASSF10lowCD68low', 'Var', (83, 100))
110415	32313718	As shown in Figure 3(d,e) and Table 2, patients with low RASSF10 expression and high CD68 expression exhibited not only a higher WHO/ISUP grading (p < .001), TNM stage (p = .013), and SSIGN score (p = .024) but also worse OS (p < .001) and PFS (p < .001).	('low', 'NegReg', (53, 56))	('patients', 'Species', '9606', (39, 47))	('SSIGN score', 'CPA', (184, 195))	('higher', 'PosReg', (122, 128))	('WHO/ISUP grading', 'CPA', (129, 145))	('expression', 'MPA', (65, 75))	('expression', 'MPA', (90, 100))	('CD68', 'Gene', (85, 89))	('TNM stage', 'CPA', (158, 167))	('high', 'Var', (80, 84))	('RASSF10', 'Gene', (57, 64))
110419	32313718	To further determine the prognostic value of RASSF10 and TAMs in assessing the survival of ccRCC patients, univariate and multivariate Cox regression analyses were performed to determine whether RASSF10 and TAMs were independent risk factors for evaluating OS and PFS in ccRCC patients.	('TAMs', 'Chemical', '-', (57, 61))	('PFS', 'Disease', (264, 267))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('RCC', 'Disease', (93, 96))	('RASSF10', 'Var', (195, 202))	('RCC', 'Disease', 'MESH:C538614', (273, 276))	('RCC', 'Disease', (273, 276))	('patients', 'Species', '9606', (277, 285))	('TAMs', 'Chemical', '-', (207, 211))	('ccRCC', 'Phenotype', 'HP:0006770', (271, 276))	('patients', 'Species', '9606', (97, 105))
110420	32313718	Even after multivariable adjustment (including age, gender, WHO/ISUP grading, TNM stage, SSIGN score, RASSF10, and CD68 or CD163), RASSF10, CD68 or CD163, TNM stage, and SSIGN score were identified as independent risk factors for the prognosis of ccRCC patients in both cohort 1, cohort 2, and the combined cohort (Table 3; Supplementary Tables S19-23).	('patients', 'Species', '9606', (253, 261))	('CD163', 'Var', (148, 153))	('CD68', 'Var', (140, 144))	('RCC', 'Disease', 'MESH:C538614', (249, 252))	('RCC', 'Disease', (249, 252))	('ccRCC', 'Phenotype', 'HP:0006770', (247, 252))	('RASSF10', 'Var', (131, 138))	('CD68', 'Var', (115, 119))
110421	32313718	These results demonstrate that RASSF10 and TAMs are independent risk factors for ccRCC patients' prognosis.	('TAMs', 'Chemical', '-', (43, 47))	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('RASSF10', 'Var', (31, 38))	('patients', 'Species', '9606', (87, 95))
110432	32313718	Moreover, the combination of RASSF10 and TAMs resulted in a higher index than that of each alone in the postoperative prognosis of ccRCC patients, and the integration of RASSF10 and TAMs with the TNM stage or SSIGN score resulted in better accuracy in predicting the prognosis of ccRCC patients.	('RASSF10', 'Var', (29, 36))	('RCC', 'Disease', 'MESH:C538614', (282, 285))	('ccRCC', 'Phenotype', 'HP:0006770', (280, 285))	('RCC', 'Disease', (282, 285))	('higher', 'PosReg', (60, 66))	('TAMs', 'Chemical', '-', (41, 45))	('TAMs', 'Chemical', '-', (182, 186))	('patients', 'Species', '9606', (286, 294))	('patients', 'Species', '9606', (137, 145))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('index', 'MPA', (67, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('RASSF10', 'Var', (170, 177))
110435	32313718	The methylation and downregulation of RASSF10 could be associated with an advanced tumor stage and an advanced age of patients with prostate cancer.	('prostate cancer', 'Disease', (132, 147))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('downregulation', 'NegReg', (20, 34))	('RASSF10', 'Gene', (38, 45))	('methylation', 'Var', (4, 15))	('associated', 'Reg', (55, 65))	('prostate cancer', 'Disease', 'MESH:D011471', (132, 147))	('prostate cancer', 'Phenotype', 'HP:0012125', (132, 147))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('patients', 'Species', '9606', (118, 126))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))
110456	32313718	Moreover, in contrast to any single variable (e.g., RASSF10, TAMs, TNM stage, and SSIGN classifier), the integrated system model (RASSF10-TAMs-TNM stage or SSIGN) exhibited a better prognostic value for predicting the prognosis of ccRCC patients.	('TAMs', 'Chemical', '-', (61, 65))	('RASSF10-TAMs-TNM', 'Var', (130, 146))	('TAMs', 'Chemical', '-', (138, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (231, 236))	('RCC', 'Disease', 'MESH:C538614', (233, 236))	('patients', 'Species', '9606', (237, 245))	('RCC', 'Disease', (233, 236))
110464	28951458	Recently, HIF2alpha antagonists PT2385 and PT2399 were developed and are being evaluated in a Phase I clinical trial for advanced or metastatic clear cell RCC (ccRCC).	('RCC', 'Disease', (155, 158))	('RCC', 'Disease', (162, 165))	('RCC', 'Phenotype', 'HP:0005584', (162, 165))	('PT2399', 'Var', (43, 49))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('PT2399', 'Chemical', 'MESH:C000614278', (43, 49))	('PT2385', 'Var', (32, 38))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('RCC', 'Disease', 'MESH:C538614', (155, 158))
110465	28951458	In this study, we identified signals activated by HIF2alpha deficiency as candidate mediators of resistance to the multi-kinase inhibitor sunitinib.	('kinase inhibitor', 'biological_process', 'GO:0033673', ('121', '137'))	('sunitinib', 'Chemical', 'MESH:D000077210', (138, 147))	('deficiency', 'Var', (60, 70))	('HIF2alpha', 'Gene', (50, 59))
110466	28951458	We established sunitinib-resistant tumor cells in vivo and created HIF2alpha-deficient variants of these cells using CRISPR/Cas9 technology.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('Cas', 'cellular_component', 'GO:0005650', ('124', '127'))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('variants', 'Var', (87, 95))	('tumor', 'Disease', (35, 40))	('sunitinib', 'Chemical', 'MESH:D000077210', (15, 24))	('HIF2alpha-deficient', 'Gene', (67, 86))
110468	28951458	Accordingly, treatment with a PHGDH inhibitor reduced the growth of HIF2alpha-deficient tumor cells in vivo and in vitro by inducing apoptosis.	('inhibitor', 'Var', (36, 45))	('HIF2alpha-deficient tumor', 'Disease', (68, 93))	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('apoptosis', 'CPA', (133, 142))	('PHGDH', 'Gene', (30, 35))	('inducing', 'Reg', (124, 132))	('HIF2alpha-deficient tumor', 'Disease', 'MESH:D009369', (68, 93))	('growth', 'MPA', (58, 64))	('reduced', 'NegReg', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('PHGDH', 'Gene', '26227', (30, 35))
110477	28951458	In addition, PT2399 has also been shown to lead to improved outcomes with regard to progression-free survival in patients with advanced or metastatic ccRCC who had prior TKIs.	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('RCC', 'Disease', (152, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('improved', 'PosReg', (51, 59))	('patients', 'Species', '9606', (113, 121))	('PT2399', 'Var', (13, 19))	('PT2399', 'Chemical', 'MESH:C000614278', (13, 19))	('progression-free survival', 'CPA', (84, 109))
110478	28951458	Although HIF2alpha antagonists have shown promising potency, ccRCCs requiring long treatment periods with HIF2alpha antagonists acquired resistance through HIF mutations that prevent PT2399 from entering the cavity or preserve HIF2 dimers due to structural changes.	('RCC', 'Disease', (63, 66))	('mutations', 'Var', (160, 169))	('prevent', 'Reg', (175, 182))	('RCC', 'Disease', 'MESH:C538614', (63, 66))	('PT2399', 'Chemical', 'MESH:C000614278', (183, 189))	('PT2399', 'Gene', (183, 189))	('entering the', 'MPA', (195, 207))	('resistance', 'MPA', (137, 147))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('HIF2 dimers', 'MPA', (227, 238))
110479	28951458	Accordingly, we established sunitinib-resistant 786-o (SU-R-786-o) ccRCC cells and knocked out HIF2alpha in this cell line (HIF2alpha-KO-SU-R-786-o cells) in order to elucidate the survival mechanism of HIF2alpha-deficient ccRCC cells.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('SU-R', 'Gene', '6833', (137, 141))	('SU-R', 'Gene', (55, 59))	('RCC', 'Disease', (225, 228))	('RCC', 'Phenotype', 'HP:0005584', (225, 228))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('SU-R', 'Gene', '6833', (55, 59))	('HIF2alpha', 'Gene', (95, 104))	('SU-R', 'Gene', (137, 141))	('knocked', 'Var', (83, 90))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('sunitinib', 'Chemical', 'MESH:D000077210', (28, 37))
110520	28951458	Cell proliferation was inhibited by si-PHGDH transfection in HIF2alpha-KO-SU-R-786-o cells compared to empty cells (Fig.	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('PHGDH', 'Gene', (39, 44))	('inhibited', 'NegReg', (23, 32))	('transfection', 'Var', (45, 57))	('SU-R', 'Gene', (74, 78))	('PHGDH', 'Gene', '26227', (39, 44))	('SU-R', 'Gene', '6833', (74, 78))	('Cell proliferation', 'CPA', (0, 18))
110522	28951458	In addition, CBR-5884 significantly induced apoptosis in HIF2alpha-KO-SU-R-786-o cells (Fig.	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('apoptosis', 'CPA', (44, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('SU-R', 'Gene', (70, 74))	('SU-R', 'Gene', '6833', (70, 74))	('induced', 'PosReg', (36, 43))	('CBR-5884', 'Var', (13, 21))
110525	28951458	We found that tumour growth was significantly suppressed in the mice treated with NCT-503 compared with that in vehicle-treated mice (Fig.	('tumour', 'Disease', (14, 20))	('mice', 'Species', '10090', (128, 132))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('NCT-503', 'Var', (82, 89))	('tumour', 'Disease', 'MESH:D009369', (14, 20))	('mice', 'Species', '10090', (64, 68))	('suppressed', 'NegReg', (46, 56))
110531	28951458	The number of colonies were significantly increased in PHGDH overexpressed 786-o or A498 cells compared to parental cells (Fig.	('increased', 'PosReg', (42, 51))	('overexpressed', 'Var', (61, 74))	('PHGDH', 'Gene', '26227', (55, 60))	('PHGDH', 'Gene', (55, 60))
110532	28951458	According to TCGA database, patients with PHGDH gene amplification (n = 24) had poor overall survival and disease-free survival in comparison to patients without amplification (n = 500; P = 0.0003 and 0.0329, respectively; Fig.	('patients', 'Species', '9606', (145, 153))	('poor', 'NegReg', (80, 84))	('disease-free survival', 'CPA', (106, 127))	('PHGDH', 'Gene', '26227', (42, 47))	('amplification', 'Var', (53, 66))	('PHGDH', 'Gene', (42, 47))	('patients', 'Species', '9606', (28, 36))	('overall survival', 'CPA', (85, 101))
110533	28951458	A multivariate Cox proportional hazards model also showed that PHGDH gene amplification was an independent predictor of overall survival (Fig.	('amplification', 'Var', (74, 87))	('PHGDH', 'Gene', '26227', (63, 68))	('PHGDH', 'Gene', (63, 68))	('Cox', 'Gene', '1351', (15, 18))	('overall survival', 'MPA', (120, 136))	('Cox', 'Gene', (15, 18))
110534	28951458	We also analysed relationship between PHGDH copy number alteration and Von Hippel-Lindau (VHL) mutation, HIF1A, or HIF2A.	('VHL', 'Gene', '7428', (90, 93))	('HIF1A', 'Gene', (105, 110))	('HIF2A', 'Gene', (115, 120))	('HIF1A', 'Gene', '3091', (105, 110))	('Von Hippel-Lindau', 'Gene', '7428', (71, 88))	('PHGDH', 'Gene', '26227', (38, 43))	('Von Hippel-Lindau', 'Gene', (71, 88))	('HIF2A', 'Gene', '2034', (115, 120))	('PHGDH', 'Gene', (38, 43))	('analysed', 'Reg', (8, 16))	('VHL', 'Gene', (90, 93))	('copy number alteration', 'Var', (44, 66))	('mutation', 'Var', (95, 103))
110535	28951458	There was no significant relationship between PHGDH copy number alteration and VHL mutation (P = 0.491), or HIF1A expression (P = 0.0649) (Suppl.	('VHL', 'Gene', '7428', (79, 82))	('copy number alteration', 'Var', (52, 74))	('mutation', 'Var', (83, 91))	('PHGDH', 'Gene', '26227', (46, 51))	('HIF1A', 'Gene', (108, 113))	('HIF1A', 'Gene', '3091', (108, 113))	('VHL', 'Gene', (79, 82))	('PHGDH', 'Gene', (46, 51))
110536	28951458	However, there was a significant negative correlation between PHGDH copy number alteration and EPAS1 (HIF2A) expression (P = 0.0062) (Suppl.	('EPAS1', 'Gene', '2034', (95, 100))	('expression', 'MPA', (109, 119))	('EPAS1', 'Gene', (95, 100))	('PHGDH', 'Gene', '26227', (62, 67))	('HIF2A', 'Gene', (102, 107))	('PHGDH', 'Gene', (62, 67))	('negative', 'NegReg', (33, 41))	('HIF2A', 'Gene', '2034', (102, 107))	('copy number alteration', 'Var', (68, 90))
110540	28951458	In the absence of oxygen or the presence of a mutated VHL gene, HIF1alpha and HIF2alpha are stabilised and induce the expression of various transcriptional target genes, such as VEGF, PDGF, and TGF-alpha, to facilitate angiogenesis, migration, and proliferation through the development of an aggressive phenotype and resistance to chemotherapy and radiation therapy, thereby supporting the metabolic shift that underlies RCC tumourigenicity.	('tumour', 'Phenotype', 'HP:0002664', (425, 431))	('aggressive phenotype', 'CPA', (292, 312))	('VHL', 'Gene', (54, 57))	('mutated', 'Var', (46, 53))	('tumour', 'Disease', 'MESH:D009369', (425, 431))	('tumour', 'Disease', (425, 431))	('PDGF', 'Gene', (184, 188))	('facilitate', 'PosReg', (208, 218))	('VEGF', 'Gene', '7422', (178, 182))	('VHL', 'Gene', '7428', (54, 57))	('TGF-alpha', 'Gene', '7039', (194, 203))	('VEGF', 'Gene', (178, 182))	('PDGF', 'molecular_function', 'GO:0005161', ('184', '188'))	('RCC', 'Disease', (421, 424))	('HIF1alpha', 'Gene', '3091', (64, 73))	('RCC', 'Phenotype', 'HP:0005584', (421, 424))	('angiogenesis', 'biological_process', 'GO:0001525', ('219', '231'))	('expression', 'MPA', (118, 128))	('migration', 'CPA', (233, 242))	('TGF-alpha', 'Gene', (194, 203))	('proliferation', 'CPA', (248, 261))	('HIF1alpha', 'Gene', (64, 73))	('RCC', 'Disease', 'MESH:C538614', (421, 424))	('induce', 'PosReg', (107, 113))	('HIF2alpha', 'Var', (78, 87))	('oxygen', 'Chemical', 'MESH:D010100', (18, 24))	('angiogenesis', 'CPA', (219, 231))
110544	28951458	In addition, they identified HIF mutations that prevented PT2399 from entering the cavity or preserved HIF-2 dimers due to structural changes, thereby contributing to the resistance mechanism.	('PT2399', 'Chemical', 'MESH:C000614278', (58, 64))	('contributing', 'Reg', (151, 163))	('PT2399', 'Gene', (58, 64))	('HIF-2', 'Gene', (103, 108))	('entering the cavity', 'MPA', (70, 89))	('dimers', 'MPA', (109, 115))	('prevented', 'NegReg', (48, 57))	('mutations', 'Var', (33, 42))	('structural changes', 'MPA', (123, 141))
110548	28951458	In a ccRCC cohort from TCGA database, patients with PHGDH gene amplification had poor overall survival and disease-free survival in comparison to patients without amplification; therefore, PHGDH could be targeted not only for patients showing resistance to HIF2alpha antagonists but also for patients showing PHGDH gene amplification.	('PHGDH', 'Gene', '26227', (189, 194))	('PHGDH', 'Gene', '26227', (309, 314))	('RCC', 'Phenotype', 'HP:0005584', (7, 10))	('patients', 'Species', '9606', (38, 46))	('RCC', 'Disease', 'MESH:C538614', (7, 10))	('PHGDH', 'Gene', (189, 194))	('PHGDH', 'Gene', (309, 314))	('PHGDH', 'Gene', '26227', (52, 57))	('patients', 'Species', '9606', (226, 234))	('PHGDH', 'Gene', (52, 57))	('patients', 'Species', '9606', (292, 300))	('RCC', 'Disease', (7, 10))	('amplification', 'Var', (63, 76))	('patients', 'Species', '9606', (146, 154))
110549	28951458	TCGA database also showed no significant relationship of PHGDH copy number alteration with VHL mutation, or HIF1A expression but a significant negative correlation of it with EPAS1 (HIF2A) expression.	('negative', 'NegReg', (143, 151))	('EPAS1', 'Gene', (175, 180))	('PHGDH', 'Gene', (57, 62))	('VHL', 'Gene', (91, 94))	('HIF2A', 'Gene', '2034', (182, 187))	('EPAS1', 'Gene', '2034', (175, 180))	('expression', 'MPA', (189, 199))	('VHL', 'Gene', '7428', (91, 94))	('copy number', 'Var', (63, 74))	('HIF1A', 'Gene', (108, 113))	('HIF2A', 'Gene', (182, 187))	('HIF1A', 'Gene', '3091', (108, 113))	('PHGDH', 'Gene', '26227', (57, 62))
110557	28951458	Notably, in our study, endogenous metabolites were clearly altered among 786-o parent, SU-R-786-o, and HIF2alpha-KO-SU-R-786-o cells.	('altered', 'Reg', (59, 66))	('SU-R', 'Gene', '6833', (116, 120))	('SU-R', 'Gene', (87, 91))	('786-o', 'Var', (73, 78))	('SU-R', 'Gene', '6833', (87, 91))	('SU-R', 'Gene', (116, 120))	('endogenous metabolites', 'MPA', (23, 45))
110562	31258735	PPARalpha gene is a diagnostic and prognostic biomarker in clear cell renal cell carcinoma by integrated bioinformatics analysis Genetic alterations in lipid metabolism genes are correlated with progression and poor prognosis of Clear cell renal cell carcinoma (ccRCC).	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (70, 90))	('PPARalpha', 'Gene', '5465', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('PPARalpha', 'Gene', (0, 9))	('lipid metabolism', 'biological_process', 'GO:0006629', ('152', '168'))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (59, 90))	('lipid', 'Chemical', 'MESH:D008055', (152, 157))	('lipid metabolism genes', 'Gene', (152, 174))	('ccRCC', 'Phenotype', 'HP:0006770', (262, 267))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (229, 260))	('alterations', 'Var', (137, 148))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (240, 260))	('RCC', 'Disease', (264, 267))	('RCC', 'Phenotype', 'HP:0005584', (264, 267))	('Clear cell renal cell carcinoma', 'Disease', (229, 260))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (59, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('RCC', 'Disease', 'MESH:C538614', (264, 267))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (229, 260))	('correlated', 'Reg', (179, 189))	('clear cell renal cell carcinoma', 'Disease', (59, 90))
110623	31258735	Moreover, we validated it in GEO database, we selected GSE53757 and GSE6344 for validation and the result was consistent with TCGA (Figure S1B-C).	('GSE6344', 'Chemical', '-', (68, 75))	('GSE53757', 'Var', (55, 63))	('GSE6344', 'Var', (68, 75))
110674	31258735	Spaner's research suggested PPARalpha antagonist MK886 induces chronic lymphocytic leukemia (CLL) cell death and xenografts tumor growth by reducing PPARalpha mediated interleukin-10 (IL-10) and phospho-STAT3 levels in CD5 (+) Daudicells.	('IL-10', 'Gene', (184, 189))	('CLL', 'Phenotype', 'HP:0005550', (93, 96))	('tumor', 'Disease', (124, 129))	('death', 'Disease', (103, 108))	('interleukin-10', 'Gene', (168, 182))	('cell death', 'biological_process', 'GO:0008219', ('98', '108'))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('CD5', 'Gene', (219, 222))	('induces', 'PosReg', (55, 62))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (63, 91))	('MK886', 'Var', (49, 54))	('PPARalpha', 'MPA', (149, 158))	('interleukin-10', 'Gene', '3586', (168, 182))	('chronic lymphocytic leukemia', 'Disease', (63, 91))	('STAT3', 'Gene', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('CD5', 'Gene', '921', (219, 222))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (63, 91))	('leukemia', 'Phenotype', 'HP:0001909', (83, 91))	('death', 'Disease', 'MESH:D003643', (103, 108))	('STAT3', 'Gene', '6774', (203, 208))	('IL-10', 'molecular_function', 'GO:0005141', ('184', '189'))	('reducing', 'NegReg', (140, 148))	('MK886', 'Chemical', 'MESH:C060893', (49, 54))	('IL-10', 'Gene', '3586', (184, 189))
110675	31258735	In addition, in two xenograft mouse models of CLL, NXT629 reduced the number of viable CLL cells in vivo .	('mouse', 'Species', '10090', (30, 35))	('CLL', 'Phenotype', 'HP:0005550', (87, 90))	('CLL', 'Phenotype', 'HP:0005550', (46, 49))	('NXT629', 'Var', (51, 57))	('reduced', 'NegReg', (58, 65))	('number of viable CLL cells', 'CPA', (70, 96))
110678	31258735	found that inhibition of PPARalpha induces cell cycle arrest and apoptosis, and synergizes with Glycolysis inhibition in kidney cancer cells.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('43', '60'))	('kidney cancer', 'Disease', 'MESH:D007680', (121, 134))	('kidney cancer', 'Phenotype', 'HP:0009726', (121, 134))	('Glycolysis', 'biological_process', 'GO:0006096', ('96', '106'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (43, 60))	('apoptosis', 'CPA', (65, 74))	('inhibition', 'Var', (11, 21))	('kidney cancer', 'Disease', (121, 134))	('arrest', 'Disease', 'MESH:D006323', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('apoptosis', 'biological_process', 'GO:0097194', ('65', '74'))	('apoptosis', 'biological_process', 'GO:0006915', ('65', '74'))	('arrest', 'Disease', (54, 60))	('PPARalpha', 'Gene', (25, 34))
110719	29290798	Therefore, inhibiting Notch signaling yields a disproportionate number of tip cells, resulting in excessive sprouting and immature vasculature, which has been shown to inhibit tumor growth, likely due to inefficient perfusion.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('inhibiting', 'Var', (11, 21))	('tumor', 'Disease', (176, 181))	('Notch signaling', 'Gene', (22, 37))	('inhibit', 'NegReg', (168, 175))	('signaling', 'biological_process', 'GO:0023052', ('28', '37'))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
110721	29290798	Mice were treated with an anti-angiogenic VEGF receptor targeting and an inhibitor of Notch pathway activation.	('Notch pathway', 'Pathway', (86, 99))	('targeting', 'Var', (56, 65))	('Mice', 'Species', '10090', (0, 4))	('anti-angiogenic VEGF receptor', 'Protein', (26, 55))
110772	29290798	TI for the Switch group mimicked that of the SU group for the first 3 weeks after the start of treatment, but it increased after the switch to GSI and became non-significant from the GSI and Control groups 1 week after the switch.	('GSI', 'Chemical', '-', (143, 146))	('increased', 'PosReg', (113, 122))	('switch', 'Var', (133, 139))	('GSI', 'Chemical', '-', (183, 186))	('SU', 'Chemical', 'MESH:D000077210', (45, 47))
110775	29290798	The peak intensity signal (PI), captured 1 min after the injection of contrast, was reduced for the SU and Switch groups in comparison to the Control and GSI groups, but the results were only statistically significant (p < 0.05) 3 weeks after the start of treatment (Figure 6).	('SU', 'Chemical', 'MESH:D000077210', (100, 102))	('peak intensity signal', 'MPA', (4, 25))	('GSI', 'Chemical', '-', (154, 157))	('reduced', 'NegReg', (84, 91))	('Switch', 'Var', (107, 113))
110785	29290798	The volume for the Switch group was similar to that of SU initally, but the change to GSI produced an enhancement in the tumor growth, as was the case with the GSI group, so that the tumor volume grew to be significant from the SU group (p < 0.05) one week after the switch.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('GSI', 'Gene', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('GSI', 'Chemical', '-', (160, 163))	('SU', 'Chemical', 'MESH:D000077210', (55, 57))	('SU', 'Chemical', 'MESH:D000077210', (228, 230))	('tumor', 'Disease', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('enhancement', 'PosReg', (102, 113))	('change', 'Var', (76, 82))	('GSI', 'Chemical', '-', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
110814	29290798	Notch inhibition promotes expression of VEGFR-2, so it is not surprising that the TI of the GSI group remained high throughout the experiment (Figure 5).	('expression', 'MPA', (26, 36))	('promotes', 'PosReg', (17, 25))	('GSI', 'Chemical', '-', (92, 95))	('Notch inhibition', 'Var', (0, 16))	('inhibition', 'Var', (6, 16))	('VEGFR-2', 'Gene', (40, 47))
110819	29290798	First, while this is a spontaneously arising kidney tumor from a Balb/C mouse, it lacks the common feature of human renal cell carcinoma, which is inactivation of the von Hippel-Lindau (VHL) gene.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('inactivation', 'Var', (147, 159))	('kidney tumor', 'Disease', (45, 57))	('mouse', 'Species', '10090', (72, 77))	('renal cell carcinoma', 'Disease', (116, 136))	('kidney tumor', 'Disease', 'MESH:D007674', (45, 57))	('human', 'Species', '9606', (110, 115))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (116, 136))	('kidney tumor', 'Phenotype', 'HP:0009726', (45, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('VHL', 'Disease', 'MESH:D006623', (186, 189))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (116, 136))	('VHL', 'Disease', (186, 189))
110823	29290798	Our model has a well-characterized VHL mutation and is known to demonstrate customary features of human clear cell renal cell carcinoma.	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (104, 135))	('clear cell renal cell carcinoma', 'Disease', (104, 135))	('mutation', 'Var', (39, 47))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (115, 135))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (104, 135))	('VHL', 'Disease', 'MESH:D006623', (35, 38))	('VHL', 'Disease', (35, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('human', 'Species', '9606', (98, 103))
110829	29290798	Normalization of tumor vasculature has been shown to enhance therapeutic effect in different types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', (17, 22))	('Normalization', 'Var', (0, 13))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('enhance', 'PosReg', (53, 60))	('therapeutic effect', 'CPA', (61, 79))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
110856	27517492	These results indicated that USP19 is a key factor in modulating DNA damage repair by targeting HDAC1/2 K63-linked ubiquitination, cells with deletion or decreased expression of USP19 might cause genome instability and even contribute to tumorigenesis.	('decreased', 'NegReg', (154, 163))	('USP19', 'Gene', '10869', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('expression', 'MPA', (164, 174))	('HDAC1/2 K63', 'Gene', (96, 107))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('HDAC1/2 K63', 'Gene', '3065', (96, 107))	('contribute', 'Reg', (224, 234))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('USP19', 'Gene', (29, 34))	('USP', 'molecular_function', 'GO:0051748', ('29', '32'))	('tumor', 'Disease', (238, 243))	('genome instability', 'CPA', (196, 214))	('USP19', 'Gene', '10869', (29, 34))	('deletion', 'Var', (142, 150))	('USP19', 'Gene', (178, 183))	('USP', 'molecular_function', 'GO:0051748', ('178', '181'))	('cause', 'Reg', (190, 195))
110863	27517492	Depletion of HDAC1 and HDAC2 in cells impairs DNA repair and then leads to sustained DNA-damage signaling.	('DNA', 'MPA', (46, 49))	('HDAC2', 'Gene', (23, 28))	('HDAC2', 'Gene', '3066', (23, 28))	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('signaling', 'biological_process', 'GO:0023052', ('96', '105'))	('DNA repair', 'biological_process', 'GO:0006281', ('46', '56'))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('DNA-damage signaling', 'MPA', (85, 105))	('HDAC1', 'Gene', (13, 18))	('Depletion', 'Var', (0, 9))	('impairs', 'NegReg', (38, 45))	('leads to', 'Reg', (66, 74))	('HDAC1', 'Gene', '3065', (13, 18))
110870	27517492	In this study, by using siRNA library screening for genes that may affect mitosis progression through time-lapes, we found USP19 knock down leads to obvious chromosome mis-segregation.	('leads to', 'Reg', (140, 148))	('USP19', 'Gene', '10869', (123, 128))	('USP', 'molecular_function', 'GO:0051748', ('123', '126'))	('chromosome mis-segregation', 'CPA', (157, 183))	('mitosis', 'biological_process', 'GO:0000278', ('74', '81'))	('mitosis', 'Disease', (74, 81))	('mitosis', 'Disease', 'None', (74, 81))	('knock down', 'Var', (129, 139))	('USP19', 'Gene', (123, 128))	('chromosome', 'cellular_component', 'GO:0005694', ('157', '167'))
110876	27517492	In a separate mitosis screening study, we found that USP19 knockdown in HeLa cells could result in obvious increase of chromosome segregation errors (from 8% to 25%), which could be confirmed by two separate USP19 siRNA (Figures 1A-1C).	('mitosis', 'Disease', (14, 21))	('chromosome', 'cellular_component', 'GO:0005694', ('119', '129'))	('mitosis', 'Disease', 'None', (14, 21))	('HeLa', 'CellLine', 'CVCL:0030', (72, 76))	('chromosome segregation', 'biological_process', 'GO:0007059', ('119', '141'))	('increase', 'PosReg', (107, 115))	('USP', 'molecular_function', 'GO:0051748', ('208', '211'))	('USP19', 'Gene', (208, 213))	('USP19', 'Gene', (53, 58))	('USP', 'molecular_function', 'GO:0051748', ('53', '56'))	('USP19', 'Gene', '10869', (208, 213))	('chromosome segregation errors', 'CPA', (119, 148))	('USP19', 'Gene', '10869', (53, 58))	('knockdown', 'Var', (59, 68))	('mitosis', 'biological_process', 'GO:0000278', ('14', '21'))
110878	27517492	Although similar level of chromosome lagging (about 7%) occurred in control and USP19 knock down cells, an obvious increase of anaphase bridge was detected in cells with USP19 knock-down (Figure 1D).	('anaphase bridge', 'CPA', (127, 142))	('anaphase', 'biological_process', 'GO:0051322', ('127', '135'))	('USP19', 'Gene', (80, 85))	('USP19', 'Gene', (170, 175))	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('increase', 'PosReg', (115, 123))	('knock-down', 'Var', (176, 186))	('USP19', 'Gene', '10869', (80, 85))	('USP19', 'Gene', '10869', (170, 175))	('USP', 'molecular_function', 'GO:0051748', ('170', '173'))	('chromosome lagging', 'CPA', (26, 44))	('USP', 'molecular_function', 'GO:0051748', ('80', '83'))
110880	27517492	The chromosome segregation errors induced by USP19 knockdown was reversed by the expression of siRNA-resistant wild-type USP19 (Figure 1F).	('chromosome segregation errors', 'CPA', (4, 33))	('USP19', 'Gene', (45, 50))	('USP', 'molecular_function', 'GO:0051748', ('45', '48'))	('USP19', 'Gene', (121, 126))	('chromosome', 'cellular_component', 'GO:0005694', ('4', '14'))	('USP19', 'Gene', '10869', (45, 50))	('USP19', 'Gene', '10869', (121, 126))	('chromosome segregation', 'biological_process', 'GO:0007059', ('4', '26'))	('USP', 'molecular_function', 'GO:0051748', ('121', '124'))	('knockdown', 'Var', (51, 60))
110881	27517492	These data indicate that knock down of USP19 could induce chromosome bridge formation, suggesting USP19 might be involved in preventing this type of chromosome segregation error.	('knock down', 'Var', (25, 35))	('USP', 'molecular_function', 'GO:0051748', ('98', '101'))	('chromosome segregation', 'biological_process', 'GO:0007059', ('149', '171'))	('USP19', 'Gene', (39, 44))	('induce', 'Reg', (51, 57))	('chromosome', 'cellular_component', 'GO:0005694', ('149', '159'))	('USP19', 'Gene', (98, 103))	('USP19', 'Gene', '10869', (39, 44))	('USP19', 'Gene', '10869', (98, 103))	('USP', 'molecular_function', 'GO:0051748', ('39', '42'))	('formation', 'biological_process', 'GO:0009058', ('76', '85'))	('chromosome bridge formation', 'CPA', (58, 85))	('chromosome', 'cellular_component', 'GO:0005694', ('58', '68'))
110886	27517492	Notably, we found the gamma- H2AX level was much higher in USP19 knock down cell compared to control cells.	('knock down', 'Var', (65, 75))	('USP19', 'Gene', '10869', (59, 64))	('H2AX', 'Gene', '3014', (29, 33))	('H2AX', 'Gene', (29, 33))	('USP', 'molecular_function', 'GO:0051748', ('59', '62'))	('higher', 'PosReg', (49, 55))	('USP19', 'Gene', (59, 64))
110887	27517492	Consistently, CHK1/2 activity seems could not be lower down in USP19 knock down cells, indicating that DNA damage constitutively exist in these cells.	('USP19', 'Gene', '10869', (63, 68))	('knock down', 'Var', (69, 79))	('CHK1', 'Gene', (14, 18))	('USP', 'molecular_function', 'GO:0051748', ('63', '66'))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('CHK1', 'Gene', '1111', (14, 18))	('USP19', 'Gene', (63, 68))
110890	27517492	However, when USP19 was knocked down, the accumulated gamma- H2AX foci could not disappear efficiently, indicating a defect of DNA repair in USP19 knockdown cells (Figure 2B and 2C).	('USP19', 'Gene', (14, 19))	('USP19', 'Gene', '10869', (14, 19))	('defect', 'NegReg', (117, 123))	('USP19', 'Gene', (141, 146))	('USP', 'molecular_function', 'GO:0051748', ('14', '17'))	('USP19', 'Gene', '10869', (141, 146))	('DNA repair', 'biological_process', 'GO:0006281', ('127', '137'))	('DNA repair', 'MPA', (127, 137))	('H2AX', 'Gene', '3014', (61, 65))	('H2AX', 'Gene', (61, 65))	('USP', 'molecular_function', 'GO:0051748', ('141', '144'))	('knockdown', 'Var', (147, 156))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))
110892	27517492	These results suggest that USP19 might plays critical role in DNA damage repair, depletion of USP19 could lead to accumulated DNA damage and then result in chromosome mis-segregation.	('chromosome', 'cellular_component', 'GO:0005694', ('156', '166'))	('USP19', 'Gene', (94, 99))	('USP19', 'Gene', '10869', (27, 32))	('lead', 'Reg', (106, 110))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('depletion', 'Var', (81, 90))	('chromosome mis-segregation', 'CPA', (156, 182))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('USP19', 'Gene', '10869', (94, 99))	('USP', 'molecular_function', 'GO:0051748', ('27', '30'))	('DNA damage', 'MPA', (126, 136))	('USP', 'molecular_function', 'GO:0051748', ('94', '97'))	('USP19', 'Gene', (27, 32))	('result in', 'Reg', (146, 155))
110900	27517492	HEK293T cells were transfected with HDAC1 or HDAC2 together with wild type of USP19 or USP19 CA mutant in which the active site Cys-506 was mutated to Ala to block the activity of deubiquitinase USP19.	('block', 'NegReg', (158, 163))	('USP19', 'Gene', '10869', (87, 92))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('USP19', 'Gene', '10869', (78, 83))	('activity', 'MPA', (168, 176))	('USP19', 'Gene', (87, 92))	('mutant', 'Var', (96, 102))	('USP', 'molecular_function', 'GO:0051748', ('195', '198'))	('HDAC2', 'Gene', (45, 50))	('USP19', 'Gene', (78, 83))	('HDAC2', 'Gene', '3066', (45, 50))	('mutated', 'Var', (140, 147))	('USP19', 'Gene', '10869', (195, 200))	('HDAC1', 'Gene', (36, 41))	('USP', 'molecular_function', 'GO:0051748', ('78', '81'))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('180', '194'))	('USP19', 'Gene', (195, 200))	('Cys-506 was mutated to Ala', 'Mutation', 'p.C506A', (128, 154))	('HDAC1', 'Gene', '3065', (36, 41))	('USP', 'molecular_function', 'GO:0051748', ('87', '90'))
110902	27517492	As shown is Figure 4A, the ubiquitination for both HDAC1 and HDAC2 was dramatically dropped down in USP19 transfected cells.	('USP', 'molecular_function', 'GO:0051748', ('100', '103'))	('HDAC2', 'Gene', (61, 66))	('USP19', 'Gene', (100, 105))	('dropped down', 'NegReg', (84, 96))	('USP19', 'Gene', '10869', (100, 105))	('HDAC1', 'Gene', '3065', (51, 56))	('ubiquitination', 'MPA', (27, 41))	('HDAC2', 'Gene', '3066', (61, 66))	('HDAC1', 'Gene', (51, 56))	('transfected', 'Var', (106, 117))
110905	27517492	Surprisingly, we found that neither USP19 knockdown nor its overexpression could infiuence HDAC1/2 stability (Figure 4B and 4C), indicating that USP19-mediated deubiquitination of HDAC1/2 does not affect their degradation.	('degradation', 'biological_process', 'GO:0009056', ('210', '221'))	('infiuence', 'Reg', (81, 90))	('degradation', 'MPA', (210, 221))	('HDAC1/2', 'Gene', '3065;3066', (180, 187))	('USP19', 'Gene', (145, 150))	('HDAC1/2', 'Gene', '3065;3066', (91, 98))	('deubiquitination', 'MPA', (160, 176))	('USP', 'molecular_function', 'GO:0051748', ('36', '39'))	('USP19', 'Gene', '10869', (36, 41))	('HDAC1/2', 'Gene', (91, 98))	('USP19', 'Gene', '10869', (145, 150))	('USP19', 'Gene', (36, 41))	('USP', 'molecular_function', 'GO:0051748', ('145', '148'))	('deubiquitination', 'biological_process', 'GO:0016579', ('160', '176'))	('HDAC1/2', 'Gene', (180, 187))	('knockdown', 'Var', (42, 51))
110911	27517492	By using the GFP reporter system, which is revealed by random-plasmid integration as well as I-Sce1-based homologous recombination, we monitored the percentage of cells which can be able to induce NHEJ or HR repair and found that USP19 knock down could definitely lead to a substantial defect in NHEJ but slight reduce in HR (Figure 5A and 5B).	('USP19', 'Gene', '10869', (230, 235))	('NHEJ', 'biological_process', 'GO:0006303', ('296', '300'))	('defect', 'NegReg', (286, 292))	('NHEJ', 'MPA', (296, 300))	('reduce', 'NegReg', (312, 318))	('USP', 'molecular_function', 'GO:0051748', ('230', '233'))	('knock down', 'Var', (236, 246))	('NHEJ', 'biological_process', 'GO:0006303', ('197', '201'))	('lead', 'Reg', (264, 268))	('USP19', 'Gene', (230, 235))	('homologous recombination', 'biological_process', 'GO:0035825', ('106', '130'))
110914	27517492	As to its essential role in DNA repair and in maintaining chromosome stability, USP19 might be critical for cells to prevent genome instability and its deletion might be contributed to tumorigenesis.	('tumor', 'Disease', (185, 190))	('genome', 'MPA', (125, 131))	('deletion', 'Var', (152, 160))	('USP19', 'Gene', (80, 85))	('contributed', 'Reg', (170, 181))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('USP19', 'Gene', '10869', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('DNA repair', 'biological_process', 'GO:0006281', ('28', '38'))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('USP', 'molecular_function', 'GO:0051748', ('80', '83'))	('chromosome', 'cellular_component', 'GO:0005694', ('58', '68'))
110915	27517492	So we next investigated whether deregulation of USP19 expression is associated with human cancers and checked its copy number state in various types of human tumor samples from the database of cBioportal for cancer genomics (http://www.cbioportal.org/index.do).	('USP', 'molecular_function', 'GO:0051748', ('48', '51'))	('cancers', 'Disease', (90, 97))	('cancer', 'Disease', (208, 214))	('USP19', 'Gene', '10869', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('human', 'Species', '9606', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('USP19', 'Gene', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('human', 'Species', '9606', (84, 89))	('tumor', 'Disease', (158, 163))	('associated', 'Reg', (68, 78))	('deregulation', 'Var', (32, 44))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancer', 'Disease', (90, 96))
110917	27517492	The result showed that 1%-12% deep deletion of USP19 is observed in several different tumors types, including kidney renal clear cell carcinoma (TCGA provisional), stomach adenocarcinoma (TCGA Nature, 2014), cervical squamous cell carcinoma (TCGA provisional), esophageal carcinoma (TCGA provisional) and brain lower grade glioma (TCGA provisional) (Figure 6A).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (217, 240))	('esophageal carcinoma', 'Disease', (261, 281))	('glioma', 'Disease', (323, 329))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('glioma', 'Disease', 'MESH:D005910', (323, 329))	('deep deletion', 'Var', (30, 43))	('USP19', 'Gene', '10869', (47, 52))	('squamous cell carcinoma', 'Disease', (217, 240))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (110, 143))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (261, 281))	('tumors', 'Disease', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('glioma', 'Phenotype', 'HP:0009733', (323, 329))	('USP19', 'Gene', (47, 52))	('stomach adenocarcinoma', 'Disease', (164, 186))	('kidney renal clear cell carcinoma', 'Disease', (110, 143))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (217, 240))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (261, 281))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (164, 186))	('USP', 'molecular_function', 'GO:0051748', ('47', '50'))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))
110919	27517492	It has been shown that certain errors, such as the mis-regulation of spindle-assembly checkpoint (SAC) activation in mitosis usually cause chromosome mis-segregation, which majorly in the form of chromosome lagging..	('mitosis', 'Disease', 'None', (117, 124))	('chromosome', 'cellular_component', 'GO:0005694', ('196', '206'))	('regulation of spindle-assembly', 'biological_process', 'GO:0090169', ('55', '85'))	('chromosome mis-segregation', 'CPA', (139, 165))	('spindle', 'cellular_component', 'GO:0005819', ('69', '76'))	('SAC', 'biological_process', 'GO:0071173', ('98', '101'))	('mis-regulation', 'Var', (51, 65))	('mitosis', 'biological_process', 'GO:0000278', ('117', '124'))	('cause', 'Reg', (133, 138))	('SAC', 'cellular_component', 'GO:0035003', ('98', '101'))	('spindle-assembly checkpoint', 'biological_process', 'GO:0071173', ('69', '96'))	('chromosome', 'cellular_component', 'GO:0005694', ('139', '149'))	('mitosis', 'Disease', (117, 124))
110920	27517492	However, more and more studies are providing evidences that pre-mitotic replication stress or other double strand DNA damage will generate chromosome stress and finally lead to various chromosome abnormalities, including the formation of chromatin bridge and acentric fragment.	('chromosome abnormalities', 'Disease', (185, 209))	('chromosome', 'cellular_component', 'GO:0005694', ('185', '195'))	('double strand DNA damage', 'Var', (100, 124))	('chromatin', 'cellular_component', 'GO:0000785', ('238', '247'))	('chromatin bridge', 'MPA', (238, 254))	('chromosome abnormalities', 'Disease', 'MESH:D002869', (185, 209))	('chromosome stress', 'MPA', (139, 156))	('generate', 'Reg', (130, 138))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('chromosome', 'cellular_component', 'GO:0005694', ('139', '149'))	('pre', 'molecular_function', 'GO:0003904', ('60', '63'))	('acentric fragment', 'MPA', (259, 276))	('lead to', 'Reg', (169, 176))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (185, 209))	('formation', 'biological_process', 'GO:0009058', ('225', '234'))
110927	27517492	Knockdown of USP19 leads to obvious reduction of NHEJ and cells with USP19 depletion showed much more accumulation for DNA damage foci compared to control cells, indicating USP19 is indispensable for normally DNA damage response.	('damage foci', 'Disease', 'MESH:C565785', (123, 134))	('NHEJ', 'biological_process', 'GO:0006303', ('49', '53'))	('USP19', 'Gene', '10869', (69, 74))	('depletion', 'Var', (75, 84))	('USP', 'molecular_function', 'GO:0051748', ('173', '176'))	('reduction', 'NegReg', (36, 45))	('USP19', 'Gene', '10869', (173, 178))	('DNA damage response', 'biological_process', 'GO:0006974', ('209', '228'))	('USP19', 'Gene', (69, 74))	('USP19', 'Gene', '10869', (13, 18))	('USP19', 'Gene', (173, 178))	('USP', 'molecular_function', 'GO:0051748', ('69', '72'))	('USP', 'molecular_function', 'GO:0051748', ('13', '16'))	('USP19', 'Gene', (13, 18))	('damage foci', 'Disease', (123, 134))	('DNA', 'cellular_component', 'GO:0005574', ('209', '212'))	('accumulation', 'PosReg', (102, 114))	('DNA damage foci', 'cellular_component', 'GO:0035861', ('119', '134'))	('NHEJ', 'MPA', (49, 53))
110930	27517492	Due to their defect in DNA repair, cells with USP19 depletion showed accumulated DNA damage and chromosome error, which might be contribute to genomic instability and even tumorigenesis (Figure 6D).	('DNA damage', 'CPA', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('defect', 'NegReg', (13, 19))	('accumulated', 'PosReg', (69, 80))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('chromosome error', 'Disease', (96, 112))	('USP19', 'Gene', (46, 51))	('DNA repair', 'biological_process', 'GO:0006281', ('23', '33'))	('USP19', 'Gene', '10869', (46, 51))	('contribute', 'Reg', (129, 139))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('depletion', 'Var', (52, 61))	('USP', 'molecular_function', 'GO:0051748', ('46', '49'))	('chromosome error', 'Disease', 'MESH:D012030', (96, 112))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('genomic instability', 'CPA', (143, 162))	('DNA', 'cellular_component', 'GO:0005574', ('23', '26'))
110961	33327252	MIF was knocked down in Caki-2 cells, and a wound healing assay was performed to evaluate migratory activity.	('MIF', 'Gene', (0, 3))	('knocked', 'Var', (8, 15))	('Caki-2', 'CellLine', 'CVCL:0235', (24, 30))	('wound healing', 'biological_process', 'GO:0042060', ('44', '57'))	('migratory activity', 'CPA', (90, 108))
110972	33327252	Previously, Du et al reported that MIF knockdown in clear cell renal cell carcinoma (CCRCC) cells leads to decreased proliferation in vitro.	('clear cell renal cell carcinoma', 'Disease', (52, 83))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (63, 83))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('MIF', 'Gene', (35, 38))	('RCC', 'Disease', (87, 90))	('proliferation', 'CPA', (117, 130))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (52, 83))	('knockdown', 'Var', (39, 48))	('CCRCC', 'Phenotype', 'HP:0006770', (85, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('decreased', 'NegReg', (107, 116))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (52, 83))
111001	33327252	The primary antibodies used for immunoblotting were anti-MIF (ab55445, Abcam, Cambridge, United Kingdom), and anti-GAPDH (ab8245, Abcam, Cambridge, United Kingdom) antibodies.	('ab8245', 'Var', (122, 128))	('GAPDH', 'Gene', '2597', (115, 120))	('GAPDH', 'Gene', (115, 120))	('anti-MIF', 'Gene', (52, 60))
111025	33327252	Since tumor growth and metastasis occur only in MIF-containing immunocompetent mice, MIF mediates the interaction between malignant cells and the host immune system, conferring tumor metastatic potential.	('mice', 'Species', '10090', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('mediates', 'Reg', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('metastasis', 'CPA', (23, 33))	('MIF', 'Var', (85, 88))	('tumor', 'Disease', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('interaction', 'Interaction', (102, 113))
111037	33327252	It has been shown that neutralizing anti-MIF antibodies inhibit tumor angiogenesis in murine malignant lymphoma, murine colon cancer, and a human melanoma model.	('malignant lymphoma', 'Disease', 'MESH:D008223', (93, 111))	('murine', 'Species', '10090', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('inhibit', 'NegReg', (56, 63))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('angiogenesis', 'biological_process', 'GO:0001525', ('70', '82'))	('colon cancer', 'Phenotype', 'HP:0003003', (120, 132))	('lymphoma', 'Phenotype', 'HP:0002665', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('colon cancer', 'Disease', 'MESH:D015179', (120, 132))	('malignant lymphoma', 'Disease', (93, 111))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('human', 'Species', '9606', (140, 145))	('tumor', 'Disease', (64, 69))	('murine', 'Species', '10090', (113, 119))	('antibodies', 'Var', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('colon cancer', 'Disease', (120, 132))
111039	33327252	In their functional test, MIF knockdown led to a more than 75% decrease in the number and size of the colonies, which may have reflected a decrease in cancer cell proliferation.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cell proliferation', 'biological_process', 'GO:0008283', ('158', '176'))	('MIF', 'Gene', (26, 29))	('decrease', 'NegReg', (63, 71))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('knockdown', 'Var', (30, 39))	('decrease', 'NegReg', (139, 147))
111043	33327252	In our study, knockdown of MIF in Caki-2 cells reduced cell proliferation without changing the migratory activity of the cells.	('cell proliferation', 'biological_process', 'GO:0008283', ('55', '73'))	('cell proliferation', 'CPA', (55, 73))	('knockdown', 'Var', (14, 23))	('Caki-2', 'CellLine', 'CVCL:0235', (34, 40))	('reduced', 'NegReg', (47, 54))	('MIF', 'Gene', (27, 30))
111048	33327252	The findings of several studies are in agreement with our results showing that MIF expression is related to low grade and early stage tumors.	('MIF', 'Gene', (79, 82))	('related', 'Reg', (97, 104))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('low grade', 'CPA', (108, 117))	('expression', 'Var', (83, 93))
111163	31856918	The objective response rate (ORR) was greater in patients treated with nivolumab compared to everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P < 0.001).	('nivolumab', 'Chemical', 'MESH:D000077594', (71, 80))	('everolimus', 'Chemical', 'MESH:D000068338', (93, 103))	('nivolumab', 'Var', (71, 80))	('patients', 'Species', '9606', (49, 57))	('objective', 'MPA', (4, 13))
111260	31856918	Conversely, results of Keynote-426 demonstrated OS, PFS, and ORR benefits with the combination across all risk groups and regardless of tumor-based PD-L1 expression level (Table 4).	('benefits', 'PosReg', (65, 73))	('PD-L1', 'Gene', '29126', (148, 153))	('combination', 'Var', (83, 94))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('PFS', 'CPA', (52, 55))	('PD-L1', 'Gene', (148, 153))
111268	31856918	Specifically, in 46 patients with a CPS of at >=1, confirmed ORR was 50.0%, and in 53 patients with a CPS < 1, it was 26%.	('CPS < 1', 'Gene', (102, 109))	('CPS of at', 'Var', (36, 45))	('CPS < 1', 'Gene', '1373', (102, 109))	('CPS', 'Chemical', '-', (36, 39))	('patients', 'Species', '9606', (20, 28))	('CPS', 'Chemical', '-', (102, 105))	('patients', 'Species', '9606', (86, 94))
111342	31856918	Category 1 evidence from aRCC trials demonstrated that while patients in the standard-therapy group reported a clinically meaningful deterioration from baseline and bothersome symptoms, more patients treated with nivolumab, nivolumab plus ipilimumab or atezolizumab plus bevacizumab reported more symptom stability or an improvement in health related quality of life.	('deterioration', 'NegReg', (133, 146))	('symptom', 'MPA', (297, 304))	('patients', 'Species', '9606', (191, 199))	('atezolizumab plus bevacizumab', 'Disease', 'MESH:D007625', (253, 282))	('RCC', 'Disease', (26, 29))	('health related quality of life', 'CPA', (336, 366))	('atezolizumab plus bevacizumab', 'Disease', (253, 282))	('nivolumab', 'Chemical', 'MESH:D000077594', (224, 233))	('nivolumab', 'Chemical', 'MESH:D000077594', (213, 222))	('improvement', 'PosReg', (321, 332))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('patients', 'Species', '9606', (61, 69))	('more', 'PosReg', (292, 296))	('ipilimumab', 'Chemical', 'MESH:D000074324', (239, 249))	('nivolumab', 'Var', (224, 233))
111384	31400752	Induced by ADAMTS9-AS2 overexpression, cell proliferation and chemoresistance exhibited an obvious reduction, FOXO1 expression showed an evident increase, but all were reversed after miR-27a-3p was simultaneously overexpressed.	('expression', 'MPA', (116, 126))	('miR-27a', 'Gene', (183, 190))	('ADAMTS9-AS2', 'Gene', '100507098;56999', (11, 22))	('increase', 'PosReg', (145, 153))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('overexpression', 'Var', (23, 37))	('reduction', 'NegReg', (99, 108))	('FOXO1', 'Gene', '2308', (110, 115))	('miR-27a', 'Gene', '407018', (183, 190))	('FOXO1', 'Gene', (110, 115))	('chemoresistance', 'CPA', (62, 77))	('cell proliferation', 'CPA', (39, 57))	('ADAMTS9-AS2', 'Gene', (11, 22))
111415	31400752	Results showed that KIRC patients with high-expressed ADAMTS9-AS2 had evidently better overall and disease-free survival (Figure 1C, 1D, n=258, p=0.00039).	('disease-free survival', 'CPA', (99, 120))	('high-expressed', 'Var', (39, 53))	('ADAMTS9-AS2', 'Gene', '100507098;56999', (54, 65))	('patients', 'Species', '9606', (25, 33))	('better', 'PosReg', (80, 86))	('ADAMTS9-AS2', 'Gene', (54, 65))	('overall', 'CPA', (87, 94))
111417	31400752	These findings reveale that high-expressed ADAMTS9-AS2 is associated with better prognosis of KIRC patients, highlighting its potential to be a specific target for indicated cancer.	('better', 'PosReg', (74, 80))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('patients', 'Species', '9606', (99, 107))	('ADAMTS9-AS2', 'Gene', '100507098;56999', (43, 54))	('ADAMTS9-AS2', 'Gene', (43, 54))	('high-expressed', 'Var', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
111449	31400752	Mutation of the ADAMTS9-AS2 binding sequence with miR-27a-3p inhibited miR-27a-3p precipitation.	('inhibited', 'NegReg', (61, 70))	('miR-27a', 'Gene', (71, 78))	('miR-27a', 'Gene', (50, 57))	('Mutation', 'Var', (0, 8))	('binding', 'Interaction', (28, 35))	('ADAMTS9-AS2', 'Gene', '100507098;56999', (16, 27))	('ADAMTS9-AS2', 'Gene', (16, 27))	('miR-27a', 'Gene', '407018', (71, 78))	('miR-27a', 'Gene', '407018', (50, 57))	('binding', 'molecular_function', 'GO:0005488', ('28', '35'))
111451	31400752	To investigate the impact of ADAMTS9-AS2 or miR-27a-3p on ccRCC, cell proliferation was subsequently analyzed by 3-(4, 5-dimethylthiazol-2- yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfop-henyl)-2H-tetrazolium (MTS) assay in both 786-O and caki-1 cells after ADAMTS9-AS2/miR-27a-3p overexpression or knockdown.	('ADAMTS9-AS2', 'Gene', (254, 265))	('miR-27a', 'Gene', '407018', (44, 51))	('miR-27a', 'Gene', (266, 273))	('ADAMTS9-AS2', 'Gene', '100507098;56999', (29, 40))	('miR-27a', 'Gene', (44, 51))	('RCC', 'Disease', (60, 63))	('ADAMTS9-AS2', 'Gene', (29, 40))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('knockdown', 'Var', (295, 304))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('cell proliferation', 'biological_process', 'GO:0008283', ('65', '83'))	('miR-27a', 'Gene', '407018', (266, 273))	('3-(4, 5-dimethylthiazol-2- yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfop-henyl)-2H-tetrazolium', 'Chemical', 'MESH:C070380', (113, 204))	('ADAMTS9-AS2', 'Gene', '100507098;56999', (254, 265))
111453	31400752	The miR-27a-3p mimic or inhibitor was respectively transfected into cells for miR-27a-3p overexpression or knockdown.	('knockdown', 'Var', (107, 116))	('miR-27a', 'Gene', '407018', (78, 85))	('miR-27a', 'Gene', '407018', (4, 11))	('overexpression', 'PosReg', (89, 103))	('miR-27a', 'Gene', (78, 85))	('miR-27a', 'Gene', (4, 11))
111456	31400752	In the knockdown experiments, ADAMTS9-AS2 knockdown led to the increased proliferation of ccRCC cells, which was the opposite result of that obtained with the miR-27a-3p knockdown (Figure 4C, 4D, P<0.05).	('increased', 'PosReg', (63, 72))	('proliferation', 'CPA', (73, 86))	('miR-27a', 'Gene', '407018', (159, 166))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('ADAMTS9-AS2', 'Gene', '100507098;56999', (30, 41))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('ADAMTS9-AS2', 'Gene', (30, 41))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('knockdown', 'Var', (42, 51))	('miR-27a', 'Gene', (159, 166))
111457	31400752	Consistently, we observed that the colony formation of ccRCC cells was significantly inhibited in 786-O and caki-1 cells with ADAMTS9-AS2 overexpression (Figure 4E, P<0.01) or miR-27a-3p knockdown (Figure 4F, P<0.01), according to the crystal violet staining.	('ADAMTS9-AS2', 'Gene', (126, 137))	('miR-27a', 'Gene', (176, 183))	('inhibited', 'NegReg', (85, 94))	('knockdown', 'Var', (187, 196))	('miR-27a', 'Gene', '407018', (176, 183))	('crystal violet', 'Chemical', 'MESH:D005840', (235, 249))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('formation', 'biological_process', 'GO:0009058', ('42', '51'))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))	('ADAMTS9-AS2', 'Gene', '100507098;56999', (126, 137))	('overexpression', 'PosReg', (138, 152))
111461	31400752	As expected, 5-Fu led to the inhibition of cell proliferation in a dose-dependent manner.	('inhibition', 'NegReg', (29, 39))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('29', '61'))	('cell proliferation', 'CPA', (43, 61))	('5-Fu', 'Chemical', 'MESH:D005472', (13, 17))	('5-Fu', 'Var', (13, 17))
111462	31400752	We found that the sensitivity of ccRCC cells to 5-Fu treatment was increased by either ADAMTS9-AS2 overexpression (Figure 5A, P<0.05) or miR-27a-3p knockdown (Figure 5B, P<0.05), and thus cell proliferation was inhibited.	('RCC', 'Disease', (35, 38))	('cell proliferation', 'CPA', (188, 206))	('inhibited', 'NegReg', (211, 220))	('miR-27a', 'Gene', '407018', (137, 144))	('ADAMTS9-AS2', 'Gene', '100507098;56999', (87, 98))	('ADAMTS9-AS2', 'Gene', (87, 98))	('5-Fu', 'Chemical', 'MESH:D005472', (48, 52))	('overexpression', 'PosReg', (99, 113))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('sensitivity', 'MPA', (18, 29))	('miR-27a', 'Gene', (137, 144))	('increased', 'PosReg', (67, 76))	('cell proliferation', 'biological_process', 'GO:0008283', ('188', '206'))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('knockdown', 'Var', (148, 157))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
111463	31400752	Conversely, ADAMTS9-AS2 knockdown (Figure 5C, P<0.05) and miR-27a-3p overexpression (Figure 5D, P<0.05) resulted in the insensitivity of ccRCC cells to increased 5-Fu and, moreover, partially alleviated the growth inhibition of ccRCC cells.	('miR-27a', 'Gene', '407018', (58, 65))	('5-Fu', 'Chemical', 'MESH:D005472', (162, 166))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('RCC', 'Disease', (139, 142))	('miR-27a', 'Gene', (58, 65))	('5-Fu', 'MPA', (162, 166))	('increased', 'PosReg', (152, 161))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('insensitivity', 'MPA', (120, 133))	('RCC', 'Disease', (230, 233))	('RCC', 'Phenotype', 'HP:0005584', (230, 233))	('knockdown', 'Var', (24, 33))	('ccRCC', 'Phenotype', 'HP:0006770', (228, 233))	('growth inhibition', 'CPA', (207, 224))	('ADAMTS9-AS2', 'Gene', '100507098;56999', (12, 23))	('ADAMTS9-AS2', 'Gene', (12, 23))	('RCC', 'Disease', 'MESH:C538614', (230, 233))	('alleviated', 'NegReg', (192, 202))
111466	31400752	Consistently, ADAMTS9-AS2 overexpression (Supplementary Figure 4A, P<0.05) and miR-27a-3p knockdown (Supplementary Figure 4B, P<0.05) led to the increased sensitivity of ccRCC cells to Cisplatin treatment, and both ADAMTS9-AS2 knockdown (Supplementary Figure 4C, P<0.05) and miR-27a-3p overexpression (Supplementary Figure 4D, P<0.05) contributed to the decreased sensitivity of ccRCC cells to Cisplatin.	('miR-27a', 'Gene', (79, 86))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('miR-27a', 'Gene', (275, 282))	('ADAMTS9-AS2', 'Gene', '100507098;56999', (215, 226))	('ADAMTS9-AS2', 'Gene', (215, 226))	('Cisplatin', 'Chemical', 'MESH:D002945', (394, 403))	('knockdown', 'Var', (90, 99))	('ccRCC', 'Phenotype', 'HP:0006770', (170, 175))	('increased', 'PosReg', (145, 154))	('miR-27a', 'Gene', '407018', (79, 86))	('Cisplatin', 'Chemical', 'MESH:D002945', (185, 194))	('ADAMTS9-AS2', 'Gene', '100507098;56999', (14, 25))	('ccRCC', 'Phenotype', 'HP:0006770', (379, 384))	('RCC', 'Disease', (381, 384))	('RCC', 'Phenotype', 'HP:0005584', (381, 384))	('ADAMTS9-AS2', 'Gene', (14, 25))	('sensitivity', 'MPA', (155, 166))	('sensitivity', 'MPA', (364, 375))	('miR-27a', 'Gene', '407018', (275, 282))	('decreased', 'NegReg', (354, 363))	('RCC', 'Disease', 'MESH:C538614', (381, 384))	('RCC', 'Disease', (172, 175))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))
111474	31400752	Based on the predicted binding sites of miR-27a-3p, FOXO1 3' untranslated region (3'UTR) WT and mutant type (MUT) luciferase reporter plasmids were generated (Figure 6B).	('mutant', 'Var', (96, 102))	('binding', 'molecular_function', 'GO:0005488', ('23', '30'))	('miR-27a', 'Gene', (40, 47))	('FOXO1', 'Gene', (52, 57))	('FOXO1', 'Gene', '2308', (52, 57))	('miR-27a', 'Gene', '407018', (40, 47))
111477	31400752	Furthermore, FOXO1 expression at both the mRNA and protein levels were reduced by miR-27a-3p overexpression and increased by miR-27a-3p knockdown in ccRCC cells, as determined by qRT-PCR and western blot assays (Figure 6D, 6E, P<0.05, P<0.01).	('expression', 'MPA', (19, 29))	('miR-27a', 'Gene', (125, 132))	('FOXO1', 'Gene', (13, 18))	('FOXO1', 'Gene', '2308', (13, 18))	('miR-27a', 'Gene', (82, 89))	('knockdown', 'Var', (136, 145))	('ccRCC', 'Phenotype', 'HP:0006770', (149, 154))	('miR-27a', 'Gene', '407018', (125, 132))	('reduced', 'NegReg', (71, 78))	('increased', 'PosReg', (112, 121))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (151, 154))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('miR-27a', 'Gene', '407018', (82, 89))	('overexpression', 'PosReg', (93, 107))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
111481	31400752	To test this hypothesis, we knocked down FOXO1 and performed MTS cell proliferation assays in the presence of 5-Fu or Cisplatin.	('Cisplatin', 'Chemical', 'MESH:D002945', (118, 127))	('MTS cell proliferation assays', 'CPA', (61, 90))	('5-Fu', 'Chemical', 'MESH:D005472', (110, 114))	('FOXO1', 'Gene', (41, 46))	('FOXO1', 'Gene', '2308', (41, 46))	('cell proliferation', 'biological_process', 'GO:0008283', ('65', '83'))	('knocked', 'Var', (28, 35))
111485	31400752	As shown in Figure 7A, cells in the presence of 5-Fu or Cisplatin exhibited lower chemoresistance in the si-FOXO1 group compared to the NC group (P < 0.05).	('5-Fu', 'Chemical', 'MESH:D005472', (48, 52))	('FOXO1', 'Gene', '2308', (108, 113))	('5-Fu', 'Var', (48, 52))	('lower', 'NegReg', (76, 81))	('chemoresistance', 'CPA', (82, 97))	('Cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('FOXO1', 'Gene', (108, 113))	('Cisplatin', 'Var', (56, 65))
111589	30189720	Another well-known prognostic model, the Memorial Sloan Kettering Cancer Center (MSKCC) risk model, had already been introduced in the era of conventional immunotherapy and had five predictors: KPS < 80%, time from diagnosis to treatment interval < 1 year, high serum lactate dehydrogenase, anemia, and hypercalcemia.	('hypercalcemia', 'Phenotype', 'HP:0003072', (303, 316))	('high serum lactate dehydrogenase', 'MPA', (257, 289))	('anemia', 'Disease', (291, 297))	('high serum lactate dehydrogenase', 'Phenotype', 'HP:0025435', (257, 289))	('high serum lactate', 'Phenotype', 'HP:0002151', (257, 275))	('anemia', 'Disease', 'MESH:D000740', (291, 297))	('hypercalcemia', 'Disease', 'MESH:D006934', (303, 316))	('Memorial Sloan Kettering Cancer', 'Disease', (41, 72))	('hypercalcemia', 'Disease', (303, 316))	('Memorial Sloan Kettering Cancer', 'Disease', 'MESH:D008569', (41, 72))	('KPS < 80%', 'Var', (194, 203))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('anemia', 'Phenotype', 'HP:0001903', (291, 297))
111615	30189720	The c-indices were 0.632 (standard error [SE], 0.059) for first-line PFS and 0.748 (SE, 0.052) for CSS.	('CSS', 'Chemical', '-', (99, 102))	('CSS', 'Disease', (99, 102))	('0.748', 'Var', (77, 82))
111620	30189720	The c-indices were 0.643 (SE, 0.097) for first-line PFS and 0.655 (SE, 0.089) for CSS.	('CSS', 'Disease', (82, 85))	('0.655', 'Var', (60, 65))	('CSS', 'Chemical', '-', (82, 85))
111658	29534679	Early mutations and inactivation of VHL is commonly seen in ccRCC.	('inactivation', 'Var', (20, 32))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('Early mutations', 'Var', (0, 15))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('VHL', 'Disease', (36, 39))	('VHL', 'Disease', 'MESH:D006623', (36, 39))
111667	29534679	We summarized the copy number mutations and single nucleotide variation of EC1 and top five recurrent mutation genes are VHL, PBRM1, MUC4, BAP1 and SETD2 (42.57%, 25.74%, 20.79%, 19.80%, 13.86%).	('SETD2', 'Gene', (148, 153))	('MUC4', 'Gene', (133, 137))	('PBRM1', 'Gene', (126, 131))	('EC1', 'Gene', (75, 78))	('BAP1', 'Gene', '8314', (139, 143))	('PBRM1', 'Gene', '55193', (126, 131))	('VHL', 'Disease', 'MESH:D006623', (121, 124))	('SETD2', 'Gene', '29072', (148, 153))	('MUC4', 'Gene', '4585', (133, 137))	('VHL', 'Disease', (121, 124))	('BAP1', 'Gene', (139, 143))	('EC1', 'Gene', '4819', (75, 78))	('single nucleotide variation', 'Var', (44, 71))
111670	29534679	A significant increase in BAP1 mutation frequency was observed in EC1compared with the remainder of the samples, which is consistent with BAP1 is a potential tumor suppressor and relevant to bad outcome in ccRCC.	('BAP1', 'Gene', (26, 30))	('tumor', 'Disease', (158, 163))	('BAP1', 'Gene', '8314', (138, 142))	('tumor suppressor', 'biological_process', 'GO:0051726', ('158', '174'))	('EC1', 'Gene', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (208, 211))	('EC1', 'Gene', '4819', (66, 69))	('mutation', 'Var', (31, 39))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('RCC', 'Disease', (208, 211))	('BAP1', 'Gene', (138, 142))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('158', '174'))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('BAP1', 'Gene', '8314', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('increase', 'PosReg', (14, 22))
111672	29534679	However, loss of 9q21 presents a higher frequency in EC1 and three common tumor suppressor genes (TSG) are deleted in this area including CDKN2A, CDKN2B and MTAP.	('EC1', 'Gene', '4819', (53, 56))	('CDKN2A', 'Gene', (138, 144))	('CDKN2A', 'Gene', '1029', (138, 144))	('MTAP', 'Gene', '4507', (157, 161))	('CDKN2B', 'Gene', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor suppressor', 'biological_process', 'GO:0051726', ('74', '90'))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CDKN2B', 'Gene', '1030', (146, 152))	('loss', 'Var', (9, 13))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('74', '90'))	('tumor', 'Disease', (74, 79))	('MTAP', 'Gene', (157, 161))	('EC1', 'Gene', (53, 56))	('9q21', 'Gene', (17, 21))
111674	29534679	The deletion, mutation or promoter methylation of the two genes are common in various cancers, which help to the unlimited growth of cancer cells and CDKN2A is associated with metastatic cancer.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))	('associated', 'Reg', (160, 170))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('common', 'Reg', (68, 74))	('cancer', 'Disease', (86, 92))	('CDKN2A', 'Gene', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (133, 139))	('deletion', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Disease', (187, 193))	('CDKN2A', 'Gene', '1029', (150, 156))	('mutation', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('promoter', 'MPA', (26, 34))
111689	29534679	LAMB3 is core enrichment gene in Focal Adhesion and Pathways in Cancer (Additional file 5: Table S4) and research shows that repressing LAMB3 inhibit mutant KRAS-Driven tumor growth.	('LAMB3', 'Gene', (136, 141))	('LAMB3', 'Gene', (0, 5))	('KRAS', 'Gene', '3845', (157, 161))	('Cancer', 'Disease', (64, 70))	('inhibit', 'NegReg', (142, 149))	('repressing', 'Var', (125, 135))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('LAMB3', 'Gene', '3914', (136, 141))	('LAMB3', 'Gene', '3914', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('core', 'cellular_component', 'GO:0019013', ('9', '13'))	('KRAS', 'Gene', (157, 161))	('mutant', 'Var', (150, 156))	('Focal Adhesion', 'cellular_component', 'GO:0005925', ('33', '47'))	('men', 'Species', '9606', (20, 23))
111690	29534679	LAMB3 is also associated with EMT, a crucial change that happens to cancer cells before metastasis, and several researches conclude that high expression of LAMB3 is correlated with tumor metastasis including oral squamous cell carcinoma, bladder cancer and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('EMT', 'biological_process', 'GO:0001837', ('30', '33'))	('tumor metastasis', 'Disease', (181, 197))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('cancer', 'Disease', (264, 270))	('LAMB3', 'Gene', (0, 5))	('bladder cancer', 'Disease', 'MESH:D001749', (238, 252))	('bladder cancer', 'Disease', (238, 252))	('cancer', 'Disease', (246, 252))	('high expression', 'Var', (137, 152))	('LAMB3', 'Gene', '3914', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('bladder cancer', 'Phenotype', 'HP:0009725', (238, 252))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (213, 236))	('EMT', 'Disease', (30, 33))	('LAMB3', 'Gene', '3914', (0, 5))	('associated', 'Reg', (14, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (257, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('squamous cell carcinoma', 'Disease', (213, 236))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('tumor metastasis', 'Disease', 'MESH:D009362', (181, 197))	('breast cancer', 'Disease', 'MESH:D001943', (257, 270))	('breast cancer', 'Disease', (257, 270))	('cancer', 'Disease', (68, 74))	('LAMB3', 'Gene', (156, 161))	('correlated', 'Reg', (165, 175))
111710	29534679	93 significant hypomethylation CpG sites were found in EC1 subgroup (absolute beta-values difference 0.2 & Padj < 0.01) and 60 are located in the protein coding region (Fig.	('hypomethylation', 'Var', (15, 30))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('EC1', 'Gene', '4819', (55, 58))	('EC1', 'Gene', (55, 58))
111712	29534679	We also observed epigenetic silencing of TOLLIP in EC1 and TOLLIP deficiency is associated with decreased T-cell responses, which may reflect the immune suppression phenomenon in EC1.	('T-cell responses', 'CPA', (106, 122))	('TOLLIP', 'Gene', (59, 65))	('TOLLIP', 'Gene', '54472', (41, 47))	('TOLLIP', 'Gene', '54472', (59, 65))	('decreased', 'NegReg', (96, 105))	('EC1', 'Gene', '4819', (179, 182))	('EC1', 'Gene', (51, 54))	('EC1', 'Gene', (179, 182))	('EC1', 'Gene', '4819', (51, 54))	('deficiency', 'Var', (66, 76))	('men', 'Species', '9606', (170, 173))	('epigenetic silencing', 'Var', (17, 37))	('TOLLIP', 'Gene', (41, 47))
111714	29534679	We find that most of the genes that enrichment or hypomethylation in EC1 are negatively related to prognosis.	('men', 'Species', '9606', (42, 45))	('related', 'Reg', (88, 95))	('EC1', 'Gene', '4819', (69, 72))	('EC1', 'Gene', (69, 72))	('prognosis', 'CPA', (99, 108))	('negatively', 'NegReg', (77, 87))	('hypomethylation', 'Var', (50, 65))
111720	29534679	The explanation may lie in the origin that ccRCC stem from renal tubular epithelial cells and the three subtypes present similar genetic changes including loss of 3p, gain of 5q and somatic mutations or epigenetic alterations of VHL.	('loss of', 'Var', (155, 162))	('gain', 'PosReg', (167, 171))	('epigenetic alterations', 'Var', (203, 225))	('VHL', 'Disease', (229, 232))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('VHL', 'Disease', 'MESH:D006623', (229, 232))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
111722	29534679	Further analysis indicates the up-regulated pathways and hypomethylation genes mainly concentrate on Focal adhesion and mobility in EC1.	('up-regulated', 'PosReg', (31, 43))	('Focal adhesion', 'cellular_component', 'GO:0005925', ('101', '115'))	('EC1', 'Gene', (132, 135))	('Focal adhesion', 'CPA', (101, 115))	('hypomethylation', 'Var', (57, 72))	('EC1', 'Gene', '4819', (132, 135))	('mobility', 'CPA', (120, 128))
111723	29534679	This kind of panel of genes in EC1 regulate EMT and cell cycle, causing tumor invasion and metastasis even before diagnosis and become aggressive and lethal compared with other subtypes.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('genes', 'Var', (22, 27))	('cell cycle', 'biological_process', 'GO:0007049', ('52', '62'))	('EC1', 'Gene', (31, 34))	('cell cycle', 'CPA', (52, 62))	('tumor', 'Disease', (72, 77))	('EC1', 'Gene', '4819', (31, 34))	('metastasis', 'CPA', (91, 101))	('EMT', 'CPA', (44, 47))	('regulate', 'Reg', (35, 43))	('EMT', 'biological_process', 'GO:0001837', ('44', '47'))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('causing', 'Reg', (64, 71))
111727	29534679	We have discovered VHL and other structural alterations in most samples across subtypes and reasoned that EC1 subtype may have acquired other genetic variations that enhance its ability of invasion and proliferation, contribute to a more aggressive phenotype and cover up the signature of VHL inactivation.	('variations', 'Var', (150, 160))	('EC1', 'Gene', (106, 109))	('VHL', 'Disease', 'MESH:D006623', (19, 22))	('EC1', 'Gene', '4819', (106, 109))	('more', 'PosReg', (233, 237))	('inactivation', 'Var', (293, 305))	('aggressive phenotype', 'CPA', (238, 258))	('alterations', 'Var', (44, 55))	('VHL', 'Disease', (289, 292))	('enhance', 'PosReg', (166, 173))	('invasion', 'CPA', (189, 197))	('VHL', 'Disease', 'MESH:D006623', (289, 292))	('contribute to', 'Reg', (217, 230))	('VHL', 'Disease', (19, 22))
111752	29262564	As a single miRNA may target up to several hundred mRNAs, aberrant miRNA expression may affect a multitude of transcripts and profoundly influence cancer-related signaling pathways.	('signaling', 'biological_process', 'GO:0023052', ('162', '171'))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('affect', 'Reg', (88, 94))	('influence', 'Reg', (137, 146))	('aberrant', 'Var', (58, 66))	('miR', 'Gene', (67, 70))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('miR', 'Gene', '220972', (12, 15))	('cancer', 'Disease', (147, 153))	('miR', 'Gene', '220972', (67, 70))	('multitude of transcripts', 'MPA', (97, 121))	('miR', 'Gene', (12, 15))
111871	28984183	Basically, we assumed that the true signal S i (what we want to estimate) follows a negative binomial distribution and background noise B i (sequencing errors or misalignment, etc.)	('error', 'Disease', 'MESH:D012030', (152, 157))	('error', 'Disease', (152, 157))	('misalignment', 'Var', (162, 174))
111923	28984183	4, XBSeq2 consumes the least amount of time compared to other three methods and also has a significant increase in efficiency compared to XBSeq.	('XBSeq', 'Chemical', '-', (3, 8))	('increase', 'PosReg', (103, 111))	('XBSeq', 'Chemical', '-', (138, 143))	('efficiency', 'MPA', (115, 125))	('XBSeq2', 'Var', (3, 9))
111941	31015801	We also identified the differentially expressed genes upon HHLA2 knockdown in ccRCC cell lines by using gene microarray analysis.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('HHLA2', 'Gene', (59, 64))	('knockdown', 'Var', (65, 74))	('HHLA2', 'Gene', '11148', (59, 64))
111943	31015801	Moreover, our immunohistochemistry study showed that the staining intensity of HHLA2 in human ccRCC tissues was significantly higher than that in the adjacent normal tissues, and the overall survival rate of ccRCC patients with higher HHLA2 expression was significantly poorer than that of the patients with lower HHLA2 expression.	('patients', 'Species', '9606', (214, 222))	('HHLA2', 'Gene', '11148', (314, 319))	('higher', 'PosReg', (126, 132))	('HHLA2', 'Gene', (79, 84))	('human', 'Species', '9606', (88, 93))	('RCC', 'Disease', (210, 213))	('RCC', 'Phenotype', 'HP:0005584', (210, 213))	('ccRCC', 'Phenotype', 'HP:0006770', (208, 213))	('higher', 'PosReg', (228, 234))	('staining intensity', 'MPA', (57, 75))	('HHLA2', 'Gene', '11148', (79, 84))	('expression', 'Var', (241, 251))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RCC', 'Disease', 'MESH:C538614', (210, 213))	('RCC', 'Disease', (96, 99))	('HHLA2', 'Gene', (235, 240))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('poorer', 'NegReg', (270, 276))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('HHLA2', 'Gene', (314, 319))	('HHLA2', 'Gene', '11148', (235, 240))	('patients', 'Species', '9606', (294, 302))	('survival rate', 'CPA', (191, 204))
111946	31015801	Our cellular study showed that upon knockdown of HHLA2 expression in human ccRCC cell lines, the cell viability, the migration and the invasion ability were significantly inhibited, while the cell cycle arrest at G1 phase was induced and the expressions of Cyclin D1, c-Myc and Cyclin E1 were decreased.	('Cyclin D1', 'Gene', (257, 266))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('inhibited', 'NegReg', (171, 180))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (192, 209))	('HHLA2', 'Gene', (49, 54))	('Cyclin E1', 'Gene', (278, 287))	('Cyclin', 'molecular_function', 'GO:0016538', ('278', '284'))	('G1 phase', 'biological_process', 'GO:0051318', ('213', '221'))	('arrest', 'Disease', (203, 209))	('knockdown', 'Var', (36, 45))	('Cyclin E1', 'Gene', '898', (278, 287))	('expressions', 'MPA', (242, 253))	('cell viability', 'CPA', (97, 111))	('invasion ability', 'CPA', (135, 151))	('HHLA2', 'Gene', '11148', (49, 54))	('human', 'Species', '9606', (69, 74))	('c-Myc', 'Gene', (268, 273))	('decreased', 'NegReg', (293, 302))	('arrest', 'Disease', 'MESH:D006323', (203, 209))	('Cyclin', 'molecular_function', 'GO:0016538', ('257', '263'))	('c-Myc', 'Gene', '4609', (268, 273))	('induced', 'PosReg', (226, 233))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('192', '209'))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('Cyclin D1', 'Gene', '595', (257, 266))	('migration and', 'CPA', (117, 130))	('expression', 'Var', (55, 65))
111947	31015801	In addition, according to the microarray data, the expressions of epithelia-to-mesenchymal transition markers, such as E-cadherin, N-cadherin and Vimentin, were significantly changed after knockdown of HHLA2 expression.	('epithelia-to-mesenchymal transition', 'CPA', (66, 101))	('Vimentin', 'Gene', (146, 154))	('Vimentin', 'cellular_component', 'GO:0045098', ('146', '154'))	('E-cadherin', 'Gene', (119, 129))	('cadherin', 'molecular_function', 'GO:0008014', ('121', '129'))	('cadherin', 'molecular_function', 'GO:0008014', ('133', '141'))	('N-cadherin', 'Gene', (131, 141))	('expressions', 'MPA', (51, 62))	('E-cadherin', 'Gene', '999', (119, 129))	('Vimentin', 'Gene', '7431', (146, 154))	('Vimentin', 'cellular_component', 'GO:0045099', ('146', '154'))	('HHLA2', 'Gene', (202, 207))	('N-cadherin', 'Gene', '1000', (131, 141))	('HHLA2', 'Gene', '11148', (202, 207))	('changed', 'Reg', (175, 182))	('knockdown', 'Var', (189, 198))
112001	31015801	2c), and the overall survival rate of ccRCC patients with low HHLA2 expression was significantly higher than that of the patients with high HHLA2 expression (HR = 3.141, 95% CI 1.831-9.238, P = 0.007, Fig.	('higher', 'PosReg', (97, 103))	('patients', 'Species', '9606', (44, 52))	('HHLA2', 'Gene', (140, 145))	('RCC', 'Disease', (40, 43))	('survival', 'CPA', (21, 29))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('low', 'NegReg', (58, 61))	('expression', 'Var', (68, 78))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('HHLA2', 'Gene', (62, 67))	('HHLA2', 'Gene', '11148', (140, 145))	('HHLA2', 'Gene', '11148', (62, 67))	('patients', 'Species', '9606', (121, 129))
112005	31015801	Therefore, our present results unveil that the abnormal expression of HHLA2 might promote the cancer progression in certain biological process but not via the regulation of CD8+ T cell infiltration or intratumoral angiogenesis.	('CD8', 'Gene', '925', (173, 176))	('HHLA2', 'Gene', '11148', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('promote', 'PosReg', (82, 89))	('abnormal expression', 'Var', (47, 66))	('tumor', 'Disease', (206, 211))	('regulation', 'biological_process', 'GO:0065007', ('159', '169'))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('HHLA2', 'Gene', (70, 75))	('CD8', 'Gene', (173, 176))	('biological process', 'biological_process', 'GO:0008150', ('124', '142'))	('angiogenesis', 'biological_process', 'GO:0001525', ('214', '226'))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
112009	31015801	Then, we further assessed the migration ability of the ccRCC cell lines after knockdown HHLA2 expression in the LV-HHLA2-sh1 as well as LV-HHLA2-sh2 group in contrast to the LV-NC group, and as shown in Fig.	('HHLA2', 'Gene', (139, 144))	('migration ability', 'CPA', (30, 47))	('HHLA2', 'Gene', '11148', (115, 120))	('HHLA2', 'Gene', (88, 93))	('HHLA2', 'Gene', '11148', (139, 144))	('assessed', 'Reg', (17, 25))	('knockdown', 'Var', (78, 87))	('HHLA2', 'Gene', '11148', (88, 93))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))	('HHLA2', 'Gene', (115, 120))
112010	31015801	3d-f, at the time point of 48 h, the relative distance of LV-HHLA2-sh1 (P < 0.0001 in 786-O cells, and P < 0.0001 in ACHN cells) as well as LV-HHLA2-sh2 (P < 0.0001 in 786-O cells, and P < 0.0001 in ACHN cells) group was significantly increased in contrast to the LV-NC group, suggesting that knockdown of HHLA2 expression significantly reduce the migration ability of ccRCC cell lines.	('RCC', 'Phenotype', 'HP:0005584', (371, 374))	('ACHN', 'Gene', (117, 121))	('HHLA2', 'Gene', (61, 66))	('HHLA2', 'Gene', '11148', (306, 311))	('migration ability of', 'CPA', (348, 368))	('knockdown', 'Var', (293, 302))	('ACHN', 'Gene', (199, 203))	('HHLA2', 'Gene', '11148', (61, 66))	('HHLA2', 'Gene', (143, 148))	('ACHN', 'Gene', '55323', (199, 203))	('reduce', 'NegReg', (337, 343))	('ACHN', 'Gene', '55323', (117, 121))	('RCC', 'Disease', 'MESH:C538614', (371, 374))	('RCC', 'Disease', (371, 374))	('HHLA2', 'Gene', (306, 311))	('HHLA2', 'Gene', '11148', (143, 148))	('ccRCC', 'Phenotype', 'HP:0006770', (369, 374))
112013	31015801	4a-c, the knockdown expression of HHLA2 significantly increased the ratio of G1 phase and induced cell cycle arrest in human ccRCC cell lines, we then further examined the expressions of Cyclin D1, c-Myc and Cyclin E1 at the protein level in knockdown group cells in contrast to the control group cells.	('Cyclin E1', 'Gene', (208, 217))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (98, 115))	('G1 phase', 'MPA', (77, 85))	('arrest', 'Disease', (109, 115))	('HHLA2', 'Gene', '11148', (34, 39))	('knockdown expression', 'Var', (10, 30))	('Cyclin E1', 'Gene', '898', (208, 217))	('Cyclin', 'molecular_function', 'GO:0016538', ('208', '214'))	('c-Myc', 'Gene', (198, 203))	('human', 'Species', '9606', (119, 124))	('c-Myc', 'Gene', '4609', (198, 203))	('arrest', 'Disease', 'MESH:D006323', (109, 115))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('protein', 'cellular_component', 'GO:0003675', ('225', '232'))	('ccRCC', 'Phenotype', 'HP:0006770', (125, 130))	('RCC', 'Disease', (127, 130))	('ratio', 'MPA', (68, 73))	('Cyclin D1', 'Gene', '595', (187, 196))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('98', '115'))	('Cyclin', 'molecular_function', 'GO:0016538', ('187', '193'))	('Cyclin D1', 'Gene', (187, 196))	('HHLA2', 'Gene', (34, 39))	('increased', 'PosReg', (54, 63))	('G1 phase', 'biological_process', 'GO:0051318', ('77', '85'))	('induced', 'Reg', (90, 97))	('RCC', 'Disease', 'MESH:C538614', (127, 130))
112016	31015801	5c, d. Therefore, the data from the present microarray analysis also support the conclusion from the cellular function study after knockdown of HHLA2 expression in certain pathways.	('HHLA2', 'Gene', '11148', (144, 149))	('HHLA2', 'Gene', (144, 149))	('knockdown', 'Var', (131, 140))
112017	31015801	Then, we further performed the study to examine the change of EMT markers after HHLA2 knockdown expression in ccRCC cell lines, including E-cadherin, N-cadherin and Vimentin (as shown in Fig.	('Vimentin', 'cellular_component', 'GO:0045098', ('165', '173'))	('Vimentin', 'Gene', (165, 173))	('E-cadherin', 'Gene', '999', (138, 148))	('cadherin', 'molecular_function', 'GO:0008014', ('152', '160'))	('N-cadherin', 'Gene', (150, 160))	('HHLA2', 'Gene', '11148', (80, 85))	('Vimentin', 'Gene', '7431', (165, 173))	('cadherin', 'molecular_function', 'GO:0008014', ('140', '148'))	('Vimentin', 'cellular_component', 'GO:0045099', ('165', '173'))	('N-cadherin', 'Gene', '1000', (150, 160))	('EMT', 'biological_process', 'GO:0001837', ('62', '65'))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('knockdown expression', 'Var', (86, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))	('E-cadherin', 'Gene', (138, 148))	('HHLA2', 'Gene', (80, 85))
112018	31015801	The statistical results showed that, after knockdown of HHLA2 in 786-O and ACHN, the expression of E-cadherin was significantly increased (Fig.	('expression', 'MPA', (85, 95))	('HHLA2', 'Gene', '11148', (56, 61))	('cadherin', 'molecular_function', 'GO:0008014', ('101', '109'))	('ACHN', 'Gene', '55323', (75, 79))	('increased', 'PosReg', (128, 137))	('knockdown', 'Var', (43, 52))	('E-cadherin', 'Gene', (99, 109))	('E-cadherin', 'Gene', '999', (99, 109))	('HHLA2', 'Gene', (56, 61))	('ACHN', 'Gene', (75, 79))
112025	31015801	It has been demonstrated that over-expression of HHLA2 in tumor microenvironment could dampen the T-cell mediated anti-tumor response, break the immune surveillance, and promote tumor immune invasion.	('break', 'NegReg', (135, 140))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('dampen', 'NegReg', (87, 93))	('immune surveillance', 'CPA', (145, 164))	('T-cell', 'CPA', (98, 104))	('over-expression', 'Var', (30, 45))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('HHLA2', 'Gene', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('HHLA2', 'Gene', '11148', (49, 54))	('promote', 'PosReg', (170, 177))
112027	31015801	Further studies demonstrated that higher expression level of HHLA2 in human lung cancer tissues significantly associated with EGFR mutation, higher intensities of TILs and PD-L1 status, suggesting an effective immunotherapy strategy for PD-L1-negative patients.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('EGFR', 'Gene', '1956', (126, 130))	('mutation', 'Var', (131, 139))	('EGFR', 'molecular_function', 'GO:0005006', ('126', '130'))	('patients', 'Species', '9606', (252, 260))	('lung cancer', 'Disease', (76, 87))	('associated', 'Reg', (110, 120))	('PD-L1', 'Gene', (237, 242))	('PD-L1', 'Gene', '29126', (237, 242))	('HHLA2', 'Gene', (61, 66))	('higher', 'PosReg', (34, 40))	('human', 'Species', '9606', (70, 75))	('PD-L1', 'Gene', (172, 177))	('PD-L1', 'Gene', '29126', (172, 177))	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('EGFR', 'Gene', (126, 130))	('HHLA2', 'Gene', '11148', (61, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('expression level', 'MPA', (41, 57))
112033	31015801	However, when we used the RNAi approach to establish the knockdown of HHLA2 expression in human ccRCC cell lines, we found that HHLA2 knockdown could significantly decreased the cell viability, migration ability, invasion ability, and induced the cell cycle arrest at G1 phase.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('247', '264'))	('cell viability', 'CPA', (178, 192))	('human', 'Species', '9606', (90, 95))	('HHLA2', 'Gene', (128, 133))	('arrest', 'Disease', (258, 264))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('HHLA2', 'Gene', (70, 75))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (247, 264))	('HHLA2', 'Gene', '11148', (128, 133))	('invasion ability', 'CPA', (213, 229))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('arrest', 'Disease', 'MESH:D006323', (258, 264))	('G1 phase', 'biological_process', 'GO:0051318', ('268', '276'))	('HHLA2', 'Gene', '11148', (70, 75))	('RNAi', 'biological_process', 'GO:0016246', ('26', '30'))	('induced', 'Reg', (235, 242))	('decreased', 'NegReg', (164, 173))	('knockdown', 'Var', (134, 143))	('migration ability', 'CPA', (194, 211))
112034	31015801	The cellular studies further confirmed that the expressions of Cyclin D1, c-Myc and Cyclin E1 were significantly decreased after knockdown of HHLA2 expression.	('HHLA2', 'Gene', '11148', (142, 147))	('Cyclin E1', 'Gene', '898', (84, 93))	('Cyclin', 'molecular_function', 'GO:0016538', ('84', '90'))	('Cyclin E1', 'Gene', (84, 93))	('c-Myc', 'Gene', '4609', (74, 79))	('Cyclin', 'molecular_function', 'GO:0016538', ('63', '69'))	('knockdown', 'Var', (129, 138))	('expressions', 'MPA', (48, 59))	('c-Myc', 'Gene', (74, 79))	('Cyclin D1', 'Gene', '595', (63, 72))	('HHLA2', 'Gene', (142, 147))	('decreased', 'NegReg', (113, 122))	('Cyclin D1', 'Gene', (63, 72))
112036	31015801	The co-down-regulated as well as the co-up-regulated gene profiles were analyzed, and among the top 20 pathways, we further investigated the epithelial-to-mesenchymal transition (EMT) upon knockdown of HHLA2 expression in ccRCC cell lines.	('RCC', 'Disease', (224, 227))	('RCC', 'Phenotype', 'HP:0005584', (224, 227))	('EMT', 'biological_process', 'GO:0001837', ('179', '182'))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('141', '177'))	('ccRCC', 'Phenotype', 'HP:0006770', (222, 227))	('epithelial-to-mesenchymal transition', 'CPA', (141, 177))	('investigated', 'Reg', (124, 136))	('HHLA2', 'Gene', (202, 207))	('HHLA2', 'Gene', '11148', (202, 207))	('knockdown', 'Var', (189, 198))	('RCC', 'Disease', 'MESH:C538614', (224, 227))
112037	31015801	Our results showed that the EMT marker E-cadherin expression was significantly increased, and N-cadherin as well as Vimentin was significantly decreased after knockdown of HHLA2 expression, suggesting that HHLA2 was involved in the cancer progression of human ccRCC by promoting EMT.	('RCC', 'Disease', 'MESH:C538614', (262, 265))	('cancer', 'Disease', (232, 238))	('promoting', 'PosReg', (269, 278))	('involved', 'Reg', (216, 224))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('expression', 'MPA', (50, 60))	('human', 'Species', '9606', (254, 259))	('Vimentin', 'cellular_component', 'GO:0045098', ('116', '124'))	('HHLA2', 'Gene', (206, 211))	('Vimentin', 'Gene', '7431', (116, 124))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('decreased', 'NegReg', (143, 152))	('EMT', 'biological_process', 'GO:0001837', ('28', '31'))	('HHLA2', 'Gene', (172, 177))	('EMT', 'biological_process', 'GO:0001837', ('279', '282'))	('Vimentin', 'Gene', (116, 124))	('cadherin', 'molecular_function', 'GO:0008014', ('96', '104'))	('RCC', 'Disease', (262, 265))	('RCC', 'Phenotype', 'HP:0005584', (262, 265))	('EMT', 'MPA', (28, 31))	('HHLA2', 'Gene', '11148', (206, 211))	('EMT', 'CPA', (279, 282))	('increased', 'PosReg', (79, 88))	('cadherin', 'molecular_function', 'GO:0008014', ('41', '49'))	('knockdown', 'Var', (159, 168))	('E-cadherin', 'Gene', (39, 49))	('E-cadherin', 'Gene', '999', (39, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (260, 265))	('N-cadherin', 'Gene', (94, 104))	('Vimentin', 'cellular_component', 'GO:0045099', ('116', '124'))	('N-cadherin', 'Gene', '1000', (94, 104))	('HHLA2', 'Gene', '11148', (172, 177))
112041	31015801	Collectively, our present study reported the clinical significance of abnormal HHLA2 expression in human ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (105, 110))	('RCC', 'Disease', (107, 110))	('abnormal', 'Var', (70, 78))	('HHLA2', 'Gene', (79, 84))	('HHLA2', 'Gene', '11148', (79, 84))	('human', 'Species', '9606', (99, 104))
112043	31015801	Our present findings suggested that HHLA2 expression in human clear cell renal cell carcinoma is significantly associated with patient's prognosis and promotes cancer progression, and could serve as important prognostic predictor and therapeutic target for this malignancy.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (62, 93))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (73, 93))	('HHLA2', 'Gene', (36, 41))	('patient', 'Species', '9606', (127, 134))	('cancer', 'Disease', (160, 166))	('malignancy', 'Disease', (262, 272))	('promotes', 'PosReg', (151, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('associated', 'Reg', (111, 121))	('human', 'Species', '9606', (56, 61))	('HHLA2', 'Gene', '11148', (36, 41))	('expression', 'Var', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (62, 93))	('clear cell renal cell carcinoma', 'Disease', (62, 93))	('malignancy', 'Disease', 'MESH:D009369', (262, 272))
112085	33862522	While VHL had a high mutation rate in all the subtypes, VHL mutations were less frequently observed in the C1 subtype than in the C2 and C3 subtypes (Table 2).	('VHL', 'Gene', (56, 59))	('VHL', 'Gene', '7428', (56, 59))	('VHL', 'Gene', (6, 9))	('VHL', 'Gene', '7428', (6, 9))	('mutations', 'Var', (60, 69))
112086	33862522	In addition, FLG, MUC16, and FBN2 mutations were specifically observed in the C1, C2, and C3 subtypes, respectively (Table 2).	('FLG', 'Gene', (13, 16))	('FLG', 'Gene', '2312', (13, 16))	('MUC16', 'Gene', '94025', (18, 23))	('C1, C2, and C3', 'Gene', '3183', (78, 92))	('FBN2', 'Gene', '2201', (29, 33))	('FBN2', 'Gene', (29, 33))	('MUC16', 'Gene', (18, 23))	('mutations', 'Var', (34, 43))	('observed', 'Reg', (62, 70))
112087	33862522	Based on TCGA-KIRC cohort, K-M analysis also revealed that VHL, FLG and MUC16 mutation status did not show survival differences (Fig.	('VHL', 'Gene', '7428', (59, 62))	('FLG', 'Gene', (64, 67))	('FLG', 'Gene', '2312', (64, 67))	('MUC16', 'Gene', (72, 77))	('mutation', 'Var', (78, 86))	('MUC16', 'Gene', '94025', (72, 77))	('VHL', 'Gene', (59, 62))
112088	33862522	4A-C) while patients with FBN2 mutation have superior OS (Fig.	('FBN2', 'Gene', (26, 30))	('patients', 'Species', '9606', (12, 20))	('mutation', 'Var', (31, 39))	('FBN2', 'Gene', '2201', (26, 30))	('superior', 'PosReg', (45, 53))
112095	33862522	reported that the use of CT features is a potential and feasible approach for predicting BAP1 mutations in ccRCC patients.	('BAP1', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('patients', 'Species', '9606', (113, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('ccRCC', 'Disease', (107, 112))	('BAP1', 'Gene', '8314', (89, 93))
112096	33862522	Moreover, a study involving 233 ccRCC patients identified associations between some CT features, such as well-defined tumor margins and nodular tumor enhancement, and the presence of mutations in several genes (VHL, PBRM1, SETD2, KDM5C, and BAP1).	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('PBRM1', 'Gene', (216, 221))	('BAP1', 'Gene', (241, 245))	('enhancement', 'PosReg', (150, 161))	('patients', 'Species', '9606', (38, 46))	('VHL', 'Gene', (211, 214))	('ccRCC', 'Disease', (32, 37))	('mutations', 'Var', (183, 192))	('associations', 'Interaction', (58, 70))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('KDM5C', 'Gene', '8242', (230, 235))	('SETD2', 'Gene', (223, 228))	('tumor', 'Disease', (144, 149))	('ccRCC', 'Phenotype', 'HP:0006770', (32, 37))	('VHL', 'Gene', '7428', (211, 214))	('SETD2', 'Gene', '29072', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('nodular tumor', 'Disease', (136, 149))	('BAP1', 'Gene', '8314', (241, 245))	('PBRM1', 'Gene', '55193', (216, 221))	('nodular tumor', 'Disease', 'MESH:D008224', (136, 149))	('KDM5C', 'Gene', (230, 235))	('tumor', 'Disease', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
112098	33862522	Genetically, ccRCC is characterized by a high proportion of VHL mutations, which play a central role in the current understanding of the fundamental principles of ccRCC development.	('VHL', 'Gene', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('VHL', 'Gene', '7428', (60, 63))	('ccRCC', 'Disease', (13, 18))	('mutations', 'Var', (64, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (163, 168))
112100	33862522	Accordingly, it is a reasonable phenomenon that the features of medical images could, in a certain way, reflect VHL mutations.	('VHL', 'Gene', '7428', (112, 115))	('mutations', 'Var', (116, 125))	('reflect', 'Reg', (104, 111))	('VHL', 'Gene', (112, 115))
112101	33862522	A previous study revealed that VHL mutations are significantly associated with ill-defined tumor margins, multicystic tumors, nodular tumor enhancement, and the intratumoral vasculature.	('multicystic tumors', 'Disease', (106, 124))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('nodular tumor', 'Disease', (126, 139))	('nodular tumor', 'Disease', 'MESH:D008224', (126, 139))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (91, 96))	('VHL', 'Gene', '7428', (31, 34))	('multicystic tumors', 'Disease', 'MESH:D021782', (106, 124))	('associated', 'Reg', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('ill-defined tumor', 'Disease', 'MESH:D002908', (79, 96))	('ill-defined tumor', 'Disease', (79, 96))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', (118, 123))	('VHL', 'Gene', (31, 34))	('mutations', 'Var', (35, 44))
112102	33862522	In the present study, the proportion of VHL mutations was found to differ in different subtypes; in particular, it was low in the C1 subtype.	('low', 'NegReg', (119, 122))	('mutations', 'Var', (44, 53))	('VHL', 'Gene', (40, 43))	('VHL', 'Gene', '7428', (40, 43))
112103	33862522	However, a recent meta-analysis suggested that VHL mutations are not significantly associated with the survival of ccRCC patients In addition, FLG, MUC16, and FBN2 mutations specifically occurred in the C1, C2, and C3 subtypes, respectively.	('FLG', 'Gene', '2312', (143, 146))	('MUC16', 'Gene', (148, 153))	('occurred', 'Reg', (187, 195))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('FLG', 'Gene', (143, 146))	('FBN2', 'Gene', '2201', (159, 163))	('C1, C2, and C3', 'Gene', '3183', (203, 217))	('FBN2', 'Gene', (159, 163))	('VHL', 'Gene', (47, 50))	('MUC16', 'Gene', '94025', (148, 153))	('VHL', 'Gene', '7428', (47, 50))	('mutations', 'Var', (164, 173))	('patients', 'Species', '9606', (121, 129))	('ccRCC', 'Disease', (115, 120))
112104	33862522	FLG have been reported that significantly mutated or amplified in some types of cancer.	('amplified', 'Reg', (53, 62))	('mutated', 'Var', (42, 49))	('FLG', 'Gene', (0, 3))	('FLG', 'Gene', '2312', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
112107	33862522	Several previous studies have revealed that MUC16 mutation is closely related to prognosis of many types of cancer.	('MUC16', 'Gene', '94025', (44, 49))	('mutation', 'Var', (50, 58))	('MUC16', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('related', 'Reg', (70, 77))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
112111	33862522	Hypermethylation of FBN2 has been previously reported in renal cell carcinoma and knockdown for FBN2 also lead to an anchorage-independent growth advantage.	('FBN2', 'Gene', '2201', (96, 100))	('reported', 'Reg', (45, 53))	('FBN2', 'Gene', (20, 24))	('FBN2', 'Gene', (96, 100))	('Hypermethylation', 'Var', (0, 16))	('knockdown', 'Var', (82, 91))	('renal cell carcinoma', 'Disease', (57, 77))	('lead to', 'Reg', (106, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (57, 77))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (57, 77))	('anchorage-independent growth advantage', 'CPA', (117, 155))	('FBN2', 'Gene', '2201', (20, 24))
112112	33862522	We found that FBN2 mutation is related to the prognosis of ccRCC.	('FBN2', 'Gene', (14, 18))	('mutation', 'Var', (19, 27))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('ccRCC', 'Disease', (59, 64))	('related', 'Reg', (31, 38))	('FBN2', 'Gene', '2201', (14, 18))
112113	33862522	FBN2 mutation also related with patients' OS, it may present as potential biomarker for ccRCC.	('patients', 'Species', '9606', (32, 40))	('FBN2', 'Gene', (0, 4))	('ccRCC', 'Disease', (88, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('related', 'Reg', (19, 26))	('mutation', 'Var', (5, 13))	('FBN2', 'Gene', '2201', (0, 4))
112121	33862522	Research conception, design and manuscript revision: Peng Lin, Yi-qun Lin, Rui-zhi Gao, Rong Wen, Hui-Qin, Yun He and Hong Yang Data processing, statistical analysis, drafting of the manuscript: Peng Lin, Yi-qun Lin and Rui-zhi Gao Detection of multi-omics subtypes: Rong Wen, Hui-Qin, Yun He Delineation region of interest (ROI) of the tumor contours: Yi-qun Lin The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('tumor', 'Disease', (337, 342))	('Qin', 'Gene', '2290', (102, 105))	('Qin', 'Gene', '2290', (281, 284))	('Yi-qun Lin', 'Var', (353, 363))	('Qin', 'Gene', (102, 105))	('Qin', 'Gene', (281, 284))	('tumor', 'Disease', 'MESH:D009369', (337, 342))
112158	30082525	The luciferase reporter constructs with the 3'UTR of YWHAZ containing the putative or mutant miR-375 binding site were generated using the dual-luciferase miRNA Target Expression vector pmirGlokit (Promega, WI, USA).	('YWHAZ', 'Gene', (53, 58))	('mutant', 'Var', (86, 92))	('YWHAZ', 'Gene', '7534', (53, 58))	('miR', 'Gene', '220972', (155, 158))	('miR', 'Gene', (155, 158))	('binding', 'molecular_function', 'GO:0005488', ('101', '108'))	('miR', 'Gene', '220972', (93, 96))	('miR', 'Gene', (93, 96))
112159	30082525	Cells were seeded into 24-well plates and co-transfected with 500 ng of the wild-type or mutated YWHAZ 3'UTR constructs, together with 30 nmol/L of miR-375 mimics or negative controls.	('YWHAZ', 'Gene', (97, 102))	('YWHAZ', 'Gene', '7534', (97, 102))	('mutated', 'Var', (89, 96))
112161	30082525	The primary antibodies used in this study were anti-YWHAZ (1:150; Abcam, USA) and anti-beta-actin (1:1500; Santa Cruz, USA).	('YWHAZ', 'Gene', (52, 57))	('1:150', 'Var', (59, 64))	('YWHAZ', 'Gene', '7534', (52, 57))	('beta-actin', 'Gene', '728378', (87, 97))	('1:1500', 'Var', (99, 105))	('beta-actin', 'Gene', (87, 97))
112172	30082525	Moreover, results showed that the miR-375 overexpression group exhibited significantly inhibited migratory (miR-375 mimics vs. control, P = 0.008 in 786-O; P = 0.003 in A498) and invasive capacity (miR-375 mimics vs. control, P = 0.004 in 786-O; P = 0.008 in A498; Figure 2c and 2d).	('migratory', 'CPA', (97, 106))	('miR-375', 'Gene', (34, 41))	('miR-375', 'Var', (198, 205))	('inhibited', 'NegReg', (87, 96))	('overexpression', 'PosReg', (42, 56))	('A498', 'CellLine', 'CVCL:1056', (169, 173))	('A498', 'CellLine', 'CVCL:1056', (259, 263))	('invasive capacity', 'CPA', (179, 196))
112177	30082525	We synthesized the 3'UTR of YWHAZ containing the putative miR-375 binding sites without (wild-type [WT]) or with (mutant [MUT]) mutations, then inserted it into a pmirGlo vector.	('YWHAZ', 'Gene', '7534', (28, 33))	('binding', 'molecular_function', 'GO:0005488', ('66', '73'))	('mutations', 'Var', (128, 137))	('binding', 'Interaction', (66, 73))	('miR-375', 'Gene', (58, 65))	('YWHAZ', 'Gene', (28, 33))
112180	30082525	However, no remarkable changes in luciferase activity were observed in the pmirGlo-YWHAZ-MUT and miR-375 mimic group.	('activity', 'MPA', (45, 53))	('miR-375', 'Var', (97, 104))	('luciferase activity', 'molecular_function', 'GO:0045289', ('34', '53'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('34', '53'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('34', '53'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('34', '53'))	('luciferase', 'Enzyme', (34, 44))	('YWHAZ', 'Gene', (83, 88))	('luciferase activity', 'molecular_function', 'GO:0047077', ('34', '53'))	('YWHAZ', 'Gene', '7534', (83, 88))
112191	30082525	Meanwhile, the same group found that miR-375 could inhibit colorectal cancer cells' proliferation by downregulating JAK2/STAT3 and MAP3K8/ERK signaling pathways.	('MAP3K', 'molecular_function', 'GO:0004709', ('131', '136'))	('STAT3', 'Gene', '6774', (121, 126))	('ERK', 'Gene', (138, 141))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('MAP3K8', 'Gene', '1326', (131, 137))	('signaling', 'biological_process', 'GO:0023052', ('142', '151'))	('downregulating', 'NegReg', (101, 115))	('ERK', 'molecular_function', 'GO:0004707', ('138', '141'))	('ERK', 'Gene', '2048', (138, 141))	('JAK2', 'Gene', '3717', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('JAK', 'molecular_function', 'GO:0004713', ('116', '119'))	('inhibit', 'NegReg', (51, 58))	('colorectal cancer', 'Disease', 'MESH:D015179', (59, 76))	('STAT3', 'Gene', (121, 126))	('MAP3K8', 'Gene', (131, 137))	('colorectal cancer', 'Disease', (59, 76))	('miR-375', 'Var', (37, 44))	('JAK2', 'Gene', (116, 120))
112203	30082525	We wonder whether the antitumor effect of miR-375 is mediated by targeting of the oncogene YWHAZ mRNA.	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('YWHAZ', 'Gene', '7534', (91, 96))	('YWHAZ', 'Gene', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('miR-375', 'Var', (42, 49))
112205	30082525	However, the antimigration and anti-invasion effect of miR-375 cannot be reversed by YWHAZ, indicating additional pathways exist to mediate the tumor suppressor effect of miR-375, and high-throughput sequencing techniques could be applied to explore the underlying mechanism, which warrant further studies.	('anti-invasion', 'CPA', (31, 44))	('tumor', 'Disease', (144, 149))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('144', '160'))	('YWHAZ', 'Gene', (85, 90))	('miR-375', 'Var', (171, 178))	('antimigration', 'CPA', (13, 26))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('YWHAZ', 'Gene', '7534', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor suppressor', 'biological_process', 'GO:0051726', ('144', '160'))
112208	30082525	Further studies should be focused on the more comprehensive molecular mechanism of miR-375 in ccRCC, and the effect of miR-375/YWHAX axis in vivo.	('ccRCC', 'Disease', (94, 99))	('miR-375', 'Var', (83, 90))	('YWHAX', 'Chemical', '-', (127, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))
112251	31097685	Interestingly, CD95L surface expression was high in all cell lines analyzed, and CD95 but not TNF-R1 clustered at cell contact sites.	('CD95L', 'Gene', '356', (15, 20))	('CD95L', 'Gene', (15, 20))	('CD95', 'Var', (81, 85))	('TNF-R1', 'Gene', '7132', (94, 100))	('TNF-R1', 'Gene', (94, 100))
112259	31097685	One particular type of RCC, the clear cell RCC (ccRCC), often exhibits mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and in PBRM1, a component of the PBAF chromatin-remodeling complex.	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (88, 117))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('RCC', 'Disease', (50, 53))	('mutations', 'Var', (71, 80))	('RCC', 'Disease', (43, 46))	('exhibits', 'Reg', (62, 70))	('PBRM1', 'Gene', '55193', (141, 146))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('112', '128'))	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('172', '192'))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('PBRM1', 'Gene', (141, 146))	('tumor suppressor', 'biological_process', 'GO:0051726', ('112', '128'))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('RCC', 'Disease', (23, 26))	('chromatin-remodeling complex', 'cellular_component', 'GO:0016585', ('172', '200'))
112321	31097685	Taken together, loss of c-FLIP leads to spontaneous apoptosis in clearCa cell lines, whereas expression of one isoform is sufficient for cell viability.	('loss', 'Var', (16, 20))	('apoptosis', 'biological_process', 'GO:0097194', ('52', '61'))	('c-FLIP', 'Gene', '8837', (24, 30))	('c-FLIP', 'Gene', (24, 30))	('apoptosis', 'biological_process', 'GO:0006915', ('52', '61'))
112328	31097685	4a), showing that the inserted mutations were sufficient to prevent mRNA degradation by c-FLIPL/S-targeting shRNA.	('prevent', 'NegReg', (60, 67))	('mutations', 'Var', (31, 40))	('c-FLIPL', 'Gene', '8837', (88, 95))	('mRNA degradation', 'biological_process', 'GO:0006402', ('68', '84'))	('c-FLIPL', 'Gene', (88, 95))	('mRNA degradation', 'MPA', (68, 84))
112335	31097685	Next to apoptosis regulation, CD95 and c-FLIP were also shown to activate NF-kappaB and ERK and CD95 expression is high in all clearCa cell lines (Fig.	('CD95', 'Var', (30, 34))	('ERK', 'Gene', '5594', (88, 91))	('NF-kappaB', 'Gene', (74, 83))	('apoptosis', 'biological_process', 'GO:0097194', ('8', '17'))	('apoptosis', 'biological_process', 'GO:0006915', ('8', '17'))	('c-FLIP', 'Gene', '8837', (39, 45))	('activate', 'PosReg', (65, 73))	('c-FLIP', 'Gene', (39, 45))	('regulation', 'biological_process', 'GO:0065007', ('18', '28'))	('ERK', 'Gene', (88, 91))	('CD95', 'Gene', (96, 100))	('ERK', 'molecular_function', 'GO:0004707', ('88', '91'))	('expression', 'MPA', (101, 111))	('clearCa', 'Disease', (127, 134))	('NF-kappaB', 'Gene', '4790', (74, 83))
112340	31097685	As clusters of CD95 may lead to DISC formation and subsequent c-FLIP-dependent activation of survival pathways, we analyzed phosphorylation of the RelA/p65 NF-kappaB subunit as well as the MAP kinases Erk1/2.	('DISC formation', 'CPA', (32, 46))	('As c', 'Gene', '29108', (0, 4))	('RelA', 'Gene', (147, 151))	('phosphorylation', 'biological_process', 'GO:0016310', ('124', '139'))	('c-FLIP', 'Gene', (62, 68))	('RelA', 'Gene', '5970', (147, 151))	('activation', 'PosReg', (79, 89))	('CD95', 'Var', (15, 19))	('NF-kappaB', 'Gene', (156, 165))	('MAP', 'molecular_function', 'GO:0004239', ('189', '192'))	('p65', 'Gene', (152, 155))	('DISC formation', 'biological_process', 'GO:0071550', ('32', '46'))	('survival pathways', 'Pathway', (93, 110))	('Erk1', 'molecular_function', 'GO:0004707', ('201', '205'))	('NF-kappaB', 'Gene', '4790', (156, 165))	('c-FLIP', 'Gene', '8837', (62, 68))	('DISC', 'cellular_component', 'GO:0031264', ('32', '36'))	('p65', 'Gene', '5970', (152, 155))	('lead to', 'Reg', (24, 31))	('As c', 'Gene', (0, 4))
112346	31097685	Importantly, TPCA-1 but not PD0325901 reduced viability of clearCa-4 cells showing that activation of IKK-beta but not Erk1/2 is required for cell survival (Fig.	('Ca-4', 'CellLine', 'CVCL:Z839', (64, 68))	('Erk1', 'molecular_function', 'GO:0004707', ('119', '123'))	('IKK-beta', 'Gene', (102, 110))	('reduced', 'NegReg', (38, 45))	('IKK-beta', 'Gene', '3551', (102, 110))	('IKK', 'molecular_function', 'GO:0008384', ('102', '105'))	('viability', 'CPA', (46, 55))	('TPCA-1', 'Var', (13, 19))	('PD0325901', 'Chemical', 'MESH:C506614', (28, 37))
112364	31097685	We confirmed that this effect was owing to the absence of c-FLIP only, as re-expression of mutated c-FLIPL (c-FLIPRESIST) was sufficient to restore cell viability.	('c-FLIPL', 'Gene', '8837', (99, 106))	('c-FLIP', 'Gene', (108, 114))	('c-FLIP', 'Gene', '8837', (108, 114))	('restore', 'PosReg', (140, 147))	('c-FLIPR', 'Gene', (108, 115))	('mutated', 'Var', (91, 98))	('c-FLIPL', 'Gene', (99, 106))	('cell viability', 'CPA', (148, 162))	('c-FLIPR', 'Gene', '8837', (108, 115))	('c-FLIP', 'Gene', '8837', (99, 105))	('c-FLIP', 'Gene', (99, 105))	('c-FLIP', 'Gene', '8837', (58, 64))	('c-FLIP', 'Gene', (58, 64))
112367	31097685	We found that CD95, but not TNF-R1 formed clusters at cell-cell contact sites.	('TNF-R1', 'Gene', (28, 34))	('CD95', 'Var', (14, 18))	('TNF-R1', 'Gene', '7132', (28, 34))
112371	31097685	For instance, knockdown of c-FLIP resulted in higher death rates upon stimulation with death ligands in breast cancer cells, melanoma cells, non-small cell lung carcinoma cells, and urothelial carcinoma cells.	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('stimulation', 'Interaction', (70, 81))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (141, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('urothelial carcinoma', 'Disease', (182, 202))	('breast cancer', 'Disease', (104, 117))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (145, 170))	('carcinoma', 'Disease', (193, 202))	('c-FLIP', 'Gene', '8837', (27, 33))	('higher', 'PosReg', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('carcinoma', 'Disease', 'MESH:D002277', (161, 170))	('death rates', 'MPA', (53, 64))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (182, 202))	('carcinoma', 'Disease', 'MESH:D002277', (193, 202))	('rat', 'Species', '10116', (59, 62))	('c-FLIP', 'Gene', (27, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('knockdown', 'Var', (14, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('carcinoma', 'Disease', (161, 170))
112372	31097685	To our knowledge, a single report shows that loss of c-FLIP leads to TRAIL-R2-dependent spontaneous caspase-8 activation and subsequent apoptosis in MCF-7 cells, which lack caspase-3, a main effector caspase in apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('211', '220'))	('activation', 'PosReg', (110, 120))	('apoptosis', 'CPA', (136, 145))	('caspase-8', 'Gene', (100, 109))	('caspase-3', 'Gene', (173, 182))	('c-FLIP', 'Gene', '8837', (53, 59))	('c-FLIP', 'Gene', (53, 59))	('apoptosis', 'biological_process', 'GO:0006915', ('211', '220'))	('apoptosis', 'biological_process', 'GO:0097194', ('136', '145'))	('TRAIL-R2', 'Gene', (69, 77))	('caspase-3', 'Gene', '836', (173, 182))	('MCF-7', 'CellLine', 'CVCL:0031', (149, 154))	('caspase-8', 'Gene', '841', (100, 109))	('apoptosis', 'biological_process', 'GO:0006915', ('136', '145'))	('TRAIL-R2', 'Gene', '8795', (69, 77))	('loss', 'Var', (45, 49))
112373	31097685	in the MCF-7 cell line are clearly different from our observations, as they claim a ligand-independent activation of caspases upon c-FLIP knockdown.	('knockdown', 'Var', (138, 147))	('ligand', 'molecular_function', 'GO:0005488', ('84', '90'))	('c-FLIP', 'Gene', '8837', (131, 137))	('c-FLIP', 'Gene', (131, 137))	('MCF-7', 'CellLine', 'CVCL:0031', (7, 12))	('caspases', 'Gene', (117, 125))	('caspases', 'Gene', '841;842;843', (117, 125))	('activation', 'PosReg', (103, 113))
112383	31097685	However, knockdown of c-FLIP led to an increase in RelA/p65 phosphorylation, indicating that c-FLIP inhibits NF-kappaB in ccRCC, which is consistent with reports showing an inhibitory role of c-FLIP on NF-kB in the context of death receptor signaling.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('p65', 'Gene', '5970', (56, 59))	('c-FLIP', 'Gene', '8837', (93, 99))	('RelA', 'Gene', (51, 55))	('increase', 'PosReg', (39, 47))	('inhibits', 'NegReg', (100, 108))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('c-FLIP', 'Gene', (22, 28))	('RelA', 'Gene', '5970', (51, 55))	('c-FLIP', 'Gene', '8837', (192, 198))	('knockdown', 'Var', (9, 18))	('c-FLIP', 'Gene', (93, 99))	('NF-kappaB', 'Gene', (109, 118))	('phosphorylation', 'biological_process', 'GO:0016310', ('60', '75'))	('p65', 'Gene', (56, 59))	('NF-kappaB', 'Gene', '4790', (109, 118))	('c-FLIP', 'Gene', '8837', (22, 28))	('signaling', 'biological_process', 'GO:0023052', ('241', '250'))	('c-FLIP', 'Gene', (192, 198))
112387	31097685	For instance, it was shown that CD95 can actually promote tumor formation in mouse models of liver cancer and ovarian cancer and knockdown of CD95 in cancer cell lines impaired their proliferation.	('promote', 'PosReg', (50, 57))	('ovarian cancer', 'Disease', (110, 124))	('liver cancer', 'Phenotype', 'HP:0002896', (93, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (110, 124))	('proliferation', 'CPA', (183, 196))	('CD95', 'Var', (32, 36))	('CD95', 'Gene', (142, 146))	('liver cancer', 'Disease', (93, 105))	('tumor', 'Disease', (58, 63))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('rat', 'Species', '10116', (190, 193))	('knockdown', 'Var', (129, 138))	('cancer', 'Disease', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('mouse', 'Species', '10090', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ovarian cancer', 'Disease', 'MESH:D010051', (110, 124))	('impaired', 'NegReg', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('liver cancer', 'Disease', 'MESH:D006528', (93, 105))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (99, 105))	('formation', 'biological_process', 'GO:0009058', ('64', '73'))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
112390	31097685	Indeed, there are certain similarities between DICE and the cell death we observe upon c-FLIP knockdown in ccRCC cells.	('knockdown', 'Var', (94, 103))	('c-FLIP', 'Gene', '8837', (87, 93))	('c-FLIP', 'Gene', (87, 93))	('cell death', 'biological_process', 'GO:0008219', ('60', '70'))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))
112393	31097685	In contrast, the cell death we observed upon c-FLIP knockdown in clearCa cells exhibited classical signs of apoptosis such as caspase activation, phosphatidylserine exposure, and formation of apoptotic bodies.	('c-FLIP', 'Gene', '8837', (45, 51))	('c-FLIP', 'Gene', (45, 51))	('caspase activation', 'biological_process', 'GO:0006919', ('126', '144'))	('formation', 'biological_process', 'GO:0009058', ('179', '188'))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('phosphatidylserine exposure', 'MPA', (146, 173))	('cell death', 'biological_process', 'GO:0008219', ('17', '27'))	('caspase', 'CPA', (126, 133))	('knockdown', 'Var', (52, 61))
112394	31097685	Furthermore, c-FLIP knockdown-induced cell death of ccRCC cells was inhibited by the pan-caspase inhibitor QVD but not by the necroptosis inhibitor Nec-1.	('knockdown-induced', 'Var', (20, 37))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('inhibited', 'NegReg', (68, 77))	('necroptosis', 'biological_process', 'GO:0097528', ('126', '137'))	('cell death', 'CPA', (38, 48))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('necroptosis', 'biological_process', 'GO:0070266', ('126', '137'))	('c-FLIP', 'Gene', '8837', (13, 19))	('c-FLIP', 'Gene', (13, 19))	('cell death', 'biological_process', 'GO:0008219', ('38', '48'))
112398	31097685	Summarized, we demonstrated that c-FLIP mediates resistance to CD95L-induced apoptosis and that loss of c-FLIP leads to spontaneous apoptosis in RCC.	('c-FLIP', 'Gene', '8837', (104, 110))	('c-FLIP', 'Gene', (104, 110))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('apoptosis', 'biological_process', 'GO:0097194', ('132', '141'))	('spontaneous apoptosis', 'CPA', (120, 141))	('loss', 'Var', (96, 100))	('rat', 'Species', '10116', (22, 25))	('c-FLIP', 'Gene', '8837', (33, 39))	('c-FLIP', 'Gene', (33, 39))	('apoptosis', 'biological_process', 'GO:0006915', ('132', '141'))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('CD95L', 'Gene', '356', (63, 68))	('CD95L', 'Gene', (63, 68))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))
112422	31097685	Horseradish peroxidase-coupled secondary antibodies: anti-mouse IgG (sc-2055, Santa Cruz), anti-mouse IgG1 (1070-05, SouthernBiotech), anti-mouse IgG2a (1080-05, SouthernBiotech), anti-mouse IgG2b (1090-05, SouthernBiotech), anti-goat IgG (6160-05, SouthernBiotech), anti-rabbit IgG (4030-05, SouthernBiotech), anti-rat IgG (3050-05, SouthernBiotech).	('mouse', 'Species', '10090', (140, 145))	('mouse', 'Species', '10090', (185, 190))	('mouse', 'Species', '10090', (58, 63))	('mouse', 'Species', '10090', (96, 101))	('anti-mouse', 'Var', (180, 190))	('anti-mouse', 'Var', (135, 145))	('rabbit', 'Species', '9986', (272, 278))	('goat', 'Species', '9925', (230, 234))	('IgG2a', 'cellular_component', 'GO:0071735', ('146', '151'))	('anti-mouse', 'Var', (91, 101))	('Horseradish', 'Species', '3704', (0, 11))	('IgG1', 'cellular_component', 'GO:0071735', ('102', '106'))	('rat', 'Species', '10116', (316, 319))	('IgG2b', 'cellular_component', 'GO:0071735', ('191', '196'))	('4030-05', 'Var', (284, 291))
112516	32127786	ANPEP was thought as an important therapeutic target for cancers and inhibition of it could suppress tumor cells proliferation and migration.	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('ANPEP', 'Gene', '290', (0, 5))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('suppress', 'NegReg', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('ANPEP', 'Gene', (0, 5))	('inhibition', 'Var', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
112520	32127786	In CHRCC, downregulated peroxisomal acyl-coenzyme A oxidase 1 (ACOX1)-mediated fatty acid degradation and downregulated glutathione S-transferase alpha 1 and 2 (GSTA1 and -2)-mediated dysfunction of glutathione metabolism triggers oxidation and promotes CHRCC carcinogenesis.	('CHRCC', 'Disease', 'MESH:D002292', (3, 8))	('downregulated', 'NegReg', (106, 119))	('downregulated', 'NegReg', (10, 23))	('fatty acid degradation', 'biological_process', 'GO:0009062', ('79', '101'))	('GSTA1 and -2', 'Gene', '2938;2939', (161, 173))	('peroxisomal acyl-coenzyme A oxidase 1', 'Gene', (24, 61))	('CHRCC', 'Disease', 'MESH:D002292', (254, 259))	('fatty acid', 'Chemical', 'MESH:D005227', (79, 89))	('peroxisomal', 'cellular_component', 'GO:0005777', ('24', '35'))	('ACOX1', 'Gene', '51', (63, 68))	('peroxisomal acyl-coenzyme A oxidase 1', 'Gene', '51', (24, 61))	('glutathione metabolism', 'biological_process', 'GO:0006749', ('199', '221'))	('glutathione', 'Chemical', 'MESH:D005978', (120, 131))	('glutathione', 'Chemical', 'MESH:D005978', (199, 210))	('oxidation', 'MPA', (231, 240))	('CHRCC', 'Disease', (3, 8))	('dysfunction', 'Var', (184, 195))	('fatty acid degradation', 'MPA', (79, 101))	('ACOX1', 'Gene', (63, 68))	('triggers', 'Reg', (222, 230))	('CHRCC', 'Disease', (254, 259))	('glutathione S-transferase alpha 1 and 2', 'Gene', '2938;2939', (120, 159))	('promotes', 'PosReg', (245, 253))
112536	32127786	PYGL inhibitors are already in development for treating type 2 diabetes and they are unlikely to be toxic to most cells because patients affected by Hers disease (an inherited glycogen storage disorder caused by deficiency of PYGL).	('PYGL', 'Gene', '5836', (226, 230))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (56, 71))	('diabetes', 'Disease', (63, 71))	('PYGL', 'Gene', '5836', (0, 4))	('diabetes', 'Disease', 'MESH:D003920', (63, 71))	('deficiency', 'Var', (212, 222))	('glycogen storage disorder', 'Disease', 'MESH:D006008', (176, 201))	('PYGL', 'Gene', (226, 230))	('storage', 'biological_process', 'GO:0051235', ('185', '192'))	('PYGL', 'Gene', (0, 4))	('patients', 'Species', '9606', (128, 136))	('glycogen storage disorder', 'Disease', (176, 201))
112582	29588458	If the tumour samples are simulated based on the tumour group signature, the expected amount of negatively enriched tumour samples in 95% of cases would be at least 2.3 up to 3.2 times lower for erlotinib, a drug which is negatively correlated to the group signature at P < 0.01, and 8.7 up to 21 times lower for tenofovir, which is only slightly negatively correlated to the group signature with P = 0.15 (Fig.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('erlotinib', 'Chemical', 'MESH:D000069347', (195, 204))	('erlotinib', 'Var', (195, 204))	('lower', 'NegReg', (185, 190))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('tumour', 'Disease', (116, 122))	('tenofovir', 'Chemical', 'MESH:D000068698', (313, 322))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (7, 13))	('tumour', 'Disease', (7, 13))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('tumour', 'Disease', (49, 55))
112599	29588458	Repeated RNA-seq analysis of the same tissue sample, and to a lesser degree a new tissue sample from the same patient, already shows remarkable consistency in connectivity scores calculated with the current method and increases as the P-value of the connectivity score decreases.	('RNA', 'cellular_component', 'GO:0005562', ('9', '12'))	('P-value', 'Var', (235, 242))	('connectivity scores', 'MPA', (159, 178))	('decreases', 'NegReg', (269, 278))	('patient', 'Species', '9606', (110, 117))
112624	29108259	Notably, we found that the deletion of MPDZ was the common CNV, which was present in 28.65% of ccRCC patients.	('RCC', 'Disease', (97, 100))	('patients', 'Species', '9606', (101, 109))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('deletion', 'Var', (27, 35))	('MPDZ', 'Gene', '8777', (39, 43))	('MPDZ', 'Gene', (39, 43))
112626	29108259	The deletion of MPDZ significantly increased ccRCC risk (P=0.0025).	('increased', 'PosReg', (35, 44))	('MPDZ', 'Gene', '8777', (16, 20))	('MPDZ', 'Gene', (16, 20))	('deletion', 'Var', (4, 12))	('RCC', 'Disease', (47, 50))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))
112627	29108259	Low MPDZ expression associated with its deletion was significantly associated with adverse outcomes in ccRCC patients (P=0.0342).	('patients', 'Species', '9606', (109, 117))	('deletion', 'Var', (40, 48))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('expression', 'MPA', (9, 19))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('MPDZ', 'Gene', '8777', (4, 8))	('Low', 'NegReg', (0, 3))	('MPDZ', 'Gene', (4, 8))
112635	29108259	Some genes CNVs, especially gene deletions, have been demonstrated to affect the overall clinical outlook of ccRCC and have been used for tumor diagnosis.	('affect', 'Reg', (70, 76))	('tumor', 'Disease', (138, 143))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('deletions', 'Var', (33, 42))	('CNVs', 'Var', (11, 15))
112643	29108259	Clinical association analyses indicated that MPDZ deletion is related to poor survival in nasopharyngeal carcinoma.	('deletion', 'Var', (50, 58))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (90, 114))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (90, 114))	('nasopharyngeal carcinoma', 'Disease', (90, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('MPDZ', 'Gene', '8777', (45, 49))	('poor', 'NegReg', (73, 77))	('MPDZ', 'Gene', (45, 49))
112644	29108259	However, the clinical relevance of MPDZ genetic alterations in ccRCC has not been addressed.	('MPDZ', 'Gene', '8777', (35, 39))	('MPDZ', 'Gene', (35, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('genetic alterations', 'Var', (40, 59))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
112648	29108259	In the present study, we found that the deletion of MPDZ was frequently detected in ccRCC patients and the deletion of MPDZ was negatively correlated with its transcriptional expression.	('MPDZ', 'Gene', '8777', (52, 56))	('MPDZ', 'Gene', (52, 56))	('deletion', 'Var', (40, 48))	('patients', 'Species', '9606', (90, 98))	('negatively', 'NegReg', (128, 138))	('detected', 'Reg', (72, 80))	('MPDZ', 'Gene', '8777', (119, 123))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('MPDZ', 'Gene', (119, 123))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('deletion', 'Var', (107, 115))	('RCC', 'Disease', (86, 89))	('transcriptional expression', 'MPA', (159, 185))
112649	29108259	We also found that both the deletion of MPDZ and the expression of MPDZ were significantly associated with poor outcomes in patients with ccRCC.	('MPDZ', 'Gene', '8777', (40, 44))	('MPDZ', 'Gene', '8777', (67, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('MPDZ', 'Gene', (40, 44))	('MPDZ', 'Gene', (67, 71))	('expression', 'MPA', (53, 63))	('RCC', 'Disease', (140, 143))	('deletion', 'Var', (28, 36))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('patients', 'Species', '9606', (124, 132))	('associated', 'Reg', (91, 101))
112650	29108259	The molecular link between the deletion of MPDZ and cancer-specific outcomes suggests that MPDZ is a potential tumor suppressor gene in ccRCC.	('RCC', 'Disease', (138, 141))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('MPDZ', 'Gene', '8777', (43, 47))	('tumor', 'Disease', (111, 116))	('deletion', 'Var', (31, 39))	('MPDZ', 'Gene', '8777', (91, 95))	('tumor suppressor', 'biological_process', 'GO:0051726', ('111', '127'))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('MPDZ', 'Gene', (43, 47))	('MPDZ', 'Gene', (91, 95))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('111', '127'))
112653	29108259	The CNV of MPDZ was frequently detected in ccRCC patients as follows: 28.65% of deletions and 2.88% of amplifications (Figure 1A).	('amplifications', 'MPA', (103, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('MPDZ', 'Gene', (11, 15))	('deletions', 'Var', (80, 89))	('patients', 'Species', '9606', (49, 57))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('MPDZ', 'Gene', '8777', (11, 15))	('RCC', 'Disease', (45, 48))
112655	29108259	Because gene deletion may lead to adverse outcomes in ccRCC, we further analyzed the relationship between the deletion of MPDZ and pathologic features.	('RCC', 'Disease', (56, 59))	('lead to', 'Reg', (26, 33))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('gene deletion', 'Var', (8, 21))	('MPDZ', 'Gene', '8777', (122, 126))	('MPDZ', 'Gene', (122, 126))
112656	29108259	The relationship between the deletion of MPDZ and pathologic features that correlate with adverse outcomes are listed in Table 1.	('deletion', 'Var', (29, 37))	('MPDZ', 'Gene', '8777', (41, 45))	('MPDZ', 'Gene', (41, 45))
112657	29108259	We found that the deletion of MPDZ was significantly correlated with gender (P=0.0096), Fuhrman nuclear grade (P<0.0001), AJCC stage (P<0.0001), pathological T stage (P<0.0001) and pathological M stage (P=0.0015), but not with age, pathological N stage, total lymph nodes and lymph node status.	('AJCC stage', 'Disease', (122, 132))	('correlated', 'Reg', (53, 63))	('MPDZ', 'Gene', '8777', (30, 34))	('MPDZ', 'Gene', (30, 34))	('deletion', 'Var', (18, 26))
112658	29108259	A subgroup analysis by pathological T stage revealed that the deletion of MPDZ in T1 was significantly different from T2, T3 and T4 (P<0.05), but not in any other two groups.	('MPDZ', 'Gene', (74, 78))	('deletion', 'Var', (62, 70))	('different', 'Reg', (103, 112))	('MPDZ', 'Gene', '8777', (74, 78))
112659	29108259	Due to the deletion of MPDZ was significantly correlated with Fuhrman nuclear grade and AJCC stage, the competing risk model was applied to survival analysis.	('AJCC stage', 'Disease', (88, 98))	('deletion', 'Var', (11, 19))	('MPDZ', 'Gene', '8777', (23, 27))	('correlated', 'Reg', (46, 56))	('MPDZ', 'Gene', (23, 27))
112660	29108259	The deletion of MPDZ is significantly associated with poor outcomes in ccRCC patients (P=0.0025; Figure 2A).	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('associated', 'Reg', (38, 48))	('RCC', 'Disease', (73, 76))	('MPDZ', 'Gene', '8777', (16, 20))	('patients', 'Species', '9606', (77, 85))	('MPDZ', 'Gene', (16, 20))	('deletion', 'Var', (4, 12))
112661	29108259	A subgroup analysis by clinical stage and Fuhrman nuclear grade (G) revealed that the deletion of MPDZ was associated with overall survival in stage III-IV (P=0.0337; Figure 2C), G 1-2 (P=0.0385; Figure 2D) and G 3-4 (P=0.0052; Figure 2E), but not in stage I-II (P=0.0903; Figure 2B).	('overall survival', 'MPA', (123, 139))	('MPDZ', 'Gene', '8777', (98, 102))	('associated with', 'Reg', (107, 122))	('MPDZ', 'Gene', (98, 102))	('deletion', 'Var', (86, 94))
112663	29108259	Whether in copy number or copy number with a gene level database, the CNV of MPDZ is significantly associated with worse CSS in patients with ccRCC (Supplementary Figure 2A-2C).	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('MPDZ', 'Gene', '8777', (77, 81))	('CSS', 'Disease', (121, 124))	('MPDZ', 'Gene', (77, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('CNV', 'Var', (70, 73))	('patients', 'Species', '9606', (128, 136))	('RCC', 'Disease', (144, 147))	('associated', 'Reg', (99, 109))
112665	29108259	The MPDZ transcriptional expression in the low copy number group was significantly lower than that in high copy number group along with changes in the clinical stage and Fuhrman nuclear grade (G), respectively (Figure 3A-3B).	('low copy number', 'Var', (43, 58))	('MPDZ', 'Gene', '8777', (4, 8))	('lower', 'NegReg', (83, 88))	('MPDZ', 'Gene', (4, 8))
112666	29108259	We further investigated MPDZ expression levels between the deletion and wild-type group.	('MPDZ', 'Gene', (24, 28))	('investigated', 'Reg', (11, 23))	('deletion', 'Var', (59, 67))	('MPDZ', 'Gene', '8777', (24, 28))
112667	29108259	Consistent with previous results, the expression of MPDZ was significantly downregulated in the deletion group compared with the wild-type group (P<0.05, Figure 3C).	('MPDZ', 'Gene', '8777', (52, 56))	('downregulated', 'NegReg', (75, 88))	('MPDZ', 'Gene', (52, 56))	('expression', 'MPA', (38, 48))	('deletion', 'Var', (96, 104))
112668	29108259	Furthermore, compared with the wild-type group, the expression of MPDZ in the deletion group was significantly downregulated in stage I, stage IV and G4 (P<0.05; Figure 3D-3E), but not in stage II, stage III, G2 and G3, respectively (Figure 3D-3E).	('MPDZ', 'Gene', (66, 70))	('deletion', 'Var', (78, 86))	('expression', 'MPA', (52, 62))	('downregulated', 'NegReg', (111, 124))	('MPDZ', 'Gene', '8777', (66, 70))
112669	29108259	Because the deletion of MPDZ is an important regulation mechanism for its transcriptional expression, we further investigated MPDZ expression levels in 72 carcinoma tissues and adjacent tissues.	('carcinoma', 'Disease', 'MESH:D002277', (155, 164))	('deletion', 'Var', (12, 20))	('MPDZ', 'Gene', (24, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('regulation', 'biological_process', 'GO:0065007', ('45', '55'))	('carcinoma', 'Disease', (155, 164))	('MPDZ', 'Gene', '8777', (126, 130))	('MPDZ', 'Gene', '8777', (24, 28))	('MPDZ', 'Gene', (126, 130))
112685	29108259	To our knowledge, this is the first analysis on the association between the deletion of MPDZ and outcomes in patients with ccRCC.	('deletion', 'Var', (76, 84))	('patients', 'Species', '9606', (109, 117))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('MPDZ', 'Gene', '8777', (88, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('association', 'Interaction', (52, 63))	('MPDZ', 'Gene', (88, 92))
112687	29108259	Due to MPDZ is a protective factor in the renal osmoadaptive response, the deletion of MPDZ may accelerate the progress of ccRCC under the osmotic pressure.	('MPDZ', 'Gene', (87, 91))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('deletion', 'Var', (75, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('accelerate', 'PosReg', (96, 106))	('progress', 'MPA', (111, 119))	('MPDZ', 'Gene', '8777', (7, 11))	('MPDZ', 'Gene', '8777', (87, 91))	('MPDZ', 'Gene', (7, 11))
112689	29108259	Genetic changes by CNV play an important role in ccRCC and are probably good molecular biomarkers for diagnosis and prognosis of patients.	('patients', 'Species', '9606', (129, 137))	('Genetic changes', 'Var', (0, 15))	('CNV', 'Gene', (19, 22))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('role', 'Reg', (41, 45))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
112690	29108259	Recently, CNV silencing of many novel genes that function as putative tumor suppressor genes has been reported to contribute to human cancer.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CNV silencing', 'Var', (10, 23))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('tumor', 'Disease', (70, 75))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('human', 'Species', '9606', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('contribute', 'Reg', (114, 124))
112692	29108259	In addition, we found that there was an unusually simple mutation of MPDZ in ccRCC, which hasn't influence on patients' survival (Supplementary Figure 4A-4C).	('mutation', 'Var', (57, 65))	('MPDZ', 'Gene', (69, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('patients', 'Species', '9606', (110, 118))	('MPDZ', 'Gene', '8777', (69, 73))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
112693	29108259	Because the percentage of deletion has the highest proportion in the CNV of MPDZ, much of the concern among CNV should be focused on the deletion in that the deletion of MPDZ is negatively correlated with its transcriptional expression.	('MPDZ', 'Gene', '8777', (170, 174))	('MPDZ', 'Gene', '8777', (76, 80))	('MPDZ', 'Gene', (170, 174))	('transcriptional expression', 'MPA', (209, 235))	('MPDZ', 'Gene', (76, 80))	('deletion', 'Var', (26, 34))	('deletion', 'Var', (158, 166))	('negatively', 'NegReg', (178, 188))
112695	29108259	In addition, we also observed that the deletion of MPDZ is significantly associated with poor outcomes in patients with ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (120, 125))	('deletion', 'Var', (39, 47))	('associated', 'Reg', (73, 83))	('patients', 'Species', '9606', (106, 114))	('MPDZ', 'Gene', '8777', (51, 55))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))	('MPDZ', 'Gene', (51, 55))
112697	29108259	Accounting for the deletion is a common form in the CNV of MPDZ, and the deletion of MPDZ can decrease its expression.	('expression', 'MPA', (107, 117))	('MPDZ', 'Gene', '8777', (85, 89))	('MPDZ', 'Gene', '8777', (59, 63))	('MPDZ', 'Gene', (85, 89))	('deletion', 'Var', (73, 81))	('MPDZ', 'Gene', (59, 63))	('decrease', 'NegReg', (94, 102))
112699	29108259	We found that the deletion of MPDZ is associated with poor outcomes in patients with ccRCC.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('associated', 'Reg', (38, 48))	('RCC', 'Disease', (87, 90))	('patients', 'Species', '9606', (71, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('MPDZ', 'Gene', '8777', (30, 34))	('MPDZ', 'Gene', (30, 34))	('deletion', 'Var', (18, 26))
112701	29108259	Interestingly, we found that MPDZ methylation was also associated with poor outcomes in patients with ccRCC (Supplementary Figure 5).	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('methylation', 'Var', (34, 45))	('MPDZ', 'Gene', '8777', (29, 33))	('patients', 'Species', '9606', (88, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('associated', 'Reg', (55, 65))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('MPDZ', 'Gene', (29, 33))	('RCC', 'Disease', (104, 107))
112717	29108259	In summary, our study showed that the genetic silencing of the MPDZ gene by deletions was associated with poor outcomes in patients with ccRCC.	('MPDZ', 'Gene', (63, 67))	('silencing', 'NegReg', (46, 55))	('patients', 'Species', '9606', (123, 131))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('genetic', 'Var', (38, 45))	('deletions', 'Var', (76, 85))	('MPDZ', 'Gene', '8777', (63, 67))
112718	29108259	It provides knowledge regarding the deletion of MPDZ and expression variations and supports the potential role of prognostic significance, which has important clinical diagnostic and therapeutic implications in ccRCC.	('MPDZ', 'Gene', (48, 52))	('deletion', 'Var', (36, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (211, 216))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('RCC', 'Disease', (213, 216))	('MPDZ', 'Gene', '8777', (48, 52))
112719	29108259	MEGA 4 software, which includes neighbor-joining (NJ), Maximum Likelihood (ML) and Bayesian Markov Chain Monte Carlo (MCMC) approaches, was applied to generate an evolutionary tree to explain the phylogenetic relationships of the MPDZ transcript variant 1-X16.	('MPDZ', 'Gene', (230, 234))	('MPDZ', 'Gene', '8777', (230, 234))	('variant', 'Var', (246, 253))	('ML', 'Disease', 'MESH:C537366', (75, 77))
112724	29108259	Based on a similar scheme, there were 520 ccRCC patients with MPDZ gene CNV information and 505 ccRCC patients with the clinical pathologic parameters available were obtained for the deletion of MPDZ and survival analysis.	('MPDZ', 'Gene', (62, 66))	('patients', 'Species', '9606', (102, 110))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (42, 47))	('RCC', 'Disease', (44, 47))	('RCC', 'Disease', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('MPDZ', 'Gene', '8777', (195, 199))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('patients', 'Species', '9606', (48, 56))	('MPDZ', 'Gene', (195, 199))	('deletion', 'Var', (183, 191))	('MPDZ', 'Gene', '8777', (62, 66))
112735	29108259	MPDZ multiple PDZ domain protein ccRCC clear cell renal cell carcinoma CNV copy number variation TCGA the cancer genome atlas	('RCC', 'Disease', (35, 38))	('copy number variation', 'Var', (75, 96))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (39, 70))	('clear cell renal cell carcinoma', 'Disease', (39, 70))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (50, 70))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (39, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('cancer', 'Disease', (106, 112))	('MPDZ', 'Gene', '8777', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('MPDZ', 'Gene', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
112750	28984208	Most successful examples of DNA mutations as biomarkers were found in well-studied cancer genes, such as EGFR, KRAS, and BRAF.	('BRAF', 'Gene', (121, 125))	('KRAS', 'Gene', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('KRAS', 'Gene', '3845', (111, 115))	('EGFR', 'Gene', '1956', (105, 109))	('EGFR', 'molecular_function', 'GO:0005006', ('105', '109'))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('mutations', 'Var', (32, 41))	('EGFR', 'Gene', (105, 109))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('BRAF', 'Gene', '673', (121, 125))	('cancer', 'Disease', (83, 89))
112758	28984208	Notably, in KIRC it is the tumor-suppressor genes that are most prone to mutation, whereas in other cancer types mutation is most common in oncogenes.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('27', '43'))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('27', '43'))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('mutation', 'Var', (73, 81))
112779	28984208	In KIRC, we found only one mutation biomarker, MTHFD1 (p adjust = 0.01), which was mutated in five of 414 samples.	('MTHFD1', 'Gene', (47, 53))	('mutated', 'Var', (83, 90))	('MTHFD1', 'Gene', '4522', (47, 53))
112780	28984208	Among all the cancers we examined, UCEC had the largest number of SNV survival biomarkers with somatic mutations in 31 genes.	('cancers', 'Disease', (14, 21))	('mutations', 'Var', (103, 112))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('UCEC', 'Disease', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancers', 'Disease', 'MESH:D009369', (14, 21))
112795	28984208	Since most driver mutations previously reported in KIRC are in tumor-suppressor genes (i.e., are of limited clinical use), our finding of a large number of protein biomarkers has important implications for the development of precision medicine approaches to treat patients with KIRC.	('tumor', 'Disease', (63, 68))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('63', '79'))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('63', '79'))	('patients', 'Species', '9606', (264, 272))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mutations', 'Var', (18, 27))
112808	28984208	Our results showed that the overlapping genes were involved in the KEGG's cancer-related signaling transduction pathways (hsa05215: prostate cancer, p = 2.2 x 10-3; hsa05223: non-small cell lung cancer, p = 0.024; and hsa04012: ErbB signaling pathway, p = 0.029).	('prostate cancer', 'Disease', (132, 147))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (179, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('ErbB', 'Gene', '1956', (228, 232))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('ErbB signaling pathway', 'biological_process', 'GO:0038127', ('228', '250'))	('cell lung cancer', 'Disease', 'MESH:D008175', (185, 201))	('cancer', 'Disease', (141, 147))	('cell lung cancer', 'Disease', (185, 201))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (195, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (175, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('ErbB', 'Gene', (228, 232))	('prostate cancer', 'Disease', 'MESH:D011471', (132, 147))	('involved', 'Reg', (51, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (132, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('hsa05223', 'Var', (165, 173))	('transduction', 'biological_process', 'GO:0009293', ('99', '111'))
112827	28984208	As a result, we found seven stage-specific protein biomarkers among the 52 general biomarkers: ACC1, Cyclin_B1, FASN, GATA3, GAB2, MAPK_pT202_Y204, and Rad51.	('FASN', 'Gene', (112, 116))	('Cyclin_B1', 'Gene', '891', (101, 110))	('Rad51', 'Gene', (152, 157))	('GAB2', 'Gene', (125, 129))	('Rad51', 'Gene', '5888', (152, 157))	('FASN', 'Gene', '2194', (112, 116))	('GATA3', 'Gene', (118, 123))	('Cyclin_B1', 'Gene', (101, 110))	('ACC1', 'Gene', (95, 99))	('Rad', 'biological_process', 'GO:1990116', ('152', '155'))	('ACC1', 'Gene', '31', (95, 99))	('GATA3', 'Gene', '2625', (118, 123))	('MAPK', 'molecular_function', 'GO:0004707', ('131', '135'))	('MAPK_pT202_Y204', 'Var', (131, 146))	('Cyclin', 'molecular_function', 'GO:0016538', ('101', '107'))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('GAB2', 'Gene', '9846', (125, 129))
112860	28984208	With nominal p value threshold at 0.01, frameshift deletions in SETD2 was found to be significant (p = 4.88 x 10-3).	('SETD2', 'Gene', (64, 69))	('frameshift deletions', 'Var', (40, 60))	('SETD2', 'Gene', '29072', (64, 69))
112869	28984208	For each cancer type, we included two somatic mutation types: insertion/deletion (indel) and SNV.	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('insertion/deletion', 'Var', (62, 80))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
112885	27488093	We found that patients with high HIF-2alpha, CD31 expression showed greater relative PFS and OS benefit and patients with high CAIX expression presented greater relative OS benefit from sunitinib than from sorafenib, patients with high VEGFR1 or PDGFRB expression levels exhibited worse relative PFS benefit from sunitinib than from sorafenib.	('sorafenib', 'Chemical', 'MESH:D000077157', (206, 215))	('CAIX', 'Gene', (127, 131))	('HIF-2alpha', 'Gene', '2034', (33, 43))	('CAIX', 'Gene', '768', (127, 131))	('patients', 'Species', '9606', (108, 116))	('patients', 'Species', '9606', (14, 22))	('CD31', 'Gene', '5175', (45, 49))	('VEGFR1', 'Gene', '2321', (236, 242))	('VEGFR1', 'Gene', (236, 242))	('sunitinib', 'Chemical', 'MESH:D000077210', (313, 322))	('HIF-2alpha', 'Gene', (33, 43))	('sunitinib', 'Chemical', 'MESH:D000077210', (186, 195))	('CD31', 'Gene', (45, 49))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (217, 225))	('PFS', 'CPA', (85, 88))	('PDGFRB', 'Gene', '5159', (246, 252))	('PDGFRB', 'Gene', (246, 252))	('sorafenib', 'Chemical', 'MESH:D000077157', (333, 342))
112893	27488093	Molecular-targeted therapy improved prognosis of mRCC compared with cytokine therapy.	('improved', 'PosReg', (27, 35))	('Molecular-targeted', 'Var', (0, 18))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('prognosis', 'MPA', (36, 45))
112896	27488093	VEGF signalling pathway inhibitors have been associated with various toxicities, including an increased risk of fatal adverse events.	('toxicities', 'Disease', (69, 79))	('VEGF', 'Gene', '7422', (0, 4))	('fatal', 'Disease', (112, 117))	('toxicities', 'Disease', 'MESH:D064420', (69, 79))	('inhibitors', 'Var', (24, 34))	('VEGF', 'Gene', (0, 4))	('signalling pathway', 'biological_process', 'GO:0007165', ('5', '23'))
112955	27488093	Patients with high HIF-2alpha expression showed a greater relative PFS benefit from sunitinib than from sorafenib (hazard ratio: 0.691, 95% CI: 0.343-1.395).	('sorafenib', 'Chemical', 'MESH:D000077157', (104, 113))	('HIF-2alpha', 'Gene', (19, 29))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('sunitinib', 'Chemical', 'MESH:D000077210', (84, 93))	('PFS', 'MPA', (67, 70))	('benefit', 'PosReg', (71, 78))	('HIF-2alpha', 'Gene', '2034', (19, 29))
112957	27488093	Patients with high HIF-2alpha expression displayed a longer OS than those with low HIF-2alpha expression in the sunitinib group (37 months vs 20 months; p = 0.047).	('HIF-2alpha', 'Gene', (83, 93))	('HIF-2alpha', 'Gene', (19, 29))	('high', 'Var', (14, 18))	('HIF-2alpha', 'Gene', '2034', (83, 93))	('Patients', 'Species', '9606', (0, 8))	('sunitinib', 'Chemical', 'MESH:D000077210', (112, 121))	('HIF-2alpha', 'Gene', '2034', (19, 29))
112960	27488093	Patients with high CD31 expression showed a greater relative PFS and OS benefits from sunitinib than from sorafenib, whereas those with low CD31 expression presented a worse relative PFS and OS benefits (hazard ratio and 95% CI on Fig.	('PFS', 'MPA', (61, 64))	('CD31', 'Gene', (19, 23))	('sunitinib', 'Chemical', 'MESH:D000077210', (86, 95))	('CD31', 'Gene', '5175', (140, 144))	('CD31', 'Gene', '5175', (19, 23))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('CD31', 'Gene', (140, 144))	('sorafenib', 'Chemical', 'MESH:D000077157', (106, 115))
112962	27488093	Patients with high CAIX expression showed a greater relative OS benefit from sunitinib than from sorafenib (0.666, 0.296-1.499).	('CAIX', 'Gene', (19, 23))	('sorafenib', 'Chemical', 'MESH:D000077157', (97, 106))	('high', 'Var', (14, 18))	('CAIX', 'Gene', '768', (19, 23))	('Patients', 'Species', '9606', (0, 8))	('sunitinib', 'Chemical', 'MESH:D000077210', (77, 86))	('benefit', 'PosReg', (64, 71))
112965	27488093	In the sorafenib group, patients with high VEGFR1 expression showed a much longer PFS than those with low VEGFR1 expression (41 months vs. 10.1 months; p = 0.032), whereas this effect was not noted in the sunitinib group (13.4 vs. 16.15 months; p = 0.508) (Fig.	('VEGFR1', 'Gene', (106, 112))	('sorafenib', 'Chemical', 'MESH:D000077157', (7, 16))	('longer', 'PosReg', (75, 81))	('PFS', 'MPA', (82, 85))	('expression', 'Var', (50, 60))	('high', 'Var', (38, 42))	('VEGFR1', 'Gene', '2321', (43, 49))	('sunitinib', 'Chemical', 'MESH:D000077210', (205, 214))	('patients', 'Species', '9606', (24, 32))	('VEGFR1', 'Gene', (43, 49))	('VEGFR1', 'Gene', '2321', (106, 112))
112987	27488093	High levels of HIF-2alpha confer more favourable response to sunitinib therapy in two articles and agreed well with the present results.	('HIF-2alpha', 'Gene', (15, 25))	('High', 'Var', (0, 4))	('HIF-2alpha', 'Gene', '2034', (15, 25))	('response', 'MPA', (49, 57))	('sunitinib', 'Chemical', 'MESH:D000077210', (61, 70))
112990	27488093	High CAIX expression is associated with a better prognosis in localised RCC and mRCC, similar to the tendency reflected in our trail, while high CAIX expression predicted more benefit relative to sunitinib treatment than sorafenib treatment.	('sunitinib', 'Chemical', 'MESH:D000077210', (196, 205))	('CAIX', 'Gene', (145, 149))	('High', 'Var', (0, 4))	('sorafenib', 'Chemical', 'MESH:D000077157', (221, 230))	('CAIX', 'Gene', (5, 9))	('RCC', 'Disease', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('CAIX', 'Gene', '768', (145, 149))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('CAIX', 'Gene', '768', (5, 9))
113024	33574053	Further analyses revealed that the m6Ascore was an independent prognostic factor of ccRCC.	('ccRCC', 'Disease', (84, 89))	('m6Ascore', 'Chemical', '-', (35, 43))	('m6Ascore', 'Var', (35, 43))
113025	33574053	Finally, we verified the prognostic value of the m6Ascore in the programmed cell death protein 1 (PD-1) blockade therapy of patients with advanced ccRCC.	('programmed cell death', 'biological_process', 'GO:0012501', ('65', '86'))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('m6Ascore', 'Chemical', '-', (49, 57))	('programmed cell death protein 1', 'Gene', '5133', (65, 96))	('ccRCC', 'Disease', (147, 152))	('programmed cell death protein 1', 'Gene', (65, 96))	('patients', 'Species', '9606', (124, 132))	('m6Ascore', 'Var', (49, 57))
113026	33574053	This study demonstrated the correlation between m6A modification and the tumor immune landscape in ccRCC.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('ccRCC', 'Disease', (99, 104))	('m6A', 'Gene', '56339', (48, 51))	('tumor', 'Disease', (73, 78))	('modification', 'Var', (52, 64))	('m6A', 'Gene', (48, 51))
113033	33574053	Evidently, aberrant expression of m6A regulators is associated with tumorigenesis, malignant tumor progression and immunomodulatory abnormality.	('tumor', 'Disease', (68, 73))	('m6A', 'Gene', '56339', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('malignant tumor', 'Disease', (83, 98))	('immunomodulatory abnormality', 'Phenotype', 'HP:0002958', (115, 143))	('associated', 'Reg', (52, 62))	('aberrant expression', 'Var', (11, 30))	('tumor', 'Disease', (93, 98))	('malignant tumor', 'Disease', 'MESH:D009369', (83, 98))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('m6A', 'Gene', (34, 37))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
113039	33574053	Wang et al reported that METTL3-mediated m6A modification increased the translation of certain immune transcripts and physiologically promoted the activation of dendritic cells (DCs) and DC-based T-cell responses.	('dendritic cells', 'CPA', (161, 176))	('m6A', 'Gene', '56339', (41, 44))	('translation', 'biological_process', 'GO:0006412', ('72', '83'))	('increased', 'PosReg', (58, 67))	('METTL3', 'Gene', '56339', (25, 31))	('METTL3', 'Gene', (25, 31))	('promoted', 'PosReg', (134, 142))	('modification', 'Var', (45, 57))	('translation', 'MPA', (72, 83))	('activation', 'PosReg', (147, 157))	('m6A', 'Gene', (41, 44))	('DC-based T-cell responses', 'CPA', (187, 212))
113040	33574053	Li et al showed that deletion of METTL3 in T cells disrupted the homeostasis and differentiation of T cells.	('homeostasis', 'biological_process', 'GO:0042592', ('65', '76'))	('deletion', 'Var', (21, 29))	('METTL3', 'Gene', '56339', (33, 39))	('disrupted', 'NegReg', (51, 60))	('homeostasis', 'MPA', (65, 76))	('METTL3', 'Gene', (33, 39))	('differentiation of', 'CPA', (81, 99))
113041	33574053	Han et al found that deletion of YTHDF1 elevated the antitumor response of antigen-specific CD8+ T cells and enhanced the efficacy of anti-PD-L1 therapy.	('CD8', 'Gene', (92, 95))	('PD-L1', 'Gene', (139, 144))	('YTHDF1', 'Gene', '54915', (33, 39))	('YTHDF1', 'Gene', (33, 39))	('elevated', 'PosReg', (40, 48))	('CD8', 'Gene', '925', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('PD-L1', 'Gene', '29126', (139, 144))	('deletion', 'Var', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('enhanced', 'PosReg', (109, 117))	('tumor', 'Disease', (57, 62))
113059	33574053	Gene set variation analysis (GSVA):a non-parametric and unsupervised method commonly used for estimating pathway variations in the samples of expression datasets:was performed to explore the differences in biological processes among m6A modification patterns.	('m6A', 'Gene', (233, 236))	('m6A', 'Gene', '56339', (233, 236))	('modification', 'Var', (237, 249))	('GSVA', 'Chemical', '-', (29, 33))
113067	33574053	Spearman's correlation analysis was performed to investigate the correlation between m6Ascore and other relevant biological processes using the gene sets reported by Mariathasan et al (online supplemental table S3), including (1) antigen processing machinery (APM), (2) effector CD8 T-cell signature, (3) immune checkpoint, (4) nucleotide excision repair, (5) mismatch repair, (6) DNA replication, (7) DNA damage repair, (8) epithelial-mesenchymal transition markers, (9) Wnt targets, (10) pan-fibroblast transforming growth factor-beta response signature, and (11) angiogenesis signature.	('transforming growth factor-beta', 'molecular_function', 'GO:0005160', ('505', '536'))	('angiogenesis signature', 'CPA', (566, 588))	('m6Ascore', 'Chemical', '-', (85, 93))	('DNA', 'cellular_component', 'GO:0005574', ('381', '384'))	('mismatch', 'Var', (360, 368))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('328', '354'))	('mismatch repair', 'biological_process', 'GO:0006298', ('360', '375'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('425', '458'))	('CD8', 'Gene', (279, 282))	('antigen processing', 'biological_process', 'GO:0019882', ('230', '248'))	('CD8', 'Gene', '925', (279, 282))	('angiogenesis', 'biological_process', 'GO:0001525', ('566', '578'))	('DNA replication', 'biological_process', 'GO:0006260', ('381', '396'))	('DNA', 'cellular_component', 'GO:0005574', ('402', '405'))
113074	33574053	Somatic mutations and CNVs were integrated to explore the prevalence of m6A regulator variations in ccRCC.	('m6A', 'Gene', (72, 75))	('ccRCC', 'Disease', (100, 105))	('m6A', 'Gene', '56339', (72, 75))	('variations', 'Var', (86, 96))
113107	33574053	m6Acluster-C1 and C2 exhibited frequent amplification and deletion of most IM genes.	('amplification', 'MPA', (40, 53))	('m6A', 'Gene', '56339', (0, 3))	('IM genes', 'Gene', (75, 83))	('deletion', 'Var', (58, 66))	('m6A', 'Gene', (0, 3))
113121	33574053	It was shown that m6Ascore was negatively correlated with APM (r = -0.22, p<0.001), but positively correlated with mismatch repair-relevant signatures, including mismatch repair, DNA damage repair and DNA replication.	('mismatch repair', 'MPA', (162, 177))	('DNA replication', 'biological_process', 'GO:0006260', ('201', '216'))	('m6Ascore', 'Var', (18, 26))	('negatively', 'NegReg', (31, 41))	('mismatch repair', 'biological_process', 'GO:0006298', ('115', '130'))	('DNA damage repair', 'MPA', (179, 196))	('DNA', 'cellular_component', 'GO:0005574', ('201', '204'))	('m6Ascore', 'Chemical', '-', (18, 26))	('mismatch repair-relevant signatures', 'MPA', (115, 150))	('APM', 'MPA', (58, 61))	('correlated', 'Reg', (99, 109))	('DNA', 'MPA', (201, 204))	('mismatch repair', 'biological_process', 'GO:0006298', ('162', '177'))	('DNA', 'cellular_component', 'GO:0005574', ('179', '182'))
113125	33574053	Patients with high m6Ascores demonstrated significant survival impairment (figure 5E).	('m6Ascores', 'Var', (19, 28))	('survival impairment', 'CPA', (54, 73))	('Patients', 'Species', '9606', (0, 8))	('m6Ascore', 'Chemical', '-', (19, 27))
113126	33574053	We further performed multivariate Cox regression analysis (with factors related to patient sex, age, grade and TNM status included) to investigate the independent prognostic value of m6Ascore, revealing that m6Ascore serves as an independent prognostic biomarker for ccRCC patients (figure 5F).	('ccRCC', 'Disease', (267, 272))	('patient', 'Species', '9606', (273, 280))	('patients', 'Species', '9606', (273, 281))	('m6Ascore', 'Var', (208, 216))	('TNM', 'Gene', '10178', (111, 114))	('m6Ascore', 'Chemical', '-', (183, 191))	('patient', 'Species', '9606', (83, 90))	('m6Ascore', 'Chemical', '-', (208, 216))	('TNM', 'Gene', (111, 114))
113127	33574053	The prognostic value of m6Ascore in ccRCC was validated in another cohort (91 cases) from the ICGC database (figure 5G).	('m6Ascore', 'Chemical', '-', (24, 32))	('m6Ascore', 'Var', (24, 32))	('ccRCC', 'Disease', (36, 41))
113129	33574053	We also found that high m6Ascore was relatively depleted for PBRM1 mutations (26% vs 44%) (p=0.009).	('PBRM1', 'Gene', (61, 66))	('PBRM1', 'Gene', '55193', (61, 66))	('m6Ascore', 'Chemical', '-', (24, 32))	('mutations', 'Var', (67, 76))	('depleted', 'NegReg', (48, 56))
113132	33574053	In the anti-PD-1 cohort, the low m6Ascore group presented a markedly prolonged survival (figure 6A, B).	('m6Ascore', 'Chemical', '-', (33, 41))	('prolonged', 'PosReg', (69, 78))	('survival', 'CPA', (79, 87))	('low m6Ascore', 'Var', (29, 41))
113133	33574053	In addition, we found that high m6Ascore was relatively depleted for PBRM1 mutations (29% vs 62%) (p<0.001) (figure 6C, D).	('m6Ascore', 'MPA', (32, 40))	('PBRM1', 'Gene', (69, 74))	('mutations', 'Var', (75, 84))	('m6Ascore', 'Chemical', '-', (32, 40))	('PBRM1', 'Gene', '55193', (69, 74))	('depleted', 'NegReg', (56, 64))
113134	33574053	Increasing evidence reveals that m6A modification plays critical roles in tumorigenesis, therapeutic resistance and immune response via collaboration among m6A regulators.	('modification', 'Var', (37, 49))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('m6A', 'Gene', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('m6A', 'Gene', (33, 36))	('immune response', 'CPA', (116, 131))	('m6A', 'Gene', '56339', (156, 159))	('tumor', 'Disease', (74, 79))	('m6A', 'Gene', '56339', (33, 36))	('therapeutic resistance', 'CPA', (89, 111))	('immune response', 'biological_process', 'GO:0006955', ('116', '131'))
113146	33574053	Based on the results described above, we speculated that IGF2BP3-mediated m6A modification may promote the infiltration of Th2 cells, thus decreasing the intratumoral antitumor immune response.	('decreasing', 'NegReg', (139, 149))	('IGF2BP3', 'Gene', '10643', (57, 64))	('IGF2BP3', 'Gene', (57, 64))	('promote', 'PosReg', (95, 102))	('modification', 'Var', (78, 90))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('m6A', 'Gene', (74, 77))	('tumor', 'Disease', (159, 164))	('m6A', 'Gene', '56339', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('infiltration', 'CPA', (107, 119))	('Th2', 'Chemical', '-', (123, 126))	('immune response', 'biological_process', 'GO:0006955', ('177', '192'))
113148	33574053	Integrated analyses revealed that m6Ascore is a robust and independent prognostic factor for ccRCC.	('m6Ascore', 'Chemical', '-', (34, 42))	('m6Ascore', 'Var', (34, 42))	('ccRCC', 'Disease', (93, 98))
113149	33574053	Our study also found that m6Ascore was negatively correlated with APM and high m6Ascore was relatively depleted for PBRM1 mutations.	('PBRM1', 'Gene', (116, 121))	('m6Ascore', 'Chemical', '-', (26, 34))	('APM', 'Disease', (66, 69))	('m6Ascore', 'Chemical', '-', (79, 87))	('PBRM1', 'Gene', '55193', (116, 121))	('negatively', 'NegReg', (39, 49))	('mutations', 'Var', (122, 131))
113151	33574053	PBRM1 mutations were found to be related to improved response, progression-free survival (PFS) and OS with anti-PD-1 therapy in patients with advanced ccRCC.	('PBRM1', 'Gene', (0, 5))	('response', 'MPA', (53, 61))	('PBRM1', 'Gene', '55193', (0, 5))	('ccRCC', 'Disease', (151, 156))	('improved', 'PosReg', (44, 52))	('progression-free', 'Disease', (63, 79))	('patients', 'Species', '9606', (128, 136))	('mutations', 'Var', (6, 15))
113158	33574053	In this study, we verified the prognostic value of the m6Ascore in the anti-PD-1 therapy of patients with advanced ccRCC.	('patients', 'Species', '9606', (92, 100))	('m6Ascore', 'Chemical', '-', (55, 63))	('ccRCC', 'Disease', (115, 120))	('m6Ascore', 'Var', (55, 63))
113168	33194712	Most patients had intermediate risk (85%, IMDC) with clear cell (56%), papillary (26%), unclassified (11%), chromophobe (4%), and translocation (4%) RCC.	('RCC', 'Disease', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('patients', 'Species', '9606', (5, 13))	('translocation', 'Var', (130, 143))	('clear', 'Disease', (53, 58))	('papillary', 'Disease', (71, 80))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
113204	33194712	Germline testing results were available in only four patients and detected a pathogenic alteration in SMARCB1 in one patient with unclassified RCC and negative family history of cancer, and a variant of unknown significance in one patient with clear cell RCC (ccRCC).	('RCC', 'Disease', 'MESH:C538614', (262, 265))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('pathogenic', 'Reg', (77, 87))	('patient', 'Species', '9606', (231, 238))	('patients', 'Species', '9606', (53, 61))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('RCC', 'Disease', (255, 258))	('RCC', 'Phenotype', 'HP:0005584', (255, 258))	('patient', 'Species', '9606', (53, 60))	('alteration', 'Var', (88, 98))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('patient', 'Species', '9606', (117, 124))	('RCC', 'Disease', 'MESH:C538614', (255, 258))	('RCC', 'Disease', (143, 146))	('RCC', 'Disease', (262, 265))	('RCC', 'Phenotype', 'HP:0005584', (262, 265))	('cancer', 'Disease', (178, 184))	('SMARCB1', 'Gene', '6598', (102, 109))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('SMARCB1', 'Gene', (102, 109))
113205	33194712	The study cohort consisted of patients with clear cell (n = 15), papillary (n = 7 including 3 patients with clear cell component), unclassified (n = 3), chromophobe (n = 1), and translocation (n = 1).	('clear cell', 'Disease', (44, 54))	('patients', 'Species', '9606', (94, 102))	('translocation', 'Var', (178, 191))	('papillary', 'Disease', (65, 74))	('patients', 'Species', '9606', (30, 38))
113275	30787564	Chromosomal aberrations in renal cell carcinoma: An overview with implications for clinical practice Chromosomal instability and aberrations are known in many cancers including renal cell carcinoma.	('cancers', 'Disease', (159, 166))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (27, 47))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (27, 47))	('renal cell carcinoma', 'Disease', (177, 197))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (177, 197))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (101, 124))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (177, 197))	('Chromosomal aberrations', 'Phenotype', 'HP:0040012', (0, 23))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('aberrations', 'Var', (129, 140))	('renal cell carcinoma', 'Disease', (27, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
113287	30787564	With improved detection of these changes, possibility of better understanding of carcinogenesis and treatment strategies is emerging in many cancers.	('carcinogenesis', 'Disease', 'MESH:D063646', (81, 95))	('changes', 'Var', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('carcinogenesis', 'Disease', (81, 95))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Disease', (141, 148))
113297	30787564	In this review, we discuss chromosomal aberrations, that is, structural and copy number alterations, in renal cell carcinoma with focus on abilities of these changes to be used for effective diagnostic and prognostic investigations.	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (104, 124))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (27, 50))	('copy number', 'Var', (76, 87))	('renal cell carcinoma', 'Disease', (104, 124))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (104, 124))
113301	30787564	In addition to above syndromes, chromosome 3p translocation (Cohen et al.,), tuberous sclerosis, and succinate dehydrogenase gene mutation (Ricketts et al., 2008) predispose to rare forms of early-onset hereditary renal cancer.	('renal cancer', 'Phenotype', 'HP:0009726', (214, 226))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (77, 95))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('predispose', 'Reg', (163, 173))	('chromosome 3p translocation', 'Var', (32, 59))	('tuberous sclerosis', 'Disease', (77, 95))	('hereditary renal cancer', 'Disease', 'MESH:D007680', (203, 226))	('hereditary renal cancer', 'Disease', (203, 226))	('chromosome', 'cellular_component', 'GO:0005694', ('32', '42'))
113302	30787564	Five genes that have well-known associations with renal cancer were shown to be mutated in a substantial proportion of the clear-cell renal cell carcinoma (ccRCC) samples (Gwangwu et al.	('renal cancer', 'Disease', 'MESH:D007680', (50, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutated', 'Var', (80, 87))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('renal cell carcinoma', 'Disease', (134, 154))	('renal cancer', 'Disease', (50, 62))	('RCC', 'Disease', (158, 161))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (134, 154))	('renal cancer', 'Phenotype', 'HP:0009726', (50, 62))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (134, 154))
113306	30787564	Large-scale cancer genomic projects have been undertaken and have revealed several novel prevalent mutations in ccRCC, including PBRM1 (29%-41% of tumor samples), SETD2 (8%-12%), BAP1 (6%-10%), KDM5C (4%-7%), and MTOR (5%-6%) (Xu et al., 2016).	('PBRM1', 'Gene', (129, 134))	('SETD2', 'Gene', (163, 168))	('KDM5C', 'Gene', '8242', (194, 199))	('SETD2', 'Gene', '29072', (163, 168))	('tumor', 'Disease', (147, 152))	('RCC', 'Disease', (114, 117))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('BAP1', 'Gene', '8314', (179, 183))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('KDM5C', 'Gene', (194, 199))	('MTOR', 'Gene', (213, 217))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('MTOR', 'Gene', '2475', (213, 217))	('PBRM1', 'Gene', '55193', (129, 134))	('BAP1', 'Gene', (179, 183))	('cancer', 'Disease', (12, 18))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
113308	30787564	Papillary RCC is characterized by trisomy of chromosome 7 and 17 and loss of Y chromosome (Kovacs et al., 1997).	('loss', 'NegReg', (69, 73))	('trisomy', 'Var', (34, 41))	('Papillary RCC', 'Disease', 'MESH:C538614', (0, 13))	('chromosome', 'cellular_component', 'GO:0005694', ('45', '55'))	('Papillary RCC', 'Disease', (0, 13))	('Y chromosome', 'cellular_component', 'GO:0000806', ('77', '89'))
113310	30787564	Collecting duct carcinoma shows a wide variety of aberrations involving chromosomes 1, X, Y with either translocations or deletions.	('translocations', 'Var', (104, 118))	('deletions', 'Var', (122, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('duct carcinoma', 'Disease', (11, 25))	('duct carcinoma', 'Disease', 'MESH:D021441', (11, 25))
113313	30787564	The only cytogenetic marker added to a prognostic nomogram for all stages of ccRCC following nephrectomy, including TNM stage and Fuhrman grade, was the loss of chromosome 9p based on karyotyping, reaching predictive accuracy of 89% (Klatte et al., 2009a).	('TNM', 'Gene', '10178', (116, 119))	('TNM', 'Gene', (116, 119))	('loss', 'Var', (153, 157))	('chromosome', 'cellular_component', 'GO:0005694', ('161', '171'))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
113317	30787564	The main advantage of array CGH (aCGH) is its ability to identify aneuploidies, deletions, gains including duplications or amplifications of any locus represented on an array simultaneously Microsatellites [Figure 4] are short tandem repeats of DNA sequences that are made of units of 1-4 nucleotides.	('gains', 'Var', (91, 96))	('Microsatellites', 'Var', (190, 205))	('deletions', 'Var', (80, 89))	('duplications', 'Var', (107, 119))	('aneuploidies', 'Disease', (66, 78))	('aneuploidies', 'Disease', 'MESH:D000782', (66, 78))	('DNA', 'cellular_component', 'GO:0005574', ('245', '248'))
113318	30787564	Using paired control (blood or normal renal tissue) and tumor DNA, microsatellite analysis is a sensitive technique for detecting LOH in tumors.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Disease', (137, 142))	('LOH', 'Var', (130, 133))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
113322	30787564	Loss of short arm of chromosome 3 is the most frequent chromosomal CNV in ccRCC, reported in more than 70% of sporadic cases.	('short arm', 'Phenotype', 'HP:0009824', (8, 17))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('chromosome', 'cellular_component', 'GO:0005694', ('21', '31'))	('Loss', 'Var', (0, 4))
113325	30787564	In addition, deletion of Y chromosome is a common nonrandom CNV observed in ccRCC (Kovacs and Frisch, 1989).	('Y chromosome', 'Gene', (25, 37))	('deletion', 'Var', (13, 21))	('RCC', 'Disease', (78, 81))	('Y chromosome', 'cellular_component', 'GO:0000806', ('25', '37'))	('RCC', 'Disease', 'MESH:C538614', (78, 81))
113326	30787564	The loss of Y chromosome was associated with distant metastasis in ccRCC and some other adverse histological features.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('Y chromosome', 'cellular_component', 'GO:0000806', ('12', '24'))	('RCC', 'Disease', (69, 72))	('Y chromosome', 'Protein', (12, 24))	('associated', 'Reg', (29, 39))	('distant metastasis', 'CPA', (45, 63))	('loss', 'Var', (4, 8))
113335	30787564	Furthermore, for clear-cell RCC, it was possible to define alterations which are associated with metastatic disease: Loss of 9, 10, 14 (Junker et al.	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('metastatic disease', 'Disease', (97, 115))	('Loss of', 'Var', (117, 124))	('RCC', 'Disease', (28, 31))
113341	30787564	Targeted therapy has improved treatment outcome as the overall and cancer-specific survival of metastatic RCC patients has improved in the targeted therapy era compared to the immunotherapy era (Yap et al.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('Yap', 'Gene', (195, 198))	('targeted therapy', 'Var', (139, 155))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Yap', 'Gene', '10413', (195, 198))	('RCC', 'Disease', (106, 109))	('improved', 'PosReg', (123, 131))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('patients', 'Species', '9606', (110, 118))
113342	30787564	NGS or exome sequencing studies have discovered several novel genes involved in chromatin modification which are mutated in ccRCC (Duns et al.	('chromatin modification', 'biological_process', 'GO:0016569', ('80', '102'))	('chromatin', 'cellular_component', 'GO:0000785', ('80', '89'))	('mutated', 'Var', (113, 120))	('RCC', 'Disease', (126, 129))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('chromatin modification', 'biological_process', 'GO:0006325', ('80', '102'))
113344	30787564	PBRM1 mutations are found in up to 41% of ccRCC, making it the second most mutated gene after VHL (Veral et al.	('PBRM1', 'Gene', (0, 5))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('PBRM1', 'Gene', '55193', (0, 5))	('RCC', 'Disease', (44, 47))	('VHL', 'Disease', (94, 97))	('VHL', 'Disease', 'MESH:D006623', (94, 97))	('mutations', 'Var', (6, 15))
113345	30787564	The roles of these chromatin modification genes and their proteins products are not fully understood yet, but various studies have shown that the mutational status of these genes may possess prognostic influence on ccRCC.	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('RCC', 'Disease', (217, 220))	('mutational', 'Var', (146, 156))	('chromatin modification', 'biological_process', 'GO:0006325', ('19', '41'))	('chromatin modification', 'biological_process', 'GO:0016569', ('19', '41'))	('chromatin', 'cellular_component', 'GO:0000785', ('19', '28'))
113346	30787564	Other genetic aberrations of interest, such as changes at chromosome regions 5q, 8p, 9p, and 14, may affect the prognosis of ccRCC.	('affect', 'Reg', (101, 107))	('changes', 'Var', (47, 54))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('chromosome', 'cellular_component', 'GO:0005694', ('58', '68'))
113347	30787564	LOH in 8p, 9p, and 14q has been associated with higher grade, stage, unfavorable prognosis, and tumor recurrence (Presti et al.	('higher grade', 'CPA', (48, 60))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('LOH in', 'Var', (0, 6))	('stage', 'CPA', (62, 67))	('tumor', 'Disease', (96, 101))	('associated', 'Reg', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
113352	30787564	Hereditary pRCC associated with Type 1 tumors is caused by the mutation of the MET proto-oncogene at 7q31.	('caused by', 'Reg', (49, 58))	('pRCC', 'Gene', '5546', (11, 15))	('mutation', 'Var', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Type 1 tumors', 'Disease', 'MESH:D009369', (32, 45))	('pRCC', 'Gene', (11, 15))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('Type 1 tumors', 'Disease', (32, 45))
113364	30787564	These genetic changes may play an important role in tumorigenesis and affect the progression or prognosis of the tumor.	('affect', 'Reg', (70, 76))	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('progression', 'CPA', (81, 92))	('tumor', 'Disease', (52, 57))	('genetic changes', 'Var', (6, 21))	('prognosis of', 'CPA', (96, 108))	('play', 'Reg', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
113366	29113209	Prognostic value of copper transporter 1 expression in patients with clear cell renal cell carcinoma Clear cell renal cell carcinoma (ccRCC) features a Von Hippel-Lindau mutation, associated with a hypoxia-inducible factor (HIF) imbalance.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (69, 100))	('mutation', 'Var', (170, 178))	('copper transporter 1', 'Gene', (20, 40))	('imbalance', 'Phenotype', 'HP:0002172', (229, 238))	('patients', 'Species', '9606', (55, 63))	('Von Hippel-Lindau', 'Gene', '7428', (152, 169))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (69, 100))	('Von Hippel-Lindau', 'Gene', (152, 169))	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('hypoxia', 'Disease', (198, 205))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (112, 132))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (101, 132))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('copper transporter 1', 'Gene', '1317', (20, 40))	('RCC', 'Disease', (136, 139))	('Clear cell renal cell carcinoma', 'Disease', (101, 132))	('clear cell renal cell carcinoma', 'Disease', (69, 100))	('hypoxia', 'Disease', 'MESH:D000860', (198, 205))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (80, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('RCC', 'Disease', 'MESH:C538614', (136, 139))
113371	29113209	The present data indicated that high tumor CTR1 expression was independently associated with poor overall survival (OS) [hazard ratio, 2.291; 95% confidence interval (CI), 1.389-3.777; P<0.001] and disease-free survival (DFS) (hazard ratio, 2.210; 95% CI, 1.299-3.759; P=0.003) rates in patients with ccRCC.	('RCC', 'Disease', 'MESH:C538614', (303, 306))	('high', 'Var', (32, 36))	('RCC', 'Disease', (303, 306))	('RCC', 'Phenotype', 'HP:0005584', (303, 306))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('ccRCC', 'Phenotype', 'HP:0006770', (301, 306))	('expression', 'MPA', (48, 58))	('CTR1', 'Gene', (43, 47))	('patients', 'Species', '9606', (287, 295))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('OS', 'Chemical', '-', (116, 118))	('overall survival', 'CPA', (98, 114))	('poor', 'NegReg', (93, 97))	('CTR1', 'Gene', '1317', (43, 47))	('disease-free survival', 'CPA', (198, 219))
113381	29113209	Copper, as an essential trace mineral, serves an important role in the regulation of human physiological functions; its aberrant upregulation may promote tumor angiogenesis and progression in various types of cancer.	('aberrant', 'Var', (120, 128))	('upregulation', 'PosReg', (129, 141))	('Copper', 'Chemical', 'MESH:D003300', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('angiogenesis', 'biological_process', 'GO:0001525', ('160', '172'))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('regulation', 'biological_process', 'GO:0065007', ('71', '81'))	('cancer', 'Disease', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('promote', 'PosReg', (146, 153))	('human', 'Species', '9606', (85, 90))	('tumor', 'Disease', (154, 159))
113386	29113209	In RCC, the most common histological type is clear cell renal cell carcinoma (ccRCC; 70-85%), which exhibits a Von Hippel-Lindau (VHL) mutation, leading to an activation of HIF signaling.	('signaling', 'biological_process', 'GO:0023052', ('177', '186'))	('HIF signaling', 'MPA', (173, 186))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (45, 76))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (51, 76))	('cell renal cell carcinoma', 'Disease', (51, 76))	('RCC', 'Disease', (3, 6))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('VHL', 'Disease', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (3, 6))	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('activation', 'PosReg', (159, 169))	('Von Hippel-Lindau', 'Gene', '7428', (111, 128))	('Von Hippel-Lindau', 'Gene', (111, 128))	('mutation', 'Var', (135, 143))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (56, 76))	('VHL', 'Disease', 'MESH:D006623', (130, 133))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))
113416	29113209	Kaplan-Meier curves revealed that patients with ccRCC with high CTR1 expression had a significantly poorer OS (P<0.001; Fig.	('OS', 'Chemical', '-', (107, 109))	('CTR1', 'Gene', (64, 68))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('RCC', 'Disease', (50, 53))	('poorer', 'NegReg', (100, 106))	('high', 'Var', (59, 63))	('patients', 'Species', '9606', (34, 42))	('CTR1', 'Gene', '1317', (64, 68))
113420	29113209	The results revealed that high CTR1 expression was associated with a poor prognosis in the low (OS, P<0.001; DFS, P=0.016; Fig.	('high', 'Var', (26, 30))	('CTR1', 'Gene', '1317', (31, 35))	('expression', 'MPA', (36, 46))	('CTR1', 'Gene', (31, 35))	('OS', 'Chemical', '-', (96, 98))
113422	29113209	A univariate analysis highlighted the prognostic value of high CTR1 expression in the prediction of a poor OS (P<0.001) and DFS (P<0.001) (Table II).	('poor OS', 'Disease', (102, 109))	('OS', 'Chemical', '-', (107, 109))	('expression', 'MPA', (68, 78))	('CTR1', 'Gene', '1317', (63, 67))	('CTR1', 'Gene', (63, 67))	('high', 'Var', (58, 62))	('DFS', 'Disease', (124, 127))
113425	29113209	The analysis revealed that high expression of CTR1 in ccRCC was associated with a higher risk of mortality (hazard ratio, 2.291; 95% CI, 1.389-3.777; P<0.001) and a shorter DFS time (hazard ratio, 2.210; 95% CI, 1.299-3.759; P=0.003; Table III).	('CTR1', 'Gene', (46, 50))	('shorter', 'NegReg', (165, 172))	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('DFS time', 'MPA', (173, 181))	('high expression', 'Var', (27, 42))	('CTR1', 'Gene', '1317', (46, 50))
113426	29113209	These results suggested that high tumor CTR1 expression was an independent poor prognostic marker in ccRCC adjusted with T stage, distant metastasis, Fuhrman grade, necrosis and ECOG PS.	('high', 'Var', (29, 33))	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('necrosis', 'Disease', (165, 173))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('tumor', 'Disease', (34, 39))	('CTR1', 'Gene', (40, 44))	('necrosis', 'Disease', 'MESH:D009336', (165, 173))	('necrosis', 'biological_process', 'GO:0070265', ('165', '173'))	('necrosis', 'biological_process', 'GO:0008219', ('165', '173'))	('necrosis', 'biological_process', 'GO:0019835', ('165', '173'))	('expression', 'MPA', (45, 55))	('necrosis', 'biological_process', 'GO:0008220', ('165', '173'))	('CTR1', 'Gene', '1317', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('necrosis', 'biological_process', 'GO:0001906', ('165', '173'))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
113438	29113209	In addition, high tumor CTR1 expression was positively associated with various clinical characteristics and a higher SSIGN score, and could be used to stratify the outcome of patients in different SSIGN risk groups.	('SSIGN score', 'Disease', (117, 128))	('CTR1', 'Gene', '1317', (24, 28))	('tumor', 'Disease', (18, 23))	('high', 'Var', (13, 17))	('associated', 'Reg', (55, 65))	('patients', 'Species', '9606', (175, 183))	('CTR1', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('expression', 'MPA', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
113447	29113209	In addition, knockdown of CTR1 in human breast cancer cells was identified to inhibit EMT formation through HIF1-alpha inhibition.	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('HIF1-alpha', 'Gene', (108, 118))	('human', 'Species', '9606', (34, 39))	('breast cancer', 'Disease', (40, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('CTR1', 'Gene', (26, 30))	('EMT formation', 'CPA', (86, 99))	('formation', 'biological_process', 'GO:0009058', ('90', '99'))	('inhibition', 'NegReg', (119, 129))	('inhibit', 'NegReg', (78, 85))	('HIF1-alpha', 'Gene', '3091', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('EMT', 'biological_process', 'GO:0001837', ('86', '89'))	('knockdown', 'Var', (13, 22))	('CTR1', 'Gene', '1317', (26, 30))
113449	29113209	Since dysregulation of the VHL/HIF pathway is a dominant driving force for ccRCC initiation, and evidence suggests that copper and ceruloplasmin levels are upregulated in ccRCC, it is tempting to speculate that in the present study, the poor prognostic effect of high CTR1 expression may be associated with the copper level and the HIF pathway in ccRCC cells.	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('high', 'Var', (263, 267))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('VHL', 'Disease', (27, 30))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('CTR1', 'Gene', '1317', (268, 272))	('upregulated', 'PosReg', (156, 167))	('VHL', 'Disease', 'MESH:D006623', (27, 30))	('ceruloplasmin', 'Gene', (131, 144))	('ccRCC', 'Phenotype', 'HP:0006770', (347, 352))	('RCC', 'Disease', (349, 352))	('RCC', 'Phenotype', 'HP:0005584', (349, 352))	('ceruloplasmin', 'Gene', '1356', (131, 144))	('RCC', 'Disease', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('ccRCC', 'Phenotype', 'HP:0006770', (171, 176))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('RCC', 'Disease', 'MESH:C538614', (349, 352))	('copper', 'Chemical', 'MESH:D003300', (311, 317))	('copper', 'Chemical', 'MESH:D003300', (120, 126))	('CTR1', 'Gene', (268, 272))
113454	29113209	The present study revealed that high CTR1 expression indicated a poor prognosis for patients with ccRCC, which is in contrary to CTR2.	('high', 'Var', (32, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('CTR2', 'Gene', (129, 133))	('patients', 'Species', '9606', (84, 92))	('expression', 'MPA', (42, 52))	('CTR1', 'Gene', (37, 41))	('CTR2', 'Gene', '1318', (129, 133))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('CTR1', 'Gene', '1317', (37, 41))
113467	29113209	In conclusion, the present study indicated that the high expression of tumor CTR1 is associated with poor survival in patients with ccRCC.	('poor', 'NegReg', (101, 105))	('CTR1', 'Gene', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('high', 'Var', (52, 56))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('RCC', 'Disease', (134, 137))	('RCC', 'Phenotype', 'HP:0005584', (134, 137))	('tumor', 'Disease', (71, 76))	('patients', 'Species', '9606', (118, 126))	('CTR1', 'Gene', '1317', (77, 81))
113552	29182544	Mutations in the genes encoding certain TRIMs have been associated with human diseases, classified as immunological diseases, or developmental disorders.	('immunological diseases', 'Disease', (102, 124))	('TRIMs', 'Gene', (40, 45))	('human diseases', 'Disease', (72, 86))	('human', 'Species', '9606', (72, 77))	('immunological diseases', 'Disease', 'MESH:D007154', (102, 124))	('associated', 'Reg', (56, 66))	('Mutations', 'Var', (0, 9))	('developmental disorders', 'Disease', (129, 152))	('developmental disorders', 'Disease', 'MESH:D002658', (129, 152))
113568	29182544	By employing TRIM8 deletion mutants, it has been demonstrated that the TRIM8-RING domain alone (42 aa) is necessary and sufficient for inducing p53 stabilization, p53-dependent inhibition of cell proliferation, p53 transcriptional activation, and MDM2 degradation.	('degradation', 'biological_process', 'GO:0009056', ('252', '263'))	('degradation', 'MPA', (252, 263))	('transcriptional', 'MPA', (215, 230))	('p53', 'Gene', '7157', (144, 147))	('TRIM8', 'Gene', (71, 76))	('MDM2', 'Gene', (247, 251))	('TRIM8', 'Gene', '81603', (71, 76))	('cell proliferation', 'CPA', (191, 209))	('stabilization', 'MPA', (148, 161))	('p53', 'Gene', (144, 147))	('MDM2', 'Gene', '4193', (247, 251))	('p53', 'Gene', '7157', (163, 166))	('activation', 'PosReg', (231, 241))	('inducing', 'PosReg', (135, 143))	('TRIM8', 'Gene', (13, 18))	('p53', 'Gene', '7157', (211, 214))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('177', '209'))	('TRIM8', 'Gene', '81603', (13, 18))	('inhibition', 'NegReg', (177, 187))	('p53', 'Gene', (163, 166))	('p53', 'Gene', (211, 214))	('deletion', 'Var', (19, 27))
113570	29182544	In particular, TRIM19 (also known as promyelocytic leukaemia protein-PML) is able to support p53-Thr18 phosphorylation in response to DNA damage by recruiting p53 into PML nuclear bodies (NBs), and protecting it from MDM2 degradation, while TRIM13 directly co-localizes with MDM2 in nuclear structures and mediates MDM2 polyubiquitination and degradation with the consequent increase in p53 stability and activity.	('p53', 'Gene', '7157', (159, 162))	('MDM2', 'Gene', (315, 319))	('MDM2', 'Gene', '4193', (275, 279))	('phosphorylation', 'biological_process', 'GO:0016310', ('103', '118'))	('activity', 'MPA', (405, 413))	('stability', 'MPA', (391, 400))	('p53', 'Gene', (159, 162))	('MDM2 polyubiquitination', 'Disease', 'None', (315, 338))	('promyelocytic leukaemia', 'Disease', 'MESH:D015473', (37, 60))	('MDM2', 'Gene', '4193', (315, 319))	('degradation', 'biological_process', 'GO:0009056', ('343', '354'))	('degradation', 'biological_process', 'GO:0009056', ('222', '233'))	('MDM2', 'Gene', (217, 221))	('p53', 'Gene', '7157', (387, 390))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))	('TRIM13', 'Gene', '10206', (241, 247))	('p53', 'Gene', '7157', (93, 96))	('MDM2', 'Gene', '4193', (217, 221))	('TRIM19', 'Var', (15, 21))	('degradation', 'MPA', (343, 354))	('p53', 'Gene', (387, 390))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))	('increase', 'PosReg', (375, 383))	('p53', 'Gene', (93, 96))	('promyelocytic leukaemia', 'Phenotype', 'HP:0004836', (37, 60))	('MDM2', 'Gene', (275, 279))	('Thr18', 'Chemical', '-', (97, 102))	('MDM2 polyubiquitination', 'Disease', (315, 338))	('promyelocytic leukaemia', 'Disease', (37, 60))	('TRIM13', 'Gene', (241, 247))
113574	29182544	RCC is a family of cancers including five major subtypes (clear cell, papillary type I and type II, chromophobe, collecting duct, and unclassified RCC) that originate from the renal tubular epithelium, but unlike other epithelial cancers originating from other districts such as the colon, breast, lung, stomach and bladder, p53 mutations in RCC are particularly rare, especially in the ccRCC subtype.	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancers', 'Disease', (19, 26))	('p53', 'Gene', '7157', (325, 328))	('RCC', 'Disease', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('p53', 'Gene', (325, 328))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('cancers', 'Disease', (230, 237))	('papillary type', 'Phenotype', 'HP:0007482', (70, 84))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('RCC', 'Disease', (389, 392))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('RCC', 'Disease', (342, 345))	('RCC', 'Disease', (0, 3))	('RCC', 'Disease', 'MESH:C538614', (389, 392))	('cancers', 'Disease', 'MESH:D009369', (230, 237))	('RCC', 'Disease', 'MESH:C538614', (342, 345))	('mutations', 'Var', (329, 338))	('RCC', 'Disease', 'MESH:C538614', (0, 3))
113585	29182544	Interestingly, the inhibition of miR-17-5p and/or miR-106-5p leads to the recovery of TRIM8-mediated p53 tumour suppressor activity, which in turn strongly inhibits MYCN-dependent cell proliferation.	('TRIM8', 'Gene', (86, 91))	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('MYCN', 'Gene', (165, 169))	('MYCN', 'Gene', '4613', (165, 169))	('TRIM8', 'Gene', '81603', (86, 91))	('miR-17-5p', 'Gene', (33, 42))	('cell proliferation', 'biological_process', 'GO:0008283', ('180', '198'))	('tumour', 'Disease', (105, 111))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('inhibition', 'NegReg', (19, 29))	('inhibits', 'NegReg', (156, 164))	('recovery', 'PosReg', (74, 82))	('miR-17-5p', 'Gene', '406952', (33, 42))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('miR-106-5p', 'Chemical', '-', (50, 60))	('miR-106-5p', 'Var', (50, 60))
113591	29182544	Cancer cells may acquire resistance to chemotherapy, or may have a high basal level of resistance through a variety of mechanisms, which can be summarized as follows: (1) decrease of drug concentration in the cell due to the activation of transporter proteins encoded by Multiple Drug Resistance genes (MDR); (2) increased detoxification of the drug within the cell; (3) increased repair of the damaged target; (4) abrogation of apoptosis or cell cycle arrest, for example, due to the mutation or inactivation of tumour suppressor genes, i.e., p53.	('tumour', 'Phenotype', 'HP:0002664', (513, 519))	('p53', 'Gene', (544, 547))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('442', '459'))	('tumour', 'Disease', 'MESH:D009369', (513, 519))	('tumour', 'Disease', (513, 519))	('increased', 'PosReg', (313, 322))	('decrease', 'NegReg', (171, 179))	('Drug Resistance', 'Phenotype', 'HP:0020174', (280, 295))	('activation', 'PosReg', (225, 235))	('mutation', 'Var', (485, 493))	('cell cycle arrest', 'CPA', (442, 459))	('detoxification', 'biological_process', 'GO:0098754', ('323', '337'))	('decrease of drug concentration', 'Phenotype', 'HP:0020171', (171, 201))	('detoxification', 'MPA', (323, 337))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('drug concentration in', 'MPA', (183, 204))	('Drug Resistance', 'biological_process', 'GO:0009315', ('280', '295'))	('Drug Resistance', 'biological_process', 'GO:0042493', ('280', '295'))	('apoptosis', 'biological_process', 'GO:0097194', ('429', '438'))	('apoptosis', 'biological_process', 'GO:0006915', ('429', '438'))	('MDR', 'molecular_function', 'GO:0004745', ('303', '306'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (442, 459))	('p53', 'Gene', '7157', (544, 547))	('apoptosis', 'CPA', (429, 438))	('inactivation', 'NegReg', (497, 509))	('increased', 'PosReg', (371, 380))	('abrogation', 'NegReg', (415, 425))
113593	29182544	Indeed, in several tumours, the p53 pathway may be inactivated by alterations in its regulators or by yet unknown mechanisms, leading to resistance to cytotoxic therapies.	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('inactivated', 'NegReg', (51, 62))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumours', 'Disease', (19, 26))	('leading to', 'Reg', (126, 136))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('resistance to cytotoxic therapies', 'MPA', (137, 170))	('regulators', 'MPA', (85, 95))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('alterations', 'Var', (66, 77))
113595	29182544	Recent results in ccRCC, an aggressive drug resistant cancer showing wild type p53, are shedding light on the strong correlation that exists between TRIM8 deficit, p53 inactivation, and chemoresistance.	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('TRIM8', 'Gene', (149, 154))	('chemoresistance', 'CPA', (186, 201))	('inactivation', 'Var', (168, 180))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('TRIM8', 'Gene', '81603', (149, 154))	('cancer', 'Disease', (54, 60))	('p53', 'Gene', (164, 167))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('drug resistant cancer', 'Phenotype', 'HP:0020174', (39, 60))	('RCC', 'Disease', (20, 23))	('p53', 'Gene', '7157', (164, 167))
113596	29182544	The recovery of TRIM8 expression in ccRCC-derived cell lines was able to induce a great p53-dependent reduction in the proliferation rate, which became more pronounced when the cells were treated with the chemotherapy drugs Nutlin-3 and Cisplatin, but more interestingly, when the cells were newly sensitive to treatment with Axitinib and Sorafenib, two specific drugs currently used in the treatment of many cancers, including ccRCC.	('RCC', 'Disease', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (409, 415))	('expression', 'Var', (22, 32))	('p53', 'Gene', '7157', (88, 91))	('Nutlin-3', 'Chemical', 'MESH:C482205', (224, 232))	('Cisplatin', 'Chemical', 'MESH:D002945', (237, 246))	('Sorafenib', 'Chemical', 'MESH:D000077157', (339, 348))	('RCC', 'Disease', 'MESH:C538614', (38, 41))	('TRIM8', 'Gene', (16, 21))	('p53', 'Gene', (88, 91))	('cancers', 'Disease', 'MESH:D009369', (409, 416))	('TRIM8', 'Gene', '81603', (16, 21))	('Axitinib', 'Chemical', 'MESH:D000077784', (326, 334))	('RCC', 'Disease', (430, 433))	('RCC', 'Disease', 'MESH:C538614', (430, 433))	('reduction', 'NegReg', (102, 111))	('cancers', 'Phenotype', 'HP:0002664', (409, 416))	('cancers', 'Disease', (409, 416))	('proliferation rate', 'CPA', (119, 137))
113602	29182544	Many solid tumours exhibit activated NF-kappaB that may be the result of either exposure to proinflammatory stimuli in the tumour microenvironment or mutational activation of upstream components in IkappaB kinase (IKK)-NF-kappaB signaling pathways.	('solid tumours', 'Disease', 'MESH:D009369', (5, 18))	('NF-kappaB', 'Gene', (37, 46))	('NF-kappaB', 'Gene', '4790', (219, 228))	('tumour', 'Disease', 'MESH:D009369', (123, 129))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('tumour', 'Disease', (123, 129))	('solid tumours', 'Disease', (5, 18))	('tumour', 'Disease', 'MESH:D009369', (11, 17))	('mutational', 'Var', (150, 160))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('signaling', 'biological_process', 'GO:0023052', ('229', '238'))	('IKK', 'molecular_function', 'GO:0008384', ('214', '217'))	('NF-kappaB', 'Gene', (219, 228))	('activation', 'PosReg', (161, 171))	('NF-kappaB', 'Gene', '4790', (37, 46))	('tumour', 'Disease', (11, 17))	('activated', 'PosReg', (27, 36))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
113638	29182544	That is very interesting since STAT3 activation sustains tumour growth properties, including the support of stemness, in diverse cancer types including those of the breast, prostate, and brain and targeting STAT3 or its crucial upstream activators could result in the disruption of GSC maintenance and this pathway could represent a potential therapeutic target.	('targeting', 'Var', (197, 206))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumour', 'Disease', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (57, 63))	('STAT3', 'Gene', '6774', (207, 212))	('STAT3', 'Gene', (31, 36))	('cancer', 'Disease', (129, 135))	('disruption', 'MPA', (268, 278))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('GSC', 'cellular_component', 'GO:0032593', ('282', '285'))	('stemness', 'Disease', 'MESH:D020295', (108, 116))	('stemness', 'Disease', (108, 116))	('STAT3', 'Gene', (207, 212))	('result in', 'Reg', (254, 263))	('GSC maintenance', 'CPA', (282, 297))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('STAT3', 'Gene', '6774', (31, 36))
113639	29182544	Indeed, by targeting either TRIM8 or STAT3, researchers would be able to disrupt their positive feedback loop and attenuate the self-renewal capacity and tumour propagation of GBM.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('TRIM8', 'Gene', '81603', (28, 33))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('self-renewal capacity', 'CPA', (128, 149))	('STAT3', 'Gene', '6774', (37, 42))	('disrupt', 'NegReg', (73, 80))	('STAT3', 'Gene', (37, 42))	('tumour', 'Disease', (154, 160))	('attenuate', 'NegReg', (114, 123))	('targeting', 'Var', (11, 20))	('positive feedback loop', 'MPA', (87, 109))	('TRIM8', 'Gene', (28, 33))
113670	33845847	In addition, 18% of mutations in the PTTG family genes were associated with short-term survival in kidney renal clear cell carcinoma patients.	('PTTG', 'Gene', (37, 41))	('patients', 'Species', '9606', (133, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (99, 132))	('associated with', 'Reg', (60, 75))	('kidney renal clear cell carcinoma', 'Disease', (99, 132))	('PTTG', 'Gene', '9232', (37, 41))	('mutations', 'Var', (20, 29))
113683	33845847	Even though extensive researches have been conducted to investigate the role of PTTG family genes in human malignant tumors, the utility of the PTTG family genes for the kidney renal clear cell carcinoma diagnosis and prognosistic role of PTTG deletion in kidney renal clear cell carcinoma remains unclear.	('malignant tumors', 'Disease', 'MESH:D009369', (107, 123))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('PTTG', 'Gene', '9232', (144, 148))	('PTTG', 'Gene', '9232', (239, 243))	('PTTG', 'Gene', (239, 243))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (256, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('PTTG', 'Gene', (144, 148))	('human', 'Species', '9606', (101, 106))	('kidney renal clear cell carcinoma', 'Disease', (170, 203))	('PTTG', 'Gene', '9232', (80, 84))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (170, 203))	('deletion', 'Var', (244, 252))	('malignant tumors', 'Disease', (107, 123))	('PTTG', 'Gene', (80, 84))	('kidney renal clear cell carcinoma', 'Disease', (256, 289))
113734	33845847	And a statistically significant correlation was found between genetic mutations of PTTG family numbers and OS (p=9.838 E-3) in kidney renal clear cell carcinoma patients.	('kidney renal clear cell carcinoma', 'Disease', (127, 160))	('PTTG', 'Gene', '9232', (83, 87))	('patients', 'Species', '9606', (161, 169))	('PTTG', 'Gene', (83, 87))	('genetic mutations', 'Var', (62, 79))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (127, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
113741	33845847	After confirming the correlation between genetic mutations in PTTG family numbers and prognose values, similar genes of the PTTG family (90 in total) obtained from GEPIA2 and Metascape were used for GO enrichment to explore the interaction between similar genes.	('mutations', 'Var', (49, 58))	('PTTG', 'Gene', '9232', (62, 66))	('PTTG', 'Gene', '9232', (124, 128))	('PTTG', 'Gene', (62, 66))	('PTTG', 'Gene', (124, 128))
113752	33845847	Moreover, the mutation rate (18%) of PTTGs was observed in kidney renal clear cell carcinoma patients and the genetic alteration in PTTGs was associated with shorter OS.	('PTTG', 'Gene', (37, 41))	('kidney renal clear cell carcinoma', 'Disease', (59, 92))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (59, 92))	('patients', 'Species', '9606', (93, 101))	('PTTG', 'Gene', '9232', (132, 136))	('observed', 'Reg', (47, 55))	('PTTG', 'Gene', (132, 136))	('genetic alteration', 'Var', (110, 128))	('PTTG', 'Gene', '9232', (37, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
113758	33845847	In addition, high PTTG1 expression was also significantly associated with shorter survival in patients with kidney renal clear cell carcinoma, suggesting that PTTG1 was involved in the development of kidney renal clear cell carcinoma tumors.	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (200, 233))	('survival', 'MPA', (82, 90))	('PTTG1', 'Gene', '9232', (159, 164))	('involved', 'Reg', (169, 177))	('patients', 'Species', '9606', (94, 102))	('high', 'Var', (13, 17))	('expression', 'MPA', (24, 34))	('kidney renal clear cell carcinoma tumors', 'Disease', (200, 240))	('PTTG1', 'Gene', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('shorter', 'NegReg', (74, 81))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (108, 141))	('kidney renal clear cell carcinoma tumors', 'Disease', 'MESH:C538614', (200, 240))	('PTTG1', 'Gene', (159, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('kidney renal clear cell carcinoma', 'Disease', (108, 141))	('PTTG1', 'Gene', '9232', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))
113764	33845847	Previous studies have also reported high expression of PTTG3P in breast cancer and it has been found that PTTG3P expression is inversely correlated with estrogen receptor (ER) and progesterone receptor (PR) status, and high expression of PTTG3P is associated with poor prognosis of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('estrogen receptor', 'Gene', '2099', (153, 170))	('expression', 'MPA', (113, 123))	('PTTG3P', 'Gene', (106, 112))	('expression', 'MPA', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('PTTG3P', 'Gene', (238, 244))	('PTTG3P', 'Gene', '26255', (106, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (282, 295))	('correlated', 'Reg', (137, 147))	('PR', 'Gene', '5241', (203, 205))	('ER', 'Gene', '2099', (172, 174))	('PTTG3P', 'Gene', '26255', (238, 244))	('breast cancer', 'Disease', 'MESH:D001943', (282, 295))	('PTTG3P', 'Gene', (55, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('estrogen receptor', 'Gene', (153, 170))	('breast cancer', 'Disease', (282, 295))	('PTTG3P', 'Gene', '26255', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('progesterone receptor', 'Gene', (180, 201))	('progesterone receptor', 'Gene', '5241', (180, 201))	('high expression', 'Var', (219, 234))	('breast cancer', 'Disease', (65, 78))
113789	33672457	The combination therapy with bevacizumab and atezolizumab has revealed beneficial outcomes in the high PD-L1 expression population in a randomized trial.	('PD-L1', 'Gene', '29126', (103, 108))	('high', 'Var', (98, 102))	('bevacizumab', 'Chemical', 'MESH:D000068258', (29, 40))	('atezolizumab', 'Chemical', 'MESH:C000594389', (45, 57))	('beneficial', 'PosReg', (71, 81))	('PD-L1', 'Gene', (103, 108))
113800	33672457	CD80, CD86, CD276, CD274, CTLA4, PDCD1LG2, and PDCD1 had significant differences across three subgroups (Figure 7C and Figure 4C).	('PDCD1', 'Gene', '5133', (47, 52))	('CTLA4', 'Gene', (26, 31))	('CD86', 'Var', (6, 10))	('CD276', 'Gene', (12, 17))	('CD276', 'Gene', '80381', (12, 17))	('CD274', 'Gene', (19, 24))	('PDCD1LG2', 'Gene', (33, 41))	('CTLA4', 'Gene', '1493', (26, 31))	('PDCD1LG2', 'Gene', '80380', (33, 41))	('differences', 'Reg', (69, 80))	('PDCD1', 'Gene', (33, 38))	('CD274', 'Gene', '29126', (19, 24))	('PDCD1', 'Gene', '5133', (33, 38))	('CD80', 'Var', (0, 4))	('PDCD1', 'Gene', (47, 52))
113807	33672457	This may be due to the following: (1) Aberrant DNA methylation may result in a poor survival rate in tumor patients.	('result', 'Reg', (67, 73))	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('patients', 'Species', '9606', (107, 115))	('DNA methylation', 'biological_process', 'GO:0006306', ('47', '62'))	('Aberrant', 'Var', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('survival rate', 'CPA', (84, 97))	('DNA', 'Protein', (47, 50))	('poor', 'NegReg', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
113812	33672457	MMR (MLH1, PMS2, MSH2, or MSH6) deficiency, which is driven by inactivating methylation, was correlated with older age, advanced stage (II-IV), high grade of differentiation (G3), and larger tumor size.	('MSH6', 'Gene', '2956', (26, 30))	('MLH1', 'Gene', (5, 9))	('MSH2', 'Gene', (17, 21))	('correlated', 'Reg', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('PMS2', 'Gene', (11, 15))	('MSH2', 'Gene', '4436', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('PMS2', 'Gene', '5395', (11, 15))	('methylation', 'biological_process', 'GO:0032259', ('76', '87'))	('MSH6', 'Gene', (26, 30))	('MMR', 'biological_process', 'GO:0006298', ('0', '3'))	('deficiency', 'Var', (32, 42))	('MLH1', 'Gene', '4292', (5, 9))
113814	33672457	Similarly, another previous study showed that the high methylation cluster had low immune infiltration in breast tumors and skin cutaneous melanomas.	('high methylation', 'Var', (50, 66))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))	('breast tumors', 'Phenotype', 'HP:0100013', (106, 119))	('melanomas', 'Phenotype', 'HP:0002861', (139, 148))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('breast tumors', 'Disease', 'MESH:D001943', (106, 119))	('skin cutaneous melanomas', 'Disease', (124, 148))	('low', 'NegReg', (79, 82))	('breast tumors', 'Disease', (106, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('skin cutaneous melanomas', 'Disease', 'MESH:C562393', (124, 148))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (129, 148))	('immune infiltration', 'CPA', (83, 102))
113815	33672457	RASAL1 silencing promotes kidney fibroblast and fibrogenesis activation through hypermethylation.	('RASAL1', 'Gene', (0, 6))	('promotes', 'PosReg', (17, 25))	('hypermethylation', 'Var', (80, 96))	('RASAL1', 'Gene', '8437', (0, 6))	('silencing', 'Var', (7, 16))
113820	33672457	Furthermore, several previous studies showed that high immune infiltration is associated with high LD-1 (PDCD1) expression.	('PDCD1', 'Gene', '5133', (105, 110))	('high', 'Var', (94, 98))	('PDCD1', 'Gene', (105, 110))	('expression', 'MPA', (112, 122))
113828	33672457	In our study, cluster 2, with high methylation, had low inflammation, whereas cluster 3, with low methylation, had high inflammation.	('inflammation', 'Disease', 'MESH:D007249', (56, 68))	('inflammation', 'Disease', (56, 68))	('methylation', 'biological_process', 'GO:0032259', ('98', '109'))	('inflammation', 'Disease', 'MESH:D007249', (120, 132))	('inflammation', 'biological_process', 'GO:0006954', ('56', '68'))	('methylation', 'Var', (35, 46))	('inflammation', 'Disease', (120, 132))	('low', 'NegReg', (52, 55))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))	('inflammation', 'biological_process', 'GO:0006954', ('120', '132'))
113829	33672457	Mutations to thymine are caused by the methylation of cytosine.	('cytosine', 'Chemical', 'MESH:D003596', (54, 62))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('thymine', 'Chemical', 'MESH:D013941', (13, 20))	('Mutations', 'Var', (0, 9))	('methylation', 'MPA', (39, 50))	('caused by', 'Reg', (25, 34))
113831	33672457	Hypomethylated loci in tumors always coordinate with DNA break hotspots.	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('Hypomethylated', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
113833	33672457	CD80, CD86, CD276, CD274, CTLA4, and PDCD1LG2 had significant differences across three subgroups (Figure 7C and Figure 4C).	('PDCD1LG2', 'Gene', (37, 45))	('CTLA4', 'Gene', (26, 31))	('CD86', 'Var', (6, 10))	('CD276', 'Gene', (12, 17))	('CD276', 'Gene', '80381', (12, 17))	('CD274', 'Gene', (19, 24))	('differences', 'Reg', (62, 73))	('CTLA4', 'Gene', '1493', (26, 31))	('PDCD1LG2', 'Gene', '80380', (37, 45))	('CD274', 'Gene', '29126', (19, 24))	('CD80', 'Var', (0, 4))
113852	31777589	In conclusion, multiple FA metabolic enzymes, such as FASN, HADHA, and ACAT1, were potential prognostic markers of ccRCC, which implied alterations in FA metabolism might be involved in ccRCC tumorigenesis and progression.	('RCC', 'Disease', 'MESH:D002292', (117, 120))	('tumor', 'Disease', (192, 197))	('RCC', 'Disease', (117, 120))	('involved', 'Reg', (174, 182))	('FASN', 'Gene', '2194', (54, 58))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('ACAT1', 'Gene', (71, 76))	('metabolism', 'biological_process', 'GO:0008152', ('154', '164'))	('alterations', 'Var', (136, 147))	('RCC', 'Disease', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('RCC', 'Disease', 'MESH:D002292', (188, 191))	('FASN', 'Gene', (54, 58))
113885	31777589	As illustrated in Figure 2, the mean ACLY mRNA expression was elevated 2.49-fold (P<0.001, U133A microarray) and 2.53-fold (P<0.001, U133A/B microarray) in ccRCC compared with normal kidney tissues, respectively.	('ACLY', 'Gene', '47', (37, 41))	('RCC', 'Disease', 'MESH:D002292', (158, 161))	('RCC', 'Disease', (158, 161))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('U133A', 'Var', (91, 96))	('ACLY', 'Gene', (37, 41))	('elevated', 'PosReg', (62, 70))
113888	31777589	To be specific, there were a slightly increasing trend in U133A microarray, 1.08-fold (P=0.139 for ACC) and 1.09-fold (P=0.109 for FASN), while a slightly decreasing trend in U133A/B microarray, -1.21-fold (P=0.689 for ACC), and -1.08-fold (P=0.719 for FASN).	('U133A', 'Var', (58, 63))	('ACC', 'Gene', (219, 222))	('FASN', 'Gene', '2194', (253, 257))	('ACC', 'Gene', '31', (99, 102))	('ACC', 'Gene', '31', (219, 222))	('FASN', 'Gene', (131, 135))	('ACC', 'Gene', (99, 102))	('FASN', 'Gene', '2194', (131, 135))	('FASN', 'Gene', (253, 257))
113902	31777589	As for FA catabolic enzymes (table 3), in stage I, III, and IV ccRCC patients, we found that CPT1A (HR 95% CI=0.35 (0.17-0.72), 0.54 (0.30-0.96), 0.49 (0.28-0.87), respectively), ACAT1 (HR 95% CI=0.50 (0.28-0.91), 0.52 (0.30-0.92), 0.45 (0.28-0.74), respectively) mRNA expressions were associated with favorable OS.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('0.54', 'Var', (128, 132))	('0.49', 'Var', (146, 150))	('0.52', 'Var', (214, 218))	('mRNA expressions', 'MPA', (264, 280))	('ACAT1', 'MPA', (179, 184))	('CPT1A', 'Gene', (93, 98))	('0.45', 'Var', (232, 236))	('CPT', 'molecular_function', 'GO:0004142', ('93', '96'))	('CPT', 'molecular_function', 'GO:0004095', ('93', '96'))	('patients', 'Species', '9606', (69, 77))	('RCC', 'Disease', 'MESH:D002292', (65, 68))	('RCC', 'Disease', (65, 68))
113903	31777589	And in stage II, III, and IV ccRCC patients, HADHB (HR 95% CI=0.31 (0.10-0.98), 0.47 (0.27-0.84), 0.42 (0.26-0.69), respectively) mRNA expressions was associated with favorable prognosis.	('HADHB', 'Gene', (45, 50))	('mRNA', 'Var', (130, 134))	('patients', 'Species', '9606', (35, 43))	('0.42', 'Var', (98, 102))	('RCC', 'Disease', 'MESH:D002292', (31, 34))	('RCC', 'Disease', (31, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
113904	31777589	Meanwhile, HADHA mRNA was related to better OS in stage I (HR 95% CI=0.44 (0.24-0.82)) and IV (HR 95% CI=0.37 (0.21-0.61)) ccRCC patients.	('patients', 'Species', '9606', (129, 137))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('RCC', 'Disease', 'MESH:D002292', (125, 128))	('HADHA', 'Var', (11, 16))
113975	31131187	PLCL1 dysregulation in ccRCC suggested that PLCL1 may influence the progression of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (23, 28))	('progression', 'CPA', (68, 79))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('dysregulation', 'Var', (6, 19))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('RCC', 'Disease', (85, 88))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('PLCL1', 'Gene', (44, 49))	('PLCL1', 'Gene', (0, 5))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('RCC', 'Disease', (25, 28))	('influence', 'Reg', (54, 63))
113998	31131187	Moreover, the GSEA analysis suggested that the function of PLCL1 was enriched in the peroxisome proliferators-activated receptors (PPAR) pathway and could transactivate the PPRE (peroxisome proliferator response element) on the UCP1 enhancer to promote the expression of UCP1 based on the data from TCGA database27 (Figure 3F).	('UCP1', 'Gene', '7350', (228, 232))	('UCP1', 'Gene', (228, 232))	('PLCL1', 'Gene', (59, 64))	('peroxisome proliferators-activated receptors', 'Gene', (85, 129))	('promote', 'PosReg', (245, 252))	('peroxisome', 'cellular_component', 'GO:0005777', ('85', '95'))	('UCP1', 'Gene', '7350', (271, 275))	('PPAR', 'Gene', (131, 135))	('expression', 'MPA', (257, 267))	('transactivate', 'Var', (155, 168))	('peroxisome', 'cellular_component', 'GO:0005777', ('179', '189'))	('UCP1', 'Gene', (271, 275))	('PPRE', 'Gene', (173, 177))	('peroxisome proliferators-activated receptors', 'Gene', '5465', (85, 129))	('GSEA', 'Chemical', '-', (14, 18))	('PPAR', 'Gene', '5465', (131, 135))
114000	31131187	Similarly, the knockdown of PLCL1 in cells was accompanied by a decrease in UCP1 (Figure 3G).	('PLCL1', 'Gene', (28, 33))	('decrease', 'NegReg', (64, 72))	('knockdown', 'Var', (15, 24))	('UCP1', 'Gene', '7350', (76, 80))	('UCP1', 'Gene', (76, 80))
114009	31131187	On the basis of overexpressing PLCL1, we constructed UCP1-knockdown cells by transfecting UCP1 small interfering RNA (siRNA) (Figure  5 A).	('UCP1', 'Gene', '7350', (53, 57))	('UCP1', 'Gene', (53, 57))	('small interfering', 'Var', (95, 112))	('UCP1', 'Gene', '7350', (90, 94))	('RNA', 'cellular_component', 'GO:0005562', ('113', '116'))	('UCP1', 'Gene', (90, 94))
114012	31131187	As previously mentioned, overexpressing PLCL1 could significantly decrease the proliferation ability of ccRCC cells.	('decrease', 'NegReg', (66, 74))	('proliferation ability of', 'CPA', (79, 103))	('PLCL1', 'Gene', (40, 45))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('overexpressing', 'Var', (25, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))	('RCC', 'Disease', 'MESH:C538614', (106, 109))
114013	31131187	The CCK8 assay indicated that silencing UCP1 could attenuate the inhibition of cell proliferation induced by PLCL1 to a certain degree (Figure 5B; Figure 5A,B, Supporting Information).	('inhibition', 'NegReg', (65, 75))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('65', '97'))	('cell proliferation', 'CPA', (79, 97))	('attenuate', 'NegReg', (51, 60))	('silencing', 'Var', (30, 39))	('PLCL1', 'Gene', (109, 114))	('UCP1', 'Gene', '7350', (40, 44))	('UCP1', 'Gene', (40, 44))
114014	31131187	Similar conclusions could be found in that silencing UCP1 could partly reverse the inhibition of migration and invasion induced by PLCL1 (Figure 5C).	('silencing', 'Var', (43, 52))	('UCP1', 'Gene', '7350', (53, 57))	('UCP1', 'Gene', (53, 57))	('inhibition', 'NegReg', (83, 93))
114017	31131187	On this basis, silencing UCP1 could significantly increase the accumulation of lipids accompanied by the increase in lipid droplet diameter and cell diameter (Figure 5D).	('UCP1', 'Gene', '7350', (25, 29))	('lipid', 'Chemical', 'MESH:D008055', (79, 84))	('lipids', 'Chemical', 'MESH:D008055', (79, 85))	('lipid', 'Chemical', 'MESH:D008055', (117, 122))	('cell diameter', 'CPA', (144, 157))	('UCP1', 'Gene', (25, 29))	('silencing', 'Var', (15, 24))	('increase', 'PosReg', (50, 58))	('increase', 'PosReg', (105, 113))	('lipid droplet', 'cellular_component', 'GO:0005811', ('117', '130'))	('lipid droplet diameter', 'MPA', (117, 139))	('accumulation of lipids', 'MPA', (63, 85))
114018	31131187	In other words, silencing UCP1 could largely reverse the biological effects induced by PLCL1.	('reverse', 'NegReg', (45, 52))	('UCP1', 'Gene', '7350', (26, 30))	('UCP1', 'Gene', (26, 30))	('silencing', 'Var', (16, 25))	('biological effects', 'MPA', (57, 75))
114021	31131187	To further verify this phenomenon, we examined the mRNA level of UCP1 in ccRCC cells stably overexpressing PLCL1 and those with PLCL1 knocked down.	('knocked down', 'Var', (134, 146))	('PLCL1', 'Gene', (107, 112))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('UCP1', 'Gene', (65, 69))	('UCP1', 'Gene', '7350', (65, 69))	('PLCL1', 'Gene', (128, 133))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))
114025	31131187	The results showed that there was a significant decrease over time in UCP1 protein levels in PLCL1-knockdown cells and that the UCP1 protein levels were only slightly decreased after CHX treatment in control cells (Figure 6B).	('PLCL1-knockdown', 'Var', (93, 108))	('CHX', 'Disease', 'None', (183, 186))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('CHX', 'Disease', (183, 186))	('PLCL1-knockdown', 'Gene', (93, 108))	('decrease', 'NegReg', (48, 56))	('UCP1', 'Gene', (128, 132))	('UCP1', 'Gene', '7350', (128, 132))	('UCP1', 'Gene', '7350', (70, 74))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('UCP1', 'Gene', (70, 74))
114032	31131187	The results showed that the level of ubiquitinated UCP1 was significantly increased in PLCL1-knockdown cells (Figure 6F).	('PLCL1-knockdown', 'Var', (87, 102))	('UCP1', 'Gene', '7350', (51, 55))	('increased', 'PosReg', (74, 83))	('PLCL1-knockdown', 'Gene', (87, 102))	('UCP1', 'Gene', (51, 55))	('level of ubiquitinated', 'MPA', (28, 50))
114121	32638386	Overall, BMI was associated positively with ccRCC risk, but inversely with pRCC risk.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Disease', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('pRCC', 'Gene', (75, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('pRCC', 'Gene', '5546', (75, 79))	('BMI', 'Var', (9, 12))	('pRCC', 'Phenotype', 'HP:0006766', (75, 79))
114135	32638386	3 ,  4 ,  5 ,  6 ,  7 ,  8  Furthermore, alcohol consumption has been associated with a decreased RCC risk in multiple prospective epidemiological studies.	('RCC', 'Disease', (98, 101))	('alcohol', 'Chemical', 'MESH:D000438', (41, 48))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('decreased', 'NegReg', (88, 97))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('alcohol consumption', 'Var', (41, 60))
114183	32638386	BMI change per 1 kg/m2 increment since age 20 was associated with a nonstatistically significantly increased RCC risk.	('men', 'Species', '9606', (28, 31))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('change', 'Var', (4, 10))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))
114191	32638386	Furthermore, an increase in change in BMI since age 20 was associated with an increase in risk for ccRCC, and a decrease in pRCC risk.	('pRCC', 'Phenotype', 'HP:0006766', (124, 128))	('pRCC', 'Gene', '5546', (124, 128))	('decrease', 'NegReg', (112, 120))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('RCC', 'Disease', (101, 104))	('BMI', 'Gene', (38, 41))	('change', 'Var', (28, 34))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('pRCC', 'Gene', (124, 128))
114192	32638386	Trouser size in men was associated with a statistically significantly increased ccRCC risk per size increase, while no association was found with pRCC risk.	('pRCC', 'Phenotype', 'HP:0006766', (146, 150))	('pRCC', 'Gene', '5546', (146, 150))	('increased', 'PosReg', (70, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('men', 'Species', '9606', (16, 19))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('Trouser', 'Var', (0, 7))	('pRCC', 'Gene', (146, 150))	('RCC', 'Disease', 'MESH:C538614', (147, 150))
114239	32638386	35  Therefore, the inactivation of VHL in ccRCC and the obesity-related increase in IGF-I may amplify the process of tumorigenesis.	('obesity', 'Disease', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('increase', 'PosReg', (72, 80))	('IGF-I', 'Gene', (84, 89))	('tumor', 'Disease', (117, 122))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (42, 47))	('RCC', 'Disease', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('amplify', 'PosReg', (94, 101))	('obesity', 'Phenotype', 'HP:0001513', (56, 63))	('VHL', 'Gene', (35, 38))	('inactivation', 'Var', (19, 31))	('obesity', 'Disease', 'MESH:D009765', (56, 63))	('IGF-I', 'Gene', '3479', (84, 89))	('VHL', 'Gene', '7428', (35, 38))
114284	30108105	Inhibition of the glutamine-MDH2 axis suppresses in vitro phenotypes in a L-2-HG dependent manner.	('MDH2', 'Gene', '4191', (28, 32))	('MDH2', 'Gene', (28, 32))	('MDH', 'molecular_function', 'GO:0033720', ('28', '31'))	('Inhibition', 'Var', (0, 10))	('suppresses', 'NegReg', (38, 48))	('glutamine', 'Chemical', 'MESH:C578860', (18, 27))	('L-2', 'Gene', (74, 77))	('L-2', 'Gene', '8496', (74, 77))	('MDH', 'molecular_function', 'GO:0030060', ('28', '31'))	('MDH', 'molecular_function', 'GO:0018468', ('28', '31'))
114287	30108105	Finally, increased L-2-HG levels, L2HGDH copy loss, and lower L2HGDH expression are associated with tumor progression and/or worsened prognosis in RCC patients.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('L2HGDH', 'Gene', (34, 40))	('tumor', 'Disease', (100, 105))	('L2HGDH', 'Gene', (62, 68))	('increased', 'PosReg', (9, 18))	('copy', 'Var', (41, 45))	('worsened', 'NegReg', (125, 133))	('lower', 'NegReg', (56, 61))	('expression', 'MPA', (69, 79))	('L2HGDH', 'Gene', '79944', (34, 40))	('patients', 'Species', '9606', (151, 159))	('associated', 'Reg', (84, 94))	('RCC', 'Disease', (147, 150))	('L2HGDH', 'Gene', '79944', (62, 68))	('RCC', 'Disease', 'MESH:D002292', (147, 150))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('L-2', 'Gene', (19, 22))	('L-2', 'Gene', '8496', (19, 22))
114289	30108105	Cancer-associated mutations in metabolic enzymes have led to the identification of oncometabolites including fumarate, succinate and D-2-hydroxyglutarate (D-2-HG).	('fumarate', 'MPA', (109, 117))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('succinate', 'MPA', (119, 128))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (133, 153))	('D-2-hydroxyglutarate', 'MPA', (133, 153))	('succinate', 'Chemical', 'MESH:D013386', (119, 128))	('fumarate', 'Chemical', 'MESH:D005650', (109, 117))	('mutations', 'Var', (18, 27))
114294	30108105	For example, the in vivo efficacy of mutant IDH inhibitors for glioma has yielded conflicting results.	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('mutant', 'Var', (37, 43))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', '3417', (44, 47))	('glioma', 'Disease', (63, 69))
114302	30108105	Inheritance of biallelic mutant L2HGDH results in a rare inborn error of metabolism referred to as L-2-HG aciduria that has been linked with brain tumors.	('brain tumors', 'Disease', 'MESH:D001932', (141, 153))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('L2HGDH', 'Gene', '79944', (32, 38))	('brain tumors', 'Disease', (141, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('metabolism', 'biological_process', 'GO:0008152', ('73', '83'))	('results in', 'Reg', (39, 49))	('L-2-HG aciduria', 'Phenotype', 'HP:0040144', (99, 114))	('inborn error of metabolism', 'Disease', 'MESH:D008661', (57, 83))	('inborn error of metabolism', 'Disease', (57, 83))	('brain tumors', 'Phenotype', 'HP:0030692', (141, 153))	('L2HGDH', 'Gene', (32, 38))	('linked', 'Reg', (129, 135))	('biallelic mutant', 'Var', (15, 31))	('L-2', 'Gene', (99, 102))	('L-2', 'Gene', '8496', (99, 102))	('aciduria', 'Phenotype', 'HP:0012072', (106, 114))
114303	30108105	The concept that small molecules can promote malignancy has now presented novel therapeutic opportunities.	('small', 'Var', (17, 22))	('malignancy', 'Disease', (45, 55))	('malignancy', 'Disease', 'MESH:D009369', (45, 55))	('promote', 'PosReg', (37, 44))
114304	30108105	In the case of IDH gain of function mutations in leukemia, which result in raised D-2-HG levels, specific inhibitors that selectively inhibit mutant IDH (as opposed to wild-type IDH) are now approved for use.	('IDH', 'Gene', '3417', (178, 181))	('IDH gain', 'Disease', (15, 23))	('IDH', 'Gene', (149, 152))	('IDH gain', 'Disease', 'MESH:D015430', (15, 23))	('leukemia', 'Disease', (49, 57))	('inhibit', 'NegReg', (134, 141))	('raised', 'PosReg', (75, 81))	('IDH', 'Gene', '3417', (149, 152))	('mutations', 'Var', (36, 45))	('mutant', 'Var', (142, 148))	('IDH', 'Gene', '3417', (15, 18))	('leukemia', 'Disease', 'MESH:D007938', (49, 57))	('IDH', 'Gene', (15, 18))	('leukemia', 'Phenotype', 'HP:0001909', (49, 57))	('D-2-HG levels', 'MPA', (82, 95))	('IDH', 'Gene', (178, 181))
114318	30108105	For L2HGDH or MDH knockdown, the following shRNAs in pLKO.1 vector (Sigma) were used: shL2HGDH (sh3, TRCN0000064323), shL2HGD (sh4, TRCN0000064324) and shL2HGDH (sh5, TRCN0000064325), shMDH1 (TRCN0000275199), shMDH1 (TRCN0000028484) and shMDH2 (TRCN0000028485).	('L2HGDH', 'Gene', (154, 160))	('L2HGDH', 'Gene', (4, 10))	('L2HGDH', 'Gene', '79944', (154, 160))	('MDH', 'molecular_function', 'GO:0018468', ('14', '17'))	('MDH1', 'Gene', '4190', (186, 190))	('L2HGDH', 'Gene', '79944', (4, 10))	('L2HGDH', 'Gene', (88, 94))	('MDH2', 'Gene', '4191', (239, 243))	('HGD', 'molecular_function', 'GO:0043718', ('122', '125'))	('L2HGDH', 'Gene', '79944', (88, 94))	('MDH', 'molecular_function', 'GO:0030060', ('14', '17'))	('MDH1', 'Gene', (211, 215))	('MDH', 'molecular_function', 'GO:0033720', ('14', '17'))	('TRCN0000028484', 'Var', (217, 231))	('sh4', 'Var', (127, 130))	('MDH1', 'Gene', (186, 190))	('TRCN0000275199', 'Var', (192, 206))	('TRCN0000028485', 'Var', (245, 259))	('MDH2', 'Gene', (239, 243))	('sh5', 'Var', (162, 165))	('MDH1', 'Gene', '4190', (211, 215))
114323	30108105	A498 cells stably expressing L2HGDH were treated with 30 nM of control siRNA (#D-001800-01), KDM6A siRNA#1 (#J-014140-10) and KDM6A siRNA#2 (# J-014140-12) ON-TARGET plus siRNA (Dharmacon) using Lipofectamine  RNAiMAX (Invitrogen, cat# 13778030) transfection reagent for 72 hrs.	('KDM6A', 'Gene', (126, 131))	('L2HGDH', 'Gene', '79944', (29, 35))	('A498', 'CellLine', 'CVCL:1056', (0, 4))	('KDM6A', 'Gene', '7403', (93, 98))	('KDM6A', 'Gene', (93, 98))	('KDM6A', 'Gene', '7403', (126, 131))	('#J-014140-10', 'Var', (108, 120))	('# J-014140-12', 'Var', (141, 154))	('L2HGDH', 'Gene', (29, 35))	('cat', 'molecular_function', 'GO:0004096', ('231', '234'))	('#D-001800-01', 'Var', (78, 90))
114336	30108105	Real-time qPCR was done using TaqMan expression assay probes (Invitrogen) for human L2HGDH (Hs00227575), SPOCK2 (Hs00360339) and SHISA2 (Hs01590823) in QuantStudio 6K Flex real-time PCR system (Applied Biosystem).	('L2HGDH', 'Gene', '79944', (84, 90))	('SPOCK2', 'Gene', (105, 111))	('SHISA2', 'Gene', (129, 135))	('Hs01590823', 'Chemical', 'MESH:C044105', (137, 147))	('Hs00227575', 'Var', (92, 102))	('SPOCK2', 'Gene', '9806', (105, 111))	('SHISA2', 'Gene', '387914', (129, 135))	('Hs01590823', 'Var', (137, 147))	('Hs00360339', 'Var', (113, 123))	('L2HGDH', 'Gene', (84, 90))	('human', 'Species', '9606', (78, 83))
114349	30108105	As a functional readout of raised 2-HG levels, we assessed the effects of L2HGDH knockdown on DNA 5-hyroxymethylcytosine (5-hmC) levels as prior studies demonstrate that L-2-HG can competitively inhibit alpha-KG dioxygenases including the TET enzymes.	('L-2', 'Gene', '8496', (170, 173))	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('L2HGDH', 'Gene', '79944', (74, 80))	('5-hmC', 'Chemical', 'MESH:C509711', (122, 127))	('knockdown', 'Var', (81, 90))	('alpha-KG dioxygenases', 'Enzyme', (203, 224))	('TET enzymes', 'Enzyme', (239, 250))	('inhibit', 'NegReg', (195, 202))	('5-hyroxymethylcytosine', 'Chemical', 'MESH:C068492', (98, 120))	('L-2', 'Gene', (170, 173))	('alpha-KG', 'Chemical', 'MESH:D020410', (203, 211))	('L2HGDH', 'Gene', (74, 80))
114350	30108105	Consistent with these findings, L2HGDH knockdown led to reduced DNA 5-hmC levels in renal epithelial cells (Supplementary Fig.S1C).	('L2HGDH', 'Gene', '79944', (32, 38))	('DNA 5-hmC levels', 'MPA', (64, 80))	('reduced', 'NegReg', (56, 63))	('knockdown', 'Var', (39, 48))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('5-hmC', 'Chemical', 'MESH:C509711', (68, 73))	('L2HGDH', 'Gene', (32, 38))
114351	30108105	L2HGDH knockdown resulted in a modest increase in proliferation in HK-2 cells (Supplementary Fig.	('increase', 'PosReg', (38, 46))	('L2HGDH', 'Gene', (0, 6))	('HK-2', 'CellLine', 'CVCL:0302', (67, 71))	('HK-2', 'molecular_function', 'GO:0008256', ('67', '71'))	('L2HGDH', 'Gene', '79944', (0, 6))	('knockdown', 'Var', (7, 16))
114352	30108105	We investigated additional in vitro phenotypes and found that knockdown of L2HGDH promoted a migratory phenotype as assessed by a wound healing scratch assay (Fig.1B-C).	('L2HGDH', 'Gene', '79944', (75, 81))	('promoted', 'PosReg', (82, 90))	('wound healing', 'biological_process', 'GO:0042060', ('130', '143'))	('L2HGDH', 'Gene', (75, 81))	('migratory phenotype', 'CPA', (93, 112))	('knockdown', 'Var', (62, 71))
114354	30108105	L-2-HG ester treatment also promoted a migratory phenotype in HK-2 cells phenocopying the results of L2HGDH knockdown (Fig.	('knockdown', 'Var', (108, 117))	('L-2-HG ester', 'Chemical', 'MESH:C037856', (0, 12))	('L2HGDH', 'Gene', '79944', (101, 107))	('migratory phenotype', 'CPA', (39, 58))	('promoted', 'PosReg', (28, 36))	('HK-2', 'molecular_function', 'GO:0008256', ('62', '66'))	('L2HGDH', 'Gene', (101, 107))	('HK-2', 'CellLine', 'CVCL:0302', (62, 66))
114358	30108105	As an additional control, we stably transduced RCC cells with a L2HGDH point mutant (A241G) which results in a substitution of lysine with glutamate (K81E) previously reported in patients with L-2-HG aciduria and found to lack catalytic activity.	('results in', 'Reg', (98, 108))	('L-2', 'Gene', (193, 196))	('RCC', 'Disease', 'MESH:D002292', (47, 50))	('L-2-HG aciduria', 'Phenotype', 'HP:0040144', (193, 208))	('A241G', 'Var', (85, 90))	('A241G', 'Mutation', 'rs970541687', (85, 90))	('L-2', 'Gene', '8496', (193, 196))	('patients', 'Species', '9606', (179, 187))	('lysine', 'Chemical', 'MESH:C114808', (127, 133))	('K81E', 'Var', (150, 154))	('L2HGDH', 'Gene', (64, 70))	('L2HGDH', 'Gene', '79944', (64, 70))	('K81E', 'Mutation', 'rs970541687', (150, 154))	('aciduria', 'Phenotype', 'HP:0012072', (200, 208))	('catalytic activity', 'molecular_function', 'GO:0003824', ('227', '245'))	('RCC', 'Disease', (47, 50))	('catalytic activity', 'MPA', (227, 245))	('glutamate', 'Chemical', 'None', (139, 148))	('substitution', 'Var', (111, 123))
114359	30108105	In multiple lines tested, WT L2HGDH was able to significantly lower L-2-HG levels whereas only slight reductions in L-2-HG were noted with the A241G mutant (Fig.	('L-2', 'Gene', (68, 71))	('L-2', 'Gene', (116, 119))	('L2HGDH', 'Gene', '79944', (29, 35))	('A241G', 'Var', (143, 148))	('L-2', 'Gene', '8496', (116, 119))	('L-2', 'Gene', '8496', (68, 71))	('A241G', 'Mutation', 'rs970541687', (143, 148))	('lower', 'NegReg', (62, 67))	('L2HGDH', 'Gene', (29, 35))
114361	30108105	Consistent with increased TET activity due to reduced L-2-HG, 5-hmC levels were increased in WT cells relative to control vector or A241G transduced cells (Supplementary Fig.	('A241G', 'Mutation', 'rs970541687', (132, 137))	('increased', 'PosReg', (80, 89))	('TET activity', 'MPA', (26, 38))	('increased', 'PosReg', (16, 25))	('A241G', 'Var', (132, 137))	('reduced', 'NegReg', (46, 53))	('5-hmC', 'Chemical', 'MESH:C509711', (62, 67))	('L-2', 'Gene', (54, 57))	('L-2', 'Gene', '8496', (54, 57))
114362	30108105	Similar to our loss of function studies, L2HGDH restoration in RCC cells reduced migration as determined by scratch assay (Fig.	('RCC', 'Disease', 'MESH:D002292', (63, 66))	('RCC', 'Disease', (63, 66))	('reduced', 'NegReg', (73, 80))	('restoration', 'Var', (48, 59))	('L2HGDH', 'Gene', (41, 47))	('L2HGDH', 'Gene', '79944', (41, 47))	('migration', 'CPA', (81, 90))
114371	30108105	In both OSRC-2 and A498 RCC lines, tumors with WT L2HGDH grew more slowly than tumors expressing the A241G mutant (Fig.	('RCC', 'Disease', 'MESH:D002292', (24, 27))	('RCC', 'Disease', (24, 27))	('slowly', 'NegReg', (67, 73))	('OSRC-2', 'CellLine', 'CVCL:1901', (8, 14))	('L2HGDH', 'Gene', '79944', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('A241G', 'Var', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('grew', 'CPA', (57, 61))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('A498', 'CellLine', 'CVCL:1056', (19, 23))	('A241G', 'Mutation', 'rs970541687', (101, 106))	('L2HGDH', 'Gene', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
114372	30108105	End of study tumors for WT tumors were less weight than A241G mutant tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('A241G', 'Var', (56, 61))	('less', 'NegReg', (39, 43))	('tumors', 'Disease', (27, 33))	('weight', 'MPA', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors for WT tumors', 'Disease', 'MESH:D009369', (13, 33))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('A241G', 'Mutation', 'rs970541687', (56, 61))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors for WT tumors', 'Disease', (13, 33))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
114384	30108105	In both A498 and RXF-393 RCC cells, the predominant form of L-2-HG derived from U-13C5 glutamine is the m+5 fraction (C13 label incorporated into all 5 molecules of L-2-HG) (Fig.	('C13', 'Gene', '3229', (118, 121))	('C13', 'Gene', (118, 121))	('L-2', 'Gene', (165, 168))	('L-2', 'Gene', '8496', (165, 168))	('RXF-393 RCC', 'CellLine', 'CVCL:1673', (17, 28))	('U-13C5 glutamine', 'Var', (80, 96))	('A498', 'CellLine', 'CVCL:1056', (8, 12))	('U-13C5 glutamine', 'Chemical', 'MESH:C513342', (80, 96))	('L-2', 'Gene', (60, 63))	('L-2', 'Gene', '8496', (60, 63))
114388	30108105	L2HGDH re-expression in A498 cells led to reduced accumulation of labeled L-2-HG following incubation with U-13C5 as demonstrated by reduced levels of m+5 and m+3 L-2-HG isotopologues (Fig.	('levels of m+5', 'MPA', (141, 154))	('reduced', 'NegReg', (42, 49))	('accumulation of', 'MPA', (50, 65))	('U-13C5', 'Chemical', 'MESH:C513342', (107, 113))	('A498', 'CellLine', 'CVCL:1056', (24, 28))	('L-2', 'Gene', (163, 166))	('L2HGDH', 'Gene', (0, 6))	('L-2', 'Gene', '8496', (163, 166))	('L-2', 'Gene', '8496', (74, 77))	('L2HGDH', 'Gene', '79944', (0, 6))	('reduced', 'NegReg', (133, 140))	('L-2', 'Gene', (74, 77))	('re-expression', 'Var', (7, 20))
114404	30108105	Collectively, these data demonstrate that glutamine metabolism promotes L-2-HG accumulation and that inhibition of this pathway can suppress tumor phenotypes.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('inhibition', 'Var', (101, 111))	('glutamine metabolism', 'MPA', (42, 62))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('suppress', 'NegReg', (132, 140))	('promotes', 'PosReg', (63, 71))	('tumor', 'Disease', (141, 146))	('L-2', 'Gene', (72, 75))	('L-2', 'Gene', '8496', (72, 75))	('glutamine', 'Chemical', 'MESH:C578860', (42, 51))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('42', '62'))
114406	30108105	We identified shRNA constructs that knockdown expression of both cytosolic MDH (MDH1) and mitochondrial MDH (MDH2) (Fig.	('MDH', 'molecular_function', 'GO:0018468', ('80', '83'))	('MDH', 'molecular_function', 'GO:0033720', ('109', '112'))	('MDH (MDH1) and mitochondrial MDH', 'Disease', 'MESH:D028361', (75, 107))	('MDH', 'molecular_function', 'GO:0033720', ('80', '83'))	('MDH', 'molecular_function', 'GO:0030060', ('104', '107'))	('MDH', 'molecular_function', 'GO:0033720', ('75', '78'))	('MDH', 'molecular_function', 'GO:0018468', ('109', '112'))	('knockdown', 'Var', (36, 45))	('MDH', 'molecular_function', 'GO:0018468', ('104', '107'))	('MDH', 'molecular_function', 'GO:0030060', ('109', '112'))	('MDH2', 'Gene', '4191', (109, 113))	('MDH2', 'Gene', (109, 113))	('MDH', 'molecular_function', 'GO:0033720', ('104', '107'))	('MDH', 'molecular_function', 'GO:0030060', ('80', '83'))	('MDH', 'molecular_function', 'GO:0030060', ('75', '78'))	('MDH', 'molecular_function', 'GO:0018468', ('75', '78'))
114407	30108105	While knockdown of MDH1 reduced L-2-HG levels in RXF-393 cells (Supplemental Fig.	('RXF-393', 'CellLine', 'CVCL:1673', (49, 56))	('reduced', 'NegReg', (24, 31))	('MDH1', 'Gene', (19, 23))	('MDH', 'molecular_function', 'GO:0018468', ('19', '22'))	('MDH', 'molecular_function', 'GO:0030060', ('19', '22'))	('L-2', 'Gene', (32, 35))	('L-2', 'Gene', '8496', (32, 35))	('knockdown', 'Var', (6, 15))	('MDH1', 'Gene', '4190', (19, 23))	('MDH', 'molecular_function', 'GO:0033720', ('19', '22'))
114408	30108105	S8B), MDH2 knockdown had a more pronounced effect on L-2-HG levels (Fig.	('MDH', 'molecular_function', 'GO:0018468', ('6', '9'))	('MDH2', 'Gene', '4191', (6, 10))	('MDH2', 'Gene', (6, 10))	('MDH', 'molecular_function', 'GO:0033720', ('6', '9'))	('effect', 'Reg', (43, 49))	('S8B', 'Chemical', 'MESH:C039415', (0, 3))	('L-2', 'Gene', (53, 56))	('L-2', 'Gene', '8496', (53, 56))	('knockdown', 'Var', (11, 20))	('MDH', 'molecular_function', 'GO:0030060', ('6', '9'))
114411	30108105	Similarly, MDH2 knockdown significantly reduced L-2-HG levels in OSRC-2 cells (Fig.	('OSRC-2', 'CellLine', 'CVCL:1901', (65, 71))	('MDH', 'molecular_function', 'GO:0018468', ('11', '14'))	('MDH', 'molecular_function', 'GO:0033720', ('11', '14'))	('L-2', 'Gene', (48, 51))	('L-2', 'Gene', '8496', (48, 51))	('knockdown', 'Var', (16, 25))	('MDH2', 'Gene', '4191', (11, 15))	('reduced', 'NegReg', (40, 47))	('MDH2', 'Gene', (11, 15))	('MDH', 'molecular_function', 'GO:0030060', ('11', '14'))
114412	30108105	We also observed that MDH2 knockdown reduced proliferation in OSRC-2 cells (Fig.	('knockdown', 'Var', (27, 36))	('MDH', 'molecular_function', 'GO:0030060', ('22', '25'))	('MDH', 'molecular_function', 'GO:0018468', ('22', '25'))	('MDH', 'molecular_function', 'GO:0033720', ('22', '25'))	('reduced', 'NegReg', (37, 44))	('MDH2', 'Gene', '4191', (22, 26))	('OSRC-2', 'CellLine', 'CVCL:1901', (62, 68))	('MDH2', 'Gene', (22, 26))	('proliferation in OSRC-2 cells', 'CPA', (45, 74))
114413	30108105	Based on prior studies, we assessed effects of MDH2 knockdown on migration.	('MDH', 'molecular_function', 'GO:0033720', ('47', '50'))	('knockdown', 'Var', (52, 61))	('MDH', 'molecular_function', 'GO:0030060', ('47', '50'))	('MDH', 'molecular_function', 'GO:0018468', ('47', '50'))	('MDH2', 'Gene', '4191', (47, 51))	('MDH2', 'Gene', (47, 51))
114414	30108105	Similar to prior manipulations that lowered L-2-HG levels, MDH2 knockdown reduced cell migration.	('cell migration', 'CPA', (82, 96))	('MDH2', 'Gene', '4191', (59, 63))	('MDH2', 'Gene', (59, 63))	('cell migration', 'biological_process', 'GO:0016477', ('82', '96'))	('knockdown', 'Var', (64, 73))	('MDH', 'molecular_function', 'GO:0030060', ('59', '62'))	('L-2', 'Gene', (44, 47))	('L-2', 'Gene', '8496', (44, 47))	('reduced', 'NegReg', (74, 81))	('MDH', 'molecular_function', 'GO:0018468', ('59', '62'))	('MDH', 'molecular_function', 'GO:0033720', ('59', '62'))
114416	30108105	Collectively, these data demonstrate that MDH2 promotes L-2-HG accumulation and that inhibition of MDH2 can suppress in vitro tumor phenotypes in RCC cells with raised L-2-HG.	('promotes', 'PosReg', (47, 55))	('MDH2', 'Gene', '4191', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('L-2', 'Gene', (168, 171))	('RCC', 'Disease', (146, 149))	('MDH', 'molecular_function', 'GO:0018468', ('42', '45'))	('MDH2', 'Gene', (99, 103))	('L-2', 'Gene', '8496', (168, 171))	('RCC', 'Disease', 'MESH:D002292', (146, 149))	('MDH', 'molecular_function', 'GO:0018468', ('99', '102'))	('MDH2', 'Gene', (42, 46))	('L-2', 'Gene', (56, 59))	('MDH', 'molecular_function', 'GO:0030060', ('42', '45'))	('suppress', 'NegReg', (108, 116))	('tumor', 'Disease', (126, 131))	('MDH', 'molecular_function', 'GO:0033720', ('42', '45'))	('MDH', 'molecular_function', 'GO:0030060', ('99', '102'))	('inhibition', 'Var', (85, 95))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('L-2', 'Gene', '8496', (56, 59))	('MDH', 'molecular_function', 'GO:0033720', ('99', '102'))	('MDH2', 'Gene', '4191', (99, 103))
114420	30108105	Consistent with these data, WT L2HGDH lowered H3K27me3 levels in RCC cells whereas the A241G mutant did not (Fig.	('A241G', 'Var', (87, 92))	('H3K27me3 levels', 'MPA', (46, 61))	('L2HGDH', 'Gene', (31, 37))	('lowered', 'NegReg', (38, 45))	('A241G', 'Mutation', 'rs970541687', (87, 92))	('L2HGDH', 'Gene', '79944', (31, 37))	('RCC', 'Disease', 'MESH:D002292', (65, 68))	('RCC', 'Disease', (65, 68))
114423	30108105	Recurring mutations of KDM6A (also referred to as UTX) which encodes a H3K27 demethylase have been identified in renal cancer.	('KDM6A', 'Gene', '7403', (23, 28))	('renal cancer', 'Disease', 'MESH:D007680', (113, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('UTX', 'Gene', (50, 53))	('KDM6A', 'Gene', (23, 28))	('mutations', 'Var', (10, 19))	('UTX', 'Gene', '7403', (50, 53))	('renal cancer', 'Disease', (113, 125))	('identified', 'Reg', (99, 109))	('renal cancer', 'Phenotype', 'HP:0009726', (113, 125))
114425	30108105	Immunoblotting confirmed knockdown of KDM6A at the protein level (Fig.	('KDM6A', 'Gene', (38, 43))	('KDM6A', 'Gene', '7403', (38, 43))	('knockdown', 'Var', (25, 34))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
114426	30108105	KDM6A knockdown in A498/L2HGDH cells enhanced migration and therefore phenocopied the enhanced migration of high L-2-HG cells (Fig.	('L2HGDH', 'Gene', (24, 30))	('migration', 'CPA', (46, 55))	('KDM6A', 'Gene', '7403', (0, 5))	('enhanced', 'PosReg', (86, 94))	('L2HGDH', 'Gene', '79944', (24, 30))	('A498', 'CellLine', 'CVCL:1056', (19, 23))	('knockdown', 'Var', (6, 15))	('enhanced', 'PosReg', (37, 45))	('L-2', 'Gene', (113, 116))	('L-2', 'Gene', '8496', (113, 116))	('KDM6A', 'Gene', (0, 5))
114430	30108105	Notably, EZH2 knockdown resulted in reduced cell migration as determined by transwell chamber assay (Fig.	('cell migration', 'biological_process', 'GO:0016477', ('44', '58'))	('reduced', 'NegReg', (36, 43))	('knockdown', 'Var', (14, 23))	('EZH2', 'Gene', (9, 13))	('EZH2', 'Gene', '2146', (9, 13))	('cell migration', 'CPA', (44, 58))
114438	30108105	Chromosomal losses of 14q resulting in loss of heterozygosity (LOH) has previously been shown to be associated with worsened prognosis in ccRCC patients.	('Chromosomal losses', 'Var', (0, 18))	('14q', 'Gene', (22, 25))	('RCC', 'Disease', (140, 143))	('patients', 'Species', '9606', (144, 152))	('RCC', 'Disease', 'MESH:D002292', (140, 143))	('loss of', 'NegReg', (39, 46))	('heterozygosity', 'MPA', (47, 61))
114443	30108105	These data further support copy loss as a mechanism of reduced L2HGDH expression and that the L2HGDH locus is commonly included in 14q losses present in ccRCC.	('RCC', 'Disease', 'MESH:D002292', (155, 158))	('RCC', 'Disease', (155, 158))	('reduced', 'NegReg', (55, 62))	('copy loss', 'Var', (27, 36))	('expression', 'MPA', (70, 80))	('L2HGDH', 'Gene', (63, 69))	('L2HGDH', 'Gene', (94, 100))	('L2HGDH', 'Gene', '79944', (63, 69))	('L2HGDH', 'Gene', '79944', (94, 100))
114444	30108105	Consistent with these data, LOH at the L2HGDH locus was associated with worsened survival in the TCGA data set (Fig.	('L2HGDH', 'Gene', '79944', (39, 45))	('LOH', 'Var', (28, 31))	('survival', 'MPA', (81, 89))	('L2HGDH', 'Gene', (39, 45))	('worsened', 'NegReg', (72, 80))
114451	30108105	In particular, our in vivo studies demonstrate that restoration of L2HGDH can suppress tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('L2HGDH', 'Gene', '79944', (67, 73))	('restoration', 'Var', (52, 63))	('tumor', 'Disease', (87, 92))	('suppress', 'NegReg', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('L2HGDH', 'Gene', (67, 73))
114461	30108105	reported that IDH1 knockdown via shRNA in IDH1 mutant (heterozygous) TS603 glioma cells could suppress tumor growth.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('IDH1', 'Gene', '3417', (42, 46))	('tumor', 'Disease', (103, 108))	('IDH1', 'Gene', (14, 18))	('suppress', 'NegReg', (94, 102))	('glioma', 'Disease', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('IDH1', 'Gene', (42, 46))	('mutant', 'Var', (47, 53))	('glioma', 'Disease', 'MESH:D005910', (75, 81))	('IDH1', 'Gene', '3417', (14, 18))
114463	30108105	demonstrate that non-mutated IDH1 is overexpressed in glioblastoma and that knockdown of wild type IDH1 can suppress glioma growth in vivo.	('glioblastoma', 'Disease', 'MESH:D005909', (54, 66))	('IDH1', 'Gene', (29, 33))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('IDH1', 'Gene', '3417', (29, 33))	('non-mutated', 'Var', (17, 28))	('IDH1', 'Gene', (99, 103))	('overexpressed', 'PosReg', (37, 50))	('glioma', 'Disease', (117, 123))	('IDH1', 'Gene', '3417', (99, 103))	('suppress', 'NegReg', (108, 116))	('glioblastoma', 'Disease', (54, 66))
114465	30108105	Moreover, recent transgenic models have demonstrated conflicting results on the role of mutant IDH in glioma progression.	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('mutant', 'Var', (88, 94))	('IDH', 'Gene', '3417', (95, 98))	('IDH', 'Gene', (95, 98))	('glioma', 'Disease', (102, 108))
114466	30108105	In contrast, preclinical and clinical studies, particularly in leukemia, have provided clear rationale for the use of mutant IDH enzyme inhibitors to the point that they are now approved for use in the setting of IDH mutation.	('IDH', 'Gene', '3417', (213, 216))	('leukemia', 'Disease', (63, 71))	('leukemia', 'Phenotype', 'HP:0001909', (63, 71))	('leukemia', 'Disease', 'MESH:D007938', (63, 71))	('IDH', 'Gene', (125, 128))	('mutant', 'Var', (118, 124))	('IDH', 'Gene', '3417', (125, 128))	('IDH', 'Gene', (213, 216))
114467	30108105	However, the effects are likely related to differentiation as in vitro studies in leukemia demonstrate that pharmacologic inhibition of mutant IDH may actually increase proliferation.	('leukemia', 'Disease', (82, 90))	('IDH', 'Gene', '3417', (143, 146))	('increase', 'PosReg', (160, 168))	('proliferation', 'CPA', (169, 182))	('mutant', 'Var', (136, 142))	('leukemia', 'Phenotype', 'HP:0001909', (82, 90))	('leukemia', 'Disease', 'MESH:D007938', (82, 90))	('IDH', 'Gene', (143, 146))
114469	30108105	Prior studies indicate that D-2-HG can promote mesenchymal phenotypes in breast and colon cancer cells.	('colon cancer', 'Phenotype', 'HP:0003003', (84, 96))	('promote', 'PosReg', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('D-2-HG', 'Var', (28, 34))	('breast and colon cancer', 'Disease', 'MESH:D001943', (73, 96))	('mesenchymal phenotypes', 'CPA', (47, 69))
114472	30108105	Bioinformatic analyses demonstrate that copy loss of L2HGDH is linked with 14q losses in ccRCC.	('14q', 'MPA', (75, 78))	('L2HGDH', 'Gene', '79944', (53, 59))	('RCC', 'Disease', 'MESH:D002292', (91, 94))	('RCC', 'Disease', (91, 94))	('L2HGDH', 'Gene', (53, 59))	('losses', 'NegReg', (79, 85))	('copy loss', 'Var', (40, 49))
114473	30108105	Loss of 14q is associated with worsened outcomes in RCC patients.	('RCC', 'Disease', (52, 55))	('patients', 'Species', '9606', (56, 64))	('RCC', 'Disease', 'MESH:D002292', (52, 55))	('Loss of 14q', 'Var', (0, 11))
114478	30108105	As noted before, mutations of KDM6A (also referred to as UTX), which encodes the enzyme that demethylates H3K27, have been reported in renal cancer.	('renal cancer', 'Phenotype', 'HP:0009726', (135, 147))	('renal cancer', 'Disease', 'MESH:D007680', (135, 147))	('KDM6A', 'Gene', '7403', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('renal cancer', 'Disease', (135, 147))	('UTX', 'Gene', '7403', (57, 60))	('UTX', 'Gene', (57, 60))	('mutations', 'Var', (17, 26))	('KDM6A', 'Gene', (30, 35))	('reported', 'Reg', (123, 131))
114479	30108105	Notably, multiple studies have now reported that KDMs are HIF target genes which is particularly relevant in ccRCC in which inactivating mutations of VHL and ensuing HIF stabilization is a common event.	('RCC', 'Disease', 'MESH:D002292', (111, 114))	('RCC', 'Disease', (111, 114))	('VHL', 'Gene', (150, 153))	('inactivating mutations', 'Var', (124, 146))	('VHL', 'Gene', '7428', (150, 153))
114487	30108105	Finally, our data add to the growing body of evidence that inhibition of glutamine metabolism may have therapeutic relevance in renal cancer.	('glutamine metabolism', 'MPA', (73, 93))	('renal cancer', 'Disease', (128, 140))	('inhibition', 'Var', (59, 69))	('renal cancer', 'Phenotype', 'HP:0009726', (128, 140))	('glutamine', 'Chemical', 'MESH:C578860', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('renal cancer', 'Disease', 'MESH:D007680', (128, 140))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('73', '93'))
114497	30108105	In turn, re-expression of L2HGDH in kidney cancer cells reduced in vivo tumor growth.	('re-expression', 'Var', (9, 22))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('kidney cancer', 'Disease', (36, 49))	('tumor', 'Disease', (72, 77))	('reduced', 'NegReg', (56, 63))	('L2HGDH', 'Gene', '79944', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('kidney cancer', 'Disease', 'MESH:D007680', (36, 49))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('kidney cancer', 'Phenotype', 'HP:0009726', (36, 49))	('L2HGDH', 'Gene', (26, 32))
114499	30108105	Additionally, our studies indicate that alterations of the L-2-HG/L2HGDH are associated with patient outcomes and tumor progression.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('L-2', 'Gene', (59, 62))	('L-2', 'Gene', '8496', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('L2HGDH', 'Gene', (66, 72))	('alterations', 'Var', (40, 51))	('tumor', 'Disease', (114, 119))	('patient', 'Species', '9606', (93, 100))	('patient outcomes', 'CPA', (93, 109))	('L2HGDH', 'Gene', '79944', (66, 72))	('associated', 'Reg', (77, 87))
114504	32492043	We identified that TEMS reduced cellular viability in all renal cell lines, with increased sensitivity in the presence of an autophagy inhibitor.	('reduced', 'NegReg', (24, 31))	('TEMS', 'Chemical', 'MESH:C401859', (19, 23))	('TEMS', 'Var', (19, 23))	('autophagy', 'biological_process', 'GO:0016236', ('125', '134'))	('cellular viability', 'CPA', (32, 50))	('autophagy', 'biological_process', 'GO:0006914', ('125', '134'))
114508	32492043	Inhibiting MAPK partially antagonized LPA-induced LD changes.	('LPA', 'Chemical', 'MESH:C032881', (38, 41))	('MAPK', 'molecular_function', 'GO:0004707', ('11', '15'))	('Inhibiting', 'Var', (0, 10))	('antagonized', 'NegReg', (26, 37))	('MAPK', 'Protein', (11, 15))
114511	32492043	Contributing factors to disease pathogenesis include smoking, obesity, as well as mutations in Von Hippel-Lindau (VHL).	('Von Hippel-Lindau', 'Gene', '7428', (95, 112))	('VHL', 'Gene', '7428', (114, 117))	('obesity', 'Phenotype', 'HP:0001513', (62, 69))	('Von Hippel-Lindau', 'Gene', (95, 112))	('mutations', 'Var', (82, 91))	('obesity', 'Disease', 'MESH:D009765', (62, 69))	('pathogenesis', 'biological_process', 'GO:0009405', ('32', '44'))	('obesity', 'Disease', (62, 69))	('VHL', 'Gene', (114, 117))
114528	32492043	Finally, we investigated whether the presence of LPA could hinder the effect of TEMS treatment in the ccRCC cell lines in terms of lipid droplet abundance and AKT/mTOR signaling.	('LPA', 'Chemical', 'MESH:C032881', (49, 52))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('lipid droplet abundance', 'MPA', (131, 154))	('TEMS', 'Chemical', 'MESH:C401859', (80, 84))	('hinder', 'NegReg', (59, 65))	('presence', 'Var', (37, 45))	('lipid', 'Chemical', 'MESH:D008055', (131, 136))	('AKT/mTOR signaling', 'Pathway', (159, 177))	('lipid droplet', 'cellular_component', 'GO:0005811', ('131', '144'))	('signaling', 'biological_process', 'GO:0023052', ('168', '177'))	('RCC', 'Disease', (104, 107))
114541	32492043	After overnight adherence, cells were transfected with the following siRNA using Dharmafect I (#NC1308404, Fisher Scientific, Pittsburgh, PA) according to previously published methods: ribosomal protein S6 (RPS6) siRNA (#L-003024-00-0005), ribosomal protein S6 kinase B1 (p70S6K1) siRNA (#L-003616-00-0005), or non-targeting ON-TARGETplus (D-001810-10-20) siRNA (Dharmacon, Lafayette, CO).	('RPS6', 'Gene', '6194', (207, 211))	('ribosomal protein S6', 'Gene', '6194', (240, 260))	('ribosomal protein S6', 'Gene', '6194', (185, 205))	('PA', 'Chemical', 'MESH:D011478', (138, 140))	('p70S6K', 'Gene', (272, 278))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('185', '202'))	('RPS6', 'Gene', (207, 211))	('protein', 'cellular_component', 'GO:0003675', ('250', '257'))	('p70S6K', 'Gene', '6198', (272, 278))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('240', '257'))	('ribosomal protein S6', 'Gene', (185, 205))	('#L-003616-00-0005', 'Var', (288, 305))	('ribosomal protein S6 kinase B1', 'Gene', '6198', (240, 270))	('D-001810-10-20', 'Var', (340, 354))	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))	('ribosomal protein S6 kinase B1', 'Gene', (240, 270))
114544	32492043	The samples were then run on 10% SDS-PAGE gels and analyzed by western blotting using primary antibodies at the following dilutions: (1) Beclin-1 rabbit polyclonal (#3738, 1:1000), DRP1 rabbit monoclonal (#8570, 1:1000), hVPS34 rabbit monoclonal (#3358, 1:1000), LC3B rabbit polyclonal (#2775, 1:1000), p-AKT (Ser-473) rabbit monoclonal (#4060, 1:1000), p-GSK3 (Ser-21/Ser-9) rabbit polyclonal (#9331, 1:1000), p-S6 ribosomal protein (Ser-235/236) rabbit monoclonal (#4858, 1:1000), Pan-Actin rabbit polyclonal (#4968, 1:500), PARP rabbit polyclonal (#9542, 1:1000), p-DRP1 (Ser-616) rabbit monoclonal (#4494, 1:1000), p-p42/44 MAPK (Thr-202/Tyr-204) rabbit polyclonal (#9101, 1:750), Pan-AKT rabbit monoclonal (#4685, 1:1000), p42/44 MAPK rabbit monoclonal (#4695, 1:1000), p70S6K rabbit monoclonal (#2708, 1:1000), and S6 rabbit monoclonal (#2217, 1:1000) which were obtained from Cell Signaling Technology (Danvers, MA); (2) p62 mouse monoclonal (#610832, 1:1000) was obtained from BD Biosciences (San Jose, CA, USA); (3) Perilipin mouse monoclonal (#SC-390169, 1:500), TOM20 rabbit polyclonal (#SC-11415, 1:7500), TOM40 mouse monoclonal (#SC-365467, 1:1000), and TOM70 mouse monoclonal (#SC-390545, 1:1000) were obtained from Santa Cruz Biotechnology (Dallas, TX, USA); and (4) ATG7 rabbit polyclonal (#PM039, 1:1000) from MBL International Corporation (Woburn, MA, USA).	('MAPK', 'molecular_function', 'GO:0004707', ('735', '739'))	('p70S6K', 'Gene', '6198', (775, 781))	('Ser', 'cellular_component', 'GO:0005790', ('362', '365'))	('Ser', 'Chemical', 'MESH:D012694', (362, 365))	('TOM40', 'Gene', '10452', (1118, 1123))	('p62', 'Gene', '8878', (928, 931))	('MAPK', 'molecular_function', 'GO:0004707', ('628', '632'))	('p62', 'Gene', (928, 931))	('DRP1', 'Gene', '10059', (569, 573))	('Perilipin', 'Gene', '5346', (1025, 1034))	('Signaling', 'biological_process', 'GO:0023052', ('888', '897'))	('Thr-202/Tyr', 'Mutation', 'p.T202Y', (634, 645))	('TOM20', 'Gene', '9804', (1073, 1078))	('MBL', 'Gene', (1327, 1330))	('p42/44 MAPK', 'Gene', '5594;5595', (728, 739))	('hVPS34', 'Gene', (221, 227))	('Perilipin', 'Gene', (1025, 1034))	('TOM70', 'Gene', (1167, 1172))	('Beclin-1', 'Gene', '8678', (137, 145))	('PA', 'Chemical', 'MESH:D011478', (37, 39))	('#SC-390169', 'Var', (1053, 1063))	('DRP1', 'Gene', (181, 185))	('TOM40', 'Gene', (1118, 1123))	('ATG7', 'Gene', '10533', (1282, 1286))	('Ser', 'Chemical', 'MESH:D012694', (575, 578))	('PARP', 'Gene', '142', (527, 531))	('Ser', 'Chemical', 'MESH:D012694', (369, 372))	('LC3B', 'Gene', (263, 267))	('Beclin-1', 'Gene', (137, 145))	('p42/44 MAPK', 'Gene', (728, 739))	('LC3B', 'Gene', '81631', (263, 267))	('PARP', 'Gene', (527, 531))	('p70S6K', 'Gene', (775, 781))	('MBL', 'Gene', '50639', (1327, 1330))	('TOM70', 'Gene', '9868', (1167, 1172))	('DRP1', 'Gene', (569, 573))	('PA', 'Chemical', 'MESH:D011478', (527, 529))	('p42/44 MAPK', 'Gene', '5594;5595', (621, 632))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('416', '433'))	('Ser', 'cellular_component', 'GO:0005790', ('310', '313'))	('hVPS34', 'Gene', '5289', (221, 227))	('ATG7', 'Gene', (1282, 1286))	('GSK', 'molecular_function', 'GO:0050321', ('356', '359'))	('protein', 'cellular_component', 'GO:0003675', ('426', '433'))	('DRP1', 'Gene', '10059', (181, 185))	('Ser', 'Chemical', 'MESH:D012694', (310, 313))	('Ser', 'cellular_component', 'GO:0005790', ('369', '372'))	('Ser', 'cellular_component', 'GO:0005790', ('435', '438'))	('Ser', 'cellular_component', 'GO:0005790', ('575', '578'))	('TOM20', 'Gene', (1073, 1078))	('Ser-21/Ser', 'Mutation', 'rs1010038952', (362, 372))	('Ser', 'Chemical', 'MESH:D012694', (435, 438))	('rat', 'Species', '10116', (1350, 1353))	('p42/44 MAPK', 'Gene', (621, 632))
114546	32492043	Real-time PCR utilized the TaqMan RNA-to-CT One-Step Kit (#4392938, ThermoFisher Scientific, Waltham, MA) and the following FAM-labelled probes and primers: (1) Phospholipid Phosphatase 1 (PLPP1), Hs00170356_m1; (2) Diacylglycerol O-acyltransferase 2 (DGAT2), Hs01045913_m1; (3) Perilipin 1 (PLIN1), Hs00160173_m1; (4) Cell death-inducing DFFA-like effector c (CIDEC), Hs00535724_gH; (5) Adipose Triglyceride Lipase (ATGL/PNPLA2) Hs00386101_m1; and (6) Autotaxin (ATX/ENPP2), Hs00905117_m1.	('Perilipin 1', 'Gene', '5346', (279, 290))	('CIDEC', 'Gene', '63924', (361, 366))	('ATX', 'Gene', (464, 467))	('Hs00905117_m1', 'Var', (476, 489))	('Cell death-inducing DFFA-like effector c', 'Gene', (319, 359))	('Cell death', 'biological_process', 'GO:0008219', ('319', '329'))	('Phospholipid Phosphatase 1', 'Gene', (161, 187))	('ATX', 'Gene', '5168', (464, 467))	('Diacylglycerol O-acyltransferase 2', 'Gene', (216, 250))	('ENPP2', 'Gene', '5168', (468, 473))	('Diacylglycerol O-acyltransferase 2', 'Gene', '84649', (216, 250))	('Perilipin 1', 'Gene', (279, 290))	('Autotaxin', 'Gene', '5168', (453, 462))	('ATGL', 'Gene', (417, 421))	('RNA', 'cellular_component', 'GO:0005562', ('34', '37'))	('Adipose Triglyceride Lipase', 'Gene', '57104', (388, 415))	('Autotaxin', 'Gene', (453, 462))	('ENPP2', 'Gene', (468, 473))	('PLIN1', 'Gene', '5346', (292, 297))	('Kit', 'Gene', (53, 56))	('Hs00535724_gH', 'Var', (369, 382))	('Kit', 'Gene', '3815', (53, 56))	('PLIN1', 'Gene', (292, 297))	('PNPLA2', 'Gene', '57104', (422, 428))	('Phosphatase', 'molecular_function', 'GO:0016791', ('174', '185'))	('DGAT2', 'Gene', (252, 257))	('Phospholipid Phosphatase 1', 'Gene', '8611', (161, 187))	('PLPP1', 'Gene', '8611', (189, 194))	('ATGL', 'Gene', '57104', (417, 421))	('Cell death-inducing DFFA-like effector c', 'Gene', '63924', (319, 359))	('PNPLA2', 'Gene', (422, 428))	('PLPP1', 'Gene', (189, 194))	('DGAT2', 'Gene', '84649', (252, 257))	('CIDEC', 'Gene', (361, 366))	('Adipose Triglyceride Lipase', 'Gene', (388, 415))
114558	32492043	It is well established that genomic aberrations are characteristic of numerous cancer types and such alterations provide insight into patient survival as well as response to chemotherapeutic regimens.	('genomic aberrations', 'Var', (28, 47))	('rat', 'Species', '10116', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('rat', 'Species', '10116', (40, 43))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('patient', 'Species', '9606', (134, 141))
114566	32492043	As presented in Fig 1B, the activation status of phospho-S6 was elevated in 769-P and 786-O cells relative to A-498 cells whereas phospho-AKT was markedly elevated in 786-O and A-498 cells relative to 769-P cells.	('elevated', 'PosReg', (64, 72))	('activation', 'MPA', (28, 38))	('phospho-AKT', 'MPA', (130, 141))	('A-498', 'CellLine', 'CVCL:1056', (110, 115))	('elevated', 'PosReg', (155, 163))	('phospho-S6', 'Var', (49, 59))	('A-498', 'CellLine', 'CVCL:1056', (177, 182))
114580	32492043	Specifically, the cell numbers of HK-2, 786-O, 769-P, and A-498 were reduced by 42.6%/70.5%, 26.9%/67.7%, 16.8%/55.5%, and 19.3%/53.4%, respectively on day 1/day 3 of treatment, respectively, although this was not accompanied by alterations in PARP cleavage (a marker of caspase-dependent apoptosis) (Fig 2A).	('A-498', 'Var', (58, 63))	('cell numbers', 'CPA', (18, 30))	('reduced', 'NegReg', (69, 76))	('PARP', 'Gene', (244, 248))	('769-P', 'Var', (47, 52))	('A-498', 'CellLine', 'CVCL:1056', (58, 63))	('HK-2', 'molecular_function', 'GO:0008256', ('34', '38'))	('apoptosis', 'biological_process', 'GO:0006915', ('289', '298'))	('rat', 'Species', '10116', (233, 236))	('apoptosis', 'biological_process', 'GO:0097194', ('289', '298'))	('PARP', 'Gene', '142', (244, 248))	('HK-2', 'Var', (34, 38))
114587	32492043	Using the Amplex Red Assay, we noted that cholesterol was significantly higher in the malignant ccRCC cells (769-P, 786-O, and A-498) relative to the normal immortalized kidney HK-2 cell line (Fig 3C).	('A-498', 'Var', (127, 132))	('HK-2', 'molecular_function', 'GO:0008256', ('177', '181'))	('A-498', 'CellLine', 'CVCL:1056', (127, 132))	('cholesterol', 'MPA', (42, 53))	('769-P', 'Var', (109, 114))	('RCC', 'Disease', (98, 101))	('cholesterol', 'Chemical', 'MESH:D002784', (42, 53))	('higher', 'PosReg', (72, 78))	('RCC', 'Disease', 'MESH:C538614', (98, 101))
114597	32492043	Further, marked alterations in the lipidated form of LC3B was noted in the malignant renal cell lines and the total protein levels of the DNA repair mediator PARP were reduced upon TEMS treatment suggesting that mTORC1 inhibition may deregulate autophagy as well as downregulate the DNA repair mechanism.	('mTORC1', 'Gene', '382056', (212, 218))	('PARP', 'Gene', (158, 162))	('LC3B', 'Gene', '81631', (53, 57))	('autophagy', 'CPA', (245, 254))	('DNA', 'cellular_component', 'GO:0005574', ('283', '286'))	('deregulate', 'NegReg', (234, 244))	('PARP', 'Gene', '142', (158, 162))	('reduced', 'NegReg', (168, 175))	('downregulate', 'NegReg', (266, 278))	('autophagy', 'biological_process', 'GO:0006914', ('245', '254'))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('lipid', 'Chemical', 'MESH:D008055', (35, 40))	('protein levels', 'MPA', (116, 130))	('DNA repair', 'biological_process', 'GO:0006281', ('138', '148'))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('mTORC1', 'cellular_component', 'GO:0031931', ('212', '218'))	('rat', 'Species', '10116', (20, 23))	('DNA repair mechanism', 'CPA', (283, 303))	('inhibition', 'Var', (219, 229))	('alterations', 'Reg', (16, 27))	('DNA repair', 'biological_process', 'GO:0006281', ('283', '293'))	('mTORC1', 'Gene', (212, 218))	('autophagy', 'biological_process', 'GO:0016236', ('245', '254'))	('LC3B', 'Gene', (53, 57))	('TEMS', 'Chemical', 'MESH:C401859', (181, 185))
114602	32492043	As shown in Fig 4A, oleic acid treatment increased lipid droplet size in all four cell lines with statistically significant alterations in HK-2, 769-P, and A-498 cells; in 769-P cells, the number of lipid droplets also significantly increased.	('A-498', 'CellLine', 'CVCL:1056', (156, 161))	('increased', 'PosReg', (41, 50))	('alterations', 'Reg', (124, 135))	('769-P cells', 'Var', (172, 183))	('number of lipid droplets', 'MPA', (189, 213))	('lipid', 'Chemical', 'MESH:D008055', (199, 204))	('lipid', 'Chemical', 'MESH:D008055', (51, 56))	('HK-2', 'molecular_function', 'GO:0008256', ('139', '143'))	('increased lipid', 'Phenotype', 'HP:0003077', (41, 56))	('oleic acid', 'Chemical', 'MESH:D019301', (20, 30))	('lipid droplet', 'cellular_component', 'GO:0005811', ('51', '64'))	('lipid droplet size', 'MPA', (51, 69))	('rat', 'Species', '10116', (128, 131))	('increased', 'PosReg', (233, 242))	('increased lipid droplet', 'Phenotype', 'HP:0012240', (41, 64))
114608	32492043	Indeed, induction of autophagy with mTORC1 inhibition has previously been reported, and thus may provide a mechanism underlying low patient response rates in clinical trials to mTOR inhibitors.	('rat', 'Species', '10116', (149, 152))	('autophagy', 'biological_process', 'GO:0006914', ('21', '30'))	('autophagy', 'CPA', (21, 30))	('inhibition', 'Var', (43, 53))	('mTORC1', 'cellular_component', 'GO:0031931', ('36', '42'))	('mTORC1', 'Gene', (36, 42))	('induction', 'Reg', (8, 17))	('autophagy', 'biological_process', 'GO:0016236', ('21', '30'))	('patient', 'Species', '9606', (132, 139))	('mTORC1', 'Gene', '382056', (36, 42))
114623	32492043	As shown in Fig 6B, we observed that the reduction in protein expression in phospho-S6, TOM20, TOM70, LC3B-II, and p62 under both culture conditions (consistently noted in SFM) were increased nearly to baseline control levels in the presence of LPA with TEMS.	('phospho-S6', 'Var', (76, 86))	('TEMS', 'Chemical', 'MESH:C401859', (254, 258))	('TOM20', 'Gene', '9804', (88, 93))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('TOM70', 'Gene', (95, 100))	('LPA', 'Chemical', 'MESH:C032881', (245, 248))	('LC3B', 'Gene', '81631', (102, 106))	('TOM70', 'Gene', '9868', (95, 100))	('p62', 'Gene', '8878', (115, 118))	('TOM20', 'Gene', (88, 93))	('p62', 'Gene', (115, 118))	('protein expression', 'MPA', (54, 72))	('LC3B', 'Gene', (102, 106))	('reduction', 'NegReg', (41, 50))
114642	32492043	These findings suggest that LPA can enhance the tumor-promoting effect of kidney cells in vitro.	('LPA', 'Chemical', 'MESH:C032881', (28, 31))	('tumor', 'Disease', (48, 53))	('LPA', 'Var', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('enhance', 'PosReg', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
114645	32492043	We also analyzed LD abundance using LipidTOX (Fig 8C and 8D) and noted increased numbers of finer LDs associated following MAPK inhibition; however, the larger LDs induced by LPA alone were reduced following co-treatment with TEMS.	('MAPK', 'Gene', (123, 127))	('MAPK', 'molecular_function', 'GO:0004707', ('123', '127'))	('LipidTOX', 'Chemical', '-', (36, 44))	('reduced', 'NegReg', (190, 197))	('inhibition', 'Var', (128, 138))	('LPA', 'Chemical', 'MESH:C032881', (175, 178))	('TEMS', 'Chemical', 'MESH:C401859', (226, 230))
114648	32492043	Kidney tumors harbor a myriad of genetic alterations, including mutation or loss of the VHL gene, a tumor suppressor which is a common occurrence in >90% of clear cell kidney cancer cases.	('tumor', 'Disease', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('VHL', 'Gene', '7428', (88, 91))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('100', '116'))	('Kidney tumors', 'Disease', (0, 13))	('loss', 'NegReg', (76, 80))	('Kidney tumors', 'Phenotype', 'HP:0009726', (0, 13))	('clear cell kidney cancer', 'Disease', 'MESH:D007680', (157, 181))	('clear cell kidney cancer', 'Disease', (157, 181))	('tumor suppressor', 'biological_process', 'GO:0051726', ('100', '116'))	('rat', 'Species', '10116', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutation', 'Var', (64, 72))	('clear cell kidney cancer', 'Phenotype', 'HP:0006770', (157, 181))	('kidney cancer', 'Phenotype', 'HP:0009726', (168, 181))	('tumor', 'Disease', (7, 12))	('VHL', 'Gene', (88, 91))	('Kidney tumors', 'Disease', 'MESH:D007680', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (7, 12))
114649	32492043	The ccRCC cell lines used for this study (769-P, 786-O and A-498) are associated with aberrations in VHL (TCGA data: Fig 1A).	('VHL', 'Gene', (101, 104))	('aberrations', 'Var', (86, 97))	('VHL', 'Gene', '7428', (101, 104))	('A-498', 'CellLine', 'CVCL:1056', (59, 64))	('associated', 'Reg', (70, 80))	('769-P', 'Var', (42, 47))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('A-498', 'Var', (59, 64))	('RCC', 'Disease', (6, 9))	('rat', 'Species', '10116', (90, 93))
114653	32492043	We now have identified that the mTOR inhibitor TEMS alters LD quality in both RCC and normal immortalized HK-2 cells, possibly to enhance lipid mobilization, which antagonizes cellular sensitivity to the treatment (Figs 2B and 3A).	('lipid', 'Chemical', 'MESH:D008055', (138, 143))	('HK-2', 'molecular_function', 'GO:0008256', ('106', '110'))	('RCC', 'Disease', (78, 81))	('alters', 'Reg', (52, 58))	('LD quality', 'MPA', (59, 69))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('TEMS', 'Chemical', 'MESH:C401859', (47, 51))	('TEMS', 'Var', (47, 51))	('enhance', 'PosReg', (130, 137))	('lipid mobilization', 'MPA', (138, 156))
114659	32492043	Furthermore, there is another report that describes that inhibitors of mTOR can lead to hyperfused and branched mitochondria, for which the underlying mechanism is thought to involve reduced expression of the mitochondrial fission process 1 (MTFP1) and DRP1 mitochondrial recruitment which may then regulate cellular survival.	('inhibitors', 'Var', (57, 67))	('mitochondrial fission process 1', 'Gene', '51537', (209, 240))	('MTFP1', 'Gene', '51537', (242, 247))	('mitochondria', 'cellular_component', 'GO:0005739', ('112', '124'))	('hyperfused', 'CPA', (88, 98))	('mitochondrial fission process 1', 'Gene', (209, 240))	('DRP1', 'Gene', '10059', (253, 257))	('DRP1', 'Gene', (253, 257))	('reduced', 'NegReg', (183, 190))	('regulate', 'Reg', (299, 307))	('recruitment', 'PosReg', (272, 283))	('mTOR', 'Gene', (71, 75))	('cellular survival', 'CPA', (308, 325))	('MTFP1', 'Gene', (242, 247))	('mitochondrial fission', 'biological_process', 'GO:0000266', ('209', '230'))	('expression', 'MPA', (191, 201))	('mitochondrial', 'MPA', (258, 271))
114667	32492043	Indeed, we noted that LPA could antagonize the cellular responsiveness of malignant renal cell lines to TEMS, in terms of LDs and mitochondrial remodelling.	('cellular responsiveness', 'MPA', (47, 70))	('LDs', 'MPA', (122, 125))	('TEMS', 'Chemical', 'MESH:C401859', (104, 108))	('antagonize', 'NegReg', (32, 42))	('LPA', 'Chemical', 'MESH:C032881', (22, 25))	('mitochondrial remodelling', 'CPA', (130, 155))	('LPA', 'Var', (22, 25))
114683	32492043	Herein, we identify that LPA can antagonize the cellular response of renal cancer cells to TEMS, specifically altering lipid droplets and mitochondrial networks.	('lipid', 'Chemical', 'MESH:D008055', (119, 124))	('LPA', 'Var', (25, 28))	('mitochondrial networks', 'MPA', (138, 160))	('renal cancer', 'Disease', (69, 81))	('antagonize', 'NegReg', (33, 43))	('altering', 'Reg', (110, 118))	('renal cancer', 'Disease', 'MESH:D007680', (69, 81))	('renal cancer', 'Phenotype', 'HP:0009726', (69, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('TEMS', 'Chemical', 'MESH:C401859', (91, 95))	('lipid droplets', 'MPA', (119, 133))	('LPA', 'Chemical', 'MESH:C032881', (25, 28))
114684	32492043	Moreover, in normal immortalized renal cells, we discovered that LPA induced LD formation in a MAPK-dependent manner, which was accompanied by changes in DGAT2 and cellular viability.	('LPA', 'Chemical', 'MESH:C032881', (65, 68))	('LD formation', 'CPA', (77, 89))	('DGAT2', 'Gene', (154, 159))	('changes', 'Reg', (143, 150))	('MAPK', 'molecular_function', 'GO:0004707', ('95', '99'))	('LPA', 'Var', (65, 68))	('formation', 'biological_process', 'GO:0009058', ('80', '89'))	('DGAT2', 'Gene', '84649', (154, 159))
114725	30883740	Increased expression of EMT markers such as vimentin, Snail/Slug and N-cadherin, and the CSC marker CD105 was found by IHC in the spheres derived from Caki-1 compared to the corresponding adherent cells, whereas a decreased expression of E-cadherin was observed (Figure 1E).	('CD10', 'Gene', (100, 104))	('Snail', 'Gene', (54, 59))	('Caki-1', 'Var', (151, 157))	('cadherin', 'molecular_function', 'GO:0008014', ('71', '79'))	('N-cadherin', 'Gene', (69, 79))	('N-cadherin', 'Gene', '1000', (69, 79))	('cadherin', 'molecular_function', 'GO:0008014', ('240', '248'))	('EMT', 'biological_process', 'GO:0001837', ('24', '27'))	('expression', 'MPA', (10, 20))	('vimentin', 'cellular_component', 'GO:0045098', ('44', '52'))	('Slug', 'Gene', (60, 64))	('Snail', 'Gene', '6615', (54, 59))	('EMT', 'Gene', (24, 27))	('EMT', 'Gene', '3702', (24, 27))	('Increased', 'PosReg', (0, 9))	('CD10', 'Gene', '4311', (100, 104))	('E-cadherin', 'Gene', (238, 248))	('E-cadherin', 'Gene', '999', (238, 248))	('vimentin', 'cellular_component', 'GO:0045099', ('44', '52'))	('vimentin', 'Gene', '7431', (44, 52))	('vimentin', 'Gene', (44, 52))	('Slug', 'Gene', '6591', (60, 64))
114726	30883740	Similarly, 769P, A498, and ACHN showed EMT (data not shown).	('EMT', 'biological_process', 'GO:0001837', ('39', '42'))	('ACHN', 'Gene', '55323', (27, 31))	('A498', 'Var', (17, 21))	('EMT', 'Gene', (39, 42))	('ACHN', 'Gene', (27, 31))	('EMT', 'Gene', '3702', (39, 42))
114728	30883740	Similarly, 769P, A498, and ACHN showed revertible EMT phenotype (data not shown).	('EMT', 'biological_process', 'GO:0001837', ('50', '53'))	('ACHN', 'Gene', '55323', (27, 31))	('A498', 'Var', (17, 21))	('EMT', 'Gene', (50, 53))	('ACHN', 'Gene', (27, 31))	('EMT', 'Gene', '3702', (50, 53))
114732	30883740	A498 and 769P did not show HIF1alpha expression due to homozygous deletion of HIF1alpha 30, instead they did express high levels of HIF2alpha (see supplementary material, Figure S1D).	('HIF1alpha', 'Gene', '3091', (78, 87))	('HIF2alpha', 'Gene', (132, 141))	('HIF1alpha', 'Gene', (27, 36))	('HIF1alpha', 'Gene', '3091', (27, 36))	('HIF1alpha', 'Gene', (78, 87))	('HIF2alpha', 'Gene', '2034', (132, 141))	('deletion', 'Var', (66, 74))
114771	30883740	Mice injected with Caki-1 or 769P sphere-derived cells developed micrometastases in the lungs and liver, whereas mice injected with parental cells did not show micrometastasis (Figure 4F and see supplementary material, Figure S5D,E).	('micrometastases in the lungs', 'CPA', (65, 93))	('Caki-1', 'Var', (19, 25))	('mice', 'Species', '10090', (113, 117))	('Mice', 'Species', '10090', (0, 4))
114784	30883740	In particular, the median OS for ccRCC patients with high IL-8 levels was 48 months, whereas patients with low IL-8 levels showed a median OS of 84 months (Figure 5D).	('ccRCC', 'Disease', (33, 38))	('high', 'Var', (53, 57))	('IL-8', 'molecular_function', 'GO:0005153', ('111', '115'))	('patients', 'Species', '9606', (39, 47))	('IL-8', 'molecular_function', 'GO:0005153', ('58', '62'))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('patients', 'Species', '9606', (93, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))
114796	30883740	This is in line with previous studies in HCC, breast and pancreatic cancers where anti-IL-8/CXCR1 impaired CSC features 34, 35, 41.	('anti-IL-8/CXCR1', 'Var', (82, 97))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('IL-8', 'molecular_function', 'GO:0005153', ('87', '91'))	('HCC', 'Disease', (41, 44))	('impaired', 'NegReg', (98, 106))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (57, 75))	('breast and pancreatic cancers', 'Disease', 'MESH:D010190', (46, 75))	('CSC features 34', 'MPA', (107, 122))
114822	29843367	The combination of low CD151 expression and high RNASEH2A expression resulted in impaired proliferation in four kidney cancer cell lines, suggesting potential synthetic dosage lethality (SDL) interactions between the two genes.	('high', 'Var', (44, 48))	('RNASEH2A', 'Gene', (49, 57))	('proliferation', 'CPA', (90, 103))	('low', 'NegReg', (19, 22))	('kidney cancer', 'Disease', (112, 125))	('CD151', 'Gene', (23, 28))	('RNASEH2A', 'Gene', '10535', (49, 57))	('impaired', 'NegReg', (81, 89))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('kidney cancer', 'Phenotype', 'HP:0009726', (112, 125))	('kidney cancer', 'Disease', 'MESH:D007680', (112, 125))	('expression', 'MPA', (29, 39))	('si', 'Chemical', 'MESH:D012825', (35, 37))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
114826	29843367	Genomic instability facilitates tumor initiation and progression.	('progression', 'CPA', (53, 64))	('facilitates', 'PosReg', (20, 31))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('Genomic instability', 'Var', (0, 19))	('tumor', 'Disease', (32, 37))
114828	29843367	Loss-of-function mutations in the nucleotide degrading enzymes sterile alpha motif (SAM) domain and HD domain-containing protein 1 (SAMHD1), Three prime repair exonuclease 1 (TREX1), and ribonuclease H2 subunits A, B, and C (RNASEH2A, RNASEH2B, RNASEH2C) in human germline mainly result in a hyper-inflammatory Aicardi-Goutieres syndrome (AGS), and in the development of malignancy in AGS patient is rare.	('HD', 'Disease', 'MESH:D006816', (100, 102))	('AGS', 'Disease', (339, 342))	('hyper-inflammatory Aicardi-Goutieres syndrome', 'Disease', 'MESH:C535607', (292, 337))	('SAMHD1', 'Gene', '25939', (132, 138))	('patient', 'Species', '9606', (389, 396))	('RNASEH2A', 'Gene', '10535', (225, 233))	('SAMHD1', 'Gene', (132, 138))	('mutations', 'Var', (17, 26))	('malignancy', 'Disease', 'MESH:D009369', (371, 381))	('result in', 'Reg', (280, 289))	('RNASEH2C', 'Gene', (245, 253))	('RNASEH2B', 'Gene', '79621', (235, 243))	('AGS', 'Disease', (385, 388))	('hyper-inflammatory Aicardi-Goutieres syndrome', 'Disease', (292, 337))	('AGS', 'Disease', 'MESH:C535607', (339, 342))	('TREX1', 'Gene', '11277', (175, 180))	('RNASEH2C', 'Gene', '84153', (245, 253))	('RNASEH2B', 'Gene', (235, 243))	('malignancy', 'Disease', (371, 381))	('Three prime repair exonuclease 1', 'Gene', (141, 173))	('HD', 'Disease', 'MESH:D006816', (135, 137))	('RNASEH2A', 'Gene', (225, 233))	('TREX1', 'Gene', (175, 180))	('AGS', 'Disease', 'MESH:C535607', (385, 388))	('Three prime repair exonuclease 1', 'Gene', '11277', (141, 173))	('Loss-of-function', 'NegReg', (0, 16))	('human', 'Species', '9606', (258, 263))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))
114838	29843367	It has been reported that certain genes have synthetic dosage lethality (SDL) interactions with genes that are frequently overexpressed in tumors and that inhibition of the SDL partners can decrease cancer proliferation.	('synthetic', 'MPA', (45, 54))	('decrease', 'NegReg', (190, 198))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Disease', (139, 145))	('cancer', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('inhibition', 'Var', (155, 165))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('genes', 'Protein', (96, 101))	('interactions', 'Interaction', (78, 90))
114847	29843367	In search of an alternative pathway that promotes tumor proliferation, we performed gene correlation studies in five kidney cancer patient samples with high RNASEH2A expression, low CDK1 expression, and bad clinical outcomes (death).	('death', 'Disease', 'MESH:D003643', (226, 231))	('si', 'Chemical', 'MESH:D012825', (193, 195))	('RNASEH2A', 'Gene', (157, 165))	('tumor', 'Disease', (50, 55))	('death', 'Disease', (226, 231))	('kidney cancer', 'Disease', 'MESH:D007680', (117, 130))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('si', 'Chemical', 'MESH:D012825', (172, 174))	('expression', 'MPA', (166, 176))	('RNASEH2A', 'Gene', '10535', (157, 165))	('low', 'NegReg', (178, 181))	('kidney cancer', 'Phenotype', 'HP:0009726', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('kidney cancer', 'Disease', (117, 130))	('CDK1', 'Gene', '983', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('patient', 'Species', '9606', (131, 138))	('expression', 'MPA', (187, 197))	('CDK1', 'Gene', (182, 186))	('CDK', 'molecular_function', 'GO:0004693', ('182', '185'))	('high', 'Var', (152, 156))
114851	29843367	To study the interactions among RNASEH2A, CDK1, and CD151 and their impact on tumor proliferation, we performed si-RNA knockdown studies on three ccRCC cell lines (786O, A704, KMRC3, all with VHL mutation) and one kidney urothelial carcinoma cell line (BFTC909, without VHL mutation).	('RCC', 'Disease', (148, 151))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('VHL', 'Disease', (192, 195))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('CDK1', 'Gene', '983', (42, 46))	('RNASEH2A', 'Gene', '10535', (32, 40))	('CDK1', 'Gene', (42, 46))	('BFTC909', 'CellLine', 'CVCL:1084', (253, 260))	('VHL', 'Disease', (270, 273))	('kidney urothelial carcinoma', 'Disease', 'MESH:D007674', (214, 241))	('kidney urothelial carcinoma', 'Phenotype', 'HP:0030409', (214, 241))	('kidney urothelial carcinoma', 'Disease', (214, 241))	('tumor', 'Disease', (78, 83))	('RNA', 'cellular_component', 'GO:0005562', ('115', '118'))	('VHL', 'Disease', 'MESH:D006623', (192, 195))	('CDK', 'molecular_function', 'GO:0004693', ('42', '45'))	('mutation', 'Var', (196, 204))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('RNASEH2A', 'Gene', (32, 40))	('one kidney', 'Phenotype', 'HP:0000122', (210, 220))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('VHL', 'Disease', 'MESH:D006623', (270, 273))
114852	29843367	As shown in Figure 3A, CDK1 knockdown resulted in the upregulation of RNASEH2A and CD151 in all cell lines, however it did not significantly impair tumor proliferation (except for a mild effect on A704).	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('CDK1', 'Gene', (23, 27))	('CDK1', 'Gene', '983', (23, 27))	('RNASEH2A', 'Gene', (70, 78))	('tumor', 'Disease', (148, 153))	('upregulation', 'PosReg', (54, 66))	('RNASEH2A', 'Gene', '10535', (70, 78))	('si', 'Chemical', 'MESH:D012825', (127, 129))	('knockdown', 'Var', (28, 37))	('CDK', 'molecular_function', 'GO:0004693', ('23', '26'))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('CD151', 'Gene', (83, 88))
114853	29843367	Interestingly, in BFTC909, CDK1 could not be knocked down after a 96-hour si-CDK1 transfection, and the tumor survival rate even increased.	('CDK', 'molecular_function', 'GO:0004693', ('77', '80'))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('transfection', 'Var', (82, 94))	('CDK1', 'Gene', (77, 81))	('CDK1', 'Gene', '983', (77, 81))	('tumor', 'Disease', (104, 109))	('increased', 'PosReg', (129, 138))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('CDK1', 'Gene', '983', (27, 31))	('CDK1', 'Gene', (27, 31))	('BFTC909', 'CellLine', 'CVCL:1084', (18, 25))	('CDK', 'molecular_function', 'GO:0004693', ('27', '30'))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
114854	29843367	Furthermore, RNASEH2A knockdown resulted in CD151 upregulation and decreased proliferation in all ccRCC cell lines.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('RNASEH2A', 'Gene', '10535', (13, 21))	('upregulation', 'PosReg', (50, 62))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('knockdown', 'Var', (22, 31))	('CD151', 'Gene', (44, 49))	('decreased', 'NegReg', (67, 76))	('RNASEH2A', 'Gene', (13, 21))	('RCC', 'Disease', (100, 103))	('proliferation', 'CPA', (77, 90))
114857	29843367	Cell viability assays were performed in ccRCC cell line 786O after transfection with si-CDK1, si-RNASEH2A, and si-CD151, which showed comparable results to the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays (Figure 4).	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('CDK1', 'Gene', '983', (88, 92))	('MTT', 'Chemical', 'MESH:C070243', (222, 225))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('CDK1', 'Gene', (88, 92))	('RNASEH2A', 'Gene', (97, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('CDK', 'molecular_function', 'GO:0004693', ('88', '91'))	('3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide', 'Chemical', 'MESH:C022616', (160, 220))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('RNASEH2A', 'Gene', '10535', (97, 105))	('si-CD151', 'Var', (111, 119))	('RCC', 'Disease', (42, 45))	('si', 'Chemical', 'MESH:D012825', (94, 96))
114862	29843367	In KIRC, patients with scores lower than the cutoff (-1.925) had a significantly worse overall survival rate compared to those with scores above the cutoff value (mean survival of 955.3 days versus 2242.2 days, hazard ratio (HR) = 4.53 (3.05-6.73), p = 2.2 x 10-16, Figure 6A).	('lower', 'NegReg', (30, 35))	('patients', 'Species', '9606', (9, 17))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('scores', 'Var', (23, 29))	('overall', 'MPA', (87, 94))	('worse', 'NegReg', (81, 86))
114864	29843367	In another ccRCC cohort, namely, the E-GEOD-22541 expression array data (n = 44), patients with scores lower than -1.596 also showed lower disease-free survival when compared to those with higher scores (mean survival of 390.0 days versus 1889.2 days, HR = 2.99 (1.07-8.35), p = 7.1 x 10-4, Figure 6C).	('si', 'Chemical', 'MESH:D012825', (56, 58))	('patients', 'Species', '9606', (82, 90))	('scores lower than -1.596', 'Var', (96, 120))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('ccRCC', 'Phenotype', 'HP:0006770', (11, 16))	('RCC', 'Disease', (13, 16))	('disease-free survival', 'CPA', (139, 160))	('lower', 'NegReg', (133, 138))
114872	29843367	Similarly, in our study, CDK1 knockdown in RCC cell lines did not have a pronounced effect on tumor growth.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('CDK1', 'Gene', (25, 29))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('CDK1', 'Gene', '983', (25, 29))	('knockdown', 'Var', (30, 39))	('CDK', 'molecular_function', 'GO:0004693', ('25', '28'))
114875	29843367	In contrast to CDK1 knockdown, transfection of RCC cell lines with either si-RNASEH2A or si-CD151 resulted in impaired tumor proliferation.	('CDK1', 'Gene', '983', (15, 19))	('RNASEH2A', 'Gene', '10535', (77, 85))	('CDK1', 'Gene', (15, 19))	('impaired tumor', 'Disease', (110, 124))	('si-CD151', 'Var', (89, 97))	('CDK', 'molecular_function', 'GO:0004693', ('15', '18'))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('RNASEH2A', 'Gene', (77, 85))	('impaired tumor', 'Disease', 'MESH:D015417', (110, 124))
114876	29843367	Upregulation of CD151 and RNASEH2A was noted 48 h after si-RNASEH2A and si-CD151 knockdown, respectively, in all kidney cancer cell lines.	('Upregulation', 'PosReg', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('kidney cancer', 'Phenotype', 'HP:0009726', (113, 126))	('RNASEH2A', 'Gene', (59, 67))	('RNASEH2A', 'Gene', '10535', (26, 34))	('kidney cancer', 'Disease', (113, 126))	('RNASEH2A', 'Gene', '10535', (59, 67))	('CD151', 'Gene', (16, 21))	('si-CD151', 'Var', (72, 80))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('kidney cancer', 'Disease', 'MESH:D007680', (113, 126))	('RNASEH2A', 'Gene', (26, 34))
114884	29843367	Furthermore, according to the potential SDL relationships between CD151 and RNASEH2A identified by this study, CD151-high RCCs could be treated with RNASEH2A inhibitors.	('RNASEH2A', 'Gene', (76, 84))	('RNASEH2A', 'Gene', (149, 157))	('CD151-high', 'Var', (111, 121))	('RNASEH2A', 'Gene', '10535', (76, 84))	('RNASEH2A', 'Gene', '10535', (149, 157))	('RCCs', 'Phenotype', 'HP:0005584', (122, 126))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))
114939	33578578	Loss, mutation, or methylation inactivation of the VHL gene disturbs PVHL synthesis, which is an important molecular basis for VHL disease.	('VHL', 'Gene', (70, 73))	('PVHL', 'Gene', '7428', (69, 73))	('VHL', 'Gene', '7428', (51, 54))	('PVHL', 'Gene', (69, 73))	('VHL', 'Gene', '7428', (70, 73))	('methylation inactivation', 'Var', (19, 43))	('VHL disease', 'Disease', 'MESH:D006623', (127, 138))	('synthesis', 'biological_process', 'GO:0009058', ('74', '83'))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('mutation', 'Var', (6, 14))	('VHL', 'Gene', (127, 130))	('Loss', 'NegReg', (0, 4))	('VHL', 'Gene', '7428', (127, 130))	('VHL disease', 'Disease', (127, 138))	('VHL', 'Gene', (51, 54))	('disturbs', 'NegReg', (60, 68))
115008	28384121	In vitro culture of exosomes induced natural killer cell dysfunction mediated by activation of the TGF-beta/SMAD signaling pathway, and abrogated by knockdown TGF-beta.	('TGF-beta', 'Gene', (159, 167))	('knockdown', 'Var', (149, 158))	('natural killer cell dysfunction', 'Phenotype', 'HP:0012178', (37, 68))	('activation', 'PosReg', (81, 91))	('killer cell dysfunction', 'Disease', (45, 68))	('natural', 'Disease', (37, 44))	('signaling pathway', 'biological_process', 'GO:0007165', ('113', '130'))	('abrogated', 'NegReg', (136, 145))	('killer cell dysfunction', 'Disease', 'MESH:D000077428', (45, 68))	('TGF-beta', 'Gene', '7040', (99, 107))	('TGF-beta', 'Gene', '7040', (159, 167))	('TGF-beta', 'Gene', (99, 107))
115041	28384121	TINK cells had an abnormal phenotype, with lower frequencies of NK cells expressing the activating receptor NKp46, NKG2D, NKG2C (Figure 1D, 1E) and increased frequencies of NK cells expressing the inhibitory receptor NKG2A, CD158a and CD158b (Figure 1D, 1E) compared to NK cells from M region or NT tissue.	('lower frequencies of NK cells', 'Phenotype', 'HP:0040218', (43, 72))	('CD158b', 'Gene', (235, 241))	('increased', 'PosReg', (148, 157))	('NKG2C', 'Var', (122, 127))	('NKG2D', 'Var', (115, 120))	('CD158b', 'Gene', '100132285', (235, 241))	('CD158a', 'Gene', '3802', (224, 230))	('NT', 'Chemical', '-', (296, 298))	('CD158a', 'Gene', (224, 230))	('NKp46', 'Gene', (108, 113))	('NKG2A', 'Var', (217, 222))	('lower', 'NegReg', (43, 48))
115047	28384121	There was a significant reduction in the levels of IFN-gamma and TNF-alpha produced by TINK cells compared with other two groups (Figure 2A).	('IFN-gamma', 'Gene', '3458', (51, 60))	('IFN-gamma', 'Gene', (51, 60))	('TNF-alpha', 'Gene', '7124', (65, 74))	('TNF-alpha', 'Gene', (65, 74))	('reduction', 'NegReg', (24, 33))	('TINK cells', 'Var', (87, 97))
115062	28384121	GW4869, a well-known inhibitor of exosome secretion, was used to reduce the release of exosomes from ccRCC cells.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('GW4869', 'Chemical', 'MESH:C468773', (0, 6))	('exosome', 'cellular_component', 'GO:0070062', ('34', '41'))	('release of exosomes', 'MPA', (76, 95))	('GW4869', 'Var', (0, 6))	('reduce', 'NegReg', (65, 71))	('secretion', 'biological_process', 'GO:0046903', ('42', '51'))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))
115091	28384121	Consistently, exosomes derived from siR-TGF-beta1 transfected 786-O cells reversed the decrease in the cytotoxicity of NK cells compared with that of exosomes secreted by 786-O cells (Figure 6C).	('cytotoxicity', 'Disease', 'MESH:D064420', (103, 115))	('siR-TGF-beta1', 'Gene', (36, 49))	('siR-TGF-beta1', 'Gene', '7040', (36, 49))	('decrease', 'NegReg', (87, 95))	('transfected', 'Var', (50, 61))	('cytotoxicity', 'Disease', (103, 115))
115123	28384121	To be added, we demonstrated that knockdown the TGF-beta1 could improve the antitumor activity of NK cells in vitro.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('improve', 'PosReg', (64, 71))	('TGF-beta1', 'Gene', '7040', (48, 57))	('TGF-beta1', 'Gene', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('knockdown', 'Var', (34, 43))
115150	28384121	Purified NK cells were cultured in RPMI 1640 supplemented with 10% FBS containing IL-15 (10 ng/ml; PeproTech) in 96-well cell culture cluster flat bottom plates either in the presence of primary cells from NT, M, T, T+transwell(96-well/1mum micropores, Millipore), T+GW4869 at a 20:1, 40:1, 80:1 ratio.	('IL-15', 'Gene', (82, 87))	('T+GW4869', 'Var', (265, 273))	('IL-15', 'Gene', '3600', (82, 87))	('RPMI 1640', 'Chemical', '-', (35, 44))	('GW4869', 'Chemical', 'MESH:C468773', (267, 273))	('NT', 'Chemical', '-', (206, 208))	('IL-15', 'molecular_function', 'GO:0016170', ('82', '87'))
115172	28093071	We furthermore observed re-expression of both genes after treatment with epigenetically active drugs in most NSCLC cell lines with downregulated SPAG6 and L1TD1 mRNA expression.	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('SPAG6', 'Gene', (145, 150))	('N', 'Chemical', 'MESH:D009584', (109, 110))	('expression', 'Species', '29278', (27, 37))	('epigenetically active drugs', 'Var', (73, 100))	('L1TD1', 'Gene', (155, 160))	('mRNA expression', 'MPA', (161, 176))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('SPAG6', 'Gene', '9576', (145, 150))	('expression', 'Species', '29278', (166, 176))	('downregulated', 'NegReg', (131, 144))	('N', 'Chemical', 'MESH:D009584', (163, 164))	('NSCLC', 'Disease', (109, 114))
115174	28093071	ROC curve analyses demonstrated that methylation of both genes is able to distinguish between TU and NL samples of these patients.	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('methylation', 'Var', (37, 48))	('distinguish', 'Reg', (74, 85))	('TU', 'Phenotype', 'HP:0002664', (94, 96))	('N', 'Chemical', 'MESH:D009584', (101, 102))	('patients', 'Species', '9606', (121, 129))
115175	28093071	Immunohistochemistry revealed a close association between SPAG6/L1TD1 methylation and downregulated protein expression of these genes.	('SPAG6', 'Gene', '9576', (58, 63))	('methylation', 'biological_process', 'GO:0032259', ('70', '81'))	('protein expression', 'MPA', (100, 118))	('expression', 'Species', '29278', (108, 118))	('downregulated', 'NegReg', (86, 99))	('methylation', 'Var', (70, 81))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('SPAG6', 'Gene', (58, 63))
115176	28093071	Moreover, by performing functional assays we observed reduced cell growth, proliferation and viability of pCMV6-L1TD1 transfected NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('pCMV6-L1TD1', 'Gene', (106, 117))	('transfected', 'Var', (118, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('reduced', 'NegReg', (54, 61))	('viability', 'CPA', (93, 102))	('cell growth', 'biological_process', 'GO:0016049', ('62', '73'))	('proliferation', 'CPA', (75, 88))	('NSCLC', 'Disease', (130, 135))	('cell growth', 'CPA', (62, 73))
115177	28093071	In addition, reduced volumes of tumors derived from pCMV6-L1TD1 compared to pCMV6-ENTRY transfected NCI-H1975 cells were seen in a xenograft tumor model.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('pCMV6-L1TD1', 'Var', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('reduced', 'NegReg', (13, 20))	('NCI-H1975 cells', 'CellLine', 'CVCL:1511', (100, 115))	('N', 'Chemical', 'MESH:D009584', (83, 84))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('N', 'Chemical', 'MESH:D009584', (100, 101))	('tumor', 'Disease', (32, 37))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
115181	28093071	It has been shown that methylation plays an important role in various molecular and cellular processes including embryonic development and genomic imprinting as well as in the pathogenesis of malignant diseases.	('methylation', 'Var', (23, 34))	('malignant diseases', 'Disease', 'MESH:D009369', (192, 210))	('pathogenesis', 'biological_process', 'GO:0009405', ('176', '188'))	('role', 'Reg', (54, 58))	('methylation', 'biological_process', 'GO:0032259', ('23', '34'))	('malignant diseases', 'Disease', (192, 210))
115184	28093071	A synergistic effect on re-expression of by methylation silenced genes by DNMT inhibitors in combination with histone deacetylase inhibitors like trichostatin A (TSA) was reported.	('trichostatin A', 'Chemical', 'MESH:C012589', (146, 160))	('N', 'Chemical', 'MESH:D009584', (75, 76))	('re-expression', 'MPA', (24, 37))	('expression', 'Species', '29278', (27, 37))	('TSA', 'molecular_function', 'GO:0033984', ('162', '165'))	('inhibitors', 'Var', (79, 89))	('DNMT', 'Gene', (74, 78))	('TSA', 'Chemical', 'MESH:C012589', (162, 165))	('methylation', 'biological_process', 'GO:0032259', ('44', '55'))	('by methylation', 'MPA', (41, 55))
115202	28093071	Furthermore, our results indicate that L1TD1 functions as a tumor cell growth suppressor in NSCLC cells.	('cell growth', 'biological_process', 'GO:0016049', ('66', '77'))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('NSCLC', 'Disease', (92, 97))	('L1TD1', 'Var', (39, 44))	('tumor', 'Disease', (60, 65))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))
115204	28093071	For analyses of single nucleotide variants (SNVs) and deletions of SPAG6 and L1TD1 lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) datasets were used.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('LUAD', 'Phenotype', 'HP:0030078', (104, 108))	('lung adenocarcinoma', 'Disease', (83, 102))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (114, 142))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (83, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('N', 'Chemical', 'MESH:D009584', (45, 46))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (83, 102))	('SPAG6', 'Gene', (67, 72))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (114, 142))	('L1TD1', 'Gene', (77, 82))	('SPAG6', 'Gene', '9576', (67, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('deletions', 'Var', (54, 63))	('lung squamous cell carcinoma', 'Disease', (114, 142))	('LUSC', 'Phenotype', 'HP:0030359', (144, 148))
115212	28093071	In addition, DNA of breast cancer (MCF-7, MDA-MB-453, MDA-MB-468, MDA-MB-231, BT20), colon cancer (HCT-15, HT29), ovarian cancer (SK-OV3, A2780), pancreatic cancer (AsPC-1, BxPC-3) as well as head and neck cancer cell lines (CAL27, FaDu) were provided by various members of the Medical University of Vienna, Austria.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('colon cancer', 'Disease', 'MESH:D015179', (85, 97))	('ovarian cancer', 'Disease', 'MESH:D010051', (114, 128))	('HT29', 'CellLine', 'CVCL:0320', (107, 111))	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (54, 64))	('BxPC-3', 'CellLine', 'CVCL:0186', (173, 179))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (66, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('pancreatic cancer', 'Disease', 'MESH:D010190', (146, 163))	('colon cancer', 'Disease', (85, 97))	('head and neck cancer', 'Phenotype', 'HP:0012288', (192, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('neck cancer', 'Disease', 'MESH:D006258', (201, 212))	('MDA-MB-468', 'Var', (54, 64))	('ovarian cancer', 'Disease', (114, 128))	('neck cancer', 'Disease', (201, 212))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('breast cancer', 'Disease', (20, 33))	('pancreatic cancer', 'Disease', (146, 163))	('MDA-MB-453', 'CellLine', 'CVCL:0418', (42, 52))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('CAL27', 'CellLine', 'CVCL:1107', (225, 230))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('colon cancer', 'Phenotype', 'HP:0003003', (85, 97))	('MCF-7', 'CellLine', 'CVCL:0031', (35, 40))	('neck', 'cellular_component', 'GO:0044326', ('201', '205'))	('N', 'Chemical', 'MESH:D009584', (14, 15))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('SK-OV3', 'CellLine', 'CVCL:0532', (130, 136))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (146, 163))
115220	28093071	Expression of SPAG6 was determined using Taqman Gene Expression Assays Hs00542625_m1 (SPAG6) and Hs03929097_g1 (GAPDH) in a StepOne cycler (Applied Biosystems) and expression of L1TD1 was determined using Qiagen's QuantiTect  SYBR Green PCR Kit (primer sequences see Additional file 1: Table S3).	('Hs03929097_g1', 'Var', (97, 110))	('SPAG6', 'Gene', (14, 19))	('SYBR Green', 'Chemical', '-', (226, 236))	('expression', 'Species', '29278', (164, 174))	('SPAG6', 'Gene', (86, 91))	('SPAG6', 'Gene', '9576', (14, 19))	('SPAG6', 'Gene', '9576', (86, 91))	('Hs00542625_m1', 'Var', (71, 84))	('Expression', 'Species', '29278', (0, 10))	('Gene Expression', 'biological_process', 'GO:0010467', ('48', '63'))	('GAPDH', 'Gene', '2597', (112, 117))	('GAPDH', 'Gene', (112, 117))	('Expression', 'Species', '29278', (53, 63))
115223	28093071	Samples were stained with the rabbit polyclonal antibodies HPA038440 (SPAG6 1:100, Sigma Aldrich) and HPA028501 (L1TD1 1:100, Sigma Aldrich).	('SPAG6', 'Gene', (70, 75))	('HPA028501', 'Var', (102, 111))	('rabbit', 'Species', '9986', (30, 36))	('SPAG6', 'Gene', '9576', (70, 75))
115225	28093071	NCI-H1975 cells were transfected with pCMV6-ENTRY (PS100001, Origene) and pCMV6-L1TD1 (RC219014, Origene) expression vectors using Lipofectamine  LTX reagent (Invitrogen).	('NCI-H1975 cells', 'CellLine', 'CVCL:1511', (0, 15))	('RC219014', 'Var', (87, 95))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('expression vectors', 'Species', '29278', (106, 124))	('PS100001', 'Var', (51, 59))	('N', 'Chemical', 'MESH:D009584', (45, 46))	('Lipofectamine  LTX', 'Chemical', '-', (131, 149))
115259	28093071	While most of the 56 CpG sites analysed were found to be SPAG6 methylated in A549 (79%) and in NCI-H1975 (92%) cells, only a few CpG sites were methylated in NHBECs (4%, Fig.	('N', 'Chemical', 'MESH:D009584', (95, 96))	('SPAG6', 'Gene', (57, 62))	('NCI-H1975', 'CellLine', 'CVCL:1511', (95, 104))	('methylated', 'Var', (63, 73))	('N', 'Chemical', 'MESH:D009584', (158, 159))	('SPAG6', 'Gene', '9576', (57, 62))	('A549', 'CellLine', 'CVCL:0023', (77, 81))
115260	28093071	Differences in the percentage of SPAG6 methylated CpG sites between NSCLC cells and NHBECs were statistically significant (p < 0.0001).	('N', 'Chemical', 'MESH:D009584', (84, 85))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('SPAG6', 'Gene', (33, 38))	('N', 'Chemical', 'MESH:D009584', (68, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('SPAG6', 'Gene', '9576', (33, 38))	('methylated', 'Var', (39, 49))	('NSCLC', 'Disease', (68, 73))
115263	28093071	Moreover, we determined methylation of SPAG6 and L1TD1 in 5 breast cancer, 2 colon cancer, 2 ovarian cancer, 2 pancreatic cancer as well as 2 head and neck cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('colon cancer', 'Disease', 'MESH:D015179', (77, 89))	('methylation', 'Var', (24, 35))	('pancreatic cancer', 'Disease', (111, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('ovarian cancer', 'Disease', (93, 107))	('SPAG6', 'Gene', (39, 44))	('ovarian cancer', 'Phenotype', 'HP:0100615', (93, 107))	('colon cancer', 'Disease', (77, 89))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (111, 128))	('breast cancer', 'Disease', (60, 73))	('determined', 'Reg', (13, 23))	('L1TD1', 'Gene', (49, 54))	('neck', 'cellular_component', 'GO:0044326', ('151', '155'))	('head and neck cancer', 'Phenotype', 'HP:0012288', (142, 162))	('colon cancer', 'Phenotype', 'HP:0003003', (77, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ovarian cancer', 'Disease', 'MESH:D010051', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('SPAG6', 'Gene', '9576', (39, 44))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('neck cancer', 'Disease', 'MESH:D006258', (151, 162))	('neck cancer', 'Disease', (151, 162))
115264	28093071	All these tumor cell lines were found to be SPAG6 and L1TD1 methylated with percentages of methylation ranging between 71% (SK-OV3 cells) and 98% (FaDu cells) for SPAG6 methylation and between 88% (BxPC-3 cells) and 100% (FaDu cells) for L1TD1 methylation (Additional file 1: Table S4).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('methylation', 'biological_process', 'GO:0032259', ('244', '255'))	('tumor', 'Disease', (10, 15))	('SPAG6', 'Gene', (163, 168))	('BxPC-3', 'CellLine', 'CVCL:0186', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('SK-OV3', 'CellLine', 'CVCL:0532', (124, 130))	('methylation', 'biological_process', 'GO:0032259', ('169', '180'))	('SPAG6', 'Gene', '9576', (163, 168))	('methylation', 'Var', (169, 180))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))	('SPAG6', 'Gene', (44, 49))	('L1TD1', 'Gene', (54, 59))	('methylation', 'MPA', (91, 102))	('SPAG6', 'Gene', '9576', (44, 49))
115266	28093071	Differences in SPAG6 and L1TD1 methylation between TU and NL samples were statistically significant (p < 0.0001, respectively) demonstrating that both genes are tumor-specifically methylated (Fig.	('Differences', 'Reg', (0, 11))	('L1TD1', 'Gene', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('SPAG6', 'Gene', (15, 20))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('methylation', 'Var', (31, 42))	('SPAG6', 'Gene', '9576', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('TU', 'Phenotype', 'HP:0002664', (51, 53))	('tumor', 'Disease', (161, 166))
115269	28093071	Considering patients with a T/N ratio >= 1.5 as methylated, 79% of them were SPAG6 methylated and 81% of them were L1TD1 methylated, respectively.	('patients', 'Species', '9606', (12, 20))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('SPAG6', 'Gene', (77, 82))	('methylated', 'Var', (83, 93))	('SPAG6', 'Gene', '9576', (77, 82))
115273	28093071	To investigate if other mechanisms besides methylation are involved in transcriptional regulation of SPAG6 and L1TD1, we analysed SNVs as well as homozygous and heterozygous deletions in LUAD and LUSC SNP and aCGH datasets of NSCLC patients.	('LUSC', 'Phenotype', 'HP:0030359', (196, 200))	('NSCLC', 'Disease', 'MESH:D002289', (226, 231))	('N', 'Chemical', 'MESH:D009584', (226, 227))	('SPAG6', 'Gene', (101, 106))	('patients', 'Species', '9606', (232, 240))	('methylation', 'biological_process', 'GO:0032259', ('43', '54'))	('regulation', 'biological_process', 'GO:0065007', ('87', '97'))	('SPAG6', 'Gene', '9576', (101, 106))	('deletions', 'Var', (174, 183))	('LUAD', 'Phenotype', 'HP:0030078', (187, 191))	('NSCLC', 'Phenotype', 'HP:0030358', (226, 231))	('LUAD', 'Disease', (187, 191))	('N', 'Chemical', 'MESH:D009584', (202, 203))	('N', 'Chemical', 'MESH:D009584', (131, 132))	('NSCLC', 'Disease', (226, 231))
115277	28093071	Homozygous SPAG6 deletions were detected in only 1% and heterozygous SPAG6 deletions were found in 40% of these patients.	('SPAG6', 'Gene', '9576', (69, 74))	('deletions', 'Var', (17, 26))	('SPAG6', 'Gene', '9576', (11, 16))	('patients', 'Species', '9606', (112, 120))	('SPAG6', 'Gene', (69, 74))	('SPAG6', 'Gene', (11, 16))
115278	28093071	Similar frequencies of SNVs and deletions were found for L1TD1 (Additional file 4: Figure S3).	('deletions', 'Var', (32, 41))	('L1TD1', 'Gene', (57, 62))	('N', 'Chemical', 'MESH:D009584', (24, 25))
115281	28093071	SPAG6 and L1TD1 protein expression was observed in bronchial and bronchiolar epithelial cells of NL samples.	('expression', 'Species', '29278', (24, 34))	('L1TD1', 'Var', (10, 15))	('protein', 'cellular_component', 'GO:0003675', ('16', '23'))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('SPAG6', 'Gene', (0, 5))	('SPAG6', 'Gene', '9576', (0, 5))
115286	28093071	When we compared SPAG6 and L1TD1 methylation with their protein expression in TU samples, we observed downregulated SPAG6 protein expression in 77% of SPAG6 methylated TU samples and downregulated L1TD1 protein expression in 52% of L1TD1 methylated TU samples, respectively (Fig.	('protein', 'Protein', (122, 129))	('expression', 'MPA', (130, 140))	('SPAG6', 'Gene', '9576', (151, 156))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('SPAG6', 'Gene', '9576', (116, 121))	('SPAG6', 'Gene', (17, 22))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('TU', 'Phenotype', 'HP:0002664', (78, 80))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('expression', 'Species', '29278', (211, 221))	('expression', 'Species', '29278', (130, 140))	('downregulated', 'NegReg', (183, 196))	('methylation', 'biological_process', 'GO:0032259', ('33', '44'))	('SPAG6', 'Gene', (151, 156))	('downregulated', 'NegReg', (102, 115))	('methylated', 'Var', (157, 167))	('SPAG6', 'Gene', (116, 121))	('expression', 'MPA', (211, 221))	('TU', 'Phenotype', 'HP:0002664', (249, 251))	('SPAG6', 'Gene', '9576', (17, 22))	('protein', 'Protein', (203, 210))	('TU', 'Phenotype', 'HP:0002664', (168, 170))	('L1TD1', 'Gene', (197, 202))	('expression', 'Species', '29278', (64, 74))
115288	28093071	We found a strong reduction in tumor cell growth of pCMV6-L1TD1 compared to pCMV6-ENTRY transfected cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('pCMV6-L1TD1', 'Var', (52, 63))	('tumor', 'Disease', (31, 36))	('N', 'Chemical', 'MESH:D009584', (83, 84))	('cell growth', 'biological_process', 'GO:0016049', ('37', '48'))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('reduction', 'NegReg', (18, 27))
115290	28093071	Moreover, we analysed tumor cell proliferation in a time-dependent manner and observed a reduced proliferation rate of pCMV6-L1TD1 compared to pCMV6-ENTRY and to pCMV6-GFP transfected cells (Fig.	('cell proliferation', 'biological_process', 'GO:0008283', ('28', '46'))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('proliferation rate', 'CPA', (97, 115))	('N', 'Chemical', 'MESH:D009584', (150, 151))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('reduced', 'NegReg', (89, 96))	('pCMV6-L1TD1', 'Var', (119, 130))
115291	28093071	In addition, we found a reduced colony-forming ability and tumor cell viability of pCMV6-L1TD1 transfected cells compared to control cells (Fig.	('tumor', 'Disease', (59, 64))	('reduced', 'NegReg', (24, 31))	('pCMV6-L1TD1', 'Var', (83, 94))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('colony-forming ability', 'CPA', (32, 54))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
115292	28093071	Differences in tumor cell viability between pCMV6-L1TD1 and pCMV6-ENTRY transfected cells were statistically significant after 48 (p = 0.0064) and 72 h (p < 0.0001), while differences between pCMV6-L1TD1 and pCMV6-GFP transfected cells did not reach statistical significance.	('N', 'Chemical', 'MESH:D009584', (67, 68))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('pCMV6-L1TD1', 'Var', (44, 55))
115294	28093071	However, no impact of ectopic SPAG6 expression on tumor cell growth, proliferation, viability or colony-forming abilities were seen (data not shown).	('SPAG6', 'Gene', '9576', (30, 35))	('cell growth', 'biological_process', 'GO:0016049', ('56', '67'))	('colony-forming abilities', 'CPA', (97, 121))	('ectopic', 'Var', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('expression', 'Species', '29278', (36, 46))	('SPAG6', 'Gene', (30, 35))	('tumor', 'Disease', (50, 55))
115295	28093071	Because in vitro experiments suggested tumor-cell growth suppressing properties of L1TD1, we additionally performed in vivo studies using immunodeficient mice.	('mice', 'Species', '10090', (154, 158))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('L1TD1', 'Var', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('immunodeficient', 'Disease', 'MESH:D007153', (138, 153))	('immunodeficient', 'Disease', (138, 153))	('cell growth', 'biological_process', 'GO:0016049', ('45', '56'))
115300	28093071	Size measurement of dissected tumors confirmed size differences of tumors derived from pCMV6-L1TD1 and from pCMV6-ENTRY transfected cells which were seen during the experiment (Fig.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('N', 'Chemical', 'MESH:D009584', (115, 116))	('pCMV6-L1TD1', 'Var', (87, 98))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
115301	28093071	Expression of L1TD1 in tumors derived from pCMV6-L1TD1 transfected NCI-H1975 cells was confirmed by RT-PCR (Additional file 5: Figure S4).	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('Expression', 'Species', '29278', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('pCMV6-L1TD1', 'Var', (43, 54))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('NCI-H1975 cells', 'CellLine', 'CVCL:1511', (67, 82))
115311	28093071	While tumor-specific downregulation of SPAG6 mRNA expression was observed in all tumor types investigated except hepatocellular and prostate carcinomas, downregulated L1TD1 mRNA expression was found in NSCLCs, breast, colorectal and prostate carcinomas but not in head and neck, kidney and hepatocellular carcinomas.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (290, 314))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('downregulated', 'NegReg', (153, 166))	('mRNA expression', 'MPA', (45, 60))	('prostate carcinomas', 'Disease', 'MESH:D011472', (132, 151))	('SPAG6', 'Gene', (39, 44))	('downregulation', 'NegReg', (21, 35))	('prostate carcinomas', 'Disease', 'MESH:D011472', (233, 252))	('N', 'Chemical', 'MESH:D009584', (202, 203))	('kidney and hepatocellular carcinomas', 'Disease', 'MESH:D006528', (279, 315))	('tumor', 'Disease', (81, 86))	('L1TD1', 'Var', (167, 172))	('hepatocellular', 'Disease', (113, 127))	('colorectal and prostate carcinomas', 'Disease', 'MESH:D015179', (218, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('expression', 'Species', '29278', (178, 188))	('breast', 'Disease', (210, 216))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('NSCLC', 'Disease', 'MESH:D002289', (202, 207))	('N', 'Chemical', 'MESH:D009584', (175, 176))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('neck', 'cellular_component', 'GO:0044326', ('273', '277'))	('prostate carcinomas', 'Disease', (132, 151))	('expression', 'Species', '29278', (50, 60))	('tumor', 'Disease', (6, 11))	('NSCLC', 'Disease', (202, 207))	('N', 'Chemical', 'MESH:D009584', (47, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('prostate carcinomas', 'Disease', (233, 252))	('NSCLCs', 'Phenotype', 'HP:0030358', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (290, 315))	('carcinomas', 'Phenotype', 'HP:0030731', (242, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('carcinomas', 'Phenotype', 'HP:0030731', (305, 315))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('SPAG6', 'Gene', '9576', (39, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (202, 207))
115312	28093071	Overall, these data suggest that deregulated expression of SPAG6 and L1TD1 may play a role not only in the pathogenesis of NSCLCs but also in tumors of other entities and that expression of these 2 genes differs between certain tumor types.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('play', 'Reg', (79, 83))	('role', 'Reg', (86, 90))	('SPAG6', 'Gene', '9576', (59, 64))	('expression', 'Species', '29278', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumors', 'Disease', (142, 148))	('deregulated', 'Var', (33, 44))	('tumor', 'Disease', (142, 147))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('expression', 'Species', '29278', (176, 186))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('SPAG6', 'Gene', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('NSCLC', 'Disease', (123, 128))	('NSCLCs', 'Phenotype', 'HP:0030358', (123, 129))	('L1TD1', 'Gene', (69, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('expression', 'MPA', (45, 55))	('tumor', 'Disease', (228, 233))	('pathogenesis', 'biological_process', 'GO:0009405', ('107', '119'))
115317	28093071	In addition, we found an association between SPAG6 and L1TD1 methylation and loss of SPAG6 and L1TD1 protein expression when we performed IHC of FFPE tissue samples from NSCLC patients.	('patients', 'Species', '9606', (176, 184))	('SPAG6', 'Gene', '9576', (85, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (170, 175))	('expression', 'MPA', (109, 119))	('methylation', 'Var', (61, 72))	('SPAG6', 'Gene', (45, 50))	('SPAG6', 'Gene', '9576', (45, 50))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('L1TD1', 'Gene', (55, 60))	('NSCLC', 'Disease', (170, 175))	('protein', 'Protein', (101, 108))	('loss', 'NegReg', (77, 81))	('SPAG6', 'Gene', (85, 90))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('L1TD1', 'Gene', (95, 100))	('expression', 'Species', '29278', (109, 119))
115318	28093071	While most of the SPAG6 or L1TD1 methylated TU samples did not express these proteins, not methylated TU samples mostly expressed SPAG6 or L1TD1.	('TU', 'Phenotype', 'HP:0002664', (44, 46))	('SPAG6', 'Gene', '9576', (18, 23))	('TU', 'Phenotype', 'HP:0002664', (102, 104))	('SPAG6', 'Gene', (18, 23))	('SPAG6', 'Gene', (130, 135))	('L1TD1', 'Var', (139, 144))	('SPAG6', 'Gene', '9576', (130, 135))
115320	28093071	Our hypothesis that methylation is one of the mechanisms responsible for inactivation of these genes is further supported by the fact that SNVs and homozygous deletions of SPAG6 and L1TD1 were rarely detected in LUAD and LUSC SNP and in aCGH datasets of NSCLC patients.	('LUAD', 'Phenotype', 'HP:0030078', (212, 216))	('NSCLC', 'Disease', (254, 259))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))	('L1TD1', 'Gene', (182, 187))	('LUSC', 'Phenotype', 'HP:0030359', (221, 225))	('NSCLC', 'Disease', 'MESH:D002289', (254, 259))	('SPAG6', 'Gene', '9576', (172, 177))	('N', 'Chemical', 'MESH:D009584', (140, 141))	('patients', 'Species', '9606', (260, 268))	('NSCLC', 'Phenotype', 'HP:0030358', (254, 259))	('N', 'Chemical', 'MESH:D009584', (254, 255))	('N', 'Chemical', 'MESH:D009584', (227, 228))	('deletions', 'Var', (159, 168))	('SPAG6', 'Gene', (172, 177))
115323	28093071	Methylation of certain TSGs in NSCLCs is tumor-subtype specific.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('Methylation', 'Var', (0, 11))	('NSCLC', 'Disease', (31, 36))	('NSCLCs', 'Phenotype', 'HP:0030358', (31, 37))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (31, 36))
115324	28093071	While for instance APC and CDH13 methylation was detected more frequently in lung adenocarcinomas compared to lung squamous cell carcinomas, p16 methylation was detected more frequently in lung squamous cell carcinomas than in lung adenocarcinomas.	('methylation', 'Var', (33, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('carcinomas', 'Phenotype', 'HP:0030731', (208, 218))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (189, 218))	('methylation', 'biological_process', 'GO:0032259', ('145', '156'))	('CDH13', 'Gene', (27, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('lung squamous cell carcinomas', 'Disease', (110, 139))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (110, 138))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (227, 246))	('p16 methylation', 'Var', (141, 156))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (77, 97))	('detected', 'Reg', (161, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('lung squamous cell carcinomas', 'Disease', (189, 218))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (115, 139))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (194, 218))	('detected', 'Reg', (49, 57))	('carcinomas', 'Phenotype', 'HP:0030731', (237, 247))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (189, 217))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (227, 247))	('methylation', 'biological_process', 'GO:0032259', ('33', '44'))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('methylation', 'Var', (145, 156))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (77, 97))	('APC', 'cellular_component', 'GO:0005680', ('19', '22'))	('APC', 'Disease', 'MESH:D011125', (19, 22))	('APC', 'Disease', (19, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (227, 247))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('lung adenocarcinomas', 'Disease', (77, 97))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (110, 139))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (194, 217))	('lung adenocarcinomas', 'Disease', (227, 247))
115326	28093071	These observations suggest that methylation of SPAG6 and L1TD1 is a common feature in all histological subtypes of NSCLCs.	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))	('methylation', 'Var', (32, 43))	('SPAG6', 'Gene', '9576', (47, 52))	('NSCLC', 'Disease', (115, 120))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('SPAG6', 'Gene', (47, 52))	('NSCLCs', 'Phenotype', 'HP:0030358', (115, 121))	('L1TD1', 'Gene', (57, 62))	('common', 'Reg', (68, 74))
115327	28093071	Methylation of several genes was shown to be associated with shorter survival of NSCLC patients (e.g.	('shorter', 'NegReg', (61, 68))	('Methylation', 'Var', (0, 11))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('NSCLC', 'Disease', (81, 86))	('patients', 'Species', '9606', (87, 95))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('survival', 'MPA', (69, 77))
115329	28093071	In our study, we did not find a correlation between SPAG6 or L1TD1 methylation and OS as well as DFS of NSCLC patients or any other clinico-pathological characteristic of these patients.	('SPAG6', 'Gene', (52, 57))	('OS', 'Chemical', '-', (83, 85))	('SPAG6', 'Gene', '9576', (52, 57))	('patients', 'Species', '9606', (177, 185))	('NSCLC', 'Disease', (104, 109))	('methylation', 'biological_process', 'GO:0032259', ('67', '78'))	('L1TD1', 'Gene', (61, 66))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('patients', 'Species', '9606', (110, 118))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))	('methylation', 'Var', (67, 78))
115330	28093071	However, analyses of gene expression microarray data indicate that low SPAG6 expression is associated with a shorter OS of lung squamous cell carcinoma patients and low L1TD1 expression with a shorter OS of lung adenocarcinoma patients.	('low', 'Var', (67, 70))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (207, 226))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('OS of lung squamous cell carcinoma', 'Disease', (117, 151))	('expression', 'Species', '29278', (77, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('OS of lung squamous cell carcinoma', 'Disease', 'MESH:C567932', (117, 151))	('SPAG6', 'Gene', (71, 76))	('OS of lung adenocarcinoma', 'Disease', 'MESH:C567932', (201, 226))	('L1TD1', 'Gene', (169, 174))	('patients', 'Species', '9606', (227, 235))	('low', 'NegReg', (165, 168))	('gene expression', 'biological_process', 'GO:0010467', ('21', '36'))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (123, 151))	('expression', 'Species', '29278', (26, 36))	('patients', 'Species', '9606', (152, 160))	('expression', 'Species', '29278', (175, 185))	('expression', 'MPA', (77, 87))	('OS of lung adenocarcinoma', 'Disease', (201, 226))	('SPAG6', 'Gene', '9576', (71, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
115334	28093071	Indeed, in vitro experiments showed reduced cell growth, proliferation, viability and colony-forming abilities of pCMV6-L1TD1 transfected cells suggesting that it may be a potential TSG in NSCLCs.	('colony-forming abilities', 'CPA', (86, 110))	('NSCLC', 'Disease', (189, 194))	('transfected', 'Var', (126, 137))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('cell growth', 'biological_process', 'GO:0016049', ('44', '55'))	('viability', 'CPA', (72, 81))	('NSCLCs', 'Phenotype', 'HP:0030358', (189, 195))	('cell growth', 'CPA', (44, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (189, 194))	('reduced', 'NegReg', (36, 43))	('pCMV6-L1TD1 transfected', 'Var', (114, 137))
115335	28093071	Because of these encouraging results and to further support our hypothesis that L1TD1 has tumor-cell growth suppressing properties, we additionally performed xenograft experiments to investigate the growth of tumors induced by L1TD1-overexpressing and wildtype NSCLC cells.	('tumors', 'Disease', (209, 215))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('tumor', 'Disease', (209, 214))	('NSCLC', 'Disease', (261, 266))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (261, 266))	('cell growth', 'biological_process', 'GO:0016049', ('96', '107'))	('L1TD1', 'Var', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('NSCLC', 'Phenotype', 'HP:0030358', (261, 266))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
115336	28093071	Interestingly, we observed significantly smaller tumors induced by pCMV6-L1TD1 compared to pCMV6-ENTRY transfected NCI-H1975 cells indicating that L1TD1 indeed has tumor-cell growth suppressing properties.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('N', 'Chemical', 'MESH:D009584', (98, 99))	('L1TD1', 'Var', (147, 152))	('smaller', 'NegReg', (41, 48))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (49, 54))	('pCMV6-L1TD1', 'Var', (67, 78))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('cell growth', 'biological_process', 'GO:0016049', ('170', '181'))	('NCI-H1975 cells', 'CellLine', 'CVCL:1511', (115, 130))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('N', 'Chemical', 'MESH:D009584', (115, 116))
115341	28093071	Our results demonstrate that tumor-specific methylation of SPAG6 and L1TD1 is a frequently occurring event in NSCLCs and they suggest that methylation plays an important role in the transcriptional regulation of these genes.	('methylation', 'Var', (44, 55))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('SPAG6', 'Gene', '9576', (59, 64))	('L1TD1', 'Gene', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('NSCLC', 'Disease', (110, 115))	('occurring', 'Reg', (91, 100))	('methylation', 'biological_process', 'GO:0032259', ('139', '150'))	('regulation', 'biological_process', 'GO:0065007', ('198', '208'))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('tumor', 'Disease', (29, 34))	('NSCLCs', 'Phenotype', 'HP:0030358', (110, 116))	('SPAG6', 'Gene', (59, 64))	('methylation', 'biological_process', 'GO:0032259', ('44', '55'))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
115343	28093071	In addition, or findings indicate that methylation of these genes may be of relevance not only in NSCLCs but also in other malignancies.	('malignancies', 'Disease', 'MESH:D009369', (123, 135))	('methylation', 'Var', (39, 50))	('NSCLCs', 'Phenotype', 'HP:0030358', (98, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('relevance', 'Reg', (76, 85))	('malignancies', 'Disease', (123, 135))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('NSCLC', 'Disease', (98, 103))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))
115344	28093071	Moreover, in vitro and in vivo experiments showed that L1TD1 has tumor-cell growth suppressing properties in NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('tumor', 'Disease', (65, 70))	('cell growth', 'biological_process', 'GO:0016049', ('71', '82'))	('L1TD1', 'Var', (55, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('NSCLC', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
115345	28093071	Taken together we identified methylation as a potential mechanism for frequent downregulation of SPAG6 and L1TD1 in NSCLCs and suggest a putative role of L1TD1 in tumor cell development.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('methylation', 'Var', (29, 40))	('methylation', 'biological_process', 'GO:0032259', ('29', '40'))	('NSCLCs', 'Phenotype', 'HP:0030358', (116, 122))	('SPAG6', 'Gene', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('L1TD1', 'Gene', (107, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('cell development', 'biological_process', 'GO:0048468', ('169', '185'))	('SPAG6', 'Gene', '9576', (97, 102))	('tumor', 'Disease', (163, 168))	('downregulation', 'NegReg', (79, 93))	('NSCLC', 'Disease', (116, 121))
115352	30588245	We revealed that over-expression MAN1C1 showed anti-tumor effect by inducing apoptosis, as determined by Cell Counting Kit-8 (CCK-8) assay, cell cycle analysis, and western blot analysis.	('inducing', 'Reg', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cell cycle', 'biological_process', 'GO:0007049', ('140', '150'))	('tumor', 'Disease', (52, 57))	('MAN1C1', 'Gene', (33, 39))	('apoptosis', 'CPA', (77, 86))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('over-expression', 'Var', (17, 32))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('MAN1C1', 'Gene', '57134', (33, 39))
115355	30588245	Conclusion: We find that re-expression of silenced MAN1C1 in ccRCC cell lines inhibited cell viability, colony formation, induced apoptosis, suppressed cell invasion and migration.	('RCC', 'Disease', (63, 66))	('inhibited', 'NegReg', (78, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('apoptosis', 'CPA', (130, 139))	('formation', 'biological_process', 'GO:0009058', ('111', '120'))	('RCC', 'Disease', 'MESH:C538614', (63, 66))	('silenced', 'Var', (42, 50))	('induced', 'Reg', (122, 129))	('suppressed', 'NegReg', (141, 151))	('MAN1C1', 'Gene', '57134', (51, 57))	('cell viability', 'CPA', (88, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('colony formation', 'CPA', (104, 120))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('MAN1C1', 'Gene', (51, 57))
115373	30588245	These modifications affect cell growth, cell-cell adhesion, cell motility and protein phosphorylation; therefore, the activity of the enzymes involved in Nglycosylation must be tightly regulated because N-glycan composition determines the fate of the protein, including whether or not the protein will be folded in the ER lumen or retrotranslocated into the cytosol and degraded.	('modifications', 'Var', (6, 19))	('N-glycan', 'Chemical', '-', (203, 211))	('cell motility', 'biological_process', 'GO:0048870', ('60', '73'))	('N', 'Chemical', 'MESH:D009584', (154, 155))	('ER lumen', 'cellular_component', 'GO:0005788', ('319', '327'))	('cytosol', 'cellular_component', 'GO:0005829', ('358', '365'))	('N', 'Chemical', 'MESH:D009584', (203, 204))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('40', '58'))	('protein', 'cellular_component', 'GO:0003675', ('251', '258'))	('protein phosphorylation', 'biological_process', 'GO:0006468', ('78', '101'))	('cell growth', 'biological_process', 'GO:0016049', ('27', '38'))	('affect', 'Reg', (20, 26))	('determines', 'Reg', (224, 234))	('protein', 'cellular_component', 'GO:0003675', ('289', '296'))
115456	30588245	This indicated that EMT is suppressed following MAN1C1 over-expression.	('EMT', 'Gene', (20, 23))	('EMT', 'Gene', '3702', (20, 23))	('suppressed', 'NegReg', (27, 37))	('MAN1C1', 'Gene', '57134', (48, 54))	('over-expression', 'Var', (55, 70))	('EMT', 'biological_process', 'GO:0001837', ('20', '23'))	('MAN1C1', 'Gene', (48, 54))
115458	30588245	Results from the previous studies suggest that increased expression of alpha-1,2 mannosidases has been associated with many cancers, and our observation that MAN2C1 associates with prostate tumourigenesis is consistent with the report that MAN2C1 is associated with tumourigenic activity in B cells and nasopharynegeal carcinoma.	('carcinoma', 'Disease', (319, 328))	('tumour', 'Disease', (190, 196))	('associated', 'Reg', (103, 113))	('alpha-1,2', 'Gene', '146', (71, 80))	('tumour', 'Disease', 'MESH:D009369', (190, 196))	('MAN2C1', 'Var', (158, 164))	('associates with', 'Reg', (165, 180))	('tumour', 'Disease', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('increased', 'PosReg', (47, 56))	('carcinoma', 'Disease', 'MESH:D002277', (319, 328))	('tumour', 'Phenotype', 'HP:0002664', (266, 272))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('tumour', 'Disease', 'MESH:D009369', (266, 272))
115459	30588245	Interestingly, recently-developed MAN2C1 transgenic mice are prone to enhance tumour growth, invasion and metastasis.	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('enhance', 'PosReg', (70, 77))	('MAN2C1', 'Gene', (34, 40))	('tumour', 'Disease', (78, 84))	('transgenic', 'Var', (41, 51))	('transgenic mice', 'Species', '10090', (41, 56))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
115471	30588245	For example, aberrant N-glycosylation of E-cadherin is associated with carcinogenesis secondary to altered cell-cell adhesion and communication.	('glycosylation', 'biological_process', 'GO:0070085', ('24', '37'))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('carcinogenesis', 'Disease', (71, 85))	('cell-cell adhesion', 'CPA', (107, 125))	('associated', 'Reg', (55, 65))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('107', '125'))	('cadherin', 'molecular_function', 'GO:0008014', ('43', '51'))	('N-glycosylation', 'MPA', (22, 37))	('altered', 'Reg', (99, 106))	('E-cadherin', 'Gene', (41, 51))	('E-cadherin', 'Gene', '999', (41, 51))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))	('aberrant', 'Var', (13, 21))
115483	33322148	In addition, after cisplatin treatment, the death rate of tumor cells treated with A939572 was significantly greater than that of untreated cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('death', 'Disease', 'MESH:D003643', (44, 49))	('death', 'Disease', (44, 49))	('A939572', 'Chemical', '-', (83, 90))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('A939572', 'Var', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('greater', 'PosReg', (109, 116))
115484	33322148	In conclusion, our findings delineate a ccRCC lipidomic signature and showed that SCD1 inhibition significantly reduced cancer cell proliferation and increased cisplatin sensitivity, suggesting that this pathway can be involved in ccRCC chemotherapy resistance.	('cancer', 'Disease', (120, 126))	('cisplatin', 'Chemical', 'MESH:D002945', (160, 169))	('RCC', 'Phenotype', 'HP:0005584', (233, 236))	('ccRCC', 'Phenotype', 'HP:0006770', (231, 236))	('RCC', 'Disease', (233, 236))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('SCD1', 'Gene', '6319', (82, 86))	('reduced', 'NegReg', (112, 119))	('RCC', 'Disease', 'MESH:C538614', (233, 236))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('lipid', 'Chemical', 'MESH:D008055', (46, 51))	('SCD1', 'Gene', (82, 86))	('cisplatin sensitivity', 'MPA', (160, 181))	('inhibition', 'Var', (87, 97))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('cell proliferation', 'biological_process', 'GO:0008283', ('127', '145'))	('increased', 'PosReg', (150, 159))
115491	33322148	Indeed, we showed that, in clear cell renal cell carcinoma (ccRCC), a metabolic reprogramming occurs, involving the glucose metabolism and the pentose phosphate pathway, and that patients with high levels of glycolytic enzymes had reduced survival rates.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (38, 58))	('pentose', 'Pathway', (143, 150))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('survival rates', 'CPA', (239, 253))	('glucose metabolism', 'biological_process', 'GO:0006006', ('116', '134'))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (27, 58))	('patients', 'Species', '9606', (179, 187))	('reduced', 'NegReg', (231, 238))	('glucose metabolism', 'Disease', (116, 134))	('metabolic reprogramming', 'CPA', (70, 93))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (27, 58))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('RCC', 'Disease', (62, 65))	('pentose phosphate', 'Chemical', 'MESH:D010428', (143, 160))	('high', 'Var', (193, 197))	('glucose metabolism', 'Disease', 'MESH:D044882', (116, 134))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('clear cell renal cell carcinoma', 'Disease', (27, 58))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('143', '168'))
115500	33322148	These functional approaches showed that alterations in glycerophospholipid metabolism, in arachidonic acid and prostaglandin production, in biosynthesis of unsaturated fatty acid and fatty acid elongation, had the highest impact on the ccRCC lipidome (Figure 1d,e).	('lipid', 'Chemical', 'MESH:D008055', (242, 247))	('arachidonic acid', 'Chemical', 'MESH:D016718', (90, 106))	('arachidonic acid', 'MPA', (90, 106))	('fatty acid', 'Chemical', 'MESH:D005227', (168, 178))	('biosynthesis', 'biological_process', 'GO:0009058', ('140', '152'))	('RCC', 'Phenotype', 'HP:0005584', (238, 241))	('fatty acid elongation', 'biological_process', 'GO:0030497', ('183', '204'))	('impact', 'Reg', (222, 228))	('RCC', 'Disease', (238, 241))	('glycerophospholipid metabolism', 'Disease', 'MESH:D008659', (55, 85))	('fatty acid', 'Chemical', 'MESH:D005227', (183, 193))	('alterations', 'Var', (40, 51))	('glycerophospholipid metabolism', 'Disease', (55, 85))	('prostaglandin', 'Chemical', 'MESH:D011453', (111, 124))	('unsaturated fatty acid', 'Chemical', 'MESH:D005231', (156, 178))	('RCC', 'Disease', 'MESH:C538614', (238, 241))	('ccRCC', 'Phenotype', 'HP:0006770', (236, 241))	('lipid', 'Chemical', 'MESH:D008055', (69, 74))	('glycerophospholipid metabolism', 'biological_process', 'GO:0006650', ('55', '85'))
115526	33322148	Primary renal cancer cells treated with a small molecule SCD1 inhibitor, A939572, proliferated at a slower rate than non-treated cancer cells.	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Primary renal cancer', 'Disease', (0, 20))	('A939572', 'Chemical', '-', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('SCD1', 'Gene', (57, 61))	('slower', 'NegReg', (100, 106))	('Primary renal cancer', 'Disease', 'MESH:D007680', (0, 20))	('renal cancer', 'Phenotype', 'HP:0009726', (8, 20))	('proliferated', 'CPA', (82, 94))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('SCD1', 'Gene', '6319', (57, 61))	('A939572', 'Var', (73, 80))
115527	33322148	In addition, after cisplatin treatment, the death rate of tumor cells treated with A939572 was significantly greater than that of untreated cancer cells (p < 0.001, Figure 9b).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('death', 'Disease', 'MESH:D003643', (44, 49))	('death', 'Disease', (44, 49))	('A939572', 'Chemical', '-', (83, 90))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('A939572', 'Var', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('greater', 'PosReg', (109, 116))
115528	33322148	The 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay confirmed these findings, demonstrating a decreased cell viability when tumor cells were treated with A939572 before cisplatin incubation (Figure 9c).	('decreased', 'NegReg', (120, 129))	('A939572', 'Var', (180, 187))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('A939572', 'Chemical', '-', (180, 187))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide', 'Chemical', 'MESH:C022616', (4, 65))	('cisplatin', 'Chemical', 'MESH:D002945', (195, 204))	('MTT', 'Chemical', 'MESH:C070243', (67, 70))	('cell viability', 'CPA', (130, 144))
115567	33322148	Interestingly, inhibition of SCD1 activity reduced cell viability and sensitized cancer cells to cisplatin-induced apoptotic death.	('activity', 'MPA', (34, 42))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('SCD1', 'Gene', (29, 33))	('sensitized', 'Reg', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('cancer', 'Disease', (81, 87))	('cell viability', 'CPA', (51, 65))	('death', 'Disease', 'MESH:D003643', (125, 130))	('SCD1', 'Gene', '6319', (29, 33))	('reduced', 'NegReg', (43, 50))	('death', 'Disease', (125, 130))	('inhibition', 'Var', (15, 25))
115570	33322148	Interestingly, the treatment of cancer cells with SCD1 inhibitors can trigger the AMPK-dependent autophagic pathway, providing a resistance mechanism against SCD1 inhibition.	('AMPK', 'molecular_function', 'GO:0047322', ('82', '86'))	('SCD1', 'Gene', '6319', (158, 162))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('SCD1', 'Gene', (50, 54))	('inhibitors', 'Var', (55, 65))	('cancer', 'Disease', (32, 38))	('AMPK', 'Gene', '5562', (82, 86))	('AMPK', 'Gene', (82, 86))	('trigger', 'Reg', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('AMPK', 'molecular_function', 'GO:0050405', ('82', '86'))	('SCD1', 'Gene', '6319', (50, 54))	('SCD1', 'Gene', (158, 162))	('AMPK', 'molecular_function', 'GO:0004691', ('82', '86'))
115606	33322148	Cell viability after exposure to 75 nmol/L of A939572 or to A939572 and 10 muM cis-Diamminedichloroplatinum (II) (cisplatin) was evaluated using MTT assay as previously described.	('A939572', 'Var', (46, 53))	('cis-Diamminedichloroplatinum (II)', 'Chemical', 'MESH:D002945', (79, 112))	('A939572', 'Var', (60, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('Cell viability', 'CPA', (0, 14))	('A939572', 'Chemical', '-', (46, 53))	('MTT', 'Chemical', 'MESH:C070243', (145, 148))	('A939572', 'Chemical', '-', (60, 67))
115611	33322148	The accumulation of very long-chain FAs and PUFAs is sustained by overexpression of SCD1 and ELOVLs, and the inhibition of SCD1 activity decreases cell viability and improves cisplatin susceptibility, suggesting that this pathway can regulate chemotherapy resistance in ccRCC.	('RCC', 'Disease', (272, 275))	('cisplatin susceptibility', 'MPA', (175, 199))	('cell viability', 'CPA', (147, 161))	('ccRCC', 'Phenotype', 'HP:0006770', (270, 275))	('SCD1', 'Gene', '6319', (123, 127))	('inhibition', 'Var', (109, 119))	('PUFAs', 'Chemical', 'MESH:D005231', (44, 49))	('SCD1', 'Gene', (84, 88))	('RCC', 'Disease', 'MESH:C538614', (272, 275))	('regulate', 'Reg', (234, 242))	('SCD1', 'Gene', (123, 127))	('decreases', 'NegReg', (137, 146))	('SCD1', 'Gene', '6319', (84, 88))	('RCC', 'Phenotype', 'HP:0005584', (272, 275))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('improves', 'PosReg', (166, 174))
115670	32030920	Clinicopathological features of the high- and low-TNFR1 expression groups are summarized in Table 2 and Supplementary Table 2.	('men', 'Species', '9606', (110, 113))	('TNFR1', 'Gene', '7132', (50, 55))	('TNFR1', 'Gene', (50, 55))	('high-', 'Var', (36, 41))
115710	32030920	Several sequencing-based research have implicated TP53, NF2, and CDKN2A aberrations in sarcomatoid transformation of ccRCC, but the mechanism underlying sarcomatoid transformation has not been clarified in the majority of cases.	('CDKN2A', 'Gene', '1029', (65, 71))	('sarcomatoid transformation', 'Disease', 'MESH:D002292', (153, 179))	('implicated', 'Reg', (39, 49))	('aberrations', 'Var', (72, 83))	('NF2', 'Gene', (56, 59))	('NF2', 'Gene', '4771', (56, 59))	('TP53', 'Gene', '7157', (50, 54))	('sarcomatoid transformation', 'Disease', (87, 113))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('ccRCC', 'Disease', (117, 122))	('sarcomatoid transformation', 'Disease', 'MESH:D002292', (87, 113))	('TP53', 'Gene', (50, 54))	('CDKN2A', 'Gene', (65, 71))	('sarcomatoid transformation', 'Disease', (153, 179))	('ccRCC', 'Disease', 'MESH:D002292', (117, 122))
115786	30518081	In summary, the aggressive evolutionary subtypes, that is, tumors with high chromosomal complexity and low ITH displayed a rapid progression to multiple metastases, whereas the opposite, that is, tumors with low chromosomal complexity but high ITH showed an attenuated temporal tumor progression, with tendency to develop late single metastasis.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('high chromosomal complexity', 'Var', (71, 98))	('metastases', 'Disease', (153, 163))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('metastases', 'Disease', 'MESH:D009362', (153, 163))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('temporal tumor', 'Disease', 'MESH:C536956', (269, 283))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('low ITH', 'Var', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('temporal tumor', 'Disease', (269, 283))
115788	30518081	Genetic and epigenetic changes contribute to modify and adapt tumor cell fitness to the new requirements, thus selecting specific clones not only to invade or metastasize, but also to resist to drugs.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('invade', 'CPA', (149, 155))	('resist', 'CPA', (184, 190))	('modify', 'Reg', (45, 51))	('epigenetic changes', 'Var', (12, 30))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
115824	30413032	Therefore, deregulation of NF-kappaB activation pathways may result in autoimmune diseases and tumorigenesis.	('autoimmune diseases', 'Phenotype', 'HP:0002960', (71, 90))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('27', '47'))	('deregulation', 'Var', (11, 23))	('result in', 'Reg', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('NF-kappaB', 'Gene', '4790', (27, 36))	('autoimmune diseases', 'Disease', 'MESH:D001327', (71, 90))	('NF-kappaB', 'Gene', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('autoimmune diseases', 'Disease', (71, 90))	('tumor', 'Disease', (95, 100))
115826	30413032	Moreover, aberrant NF-kappaB signaling is associated with aggressiveness, recurrence, and therapeutic resistance of tumors.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('signaling', 'biological_process', 'GO:0023052', ('29', '38'))	('NF-kappaB', 'Gene', (19, 28))	('recurrence', 'CPA', (74, 84))	('therapeutic resistance', 'CPA', (90, 112))	('associated', 'Reg', (42, 52))	('aggressiveness', 'Disease', (58, 72))	('aberrant', 'Var', (10, 18))	('aggressiveness', 'Phenotype', 'HP:0000718', (58, 72))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('NF-kappaB', 'Gene', '4790', (19, 28))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('aggressiveness', 'Disease', 'MESH:D001523', (58, 72))
115830	30413032	This suggests that blockage of NF-kappaB would prevent this outcome.	('NF-kappaB', 'Gene', (31, 40))	('blockage', 'Var', (19, 27))	('NF-kappaB', 'Gene', '4790', (31, 40))
115837	30413032	p105 and p100 phosphorylation result in their 26S proteasome-induced processing via the activity of Skp-Cullin-F-box (SCF) ubiquitin E3 ligase.	('proteasome', 'molecular_function', 'GO:0004299', ('50', '60'))	('26S proteasome', 'cellular_component', 'GO:0005837', ('46', '60'))	('SCF', 'Gene', (118, 121))	('26S proteasome', 'cellular_component', 'GO:0000502', ('46', '60'))	('p105', 'Gene', '4790', (0, 4))	('p105', 'Gene', (0, 4))	('SCF', 'Gene', '4254', (118, 121))	('26S proteasome-induced processing', 'MPA', (46, 79))	('activity', 'MPA', (88, 96))	('phosphorylation', 'MPA', (14, 29))	('26S proteasome', 'cellular_component', 'GO:0000504', ('46', '60'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('123', '132'))	('SCF', 'molecular_function', 'GO:0005173', ('118', '121'))	('phosphorylation', 'biological_process', 'GO:0016310', ('14', '29'))	('Skp-Cullin-F-box', 'Gene', '4254', (100, 116))	('p100', 'Var', (9, 13))	('Skp-Cullin-F-box', 'Gene', (100, 116))
115854	30413032	Alterations in the non-canonical NF-kappaB activation are linked to inflammation, autoimmune diseases, lymphoid malignancies, and osteoporosis.	('autoimmune diseases', 'Disease', (82, 101))	('NF-kappaB', 'Gene', (33, 42))	('linked', 'Reg', (58, 64))	('inflammation', 'biological_process', 'GO:0006954', ('68', '80'))	('activation', 'PosReg', (43, 53))	('Alterations', 'Var', (0, 11))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (82, 101))	('inflammation', 'Disease', 'MESH:D007249', (68, 80))	('NF-kappaB', 'Gene', '4790', (33, 42))	('inflammation', 'Disease', (68, 80))	('lymphoid malignancies', 'Disease', 'MESH:D008223', (103, 124))	('lymphoid malignancies', 'Disease', (103, 124))	('lymphoid malignancies', 'Phenotype', 'HP:0002665', (103, 124))	('osteoporosis', 'Disease', (130, 142))	('osteoporosis', 'Phenotype', 'HP:0000939', (130, 142))	('rat', 'Species', '10116', (4, 7))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('33', '53'))	('osteoporosis', 'Disease', 'MESH:D010024', (130, 142))	('autoimmune diseases', 'Disease', 'MESH:D001327', (82, 101))
115881	30413032	Importantly, silencing IKK subunits using small interfering RNA (siRNA) or treatment with IKK inhibitor helps sensitize cancer cells to chemotherapy and trigger cell death.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('sensitize', 'Reg', (110, 119))	('cell death', 'biological_process', 'GO:0008219', ('161', '171'))	('RNA', 'cellular_component', 'GO:0005562', ('60', '63'))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('small interfering RNA', 'MPA', (42, 63))	('cell death', 'CPA', (161, 171))	('IKK', 'molecular_function', 'GO:0008384', ('23', '26'))	('IKK', 'molecular_function', 'GO:0008384', ('90', '93'))	('trigger', 'Reg', (153, 160))	('silencing', 'Var', (13, 22))
115883	30413032	Also, genetic instability can be acquired via the DNA damage induced by oxidative stress, which activates NF-kappaB.	('NF-kappaB', 'Gene', '4790', (106, 115))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('NF-kappaB', 'Gene', (106, 115))	('genetic', 'Var', (6, 13))	('oxidative stress', 'Phenotype', 'HP:0025464', (72, 88))	('activates', 'PosReg', (96, 105))
115884	30413032	NF-kappaB's direct role in cancer is based on the mutations of NF-kappaB regulatory proteins.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('NF-kappaB', 'Gene', '4790', (0, 9))	('mutations', 'Var', (50, 59))	('NF-kappaB', 'Gene', '4790', (63, 72))	('NF-kappaB', 'Gene', (0, 9))	('NF-kappaB', 'Gene', (63, 72))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
115885	30413032	Mostly, gain-of-function mutations of upstream NF-kappaB activators are responsible for NF-kappaB-driven cancers.	('mutations', 'Var', (25, 34))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('NF-kappaB', 'Gene', (88, 97))	('cancers', 'Disease', (105, 112))	('NF-kappaB', 'Gene', (47, 56))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('gain-of-function', 'PosReg', (8, 24))	('NF-kappaB', 'Gene', '4790', (88, 97))	('NF-kappaB', 'Gene', '4790', (47, 56))
115917	30413032	The improvement of antitumor activity in vitro can also be obtained by blockade of transforming growth factor (TGF)-beta signaling.	('signaling', 'biological_process', 'GO:0023052', ('121', '130'))	('blockade', 'Var', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('improvement', 'PosReg', (4, 15))
115919	30413032	Clinical studies are currently carried on TILs combined with anti- CTL-associated protein (CTLA)-4 monoclonal antibodies (mAbs) (ipilimumab) (NCT01701674), peginterferon alpha-2b upregulating human leukocyte antigen (HLA) expression on tumor cells (NCT02379195), and nivolumab (anti-PD-1 mAbs) with or without IFN-alpha (NCT03638375) for metastatic melanoma treatment.	('nivolumab', 'Chemical', 'MESH:D000077594', (267, 276))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('upregulating', 'PosReg', (179, 191))	('human', 'Species', '9606', (192, 197))	('melanoma', 'Phenotype', 'HP:0002861', (349, 357))	('melanoma', 'Disease', (349, 357))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('melanoma', 'Disease', 'MESH:D008545', (349, 357))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('CTL-associated protein (CTLA)-4', 'Gene', '1493', (67, 98))	('NCT02379195', 'Var', (249, 260))	('peginterferon', 'Var', (156, 169))	('ipilimumab', 'Chemical', 'MESH:D000074324', (129, 139))	('tumor', 'Disease', (236, 241))	('IFN-alpha', 'Gene', '3439', (310, 319))	('IFN-alpha', 'Gene', (310, 319))
115920	30413032	Other clinical trials implementing TILs are focused on the treatment of nasopharyngeal carcinoma (NCT02421640), malignant pleural mesothelioma (NCT02414945), cervical carcinoma (NCT03108495), and squamous cell carcinoma of the head and neck (NCT03083873).	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('squamous cell carcinoma', 'Disease', (196, 219))	('malignant pleural mesothelioma', 'Disease', (112, 142))	('NCT02421640', 'Var', (98, 109))	('cervical carcinoma', 'Disease', 'MESH:D002575', (158, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (210, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('NCT02414945', 'Var', (144, 155))	('nasopharyngeal carcinoma', 'Disease', (72, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (196, 219))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (112, 142))	('neck', 'cellular_component', 'GO:0044326', ('236', '240'))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (72, 96))	('NCT03083873', 'Var', (242, 253))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (196, 219))	('cervical carcinoma', 'Disease', (158, 176))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (122, 142))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (72, 96))	('NCT03108495', 'Var', (178, 189))
115922	30413032	For non-small cell lung cancer (NSCLC), TILs with durvalumab (anti-PD-ligand 1 (PD-L1) mAbs) (NCT03419559), nivolumab, and other drugs are under clinical trials (NCT03215810).	('lung cancer', 'Phenotype', 'HP:0100526', (19, 30))	('PD-L1', 'Gene', (80, 85))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (4, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (32, 37))	('ligand', 'molecular_function', 'GO:0005488', ('70', '76'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (8, 30))	('durvalumab', 'Chemical', 'MESH:C000613593', (50, 60))	('PD-L1', 'Gene', '29126', (80, 85))	('nivolumab', 'Chemical', 'MESH:D000077594', (108, 117))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (4, 30))	('anti-PD-ligand 1', 'Gene', '29126', (62, 78))	('NSCLC', 'Disease', (32, 37))	('NCT03419559', 'Var', (94, 105))	('non-small cell lung cancer', 'Disease', (4, 30))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))	('anti-PD-ligand 1', 'Gene', (62, 78))
115923	30413032	TILs are also tested in treatment of uveal neoplasms (NCT03467516), platinum-resistant high-grade serous ovarian, fallopian tube, or primary peritoneal cancer (NCT01883297).	('primary peritoneal cancer', 'Disease', (133, 158))	('neoplasms', 'Phenotype', 'HP:0002664', (43, 52))	('uveal neoplasms', 'Disease', (37, 52))	('primary peritoneal cancer', 'Phenotype', 'HP:0030406', (133, 158))	('fallopian tube', 'Disease', (114, 128))	('fallopian tube', 'Disease', 'MESH:D005184', (114, 128))	('platinum', 'Chemical', 'MESH:D010984', (68, 76))	('primary peritoneal cancer', 'Disease', 'MESH:D010534', (133, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('NCT03467516', 'Var', (54, 65))	('neoplasm', 'Phenotype', 'HP:0002664', (43, 51))	('uveal neoplasms', 'Disease', 'MESH:D014604', (37, 52))
115926	30413032	In metastatic melanoma, injection of T-VEC results in local inflammation, the presence of type I IFNs, and granulocyte-macrophage-colony-stimulating factor (GM-CSF)-attracted DCs, leading to subsequent cell killing.	('melanoma', 'Disease', (14, 22))	('inflammation', 'biological_process', 'GO:0006954', ('60', '72'))	('granulocyte-macrophage-colony-stimulating factor', 'molecular_function', 'GO:0005129', ('107', '155'))	('results in', 'Reg', (43, 53))	('inflammation', 'Disease', 'MESH:D007249', (60, 72))	('cell killing', 'CPA', (202, 214))	('granulocyte-macrophage-colony-stimulating factor', 'Gene', (107, 155))	('cell killing', 'biological_process', 'GO:0001906', ('202', '214'))	('GM-CSF', 'Gene', (157, 163))	('inflammation', 'Disease', (60, 72))	('GM-CSF', 'Gene', '1437', (157, 163))	('granulocyte-macrophage-colony-stimulating factor', 'Gene', '1437', (107, 155))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('IFN', 'Gene', '3439', (97, 100))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('IFN', 'Gene', (97, 100))	('injection', 'Var', (24, 33))
115931	30413032	Importantly, in preclinical studies on a mouse model, the use of anti-PD-1 or anti-CTLA-4 mAbs together with CVA improved anti-tumor response.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('anti-CTLA-4', 'Var', (78, 89))	('tumor', 'Disease', (127, 132))	('anti-PD-1', 'Var', (65, 74))	('mouse', 'Species', '10090', (41, 46))	('improved', 'PosReg', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
115941	30413032	ONCOS-102 (Oncos therapeutics) with Delta24 deletion within Rb-binding E1A gene, insertion of GM-CSF-encoding gene and replacement of serotype 3 AV knob protein was also granted by FDA as an orphan drug against ovarian cancer, glioma, and malignant mesothelioma.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (239, 261))	('Rb', 'Phenotype', 'HP:0009919', (60, 62))	('glioma', 'Disease', 'MESH:D005910', (227, 233))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('GM-CSF', 'Gene', '1437', (94, 100))	('Rb-binding E1A', 'Gene', (60, 74))	('ovarian cancer', 'Disease', (211, 225))	('protein', 'cellular_component', 'GO:0003675', ('153', '160'))	('ONCOS-102', 'Chemical', '-', (0, 9))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (239, 261))	('malignant mesothelioma', 'Disease', (239, 261))	('ovarian cancer', 'Disease', 'MESH:D010051', (211, 225))	('ovarian cancer', 'Phenotype', 'HP:0100615', (211, 225))	('GM-CSF', 'Gene', (94, 100))	('Delta24 deletion', 'Var', (36, 52))	('binding', 'molecular_function', 'GO:0005488', ('63', '70'))	('glioma', 'Disease', (227, 233))
115945	30413032	AxdAdB-3 is characterized by mutated Rb-binding domain of E1A and lack of E1B-55K and is derived from E1B-55K-deficient AxE1AdB.	('E1B', 'Gene', '594', (102, 105))	('E1B', 'Gene', '594', (74, 77))	('lack', 'NegReg', (66, 70))	('E1A', 'Gene', (58, 61))	('Rb-binding', 'Protein', (37, 47))	('binding', 'molecular_function', 'GO:0005488', ('40', '47'))	('mutated', 'Var', (29, 36))	('E1B', 'Gene', (74, 77))	('E1B', 'Gene', (102, 105))	('Rb', 'Phenotype', 'HP:0009919', (37, 39))
115947	30413032	Oncolytic AV type 5, dl922-947 mutant with deletions in E1A-conserved region 2 (CR2) and subsequent Rb-binding deficiency, is a candidate for anaplastic thyroid carcinoma treatment.	('thyroid carcinoma', 'Disease', 'MESH:D013964', (153, 170))	('Rb-binding', 'Protein', (100, 110))	('deletions', 'Var', (43, 52))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (142, 170))	('CR2', 'Gene', (80, 83))	('deficiency', 'Disease', (111, 121))	('CR2', 'Species', '2498238', (80, 83))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (153, 170))	('thyroid carcinoma', 'Disease', (153, 170))	('binding', 'molecular_function', 'GO:0005488', ('103', '110'))	('deficiency', 'Disease', 'MESH:D007153', (111, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('Rb', 'Phenotype', 'HP:0009919', (100, 102))
115948	30413032	In 8505-c and BHT101-5 human thyroid carcinoma anaplastic cell lines and TPC1 papillary cells, dl922-947 decreased C-X-C motif chemokine ligand 8 (CXCL8) promoter binding by p65.	('C-X-C motif chemokine ligand 8', 'Gene', (115, 145))	('CXCL8', 'Gene', '3576', (147, 152))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (29, 46))	('promoter binding', 'molecular_function', 'GO:0010843', ('154', '170'))	('C-X-C motif chemokine ligand 8', 'Gene', '3576', (115, 145))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (29, 46))	('CXCL8', 'Gene', (147, 152))	('dl922-947', 'Var', (95, 104))	('p65', 'Gene', (174, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('thyroid carcinoma', 'Disease', (29, 46))	('TPC1', 'Gene', (73, 77))	('human', 'Species', '9606', (23, 28))	('p65', 'Gene', '5970', (174, 177))	('TPC1', 'Gene', '53373', (73, 77))	('ligand', 'molecular_function', 'GO:0005488', ('137', '143'))	('decreased', 'NegReg', (105, 114))
115949	30413032	In addition, dl922-947 reduced CCL2 promoter binding by NF-kappaB in 8505-c and TPC1 cells by displacing p65 from the promoters.	('CCL2', 'Gene', '6347', (31, 35))	('p65', 'Gene', (105, 108))	('displacing', 'NegReg', (94, 104))	('p65', 'Gene', '5970', (105, 108))	('NF-kappaB', 'Gene', '4790', (56, 65))	('CCL', 'molecular_function', 'GO:0044101', ('31', '34'))	('CCL2', 'Gene', (31, 35))	('TPC1', 'Gene', '53373', (80, 84))	('dl922-947', 'Var', (13, 22))	('reduced', 'NegReg', (23, 30))	('NF-kappaB', 'Gene', (56, 65))	('promoter binding', 'molecular_function', 'GO:0010843', ('36', '52'))	('TPC1', 'Gene', (80, 84))
115951	30413032	In vivo experiment on anaplastic thyroid carcinoma xenograft mouse model revealed that dl922-947 reduces CXCL8 expression and angiogenesis.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (33, 50))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (22, 50))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (33, 50))	('thyroid carcinoma', 'Disease', (33, 50))	('angiogenesis', 'CPA', (126, 138))	('reduces', 'NegReg', (97, 104))	('mouse', 'Species', '10090', (61, 66))	('dl922-947', 'Var', (87, 96))	('CXCL8', 'Gene', '3576', (105, 110))	('CXCL8', 'Gene', (105, 110))	('angiogenesis', 'biological_process', 'GO:0001525', ('126', '138'))
115959	30413032	In addition, inhibition of NF-kappaB resulted in restored chemosensitivity of SKOV3 cells because of increased apoptosis.	('SKOV3', 'CellLine', 'CVCL:0532', (78, 83))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('inhibition', 'Var', (13, 23))	('restored', 'PosReg', (49, 57))	('NF-kappaB', 'Gene', '4790', (27, 36))	('chemosensitivity of', 'CPA', (58, 77))	('NF-kappaB', 'Gene', (27, 36))	('apoptosis', 'CPA', (111, 120))
115963	30413032	The E1A 243R and p53-binding E1B 55K AV proteins are known as inhibitors of inflammation upon virus infection, whereas E1B 19K counteracts inflammation in the presence of the two E1A 243R and E1B 55K.	('E1B', 'Gene', '594', (119, 122))	('inflammation', 'biological_process', 'GO:0006954', ('139', '151'))	('E1B', 'Gene', (29, 32))	('p53', 'Gene', (17, 20))	('inflammation', 'Disease', 'MESH:D007249', (76, 88))	('inflammation', 'Disease', 'MESH:D007249', (139, 151))	('E1A 243R', 'Var', (4, 12))	('E1B', 'Gene', (192, 195))	('inflammation', 'Disease', (76, 88))	('E1B', 'Gene', '594', (29, 32))	('inflammation', 'Disease', (139, 151))	('inflammation', 'biological_process', 'GO:0006954', ('76', '88'))	('p53-binding', 'molecular_function', 'GO:0002039', ('17', '28'))	('E1B', 'Gene', (119, 122))	('E1B', 'Gene', '594', (192, 195))	('inhibitors', 'MPA', (62, 72))	('inflammation upon virus infection', 'Disease', 'MESH:D007249', (76, 109))	('inflammation upon virus infection', 'Disease', (76, 109))	('p53', 'Gene', '7157', (17, 20))
115965	30413032	However, human lung adenocarcinoma A549 cells that underwent apoptosis upon infection with Ad5 mutant with E1B 19K-encoding gene deletion (H5dl337) were unable to inhibit NF-kappaB activation and proinflammatory cytokine responses in macrophages.	('inhibit', 'NegReg', (163, 170))	('NF-kappaB', 'Gene', '4790', (171, 180))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (15, 34))	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('171', '191'))	('lung adenocarcinoma A549', 'Disease', (15, 39))	('activation', 'MPA', (181, 191))	('lung adenocarcinoma A549', 'Disease', 'MESH:D000077192', (15, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('Ad5', 'Gene', (91, 94))	('NF-kappaB', 'Gene', (171, 180))	('human', 'Species', '9606', (9, 14))	('E1B', 'Gene', (107, 110))	('mutant', 'Var', (95, 101))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))	('E1B', 'Gene', '594', (107, 110))
115966	30413032	In order to enhance the antitumor effect, NF-kappaB activation can be induced via TLR9 by oncolytic Ad5D24-CpG, containing cytosine:guanine (CpG) islands within the genome.	('tumor', 'Disease', (28, 33))	('TLR9', 'Gene', (82, 86))	('cytosine', 'Chemical', 'MESH:D003596', (123, 131))	('NF-kappaB', 'Gene', '4790', (42, 51))	('guanine', 'Chemical', 'MESH:D006147', (132, 139))	('Ad5D24-CpG', 'Var', (100, 110))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('42', '62'))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('enhance', 'PosReg', (12, 19))	('NF-kappaB', 'Gene', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('TLR9', 'Gene', '54106', (82, 86))	('activation', 'PosReg', (52, 62))
115967	30413032	Importantly, stimulation of TLR9 induces DCs to type I IFN-mediated activation and proinflammatory IL-12 secretion.	('stimulation', 'Var', (13, 24))	('TLR9', 'Gene', '54106', (28, 32))	('DCs', 'MPA', (41, 44))	('IFN', 'Gene', '3439', (55, 58))	('IL-12 secretion', 'biological_process', 'GO:0072610', ('99', '114'))	('IL-12', 'molecular_function', 'GO:0005143', ('99', '104'))	('IFN', 'Gene', (55, 58))	('IL-1', 'Gene', '3552', (99, 103))	('IL-1', 'Gene', (99, 103))	('TLR9', 'Gene', (28, 32))
115971	30413032	The efficacy of Ad5D24-CpG was also tested in mouse model of melanoma over-expressing chicken ovalbumin (OVA).	('ovalbumin', 'Gene', (94, 103))	('mouse', 'Species', '10090', (46, 51))	('chicken', 'Species', '9031', (86, 93))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('ovalbumin', 'Gene', '396058', (94, 103))	('Ad5D24-CpG', 'Var', (16, 26))
115973	30413032	Also, in mouse xenograft model of human lung cancer, tumor growth was reduced by using Ad5D24-CpG in combination with paclitaxel.	('human', 'Species', '9606', (34, 39))	('reduced', 'NegReg', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('mouse', 'Species', '10090', (9, 14))	('paclitaxel', 'Chemical', 'MESH:D017239', (118, 128))	('lung cancer', 'Disease', 'MESH:D008175', (40, 51))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('Ad5D24-CpG', 'Var', (87, 97))	('lung cancer', 'Disease', (40, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))
115976	30413032	Moreover, HSV-1 infects different cell types, and the presence of a separate attachment and fusion glycoproteins within its envelope is beneficial for modification to improve tumor targeting.	('rat', 'Species', '10116', (72, 75))	('tumor', 'Disease', (175, 180))	('improve', 'PosReg', (167, 174))	('HSV-1 infects', 'Disease', (10, 23))	('HSV-1 infects', 'Disease', 'MESH:C536395', (10, 23))	('envelope', 'cellular_component', 'GO:0031975', ('124', '132'))	('modification', 'Var', (151, 163))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('envelope', 'cellular_component', 'GO:0009274', ('124', '132'))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
115977	30413032	The US FDA and European Medicines Agency approved T-VEC (IMLYGIC, Amgen) of GM-CSF-expressing HSV-1 with deletion of gamma134.5 gene encoding infected cell protein (ICP)34.5 neurovirulence factor and ICP47-encoding alpha47 gene deletion in inoperable stage IIIb to IV melanoma.	('deletion', 'Var', (105, 113))	('HSV-1', 'Species', '10298', (94, 99))	('alpha47', 'Gene', (215, 222))	('gamma134.5', 'Gene', (117, 127))	('ICP47-encoding', 'Gene', (200, 214))	('IV melanoma', 'Disease', (265, 276))	('GM-CSF', 'Gene', (76, 82))	('GM-CSF', 'Gene', '1437', (76, 82))	('IV melanoma', 'Disease', 'MESH:D008545', (265, 276))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('HSV-1', 'Gene', (94, 99))	('melanoma', 'Phenotype', 'HP:0002861', (268, 276))
115978	30413032	Also, FDA granted G207 with gamma134.5 and large subunit of ribonucleotide reductase (UL39) gene deletions (MediGene AG, Martinsried, Germany) as an orphan drug in glioma treatment.	('glioma', 'Disease', 'MESH:D005910', (164, 170))	('UL39', 'Gene', (86, 90))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('deletions', 'Var', (97, 106))	('glioma', 'Disease', (164, 170))
115981	30413032	Importantly, 5-FU, CPT-11, but not methotrexate (MTX), activate NF-kappaB in HT29 cells.	('5-FU', 'Chemical', 'MESH:D005472', (13, 17))	('CPT-11', 'Var', (19, 25))	('methotrexate', 'Chemical', 'MESH:D008727', (35, 47))	('NF-kappaB', 'Gene', '4790', (64, 73))	('CPT-11', 'Chemical', 'MESH:D000077146', (19, 25))	('CPT', 'molecular_function', 'GO:0004142', ('19', '22'))	('activate', 'PosReg', (55, 63))	('HT29 cells', 'CellLine', 'CVCL:0320', (77, 87))	('NF-kappaB', 'Gene', (64, 73))	('CPT', 'molecular_function', 'GO:0004095', ('19', '22'))	('MTX', 'Chemical', 'MESH:D008727', (49, 52))
115986	30413032	For gamma134.5 gene-deficient HSV-1 mutant R849 with lacZ encoding bacterial beta-galactosidase substitution, it has been demonstrated that TSA, which enhances p65 acetylation and nuclear accumulation, promotes viral replication in oral squamous cell carcinoma (SCC) SAS cells.	('oral squamous cell carcinoma', 'Disease', (232, 260))	('HSV-1', 'Gene', (30, 35))	('nuclear accumulation', 'MPA', (180, 200))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (237, 260))	('mutant R849', 'Var', (36, 47))	('viral replication', 'biological_process', 'GO:0008166', ('211', '228'))	('TSA', 'Chemical', 'MESH:C012589', (140, 143))	('SCC', 'Phenotype', 'HP:0002860', (262, 265))	('acetylation', 'MPA', (164, 175))	('promotes', 'PosReg', (202, 210))	('TSA', 'molecular_function', 'GO:0033984', ('140', '143'))	('viral replication', 'biological_process', 'GO:0019079', ('211', '228'))	('enhances', 'PosReg', (151, 159))	('viral replication', 'biological_process', 'GO:0019058', ('211', '228'))	('p65', 'Gene', (160, 163))	('viral replication', 'CPA', (211, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('rat', 'Species', '10116', (129, 132))	('HSV-1', 'Species', '10298', (30, 35))	('p65', 'Gene', '5970', (160, 163))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (232, 260))
115996	30413032	H-1PV, whose replication is S-phase-dependent, evokes proinflammatory responses and is a hope for therapies of central nervous system tumors, including glioblastoma.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('central nervous system tumors', 'Disease', (111, 140))	('glioblastoma', 'Phenotype', 'HP:0012174', (152, 164))	('S-phase', 'biological_process', 'GO:0051320', ('28', '35'))	('proinflammatory responses', 'MPA', (54, 79))	('evokes', 'PosReg', (47, 53))	('nervous system tumors', 'Phenotype', 'HP:0004375', (119, 140))	('glioblastoma', 'Disease', 'MESH:D005909', (152, 164))	('central nervous system tumors', 'Phenotype', 'HP:0100006', (111, 140))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('glioblastoma', 'Disease', (152, 164))	('H-1PV', 'Var', (0, 5))	('central nervous system tumors', 'Disease', 'MESH:D016543', (111, 140))
116004	30413032	Moreover, NF-kappaB DNA binding and transcriptional activity were significantly reduced upon rPVH1-yCD/5-FC treatment.	('NF-kappaB', 'Gene', '4790', (10, 19))	('reduced', 'NegReg', (80, 87))	('DNA binding', 'molecular_function', 'GO:0003677', ('20', '31'))	('NF-kappaB', 'Gene', (10, 19))	('DNA', 'cellular_component', 'GO:0005574', ('20', '23'))	('transcriptional activity', 'MPA', (36, 60))	('rPVH1-yCD/5-FC', 'Var', (93, 107))
116005	30413032	Importantly, the antitumor activity of wt H-1PV and rPVH1-yCD/5-FC is likely to be associated with attenuation of both NF-kappaB and Akt/phosphatidylinositol 3-kinase (PI3K) activity.	('tumor', 'Disease', (21, 26))	('Akt', 'Gene', '207', (133, 136))	('attenuation', 'NegReg', (99, 110))	('NF-kappaB', 'Gene', '4790', (119, 128))	('PI3K', 'molecular_function', 'GO:0016303', ('168', '172'))	('NF-kappaB', 'Gene', (119, 128))	('Akt', 'Gene', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('rPVH1-yCD/5-FC', 'Var', (52, 66))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
116007	30413032	These observations suggest that inhibitors of these signaling pathways may increase the effectiveness of pancreatic cancer therapy.	('inhibitors', 'Var', (32, 42))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (105, 122))	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('pancreatic cancer', 'Disease', (105, 122))	('pancreatic cancer', 'Disease', 'MESH:D010190', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('increase', 'PosReg', (75, 83))
116011	30413032	In vitro studies on 786-O cell line treated with JSH-23, which inhibits LPS-induced NF-kappaB nuclear translocation, but not IkappaB degradation, demonstrated that JSH-23 significantly diminished LPS-induced NF-kappaB nuclear translocation, as well as susceptibility to EMCV virulence.	('virulence', 'biological_process', 'GO:0009406', ('275', '284'))	('virulence', 'biological_process', 'GO:0016032', ('275', '284'))	('LPS', 'Chemical', 'MESH:D008070', (196, 199))	('NF-kappaB', 'Gene', (208, 217))	('EMCV', 'Species', '12104', (270, 274))	('NF-kappaB', 'Gene', (84, 93))	('virulence', 'biological_process', 'GO:0009405', ('275', '284'))	('degradation', 'biological_process', 'GO:0009056', ('133', '144'))	('rat', 'Species', '10116', (153, 156))	('diminished', 'NegReg', (185, 195))	('LPS', 'Chemical', 'MESH:D008070', (72, 75))	('NF-kappaB', 'Gene', '4790', (208, 217))	('NF-kappaB', 'Gene', '4790', (84, 93))	('JSH-23', 'Var', (164, 170))
116014	30413032	The loss of VHL results in hypoxia-inducible factor (HIF)-2alpha stabilization at tumor enhancers.	('VHL', 'Gene', (12, 15))	('VHL', 'Gene', '7428', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('hypoxia-inducible factor (HIF)-2alpha', 'Gene', '2034', (27, 64))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('stabilization', 'MPA', (65, 78))	('tumor', 'Disease', (82, 87))	('loss', 'Var', (4, 8))
116020	30413032	IKK-inhibitors, BMS-345541 and TPCA-1, counteract cell proliferation, p65 nuclear translocation, and NF-kappaB-regulated CXCL8 gene expression in glioma cells.	('BMS-345541', 'Var', (16, 26))	('p65', 'Gene', '5970', (70, 73))	('gene expression', 'biological_process', 'GO:0010467', ('127', '142'))	('glioma', 'Disease', (146, 152))	('CXCL8', 'Gene', '3576', (121, 126))	('IKK', 'molecular_function', 'GO:0008384', ('0', '3'))	('CXCL8', 'Gene', (121, 126))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('glioma', 'Disease', 'MESH:D005910', (146, 152))	('NF-kappaB', 'Gene', '4790', (101, 110))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('rat', 'Species', '10116', (62, 65))	('NF-kappaB', 'Gene', (101, 110))	('p65', 'Gene', (70, 73))
116022	30413032	Particularly, BMS-345541 inhibits the action of IFN against EMCV, which exert a CPE in U87 cells.	('action', 'MPA', (38, 44))	('CPE', 'MPA', (80, 83))	('inhibits', 'NegReg', (25, 33))	('EMCV', 'Species', '12104', (60, 64))	('IFN', 'Gene', '3439', (48, 51))	('U87', 'CellLine', 'CVCL:0022', (87, 90))	('IFN', 'Gene', (48, 51))	('BMS-345541', 'Var', (14, 24))
116023	30413032	Importantly, the correlation between this effect and suppression of NF-kappaB by BMS-345541 was observed.	('BMS-345541', 'Var', (81, 91))	('NF-kappaB', 'Gene', '4790', (68, 77))	('suppression', 'NegReg', (53, 64))	('NF-kappaB', 'Gene', (68, 77))
116028	30413032	When combining M1 with H89, a protein kinase A (PKA) and NF-kappaB transcriptional inhibitor, the antiviral response is inhibited and M1-induced oncolysis is elevated.	('antiviral response', 'MPA', (98, 116))	('NF-kappaB', 'Gene', (57, 66))	('PKA', 'molecular_function', 'GO:0004691', ('48', '51'))	('inhibited', 'NegReg', (120, 129))	('PKA', 'cellular_component', 'GO:0005952', ('48', '51'))	('antiviral response', 'biological_process', 'GO:0051607', ('98', '116'))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('H89', 'Var', (23, 26))	('M1-induced oncolysis', 'CPA', (134, 154))	('elevated', 'PosReg', (158, 166))	('NF-kappaB', 'Gene', '4790', (57, 66))
116034	30413032	AF2240 is regarded as a good and efficient candidate in oncolytic virotherapy due to its high immunogenicity and selectivity toward tumors.	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('AF2240', 'Var', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
116037	30413032	AF2240 triggers p38 mitogen-activated protein kinase phosphorylation upstream of IkappaBalpha processing and NF-kappaB nuclear translocation in 786-O cells.	('NF-kappaB', 'Gene', '4790', (109, 118))	('AF2240', 'Var', (0, 6))	('NF-kappaB', 'Gene', (109, 118))	('p38', 'Gene', (16, 19))	('IkappaBalpha', 'Gene', '4792', (81, 93))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('IkappaBalpha', 'Gene', (81, 93))	('phosphorylation', 'biological_process', 'GO:0016310', ('53', '68'))	('p38', 'Gene', '1432', (16, 19))
116050	30413032	GSK-3ss, which has an impact on NF-kappaB-regulated genes, can be inhibited by AR-A014418, which also counteracts RV-induced NF-kappaB activation in HCT116 cells.	('GSK-3ss', 'Gene', (0, 7))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('impact', 'Reg', (22, 28))	('NF-kappaB', 'Gene', (32, 41))	('AR-A014418', 'Var', (79, 89))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('125', '145'))	('NF-kappaB', 'Gene', '4790', (125, 134))	('RV', 'Species', '10891', (114, 116))	('inhibited', 'NegReg', (66, 75))	('HCT116', 'CellLine', 'CVCL:0291', (149, 155))	('NF-kappaB', 'Gene', '4790', (32, 41))	('NF-kappaB', 'Gene', (125, 134))
116071	30413032	As shown in human prostate tumor xenografts, RSV leads to oncolysis of prostatic cancer cells in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('prostate tumor', 'Phenotype', 'HP:0100787', (18, 32))	('RSV', 'Species', '12814', (45, 48))	('RSV', 'Var', (45, 48))	('prostatic cancer', 'Disease', 'MESH:D011471', (71, 87))	('prostatic cancer', 'Phenotype', 'HP:0012125', (71, 87))	('oncolysis', 'MPA', (58, 67))	('prostate tumor', 'Disease', 'MESH:D011471', (18, 32))	('human', 'Species', '9606', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('prostatic cancer', 'Disease', (71, 87))	('prostate tumor', 'Disease', (18, 32))
116083	30413032	In glioma cells, TPCA-1 and BMS-345541 inhibited NF-kappaB activation and CXCL8 gene expression, as well as IFN-activated gene expression.	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('49', '69'))	('inhibited', 'NegReg', (39, 48))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('gene expression', 'biological_process', 'GO:0010467', ('80', '95'))	('gene expression', 'biological_process', 'GO:0010467', ('122', '137'))	('IFN', 'Gene', '3439', (108, 111))	('BMS-345541', 'Var', (28, 38))	('CXCL8', 'Gene', '3576', (74, 79))	('glioma', 'Disease', (3, 9))	('CXCL8', 'Gene', (74, 79))	('NF-kappaB', 'Gene', '4790', (49, 58))	('activation', 'PosReg', (59, 69))	('NF-kappaB', 'Gene', (49, 58))	('IFN', 'Gene', (108, 111))
116084	30413032	BMS-345541 has been demonstrated to counteract antiviral IFN effect against VSV in glioma cells since VSV is considered as a promising tool in oncolytic therapies of malignant brain tumors.	('glioma', 'Disease', (83, 89))	('VSV', 'Species', '11276', (76, 79))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('malignant brain tumors', 'Disease', 'MESH:D001932', (166, 188))	('IFN', 'Gene', '3439', (57, 60))	('IFN', 'Gene', (57, 60))	('VSV', 'Species', '11276', (102, 105))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('rat', 'Species', '10116', (27, 30))	('BMS-345541', 'Var', (0, 10))	('brain tumors', 'Phenotype', 'HP:0030692', (176, 188))	('malignant brain tumors', 'Disease', (166, 188))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
116092	30413032	When treated with curcumin and then infected with recombinant M protein mutant VSV, rM51R-M, the cells became sensitized to VSV-induced apoptosis and showed the reduction on phospho (p)-NF-kappaB expression.	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('apoptosis', 'CPA', (136, 145))	('VSV', 'Gene', (79, 82))	('curcumin', 'Chemical', 'MESH:D003474', (18, 26))	('apoptosis', 'biological_process', 'GO:0097194', ('136', '145'))	('expression', 'MPA', (196, 206))	('sensitized', 'Reg', (110, 120))	('rM51R-M', 'Var', (84, 91))	('reduction', 'NegReg', (161, 170))	('apoptosis', 'biological_process', 'GO:0006915', ('136', '145'))	('NF-kappaB', 'Gene', '4790', (186, 195))	('VSV', 'Species', '11276', (79, 82))	('VSV', 'Species', '11276', (124, 127))	('NF-kappaB', 'Gene', (186, 195))
116097	30413032	Inhibition of NF-kappaB by BMS-345541 led to attenuation of VSV replication in U266 and 5TGM1 MM cell lines.	('Inhibition', 'NegReg', (0, 10))	('VSV', 'Species', '11276', (60, 63))	('NF-kappaB', 'Gene', '4790', (14, 23))	('NF-kappaB', 'Gene', (14, 23))	('BMS-345541', 'Var', (27, 37))	('attenuation', 'NegReg', (45, 56))	('VSV replication', 'CPA', (60, 75))	('U266', 'CellLine', 'CVCL:0566', (79, 83))
116116	30319937	Treatment with targeted therapies has resulted in improved patient outcomes in the context of advanced metastatic RCC, with randomised controlled trials demonstrating improvements in both progression-free and overall survival compared with previous standard-of-care systemic therapies.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('patient', 'Species', '9606', (59, 66))	('improvements', 'PosReg', (167, 179))	('improved', 'PosReg', (50, 58))	('targeted', 'Var', (15, 23))	('men', 'Species', '9606', (5, 8))	('men', 'Species', '9606', (174, 177))
116120	30319937	The genetic basis of ccRCC is via a biallelic inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene located on the short arm of chromosome 3 (3p25.3), which encodes for the degradation of hypoxia-inducible factor.	('hypoxia', 'Disease', (201, 208))	('short arm', 'Phenotype', 'HP:0009824', (128, 137))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('chromosome', 'cellular_component', 'GO:0005694', ('141', '151'))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('degradation', 'biological_process', 'GO:0009056', ('186', '197'))	('RCC', 'Disease', (23, 26))	('biallelic inactivation', 'Var', (36, 58))	('von Hippel-Lindau (VHL) tumour', 'Disease', 'MESH:D006623', (66, 96))	('hypoxia', 'Disease', 'MESH:D000860', (201, 208))
116122	30319937	Although VHL mutations are present in an estimated 70% of clear cell cancers, genetic heterogeneity is a hallmark of progressive disease with several other genes responsible for disease advancement and resistance to therapy.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('advancement', 'Disease', 'MESH:D020178', (186, 197))	('advancement', 'Disease', (186, 197))	('VHL', 'Disease', 'MESH:D006623', (9, 12))	('mutations', 'Var', (13, 22))	('VHL', 'Disease', (9, 12))	('cancers', 'Disease', (69, 76))
116132	30319937	Targeting VEGF receptors 1-3, AXL, MET, RET, KIT, FLT3, ROS1, MER, TYRO3, TRKB and TIE-2, the mechanism of cabozantinib inhibits both the VEGF pathways, and downstream targets MET and AXL which are implicated in tumour resistance in patients treated with VEGF therapy alone, such as sunitinib.	('inhibits', 'NegReg', (120, 128))	('MET', 'Enzyme', (176, 179))	('MER', 'Gene', (62, 65))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('TRKB', 'Gene', '4915', (74, 78))	('RET', 'Gene', '5979', (40, 43))	('tumour', 'Disease', 'MESH:D009369', (212, 218))	('AXL', 'Gene', (30, 33))	('MER', 'Gene', '10461', (62, 65))	('tumour', 'Disease', (212, 218))	('ROS1', 'Gene', (56, 60))	('VEGF', 'Gene', '7422', (138, 142))	('TYRO3', 'Gene', (67, 72))	('VEGF', 'Gene', (138, 142))	('TIE-2', 'Gene', (83, 88))	('VEGF', 'Gene', '7422', (255, 259))	('cabozantinib', 'Chemical', 'MESH:C558660', (107, 119))	('VEGF', 'Gene', '7422', (10, 14))	('FLT3', 'Gene', (50, 54))	('sunitinib', 'Chemical', 'MESH:D000077210', (283, 292))	('VEGF', 'Gene', (10, 14))	('VEGF', 'Gene', (255, 259))	('TYRO3', 'Gene', '7301', (67, 72))	('AXL', 'Gene', '558', (184, 187))	('FLT3', 'Gene', '2322', (50, 54))	('RET', 'Gene', (40, 43))	('TIE-2', 'Gene', '7010', (83, 88))	('TRKB', 'Gene', (74, 78))	('patients', 'Species', '9606', (233, 241))	('ROS1', 'Gene', '6098', (56, 60))	('AXL', 'Gene', '558', (30, 33))	('cabozantinib', 'Var', (107, 119))	('AXL', 'Gene', (184, 187))	('KIT', 'molecular_function', 'GO:0005020', ('45', '48'))
116139	30319937	The FDA subsequently approved cabozantinib as a first-line therapy for the management of metastatic ccRCC, following completion of the phase II CABOSUN trial, which demonstrated benefits of cabozantinib compared with sunitinib (which is the standard first-line therapy) in terms of progression-free survival and radiological tumour response (although there was no benefit in overall survival).	('cabozantinib', 'Chemical', 'MESH:C558660', (30, 42))	('sunitinib', 'Chemical', 'MESH:D000077210', (217, 226))	('tumour', 'Disease', 'MESH:D009369', (325, 331))	('tumour', 'Disease', (325, 331))	('progression-free survival', 'CPA', (282, 307))	('cabozantinib', 'Var', (190, 202))	('men', 'Species', '9606', (81, 84))	('benefits', 'PosReg', (178, 186))	('RCC', 'Disease', (102, 105))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('cabozantinib', 'Chemical', 'MESH:C558660', (190, 202))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('tumour', 'Phenotype', 'HP:0002664', (325, 331))
116148	30319937	A recent systematic review which evaluated the cost-effectiveness of cabozantinib compared with other second-line therapies found that although cabozantinib was associated with favourable progression-free and overall survival, it was also one of the most expensive drugs (compared with everolimus, axitinib, nivolumab and sunitinib).	('cabozantinib', 'Var', (144, 156))	('everolimus', 'Chemical', 'MESH:D000068338', (286, 296))	('nivolumab', 'Chemical', 'MESH:D000077594', (308, 317))	('cabozantinib', 'Chemical', 'MESH:C558660', (69, 81))	('progression-free', 'CPA', (188, 204))	('cabozantinib', 'Chemical', 'MESH:C558660', (144, 156))	('axitinib', 'Chemical', 'MESH:D000077784', (298, 306))	('sunitinib', 'Chemical', 'MESH:D000077210', (322, 331))	('overall survival', 'CPA', (209, 225))
116164	27713173	Recently, post-translational histone modification has become more and more popular in cancer research due to their ability to regulate gene transcription.	('transcription', 'biological_process', 'GO:0006351', ('140', '153'))	('histone modification', 'biological_process', 'GO:0016570', ('29', '49'))	('regulate', 'Reg', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('gene transcription', 'MPA', (135, 153))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('post-translational', 'Var', (10, 28))	('cancer', 'Disease', (86, 92))
116170	27713173	According to recent findings, Dot1l-mediated H3K79 methylation is associated with many biological processes including transcriptional regulation, DNA damage response, cell cycle progression, somatic reprogramming and embryonic cell development.	('DNA damage', 'MPA', (146, 156))	('associated', 'Reg', (66, 76))	('regulation', 'biological_process', 'GO:0065007', ('134', '144'))	('DNA', 'cellular_component', 'GO:0005574', ('146', '149'))	('methylation', 'biological_process', 'GO:0032259', ('51', '62'))	('Dot1l-mediated', 'Gene', (30, 44))	('H3K79', 'Protein', (45, 50))	('methylation', 'Var', (51, 62))	('DNA damage response', 'biological_process', 'GO:0006974', ('146', '165'))	('cell cycle progression', 'CPA', (167, 189))	('H3', 'Chemical', 'MESH:C012616', (45, 47))	('cell cycle', 'biological_process', 'GO:0007049', ('167', '177'))	('cell development', 'biological_process', 'GO:0048468', ('227', '243'))
116173	27713173	As a promising biochemical target, one of the Dot1l inhibitors is already under investigation in a Phase I clinical trial in MLL patients.	('patients', 'Species', '9606', (129, 137))	('Dot1l', 'Gene', (46, 51))	('MLL', 'Gene', '4297', (125, 128))	('inhibitors', 'Var', (52, 62))	('MLL', 'Gene', (125, 128))
116188	27713173	Patients with higher Dot1lexpression trended to be older (P=0.015), have higher pT/pM stage (P=0.006/0.022) and have higher TNM grade (P=0.001).	('Dot1lexpression', 'Var', (21, 36))	('pT/pM stage', 'CPA', (80, 91))	('TNM', 'Gene', '10178', (124, 127))	('Patients', 'Species', '9606', (0, 8))	('higher', 'PosReg', (117, 123))	('TNM', 'Gene', (124, 127))	('higher', 'PosReg', (73, 79))
116189	27713173	As presented in Figure 2, patients in high Dot1l group had a worse OS (P<0.001, Figure 2A) and RFS (P<0.001, Figure 2B) than those in low Dot1l group.	('high Dot1l', 'Var', (38, 48))	('RFS', 'MPA', (95, 98))	('patients', 'Species', '9606', (26, 34))
116201	27713173	By multivariate analysis, our research confirmed that Dot1l could be regarded as an independent prognostic factor for ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('Dot1l', 'Var', (54, 59))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))	('patients', 'Species', '9606', (124, 132))
116205	27713173	It is well established that epigenetic modifications play a major role in genesis and development of cancer.	('cancer', 'Disease', (101, 107))	('epigenetic modifications', 'Var', (28, 52))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
116206	27713173	Among those modifications, histone methylation acts as a key step because of its contribution to cell-cycle progression, somatic reprogramming and tumor genesis.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('histone methylation', 'biological_process', 'GO:0016571', ('27', '46'))	('histone', 'Var', (27, 34))	('somatic reprogramming', 'CPA', (121, 142))	('modifications', 'Var', (12, 25))	('cell-cycle progression', 'CPA', (97, 119))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cell-cycle', 'biological_process', 'GO:0007049', ('97', '107'))
116210	27713173	In prostate cancer, Dot1l directly methylates androgen receptor to regulate its activity.	('androgen receptor', 'Protein', (46, 63))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('regulate', 'Reg', (67, 75))	('activity', 'MPA', (80, 88))	('prostate cancer', 'Disease', (3, 18))	('methylates', 'Var', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('Dot1l', 'Gene', (20, 25))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
116214	27713173	Moreover, we found that Dot1l copies had some mutations in ccRCC samples from the DNA information of 2013 TCGA cohort data, which indicated that Dot1l might be associated with ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('mutations', 'Var', (46, 55))	('Dot1l', 'Gene', (145, 150))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (178, 181))	('RCC', 'Disease', (61, 64))	('ccRCC', 'Phenotype', 'HP:0006770', (176, 181))	('Dot1l', 'Gene', (24, 29))	('associated', 'Reg', (160, 170))
116216	27713173	Firstly, Dot1l mediated methylation of H3K79 has been implicated in transcriptional elongation and cell cycle regulation, which influence the cell division and differentiation and then generate cancer cells.	('influence', 'Reg', (128, 137))	('cancer', 'Disease', (194, 200))	('Dot1l', 'Gene', (9, 14))	('H3', 'Chemical', 'MESH:C012616', (39, 41))	('cell cycle regulation', 'CPA', (99, 120))	('methylation', 'Var', (24, 35))	('implicated', 'Reg', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('99', '120'))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('generate', 'Reg', (185, 193))	('cell division', 'biological_process', 'GO:0051301', ('142', '155'))	('cell division', 'CPA', (142, 155))	('H3K79', 'Protein', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
116218	27713173	De Vos D et al, then demonstrated that H3K79me3level increases progressively in mutant cells.	('increases', 'PosReg', (53, 62))	('H3', 'Chemical', 'MESH:C012616', (39, 41))	('H3K79me3level', 'Var', (39, 52))	('mutant', 'Var', (80, 86))
116220	27713173	An interesting phenomenon has been noticed that H3K79 mono- and di-methylation leads to activation of gene transcription, while H3K79 tri-methylation results in gene repression.	('H3', 'Chemical', 'MESH:C012616', (128, 130))	('activation', 'PosReg', (88, 98))	('H3K79', 'Var', (128, 133))	('mono-', 'Var', (54, 59))	('methylation', 'biological_process', 'GO:0032259', ('67', '78'))	('methylation', 'biological_process', 'GO:0032259', ('138', '149'))	('transcription', 'biological_process', 'GO:0006351', ('107', '120'))	('H3K79 mono-', 'Var', (48, 59))	('gene transcription', 'MPA', (102, 120))	('H3', 'Chemical', 'MESH:C012616', (48, 50))
116221	27713173	Thirdly, Dot1l has been proved to play a key role in haematopoiesis, and the high expression of Dot1l tends to cause MLL.	('Dot1l', 'Gene', (96, 101))	('high expression', 'Var', (77, 92))	('MLL', 'Gene', '4297', (117, 120))	('MLL', 'Gene', (117, 120))	('cause', 'Reg', (111, 116))
116230	27713173	Clinically, ccRCC patients with high Dot1l expression might need adjuvant therapy or a more proactive follow-up after surgery, even if they are low-risk patients based on classic clinicopathologic features.	('high', 'Var', (32, 36))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('ccRCC', 'Phenotype', 'HP:0006770', (12, 17))	('RCC', 'Disease', (14, 17))	('patients', 'Species', '9606', (153, 161))	('patients', 'Species', '9606', (18, 26))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
116284	32150972	Molecules with amine groups tend rather to induce papillary or medullary renal tumors, or urothelial tumors.	('amine groups', 'Var', (15, 27))	('renal tumors', 'Disease', (73, 85))	('amine', 'Chemical', 'MESH:D000588', (15, 20))	('urothelial tumors', 'Disease', (90, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('renal tumors', 'Phenotype', 'HP:0009726', (73, 85))	('rat', 'Species', '10116', (33, 36))	('papillary', 'Disease', (50, 59))	('medullary renal tumors', 'Phenotype', 'HP:0008659', (63, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('urothelial tumors', 'Disease', 'MESH:D001749', (90, 107))	('renal tumor', 'Phenotype', 'HP:0009726', (73, 84))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('renal tumors', 'Disease', 'MESH:D007674', (73, 85))	('induce', 'PosReg', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
116316	32150972	In this study, the diabetic balance had no influence on the incidence of renal tumors, but insulin seemed to speed up tumor growth.	('renal tumors', 'Disease', (73, 85))	('insulin', 'molecular_function', 'GO:0016088', ('91', '98'))	('diabetic', 'Disease', (19, 27))	('tumor', 'Disease', (79, 84))	('insulin', 'Var', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('speed up', 'PosReg', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('renal tumors', 'Phenotype', 'HP:0009726', (73, 85))	('renal tumor', 'Phenotype', 'HP:0009726', (73, 84))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('diabetic', 'Disease', 'MESH:D003920', (19, 27))	('renal tumors', 'Disease', 'MESH:D007674', (73, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
116335	32150972	it was shown that formic acid FNT could induce a high frequency of renal carcinomas in Sprague Dawley rats (41.7%; 25/60 rats) and female Buffalo type rats (33.3%; 10/30 rats).	('rats', 'Species', '10116', (102, 106))	('renal carcinoma', 'Phenotype', 'HP:0005584', (67, 82))	('renal carcinomas', 'Disease', (67, 83))	('rats', 'Species', '10116', (151, 155))	('Sprague Dawley rats', 'Species', '10116', (87, 106))	('rats', 'Species', '10116', (121, 125))	('renal carcinomas', 'Phenotype', 'HP:0005584', (67, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('rats', 'Species', '10116', (170, 174))	('formic acid', 'Chemical', 'MESH:C030544', (18, 29))	('induce', 'Reg', (40, 46))	('renal carcinomas', 'Disease', 'MESH:C538614', (67, 83))	('formic acid', 'Var', (18, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
116367	32150972	have suggested that the renal tumors induced by diethylstilbestrol in hamsters were renal adenocarcinomas.	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('diethylstilbestrol', 'Var', (48, 66))	('renal adenocarcinomas', 'Disease', 'MESH:C538614', (84, 105))	('renal tumors', 'Phenotype', 'HP:0009726', (24, 36))	('renal tumor', 'Phenotype', 'HP:0009726', (24, 35))	('renal adenocarcinomas', 'Disease', (84, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('renal tumors', 'Disease', 'MESH:D007674', (24, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('diethylstilbestrol', 'Chemical', 'MESH:D004054', (48, 66))	('renal tumors', 'Disease', (24, 36))
116379	32150972	The carcinogenic effects on the Wistar rat kidneys could also be observed after the transplacental inoculation of the polyomavirus.	('polyomavirus', 'Var', (118, 130))	('carcinogenic', 'Disease', 'MESH:D063646', (4, 16))	('carcinogenic', 'Disease', (4, 16))	('polyomavirus', 'Species', '36362', (118, 130))	('rat', 'Species', '10116', (39, 42))
116381	32150972	All polyomavirus stumps seemed to induce the same sarcomatogenous effects for the kidney.	('polyomavirus', 'Var', (4, 16))	('induce', 'Reg', (34, 40))	('polyomavirus', 'Species', '36362', (4, 16))	('sarcomatogenous effects', 'MPA', (50, 73))
116398	32150972	More specifically the exact sequences of genetic mutations leading to kidney cancer following exposure to all those agents remain mostly unknown, as well as if exposure to one specific agent always leads to the same cascade(s) of mutations or not.	('mutations', 'Var', (49, 58))	('kidney cancer', 'Phenotype', 'HP:0009726', (70, 83))	('kidney cancer', 'Disease', 'MESH:D007680', (70, 83))	('kidney cancer', 'Disease', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('leading to', 'Reg', (59, 69))
116399	32150972	published in 2019, it was shown, for example, that exposure to angiotensin II lead to GC   T:A transversions in the transgenic lacI genes of Big Blue rats, but in most of the aforementioned models induced by carcinogens especially, the pathophysiology underlying renal carcinogenesis would need to be studied more in depth to allow us to better understand, and maybe prevent, renal cancer development.	('angiotensin II', 'Gene', (63, 77))	('transversions', 'Var', (95, 108))	('lacI', 'Gene', '21788', (127, 131))	('rats', 'Species', '10116', (150, 154))	('renal carcinogenesis', 'Disease', 'MESH:D063646', (263, 283))	('renal cancer', 'Disease', (376, 388))	('lacI', 'Gene', (127, 131))	('angiotensin II', 'Gene', '24179', (63, 77))	('transgenic', 'Species', '10090', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('renal cancer', 'Phenotype', 'HP:0009726', (376, 388))	('renal cancer', 'Disease', 'MESH:D007680', (376, 388))	('renal carcinogenesis', 'Disease', (263, 283))
116404	31850854	In this study, three expression profile data sets (GSE15641, GSE16441 and GSE66270) were integrated to identify candidate genes that could elucidate functional pathways in ccRCC.	('GSE16441', 'Var', (61, 69))	('GSE66270', 'Var', (74, 82))	('GSE15641', 'Var', (51, 59))	('ccRCC', 'Disease', (172, 177))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('ccRCC', 'Phenotype', 'HP:0006770', (172, 177))	('ccRCC', 'Disease', 'MESH:D002292', (172, 177))
116430	31850854	GO analysis results showed that changes in BP of DEGs were significantly enriched in angiogenesis, extracellular matrix organization, response to hypoxia, excretion and response to drug (Table 1).	('excretion', 'biological_process', 'GO:0007588', ('155', '164'))	('response to drug', 'biological_process', 'GO:0042493', ('169', '185'))	('hypoxia', 'Disease', 'MESH:D000860', (146, 153))	('extracellular matrix organization', 'biological_process', 'GO:0030198', ('99', '132'))	('angiogenesis', 'biological_process', 'GO:0001525', ('85', '97'))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('99', '119'))	('response to hypoxia', 'biological_process', 'GO:0001666', ('134', '153'))	('response to drug', 'MPA', (169, 185))	('angiogenesis', 'CPA', (85, 97))	('extracellular matrix organization', 'CPA', (99, 132))	('excretion', 'MPA', (155, 164))	('hypoxia', 'Disease', (146, 153))	('changes', 'Var', (32, 39))
116441	31850854	Using the data from gene expression profiling interactive analysis (GEPIA), we noted that ccRCC patients who had an association of genomic alterations in CCND1 showed reductions in overall and disease-free survival (P=2.5E-05 for overall survival and P=6.7E-05 for disease-free survival) (Figure 3A-3B).	('disease-free survival', 'CPA', (193, 214))	('ccRCC', 'Disease', 'MESH:D002292', (90, 95))	('CCND1', 'Gene', '595', (154, 159))	('gene expression', 'biological_process', 'GO:0010467', ('20', '35'))	('alterations', 'Var', (139, 150))	('CCND1', 'Gene', (154, 159))	('overall', 'CPA', (181, 188))	('reductions', 'NegReg', (167, 177))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('patients', 'Species', '9606', (96, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('ccRCC', 'Disease', (90, 95))
116442	31850854	In addition, the PECAM1/CD31 alteration was significantly associated with worse overall survival (P=3.3E-05 for overall survival) while disease-free survival was not statistically significant (P=0.24 for disease-free survival) (Figure 3C-3D).	('overall survival', 'MPA', (80, 96))	('PECAM1', 'Gene', (17, 23))	('CD31', 'Gene', (24, 28))	('worse', 'NegReg', (74, 79))	('PECAM1', 'Gene', '5175', (17, 23))	('CD31', 'Gene', '5175', (24, 28))	('alteration', 'Var', (29, 39))
116457	31850854	Importantly, CCND1 amplification markedly correlated with poor OS (hazard ratio [HR]=0.408, p<0.001).	('CCND1', 'Gene', '595', (13, 18))	('poor OS', 'Disease', (58, 65))	('amplification', 'Var', (19, 32))	('correlated', 'Reg', (42, 52))	('CCND1', 'Gene', (13, 18))
116461	31850854	Significantly, PECAM1/CD31 amplification markedly correlated with poor OS (HR=0.448, p<0.001).	('poor OS', 'Disease', (66, 73))	('CD31', 'Gene', (22, 26))	('correlated', 'Reg', (50, 60))	('PECAM1', 'Gene', '5175', (15, 21))	('CD31', 'Gene', '5175', (22, 26))	('amplification', 'Var', (27, 40))	('PECAM1', 'Gene', (15, 21))
116467	31850854	We have already discussed the better prognosis of ccRCC patients with high expression of CCND1 and PECAM1/CD31.	('PECAM1', 'Gene', (99, 105))	('patients', 'Species', '9606', (56, 64))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (50, 55))	('ccRCC', 'Disease', (50, 55))	('CD31', 'Gene', '5175', (106, 110))	('ccRCC', 'Disease', 'MESH:D002292', (50, 55))	('CD31', 'Gene', (106, 110))	('CCND1', 'Gene', (89, 94))	('PECAM1', 'Gene', '5175', (99, 105))	('high', 'Var', (70, 74))	('CCND1', 'Gene', '595', (89, 94))
116469	31850854	As shown in Supplementary Figure 2, the high expression of CCND1 is not only related to the better prognosis of patients with kidney renal clear cell carcinoma, but also related to the better prognosis of liver hepatocellular carcinoma.	('high', 'Var', (40, 44))	('related', 'Reg', (170, 177))	('related', 'Reg', (77, 84))	('patients', 'Species', '9606', (112, 120))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (126, 159))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (211, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('expression', 'MPA', (45, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('CCND1', 'Gene', (59, 64))	('liver hepatocellular carcinoma', 'Disease', (205, 235))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (205, 235))	('CCND1', 'Gene', '595', (59, 64))	('kidney renal clear cell carcinoma', 'Disease', (126, 159))
116470	31850854	However, the high expression of CCND1 is associated with poor prognosis of head and neck squamous cell carcinoma, lung adenocarcinoma, mesothelioma and pancreatic adenocarcinoma.	('associated', 'Reg', (41, 51))	('pancreatic adenocarcinoma', 'Disease', (152, 177))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (114, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('lung adenocarcinoma', 'Disease', (114, 133))	('high', 'Var', (13, 17))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010195', (152, 177))	('CCND1', 'Gene', '595', (32, 37))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (75, 112))	('CCND1', 'Gene', (32, 37))	('neck', 'cellular_component', 'GO:0044326', ('84', '88'))	('mesothelioma', 'Disease', (135, 147))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (84, 112))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (114, 133))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (152, 177))	('neck squamous cell carcinoma', 'Disease', (84, 112))	('mesothelioma', 'Disease', 'MESH:D008654', (135, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))
116480	31850854	Numerous studies have demonstrated that development of ccRCC is the result of an accumulation of cellular and molecular aberrations, including epigenetic, transcriptomic, miRNA, proteomic and metabolomic abnormalities.	('miRNA', 'MPA', (171, 176))	('ccRCC', 'Disease', 'MESH:D002292', (55, 60))	('metabolomic abnormalities', 'Disease', 'MESH:D002869', (192, 217))	('aberrations', 'Disease', (120, 131))	('aberrations', 'Disease', 'MESH:D002869', (120, 131))	('metabolomic abnormalities', 'Disease', (192, 217))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))	('ccRCC', 'Disease', (55, 60))	('epigenetic', 'Var', (143, 153))
116508	31850854	Mutations in Wnt signaling pathway components are linked to many diseases, including cancer.	('Wnt signaling pathway', 'Pathway', (13, 34))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('linked', 'Reg', (50, 56))	('Mutations', 'Var', (0, 9))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('13', '34'))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
116513	31850854	Wnt signaling is involved in determining cell fate, and mutations in Wnt signaling pathway components are reported to be strongly associated with different types of human cancers, such as lung, breast and ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('mutations', 'Var', (56, 65))	('human', 'Species', '9606', (165, 170))	('breast and ovarian cancer', 'Disease', 'MESH:D061325', (194, 219))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('69', '90'))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('Wnt signaling pathway', 'Gene', (69, 90))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cancers', 'Disease', (171, 178))	('ovarian cancer', 'Phenotype', 'HP:0100615', (205, 219))	('lung', 'Disease', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('signaling', 'biological_process', 'GO:0023052', ('4', '13'))	('associated', 'Reg', (130, 140))
116516	31850854	PI3K signaling plays an important role in cellular physiology, coordinates insulin signaling during organism growth, and mediates key cellular processes such as glucose homeostasis, protein synthesis, cell proliferation and survival.	('glucose homeostasis', 'biological_process', 'GO:0042593', ('161', '180'))	('insulin', 'molecular_function', 'GO:0016088', ('75', '82'))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('PI3K', 'Var', (0, 4))	('cell proliferation', 'biological_process', 'GO:0008283', ('201', '219'))	('signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('protein', 'cellular_component', 'GO:0003675', ('182', '189'))	('PI3K signaling', 'biological_process', 'GO:0014065', ('0', '14'))	('protein synthesis', 'biological_process', 'GO:0006412', ('182', '199'))	('cell proliferation', 'CPA', (201, 219))	('glucose', 'Chemical', 'MESH:D005947', (161, 168))	('insulin signaling', 'MPA', (75, 92))
116518	31850854	PI3K signaling impacts on many processes that regulate the hallmarks of cancer, including cell proliferation, survival, and genomic instability, and metabolism.	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('PI3K signaling', 'Var', (0, 14))	('metabolism', 'biological_process', 'GO:0008152', ('149', '159'))	('impacts', 'Reg', (15, 22))	('PI3K signaling', 'biological_process', 'GO:0014065', ('0', '14'))	('genomic instability', 'CPA', (124, 143))	('metabolism', 'CPA', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (59, 78))	('cell proliferation', 'CPA', (90, 108))	('survival', 'CPA', (110, 118))	('cell proliferation', 'biological_process', 'GO:0008283', ('90', '108'))	('hallmarks of cancer', 'Disease', (59, 78))
116520	31850854	Furthermore, we believe that alterations in ICAM1, CXCR4, TYROBP, FN1, and CAV1 are significantly associated with worse prognosis, indicating that these genes may play important roles in creating aggressive malignant phenotypes of ccRCC.	('ccRCC', 'Disease', (231, 236))	('ccRCC', 'Disease', 'MESH:D002292', (231, 236))	('CAV1', 'Gene', '857', (75, 79))	('ICAM1', 'Gene', (44, 49))	('FN1', 'Gene', '2335', (66, 69))	('CAV1', 'Gene', (75, 79))	('CXCR4', 'molecular_function', 'GO:0038147', ('51', '56'))	('alterations', 'Var', (29, 40))	('TYROBP', 'Gene', (58, 64))	('ICAM1', 'Gene', '3383', (44, 49))	('TYROBP', 'Gene', '7305', (58, 64))	('ccRCC', 'Phenotype', 'HP:0006770', (231, 236))	('FN1', 'Gene', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (233, 236))	('CXCR4', 'Gene', '7852', (51, 56))	('associated', 'Reg', (98, 108))	('CXCR4', 'Gene', (51, 56))
116526	31850854	NCBI-GEO is regarded as a free public database of transcriptional expression profile and we obtained the gene expression profile of GSE15641, GSE16441 and GSE66270 in kidney cancer and normal kidney tissues.	('gene expression', 'biological_process', 'GO:0010467', ('105', '120'))	('GSE66270', 'Var', (155, 163))	('kidney cancer', 'Disease', (167, 180))	('kidney cancer', 'Disease', 'MESH:D007680', (167, 180))	('GSE15641', 'Var', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('GSE16441', 'Var', (142, 150))	('kidney cancer', 'Phenotype', 'HP:0009726', (167, 180))
116557	31481081	We further provided striking evidences that knockdown of UXT inhibits proliferation, colony formation, migration and invasion of renal cancer cells, in an EZH2-dependent manner.	('renal cancer', 'Phenotype', 'HP:0009726', (129, 141))	('renal cancer', 'Disease', 'MESH:D007680', (129, 141))	('formation', 'biological_process', 'GO:0009058', ('92', '101'))	('invasion of', 'CPA', (117, 128))	('proliferation', 'CPA', (70, 83))	('EZH2', 'Gene', '2146', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('EZH2', 'Gene', (155, 159))	('colony formation', 'CPA', (85, 101))	('knockdown', 'Var', (44, 53))	('renal cancer', 'Disease', (129, 141))	('inhibits', 'NegReg', (61, 69))	('UXT', 'Gene', (57, 60))	('UXT', 'Gene', '8409', (57, 60))	('migration', 'CPA', (103, 112))
116569	31481081	Deregulations of AR, GATA4, NF-kappaB and EVI1 signaling pathways are key factors that contribute to the progression of various malignancies.	('contribute', 'Reg', (87, 97))	('Deregulations', 'Var', (0, 13))	('malignancies', 'Disease', 'MESH:D009369', (128, 140))	('NF-kappaB', 'Gene', '4790', (28, 37))	('EVI1', 'Gene', '2122', (42, 46))	('NF-kappaB', 'Gene', (28, 37))	('EVI1', 'Gene', (42, 46))	('GATA4', 'Gene', '2626', (21, 26))	('AR', 'Gene', '367', (17, 19))	('signaling', 'biological_process', 'GO:0023052', ('47', '56'))	('malignancies', 'Disease', (128, 140))	('GATA4', 'Gene', (21, 26))
116579	31481081	Moreover, in RCC cells, the knockdown of UXT resulted in the inhibition of cell proliferation, colony formation, and cell migration.	('UXT', 'Gene', '8409', (41, 44))	('cell migration', 'biological_process', 'GO:0016477', ('117', '131'))	('cell migration', 'CPA', (117, 131))	('inhibition', 'NegReg', (61, 71))	('colony formation', 'CPA', (95, 111))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('61', '93'))	('formation', 'biological_process', 'GO:0009058', ('102', '111'))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', (13, 16))	('knockdown', 'Var', (28, 37))	('UXT', 'Gene', (41, 44))	('cell proliferation', 'CPA', (75, 93))
116620	31481081	Next, we delineated the domains that respond for the interaction between UXT and EZH2 by co-expression of EGFP-myc-UXT and Flag-EZH2 deletion mutants.	('EZH2', 'Gene', (81, 85))	('EZH2', 'Gene', '2146', (81, 85))	('UXT', 'Gene', (73, 76))	('deletion mutants', 'Var', (133, 149))	('UXT', 'Gene', (115, 118))	('UXT', 'Gene', '8409', (73, 76))	('EZH2', 'Gene', (128, 132))	('myc', 'Gene', (111, 114))	('EZH2', 'Gene', '2146', (128, 132))	('UXT', 'Gene', '8409', (115, 118))	('interaction', 'Interaction', (53, 64))	('myc', 'Gene', '4609', (111, 114))
116622	31481081	A series of EZH2 deletion mutants, which contain the Domain I [amino acids (aa) 1-170], Domain II [aa 170-340], SUZ12 binding domain [aa 341-559], and SET domain [aa 560-751], was co-expressed with EGFP-myc-UXT in HEK293T cells for co-immunoprecipitation assays (Fig.	('SUZ12', 'Gene', (112, 117))	('myc', 'Gene', (203, 206))	('HEK293T', 'CellLine', 'CVCL:0063', (214, 221))	('deletion mutants', 'Var', (17, 33))	('UXT', 'Gene', (207, 210))	('mutants', 'Var', (26, 33))	('myc', 'Gene', '4609', (203, 206))	('SUZ12', 'Gene', '23512', (112, 117))	('UXT', 'Gene', '8409', (207, 210))	('EZH2', 'Gene', '2146', (12, 16))	('binding', 'molecular_function', 'GO:0005488', ('118', '125'))	('EZH2', 'Gene', (12, 16))
116629	31481081	However, knockout of EZH2 led to disruption of EED binding to UXT but did not disrupt the binding to SUZ12 (Fig.	('UXT', 'Gene', '8409', (62, 65))	('knockout', 'Var', (9, 17))	('EED', 'Gene', '8726', (47, 50))	('binding', 'molecular_function', 'GO:0005488', ('51', '58'))	('binding', 'molecular_function', 'GO:0005488', ('90', '97'))	('EED', 'Gene', (47, 50))	('EZH2', 'Gene', (21, 25))	('binding', 'Interaction', (51, 58))	('EZH2', 'Gene', '2146', (21, 25))	('disruption', 'NegReg', (33, 43))	('SUZ12', 'Gene', '23512', (101, 106))	('SUZ12', 'Gene', (101, 106))	('UXT', 'Gene', (62, 65))
116641	31481081	We found that HOXA9 and DAB2IP were upregulated by shRNA-mediated UXT knockdown in the EZH2-WT cells (Fig.	('upregulated', 'PosReg', (36, 47))	('UXT', 'Gene', (66, 69))	('knockdown', 'Var', (70, 79))	('UXT', 'Gene', '8409', (66, 69))	('shRNA-mediated', 'Gene', (51, 65))	('HOXA9', 'Gene', '3205', (14, 19))	('EZH2', 'Gene', '2146', (87, 91))	('EZH2', 'Gene', (87, 91))	('HOXA9', 'Gene', (14, 19))	('DAB2IP', 'Gene', (24, 30))	('DAB2IP', 'Gene', '153090', (24, 30))
116644	31481081	Consistent with these results, knockdown of UXT in the EZH2-WT cells inhibited the EZH2 histone methyltransferase activity, indicated by the decrease of H3K27 methylation and increase of protein levels of HOXA9 and DAB2IP (Fig.	('histone methyltransferase', 'Gene', '56979', (88, 113))	('UXT', 'Gene', (44, 47))	('DAB2IP', 'Gene', '153090', (215, 221))	('decrease', 'NegReg', (141, 149))	('H3', 'Chemical', 'MESH:C012616', (153, 155))	('EZH2', 'Gene', '2146', (55, 59))	('EZH2', 'Gene', (55, 59))	('HOXA9', 'Gene', (205, 210))	('methylation', 'MPA', (159, 170))	('DAB2IP', 'Gene', (215, 221))	('protein levels', 'MPA', (187, 201))	('histone methyltransferase activity', 'molecular_function', 'GO:0008469', ('88', '122'))	('histone methyltransferase', 'Gene', (88, 113))	('HOXA9', 'Gene', '3205', (205, 210))	('UXT', 'Gene', '8409', (44, 47))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))	('activity', 'MPA', (114, 122))	('H3K27', 'Protein', (153, 158))	('EZH2', 'Gene', '2146', (83, 87))	('methylation', 'biological_process', 'GO:0032259', ('159', '170'))	('EZH2', 'Gene', (83, 87))	('increase', 'PosReg', (175, 183))	('inhibited', 'NegReg', (69, 78))	('histone methyltransferase activity', 'molecular_function', 'GO:0042054', ('88', '122'))	('knockdown', 'Var', (31, 40))
116646	31481081	In addition, by using quantitative chromatin immunoprecipitation (qChIP) assays, lower levels of H3K27 trimethylation(H3K27me3)on the HOXA9 promoter was detected in UXT knockdown cells comparing to the control cells (Fig.	('UXT', 'Gene', (165, 168))	('chromatin', 'cellular_component', 'GO:0000785', ('35', '44'))	('UXT', 'Gene', '8409', (165, 168))	('lower', 'NegReg', (81, 86))	('H3', 'Chemical', 'MESH:C012616', (118, 120))	('HOXA9', 'Gene', (134, 139))	('H3K27', 'Protein', (97, 102))	('knockdown', 'Var', (169, 178))	('H3', 'Chemical', 'MESH:C012616', (97, 99))	('HOXA9', 'Gene', '3205', (134, 139))
116653	31481081	Secondly, knockdown of UXT inhibited migration and invasion of ACHN and 786-O cells (Fig.	('knockdown', 'Var', (10, 19))	('UXT', 'Gene', (23, 26))	('UXT', 'Gene', '8409', (23, 26))	('inhibited', 'NegReg', (27, 36))
116688	31481081	Mechanistically, EZH2 methylates H3K27 to promote transcriptional silencing of many tumor suppressor genes.	('methylates', 'Var', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('EZH2', 'Gene', (17, 21))	('H3', 'Chemical', 'MESH:C012616', (33, 35))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('transcriptional silencing', 'MPA', (50, 75))	('tumor suppressor', 'biological_process', 'GO:0051726', ('84', '100'))	('H3K27', 'Protein', (33, 38))	('tumor', 'Disease', (84, 89))	('promote', 'PosReg', (42, 49))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('84', '100'))	('EZH2', 'Gene', '2146', (17, 21))
116689	31481081	In addition to histone, many other non-histone proteins also methylated by EZH2, and the interaction between EZH2 and these non-histone substrates plays important role in the development and progression of a variety of cancers.	('methylated', 'Var', (61, 71))	('interaction', 'Interaction', (89, 100))	('EZH2', 'Gene', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('role', 'Reg', (163, 167))	('EZH2', 'Gene', (109, 113))	('cancers', 'Disease', 'MESH:D009369', (219, 226))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('cancers', 'Disease', (219, 226))	('EZH2', 'Gene', '2146', (109, 113))	('EZH2', 'Gene', '2146', (75, 79))	('plays', 'Reg', (147, 152))
116727	29038551	After generating a digital image of the H&E slide, the tissue was decolorized and individual EC or lymphocyte nuclei were marked by CD31 (purple) and CD45 (brown), respectively (Figs S2, S3).	('H&E', 'Chemical', 'MESH:D006371', (40, 43))	('CD31', 'Gene', '5175', (132, 136))	('CD45', 'Gene', '5788', (150, 154))	('and', 'Var', (146, 149))	('CD45', 'Gene', (150, 154))	('CD31', 'Gene', (132, 136))
116736	29038551	We observed an overall difference in the vectors from pixels in CD31 positive areas compared to those from CD31 negative areas (n = 6,000 Wilcoxon Rank-Sum test p < 0.001; Fig.	('CD31', 'Gene', (107, 111))	('difference', 'Reg', (23, 33))	('CD31', 'Gene', '5175', (107, 111))	('CD31', 'Gene', (64, 68))	('positive', 'Var', (69, 77))	('CD31', 'Gene', '5175', (64, 68))	('vectors', 'MPA', (41, 48))
116786	29038551	This result suggests ongoing angiogenesis in tumors with a short DFS.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('angiogenesis', 'CPA', (29, 41))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('angiogenesis', 'biological_process', 'GO:0001525', ('29', '41'))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('short DFS', 'Var', (59, 68))
116799	29038551	H&E slides were decolorized and subsequently stained by immunohistochemistry (IHC) with antibodies reactive to CD31 (V-purple, endothelial cells), and CD45 (DAB, lymphocytes) (Figs S1, S2).	('CD45', 'Gene', '5788', (151, 155))	('DAB', 'Chemical', '-', (157, 160))	('CD31', 'Gene', '5175', (111, 115))	('and', 'Var', (147, 150))	('H&E', 'Chemical', 'MESH:D006371', (0, 3))	('CD45', 'Gene', (151, 155))	('CD31', 'Gene', (111, 115))
116870	28418894	At multivariate analysis by Cox regression modeling, tumor size, the presence of visceral metastases, high Fuhrman grade and low urinary levels of RKIP were independent adverse prognostic factors for CSS (Supplementary Table 3).	('RKIP', 'Gene', (147, 151))	('visceral metastases', 'Disease', (81, 100))	('CSS', 'Disease', (200, 203))	('high', 'Var', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('CSS', 'Chemical', '-', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('visceral metastases', 'Disease', 'MESH:D009362', (81, 100))	('tumor', 'Disease', (53, 58))	('RKIP', 'Gene', '5037', (147, 151))
116873	28418894	The PFS was significantly decreased for patients with low levels of RKIP (P<0.0001).	('patients', 'Species', '9606', (40, 48))	('PFS', 'MPA', (4, 7))	('RKIP', 'Gene', '5037', (68, 72))	('RKIP', 'Gene', (68, 72))	('decreased', 'NegReg', (26, 35))	('low levels', 'Var', (54, 64))
116874	28418894	Univariate analyses for the predefined variables showed that tumor size, pathological stage, presence of visceral metastases, TNM stage, Fuhrman grade, and low levels of RKIP were significantly associated with the risk of progression (all P<0.0001).	('tumor', 'Disease', (61, 66))	('TNM', 'Gene', '10178', (126, 129))	('RKIP', 'Gene', '5037', (170, 174))	('RKIP', 'Gene', (170, 174))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('visceral metastases', 'Disease', 'MESH:D009362', (105, 124))	('associated', 'Reg', (194, 204))	('TNM', 'Gene', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('low levels', 'Var', (156, 166))	('visceral metastases', 'Disease', (105, 124))
116880	28418894	These data suggested that RKIP may be excreted in urine samples in both monomeric and dimeric form and confirmed that protein dimerization is mediated by S153 phosphorylation.	('protein dimerization', 'MPA', (118, 138))	('phosphorylation', 'biological_process', 'GO:0016310', ('159', '174'))	('RKIP', 'Gene', '5037', (26, 30))	('mediated', 'Reg', (142, 150))	('RKIP', 'Gene', (26, 30))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))	('S153', 'Var', (154, 158))
116897	28418894	Furthermore, Kaplan-Mayer curves revealed that ccRCC patients with less than 10 ng/mg/g Pr/uCR at diagnosis had a higher risk of disease progression and death after a median of 41 months follow-up (Figure 5).	('less', 'Var', (67, 71))	('patients', 'Species', '9606', (53, 61))	('ccRCC', 'Disease', (47, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('disease progression', 'CPA', (129, 148))	('death', 'Disease', 'MESH:D003643', (153, 158))	('death', 'Disease', (153, 158))
116904	28418894	We speculated that impaired expression of RKIP might activate the EMT both in CKD and ccRCC, albeit through distinct mechanisms.	('RKIP', 'Gene', (42, 46))	('RKIP', 'Gene', '5037', (42, 46))	('impaired', 'Var', (19, 27))	('CKD', 'Phenotype', 'HP:0012622', (78, 81))	('expression', 'MPA', (28, 38))	('EMT', 'biological_process', 'GO:0001837', ('66', '69'))	('CKD', 'Disease', 'MESH:D012080', (78, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('ccRCC', 'Disease', (86, 91))	('activate', 'PosReg', (53, 61))	('CKD', 'Disease', (78, 81))	('EMT', 'CPA', (66, 69))
116907	28418894	As reported by Deiss and co-workers, RKIP dimer formation is necessary to switch its target from RAF-1 to G protein-coupled receptor kinase (GRK) 2 and the phosphorylation of Ser-153 also increases the affinity of RKIP for GRK2.	('Ser', 'Chemical', 'MESH:D012694', (175, 178))	('Ser-153', 'Var', (175, 182))	('increases', 'PosReg', (188, 197))	('GRK2', 'molecular_function', 'GO:0047696', ('223', '227'))	('formation', 'biological_process', 'GO:0009058', ('48', '57'))	('phosphorylation', 'Var', (156, 171))	('phosphorylation', 'biological_process', 'GO:0016310', ('156', '171'))	('GRK) 2', 'molecular_function', 'GO:0047696', ('141', '147'))	('RKIP', 'Gene', '5037', (214, 218))	('GRK2', 'Gene', '156', (223, 227))	('RKIP', 'Gene', '5037', (37, 41))	('RKIP', 'Gene', (214, 218))	('Ser', 'cellular_component', 'GO:0005790', ('175', '178'))	('RKIP', 'Gene', (37, 41))	('affinity', 'Interaction', (202, 210))	('GRK2', 'Gene', (223, 227))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
116935	28418894	FlexAnalysis 3.3 software was used for spectra processing then Biotools 3.2 and MASCOT search algorithm (http://www.matrixscience.com/) online version 2.4 against the NCBInr and Swissprot databases were used for protein identification using the following parameters: Homo Sapiens as taxonomic category, trypsin as enzyme, carbamidomethyl as fixed modification for cysteine residues, oxidation of methionine as variable modification, and one missing cleavage and 50 ppm as mass tolerance for the monoisotopic peptide masses and 0,3 Da mass tolerance for MS-MS analysis.	('cysteine residues', 'MPA', (364, 381))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('carbamidomethyl', 'Var', (322, 337))	('Homo Sapiens', 'Species', '9606', (267, 279))	('oxidation', 'Var', (383, 392))
116942	28418894	Clarity   Western ECL substrate (BIORAD, Hercules, CA, USA) was used to detect RKIP and p-RIKP through the Versadoc Molecular Imager  (Bio-Rad).	('RKIP', 'Gene', '5037', (79, 83))	('Rad', 'biological_process', 'GO:1990116', ('139', '142'))	('RKIP', 'Gene', (79, 83))	('p-RIKP', 'Var', (88, 94))
116984	32256450	Luciferase reporter assays showed miR-183-5p and miR-21 bound to OTUD6B-AS1.	('OTUD6B-AS1', 'Gene', (65, 75))	('miR-183-5p', 'Var', (34, 44))	('OTUD6B-AS1', 'Gene', '100506365', (65, 75))	('bound', 'Interaction', (56, 61))	('miR-21', 'Gene', (49, 55))	('miR-183-5p', 'Chemical', '-', (34, 44))	('miR-21', 'Gene', '406991', (49, 55))
116985	32256450	Moreover, overexpression of miR-183-5p and miR-21 compromised the inhibitory effects of OTUD6B-AS1 on viability, migration, and invasion of thyroid carcinoma cells.	('viability', 'CPA', (102, 111))	('miR-183-5p', 'Chemical', '-', (28, 38))	('miR-21', 'Gene', '406991', (43, 49))	('OTUD6B-AS1', 'Gene', (88, 98))	('miR-183-5p', 'Var', (28, 38))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (140, 157))	('OTUD6B-AS1', 'Gene', '100506365', (88, 98))	('miR-21', 'Gene', (43, 49))	('migration', 'CPA', (113, 122))	('thyroid carcinoma', 'Disease', (140, 157))	('overexpression', 'PosReg', (10, 24))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (140, 157))	('inhibitory effects', 'MPA', (66, 84))	('compromised', 'NegReg', (50, 61))	('invasion', 'CPA', (128, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
116987	32256450	OTUD6B-AS1 inhibits viability, migration, and invasion of thyroid carcinoma by targeting miR-183-5p and miR-21.	('thyroid carcinoma', 'Disease', (58, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('OTUD6B-AS1', 'Gene', (0, 10))	('viability', 'CPA', (20, 29))	('miR-183-5p', 'Var', (89, 99))	('migration', 'CPA', (31, 40))	('OTUD6B-AS1', 'Gene', '100506365', (0, 10))	('inhibits', 'NegReg', (11, 19))	('miR-21', 'Gene', (104, 110))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (58, 75))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (58, 75))	('miR-21', 'Gene', '406991', (104, 110))	('miR-183-5p', 'Chemical', '-', (89, 99))	('invasion', 'CPA', (46, 54))
116993	32256450	In addition, dysregulation of lncRNAs is associated with poor prognoses thyroid carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('associated', 'Reg', (41, 51))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (72, 89))	('lncRNAs', 'Protein', (30, 37))	('dysregulation', 'Var', (13, 26))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (72, 90))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (72, 90))	('thyroid carcinomas', 'Disease', (72, 90))
117023	32256450	The primers used to determine the expression of OTUD6B-AS1, miR-183-5p, and miR-21 are listed in Table 2.	('miR-183-5p', 'Var', (60, 70))	('OTUD6B-AS1', 'Gene', '100506365', (48, 58))	('miR-21', 'Gene', (76, 82))	('miR-183-5p', 'Chemical', '-', (60, 70))	('miR-21', 'Gene', '406991', (76, 82))	('OTUD6B-AS1', 'Gene', (48, 58))
117047	32256450	Two miRNAs, miR-183-5p and miR-21, were found to be potential targets of OTUD6B-AS1 (Figure 5A).	('miR-21', 'Gene', (27, 33))	('OTUD6B-AS1', 'Gene', (73, 83))	('OTUD6B-AS1', 'Gene', '100506365', (73, 83))	('miR-183-5p', 'Chemical', '-', (12, 22))	('miR-21', 'Gene', '406991', (27, 33))	('miR-183-5p', 'Var', (12, 22))
117048	32256450	The sequences of the binding sites of lncRNA OTUD6B-AS1 with miR-21 and miR-183-5p were shown in Figure 5B.	('OTUD6B-AS1', 'Gene', (45, 55))	('miR-183-5p', 'Chemical', '-', (72, 82))	('OTUD6B-AS1', 'Gene', '100506365', (45, 55))	('miR-21', 'Gene', '406991', (61, 67))	('miR-183-5p', 'Var', (72, 82))	('binding', 'molecular_function', 'GO:0005488', ('21', '28'))	('miR-21', 'Gene', (61, 67))
117050	32256450	psiCHECK-2-WT was co-transfected with miR-183-5p or miR-21 in 293T cells.	('miR-183-5p', 'Chemical', '-', (38, 48))	('293T', 'CellLine', 'CVCL:0063;0.08513991168153145', (62, 66))	('miR-21', 'Gene', (52, 58))	('miR-183-5p', 'Var', (38, 48))	('miR-21', 'Gene', '406991', (52, 58))
117051	32256450	A scramble RNA (NC) was used as a control for miR-183-5p and miR-21.	('miR-21', 'Gene', (61, 67))	('miR-21', 'Gene', '406991', (61, 67))	('miR-183-5p', 'Chemical', '-', (46, 56))	('miR-183-5p', 'Var', (46, 56))	('RNA', 'cellular_component', 'GO:0005562', ('11', '14'))
117052	32256450	Decreased luciferase activities were observed in cells co-transfected with psiCHECK-2-WT and its potential target miR-21 or miR-183-5p (Figure 5C).	('miR-21', 'Gene', '406991', (114, 120))	('activities', 'MPA', (21, 31))	('Decreased', 'NegReg', (0, 9))	('miR-183-5p', 'Chemical', '-', (124, 134))	('miR-21', 'Gene', (114, 120))	('miR-183-5p', 'Var', (124, 134))	('luciferase', 'Enzyme', (10, 20))
117054	32256450	These data indicated that miR-21 and miR-183-5p are bound to OTUD6B-AS1.	('miR-21', 'Gene', '406991', (26, 32))	('bound', 'Interaction', (52, 57))	('OTUD6B-AS1', 'Gene', '100506365', (61, 71))	('miR-183-5p', 'Chemical', '-', (37, 47))	('OTUD6B-AS1', 'Gene', (61, 71))	('miR-21', 'Gene', (26, 32))	('miR-183-5p', 'Var', (37, 47))
117055	32256450	In order to determine the binding specificity of miR-21 and miR-183-5p, the binding sites of miR-21 and miR-183-5p were mutated in luciferase reporter plasmids psiCHECK-2-WT, named psiCHECK-2-mutant.	('miR-21', 'Gene', '406991', (93, 99))	('miR-183-5p', 'Gene', (104, 114))	('miR-183-5p', 'Chemical', '-', (104, 114))	('miR-21', 'Gene', '406991', (49, 55))	('miR-21', 'Gene', (49, 55))	('binding', 'molecular_function', 'GO:0005488', ('76', '83'))	('binding', 'molecular_function', 'GO:0005488', ('26', '33'))	('miR-21', 'Gene', (93, 99))	('miR-183-5p', 'Chemical', '-', (60, 70))	('mutated', 'Var', (120, 127))
117056	32256450	No significant differences were observed in cells co-transfected with psiCHECK-2-mutant and miR-21 or miR-183-5p (Figure 5C), nor in cells co-transfected with psiCHECK-2-mutant and miR-21 inhibitor or miR-183-5p (Figure 5C).	('miR-183-5p', 'Chemical', '-', (102, 112))	('miR-21', 'Gene', (181, 187))	('miR-183-5p', 'Var', (102, 112))	('miR-21', 'Gene', '406991', (92, 98))	('miR-183-5p', 'Chemical', '-', (201, 211))	('miR-21', 'Gene', (92, 98))	('miR-21', 'Gene', '406991', (181, 187))	('psiCHECK-2-mutant', 'Var', (70, 87))
117057	32256450	These data indicate that mutations in the binding sites of miR-21 and miR-183-5p compromised the binding of miR-21 and miR-183-5p to OTUD6B-AS1.	('OTUD6B-AS1', 'Gene', '100506365', (133, 143))	('mutations', 'Var', (25, 34))	('miR-183-5p', 'Chemical', '-', (70, 80))	('binding', 'molecular_function', 'GO:0005488', ('97', '104'))	('miR-183-5p', 'Gene', (70, 80))	('compromised', 'NegReg', (81, 92))	('miR-21', 'Gene', (59, 65))	('binding', 'Interaction', (42, 49))	('miR-21', 'Gene', (108, 114))	('binding', 'Interaction', (97, 104))	('miR-21', 'Gene', '406991', (59, 65))	('miR-183-5p', 'Chemical', '-', (119, 129))	('OTUD6B-AS1', 'Gene', (133, 143))	('miR-183-5p', 'Gene', (119, 129))	('binding', 'molecular_function', 'GO:0005488', ('42', '49'))	('miR-21', 'Gene', '406991', (108, 114))
117058	32256450	In addition, we examined the expression of miR-183-5p and miR-21 in normal thyroid cells Nthy-ori, and thyroid carcinoma cells SW579 and TPC-1 using qRT-PCR.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (103, 120))	('thyroid carcinoma', 'Disease', (103, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('miR-21', 'Gene', (58, 64))	('TPC-1', 'Gene', (137, 142))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (103, 120))	('miR-183-5p', 'Chemical', '-', (43, 53))	('miR-21', 'Gene', '406991', (58, 64))	('TPC-1', 'Gene', '53373', (137, 142))	('miR-183-5p', 'Var', (43, 53))
117060	32256450	Moreover, decreased expression of miR-183-5p and miR-21 was observed in SW579 and TPC-1 cells that overexpressed OTUD6B-AS1 (Figure 5E).	('decreased', 'NegReg', (10, 19))	('expression', 'MPA', (20, 30))	('miR-183-5p', 'Var', (34, 44))	('TPC-1', 'Gene', (82, 87))	('TPC-1', 'Gene', '53373', (82, 87))	('miR-21', 'Gene', (49, 55))	('OTUD6B-AS1', 'Gene', (113, 123))	('miR-183-5p', 'Chemical', '-', (34, 44))	('miR-21', 'Gene', '406991', (49, 55))	('OTUD6B-AS1', 'Gene', '100506365', (113, 123))
117061	32256450	Taken together, these findings support the prediction that miR-21 and miR-183-5p are the direct target of OTUD6B-AS1.	('miR-183-5p', 'Chemical', '-', (70, 80))	('OTUD6B-AS1', 'Gene', '100506365', (106, 116))	('miR-21', 'Gene', (59, 65))	('miR-183-5p', 'Var', (70, 80))	('miR-21', 'Gene', '406991', (59, 65))	('OTUD6B-AS1', 'Gene', (106, 116))
117063	32256450	To verify this speculation, we investigated whether the up-regulation of miR-183-5p and miR-21 can compromise the inhibitory effects of OTUD6B-AS1.	('OTUD6B-AS1', 'Gene', '100506365', (136, 146))	('inhibitory effects', 'MPA', (114, 132))	('up-regulation', 'PosReg', (56, 69))	('miR-21', 'Gene', '406991', (88, 94))	('compromise', 'NegReg', (99, 109))	('miR-183-5p', 'Chemical', '-', (73, 83))	('OTUD6B-AS1', 'Gene', (136, 146))	('miR-21', 'Gene', (88, 94))	('regulation', 'biological_process', 'GO:0065007', ('59', '69'))	('miR-183-5p', 'Var', (73, 83))
117064	32256450	The mimics of miR-183-5p and miR-21 were transfected into SW579 and TPC-1 cells.	('miR-21', 'Gene', '406991', (29, 35))	('miR-183-5p', 'Chemical', '-', (14, 24))	('TPC-1', 'Gene', (68, 73))	('miR-183-5p', 'Var', (14, 24))	('miR-21', 'Gene', (29, 35))	('TPC-1', 'Gene', '53373', (68, 73))
117065	32256450	The increased expression of miR-183-5p and miR-21 was verified using qRT-PCR.	('miR-183-5p', 'Chemical', '-', (28, 38))	('miR-21', 'Gene', '406991', (43, 49))	('miR-183-5p', 'Var', (28, 38))	('expression', 'MPA', (14, 24))	('miR-21', 'Gene', (43, 49))
117066	32256450	Compared with Cells group, miR-183-5p and miR-21 expression were significantly increased after transfected miR-183-5p and miR-21 mimic into SW579 and TPC-1 cells (Figures 6A,C).	('miR-183-5p', 'Chemical', '-', (27, 37))	('increased', 'PosReg', (79, 88))	('miR-183-5p', 'Chemical', '-', (107, 117))	('miR-21', 'Gene', (42, 48))	('TPC-1', 'Gene', (150, 155))	('miR-21', 'Gene', '406991', (122, 128))	('expression', 'MPA', (49, 59))	('miR-183-5p', 'Var', (107, 117))	('TPC-1', 'Gene', '53373', (150, 155))	('miR-21', 'Gene', '406991', (42, 48))	('miR-183-5p', 'MPA', (27, 37))	('miR-21', 'Gene', (122, 128))
117067	32256450	Additionally, compared with OTUD6B-AS1 group, miR-183-5p and miR-21 expression were significantly increased after co-transfected OTUD6B-AS1, miR-183-5p, and (or) miR-21 mimic into SW579 and TPC-1 cells (Figures 6B,D).	('TPC-1', 'Gene', (190, 195))	('miR-183-5p', 'Chemical', '-', (141, 151))	('expression', 'MPA', (68, 78))	('TPC-1', 'Gene', '53373', (190, 195))	('OTUD6B-AS1', 'Gene', '100506365', (28, 38))	('miR-21', 'Gene', '406991', (162, 168))	('OTUD6B-AS1', 'Gene', '100506365', (129, 139))	('miR-183-5p', 'Gene', (46, 56))	('miR-21', 'Gene', '406991', (61, 67))	('miR-183-5p', 'Chemical', '-', (46, 56))	('miR-21', 'Gene', (162, 168))	('increased', 'PosReg', (98, 107))	('OTUD6B-AS1', 'Gene', (129, 139))	('miR-183-5p', 'Var', (141, 151))	('OTUD6B-AS1', 'Gene', (28, 38))	('miR-21', 'Gene', (61, 67))
117068	32256450	Compared with Cells group, miR-21 or miR-183-5p overexpression increased the viability of the SW579 and TPC-1 cells (Figures 6E,F).	('TPC-1', 'Gene', '53373', (104, 109))	('TPC-1', 'Gene', (104, 109))	('increased', 'PosReg', (63, 72))	('miR-21', 'Gene', (27, 33))	('miR-183-5p', 'Chemical', '-', (37, 47))	('miR-21', 'Gene', '406991', (27, 33))	('viability', 'CPA', (77, 86))	('miR-183-5p', 'Var', (37, 47))
117069	32256450	miR-21 or miR-183-5p overexpression also increased the viability of the OTUD6B-AS1-SW579 and TPC-1 cells (Figures 6E,F).	('OTUD6B-AS1', 'Gene', (72, 82))	('increased', 'PosReg', (41, 50))	('miR-183-5p', 'Chemical', '-', (10, 20))	('B-AS1-SW579', 'CellLine', 'CVCL:3603;-0.02985383886760931', (77, 88))	('miR-21', 'Gene', (0, 6))	('OTUD6B-AS1', 'Gene', '100506365', (72, 82))	('overexpression', 'PosReg', (21, 35))	('TPC-1', 'Gene', (93, 98))	('viability', 'CPA', (55, 64))	('miR-183-5p', 'Var', (10, 20))	('miR-21', 'Gene', '406991', (0, 6))	('TPC-1', 'Gene', '53373', (93, 98))
117071	32256450	Transwell migration and invasion assays also showed that increased migration and invasion abilities were observed in OTUD6B-AS1-SW579 and TPC-1 cells transfected with miR-183-5p and miR-21, compared to those cells transfected with the NC group (Figure 7).	('OTUD6B-AS1', 'Gene', (117, 127))	('miR-183-5p', 'Var', (167, 177))	('miR-21', 'Gene', (182, 188))	('OTUD6B-AS1', 'Gene', '100506365', (117, 127))	('migration', 'CPA', (67, 76))	('B-AS1-SW579', 'CellLine', 'CVCL:3603;-0.02985383886760931', (122, 133))	('miR-183-5p', 'Chemical', '-', (167, 177))	('increased', 'PosReg', (57, 66))	('TPC-1', 'Gene', (138, 143))	('miR-21', 'Gene', '406991', (182, 188))	('invasion abilities', 'CPA', (81, 99))	('TPC-1', 'Gene', '53373', (138, 143))
117072	32256450	Additionally, miR-21 and miR-183-5p overexpression had stacked effect to reverse the effect of OTUD6B-AS1 on the viability, migration, and invasion abilities (Figures 6E,F, 7).	('miR-21', 'Gene', '406991', (14, 20))	('miR-183-5p', 'Chemical', '-', (25, 35))	('migration', 'CPA', (124, 133))	('miR-21', 'Gene', (14, 20))	('invasion abilities', 'CPA', (139, 157))	('miR-183-5p', 'Var', (25, 35))	('OTUD6B-AS1', 'Gene', (95, 105))	('OTUD6B-AS1', 'Gene', '100506365', (95, 105))
117075	32256450	The dysregulation of lncRNA expression which acted as oncogenes or tumor-suppressor genes have great significance for the occurrence, development, metastasis, clinical stage and prognosis of thyroid cancer.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('lncRNA expression', 'Protein', (21, 38))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('67', '83'))	('dysregulation', 'Var', (4, 17))	('tumor-suppressor', 'Gene', (67, 83))	('thyroid cancer', 'Phenotype', 'HP:0002890', (191, 205))	('thyroid cancer', 'Disease', (191, 205))	('significance', 'Reg', (101, 113))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('thyroid cancer', 'Disease', 'MESH:D013964', (191, 205))	('tumor-suppressor', 'Gene', '7248', (67, 83))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('67', '83'))
117090	32256450	One of the important findings of this study is our identification of two downstream targets of OTUD6B-AS1, miR-183-5p, and miR-21.	('miR-21', 'Gene', (123, 129))	('miR-183-5p', 'Chemical', '-', (107, 117))	('OTUD6B-AS1', 'Gene', (95, 105))	('miR-183-5p', 'Var', (107, 117))	('miR-21', 'Gene', '406991', (123, 129))	('OTUD6B-AS1', 'Gene', '100506365', (95, 105))
117098	32256450	The function of miR-183-5p in cancer is controversial.	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('miR-183-5p', 'Chemical', '-', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('miR-183-5p', 'Var', (16, 26))
117100	32256450	Previous studies indicate that miR-183-5p is an oncogenic miRNA in breast cancer, hepatocellular carcinoma, colon cancer, colorectal cancer, bladder cancer, and pancreatic cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('miR-183-5p', 'Chemical', '-', (31, 41))	('colorectal cancer', 'Disease', (122, 139))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('colon cancer', 'Disease', (108, 120))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (82, 106))	('bladder cancer', 'Disease', 'MESH:D001749', (141, 155))	('pancreatic cancer', 'Disease', 'MESH:D010190', (161, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('bladder cancer', 'Disease', (141, 155))	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('bladder cancer', 'Phenotype', 'HP:0009725', (141, 155))	('colon cancer', 'Phenotype', 'HP:0003003', (108, 120))	('miR-183-5p', 'Var', (31, 41))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (82, 106))	('pancreatic cancer', 'Disease', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('breast cancer', 'Disease', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('colorectal cancer', 'Disease', 'MESH:D015179', (122, 139))	('colon cancer', 'Disease', 'MESH:D015179', (108, 120))	('hepatocellular carcinoma', 'Disease', (82, 106))
117101	32256450	There are also several studies indicating that miR-183-5p functions as a tumor suppressor in lung cancer, acute myeloid leukemia, gastric cancer, and osteosarcoma.	('osteosarcoma', 'Disease', (150, 162))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (106, 128))	('leukemia', 'Phenotype', 'HP:0001909', (120, 128))	('osteosarcoma', 'Disease', 'MESH:D012516', (150, 162))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (112, 128))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('73', '89'))	('gastric cancer', 'Phenotype', 'HP:0012126', (130, 144))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor suppressor', 'biological_process', 'GO:0051726', ('73', '89'))	('lung cancer', 'Disease', (93, 104))	('osteosarcoma', 'Phenotype', 'HP:0002669', (150, 162))	('miR-183-5p', 'Var', (47, 57))	('gastric cancer', 'Disease', (130, 144))	('acute myeloid leukemia', 'Disease', (106, 128))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (130, 144))	('miR-183-5p', 'Chemical', '-', (47, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (106, 128))
117102	32256450	In thyroid carcinomas, miR-183-5p functions as an oncogene and promotes proliferation, migration, and invasion by targeting PDCD4.	('migration', 'CPA', (87, 96))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (3, 20))	('miR-183-5p', 'Var', (23, 33))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (3, 21))	('proliferation', 'CPA', (72, 85))	('promotes', 'PosReg', (63, 71))	('invasion', 'CPA', (102, 110))	('thyroid carcinomas', 'Disease', (3, 21))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (3, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('miR-183-5p', 'Chemical', '-', (23, 33))	('PDCD4', 'Gene', (124, 129))	('PDCD4', 'Gene', '27250', (124, 129))	('targeting', 'Reg', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (11, 21))
117103	32256450	Our work also found that miR-183-5p overexpression promoted the viability, migration, and invasion, reversed OTUD6B-AS1 effect in thyroid carcinomas, which supports the function of miR-183-5p as an oncogene in thyroid carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('OTUD6B-AS1', 'Gene', (109, 119))	('viability', 'CPA', (64, 73))	('miR-183-5p', 'Chemical', '-', (181, 191))	('miR-183-5p', 'Var', (25, 35))	('invasion', 'CPA', (90, 98))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (130, 148))	('thyroid carcinomas', 'Disease', (130, 148))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (210, 228))	('promoted', 'PosReg', (51, 59))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (130, 147))	('thyroid carcinomas', 'Disease', (210, 228))	('migration', 'CPA', (75, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('miR-183-5p', 'Chemical', '-', (25, 35))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (210, 227))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (130, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('carcinomas', 'Phenotype', 'HP:0030731', (218, 228))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (210, 228))	('OTUD6B-AS1', 'Gene', '100506365', (109, 119))
117105	32256450	OTUD6B-AS1 and miR-183-5p, constitute another regulatory axis of thyroid carcinomas.	('OTUD6B-AS1', 'Gene', (0, 10))	('OTUD6B-AS1', 'Gene', '100506365', (0, 10))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (65, 83))	('miR-183-5p', 'Chemical', '-', (15, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (65, 83))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (65, 82))	('miR-183-5p', 'Var', (15, 25))	('thyroid carcinomas', 'Disease', (65, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
117106	32256450	Additionally, miR-21 and miR-183-5p overexpression had stacked effect to reverse the effect of OTUD6B-AS1 on the viability, migration, and invasion abilities.	('miR-21', 'Gene', '406991', (14, 20))	('miR-183-5p', 'Chemical', '-', (25, 35))	('migration', 'CPA', (124, 133))	('miR-21', 'Gene', (14, 20))	('invasion abilities', 'CPA', (139, 157))	('miR-183-5p', 'Var', (25, 35))	('OTUD6B-AS1', 'Gene', (95, 105))	('OTUD6B-AS1', 'Gene', '100506365', (95, 105))
117115	32256450	However, the current study did not reveal the targets of miR-21 and miR-183-5p and the downstream signaling pathway.	('miR-183-5p', 'Var', (68, 78))	('miR-21', 'Gene', '406991', (57, 63))	('signaling pathway', 'biological_process', 'GO:0007165', ('98', '115'))	('miR-21', 'Gene', (57, 63))	('miR-183-5p', 'Chemical', '-', (68, 78))
117116	32256450	In conclusion, OTUD6B-AS1 which acts as a tumor suppressor inhibits the viability, migration, and invasion of thyroid carcinomas by targeting miR-183-5p and miR-21.	('miR-183-5p', 'Chemical', '-', (142, 152))	('viability', 'CPA', (72, 81))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (110, 128))	('thyroid carcinomas', 'Disease', (110, 128))	('targeting', 'Reg', (132, 141))	('tumor', 'Disease', (42, 47))	('miR-21', 'Gene', (157, 163))	('invasion', 'CPA', (98, 106))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (110, 127))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (110, 128))	('migration', 'CPA', (83, 92))	('inhibits', 'NegReg', (59, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('OTUD6B-AS1', 'Gene', '100506365', (15, 25))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('42', '58'))	('miR-183-5p', 'Var', (142, 152))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor suppressor', 'biological_process', 'GO:0051726', ('42', '58'))	('OTUD6B-AS1', 'Gene', (15, 25))	('miR-21', 'Gene', '406991', (157, 163))
117119	28646535	Targeting STAT3 by HO3867 induces apoptosis in ovarian clear cell carcinoma Advanced ovarian clear cell carcinoma (OCCC) carries a very poor prognosis in large part secondary to the extremely high rate of resistance to standard platinum and taxane chemotherapy.	('taxane', 'Chemical', 'MESH:C080625', (241, 247))	('apoptosis', 'biological_process', 'GO:0006915', ('34', '43'))	('Advanced ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (76, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('ovarian clear cell carcinoma', 'Disease', (47, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('HO3867', 'Var', (19, 25))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (85, 113))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (47, 75))	('platinum', 'Chemical', 'MESH:D010984', (228, 236))	('apoptosis', 'CPA', (34, 43))	('apoptosis', 'biological_process', 'GO:0097194', ('34', '43'))	('Advanced ovarian clear', 'Phenotype', 'HP:0008209', (76, 98))	('STAT3', 'Gene', '6774', (10, 15))	('Advanced ovarian clear cell carcinoma', 'Disease', (76, 113))	('STAT3', 'Gene', (10, 15))
117121	28646535	Preliminary work in our lab has demonstrated constitutive activation of STAT3 (pSTAT3Tyr705 or pSTAT3727) in OCCC cell lines as well as human OCCC tumor tissue samples.	('human', 'Species', '9606', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('pSTAT3727', 'Var', (95, 104))	('STAT3', 'Gene', (72, 77))	('pSTAT3Tyr705', 'Var', (79, 91))	('OCCC tumor', 'Disease', (142, 152))	('activation', 'PosReg', (58, 68))	('OCCC tumor', 'Disease', 'MESH:D009369', (142, 152))
117123	28646535	Results demonstrate that treatment with HO-3867 decreased expression of pSTAT3 Tyr705 as well pSTAT3 Ser727, while total STAT3 remained constant.	('Ser', 'cellular_component', 'GO:0005790', ('101', '104'))	('Tyr705', 'Chemical', '-', (79, 85))	('expression', 'MPA', (58, 68))	('decreased', 'NegReg', (48, 57))	('pSTAT3 Ser727', 'Var', (94, 107))	('HO-3867', 'Chemical', 'MESH:C541427', (40, 47))	('Ser727', 'Chemical', '-', (101, 107))	('pSTAT3', 'Gene', (72, 78))
117126	28646535	Treatment with HO-3867 resulted in a decrease in Bcl-2 and increase of cleavage of caspase 3, caspase 7, and PARP, confirming induction of apoptosis after treatment with HO-3867.	('Bcl-2', 'molecular_function', 'GO:0015283', ('49', '54'))	('caspase 3', 'Gene', (83, 92))	('decrease', 'NegReg', (37, 45))	('Bcl-2', 'Gene', (49, 54))	('cleavage', 'MPA', (71, 79))	('Bcl-2', 'Gene', '596', (49, 54))	('HO-3867', 'Var', (15, 22))	('caspase 3', 'Gene', '836', (83, 92))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('126', '148'))	('HO-3867', 'Chemical', 'MESH:C541427', (170, 177))	('HO-3867', 'Chemical', 'MESH:C541427', (15, 22))	('caspase 7', 'Gene', (94, 103))	('PARP', 'Gene', '1302', (109, 113))	('PARP', 'Gene', (109, 113))	('caspase 7', 'Gene', '840', (94, 103))	('increase', 'PosReg', (59, 67))
117127	28646535	In addition, HO-3867 significantly inhibited formation of HUVEC cells capillary-like structures and invasion at both 5 and 10muM concentrations.	('HUVEC', 'CellLine', 'CVCL:2959', (58, 63))	('HO-3867', 'Var', (13, 20))	('muM', 'Gene', '56925', (125, 128))	('formation of HUVEC cells capillary-like structures', 'CPA', (45, 95))	('inhibited', 'NegReg', (35, 44))	('invasion', 'CPA', (100, 108))	('muM', 'Gene', (125, 128))	('formation', 'biological_process', 'GO:0009058', ('45', '54'))	('HO-3867', 'Chemical', 'MESH:C541427', (13, 20))
117140	28646535	OCCC is characterized by a high rate of ARID1A and PI3K mutations which have been shown to cooperate in animal models to promote OCCC tumor growth through sustained IL-6 overproduction leading to increased activation of STAT3.	('increased activation', 'PosReg', (196, 216))	('ARID1A', 'Gene', (40, 46))	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('mutations', 'Var', (56, 65))	('IL-6', 'molecular_function', 'GO:0005138', ('165', '169'))	('OCCC tumor', 'Disease', 'MESH:D009369', (129, 139))	('STAT3', 'MPA', (220, 225))	('overproduction', 'PosReg', (170, 184))	('IL-6', 'Gene', '3569', (165, 169))	('PI3K', 'Gene', (51, 55))	('IL-6', 'Gene', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('OCCC tumor', 'Disease', (129, 139))	('promote', 'PosReg', (121, 128))	('ARID1A', 'Gene', '8289', (40, 46))	('OCCC', 'Disease', (0, 4))
117142	28646535	We have previously shown that activation of STAT3 is necessary for HGSOC tumor progression/metastasis and targeting STAT3 with HO-3867 (a member of a novel class of anti-cancer drugs, diarylipenylpiperiden-4-ones (DAP's) significantly suppressed tumor growth and metastasis.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('diarylipenylpiperiden-4-ones', 'Chemical', '-', (184, 212))	('DAP', 'Gene', '1611', (214, 217))	('suppressed', 'NegReg', (235, 245))	('cancer', 'Disease', (170, 176))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('targeting', 'Var', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('tumor', 'Disease', (246, 251))	('DAP', 'Gene', (214, 217))	('HO-3867', 'Chemical', 'MESH:C541427', (127, 134))
117159	28646535	We received 7 OCCC tissue samples from consented patients with OCCC at our institution and analyzed the expression of pSTAT3 Tyr705, pSTAT3 Ser727 and total STAT3.	('Ser727', 'Var', (140, 146))	('Ser727', 'Chemical', '-', (140, 146))	('Tyr705', 'Var', (125, 131))	('Tyr705', 'Chemical', '-', (125, 131))	('pSTAT3', 'Gene', (118, 124))	('Ser', 'cellular_component', 'GO:0005790', ('140', '143'))	('pSTAT3', 'Gene', (133, 139))	('patients', 'Species', '9606', (49, 57))
117161	28646535	The studied cell lines showed moderate to high expression of pSTAT3 Tyr705, Ser727 and total STAT3, when analyzed by western blot (Fig.	('Tyr705', 'Chemical', '-', (68, 74))	('pSTAT3', 'Gene', (61, 67))	('Ser727', 'Var', (76, 82))	('Ser727', 'Chemical', '-', (76, 82))	('Ser', 'cellular_component', 'GO:0005790', ('76', '79'))	('Tyr705', 'Var', (68, 74))
117162	28646535	pSTAT3 Tyr705 showed high expressions in all tested cell lines (Fig.	('expressions', 'MPA', (26, 37))	('Tyr705', 'Var', (7, 13))	('Tyr705', 'Chemical', '-', (7, 13))	('pSTAT3', 'Gene', (0, 6))
117164	28646535	In our previous studies with HGSOC, we found that the knockdown of STAT3 causes reduction in tumor growth and metastases in vivo.	('metastases', 'Disease', (110, 120))	('knockdown', 'Var', (54, 63))	('reduction', 'NegReg', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('metastases', 'Disease', 'MESH:D009362', (110, 120))	('tumor', 'Disease', (93, 98))	('STAT3', 'Gene', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
117166	28646535	2A shows the western blot expression of pSTAT3 Tyr705 in 4 of the tested OE clones.	('Tyr705', 'Chemical', '-', (47, 53))	('pSTAT3', 'Gene', (40, 46))	('Tyr705', 'Var', (47, 53))
117176	28646535	3A clearly shows that the expression levels of both pSTAT Tyr705 and pSTAT Ser727 drastically decreases even in the lowest dose of 5 muM and is almost non-existent in the higher dose of 10muM for both the tested OCCC cell lines (Fig.	('pSTAT', 'Gene', (69, 74))	('muM', 'Gene', (133, 136))	('Ser', 'cellular_component', 'GO:0005790', ('75', '78'))	('Tyr705', 'Chemical', '-', (58, 64))	('muM', 'Gene', (188, 191))	('decreases', 'NegReg', (94, 103))	('pSTAT Tyr705', 'Var', (52, 64))	('muM', 'Gene', '56925', (133, 136))	('expression levels', 'MPA', (26, 43))	('muM', 'Gene', '56925', (188, 191))	('Ser727', 'Chemical', '-', (75, 81))
117190	28646535	The proliferation and survival of OCCC cells were inhibited by HO-3867 in a dose-dependent manner (Fig.	('survival of OCCC cells', 'CPA', (22, 44))	('HO-3867', 'Chemical', 'MESH:C541427', (63, 70))	('HO-3867', 'Var', (63, 70))	('inhibited', 'NegReg', (50, 59))
117191	28646535	Therefore, in order to confirm if the activity of HO-3867 also activates the caspase cascade, we performed western blot on OVTOKO, ES-2, OVISE and JHOC cells and found that PARP, cleaved caspase 3 and cleaved caspase 9 were all upregulated post treatment with HO-3867 (Fig.	('HO', 'Chemical', 'MESH:D006695', (50, 52))	('cleaved', 'MPA', (201, 208))	('caspase 9', 'Gene', (209, 218))	('caspase cascade', 'Pathway', (77, 92))	('HO-3867', 'Var', (50, 57))	('caspase 9', 'Gene', '842', (209, 218))	('caspase 3', 'Gene', (187, 196))	('HO', 'Chemical', 'MESH:D006695', (148, 150))	('HO-3867', 'Chemical', 'MESH:C541427', (50, 57))	('HO-3867', 'Chemical', 'MESH:C541427', (260, 267))	('cleaved', 'MPA', (179, 186))	('caspase 3', 'Gene', '836', (187, 196))	('PARP', 'Gene', '1302', (173, 177))	('upregulated', 'PosReg', (228, 239))	('PARP', 'Gene', (173, 177))	('HO', 'Chemical', 'MESH:D006695', (260, 262))
117196	28646535	The HO-3867-treated STAT3-overexpressing cells showed increase cell proliferation and decrease apoptotic proteins, in comparison with HO-3867 alone treated cells (Fig.	('HO-3867', 'Chemical', 'MESH:C541427', (4, 11))	('HO-3867-treated', 'Var', (4, 19))	('increase', 'PosReg', (54, 62))	('cell proliferation', 'CPA', (63, 81))	('decrease', 'NegReg', (86, 94))	('HO-3867', 'Chemical', 'MESH:C541427', (134, 141))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))	('apoptotic proteins', 'MPA', (95, 113))
117201	28646535	Since HO-3867 can block secretion of important angiogenic proteins, we next examined if HO3867 treatment suppresses the growth and differentiation of human umbilical vein endothelial cells (HUVEC) in response to treatment with VEGF.	('HO', 'Chemical', 'MESH:D006695', (88, 90))	('HO-3867', 'Chemical', 'MESH:C541427', (6, 13))	('HO3867', 'Var', (88, 94))	('human', 'Species', '9606', (150, 155))	('suppresses', 'NegReg', (105, 115))	('HO', 'Chemical', 'MESH:D006695', (6, 8))	('secretion', 'MPA', (24, 33))	('HUVEC', 'CellLine', 'CVCL:2959', (190, 195))	('VEGF', 'Gene', '7422', (227, 231))	('secretion', 'biological_process', 'GO:0046903', ('24', '33'))	('VEGF', 'Gene', (227, 231))
117204	28646535	A 3D angiogenesis model utilizing VEGF stimulated HUVEC spheroids embedded in a collagen matrix recapitulates the inhibition of tube-like formation by HO3867 seen in the two-dimensional model.	('VEGF', 'Gene', '7422', (34, 38))	('HO', 'Chemical', 'MESH:D006695', (151, 153))	('collagen', 'molecular_function', 'GO:0005202', ('80', '88'))	('HO3867', 'Var', (151, 157))	('angiogenesis', 'biological_process', 'GO:0001525', ('5', '17'))	('formation', 'biological_process', 'GO:0009058', ('138', '147'))	('HUVEC', 'CellLine', 'CVCL:2959', (50, 55))	('VEGF', 'Gene', (34, 38))	('tube-like formation', 'CPA', (128, 147))
117206	28646535	Fewer number and shorter length of the sprouts demonstrates the anti-angiogenic activity of HO3867 in comparison to the control group (Fig.	('shorter', 'NegReg', (17, 24))	('HO', 'Chemical', 'MESH:D006695', (92, 94))	('HO3867', 'Var', (92, 98))	('anti-angiogenic', 'MPA', (64, 79))
117207	28646535	HO3867 treatment also significantly blocked the invasion of VEGF-stimulated HUVECs through a Boyden chamber (Fig.	('VEGF', 'Gene', '7422', (60, 64))	('HO', 'Chemical', 'MESH:D006695', (0, 2))	('blocked', 'NegReg', (36, 43))	('VEGF', 'Gene', (60, 64))	('HUVEC', 'CellLine', 'CVCL:2959', (76, 81))	('invasion', 'CPA', (48, 56))	('HO3867', 'Var', (0, 6))
117211	28646535	The microtubule structures were additionally affected by the HO-3867 treatment.	('microtubule', 'cellular_component', 'GO:0005874', ('4', '15'))	('HO-3867', 'Var', (61, 68))	('affected', 'Reg', (45, 53))	('HO-3867', 'Chemical', 'MESH:C541427', (61, 68))	('microtubule structures', 'MPA', (4, 26))
117213	28646535	Our results indicate high levels of expression of phosphorylated STAT3 (pSTAT3Tyr705 and Ser727) in ovarian clear cell carcinoma (OCCC) which may prove to be an important pathway for OCCC cell survival, proliferation, and angiogenesis.	('expression', 'MPA', (36, 46))	('Ser727', 'Chemical', '-', (89, 95))	('angiogenesis', 'biological_process', 'GO:0001525', ('222', '234'))	('Ser', 'cellular_component', 'GO:0005790', ('89', '92'))	('pSTAT3Tyr705', 'Var', (72, 84))	('ovarian clear cell carcinoma', 'Disease', (100, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (100, 128))	('Ser727', 'Var', (89, 95))
117215	28646535	As described above, ARID1A and PI3K mutations are detected in more than 55% and 30% of OCCC cases respectively.	('ARID1A', 'Gene', '8289', (20, 26))	('ARID1A', 'Gene', (20, 26))	('mutations', 'Var', (36, 45))	('PI3K mutations', 'Var', (31, 45))	('PI3K', 'molecular_function', 'GO:0016303', ('31', '35'))
117216	28646535	Co-existent ARID1A and PI3K mutations have been shown to promote OCCC tumor growth through overproduction of IL-6 and activation of STAT3 lending STAT3 an attractive target for therapy.	('activation', 'PosReg', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('OCCC tumor', 'Disease', (65, 75))	('IL-6', 'Gene', (109, 113))	('PI3K mutations', 'Var', (23, 37))	('promote', 'PosReg', (57, 64))	('IL-6', 'molecular_function', 'GO:0005138', ('109', '113'))	('IL-6', 'Gene', '3569', (109, 113))	('OCCC tumor', 'Disease', 'MESH:D009369', (65, 75))	('overproduction', 'PosReg', (91, 105))	('ARID1A', 'Gene', '8289', (12, 18))	('STAT3', 'MPA', (132, 137))	('ARID1A', 'Gene', (12, 18))	('PI3K', 'molecular_function', 'GO:0016303', ('23', '27'))	('mutations', 'Var', (28, 37))
117220	28646535	It is clearly evident from our study that the expression of STAT3 might affect patient survival in OCCC, and targeting STAT3 using small molecule inhibitors could possibly inhibit OCCC tumor growth and help overcome the chemotherapeutic resistance in OCCC tumors.	('OCCC tumor', 'Disease', (180, 190))	('OCCC tumors', 'Disease', (251, 262))	('expression', 'Var', (46, 56))	('affect', 'Reg', (72, 78))	('targeting', 'Var', (109, 118))	('patient survival', 'CPA', (79, 95))	('tumors', 'Phenotype', 'HP:0002664', (256, 262))	('OCCC tumors', 'Disease', 'MESH:D009369', (251, 262))	('OCCC tumor', 'Disease', 'MESH:D009369', (251, 261))	('patient', 'Species', '9606', (79, 86))	('OCCC tumor', 'Disease', 'MESH:D009369', (180, 190))	('STAT3', 'Gene', (60, 65))	('STAT3', 'Gene', (119, 124))	('inhibit', 'NegReg', (172, 179))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('OCCC', 'Disease', (99, 103))
117224	28646535	HO-3867 significantly inhibits pSTAT3 in OCCC cells, through the upstream pathways of STAT3 such as JAK and TYK2.	('HO-3867', 'Chemical', 'MESH:C541427', (0, 7))	('TYK2', 'Gene', '7297', (108, 112))	('TYK2', 'Gene', (108, 112))	('HO-3867', 'Var', (0, 7))	('JAK', 'molecular_function', 'GO:0004713', ('100', '103'))	('pSTAT3', 'Gene', (31, 37))	('inhibits', 'NegReg', (22, 30))
117225	28646535	In addition, the current study showed an enhanced poly-ubiquitination of pSTAT3 by HO-3867 treatment in OCCC.	('enhanced', 'PosReg', (41, 49))	('HO-3867', 'Chemical', 'MESH:C541427', (83, 90))	('poly-ubiquitination', 'MPA', (50, 69))	('HO-3867', 'Var', (83, 90))	('pSTAT3', 'Protein', (73, 79))
117237	28646535	Our results indicate high levels of expression of phosphorylated STAT3 (pSTAT3Tyr705 and Ser727) in ovarian clear cell carcinoma (OCCC), which may prove to be an important chemo-resistant pathway for OCCC.	('expression', 'MPA', (36, 46))	('Ser727', 'Chemical', '-', (89, 95))	('Ser', 'cellular_component', 'GO:0005790', ('89', '92'))	('pSTAT3Tyr705', 'Var', (72, 84))	('ovarian clear cell carcinoma', 'Disease', (100, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (100, 128))	('Ser727', 'Var', (89, 95))
117279	31626592	We used the following formula to calculate the prognostic risk scores for the training groups using the gene expression values and the regression coefficients of the risk genes: Training group risk score for OS = (-0.1504 x expression value of PRKCQ) + (0.1673 x expression value of BID) + (-0.0944 x expression value of BAG1) + (0.1141 x expression value of BIRC5) + (0.0727 x expression value of ATG16L2); Training group risk score for DFS= (0.0103 x expression value of EIF4EBP1) + (0.1197 x expression value of ATG9B) + (-0.0923 x expression value of BAG1) + (0.2991 x expression value of BIRC5).	('ATG9B', 'Gene', (515, 520))	('BAG1', 'Gene', (321, 325))	('PRKCQ', 'Gene', '5588', (244, 249))	('ATG9B', 'Gene', '285973', (515, 520))	('BAG1', 'Gene', '573', (555, 559))	('EIF4EBP1', 'Gene', '1978', (473, 481))	('EIF4', 'cellular_component', 'GO:0008304', ('473', '477'))	('ATG16L2', 'Gene', (398, 405))	('BIRC5', 'Gene', '332', (359, 364))	('BIRC5', 'Gene', (359, 364))	('EIF4EBP1', 'Gene', (473, 481))	('0.0103 x', 'Var', (444, 452))	('BAG1', 'Gene', (555, 559))	('BID', 'Gene', (283, 286))	('ATG16L2', 'Gene', '89849', (398, 405))	('PRKCQ', 'Gene', (244, 249))	('BID', 'Gene', '637', (283, 286))	('BIRC5', 'Gene', '332', (593, 598))	('BIRC5', 'Gene', (593, 598))	('BAG1', 'Gene', '573', (321, 325))	('gene expression', 'biological_process', 'GO:0010467', ('104', '119'))
117309	31626592	Our results indicated that high expression of BAG1 increased the resistance of ccRCC cell lines to drugs such as Bortezomib, Idelalisib, Shikonin, YM201636, Cabozantinib, and NG-25 (p < 0.05), and increased sensitivity of ccRCC cell lines to other drugs such as Erlotinib, AZ628, Lapatinib, A-770041, and HG-5-88-01(p < 0.05; Figure 9A).	('Lapatinib, A-770041', 'Chemical', 'MESH:C490728', (280, 299))	('Cabozantinib', 'Chemical', 'MESH:C558660', (157, 169))	('increased', 'PosReg', (197, 206))	('high expression', 'Var', (27, 42))	('Erlotinib', 'Chemical', 'MESH:C400278', (262, 271))	('NG-25', 'Gene', '58530', (175, 180))	('BAG1', 'Gene', '573', (46, 50))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('NG-25', 'Gene', (175, 180))	('RCC', 'Disease', (81, 84))	('YM201636', 'Chemical', 'MESH:C540576', (147, 155))	('sensitivity', 'MPA', (207, 218))	('Shikonin', 'Chemical', 'MESH:C016101', (137, 145))	('RCC', 'Disease', (224, 227))	('RCC', 'Phenotype', 'HP:0005584', (224, 227))	('BAG1', 'Gene', (46, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (222, 227))	('Bortezomib', 'Chemical', 'MESH:C400082', (113, 123))	('increased', 'PosReg', (51, 60))	('RCC', 'Disease', 'MESH:D002292', (81, 84))	('YM201636', 'Var', (147, 155))	('AZ628', 'Chemical', 'MESH:C000592454', (273, 278))	('resistance', 'MPA', (65, 75))	('RCC', 'Disease', 'MESH:D002292', (224, 227))	('HG-5-88-01', 'CellLine', 'CVCL:X224', (305, 315))
117310	31626592	On the other hand, high expression of BIRC5 expression increased resistance of ccRCC cell lines to drugs such as Salubrinal, PHA-665752, GNF-2, Imatinib, Nilotinib, and Selumetinib (p < 0.05), and increased sensitivity of ccRCC cell lines to other drugs such as CGP-60474, BMS-536924, JW-7-52-1, Panobinostat, Dasatinib, WH-4-023, Rapamycin, Saracatinib, and Bryostatin 1(p < 0.05; Figure 9B).	('BIRC5', 'Gene', (38, 43))	('increased', 'PosReg', (55, 64))	('WH-4-023', 'Chemical', 'MESH:C055514', (321, 329))	('increased', 'PosReg', (197, 206))	('Selumetinib', 'Chemical', 'MESH:C517975', (169, 180))	('high expression', 'Var', (19, 34))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('sensitivity', 'MPA', (207, 218))	('BMS-536924', 'Chemical', 'MESH:C504983', (273, 283))	('Saracatinib', 'Chemical', 'MESH:C515233', (342, 353))	('RCC', 'Disease', (224, 227))	('RCC', 'Phenotype', 'HP:0005584', (224, 227))	('CGP-60474', 'Chemical', 'MESH:C502153', (262, 271))	('ccRCC', 'Phenotype', 'HP:0006770', (222, 227))	('Nilotinib', 'Chemical', 'MESH:C498826', (154, 163))	('RCC', 'Disease', 'MESH:D002292', (81, 84))	('Rapamycin', 'Chemical', 'MESH:D020123', (331, 340))	('Dasatinib', 'Chemical', 'MESH:C488369', (310, 319))	('resistance', 'MPA', (65, 75))	('RCC', 'Disease', 'MESH:D002292', (224, 227))	('Imatinib', 'Chemical', 'MESH:C097613', (144, 152))	('PHA-665752', 'Chemical', 'MESH:C480541', (125, 135))	('BIRC5', 'Gene', '332', (38, 43))	('Bryostatin', 'Chemical', 'MESH:D054713', (359, 369))
117330	31626592	Previous studies have shown that over-expression of PRKCQ, a member of the novel PKC family significantly enhances growth, migration and drug resistance of breast cancer cells; furthermore, silencing of PRKCQ inhibits breast cancer cell growth by promoting apoptosis.	('cell growth', 'biological_process', 'GO:0016049', ('232', '243'))	('PRKCQ', 'Gene', (203, 208))	('silencing', 'Var', (190, 199))	('PRKCQ', 'Gene', (52, 57))	('apoptosis', 'biological_process', 'GO:0097194', ('257', '266'))	('enhances', 'PosReg', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('apoptosis', 'biological_process', 'GO:0006915', ('257', '266'))	('drug resistance', 'biological_process', 'GO:0009315', ('137', '152'))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('drug resistance', 'biological_process', 'GO:0042493', ('137', '152'))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('PKC', 'Gene', (81, 84))	('PRKCQ', 'Gene', '5588', (203, 208))	('breast cancer', 'Disease', (156, 169))	('PRKCQ', 'Gene', '5588', (52, 57))	('drug resistance', 'Phenotype', 'HP:0020174', (137, 152))	('PKC', 'molecular_function', 'GO:0004697', ('81', '84'))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('PKC', 'Gene', '5583;5588', (81, 84))	('apoptosis', 'CPA', (257, 266))	('breast cancer', 'Disease', 'MESH:D001943', (218, 231))	('over-expression', 'PosReg', (33, 48))	('breast cancer', 'Disease', (218, 231))	('promoting', 'PosReg', (247, 256))	('inhibits', 'NegReg', (209, 217))	('growth', 'CPA', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
117340	31626592	BAG1 expression is up-regulated in acute myeloid leukemia (AML), and its silencing promotes AML cell apoptosis.	('expression', 'MPA', (5, 15))	('AML', 'Phenotype', 'HP:0004808', (59, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('101', '110'))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (35, 57))	('BAG1', 'Gene', '573', (0, 4))	('apoptosis', 'biological_process', 'GO:0006915', ('101', '110'))	('promotes', 'PosReg', (83, 91))	('BAG1', 'Gene', (0, 4))	('myeloid leukemia', 'Disease', (41, 57))	('up-regulated', 'PosReg', (19, 31))	('silencing', 'Var', (73, 82))	('AML', 'Disease', 'MESH:D015470', (92, 95))	('leukemia', 'Phenotype', 'HP:0001909', (49, 57))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (41, 57))	('myeloid leukemia', 'Disease', 'MESH:D007951', (41, 57))	('AML', 'Disease', 'MESH:D015470', (59, 62))	('AML', 'Phenotype', 'HP:0004808', (92, 95))	('AML', 'Disease', (92, 95))	('AML', 'Disease', (59, 62))
117347	31626592	In this study, we found that high expression of EIF4EBP1 was associated with worse patient prognosis.	('high', 'Var', (29, 33))	('EIF4', 'cellular_component', 'GO:0008304', ('48', '52'))	('EIF4EBP1', 'Gene', (48, 56))	('patient', 'Species', '9606', (83, 90))	('associated', 'Reg', (61, 71))	('EIF4EBP1', 'Gene', '1978', (48, 56))
117352	31626592	High BIRC5 expression is associated with tumor progression in lung adenocarcinoma and poor patient prognosis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('associated with', 'Reg', (25, 40))	('High', 'Var', (0, 4))	('tumor', 'Disease', (41, 46))	('BIRC5', 'Gene', '332', (5, 10))	('expression', 'MPA', (11, 21))	('BIRC5', 'Gene', (5, 10))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (62, 81))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('patient', 'Species', '9606', (91, 98))	('lung adenocarcinoma', 'Disease', (62, 81))
117353	31626592	In acute myelocytic leukemia (AML), knock-down of BIRC5 induces apoptosis and is therefore regarded as a potential therapeutic target for AML patients.	('AML', 'Phenotype', 'HP:0004808', (138, 141))	('AML', 'Disease', (138, 141))	('apoptosis', 'CPA', (64, 73))	('induces', 'Reg', (56, 63))	('acute myelocytic leukemia', 'Disease', 'MESH:D015470', (3, 28))	('myelocytic leukemia', 'Phenotype', 'HP:0012324', (9, 28))	('acute myelocytic leukemia', 'Phenotype', 'HP:0004808', (3, 28))	('knock-down', 'Var', (36, 46))	('acute myelocytic leukemia', 'Disease', (3, 28))	('AML', 'Disease', 'MESH:D015470', (30, 33))	('leukemia', 'Phenotype', 'HP:0001909', (20, 28))	('BIRC5', 'Gene', '332', (50, 55))	('BIRC5', 'Gene', (50, 55))	('AML', 'Disease', (30, 33))	('AML', 'Phenotype', 'HP:0004808', (30, 33))	('apoptosis', 'biological_process', 'GO:0097194', ('64', '73'))	('apoptosis', 'biological_process', 'GO:0006915', ('64', '73'))	('AML', 'Disease', 'MESH:D015470', (138, 141))	('patients', 'Species', '9606', (142, 150))
117354	31626592	In this study, we demonstrate that high BIRC5 expression is associated with worse prognosis in ccRCC patients and elevated drug resistance in ccRCC cell lines.	('drug resistance', 'Phenotype', 'HP:0020174', (123, 138))	('RCC', 'Disease', 'MESH:D002292', (144, 147))	('RCC', 'Disease', (97, 100))	('patients', 'Species', '9606', (101, 109))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('drug resistance', 'biological_process', 'GO:0042493', ('123', '138'))	('drug resistance', 'biological_process', 'GO:0009315', ('123', '138'))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('RCC', 'Disease', 'MESH:D002292', (97, 100))	('elevated', 'PosReg', (114, 122))	('BIRC5', 'Gene', '332', (40, 45))	('RCC', 'Disease', (144, 147))	('drug resistance', 'MPA', (123, 138))	('BIRC5', 'Gene', (40, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('expression', 'MPA', (46, 56))	('high', 'Var', (35, 39))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))
117358	31626592	In summary, our study demonstrates that differentially expressed ARGs have great potential as diagnostic and prognostic biomarkers and therapeutic targets in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (158, 163))	('RCC', 'Disease', 'MESH:D002292', (160, 163))	('differentially expressed', 'Var', (40, 64))	('RCC', 'Disease', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('ARGs', 'Protein', (65, 69))
117377	30514329	Mutated Von Hippel-Lindau-renal cell carcinoma (RCC) promotes patients specific natural killer (NK) cytotoxicity Previous evidence demonstrated that restoration of wild type VHL in human renal cancer cells decreased in vitro NK susceptibility.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('Von Hippel-Lindau-renal cell carcinoma', 'Disease', 'MESH:D006623', (8, 46))	('renal cancer', 'Disease', (187, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('VHL', 'Gene', '7428', (174, 177))	('renal cancer', 'Phenotype', 'HP:0009726', (187, 199))	('patients', 'Species', '9606', (62, 70))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (26, 46))	('Von Hippel-Lindau-renal cell carcinoma', 'Disease', (8, 46))	('renal cancer', 'Disease', 'MESH:D007680', (187, 199))	('human', 'Species', '9606', (181, 186))	('decreased', 'NegReg', (206, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('cytotoxicity', 'Disease', (100, 112))	('Mutated', 'Var', (0, 7))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('cytotoxicity', 'Disease', 'MESH:D064420', (100, 112))	('VHL', 'Gene', (174, 177))
117383	30514329	VHL mutations were detected in 26/55 (47%) RCC patients.	('patients', 'Species', '9606', (47, 55))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('detected', 'Reg', (19, 27))	('VHL', 'Gene', (0, 3))	('RCC', 'Disease', (43, 46))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('mutations', 'Var', (4, 13))	('VHL', 'Gene', '7428', (0, 3))
117390	30514329	VHL tumoral mutations improve NKs effectiveness in RCC patients and need to be considered in the evaluation of immune response.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('improve', 'PosReg', (22, 29))	('mutations', 'Var', (12, 21))	('VHL tumoral', 'Disease', 'MESH:D006623', (0, 11))	('VHL tumoral', 'Disease', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('NKs', 'Protein', (30, 33))	('effectiveness', 'MPA', (34, 47))	('patients', 'Species', '9606', (55, 63))	('immune response', 'biological_process', 'GO:0006955', ('111', '126'))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
117394	30514329	The most common histotype is clear cell-RCC (ccRCC) (70-80%) of which 50-70% carry Von Hippel-Lindau (VHL) gene mutations (VHL promoter hyper methylation and biallelic VHL inactivation).	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('methylation', 'biological_process', 'GO:0032259', ('142', '153'))	('RCC', 'Disease', (40, 43))	('VHL', 'Gene', (123, 126))	('VHL', 'Gene', (168, 171))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('VHL', 'Gene', (102, 105))	('mutations', 'Var', (112, 121))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('VHL', 'Gene', '7428', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('VHL', 'Gene', '7428', (168, 171))	('RCC', 'Disease', (47, 50))	('VHL', 'Gene', '7428', (102, 105))
117396	30514329	Although VHL plays a key role in RCC pathogenesis, the prognostic meaning of VHL mutations is controversial.	('VHL', 'Gene', (9, 12))	('VHL', 'Gene', (77, 80))	('VHL', 'Gene', '7428', (9, 12))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('VHL', 'Gene', '7428', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('pathogenesis', 'biological_process', 'GO:0009405', ('37', '49'))	('mutations', 'Var', (81, 90))
117397	30514329	VHL mutations were reported not to affect prognosis or to improving it.	('mutations', 'Var', (4, 13))	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', (0, 3))
117400	30514329	Certain VHL mutations correlate with low expression of classical HLA-I molecules and HLA-E expression that determine higher NK susceptibility reducing the engagement of KIR and NKG2A inhibitory receptors, respectively.	('VHL', 'Gene', '7428', (8, 11))	('expression', 'MPA', (41, 51))	('mutations', 'Var', (12, 21))	('engagement', 'Interaction', (155, 165))	('reducing', 'NegReg', (142, 150))	('HLA-E', 'Gene', '3133', (85, 90))	('KIR', 'Gene', '3805', (169, 172))	('HLA-E', 'Gene', (85, 90))	('VHL', 'Gene', (8, 11))	('KIR', 'Gene', (169, 172))
117406	30514329	To investigate on the role of tumoral VHL status versus NK capability in renal cancer patients, 51 RCC patients were characterized for VHL mutational status and NK cytolytic activity toward A498-VHL-MUT and CAKI-1-VHL-WT human renal cancer cells.	('tumoral VHL', 'Disease', (30, 41))	('VHL', 'Gene', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('VHL', 'Gene', (214, 217))	('mutational', 'Var', (139, 149))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', (99, 102))	('VHL', 'Gene', (38, 41))	('patients', 'Species', '9606', (86, 94))	('VHL', 'Gene', '7428', (135, 138))	('renal cancer', 'Disease', (227, 239))	('VHL', 'Gene', '7428', (214, 217))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('renal cancer', 'Phenotype', 'HP:0009726', (227, 239))	('tumoral VHL', 'Disease', 'MESH:D006623', (30, 41))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('VHL', 'Gene', (195, 198))	('A498-VHL-MUT and CAKI-1-VHL-WT human renal cancer', 'Disease', 'MESH:D006623', (190, 239))	('VHL', 'Gene', '7428', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('renal cancer', 'Disease', (73, 85))	('renal cancer', 'Phenotype', 'HP:0009726', (73, 85))	('renal cancer', 'Disease', 'MESH:D007680', (227, 239))	('VHL', 'Gene', '7428', (195, 198))	('renal cancer', 'Disease', 'MESH:D007680', (73, 85))	('patients', 'Species', '9606', (103, 111))
117458	30514329	As shown in Tables 1 and 2, VHL was mutated in 26/55 (47%) cases, with missense mutations in 7/26 (27%), nonsense in 3/26 (12%), splice site in 2/26 (7%), frameshift deletions in 11/26 (42%) and frameshift insertions in 3/26 (12%) cases.	('frameshift deletions', 'Var', (155, 175))	('splice site', 'Var', (129, 140))	('missense mutations', 'Var', (71, 89))	('nonsense', 'Var', (105, 113))	('frameshift insertions', 'Var', (195, 216))	('VHL', 'Gene', (28, 31))	('VHL', 'Gene', '7428', (28, 31))
117460	30514329	IL-2 activated whole-blood samples were co-cultured with target cells K562, A498-VHL-MUT (containing a 4-nt deletion at nt 639-642 in VHL exon 2) and CAKI-1-VHL-WT cell lines.	('IL-2', 'molecular_function', 'GO:0005134', ('0', '4'))	('A498-VHL-MUT', 'Disease', (76, 88))	('VHL', 'Gene', (81, 84))	('VHL', 'Gene', '7428', (81, 84))	('VHL', 'Gene', (157, 160))	('CAKI-1-VHL-WT', 'Disease', 'MESH:D006623', (150, 163))	('VHL', 'Gene', (134, 137))	('K562', 'CellLine', 'CVCL:0004', (70, 74))	('CAKI-1-VHL-WT', 'Disease', (150, 163))	('VHL', 'Gene', '7428', (157, 160))	('VHL', 'Gene', '7428', (134, 137))	('deletion at nt 639-642', 'Var', (108, 130))	('A498-VHL-MUT', 'Disease', 'MESH:D006623', (76, 88))
117461	30514329	As reported in Additional file 2: Figure S1 the target cells K562 are MHC-I negative, while A498 and CAKI-1 cell lines express high levels of MHC-I molecules (81 and 86.2% respectively).	('negative', 'NegReg', (76, 84))	('MHC-I', 'Gene', (70, 75))	('K562', 'Var', (61, 65))	('K562', 'CellLine', 'CVCL:0004', (61, 65))
117467	30514329	The higher percent of CD107a+NK induced in VHL-MUT patients by the culture with A498 and 786-O VHL-MUT cell lines suggest that RCC-VHL mutated tumors displayed higher susceptibility to NK lysis .	('CD107a', 'Gene', (22, 28))	('RCC-VHL', 'Disease', (127, 134))	('CD107a', 'Gene', '3916', (22, 28))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('RCC-VHL', 'Disease', 'MESH:C538614', (127, 134))	('VHL-MUT', 'Disease', (95, 102))	('tumors', 'Disease', (143, 149))	('VHL-MUT', 'Disease', (43, 50))	('mutated', 'Var', (135, 142))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('lysis', 'biological_process', 'GO:0019835', ('188', '193'))	('NK lysis', 'Disease', (185, 193))	('VHL-MUT', 'Disease', 'MESH:D006623', (95, 102))	('VHL-MUT', 'Disease', 'MESH:D006623', (43, 50))	('patients', 'Species', '9606', (51, 59))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
117470	30514329	1D) versus 13 VHL-WT (E) and 14 VHL-MUT (F) RCC patients in the presence of target cells (K562, A498 and CAKI-1).	('VHL-MUT', 'Disease', (32, 39))	('K562', 'Var', (90, 94))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('VHL-MUT', 'Disease', 'MESH:D006623', (32, 39))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('K562', 'CellLine', 'CVCL:0004', (90, 94))	('VHL-WT', 'Disease', 'MESH:D006623', (14, 20))	('A498', 'Var', (96, 100))	('VHL-WT', 'Disease', (14, 20))	('patients', 'Species', '9606', (48, 56))
117496	30514329	In the present study RCC-VHL mutational status was correlated to patients NK cytotoxicity through ex vivo evaluation toward human renal cancer cell lines A498 VHL-MUT and CAKI-1-VHL-WT.	('renal cancer', 'Disease', (130, 142))	('VHL-MUT and CAKI-1-VHL-WT', 'Disease', 'MESH:D006623', (159, 184))	('RCC-VHL', 'Disease', 'MESH:C538614', (21, 28))	('renal cancer', 'Phenotype', 'HP:0009726', (130, 142))	('RCC-VHL', 'Disease', (21, 28))	('mutational', 'Var', (29, 39))	('cytotoxicity', 'Disease', (77, 89))	('renal cancer', 'Disease', 'MESH:D007680', (130, 142))	('human', 'Species', '9606', (124, 129))	('patients', 'Species', '9606', (65, 73))	('cytotoxicity', 'Disease', 'MESH:D064420', (77, 89))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('correlated', 'Reg', (51, 61))
117504	30514329	Nowadays the effects of VHL mutations on NK activity is controversial.	('VHL', 'Gene', '7428', (24, 27))	('mutations', 'Var', (28, 37))	('VHL', 'Gene', (24, 27))
117505	30514329	Previous evidence demonstrated that restoration of wild type VHL in human renal cancer cells decreased their NK susceptibility while VHL mutations increased resistance to NK-mediated lysis through EPAS1/HIF-2alpha stabilization.	('EPAS1', 'Gene', (197, 202))	('human', 'Species', '9606', (68, 73))	('increased', 'PosReg', (147, 156))	('HIF-2alpha', 'Gene', '2034', (203, 213))	('renal cancer', 'Disease', 'MESH:D007680', (74, 86))	('VHL', 'Gene', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('renal cancer', 'Phenotype', 'HP:0009726', (74, 86))	('lysis', 'biological_process', 'GO:0019835', ('183', '188'))	('decreased', 'NegReg', (93, 102))	('mutations', 'Var', (137, 146))	('VHL', 'Gene', '7428', (133, 136))	('VHL', 'Gene', (61, 64))	('VHL', 'Gene', '7428', (61, 64))	('renal cancer', 'Disease', (74, 86))	('EPAS1', 'Gene', '2034', (197, 202))	('HIF-2alpha', 'Gene', (203, 213))	('resistance to NK-mediated lysis', 'MPA', (157, 188))
117522	30514329	Since VHL mutations induces PD-L1 expression in RCC, NK function may be a crucial element in nivolumab sensitivity.	('PD-L1', 'Gene', '29126', (28, 33))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('expression', 'MPA', (34, 44))	('induces', 'Reg', (20, 27))	('VHL', 'Gene', (6, 9))	('VHL', 'Gene', '7428', (6, 9))	('PD-L1', 'Gene', (28, 33))	('mutations', 'Var', (10, 19))	('nivolumab', 'Chemical', 'MESH:D000077594', (93, 102))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
117528	30514329	TKIs affect the frequency and composition of tumor immune cell subpopulations including Tregs, myeloid-derived suppressor cells as well as T and NK cells.	('Tregs', 'CPA', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('TKIs', 'Var', (0, 4))	('tumor', 'Disease', (45, 50))	('affect', 'Reg', (5, 11))	('T and', 'CPA', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
117530	30514329	VHL tumoral mutations improve the NKs effectiveness in RCC patients and thus need to be considered in the evaluation of TKIs or immune based therapies.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('improve', 'PosReg', (22, 29))	('NKs', 'Protein', (34, 37))	('RCC', 'Disease', (55, 58))	('mutations', 'Var', (12, 21))	('VHL tumoral', 'Disease', 'MESH:D006623', (0, 11))	('VHL tumoral', 'Disease', (0, 11))	('patients', 'Species', '9606', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
117573	30100272	Atypical response patterns to ICI were first described in clinical studies evaluating ipilimumab in melanoma and have since been observed in most clinical trials evaluating ICI regardless of tumor type.	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('ipilimumab', 'Chemical', 'MESH:D000074324', (86, 96))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('ipilimumab', 'Var', (86, 96))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))
117603	33986386	A time-course, dose-dependent analysis revealed that KTZ selectively decreased secreted Exo in tumoral cell lines.	('tumoral', 'Disease', (95, 102))	('tumoral', 'Disease', 'MESH:D009369', (95, 102))	('secreted Exo', 'MPA', (79, 91))	('decreased', 'NegReg', (69, 78))	('KTZ', 'Var', (53, 56))	('KTZ', 'Chemical', 'MESH:D007654', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))
117607	33986386	In sunitinib resistant 786-O cells lines, the addition of KTZ potentiates the efficacy of sunitinib by causing Exo inhibition, decreased tumor proliferation, and diminished clonogenic ability of RCC cells.	('Exo', 'MPA', (111, 114))	('sunitinib', 'Chemical', 'MESH:D000077210', (3, 12))	('decreased tumor', 'Disease', 'MESH:D002303', (127, 142))	('RCC', 'Phenotype', 'HP:0005584', (195, 198))	('efficacy', 'MPA', (78, 86))	('sunitinib', 'Chemical', 'MESH:D000077210', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('KTZ', 'Var', (58, 61))	('diminished', 'NegReg', (162, 172))	('KTZ', 'Chemical', 'MESH:D007654', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('potentiates', 'PosReg', (62, 73))	('RCC', 'Disease', (195, 198))	('decreased tumor', 'Disease', (127, 142))
117628	33986386	Dose response studies (using MTT cell viability assays) were performed to determine the physiologically relevant, non-cytotoxic dose range of KTZ at which it inhibited exosome biogenesis and secretion.	('secretion', 'MPA', (191, 200))	('KTZ', 'Var', (142, 145))	('KTZ', 'Chemical', 'MESH:D007654', (142, 145))	('secretion', 'biological_process', 'GO:0046903', ('191', '200'))	('exosome', 'cellular_component', 'GO:0070062', ('168', '175'))	('inhibited', 'NegReg', (158, 167))	('MTT', 'Chemical', '-', (29, 32))	('exosome biogenesis', 'biological_process', 'GO:0097734', ('168', '186'))	('exosome biogenesis', 'MPA', (168, 186))
117629	33986386	Figure S1 shows that 1uM KTZ was observed to be non-cytotoxic in the control HEK 293-T as well as three RCC cells.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('HEK 293-T', 'CellLine', 'CVCL:0063', (77, 86))	('S', 'Chemical', 'MESH:D013455', (7, 8))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('1uM KTZ', 'Var', (21, 28))	('KTZ', 'Chemical', 'MESH:D007654', (25, 28))	('RCC', 'Disease', (104, 107))
117634	33986386	Also, exosome quantification using MACSQuant analysis indicated that KTZ (1 microM) significantly suppressed exosome secretion in 786-O-CD63 GFP (Fig.	('CD63', 'Gene', (136, 140))	('KTZ', 'Var', (69, 72))	('S', 'Chemical', 'MESH:D013455', (38, 39))	('KTZ', 'Chemical', 'MESH:D007654', (69, 72))	('suppressed', 'NegReg', (98, 108))	('exosome', 'cellular_component', 'GO:0070062', ('6', '13'))	('P', 'Chemical', 'MESH:D010758', (143, 144))	('CD63', 'Gene', '967', (136, 140))	('secretion', 'biological_process', 'GO:0046903', ('117', '126'))	('exosome', 'cellular_component', 'GO:0070062', ('109', '116'))	('exosome secretion', 'MPA', (109, 126))
117651	33986386	We then employed MAPKs pathway selective inhibitors had the ability to alter exosome biogenesis or trafficking.	('alter', 'Reg', (71, 76))	('exosome biogenesis', 'biological_process', 'GO:0097734', ('77', '95'))	('exosome', 'cellular_component', 'GO:0070062', ('77', '84'))	('inhibitors', 'Var', (41, 51))	('trafficking', 'MPA', (99, 110))	('exosome biogenesis', 'MPA', (77, 95))	('MAPKs', 'Gene', (17, 22))	('P', 'Chemical', 'MESH:D010758', (19, 20))
117652	33986386	We used Alix, nSMase, and Rab27a expression markers was used to test the function of selective inhibitors U0126, SB203580, SP600125 on exosomes.	('SB203580', 'Var', (113, 121))	('SB203580', 'Chemical', 'MESH:C093642', (113, 121))	('SP600125', 'Chemical', 'MESH:C432165', (123, 131))	('Alix', 'Gene', (8, 12))	('Rab27a', 'Gene', '5873', (26, 32))	('nSMase', 'Gene', (14, 20))	('U0126', 'Var', (106, 111))	('SP600125', 'Var', (123, 131))	('Rab27a', 'Gene', (26, 32))	('U0126', 'Chemical', 'MESH:C113580', (106, 111))	('Alix', 'Gene', '10015', (8, 12))	('test', 'Reg', (64, 68))	('nSMase', 'Gene', '6610', (14, 20))
117653	33986386	U0126 inhibits the ERK, SB203580 binds to p38, and SP600125 stops the activation of JNK (Fig.	('p38', 'Gene', (42, 45))	('inhibits', 'NegReg', (6, 14))	('stops', 'NegReg', (60, 65))	('ERK', 'Gene', '5594', (19, 22))	('JNK', 'molecular_function', 'GO:0004705', ('84', '87'))	('JNK', 'Gene', (84, 87))	('U0126', 'Var', (0, 5))	('activation', 'MPA', (70, 80))	('SB203580', 'Chemical', 'MESH:C093642', (24, 32))	('ERK', 'Gene', (19, 22))	('binds', 'Interaction', (33, 38))	('SB203580', 'Var', (24, 32))	('p38', 'Gene', '5594', (42, 45))	('JNK', 'Gene', '5599', (84, 87))	('SP600125', 'Chemical', 'MESH:C432165', (51, 59))	('ERK', 'molecular_function', 'GO:0004707', ('19', '22'))	('U0126', 'Chemical', 'MESH:C113580', (0, 5))	('SP600125', 'Var', (51, 59))
117666	33986386	Thus, KTZ potentiates the efficacy of sunitinib in suppressing the proliferation and clonogenic ability of RCC cells.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('sunitinib', 'Chemical', 'MESH:D000077210', (38, 47))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('RCC', 'Disease', (107, 110))	('suppressing', 'NegReg', (51, 62))	('KTZ', 'Var', (6, 9))	('KTZ', 'Chemical', 'MESH:D007654', (6, 9))
117690	33986386	Exosome quantification using NP100 nanopore (Izon) indicated that KTZ (1 microM) significantly suppressed exosome secretion in 786-O-SR by ~ 60%, as compared to the controls (Fig.	('suppressed', 'NegReg', (95, 105))	('KTZ', 'Chemical', 'MESH:D007654', (66, 69))	('P', 'Chemical', 'MESH:D010758', (30, 31))	('exosome secretion', 'MPA', (106, 123))	('exosome', 'cellular_component', 'GO:0070062', ('106', '113'))	('Exosome', 'cellular_component', 'GO:0070062', ('0', '7'))	('KTZ', 'Var', (66, 69))	('S', 'Chemical', 'MESH:D013455', (133, 134))	('secretion', 'biological_process', 'GO:0046903', ('114', '123'))
117692	33986386	It has been well demonstrated that the combination therapy of KTZ and sunitinib also exhibited a dose-dependent growth inhibition of 786-O-SR cells and Cyclin D1 (Fig.	('Cyclin D1', 'Gene', (152, 161))	('combination', 'Interaction', (39, 50))	('S', 'Chemical', 'MESH:D013455', (139, 140))	('growth inhibition', 'CPA', (112, 129))	('sunitinib', 'Chemical', 'MESH:D000077210', (70, 79))	('Cyclin', 'molecular_function', 'GO:0016538', ('152', '158'))	('KTZ', 'Var', (62, 65))	('KTZ', 'Chemical', 'MESH:D007654', (62, 65))	('Cyclin D1', 'Gene', '595', (152, 161))
117694	33986386	Finally, our results demonstrated that KTZ in renal malignancies play a role in sunitinib resistance or sensitive and that inhibition of these exosome may delay or prevent the development of resistant tumors.	('sunitinib resistance', 'MPA', (80, 100))	('inhibition', 'Var', (123, 133))	('prevent', 'NegReg', (164, 171))	('sunitinib', 'Chemical', 'MESH:D000077210', (80, 89))	('resistant tumors', 'Disease', 'MESH:D060467', (191, 207))	('renal malignancies', 'Disease', 'MESH:D007680', (46, 64))	('renal malignancies', 'Phenotype', 'HP:0009726', (46, 64))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('KTZ', 'Chemical', 'MESH:D007654', (39, 42))	('renal malignancies', 'Disease', (46, 64))	('delay', 'NegReg', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('exosome', 'cellular_component', 'GO:0070062', ('143', '150'))	('resistant tumors', 'Disease', (191, 207))	('sensitive', 'MPA', (104, 113))
117703	33986386	In prostate cancer studies, we have documented that KTZ effectively and reproducibly inhibits exosome biogenesis in a dose dependent fashion lines.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('inhibits', 'NegReg', (85, 93))	('KTZ', 'Var', (52, 55))	('KTZ', 'Chemical', 'MESH:D007654', (52, 55))	('exosome', 'cellular_component', 'GO:0070062', ('94', '101'))	('exosome biogenesis', 'MPA', (94, 112))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('exosome biogenesis', 'biological_process', 'GO:0097734', ('94', '112'))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
117707	33986386	Furthermore, we observed that KTZ led to suppression of multiple pathways leading to exosome biogenesis and secretion.	('exosome biogenesis', 'biological_process', 'GO:0097734', ('85', '103'))	('exosome', 'cellular_component', 'GO:0070062', ('85', '92'))	('KTZ', 'Var', (30, 33))	('KTZ', 'Chemical', 'MESH:D007654', (30, 33))	('secretion', 'biological_process', 'GO:0046903', ('108', '117'))	('secretion', 'MPA', (108, 117))	('exosome biogenesis', 'MPA', (85, 103))	('suppression', 'NegReg', (41, 52))
117724	33986386	In our data, KTZ inhibited exosome biogenesis and secretion through inhibition of protein expression of Alix, nSMase, and Rab27a related to exosome biogenesis and secretion in RCC cells.	('nSMase', 'Gene', '6610', (110, 116))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('KTZ', 'Chemical', 'MESH:D007654', (13, 16))	('Alix', 'Gene', (104, 108))	('secretion', 'biological_process', 'GO:0046903', ('163', '172'))	('exosome', 'cellular_component', 'GO:0070062', ('27', '34'))	('Rab27a', 'Gene', '5873', (122, 128))	('nSMase', 'Gene', (110, 116))	('protein expression', 'MPA', (82, 100))	('secretion', 'biological_process', 'GO:0046903', ('50', '59'))	('RCC', 'Disease', (176, 179))	('exosome biogenesis', 'MPA', (27, 45))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('exosome biogenesis', 'biological_process', 'GO:0097734', ('27', '45'))	('inhibited', 'NegReg', (17, 26))	('KTZ', 'Var', (13, 16))	('inhibition', 'NegReg', (68, 78))	('secretion', 'MPA', (50, 59))	('exosome biogenesis', 'biological_process', 'GO:0097734', ('140', '158'))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('Alix', 'Gene', '10015', (104, 108))	('exosome', 'cellular_component', 'GO:0070062', ('140', '147'))	('Rab27a', 'Gene', (122, 128))
117760	33986386	The system was calibrated for voltage, stretch, pressure, and baseline current using two standard beads: CPC100B (mode diameter: 114 nm, concentration: 1.0E13/ml) and CPC70D (mode diameter: 70 nm, concentration: 3.0E13/ml).	('CPC100B', 'Var', (105, 112))	('P', 'Chemical', 'MESH:D010758', (106, 107))	('P', 'Chemical', 'MESH:D010758', (168, 169))	('CPC70D', 'Var', (167, 173))	('CPC', 'cellular_component', 'GO:0032133', ('167', '170'))	('CPC', 'cellular_component', 'GO:0032133', ('105', '108'))
117789	33145941	In this study, we propose that TFE3 but not TFEB is essential for tumour survival which was associated with the poorer survival of cancer patients.	('cancer', 'Disease', (131, 137))	('TFEB', 'Gene', '7942', (44, 48))	('TFEB', 'Gene', (44, 48))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('TFE3', 'Var', (31, 35))	('tumour', 'Disease', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('patients', 'Species', '9606', (138, 146))
117792	33145941	Finally, we observed the therapeutic benefit of Sun plus PD-L1 inhibition which enhanced CD8+ cytolytic activity and thus tumour suppression in a xenografted mouse model.	('tumour suppression', 'Disease', (122, 140))	('CD8', 'Gene', (89, 92))	('mouse', 'Species', '10090', (158, 163))	('tumour suppression', 'Disease', 'MESH:D009369', (122, 140))	('CD8', 'Gene', '925', (89, 92))	('PD-L1', 'Gene', (57, 62))	('Sun', 'Chemical', 'MESH:D000077210', (48, 51))	('enhanced', 'PosReg', (80, 88))	('inhibition', 'Var', (63, 73))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
117808	33145941	21  Furthermore, TFEB or TFE3 fusion and overexpression caused by chromosomal translocation events is linked with a poor prognosis in a subset of RCC patients with elevated recurrence and metastasis.	('fusion', 'Var', (30, 36))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('TFEB', 'Gene', '7942', (17, 21))	('TFEB', 'Gene', (17, 21))	('patients', 'Species', '9606', (150, 158))	('TFE3', 'Gene', (25, 29))	('chromosomal translocation events', 'Var', (66, 98))	('overexpression', 'PosReg', (41, 55))
117812	33145941	Importantly, TFE3 but not TFEB is essential for the survival of tumour cells.	('TFEB', 'Gene', '7942', (26, 30))	('TFE3', 'Var', (13, 17))	('TFEB', 'Gene', (26, 30))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Disease', (64, 70))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
117835	33145941	To measure TFE3 nuclear translocation, cells following TFE3-GFP transfection and Sun (5 micromol/L) treatments were incubated with DAPI for 10 minutes.	('TFE3-GFP', 'Gene', (55, 63))	('transfection', 'Var', (64, 76))	('DAPI', 'Chemical', 'MESH:C007293', (131, 135))	('Sun', 'Chemical', 'MESH:D000077210', (81, 84))
117842	33145941	The antibodies used to stain TILs were listed as followed: anti-CD3-FITC (100203; Biolegend), anti-CD4-APC (100516; Biolegend), anti-CD8-Percp/Cy5.5 (100734; Biolegend) and anti-GZMB-PE (104508; Biolegend).	('anti-CD3-FITC', 'Var', (59, 72))	('100516;', 'Var', (108, 115))	('CD8', 'Gene', (133, 136))	('CD8', 'Gene', '925', (133, 136))	('FITC', 'Chemical', 'MESH:D016650', (68, 72))	('APC', 'cellular_component', 'GO:0005680', ('103', '106'))	('GZMB', 'Gene', '3002', (178, 182))	('GZMB', 'Gene', (178, 182))	('CD4', 'Gene', (99, 102))	('100734;', 'Var', (150, 157))	('100203', 'Var', (74, 80))	('CD4', 'Gene', '920', (99, 102))
117852	33145941	As shown in Figure 1A, TFE3 but not TFEB was negatively correlated with the survival of patients in clear cell RCC.	('TFEB', 'Gene', (36, 40))	('TFE3', 'Var', (23, 27))	('negatively', 'NegReg', (45, 55))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('patients', 'Species', '9606', (88, 96))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('correlated with', 'Reg', (56, 71))	('TFEB', 'Gene', '7942', (36, 40))
117855	33145941	To determine whether this difference defines the proliferative advantage of ccRCC, we tried to knockdown TFEB and TFE3 in 786-O cells (Figure 1D,E).	('TFEB', 'Gene', '7942', (105, 109))	('TFEB', 'Gene', (105, 109))	('TFE3', 'Gene', (114, 118))	('RCC', 'Disease', (78, 81))	('knockdown', 'Var', (95, 104))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))
117856	33145941	As a result, knockdown of TFEB did not affect cell proliferation.	('TFEB', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))	('TFEB', 'Gene', '7942', (26, 30))	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))
117858	33145941	In addition, we also knocked down TFEB and TFE3 in hepatocellular carcinoma cells and got similar results (Figure S1A-D).	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (51, 75))	('TFEB', 'Gene', '7942', (34, 38))	('TFE3', 'Gene', (43, 47))	('hepatocellular carcinoma', 'Disease', (51, 75))	('knocked', 'Var', (21, 28))	('TFEB', 'Gene', (34, 38))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (51, 75))
117864	33145941	We also found that expression of TFE3 but not TFEB was positively correlated with the levels of PD-L1 in RCC tumour cell lines by CCLE database (Figure 2G and S2B).	('correlated', 'Reg', (66, 76))	('TFEB', 'Gene', (46, 50))	('levels', 'MPA', (86, 92))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC tumour', 'Disease', (105, 115))	('RCC tumour', 'Disease', 'MESH:C538614', (105, 115))	('TFEB', 'Gene', '7942', (46, 50))	('TFE3', 'Var', (33, 37))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
117875	33145941	In contrast, the ectopic expression of TFE3 induced PD-L1 expression in the presence of Sun (Figure 4H).	('Sun', 'Chemical', 'MESH:D000077210', (88, 91))	('TFE3', 'Gene', (39, 43))	('induced', 'Reg', (44, 51))	('expression', 'MPA', (58, 68))	('ectopic expression', 'Var', (17, 35))	('PD-L1', 'Gene', (52, 57))
117880	33145941	There was a reduction in tumour growth in mice treated with either anti-PD-L1 alone or Sun alone compared with the control group (Figure 5B-D).	('reduction', 'NegReg', (12, 21))	('mice', 'Species', '10090', (42, 46))	('anti-PD-L1', 'Var', (67, 77))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumour growth', 'Disease', (25, 38))	('Sun', 'Chemical', 'MESH:D000077210', (87, 90))	('tumour growth', 'Disease', 'MESH:D006130', (25, 38))
117888	33145941	More interestingly, TFE3 but not TFEB has intrinsic effects on cell proliferation and survival in ccRCC and LIHC.	('TFEB', 'Gene', '7942', (33, 37))	('LIHC', 'Disease', (108, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('TFEB', 'Gene', (33, 37))	('TFE3', 'Var', (20, 24))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))	('effects', 'Reg', (52, 59))	('cell proliferation', 'CPA', (63, 81))	('survival', 'CPA', (86, 94))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
117890	33145941	We also knocked down TFE3 and TFEB in lung cancer and breast cancer cells where their expression has no negative correlation with patient prognosis and it was found that alteration of the TFE3 or TFEB expression has little effect on tumour maintenance or progression (data not shown).	('lung cancer', 'Disease', (38, 49))	('TFEB', 'Gene', (196, 200))	('progression', 'CPA', (255, 266))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Disease', (54, 67))	('tumour', 'Phenotype', 'HP:0002664', (233, 239))	('TFEB', 'Gene', '7942', (196, 200))	('TFEB', 'Gene', (30, 34))	('tumour', 'Disease', 'MESH:D009369', (233, 239))	('tumour', 'Disease', (233, 239))	('knocked', 'Reg', (8, 15))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))	('alteration', 'Var', (170, 180))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('TFEB', 'Gene', '7942', (30, 34))	('TFE3', 'Gene', (188, 192))	('TFE3', 'Gene', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('patient', 'Species', '9606', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
117903	33145941	In summary, it is indicated that TFE3, like TFEB, is also a potent tumour promotor based on its significant proliferative effect.	('TFEB', 'Gene', '7942', (44, 48))	('TFEB', 'Gene', (44, 48))	('proliferative effect', 'CPA', (108, 128))	('tumour promotor', 'Disease', 'MESH:D009369', (67, 82))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('TFE3', 'Var', (33, 37))	('tumour promotor', 'Disease', (67, 82))
117906	30149673	Clinicopathologic Significance of VHL Gene Alteration in Clear-Cell Renal Cell Carcinoma: An Updated Meta-Analysis and Review The von Hippel-Lindau (VHL) gene is inactivated frequently in sporadic clear-cell renal cell carcinomas (ccRCCs) by genetic alteration (mutation, loss of heterozygosity, or promoter hypermethylation).	('clear-cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (197, 229))	('clear-cell renal cell carcinomas', 'Disease', 'MESH:C538614', (197, 229))	('ccRCCs', 'Phenotype', 'HP:0006770', (231, 237))	('Clear-Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (57, 88))	('RCC', 'Phenotype', 'HP:0005584', (233, 236))	('RCC', 'Disease', (233, 236))	('VHL', 'Gene', '7428', (149, 152))	('clear-cell renal cell carcinomas', 'Disease', (197, 229))	('RCC', 'Disease', 'MESH:C538614', (233, 236))	('promoter hypermethylation', 'Var', (299, 324))	('von Hippel-Lindau', 'Gene', (130, 147))	('loss of heterozygosity', 'Var', (272, 294))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (208, 228))	('VHL', 'Gene', (34, 37))	('Clear-Cell Renal Cell Carcinoma', 'Disease', (57, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('carcinomas', 'Phenotype', 'HP:0030731', (219, 229))	('Clear-Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (57, 88))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (208, 229))	('von Hippel-Lindau', 'Gene', '7428', (130, 147))	('Carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('VHL', 'Gene', '7428', (34, 37))	('VHL', 'Gene', (149, 152))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (68, 88))
117907	30149673	However, the pathological or prognostic significance of VHL gene alteration has not been well defined.	('VHL', 'Gene', (56, 59))	('VHL', 'Gene', '7428', (56, 59))	('alteration', 'Var', (65, 75))
117908	30149673	We conducted this meta-analysis to evaluate the association between VHL alteration and clinopathologic findings in ccRCCs.	('ccRCCs', 'Phenotype', 'HP:0006770', (115, 121))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('VHL', 'Gene', (68, 71))	('alteration', 'Var', (72, 82))	('VHL', 'Gene', '7428', (68, 71))
117910	30149673	VHL alteration was not significantly associated with nuclear grade (OR = 0.79, 95% CI: 0.59-1.06, p = 0.12) or disease stage (OR = 1.07, 95% CI: 0.79-1.46, p = 0.65).	('alteration', 'Var', (4, 14))	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', (0, 3))
117911	30149673	There was also no significant correlation between VHL alteration and OS (HR = 0.75, 95% CI: 0.43-1.29, p = 0.30).	('alteration', 'Var', (54, 64))	('VHL', 'Gene', (50, 53))	('VHL', 'Gene', '7428', (50, 53))
117912	30149673	When we pooled HRs for OS according to the VHL alteration types, the combined HRs were 0.72 (95% CI: 0.47-1.11, p = 0.14) for VHL mutations and 1.32 (95% CI: 0.70-2.47, p = 0.39) for methylation.	('methylation', 'biological_process', 'GO:0032259', ('183', '194'))	('VHL', 'Gene', (43, 46))	('VHL', 'Gene', '7428', (43, 46))	('mutations', 'Var', (130, 139))	('VHL', 'Gene', (126, 129))	('VHL', 'Gene', '7428', (126, 129))	('methylation', 'Var', (183, 194))
117913	30149673	In conclusion, this meta-analysis indicates that VHL gene alteration is not significantly associated with the pathological features and survival in patients with ccRCC.	('patients', 'Species', '9606', (148, 156))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))	('associated', 'Reg', (90, 100))	('alteration', 'Var', (58, 68))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('VHL', 'Gene', (49, 52))	('RCC', 'Disease', (164, 167))	('VHL', 'Gene', '7428', (49, 52))
117922	30149673	Functional loss of VHL protein (pVHL), which is induced from VHL gene alteration, allows HIFs to act as a transcription factor of various pro-tumorigenic genes including vascular endothelial growth factor (VEGF) and subsequently leads to renal tumorigenesis and progression by inducing angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('transcription factor', 'molecular_function', 'GO:0000981', ('106', '126'))	('VHL', 'Gene', '7428', (33, 36))	('transcription', 'biological_process', 'GO:0006351', ('106', '119'))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('170', '204'))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('VHL', 'Gene', (61, 64))	('progression', 'CPA', (262, 273))	('leads to', 'Reg', (229, 237))	('vascular endothelial growth factor', 'Gene', '7422', (170, 204))	('angiogenesis', 'CPA', (286, 298))	('loss', 'NegReg', (11, 15))	('VEGF', 'Gene', '7422', (206, 210))	('tumor', 'Disease', (142, 147))	('VHL', 'Gene', (19, 22))	('vascular endothelial growth factor', 'Gene', (170, 204))	('inducing', 'PosReg', (277, 285))	('VHL', 'Gene', '7428', (61, 64))	('VEGF', 'Gene', (206, 210))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', (244, 249))	('VHL', 'Gene', (33, 36))	('pVHL', 'Gene', '7428', (32, 36))	('VHL', 'Gene', '7428', (19, 22))	('angiogenesis', 'biological_process', 'GO:0001525', ('286', '298'))	('alteration', 'Var', (70, 80))	('pVHL', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
117923	30149673	The VHL gene alteration events include VHL gene mutation, promoter hypermethylation, and loss of heterozygosity (LOH) by allele deletion with concomitant alteration of the contralateral gene.	('allele deletion', 'Var', (121, 136))	('VHL', 'Gene', (39, 42))	('alteration', 'Reg', (154, 164))	('mutation', 'Var', (48, 56))	('VHL', 'Gene', '7428', (39, 42))	('promoter hypermethylation', 'MPA', (58, 83))	('VHL', 'Gene', (4, 7))	('loss of', 'NegReg', (89, 96))	('VHL', 'Gene', '7428', (4, 7))
117924	30149673	These genetic or epigenetic alterations play a major role in the deregulated expression of VHL gene.	('VHL', 'Gene', '7428', (91, 94))	('VHL', 'Gene', (91, 94))	('epigenetic alterations', 'Var', (17, 39))	('deregulated expression', 'MPA', (65, 87))
117925	30149673	Somatic VHL mutations are identified in 30-60% of ccRCCs, accounting for the vast majority of sporadic ccRCCs.	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('VHL', 'Gene', '7428', (8, 11))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('mutations', 'Var', (12, 21))	('ccRCCs', 'Phenotype', 'HP:0006770', (50, 56))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('ccRCCs', 'Phenotype', 'HP:0006770', (103, 109))	('VHL', 'Gene', (8, 11))
117926	30149673	The majority of ccRCCs containing somatic VHL mutations also exhibits contralateral allele loss (LOH), consistent with a two-hit hypothesis of tumorigenesis.	('RCC', 'Disease', (18, 21))	('RCC', 'Phenotype', 'HP:0005584', (18, 21))	('mutations', 'Var', (46, 55))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('ccRCCs', 'Phenotype', 'HP:0006770', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('VHL', 'Gene', (42, 45))	('RCC', 'Disease', 'MESH:C538614', (18, 21))	('VHL', 'Gene', '7428', (42, 45))
117927	30149673	Together with 3p LOH, VHL mutation is considered a rate-limiting event in the development of RCC.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('VHL', 'Gene', (22, 25))	('RCC', 'Disease', (93, 96))	('mutation', 'Var', (26, 34))	('VHL', 'Gene', '7428', (22, 25))
117928	30149673	Hypermethylation of DNA in the promoter region of VHL gene results in transcriptional gene silencing.	('VHL', 'Gene', (50, 53))	('transcriptional gene silencing', 'biological_process', 'GO:0006342', ('70', '100'))	('Hypermethylation', 'Var', (0, 16))	('VHL', 'Gene', '7428', (50, 53))	('DNA', 'cellular_component', 'GO:0005574', ('20', '23'))	('transcriptional gene', 'MPA', (70, 90))
117929	30149673	VHL promoter methylation has been observed in 10-20% of sporadic ccRCCs.	('ccRCCs', 'Phenotype', 'HP:0006770', (65, 71))	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('methylation', 'Var', (13, 24))	('RCC', 'Disease', (67, 70))	('VHL', 'Gene', (0, 3))	('observed', 'Reg', (34, 42))	('VHL', 'Gene', '7428', (0, 3))
117931	30149673	Some studies found that VHL alteration correlated with favorable pathological features or prognosis.	('VHL', 'Gene', (24, 27))	('VHL', 'Gene', '7428', (24, 27))	('alteration', 'Var', (28, 38))
117932	30149673	observed an association of VHL alteration with advanced tumor stage.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('association', 'Interaction', (12, 23))	('alteration', 'Var', (31, 41))	('VHL', 'Gene', (27, 30))	('VHL', 'Gene', '7428', (27, 30))
117933	30149673	reported that VHL methylation was associated with worse survival.	('VHL', 'Gene', (14, 17))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('methylation', 'Var', (18, 29))	('VHL', 'Gene', '7428', (14, 17))
117935	30149673	Therefore, we conducted this meta-analysis to gain a better insight into the clinicopathologic significance of VHL gene alteration in patients with ccRCC.	('VHL', 'Gene', (111, 114))	('alteration', 'Var', (120, 130))	('VHL', 'Gene', '7428', (111, 114))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('patients', 'Species', '9606', (134, 142))	('RCC', 'Disease', (150, 153))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))
117937	30149673	DNA-single-strand conformation polymorphism (DNA-SSCP) or polymerase chain reaction (PCR) followed by direct sequencing was used to detect VHL mutations, and methylation-specific PCR was used to assess VHL promoter methylation status.	('methylation', 'biological_process', 'GO:0032259', ('158', '169'))	('VHL', 'Gene', (139, 142))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('VHL', 'Gene', '7428', (139, 142))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('VHL', 'Gene', (202, 205))	('VHL', 'Gene', '7428', (202, 205))	('mutations', 'Var', (143, 152))	('methylation', 'biological_process', 'GO:0032259', ('215', '226'))
117938	30149673	The incidence of VHL gene alteration including mutations, methylation, or LOH was various from 28.6% to 88.8%: mutations ranged from 26% to 72.2% and methylation ranged from 16% to 31.3%.	('mutations', 'Var', (111, 120))	('methylation', 'Var', (150, 161))	('mutations', 'Var', (47, 56))	('VHL', 'Gene', (17, 20))	('methylation', 'biological_process', 'GO:0032259', ('58', '69'))	('VHL', 'Gene', '7428', (17, 20))	('methylation', 'biological_process', 'GO:0032259', ('150', '161'))
117939	30149673	While four studies reported VHL alteration as a favorable pathological or prognostic factor, one observed its association with worse survival.	('VHL', 'Gene', (28, 31))	('alteration', 'Var', (32, 42))	('VHL', 'Gene', '7428', (28, 31))
117940	30149673	The remaining five studies failed to demonstrate the significant pathological or prognostic value of VHL alteration in ccRCCs.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('VHL', 'Gene', (101, 104))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('alteration', 'Var', (105, 115))	('RCC', 'Disease', (121, 124))	('VHL', 'Gene', '7428', (101, 104))	('ccRCCs', 'Phenotype', 'HP:0006770', (119, 125))
117944	30149673	There was also no significant association between VHL alteration and disease stage (III-IV) (OR = 1.07, 95% CI: 0.79-1.46, p = 0.65) (Figure 2B).	('disease stage', 'Disease', (69, 82))	('alteration', 'Var', (54, 64))	('VHL', 'Gene', (50, 53))	('VHL', 'Gene', '7428', (50, 53))
117945	30149673	From four studies, a total of 593 patients with VHL alteration (mutation, LOH, or methylation) were included in the meta-analysis of HRs for OS.	('VHL', 'Gene', '7428', (48, 51))	('mutation', 'Var', (64, 72))	('methylation', 'Var', (82, 93))	('alteration', 'Var', (52, 62))	('patients', 'Species', '9606', (34, 42))	('methylation', 'biological_process', 'GO:0032259', ('82', '93'))	('VHL', 'Gene', (48, 51))
117946	30149673	VHL alteration showed no significant impact on OS (HR = 0.75, 95% CI: 0.43-1.29, p = 0.30) (Figure 3A).	('alteration', 'Var', (4, 14))	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', (0, 3))
117947	30149673	When we pooled HRs for OS according to the VHL alteration type (mutations or methylation), the combined HRs were 0.72 (95% CI: 0.47-1.11, p = 0.14, I2 = 56%, random-effects model) for VHL mutations (Figure 3B) and 1.32 (95% CI: 0.70-2.47, p = 0.39, I2 = 51%, random-effects model) for methylation (Figure 3C), indicating no significant prognostic impact in ccRCCs.	('methylation', 'biological_process', 'GO:0032259', ('77', '88'))	('VHL', 'Gene', (184, 187))	('RCC', 'Disease', 'MESH:C538614', (359, 362))	('VHL', 'Gene', (43, 46))	('RCC', 'Disease', (359, 362))	('RCC', 'Phenotype', 'HP:0005584', (359, 362))	('methylation', 'MPA', (285, 296))	('VHL', 'Gene', '7428', (184, 187))	('VHL', 'Gene', '7428', (43, 46))	('mutations', 'Var', (188, 197))	('ccRCCs', 'Phenotype', 'HP:0006770', (357, 363))	('methylation', 'biological_process', 'GO:0032259', ('285', '296'))
117948	30149673	Although VHL gene alteration accounts for the vast majority of sporadic ccRCCs and provides plausible therapeutic target for anti-angiogenic agents, its clinicopathologic significance is still controversial with conflicting results among studies.	('VHL', 'Gene', (9, 12))	('VHL', 'Gene', '7428', (9, 12))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('alteration', 'Var', (18, 28))	('ccRCCs', 'Phenotype', 'HP:0006770', (72, 78))
117950	30149673	Our results failed to demonstrate the significant association of VHL alteration with pathological features and prognosis in ccRCCs.	('VHL', 'Gene', '7428', (65, 68))	('ccRCCs', 'Phenotype', 'HP:0006770', (124, 130))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('RCC', 'Disease', (126, 129))	('alteration', 'Var', (69, 79))	('VHL', 'Gene', (65, 68))	('RCC', 'Disease', 'MESH:C538614', (126, 129))
117953	30149673	With functional loss of pVHL arising from the genetic or epigenetic changes of VHL (VHL alteration), HIFs can act as a transcription factor of various pro-tumorigenic genes including VEGF.	('VEGF', 'Gene', (183, 187))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('pVHL', 'Gene', (24, 28))	('epigenetic changes', 'Var', (57, 75))	('VHL', 'Gene', '7428', (79, 82))	('VHL', 'Gene', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('VHL', 'Gene', '7428', (84, 87))	('VEGF', 'Gene', '7422', (183, 187))	('tumor', 'Disease', (155, 160))	('loss', 'NegReg', (16, 20))	('VHL', 'Gene', (25, 28))	('transcription', 'biological_process', 'GO:0006351', ('119', '132'))	('transcription factor', 'molecular_function', 'GO:0000981', ('119', '139'))	('VHL', 'Gene', '7428', (25, 28))	('VHL', 'Gene', (79, 82))	('pVHL', 'Gene', '7428', (24, 28))	('genetic', 'Var', (46, 53))
117955	30149673	Therefore, it is logical to assume that VHL alteration may have important implications for disease prognosis.	('VHL', 'Gene', (40, 43))	('implications', 'Reg', (74, 86))	('alteration', 'Var', (44, 54))	('VHL', 'Gene', '7428', (40, 43))
117956	30149673	The clinicopathologic impacts of somatic VHL mutations or promoter methylation have been studied in a variety of case series with RCCs.	('mutations', 'Var', (45, 54))	('methylation', 'biological_process', 'GO:0032259', ('67', '78'))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('VHL', 'Gene', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('VHL', 'Gene', '7428', (41, 44))
117960	30149673	VHL mutations or promoter hypermethylation were identified in 45% of ccRCC and the rate of LOH was 93% of the cases.	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('VHL', 'Gene', (0, 3))	('promoter hypermethylation', 'Var', (17, 42))	('mutations', 'Var', (4, 13))	('VHL', 'Gene', '7428', (0, 3))
117961	30149673	The presence of VHL alteration significantly correlated with a standard prognostic factor, pT3 tumor stage (p = 0.009).	('VHL', 'Gene', (16, 19))	('alteration', 'Var', (20, 30))	('tumor', 'Disease', (95, 100))	('VHL', 'Gene', '7428', (16, 19))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('presence', 'Var', (4, 12))	('correlated', 'Reg', (45, 55))
117962	30149673	conducted a prospective, longitudinal cohort study of 50 patients diagnosed with ccRCC and analyzed VHL mutations and hypermethylation as well as VHL, HIF1-alpha, VEGF, ERK1/2 and ERK5 protein expression.	('ERK5', 'Gene', (180, 184))	('ERK1/2', 'Gene', (169, 175))	('ERK1/2', 'Gene', '5595;5594', (169, 175))	('VHL', 'Gene', (100, 103))	('VEGF', 'Gene', '7422', (163, 167))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('mutations', 'Var', (104, 113))	('ERK', 'molecular_function', 'GO:0004707', ('180', '183'))	('VEGF', 'Gene', (163, 167))	('HIF1-alpha', 'Gene', '3091', (151, 161))	('ERK1', 'molecular_function', 'GO:0004707', ('169', '173'))	('ERK5', 'Gene', '5598', (180, 184))	('VHL', 'Gene', '7428', (100, 103))	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('VHL', 'Gene', (146, 149))	('VHL', 'Gene', '7428', (146, 149))	('patients', 'Species', '9606', (57, 65))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('hypermethylation', 'MPA', (118, 134))	('HIF1-alpha', 'Gene', (151, 161))
117963	30149673	VHL mutations and methylation were identified in 26.5% and 21.7% of cases, respectively.	('mutations', 'Var', (4, 13))	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', (0, 3))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))
117965	30149673	Contrary to the findings above, however, VHL alteration has shown favorable survival outcomes in other studies.	('VHL', 'Gene', '7428', (41, 44))	('alteration', 'Var', (45, 55))	('VHL', 'Gene', (41, 44))
117966	30149673	analyzed 187 Japanese patients with sporadic ccRCC for VHL alteration events (mutations and hypermethylation).	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('patients', 'Species', '9606', (22, 30))	('mutations', 'Var', (78, 87))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('hypermethylation', 'Var', (92, 108))	('VHL', 'Gene', (55, 58))	('RCC', 'Disease', (47, 50))	('VHL', 'Gene', '7428', (55, 58))
117967	30149673	VHL alteration was detected in 108 tumor samples: intragenic mutations in 98 patients (52%) and hypermethylation in 10 (5.3%).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('patients', 'Species', '9606', (77, 85))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('hypermethylation', 'Var', (96, 112))
117968	30149673	VHL mutations were associated with better DSS in patients with stage 1-III disease, but not in those with stage IV disease, suggesting that VHL mutation may contribute most before the disease proceed to advanced or metastatic stage.	('DSS', 'MPA', (42, 45))	('DSS', 'Chemical', '-', (42, 45))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', (140, 143))	('patients', 'Species', '9606', (49, 57))	('mutations', 'Var', (4, 13))	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', '7428', (140, 143))
117970	30149673	At least one or more VHL abnormalities were detected in 87 cases (88.8%): mutations in in 68 patients (69.4%), LOH in 71 (72.4%), and hypermethylation in 13 (13.3%).	('mutations in', 'Var', (74, 86))	('hypermethylation', 'Var', (134, 150))	('VHL abnormalities', 'Disease', 'MESH:D006623', (21, 38))	('LOH', 'Var', (111, 114))	('patients', 'Species', '9606', (93, 101))	('VHL abnormalities', 'Disease', (21, 38))
117971	30149673	Patients with tumors of wild-type VHL were associated with nodal involvement (p = 0.019) and showed worse DSS compared with those with ccRCC carrying one or two VHL inactivating events (33 months vs. 107 months, p = 0.016).	('nodal involvement', 'CPA', (59, 76))	('DSS', 'MPA', (106, 109))	('DSS', 'Chemical', '-', (106, 109))	('VHL', 'Gene', '7428', (161, 164))	('VHL', 'Gene', '7428', (34, 37))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('VHL', 'Gene', (161, 164))	('wild-type', 'Var', (24, 33))	('VHL', 'Gene', (34, 37))	('Patients', 'Species', '9606', (0, 8))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('associated', 'Reg', (43, 53))	('RCC', 'Disease', (137, 140))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
117972	30149673	There are two meta-analyses in the literature that investigated the pathological or prognostic impact of VHL alteration in RCC.	('VHL', 'Gene', (105, 108))	('alteration', 'Var', (109, 119))	('VHL', 'Gene', '7428', (105, 108))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (123, 126))
117976	30149673	However, they included studies with other histotypes of RCC which rarely carry VHL alteration and did not evaluate the prognostic significance of VHL methylation.	('VHL', 'Gene', '7428', (79, 82))	('VHL', 'Gene', (146, 149))	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('VHL', 'Gene', '7428', (146, 149))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('alteration', 'Var', (83, 93))	('VHL', 'Gene', (79, 82))	('methylation', 'biological_process', 'GO:0032259', ('150', '161'))
117977	30149673	Ultimately, it is not clear that VHL gene alteration has specific pathological or prognostic value in sporadic ccRCCs.	('VHL', 'Gene', (33, 36))	('alteration', 'Var', (42, 52))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('VHL', 'Gene', '7428', (33, 36))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('ccRCCs', 'Phenotype', 'HP:0006770', (111, 117))
117981	30149673	Our results revealed that VHL alteration was not significantly associated with NG (OR = 0.79, 95% CI: 0.59-1.06, p = 0.12) and disease stage (OR = 1.07, 95% CI: 0.79-1.46, p = 0.65).	('VHL', 'Gene', (26, 29))	('VHL', 'Gene', '7428', (26, 29))	('alteration', 'Var', (30, 40))
117982	30149673	In addition, there was no significant association between VHL alteration and prognosis of ccRCCs (HR = 0.75, 95% CI: 0.43-1.29, p = 0.30).	('ccRCCs', 'Phenotype', 'HP:0006770', (90, 96))	('RCC', 'Disease', (92, 95))	('VHL', 'Gene', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('alteration', 'Var', (62, 72))	('VHL', 'Gene', '7428', (58, 61))
117983	30149673	These results indicate that VHL alteration has no significant pathological or prognostic impact in patients with ccRCC.	('alteration', 'Var', (32, 42))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('patients', 'Species', '9606', (99, 107))	('VHL', 'Gene', (28, 31))	('VHL', 'Gene', '7428', (28, 31))
117984	30149673	As mentioned above, VHL gene alteration is a broad concept of genetic abnormality which includes mutations, promoter hypermethylation, and LOH.	('mutations', 'Var', (97, 106))	('LOH', 'Var', (139, 142))	('promoter hypermethylation', 'Var', (108, 133))	('genetic abnormality', 'Disease', (62, 81))	('VHL', 'Gene', (20, 23))	('genetic abnormality', 'Disease', 'MESH:D030342', (62, 81))	('VHL', 'Gene', '7428', (20, 23))	('alteration', 'Var', (29, 39))
117985	30149673	Thus, we further performed the subgroup analyses to determine the difference of the polled HR for two major VHL alteration events (mutation and hypermethylation).	('hypermethylation', 'MPA', (144, 160))	('VHL', 'Gene', '7428', (108, 111))	('VHL', 'Gene', (108, 111))	('mutation', 'Var', (131, 139))
117986	30149673	However, the results showed that both mutation (HR = 0.72, 95% CI: 0.47-1.11, p = 0.14) and hypermethylation (HR = 1.32, 95% CI: 0.70-2.47, p = 0.39) were not significantly correlated with prognosis of ccRCCs.	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('correlated', 'Reg', (173, 183))	('RCC', 'Disease', (204, 207))	('RCC', 'Phenotype', 'HP:0005584', (204, 207))	('ccRCCs', 'Phenotype', 'HP:0006770', (202, 208))	('hypermethylation', 'Var', (92, 108))	('mutation', 'Var', (38, 46))
117987	30149673	reported an interesting result regarding VHL gene variation and prognosis in early-stage ccRCCs.	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('ccRCCs', 'Phenotype', 'HP:0006770', (89, 95))	('variation', 'Var', (50, 59))	('VHL', 'Gene', (41, 44))	('VHL', 'Gene', '7428', (41, 44))
117988	30149673	Tumors carrying biallelic alterations (mutation in homozygosis or presence at the same time of LOH and mutation, LOH and methylation, or methylation and mutation) had a shorter DSS compared with those with no VHL alteration.	('methylation', 'biological_process', 'GO:0032259', ('137', '148'))	('methylation', 'biological_process', 'GO:0032259', ('121', '132'))	('methylation', 'Var', (137, 148))	('biallelic', 'Var', (16, 25))	('VHL', 'Gene', (209, 212))	('LOH', 'Var', (113, 116))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('VHL', 'Gene', '7428', (209, 212))	('shorter', 'NegReg', (169, 176))	('methylation', 'Var', (121, 132))	('DSS', 'MPA', (177, 180))	('DSS', 'Chemical', '-', (177, 180))	('mutation', 'Var', (103, 111))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutation', 'Var', (153, 161))
117989	30149673	Loss of function (LOF) mutations can be defined as events which alter VHL transcriptional read through such as nonsense or frameshift mutations predicted to interfere with protein stability and missense mutation which alter VHL start codon.	('VHL', 'Gene', (70, 73))	('frameshift mutations', 'Var', (123, 143))	('VHL', 'Gene', '7428', (224, 227))	('VHL', 'Gene', '7428', (70, 73))	('interfere', 'NegReg', (157, 166))	('protein stability', 'MPA', (172, 189))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('missense mutation', 'Var', (194, 211))	('mutations', 'Var', (23, 32))	('Loss of function', 'NegReg', (0, 16))	('VHL', 'Gene', (224, 227))	('nonsense', 'Var', (111, 119))
117990	30149673	Several studies reported that LOF mutations rather than other types of VHL alteration showed a meaningful correlation with worse survival.	('VHL', 'Gene', (71, 74))	('LOF', 'NegReg', (30, 33))	('mutations', 'Var', (34, 43))	('VHL', 'Gene', '7428', (71, 74))
117991	30149673	Interestingly, LOF mutations acted as a good predictive marker for VEGF-targeted therapy in patients with RCC.	('VEGF', 'Gene', '7422', (67, 71))	('patients', 'Species', '9606', (92, 100))	('mutations', 'Var', (19, 28))	('VEGF', 'Gene', (67, 71))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('RCC', 'Disease', 'MESH:C538614', (106, 109))
117993	30149673	In patients with tumors containing VHL mutations or methylation, the response rate was 37% compared with 31% in the wild-type group (p = 0.34).	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('mutations', 'Var', (39, 48))	('patients', 'Species', '9606', (3, 11))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('VHL', 'Gene', (35, 38))	('methylation', 'Var', (52, 63))	('VHL', 'Gene', '7428', (35, 38))
117994	30149673	However, patients with LOF mutations obtained a significantly higher response rate than those with VHL-wild-type tumor (52% vs. 31%, p = 0.04).	('mutations', 'Var', (27, 36))	('patients', 'Species', '9606', (9, 17))	('higher', 'PosReg', (62, 68))	('VHL-wild-type tumor', 'Disease', 'MESH:D006623', (99, 118))	('response', 'MPA', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('VHL-wild-type tumor', 'Disease', (99, 118))
117997	30149673	In conclusion, this meta-analysis indicates that VHL gene alteration is not significantly associated with the pathological features or survival in patients with ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('RCC', 'Disease', (163, 166))	('associated', 'Reg', (90, 100))	('patients', 'Species', '9606', (147, 155))	('alteration', 'Var', (58, 68))	('VHL', 'Gene', (49, 52))	('VHL', 'Gene', '7428', (49, 52))
117999	30149673	The following searching terms were used: "kidney" or "renal" and "carcinoma" or "cancer" or "neoplasm" or "malignancy" and "von Hippel-Lindau" or "VHL" and "alteration" or "mutation" or "methylation" or "loss of heterozygosity."	('"neoplasm" or "malignancy', 'Disease', (92, 117))	('von Hippel-Lindau', 'Gene', '7428', (124, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('mutation" or "methylation', 'Var', (173, 198))	('von Hippel-Lindau', 'Gene', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('neoplasm', 'Phenotype', 'HP:0002664', (93, 101))	('"neoplasm" or "malignancy', 'Disease', 'MESH:D009369', (92, 117))	('VHL', 'Gene', (147, 150))	('"carcinoma" or "cancer', 'Disease', (65, 87))	('loss of', 'NegReg', (204, 211))	('"carcinoma" or "cancer', 'Disease', 'MESH:D009369', (65, 87))	('VHL', 'Gene', '7428', (147, 150))	('methylation', 'Var', (187, 198))
118002	30149673	The following data were extracted from the included studies: first author, year of publication, country, number of patients, methods for VHL gene alteration, and pathological or survival data for ORs and HRs with their 95% CIs.	('patients', 'Species', '9606', (115, 123))	('VHL', 'Gene', (137, 140))	('gene alteration', 'Var', (141, 156))	('VHL', 'Gene', '7428', (137, 140))	('alteration', 'Var', (146, 156))
118003	30149673	The strength of the association between VHL alteration and pathological features was shown as ORs and their 95% CIs.	('VHL', 'Gene', (40, 43))	('alteration', 'Var', (44, 54))	('VHL', 'Gene', '7428', (40, 43))
118004	30149673	The pooled OR or HR < 1.0 implies better pathological or survival outcomes for ccRCCs with VHL alteration.	('ccRCCs', 'Phenotype', 'HP:0006770', (79, 85))	('better', 'PosReg', (34, 40))	('alteration', 'Var', (95, 105))	('VHL', 'Gene', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('VHL', 'Gene', '7428', (91, 94))	('RCC', 'Disease', (81, 84))	('survival outcomes', 'CPA', (57, 74))
118006	30149673	ccRCC clear-cell renal cell carcinoma  CI confidence interval  DSS disease-specific survival  HR hazard ratio  LOF loss of function  LOH loss of heterozygosity  NG nuclear grade  OR odd ratio  OS overall survival  PCR polymerase chain reaction   VHL   von Hippel-Lindau	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (17, 37))	('LOF', 'NegReg', (111, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('RCC', 'Disease', (2, 5))	('DSS', 'Chemical', '-', (63, 66))	('VHL   von Hippel-Lindau', 'Disease', 'MESH:D006623', (246, 269))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('loss', 'Var', (137, 141))	('clear-cell renal cell carcinoma  CI', 'Disease', 'MESH:C538614', (6, 41))	('clear-cell renal cell carcinoma  CI', 'Disease', (6, 41))	('VHL   von Hippel-Lindau', 'Disease', (246, 269))
118008	33953831	We investigated the effect of specific Nrf2, SOD2, GPX1 gene variants and GSTP1ABCD haplotype on ccRCC risk and prognosis and evaluated the association between GSTP1 and regulatory (JNK1/2) and executor (caspase-3) apoptotic molecule expression in ccRCC tissue samples and the presence of GSTP1 : JNK1/2 protein : protein interactions.	('JNK1/2', 'Gene', '5599;5601', (182, 188))	('or', 'Gene', '31118', (200, 202))	('GSTP1', 'Gene', '2950', (74, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (248, 253))	('or', 'Gene', '31118', (177, 179))	('RCC', 'Disease', (250, 253))	('RCC', 'Disease', (99, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('GSTP1', 'Gene', (74, 79))	('association', 'Interaction', (140, 151))	('GPX1', 'Gene', (51, 55))	('GSTP1', 'Gene', '2950', (289, 294))	('SOD2', 'molecular_function', 'GO:0004784', ('45', '49'))	('JNK1/2', 'Gene', (182, 188))	('RCC', 'Disease', 'MESH:C538614', (250, 253))	('caspase-3', 'Gene', '836', (204, 213))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('JNK1/2', 'Gene', '5599;5601', (297, 303))	('GSTP1', 'Gene', (289, 294))	('Nrf2', 'Gene', '4780', (39, 43))	('SOD2', 'Gene', (45, 49))	('caspase-3', 'Gene', (204, 213))	('protein', 'cellular_component', 'GO:0003675', ('304', '311'))	('GSTP1', 'Gene', '2950', (160, 165))	('JNK', 'molecular_function', 'GO:0004705', ('297', '300'))	('SOD2', 'Gene', '6648', (45, 49))	('JNK1/2', 'Gene', (297, 303))	('GSTP1', 'Gene', (160, 165))	('Nrf2', 'Gene', (39, 43))	('GPX1', 'Gene', '2876', (51, 55))	('variants', 'Var', (61, 69))	('JNK', 'molecular_function', 'GO:0004705', ('182', '185'))	('protein', 'Protein', (304, 311))	('protein', 'cellular_component', 'GO:0003675', ('314', '321'))	('interactions', 'Interaction', (322, 334))
118011	33953831	An increased risk of ccRCC development was found among carriers of variant genotypes of both SOD2 rs4880 and GSTP1 rs1695 polymorphisms.	('GSTP1', 'Gene', (109, 114))	('SOD2', 'Gene', '6648', (93, 97))	('SOD2', 'Gene', (93, 97))	('variant', 'Var', (67, 74))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (21, 26))	('RCC', 'Disease', (23, 26))	('SOD2', 'molecular_function', 'GO:0004784', ('93', '97'))	('rs1695', 'Var', (115, 121))	('GSTP1', 'Gene', '2950', (109, 114))	('rs4880', 'Var', (98, 104))	('rs4880', 'Mutation', 'rs4880', (98, 104))	('or', 'Gene', '31118', (127, 129))	('rs1695', 'Mutation', 'rs1695', (115, 121))
118012	33953831	Nrf2 rs6721961 genetic polymorphism in combination with both rs4880 and rs1695 showed higher ccRCC risk as well.	('or', 'Gene', '31118', (28, 30))	('rs6721961', 'Var', (5, 14))	('Nrf2', 'Gene', '4780', (0, 4))	('rs4880', 'Var', (61, 67))	('rs6721961', 'Mutation', 'rs6721961', (5, 14))	('RCC', 'Disease', (95, 98))	('rs1695', 'Var', (72, 78))	('Nrf2', 'Gene', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('rs4880', 'Mutation', 'rs4880', (61, 67))	('higher', 'PosReg', (86, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('rs1695', 'Mutation', 'rs1695', (72, 78))
118014	33953831	Furthermore, GSTP1 variant forms seem to affect the overall survival in ccRCC patients, and the proposed molecular mechanism underlying the GSTP1 prognostic role might be the presence of GSTP1 : JNK1/2 protein : protein interactions.	('or', 'Gene', '31118', (28, 30))	('GSTP1', 'Gene', (140, 145))	('GSTP1', 'Gene', '2950', (187, 192))	('GSTP1', 'Gene', (13, 18))	('patients', 'Species', '9606', (78, 86))	('variant', 'Var', (19, 26))	('GSTP1', 'Gene', (187, 192))	('protein', 'cellular_component', 'GO:0003675', ('202', '209'))	('JNK1/2', 'Gene', '5599;5601', (195, 201))	('or', 'Gene', '31118', (8, 10))	('RCC', 'Disease', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('JNK1/2', 'Gene', (195, 201))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('affect', 'Reg', (41, 47))	('interactions', 'Interaction', (220, 232))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('JNK', 'molecular_function', 'GO:0004705', ('195', '198'))	('GSTP1', 'Gene', '2950', (140, 145))	('protein ', 'Protein', (202, 210))	('GSTP1', 'Gene', '2950', (13, 18))
118016	33953831	Disturbance of this fine balance between reactive oxygen species (ROS) production and their disintegration leads to oxidative stress and cellular damage on multiple levels.	('oxidative stress', 'Phenotype', 'HP:0025464', (116, 132))	('reactive oxygen species', 'MPA', (41, 64))	('ROS', 'Chemical', 'MESH:D017382', (66, 69))	('cellular damage', 'CPA', (137, 152))	('leads to', 'Reg', (107, 115))	('Disturbance', 'Var', (0, 11))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (41, 64))	('oxidative stress', 'MPA', (116, 132))
118040	33953831	In addition to acting as a signaling molecule, H2O2 facilitates activation of AMP-activated kinase and promotes glycolysis which is a key change for cancer cells.	('signaling', 'biological_process', 'GO:0023052', ('27', '36'))	('cancer', 'Disease', (149, 155))	('AMP-activated kinase', 'Pathway', (78, 98))	('activation', 'MPA', (64, 74))	('or', 'Gene', '31118', (146, 148))	('glycolysis', 'MPA', (112, 122))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('glycolysis', 'biological_process', 'GO:0006096', ('112', '122'))	('H2O2', 'Chemical', 'MESH:D006861', (47, 51))	('H2O2', 'Var', (47, 51))	('promotes', 'PosReg', (103, 111))	('signaling molecule', 'molecular_function', 'GO:0048018', ('27', '45'))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
118046	33953831	The widely analyzed Nrf2 SNP polymorphism rs6721961 involves substitution of C to A, positioned at -617 of the proximal promoter.	('rs6721961', 'Mutation', 'rs6721961', (42, 51))	('Nrf2', 'Gene', '4780', (20, 24))	('substitution', 'Var', (61, 73))	('Nrf2', 'Gene', (20, 24))	('rs6721961', 'Var', (42, 51))	('or', 'Gene', '31118', (34, 36))	('C to A', 'MPA', (77, 83))
118047	33953831	Definite consequent functional changes are still unsolved, and it is discussed whether higher or lower transcriptional activity is associated with a variant-type genotype (-617AA).	('or', 'Gene', '31118', (94, 96))	('-617AA', 'Var', (172, 178))	('lower', 'NegReg', (97, 102))	('transcriptional activity', 'MPA', (103, 127))
118049	33953831	In the case of GSTP1 gene polymorphisms, two most commonly occurring SNPs are rs1695 and rs1138272.	('rs1695', 'Var', (78, 84))	('GSTP1', 'Gene', '2950', (15, 20))	('rs1138272', 'Mutation', 'rs1138272', (89, 98))	('rs1138272', 'Var', (89, 98))	('rs1695', 'Mutation', 'rs1695', (78, 84))	('GSTP1', 'Gene', (15, 20))	('or', 'Gene', '31118', (31, 33))
118050	33953831	Substitution of A313G in the case of rs1695 causes change of isoleucine with valine at position 105 (Ile105Val).	('Substitution', 'Var', (0, 12))	('rs1695', 'Mutation', 'rs1695', (37, 43))	('A313G', 'Mutation', 'rs1695', (16, 21))	('isoleucine with valine at position 105', 'Mutation', 'rs1695', (61, 99))	('change', 'Reg', (51, 57))	('Ile105Val', 'Chemical', '-', (101, 110))	('rs1695', 'Var', (37, 43))	('isoleucine with valine at position 105', 'MPA', (61, 99))
118051	33953831	This Val allele variant represents a more potent c-Jun N-terminal kinase 1 (JNK1) inhibitor and has a stronger antiapoptotic effect.	('stronger', 'PosReg', (102, 110))	('variant', 'Var', (16, 23))	('c-Jun N-terminal kinase 1', 'Gene', '5599', (49, 74))	('JNK1', 'Gene', '5599', (76, 80))	('JNK', 'molecular_function', 'GO:0004705', ('76', '79'))	('Val', 'Chemical', 'MESH:D014633', (5, 8))	('antiapoptotic effect', 'MPA', (111, 131))	('c-Jun N-terminal kinase 1', 'Gene', (49, 74))	('or', 'Gene', '31118', (89, 91))	('JNK1', 'Gene', (76, 80))	('or', 'Gene', '31118', (38, 40))
118052	33953831	The presence of T instead of C at position 341 results in coding of protein with valine instead of alanine (rs1138272, Ala114Val).	('rs1138272', 'Var', (108, 117))	('Ala114Val', 'SUBSTITUTION', 'None', (119, 128))	('results in', 'Reg', (47, 57))	('Ala114Val', 'Var', (119, 128))	('valine', 'Chemical', 'MESH:D014633', (81, 87))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('alanine', 'Chemical', 'MESH:D000409', (99, 106))	('rs1138272', 'Mutation', 'rs1138272', (108, 117))
118053	33953831	It is assumed that the 341T variant of GSTP might have decreased activity or modified substrate specificity.	('activity', 'MPA', (65, 73))	('341T', 'Var', (23, 27))	('decreased', 'NegReg', (55, 64))	('or', 'Gene', '31118', (74, 76))	('modified', 'Reg', (77, 85))	('substrate specificity', 'MPA', (86, 107))	('GSTP', 'Gene', '2950', (39, 43))	('GSTP', 'Gene', (39, 43))
118055	33953831	When it comes to SOD2 polymorphism, rs4880 corresponds to substitution of C>T in exon 2 leading to change from alanine to valine at position 16.	('or', 'Gene', '31118', (27, 29))	('alanine to valine at position 16', 'Mutation', 'rs4880', (111, 143))	('rs4880', 'Var', (36, 42))	('SOD2', 'Gene', '6648', (17, 21))	('rs4880', 'Mutation', 'rs4880', (36, 42))	('or', 'Gene', '31118', (44, 46))	('alanine to valine at', 'MPA', (111, 131))	('SOD2', 'molecular_function', 'GO:0004784', ('17', '21'))	('SOD2', 'Gene', (17, 21))	('C>T', 'Gene', (74, 77))	('change', 'Reg', (99, 105))
118056	33953831	Since there is a channel within the inner mitochondrial membrane that cannot import the Val16 variant of SOD2 as efficiently as Ala16, the Val16 variant remains trapped and later degraded by the proteasome.	('SOD2', 'molecular_function', 'GO:0004784', ('105', '109'))	('variant', 'Var', (94, 101))	('or', 'Gene', '31118', (80, 82))	('degraded', 'NegReg', (179, 187))	('proteasome', 'cellular_component', 'GO:0000502', ('195', '205'))	('proteasome', 'molecular_function', 'GO:0004299', ('195', '205'))	('Val16', 'Chemical', '-', (139, 144))	('Val16', 'Chemical', '-', (88, 93))	('SOD2', 'Gene', '6648', (105, 109))	('inner mitochondrial membrane', 'cellular_component', 'GO:0005743', ('36', '64'))	('SOD2', 'Gene', (105, 109))	('Ala16', 'Chemical', '-', (128, 133))	('Val16', 'Gene', (88, 93))
118057	33953831	The mostly studied SNP in the case of the GPX1 gene is rs1050450 (Pro200Leu).	('rs1050450', 'Mutation', 'rs1050450', (55, 64))	('Pro200Leu', 'Mutation', 'rs1050450', (66, 75))	('GPX1', 'Gene', '2876', (42, 46))	('GPX1', 'Gene', (42, 46))	('rs1050450', 'Var', (55, 64))
118060	33953831	Considering the potential functional significance of polymorphisms in genes encoding the Nrf2 transcriptional factor, as well as antioxidant SOD2, GPX1, and detoxification GSTP1 enzymes in both the onset and prognosis of clear cell RCC, the aim of this study was to evaluate the effect of specific Nrf2, SOD2, and GPX1 gene variants and GSTP1ABCD haplotype on the risk, development, and postoperative prognosis in patients with ccRCC.	('or', 'Gene', '31118', (114, 116))	('Nrf2', 'Gene', (298, 302))	('GSTP1', 'Gene', (172, 177))	('GSTP1', 'Gene', (337, 342))	('SOD2', 'Gene', '6648', (304, 308))	('detoxification', 'biological_process', 'GO:0098754', ('157', '171'))	('GPX1', 'Gene', (147, 151))	('Nrf2', 'Gene', '4780', (89, 93))	('RCC', 'Disease', (232, 235))	('GPX1', 'Gene', (314, 318))	('RCC', 'Disease', (430, 433))	('ccRCC', 'Phenotype', 'HP:0006770', (428, 433))	('SOD2', 'Gene', (141, 145))	('RCC', 'Disease', 'MESH:C538614', (232, 235))	('Nrf2', 'Gene', (89, 93))	('RCC', 'Disease', 'MESH:C538614', (430, 433))	('Nrf2', 'Gene', '4780', (298, 302))	('GPX1', 'Gene', '2876', (147, 151))	('patients', 'Species', '9606', (414, 422))	('SOD2', 'molecular_function', 'GO:0004784', ('141', '145'))	('SOD2', 'Gene', '6648', (141, 145))	('SOD2', 'molecular_function', 'GO:0004784', ('304', '308'))	('variants', 'Var', (324, 332))	('SOD2', 'Gene', (304, 308))	('GPX1', 'Gene', '2876', (314, 318))	('GSTP1', 'Gene', '2950', (172, 177))	('GSTP1', 'Gene', '2950', (337, 342))	('or', 'Gene', '31118', (58, 60))
118076	33953831	Genotyping of GSTP1 (rs1695 and rs1138272), SOD2 (rs4880), and GPX1 (rs1050450) was done by applying quantitative polymerase chain reaction (qPCR) on Mastercycler ep realplex (Eppendorf, Hamburg, Germany) using appropriate assays of Applied Biosystems TaqMan Drug Metabolism Genotyping (Life Technologies, Applied Biosystems, Carlsbad, CA, USA).	('or', 'Gene', '31118', (182, 184))	('rs1050450', 'Mutation', 'rs1050450', (69, 78))	('SOD2', 'molecular_function', 'GO:0004784', ('44', '48'))	('GPX1', 'Gene', '2876', (63, 67))	('GPX1', 'Gene', (63, 67))	('rs1138272', 'Mutation', 'rs1138272', (32, 41))	('GSTP1', 'Gene', (14, 19))	('rs1138272', 'Var', (32, 41))	('rs4880', 'Var', (50, 56))	('rs1695', 'Var', (21, 27))	('SOD2', 'Gene', '6648', (44, 48))	('rs4880', 'Mutation', 'rs4880', (50, 56))	('Drug Metabolism', 'biological_process', 'GO:0017144', ('259', '274'))	('SOD2', 'Gene', (44, 48))	('rs1695', 'Mutation', 'rs1695', (21, 27))	('GSTP1', 'Gene', '2950', (14, 19))	('Biosystems TaqMan Drug Metabolism', 'Disease', 'MESH:D065606', (241, 274))	('Biosystems TaqMan Drug Metabolism', 'Disease', (241, 274))
118077	33953831	Assays C_3237198_20 in the case of GSTP1 rs1695, C_1049615_20 for GSTP1 rs1138272, and C_8709053_10 were used for SOD2.	('C_3237198_20', 'Var', (7, 19))	('or', 'Gene', '31118', (63, 65))	('SOD2', 'Gene', '6648', (114, 118))	('or', 'Gene', '31118', (111, 113))	('SOD2', 'molecular_function', 'GO:0004784', ('114', '118'))	('rs1695', 'Mutation', 'rs1695', (41, 47))	('GSTP1', 'Gene', (35, 40))	('GSTP1', 'Gene', (66, 71))	('rs1695', 'Var', (41, 47))	('SOD2', 'Gene', (114, 118))	('C_8709053_10', 'Var', (87, 99))	('rs1138272', 'Mutation', 'rs1138272', (72, 81))	('C_1049615_20', 'Var', (49, 61))	('rs1138272', 'Var', (72, 81))	('GSTP1', 'Gene', '2950', (35, 40))	('GSTP1', 'Gene', '2950', (66, 71))
118078	33953831	For the GPX1 rs1050450 polymorphism, a custom-designed assay with sequences 5' VIC-ACAGCTGGGCCCTT-MGB-3' and 5' FAM-ACAGCTGAGCCCTT-MGB-3' was used.	('rs1050450', 'Var', (13, 22))	('or', 'Gene', '31118', (28, 30))	('or', 'Gene', '31118', (1, 3))	('GPX1', 'Gene', '2876', (8, 12))	('GPX1', 'Gene', (8, 12))	('rs1050450', 'Mutation', 'rs1050450', (13, 22))
118096	33953831	The risk each genetic variant carries for ccRCC development was computed by odds ratios (OR) and 95% confidence intervals (CI) by logistic regression analysis.	('OR', 'Gene', '31118', (89, 91))	('variant', 'Var', (22, 29))	('or', 'Gene', '31118', (39, 41))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (42, 47))	('RCC', 'Disease', (44, 47))
118109	33953831	No significant ccRCC risk was revealed for subjects carrying the C/A and A/A Nrf2 genotype in comparison with carriers of the C/C genotype (OR = 0.692, 95%CI = 0.370-1.295, p = 0.250).	('OR', 'Gene', '31118', (140, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (15, 20))	('Nrf2', 'Gene', (77, 81))	('A/A', 'Var', (73, 76))	('or', 'Gene', '31118', (40, 42))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('C/A', 'Var', (65, 68))	('RCC', 'Disease', (17, 20))	('Nrf2', 'Gene', '4780', (77, 81))
118110	33953831	On the contrary, the risk for ccRCC development was highly increased in individuals with at least one SOD2 Val allele or precisely Ala/Val and Val/Val SOD2 genotypes (OR = 4.521, 95%CI = 2.167-9.432, p < 0.001).	('or', 'Gene', '31118', (27, 29))	('SOD2', 'molecular_function', 'GO:0004784', ('102', '106'))	('Val', 'Chemical', 'MESH:D014633', (107, 110))	('increased', 'PosReg', (59, 68))	('SOD2', 'Gene', (151, 155))	('SOD2', 'molecular_function', 'GO:0004784', ('151', '155'))	('Ala', 'Chemical', 'MESH:D000409', (131, 134))	('SOD2', 'Gene', '6648', (151, 155))	('Val', 'Chemical', 'MESH:D014633', (143, 146))	('SOD2', 'Gene', (102, 106))	('RCC', 'Disease', (32, 35))	('or', 'Gene', '31118', (118, 120))	('Val', 'Chemical', 'MESH:D014633', (135, 138))	('SOD2', 'Gene', '6648', (102, 106))	('Val', 'Var', (107, 110))	('OR', 'Gene', '31118', (167, 169))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('Val', 'Chemical', 'MESH:D014633', (147, 150))
118111	33953831	Regarding GPX1 polymorphism, the risk for ccRCC development was reduced in subjects carrying Pro/Leu and Leu/Leu genotypes when compared to individuals with the Pro/Pro genotype (OR = 0.567, 95%CI = 0.323-0.994, p = 0.048).	('GPX1', 'Gene', '2876', (10, 14))	('Leu/Leu', 'Var', (105, 112))	('Leu', 'Chemical', 'MESH:D007930', (97, 100))	('GPX1', 'Gene', (10, 14))	('Pro', 'Chemical', 'MESH:D011392', (165, 168))	('or', 'Gene', '31118', (39, 41))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('Pro', 'Chemical', 'MESH:D011392', (161, 164))	('RCC', 'Disease', (44, 47))	('OR', 'Gene', '31118', (179, 181))	('ccRCC', 'Phenotype', 'HP:0006770', (42, 47))	('Leu', 'Chemical', 'MESH:D007930', (105, 108))	('or', 'Gene', '31118', (20, 22))	('reduced', 'NegReg', (64, 71))	('Leu', 'Chemical', 'MESH:D007930', (109, 112))	('Pro/Leu', 'Var', (93, 100))	('Pro', 'Chemical', 'MESH:D011392', (93, 96))
118112	33953831	GSTP1 polymorphisms rs1695 and rs1138272 were studied individually and in combination, as well as the GSTP1ABCD haplotype.	('GSTP1', 'Gene', (102, 107))	('GSTP1', 'Gene', (0, 5))	('rs1695', 'Var', (20, 26))	('or', 'Gene', '31118', (11, 13))	('rs1695', 'Mutation', 'rs1695', (20, 26))	('GSTP1', 'Gene', '2950', (102, 107))	('GSTP1', 'Gene', '2950', (0, 5))	('rs1138272', 'Mutation', 'rs1138272', (31, 40))	('rs1138272', 'Var', (31, 40))
118113	33953831	As presented, subjects with the Ile/Val and Val/Val rs1695 genotype combined with the Ala/Ala rs1138272 genotype had more than 3-fold increased risk for developing clear cell renal cell carcinoma in comparison with carriers of referent genotypes for both polymorphisms (OR = 3.250, 95%CI = 1.668-6.331, p = 0.001).	('OR', 'Gene', '31118', (270, 272))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (164, 195))	('rs1695', 'Var', (52, 58))	('or', 'Gene', '31118', (247, 249))	('Ala', 'Chemical', 'MESH:D000409', (90, 93))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (164, 195))	('or', 'Gene', '31118', (150, 152))	('rs1695', 'Mutation', 'rs1695', (52, 58))	('rs1138272', 'Var', (94, 103))	('Val', 'Chemical', 'MESH:D014633', (48, 51))	('or', 'Gene', '31118', (118, 120))	('or', 'Gene', '31118', (260, 262))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (175, 195))	('clear cell renal cell carcinoma', 'Disease', (164, 195))	('rs1138272', 'Mutation', 'rs1138272', (94, 103))	('Ala', 'Chemical', 'MESH:D000409', (86, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('Val', 'Chemical', 'MESH:D014633', (36, 39))	('Val', 'Chemical', 'MESH:D014633', (44, 47))
118115	33953831	When observed altogether, subjects with the C/C Nrf2 genotype who were, at the same time, carrying the Ala/Val or Val/Val SOD2 genotype, exhibited three-fold increased ccRCC risk (OR 3.234, 95%CI = 1.436-7.280, p = 0.005), while subjects with C/A or A/A Nrf2 in combination with the Ala/Val or Val/Val SOD2 genotype had 2.9-fold increased risk for ccRCC development (OR = 2.918, 95%CI = 1.131-7.532, p = 0.027).	('Val', 'Chemical', 'MESH:D014633', (114, 117))	('Val', 'Chemical', 'MESH:D014633', (107, 110))	('or', 'Gene', '31118', (345, 347))	('Ala', 'Chemical', 'MESH:D000409', (283, 286))	('OR', 'Gene', '31118', (180, 182))	('SOD2', 'Gene', '6648', (122, 126))	('or', 'Gene', '31118', (247, 249))	('SOD2', 'molecular_function', 'GO:0004784', ('302', '306'))	('Nrf2', 'Gene', '4780', (254, 258))	('SOD2', 'Gene', (302, 306))	('RCC', 'Disease', (170, 173))	('Nrf2', 'Gene', '4780', (48, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (168, 173))	('Val', 'Chemical', 'MESH:D014633', (294, 297))	('Val', 'Chemical', 'MESH:D014633', (287, 290))	('SOD2', 'Gene', '6648', (302, 306))	('or', 'Gene', '31118', (111, 113))	('or', 'Gene', '31118', (291, 293))	('Val', 'Chemical', 'MESH:D014633', (118, 121))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('Nrf2', 'Gene', (254, 258))	('Nrf2', 'Gene', (48, 52))	('RCC', 'Disease', 'MESH:C538614', (350, 353))	('RCC', 'Disease', (350, 353))	('ccRCC', 'Phenotype', 'HP:0006770', (348, 353))	('OR', 'Gene', '31118', (367, 369))	('Ala', 'Chemical', 'MESH:D000409', (103, 106))	('C/C', 'Var', (44, 47))	('SOD2', 'molecular_function', 'GO:0004784', ('122', '126'))	('Val', 'Chemical', 'MESH:D014633', (298, 301))	('SOD2', 'Gene', (122, 126))
118116	33953831	Almost equally higher risk was found among carriers of combined C/C Nrf2 and Ile/Val or Val/Val GSTP1 rs1695 genotypes (OR = 3.211, 95% CI 1.516-6.814, p = 0.002).	('OR', 'Gene', '31118', (120, 122))	('Nrf2', 'Gene', (68, 72))	('rs1695', 'Var', (102, 108))	('C/C', 'Var', (64, 67))	('GSTP1', 'Gene', (96, 101))	('Val', 'Chemical', 'MESH:D014633', (88, 91))	('Val', 'Chemical', 'MESH:D014633', (81, 84))	('or', 'Gene', '31118', (85, 87))	('rs1695', 'Mutation', 'rs1695', (102, 108))	('Val', 'Chemical', 'MESH:D014633', (92, 95))	('Nrf2', 'Gene', '4780', (68, 72))	('GSTP1', 'Gene', '2950', (96, 101))
118117	33953831	Logistic regression showed no substantial risk when Nrf2 genotypes were analyzed in combination with GPX1 and GSTP1 rs1138272 genotypes.	('GSTP1', 'Gene', '2950', (110, 115))	('Nrf2', 'Gene', '4780', (52, 56))	('rs1138272', 'Mutation', 'rs1138272', (116, 125))	('GPX1', 'Gene', '2876', (101, 105))	('rs1138272', 'Var', (116, 125))	('GPX1', 'Gene', (101, 105))	('Nrf2', 'Gene', (52, 56))	('GSTP1', 'Gene', (110, 115))
118118	33953831	The increased ccRCC risk was the most pronounced when SOD2 and either GSTP1 rs1695 or rs1138272 polymorphisms were examined.	('GSTP1', 'Gene', '2950', (70, 75))	('or', 'Gene', '31118', (83, 85))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('RCC', 'Disease', (16, 19))	('SOD2', 'Gene', '6648', (54, 58))	('or', 'Gene', '31118', (101, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (14, 19))	('GSTP1', 'Gene', (70, 75))	('SOD2', 'Gene', (54, 58))	('rs1695', 'Var', (76, 82))	('SOD2', 'molecular_function', 'GO:0004784', ('54', '58'))	('rs1138272', 'Mutation', 'rs1138272', (86, 95))	('rs1138272', 'Var', (86, 95))	('rs1695', 'Mutation', 'rs1695', (76, 82))
118119	33953831	Ala/Val and Val/Val SOD2 genotypes in combination with Ile/Val and Val/Val rs1695 genotypes were associated with almost 20-fold increased risk (OR = 19.724, 95%CI = 4.267-91.165, p < 0.001), while 4-fold increased risk for ccRCC development was observed when in combination with the Ala/Ala GSTP1 rs1138272 genotype (OR = 4.374, 95%CI = 2.012-9.508, p < 0.001).	('Val', 'Chemical', 'MESH:D014633', (59, 62))	('GSTP1', 'Gene', (291, 296))	('Val', 'Chemical', 'MESH:D014633', (4, 7))	('rs1138272', 'Mutation', 'rs1138272', (297, 306))	('Ala', 'Chemical', 'MESH:D000409', (283, 286))	('OR', 'Gene', '31118', (317, 319))	('rs1695', 'Var', (75, 81))	('RCC', 'Disease', (225, 228))	('Val', 'Chemical', 'MESH:D014633', (71, 74))	('Val', 'Chemical', 'MESH:D014633', (16, 19))	('ccRCC', 'Phenotype', 'HP:0006770', (223, 228))	('SOD2', 'molecular_function', 'GO:0004784', ('20', '24'))	('rs1695', 'Mutation', 'rs1695', (75, 81))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('Ala', 'Chemical', 'MESH:D000409', (287, 290))	('Ala', 'Chemical', 'MESH:D000409', (0, 3))	('SOD2', 'Gene', (20, 24))	('or', 'Gene', '31118', (220, 222))	('OR', 'Gene', '31118', (144, 146))	('Val', 'Chemical', 'MESH:D014633', (67, 70))	('Val', 'Chemical', 'MESH:D014633', (12, 15))	('GSTP1', 'Gene', '2950', (291, 296))	('SOD2', 'Gene', '6648', (20, 24))
118120	33953831	Finally, the presence of the GPX1 Pro/Pro genotype combined with either the Ala/Val or Val/Val SOD2 genotype and Ile/Val or Val/Val GSTP1 rs1695 genotype leads to significantly higher risk for this cancer (OR = 3.653, 95%CI = 1.148-11.630, p = 0.028 and OR = 5.476, 95%CI = 2.127-14.102, p < 0.001, respectively).	('or', 'Gene', '31118', (121, 123))	('GSTP1', 'Gene', '2950', (132, 137))	('OR', 'Gene', '31118', (206, 208))	('OR', 'Gene', '31118', (254, 256))	('GPX1', 'Gene', (29, 33))	('Pro', 'Chemical', 'MESH:D011392', (38, 41))	('GSTP1', 'Gene', (132, 137))	('Val', 'Chemical', 'MESH:D014633', (128, 131))	('or', 'Gene', '31118', (190, 192))	('cancer', 'Disease', (198, 204))	('Ala', 'Chemical', 'MESH:D000409', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('rs1695', 'Var', (138, 144))	('SOD2', 'Gene', (95, 99))	('SOD2', 'molecular_function', 'GO:0004784', ('95', '99'))	('Val', 'Chemical', 'MESH:D014633', (87, 90))	('or', 'Gene', '31118', (84, 86))	('Val', 'Chemical', 'MESH:D014633', (80, 83))	('GPX1', 'Gene', '2876', (29, 33))	('SOD2', 'Gene', '6648', (95, 99))	('Pro', 'Chemical', 'MESH:D011392', (34, 37))	('rs1695', 'Mutation', 'rs1695', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('Val', 'Chemical', 'MESH:D014633', (117, 120))	('Val', 'Chemical', 'MESH:D014633', (124, 127))	('Val', 'Chemical', 'MESH:D014633', (91, 94))
118121	33953831	In the next step, haplotype analysis of GSTP1 rs1695 and rs1138272 polymorphisms was performed and is presented in Table 4.	('GSTP1', 'Gene', (40, 45))	('or', 'Gene', '31118', (72, 74))	('rs1695', 'Mutation', 'rs1695', (46, 52))	('rs1138272', 'Mutation', 'rs1138272', (57, 66))	('rs1138272', 'Var', (57, 66))	('GSTP1', 'Gene', '2950', (40, 45))	('or', 'Gene', '31118', (89, 91))	('rs1695', 'Var', (46, 52))
118122	33953831	The GSTP1A genotype represents a combination of A313 and C114, meaning that the enzyme has isoleucine at position 105 and alanine at 114.	('A313', 'Var', (48, 52))	('GSTP1', 'Gene', (4, 9))	('isoleucine', 'Chemical', 'MESH:D007532', (91, 101))	('isoleucine', 'MPA', (91, 101))	('A313', 'Chemical', 'MESH:D014801', (48, 52))	('GSTP1', 'Gene', '2950', (4, 9))	('alanine', 'MPA', (122, 129))	('C114', 'Var', (57, 61))	('alanine', 'Chemical', 'MESH:D000409', (122, 129))
118123	33953831	The genotype with G313 and C114 or valine at 105 and alanine at 114 is GSTP1B.	('valine at', 'Var', (35, 44))	('G313', 'Var', (18, 22))	('GSTP1', 'Gene', (71, 76))	('G313', 'Chemical', '-', (18, 22))	('GSTP1', 'Gene', '2950', (71, 76))	('or', 'Gene', '31118', (32, 34))	('alanine at 114', 'Var', (53, 67))	('alanine', 'Chemical', 'MESH:D000409', (53, 60))	('valine', 'Chemical', 'MESH:D014633', (35, 41))
118124	33953831	The presence of G313 and T114 or valine at both 105 and 114 represents GSTP1C, while the form consisting of isoleucine at position 105 and valine at 114 (A313 and T114) is GSTP1D.	('valine', 'Chemical', 'MESH:D014633', (139, 145))	('GSTP1', 'Gene', (71, 76))	('T114', 'Var', (25, 29))	('or', 'Gene', '31118', (90, 92))	('valine', 'Chemical', 'MESH:D014633', (33, 39))	('valine at', 'Var', (33, 42))	('T114', 'Chemical', '-', (163, 167))	('isoleucine', 'Chemical', 'MESH:D007532', (108, 118))	('GSTP1', 'Gene', '2950', (71, 76))	('A313', 'Chemical', 'MESH:D014801', (154, 158))	('G313', 'Var', (16, 20))	('GSTP1', 'Gene', (172, 177))	('or', 'Gene', '31118', (30, 32))	('GSTP1', 'Gene', '2950', (172, 177))	('T114', 'Chemical', '-', (25, 29))	('G313', 'Chemical', '-', (16, 20))
118126	33953831	Regarding the effect of the GSTP1ABCD haplotype on ccRCC susceptibility, the haplotype consisting of variant alleles of both polymorphisms *G and *T was associated with 3.5-fold increased risk (OR = 3.50, 95%CI = 1.49-8.22, p = 0.004).	('variant', 'Var', (101, 108))	('GSTP1', 'Gene', (28, 33))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('or', 'Gene', '31118', (130, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))	('GSTP1', 'Gene', '2950', (28, 33))	('OR', 'Gene', '31118', (194, 196))
118130	33953831	Statistically significant difference in frequencies was observed among carriers of Pro/Leu and Leu/Leu genotypes of the examined GPX1 polymorphism (p = 0.024).	('Leu/Leu', 'Var', (95, 102))	('Leu', 'Chemical', 'MESH:D007930', (87, 90))	('or', 'Gene', '31118', (139, 141))	('Leu', 'Chemical', 'MESH:D007930', (95, 98))	('Leu', 'Chemical', 'MESH:D007930', (99, 102))	('Pro/Leu', 'Var', (83, 90))	('GPX1', 'Gene', '2876', (129, 133))	('GPX1', 'Gene', (129, 133))	('Pro', 'Chemical', 'MESH:D011392', (83, 86))
118134	33953831	Although without reaching statistical significance, the GSTP1-variant genotype consisting of at least one Val105 allele in the case of rs1695, in combination with at least one Val114 allele in the case of rs1138272, expressed the highest hazard ratio in ccRCC patients (model 1 HR = 1.627, 95%CI = 0.664-3.986, p = 0.287; model 2 HR = 3.897, 95%CI = 0.681-22.304, p = 0.126).	('Val', 'Chemical', 'MESH:D014633', (106, 109))	('rs1695', 'Mutation', 'rs1695', (135, 141))	('GSTP1', 'Gene', '2950', (56, 61))	('rs1138272', 'Mutation', 'rs1138272', (205, 214))	('rs1138272', 'Var', (205, 214))	('Val', 'Chemical', 'MESH:D014633', (176, 179))	('RCC', 'Disease', 'MESH:C538614', (256, 259))	('patients', 'Species', '9606', (260, 268))	('RCC', 'Disease', (256, 259))	('ccRCC', 'Phenotype', 'HP:0006770', (254, 259))	('GSTP1', 'Gene', (56, 61))	('rs1695', 'Var', (135, 141))
118136	33953831	The Kaplan-Meier survival curves for overall mortality according to Nrf2, GSTP1, SOD2, and GPX1 genes in ccRCC patients are presented in Figure 1.	('Nrf2', 'Gene', (68, 72))	('GSTP1', 'Gene', '2950', (74, 79))	('SOD2', 'Gene', (81, 85))	('GSTP1', 'Gene', (74, 79))	('mortality', 'Disease', (45, 54))	('ccRCC', 'Phenotype', 'HP:0006770', (105, 110))	('RCC', 'Disease', (107, 110))	('SOD2', 'Gene', '6648', (81, 85))	('GPX1', 'Gene', (91, 95))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('or', 'Gene', '31118', (46, 48))	('mortality', 'Disease', 'MESH:D003643', (45, 54))	('genes', 'Var', (96, 101))	('Nrf2', 'Gene', '4780', (68, 72))	('SOD2', 'molecular_function', 'GO:0004784', ('81', '85'))	('or', 'Gene', '31118', (34, 36))	('GPX1', 'Gene', '2876', (91, 95))	('or', 'Gene', '31118', (58, 60))	('patients', 'Species', '9606', (111, 119))
118138	33953831	However, patients who were carrying any of variant GSTP1 genotypes were recognized as patients with shorter overall survival (log-rank p = 0.038) (Figure 1(b)).	('patients', 'Species', '9606', (9, 17))	('overall survival', 'MPA', (108, 124))	('GSTP1', 'Gene', '2950', (51, 56))	('variant', 'Var', (43, 50))	('GSTP1', 'Gene', (51, 56))	('or', 'Gene', '31118', (102, 104))	('patients', 'Species', '9606', (86, 94))
118149	33953831	In recent years, attention has been raised toward genetic variants, often referred to as "quantitative trait loci" that could contribute to a small, but significant, risk not only for the development but also for the progression of complex disorder such as cancer.	('or', 'Gene', '31118', (210, 212))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('variants', 'Var', (58, 66))	('or', 'Gene', '31118', (181, 183))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('or', 'Gene', '31118', (243, 245))	('cancer', 'Disease', (257, 263))	('complex disorder', 'Disease', (232, 248))	('complex disorder', 'Disease', 'MESH:C537708', (232, 248))
118153	33953831	We noticed an increased risk of ccRCC development among carriers of variant genotypes of both SOD2 rs4880 and GSTP1 rs1695 polymorphisms.	('ccRCC', 'Phenotype', 'HP:0006770', (32, 37))	('rs1695', 'Var', (116, 122))	('GSTP1', 'Gene', '2950', (110, 115))	('SOD2', 'Gene', '6648', (94, 98))	('SOD2', 'Gene', (94, 98))	('or', 'Gene', '31118', (128, 130))	('rs1695', 'Mutation', 'rs1695', (116, 122))	('SOD2', 'molecular_function', 'GO:0004784', ('94', '98'))	('variant', 'Var', (68, 75))	('rs4880', 'Var', (99, 105))	('rs4880', 'Mutation', 'rs4880', (99, 105))	('GSTP1', 'Gene', (110, 115))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('RCC', 'Disease', (34, 37))
118154	33953831	Nrf2 rs6721961 genetic polymorphism in combination with both rs4880 and rs1695 showed higher risk for this type of tumor as well.	('or', 'Gene', '31118', (28, 30))	('rs6721961', 'Var', (5, 14))	('Nrf2', 'Gene', '4780', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('or', 'Gene', '31118', (118, 120))	('rs4880', 'Var', (61, 67))	('rs6721961', 'Mutation', 'rs6721961', (5, 14))	('Nrf2', 'Gene', (0, 4))	('rs1695', 'Var', (72, 78))	('rs4880', 'Mutation', 'rs4880', (61, 67))	('or', 'Gene', '31118', (99, 101))	('rs1695', 'Mutation', 'rs1695', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
118155	33953831	Since two examined SNPs of GSTP1, rs1695 and rs1138272, are close in their position, haplotype analysis was performed.	('rs1695', 'Var', (34, 40))	('GSTP1', 'Gene', (27, 32))	('rs1695', 'Mutation', 'rs1695', (34, 40))	('or', 'Gene', '31118', (112, 114))	('GSTP1', 'Gene', '2950', (27, 32))	('rs1138272', 'Mutation', 'rs1138272', (45, 54))	('rs1138272', 'Var', (45, 54))
118156	33953831	It revealed that significant risk of ccRCC development is associated with a genotype consisting of variant forms of both polymorphisms, while the molecular mechanism underlying the role of GSTP1 forms in RCC progression might be explained by the presence of GSTP1 : JNK1/2 protein : protein interactions.	('interactions', 'Interaction', (291, 303))	('GSTP1', 'Gene', (258, 263))	('RCC', 'Disease', (204, 207))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('or', 'Gene', '31118', (126, 128))	('JNK1/2', 'Gene', '5599;5601', (266, 272))	('protein', 'cellular_component', 'GO:0003675', ('283', '290'))	('or', 'Gene', '31118', (196, 198))	('GSTP1', 'Gene', '2950', (189, 194))	('JNK1/2', 'Gene', (266, 272))	('or', 'Gene', '31118', (108, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('GSTP1', 'Gene', (189, 194))	('variant', 'Var', (99, 106))	('JNK', 'molecular_function', 'GO:0004705', ('266', '269'))	('RCC', 'Disease', (39, 42))	('GSTP1', 'Gene', '2950', (258, 263))	('protein', 'cellular_component', 'GO:0003675', ('273', '280'))
118158	33953831	The importance of SNP rs6721961 for further Nrf2 activity has been shown, since this polymorphism is positioned in the middle of the ARE motif and affects the binding of Nrf2 to the ARE.	('Nrf2', 'Gene', (44, 48))	('activity', 'MPA', (49, 57))	('rs6721961', 'Var', (22, 31))	('or', 'Gene', '31118', (90, 92))	('Nrf2', 'Gene', '4780', (44, 48))	('or', 'Gene', '31118', (33, 35))	('binding', 'molecular_function', 'GO:0005488', ('159', '166'))	('binding', 'Interaction', (159, 166))	('affects', 'Reg', (147, 154))	('ARE', 'Protein', (182, 185))	('Nrf2', 'Gene', '4780', (170, 174))	('rs6721961', 'Mutation', 'rs6721961', (22, 31))	('or', 'Gene', '31118', (7, 9))	('Nrf2', 'Gene', (170, 174))
118165	33953831	found no association between SNP rs6721961 and risk for urinary bladder cancer.	('urinary bladder cancer', 'Disease', (56, 78))	('bladder cancer', 'Phenotype', 'HP:0009725', (64, 78))	('urinary bladder cancer', 'Disease', 'MESH:D001749', (56, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('rs6721961', 'Mutation', 'rs6721961', (33, 42))	('or', 'Gene', '31118', (53, 55))	('SNP', 'Gene', (29, 32))	('rs6721961', 'Var', (33, 42))
118167	33953831	Still, in already developed renal cell carcinoma, higher expression of Nrf2 protein in carriers of the C/C genotype seems to point out the patients with poor prognosis and shorter overall survival.	('C/C', 'Var', (103, 106))	('expression', 'MPA', (57, 67))	('or', 'Gene', '31118', (155, 157))	('higher', 'PosReg', (50, 56))	('patients', 'Species', '9606', (139, 147))	('Nrf2', 'Gene', (71, 75))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (28, 48))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('protein', 'Protein', (76, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('or', 'Gene', '31118', (174, 176))	('renal cell carcinoma', 'Disease', (28, 48))	('Nrf2', 'Gene', '4780', (71, 75))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (28, 48))
118169	33953831	According to our follow-up analysis, patients with the C/C genotype did have shorter overall survival compared to C/A and A/A carriers, although it was not statistically significant.	('or', 'Gene', '31118', (79, 81))	('patients', 'Species', '9606', (37, 45))	('C/C', 'Var', (55, 58))	('overall survival', 'MPA', (85, 101))	('or', 'Gene', '31118', (3, 5))
118174	33953831	There was significant difference in distribution of the rs1695 genotype among patients and controls, but no association between ccRCC and rs1138272.	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('patients', 'Species', '9606', (78, 86))	('rs1695', 'Var', (56, 62))	('RCC', 'Disease', (130, 133))	('rs1138272', 'Mutation', 'rs1138272', (138, 147))	('rs1138272', 'Var', (138, 147))	('rs1695', 'Mutation', 'rs1695', (56, 62))
118177	33953831	Since the overall functions of GSTs also include the regulation of cell signaling, the GSTP1C haplotype has been considered a better c-Jun N-terminal kinase 1 inhibitor than the reference GSTP1A haplotype.	('GSTP1', 'Gene', (188, 193))	('c-Jun N-terminal kinase 1', 'Gene', (133, 158))	('c-Jun N-terminal kinase 1', 'Gene', '5599', (133, 158))	('GSTP1', 'Gene', (87, 92))	('or', 'Gene', '31118', (166, 168))	('GSTs', 'Gene', '373156', (31, 35))	('regulation', 'biological_process', 'GO:0065007', ('53', '63'))	('GSTP1', 'Gene', '2950', (188, 193))	('haplotype', 'Var', (94, 103))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))	('GSTP1', 'Gene', '2950', (87, 92))	('cell signaling', 'MPA', (67, 81))	('GSTs', 'Gene', (31, 35))
118178	33953831	In line with these results, our study showed higher risk for ccRCC for carriers of the GSTP1C haplotype.	('RCC', 'Disease', (63, 66))	('GSTP1', 'Gene', '2950', (87, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('GSTP1', 'Gene', (87, 92))	('carriers', 'Reg', (71, 79))	('haplotype', 'Var', (94, 103))	('or', 'Gene', '31118', (68, 70))	('or', 'Gene', '31118', (58, 60))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
118187	33953831	showed that protein produced in carriers of the Val105 and Val114 genotype acts as a better JNK inhibitor.	('Val', 'Chemical', 'MESH:D014633', (59, 62))	('protein', 'cellular_component', 'GO:0003675', ('12', '19'))	('Val105', 'Var', (48, 54))	('Val', 'Chemical', 'MESH:D014633', (48, 51))	('Val114', 'Var', (59, 65))	('JNK', 'Gene', (92, 95))	('JNK', 'Gene', '5599', (92, 95))	('JNK', 'molecular_function', 'GO:0004705', ('92', '95'))	('or', 'Gene', '31118', (103, 105))
118192	33953831	Involvement of polymorphism rs4880 in cancer susceptibility has been extensively investigated.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('or', 'Gene', '31118', (20, 22))	('rs4880', 'Var', (28, 34))	('rs4880', 'Mutation', 'rs4880', (28, 34))
118195	33953831	Those studies that actually reported increased risk for breast cancer usually reported the Ala/Ala genotype to be the most frequent, although the carriers of the Val16 variant are expected to be at greater cancer risk.	('Ala/Ala', 'Disease', (91, 98))	('Val16', 'Chemical', '-', (162, 167))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Ala', 'Chemical', 'MESH:D000409', (91, 94))	('Ala', 'Chemical', 'MESH:D000409', (95, 98))	('or', 'Gene', '31118', (81, 83))	('or', 'Gene', '31118', (53, 55))	('cancer', 'Disease', (206, 212))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('Val16', 'Gene', (162, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('variant', 'Var', (168, 175))	('breast cancer', 'Disease', (56, 69))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', (63, 69))	('or', 'Gene', '31118', (31, 33))
118199	33953831	When analyzed in combination with Nrf2, GPX1, and both rs1695 and rs1138272 GSTP1 SNPs, significant risk was also noted.	('rs1695', 'Mutation', 'rs1695', (55, 61))	('GSTP1', 'Gene', '2950', (76, 81))	('Nrf2', 'Gene', '4780', (34, 38))	('Nrf2', 'Gene', (34, 38))	('GPX1', 'Gene', (40, 44))	('GSTP1', 'Gene', (76, 81))	('GPX1', 'Gene', '2876', (40, 44))	('rs1138272', 'Mutation', 'rs1138272', (66, 75))	('rs1695', 'Var', (55, 61))	('rs1138272', 'Var', (66, 75))
118201	33953831	It is suggested that the Val16 variant of SOD2 comprises parts of beta-sheet structure and therefore is inefficiently transported into the mitochondrial cytosol which diminishes its function and further leads to inadequate superoxide anion neutralization.	('Val16', 'Chemical', '-', (25, 30))	('SOD2', 'Gene', (42, 46))	('leads to', 'Reg', (203, 211))	('Val16', 'Var', (25, 30))	('or', 'Gene', '31118', (124, 126))	('or', 'Gene', '31118', (97, 99))	('cytosol', 'cellular_component', 'GO:0005829', ('153', '160'))	('function', 'MPA', (182, 190))	('superoxide anion neutralization', 'MPA', (223, 254))	('beta-sheet structure', 'MPA', (66, 86))	('inadequate', 'NegReg', (212, 222))	('SOD2', 'molecular_function', 'GO:0004784', ('42', '46'))	('superoxide anion', 'Chemical', 'MESH:D013481', (223, 239))	('SOD2', 'Gene', '6648', (42, 46))	('diminishes', 'NegReg', (167, 177))
118206	33953831	Many authors advocate SNP rs1050450 in the GPX1 gene to contribute to susceptibility to various cancers.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('SNP rs1050450', 'Var', (22, 35))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('or', 'Gene', '31118', (9, 11))	('rs1050450', 'Mutation', 'rs1050450', (26, 35))	('susceptibility', 'Reg', (70, 84))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('GPX1', 'Gene', '2876', (43, 47))	('GPX1', 'Gene', (43, 47))	('cancers', 'Disease', (96, 103))
118207	33953831	Namely, meta-analysis investigating the effect of this polymorphism revealed that variant genotypes (Pro/Leu and Leu/Leu) were associated with increased risk for lung cancer, bladder cancer, prostate cancer, head and neck cancer, and brain cancer.	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('Leu', 'Chemical', 'MESH:D007930', (117, 120))	('head and neck cancer', 'Disease', 'MESH:D006258', (208, 228))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('bladder cancer', 'Disease', 'MESH:D001749', (175, 189))	('brain cancer', 'Phenotype', 'HP:0030692', (234, 246))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('bladder cancer', 'Disease', (175, 189))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('or', 'Gene', '31118', (159, 161))	('Leu/Leu', 'Var', (113, 120))	('associated', 'Reg', (127, 137))	('Pro', 'Chemical', 'MESH:D011392', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('bladder cancer', 'Phenotype', 'HP:0009725', (175, 189))	('brain cancer', 'Disease', 'MESH:D001932', (234, 246))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('neck', 'cellular_component', 'GO:0044326', ('217', '221'))	('Leu', 'Chemical', 'MESH:D007930', (105, 108))	('prostate cancer', 'Disease', 'MESH:D011471', (191, 206))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('Leu', 'Chemical', 'MESH:D007930', (113, 116))	('prostate cancer', 'Phenotype', 'HP:0012125', (191, 206))	('prostate cancer', 'Disease', (191, 206))	('lung cancer', 'Disease', (162, 173))	('head and neck cancer', 'Phenotype', 'HP:0012288', (208, 228))	('brain cancer', 'Disease', (234, 246))	('or', 'Gene', '31118', (60, 62))	('Pro/Leu', 'Var', (101, 108))
118209	33953831	Our results did not reveal increased risk for carriers of Pro/Leu and Leu/Leu; on the contrary, risk was reduced among these subjects.	('Leu', 'Chemical', 'MESH:D007930', (70, 73))	('or', 'Gene', '31118', (43, 45))	('Pro/Leu', 'Var', (58, 65))	('Pro', 'Chemical', 'MESH:D011392', (58, 61))	('Leu', 'Chemical', 'MESH:D007930', (74, 77))	('Leu/Leu', 'Var', (70, 77))	('Leu', 'Chemical', 'MESH:D007930', (62, 65))
118210	33953831	Follow-up analysis revealed that these variant allele carriers had shorter cumulative survival, but this was not statistically significant.	('cumulative survival', 'CPA', (75, 94))	('or', 'Gene', '31118', (69, 71))	('variant', 'Var', (39, 46))
118212	33953831	Considering the fact that the variant GPX1 exhibits lower enzyme activity, the explanation of such phenomenon in ccRCC is challenging.	('GPX1', 'Gene', '2876', (38, 42))	('enzyme activity', 'molecular_function', 'GO:0003824', ('58', '73'))	('GPX1', 'Gene', (38, 42))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (113, 118))	('RCC', 'Disease', (115, 118))	('lower', 'NegReg', (52, 57))	('variant', 'Var', (30, 37))	('enzyme activity', 'MPA', (58, 73))
118214	33953831	Further studies are needed to elucidate the mechanisms by which alteration in H2O2 reduction is associated with better survival and lower susceptibility to clear cell renal cell carcinoma.	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (156, 187))	('alteration', 'Var', (64, 74))	('H2O2', 'Gene', (78, 82))	('clear cell renal cell carcinoma', 'Disease', (156, 187))	('H2O2', 'Chemical', 'MESH:D006861', (78, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (167, 187))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (156, 187))	('reduction', 'NegReg', (83, 92))	('better', 'PosReg', (112, 118))
118221	33953831	Namely, increased ccRCC susceptibility was observed among carriers of individual variant genotypes of both SOD2 rs4880 and GSTP1 rs1695 polymorphisms, as well as in combination with Nrf2 rs6721961 genetic polymorphism.	('or', 'Gene', '31118', (210, 212))	('or', 'Gene', '31118', (141, 143))	('SOD2', 'Gene', '6648', (107, 111))	('Nrf2', 'Gene', '4780', (182, 186))	('SOD2', 'Gene', (107, 111))	('rs1695', 'Var', (129, 135))	('GSTP1', 'Gene', (123, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (18, 23))	('rs4880', 'Var', (112, 118))	('increased', 'PosReg', (8, 17))	('Nrf2', 'Gene', (182, 186))	('rs6721961', 'Mutation', 'rs6721961', (187, 196))	('GSTP1', 'Gene', '2950', (123, 128))	('rs1695', 'Mutation', 'rs1695', (129, 135))	('rs4880', 'Mutation', 'rs4880', (112, 118))	('SOD2', 'molecular_function', 'GO:0004784', ('107', '111'))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('RCC', 'Disease', (20, 23))
118222	33953831	Furthermore, GSTP1ABCD haplotype analysis revealed significant risk of ccRCC development in carriers of the GSTP1C haplotype consisting of variant forms of both GSTP1 polymorphisms comprising this haplotype.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('GSTP1', 'Gene', (161, 166))	('RCC', 'Disease', (73, 76))	('GSTP1', 'Gene', '2950', (108, 113))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('variant', 'Var', (139, 146))	('GSTP1', 'Gene', (13, 18))	('or', 'Gene', '31118', (8, 10))	('or', 'Gene', '31118', (148, 150))	('risk', 'Reg', (63, 67))	('GSTP1', 'Gene', '2950', (161, 166))	('GSTP1', 'Gene', (108, 113))	('GSTP1', 'Gene', '2950', (13, 18))	('or', 'Gene', '31118', (172, 174))
118223	33953831	Our study also provides evidence in favor of hypothesis that certain GST variant genotypes represent not only significant genetic risk factors for ccRCC development but also a significant prognostic factor.	('RCC', 'Disease', (149, 152))	('GST', 'Gene', (69, 72))	('or', 'Gene', '31118', (139, 141))	('or', 'Gene', '31118', (39, 41))	('GST', 'Gene', '373156', (69, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (147, 152))	('or', 'Gene', '31118', (144, 146))	('or', 'Gene', '31118', (203, 205))	('variant', 'Var', (73, 80))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
118224	33953831	In this line, GSTP1 variant forms seem to affect the overall survival in patients with ccRCC and the proposed molecular mechanism underlying the role of GSTP1 forms in RCC progression might be the presence of GSTP1 : JNK1/2 protein : protein interactions.	('protein ', 'Protein', (224, 232))	('JNK', 'molecular_function', 'GO:0004705', ('217', '220'))	('GSTP1', 'Gene', '2950', (209, 214))	('protein', 'cellular_component', 'GO:0003675', ('234', '241'))	('GSTP1', 'Gene', (209, 214))	('GSTP1', 'Gene', '2950', (153, 158))	('or', 'Gene', '31118', (160, 162))	('RCC', 'Disease', (89, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('GSTP1', 'Gene', (153, 158))	('RCC', 'Disease', (168, 171))	('affect', 'Reg', (42, 48))	('JNK1/2', 'Gene', '5599;5601', (217, 223))	('protein', 'cellular_component', 'GO:0003675', ('224', '231'))	('or', 'Gene', '31118', (29, 31))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('GSTP1', 'Gene', '2950', (14, 19))	('patients', 'Species', '9606', (73, 81))	('JNK1/2', 'Gene', (217, 223))	('GSTP1', 'Gene', (14, 19))	('interactions', 'Interaction', (242, 254))	('variant', 'Var', (20, 27))
118237	33643028	These ultrastructural studies indicate that at the autophagosome initiation stage, inhibition of mTOR induced the formation of ATG1/Unc-51-like kinases (ULK) complex (ULK1/2, ATG13, FIP200, and ATG101).	('autophagosome', 'cellular_component', 'GO:0005776', ('51', '64'))	('ATG101', 'Gene', (194, 200))	('ATG1', 'Gene', (127, 131))	('ATG1', 'Gene', (175, 179))	('ATG13', 'Gene', (175, 180))	('inhibition', 'Var', (83, 93))	('FIP200', 'Gene', '9821', (182, 188))	('ATG101', 'Gene', '60673', (194, 200))	('ULK) complex', 'cellular_component', 'GO:1990316', ('153', '165'))	('mTOR', 'Gene', (97, 101))	('ATG1', 'Gene', '8408', (194, 198))	('mTOR', 'Gene', '2475', (97, 101))	('ULK1/2', 'Gene', (167, 173))	('ATG1', 'Gene', '8408', (127, 131))	('ATG1', 'Gene', '8408', (175, 179))	('formation', 'biological_process', 'GO:0009058', ('114', '123'))	('ATG13', 'Gene', '9776', (175, 180))	('ULK1/2', 'Gene', '8408;9706', (167, 173))	('ATG1', 'Gene', (194, 198))	('FIP200', 'Gene', (182, 188))
118239	33643028	The production of PI3P recruits certain effectors, including proteins like double FYVE-containing protein 1 (DFCP1), and WD-repeat protein interacting with phosphoinositides (WIPIs) to form omegasomes (nucleation sites).	('double FYVE-containing protein 1', 'Gene', (75, 107))	('DFCP1', 'Gene', (109, 114))	('phosphoinositides', 'Chemical', 'MESH:D010716', (156, 173))	('PI3P', 'Var', (18, 22))	('interacting', 'Interaction', (139, 150))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('DFCP1', 'Gene', '53349', (109, 114))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('WIPIs', 'Chemical', '-', (175, 180))	('double FYVE-containing protein 1', 'Gene', '53349', (75, 107))	('PI3P', 'Chemical', 'MESH:C055525', (18, 22))
118257	33643028	found that most ccRCCs harbor allelic loss and/or mutation of ATG7.	('RCC', 'Disease', (18, 21))	('ATG7', 'Gene', (62, 66))	('RCC', 'Phenotype', 'HP:0005584', (18, 21))	('mutation', 'Var', (50, 58))	('ATG7', 'Gene', '10533', (62, 66))	('RCC', 'Disease', 'MESH:C538614', (18, 21))
118263	33643028	Research has shown that genetic dysregulation of autophagy is a key characteristic of different subtypes of RCC (X. D.).	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('autophagy', 'biological_process', 'GO:0016236', ('49', '58'))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('genetic dysregulation', 'Var', (24, 45))	('autophagy', 'biological_process', 'GO:0006914', ('49', '58'))	('autophagy', 'CPA', (49, 58))
118265	33643028	It is well known that loss of VHL leads to induction of the hypoxia inducible factor (HIF), which in turn promotes tumor growth.	('hypoxia', 'Disease', (60, 67))	('hypoxia', 'Disease', 'MESH:D000860', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('promotes', 'PosReg', (106, 114))	('VHL', 'Gene', (30, 33))	('tumor', 'Disease', (115, 120))	('VHL', 'Gene', '7428', (30, 33))	('induction', 'Reg', (43, 52))	('loss', 'Var', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
118267	33643028	They found that inhibition of autophagy by knockdown of ATG5 resulted in the massive death of VHL(-) cells as compared to VHL(+) cells, indicating that VHL(-) cells could be more dependent on autophagy and therefore more sensitive to inhibition.	('VHL', 'Gene', (152, 155))	('VHL', 'Gene', '7428', (94, 97))	('autophagy', 'biological_process', 'GO:0006914', ('192', '201'))	('ATG5', 'Gene', '9474', (56, 60))	('VHL', 'Gene', '7428', (152, 155))	('inhibition', 'NegReg', (16, 26))	('death', 'Disease', 'MESH:D003643', (85, 90))	('death', 'Disease', (85, 90))	('knockdown', 'Var', (43, 52))	('autophagy', 'biological_process', 'GO:0016236', ('30', '39'))	('ATG5', 'Gene', (56, 60))	('VHL', 'Gene', (122, 125))	('autophagy', 'biological_process', 'GO:0006914', ('30', '39'))	('VHL', 'Gene', '7428', (122, 125))	('autophagy', 'biological_process', 'GO:0016236', ('192', '201'))	('VHL', 'Gene', (94, 97))	('autophagy', 'CPA', (30, 39))
118269	33643028	Recently, it was reported that VHL mutation in RCC cells induced autophagy by up-regulating the inositol 1,4,5- trisphosphate receptor, type 1 (ITPR1).	('VHL', 'Gene', '7428', (31, 34))	('autophagy', 'CPA', (65, 74))	('autophagy', 'biological_process', 'GO:0016236', ('65', '74'))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('up-regulating', 'PosReg', (78, 91))	('ITPR1', 'Gene', (144, 149))	('autophagy', 'biological_process', 'GO:0006914', ('65', '74'))	('induced', 'Reg', (57, 64))	('ITPR1', 'Gene', '3708', (144, 149))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('inositol 1,4,5- trisphosphate receptor, type 1', 'Gene', '3708', (96, 142))	('mutation', 'Var', (35, 43))	('RCC', 'Disease', (47, 50))	('VHL', 'Gene', (31, 34))
118281	33643028	After the treatment of chloroquine (CQ) and MG132, the binding of p53 with TGase 2 and p62 was potentiated.	('MG132', 'Var', (44, 49))	('chloroquine', 'Chemical', 'MESH:D002738', (23, 34))	('p53', 'Gene', '7157', (66, 69))	('potentiated', 'PosReg', (95, 106))	('TGase 2', 'Gene', '7052', (75, 82))	('p62', 'Gene', '8878', (87, 90))	('binding', 'Interaction', (55, 62))	('p62', 'Gene', (87, 90))	('CQ', 'Chemical', 'MESH:D002738', (36, 38))	('binding', 'molecular_function', 'GO:0005488', ('55', '62'))	('TGase 2', 'Gene', (75, 82))	('MG132', 'Chemical', 'MESH:C072553', (44, 49))	('p53', 'Gene', (66, 69))
118285	33643028	The silencing of a lncRNA, known as the HOXA transcript at the distal tip (HOTTIP), can induce autophagy by increasing a multitude of autophagy-related genes including Beclin1, LC3B, and LAMP2 through the PI3K/Akt/Atg13 signaling pathway.	('LAMP2', 'Gene', '3920', (187, 192))	('Atg13', 'Gene', '9776', (214, 219))	('autophagy', 'CPA', (95, 104))	('induce', 'PosReg', (88, 94))	('HOXA', 'Gene', (40, 44))	('signaling pathway', 'biological_process', 'GO:0007165', ('220', '237'))	('Beclin1', 'Gene', (168, 175))	('autophagy', 'biological_process', 'GO:0016236', ('134', '143'))	('increasing', 'PosReg', (108, 118))	('LC3B', 'Gene', (177, 181))	('silencing', 'Var', (4, 13))	('Akt', 'Gene', (210, 213))	('LAMP2', 'Gene', (187, 192))	('LC3B', 'Gene', '81631', (177, 181))	('Atg13', 'Gene', (214, 219))	('Akt', 'Gene', '207', (210, 213))	('autophagy', 'biological_process', 'GO:0016236', ('95', '104'))	('autophagy', 'biological_process', 'GO:0006914', ('134', '143'))	('HOTTIP', 'Gene', (75, 81))	('lncRNA', 'Protein', (19, 25))	('autophagy-related genes', 'Gene', (134, 157))	('HOXA', 'Gene', '3197', (40, 44))	('HOTTIP', 'Gene', '100316868', (75, 81))	('Beclin1', 'Gene', '8678', (168, 175))	('PI3K', 'molecular_function', 'GO:0016303', ('205', '209'))	('autophagy', 'biological_process', 'GO:0006914', ('95', '104'))
118289	33643028	found that NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, induced cell apoptosis and autophagy in RCC (H.).	('NVP', 'Chemical', 'MESH:D019829', (11, 14))	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('autophagy', 'biological_process', 'GO:0016236', ('84', '93'))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('BEZ235', 'Chemical', 'MESH:C531198', (15, 21))	('autophagy', 'biological_process', 'GO:0006914', ('84', '93'))	('apoptosis', 'biological_process', 'GO:0097194', ('70', '79'))	('apoptosis', 'biological_process', 'GO:0006915', ('70', '79'))	('autophagy', 'CPA', (84, 93))	('mTOR', 'Gene', '2475', (41, 45))	('PI3K', 'molecular_function', 'GO:0016303', ('36', '40'))	('cell apoptosis', 'CPA', (65, 79))	('mTOR', 'Gene', (41, 45))	('induced', 'PosReg', (57, 64))	('NVP-BEZ235', 'Var', (11, 21))
118294	33643028	During metabolic stress, high AMP/ATP ratio adenosine activates monophosphate-activated protein kinase (AMPK).	('AMPK', 'molecular_function', 'GO:0047322', ('104', '108'))	('monophosphate-activated', 'MPA', (64, 87))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('activates', 'PosReg', (54, 63))	('ATP', 'Chemical', 'MESH:D000255', (34, 37))	('AMPK', 'Gene', '5563', (104, 108))	('AMP', 'Chemical', 'MESH:D000249', (30, 33))	('high', 'Var', (25, 29))	('AMPK', 'molecular_function', 'GO:0004691', ('104', '108'))	('AMPK', 'molecular_function', 'GO:0050405', ('104', '108'))	('AMPK', 'Gene', (104, 108))	('adenosine', 'Chemical', 'MESH:D000241', (44, 53))	('AMP', 'Chemical', 'MESH:D000249', (104, 107))
118296	33643028	In addition, the AMPK pathway modulates autophagy via an alternative mechanism, in which AMPK stimulates ULK1 and facilitates autophagy due to the phosphorylation of Ser317 and Ser777.	('Ser', 'cellular_component', 'GO:0005790', ('177', '180'))	('autophagy', 'CPA', (40, 49))	('Ser317', 'Chemical', '-', (166, 172))	('autophagy', 'biological_process', 'GO:0016236', ('40', '49'))	('autophagy', 'biological_process', 'GO:0006914', ('126', '135'))	('autophagy', 'CPA', (126, 135))	('Ser317', 'Var', (166, 172))	('AMPK', 'molecular_function', 'GO:0050405', ('17', '21'))	('AMPK', 'Gene', '5563', (89, 93))	('phosphorylation', 'CPA', (147, 162))	('facilitates', 'PosReg', (114, 125))	('AMPK', 'Gene', (17, 21))	('ULK1', 'Gene', '8408', (105, 109))	('AMPK', 'molecular_function', 'GO:0050405', ('89', '93'))	('autophagy', 'biological_process', 'GO:0006914', ('40', '49'))	('Ser777', 'Var', (177, 183))	('modulates', 'Reg', (30, 39))	('Ser777', 'Chemical', '-', (177, 183))	('AMPK', 'molecular_function', 'GO:0004691', ('17', '21'))	('ULK1', 'Gene', (105, 109))	('AMPK', 'molecular_function', 'GO:0004691', ('89', '93'))	('AMPK', 'Gene', (89, 93))	('Ser', 'cellular_component', 'GO:0005790', ('166', '169'))	('stimulates', 'PosReg', (94, 104))	('AMPK', 'molecular_function', 'GO:0047322', ('17', '21'))	('autophagy', 'biological_process', 'GO:0016236', ('126', '135'))	('phosphorylation', 'biological_process', 'GO:0016310', ('147', '162'))	('AMPK', 'molecular_function', 'GO:0047322', ('89', '93'))	('AMPK', 'Gene', '5563', (17, 21))
118304	33643028	Reduced and aberrant expression of autophagy genes and proteins may affect various aspects of RCC pathology.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (94, 97))	('proteins', 'Protein', (55, 63))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('autophagy', 'biological_process', 'GO:0016236', ('35', '44'))	('autophagy genes', 'Gene', (35, 50))	('affect', 'Reg', (68, 74))	('autophagy', 'biological_process', 'GO:0006914', ('35', '44'))	('aberrant expression', 'Var', (12, 31))
118322	33643028	Mutations and/or inactivation of the VHL tumor suppressor gene exist in most RCC and are relevant to poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('inactivation', 'Var', (17, 29))	('VHL tumor', 'Disease', (37, 46))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('VHL tumor', 'Disease', 'MESH:D006623', (37, 46))	('Mutations', 'Var', (0, 9))	('tumor suppressor', 'biological_process', 'GO:0051726', ('41', '57'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('41', '57'))
118326	33643028	They found that STF-62247 induced autophagy in a HIF-independent manner.	('autophagy', 'CPA', (34, 43))	('autophagy', 'biological_process', 'GO:0016236', ('34', '43'))	('STF-62247', 'Var', (16, 25))	('autophagy', 'biological_process', 'GO:0006914', ('34', '43'))	('STF-62247', 'Chemical', 'MESH:C530878', (16, 25))
118328	33643028	In addition, STF-62247 increased the radiosensitivity of VHL-deficient RCC cells and 786-O cells by inducing autophagy.	('VHL-deficient RCC', 'Disease', 'MESH:C538614', (57, 74))	('autophagy', 'biological_process', 'GO:0016236', ('109', '118'))	('VHL-deficient RCC', 'Disease', (57, 74))	('autophagy', 'biological_process', 'GO:0006914', ('109', '118'))	('STF-62247', 'Chemical', 'MESH:C530878', (13, 22))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('STF-62247', 'Var', (13, 22))	('increased', 'PosReg', (23, 32))	('radiosensitivity', 'CPA', (37, 53))	('autophagy', 'CPA', (109, 118))	('inducing', 'PosReg', (100, 108))
118338	33643028	It has been found that autophagy induced by heteronemin partially antagonized cytotoxicity and apoptotic signaling in human renal carcinoma A498 cells.	('antagonized', 'NegReg', (66, 77))	('renal carcinoma', 'Phenotype', 'HP:0005584', (124, 139))	('apoptotic signaling', 'CPA', (95, 114))	('cytotoxicity', 'Disease', (78, 90))	('A498', 'CellLine', 'CVCL:1056', (140, 144))	('heteronemin', 'Var', (44, 55))	('heteronemin', 'Chemical', 'MESH:C493748', (44, 55))	('autophagy', 'biological_process', 'GO:0016236', ('23', '32'))	('renal carcinoma', 'Disease', 'MESH:C538614', (124, 139))	('cytotoxicity', 'Disease', 'MESH:D064420', (78, 90))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('autophagy', 'CPA', (23, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('human', 'Species', '9606', (118, 123))	('renal carcinoma', 'Disease', (124, 139))	('autophagy', 'biological_process', 'GO:0006914', ('23', '32'))
118357	31236852	Checkpoint inhibitor therapy, i.e., anti-CTLA-4 and anti-PD-1, has been approved to be an effective therapeutic approach in a variety of cancers (Mariathasan et al.,).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('anti-PD-1', 'Var', (52, 61))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('anti-CTLA-4', 'Var', (36, 47))
118377	31236852	To investigate whether ccRCC tumor cells express VISTA, sequential tumor sections were stained by anti-pan-cytokeratin and anti-VISTA, respectively.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('anti-VISTA', 'Var', (123, 133))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', (67, 72))	('RCC', 'Disease', 'MESH:D002292', (25, 28))	('RCC', 'Disease', (25, 28))
118405	31236852	To assess the function of VISTA, Balb/c mice were subcutaneously inoculated with RENCA cells and treated therapeutically with control Ig, anti-VISTA, anti-PD-1, or anti-VISTA plus anti-PD-1 antibodies on day 7, 10, 13, 16, and 19 via intraperitoneal injection.	('mice', 'Species', '10090', (40, 44))	('anti-VISTA', 'Var', (138, 148))	('anti-PD-1', 'Var', (150, 159))
118416	31236852	Notably, VISTA expression strongly correlated with poor CD8+ T cell responses and blockade of VISTA signaling significantly reduced the growth of murine RENCA RCC model.	('RCC', 'Disease', 'MESH:D002292', (159, 162))	('murine', 'Species', '10090', (146, 152))	('reduced', 'NegReg', (124, 131))	('blockade', 'Var', (82, 90))	('VISTA', 'Gene', (94, 99))	('CD8', 'Gene', (56, 59))	('VISTA', 'Gene', (9, 14))	('CD8', 'Gene', '925', (56, 59))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))
118418	32567127	Pivotal biomarker expression and drug screening in advanced ccRCC Dear Editor, Our previous results demonstrated that reducing lipid accumulation, called "Tumor Slimming," can inhibit the growth and metastasis of tumor cells, 1 ,  2  whereas we have hardly found drugs to directly affect the slimming of renal cancer cells.	('tumor', 'Disease', (213, 218))	('lipid accumulation', 'MPA', (127, 145))	('renal cancer', 'Disease', 'MESH:D007680', (304, 316))	('renal cancer', 'Phenotype', 'HP:0009726', (304, 316))	('lipid', 'Chemical', 'MESH:D008055', (127, 132))	('Tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('reducing', 'Var', (118, 126))	('renal cancer', 'Disease', (304, 316))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('inhibit', 'NegReg', (176, 183))
118434	32567127	Nystatin, W-13, and arachidonyltrifluoromethane had the highest negative enrichment scores (-0.935, -0.859, and -0.85, respectively) (Figure 2B).	('arachidonyltrifluoromethane', 'Var', (20, 47))	('Nystatin', 'Chemical', 'MESH:D009761', (0, 8))	('arachidonyltrifluoromethane', 'Chemical', 'MESH:C081565', (20, 47))	('negative', 'NegReg', (64, 72))	('W-13', 'Chemical', 'MESH:C033772', (10, 14))
118447	29861861	Moreover, our analysis uncovers novel functionally relevant and actionable targets, among which we have experimentally validated abnormal splicing of spleen tyrosine kinase as a key factor for cell proliferation in renal cancer.	('splicing', 'biological_process', 'GO:0045292', ('138', '146'))	('renal cancer', 'Disease', 'MESH:D007680', (215, 227))	('abnormal splicing', 'Var', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cell proliferation', 'biological_process', 'GO:0008283', ('193', '211'))	('renal cancer', 'Disease', (215, 227))	('renal cancer', 'Phenotype', 'HP:0009726', (215, 227))
118451	29861861	This has enabled us to identify driver abnormalities of several cancers, in particular those with a less heterogeneous molecular landscape.	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('abnormalities', 'Var', (39, 52))	('cancers', 'Disease', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
118455	29861861	For example, HotNet finds concentrated subnetworks of recurrent mutations by calculating an influence measure between all pairs of mutated genes, and has been successful in exploring defective interaction modules in several cancer types.	('influence measure', 'MPA', (92, 109))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('mutations', 'Var', (64, 73))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Disease', (224, 230))
118460	29861861	We use several lines of evidence to show that these aberration hubs represent important cancer-related factors.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('aberration', 'Var', (52, 62))	('hub', 'Gene', '1993', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('hub', 'Gene', (63, 66))
118482	29861861	We observed that only one of these 74 molecules (CDKN1B) is significantly mutated in breast cancers, and that 50 of them are not differentially expressed at mRNA level in tumors (all together or at subtype-level) when compared to non-tumor control samples (Supplementary Table 9).	('breast cancers', 'Disease', 'MESH:D001943', (85, 99))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('breast cancers', 'Disease', (85, 99))	('non-tumor', 'Disease', 'MESH:D009369', (230, 239))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('CDKN1B', 'Gene', (49, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('mutated', 'Var', (74, 81))	('non-tumor', 'Disease', (230, 239))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('breast cancers', 'Phenotype', 'HP:0003002', (85, 99))	('tumors', 'Disease', (171, 177))	('CDKN1B', 'Gene', '1027', (49, 55))
118494	29861861	We applied the same analysis to ccRCC using information about somatic non-silent mutations and abnormal gene expression patterns that have been recently identified through the CAGEKID program (Supplementary Tables 7-8; see Methods for details).	('ccRCC', 'Phenotype', 'HP:0006770', (32, 37))	('gene expression', 'biological_process', 'GO:0010467', ('104', '119'))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('non-silent mutations', 'Var', (70, 90))	('RCC', 'Disease', (34, 37))
118495	29861861	AbHAC analysis of these datasets identified 47 aberration hubs in renal tumors (FDR < 0.05; Supplementary Table 12).	('AbHAC', 'Chemical', '-', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('aberration', 'Var', (47, 57))	('hub', 'Gene', '1993', (58, 61))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('renal tumors', 'Phenotype', 'HP:0009726', (66, 78))	('hub', 'Gene', (58, 61))	('renal tumors', 'Disease', 'MESH:D007674', (66, 78))	('renal tumors', 'Disease', (66, 78))
118504	29861861	This was due to an aberrant splicing pattern introducing a new exon to SYK transcripts resulting in a longer isoform of the protein in tumor samples (SYK-L with 635 amino acids coded by transcripts ENST00000375754 and ENST00000375746) compared to a shorter isoform (SYK-S with 612 amino acids coded by transcripts ENST00000375751 and ENST00000375747) (Figure 3c and Supplementary Figure 4).	('ENST00000375746', 'Var', (218, 233))	('SYK', 'Gene', '6850', (71, 74))	('ENST00000375754', 'Var', (198, 213))	('SYK', 'Gene', (266, 269))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('SYK', 'Gene', (150, 153))	('longer', 'PosReg', (102, 108))	('splicing', 'biological_process', 'GO:0045292', ('28', '36'))	('SYK', 'Gene', '6850', (266, 269))	('SYK', 'Gene', '6850', (150, 153))	('tumor', 'Disease', (135, 140))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('isoform of the', 'MPA', (109, 123))	('ENST00000375747', 'Var', (334, 349))	('SYK', 'Gene', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
118508	29861861	Interestingly, a similar pattern has recently been reported in ovarian cancer, where abnormal splicing of SYK supports cancer cell proliferation and survival.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('SYK', 'Gene', (106, 109))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('cancer', 'Disease', (119, 125))	('cell proliferation', 'biological_process', 'GO:0008283', ('126', '144'))	('splicing', 'biological_process', 'GO:0045292', ('94', '102'))	('SYK', 'Gene', '6850', (106, 109))	('supports', 'PosReg', (110, 118))	('abnormal splicing', 'Var', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('ovarian cancer', 'Disease', 'MESH:D010051', (63, 77))	('survival', 'CPA', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('ovarian cancer', 'Disease', (63, 77))
118510	29861861	Silencing of the SYK long isoform by two independent specific siRNAs substantially reduced proliferation of renal cancer cells in 786-O and A498 cell lines as measured by colony-formation and viability assays (Figure 4a-4e).	('renal cancer', 'Disease', (108, 120))	('reduced', 'NegReg', (83, 90))	('A498', 'CellLine', 'CVCL:1056', (140, 144))	('renal cancer', 'Phenotype', 'HP:0009726', (108, 120))	('SYK', 'Gene', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('renal cancer', 'Disease', 'MESH:D007680', (108, 120))	('SYK', 'Gene', '6850', (17, 20))	('proliferation', 'CPA', (91, 104))	('formation', 'biological_process', 'GO:0009058', ('178', '187'))	('Silencing', 'Var', (0, 9))
118542	29861861	Although we had previously identified it as being affected by abnormal splicing patterns in ccRCC, it was not among the top-ranked genes.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Disease', (94, 97))	('abnormal splicing patterns', 'Var', (62, 88))	('splicing', 'biological_process', 'GO:0045292', ('71', '79'))	('affected', 'Reg', (50, 58))
118550	29861861	According to the close cross-talk between VEGF receptor and Src signaling, inhibition of aberrantly regulated proteins of the Src pathway may provide an additional route to control of tumor angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('Src', 'Gene', '6714', (60, 63))	('inhibition', 'Var', (75, 85))	('proteins', 'Protein', (110, 118))	('Src', 'Gene', (126, 129))	('Src', 'Gene', '6714', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('angiogenesis', 'biological_process', 'GO:0001525', ('190', '202'))	('signaling', 'biological_process', 'GO:0023052', ('64', '73'))	('VEGF', 'Gene', '7422', (42, 46))	('tumor', 'Disease', (184, 189))	('VEGF', 'Gene', (42, 46))	('Src', 'Gene', (60, 63))
118594	29371925	2DG affected lactate production, energy state and reduced pyridine nucleotide level in high-grade ccRCC cultures, but the energy state only in low-grade.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('energy state', 'MPA', (33, 45))	('affected', 'Reg', (4, 12))	('pyridine nucleotide level', 'MPA', (58, 83))	('2DG', 'Chemical', 'MESH:D003847', (0, 3))	('lactate', 'Chemical', 'MESH:D019344', (13, 20))	('reduced', 'NegReg', (50, 57))	('lactate production', 'MPA', (13, 31))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('2DG', 'Var', (0, 3))	('RCC', 'Disease', (100, 103))	('pyridine nucleotide', 'Chemical', '-', (58, 77))
118636	29371925	After 24 hours of treatment the residual glucose level in the medium of normal cortex and ccRCC cultures was significantly higher than in corresponding control medium (Figure 5A) proving that 5 mM 2DG efficiently inhibited the first step of glycolytic pathway.	('2DG', 'Chemical', 'MESH:D003847', (197, 200))	('higher', 'PosReg', (123, 129))	('glycolytic pathway', 'Pathway', (241, 259))	('inhibited', 'NegReg', (213, 222))	('RCC', 'Disease', (92, 95))	('5 mM 2DG', 'Var', (192, 200))	('glucose level', 'MPA', (41, 54))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('first step', 'Pathway', (227, 237))	('glucose', 'Chemical', 'MESH:D005947', (41, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))
118686	29371925	In addition, the metabolic characteristics of our high-grade ccRCC cells justify the described higher 18F-fluorodeoxyglucose uptake of high-grade ccRCC with respect to the low-grade tumors that likely relay on a prevalent oxidative mitochondrial metabolism as the normal cortex cells.	('RCC', 'Disease', (63, 66))	('18F-fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (102, 124))	('RCC', 'Disease', (148, 151))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('high-grade', 'Var', (135, 145))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('higher', 'PosReg', (95, 101))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('uptake', 'biological_process', 'GO:0098657', ('125', '131'))	('18F-fluorodeoxyglucose uptake', 'MPA', (102, 131))	('metabolism', 'biological_process', 'GO:0008152', ('246', '256'))	('uptake', 'biological_process', 'GO:0098739', ('125', '131'))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('metabolic', 'MPA', (17, 26))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
118702	29371925	Real-time PCR was performed with TaqMan Gene Expression Assay kits for PLIN2 transcript (Hs 00605340_m1) and for GAPDH (Hs99998805_m1 kit) according to manufacturer's instructions (Applied Biosystems, Foster City, CA).	('GAPDH', 'Gene', (113, 118))	('PLIN2', 'Gene', (71, 76))	('PLIN2', 'Gene', '123', (71, 76))	('GAPDH', 'Gene', '2597', (113, 118))	('Hs 00605340_m1', 'Var', (89, 103))	('Gene Expression', 'biological_process', 'GO:0010467', ('40', '55'))
118797	27899233	Three of these seven patients (P28, P44, P101) had multiple metastatic tumors resected at the same time with discrepant subtypes (Fig.	('P101', 'Gene', (41, 45))	('P44', 'Gene', (36, 39))	('P28', 'Var', (31, 34))	('P101', 'Gene', '23533', (41, 45))	('P44', 'Gene', '10561', (36, 39))	('P28', 'cellular_component', 'GO:0070744', ('31', '34'))	('patients', 'Species', '9606', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
118904	29180877	Methylation of CpG at the promoter region of tumor-suppressor gene results in stable gene silencing through direct inhibition of transcription factor binding or by recruitment of methyl-binding domain proteins, which can cause gene product expression to decline or be absent.	('transcription factor binding', 'molecular_function', 'GO:0008134', ('129', '157'))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('decline', 'NegReg', (254, 261))	('gene silencing', 'biological_process', 'GO:0016458', ('85', '99'))	('gene product expression', 'MPA', (227, 250))	('Methylation', 'Var', (0, 11))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('binding', 'molecular_function', 'GO:0005488', ('186', '193'))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('45', '61'))	('inhibition', 'NegReg', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('silencing', 'NegReg', (90, 99))	('transcription', 'Protein', (129, 142))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('45', '61'))	('gene', 'MPA', (85, 89))	('methyl-binding domain proteins', 'Protein', (179, 209))	('recruitment', 'PosReg', (164, 175))	('transcription', 'biological_process', 'GO:0006351', ('129', '142'))
118917	33718220	Downregulation of METTL7B Inhibits Proliferation of Human Clear Cell Renal Cancer Cells In Vivo and In Vitro Clear cell renal cell carcinoma (ccRCC) is the most aggressive urologic tumor, and its incidence and diagonosis have been continuously increasing.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('METTL7B', 'Gene', '196410', (18, 25))	('aggressive urologic tumor', 'Disease', 'MESH:D014571', (161, 186))	('Clear Cell Renal Cancer', 'Disease', 'MESH:C538614', (58, 81))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('METTL7B', 'Gene', (18, 25))	('Downregulation', 'Var', (0, 14))	('Inhibits', 'NegReg', (26, 34))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('Clear Cell Renal Cancer', 'Disease', (58, 81))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (109, 140))	('Clear cell renal cell carcinoma', 'Disease', (109, 140))	('Human', 'Species', '9606', (52, 57))	('Clear Cell Renal Cancer', 'Phenotype', 'HP:0006770', (58, 81))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (120, 140))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('tumor', 'Disease', (181, 186))	('Proliferation', 'CPA', (35, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('aggressive urologic tumor', 'Disease', (161, 186))	('Renal Cancer', 'Phenotype', 'HP:0009726', (69, 81))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (109, 140))	('tumor', 'Disease', 'MESH:D009369', (181, 186))
118920	33718220	In addition, METTL7B knockdown promoted cell cycle arrest at G0/G1phase and induced cellular apoptosis.	('arrest', 'Disease', 'MESH:D006323', (51, 57))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('arrest', 'Disease', (51, 57))	('G1phase', 'biological_process', 'GO:0051318', ('64', '71'))	('METTL7B', 'Gene', (13, 20))	('promoted', 'PosReg', (31, 39))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (40, 57))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('40', '57'))	('knockdown', 'Var', (21, 30))	('cellular apoptosis', 'CPA', (84, 102))	('induced', 'Reg', (76, 83))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))
118923	33718220	So the funtions of this protein family were predicted to methylate RNA (METTL3, METTL14, METTL1), DNA (METTL4), or protein (METTL10 and METTL11A).	('METTL1', 'Gene', '4234', (124, 130))	('DNA', 'MPA', (98, 101))	('METTL3', 'Gene', '56339', (72, 78))	('METTL1', 'Gene', (124, 130))	('METTL11A', 'Gene', (136, 144))	('METTL11A', 'Gene', '28989', (136, 144))	('RNA', 'cellular_component', 'GO:0005562', ('67', '70'))	('METTL1', 'Gene', '4234', (136, 142))	('METTL1', 'Gene', '4234', (89, 95))	('METTL4', 'Gene', (103, 109))	('METTL14', 'Gene', '57721', (80, 87))	('METTL10', 'Gene', '399818', (124, 131))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('METTL4', 'Gene', '64863', (103, 109))	('METTL1', 'Gene', '4234', (80, 86))	('METTL1', 'Gene', (136, 142))	('METTL1', 'Gene', (89, 95))	('methylate', 'Var', (57, 66))	('METTL10', 'Gene', (124, 131))	('METTL1', 'Gene', (80, 86))	('METTL14', 'Gene', (80, 87))	('METTL3', 'Gene', (72, 78))	('protein', 'Protein', (115, 122))	('DNA', 'cellular_component', 'GO:0005574', ('98', '101'))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))
118928	33718220	METTL7B also enhanced migration and invasion of thyroid carcinoma cells through promote TGF-beta1-induced epithelial-mesenchymal transition (EMT).	('invasion', 'CPA', (36, 44))	('enhanced', 'PosReg', (13, 21))	('METTL7B', 'Var', (0, 7))	('epithelial-mesenchymal transition', 'CPA', (106, 139))	('EMT', 'biological_process', 'GO:0001837', ('141', '144'))	('migration', 'CPA', (22, 31))	('TGF-beta1', 'Gene', '7040', (88, 97))	('TGF-beta1', 'Gene', (88, 97))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('106', '139'))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (48, 65))	('promote', 'PosReg', (80, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
118950	33718220	In addition, based on the AnnexinV-FITC/PI staining assay, the percentages of apoptotic cells in shMETTL7B cells were significantly higher than that in shNC cells ( Figure 3C ).	('higher', 'PosReg', (132, 138))	('AnnexinV-FITC', 'Chemical', '-', (26, 39))	('apoptotic cells', 'CPA', (78, 93))	('shMETTL7B', 'Var', (97, 106))
118951	33718220	The results showed that knocking down METTL7B significantly decreased the expression of CCND1 (Cyclin D1), but increased CDKN2D(cyclin dependent kinase inhibitor 2D) ( Figure 4 ).	('expression', 'MPA', (74, 84))	('knocking down', 'Var', (24, 37))	('decreased', 'NegReg', (60, 69))	('Cyclin', 'molecular_function', 'GO:0016538', ('95', '101'))	('increased', 'PosReg', (111, 120))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('145', '161'))	('CCND1', 'Gene', (88, 93))	('Cyclin D1', 'Gene', '595', (95, 104))	('Cyclin D1', 'Gene', (95, 104))	('cyclin dependent kinase inhibitor 2D', 'Gene', '1032', (128, 164))	('METTL7B', 'Gene', (38, 45))	('cyclin dependent kinase inhibitor 2D', 'Gene', (128, 164))	('cyclin dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('128', '161'))
118952	33718220	The results showed that knocking down METTL7B could significantly increase the expression of the epithelial markers E-cadherin, and inhibit the expression of mesenchymal markers N-cadherin, Vimentin, and Slug without affecting Snail and Twist expression in 796-P cells ( Figure 6 ).	('E-cadherin', 'Gene', (116, 126))	('E-cadherin', 'Gene', '999', (116, 126))	('Snail', 'Gene', (227, 232))	('mesenchymal', 'CPA', (158, 169))	('Vimentin', 'Gene', '7431', (190, 198))	('Vimentin', 'cellular_component', 'GO:0045099', ('190', '198'))	('knocking down', 'Var', (24, 37))	('expression', 'MPA', (79, 89))	('expression', 'MPA', (144, 154))	('Twist', 'Gene', '7291', (237, 242))	('Vimentin', 'Gene', (190, 198))	('Slug', 'Gene', (204, 208))	('inhibit', 'NegReg', (132, 139))	('cadherin', 'molecular_function', 'GO:0008014', ('180', '188'))	('Snail', 'Gene', '6615', (227, 232))	('Vimentin', 'cellular_component', 'GO:0045098', ('190', '198'))	('METTL7B', 'Gene', (38, 45))	('cadherin', 'molecular_function', 'GO:0008014', ('118', '126'))	('increase', 'PosReg', (66, 74))	('N-cadherin', 'Protein', (178, 188))	('Twist', 'Gene', (237, 242))	('Slug', 'Gene', '6591', (204, 208))
118960	33718220	Furthmore, high amounts of CDKN2D also can inhibit CDK4/6 activity and further arrest the cell cycle progression from G1 to S phase.	('arrest', 'NegReg', (79, 85))	('CDKN2D', 'Var', (27, 33))	('activity', 'MPA', (58, 66))	('CDK', 'molecular_function', 'GO:0004693', ('51', '54'))	('cell cycle progression', 'CPA', (90, 112))	('S phase', 'biological_process', 'GO:0051320', ('124', '131'))	('inhibit', 'NegReg', (43, 50))	('CDK4/6', 'Gene', '1019;1021', (51, 57))	('cell cycle', 'biological_process', 'GO:0007049', ('90', '100'))	('CDK4/6', 'Gene', (51, 57))
118962	33718220	In addition, the expression of Slug (transcription factors) was significantly repressed in METTL7B knockdown cells, whereas the expression of Twist1, Snail, Zeb1, or Zeb2 was not changed in this context.	('Zeb2', 'Gene', (166, 170))	('Zeb1', 'Gene', (157, 161))	('Zeb2', 'Gene', '9839', (166, 170))	('METTL7B', 'Gene', (91, 98))	('Zeb1', 'Gene', '6935', (157, 161))	('Twist1', 'Gene', (142, 148))	('expression', 'MPA', (17, 27))	('transcription', 'biological_process', 'GO:0006351', ('37', '50'))	('repressed', 'NegReg', (78, 87))	('knockdown', 'Var', (99, 108))	('Slug', 'Gene', (31, 35))	('Twist1', 'Gene', '7291', (142, 148))
119011	33692953	Ultimately, nine optimal prognostic HRLs were obtained and incorporated into the risk model: ITPR1-DT, AC008760.2, AC084876.1, AC002070.1, LINC02027, AC147651.1, FOXD2-AS1, LINC00944, and LINC01615 ( Figure 2C ).	('LINC01615', 'Gene', (188, 197))	('AC147651.1', 'Var', (150, 160))	('LINC01615', 'Gene', '101929484', (188, 197))	('ITPR1', 'Gene', (93, 98))	('AC002070.1', 'Var', (127, 137))	('LINC00944', 'Gene', '387895', (173, 182))	('FOXD2-AS1', 'Gene', (162, 171))	('FOXD2-AS1', 'Gene', '84793;2306;5729', (162, 171))	('ITPR1', 'Gene', '3708', (93, 98))	('LINC00944', 'Gene', (173, 182))	('LINC02027', 'Var', (139, 148))
119015	33692953	Moreover, as the risk score increased, the expressions of the protective lncRNAs (AC008760.2, LINC00944, LINC01615, ITPR1-DT, AC084876.1, and FOXD2-AS1) decreased, whereas those of the risk lncRNAs (AC147651.1, LINC02027, and AC002070.1) increased ( Figure 5E ) in the training dataset.	('expressions', 'MPA', (43, 54))	('LINC01615', 'Gene', (105, 114))	('LINC01615', 'Gene', '101929484', (105, 114))	('ITPR1', 'Gene', (116, 121))	('ITPR1', 'Gene', '3708', (116, 121))	('LINC00944', 'Gene', '387895', (94, 103))	('FOXD2-AS1', 'Gene', (142, 151))	('LINC00944', 'Gene', (94, 103))	('decreased', 'NegReg', (153, 162))	('FOXD2-AS1', 'Gene', '84793;2306;5729', (142, 151))	('AC084876.1', 'Var', (126, 136))
119047	33692953	Among all the HRLs, nine lncRNAs (i.e., ITPR1-DT, AC008760.2, AC084876.1, AC002070.1, LINC02027, AC147651.1, FOXD2-AS1, LINC00944, and LINC01615) were identified to be independently associated with prognosis and were thus used to develop the prognostic model.	('LINC00944', 'Gene', (120, 129))	('AC147651.1', 'Var', (97, 107))	('ITPR1', 'Gene', (40, 45))	('associated', 'Reg', (182, 192))	('FOXD2-AS1', 'Gene', (109, 118))	('FOXD2-AS1', 'Gene', '84793;2306;5729', (109, 118))	('ITPR1', 'Gene', '3708', (40, 45))	('AC002070.1', 'Var', (74, 84))	('prognosis', 'Disease', (198, 207))	('AC084876.1', 'Var', (62, 72))	('LINC01615', 'Gene', '101929484', (135, 144))	('AC008760.2', 'Var', (50, 60))	('LINC02027', 'Var', (86, 95))	('LINC01615', 'Gene', (135, 144))	('LINC00944', 'Gene', '387895', (120, 129))
119100	32195359	PBRM1 mutation and preliminary response to immune checkpoint blockade treatment in non-small cell lung cancer Polybromo-1 (PBRM1) gene is a promising biomarker for immunotherapy in clear cell renal cell carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (181, 212))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (83, 109))	('mutation', 'Var', (6, 14))	('Polybromo-1', 'Gene', (110, 121))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', (123, 128))	('PBRM1', 'Gene', '55193', (0, 5))	('PBRM1', 'Gene', '55193', (123, 128))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (83, 109))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (192, 212))	('Polybromo-1', 'Gene', '55193', (110, 121))	('non-small cell lung cancer', 'Disease', (83, 109))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (181, 212))	('clear cell renal cell carcinoma', 'Disease', (181, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (87, 109))
119101	32195359	But to our knowledge, the frequency and clinical relevance of PBRM1 mutation in lung cancer remain unknown.	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('mutation', 'Var', (68, 76))	('lung cancer', 'Disease', (80, 91))	('PBRM1', 'Gene', (62, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('PBRM1', 'Gene', '55193', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
119102	32195359	We conducted a retrospective study to evaluate the prevalence of PBRM1 mutation and its correlation with preliminary response to immunotherapy in non-small cell lung cancer (NSCLC).	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('mutation', 'Var', (71, 79))	('PBRM1', 'Gene', (65, 70))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (146, 172))	('PBRM1', 'Gene', '55193', (65, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('NSCLC', 'Phenotype', 'HP:0030358', (174, 179))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (150, 172))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (146, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('non-small cell lung cancer', 'Disease', (146, 172))	('NSCLC', 'Disease', (174, 179))
119103	32195359	Our results indicated that PBRM1 mutation was more likely to be a negative predictive biomarker for immunotherapy in NSCLC.	('NSCLC', 'Disease', (117, 122))	('mutation', 'Var', (33, 41))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('PBRM1', 'Gene', (27, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('PBRM1', 'Gene', '55193', (27, 32))
119109	32195359	Previous studies have found that PBRM1 mutation was a promising biomarker for immunotherapy in ccRCC.	('PBRM1', 'Gene', '55193', (33, 38))	('mutation', 'Var', (39, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('ccRCC', 'Disease', (95, 100))	('ccRCC', 'Disease', 'MESH:C538614', (95, 100))	('PBRM1', 'Gene', (33, 38))
119112	32195359	To our knowledge, the frequency and clinical relevance of PBRM1 mutation in lung cancer remain unknown.	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('mutation', 'Var', (64, 72))	('lung cancer', 'Disease', (76, 87))	('PBRM1', 'Gene', (58, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('PBRM1', 'Gene', '55193', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
119113	32195359	Therefore, we conducted a retrospective study to evaluate the prevalence of PBRM1 mutation and its correlation with preliminary response to ICB therapy in non-small cell lung cancer (NSCLC).	('NSCLC', 'Phenotype', 'HP:0030358', (183, 188))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (159, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('mutation', 'Var', (82, 90))	('NSCLC', 'Disease', (183, 188))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (155, 181))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (155, 181))	('ICB', 'Chemical', '-', (140, 143))	('PBRM1', 'Gene', (76, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('PBRM1', 'Gene', '55193', (76, 81))	('non-small cell lung cancer', 'Disease', (155, 181))
119115	32195359	1), PBRM1 mutation was identified in 84 NSCLC patients (3.04%, Supplementary Table 1).	('patients', 'Species', '9606', (46, 54))	('PBRM1', 'Gene', (4, 9))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('mutation', 'Var', (10, 18))	('PBRM1', 'Gene', '55193', (4, 9))	('NSCLC', 'Disease', (40, 45))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
119116	32195359	Fifty-one patients were found to have PBRM1 loss-of-function (LOF) mutation, accounting for 60.17% of the mutated patients (Supplementary Fig.	('mutation', 'Var', (67, 75))	('PBRM1', 'Gene', (38, 43))	('PBRM1', 'Gene', '55193', (38, 43))	('patients', 'Species', '9606', (10, 18))	('patients', 'Species', '9606', (114, 122))	('loss-of-function', 'NegReg', (44, 60))
119118	32195359	No significant difference in smoking status was observed between patients with PBRM1 mutation type (MT) and PBRM1 wild type (WT).	('PBRM1', 'Gene', '55193', (108, 113))	('mutation type', 'Var', (85, 98))	('PBRM1', 'Gene', (79, 84))	('PBRM1', 'Gene', '55193', (79, 84))	('patients', 'Species', '9606', (65, 73))	('PBRM1', 'Gene', (108, 113))
119119	32195359	A combined cohort of 441 ICB-treated patients (385 from Memorial Sloan Kettering Cancer Center (MSKCC), 56 from Dana Farber Cancer Institute (DFCI)) were further analyzed to access the association between PBRM1 mutation and response to ICB therapy.	('Cancer', 'Disease', 'MESH:D009369', (124, 130))	('PBRM1', 'Gene', (205, 210))	('Cancer', 'Disease', (81, 87))	('PBRM1', 'Gene', '55193', (205, 210))	('Cancer', 'Phenotype', 'HP:0002664', (81, 87))	('patients', 'Species', '9606', (37, 45))	('ICB', 'Chemical', '-', (236, 239))	('Cancer', 'Disease', 'MESH:D009369', (81, 87))	('Memorial Sloan Kettering Cancer', 'Disease', (56, 87))	('Memorial Sloan Kettering Cancer', 'Disease', 'MESH:D008569', (56, 87))	('ICB', 'Chemical', '-', (25, 28))	('Cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Cancer', 'Disease', (124, 130))	('mutation', 'Var', (211, 219))
119123	32195359	To further investigate the role of PBRM1 mutation, we performed the multivariate Cox regression analysis including covariates (mono vs. combo therapy, lines of treatment, smoking, sex, age) using a 211 patients' subgroup with available data.	('mutation', 'Var', (41, 49))	('patients', 'Species', '9606', (202, 210))	('PBRM1', 'Gene', '55193', (35, 40))	('PBRM1', 'Gene', (35, 40))
119124	32195359	We found that the PBRM1 mutation was still negatively associated with poor OS (hazard ratio 2.16, 95% confidence interval 1.03-4.51, P = 0.041) after adjusting these covariates.	('poor OS', 'Disease', (70, 77))	('OS', 'Chemical', '-', (75, 77))	('PBRM1', 'Gene', (18, 23))	('negatively', 'NegReg', (43, 53))	('mutation', 'Var', (24, 32))	('PBRM1', 'Gene', '55193', (18, 23))
119126	32195359	Among them, 15 patients were detected with PBRM1 mutation.	('patients', 'Species', '9606', (15, 23))	('PBRM1', 'Gene', (43, 48))	('PBRM1', 'Gene', '55193', (43, 48))	('detected', 'Reg', (29, 37))	('mutation', 'Var', (49, 57))
119128	32195359	In the cohort of non-ICB-treated patients (Nos = 454, PBRM1 MT = 15), there seems to be marginally significant difference in OS between the PBRM1 mutation subgroup and the PBRM1 WT subgroup, with the survival curves overlapped visually (P = 0.048; Fig.	('PBRM1', 'Gene', (54, 59))	('patients', 'Species', '9606', (33, 41))	('PBRM1', 'Gene', (140, 145))	('OS', 'Chemical', '-', (125, 127))	('PBRM1', 'Gene', '55193', (54, 59))	('PBRM1', 'Gene', '55193', (140, 145))	('PBRM1', 'Gene', (172, 177))	('difference', 'Reg', (111, 121))	('ICB', 'Chemical', '-', (21, 24))	('PBRM1', 'Gene', '55193', (172, 177))	('mutation', 'Var', (146, 154))
119132	32195359	In this retrospective study, we combined data from three institutions to investigate the clinical efficacy of ICB therapy in NSCLC patients with or without PBRM1 mutation.	('patients', 'Species', '9606', (131, 139))	('ICB', 'Chemical', '-', (110, 113))	('NSCLC', 'Disease', (125, 130))	('PBRM1', 'Gene', '55193', (156, 161))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('mutation', 'Var', (162, 170))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))	('PBRM1', 'Gene', (156, 161))
119134	32195359	The prevalence of PBRM1 mutation (NSCLC: 84/2767, 3.04%; ccRCC: 162/402, 40.30% in The Cancer Genome Atlas (TCGA)) and the proportion of truncating mutation (NSCLC: 51/84, 60.17%; ccRCC: 144/162, 93.51% in TCGA) were relatively low in NSCLC (Supplementary Fig.	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('ccRCC', 'Disease', (57, 62))	('PBRM1', 'Gene', (18, 23))	('truncating', 'MPA', (137, 147))	('NSCLC', 'Disease', 'MESH:D002289', (235, 240))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (87, 106))	('NSCLC', 'Disease', (158, 163))	('ccRCC', 'Disease', 'MESH:C538614', (180, 185))	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('NSCLC', 'Disease', (235, 240))	('NSCLC', 'Phenotype', 'HP:0030358', (158, 163))	('Cancer Genome Atlas', 'Disease', (87, 106))	('ccRCC', 'Disease', (180, 185))	('NSCLC', 'Phenotype', 'HP:0030358', (235, 240))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('mutation', 'Var', (24, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))	('NSCLC', 'Disease', (34, 39))	('ccRCC', 'Disease', 'MESH:C538614', (57, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (34, 39))	('PBRM1', 'Gene', '55193', (18, 23))
119138	32195359	Besides, PBRM1 mutation was not a remarkable prognostic factor in NSCLC patients according to our analysis in non-ICB-treated patients.	('mutation', 'Var', (15, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('ICB', 'Chemical', '-', (114, 117))	('NSCLC', 'Disease', (66, 71))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('patients', 'Species', '9606', (126, 134))	('PBRM1', 'Gene', (9, 14))	('PBRM1', 'Gene', '55193', (9, 14))	('patients', 'Species', '9606', (72, 80))
119140	32195359	To our knowledge, our study was the first study to estimate the role of PBRM1 mutation in both ICB and non-ICB-treated NSCLC cohorts.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('mutation', 'Var', (78, 86))	('ICB', 'Chemical', '-', (107, 110))	('ICB', 'Chemical', '-', (95, 98))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('PBRM1', 'Gene', (72, 77))	('PBRM1', 'Gene', '55193', (72, 77))	('ICB', 'Disease', (95, 98))	('NSCLC', 'Disease', (119, 124))
119144	32195359	In addition, the number of PBRM1-mutated patients was limited, this low frequency may limit the utility of PBRM1 mutation as a predictive biomarker, and we still have to interpret the results with caution.	('mutation', 'Var', (113, 121))	('limit', 'NegReg', (86, 91))	('PBRM1', 'Gene', (27, 32))	('patients', 'Species', '9606', (41, 49))	('PBRM1', 'Gene', (107, 112))	('PBRM1', 'Gene', '55193', (107, 112))	('PBRM1', 'Gene', '55193', (27, 32))
119145	32195359	Moreover, PBRM1 mutation did not help predict benefit from the first-line ICB treatment for ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('mutation', 'Var', (16, 24))	('ccRCC', 'Disease', (92, 97))	('ccRCC', 'Disease', 'MESH:C538614', (92, 97))	('ICB', 'Chemical', '-', (74, 77))	('PBRM1', 'Gene', (10, 15))	('PBRM1', 'Gene', '55193', (10, 15))
119147	32195359	It is still unknown whether PBRM1 mutation can be a predictive biomarker for the first-line ICB therapy.	('ICB', 'Chemical', '-', (92, 95))	('PBRM1', 'Gene', (28, 33))	('PBRM1', 'Gene', '55193', (28, 33))	('mutation', 'Var', (34, 42))
119150	32195359	We first estimated the prevalence of PBRM1 mutation in the whole NSCLC cohort.	('PBRM1', 'Gene', (37, 42))	('PBRM1', 'Gene', '55193', (37, 42))	('mutation', 'Var', (43, 51))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('NSCLC', 'Disease', (65, 70))
119151	32195359	PBRM1 mutation was defined as any SNV or indel, including putative truncating mutations (nonsense mutations, frameshift, insertions and deletions, and splice-site mutations) and other alterations presumed not to be truncating (In-frame insertions and deletions, missense mutations etc.).	('deletions', 'Var', (136, 145))	('mutation', 'Var', (6, 14))	('PBRM1', 'Gene', (0, 5))	('insertions', 'Var', (121, 131))	('PBRM1', 'Gene', '55193', (0, 5))	('deletions', 'Var', (251, 260))	('frameshift', 'Var', (109, 119))
119153	32195359	Moreover, we classified PBRM1 mutations into two type: LOF (any truncating mutation and homozygous deletion) and non-LOF.	('PBRM1', 'Gene', (24, 29))	('PBRM1', 'Gene', '55193', (24, 29))	('mutations', 'Var', (30, 39))
119154	32195359	A subset of ICB-treated patients (N = 441, 385 from MSKCC, 56 from DFCI) with annotated clinical records were further analyzed for the association between PBRM1 mutation and response to ICB therapy.	('ICB', 'Chemical', '-', (12, 15))	('ICB', 'Chemical', '-', (186, 189))	('mutation', 'Var', (161, 169))	('PBRM1', 'Gene', (155, 160))	('patients', 'Species', '9606', (24, 32))	('PBRM1', 'Gene', '55193', (155, 160))	('association', 'Interaction', (135, 146))
119157	32195359	The results of subgroup analysis were also displayed according to the status of PBRM1 LOF mutations.	('PBRM1', 'Gene', '55193', (80, 85))	('LOF', 'NegReg', (86, 89))	('mutations', 'Var', (90, 99))	('PBRM1', 'Gene', (80, 85))
119159	32195359	In order to further clarify the role of PBRM1 mutation, we classified the ICB-treated patients into two groups (TMB-High and TMB-low, cut-off data: TMB = 10 mut/Mb), and compared their OS.	('ICB-treated', 'Disease', (74, 85))	('PBRM1', 'Gene', (40, 45))	('PBRM1', 'Gene', '55193', (40, 45))	('ICB', 'Chemical', '-', (74, 77))	('TMB', 'Chemical', '-', (148, 151))	('TMB', 'Chemical', '-', (112, 115))	('TMB', 'Chemical', '-', (125, 128))	('mutation', 'Var', (46, 54))	('OS', 'Chemical', '-', (185, 187))	('patients', 'Species', '9606', (86, 94))
119166	28978636	Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways.	('drug resistance', 'biological_process', 'GO:0009315', ('28', '43'))	('drug resistance', 'biological_process', 'GO:0042493', ('28', '43'))	('alternative survival pathways', 'Pathway', (114, 143))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('drug resistance', 'Phenotype', 'HP:0020174', (28, 43))	('epigenetic mechanisms', 'Var', (78, 99))	('activate', 'PosReg', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('drug resistance', 'MPA', (28, 43))
119170	28978636	Modulating EZH2 expression or activity suppressed phosphorylation of certain RTK, restoring the anti-tumor effects of sunitnib in models of acquired or intrinsically resistant ccRCC.	('Modulating', 'Var', (0, 10))	('phosphorylation', 'MPA', (50, 65))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('EZH2', 'Gene', (11, 15))	('restoring', 'PosReg', (82, 91))	('phosphorylation', 'biological_process', 'GO:0016310', ('50', '65'))	('sunitnib', 'Chemical', '-', (118, 126))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('ccRCC', 'Phenotype', 'HP:0006770', (176, 181))	('RCC', 'Disease', (178, 181))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('suppressed', 'NegReg', (39, 49))	('activity', 'MPA', (30, 38))
119177	28978636	Epigenetic modifications have been implicated in cancer progression and are potential drivers of drug resistance.	('drug resistance', 'biological_process', 'GO:0042493', ('97', '112'))	('Epigenetic modifications', 'Var', (0, 24))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('drug resistance', 'Phenotype', 'HP:0020174', (97, 112))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('drug resistance', 'biological_process', 'GO:0009315', ('97', '112'))	('cancer', 'Disease', (49, 55))	('implicated', 'Reg', (35, 45))
119179	28978636	Inhibition of EZH2 has resulted in the attenuation of drug resistance in tumor and stem cells by suppressing its repressive function on target tumor suppressor genes.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('143', '159'))	('repressive function on target', 'MPA', (113, 142))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', (143, 148))	('EZH2', 'Gene', (14, 18))	('drug resistance', 'MPA', (54, 69))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('attenuation', 'NegReg', (39, 50))	('drug resistance', 'Phenotype', 'HP:0020174', (54, 69))	('tumor suppressor', 'biological_process', 'GO:0051726', ('143', '159'))	('tumor', 'Disease', (73, 78))	('drug resistance', 'biological_process', 'GO:0042493', ('54', '69'))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('drug resistance', 'biological_process', 'GO:0009315', ('54', '69'))	('suppressing', 'NegReg', (97, 108))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
119187	28978636	Utilizing also human RCC cell line (acquired resistance) we report that sunitinib resistance is associated with increased EZH2 expression and induces global phosphorylation of kinases in both serine and tyrosine residues.	('EZH2', 'Gene', (122, 126))	('phosphorylation', 'biological_process', 'GO:0016310', ('157', '172'))	('serine', 'Chemical', 'MESH:D012694', (192, 198))	('expression', 'MPA', (127, 137))	('sunitinib', 'Var', (72, 81))	('global phosphorylation', 'MPA', (150, 172))	('sunitinib', 'Chemical', 'MESH:D000077210', (72, 81))	('induces', 'PosReg', (142, 149))	('increased', 'PosReg', (112, 121))	('human', 'Species', '9606', (15, 20))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('RCC', 'Disease', (21, 24))	('tyrosine', 'Chemical', 'MESH:D014443', (203, 211))
119188	28978636	Furthermore, molecular and pharmacological inhibition of EZH2 in both cells lines and PDX, respectively, attenuated the global kinase phosphorylation, increased activation of tumor suppressors and consequently re-established sensitivity to sunitinib.	('EZH2', 'Gene', (57, 61))	('sunitinib', 'Chemical', 'MESH:D000077210', (240, 249))	('re-established', 'PosReg', (210, 224))	('tumor', 'Disease', (175, 180))	('inhibition', 'Var', (43, 53))	('increased activation', 'PosReg', (151, 171))	('global kinase phosphorylation', 'MPA', (120, 149))	('attenuated', 'NegReg', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('phosphorylation', 'biological_process', 'GO:0016310', ('134', '149'))	('sensitivity to sunitinib', 'MPA', (225, 249))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
119190	28978636	RP-R-01 and RP-R-02 are patient-derived xenograft (PDX) of clear cell renal cell carcinoma (ccRCC) models previously described RP-R-02LM is a metastatic ccRCC that spontaneously metastasizes to the lungs from primary tumors implanted either subcutaneously under the skin or orthotopically in the kidney sub-capsule.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (155, 158))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (70, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('subcutaneously under the skin', 'Phenotype', 'HP:0001482', (241, 270))	('RCC', 'Disease', 'MESH:C538614', (155, 158))	('ccRCC', 'Phenotype', 'HP:0006770', (153, 158))	('primary tumors', 'Disease', 'MESH:D009369', (209, 223))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (59, 90))	('patient', 'Species', '9606', (24, 31))	('RP-R-02LM', 'Var', (127, 136))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('capsule', 'cellular_component', 'GO:0042603', ('307', '314'))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (59, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Disease', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('clear cell renal cell carcinoma', 'Disease', (59, 90))	('primary tumors', 'Disease', (209, 223))
119195	28978636	For drug treatment studies, RP-R-02LM viable tumors were selected and dissected into ~1mm2 tumor pieces and implanted either subcutaneously or orthotopically into mice.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('mm2', 'Gene', '10687', (87, 90))	('tumor', 'Disease', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('mm2', 'Gene', (87, 90))	('RP-R-02LM', 'Var', (28, 37))	('mice', 'Species', '10090', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
119200	28978636	For survival studies using sunitinib, we implanted RP-R-02LM tumor pieces (~1mm2) into the kidney sub-capsule of 20 mice.	('mice', 'Species', '10090', (116, 120))	('sunitinib', 'Chemical', 'MESH:D000077210', (27, 36))	('mm2', 'Gene', (77, 80))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mm2', 'Gene', '10687', (77, 80))	('capsule', 'cellular_component', 'GO:0042603', ('102', '109'))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('RP-R-02LM', 'Var', (51, 60))	('tumor', 'Disease', (61, 66))
119203	28978636	In a second set of experiments, mice implanted with RP-R-02LM tumor pieces were grouped into control, sunitinib treated group, EPZ011989 (Epizyme Incorporation, Cambridge MA) treated group, or a combination group (n= 5/group).	('EPZ011989', 'Var', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('rat', 'Species', '10116', (153, 156))	('tumor', 'Disease', (62, 67))	('mice', 'Species', '10090', (32, 36))	('sunitinib', 'Chemical', 'MESH:D000077210', (102, 111))	('RP-R-02LM', 'Var', (52, 61))	('EPZ011989', 'Chemical', '-', (127, 136))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
119234	28978636	To examine the expressions of our proteins of interest, tissue sections were blocked with 2.5% horse serum (Vector Laboratories) and incubated overnight in primary antibodies against Ki67 (1:500, Thermo Fisher), E-cadherin (1:1000, Cell Signaling), EZH2 (1:1000, Cell Signaling), H3K27me3 (1:1000, Cell Signaling) and CD31 (1:100, Dianova).	('H3K27me3', 'Var', (280, 288))	('CD31', 'Gene', (318, 322))	('rat', 'Species', '10116', (119, 122))	('cadherin', 'molecular_function', 'GO:0008014', ('214', '222'))	('CD31', 'Gene', '5175', (318, 322))	('Signaling', 'biological_process', 'GO:0023052', ('237', '246'))	('Signaling', 'biological_process', 'GO:0023052', ('268', '277'))	('E-cadherin', 'Gene', (212, 222))	('E-cadherin', 'Gene', '999', (212, 222))	('Signaling', 'biological_process', 'GO:0023052', ('303', '312'))	('horse', 'Species', '9796', (95, 100))
119264	28978636	Surprisingly, RP-R02LM formed spontaneous lung metastases (Figs.	('RP-R02LM', 'Var', (14, 22))	('lung metastases', 'Disease', (42, 57))	('lung metastases', 'Disease', 'MESH:D009362', (42, 57))
119266	28978636	RP-R02LM tumors at the primary site, as well as the metastatic site, maintained the clear cell phenotype after several passages with a high incidence (>95%) of spontaneous lung metastases at every passage (Fig.	('lung metastases', 'Disease', (172, 187))	('lung metastases', 'Disease', 'MESH:D009362', (172, 187))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('clear', 'MPA', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('RP-R02LM', 'Var', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
119268	28978636	The growth rate of RP-R-02LM was faster (100mm2 at day 31) than the parental RP-R-02 (100mm2 at day 49) (Supplemental Fig.	('mm2', 'Gene', (89, 92))	('RP-R-02LM', 'Var', (19, 28))	('growth', 'MPA', (4, 10))	('faster', 'PosReg', (33, 39))	('rat', 'Species', '10116', (11, 14))	('mm2', 'Gene', '10687', (44, 47))	('mm2', 'Gene', '10687', (89, 92))	('mm2', 'Gene', (44, 47))
119269	28978636	Non-invasive MRI showed that metastatic burden was independent of primary tumor volume in mice bearing orthotopic RP-R-02LM (Supplemental Fig.	('RP-R-02LM', 'Var', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mice', 'Species', '10090', (90, 94))	('tumor', 'Disease', (74, 79))
119272	28978636	Evidence of epithelial-to-mesenchymal transition (EMT) was also observed with increase in N-cadherin, ZEB1 and HIF2a levels and decrease in VASH1 and E-cadherin expression in RP-R-02LM compared to RP-R-02 (Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('152', '160'))	('EMT', 'biological_process', 'GO:0001837', ('50', '53'))	('epithelial-to-mesenchymal transition', 'CPA', (12, 48))	('RP-R-02LM', 'Var', (175, 184))	('increase', 'PosReg', (78, 86))	('ZEB1', 'Gene', (102, 106))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('12', '48'))	('HIF2a', 'Gene', (111, 116))	('expression', 'MPA', (161, 171))	('HIF2a', 'Gene', '2034', (111, 116))	('N-cadherin', 'Gene', (90, 100))	('N-cadherin', 'Gene', '1000', (90, 100))	('ZEB1', 'Gene', '6935', (102, 106))	('decrease', 'NegReg', (128, 136))	('VASH1', 'Gene', '22846', (140, 145))	('E-cadherin', 'Gene', (150, 160))	('E-cadherin', 'Gene', '999', (150, 160))	('cadherin', 'molecular_function', 'GO:0008014', ('92', '100'))	('VASH1', 'Gene', (140, 145))
119276	28978636	To our surprise, RP-R-02LM grown subcutaneously was intrinsically resistant to sunitinib (Fig.	('sunitinib', 'Chemical', 'MESH:D000077210', (79, 88))	('RP-R-02LM', 'Var', (17, 26))	('resistant', 'MPA', (66, 75))
119278	28978636	However, when we investigated the effect of sunitinib on overall survival, mice treated with sunitinib had a survival benefit compared to control mice (Fig.	('mice', 'Species', '10090', (75, 79))	('sunitinib', 'Chemical', 'MESH:D000077210', (93, 102))	('sunitinib', 'Var', (93, 102))	('mice', 'Species', '10090', (146, 150))	('survival benefit', 'CPA', (109, 125))	('sunitinib', 'Chemical', 'MESH:D000077210', (44, 53))
119288	28978636	A close observation of tumor metastases in the RP-R-02LM indicated an anti-metastatic effect in both sunitinib and bevacizumab treated groups, though the effect was greater in the sunitinib treated group despite the lack of control of the primary tumor (Fig.	('anti-metastatic effect', 'CPA', (70, 92))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('RP-R-02LM', 'Var', (47, 56))	('tumor metastases', 'Disease', (23, 39))	('tumor', 'Disease', (247, 252))	('bevacizumab', 'Chemical', 'MESH:D000068258', (115, 126))	('tumor metastases', 'Disease', 'MESH:D009362', (23, 39))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('sunitinib', 'Chemical', 'MESH:D000077210', (101, 110))	('sunitinib', 'Chemical', 'MESH:D000077210', (180, 189))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (247, 252))
119291	28978636	The analysis identified dynamic changes in the phosphorylation of several kinases and anti-apoptotic associated proteins including, AKT, EGFR, FAK, CDK1, PI3K, JAK2, and mTORC as tumors progressed from a sensitive to a resistant state (p>0.05) (Fig.	('changes', 'Reg', (32, 39))	('mTORC', 'Gene', (170, 175))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('EGFR', 'molecular_function', 'GO:0005006', ('137', '141'))	('FAK', 'molecular_function', 'GO:0004717', ('143', '146'))	('EGFR', 'Gene', (137, 141))	('JAK2', 'Gene', (160, 164))	('PI3K', 'Var', (154, 158))	('AKT', 'Gene', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('JAK', 'molecular_function', 'GO:0004713', ('160', '163'))	('CDK', 'molecular_function', 'GO:0004693', ('148', '151'))	('phosphorylation', 'MPA', (47, 62))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('FAK', 'Gene', (143, 146))	('PI3K', 'molecular_function', 'GO:0016303', ('154', '158'))	('EGFR', 'Gene', '1956', (137, 141))	('AKT', 'Gene', '207', (132, 135))	('JAK2', 'Gene', '3717', (160, 164))	('tumors', 'Disease', (179, 185))	('FAK', 'Gene', '5747', (143, 146))	('CDK1', 'Gene', '983', (148, 152))	('CDK1', 'Gene', (148, 152))
119309	28978636	This opposite effect of sunitinib was consistent with our analysis of individual kinases and indicates a reprogramming induced by sunitinib that is unique to the resistant cells.	('sunitinib', 'Chemical', 'MESH:D000077210', (130, 139))	('reprogramming', 'CPA', (105, 118))	('sunitinib', 'Var', (130, 139))	('sunitinib', 'Chemical', 'MESH:D000077210', (24, 33))
119315	28978636	Interestingly, 786-0R cells with the EZH2 knock down responded similarly to 786-0 cells, indicating a role for EZH2 in sunitinib resistance.	('knock down', 'Var', (42, 52))	('sunitinib', 'Chemical', 'MESH:D000077210', (119, 128))	('sunitinib resistance', 'MPA', (119, 139))	('EZH2', 'Gene', (37, 41))
119320	28978636	Interestingly, most the tyrosine enriched phospho-kinases were decreased in EZH2 knockdown cells and further significantly decreased in the presence also of sunitinib (p>0.05).	('tyrosine', 'Enzyme', (24, 32))	('tyrosine', 'Chemical', 'MESH:D014443', (24, 32))	('decreased', 'NegReg', (123, 132))	('decreased', 'NegReg', (63, 72))	('knockdown', 'Var', (81, 90))	('EZH2', 'Gene', (76, 80))	('sunitinib', 'Chemical', 'MESH:D000077210', (157, 166))
119330	28978636	This is consistent with the observation that there are multiple differences between the RP-R-02 and the RP-R-02LM tumors (i.e.	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('RP-R-02LM', 'Var', (104, 113))
119334	28978636	We then generated a list of 1847 genes that were differentially expressed in the sunitinib resistant cells and "return to normal" upon EZH2 inhibition or knockdown, in both the cell line and tumor systems (Fig.	('rat', 'Species', '10116', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('knockdown', 'Var', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('sunitinib', 'Chemical', 'MESH:D000077210', (81, 90))
119337	28978636	Both DAB2IP and PTPN3 decrease in expression in resistant cells, but increase upon EZH2 knockdown (Fig.	('PTPN3', 'Gene', (16, 21))	('increase', 'PosReg', (69, 77))	('expression', 'MPA', (34, 44))	('decrease', 'NegReg', (22, 30))	('DAB2IP', 'Gene', (5, 11))	('knockdown', 'Var', (88, 97))	('EZH2', 'Gene', (83, 87))	('PTPN3', 'Gene', '5774', (16, 21))	('DAB2IP', 'Gene', '153090', (5, 11))
119346	28978636	We also observed decreased metastases in the combination, although the inhibition was not greater than with single agent sunitinib (Fig.	('metastases', 'Disease', 'MESH:D009362', (27, 37))	('decreased', 'NegReg', (17, 26))	('sunitinib', 'Chemical', 'MESH:D000077210', (121, 130))	('combination', 'Var', (45, 56))	('metastases', 'Disease', (27, 37))
119349	28978636	Treatment with EPZ011989 resulted in smaller lung nodules.	('smaller lung', 'Phenotype', 'HP:0002089', (37, 49))	('smaller', 'NegReg', (37, 44))	('EPZ011989', 'Chemical', '-', (15, 24))	('EPZ011989', 'Var', (15, 24))	('lung nodules', 'CPA', (45, 57))
119351	28978636	Taken together, our data provide evidence that EZH2 plays a significant role in resistance to RTKi such as sunitinib, and inhibition of its activity re-establishes drug sensitivity.	('EZH2', 'Gene', (47, 51))	('inhibition', 'Var', (122, 132))	('sunitinib', 'Chemical', 'MESH:D000077210', (107, 116))	('re-establishes', 'Reg', (149, 163))	('resistance to', 'MPA', (80, 93))	('drug sensitivity', 'Phenotype', 'HP:0020174', (164, 180))	('drug sensitivity', 'MPA', (164, 180))	('activity', 'MPA', (140, 148))
119355	28978636	In addition, when we stratified into low, intermediate and high, we again observed poor survival benefit for patients with high EZH2 expression (Supplemental Fig.	('expression', 'MPA', (133, 143))	('patients', 'Species', '9606', (109, 117))	('rat', 'Species', '10116', (23, 26))	('high', 'Var', (123, 127))	('EZH2', 'Gene', (128, 132))
119363	28978636	A significant increase in HIF2alpha was observed in the RP-R-02LM.	('HIF2alpha', 'Gene', '2034', (26, 35))	('RP-R-02LM', 'Var', (56, 65))	('increase', 'PosReg', (14, 22))	('HIF2alpha', 'Gene', (26, 35))
119366	28978636	To our knowledge, RP-R02LM is the first ccRCC PDX model with high incidence of spontaneous lung metastases to be reported in the literature, and therefore represents a valuable tool to study the molecular mechanisms involved in disease progression and for drug development.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('RCC', 'Disease', (42, 45))	('rat', 'Species', '10116', (133, 136))	('lung metastases', 'Disease', (91, 106))	('lung metastases', 'Disease', 'MESH:D009362', (91, 106))	('RP-R02LM', 'Var', (18, 26))
119378	28978636	Acidic motifs have been identified as potential downstream substrates of receptor tyrosine kinase signaling pathways.	('Acidic motifs', 'Var', (0, 13))	('receptor tyrosine kinase signaling pathways', 'Pathway', (73, 116))	('rat', 'Species', '10116', (64, 67))	('tyrosine', 'Chemical', 'MESH:D014443', (82, 90))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))
119389	28978636	Upon knockdown of EZH2 we observed a significant decrease in FAK expression at the gene level.	('FAK', 'molecular_function', 'GO:0004717', ('61', '64'))	('knockdown', 'Var', (5, 14))	('FAK', 'Gene', (61, 64))	('FAK', 'Gene', '5747', (61, 64))	('decrease', 'NegReg', (49, 57))	('EZH2', 'Gene', (18, 22))
119396	28978636	Our data confirm the clinical relevance of EZH2 by showing a shorter overall survival in ccRCC patients with high EZH2 expressing tumors.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('overall survival', 'MPA', (69, 85))	('shorter', 'NegReg', (61, 68))	('high', 'Var', (109, 113))	('patients', 'Species', '9606', (95, 103))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (89, 94))	('RCC', 'Disease', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('EZH2', 'Gene', (114, 118))
119414	32228647	Nine of the 12 peptides assessed by immunogenicity analysis were able to activate naive CD8+ T cells, including peptides derived from EGLN3.	('CD8', 'Gene', '925', (88, 91))	('EGLN3', 'Var', (134, 139))	('activate', 'PosReg', (73, 81))	('CD8', 'Gene', (88, 91))
119468	32228647	The panel was designed using Design Studio (Illumina) and includes probes to sequence regions of interest in 32 genes which were known to be frequently mutated in RCC samples from TCGA or identified in other RCC studies.	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('mutated', 'Var', (152, 159))	('RCC', 'Disease', (163, 166))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('RCC', 'Disease', (208, 211))
119537	32228647	Since the effect of clinically approved DNA demethylating agents like decitabine on the processing and presentation of antigens has recently been proposed, epigenetic therapy might induce the expression of the corresponding immunogenic antigens in ccRCC.	('decitabine', 'Chemical', 'MESH:D000077209', (70, 80))	('induce', 'PosReg', (181, 187))	('expression', 'MPA', (192, 202))	('epigenetic therapy', 'Var', (156, 174))	('RCC', 'Disease', 'MESH:C538614', (250, 253))	('ccRCC', 'Phenotype', 'HP:0006770', (248, 253))	('RCC', 'Disease', (250, 253))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))
119542	32228647	Three of the candidates, namely MET, TSC2, and RB1, that were affected by somatic mutations in TCGA patient cohort are genes found to be frequently mutated in ccRCC, either in literature or in own data analyses (unpublished data), and were therefore selected for deep sequencing in patient cohort 1.	('RB1', 'Gene', '5925', (47, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (159, 164))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('patient', 'Species', '9606', (100, 107))	('TCGA', 'Gene', (95, 99))	('mutations', 'Var', (82, 91))	('patient', 'Species', '9606', (282, 289))	('RCC', 'Disease', (161, 164))	('TSC2', 'Gene', '7249', (37, 41))	('RB1', 'Gene', (47, 50))	('TSC2', 'Gene', (37, 41))
119544	32228647	Forty-five of the detected variants result in amino acid substitutions, potentially leading to patient and tumor-specific mutated peptides, the so-called neo-epitopes or neo-antigens.	('variants', 'Var', (27, 35))	('patient', 'Species', '9606', (95, 102))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('patient', 'MPA', (95, 102))	('leading', 'Reg', (84, 91))	('result in', 'Reg', (36, 45))	('substitutions', 'Var', (57, 70))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
119548	32228647	Most of the mutations of MET, TSC2, and RB1 that were detected in cohort 1 of this study were private and would therefore not qualify for a broadly applicable "off-the-shelf" cancer vaccine or ACT approach.	('TSC2', 'Gene', (30, 34))	('mutations', 'Var', (12, 21))	('cancer', 'Disease', (175, 181))	('MET', 'Gene', (25, 28))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('RB1', 'Gene', (40, 43))	('RB1', 'Gene', '5925', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('TSC2', 'Gene', '7249', (30, 34))
119561	32228647	Thereby the immunogenicity of nine peptides derived from EGLN3, NNMT, and ANGPTL4 and restricted to the HLA alleles A*02, B*07, B*08, B*15, and B*40 was proven (Table 2).	('ANGPTL4', 'Gene', '51129', (74, 81))	('ANGPTL4', 'Gene', (74, 81))	('NNMT', 'Gene', '4837', (64, 68))	('A*02', 'Var', (116, 120))	('B*07', 'Var', (122, 126))	('NNMT', 'Gene', (64, 68))	('EGLN3', 'Var', (57, 62))
119573	32228647	Abundance of creatine and pantothenic acid on the other hand was decreased in EGLN3 knockdown cells.	('decreased', 'NegReg', (65, 74))	('knockdown', 'Var', (84, 93))	('creatine', 'Chemical', 'MESH:D003401', (13, 21))	('pantothenic acid', 'Chemical', 'MESH:D010205', (26, 42))	('EGLN3', 'Gene', (78, 83))
119575	32228647	Whereas mitochondrial respiration and ATP production were increased in A498 cells with EGLN3 depletion, respiration in 786-O cells was decreased (Fig.	('ATP production', 'MPA', (38, 52))	('respiration', 'biological_process', 'GO:0007585', ('22', '33'))	('respiration', 'MPA', (104, 115))	('increased', 'PosReg', (58, 67))	('ATP', 'Chemical', 'MESH:D000255', (38, 41))	('respiration', 'biological_process', 'GO:0045333', ('22', '33'))	('EGLN3 depletion', 'Var', (87, 102))	('mitochondrial respiration', 'MPA', (8, 33))	('respiration', 'biological_process', 'GO:0007585', ('104', '115'))	('decreased', 'NegReg', (135, 144))	('depletion', 'Var', (93, 102))	('respiration', 'biological_process', 'GO:0045333', ('104', '115'))
119605	32228647	Thus, in the future, site-specific DNA methylation could represent a strategy to inhibit the expression of affected candidates and could be beneficial also for patients with metastatic disease.	('patients', 'Species', '9606', (160, 168))	('DNA methylation', 'biological_process', 'GO:0006306', ('35', '50'))	('inhibit', 'NegReg', (81, 88))	('metastatic disease', 'Disease', (174, 192))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('expression', 'MPA', (93, 103))	('site-specific', 'Var', (21, 34))
119610	32228647	Therefore, demethylation induced by demethylating agents in RCC might result in restoration or induction of HLA-presented antigen targets.	('demethylating', 'Var', (36, 49))	('induction', 'MPA', (95, 104))	('RCC', 'Disease', (60, 63))	('demethylation', 'biological_process', 'GO:0070988', ('11', '24'))	('HLA-presented antigen', 'Protein', (108, 129))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('result', 'Reg', (70, 76))	('restoration', 'MPA', (80, 91))	('demethylation', 'MPA', (11, 24))
119625	32228647	Based on our ligandomics analysis, 13 EGLN3-derived peptides were ccRCC-specifically presented, two of which were among the most frequently presented peptides.	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('RCC', 'Disease', (68, 71))	('EGLN3-derived', 'Var', (38, 51))
119627	32228647	The presence of EGLN3-derived peptides was furthermore associated with higher expression of PD1, and CD8+ and regulatory T cell infiltration, indicating interactions with the immune system.	('higher', 'PosReg', (71, 77))	('CD8', 'Gene', '925', (101, 104))	('expression', 'MPA', (78, 88))	('EGLN3-derived', 'Var', (16, 29))	('interactions', 'Interaction', (153, 165))	('PD1', 'Gene', (92, 95))	('CD8', 'Gene', (101, 104))
119628	32228647	Thus, we decided to further investigate the function of EGLN3 in ccRCC and performed experiments in different ccRCC cell culture models.	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('EGLN3', 'Var', (56, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('RCC', 'Disease', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))
119630	32228647	In further analyses, we showed that EGLN3 acts pro-proliferative and anti-apoptotic, and hence, could contribute to ccRCC malignant transformation and progression.	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('ccRCC malignant transformation', 'Disease', (116, 146))	('progression', 'CPA', (151, 162))	('contribute', 'Reg', (102, 112))	('pro-proliferative', 'CPA', (47, 64))	('ccRCC malignant transformation', 'Disease', 'MESH:D009369', (116, 146))	('EGLN3', 'Var', (36, 41))	('anti-apoptotic', 'CPA', (69, 83))
119633	32228647	Thus, one limitation of our study is that other model systems that better resemble the in vivo tumor situation, such as microtumors or cancer organoids, might be more appropriate to understand the function of EGLN3 in ccRCC and to assess its feasibility as a drug target.	('EGLN3', 'Var', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('cancer', 'Disease', (135, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (218, 223))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('microtumors', 'Disease', 'None', (120, 131))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('microtumors', 'Disease', (120, 131))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('RCC', 'Disease', (220, 223))	('tumor', 'Disease', (95, 100))
119708	27615548	In various human cancers such as lung cancer, it is now standard of care to use genetic alterations in exploring cancer biology and selecting patients for targeted therapies.	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('genetic alterations', 'Var', (80, 99))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('human', 'Species', '9606', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancer', 'Disease', (113, 119))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancers', 'Disease', (17, 24))	('cancer', 'Disease', (17, 23))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('cancer', 'Disease', (38, 44))	('patients', 'Species', '9606', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('lung cancer', 'Disease', (33, 44))
61252	27615548	Remarkably, these genes encode chromatin and epigenetic regulatory proteins, and most mutations are predicted to result in functional loss, favoring their roles as tumor suppressors.	('mutations', 'Var', (86, 95))	('tumor', 'Disease', (164, 169))	('epigenetic', 'Protein', (45, 55))	('chromatin', 'cellular_component', 'GO:0000785', ('31', '40'))	('encode', 'Reg', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('loss', 'NegReg', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
119735	27615548	Among the prevalent non-VHL alterations, BAP1, SETD2, and TP53 mutations are associated with a poor prognosis.	('mutations', 'Var', (63, 72))	('VHL', 'Gene', '7428', (24, 27))	('SETD2', 'Gene', '29072', (47, 52))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('BAP1', 'Gene', (41, 45))	('SETD2', 'Gene', (47, 52))	('VHL', 'Gene', (24, 27))	('BAP1', 'Gene', '8314', (41, 45))
119756	27615548	paper is that different regions of the tumor have different mutations in the very same genes, especially at SETD2, which underscores the importance of changing particular tumor-cell functions as the tumor expands and evolves.	('tumor', 'Disease', (199, 204))	('SETD2', 'Gene', (108, 113))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('SETD2', 'Gene', '29072', (108, 113))	('tumor', 'Disease', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))
119768	27615548	For example, mTOR pathway activation due to either MTOR activation mutations or TSC1 loss-of-function mutations occurred at high frequencies in ccRCC where VHL mutation is the universal tumor-initiating event.	('MTOR', 'Gene', '2475', (51, 55))	('loss-of-function', 'NegReg', (85, 101))	('tumor', 'Disease', (186, 191))	('VHL', 'Gene', (156, 159))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('activation', 'PosReg', (26, 36))	('mutations', 'Var', (102, 111))	('activation', 'PosReg', (56, 66))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('VHL', 'Gene', '7428', (156, 159))	('mTOR', 'Gene', (13, 17))	('TSC1', 'Gene', (80, 84))	('mutations', 'Var', (67, 76))	('mTOR', 'Gene', '2475', (13, 17))	('TSC1', 'Gene', '7248', (80, 84))	('MTOR', 'Gene', (51, 55))
119775	27615548	The source of the river is analogous to the trunk mutations and contains the ubiquitous driver events, generally the initiating drivers such as VHL mutation and chromosome 3p loss (Figure 1).	('chromosome 3p loss', 'Var', (161, 179))	('trunk', 'cellular_component', 'GO:0043198', ('44', '49'))	('chromosome', 'cellular_component', 'GO:0005694', ('161', '171'))	('VHL', 'Gene', (144, 147))	('mutation', 'Var', (148, 156))	('VHL', 'Gene', '7428', (144, 147))
119776	27615548	The heterogeneous mutations previously ascribed to the branches of the tree model become tributaries along the river, retaining the capability to become driver mutations and to converge with other spatially or temporally distinct mutations affecting the same gene or components along critical oncogenic or tumor suppressor pathways inherent to a given cancer type.	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('cancer', 'Disease', 'MESH:D009369', (352, 358))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('cancer', 'Disease', (352, 358))	('tumor suppressor', 'biological_process', 'GO:0051726', ('306', '322'))	('tumor', 'Disease', (306, 311))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('306', '322'))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('oncogenic', 'Pathway', (293, 302))	('mutations', 'Var', (18, 27))
119777	27615548	Study of one patient is highly instructive, in which two distinct and spatially separate mutations in TSC1 and MTOR join along the PI3K/AKT/mTOR pathway and activate mTOR kinase through different mechanisms.	('TSC1', 'Gene', '7248', (102, 106))	('activate', 'PosReg', (157, 165))	('mTOR', 'Gene', (166, 170))	('patient', 'Species', '9606', (13, 20))	('mTOR', 'Gene', '2475', (166, 170))	('MTOR', 'Gene', '2475', (111, 115))	('PI3K', 'molecular_function', 'GO:0016303', ('131', '135'))	('AKT', 'Gene', '207', (136, 139))	('TSC1', 'Gene', (102, 106))	('mutations', 'Var', (89, 98))	('mTOR', 'Gene', (140, 144))	('join', 'Reg', (116, 120))	('mTOR', 'Gene', '2475', (140, 144))	('MTOR', 'Gene', (111, 115))	('AKT', 'Gene', (136, 139))
119785	27615548	Sequencing analysis of his primary tumor with MSK-IMPACT, a massively parallel ultradeep targeted exon capture NGS assay, detected chromosome 3p loss and somatic mutations in VHL, AKT2, PBRM1, and BAP1 (Figure 2B and 2C).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('PBRM1', 'Gene', '55193', (186, 191))	('mutations', 'Var', (162, 171))	('AKT2', 'Gene', (180, 184))	('chromosome', 'cellular_component', 'GO:0005694', ('131', '141'))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('loss', 'NegReg', (145, 149))	('AKT2', 'Gene', '208', (180, 184))	('tumor', 'Disease', (35, 40))	('VHL', 'Gene', (175, 178))	('BAP1', 'Gene', '8314', (197, 201))	('VHL', 'Gene', '7428', (175, 178))	('PBRM1', 'Gene', (186, 191))	('BAP1', 'Gene', (197, 201))
119787	27615548	Intriguingly, the co-occurrence of PBRM1 and BAP1 mutations in ccRCC tumors has been shown to associate with a very poor clinical outcome, which contrasts the observed, exceptional clinical outcome of our patient.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('BAP1', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('ccRCC tumors', 'Disease', 'MESH:D009369', (63, 75))	('BAP1', 'Gene', '8314', (45, 49))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('ccRCC tumors', 'Disease', (63, 75))	('PBRM1', 'Gene', (35, 40))	('PBRM1', 'Gene', '55193', (35, 40))	('patient', 'Species', '9606', (205, 212))
119790	27615548	As shown in Figure 2C, genomic analysis of the metastatic bone lesion was significant for somatic mutations in VHL, PRBM1, AKT2, and HIST1H1C.	('HIST1H1C', 'Gene', '3006', (133, 141))	('VHL', 'Gene', (111, 114))	('VHL', 'Gene', '7428', (111, 114))	('PRBM1', 'Gene', (116, 121))	('HIST1H1C', 'Gene', (133, 141))	('mutations', 'Var', (98, 107))	('AKT2', 'Gene', (123, 127))	('AKT2', 'Gene', '208', (123, 127))
119791	27615548	Most importantly, the BAP1 mutation found in the primary tumor was absent in the bone metastasis, which favors the intratumoral heterogeneity stipulated as Figure 3 Scenario 2 where PBRM1 and BAP1 mutations were present in different subclones within the primary tumor.	('bone metastasis', 'CPA', (81, 96))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('BAP1', 'Gene', (192, 196))	('tumor', 'Disease', (262, 267))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('BAP1', 'Gene', '8314', (192, 196))	('PBRM1', 'Gene', (182, 187))	('mutation', 'Var', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('absent', 'NegReg', (67, 73))	('BAP1', 'Gene', '8314', (22, 26))	('BAP1', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('PBRM1', 'Gene', '55193', (182, 187))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('tumor', 'Disease', (120, 125))
119792	27615548	Of note, the presence of HIST1H1C in his metastatic site but not his primary supports the further evolution of the metastatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('HIST1H1C', 'Gene', '3006', (25, 33))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('presence', 'Var', (13, 21))	('HIST1H1C', 'Gene', (25, 33))
119803	27615548	Our patient's exceptional response to Everolimus was particularly surprising, especially in view of his mutations of BAP1 and PBRM1 present in the primary tumor, which would suggest an aggressive disease course.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('mutations', 'Var', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('PBRM1', 'Gene', (126, 131))	('BAP1', 'Gene', '8314', (117, 121))	('aggressive disease', 'Disease', 'MESH:D001523', (185, 203))	('tumor', 'Disease', (155, 160))	('patient', 'Species', '9606', (4, 11))	('PBRM1', 'Gene', '55193', (126, 131))	('BAP1', 'Gene', (117, 121))	('aggressive disease', 'Disease', (185, 203))	('suggest', 'Reg', (174, 181))	('Everolimus', 'Chemical', 'MESH:D000068338', (38, 48))
119807	27615548	For the patient's primary tumor we found truncal mutations in both VHL and AKT2, with what were presumed to be concurrent mutations of PBRM1 and BAP1 as demonstrated in Scenario 1 of Figure 3.	('VHL', 'Gene', '7428', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('BAP1', 'Gene', '8314', (145, 149))	('AKT2', 'Gene', (75, 79))	('PBRM1', 'Gene', '55193', (135, 140))	('PBRM1', 'Gene', (135, 140))	('patient', 'Species', '9606', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('AKT2', 'Gene', '208', (75, 79))	('truncal mutations', 'Var', (41, 58))	('BAP1', 'Gene', (145, 149))	('VHL', 'Gene', (67, 70))
119808	27615548	In the Scenario 2 there are two clones, both of which contained the truncal mutations in VHL and AKT2.	('AKT2', 'Gene', (97, 101))	('AKT2', 'Gene', '208', (97, 101))	('VHL', 'Gene', (89, 92))	('VHL', 'Gene', '7428', (89, 92))	('truncal mutations', 'Var', (68, 85))	('contained', 'Reg', (54, 63))
119809	27615548	The first subclone contained an additional PBRM1 mutation, whereas the second subclone contained a mutation in BAP1.	('PBRM1', 'Gene', (43, 48))	('BAP1', 'Gene', '8314', (111, 115))	('PBRM1', 'Gene', '55193', (43, 48))	('mutation', 'Var', (99, 107))	('mutation', 'Var', (49, 57))	('BAP1', 'Gene', (111, 115))
119810	27615548	The PBRM1 mutation subclone was the clone later identified in his metastatic tumor while the BAP1 mutation clone was absent.	('BAP1', 'Gene', '8314', (93, 97))	('PBRM1', 'Gene', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('mutation', 'Var', (10, 18))	('PBRM1', 'Gene', '55193', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('BAP1', 'Gene', (93, 97))	('tumor', 'Disease', (77, 82))
119813	27615548	Analysis of this patient's primary and metastatic tumors shows that the AKT2 mutation was a truncal event in this patient's tumorigenesis.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('AKT2', 'Gene', (72, 76))	('AKT2', 'Gene', '208', (72, 76))	('mutation', 'Var', (77, 85))	('patient', 'Species', '9606', (17, 24))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('patient', 'Species', '9606', (114, 121))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
119816	27615548	Hence, the patient's prolonged treatment response to Everolimus could be possibly explained by the AKT2 mutation, which awaits functional confirmation.	('Everolimus', 'Chemical', 'MESH:D000068338', (53, 63))	('patient', 'Species', '9606', (11, 18))	('mutation', 'Var', (104, 112))	('AKT2', 'Gene', (99, 103))	('AKT2', 'Gene', '208', (99, 103))	('explained by', 'Reg', (82, 94))
119821	27615548	As seen in Figure 2C, while VHL mutation (30%) is the truncal event of this patient, as commonly occurred in the majority of ccRCC tumors, the detected AKT2 mutation was equally prevalent (26%), suggesting that AKT2 mutation could also be truncal.	('AKT2', 'Gene', (152, 156))	('occurred', 'Reg', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('AKT2', 'Gene', (211, 215))	('AKT2', 'Gene', '208', (152, 156))	('mutation', 'Var', (157, 165))	('AKT2', 'Gene', '208', (211, 215))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('ccRCC tumors', 'Disease', 'MESH:D009369', (125, 137))	('patient', 'Species', '9606', (76, 83))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('ccRCC', 'Phenotype', 'HP:0006770', (125, 130))	('VHL', 'Gene', (28, 31))	('ccRCC tumors', 'Disease', (125, 137))	('VHL', 'Gene', '7428', (28, 31))
119822	27615548	Thirdly, "position matters", the missense N325S mutation of this AKT2 occurs at the kinase domain, which could have rendered enhanced AKT2 kinase activity.	('missense N325S', 'Var', (33, 47))	('N325S', 'Mutation', 'rs374756725', (42, 47))	('AKT2', 'Gene', '208', (65, 69))	('kinase activity', 'MPA', (139, 154))	('AKT2', 'Gene', '208', (134, 138))	('AKT2', 'Gene', (134, 138))	('enhanced', 'PosReg', (125, 133))	('AKT2', 'Gene', (65, 69))
119823	27615548	Accordingly, tumor cells or clones with this AKT2 mutation are likely highly dependent on the constant activation of the mTOR pathway, making them exquisitely sensitive to drugs like Everolimus, which is in line with the braided river model outlined in Figure 1.	('tumor', 'Disease', (13, 18))	('sensitive', 'MPA', (159, 168))	('mTOR', 'Gene', '2475', (121, 125))	('mTOR', 'Gene', (121, 125))	('Everolimus', 'Chemical', 'MESH:D000068338', (183, 193))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('activation', 'PosReg', (103, 113))	('AKT2', 'Gene', (45, 49))	('AKT2', 'Gene', '208', (45, 49))	('mutation', 'Var', (50, 58))
119826	27615548	While our patient had mutations of both PBRM1 and BAP1 in the primary kidney tumor, sequencing from the bone lesion from the rib suggested that the PBRM1 subclone had metastasized.	('PBRM1', 'Gene', (40, 45))	('PBRM1', 'Gene', '55193', (40, 45))	('BAP1', 'Gene', '8314', (50, 54))	('kidney tumor', 'Disease', (70, 82))	('patient', 'Species', '9606', (10, 17))	('PBRM1', 'Gene', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutations', 'Var', (22, 31))	('BAP1', 'Gene', (50, 54))	('kidney tumor', 'Phenotype', 'HP:0009726', (70, 82))	('PBRM1', 'Gene', '55193', (148, 153))	('kidney tumor', 'Disease', 'MESH:D007674', (70, 82))
119829	27615548	We can postulate that as the patient's disease progressed and his cancer evolved, further mutations occurred or adapted, possibly as a result of systemic treatment he received.	('patient', 'Species', '9606', (29, 36))	('mutations', 'Var', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('occurred', 'Reg', (100, 108))	('cancer', 'Disease', (66, 72))
119831	27615548	Here we describe a case in which analysis of the patient's primary tumor suggested concurrent PBRM1 and BAP1 mutations, predicting an aggressive and unresponsive clinical course.	('PBRM1', 'Gene', '55193', (94, 99))	('BAP1', 'Gene', '8314', (104, 108))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('BAP1', 'Gene', (104, 108))	('patient', 'Species', '9606', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('predicting', 'Reg', (120, 130))	('mutations', 'Var', (109, 118))	('PBRM1', 'Gene', (94, 99))
119833	27615548	Analysis of a metastatic site after the patient progressed revealed a truncal event in the mTOR pathway gene AKT2 and a concurrent PBRM1 mutation.	('patient', 'Species', '9606', (40, 47))	('mutation', 'Var', (137, 145))	('AKT2', 'Gene', (109, 113))	('AKT2', 'Gene', '208', (109, 113))	('truncal', 'MPA', (70, 77))	('mTOR', 'Gene', (91, 95))	('mTOR', 'Gene', '2475', (91, 95))	('PBRM1', 'Gene', (131, 136))	('PBRM1', 'Gene', '55193', (131, 136))
119835	27615548	Based on primary-metastatic tumor pair genomic sequencing, PBRM1 and BAP1 mutations diverged instead of converged in the primary tumor, and the PBRM1 but not the BAP1 mutant clone metastasized, which helps interpret the observed unexpected clinical outcome (Figure 3).	('tumor', 'Disease', (28, 33))	('metastasized', 'CPA', (180, 192))	('BAP1', 'Gene', '8314', (162, 166))	('BAP1', 'Gene', (69, 73))	('PBRM1', 'Gene', (144, 149))	('mutations', 'Var', (74, 83))	('PBRM1', 'Gene', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('PBRM1', 'Gene', '55193', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('BAP1', 'Gene', (162, 166))	('PBRM1', 'Gene', '55193', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('BAP1', 'Gene', '8314', (69, 73))
119849	27615548	Interestingly, patients with PBRM1 mutations, however, had similar PFS to first-line Sunitinib or Everolimus (11.0 vs. 11.5 months, HR 1.07, 95% CI 0.66-1.74).	('patients', 'Species', '9606', (15, 23))	('PBRM1', 'Gene', '55193', (29, 34))	('Everolimus', 'Chemical', 'MESH:D000068338', (98, 108))	('Sunitinib', 'Chemical', 'MESH:D000077210', (85, 94))	('PBRM1', 'Gene', (29, 34))	('mutations', 'Var', (35, 44))
119850	27615548	In contrast to patients with PBRM1 mutations, who did well regardless of therapy, patients with KDM5C mutations have a notable prolonged PFS on Sunitinib (20.6 months) versus Everolimus (9.8 months).	('KDM5C', 'Gene', '8242', (96, 101))	('PBRM1', 'Gene', (29, 34))	('patients', 'Species', '9606', (15, 23))	('PBRM1', 'Gene', '55193', (29, 34))	('prolonged', 'PosReg', (127, 136))	('patients', 'Species', '9606', (82, 90))	('Everolimus', 'Chemical', 'MESH:D000068338', (175, 185))	('mutations', 'Var', (102, 111))	('Sunitinib', 'Chemical', 'MESH:D000077210', (144, 153))	('KDM5C', 'Gene', (96, 101))	('PFS on Sunitinib', 'MPA', (137, 153))
119854	27615548	Exceptional responses (defined as duration of therapy of more than 21 months) were associated with somatic genetic alterations in KDM5C, PBRM1 and VHL, which was consistent with the findings from RECORD-3.	('genetic alterations', 'Var', (107, 126))	('PBRM1', 'Gene', (137, 142))	('KDM5C', 'Gene', (130, 135))	('PBRM1', 'Gene', '55193', (137, 142))	('VHL', 'Gene', (147, 150))	('KDM5C', 'Gene', '8242', (130, 135))	('VHL', 'Gene', '7428', (147, 150))
119860	27615548	In RCC, mutations in TSC1 and MTOR are associated with response to mTOR inhibitors.	('associated with', 'Reg', (39, 54))	('TSC1', 'Gene', '7248', (21, 25))	('mutations', 'Var', (8, 17))	('mTOR', 'Gene', (67, 71))	('MTOR', 'Gene', (30, 34))	('TSC1', 'Gene', (21, 25))	('mTOR', 'Gene', '2475', (67, 71))	('RCC', 'Disease', (3, 6))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('RCC', 'Disease', 'MESH:C538614', (3, 6))	('MTOR', 'Gene', '2475', (30, 34))
119861	27615548	A large retrospective study of 79 patients with RCC treated with mTOR inhibitors confirmed that mutations in MTOR, TSC1, or TSC2 were more common in responders.	('mTOR', 'Gene', (65, 69))	('mTOR', 'Gene', '2475', (65, 69))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('TSC1', 'Gene', (115, 119))	('MTOR', 'Gene', (109, 113))	('RCC', 'Disease', (48, 51))	('common', 'Reg', (139, 145))	('TSC2', 'Gene', '7249', (124, 128))	('TSC2', 'Gene', (124, 128))	('TSC1', 'Gene', '7248', (115, 119))	('MTOR', 'Gene', '2475', (109, 113))	('patients', 'Species', '9606', (34, 42))	('responders', 'Disease', (149, 159))	('mutations', 'Var', (96, 105))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
119862	27615548	Notably, although the presence of these mutations can suggest patients more likely to respond to mTOR inhibitors, the inverse is not true.	('mTOR', 'Gene', '2475', (97, 101))	('more', 'PosReg', (71, 75))	('mTOR', 'Gene', (97, 101))	('mutations', 'Var', (40, 49))	('patients', 'Species', '9606', (62, 70))
119863	27615548	In that study, the majority of responders had no mutations in MTOR, TSC1, TSC2 or other genes in the pathway (including PIK3CA and PTEN).	('PIK3CA', 'Gene', (120, 126))	('TSC1', 'Gene', '7248', (68, 72))	('mutations', 'Var', (49, 58))	('PTEN', 'Gene', (131, 135))	('MTOR', 'Gene', '2475', (62, 66))	('PTEN', 'Gene', '5728', (131, 135))	('TSC1', 'Gene', (68, 72))	('PIK3CA', 'Gene', '5290', (120, 126))	('TSC2', 'Gene', '7249', (74, 78))	('TSC2', 'Gene', (74, 78))	('MTOR', 'Gene', (62, 66))
119866	27615548	Based on available data, distinct molecular subtypes of ccRCC according to the mutation status of PBRM1, BAP1 and KDM5C could have potential biomarker values for patients with metastatic ccRCC treated with targeted agents.	('PBRM1', 'Gene', (98, 103))	('patients', 'Species', '9606', (162, 170))	('PBRM1', 'Gene', '55193', (98, 103))	('KDM5C', 'Gene', '8242', (114, 119))	('BAP1', 'Gene', '8314', (105, 109))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))	('KDM5C', 'Gene', (114, 119))	('mutation', 'Var', (79, 87))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (187, 192))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('RCC', 'Disease', (189, 192))	('BAP1', 'Gene', (105, 109))
119891	33977237	Following these findings, a pathological diagnosis of pT1aNxMx, CCPRCC, G2, Fuhrman grade 2, INFa, v0, ly0 was made.	('CCPRCC', 'Gene', '5546', (64, 70))	('INFa', 'Gene', '3451', (93, 97))	('CCPRCC', 'Gene', (64, 70))	('pT1aNxMx', 'Var', (54, 62))	('INFa', 'Gene', (93, 97))
119919	31777602	LAT, HOXD3 and NFE2L3 identified as novel DNA methylation-driven genes and prognostic markers in human clear cell renal cell carcinoma by integrative bioinformatics approaches Background: Abnormal DNA methylation of is one of the important mechanisms leading to tumor pathogenesis.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (103, 134))	('NFE2L3', 'Gene', '9603', (15, 21))	('human', 'Species', '9606', (97, 102))	('methyl', 'Chemical', 'MESH:C031105', (46, 52))	('LAT', 'Gene', '27040', (0, 3))	('clear cell renal cell carcinoma', 'Disease', (103, 134))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (114, 134))	('Abnormal DNA methylation', 'Var', (188, 212))	('DNA methylation', 'biological_process', 'GO:0006306', ('42', '57'))	('DNA', 'cellular_component', 'GO:0005574', ('197', '200'))	('leading', 'Reg', (251, 258))	('DNA methylation', 'biological_process', 'GO:0006306', ('197', '212'))	('NFE2L3', 'Gene', (15, 21))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (103, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('tumor', 'Disease', (262, 267))	('methyl', 'Chemical', 'MESH:C031105', (201, 207))	('HOXD3', 'Gene', '3232', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('HOXD3', 'Gene', (5, 10))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('LAT', 'Gene', (0, 3))	('pathogenesis', 'biological_process', 'GO:0009405', ('268', '280'))
119924	31777602	The methylation alterations of the three genes were validated via two GEO datasets (GSE70303 and GSE113501), and the genes expression level was verified through two GEO datasets (GSE6344 and GSE53757).	('methyl', 'Chemical', 'MESH:C031105', (4, 10))	('GSE6344', 'Var', (179, 186))	('methylation', 'MPA', (4, 15))	('GSE70303', 'Var', (84, 92))	('GSE113501', 'Var', (97, 106))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))
119927	31777602	The CpG sites of LAT (cg16462073), HOXD3 (cg24000528) and NFE2L3 (cg16882373) that may affect respective gene expressions were also identified.	('cg16462073', 'Var', (22, 32))	('HOXD3', 'Gene', '3232', (35, 40))	('cg24000528', 'Var', (42, 52))	('affect', 'Reg', (87, 93))	('NFE2L3', 'Gene', (58, 64))	('cg16882373', 'Var', (66, 76))	('LAT', 'Gene', (17, 20))	('gene expressions', 'MPA', (105, 121))	('HOXD3', 'Gene', (35, 40))	('LAT', 'Gene', '27040', (17, 20))	('NFE2L3', 'Gene', '9603', (58, 64))
119928	31777602	For the survival analysis, we found that hypomethylation and over-expression of LAT and NFE2L3 were correlated with poor survival, while hypermethylation and low-expression HOXD3 was correlated with poor survival of clear cell renal cell carcinoma patients.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (227, 247))	('methyl', 'Chemical', 'MESH:C031105', (45, 51))	('methyl', 'Chemical', 'MESH:C031105', (142, 148))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (216, 247))	('hypomethylation', 'Var', (41, 56))	('NFE2L3', 'Gene', '9603', (88, 94))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (216, 247))	('LAT', 'Gene', '27040', (80, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('HOXD3', 'Gene', '3232', (173, 178))	('over-expression', 'PosReg', (61, 76))	('HOXD3', 'Gene', (173, 178))	('patients', 'Species', '9606', (248, 256))	('NFE2L3', 'Gene', (88, 94))	('LAT', 'Gene', (80, 83))	('clear cell renal cell carcinoma', 'Disease', (216, 247))
119942	31777602	In the different stages of cancer development, abnormal hypermethylation of CpG islands in gene promoter regions will occur, which results in transcriptional silencing and abnormal expression of multiple key genes.	('transcriptional', 'MPA', (142, 157))	('results in', 'Reg', (131, 141))	('expression', 'MPA', (181, 191))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('hypermethylation', 'Var', (56, 72))	('abnormal', 'Reg', (172, 180))	('methyl', 'Chemical', 'MESH:C031105', (61, 67))	('silencing', 'NegReg', (158, 167))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
119943	31777602	Alterations in DNA methylation including hypermethylation of tumor suppressor genes and hypomethylation of oncogenes have been widely recognized as important regulators in cancer development.	('hypermethylation', 'Var', (41, 57))	('hypomethylation', 'MPA', (88, 103))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('Alterations', 'Var', (0, 11))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('methyl', 'Chemical', 'MESH:C031105', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('methyl', 'Chemical', 'MESH:C031105', (46, 52))	('methyl', 'Chemical', 'MESH:C031105', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('tumor suppressor', 'biological_process', 'GO:0051726', ('61', '77'))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('DNA', 'Gene', (15, 18))	('DNA methylation', 'biological_process', 'GO:0006306', ('15', '30'))	('cancer', 'Disease', (172, 178))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('61', '77'))	('tumor', 'Disease', (61, 66))
119944	31777602	found that DNA methylation was correlated with the clinical progressions of ccRCC.	('ccRCC', 'Disease', 'MESH:D002292', (76, 81))	('methylation', 'Var', (15, 26))	('DNA methylation', 'biological_process', 'GO:0006306', ('11', '26'))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('methyl', 'Chemical', 'MESH:C031105', (15, 21))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('ccRCC', 'Disease', (76, 81))	('correlated', 'Reg', (31, 41))	('clinical', 'Species', '191496', (51, 59))
119945	31777602	also discovered that the low expression of numerous tumor suppressor genes aroused by hypermethylation of enhancers and promoter regions leads to enhanced tumor cell biological activities in ccRCC.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('hypermethylation', 'Var', (86, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (191, 196))	('ccRCC', 'Disease', (191, 196))	('RCC', 'Phenotype', 'HP:0005584', (193, 196))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (52, 57))	('ccRCC', 'Disease', 'MESH:D002292', (191, 196))	('tumor', 'Disease', (155, 160))	('low', 'NegReg', (25, 28))	('methyl', 'Chemical', 'MESH:C031105', (91, 97))	('enhanced', 'PosReg', (146, 154))	('tumor suppressor', 'biological_process', 'GO:0051726', ('52', '68'))	('expression', 'MPA', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('52', '68'))
119965	31777602	GSE70303 includes 6 normal renal samples and 6 ccRCC samples, GSE113501 includes 12 normal samples and 132 ccRCC samples.	('GSE113501', 'Var', (62, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('ccRCC', 'Disease', (47, 52))	('ccRCC', 'Disease', 'MESH:D002292', (47, 52))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('ccRCC', 'Disease', (107, 112))	('ccRCC', 'Disease', 'MESH:D002292', (107, 112))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('GSE70303', 'Var', (0, 8))
119982	31777602	Result showed that all methylation degrees of LAT, HOXD3 and NFE2L3 were negatively correlated with respective expressions in ccRCC, Figure 4A-C (right panel).	('NFE2L3', 'Gene', (61, 67))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('methylation', 'Var', (23, 34))	('LAT', 'Gene', '27040', (46, 49))	('HOXD3', 'Gene', '3232', (51, 56))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('negatively', 'NegReg', (73, 83))	('ccRCC', 'Disease', (126, 131))	('methylation', 'biological_process', 'GO:0032259', ('23', '34'))	('NFE2L3', 'Gene', '9603', (61, 67))	('ccRCC', 'Disease', 'MESH:D002292', (126, 131))	('HOXD3', 'Gene', (51, 56))	('methyl', 'Chemical', 'MESH:C031105', (23, 29))	('expressions', 'MPA', (111, 122))	('LAT', 'Gene', (46, 49))
119985	31777602	Combining the positional information of the CpG sites on the chromosome on the Illumina HumanMethylation450 BeadChip and correlation coefficient scores, we selected the following CpG sites for further correlation expression analysis: LAT (cg16462073), HOXD3 (cg24000528) and NFE2L3 (cg16882373) (Table 4).	('HOXD3', 'Gene', (252, 257))	('NFE2L3', 'Gene', '9603', (275, 281))	('chromosome', 'cellular_component', 'GO:0005694', ('61', '71'))	('cg16462073', 'Var', (239, 249))	('LAT', 'Gene', (234, 237))	('NFE2L3', 'Gene', (275, 281))	('cg16882373', 'Var', (283, 293))	('HOXD3', 'Gene', '3232', (252, 257))	('LAT', 'Gene', '27040', (234, 237))	('cg24000528', 'Var', (259, 269))	('Human', 'Species', '9606', (88, 93))
119993	31777602	The hyper-methylation low-expression 5-year survival rate of LAT and NFE2L3 were higher, while the hypo-methylation high-expression 5-year survival rate of the gene HOXD3 was higher (Figure 6).	('methyl', 'Chemical', 'MESH:C031105', (104, 110))	('NFE2L3', 'Gene', '9603', (69, 75))	('methyl', 'Chemical', 'MESH:C031105', (10, 16))	('HOXD3', 'Gene', (165, 170))	('LAT', 'Gene', (61, 64))	('higher', 'PosReg', (81, 87))	('low-expression', 'NegReg', (22, 36))	('LAT', 'Gene', '27040', (61, 64))	('hyper-methylation', 'Var', (4, 21))	('NFE2L3', 'Gene', (69, 75))	('methylation', 'biological_process', 'GO:0032259', ('104', '115'))	('HOXD3', 'Gene', '3232', (165, 170))	('methylation', 'biological_process', 'GO:0032259', ('10', '21'))
120005	31777602	More evidence suggest that aberrant methylation profiles are one of the important potential mechanisms that causes severe diseases including cancers.	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('aberrant', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('methyl', 'Chemical', 'MESH:C031105', (36, 42))	('methylation', 'MPA', (36, 47))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('causes', 'Reg', (108, 114))	('cancers', 'Disease', (141, 148))
120006	31777602	In particular, hyper- or hypo-methylation in the promoter regions of genes influences the expressions of respective mRNA, which affects various stages in the tumor development.	('tumor', 'Disease', (158, 163))	('hypo-methylation', 'Var', (25, 41))	('hyper-', 'Var', (15, 21))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('mRNA', 'MPA', (116, 120))	('methyl', 'Chemical', 'MESH:C031105', (30, 36))	('expressions', 'MPA', (90, 101))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('affects', 'Reg', (128, 135))	('influences', 'Reg', (75, 85))
120028	31777602	Hypo-high expression of NFE2L3 may cause the tumor cells escaping from the detection of the immune system by inhibiting the anti-tumor immune effect, and consequently lead to proliferation and metastasis of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (207, 212))	('ccRCC', 'Disease', (207, 212))	('inhibiting', 'NegReg', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (129, 134))	('NFE2L3', 'Gene', (24, 30))	('lead to', 'Reg', (167, 174))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('ccRCC', 'Disease', 'MESH:D002292', (207, 212))	('metastasis', 'CPA', (193, 203))	('RCC', 'Phenotype', 'HP:0005584', (209, 212))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('NFE2L3', 'Gene', '9603', (24, 30))	('cause', 'Reg', (35, 40))	('Hypo-high expression', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('proliferation', 'CPA', (175, 188))
120029	31777602	Risk model construction, survival curve and ROC curve judgement were then proceeded, and the best risk model was obtained, risk score = LAT (gene expression level) * 0.2693 + HOXD3* (-0.3462) + NFE2L3 * 0.2414; with the median value 0.9140593 of risk score as the cut-off value, the 5-year survival rate in high-risk group of patients (risk score > 0.9140593) was 49.1% (95% CI, 40.5% - 59.7%), and that in low-risk group of patients was 76.2% (95% CI, 68.5% - 84.9%) and AUC was 0.698 as judged by ROC curve, having a good application value.	('risk score > 0.9140593', 'Var', (336, 358))	('HOXD3', 'Gene', (175, 180))	('LAT', 'Gene', (136, 139))	('NFE2L3', 'Gene', '9603', (194, 200))	('patients', 'Species', '9606', (326, 334))	('gene expression', 'biological_process', 'GO:0010467', ('141', '156'))	('patients', 'Species', '9606', (425, 433))	('0.9140593', 'Var', (233, 242))	('LAT', 'Gene', '27040', (136, 139))	('HOXD3', 'Gene', '3232', (175, 180))	('NFE2L3', 'Gene', (194, 200))
120043	28819235	In the validation cohort, MFI2-AS1 expression was independently associated with shorter disease-free survival (Hazard Ratio (HR) for relapse 3.5, p = 0.0001).	('MFI2-AS1', 'Gene', '100507057;4241;5729', (26, 34))	('disease-free survival', 'CPA', (88, 109))	('shorter', 'NegReg', (80, 87))	('expression', 'Var', (35, 45))	('MFI2-AS1', 'Gene', (26, 34))
120055	28819235	Historically, ccRCC is known for alterations of the VHL protein, which leads to the activation of the hypoxia inducible factor pathway that promotes angiogenesis.	('VHL', 'Gene', '7428', (52, 55))	('angiogenesis', 'CPA', (149, 161))	('activation', 'PosReg', (84, 94))	('promotes', 'PosReg', (140, 148))	('hypoxia', 'Disease', 'MESH:D000860', (102, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (14, 19))	('alterations', 'Var', (33, 44))	('hypoxia', 'Disease', (102, 109))	('angiogenesis', 'biological_process', 'GO:0001525', ('149', '161'))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('VHL', 'Gene', (52, 55))
120064	28819235	Thus, we chose to discriminate between patients with Leibovich scores <5 and those with scores >=5 to account for intermediate-risk patients with aggressive features and comply with current adjuvant trials.	('scores <5', 'Var', (63, 72))	('patients', 'Species', '9606', (132, 140))	('Leibovich', 'Gene', (53, 62))	('patients', 'Species', '9606', (39, 47))
120067	28819235	Patients with TFE3 or TFEB translocations and hereditary cancers were excluded because the natural history and oncogenic alterations might differ from those associated with sporadic ccRCC.	('TFEB', 'Gene', '7942', (22, 26))	('translocations', 'Var', (27, 41))	('TFE3', 'Gene', '7030', (14, 18))	('hereditary cancers', 'Disease', (46, 64))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('TFEB', 'Gene', (22, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (182, 187))	('Patients', 'Species', '9606', (0, 8))	('hereditary cancers', 'Disease', 'MESH:D009369', (46, 64))	('TFE3', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('ccRCC', 'Disease', (182, 187))
120087	28819235	We sought to identify pathways and mechanisms that could be altered by the dysregulation of MFI2-AS1 expression.	('MFI2-AS1', 'Gene', '100507057;4241;5729', (92, 100))	('dysregulation', 'Var', (75, 88))	('MFI2-AS1', 'Gene', (92, 100))	('altered', 'Reg', (60, 67))
120098	28819235	Correlations between MFI-2AS1 expression and copy-number variations found a high correlation with amplification of its locus at 3q29 (correlation coefficient = 0.34, corrected p-value = 4,44 x 10-16).	('correlation', 'Interaction', (81, 92))	('MFI-2AS1', 'Gene', (21, 29))	('amplification', 'Var', (98, 111))	('copy-number variations', 'Var', (45, 67))	('MFI-2AS1', 'Gene', '100507057', (21, 29))
120099	28819235	Among 13656 genes, we identified 541 genes that were upregulated in tumors with high expression of MFI2-AS1.	('MFI2-AS1', 'Gene', (99, 107))	('MFI2-AS1', 'Gene', '100507057;4241;5729', (99, 107))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('high expression', 'Var', (80, 95))	('upregulated', 'PosReg', (53, 64))
120125	28819235	To evaluate the clinical utility of MFI2-AS1 expression for DFS prediction, we stratified Leibovich subgroups according to MFI2-AS1 expression, namely Leibovich >=5+ MFI2-AS1 expression (L+ M+), Leibovich >=5+ no expression of MFI2-AS1 (L+ M-), Leibovich <5+ MFI2-AS1 expression (L- M+), and Leibovich <5+ no expression of MFI2-AS1 (L- M-).	('MFI2-AS1', 'Gene', (227, 235))	('MFI2-AS1', 'Gene', '100507057;4241;5729', (227, 235))	('MFI2-AS1', 'Gene', (323, 331))	('MFI2-AS1', 'Gene', '100507057;4241;5729', (323, 331))	('MFI2-AS1', 'Gene', (166, 174))	('Leibovich <5+', 'Var', (245, 258))	('MFI2-AS1', 'Gene', (36, 44))	('MFI2-AS1', 'Gene', (259, 267))	('MFI2-AS1', 'Gene', '100507057;4241;5729', (166, 174))	('MFI2-AS1', 'Gene', '100507057;4241;5729', (36, 44))	('MFI2-AS1', 'Gene', '100507057;4241;5729', (259, 267))	('MFI2-AS1', 'Gene', (123, 131))	('MFI2-AS1', 'Gene', '100507057;4241;5729', (123, 131))
120142	28819235	Detectable expression of MFI2-AS1 may result from amplification of its locus at 3q29, an event that may promote oncogenic mechanisms.	('MFI2-AS1', 'Gene', (25, 33))	('amplification', 'Var', (50, 63))	('MFI2-AS1', 'Gene', '100507057;4241;5729', (25, 33))	('result from', 'Reg', (38, 49))	('expression', 'MPA', (11, 21))	('promote', 'PosReg', (104, 111))
120160	33842477	The significant role that 2-HG plays has been certified in the pathophysiology of 2-hydroxyglutaric aciduria (2HGA), tumors harboring mutant isocitrate dehydrogenase 1/2 (IDH1/2mt), and in clear cell renal cell carcinoma (ccRCC).	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (189, 220))	('2-hydroxyglutaric aciduria', 'Phenotype', 'HP:0032278', (82, 108))	('2HGA', 'Phenotype', 'HP:0032278', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('aciduria', 'Phenotype', 'HP:0012072', (100, 108))	('tumors', 'Disease', (117, 123))	('mutant', 'Var', (134, 140))	('RCC', 'Disease', (224, 227))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (189, 220))	('ccRCC', 'Phenotype', 'HP:0006770', (222, 227))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (200, 220))	('isocitrate', 'Chemical', 'MESH:C034219', (141, 151))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('hydrogen', 'Chemical', 'MESH:D006859', (154, 162))	('2-HG', 'Chemical', 'MESH:C019417', (26, 30))	('RCC', 'Disease', 'MESH:C538614', (224, 227))	('clear cell renal cell carcinoma', 'Disease', (189, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))
120176	33842477	L-2HGA and the type I D-2HGA are derived from a mutation of L2HGDH and D2HGDH, respectively; the etiology of the type II D-2HGA is the gain-of-function mutation of IDH2, and that of the D,L-2-HGA is the mutation of SLC25A1, which acts as a mitochondrial citrate carrier.	('citrate', 'Chemical', 'MESH:D019343', (254, 261))	('gain-of-function', 'PosReg', (135, 151))	('D-2HG', 'Chemical', '-', (22, 27))	('L2HGDH', 'Gene', '79944', (60, 66))	('2HGA', 'Phenotype', 'HP:0032278', (2, 6))	('carrier', 'molecular_function', 'GO:0005215', ('262', '269'))	('2-HGA', 'Phenotype', 'HP:0032278', (190, 195))	('2HGA', 'Phenotype', 'HP:0032278', (24, 28))	('SLC25A1', 'Gene', '6576', (215, 222))	('IDH2', 'Gene', (164, 168))	('SLC25A1', 'Gene', (215, 222))	('D-2HG', 'Chemical', '-', (121, 126))	('2HGA', 'Phenotype', 'HP:0032278', (123, 127))	('D2HGDH', 'Gene', (71, 77))	('L-2HG', 'Chemical', '-', (0, 5))	('2-HG', 'Chemical', 'MESH:C019417', (190, 194))	('D-2HGA', 'Var', (121, 127))	('D2HGDH', 'Gene', '728294', (71, 77))	('L2HGDH', 'Gene', (60, 66))
120179	33842477	Two genomic sequencing studies published in 2008 and 2009 discovered the high mutation rate of IDH1 in glioblastoma and acute myeloid leukemia (AML), respectively.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (120, 142))	('AML', 'Phenotype', 'HP:0004808', (144, 147))	('AML', 'Disease', (144, 147))	('mutation', 'Var', (78, 86))	('leukemia', 'Phenotype', 'HP:0001909', (134, 142))	('acute myeloid leukemia', 'Disease', (120, 142))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (126, 142))	('IDH1', 'Gene', (95, 99))	('AML', 'Disease', 'MESH:D015470', (144, 147))	('glioblastoma', 'Disease', (103, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (103, 115))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (120, 142))	('glioblastoma', 'Phenotype', 'HP:0012174', (103, 115))
120180	33842477	A series of researches after then demonstrated the existence of IDH1/2mt in 70-80% of grade II/III glioma and secondary glioblastoma, and also in about 20% of AML.	('AML', 'Phenotype', 'HP:0004808', (159, 162))	('secondary glioblastoma', 'Disease', 'MESH:D005909', (110, 132))	('AML', 'Disease', (159, 162))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('IDH1/2mt', 'Var', (64, 72))	('secondary glioblastoma', 'Disease', (110, 132))	('III glioma', 'Disease', 'MESH:D005910', (95, 105))	('AML', 'Disease', 'MESH:D015470', (159, 162))	('III glioma', 'Disease', (95, 105))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))
120181	33842477	Besides that, IDH1/2 mutation also consists in chondrosarcoma, osteosarcoma, cholangiocarcinoma, and prostate cancer.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (77, 95))	('prostate cancer', 'Disease', (101, 116))	('chondrosarcoma', 'Disease', 'MESH:D002813', (47, 61))	('chondrosarcoma', 'Disease', (47, 61))	('consists in', 'Reg', (35, 46))	('osteosarcoma', 'Phenotype', 'HP:0002669', (63, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('IDH1/2', 'Gene', (14, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('osteosarcoma', 'Disease', (63, 75))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (77, 95))	('osteosarcoma', 'Disease', 'MESH:D012516', (63, 75))	('mutation', 'Var', (21, 29))	('prostate cancer', 'Disease', 'MESH:D011471', (101, 116))	('prostate cancer', 'Phenotype', 'HP:0012125', (101, 116))	('cholangiocarcinoma', 'Disease', (77, 95))
120182	33842477	To date, D-2HG has been supposed to trigger oncogenesis by altering the methylation pattern of DNA and histone, expression and activity of DNA repair proteins, collagen maturation, and immune response, although increasing attention is being paid to its antitumor effect.	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))	('DNA', 'Protein', (95, 98))	('D-2HG', 'Var', (9, 14))	('histone', 'Protein', (103, 110))	('activity', 'MPA', (127, 135))	('expression', 'MPA', (112, 122))	('tumor', 'Disease', (257, 262))	('oncogenesis', 'CPA', (44, 55))	('methylation', 'biological_process', 'GO:0032259', ('72', '83'))	('altering', 'Reg', (59, 67))	('immune response', 'CPA', (185, 200))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('D-2HG', 'Chemical', '-', (9, 14))	('methylation pattern', 'MPA', (72, 91))	('oncogenesis', 'biological_process', 'GO:0007048', ('44', '55'))	('immune response', 'biological_process', 'GO:0006955', ('185', '200'))	('collagen maturation', 'CPA', (160, 179))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('DNA repair', 'biological_process', 'GO:0006281', ('139', '149'))	('collagen', 'molecular_function', 'GO:0005202', ('160', '168'))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))
120183	33842477	As for the other enantiomers, L-2HG, its accumulation has been reported in clear cell renal cell carcinoma (ccRCC), which resulted from the copy number loss of L2HGDH.	('RCC', 'Disease', (110, 113))	('L2HGDH', 'Gene', '79944', (160, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('loss', 'NegReg', (152, 156))	('accumulation', 'PosReg', (41, 53))	('copy number', 'Var', (140, 151))	('clear cell renal cell carcinoma', 'Disease', (75, 106))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (75, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (75, 106))	('L-2HG', 'Chemical', '-', (30, 35))	('L2HGDH', 'Gene', (160, 166))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (86, 106))
120184	33842477	Increased L-2HG in ccRCC suppresses the methylcytosine dioxygenase (TET) and KDM6A, leading to hypermethylation of DNA and histone.	('RCC', 'Disease', (21, 24))	('hypermethylation', 'MPA', (95, 111))	('TET', 'Chemical', '-', (68, 71))	('oxygen', 'Chemical', 'MESH:D010100', (57, 63))	('histone', 'Protein', (123, 130))	('DNA', 'Protein', (115, 118))	('DNA', 'cellular_component', 'GO:0005574', ('115', '118'))	('ccRCC', 'Phenotype', 'HP:0006770', (19, 24))	('suppresses', 'NegReg', (25, 35))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('L-2HG', 'Var', (10, 15))	('L-2HG', 'Chemical', '-', (10, 15))	('KDM6A', 'Gene', (77, 82))	('methylcytosine dioxygenase', 'MPA', (40, 66))
120191	33842477	It was revealed that the mutation of IDH occurred earlier than the mutation of TP53 or the loss of 1p/19q.	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('mutation', 'Var', (25, 33))	('1p/19q', 'Protein', (99, 105))	('IDH', 'Gene', (37, 40))
120193	33842477	These facts suggest that IDH mutation represents an early event in gliomagenesis and leukemogenesis.	('mutation', 'Var', (29, 37))	('IDH', 'Gene', (25, 28))	('glioma', 'Disease', (67, 73))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('leukemogenesis', 'Disease', (85, 99))
120194	33842477	Introducing IDH1 R132H facilitated anchorage-independent growth of astrocytes lacking CDKN2A, ATRX, and PTEN, and the expression of IDH1/2 mutant impaired hepatocyte differentiation.	('ATRX', 'Gene', '546', (94, 98))	('impaired', 'NegReg', (146, 154))	('IDH1/2', 'Gene', (132, 138))	('lacking', 'NegReg', (78, 85))	('R132H', 'Var', (17, 22))	('IDH1', 'Gene', (12, 16))	('CDKN2A', 'Gene', '1029', (86, 92))	('R132H', 'Mutation', 'rs121913500', (17, 22))	('hepatocyte differentiation', 'biological_process', 'GO:0070365', ('155', '181'))	('hepatocyte differentiation', 'CPA', (155, 181))	('facilitated', 'PosReg', (23, 34))	('mutant', 'Var', (139, 145))	('ATRX', 'Gene', (94, 98))	('anchorage-independent growth', 'CPA', (35, 63))	('PTEN', 'Gene', (104, 108))	('CDKN2A', 'Gene', (86, 92))	('PTEN', 'Gene', '5728', (104, 108))
120197	33842477	These mutations in the active site of IDH disturb the interaction between its binding pocket and the beta-carboxyl of isocitrate.	('binding', 'Interaction', (78, 85))	('IDH', 'Gene', (38, 41))	('beta-carboxyl of isocitrate', 'Chemical', '-', (101, 128))	('binding', 'molecular_function', 'GO:0005488', ('78', '85'))	('interaction', 'Interaction', (54, 65))	('disturb', 'Reg', (42, 49))	('mutations', 'Var', (6, 15))
120198	33842477	It was reported that IDH1 R132 substitution altered the spatial position of Y139, and then the hydroxyl moiety of Y139 occupied the space of isocitrate and led to a closed conformation, thus favoring the binding of NADPH and the subsequent reduction of alpha-KG.	('IDH1 R132', 'Gene', (21, 30))	('closed conformation', 'MPA', (165, 184))	('NADPH', 'Gene', '1666', (215, 220))	('Y139', 'Var', (114, 118))	('spatial position', 'MPA', (56, 72))	('isocitrate', 'Chemical', 'MESH:C034219', (141, 151))	('favoring', 'PosReg', (191, 199))	('alpha-KG', 'Chemical', 'MESH:D007656', (253, 261))	('binding', 'molecular_function', 'GO:0005488', ('204', '211'))	('led to', 'Reg', (156, 162))	('altered', 'Reg', (44, 51))	('alpha-KG', 'Protein', (253, 261))	('binding', 'Interaction', (204, 211))	('reduction', 'NegReg', (240, 249))	('substitution', 'Var', (31, 43))	('Y139', 'Chemical', '-', (76, 80))	('Y139', 'Chemical', '-', (114, 118))	('NADPH', 'Gene', (215, 220))
120199	33842477	The disability in interacting with isocitrate of the mutant subunit could impede the conformation change of the wild-type (WT) one.	('interacting', 'Interaction', (18, 29))	('conformation change', 'MPA', (85, 104))	('isocitrate', 'Chemical', 'MESH:C034219', (35, 45))	('impede', 'NegReg', (74, 80))	('mutant', 'Var', (53, 59))
120204	33842477	L2HGDH knockdown promoted malignant phenotypes, while its expression did the opposite; moreover, its under-expression is associated with poor prognosis.	('under-expression', 'NegReg', (101, 117))	('promoted', 'PosReg', (17, 25))	('malignant phenotypes', 'CPA', (26, 46))	('L2HGDH', 'Gene', (0, 6))	('knockdown', 'Var', (7, 16))	('L2HGDH', 'Gene', '79944', (0, 6))
120208	33842477	L-2HG is significantly more potent in inhibiting these enzymes than D-2HG.	('D-2HG', 'Chemical', '-', (68, 73))	('L-2HG', 'Chemical', '-', (0, 5))	('inhibiting', 'NegReg', (38, 48))	('L-2HG', 'Var', (0, 5))
120211	33842477	When IDH is mutant, alpha-KG is consumed to generate a concentration as high as 3-35 mM of D-2HG, which far exceeds the IC50 of these alpha-KG-dependent dioxygenases; this provides clues to detect the mechanism of the tumorigenic effect of D-2HG, and similarly of L-2HG.	('C', 'Chemical', 'MESH:D002244', (121, 122))	('D-2HG', 'Chemical', '-', (91, 96))	('D-2HG', 'Var', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('D-2HG', 'Chemical', '-', (240, 245))	('mutant', 'Var', (12, 18))	('oxygen', 'Chemical', 'MESH:D010100', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('alpha-KG', 'Chemical', 'MESH:D007656', (134, 142))	('alpha-KG', 'Chemical', 'MESH:D007656', (20, 28))	('tumor', 'Disease', (218, 223))	('L-2HG', 'Chemical', '-', (264, 269))
120213	33842477	A similar phenomenon was also discovered in AML patients, and the IDH1/2 mutation exhibited an enrichment in patients with intermediate-risk cytogenetics.	('AML', 'Disease', 'MESH:D015470', (44, 47))	('patients', 'Species', '9606', (109, 117))	('AML', 'Disease', (44, 47))	('AML', 'Phenotype', 'HP:0004808', (44, 47))	('IDH1/2', 'Gene', (66, 72))	('mutation', 'Var', (73, 81))	('patients', 'Species', '9606', (48, 56))
120214	33842477	Subsequently, it was uncovered that the expression of IDH1mt could mirror the G-CIMP in low-grade glioma, and IDH1/2mt was found to increase the global level of 5-mC.	('IDH1/2mt', 'Var', (110, 118))	('increase', 'PosReg', (132, 140))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('C', 'Chemical', 'MESH:D002244', (80, 81))	('C', 'Chemical', 'MESH:D002244', (164, 165))	('glioma', 'Disease', (98, 104))	('G-CIMP', 'Chemical', '-', (78, 84))	('global level of 5-mC', 'MPA', (145, 165))	('IDH1mt', 'Var', (54, 60))
120215	33842477	The mutation of IDH1 and IDH2 is mutually exclusive with each other, suggesting that they transform cells in a similar way; consistent with that, the methylation change is similar between IDH1mt and IDH2mt AML samples.	('AML', 'Phenotype', 'HP:0004808', (206, 209))	('IDH1mt', 'Var', (188, 194))	('AML', 'Disease', 'MESH:D015470', (206, 209))	('methylation', 'MPA', (150, 161))	('methylation', 'biological_process', 'GO:0032259', ('150', '161'))	('AML', 'Disease', (206, 209))
120216	33842477	According to this, the 2016 WHO brain tumor classification classified (anaplastic) astrocytoma based on the existence of IDH mutation, and the diagnosis of (anaplastic) oligodendroglioma requires coexistence of IDH mutation and 1p/19q co-deletion.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('brain tumor', 'Disease', (32, 43))	('astrocytoma', 'Disease', 'MESH:D001254', (83, 94))	('astrocytoma', 'Disease', (83, 94))	('brain tumor', 'Phenotype', 'HP:0030692', (32, 43))	('IDH', 'Gene', (211, 214))	('oligodendroglioma', 'Disease', (169, 186))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('astrocytoma', 'Phenotype', 'HP:0009592', (83, 94))	('oligodendroglioma', 'Disease', 'MESH:D009837', (169, 186))	('1p/19q co-deletion', 'Var', (228, 246))	('brain tumor', 'Disease', 'MESH:D001932', (32, 43))
120218	33842477	Indeed, D-2HG treatment recapitulated IDH1-induced differentiation block and cytokine-independence in hematopoietic cells.	('recapitulated', 'NegReg', (24, 37))	('differentiation block', 'Disease', (51, 72))	('differentiation block', 'Disease', 'MESH:D006327', (51, 72))	('IDH1-induced', 'Gene', (38, 50))	('D-2HG', 'Var', (8, 13))	('D-2HG', 'Chemical', '-', (8, 13))
120219	33842477	Similarly, D-2HG supplement promoted anchorage-independent growth in glioma cells.	('glioma', 'Disease', (69, 75))	('anchorage-independent growth', 'CPA', (37, 65))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('D-2HG', 'Chemical', '-', (11, 16))	('D-2HG supplement', 'Var', (11, 27))	('promoted', 'PosReg', (28, 36))
120220	33842477	To investigate the tumorigenic mechanism of D-2HG and considering that D-2HG inhibits alpha-KG-dependent dioxygenases, a group transfected TF-1 human erythroleukemia cell line with a pool of shRNA targeting these enzymes.	('erythroleukemia', 'Disease', 'MESH:D004915', (150, 165))	('alpha-KG', 'Chemical', 'MESH:D007656', (86, 94))	('leukemia', 'Phenotype', 'HP:0001909', (157, 165))	('D-2HG', 'Chemical', '-', (71, 76))	('D-2HG', 'Chemical', '-', (44, 49))	('alpha-KG-dependent dioxygenases', 'Enzyme', (86, 117))	('human', 'Species', '9606', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('TF-1', 'CellLine', 'CVCL:0559', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('oxygen', 'Chemical', 'MESH:D010100', (107, 113))	('erythroleukemia', 'Disease', (150, 165))	('tumor', 'Disease', (19, 24))	('inhibits', 'NegReg', (77, 85))	('D-2HG', 'Var', (71, 76))
120221	33842477	A relative enrichment of shRNAs targeting TET2 but not its paralog TET1 was detected after a period of culturing; TET2 knockdown recapitulated the transforming effect of IDH1mt and D-2HG in TF-1 cells, indicating that TET2 may mediate transformation induced by IDH1mt and D-2HG.	('TET2', 'Gene', (42, 46))	('TET2', 'Gene', '54790', (114, 118))	('TET2', 'Gene', '54790', (218, 222))	('TF-1', 'CellLine', 'CVCL:0559', (190, 194))	('TET2', 'Gene', (114, 118))	('D-2HG', 'Chemical', '-', (181, 186))	('D-2HG', 'Chemical', '-', (272, 277))	('TET1', 'Gene', (67, 71))	('knockdown', 'Var', (119, 128))	('TET2', 'Gene', (218, 222))	('TET2', 'Gene', '54790', (42, 46))	('TET1', 'Gene', '80312', (67, 71))
120223	33842477	The co-expression of IDH1/2mt and the catalytic domain of TET1 or TET2 decrease 5-hmC to a nearly undetectable level, suggesting that IDHmt caused abnormal DNA methylation by inhibiting TETs.	('inhibiting', 'NegReg', (175, 185))	('TET2', 'Gene', (66, 70))	('TET1', 'Gene', (58, 62))	('DNA methylation', 'biological_process', 'GO:0006306', ('156', '171'))	('decrease', 'NegReg', (71, 79))	('DNA', 'cellular_component', 'GO:0005574', ('156', '159'))	('IDHmt', 'Var', (134, 139))	('C', 'Chemical', 'MESH:D002244', (84, 85))	('TETs', 'MPA', (186, 190))	('TET1', 'Gene', '80312', (58, 62))	('TETs', 'Chemical', 'MESH:C010349', (186, 190))	('5-hmC', 'MPA', (80, 85))	('TET2', 'Gene', '54790', (66, 70))	('DNA methylation', 'MPA', (156, 171))
120224	33842477	What is more, TET2 mutation is frequently observed in myeloid cancers, in about 24% of secondary AML and 22% of chronic myelomonocytic leukemia, while it is mutually exclusive with mutation in IDH.	('TET2', 'Gene', (14, 18))	('myelomonocytic leukemia', 'Disease', (120, 143))	('mutation', 'Var', (19, 27))	('AML', 'Phenotype', 'HP:0004808', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('AML', 'Disease', (97, 100))	('myelomonocytic leukemia', 'Disease', 'MESH:D054429', (120, 143))	('myeloid cancers', 'Disease', (54, 69))	('myeloid cancers', 'Disease', 'MESH:D009369', (54, 69))	('leukemia', 'Phenotype', 'HP:0001909', (135, 143))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('TET2', 'Gene', '54790', (14, 18))	('AML', 'Disease', 'MESH:D015470', (97, 100))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (112, 143))	('observed', 'Reg', (42, 50))
120226	33842477	The deficiency of TET2 induced a similar methylome with that IDHmt does in glioma.	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('TET2', 'Gene', (18, 22))	('methylome', 'MPA', (41, 50))	('induced', 'Reg', (23, 30))	('glioma', 'Disease', (75, 81))	('deficiency', 'Var', (4, 14))	('TET2', 'Gene', '54790', (18, 22))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
120227	33842477	These facts all suggest that TET2 deficiency mediates the tumorigenic effects of mutant IDH and D-2HG.	('TET2', 'Gene', '54790', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('deficiency', 'Var', (34, 44))	('TET2', 'Gene', (29, 33))	('D-2HG', 'Var', (96, 101))	('IDH', 'Gene', (88, 91))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mutant', 'Var', (81, 87))	('D-2HG', 'Chemical', '-', (96, 101))
120229	33842477	The infection of mutant IDH enriched 5-mC at the promoter of differentiation-associated genes and induced genes associated with stem cell.	('infection', 'Disease', (4, 13))	('IDH', 'Gene', (24, 27))	('infection', 'Disease', 'MESH:D007239', (4, 13))	('induced', 'PosReg', (98, 105))	('C', 'Chemical', 'MESH:D002244', (40, 41))	('differentiation-associated genes', 'Gene', (61, 93))	('mutant', 'Var', (17, 23))	('genes', 'MPA', (106, 111))
120231	33842477	In conclusion, aberrant DNA methylation mediated the oncogenic effect of IDHmt and D-2HG.	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('D-2HG', 'Var', (83, 88))	('oncogenic effect', 'CPA', (53, 69))	('DNA methylation', 'biological_process', 'GO:0006306', ('24', '39'))	('D-2HG', 'Chemical', '-', (83, 88))	('DNA methylation', 'Protein', (24, 39))	('aberrant', 'Var', (15, 23))
120233	33842477	Both increased L-2HG and L2HGDH knockdown led to diminished 5-hmC level, which is strongly associated with tumor aggressiveness and an unfavorable prognosis, and restoring the activity of TET2 leads to inhibition of ccRCC growth both in vitro and in vivo.	('L-2HG', 'Var', (15, 20))	('C', 'Chemical', 'MESH:D002244', (220, 221))	('ccRCC', 'Phenotype', 'HP:0006770', (216, 221))	('activity', 'MPA', (176, 184))	('increased', 'PosReg', (5, 14))	('TET2', 'Gene', '54790', (188, 192))	('L2HGDH', 'Gene', (25, 31))	('aggressiveness', 'Phenotype', 'HP:0000718', (113, 127))	('tumor aggressiveness', 'Disease', (107, 127))	('RCC', 'Disease', (218, 221))	('L2HGDH', 'Gene', '79944', (25, 31))	('diminished', 'NegReg', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('C', 'Chemical', 'MESH:D002244', (64, 65))	('inhibition', 'NegReg', (202, 212))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (107, 127))	('knockdown', 'Var', (32, 41))	('L-2HG', 'Chemical', '-', (15, 20))	('TET2', 'Gene', (188, 192))	('5-hmC level', 'MPA', (60, 71))	('C', 'Chemical', 'MESH:D002244', (219, 220))
120238	33842477	As reported, the mutant IDH2 or its product D-2HG compromised MyoD-driven differentiation in fibroblast cell line.	('D-2HG', 'Chemical', '-', (44, 49))	('IDH2', 'Gene', (24, 28))	('MyoD', 'Gene', '4654', (62, 66))	('MyoD', 'Gene', (62, 66))	('compromised', 'NegReg', (50, 61))	('mutant', 'Var', (17, 23))
120239	33842477	Mechanistically, D-2HG induced H3K9me3 at those MyoD-binding loci, decreasing their accessibility to MyoD.	('MyoD', 'Gene', '4654', (101, 105))	('decreasing', 'NegReg', (67, 77))	('H3K9me3', 'Protein', (31, 38))	('induced', 'Reg', (23, 30))	('D-2HG', 'Chemical', '-', (17, 22))	('D-2HG', 'Var', (17, 22))	('MyoD', 'Gene', '4654', (48, 52))	('MyoD-binding', 'molecular_function', 'GO:0043426', ('48', '60'))	('MyoD', 'Gene', (48, 52))	('MyoD', 'Gene', (101, 105))
120240	33842477	Likewise, IDH2mt expression or D-2HG treatment block adipocyte differentiation; this is correlated with an enrichment of the repressive mark H3K9me3 at some lineage-specific gene.	('D-2HG', 'Chemical', '-', (31, 36))	('adipocyte differentiation', 'CPA', (53, 78))	('D-2HG', 'Var', (31, 36))	('adipocyte differentiation', 'biological_process', 'GO:0045444', ('53', '78'))	('block', 'NegReg', (47, 52))	('IDH2mt expression', 'Var', (10, 27))
120243	33842477	As reported, L2HGDH overexpress decreased H3K27me3 and H3K9me3 in RCC cell line.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('L2HGDH', 'Gene', (13, 19))	('overexpress', 'Var', (20, 31))	('H3K9me3', 'Protein', (55, 62))	('L2HGDH', 'Gene', '79944', (13, 19))	('H3K27me3', 'Protein', (42, 50))	('RCC', 'Disease', (66, 69))
120245	33842477	In accordance with that, the H3K27 histone demethylase KDM6A is frequently mutated in renal carcinoma, KDM6A knockdown recapitulates the malignant phenotypes that L-2HG induced, and PRC2 knockdown did the opposite.	('KDM6A', 'Gene', (103, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('demethylase', 'Gene', (43, 54))	('demethylase', 'Gene', '8932', (43, 54))	('C', 'Chemical', 'MESH:D002244', (184, 185))	('renal carcinoma', 'Disease', 'MESH:C538614', (86, 101))	('L-2HG', 'Chemical', '-', (163, 168))	('knockdown', 'Var', (109, 118))	('renal carcinoma', 'Disease', (86, 101))	('renal carcinoma', 'Phenotype', 'HP:0005584', (86, 101))
120256	33842477	Although D-2HG was not discussed in this research, it can be concluded that expression of IDHmt upregulated HIF-1alpha.	('IDHmt', 'Gene', (90, 95))	('HIF-1alpha', 'Gene', (108, 118))	('upregulated', 'PosReg', (96, 107))	('D-2HG', 'Chemical', '-', (9, 14))	('expression', 'Var', (76, 86))	('HIF-1alpha', 'Gene', '3091', (108, 118))
120258	33842477	EGLN1 knockdown comprised the proliferation of IDH1mt astrocyte while downregulating HIF-1alpha did the opposite; these results suggest that IDHmt-derived D-2HG activates EGLN1, and subsequent downregulation of HIF-1alpha may lead to the tumorigenesis of glioma.	('HIF-1alpha', 'Gene', '3091', (211, 221))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('HIF-1alpha', 'Gene', (85, 95))	('D-2HG', 'Chemical', '-', (155, 160))	('EGLN1', 'Gene', '54583', (0, 5))	('EGLN1', 'Gene', (0, 5))	('lead to', 'Reg', (226, 233))	('HIF-1alpha', 'Gene', (211, 221))	('glioma', 'Disease', (255, 261))	('glioma', 'Disease', 'MESH:D005910', (255, 261))	('tumor', 'Disease', (238, 243))	('activates', 'PosReg', (161, 170))	('EGLN1', 'Gene', '54583', (171, 176))	('downregulation', 'NegReg', (193, 207))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('glioma', 'Phenotype', 'HP:0009733', (255, 261))	('EGLN1', 'Gene', (171, 176))	('HIF-1alpha', 'Gene', '3091', (85, 95))	('D-2HG', 'Var', (155, 160))
120261	33842477	D-2HG rather than L-2HG could recapture the transforming effect of IDHmt expression, and this is related to its discrimination in inhibiting EGLN1.	('inhibiting', 'NegReg', (130, 140))	('L-2HG', 'Chemical', '-', (18, 23))	('D-2HG', 'Var', (0, 5))	('IDHmt expression', 'Gene', (67, 83))	('EGLN1', 'Gene', '54583', (141, 146))	('transforming', 'MPA', (44, 56))	('D-2HG', 'Chemical', '-', (0, 5))	('recapture', 'NegReg', (30, 39))	('EGLN1', 'Gene', (141, 146))
120262	33842477	It seems that, in astrocytes and hematopoietic cells, HIF may act as a tumor suppressor, and the mutation of IDH inhibits HIF signaling through D-2HG and promotes oncogenesis.	('tumor suppressor', 'biological_process', 'GO:0051726', ('71', '87'))	('mutation', 'Var', (97, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('71', '87'))	('promotes', 'PosReg', (154, 162))	('oncogenesis', 'CPA', (163, 174))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('D-2HG', 'Chemical', '-', (144, 149))	('D-2HG', 'MPA', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('HIF signaling', 'MPA', (122, 135))	('signaling', 'biological_process', 'GO:0023052', ('126', '135'))	('IDH', 'Gene', (109, 112))	('tumor', 'Disease', (71, 76))	('inhibits', 'NegReg', (113, 121))	('oncogenesis', 'biological_process', 'GO:0007048', ('163', '174'))
120265	33842477	They attributed the result that PHD2 catalysis proceeded in the presence of D-2HG rather than L-2HG in the research of Koivunen P. to the more potent inhibition of L-2HG than D-2HG and/or the contamination of D-2HG by alpha-KG.	('PHD2', 'Gene', '54583', (32, 36))	('PHD2', 'Gene', (32, 36))	('L-2HG', 'Chemical', '-', (94, 99))	('alpha-KG', 'Chemical', 'MESH:D007656', (218, 226))	('D-2HG', 'Chemical', '-', (175, 180))	('D-2HG', 'Chemical', '-', (209, 214))	('PHD', 'molecular_function', 'GO:0050175', ('32', '35'))	('inhibition', 'NegReg', (150, 160))	('L-2HG', 'Var', (164, 169))	('D-2HG', 'Var', (76, 81))	('Koivunen P', 'Chemical', '-', (119, 129))	('D-2HG', 'Chemical', '-', (76, 81))	('L-2HG', 'Chemical', '-', (164, 169))
120266	33842477	Further researches are required to explore the conditions dictating the influence of D-2HG on PHD and the mechanisms behind it.	('PHD', 'molecular_function', 'GO:0050175', ('94', '97'))	('D-2HG', 'Var', (85, 90))	('D-2HG', 'Chemical', '-', (85, 90))	('PHD', 'Disease', 'MESH:D011547', (94, 97))	('PHD', 'Disease', (94, 97))
120270	33842477	L-2HG and D-2HG are found to inhibit ALKBH2/3 in a pathophysiologically relevant level, restraining their activity in repairing m1A and m3C in ssDNA and dsDNA.	('dsDNA', 'Disease', (153, 158))	('m3C', 'Chemical', '-', (136, 139))	('restraining', 'NegReg', (88, 99))	('inhibit', 'NegReg', (29, 36))	('D-2HG', 'Var', (10, 15))	('L-2HG', 'Var', (0, 5))	('m1A', 'Chemical', '-', (128, 131))	('ssDNA', 'Disease', (143, 148))	('ALKBH2/3', 'Gene', (37, 45))	('D-2HG', 'Chemical', '-', (10, 15))	('L-2HG', 'Chemical', '-', (0, 5))	('activity', 'MPA', (106, 114))	('ALKBH2/3', 'Gene', '121642;221120', (37, 45))
120271	33842477	DNA repair deficiency may help to accumulate mutations in the genome, thereby contributing to tumorigenesis; this is consistent with the fact IDH mutation is an early event in gliomagenesis and leukemogenesis as well as the higher mutation load in IDmt LGG compared with IDHwt LGG in TCGA database.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('DNA repair', 'biological_process', 'GO:0006281', ('0', '10'))	('glioma', 'Disease', (176, 182))	('contributing', 'Reg', (78, 90))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('C', 'Chemical', 'MESH:D002244', (285, 286))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('tumor', 'Disease', (94, 99))	('IDmt LGG', 'Var', (248, 256))	('leukemogenesis', 'Disease', (194, 208))	('mutation', 'Var', (146, 154))	('mutation', 'Var', (231, 239))
120273	33842477	This phenomenon was related to the inhibition of D-2HG on prolyl-4-hydroxylases I, II, and III (C-P4H I-III), and procollagen-lysine 2-oxoglutarate 5-dioxygenases 1, 2, and 3 (Plod1-3), which mediated collagen hydroxylation.	('prolyl-4-hydroxylases I', 'Enzyme', (58, 81))	('collagen hydroxylation', 'MPA', (201, 223))	('C', 'Chemical', 'MESH:D002244', (96, 97))	('procollagen-lysine 2-oxoglutarate 5-dioxygenases 1, 2, and 3', 'Gene', '5351;5352;8985', (114, 174))	('D-2HG', 'Var', (49, 54))	('D-2HG', 'Chemical', '-', (49, 54))	('Plod1-3', 'Gene', (176, 183))	('Plod1-3', 'Gene', '5351;5352;8985', (176, 183))	('inhibition', 'NegReg', (35, 45))	('collagen', 'molecular_function', 'GO:0005202', ('201', '209'))
120275	33842477	Mutation of genes encoding collagen is frequent in glioblastoma (GBM); what is more, IDHmt seldom coexists with basement membrane-related gene mutations.	('basement membrane', 'cellular_component', 'GO:0005604', ('112', '129'))	('frequent', 'Reg', (39, 47))	('Mutation', 'Var', (0, 8))	('collagen', 'molecular_function', 'GO:0005202', ('27', '35'))	('glioblastoma', 'Disease', (51, 63))	('glioblastoma', 'Disease', 'MESH:D005909', (51, 63))	('GBM', 'Phenotype', 'HP:0012174', (65, 68))	('glioblastoma', 'Phenotype', 'HP:0012174', (51, 63))
120276	33842477	Therefore, collagen immaturation mediated by D-2HG may be involved in GBM tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('involved', 'Reg', (58, 66))	('GBM', 'Disease', (70, 73))	('D-2HG', 'Var', (45, 50))	('collagen', 'molecular_function', 'GO:0005202', ('11', '19'))	('tumor', 'Disease', (74, 79))	('D-2HG', 'Chemical', '-', (45, 50))	('GBM', 'Phenotype', 'HP:0012174', (70, 73))
120277	33842477	D-2HG is not only a cancer cell-autonomous oncometabolite, but it also contributes to an immunosuppressive milieu by exerting on immune cells both directly and indirectly (Figure 2).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('immunosuppressive milieu', 'MPA', (89, 113))	('D-2HG', 'Var', (0, 5))	('D-2HG', 'Chemical', '-', (0, 5))	('exerting', 'Reg', (117, 125))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))
120278	33842477	By inhibiting the expression and activation of STAT1, D-2HG attenuates chemokine CXCL10 secretion in glioma cell lines, thereby suppressing cytotoxic T lymphocyte infiltration in the tumor site.	('STAT1', 'Gene', '6772', (47, 52))	('secretion', 'biological_process', 'GO:0046903', ('88', '97'))	('D-2HG', 'Var', (54, 59))	('activation', 'PosReg', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('CXCL10', 'Gene', '3627', (81, 87))	('inhibiting', 'NegReg', (3, 13))	('CXCL10', 'Gene', (81, 87))	('glioma', 'Disease', (101, 107))	('D-2HG', 'Chemical', '-', (54, 59))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('expression', 'MPA', (18, 28))	('tumor', 'Disease', (183, 188))	('suppressing', 'NegReg', (128, 139))	('STAT1', 'Gene', (47, 52))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('attenuates', 'NegReg', (60, 70))
120280	33842477	Although D-2HG is poorly cell-penetrative, the transporter SLC13A3 can import D-2HG into T lymphocyte.	('D-2HG', 'Chemical', '-', (78, 83))	('D-2HG', 'Var', (78, 83))	('D-2HG', 'Chemical', '-', (9, 14))	('SLC13A3', 'Gene', '64849', (59, 66))	('SLC13A3', 'Gene', (59, 66))
120281	33842477	An excess of D-2HG in T lymphocyte suppresses ATPase, subsequently reducing ATP and attenuating PLC-gamma phosphorylation, which both resulted in decreased nuclear translocation of the nuclear factor of activated T cells (NFAT), which is of much concern in T lymphocyte cell activation.	('cell activation', 'biological_process', 'GO:0001775', ('270', '285'))	('D-2HG', 'Var', (13, 18))	('reducing', 'NegReg', (67, 75))	('phosphorylation', 'biological_process', 'GO:0016310', ('106', '121'))	('ATP', 'Chemical', 'MESH:D000255', (76, 79))	('D-2HG', 'Chemical', '-', (13, 18))	('ATP', 'Chemical', 'MESH:D000255', (46, 49))	('ATPase', 'Gene', '1769', (46, 52))	('decreased', 'NegReg', (146, 155))	('attenuating', 'NegReg', (84, 95))	('nuclear translocation', 'MPA', (156, 177))	('C', 'Chemical', 'MESH:D002244', (98, 99))	('PLC', 'cellular_component', 'GO:0042824', ('96', '99'))	('PLC-gamma phosphorylation', 'MPA', (96, 121))	('suppresses', 'NegReg', (35, 45))	('ATP', 'MPA', (76, 79))	('ATPase', 'Gene', (46, 52))
120282	33842477	Moreover, D-2HG also diminished putrescine, which stimulated T lymphocyte cell proliferation.	('T lymphocyte cell proliferation', 'CPA', (61, 92))	('cell proliferation', 'biological_process', 'GO:0008283', ('74', '92'))	('putrescine', 'MPA', (32, 42))	('D-2HG', 'Var', (10, 15))	('stimulated', 'PosReg', (50, 60))	('D-2HG', 'Chemical', '-', (10, 15))	('diminished', 'NegReg', (21, 31))	('putrescine', 'Chemical', 'MESH:D011700', (32, 42))
120283	33842477	D-2HG impairs Th17 polarization by destabilizing HIF-1; this is enantiomer-specific since L-2HG did not exert such effect, although IDHmt glioblastoma expresses significantly lower PD-L1 compared with IDHwt, and there is another research revealing that D-2HG induces transient PD-L1 promoter hypermethylation, thus lowering the expression of PD-L1.	('PD-L1', 'Gene', (342, 347))	('impairs', 'NegReg', (6, 13))	('IDHmt glioblastoma', 'Disease', (132, 150))	('PD-L1', 'Gene', '29126', (342, 347))	('IDHmt glioblastoma', 'Disease', 'MESH:D005909', (132, 150))	('promoter hypermethylation', 'MPA', (283, 308))	('destabilizing', 'NegReg', (35, 48))	('HIF-1', 'Gene', '3091', (49, 54))	('HIF-1', 'Gene', (49, 54))	('PD-L1', 'Gene', (277, 282))	('PD-L1', 'Gene', (181, 186))	('PD-L1', 'Gene', '29126', (277, 282))	('D-2HG', 'Var', (253, 258))	('PD-L1', 'Gene', '29126', (181, 186))	('glioblastoma', 'Phenotype', 'HP:0012174', (138, 150))	('L-2HG', 'Chemical', '-', (90, 95))	('lower', 'NegReg', (175, 180))	('D-2HG', 'Chemical', '-', (0, 5))	('lowering', 'NegReg', (315, 323))	('D-2HG', 'Chemical', '-', (253, 258))	('Th17 polarization', 'CPA', (14, 31))	('expression', 'MPA', (328, 338))
120284	33842477	On the whole, D-2HG suppresses antitumor T cell immunity.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('D-2HG', 'Var', (14, 19))	('suppresses', 'NegReg', (20, 30))	('D-2HG', 'Chemical', '-', (14, 19))
120285	33842477	Combining IDH1 inhibitor with anti-PD-1 improved prognosis in C57BL/6J mice bearing IDH1mt glioma.	('mice', 'Species', '10090', (71, 75))	('C', 'Chemical', 'MESH:D002244', (62, 63))	('prognosis', 'CPA', (49, 58))	('glioma', 'Disease', (91, 97))	('PD-1', 'Gene', '18566', (35, 39))	('improved', 'PosReg', (40, 48))	('IDH1mt', 'Var', (84, 90))	('PD-1', 'Gene', (35, 39))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('glioma', 'Disease', 'MESH:D005910', (91, 97))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
120287	33842477	Tumor vaccine is another way of immunotherapy besides blocking the immune checkpoint, and the mutant IDH is quite a tumor-specific neoantigen.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('immune checkpoint', 'CPA', (67, 84))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('mutant', 'Var', (94, 100))	('IDH', 'Gene', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('blocking', 'NegReg', (54, 62))	('tumor', 'Disease', (116, 121))
120288	33842477	Vaccination of transgenic mice expressing human major histocompatibility complexes (MHCs) with a peptide in the IDH1mt induced a CD4 + T-dependent immune response suppresses the growth of the IDH1mt sarcoma in an MHC-humanized animal model.	('suppresses', 'NegReg', (163, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('IDH1mt', 'Gene', (112, 118))	('C', 'Chemical', 'MESH:D002244', (86, 87))	('human', 'Species', '9606', (217, 222))	('human', 'Species', '9606', (42, 47))	('immune response', 'biological_process', 'GO:0006955', ('147', '162'))	('transgenic mice', 'Species', '10090', (15, 30))	('growth', 'MPA', (178, 184))	('C', 'Chemical', 'MESH:D002244', (129, 130))	('C', 'Chemical', 'MESH:D002244', (215, 216))	('peptide', 'Var', (97, 104))	('sarcoma', 'Disease', 'MESH:D012509', (199, 206))	('CD4', 'Gene', (129, 132))	('CD4', 'Gene', '920', (129, 132))	('sarcoma', 'Disease', (199, 206))
120289	33842477	Consistent with this, another group immunized mice bearing intracranial glioma with peptides encompassing the IDH1 mutation site, which significantly prolonged the survival of mice bearing IDH1mt and even cured 25% of them.	('prolonged', 'PosReg', (150, 159))	('intracranial glioma', 'Disease', (59, 78))	('cured', 'NegReg', (205, 210))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('survival', 'CPA', (164, 172))	('IDH1mt', 'Var', (189, 195))	('mice', 'Species', '10090', (176, 180))	('mice', 'Species', '10090', (46, 50))	('intracranial glioma', 'Disease', 'MESH:D005910', (59, 78))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('mutation', 'Var', (115, 123))	('IDH1', 'Gene', (110, 114))
120292	33842477	Apart from adaptive immunity, D-2HG also limits the innate defense against tumor.	('D-2HG', 'Chemical', '-', (30, 35))	('D-2HG', 'Var', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('limits', 'NegReg', (41, 47))
120298	33842477	Downregulating NKG2D helps tumor cells to escape cytolysis by NK cells, and the pretreatment of D-2HG confers IDHwt astrocytes resistance to that, restoring NKG2DL expression by the DNMT inhibitor decitabine, which significantly prompted NK-induced cytotoxicity.	('restoring', 'PosReg', (147, 156))	('cytotoxicity', 'Disease', (249, 261))	('cytotoxicity', 'Disease', 'MESH:D064420', (249, 261))	('NKG2D', 'Gene', (15, 20))	('NKG2D', 'Gene', (157, 162))	('tumor', 'Disease', (27, 32))	('NKG2D', 'Gene', '22914', (15, 20))	('decitabine', 'Chemical', 'MESH:D000077209', (197, 207))	('NKG2D', 'Gene', '22914', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('Downregulating', 'Var', (0, 14))	('NKG2DL', 'Gene', (157, 163))	('D-2HG', 'Chemical', '-', (96, 101))	('NKG2DL', 'Gene', '3821', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cytolysis', 'biological_process', 'GO:0019835', ('49', '58'))	('expression', 'MPA', (164, 174))	('DNMT', 'Gene', '1786', (182, 186))	('DNMT', 'Gene', (182, 186))
120299	33842477	From the above, we can conclude that 2-HG triggers tumorigenesis through multiple mechanisms.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('2-HG', 'Var', (37, 41))	('tumor', 'Disease', (51, 56))	('triggers', 'Reg', (42, 50))	('2-HG', 'Chemical', 'MESH:C019417', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
120301	33842477	For example, D-2HG sensitizes IDHmt malignancies to DNA damage.	('D-2HG', 'Var', (13, 18))	('malignancies', 'Disease', (36, 48))	('D-2HG', 'Chemical', '-', (13, 18))	('sensitizes', 'Reg', (19, 29))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('malignancies', 'Disease', 'MESH:D009369', (36, 48))
120302	33842477	Chemotherapy combining procarbazine, CCNU/lomustine, and vincristine (PCV) attains a better prognosis in oligodendroglial patients harboring IDHmt compared with those with the WT allele.	('procarbazine', 'Chemical', 'MESH:D011344', (23, 35))	('lomustine', 'Chemical', 'MESH:D008130', (42, 51))	('C', 'Chemical', 'MESH:D002244', (37, 38))	('oligodendroglial', 'Disease', (105, 121))	('patients', 'Species', '9606', (122, 130))	('CCNU', 'Chemical', 'MESH:D008130', (37, 41))	('C', 'Chemical', 'MESH:D002244', (71, 72))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('IDHmt', 'Var', (141, 146))	('vincristine', 'Chemical', 'MESH:D014750', (57, 68))	('C', 'Chemical', 'MESH:D002244', (38, 39))
120303	33842477	Mechanistically, among the three regimens in PCV therapy, CCNU and procarbazine are DNA alkylating agents, and the DNA repair enzymes ALKBH2/3 are inhibited by D-2HG, thereby sensitizing tumor cells to them.	('C', 'Chemical', 'MESH:D002244', (58, 59))	('D-2HG', 'Chemical', '-', (160, 165))	('ALKBH2/3', 'Gene', '121642;221120', (134, 142))	('CCNU', 'Chemical', 'MESH:D008130', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('DNA repair', 'biological_process', 'GO:0006281', ('115', '125'))	('procarbazine', 'Chemical', 'MESH:D011344', (67, 79))	('C', 'Chemical', 'MESH:D002244', (46, 47))	('DNA', 'cellular_component', 'GO:0005574', ('115', '118'))	('tumor', 'Disease', (187, 192))	('sensitizing', 'Reg', (175, 186))	('inhibited', 'NegReg', (147, 156))	('ALKBH2/3', 'Gene', (134, 142))	('C', 'Chemical', 'MESH:D002244', (59, 60))	('D-2HG', 'Var', (160, 165))
120306	33842477	D-2HG attenuates the transcription of ATM by increasing the repressive mark H3K9me3 at its promoter, making for a susceptibility to DNA damage.	('ATM', 'Gene', '472', (38, 41))	('attenuates', 'NegReg', (6, 16))	('D-2HG', 'Var', (0, 5))	('repressive mark', 'MPA', (60, 75))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('D-2HG', 'Chemical', '-', (0, 5))	('transcription', 'MPA', (21, 34))	('transcription', 'biological_process', 'GO:0006351', ('21', '34'))	('increasing', 'PosReg', (45, 55))	('ATM', 'Gene', (38, 41))	('susceptibility', 'Reg', (114, 128))	('H3K9me3', 'Protein', (76, 83))
120308	33842477	KDM4B overexpression rescues the DNA repair deficiency in IDH mutant cell but not in IDH WT cells.	('DNA repair', 'biological_process', 'GO:0006281', ('33', '43'))	('rescues', 'PosReg', (21, 28))	('deficiency', 'NegReg', (44, 54))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('KDM4B', 'Gene', (0, 5))	('IDH mutant', 'Var', (58, 68))	('KDM4B', 'Gene', '23030', (0, 5))	('DNA repair', 'MPA', (33, 43))
120309	33842477	In general, D-2HG suppresses DNA repair; as a consequence, synthetic lethal interaction can be established between IDHmt and DNA damage agents.	('D-2HG', 'Chemical', '-', (12, 17))	('DNA repair', 'biological_process', 'GO:0006281', ('29', '39'))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('DNA', 'cellular_component', 'GO:0005574', ('125', '128'))	('suppresses', 'NegReg', (18, 28))	('DNA repair', 'MPA', (29, 39))	('D-2HG', 'Var', (12, 17))
120314	33842477	Both colorectal carcinoma and astrocyte cell lines expressing IDH1/2mt exhibited a hypersensitivity to ionizing radiation or H2O2 compared with those with IDH1/2wt.	('hypersensitivity', 'biological_process', 'GO:0002524', ('83', '99'))	('IDH1/2mt', 'Var', (62, 70))	('H2O2', 'Chemical', 'MESH:D006861', (125, 129))	('colorectal carcinoma', 'Disease', (5, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('hypersensitivity to ionizing radiation', 'Disease', 'MESH:D004194', (83, 121))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (5, 25))	('hypersensitivity to ionizing radiation', 'Disease', (83, 121))	('hypersensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (83, 121))
120317	33842477	The vulnerability to oxidative stress also derives from the competitive inhibition of D-2HG on BCAT1/2, which lowers glutamate and prompts a dependence on the glutaminase to generate glutamate and downstream glutathione, which functions in neutralize intracellular reactive oxygen species (ROS).	('reactive oxygen species', 'Chemical', 'MESH:D017382', (265, 288))	('BCAT', 'molecular_function', 'GO:0043840', ('95', '99'))	('glutaminase', 'Gene', '2744', (159, 170))	('lowers', 'NegReg', (110, 116))	('BCAT1/2', 'Gene', (95, 102))	('BCAT1/2', 'Gene', '586;587', (95, 102))	('glutathione', 'Chemical', 'MESH:D005978', (208, 219))	('glutamate', 'Chemical', 'MESH:D018698', (117, 126))	('oxidative stress', 'Phenotype', 'HP:0025464', (21, 37))	('D-2HG', 'Chemical', '-', (86, 91))	('intracellular', 'cellular_component', 'GO:0005622', ('251', '264'))	('D-2HG', 'Var', (86, 91))	('glutaminase', 'Gene', (159, 170))	('glutamate', 'Chemical', 'MESH:D018698', (183, 192))	('ROS', 'Chemical', 'MESH:D017382', (290, 293))	('glutamate', 'MPA', (117, 126))	('inhibition', 'NegReg', (72, 82))
120318	33842477	Hence, ablating glutaminase in IDHmt glioma extensively sensitizes cells to oxidative damage and radiation.	('glutaminase', 'Gene', (16, 27))	('IDHmt glioma', 'Disease', (31, 43))	('sensitizes', 'Reg', (56, 66))	('ablating', 'Var', (7, 15))	('glutaminase', 'Gene', '2744', (16, 27))	('IDHmt glioma', 'Disease', 'MESH:D005910', (31, 43))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
120320	33842477	The expression of IDHmt reduces intracellular NAD+ by downregulating nicotinate phosphoribosyltransferase (Naprt1) in the NAD+ salvage pathway; a further depletion of NAD+ by targeting nicotinamide phosphoribosyltransferase (NAMPT), another enzyme in the metabolic pathway, induced a synthetic lethality with IDH mutation.	('NAD+', 'Chemical', 'MESH:D009243', (122, 126))	('depletion', 'NegReg', (154, 163))	('NAD+ salvage pathway', 'biological_process', 'GO:0034355', ('122', '142'))	('nicotinamide phosphoribosyltransferase', 'Gene', '10135', (185, 223))	('NAD+', 'Pathway', (122, 126))	('mutation', 'Var', (313, 321))	('downregulating', 'NegReg', (54, 68))	('Naprt1', 'Gene', '93100', (107, 113))	('nicotinamide phosphoribosyltransferase', 'Gene', (185, 223))	('NAD+', 'Chemical', 'MESH:D009243', (167, 171))	('IDH', 'Gene', (309, 312))	('NAMPT', 'Gene', '10135', (225, 230))	('synthetic lethality', 'MPA', (284, 303))	('intracellular', 'cellular_component', 'GO:0005622', ('32', '45'))	('NAD+', 'Chemical', 'MESH:D009243', (46, 50))	('nicotinate phosphoribosyltransferase', 'Gene', (69, 105))	('reduces', 'NegReg', (24, 31))	('NAMPT', 'Gene', (225, 230))	('intracellular NAD+', 'MPA', (32, 50))	('IDHmt', 'Gene', (18, 23))	('Naprt1', 'Gene', (107, 113))	('nicotinate phosphoribosyltransferase', 'Gene', '93100', (69, 105))
120322	33842477	D-2HG also inhibits the mitochondrial electron transport chain (ETC) by compromising the activity of cytochrome c oxidase (COX), resulting in a lower mitochondrial threshold to induce apoptosis, which sensitized those AML cells with IDH1mt to the inhibitor of the anti-apoptotic protein BCL-2.	('mitochondrial electron transport', 'MPA', (24, 56))	('AML', 'Disease', 'MESH:D015470', (218, 221))	('AML', 'Disease', (218, 221))	('cytochrome c', 'molecular_function', 'GO:0009461', ('101', '113'))	('AML', 'Phenotype', 'HP:0004808', (218, 221))	('BCL-2', 'Gene', '596', (287, 292))	('C', 'Chemical', 'MESH:D002244', (123, 124))	('protein', 'cellular_component', 'GO:0003675', ('279', '286'))	('compromising', 'NegReg', (72, 84))	('activity', 'MPA', (89, 97))	('BCL-2', 'Gene', (287, 292))	('mitochondrial electron transport', 'biological_process', 'GO:0042775', ('24', '56'))	('C', 'Chemical', 'MESH:D002244', (66, 67))	('D-2HG', 'Var', (0, 5))	('electron transport chain', 'biological_process', 'GO:0022900', ('38', '62'))	('C', 'Chemical', 'MESH:D002244', (288, 289))	('mitochondrial threshold', 'MPA', (150, 173))	('lower', 'NegReg', (144, 149))	('D-2HG', 'Chemical', '-', (0, 5))	('apoptosis', 'CPA', (184, 193))	('BCL-2', 'molecular_function', 'GO:0015283', ('287', '292'))	('cytochrome c', 'molecular_function', 'GO:0045155', ('101', '113'))	('inhibits', 'NegReg', (11, 19))	('apoptosis', 'biological_process', 'GO:0097194', ('184', '193'))	('cytochrome c', 'MPA', (101, 113))	('apoptosis', 'biological_process', 'GO:0006915', ('184', '193'))	('mitochondrial electron transport chain', 'cellular_component', 'GO:0005746', ('24', '62'))
120323	33842477	Similarly, in another study, IDHmt-derived D-2HG inhibits succinate dehydrogenase (SDH), the accumulated succinate hypersuccinylate mitochondria, and finally induces the mitochondrial membrane localization of BCL-2.	('induces', 'Reg', (158, 165))	('BCL-2', 'Gene', '596', (209, 214))	('BCL-2', 'Gene', (209, 214))	('mitochondrial membrane localization', 'MPA', (170, 205))	('succinate dehydrogenase', 'Gene', (58, 81))	('succinate', 'Chemical', 'MESH:D019802', (105, 114))	('SDH', 'Gene', (83, 86))	('D-2HG', 'Chemical', '-', (43, 48))	('succinate hypersuccinylate mitochondria', 'MPA', (105, 144))	('succinate dehydrogenase', 'Gene', '6390', (58, 81))	('mitochondria', 'cellular_component', 'GO:0005739', ('132', '144'))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('170', '192'))	('localization', 'biological_process', 'GO:0051179', ('193', '205'))	('BCL-2', 'molecular_function', 'GO:0015283', ('209', '214'))	('accumulated', 'PosReg', (93, 104))	('inhibits', 'NegReg', (49, 57))	('SDH', 'Gene', '6390', (83, 86))	('D-2HG', 'Var', (43, 48))	('succinate', 'Chemical', 'MESH:D019802', (58, 67))
120324	33842477	Another member of the BCL-2 family, Mcl-1, is downregulated in IDH1mt glioma cells, inducing a dependence on the anti-apoptosis protein Bcl-xL and thus the synthetic lethality of IDH1mt with Bcl-xL inhibitor.	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('synthetic lethality', 'CPA', (156, 175))	('BCL-2', 'molecular_function', 'GO:0015283', ('22', '27'))	('Bcl-xL', 'Gene', (136, 142))	('anti-apoptosis', 'biological_process', 'GO:0043066', ('113', '127'))	('dependence', 'MPA', (95, 105))	('downregulated', 'NegReg', (46, 59))	('Mcl-1', 'Gene', '4170', (36, 41))	('anti-apoptosis', 'MPA', (113, 127))	('Bcl-xL', 'Gene', '598', (136, 142))	('Bcl-xL', 'Gene', (191, 197))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('IDH1mt', 'Var', (63, 69))	('Bcl-xL', 'Gene', '598', (191, 197))	('inducing', 'Reg', (84, 92))	('BCL-2', 'Gene', '596', (22, 27))	('BCL-2', 'Gene', (22, 27))	('glioma', 'Disease', (70, 76))	('Mcl-1', 'Gene', (36, 41))	('glioma', 'Disease', 'MESH:D005910', (70, 76))
120325	33842477	Although 2-HG is identified as an oncometabolite, which facilitates tumor initiation, there is a paradox that IDHmt foreshadows a benign prognosis in glioma, and a similar trend also exists in AML.	('tumor', 'Disease', (68, 73))	('IDHmt', 'Var', (110, 115))	('AML', 'Phenotype', 'HP:0004808', (193, 196))	('AML', 'Disease', (193, 196))	('facilitates', 'PosReg', (56, 67))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('glioma', 'Disease', (150, 156))	('2-HG', 'Chemical', 'MESH:C019417', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('AML', 'Disease', 'MESH:D015470', (193, 196))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
120327	33842477	In the research of both enantiomers of 2-HG and the expression of IDHmt inhibited ATP synthase, thereby inactivating mTOR and cell growth.	('mTOR', 'Gene', (117, 121))	('IDHmt', 'Gene', (66, 71))	('mTOR', 'Gene', '2475', (117, 121))	('ATP synthase', 'molecular_function', 'GO:0016468', ('82', '94'))	('ATP', 'Chemical', 'MESH:D000255', (82, 85))	('ATP synthase', 'Enzyme', (82, 94))	('cell growth', 'biological_process', 'GO:0016049', ('126', '137'))	('inhibited', 'NegReg', (72, 81))	('expression', 'Var', (52, 62))	('inactivating', 'NegReg', (104, 116))	('2-HG', 'Chemical', 'MESH:C019417', (39, 43))	('ATP synthase', 'molecular_function', 'GO:0016467', ('82', '94'))
120329	33842477	Rui Su et al., reported that exogenous D-2HG inhibited FTO, a RNA demethylase, which caused a decrease in MYC and CEBPA transcripts, suppressing tumor growth through the FTO/m6A/MYC/CEBPA axis.	('MYC', 'Gene', (178, 181))	('CEBPA', 'Gene', '1050', (114, 119))	('suppressing', 'NegReg', (133, 144))	('FTO', 'Gene', '79068', (170, 173))	('inhibited', 'NegReg', (45, 54))	('decrease', 'NegReg', (94, 102))	('CEBPA', 'Gene', (114, 119))	('MYC', 'Gene', (106, 109))	('FTO', 'Gene', (170, 173))	('MYC', 'Gene', '4609', (178, 181))	('tumor', 'Disease', (145, 150))	('demethylase', 'Gene', (66, 77))	('demethylase', 'Gene', '8932', (66, 77))	('D-2HG', 'Var', (39, 44))	('CEBPA', 'Gene', '1050', (182, 187))	('RNA', 'cellular_component', 'GO:0005562', ('62', '65'))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('FTO', 'Gene', '79068', (55, 58))	('MYC', 'Gene', '4609', (106, 109))	('CEBPA', 'Gene', (182, 187))	('FTO', 'Gene', (55, 58))	('D-2HG', 'Chemical', '-', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))
120331	33842477	Consistent with this, in a subsequent study of the same group, targeting FTO induced a similar effect on FTO/m6A/MYC/CEBPA axis signaling through the same mechanism, leading to cell-cycle arrest in cancer stem cells.	('C', 'Chemical', 'MESH:D002244', (115, 116))	('MYC', 'Gene', (113, 116))	('FTO', 'Gene', '79068', (105, 108))	('arrest', 'Disease', (188, 194))	('FTO', 'Gene', (105, 108))	('cancer', 'Disease', (198, 204))	('FTO', 'Gene', '79068', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('targeting', 'Var', (63, 72))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('FTO', 'Gene', (73, 76))	('CEBPA', 'Gene', '1050', (117, 122))	('leading to', 'Reg', (166, 176))	('MYC', 'Gene', '4609', (113, 116))	('arrest', 'Disease', 'MESH:D006323', (188, 194))	('CEBPA', 'Gene', (117, 122))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('177', '194'))	('signaling', 'biological_process', 'GO:0023052', ('128', '137'))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('C', 'Chemical', 'MESH:D002244', (117, 118))
120333	33842477	Besides, D-2HG hinders neutrophil chemotaxis, which helps to establish an immunosuppressive ecology in the tumor microenvironment (TME).	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('hinders', 'NegReg', (15, 22))	('iron', 'Chemical', 'MESH:D007501', (121, 125))	('neutrophil chemotaxis', 'biological_process', 'GO:0030593', ('23', '44'))	('D-2HG', 'Var', (9, 14))	('neutrophil chemotaxis', 'CPA', (23, 44))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('neutrophil chemotaxis', 'Phenotype', 'HP:0040238', (23, 44))	('D-2HG', 'Chemical', '-', (9, 14))
120344	33842477	As described above, intracellular L-2HG elevates in the face of low-oxygen condition; it helps in alleviating hypoxia-induced reductive stress.	('oxygen', 'Chemical', 'MESH:D010100', (68, 74))	('low-oxygen condition', 'Phenotype', 'HP:0012418', (64, 84))	('hypoxia', 'Disease', 'MESH:D000860', (110, 117))	('hypoxia', 'Disease', (110, 117))	('elevates', 'PosReg', (40, 48))	('intracellular', 'cellular_component', 'GO:0005622', ('20', '33'))	('L-2HG', 'Var', (34, 39))	('L-2HG', 'Chemical', '-', (34, 39))
120349	33842477	L2HGDH knockdown not only mitigated mitochondrial membrane hyperpolarization but also impeded the generation of mitoSOX, indicating that L-2HG metabolism was implicated in maintaining redox balance.	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('36', '58'))	('membrane hyperpolarization', 'biological_process', 'GO:0060081', ('50', '76'))	('generation of mitoSOX', 'MPA', (98, 119))	('impeded', 'NegReg', (86, 93))	('L2HGDH', 'Gene', (0, 6))	('mitochondrial membrane hyperpolarization', 'MPA', (36, 76))	('metabolism', 'biological_process', 'GO:0008152', ('143', '153'))	('knockdown', 'Var', (7, 16))	('mitigated', 'NegReg', (26, 35))	('L2HGDH', 'Gene', '79944', (0, 6))	('L-2HG', 'Chemical', '-', (137, 142))
120350	33842477	It is explicit that being an alpha-KG-dependent dioxygenase, PHD, the key enzyme in regulating the stability of HIF-1alpha, can be suppressed by L-2HG.	('L-2HG', 'Var', (145, 150))	('HIF-1alpha', 'Gene', '3091', (112, 122))	('alpha-KG', 'Chemical', 'MESH:D007656', (29, 37))	('PHD', 'Disease', 'MESH:D011547', (61, 64))	('L-2HG', 'Chemical', '-', (145, 150))	('PHD', 'Disease', (61, 64))	('PHD', 'molecular_function', 'GO:0050175', ('61', '64'))	('HIF-1alpha', 'Gene', (112, 122))	('suppressed', 'NegReg', (131, 141))	('oxygen', 'Chemical', 'MESH:D010100', (50, 56))
120353	33842477	Therefore, L-2HG may assist in cell's adaption to hypoxia via sustaining the activity of HIF pathway.	('HIF pathway', 'Pathway', (89, 100))	('hypoxia', 'Disease', 'MESH:D000860', (50, 57))	('hypoxia', 'Disease', (50, 57))	('activity', 'MPA', (77, 85))	('L-2HG', 'Var', (11, 16))	('L-2HG', 'Chemical', '-', (11, 16))
120354	33842477	In summary, L-2HG partakes in acclimatizing hypoxia by regulating redox homeostasis and the activity of HIF pathway.	('hypoxia', 'Disease', (44, 51))	('regulating', 'Reg', (55, 65))	('HIF pathway', 'Pathway', (104, 115))	('hypoxia', 'Disease', 'MESH:D000860', (44, 51))	('L-2HG', 'Var', (12, 17))	('L-2HG', 'Chemical', '-', (12, 17))	('redox homeostasis', 'MPA', (66, 83))	('homeostasis', 'biological_process', 'GO:0042592', ('72', '83'))	('activity', 'MPA', (92, 100))
120357	33842477	Although its downstream effect remains obscure, it does suggest that besides sensing oxygen directly, TET and KDM4C can sense changes in oxygen concentration indirectly through L-2HG.	('KDM4C', 'Gene', '23081', (110, 115))	('oxygen', 'Chemical', 'MESH:D010100', (85, 91))	('TET', 'Chemical', '-', (102, 105))	('oxygen', 'Chemical', 'MESH:D010100', (137, 143))	('L-2HG', 'Var', (177, 182))	('L-2HG', 'Chemical', '-', (177, 182))	('sense changes in oxygen concentration', 'MPA', (120, 157))	('KDM4C', 'Gene', (110, 115))
120359	33842477	A conceivable explanation is that D-2HG elevates marginally relative to L-2HG; more importantly, D-2HG functions as a weak antagonist of alpha-KG-dependent dioxygenase, which is far less efficient than L-2HG.	('L-2HG', 'Chemical', '-', (202, 207))	('L-2HG', 'Chemical', '-', (72, 77))	('oxygen', 'Chemical', 'MESH:D010100', (158, 164))	('D-2HG', 'Chemical', '-', (34, 39))	('alpha-KG', 'Chemical', 'MESH:D007656', (137, 145))	('alpha-KG-dependent dioxygenase', 'Enzyme', (137, 167))	('D-2HG', 'Var', (97, 102))	('D-2HG', 'Chemical', '-', (97, 102))
120364	33842477	As mentioned in the research of CD8 + T cell produced millimolar L-2HG in response to TCR triggering, resulting in an enrichment of active H3K4me3 mark and RNA pol II at CD62L, polarizing it to memory subsets.	('L-2HG', 'Chemical', '-', (65, 70))	('C', 'Chemical', 'MESH:D002244', (87, 88))	('CD8', 'Gene', '925', (32, 35))	('CD62L', 'Gene', '6402', (170, 175))	('memory', 'biological_process', 'GO:0007613', ('194', '200'))	('TCR', 'cellular_component', 'GO:0042101', ('86', '89'))	('C', 'Chemical', 'MESH:D002244', (170, 171))	('H3K4me3 mark', 'Protein', (139, 151))	('TCR', 'biological_process', 'GO:0006283', ('86', '89'))	('C', 'Chemical', 'MESH:D002244', (32, 33))	('CD62L', 'Gene', (170, 175))	('CD8', 'Gene', (32, 35))	('enrichment', 'MPA', (118, 128))	('RNA', 'Enzyme', (156, 159))	('RNA', 'cellular_component', 'GO:0005562', ('156', '159'))	('L-2HG', 'Var', (65, 70))
120365	33842477	Moreover, accumulating L-2HG prompted a global increase of H3K27me3 and 5mC and knockdown of H3K27me2/3 demethylase Utx; and TET2 also motivated the expression of CD62L, indicating that epigenetic inhibition somewhere else in the genome triggers the transcription of CD62L.	('TET2', 'Gene', (125, 129))	('L-2HG', 'Var', (23, 28))	('5mC', 'MPA', (72, 75))	('increase', 'PosReg', (47, 55))	('Utx', 'Gene', '7403', (116, 119))	('H3K27me2/3', 'Var', (93, 103))	('CD62L', 'Gene', '6402', (267, 272))	('H3K27me3', 'Protein', (59, 67))	('CD62L', 'Gene', (267, 272))	('CD62L', 'Gene', '6402', (163, 168))	('TET2', 'Gene', '54790', (125, 129))	('Utx', 'Gene', (116, 119))	('5mC', 'Chemical', '-', (72, 75))	('motivated', 'Reg', (135, 144))	('transcription', 'biological_process', 'GO:0006351', ('250', '263'))	('expression', 'MPA', (149, 159))	('demethylase', 'Gene', '8932', (104, 115))	('demethylase', 'Gene', (104, 115))	('CD62L', 'Gene', (163, 168))	('knockdown', 'Var', (80, 89))	('L-2HG', 'Chemical', '-', (23, 28))	('epigenetic inhibition', 'Var', (186, 207))
120366	33842477	Although it was a little regrettable that the study did not identify these genes, it unveiled L-2HG's identity of "immunometabolite" unprecedentedly, which mattered a lot in the fate decision of CD8 + T lymphocytes through a metabolic-epigenetic axis.	('L-2HG', 'Var', (94, 99))	('CD8', 'Gene', '925', (195, 198))	('L-2HG', 'Chemical', '-', (94, 99))	('CD8', 'Gene', (195, 198))
120367	33842477	A recent study further revealed that with Utx bound directly to Prdm1, through reduced demethylation of histone H3K27me3, its deficiency hampers the transcription of Prdm1-encoding Blimp1 that is an effector-associated transcription factor, triggering a memory-like phenotype.	('transcription', 'biological_process', 'GO:0006351', ('219', '232'))	('deficiency', 'Var', (126, 136))	('Prdm1', 'Gene', (64, 69))	('hampers', 'NegReg', (137, 144))	('Blimp1', 'Gene', '639', (181, 187))	('histone H3K27me', 'biological_process', 'GO:0070734', ('104', '119'))	('transcription', 'MPA', (149, 162))	('transcription', 'biological_process', 'GO:0006351', ('149', '162'))	('Utx', 'Gene', '7403', (42, 45))	('histone H3K27me3', 'Protein', (104, 120))	('reduced', 'NegReg', (79, 86))	('Blimp1', 'Gene', (181, 187))	('memory', 'biological_process', 'GO:0007613', ('254', '260'))	('demethylation', 'MPA', (87, 100))	('Prdm1', 'Gene', '639', (166, 171))	('Utx', 'Gene', (42, 45))	('transcription factor', 'molecular_function', 'GO:0000981', ('219', '239'))	('Prdm1', 'Gene', (166, 171))	('Prdm1', 'Gene', '639', (64, 69))	('demethylation', 'biological_process', 'GO:0070988', ('87', '100'))
120368	33842477	Therefore, L-2HG dictates CD8 + T lymphocyte fate through the metabolism-epigenetics axis.	('dictates', 'Reg', (17, 25))	('metabolism', 'biological_process', 'GO:0008152', ('62', '72'))	('CD8', 'Gene', '925', (26, 29))	('L-2HG', 'Var', (11, 16))	('L-2HG', 'Chemical', '-', (11, 16))	('CD8', 'Gene', (26, 29))
120370	33842477	Similar to L-2HG, D-2HG has also been demonstrated to be a mediator in T lymphocyte differentiation.	('T lymphocyte differentiation', 'CPA', (71, 99))	('D-2HG', 'Var', (18, 23))	('D-2HG', 'Chemical', '-', (18, 23))	('L-2HG', 'Chemical', '-', (11, 16))	('T lymphocyte differentiation', 'biological_process', 'GO:0030217', ('71', '99'))
120379	33842477	As regards oncotherapy, a pretreatment of L-2HG significantly exaggerated the persistence and antitumor capacity of adoptively transferred CD8 + T lymphocytes.	('CD8', 'Gene', (139, 142))	('CD8', 'Gene', '925', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('persistence', 'CPA', (78, 89))	('L-2HG', 'Var', (42, 47))	('exaggerated', 'PosReg', (62, 73))	('tumor', 'Disease', (98, 103))	('L-2HG', 'Chemical', '-', (42, 47))
120381	33842477	Due to their excellent performance in clinical trial, the IDH inhibitors ivosidenib and enasidenib are approved by Food and Drug Administration (FDA) to treat adults with relapsed and refractory AML with IDH1/2 mutation.	('IDH1/2', 'Gene', (204, 210))	('AML', 'Phenotype', 'HP:0004808', (195, 198))	('relapsed', 'Disease', (171, 179))	('enasidenib', 'Chemical', 'MESH:C000605269', (88, 98))	('ivosidenib', 'Chemical', 'MESH:C000627630', (73, 83))	('AML', 'Disease', 'MESH:D015470', (195, 198))	('mutation', 'Var', (211, 219))	('AML', 'Disease', (195, 198))
120384	33842477	As L-2HG is structurally analogous to D-2HG, they may share some common mechanisms such as suppressing alpha-KG-dependent dioxygenases.	('suppressing', 'NegReg', (91, 102))	('D-2HG', 'Chemical', '-', (38, 43))	('alpha-KG-dependent dioxygenases', 'MPA', (103, 134))	('L-2HG', 'Var', (3, 8))	('oxygen', 'Chemical', 'MESH:D010100', (124, 130))	('alpha-KG', 'Chemical', 'MESH:D007656', (103, 111))	('L-2HG', 'Chemical', '-', (3, 8))
120385	33842477	L-2HG generates in acidic environment and participates in the adaption to hypoxia.	('hypoxia', 'Disease', 'MESH:D000860', (74, 81))	('hypoxia', 'Disease', (74, 81))	('L-2HG', 'Var', (0, 5))	('iron', 'Chemical', 'MESH:D007501', (29, 33))	('L-2HG', 'Chemical', '-', (0, 5))	('participates', 'Reg', (42, 54))
120387	33842477	Because the TME is quite a hypoxia and acidic milieu, L-2HG may help these areas establish an adaption to limited oxygen supply and, at the same time, generate phenotype heterogeneity, which contributes to variant therapeutic responses in the intratumoral religion through epigenetics and other mechanisms.	('epigenetics', 'Var', (273, 284))	('tumor', 'Disease', (248, 253))	('phenotype', 'MPA', (160, 169))	('L-2HG', 'Var', (54, 59))	('adaption', 'MPA', (94, 102))	('hypoxia', 'Disease', (27, 34))	('oxygen', 'Chemical', 'MESH:D010100', (114, 120))	('hypoxia', 'Disease', 'MESH:D000860', (27, 34))	('L-2HG', 'Chemical', '-', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('contributes', 'Reg', (191, 202))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
120391	33842477	Recently, L-2HG is demonstrated to promote axon regeneration in the central nervous system.	('axon', 'cellular_component', 'GO:0030424', ('43', '47'))	('axon regeneration', 'biological_process', 'GO:0031103', ('43', '60'))	('axon regeneration', 'Phenotype', 'HP:0003450', (43, 60))	('promote', 'PosReg', (35, 42))	('L-2HG', 'Var', (10, 15))	('L-2HG', 'Chemical', '-', (10, 15))	('axon regeneration in the central nervous system', 'CPA', (43, 90))
120401	33643820	Mechanistically, we discovered that siRNA knockdown or pharmacological inhibition of SUV39H1 induced iron accumulation and lipid peroxidation, leading to ferroptosis that disrupted ccRCC cell growth in vitro and in vivo.	('RCC', 'Phenotype', 'HP:0005584', (183, 186))	('cell growth', 'biological_process', 'GO:0016049', ('187', '198'))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('lipid', 'Chemical', 'MESH:D008055', (123, 128))	('ferroptosis', 'Disease', (154, 165))	('RCC', 'Disease', (183, 186))	('disrupted', 'NegReg', (171, 180))	('ccRCC', 'Phenotype', 'HP:0006770', (181, 186))	('iron', 'Chemical', 'MESH:D007501', (101, 105))	('SUV39H1', 'Gene', (85, 92))	('leading to', 'Reg', (143, 153))	('lipid peroxidation', 'MPA', (123, 141))	('iron accumulation', 'MPA', (101, 118))	('ferroptosis', 'biological_process', 'GO:0097707', ('154', '165'))	('knockdown', 'Var', (42, 51))
120402	33643820	We also show that SUV39H1 deficiency modulated the H3K9me3 status of the DPP4 (dipeptidyl-peptidase-4) gene promoter, resulting in upregulation of its expression that contributes to ferroptosis.	('dipeptidyl-peptidase-4', 'Gene', (79, 101))	('deficiency', 'Var', (26, 36))	('ferroptosis', 'biological_process', 'GO:0097707', ('182', '193'))	('upregulation', 'PosReg', (131, 143))	('contributes', 'Reg', (167, 178))	('SUV39H1', 'Gene', (18, 25))	('DPP4', 'Gene', '1803', (73, 77))	('modulated', 'Reg', (37, 46))	('expression', 'MPA', (151, 161))	('ferroptosis', 'Disease', (182, 193))	('dipeptidyl-peptidase-4', 'Gene', '1803', (79, 101))	('DPP4', 'Gene', (73, 77))
120404	33643820	SUV39H1 is an epigenetic repressor to suppress DPP4 expression.	('DPP4', 'Gene', (47, 51))	('expression', 'MPA', (52, 62))	('SUV39H1', 'Var', (0, 7))	('DPP4', 'Gene', '1803', (47, 51))	('suppress', 'NegReg', (38, 46))
120405	33643820	Function loss of SUV39H1 in ccRCC tumors contributes the hypomethylation of the DPP4 promoter to upregulate DPP4 expression and induces DPP4-mediated ferroptosis to suppress cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('174', '192'))	('DPP4', 'Gene', '1803', (108, 112))	('upregulate', 'PosReg', (97, 107))	('DPP4', 'Gene', (136, 140))	('ccRCC tumors', 'Disease', (28, 40))	('hypomethylation', 'MPA', (57, 72))	('DPP4', 'Gene', (80, 84))	('expression', 'MPA', (113, 123))	('ferroptosis', 'biological_process', 'GO:0097707', ('150', '161'))	('ccRCC tumors', 'Disease', 'MESH:D009369', (28, 40))	('SUV39H1', 'Gene', (17, 24))	('DPP4', 'Gene', (108, 112))	('cell proliferation', 'CPA', (174, 192))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('DPP4', 'Gene', '1803', (136, 140))	('suppress', 'NegReg', (165, 173))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('DPP4', 'Gene', '1803', (80, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (28, 33))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('loss', 'Var', (9, 13))	('induces', 'Reg', (128, 135))
120416	33643820	SUV39H1 is generally regarded as a tumor suppressor, due to its roles in suppressing genes required for proliferation and in promoting senescence.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('senescence', 'CPA', (135, 145))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('promoting', 'PosReg', (125, 134))	('tumor suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('tumor', 'Disease', (35, 40))	('SUV39H1', 'Var', (0, 7))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))	('senescence', 'biological_process', 'GO:0010149', ('135', '145'))	('suppressing', 'NegReg', (73, 84))
120417	33643820	However, increasing evidence indicates that SUV39H1 may also serve as an oncogene in some human cancers.	('SUV39H1', 'Var', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('human', 'Species', '9606', (90, 95))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancers', 'Disease', (96, 103))
120419	33643820	SUV39H1 has been reported to function as an oncogene in melanoma via inhibiting the expression of retinoblastoma (RB).	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('SUV39H1', 'Var', (0, 7))	('inhibiting', 'NegReg', (69, 79))	('retinoblastoma', 'Phenotype', 'HP:0009919', (98, 112))	('expression', 'MPA', (84, 94))	('retinoblastoma', 'Gene', '5925', (98, 112))	('retinoblastoma', 'Gene', (98, 112))	('RB', 'Phenotype', 'HP:0009919', (114, 116))
120421	33643820	Ferroptosis, an iron-dependent form of non-apoptotic regulated cell death, was originally identified in cancer cells with oncogenic RAS mutations.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Ferroptosis', 'biological_process', 'GO:0097707', ('0', '11'))	('regulated cell death', 'biological_process', 'GO:0012501', ('53', '73'))	('iron', 'Chemical', 'MESH:D007501', (16, 20))	('mutations', 'Var', (136, 145))	('Ferroptosis', 'Disease', (0, 11))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
120424	33643820	Recent work has also indicated that dysfunction of ferroptosis is closely related to tumor progression.	('tumor', 'Disease', (85, 90))	('related', 'Reg', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('dysfunction', 'Var', (36, 47))	('ferroptosis', 'biological_process', 'GO:0097707', ('51', '62'))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('ferroptosis', 'Protein', (51, 62))
120432	33643820	Finally, we investigated the exact mechanism underlying the effects of SUV39H1 on ccRCC tumor growth.	('SUV39H1', 'Var', (71, 78))	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('ccRCC tumor', 'Disease', 'MESH:D009369', (82, 93))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('ccRCC tumor', 'Disease', (82, 93))
120433	33643820	Our study provides proof-of-concept that targeting an epigenetic factor could be a promising strategy for ccRCC treatment.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('epigenetic factor', 'Var', (54, 71))
120448	33643820	Chemical reagents, including ferrostatin-1 (CSN12654), z-VAD-FMK (CSN19230), necrostatin 1 (CSN11637), bafilomycin A1 (CSN10374), VX-765 (CSN15837), UNC0638 (CSN16350) and chaetocin (CSN19229) were provided by CSNpharm (Chicago, IL, USA).	('UNC0638', 'Chemical', 'MESH:C561310', (149, 156))	('CSN', 'cellular_component', 'GO:0008180', ('92', '95'))	('CSN', 'cellular_component', 'GO:0008180', ('138', '141'))	('CSN19229', 'Var', (183, 191))	('CSN', 'cellular_component', 'GO:0008180', ('119', '122'))	('necrostatin 1', 'Chemical', 'MESH:C507699', (77, 90))	('CSN', 'cellular_component', 'GO:0008180', ('66', '69'))	('CSN', 'cellular_component', 'GO:0008180', ('158', '161'))	('chaetocin', 'Chemical', 'MESH:C002511', (172, 181))	('CSN16350', 'Var', (158, 166))	('CSN12654', 'Var', (44, 52))	('CSN15837', 'Var', (138, 146))	('z-VAD-FMK', 'Chemical', 'MESH:C096713', (55, 64))	('bafilomycin A1', 'Chemical', 'MESH:C040929', (103, 117))	('CSN', 'cellular_component', 'GO:0008180', ('183', '186'))	('CSN10374', 'Var', (119, 127))	('CSN', 'cellular_component', 'GO:0008180', ('44', '47'))	('ferrostatin-1', 'Chemical', 'MESH:C573944', (29, 42))
120449	33643820	The sequence-specific siRNAs used to knock down SUV39H1 and DPP4 expression are listed in Supporting Information Table S3.	('knock', 'Var', (37, 42))	('DPP4', 'Gene', (60, 64))	('SUV39H1', 'Gene', (48, 55))	('DPP4', 'Gene', '1803', (60, 64))
120476	33643820	A survival analysis was performed to investigate the prognostic value of SUV39H1 expression level in ccRCC, and the results show that patients exhibiting high SUV39H1 expression had significantly shorter OS than those with low SUV39H1 expression (Fig.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('shorter', 'NegReg', (196, 203))	('patients', 'Species', '9606', (134, 142))	('high SUV39H1 expression', 'Var', (154, 177))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))
120477	33643820	Moreover, SUV39H1 expression level had significant prognostic value for ccRCC with a high histological grade (Grades 3+4), intermediate and advanced tumor stages (Stages II+III+IV), large tumors (tumor size >= 1.5 cm), deep invasion (T2+T3+T4), and negative for lymph node metastasis (N0 stage), while there was no significant prognostic value for patients with distant metastasis (Fig.	('tumor', 'Disease', (188, 193))	('patients', 'Species', '9606', (348, 356))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('expression', 'MPA', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumors', 'Disease', (188, 194))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('SUV39H1', 'Var', (10, 17))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumor', 'Disease', (149, 154))
120480	33643820	Consistent with this, ccRCC tumor tissues exhibited increased levels of SUV39H1 mRNA and protein compared with normal tissues (Fig.	('levels', 'MPA', (62, 68))	('increased', 'PosReg', (52, 61))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))	('ccRCC tumor', 'Disease', (22, 33))	('SUV39H1', 'Var', (72, 79))	('RCC', 'Phenotype', 'HP:0005584', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('ccRCC tumor', 'Disease', 'MESH:D009369', (22, 33))	('ccRCC', 'Phenotype', 'HP:0006770', (22, 27))
120487	33643820	We next investigated whether SUV39H1 expression level is an independent prognostic factor for ccRCC patient outcomes.	('RCC', 'Disease', (96, 99))	('SUV39H1', 'Var', (29, 36))	('patient', 'Species', '9606', (100, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
120488	33643820	The results indicate that SUV39H1 expression level, as well as TNM stage, Fuhrman grade and tumor size, was an independent prognostic predictor for OS and RFS of ccRCC patients (Table 2).	('RFS of ccRCC', 'Disease', (155, 167))	('expression', 'MPA', (34, 44))	('SUV39H1', 'Var', (26, 33))	('TNM', 'Gene', '10178', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('TNM', 'Gene', (63, 66))	('patients', 'Species', '9606', (168, 176))	('ccRCC', 'Phenotype', 'HP:0006770', (162, 167))	('tumor', 'Disease', (92, 97))	('RFS of ccRCC', 'Disease', 'MESH:D005198', (155, 167))
120489	33643820	As shown in Table 3, the C-index values were increased and the AIC values were decreased for OS or RFS when SUV39H1 expression level was considered together with conventional prognostic factors, suggesting the SUV39H1 expression level has good predictive ability for ccRCC prognosis.	('RCC', 'Disease', (269, 272))	('RFS', 'Disease', (99, 102))	('increased', 'PosReg', (45, 54))	('decreased', 'NegReg', (79, 88))	('RFS', 'Disease', 'MESH:D005198', (99, 102))	('SUV39H1', 'Var', (210, 217))	('AIC values', 'MPA', (63, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (267, 272))	('RCC', 'Phenotype', 'HP:0005584', (269, 272))	('C-index values', 'MPA', (25, 39))	('RCC', 'Disease', 'MESH:C538614', (269, 272))
120502	33643820	Caki-1 cells with stable depletion of SUV39H1 significantly impaired tumor growth, as indicated by tumor volume, weight and size (Fig.	('impaired tumor', 'Disease', 'MESH:D060825', (60, 74))	('tumor', 'Disease', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('SUV39H1', 'Var', (38, 45))	('depletion', 'Var', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('impaired tumor', 'Disease', (60, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('Caki-1', 'CellLine', 'CVCL:0234', (0, 6))
120505	33643820	We next attempted to determine whether SUV39H1 depletion inhibits ccRCC tumor growth by inducing any of these forms of RCD.	('ccRCC tumor', 'Disease', (66, 77))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('ccRCC tumor', 'Disease', 'MESH:D009369', (66, 77))	('depletion', 'Var', (47, 56))	('SUV39H1', 'Gene', (39, 46))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('inducing', 'Reg', (88, 96))	('inhibits', 'NegReg', (57, 65))	('RCD', 'biological_process', 'GO:0012501', ('119', '122'))
120506	33643820	The death of SUV39H1-depleted cells was significantly reduced by treatment with ferrostatin-1, an inhibitor of ferroptosis, suggesting that SUV39H1 knockdown may attenuate cell growth partly by inducing ferroptosis (Fig.	('ferroptosis', 'CPA', (203, 214))	('cell growth', 'biological_process', 'GO:0016049', ('172', '183'))	('ferroptosis', 'biological_process', 'GO:0097707', ('203', '214'))	('attenuate', 'NegReg', (162, 171))	('inducing', 'NegReg', (194, 202))	('ferroptosis', 'biological_process', 'GO:0097707', ('111', '122'))	('SUV39H1', 'Gene', (140, 147))	('cell growth', 'CPA', (172, 183))	('ferrostatin-1', 'Chemical', 'MESH:C573944', (80, 93))	('knockdown', 'Var', (148, 157))
120508	33643820	As expected, we found that SUV39H1 knockdown increased intracellular lipid ROS, mitochondrial superoxide levels, intracellular iron and Fe2+ levels, and induced ferroptosis associated morphological changes in ccRCC cells (Fig.	('knockdown', 'Var', (35, 44))	('mitochondrial superoxide levels', 'MPA', (80, 111))	('superoxide', 'Chemical', 'MESH:D013481', (94, 104))	('increased', 'PosReg', (45, 54))	('RCC', 'Disease', (211, 214))	('RCC', 'Phenotype', 'HP:0005584', (211, 214))	('intracellular', 'cellular_component', 'GO:0005622', ('113', '126'))	('RCC', 'Disease', 'MESH:C538614', (211, 214))	('ccRCC', 'Phenotype', 'HP:0006770', (209, 214))	('intracellular', 'cellular_component', 'GO:0005622', ('55', '68'))	('lipid ROS', 'Chemical', '-', (69, 78))	('ferroptosis', 'biological_process', 'GO:0097707', ('161', '172'))	('intracellular lipid ROS', 'MPA', (55, 78))	('Fe2+', 'Chemical', '-', (136, 140))	('SUV39H1', 'Gene', (27, 34))	('induced', 'Reg', (153, 160))	('iron', 'Chemical', 'MESH:D007501', (127, 131))	('ferroptosis', 'CPA', (161, 172))
120509	33643820	Together, our results suggest that SUV39H1 knockdown attenuates tumor growth partly by inducing ferroptotic cell death in ccRCC.	('RCC', 'Disease', (124, 127))	('SUV39H1', 'Gene', (35, 42))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('tumor', 'Disease', (64, 69))	('ferroptotic cell death', 'CPA', (96, 118))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('cell death', 'biological_process', 'GO:0008219', ('108', '118'))	('inducing', 'Reg', (87, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (122, 127))	('knockdown', 'Var', (43, 52))	('attenuates', 'NegReg', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
120520	33643820	Together, we reveal that the inhibition of SUV39H1 enzymatic activity could induce ccRCC cell ferroptosis.	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('induce', 'Reg', (76, 82))	('ferroptosis', 'biological_process', 'GO:0097707', ('94', '105'))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('SUV39H1', 'Gene', (43, 50))	('RCC', 'Disease', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('inhibition', 'Var', (29, 39))
120522	33643820	In vitro experiments showed that chaetocin inhibited ccRCC cell proliferation and colony formation, and increased cell death in a dose-dependent manner (Fig.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('RCC', 'Disease', (55, 58))	('inhibited', 'NegReg', (43, 52))	('chaetocin', 'Var', (33, 42))	('colony formation', 'CPA', (82, 98))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('cell death', 'biological_process', 'GO:0008219', ('114', '124'))	('cell death', 'CPA', (114, 124))	('chaetocin', 'Chemical', 'MESH:C002511', (33, 42))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('formation', 'biological_process', 'GO:0009058', ('89', '98'))
120524	33643820	To assess the anti-tumor effects of chaetocin in vivo, we treated a patient-derived xenograft (PDX) ccRCC model with chaetocin and found chaetocin treatment resulted in substantially inhibited tumor growth, as indicated by tumor volume, size and weight (Fig.	('chaetocin', 'Chemical', 'MESH:C002511', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('chaetocin', 'Chemical', 'MESH:C002511', (137, 146))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('chaetocin', 'Chemical', 'MESH:C002511', (117, 126))	('chaetocin', 'Var', (137, 146))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('inhibited', 'NegReg', (183, 192))	('patient', 'Species', '9606', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))
120526	33643820	In summary, our results show that inhibiting SUV39H1 enzymatic activity induces ferroptosis and suppresses ccRCC tumor growth, indicating that SUV39H1 may be an effective therapeutic target for treating ccRCC.	('inhibiting', 'Var', (34, 44))	('ferroptosis', 'CPA', (80, 91))	('ferroptosis', 'biological_process', 'GO:0097707', ('80', '91'))	('RCC', 'Disease', (205, 208))	('RCC', 'Phenotype', 'HP:0005584', (205, 208))	('induces', 'Reg', (72, 79))	('ccRCC tumor', 'Disease', (107, 118))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('ccRCC tumor', 'Disease', 'MESH:D009369', (107, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (203, 208))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('suppresses', 'NegReg', (96, 106))	('SUV39H1', 'Gene', (45, 52))
120527	33643820	Given that SUV39H1 depletion also induces G2/M cell cycle arrest, we next asked whether cell cycle arrest is mediated by ferroptosis.	('depletion', 'Var', (19, 28))	('arrest', 'Disease', (58, 64))	('arrest', 'Disease', 'MESH:D006323', (58, 64))	('induces', 'Reg', (34, 41))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('88', '105'))	('ferroptosis', 'biological_process', 'GO:0097707', ('121', '132'))	('SUV39H1 depletion', 'Var', (11, 28))	('arrest', 'Disease', 'MESH:D006323', (99, 105))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('47', '64'))	('arrest', 'Disease', (99, 105))
120528	33643820	Result showed that the inhibition of ferroptosis barely impacts the occurrence of G2/M cell cycle arrest, indicating the regulation of cell cycle is independent of ferroptosis in SUV39H1 suppressed ccRCC cells (Supporting Information Fig.	('arrest', 'Disease', (98, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (198, 203))	('RCC', 'Disease', (200, 203))	('RCC', 'Phenotype', 'HP:0005584', (200, 203))	('RCC', 'Disease', 'MESH:C538614', (200, 203))	('regulation of cell cycle', 'biological_process', 'GO:0051726', ('121', '145'))	('ferroptosis', 'biological_process', 'GO:0097707', ('37', '48'))	('ferroptosis', 'biological_process', 'GO:0097707', ('164', '175'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('87', '104'))	('arrest', 'Disease', 'MESH:D006323', (98, 104))	('SUV39H1 suppressed', 'Var', (179, 197))	('G2/M', 'CPA', (82, 86))
120530	33643820	Our data indicate that knockdown or inhibition of SUV39H1 has no significant impact on apoptosis phenotype of ccRCC cells (Supporting Information Fig.	('apoptosis phenotype', 'CPA', (87, 106))	('inhibition', 'Var', (36, 46))	('SUV39H1', 'Gene', (50, 57))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))
120531	33643820	Besides, we want to know whether SUV39H1 knockdown or inhibition have cell cytotoxicity in the normal kidney cell line HK-2.	('HK-2', 'molecular_function', 'GO:0008256', ('119', '123'))	('toxicity', 'Disease', 'MESH:D064420', (79, 87))	('toxicity', 'Disease', (79, 87))	('inhibition', 'NegReg', (54, 64))	('SUV39H1', 'Gene', (33, 40))	('HK-2', 'CellLine', 'CVCL:0302', (119, 123))	('knockdown', 'Var', (41, 50))
120532	33643820	Results showed that SUV39H1 knockdown or inhibition of SUV39H1 enzymatic activity by chaetocin have some extent effect of cell cytotoxicity in HK-2 cells, which is relatively marginal compared with that in ccRCC cells (Supporting Information Fig.	('SUV39H1', 'Gene', (55, 62))	('chaetocin', 'Chemical', 'MESH:C002511', (85, 94))	('HK-2', 'molecular_function', 'GO:0008256', ('143', '147'))	('RCC', 'Phenotype', 'HP:0005584', (208, 211))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('RCC', 'Disease', (208, 211))	('HK-2', 'CellLine', 'CVCL:0302', (143, 147))	('ccRCC', 'Phenotype', 'HP:0006770', (206, 211))	('toxicity', 'Disease', 'MESH:D064420', (131, 139))	('knockdown', 'Var', (28, 37))	('toxicity', 'Disease', (131, 139))	('inhibition', 'NegReg', (41, 51))	('SUV39H1', 'Gene', (20, 27))
120535	33643820	The GO analysis results showed that the upregulated DEGs were enriched with proteins involved in the endoplasmic reticulum lumen, and the KEGG analysis indicated that SUV39H1 may participate in lysosome function and sphingolipid metabolism in ccRCC (Fig.	('sphingolipid metabolism', 'Disease', (216, 239))	('RCC', 'Disease', (245, 248))	('SUV39H1', 'Var', (167, 174))	('RCC', 'Phenotype', 'HP:0005584', (245, 248))	('endoplasmic reticulum lumen', 'cellular_component', 'GO:0005788', ('101', '128'))	('RCC', 'Disease', 'MESH:C538614', (245, 248))	('ccRCC', 'Phenotype', 'HP:0006770', (243, 248))	('lysosome', 'cellular_component', 'GO:0005764', ('194', '202'))	('sphingolipid metabolism', 'biological_process', 'GO:0006665', ('216', '239'))	('sphingolipid metabolism', 'Disease', 'MESH:D013106', (216, 239))	('participate', 'Reg', (179, 190))	('upregulated', 'PosReg', (40, 51))
120538	33643820	We found two ferroptosis associated genes (TFRC and DPP4) expression levels were significantly changed among the Top200 upregulated DEGs (ranked by Padj) in response to SUV39H1 knockdown (Supporting Information Table S9).	('TFRC', 'Gene', (43, 47))	('expression levels', 'MPA', (58, 75))	('DPP4', 'Gene', '1803', (52, 56))	('SUV39H1 knockdown', 'Var', (169, 186))	('upregulated', 'PosReg', (120, 131))	('ferroptosis', 'biological_process', 'GO:0097707', ('13', '24'))	('knockdown', 'Var', (177, 186))	('changed', 'Reg', (95, 102))	('TFRC', 'Gene', '7037', (43, 47))	('DPP4', 'Gene', (52, 56))
120539	33643820	Next, RT-qPCR was performed to verify the expression level of TFRC and DPP4, as well as GPX4, FTH1 and SLC7A11, and we found that DPP4 was the most significantly upregulated gene after SUV39H1 knockdown (Fig.	('GPX4', 'Gene', '2879', (88, 92))	('DPP4', 'Gene', (71, 75))	('FTH1', 'Gene', '2495', (94, 98))	('TFRC', 'Gene', (62, 66))	('DPP4', 'Gene', (130, 134))	('knockdown', 'Var', (193, 202))	('DPP4', 'Gene', '1803', (130, 134))	('upregulated', 'PosReg', (162, 173))	('SLC7A11', 'Gene', (103, 110))	('FTH1', 'Gene', (94, 98))	('DPP4', 'Gene', '1803', (71, 75))	('SLC7A11', 'Gene', '23657', (103, 110))	('TFRC', 'Gene', '7037', (62, 66))	('GPX4', 'Gene', (88, 92))
120540	33643820	To confirm this finding, we performed Western blot analyses to detect DPP4 protein expression levels in SUV39H1 deficiency cells.	('deficiency', 'Var', (112, 122))	('DPP4', 'Gene', '1803', (70, 74))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('DPP4', 'Gene', (70, 74))	('SUV39H1', 'Gene', (104, 111))
120543	33643820	As SUV39H1 primarily catalyzes H3K9me3 status, we next asked whether SUV39H1 modulates the H3K9me3 status of the DPP4 promoter to regulate its expression.	('DPP4', 'Gene', (113, 117))	('expression', 'MPA', (143, 153))	('regulate', 'Reg', (130, 138))	('DPP4', 'Gene', '1803', (113, 117))	('SUV39H1', 'Var', (69, 76))
120544	33643820	To test this, we performed ChIP-qPCR analysis in ccRCC cells upon SUV39H1 depletion or inhibition.	('inhibition', 'NegReg', (87, 97))	('depletion', 'Var', (74, 83))	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('SUV39H1', 'Gene', (66, 73))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
120545	33643820	The results show that H3K9me3 modification in the DPP4 promoter region was noticeably decreased following SUV39H1 knockdown or inhibition (Fig.	('DPP4', 'Gene', (50, 54))	('knockdown', 'Var', (114, 123))	('DPP4', 'Gene', '1803', (50, 54))	('decreased', 'NegReg', (86, 95))	('inhibition', 'NegReg', (127, 137))	('SUV39H1', 'Gene', (106, 113))	('H3K9me3', 'Protein', (22, 29))
120548	33643820	We first detected the subcellular localization of the upregulated DPP4 protein in ccRCC cells, and result showed that SUV39H1 deficiency increased the expression of DPP4 in both membrane and nuclear of ccRCC cells (Supporting Information Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('upregulated', 'PosReg', (54, 65))	('deficiency', 'Var', (126, 136))	('RCC', 'Disease', (204, 207))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('RCC', 'Phenotype', 'HP:0005584', (204, 207))	('ccRCC', 'Phenotype', 'HP:0006770', (202, 207))	('RCC', 'Disease', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('localization', 'biological_process', 'GO:0051179', ('34', '46'))	('DPP4', 'Gene', (165, 169))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('increased', 'PosReg', (137, 146))	('DPP4', 'Gene', '1803', (66, 70))	('expression', 'MPA', (151, 161))	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('SUV39H1', 'Gene', (118, 125))	('membrane', 'cellular_component', 'GO:0016020', ('178', '186'))	('DPP4', 'Gene', (66, 70))	('DPP4', 'Gene', '1803', (165, 169))
120550	33643820	Two ccRCC cell lines 786-O (mutant P53) and Caki-1 (wild-type P53) were used in our study and both cell lines showed ferroptosis after SUV39H1 depleted, which indicated that the regulation role of DPP4 is independent of P53 status in ccRCC cells.	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('ferroptosis', 'biological_process', 'GO:0097707', ('117', '128'))	('mutant', 'Var', (28, 34))	('DPP4', 'Gene', (197, 201))	('ferroptosis', 'CPA', (117, 128))	('RCC', 'Disease', (236, 239))	('RCC', 'Phenotype', 'HP:0005584', (236, 239))	('ccRCC', 'Phenotype', 'HP:0006770', (4, 9))	('RCC', 'Disease', 'MESH:C538614', (236, 239))	('Caki-1', 'CellLine', 'CVCL:0234', (44, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (234, 239))	('regulation', 'biological_process', 'GO:0065007', ('178', '188'))	('DPP4', 'Gene', '1803', (197, 201))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))
120551	33643820	Together, our data indicate that SUV39H1 deficiency upregulate the expression of membrane and nucleus DPP4, which is P53-independent in ccRCC.	('RCC', 'Disease', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('membrane', 'Gene', (81, 89))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('DPP4', 'Gene', (102, 106))	('nucleus', 'cellular_component', 'GO:0005634', ('94', '101'))	('SUV39H1', 'Gene', (33, 40))	('deficiency', 'Var', (41, 51))	('DPP4', 'Gene', '1803', (102, 106))	('expression', 'MPA', (67, 77))	('upregulate', 'PosReg', (52, 62))	('membrane', 'cellular_component', 'GO:0016020', ('81', '89'))
120553	33643820	S10B and S10C), indicating DPP4 may interact with NOX1 to induce ferroptosis in SUV39H1 deficient ccRCC cells.	('deficient', 'NegReg', (88, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('S10B', 'SUBSTITUTION', 'None', (0, 4))	('S10C', 'Mutation', 'p.S10C', (9, 13))	('SUV39H1', 'Gene', (80, 87))	('ferroptosis', 'CPA', (65, 76))	('induce', 'PosReg', (58, 64))	('NOX1', 'Gene', (50, 54))	('NOX1', 'Gene', '27035', (50, 54))	('interact', 'Interaction', (36, 44))	('DPP4', 'Gene', '1803', (27, 31))	('DPP4', 'Gene', (27, 31))	('S10B', 'Var', (0, 4))	('ferroptosis', 'biological_process', 'GO:0097707', ('65', '76'))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('S10C', 'Var', (9, 13))
120557	33643820	Furthermore, DPP4 knockdown or enzyme inhibition partially restored cell growth in SUV39H1-deficient ccRCC cells (Fig.	('knockdown', 'Var', (18, 27))	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('cell growth', 'biological_process', 'GO:0016049', ('68', '79'))	('restored', 'PosReg', (59, 67))	('DPP4', 'Gene', (13, 17))	('SUV39H1-deficient', 'Gene', (83, 100))	('cell growth', 'CPA', (68, 79))	('DPP4', 'Gene', '1803', (13, 17))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))
120563	33643820	Finally, patients with a high level of SUV39H1 expression and a low level of DPP4 expression had an even worse prognosis (Fig.	('patients', 'Species', '9606', (9, 17))	('SUV39H1', 'Var', (39, 46))	('DPP4', 'Gene', (77, 81))	('DPP4', 'Gene', '1803', (77, 81))
120569	33643820	Aberrant histone modification is one of the most common events observed in carcinogenesis.	('Aberrant', 'Var', (0, 8))	('histone modification', 'biological_process', 'GO:0016570', ('9', '29'))	('carcinogenesis', 'Disease', (75, 89))	('carcinogenesis', 'Disease', 'MESH:D063646', (75, 89))
120572	33643820	In the present study, we show that SUV39H1 plays a critical role in ccRCC progression and prognosis, and impacts tumor growth by regulating ferroptotic cell death.	('impacts tumor', 'Disease', 'MESH:D014095', (105, 118))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('impacts tumor', 'Disease', (105, 118))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('regulating', 'Reg', (129, 139))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('SUV39H1', 'Var', (35, 42))	('cell death', 'biological_process', 'GO:0008219', ('152', '162'))	('ferroptotic cell death', 'CPA', (140, 162))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
120573	33643820	By analyzing data from the public TCGA database and our own ccRCC cohorts, we found that SUV39H1 is overexpressed in ccRCC tumors, and that SUV39H1 expression levels are significantly correlated with shortened OS and RFS in ccRCC patients.	('overexpressed', 'PosReg', (100, 113))	('ccRCC tumors', 'Disease', 'MESH:D009369', (117, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('RCC', 'Disease', (226, 229))	('RCC', 'Phenotype', 'HP:0005584', (226, 229))	('correlated with', 'Reg', (184, 199))	('SUV39H1', 'Gene', (89, 96))	('SUV39H1', 'Var', (140, 147))	('RFS', 'Disease', 'MESH:D005198', (217, 220))	('ccRCC', 'Phenotype', 'HP:0006770', (224, 229))	('RCC', 'Disease', 'MESH:C538614', (226, 229))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('RCC', 'Disease', (119, 122))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('shortened OS', 'Disease', (200, 212))	('patients', 'Species', '9606', (230, 238))	('RFS', 'Disease', (217, 220))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('ccRCC tumors', 'Disease', (117, 129))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('expression', 'MPA', (148, 158))
120575	33643820	In addition, we demonstrated that knocking down SUV39H1 expression or pharmacologically inhibiting SUV39H1 activity suppresses ccRCC cell growth in vitro and in vivo.	('SUV39H1', 'Gene', (48, 55))	('activity', 'MPA', (107, 115))	('suppresses', 'NegReg', (116, 126))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('RCC', 'Disease', (129, 132))	('expression', 'MPA', (56, 66))	('SUV39H1', 'Gene', (99, 106))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('cell growth', 'biological_process', 'GO:0016049', ('133', '144'))	('inhibiting', 'NegReg', (88, 98))	('knocking down', 'Var', (34, 47))
120577	33643820	Thus, our findings provide an insight into the functional role of SUV39H1 in ccRCC progression and prognosis, and suggest that SUV39H1 could be used as a prognostic marker for ccRCC progression and a therapeutic target for ccRCC treatment.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('RCC', 'Disease', (225, 228))	('RCC', 'Phenotype', 'HP:0005584', (225, 228))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('SUV39H1', 'Var', (127, 134))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('ccRCC', 'Phenotype', 'HP:0006770', (223, 228))	('RCC', 'Disease', (178, 181))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('ccRCC', 'Phenotype', 'HP:0006770', (176, 181))	('SUV39H1', 'Gene', (66, 73))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
120582	33643820	Here, we found that SUV39H1 expression level is an independent prognostic factor for ccRCC patient outcome.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('SUV39H1', 'Var', (20, 27))	('patient', 'Species', '9606', (91, 98))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
120584	33643820	Importantly, when combined with several clinical features, analyzing SUV39H1 expression levels could predict ccRCC patient outcomes with greater accuracy than the conventional SSIGN prognostic model, which is a powerful predictor of prognosis in ccRCC patients who have undergone radical nephrectomy.	('patient', 'Species', '9606', (252, 259))	('RCC', 'Disease', 'MESH:C538614', (248, 251))	('ccRCC', 'Phenotype', 'HP:0006770', (246, 251))	('RCC', 'Disease', (248, 251))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('RCC', 'Disease', (111, 114))	('predict', 'Reg', (101, 108))	('patients', 'Species', '9606', (252, 260))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('patient', 'Species', '9606', (115, 122))	('SUV39H1', 'Var', (69, 76))	('RCC', 'Phenotype', 'HP:0005584', (248, 251))
120585	33643820	Ideally, with more and more external validations of our findings, we believe that SUV39H1 could be considered as a powerful predictor of prognosis in ccRCC patients.	('patients', 'Species', '9606', (156, 164))	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('ccRCC', 'Phenotype', 'HP:0006770', (150, 155))	('RCC', 'Disease', (152, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('SUV39H1', 'Var', (82, 89))
120589	33643820	Here we show that SUV39H1 deficiency increases intracellular lipid ROS, mitochondrial superoxide and iron levels, indicating that the HMTase SUV39H1 may regulate ferroptosis in ccRCC cells.	('lipid ROS', 'Chemical', '-', (61, 70))	('intracellular lipid ROS', 'MPA', (47, 70))	('HMTase', 'Gene', '56979', (134, 140))	('RCC', 'Phenotype', 'HP:0005584', (179, 182))	('RCC', 'Disease', (179, 182))	('superoxide', 'Chemical', 'MESH:D013481', (86, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (177, 182))	('HMTase', 'Gene', (134, 140))	('iron levels', 'MPA', (101, 112))	('iron', 'Chemical', 'MESH:D007501', (101, 105))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('ferroptosis', 'biological_process', 'GO:0097707', ('162', '173'))	('SUV39H1', 'Gene', (18, 25))	('intracellular', 'cellular_component', 'GO:0005622', ('47', '60'))	('deficiency', 'Var', (26, 36))	('regulate', 'Reg', (153, 161))	('ferroptosis', 'CPA', (162, 173))	('increases', 'PosReg', (37, 46))	('mitochondrial superoxide', 'MPA', (72, 96))
120591	33643820	Our findings provide the insight into the role of epigenetic alteration in regulating ferroptosis, as well as the biological processes underlying ccRCC progression.	('RCC', 'Disease', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('epigenetic alteration', 'Var', (50, 71))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('ferroptosis', 'Protein', (86, 97))	('ferroptosis', 'biological_process', 'GO:0097707', ('86', '97'))
120594	33643820	However, our RNA-seq data show that there is no significant expression change for GPX4 after SUV39H1 knockdown.	('expression', 'MPA', (60, 70))	('GPX4', 'Gene', (82, 86))	('GPX4', 'Gene', '2879', (82, 86))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('knockdown', 'Var', (101, 110))
120599	33643820	In our study, we demonstrated that SUV39H1 deficiency upregulated DPP4 expression.	('expression', 'MPA', (71, 81))	('SUV39H1', 'Gene', (35, 42))	('DPP4', 'Gene', '1803', (66, 70))	('upregulated', 'PosReg', (54, 65))	('DPP4', 'Gene', (66, 70))	('deficiency', 'Var', (43, 53))
120600	33643820	Knocking down DPP4 expression or inhibiting DPP4 enzyme activity restored intracellular lipid ROS and iron levels, and partially restored cell growth in SUV39H1-deficient ccRCC cells, suggesting that DPP4 is a functional target of SUV39H1 in mediating ccRCC ferroptosis and cell proliferation.	('DPP4', 'Gene', '1803', (14, 18))	('enzyme activity', 'molecular_function', 'GO:0003824', ('49', '64'))	('cell growth', 'biological_process', 'GO:0016049', ('138', '149'))	('ferroptosis', 'biological_process', 'GO:0097707', ('258', '269'))	('cell growth', 'CPA', (138, 149))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('restored', 'PosReg', (65, 73))	('cell proliferation', 'biological_process', 'GO:0008283', ('274', '292'))	('ccRCC ferroptosis', 'Disease', 'None', (252, 269))	('DPP4', 'Gene', '1803', (44, 48))	('iron levels', 'MPA', (102, 113))	('iron', 'Chemical', 'MESH:D007501', (102, 106))	('intracellular', 'cellular_component', 'GO:0005622', ('74', '87'))	('expression', 'MPA', (19, 29))	('activity', 'MPA', (56, 64))	('DPP4', 'Gene', (14, 18))	('inhibiting', 'NegReg', (33, 43))	('DPP4', 'Gene', (44, 48))	('lipid ROS', 'Chemical', '-', (88, 97))	('intracellular lipid ROS', 'MPA', (74, 97))	('DPP4', 'Gene', '1803', (200, 204))	('RCC', 'Disease', (254, 257))	('RCC', 'Phenotype', 'HP:0005584', (254, 257))	('ccRCC', 'Phenotype', 'HP:0006770', (252, 257))	('RCC', 'Disease', (173, 176))	('Knocking down', 'Var', (0, 13))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('ccRCC', 'Phenotype', 'HP:0006770', (171, 176))	('ccRCC ferroptosis', 'Disease', (252, 269))	('RCC', 'Disease', 'MESH:C538614', (254, 257))	('restored', 'PosReg', (129, 137))	('DPP4', 'Gene', (200, 204))
120601	33643820	Furthermore, we found that SUV39H1 deficiency upregulates DPP4 expression by decreasing H3K9me3 levels at the DPP4 promoter.	('DPP4', 'Gene', '1803', (110, 114))	('decreasing', 'NegReg', (77, 87))	('DPP4', 'Gene', '1803', (58, 62))	('upregulates', 'PosReg', (46, 57))	('expression', 'MPA', (63, 73))	('deficiency', 'Var', (35, 45))	('DPP4', 'Gene', (58, 62))	('DPP4', 'Gene', (110, 114))	('SUV39H1', 'Gene', (27, 34))	('H3K9me3 levels', 'MPA', (88, 102))
120602	33643820	Taken together, these results demonstrate that SUV39H1 negatively regulates DPP4 expression by modulating H3K9me3 levels at the DPP4 promoter during ccRCC cell growth.	('H3K9me3 levels', 'MPA', (106, 120))	('DPP4', 'Gene', '1803', (128, 132))	('SUV39H1', 'Var', (47, 54))	('negatively', 'NegReg', (55, 65))	('DPP4', 'Gene', '1803', (76, 80))	('cell growth', 'biological_process', 'GO:0016049', ('155', '166'))	('regulates', 'Reg', (66, 75))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (151, 154))	('modulating', 'Reg', (95, 105))	('DPP4', 'Gene', (128, 132))	('DPP4', 'Gene', (76, 80))	('ccRCC', 'Phenotype', 'HP:0006770', (149, 154))	('expression', 'MPA', (81, 91))
120603	33643820	Thus, our study provides a mechanistic insight into the impact of SUV39H1 on ccRCC tumor growth, which may provide a strategy for ccRCC treatment.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('ccRCC tumor', 'Disease', 'MESH:D009369', (77, 88))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (130, 135))	('ccRCC tumor', 'Disease', (77, 88))	('SUV39H1', 'Var', (66, 73))	('impact', 'Reg', (56, 62))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
120604	33643820	Although our study presents meaningful findings regarding the role of SUV39H1 in ccRCC progression, it does have several limitations.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('SUV39H1', 'Var', (70, 77))
120608	33643820	However, chaetocin is a non-selective histone lysine methyltransferase inhibitor which targeted SUV39H1, G9a and DIM5 at the same time.	('G9a', 'Gene', (105, 108))	('lysine', 'Chemical', 'MESH:D008239', (46, 52))	('G9a', 'Gene', '10919', (105, 108))	('SUV39H1', 'Var', (96, 103))	('chaetocin', 'Chemical', 'MESH:C002511', (9, 18))
120609	33643820	Additionally, our data show that suppressing ferroptosis only partially restored cell growth in SUV39H1-deficient ccRCC cells, suggesting the SUV39H1 may also regulate ccRCC cell proliferation through other ferroptosis-independent mechanisms.	('cell proliferation', 'biological_process', 'GO:0008283', ('174', '192'))	('ferroptosis', 'biological_process', 'GO:0097707', ('45', '56'))	('RCC', 'Disease', (170, 173))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('cell growth', 'CPA', (81, 92))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('ccRCC', 'Phenotype', 'HP:0006770', (168, 173))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('ferroptosis', 'biological_process', 'GO:0097707', ('207', '218'))	('cell growth', 'biological_process', 'GO:0016049', ('81', '92'))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('regulate', 'Reg', (159, 167))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))	('SUV39H1', 'Var', (142, 149))
120610	33643820	As shown in our data, SUV39H deficiency could also induce G2/M cell cycle arrest, which is independent of ferroptosis.	('SUV39H', 'Gene', (22, 28))	('ferroptosis', 'biological_process', 'GO:0097707', ('106', '117'))	('induce', 'Reg', (51, 57))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('63', '80'))	('arrest', 'Disease', 'MESH:D006323', (74, 80))	('SUV39H', 'Gene', '6839', (22, 28))	('deficiency', 'Var', (29, 39))	('arrest', 'Disease', (74, 80))
120612	33643820	In conclusion, our study provides the mechanistic insight into SUV39H1-dependent epigenetic regulation of ccRCC tumor growth, indicating that SUV39H1 may serve as a prognostic biomarker for ccRCC progression and a therapeutic target for ccRCC treatment.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('ccRCC tumor', 'Disease', (106, 117))	('regulation', 'biological_process', 'GO:0065007', ('92', '102'))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('ccRCC tumor', 'Disease', 'MESH:D009369', (106, 117))	('RCC', 'Disease', (239, 242))	('RCC', 'Phenotype', 'HP:0005584', (239, 242))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('RCC', 'Disease', 'MESH:C538614', (239, 242))	('RCC', 'Disease', (192, 195))	('RCC', 'Phenotype', 'HP:0005584', (192, 195))	('ccRCC', 'Phenotype', 'HP:0006770', (237, 242))	('ccRCC', 'Phenotype', 'HP:0006770', (190, 195))	('SUV39H1', 'Var', (142, 149))
120617	33425212	A nine-redox-related lncRNA signature consisted of AC025580.3, COLCA1, AC027601.2, DLEU2, AC004918.3, AP006621.2, AL031670.1, SPINT1-AS1, and LAMA5-AS1 was significantly associated with overall survival in ccRCC patients.	('DLEU2', 'Gene', '8847', (83, 88))	('DLEU2', 'Gene', (83, 88))	('AS1', 'Gene', (133, 136))	('overall', 'MPA', (186, 193))	('AC027601.2', 'Var', (71, 81))	('AP006621.2', 'Var', (102, 112))	('associated with', 'Reg', (170, 185))	('SPINT1', 'Gene', (126, 132))	('AS1', 'Gene', (148, 151))	('ccRCC', 'Disease', (206, 211))	('AL031670.1', 'Var', (114, 124))	('RCC', 'Phenotype', 'HP:0005584', (208, 211))	('AC004918.3', 'Var', (90, 100))	('AS1', 'Gene', '5729', (133, 136))	('COLCA1', 'Gene', (63, 69))	('ccRCC', 'Phenotype', 'HP:0006770', (206, 211))	('AC025580.3', 'Var', (51, 61))	('LAMA5', 'Gene', (142, 147))	('SPINT1', 'Gene', '6692', (126, 132))	('AS1', 'Gene', '5729', (148, 151))	('LAMA5', 'Gene', '3911', (142, 147))	('COLCA1', 'Gene', '399948', (63, 69))
120636	33425212	Regulation of reactive oxygen species (ROS) production is crucial in highly proliferative cancer cells, owing to the presence of oncogenic mutations that promote aberrant metabolism and gene expression.	('ROS', 'Chemical', 'MESH:D017382', (39, 42))	('aberrant metabolism', 'MPA', (162, 181))	('promote', 'PosReg', (154, 161))	('mutations', 'Var', (139, 148))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('metabolism', 'biological_process', 'GO:0008152', ('171', '181'))	('gene expression', 'biological_process', 'GO:0010467', ('186', '201'))	('gene expression', 'MPA', (186, 201))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (14, 37))
120643	31861720	Signal transducer and activator of transcription-3 (STAT3) and STAT5 are aberrantly activated through tyrosine phosphorylation in a wide variety of cancer types, including EOC.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('STAT5', 'Gene', (63, 68))	('EOC', 'Phenotype', 'HP:0025318', (172, 175))	('activated', 'PosReg', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('transcription', 'biological_process', 'GO:0006351', ('35', '48'))	('EOC', 'Disease', (172, 175))	('EOC', 'Disease', 'MESH:D010051', (172, 175))	('tyrosine', 'Chemical', 'MESH:D014443', (102, 110))	('Signal transducer and activator of transcription-3', 'Gene', '6774', (0, 50))	('tyrosine phosphorylation', 'Var', (102, 126))	('phosphorylation', 'biological_process', 'GO:0016310', ('111', '126'))
120659	31861720	In particular, mice carrying homozygous deletion for STAT5 (STAT5a-/-5b-/-) which later turned out to be hypermorphic STAT5 deletion mice lacking the N-domains were infertile, with defects in the differentiation of functional corpora lutea, disrupting ovarian development.	('mice', 'Species', '10090', (133, 137))	('N-domains', 'MPA', (150, 159))	('infertile', 'Disease', (165, 174))	('deletion', 'Var', (40, 48))	('STAT5a', 'Gene', '20850', (60, 66))	('lacking', 'NegReg', (138, 145))	('disrupting', 'NegReg', (241, 251))	('mice', 'Species', '10090', (15, 19))	('ovarian development', 'biological_process', 'GO:0008585', ('252', '271'))	('STAT5', 'Gene', (53, 58))	('ovarian', 'Disease', 'MESH:D010049', (252, 259))	('ovarian', 'Disease', (252, 259))	('STAT5a', 'Gene', (60, 66))	('defects', 'NegReg', (181, 188))	('deletion', 'Var', (124, 132))
120660	31861720	Clinically, aberrant activation of STAT3 and, to some extent, STAT5, is associated with both solid and hematopoietic cancers.	('STAT3', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('STAT5', 'Gene', (62, 67))	('associated', 'Reg', (72, 82))	('hematopoietic cancers', 'Disease', 'MESH:D009369', (103, 124))	('aberrant', 'Var', (12, 20))	('hematopoietic cancers', 'Disease', (103, 124))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('activation', 'PosReg', (21, 31))
120663	31861720	Compared to normal or benign ovarian tumors, pY-STAT3/pY-STAT5 protein expression was significantly higher in the malignant EOC tissues, supporting its role in ovarian carcinogenesis.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('benign ovarian tumors', 'Disease', (22, 43))	('ovarian carcinogenesis', 'Disease', (160, 182))	('pY', 'Chemical', '-', (54, 56))	('EOC', 'Phenotype', 'HP:0025318', (124, 127))	('ovarian tumors', 'Phenotype', 'HP:0100615', (29, 43))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('ovarian carcinogenesis', 'Disease', 'MESH:D010049', (160, 182))	('EOC', 'Disease', 'MESH:D010051', (124, 127))	('higher', 'PosReg', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('pY', 'Chemical', '-', (45, 47))	('EOC', 'Disease', (124, 127))	('benign ovarian tumors', 'Disease', 'MESH:D010051', (22, 43))	('pY-STAT3/pY-STAT5', 'Var', (45, 62))
120664	31861720	The activation of the STAT3 pathway and the increase in pY-STAT3 (Tyr705) expression directly correlated with higher clinical stage, lower degree of differentiation, presence of lymph node metastasis, and more reduced survival in EOC.	('lower', 'NegReg', (133, 138))	('EOC', 'Phenotype', 'HP:0025318', (230, 233))	('survival', 'CPA', (218, 226))	('reduced', 'NegReg', (210, 217))	('Tyr705', 'Chemical', '-', (66, 72))	('STAT3 pathway', 'Pathway', (22, 35))	('EOC', 'Disease', 'MESH:D010051', (230, 233))	('increase', 'PosReg', (44, 52))	('pY-STAT3', 'Var', (56, 64))	('EOC', 'Disease', (230, 233))	('pY', 'Chemical', '-', (56, 58))	('higher', 'PosReg', (110, 116))	('activation', 'PosReg', (4, 14))
120665	31861720	Moreover, elevated pY-STAT3 expression in the omentum was associated with poor survival in patients with high-grade EOC.	('patients', 'Species', '9606', (91, 99))	('EOC', 'Disease', 'MESH:D010051', (116, 119))	('poor', 'NegReg', (74, 78))	('pY', 'Chemical', '-', (19, 21))	('EOC', 'Disease', (116, 119))	('elevated', 'PosReg', (10, 18))	('EOC', 'Phenotype', 'HP:0025318', (116, 119))	('pY-STAT3', 'Var', (19, 27))
120667	31861720	Specifically, nuclear pY-STAT3 expression was found to be associated with clear cell and serous carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('nuclear pY-STAT3 expression', 'Var', (14, 41))	('associated', 'Reg', (58, 68))	('clear cell', 'Disease', (74, 84))	('pY', 'Chemical', '-', (22, 24))	('serous carcinoma', 'Disease', (89, 105))	('serous carcinoma', 'Disease', 'MESH:D018284', (89, 105))
120671	31861720	As a primary event during malignant transformation, somatic STAT3 and STAT5 driver mutations have been identified in hematopoietic neoplasms.	('mutations', 'Var', (83, 92))	('STAT5', 'Gene', (70, 75))	('hematopoietic neoplasms', 'Phenotype', 'HP:0004377', (117, 140))	('hematopoietic neoplasms', 'Disease', (117, 140))	('neoplasms', 'Phenotype', 'HP:0002664', (131, 140))	('hematopoietic neoplasms', 'Disease', 'MESH:D019337', (117, 140))
120672	31861720	For example, somatic mutations in the STAT3 gene were found in 40% of granular lymphocytic leukemia and T-cell lymphoma patients, with recurrent mutations located on the gene segment encoding the SH2 domain, which mediates STAT3 dimerization and activation.	('T-cell lymphoma', 'Disease', (104, 119))	('mutations', 'Var', (145, 154))	('leukemia', 'Phenotype', 'HP:0001909', (91, 99))	('found', 'Reg', (54, 59))	('cell lymphoma', 'Phenotype', 'HP:0012191', (106, 119))	('patients', 'Species', '9606', (120, 128))	('granular lymphocytic leukemia', 'Disease', (70, 99))	('granular lymphocytic leukemia', 'Disease', 'MESH:D054066', (70, 99))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (104, 119))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (104, 119))	('STAT3', 'Gene', (38, 43))	('lymphoma', 'Phenotype', 'HP:0002665', (111, 119))	('mutations', 'Var', (21, 30))
120673	31861720	Also, a small percentage of granular lymphocytic leukemia patients harbored STAT5B mutations, resulting in increased transcriptional activity and phosphorylation.	('mutations', 'Var', (83, 92))	('increased', 'PosReg', (107, 116))	('leukemia', 'Phenotype', 'HP:0001909', (49, 57))	('STAT5B', 'Gene', (76, 82))	('granular lymphocytic leukemia', 'Disease', (28, 57))	('transcriptional activity', 'MPA', (117, 141))	('granular lymphocytic leukemia', 'Disease', 'MESH:D054066', (28, 57))	('phosphorylation', 'biological_process', 'GO:0016310', ('146', '161'))	('patients', 'Species', '9606', (58, 66))	('phosphorylation', 'MPA', (146, 161))	('STAT5B', 'Gene', '6777', (76, 82))
120677	31861720	Typically, STAT3/STAT5 are activated by phosphorylation on critical residues (STAT3 Tyr residue 705 and Ser727 (ERK, JNK, and other stress kinases); STAT5A Tyr residue 694, Ser725 (CDK8) and Ser779 (PAK1/2) and STAT5B Tyr residue 699 and Ser730 (CDK8)).	('Ser725', 'Var', (173, 179))	('Ser', 'cellular_component', 'GO:0005790', ('173', '176'))	('Tyr', 'Chemical', 'MESH:D014443', (156, 159))	('STAT5A', 'Gene', (149, 155))	('Tyr', 'Chemical', 'MESH:D014443', (84, 87))	('Ser', 'cellular_component', 'GO:0005790', ('238', '241'))	('CDK', 'molecular_function', 'GO:0004693', ('181', '184'))	('Ser730', 'Var', (238, 244))	('Ser779', 'Var', (191, 197))	('STAT5B', 'Gene', '6777', (211, 217))	('ERK', 'molecular_function', 'GO:0004707', ('112', '115'))	('Ser779', 'Chemical', '-', (191, 197))	('Ser727', 'Chemical', '-', (104, 110))	('CDK8', 'Gene', (246, 250))	('Ser', 'cellular_component', 'GO:0005790', ('104', '107'))	('Tyr', 'Chemical', 'MESH:D014443', (218, 221))	('CDK8', 'Gene', (181, 185))	('PAK1/2', 'Gene', (199, 205))	('Ser', 'cellular_component', 'GO:0005790', ('191', '194'))	('JNK', 'Gene', (117, 120))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('JNK', 'Gene', '5599', (117, 120))	('Ser725', 'Chemical', '-', (173, 179))	('PAK1/2', 'Gene', '5058;5062', (199, 205))	('JNK', 'molecular_function', 'GO:0004705', ('117', '120'))	('CDK', 'molecular_function', 'GO:0004693', ('246', '249'))	('ERK', 'Gene', (112, 115))	('CDK8', 'Gene', '1024', (246, 250))	('Ser730', 'Chemical', '-', (238, 244))	('CDK8', 'Gene', '1024', (181, 185))	('Tyr residue 694', 'Var', (156, 171))	('STAT5A', 'Gene', '6776', (149, 155))	('ERK', 'Gene', '2048', (112, 115))	('STAT5B', 'Gene', (211, 217))
120682	31861720	Notably, Tyr phosphorylation of JAK2 can be diminished by wild type but not mutant p53 in EOC cells.	('Tyr phosphorylation', 'MPA', (9, 28))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('diminished', 'NegReg', (44, 54))	('EOC', 'Phenotype', 'HP:0025318', (90, 93))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('mutant', 'Var', (76, 82))	('JAK2', 'Protein', (32, 36))	('Tyr', 'Chemical', 'MESH:D014443', (9, 12))	('EOC', 'Disease', 'MESH:D010051', (90, 93))	('JAK', 'molecular_function', 'GO:0004713', ('32', '35'))	('EOC', 'Disease', (90, 93))
120683	31861720	Since there is a high frequency of somatic TP53 mutation in high-grade serous carcinoma (HGSC), this suggests that STAT3 phosphorylation and its DNA binding activity can be modulated by the p53 status in HGSC.	('DNA', 'cellular_component', 'GO:0005574', ('145', '148'))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('DNA binding', 'Interaction', (145, 156))	('p53', 'Gene', (190, 193))	('p53', 'Gene', '7157', (190, 193))	('DNA binding', 'molecular_function', 'GO:0003677', ('145', '156'))	('serous carcinoma', 'Disease', (71, 87))	('mutation', 'Var', (48, 56))	('STAT3 phosphorylation', 'MPA', (115, 136))	('serous carcinoma', 'Disease', 'MESH:D018284', (71, 87))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('phosphorylation', 'biological_process', 'GO:0016310', ('121', '136'))
120695	31861720	Oncogenic RAS and RAF mutations are prevalent in EOC, and these driver mutations are highly associated with aberrant ERK signaling, resulting in uncontrolled cellular proliferation.	('RAF', 'Gene', '22882', (18, 21))	('signaling', 'biological_process', 'GO:0023052', ('121', '130'))	('ERK', 'Gene', (117, 120))	('RAF', 'Gene', (18, 21))	('RAS', 'Gene', (10, 13))	('EOC', 'Phenotype', 'HP:0025318', (49, 52))	('uncontrolled', 'MPA', (145, 157))	('ERK', 'molecular_function', 'GO:0004707', ('117', '120'))	('mutations', 'Var', (22, 31))	('EOC', 'Disease', (49, 52))	('EOC', 'Disease', 'MESH:D010051', (49, 52))	('associated', 'Reg', (92, 102))	('ERK', 'Gene', '2048', (117, 120))
120698	31861720	Aberrant phosphorylation of ERK mediates phosphorylation of S727-STAT3 (Figure 1) and contributes to cisplatin resistance in certain EOC cell lines.	('ERK', 'Gene', (28, 31))	('ERK', 'Gene', '2048', (28, 31))	('phosphorylation', 'biological_process', 'GO:0016310', ('9', '24'))	('S727-STAT3', 'Var', (60, 70))	('Aberrant', 'Var', (0, 8))	('phosphorylation', 'biological_process', 'GO:0016310', ('41', '56'))	('contributes to', 'Reg', (86, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('EOC', 'Disease', (133, 136))	('EOC', 'Disease', 'MESH:D010051', (133, 136))	('phosphorylation', 'MPA', (41, 56))	('cisplatin resistance', 'MPA', (101, 121))	('ERK', 'molecular_function', 'GO:0004707', ('28', '31'))	('EOC', 'Phenotype', 'HP:0025318', (133, 136))	('phosphorylation', 'MPA', (9, 24))
120711	31861720	Interestingly, upon Tyr372 phosphorylation of EZH2 by protein kinase A, pY372-EZH2 efficiently interacted with STAT3 protein.	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('Tyr372', 'Chemical', '-', (20, 26))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('protein kinase A', 'Enzyme', (54, 70))	('EZH2', 'Gene', '2146', (46, 50))	('interacted', 'Interaction', (95, 105))	('pY', 'Chemical', '-', (72, 74))	('Tyr372', 'Var', (20, 26))	('EZH2', 'Gene', (46, 50))	('EZH2', 'Gene', (78, 82))	('EZH2', 'Gene', '2146', (78, 82))
120713	31861720	Furthermore, tyrosine phosphorylation of EZH2 by JAK3 in lymphoid neoplasia was reported to promote dissociation of the polycomb repressive complex 2 (PRC2) complex leading to decreased global H3K27me3 levels while it switches EZH2 to a transcriptional activator, but studies in EOC are lacking.	('PRC2', 'Gene', (151, 155))	('lymphoid neoplasia', 'Disease', (57, 75))	('EOC', 'Phenotype', 'HP:0025318', (279, 282))	('EZH2', 'Gene', (41, 45))	('EZH2', 'Gene', '2146', (41, 45))	('global H3K27me3 levels', 'MPA', (186, 208))	('decreased', 'NegReg', (176, 185))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('tyrosine', 'Chemical', 'MESH:D014443', (13, 21))	('JAK3', 'Gene', '3718', (49, 53))	('lymphoid neoplasia', 'Phenotype', 'HP:0002665', (57, 75))	('neoplasia', 'Phenotype', 'HP:0002664', (66, 75))	('PRC2) complex', 'cellular_component', 'GO:0035098', ('151', '164'))	('EOC', 'Disease', (279, 282))	('tyrosine phosphorylation', 'Var', (13, 37))	('promote', 'PosReg', (92, 99))	('EZH2', 'Gene', '2146', (227, 231))	('lymphoid neoplasia', 'Disease', 'MESH:D009369', (57, 75))	('EOC', 'Disease', 'MESH:D010051', (279, 282))	('EZH2', 'Gene', (227, 231))	('JAK', 'molecular_function', 'GO:0004713', ('49', '52'))	('dissociation', 'MPA', (100, 112))	('JAK3', 'Gene', (49, 53))
120721	31861720	Inhibition of STAT3 signaling leads to apoptosis of ovarian clear cell carcinoma and decreased BCL-2 expression.	('apoptosis of ovarian clear cell carcinoma', 'Disease', (39, 80))	('decreased', 'NegReg', (85, 94))	('apoptosis', 'biological_process', 'GO:0097194', ('39', '48'))	('BCL-2', 'Gene', (95, 100))	('apoptosis of ovarian clear cell carcinoma', 'Disease', 'MESH:D010051', (39, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('apoptosis', 'biological_process', 'GO:0006915', ('39', '48'))	('BCL-2', 'molecular_function', 'GO:0015283', ('95', '100'))	('Inhibition', 'Var', (0, 10))	('signaling', 'biological_process', 'GO:0023052', ('20', '29'))	('BCL-2', 'Gene', '596', (95, 100))
120725	31861720	In paclitaxel-resistant ovarian cancer cells, blocking of STAT3 activity suppresses STAT3 downstream antiapoptotic regulatory genes BCL2L1, MCL1, and BIRC5, which increases paclitaxel sensitivity in paclitaxel-resistant ovarian cancer cells in vitro.	('increases', 'PosReg', (163, 172))	('MCL1', 'Gene', (140, 144))	('ovarian cancer', 'Disease', (220, 234))	('blocking', 'Var', (46, 54))	('paclitaxel', 'Chemical', 'MESH:D017239', (3, 13))	('BCL2', 'molecular_function', 'GO:0015283', ('132', '136'))	('BCL2L1', 'Gene', '598', (132, 138))	('ovarian cancer', 'Disease', 'MESH:D010051', (24, 38))	('MCL1', 'Gene', '4170', (140, 144))	('paclitaxel sensitivity', 'MPA', (173, 195))	('ovarian cancer', 'Phenotype', 'HP:0100615', (220, 234))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('paclitaxel', 'Chemical', 'MESH:D017239', (199, 209))	('suppresses', 'NegReg', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('ovarian cancer', 'Disease', (24, 38))	('BCL2L1', 'Gene', (132, 138))	('STAT3 downstream antiapoptotic regulatory genes', 'MPA', (84, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (24, 38))	('paclitaxel', 'Chemical', 'MESH:D017239', (173, 183))	('BIRC5', 'Gene', '332', (150, 155))	('STAT3 activity', 'Gene', (58, 72))	('BIRC5', 'Gene', (150, 155))	('ovarian cancer', 'Disease', 'MESH:D010051', (220, 234))
120726	31861720	Similarly, abrogation of constitutive STAT3 activity shows significant reductions in the expression of the BCL-2, BCL-XL, and Survivin protein, which circumvents cisplatin resistance in EOC.	('BCL-2', 'molecular_function', 'GO:0015283', ('107', '112'))	('expression', 'MPA', (89, 99))	('EOC', 'Disease', (186, 189))	('cisplatin', 'Chemical', 'MESH:D002945', (162, 171))	('BCL-XL', 'Gene', '598', (114, 120))	('abrogation', 'Var', (11, 21))	('Survivin protein', 'Protein', (126, 142))	('reductions', 'NegReg', (71, 81))	('BCL-2', 'Gene', (107, 112))	('BCL-2', 'Gene', '596', (107, 112))	('EOC', 'Phenotype', 'HP:0025318', (186, 189))	('circumvents', 'NegReg', (150, 161))	('cisplatin resistance', 'MPA', (162, 182))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('BCL-XL', 'Gene', (114, 120))	('EOC', 'Disease', 'MESH:D010051', (186, 189))
120728	31861720	miR-17-5p, miR-133b, miR-134, miR-13, miR-147, miR-182, miR-204, miR-874 are among a few miRNAs that require either STAT3 or STAT5 to induce apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('141', '150'))	('miR-874', 'Gene', '100126343', (65, 72))	('miR-17-5p', 'Gene', (0, 9))	('miR-133b', 'Gene', '442890', (11, 19))	('miR-182', 'Gene', (47, 54))	('apoptosis', 'biological_process', 'GO:0006915', ('141', '150'))	('miR-133b', 'Gene', (11, 19))	('miR-204', 'Gene', '406987', (56, 63))	('miR-147', 'Gene', (38, 45))	('miR-13', 'Var', (30, 36))	('miR-182', 'Gene', '406958', (47, 54))	('miR-874', 'Gene', (65, 72))	('miR-134', 'Gene', '406924', (21, 28))	('miR-204', 'Gene', (56, 63))	('miR-134', 'Gene', (21, 28))	('miR-17-5p', 'Gene', '406952', (0, 9))	('miR-147', 'Gene', '406939', (38, 45))
120729	31861720	In EOC, miRNA-519a promotes apoptosis of SKOV3 cells by directly targeting the 3'UTR of STAT3, which results in a decrease of the mRNA and protein expression levels of STAT3, Mcl-1, and BCL-XL (For a detailed list, see Table A1).	('Mcl-1', 'Gene', '4170', (175, 180))	('promotes', 'PosReg', (19, 27))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('STAT3', 'MPA', (168, 173))	('EOC', 'Phenotype', 'HP:0025318', (3, 6))	('apoptosis', 'biological_process', 'GO:0097194', ('28', '37'))	('EOC', 'Disease', 'MESH:D010051', (3, 6))	('Mcl-1', 'Gene', (175, 180))	('miRNA-519a', 'Var', (8, 18))	('apoptosis', 'CPA', (28, 37))	('STAT3', 'Gene', (88, 93))	('EOC', 'Disease', (3, 6))	('BCL-XL', 'Gene', (186, 192))	('targeting', 'Reg', (65, 74))	('apoptosis', 'biological_process', 'GO:0006915', ('28', '37'))	('decrease', 'NegReg', (114, 122))	('SKOV3', 'CellLine', 'CVCL:0532', (41, 46))	('BCL-XL', 'Gene', '598', (186, 192))
120737	31861720	Expression of phosphorylated STAT3 coupled with Ki-67 expression, was found to be increased in primary human ovarian carcinoma, particularly in patients with high nuclear expression of pY-STAT3 exhibited poor prognosis.	('Ki-67', 'Gene', (48, 53))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (109, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('human', 'Species', '9606', (103, 108))	('pY-STAT3', 'Var', (185, 193))	('Expression', 'MPA', (0, 10))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (109, 126))	('ovarian carcinoma', 'Disease', (109, 126))	('patients', 'Species', '9606', (144, 152))	('pY', 'Chemical', '-', (185, 187))	('increased', 'PosReg', (82, 91))
120738	31861720	EOC cells cultured under hypoxic conditions revealed higher levels of pY-STAT3 (Tyr705); however, with knockdown of STAT3 expression, the proliferation rate of cancer cells was significantly reduced.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('EOC', 'Phenotype', 'HP:0025318', (0, 3))	('cancer', 'Disease', (160, 166))	('Tyr705', 'Chemical', '-', (80, 86))	('hypoxic conditions', 'Disease', (25, 43))	('reduced', 'NegReg', (191, 198))	('EOC', 'Disease', (0, 3))	('EOC', 'Disease', 'MESH:D010051', (0, 3))	('hypoxic conditions', 'Disease', 'MESH:D009135', (25, 43))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('STAT3', 'Gene', (116, 121))	('pY', 'Chemical', '-', (70, 72))	('knockdown', 'Var', (103, 112))
120750	31861720	Immunohistochemical staining of patient-derived ovarian epithelial carcinoma tissues identified significant overlap of expression between VEGF, pY-STAT3, and pY-STAT5 in ovarian carcinoma cells, compared to the benign and normal group.	('expression', 'MPA', (119, 129))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (170, 187))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (170, 187))	('ovarian epithelial carcinoma', 'Phenotype', 'HP:0025318', (48, 76))	('ovarian carcinoma', 'Disease', (170, 187))	('pY-STAT3', 'Var', (144, 152))	('ovarian epithelial carcinoma', 'Disease', (48, 76))	('pY', 'Chemical', '-', (144, 146))	('pY', 'Chemical', '-', (158, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('ovarian epithelial carcinoma', 'Disease', 'MESH:D010051', (48, 76))	('epithelial carcinoma', 'Phenotype', 'HP:0031492', (56, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('patient', 'Species', '9606', (32, 39))	('pY-STAT5', 'Var', (158, 166))	('VEGF', 'Gene', (138, 142))
120758	31861720	The fact that STAT3 is critically involved in the VEGF pathway and tumor angiogenesis indicates that blockade of STAT3 is a therapeutic target to heighten an effective antiangiogenic treatment in EOC.	('blockade', 'Var', (101, 109))	('EOC', 'Phenotype', 'HP:0025318', (196, 199))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('EOC', 'Disease', 'MESH:D010051', (196, 199))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('EOC', 'Disease', (196, 199))	('STAT3', 'Gene', (113, 118))	('tumor', 'Disease', (67, 72))	('heighten', 'PosReg', (146, 154))	('angiogenesis', 'biological_process', 'GO:0001525', ('73', '85'))
120762	31861720	Accumulation of pY-STAT3 expression coupled with loss of protein inhibitor of activated STAT3 (PIAS3) in fallopian tube secretory epithelial cells displayed common peritoneal metastatic nodules that eventually led to the progression of HGSC.	('loss', 'NegReg', (49, 53))	('Accumulation', 'PosReg', (0, 12))	('PIAS3', 'Gene', (95, 100))	('pY', 'Chemical', '-', (16, 18))	('fallopian tube', 'Disease', (105, 119))	('HGSC', 'Disease', (236, 240))	('protein inhibitor of activated STAT3', 'Gene', (57, 93))	('PIAS3', 'Gene', '10401', (95, 100))	('protein inhibitor of activated STAT3', 'Gene', '10401', (57, 93))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('fallopian tube', 'Disease', 'MESH:D005184', (105, 119))	('pY-STAT3', 'Var', (16, 24))	('led to', 'Reg', (210, 216))
120763	31861720	AKT2, one of the most frequent amplicon alterations in HGSC, activates PKM2-STAT3/NF-kappaB axis, ultimately results in increased migratory and invasive potential of EOC cells as well as promoting lung metastasis in mouse models.	('AKT2', 'Gene', '11652', (0, 4))	('mouse', 'Species', '10090', (216, 221))	('EOC', 'Disease', (166, 169))	('lung metastasis', 'CPA', (197, 212))	('AKT2', 'Gene', (0, 4))	('activates', 'PosReg', (61, 70))	('PKM2', 'Gene', '18746', (71, 75))	('alterations', 'Var', (40, 51))	('EOC', 'Phenotype', 'HP:0025318', (166, 169))	('promoting', 'PosReg', (187, 196))	('increased', 'PosReg', (120, 129))	('EOC', 'Disease', 'MESH:D010051', (166, 169))	('PKM2', 'Gene', (71, 75))
120768	31861720	In EOC, inhibition of EGFR or STAT3 activity reduced N-cadherin, Vimentin expression, decreased colony-forming ability, cell motility, and migration behavior.	('Vimentin', 'Gene', (65, 73))	('EOC', 'Disease', (3, 6))	('Vimentin', 'cellular_component', 'GO:0045099', ('65', '73'))	('expression', 'MPA', (74, 84))	('migration behavior', 'CPA', (139, 157))	('EGFR', 'Gene', '1956', (22, 26))	('inhibition', 'Var', (8, 18))	('cadherin', 'molecular_function', 'GO:0008014', ('55', '63'))	('cell motility', 'biological_process', 'GO:0048870', ('120', '133'))	('EOC', 'Disease', 'MESH:D010051', (3, 6))	('decreased', 'NegReg', (86, 95))	('Vimentin', 'cellular_component', 'GO:0045098', ('65', '73'))	('EOC', 'Phenotype', 'HP:0025318', (3, 6))	('EGFR', 'molecular_function', 'GO:0005006', ('22', '26'))	('reduced', 'NegReg', (45, 52))	('cell motility', 'CPA', (120, 133))	('Vimentin', 'Gene', '7431', (65, 73))	('colony-forming ability', 'CPA', (96, 118))	('N-cadherin', 'Gene', (53, 63))	('EGFR', 'Gene', (22, 26))	('N-cadherin', 'Gene', '1000', (53, 63))
120772	31861720	Over 90% of ascites cells derived from EOC patients showed activated pY-STAT3 signaling (Tyr705), which increased the migratory potential of EOC cells, and it also increased widespread peritoneal metastasis.	('activated', 'PosReg', (59, 68))	('EOC', 'Disease', 'MESH:D010051', (141, 144))	('ascites', 'Disease', 'MESH:D001201', (12, 19))	('increased', 'PosReg', (164, 173))	('widespread peritoneal metastasis', 'CPA', (174, 206))	('EOC', 'Disease', 'MESH:D010051', (39, 42))	('EOC', 'Phenotype', 'HP:0025318', (141, 144))	('Tyr705', 'Var', (89, 95))	('EOC', 'Phenotype', 'HP:0025318', (39, 42))	('ascites', 'Phenotype', 'HP:0001541', (12, 19))	('migratory potential', 'CPA', (118, 137))	('patients', 'Species', '9606', (43, 51))	('EOC', 'Disease', (141, 144))	('pY', 'Chemical', '-', (69, 71))	('Tyr705', 'Chemical', '-', (89, 95))	('signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('increased', 'PosReg', (104, 113))	('EOC', 'Disease', (39, 42))	('pY-STAT3 signaling', 'MPA', (69, 87))	('ascites', 'Disease', (12, 19))
120776	31861720	Therefore, inhibition of STAT3 signaling effectively eliminates the formation of the metastatic niche, and it suppresses cancer cell persistence after chemotherapy.	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('suppresses', 'NegReg', (110, 120))	('eliminates', 'NegReg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('inhibition', 'Var', (11, 21))	('formation', 'biological_process', 'GO:0009058', ('68', '77'))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('formation of the metastatic niche', 'CPA', (68, 101))	('cancer', 'Disease', (121, 127))
120816	31861720	One study indicated exosomes transfer miRNAs, including miR-29a-3p and miR-21-5p, to synergistically induce the Treg/Th17 cell imbalance through direct targeting of STAT3 in CD4+ T cells.	('imbalance', 'Phenotype', 'HP:0002172', (127, 136))	('CD4', 'Gene', '920', (174, 177))	('miR-21-5p', 'Gene', (71, 80))	('induce', 'PosReg', (101, 107))	('miR-21-5p', 'Gene', '406997', (71, 80))	('STAT3', 'Gene', (165, 170))	('CD4', 'Gene', (174, 177))	('miR-29a-3p', 'Var', (56, 66))	('Treg/Th17 cell imbalance', 'CPA', (112, 136))
120839	31861720	EOC patients with a high number of M2 CD68+ and CD163+ macrophages were associated with advanced stage and poor progression-free and overall survival.	('EOC', 'Phenotype', 'HP:0025318', (0, 3))	('CD163+', 'Var', (48, 54))	('progression-free', 'CPA', (112, 128))	('advanced stage', 'CPA', (88, 102))	('EOC', 'Disease', (0, 3))	('EOC', 'Disease', 'MESH:D010051', (0, 3))	('patients', 'Species', '9606', (4, 12))	('poor', 'NegReg', (107, 111))	('M2 CD68+', 'Var', (35, 43))
120840	31861720	Accordingly, ovarian cancer patients with high M1 to M2 ratio of TAMs were associated with extended survival rate, indicating the pro-tumorigenic role of M2 macrophages.	('high M1', 'Var', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('ovarian cancer', 'Phenotype', 'HP:0100615', (13, 27))	('extended', 'PosReg', (91, 99))	('ovarian cancer', 'Disease', 'MESH:D010051', (13, 27))	('TAMs', 'Chemical', '-', (65, 69))	('survival rate', 'CPA', (100, 113))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('ovarian cancer', 'Disease', (13, 27))	('patients', 'Species', '9606', (28, 36))	('tumor', 'Disease', (134, 139))
120842	31861720	Also, the expression of transmembrane protein B4-T7 in TAMs, but not in ovarian carcinoma cells suppressed the T-cell immune response, inversely correlated with patient survival.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('transmembrane', 'cellular_component', 'GO:0044214', ('24', '37'))	('transmembrane', 'cellular_component', 'GO:0016021', ('24', '37'))	('ovarian carcinoma', 'Disease', (72, 89))	('patient', 'Species', '9606', (161, 168))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (72, 89))	('immune response', 'biological_process', 'GO:0006955', ('118', '133'))	('TAMs', 'Chemical', '-', (55, 59))	('suppressed', 'NegReg', (96, 106))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (72, 89))	('T-cell immune response', 'CPA', (111, 133))	('expression', 'Var', (10, 20))
120857	31861720	More importantly, Ruxolitinib substantially enhances the anti-tumor activity of chemotherapy agents, including paclitaxel, cisplatin, carboplatin, doxorubicin, and topotecan in EOC cells.	('topotecan', 'Chemical', 'MESH:D019772', (164, 173))	('cisplatin', 'Chemical', 'MESH:D002945', (123, 132))	('carboplatin', 'Chemical', 'MESH:D016190', (134, 145))	('EOC', 'Disease', (177, 180))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Ruxolitinib', 'Chemical', 'MESH:C540383', (18, 29))	('Ruxolitinib', 'Var', (18, 29))	('enhances', 'PosReg', (44, 52))	('paclitaxel', 'Chemical', 'MESH:D017239', (111, 121))	('tumor', 'Disease', (62, 67))	('doxorubicin', 'Chemical', 'MESH:D004317', (147, 158))	('EOC', 'Phenotype', 'HP:0025318', (177, 180))	('EOC', 'Disease', 'MESH:D010051', (177, 180))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
120867	31861720	In vitro, MLS-2384 suppresses the viability of A2780 cells, which is consistent with the inhibition of phosphorylation of JAK2, SRC, and STAT3.	('JAK', 'molecular_function', 'GO:0004713', ('122', '125'))	('viability', 'CPA', (34, 43))	('inhibition of phosphorylation', 'biological_process', 'GO:0042326', ('89', '118'))	('MLS-2384', 'Var', (10, 18))	('suppresses', 'NegReg', (19, 29))	('inhibition', 'NegReg', (89, 99))	('JAK2', 'Protein', (122, 126))	('A2780', 'CellLine', 'CVCL:0134', (47, 52))	('phosphorylation', 'MPA', (103, 118))	('MLS-2384', 'Chemical', 'MESH:C000592914', (10, 18))	('SRC', 'Gene', (128, 131))	('SRC', 'Gene', '6714', (128, 131))
120869	31861720	AZD1480, a selective JAK2 inhibitor, reduced tumor growth, decreased peritoneal dissemination and diminished ascites production in a murine model for advanced EOC.	('ascites', 'Disease', (109, 116))	('ascites', 'Phenotype', 'HP:0001541', (109, 116))	('diminished', 'NegReg', (98, 108))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('EOC', 'Phenotype', 'HP:0025318', (159, 162))	('ascites', 'Disease', 'MESH:D001201', (109, 116))	('decreased', 'NegReg', (59, 68))	('JAK', 'molecular_function', 'GO:0004713', ('21', '24'))	('peritoneal dissemination', 'CPA', (69, 93))	('tumor', 'Disease', (45, 50))	('AZD1480', 'Var', (0, 7))	('AZD1480', 'Chemical', 'MESH:C545606', (0, 7))	('EOC', 'Disease', 'MESH:D010051', (159, 162))	('murine', 'Species', '10090', (133, 139))	('reduced', 'NegReg', (37, 44))	('EOC', 'Disease', (159, 162))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
120871	31861720	The anticancer analogs from curcumin, diarylidenyl piperidone (DAP) derivatives such as HO-3867, HO-4200, HO-4318, inhibit STAT3 activity and sensitize drug-resistant ovarian carcinoma and clear cell carcinoma cells to paclitaxel or cisplatin.	('HO-4318', 'Var', (106, 113))	('diarylidenyl piperidone', 'Chemical', '-', (38, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('clear cell carcinoma', 'Disease', 'MESH:D002292', (189, 209))	('curcumin', 'Chemical', 'MESH:D003474', (28, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('HO', 'CellLine', 'CVCL:M698', (106, 108))	('cancer', 'Disease', (8, 14))	('DAP', 'Chemical', '-', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('HO', 'CellLine', 'CVCL:M698', (97, 99))	('drug-resistant ovarian carcinoma', 'Disease', 'MESH:D010051', (152, 184))	('HO-4318', 'CellLine', 'CVCL:M698', (106, 113))	('sensitize', 'Reg', (142, 151))	('HO', 'CellLine', 'CVCL:M698', (88, 90))	('HO-3867', 'CellLine', 'CVCL:6E15', (88, 95))	('STAT3 activity', 'MPA', (123, 137))	('drug-resistant ovarian carcinoma', 'Disease', (152, 184))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (167, 184))	('HO-4200', 'Var', (97, 104))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('inhibit', 'NegReg', (115, 122))	('clear cell carcinoma', 'Disease', (189, 209))	('HO-3867', 'Var', (88, 95))	('paclitaxel', 'Chemical', 'MESH:D017239', (219, 229))	('cisplatin', 'Chemical', 'MESH:D002945', (233, 242))
120874	31861720	Additionally, HO-3867 targets hypoxia-stimulated pY-STAT3 (Tyr705) via the ubiquitin-proteasome degradation pathway, leading to tumor growth suppression in xenograft mice and the downregulation of proteins involved in cell survival, proliferation, and angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('proteasome', 'molecular_function', 'GO:0004299', ('85', '95'))	('HO-3867', 'Var', (14, 21))	('pY', 'Chemical', '-', (49, 51))	('ubiquitin-proteasome', 'MPA', (75, 95))	('suppression', 'NegReg', (141, 152))	('downregulation', 'NegReg', (179, 193))	('proteasome', 'cellular_component', 'GO:0000502', ('85', '95'))	('hypoxia', 'Disease', (30, 37))	('Tyr705', 'Chemical', '-', (59, 65))	('tumor', 'Disease', (128, 133))	('angiogenesis', 'biological_process', 'GO:0001525', ('252', '264'))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('proteasome degradation', 'biological_process', 'GO:1903009', ('85', '107'))	('hypoxia', 'Disease', 'MESH:D000860', (30, 37))	('ubiquitin', 'molecular_function', 'GO:0031386', ('75', '84'))	('proteins', 'Protein', (197, 205))	('HO-3867', 'CellLine', 'CVCL:6E15', (14, 21))	('mice', 'Species', '10090', (166, 170))
120875	31861720	Furthermore, HO-4200 and HO-4318 significantly inhibited fatty acid synthase and pY-STAT3 and decreased the expression of STAT3 target proteins in primary platinum-resistant EOC cells, resulting in decreased expression of Ki67 and VEGF in ex-vivo human tumor specimens.	('HO-4200', 'Var', (13, 20))	('EOC', 'Disease', 'MESH:D010051', (174, 177))	('HO-4318', 'Var', (25, 32))	('pY', 'Chemical', '-', (81, 83))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('VEGF', 'Protein', (231, 235))	('expression', 'MPA', (208, 218))	('EOC', 'Phenotype', 'HP:0025318', (174, 177))	('human', 'Species', '9606', (247, 252))	('fatty acid synthase', 'Gene', '2194', (57, 76))	('HO', 'CellLine', 'CVCL:M698', (25, 27))	('Ki67', 'Gene', (222, 226))	('HO-4318', 'CellLine', 'CVCL:M698', (25, 32))	('decreased', 'NegReg', (198, 207))	('EOC', 'Disease', (174, 177))	('decreased', 'NegReg', (94, 103))	('tumor', 'Disease', (253, 258))	('platinum', 'Chemical', 'MESH:D010984', (155, 163))	('inhibited', 'NegReg', (47, 56))	('HO', 'CellLine', 'CVCL:M698', (13, 15))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('expression', 'MPA', (108, 118))	('fatty acid synthase', 'Gene', (57, 76))
120881	31861720	Research in past decades has facilitated our comprehension of the critical roles of aberrant STAT3/STAT5 activation in EOC cells as well as in the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('EOC', 'Disease', (119, 122))	('activation', 'PosReg', (105, 115))	('EOC', 'Disease', 'MESH:D010051', (119, 122))	('STAT3/STAT5', 'MPA', (93, 104))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('aberrant', 'Var', (84, 92))	('EOC', 'Phenotype', 'HP:0025318', (119, 122))
120883	31861720	Accordingly, multiple studies have provided ample evidence to show that interfering with STAT3/STAT5 signaling, through knockdown or inhibitor intervention, resulted in antitumor effects in both in vitro and in vivo animal models carrying human tumors.	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('STAT3/STAT5 signaling', 'MPA', (89, 110))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('interfering', 'NegReg', (72, 83))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('knockdown', 'Var', (120, 129))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', (245, 250))	('human', 'Species', '9606', (239, 244))	('tumors', 'Disease', (245, 251))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))
120905	31577764	Recently, mounting evidence suggested that downregulation of SPOP expression extensively occurs in various tumor tissues due to mutations and DNA methylations.	('DNA', 'cellular_component', 'GO:0005574', ('142', '145'))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('downregulation', 'NegReg', (43, 57))	('mutations', 'Var', (128, 137))	('N', 'Chemical', 'MESH:D009584', (143, 144))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('SPOP', 'Gene', (61, 65))	('SPOP', 'Gene', '8405', (61, 65))
120928	31577764	Moreover, subgroup analysis based on the sample size indicated that low SPOP expression was a poor prognostic biomarker in the large sample size group (n >= 90, high/low: HR = 0.60; 95% CI: 0.50-0.72, P < .001).	('low', 'Var', (68, 71))	('SPOP', 'Gene', '8405', (72, 76))	('SPOP', 'Gene', (72, 76))
120931	31577764	Since the studies evaluating PFS with aberrant SPOP expression were of severe heterogeneity (I2 = 93.0%; P < .001), a random-effects model was used to pool the HRs, and no statistically significant relevance was observed (high/low: HR = 2.07; 95% CI: 0.16-26.70, P = .578) (Fig.	('SPOP', 'Gene', '8405', (47, 51))	('SPOP', 'Gene', (47, 51))	('aberrant', 'Var', (38, 46))
120939	31577764	Recently, whole-exome sequencing studies revealed that genomic mutations in SPOP are frequently present in various tumors, and interestingly, in prostate and endometrial cancer, all mutation regions of SPOP are localized to its MATH domain.	('mutations', 'Var', (63, 72))	('prostate and endometrial cancer', 'Disease', 'MESH:D016889', (145, 176))	('present', 'Reg', (96, 103))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('endometrial cancer', 'Phenotype', 'HP:0012114', (158, 176))	('SPOP', 'Gene', '8405', (76, 80))	('tumors', 'Disease', (115, 121))	('SPOP', 'Gene', (76, 80))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('SPOP', 'Gene', '8405', (202, 206))	('SPOP', 'Gene', (202, 206))
120940	31577764	In addition to mutations, epigenetic silencing also widely contributes to the downregulation of SPOP expression.	('epigenetic silencing', 'Var', (26, 46))	('SPOP', 'Gene', '8405', (96, 100))	('downregulation', 'NegReg', (78, 92))	('SPOP', 'Gene', (96, 100))
120942	31577764	Similarly, in NSCLC, hypermethylation of CpG islands of SPOP prevented it from binding to another transcription factor, C/EBPalpha, and promoted invasion, migration, proliferation in vitro and tumor growth in vivo.	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('proliferation', 'CPA', (166, 179))	('C/EBPalpha', 'Gene', '1050', (120, 130))	('promoted', 'PosReg', (136, 144))	('transcription factor', 'molecular_function', 'GO:0000981', ('98', '118'))	('transcription', 'biological_process', 'GO:0006351', ('98', '111'))	('NSCLC', 'Disease', (14, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('tumor', 'Disease', (193, 198))	('invasion', 'CPA', (145, 153))	('prevented', 'NegReg', (61, 70))	('hypermethylation', 'Var', (21, 37))	('migration', 'CPA', (155, 164))	('SPOP', 'Gene', '8405', (56, 60))	('C/EBPalpha', 'Gene', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('binding', 'molecular_function', 'GO:0005488', ('79', '86'))	('binding', 'Interaction', (79, 86))	('SPOP', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))
120956	31577764	The underlying mechanisms involved in the relationship between low SPOP expression and poor prognosis of cancer patients have been universally investigated.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('patients', 'Species', '9606', (112, 120))	('SPOP', 'Gene', '8405', (67, 71))	('SPOP', 'Gene', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('low', 'Var', (63, 66))
120958	31577764	Particularly in prostate cancer, previous publications had reported an abundance of substrate proteins because of recurrent SPOP mutations.	('SPOP', 'Gene', '8405', (124, 128))	('prostate cancer', 'Disease', (16, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('mutations', 'Var', (129, 138))	('SPOP', 'Gene', (124, 128))	('prostate cancer', 'Disease', 'MESH:D011471', (16, 31))	('prostate cancer', 'Phenotype', 'HP:0012125', (16, 31))
120962	31577764	Geng et al reported that SPOP mutants lost the ability to modulate SRC-3 and AR transcriptional activity.	('SPOP', 'Gene', (25, 29))	('SRC-3', 'Gene', '8202', (67, 72))	('ability', 'MPA', (47, 54))	('AR', 'Gene', '367', (77, 79))	('lost', 'NegReg', (38, 42))	('mutants', 'Var', (30, 37))	('modulate', 'MPA', (58, 66))	('SPOP', 'Gene', '8405', (25, 29))	('SRC-3', 'Gene', (67, 72))
120963	31577764	A follow-up study also showed that SPOP mutation drove prostate tumorigenesis depending on coactivation of both SRC-3-mediated phosphatidylinositol-3 -kinase (PI3K)/mammalian target of rapamycin (mTOR) and AR signaling.	('mutation', 'Var', (40, 48))	('tumor', 'Disease', (64, 69))	('PI3K', 'molecular_function', 'GO:0016303', ('159', '163'))	('SRC-3', 'Gene', '8202', (112, 117))	('SPOP', 'Gene', '8405', (35, 39))	('mammalian target of rapamycin', 'Gene', '2475', (165, 194))	('mammalian target of rapamycin', 'Gene', (165, 194))	('phosphatidylinositol-3 -kinase', 'Gene', '5293', (127, 157))	('signaling', 'biological_process', 'GO:0023052', ('209', '218'))	('SPOP', 'Gene', (35, 39))	('prostate', 'Disease', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mTOR', 'Gene', '2475', (196, 200))	('SRC-3', 'Gene', (112, 117))	('mTOR', 'Gene', (196, 200))	('AR', 'Gene', '367', (206, 208))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('phosphatidylinositol-3 -kinase', 'Gene', (127, 157))
120965	31577764	They also highlighted that mutant SPOP leads to elevated programmed death-ligand 1 levels and reduced numbers of CD8+ tumor-infiltrating lymphocytes in prostate cancer.	('SPOP', 'Gene', '8405', (34, 38))	('ligand', 'molecular_function', 'GO:0005488', ('74', '80'))	('prostate cancer', 'Disease', (152, 167))	('SPOP', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('CD8', 'Gene', (113, 116))	('mutant', 'Var', (27, 33))	('reduced', 'NegReg', (94, 101))	('CD8', 'Gene', '925', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('prostate cancer', 'Disease', 'MESH:D011471', (152, 167))	('prostate cancer', 'Phenotype', 'HP:0012125', (152, 167))	('tumor', 'Disease', (118, 123))	('programmed death-ligand 1 levels', 'MPA', (57, 89))	('elevated', 'PosReg', (48, 56))
120966	31577764	In breast cancer, a loss of heterozygosity of SPOP frequently contributes to breast cancer cell growth and invasive phenotype via targeting progesterone receptor.	('breast cancer', 'Disease', (77, 90))	('progesterone receptor', 'Gene', '5241', (140, 161))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('loss of heterozygosity', 'Var', (20, 42))	('targeting', 'Reg', (130, 139))	('contributes', 'Reg', (62, 73))	('breast cancer', 'Disease', (3, 16))	('invasive', 'Disease', 'MESH:D009361', (107, 115))	('SPOP', 'Gene', '8405', (46, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cell growth', 'biological_process', 'GO:0016049', ('91', '102'))	('SPOP', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('invasive', 'Disease', (107, 115))	('progesterone receptor', 'Gene', (140, 161))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
120967	31577764	The ectopic expression of SPOP also affects primary tumorigenesis by targeting epithelial-mesenchymal transition (EMT)-inducing C-Myc.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('affects', 'Reg', (36, 43))	('tumor', 'Disease', (52, 57))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('79', '112'))	('targeting', 'Reg', (69, 78))	('C-Myc', 'Gene', '4609', (128, 133))	('EMT', 'biological_process', 'GO:0001837', ('114', '117'))	('SPOP', 'Gene', '8405', (26, 30))	('ectopic expression', 'Var', (4, 22))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('C-Myc', 'Gene', (128, 133))	('SPOP', 'Gene', (26, 30))
120971	31577764	Additionally, Luo et al in 2017 showed that SPOP mutation protected SIRT2 protein from ubiquitination in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('SIRT2', 'Gene', '22933', (68, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('ubiquitination', 'MPA', (87, 101))	('SIRT2', 'Gene', (68, 73))	('mutation', 'Var', (49, 57))	('SPOP', 'Gene', '8405', (44, 48))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('NSCLC', 'Disease', (105, 110))	('SPOP', 'Gene', (44, 48))
121007	32280701	A study based on TCGA database identified four miRNAs, miR-149-5p, miRNA-21-5p, miRNA-9-5p, and miRNA-30b-5p, as independent prognostic indicators in patients with ccRCC.	('miRNA-21', 'Gene', '406991', (67, 75))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('ccRCC', 'Phenotype', 'HP:0006770', (164, 169))	('miR-149', 'Gene', (55, 62))	('ccRCC', 'Disease', (164, 169))	('miRNA-21', 'Gene', (67, 75))	('miRNA-9-5p', 'Var', (80, 90))	('miR-149', 'Gene', '406941', (55, 62))	('miRNA-30b-5p', 'Var', (96, 108))
121034	31772326	In line, overexpression of LCN-2 is associated with reduced disease-free survival in breast cancer patients and enhanced tumour progression, whereas depletion of LCN-2 inhibited tumour growth, neovascularisation, and metastasis in experimental mammary tumour models.	('depletion', 'Var', (149, 158))	('reduced', 'NegReg', (52, 59))	('LCN-2', 'Gene', '3934', (27, 32))	('tumour', 'Disease', (252, 258))	('LCN-2', 'Gene', (27, 32))	('enhanced', 'PosReg', (112, 120))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('tumour', 'Disease', 'MESH:D009369', (178, 184))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('tumour', 'Disease', (178, 184))	('tumour', 'Disease', (121, 127))	('disease-free survival', 'CPA', (60, 81))	('overexpression', 'PosReg', (9, 23))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('breast cancer', 'Disease', (85, 98))	('patients', 'Species', '9606', (99, 107))	('inhibited', 'NegReg', (168, 177))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('metastasis', 'CPA', (217, 227))	('LCN-2', 'Gene', '3934', (162, 167))	('tumour', 'Phenotype', 'HP:0002664', (252, 258))	('neovascularisation', 'CPA', (193, 211))	('LCN-2', 'Gene', (162, 167))	('tumour', 'Disease', 'MESH:D009369', (252, 258))
121045	31772326	Human renal cancer cell lines CAKI 1, 786-O, A498, and RCC4 cells were a kind gift of PD Dr. Anja Urbschat and were cultured in Dulbecco's modified Eagle's medium (DMEM; Gibco, Dreieich, Germany, 41965) with high glucose, supplemented with penicillin (100 U/ml) (Sigma Aldrich, Taufkirchen, Germany, P4333), streptomycin (100 mg/ml) (Sigma Aldrich, S8636) and 10% FCS (Capricorn Scientific, Ebsdorfergrund, Germany, FBS-11A).	('Human', 'Species', '9606', (0, 5))	('100 mg/ml', 'Var', (322, 331))	('renal cancer', 'Disease', (6, 18))	('renal cancer', 'Phenotype', 'HP:0009726', (6, 18))	('RCC4', 'Gene', (55, 59))	('RCC4', 'Gene', '84925', (55, 59))	('glucose', 'Chemical', 'MESH:D005947', (213, 220))	('streptomycin', 'Chemical', 'MESH:D013307', (308, 320))	('renal cancer', 'Disease', 'MESH:D007680', (6, 18))	('PD', 'Disease', 'MESH:D010300', (86, 88))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('high glucose', 'Phenotype', 'HP:0003074', (208, 220))	('penicillin', 'Chemical', 'MESH:D010406', (240, 250))
121050	31772326	Spheroids were stimulated with holo-, apo- or a non-iron-binding LCN-2 mutant (1 microg/ml) every second day for 12 days.	('iron-binding', 'molecular_function', 'GO:0005506', ('52', '64'))	('LCN-2', 'Gene', '3934', (65, 70))	('iron', 'Chemical', 'MESH:D007501', (52, 56))	('mutant', 'Var', (71, 77))	('LCN-2', 'Gene', (65, 70))
121078	31772326	QuikChange II XL Site-Directed Mutagenesis Kit (Agilent Technologies, Waldbronn, Germany, 200522) was used to subsequently insert point mutations into the pGEX-4T3_LCN-2 plasmid, resulting in an amino acid exchange.	('point mutations', 'Var', (130, 145))	('LCN-2', 'Gene', '3934', (164, 169))	('Mutagenesis', 'biological_process', 'GO:0006280', ('31', '42'))	('insert', 'Reg', (123, 129))	('Kit', 'Gene', (43, 46))	('LCN-2', 'Gene', (164, 169))	('amino acid', 'MPA', (195, 205))	('Kit', 'Gene', '3815', (43, 46))
121080	31772326	Arginine 81 was mutated to glycine 81, lysine 125 to glutamine 125 and lysine 134 to glutamine 134, finally yielding the pGEX-4T3_LCN-2_mutant plasmid.	('LCN-2', 'Gene', '3934', (130, 135))	('Arginine 81 was mutated to glycine', 'Mutation', 'p.R81G', (0, 34))	('lysine 134 to glutamine', 'Mutation', 'p.K134Q', (71, 94))	('yielding', 'Reg', (108, 116))	('lysine 125 to glutamine', 'Mutation', 'p.K125Q', (39, 62))	('LCN-2', 'Gene', (130, 135))	('lysine', 'Var', (71, 77))
121086	31772326	For acquisition of spectra of both iron-loaded (holo-) LCN-2 and mutant LCN-2, the protein solution was mixed with an aliquot of 5 mM iron-catechol (3:1 mol:mol) solution, resulting in equimolar concentration of LCN-2 and iron-catechol.	('iron-catechol', 'Chemical', '-', (134, 147))	('LCN-2', 'Gene', (55, 60))	('iron', 'Chemical', 'MESH:D007501', (222, 226))	('LCN-2', 'Gene', '3934', (212, 217))	('iron', 'Chemical', 'MESH:D007501', (134, 138))	('mutant', 'Var', (65, 71))	('equimolar concentration', 'MPA', (185, 208))	('LCN-2', 'Gene', '3934', (55, 60))	('LCN-2', 'Gene', '3934', (72, 77))	('LCN-2', 'Gene', (212, 217))	('iron', 'Chemical', 'MESH:D007501', (35, 39))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('iron-catechol', 'Chemical', '-', (222, 235))	('LCN-2', 'Gene', (72, 77))
121090	31772326	Cells were added into the upper chamber of a two-chamber CIM plate (OLS) and stimulated with apo-, holo- or mutant LCN-2 (1 microg/ml).	('holo-', 'Var', (99, 104))	('LCN-2', 'Gene', '3934', (115, 120))	('mutant', 'Var', (108, 114))	('LCN-2', 'Gene', (115, 120))
121093	31772326	Cells were stimulated with apo-, holo- or mutant LCN-2 (1 microg/ml).	('LCN-2', 'Gene', (49, 54))	('mutant', 'Var', (42, 48))	('LCN-2', 'Gene', '3934', (49, 54))	('holo-', 'Var', (33, 38))
121105	31772326	Staining of patient-derived single-cell suspensions contained CD45 AF700 (Biolegend, San Diegeo, CA, USA, 368513) to exclude immune cells and CD326 PE-CF594 (BD Biosciences, San Jose, CA, USA, 565399) to gate CD326+ healthy and tumour epithelial cells, respectively.	('tumour', 'Disease', (228, 234))	('CD45 AF700', 'Var', (62, 72))	('CD326 PE-CF594', 'Var', (142, 156))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))	('patient', 'Species', '9606', (12, 19))	('tumour', 'Disease', 'MESH:D009369', (228, 234))
121128	31772326	CD326+ tumour cells expressed significantly more LCN-2R.	('LCN-2', 'Gene', (49, 54))	('more', 'PosReg', (44, 48))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('LCN-2', 'Gene', '3934', (49, 54))	('CD326+', 'Var', (0, 6))	('tumour', 'Disease', 'MESH:D009369', (7, 13))	('tumour', 'Disease', (7, 13))
121144	31772326	In order to test the assumption that LCN-2 transports iron to tumour cells, we generated a recombinant LCN-2 mutant protein (Fig.	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('LCN-2', 'Gene', (37, 42))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('LCN-2', 'Gene', '3934', (103, 108))	('LCN-2', 'Gene', '3934', (37, 42))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('tumour', 'Disease', (62, 68))	('mutant', 'Var', (109, 115))	('iron', 'Chemical', 'MESH:D007501', (54, 58))	('LCN-2', 'Gene', (103, 108))	('protein', 'Protein', (116, 123))
121145	31772326	The positively charged amino acids arginine 81 (R81), lysine 125 (K125) and lysine 134 (K134) within the LCN-2 calyx confer binding of iron, as they form non-covalent cation-pi interactions with electron-rich, aromatic structures of catecholate-type low-molecular-weight molecules, such as bacterial siderophores.	('K125', 'Var', (66, 70))	('lysine', 'Chemical', 'MESH:D008239', (76, 82))	('K125', 'Chemical', '-', (66, 70))	('K134', 'Chemical', 'MESH:C116725', (88, 92))	('catecholate', 'Chemical', '-', (233, 244))	('LCN-2', 'Gene', (105, 110))	('arginine', 'Chemical', 'MESH:D001120', (35, 43))	('binding', 'Interaction', (124, 131))	('lysine 134 (K134', 'Var', (76, 92))	('iron', 'Chemical', 'MESH:D007501', (135, 139))	('form', 'Reg', (149, 153))	('lysine', 'Chemical', 'MESH:D008239', (54, 60))	('LCN-2', 'Gene', '3934', (105, 110))	('binding', 'molecular_function', 'GO:0005488', ('124', '131'))	('non-covalent cation-pi', 'MPA', (154, 176))
121150	31772326	Upon iron loading, holo-LCN-2 displayed a maximum at 497 nm (red line), whereas iron loading of the mutant LCN-2 protein displayed a shift of the peak to 572 nm (green line), indicating substantially impaired iron binding.	('iron', 'Chemical', 'MESH:D007501', (209, 213))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('LCN-2', 'Gene', '3934', (24, 29))	('mutant', 'Var', (100, 106))	('iron binding', 'molecular_function', 'GO:0005506', ('209', '221'))	('impaired', 'NegReg', (200, 208))	('LCN-2', 'Gene', '3934', (107, 112))	('iron binding', 'Interaction', (209, 221))	('iron', 'Chemical', 'MESH:D007501', (80, 84))	('iron', 'Chemical', 'MESH:D007501', (5, 9))	('LCN-2', 'Gene', (24, 29))	('LCN-2', 'Gene', (107, 112))
121151	31772326	To test whether recombinant proteins are taken up by tumour cells, renal ccRCC CAKI1 cells were stimulated with apo-, holo- and mutant LCN-2.	('LCN-2', 'Gene', (135, 140))	('holo-', 'Var', (118, 123))	('tumour', 'Disease', (53, 59))	('apo-', 'Var', (112, 116))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('mutant', 'Var', (128, 134))	('RCC', 'Disease', (75, 78))	('LCN-2', 'Gene', '3934', (135, 140))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (53, 59))
121153	31772326	We observed that iron-free (apo), iron-loaded (holo) as well as the mutant protein were internalised by tumour cells in comparison with unstimulated controls and uptake occurred to a similar extent.	('iron', 'Chemical', 'MESH:D007501', (34, 38))	('uptake', 'biological_process', 'GO:0098657', ('162', '168'))	('uptake', 'biological_process', 'GO:0098739', ('162', '168'))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('protein', 'Protein', (75, 82))	('iron', 'Chemical', 'MESH:D007501', (17, 21))	('internalised', 'MPA', (88, 100))	('tumour', 'Disease', (104, 110))	('mutant', 'Var', (68, 74))
121154	31772326	To clarify whether LCN-2 effectively delivered iron to tumour cells, we isolated primary human patient-derived tumour cells (T-TEC) and measured cell lysates of apo-, holo- and mutant LCN-2-stimulated T-TEC by AAS for their iron amount in comparison with unstimulated cells (Ctrl) (Fig.	('tumour', 'Disease', (55, 61))	('human', 'Species', '9606', (89, 94))	('iron', 'Chemical', 'MESH:D007501', (224, 228))	('LCN-2', 'Gene', (184, 189))	('patient', 'Species', '9606', (95, 102))	('LCN-2', 'Gene', (19, 24))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('LCN-2', 'Gene', '3934', (184, 189))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('mutant', 'Var', (177, 183))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('iron amount', 'MPA', (224, 235))	('LCN-2', 'Gene', '3934', (19, 24))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('iron', 'Chemical', 'MESH:D007501', (47, 51))	('tumour', 'Disease', (111, 117))
121156	31772326	In contrast, stimulation with apo-LCN-2 or the mutant protein remained without effect regarding the intracellular iron amount.	('LCN-2', 'Gene', '3934', (34, 39))	('intracellular', 'cellular_component', 'GO:0005622', ('100', '113'))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('intracellular iron amount', 'MPA', (100, 125))	('iron', 'Chemical', 'MESH:D007501', (114, 118))	('LCN-2', 'Gene', (34, 39))	('mutant', 'Var', (47, 53))
121159	31772326	The mutant LCN-2 had no effect (Fig.	('LCN-2', 'Gene', '3934', (11, 16))	('LCN-2', 'Gene', (11, 16))	('mutant', 'Var', (4, 10))
121166	31772326	Cellular proliferation remained unaltered upon stimulation with apo-, holo- or mutant LCN-2 protein (Supplementary.	('mutant', 'Var', (79, 85))	('LCN-2', 'Gene', '3934', (86, 91))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('Cellular proliferation', 'CPA', (0, 22))	('protein', 'Protein', (92, 99))	('LCN-2', 'Gene', (86, 91))
121168	31772326	CAKI 1 tumour spheroids were stimulated with 1 microg/ml apo-, holo- or the non-iron-binding LCN-2 mutant every second day over a period of 12 days.	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('LCN-2', 'Gene', '3934', (93, 98))	('iron-binding', 'molecular_function', 'GO:0005506', ('80', '92'))	('mutant', 'Var', (99, 105))	('iron', 'Chemical', 'MESH:D007501', (80, 84))	('tumour spheroids', 'Disease', 'MESH:D009369', (7, 23))	('LCN-2', 'Gene', (93, 98))	('tumour spheroids', 'Disease', (7, 23))
121170	31772326	Stimulation with the mutant LCN-2 showed similar effects as apo-LCN-2.	('LCN-2', 'Gene', '3934', (64, 69))	('mutant', 'Var', (21, 27))	('LCN-2', 'Gene', '3934', (28, 33))	('LCN-2', 'Gene', (64, 69))	('LCN-2', 'Gene', (28, 33))
121180	31772326	We stimulated CAKI 1 spheroids over a period of 12 days every second day with apo-, holo- or the mutant LCN-2 (1 microg/ml).	('LCN-2', 'Gene', '3934', (104, 109))	('mutant', 'Var', (97, 103))	('LCN-2', 'Gene', (104, 109))
121181	31772326	We found that the holo-LCN-2 stimulation significantly promoted the dissemination and invasion of cells from the spheroid into the collagen matrix, whereas apo- and mutant LCN-2-stimulated spheroids remained unaltered compared with control spheroids.	('mutant', 'Var', (165, 171))	('LCN-2', 'Gene', (23, 28))	('LCN-2', 'Gene', '3934', (172, 177))	('dissemination', 'CPA', (68, 81))	('promoted', 'PosReg', (55, 63))	('LCN-2', 'Gene', '3934', (23, 28))	('LCN-2', 'Gene', (172, 177))	('collagen', 'molecular_function', 'GO:0005202', ('131', '139'))
121190	31772326	However, we observed two populations of patients in our cohort: one with a high LCN-2 mRNA expression and one with low LCN-2 mRNA expression.	('LCN-2', 'Gene', '3934', (119, 124))	('LCN-2', 'Gene', (80, 85))	('patients', 'Species', '9606', (40, 48))	('high', 'Var', (75, 79))	('LCN-2', 'Gene', (119, 124))	('mRNA expression', 'MPA', (86, 101))	('LCN-2', 'Gene', '3934', (80, 85))
121192	31772326	Since previous studies in renal cancer pointed to a close association of high LCN-2 expression and reduced progression-free survival in pRCC, ccRCC and sunitinib-treated RCC patients, it might be very interesting to follow-up the association of these high LCN-2-expressing tumours with overall or progression-free survival.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('renal cancer', 'Disease', 'MESH:D007680', (26, 38))	('tumours', 'Disease', (273, 280))	('tumour', 'Phenotype', 'HP:0002664', (273, 279))	('pRCC', 'Gene', '5546', (136, 140))	('LCN-2', 'Gene', '3934', (256, 261))	('tumours', 'Phenotype', 'HP:0002664', (273, 280))	('RCC', 'Disease', (170, 173))	('tumours', 'Disease', 'MESH:D009369', (273, 280))	('progression-free survival', 'CPA', (107, 132))	('LCN-2', 'Gene', (256, 261))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('RCC', 'Disease', (137, 140))	('LCN-2', 'Gene', '3934', (78, 83))	('pRCC', 'Gene', (136, 140))	('LCN-2', 'Gene', (78, 83))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('expression', 'MPA', (84, 94))	('RCC', 'Disease', (144, 147))	('renal cancer', 'Disease', (26, 38))	('renal cancer', 'Phenotype', 'HP:0009726', (26, 38))	('sunitinib', 'Chemical', 'MESH:D000077210', (152, 161))	('patients', 'Species', '9606', (174, 182))	('high', 'Var', (73, 77))	('reduced', 'NegReg', (99, 106))
121217	31772326	We tested this hypothesis by generating a mutant LCN-2 protein, deficient of its iron-binding capacity.	('LCN-2', 'Gene', (49, 54))	('iron', 'Chemical', 'MESH:D007501', (81, 85))	('mutant', 'Var', (42, 48))	('deficient', 'NegReg', (64, 73))	('iron-binding capacity', 'MPA', (81, 102))	('protein', 'Protein', (55, 62))	('tested', 'Reg', (3, 9))	('LCN-2', 'Gene', '3934', (49, 54))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('iron-binding', 'molecular_function', 'GO:0005506', ('81', '93'))
121219	31772326	However, it was surprising that the mutant LCN-2 form, which is unable to bind iron, differed significantly from the apo form of LCN-2.	('LCN-2', 'Gene', '3934', (43, 48))	('iron', 'Chemical', 'MESH:D007501', (79, 83))	('LCN-2', 'Gene', (129, 134))	('LCN-2', 'Gene', (43, 48))	('mutant', 'Var', (36, 42))	('LCN-2', 'Gene', '3934', (129, 134))
121221	31772326	In our set-up, we ruled out this possibility due to the fact that the intracellular iron amount of cells treated with either apo- or the mutant LCN-2 did not differ.	('intracellular', 'cellular_component', 'GO:0005622', ('70', '83'))	('LCN-2', 'Gene', '3934', (144, 149))	('iron', 'Chemical', 'MESH:D007501', (84, 88))	('LCN-2', 'Gene', (144, 149))	('mutant', 'Var', (137, 143))
121223	31772326	In the case of the mutant form, no iron binding is possible, and thus, no antitumour effect is observed.	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('tumour', 'Disease', (78, 84))	('iron binding', 'molecular_function', 'GO:0005506', ('35', '47'))	('iron', 'Chemical', 'MESH:D007501', (35, 39))	('mutant', 'Var', (19, 25))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
121243	29747161	Most sporadic ccRCCs in humans carry inactivating mutations in the VHL tumor suppressor gene, which lead to constitutive stabilization of the hypoxia inducible transcription factors HIF-1alpha and HIF-2alpha.	('tumor suppressor', 'biological_process', 'GO:0051726', ('71', '87'))	('VHL tumor', 'Disease', (67, 76))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('71', '87'))	('RCC', 'Disease', (16, 19))	('transcription', 'biological_process', 'GO:0006351', ('160', '173'))	('constitutive', 'MPA', (108, 120))	('HIF-2alpha', 'Gene', (197, 207))	('VHL tumor', 'Disease', 'MESH:D006623', (67, 76))	('humans', 'Species', '9606', (24, 30))	('inactivating mutations', 'Var', (37, 59))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('hypoxia', 'Disease', 'MESH:D000860', (142, 149))	('lead to', 'Reg', (100, 107))	('HIF-2alpha', 'Gene', '2034', (197, 207))	('hypoxia', 'Disease', (142, 149))
121256	29747161	In fact, only after inactivation of the tumor suppressor genes Trp53 and Rb together with Vhl do mice spontaneously develop ccRCC.	('Trp53', 'Gene', (63, 68))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('inactivation', 'Var', (20, 32))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('develop', 'Reg', (116, 123))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mice', 'Species', '10090', (97, 101))	('Trp53', 'Gene', '22059', (63, 68))	('Vhl', 'Gene', '22346', (90, 93))	('RCC', 'Disease', (126, 129))	('tumor', 'Disease', (40, 45))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('tumor suppressor', 'biological_process', 'GO:0051726', ('40', '56'))	('Vhl', 'Gene', (90, 93))
121349	29747161	We also plan to use this efficient platform to study mechanisms of transformation using genome engineering to introduce canonical ccRCC mutations (VHL, BAP1, SETD2, PBRM1) sequentially/simultaneously into primary tubule cells and assessing the angiogenic sprouting response of endothelial cells.	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('RCC', 'Disease', (132, 135))	('angiogenic sprouting response', 'CPA', (244, 273))	('BAP1', 'Gene', '8314', (152, 156))	('PBRM1', 'Gene', (165, 170))	('PBRM1', 'Gene', '55193', (165, 170))	('VHL', 'Gene', (147, 150))	('SETD2', 'Gene', '29072', (158, 163))	('mutations', 'Var', (136, 145))	('BAP1', 'Gene', (152, 156))	('SETD2', 'Gene', (158, 163))	('VHL', 'Gene', '7428', (147, 150))
121354	29747161	Encouragingly, novel HIF2 antagonists have been shown to disrupt ccRCC growth in a patient-derived xenograft model, but this effect was limited to only half of patient tumors tested.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('antagonists', 'Var', (26, 37))	('HIF2', 'Gene', (21, 25))	('patient', 'Species', '9606', (83, 90))	('patient', 'Species', '9606', (160, 167))	('disrupt', 'NegReg', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
121438	31829518	We also report for the first time that the expression of PD-1 in metastatic ccRCC tumors is associated with poor cancer-specific survival.	('PD-1', 'Gene', '5133', (57, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('expression', 'Var', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('ccRCC tumors', 'Disease', 'MESH:D002292', (76, 88))	('associated', 'Reg', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('PD-1', 'Gene', (57, 61))	('ccRCC tumors', 'Disease', (76, 88))	('poor', 'NegReg', (108, 112))
121480	30416377	However, the concrete mechanism by which eIF3b is involve in carcinogenesis remains elusive.	('involve', 'Reg', (50, 57))	('eIF3', 'cellular_component', 'GO:0005852', ('41', '45'))	('carcinogenesis', 'Disease', (61, 75))	('eIF3b', 'Var', (41, 46))	('carcinogenesis', 'Disease', 'MESH:D063646', (61, 75))
121485	30416377	Some studies have indicated that the remaining subunits, eIF3b, eIF3d, eIF3g, and eIF3i, have a stable but flexible connection with the octameric structural core.	('eIF3', 'cellular_component', 'GO:0005852', ('57', '61'))	('eIF3g', 'Gene', '8666', (71, 76))	('eIF3b', 'Var', (57, 62))	('core', 'cellular_component', 'GO:0019013', ('157', '161'))	('eIF3i', 'Gene', '8668', (82, 87))	('eIF3i', 'Gene', (82, 87))	('eIF3d', 'Gene', (64, 69))	('eIF3', 'cellular_component', 'GO:0005852', ('71', '75'))	('eIF3', 'cellular_component', 'GO:0005852', ('64', '68'))	('eIF3g', 'Gene', (71, 76))	('eIF3', 'cellular_component', 'GO:0005852', ('82', '86'))	('eIF3d', 'Gene', '8664', (64, 69))
121486	30416377	However, another study proposed that eIF3a, eIF3b, eIF3g, and eIF3i in humans form the Yeast-Like Core (YLC) (Fig.	('eIF3', 'cellular_component', 'GO:0005852', ('37', '41'))	('humans', 'Species', '9606', (71, 77))	('eIF3b', 'Var', (44, 49))	('eIF3a', 'Gene', (37, 42))	('eIF3g', 'Gene', '8666', (51, 56))	('eIF3', 'cellular_component', 'GO:0005852', ('44', '48'))	('eIF3', 'cellular_component', 'GO:0005852', ('62', '66'))	('eIF3g', 'Gene', (51, 56))	('eIF3', 'cellular_component', 'GO:0005852', ('51', '55'))	('eIF3a', 'Gene', '8669', (37, 42))	('Yeast', 'Species', '4932', (87, 92))	('eIF3i', 'Gene', (62, 67))	('eIF3i', 'Gene', '8668', (62, 67))
121493	30416377	eIF3b is also known as Prt1 homolog, P110, P116, eIF-3-Eta, eIF3S9 and HPrt1.	('eIF-3', 'cellular_component', 'GO:0005852', ('49', '54'))	('eIF-3-Eta', 'Gene', (49, 58))	('HPrt1', 'Gene', '3251', (71, 76))	('eIF3', 'cellular_component', 'GO:0005852', ('0', '4'))	('P116', 'Var', (43, 47))	('eIF3S9', 'Gene', '8662', (60, 66))	('eIF3S9', 'Gene', (60, 66))	('HPrt1', 'Gene', (71, 76))	('P110', 'Gene', (37, 41))	('eIF-3-Eta', 'Gene', '8662', (49, 58))	('Prt', 'molecular_function', 'GO:0004048', ('23', '26'))	('P110', 'Gene', '100616443', (37, 41))	('eIF3', 'cellular_component', 'GO:0005852', ('60', '64'))	('HPrt', 'molecular_function', 'GO:0004422', ('71', '75'))
121498	30416377	The WD40beta domain of eIF3b (residues 306 -705), a nine-bladed beta-propeller fold, is highly conserved from yeast to humans.	('residues 306', 'Var', (30, 42))	('eIF3', 'cellular_component', 'GO:0005852', ('23', '27'))	('humans', 'Species', '9606', (119, 125))	('yeast', 'Species', '4932', (110, 115))	('eIF3b', 'Gene', (23, 28))
121503	30416377	Research has shown that targeting kinase or phosphatase activity upstream of eIF3b is a way to control eIF3b-mediated translation for tumor treatment, particularly via the phosphorylation of the eIF3 complex at seven phosphorylation sites (Ser-83, Ser-85, Ser-119, Ser-125, Ser-152, Ser-154, and Ser-164) and one acetylation site (Met-1).	('Met-1', 'Gene', (331, 336))	('Ser-125', 'Var', (265, 272))	('eIF3', 'Gene', '8661', (77, 81))	('Ser', 'cellular_component', 'GO:0005790', ('274', '277'))	('eIF3', 'cellular_component', 'GO:0005852', ('103', '107'))	('eIF3', 'Gene', '8661', (195, 199))	('translation', 'biological_process', 'GO:0006412', ('118', '129'))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('Ser', 'Chemical', 'MESH:D012694', (274, 277))	('Ser', 'Chemical', 'MESH:D012694', (283, 286))	('Ser', 'cellular_component', 'GO:0005790', ('256', '259'))	('phosphorylation', 'biological_process', 'GO:0016310', ('217', '232'))	('Ser-85', 'Var', (248, 254))	('Ser', 'Chemical', 'MESH:D012694', (296, 299))	('Ser-83', 'Var', (240, 246))	('Ser-119', 'Var', (256, 263))	('eIF3', 'Gene', (103, 107))	('Ser', 'Chemical', 'MESH:D012694', (265, 268))	('Ser', 'cellular_component', 'GO:0005790', ('283', '286'))	('Ser', 'cellular_component', 'GO:0005790', ('248', '251'))	('Ser', 'cellular_component', 'GO:0005790', ('296', '299'))	('phosphorylation', 'biological_process', 'GO:0016310', ('172', '187'))	('Ser', 'Chemical', 'MESH:D012694', (256, 259))	('Ser-154', 'Var', (283, 290))	('control', 'MPA', (95, 102))	('phosphatase activity', 'molecular_function', 'GO:0016791', ('44', '64'))	('Ser-152', 'Var', (274, 281))	('Ser', 'Chemical', 'MESH:D012694', (248, 251))	('Ser', 'Chemical', 'MESH:D012694', (240, 243))	('phosphorylation', 'MPA', (172, 187))	('Ser', 'cellular_component', 'GO:0005790', ('265', '268'))	('eIF3', 'cellular_component', 'GO:0005852', ('77', '81'))	('eIF3', 'Gene', '8661', (103, 107))	('eIF3', 'Gene', (77, 81))	('eIF3', 'cellular_component', 'GO:0005852', ('195', '199'))	('tumor', 'Disease', (134, 139))	('eIF3', 'Gene', (195, 199))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('Ser', 'cellular_component', 'GO:0005790', ('240', '243'))	('Met-1', 'Gene', '3004', (331, 336))
121504	30416377	Consistently, phosphorylation of other members of the eIF family has been linked to tumorigenesis.	('phosphorylation', 'Var', (14, 29))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('phosphorylation', 'biological_process', 'GO:0016310', ('14', '29'))	('tumor', 'Disease', (84, 89))	('linked', 'Reg', (74, 80))
121505	30416377	For example, inhibition of eIF2alpha phosphorylation can promote tumorigenesis through the overexpression of PKR (protein kinase RNA-activated).	('RNA', 'cellular_component', 'GO:0005562', ('129', '132'))	('PKR', 'Gene', (109, 112))	('overexpression', 'PosReg', (91, 105))	('tumor', 'Disease', (65, 70))	('promote', 'PosReg', (57, 64))	('eIF2alpha', 'Gene', (27, 36))	('inhibition', 'Var', (13, 23))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('eIF2alpha', 'Gene', '83939', (27, 36))	('phosphorylation', 'Protein', (37, 52))	('eIF2', 'cellular_component', 'GO:0005850', ('27', '31'))	('phosphorylation', 'biological_process', 'GO:0016310', ('37', '52'))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('PKR', 'Gene', '5610', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
121506	30416377	By contrast, another study reported that eIF2alpha phosphorylation may prevent cancer development and progression.	('prevent', 'NegReg', (71, 78))	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('eIF2alpha', 'Gene', (41, 50))	('cancer', 'Disease', (79, 85))	('eIF2alpha', 'Gene', '83939', (41, 50))	('eIF2', 'cellular_component', 'GO:0005850', ('41', '45'))	('phosphorylation', 'Var', (51, 66))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
121509	30416377	Although the mechanisms appear complex, these findings do provide evidence that phosphorylation of the eIFs is associated with tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('phosphorylation', 'biological_process', 'GO:0016310', ('80', '95'))	('eIFs', 'Protein', (103, 107))	('associated', 'Reg', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('phosphorylation', 'Var', (80, 95))
121514	30416377	A groundbreaking study demonstrated the interaction among P311, the transforming growth factor (TGF) 5' untranslated regions (UTRs) and eIF3b in an RNA-independent manner can promote the translation of TGF-1, 2, and 3 in NIH-3T3 cells.	('TGF-1', 'Gene', (202, 207))	('translation', 'MPA', (187, 198))	('translation', 'biological_process', 'GO:0006412', ('187', '198'))	('eIF3b', 'Gene', (136, 141))	('TGF', 'Gene', (96, 99))	('promote', 'PosReg', (175, 182))	('RNA', 'cellular_component', 'GO:0005562', ('148', '151'))	('eIF3', 'cellular_component', 'GO:0005852', ('136', '140'))	('interaction', 'Interaction', (40, 51))	('NIH-3T3', 'CellLine', 'CVCL:0594', (221, 228))	('P311', 'Var', (58, 62))
121524	30416377	As mentioned above, Prt1, which later becomes Prt1p, is the homolog of eIF3b in S. cerevisiae, and when Prt1 is mutated, it can inhibit global protein synthesis and bring about G1 phase arrest.	('mutated', 'Var', (112, 119))	('protein synthesis', 'biological_process', 'GO:0006412', ('143', '160'))	('bring about', 'Reg', (165, 176))	('inhibit', 'NegReg', (128, 135))	('global protein synthesis', 'MPA', (136, 160))	('Prt1p', 'Gene', '854543', (46, 51))	('G1 phase', 'biological_process', 'GO:0051318', ('177', '185'))	('S. cerevisiae', 'Species', '4932', (80, 93))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('Prt', 'molecular_function', 'GO:0004048', ('104', '107'))	('eIF3', 'cellular_component', 'GO:0005852', ('71', '75'))	('Prt', 'molecular_function', 'GO:0004048', ('20', '23'))	('G1 phase arrest', 'CPA', (177, 192))	('Prt1', 'Gene', (104, 108))	('Prt', 'molecular_function', 'GO:0004048', ('46', '49'))	('Prt1p', 'Gene', (46, 51))
121529	30416377	One study showed that ectopic expression of eIFs in stably transfected NIH3T3 cells leads to several carcinogenic characteristics, including an increased protein synthesis rate, the ability for anchorage-independent growth, inhibition of apoptosis, and other malignant phenotypes.	('apoptosis', 'CPA', (238, 247))	('inhibition', 'NegReg', (224, 234))	('protein synthesis', 'biological_process', 'GO:0006412', ('154', '171'))	('inhibition of apoptosis', 'biological_process', 'GO:0043066', ('224', '247'))	('ectopic expression', 'Var', (22, 40))	('protein synthesis rate', 'MPA', (154, 176))	('NIH3T3', 'CellLine', 'CVCL:0594', (71, 77))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('carcinogenic', 'Disease', 'MESH:D063646', (101, 113))	('carcinogenic', 'Disease', (101, 113))	('increased', 'PosReg', (144, 153))	('eIFs', 'Gene', (44, 48))
121530	30416377	Also, high levels of eIF3b have been detected in several tumors, such as hepatocellular carcinoma (HCC), osteosarcoma, clear cell renal cell carcinoma (ccRCC), bladder cancer, prostate cancer, esophageal squamous cell carcinoma (ESCC), glioblastoma, colon cancer, breast cancer and gastric cancer.	('colon cancer', 'Disease', 'MESH:D015179', (250, 262))	('gastric cancer', 'Phenotype', 'HP:0012126', (282, 296))	('hepatocellular carcinoma', 'Disease', (73, 97))	('glioblastoma', 'Disease', 'MESH:D005909', (236, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (119, 150))	('eIF3', 'cellular_component', 'GO:0005852', ('21', '25'))	('detected', 'Reg', (37, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('esophageal squamous cell carcinoma', 'Disease', (193, 227))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('bladder cancer', 'Disease', 'MESH:D001749', (160, 174))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('glioblastoma', 'Disease', (236, 248))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (204, 227))	('colon cancer', 'Disease', (250, 262))	('prostate cancer', 'Disease', 'MESH:D011471', (176, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('bladder cancer', 'Disease', (160, 174))	('glioblastoma', 'Phenotype', 'HP:0012174', (236, 248))	('clear cell renal cell carcinoma', 'Disease', (119, 150))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (130, 150))	('prostate cancer', 'Phenotype', 'HP:0012125', (176, 191))	('gastric cancer', 'Disease', (282, 296))	('osteosarcoma', 'Disease', (105, 117))	('osteosarcoma', 'Disease', 'MESH:D012516', (105, 117))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))	('prostate cancer', 'Disease', (176, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (73, 97))	('HCC', 'Phenotype', 'HP:0001402', (99, 102))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (193, 227))	('breast cancer', 'Phenotype', 'HP:0003002', (264, 277))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (119, 150))	('gastric cancer', 'Disease', 'MESH:D013274', (282, 296))	('colon cancer', 'Phenotype', 'HP:0003003', (250, 262))	('breast cancer', 'Disease', 'MESH:D001943', (264, 277))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (73, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('breast cancer', 'Disease', (264, 277))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('eIF3b', 'Var', (21, 26))	('osteosarcoma', 'Phenotype', 'HP:0002669', (105, 117))	('tumors', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))
121531	30416377	In ccRCC, high expression of eIF3b is not only associated with an aggressive tumor phenotype, but also is an independent predictor of patient prognosis.	('eIF3b', 'Gene', (29, 34))	('aggressive tumor', 'Disease', 'MESH:D001523', (66, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('high expression', 'Var', (10, 25))	('aggressive tumor', 'Disease', (66, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ccRCC', 'Disease', (3, 8))	('eIF3', 'cellular_component', 'GO:0005852', ('29', '33'))	('associated', 'Reg', (47, 57))	('patient', 'Species', '9606', (134, 141))
121532	30416377	Overexpression of eIF3b in ESCC was found to be associated with lymph node metastasis, tumor depth, and advanced TNM stage, and ESCC patients with a high- level of eIF3b expression have a shorter overall survival and disease-free survival than those with lower eIF3b expression (Fig.	('eIF3', 'cellular_component', 'GO:0005852', ('18', '22'))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('TNM', 'Gene', (113, 116))	('TNM', 'Gene', '10178', (113, 116))	('associated', 'Reg', (48, 58))	('disease-free survival', 'CPA', (217, 238))	('patients', 'Species', '9606', (133, 141))	('tumor', 'Disease', (87, 92))	('lymph node metastasis', 'CPA', (64, 85))	('eIF3', 'cellular_component', 'GO:0005852', ('261', '265'))	('eIF3b', 'Var', (164, 169))	('high-', 'Var', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('eIF3', 'cellular_component', 'GO:0005852', ('164', '168'))	('overall survival', 'CPA', (196, 212))	('shorter', 'NegReg', (188, 195))
121533	30416377	High eIF3b expression also associated with androgen independence and worse disease- specific -survival in prostate cancer patients.	('disease- specific -survival', 'CPA', (75, 102))	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('eIF3b', 'Gene', (5, 10))	('eIF3', 'cellular_component', 'GO:0005852', ('5', '9'))	('High', 'Var', (0, 4))	('worse', 'NegReg', (69, 74))	('expression', 'MPA', (11, 21))	('associated with', 'Reg', (27, 42))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('prostate cancer', 'Disease', (106, 121))	('patients', 'Species', '9606', (122, 130))	('androgen independence', 'CPA', (43, 64))	('prostate cancer', 'Disease', 'MESH:D011471', (106, 121))
121534	30416377	Another study showed that eIF3b can inhibit cell proliferation by interfering with cell cycle progression and promoting apoptosis in vitro in ccRCC, ESCC, osteosarcoma, bladder cancer and glioblastoma.	('bladder cancer', 'Disease', 'MESH:D001749', (169, 183))	('ESCC', 'Disease', (149, 153))	('cell proliferation', 'CPA', (44, 62))	('glioblastoma', 'Disease', (188, 200))	('bladder cancer', 'Disease', (169, 183))	('osteosarcoma', 'Disease', (155, 167))	('osteosarcoma', 'Disease', 'MESH:D012516', (155, 167))	('promoting', 'PosReg', (110, 119))	('glioblastoma', 'Phenotype', 'HP:0012174', (188, 200))	('cell cycle', 'biological_process', 'GO:0007049', ('83', '93'))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('bladder cancer', 'Phenotype', 'HP:0009725', (169, 183))	('ccRCC', 'Disease', (142, 147))	('cell proliferation', 'biological_process', 'GO:0008283', ('44', '62'))	('cell cycle progression', 'CPA', (83, 105))	('eIF3b', 'Var', (26, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('interfering', 'NegReg', (66, 77))	('osteosarcoma', 'Phenotype', 'HP:0002669', (155, 167))	('inhibit', 'NegReg', (36, 43))	('apoptosis', 'biological_process', 'GO:0097194', ('120', '129'))	('apoptosis', 'biological_process', 'GO:0006915', ('120', '129'))	('glioblastoma', 'Disease', 'MESH:D005909', (188, 200))	('apoptosis', 'CPA', (120, 129))	('eIF3', 'cellular_component', 'GO:0005852', ('26', '30'))
121536	30416377	Interestingly, eIF3b depletion in ccRCC cells damaged the actin cytoskeleton and focal adhesions via the down-regulation of integrin alpha5 protein levels.	('eIF3b', 'Gene', (15, 20))	('integrin alpha5', 'Gene', (124, 139))	('integrin alpha5', 'Gene', '3678', (124, 139))	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('58', '76'))	('down-regulation', 'NegReg', (105, 120))	('damaged', 'NegReg', (46, 53))	('actin', 'MPA', (58, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (34, 39))	('regulation', 'biological_process', 'GO:0065007', ('110', '120'))	('eIF3', 'cellular_component', 'GO:0005852', ('15', '19'))	('depletion', 'Var', (21, 30))
121538	30416377	The impact of eIF3b deletion on ccRCC is mediated via the Akt pathway.	('ccRCC', 'Phenotype', 'HP:0006770', (32, 37))	('ccRCC', 'Disease', (32, 37))	('eIF3', 'cellular_component', 'GO:0005852', ('14', '18'))	('Akt', 'Gene', '207', (58, 61))	('eIF3b', 'Gene', (14, 19))	('deletion', 'Var', (20, 28))	('Akt', 'Gene', (58, 61))
121539	30416377	eIF3b depletion can lead to increased protein expression of tumor necrosis factor receptor superfamily member 21 (TNFRSF21) in osteosarcoma, and several studies have reported that TNFRSF21 is a key molecule in inflammation, immune regulation and malignant progression.	('necrosis', 'biological_process', 'GO:0008220', ('66', '74'))	('eIF3', 'cellular_component', 'GO:0005852', ('0', '4'))	('tumor necrosis factor receptor superfamily member 21', 'Gene', '27242', (60, 112))	('inflammation', 'Disease', 'MESH:D007249', (210, 222))	('increased', 'PosReg', (28, 37))	('osteosarcoma', 'Phenotype', 'HP:0002669', (127, 139))	('necrosis', 'biological_process', 'GO:0070265', ('66', '74'))	('necrosis', 'biological_process', 'GO:0019835', ('66', '74'))	('necrosis', 'biological_process', 'GO:0001906', ('66', '74'))	('TNFRSF21', 'Gene', (180, 188))	('TNFRSF21', 'Gene', '27242', (180, 188))	('inflammation', 'Disease', (210, 222))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('TNFRSF21', 'Gene', (114, 122))	('TNFRSF21', 'Gene', '27242', (114, 122))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('osteosarcoma', 'Disease', (127, 139))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('60', '81'))	('protein expression', 'MPA', (38, 56))	('necrosis', 'biological_process', 'GO:0008219', ('66', '74'))	('osteosarcoma', 'Disease', 'MESH:D012516', (127, 139))	('inflammation', 'biological_process', 'GO:0006954', ('210', '222'))	('depletion', 'Var', (6, 15))	('eIF3b', 'Protein', (0, 5))	('regulation', 'biological_process', 'GO:0065007', ('231', '241'))
121540	30416377	How alteration of the expression levels of different eIF3 subunits promotes tumorigenesis remains to be elucidated, but a possible explanation for these observations is that abnormal expression of eIFs might affect cell proliferation, apoptosis, migration, and invasion as well as, might change the translation efficiency of specific mRNAs, such as those encoding key proteins involved in the formation of various tumors.	('abnormal', 'Var', (174, 182))	('eIF3', 'Gene', '8661', (53, 57))	('translation', 'biological_process', 'GO:0006412', ('299', '310'))	('tumor', 'Disease', (76, 81))	('tumors', 'Disease', 'MESH:D009369', (414, 420))	('migration', 'CPA', (246, 255))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('translation efficiency', 'MPA', (299, 321))	('apoptosis', 'CPA', (235, 244))	('formation', 'biological_process', 'GO:0009058', ('393', '402'))	('eIFs', 'Gene', (197, 201))	('eIF3', 'cellular_component', 'GO:0005852', ('53', '57'))	('tumor', 'Disease', (414, 419))	('cell proliferation', 'biological_process', 'GO:0008283', ('215', '233'))	('tumor', 'Disease', 'MESH:D009369', (414, 419))	('cell proliferation', 'CPA', (215, 233))	('affect', 'Reg', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (414, 420))	('invasion', 'CPA', (261, 269))	('eIF3', 'Gene', (53, 57))	('change', 'Reg', (288, 294))	('tumor', 'Phenotype', 'HP:0002664', (414, 419))	('apoptosis', 'biological_process', 'GO:0097194', ('235', '244'))	('apoptosis', 'biological_process', 'GO:0006915', ('235', '244'))	('tumors', 'Disease', (414, 420))
121543	30416377	Several previous studies have focused on the elevated expression of eIF3b in almost all tumor types and how eIF3b contributes to tumorigenesis.	('expression', 'MPA', (54, 64))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('eIF3b', 'Gene', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('eIF3', 'cellular_component', 'GO:0005852', ('68', '72'))	('contributes', 'Reg', (114, 125))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('elevated', 'PosReg', (45, 53))	('eIF3', 'cellular_component', 'GO:0005852', ('108', '112'))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', (88, 93))	('eIF3b', 'Var', (108, 113))
121578	32879362	They include: AC005104.1, AC093278.2, AC098484.1, AL360181.2, EMX2OS, LINC01011, SPINT1-AS1, AP001372.2, AC007637.1, AL354733.3, AP001189.3 and LINC00886.	('EMX2OS', 'Gene', (62, 68))	('SPINT1', 'Gene', (81, 87))	('LINC00886', 'Gene', (144, 153))	('SPINT1', 'Gene', '6692', (81, 87))	('AS1', 'Gene', '5729', (88, 91))	('AS1', 'Gene', (88, 91))	('LINC01011', 'Gene', '401232', (70, 79))	('AP001189.3', 'Var', (129, 139))	('LINC00886', 'Gene', '730091', (144, 153))	('AL354733.3', 'Var', (117, 127))	('AL360181.2', 'Var', (50, 60))	('AP001372.2', 'Var', (93, 103))	('EMX2OS', 'Gene', '196047', (62, 68))	('AC007637.1', 'Var', (105, 115))	('AL354733', 'Chemical', '-', (117, 125))	('AC098484.1', 'Var', (38, 48))	('LINC01011', 'Gene', (70, 79))
121583	32879362	On the other hand, the expression levels of AC093278.2, AC098484.1, and EMX2OS were decreased from stage I to stage IV.	('EMX2OS', 'Gene', '196047', (72, 78))	('EMX2OS', 'Gene', (72, 78))	('AC093278.2', 'Var', (44, 54))	('expression levels', 'MPA', (23, 40))	('decreased', 'NegReg', (84, 93))	('AC098484.1', 'Var', (56, 66))
121584	32879362	Moreover, based on the grade, expression levels of AC007637.1, AC093278.2, AC098484.1, AL354733.3, AP001189.3, AP001372.2, and EMX2OS decreased from grade 1 to grade 4 (Supplementary Fig.	('decreased', 'NegReg', (134, 143))	('expression levels', 'MPA', (30, 47))	('AP001189.3', 'Var', (99, 109))	('AC098484.1', 'Var', (75, 85))	('AC007637.1', 'Var', (51, 61))	('EMX2OS', 'Gene', '196047', (127, 133))	('AL354733.3', 'Var', (87, 97))	('AC093278.2', 'Var', (63, 73))	('AL354733', 'Chemical', '-', (87, 95))	('EMX2OS', 'Gene', (127, 133))
121593	32879362	Current literature shows that the non-coding RNAs, specifically lncRNAs, are tightly associated with tumorigenesis and progression of tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('associated', 'Reg', (85, 95))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('lncRNAs', 'Gene', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('non-coding', 'Var', (34, 44))	('tumor', 'Disease', (134, 139))
121594	32879362	Also, cumulative evidence reveals that dysregulated lncRNAs may serve as a critical biomarker for many types of cancers, in particular, esophageal squamous cell carcinoma and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('esophageal squamous cell carcinoma', 'Disease', (136, 170))	('breast cancer', 'Disease', (175, 188))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (136, 170))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('dysregulated', 'Var', (39, 51))	('cancers', 'Disease', (112, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lncRNAs', 'Protein', (52, 59))
121595	32879362	Some recent studies have suggested that aberrant lncRNA expression is associated with ccRCC, and many potential biomarkers have been uncovered in ccRCC.	('RCC', 'Disease', (148, 151))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('associated', 'Reg', (70, 80))	('lncRNA', 'Protein', (49, 55))	('aberrant', 'Var', (40, 48))
121613	32879362	In addition, 3 lncRNAs including, AC005104.1, AL360181.2, and LINC01011) showed a significantly high expression level in cluster 1 when compared to cluster 2.	('LINC01011', 'Gene', '401232', (62, 71))	('expression level', 'MPA', (101, 117))	('AL360181.2', 'Var', (46, 56))	('LINC01011', 'Gene', (62, 71))	('AC005104.1', 'Var', (34, 44))
121615	32879362	including AC005104.1, AC093278.2, AC098484.1, AL360181.2, LINC01011, AP001372.2, AC007637.1, AL354733.3, and AP001189.3, which were the first time that served as markers in the current research.	('AC093278.2', 'Var', (22, 32))	('LINC01011', 'Gene', '401232', (58, 67))	('AL354733', 'Chemical', '-', (93, 101))	('AP001189.3', 'Var', (109, 119))	('AC005104.1', 'Var', (10, 20))	('AL360181.2', 'Var', (46, 56))	('AP001372.2', 'Var', (69, 79))	('AC098484.1', 'Var', (34, 44))	('AL354733.3', 'Var', (93, 103))	('AC007637.1', 'Var', (81, 91))	('LINC01011', 'Gene', (58, 67))
121623	32879362	The four microarray datasets (GSE46699, GSE36895, GSE15641, and GSE53757) were downloaded from the GEO database (www.ncbi.nlm.nih.gov/geo) as per the keyword 'renal cell carcinoma'.	('GSE53757', 'Var', (64, 72))	('GSE36895', 'Var', (40, 48))	('GSE15641', 'Var', (50, 58))	('GSE46699', 'Var', (30, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (159, 179))	('renal cell carcinoma', 'Disease', (159, 179))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (159, 179))
121624	32879362	Dataset GSE46699 comprised 63 adjacent normal kidney specimens and 67 ccRCC samples whereas, the GSE36895 dataset comprised 23 adjacent normal kidney samples and 29 ccRCC samples.	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('GSE46699', 'Var', (8, 16))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('RCC', 'Disease', (167, 170))
121644	30555801	Clear cell renal cell carcinomas (ccRCC) harbor mutations in the VHL gene, whereas papillary RCC (pRCC) have a functional VHL.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('VHL', 'Gene', '7428', (65, 68))	('RCC', 'Disease', (93, 96))	('RCC', 'Disease', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (34, 39))	('RCC', 'Disease', (99, 102))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('pRCC', 'Gene', '5546', (98, 102))	('mutations', 'Var', (48, 57))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('Clear cell renal cell carcinomas', 'Disease', (0, 32))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('pRCC', 'Gene', (98, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('papillary RCC', 'Gene', (83, 96))	('Clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (0, 32))	('papillary RCC', 'Gene', '5546', (83, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('VHL', 'Gene', (122, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (11, 32))	('VHL', 'Gene', (65, 68))	('Clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (0, 32))	('VHL', 'Gene', '7428', (122, 125))
121645	30555801	These natural occurring VHL variants in RCC enable the testing, in clinical samples, of the hypothesis that ascorbate modulates HIF-alpha levels through its role as a cofactor for the HIF hydroxylases.	('VHL', 'Gene', '7428', (24, 27))	('variants', 'Var', (28, 36))	('ascorbate', 'Chemical', 'MESH:D001205', (108, 117))	('RCC', 'Disease', (40, 43))	('clinical samples', 'Species', '191496', (67, 83))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('VHL', 'Gene', (24, 27))
121659	30555801	Hydroxylation of an asparagine in the C-terminal transactivation domain of HIF-alpha by the enzyme factor-inhibiting HIF (FIH) leads to repression of transcriptional activity by inhibiting interaction with the p300 coactivator.	('interaction', 'Interaction', (189, 200))	('transactivation', 'biological_process', 'GO:2000144', ('49', '64'))	('inhibiting', 'NegReg', (178, 188))	('repression', 'NegReg', (136, 146))	('Hydroxylation', 'Var', (0, 13))	('asparagine', 'Chemical', 'MESH:D001216', (20, 30))	('transcriptional activity', 'MPA', (150, 174))
121662	30555801	A number of studies have demonstrated that low intracellular ascorbate concentration exacerbates HIF-1 activation in cancer and normal cells.	('HIF-1', 'Gene', '3091', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('low', 'Var', (43, 46))	('intracellular', 'cellular_component', 'GO:0005622', ('47', '60'))	('activation', 'MPA', (103, 113))	('HIF-1', 'Gene', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('exacerbates', 'PosReg', (85, 96))	('ascorbate', 'Chemical', 'MESH:D001205', (61, 70))	('cancer', 'Disease', (117, 123))
121672	30555801	About 90% of ccRCC tumors harbor biallelic alterations in the VHL tumor suppressor gene, while pRCCs retain a functional VHL protein.	('VHL', 'Gene', '7428', (121, 124))	('ccRCC tumors', 'Disease', 'MESH:D009369', (13, 25))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('66', '82'))	('VHL', 'Gene', '7428', (62, 65))	('tumor suppressor', 'biological_process', 'GO:0051726', ('66', '82'))	('pRCC', 'Gene', '5546', (95, 99))	('VHL tumor', 'Disease', (62, 71))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('VHL tumor', 'Disease', 'MESH:D006623', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('VHL', 'Gene', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('pRCC', 'Gene', (95, 99))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('biallelic alterations', 'Var', (33, 54))	('ccRCC tumors', 'Disease', (13, 25))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('VHL', 'Gene', (62, 65))
121674	30555801	The presence of natural occurring VHL variants in RCC allowed us to investigate the role of VHL in the response of HIFs to ascorbate.	('ascorbate', 'Chemical', 'MESH:D001205', (123, 132))	('variants', 'Var', (38, 46))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('VHL', 'Gene', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('VHL', 'Gene', '7428', (92, 95))	('investigate', 'Reg', (68, 79))	('VHL', 'Gene', (34, 37))	('VHL', 'Gene', '7428', (34, 37))
121745	30555801	In ccRCC patients with higher HIF-2 pathway scores, all-cause mortality and disease-free survival tended to be worse, although significance was not reached (p = 0.063 and p = 0.092, respectively; Table S3).	('patients', 'Species', '9606', (9, 17))	('scores', 'Var', (44, 50))	('higher', 'PosReg', (23, 29))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('worse', 'NegReg', (111, 116))	('RCC', 'Disease', (5, 8))	('all-cause', 'CPA', (52, 61))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('disease-free survival', 'CPA', (76, 97))	('HIF-2 pathway', 'Gene', (30, 43))
121761	30555801	The current investigation into the two renal cell carcinoma sub-types has allowed us to investigate the potential interaction between ascorbate and the HIF hydroxylases in tumors using ccRCC as an example of naturally occurring tumor mutations, resulting in a dysfunctional VHL protein.	('RCC', 'Disease', (187, 190))	('RCC', 'Phenotype', 'HP:0005584', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Disease', (172, 177))	('protein', 'cellular_component', 'GO:0003675', ('278', '285'))	('ccRCC', 'Phenotype', 'HP:0006770', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('RCC', 'Disease', 'MESH:C538614', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('dysfunctional VHL', 'Disease', 'MESH:D006623', (260, 277))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (39, 59))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('ascorbate', 'Chemical', 'MESH:D001205', (134, 143))	('dysfunctional VHL', 'Disease', (260, 277))	('mutations', 'Var', (234, 243))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('renal cell carcinoma', 'Disease', (39, 59))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (39, 59))	('tumor', 'Disease', (228, 233))
121762	30555801	This mutation prevents degradation of the hydroxylated HIF-alpha chains and increases subsequent transcriptional activity of the HIFs in ccRCC, and is therefore independent of the hypoxic status of the tumor, or the availability of other hydroxylase substrates or co-factors, including ascorbate (Figure 6).	('tumor', 'Disease', (202, 207))	('ascorbate', 'Chemical', 'MESH:D001205', (286, 295))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('increases', 'PosReg', (76, 85))	('HIF-alpha chains', 'Protein', (55, 71))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('degradation', 'biological_process', 'GO:0009056', ('23', '34'))	('degradation', 'MPA', (23, 34))	('transcriptional activity', 'MPA', (97, 121))	('prevents', 'NegReg', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('mutation', 'Var', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
121765	30555801	It is also possible that HIF activation is regulated by variations in the PHD or FIH enzymes.	('PHD', 'Disease', (74, 77))	('HIF', 'CPA', (25, 28))	('variations', 'Var', (56, 66))	('PHD', 'molecular_function', 'GO:0050175', ('74', '77'))	('PHD', 'Disease', 'MESH:D011547', (74, 77))
121768	30555801	Modulation of the HIF pathways in RCC by any means is likely to impact on tumor growth and progression.	('Modulation', 'Var', (0, 10))	('progression', 'CPA', (91, 102))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('impact', 'Reg', (64, 70))	('tumor', 'Disease', (74, 79))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('HIF pathways', 'Pathway', (18, 30))	('RCC', 'Disease', (34, 37))
121770	30555801	This seems to be especially evident in VHL-defective ccRCC, where HIF-1 can have tumor suppressive effects, whereas HIF-2 appears to be the major player in tumorigenesis and is associated with higher grade, stage and poor patient outcome.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('RCC', 'Disease', (55, 58))	('VHL-defective', 'Disease', (39, 52))	('HIF-1', 'Gene', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('patient', 'Species', '9606', (222, 229))	('HIF-2', 'Var', (116, 121))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('VHL-defective', 'Disease', 'MESH:D006623', (39, 52))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('associated with', 'Reg', (177, 192))	('HIF-1', 'Gene', '3091', (66, 71))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('tumor', 'Disease', (81, 86))
121778	30555801	Our finding that VEGF tended to increase in higher-grade ccRCC supports evidence that high VEGF expression is a poor prognostic indicator for patients with ccRCC and is thus a preferential target for therapy.	('VEGF', 'Gene', '7422', (91, 95))	('VEGF', 'Gene', '7422', (17, 21))	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (156, 161))	('expression', 'MPA', (96, 106))	('VEGF', 'Gene', (91, 95))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))	('VEGF', 'Gene', (17, 21))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('patients', 'Species', '9606', (142, 150))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('high', 'Var', (86, 90))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
121792	30555801	In contrast, we suggest that manipulating ascorbate levels in ccRCC would not affect the hypoxic response and thus would not change tumor aggression that is dependent on this pathway.	('tumor aggression', 'Disease', 'MESH:D001523', (132, 148))	('ascorbate', 'Chemical', 'MESH:D001205', (42, 51))	('hypoxic', 'MPA', (89, 96))	('manipulating', 'Var', (29, 41))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('RCC', 'Disease', (64, 67))	('aggression', 'Phenotype', 'HP:0000718', (138, 148))	('tumor aggression', 'Disease', (132, 148))	('aggression', 'biological_process', 'GO:0002118', ('138', '148'))
121812	33126775	The reformed landscape of histone modifications in cancer modifies the plasticity of the DNA, promotes infinite cell cycle progression, and allows the uncontrolled transcription of (onco-) genes.	('cell cycle', 'biological_process', 'GO:0007049', ('112', '122'))	('transcription', 'biological_process', 'GO:0006351', ('164', '177'))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('allows', 'Reg', (140, 146))	('cancer', 'Disease', (51, 57))	('plasticity', 'MPA', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('infinite cell cycle progression', 'CPA', (103, 134))	('modifies', 'Reg', (58, 66))	('modifications', 'Var', (34, 47))	('promotes', 'PosReg', (94, 102))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
121819	33126775	HDACs play another important role in the epigenetic silencing of the Von Hippel-Lindau gene (vhl), harboring the driver mutation to advance RCC by dysregulating hypoxia-inducible factors (HIFs).	('Von Hippel-Lindau', 'Disease', (69, 86))	('HDAC', 'Gene', (0, 4))	('dysregulating', 'Reg', (147, 160))	('epi', 'Gene', '7035', (41, 44))	('HDAC', 'Gene', '9734', (0, 4))	('HIFs', 'Disease', 'None', (188, 192))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('mutation', 'Var', (120, 128))	('vhl', 'Gene', (93, 96))	('hypoxia', 'Disease', 'MESH:D000860', (161, 168))	('Von Hippel-Lindau', 'Disease', 'MESH:D006623', (69, 86))	('hypoxia', 'Disease', (161, 168))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('epi', 'Gene', (41, 44))	('HIFs', 'Disease', (188, 192))	('vhl', 'Gene', '7428', (93, 96))
121828	33126775	This pronounced interaction of these agents with sorafenib has been used to initiate different clinical studies for varying cancer types (ClinicalTrials.gov Identifiers: NCT01159301, NCT00823290, NCT01005797, NCT01075113, NCT00635791), but until now, none of them have been approved for the treatment of RCC.	('cancer', 'Disease', (124, 130))	('sorafenib', 'Chemical', 'MESH:D000077157', (49, 58))	('NCT00823290', 'Var', (183, 194))	('RCC', 'Phenotype', 'HP:0005584', (304, 307))	('NCT01159301', 'Var', (170, 181))	('RCC', 'Disease', 'MESH:C538614', (304, 307))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('RCC', 'Disease', (304, 307))	('NCT01005797', 'Var', (196, 207))	('NCT00635791', 'Var', (222, 233))	('NCT01075113', 'Var', (209, 220))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
121833	33126775	However, not all ccRCC lesions present this phenotype or a similar genetic landscape, i.e., vhl mutation, and might remain insensitive to this four-drug combination.	('vhl', 'Gene', '7428', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('mutation', 'Var', (96, 104))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('ccRCC', 'Phenotype', 'HP:0006770', (17, 22))	('vhl', 'Gene', (92, 95))
121851	33126775	In parallel, we tested the single drugs at dose ranges adjusted to the clinically used doses (CUDs) in non-cancerous HEK-293T cells (Figure S2) and calculated the effective doses (EDs) reducing the cell viability by 20% (ED20) and ED10.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('reducing', 'NegReg', (185, 193))	('cell viability', 'CPA', (198, 212))	('ED10', 'Var', (231, 235))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('HEK-293T', 'CellLine', 'CVCL:0063', (117, 125))	('cancer', 'Disease', (107, 113))
121887	33126775	The results were similar when administering the treatment after 24 (Figure 3b) or 48 h (Figure 3c) of spheroid formation; however, the activity mainly resulted from the presence of panobinostat reducing the size of the margin to almost the same extent (Figure 3b and Figure S8e).	('size', 'MPA', (207, 211))	('formation', 'biological_process', 'GO:0009058', ('111', '120'))	('presence', 'Var', (169, 177))	('reducing', 'NegReg', (194, 202))	('panobinostat', 'Gene', (181, 193))	('panobinostat', 'Chemical', 'MESH:D000077767', (181, 193))
121896	33126775	Crizotinib, a MET inhibitor, did enhance the cytotoxic activity but in an antagonistic fashion, being active as monotherapy (Figure 5a).	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('MET', 'Gene', '79811', (14, 17))	('Crizotinib', 'Var', (0, 10))	('MET', 'Gene', (14, 17))	('cytotoxic activity', 'CPA', (45, 63))	('enhance', 'PosReg', (33, 40))
121918	33126775	The 'one size fits all' approach of cancer therapy, where patients are given a treatment based on their cancer type, a common genetic marker, or a mutant oncogene, remains unsatisfactory.	('mutant', 'Var', (147, 153))	('fits', 'Disease', 'MESH:D012640', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (36, 42))	('fits', 'Disease', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
121921	33126775	The cell cycle regulation protein p53 is normally expressed in Caki-1 cell but mutated in 786-O cells.	('Caki-1', 'CellLine', 'CVCL:0234', (63, 69))	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('mutated', 'Var', (79, 86))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('4', '25'))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))
121922	33126775	In addition, where Caki-1 cells carry a wildtype vhl gene normally coordinating the expression of vascular endothelial and platelet-derived growth factor, 786-O cells carry a mutation and are therefore overexpressing both GF.	('vhl', 'Gene', (49, 52))	('mutation', 'Var', (175, 183))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('123', '153'))	('Caki-1', 'CellLine', 'CVCL:0234', (19, 25))	('vhl', 'Gene', '7428', (49, 52))	('expression', 'MPA', (84, 94))	('overexpressing', 'PosReg', (202, 216))
121924	33126775	Because of the oncogenic mutations and other cell-specific properties, whose interplay intrinsically guided the selection, the strongest anticancer activity was obtained by this drug combination containing two HDACIs and one TKI inhibitor.	('HDAC', 'Gene', '9734', (210, 214))	('mutations', 'Var', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('HDAC', 'Gene', (210, 214))	('cancer', 'Disease', (141, 147))
121955	33126775	Remarkably, after the addition of either pictilisib or saracatinib, the sensitivity to this four-drug ODC was enhanced in 3-Dc as well as in 3-Dcc when fibroblasts were present (Figure 5).	('saracatinib', 'Chemical', 'MESH:C515233', (55, 66))	('3-Dc', 'Chemical', '-', (141, 145))	('3-Dc', 'Disease', (122, 126))	('pictilisib', 'Var', (41, 51))	('pictilisib', 'Chemical', 'MESH:C532162', (41, 51))	('ODC', 'Chemical', '-', (102, 105))	('enhanced', 'PosReg', (110, 118))	('Dcc', 'Gene', '1630', (143, 146))	('3-Dc', 'Chemical', '-', (122, 126))	('sensitivity to this four-drug ODC', 'MPA', (72, 105))	('Dcc', 'Gene', (143, 146))	('Dcc', 'cellular_component', 'GO:0120206', ('143', '146'))
121959	33126775	Further, it has been demonstrated that direct blockade of the Src kinase SRC-3 enhanced the anticancer activity of SAHA, and a similar result was obtained in our experiments through the combination of SAHA and saracatinib (Figure 5c).	('SRC-3', 'Gene', '8202', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Src', 'Gene', (62, 65))	('Src', 'Gene', '6714', (62, 65))	('enhanced', 'PosReg', (79, 87))	('SRC-3', 'Gene', (73, 78))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('blockade', 'Var', (46, 54))	('cancer', 'Disease', (96, 102))	('rat', 'Species', '10116', (28, 31))	('saracatinib', 'Chemical', 'MESH:C515233', (210, 221))
122061	33963171	In addition, high CCL18 and LAMA4 expression in kidney cancer facilitates tumor progression, while its effect can be reversed by miR-622, and C-C motif chemokine 18(CCL18) and laminin subunit alpha-4 (LAMA4) play key roles in tumor progression.	('LAMA4', 'Gene', (28, 33))	('expression', 'MPA', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('C-C motif chemokine 18', 'Gene', (142, 164))	('tumor', 'Disease', (74, 79))	('CCL18', 'Gene', (165, 170))	('LAMA4', 'Gene', '3910', (28, 33))	('kidney cancer', 'Disease', 'MESH:D007680', (48, 61))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('high', 'Var', (13, 17))	('C-C motif chemokine 18', 'Gene', '6362', (142, 164))	('LAMA4', 'Gene', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('CCL18', 'Gene', '6362', (165, 170))	('laminin subunit alpha-4', 'Gene', (176, 199))	('kidney cancer', 'Phenotype', 'HP:0009726', (48, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CCL', 'molecular_function', 'GO:0044101', ('165', '168'))	('kidney cancer', 'Disease', (48, 61))	('LAMA4', 'Gene', '3910', (201, 206))	('miR-622', 'Gene', (129, 136))	('CCL18', 'Gene', (18, 23))	('miR-622', 'Gene', '693207', (129, 136))	('facilitates', 'PosReg', (62, 73))	('CCL', 'molecular_function', 'GO:0044101', ('18', '21'))	('laminin subunit alpha-4', 'Gene', '3910', (176, 199))	('CCL18', 'Gene', '6362', (18, 23))	('tumor', 'Disease', (226, 231))
122067	33963171	The expression of PI3K and Akt can be downregulated by miR-338-3p, miR-15a, and miR-488 or upregulated by KIFC (Kinesin family member C1), eIF4E (eukaryotic initiation factor 4E), and HMGN5 (High-mobility group nucleosome binding domain 5) in RCC.	('Kinesin', 'molecular_function', 'GO:0003777', ('112', '119'))	('eukaryotic initiation factor 4E', 'Gene', '1977', (146, 177))	('miR-15a', 'Gene', (67, 74))	('expression', 'MPA', (4, 14))	('eIF4E', 'Gene', (139, 144))	('eukaryotic initiation factor 4E', 'Gene', (146, 177))	('RCC', 'Disease', (243, 246))	('RCC', 'Phenotype', 'HP:0005584', (243, 246))	('miR-488', 'Gene', (80, 87))	('eIF4', 'cellular_component', 'GO:0008304', ('139', '143'))	('PI3K', 'Gene', (18, 22))	('upregulated', 'PosReg', (91, 102))	('eIF4E', 'Gene', '1977', (139, 144))	('RCC', 'Disease', 'MESH:C538614', (243, 246))	('Akt', 'Gene', (27, 30))	('High-mobility group nucleosome binding domain 5', 'Gene', '79366', (191, 238))	('miR-15a', 'Gene', '406948', (67, 74))	('downregulated', 'NegReg', (38, 51))	('Akt', 'Gene', '207', (27, 30))	('KIFC (Kinesin family member C1', 'Gene', '3833', (106, 136))	('miR-488', 'Gene', '574441', (80, 87))	('nucleosome', 'cellular_component', 'GO:0000786', ('211', '221'))	('miR-338-3p', 'Var', (55, 65))	('nucleosome binding', 'molecular_function', 'GO:0031491', ('211', '229'))	('HMGN5', 'Gene', '79366', (184, 189))	('High-mobility group nucleosome binding domain 5', 'Gene', (191, 238))	('PI3K', 'molecular_function', 'GO:0016303', ('18', '22'))	('HMGN5', 'Gene', (184, 189))
122068	33963171	In addition, overexpression of miR-338-3p, miR-15a, and miR-488 leads to repression of renal cancer progression induced by KIFC1, eIF4E, and HMGN5, respectively.	('HMGN5', 'Gene', '79366', (141, 146))	('eIF4', 'cellular_component', 'GO:0008304', ('130', '134'))	('renal cancer', 'Disease', (87, 99))	('miR-488', 'Gene', (56, 63))	('eIF4E', 'Gene', '1977', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('renal cancer', 'Phenotype', 'HP:0009726', (87, 99))	('HMGN5', 'Gene', (141, 146))	('eIF4E', 'Gene', (130, 135))	('miR-488', 'Gene', '574441', (56, 63))	('KIFC1', 'Gene', '3833', (123, 128))	('KIFC1', 'Gene', (123, 128))	('renal cancer', 'Disease', 'MESH:D007680', (87, 99))	('miR-15a', 'Gene', '406948', (43, 50))	('repression', 'NegReg', (73, 83))	('miR-15a', 'Gene', (43, 50))	('miR-338-3p', 'Var', (31, 41))
122069	33963171	KIFC1, eIF4E, and HMGN5 have been reported to act as oncogenes in various cancers Moreover, the expression of PTEN, which is a master regulator of the PI3K/Akt pathway, could be augmented by miR-520/372/373 and miR-203 or diminished by SPOP in RCC.	('PTEN', 'Gene', '5728', (110, 114))	('RCC', 'Disease', (244, 247))	('RCC', 'Phenotype', 'HP:0005584', (244, 247))	('augmented', 'PosReg', (178, 187))	('miR-203', 'Gene', (211, 218))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('KIFC1', 'Gene', '3833', (0, 5))	('SPOP', 'Gene', (236, 240))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('RCC', 'Disease', 'MESH:C538614', (244, 247))	('Akt', 'Gene', (156, 159))	('PI3K', 'molecular_function', 'GO:0016303', ('151', '155'))	('miR-203', 'Gene', '406986', (211, 218))	('expression', 'MPA', (96, 106))	('Akt', 'Gene', '207', (156, 159))	('diminished', 'NegReg', (222, 232))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('HMGN5', 'Gene', '79366', (18, 23))	('PTEN', 'Gene', (110, 114))	('eIF4E', 'Gene', (7, 12))	('miR-520/372/373', 'Var', (191, 206))	('HMGN5', 'Gene', (18, 23))	('KIFC1', 'Gene', (0, 5))	('eIF4E', 'Gene', '1977', (7, 12))	('eIF4', 'cellular_component', 'GO:0008304', ('7', '11'))	('SPOP', 'Gene', '8405', (236, 240))
122070	33963171	Overexpression of miR-520/372/373 results in attenuated renal tumor development by impairing SPOP, and speckle-type POZ protein (SPOP) has been reported to act as an oncogene in renal cancer (Table 1).	('attenuated renal tumor', 'Disease', (45, 67))	('impairing', 'NegReg', (83, 92))	('speckle-type POZ protein', 'Gene', (103, 127))	('renal cancer', 'Phenotype', 'HP:0009726', (178, 190))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('renal cancer', 'Disease', 'MESH:D007680', (178, 190))	('renal cancer', 'Disease', (178, 190))	('SPOP', 'Gene', '8405', (93, 97))	('SPOP', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('SPOP', 'Gene', '8405', (129, 133))	('renal tumor', 'Phenotype', 'HP:0009726', (56, 67))	('SPOP', 'Gene', (129, 133))	('attenuated renal tumor', 'Disease', 'MESH:C538265', (45, 67))	('miR-520/372/373', 'Var', (18, 33))	('speckle-type POZ protein', 'Gene', '8405', (103, 127))
122073	33963171	Additionally, the expression of P-Akt and P-ERK can be improved by splicing factor 2 (SF2) and reduced by miR-766-3p in RCC.	('P-ERK', 'Gene', (42, 47))	('improved', 'PosReg', (55, 63))	('SF2', 'Gene', '6426', (86, 89))	('splicing', 'biological_process', 'GO:0045292', ('67', '75'))	('ERK', 'molecular_function', 'GO:0004707', ('44', '47'))	('P-ERK', 'Gene', '9451', (42, 47))	('SF2', 'Gene', (86, 89))	('Akt', 'Gene', '207', (34, 37))	('expression', 'MPA', (18, 28))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('reduced', 'NegReg', (95, 102))	('splicing factor 2', 'Gene', '6426', (67, 84))	('miR-766-3p', 'Chemical', '-', (106, 116))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('Akt', 'Gene', (34, 37))	('miR-766-3p', 'Var', (106, 116))	('splicing factor 2', 'Gene', (67, 84))
122074	33963171	Overexpression of miR-766-3p leads to suppression of tumor growth by regulating SF2, and SF2 belongs to the splicing factor family and promotes carcinoma formation.	('carcinoma', 'Disease', (144, 153))	('SF2', 'Gene', (89, 92))	('miR-766-3p', 'Var', (18, 28))	('formation', 'biological_process', 'GO:0009058', ('154', '163'))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('SF2', 'Gene', '6426', (89, 92))	('carcinoma', 'Disease', 'MESH:D009369', (144, 153))	('splicing', 'biological_process', 'GO:0045292', ('108', '116'))	('tumor', 'Disease', (53, 58))	('SF2', 'Gene', '6426', (80, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('suppression', 'NegReg', (38, 49))	('promotes', 'PosReg', (135, 143))	('miR-766-3p', 'Chemical', '-', (18, 28))	('SF2', 'Gene', (80, 83))
122082	33963171	Similarly, miR-218 not only decreases the expression of VEGFA and p-PI3K/p-Akt/p-mTOR and restrains the migration ability of HUVECs (human umbilical vein endothelial cells), but also diminishes tumor angiogenesis in RCC by downregulating GRB2-associated binding protein 2 (GAB2).	('expression', 'MPA', (42, 52))	('angiogenesis', 'biological_process', 'GO:0001525', ('200', '212'))	('tumor', 'Disease', (194, 199))	('decreases', 'NegReg', (28, 37))	('VEGFA', 'Gene', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('GAB2', 'Gene', '9846', (273, 277))	('Akt', 'Gene', (75, 78))	('GAB2', 'Gene', (273, 277))	('mTOR', 'Gene', (81, 85))	('human', 'Species', '9606', (133, 138))	('GRB2-associated binding protein 2', 'Gene', (238, 271))	('migration ability', 'CPA', (104, 121))	('RCC', 'Disease', (216, 219))	('RCC', 'Phenotype', 'HP:0005584', (216, 219))	('Akt', 'Gene', '207', (75, 78))	('PI3K', 'molecular_function', 'GO:0016303', ('68', '72'))	('miR-218', 'Var', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('binding', 'molecular_function', 'GO:0005488', ('254', '261'))	('VEGFA', 'Gene', '7422', (56, 61))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('miR-218', 'Chemical', '-', (11, 18))	('mTOR', 'Gene', '2475', (81, 85))	('protein', 'cellular_component', 'GO:0003675', ('262', '269'))	('downregulating', 'NegReg', (223, 237))	('restrains', 'NegReg', (90, 99))	('diminishes', 'NegReg', (183, 193))	('GRB2-associated binding protein 2', 'Gene', '9846', (238, 271))
122086	33963171	In addition miR-148b-3p impairs the expression of VEGF-A and platelet-derived growth factor-BB/D(PDGF-BB/D) in RCC, and PDGF-BB/D act as pro-angiogenic actors in multiple cancers (Table 1).	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('PDGF-BB/D', 'Gene', '80310', (97, 106))	('VEGF-A', 'Gene', (50, 56))	('PDGF', 'molecular_function', 'GO:0005161', ('97', '101'))	('multiple cancers', 'Disease', (162, 178))	('PDGF', 'molecular_function', 'GO:0005161', ('120', '124'))	('miR-148b-3p', 'Chemical', '-', (12, 23))	('PDGF-BB/D', 'Gene', (97, 106))	('PDGF-BB/D', 'Gene', '80310', (120, 129))	('PDGF-BB/D', 'Gene', (120, 129))	('VEGF-A', 'Gene', '7422', (50, 56))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('61', '91'))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('miR-148b-3p', 'Var', (12, 23))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('multiple cancers', 'Disease', 'MESH:D009369', (162, 178))	('impairs', 'NegReg', (24, 31))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('expression', 'MPA', (36, 46))
122098	33963171	Indeed, PDK1 high expression in ccRCC cells boosts ECAR (extracellular acidification rate) under hypoxic conditions, improves ATP production, and diminishes the oxygen consumption rate (OCR) of tumor cells, whereas these effects can be reversed by miR-409-3p.	('ATP', 'Chemical', 'MESH:D000255', (126, 129))	('tumor', 'Disease', (194, 199))	('improves', 'PosReg', (117, 125))	('extracellular', 'cellular_component', 'GO:0005576', ('57', '70'))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('miR-409', 'Gene', (248, 255))	('miR-409', 'Gene', '574413', (248, 255))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('ATP production', 'MPA', (126, 140))	('PDK1', 'Gene', '5163', (8, 12))	('RCC', 'Disease', (34, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('oxygen consumption rate', 'MPA', (161, 184))	('acidification', 'biological_process', 'GO:0045851', ('71', '84'))	('diminishes', 'NegReg', (146, 156))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('boosts', 'PosReg', (44, 50))	('PDK1', 'molecular_function', 'GO:0004740', ('8', '12'))	('high expression', 'Var', (13, 28))	('oxygen', 'Chemical', 'MESH:D010100', (161, 167))	('hypoxic', 'Disease', 'MESH:D000860', (97, 104))	('hypoxic', 'Disease', (97, 104))	('PDK1', 'Gene', (8, 12))
122114	33963171	Indeed, IMPA2 underexpression in ccRCC diminishes the expression of N-cadherin and Slug, and sabotages tumor metastasis by downregulating miR-25-3p.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('IMPA2', 'Gene', (8, 13))	('Slug', 'Gene', '6591', (83, 87))	('miR', 'Gene', '220972', (138, 141))	('underexpression', 'Var', (14, 29))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('RCC', 'Disease', (35, 38))	('N-cadherin', 'Gene', (68, 78))	('sabotages', 'NegReg', (93, 102))	('N-cadherin', 'Gene', '1000', (68, 78))	('miR', 'Gene', (138, 141))	('downregulating', 'NegReg', (123, 137))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('tumor metastasis', 'Disease', 'MESH:D009362', (103, 119))	('IMPA2', 'Gene', '3613', (8, 13))	('Slug', 'Gene', (83, 87))	('expression', 'MPA', (54, 64))	('tumor metastasis', 'Disease', (103, 119))	('diminishes', 'NegReg', (39, 49))	('cadherin', 'molecular_function', 'GO:0008014', ('70', '78'))
122134	33963171	Likewise, miR-543 and miR-125b facilitate tumor growth through negatively regulating DKK1 and DKK3, respectively, in RCC.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('miR-543', 'Gene', '100126335', (10, 17))	('RCC', 'Disease', (117, 120))	('miR-125b', 'Var', (22, 30))	('miR-543', 'Gene', (10, 17))	('tumor', 'Disease', (42, 47))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('DKK1', 'Gene', '22943', (85, 89))	('facilitate', 'PosReg', (31, 41))	('DKK1', 'Gene', (85, 89))	('DKK3', 'Gene', '27122', (94, 98))	('DKK3', 'Gene', (94, 98))	('miR-125b', 'Chemical', '-', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('negatively regulating', 'NegReg', (63, 84))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
122142	33963171	In contrast, miR-381-3p inhibits TNF-induced apoptosis and necroptosis through downregulating caspase-8, caspase-3, and RIPK3 (receptor-interacting protein kinase 1) in renal cancer, whereas it has no effect on TNF-induced NF-kappaB activation, thus facilitating tumor progression and implying a poor outcome for papillary RCC patients; these findings suggest that the NF kappaB pathway has different functions in different cells.	('RIPK3', 'Gene', '11035', (120, 125))	('receptor-interacting protein kinase 1', 'Gene', '8737', (127, 164))	('RCC', 'Phenotype', 'HP:0005584', (323, 326))	('inhibits', 'NegReg', (24, 32))	('papillary RCC', 'Disease', 'MESH:C538614', (313, 326))	('caspase-3', 'Gene', '836', (105, 114))	('papillary RCC', 'Disease', (313, 326))	('caspase-3', 'Gene', (105, 114))	('necroptosis', 'biological_process', 'GO:0070266', ('59', '70'))	('NF-kappaB', 'Gene', (223, 232))	('TNF', 'Gene', '7124', (211, 214))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('223', '243'))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('necroptosis', 'biological_process', 'GO:0097528', ('59', '70'))	('miR-381-3p', 'Chemical', '-', (13, 23))	('necroptosis', 'CPA', (59, 70))	('receptor-interacting protein kinase 1', 'Gene', (127, 164))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('NF-kappaB', 'Gene', '4790', (223, 232))	('tumor', 'Disease', (263, 268))	('caspase-8', 'Gene', '841', (94, 103))	('TNF', 'Gene', (33, 36))	('apoptosis', 'CPA', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('NF kappaB', 'Gene', (369, 378))	('renal cancer', 'Disease', (169, 181))	('RIPK3', 'Gene', (120, 125))	('renal cancer', 'Phenotype', 'HP:0009726', (169, 181))	('patients', 'Species', '9606', (327, 335))	('TNF', 'Gene', '7124', (33, 36))	('downregulating', 'NegReg', (79, 93))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('miR-381-3p', 'Var', (13, 23))	('NF kappaB', 'Gene', '4790', (369, 378))	('TNF', 'Gene', (211, 214))	('caspase-8', 'Gene', (94, 103))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('renal cancer', 'Disease', 'MESH:D007680', (169, 181))
122144	33963171	The expression of KRAS can be attenuated by solute carrier family 4 (SLC4A4) and increased by miR-223-3p in ccRCC.	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('KRAS', 'Gene', (18, 22))	('miR-223-3p', 'Var', (94, 104))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('SLC4A4', 'Gene', (69, 75))	('SLC4A4', 'Gene', '8671', (69, 75))	('expression', 'MPA', (4, 14))	('miR-223-3p', 'Chemical', '-', (94, 104))	('carrier', 'molecular_function', 'GO:0005215', ('51', '58'))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('increased', 'PosReg', (81, 90))	('attenuated', 'NegReg', (30, 40))
122174	33963171	For instance, the expression of miR-10a-5p, miR-10b-5p, miR-106a-5p, and miR-142-5p is decreased in RCC nephrectomy specimens and has a sensitivity of 91.7% and specificity of 94% for distinguishing cancer from benign tissues.	('miR-106a', 'Gene', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('miR-10b', 'Gene', (44, 51))	('decreased', 'NegReg', (87, 96))	('miR-142-5p', 'Chemical', '-', (73, 83))	('miR-10a', 'Gene', '406902', (32, 39))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('miR-142-5p', 'Var', (73, 83))	('expression', 'MPA', (18, 28))	('cancer', 'Disease', (199, 205))	('RCC nephrectomy', 'Disease', 'MESH:C538614', (100, 115))	('miR-10b', 'Gene', '406903', (44, 51))	('RCC nephrectomy', 'Disease', (100, 115))	('miR-106a', 'Gene', '406899', (56, 64))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('miR-10a', 'Gene', (32, 39))
122182	33963171	Furthermore, miR-99a-3p suppresses RCC development and facilitates TKI treatment by modifying RRM2 (ribonucleotide reductase regulatory subunit M2).	('miR-99a-3p', 'Chemical', '-', (13, 23))	('RCC', 'Disease', (35, 38))	('ribonucleotide reductase regulatory subunit M2', 'Gene', (100, 146))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('miR-99a-3p', 'Var', (13, 23))	('TKI', 'Disease', (67, 70))	('modifying', 'Reg', (84, 93))	('facilitates', 'PosReg', (55, 66))	('RRM2', 'Gene', '6241', (94, 98))	('RRM2', 'Gene', (94, 98))	('suppresses', 'NegReg', (24, 34))	('ribonucleotide reductase regulatory subunit M2', 'Gene', '6241', (100, 146))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
122192	33963171	In addition, RCC patients with high expression of miR-144-5p have better disease-free survival (DFS) than those with low expression of miR-144-5p.	('miR-144', 'Gene', '406936', (135, 142))	('better', 'PosReg', (66, 72))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('disease-free survival', 'CPA', (73, 94))	('RCC', 'Disease', (13, 16))	('patients', 'Species', '9606', (17, 25))	('high expression', 'Var', (31, 46))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('miR-144', 'Gene', (135, 142))	('miR-144', 'Gene', (50, 57))	('miR-144', 'Gene', '406936', (50, 57))
122205	31270960	High linc00152 expression levels are associated with chemoresistance as well as poor prognosis and shorter survival.	('High', 'Var', (0, 4))	('chemoresistance', 'CPA', (53, 68))	('linc00152', 'Gene', (5, 14))	('expression levels', 'MPA', (15, 32))	('associated', 'Reg', (37, 47))	('linc00152', 'Gene', '112597', (5, 14))
122226	31270960	Their qRT-PCR and transwell assay results indicated that the knockdown of linc00152 prevents PDAC cell proliferation and invasion, thereby verifying the oncogenic property of linc00152.	('linc00152', 'Gene', '112597', (74, 83))	('prevents', 'NegReg', (84, 92))	('cell proliferation', 'biological_process', 'GO:0008283', ('98', '116'))	('linc00152', 'Gene', '112597', (175, 184))	('knockdown', 'Var', (61, 70))	('linc00152', 'Gene', (74, 83))	('invasion', 'CPA', (121, 129))	('PDAC', 'Disease', (93, 97))	('PDAC', 'Phenotype', 'HP:0006725', (93, 97))	('linc00152', 'Gene', (175, 184))
122236	31270960	Specifically, Zhang et al 41 determined the knockdown of linc00152 can inhibit the cell cycle (especially the G1 phase) to delay cell proliferation.	('cell proliferation', 'CPA', (129, 147))	('linc00152', 'Gene', '112597', (57, 66))	('G1 phase', 'biological_process', 'GO:0051318', ('110', '118'))	('inhibit', 'NegReg', (71, 78))	('delay', 'NegReg', (123, 128))	('cell proliferation', 'biological_process', 'GO:0008283', ('129', '147'))	('cell cycle', 'biological_process', 'GO:0007049', ('83', '93'))	('linc00152', 'Gene', (57, 66))	('knockdown', 'Var', (44, 53))
122249	31270960	Additionally, downregulated linc00152 expression decreases cell proliferation and shortens the S phase, possibly because of the epigenetic suppression of P16 and inhibition of miR-205.	('inhibition', 'NegReg', (162, 172))	('S phase', 'CPA', (95, 102))	('epigenetic', 'Var', (128, 138))	('miR-205', 'Gene', '406988', (176, 183))	('linc00152', 'Gene', (28, 37))	('P16', 'Gene', '1029', (154, 157))	('downregulated', 'NegReg', (14, 27))	('cell proliferation', 'CPA', (59, 77))	('decreases', 'NegReg', (49, 58))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('linc00152', 'Gene', '112597', (28, 37))	('S phase', 'biological_process', 'GO:0051320', ('95', '102'))	('shortens', 'NegReg', (82, 90))	('miR-205', 'Gene', (176, 183))	('P16', 'Gene', (154, 157))
122251	31270960	A cell viability assay indicated that inhibited linc00152 expression can disrupt cell proliferation.	('cell proliferation', 'CPA', (81, 99))	('inhibited', 'Var', (38, 47))	('linc00152', 'Gene', (48, 57))	('disrupt', 'NegReg', (73, 80))	('expression', 'MPA', (58, 68))	('cell proliferation', 'biological_process', 'GO:0008283', ('81', '99'))	('linc00152', 'Gene', '112597', (48, 57))
122259	31270960	When we investigated the relationship between linc00152 and gastric carcinogenesis, we observed that linc00152 can specifically recognize the EGFR-binding site and activate the PI3K/AKT signaling pathway to promote the proliferation of gastric cancer cells.31 Moreover, PI3K signals help regulate many cellular functions such as proliferation, differentiation, apoptosis, and glucose transport.	('PI3K', 'molecular_function', 'GO:0016303', ('270', '274'))	('signaling pathway', 'biological_process', 'GO:0007165', ('186', '203'))	('EGFR', 'Gene', '1956', (142, 146))	('linc00152', 'Gene', (101, 110))	('PI3K', 'molecular_function', 'GO:0016303', ('177', '181'))	('gastric carcinogenesis', 'Disease', (60, 82))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (60, 82))	('gastric cancer', 'Disease', (236, 250))	('differentiation', 'CPA', (344, 359))	('cellular functions', 'CPA', (302, 320))	('AKT', 'Gene', '207', (182, 185))	('PI3K', 'Var', (270, 274))	('apoptosis', 'CPA', (361, 370))	('glucose', 'Chemical', 'MESH:D005947', (376, 383))	('regulate', 'Reg', (288, 296))	('EGFR', 'Gene', (142, 146))	('gastric cancer', 'Disease', 'MESH:D013274', (236, 250))	('apoptosis', 'biological_process', 'GO:0097194', ('361', '370'))	('AKT signaling', 'biological_process', 'GO:0043491', ('182', '195'))	('glucose transport', 'biological_process', 'GO:1904659', ('376', '393'))	('apoptosis', 'biological_process', 'GO:0006915', ('361', '370'))	('linc00152', 'Gene', '112597', (46, 55))	('proliferation', 'CPA', (329, 342))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('linc00152', 'Gene', (46, 55))	('EGFR-binding', 'molecular_function', 'GO:0005154', ('142', '154'))	('gastric cancer', 'Phenotype', 'HP:0012126', (236, 250))	('glucose transport', 'CPA', (376, 393))	('linc00152', 'Gene', '112597', (101, 110))	('AKT', 'Gene', (182, 185))
122260	31270960	The signaling pathway comprising type IA PI3K and its downstream molecular protein kinase B (PKB or AKT) was recently determined to be closely related to the development and progression of human tumors.32 This pathway regulates the proliferation and survival of tumor cells, and its abnormal activity can lead to the development of malignant cells, while also facilitating cellular migration, adhesion, tumor angiogenesis, and the degradation of the extracellular matrix (Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('tumor', 'Disease', (195, 200))	('PI3K', 'molecular_function', 'GO:0016303', ('41', '45'))	('tumor', 'Disease', 'MESH:D009369', (403, 408))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('lead to', 'Reg', (305, 312))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('regulates', 'Reg', (218, 227))	('AKT', 'Gene', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (403, 408))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('450', '470'))	('facilitating', 'PosReg', (360, 372))	('abnormal', 'Var', (283, 291))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('degradation', 'biological_process', 'GO:0009056', ('431', '442'))	('tumors', 'Disease', (195, 201))	('cellular migration', 'CPA', (373, 391))	('human', 'Species', '9606', (189, 194))	('tumor', 'Disease', (262, 267))	('adhesion', 'CPA', (393, 401))	('AKT', 'Gene', '207', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('survival', 'CPA', (250, 258))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('signaling pathway', 'biological_process', 'GO:0007165', ('4', '21'))	('development of malignant cells', 'CPA', (317, 347))	('PKB', 'Gene', '207', (93, 96))	('degradation of the extracellular matrix', 'MPA', (431, 470))	('proliferation', 'CPA', (232, 245))	('PKB', 'Gene', (93, 96))	('tumor', 'Disease', (403, 408))	('angiogenesis', 'biological_process', 'GO:0001525', ('409', '421'))
122265	31270960	Therefore, inhibiting linc00152 activity may be a viable strategy for treating esophageal cancer.	('esophageal cancer', 'Disease', (79, 96))	('linc00152', 'Gene', '112597', (22, 31))	('inhibiting', 'Var', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('activity', 'MPA', (32, 40))	('linc00152', 'Gene', (22, 31))
122305	30334000	Contemporary ccRCC genomic studies demonstrated that loss of heterozygosity (LOH) of chromosome 3p occurs at >90% and mutations/methylation of VHL, residing at 3p25, occurs at >70%/10-15%, confirming that inactivation of VHL serves as the fundamental driver event of human ccRCC.	('RCC', 'Disease', 'MESH:C538614', (275, 278))	('mutations/methylation', 'Var', (118, 139))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('chromosome', 'cellular_component', 'GO:0005694', ('85', '95'))	('RCC', 'Disease', (15, 18))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('methylation', 'biological_process', 'GO:0032259', ('128', '139'))	('loss', 'NegReg', (53, 57))	('VHL', 'Gene', (143, 146))	('inactivation', 'Var', (205, 217))	('human', 'Species', '9606', (267, 272))	('RCC', 'Disease', (275, 278))	('RCC', 'Phenotype', 'HP:0005584', (275, 278))
122312	30334000	These efforts were made possible by the rapid progress in next-generation sequencing technologies and large-scale consortium efforts, revealing several novel gene mutations in ccRCC, including the tumor suppressor genes PBRM1 (40%), SETD2 (15%), BAP1 (15%), and KDM5C (7%), and the oncogene MTOR (5%).	('mutations', 'Var', (163, 172))	('tumor suppressor', 'biological_process', 'GO:0051726', ('197', '213'))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('197', '213'))	('MTOR', 'Gene', (291, 295))	('SETD2', 'Gene', '29072', (233, 238))	('MTOR', 'Gene', '2475', (291, 295))	('PBRM1', 'Gene', (220, 225))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('SETD2', 'Gene', (233, 238))	('RCC', 'Disease', (178, 181))	('KDM5C', 'Gene', (262, 267))	('tumor', 'Disease', (197, 202))	('KDM5C', 'Gene', '8242', (262, 267))
122314	30334000	Furthermore, KDM5C resides at X chromosome, thereby mutations on the sole wild type allele in male patients cause complete loss of function of KDM5C, which could contribute to the 2 : 1 male predominance in ccRCC.	('mutations', 'Var', (52, 61))	('X chromosome', 'cellular_component', 'GO:0000805', ('30', '42'))	('loss of function', 'NegReg', (123, 139))	('KDM5C', 'Gene', (13, 18))	('patients', 'Species', '9606', (99, 107))	('RCC', 'Phenotype', 'HP:0005584', (209, 212))	('KDM5C', 'Gene', (143, 148))	('RCC', 'Disease', 'MESH:C538614', (209, 212))	('RCC', 'Disease', (209, 212))	('KDM5C', 'Gene', '8242', (143, 148))	('KDM5C', 'Gene', '8242', (13, 18))
122316	30334000	Ten genes, VHL, PBRM1, BAP1, SETD2, KDM5C, TP53, PIK3CA, MTOR, TSC1, and NF2 altogether mutated in 93% of ccRCC, are included for the discussion/classification in this review (Fig.	('SETD2', 'Gene', '29072', (29, 34))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('NF2', 'Gene', (73, 76))	('KDM5C', 'Gene', '8242', (36, 41))	('PIK3CA', 'Gene', '5290', (49, 55))	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('MTOR', 'Gene', (57, 61))	('VHL', 'Gene', (11, 14))	('MTOR', 'Gene', '2475', (57, 61))	('TP53', 'Gene', (43, 47))	('PBRM1', 'Gene', (16, 21))	('BAP1', 'Gene', (23, 27))	('KDM5C', 'Gene', (36, 41))	('PIK3CA', 'Gene', (49, 55))	('TSC1', 'Gene', (63, 67))	('SETD2', 'Gene', (29, 34))	('TSC1', 'Gene', '7248', (63, 67))	('mutated', 'Var', (88, 95))	('NF2', 'Gene', '4771', (73, 76))	('TP53', 'Gene', '7157', (43, 47))
122317	30334000	Accordingly, VHL mutation can serve as a good diagnostic tool but carries no clinical impact for ccRCC in subset analysis.	('mutation', 'Var', (17, 25))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('VHL', 'Gene', (13, 16))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('clinical', 'Species', '191496', (77, 85))
122318	30334000	BAP1 mutations are associated with high grade, large tumors, and poor overall clinical outcome even on targeted therapy.	('associated', 'Reg', (19, 29))	('BAP1', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('clinical', 'Species', '191496', (78, 86))	('high grade', 'CPA', (35, 45))	('tumors', 'Disease', (53, 59))
122319	30334000	For example, progression free survival (PFS) of BAP1 mutant (MT) vs. BAP1 wild-type (WT) patients on first line sunitinib, a VEGFR TKI, was 8.1 vs. 11.0 months, and on first line everolimus, an MTORC1 inhibitor, was 4.9 vs. 10.5 months in RECORD-3 trial, one large randomized phase II study, suggesting that BAP1 mutant patients may not benefit from everolimus.	('MTORC1', 'Gene', '382056', (194, 200))	('sunitinib', 'Chemical', 'MESH:D000077210', (112, 121))	('mutant', 'Var', (313, 319))	('BAP1', 'Gene', (48, 52))	('VEGFR', 'Gene', '3791', (125, 130))	('patients', 'Species', '9606', (89, 97))	('everolimus', 'Chemical', 'MESH:D000068338', (350, 360))	('mutant', 'Var', (53, 59))	('everolimus', 'Chemical', 'MESH:D000068338', (179, 189))	('VEGFR', 'Gene', (125, 130))	('BAP1', 'Gene', (308, 312))	('MTORC1', 'Gene', (194, 200))	('MTORC1', 'cellular_component', 'GO:0031931', ('194', '200'))	('patients', 'Species', '9606', (320, 328))
122320	30334000	Furthermore, BAP1 mutated mouse ccRCC tumors exhibited high grade features.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('RCC tumors', 'Disease', 'MESH:C538614', (34, 44))	('BAP1', 'Gene', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('mutated', 'Var', (18, 25))	('RCC tumors', 'Disease', (34, 44))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('mouse', 'Species', '10090', (26, 31))
122321	30334000	TP53 mutations occur at lower frequency (2.2%) in the primary tumors of non-metastatic ccRCC patients, at higher frequency (8%) in primaries of metastatic ccRCC, and at even higher frequencies (>10%) when multiple regions or matched primary-metastasis pairs were sequenced (Hsieh et al.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('mutations', 'Var', (5, 14))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', (157, 160))	('patients', 'Species', '9606', (93, 101))
122322	30334000	TP53 mutation in ccRCC associate with high grade in both human and mouse ccRCC tumors and significantly decreased cancer specific survival even after correction for SSIGN (stage, size, grade, and necrosis) score.	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('necrosis', 'biological_process', 'GO:0070265', ('196', '204'))	('RCC', 'Disease', (75, 78))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('necrosis', 'biological_process', 'GO:0019835', ('196', '204'))	('necrosis', 'biological_process', 'GO:0001906', ('196', '204'))	('human', 'Species', '9606', (57, 62))	('TP53', 'Gene', '7157', (0, 4))	('necrosis', 'Disease', 'MESH:D009336', (196, 204))	('decreased', 'NegReg', (104, 113))	('RCC', 'Disease', (19, 22))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('necrosis', 'Disease', (196, 204))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('necrosis', 'biological_process', 'GO:0008219', ('196', '204'))	('mouse', 'Species', '10090', (67, 72))	('TP53', 'Gene', (0, 4))	('RCC tumors', 'Disease', (75, 85))	('necrosis', 'biological_process', 'GO:0008220', ('196', '204'))	('RCC tumors', 'Disease', 'MESH:C538614', (75, 85))	('mutation', 'Var', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('cancer', 'Disease', (114, 120))
122323	30334000	KDM5C mutations occurred mainly in male patients and were associated with much longer 1st line PFS (PFS1L) on sunitinib (20.6 months) than everolimus (9.8 months) whereas KDM5C wild-type patients exhibited similar PFS1L on either sunitinib (8.3 months) or everolimus (8.2 months).	('patients', 'Species', '9606', (187, 195))	('1st', 'MPA', (86, 89))	('everolimus', 'Chemical', 'MESH:D000068338', (139, 149))	('patients', 'Species', '9606', (40, 48))	('KDM5C', 'Gene', (171, 176))	('sunitinib', 'Chemical', 'MESH:D000077210', (110, 119))	('everolimus', 'Chemical', 'MESH:D000068338', (256, 266))	('KDM5C', 'Gene', (0, 5))	('longer', 'PosReg', (79, 85))	('KDM5C', 'Gene', '8242', (171, 176))	('KDM5C', 'Gene', '8242', (0, 5))	('sunitinib', 'Chemical', 'MESH:D000077210', (230, 239))	('mutations', 'Var', (6, 15))
122324	30334000	Enrichment of KDM5C mutation tumors in responders to anti-VEGF/VEGFR agents was also reported by independent researchers.	('VEGF', 'Gene', (63, 67))	('VEGF', 'Gene', (58, 62))	('VEGFR', 'Gene', '3791', (63, 68))	('tumors', 'Disease', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mutation', 'Var', (20, 28))	('VEGF', 'Gene', '7422', (63, 67))	('VEGF', 'Gene', '7422', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('VEGFR', 'Gene', (63, 68))	('KDM5C', 'Gene', (14, 19))	('KDM5C', 'Gene', '8242', (14, 19))
122325	30334000	Notably, KDM5C mutations tend to co-occur with PBRM1 mutations, whereas both KDM5C and PBRM1 mutations tend to occur in a mutually exclusive manner with BAP1 mutations.	('PBRM1', 'Gene', (47, 52))	('KDM5C', 'Gene', '8242', (9, 14))	('KDM5C', 'Gene', (77, 82))	('mutations', 'Var', (15, 24))	('KDM5C', 'Gene', '8242', (77, 82))	('mutations', 'Var', (53, 62))	('co-occur', 'Reg', (33, 41))	('KDM5C', 'Gene', (9, 14))
122327	30334000	PBRM1 mutations in small renal masses (<4 cm) were associated with tumor invasiveness, and mice bearing mutations in VHL and PBRM1 (VHL-/-;PBRM1-/-) developed ccRCC.	('mice', 'Species', '10090', (91, 95))	('mutations', 'Var', (104, 113))	('PBRM1', 'Gene', (0, 5))	('tumor invasiveness', 'Disease', (67, 85))	('developed', 'PosReg', (149, 158))	('associated', 'Reg', (51, 61))	('tumor invasiveness', 'Disease', 'MESH:D009369', (67, 85))	('small renal', 'Phenotype', 'HP:0000089', (19, 30))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('RCC', 'Disease', (161, 164))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('renal masses', 'Phenotype', 'HP:0009726', (25, 37))	('PBRM1', 'Gene', (125, 130))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('mutations', 'Var', (6, 15))	('VHL', 'Gene', (117, 120))
122329	30334000	Of note, a long latency period for mouse kidney epithelium with deletion of both VHL and PBRM1 to develop ccRCC was observed, and the preferred third driver event for the development of ccRCC was the activation of MTORC1.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('MTORC1', 'Gene', '382056', (214, 220))	('VHL', 'Gene', (81, 84))	('PBRM1', 'Gene', (89, 94))	('deletion', 'Var', (64, 72))	('MTORC1', 'cellular_component', 'GO:0031931', ('214', '220'))	('mouse', 'Species', '10090', (35, 40))	('RCC', 'Disease', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('MTORC1', 'Gene', (214, 220))
122330	30334000	Of note, PBRM1 mutant patients experienced longer PFS1L on everolimus (12.8 months) than the whole cohort receiving everolimus (8.3 months).	('longer', 'PosReg', (43, 49))	('patients', 'Species', '9606', (22, 30))	('everolimus', 'Chemical', 'MESH:D000068338', (116, 126))	('mutant', 'Var', (15, 21))	('PFS1L on everolimus', 'MPA', (50, 69))	('PBRM1', 'Gene', (9, 14))	('everolimus', 'Chemical', 'MESH:D000068338', (59, 69))
122332	30334000	MTOR gene mutations occur in ~5% of ccRCC that cluster at conserve domains and result in enhanced MTORC1 signaling.	('RCC', 'Disease', (38, 41))	('enhanced', 'PosReg', (89, 97))	('MTORC1', 'Gene', (98, 104))	('MTOR', 'Gene', (98, 102))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('MTORC1', 'Gene', '382056', (98, 104))	('mutations', 'Var', (10, 19))	('MTOR', 'Gene', '2475', (0, 4))	('MTORC1', 'cellular_component', 'GO:0031931', ('98', '104'))	('MTOR', 'Gene', (0, 4))	('MTOR', 'Gene', '2475', (98, 102))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
122334	30334000	Accordingly, mutations in MTOR, TSC1, TSC2, and PI3K were enriched in ccRCC patients most benefited from treatment with mTORC1 inhibitors everolimus and temsirolimus.	('benefited', 'PosReg', (90, 99))	('patients', 'Species', '9606', (76, 84))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('mTORC1', 'Gene', '382056', (120, 126))	('TSC1', 'Gene', (32, 36))	('TSC2', 'Gene', (38, 42))	('everolimus', 'Chemical', 'MESH:D000068338', (138, 148))	('RCC', 'Disease', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('mTORC1', 'cellular_component', 'GO:0031931', ('120', '126'))	('mTORC1', 'Gene', (120, 126))	('MTOR', 'Gene', (26, 30))	('PI3K', 'molecular_function', 'GO:0016303', ('48', '52'))	('PI3K', 'Gene', (48, 52))	('mutations', 'Var', (13, 22))	('MTOR', 'Gene', '2475', (26, 30))	('TSC2', 'Gene', '7249', (38, 42))	('TSC1', 'Gene', '7248', (32, 36))
122335	30334000	mutations detected in metastasis were shown to be superior to primary in treatment prediction and should be weighed differently for precision cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mutations', 'Var', (0, 9))	('cancer', 'Disease', (142, 148))
122336	30334000	SETD2 mutations in ccRCC are the best example highlighting intra-tumor heterogeneity and convergent evolution, i.e.	('intra-tumor', 'Disease', (59, 70))	('SETD2', 'Gene', '29072', (0, 5))	('SETD2', 'Gene', (0, 5))	('intra-tumor', 'Disease', 'MESH:D009369', (59, 70))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('RCC', 'Disease', (21, 24))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('mutations', 'Var', (6, 15))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
122337	30334000	through multi-region sequencing of tumors from the same patient multiple variants of SETD2 mutation were identified.	('mutation', 'Var', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('SETD2', 'Gene', '29072', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('SETD2', 'Gene', (85, 90))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('patient', 'Species', '9606', (56, 63))
122339	30334000	Several lines of evidence indicate the importance of SETD2 mutations in ccRCC progression, especially in metastasis, thereby impacting cancer survival.	('cancer', 'Disease', (135, 141))	('SETD2', 'Gene', (53, 58))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('mutations', 'Var', (59, 68))	('impacting', 'Reg', (125, 134))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('SETD2', 'Gene', '29072', (53, 58))
122340	30334000	Genomic analysis of the primary tumors from TCGA 421 patients and MSK 188 patients that consists patients of all stages, SETD2 mutations (11.6% TCGA, 7.4% MSK) were associated with worse cancer specific survival, which was later validated with a combined cohort of 1049 patients.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('worse', 'NegReg', (181, 186))	('patients', 'Species', '9606', (270, 278))	('cancer', 'Disease', (187, 193))	('patients', 'Species', '9606', (53, 61))	('patients', 'Species', '9606', (74, 82))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('SETD2', 'Gene', '29072', (121, 126))	('tumors', 'Disease', (32, 38))	('mutations', 'Var', (127, 136))	('SETD2', 'Gene', (121, 126))	('patients', 'Species', '9606', (97, 105))
122341	30334000	Furthermore, examination of the primary tumors of metastatic ccRCC patients demonstrated enrichment of SETD2 mutations to 30%.	('RCC', 'Disease', (63, 66))	('patients', 'Species', '9606', (67, 75))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('SETD2', 'Gene', '29072', (103, 108))	('mutations', 'Var', (109, 118))	('SETD2', 'Gene', (103, 108))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('tumors', 'Disease', (40, 46))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
122342	30334000	Of note, although SETD2 mutations were associated with metastasis of ccRCC, they were not associated poor targeted treatment outcome contrasting patients with BAP1 mutations.	('associated with', 'Reg', (39, 54))	('patients', 'Species', '9606', (145, 153))	('metastasis', 'CPA', (55, 65))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('SETD2', 'Gene', '29072', (18, 23))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('SETD2', 'Gene', (18, 23))	('mutations', 'Var', (24, 33))
122344	30334000	Interestingly, SETD2 mutations also occur in other RCC types, and co-occur with NF2 mutations in unclassified RCC.	('RCC', 'Disease', (110, 113))	('NF2', 'Gene', '4771', (80, 83))	('SETD2', 'Gene', '29072', (15, 20))	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('SETD2', 'Gene', (15, 20))	('RCC', 'Disease', (51, 54))	('mutations', 'Var', (84, 93))	('NF2', 'Gene', (80, 83))	('co-occur', 'Reg', (66, 74))	('occur', 'Reg', (36, 41))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('mutations', 'Var', (21, 30))
122345	30334000	Moreover, two cases of cancer of unknown primary carry concurrent SETD2 and NF2 mutations and exhibit clear cell morphology and positivity for CA9.	('CA9', 'Gene', '768', (143, 146))	('CA9', 'Gene', (143, 146))	('mutations', 'Var', (80, 89))	('NF2', 'Gene', (76, 79))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('NF2', 'Gene', '4771', (76, 79))	('SETD2', 'Gene', '29072', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('SETD2', 'Gene', (66, 71))
122369	30334000	Deletion of CDKN2A (53% vs. 26%; P < 0.0001) and mutations in PTEN (11% vs 1%; P < 0.0001) were more frequent in m3 tumours.	('PTEN', 'Gene', (62, 66))	('frequent', 'Reg', (101, 109))	('mutations', 'Var', (49, 58))	('CDKN2A', 'Gene', (12, 18))	('PTEN', 'Gene', '5728', (62, 66))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('CDKN2A', 'Gene', '1029', (12, 18))	('tumours', 'Disease', 'MESH:D009369', (116, 123))	('tumours', 'Disease', (116, 123))	('Deletion', 'Var', (0, 8))
122370	30334000	The m4 group showed higher frequencies of BAP1 mutations (17% vs. 7%; P = 0.002) and base-excision repair; however, this group also harboured more mTOR mutations (12% vs. 4%; P = 0.01) and ribosomal gene sets.	('mutations', 'Var', (152, 161))	('BAP1', 'Gene', (42, 46))	('mTOR', 'Gene', '2475', (147, 151))	('mutations', 'Var', (47, 56))	('more', 'PosReg', (142, 146))	('base-excision', 'CPA', (85, 98))	('base-excision repair', 'biological_process', 'GO:0006284', ('85', '105'))	('mTOR', 'Gene', (147, 151))
122384	30334000	At the opposite ccrcc3 had the lower inflammation score and the lower frequency of sarcomatoid component but has also low frequencies of VHL and PBRM1 mutations.	('inflammation', 'Disease', 'MESH:D007249', (37, 49))	('lower', 'NegReg', (64, 69))	('inflammation', 'biological_process', 'GO:0006954', ('37', '49'))	('sarcomatoid component', 'Disease', (83, 104))	('VHL', 'Gene', (137, 140))	('lower inflammation score', 'Phenotype', 'HP:0012648', (31, 55))	('inflammation', 'Disease', (37, 49))	('lower', 'NegReg', (31, 36))	('sarcomatoid component', 'Disease', 'MESH:C538614', (83, 104))	('PBRM1', 'Gene', (145, 150))	('mutations', 'Var', (151, 160))
122387	30334000	Somatic PBRM1 mutations were most frequently identified in ccrcc1/ccrcc2 tumors but rarely found in ccrcc3/ccrcc4 tumors.	('ccrcc2 tumors', 'Disease', (66, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('identified', 'Reg', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('ccrcc2 tumors', 'Disease', 'MESH:D009369', (66, 79))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (73, 79))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (14, 23))	('PBRM1', 'Gene', (8, 13))
122388	30334000	In both series, somatic VHL mutations were more frequently distributed in ccrcc1/ccrcc2 tumors.	('ccrcc2 tumors', 'Disease', 'MESH:D009369', (81, 94))	('ccrcc2 tumors', 'Disease', (81, 94))	('distributed', 'Reg', (59, 70))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('VHL', 'Gene', (24, 27))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('mutations', 'Var', (28, 37))
122389	30334000	The BAP1 and SETD2 mutations also showed association with the molecular subtypes: BAP1 was most mutated in the ccrcc4 tumors (p = 0.0098) and SETD2 was most mutated in the ccrcc1 tumors (p = 0.06).	('mutated', 'Var', (96, 103))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('BAP1', 'Gene', (82, 86))	('BAP1', 'Gene', (4, 8))	('ccrcc1 tumors', 'Disease', (172, 185))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mutations', 'Var', (19, 28))	('ccrcc1 tumors', 'Disease', 'MESH:D009369', (172, 185))	('SETD2', 'Gene', '29072', (13, 18))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('SETD2', 'Gene', (13, 18))	('SETD2', 'Gene', '29072', (142, 147))	('tumors', 'Disease', (118, 124))	('SETD2', 'Gene', (142, 147))
122404	30334000	Worse clinical outcomes were associated with high glutathione-related metabolites observed in mCluster 2 or with high dipeptides in mCluster 3, whereas better clinical outcomes were associated with low glutathione in mCluster 4 and low dipeptide in mCluster 1, which may present therapeutic opportunity through further disrupting the redox or lysosome pathways, respectively.	('lysosome', 'cellular_component', 'GO:0005764', ('343', '351'))	('low', 'NegReg', (198, 201))	('high glutathione-related metabolites', 'MPA', (45, 81))	('high dipeptides', 'Var', (113, 128))	('clinical', 'Species', '191496', (159, 167))	('redox', 'Pathway', (334, 339))	('glutathione', 'Chemical', 'MESH:D005978', (202, 213))	('glutathione', 'Chemical', 'MESH:D005978', (50, 61))	('dipeptides', 'Chemical', 'MESH:D004151', (118, 128))	('low glutathione', 'Phenotype', 'HP:0003343', (198, 213))	('glutathione', 'MPA', (202, 213))	('low dipeptide', 'Var', (232, 245))	('dipeptide', 'Chemical', 'MESH:D004151', (118, 127))	('dipeptide', 'Chemical', 'MESH:D004151', (236, 245))	('lysosome pathways', 'Pathway', (343, 360))	('clinical', 'Species', '191496', (6, 14))	('disrupting', 'Reg', (319, 329))
122415	30334000	First, most of mutated genes are tumor suppressor genes and mutations lead to loss of function.	('genes', 'Gene', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor suppressor', 'biological_process', 'GO:0051726', ('33', '49'))	('mutated', 'Var', (15, 22))	('tumor', 'Disease', (33, 38))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('33', '49'))	('loss of function', 'NegReg', (78, 94))
122417	30334000	PBRM1 or BAP1 mutations could be different when sequencing primary vs. metastatic tumors.	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('PBRM1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
122528	31781309	Tumor development is highly dependent on TME, and any alterations of the composition of TME may influence the evolution of malignancies.	('malignancies', 'Disease', 'MESH:D009369', (123, 135))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor development', 'CPA', (0, 17))	('malignancies', 'Disease', (123, 135))	('alterations', 'Var', (54, 65))	('influence', 'Reg', (96, 105))
122533	31781309	Survival curves according to Kaplan-Meier showed that low-immune scores as well as stromal scores predicted a favorable prognosis in ccRCC patients.	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('patients', 'Species', '9606', (139, 147))	('ccRCC', 'Disease', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('ccRCC', 'Disease', 'MESH:D002292', (133, 138))	('low-immune scores', 'Var', (54, 71))
122539	31781309	reported that inhibition of the NF kappa B signaling pathway attenuated the progression of RCC.	('RCC', 'Disease', 'MESH:D002292', (91, 94))	('RCC', 'Disease', (91, 94))	('NF kappa B signaling pathway', 'Pathway', (32, 60))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('signaling pathway', 'biological_process', 'GO:0007165', ('43', '60'))	('attenuated', 'NegReg', (61, 71))	('inhibition', 'Var', (14, 24))
122543	31781309	A previous study showed that the RCC patients with high expression of IL10 had a lower incidence of distant metastasis.	('lower', 'NegReg', (81, 86))	('IL10', 'Gene', (70, 74))	('patients', 'Species', '9606', (37, 45))	('RCC', 'Disease', 'MESH:D002292', (33, 36))	('RCC', 'Disease', (33, 36))	('IL10', 'Gene', '3586', (70, 74))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('IL10', 'molecular_function', 'GO:0005141', ('70', '74'))	('high expression', 'Var', (51, 66))	('distant metastasis', 'CPA', (100, 118))
122550	31781309	In addition, PD-1 and PDL-1 were also increased in the high-stromal score group.	('PDL-1', 'Gene', (22, 27))	('PD-1', 'Gene', (13, 17))	('PD-1', 'Gene', '5133', (13, 17))	('high-stromal', 'Var', (55, 67))	('increased', 'PosReg', (38, 47))	('PDL-1', 'Gene', '29126', (22, 27))
122560	29151960	Nephrometry Score: A Preoperative Risk Factor Predicting the Fuhrman Grade of Clear-Cell Renal Carcinoma Objective: The purpose of this study was to evaluate the efficacy and feasibility of the R.E.N.A.L.	('Clear-Cell Renal Carcinoma', 'Disease', 'MESH:C538614', (78, 104))	('Carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('Clear-Cell Renal Carcinoma', 'Disease', (78, 104))	('Renal Carcinoma', 'Phenotype', 'HP:0005584', (89, 104))	('R.E.N.A.L', 'Var', (194, 203))
122586	29151960	R was significantly correlated with the HFG group, tumors with R scores of 2 points showed 11.59-fold higher risk for HFG postoperatively than those with R scores of 1 point.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('HFG', 'Chemical', '-', (118, 121))	('HFG', 'Chemical', '-', (40, 43))	('HFG', 'Disease', (118, 121))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('R scores', 'Var', (63, 71))
122587	29151960	Additionally, R scores of 3 points showed 17.56-fold higher risk for HFG postoperatively than those with R scores of 2 points.	('R scores', 'Var', (14, 22))	('HFG', 'Chemical', '-', (69, 72))	('HFG', 'Disease', (69, 72))
122593	29151960	Furthermore, biopsies may facilitate tumor seeding along the needle tract.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('biopsies', 'Var', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('facilitate', 'PosReg', (26, 36))
122635	28319095	Dysfunction of these proteins leads to alterations in ER calcium homeostasis, including ER calcium depletion, and ultimately results in ER stress.	('Dysfunction', 'Var', (0, 11))	('homeostasis', 'biological_process', 'GO:0042592', ('65', '76'))	('calcium', 'Chemical', 'MESH:D002118', (91, 98))	('ER calcium homeostasis', 'MPA', (54, 76))	('ER stress', 'MPA', (136, 145))	('calcium', 'Chemical', 'MESH:D002118', (57, 64))	('ER calcium depletion', 'MPA', (88, 108))	('alterations', 'Reg', (39, 50))	('results in', 'Reg', (125, 135))
122643	28319095	The viability of cells was assessed by microscopy and cell proliferation assays (MTS assay), and the results indicated that depletion of RCN1 resulted in a lower number of surviving HEK293T and HepG2 cells after TM treatment (Figures 1a and d, Supplementary Figure S1a).	('RCN1', 'Gene', (137, 141))	('HepG2', 'CellLine', 'CVCL:0027', (194, 199))	('MTS', 'Gene', (81, 84))	('HEK293T', 'CellLine', 'CVCL:0063', (182, 189))	('TM', 'Chemical', 'MESH:D014415', (212, 214))	('MTS', 'Gene', '8201', (81, 84))	('cell proliferation', 'biological_process', 'GO:0008283', ('54', '72'))	('depletion', 'Var', (124, 133))	('lower', 'NegReg', (156, 161))	('RCN1', 'Gene', '5954', (137, 141))
122645	28319095	Depletion of RCN1 dramatically increased the number of TUNEL-labeled cells (Figure 1e, Supplementary Figure S1b); similar results were also observed after treatment with TG (thapsigargin, another ER stress-inducing drug)-treated HepG2 cells (Figures 1f and g).	('TUNEL-labeled cells', 'MPA', (55, 74))	('RCN1', 'Gene', '5954', (13, 17))	('RCN1', 'Gene', (13, 17))	('thapsigargin', 'Chemical', 'MESH:D019284', (174, 186))	('HepG2', 'CellLine', 'CVCL:0027', (229, 234))	('increased', 'PosReg', (31, 40))	('Depletion', 'Var', (0, 9))	('TG', 'Chemical', 'MESH:D019284', (170, 172))
122647	28319095	Annexin V/PI (propidium iodide) labeling assays revealed that depletion of RCN1 during ER stress, but not under normal conditions, significantly elevated the number of cells in early apoptosis, as detected by flow cytometry analysis (Figures 1i-k, Supplementary Figure S1e-g), whereas overexpression of 3 x Flag-RCN1 decreased the number of cells in early apoptosis and the cleaved caspase-3 levels during ER stress (Figures 1l and m, Supplementary Figure S1h) but not under normal conditions (Supplementary Figure S1i-k).	('RCN1', 'Gene', (312, 316))	('elevated', 'PosReg', (145, 153))	('Annexin V', 'Gene', '308', (0, 9))	('Annexin V', 'Gene', (0, 9))	('caspase-3', 'Gene', (382, 391))	('RCN1', 'Gene', '5954', (75, 79))	('apoptosis', 'biological_process', 'GO:0006915', ('356', '365'))	('caspase-3', 'Gene', '836', (382, 391))	('apoptosis', 'biological_process', 'GO:0097194', ('356', '365'))	('depletion', 'Var', (62, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('183', '192'))	('apoptosis', 'biological_process', 'GO:0006915', ('183', '192'))	('RCN1', 'Gene', '5954', (312, 316))	('RCN1', 'Gene', (75, 79))
122658	28319095	To investigate whether the PERK- or IRE1-mediated pathways contribute to increased apoptosis caused by RCN1 depletion during ER stress, we used inhibitors of these transducers.	('PERK', 'Gene', (27, 31))	('increased', 'PosReg', (73, 82))	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('PERK', 'Gene', '9451', (27, 31))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('RCN1', 'Gene', '5954', (103, 107))	('IRE1', 'Gene', '2081', (36, 40))	('RCN1', 'Gene', (103, 107))	('IRE1', 'Gene', (36, 40))	('apoptosis', 'CPA', (83, 92))	('depletion', 'Var', (108, 117))
122659	28319095	Pretreatment with GSK2606414, a PERK inhibitor, efficiently blocked the CHOP induction caused by depletion of RCN1 after TG treatment (Figure 3a).	('CHOP', 'Gene', (72, 76))	('PERK', 'Gene', '9451', (32, 36))	('blocked', 'NegReg', (60, 67))	('TG', 'Chemical', 'MESH:D019284', (121, 123))	('PERK', 'Gene', (32, 36))	('RCN1', 'Gene', '5954', (110, 114))	('RCN1', 'Gene', (110, 114))	('GSK', 'molecular_function', 'GO:0050321', ('18', '21'))	('GSK2606414', 'Chemical', 'MESH:C576403', (18, 28))	('CHOP', 'Gene', '1649', (72, 76))	('GSK2606414', 'Var', (18, 28))	('depletion', 'MPA', (97, 106))
122662	28319095	To further confirm that the PERK-mediated signaling pathway is involved in increased apoptosis caused by RCN1 depletion during ER stress, we selected efficient small interfering RNAs (siRNAs) targeting CHOP (Supplementary Figure S3c) and determined that depletion of CHOP in RCN1-knockdown HepG2 cells also mitigated the increased early apoptosis after treatment with TM (Figures 3f and g).	('signaling pathway', 'biological_process', 'GO:0007165', ('42', '59'))	('apoptosis', 'biological_process', 'GO:0097194', ('85', '94'))	('apoptosis', 'biological_process', 'GO:0006915', ('85', '94'))	('RCN1', 'Gene', '5954', (105, 109))	('apoptosis', 'biological_process', 'GO:0097194', ('337', '346'))	('PERK', 'Gene', (28, 32))	('apoptosis', 'biological_process', 'GO:0006915', ('337', '346'))	('CHOP', 'Gene', '1649', (267, 271))	('CHOP', 'Gene', '1649', (202, 206))	('mitigated', 'NegReg', (307, 316))	('RCN1', 'Gene', (275, 279))	('PERK', 'Gene', '9451', (28, 32))	('depletion', 'Var', (254, 263))	('TM', 'Chemical', 'MESH:D014415', (368, 370))	('RCN1', 'Gene', '5954', (275, 279))	('CHOP', 'Gene', (267, 271))	('HepG2', 'CellLine', 'CVCL:0027', (290, 295))	('CHOP', 'Gene', (202, 206))	('RCN1', 'Gene', (105, 109))
122667	28319095	Immunoprecipitation revealed that exogenously expressed IP3R1-TM-GFP (GFP-tagged IP3R1 truncation mutants containing the transmembrane domain) specifically interacted with 3 x Flag-RCN1 (Figures 4d and e), whereas IP3R3-TM-GFP exhibited much less interaction (Supplementary Figure S4a).	('IP3R3', 'Gene', '3710', (214, 219))	('IP3R3', 'Gene', (214, 219))	('RCN1', 'Gene', '5954', (181, 185))	('RCN1', 'Gene', (181, 185))	('IP3R1', 'Gene', (81, 86))	('TM', 'Chemical', 'MESH:D014415', (220, 222))	('interacted', 'Interaction', (156, 166))	('IP3R1', 'Gene', '3708', (81, 86))	('TM', 'Chemical', 'MESH:D014415', (62, 64))	('transmembrane', 'cellular_component', 'GO:0044214', ('121', '134'))	('mutants', 'Var', (98, 105))	('transmembrane', 'cellular_component', 'GO:0016021', ('121', '134'))	('IP3R1', 'Gene', '3708', (56, 61))	('IP3R1', 'Gene', (56, 61))
122669	28319095	We then generated a series of truncated or depletion mutants of IP3R1 and RCN1 to dissect the functional domains of the RCN1-IP3R1 interaction.	('RCN1', 'Gene', (120, 124))	('IP3R1', 'Gene', '3708', (125, 130))	('RCN1', 'Gene', '5954', (74, 78))	('depletion mutants', 'Var', (43, 60))	('IP3R1', 'Gene', (64, 69))	('IP3R1', 'Gene', '3708', (64, 69))	('IP3R1', 'Gene', (125, 130))	('RCN1', 'Gene', (74, 78))	('RCN1', 'Gene', '5954', (120, 124))
122672	28319095	We also generated a series of EF-hand depletion mutants of RCN1 to dissect the functional domains necessary for RCN1 interaction with IP3R1.	('RCN1', 'Gene', (112, 116))	('RCN1', 'Gene', '5954', (59, 63))	('RCN1', 'Gene', (59, 63))	('interaction', 'Interaction', (117, 128))	('mutants', 'Var', (48, 55))	('IP3R1', 'Gene', '3708', (134, 139))	('IP3R1', 'Gene', (134, 139))	('RCN1', 'Gene', '5954', (112, 116))
122673	28319095	The first two EF-hand depletion mutants of RCN1 were not able to interact with IP3R1 (Supplementary Figures S4b and c), whereas RCN1 truncation mutants containing the first two EF-hands (3 x Flag-RCN1-EFh1+2) interacted with IP3R1-TM-GFP (Figures 4i and j), thus confirming that the first two EF-hands of RCN1 are critical to the interaction with IP3R1.	('RCN1', 'Gene', '5954', (196, 200))	('IP3R1', 'Gene', (225, 230))	('RCN1', 'Gene', (196, 200))	('RCN1', 'Gene', (305, 309))	('TM', 'Chemical', 'MESH:D014415', (231, 233))	('RCN1', 'Gene', '5954', (305, 309))	('IP3R1', 'Gene', '3708', (225, 230))	('mutants', 'Var', (32, 39))	('IP3R1', 'Gene', (79, 84))	('RCN1', 'Gene', '5954', (128, 132))	('RCN1', 'Gene', (128, 132))	('IP3R1', 'Gene', '3708', (79, 84))	('IP3R1', 'Gene', '3708', (347, 352))	('IP3R1', 'Gene', (347, 352))	('RCN1', 'Gene', '5954', (43, 47))	('RCN1', 'Gene', (43, 47))
122681	28319095	Flow cytometry analysis demonstrated that depletion of IP3R1 significantly alleviated the increased number of early apoptotic cells caused by depletion of RCN1 after TM treatment (Figures 5b and c).	('IP3R1', 'Gene', '3708', (55, 60))	('TM', 'Chemical', 'MESH:D014415', (166, 168))	('RCN1', 'Gene', '5954', (155, 159))	('alleviated', 'NegReg', (75, 85))	('RCN1', 'Gene', (155, 159))	('depletion', 'Var', (142, 151))	('IP3R1', 'Gene', (55, 60))
122682	28319095	In addition, flow cytometry analysis revealed that after TG treatment, inhibition of IP3R1 by 2-APB (2-aminoethoxydiphenyl borate) and Xec (Xestospongin C) significantly alleviated the increase in early apoptosis cells in RCN1-knockdown cells (Figure 5d, Supplementary Figure S5a), but not in RCN1-overexpressing cells (Figure 5e, Supplementary Figure S5b).	('inhibition', 'Var', (71, 81))	('Xec', 'Chemical', 'MESH:C511704', (135, 138))	('2-aminoethoxydiphenyl borate', 'Chemical', 'MESH:C109986', (101, 129))	('apoptosis', 'biological_process', 'GO:0006915', ('203', '212'))	('IP3R1', 'Gene', (85, 90))	('2-APB', 'Chemical', 'MESH:C109986', (94, 99))	('early apoptosis cells', 'CPA', (197, 218))	('alleviated', 'NegReg', (170, 180))	('IP3R1', 'Gene', '3708', (85, 90))	('RCN1', 'Gene', '5954', (293, 297))	('RCN1', 'Gene', (293, 297))	('TG', 'Chemical', 'MESH:D019284', (57, 59))	('RCN1', 'Gene', '5954', (222, 226))	('RCN1', 'Gene', (222, 226))	('apoptosis', 'biological_process', 'GO:0097194', ('203', '212'))
122684	28319095	Considering the connection between the UPR and apoptosis, we investigated whether IP3R1 participates in the augmented UPR signaling caused by RCN1 depletion.	('apoptosis', 'biological_process', 'GO:0097194', ('47', '56'))	('apoptosis', 'biological_process', 'GO:0006915', ('47', '56'))	('IP3R1', 'Gene', '3708', (82, 87))	('IP3R1', 'Gene', (82, 87))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('UPR signaling', 'MPA', (118, 131))	('augmented', 'PosReg', (108, 117))	('RCN1', 'Gene', '5954', (142, 146))	('RCN1', 'Gene', (142, 146))	('depletion', 'Var', (147, 156))
122685	28319095	Western blots revealed that inhibition of IP3R1 alleviated the increased CHOP level induced by depletion of RCN1 after TG treatment (Figure 5h), thus suggesting that ER calcium disturbance caused by RCN1 depletion participates in PERK-CHOP signaling during ER stress.	('IP3R1', 'Gene', '3708', (42, 47))	('CHOP', 'Gene', (73, 77))	('PERK-CHOP', 'Gene', (230, 239))	('calcium', 'Chemical', 'MESH:D002118', (169, 176))	('RCN1', 'Gene', (199, 203))	('CHOP', 'Gene', '1649', (235, 239))	('TG', 'Chemical', 'MESH:D019284', (119, 121))	('increased CHOP', 'Phenotype', 'HP:0007906', (63, 77))	('RCN1', 'Gene', '5954', (199, 203))	('signaling', 'biological_process', 'GO:0023052', ('240', '249'))	('RCN1', 'Gene', (108, 112))	('increased', 'PosReg', (63, 72))	('CHOP', 'Gene', (235, 239))	('depletion', 'Var', (95, 104))	('inhibition', 'Var', (28, 38))	('RCN1', 'Gene', '5954', (108, 112))	('CHOP', 'Gene', '1649', (73, 77))	('IP3R1', 'Gene', (42, 47))	('PERK-CHOP', 'Gene', '9451;1649', (230, 239))	('alleviated', 'NegReg', (48, 58))	('depletion', 'Var', (204, 213))
122690	28319095	Western blot analysis revealed that the protein level of RCN1 was decreased when the cells were pre-treated with pyrrolidine dithiocarbamate and BAY but was increased after pretreatment with sp600125 (Figures 6e and g).	('pyrrolidine dithiocarbamate', 'Chemical', 'MESH:C020972', (113, 140))	('pyrrolidine dithiocarbamate', 'MPA', (113, 140))	('RCN1', 'Gene', '5954', (57, 61))	('decreased', 'NegReg', (66, 75))	('sp600125', 'Chemical', 'MESH:C432165', (191, 199))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('pre', 'molecular_function', 'GO:0003904', ('96', '99'))	('sp600125', 'Var', (191, 199))	('increased', 'PosReg', (157, 166))	('protein level', 'MPA', (40, 53))	('RCN1', 'Gene', (57, 61))
122700	28319095	Under conditions of ER stress, depletion of RCN1 results in disturbances in ER calcium homeostasis, upregulation of the PERK-CHOP signaling pathway and subsequent apoptosis and NF-kappaB activation.	('apoptosis', 'biological_process', 'GO:0006915', ('163', '172'))	('apoptosis', 'CPA', (163, 172))	('PERK-CHOP', 'Gene', (120, 129))	('ER calcium homeostasis', 'MPA', (76, 98))	('PERK-CHOP', 'Gene', '9451;1649', (120, 129))	('activation', 'PosReg', (187, 197))	('NF-kappaB', 'Gene', (177, 186))	('homeostasis', 'biological_process', 'GO:0042592', ('87', '98'))	('signaling pathway', 'biological_process', 'GO:0007165', ('130', '147'))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('177', '197'))	('apoptosis', 'biological_process', 'GO:0097194', ('163', '172'))	('depletion', 'Var', (31, 40))	('RCN1', 'Gene', '5954', (44, 48))	('disturbances', 'MPA', (60, 72))	('calcium', 'Chemical', 'MESH:D002118', (79, 86))	('upregulation', 'PosReg', (100, 112))	('NF-kappaB', 'Gene', '4790', (177, 186))	('RCN1', 'Gene', (44, 48))
122723	28319095	Here, our data indicate that depletion of RCN1 increases NF-kappaB signaling and activates IRE1 and PERK.	('IRE1', 'Gene', (91, 95))	('PERK', 'Gene', (100, 104))	('depletion', 'Var', (29, 38))	('NF-kappaB', 'Gene', (57, 66))	('RCN1', 'Gene', '5954', (42, 46))	('RCN1', 'Gene', (42, 46))	('PERK', 'Gene', '9451', (100, 104))	('activates', 'PosReg', (81, 90))	('IRE1', 'Gene', '2081', (91, 95))	('increases', 'PosReg', (47, 56))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))	('NF-kappaB', 'Gene', '4790', (57, 66))
122734	28319095	The drugs used were TG (Sigma), TM (Sigma), sp600125 (Cell Signaling), 2-APB (Sigma), Xec, pyrrolidine dithiocarbamate, BAY 11-7082, GSK2606414 and STF883010 (Selleckchem, Houston, TX, USA).	('TG', 'Chemical', 'MESH:D019284', (20, 22))	('GSK2606414', 'Chemical', 'MESH:C576403', (133, 143))	('TM', 'Chemical', 'MESH:D014415', (32, 34))	('pyrrolidine', 'Var', (91, 102))	('GSK', 'molecular_function', 'GO:0050321', ('133', '136'))	('GSK2606414', 'Var', (133, 143))	('sp600125', 'Chemical', 'MESH:C432165', (44, 52))	('BAY 11-7082', 'Chemical', 'MESH:C434003', (120, 131))	('2-APB', 'Chemical', 'MESH:C109986', (71, 76))	('sp600125', 'Var', (44, 52))	('Signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('pyrrolidine dithiocarbamate', 'Chemical', 'MESH:C020972', (91, 118))	('Xec', 'Chemical', 'MESH:C511704', (86, 89))	('STF883010', 'Var', (148, 157))
122762	32382344	Kaplan-Meier survival analysis indicated that ccRCC with high lncRNA AGAP2-AS1 exhibited a worse prognosis compared with low AGAP2-AS1 (P<0.001).	('AGAP2', 'Gene', (69, 74))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('AS1', 'Gene', '5729', (131, 134))	('AS1', 'Gene', (131, 134))	('AGAP2', 'Gene', (125, 130))	('AS1', 'Gene', '5729', (75, 78))	('AS1', 'Gene', (75, 78))	('high lncRNA', 'Var', (57, 68))	('AGAP2', 'Gene', '116986', (69, 74))	('AGAP2', 'Gene', '116986', (125, 130))	('RCC', 'Disease', (48, 51))
122763	32382344	The univariate analysis revealed that high expression of AGAP2-AS1 was significantly associated with poor overall survival [hazard ratio (HR).	('poor', 'NegReg', (101, 105))	('AGAP2', 'Gene', '116986', (57, 62))	('high expression', 'Var', (38, 53))	('AGAP2', 'Gene', (57, 62))	('overall survival', 'MPA', (106, 122))	('AS1', 'Gene', '5729', (63, 66))	('AS1', 'Gene', (63, 66))
122766	32382344	Therefore, the high expression of AGAP2-AS1 may be an independent predictor of poor survival in patients with ccRCC.	('high', 'Var', (15, 19))	('AS1', 'Gene', (40, 43))	('AS1', 'Gene', '5729', (40, 43))	('AGAP2', 'Gene', '116986', (34, 39))	('RCC', 'Disease', (112, 115))	('patients', 'Species', '9606', (96, 104))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('AGAP2', 'Gene', (34, 39))
122809	32382344	The univariate analysis, which was performed using a Cox regression, revealed that high AGAP2-AS1 correlated significantly with poor OS [hazard ratio (HR), 1.85; 95% confidence interval (CI), 1.48-2.33; P<0.001].	('AGAP2', 'Gene', '116986', (88, 93))	('poor OS', 'Disease', (128, 135))	('AGAP2', 'Gene', (88, 93))	('high', 'Var', (83, 87))	('AS1', 'Gene', '5729', (94, 97))	('AS1', 'Gene', (94, 97))
122812	32382344	The results demonstrated that high expression of AGAP2-AS1 was associated with poor OS in patients with ccRCC and a high HR.	('AGAP2', 'Gene', (49, 54))	('poor OS', 'Disease', (79, 86))	('high', 'Var', (30, 34))	('RCC', 'Disease', (106, 109))	('AGAP2', 'Gene', '116986', (49, 54))	('patients', 'Species', '9606', (90, 98))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('AS1', 'Gene', '5729', (55, 58))	('AS1', 'Gene', (55, 58))
122821	32382344	lncRNA AGAP2-AS1 ectopic expression has been indicated in numerous types of carcinoma, including in hepatocellular carcinoma, non-small cell lung cancer, gastric cancer and glioma.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (126, 152))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (100, 124))	('lung cancer', 'Disease', (141, 152))	('AS1', 'Gene', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (130, 152))	('carcinoma', 'Disease', 'MESH:D009369', (115, 124))	('carcinoma', 'Disease', 'MESH:D009369', (76, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (154, 168))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (100, 124))	('indicated', 'Reg', (45, 54))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))	('AGAP2', 'Gene', (7, 12))	('hepatocellular carcinoma', 'Disease', (100, 124))	('AS1', 'Gene', '5729', (13, 16))	('gastric cancer', 'Disease', (154, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('ectopic expression', 'Var', (17, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('glioma', 'Disease', (173, 179))	('carcinoma', 'Disease', (76, 85))	('carcinoma', 'Disease', (115, 124))	('AGAP2', 'Gene', '116986', (7, 12))	('gastric cancer', 'Disease', 'MESH:D013274', (154, 168))	('glioma', 'Disease', 'MESH:D005910', (173, 179))
122826	32382344	In the present study, high throughput RNA sequencing data of ccRCC were downloaded from the TCGA database, and the outcomes demonstrated that high lncRNA AGAP2-AS1 was significantly associated with worse survival status.	('RCC', 'Disease', (63, 66))	('associated', 'Reg', (182, 192))	('high lncRNA', 'Var', (142, 153))	('AGAP2', 'Gene', '116986', (154, 159))	('AS1', 'Gene', (160, 163))	('AS1', 'Gene', '5729', (160, 163))	('RNA', 'cellular_component', 'GO:0005562', ('38', '41'))	('AGAP2', 'Gene', (154, 159))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
122829	32382344	AGAP2-AS1, as a non-coding RNA, has been demonstrated to promote anaplastic glioma cells proliferation, migration and invasion, and the knockdown of AGAP2-AS1 has been indicated to increase apoptosis cell rates.	('glioma', 'Disease', (76, 82))	('migration', 'CPA', (104, 113))	('RNA', 'cellular_component', 'GO:0005562', ('27', '30'))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('AS1', 'Gene', (6, 9))	('AGAP2', 'Gene', (0, 5))	('AS1', 'Gene', (155, 158))	('increase', 'PosReg', (181, 189))	('promote', 'PosReg', (57, 64))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('apoptosis', 'biological_process', 'GO:0097194', ('190', '199'))	('apoptosis', 'biological_process', 'GO:0006915', ('190', '199'))	('AGAP2', 'Gene', (149, 154))	('AGAP2', 'Gene', '116986', (0, 5))	('knockdown', 'Var', (136, 145))	('apoptosis cell rates', 'CPA', (190, 210))	('invasion', 'CPA', (118, 126))	('AS1', 'Gene', '5729', (6, 9))	('AS1', 'Gene', '5729', (155, 158))	('AGAP2', 'Gene', '116986', (149, 154))
122833	32382344	In the present study, the aberrant expression of AGAP2-AS1 was enriched in the process of angiogenesis, which may be activated by the PI3K/Akt pathway.	('aberrant', 'Var', (26, 34))	('angiogenesis', 'CPA', (90, 102))	('AGAP2', 'Gene', (49, 54))	('Akt', 'Gene', '207', (139, 142))	('angiogenesis', 'biological_process', 'GO:0001525', ('90', '102'))	('Akt', 'Gene', (139, 142))	('expression', 'MPA', (35, 45))	('PI3K', 'molecular_function', 'GO:0016303', ('134', '138'))	('AGAP2', 'Gene', '116986', (49, 54))	('AS1', 'Gene', '5729', (55, 58))	('AS1', 'Gene', (55, 58))
122835	32382344	Furthermore, the prognostic value of AGAP2-AS1 expression was examined in different subgroups of ccRCC and it was indicated that high lncRNA AGAP2-AS1 expression was significantly associated with G1/G2, stage I/II and M0 cases, highlighting the potential value of AGAP2-AS1 in the development of ccRCC.	('AGAP2', 'Gene', (264, 269))	('AGAP2', 'Gene', '116986', (37, 42))	('AS1', 'Gene', '5729', (43, 46))	('RCC', 'Disease', (99, 102))	('RCC', 'Disease', (298, 301))	('associated', 'Reg', (180, 190))	('AS1', 'Gene', '5729', (270, 273))	('AS1', 'Gene', '5729', (147, 150))	('G1/G2', 'Disease', (196, 201))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('AGAP2', 'Gene', '116986', (264, 269))	('RCC', 'Disease', 'MESH:C538614', (298, 301))	('AS1', 'Gene', (147, 150))	('AGAP2', 'Gene', (141, 146))	('expression', 'MPA', (151, 161))	('stage I/II', 'Disease', (203, 213))	('AS1', 'Gene', (43, 46))	('AGAP2', 'Gene', (37, 42))	('high', 'Var', (129, 133))	('AS1', 'Gene', (270, 273))	('AGAP2', 'Gene', '116986', (141, 146))
122853	31354221	In addition, it was found that HKII increased the phosphorylation of Ser293 on PDHA1, decreasing pyruvate dehydrogenase (PDH) complex activity and thus rerouting the metabolic pathway and promoting the Warburg effect.	('phosphorylation', 'MPA', (50, 65))	('HKII', 'Gene', (31, 35))	('PDH', 'molecular_function', 'GO:0004739', ('121', '124'))	('PDH', 'Gene', (79, 82))	('HKII', 'Gene', '3099', (31, 35))	('Warburg effect', 'CPA', (202, 216))	('promoting', 'PosReg', (188, 197))	('decreasing pyruvate', 'Phenotype', 'HP:0003542', (86, 105))	('increased', 'PosReg', (36, 45))	('phosphorylation', 'biological_process', 'GO:0016310', ('50', '65'))	('decreasing', 'NegReg', (86, 96))	('Ser293', 'Var', (69, 75))	('Ser', 'cellular_component', 'GO:0005790', ('69', '72'))	('activity', 'MPA', (134, 142))	('pyruvate dehydrogenase', 'Gene', '54704', (97, 119))	('pyruvate dehydrogenase', 'Gene', (97, 119))	('rerouting', 'PosReg', (152, 161))	('PDH', 'Gene', '54704', (121, 124))	('PDH', 'molecular_function', 'GO:0004246', ('121', '124'))	('PDH', 'Gene', '54704', (79, 82))	('PDH', 'molecular_function', 'GO:0033718', ('121', '124'))	('PDH', 'Gene', (121, 124))	('PDHA1', 'Gene', (79, 84))	('PDHA1', 'Gene', '5160', (79, 84))	('metabolic pathway', 'Pathway', (166, 183))
122860	31354221	HKII acts as a sensor for N-acetylglucosamine, and dissociation of HKII from voltage-dependent anion channel (VDAC) induces interleukin (IL)-1beta and IL-18 production in an NLRP3-dependent manner.	('interleukin (IL)-1beta', 'Gene', (124, 146))	('IL-18', 'Gene', '3606', (151, 156))	('HKII', 'Gene', '3099', (67, 71))	('dissociation', 'Var', (51, 63))	('IL-18', 'Gene', (151, 156))	('induces', 'Reg', (116, 123))	('HKII', 'Gene', '3099', (0, 4))	('IL-18 production', 'biological_process', 'GO:0032621', ('151', '167'))	('NLRP3', 'Gene', (174, 179))	('HKII', 'Gene', (67, 71))	('NLRP3', 'Gene', '114548', (174, 179))	('N-acetylglucosamine', 'Chemical', 'MESH:D000117', (26, 45))	('interleukin (IL)-1beta', 'Gene', '3553', (124, 146))	('IL-18', 'molecular_function', 'GO:0045515', ('151', '156'))	('IL)-1', 'molecular_function', 'GO:0005149', ('137', '142'))	('HKII', 'Gene', (0, 4))
122861	31354221	Phosphorylation of Thr473 of HKII by protein kinase B (AKT) increases HKII mitochondrial localization.	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('protein kinase', 'Gene', '64030', (37, 51))	('AKT', 'Gene', (55, 58))	('HKII', 'Gene', (70, 74))	('protein kinase', 'Gene', (37, 51))	('mitochondrial localization', 'biological_process', 'GO:0051646', ('75', '101'))	('Thr473', 'Chemical', '-', (19, 25))	('Phosphorylation', 'Var', (0, 15))	('HKII', 'Gene', (29, 33))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('HKII', 'Gene', '3099', (70, 74))	('HKII', 'Gene', '3099', (29, 33))	('AKT', 'Gene', '207', (55, 58))	('increases', 'PosReg', (60, 69))	('mitochondrial localization', 'MPA', (75, 101))
122871	31354221	The phosphorylation of Ser293, Ser300, and Ser232, the acetylation of Lys321, and the desuccinylation of Lys83 and Lys244 on PDHA1 decrease PDC activity and eventually promote tumor growth, confirming that PDC is an important regulation node for metabolism and signal transduction.	('PDC', 'Gene', '5132', (140, 143))	('Ser300', 'Chemical', '-', (31, 37))	('Lys244', 'Chemical', '-', (115, 121))	('metabolism', 'biological_process', 'GO:0008152', ('246', '256'))	('promote', 'PosReg', (168, 175))	('Ser', 'cellular_component', 'GO:0005790', ('23', '26'))	('acetylation', 'MPA', (55, 66))	('regulation', 'biological_process', 'GO:0065007', ('226', '236'))	('PDHA1', 'Gene', '5160', (125, 130))	('activity', 'MPA', (144, 152))	('PDHA1', 'Gene', (125, 130))	('Ser293', 'Var', (23, 29))	('tumor', 'Disease', (176, 181))	('PDC', 'Gene', (140, 143))	('Ser232', 'Chemical', '-', (43, 49))	('decrease', 'NegReg', (131, 139))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('PDC', 'Gene', '5132', (206, 209))	('desuccinylation', 'MPA', (86, 101))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('Ser', 'cellular_component', 'GO:0005790', ('43', '46'))	('Ser', 'cellular_component', 'GO:0005790', ('31', '34'))	('Ser300', 'Var', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('Ser232', 'Var', (43, 49))	('phosphorylation', 'MPA', (4, 19))	('Lys83', 'Chemical', '-', (105, 110))	('PDC', 'Gene', (206, 209))	('Lys244', 'Var', (115, 121))	('Lys321', 'Chemical', '-', (70, 76))	('signal transduction', 'biological_process', 'GO:0007165', ('261', '280'))
122872	31354221	It was reported that von Hippel-Lindau (VHL) mutants in clear cell renal cell carcinoma (ccRCC) lead to activation of hypoxia-inducible factor (HIF)1alpha, increased glycolysis, and increased expression of HKII, GLUT1/3, pyruvate kinase 2 (PKM2), PDHK1, and lactate dehydrogenase A (LDHA).	('increased', 'PosReg', (182, 191))	('GLUT1/3', 'Gene', '6513;6515', (212, 219))	('mutants', 'Var', (45, 52))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (67, 87))	('increased', 'PosReg', (156, 165))	('RCC', 'Disease', (91, 94))	('lactate dehydrogenase A', 'Gene', '3939', (258, 281))	('GLUT1/3', 'Gene', (212, 219))	('LDHA', 'Gene', '3939', (283, 287))	('clear cell renal cell carcinoma', 'Disease', (56, 87))	('lactate dehydrogenase A', 'Gene', (258, 281))	('glycolysis', 'MPA', (166, 176))	('HK', 'Gene', '3098', (206, 208))	('von Hippel-Lindau', 'Gene', (21, 38))	('expression', 'MPA', (192, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (89, 94))	('hypoxia-inducible factor (HIF)1alpha', 'Gene', '3091', (118, 154))	('PDH', 'Gene', '54704', (247, 250))	('VHL', 'Disease', (40, 43))	('activation', 'PosReg', (104, 114))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (56, 87))	('von Hippel-Lindau', 'Gene', '7428', (21, 38))	('LDHA', 'Gene', (283, 287))	('pyruvate', 'Chemical', 'MESH:D019289', (221, 229))	('glycolysis', 'biological_process', 'GO:0006096', ('166', '176'))	('HKII', 'Gene', (206, 210))	('HKII', 'Gene', '3099', (206, 210))	('PKM2', 'Gene', (240, 244))	('PDH', 'Gene', (247, 250))	('PKM2', 'Gene', '5315', (240, 244))	('PDHK', 'molecular_function', 'GO:0004740', ('247', '251'))	('HK', 'Gene', '3098', (249, 251))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (56, 87))	('VHL', 'Disease', 'MESH:D006623', (40, 43))
122877	31354221	Wild type HKII, HKII mutant, wild type PDHA1, PDHA1 S293A, and PDHA1 S293E were cloned into pcDNA3.1-Flag, pcDNA3.1-Myc, and pcDNA3.1-HA vectors, respectively.	('HKII', 'Gene', '3099', (16, 20))	('PDHA1', 'Gene', '5160', (46, 51))	('S293A', 'Var', (52, 57))	('PDHA1', 'Gene', (46, 51))	('Myc', 'Gene', (116, 119))	('mutant', 'Var', (21, 27))	('PDHA1', 'Gene', (39, 44))	('Myc', 'Gene', '4609', (116, 119))	('S293E', 'Mutation', 'p.S293E', (69, 74))	('PDHA1', 'Gene', '5160', (39, 44))	('HKII', 'Gene', '3099', (10, 14))	('PDHA1', 'Gene', '5160', (63, 68))	('HKII', 'Gene', (16, 20))	('PDHA1', 'Gene', (63, 68))	('S293A', 'SUBSTITUTION', 'None', (52, 57))	('HKII', 'Gene', (10, 14))
122878	31354221	A HKII-specific siRNA (5'-TCGCATCTGCTTGCCTACTTCTTCA-3') was used to knock down HKII gene, and a non-silencing siRNA oligonucleotide was used as a negative control.	('oligonucleotide', 'Chemical', 'MESH:D009841', (116, 131))	('HKII', 'Gene', (79, 83))	('HKII', 'Gene', '3099', (2, 6))	('HKII', 'Gene', '3099', (79, 83))	('TCA', 'Chemical', 'MESH:D014233', (48, 51))	('knock', 'Var', (68, 73))	('HKII', 'Gene', (2, 6))
122891	31354221	Cells were then incubated overnight at 4  C with anti-PDHA1, anti-S293-phosphorylated PDHA1, and anti-HKII antibodies, and on the following day were detected with Alexa Fluor 555 goat anti-mouse IgG antibody.	('PDHA1', 'Gene', (86, 91))	('mouse', 'Species', '10090', (189, 194))	('HKII', 'Gene', '3099', (102, 106))	('antibody', 'molecular_function', 'GO:0003823', ('199', '207'))	('anti-S293-phosphorylated', 'Var', (61, 85))	('IgG antibody', 'cellular_component', 'GO:0071736', ('195', '207'))	('PDHA1', 'Gene', '5160', (54, 59))	('goat', 'Species', '9925', (179, 183))	('PDHA1', 'Gene', (54, 59))	('Alexa Fluor 555', 'Chemical', 'MESH:C000608607', (163, 178))	('HKII', 'Gene', (102, 106))	('S293', 'CellLine', 'CVCL:A784', (66, 70))	('IgG antibody', 'Phenotype', 'HP:0003237', (195, 207))	('PDHA1', 'Gene', '5160', (86, 91))
122898	31354221	PDHA1 knock-down cells were transfected with HKII, wild type PDHA1, PDHA1 S293A, and PDHA1 S293E, respectively, and seeded into 96-well plates.	('HKII', 'Gene', (45, 49))	('S293A', 'SUBSTITUTION', 'None', (74, 79))	('PDHA1', 'Gene', '5160', (61, 66))	('HKII', 'Gene', '3099', (45, 49))	('S293E', 'Var', (91, 96))	('PDHA1', 'Gene', (61, 66))	('S293A', 'Var', (74, 79))	('PDHA1', 'Gene', (85, 90))	('PDHA1', 'Gene', '5160', (0, 5))	('PDHA1', 'Gene', '5160', (68, 73))	('PDHA1', 'Gene', (0, 5))	('S293E', 'Mutation', 'p.S293E', (91, 96))	('PDHA1', 'Gene', '5160', (85, 90))	('PDHA1', 'Gene', (68, 73))
122908	31354221	Sections were stained with HKII (1:100), P-S293-PDHA1 (1:30), and Ki67 (1:100) antibodies using an Ultraview Detection Kit (Roche Diagnostics).	('P-S293-PDHA1', 'Gene', '5160', (41, 53))	('HKII', 'Gene', '3099', (27, 31))	('Ki67', 'Var', (66, 70))	('P-S293-PDHA1', 'Gene', (41, 53))	('HKII', 'Gene', (27, 31))
122911	31354221	In addition, wild type HKII, but not its catalytically inactive mutant HKIImut, increased pan-phosphorylation of PDHA1 (Figure 1C,E,F), and 3BP, an HKII inhibitor, decreased the pan-phosphorylation of PDHA1 (Figure 1D).	('phosphorylation', 'biological_process', 'GO:0016310', ('94', '109'))	('decreased', 'NegReg', (164, 173))	('HKII', 'Gene', (148, 152))	('pan-phosphorylation', 'MPA', (90, 109))	('PDHA1', 'Gene', (201, 206))	('increased', 'PosReg', (80, 89))	('PDHA1', 'Gene', '5160', (201, 206))	('HKII', 'Gene', '3099', (148, 152))	('PDHA1', 'Gene', (113, 118))	('HKII', 'Gene', (23, 27))	('HKII', 'Gene', (71, 75))	('pan-phosphorylation', 'MPA', (178, 197))	('PDHA1', 'Gene', '5160', (113, 118))	('phosphorylation', 'biological_process', 'GO:0016310', ('182', '197'))	('3BP', 'Var', (140, 143))	('HKII', 'Gene', '3099', (23, 27))	('HKII', 'Gene', '3099', (71, 75))
122912	31354221	The phosphorylation levels of S293 of PDHA1 increased 100-fold after HKII treatment, suggesting that the PDH complex can be regulated by HKII.	('HKII', 'Gene', (69, 73))	('HKII', 'Gene', '3099', (137, 141))	('PDH', 'molecular_function', 'GO:0004246', ('105', '108'))	('PDH', 'Gene', '54704', (105, 108))	('HKII', 'Gene', '3099', (69, 73))	('PDH', 'Gene', (38, 41))	('phosphorylation levels', 'MPA', (4, 26))	('HKII', 'Gene', (137, 141))	('S293', 'CellLine', 'CVCL:A784', (30, 34))	('PDHA1', 'Gene', '5160', (38, 43))	('PDH', 'molecular_function', 'GO:0004739', ('105', '108'))	('PDH', 'molecular_function', 'GO:0033718', ('105', '108'))	('increased', 'PosReg', (44, 53))	('PDHA1', 'Gene', (38, 43))	('S293', 'Var', (30, 34))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('PDH', 'Gene', (105, 108))	('PDH', 'Gene', '54704', (38, 41))
122918	31354221	The P-S293 levels of purified PDHA1 increased after HKII, but not HKII mutant, treatment (Figure 2A-C), confirming that S293 of PDHA1 may be the substrate of HKII.	('HKII', 'Gene', (66, 70))	('HKII', 'Gene', (52, 56))	('PDHA1', 'Gene', '5160', (128, 133))	('HKII', 'Gene', '3099', (158, 162))	('PDHA1', 'Gene', (128, 133))	('S293', 'CellLine', 'CVCL:A784', (120, 124))	('rat', 'Species', '10116', (150, 153))	('PDHA1', 'Gene', '5160', (30, 35))	('increased', 'PosReg', (36, 45))	('PDHA1', 'Gene', (30, 35))	('HKII', 'Gene', '3099', (66, 70))	('HKII', 'Gene', '3099', (52, 56))	('P-S293 levels', 'MPA', (4, 17))	('S293', 'CellLine', 'CVCL:A784', (6, 10))	('S293', 'Var', (120, 124))	('HKII', 'Gene', (158, 162))
122919	31354221	It was also found that 3BP decreased the phosphorylation levels of S293 on PDHA1 in a dose-dependent manner (Figure 2D,E).	('phosphorylation', 'biological_process', 'GO:0016310', ('41', '56'))	('S293', 'CellLine', 'CVCL:A784', (67, 71))	('PDHA1', 'Gene', '5160', (75, 80))	('decreased', 'NegReg', (27, 36))	('PDHA1', 'Gene', (75, 80))	('S293', 'Var', (67, 71))	('phosphorylation levels', 'MPA', (41, 63))
122920	31354221	Interestingly, HKII increased the phosphorylation of PDHA1 but not of its non-phosphorylation mimetic S293A and phosphorylation mimetic S293E mutants, indicating that S293 may be the substrate of HKII (Figure 2F,G).	('increased', 'PosReg', (20, 29))	('phosphorylation', 'MPA', (34, 49))	('HKII', 'Gene', '3099', (196, 200))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('PDHA1', 'Gene', (53, 58))	('S293', 'CellLine', 'CVCL:A784', (102, 106))	('S293', 'CellLine', 'CVCL:A784', (136, 140))	('S293', 'CellLine', 'CVCL:A784', (167, 171))	('HKII', 'Gene', '3099', (15, 19))	('HKII', 'Gene', (15, 19))	('S293A', 'SUBSTITUTION', 'None', (102, 107))	('PDHA1', 'Gene', '5160', (53, 58))	('phosphorylation', 'biological_process', 'GO:0016310', ('78', '93'))	('rat', 'Species', '10116', (188, 191))	('S293A', 'Var', (102, 107))	('HKII', 'Gene', (196, 200))	('S293E', 'Mutation', 'p.S293E', (136, 141))	('phosphorylation', 'biological_process', 'GO:0016310', ('112', '127'))
122924	31354221	It has been reported that S293, S300, and S232 of PDHA1 are phosphorylated by PDK1, PDK2, PDK3, and PDK4.	('PDK4', 'molecular_function', 'GO:0004740', ('100', '104'))	('S232', 'Var', (42, 46))	('PDK2', 'Gene', (84, 88))	('PDK1', 'Gene', (78, 82))	('S293', 'CellLine', 'CVCL:A784', (26, 30))	('PDK4', 'Gene', '5166', (100, 104))	('S300', 'Var', (32, 36))	('PDK2', 'molecular_function', 'GO:0004740', ('84', '88'))	('PDHA1', 'Gene', (50, 55))	('PDK3', 'Gene', '5165', (90, 94))	('PDK4', 'Gene', (100, 104))	('PDHA1', 'Gene', '5160', (50, 55))	('PDK3', 'Gene', (90, 94))	('PDK3', 'molecular_function', 'GO:0004740', ('90', '94'))	('S293', 'Var', (26, 30))	('PDK1', 'molecular_function', 'GO:0004740', ('78', '82'))	('PDK2', 'Gene', '5164', (84, 88))	('PDK1', 'Gene', '5163', (78, 82))
122925	31354221	To exclude the effects of PDK1-4 on the phosphorylation levels of PDHA1, we knocked down PDK1-4.	('PDHA1', 'Gene', (66, 71))	('PDK1', 'molecular_function', 'GO:0004740', ('89', '93'))	('knocked', 'Var', (76, 83))	('PDK1-4', 'Gene', '5163;5164;5165;5166', (26, 32))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('PDK1', 'molecular_function', 'GO:0004740', ('26', '30'))	('PDK1-4', 'Gene', (26, 32))	('PDK1-4', 'Gene', (89, 95))	('PDK1-4', 'Gene', '5163;5164;5165;5166', (89, 95))	('PDHA1', 'Gene', '5160', (66, 71))
122926	31354221	Our results show that HKII increased the phosphorylation levels of S293 of PDHA1 (Figure 2K-N), whereas 3BP decreased the phosphorylation levels of S293 on PDHA1 in a dose-dependent manner in PDK1 knockdown cells (Figure 2E).	('HKII', 'Gene', '3099', (22, 26))	('increased', 'PosReg', (27, 36))	('PDK1', 'Gene', '5163', (192, 196))	('S293', 'CellLine', 'CVCL:A784', (67, 71))	('phosphorylation', 'biological_process', 'GO:0016310', ('41', '56'))	('PDHA1', 'Gene', '5160', (75, 80))	('PDHA1', 'Gene', '5160', (156, 161))	('PDK1', 'Gene', (192, 196))	('PDHA1', 'Gene', (75, 80))	('PDHA1', 'Gene', (156, 161))	('phosphorylation levels', 'MPA', (122, 144))	('decreased', 'NegReg', (108, 117))	('PDK1', 'molecular_function', 'GO:0004740', ('192', '196'))	('S293', 'Var', (67, 71))	('phosphorylation levels', 'MPA', (41, 63))	('phosphorylation', 'biological_process', 'GO:0016310', ('122', '137'))	('HKII', 'Gene', (22, 26))	('S293', 'CellLine', 'CVCL:A784', (148, 152))
122927	31354221	Interestingly, the glucose analogue 2-DG did not prevent HKII-mediated phosphorylation of PDHA1 in HeLa cells and in PDK1 knockdown HeLa cells (Figure 2O,P).	('PDHA1', 'Gene', '5160', (90, 95))	('HeLa', 'CellLine', 'CVCL:0030', (132, 136))	('2-DG', 'Chemical', 'MESH:D003847', (36, 40))	('PDHA1', 'Gene', (90, 95))	('PDK1', 'molecular_function', 'GO:0004740', ('117', '121'))	('knockdown', 'Var', (122, 131))	('glucose', 'Chemical', 'MESH:D005947', (19, 26))	('PDK1', 'Gene', '5163', (117, 121))	('HeLa', 'CellLine', 'CVCL:0030', (99, 103))	('phosphorylation', 'biological_process', 'GO:0016310', ('71', '86'))	('HKII', 'Gene', (57, 61))	('PDK1', 'Gene', (117, 121))	('HKII', 'Gene', '3099', (57, 61))
122928	31354221	These results collectively support that HKII phosphorylates S293 of PDHA1.	('S293', 'CellLine', 'CVCL:A784', (60, 64))	('HKII', 'Gene', (40, 44))	('S293', 'Var', (60, 64))	('HKII', 'Gene', '3099', (40, 44))	('PDHA1', 'Gene', '5160', (68, 73))	('PDHA1', 'Gene', (68, 73))
122931	31354221	Conversely, knocking down HKII decreased PDHA1 phosphorylation levels and increased the activity of the PDH complex (Figure 3B).	('PDHA1', 'Gene', (41, 46))	('PDH', 'molecular_function', 'GO:0033718', ('104', '107'))	('PDH', 'Gene', '54704', (104, 107))	('HKII', 'Gene', '3099', (26, 30))	('phosphorylation levels', 'MPA', (47, 69))	('PDH', 'Gene', (41, 44))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('decreased', 'NegReg', (31, 40))	('activity', 'MPA', (88, 96))	('increased', 'PosReg', (74, 83))	('knocking down', 'Var', (12, 25))	('HKII', 'Gene', (26, 30))	('PDH', 'molecular_function', 'GO:0004246', ('104', '107'))	('PDH', 'Gene', (104, 107))	('PDH', 'Gene', '54704', (41, 44))	('PDHA1', 'Gene', '5160', (41, 46))	('PDH', 'molecular_function', 'GO:0004739', ('104', '107'))
122933	31354221	The results show that, in these cells, HKII increased the phosphorylation levels of PDHA1 S293 but decreased the activity of the PDH complex significantly (Figure 3C).	('PDH', 'Gene', (84, 87))	('decreased', 'NegReg', (99, 108))	('HKII', 'Gene', '3099', (39, 43))	('PDHA1', 'Gene', '5160', (84, 89))	('S293', 'Var', (90, 94))	('PDHA1', 'Gene', (84, 89))	('PDH', 'Gene', (129, 132))	('PDH', 'molecular_function', 'GO:0004246', ('129', '132'))	('PDH', 'Gene', '54704', (84, 87))	('PDH', 'Gene', '54704', (129, 132))	('HKII', 'Gene', (39, 43))	('PDH', 'molecular_function', 'GO:0004739', ('129', '132'))	('phosphorylation levels', 'MPA', (58, 80))	('PDH', 'molecular_function', 'GO:0033718', ('129', '132'))	('activity', 'MPA', (113, 121))	('phosphorylation', 'biological_process', 'GO:0016310', ('58', '73'))	('increased', 'PosReg', (44, 53))	('S293', 'CellLine', 'CVCL:A784', (90, 94))
122940	31354221	To test the effects of HKII on the oxygen consumption rate (OCR) of cells, HKII was knocked down in HeLa cells, which resulted in decreased OCRs (Figure 5A).	('OCRs', 'MPA', (140, 144))	('HKII', 'Gene', '3099', (75, 79))	('rat', 'Species', '10116', (54, 57))	('oxygen', 'Chemical', 'MESH:D010100', (35, 41))	('HKII', 'Gene', (23, 27))	('HeLa', 'CellLine', 'CVCL:0030', (100, 104))	('HKII', 'Gene', (75, 79))	('decreased', 'NegReg', (130, 139))	('HKII', 'Gene', '3099', (23, 27))	('knocked down', 'Var', (84, 96))
122941	31354221	HKII knockdown slightly decreased basal respiration, but incubation with oligomycin prevented ATP production.	('basal respiration', 'MPA', (34, 51))	('decreased', 'NegReg', (24, 33))	('knockdown', 'Var', (5, 14))	('HKII', 'Gene', '3099', (0, 4))	('respiration', 'biological_process', 'GO:0045333', ('40', '51'))	('respiration', 'biological_process', 'GO:0007585', ('40', '51'))	('ATP', 'Chemical', 'MESH:D000255', (94, 97))	('oligomycin', 'Chemical', 'MESH:D009840', (73, 83))	('rat', 'Species', '10116', (45, 48))	('HKII', 'Gene', (0, 4))
122944	31354221	As can be seen in Figure 5A, knocking down HKII decreased basal respiration and maximal respiration.	('respiration', 'biological_process', 'GO:0045333', ('64', '75'))	('basal respiration', 'MPA', (58, 75))	('knocking down', 'Var', (29, 42))	('decreased', 'NegReg', (48, 57))	('maximal', 'CPA', (80, 87))	('respiration', 'biological_process', 'GO:0007585', ('88', '99'))	('HKII', 'Gene', '3099', (43, 47))	('HKII', 'Gene', (43, 47))	('respiration', 'biological_process', 'GO:0007585', ('64', '75'))	('respiration', 'biological_process', 'GO:0045333', ('88', '99'))	('rat', 'Species', '10116', (69, 72))	('rat', 'Species', '10116', (93, 96))
122945	31354221	Consistent with these results, overexpression of HKII increased the basal respiration and maximal respiration of HeLa cells, and 3BP prevented HKII-mediated increase in OCR (Figure 5B).	('respiration', 'biological_process', 'GO:0007585', ('98', '109'))	('HKII', 'Gene', (49, 53))	('rat', 'Species', '10116', (103, 106))	('basal', 'CPA', (68, 73))	('HKII', 'Gene', '3099', (143, 147))	('HeLa', 'CellLine', 'CVCL:0030', (113, 117))	('HKII', 'Gene', '3099', (49, 53))	('respiration', 'biological_process', 'GO:0007585', ('74', '85'))	('increased', 'PosReg', (54, 63))	('maximal respiration', 'CPA', (90, 109))	('3BP', 'Var', (129, 132))	('respiration', 'biological_process', 'GO:0045333', ('98', '109'))	('HKII', 'Gene', (143, 147))	('rat', 'Species', '10116', (79, 82))	('OCR', 'MPA', (169, 172))	('respiration', 'biological_process', 'GO:0045333', ('74', '85'))	('prevented', 'NegReg', (133, 142))
122946	31354221	Lastly, overexpression of HKII accelerated HEK293T proliferation, whereas knocking down HKII decreased HEK293T proliferation (Figure 5C).	('HEK293T proliferation', 'CPA', (43, 64))	('HKII', 'Gene', '3099', (88, 92))	('HKII', 'Gene', '3099', (26, 30))	('rat', 'Species', '10116', (118, 121))	('HEK293T', 'CellLine', 'CVCL:0063', (43, 50))	('rat', 'Species', '10116', (37, 40))	('HKII', 'Gene', (88, 92))	('decreased', 'NegReg', (93, 102))	('HKII', 'Gene', (26, 30))	('HEK293T', 'MPA', (103, 110))	('knocking down', 'Var', (74, 87))	('rat', 'Species', '10116', (58, 61))	('accelerated', 'PosReg', (31, 42))	('HEK293T', 'CellLine', 'CVCL:0063', (103, 110))
122948	31354221	Interestingly, the growth-promoting effects of HKII were blocked by overexpression of mutant PDHA1 S293A (Figure 5D).	('HKII', 'Gene', '3099', (47, 51))	('growth-promoting', 'CPA', (19, 35))	('mutant', 'Var', (86, 92))	('overexpression', 'PosReg', (68, 82))	('S293A', 'SUBSTITUTION', 'None', (99, 104))	('S293A', 'Var', (99, 104))	('HKII', 'Gene', (47, 51))	('PDHA1', 'Gene', '5160', (93, 98))	('PDHA1', 'Gene', (93, 98))
122949	31354221	To determine the effects of endogenous PDHA1 on cell growth, PDHA1 was knocked down in HEK293T cells, and then HKII and wild type PDHA1 or mutant PDHA1 S293A were re-introduced.	('PDHA1', 'Gene', '5160', (146, 151))	('S293A', 'SUBSTITUTION', 'None', (152, 157))	('S293A', 'Var', (152, 157))	('knocked', 'Var', (71, 78))	('PDHA1', 'Gene', (39, 44))	('PDHA1', 'Gene', '5160', (61, 66))	('HKII', 'Gene', (111, 115))	('PDHA1', 'Gene', '5160', (39, 44))	('PDHA1', 'Gene', (61, 66))	('mutant', 'Var', (139, 145))	('PDHA1', 'Gene', '5160', (130, 135))	('PDHA1', 'Gene', (130, 135))	('HKII', 'Gene', '3099', (111, 115))	('cell growth', 'biological_process', 'GO:0016049', ('48', '59'))	('HEK293T', 'CellLine', 'CVCL:0063', (87, 94))	('PDHA1', 'Gene', (146, 151))
122950	31354221	The results show that HEK293T cells transfected with HKII & PDHA1 grew faster than cells transfected with HKII & PDHA1 S293A ( Figure 5E).	('HKII', 'Gene', '3099', (53, 57))	('HKII', 'Gene', '3099', (106, 110))	('HEK293T', 'CellLine', 'CVCL:0063', (22, 29))	('PDHA1', 'Gene', '5160', (60, 65))	('PDHA1', 'Gene', (60, 65))	('HKII', 'Gene', (53, 57))	('PDHA1', 'Gene', (113, 118))	('grew', 'PosReg', (66, 70))	('PDHA1', 'Gene', '5160', (113, 118))	('S293A', 'SUBSTITUTION', 'None', (119, 124))	('S293A', 'Var', (119, 124))	('HKII', 'Gene', (106, 110))
122955	31354221	In ccRCC, HKII was overexpressed with elevated phosphorylation of S293 of PDHA1 and increased expression of Ki67, an indicator of disease progression (Figure 6A).	('PDHA1', 'Gene', '5160', (74, 79))	('phosphorylation', 'MPA', (47, 62))	('PDHA1', 'Gene', (74, 79))	('HKII', 'Gene', '3099', (10, 14))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('RCC', 'Disease', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('Ki67', 'Var', (108, 112))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('increased', 'PosReg', (84, 93))	('expression', 'MPA', (94, 104))	('S293', 'CellLine', 'CVCL:A784', (66, 70))	('elevated', 'PosReg', (38, 46))	('HKII', 'Gene', (10, 14))
122956	31354221	The increased expression levels of HKII correlated with phosphorylation of P293 of PDHA1 in tumor tissues (Figure 6B).	('phosphorylation', 'biological_process', 'GO:0016310', ('56', '71'))	('expression levels', 'MPA', (14, 31))	('HKII', 'Gene', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (92, 97))	('P293', 'Var', (75, 79))	('P293', 'CellLine', 'CVCL:0045', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('phosphorylation', 'MPA', (56, 71))	('HKII', 'Gene', '3099', (35, 39))	('PDHA1', 'Gene', (83, 88))	('increased', 'PosReg', (4, 13))	('PDHA1', 'Gene', '5160', (83, 88))
122966	31354221	PDHK1 phosphorylates Ser293 of PDHA1 and inhibits the activity of PDC.	('PDHA1', 'Gene', (31, 36))	('inhibits', 'NegReg', (41, 49))	('PDC', 'Gene', '5132', (66, 69))	('Ser', 'cellular_component', 'GO:0005790', ('21', '24'))	('PDH', 'Gene', (0, 3))	('Ser293', 'Var', (21, 27))	('HK', 'Gene', '3098', (2, 4))	('activity', 'MPA', (54, 62))	('PDH', 'Gene', (31, 34))	('PDC', 'Gene', (66, 69))	('PDH', 'Gene', '54704', (0, 3))	('PDH', 'Gene', '54704', (31, 34))	('PDHK', 'molecular_function', 'GO:0004740', ('0', '4'))	('PDHA1', 'Gene', '5160', (31, 36))
122967	31354221	Y381 phosphorylation of PDP1 recruits ACAT1 to PDC, and K321 acetylation inhibits PDHA1 by recruiting PDK1, promoting glycolysis in cancer cells and consequently tumor growth.	('ACAT1', 'Gene', '38', (38, 43))	('PDK1', 'Gene', (102, 106))	('tumor', 'Disease', (162, 167))	('PDC', 'Gene', (47, 50))	('Y381', 'Var', (0, 4))	('K321 acetylation', 'Var', (56, 72))	('PDK1', 'molecular_function', 'GO:0004740', ('102', '106'))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('glycolysis', 'MPA', (118, 128))	('phosphorylation', 'biological_process', 'GO:0016310', ('5', '20'))	('promoting', 'PosReg', (108, 117))	('K321', 'Chemical', '-', (56, 60))	('PDP1', 'Gene', (24, 28))	('PDP1', 'Gene', '54704', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('PDK1', 'Gene', '5163', (102, 106))	('PDHA1', 'Gene', (82, 87))	('PDHA1', 'Gene', '5160', (82, 87))	('glycolysis', 'biological_process', 'GO:0006096', ('118', '128'))	('PDC', 'Gene', '5132', (47, 50))	('cancer', 'Disease', (132, 138))	('inhibits', 'NegReg', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('ACAT1', 'Gene', (38, 43))
122971	31354221	It was also reported that PDH is an important regulator of senescence induced by BRAFV600E, which is commonly mutated in melanoma and other cancers, further confirming that PDC is a regulatory node for metabolism and signal transduction.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', (121, 129))	('PDC', 'Gene', (173, 176))	('signal transduction', 'biological_process', 'GO:0007165', ('217', '236'))	('senescence', 'MPA', (59, 69))	('PDH', 'molecular_function', 'GO:0004246', ('26', '29'))	('PDH', 'molecular_function', 'GO:0033718', ('26', '29'))	('PDH', 'Gene', '54704', (26, 29))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('BRAFV600E', 'Var', (81, 90))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('senescence', 'biological_process', 'GO:0010149', ('59', '69'))	('PDH', 'molecular_function', 'GO:0004739', ('26', '29'))	('PDC', 'Gene', '5132', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('metabolism', 'biological_process', 'GO:0008152', ('202', '212'))	('PDH', 'Gene', (26, 29))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('BRAFV600E', 'Mutation', 'rs113488022', (81, 90))
122973	31354221	Although the protein kinase activity of PKM2 is controversial, PKM2 was reported to translocate into the nucleus and phosphorylate Thr11 of histone 3, Tyr705 of STAT3, Tyr207 of Bub3, Y118 of MLC2, and S202 & 203 of AKT1S1 .	('Tyr705', 'Chemical', '-', (151, 157))	('Bub3', 'Gene', '9184', (178, 182))	('PKM2', 'Gene', (63, 67))	('AKT1S1', 'Gene', (216, 222))	('PKM2', 'Gene', '5315', (63, 67))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('translocate into the nucleus', 'MPA', (84, 112))	('Bub3', 'Gene', (178, 182))	('Tyr207', 'Chemical', '-', (168, 174))	('S202 &', 'Var', (202, 208))	('protein kinase', 'Gene', '64030', (13, 27))	('protein kinase activity', 'molecular_function', 'GO:0004672', ('13', '36'))	('Tyr207', 'Var', (168, 174))	('Y118', 'Var', (184, 188))	('MLC2', 'Gene', (192, 196))	('nucleus', 'cellular_component', 'GO:0005634', ('105', '112'))	('phosphorylate', 'MPA', (117, 130))	('STAT3', 'Gene', (161, 166))	('Tyr705', 'Var', (151, 157))	('Thr11', 'Chemical', '-', (131, 136))	('Thr11', 'Var', (131, 136))	('protein kinase', 'Gene', (13, 27))	('STAT3', 'Gene', '6774', (161, 166))	('MLC2', 'Gene', '4633', (192, 196))	('AKT1S1', 'Gene', '84335', (216, 222))	('PKM2', 'Gene', (40, 44))	('PKM2', 'Gene', '5315', (40, 44))
122979	31354221	Although many specific genes such as VHL, PBRM1, SETD2, BAP1, and KDM5C, are mutated in ccRCC, and HIF1alpha and HIF2alpha are targeted to inhibit the proliferation and growth of cancer cells, hypoxia induces the expression of HKII and stimulates the proliferation of human hepatoma cells.	('VHL', 'Disease', (37, 40))	('hypoxia', 'Disease', (193, 200))	('HIF2alpha', 'Gene', '2034', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('BAP1', 'Gene', '8314', (56, 60))	('PBRM1', 'Gene', (42, 47))	('mutated', 'Var', (77, 84))	('HIF1alpha', 'Gene', '3091', (99, 108))	('growth', 'CPA', (169, 175))	('rat', 'Species', '10116', (158, 161))	('hypoxia', 'Disease', 'MESH:D000860', (193, 200))	('RCC', 'Disease', (90, 93))	('HKII', 'Gene', (227, 231))	('KDM5C', 'Gene', '8242', (66, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('HIF1alpha', 'Gene', (99, 108))	('proliferation', 'CPA', (151, 164))	('hepatoma', 'Disease', (274, 282))	('BAP1', 'Gene', (56, 60))	('HKII', 'Gene', '3099', (227, 231))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('SETD2', 'Gene', (49, 54))	('VHL', 'Disease', 'MESH:D006623', (37, 40))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('expression', 'MPA', (213, 223))	('proliferation', 'CPA', (251, 264))	('human', 'Species', '9606', (268, 273))	('HIF2alpha', 'Gene', (113, 122))	('SETD2', 'Gene', '29072', (49, 54))	('rat', 'Species', '10116', (258, 261))	('KDM5C', 'Gene', (66, 71))	('stimulates', 'PosReg', (236, 246))	('inhibit', 'NegReg', (139, 146))	('induces', 'PosReg', (201, 208))	('hepatoma', 'Disease', 'MESH:D006528', (274, 282))	('PBRM1', 'Gene', '55193', (42, 47))	('cancer', 'Disease', (179, 185))
122982	31354221	It was found that HKII was a bifunctional enzyme, inhibited the activity of PDH complex and promoted Warburg effect through phosphorylating S293 of PDHA1.	('S293', 'Var', (140, 144))	('HKII', 'Gene', (18, 22))	('PDHA1', 'Gene', (148, 153))	('PDH', 'Gene', '54704', (148, 151))	('PDH', 'Gene', '54704', (76, 79))	('promoted', 'PosReg', (92, 100))	('Warburg effect', 'CPA', (101, 115))	('phosphorylating', 'MPA', (124, 139))	('S293', 'CellLine', 'CVCL:A784', (140, 144))	('PDH', 'molecular_function', 'GO:0004739', ('76', '79'))	('activity', 'MPA', (64, 72))	('HKII', 'Gene', '3099', (18, 22))	('PDH', 'molecular_function', 'GO:0004246', ('76', '79'))	('PDH', 'Gene', (148, 151))	('PDH', 'Gene', (76, 79))	('PDH', 'molecular_function', 'GO:0033718', ('76', '79'))	('inhibited', 'NegReg', (50, 59))	('PDHA1', 'Gene', '5160', (148, 153))
122995	31227023	Based on the current understanding, programmed death-1 (PD-1) can combine with programmed death-ligand 1 (PD-L1) to confine T cell activity in the tumor microenvironment, and inhibition of the PD-1/PD-L1 pathway can increase the anti-tumor immune response.	('tumor', 'Disease', (234, 239))	('PD-1', 'Gene', (193, 197))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('PD-1', 'Gene', '5133', (193, 197))	('tumor', 'Disease', (147, 152))	('programmed death-ligand 1', 'Gene', (79, 104))	('PD-L1', 'Gene', (198, 203))	('inhibition', 'Var', (175, 185))	('ligand', 'molecular_function', 'GO:0005488', ('96', '102'))	('programmed death-1', 'Gene', (36, 54))	('programmed death-1', 'Gene', '5133', (36, 54))	('PD-L1', 'Gene', '29126', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('programmed death-ligand 1', 'Gene', '29126', (79, 104))	('PD-1', 'Gene', (56, 60))	('PD-1', 'Gene', '5133', (56, 60))	('increase', 'PosReg', (216, 224))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('immune response', 'biological_process', 'GO:0006955', ('240', '255'))	('PD-L1', 'Gene', (106, 111))	('PD-L1', 'Gene', '29126', (106, 111))
123002	31227023	The functional significance of missense mutations was predicted via several algorithms, including SIFT, PolyPhen2 HDIV, PolyPhen2 HVAR, LRT, MutationTaster, MutationAssessor, and FATHMM.	('missense mutations', 'Var', (31, 49))	('PolyPhen2', 'Var', (120, 129))	('SIFT', 'Disease', 'None', (98, 102))	('SIFT', 'Disease', (98, 102))
123006	31227023	In the present study, VHL was somatically mutated in 10 ccRCC specimens, including five frameshift mutations, namely, p. K159fs, p. L135fs, p. P2fs, p. S183fs, and p. R58fs, all of which had not been reported previously and were deemed to be very strong evidence of pathogenicity.	('R58fs', 'FRAMESHIFT', 'None', (167, 172))	('K159fs', 'Var', (121, 127))	('VHL', 'Disease', 'MESH:D006623', (22, 25))	('P2fs', 'Var', (143, 147))	('P2fs', 'FRAMESHIFT', 'None', (143, 147))	('K159fs', 'FRAMESHIFT', 'None', (121, 127))	('S183fs', 'Var', (152, 158))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('L135fs', 'FRAMESHIFT', 'None', (132, 138))	('VHL', 'Disease', (22, 25))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('L135fs', 'Var', (132, 138))	('R58fs', 'Var', (167, 172))	('S183fs', 'FRAMESHIFT', 'None', (152, 158))
123008	31227023	Most of the mutations in PBRM1 were frameshift mutations, which had not been reported previously and were predicted to be deleterious.	('PBRM1', 'Gene', (25, 30))	('mutations', 'Var', (12, 21))	('PBRM1', 'Gene', '55193', (25, 30))	('frameshift', 'Var', (36, 46))
123011	31227023	For instance, BAP1 was somatically mutated in 3 ccRCC specimens in the present study, namely a frameshift deletion (p. S432fs) and insertion (p. P462fs) in sample 9, a deletion-insertion mutation [p. E642_I643delins (39)] in sample 13, and a frameshift insertion (p. P339fs) and deletion-insertion mutation [p. I191_D192delins (18)] in sample 20.	('BAP1', 'Gene', '8314', (14, 18))	('S432fs', 'Var', (119, 125))	('D192delins', 'Mutation', 'p.192delinsD', (316, 326))	('P339fs', 'Var', (267, 273))	('P462fs', 'Var', (145, 151))	('S432fs', 'FRAMESHIFT', 'None', (119, 125))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('BAP1', 'Gene', (14, 18))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('RCC', 'Disease', (50, 53))	('p. E642_I643delins', 'Mutation', 'p.642,643delinsI', (197, 215))	('P462fs', 'FRAMESHIFT', 'None', (145, 151))	('P339fs', 'FRAMESHIFT', 'None', (267, 273))
123012	31227023	Mutated BAP1 or loss of BAP1 expression was reported to be associated with poor outcome in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('RCC', 'Disease', (93, 96))	('BAP1', 'Gene', (24, 28))	('BAP1', 'Gene', '8314', (8, 12))	('loss', 'NegReg', (16, 20))	('BAP1', 'Gene', (8, 12))	('expression', 'MPA', (29, 39))	('Mutated', 'Var', (0, 7))	('BAP1', 'Gene', '8314', (24, 28))
123016	31227023	Three somatic mutations in DEPDC4 were identified in ccRCC specimens, namely 2 frameshift deletions (p. F150fs and p. R21fs) and 1 deletion-insertion [p. E147_L148delins (8)], all of which were predicted to be deleterious.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('RCC', 'Disease', (55, 58))	('R21fs', 'FRAMESHIFT', 'None', (118, 123))	('[p. E147_L148delins', 'Var', (150, 169))	('frameshift deletions', 'Reg', (79, 99))	('R21fs', 'Var', (118, 123))	('DEPDC4', 'Gene', (27, 33))	('L148delins', 'Mutation', 'p.148delinsL', (159, 169))	('DEPDC4', 'Gene', '120863', (27, 33))	('F150fs', 'Var', (104, 110))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('F150fs', 'FRAMESHIFT', 'None', (104, 110))
123021	31227023	Among the 20 ccRCC specimens in the present study, DDX51 was somatically mutated in 5 specimens with six mutations, namely, a deletion-insertion mutation [p. K611_V612delins (35)] in 1 specimen, a missense mutation (p. S116N) in 2 specimens, two frameshift insertion mutations (p. G147fs and p. H28fs) in 1 specimen, and a frameshift deletion (p.A273fs) in 1 specimen.	('S116N', 'SUBSTITUTION', 'None', (219, 224))	('p.A273fs', 'Mutation', 'p.A273fsX', (344, 352))	('H28fs', 'FRAMESHIFT', 'None', (295, 300))	('H28fs', 'Var', (295, 300))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('DDX51', 'Gene', (51, 56))	('RCC', 'Disease', (15, 18))	('S116N', 'Var', (219, 224))	('p.A273fs', 'Var', (344, 352))	('G147fs', 'FRAMESHIFT', 'None', (281, 287))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('G147fs', 'Var', (281, 287))	('V612delins', 'Mutation', 'p.612delinsV', (163, 173))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('DDX51', 'Gene', '317781', (51, 56))	('frameshift deletion', 'Reg', (323, 342))
123022	31227023	Notably, the frameshift deletion (p. A273fs) was located in the DEAD protein domain of DDX51 (Fig.	('frameshift', 'Reg', (13, 23))	('DDX51', 'Gene', (87, 92))	('DDX51', 'Gene', '317781', (87, 92))	('A273fs', 'FRAMESHIFT', 'None', (37, 43))	('A273fs', 'Var', (37, 43))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))
123023	31227023	The missense mutation in DDX51 in both specimens was predicted to be benign or neutral, whereas the deletion-insertion mutation and three frameshift mutations were most likely to be deleterious according to the ACMG guidelines.	('DDX51', 'Gene', (25, 30))	('missense mutation', 'Var', (4, 21))	('deletion-insertion mutation', 'Var', (100, 127))	('DDX51', 'Gene', '317781', (25, 30))
123024	31227023	Furthermore, somatic mutations in DDX51 were also identified in two other RCC subtypes, including a frameshift deletion (p. R519fs) in PRCC predicted to be deleterious and a missense mutation (p. P123R) in ChRCC predicted to be benign or neutral.	('PRCC', 'Phenotype', 'HP:0006766', (135, 139))	('P123R', 'Var', (196, 201))	('identified', 'Reg', (50, 60))	('P123R', 'SUBSTITUTION', 'None', (196, 201))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('PRCC', 'Gene', '5546', (135, 139))	('DDX51', 'Gene', (34, 39))	('R519fs', 'Var', (124, 130))	('RCC', 'Phenotype', 'HP:0005584', (208, 211))	('R519fs', 'FRAMESHIFT', 'None', (124, 130))	('RCC', 'Disease', (208, 211))	('DDX51', 'Gene', '317781', (34, 39))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('RCC', 'Disease', (136, 139))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('PRCC', 'Gene', (135, 139))	('RCC', 'Disease', 'MESH:C538614', (136, 139))
123028	31227023	We identified 6 genes, VHL, INADL, MUC4, RAD21, CSPG4, and BAP1, that were somatically mutated in 3 of the 4 PD-L1-positive ccRCC specimens.	('mutated', 'Var', (87, 94))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('VHL', 'Disease', 'MESH:D006623', (23, 26))	('RAD21', 'Gene', (41, 46))	('INADL', 'Gene', '10207', (28, 33))	('INADL', 'Gene', (28, 33))	('BAP1', 'Gene', '8314', (59, 63))	('RAD21', 'Gene', '5885', (41, 46))	('MUC4', 'Gene', '4585', (35, 39))	('PD-L1', 'Gene', (109, 114))	('MUC4', 'Gene', (35, 39))	('PD-L1', 'Gene', '29126', (109, 114))	('CSPG4', 'Gene', (48, 53))	('CSPG4', 'Gene', '1464', (48, 53))	('VHL', 'Disease', (23, 26))	('BAP1', 'Gene', (59, 63))	('RAD', 'biological_process', 'GO:1990116', ('41', '44'))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (124, 129))
123029	31227023	Nevertheless, only mutated RAD21 and BAP1 were associated with PD-L1 expression in tumor cells.	('RAD21', 'Gene', '5885', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('RAD', 'biological_process', 'GO:1990116', ('27', '30'))	('mutated', 'Var', (19, 26))	('expression', 'MPA', (69, 79))	('BAP1', 'Gene', '8314', (37, 41))	('PD-L1', 'Gene', (63, 68))	('BAP1', 'Gene', (37, 41))	('RAD21', 'Gene', (27, 32))	('associated', 'Reg', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('PD-L1', 'Gene', '29126', (63, 68))
123031	31227023	The somatic mutations in BAP1 (p. P352fs, p. H193Q, p. S432fs, and p. P462fs) and RAD21 (p. F2 L, p. F304S, p. R402fs, and p. L515fs) detected in the 3 PD-L1-positive ccRCC samples were all predicted to be deleterious.	('BAP1', 'Gene', (25, 29))	('PD-L1', 'Gene', '29126', (152, 157))	('p. F2 L', 'Mutation', 'p.F2L', (89, 96))	('PD-L1', 'Gene', (152, 157))	('RAD21', 'Gene', '5885', (82, 87))	('P352fs', 'Var', (34, 40))	('S432fs', 'FRAMESHIFT', 'None', (55, 61))	('P462fs', 'Var', (70, 76))	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('ccRCC', 'Phenotype', 'HP:0006770', (167, 172))	('RCC', 'Disease', (169, 172))	('S432fs', 'Var', (55, 61))	('F304S', 'Var', (101, 106))	('L515fs', 'FRAMESHIFT', 'None', (126, 132))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('P462fs', 'FRAMESHIFT', 'None', (70, 76))	('R402fs', 'Var', (111, 117))	('BAP1', 'Gene', '8314', (25, 29))	('H193Q', 'SUBSTITUTION', 'None', (45, 50))	('H193Q', 'Var', (45, 50))	('RAD', 'biological_process', 'GO:1990116', ('82', '85'))	('p. F2 L', 'Var', (89, 96))	('L515fs', 'Var', (126, 132))	('RAD21', 'Gene', (82, 87))	('F304S', 'SUBSTITUTION', 'None', (101, 106))	('R402fs', 'FRAMESHIFT', 'None', (111, 117))	('P352fs', 'FRAMESHIFT', 'None', (34, 40))
123044	27932890	A Kaplan-Meier analysis with log-rank test found that patients with high HMGA2 expression had a poor outcome and that patients with low HMGA2 expression had better survival.	('HMGA2', 'Gene', (73, 78))	('expression', 'MPA', (79, 89))	('high', 'Var', (68, 72))	('HMGA2', 'Gene', '8091', (136, 141))	('patients', 'Species', '9606', (54, 62))	('better', 'PosReg', (157, 163))	('HMGA2', 'Gene', (136, 141))	('HMGA2', 'Gene', '8091', (73, 78))	('patients', 'Species', '9606', (118, 126))
123086	27932890	A Kaplan-Meier survival analysis showed that high HMGA2 expression was associated with decreased OS (P<0.001), as shown in Figure 3.	('high', 'Var', (45, 49))	('HMGA2', 'Gene', (50, 55))	('HMGA2', 'Gene', '8091', (50, 55))	('decreased', 'NegReg', (87, 96))
123089	27932890	Further, multivariate Cox regression analysis determined that high HMGA2 expression was a significant negative independent prognostic indicator for patients with ccRCC in an analysis of OS (HR 3.116; 95% CI: 1.643-5.901; P<0.001).	('negative', 'NegReg', (102, 110))	('patients', 'Species', '9606', (148, 156))	('HMGA2', 'Gene', '8091', (67, 72))	('HMGA2', 'Gene', (67, 72))	('expression', 'MPA', (73, 83))	('Cox', 'Gene', '1351', (22, 25))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('RCC', 'Disease', (164, 167))	('high', 'Var', (62, 66))	('Cox', 'Gene', (22, 25))
123107	27932890	In the present cohort, the high HMGA2 expression group was more likely to have higher rates of lymph node invasion and vascular invasion than those in the low expression group.	('HMGA2', 'Gene', (32, 37))	('high', 'Var', (27, 31))	('HMGA2', 'Gene', '8091', (32, 37))	('vascular invasion', 'CPA', (119, 136))
123109	27932890	The ectopic expression of HMGA2 in epithelial cells induces epithelial-mesenchymal transition (EMT), which has been implicated in the acquisition of metastatic characteristics in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('HMGA2', 'Gene', '8091', (26, 31))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('60', '93'))	('HMGA2', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('EMT', 'biological_process', 'GO:0001837', ('95', '98'))	('induces', 'Reg', (52, 59))	('ectopic expression', 'Var', (4, 22))	('epithelial-mesenchymal transition', 'CPA', (60, 93))	('tumor', 'Disease', (179, 184))
123121	27932890	The abnormal expression of HMGA2 may play a role in the carcinogenesis of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('play', 'Reg', (37, 41))	('HMGA2', 'Gene', '8091', (27, 32))	('role', 'Reg', (44, 48))	('carcinogenesis', 'Disease', 'MESH:D063646', (56, 70))	('HMGA2', 'Gene', (27, 32))	('carcinogenesis', 'Disease', (56, 70))
123131	33157517	More importantly, larger scale genomic aberrations including somatic copy number alteration (SCNA) or loss of heterozygosity (LOH) differentiate the metastasis lesions from primary tumour.	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('tumour', 'Disease', 'MESH:D009369', (181, 187))	('tumour', 'Disease', (181, 187))	('metastasis lesions', 'CPA', (149, 167))	('loss', 'Var', (102, 106))
123138	33157517	VHL (von Hippel-Landau, on chromosome 3p25) gene inactivation, either by somatic mutation, chromosomal loss or epigenetic silencing, presents in the majority of ccRCC (the major subtype of RCC) patients.	('patients', 'Species', '9606', (194, 202))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('von Hippel-Landau', 'Gene', '7428', (5, 22))	('inactivation', 'NegReg', (49, 61))	('RCC', 'Disease', (163, 166))	('ccRCC', 'Phenotype', 'HP:0006770', (161, 166))	('chromosome', 'cellular_component', 'GO:0005694', ('27', '37'))	('epigenetic silencing', 'Var', (111, 131))	('von Hippel-Landau', 'Gene', (5, 22))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('RCC', 'Disease', (189, 192))	('chromosomal loss', 'Var', (91, 107))
123139	33157517	It is widely known that the inactivation of VHL protein (pVHL) can lead to the abnormal expression of genes that play crucial roles in tumorigenesis, such as hypoxia inducible factors (HIFs) and vascular endothelial growth factor (VEGF).	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('HIFs', 'Disease', (185, 189))	('lead to', 'Reg', (67, 74))	('VHL', 'Gene', (44, 47))	('hypoxia', 'Disease', (158, 165))	('vascular endothelial growth factor', 'Gene', '7422', (195, 229))	('inactivation', 'Var', (28, 40))	('VHL', 'Gene', (58, 61))	('HIFs', 'Disease', 'None', (185, 189))	('VEGF', 'Gene', '7422', (231, 235))	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('vascular endothelial growth factor', 'Gene', (195, 229))	('hypoxia', 'Disease', 'MESH:D000860', (158, 165))	('tumor', 'Disease', (135, 140))	('VEGF', 'Gene', (231, 235))	('VHL', 'Gene', '7428', (44, 47))	('VHL', 'Gene', '7428', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('abnormal expression', 'MPA', (79, 98))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('195', '229'))	('pVHL', 'Gene', '7428', (57, 61))	('pVHL', 'Gene', (57, 61))
123141	33157517	Previous study comprising a single-centre retrospective evaluation of m-RCC patients with bone metastasis at the University of Texas MD Anderson Cancer Centre has shown that m-RCC patients demonstrate a median overall survival (OS) of 24 months with TKI treatment compared with 18 months without the TKI treatment.	('overall survival', 'MPA', (210, 226))	('patients', 'Species', '9606', (76, 84))	('TKI treatment', 'Var', (250, 263))	('RCC', 'Disease', (176, 179))	('Cancer', 'Disease', 'MESH:D009369', (145, 151))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('Cancer', 'Phenotype', 'HP:0002664', (145, 151))	('Cancer', 'Disease', (145, 151))	('patients', 'Species', '9606', (180, 188))
123158	33157517	For further single nucleotide variants (SNVs) and INDEL calling, the aligned reads are realigned to the genome and base quality recalibration is performed using the Genome Analysis Toolkit (GATK 3.7) based on dbSNP 138.	('kit', 'Gene', (185, 188))	('kit', 'Gene', '3815', (185, 188))	('single nucleotide', 'Var', (12, 29))
123160	33157517	The following criteria are applied to the called SNVs: (i) at least 10 x coverage is required for the normal and tumour samples; (ii) variants listed in dbSNP 138 and dbsnp147 are removed, and (iii) variants listed in The 1000 Genomes Project are removed.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('dbsnp147', 'Gene', (167, 175))	('variants', 'Var', (134, 142))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('dbSNP 138', 'Gene', (153, 162))	('tumour', 'Disease', (113, 119))
123161	33157517	The following criteria are applied to the called indels: (i) At least 10 x total coverage is required for the tumour samples, (ii) variants listed in dbSNP 138 are removed, and (iii) variants listed in The 1000 Genomes Project are removed.	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('variants', 'Var', (131, 139))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('dbSNP', 'Gene', (150, 155))	('tumour', 'Disease', (110, 116))
123167	33157517	There are 96 possible substitution patterns when considering trinucleotide sequences, because there are six substitution patterns for each base mutation (C>A, C>T, C>G, T>A, T>C, and T>G).	('T>A', 'Var', (169, 172))	('C>T', 'Var', (159, 162))	('C>A', 'Var', (154, 157))	('C>G', 'Var', (164, 167))	('T>G', 'Var', (183, 186))	('trinucleotide', 'Chemical', '-', (61, 74))	('T>C', 'Var', (174, 177))
123184	33157517	Of a total of 217 mutations found in the tumours for patient 1 (5 shared, 168 metastasis-specific, 44 primary-tumour-specific), 212 (97.7%) are different between primary tumour and metastasis, indicating a high degree of divergence and therefore parallel evolution.	('different', 'Reg', (144, 153))	('tumour', 'Disease', (170, 176))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('patient', 'Species', '9606', (53, 60))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('tumours', 'Disease', 'MESH:D009369', (41, 48))	('tumour', 'Disease', (41, 47))	('tumours', 'Disease', (41, 48))	('tumour', 'Disease', 'MESH:D009369', (170, 176))	('tumour', 'Disease', (110, 116))	('mutations', 'Var', (18, 27))
123185	33157517	Similarly, of a total of 196 mutations found in the tumours for patient 2 (52 shared, 109 metastasis-specific, 35 primary-tumour-specific), 144 (73.5%) are different between primary tumour and metastasis (Table S4).	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('patient', 'Species', '9606', (64, 71))	('tumours', 'Disease', (52, 59))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (29, 38))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('tumour', 'Disease', (122, 128))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('different', 'Reg', (156, 165))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('tumour', 'Disease', (182, 188))	('tumour', 'Disease', (52, 58))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('tumours', 'Disease', 'MESH:D009369', (52, 59))
123193	33157517	We constructed the tumour phylogeny for each patient using the missense SNAs and CNAs (Fig.	('tumour', 'Disease', 'MESH:D009369', (19, 25))	('missense SNAs', 'Var', (63, 76))	('tumour', 'Disease', (19, 25))	('patient', 'Species', '9606', (45, 52))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
123194	33157517	The tumour phylogeny of the missense SNAs and CNAs further suggested the clonal origin and parallel evolution.	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('missense SNAs', 'Var', (28, 41))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('CNAs', 'Disease', (46, 50))	('tumour', 'Disease', (4, 10))
123198	33157517	1B and 1C, no significant difference was observed in median number of missense SNAs between primary tumours and metastases of patient 3 to 8 (41.5 versus 56.5, Student's t-test, P = 0.58).	('primary tumours', 'Disease', 'MESH:D009369', (92, 107))	('primary tumours', 'Disease', (92, 107))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('patient', 'Species', '9606', (126, 133))	('missense SNAs', 'Var', (70, 83))	('metastases', 'Disease', (112, 122))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))
123203	33157517	So, there are 6 classed of case substitutions (C>A, C>G, C>T, T>A, T>C, T>G) and 16 possible sequence contexts for each mutated base, 96-trinucleotide are possible.	('C>T', 'Var', (57, 60))	('trinucleotide', 'Chemical', '-', (137, 150))	('T>C, T>G', 'Var', (67, 75))	('C>A', 'Var', (47, 50))	('C>G', 'Var', (52, 55))	('T>A', 'Var', (62, 65))
123206	33157517	An unexpectedly high frequency of T>A transversion is identified in patient 3; this result is consistent with exposure to aristolochic acid (AA), which leads to a very high mutational burden in urothelial carcinoma.	('aristolochic acid', 'Chemical', 'MESH:C000228', (122, 139))	('aristolochic acid', 'Var', (122, 139))	('patient', 'Species', '9606', (68, 75))	('urothelial carcinoma', 'Disease', (194, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (194, 214))
123212	33157517	Notably, the frequent of arm-level events involved LOH at 3p, 4p, 4q, 9p, 9q, 14q and 17p are usually shared events among both the primary and metastatic tumours (Fig.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('tumours', 'Disease', 'MESH:D009369', (154, 161))	('LOH at 3p', 'Var', (51, 60))	('tumours', 'Disease', (154, 161))
123213	33157517	Similarly, the frequent arm-level events involved loss of 3p, gain of 5q, loss of 9p and loss of 14q, which are usually shared events among both the primary and metastatic tumours (Fig.	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('gain', 'PosReg', (62, 66))	('loss', 'NegReg', (50, 54))	('tumours', 'Phenotype', 'HP:0002664', (172, 179))	('loss of 9p', 'Var', (74, 84))	('loss of 14q', 'Var', (89, 100))	('tumours', 'Disease', 'MESH:D009369', (172, 179))	('arm-level', 'Disease', (24, 33))	('tumours', 'Disease', (172, 179))
123214	33157517	We discovered LOH at 14q and 17p are significantly enrichment in metastatic lesions compared to the primary tumours (Fig.	('metastatic lesions', 'CPA', (65, 83))	('primary tumours', 'Disease', (100, 115))	('primary tumours', 'Disease', 'MESH:D009369', (100, 115))	('LOH', 'Var', (14, 17))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))
123215	33157517	The wider involvement of LOH mutations in cancer is assumed to be related to unmasking a somatically mutated tumour suppressor gene through loss of the wild type allele.	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('mutations', 'Var', (29, 38))	('tumour', 'Disease', (109, 115))	('cancer', 'Disease', (42, 48))	('LOH', 'Gene', (25, 28))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('loss', 'NegReg', (140, 144))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
123216	33157517	S2B and S2C) and 14q loss was associated with shorter overall survival in ccRCC patients (Fig.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('patients', 'Species', '9606', (80, 88))	('S2C', 'Var', (8, 11))	('overall survival', 'MPA', (54, 70))	('shorter', 'NegReg', (46, 53))	('loss', 'NegReg', (21, 25))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))	('S2B', 'Var', (0, 3))
123217	33157517	Moreover, consistent with previous studies, LOH at 3p as potential truncal driver events which spans all the known driver alterations in ccRCC including VHL, PBRM1, BAP1 and SETD2 for all 8 patients.	('LOH', 'Var', (44, 47))	('VHL', 'Gene', (153, 156))	('BAP1', 'Gene', (165, 169))	('patients', 'Species', '9606', (190, 198))	('PBRM1', 'Gene', (158, 163))	('VHL', 'Gene', '7428', (153, 156))	('SETD2', 'Gene', '29072', (174, 179))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('PBRM1', 'Gene', '55193', (158, 163))	('SETD2', 'Gene', (174, 179))	('BAP1', 'Gene', '8314', (165, 169))
123224	33157517	among these patients, 22 patients had bone metastases (13 for targeted therapy and 9 for both targeted and metastasectomy therapies); the median survival for targeted therapy was 19 months, whereas that for metastasectomy combined with targeted therapy was 39 months (Fig.	('patients', 'Species', '9606', (12, 20))	('bone metastases', 'Disease', 'MESH:D009362', (38, 53))	('bone metastases', 'Disease', (38, 53))	('targeted', 'Var', (158, 166))	('patients', 'Species', '9606', (25, 33))
123230	33157517	Consistent with previous reports, we noted that multiple focal SCNAs, such as loss of 14q31.1 and loss of 9p21.3, were selected in metastatic tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('loss of 9p21.3', 'Var', (98, 112))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', (142, 148))	('loss of 14q31.1', 'Var', (78, 93))
123231	33157517	Since the gain of copy number in oncogenes may promote the gene expression change involving tumorigenesis, we performed KEGG pathways analysis using genes within the selected copy number gain regions to explore the underlying oncogenic pathways.	('gain', 'PosReg', (10, 14))	('oncogenes', 'Gene', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('promote', 'PosReg', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('gene expression', 'biological_process', 'GO:0010467', ('59', '74'))	('gene expression change', 'MPA', (59, 81))	('tumor', 'Disease', (92, 97))	('copy number', 'Var', (18, 29))
123232	33157517	To further validate gain of copy number would promote the gene expression of histone genes, we downloaded the gene expression dataset of ccRCC from TCGA.	('promote', 'PosReg', (46, 53))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('gene expression', 'MPA', (58, 73))	('RCC', 'Disease', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('copy number', 'Var', (28, 39))	('gene expression', 'biological_process', 'GO:0010467', ('58', '73'))	('gene expression', 'biological_process', 'GO:0010467', ('110', '125'))
123236	33157517	PBRM1 is mutated and/or copy number loss in more than 80% of ccRCC.	('RCC', 'Disease', (63, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('copy number loss', 'Var', (24, 40))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
123240	33157517	Consistent with previous study, deletion of HIST1H1C (H1.2) has been shown to render cancer cells resistant to DNA damaging agents, the lower level of H1.2 expression in ccRCC cell lines, the lower number of double strand break foci inducing by camptothecin (Fig.	('deletion', 'Var', (32, 40))	('HIST1H1C', 'Gene', (44, 52))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('camptothecin', 'Chemical', 'MESH:D002166', (245, 257))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('H1.2', 'Gene', (151, 155))	('H1.2', 'Gene', '3006', (151, 155))	('HIST1H1C', 'Gene', '3006', (44, 52))	('lower', 'NegReg', (136, 141))	('lower', 'NegReg', (192, 197))	('H1.2', 'Gene', (54, 58))	('cancer', 'Disease', (85, 91))	('H1.2', 'Gene', '3006', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('double strand break foci', 'MPA', (208, 232))	('expression', 'MPA', (156, 166))	('ccRCC', 'Phenotype', 'HP:0006770', (170, 175))	('RCC', 'Disease', (172, 175))
123241	33157517	Next, we selected one novel strongly selected event, loss of 14q32.31 to demonstrate whether knockdown the involved genes will promote tumor cell invasion.	('knockdown', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('promote', 'PosReg', (127, 134))	('tumor', 'Disease', (135, 140))	('loss', 'Var', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
123246	33157517	As expected, knockdown either of the three genes promote tumor cell invasion capacity (Fig.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('promote', 'PosReg', (49, 56))	('tumor', 'Disease', (57, 62))	('knockdown', 'Var', (13, 22))
123254	33157517	These results are consistent with a recent study which shows chromosome instability driving metastasis in lung cancers.	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('chromosome instability', 'Phenotype', 'HP:0040012', (61, 83))	('chromosome instability', 'Var', (61, 83))	('lung cancers', 'Disease', 'MESH:D008175', (106, 118))	('metastasis', 'CPA', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('lung cancers', 'Phenotype', 'HP:0100526', (106, 118))	('chromosome', 'cellular_component', 'GO:0005694', ('61', '71'))	('lung cancers', 'Disease', (106, 118))
123255	33157517	We also found that copy number gain of histone genes may facilitate to maintain the genome stability in metastatic tumor.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('histone', 'Protein', (39, 46))	('tumor', 'Disease', (115, 120))	('copy number gain', 'Var', (19, 35))	('genome stability', 'CPA', (84, 100))	('facilitate', 'PosReg', (57, 67))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
123257	33157517	Moreover, deletion of H1.2 render cancer cells resistant to DNA damaging agents.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('resistant', 'CPA', (47, 56))	('H1.2', 'Gene', (22, 26))	('cancer', 'Disease', (34, 40))	('deletion', 'Var', (10, 18))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('H1.2', 'Gene', '3006', (22, 26))
123258	33157517	Classically, defects in the DNA damage repair have been exploited therapeutically in the treatment of cancer with radiation therapies or genotoxic chemotherapies.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('defects', 'Var', (13, 20))
123259	33157517	Synthetic lethality analysis suggested that TOP1 inhibitor might be effective in ccRCC with defective PBRM1.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('PBRM1', 'Gene', (102, 107))	('PBRM1', 'Gene', '55193', (102, 107))	('TOP1', 'Gene', '7150', (44, 48))	('TOP1', 'Gene', (44, 48))	('defective', 'Var', (92, 101))
123265	33157517	When comparing 50 ccRCC patients treated with CRLX101+bevacizumab with 19 ccRCC patients having received bevacizumab monotherapy, median PFS was higher in combined therapy (3.7 versus 3.4 months).	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('PFS', 'MPA', (137, 140))	('RCC', 'Disease', (76, 79))	('patients', 'Species', '9606', (80, 88))	('bevacizumab', 'Chemical', 'MESH:D000068258', (105, 116))	('bevacizumab', 'Chemical', 'MESH:D000068258', (54, 65))	('patients', 'Species', '9606', (24, 32))	('CRLX101+bevacizumab', 'Var', (46, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (18, 23))	('RCC', 'Disease', (20, 23))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))	('higher', 'PosReg', (145, 151))
123268	33157517	Additionally, we also identified multiple selected SCNAs with copy number loss during ccRCC metastasis, such as 14q32.31, 14q32.2, 9p11.1, 3p14.3, 3p21.1 and 3p21.2.	('14q32.2', 'Var', (122, 129))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('3p14.3', 'Var', (139, 145))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('3p21.1', 'Var', (147, 153))	('9p11.1', 'Var', (131, 137))	('copy number loss', 'Var', (62, 78))
123270	33157517	As expected, knockdown either of the three genes within this region promotes tumor cell invasion.	('promotes', 'PosReg', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('knockdown', 'Var', (13, 22))	('tumor', 'Disease', (77, 82))
123276	33157517	Consistent with our conclusions, a recent evolutionary study of matched primary metastasis biopsies from 100 ccRCC cases with targeted driver panel sequencing also find that loss of 14q is one of the hallmark genomic driver of ccRCC metastasis.	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Disease', 'MESH:C538614', (229, 232))	('RCC', 'Disease', (229, 232))	('ccRCC', 'Phenotype', 'HP:0006770', (227, 232))	('loss of 14q', 'Var', (174, 185))
123282	33157517	This work was supported by  (XDA16010102 to W.C.), the  (2018YFC2000100, 2019YFA0110900 to W.C.), CAS (QYZDB-SSW-SMC039 to W.C.), the  (81422035 and 81672541 to W.C., 81772731 to K.C.	('2019YFA0110900', 'Var', (73, 87))	('81672541 to', 'Var', (149, 160))	('CAS', 'Gene', (98, 101))	('CAS', 'Gene', '9564', (98, 101))	('XDA16010102', 'Var', (29, 40))	('81772731', 'Var', (167, 175))	('2018YFC2000100', 'Var', (57, 71))	('81422035', 'Var', (136, 144))	('SMC', 'cellular_component', 'GO:0016029', ('113', '116'))	('CAS', 'cellular_component', 'GO:0005650', ('98', '101'))
123286	32966238	AHNAK2 expression was significantly high in patients with advanced stage, advanced T classification, lymph node metastasis, increased BRAF mutations and decreased RAS mutations.	('high', 'PosReg', (36, 40))	('lymph node metastasis', 'CPA', (101, 122))	('patients', 'Species', '9606', (44, 52))	('mutations', 'Var', (139, 148))	('increased', 'PosReg', (124, 133))	('BRAF', 'Gene', '673', (134, 138))	('expression', 'MPA', (7, 17))	('AHNAK2', 'Gene', (0, 6))	('decreased', 'NegReg', (153, 162))	('BRAF', 'Gene', (134, 138))	('AHNAK2', 'Gene', '113146', (0, 6))	('RAS mutations', 'MPA', (163, 176))	('advanced T classification', 'CPA', (74, 99))
123291	32966238	Methylation may act as an upstream regulator to inhibit the expression and biological function of AHNAK2.	('expression', 'MPA', (60, 70))	('biological function', 'MPA', (75, 94))	('Methylation', 'Var', (0, 11))	('AHNAK2', 'Gene', (98, 104))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('AHNAK2', 'Gene', '113146', (98, 104))	('inhibit', 'NegReg', (48, 55))
123313	32966238	Kaplan-Meier (K-M) survival analysis showed that the high AHNAK2 (H-AHNAK2) group was associated with worse progression-free survival (PFS) than the low AHNAK2 (L-AHNAK2) group (P=0.0005) (Figure 1D).	('worse', 'NegReg', (102, 107))	('high', 'Var', (53, 57))	('AHNAK2', 'Gene', '113146', (153, 159))	('AHNAK2', 'Gene', (68, 74))	('AHNAK2', 'Gene', (58, 64))	('AHNAK2', 'Gene', '113146', (68, 74))	('progression-free survival', 'CPA', (108, 133))	('AHNAK2', 'Gene', '113146', (58, 64))	('AHNAK2', 'Gene', (163, 169))	('AHNAK2', 'Gene', '113146', (163, 169))	('AHNAK2', 'Gene', (153, 159))
123316	32966238	We analyzed the relationships between AHNAK2 and clinical parameters, including age, gender, stage, metastasis, N classification, T classification, pathologic type, and mutations in BRAF and RAS (Table 2, Supplementary Figure 1).	('mutations', 'Var', (169, 178))	('AHNAK2', 'Gene', (38, 44))	('BRAF', 'Gene', '673', (182, 186))	('RAS', 'Gene', (191, 194))	('AHNAK2', 'Gene', '113146', (38, 44))	('BRAF', 'Gene', (182, 186))
123317	32966238	AHNAK2 expression was significantly high in patients with an advanced stage, an advanced T classification, lymph node metastasis, increased BRAF mutations, decreased RAS mutations, and lower follicular PTC and higher tall-cell PTC proportions.	('PTC', 'Gene', '5979', (227, 230))	('PTC', 'Phenotype', 'HP:0002895', (227, 230))	('mutations', 'Var', (145, 154))	('lower', 'NegReg', (185, 190))	('patients', 'Species', '9606', (44, 52))	('TC', 'Phenotype', 'HP:0002890', (228, 230))	('increased', 'PosReg', (130, 139))	('TC', 'Phenotype', 'HP:0002890', (203, 205))	('BRAF', 'Gene', '673', (140, 144))	('expression', 'MPA', (7, 17))	('decreased', 'NegReg', (156, 165))	('BRAF', 'Gene', (140, 144))	('RAS', 'Protein', (166, 169))	('AHNAK2', 'Gene', '113146', (0, 6))	('higher', 'PosReg', (210, 216))	('high', 'PosReg', (36, 40))	('lymph node metastasis', 'CPA', (107, 128))	('AHNAK2', 'Gene', (0, 6))	('PTC', 'Gene', (202, 205))	('PTC', 'Phenotype', 'HP:0002895', (202, 205))	('PTC', 'Gene', (227, 230))	('PTC', 'Gene', '5979', (202, 205))
123318	32966238	Interestingly, in the study of the relationship between AHNAK2 expression and gene mutations in PTC (Supplementary Figure 1A), we found that AHNAK2 expression was positively correlated with BRAF mutations (Supplementary Figure 1B) and negatively correlated with RAS (NRAS, HRAS and KRAS) mutations (Supplementary Figure 1C-1E).	('KRAS', 'Gene', '3845', (282, 286))	('PTC', 'Gene', (96, 99))	('TC', 'Phenotype', 'HP:0002890', (97, 99))	('PTC', 'Gene', '5979', (96, 99))	('negatively', 'NegReg', (235, 245))	('PTC', 'Phenotype', 'HP:0002895', (96, 99))	('BRAF', 'Gene', '673', (190, 194))	('KRAS', 'Gene', (282, 286))	('BRAF', 'Gene', (190, 194))	('HRAS', 'Gene', '3265', (273, 277))	('NRAS', 'Gene', '4893', (267, 271))	('AHNAK2', 'Gene', '113146', (56, 62))	('HRAS', 'Gene', (273, 277))	('AHNAK2', 'Gene', (56, 62))	('mutations', 'Var', (195, 204))	('correlated', 'Reg', (174, 184))	('AHNAK2', 'Gene', '113146', (141, 147))	('RAS', 'Disease', (262, 265))	('NRAS', 'Gene', (267, 271))	('AHNAK2', 'Gene', (141, 147))	('expression', 'MPA', (148, 158))
123334	32966238	Among the DNA methylation sites of AHNAK2, cg06799735, cg01513078, cg11138227 and cg23385208 had the most significant negative correlations with the AHNAK2 expression level (Table 3).	('cg11138227', 'Var', (67, 77))	('expression level', 'MPA', (156, 172))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('cg23385208', 'Var', (82, 92))	('cg06799735', 'Var', (43, 53))	('negative', 'NegReg', (118, 126))	('cg01513078', 'Var', (55, 65))	('AHNAK2', 'Gene', (35, 41))	('AHNAK2', 'Gene', (149, 155))	('AHNAK2', 'Gene', '113146', (149, 155))	('AHNAK2', 'Gene', '113146', (35, 41))	('DNA methylation', 'biological_process', 'GO:0006306', ('10', '25'))
123335	32966238	Moreover, we found significant connections between AHNAK2 methylation and clinical parameters such as tumor purity, stage, T classification, N classification and histological type (Figure 5C-5G).	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('AHNAK2', 'Gene', (51, 57))	('methylation', 'Var', (58, 69))	('connections', 'Reg', (31, 42))	('methylation', 'biological_process', 'GO:0032259', ('58', '69'))	('T classification', 'CPA', (123, 139))	('AHNAK2', 'Gene', '113146', (51, 57))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
123337	32966238	Based on RNAseq, we screened 9,944 genes related to AHNAK2 methylation (false discovery rate (FDR) <0.01) (Figure 5H).	('false', 'biological_process', 'GO:0071877', ('72', '77'))	('AHNAK2', 'Gene', (52, 58))	('false', 'biological_process', 'GO:0071878', ('72', '77'))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('methylation', 'Var', (59, 70))	('AHNAK2', 'Gene', '113146', (52, 58))
123338	32966238	The top 50 significant genes that were positively and negatively correlated with AHNAK2 methylation are presented as two heatmaps in Figure 5I.	('methylation', 'Var', (88, 99))	('AHNAK2', 'Gene', (81, 87))	('AHNAK2', 'Gene', '113146', (81, 87))	('negatively', 'NegReg', (54, 64))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))
123339	32966238	The GO (biological process) analysis results derived by GSEA were significant; the results indicated that AHNAK2 methylation coexpressed genes participate primarily in metabolism-related pathways, while genes related to activities such as the adaptive immune response, granulocyte activation, leukocyte migration, regulation of leukocyte activation, and positive regulation of the defense response were inhibited.	('granulocyte activation', 'CPA', (269, 291))	('methylation', 'biological_process', 'GO:0032259', ('113', '124'))	('regulation', 'biological_process', 'GO:0065007', ('363', '373'))	('granulocyte activation', 'biological_process', 'GO:0036230', ('269', '291'))	('methylation', 'Var', (113, 124))	('AHNAK2', 'Gene', (106, 112))	('GSEA', 'Chemical', '-', (56, 60))	('adaptive immune response', 'biological_process', 'GO:0002250', ('243', '267'))	('biological process', 'biological_process', 'GO:0008150', ('8', '26'))	('metabolism', 'biological_process', 'GO:0008152', ('168', '178'))	('participate', 'Reg', (143, 154))	('AHNAK2', 'Gene', '113146', (106, 112))	('leukocyte migration', 'biological_process', 'GO:0050900', ('293', '312'))	('leukocyte migration', 'CPA', (293, 312))	('regulation of leukocyte activation', 'biological_process', 'GO:0002694', ('314', '348'))	('metabolism-related pathways', 'Pathway', (168, 195))	('defense response', 'biological_process', 'GO:0006952', ('381', '397'))
123341	32966238	These results illustrate the extensive effects of AHNAK2 methylation on transcriptome and immune-related pathways.	('methylation', 'Var', (57, 68))	('AHNAK2', 'Gene', '113146', (50, 56))	('transcriptome', 'MPA', (72, 85))	('effects', 'Reg', (39, 46))	('immune-related', 'CPA', (90, 104))	('methylation', 'biological_process', 'GO:0032259', ('57', '68'))	('AHNAK2', 'Gene', (50, 56))
123346	32966238	K-M survival analysis showed that the high AHNAK2 group had significant associations with short OS in bladder urothelial carcinoma (BLCA), glioblastoma multiforme (GBM), lung adenocarcinoma (LUAD), mesothelioma (MESO), pancreatic adenocarcinoma (PAAD), skin cutaneous melanoma (SKCM) and uveal melanoma (UVM) (Figure 7D-7J).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('AHNAK2', 'Gene', '113146', (43, 49))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('UVM', 'Phenotype', 'HP:0007716', (304, 307))	('LUAD', 'Phenotype', 'HP:0030078', (191, 195))	('AHNAK2', 'Gene', (43, 49))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (219, 244))	('high', 'Var', (38, 42))	('lung adenocarcinoma', 'Disease', (170, 189))	('uveal melanoma', 'Disease', 'MESH:C536494', (288, 302))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (219, 244))	('uveal melanoma', 'Disease', (288, 302))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (253, 276))	('glioblastoma multiforme', 'Disease', (139, 162))	('bladder urothelial carcinoma', 'Disease', (102, 130))	('melanoma', 'Phenotype', 'HP:0002861', (268, 276))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (258, 276))	('skin cutaneous melanoma', 'Disease', (253, 276))	('associations', 'Interaction', (72, 84))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (139, 162))	('PAAD', 'Phenotype', 'HP:0006725', (246, 250))	('glioblastoma', 'Phenotype', 'HP:0012174', (139, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (170, 189))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (102, 130))	('uveal melanoma', 'Phenotype', 'HP:0007716', (288, 302))	('mesothelioma', 'Disease', (198, 210))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (170, 189))	('mesothelioma', 'Disease', 'MESH:D008654', (198, 210))	('pancreatic adenocarcinoma', 'Disease', (219, 244))
123365	32966238	AHNAK2 expression is significantly high in patients with an advanced cancer stage, an advanced T classification, lymph node metastasis, and increased BRAF mutations, showing a positive correlation with PTC progression.	('high', 'PosReg', (35, 39))	('TC', 'Phenotype', 'HP:0002890', (203, 205))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('mutations', 'Var', (155, 164))	('patients', 'Species', '9606', (43, 51))	('lymph node metastasis', 'CPA', (113, 134))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('expression', 'MPA', (7, 17))	('AHNAK2', 'Gene', (0, 6))	('BRAF', 'Gene', (150, 154))	('BRAF', 'Gene', '673', (150, 154))	('PTC', 'Gene', (202, 205))	('PTC', 'Phenotype', 'HP:0002895', (202, 205))	('AHNAK2', 'Gene', '113146', (0, 6))	('PTC', 'Gene', '5979', (202, 205))	('increased', 'PosReg', (140, 149))	('cancer', 'Disease', (69, 75))
123367	32966238	Interestingly, the two genes with the highest mutation rates in PTC exhibited a notable trend: BRAF mutations were positively associated with AHNAK2 expression, while RAS mutations were negatively correlated with AHNAK2 expression.	('mutations', 'Var', (100, 109))	('associated', 'Interaction', (126, 136))	('PTC', 'Gene', (64, 67))	('BRAF', 'Gene', '673', (95, 99))	('AHNAK2', 'Gene', (213, 219))	('TC', 'Phenotype', 'HP:0002890', (65, 67))	('AHNAK2', 'Gene', '113146', (213, 219))	('PTC', 'Gene', '5979', (64, 67))	('BRAF', 'Gene', (95, 99))	('expression', 'MPA', (149, 159))	('AHNAK2', 'Gene', (142, 148))	('PTC', 'Phenotype', 'HP:0002895', (64, 67))	('AHNAK2', 'Gene', '113146', (142, 148))
123379	32966238	reported that the methylation of AHNAK2 is associated with chemotherapy resistance in Epstein-Barr virus (EBV)-associated gastric cancer.	('EBV', 'Species', '10376', (106, 109))	('AHNAK2', 'Gene', '113146', (33, 39))	('chemotherapy resistance', 'MPA', (59, 82))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))	('gastric cancer', 'Disease', (122, 136))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('methylation', 'Var', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('associated', 'Reg', (43, 53))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('AHNAK2', 'Gene', (33, 39))	('Epstein-Barr virus', 'Disease', (86, 104))
123380	32966238	Our research on PTC epigenetics has also shown that methylation may act as an upstream regulatory mechanism of AHNAK2 expression to inhibit its biological function.	('inhibit', 'NegReg', (132, 139))	('PTC', 'Gene', (16, 19))	('TC', 'Phenotype', 'HP:0002890', (17, 19))	('PTC', 'Phenotype', 'HP:0002895', (16, 19))	('PTC', 'Gene', '5979', (16, 19))	('biological function', 'MPA', (144, 163))	('AHNAK2', 'Gene', (111, 117))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('methylation', 'Var', (52, 63))	('AHNAK2', 'Gene', '113146', (111, 117))
123389	32966238	AHNAK2 may promote the progression of PTC through cell adhesion-, cell junction-, and immune-related pathways, and methylation may serve as an upstream regulator to inhibit the expression and biological functions of AHNAK2.	('methylation', 'Var', (115, 126))	('cell junction-', 'CPA', (66, 80))	('cell adhesion', 'biological_process', 'GO:0007155', ('50', '63'))	('cell junction', 'cellular_component', 'GO:0030054', ('66', '79'))	('cell adhesion-', 'CPA', (50, 64))	('AHNAK2', 'Gene', (216, 222))	('AHNAK2', 'Gene', (0, 6))	('promote', 'PosReg', (11, 18))	('PTC', 'Gene', (38, 41))	('immune-related', 'CPA', (86, 100))	('AHNAK2', 'Gene', '113146', (216, 222))	('TC', 'Phenotype', 'HP:0002890', (39, 41))	('AHNAK2', 'Gene', '113146', (0, 6))	('inhibit', 'NegReg', (165, 172))	('PTC', 'Gene', '5979', (38, 41))	('expression', 'MPA', (177, 187))	('PTC', 'Phenotype', 'HP:0002895', (38, 41))	('methylation', 'biological_process', 'GO:0032259', ('115', '126'))
123411	32966238	We downloaded and visualized the correlation results between AHNAK2 methylation and clinical parameters from LinkedOmics.	('methylation', 'Var', (68, 79))	('AHNAK2', 'Gene', (61, 67))	('AHNAK2', 'Gene', '113146', (61, 67))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))
123424	32194746	Small interfering RNA-mediated knockdown of CDCA2 expression inhibited the viability and proliferation of 786-O and CAKI-1 cells, as measured by an MTT assay, colony formation assay and flow cytometry.	('proliferation', 'CPA', (89, 102))	('viability', 'CPA', (75, 84))	('inhibited', 'NegReg', (61, 70))	('CDCA2', 'Gene', (44, 49))	('CDCA2', 'Gene', '157313', (44, 49))	('RNA', 'cellular_component', 'GO:0005562', ('18', '21'))	('formation', 'biological_process', 'GO:0009058', ('166', '175'))	('MTT', 'Chemical', 'MESH:C070243', (148, 151))	('knockdown', 'Var', (31, 40))
123438	32194746	Furthermore, silencing the CDCA2 gene can lead to cell cycle arrest, inhibition of cell proliferation and apoptosis However, the expression of CDCA2 and its function in ccRCC remain unclear.	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))	('ccRCC', 'Disease', 'MESH:C538614', (169, 174))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (50, 67))	('cell proliferation', 'CPA', (83, 101))	('apoptosis', 'CPA', (106, 115))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('69', '101'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('50', '67'))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('CDCA2', 'Gene', (143, 148))	('CDCA2', 'Gene', '157313', (143, 148))	('CDCA2', 'Gene', (27, 32))	('CDCA2', 'Gene', '157313', (27, 32))	('cell cycle arrest', 'CPA', (50, 67))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('inhibition', 'NegReg', (69, 79))	('silencing', 'Var', (13, 22))	('ccRCC', 'Disease', (169, 174))
123440	32194746	Furthermore, silencing CDCA2 induced G1 arrest and promoted apoptosis in 786-O and CAKI-1 cells.	('G1 arrest', 'CPA', (37, 46))	('CDCA2', 'Gene', '157313', (23, 28))	('apoptosis', 'CPA', (60, 69))	('promoted', 'PosReg', (51, 59))	('apoptosis', 'biological_process', 'GO:0097194', ('60', '69'))	('apoptosis', 'biological_process', 'GO:0006915', ('60', '69'))	('silencing', 'Var', (13, 22))	('CDCA2', 'Gene', (23, 28))
123454	32194746	The effect of CDCA2 silencing on the proliferation of 786-O and CAKI-1 cells was assessed using an MTT assay.	('CDCA2', 'Gene', '157313', (14, 19))	('CDCA2', 'Gene', (14, 19))	('silencing', 'Var', (20, 29))	('MTT', 'Chemical', 'MESH:C070243', (99, 102))
123493	32194746	CDCA2 knockdown significantly inhibited ccRCC cell viability compared to the control group (both P<0.05; Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('CDCA2', 'Gene', (0, 5))	('inhibited', 'NegReg', (30, 39))	('ccRCC', 'Disease', (40, 45))	('CDCA2', 'Gene', '157313', (0, 5))	('ccRCC', 'Disease', 'MESH:C538614', (40, 45))	('knockdown', 'Var', (6, 15))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))
123495	32194746	Fewer and smaller colonies were observed in cells with CDCA2 knockdown compared with control cells (both P<0.05; Fig.	('colonies', 'CPA', (18, 26))	('smaller', 'NegReg', (10, 17))	('knockdown', 'Var', (61, 70))	('CDCA2', 'Gene', '157313', (55, 60))	('CDCA2', 'Gene', (55, 60))
123496	32194746	These data demonstrated that silencing of CDCA2 inhibits the growth of ccRCC cells, and that CDCA2 promotes ccRCC cell viability and proliferation.	('ccRCC', 'Disease', (108, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('ccRCC', 'Disease', 'MESH:C538614', (108, 113))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('ccRCC', 'Disease', (71, 76))	('inhibits', 'NegReg', (48, 56))	('silencing', 'Var', (29, 38))	('promotes', 'PosReg', (99, 107))	('ccRCC', 'Disease', 'MESH:C538614', (71, 76))	('CDCA2', 'Gene', (42, 47))	('CDCA2', 'Gene', '157313', (42, 47))	('CDCA2', 'Gene', (93, 98))	('CDCA2', 'Gene', '157313', (93, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('proliferation', 'CPA', (133, 146))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
123497	32194746	In order to determine whether cell cycle arrest drove the inhibition of cell proliferation that was observed with CDCA2 knockdown, flow cytometry was used to analyze cell cycle distribution 24 h post-transfection.	('CDCA2', 'Gene', (114, 119))	('cell cycle', 'biological_process', 'GO:0007049', ('166', '176'))	('knockdown', 'Var', (120, 129))	('cell proliferation', 'CPA', (72, 90))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('30', '47'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (30, 47))	('inhibition', 'NegReg', (58, 68))	('CDCA2', 'Gene', '157313', (114, 119))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('58', '90'))
123501	32194746	These results demonstrated that silencing CDCA2 inhibits the expression of cell cycle proteins in ccRCC cells, causing G1 arrest.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('inhibits', 'NegReg', (48, 56))	('ccRCC', 'Disease', (98, 103))	('ccRCC', 'Disease', 'MESH:C538614', (98, 103))	('causing', 'Reg', (111, 118))	('cell cycle proteins', 'Protein', (75, 94))	('CDCA2', 'Gene', (42, 47))	('G1 arrest', 'CPA', (119, 128))	('silencing', 'Var', (32, 41))	('CDCA2', 'Gene', '157313', (42, 47))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('expression', 'MPA', (61, 71))	('cell cycle', 'biological_process', 'GO:0007049', ('75', '85'))
123502	32194746	Dysfunction in apoptosis caused by the dysregulation of apoptosis-associated proteins plays an important role in the development of cancer.	('apoptosis', 'CPA', (15, 24))	('dysregulation', 'Var', (39, 52))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('apoptosis', 'biological_process', 'GO:0097194', ('15', '24'))	('apoptosis', 'biological_process', 'GO:0006915', ('15', '24'))	('apoptosis', 'biological_process', 'GO:0097194', ('56', '65'))	('apoptosis', 'biological_process', 'GO:0006915', ('56', '65'))	('apoptosis-associated proteins', 'Protein', (56, 85))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
123504	32194746	CDCA2 knockdown increased the proportion of 786-O and CAKI-1 apoptotic cells (Fig.	('786-O', 'CPA', (44, 49))	('CDCA2', 'Gene', (0, 5))	('CDCA2', 'Gene', '157313', (0, 5))	('increased', 'PosReg', (16, 25))	('knockdown', 'Var', (6, 15))	('CAKI-1 apoptotic cells', 'CPA', (54, 76))
123506	32194746	These results revealed that silencing CDCA2 induces apoptosis in ccRCC cells.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('CDCA2', 'Gene', (38, 43))	('CDCA2', 'Gene', '157313', (38, 43))	('ccRCC', 'Disease', (65, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('apoptosis', 'CPA', (52, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('52', '61'))	('ccRCC', 'Disease', 'MESH:C538614', (65, 70))	('silencing', 'Var', (28, 37))	('induces', 'Reg', (44, 51))	('apoptosis', 'biological_process', 'GO:0006915', ('52', '61'))
123510	32194746	DDR defects can lead to apoptosis, genomic instability, dysregulation of cells and an increased risk of cancer.	('lead to', 'Reg', (16, 23))	('genomic instability', 'CPA', (35, 54))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('DDR', 'Gene', (0, 3))	('apoptosis', 'CPA', (24, 33))	('apoptosis', 'biological_process', 'GO:0097194', ('24', '33'))	('defects', 'Var', (4, 11))	('apoptosis', 'biological_process', 'GO:0006915', ('24', '33'))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('dysregulation', 'MPA', (56, 69))
123513	32194746	The present study demonstrated that CDCA2 is widely upregulated in ccRCC, and the experiments in ccRCC cell lines revealed that CDCA2 knockdown can significantly inhibit cell proliferation by promoting G1 phase arrest and apoptosis.	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('apoptosis', 'CPA', (222, 231))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('CDCA2', 'Gene', '157313', (36, 41))	('CDCA2', 'Gene', (36, 41))	('G1 phase', 'biological_process', 'GO:0051318', ('202', '210'))	('upregulated', 'PosReg', (52, 63))	('G1 phase arrest', 'CPA', (202, 217))	('ccRCC', 'Disease', 'MESH:C538614', (67, 72))	('apoptosis', 'biological_process', 'GO:0097194', ('222', '231'))	('CDCA2', 'Gene', '157313', (128, 133))	('CDCA2', 'Gene', (128, 133))	('apoptosis', 'biological_process', 'GO:0006915', ('222', '231'))	('ccRCC', 'Disease', 'MESH:C538614', (97, 102))	('inhibit', 'NegReg', (162, 169))	('promoting', 'PosReg', (192, 201))	('ccRCC', 'Disease', (67, 72))	('cell proliferation', 'biological_process', 'GO:0008283', ('170', '188'))	('knockdown', 'Var', (134, 143))	('cell proliferation', 'CPA', (170, 188))	('ccRCC', 'Disease', (97, 102))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
123515	32194746	Since CDCA2 knockdown can cause G1 arrest in ccRCC cells, the present study assessed changes in cyclin D1 and CDK4 protein levels, key downstream regulators of the G1 to S transition.	('cyclin D1', 'Gene', (96, 105))	('G1 arrest', 'CPA', (32, 41))	('cause', 'Reg', (26, 31))	('CDCA2', 'Gene', (6, 11))	('knockdown', 'Var', (12, 21))	('CDCA2', 'Gene', '157313', (6, 11))	('cyclin', 'molecular_function', 'GO:0016538', ('96', '102'))	('CDK4', 'Gene', '1019', (110, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('CDK', 'molecular_function', 'GO:0004693', ('110', '113'))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('CDK4', 'Gene', (110, 114))	('cyclin D1', 'Gene', '595', (96, 105))	('ccRCC', 'Disease', (45, 50))	('ccRCC', 'Disease', 'MESH:C538614', (45, 50))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))
123516	32194746	CDK4 and cyclin D1 expression levels were demonstrated to be decreased in 786-O and CAKI-1 cells with CDCA2 knockdown.	('knockdown', 'Var', (108, 117))	('cyclin D1', 'Gene', '595', (9, 18))	('CDCA2', 'Gene', (102, 107))	('CDCA2', 'Gene', '157313', (102, 107))	('CDK', 'molecular_function', 'GO:0004693', ('0', '3'))	('cyclin D1', 'Gene', (9, 18))	('CDK4', 'Gene', (0, 4))	('expression levels', 'MPA', (19, 36))	('cyclin', 'molecular_function', 'GO:0016538', ('9', '15'))	('decreased', 'NegReg', (61, 70))	('CDK4', 'Gene', '1019', (0, 4))
123517	32194746	Similarly, it was observed that silencing of CDCA2 significantly downregulated the apoptosis-associated protein Bcl-2 in 786-O and CAKI-1 cells, consistent with the results of the apoptosis assays.	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('apoptosis', 'biological_process', 'GO:0097194', ('180', '189'))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('downregulated', 'NegReg', (65, 78))	('silencing', 'Var', (32, 41))	('apoptosis', 'biological_process', 'GO:0006915', ('180', '189'))	('Bcl-2', 'Gene', (112, 117))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('Bcl-2', 'Gene', '596', (112, 117))	('Bcl-2', 'molecular_function', 'GO:0015283', ('112', '117'))	('CDCA2', 'Gene', (45, 50))	('CDCA2', 'Gene', '157313', (45, 50))
123518	32194746	Overall, the results of the present study demonstrated that CDCA2 is upregulated in ccRCC, and knockdown of CDCA2 promotes G1 arrest by inhibiting the expression of CDK4 and cyclin D1.	('cyclin', 'molecular_function', 'GO:0016538', ('174', '180'))	('upregulated', 'PosReg', (69, 80))	('CDK4', 'Gene', '1019', (165, 169))	('CDCA2', 'Gene', '157313', (108, 113))	('CDCA2', 'Gene', (108, 113))	('ccRCC', 'Disease', 'MESH:C538614', (84, 89))	('CDCA2', 'Gene', (60, 65))	('CDCA2', 'Gene', '157313', (60, 65))	('promotes', 'PosReg', (114, 122))	('cyclin D1', 'Gene', (174, 183))	('ccRCC', 'Disease', (84, 89))	('inhibiting', 'NegReg', (136, 146))	('expression', 'MPA', (151, 161))	('cyclin D1', 'Gene', '595', (174, 183))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('G1 arrest', 'CPA', (123, 132))	('knockdown', 'Var', (95, 104))	('CDK4', 'Gene', (165, 169))	('CDK', 'molecular_function', 'GO:0004693', ('165', '168'))
123519	32194746	In addition, CDCA2 knockdown promoted apoptosis by inhibiting Bcl-2 expression.	('promoted', 'PosReg', (29, 37))	('Bcl-2', 'Gene', (62, 67))	('Bcl-2', 'Gene', '596', (62, 67))	('expression', 'MPA', (68, 78))	('knockdown', 'Var', (19, 28))	('apoptosis', 'biological_process', 'GO:0097194', ('38', '47'))	('CDCA2', 'Gene', (13, 18))	('apoptosis', 'CPA', (38, 47))	('CDCA2', 'Gene', '157313', (13, 18))	('apoptosis', 'biological_process', 'GO:0006915', ('38', '47'))	('inhibiting', 'NegReg', (51, 61))	('Bcl-2', 'molecular_function', 'GO:0015283', ('62', '67'))
123646	32496306	ciRS-7 knockdown in 786O and 769P cells markedly inhibited their proliferative and invasive abilities.	('knockdown', 'Var', (7, 16))	('inhibited', 'NegReg', (49, 58))	('ciRS-7', 'Gene', (0, 6))	('ciRS-7', 'Gene', '103611090', (0, 6))
123651	32496306	In addition to risk factors such as obesity, tobacco use, and hypertension, genetic mutations and abnormal post-translational protein modifications play crucial roles in the genesis and progression of tumors.	('genetic mutations', 'Var', (76, 93))	('obesity', 'Disease', 'MESH:D009765', (36, 43))	('obesity', 'Phenotype', 'HP:0001513', (36, 43))	('roles', 'Reg', (161, 166))	('obesity', 'Disease', (36, 43))	('hypertension', 'Disease', 'MESH:D006973', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tobacco', 'Species', '4097', (45, 52))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))	('hypertension', 'Disease', (62, 74))	('hypertension', 'Phenotype', 'HP:0000822', (62, 74))
123652	32496306	For instance, von Hippel-Lindau (VHL) gene mutations are common in majority of patients with ccRCC, and these mutations lead to ccRCC metastasis by promoting angiogenesis.	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('von Hippel-Lindau', 'Gene', (14, 31))	('mutations', 'Var', (110, 119))	('promoting', 'PosReg', (148, 157))	('lead to', 'Reg', (120, 127))	('VHL', 'Gene', (33, 36))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('angiogenesis', 'biological_process', 'GO:0001525', ('158', '170'))	('RCC', 'Disease', (95, 98))	('mutations', 'Var', (43, 52))	('VHL', 'Gene', '7428', (33, 36))	('angiogenesis', 'CPA', (158, 170))	('RCC', 'Disease', (130, 133))	('von Hippel-Lindau', 'Gene', '7428', (14, 31))	('patients', 'Species', '9606', (79, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('RCC', 'Disease', 'MESH:C538614', (130, 133))
123679	32496306	An aliquot of CCK-8 solution (10 muL) (Dojindo, Japan) was added to the plates at each time point and incubated at 37 C for 2 h, followed by the detection of the A450nm.	('A450nm', 'Var', (162, 168))	('muL', 'Gene', (33, 36))	('CCK-8', 'Chemical', '-', (14, 19))	('muL', 'Gene', '4591', (33, 36))
123696	32496306	The Kaplan-Meier plot demonstrated a shorter PFS in patients with high ciRS-7 expression compared with those with low ciRS-7 expression [Figure 1C].	('ciRS-7', 'Gene', (71, 77))	('ciRS-7', 'Gene', '103611090', (118, 124))	('PFS', 'MPA', (45, 48))	('ciRS-7', 'Gene', '103611090', (71, 77))	('patients', 'Species', '9606', (52, 60))	('high', 'Var', (66, 70))	('ciRS-7', 'Gene', (118, 124))	('shorter', 'NegReg', (37, 44))
123698	32496306	As shown in Figure 2B, the A450nm values of the cells transfected with the siRNAs were lower than those transfected with siNC, indicating that the silencing of ciRS-7 significantly suppressed the proliferative ability of the ccRCC cells.	('RCC', 'Disease', (227, 230))	('ciRS-7', 'Gene', (160, 166))	('RCC', 'Disease', 'MESH:C538614', (227, 230))	('suppressed', 'NegReg', (181, 191))	('siNC', 'Disease', (121, 125))	('ciRS-7', 'Gene', '103611090', (160, 166))	('ccRCC', 'Phenotype', 'HP:0006770', (225, 230))	('siNC', 'Disease', 'None', (121, 125))	('proliferative ability', 'CPA', (196, 217))	('silencing', 'Var', (147, 156))
123700	32496306	To this end, we performed transwell invasion assays with matrigel after silencing ciRS-7 in the cells.	('ciRS-7', 'Gene', (82, 88))	('ciRS-7', 'Gene', '103611090', (82, 88))	('silencing', 'Var', (72, 81))
123702	32496306	Since silencing ciRS-7 significantly suppressed the proliferative and invasive abilities of cells, we next investigated the possible mechanisms by which ciRS-7 promoted ccRCC progression.	('promoted', 'PosReg', (160, 168))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))	('ciRS-7', 'Gene', '103611090', (153, 159))	('ciRS-7', 'Gene', '103611090', (16, 22))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('RCC', 'Disease', (171, 174))	('silencing', 'Var', (6, 15))	('ciRS-7', 'Gene', (16, 22))	('suppressed', 'NegReg', (37, 47))	('ciRS-7', 'Gene', (153, 159))
123705	32496306	Our results demonstrated that ciRS-7 silencing resulted in reduced phosphorylated-EGFR (p-EGFR) expression, whereas total EGFR expression was not altered [Figure 3].	('EGFR', 'molecular_function', 'GO:0005006', ('82', '86'))	('EGFR', 'Gene', (82, 86))	('reduced', 'NegReg', (59, 66))	('ciRS-7', 'Gene', (30, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('122', '126'))	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('90', '94'))	('expression', 'MPA', (96, 106))	('silencing', 'Var', (37, 46))	('EGFR', 'Gene', (90, 94))	('ciRS-7', 'Gene', '103611090', (30, 36))	('EGFR', 'Gene', '1956', (82, 86))	('EGFR', 'Gene', '1956', (122, 126))	('EGFR', 'Gene', (122, 126))
123712	32496306	In addition, ciRS-7 silencing markedly inhibited ccRCC cell proliferation and invasion and contributed to inactivation of the EGFR/Akt signaling pathway.	('inhibited', 'NegReg', (39, 48))	('EGFR', 'Gene', (126, 130))	('Akt', 'Gene', (131, 134))	('invasion', 'CPA', (78, 86))	('ciRS-7', 'Gene', (13, 19))	('cell proliferation', 'biological_process', 'GO:0008283', ('55', '73'))	('EGFR', 'molecular_function', 'GO:0005006', ('126', '130'))	('signaling pathway', 'biological_process', 'GO:0007165', ('135', '152'))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('EGFR', 'Gene', '1956', (126, 130))	('Akt signaling', 'biological_process', 'GO:0043491', ('131', '144'))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('ciRS-7', 'Gene', '103611090', (13, 19))	('silencing', 'Var', (20, 29))	('inactivation', 'NegReg', (106, 118))	('Akt', 'Gene', '207', (131, 134))	('RCC', 'Disease', (51, 54))
123773	32028264	Based on the respective expression levels, we then established the following risk score formula: Risk score = (0.08995984 * SHC1) + (0.05754872 * IRF7) + (-0.13910054 * KDR) + (0.01889022 * JAK3) + (0.02791388 * CXCL5) The C-index of the risk score in the TCGA discovery set was 0.666 (95% confidence interval [CI], 0.603-0.729; Figure 1D).	('SHC1', 'Gene', '6464', (124, 128))	('IRF7', 'Gene', (146, 150))	('SHC1', 'Gene', (124, 128))	('JAK', 'molecular_function', 'GO:0004713', ('190', '193'))	('CXCL5', 'Gene', (212, 217))	('JAK3', 'Gene', (190, 194))	('CXCL5', 'Gene', '6374', (212, 217))	('IRF7', 'Gene', '3665', (146, 150))	('KDR', 'Gene', (169, 172))	('JAK3', 'Gene', '3718', (190, 194))	('KDR', 'Gene', '3791', (169, 172))	('0.08995984 *', 'Var', (111, 123))
123819	32028264	In contrast, the impact of SHC1 and IRF7 dysregulation in ccRCC remains unclear.	('IRF7', 'Gene', (36, 40))	('dysregulation', 'Var', (41, 54))	('IRF7', 'Gene', '3665', (36, 40))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('ccRCC', 'Disease', (58, 63))	('ccRCC', 'Disease', 'MESH:D002292', (58, 63))	('SHC1', 'Gene', '6464', (27, 31))	('SHC1', 'Gene', (27, 31))
123841	32028264	This would suggest that the antitumor effects of high T-cell infiltration are counterbalanced by strong immunosuppressive pathways activated by overexpressed immune checkpoint proteins.	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('high', 'Var', (49, 53))
124111	31859241	These studies were aided by the fact that the most commonly mutated genes in ccRCC are two hit tumor suppressor genes, and mutations result in loss of the protein.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('protein', 'Protein', (155, 162))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('95', '111'))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('loss', 'NegReg', (143, 147))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor suppressor', 'biological_process', 'GO:0051726', ('95', '111'))	('RCC', 'Disease', 'MESH:D002292', (79, 82))	('mutations', 'Var', (123, 132))	('tumor', 'Disease', (95, 100))	('RCC', 'Disease', (79, 82))
124118	31859241	In these tumors, the more advanced patterns continued to show loss of PBRM1, supporting the notion that loss of PBRM1 is a truncal event.	('loss', 'NegReg', (62, 66))	('PBRM1', 'Gene', (112, 117))	('loss', 'Var', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('PBRM1', 'Gene', (70, 75))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
124138	29390196	Segmental enhancement inversion was an independent predictor of oncocytomas (OR: 16.21 [1.0, 275.4], p=0.049), with moderate inter-reader agreement (kappa=0.49).	('oncocytomas', 'Disease', (64, 75))	('Segmental', 'Var', (0, 9))	('oncocytomas', 'Disease', 'MESH:D018249', (64, 75))	('men', 'Species', '9606', (3, 6))	('men', 'Species', '9606', (143, 146))	('men', 'Species', '9606', (17, 20))
124213	29390196	These authors also reported a sensitivity of 100% and specificity of 89% combining quantitative T2W and DCE-MRI, contrasting with our data, which did not show the degree of contrast enhancement or the enhancement characteristics on post-contrast multiphasic MRI to be significant predictors of mfAML histology.	('AML', 'Disease', (296, 299))	('men', 'Species', '9606', (189, 192))	('DCE-MRI', 'Var', (104, 111))	('men', 'Species', '9606', (208, 211))	('DCE', 'Chemical', '-', (104, 107))	('AML', 'Disease', 'MESH:D015470', (296, 299))
124229	29390196	Segmental enhancement inversion is an independent predictor of oncocytoma (OR: 16.21 [1.0, 275.4], p=0.049), although inter-reader agreement is only moderate (kappa=0.49).	('enhancement', 'PosReg', (10, 21))	('oncocytoma', 'Disease', 'MESH:D018249', (63, 73))	('Segmental', 'Var', (0, 9))	('men', 'Species', '9606', (3, 6))	('men', 'Species', '9606', (136, 139))	('oncocytoma', 'Disease', (63, 73))	('men', 'Species', '9606', (17, 20))
124233	29464030	Under-expression of CK2beta subunit in ccRCC represents a complementary biomarker of p-STAT3 Ser727 that correlates with patient survival Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of renal cancer.	('STAT3', 'Gene', (87, 92))	('CK2beta', 'Gene', (20, 27))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (149, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('subtype of renal cancer', 'Disease', (212, 235))	('STAT3', 'Gene', '6774', (87, 92))	('patient', 'Species', '9606', (121, 128))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (138, 169))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('Ser', 'cellular_component', 'GO:0005790', ('93', '96'))	('RCC', 'Disease', (41, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('Under-expression', 'Var', (0, 16))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('RCC', 'Disease', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('CK2beta', 'Gene', '1460', (20, 27))	('ccRCC', 'Phenotype', 'HP:0006770', (171, 176))	('subtype of renal cancer', 'Disease', 'MESH:D007680', (212, 235))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (138, 169))	('renal cancer', 'Phenotype', 'HP:0009726', (223, 235))	('Ser727', 'Chemical', '-', (93, 99))	('Clear cell renal cell carcinoma', 'Disease', (138, 169))
124251	29464030	STAT3 activation is reflected through its phosphorylation at Tyr705 and Ser727 residues, both of which are increased in ccRCC tumors.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (120, 125))	('increased', 'PosReg', (107, 116))	('phosphorylation', 'MPA', (42, 57))	('ccRCC tumors', 'Disease', (120, 132))	('STAT3', 'Gene', '6774', (0, 5))	('Ser727', 'Chemical', '-', (72, 78))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('Tyr705', 'Chemical', '-', (61, 67))	('STAT3', 'Gene', (0, 5))	('Ser', 'cellular_component', 'GO:0005790', ('72', '75'))	('Ser727 residues', 'Var', (72, 87))	('ccRCC tumors', 'Disease', 'MESH:D009369', (120, 132))
124254	29464030	Moreover, CK2 activity is necessary for STAT3 activation by IL-6 family cytokines and cell treatment with CK2 inhibitors affect STAT3 phosphorylation on Ser727.	('men', 'Species', '9606', (96, 99))	('affect', 'Reg', (121, 127))	('CK2', 'Gene', '13000', (106, 109))	('STAT3', 'Gene', '6774', (128, 133))	('CK2', 'Gene', '13000', (10, 13))	('IL-6', 'Gene', (60, 64))	('IL-6', 'molecular_function', 'GO:0005138', ('60', '64'))	('STAT3', 'Gene', (128, 133))	('STAT3', 'Gene', '6774', (40, 45))	('IL-6', 'Gene', '3569', (60, 64))	('Ser', 'cellular_component', 'GO:0005790', ('153', '156'))	('STAT3', 'Gene', (40, 45))	('phosphorylation', 'biological_process', 'GO:0016310', ('134', '149'))	('CK2', 'Gene', (106, 109))	('Ser727', 'Chemical', '-', (153, 159))	('CK2', 'Gene', (10, 13))	('inhibitors', 'Var', (110, 120))
124273	29464030	The CK2alpha' values in the G3/G4 tumors were dispersed and the number of tumors too low to reach statistical significance when compared with values observed in G1/G2 tumors.	("CK2alpha'", 'Gene', (4, 13))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('G3/G4', 'Var', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	("CK2alpha'", 'Gene', '1459', (4, 13))	('tumors', 'Disease', (167, 173))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumors', 'Disease', (74, 80))
124275	29464030	On the other hand, CK2beta subunit (6D5 antibody) increased in the G1/G2 group but decreased in the more advanced tumors (G3/G4).	('antibody', 'cellular_component', 'GO:0042571', ('40', '48'))	('advanced tumors', 'Disease', (105, 120))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('decreased', 'NegReg', (83, 92))	('increased', 'PosReg', (50, 59))	('antibody', 'cellular_component', 'GO:0019814', ('40', '48'))	('CK2beta', 'Gene', (19, 26))	('antibody', 'cellular_component', 'GO:0019815', ('40', '48'))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('CK2beta', 'Gene', '1460', (19, 26))	('advanced tumors', 'Disease', 'MESH:D020178', (105, 120))	('antibody', 'molecular_function', 'GO:0003823', ('40', '48'))	('G1/G2', 'Var', (67, 72))
124298	29464030	In contrast to CK2alpha/alpha', nuclear CK2beta staining showed only moderate increases in tumor samples whereas cytosolic CK2beta showed a significant decline in G1/G2 that was particularly marked in G3/G4 samples (Figure 2C, left panel).	('CK2beta', 'Gene', '1460', (123, 130))	('CK2alpha', 'Gene', '1459', (15, 23))	('CK2beta', 'Gene', '1460', (40, 47))	('CK2alpha', 'Gene', (15, 23))	('decline', 'NegReg', (152, 159))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('CK2beta', 'Gene', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('G3/G4', 'Var', (201, 206))	('tumor', 'Disease', (91, 96))	('CK2beta', 'Gene', (123, 130))	('G1/G2', 'MPA', (163, 168))
124308	29464030	Lentiviral transduction of shRNA-CK2alpha caused the stable silencing of CK2alpha to about 40-50% of the initial value both in 786-O and HK-2 cell lines, as compared with their respective empty-vector transduced cells (shCV) (Figure 3A).	('Lentiviral', 'Var', (0, 10))	('HK-2', 'molecular_function', 'GO:0008256', ('137', '141'))	('transduction', 'biological_process', 'GO:0009293', ('11', '23'))	('CK2alpha', 'Gene', '1459', (33, 41))	('CK2alpha', 'Gene', (33, 41))	('transduction', 'Var', (11, 23))	('silencing', 'NegReg', (60, 69))	('HK-2', 'Gene', '3099', (137, 141))	('CK2alpha', 'Gene', '1459', (73, 81))	('HK-2', 'Gene', (137, 141))	('CK2alpha', 'Gene', (73, 81))
124311	29464030	Lentiviral transduction of shRNA-CK2beta provoked a decrease in CK2beta to about 30% of the initial value in 786-O and to less than 10% in HK-2 cells.	('Lentiviral', 'Var', (0, 10))	('transduction', 'biological_process', 'GO:0009293', ('11', '23'))	('HK-2', 'Gene', '3099', (139, 143))	('HK-2', 'molecular_function', 'GO:0008256', ('139', '143'))	('CK2beta', 'Gene', (33, 40))	('HK-2', 'Gene', (139, 143))	('CK2beta', 'Gene', (64, 71))	('CK2beta', 'Gene', '1460', (33, 40))	('decrease', 'NegReg', (52, 60))	('CK2beta', 'Gene', '1460', (64, 71))
124321	29464030	This agrees with that observed recently in C2C12 myoblast cell line after knocking out CK2 subunits.	('CK2', 'Gene', '13000', (87, 90))	('knocking out', 'Var', (74, 86))	('C2C12', 'CellLine', 'CVCL:0188', (43, 48))	('CK2', 'Gene', (87, 90))
124326	29464030	In both cell lines, silencing of CK2alpha, and in particular of CK2beta, caused a marked decrease in E-cadherin.	('cadherin', 'molecular_function', 'GO:0008014', ('103', '111'))	('E-cadherin', 'Gene', (101, 111))	('E-cadherin', 'Gene', '999', (101, 111))	('decrease', 'NegReg', (89, 97))	('CK2alpha', 'Gene', '1459', (33, 41))	('CK2alpha', 'Gene', (33, 41))	('CK2beta', 'Gene', (64, 71))	('silencing', 'Var', (20, 29))	('CK2beta', 'Gene', '1460', (64, 71))
124328	29464030	In agreement with this, CK2beta silencing caused an increase in snail1 protein levels in 786-O and in HK-2 cells although both basal and stimulated levels were more robust in 786-O cells (Figure 4A).	('snail1', 'Gene', (64, 70))	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('CK2beta', 'Gene', (24, 31))	('snail1', 'Gene', '6615', (64, 70))	('increase', 'PosReg', (52, 60))	('CK2beta', 'Gene', '1460', (24, 31))	('men', 'Species', '9606', (8, 11))	('silencing', 'Var', (32, 41))	('HK-2', 'molecular_function', 'GO:0008256', ('102', '106'))	('HK-2', 'Gene', '3099', (102, 106))	('HK-2', 'Gene', (102, 106))
124334	29464030	To this purpose, HK-2 cells were transfected with a vector containing a synthetic CK2beta optimized coding sequence carrying base mutations that would weaken its recognition by the shCK2beta without introducing any mutation into the CK2beta expressed protein.	('HK-2', 'Gene', (17, 21))	('CK2beta', 'Gene', '1460', (233, 240))	('recognition', 'MPA', (162, 173))	('CK2beta', 'Gene', (183, 190))	('HK-2', 'molecular_function', 'GO:0008256', ('17', '21'))	('base mutations', 'Var', (125, 139))	('CK2beta', 'Gene', '1460', (183, 190))	('weaken', 'NegReg', (151, 157))	('protein', 'cellular_component', 'GO:0003675', ('251', '258'))	('HK-2', 'Gene', '3099', (17, 21))	('CK2beta', 'Gene', (82, 89))	('CK2beta', 'Gene', '1460', (82, 89))	('CK2beta', 'Gene', (233, 240))
124343	29464030	STAT3 phosphorylation has been shown to affect HIF-2alpha levels in 786-O cells and HIF-1alpha and HIF-2alpha in Caki-1 renal cancer cells, and STAT3 phosphorylation at Tyr705 and Ser727 residues is increased in ccRCC tumors.	('ccRCC tumors', 'Disease', 'MESH:D009369', (212, 224))	('Ser727 residues', 'Var', (180, 195))	('phosphorylation', 'biological_process', 'GO:0016310', ('6', '21'))	('STAT3', 'Gene', '6774', (0, 5))	('STAT3', 'Gene', '6774', (144, 149))	('HIF-1alpha and HIF-2alpha in Caki-1 renal cancer', 'Disease', 'MESH:D007680', (84, 132))	('Ser', 'cellular_component', 'GO:0005790', ('180', '183'))	('HIF-2alpha', 'Gene', (99, 109))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('HIF-2alpha', 'Gene', '2034', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (212, 217))	('Tyr705', 'Chemical', '-', (169, 175))	('Ser727', 'Chemical', '-', (180, 186))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('increased', 'PosReg', (199, 208))	('phosphorylation', 'biological_process', 'GO:0016310', ('150', '165'))	('renal cancer', 'Phenotype', 'HP:0009726', (120, 132))	('RCC', 'Phenotype', 'HP:0005584', (214, 217))	('HIF-2alpha', 'Gene', (47, 57))	('ccRCC tumors', 'Disease', (212, 224))	('affect', 'Reg', (40, 46))	('STAT3', 'Gene', (0, 5))	('HIF-2alpha', 'Gene', '2034', (99, 109))	('STAT3', 'Gene', (144, 149))
124344	29464030	Previous reports have shown that exposure of cells to CK2 chemical inhibitors (which block the activity of both CK2 holoenzyme and free catalytic subunits) TBB or CX-4945 diminished p-STAT3 Tyr705 as well as p-STAT3 Ser727 phosphorylation in response to different stimuli.	('Ser', 'cellular_component', 'GO:0005790', ('216', '219'))	('STAT3', 'Gene', '6774', (210, 215))	('diminished', 'NegReg', (171, 181))	('CX-4945', 'Var', (163, 170))	('STAT3', 'Gene', '6774', (184, 189))	('STAT3', 'Gene', (210, 215))	('TBB', 'Var', (156, 159))	('CK2', 'Gene', (54, 57))	('STAT3', 'Gene', (184, 189))	('Tyr705', 'Chemical', '-', (190, 196))	('Ser727', 'Chemical', '-', (216, 222))	('CK2', 'Gene', (112, 115))	('phosphorylation', 'biological_process', 'GO:0016310', ('223', '238'))	('CK2', 'Gene', '13000', (54, 57))	('TBB', 'Chemical', '-', (156, 159))	('CK2', 'Gene', '13000', (112, 115))
124345	29464030	More recently, recombinant human CK2 holoenzyme has been shown to phosphorylate 'in vitro' recombinant human STAT3 on Ser727 but the potential role of CK2beta in regulating STAT3 phosphorylation, in particular at Ser727, was not evaluated.	('CK2beta', 'Gene', (151, 158))	('CK2', 'Gene', '13000', (151, 154))	('STAT3', 'Gene', '6774', (173, 178))	('phosphorylation', 'biological_process', 'GO:0016310', ('179', '194'))	('human', 'Species', '9606', (103, 108))	('CK2beta', 'Gene', '1460', (151, 158))	('Ser727', 'Chemical', '-', (213, 219))	('human', 'Species', '9606', (27, 32))	('STAT3', 'Gene', (173, 178))	('Ser', 'cellular_component', 'GO:0005790', ('213', '216'))	('CK2', 'Gene', (33, 36))	('STAT3', 'Gene', '6774', (109, 114))	('Ser727', 'Var', (118, 124))	('Ser727', 'Chemical', '-', (118, 124))	('Ser', 'cellular_component', 'GO:0005790', ('118', '121'))	('CK2', 'Gene', (151, 154))	('STAT3', 'Gene', (109, 114))	('CK2', 'Gene', '13000', (33, 36))
124348	29464030	In contrast p-STAT3 Ser727 levels tended to decrease after CK2alpha silencing and decreased significantly after CK2beta silencing.	('STAT3', 'Gene', (14, 19))	('CK2beta', 'Gene', '1460', (112, 119))	('decrease', 'NegReg', (44, 52))	('Ser727', 'Chemical', '-', (20, 26))	('Ser', 'cellular_component', 'GO:0005790', ('20', '23'))	('CK2alpha', 'Gene', '1459', (59, 67))	('CK2beta', 'Gene', (112, 119))	('silencing', 'Var', (68, 77))	('STAT3', 'Gene', '6774', (14, 19))	('decreased', 'NegReg', (82, 91))	('CK2alpha', 'Gene', (59, 67))
124349	29464030	Downregulation of CK2alpha did not significantly alter STAT3 phosphorylation at Tyr705 in 786-O cells whereas CK2beta downregulation caused a small but significant increase in p-STAT3 Tyr705.	('downregulation', 'NegReg', (118, 132))	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))	('CK2beta', 'Gene', (110, 117))	('STAT3', 'Gene', (55, 60))	('Tyr705', 'Chemical', '-', (80, 86))	('Tyr705', 'Chemical', '-', (184, 190))	('Downregulation', 'Var', (0, 14))	('CK2beta', 'Gene', '1460', (110, 117))	('CK2alpha', 'Gene', '1459', (18, 26))	('STAT3', 'Gene', '6774', (178, 183))	('STAT3', 'Gene', '6774', (55, 60))	('increase', 'PosReg', (164, 172))	('STAT3', 'Gene', (178, 183))	('CK2alpha', 'Gene', (18, 26))
124356	29464030	When analyzing all patients together, we observed a negative but non-significant correlation between p-STAT3 Ser727 and cytosolic CK2beta with Spearman Index of -0.057.	('Ser727', 'Chemical', '-', (109, 115))	('patients', 'Species', '9606', (19, 27))	('STAT3', 'Gene', (103, 108))	('CK2beta', 'Gene', (130, 137))	('negative', 'NegReg', (52, 60))	('CK2beta', 'Gene', '1460', (130, 137))	('STAT3', 'Gene', '6774', (103, 108))	('Ser727', 'Var', (109, 115))	('Ser', 'cellular_component', 'GO:0005790', ('109', '112'))	('cytosolic', 'MPA', (120, 129))
124357	29464030	Although the correlation was weak between both factors, we aimed to explore the impact, if any, of CK2betacyt higher or equal 41 (median value) on the survival profile of patients with p-STAT3 Ser727 levels >100 or <100, which were previously correlated with poor or good prognosis, according to patient survival, respectively.	('STAT3', 'Gene', '6774', (187, 192))	('patient', 'Species', '9606', (171, 178))	('patient', 'Species', '9606', (296, 303))	('STAT3', 'Gene', (187, 192))	('patients', 'Species', '9606', (171, 179))	('<100', 'Var', (215, 219))	('CK2beta', 'Gene', (99, 106))	('Ser727', 'Chemical', '-', (193, 199))	('CK2beta', 'Gene', '1460', (99, 106))	('Ser', 'cellular_component', 'GO:0005790', ('193', '196'))
124386	29464030	Activator of transcription STAT3 is a potent regulator of HIF-1alpha and HIF-2alpha expression and STAT3 phosphorylation at Tyr705 and Ser727 residues is increased in ccRCC tumors.	('phosphorylation', 'MPA', (105, 120))	('transcription', 'biological_process', 'GO:0006351', ('13', '26'))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('ccRCC', 'Phenotype', 'HP:0006770', (167, 172))	('Tyr705', 'Chemical', '-', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('Ser', 'cellular_component', 'GO:0005790', ('135', '138'))	('Ser727', 'Chemical', '-', (135, 141))	('increased', 'PosReg', (154, 163))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (58, 83))	('ccRCC tumors', 'Disease', (167, 179))	('STAT3', 'Gene', (99, 104))	('ccRCC tumors', 'Disease', 'MESH:D009369', (167, 179))	('STAT3', 'Gene', (27, 32))	('Ser727 residues', 'Var', (135, 150))	('STAT3', 'Gene', '6774', (99, 104))	('STAT3', 'Gene', '6774', (27, 32))	('phosphorylation', 'biological_process', 'GO:0016310', ('105', '120'))
124387	29464030	Previous reports have shown that CK2 modulates STAT3 activation since TBB and CX-4945 (two CK2 chemical inhibitors that block the activity of both CK2 holoenzyme and free catalytic subunits) diminished STAT3 phosphorylation on Tyr705 and Ser727 residues triggered in response to different stimuli in cultured cells.	('CK2', 'Gene', '13000', (147, 150))	('Tyr705', 'Chemical', '-', (227, 233))	('STAT3', 'Gene', (202, 207))	('CK2', 'Gene', (91, 94))	('CK2', 'Gene', '13000', (33, 36))	('STAT3', 'Gene', '6774', (47, 52))	('phosphorylation', 'biological_process', 'GO:0016310', ('208', '223'))	('CK2', 'Gene', (33, 36))	('STAT3', 'Gene', (47, 52))	('CK2', 'Gene', '13000', (91, 94))	('Ser727', 'Var', (238, 244))	('Ser727', 'Chemical', '-', (238, 244))	('CK2', 'Gene', (147, 150))	('TBB', 'Chemical', '-', (70, 73))	('Ser', 'cellular_component', 'GO:0005790', ('238', '241'))	('STAT3', 'Gene', '6774', (202, 207))	('diminished', 'NegReg', (191, 201))
124388	29464030	STAT3 phosphorylation at Tyr705 is catalyzed by Jak1 or Jak2 kinases and both are activated by binding to CK2.	('Jak1', 'Gene', (48, 52))	('Jak2', 'Gene', '3717', (56, 60))	('CK2', 'Gene', '13000', (106, 109))	('Tyr705', 'Chemical', '-', (25, 31))	('Jak', 'molecular_function', 'GO:0004713', ('56', '59'))	('Jak', 'molecular_function', 'GO:0004713', ('48', '51'))	('phosphorylation', 'biological_process', 'GO:0016310', ('6', '21'))	('STAT3', 'Gene', '6774', (0, 5))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))	('Jak1', 'Gene', '3716', (48, 52))	('CK2', 'Gene', (106, 109))	('STAT3', 'Gene', (0, 5))	('binding', 'Interaction', (95, 102))	('at Tyr705', 'Var', (22, 31))	('Jak2', 'Gene', (56, 60))
124391	29464030	As far as STAT3 phosphorylation on Ser727, overexpression of CK2 has been shown to decrease it in C6 glioma cells through a mechanism involving CK2 activation of protein phosphatase PP2A.	('Ser', 'cellular_component', 'GO:0005790', ('35', '38'))	('activation', 'PosReg', (148, 158))	('CK2', 'Gene', (61, 64))	('Ser727', 'Chemical', '-', (35, 41))	('overexpression', 'Var', (43, 57))	('C6 glioma', 'Disease', (98, 107))	('decrease', 'NegReg', (83, 91))	('C6 glioma', 'Disease', 'MESH:C567307', (98, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('PP2A', 'Gene', '5524', (182, 186))	('CK2', 'Gene', '13000', (144, 147))	('phosphorylation', 'biological_process', 'GO:0016310', ('16', '31'))	('CK2', 'Gene', (144, 147))	('STAT3', 'Gene', (10, 15))	('phosphatase', 'molecular_function', 'GO:0016791', ('170', '181'))	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('STAT3', 'Gene', '6774', (10, 15))	('PP2A', 'Gene', (182, 186))	('CK2', 'Gene', '13000', (61, 64))
124393	29464030	These authors also indicate that STAT3 phosphorylation on Ser727 in chronic lymphocytic leukemia (CLL) is more elaborate since it requires the assembly of a CK2/CD5/B-Cell Linker Protein (BLNK)/STAT3 complex.	('BLNK', 'Gene', '29760', (188, 192))	('STAT3', 'Gene', '6774', (33, 38))	('Ser727', 'Chemical', '-', (58, 64))	('phosphorylation', 'biological_process', 'GO:0016310', ('39', '54'))	('Ser', 'cellular_component', 'GO:0005790', ('58', '61'))	('CLL', 'Disease', 'MESH:D015451', (98, 101))	('CLL', 'Phenotype', 'HP:0005550', (98, 101))	('Ser727', 'Var', (58, 64))	('STAT3', 'Gene', (194, 199))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (68, 96))	('CK2/CD5/B-Cell Linker Protein', 'Gene', '29760;921', (157, 186))	('STAT3', 'Gene', '6774', (194, 199))	('chronic lymphocytic leukemia', 'Disease', (68, 96))	('BLNK', 'Gene', (188, 192))	('CK2/CD5/B-Cell Linker Protein', 'Gene', (157, 186))	('STAT3', 'Gene', (33, 38))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (68, 96))	('leukemia', 'Phenotype', 'HP:0001909', (88, 96))	('CLL', 'Disease', (98, 101))
124399	29464030	We have recently observed that STAT3 phosphorylation both at Tyr705 and Ser727 residues is increased in ccRCC tumor samples, and that Ser727 is an independent prognostic factor in ccRCC.	('Ser', 'cellular_component', 'GO:0005790', ('134', '137'))	('Tyr705', 'Chemical', '-', (61, 67))	('STAT3', 'Gene', (31, 36))	('Ser727', 'Var', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('Ser727', 'Chemical', '-', (72, 78))	('phosphorylation', 'biological_process', 'GO:0016310', ('37', '52'))	('Ser', 'cellular_component', 'GO:0005790', ('72', '75'))	('increased', 'PosReg', (91, 100))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('RCC', 'Disease', (106, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))	('STAT3', 'Gene', '6774', (31, 36))	('Ser727', 'Chemical', '-', (134, 140))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('RCC', 'Disease', (182, 185))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('Ser727', 'Var', (72, 78))	('tumor', 'Disease', (110, 115))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
124429	29464030	Secondary antibodies were obtained from Bio-Rad: IgG Goat Anti-Rabbit IgG (H+L)-HRP conjugate (170-6515, BioRad) and IgG Goat-Anti Mouse IgG (H+L)-HRP conjugate (170-6516, BioRad).	('170-6515', 'Var', (95, 103))	('Rabbit', 'Species', '9986', (63, 69))	('Rad', 'Gene', (108, 111))	('Mouse', 'Species', '10090', (131, 136))	('Goat', 'Species', '9925', (53, 57))	('Rad', 'Gene', '6236', (108, 111))	('170-6516', 'Var', (162, 170))	('Rad', 'Gene', (44, 47))	('Rad', 'Gene', '6236', (44, 47))	('Goat', 'Species', '9925', (121, 125))	('Rad', 'biological_process', 'GO:1990116', ('44', '47'))	('Rad', 'Gene', '6236', (175, 178))	('Rad', 'Gene', (175, 178))
124438	29229903	Loss of PBRM1 rescues VHL dependent replication stress to promote renal carcinogenesis Inactivation of the VHL (Von Hippel Lindau) tumour suppressor has long been recognised as necessary for the pathogenesis of clear cell renal cancer (ccRCC); however, the molecular mechanisms underlying transformation and the requirement for additional genetic hits remain unclear.	('renal cancer', 'Phenotype', 'HP:0009726', (222, 234))	('VHL', 'Gene', (22, 25))	('clear cell renal cancer', 'Phenotype', 'HP:0006770', (211, 234))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('renal carcinogenesis', 'Disease', 'MESH:D007674', (66, 86))	('pathogenesis', 'biological_process', 'GO:0009405', ('195', '207'))	('VHL (Von Hippel Lindau) tumour', 'Disease', 'MESH:D006623', (107, 137))	('VHL', 'Gene', '22346', (22, 25))	('VHL', 'Gene', (107, 110))	('clear cell renal cancer', 'Disease', (211, 234))	('PBRM1', 'Gene', (8, 13))	('RCC', 'Phenotype', 'HP:0005584', (238, 241))	('RCC', 'Disease', (238, 241))	('PBRM1', 'Gene', '66923', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('clear cell renal cancer', 'Disease', 'MESH:C538614', (211, 234))	('Loss', 'Var', (0, 4))	('VHL', 'Gene', '22346', (107, 110))	('RCC', 'Disease', 'MESH:C538614', (238, 241))	('ccRCC', 'Phenotype', 'HP:0006770', (236, 241))	('renal carcinogenesis', 'Disease', (66, 86))
124439	29229903	By contrast, concomitant loss of the chromatin remodelling factor PBRM1 (mutated in 40% of ccRCC) rescues VHL-induced replication stress, maintaining cellular fitness and allowing proliferation.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('maintaining', 'PosReg', (138, 149))	('rescues', 'PosReg', (98, 105))	('mutated', 'Var', (73, 80))	('RCC', 'Disease', (93, 96))	('rat', 'Species', '10116', (187, 190))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('chromatin', 'cellular_component', 'GO:0000785', ('37', '46'))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('37', '58'))	('PBRM1', 'Gene', (66, 71))	('VHL-induced replication stress', 'MPA', (106, 136))	('loss', 'NegReg', (25, 29))	('cellular fitness', 'CPA', (150, 166))
124440	29229903	In line with these data we demonstrate that combined deletion of Vhl and Pbrm1 in the mouse kidney is sufficient for the development of fully-penetrant, multifocal carcinomas, closely mimicking human ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (202, 205))	('fully-penetrant', 'CPA', (136, 151))	('multifocal carcinomas', 'Phenotype', 'HP:0006625', (153, 174))	('mouse', 'Species', '10090', (86, 91))	('deletion', 'Var', (53, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (200, 205))	('human', 'Species', '9606', (194, 199))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('rat', 'Species', '10116', (34, 37))	('Vhl', 'Gene', (65, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))	('RCC', 'Disease', (202, 205))	('multifocal carcinomas', 'Disease', (153, 174))	('multifocal carcinomas', 'Disease', 'None', (153, 174))	('Pbrm1', 'Gene', (73, 78))
124441	29229903	Our results illustrate how VHL and PBRM1 co-operate to drive renal transformation and uncover replication stress as an underlying vulnerability of all VHL mutated renal cancers that could be therapeutically exploited.	('rat', 'Species', '10116', (18, 21))	('mutated', 'Var', (155, 162))	('renal cancers', 'Disease', 'MESH:D007680', (163, 176))	('rat', 'Species', '10116', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('renal cancers', 'Disease', (163, 176))	('renal cancer', 'Phenotype', 'HP:0009726', (163, 175))	('VHL', 'Gene', (151, 154))	('drive', 'PosReg', (55, 60))	('PBRM1', 'Gene', (35, 40))	('renal transformation', 'CPA', (61, 81))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
124442	29229903	Mutations in VHL have been linked to clear cell renal cancer, but the molecular mechanisms involved remain unclear.	('linked', 'Reg', (27, 33))	('clear cell renal cancer', 'Phenotype', 'HP:0006770', (37, 60))	('VHL', 'Gene', (13, 16))	('renal cancer', 'Phenotype', 'HP:0009726', (48, 60))	('Mutations', 'Var', (0, 9))	('clear cell renal cancer', 'Disease', 'MESH:C538614', (37, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('clear cell renal cancer', 'Disease', (37, 60))
124443	29229903	Here the authors generate a mouse model closely mimicking the human disease and show that VHL loss induces DNA replication stress that is rescued by the concomitant loss of PBRM1 permitting transformation.	('PBRM1', 'Gene', (173, 178))	('induces', 'Reg', (99, 106))	('mouse', 'Species', '10090', (28, 33))	('human', 'Species', '9606', (62, 67))	('DNA replication', 'biological_process', 'GO:0006260', ('107', '122'))	('VHL loss', 'Disease', 'MESH:D006623', (90, 98))	('DNA replication stress', 'MPA', (107, 129))	('rat', 'Species', '10116', (21, 24))	('VHL loss', 'Disease', (90, 98))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))	('loss', 'Var', (165, 169))
124447	29229903	Clear cell RCC (ccRCC), the commonest histological subtype, is characterised by the inactivation of VHL tumour suppressor gene.	('RCC', 'Disease', (18, 21))	('RCC', 'Phenotype', 'HP:0005584', (18, 21))	('inactivation', 'Var', (84, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (16, 21))	('VHL tumour', 'Disease', (100, 110))	('VHL tumour', 'Disease', 'MESH:D006623', (100, 110))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (18, 21))
124448	29229903	VHL is responsible for the ccRCC-predisposing syndrome, von Hippel-Lindau and is inactivated by either mutation or methylation in over 80% of sporadic cases.	('methylation', 'Var', (115, 126))	('von Hippel-Lindau', 'Disease', (56, 73))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('VHL', 'Gene', (0, 3))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (56, 73))	('responsible', 'Reg', (7, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (27, 32))	('mutation', 'Var', (103, 111))	('methylation', 'biological_process', 'GO:0032259', ('115', '126'))
124449	29229903	Chromosome 3p loss and VHL mutation or methylation, are early, truncal events during RCC development and therefore considered crucial for renal transformation.	('Chromosome', 'Gene', (0, 10))	('methylation', 'Var', (39, 50))	('VHL', 'Gene', (23, 26))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('mutation', 'Var', (27, 35))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', (85, 88))	('loss', 'NegReg', (14, 18))
124450	29229903	VHL is implicated in a number of cellular functions, disruption of any or all of which could contribute to carcinogenesis.	('disruption', 'Var', (53, 63))	('contribute', 'Reg', (93, 103))	('VHL', 'Gene', (0, 3))	('implicated', 'Reg', (7, 17))	('carcinogenesis', 'Disease', 'MESH:D063646', (107, 121))	('carcinogenesis', 'Disease', (107, 121))
124454	29229903	Second, large-scale sequencing efforts have shown that biallelic intragenic VHL mutations are not observed in sporadic ccRCC but instead one copy of the gene is always lost as a part of chromosome 3p deletion, simultaneously affecting a number of other genes.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('VHL', 'Gene', (76, 79))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('mutations', 'Var', (80, 89))	('lost', 'NegReg', (168, 172))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('chromosome', 'cellular_component', 'GO:0005694', ('186', '196'))	('affecting', 'Reg', (225, 234))
124455	29229903	Third, deletion of Vhl or activation of its main downstream effectors (Hif1a/Hif2a) within the mouse kidney does not lead to tumour development.	('Hif2a', 'Gene', '13819', (77, 82))	('Hif1a', 'Gene', '15251', (71, 76))	('Vhl', 'Gene', (19, 22))	('Hif2a', 'Gene', (77, 82))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('Hif1a', 'Gene', (71, 76))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('tumour', 'Disease', (125, 131))	('deletion', 'Var', (7, 15))	('mouse', 'Species', '10090', (95, 100))
124459	29229903	Our data show that loss of VHL alone induces replication stress and DNA damage accumulation, responses that curtail cellular proliferation and transformation.	('induces', 'Reg', (37, 44))	('rat', 'Species', '10116', (132, 135))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('cellular proliferation', 'CPA', (116, 138))	('replication', 'MPA', (45, 56))	('curtail', 'NegReg', (108, 115))	('loss', 'Var', (19, 23))	('VHL', 'Gene', (27, 30))	('transformation', 'CPA', (143, 157))	('DNA damage accumulation', 'MPA', (68, 91))
124460	29229903	Significantly, the concomitant loss of PBRM1 rescues VHL-dependent replication stress, conferring a survival and proliferative advantage and thereby permitting renal carcinogenesis.	('VHL-dependent replication stress', 'MPA', (53, 85))	('permitting renal carcinogenesis', 'Disease', (149, 180))	('rescues', 'PosReg', (45, 52))	('loss', 'Var', (31, 35))	('proliferative advantage', 'CPA', (113, 136))	('survival', 'CPA', (100, 108))	('permitting renal carcinogenesis', 'Disease', 'MESH:D007674', (149, 180))	('rat', 'Species', '10116', (120, 123))	('PBRM1', 'Gene', (39, 44))
124462	29229903	To identify interactions arising from the concurrent loss of VHL and PBRM1 within the context of normal cellular physiology, we generated primary mouse embryonic fibroblasts (MEFs) from either wild-type (WT), Vhl fl/fl, Pbrm1 fl/fl or double-mutant (Vhl fl/fl;Pbrm1 fl/fl) conditional mice.	('Pbrm1', 'Gene', (260, 265))	('rat', 'Species', '10116', (132, 135))	('MEFs', 'CellLine', 'CVCL:9115', (175, 179))	('mice', 'Species', '10090', (285, 289))	('mouse', 'Species', '10090', (146, 151))	('PBRM1', 'Gene', (69, 74))	('interactions', 'Interaction', (12, 24))	('fl/fl', 'Var', (226, 231))	('Pbrm1', 'Gene', (220, 225))	('WT', 'Disease', 'MESH:C536751', (204, 206))	('double-mutant', 'Var', (235, 248))
124472	29229903	To ascertain the relevance of these observations within differentiated renal tubular epithelia (the presumed cell of origin of human ccRCC), we sought to generate genetically engineered mice with renal tubular specific deletion of Vhl, Pbrm1 or both Vhl and Pbrm1.	('renal tubular epithelia', 'Disease', (71, 94))	('human', 'Species', '9606', (127, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('Vhl', 'Gene', (250, 253))	('Pbrm1', 'Gene', (236, 241))	('Vhl', 'Gene', (231, 234))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('renal tubular epithelia', 'Disease', 'MESH:D005198', (71, 94))	('RCC', 'Disease', (135, 138))	('Pbrm1', 'Gene', (258, 263))	('mice', 'Species', '10090', (186, 190))	('deletion', 'Var', (219, 227))	('rat', 'Species', '10116', (158, 161))
124481	29229903	Loss of VHL results in activation of cellular responses to hypoxia despite normal oxygen conditions.	('oxygen', 'Chemical', 'MESH:D010100', (82, 88))	('activation', 'PosReg', (23, 33))	('hypoxia', 'Disease', (59, 66))	('hypoxia', 'Disease', 'MESH:D000860', (59, 66))	('Loss', 'Var', (0, 4))	('VHL', 'Gene', (8, 11))
124485	29229903	We observed no change in RAD51 and RPA32 transcript levels suggesting that transcriptional repression does not significantly account for the observed depletion of RAD51 and RPA upon loss of VHL (Supplementary Fig.	('RPA', 'Gene', (35, 38))	('RAD51', 'Gene', '19361', (25, 30))	('loss', 'Var', (182, 186))	('RPA', 'Gene', '68275', (173, 176))	('VHL', 'Gene', (190, 193))	('RAD', 'biological_process', 'GO:1990116', ('163', '166'))	('RPA32', 'Gene', '108689', (35, 40))	('RAD51', 'Gene', (25, 30))	('RPA32', 'Gene', (35, 40))	('RPA', 'Gene', (173, 176))	('RAD51', 'Gene', (163, 168))	('RAD51', 'Gene', '19361', (163, 168))	('RAD', 'biological_process', 'GO:1990116', ('25', '28'))	('RPA', 'cellular_component', 'GO:0005662', ('173', '176'))	('RPA', 'cellular_component', 'GO:0005662', ('35', '38'))	('RPA', 'Gene', '68275', (35, 38))
124486	29229903	As both RAD51 and RPA have essential roles in preventing the degradation of stalled forks and ensuring protection of nascent DNA we used DNA fibre assays to investigate fork stability in the context of Vhl deletion.	('RAD', 'biological_process', 'GO:1990116', ('8', '11'))	('RPA', 'cellular_component', 'GO:0005662', ('18', '21'))	('RPA', 'Gene', (18, 21))	('RAD51', 'Gene', '19361', (8, 13))	('RAD51', 'Gene', (8, 13))	('degradation', 'biological_process', 'GO:0009056', ('61', '72'))	('deletion', 'Var', (206, 214))	('degradation', 'MPA', (61, 72))	('Vhl', 'Gene', (202, 205))	('DNA', 'cellular_component', 'GO:0005574', ('137', '140'))	('RPA', 'Gene', '68275', (18, 21))	('DNA', 'cellular_component', 'GO:0005574', ('125', '128'))
124489	29229903	Vhl -/- MEFs displayed a significant reduction of median CIdU:IdU tract ratios (Fig.	('IdU', 'Chemical', 'MESH:D007065', (58, 61))	('rat', 'Species', '10116', (72, 75))	('IdU', 'Chemical', 'MESH:D007065', (62, 65))	('reduction', 'NegReg', (37, 46))	('Vhl -/- MEFs', 'Var', (0, 12))	('median CIdU:IdU tract ratios', 'MPA', (50, 78))	('MEFs', 'CellLine', 'CVCL:9115', (8, 12))
124491	29229903	Though RAD51 and RPA remain significantly reduced in double-mutant cells, these cells display no replication fork defects (Fig.	('RAD51', 'Gene', (7, 12))	('double-mutant', 'Var', (53, 66))	('reduced', 'NegReg', (42, 49))	('RAD', 'biological_process', 'GO:1990116', ('7', '10'))	('replication fork', 'cellular_component', 'GO:0005657', ('97', '113'))	('RPA', 'Gene', '68275', (17, 20))	('replication fork defects', 'CPA', (97, 121))	('RPA', 'cellular_component', 'GO:0005662', ('17', '20'))	('RPA', 'Gene', (17, 20))	('RAD51', 'Gene', '19361', (7, 12))
124496	29229903	Although we detected no change in the total levels of cellular H3K9me3 between different genotypes, there was a striking difference in its distribution, with Pbrm1 -/- and Vhl -/-;Pbrm1 -/- MEFs displaying more diffuse staining patterns and a significant reduction in the number of distinct foci (Fig.	('diffuse staining patterns', 'MPA', (211, 236))	('more', 'PosReg', (206, 210))	('number of distinct foci', 'MPA', (272, 295))	('MEFs', 'CellLine', 'CVCL:9115', (190, 194))	('Pbrm1 -/-', 'Var', (158, 167))	('reduction', 'NegReg', (255, 264))
124503	29229903	To assess in vivo proliferative differences we quantified the allelic frequency of the recombined Vhl allele (Vhl -) in young (<12 months) and aged (>20 months) Vhl -/- and Vhl -/-;Pbrm1 -/- mutant mice.	('Pbrm1', 'Gene', (181, 186))	('mutant', 'Var', (191, 197))	('rat', 'Species', '10116', (25, 28))	('mice', 'Species', '10090', (198, 202))	('Vhl -', 'Gene', (110, 115))
124505	29229903	In contrast, Vhl -/-;Pbrm1 -/- mice showed a 5-fold increase in Vhl - allelic content with increasing age, indicating that double-mutant epithelia gain a significant proliferative advantage over Vhl-deleted cells.	('epithelia gain', 'Disease', 'MESH:D015430', (137, 151))	('rat', 'Species', '10116', (173, 176))	('proliferative advantage', 'CPA', (166, 189))	('double-mutant', 'Var', (123, 136))	('increase', 'PosReg', (52, 60))	('epithelia gain', 'Disease', (137, 151))	('mice', 'Species', '10090', (31, 35))	('Vhl - allelic content', 'MPA', (64, 85))
124506	29229903	The expansion of double-mutant epithelial cells was further confirmed by CA9 immunohistochemistry (a marker of VHL loss) demonstrating a clear increase in the number of positively staining double-mutant epithelia over time (Fig.	('double-mutant', 'Var', (189, 202))	('VHL loss', 'Disease', 'MESH:D006623', (111, 119))	('VHL loss', 'Disease', (111, 119))	('increase', 'PosReg', (143, 151))	('rat', 'Species', '10116', (128, 131))
124507	29229903	These observations support our hypothesis that loss of PBRM1 improves the cellular fitness of VHL-defective cells permitting cellular growth and enhancing their proliferative capacity.	('cellular growth', 'biological_process', 'GO:0016049', ('125', '140'))	('cellular fitness', 'CPA', (74, 90))	('proliferative capacity', 'CPA', (161, 183))	('improves', 'PosReg', (61, 69))	('cellular growth', 'CPA', (125, 140))	('rat', 'Species', '10116', (168, 171))	('loss', 'Var', (47, 51))	('PBRM1', 'Gene', (55, 60))	('enhancing', 'PosReg', (145, 154))
124508	29229903	To ascertain whether biallelic deletion of Vhl and Pbrm1 is indeed sufficient to promote renal transformation, Vhl -/-, Pbrm1 -/- and Vhl -/-;Pbrm1 -/- mice as well as control animals were aged and observed for tumour development.	('tumour', 'Disease', 'MESH:D009369', (211, 217))	('renal transformation', 'CPA', (89, 109))	('tumour', 'Disease', (211, 217))	('promote', 'PosReg', (81, 88))	('Vhl', 'Gene', (43, 46))	('mice', 'Species', '10090', (152, 156))	('biallelic', 'Var', (21, 30))	('Pbrm1', 'Gene', (51, 56))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))
124520	29229903	Our data shows that loss of VHL induces replication stress and DNA damage accumulation, responses that curtail cellular proliferation and transformation.	('cellular proliferation', 'CPA', (111, 133))	('replication', 'MPA', (40, 51))	('loss', 'Var', (20, 24))	('transformation', 'CPA', (138, 152))	('DNA damage accumulation', 'MPA', (63, 86))	('curtail', 'NegReg', (103, 110))	('rat', 'Species', '10116', (127, 130))	('VHL', 'Gene', (28, 31))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('induces', 'Reg', (32, 39))
124521	29229903	Significantly, we find that loss of PBRM1, through modulation of H3K9me3-marked heterochromatin, rescues VHL-dependent replication stress and confers a survival and proliferative advantage, thereby permitting renal carcinogenesis (Fig.	('heterochromatin', 'cellular_component', 'GO:0000792', ('80', '95'))	('loss', 'Var', (28, 32))	('permitting renal carcinogenesis', 'Disease', (198, 229))	('PBRM1', 'Gene', (36, 41))	('VHL-dependent replication stress', 'MPA', (105, 137))	('H3K9me3-marked', 'Protein', (65, 79))	('rescues', 'PosReg', (97, 104))	('rat', 'Species', '10116', (172, 175))	('proliferative advantage', 'CPA', (165, 188))	('permitting renal carcinogenesis', 'Disease', 'MESH:D007674', (198, 229))	('survival', 'CPA', (152, 160))
124527	29229903	Importantly, our results provide a biological explanation for the lack of transformation upon loss of VHL alone and the need for additional genetic hits to initiate renal carcinogenesis.	('VHL', 'Gene', (102, 105))	('renal carcinogenesis', 'Disease', 'MESH:D007674', (165, 185))	('renal carcinogenesis', 'Disease', (165, 185))	('loss', 'Var', (94, 98))
124528	29229903	To overcome oncogene-induced replication stress and allow tumour progression, a second, essential step in cancer development involves suppression of the DDR responses, commonly achieved through mutations targeting TP53, ATM or MDM2 genes.	('MDM2', 'Gene', '17246', (227, 231))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('ATM', 'Gene', '11920', (220, 223))	('mutations', 'Var', (194, 203))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('DDR responses', 'MPA', (153, 166))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('ATM', 'Gene', (220, 223))	('tumour', 'Disease', (58, 64))	('suppression', 'NegReg', (134, 145))	('cancer', 'Disease', (106, 112))	('TP53', 'Gene', (214, 218))	('TP53', 'Gene', '22059', (214, 218))	('MDM2', 'Gene', (227, 231))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
124529	29229903	Mutations of these genes though commonly observed in other tumour types are rare in ccRCC.	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumour', 'Disease', (59, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('Mutations', 'Var', (0, 9))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))
124531	29229903	Furthermore, modulation of H3K9me3 can rescue the DNA repair defects observed with ATM deficiency as well as the damage accumulation and early senescence associated with progeria.	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('DNA repair', 'MPA', (50, 60))	('H3K9me3', 'Protein', (27, 34))	('damage accumulation', 'MPA', (113, 132))	('DNA repair', 'biological_process', 'GO:0006281', ('50', '60'))	('deficiency', 'Disease', (87, 97))	('rescue', 'PosReg', (39, 45))	('deficiency', 'Disease', 'MESH:D007153', (87, 97))	('ATM', 'Gene', '11920', (83, 86))	('senescence', 'biological_process', 'GO:0010149', ('143', '153'))	('modulation', 'Var', (13, 23))	('ATM', 'Gene', (83, 86))	('early senescence', 'CPA', (137, 153))
124532	29229903	Therefore, one mechanism by which loss of heterochromatin organisation (in the absence of PBRM1) could rescue the VHL-induced replication defects is through alterations in DDR signalling.	('heterochromatin', 'MPA', (42, 57))	('rescue', 'PosReg', (103, 109))	('loss', 'Var', (34, 38))	('DDR signalling', 'MPA', (172, 186))	('VHL-induced', 'Gene', (114, 125))	('heterochromatin', 'cellular_component', 'GO:0000792', ('42', '57'))	('heterochromatin organisation', 'biological_process', 'GO:0070828', ('42', '70'))	('replication defects', 'MPA', (126, 145))	('rat', 'Species', '10116', (161, 164))	('signalling', 'biological_process', 'GO:0023052', ('176', '186'))	('PBRM1', 'Gene', (90, 95))	('alterations', 'Reg', (157, 168))
124533	29229903	Whatever the precise mechanism of replication stress rescue, both our in vitro and in vivo data clearly show that loss of PBRM1 restores the cellular fitness and proliferative potential of Vhl-deleted cells and is therefore critical for renal transformation.	('proliferative potential', 'CPA', (162, 185))	('rat', 'Species', '10116', (169, 172))	('PBRM1', 'Gene', (122, 127))	('loss', 'Var', (114, 118))	('cellular fitness', 'CPA', (141, 157))	('restores', 'PosReg', (128, 136))
124539	29229903	induced Vhl and Pbrm1 deletion using a traditional Ksp-Cre driver with mice developing renal hydronephrosis, polycystic kidneys, renal failure and occasional renal tumours (observed in 30% of mice).	('mice', 'Species', '10090', (71, 75))	('hydronephrosis', 'Phenotype', 'HP:0000126', (93, 107))	('Vhl', 'Gene', (8, 11))	('Pbrm1', 'Gene', (16, 21))	('mice', 'Species', '10090', (192, 196))	('polycystic kidneys', 'Phenotype', 'HP:0000113', (109, 127))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('tumours', 'Phenotype', 'HP:0002664', (164, 171))	('polycystic kidneys, renal failure', 'Disease', 'MESH:D051437', (109, 142))	('deletion', 'Var', (22, 30))	('renal tumours', 'Disease', 'MESH:D007680', (158, 171))	('renal failure', 'Phenotype', 'HP:0000083', (129, 142))	('developing', 'Reg', (76, 86))	('renal hydronephrosis', 'Disease', 'MESH:D007674', (87, 107))	('renal hydronephrosis', 'Disease', (87, 107))	('renal tumours', 'Disease', (158, 171))
124541	29229903	In contrast to these studies, our use of Pax8-CreER T2 transgene allows for temporal and spatial control of Vhl and Pbrm1 deletion and, therefore, the specific targeting of fully developed renal tubular epithelium.	('Pbrm1', 'Gene', (116, 121))	('Pax8', 'Gene', (41, 45))	('deletion', 'Var', (122, 130))	('Vhl', 'Gene', (108, 111))	('Pax8', 'Gene', '18510', (41, 45))
124543	29229903	Furthermore, the inducible nature of our model avoids potential confounding by effects of Vhl and Pbrm1 deletion during renal embryogenesis (as observed in the other RCC mouse models).	('embryogenesis', 'biological_process', 'GO:0009790', ('126', '139'))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('Pbrm1', 'Gene', (98, 103))	('RCC', 'Disease', (166, 169))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('embryogenesis', 'biological_process', 'GO:0009793', ('126', '139'))	('mouse', 'Species', '10090', (170, 175))	('deletion', 'Var', (104, 112))	('embryogenesis', 'biological_process', 'GO:0009792', ('126', '139'))	('Vhl', 'Gene', (90, 93))
124557	29229903	To induce deletion of target genes 4-week to 6-week-old experimental and control animals were injected intraperitoneally with 2 mg of tamoxifen (Sigma, UK) for 5 consecutive days.	('induce', 'Reg', (3, 9))	('tamoxifen', 'Chemical', 'MESH:D013629', (134, 143))	('deletion', 'Var', (10, 18))
124570	29229903	We used the following primary antibodies: VHL (sc-5575, 1:250; Santa Cruz), PBRM1 (A301-590A, 1:1000; Bethyl Laboratories), alpha-Tubulin (T5168, 1:2000; Sigma), RAD51 (sc-8349, 1:100; Santa Cruz), RPA32 (A300-244A, 1:500; Bethyl Laboratories), pATM (ab36810, 1:1000; Abcam), ATM (ab85213, 1:1000; Abcam), pDNA-PKc (ab18192, 1:1000; Abcam), DNA-PKc (ab70250, 1:1000; Abcam), pCHK1 (#2348 S, 1:500; Cell Signalling), CHK1 (#2360, 1:1000; Cell Signalling), H3K9me3 (ab8898, 1:1000; Abcam), H3K27me3 (ab6002, 1:1000; Abcam), H3K9me2 (ab8898, 1:1000; Abcam), H4K20me3 (ab9053, 1:1000; Abcam), HP1a (ab77256, 1:1000, Abcam), KAP1 (ab10484, 1:1000; Abcam) and H3 (4499, 1:2000; Cell Signalling).	('HP1a', 'Gene', '12419', (589, 593))	('KAP1', 'Gene', (620, 624))	('CHK1', 'Gene', (416, 420))	('CHK1', 'Gene', '12649', (376, 380))	('ATM', 'Gene', (246, 249))	('RAD51', 'Gene', '19361', (162, 167))	('ab9053', 'Var', (565, 571))	('RPA', 'cellular_component', 'GO:0005662', ('198', '201'))	('CHK1', 'Gene', '12649', (416, 420))	('Signalling', 'biological_process', 'GO:0023052', ('677', '687'))	('ATM', 'Gene', '11920', (246, 249))	('ab10484', 'Var', (626, 633))	('ATM', 'Gene', (276, 279))	('Signalling', 'biological_process', 'GO:0023052', ('442', '452'))	('HP1a', 'Gene', (589, 593))	('rat', 'Species', '10116', (234, 237))	('ATM', 'Gene', '11920', (276, 279))	('DNA', 'cellular_component', 'GO:0005574', ('341', '344'))	('PKc', 'molecular_function', 'GO:0004697', ('345', '348'))	('RAD51', 'Gene', (162, 167))	('rat', 'Species', '10116', (113, 116))	('PKc', 'molecular_function', 'GO:0004697', ('311', '314'))	('CHK1', 'Gene', (376, 380))	('RPA32', 'Gene', '108689', (198, 203))	('KAP1', 'Gene', '21849', (620, 624))	('RPA32', 'Gene', (198, 203))	('Signalling', 'biological_process', 'GO:0023052', ('403', '413'))	('RAD', 'biological_process', 'GO:1990116', ('162', '165'))
124582	29229903	We used the following primary antibodies: gammaH2AX (9718, 1:1,000; Cell Signalling and ab26350, 1:500; Abcam), 53BP1 (IHC-00001, 1:500; Bethyl Laboratories), pATR (#2853, 1:500; Cell Signalling), pCHK1 (#2348S, 1:50, Cell Signalling), H3K9me3 (ab8898, 1:1000; Abcam), H2AZ (ab4174, 1:100; Abcam), H3K27me3 (ab6002, 1:500; Abcam), H3K9me2 (ab8898, 1:200; Abcam), H4K20me3 (ab9053, 1:100; Abcam), HP1a (ab77256, 1:200; Abcam) and KAP1 (ab10484, 1:500; Abcam).	('Signalling', 'biological_process', 'GO:0023052', ('223', '233'))	('ATR', 'Gene', (160, 163))	('KAP1', 'Gene', '21849', (429, 433))	('Signalling', 'biological_process', 'GO:0023052', ('184', '194'))	('KAP1', 'Gene', (429, 433))	('HP1a', 'Gene', '12419', (396, 400))	('Signalling', 'biological_process', 'GO:0023052', ('73', '83'))	('ab9053', 'Var', (373, 379))	('H2AZ', 'Gene', (269, 273))	('CHK1', 'Gene', (198, 202))	('ab10484', 'Var', (435, 442))	('H2AZ', 'Gene', '51788', (269, 273))	('gammaH2AX', 'Gene', (42, 51))	('rat', 'Species', '10116', (148, 151))	('H3K27me3', 'Var', (298, 306))	('53BP1', 'Gene', (112, 117))	('53BP1', 'Gene', '27223', (112, 117))	('ab8898', 'Var', (340, 346))	('CHK1', 'Gene', '12649', (198, 202))	('ATR', 'Gene', '245000', (160, 163))	('H3K9me2', 'Protein', (331, 338))	('HP1a', 'Gene', (396, 400))	('gammaH2AX', 'Gene', '15270', (42, 51))	('ab6002', 'Var', (308, 314))
124592	29229903	The slides were then treated with 2.5 N HCl for 60 min at 37  C, washed in PBS and incubated in blocking buffer (5% BSA/PBS) for 30 min at room temperature followed by incubation with a mouse anti-BrdU antibody (to detect IdU) (347590, 1:50, BD Biosciences) and a rat anti-BrdU antibody (to detect CldU) (ab6326, 1:200, Abcam).	('antibody', 'cellular_component', 'GO:0019814', ('202', '210'))	('antibody', 'cellular_component', 'GO:0019815', ('278', '286'))	('PBS', 'Disease', 'MESH:D011535', (120, 123))	('CldU', 'Chemical', '-', (298, 302))	('rat', 'Species', '10116', (149, 152))	('antibody', 'molecular_function', 'GO:0003823', ('202', '210'))	('347590', 'Var', (228, 234))	('HCl', 'Chemical', '-', (40, 43))	('antibody', 'cellular_component', 'GO:0042571', ('202', '210'))	('antibody', 'cellular_component', 'GO:0019814', ('278', '286'))	('PBS', 'Disease', (120, 123))	('PBS', 'Disease', 'MESH:D011535', (75, 78))	('mouse', 'Species', '10090', (186, 191))	('antibody', 'molecular_function', 'GO:0003823', ('278', '286'))	('antibody', 'cellular_component', 'GO:0019815', ('202', '210'))	('antibody', 'cellular_component', 'GO:0042571', ('278', '286'))	('PBS', 'Disease', (75, 78))	('IdU', 'Chemical', 'MESH:D007065', (222, 225))	('rat', 'Species', '10116', (264, 267))
124596	29229903	Real-time quantitative PCRs were carried out following the manufacture's protocol using the following probes: Mm00488047_m1 (RPA2), Mm00487905_m1 (Rad51), Mm00437762_m1 (B2M), Mm03024075_m1 (HPRT).	('Rad', 'biological_process', 'GO:1990116', ('147', '150'))	('Mm00487905_m1', 'Var', (132, 145))	('HPRT', 'Gene', (191, 195))	('RPA2', 'Gene', '19891', (125, 129))	('HPRT', 'Gene', '15452', (191, 195))	('HPRT', 'molecular_function', 'GO:0004422', ('191', '195'))	('Rad51', 'Gene', '19361', (147, 152))	('Mm00488047_m1', 'Var', (110, 123))	('Mm00437762_m1', 'Var', (155, 168))	('RPA2', 'Gene', (125, 129))	('RPA', 'cellular_component', 'GO:0005662', ('125', '128'))	('Rad51', 'Gene', (147, 152))	('Mm03024075_m1', 'Var', (176, 189))
124611	29229903	For quantitative PCR (qPCR) of the Vhl deletion, SYBR Green PCR Master Mix (Applied Biosystems) was used and amplification and analysis was carried out on QuantStudio 6 (Thermo Fisher Scientific).	('Vhl', 'Gene', (35, 38))	('deletion', 'Var', (39, 47))	('SYBR Green', 'Chemical', '-', (49, 59))
124637	28545998	Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, harbor genetic and epigenetic alteration of the von Hippel- Lindau (VHL) gene and consequently the stabilization of the transcriptional factor hypoxia inducible factors (HIFs) with down-stream upregulation of VEGF.	('kidney cancer', 'Disease', 'MESH:D007680', (65, 78))	('von Hippel- Lindau', 'Gene', '7428', (128, 146))	('VEGF', 'Gene', '7422', (289, 293))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('down-stream', 'NegReg', (261, 272))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('VEGF', 'Gene', (289, 293))	('RCC', 'Disease', (35, 38))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('kidney cancer', 'Phenotype', 'HP:0009726', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('kidney cancer', 'Disease', (65, 78))	('von Hippel- Lindau', 'Gene', (128, 146))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('VHL', 'Disease', 'MESH:D006623', (148, 151))	('hypoxia', 'Disease', (223, 230))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('stabilization', 'MPA', (179, 192))	('epigenetic alteration', 'Var', (99, 120))	('hypoxia', 'Disease', 'MESH:D000860', (223, 230))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('upregulation', 'PosReg', (273, 285))	('VHL', 'Disease', (148, 151))
124704	28545998	The original approval of axitinib has validated retrospective studies suggesting that sequencing of TKIs can still induce disease control despite progression following frontline therapies with anti-VEGF therapies.	('sequencing', 'Var', (86, 96))	('disease control', 'Disease', (122, 137))	('induce', 'Reg', (115, 121))	('VEGF', 'Gene', (198, 202))	('axitinib', 'Chemical', 'MESH:D000077784', (25, 33))	('TKIs', 'Gene', (100, 104))	('VEGF', 'Gene', '7422', (198, 202))
124721	28327121	BAP1 and PBRM1 in metastatic clear cell renal cell carcinoma: tumor heterogeneity and concordance with paired primary tumor BAP1 and PBRM1 are frequently mutated in primary clear cell renal cell carcinoma (ccRCC) tumors; however, the frequency and clinical relevance of these mutations in metastatic ccRCC tumors is unknown.	('clear cell renal cell carcinoma (ccRCC) tumors', 'Disease', 'MESH:C538614', (173, 219))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('tumor', 'Disease', (306, 311))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('PBRM1', 'Gene', (9, 14))	('RCC tumors', 'Disease', (302, 312))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (29, 60))	('BAP1', 'Gene', '8314', (124, 128))	('BAP1', 'Gene', (0, 4))	('PBRM1', 'Gene', '55193', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (173, 204))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (306, 312))	('RCC tumors', 'Disease', 'MESH:C538614', (302, 312))	('mutated', 'Var', (154, 161))	('PBRM1', 'Gene', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('clear cell renal cell carcinoma', 'Disease', (173, 204))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (184, 204))	('clear cell renal cell carcinoma', 'Disease', (29, 60))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (40, 60))	('BAP1', 'Gene', (124, 128))	('primary clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (165, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', (62, 67))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (173, 204))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Disease', (118, 123))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (29, 60))	('BAP1', 'Gene', '8314', (0, 4))	('PBRM1', 'Gene', '55193', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
124732	28327121	Mutations that cause loss of expression of BAP1 and PBRM1 are two of the most frequently occurring molecular events in primary clear cell renal cell carcinoma (ccRCC) with a prevalence of approximately 10 and 40%, respectively.	('PBRM1', 'Gene', '55193', (52, 57))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (138, 158))	('loss of', 'NegReg', (21, 28))	('BAP1', 'Gene', (43, 47))	('RCC', 'Disease', (162, 165))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (127, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('primary clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (119, 158))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('occurring', 'Reg', (89, 98))	('PBRM1', 'Gene', (52, 57))	('BAP1', 'Gene', '8314', (43, 47))	('Mutations', 'Var', (0, 9))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (127, 158))	('clear cell renal cell carcinoma', 'Disease', (127, 158))	('expression', 'MPA', (29, 39))
124734	28327121	While mutations in BAP1 and PBRM1 have been shown to be associated with poor cancer-specific survival, the frequency of these mutations (and their clinical relevance) in metastatic ccRCC tumors is unknown.	('RCC tumors', 'Disease', (183, 193))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('PBRM1', 'Gene', (28, 33))	('BAP1', 'Gene', '8314', (19, 23))	('associated', 'Reg', (56, 66))	('PBRM1', 'Gene', '55193', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('BAP1', 'Gene', (19, 23))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('RCC tumors', 'Disease', 'MESH:C538614', (183, 193))	('mutations', 'Var', (6, 15))	('poor', 'NegReg', (72, 76))
124736	28327121	One of the two patients with a PBRM1 mutation (EV002) had a PBRM1 mutation in all six biopsies from the primary tumor as well as in a biopsy from a metastasis obtained at the time of disease progression on everolimus treatment.	('patients', 'Species', '9606', (15, 23))	('mutation', 'Var', (37, 45))	('PBRM1', 'Gene', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('PBRM1', 'Gene', '55193', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PBRM1', 'Gene', (31, 36))	('mutation', 'Var', (66, 74))	('tumor', 'Disease', (112, 117))	('PBRM1', 'Gene', '55193', (31, 36))	('everolimus', 'Chemical', 'MESH:D000068338', (206, 216))
124737	28327121	The other patient with a PBRM1 mutation (RMH004) had a mutation in three of the five biopsies from the primary tumor and a different PBRM1 mutation in a tumor thrombus from the renal vein.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('PBRM1', 'Gene', (133, 138))	('PBRM1', 'Gene', '55193', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mutation', 'Var', (31, 39))	('patient', 'Species', '9606', (10, 17))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (153, 158))	('PBRM1', 'Gene', (25, 30))	('mutation', 'Var', (55, 63))	('PBRM1', 'Gene', '55193', (25, 30))
124738	28327121	The value of this initial exploration notwithstanding, investigations focused on larger cohorts of patients with matched primary and metastatic ccRCC tumors are necessary to obtain estimates of the prevalence of BAP1 and PBRM1 mutations in metastatic ccRCC tumors and to better inform the potential value of these alterations as potential biomarkers for response to therapy.	('RCC tumors', 'Disease', 'MESH:C538614', (253, 263))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('RCC tumors', 'Disease', (146, 156))	('BAP1', 'Gene', '8314', (212, 216))	('BAP1', 'Gene', (212, 216))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('RCC tumors', 'Disease', (253, 263))	('patients', 'Species', '9606', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('RCC tumors', 'Disease', 'MESH:C538614', (146, 156))	('PBRM1', 'Gene', (221, 226))	('PBRM1', 'Gene', '55193', (221, 226))	('mutations', 'Var', (227, 236))
124762	28327121	The IHC assays for BAP1 and PBRM1 have been validated and have been shown to be correlated with mutation status.	('correlated', 'Reg', (80, 90))	('PBRM1', 'Gene', (28, 33))	('BAP1', 'Gene', '8314', (19, 23))	('mutation', 'Var', (96, 104))	('PBRM1', 'Gene', '55193', (28, 33))	('BAP1', 'Gene', (19, 23))
124778	28327121	For the 97 patients with staining of PBRM1 in the primary tumor, we analyzed a total of 138 patient-matched metastatic tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('PBRM1', 'Gene', (37, 42))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (119, 124))	('patient', 'Species', '9606', (92, 99))	('PBRM1', 'Gene', '55193', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('patient', 'Species', '9606', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('staining', 'Var', (25, 33))	('patients', 'Species', '9606', (11, 19))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
124803	28327121	Previous investigators have reported that BAP1 mutations occur in approximately 10% of ccRCC tumors and loss of BAP1 expression is associated with reduced survival.	('BAP1', 'Gene', (112, 116))	('loss', 'NegReg', (104, 108))	('RCC tumors', 'Disease', 'MESH:C538614', (89, 99))	('BAP1', 'Gene', '8314', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('expression', 'MPA', (117, 127))	('BAP1', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('RCC tumors', 'Disease', (89, 99))	('BAP1', 'Gene', '8314', (112, 116))	('reduced', 'NegReg', (147, 154))	('survival', 'MPA', (155, 163))
124810	28327121	PBRM1 mutations have been shown to be prevalent in approximately 40% of ccRCC tumors and loss of PBRM1 expression has been shown to be associated with overall survival.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('loss', 'Var', (89, 93))	('expression', 'MPA', (103, 113))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('associated', 'Reg', (135, 145))	('RCC tumors', 'Disease', (74, 84))	('prevalent', 'Reg', (38, 47))	('PBRM1', 'Gene', (97, 102))	('PBRM1', 'Gene', '55193', (97, 102))	('mutations', 'Var', (6, 15))	('RCC tumors', 'Disease', 'MESH:C538614', (74, 84))
124829	28327121	And, given the high concordance of these mutations between primary and metastatic tumors, testing the more readily-available primary tumor might be sufficient.	('mutations', 'Var', (41, 50))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', (82, 87))
124931	32013938	Overexpression of CDK18 also led to the formation of filopodia during the early stages of cell adhesion in HeLa cells.	('CDK18', 'Gene', (18, 23))	('formation', 'MPA', (40, 49))	('HeLa', 'CellLine', 'CVCL:0030', (107, 111))	('cell adhesion', 'biological_process', 'GO:0007155', ('90', '103'))	('led to', 'Reg', (29, 35))	('CDK18', 'Gene', '5129', (18, 23))	('formation', 'biological_process', 'GO:0009058', ('40', '49'))	('Overexpression', 'Var', (0, 14))	('CDK', 'molecular_function', 'GO:0004693', ('18', '21'))
124945	32013938	LOX is a HIF target and in ccRCC, LOX has been shown to be strongly overexpressed compared to normal tissue; it is one of the genes postranscriptionally regulated by miR-141-3p and miR-145-5p; and has prognostic relevance for the overall survival of ccRCC patients.	('overexpressed', 'PosReg', (68, 81))	('LOX', 'Gene', (0, 3))	('LOX', 'Gene', (34, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (250, 255))	('ccRCC', 'Disease', (250, 255))	('RCC', 'Phenotype', 'HP:0005584', (252, 255))	('miR-141-3p', 'Var', (166, 176))	('patients', 'Species', '9606', (256, 264))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('HIF', 'Disease', (9, 12))	('ccRCC', 'Disease', 'MESH:D002292', (250, 255))	('ccRCC', 'Disease', (27, 32))	('miR-145-5p', 'Var', (181, 191))	('ccRCC', 'Phenotype', 'HP:0006770', (27, 32))	('HIF', 'Disease', 'None', (9, 12))	('ccRCC', 'Disease', 'MESH:D002292', (27, 32))	('LOX', 'Gene', '4015', (0, 3))	('LOX', 'Gene', '4015', (34, 37))
125021	28385150	Interestingly, high plasma fibrinogen levels predicted poorer outcome in a European cohort of non-metastatic renal cell carcinoma patients.	('high', 'Var', (15, 19))	('high plasma fibrinogen', 'Phenotype', 'HP:0011899', (15, 37))	('renal cell carcinoma', 'Disease', (109, 129))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (109, 129))	('poorer', 'NegReg', (55, 61))	('patients', 'Species', '9606', (130, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('fibrinogen', 'cellular_component', 'GO:0005577', ('27', '37'))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (109, 129))	('fibrinogen', 'molecular_function', 'GO:0008001', ('27', '37'))	('fibrinogen', 'Gene', '2244', (27, 37))	('fibrinogen', 'Gene', (27, 37))
125038	33659024	Kaplan-Meier curve analysis showed that IFI16 expression was related to the prognosis of patients, and high IFI16 expression indicated a worse overall survival (p = 5.1E-0.7).	('IFI16', 'Gene', (40, 45))	('worse', 'NegReg', (137, 142))	('si', 'Chemical', 'MESH:D012825', (24, 26))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('IFI16', 'Gene', (108, 113))	('related', 'Reg', (61, 68))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('IFI16', 'Gene', '3428', (108, 113))	('patients', 'Species', '9606', (89, 97))	('high', 'Var', (103, 107))	('IFI16', 'Gene', '3428', (40, 45))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('overall', 'MPA', (143, 150))
125041	33659024	Functional tests showed that knocking down IFI16 expression inhibited migration and invasion in vitro.	('knocking down', 'Var', (29, 42))	('IFI16', 'Gene', '3428', (43, 48))	('inhibited', 'NegReg', (60, 69))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('IFI16', 'Gene', (43, 48))	('si', 'Chemical', 'MESH:D012825', (55, 57))
125104	33659024	However, it was significantly associated with tumor stage (I + II vs. III + IV: HR = 3.676, 95%CI = 2.366-5.711, P = 7.05E-09), histopathological grade (G1 + 2 vs. G3 + 4: HR = 2.629, 95%CI = 1.655-4.176, P = 4.26E-05), and IFI16 expression level (low vs. high: HR = 1.043, 95%CI = 1.024-1.063, P = 1.07E-05).	('associated', 'Reg', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('IFI16', 'Gene', '3428', (224, 229))	('histopathological', 'CPA', (128, 145))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('tumor', 'Disease', (46, 51))	('IFI16', 'Gene', (224, 229))	('G1', 'Var', (153, 155))	('si', 'Chemical', 'MESH:D012825', (236, 238))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
125116	33659024	The results showed that knockdown of IFI16 inhibited the proliferation of RCC cells (Figures 4B,C).	('inhibited', 'NegReg', (43, 52))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('IFI16', 'Gene', '3428', (37, 42))	('proliferation', 'CPA', (57, 70))	('IFI16', 'Gene', (37, 42))	('knockdown', 'Var', (24, 33))
125121	33659024	Therefore, the knockdown of IFI16 reduced the migration and invasion abilities of the 786-O and ACHN cells (Figures 6A,B).	('reduced', 'NegReg', (34, 41))	('IFI16', 'Gene', '3428', (28, 33))	('knockdown', 'Var', (15, 24))	('IFI16', 'Gene', (28, 33))	('si', 'Chemical', 'MESH:D012825', (64, 66))
125122	33659024	The wound scratch and transwell assays showed that kidney cancer cells with high IFI16 expression migrated and invaded faster than cells with low expression.	('faster', 'PosReg', (119, 125))	('si', 'Chemical', 'MESH:D012825', (93, 95))	('si', 'Chemical', 'MESH:D012825', (152, 154))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('kidney cancer', 'Phenotype', 'HP:0009726', (51, 64))	('kidney cancer', 'Disease', 'MESH:D007680', (51, 64))	('invaded', 'CPA', (111, 118))	('IFI16', 'Gene', '3428', (81, 86))	('high', 'Var', (76, 80))	('kidney cancer', 'Disease', (51, 64))	('IFI16', 'Gene', (81, 86))
125131	33659024	When the expression of IFI16 in tumor cells is knocked down, this effect is reversed.	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('knocked', 'Var', (47, 54))	('si', 'Chemical', 'MESH:D012825', (15, 17))	('expression', 'MPA', (9, 19))	('IFI16', 'Gene', '3428', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('IFI16', 'Gene', (23, 28))	('tumor', 'Disease', (32, 37))
125142	33659024	The Kaplan-Meier survival curve showed that high expression of IFI16 was significantly associated with a poor OS, and the results of Cox regression analysis confirmed this.	('IFI16', 'Gene', '3428', (63, 68))	('si', 'Chemical', 'MESH:D012825', (73, 75))	('si', 'Chemical', 'MESH:D012825', (153, 155))	('high expression', 'Var', (44, 59))	('IFI16', 'Gene', (63, 68))	('associated', 'Reg', (87, 97))	('si', 'Chemical', 'MESH:D012825', (143, 145))	('poor OS', 'Disease', (105, 112))	('si', 'Chemical', 'MESH:D012825', (55, 57))
125146	33659024	The CCK-8 analysis suggested that knocking down IFI16 expression in the renal cancer cell line inhibits the proliferation of RCC cells.	('IFI16', 'Gene', '3428', (48, 53))	('renal cancer', 'Disease', 'MESH:D007680', (72, 84))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('IFI16', 'Gene', (48, 53))	('renal cancer', 'Disease', (72, 84))	('si', 'Chemical', 'MESH:D012825', (15, 17))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('proliferation', 'CPA', (108, 121))	('CCK-8', 'Chemical', 'MESH:D012844', (4, 9))	('renal cancer', 'Phenotype', 'HP:0009726', (72, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('inhibits', 'NegReg', (95, 103))	('knocking down', 'Var', (34, 47))
125147	33659024	In the wound scratch assay, the migration distance of the NC group was longer than that of the si-IFI16 group, which showed that the knockdown of IFI16 reduced the migration ability of 786-O and ACHN cells.	('migration distance', 'CPA', (32, 50))	('IFI16', 'Gene', '3428', (146, 151))	('IFI16', 'Gene', (146, 151))	('reduced', 'NegReg', (152, 159))	('knockdown', 'Var', (133, 142))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('IFI16', 'Gene', '3428', (98, 103))	('IFI16', 'Gene', (98, 103))
125158	32226429	Tumor-Infiltrating T Cells From Clear Cell Renal Cell Carcinoma Patients Recognize Neoepitopes Derived From Point and Frameshift Mutations Mutation-derived neoantigens are important targets for T cell-mediated reactivity toward tumors and, due to their unique tumor expression, an attractive target for immunotherapy.	('tumor', 'Disease', (260, 265))	('Clear Cell Renal Cell Carcinoma', 'Disease', (32, 63))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('Patients', 'Species', '9606', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('Frameshift Mutations', 'Var', (118, 138))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (32, 63))	('tumors', 'Disease', (228, 234))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('tumor', 'Disease', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (32, 63))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (43, 63))	('Carcinoma', 'Phenotype', 'HP:0030731', (54, 63))
125159	32226429	Neoepitope-specific T cells have been detected across a number of solid cancers with high mutational burden tumors, but neoepitopes have been mostly selected from single nucleotide variations (SNVs), and little focus has been given to neoepitopes derived from in-frame and frameshift indels, which might be equally important and potentially highly immunogenic.	('burden tumors', 'Disease', (101, 114))	('solid cancers', 'Disease', 'MESH:D009369', (66, 79))	('burden tumors', 'Disease', 'MESH:D009369', (101, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('SNV', 'Chemical', '-', (193, 196))	('frameshift indels', 'Var', (273, 290))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('solid cancers', 'Disease', (66, 79))
125160	32226429	Clear cell renal cell carcinomas (ccRCCs) are medium-range mutational burden tumors with a high pan-cancer proportion of frameshift mutations.	('burden tumors', 'Disease', (70, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('burden tumors', 'Disease', 'MESH:D009369', (70, 83))	('Clear cell renal cell carcinomas', 'Disease', (0, 32))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('frameshift mutations', 'Var', (121, 141))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('Clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (0, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ccRCCs', 'Phenotype', 'HP:0006770', (34, 40))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (11, 32))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('Clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (0, 32))
125168	32226429	This study, for the first time, describes the T cell recognition of frameshift-derived neoepitopes in RCC and determines their immunogenic profile.	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('frameshift-derived', 'Var', (68, 86))	('cell recognition', 'biological_process', 'GO:0008037', ('48', '64'))
125175	32226429	The described neopeptides have, however, mainly been derived from single nucleotide variations (SNVs) with less focus on in-frame and frameshift indels, mutation types that are likely to be immunogenic based on their large sequence variance to the germline DNA.	('SNV', 'Chemical', '-', (96, 99))	('DNA', 'cellular_component', 'GO:0005574', ('257', '260'))	('frameshift indels', 'Var', (134, 151))	('single nucleotide variations', 'Var', (66, 94))
125176	32226429	Even though the total number of frameshift indels are lower than SNVs, they have been shown to give rise to three times as many predicted high-affinity (IC50 < 50 nM) neoantigens per mutation compared to SNVs and are highly enriched for mutant-specific binding (i.e., neopeptides for which the wild-type peptide is not predicted to bind the HLA).	('SNV', 'Chemical', '-', (65, 68))	('neoantigens', 'MPA', (167, 178))	('high-affinity', 'MPA', (138, 151))	('mutation', 'Var', (183, 191))	('SNV', 'Chemical', '-', (204, 207))	('frameshift indels', 'Var', (32, 49))	('binding', 'molecular_function', 'GO:0005488', ('253', '260'))	('mutant-specific', 'Reg', (237, 252))	('binding', 'Interaction', (253, 260))
125178	32226429	Clear cell renal cell carcinomas (ccRCCs) are medium-range mutational burden tumors that present with the highest pan-cancer proportion of frameshift indels.	('burden tumors', 'Disease', (70, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', (118, 124))	('burden tumors', 'Disease', 'MESH:D009369', (70, 83))	('Clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (0, 32))	('Clear cell renal cell carcinomas', 'Disease', (0, 32))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('Clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (0, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('frameshift indels', 'Var', (139, 156))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (11, 32))	('ccRCCs', 'Phenotype', 'HP:0006770', (34, 40))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
125183	32226429	For that reason, we evaluated the T cell recognition of neopeptides predicted from SNVs, in-frame, and frameshift indels in six ccRCC patients previously described in.	('frameshift indels', 'Var', (103, 120))	('patients', 'Species', '9606', (134, 142))	('SNV', 'Chemical', '-', (83, 86))	('RCC', 'Disease', (130, 133))	('cell recognition', 'biological_process', 'GO:0008037', ('36', '52'))	('RCC', 'Disease', 'MESH:C538614', (130, 133))
125200	32226429	Identified mutations from TFs and TCLs were used to predict 9, 10, and 11 amino acid peptides, sorted according to the eluted ligand percentile rank (EL% Rank) score of the mutated neopeptides using netMHCpan 2.8.	('mutations', 'Var', (11, 20))	('TCL', 'Gene', (34, 37))	('TCL', 'Gene', '57381', (34, 37))	('ligand', 'molecular_function', 'GO:0005488', ('126', '132'))	('netMHCpan', 'Chemical', '-', (199, 208))	('TFs', 'Gene', (26, 29))
125202	32226429	Additionally, the tumor mutational burden of non-synonymous mutations was determined from the MuPeXI output logfile summarizing peptides originating from missense variant mutations, in-frame insertions, and deletions, together with frameshift mutations.	('deletions', 'Var', (207, 216))	('missense variant mutations', 'Var', (154, 180))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
125212	32226429	The following streptavidin-conjugated fluorochromes were used: PE (Biolegend, cat#405203), allophycocyanin (APC) (Biolegend, cat#405207), phycoerythrin-cyanin 7 (PE-Cy7) (Biolegend, cat#405206), PE-CF594 (BD, cat#562284), brilliant ultraviolet (BUV)737 (BD, cat#564293), brilliant violet (BV)605 (BD, cat#563260), BV650 (BD, cat#563855), BUV395 (BD, cat#564176), and BV421 (Biolegend, cat#405226).	('APC', 'cellular_component', 'GO:0005680', ('108', '111'))	('cat', 'molecular_function', 'GO:0004096', ('325', '328'))	('cat', 'molecular_function', 'GO:0004096', ('385', '388'))	('cat', 'molecular_function', 'GO:0004096', ('125', '128'))	('APC', 'Disease', 'MESH:D011125', (108, 111))	('cat', 'molecular_function', 'GO:0004096', ('258', '261'))	('BV650', 'Var', (314, 319))	('cat', 'molecular_function', 'GO:0004096', ('182', '185'))	('cat', 'molecular_function', 'GO:0004096', ('350', '353'))	('cat', 'molecular_function', 'GO:0004096', ('78', '81'))	('cat', 'molecular_function', 'GO:0004096', ('209', '212'))	('cat', 'molecular_function', 'GO:0004096', ('301', '304'))	('APC', 'Disease', (108, 111))
125228	32226429	The mutational landscape overlapped substantially with average 50% of mutations detected in both tumor sources, and consequently, more than half of the neopeptides were predicted from both sources (57%, range 40-74%, n = 4).	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('mutations', 'Var', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))
125247	32226429	The tumor mutational burden of the patients included several non-synonymous mutation types: SNVs, frameshift indels, and in-frame indels (deletions and insertions) (Figure 2A).	('tumor', 'Disease', (4, 9))	('SNVs', 'Disease', (92, 96))	('in-frame indels', 'Var', (121, 136))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('patients', 'Species', '9606', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('SNV', 'Chemical', '-', (92, 95))	('frameshift indels', 'Var', (98, 115))
125248	32226429	As expected, SNVs accounted for the largest fraction of mutations in the tumors of all six patients and resulted in a greater number of predicted neopeptides.	('neopeptides', 'MPA', (146, 157))	('mutations', 'Var', (56, 65))	('patients', 'Species', '9606', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('SNV', 'Chemical', '-', (13, 16))
125249	32226429	The two other mutation types are less frequent; on average, across all patients, 12% of mutations and 16% of predicted neopeptides were frameshift indels (range, 9-15 and 9-25%), and 3% of mutations and 1% of predicted neopeptides were in-frame indels (range, 1-6 and 0-2.5%).	('frameshift indels', 'Var', (136, 153))	('mutations', 'Var', (88, 97))	('patients', 'Species', '9606', (71, 79))
125250	32226429	Only neopeptides derived from SNVs (41/52, 79%) and frameshift indels (11/52, 21%) were recognized by T cells in our screen.	('SNVs', 'Var', (30, 34))	('SNV', 'Chemical', '-', (30, 33))	('frameshift indels', 'Var', (52, 69))
125257	32226429	Within each mutation group, there was no significant difference between peptides based on their immunogenicity, even though, for both groups, slightly higher average delta values were detected for the immunogenic neoepitopes (SNVs: 2.6 and 5.4; frameshift indels: 9.4 and 16.7 for non-and immunogenic peptides, respectively).	('SNV', 'Chemical', '-', (226, 229))	('higher', 'PosReg', (151, 157))	('frameshift indels', 'Var', (245, 262))	('delta values', 'MPA', (166, 178))
125258	32226429	Furthermore, between the two mutation types, frameshift mutations had significantly enhanced MHC binding capacity compared to SNVs, relative to their wild-type sequence.	('frameshift mutations', 'Var', (45, 65))	('SNV', 'Chemical', '-', (126, 129))	('binding', 'molecular_function', 'GO:0005488', ('97', '104'))	('MHC', 'Protein', (93, 96))	('enhanced', 'PosReg', (84, 92))
125259	32226429	However, between the mutation types, neopeptides derived from frameshift indels are significantly less similar to wild type compared to SNV (SNVs: 0.96 and 0.97; frameshift indels: 0.9 and 0.89 for non- and immunogenic peptides, respectively).	('SNV', 'Chemical', '-', (136, 139))	('frameshift indels', 'Var', (62, 79))	('SNV', 'Chemical', '-', (141, 144))	('less', 'NegReg', (98, 102))
125268	32226429	Renal cell carcinomas are known to harbor the highest number of insertions and deletion of all cancers (ccRCCs scoring highest of renal cell cancer subtypes), and in line with this, mutational analyses revealed the presence of frameshift and in-frame indel mutations in all six patients in the study cohort.	('frameshift', 'Var', (227, 237))	('renal cell cancer', 'Phenotype', 'HP:0005584', (130, 147))	('in-frame indel mutations', 'Var', (242, 266))	('deletion', 'Var', (79, 87))	('ccRCCs', 'Phenotype', 'HP:0006770', (104, 110))	('Renal cell carcinomas', 'Disease', (0, 21))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('Renal cell carcinomas', 'Phenotype', 'HP:0005584', (0, 21))	('RCC', 'Disease', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('insertions', 'Var', (64, 74))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('renal cell cancer', 'Disease', 'MESH:C538614', (130, 147))	('patients', 'Species', '9606', (278, 286))	('renal cell cancer', 'Disease', (130, 147))	('Renal cell carcinomas', 'Disease', 'MESH:C538614', (0, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (11, 21))
125280	32226429	Although the number of RCC patients evaluated in this study is limited, the neoepitope screening presented here covers 1,545 predicted neoepitopes, derived from 572 SNV mutations and 99 frameshift/indel mutations, with ligands binding to 16 different HLA class I molecules.	('neoepitopes', 'MPA', (135, 146))	('SNV', 'Chemical', '-', (165, 168))	('mutations', 'Var', (169, 178))	('binding', 'molecular_function', 'GO:0005488', ('227', '234'))	('SNV', 'Gene', (165, 168))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('patients', 'Species', '9606', (27, 35))	('RCC', 'Disease', (23, 26))	('frameshift/indel mutations', 'Var', (186, 212))
125281	32226429	Thus, despite the limited number of patients analyzed, this represents a broad screening effort of class I neoepitopes from both SNVs and frameshift mutations, providing new insight into the neoepitope landscape in renal cell carcinoma patients.	('frameshift mutations', 'Var', (138, 158))	('patients', 'Species', '9606', (36, 44))	('renal cell carcinoma', 'Disease', (215, 235))	('patients', 'Species', '9606', (236, 244))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (215, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (215, 235))	('SNV', 'Chemical', '-', (129, 132))
125282	32226429	In line with previous studies of neoepitopes in other cancer types, all of the neoepitopes derived from mutations were unique to the given patient.	('mutations', 'Var', (104, 113))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('patient', 'Species', '9606', (139, 146))
125283	32226429	Thus, therapeutic utilization in precision-targeted approaches will require patient-specific mutational mapping and prediction of neoepitopes, which can then be applied to tailor-made therapies such as personalized cancer vaccines or adoptive transfer of expanded neoepitope-specific patient TILs.	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('mutational', 'Var', (93, 103))	('patient', 'Species', '9606', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('patient', 'Species', '9606', (284, 291))
125288	29100374	Targeting CXCR4 reverts the suppressive activity of T-regulatory cells in renal cancer With the intent to identify biomarkers in renal cell carcinoma (RCC) the functional status of T-regulatory cells (Tregs) was investigated in primary RCC.	('RCC', 'Disease', 'MESH:C538614', (236, 239))	('CXCR4', 'molecular_function', 'GO:0038147', ('10', '15'))	('Tregs', 'Chemical', '-', (201, 206))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('renal cell carcinoma', 'Disease', (129, 149))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (129, 149))	('suppressive activity', 'MPA', (28, 48))	('renal cancer', 'Disease', (74, 86))	('renal cancer', 'Phenotype', 'HP:0009726', (74, 86))	('CXCR4', 'Gene', '7852', (10, 15))	('RCC', 'Disease', (151, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('CXCR4', 'Gene', (10, 15))	('renal cancer', 'Disease', 'MESH:D007680', (74, 86))	('RCC', 'Disease', (236, 239))	('RCC', 'Phenotype', 'HP:0005584', (236, 239))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (129, 149))	('Targeting', 'Var', (0, 9))
125289	29100374	Tregs were isolated from tumoral-(TT), peritumoral tissue-(PT) and peripheral blood-(PB) of 42 primary RCC patients and function evaluated through effector T cells (Teff) proliferation, cytokines release and demethylation of Treg Specific Region (TSDR).	('demethylation', 'Var', (208, 221))	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('tumoral', 'Disease', (43, 50))	('tumoral', 'Disease', 'MESH:D009369', (43, 50))	('tumoral', 'Disease', (25, 32))	('cytokines release', 'MPA', (186, 203))	('tumoral', 'Disease', 'MESH:D009369', (25, 32))	('Tregs', 'Chemical', '-', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('demethylation', 'biological_process', 'GO:0070988', ('208', '221'))	('patients', 'Species', '9606', (107, 115))
125306	29100374	Cancer patients derived Tregs usually express a distinct profile of chemokine receptors, such as CCR4, CXCR4 and CCR5, which facilitates their migration into tumors in response to the corresponding chemokine ligands derived from tumor microenvironment.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('facilitates', 'PosReg', (125, 136))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('CXCR4', 'molecular_function', 'GO:0038147', ('103', '108'))	('CCR', 'molecular_function', 'GO:0043880', ('113', '116'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('patients', 'Species', '9606', (7, 15))	('tumors', 'Disease', (158, 164))	('Tregs', 'Chemical', '-', (24, 29))	('response', 'MPA', (168, 176))	('migration into', 'CPA', (143, 157))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', (229, 234))	('CCR5', 'Gene', '1234', (113, 117))	('CCR4', 'Gene', (97, 101))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('CXCR4', 'Var', (103, 108))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('CCR', 'molecular_function', 'GO:0043880', ('97', '100'))	('CCR4', 'Gene', '1233', (97, 101))	('CCR5', 'Gene', (113, 117))
125329	29100374	Since CXCR4 is highly expressed by Tregs, we speculate that interfering with CXCR4 signaling might inhibit the Tregs suppressive function.	('interfering', 'Var', (60, 71))	('Tregs suppressive function', 'CPA', (111, 137))	('CXCR4 signaling', 'MPA', (77, 92))	('inhibit', 'NegReg', (99, 106))	('signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('CXCR4', 'molecular_function', 'GO:0038147', ('6', '11'))	('CXCR4', 'molecular_function', 'GO:0038147', ('77', '82'))	('Tregs', 'Chemical', '-', (35, 40))	('Tregs', 'Chemical', '-', (111, 116))
125336	29100374	Moreover, a significant increase of IFN-gamma was observed when PB-Tregs were pretreated with Pep R29, AMD3100 and anti-PD1 and then added to autologous Teff cells (1:1 vs 1:1+ Peptide R29: 1+-2 vs 99+-53; 1:1 vs 1:1+AMD3100: 1+-2 vs 108+-36; 1:1 vs 1:1+ anti-PD1: 1+-2 vs 70+-45) (Figure 6D) suggesting a recover in T-effector proliferative activity.	('PD1', 'Gene', (120, 123))	('increase', 'PosReg', (24, 32))	('Tregs', 'Chemical', '-', (67, 72))	('recover', 'PosReg', (306, 313))	('T-effector proliferative activity', 'CPA', (317, 350))	('PD1', 'Gene', '5133', (260, 263))	('AMD3100', 'Var', (103, 110))	('IFN-gamma', 'Gene', (36, 45))	('PD1', 'Gene', (260, 263))	('IFN-gamma', 'Gene', '3458', (36, 45))	('PD1', 'Gene', '5133', (120, 123))	('Pep R29', 'Var', (94, 101))
125340	29100374	In here, Tregs expressing CTLA-4, ICOS, ENTPD1, CD45RA and PD-1 were the majority among tumoral Tregs and the so called effector Tregs, CD25hiFOXP3hiCD45RA- highly suppressive cells, were the most represented among tumor Tregs tissue derived.	('ENTPD1', 'Gene', '953', (40, 46))	('tumoral', 'Disease', (88, 95))	('tumoral', 'Disease', 'MESH:D009369', (88, 95))	('PD-1', 'Gene', (59, 63))	('Tregs', 'Chemical', '-', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('ICOS', 'Gene', '29851', (34, 38))	('Tregs', 'Chemical', '-', (9, 14))	('CTLA-4', 'Gene', '1493', (26, 32))	('ENTPD1', 'Gene', (40, 46))	('CTLA-4', 'Gene', (26, 32))	('ICOS', 'Gene', (34, 38))	('Tregs', 'Chemical', '-', (96, 101))	('tumor', 'Disease', (88, 93))	('CD45RA', 'Var', (48, 54))	('Tregs', 'Chemical', '-', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CD25', 'Gene', (136, 140))	('FOXP3', 'Gene', (142, 147))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('FOXP3', 'Gene', '50943', (142, 147))	('CD25', 'Gene', '3559', (136, 140))
125347	29100374	Tregs function is regulated through methylation of Treg-specific demethylated region (TSDR).	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('Tregs', 'Chemical', '-', (0, 5))	('TSDR', 'Gene', (86, 90))	('methylation', 'Var', (36, 47))
125349	29100374	TSDR-hypermetilated Tregs impaired suppressive function; recent evidence demonstrated TSDR demethylation in liver biopsy and peripheral blood samples from patients with advanced grades of HCC compared to control subjects with nonmalignant disease.	('TSDR', 'Gene', (86, 90))	('demethylation', 'Var', (91, 104))	('demethylation', 'biological_process', 'GO:0070988', ('91', '104'))	('HCC', 'Disease', (188, 191))	('Tregs', 'Chemical', '-', (20, 25))	('patients', 'Species', '9606', (155, 163))
125360	29100374	In metastatic renal carcinoma IL-2 based immunotherapy leads to substantial expansion of T-cells with a demethylated TSDR.	('IL-2', 'Gene', (30, 34))	('TSDR', 'Gene', (117, 121))	('renal carcinoma', 'Disease', 'MESH:C538614', (14, 29))	('demethylated', 'Var', (104, 116))	('IL-2', 'molecular_function', 'GO:0005134', ('30', '34'))	('renal carcinoma', 'Disease', (14, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('IL-2', 'Gene', '3558', (30, 34))	('renal carcinoma', 'Phenotype', 'HP:0005584', (14, 29))
125362	29100374	Post translational modification such as acetylation can regulate Treg-FOXP3 activity.	('Post translational modification', 'biological_process', 'GO:0043687', ('0', '31'))	('activity', 'MPA', (76, 84))	('FOXP3', 'Gene', (70, 75))	('acetylation', 'Var', (40, 51))	('regulate', 'Reg', (56, 64))	('FOXP3', 'Gene', '50943', (70, 75))
125398	29100374	For female patients, this rate was corrected by a factor of 2 because one of the two TSDR alleles is methylated as a result of X inactivation.	('patients', 'Species', '9606', (11, 19))	('TSDR', 'Gene', (85, 89))	('X inactivation', 'Var', (127, 141))
125402	29100374	After 30' the cells were washed and then stained with Fitc-anti-CD25, APC-Cy7-anti-CD4 (BD Bioscience) and 7-amino-actinomycin D (7-AAD) (BioLegend) and analyzed by flow cytometer.	('CD25', 'Gene', (64, 68))	('7-AAD', 'Chemical', 'MESH:C025942', (130, 135))	('APC', 'cellular_component', 'GO:0005680', ('70', '73'))	('Fitc', 'Chemical', '-', (54, 58))	('CD25', 'Gene', '3559', (64, 68))	('7-amino-actinomycin D', 'Chemical', 'MESH:C025942', (107, 128))	('APC-Cy7-anti-CD4', 'Var', (70, 86))
125413	33502086	Methods that a priori define groups of measurements based on known regulated targets (that we call footprints (Dugourd & Saez-Rodriguez, 2019)) of transcription factors (TFs; Alvarez et al, 2016; Garcia-Alonso et al, 2019), kinases/phosphatases (Wiredja et al, 2017), and pathway perturbations (Schubert et al, 2018) provide integrated statistics that can be interpreted as a proxy of the activity of a molecule or process.	('Garcia-Alonso', 'Disease', 'MESH:C536767', (196, 209))	('TF', 'Gene', '2152', (170, 172))	('transcription', 'biological_process', 'GO:0006351', ('147', '160'))	('pathway', 'Var', (272, 279))	('men', 'Species', '9606', (46, 49))	('Garcia-Alonso', 'Disease', (196, 209))
125491	33502086	We then looked for mechanistic hypotheses connecting TF activity deregulations and changes in flux values.	('deregulations', 'Var', (65, 78))	('TF', 'Gene', '2152', (53, 55))	('activity', 'MPA', (56, 64))	('flux values', 'MPA', (94, 105))	('changes', 'Reg', (83, 90))
125507	33502086	The network showed that the crosstalks between MAPK1, NFKB1, MYC, HIF1A, and YY1 could explain the deregulation in glutamine and reduced glutathione metabolism, as well as inosine, hypoxanthine, and adenine.	('adenine', 'MPA', (199, 206))	('glutamine', 'Chemical', 'MESH:D005973', (115, 124))	('adenine', 'Chemical', 'MESH:D000225', (199, 206))	('hypoxanthine', 'Chemical', 'MESH:D019271', (181, 193))	('inosine', 'MPA', (172, 179))	('hypoxanthine', 'MPA', (181, 193))	('deregulation', 'MPA', (99, 111))	('reduced glutathione metabolism', 'Phenotype', 'HP:0003343', (129, 159))	('glutathione metabolism', 'biological_process', 'GO:0006749', ('137', '159'))	('NFKB1', 'Gene', (54, 59))	('glutathione', 'Chemical', 'MESH:D005978', (137, 148))	('MYC', 'Gene', '4609', (61, 64))	('HIF1A', 'Gene', '3091', (66, 71))	('MAPK1', 'Gene', '5594', (47, 52))	('YY1', 'Gene', '7528', (77, 80))	('YY1', 'Gene', (77, 80))	('MAPK', 'molecular_function', 'GO:0004707', ('47', '51'))	('crosstalks', 'Var', (28, 38))	('inosine', 'Chemical', 'MESH:D007288', (172, 179))	('MAPK1', 'Gene', (47, 52))	('HIF1A', 'Gene', (66, 71))	('NFKB1', 'Gene', '4790', (54, 59))	('MYC', 'Gene', (61, 64))
125515	33502086	The link shown by COSMOS between KMT2A and adenosine is interesting, because KMT2A mutations have been reported in a number of ccRCC patients (Yan et al, 2019), suggesting that this enzyme might play a functional role in ccRCC development.	('mutations', 'Var', (83, 92))	('KMT2A', 'Gene', (33, 38))	('KMT2A', 'Gene', (77, 82))	('KMT2A', 'Gene', '4297', (33, 38))	('reported', 'Reg', (103, 111))	('patients', 'Species', '9606', (133, 141))	('KMT2A', 'Gene', '4297', (77, 82))	('ccRCC', 'Disease', (127, 132))	('adenosine', 'Chemical', 'MESH:D000241', (43, 52))	('play', 'Reg', (195, 199))	('ccRCC', 'Disease', (221, 226))	('men', 'Species', '9606', (234, 237))
125585	33502086	Then, we first set the deregulated kinases, phosphatases, and TFs as starting points and deregulated metabolites as end points ("forward" run).	('TF', 'Gene', '2152', (62, 64))	('deregulated metabolites', 'MPA', (89, 112))	('phosphatases', 'Enzyme', (44, 56))	('deregulated', 'Var', (23, 34))
125586	33502086	However, since metabolite concentration can also influence the activity of kinases and TFs through allosteric regulations, we also ran CARNIVAL by setting deregulated metabolites as starting points and deregulated TFs, kinases, and phosphatases as end points ("backward" run).	('phosphatases', 'Enzyme', (232, 244))	('TF', 'Gene', '2152', (214, 216))	('activity', 'MPA', (63, 71))	('deregulated', 'Var', (202, 213))	('kinases', 'Enzyme', (75, 82))	('TF', 'Gene', '2152', (87, 89))	('influence', 'Reg', (49, 58))	('kinases', 'Enzyme', (219, 226))
125613	31477752	Myoferlin silencing inhibits VEGFR2-mediated proliferation of metastatic clear cell renal cell carcinoma Recently, ramucirumab, a drug that targets vascular endothelial growth factor receptor (VEGFR), was clinically approved; therefore, we evaluated VEGFR2 expression and its predictive roles in tumor progression in clear cell renal cell carcinoma (CCRCC).	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (73, 104))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (84, 104))	('VEGFR2', 'Gene', '3791', (250, 256))	('VEGFR', 'Gene', '3791', (29, 34))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (317, 348))	('clear cell renal cell carcinoma', 'Disease', (73, 104))	('vascular endothelial growth factor receptor', 'Gene', (148, 191))	('VEGFR', 'Gene', (29, 34))	('tumor', 'Disease', (296, 301))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (328, 348))	('vascular endothelial growth factor receptor', 'Gene', '3791', (148, 191))	('Myoferlin', 'Gene', '26509', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (296, 301))	('VEGFR', 'Gene', '3791', (250, 255))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (79, 104))	('inhibits', 'NegReg', (20, 28))	('clear cell renal cell carcinoma', 'Disease', (317, 348))	('VEGFR', 'Gene', (250, 255))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (73, 104))	('VEGFR2', 'Gene', (29, 35))	('ramucirumab', 'Chemical', 'MESH:C543333', (115, 126))	('VEGFR', 'Gene', '3791', (193, 198))	('silencing', 'Var', (10, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (339, 348))	('CCRCC', 'Phenotype', 'HP:0006770', (350, 355))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('VEGFR', 'Gene', (193, 198))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('148', '182'))	('Myoferlin', 'Gene', (0, 9))	('VEGFR2', 'Gene', '3791', (29, 35))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (317, 348))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (323, 348))	('VEGFR2', 'Gene', (250, 256))
125631	31477752	In melanoma cell line (A374), knockdown of MYOF suppressed vasculogenic mimicry via reducing matrix metalloproteinase -2 (MMP-2) and increasing mesenchymal-epithelial transition.	('MMP-2', 'Gene', (122, 127))	('matrix metalloproteinase -2', 'Gene', '4313', (93, 120))	('increasing', 'PosReg', (133, 143))	('A374', 'CellLine', 'CVCL:V727', (23, 27))	('MYOF', 'Gene', (43, 47))	('MYOF', 'Gene', '26509', (43, 47))	('matrix metalloproteinase -2', 'Gene', (93, 120))	('suppressed', 'NegReg', (48, 58))	('mesenchymal-epithelial transition', 'CPA', (144, 177))	('MMP-2', 'Gene', '4313', (122, 127))	('vasculogenic mimicry', 'MPA', (59, 79))	('knockdown', 'Var', (30, 39))	('melanoma', 'Disease', (3, 11))	('reducing', 'NegReg', (84, 92))	('mesenchymal-epithelial transition', 'biological_process', 'GO:0060231', ('144', '177'))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('MMP-2', 'molecular_function', 'GO:0004228', ('122', '127'))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))
125633	31477752	In pancreatic ductal carcinoma cell (Panc-1), MYOF silencing decreased cancer cell migration by reducing mitochondrial respiration.	('silencing', 'Var', (51, 60))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('pancreatic ductal carcinoma', 'Disease', 'MESH:D021441', (3, 30))	('respiration', 'biological_process', 'GO:0045333', ('119', '130'))	('cancer', 'Disease', (71, 77))	('reducing', 'NegReg', (96, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('cell migration', 'biological_process', 'GO:0016477', ('78', '92'))	('MYOF', 'Gene', '26509', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('respiration', 'biological_process', 'GO:0007585', ('119', '130'))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (14, 30))	('decreased', 'NegReg', (61, 70))	('pancreatic ductal carcinoma', 'Disease', (3, 30))	('mitochondrial respiration', 'MPA', (105, 130))	('Panc-1', 'CellLine', 'CVCL:0480', (37, 43))	('MYOF', 'Gene', (46, 50))
125663	31477752	Transfection of Caki-1 with MYO366 siRNAs resulted in decreased mRNA (Fig.	('Caki-1', 'CellLine', 'CVCL:0234', (16, 22))	('decreased', 'NegReg', (54, 63))	('MYO366 siRNAs', 'Var', (28, 41))
125666	31477752	This indicated that MYOF inhibition did not affect cell migration in metastatic CCRCC.	('MYOF', 'Gene', '26509', (20, 24))	('cell migration', 'biological_process', 'GO:0016477', ('51', '65'))	('metastatic CCRCC', 'Disease', (69, 85))	('inhibition', 'Var', (25, 35))	('MYOF', 'Gene', (20, 24))	('CCRCC', 'Phenotype', 'HP:0006770', (80, 85))
125682	31477752	In our study, there were almost no differences in cell migration between the control group and the MYOF knockdown group (Fig.	('cell migration', 'biological_process', 'GO:0016477', ('50', '64'))	('MYOF', 'Gene', (99, 103))	('MYOF', 'Gene', '26509', (99, 103))	('knockdown', 'Var', (104, 113))
125687	31477752	MYOF loss blocks EGF-induced cell migration and epithelial to mesenchymal transition.	('MYOF', 'Gene', '26509', (0, 4))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('48', '84'))	('cell migration', 'biological_process', 'GO:0016477', ('29', '43'))	('EGF', 'molecular_function', 'GO:0005154', ('17', '20'))	('blocks', 'NegReg', (10, 16))	('loss', 'Var', (5, 9))	('MYOF', 'Gene', (0, 4))	('EGF-induced', 'Protein', (17, 28))	('epithelial to mesenchymal transition', 'CPA', (48, 84))
125689	31477752	Unlike that in endothelial cells or breast cancer cells, knockdown of MYOF in renal cell carcinoma cells may affect one of the VEGFR2-mediated downstream signaling pathways not related to tumor cell migration.	('tumor', 'Disease', (188, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Disease', (36, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('MYOF', 'Gene', '26509', (70, 74))	('signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('VEGFR2-mediated downstream signaling pathways', 'Pathway', (127, 172))	('knockdown', 'Var', (57, 66))	('renal cell carcinoma', 'Disease', (78, 98))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (78, 98))	('cell migration', 'biological_process', 'GO:0016477', ('194', '208'))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('affect', 'Reg', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (78, 98))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('MYOF', 'Gene', (70, 74))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
125690	31477752	Analysis of cell confluence at 48 hours revealed lower confluence in the MYOF knockdown group than in the control group.	('MYOF', 'Gene', '26509', (73, 77))	('knockdown', 'Var', (78, 87))	('confluence', 'CPA', (55, 65))	('lower', 'NegReg', (49, 54))	('MYOF', 'Gene', (73, 77))
125695	31477752	In our study, knockdown of MYOF in Caki-1 cells reduced proliferation without affecting migration.	('Caki-1', 'CellLine', 'CVCL:0234', (35, 41))	('reduced', 'NegReg', (48, 55))	('proliferation', 'CPA', (56, 69))	('MYOF', 'Gene', (27, 31))	('knockdown', 'Var', (14, 23))	('MYOF', 'Gene', '26509', (27, 31))
125696	31477752	Among many intracellular signal transduction pathways, including p38 MAPK, NFAT, RACK1, SRC, PKB/AKT, and RAS, dysregulation of the RAS/RAF/MAP kinase cascade may alter nuclear gene transcription, thereby promoting CCRCC cell proliferation.	('alter', 'Reg', (163, 168))	('CCRCC', 'Phenotype', 'HP:0006770', (215, 220))	('RACK1', 'Gene', '10399', (81, 86))	('SRC', 'Gene', '6714', (88, 91))	('RACK1', 'Gene', (81, 86))	('promoting', 'PosReg', (205, 214))	('RAF', 'Gene', '22882', (136, 139))	('MAP kinase cascade', 'biological_process', 'GO:0000165', ('140', '158'))	('SRC', 'Gene', (88, 91))	('PKB', 'Disease', 'None', (93, 96))	('nuclear gene transcription', 'MPA', (169, 195))	('MAPK', 'molecular_function', 'GO:0004707', ('69', '73'))	('RAF', 'Gene', (136, 139))	('p38', 'Gene', (65, 68))	('MAP', 'molecular_function', 'GO:0004239', ('140', '143'))	('dysregulation', 'Var', (111, 124))	('CCRCC', 'Disease', (215, 220))	('intracellular signal transduction', 'biological_process', 'GO:0035556', ('11', '44'))	('PKB', 'Disease', (93, 96))	('cell proliferation', 'biological_process', 'GO:0008283', ('221', '239'))	('intracellular', 'cellular_component', 'GO:0005622', ('11', '24'))	('p38', 'Gene', '1432', (65, 68))	('transcription', 'biological_process', 'GO:0006351', ('182', '195'))
125731	31477752	The primary antibodies used for immunoblotting were anti-MYOF (Abcam, #ab76746, UK), anti-VEGFR2 (Thermo Fisher Scientific, #RB-1526-P1, USA), and anti-GAPDH (Abcam, #ab8245, UK).	('GAPDH', 'Gene', '2597', (152, 157))	('MYOF', 'Gene', (57, 61))	('GAPDH', 'Gene', (152, 157))	('anti-VEGFR2', 'Var', (85, 96))	('MYOF', 'Gene', '26509', (57, 61))
125756	33680068	The ablation of ROM1 leads to a change from the macular/pattern dystrophy (MD/PD) phenotype characterized by a defect in cone function to a retinitis pigmentosa (RP) phenotype characterized by a dominant defect in rod function, and the formation of abnormal Prph2/ROM1 complex and total Prph2 protein decreased.	('Prph2', 'Gene', '5961', (258, 263))	('defect in cone function', 'Phenotype', 'HP:0030637', (111, 134))	('formation', 'biological_process', 'GO:0009058', ('236', '245'))	('pattern dystrophy', 'Disease', (56, 73))	('retinitis pigmentosa', 'Disease', 'MESH:C538365', (140, 160))	('pattern dystrophy', 'Disease', 'MESH:D008268', (56, 73))	('ablation', 'Var', (4, 12))	('MD/PD', 'Phenotype', 'HP:0007754', (75, 80))	('RP', 'Phenotype', 'HP:0000510', (162, 164))	('defect', 'NegReg', (111, 117))	('macular/pattern dystrophy', 'Phenotype', 'HP:0007754', (48, 73))	('Prph2', 'Gene', '5961', (287, 292))	('Prph2', 'Gene', (258, 263))	('retinitis pigmentosa', 'Disease', (140, 160))	('decreased', 'NegReg', (301, 310))	('retinitis', 'Phenotype', 'HP:0032118', (140, 149))	('protein', 'cellular_component', 'GO:0003675', ('293', '300'))	('PD', 'Disease', 'MESH:D010300', (78, 80))	('ROM1', 'Gene', (16, 20))	('formation', 'MPA', (236, 245))	('Prph2', 'Gene', (287, 292))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (140, 160))	('change', 'Reg', (32, 38))
125764	33680068	The second was the Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/), containing GSE4573, GSE31210, GSE50081, GSE37745, and GSE30219.	('GSE4573', 'Chemical', '-', (95, 102))	('GSE4573', 'Var', (95, 102))	('GSE31210', 'Var', (104, 112))	('Gene Expression', 'biological_process', 'GO:0010467', ('19', '34'))	('GSE30219', 'Var', (138, 146))	('GSE50081', 'Var', (114, 122))	('GSE37745', 'Var', (124, 132))
125785	33680068	Kaplan-Meier analysis revealed that patients with lowly expressed ROM1 demonstrated shorter overall survival (OS) time and disease-free survival (DFS) (Figures 1(d) and 1(e)).	('patients', 'Species', '9606', (36, 44))	('disease-free survival', 'CPA', (123, 144))	('lowly expressed', 'Var', (50, 65))	('shorter', 'NegReg', (84, 91))	('overall', 'MPA', (92, 99))	('ROM1', 'Gene', (66, 70))
125802	33680068	CCK-8 assay deeply demonstrated that ablated ROM1 induced cell proliferation, indicating that ROM1 modulated lung cancer cell proliferation (Figures 5(b) and 5(c)).	('lung cancer', 'Disease', (109, 120))	('ablated', 'Var', (37, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('ROM1', 'Gene', (94, 98))	('cell proliferation', 'biological_process', 'GO:0008283', ('121', '139'))	('modulated', 'Reg', (99, 108))	('CCK-8', 'Chemical', 'MESH:D012844', (0, 5))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('ROM1', 'Gene', (45, 49))	('cell proliferation', 'biological_process', 'GO:0008283', ('58', '76'))
125804	33680068	Transwell analysis results indicated that a significantly increased number of migrated and invaded lung cancer cells were demonstrated in ROM1 knockdown group (Figures 5(d) and 5(e)).	('lung cancer', 'Disease', (99, 110))	('increased', 'PosReg', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('knockdown', 'Var', (143, 152))	('ROM1', 'Gene', (138, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
125824	33680068	We found that knocking out ROM1 significantly promoted lung cancer cell proliferation.	('promoted', 'PosReg', (46, 54))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('lung cancer', 'Disease', (55, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('ROM1', 'Gene', (27, 31))	('knocking out', 'Var', (14, 26))
125826	33680068	The Transwell test showed that knocking out ROM1 significantly promoted lung cancer cell migration and invasion.	('ROM1', 'Gene', (44, 48))	('lung cancer', 'Disease', (72, 83))	('cell migration', 'biological_process', 'GO:0016477', ('84', '98'))	('promoted', 'PosReg', (63, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('invasion', 'CPA', (103, 111))	('knocking out', 'Var', (31, 43))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
125847	28672194	He established the hypothesis that faulty mitochondrial functions in tumor cells are major causes of carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('causes', 'Reg', (91, 97))	('faulty', 'Var', (35, 41))	('mitochondrial functions', 'MPA', (42, 65))	('tumor', 'Disease', (69, 74))	('carcinogenesis', 'Disease', (101, 115))	('faulty mitochondrial functions', 'Phenotype', 'HP:0003287', (35, 65))	('carcinogenesis', 'Disease', 'MESH:D063646', (101, 115))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
125865	28672194	Subsequently, immunostaining was performed with antibodies against ATP5A1 1:1000 (#ab14748, Abcam, Cambridge, UK), ATPAF1 1:1000 (#HPA044950, Sigma-Aldrich, Munich, Germany), a combined antibody against ATP5G1, ATP5G2 and ATP5G3 1:5000 (#ab180149, Abcam), GAPDH (#2118, Cell Signaling Technology), and beta-actin (#A5316, Sigma-Aldrich).	('ATP5G3', 'Gene', '518', (222, 228))	('antibody', 'cellular_component', 'GO:0019815', ('186', '194'))	('ATPAF1', 'Gene', '64756', (115, 121))	('GAPDH', 'Gene', '2597', (256, 261))	('beta-actin', 'Gene', '728378', (302, 312))	('ATP5A1', 'Gene', '498', (67, 73))	('ATPAF1', 'Gene', (115, 121))	('#A5316', 'Var', (314, 320))	('antibody', 'cellular_component', 'GO:0019814', ('186', '194'))	('ATP5G1', 'Gene', (203, 209))	('ATP5G1', 'Gene', '516', (203, 209))	('Signaling', 'biological_process', 'GO:0023052', ('275', '284'))	('ATP5G2', 'Gene', (211, 217))	('GAPDH', 'Gene', (256, 261))	('ATP5A1', 'Gene', (67, 73))	('antibody', 'molecular_function', 'GO:0003823', ('186', '194'))	('ATP5G3', 'Gene', (222, 228))	('beta-actin', 'Gene', (302, 312))	('antibody', 'cellular_component', 'GO:0042571', ('186', '194'))	('ATP5G2', 'Gene', '517', (211, 217))
125910	28672194	To the best of our knowledge, this is the first study showing dysregulation of ATP5G1 in cancer.	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('dysregulation', 'Var', (62, 75))	('cancer', 'Disease', (89, 95))	('ATP5G1', 'Gene', (79, 85))	('ATP5G1', 'Gene', '516', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
125911	28672194	Earlier studies demonstrated that siRNA knockdown of ATP5G1 resulted in reduced ATP levels as a consequence of reduced oxidative phosphorylation activity, and increased the amount of reactive oxygen species (ROS).	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('119', '144'))	('reduced', 'NegReg', (72, 79))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (183, 206))	('ATP5G1', 'Gene', (53, 59))	('ATP5G1', 'Gene', '516', (53, 59))	('knockdown', 'Var', (40, 49))	('increased', 'PosReg', (159, 168))	('oxidative phosphorylation activity', 'MPA', (119, 153))	('reduced', 'NegReg', (111, 118))	('ATP levels', 'MPA', (80, 90))	('ROS', 'Chemical', 'MESH:D017382', (208, 211))	('ATP', 'Chemical', 'MESH:D000255', (80, 83))	('ATP', 'Chemical', 'MESH:D000255', (53, 56))
125913	28672194	The subunit ATP5A1 was linked to cancer by other researchers: ATP5A1 expression facilitated the development of colorectal tumors with microsatellite instability, and its expression was up-regulated in glioblastoma and endothelial cells of tumor microenvironment.	('cancer', 'Disease', (33, 39))	('ATP5A1', 'Gene', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('development', 'CPA', (96, 107))	('tumor', 'Disease', (122, 127))	('expression', 'MPA', (170, 180))	('glioblastoma', 'Disease', 'MESH:D005909', (201, 213))	('colorectal tumors', 'Disease', 'MESH:D015179', (111, 128))	('ATP5A1', 'Gene', '498', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', (239, 244))	('glioblastoma', 'Disease', (201, 213))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('facilitated', 'PosReg', (80, 91))	('glioblastoma', 'Phenotype', 'HP:0012174', (201, 213))	('ATP5A1', 'Gene', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('up-regulated', 'PosReg', (185, 197))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('colorectal tumors', 'Disease', (111, 128))	('microsatellite instability', 'Var', (134, 160))	('ATP5A1', 'Gene', '498', (62, 68))
125917	28672194	The functional consequence of altered ATPAF1 expression remains largely unknown, but it was shown that RNAi-mediated knockdown of ATPAF1 reduces cell growth of prostate cancer cells in androgen-deficient conditions.	('cell growth', 'CPA', (145, 156))	('ATPAF1', 'Gene', '64756', (130, 136))	('prostate cancer', 'Disease', (160, 175))	('ATPAF1', 'Gene', '64756', (38, 44))	('androgen-deficient', 'Phenotype', 'HP:0008226', (185, 203))	('cell growth', 'biological_process', 'GO:0016049', ('145', '156'))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('ATPAF1', 'Gene', (130, 136))	('RNAi', 'biological_process', 'GO:0016246', ('103', '107'))	('prostate cancer', 'Disease', 'MESH:D011471', (160, 175))	('knockdown', 'Var', (117, 126))	('prostate cancer', 'Phenotype', 'HP:0012125', (160, 175))	('reduces', 'NegReg', (137, 144))	('ATPAF1', 'Gene', (38, 44))
125922	28092369	Context-dependent role for chromatin remodeling component PBRM1/BAF180 in clear cell renal cell carcinoma A subset of clear cell renal cell carcinoma (ccRCC) tumors exhibit a HIF1A gene mutation, yielding two ccRCC tumor types, H1H2 type expressing both HIF1alpha and HIF2alpha, and H2 type expressing HIF2alpha, but not functional HIF1alpha protein.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('clear cell renal cell carcinoma (ccRCC) tumors', 'Disease', 'MESH:C538614', (118, 164))	('RCC', 'Disease', (211, 214))	('HIF1A', 'Gene', (175, 180))	('ccRCC', 'Phenotype', 'HP:0006770', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('PBRM1', 'Gene', (58, 63))	('BAF180', 'Gene', (64, 70))	('clear cell renal cell carcinoma', 'Disease', (74, 105))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (85, 105))	('chromatin', 'cellular_component', 'GO:0000785', ('27', '36'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mutation', 'Var', (186, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (118, 149))	('RCC', 'Disease', 'MESH:C538614', (211, 214))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (129, 149))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (74, 105))	('clear cell renal cell carcinoma', 'Disease', (118, 149))	('RCC', 'Disease', (153, 156))	('ccRCC', 'Phenotype', 'HP:0006770', (151, 156))	('tumor', 'Disease', (215, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('tumor', 'Disease', (158, 163))	('yielding', 'Reg', (196, 204))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (74, 105))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (118, 149))	('PBRM1', 'Gene', '55193', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('27', '47'))	('BAF180', 'Gene', '55193', (64, 70))	('protein', 'cellular_component', 'GO:0003675', ('342', '349'))
125923	28092369	However, it is unclear how the H1H2 type ccRCC tumors escape HIF1's tumor-suppressive activity.	("HIF1's tumor", 'Disease', 'MESH:D009396', (61, 73))	('ccRCC tumors', 'Disease', 'MESH:D009369', (41, 53))	('escape', 'NegReg', (54, 60))	('ccRCC tumors', 'Disease', (41, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('H1H2 type', 'Var', (31, 40))	("HIF1's tumor", 'Disease', (61, 73))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
125925	28092369	Thus, our questions are if BAF180 is involved in HIF-mediated hypoxia response and if PBRM1/BAF180 mutation has any association with the HIF1A retention in H1H2 type ccRCC.	('association', 'Interaction', (116, 127))	('HIF-mediated hypoxia', 'Disease', 'MESH:D000860', (49, 69))	('ccRCC', 'Phenotype', 'HP:0006770', (166, 171))	('mutation', 'Var', (99, 107))	('HIF-mediated hypoxia', 'Disease', (49, 69))	('PBRM1', 'Gene', (86, 91))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('RCC', 'Disease', (168, 171))	('PBRM1', 'Gene', '55193', (86, 91))	('retention', 'biological_process', 'GO:0051235', ('143', '152'))
125927	28092369	However, BAF180 is expressed in HIF1-deficient H2 ccRCC cell lines and tumors, and BAF180 knockdown in H2 type ccRCC cell lines reduced cell proliferation/survival, indicating that BAF180 has tumor-promoting activity in these cells.	('HIF1-deficient', 'Disease', 'MESH:D007153', (32, 46))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('HIF1-deficient', 'Disease', (32, 46))	('tumors', 'Disease', (71, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (50, 55))	('RCC', 'Disease', (52, 55))	('reduced', 'NegReg', (128, 135))	('RCC', 'Disease', (113, 116))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('tumor', 'Disease', (192, 197))	('knockdown', 'Var', (90, 99))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cell proliferation/survival', 'CPA', (136, 163))	('tumor', 'Disease', (71, 76))	('BAF180', 'Gene', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('cell proliferation', 'biological_process', 'GO:0008283', ('136', '154'))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
125929	28092369	Thus, our studies reveal that BAF180 function in ccRCC is context dependent, and that mutation of PBRM1/BAF180 serves as an alternative strategy for ccRCC tumors to reduce HIF1 tumor-suppressive activity in H1H2 ccRCC tumors.	('PBRM1', 'Gene', (98, 103))	('ccRCC tumors', 'Disease', 'MESH:D009369', (212, 224))	('RCC', 'Disease', 'MESH:C538614', (214, 217))	('ccRCC tumors', 'Disease', 'MESH:D009369', (149, 161))	('HIF1 tumor', 'Disease', 'MESH:D009369', (172, 182))	('RCC', 'Disease', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('reduce', 'NegReg', (165, 171))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('ccRCC', 'Phenotype', 'HP:0006770', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('RCC', 'Disease', (151, 154))	('ccRCC', 'Phenotype', 'HP:0006770', (149, 154))	('PBRM1', 'Gene', '55193', (98, 103))	('RCC', 'Disease', (214, 217))	('ccRCC tumors', 'Disease', (212, 224))	('HIF1 tumor', 'Disease', (172, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('mutation', 'Var', (86, 94))	('ccRCC tumors', 'Disease', (149, 161))
125934	28092369	Recent exome sequencing of ccRCC tumors has identified almost universal mutation of the von-Hippel Lindau (VHL) tumor-suppressive gene.	('ccRCC tumors', 'Disease', 'MESH:D009369', (27, 39))	('ccRCC tumors', 'Disease', (27, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('mutation', 'Var', (72, 80))	('von-Hippel Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (88, 117))
125942	28092369	Despite positive role of both HIF1 and HIF2 in ccRCC initiation, results from clinical and laboratory studies indicate that HIF2 plays a positive role in ccRCC tumor maintenance, whereas HIF1 has a tumor-suppressive role in late stage ccRCC development and in established ccRCC tumors.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('ccRCC', 'Phenotype', 'HP:0006770', (154, 159))	('RCC', 'Disease', (156, 159))	('RCC', 'Disease', (274, 277))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('ccRCC', 'Phenotype', 'HP:0006770', (272, 277))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('HIF2', 'Var', (124, 128))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('HIF1', 'Gene', '3091', (187, 191))	('RCC', 'Disease', 'MESH:C538614', (274, 277))	('ccRCC tumors', 'Disease', (272, 284))	('HIF1', 'Gene', (187, 191))	('HIF1', 'Gene', '3091', (30, 34))	('RCC', 'Disease', (49, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('tumor', 'Disease', (278, 283))	('ccRCC tumors', 'Disease', 'MESH:D009369', (272, 284))	('HIF1', 'Gene', (30, 34))	('RCC', 'Disease', (237, 240))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('RCC', 'Disease', 'MESH:C538614', (49, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (235, 240))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('RCC', 'Disease', 'MESH:C538614', (237, 240))
125943	28092369	On the basis of the expression pattern of HIF1alpha, ccRCC tumors can be divided into two subtypes: H2 ccRCC tumors that express HIF2alpha but not a functional HIF1alpha protein, and H1H2 ccRCC tumors that express both HIF1alpha and HIF2alpha protein.	('ccRCC tumors', 'Disease', 'MESH:D009369', (188, 200))	('ccRCC tumors', 'Disease', (53, 65))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('ccRCC tumors', 'Disease', 'MESH:D009369', (53, 65))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('expression', 'Species', '29278', (20, 30))	('HIF2alpha', 'Var', (129, 138))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('protein', 'cellular_component', 'GO:0003675', ('243', '250'))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('ccRCC tumors', 'Disease', (103, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (188, 193))	('ccRCC tumors', 'Disease', 'MESH:D009369', (103, 115))	('ccRCC tumors', 'Disease', (188, 200))
125945	28092369	Exome sequencing has revealed that 40% of ccRCC tumors also harbor mutations in the polybromo-1 (PBRM1) gene that codes for the BAF180 protein (we will use the term of BAF180 for the gene and the protein, for simplicity), an accessory component of the PBAF complex, one type of SWI/SNF chromatin remodeling complex.	('PBAF complex', 'cellular_component', 'GO:0016586', ('252', '264'))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('ccRCC tumors', 'Disease', 'MESH:D009369', (42, 54))	('ccRCC', 'Phenotype', 'HP:0006770', (42, 47))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('286', '314'))	('mutations', 'Var', (67, 76))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('286', '306'))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('polybromo-1', 'Gene', '55193', (84, 95))	('ccRCC tumors', 'Disease', (42, 54))	('PBRM1', 'Gene', (97, 102))	('PBRM1', 'Gene', '55193', (97, 102))	('polybromo-1', 'Gene', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))
125949	28092369	Thus, the goal of this study was to determine if PBRM1/BAF180 is important for HIF1- and HIF2-mediated transcriptional response, and if the BAF180 gene mutation is associated with HIF1A retention in H1H2 ccRCC, a tumor-suppressive factor in established ccRCC tumors.	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('HIF1', 'Gene', '3091', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('HIF1', 'Gene', (79, 83))	('PBRM1', 'Gene', '55193', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Disease', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('retention', 'biological_process', 'GO:0051235', ('186', '195'))	('HIF1', 'Gene', '3091', (180, 184))	('BAF180', 'Gene', (140, 146))	('PBRM1', 'Gene', (49, 54))	('RCC', 'Disease', (255, 258))	('mutation', 'Var', (152, 160))	('ccRCC', 'Phenotype', 'HP:0006770', (253, 258))	('HIF1', 'Gene', (180, 184))	('associated', 'Reg', (164, 174))	('RCC', 'Disease', 'MESH:C538614', (255, 258))	('ccRCC', 'Phenotype', 'HP:0006770', (204, 209))	('RCC', 'Disease', (206, 209))	('tumor', 'Disease', (213, 218))	('ccRCC tumors', 'Disease', (253, 265))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('ccRCC tumors', 'Disease', 'MESH:D009369', (253, 265))	('RCC', 'Disease', 'MESH:C538614', (206, 209))
125950	28092369	Elucidating the function and molecular mechanism of BAF180 mutation may provide novel therapeutic target for ccRCC patients.	('patients', 'Species', '9606', (115, 123))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('RCC', 'Disease', (111, 114))	('mutation', 'Var', (59, 67))	('BAF180', 'Gene', (52, 58))
125952	28092369	Further, the BAF180-containing SWI-SNF chromatin remodeling complex is critical for HIF1-mediated transcriptional response and BAF180 is mutated in a subset of ccRCC tumors.	('ccRCC', 'Phenotype', 'HP:0006770', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('HIF1', 'Gene', (84, 88))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('39', '67'))	('ccRCC tumors', 'Disease', 'MESH:D009369', (160, 172))	('BAF180', 'Gene', (127, 133))	('mutated', 'Var', (137, 144))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('39', '59'))	('HIF1', 'Gene', '3091', (84, 88))	('ccRCC tumors', 'Disease', (160, 172))
125953	28092369	These observations prompted us to test the hypothesis that BAF180 mutation is associated with HIF1A retention in H1H2 ccRCC tumors.	('BAF180', 'Gene', (59, 65))	('associated', 'Reg', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('retention', 'biological_process', 'GO:0051235', ('100', '109'))	('ccRCC tumors', 'Disease', 'MESH:D009369', (118, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('mutation', 'Var', (66, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))	('ccRCC tumors', 'Disease', (118, 130))
125956	28092369	However, HIF1alpha is lost in KC-12, 769-P, 786-O, RCC10 or truncated in SLR 23 and A498 cells, whereas BAF180 protein expression is lost in RCC4, A704 and SLR25 cell lines (Figure 1a).	('RCC', 'Disease', (141, 144))	('lost', 'NegReg', (22, 26))	('RCC', 'Disease', 'MESH:C538614', (141, 144))	('KC-12', 'Chemical', '-', (30, 35))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('expression', 'Species', '29278', (119, 129))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('truncated', 'Var', (60, 69))	('RCC', 'Disease', (51, 54))
125957	28092369	Interestingly, there is a relationship between BAF180 and HIF1alpha protein expression, in which cell lines lack BAF180 protein expression (SLR25, A704 and RCC4) expressed full-length HIF1alpha protein (Figure 1a, indicated by a red arrow), whereas the BAF180-expressing ccRCC cell lines lacked HIF1alpha protein detection (KC-12, 769-P, 786-O and RCC10) or expressed truncated/non-functional HIF1alpha proteins (SLR23 and A498; Figure 1a).	('RCC', 'Disease', 'MESH:C538614', (348, 351))	('RCC', 'Disease', (156, 159))	('A498', 'Var', (423, 427))	('lacked', 'NegReg', (288, 294))	('KC-12', 'Chemical', '-', (324, 329))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('expression', 'Species', '29278', (76, 86))	('RCC', 'Disease', (273, 276))	('HIF1alpha protein', 'Protein', (295, 312))	('ccRCC', 'Phenotype', 'HP:0006770', (271, 276))	('RCC', 'Disease', 'MESH:C538614', (273, 276))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('RCC', 'Disease', (348, 351))	('BAF180', 'Gene', (113, 119))	('lack', 'NegReg', (108, 112))	('expression', 'Species', '29278', (128, 138))	('protein', 'cellular_component', 'GO:0003675', ('305', '312'))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))
125960	28092369	Representative images from HIF1alpha+/BAF180- and HIF1alpha-/BAF180+ ccRCC tumors are shown (Figure 1b).	('ccRCC tumors', 'Disease', 'MESH:D009369', (69, 81))	('HIF1alpha+/BAF180-', 'Var', (27, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('HIF1alpha-/BAF180+', 'Var', (50, 68))	('ccRCC tumors', 'Disease', (69, 81))
125964	28092369	Our data are consistent with previous reports that 14q33.1 where the HIF1A gene is located, is often associated with copy number loss in ccRCC tumors.	('ccRCC tumors', 'Disease', 'MESH:D009369', (137, 149))	('copy number loss', 'Var', (117, 133))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('ccRCC tumors', 'Disease', (137, 149))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('HIF1A', 'Gene', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
125966	28092369	A clonogenic assay determined that re-expression of BAF180 decreased the cell survival/proliferation of RCC4 cells in a dose-dependent manner (Figure 2c).	('expression', 'Species', '29278', (38, 48))	('decreased', 'NegReg', (59, 68))	('re-expression', 'Var', (35, 48))	('BAF180', 'Gene', (52, 58))	('cell survival/proliferation', 'CPA', (73, 100))
125969	28092369	To determine if BAF180 also exhibits tumor-suppressive activity in BAF180-expressing ccRCC cell lines (Figure 2a; 786-O, KC-12 and 769-P), we first decreased BAF180 protein levels in 786-O cells using BAF180 short hairpin RNA (shRNA; Figure 3a).	('KC-12', 'Chemical', '-', (121, 126))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('RCC', 'Disease', (87, 90))	('RNA', 'cellular_component', 'GO:0005562', ('222', '225'))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('decreased', 'NegReg', (148, 157))	('BAF180', 'Gene', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('BAF180', 'Var', (201, 207))	('protein levels', 'MPA', (165, 179))
125970	28092369	BAF180 knockdown in KC-12 and 769-P cells (Figures 3d and f), as well as RCC10 and A498 (not shown) also decreased cell survival/proliferation.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('cell survival/proliferation', 'CPA', (115, 142))	('RCC', 'Disease', (73, 76))	('KC-12', 'Chemical', '-', (20, 25))	('BAF180', 'Gene', (0, 6))	('knockdown', 'Var', (7, 16))	('decreased', 'NegReg', (105, 114))
125971	28092369	To definitively determine the function of BAF180 in BAF180-expressing ccRCC cell lines, we knocked out BAF180 gene expression in 786-O cells using CRISPR-Cas9 technology.	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('knocked', 'Var', (91, 98))	('RCC', 'Disease', (72, 75))	('expression', 'Species', '29278', (115, 125))	('Cas', 'cellular_component', 'GO:0005650', ('154', '157'))	('ccRCC', 'Phenotype', 'HP:0006770', (70, 75))	('gene expression', 'biological_process', 'GO:0010467', ('110', '125'))	('BAF180', 'Gene', (103, 109))
125972	28092369	Expression of a BAF180 single-guide RNA #1 (sgRNA#1) and Cas9 nuclease are expected to introduce double-stranded DNA breaks and subsequently mutation in exon 1 of the BAF180 gene, a location where BAF180 mutations are frequently observed in primary ccRCC tumors (Figure 3g).	('DNA', 'cellular_component', 'GO:0005574', ('113', '116'))	('ccRCC tumors', 'Disease', (249, 261))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('RNA', 'cellular_component', 'GO:0005562', ('36', '39'))	('BAF180', 'Gene', (16, 22))	('BAF180', 'Gene', (167, 173))	('BAF180', 'Gene', (197, 203))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('ccRCC', 'Phenotype', 'HP:0006770', (249, 254))	('Expression', 'Species', '29278', (0, 10))	('Cas', 'cellular_component', 'GO:0005650', ('57', '60'))	('introduce', 'Reg', (87, 96))	('ccRCC tumors', 'Disease', 'MESH:D009369', (249, 261))	('mutation', 'Var', (141, 149))	('double-stranded DNA breaks', 'MPA', (97, 123))
125974	28092369	Similarly, BAF180 sgRNA #2 led to the nucleotide deletion (Figure 3h and not shown), which resulted in a loss of BAF180 protein expression (Figure 3i and not shown) and a reduced cell survival/proliferation (Figure 3j and not shown).	('protein', 'Protein', (120, 127))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('BAF180', 'Gene', (113, 119))	('loss', 'NegReg', (105, 109))	('expression', 'Species', '29278', (128, 138))	('cell survival/proliferation', 'CPA', (179, 206))	('nucleotide deletion', 'Var', (38, 57))	('reduced', 'NegReg', (171, 178))
125977	28092369	HIF1alpha re-expression reduced 786-O cell proliferation/survival compared with parental 786-O cells (Figures 4b and c), consistent with the reported tumor-suppressive role of HIF1alpha in ccRCC cell lines.	('expression', 'Species', '29278', (13, 23))	('reduced', 'NegReg', (24, 31))	('RCC', 'Disease', (191, 194))	('HIF1alpha', 'Gene', (0, 9))	('RCC', 'Disease', 'MESH:C538614', (191, 194))	('ccRCC', 'Phenotype', 'HP:0006770', (189, 194))	('786-O cell proliferation/survival', 'CPA', (32, 65))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cell proliferation', 'biological_process', 'GO:0008283', ('38', '56'))	('re-expression', 'Var', (10, 23))	('tumor', 'Disease', (150, 155))
125979	28092369	H1H2 ccRCC cell lines (RCC4 and SLR25) express both HIF1alpha and HIF2alpha, but lack BAF180 protein expression, and re-expression of BAF180 in these cells decreased cell survival/proliferation (Figure 2).	('cell survival/proliferation', 'CPA', (166, 193))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('expression', 'Species', '29278', (120, 130))	('protein', 'Protein', (93, 100))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('decreased', 'NegReg', (156, 165))	('re-expression', 'Var', (117, 130))	('expression', 'Species', '29278', (101, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (5, 10))	('RCC', 'Disease', 'MESH:C538614', (7, 10))	('expression', 'MPA', (101, 111))	('RCC', 'Disease', (7, 10))	('lack', 'NegReg', (81, 85))	('BAF180', 'Gene', (86, 92))	('HIF2alpha', 'Var', (66, 75))
125981	28092369	In the absence of BAF180 expression (no doxycycline), HIF1A KD increased cell survival/proliferation compared with SLR25/SCR shRNA cells.	('expression', 'Species', '29278', (25, 35))	('increased', 'PosReg', (63, 72))	('doxycycline', 'Chemical', 'MESH:D004318', (40, 51))	('HIF1A', 'Var', (54, 59))	('cell survival/proliferation', 'CPA', (73, 100))
125984	28092369	Furthermore, expression of BAF180 in SLR25/HIF1A shRNA slightly increased clonogenic survival (P=0.0103) compared with the same cells without BAF180 expression, indicating that BAF180 and the remaining HIF2alpha protein cooperate, at least partially, to increase cell survival (Figures 4e and f).	('expression', 'Species', '29278', (13, 23))	('SLR25/HIF1A', 'Gene', (37, 48))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('BAF180', 'Var', (27, 33))	('expression', 'Species', '29278', (149, 159))	('expression', 'Var', (13, 23))	('cell survival', 'CPA', (263, 276))	('increased', 'PosReg', (64, 73))	('clonogenic survival', 'CPA', (74, 93))	('increase', 'PosReg', (254, 262))
125987	28092369	Although we have reported that the BRG1 knockdown significantly reduces HIF1 and HIF2 to activate their target genes, the role of BAF180 in HIF1 and HIF2 target gene activation remains unclear.	('HIF1', 'Gene', (72, 76))	('BRG1', 'Gene', (35, 39))	('activate', 'PosReg', (89, 97))	('HIF1', 'Gene', '3091', (140, 144))	('BRG1', 'Gene', '6597', (35, 39))	('knockdown', 'Var', (40, 49))	('HIF1', 'Gene', (140, 144))	('HIF2', 'Gene', (81, 85))	('HIF1', 'Gene', '3091', (72, 76))	('reduces', 'NegReg', (64, 71))
125988	28092369	To address this, we used Hep3B cells as a model, as they have a high level of HIF1alpha and HIF2alpha expression, and characterization of HIF target gene induction has been well established.	('expression', 'Species', '29278', (102, 112))	('Hep3B', 'CellLine', 'CVCL:0326', (25, 30))	('HIF1alpha', 'Gene', (78, 87))	('HIF2alpha', 'Var', (92, 101))
125989	28092369	BAF180 shRNA significantly reduced BAF180 protein levels in normoxic and HX Hep3B/BAF180 shRNA cells (Figure 5a) and BAF180 knockdown markedly reduced the HX induction of HIF1 target genes (Figure 5b), HIF2 target genes (Figure 5c) and HIF1/HIF2 common target genes (Figure 5d), albeit the levels of reduction were gene specific.	('knockdown', 'Var', (124, 133))	('reduced', 'NegReg', (27, 34))	('HIF1', 'Gene', '3091', (236, 240))	('BAF180', 'Gene', (35, 41))	('HIF1', 'Gene', '3091', (171, 175))	('reduced', 'NegReg', (143, 150))	('HIF1', 'Gene', (236, 240))	('HX induction', 'MPA', (155, 167))	('HIF1', 'Gene', (171, 175))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('HX Hep3B', 'CellLine', 'CVCL:0326', (73, 81))	('BAF180', 'Gene', (117, 123))
125991	28092369	Knockout of BAF180 in 786-O cells reduced the expression levels of HIF2 target genes (ADM, CST, GLUT1, NDRG1 and ADRP; Figure 5f).	('NDRG1', 'Gene', (103, 108))	('reduced', 'NegReg', (34, 41))	('BAF180', 'Gene', (12, 18))	('GLUT1', 'Gene', '6513', (96, 101))	('ADRP', 'Gene', (113, 117))	('expression levels', 'MPA', (46, 63))	('GLUT1', 'Gene', (96, 101))	('Knockout', 'Var', (0, 8))	('ADM', 'Gene', (86, 89))	('expression', 'Species', '29278', (46, 56))	('CST', 'Gene', (91, 94))
125992	28092369	Also KC-12/BAF180 shRNA and 769-P/BAF180 shRNA cells exhibited reduced HIF2 target gene expression in comparison with control shRNA (not shown).	('reduced', 'NegReg', (63, 70))	('KC-12', 'Chemical', '-', (5, 10))	('KC-12/BAF180', 'Var', (5, 17))	('gene expression', 'biological_process', 'GO:0010467', ('83', '98'))	('expression', 'Species', '29278', (88, 98))
125993	28092369	Conversely, BAF180 re-expression in RCC4 cells increased HIF1 and HIF2 target gene expression in a does-dependent manner (Figure 5g).	('BAF180', 'Gene', (12, 18))	('HIF1', 'Gene', (57, 61))	('re-expression', 'Var', (19, 32))	('expression', 'Species', '29278', (83, 93))	('increased', 'PosReg', (47, 56))	('gene expression', 'biological_process', 'GO:0010467', ('78', '93'))	('expression', 'MPA', (83, 93))	('expression', 'Species', '29278', (22, 32))	('increased HIF1', 'Phenotype', 'HP:0030269', (47, 61))	('HIF1', 'Gene', '3091', (57, 61))
126003	28092369	Likewise, the BAF180 gene is mutated in 40% ccRCC tumors, but the reason for BAF180 mutations in these BAF180-deficient ccRCC tumors is not known.	('ccRCC tumors', 'Disease', 'MESH:D009369', (120, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('BAF180-deficient ccRCC tumors', 'Disease', (103, 132))	('ccRCC tumors', 'Disease', (44, 56))	('ccRCC', 'Phenotype', 'HP:0006770', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (84, 93))	('BAF180', 'Gene', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('ccRCC tumors', 'Disease', 'MESH:D009369', (44, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('BAF180-deficient ccRCC tumors', 'Disease', 'MESH:D009369', (103, 132))	('BAF180', 'Gene', (14, 20))
126005	28092369	In this report, we determined that BAF180 gene mutation, and the subsequent lack of BAF180 protein expression, is observed only in ccRCC cell lines that maintain full-length HIF1alpha protein expression.	('expression', 'MPA', (99, 109))	('BAF180', 'Gene', (35, 41))	('expression', 'Species', '29278', (192, 202))	('BAF180', 'Gene', (84, 90))	('protein', 'cellular_component', 'GO:0003675', ('184', '191'))	('mutation', 'Var', (47, 55))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('lack', 'NegReg', (76, 80))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('expression', 'Species', '29278', (99, 109))
126007	28092369	Thus, our data indicate that mutation of BAF180 is an alternative strategy for ccRCCs to reduce the tumor-suppressive activity of HIF1.	('mutation', 'Var', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('HIF1', 'Gene', (130, 134))	('reduce', 'NegReg', (89, 95))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('BAF180', 'Gene', (41, 47))	('HIF1', 'Gene', '3091', (130, 134))
126008	28092369	However, BAF180 is expressed in H2 ccRCC cell lines in which the HIF1A gene is mutated.	('mutated', 'Var', (79, 86))	('HIF1A', 'Gene', (65, 70))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('ccRCC', 'Phenotype', 'HP:0006770', (35, 40))
126009	28092369	Reduction or knockout of BAF180 gene in these BAF180-expressing ccRCC cells reduces HIF2 target gene expression and cell proliferation/survival, indicating that BAF180 has oncogenic activity in this setting.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('cell proliferation', 'biological_process', 'GO:0008283', ('116', '134'))	('knockout', 'Var', (13, 21))	('HIF2 target', 'Gene', (84, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('cell proliferation/survival', 'CPA', (116, 143))	('gene expression', 'biological_process', 'GO:0010467', ('96', '111'))	('reduces', 'NegReg', (76, 83))	('expression', 'Species', '29278', (101, 111))	('BAF180', 'Gene', (25, 31))	('RCC', 'Disease', (66, 69))
126011	28092369	These findings are very novel, as the current hypothesis accepted by most investigators is that BAF180 is a bona fide tumor suppressor and loss of BAF180 promotes cancer by re-targeting the SWI/SNF complex to a set of cancer-promoting genes that are not normally regulated by the SWI/SNF complex.	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('280', '295'))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('re-targeting', 'PosReg', (173, 185))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('190', '205'))	('cancer', 'Disease', (218, 224))	('promotes', 'PosReg', (154, 162))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor suppressor', 'biological_process', 'GO:0051726', ('118', '134'))	('loss', 'Var', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Disease', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('BAF180', 'Gene', (147, 153))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('118', '134'))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
126012	28092369	Mutations in the BAF180 gene or downregulation of BAF180 gene expression has been observed in various cancer types, including ccRCC, suggesting a tumor-suppressor function.	('downregulation', 'NegReg', (32, 46))	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('expression', 'Species', '29278', (62, 72))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('146', '162'))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('BAF180', 'Gene', (50, 56))	('expression', 'MPA', (62, 72))	('tumor', 'Disease', (146, 151))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('Mutations', 'Var', (0, 9))	('gene expression', 'biological_process', 'GO:0010467', ('57', '72'))	('BAF180', 'Gene', (17, 23))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('146', '162'))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
126015	28092369	Although the previous studies did not address the molecular mechanism for BAF180 mutation in ccRCC, we have shown here for the first time that BAF180 mutation is to reduce HIF1's tumor suppressive in ccRCC.	("HIF1's tumor", 'Disease', (172, 184))	('mutation', 'Var', (150, 158))	('reduce', 'NegReg', (165, 171))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('RCC', 'Disease', (95, 98))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('ccRCC', 'Phenotype', 'HP:0006770', (200, 205))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	("HIF1's tumor", 'Disease', 'MESH:D009396', (172, 184))	('RCC', 'Disease', (202, 205))	('BAF180', 'Gene', (143, 149))
126016	28092369	This conclusion is first supported by our novel observation that BAF180 and HIF1A gene mutations are mutually exclusive in ccRCC cell lines (Figure 1a and Supplementary Figure 2a).	('BAF180', 'Gene', (65, 71))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('HIF1A', 'Gene', (76, 81))	('mutations', 'Var', (87, 96))
126020	28092369	Further, H1H2 ccRCC cell lines RCC ER, RCC FG2 and RCC MF contain BAF180 gene mutations.	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('RCC', 'Disease', (16, 19))	('ccRCC', 'Phenotype', 'HP:0006770', (14, 19))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('mutations', 'Var', (78, 87))	('RCC', 'Disease', (39, 42))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('BAF180', 'Gene', (66, 72))	('RCC', 'Disease', (31, 34))	('RCC', 'Disease', (51, 54))
126022	28092369	For example, by analysis of HIF1A copy number and exome sequencing, TCGA found that four ccRCC tumors are HIF1 activity deficient, due to loss of one HIF1A allele and have nonsense mutations in the second allele of HIF1A gene.	('HIF1', 'Gene', '3091', (150, 154))	('nonsense mutations', 'Var', (172, 190))	('loss', 'NegReg', (138, 142))	('deficient', 'NegReg', (120, 129))	('HIF1', 'Gene', (215, 219))	('ccRCC tumors', 'Disease', 'MESH:D009369', (89, 101))	('HIF1', 'Gene', '3091', (106, 110))	('HIF1', 'Gene', '3091', (28, 32))	('activity', 'MPA', (111, 119))	('ccRCC', 'Phenotype', 'HP:0006770', (89, 94))	('ccRCC tumors', 'Disease', (89, 101))	('HIF1', 'Gene', (106, 110))	('HIF1', 'Gene', (150, 154))	('HIF1', 'Gene', '3091', (215, 219))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('HIF1', 'Gene', (28, 32))
126023	28092369	Interestingly, we found that these HIF1A mutant ccRCC tumors express WT BAF180 gene.	('mutant', 'Var', (41, 47))	('ccRCC tumors', 'Disease', 'MESH:D009369', (48, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('HIF1A', 'Gene', (35, 40))	('ccRCC tumors', 'Disease', (48, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
126025	28092369	Consistent with these data, our own immunohistochemistry staining of BAF180 and HIF1alpha in ccRCC tumor tissues (BC0714a, US BioMax) found 7 HIF1alpha -/BAF180+ and 22 HIF1alpha+/BAF180- tumors out of a total of 66 ccRCC tumors.	('tumor', 'Disease', (188, 193))	('ccRCC', 'Phenotype', 'HP:0006770', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Disease', (222, 228))	('tumor', 'Disease', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('RCC', 'Disease', (218, 221))	('ccRCC tumors', 'Disease', (216, 228))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('ccRCC tumors', 'Disease', 'MESH:D009369', (216, 228))	('tumors', 'Disease', (188, 194))	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('RCC', 'Disease', (95, 98))	('tumor', 'Disease', (222, 227))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('HIF1alpha -/BAF180+', 'Var', (142, 161))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('HIF1alpha+/BAF180-', 'Var', (169, 187))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))
126046	28092369	pLKO.1 lentivirus expressing the non-targeting scrambled shRNA (SHC202), HIF1A shRNA (TRCN0000003810), HIF2A shRNA (TRCN0000003803) or PBRM1/BAF180 shRNAs (TRCN0000235892 or TRCN0000235890) were from Open Biosystems (Lafayette, CO, USA).	('TRCN0000235890', 'Var', (174, 188))	('TRCN0000235892', 'Var', (156, 170))	('TRCN0000003803', 'Var', (116, 130))	('PBRM1', 'Gene', (135, 140))	('PBRM1', 'Gene', '55193', (135, 140))	('TRCN0000003810', 'Var', (86, 100))
126069	28092369	Hep3B cells expressing shRNA against BAF180 or BRG1, or non-targeting shRNA (~60% confluency) were cultured under normoxic or HX conditions for 16 hours and nucleosomal DNA was isolated using the EZ Nucleosomal DNA prep kit (Zymo Research, Irvine, CA, USA).	('Hep3B', 'CellLine', 'CVCL:0326', (0, 5))	('DNA', 'cellular_component', 'GO:0005574', ('211', '214'))	('BRG1', 'Gene', (47, 51))	('BAF180', 'Var', (37, 43))	('DNA', 'cellular_component', 'GO:0005574', ('169', '172'))	('BRG1', 'Gene', '6597', (47, 51))
126091	30974870	Hence, when a targeted drug inhibits an oncogene, alternative pathways can reactivate and confer resistance to that particular drug, with tumour cells no longer depending on the original driving oncogene for uncontrolled cell division.	('inhibits', 'NegReg', (28, 36))	('resistance', 'MPA', (97, 107))	('oncogene', 'Protein', (40, 48))	('cell division', 'biological_process', 'GO:0051301', ('221', '234'))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('drug', 'Var', (23, 27))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('tumour', 'Disease', (138, 144))
126093	30974870	These mainly include autophagy, alternative splicing and exosomes exchanging resistant phenotype-inducing miRNAs and proteins between resistant and sensitive cells, eventually involving also tumour microenvironment cells.	('tumour', 'Disease', 'MESH:D009369', (191, 197))	('autophagy', 'biological_process', 'GO:0006914', ('21', '30'))	('autophagy', 'CPA', (21, 30))	('alternative splicing', 'Var', (32, 52))	('tumour', 'Disease', (191, 197))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('autophagy', 'biological_process', 'GO:0016236', ('21', '30'))	('splicing', 'biological_process', 'GO:0045292', ('44', '52'))
126099	30974870	Resistance to chemotherapy can arise when anti-apoptotic proteins, such as anti-apoptotic BCL-2 family members, inhibitors of apoptosis proteins (IAPs) and the caspase 8 inhibitor CASP8 and FADD like apoptosis regulator (CFLAR alias FLIP), undergo gain-of-function mutations or amplification or are overexpressed.	('mutations', 'Var', (265, 274))	('alias FLIP', 'Disease', 'None', (227, 237))	('caspase 8', 'Gene', '841', (160, 169))	('BCL-2', 'Gene', '596', (90, 95))	('FADD', 'Gene', (190, 194))	('BCL-2', 'Gene', (90, 95))	('alias FLIP', 'Disease', (227, 237))	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('CFLAR', 'Gene', '8837', (221, 226))	('CFLAR', 'Gene', (221, 226))	('CASP8', 'Gene', '841', (180, 185))	('caspase 8', 'Gene', (160, 169))	('CASP8', 'Gene', (180, 185))	('FADD', 'Gene', '8772', (190, 194))	('gain-of-function', 'PosReg', (248, 264))	('amplification', 'Var', (278, 291))	('apoptosis', 'biological_process', 'GO:0097194', ('200', '209'))	('apoptosis', 'biological_process', 'GO:0006915', ('200', '209'))	('BCL-2', 'molecular_function', 'GO:0015283', ('90', '95'))
126102	30974870	Tumours harboring TP53 mutations, which lead to expression of inactive p53 protein, account for about 50% of all human cancers.	('TP53', 'Gene', '7157', (18, 22))	('expression', 'MPA', (48, 58))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('TP53', 'Gene', (18, 22))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('mutations', 'Var', (23, 32))	('cancers', 'Disease', (119, 126))	('protein', 'Protein', (75, 82))	('p53 protein', 'Protein', (71, 82))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('human', 'Species', '9606', (113, 118))
126103	30974870	In another additional 40% of tumours, the p53 pathway is inactivated by alterations in its regulators.	('p53 pathway', 'Pathway', (42, 53))	('alterations', 'Var', (72, 83))	('tumours', 'Disease', 'MESH:D009369', (29, 36))	('tumours', 'Disease', (29, 36))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('inactivated', 'NegReg', (57, 68))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))
126111	30974870	Emerging clinical evidence shows that the deregulation of ubiquitin-mediated degradation of oncogene products or tumour suppressors is likely to be involved in the etiology of cancers.	('cancers', 'Disease', (176, 183))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('degradation', 'biological_process', 'GO:0009056', ('77', '88'))	('deregulation', 'Var', (42, 54))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('tumour', 'Disease', (113, 119))	('ubiquitin-mediated degradation', 'MPA', (58, 88))	('involved', 'Reg', (148, 156))	('ubiquitin', 'molecular_function', 'GO:0031386', ('58', '67'))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))
126125	30974870	Taking into account all the functions previously described, it is not surprising that mutations in TRIM genes or alterations in their protein functions are involved in several human diseases, first of all cancers.	('mutations', 'Var', (86, 95))	('TRIM genes', 'Gene', (99, 109))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('cancers', 'Disease', (205, 212))	('human', 'Species', '9606', (176, 181))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('alterations', 'Reg', (113, 124))	('involved', 'Reg', (156, 164))	('protein', 'Protein', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))
126126	30974870	This feature is often associated with translocation of TRIM genes and creation of oncogenic fusion products, as in the case of TRIM19/PML, TRIM27/RFP and TRIM24/TIF1alpha, but they can influence cancer progression also per se.	('PML', 'Gene', '5371', (134, 137))	('translocation', 'Var', (38, 51))	('TIF1alpha', 'Gene', (161, 170))	('TRIM24', 'Gene', '8805', (154, 160))	('cancer', 'Disease', (195, 201))	('influence', 'Reg', (185, 194))	('TIF1alpha', 'Gene', '8805', (161, 170))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('TRIM24', 'Gene', (154, 160))	('RFP', 'Gene', (146, 149))	('TRIM27', 'Gene', '5987', (139, 145))	('PML', 'Phenotype', 'HP:0004836', (134, 137))	('RFP', 'Gene', '5987', (146, 149))	('TRIM27', 'Gene', (139, 145))	('PML', 'Gene', (134, 137))	('associated', 'Reg', (22, 32))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
126127	30974870	As described before, cancer cells may acquire resistance to chemotherapy, or may have a high basal level of resistance, through a variety of mechanisms, among which the abrogation of apoptosis or cell cycle arrest due to mutation or inactivation of the tumour suppressor gene p53 certainly represents a crucial point in the evolution of cancer towards chemoresistance.	('tumour', 'Disease', 'MESH:D009369', (253, 259))	('tumour', 'Disease', (253, 259))	('apoptosis', 'CPA', (183, 192))	('tumour', 'Phenotype', 'HP:0002664', (253, 259))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (337, 343))	('cell cycle arrest', 'CPA', (196, 213))	('inactivation', 'Var', (233, 245))	('p53', 'Gene', (276, 279))	('cancer', 'Disease', (21, 27))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (196, 213))	('cancer', 'Disease', (337, 343))	('resistance', 'CPA', (46, 56))	('mutation', 'Var', (221, 229))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('apoptosis', 'biological_process', 'GO:0097194', ('183', '192'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('196', '213'))	('apoptosis', 'biological_process', 'GO:0006915', ('183', '192'))
126128	30974870	Cells that lack functional p53 are unable to respond suitably to cellular stress, they accumulate mutations that favor the development of tumours and resistance to chemo- and radio-therapy.	('resistance', 'CPA', (150, 160))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('mutations', 'Var', (98, 107))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('favor', 'PosReg', (113, 118))	('tumours', 'Disease', 'MESH:D009369', (138, 145))	('p53', 'Gene', (27, 30))	('tumours', 'Disease', (138, 145))
126129	30974870	Hence, patients with a mutated or deregulated p53 network are more prone to not respond to chemotherapy, resulting in metastasis.	('metastasis', 'CPA', (118, 128))	('p53', 'Gene', (46, 49))	('deregulated', 'Var', (34, 45))	('mutated', 'Var', (23, 30))	('patients', 'Species', '9606', (7, 15))
126130	30974870	The expression of some TRIM genes is promoted directly by p53 as TRIML2, TRIM3, TRIM8, TRIM19, TRIM22, TRIM24 and TRIM32, and some of them, in turn, can regulate the activity and stability of p53.	('stability', 'MPA', (179, 188))	('expression', 'MPA', (4, 14))	('p53', 'Var', (58, 61))	('TRIM3', 'Gene', (114, 119))	('TRIM8', 'Gene', (80, 85))	('TRIM32', 'Gene', (114, 120))	('activity', 'MPA', (166, 174))	('TRIM22', 'Gene', '10346', (95, 101))	('TRIM8', 'Gene', '81603', (80, 85))	('TRIM24', 'Gene', '8805', (103, 109))	('TRIM3', 'Gene', (73, 78))	('promoted', 'PosReg', (37, 45))	('TRIM3', 'Gene', '10612', (114, 119))	('TRIM19', 'Var', (87, 93))	('TRIML2', 'Gene', (65, 71))	('TRIM genes', 'Gene', (23, 33))	('regulate', 'Reg', (153, 161))	('TRIML2', 'Gene', '205860', (65, 71))	('TRIM3', 'Gene', '10612', (73, 78))	('TRIM32', 'Gene', '22954', (114, 120))	('TRIM22', 'Gene', (95, 101))	('p53', 'Protein', (192, 195))	('TRIM24', 'Gene', (103, 109))
126136	30974870	In particular, TRIM19 mediates the recruitment of p53 and modifying enzymes into these PML-NBs, which fosters p53 stabilization and post-translational modifications, such as CBP-dependent acetylation and Chk2-dependent phosphorylation that potentiate p53 function.	('Chk2', 'Gene', '11200', (204, 208))	('stabilization', 'MPA', (114, 127))	('fosters', 'PosReg', (102, 109))	('function', 'MPA', (255, 263))	('Chk2', 'Gene', (204, 208))	('acetylation', 'MPA', (188, 199))	('phosphorylation', 'biological_process', 'GO:0016310', ('219', '234'))	('PML', 'Gene', '5371', (87, 90))	('potentiate', 'PosReg', (240, 250))	('TRIM19', 'Var', (15, 21))	('CBP', 'molecular_function', 'GO:0008140', ('174', '177'))	('PML', 'Phenotype', 'HP:0004836', (87, 90))	('CBP', 'Gene', (174, 177))	('p53', 'Protein', (110, 113))	('PML', 'Gene', (87, 90))	('CBP', 'Gene', '1387', (174, 177))
126142	30974870	Indeed, under stress conditions, p53 induces the expression of TRIM8, which in turn directly interacts with p53 inducing its stabilization by impairing the interaction with the negative p53 regulator, MDM2.	('TRIM8', 'Gene', '81603', (63, 68))	('impairing', 'NegReg', (142, 151))	('p53', 'Var', (33, 36))	('expression', 'MPA', (49, 59))	('interaction', 'Interaction', (156, 167))	('TRIM8', 'Gene', (63, 68))	('stabilization', 'MPA', (125, 138))	('interacts', 'Reg', (93, 102))
126143	30974870	Consequently, p53 induces the transcription of the genes involved in cell cycle arrest (e.g., p21, GADD45).	('transcription', 'biological_process', 'GO:0006351', ('30', '43'))	('transcription', 'MPA', (30, 43))	('p21', 'Gene', '1026', (94, 97))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('69', '86'))	('p21', 'Gene', (94, 97))	('GADD45', 'Gene', (99, 105))	('induces', 'PosReg', (18, 25))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (69, 86))	('GADD45', 'Gene', '1647', (99, 105))	('p53', 'Var', (14, 17))
126145	30974870	Most importantly, it has been demonstrated that the recovery of TRIM8 expression in ccRCC-derived cell lines was able to induce a significant p53-dependent reduction in the proliferation rate, making cancer cells sensitive to different chemotherapy drugs as Nutlin-3, Cisplatin, Axitinib and Sorafenib.	('Axitinib', 'Chemical', 'MESH:D000077784', (279, 287))	('recovery', 'Var', (52, 60))	('TRIM8', 'Gene', '81603', (64, 69))	('Sorafenib', 'Chemical', 'MESH:D000077157', (292, 301))	('reduction', 'NegReg', (156, 165))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('proliferation rate', 'CPA', (173, 191))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('TRIM8', 'Gene', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('Nutlin-3', 'Chemical', 'MESH:C482205', (258, 266))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('Cisplatin', 'Chemical', 'MESH:D002945', (268, 277))	('cancer', 'Disease', (200, 206))
126148	30974870	MYCN is a direct target of miR-34a, whose expression is activated by p53.	('miR-34a', 'Gene', (27, 34))	('MYCN', 'Gene', (0, 4))	('MYCN', 'Gene', '4613', (0, 4))	('expression', 'MPA', (42, 52))	('miR-34a', 'Gene', '407040', (27, 34))	('p53', 'Var', (69, 72))	('activated', 'PosReg', (56, 65))
126153	30974870	However, it is known that p38 phosphorylates and activates p53 when a DNA-damaging drug is used for chemotherapy, and the blockade of p38 leads to a decreased apoptotic response to anticancer agents.	('p38', 'Gene', '1432', (26, 29))	('activates', 'PosReg', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('blockade', 'Var', (122, 130))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('p38', 'Gene', '1432', (134, 137))	('p38', 'Gene', (26, 29))	('decreased', 'NegReg', (149, 158))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('p38', 'Gene', (134, 137))	('cancer', 'Disease', (185, 191))	('p53', 'Protein', (59, 62))
126179	30974870	Indeed, ATM kinase induced by DNA damage phosphorylates both p53 (Ser15) and TRIM24 (Ser768).	('Ser', 'cellular_component', 'GO:0005790', ('66', '69'))	('TRIM24', 'Gene', '8805', (77, 83))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('Ser768', 'Var', (85, 91))	('ATM', 'Gene', '472', (8, 11))	('Ser15', 'Chemical', '-', (66, 71))	('TRIM24', 'Gene', (77, 83))	('Ser768', 'Chemical', '-', (85, 91))	('p53', 'Protein', (61, 64))	('Ser', 'cellular_component', 'GO:0005790', ('85', '88'))	('ATM', 'Gene', (8, 11))
126188	30974870	Accordingly, for several cell lines that are relatively insensitive to nutlin-3a, an inhibitor of MDM2, depletion of TRIM39 increases apoptotic cell death.	('TRIM39', 'Gene', '56658', (117, 123))	('increases', 'PosReg', (124, 133))	('apoptotic cell death', 'CPA', (134, 154))	('TRIM39', 'Gene', (117, 123))	('depletion', 'Var', (104, 113))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('134', '154'))
126227	30974870	In this complex, TRIM37 monoubiquitines NEMO at K306, consequently resulting in nuclear export of NEMO and IKK/NF-kappaB activation.	('resulting in', 'Reg', (67, 79))	('NEMO', 'Gene', (98, 102))	('nuclear export', 'biological_process', 'GO:0051168', ('80', '94'))	('NF-kappaB', 'Gene', (111, 120))	('TRIM37', 'Gene', '4591', (17, 23))	('NEMO', 'Gene', '8517', (98, 102))	('nuclear export', 'MPA', (80, 94))	('IKK', 'molecular_function', 'GO:0008384', ('107', '110'))	('monoubiquitines', 'Var', (24, 39))	('NF-kappaB', 'Gene', '4790', (111, 120))	('K306', 'Chemical', '-', (48, 52))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('111', '131'))	('NEMO', 'Gene', (40, 44))	('activation', 'PosReg', (121, 131))	('TRIM37', 'Gene', (17, 23))	('NEMO', 'Gene', '8517', (40, 44))
126236	30974870	Indeed, high TRIM31 expression is associated with an aggressive phenotype and poor prognosis in pancreatic cancer patients.	('high', 'Var', (8, 12))	('expression', 'MPA', (20, 30))	('pancreatic cancer', 'Disease', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('pancreatic cancer', 'Disease', 'MESH:D010190', (96, 113))	('TRIM31', 'Gene', '11074', (13, 19))	('TRIM31', 'Gene', (13, 19))	('patients', 'Species', '9606', (114, 122))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (96, 113))
126242	30974870	TRIM24 can also sense the non-canonical H3K23ac histone modification specifically upregulated by EGFR activation, and acts as transcriptional co-activator recruiting STAT3 to chromatin.	('STAT3', 'Gene', '6774', (166, 171))	('EGFR', 'Gene', '1956', (97, 101))	('STAT3', 'Gene', (166, 171))	('upregulated', 'PosReg', (82, 93))	('EGFR', 'Gene', (97, 101))	('activation', 'PosReg', (102, 112))	('TRIM24', 'Gene', '8805', (0, 6))	('H3K23ac', 'Var', (40, 47))	('histone modification', 'biological_process', 'GO:0016570', ('48', '68'))	('chromatin', 'cellular_component', 'GO:0000785', ('175', '184'))	('TRIM24', 'Gene', (0, 6))	('histone', 'Protein', (48, 55))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))
126251	30974870	Nonetheless, Bortezomib produces side effects, such as neuropathy, but the new-generation of proteasome inhibitors such as carfilzomib, NPI-0052 and MLN-9708 have improved pharmacological activity and reduced side effects.	('pharmacological activity', 'MPA', (172, 196))	('neuropathy', 'Disease', 'MESH:D009422', (55, 65))	('Bortezomib', 'Chemical', 'MESH:D000069286', (13, 23))	('NPI-0052', 'Var', (136, 144))	('carfilzomib', 'Chemical', 'MESH:C524865', (123, 134))	('improved', 'PosReg', (163, 171))	('MLN-9708', 'CellLine', 'CVCL:D578', (149, 157))	('MLN-9708', 'Var', (149, 157))	('neuropathy', 'Phenotype', 'HP:0009830', (55, 65))	('proteasome', 'molecular_function', 'GO:0004299', ('93', '103'))	('proteasome', 'cellular_component', 'GO:0000502', ('93', '103'))	('side effects', 'MPA', (209, 221))	('neuropathy', 'Disease', (55, 65))
126267	30974870	In the same cells, curcumin can also enhance their chemosensitivity to Temsirolimus, an mTOR inhibitor used as first-line treatment of metastatic RCC, by upregulating the YAP/p53 pathway.	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('curcumin', 'Var', (19, 27))	('RCC', 'Disease', (146, 149))	('upregulating', 'PosReg', (154, 166))	('chemosensitivity to Temsirolimus', 'MPA', (51, 83))	('curcumin', 'Chemical', 'MESH:D003474', (19, 27))	('mTOR', 'Gene', (88, 92))	('mTOR', 'Gene', '2475', (88, 92))	('YAP', 'Gene', '10413', (171, 174))	('Temsirolimus', 'Chemical', 'MESH:C401859', (71, 83))	('enhance', 'PosReg', (37, 44))	('YAP', 'Gene', (171, 174))
126270	30974870	For instance, recent reports indicate that TRIM proteins are involved in epigenetic regulation, as we have seen for example for TRIM24, suggesting that TRIM proteins could contribute to tumour suppression or development also by indirectly regulating gene expression.	('development', 'CPA', (208, 219))	('TRIM24', 'Gene', (128, 134))	('gene expression', 'MPA', (250, 265))	('regulation', 'biological_process', 'GO:0065007', ('84', '94'))	('gene expression', 'biological_process', 'GO:0010467', ('250', '265'))	('regulating', 'Reg', (239, 249))	('TRIM', 'Var', (152, 156))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('tumour suppression', 'Disease', (186, 204))	('contribute', 'Reg', (172, 182))	('tumour suppression', 'Disease', 'OMIM:146850', (186, 204))	('TRIM24', 'Gene', '8805', (128, 134))
126340	29179496	Furthermore, myoferlin hyperexpression was significantly associated with disease-free survival on Cox regression analysis (hazard ratio, 4.604; 95% confidence interval, 1.893-11.199; p = 0.001).	('disease-free survival', 'CPA', (73, 94))	('myoferlin', 'Gene', '26509', (13, 22))	('associated with', 'Reg', (57, 72))	('myoferlin', 'Gene', (13, 22))	('hyperexpression', 'Var', (23, 38))
126347	29179496	The 6-membered Ferlin family are mammalian proteins that share homology with the Fer-1 family of Caenorhabditis Elegans and include myoferlin, dysferlin, otoferlin, fer1L4, fer1L5, and fer1L6.	('myoferlin', 'Gene', (132, 141))	('Caenorhabditis Elegans', 'Species', '6239', (97, 119))	('mammalian', 'Species', '9606', (33, 42))	('fer1L4', 'Var', (165, 171))	('fer1L6', 'Var', (185, 191))	('fer1L5', 'Var', (173, 179))	('myoferlin', 'Gene', '26509', (132, 141))
126348	29179496	Fer-1 defects have been associated with infertility due to the abnormal fusion of cellular membranes in developing sperm.	('associated', 'Reg', (24, 34))	('defects', 'Var', (6, 13))	('infertility', 'Disease', 'MESH:D007247', (40, 51))	('infertility', 'Phenotype', 'HP:0000789', (40, 51))	('Fer-1', 'Gene', (0, 5))	('infertility', 'Disease', (40, 51))
126353	29179496	Furthermore, in MDA-MB-231 human breast cancer cells, myoferlin depletion induced a mesenchymal-to-epithelial transition, in vitro, and reduced tumoral proliferation and invasion, in vivo.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('tumoral proliferation', 'Disease', (144, 165))	('myoferlin', 'Gene', (54, 63))	('depletion', 'Var', (64, 73))	('human', 'Species', '9606', (27, 32))	('induced', 'Reg', (74, 81))	('mesenchymal-to-epithelial transition', 'CPA', (84, 120))	('tumoral proliferation', 'Disease', 'MESH:D065703', (144, 165))	('mesenchymal-to-epithelial transition', 'biological_process', 'GO:0060231', ('84', '120'))	('reduced', 'NegReg', (136, 143))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (16, 26))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('invasion', 'CPA', (170, 178))	('breast cancer', 'Disease', (33, 46))	('myoferlin', 'Gene', '26509', (54, 63))
126367	29179496	According to Kaplan-Meier analysis, patients with Hyper-MYOF, high T stage (>=2), or high Fuhrman nuclear grade (>=3) had poorer disease-free survival (DFS, p <0.001) compared to patients with Hypo-MYOF (Figure 2A-2C).	('disease-free survival', 'CPA', (129, 150))	('MYOF', 'Gene', (198, 202))	('patients', 'Species', '9606', (36, 44))	('MYOF', 'Gene', '26509', (56, 60))	('high Fuhrman', 'Var', (85, 97))	('patients', 'Species', '9606', (179, 187))	('MYOF', 'Gene', '26509', (198, 202))	('high', 'Var', (62, 66))	('poorer', 'NegReg', (122, 128))	('MYOF', 'Gene', (56, 60))
126372	29179496	This is the first study to demonstrate an association between high myoferlin expression and prognosis in patients with ccRCC.	('expression', 'MPA', (77, 87))	('myoferlin', 'Gene', '26509', (67, 76))	('patients', 'Species', '9606', (105, 113))	('prognosis', 'CPA', (92, 101))	('ccRCC', 'Disease', (119, 124))	('myoferlin', 'Gene', (67, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('high', 'Var', (62, 66))
126380	29179496	For example, patients with advanced ccRCC are treated using different therapies such as the tyrosine kinase inhibitors (e.g., sunitinib or pazopanib) and inhibitors of the mammalian target of rapamycin.	('sunitinib', 'Chemical', 'MESH:D000077210', (126, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('ccRCC', 'Disease', (36, 41))	('inhibitors', 'Var', (154, 164))	('patients', 'Species', '9606', (13, 21))	('mammalian target of rapamycin', 'Gene', '2475', (172, 201))	('pazopanib', 'Chemical', 'MESH:C516667', (139, 148))	('mammalian target of rapamycin', 'Gene', (172, 201))	('tyrosine kinase inhibitors', 'MPA', (92, 118))
126404	29179496	If the tumor cells showed heterogeneity of myoferlin in a core, representative value of the core was decided as a value of majority of tumor cells (more than 50%).	('core', 'cellular_component', 'GO:0019013', ('92', '96'))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('myoferlin', 'Gene', '26509', (43, 52))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', (135, 140))	('myoferlin', 'Gene', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('core', 'cellular_component', 'GO:0019013', ('58', '62'))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('heterogeneity', 'Var', (26, 39))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
126415	31138790	The LXR inverse agonist SR9243 downregulated the FA synthesis proteins sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthase (FASN) and stearoyl-coA desaturase 1 (SCD1), causing a decrease in intracellular FA content and inducing apoptosis in ccRCC cells.	('apoptosis', 'CPA', (253, 262))	('ccRCC', 'Phenotype', 'HP:0006770', (266, 271))	('RCC', 'Disease', (268, 271))	('RCC', 'Phenotype', 'HP:0005584', (268, 271))	('binding', 'molecular_function', 'GO:0005488', ('97', '104'))	('sterol regulatory element-binding protein 1c', 'Gene', '6720', (71, 115))	('FASN', 'Gene', (149, 153))	('SCD1', 'Gene', '6319', (186, 190))	('fatty acid synthase', 'Gene', (128, 147))	('intracellular FA content', 'MPA', (215, 239))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('RCC', 'Disease', 'MESH:C538614', (268, 271))	('decrease', 'NegReg', (203, 211))	('apoptosis', 'biological_process', 'GO:0097194', ('253', '262'))	('SREBP-1c', 'Gene', '6720', (117, 125))	('stearoyl-coA desaturase 1', 'Gene', (159, 184))	('fatty acid synthase', 'Gene', '2194', (128, 147))	('apoptosis', 'biological_process', 'GO:0006915', ('253', '262'))	('SCD1', 'Gene', (186, 190))	('inducing', 'Reg', (244, 252))	('stearoyl-coA desaturase 1', 'Gene', '6319', (159, 184))	('synthesis', 'biological_process', 'GO:0009058', ('52', '61'))	('downregulated', 'NegReg', (31, 44))	('SR9243', 'Chemical', 'MESH:C000602007', (24, 30))	('SR9243', 'Var', (24, 30))	('FASN', 'Gene', '2194', (149, 153))	('LXR', 'Gene', (4, 7))	('SREBP-1c', 'Gene', (117, 125))	('intracellular', 'cellular_component', 'GO:0005622', ('215', '228'))	('LXR', 'Gene', '22259', (4, 7))	('sterol regulatory element-binding protein 1c', 'Gene', (71, 115))
126416	31138790	SR9243 and LXR623 induced apoptosis in ccRCC cells but had no killing effect on normal renal tubular epithelial HK2 cells.	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('HK2', 'molecular_function', 'GO:0008256', ('112', '115'))	('LXR', 'Gene', '22259', (11, 14))	('apoptosis', 'biological_process', 'GO:0097194', ('26', '35'))	('apoptosis', 'biological_process', 'GO:0006915', ('26', '35'))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('SR9243', 'Var', (0, 6))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))	('LXR', 'Gene', (11, 14))	('SR9243', 'Chemical', 'MESH:C000602007', (0, 6))	('HK2', 'CellLine', 'CVCL:0302', (112, 115))
126437	31138790	Changes in intracellular cholesterol have profound effects on cell function, including signal transduction, membrane plasticity, and membrane migration.	('effects', 'Reg', (51, 58))	('signal transduction', 'MPA', (87, 106))	('membrane', 'cellular_component', 'GO:0016020', ('133', '141'))	('signal transduction', 'biological_process', 'GO:0007165', ('87', '106'))	('Changes', 'Var', (0, 7))	('cholesterol', 'Chemical', 'MESH:D002784', (25, 36))	('membrane plasticity', 'CPA', (108, 127))	('membrane', 'cellular_component', 'GO:0016020', ('108', '116'))	('cell function', 'CPA', (62, 75))	('intracellular', 'cellular_component', 'GO:0005622', ('11', '24'))	('membrane migration', 'CPA', (133, 151))
126453	31138790	Therefore, intervening in FA synthesis pathways may have antitumour effects in ccRCC while having no cytotoxic effects on normal cells.	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('synthesis', 'biological_process', 'GO:0009058', ('29', '38'))	('tumour', 'Disease', (61, 67))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('intervening', 'Var', (11, 22))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
126454	31138790	Flaveny found that an LXR inverse agonist, SR9243, could induce LXR and co-repressor interactions.	('LXR', 'Gene', '22259', (64, 67))	('SR9243', 'Var', (43, 49))	('SR9243', 'Chemical', 'MESH:C000602007', (43, 49))	('LXR', 'Gene', (22, 25))	('LXR', 'Gene', (64, 67))	('induce', 'PosReg', (57, 63))	('LXR', 'Gene', '22259', (22, 25))
126459	31138790	While SR9243 downregulated the FA synthesis proteins SREBP-1c, FASN and SCD1, causing a decrease in intracellular FA content and inducing apoptosis in ccRCC cells.	('intracellular', 'cellular_component', 'GO:0005622', ('100', '113'))	('SCD1', 'Gene', (72, 76))	('SR9243', 'Var', (6, 12))	('SR9243', 'Chemical', 'MESH:C000602007', (6, 12))	('FASN', 'Gene', '2194', (63, 67))	('apoptosis', 'CPA', (138, 147))	('SREBP-1c', 'Gene', '6720', (53, 61))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('RCC', 'Disease', (153, 156))	('intracellular FA content', 'MPA', (100, 124))	('SCD1', 'Gene', '6319', (72, 76))	('synthesis', 'biological_process', 'GO:0009058', ('34', '43'))	('ccRCC', 'Phenotype', 'HP:0006770', (151, 156))	('decrease', 'NegReg', (88, 96))	('downregulated', 'NegReg', (13, 26))	('apoptosis', 'biological_process', 'GO:0097194', ('138', '147'))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('SREBP-1c', 'Gene', (53, 61))	('FASN', 'Gene', (63, 67))	('apoptosis', 'biological_process', 'GO:0006915', ('138', '147'))	('inducing', 'Reg', (129, 137))
126460	31138790	SR9243 and LXR623 induced apoptosis in ccRCC cells but did not have cytotoxic effects on HK2 cells.	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('HK2', 'molecular_function', 'GO:0008256', ('89', '92'))	('LXR', 'Gene', '22259', (11, 14))	('apoptosis', 'biological_process', 'GO:0097194', ('26', '35'))	('apoptosis', 'biological_process', 'GO:0006915', ('26', '35'))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('HK2', 'CellLine', 'CVCL:0302', (89, 92))	('SR9243', 'Var', (0, 6))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))	('LXR', 'Gene', (11, 14))	('SR9243', 'Chemical', 'MESH:C000602007', (0, 6))
126462	31138790	To investigate whether SR9243 and LXR623 have killing effects on ccRCC cells, we performed CCK8 experiments with ACHN and 786-O cell lines.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('LXR', 'Gene', '22259', (34, 37))	('ACHN', 'Gene', (113, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('SR9243', 'Chemical', 'MESH:C000602007', (23, 29))	('SR9243', 'Var', (23, 29))	('LXR', 'Gene', (34, 37))	('ACHN', 'Gene', '55323', (113, 117))
126463	31138790	We found that SR9243 effectively killed cancer cells at nanomolar concentrations (786-O cells [IC50]: 51.6 nM, ACHN cells [IC50]: 178.2 nM).	('ACHN', 'Gene', (111, 115))	('SR9243', 'Chemical', 'MESH:C000602007', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('ACHN', 'Gene', '55323', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('SR9243', 'Var', (14, 20))
126466	31138790	The findings indicated that SR9243 and LXR623 kill ccRCC cells in concentration-dependent and time-dependent manners.	('LXR', 'Gene', '22259', (39, 42))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))	('LXR', 'Gene', (39, 42))	('SR9243', 'Chemical', 'MESH:C000602007', (28, 34))	('SR9243', 'Var', (28, 34))
126467	31138790	To investigate whether SR9243 and LXR623 inhibit ccRCC cell proliferation, we performed EdU cell proliferation assays and colony formation assays.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('cell proliferation', 'biological_process', 'GO:0008283', ('55', '73'))	('formation', 'biological_process', 'GO:0009058', ('129', '138'))	('LXR', 'Gene', '22259', (34, 37))	('cell proliferation', 'biological_process', 'GO:0008283', ('92', '110'))	('SR9243', 'Chemical', 'MESH:C000602007', (23, 29))	('SR9243', 'Var', (23, 29))	('inhibit', 'NegReg', (41, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('LXR', 'Gene', (34, 37))	('RCC', 'Disease', (51, 54))
126468	31138790	As shown by the EdU analysis, SR9243 and LXR623 greatly reduced the numbers of EdU-positive ACHN and 786-O cells, suggesting that SR9243 and LXR623 can effectively inhibit cell proliferation (Fig.	('LXR', 'Gene', (141, 144))	('ACHN', 'Gene', '55323', (92, 96))	('cell proliferation', 'biological_process', 'GO:0008283', ('172', '190'))	('reduced', 'NegReg', (56, 63))	('cell proliferation', 'CPA', (172, 190))	('SR9243', 'Chemical', 'MESH:C000602007', (130, 136))	('inhibit', 'NegReg', (164, 171))	('ACHN', 'Gene', (92, 96))	('SR9243', 'Var', (130, 136))	('LXR', 'Gene', '22259', (41, 44))	('SR9243', 'Chemical', 'MESH:C000602007', (30, 36))	('LXR', 'Gene', '22259', (141, 144))	('LXR', 'Gene', (41, 44))
126469	31138790	We observed that after SR9243 and LXR623 treatment, the colony formation ability of cells was significantly impaired (Fig.	('formation', 'biological_process', 'GO:0009058', ('63', '72'))	('LXR', 'Gene', '22259', (34, 37))	('colony formation ability of cells', 'CPA', (56, 89))	('SR9243', 'Chemical', 'MESH:C000602007', (23, 29))	('SR9243', 'Var', (23, 29))	('impaired', 'NegReg', (108, 116))	('LXR', 'Gene', (34, 37))
126471	31138790	Interestingly, both SR9243 and LXR623 upregulated the apoptotic protein Bax and downregulated the apoptosis-inhibiting protein Bcl2, and the expression of the apoptosis-executing protein Cleaved-Caspase3 was upregulated by both drugs (Fig.	('Caspase3', 'Gene', '836', (195, 203))	('SR9243', 'Chemical', 'MESH:C000602007', (20, 26))	('SR9243', 'Var', (20, 26))	('Bcl2', 'molecular_function', 'GO:0015283', ('127', '131'))	('Caspase3', 'Gene', (195, 203))	('LXR', 'Gene', (31, 34))	('apoptosis', 'biological_process', 'GO:0097194', ('159', '168'))	('apoptosis', 'biological_process', 'GO:0006915', ('159', '168'))	('LXR', 'Gene', '22259', (31, 34))	('downregulated', 'NegReg', (80, 93))	('Bax', 'Gene', (72, 75))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('Bax', 'Gene', '581', (72, 75))	('expression', 'MPA', (141, 151))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('Bcl2', 'Gene', (127, 131))	('upregulated', 'PosReg', (208, 219))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('Bcl2', 'Gene', '596', (127, 131))	('upregulated', 'PosReg', (38, 49))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))
126473	31138790	2i), which demonstrated that SR9243 and LXR623 induce apoptosis in ccRCC cells in vitro through an endogenous apoptotic pathway.	('apoptosis', 'CPA', (54, 63))	('SR9243', 'Var', (29, 35))	('LXR', 'Gene', '22259', (40, 43))	('RCC', 'Disease', (69, 72))	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('SR9243', 'Chemical', 'MESH:C000602007', (29, 35))	('LXR', 'Gene', (40, 43))	('apoptosis', 'biological_process', 'GO:0097194', ('54', '63'))	('apoptosis', 'biological_process', 'GO:0006915', ('54', '63'))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
126474	31138790	Through RNA-seq, we found that SR9243 downregulated FA synthesis genes, such as SREBP-1c, ACC, FASN and SCD1.	('RNA', 'cellular_component', 'GO:0005562', ('8', '11'))	('SREBP-1c', 'Gene', '6720', (80, 88))	('synthesis', 'biological_process', 'GO:0009058', ('55', '64'))	('FASN', 'Gene', (95, 99))	('SREBP-1c', 'Gene', (80, 88))	('ACC', 'Disease', (90, 93))	('SCD1', 'Gene', '6319', (104, 108))	('FASN', 'Gene', '2194', (95, 99))	('downregulated', 'NegReg', (38, 51))	('SR9243', 'Var', (31, 37))	('FA synthesis genes', 'Gene', (52, 70))	('SCD1', 'Gene', (104, 108))	('SR9243', 'Chemical', 'MESH:C000602007', (31, 37))
126475	31138790	We also found other gene changes in response to SR9243 treatment, such as a change in Porcn expression (without Porcn lipidation, WNT fails to bind to its chaperone protein).	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('Porcn', 'Gene', '64840', (86, 91))	('Porcn', 'Gene', (112, 117))	('changes', 'Reg', (25, 32))	('change', 'Reg', (76, 82))	('Porcn', 'Gene', '64840', (112, 117))	('SR9243', 'Chemical', 'MESH:C000602007', (48, 54))	('SR9243', 'Var', (48, 54))	('lipid', 'Chemical', 'MESH:D008055', (118, 123))	('Porcn', 'Gene', (86, 91))	('expression', 'MPA', (92, 102))
126476	31138790	SR9243 also upregulated the PPP1R15A gene, which is involved in the TGF-beta signalling pathway and promotes apoptosis by inducing the phosphorylation of TP53.	('signalling pathway', 'biological_process', 'GO:0007165', ('77', '95'))	('PPP1R15A', 'Gene', '23645', (28, 36))	('TP53', 'Gene', (154, 158))	('PPP1R15A', 'Gene', (28, 36))	('phosphorylation', 'biological_process', 'GO:0016310', ('135', '150'))	('apoptosis', 'CPA', (109, 118))	('promotes', 'PosReg', (100, 108))	('SR9243', 'Chemical', 'MESH:C000602007', (0, 6))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('SR9243', 'Var', (0, 6))	('phosphorylation', 'MPA', (135, 150))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))	('TP53', 'Gene', '7157', (154, 158))	('inducing', 'PosReg', (122, 130))	('upregulated', 'PosReg', (12, 23))
126477	31138790	In addition, SR9243 upregulated the HMOX1 gene, which reduces proliferation, migration and angiogenic potential by upregulating P53.	('proliferation', 'CPA', (62, 75))	('HMOX1', 'Gene', (36, 41))	('upregulated', 'PosReg', (20, 31))	('HMOX1', 'Gene', '3162', (36, 41))	('angiogenic potential', 'CPA', (91, 111))	('upregulating', 'PosReg', (115, 127))	('SR9243', 'Chemical', 'MESH:C000602007', (13, 19))	('SR9243', 'Var', (13, 19))	('P53', 'Gene', (128, 131))	('P53', 'Gene', '7157', (128, 131))	('reduces', 'NegReg', (54, 61))
126484	31138790	Based on the RNA-seq results, we speculate that SR9243 and LXR623 inhibit ccRCC cells by affecting intracellular FA and cholesterol content, respectively (Fig.	('intracellular FA', 'MPA', (99, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('cholesterol content', 'MPA', (120, 139))	('affecting', 'Reg', (89, 98))	('cholesterol', 'Chemical', 'MESH:D002784', (120, 131))	('LXR', 'Gene', '22259', (59, 62))	('inhibit', 'NegReg', (66, 73))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('intracellular', 'cellular_component', 'GO:0005622', ('99', '112'))	('SR9243', 'Chemical', 'MESH:C000602007', (48, 54))	('SR9243', 'Var', (48, 54))	('LXR', 'Gene', (59, 62))
126485	31138790	To confirm the RNA-seq results and further investigate the potential mechanisms by which SR9243 and LXR623 inhibit tumourigenesis in ccRCC cells, we investigated the effects of the two drugs on FA synthesis and cholesterol transport genes in the two cell lines.	('inhibit', 'NegReg', (107, 114))	('cholesterol', 'Chemical', 'MESH:D002784', (211, 222))	('LXR', 'Gene', (100, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('SR9243', 'Var', (89, 95))	('investigated', 'Reg', (149, 161))	('LXR', 'Gene', '22259', (100, 103))	('SR9243', 'Chemical', 'MESH:C000602007', (89, 95))	('synthesis', 'biological_process', 'GO:0009058', ('197', '206'))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('cholesterol transport', 'biological_process', 'GO:0030301', ('211', '232'))	('tumour', 'Disease', (115, 121))	('RNA', 'cellular_component', 'GO:0005562', ('15', '18'))
126486	31138790	Through quantitative reverse transcription PCR (qRT-PCR) and western blotting (WB), we found that SR9243 significantly downregulated FASN, SREBP-1c and SCD 1mRNA and protein levels (Fig.	('SREBP-1c', 'Gene', '6720', (139, 147))	('FASN', 'Gene', (133, 137))	('reverse transcription', 'biological_process', 'GO:0001171', ('21', '42'))	('FASN', 'Gene', '2194', (133, 137))	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('downregulated', 'NegReg', (119, 132))	('SCD 1', 'Gene', (152, 157))	('SREBP-1c', 'Gene', (139, 147))	('SR9243', 'Chemical', 'MESH:C000602007', (98, 104))	('SR9243', 'Var', (98, 104))	('SCD 1', 'Gene', '6319', (152, 157))
126487	31138790	The immunofluorescence experiments demonstrated that SR9243 downregulated FASN (Fig.	('FASN', 'Gene', '2194', (74, 78))	('SR9243', 'Chemical', 'MESH:C000602007', (53, 59))	('SR9243', 'Var', (53, 59))	('downregulated', 'NegReg', (60, 73))	('FASN', 'Gene', (74, 78))
126489	31138790	We found that SR9243 caused a decrease in intracellular triglyceride levels (Fig.	('triglyceride', 'Chemical', 'MESH:D014280', (56, 68))	('SR9243', 'Chemical', 'MESH:C000602007', (14, 20))	('intracellular triglyceride levels', 'MPA', (42, 75))	('decrease', 'NegReg', (30, 38))	('intracellular', 'cellular_component', 'GO:0005622', ('42', '55'))	('SR9243', 'Var', (14, 20))
126493	31138790	We found that SR9243 and LXR623 did not kill tumour cells by affecting the cholesterol synthesis pathway (Fig.	('cholesterol synthesis', 'biological_process', 'GO:0006695', ('75', '96'))	('affecting', 'Reg', (61, 70))	('SR9243', 'Chemical', 'MESH:C000602007', (14, 20))	('cholesterol synthesis pathway', 'Pathway', (75, 104))	('cholesterol', 'Chemical', 'MESH:D002784', (75, 86))	('LXR', 'Gene', '22259', (25, 28))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('LXR', 'Gene', (25, 28))	('tumour', 'Disease', (45, 51))	('SR9243', 'Var', (14, 20))
126494	31138790	To further confirm the mechanisms by which SR9243 and LXR623 act on ccRCC cells, we designed a rescue experiment.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('LXR', 'Gene', '22259', (54, 57))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('SR9243', 'Var', (43, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('SR9243', 'Chemical', 'MESH:C000602007', (43, 49))	('LXR', 'Gene', (54, 57))	('act', 'Reg', (61, 64))
126497	31138790	In Nile Red experiments, SR9243 significantly reduced the number of intracellular lipid droplets, but the number of lipid droplets significantly increased after exogenous FA addition.	('lipid', 'Chemical', 'MESH:D008055', (116, 121))	('Nile Red', 'Chemical', 'MESH:C044808', (3, 11))	('number of intracellular lipid droplets', 'MPA', (58, 96))	('reduced', 'NegReg', (46, 53))	('intracellular', 'cellular_component', 'GO:0005622', ('68', '81'))	('SR9243', 'Var', (25, 31))	('lipid', 'Chemical', 'MESH:D008055', (82, 87))	('SR9243', 'Chemical', 'MESH:C000602007', (25, 31))
126498	31138790	The above experiments demonstrated that ccRCC cells can take up exogenous FAs to neutralise the decline in FAs and rescue the cell death caused by SR9243 (Fig.	('neutralise', 'MPA', (81, 91))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('FAs', 'Chemical', 'MESH:C038178', (74, 77))	('cell death', 'CPA', (126, 136))	('cell death', 'biological_process', 'GO:0008219', ('126', '136'))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('rescue', 'PosReg', (115, 121))	('FAs', 'MPA', (107, 110))	('decline', 'MPA', (96, 103))	('SR9243', 'Var', (147, 153))	('FAs', 'Chemical', 'MESH:C038178', (107, 110))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('SR9243', 'Chemical', 'MESH:C000602007', (147, 153))
126528	31138790	Photographs of tumour tissue and tumour volume indicated that SR9243-treated 786-O cell xenografts grew much more slowly than control group (Fig.	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('tumour', 'Disease', (33, 39))	('tumour', 'Disease', (15, 21))	('grew', 'CPA', (99, 103))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('SR9243', 'Chemical', 'MESH:C000602007', (62, 68))	('SR9243-treated', 'Var', (62, 76))	('tumour', 'Disease', 'MESH:D009369', (33, 39))	('slowly', 'NegReg', (114, 120))
126529	31138790	The weight of tumours from the SR9243-treated mice was significantly lower than that of tumours from control mice (Fig.	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('lower', 'NegReg', (69, 74))	('tumours', 'Phenotype', 'HP:0002664', (14, 21))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('tumours', 'Disease', (88, 95))	('mice', 'Species', '10090', (46, 50))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('mice', 'Species', '10090', (109, 113))	('SR9243-treated', 'Var', (31, 45))	('tumours', 'Disease', 'MESH:D009369', (14, 21))	('tumours', 'Disease', (14, 21))	('SR9243', 'Chemical', 'MESH:C000602007', (31, 37))
126530	31138790	Immunohistochemistry analysis showed that the expression of FASN, SCD1, and SREBP-1c in the SR9243 group was significantly lower than that in the control group (Fig.	('SREBP-1c', 'Gene', (76, 84))	('FASN', 'Gene', '2194', (60, 64))	('lower', 'NegReg', (123, 128))	('SR9243', 'Chemical', 'MESH:C000602007', (92, 98))	('SR9243', 'Var', (92, 98))	('SREBP-1c', 'Gene', '6720', (76, 84))	('SCD1', 'Gene', '6319', (66, 70))	('expression', 'MPA', (46, 56))	('FASN', 'Gene', (60, 64))	('SCD1', 'Gene', (66, 70))
126533	31138790	Since LXR agonists have been shown to increase cholesterol reverse transport by increasing the expression of extrahepatic ABCA1, we were concerned that SR9243 may reduce the expression of extracellular ABCA1 and thus reduce the reverse transport of cholesterol, leading to an increase in plasma cholesterol.	('ABCA1', 'Gene', '19', (122, 127))	('cholesterol', 'Chemical', 'MESH:D002784', (249, 260))	('plasma cholesterol', 'MPA', (288, 306))	('increase', 'PosReg', (276, 284))	('ABCA1', 'Gene', '19', (202, 207))	('transport', 'biological_process', 'GO:0006810', ('236', '245'))	('increase', 'PosReg', (38, 46))	('cholesterol', 'Chemical', 'MESH:D002784', (295, 306))	('extracellular', 'cellular_component', 'GO:0005576', ('188', '201'))	('LXR', 'Gene', (6, 9))	('reduce', 'NegReg', (163, 169))	('expression', 'MPA', (95, 105))	('transport', 'biological_process', 'GO:0006810', ('67', '76'))	('expression', 'MPA', (174, 184))	('cholesterol', 'Chemical', 'MESH:D002784', (47, 58))	('ABCA1', 'Gene', (122, 127))	('reverse transport of cholesterol', 'MPA', (228, 260))	('reduce', 'NegReg', (217, 223))	('LXR', 'Gene', '22259', (6, 9))	('ABCA1', 'Gene', (202, 207))	('SR9243', 'Chemical', 'MESH:C000602007', (152, 158))	('SR9243', 'Var', (152, 158))	('cholesterol reverse transport', 'MPA', (47, 76))	('increase cholesterol', 'Phenotype', 'HP:0003124', (38, 58))
126535	31138790	Therefore, we performed a biochemical examination of plasma from the nude mice and found that SR9243 reduced plasma TC, LDL and HDL levels and had no significant effect on triglycerides (Fig.	('TC', 'Chemical', '-', (116, 118))	('SR9243', 'Chemical', 'MESH:C000602007', (94, 100))	('SR9243', 'Var', (94, 100))	('nude mice', 'Species', '10090', (69, 78))	('HDL levels', 'MPA', (128, 138))	('LDL', 'molecular_function', 'GO:0005322', ('120', '123'))	('HDL', 'molecular_function', 'GO:0005321', ('128', '131'))	('plasma TC', 'MPA', (109, 118))	('reduced', 'NegReg', (101, 108))	('triglycerides', 'MPA', (172, 185))	('LDL', 'MPA', (120, 123))	('triglycerides', 'Chemical', 'MESH:D014280', (172, 185))
126536	31138790	SR9243 reduced blood lipids but had no significant effect on liver and kidney function (Fig.	('reduced', 'NegReg', (7, 14))	('lipids', 'Chemical', 'MESH:D008055', (21, 27))	('SR9243', 'Var', (0, 6))	('blood lipids', 'MPA', (15, 27))	('SR9243', 'Chemical', 'MESH:C000602007', (0, 6))
126537	31138790	In summary, SR9243 inhibits lipogenesis and induces apoptosis in ccRCC cells without hepatotoxicity or nephrotoxicity.	('nephrotoxicity', 'Disease', (103, 117))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('hepatotoxicity', 'Disease', 'MESH:D056486', (85, 99))	('SR9243', 'Var', (12, 18))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('SR9243', 'Chemical', 'MESH:C000602007', (12, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('lipogenesis', 'biological_process', 'GO:0008610', ('28', '39'))	('lipogenesis', 'MPA', (28, 39))	('apoptosis', 'CPA', (52, 61))	('hepatotoxicity', 'Disease', (85, 99))	('apoptosis', 'biological_process', 'GO:0097194', ('52', '61'))	('inhibits', 'NegReg', (19, 27))	('nephrotoxicity', 'Disease', 'MESH:D007674', (103, 117))	('induces', 'Reg', (44, 51))	('apoptosis', 'biological_process', 'GO:0006915', ('52', '61'))
126540	31138790	The nuclear receptor LXR can directly regulate the expression of various genes in lipogenesis, and the LXR inverse agonist SR9243 inhibits the transcription of target genes by inducing interactions between LXR and co-repressors.	('transcription', 'MPA', (143, 156))	('LXR', 'Gene', '22259', (103, 106))	('lipogenesis', 'biological_process', 'GO:0008610', ('82', '93'))	('interactions', 'Interaction', (185, 197))	('lipogenesis', 'MPA', (82, 93))	('LXR', 'Gene', (103, 106))	('LXR', 'Gene', '22259', (21, 24))	('inducing', 'Reg', (176, 184))	('SR9243', 'Chemical', 'MESH:C000602007', (123, 129))	('SR9243', 'Var', (123, 129))	('regulate', 'Reg', (38, 46))	('expression', 'MPA', (51, 61))	('LXR', 'Gene', '22259', (206, 209))	('transcription', 'biological_process', 'GO:0006351', ('143', '156'))	('LXR', 'Gene', (21, 24))	('LXR', 'Gene', (206, 209))	('inhibits', 'NegReg', (130, 138))
126541	31138790	However, the effect of SR9243 in ccRCC has not been reported previously.	('RCC', 'Disease', (35, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('SR9243', 'Chemical', 'MESH:C000602007', (23, 29))	('SR9243', 'Var', (23, 29))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
126542	31138790	Here, we experimentally demonstrated that the LXR inverse agonist SR9243 can significantly inhibit the proliferation of 7860 and ACHN cells and induce apoptosis through the endogenous apoptotic pathway.	('induce', 'PosReg', (144, 150))	('ACHN', 'Gene', '55323', (129, 133))	('proliferation', 'CPA', (103, 116))	('inhibit', 'NegReg', (91, 98))	('apoptosis', 'biological_process', 'GO:0097194', ('151', '160'))	('ACHN', 'Gene', (129, 133))	('LXR', 'Gene', (46, 49))	('apoptosis', 'biological_process', 'GO:0006915', ('151', '160'))	('LXR', 'Gene', '22259', (46, 49))	('apoptosis', 'CPA', (151, 160))	('SR9243', 'Chemical', 'MESH:C000602007', (66, 72))	('SR9243', 'Var', (66, 72))	('endogenous apoptotic pathway', 'Pathway', (173, 201))
126543	31138790	We found that SR9243 downregulated the lipogenesis genes SREBP-1c, FASN and SCD1, which reduced the intracellular FA content to exert a tumour suppressor effect, and that ccRCC cells could exogenously take up FAs to rescue tumour death.	('FASN', 'Gene', '2194', (67, 71))	('SREBP-1c', 'Gene', '6720', (57, 65))	('intracellular', 'cellular_component', 'GO:0005622', ('100', '113'))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('SCD1', 'Gene', '6319', (76, 80))	('SR9243', 'Var', (14, 20))	('SR9243', 'Chemical', 'MESH:C000602007', (14, 20))	('SREBP-1c', 'Gene', (57, 65))	('reduced', 'NegReg', (88, 95))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('FASN', 'Gene', (67, 71))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('tumour death', 'Disease', (223, 235))	('SCD1', 'Gene', (76, 80))	('FAs', 'Chemical', 'MESH:C038178', (209, 212))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('tumour', 'Disease', (136, 142))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('intracellular FA content', 'MPA', (100, 124))	('tumour', 'Disease', (223, 229))	('tumour death', 'Disease', 'MESH:D003643', (223, 235))	('lipogenesis', 'biological_process', 'GO:0008610', ('39', '50'))	('RCC', 'Disease', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('ccRCC', 'Phenotype', 'HP:0006770', (171, 176))	('downregulated', 'NegReg', (21, 34))
126553	31138790	Inhibition of the LXR target gene FASN can affect the lipid synthesis associated with lipid rafts.	('lipid', 'Chemical', 'MESH:D008055', (54, 59))	('LXR', 'Gene', (18, 21))	('FASN', 'Gene', (34, 38))	('affect', 'Reg', (43, 49))	('FASN', 'Gene', '2194', (34, 38))	('lipid', 'Chemical', 'MESH:D008055', (86, 91))	('lipid synthesis', 'biological_process', 'GO:0008610', ('54', '69'))	('lipid synthesis associated with lipid rafts', 'MPA', (54, 97))	('Inhibition', 'Var', (0, 10))	('LXR', 'Gene', '22259', (18, 21))
126563	31138790	SR9243 selectively targets and destroys metabolic processes in tumour cells with high metabolic activity while not harming non-malignant cells that have lower metabolic activity.	('destroys', 'NegReg', (31, 39))	('metabolic processes', 'CPA', (40, 59))	('metabolic activity', 'MPA', (86, 104))	('targets', 'Reg', (19, 26))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('SR9243', 'Var', (0, 6))	('SR9243', 'Chemical', 'MESH:C000602007', (0, 6))	('tumour', 'Disease', (63, 69))
126567	31138790	SR9243 can produce a metabolic environment that does not support the growth of cancer cells but has no effect on the function of non-malignant cells.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('SR9243', 'Var', (0, 6))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('SR9243', 'Chemical', 'MESH:C000602007', (0, 6))
126568	31138790	Therefore, SR9243 may be a safe drug for the clinical treatment of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('RCC', 'Disease', (69, 72))	('SR9243', 'Var', (11, 17))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('SR9243', 'Chemical', 'MESH:C000602007', (11, 17))
126570	31138790	The reason for this ability may be related to the following points: First, oxysterol is a metabolite of cholesterol and an endogenous agonist of LXR, and cholesterol synthesis inhibitors may reduce the content of oxysterols in cells, thereby weakening the reactivity with LXR.	('LXR', 'Gene', (272, 275))	('LXR', 'Gene', (145, 148))	('content of oxysterols', 'MPA', (202, 223))	('weakening', 'NegReg', (242, 251))	('cholesterol', 'Chemical', 'MESH:D002784', (154, 165))	('LXR', 'Gene', '22259', (272, 275))	('oxysterol', 'Chemical', 'MESH:D000072376', (213, 222))	('LXR', 'Gene', '22259', (145, 148))	('oxysterol', 'Chemical', 'MESH:D000072376', (75, 84))	('cholesterol synthesis', 'biological_process', 'GO:0006695', ('154', '175'))	('cholesterol', 'Chemical', 'MESH:D002784', (104, 115))	('oxysterols', 'Chemical', 'MESH:D000072376', (213, 223))	('inhibitors', 'Var', (176, 186))	('reduce', 'NegReg', (191, 197))
126571	31138790	Oxysterol-synthesising knockout mice, such as 24S-hydroxycholesterol and 25-hydroxycholesterol knockout mice, have been shown to induce certain LXR target genes in the liver when fed cholesterol, indicating that LXR activates different types of target genes depending on the ligand and that part of the endogenous LXR ligand (oxysterol) is derived from decomposition of the cholesterol produced by de novo synthesis.	('cholesterol', 'Chemical', 'MESH:D002784', (374, 385))	('cholesterol', 'Chemical', 'MESH:D002784', (183, 194))	('LXR', 'Gene', (144, 147))	('induce', 'PosReg', (129, 135))	('-hydroxycholesterol', 'Chemical', 'MESH:D006888', (75, 94))	('ligand', 'molecular_function', 'GO:0005488', ('318', '324'))	('synthesis', 'biological_process', 'GO:0009058', ('406', '415'))	('LXR', 'Gene', '22259', (144, 147))	('oxysterol', 'Chemical', 'MESH:D000072376', (326, 335))	('25-hydroxycholesterol', 'Var', (73, 94))	('LXR', 'Gene', (212, 215))	('24S-hydroxycholesterol', 'Var', (46, 68))	('mice', 'Species', '10090', (104, 108))	('LXR', 'Gene', '22259', (212, 215))	('mice', 'Species', '10090', (32, 36))	('-hydroxycholesterol', 'Chemical', 'MESH:D006888', (49, 68))	('ligand', 'molecular_function', 'GO:0005488', ('275', '281'))	('Oxysterol', 'Chemical', 'MESH:D000072376', (0, 9))	('LXR', 'Gene', (314, 317))	('cholesterol', 'Chemical', 'MESH:D002784', (57, 68))	('24S-hydroxycholesterol', 'Chemical', 'MESH:C044563', (46, 68))	('cholesterol', 'Chemical', 'MESH:D002784', (83, 94))	('LXR', 'Gene', '22259', (314, 317))
126584	31138790	In contrast, SR9243 killed tumour cells under the action of a small IC50 in both cell lines.	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('SR9243', 'Chemical', 'MESH:C000602007', (13, 19))	('IC50', 'Var', (68, 72))	('SR9243', 'Var', (13, 19))	('tumour', 'Disease', (27, 33))
126585	31138790	Thus, we believe that SR9243 would be more effective than LXR623 in the clinical treatment of ccRCC.	('RCC', 'Disease', (96, 99))	('SR9243', 'Chemical', 'MESH:C000602007', (22, 28))	('SR9243', 'Var', (22, 28))	('LXR', 'Gene', '22259', (58, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('LXR', 'Gene', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
126590	31138790	In our experiments, we found that SR9243 targets a variety of key enzymes in FA production and that SR9243 significantly inhibited the growth of subcutaneous xenografts in nude mice but had no effect on the weight or the liver and kidney functions of nude mice.	('nude mice', 'Species', '10090', (172, 181))	('growth of subcutaneous xenografts', 'CPA', (135, 168))	('SR9243', 'Chemical', 'MESH:C000602007', (34, 40))	('SR9243', 'Chemical', 'MESH:C000602007', (100, 106))	('inhibited', 'NegReg', (121, 130))	('nude mice', 'Species', '10090', (251, 260))	('SR9243', 'Var', (100, 106))
126591	31138790	Overall, SR9243 may be a safe and effective drug for treating ccRCC.	('SR9243', 'Var', (9, 15))	('SR9243', 'Chemical', 'MESH:C000602007', (9, 15))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('RCC', 'Disease', (64, 67))
126605	31138790	The primer sequences used for real-time PCR were as follows: ABCA1-F, 5'-GGATCATGGGCCTGGACAA-3'; ABCA1-R, 5'-GGGATCACTGTAGGGCAGCA-3'; FASN-F, 5'-AGCACAGACGAGAGCACCTTTG-3'; FASN-R, 5'-CCATGCAGCTCAGCAGGTCTA-3'; LDLR-F, 5'-CTGGTCAGATGAACCCATCAAAGA-3'; LDLR-R, 5'-TCATTGCAGACGTGGGAACAG-3'; SREBF1-F, 5'-CCTAAGTCTGCGCACTGCTGTC-3'; SREBF1-R, 5'-CCATGAGCACGTCTGTGTTCC; SCD1-F, 5'-GCTACACTTGGGAGCCCTGTATG-3'; SCD1-R, 5'-AGACGATGAGCTCCTGCTGTTATG-3'; HA067803-F, 5'-TGGCACCCAGCACAATGAA-3'; and HA067803-R, 5'-CTAAGTCATAGTCCGCCTAGAAGCA-3'.	('HA067803-F', 'Var', (441, 451))	('TC', 'Chemical', '-', (305, 307))	('TC', 'Chemical', '-', (504, 506))	('SCD1', 'Gene', '6319', (401, 405))	('FASN', 'Gene', (134, 138))	('ABCA1', 'Gene', '19', (97, 102))	('TC', 'Chemical', '-', (200, 202))	('TCA', 'Chemical', 'MESH:D014233', (76, 79))	('LDLR', 'Gene', (249, 253))	('TC', 'Chemical', '-', (510, 512))	('TCA', 'Chemical', 'MESH:D014233', (113, 116))	('SCD1', 'Gene', (362, 366))	('TC', 'Chemical', '-', (113, 115))	('TC', 'Chemical', '-', (350, 352))	('LDLR', 'Gene', (209, 213))	('TCA', 'Chemical', 'MESH:D014233', (192, 195))	('TC', 'Chemical', '-', (319, 321))	('ABCA1', 'Gene', (61, 66))	('TC', 'Chemical', '-', (192, 194))	('FASN', 'Gene', (172, 176))	('TCA', 'Chemical', 'MESH:D014233', (224, 227))	('SCD1', 'Gene', (401, 405))	('SREBF1', 'Gene', '6720', (286, 292))	('TC', 'Chemical', '-', (224, 226))	('TC', 'Chemical', '-', (423, 425))	('LDLR', 'Gene', '3949', (249, 253))	('SREBF1', 'Gene', (286, 292))	('FASN', 'Gene', '2194', (134, 138))	('TCA', 'Chemical', 'MESH:D014233', (237, 240))	('LDLR', 'Gene', '3949', (209, 213))	('SREBF1', 'Gene', '6720', (326, 332))	('TC', 'Chemical', '-', (237, 239))	('TC', 'Chemical', '-', (357, 359))	('HA067803-R', 'Var', (484, 494))	('SREBF1', 'Gene', (326, 332))	('ABCA1', 'Gene', (97, 102))	('TCA', 'Chemical', 'MESH:D014233', (260, 263))	('ABCA1', 'Gene', '19', (61, 66))	('TC', 'Chemical', '-', (260, 262))	('SCD1', 'Gene', '6319', (362, 366))	('TC', 'Chemical', '-', (76, 78))	('FASN', 'Gene', '2194', (172, 176))	('TCA', 'Chemical', 'MESH:D014233', (504, 507))
126621	27764136	VHL mutations were found to be universal throughout individual tumors when it occurred (ubiquitous), while the mutations in other tumor suppressor genes tended to be detected only in parts of the tumors (subclonal).	('tumor', 'Disease', (196, 201))	('VHL', 'Disease', 'MESH:D006623', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumors', 'Disease', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Disease', (63, 68))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('130', '146'))	('tumors', 'Disease', (196, 202))	('VHL', 'Disease', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor suppressor', 'biological_process', 'GO:0051726', ('130', '146'))	('mutations', 'Var', (4, 13))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
126631	27764136	During this process of tumor evolution, one question arises: do the additional mutations exist in all the tumor cells, such that all progeny have identical genetic lesions, or do they occur in a subset of cells?	('genetic lesions', 'Disease', (156, 171))	('mutations', 'Var', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('genetic lesions', 'Disease', 'MESH:D020022', (156, 171))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (106, 111))
126636	27764136	Precision medicine assumes that tumors in different patients have different genetic mutations, and the presence of specific mutations indicate sensitivities to certain treatments.	('mutations', 'Var', (124, 133))	('tumors', 'Disease', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('indicate sensitivities', 'Reg', (134, 156))	('patients', 'Species', '9606', (52, 60))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
126639	27764136	If the tumors have regional heterogeneity, then the evaluation of a single site will likely miss many DNA mutations that are present in other regions of the same tumor and will also fail to pinpoint which mutation(s) is most prevalent and whether it should be targeted.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', (162, 167))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))	('mutations', 'Var', (106, 115))	('miss', 'NegReg', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('DNA', 'Gene', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
126641	27764136	In ccRCC, inactivation of the von-Hippel Lindau tumor suppressor gene, VHL, either through DNA mutations or promoter hypermethylation, is the founding tumorigenic event.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (48, 53))	('von-Hippel Lindau tumor', 'Disease', (30, 53))	('von-Hippel Lindau tumor', 'Disease', 'MESH:D006623', (30, 53))	('promoter hypermethylation', 'Var', (108, 133))	('inactivation', 'Var', (10, 22))	('tumor', 'Disease', (151, 156))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('48', '64'))	('ccRCC', 'Disease', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('VHL', 'Disease', 'MESH:D006623', (71, 74))	('VHL', 'Disease', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor suppressor', 'biological_process', 'GO:0051726', ('48', '64'))
126643	27764136	Three large-scale sequencing studies identified additional mutations in tumor suppressors that participate in epigenetic regulation.	('regulation', 'biological_process', 'GO:0065007', ('121', '131'))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('mutations', 'Var', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
126644	27764136	Approximately 40% of ccRCC tumors harbor mutations in the polybromo-1 (PBRM1) tumor suppressor gene, which encodes a component of a SWI/SNF chromatin-remodeling complex.	('polybromo-1', 'Gene', (58, 69))	('chromatin-remodeling complex', 'cellular_component', 'GO:0016585', ('140', '168'))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutations', 'Var', (41, 50))	('tumor', 'Disease', (27, 32))	('PBRM1', 'Gene', '55193', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('PBRM1', 'Gene', (71, 76))	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('140', '160'))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('78', '94'))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('polybromo-1', 'Gene', '55193', (58, 69))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumors', 'Disease', (27, 33))	('tumor suppressor', 'biological_process', 'GO:0051726', ('78', '94'))	('ccRCC', 'Phenotype', 'HP:0006770', (21, 26))
126645	27764136	Additionally, 10-15% of ccRCCs have mutations in either the BRCA1-associated protein 1 gene (BAP1) or SET domain containing 2 gene (SETD2), encoding a histone deubiquitinase and a histone methyltransferase, respectively.	('SETD2', 'Gene', '29072', (132, 137))	('BAP1', 'Gene', '8314', (93, 97))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('histone methyltransferase', 'Gene', '56979', (180, 205))	('SETD2', 'Gene', (132, 137))	('histone methyltransferase', 'Gene', (180, 205))	('mutations', 'Var', (36, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (24, 29))	('BAP1', 'Gene', (93, 97))	('BRCA1-associated protein 1', 'Gene', '8314', (60, 86))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('159', '173'))	('ccRCCs', 'Disease', (24, 30))	('BRCA1-associated protein 1', 'Gene', (60, 86))
126646	27764136	Furthermore, PBRM1 mutations have been found to confer a slight increase of death risk, while SETD2 or BAP1 mutations were associated with serious death risks in ccRCC patients.	('BAP1', 'Gene', '8314', (103, 107))	('associated', 'Reg', (123, 133))	('SETD2', 'Gene', (94, 99))	('mutations', 'Var', (108, 117))	('PBRM1', 'Gene', (13, 18))	('BAP1', 'Gene', (103, 107))	('death', 'Disease', 'MESH:D003643', (147, 152))	('mutations', 'Var', (19, 28))	('increase', 'PosReg', (64, 72))	('PBRM1', 'Gene', '55193', (13, 18))	('death', 'Disease', (147, 152))	('death', 'Disease', 'MESH:D003643', (76, 81))	('patients', 'Species', '9606', (168, 176))	('ccRCC', 'Phenotype', 'HP:0006770', (162, 167))	('ccRCC', 'Disease', (162, 167))	('SETD2', 'Gene', '29072', (94, 99))	('death', 'Disease', (76, 81))
126649	27764136	When all the changes were compared, chromosome 3p loss and VHL alterations were the only ubiquitous events in ccRCC, and they were defined as truncal losses.	('alterations', 'Var', (63, 74))	('VHL', 'Disease', 'MESH:D006623', (59, 62))	('loss', 'NegReg', (50, 54))	('VHL', 'Disease', (59, 62))	('chromosome 3p', 'Protein', (36, 49))	('chromosome', 'cellular_component', 'GO:0005694', ('36', '46'))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))	('ccRCC', 'Disease', (110, 115))
126650	27764136	In the case of PBRM1 mutations, 50% of tumors with PBRM1 mutations were truncal.	('truncal', 'Disease', (72, 79))	('PBRM1', 'Gene', '55193', (15, 20))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('mutations', 'Var', (57, 66))	('PBRM1', 'Gene', (51, 56))	('PBRM1', 'Gene', (15, 20))	('tumors', 'Disease', (39, 45))	('PBRM1', 'Gene', '55193', (51, 56))	('mutations', 'Var', (21, 30))
126697	27764136	The same antibody was used by others for IHC and the loss of IHC signal mostly coincided with DNA mutations in PBRM1.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('antibody', 'cellular_component', 'GO:0019815', ('9', '17'))	('antibody', 'cellular_component', 'GO:0019814', ('9', '17'))	('antibody', 'molecular_function', 'GO:0003823', ('9', '17'))	('mutations', 'Var', (98, 107))	('loss', 'NegReg', (53, 57))	('antibody', 'cellular_component', 'GO:0042571', ('9', '17'))	('PBRM1', 'Gene', (111, 116))	('PBRM1', 'Gene', '55193', (111, 116))	('IHC signal', 'MPA', (61, 71))
126702	27764136	It was also used for IHC in a recent publication to detect BRM in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), which revealed specific co-losses of BRG1 and BRM in these tumors.	('BRM', 'Gene', '6595', (59, 62))	('small cell carcinoma of the ovary', 'Disease', (66, 99))	('BRM', 'Gene', '6595', (176, 179))	('hypercalcemic type', 'Disease', (101, 119))	('BRG1', 'Gene', (167, 171))	('tumors', 'Disease', (189, 195))	('BRM', 'Gene', (59, 62))	('co-losses', 'Var', (154, 163))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('small cell carcinoma of the ovary', 'Disease', 'MESH:D018288', (66, 99))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('BRM', 'Gene', (176, 179))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (66, 86))	('BRG1', 'Gene', '6597', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('hypercalcemic type', 'Disease', 'MESH:D017827', (101, 119))
126705	27764136	There was a close correlation between loss of IHC staining of the tumor cells and the presence of BRG1 mutations.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutations', 'Var', (103, 112))	('tumor', 'Disease', (66, 71))	('BRG1', 'Gene', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('BRG1', 'Gene', '6597', (98, 102))
126747	27764136	To investigate this possibility, we next tested whether co-losses of PBRM1 and ARID1A affect tumor growth in a xenograft model when compared to single losses.	('affect', 'Reg', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('PBRM1', 'Gene', (69, 74))	('ARID1A', 'Gene', '8289', (79, 85))	('ARID1A', 'Gene', (79, 85))	('co-losses', 'Var', (56, 65))	('tested', 'Reg', (41, 47))	('PBRM1', 'Gene', '55193', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
126750	27764136	When PBRM1 expression was knocked down in 786-O VHL-deficient ccRCC cells, the tumors they generated were much larger than the ones from the control cells (Fig 6B and 6C).	('larger', 'PosReg', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('PBRM1', 'Gene', '55193', (5, 10))	('knocked', 'Var', (26, 33))	('VHL-deficient', 'Disease', (48, 61))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('VHL-deficient', 'Disease', 'MESH:D006623', (48, 61))	('PBRM1', 'Gene', (5, 10))
126752	27764136	Interestingly, when both PBRM1 and ARID1A were simultaneously knocked down in 786-O cells, much bigger tumors were seen than when only PBRM1 was suppressed (Fig 6F and 6G).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('PBRM1', 'Gene', (25, 30))	('knocked down', 'Var', (62, 74))	('ARID1A', 'Gene', '8289', (35, 41))	('PBRM1', 'Gene', (135, 140))	('ARID1A', 'Gene', (35, 41))	('PBRM1', 'Gene', '55193', (25, 30))	('PBRM1', 'Gene', '55193', (135, 140))
126753	27764136	However, when PBRM1 and ARID1A were both knocked down in 786-O cells, the tumors were not bigger than the ones with their ARID1A knocked down (Fig 6H and 6I).	('ARID1A', 'Gene', '8289', (122, 128))	('ARID1A', 'Gene', (122, 128))	('ARID1A', 'Gene', '8289', (24, 30))	('ARID1A', 'Gene', (24, 30))	('PBRM1', 'Gene', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('knocked down', 'Var', (41, 53))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('PBRM1', 'Gene', '55193', (14, 19))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
126754	27764136	Thus ARID1A knockdown seemed to have a more potent tumor-promoting effect than PBRM1 knockdown.	('ARID1A', 'Gene', '8289', (5, 11))	('ARID1A', 'Gene', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('knockdown', 'Var', (12, 21))	('tumor', 'Disease', (51, 56))	('PBRM1', 'Gene', (79, 84))	('PBRM1', 'Gene', '55193', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
126755	27764136	It is worth noting that the suppression of PBRM1 did not reduce the protein expression of ARID1A in 786-O cells (Fig 6A and S2 Fig), thus the co-loss of ARID1A in tumors with PBRM1 mutations is correlative, not a result of PBRM1 loss.	('PBRM1', 'Gene', (43, 48))	('PBRM1', 'Gene', (175, 180))	('PBRM1', 'Gene', '55193', (43, 48))	('PBRM1', 'Gene', '55193', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('ARID1A', 'Gene', '8289', (90, 96))	('tumors', 'Disease', (163, 169))	('PBRM1', 'Gene', (223, 228))	('ARID1A', 'Gene', (90, 96))	('mutations', 'Var', (181, 190))	('ARID1A', 'Gene', '8289', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('ARID1A', 'Gene', (153, 159))	('PBRM1', 'Gene', '55193', (223, 228))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))
126757	27764136	The goal of precision medicine is to treat patients with drugs that specifically attack the vulnerabilities conferred by the major driving mutations in a given cancer.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('mutations', 'Var', (139, 148))	('cancer', 'Disease', (160, 166))	('patients', 'Species', '9606', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
126758	27764136	For example, imatinib (Gleevec) is used to treat chronic myeloid leukemia to block the BCR-ABL fusion kinase and gastrointestinal stromal tumors to block hyperactive, mutant KIT, Gefitinib is used to treat non-small cell lung cancer patients with tumors exhibiting mutant EGFR, and Vemurafenib to treat melanoma because it is a potent inhibitor of hyperactive, mutant BRAF.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('myeloid leukemia', 'Disease', 'MESH:D007951', (57, 73))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (57, 73))	('tumors', 'Disease', (247, 253))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (113, 144))	('mutant', 'Var', (265, 271))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (206, 232))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('mutant', 'Var', (167, 173))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (282, 293))	('imatinib', 'Chemical', 'MESH:D000068877', (13, 21))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (210, 232))	('BCR-ABL', 'Gene', '25', (87, 94))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('EGFR', 'Gene', (272, 276))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (206, 232))	('KIT', 'molecular_function', 'GO:0005020', ('174', '177'))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('EGFR', 'molecular_function', 'GO:0005006', ('272', '276'))	('melanoma', 'Disease', 'MESH:D008545', (303, 311))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('patients', 'Species', '9606', (233, 241))	('BRAF', 'Gene', '673', (368, 372))	('KIT', 'Gene', (174, 177))	('myeloid leukemia', 'Disease', (57, 73))	('non-small cell lung cancer', 'Disease', (206, 232))	('lung cancer', 'Phenotype', 'HP:0100526', (221, 232))	('BCR-ABL', 'Gene', (87, 94))	('EGFR', 'Gene', '1956', (272, 276))	('BRAF', 'Gene', (368, 372))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('leukemia', 'Phenotype', 'HP:0001909', (65, 73))	('gastrointestinal stromal tumors to block hyperactive', 'Disease', 'MESH:D046152', (113, 165))	('Gefitinib', 'Chemical', 'MESH:D000077156', (179, 188))	('tumors', 'Disease', (138, 144))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (49, 73))	('melanoma', 'Phenotype', 'HP:0002861', (303, 311))	('melanoma', 'Disease', (303, 311))	('Gleevec', 'Chemical', 'MESH:D000068877', (23, 30))
126761	27764136	Alternatively, even if all the cancer cells have mutations in the target genes, ITH would mean a fraction of cancer cells also have mutations in other genes or epigenetic changes that would render the cells resistant to the targeted therapies.	('epigenetic changes', 'Var', (160, 178))	('mutations', 'Var', (49, 58))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('mutations', 'Var', (132, 141))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (31, 37))
126764	27764136	It is difficult to genetically engineer model organisms with half a dozen or more mutations or to induce tumors in which some mutations are only present in a fraction of the neoplasm.	('tumors', 'Disease', (105, 111))	('neoplasm', 'Disease', 'MESH:D009369', (174, 182))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('neoplasm', 'Phenotype', 'HP:0002664', (174, 182))	('mutations', 'Var', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('neoplasm', 'Disease', (174, 182))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
126774	27764136	It has been found that tumor samples harboring DNA mutations in a tumor suppressor gene also tend to lose expression of the encoded protein when examined by IHC, so we chose antibodies that were shown to pass this test where possible.	('lose', 'NegReg', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('66', '82'))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('66', '82'))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (23, 28))	('expression of the encoded', 'MPA', (106, 131))	('DNA', 'Var', (47, 50))
126778	27764136	How mechanistically such combinations impact tumor behavior and drug response are clearly worthy of further investigation.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('drug response', 'CPA', (64, 77))	('combinations', 'Var', (25, 37))	('impact tumor behavior', 'Disease', (38, 59))	('impact tumor behavior', 'Disease', 'MESH:D014095', (38, 59))
126781	27764136	Previous studies have shown that when BRG1 is deficient, cancer cells become dependent on the presence of BRM for survival.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('BRM', 'Gene', (106, 109))	('cancer', 'Disease', (57, 63))	('BRG1', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('BRM', 'Gene', '6595', (106, 109))	('deficient', 'Var', (46, 55))	('BRG1', 'Gene', '6597', (38, 42))
126800	30585695	Furthermore, simultaneous point mutations in BDs 2, 4, and 5 prevented recognition of H3K14ac, altered promoter binding and gene expression, and caused PBRM1 to relocalize to the cytoplasm.	('expression', 'Species', '29278', (129, 139))	('point mutations', 'Var', (26, 41))	('caused', 'Reg', (145, 151))	('promoter', 'MPA', (103, 111))	('BDs 2', 'Gene', (45, 50))	('H3K14ac', 'Gene', (86, 93))	('promoter binding', 'molecular_function', 'GO:0010843', ('103', '119'))	('recognition', 'MPA', (71, 82))	('relocalize', 'MPA', (161, 171))	('H3K14ac', 'Gene', '126961', (86, 93))	('altered', 'Reg', (95, 102))	('PBRM1', 'Gene', (152, 157))	('gene expression', 'biological_process', 'GO:0010467', ('124', '139'))	('gene expression', 'MPA', (124, 139))	('cytoplasm', 'cellular_component', 'GO:0005737', ('179', '188'))	('prevented', 'NegReg', (61, 70))
126801	30585695	In contrast, tumor-derived point mutations in BD2 alone lowered PBRM1's affinity to H3K14ac and also disrupted promoter binding and gene expression without altering cellular localization.	('tumor', 'Disease', (13, 18))	('H3K14ac', 'Gene', '126961', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('promoter', 'MPA', (111, 119))	('promoter binding', 'molecular_function', 'GO:0010843', ('111', '127'))	('affinity to', 'Interaction', (72, 83))	('PBRM1', 'Gene', (64, 69))	('point mutations', 'Var', (27, 42))	('gene expression', 'biological_process', 'GO:0010467', ('132', '147'))	('gene expression', 'MPA', (132, 147))	('BD2', 'Gene', (46, 49))	('BD2', 'Gene', '1673', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('lowered', 'NegReg', (56, 63))	('cellular localization', 'biological_process', 'GO:0051641', ('165', '186'))	('disrupted', 'NegReg', (101, 110))	('H3K14ac', 'Gene', (84, 91))	('expression', 'Species', '29278', (137, 147))
126802	30585695	Finally, overexpression of PBRM1 variants containing point mutations in BDs 2, 4, and 5 or BD2 alone failed to suppress tumor growth in a xenograft model.	('expression', 'Species', '29278', (13, 23))	('point mutations', 'Var', (53, 68))	('suppress', 'NegReg', (111, 119))	('BDs 2', 'Gene', (72, 77))	('PBRM1', 'Gene', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('BD2', 'Gene', (91, 94))	('BD2', 'Gene', '1673', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('variants', 'Var', (33, 41))	('tumor', 'Disease', (120, 125))
126804	30585695	Mutations in BD2 alone weaken these interactions, and this is sufficient to abolish its molecular and tumor suppressor functions.	('interactions', 'Interaction', (36, 48))	('BD2', 'Gene', '1673', (13, 16))	('tumor suppressor', 'biological_process', 'GO:0051726', ('102', '118'))	('weaken', 'NegReg', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('102', '118'))	('abolish', 'NegReg', (76, 83))	('Mutations', 'Var', (0, 9))	('BD2', 'Gene', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
126806	30585695	Among them, 70-80% of sporadic ccRCC tumors harbor biallelic inactivation of VHL (Linehan et al., 2004).	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('ccRCC tumors', 'Disease', 'MESH:D009369', (31, 43))	('biallelic inactivation', 'Var', (51, 73))	('VHL', 'Gene', (77, 80))	('VHL', 'Gene', '7428', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('ccRCC tumors', 'Disease', (31, 43))
126811	30585695	Most solid tumors harbor multiple driver mutations in cancer genes to achieve the hallmarks of cancer (Hanahan and Weinberg, 2011; Vogelstein et al., 2013).	('mutations', 'Var', (41, 50))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (82, 101))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', (54, 60))	('solid tumors', 'Disease', 'MESH:D009369', (5, 17))	('hallmarks of cancer', 'Disease', (82, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('solid tumors', 'Disease', (5, 17))
126812	30585695	Forty-one percent of ccRCC tumors have inactivating mutations in the PBRM1 gene, and they occur throughout the coding sequence (Varela et al., 2011).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('ccRCC tumors', 'Disease', 'MESH:D009369', (21, 33))	('ccRCC tumors', 'Disease', (21, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('inactivating mutations', 'Var', (39, 61))	('PBRM1', 'Gene', (69, 74))
126816	30585695	Mutations in other genes such as BAP1, SETD2, KDM5C/JARID1C, PTEN, and UTX have also been identified, but their mutation rates are much lower than that of PBRM1 (Liao et al., 2015).	('KDM5C', 'Gene', (46, 51))	('SETD2', 'Gene', (39, 44))	('KDM5C', 'Gene', '8242', (46, 51))	('JARID1C', 'Gene', (52, 59))	('UTX', 'Gene', (71, 74))	('BAP1', 'Gene', '8314', (33, 37))	('JARID1C', 'Gene', '8242', (52, 59))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', (61, 65))	('PTEN', 'Gene', '5728', (61, 65))	('BAP1', 'Gene', (33, 37))	('UTX', 'Gene', '7403', (71, 74))	('SETD2', 'Gene', '29072', (39, 44))
126818	30585695	Genomic sequencing of multiple foci of ccRCC tumors has revealed that the majority of PBRM1 mutations occur early in tumorigenesis, while mutations in the other secondary tumor suppressor genes occur later during tumor development (Gerlinger et al., 2012, 2014).	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('171', '187'))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mutations', 'Var', (92, 101))	('PBRM1', 'Gene', (86, 91))	('tumor suppressor', 'biological_process', 'GO:0051726', ('171', '187'))	('tumor', 'Disease', (213, 218))	('ccRCC tumors', 'Disease', (39, 51))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('ccRCC tumors', 'Disease', 'MESH:D009369', (39, 51))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
126821	30585695	In mice, kidney-specific deletion of either Vhl or Pbrm1 does not lead to ccRCC, but their combined loss does (Gu et al., 2017; Nargund et al., 2017).	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('Vhl', 'Gene', (44, 47))	('mice', 'Species', '10090', (3, 7))	('deletion', 'Var', (25, 33))	('Pbrm1', 'Gene', (51, 56))	('Pbrm1', 'Gene', '66923', (51, 56))	('Vhl', 'Gene', '22346', (44, 47))	('loss', 'NegReg', (100, 104))
126826	30585695	Loss-of-function mutations of PBRM1 were recently discovered to be associated with response to checkpoint inhibition therapies in ccRCC patients treated with anti-PD-1 alone or in combination with anti-CTLA-4 therapies (Miao et al., 2018).	('Loss-of-function', 'NegReg', (0, 16))	('CTLA-4', 'Gene', (202, 208))	('PBRM1', 'Gene', (30, 35))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('RCC', 'Disease', (132, 135))	('CTLA-4', 'Gene', '1493', (202, 208))	('response to checkpoint inhibition therapies', 'MPA', (83, 126))	('patients', 'Species', '9606', (136, 144))	('PD-1', 'Gene', (163, 167))	('PD-1', 'Gene', '5133', (163, 167))	('mutations', 'Var', (17, 26))
126827	30585695	In addition, PBRM1 mutations were found to enhance T-cell-mediated killing of tumor cells in an unbiased, high-throughput screen in a melanoma model (Pan et al., 2018).	('PBRM1', 'Gene', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mutations', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('tumor', 'Disease', (78, 83))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('enhance', 'PosReg', (43, 50))
126829	30585695	BDs are small domains with specific affinity for N-epsilon-lysine acetylation on histones and other proteins (Dhalluin et al., 1999; Owen et al., 2000).	('histones', 'Protein', (81, 89))	('N-epsilon-lysine', 'Chemical', '-', (49, 65))	('N-epsilon-lysine', 'Var', (49, 65))
126832	30585695	Recently, Porter and Dykhuizen (2017) confirmed that while BD2 is critical for H3K14ac binding, mutation of BD2 only moderately reduced PBRM1's binding to H3K14ac and its association with chromatin.	('BD2', 'Gene', (59, 62))	('BD2', 'Gene', '1673', (59, 62))	('PBRM1', 'Gene', (136, 141))	('binding', 'molecular_function', 'GO:0005488', ('87', '94'))	('BD2', 'Gene', (108, 111))	('BD2', 'Gene', '1673', (108, 111))	('association', 'Interaction', (171, 182))	('reduced', 'NegReg', (128, 135))	('chromatin', 'cellular_component', 'GO:0000785', ('188', '197'))	('binding', 'Interaction', (144, 151))	('Porter', 'molecular_function', 'GO:0015297', ('10', '16'))	('binding', 'molecular_function', 'GO:0005488', ('144', '151'))	('H3K14ac', 'Gene', (155, 162))	('mutation', 'Var', (96, 104))	('Porter', 'molecular_function', 'GO:0022810', ('10', '16'))	('H3K14ac', 'Gene', (79, 86))	('H3K14ac', 'Gene', '126961', (79, 86))	('H3K14ac', 'Gene', '126961', (155, 162))
126834	30585695	However, it is still not clear how critical H3K14ac recognition is to PBRM1's association with the chromatin and how mutant PBRM1 impacts tumor growth in a mouse model.	('chromatin', 'cellular_component', 'GO:0000785', ('99', '108'))	('H3K14ac', 'Gene', '126961', (44, 51))	('tumor', 'Disease', (138, 143))	('impacts', 'Reg', (130, 137))	('mutant', 'Var', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('PBRM1', 'Gene', (124, 129))	('mouse', 'Species', '10090', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('H3K14ac', 'Gene', (44, 51))	('association', 'Interaction', (78, 89))
126836	30585695	Simultaneous mutations in the involved BDs were found to completely abolish H3K14ac recognition, causing PBRM1 to detach from chromatin and relocalize to the cytoplasm.	('PBRM1', 'Gene', (105, 110))	('H3K14ac', 'Gene', (76, 83))	('H3K14ac', 'Gene', '126961', (76, 83))	('chromatin', 'cellular_component', 'GO:0000785', ('126', '135'))	('relocalize', 'MPA', (140, 150))	('detach from', 'NegReg', (114, 125))	('abolish', 'NegReg', (68, 75))	('mutations', 'Var', (13, 22))	('cytoplasm', 'cellular_component', 'GO:0005737', ('158', '167'))
126837	30585695	In addition, tumor-derived mutations in BD2 resulted in reduced recognition of H3K14ac by PBRM1.	('mutations', 'Var', (27, 36))	('tumor', 'Disease', (13, 18))	('reduced', 'NegReg', (56, 63))	('BD2', 'Gene', (40, 43))	('BD2', 'Gene', '1673', (40, 43))	('H3K14ac', 'Gene', (79, 86))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('H3K14ac', 'Gene', '126961', (79, 86))	('recognition', 'MPA', (64, 75))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('PBRM1', 'Gene', (90, 95))
126838	30585695	Although these mutations failed to significantly change PBRM1's binding to chromatin, they significantly impaired PBRM1's ability to bind to promoters and regulate gene expression and severely crippled PBRM1's tumor suppressor function.	("PBRM1's tumor", 'Disease', 'MESH:D009396', (202, 215))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('binding', 'molecular_function', 'GO:0005488', ('64', '71'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('210', '226'))	('crippled', 'NegReg', (193, 201))	('gene expression', 'MPA', (164, 179))	('impaired', 'NegReg', (105, 113))	('mutations', 'Var', (15, 24))	('ability', 'MPA', (122, 129))	("PBRM1's tumor", 'Disease', (202, 215))	('expression', 'Species', '29278', (169, 179))	('bind', 'Interaction', (133, 137))	('regulate', 'Reg', (155, 163))	('gene expression', 'biological_process', 'GO:0010467', ('164', '179'))	('PBRM1', 'Gene', (114, 119))	('chromatin', 'cellular_component', 'GO:0000785', ('75', '84'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('210', '226'))
126847	30585695	BD2, BD4, BD234, and BD245 were allowed to associate with the ligand-bound sensor for 2000 s followed by dissociation with assay buffer for 2000 s. All steps were performed at 25  C with sensors dipped into 200 muL of sample and stirred at 100 g. Reference sensors (without H3 peptide) were used for each variant tested to correct for background binding and baseline drift.	('binding', 'Interaction', (346, 353))	('BD2', 'Gene', (0, 3))	('H3', 'Gene', '126961', (274, 276))	('BD2', 'Gene', '1673', (0, 3))	('variant', 'Var', (305, 312))	('BD2', 'Gene', '1673', (10, 13))	('binding', 'molecular_function', 'GO:0005488', ('346', '353'))	('BD2', 'Gene', (10, 13))	('BD4', 'Gene', (5, 8))	('BD4', 'Gene', '140596', (5, 8))	('BD2', 'Gene', '1673', (21, 24))	('ligand', 'molecular_function', 'GO:0005488', ('62', '68'))	('BD2', 'Gene', (21, 24))
126860	30585695	H3K14ac, GeneTex (Zeeland, MI, USA) (GTX88008); GST, Cell Signaling Technology (2625); histone H3, Bethyl A300-823A (Montgomery, Texas, USA).	('H3', 'Gene', '126961', (95, 97))	('Bethyl A300-823A', 'Var', (99, 115))	('Signaling', 'biological_process', 'GO:0023052', ('58', '67'))	('H3K14ac', 'Gene', (0, 7))	('H3', 'Gene', '126961', (0, 2))	('H3K14ac', 'Gene', '126961', (0, 7))
126862	30585695	HeLa cells were transfected with WT and mutant PBRM1, and, after 36 hr, the cells were scraped and centrifuged for 5 min at 100 g. Cell pellets were resuspended in 500 muL hypotonic buffer (10 mm Tris/HCl, pH 8.0, 1.5 mm MgCl2, 10 mm KCl and protease inhibitor cocktail [Pierce, Catalog #88666]), incubated on ice for 15 min, then vortexed for 10 s after adding 25 muL Triton X-100.	('KCl', 'Chemical', 'MESH:D011189', (234, 237))	('PBRM1', 'Gene', (47, 52))	('Tris/HCl', 'Chemical', '-', (196, 204))	('Triton X-100', 'Chemical', 'MESH:D017830', (369, 381))	('MgCl2', 'Chemical', 'MESH:D015636', (221, 226))	('hypotonic', 'Disease', 'MESH:D009123', (172, 181))	('hypotonic', 'Disease', (172, 181))	('mutant', 'Var', (40, 46))	('HeLa', 'CellLine', 'CVCL:0030', (0, 4))
126866	30585695	The full-length cDNAs of human PBRM1, PBRM1 in-frame deletion of N263 (BD2IFD) mutant, and PBRM1 3m mutant was cloned into pLNCX-GFP vector plasmid.	('N263', 'Chemical', '-', (65, 69))	('mutant', 'Var', (79, 85))	('deletion', 'Var', (53, 61))	('human', 'Species', '9606', (25, 30))	('PBRM1', 'Gene', (38, 43))	('BD2', 'Gene', (71, 74))	('BD2', 'Gene', '1673', (71, 74))	('PBRM1', 'Gene', (31, 36))
126867	30585695	The constructs were transfected into AmphoPack-293 Cell Line (Clontech, Mountain View, CA, USA; Catalog #631505) to generate retrovirus, and then, 786-O PBRM1 knockdown cells were transduced to stably express wild-type or mutant PBRM1.	('PBRM1', 'Gene', (229, 234))	('mutant', 'Var', (222, 228))	('Pack-293', 'CellLine', 'CVCL:H716', (42, 50))
126894	30585695	To address this possibility, PBRM1 constructs harboring deletions of the BDs were generated, beginning with deletion of BD1 at the N terminus and containing successive deletions of each BD (DBD1-6, Fig.	('BD1', 'Gene', '1672', (120, 123))	('BD1', 'Gene', (191, 194))	('BD1-6', 'Gene', '1672;1673;55894;140596;245908;503841', (191, 196))	('BD1-6', 'Gene', (191, 196))	('BD1', 'Gene', (120, 123))	('BD1', 'Gene', '1672', (191, 194))	('deletion', 'Var', (108, 116))
126897	30585695	While deletion of BD1 (Flag-DBD1, row 2) did not affect H3K14ac binding in this assay, deletion of BDs 1 and 2 (Flag-DBD2, row 3) greatly reduced the binding of PBRM1 to H3K14ac.	('BD1', 'Gene', (18, 21))	('BDs 1 and 2', 'Gene', '1672;1673', (99, 110))	('BD1', 'Gene', '1672', (29, 32))	('H3K14ac', 'Gene', '126961', (170, 177))	('binding', 'molecular_function', 'GO:0005488', ('64', '71'))	('reduced', 'NegReg', (138, 145))	('BD2', 'Gene', (118, 121))	('BD2', 'Gene', '1673', (118, 121))	('BD1', 'Gene', (29, 32))	('PBRM1', 'Protein', (161, 166))	('BD1', 'Gene', '1672', (18, 21))	('H3K14ac', 'Gene', (56, 63))	('deletion', 'Var', (6, 14))	('H3K14ac', 'Gene', (170, 177))	('deletion', 'Var', (87, 95))	('H3K14ac', 'Gene', '126961', (56, 63))	('binding', 'molecular_function', 'GO:0005488', ('150', '157'))	('binding', 'Interaction', (150, 157))
126898	30585695	Deletion of BDs 1-4 (Flag-DBD4, row 5) further reduced binding to H3K14ac compared to deletion of BDs 1-3 (Flag-DBD3, row 4).	('BD4', 'Gene', '140596', (27, 30))	('BD4', 'Gene', (27, 30))	('BDs 1-3', 'Gene', '1672;1673;55894', (98, 105))	('BDs 1-3', 'Gene', (98, 105))	('H3K14ac', 'Gene', (66, 73))	('BD3', 'Gene', '55894', (113, 116))	('BDs 1-4', 'Gene', '1672;1673;55894;140596', (12, 19))	('Deletion', 'Var', (0, 8))	('BD3', 'Gene', (113, 116))	('binding', 'Interaction', (55, 62))	('H3K14ac', 'Gene', '126961', (66, 73))	('binding', 'molecular_function', 'GO:0005488', ('55', '62'))	('reduced', 'NegReg', (47, 54))	('BDs 1-4', 'Gene', (12, 19))
126899	30585695	Further deletion of BD5 (Flag-DBD5, row 6) completely abolished binding of H3K14ac versus the nonacetylated H3 peptide (Fig.	('binding', 'Interaction', (64, 71))	('BD5', 'Gene', (31, 34))	('H3K14ac', 'Gene', '126961', (75, 82))	('BD5', 'Gene', '245908', (31, 34))	('H3', 'Gene', '126961', (75, 77))	('binding', 'molecular_function', 'GO:0005488', ('64', '71'))	('H3', 'Gene', '126961', (108, 110))	('abolished', 'NegReg', (54, 63))	('BD5', 'Gene', (20, 23))	('BD5', 'Gene', '245908', (20, 23))	('H3K14ac', 'Gene', (75, 82))	('deletion', 'Var', (8, 16))
126901	30585695	Since the sequential deletion of BDs only reduced PBRM1's affinity to H3K14ac gradually, we used different combinations of BDs 1-4 to critically examine their contributions to H3K14ac binding.	('reduced', 'NegReg', (42, 49))	('PBRM1', 'Gene', (50, 55))	('BDs', 'Gene', (33, 36))	('binding', 'molecular_function', 'GO:0005488', ('184', '191'))	('BDs 1-4', 'Gene', (123, 130))	('H3K14ac', 'Gene', (70, 77))	('deletion', 'Var', (21, 29))	('H3K14ac', 'Gene', '126961', (70, 77))	('H3K14ac', 'Gene', (176, 183))	('affinity', 'MPA', (58, 66))	('H3K14ac', 'Gene', '126961', (176, 183))	('BDs 1-4', 'Gene', '1672;1673;55894;140596', (123, 130))
126909	30585695	Here, the N263A mutation (denoted as BD2*), which disrupts the YN motif in BD2, abolished the enhanced affinity of Flag-BD234-BD2* toward H3K14ac over the nonacetylated peptide (Fig.	('affinity', 'Interaction', (103, 111))	('H3K14ac', 'Gene', '126961', (138, 145))	('BD2', 'Gene', '1673', (126, 129))	('H3K14ac', 'Gene', (138, 145))	('N263A', 'Var', (10, 15))	('abolished', 'NegReg', (80, 89))	('N263A', 'Mutation', 'p.N263A', (10, 15))	('BD2', 'Gene', '1673', (120, 123))	('BD2', 'Gene', (75, 78))	('BD2', 'Gene', '1673', (75, 78))	('BD2', 'Gene', (37, 40))	('enhanced', 'PosReg', (94, 102))	('BD2', 'Gene', '1673', (37, 40))	('BD2', 'Gene', (120, 123))	('BD2', 'Gene', (126, 129))
126913	30585695	Leaving out BD6 did not alter H3K14ac binding, while in-frame deletion of BD5 in Flag-BD2346-BD2* abolished the recognition of H3K14ac over nonacetylated peptide (Fig.	('BD2', 'Gene', (86, 89))	('BD6', 'Gene', '503841', (12, 15))	('BD2', 'Gene', '1673', (86, 89))	('H3K14ac', 'Gene', '126961', (30, 37))	('H3K14ac', 'Gene', (127, 134))	('BD2', 'Gene', (93, 96))	('H3K14ac', 'Gene', '126961', (127, 134))	('BD2', 'Gene', '1673', (93, 96))	('BD5', 'Gene', (74, 77))	('BD6', 'Gene', (12, 15))	('BD5', 'Gene', '245908', (74, 77))	('binding', 'molecular_function', 'GO:0005488', ('38', '45'))	('recognition', 'MPA', (112, 123))	('abolished', 'NegReg', (98, 107))	('deletion', 'Var', (62, 70))	('H3K14ac', 'Gene', (30, 37))
126939	30585695	In addition to the highly conserved YN motif in BD4 (residues: 600-601), there is a second, less-conserved YN motif (residues: 608-609) in BD4.	('BD4', 'Gene', (48, 51))	('BD4', 'Gene', '140596', (48, 51))	('BD4', 'Gene', '140596', (139, 142))	('BD4', 'Gene', (139, 142))	('residues: 608-609', 'Var', (117, 134))
126940	30585695	These motifs are disrupted by the N601A (YN1) and N609A (YN2) mutations (Fig.	('N601A', 'Mutation', 'p.N601A', (34, 39))	('N601A', 'Var', (34, 39))	('disrupted', 'NegReg', (17, 26))	('N609A', 'Mutation', 'p.N609A', (50, 55))	('N609A', 'Var', (50, 55))
126944	30585695	We mutated these residues to alanine (DLF>AAA, BD4*) and found that it greatly reduced binding of BD234 to H3K14ac (Fig.	('binding', 'molecular_function', 'GO:0005488', ('87', '94'))	('reduced', 'NegReg', (79, 86))	('BD2', 'Gene', '1673', (98, 101))	('mutated', 'Var', (3, 10))	('binding', 'Interaction', (87, 94))	('H3K14ac', 'Gene', (107, 114))	('alanine', 'Chemical', 'MESH:D000409', (29, 36))	('BD4', 'Gene', '140596', (47, 50))	('BD2', 'Gene', (98, 101))	('H3K14ac', 'Gene', '126961', (107, 114))	('BD4', 'Gene', (47, 50))
126946	30585695	Simultaneous mutation of the YN motifs in BDs 2 and 5 (N263A and N739A, BD2* and BD5*) abolished the affinity of BD2345 toward H3K14ac compared to the N263A single mutation (Fig.	('abolished', 'NegReg', (87, 96))	('N739A', 'Var', (65, 70))	('H3K14ac', 'Gene', (127, 134))	('affinity', 'Interaction', (101, 109))	('H3K14ac', 'Gene', '126961', (127, 134))	('N739A', 'Mutation', 'p.N739A', (65, 70))	('BD5', 'Gene', (81, 84))	('BD2', 'Gene', (72, 75))	('BD2', 'Gene', '1673', (72, 75))	('BD5', 'Gene', '245908', (81, 84))	('N263A', 'Mutation', 'p.N263A', (151, 156))	('N263A', 'Var', (55, 60))	('BDs 2 and 5', 'Gene', '1673;245908', (42, 53))	('BD2', 'Gene', (113, 116))	('N263A', 'Mutation', 'p.N263A', (55, 60))	('BD2', 'Gene', '1673', (113, 116))
126949	30585695	A recent publication suggested that a ccRCC-derived BD4 N601K mutation could significantly reduce H3K14ac recognition in GST-BD4 and BD45 (Slaughter et al., 2018).	('reduce', 'NegReg', (91, 97))	('H3K14ac', 'Gene', (98, 105))	('H3K14ac', 'Gene', '126961', (98, 105))	('RCC', 'Disease', (40, 43))	('BD4', 'Gene', '140596', (52, 55))	('BD4', 'Gene', (52, 55))	('BD4', 'Gene', (125, 128))	('BD4', 'Gene', '140596', (125, 128))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('N601K', 'Var', (56, 61))	('N601K', 'Mutation', 'p.N601K', (56, 61))	('BD4', 'Gene', '140596', (133, 136))	('BD4', 'Gene', (133, 136))
126950	30585695	We compared it with Y600N601-AA mutant and found that it did significantly reduce the binding to H3K14ac in Flag-BD234 (Fig.	('H3K14ac', 'Gene', '126961', (97, 104))	('reduce', 'NegReg', (75, 81))	('Y600N601-AA', 'Var', (20, 31))	('N601', 'Chemical', '-', (24, 28))	('binding', 'Interaction', (86, 93))	('H3K14ac', 'Gene', (97, 104))	('binding', 'molecular_function', 'GO:0005488', ('86', '93'))	('BD2', 'Gene', (113, 116))	('BD2', 'Gene', '1673', (113, 116))
126951	30585695	Thus, this N601K mutation might change the structure of BD4 while the Y600N601-AA may not.	('structure', 'MPA', (43, 52))	('Y600N601-AA', 'Var', (70, 81))	('BD4', 'Gene', '140596', (56, 59))	('BD4', 'Gene', (56, 59))	('N601K', 'Mutation', 'p.N601K', (11, 16))	('N601', 'Chemical', '-', (11, 15))	('N601K', 'Var', (11, 16))	('N601', 'Chemical', '-', (74, 78))	('change', 'Reg', (32, 38))
126952	30585695	After defining the critical binding residues of BDs 2, 4, and 5 with smaller constructs, we investigated how mutation of these residues affects the binding between full-length PBRM1 and H3K14ac.	('binding', 'molecular_function', 'GO:0005488', ('148', '155'))	('affects', 'Reg', (136, 143))	('PBRM1', 'Gene', (176, 181))	('binding', 'Interaction', (148, 155))	('H3K14ac', 'Gene', '126961', (186, 193))	('H3K14ac', 'Gene', (186, 193))	('binding', 'molecular_function', 'GO:0005488', ('28', '35'))	('mutation', 'Var', (109, 117))
126953	30585695	The individual N263A (BD2*), DLF>AAA (BD4*), and N739A (BD5*) mutations each slightly reduced the affinity toward H3K14ac (Fig.	('N263A', 'Mutation', 'p.N263A', (15, 20))	('reduced', 'NegReg', (86, 93))	('BD4', 'Gene', '140596', (38, 41))	('BD5', 'Gene', (56, 59))	('BD4', 'Gene', (38, 41))	('BD5', 'Gene', '245908', (56, 59))	('DLF>AAA', 'Var', (29, 36))	('BD2', 'Gene', (22, 25))	('BD2', 'Gene', '1673', (22, 25))	('affinity', 'Interaction', (98, 106))	('N739A', 'Mutation', 'p.N739A', (49, 54))	('H3K14ac', 'Gene', (114, 121))	('H3K14ac', 'Gene', '126961', (114, 121))
126954	30585695	3D, rows 2, 3, and 4), while the N263A-N739A (BD2* and 5*) double mutation reduced the affinity further (Fig.	('affinity', 'Interaction', (87, 95))	('N263A-N739A', 'Var', (33, 44))	('reduced', 'NegReg', (75, 82))	('BD2', 'Gene', (46, 49))	('BD2', 'Gene', '1673', (46, 49))	('N739A', 'Mutation', 'p.N739A', (39, 44))	('N263A', 'Mutation', 'p.N263A', (33, 38))
126955	30585695	The triple mutation N263A-DLF>AAA-N739A (3m) completely abolished the ability of full-length PBRM1 to bind H3K14ac (Fig.	('N739A', 'Mutation', 'p.N739A', (34, 39))	('abolished', 'NegReg', (56, 65))	('N263A', 'Mutation', 'p.N263A', (20, 25))	('ability', 'MPA', (70, 77))	('H3K14ac', 'Gene', (107, 114))	('bind', 'Interaction', (102, 106))	('PBRM1', 'Gene', (93, 98))	('N263A-DLF>AAA-N739A', 'Var', (20, 39))	('H3K14ac', 'Gene', '126961', (107, 114))
126956	30585695	3D, row 6), indicating that concurrent mutations within BDs 2, 4, and 5 are necessary and sufficient to prevent specific recognition of H3K14ac.	('H3K14ac', 'Gene', (136, 143))	('H3K14ac', 'Gene', '126961', (136, 143))	('mutations', 'Var', (39, 48))
126958	30585695	To examine the influence of BD mutations on PBRM1 localization, we transfected HeLa cells with wild-type, the triple BD mutant, or the BD2 mutant.	('mutant', 'Var', (139, 145))	('BD2', 'Gene', (135, 138))	('BD2', 'Gene', '1673', (135, 138))	('HeLa', 'CellLine', 'CVCL:0030', (79, 83))	('localization', 'biological_process', 'GO:0051179', ('50', '62'))	('triple BD mutant', 'Var', (110, 126))
126960	30585695	In contrast, PBRM1 with a mutation only in BD2 had a similar distribution to the wild-type protein (Fig.	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('BD2', 'Gene', '1673', (43, 46))	('BD2', 'Gene', (43, 46))	('mutation', 'Var', (26, 34))
126962	30585695	It has been reported that ~ 40% of ccRCC harbor inactivating mutations in PBRM1 (Varela et al., 2011).	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('PBRM1', 'Gene', (74, 79))	('inactivating mutations', 'Var', (48, 70))
126963	30585695	Other cancers also have PBRM1 mutations.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('PBRM1', 'Gene', (24, 29))	('mutations', 'Var', (30, 39))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))
126964	30585695	Mapping the tumor-derived mutations to the available crystal structures of the PBRM1 BDs 2, 4, and 5 (Filippakopoulos et al., 2010) provides further insight into the mechanism of how these mutations described in Table 1 may affect PBRM1 function.	('affect', 'Reg', (224, 230))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('PBRM1', 'Gene', (79, 84))	('mutations', 'Var', (26, 35))	('function', 'MPA', (237, 245))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('PBRM1', 'Gene', (231, 236))	('tumor', 'Disease', (12, 17))	('mutations', 'Var', (189, 198))
126965	30585695	Mutation N263A changes the highly conserved asparagine residue at the C-terminal end of helix alphaB in BD2 (Fig.	('highly conserved asparagine residue', 'MPA', (27, 62))	('BD2', 'Gene', (104, 107))	('BD2', 'Gene', '1673', (104, 107))	('changes', 'Reg', (15, 22))	('asparagine', 'Chemical', 'MESH:D001216', (44, 54))	('N263A', 'Mutation', 'p.N263A', (9, 14))	('N263A', 'Var', (9, 14))
126967	30585695	Since I233 belongs to a group of highly conserved hydrophobic residues in helix alphaA that contribute to the stability of the BD core (Filippakopoulos et al., 2010), its mutation to T in BD2 (Fig.	('core', 'cellular_component', 'GO:0019013', ('130', '134'))	('I233', 'Var', (6, 10))	('BD2', 'Gene', '1673', (188, 191))	('mutation to T', 'Var', (171, 184))	('BD2', 'Gene', (188, 191))
126968	30585695	Similarly, mutation of A256 in helix alphaC to T is predicted to interfere with the tightly packed hydrophobic core of BD2 (Fig.	('tightly packed hydrophobic core', 'MPA', (84, 115))	('helix alphaC', 'Protein', (31, 43))	('interfere', 'NegReg', (65, 74))	('BD2', 'Gene', '1673', (119, 122))	('mutation', 'Var', (11, 19))	('BD2', 'Gene', (119, 122))	('core', 'cellular_component', 'GO:0019013', ('111', '115'))	('A256', 'Var', (23, 27))
126969	30585695	In summary, most tumor-derived mutations in PBRM1 BD2 structurally and functionally affect important conserved residues, leading to detrimental effects either on acetyl-lysine peptide recognition or BD stability.	('acetyl-lysine peptide recognition', 'MPA', (162, 195))	('acetyl-lysine', 'Chemical', '-', (162, 175))	('mutations', 'Var', (31, 40))	('tumor', 'Disease', (17, 22))	('BD stability', 'MPA', (199, 211))	('conserved residues', 'MPA', (101, 119))	('affect', 'Reg', (84, 90))	('BD2', 'Gene', (50, 53))	('BD2', 'Gene', '1673', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
126970	30585695	The DLF segment mutated to AAA in BD4 resides in a short helical turn with a highly conserved phenylalanine (Fig.	('phenylalanine', 'Chemical', 'MESH:D010649', (94, 107))	('BD4', 'Gene', '140596', (34, 37))	('BD4', 'Gene', (34, 37))	('mutated', 'Var', (16, 23))
126971	30585695	N739A also changes the highly conserved asparagine residue at the C-terminal end of helix alphaB in BD5 (Fig.	('BD5', 'Gene', '245908', (100, 103))	('changes', 'Reg', (11, 18))	('N739A', 'Mutation', 'p.N739A', (0, 5))	('asparagine', 'Chemical', 'MESH:D001216', (40, 50))	('highly conserved asparagine residue', 'MPA', (23, 58))	('N739A', 'Var', (0, 5))	('BD5', 'Gene', (100, 103))
126972	30585695	We hypothesized that these tumor-derived mutations would alter PBRM1's function through impairing its ability to recognize H3K14ac.	('mutations', 'Var', (41, 50))	('function', 'MPA', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('H3K14ac', 'Gene', (123, 130))	('alter', 'Reg', (57, 62))	('tumor', 'Disease', (27, 32))	('ability', 'MPA', (102, 109))	('H3K14ac', 'Gene', '126961', (123, 130))	('PBRM1', 'Gene', (63, 68))	('recognize', 'MPA', (113, 122))	('impairing', 'NegReg', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
126973	30585695	We used site-directed mutagenesis to introduce tumor-derived mutations into Flag-BD234.	('mutagenesis', 'biological_process', 'GO:0006280', ('22', '33'))	('mutations', 'Var', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('BD2', 'Gene', '1673', (81, 84))	('BD2', 'Gene', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
126974	30585695	The N263A mutation abolished H3K14ac recognition in BD234 but only reduced it in BD2345 (Fig.	('H3K14ac', 'Gene', (29, 36))	('H3K14ac', 'Gene', '126961', (29, 36))	('BD2', 'Gene', (52, 55))	('BD2', 'Gene', '1673', (52, 55))	('N263A', 'Var', (4, 9))	('N263A', 'Mutation', 'p.N263A', (4, 9))	('BD2', 'Gene', (81, 84))	('BD2', 'Gene', '1673', (81, 84))	('abolished', 'NegReg', (19, 28))	('recognition', 'MPA', (37, 48))
126975	30585695	3B,C, compare rows 1 and 2), so Flag-BD234 is more sensitive to the perturbation of H3K14ac recognition by mutations in BD2.	('H3K14ac', 'Gene', '126961', (84, 91))	('mutations', 'Var', (107, 116))	('BD2', 'Gene', '1673', (120, 123))	('BD2', 'Gene', (37, 40))	('BD2', 'Gene', '1673', (37, 40))	('BD2', 'Gene', (120, 123))	('H3K14ac', 'Gene', (84, 91))
126976	30585695	The BD2IFD, T232P, and L254P mutations completely abolished H3K14ac binding (Fig.	('L254P', 'Mutation', 'p.L254P', (23, 28))	('H3K14ac', 'Gene', (60, 67))	('binding', 'Interaction', (68, 75))	('H3K14ac', 'Gene', '126961', (60, 67))	('T232P', 'Var', (12, 17))	('BD2', 'Gene', '1673', (4, 7))	('abolished', 'NegReg', (50, 59))	('binding', 'molecular_function', 'GO:0005488', ('68', '75'))	('T232P', 'Mutation', 'p.T232P', (12, 17))	('BD2', 'Gene', (4, 7))	('L254P', 'Var', (23, 28))
126977	30585695	6A, rows 2, 3, and 5), while I233T reduced binding and A256T had no apparent effect (Fig.	('binding', 'Interaction', (43, 50))	('reduced', 'NegReg', (35, 42))	('A256T', 'Mutation', 'c.256A>T', (55, 60))	('binding', 'molecular_function', 'GO:0005488', ('43', '50'))	('A256T', 'Var', (55, 60))	('I233T', 'Mutation', 'p.I233T', (29, 34))	('I233T', 'Var', (29, 34))
126979	30585695	These results suggest that many tumor-derived mutations in PBRM1's BD2 impair its ability to recognize H3K14ac, indicating that this binding event may be critical for its tumor suppressor function.	('mutations', 'Var', (46, 55))	('ability', 'MPA', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('PBRM1', 'Gene', (59, 64))	('BD2', 'Gene', (67, 70))	('BD2', 'Gene', '1673', (67, 70))	('H3K14ac', 'Gene', (103, 110))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('H3K14ac', 'Gene', '126961', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('binding', 'molecular_function', 'GO:0005488', ('133', '140'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('171', '187'))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', (32, 37))	('impair', 'NegReg', (71, 77))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('171', '187'))
126981	30585695	We predicted that BD mutations that disrupted H3K14ac binding would negatively impact PBRM1's role in gene expression.	('gene expression', 'biological_process', 'GO:0010467', ('102', '117'))	('H3K14ac', 'Gene', '126961', (46, 53))	('binding', 'molecular_function', 'GO:0005488', ('54', '61'))	('expression', 'Species', '29278', (107, 117))	('negatively impact', 'NegReg', (68, 85))	('disrupted', 'NegReg', (36, 45))	('PBRM1', 'Gene', (86, 91))	('H3K14ac', 'Gene', (46, 53))	('role in gene expression', 'MPA', (94, 117))	('binding', 'Interaction', (54, 61))	('mutations', 'Var', (21, 30))
126984	30585695	Re-expression of shRNA-resistant wild-type PBRM1 or PBRM1 BD mutants (Flag-PBRM1-3m, Flag-PBRM1-BD2IFD, Flag-PBRM1-T232P) in PBRM1 knockdown cells restored PBRM1 protein similar to endogenous levels and increased PBRM1 mRNA levels in 786-O cells (Fig.	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('PBRM1', 'Gene', (156, 161))	('BD2', 'Gene', (96, 99))	('BD2', 'Gene', '1673', (96, 99))	('expression', 'Species', '29278', (3, 13))	('restored', 'PosReg', (147, 155))	('PBRM1', 'Gene', (213, 218))	('Flag-PBRM1-T232P', 'Var', (104, 120))	('protein', 'Protein', (162, 169))	('PBRM1', 'Gene', (52, 57))	('mRNA levels', 'MPA', (219, 230))	('T232P', 'Mutation', 'p.T232P', (115, 120))	('increased', 'PosReg', (203, 212))
126988	30585695	Neither the triple BD mutant nor the BD2 mutants harboring BD2IFD or T232P were able to rescue the defects in gene expression resulting from PBRM1 suppression (Fig.	('BD2', 'Gene', (59, 62))	('BD2', 'Gene', '1673', (59, 62))	('expression', 'Species', '29278', (115, 125))	('PBRM1', 'Gene', (141, 146))	('BD2', 'Gene', (37, 40))	('T232P', 'Mutation', 'p.T232P', (69, 74))	('BD2', 'Gene', '1673', (37, 40))	('gene expression', 'MPA', (110, 125))	('defects', 'MPA', (99, 106))	('T232P', 'Var', (69, 74))	('gene expression', 'biological_process', 'GO:0010467', ('110', '125'))	('suppression', 'NegReg', (147, 158))
126989	30585695	Taken together, our data suggest that BD mutations that weaken H3K14ac recognition impair the ability of PBRM1 to regulate gene expression.	('mutations', 'Var', (41, 50))	('PBRM1', 'Gene', (105, 110))	('recognition', 'MPA', (71, 82))	('H3K14ac', 'Gene', (63, 70))	('impair', 'NegReg', (83, 89))	('expression', 'Species', '29278', (128, 138))	('weaken', 'NegReg', (56, 62))	('H3K14ac', 'Gene', '126961', (63, 70))	('gene expression', 'biological_process', 'GO:0010467', ('123', '138'))	('ability', 'MPA', (94, 101))	('regulate gene expression', 'MPA', (114, 138))
126995	30585695	Select BD mutations impaired PBRM1's ability to recognize H3K14ac, regulate gene expression, and localize to promoters.	('regulate', 'Reg', (67, 75))	('H3K14ac', 'Gene', (58, 65))	('ability', 'MPA', (37, 44))	('gene expression', 'biological_process', 'GO:0010467', ('76', '91'))	('H3K14ac', 'Gene', '126961', (58, 65))	('localize', 'MPA', (97, 105))	('gene expression', 'MPA', (76, 91))	('expression', 'Species', '29278', (81, 91))	('mutations', 'Var', (10, 19))	('PBRM1', 'Gene', (29, 34))	('impaired', 'NegReg', (20, 28))
126996	30585695	Using mouse xenograft models, we tested whether the PBRM1 BD mutations abrogate its tumor suppressor function.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor suppressor', 'biological_process', 'GO:0051726', ('84', '100'))	('mutations', 'Var', (61, 70))	('PBRM1', 'Gene', (52, 57))	('tumor', 'Disease', (84, 89))	('abrogate', 'NegReg', (71, 79))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('84', '100'))	('mouse', 'Species', '10090', (6, 11))
126997	30585695	We found that 786-O PBRM1 knockdown cells generated significantly larger tumors than control cells, consistent with previous reports suggesting that PBRM1 is a potent tumor suppressor that inhibits tumor growth (Gao et al., 2017).	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor suppressor', 'biological_process', 'GO:0051726', ('167', '183'))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', (73, 79))	('inhibits', 'NegReg', (189, 197))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', (73, 78))	('knockdown', 'Var', (26, 35))	('tumor', 'Disease', (198, 203))	('PBRM1', 'Gene', (149, 154))	('larger', 'PosReg', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('PBRM1', 'Gene', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('167', '183'))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))
126999	30585695	Overexpression of the tumor-derived BD2IFD mutant or the 3m mutant failed to significantly suppress tumor growth compared to wild-type PBRM1 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('expression', 'Species', '29278', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', (100, 105))	('suppress', 'NegReg', (91, 99))	('BD2', 'Gene', (36, 39))	('BD2', 'Gene', '1673', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutant', 'Var', (43, 49))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
127000	30585695	These results demonstrate that PBRM1 BD mutants lose tumor suppression function in mouse xenografts, suggesting that H3K14ac recognition is key to PBRM1's tumor suppressor function in vivo.	('lose', 'NegReg', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('155', '171'))	("PBRM1's tumor", 'Disease', (147, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('mouse', 'Species', '10090', (83, 88))	('tumor', 'Disease', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('H3K14ac', 'Gene', (117, 124))	('mutants', 'Var', (40, 47))	('PBRM1', 'Gene', (31, 36))	('tumor suppressor', 'biological_process', 'GO:0051726', ('155', '171'))	('tumor', 'Disease', (53, 58))	("PBRM1's tumor", 'Disease', 'MESH:D009396', (147, 160))	('H3K14ac', 'Gene', '126961', (117, 124))
127014	30585695	In addition, more subtle mutation of Y600N601-AA in BD4 did not affect BD4's ability to bind to H3K14ac even though N601K did, suggesting that N601K mutation might disturb the structure of BD4 like the DLF-AAA mutation.	('N601', 'Chemical', '-', (143, 147))	('BD4', 'Gene', '140596', (189, 192))	('BD4', 'Gene', (189, 192))	('N601K', 'Mutation', 'p.N601K', (116, 121))	('N601', 'Chemical', '-', (41, 45))	('H3K14ac', 'Gene', (96, 103))	('N601K', 'Var', (143, 148))	('BD4', 'Gene', (52, 55))	('N601K', 'Mutation', 'p.N601K', (143, 148))	('H3K14ac', 'Gene', '126961', (96, 103))	('BD4', 'Gene', '140596', (71, 74))	('disturb', 'Reg', (164, 171))	('BD4', 'Gene', (71, 74))	('structure', 'MPA', (176, 185))	('BD4', 'Gene', '140596', (52, 55))	('Y600N601-AA', 'Var', (37, 48))	('N601', 'Chemical', '-', (116, 120))
127015	30585695	Here, we also identified point mutations in BDs 2, 4, and 5 that were critical for H3K14ac recognition.	('BDs 2', 'Gene', (44, 49))	('point mutations', 'Var', (25, 40))	('H3K14ac', 'Gene', '126961', (83, 90))	('H3K14ac', 'Gene', (83, 90))
127016	30585695	Interestingly, BD4 is peculiar in that the conserved N601, a residue that is predicted to be critical to recognize acetyl-lysine, appears to not be required for H3K14ac recognition.	('N601', 'Var', (53, 57))	('H3K14ac', 'Gene', (161, 168))	('acetyl-lysine', 'Chemical', '-', (115, 128))	('BD4', 'Gene', '140596', (15, 18))	('BD4', 'Gene', (15, 18))	('H3K14ac', 'Gene', '126961', (161, 168))	('N601', 'Chemical', '-', (53, 57))
127020	30585695	With N263A (BD2*), DLF>AAA (BD4*) and N739A (BD5*) integrated into full-length PBRM1 (singly or combined) we found that a point mutation in a single BD only moderately reduced PBRM1's binding to H3K14ac.	('BD5', 'Gene', (45, 48))	('N739A', 'Var', (38, 43))	('BD5', 'Gene', '245908', (45, 48))	('N263A', 'Mutation', 'p.N263A', (5, 10))	('binding', 'molecular_function', 'GO:0005488', ('184', '191'))	('BD4', 'Gene', '140596', (28, 31))	('BD4', 'Gene', (28, 31))	('H3K14ac', 'Gene', (195, 202))	('N739A', 'Mutation', 'p.N739A', (38, 43))	('BD2', 'Gene', (12, 15))	('BD2', 'Gene', '1673', (12, 15))	('PBRM1', 'Gene', (176, 181))	('H3K14ac', 'Gene', '126961', (195, 202))	('binding', 'Interaction', (184, 191))	('point mutation', 'Var', (122, 136))	('N263A', 'Var', (5, 10))	('reduced', 'NegReg', (168, 175))
127023	30585695	We further tested the impact of tumor-derived point mutations in BD2.	('BD2', 'Gene', (65, 68))	('BD2', 'Gene', '1673', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tested', 'Reg', (11, 17))	('tumor', 'Disease', (32, 37))	('point mutations', 'Var', (46, 61))
127027	30585695	This suggests that even though tumor-derived point mutations in the BDs of PBRM1 might not grossly alter chromatin association, they are sufficient for the disruption of PBRM1's molecular and tumor suppressor functions.	('tumor', 'Disease', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('PBRM1', 'Gene', (75, 80))	('chromatin', 'cellular_component', 'GO:0000785', ('105', '114'))	('tumor', 'Disease', (31, 36))	('disruption', 'NegReg', (156, 166))	('point mutations', 'Var', (45, 60))	('tumor suppressor', 'biological_process', 'GO:0051726', ('192', '208'))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('192', '208'))	('PBRM1', 'Gene', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
127028	30585695	(2018) used in vitro growth curves of Caki-2 or RCC4 cells re-expressing wild-type or BD mutants as a gauge of PBRM1's tumor suppressor function.	("PBRM1's tumor", 'Disease', 'MESH:D009396', (111, 124))	('tumor suppressor', 'biological_process', 'GO:0051726', ('119', '135'))	('RCC4', 'Gene', '84925', (48, 52))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('119', '135'))	('RCC4', 'Gene', (48, 52))	("PBRM1's tumor", 'Disease', (111, 124))	('mutants', 'Var', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
127029	30585695	In PBRM1-proficient 786-O cells, deletion or suppression of PBRM1 did not alter cell growth in culture, but it significantly enhanced tumor growth in vivo (Gao et al., 2017).	('suppression', 'NegReg', (45, 56))	('PBRM1', 'Gene', (60, 65))	('deletion', 'Var', (33, 41))	('cell growth', 'biological_process', 'GO:0016049', ('80', '91'))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('enhanced', 'PosReg', (125, 133))	('tumor', 'Disease', (134, 139))
127031	30585695	The knock-in of Pbrm1 mutants into the mouse genome combined with Vhl inactivation should be the best physiological model to evaluate the impact of these mutations.	('Pbrm1', 'Gene', (16, 21))	('Pbrm1', 'Gene', '66923', (16, 21))	('Vhl', 'Gene', '22346', (66, 69))	('Vhl', 'Gene', (66, 69))	('mutants', 'Var', (22, 29))	('mouse', 'Species', '10090', (39, 44))
127034	30585695	However, a single point mutation in BD2 alone that reduces H3K14ac recognition was sufficient to severely impair PBRM1's molecular and tumor suppressor functions despite maintaining chromatin association.	('maintaining', 'Reg', (170, 181))	('impair', 'NegReg', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('PBRM1', 'Gene', (113, 118))	('reduces', 'NegReg', (51, 58))	('H3K14ac', 'Gene', (59, 66))	('tumor', 'Disease', (135, 140))	('chromatin association', 'MPA', (182, 203))	('BD2', 'Gene', (36, 39))	('BD2', 'Gene', '1673', (36, 39))	('single point mutation', 'Var', (11, 32))	('H3K14ac', 'Gene', '126961', (59, 66))	('tumor suppressor', 'biological_process', 'GO:0051726', ('135', '151'))	('chromatin', 'cellular_component', 'GO:0000785', ('182', '191'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('135', '151'))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
127036	30585695	Many tumor-derived mutations disrupt this recognition, attesting to its importance.	('recognition', 'MPA', (42, 53))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('mutations', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('disrupt', 'NegReg', (29, 36))
127037	30585695	As PBRM1 deficiency has been shown to boost the efficacy of immune checkpoint drugs in ccRCC and other cancers (Miao et al., 2018; Pan et al., 2018), the disruption of H3K14ac recognition by PBRM1 has the potential to increase the response rate of immunotherapy and warrants further investigation.	('PBRM1 deficiency', 'Disease', 'MESH:D007153', (3, 19))	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('PBRM1', 'Gene', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('H3K14ac', 'Gene', (168, 175))	('disruption', 'Var', (154, 164))	('response rate of immunotherapy', 'CPA', (231, 261))	('RCC', 'Disease', (89, 92))	('H3K14ac', 'Gene', '126961', (168, 175))	('increase', 'PosReg', (218, 226))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('PBRM1 deficiency', 'Disease', (3, 19))	('efficacy', 'MPA', (48, 56))	('boost', 'PosReg', (38, 43))	('cancers', 'Disease', (103, 110))
127052	33562338	Regarding prognosis, PD-L1 immunostaining at the tumor center with and without the tumor front was associated with worse survival, and so was sPD-L1 at a cut-off >793 ng/mL.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('survival', 'MPA', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (83, 88))	('immunostaining', 'Var', (27, 41))	('tumor', 'Disease', (49, 54))	('worse', 'NegReg', (115, 120))	('PD-L1', 'Gene', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
127057	33562338	VHL gene malfunction is detected in the overwhelming majority of the cases, resulting in a pseudo-hypoxic status that promotes angiogenesis.	('angiogenesis', 'CPA', (127, 139))	('malfunction', 'Var', (9, 20))	('VHL', 'Gene', (0, 3))	('promotes', 'PosReg', (118, 126))	('angiogenesis', 'biological_process', 'GO:0001525', ('127', '139'))	('resulting in', 'Reg', (76, 88))	('VHL', 'Gene', '7428', (0, 3))	('pseudo-hypoxic status', 'MPA', (91, 112))
127073	33562338	Thus, the higher the percentage of PD-L1 or PD-1 positives at the tumor center, the higher the percentage was at the tumor front.	('PD-1', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('PD-L1', 'Protein', (35, 40))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', (117, 122))	('positives', 'Var', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
127076	33562338	Thus, simultaneous positivity of PD-L1 at tumor center and front was found to be correlated with simultaneous expression of PD-1 at both areas (Table S2).	('PD-L1', 'Gene', (33, 38))	('positivity', 'Var', (19, 29))	('tumor', 'Disease', (42, 47))	('PD-1', 'Gene', (124, 128))	('correlated', 'Reg', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
127100	33562338	PD-L1 staining was also higher in pT2 tumors; however, data did not reach statistical significance (Figure 2D).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('higher', 'PosReg', (24, 30))	('pT2', 'Var', (34, 37))	('staining', 'MPA', (6, 14))	('PD-L1', 'Protein', (0, 5))
127112	33562338	PD-L1 positive immunostaining at the tumor center and simultaneously at both the center and front was associated with a worse 5-year OS of CCRCC patients (Figure 4A,B).	('patients', 'Species', '9606', (145, 153))	('RCC', 'Disease', (141, 144))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('PD-L1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('positive immunostaining', 'Var', (6, 29))	('CCRCC', 'Phenotype', 'HP:0006770', (139, 144))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
127120	33562338	Thus, two groups were created: (1) PD-L1 positive cases at the center of tumors, at the infiltrating front or simultaneously at both areas, together with sPD-L1 levels above 793 ng/mL; and (2) the rest of the possible combinations (PD-L1-/sPD-L1 <=793 ng/mL; PD-L1-/sPD-L1 >793 ng/mL; PD-L1+/sPD-L1 <=793 ng/mL).	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('PD-L1-/sPD-L1 <=793', 'Var', (232, 251))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('PD-L1', 'Gene', (35, 40))
127121	33562338	CCRCC patients with tumor PD-L1 positivity and plasma levels above 793 ng/mL had significantly worse 5-year OS than patients with the rest of combinations (Figure 4D-F).	('worse', 'NegReg', (95, 100))	('CCRCC', 'Phenotype', 'HP:0006770', (0, 5))	('RCC', 'Disease', (2, 5))	('patients', 'Species', '9606', (116, 124))	('PD-L1', 'Gene', (26, 31))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('patients', 'Species', '9606', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('positivity', 'Var', (32, 42))	('tumor', 'Disease', (20, 25))
127124	33562338	Moreover, combinations of PD-L1 positivity in tumor tissues and plasma sPD-L1 were also explanatory independent variables for patients' OS.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PD-L1', 'Gene', (26, 31))	('combinations', 'Var', (10, 22))	('tumor', 'Disease', (46, 51))	('patients', 'Species', '9606', (126, 134))	('positivity', 'Var', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
127146	33562338	On the other hand, strong evidence is accumulating to consider PD-L1 expression as a likely strong prognosticator in patients with CCRCC not only in metastatic cases receiving anti-PD-1 antibodies, but also receiving sunitinib or pazopanib.	('pazopanib', 'Chemical', 'MESH:C516667', (230, 239))	('anti-PD-1 antibodies', 'Var', (176, 196))	('sunitinib', 'Chemical', 'MESH:D000077210', (217, 226))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('PD-L1', 'Gene', (63, 68))	('RCC', 'Disease', (133, 136))	('CCRCC', 'Phenotype', 'HP:0006770', (131, 136))	('patients', 'Species', '9606', (117, 125))
127151	33562338	Circulating sPD-L1 can be determined by ELISA in normal human serum and in supernatants of different cells including CD4+, CD8+, CD19+, CD14+ and CD56+ T cells, and may play an important role in immunoregulation.	('CD8', 'Gene', (123, 126))	('CD14+', 'Var', (136, 141))	('CD4', 'Gene', (117, 120))	('CD8', 'Gene', '925', (123, 126))	('CD4', 'Gene', '920', (117, 120))	('human', 'Species', '9606', (56, 61))	('CD19+', 'Var', (129, 134))
127161	33562338	What is more, we have simultaneously evaluated PD-1 and PD-L1 both in the tumor and serum of the same cohort of patients and have confirmed that sPD-L1 is definitely an independent prognostic factor that is non-associated with the tumor size, Fuhrman grade or histopathological staging.	('PD-1', 'Gene', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('patients', 'Species', '9606', (112, 120))	('tumor', 'Disease', (231, 236))	('tumor', 'Disease', (74, 79))	('sPD-L1', 'Var', (145, 151))	('PD-L1', 'Gene', (56, 61))
127207	33562338	We also advocate for the clinical utility of sPD-L1 level > 793ng/mL as an independent and novel predictor of prognosis in clinical practice for the same patients.	('> 793ng/mL', 'Var', (58, 68))	('sPD-L1', 'MPA', (45, 51))	('patients', 'Species', '9606', (154, 162))
127238	28923830	However, whether abnormal CRP expression is associated with CCRCC pathogenesis, metastasis, and OS remains to be clarified.	('associated', 'Reg', (44, 54))	('CCRCC', 'Phenotype', 'HP:0006770', (60, 65))	('CRP', 'Gene', (26, 29))	('CRP', 'Gene', '1401', (26, 29))	('pathogenesis', 'biological_process', 'GO:0009405', ('66', '78'))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('abnormal', 'Var', (17, 25))	('OS', 'Chemical', '-', (96, 98))
127241	28923830	The methylation of ATG9B promoter may interrupt the autophagy signal pathway and influence the invasive ductal carcinoma (IDC) development.	('ATG9B', 'Gene', '285973', (19, 24))	('autophagy', 'biological_process', 'GO:0016236', ('52', '61'))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('autophagy', 'biological_process', 'GO:0006914', ('52', '61'))	('influence', 'Reg', (81, 90))	('ATG9B', 'Gene', (19, 24))	('interrupt', 'NegReg', (38, 47))	('methylation', 'Var', (4, 15))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (95, 120))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (104, 120))	('invasive ductal carcinoma', 'Disease', (95, 120))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('autophagy signal pathway', 'CPA', (52, 76))
127242	28923830	discovered that the mutation of ATG9B is common in human gastric and colorectal cancers and it can be closely related to stomach and colorectal carcinogenesis, suggesting that ATG9B mutation may promote neoplasm development by deregulating autophagy.	('neoplasm', 'Disease', (203, 211))	('ATG9B', 'Gene', '285973', (32, 37))	('autophagy', 'biological_process', 'GO:0016236', ('240', '249'))	('human', 'Species', '9606', (51, 56))	('neoplasm', 'Phenotype', 'HP:0002664', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('colorectal carcinogenesis', 'Disease', (133, 158))	('autophagy', 'biological_process', 'GO:0006914', ('240', '249'))	('colorectal cancers', 'Disease', (69, 87))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('ATG9B', 'Gene', (176, 181))	('ATG9B', 'Gene', '285973', (176, 181))	('autophagy', 'CPA', (240, 249))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (133, 158))	('ATG9B', 'Gene', (32, 37))	('neoplasm', 'Disease', 'MESH:D009369', (203, 211))	('colorectal cancers', 'Disease', 'MESH:D015179', (69, 87))	('deregulating', 'NegReg', (227, 239))	('promote', 'PosReg', (195, 202))	('mutation', 'Var', (182, 190))
127246	28923830	Previous studies have shown us the aberrant expression of CRP and ATG9B and their relationship with various human diseases especially cancer development including CCRCC.	('expression', 'MPA', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('diseases especially cancer', 'Disease', (114, 140))	('aberrant', 'Var', (35, 43))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('relationship', 'Reg', (82, 94))	('ATG9B', 'Gene', '285973', (66, 71))	('diseases especially cancer', 'Disease', 'MESH:D009369', (114, 140))	('human', 'Species', '9606', (108, 113))	('CCRCC', 'Phenotype', 'HP:0006770', (163, 168))	('CRP', 'Gene', (58, 61))	('CRP', 'Gene', '1401', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('ATG9B', 'Gene', (66, 71))	('RCC', 'Disease', (165, 168))
127260	28923830	SiRNA-1 and siRNA-2 were both used to knockdown CRP, yet they had different sequences.	('CRP', 'Gene', '1401', (48, 51))	('knockdown', 'Var', (38, 47))	('CRP', 'Gene', (48, 51))
127273	28923830	The tissue sections were subsequently incubated with primary antibodies anti-CRP antibody (ab31156, 5 microg/ml, Abcam, Boston, MA, U.S.A.) and anti-ATG9B antibody (ab117591, 5 microg/ml, Abcam, Boston, MA, U.S.A.).	('ATG9B', 'Gene', (149, 154))	('antibody', 'cellular_component', 'GO:0042571', ('81', '89'))	('antibody', 'cellular_component', 'GO:0019814', ('155', '163'))	('CRP', 'Gene', (77, 80))	('antibody', 'cellular_component', 'GO:0042571', ('155', '163'))	('antibody', 'cellular_component', 'GO:0019815', ('81', '89'))	('CRP', 'Gene', '1401', (77, 80))	('ab117591', 'Var', (165, 173))	('antibody', 'cellular_component', 'GO:0019814', ('81', '89'))	('antibody', 'molecular_function', 'GO:0003823', ('81', '89'))	('antibody', 'cellular_component', 'GO:0019815', ('155', '163'))	('ab31156', 'Var', (91, 98))	('ATG9B', 'Gene', '285973', (149, 154))	('antibody', 'molecular_function', 'GO:0003823', ('155', '163'))
127279	28923830	PVDF membranes were sealed using 5% skim milk for 1 h at room temperature, and then incubated with primary antibodies anti-CRP (ab31156, 5 microg/ml, Abcam, Boston, MA, U.S.A.) and anti-ATG9B (ab117591, 2 microg/ml, Abcam, Boston, MA, U.S.A.).	('PVDF', 'Chemical', 'MESH:C024865', (0, 4))	('ATG9B', 'Gene', (186, 191))	('CRP', 'Gene', (123, 126))	('CRP', 'Gene', '1401', (123, 126))	('ATG9B', 'Gene', '285973', (186, 191))	('ab117591', 'Var', (193, 201))
127300	28923830	As was shown in Table 2, high expression of CRP or ATG9B was positively related to advanced TNM stage and distant metastases.	('ATG9B', 'Gene', (51, 56))	('metastases', 'Disease', (114, 124))	('CRP', 'Gene', (44, 47))	('TNM', 'Gene', (92, 95))	('metastases', 'Disease', 'MESH:D009362', (114, 124))	('CRP', 'Gene', '1401', (44, 47))	('high', 'Var', (25, 29))	('ATG9B', 'Gene', '285973', (51, 56))	('related', 'Reg', (72, 79))	('TNM', 'Gene', '10178', (92, 95))
127303	28923830	The results indicated that patients with high CRP expression level had a lower OS and poorer prognostic result than those who with low CRP expression level.	('OS', 'Chemical', '-', (79, 81))	('CRP', 'Gene', (46, 49))	('CRP', 'Gene', (135, 138))	('CRP', 'Gene', '1401', (46, 49))	('CRP', 'Gene', '1401', (135, 138))	('high', 'Var', (41, 45))	('patients', 'Species', '9606', (27, 35))	('lower', 'NegReg', (73, 78))
127309	28923830	The results of Hoechst 33258 staining of the tumor cell cytoplasm showed that the transfection of siRNAs significantly promoted the apoptosis in 786-O cells (Figure 3A).	('apoptosis', 'CPA', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('apoptosis', 'biological_process', 'GO:0097194', ('132', '141'))	('transfection', 'Var', (82, 94))	('promoted', 'PosReg', (119, 127))	('tumor', 'Disease', (45, 50))	('siRNAs', 'Gene', (98, 104))	('apoptosis', 'biological_process', 'GO:0006915', ('132', '141'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('56', '65'))	('Hoechst 33258', 'Chemical', 'MESH:D006690', (15, 28))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
127311	28923830	This also indicated that the apoptosis of 786-O cells could be induced through silencing CRP expression.	('apoptosis', 'CPA', (29, 38))	('CRP', 'Gene', (89, 92))	('CRP', 'Gene', '1401', (89, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('29', '38'))	('apoptosis', 'biological_process', 'GO:0006915', ('29', '38'))	('silencing', 'Var', (79, 88))
127331	28923830	Our results are consistent with previous studies, in which identical findings were demonstrated in regards of RCC OS and aberrant CRP expression.	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('RCC OS', 'Disease', 'MESH:C538614', (110, 116))	('aberrant', 'Var', (121, 129))	('CRP', 'Gene', (130, 133))	('RCC OS', 'Disease', (110, 116))	('CRP', 'Gene', '1401', (130, 133))
127332	28923830	Thus, we speculated that the aberrant overexpression of CRP and ATG9B could possibly promote CCRCC development.	('CRP', 'Gene', (56, 59))	('CRP', 'Gene', '1401', (56, 59))	('promote', 'PosReg', (85, 92))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('ATG9B', 'Gene', '285973', (64, 69))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('CCRCC', 'Phenotype', 'HP:0006770', (93, 98))	('RCC', 'Disease', (95, 98))	('overexpression', 'PosReg', (38, 52))	('ATG9B', 'Gene', (64, 69))	('aberrant', 'Var', (29, 37))
127333	28923830	The in vivo experiment results support our hypothesis that the aberrant overexpression of CRP and ATG9B could promote CCRCC development, possibly by influencing the cell cycle and apoptosis.	('CRP', 'Gene', (90, 93))	('CRP', 'Gene', '1401', (90, 93))	('ATG9B', 'Gene', '285973', (98, 103))	('cell cycle', 'CPA', (165, 175))	('apoptosis', 'biological_process', 'GO:0097194', ('180', '189'))	('aberrant', 'Var', (63, 71))	('ATG9B', 'Gene', (98, 103))	('cell cycle', 'biological_process', 'GO:0007049', ('165', '175'))	('influencing', 'Reg', (149, 160))	('apoptosis', 'biological_process', 'GO:0006915', ('180', '189'))	('promote', 'PosReg', (110, 117))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('overexpression', 'PosReg', (72, 86))	('apoptosis', 'CPA', (180, 189))	('CCRCC', 'Phenotype', 'HP:0006770', (118, 123))
127342	28923830	found aberrant promoter methylation of ATG9B in sporadic breast carcinoma.	('breast carcinoma', 'Disease', 'MESH:D001943', (57, 73))	('aberrant', 'Var', (6, 14))	('ATG9B', 'Gene', (39, 44))	('breast carcinoma', 'Phenotype', 'HP:0003002', (57, 73))	('promoter methylation', 'MPA', (15, 35))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('breast carcinoma', 'Disease', (57, 73))	('ATG9B', 'Gene', '285973', (39, 44))
127345	28923830	Based on the previous findings as well as ours, we speculated that aberrant ATG9B expression might contribute to the aberrant autophagy of CCRCC cells, which then induced CCRCC progression.	('ATG9B', 'Gene', (76, 81))	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('RCC', 'Disease', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('CCRCC', 'Phenotype', 'HP:0006770', (171, 176))	('aberrant', 'Var', (67, 75))	('contribute', 'Reg', (99, 109))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('CCRCC', 'Phenotype', 'HP:0006770', (139, 144))	('autophagy', 'biological_process', 'GO:0016236', ('126', '135'))	('ATG9B', 'Gene', '285973', (76, 81))	('autophagy', 'biological_process', 'GO:0006914', ('126', '135'))	('induced', 'Reg', (163, 170))	('autophagy', 'CPA', (126, 135))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
127356	28553932	Combined Vhl, Trp53 and Rb1 mutation causes clear cell renal cell carcinoma in mice Clear cell renal cell carcinomas (ccRCC) frequently exhibit inactivation of the VHL tumour suppressor gene and often harbour multiple copy number alterations in genes that regulate cell cycle progression.	('Rb1', 'Gene', '19645', (24, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('VHL tumour', 'Disease', (164, 174))	('VHL tumour', 'Disease', 'MESH:D006623', (164, 174))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (95, 116))	('Trp53', 'Gene', '22059', (14, 19))	('mutation', 'Var', (28, 36))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (95, 115))	('Vhl', 'Gene', '22346', (9, 12))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (44, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('Rb1', 'Gene', (24, 27))	('Trp53', 'Gene', (14, 19))	('Clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (84, 116))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (55, 75))	('causes', 'Reg', (37, 43))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('harbour', 'Reg', (201, 208))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (95, 115))	('Clear cell renal cell carcinomas', 'Disease', (84, 116))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))	('renal cell carcinoma', 'Disease', (55, 75))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (55, 75))	('Vhl', 'Gene', (9, 12))	('inactivation', 'Var', (144, 156))	('Clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (84, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('cell cycle', 'biological_process', 'GO:0007049', ('265', '275'))
127357	28553932	We show here that modelling these genetic alterations by combined renal epithelium-specific deletion of Vhl, Trp53 and Rb1 in mice caused ccRCC.	('mice', 'Species', '10090', (126, 130))	('caused', 'Reg', (131, 137))	('deletion', 'Var', (92, 100))	('Rb1', 'Gene', (119, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('Rb1', 'Gene', '19645', (119, 122))	('ccRCC', 'Disease', (138, 143))	('Trp53', 'Gene', (109, 114))	('Vhl', 'Gene', (104, 107))
127359	28553932	Exome sequencing revealed that mouse and human ccRCCs exhibit recurrent mutations in genes associated with the primary cilium, uncovering a mutational convergence on this organelle and implicating a subset of ccRCCs as genetic ciliopathies.	('mutations', 'Var', (72, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('primary cilium', 'cellular_component', 'GO:0097731', ('111', '125'))	('human', 'Species', '9606', (41, 46))	('mouse', 'Species', '10090', (31, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (209, 214))	('organelle', 'cellular_component', 'GO:0043226', ('171', '180'))	('primary cilium', 'cellular_component', 'GO:0005929', ('111', '125'))	('ccRCCs', 'Disease', (47, 53))
127365	28553932	82-92% of ccRCC tumours harbour biallelic inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene and VHL mutations occur at the earliest stage of tumor formation.	('VHL', 'Disease', (81, 84))	('mutations', 'Var', (117, 126))	('tumor', 'Disease', (158, 163))	('VHL', 'Disease', (113, 116))	('ccRCC tumours', 'Disease', 'MESH:D009369', (10, 23))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('ccRCC tumours', 'Disease', (10, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('von Hippel-Lindau (VHL) tumour', 'Disease', 'MESH:D006623', (62, 92))	('biallelic inactivation', 'Var', (32, 54))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))	('formation', 'biological_process', 'GO:0009058', ('164', '173'))	('VHL', 'Disease', 'MESH:D006623', (81, 84))	('VHL', 'Disease', 'MESH:D006623', (113, 116))
127366	28553932	Patients with VHL disease inherit a mutant VHL allele and are predisposed to develop ccRCC.	('VHL disease', 'Disease', (14, 25))	('VHL', 'Disease', (43, 46))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('ccRCC', 'Disease', (85, 90))	('VHL', 'Disease', 'MESH:D006623', (14, 17))	('VHL disease', 'Disease', 'MESH:D006623', (14, 25))	('Patients', 'Species', '9606', (0, 8))	('VHL', 'Disease', (14, 17))	('mutant', 'Var', (36, 42))	('VHL', 'Disease', 'MESH:D006623', (43, 46))
127367	28553932	However, second hit VHL loss-of-function mutations in renal epithelial cells in VHL patients are insufficient to cause ccRCC in humans and numerous renal-epithelial cell-specific Vhl knockout mice also failed to develop ccRCC (reviewed in), arguing that ccRCC formation requires mutations in addition to VHL.	('VHL', 'Disease', (20, 23))	('insufficient', 'Disease', 'MESH:D000309', (97, 109))	('VHL', 'Disease', 'MESH:D006623', (80, 83))	('mutations', 'Var', (41, 50))	('VHL', 'Disease', (304, 307))	('VHL loss', 'Disease', (20, 28))	('patients', 'Species', '9606', (84, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (254, 259))	('mice', 'Species', '10090', (192, 196))	('VHL loss', 'Disease', 'MESH:D006623', (20, 28))	('VHL', 'Disease', 'MESH:D006623', (20, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('failed', 'NegReg', (202, 208))	('ccRCC', 'Disease', (220, 225))	('insufficient', 'Disease', (97, 109))	('VHL', 'Disease', (80, 83))	('VHL', 'Disease', 'MESH:D006623', (304, 307))	('formation', 'biological_process', 'GO:0009058', ('260', '269'))	('ccRCC', 'Phenotype', 'HP:0006770', (220, 225))	('humans', 'Species', '9606', (128, 134))
127368	28553932	The presence of recurrent mutations in PBRM1, BAP1, SETD2, KDM5C, PIK3CA, PTEN, MTOR and TP53, as well as copy number losses of CDKN2A and RB1 and gains of MDM4 and MYC in human ccRCCs argues that these genetic alterations may act cooperatively with VHL loss to induce ccRCC formation.	('formation', 'biological_process', 'GO:0009058', ('275', '284'))	('ccRCC', 'Phenotype', 'HP:0006770', (178, 183))	('KDM5C', 'Gene', '8242', (59, 64))	('mutations', 'Var', (26, 35))	('MYC', 'Gene', '4609', (165, 168))	('PIK3CA', 'Gene', (66, 72))	('PTEN', 'Gene', (74, 78))	('KDM5C', 'Gene', (59, 64))	('BAP1', 'Gene', (46, 50))	('CDKN2A', 'Gene', (128, 134))	('VHL loss', 'Disease', (250, 258))	('PBRM1', 'Gene', (39, 44))	('MTOR', 'Gene', (80, 84))	('induce', 'Reg', (262, 268))	('MTOR', 'Gene', '2475', (80, 84))	('RB1', 'Gene', (139, 142))	('MDM4', 'Gene', (156, 160))	('gains', 'PosReg', (147, 152))	('VHL loss', 'Disease', 'MESH:D006623', (250, 258))	('ccRCC', 'Phenotype', 'HP:0006770', (269, 274))	('MYC', 'Gene', (165, 168))	('losses', 'NegReg', (118, 124))	('TP53', 'Gene', (89, 93))	('CDKN2A', 'Gene', '1029', (128, 134))	('human', 'Species', '9606', (172, 177))	('ccRCC formation', 'Disease', (269, 284))	('PIK3CA', 'Gene', '5290', (66, 72))	('RB1', 'Gene', '5925', (139, 142))	('SETD2', 'Gene', (52, 57))
127370	28553932	Deletion of Vhl together with Trp53 gave rise to simple and atypical cystic lesions as well as small tumours containing cells that display cytoplasmic clearing and elevated mTORC1 activity, recapitulating some of the cellular and molecular changes that are characteristic of human ccRCC.	('Vhl', 'Gene', (12, 15))	('mTORC1', 'Gene', '382056', (173, 179))	('mTORC1', 'Gene', (173, 179))	('ccRCC', 'Disease', (281, 286))	('ccRCC', 'Phenotype', 'HP:0006770', (281, 286))	('mTORC1', 'cellular_component', 'GO:0031931', ('173', '179'))	('human', 'Species', '9606', (275, 280))	('cystic lesions', 'Disease', (69, 83))	('small tumours', 'Disease', 'MESH:D055752', (95, 108))	('cystic lesions', 'Disease', 'MESH:D052177', (69, 83))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))	('small tumours', 'Disease', (95, 108))	('Deletion', 'Var', (0, 8))
127371	28553932	Similar phenotypes were observed in mice with combined Vhl deletion and heterozygous loss of Bap1 .	('Bap1', 'Gene', (93, 97))	('loss', 'NegReg', (85, 89))	('mice', 'Species', '10090', (36, 40))	('deletion', 'Var', (59, 67))	('Vhl', 'Gene', (55, 58))
127373	28553932	A very recent study showed that combined deletion of Vhl and Pbrm1 causes renal cysts with subsequent development of ccRCCs after approximately 10 months, providing an autochthonous model that reflects the VHL/PBRM1 mutant genetic subset of human ccRCC.	('causes', 'Reg', (67, 73))	('Pbrm1', 'Gene', (61, 66))	('ccRCCs', 'Disease', (117, 123))	('VHL', 'Disease', 'MESH:D006623', (206, 209))	('Vhl', 'Gene', (53, 56))	('human', 'Species', '9606', (241, 246))	('renal cysts', 'Phenotype', 'HP:0000107', (74, 85))	('VHL', 'Disease', (206, 209))	('deletion', 'Var', (41, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (247, 252))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('renal cysts', 'Disease', 'MESH:D007674', (74, 85))	('renal cysts', 'Disease', (74, 85))
127376	28553932	68% of human ccRCCs harbour a chromosomal copy number alteration in at least one of these genes and most (78%) of these tumours harbour multiple simultaneous alterations (Supplementary Figure 1a).	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('human', 'Species', '9606', (7, 12))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('tumours', 'Disease', (120, 127))	('chromosomal copy number alteration', 'Var', (30, 64))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
127377	28553932	Patients with tumours that display alteration in at least one gene in the p53/G1-S network signature have a worse outcome than those without these genetic alterations (Supplementary Figure 1b).	('tumours', 'Phenotype', 'HP:0002664', (14, 21))	('Patients', 'Species', '9606', (0, 8))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('alteration', 'Var', (35, 45))	('tumours', 'Disease', 'MESH:D009369', (14, 21))	('tumours', 'Disease', (14, 21))
127379	28553932	These data give rise to the hypothesis that during the evolution of the majority of ccRCCs there is a selection for multiple copy number alterations that are predicted to alter the integrity of the G1/S cell cycle checkpoint, promoting tumour initiation and progression.	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('203', '224'))	('tumour initiation', 'Disease', (236, 253))	('integrity', 'MPA', (181, 190))	('copy number alterations', 'Var', (125, 148))	('alter', 'Reg', (171, 176))	('tumour initiation', 'Disease', 'MESH:D009369', (236, 253))	('tumour', 'Phenotype', 'HP:0002664', (236, 242))	('progression', 'CPA', (258, 269))	('promoting', 'PosReg', (226, 235))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('alterations', 'Var', (137, 148))
127380	28553932	To functionally test this idea in mice, we genetically deleted Vhl together with two tumour suppressor genes that encode proteins that function as the key controllers of cell cycle entry in the p53/G1-S network, namely Trp53 (encoding p53) and Rb1 (encoding pRB).	('Rb1', 'Gene', (244, 247))	('Rb1', 'Gene', '19645', (244, 247))	('Trp53', 'Gene', (219, 224))	('mice', 'Species', '10090', (34, 38))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('cell cycle', 'biological_process', 'GO:0007049', ('170', '180'))	('tumour', 'Disease', (85, 91))	('pRB', 'Gene', (258, 261))	('deleted', 'Var', (55, 62))	('pRB', 'Gene', '19645', (258, 261))	('Vhl', 'Gene', (63, 66))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
127381	28553932	We generated mice that allow inducible renal epithelial cell-specific (Ksp1.3-CreERT2) homozygous deletion of loxP-flanked alleles of Rb1, Vhl/Rb1, Trp53/Rb1 and Vhl/Trp53/Rb1 to complement our previous analyses of the effects of Vhl and Vhl/Trp53 deletion.	('mice', 'Species', '10090', (13, 17))	('deletion', 'Var', (98, 106))	('Rb1', 'Gene', (154, 157))	('Rb1', 'Gene', '19645', (154, 157))	('Rb1', 'Gene', (134, 137))	('Rb1', 'Gene', '19645', (134, 137))	('Rb1', 'Gene', (143, 146))	('Rb1', 'Gene', '19645', (143, 146))	('Rb1', 'Gene', (172, 175))	('Rb1', 'Gene', '19645', (172, 175))
127384	28553932	While p53 was not detectable by immunohistochemical staining, loss of immunoreactivity for pRB confirmed Rb1 deletion in all genotypes and the nuclear accumulation of HIF-1alpha in VhlDelta/DeltaRb1Delta/Delta and VhlDelta/DeltaTrp53Delta/DeltaRb1Delta/Delta kidneys confirmed Vhl deletion (Supplementary Figure 2a).	('Trp53Delta', 'Chemical', '-', (228, 238))	('Rb1', 'Gene', (244, 247))	('Rb1', 'Gene', '19645', (244, 247))	('pRB', 'Gene', '19645', (91, 94))	('deletion', 'Var', (109, 117))	('Vhl', 'Disease', (277, 280))	('Rb1', 'Gene', (105, 108))	('Rb1', 'Gene', '19645', (105, 108))	('HIF-1alpha', 'Gene', (167, 177))	('deletion', 'Var', (281, 289))	('HIF-1alpha', 'Gene', '15251', (167, 177))	('pRB', 'Gene', (91, 94))	('Rb1', 'Gene', (195, 198))	('Rb1', 'Gene', '19645', (195, 198))
127385	28553932	Kidneys of Rb1Delta/Delta (n=35 mice) and VhlDelta/DeltaRb1Delta/Delta (n=29 mice) mice displayed occasional sites of subtle disorganization of renal tubular epithelia 50-57 weeks after gene deletion (Figure 1a,b).	('mice', 'Species', '10090', (77, 81))	('Rb1', 'Gene', (56, 59))	('Rb1', 'Gene', '19645', (56, 59))	('renal tubular epithelia', 'Disease', (144, 167))	('disorganization', 'NegReg', (125, 140))	('gene deletion', 'Var', (186, 199))	('mice', 'Species', '10090', (83, 87))	('renal tubular epithelia', 'Disease', 'MESH:D005198', (144, 167))	('mice', 'Species', '10090', (32, 36))	('Rb1', 'Gene', (11, 14))	('Rb1', 'Gene', '19645', (11, 14))
127387	28553932	In contrast, within 30-47 weeks of gene deletion, 10 of 25 VhlDelta/DeltaTrp53Delta/DeltaRb1Delta/Delta mice developed a total of 64 tumours (Figure 1f-i).	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumours', 'Phenotype', 'HP:0002664', (133, 140))	('mice', 'Species', '10090', (104, 108))	('gene deletion', 'Var', (35, 48))	('Rb1', 'Gene', (89, 92))	('Rb1', 'Gene', '19645', (89, 92))	('tumours', 'Disease', 'MESH:D009369', (133, 140))	('tumours', 'Disease', (133, 140))	('developed', 'PosReg', (109, 118))	('Trp53Delta', 'Chemical', '-', (73, 83))
127388	28553932	Mice that did not develop tumours showed an equivalent extent of tubular immunoreactivity for CA9 (Supplementary Figure 2b), a marker of Vhl deletion and HIF-alpha activation, to histologically normal tubules in kidneys with tumours, showing that the absence of tumours in these mice was not caused by failure of activation of Cre.	('tumours', 'Disease', (225, 232))	('tumours', 'Disease', (26, 33))	('Mice', 'Species', '10090', (0, 4))	('tumours', 'Phenotype', 'HP:0002664', (225, 232))	('CA9', 'Gene', '230099', (94, 97))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))	('tumours', 'Disease', 'MESH:D009369', (225, 232))	('absence of tumours', 'Disease', 'MESH:D004832', (251, 269))	('tumours', 'Disease', 'MESH:D009369', (26, 33))	('CA9', 'Gene', (94, 97))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('absence of tumours', 'Disease', (251, 269))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('tumours', 'Disease', (262, 269))	('deletion', 'Var', (141, 149))	('mice', 'Species', '10090', (279, 283))	('Vhl', 'Gene', (137, 140))	('tumours', 'Phenotype', 'HP:0002664', (262, 269))	('tumours', 'Disease', 'MESH:D009369', (262, 269))	('tumour', 'Phenotype', 'HP:0002664', (262, 268))
127393	28553932	We conclude that Vhl deletion accelerates the onset and increases the incidence of tumour formation as well as increases the number of tumours per mouse.	('tumour', 'Disease', (83, 89))	('mouse', 'Species', '10090', (147, 152))	('increases', 'PosReg', (56, 65))	('accelerates', 'PosReg', (30, 41))	('increases', 'PosReg', (111, 120))	('tumours', 'Disease', 'MESH:D009369', (135, 142))	('tumours', 'Disease', (135, 142))	('formation', 'biological_process', 'GO:0009058', ('90', '99'))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('deletion', 'Var', (21, 29))	('Vhl', 'Gene', (17, 20))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('tumour', 'Disease', (135, 141))	('tumours', 'Phenotype', 'HP:0002664', (135, 142))
127415	28553932	All tumours showed strong staining for phospho-Thr37/46-4E-BP1 (n=44), indicative of strong mTORC1 activation, a common feature of human ccRCC.	('phospho-Thr37/46-4E-BP1', 'Var', (39, 62))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('mTORC1', 'Gene', (92, 98))	('human', 'Species', '9606', (131, 136))	('Thr37', 'Chemical', '-', (47, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('activation', 'PosReg', (99, 109))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('mTORC1', 'Gene', '382056', (92, 98))	('mTORC1', 'cellular_component', 'GO:0031931', ('92', '98'))	('tumours', 'Disease', (4, 11))
127420	28553932	We conclude that even though the Cre driver induces gene deletion widely throughout the nephron, VhlDelta/DeltaTrp53Delta/DeltaRb1Delta/Delta mouse ccRCCs arise from proximal tubule epithelial cells.	('mouse', 'Species', '10090', (142, 147))	('gene deletion', 'Var', (52, 65))	('Trp53Delta', 'Chemical', '-', (111, 121))	('Rb1', 'Gene', (127, 130))	('ccRCC', 'Phenotype', 'HP:0006770', (148, 153))	('Rb1', 'Gene', '19645', (127, 130))
127428	28553932	Predominant transcriptional signatures in mouse ccRCCs included upregulation of a set of HIF-1alpha and HIF-2alpha target genes that we previously identified as being upregulated following deletion of Vhl in primary renal epithelial cells (Figure 3d), upregulation of numerous genes that regulate cell cycle progression, DNA replication and mitosis (Figure 3e) as well as upregulation of a set of genes that regulate immune responses and inflammation (Figure 3f).	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (89, 114))	('upregulation', 'PosReg', (372, 384))	('mitosis', 'Disease', (341, 348))	('mouse', 'Species', '10090', (42, 47))	('inflammation', 'Disease', 'MESH:D007249', (438, 450))	('upregulated', 'PosReg', (167, 178))	('inflammation', 'biological_process', 'GO:0006954', ('438', '450'))	('mitosis', 'Disease', 'None', (341, 348))	('DNA', 'cellular_component', 'GO:0005574', ('321', '324'))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('inflammation', 'Disease', (438, 450))	('DNA replication', 'biological_process', 'GO:0006260', ('321', '336'))	('upregulation', 'PosReg', (64, 76))	('cell cycle', 'biological_process', 'GO:0007049', ('297', '307'))	('upregulation', 'PosReg', (252, 264))	('deletion', 'Var', (189, 197))	('Vhl', 'Gene', (201, 204))	('mitosis', 'biological_process', 'GO:0000278', ('341', '348'))
127437	28553932	Notably, 2 tumours harboured amplifications (estimated copy numbers of 59 and 66) of the Myc oncogene (Figure 4a, Supplementary Figure 7d) and these tumours exhibited very high levels of Myc mRNA (Figure 3e).	('Myc', 'Gene', (89, 92))	('Myc', 'Gene', '17869', (89, 92))	('tumours', 'Disease', (149, 156))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('tumours', 'Phenotype', 'HP:0002664', (149, 156))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('Myc', 'Gene', '17869', (187, 190))	('Myc', 'Gene', (187, 190))	('amplifications', 'Var', (29, 43))	('tumours', 'Disease', 'MESH:D009369', (11, 18))	('tumours', 'Disease', (11, 18))	('tumours', 'Disease', 'MESH:D009369', (149, 156))
127438	28553932	Copy number gains or amplifications of MYC occur in 8-15% of human ccRCC and are associated with poor patient survival (Figure 4c).	('human ccRCC', 'Disease', (61, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('Copy number gains', 'Var', (0, 17))	('patient', 'Species', '9606', (102, 109))	('MYC', 'Gene', '4609', (39, 42))	('amplifications', 'Var', (21, 35))	('human', 'Species', '9606', (61, 66))	('MYC', 'Gene', (39, 42))
127441	28553932	Consistent with this notion, copy number gain of SYCP1 in human ccRCC predicts poor patient survival (Figure 4c).	('SYCP1', 'Gene', (49, 54))	('human', 'Species', '9606', (58, 63))	('poor', 'NegReg', (79, 83))	('SYCP1', 'Gene', '6847', (49, 54))	('copy number gain', 'Var', (29, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('ccRCC', 'Disease', (64, 69))	('patient survival', 'CPA', (84, 100))	('patient', 'Species', '9606', (84, 91))
127442	28553932	Single nucleotide variants (SNVs) and insertions and deletions (InDels) were identified in mouse ccRCCs versus matched liver.	('insertions', 'Var', (38, 48))	('mouse', 'Species', '10090', (91, 96))	('deletions', 'Var', (53, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))
127443	28553932	These three classes of mutations are also the most frequently occurring in human ccRCC demonstrating that the mouse model reproduces the same classes of mutations that arise in human ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('ccRCC', 'Disease', (81, 86))	('mouse', 'Species', '10090', (110, 115))	('mutations', 'Var', (23, 32))	('human', 'Species', '9606', (177, 182))	('human', 'Species', '9606', (75, 80))	('ccRCC', 'Phenotype', 'HP:0006770', (183, 188))	('ccRCC', 'Disease', (183, 188))
127444	28553932	Mouse ccRCCs exhibited 161 +- 17 non-synonymous mutations per tumour and these were almost entirely attributable to SNVs rather than InDels (Figure 5b).	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (6, 11))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('SNVs', 'Var', (116, 120))	('Mouse', 'Species', '10090', (0, 5))	('tumour', 'Disease', (62, 68))	('non-synonymous mutations', 'Var', (33, 57))
127446	28553932	To narrow the search for potential truncal or clonal cooperating mutations, we focused further analyses on the set of truncating and frameshift mutations that were present at variant allele frequency (VAF) greater than or equal to 5% plus non-synonymous coding mutations that were present at high (>25%) VAF (Supplementary Table 3).	('frameshift mutations', 'Var', (133, 153))	('VAF', 'Chemical', '-', (201, 204))	('variant', 'Var', (175, 182))	('VAF', 'Chemical', '-', (304, 307))
127448	28553932	Each of the 7 tumours exhibited one or more mutations in 12 primary cilium-related genes (Figure 5c), including Kif3a and Kif3b, which encode components of the Kinesin-2 microtubule motor complex that is necessary for the generation of primary cilia.	('primary cilium-related genes', 'Gene', (60, 88))	('primary cilium', 'cellular_component', 'GO:0005929', ('60', '74'))	('Kinesin-2', 'Gene', (160, 169))	('tumours', 'Phenotype', 'HP:0002664', (14, 21))	('microtubule', 'cellular_component', 'GO:0005874', ('170', '181'))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (44, 53))	('Kif3a', 'Gene', (112, 117))	('exhibited', 'Reg', (22, 31))	('Kif3b', 'Gene', (122, 127))	('Kinesin-2', 'Gene', '16563', (160, 169))	('Kif3b', 'Gene', '16569', (122, 127))	('tumours', 'Disease', 'MESH:D009369', (14, 21))	('primary cilium', 'cellular_component', 'GO:0097731', ('60', '74'))	('tumours', 'Disease', (14, 21))	('Kinesin', 'molecular_function', 'GO:0003777', ('160', '167'))	('Kif3a', 'Gene', '16568', (112, 117))
127450	28553932	11 of 12 of the human orthologues of these genes are mutated in small percentages of human ccRCCs, and extending the list to include other known human ciliopathy genes and genes for which there is evidence for a function in primary cilium biology, we identified that 40% of human ccRCCs harbour one or more mutations in primary cilium-related genes (Supplementary Figure 8).	('ccRCC', 'Phenotype', 'HP:0006770', (280, 285))	('mutations', 'Var', (307, 316))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('primary cilium', 'cellular_component', 'GO:0005929', ('320', '334'))	('primary cilium', 'cellular_component', 'GO:0097731', ('320', '334'))	('primary cilium', 'cellular_component', 'GO:0097731', ('224', '238'))	('human', 'Species', '9606', (145, 150))	('primary cilium-related genes', 'Gene', (320, 348))	('human', 'Species', '9606', (16, 21))	('human ccRCCs', 'Disease', (274, 286))	('primary cilium', 'cellular_component', 'GO:0005929', ('224', '238'))	('human', 'Species', '9606', (274, 279))	('human', 'Species', '9606', (85, 90))
127451	28553932	We have previously shown that Pten mutation cooperates with Vhl mutation to reduce the frequency of ciliated renal epithelial cells and induces renal cysts.	('renal cysts', 'Disease', (144, 155))	('frequency of ciliated renal epithelial cells', 'CPA', (87, 131))	('renal cysts', 'Phenotype', 'HP:0000107', (144, 155))	('Pten', 'Gene', (30, 34))	('Pten', 'Gene', '19211', (30, 34))	('reduce', 'NegReg', (76, 82))	('mutation', 'Var', (35, 43))	('renal cysts', 'Disease', 'MESH:D007674', (144, 155))	('induces', 'Reg', (136, 143))
127468	28553932	3 smaller tumours regressed during Acriflavine therapy, while other similarly sized tumours in the same mice increased in size (Figure 6c, Supplementary Figure 9).	('tumours', 'Disease', (10, 17))	('tumours', 'Disease', 'MESH:D009369', (84, 91))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('tumours', 'Disease', (84, 91))	('Acriflavine therapy', 'Var', (35, 54))	('mice', 'Species', '10090', (104, 108))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('tumours', 'Phenotype', 'HP:0002664', (10, 17))	('Acriflavine', 'Chemical', 'MESH:D000167', (35, 46))	('tumours', 'Disease', 'MESH:D009369', (10, 17))	('increased', 'PosReg', (109, 118))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))
127477	28553932	While further functional studies will be necessary to establish whether the mutations that we identified in ccRCC play a pathogenic role in the disease, given that a common phenotypic outcome of genetic alterations in diverse genes that are important for cilia biology is the induction of renal epithelial cell proliferation and cyst formation, it appears likely that primary cilium gene mutations might either permit or enhance the proliferation of VHL mutant cells.	('proliferation', 'CPA', (433, 446))	('primary cilium', 'cellular_component', 'GO:0005929', ('368', '382'))	('formation', 'biological_process', 'GO:0009058', ('334', '343'))	('mutant', 'Var', (454, 460))	('VHL', 'Disease', (450, 453))	('VHL', 'Disease', 'MESH:D006623', (450, 453))	('epithelial cell proliferation', 'biological_process', 'GO:0050673', ('295', '324'))	('enhance', 'PosReg', (421, 428))	('mutations', 'Var', (388, 397))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('primary cilium', 'cellular_component', 'GO:0097731', ('368', '382'))
127478	28553932	In this context, our previous studies have shown cooperation between loss of Vhl and loss of primary cilia in causing uncontrolled renal epithelial proliferation and development of simple and atypical cystic precursor lesions in mice.	('loss', 'Var', (85, 89))	('development', 'CPA', (166, 177))	('primary cilia', 'Protein', (93, 106))	('Vhl', 'Gene', (77, 80))	('loss', 'Var', (69, 73))	('mice', 'Species', '10090', (229, 233))
127479	28553932	It is plausible that the combination of VHL mutation, primary cilium gene mutation and additional genetic alterations, such as in the p53 and G1-S cell cycle network or in other frequently mutated tumour suppressor genes like PBRM1, BAP1 or SETD2, act cooperatively to cause the evolution of ccRCC.	('tumour', 'Disease', 'MESH:D009369', (197, 203))	('mutation', 'Var', (74, 82))	('primary cilium', 'cellular_component', 'GO:0097731', ('54', '68'))	('mutation', 'Var', (44, 52))	('cell cycle', 'biological_process', 'GO:0007049', ('147', '157'))	('PBRM1', 'Gene', (226, 231))	('tumour', 'Disease', (197, 203))	('primary cilium', 'cellular_component', 'GO:0005929', ('54', '68'))	('ccRCC', 'Phenotype', 'HP:0006770', (292, 297))	('cause', 'Reg', (269, 274))	('ccRCC', 'Disease', (292, 297))	('VHL', 'Disease', (40, 43))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))	('VHL', 'Disease', 'MESH:D006623', (40, 43))
127484	28553932	PI3K-mTORC1 pathway activation was also observed in cysts or tumours in Vhl/Pten , Vhl/Trp53 , Vhl/Trp53/Kif3a , Vhl/Bap1  and Vhl/Pbrm1  mutant mice, suggesting that PI3K-mTORC1 pathway activation might generally promote ccRCC evolution in the context of diverse cooperating mutations.	('Kif3a', 'Gene', '16568', (105, 110))	('ccRCC evolution', 'Disease', (222, 237))	('mTORC1', 'Gene', '382056', (172, 178))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('mTORC1', 'Gene', (5, 11))	('mutant', 'Var', (138, 144))	('cysts or tumours', 'Disease', 'MESH:D009369', (52, 68))	('Kif3a', 'Gene', (105, 110))	('mTORC1', 'Gene', '382056', (5, 11))	('Pten', 'Gene', (76, 80))	('cysts or tumours', 'Disease', (52, 68))	('Pten', 'Gene', '19211', (76, 80))	('mTORC1', 'cellular_component', 'GO:0031931', ('172', '178'))	('promote', 'PosReg', (214, 221))	('ccRCC', 'Phenotype', 'HP:0006770', (222, 227))	('mice', 'Species', '10090', (145, 149))	('PI3K', 'molecular_function', 'GO:0016303', ('167', '171'))	('mTORC1', 'cellular_component', 'GO:0031931', ('5', '11'))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('mTORC1', 'Gene', (172, 178))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
127488	28553932	Rb1fl/fl (FVB;129P2 background), Vhlfl/fl (C;129S background) and Trp53fl/fl (FVB;129P2 background) mice were crossed with Ksp1.3-CreERT2 (B6.Cg background) mice to generate Ksp1.3-CreERT2;Vhlfl/fl;Trp53fl/fl;Rb1fl/fl, Ksp1.3-CreERT2;Vhlfl/fl;Rb1fl/fl, Ksp1.3-CreERT2;Trp53fl/fl;Rb1fl/fl and Ksp1.3-CreERT2 Tg/+;Rb1fl/fl animals.	('mice', 'Species', '10090', (157, 161))	('mice', 'Species', '10090', (100, 104))	('Rb1', 'Gene', '19645', (0, 3))	('Trp53fl/fl', 'Var', (268, 278))	('Rb1', 'Gene', (312, 315))	('Rb1', 'Gene', (209, 212))	('Rb1', 'Gene', (243, 246))	('Rb1', 'Gene', '19645', (243, 246))	('Rb1', 'Gene', (0, 3))	('Rb1', 'Gene', '19645', (209, 212))	('Rb1', 'Gene', '19645', (312, 315))	('Rb1', 'Gene', (279, 282))	('Rb1', 'Gene', '19645', (279, 282))
127509	28553932	EXCAVATOR  was used to call copy number variations with 95% probability cut-off in tumours against the matched normal liver samples.	('tumours', 'Disease', (83, 90))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('copy number variations', 'Var', (28, 50))	('tumours', 'Disease', 'MESH:D009369', (83, 90))
127510	28553932	Lists of copy number variants were manually filtered to remove calls in which multiple tumours showed the exact start and end points of the gain or loss, as these are highly likely to represent artefacts of the calling algorithm.	('gain', 'PosReg', (140, 144))	('variants', 'Var', (21, 29))	('loss', 'NegReg', (148, 152))	('multiple tumours', 'Disease', 'MESH:D009369', (78, 94))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('multiple tumours', 'Disease', (78, 94))
127520	32102250	Among the 10 cctpRCC cases, eight (80%) were wild type for all of the genes in the panel, while two (20%) harbored VHL mutations typical of ccRCC.	('VHL', 'Gene', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('VHL', 'Gene', '7428', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))	('mutations', 'Var', (119, 128))
127521	32102250	Three of the six (50%) ccRCC control cases showed expected VHL mutations; two (33%) harbored pathogenic mutations in the p53 or the CKIT genes; and one (16%) was wild type.	('mutations', 'Var', (63, 72))	('VHL', 'Gene', '7428', (59, 62))	('CKIT', 'Gene', (132, 136))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('VHL', 'Gene', (59, 62))	('CKIT', 'Gene', '3815', (132, 136))	('RCC', 'Disease', (25, 28))
127524	32102250	The differential diagnosis between ccptRCC and ccRCC for the choice of the best therapeutic strategy likely requires the comprehensive evaluation of histology, IHC, and at least VHL mutations.	('RCC', 'Disease', (49, 52))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('VHL', 'Gene', (178, 181))	('VHL', 'Gene', '7428', (178, 181))	('mutations', 'Var', (182, 191))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
127533	32102250	Here we describe a comparative histological, IHC, and next generation sequencing (NGS) mutation analysis of 10 cctpRCC and six small ccRCC.	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (115, 118))	('RCC', 'Disease', (135, 138))	('mutation', 'Var', (87, 95))
127541	32102250	In particular, the panel includes the 124 most common variants of the VHL genes including the small deletions.	('VHL', 'Gene', (70, 73))	('variants', 'Var', (54, 62))	('VHL', 'Gene', '7428', (70, 73))
127545	32102250	The NGS profile showed that 8/10 cases (80%) were wild type for all the investigated genes, while 2/10 (20%) showed VHL gene pathogenic mutations.	('VHL', 'Gene', (116, 119))	('mutations', 'Var', (136, 145))	('VHL', 'Gene', '7428', (116, 119))	('pathogenic', 'Reg', (125, 135))
127546	32102250	In particular, one showed a mutation at the splicing site in exon 3 (c.464-1G>A) and the other in exon 2 (c.443_444delTT (p.Phe148fs) of the VHL gene (see Figure 2).	('splicing', 'biological_process', 'GO:0045292', ('44', '52'))	('VHL', 'Gene', '7428', (141, 144))	('p.Phe148fs', 'Mutation', 'rs869025653', (122, 132))	('c.464-1G>A', 'Var', (69, 79))	('c.464-1G>A', 'Mutation', 'rs5030817', (69, 79))	('c.443_444delTT', 'Mutation', 'rs869025653', (106, 120))	('VHL', 'Gene', (141, 144))	('c.443_444delTT', 'Var', (106, 120))
127547	32102250	Among the six ccRCC control cases, 3/6 cases (50%) showed expected VHL mutations and a coherent IHC profile (CK7-/AMACR-;CAIX+); one (s16%) had consistent IHC profile, but it was wild type for all the genes in the panel, and two (33%) displayed consistent IHC profile, and harbored mutations either in p53 (splicing site exon 5, IVS5+3>A) or the cKIT (splicing site exon 10, c.1594G>A (p.Val532Ile) genes (Figure 2).	('p.Val532Ile', 'Mutation', 'rs55792975', (386, 397))	('CAIX', 'Gene', '768', (121, 125))	('VHL', 'Gene', (67, 70))	('AMACR', 'Gene', (114, 119))	('p53', 'Gene', '7157', (302, 305))	('cKIT', 'Gene', '3815', (346, 350))	('c.1594G>A', 'Var', (375, 384))	('mutations', 'Var', (71, 80))	('splicing', 'biological_process', 'GO:0045292', ('352', '360'))	('VHL', 'Gene', '7428', (67, 70))	('AMACR', 'Gene', '23600', (114, 119))	('RCC', 'Disease', (16, 19))	('p53', 'Gene', (302, 305))	('CK7', 'Gene', (109, 112))	('cKIT', 'Gene', (346, 350))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('CK7', 'Gene', '3855', (109, 112))	('splicing', 'biological_process', 'GO:0045292', ('307', '315'))	('c.1594G>A', 'Mutation', 'rs55792975', (375, 384))	('CAIX', 'Gene', (121, 125))
127551	32102250	On molecular grounds, VHL gene alterations are common in most ccRCC while they are absent in cctpRCC.	('alterations', 'Var', (31, 42))	('RCC', 'Disease', (97, 100))	('VHL', 'Gene', (22, 25))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('VHL', 'Gene', '7428', (22, 25))	('common', 'Reg', (47, 53))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))
127555	32102250	This assumption is based on the data derived from The Cancer Genome Atlas where the large majority of conventional ccRCC harbored VHL alterations.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Cancer', 'Disease', (54, 60))	('Cancer', 'Disease', 'MESH:D009369', (54, 60))	('VHL', 'Gene', (130, 133))	('alterations', 'Var', (134, 145))	('VHL', 'Gene', '7428', (130, 133))
127560	32102250	Among the other three cases, one was wild type and the other two displayed pathogenic mutations in p53 and CKIT that have been described in ccRCC, also by us.	('mutations', 'Var', (86, 95))	('CKIT', 'Gene', '3815', (107, 111))	('RCC', 'Disease', (142, 145))	('p53', 'Gene', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('CKIT', 'Gene', (107, 111))	('p53', 'Gene', '7157', (99, 102))
127562	32102250	The wild type status of the remaining tumor does not exclude a large deletion of the chromosome 3p locus, encompassing VHL, and could not be detected by sequencing.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('chromosome', 'cellular_component', 'GO:0005694', ('85', '95'))	('VHL', 'Gene', (119, 122))	('VHL', 'Gene', '7428', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('deletion', 'Var', (69, 77))
127563	32102250	In addition, clear cell tumors with VHL wild type and mutations in TCEB1 have been recently described to increase HIF stabilization via the same mechanism as VHL inactivation.	('TCEB1', 'Gene', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('TCEB1', 'Gene', '6921', (67, 72))	('VHL', 'Gene', (36, 39))	('tumors', 'Disease', (24, 30))	('clear cell', 'Disease', (13, 23))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('mutations', 'Var', (54, 63))	('VHL', 'Gene', '7428', (36, 39))	('increase', 'PosReg', (105, 113))	('VHL', 'Gene', (158, 161))	('VHL', 'Gene', '7428', (158, 161))	('HIF stabilization', 'MPA', (114, 131))
127581	29851704	HIK1083 was expressed in nearly half of gastric-type carcinomas, but not in the vast majority of other subtypes.	('gastric-type carcinomas', 'Disease', 'MESH:D013274', (40, 63))	('gastric-type carcinomas', 'Disease', (40, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('HIK1083', 'Var', (0, 7))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))
127585	29851704	Aberrant p53 expression was found in only 3.6% of usual-type HPVA carcinomas, but it was more prevalent in mucinous (intestinal type and iSMILE) HPVAs and NHPVAs (particularly in gastric-type carcinoma, >50% of cases).	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('prevalent', 'Reg', (94, 103))	('Aberrant', 'Var', (0, 8))	('mucin', 'Gene', '100508689', (107, 112))	('expression', 'MPA', (13, 23))	('gastric-type carcinoma', 'Disease', 'MESH:D013274', (179, 201))	('HPV', 'Species', '10566', (145, 148))	('gastric-type carcinoma', 'Disease', (179, 201))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('HPV', 'Species', '10566', (156, 159))	('HPVA carcinomas', 'Disease', 'MESH:D002277', (61, 76))	('mucin', 'Gene', (107, 112))	('NHPVAs', 'Disease', (155, 161))	('HPV', 'Species', '10566', (61, 64))	('HPVA carcinomas', 'Disease', (61, 76))
127637	29851704	HIK1083 was expressed in 42% of gastric-type adenocarcinomas, but not in other tumor types.	('gastric-type adenocarcinomas', 'Disease', 'MESH:D013274', (32, 60))	('gastric-type adenocarcinomas', 'Disease', (32, 60))	('tumor', 'Disease', (79, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('HIK1083', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
127656	29851704	Among HPVAs, aberrant p53 expression was found in only 3.6% of usual-type carcinomas (Figure 3), but was more commonly found in both HPVAs of mucinous type (Figure 4) and in NHPVAs, including 3 of 16 mucinous HPVAs (2 of them iSMILEs) and 52% of gastric-type carcinomas.	('gastric-type carcinomas', 'Disease', 'MESH:D013274', (246, 269))	('HPV', 'Species', '10566', (6, 9))	('gastric-type carcinomas', 'Disease', (246, 269))	('carcinomas', 'Disease', (259, 269))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('mucin', 'Gene', (200, 205))	('carcinomas', 'Disease', 'MESH:D002277', (74, 84))	('HPV', 'Species', '10566', (209, 212))	('expression', 'MPA', (26, 36))	('HPVAs of mucinous type', 'Disease', 'MESH:D002288', (133, 155))	('mucin', 'Gene', '100508689', (200, 205))	('mucin', 'Gene', (142, 147))	('p53', 'Gene', '7157', (22, 25))	('aberrant', 'Var', (13, 21))	('mucin', 'Gene', '100508689', (142, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('p53', 'Gene', (22, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (259, 269))	('HPVAs of mucinous type', 'Disease', (133, 155))	('carcinomas', 'Disease', 'MESH:D002277', (259, 269))	('found', 'Reg', (119, 124))	('carcinomas', 'Disease', (74, 84))	('HPV', 'Species', '10566', (175, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('HPV', 'Species', '10566', (133, 136))
127672	29851704	In this study, 40% of gastric-type carcinomas were HIK1083-positive, less than has been previously reported (75-100%), although in one study gastric-type adenocarcinomas showed frequent focal or multifocal staining.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('gastric-type carcinomas', 'Disease', 'MESH:D013274', (22, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (159, 169))	('carcinomas', 'Phenotype', 'HP:0030731', (35, 45))	('HIK1083-positive', 'Var', (51, 67))	('gastric-type adenocarcinomas', 'Disease', 'MESH:D013274', (141, 169))	('gastric-type carcinomas', 'Disease', (22, 45))	('gastric-type adenocarcinomas', 'Disease', (141, 169))
127687	29851704	Tp53 mutation (and aberrant p53 immunostaining) is reportedly significantly less frequent in HPVAs than in other carcinomas of the gynecologic tract, most notably serous and serous-like carcinomas (carcinosarcomas and copy number-high endometrioid and clear cell carcinomas) of endometrium and ovary.	('p53', 'Gene', (28, 31))	('less', 'NegReg', (76, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('HPV', 'Species', '10566', (93, 96))	('p53', 'Gene', '7157', (1, 4))	('carcinomas', 'Phenotype', 'HP:0030731', (263, 273))	('carcinomas', 'Disease', 'MESH:D002277', (263, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('carcinomas', 'Disease', 'MESH:D002277', (113, 123))	('Tp53', 'Gene', (0, 4))	('carcinosarcomas', 'Disease', 'MESH:D002296', (198, 213))	('p53', 'Gene', (1, 4))	('carcinomas', 'Disease', (186, 196))	('Tp53', 'Gene', '7157', (0, 4))	('HPVAs', 'Disease', (93, 98))	('carcinomas', 'Disease', (263, 273))	('carcinosarcomas', 'Disease', (198, 213))	('carcinomas', 'Disease', (113, 123))	('serous', 'Disease', (163, 169))	('p53', 'Gene', '7157', (28, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('carcinomas', 'Phenotype', 'HP:0030731', (186, 196))	('carcinomas', 'Disease', 'MESH:D002277', (186, 196))	('clear cell carcinomas', 'Disease', (252, 273))	('copy number-high', 'Var', (218, 234))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (252, 273))	('mutation', 'Var', (5, 13))
127688	29851704	The TCGA study of ECAs reported only 2 adenocarcinomas (1 endocervical and 1 endometrioid) with a Tp53 mutation.	('Tp53', 'Gene', (98, 102))	('Tp53', 'Gene', '7157', (98, 102))	('adenocarcinomas', 'Disease', (39, 54))	('carcinomas', 'Phenotype', 'HP:0030731', (44, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('mutation', 'Var', (103, 111))	('adenocarcinomas', 'Disease', 'MESH:D000230', (39, 54))
127689	29851704	Previous studies have suggested a link between stage and Tp53 mutation, which makes sense if one assumes that most high-stage tumors were NHPVAs.	('Tp53', 'Gene', '7157', (57, 61))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutation', 'Var', (62, 70))	('HPV', 'Species', '10566', (139, 142))	('Tp53', 'Gene', (57, 61))
127690	29851704	A recent series reported aberrant p53 staining in 41% of gastric-type carcinomas, while in the current study 51% of gastric-type carcinomas showed aberrant p53 staining.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('gastric-type carcinomas', 'Disease', 'MESH:D013274', (57, 80))	('gastric-type carcinomas', 'Disease', 'MESH:D013274', (116, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('aberrant', 'Var', (25, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('p53', 'Gene', (156, 159))	('p53', 'Gene', '7157', (156, 159))	('gastric-type carcinomas', 'Disease', (57, 80))	('gastric-type carcinomas', 'Disease', (116, 139))	('staining', 'MPA', (38, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))
127736	29050224	Recently, by using a retrospective cohort of 20 formalin-fixed paraffin-embedded (FFPE) tissues, we evaluated the levels of specific miRNAs (miR-21-5p, miR-210-3p, miR185-5p and miR-221-3p) differentially expressed in ccRCC vs matched normal tissues.	('miR-210', 'Gene', (152, 159))	('paraffin', 'Chemical', 'MESH:D010232', (63, 71))	('miR-210', 'Gene', '406992', (152, 159))	('miR-21-5p', 'Gene', (141, 150))	('miR-221', 'Gene', '407006', (178, 185))	('miR185-5p', 'Var', (164, 173))	('miR-21-5p', 'Gene', '406997', (141, 150))	('formalin', 'Chemical', 'MESH:D005557', (48, 56))	('RCC', 'Phenotype', 'HP:0005584', (220, 223))	('miR-221', 'Gene', (178, 185))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('RCC', 'Disease', (220, 223))
127768	29050224	PCR quantification analysis of the SNORD61, SNORD68, RNU6-2 and miRNAs miR-21-5p, miR-210-3p, miR-221-3p, miR-185-5p and miR-145-5p, was performed using the miScript SYBR Green PCR kit (Qiagen, Chatsworth) with the miScript Primer Assay Hs-SNORD61 (#MS00033705), SNORD68 (#MS00033712), RNU6B-2 (#MS00033740), Hs-miR-21-5p (#MS00009079), Hs-miR-210-3p (#MS00003801), Hs-miR-221-3p (#MS00003857), Hs-miR-185-5p (#MS00003647) and Hs-miR-145-5p (#MS00003528) (Qiagen, Chatsworth, CA, USA).	('miR-221', 'Gene', '407006', (369, 376))	('SNORD68', 'Gene', '606500', (263, 270))	('SNORD68', 'Gene', (263, 270))	('RNU6-2', 'Gene', (53, 59))	('miR-21-5p', 'Gene', (71, 80))	('miR-210', 'Gene', (340, 347))	('SNORD61', 'Gene', (240, 247))	('miR-21-5p', 'Gene', '406997', (71, 80))	('miR-221', 'Gene', (94, 101))	('#MS00003647', 'Var', (410, 421))	('#MS00003801', 'Var', (352, 363))	('miR-210', 'Gene', '406992', (82, 89))	('miR-221', 'Gene', '407006', (94, 101))	('RNU6-2', 'Gene', '103625684', (53, 59))	('SNORD68', 'Gene', '606500', (44, 51))	('SNORD68', 'Gene', (44, 51))	('SNORD61', 'Gene', '26787', (35, 42))	('miR-210', 'Gene', (82, 89))	('#MS00003857', 'Var', (381, 392))	('miR-21-5p', 'Gene', (312, 321))	('#MS00033740', 'Var', (295, 306))	('miR-21-5p', 'Gene', '406997', (312, 321))	('miR-210', 'Gene', '406992', (340, 347))	('#MS00033712', 'Var', (272, 283))	('SNORD61', 'Gene', '26787', (240, 247))	('miR-221', 'Gene', (369, 376))	('#MS00003528', 'Var', (442, 453))	('SNORD61', 'Gene', (35, 42))	('#MS00009079', 'Var', (323, 334))
127797	33888849	These mutations were then converted to mutant protein sequences using customized scripts and supplemented to the search database of the corresponding cancer type (see details in "Methods").	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('mutations', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
127824	33888849	Among different CPTAC datasets (in total 13 datasets covering five cancer types), 46% of pseudogene identifications were repeatedly detected in at least two datasets.	('pseudogene', 'Var', (89, 99))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (67, 73))
127839	33888849	A paired t test analysis found 11 of the pseudogenes/lncRNAs were significantly upregulated in tumors compared to matched normal tissues.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('pseudogenes/lncRNAs', 'Var', (41, 60))	('tumors', 'Disease', (95, 101))	('upregulated', 'PosReg', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
127846	33888849	More interestingly, the peptides encoded by pseudogene RHOXF1P3 were upregulated (2- to 16-fold) in a subset of BRCA patients both in the CPTAC BRCA Discovery and Confirmatory cohorts (Fig.	('BRCA', 'Gene', (112, 116))	('RHOXF1', 'Gene', (55, 61))	('BRCA', 'Gene', (144, 148))	('peptides', 'Chemical', 'MESH:D010455', (24, 32))	('peptides', 'MPA', (24, 32))	('RHOXF1', 'Gene', '158800', (55, 61))	('upregulated', 'PosReg', (69, 80))	('BRCA', 'Phenotype', 'HP:0003002', (112, 116))	('patients', 'Species', '9606', (117, 125))	('BRCA', 'Gene', '672', (112, 116))	('BRCA', 'Phenotype', 'HP:0003002', (144, 148))	('BRCA', 'Gene', '672', (144, 148))	('pseudogene', 'Var', (44, 54))
127849	33888849	Together, our results demonstrated that pseudogene RHOXF1P3 is not only translated, but also upregulated in a subset of breast tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('breast tumors', 'Phenotype', 'HP:0100013', (120, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('breast tumors', 'Disease', 'MESH:D001943', (120, 133))	('RHOXF1', 'Gene', '158800', (51, 57))	('breast tumors', 'Disease', (120, 133))	('upregulated', 'PosReg', (93, 104))	('pseudogene', 'Var', (40, 50))	('RHOXF1', 'Gene', (51, 57))
127854	33888849	Overexpression of satellite repeats was previously observed in pancreatic and other epithelial cancers.	('pancreatic', 'Disease', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('epithelial cancers', 'Disease', (84, 102))	('satellite repeats', 'Var', (18, 35))	('pancreatic', 'Disease', 'MESH:D010195', (63, 73))	('observed', 'Reg', (51, 59))	('epithelial cancers', 'Disease', 'MESH:D009369', (84, 102))
127868	33888849	First, the abnormal proteins are hydrolyzed by proteases into peptide fragments in the cytoplasm, and then peptide fragments transported by the transporter associated with antigen processing (TAP) protein into the endoplasmic reticulum, where the peptide bind to an MHC molecule.	('transporter associated with antigen processing', 'Gene', (144, 190))	('TAP', 'Gene', '10482', (192, 195))	('antigen processing', 'biological_process', 'GO:0019882', ('172', '190'))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('214', '235'))	('peptide', 'Var', (107, 114))	('cytoplasm', 'cellular_component', 'GO:0005737', ('87', '96'))	('transporter associated with antigen processing', 'Gene', '6890', (144, 190))	('bind', 'Interaction', (255, 259))	('TAP', 'Gene', (192, 195))	('protein', 'cellular_component', 'GO:0003675', ('197', '204'))	('proteins', 'Protein', (20, 28))
127879	33888849	The role of pseudogenes in cancer development and progression has been increasingly investigated, with some of them proposed as diagnostic and prognostic markers.	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('pseudogenes', 'Var', (12, 23))	('cancer', 'Disease', (27, 33))
127881	33888849	In addition, several pseudogenes have been identified repeatedly in specific cancers and supported by multiple unique peptides, such as RHOXF1P3 and MCTS2P.	('RHOXF1', 'Gene', '158800', (136, 142))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('pseudogenes', 'Var', (21, 32))	('peptides', 'Chemical', 'MESH:D010455', (118, 126))	('RHOXF1', 'Gene', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('MCTS2P', 'Gene', '100101490', (149, 155))	('MCTS2P', 'Gene', (149, 155))
127884	33888849	revealed that hundreds of functional proteins encoded by noncanonical open reading frames are essential for cancer cell survival.	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('cancer', 'Disease', (108, 114))	('noncanonical open reading frames', 'Var', (57, 89))
127892	33888849	For each cancer type, a collection of cancer mutations detected from previous whole genome sequencing and whole exome sequencing studies were downloaded from the Cancer Genomics Data Server (CGDS, http://www.cbioportal.org/datasets) and then converted to mutant peptide sequences using customized scripts and supplemented to the search database of corresponding cancer type.	('cancer', 'Disease', 'MESH:D009369', (362, 368))	('cancer', 'Disease', (9, 15))	('mutations', 'Var', (45, 54))	('Cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('mutant', 'Var', (255, 261))	('cancer', 'Disease', (362, 368))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (362, 368))	('cancer', 'Disease', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('Cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Cancer', 'Disease', (162, 168))
127897	33888849	Peptides matched to mutant peptide sequences from non-synonymous SNPs or cancer mutations were removed and not treated as novel peptides.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('mutations', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('peptides', 'Chemical', 'MESH:D010455', (128, 136))	('non-synonymous SNPs', 'Disease', 'MESH:C580335', (50, 69))	('non-synonymous SNPs', 'Disease', (50, 69))	('mutant', 'Var', (20, 26))
127919	32311223	In the validation cohort from GSE53757, TNFSF13B, CASP5, and GJB6 correlated positively with tumor stages, while FREM1 negatively correlated with tumor stages.	('correlated', 'Reg', (66, 76))	('CASP5', 'Gene', '838', (50, 55))	('FREM1', 'Gene', '158326', (113, 118))	('GSE53757', 'Var', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('GJB6', 'Gene', '10804', (61, 65))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', (93, 98))	('TNFSF13B', 'Gene', '10673', (40, 48))	('positively', 'PosReg', (77, 87))	('CASP5', 'Gene', (50, 55))	('FREM1', 'Gene', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('TNFSF13B', 'Gene', (40, 48))	('GJB6', 'Gene', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
127954	32311223	We also obtained 72 ccRCC patients from GSE53757 with transcriptome chip data and corresponding clinical stage information.	('GSE53757', 'Var', (40, 48))	('RCC', 'Disease', (22, 25))	('RCC', 'Phenotype', 'HP:0005584', (22, 25))	('RCC', 'Disease', 'MESH:C538614', (22, 25))	('patients', 'Species', '9606', (26, 34))	('ccRCC', 'Phenotype', 'HP:0006770', (20, 25))
127970	32311223	Last, when clustering the samples, the differential genes still significantly discriminate patients of low and high scores in Figure S5.	('discriminate', 'Reg', (78, 90))	('patients', 'Species', '9606', (91, 99))	('differential genes', 'Var', (39, 57))
127983	32311223	In particular, correlation results in GSE53757 were highly accordant with survival analysis or multivariate Cox analysis in TCGA cohort (Figure 6A-D).	('GSE53757', 'Var', (38, 46))	('Cox', 'Gene', '1351', (108, 111))	('Cox', 'Gene', (108, 111))
127998	32311223	It was reported that a potential pathologic p.G76S heterozygous mutation on the TNFRSF13B gene which identified by whole-exome sequencing might upregulate cytokine-cytokine receptor interaction signaling pathway and increase serum TNFalpha, IL-17alpha, IFNgamma and BAFF levels in immune thrombocytopenia patients.	('IFNgamma', 'Gene', (253, 261))	('thrombocytopenia', 'Disease', 'MESH:D013921', (288, 304))	('IFNgamma', 'Gene', '3458', (253, 261))	('IL-17', 'molecular_function', 'GO:0030367', ('241', '246'))	('TNFalpha', 'Gene', (231, 239))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (288, 304))	('immune thrombocytopenia', 'Phenotype', 'HP:0001973', (281, 304))	('signaling pathway', 'biological_process', 'GO:0007165', ('194', '211'))	('IL-17alpha', 'Gene', (241, 251))	('BAFF', 'Gene', '10673', (266, 270))	('TNFRSF13B', 'Gene', '23495', (80, 89))	('TNFRSF13B', 'Gene', (80, 89))	('patients', 'Species', '9606', (305, 313))	('p.G76S', 'Var', (44, 50))	('IL-17alpha', 'Gene', '3605', (241, 251))	('increase', 'PosReg', (216, 224))	('p.G76S', 'Mutation', 'rs146436713', (44, 50))	('TNFalpha', 'Gene', '7124', (231, 239))	('thrombocytopenia', 'Disease', (288, 304))	('upregulate', 'PosReg', (144, 154))	('BAFF', 'Gene', (266, 270))
128009	32311223	Ding et al reported that overexpressed TNFSF13B might increases lymphocytic infiltration and inefficiently promotes ectopic B-cell differentiation in SS.	('ectopic B-cell differentiation', 'CPA', (116, 146))	('overexpressed', 'Var', (25, 38))	('TNFSF13B', 'Gene', '10673', (39, 47))	('promotes', 'PosReg', (107, 115))	('increases', 'PosReg', (54, 63))	('B-cell differentiation', 'biological_process', 'GO:0030183', ('124', '146'))	('TNFSF13B', 'Gene', (39, 47))	('lymphocytic infiltration', 'CPA', (64, 88))
128010	32311223	41  Besides, studies revealed that genetic variants of both TNFSF13B and TNFSF13B-receptor were related to SS-related lymphoma.	('TNFSF13B', 'Gene', (73, 81))	('TNFSF13B', 'Gene', '10673', (60, 68))	('lymphoma', 'Disease', (118, 126))	('related', 'Reg', (96, 103))	('lymphoma', 'Disease', 'MESH:D008223', (118, 126))	('variants', 'Var', (43, 51))	('TNFSF13B', 'Gene', (60, 68))	('lymphoma', 'Phenotype', 'HP:0002665', (118, 126))	('TNFSF13B', 'Gene', '10673', (73, 81))
128016	32311223	Dong et al identified rs507879, which was located within exon 2 of CASP5 and resulted in a missense mutation and amino acid substitution.	('CASP5', 'Gene', '838', (67, 72))	('rs507879', 'Mutation', 'rs507879', (22, 30))	('CASP5', 'Gene', (67, 72))	('amino acid', 'MPA', (113, 123))	('rs507879', 'Var', (22, 30))	('missense mutation', 'Var', (91, 108))
128018	32311223	However, a common somatic mutation in exon 2 was observed in leukemias and some malignant solid tumors including gastric, colon, and lung cancers yy.	('lung cancers', 'Disease', 'MESH:D008175', (133, 145))	('lung cancers', 'Disease', (133, 145))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('mutation', 'Var', (26, 34))	('colon', 'Disease', (122, 127))	('leukemias', 'Phenotype', 'HP:0001909', (61, 70))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('lung cancers', 'Phenotype', 'HP:0100526', (133, 145))	('leukemias', 'Disease', (61, 70))	('malignant solid tumors', 'Disease', 'MESH:D009369', (80, 102))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('leukemias', 'Disease', 'MESH:D007938', (61, 70))	('malignant solid tumors', 'Disease', (80, 102))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('observed', 'Reg', (49, 57))	('leukemia', 'Phenotype', 'HP:0001909', (61, 69))	('gastric', 'Disease', (113, 120))
128031	32047266	RASSF10 is frequently epigenetically inactivated in kidney cancer and its knockout promotes neoplasia in cancer prone mice Kidney cancer incidences are rising globally, thereby fueling the demand for targeted therapies and precision medicine.	('kidney cancer', 'Phenotype', 'HP:0009726', (52, 65))	('cancer', 'Disease', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('kidney cancer', 'Disease', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('knockout', 'Var', (74, 82))	('promotes', 'PosReg', (83, 91))	('neoplasia', 'Disease', 'MESH:D009369', (92, 101))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('RASSF10', 'Gene', '78748', (0, 7))	('RASSF10', 'Gene', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('neoplasia', 'Disease', (92, 101))	('Kidney cancer', 'Disease', 'MESH:D007680', (123, 136))	('Kidney cancer', 'Disease', (123, 136))	('kidney cancer', 'Disease', 'MESH:D007680', (52, 65))	('cancer', 'Disease', (130, 136))	('Kidney cancer', 'Phenotype', 'HP:0009726', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('neoplasia', 'Phenotype', 'HP:0002664', (92, 101))	('cancer', 'Disease', (59, 65))
128036	32047266	Especially Rassf10-/- and p53-deficient mice exhibited threefold increased rates of kidney cysts compared with p53-/- controls.	('increased', 'PosReg', (65, 74))	('Rassf10-/-', 'Var', (11, 21))	('kidney cysts', 'CPA', (84, 96))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '22059', (111, 114))	('p53', 'Gene', (26, 29))	('increased rates of kidney', 'Phenotype', 'HP:0000105', (65, 90))	('kidney cysts', 'Phenotype', 'HP:0000107', (84, 96))	('p53', 'Gene', '22059', (26, 29))	('mice', 'Species', '10090', (40, 44))
128038	32047266	Primary tumors of renal clear cell and papillary cell carcinoma confirmed that RASSF10 methylation is associated with decreased expression in comparison to normal kidney tissue.	('Primary tumors of renal clear cell and papillary cell carcinoma', 'Disease', 'MESH:C538614', (0, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('methylation', 'biological_process', 'GO:0032259', ('87', '98'))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('RASSF10', 'Gene', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('decreased', 'NegReg', (118, 127))	('expression', 'MPA', (128, 138))	('methylation', 'Var', (87, 98))
128039	32047266	In independent data sets, we could validate that RASSF10 inactivation clinically correlated with decreased survival and with progressed disease state of kidney cancer patients and polycystic kidney size.	('survival', 'MPA', (107, 115))	('disease state of kidney', 'Phenotype', 'HP:0000112', (136, 159))	('progressed', 'Disease', (125, 135))	('polycystic kidney', 'Disease', 'MESH:D007690', (180, 197))	('RASSF10', 'Gene', (49, 56))	('patients', 'Species', '9606', (167, 175))	('kidney cancer', 'Disease', 'MESH:D007680', (153, 166))	('decreased', 'NegReg', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('polycystic kidney', 'Phenotype', 'HP:0000113', (180, 197))	('progressed disease state of kidney', 'Phenotype', 'HP:0012622', (125, 159))	('polycystic kidney', 'Disease', (180, 197))	('kidney cancer', 'Phenotype', 'HP:0009726', (153, 166))	('inactivation', 'Var', (57, 69))	('kidney cancer', 'Disease', (153, 166))
128041	32047266	In combination with other markers, RASSF10 silencing can serve as diagnostic and prognostic cancer biomarker in kidney diseases.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('kidney diseases', 'Disease', (112, 127))	('RASSF10', 'Gene', (35, 42))	('silencing', 'Var', (43, 52))	('kidney diseases', 'Disease', 'MESH:D007674', (112, 127))	('kidney diseases', 'Phenotype', 'HP:0000112', (112, 127))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('kidney disease', 'Phenotype', 'HP:0000112', (112, 126))
128047	32047266	Our group focuses on epigenetically inactivated tumor suppressors as candidate biomarkers, which are predicted to play a prominent role in the near future.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('epigenetically inactivated', 'Var', (21, 47))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
128050	32047266	Epigenetic inactivation of RASSF10 by its promoter hypermethylation is a frequent event in pathogenesis of human cancers.	('promoter', 'MPA', (42, 50))	('human', 'Species', '9606', (107, 112))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('RASSF10', 'Gene', (27, 34))	('cancers', 'Disease', (113, 120))	('pathogenesis', 'biological_process', 'GO:0009405', ('91', '103'))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Epigenetic inactivation', 'Var', (0, 23))
128051	32047266	In previous studies, we have shown that the RASSF10 promoter is methylated in patient tumors samples of the adrenal gland, head and neck, sarcoma, pancreas carcinoma, and Merkel cell carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('patient', 'Species', '9606', (78, 85))	('sarcoma', 'Disease', (138, 145))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (171, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('methylated', 'Var', (64, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('Merkel cell carcinoma', 'Disease', (171, 192))	('adrenal gland', 'Disease', (108, 121))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('pancreas carcinoma', 'Disease', 'MESH:D010190', (147, 165))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('pancreas carcinoma', 'Disease', (147, 165))	('sarcoma', 'Disease', 'MESH:D012509', (138, 145))	('RASSF10', 'Gene', (44, 51))	('neck', 'cellular_component', 'GO:0044326', ('132', '136'))
128052	32047266	We showed the epigenetic inactivation of RASSF10 in breast cancer, lung cancer, skin cancer, and thyroid cancer and showed that RASSF10 inhibited the growth of breast cancer, pancreas carcinoma, and sarcoma cell lines.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('thyroid cancer', 'Phenotype', 'HP:0002890', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('epigenetic inactivation', 'Var', (14, 37))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('pancreas carcinoma', 'Disease', 'MESH:D010190', (175, 193))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('RASSF10', 'Gene', (41, 48))	('pancreas carcinoma', 'Disease', (175, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('RASSF10', 'Var', (128, 135))	('skin cancer', 'Disease', (80, 91))	('lung cancer', 'Disease', (67, 78))	('thyroid cancer', 'Disease', (97, 111))	('inhibited', 'NegReg', (136, 145))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('breast cancer', 'Disease', (52, 65))	('skin cancer', 'Phenotype', 'HP:0008069', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('growth', 'MPA', (150, 156))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('thyroid cancer', 'Disease', 'MESH:D013964', (97, 111))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('sarcoma', 'Disease', 'MESH:D012509', (199, 206))	('skin cancer', 'Disease', 'MESH:D012878', (80, 91))	('breast cancer', 'Disease', (160, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('sarcoma', 'Disease', (199, 206))
128056	32047266	Moreover, we revealed that RASSF10 is frequently epigenetically inactivated in kidney cancer, and we show the clinical potential of RASSF10 as a biomarker in different kidney diseases.	('kidney cancer', 'Disease', 'MESH:D007680', (79, 92))	('kidney cancer', 'Phenotype', 'HP:0009726', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('epigenetically inactivated', 'Var', (49, 75))	('kidney diseases', 'Disease', (168, 183))	('kidney cancer', 'Disease', (79, 92))	('RASSF10', 'Gene', (27, 34))	('kidney disease', 'Phenotype', 'HP:0000112', (168, 182))	('RASSF10', 'Gene', (132, 139))	('kidney diseases', 'Disease', 'MESH:D007674', (168, 183))	('kidney diseases', 'Phenotype', 'HP:0000112', (168, 183))
128061	32047266	At 80 weeks animals showed no differences between wt (n = 27) and Rassf10-/- (n = 44), regarding the occurrence of various diseases/neoplasia (diseased wt 56% vs. Rassf10-/- 57%).	('Rassf10-/-', 'Var', (66, 76))	('neoplasia', 'Disease', (132, 141))	('Rassf10-/-', 'Var', (163, 173))	('neoplasia', 'Disease', 'MESH:D009369', (132, 141))	('neoplasia', 'Phenotype', 'HP:0002664', (132, 141))
128065	32047266	In the Rassf1A-/- tumor-suppressor background, the additional Rassf10 knockout reduced significantly the overall survival (p = 0.018; Fig.	('tumor-suppressor', 'biological_process', 'GO:0051726', ('18', '34'))	('reduced', 'NegReg', (79, 86))	('overall survival', 'MPA', (105, 121))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('18', '34'))	('Rassf1A-/- tumor-suppressor', 'Gene', '56289', (7, 34))	('Rassf1A-/- tumor-suppressor', 'Gene', (7, 34))	('Rassf10', 'Gene', (62, 69))	('knockout', 'Var', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
128066	32047266	In detail Rassf10 knockout animals mostly suffered from lymphoma, and the mean size of measurable lymph nodes increased from 86 mg for Rassf10 wt to 285 mg Rassf10+/- to 401 mg for Rassf10-/- (Fig.	('suffered', 'Reg', (42, 50))	('lymphoma', 'Phenotype', 'HP:0002665', (56, 64))	('Rassf10-/-', 'Var', (181, 191))	('Rassf10', 'Var', (135, 142))	('increased', 'PosReg', (110, 119))	('knockout', 'Var', (18, 26))	('lymph nodes increased', 'Phenotype', 'HP:0002716', (98, 119))	('lymphoma', 'Disease', (56, 64))	('lymphoma', 'Disease', 'MESH:D008223', (56, 64))	('Rassf10', 'Gene', (10, 17))
128068	32047266	In addition, Rassf1A knockout animals not only developed megaesophagus (reported earlier), but also megaileum/megacolon at a total incidence 16%.	('Rassf1A', 'Gene', '56289', (13, 20))	('Rassf1A', 'Gene', (13, 20))	('megacolon', 'Phenotype', 'HP:0002251', (110, 119))	('knockout', 'Var', (21, 29))	('megaesophagus', 'CPA', (57, 70))	('developed', 'PosReg', (47, 56))
128069	32047266	In the p53-/- tumor-suppressor background, survival analysis by Kaplan-Meier revealed that Rassf10 knockout animals (n = 77; Rassf10+/-/Rassf10-/-) had a reduced survival rate vs. Rassf10+/+ animals (n = 24, Fig.	('tumor', 'Disease', (14, 19))	('Rassf10', 'Gene', (91, 98))	('p53', 'Gene', '22059', (7, 10))	('Rassf10+/-/Rassf10-/-', 'Var', (125, 146))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('14', '30'))	('survival rate', 'CPA', (162, 175))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('14', '30'))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('reduced', 'NegReg', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('p53', 'Gene', (7, 10))
128070	32047266	We observed diseased animals at the following rates (p53-/- background): wt 58% (14/24), Rassf10+/- 81% (30/37), and Rassf10-/- 70% (28/40).	('Rassf10-/-', 'Var', (117, 127))	('p53', 'Gene', '22059', (53, 56))	('p53', 'Gene', (53, 56))	('Rassf10+/-', 'Var', (89, 99))
128071	32047266	Interestingly, enlarged thymus and thymoma were found in 24% Rassf10-/- (8/33), in 46% Rassf10+/- (12/26) but only in 11% Rassf10-wt (2/18) animals, significant regarding Rassf10+/- vs. wt (Table 2; Fig.	('thymus and thymoma', 'Disease', 'MESH:D013945', (24, 42))	('Rassf10+/-', 'Var', (87, 97))	('thymoma', 'Phenotype', 'HP:0100522', (35, 42))	('Rassf10+/-', 'Var', (171, 181))	('Rassf10-/-', 'Var', (61, 71))	('enlarged', 'PosReg', (15, 23))	('enlarged thymus', 'Phenotype', 'HP:0010516', (15, 30))
128074	32047266	The mean thymus weight (all weighed thymus) increased by 87% heterozygous Rassf10 knockout animals (344.8 mg) compared with wildtyp (184.6 mg).	('thymus weight', 'Disease', (9, 22))	('knockout', 'Var', (82, 90))	('Rassf10', 'Gene', (74, 81))	('increased', 'PosReg', (44, 53))	('thymus weight', 'Disease', 'MESH:D015431', (9, 22))
128075	32047266	We also found a more than threefold increased occurrence of kidney cysts in Rassf10 knockout (p53-/-) animals 25% Rassf10-/-, 11% Rassf10+/- vs. 8% wt (Table 2 and Fig.	('Rassf10', 'Gene', (76, 83))	('p53', 'Gene', (94, 97))	('p53', 'Gene', '22059', (94, 97))	('kidney cysts', 'Disease', (60, 72))	('Rassf10-/-', 'Var', (114, 124))	('increased', 'PosReg', (36, 45))	('kidney cysts', 'Phenotype', 'HP:0000107', (60, 72))	('Rassf10+/-', 'Var', (130, 140))
128078	32047266	Tumor-suppressor inactivation in cancer can occur by the loss of function mutation or promoter methylation.	('loss of function', 'NegReg', (57, 73))	('mutation', 'Var', (74, 82))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('Tumor-suppressor', 'biological_process', 'GO:0051726', ('0', '16'))	('Tumor-suppressor', 'molecular_function', 'GO:0008181', ('0', '16'))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Tumor-suppressor', 'CPA', (0, 16))	('methylation', 'biological_process', 'GO:0032259', ('95', '106'))	('promoter methylation', 'Var', (86, 106))
128082	32047266	We found that RASSF10 is epigenetically inactivated by promoter hypermethylation in 60% of kidney cancer cell lines (9/15, Fig.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('kidney cancer', 'Disease', (91, 104))	('RASSF10', 'Gene', (14, 21))	('epigenetically', 'Var', (25, 39))	('kidney cancer', 'Phenotype', 'HP:0009726', (91, 104))	('kidney cancer', 'Disease', 'MESH:D007680', (91, 104))	('promoter hypermethylation', 'Var', (55, 80))
128083	32047266	We could significantly reestablish the expression of RASSF10 by DNMT inhibition treatment with 5-Aza-2'deoxycytidine in MZ1257 and MZ1973 (Fig.	('MZ1257', 'Var', (120, 126))	('MZ1973', 'CellLine', 'CVCL:E046', (131, 137))	('DNMT', 'Gene', (64, 68))	('MZ1257', 'CellLine', 'CVCL:E044', (120, 126))	('DNMT', 'Gene', '13433', (64, 68))	('expression', 'MPA', (39, 49))	('MZ1973', 'Var', (131, 137))	('RASSF10', 'Gene', (53, 60))	('Aza', 'Chemical', 'MESH:D001379', (97, 100))
128084	32047266	Primary tumors of renal clear cell and renal papillary cell carcinoma confirmed that RASSF10 methylation correlated with decreased expression in comparison with normal kidney tissue (Fig.	('RASSF10', 'Gene', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('decreased', 'NegReg', (121, 130))	('methylation', 'biological_process', 'GO:0032259', ('93', '104'))	('expression', 'MPA', (131, 141))	('Primary tumors of renal clear cell and renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (0, 69))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('methylation', 'Var', (93, 104))
128086	32047266	This result confirms the epigenetic regulation of RASSF10 in human kidney cells.	('epigenetic regulation', 'Var', (25, 46))	('regulation', 'biological_process', 'GO:0065007', ('36', '46'))	('RASSF10', 'Gene', (50, 57))	('human', 'Species', '9606', (61, 66))
128090	32047266	In renal carcinoma (papillary and clear cells) overall survival correlated with high RASSF10 expression (Fig.	('RASSF10', 'Gene', (85, 92))	('renal carcinoma', 'Disease', 'MESH:C538614', (3, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('renal carcinoma', 'Disease', (3, 18))	('renal carcinoma', 'Phenotype', 'HP:0005584', (3, 18))	('expression', 'MPA', (93, 103))	('high', 'Var', (80, 84))
128097	32047266	To gain insight in the molecular processes that are deregulated upon Rassf10 inactivation we utilized mouse embryonic fibroblasts (MEFs) isolated from Rassf10 knockout and wildtype mice.	('mice', 'Species', '10090', (181, 185))	('Rassf10', 'Gene', (69, 76))	('mouse', 'Species', '10090', (102, 107))	('Rassf10', 'Gene', (151, 158))	('MEFs', 'CellLine', 'CVCL:9115', (131, 135))	('knockout', 'Var', (159, 167))	('inactivation', 'Var', (77, 89))
128100	32047266	Other hallmarks that were significantly associated the Rassf1a knockout belong to allograft rejection, inflammatory response, complement, and interferon gamma response gene sets.	('interferon gamma', 'Gene', '15978', (142, 158))	('inflammatory response', 'CPA', (103, 124))	('Rassf1a', 'Gene', '56289', (55, 62))	('interferon gamma', 'Gene', (142, 158))	('allograft rejection', 'CPA', (82, 101))	('inflammatory response', 'biological_process', 'GO:0006954', ('103', '124'))	('Rassf1a', 'Gene', (55, 62))	('knockout', 'Var', (63, 71))	('interferon gamma', 'molecular_function', 'GO:0005133', ('142', '158'))
128101	32047266	These results suggest that upon Rassf10 depletion several oncogenic pathways including RAS signaling are activated.	('Rassf10', 'Gene', (32, 39))	('RA', 'Chemical', 'MESH:D011883', (87, 89))	('depletion', 'Var', (40, 49))	('activated', 'PosReg', (105, 114))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('oncogenic pathways', 'Pathway', (58, 76))	('RAS signaling', 'Pathway', (87, 100))
128106	32047266	In renal clear cell carcinoma, we also detected an inverse correlation between RASSF10 and MYC expression indicating that the loss of RASSF10 is associated with MYC induction (Fig.	('MYC induction', 'Disease', (161, 174))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (3, 29))	('renal clear cell carcinoma', 'Disease', (3, 29))	('associated', 'Reg', (145, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('RASSF10', 'Gene', (134, 141))	('loss', 'Var', (126, 130))
128108	32047266	Interestingly, we found that RASSF10 expression is positively associated with increased CDH1 levels in renal clear cell carcinoma (Fig.	('expression', 'Var', (37, 47))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (103, 129))	('renal clear cell carcinoma', 'Disease', (103, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('increased', 'PosReg', (78, 87))	('CDH1', 'Gene', (88, 92))	('CDH1', 'Gene', '12550', (88, 92))	('RASSF10', 'Gene', (29, 36))
128109	32047266	Our data suggest that MYC and VEGF are negatively regulated by RASSF10 and that combination of high RASSF10 and low MYC or VEGF expression is associated with a favorable prognosis for renal cancer patients.	('patients', 'Species', '9606', (197, 205))	('high', 'Var', (95, 99))	('RASSF10', 'Gene', (63, 70))	('RASSF10', 'Gene', (100, 107))	('renal cancer', 'Disease', (184, 196))	('negatively', 'NegReg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('expression', 'MPA', (128, 138))	('renal cancer', 'Disease', 'MESH:D007680', (184, 196))	('renal cancer', 'Phenotype', 'HP:0009726', (184, 196))
128111	32047266	Rassf10 knockout promotes increased numbers of thymoma (p53-/-), cystic kidneys (p53-/-), lymphoma (Rassf1A-/-, p53-/-), and splenomegaly (Rassf1A-/-, p53-/-).	('p53', 'Gene', '22059', (56, 59))	('p53', 'Gene', (81, 84))	('Rassf1A', 'Gene', '56289', (139, 146))	('Rassf1A', 'Gene', (139, 146))	('lymphoma', 'Phenotype', 'HP:0002665', (90, 98))	('splenomegaly', 'Disease', (125, 137))	('p53', 'Gene', (112, 115))	('cystic kidneys', 'Disease', 'MESH:D052177', (65, 79))	('knockout', 'Var', (8, 16))	('p53', 'Gene', (151, 154))	('p53', 'Gene', '22059', (151, 154))	('thymoma', 'Disease', 'MESH:D013945', (47, 54))	('p53', 'Gene', (56, 59))	('splenomegaly', 'Disease', 'MESH:D013163', (125, 137))	('p53', 'Gene', '22059', (81, 84))	('lymphoma', 'Disease', (90, 98))	('increased', 'PosReg', (26, 35))	('lymphoma', 'Disease', 'MESH:D008223', (90, 98))	('splenomegaly', 'Phenotype', 'HP:0001744', (125, 137))	('p53', 'Gene', '22059', (112, 115))	('Rassf1A', 'Gene', '56289', (100, 107))	('thymoma', 'Disease', (47, 54))	('Rassf1A', 'Gene', (100, 107))	('thymoma', 'Phenotype', 'HP:0100522', (47, 54))	('Rassf10', 'Gene', (0, 7))	('cystic kidneys', 'Phenotype', 'HP:0000107', (65, 79))	('cystic kidneys', 'Disease', (65, 79))
128112	32047266	Rassf10 heterozygous animals already suffer from an overall increased disease incidence (Table 2), suggesting Rassf10 is a haploinsufficient tumor suppressor, and the loss of one allele is sufficient for its loss of function and contribution to carcinogenesis.	('tumor suppressor', 'biological_process', 'GO:0051726', ('141', '157'))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('carcinogenesis', 'Disease', (245, 259))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('141', '157'))	('disease incidence', 'CPA', (70, 87))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (123, 146))	('Rassf10', 'Gene', (0, 7))	('haploinsufficient tumor', 'Disease', (123, 146))	('carcinogenesis', 'Disease', 'MESH:D063646', (245, 259))	('loss', 'Var', (167, 171))	('increased', 'PosReg', (60, 69))	('Rassf10', 'Gene', (110, 117))	('loss of function', 'NegReg', (208, 224))
128118	32047266	We reported that knockdown of RASSF10 increased mitosis and increased cell proliferation and invasion, as well as RASSF10 reexpression halted proliferation.	('mitosis', 'Disease', (48, 55))	('mitosis', 'Disease', 'None', (48, 55))	('proliferation', 'CPA', (142, 155))	('cell proliferation', 'biological_process', 'GO:0008283', ('70', '88'))	('cell proliferation', 'CPA', (70, 88))	('increased', 'PosReg', (60, 69))	('mitosis', 'biological_process', 'GO:0000278', ('48', '55'))	('RASSF10', 'Gene', (114, 121))	('knockdown', 'Var', (17, 26))	('invasion', 'CPA', (93, 101))	('halted', 'NegReg', (135, 141))	('RASSF10', 'Gene', (30, 37))	('increased', 'PosReg', (38, 47))
128120	32047266	Interestingly, we found that the loss of Rassf10 in MEFs is associated with upregulation of KRAS and IL6/JAK/STAT3 signaling (Fig.	('IL6', 'Gene', '16193', (101, 104))	('upregulation', 'PosReg', (76, 88))	('Rassf10', 'Gene', (41, 48))	('IL6', 'molecular_function', 'GO:0005138', ('101', '104'))	('STAT3', 'Gene', '20848', (109, 114))	('loss', 'Var', (33, 37))	('signaling', 'biological_process', 'GO:0023052', ('115', '124'))	('MEFs', 'CellLine', 'CVCL:9115', (52, 56))	('KRAS', 'MPA', (92, 96))	('STAT3', 'Gene', (109, 114))	('IL6', 'Gene', (101, 104))	('JAK', 'molecular_function', 'GO:0004713', ('105', '108'))
128124	32047266	Across different renal cancer entities, we found a significant epigenetic inactivation of RASSF10 (Figs.	('renal cancer', 'Disease', 'MESH:D007680', (17, 29))	('renal cancer', 'Phenotype', 'HP:0009726', (17, 29))	('epigenetic inactivation', 'Var', (63, 86))	('RASSF10', 'Gene', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('renal cancer', 'Disease', (17, 29))
128125	32047266	In addition, we can exclude mutation events in the inactivation of RASSF10 in cancer (Table S1).	('inactivation', 'Var', (51, 63))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('RASSF10', 'Gene', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
128128	32047266	The successful pharmacological inhibition of DNA methylation restored RASSF10 expression, which we reported earlier in other cancer entities.	('restored', 'PosReg', (61, 69))	('expression', 'MPA', (78, 88))	('inhibition of DNA methylation', 'biological_process', 'GO:1905642', ('31', '60'))	('RASSF10', 'Gene', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('inhibition', 'Var', (31, 41))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
128129	32047266	We suggest that for the inactivation of the haploinsufficient tumor-suppressor RASSF10 the methylation of one allele is sufficient and found that low methylation levels of RASSF10 already decreased its expression dramatically.	('tumor-suppressor', 'biological_process', 'GO:0051726', ('62', '78'))	('decreased', 'NegReg', (188, 197))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('RASSF10', 'Gene', (172, 179))	('methylation levels', 'MPA', (150, 168))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (44, 67))	('inactivation', 'Var', (24, 36))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('62', '78'))	('haploinsufficient tumor', 'Disease', (44, 67))	('expression', 'MPA', (202, 212))	('RASSF10', 'Gene', (79, 86))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))	('methylation', 'MPA', (91, 102))	('methylation', 'biological_process', 'GO:0032259', ('150', '161'))
128131	32047266	Our clinical patient data revealed that the loss of RASSF10 is a common and general event in kidney carcinogenesis (Fig.	('patient', 'Species', '9606', (13, 20))	('kidney carcinogenesis', 'Disease', (93, 114))	('kidney carcinogenesis', 'Disease', 'MESH:D063646', (93, 114))	('RASSF10', 'Gene', (52, 59))	('loss', 'Var', (44, 48))
128134	32047266	Low RASSF10 and high MYC or high VEGF was significantly associated with poor prognosis of renal papillary cell cancer patients and the combination of two markers had a higher impact on impaired probability of survival compared with the low RASSF10 alone (Figs.	('renal papillary cell cancer', 'Disease', (90, 117))	('renal papillary cell cancer', 'Disease', 'MESH:C538614', (90, 117))	('Low RASSF10', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('patients', 'Species', '9606', (118, 126))
128141	32047266	An epigenetic assay for RASSF1A methylation in prostate cancer, however, still biopsy based, is available.	('prostate cancer', 'Phenotype', 'HP:0012125', (47, 62))	('methylation', 'Var', (32, 43))	('RASSF1A', 'Gene', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('prostate cancer', 'Disease', (47, 62))	('prostate cancer', 'Disease', 'MESH:D011471', (47, 62))
128142	32047266	We could show that epigenetic editing of RASSF10 is possible, and one could think of targeted therapies in the future using virally applied CRISPR-Cas9 Epigenetic Editors to patients for reactivation of e.g.	('epigenetic editing', 'Var', (19, 37))	('patients', 'Species', '9606', (174, 182))	('RASSF10', 'Gene', (41, 48))	('Cas', 'cellular_component', 'GO:0005650', ('147', '150'))
128143	32047266	hypermethylated RASSF10 specifically in cancer (Fig.	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('RASSF10', 'Gene', (16, 23))	('hypermethylated', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
128156	32047266	At first mouse Rassf10 was cloned into pCMVTag1, linearized by digestion with ApaL1, Rassf10 was transcribed by T7 polymerase, and thereby Rassf10-RNA labeled with the RNA Labeling DIG Kit (Roche), and followed by Rassf10-RNA probe purification.	('RNA', 'cellular_component', 'GO:0005562', ('168', '171'))	('RNA', 'cellular_component', 'GO:0005562', ('222', '225'))	('Rassf10-RNA', 'Var', (139, 150))	('Rassf10', 'Gene', (85, 92))	('mouse', 'Species', '10090', (9, 14))	('Kit', 'Gene', '16590', (185, 188))	('digestion', 'biological_process', 'GO:0007586', ('63', '72'))	('RNA', 'cellular_component', 'GO:0005562', ('147', '150'))	('Kit', 'Gene', (185, 188))
128166	32047266	Reagents/equipments were GeneChip  WT PLUS Reagent Kit, P/N: 902280; GeneChip  Hybridization, Wash, and Stain Kit P/N 900720, GeneChip Scanner, GeneChip Fluidics Station 450, GeneChip Hybridization Oven 640, Bioanalyzer 2100 (Agilent) and RNA600 NanoKit (Agilent).	('Kit', 'Gene', '16590', (250, 253))	('Kit', 'Gene', (51, 54))	('Kit', 'Gene', (110, 113))	('P/N', 'Var', (114, 117))	('Kit', 'Gene', (250, 253))	('RNA', 'cellular_component', 'GO:0005562', ('239', '242'))	('Kit', 'Gene', '16590', (51, 54))	('Kit', 'Gene', '16590', (110, 113))
128173	32047266	The following antibodies were used: a-GAPDH (FL335, sc-25778 from Santa Cruz), a-RASSF10 (AP12444c-ev2020, Abgent), and HRP-coupled secondary antibodies anti-rabbit (sc2004, sc2357, Santa Cruz).	('FL335', 'Var', (45, 50))	('AP12444c-ev2020', 'Var', (90, 105))	('GAPDH', 'Gene', (38, 43))	('sc2004', 'Var', (166, 172))	('GAPDH', 'Gene', '14433', (38, 43))
128194	31339433	Sporadic ccRCC is frequently associated with alterations of the tumor suppressor VHL gene.	('alterations', 'Var', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('tumor suppressor', 'biological_process', 'GO:0051726', ('64', '80'))	('VHL', 'Gene', (81, 84))	('VHL', 'Gene', '7428', (81, 84))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('64', '80'))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('associated', 'Reg', (29, 39))	('RCC', 'Disease', 'MESH:D002292', (11, 14))	('RCC', 'Disease', (11, 14))
128195	31339433	These alterations include mutations, promoter hypermethylation, and loss of heterozygosity at the VHL locus.	('VHL', 'Gene', (98, 101))	('mutations', 'Var', (26, 35))	('VHL', 'Gene', '7428', (98, 101))	('promoter', 'MPA', (37, 45))	('loss of', 'NegReg', (68, 75))
128196	31339433	Different mutations in VHL leads to quantitative or qualitative alterations of functions of the VHL gene product: VHL protein or pVHL (referred to as VHL in this study).	('functions', 'MPA', (79, 88))	('VHL', 'Gene', '7428', (114, 117))	('VHL', 'Gene', (23, 26))	('VHL', 'Gene', (150, 153))	('VHL', 'Gene', (130, 133))	('VHL', 'Gene', '7428', (150, 153))	('alterations', 'Reg', (64, 75))	('VHL', 'Gene', (96, 99))	('pVHL', 'Gene', '7428', (129, 133))	('VHL', 'Gene', '7428', (23, 26))	('VHL', 'Gene', '7428', (130, 133))	('mutations', 'Var', (10, 19))	('pVHL', 'Gene', (129, 133))	('VHL', 'Gene', '7428', (96, 99))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))	('VHL', 'Gene', (114, 117))
128208	31339433	Then ALK5-ICD is translocated to the nucleus of tumor cells and promotes tumor progression, although the exact mechanism needs to be further elucidated.	('promotes', 'PosReg', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', (48, 53))	('nucleus', 'cellular_component', 'GO:0005634', ('37', '44'))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('ALK5-ICD', 'Var', (5, 13))
128211	31339433	EMT results in cells acquiring an invasive phenotype and TGF-beta pathway plays a pivotal role in EMT through its downstream target SNAIL1, which is a transcription factor.	('TGF-beta', 'Gene', '7039', (57, 65))	('transcription factor', 'molecular_function', 'GO:0000981', ('151', '171'))	('EMT', 'biological_process', 'GO:0001837', ('0', '3'))	('transcription', 'biological_process', 'GO:0006351', ('151', '164'))	('TGF-beta', 'Gene', (57, 65))	('EMT', 'biological_process', 'GO:0001837', ('98', '101'))	('invasive phenotype', 'CPA', (34, 52))	('EMT', 'Var', (0, 3))	('SNAIL1', 'Gene', (132, 138))	('SNAIL1', 'Gene', '6615', (132, 138))
128244	31339433	The A498 cell line is known to harbor a VHL mutation, which is causing the loss of expression of VHL.	('mutation', 'Var', (44, 52))	('VHL', 'Gene', '7428', (97, 100))	('VHL', 'Gene', (40, 43))	('A498', 'CellLine', 'CVCL:1056', (4, 8))	('VHL', 'Gene', '7428', (40, 43))	('loss of', 'NegReg', (75, 82))	('expression', 'MPA', (83, 93))	('VHL', 'Gene', (97, 100))
128256	31339433	The membranes were incubated overnight at 4 C with gentle agitation with the indicated primary antibodies; HIF-1alpha (NB100-134, Novus Biologicals, Littleton, CO, USA), HIF-2alpha (NB100-122, NB100-132, Novus Biologicals), SNAIL1 (#3879, Cell Signaling Technology, Denver, MA, USA), HA (CST #2367, Cell Signaling Technology), TbetaRI or ALK5 (V-22), (sc-398, Santa Cruz Biotechnology, Santa Cruz, CA, USA), which identifies ALK5-FL and ALK5-ICD, as previously reported, phospho-SMAD2 (CST #3108, Cell Signaling Technology), SMAD2 (CST #3103, Cell Signaling Technology), PAI-1/Serpine1 (NBP1-19773, Novus Biologicals), VHL (VHL40 or VHL-G7, Santa Cruz Biotechnology), VHL (NB100-485, Novus Biologicals), CA9 (ab15086 Abcam, Cambridge, MA, USA), GLUT-1 (PA1-46152, Thermo Fischer Scientific), E-Cadherin (ab76055, Abcam), N-Cadherin (ab18203, Abcam), and beta-actin (A5316, Sigma-Aldrich, St. Louis, MO, USA).	('VHL', 'Gene', (633, 636))	('PAI-1', 'Gene', '5054', (571, 576))	('VHL', 'Gene', (619, 622))	('N-Cadherin', 'Gene', (821, 831))	('N-Cadherin', 'Gene', '1000', (821, 831))	('Serpine1', 'Gene', '5054', (577, 585))	('VHL', 'Gene', '7428', (668, 671))	('PAI-1', 'Gene', (571, 576))	('VHL', 'Gene', (624, 627))	('SMAD2', 'Gene', (479, 484))	('A5316', 'Var', (866, 871))	('San', 'Gene', '80218', (360, 363))	('SMAD2', 'Gene', '4087', (525, 530))	('HIF-2alpha', 'Gene', '2034', (170, 180))	('HIF-1alpha', 'Gene', (107, 117))	('San', 'Gene', (641, 644))	('VHL', 'Gene', '7428', (633, 636))	('beta-actin', 'Gene', (854, 864))	('Cadherin', 'molecular_function', 'GO:0008014', ('794', '802'))	('VHL', 'Gene', '7428', (619, 622))	('VHL-G7', 'Gene', '7428', (633, 639))	('Serpine1', 'Gene', (577, 585))	('SNAIL1', 'Gene', (224, 230))	('SNAIL1', 'Gene', '6615', (224, 230))	('E-Cadherin', 'Gene', '999', (792, 802))	('TbetaRI', 'Gene', '7046', (327, 334))	('VHL', 'Gene', '7428', (624, 627))	('agitation', 'Phenotype', 'HP:0000713', (58, 67))	('NBP1', 'Gene', (587, 591))	('Cadherin', 'molecular_function', 'GO:0008014', ('823', '831'))	('agitation', 'Disease', 'MESH:D011595', (58, 67))	('agitation', 'Disease', (58, 67))	('GLUT-1', 'Gene', (745, 751))	('SMAD2', 'Gene', (525, 530))	('GLUT-1', 'Gene', '6513', (745, 751))	('San', 'Gene', (386, 389))	('Signaling', 'biological_process', 'GO:0023052', ('548', '557'))	('Signaling', 'biological_process', 'GO:0023052', ('502', '511'))	('CA9', 'Gene', (704, 707))	('San', 'Gene', '80218', (641, 644))	('HIF-2alpha', 'Gene', (170, 180))	('Signaling', 'biological_process', 'GO:0023052', ('244', '253'))	('phospho', 'Chemical', 'MESH:C033601', (471, 478))	('NBP1', 'Gene', '4682', (587, 591))	('CO', 'Chemical', 'MESH:D002245', (160, 162))	('TbetaRI', 'Gene', (327, 334))	('San', 'Gene', '80218', (386, 389))	('VHL', 'Gene', (668, 671))	('beta-actin', 'Gene', '728378', (854, 864))	('CA9', 'Gene', '768', (704, 707))	('E-Cadherin', 'Gene', (792, 802))	('HIF-1alpha', 'Gene', '3091', (107, 117))	('VHL-G7', 'Gene', (633, 639))	('San', 'Gene', (360, 363))	('SMAD2', 'Gene', '4087', (479, 484))	('Signaling', 'biological_process', 'GO:0023052', ('304', '313'))
128260	31339433	Immunoblotting was performed and then probed with either HA (CST #2367) or HIF-1alpha (NB100-134, Novus Biologicals) or HIF-2alpha (NB100-132, Novus Biologicals) or ALK5 (V22) antibody.	('antibody', 'cellular_component', 'GO:0042571', ('176', '184'))	('HIF-1alpha', 'Gene', '3091', (75, 85))	('antibody', 'cellular_component', 'GO:0019815', ('176', '184'))	('HIF-2alpha', 'Gene', (120, 130))	('HIF-1alpha', 'Gene', (75, 85))	('CST #2367', 'Var', (61, 70))	('antibody', 'cellular_component', 'GO:0019814', ('176', '184'))	('antibody', 'molecular_function', 'GO:0003823', ('176', '184'))	('NB100-134', 'Var', (87, 96))	('HIF-2alpha', 'Gene', '2034', (120, 130))
128269	31339433	The following primary antibodies were used: HIF-1alpha (NB100-134, Novus Biologicals), HIF-2alpha (NB100-132, Novus Biologicals), HA (CST #3724, Cell Signaling Technology) and HA (CST #2367, Cell Signaling Technology).	('NB100-132', 'Var', (99, 108))	('HIF-2alpha', 'Gene', (87, 97))	('HIF-1alpha', 'Gene', '3091', (44, 54))	('Signaling', 'biological_process', 'GO:0023052', ('150', '159'))	('HIF-2alpha', 'Gene', '2034', (87, 97))	('Signaling', 'biological_process', 'GO:0023052', ('196', '205'))	('HIF-1alpha', 'Gene', (44, 54))	('NB100-134', 'Var', (56, 65))
128274	31339433	Cells were stimulated with TGF-beta1 (10 ng/ml) and, untreated cells served as control.	('TGF-beta1', 'Gene', (27, 36))	('10 ng/ml', 'Var', (38, 46))	('TGF-beta1', 'Gene', '7040', (27, 36))
128305	31339433	In ACHN (VHL+/+) cells, knockdown of VHL by siRNA, together with overexpression of ALK5-HA, followed by TGF-beta treatment; showed a significant increase in the protein expression of HIF-1alpha, HIF-2alpha, GLUT-1, CA9 and SNAIL1 when compared with cells transfected with ALK5-HA and treated with TGF-beta, or cells transfected with pcDNA control and siRNA control (Figure 2(a)).	('VHL', 'Gene', '7428', (9, 12))	('ALK5-HA', 'Gene', (83, 90))	('CA9', 'Gene', (215, 218))	('HIF-2alpha', 'Gene', (195, 205))	('ACHN', 'Gene', (3, 7))	('TGF-beta', 'Gene', '7039', (297, 305))	('VHL', 'Gene', (37, 40))	('GLUT-1', 'Gene', '6513', (207, 213))	('ALK5-HA', 'Gene', (272, 279))	('GLUT-1', 'Gene', (207, 213))	('TGF-beta', 'Gene', '7039', (104, 112))	('SNAIL1', 'Gene', (223, 229))	('TGF-beta', 'Gene', (297, 305))	('SNAIL1', 'Gene', '6615', (223, 229))	('HIF-1alpha', 'Gene', '3091', (183, 193))	('CA9', 'Gene', '768', (215, 218))	('ALK5-HA', 'Gene', '7046', (83, 90))	('TGF-beta', 'Gene', (104, 112))	('protein expression', 'MPA', (161, 179))	('VHL', 'Gene', '7428', (37, 40))	('ACHN', 'Gene', '55323', (3, 7))	('knockdown', 'Var', (24, 33))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))	('ALK5-HA', 'Gene', '7046', (272, 279))	('HIF-2alpha', 'Gene', '2034', (195, 205))	('VHL', 'Gene', (9, 12))	('HIF-1alpha', 'Gene', (183, 193))	('increase', 'PosReg', (145, 153))
128316	31339433	Taken together, these results indicated that ALK5-FL induced HIF-1alpha, HIF-2alpha, GLUT-1, CA9, and SNAIL1 proteins through its kinase activity (Figure 2(d)).	('HIF-1alpha', 'Gene', '3091', (61, 71))	('HIF-2alpha', 'Gene', (73, 83))	('ALK5-FL', 'Var', (45, 52))	('HIF-2alpha', 'Gene', '2034', (73, 83))	('kinase activity', 'MPA', (130, 145))	('CA9', 'Gene', (93, 96))	('HIF-1alpha', 'Gene', (61, 71))	('SNAIL1', 'Gene', (102, 108))	('proteins', 'Protein', (109, 117))	('GLUT-1', 'Gene', '6513', (85, 91))	('SNAIL1', 'Gene', '6615', (102, 108))	('CA9', 'Gene', '768', (93, 96))	('GLUT-1', 'Gene', (85, 91))	('kinase activity', 'molecular_function', 'GO:0016301', ('130', '145'))
128363	31339433	Another study with a larger cohort showed that cytoplasmic and nuclear SNAIL1 was not associated with tumor stage and tumor size, results are in line with our findings.	('SNAIL1', 'Gene', (71, 77))	('SNAIL1', 'Gene', '6615', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('cytoplasmic', 'Var', (47, 58))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
128376	31339433	We recently showed that ALK5 overexpression in RCC cell lines leads to enhanced activation of TGF-beta signaling, and ALK5-ICD is correlated with poor prognosis and localized in the nucleus, independent of VHL status and plays a major role in tumor progression.	('VHL status', 'Disease', (206, 216))	('overexpression', 'PosReg', (29, 43))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('VHL status', 'Disease', 'MESH:D006623', (206, 216))	('TGF-beta', 'Gene', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('signaling', 'biological_process', 'GO:0023052', ('103', '112'))	('ALK5-ICD', 'Var', (118, 126))	('RCC', 'Disease', (47, 50))	('RCC', 'Disease', 'MESH:D002292', (47, 50))	('TGF-beta', 'Gene', '7039', (94, 102))	('ALK5', 'Gene', (24, 28))	('nucleus', 'cellular_component', 'GO:0005634', ('182', '189'))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('enhanced activation', 'PosReg', (71, 90))	('tumor', 'Disease', (243, 248))
128379	31339433	We observed that ALK5 activated the TGF-beta pathway and increased the expression of PAI-1 and SNAIL1; ALK5 also increased the expression of HIF-1alpha and HIF-2alpha in a VHL dependent manner (Figure 2).	('expression', 'MPA', (71, 81))	('expression', 'MPA', (127, 137))	('PAI-1', 'Gene', (85, 90))	('HIF-2alpha', 'Gene', (156, 166))	('HIF-1alpha', 'Gene', (141, 151))	('SNAIL1', 'Gene', (95, 101))	('SNAIL1', 'Gene', '6615', (95, 101))	('ALK5', 'Var', (103, 107))	('TGF-beta', 'Gene', (36, 44))	('PAI-1', 'Gene', '5054', (85, 90))	('HIF-2alpha', 'Gene', '2034', (156, 166))	('increased', 'PosReg', (57, 66))	('increased', 'PosReg', (113, 122))	('VHL', 'Gene', (172, 175))	('TGF-beta', 'Gene', '7039', (36, 44))	('HIF-1alpha', 'Gene', '3091', (141, 151))	('VHL', 'Gene', '7428', (172, 175))
128384	31339433	Apart from activating hypoxia and its's targets, ALK5 overexpression also imparted an enhanced invasive ability to both cell lines and reduced the expression of E-cadherin (Supplementary Figure 6).	('hypoxia', 'Disease', 'MESH:D000860', (22, 29))	('hypoxia', 'Disease', (22, 29))	('expression', 'MPA', (147, 157))	('invasive ability', 'CPA', (95, 111))	('enhanced', 'PosReg', (86, 94))	('reduced', 'NegReg', (135, 142))	('E-cadherin', 'Gene', (161, 171))	('E-cadherin', 'Gene', '999', (161, 171))	('overexpression', 'Var', (54, 68))	('ALK5', 'Gene', (49, 53))	('cadherin', 'molecular_function', 'GO:0008014', ('163', '171'))
128391	31339433	Notably, the tumor-promoting effects exerted by ALK5-ICD are independent of VHL status in ccRCC.	('tumor', 'Disease', (13, 18))	('VHL status', 'Disease', (76, 86))	('VHL status', 'Disease', 'MESH:D006623', (76, 86))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('ALK5-ICD', 'Var', (48, 56))	('RCC', 'Disease', 'MESH:D002292', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
128397	27741516	Moreover, SENP1 knockdown in RCC4/VHL cells downregulated expression of key glycolytic enzymes under normoxic and hypoxic conditions and inhibited cell proliferation under hypoxic conditions, possibly due to ineffective deSUMOylation and stablization of Hif-1alpha related to the SENP-1 deficiency.	('downregulated', 'NegReg', (44, 57))	('hypoxic conditions', 'Disease', (172, 190))	('expression', 'MPA', (58, 68))	('cell proliferation', 'CPA', (147, 165))	('RCC4', 'Gene', '84925', (29, 33))	('SENP1', 'Gene', '29843', (10, 15))	('Hif-1alpha', 'Gene', '3091', (254, 264))	('deSUMOylation', 'biological_process', 'GO:0016926', ('220', '233'))	('inhibited', 'NegReg', (137, 146))	('SENP1', 'Gene', (10, 15))	('SENP-1 deficiency', 'Disease', (280, 297))	('hypoxic conditions', 'Disease', (114, 132))	('cell proliferation', 'biological_process', 'GO:0008283', ('147', '165'))	('Hif-1alpha', 'Gene', (254, 264))	('hypoxic conditions', 'Disease', 'MESH:D009135', (172, 190))	('VHL', 'Gene', (34, 37))	('SENP-1 deficiency', 'Disease', 'MESH:C565162', (280, 297))	('knockdown', 'Var', (16, 25))	('RCC4', 'Gene', (29, 33))	('glycolytic', 'Enzyme', (76, 86))	('VHL', 'Gene', '7428', (34, 37))	('hypoxic conditions', 'Disease', 'MESH:D009135', (114, 132))
128403	27741516	Clear cell renal cell carcinoma (ccRCC), the most common form of RCC, is characterized by inactivation of the Von Hippel-Lindau (VHL) tumor suppressor gene and subsequent stabilization of hypoxia-inducible factors (HIF-1alpha and HIF-2alpha), which is in turn promote angiogenesis, cell migration, and increased metabolism.	('cell migration', 'CPA', (282, 296))	('stabilization', 'Var', (171, 184))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('134', '150'))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('metabolism', 'CPA', (312, 322))	('tumor suppressor', 'biological_process', 'GO:0051726', ('134', '150'))	('RCC', 'Disease', (35, 38))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('metabolism', 'biological_process', 'GO:0008152', ('312', '322'))	('RCC', 'Disease', (65, 68))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('promote', 'PosReg', (260, 267))	('HIF-1alpha', 'Gene', '3091', (215, 225))	('Von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (110, 139))	('hypoxia', 'Disease', (188, 195))	('HIF-2alpha', 'Gene', '2034', (230, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('inactivation', 'Var', (90, 102))	('angiogenesis', 'biological_process', 'GO:0001525', ('268', '280'))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('angiogenesis', 'CPA', (268, 280))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('increased', 'PosReg', (302, 311))	('hypoxia', 'Disease', 'MESH:D000860', (188, 195))	('HIF-1alpha', 'Gene', (215, 225))	('cell migration', 'biological_process', 'GO:0016477', ('282', '296'))	('HIF-2alpha', 'Gene', (230, 240))
128404	27741516	The loss or mutation of the VHL gene is found in 60-90% ccRCC cases, prompting the use of agents targeting circulating VEGF and VEGF receptors for ccRCC treatment.	('RCC', 'Disease', (149, 152))	('VEGF', 'Gene', '7422', (119, 123))	('VEGF', 'Gene', (128, 132))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('VEGF', 'Gene', '7422', (128, 132))	('VEGF', 'Gene', (119, 123))	('RCC', 'Disease', (58, 61))	('VHL', 'Gene', (28, 31))	('mutation', 'Var', (12, 20))	('loss', 'NegReg', (4, 8))	('RCC', 'Disease', 'MESH:C538614', (149, 152))	('VHL', 'Gene', '7428', (28, 31))
128406	27741516	Further studies have revealed that ccRCC is a heterogeneous cancer with disparate genetic and molecular alterations beyond VHL mutation, such as mutations in genes encoding chromatin remodeling proteins, like polybromo 1(PBRM1) and SET domain containing 2 (SETD2), both associated with high tumor stage and poor prognosis.	('mutations', 'Var', (145, 154))	('SETD2', 'Gene', (257, 262))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('high tumor', 'Disease', 'MESH:D009369', (286, 296))	('VHL', 'Gene', (123, 126))	('chromatin', 'cellular_component', 'GO:0000785', ('173', '182'))	('cancer', 'Disease', (60, 66))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('SETD2', 'Gene', '29072', (257, 262))	('VHL', 'Gene', '7428', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('173', '193'))	('associated', 'Reg', (270, 280))	('PBRM1', 'Gene', (221, 226))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('PBRM1', 'Gene', '55193', (221, 226))	('high tumor', 'Disease', (286, 296))
128408	27741516	Accumulation of epigenetic modifications has emerged as a key mechanism regulating ccRCC tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('formation', 'biological_process', 'GO:0009058', ('95', '104'))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', (85, 88))	('epigenetic modifications', 'Var', (16, 40))	('tumor', 'Disease', (89, 94))
128409	27741516	One report showed that patients with SUMOylation-defective MITF germline mutation are predisposed to melanoma and RCC through activation of HIF-1alpha.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('predisposed', 'Reg', (86, 97))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('patients', 'Species', '9606', (23, 31))	('germline mutation', 'Var', (64, 81))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('HIF-1alpha', 'Gene', '3091', (140, 150))	('MITF', 'Gene', '4286', (59, 63))	('MITF', 'Gene', (59, 63))	('activation', 'PosReg', (126, 136))	('SUMOylation-defective', 'MPA', (37, 58))	('SUMOylation', 'biological_process', 'GO:0016925', ('37', '48'))	('HIF-1alpha', 'Gene', (140, 150))
128415	27741516	The SUMOylation of HIF-1alpha serves as a signal for its ubiquitin-dependent degradation; SUMOylated HIF-1alpha binds to VHL, an E3 ligase for HIF-1alpha ubiquitination, and is degraded even under hypoxic conditions.	('VHL', 'Gene', '7428', (121, 124))	('HIF-1alpha', 'Gene', (143, 153))	('HIF-1alpha ubiquitination', 'Disease', 'MESH:C563003', (143, 168))	('degradation', 'biological_process', 'GO:0009056', ('77', '88'))	('HIF-1alpha', 'Gene', '3091', (19, 29))	('ubiquitin', 'molecular_function', 'GO:0031386', ('57', '66'))	('SUMOylation', 'biological_process', 'GO:0016925', ('4', '15'))	('HIF-1alpha', 'Gene', (101, 111))	('HIF-1alpha', 'Gene', '3091', (143, 153))	('degraded', 'MPA', (177, 185))	('HIF-1alpha ubiquitination', 'Disease', (143, 168))	('binds', 'Interaction', (112, 117))	('hypoxic conditions', 'Disease', (197, 215))	('hypoxic conditions', 'Disease', 'MESH:D009135', (197, 215))	('VHL', 'Gene', (121, 124))	('SUMOylated', 'Var', (90, 100))	('HIF-1alpha', 'Gene', '3091', (101, 111))	('HIF-1alpha', 'Gene', (19, 29))
128427	27741516	By target metabolite examination, we found that the levels of lactate and pyruvate were significantly higher in tumor from the SENP1 high-expression group than in the SENP1 low-expression group (P < 0.01, Table 2), suggesting a potential positive correlation between SENP expression level and glycolysis in ccRCC tumors.	('tumor', 'Disease', (313, 318))	('glycolysis', 'biological_process', 'GO:0006096', ('293', '303'))	('ccRCC tumors', 'Disease', 'MESH:D009369', (307, 319))	('high-expression', 'Var', (133, 148))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('lactate', 'Chemical', 'MESH:D019344', (62, 69))	('pyruvate', 'Chemical', 'MESH:D019289', (74, 82))	('glycolysis', 'MPA', (293, 303))	('higher', 'PosReg', (102, 108))	('SENP1', 'Gene', '29843', (167, 172))	('tumor', 'Disease', (112, 117))	('positive', 'PosReg', (238, 246))	('levels', 'MPA', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('SENP1', 'Gene', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (313, 319))	('SENP1', 'Gene', '29843', (127, 132))	('SENP1', 'Gene', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('ccRCC tumors', 'Disease', (307, 319))
128433	27741516	As expected, SENP1 knockdown noticeably decreased the expression levels of the majority of those hypoxia response genes, compared to control RCC4/VHL cells transfected with non-specific target shRNA.	('hypoxia', 'Disease', (97, 104))	('hypoxia', 'Disease', 'MESH:D000860', (97, 104))	('VHL', 'Gene', (146, 149))	('VHL', 'Gene', '7428', (146, 149))	('knockdown', 'Var', (19, 28))	('SENP1', 'Gene', (13, 18))	('RCC4', 'Gene', (141, 145))	('RCC4', 'Gene', '84925', (141, 145))	('expression levels', 'MPA', (54, 71))	('decreased', 'NegReg', (40, 49))	('SENP1', 'Gene', '29843', (13, 18))
128439	27741516	Consistent with our speculation, knockdown of SENP1 in RCC4/VHL cells significantly reduced cell proliferation under hypoxic conditions (Figure 2C).	('cell proliferation under', 'CPA', (92, 116))	('SENP1', 'Gene', '29843', (46, 51))	('knockdown', 'Var', (33, 42))	('VHL', 'Gene', (60, 63))	('RCC4', 'Gene', (55, 59))	('RCC4', 'Gene', '84925', (55, 59))	('hypoxic conditions', 'Disease', (117, 135))	('VHL', 'Gene', '7428', (60, 63))	('reduced', 'NegReg', (84, 91))	('cell proliferation', 'biological_process', 'GO:0008283', ('92', '110'))	('hypoxic conditions', 'Disease', 'MESH:D009135', (117, 135))	('SENP1', 'Gene', (46, 51))
128448	27741516	To further demonstrate the involvement of the SENP1/HIF-1alpha axis in the regulation of glycolysis, we transfected wildtype or SUMOylation site mutant HIF-1alpha into SENP1 stable knockdown RCC4/VHL cells, and then, measured the expression levels of some downstream genes of HIF-1alpha, which encode glycolytic enzymes, including PGK1, PFK1, ENO1, ALDOA, CA9, LDHA, and HK2.	('mutant', 'Var', (145, 151))	('glycolysis', 'biological_process', 'GO:0006096', ('89', '99'))	('HIF-1alpha', 'Gene', (276, 286))	('VHL', 'Gene', (196, 199))	('HIF-1alpha', 'Gene', (52, 62))	('SUMOylation', 'biological_process', 'GO:0016925', ('128', '139'))	('PFK1', 'Gene', (337, 341))	('RCC4', 'Gene', (191, 195))	('ENO1', 'Gene', (343, 347))	('LDHA', 'Gene', '3939', (361, 365))	('SENP1', 'Gene', '29843', (168, 173))	('VHL', 'Gene', '7428', (196, 199))	('HIF-1alpha', 'Gene', '3091', (152, 162))	('CA9', 'Gene', (356, 359))	('SENP1', 'Gene', '29843', (46, 51))	('PGK1', 'Gene', '5230', (331, 335))	('SENP1', 'Gene', (168, 173))	('ALDOA', 'Gene', (349, 354))	('RCC4', 'Gene', '84925', (191, 195))	('ENO1', 'Gene', '2023', (343, 347))	('HK2', 'Gene', (371, 374))	('PFK1', 'Gene', '5213', (337, 341))	('HK2', 'Gene', '3099', (371, 374))	('regulation', 'biological_process', 'GO:0065007', ('75', '85'))	('HIF-1alpha axis', 'Disease', 'MESH:C566610', (52, 67))	('SENP1', 'Gene', (46, 51))	('HIF-1alpha axis', 'Disease', (52, 67))	('ALDOA', 'Gene', '226', (349, 354))	('HIF-1alpha', 'Gene', '3091', (276, 286))	('PGK1', 'Gene', (331, 335))	('CA9', 'Gene', '768', (356, 359))	('HK2', 'molecular_function', 'GO:0008256', ('371', '374'))	('HIF-1alpha', 'Gene', (152, 162))	('PGK', 'molecular_function', 'GO:0004618', ('331', '334'))	('LDHA', 'Gene', (361, 365))	('HIF-1alpha', 'Gene', '3091', (52, 62))	('PFK', 'molecular_function', 'GO:0003872', ('337', '340'))
128449	27741516	As shown in Figure 3D, the mRNA levels of the metabolic genes were elevated in HIF-1alpha DM (SUMOylation site mutant) transfected cells compared to wildtype HIF-1alpha, indicating deSUMOylation of HIF-1alpha is a crucial step in regulating glycolysis by SENP1.	('glycolysis', 'biological_process', 'GO:0006096', ('241', '251'))	('SENP1', 'Gene', '29843', (255, 260))	('HIF-1alpha', 'Gene', '3091', (198, 208))	('elevated', 'PosReg', (67, 75))	('HIF-1alpha', 'Gene', '3091', (79, 89))	('HIF-1alpha', 'Gene', (198, 208))	('HIF-1alpha DM', 'Disease', 'MESH:D009223', (79, 92))	('HIF-1alpha', 'Gene', '3091', (158, 168))	('deSUMOylation', 'biological_process', 'GO:0016926', ('181', '194'))	('HIF-1alpha', 'Gene', (79, 89))	('SENP1', 'Gene', (255, 260))	('SUMOylation', 'biological_process', 'GO:0016925', ('94', '105'))	('HIF-1alpha DM', 'Disease', (79, 92))	('transfected', 'Var', (119, 130))	('mRNA levels of the metabolic genes', 'MPA', (27, 61))	('HIF-1alpha', 'Gene', (158, 168))
128456	27741516	Moreover, patients with high SENP1 expression level had shorter overall survival than patients with low SENP1 expression (mean, 108.9 versus 80.7 months, P = 0.023, Table 4, Figure 4C).	('SENP1', 'Gene', '29843', (104, 109))	('patients', 'Species', '9606', (86, 94))	('SENP1', 'Gene', '29843', (29, 34))	('shorter', 'NegReg', (56, 63))	('overall survival', 'MPA', (64, 80))	('high', 'Var', (24, 28))	('patients', 'Species', '9606', (10, 18))	('SENP1', 'Gene', (104, 109))	('SENP1', 'Gene', (29, 34))
128458	27741516	Collectively, the data suggest that high expression of SENP1 might be a prognostic indicator of worse clinical outcome in ccRCC.	('RCC', 'Disease', (124, 127))	('high expression', 'Var', (36, 51))	('SENP1', 'Gene', '29843', (55, 60))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('SENP1', 'Gene', (55, 60))
128459	27741516	As almost all of the inherited renal cancer syndromes caused by germline mutations identified to date exhibit disorders in oxygen, iron, nutrient, or energy sensing, RCC has been viewed as a metabolic disease.	('nutrient', 'MPA', (137, 145))	('metabolic disease', 'Disease', 'MESH:D008659', (191, 208))	('inherited renal cancer syndromes', 'Disease', (21, 53))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('RCC', 'Disease', (166, 169))	('oxygen', 'Chemical', 'MESH:D010100', (123, 129))	('germline mutations', 'Var', (64, 82))	('energy sensing', 'MPA', (150, 164))	('renal cancer', 'Phenotype', 'HP:0009726', (31, 43))	('iron', 'Chemical', 'MESH:D007501', (131, 135))	('iron', 'MPA', (131, 135))	('oxygen', 'MPA', (123, 129))	('caused', 'Reg', (54, 60))	('disorders', 'Reg', (110, 119))	('inherited renal cancer syndromes', 'Disease', 'MESH:D007680', (21, 53))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('metabolic disease', 'Disease', (191, 208))
128464	27741516	Here, consistent with our speculation, integrated gene expression and metabolomic analyses of 36 matched pairs of ccRCC tumor and adjacent normal tissues revealed that patients with high SENP1 expression level also exhibit enhanced glycolysis, illustrated by elevated levels of lactate and pyruvate.	('pyruvate', 'Chemical', 'MESH:D019289', (290, 298))	('elevated', 'PosReg', (259, 267))	('glycolysis', 'MPA', (232, 242))	('enhanced', 'PosReg', (223, 231))	('SENP1', 'Gene', '29843', (187, 192))	('glycolysis', 'biological_process', 'GO:0006096', ('232', '242'))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('elevated levels of lactate', 'Phenotype', 'HP:0002151', (259, 285))	('high', 'Var', (182, 186))	('lactate', 'Chemical', 'MESH:D019344', (278, 285))	('patients', 'Species', '9606', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('gene expression', 'biological_process', 'GO:0010467', ('50', '65'))	('expression', 'MPA', (193, 203))	('RCC', 'Disease', (116, 119))	('SENP1', 'Gene', (187, 192))	('tumor', 'Disease', (120, 125))
128467	27741516	As the hydroxylated proline residues in HIF alpha subunits are recognized by pVHL and targeted for proteosomal degradation, inhibition of PHD by these TCA cycle metabolites will stabilize HIF alpha subunits and lead to pseudo-hypoxia in tumor, and thereafter, promote tumor formation and development.	('development', 'CPA', (288, 299))	('hypoxia in tumor', 'Disease', 'MESH:D000860', (226, 242))	('PHD', 'molecular_function', 'GO:0050175', ('138', '141'))	('TCA cycle', 'biological_process', 'GO:0006099', ('151', '160'))	('PHD', 'Disease', (138, 141))	('hypoxia in tumor', 'Disease', (226, 242))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('lead to', 'Reg', (211, 218))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('proline', 'Chemical', 'MESH:D011392', (20, 27))	('PHD', 'Disease', 'MESH:D011547', (138, 141))	('degradation', 'biological_process', 'GO:0009056', ('111', '122'))	('pVHL', 'Gene', '7428', (77, 81))	('pVHL', 'Gene', (77, 81))	('promote', 'PosReg', (260, 267))	('TCA', 'Chemical', 'MESH:D014233', (151, 154))	('formation', 'biological_process', 'GO:0009058', ('274', '283'))	('tumor', 'Disease', (237, 242))	('tumor', 'Disease', (268, 273))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('inhibition', 'Var', (124, 134))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
128471	27741516	Furthermore, SENP1 knockdown in RCC4/VHL cells noticeably reduced levels of key glycolytic enzymes under both normoxic and hypoxic conditions, providing evidence for SENP1 upregulation of glycolysis in ccRCC.	('RCC', 'Disease', (204, 207))	('SENP1', 'Gene', (13, 18))	('hypoxic conditions', 'Disease', (123, 141))	('VHL', 'Gene', (37, 40))	('knockdown', 'Var', (19, 28))	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('RCC4', 'Gene', (32, 36))	('SENP1', 'Gene', '29843', (166, 171))	('levels of key glycolytic enzymes', 'MPA', (66, 98))	('RCC', 'Disease', (32, 35))	('VHL', 'Gene', '7428', (37, 40))	('RCC4', 'Gene', '84925', (32, 36))	('upregulation of glycolysis', 'biological_process', 'GO:0045821', ('172', '198'))	('SENP1', 'Gene', (166, 171))	('upregulation', 'PosReg', (172, 184))	('hypoxic conditions', 'Disease', 'MESH:D009135', (123, 141))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('reduced', 'NegReg', (58, 65))	('SENP1', 'Gene', '29843', (13, 18))
128477	27741516	Furthermore, when the SUMOylation sites of HIF-1alpha (K391 and K477) were mutated, overexpression of this mutant HIF-1alpha in SENP1-knockdown RCC4/VHL cells increased the expression levels of key glycolytic enzymes compared to wild-type HIF-1alpha, suggesting deSUMOylating of HIF-1alpha is an important step for SENP1 regulation of glycolysis.	('overexpression', 'PosReg', (84, 98))	('SENP1', 'Gene', (315, 320))	('glycolysis', 'biological_process', 'GO:0006096', ('335', '345'))	('HIF-1alpha', 'Gene', '3091', (114, 124))	('SUMOylation', 'biological_process', 'GO:0016925', ('22', '33'))	('VHL', 'Gene', '7428', (149, 152))	('HIF-1alpha', 'Gene', (43, 53))	('mutated', 'Var', (75, 82))	('expression levels', 'MPA', (173, 190))	('HIF-1alpha', 'Gene', '3091', (279, 289))	('regulation', 'biological_process', 'GO:0065007', ('321', '331'))	('RCC4', 'Gene', (144, 148))	('HIF-1alpha', 'Gene', '3091', (239, 249))	('SENP1', 'Gene', '29843', (128, 133))	('HIF-1alpha', 'Gene', (114, 124))	('SENP1', 'Gene', (128, 133))	('mutant', 'Var', (107, 113))	('RCC4', 'Gene', '84925', (144, 148))	('HIF-1alpha', 'Gene', (279, 289))	('K477', 'Var', (64, 68))	('increased', 'PosReg', (159, 168))	('K391', 'Var', (55, 59))	('HIF-1alpha', 'Gene', (239, 249))	('SENP1', 'Gene', '29843', (315, 320))	('VHL', 'Gene', (149, 152))	('HIF-1alpha', 'Gene', '3091', (43, 53))
128483	27741516	One report showed that SUMOylation-defective MITF germline mutation predisposes carriers to melanoma and renal carcinoma, but, so far, there is no report on a clear role of SENP1 in renal cell carcinoma.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (182, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('germline mutation', 'Var', (50, 67))	('melanoma and renal carcinoma', 'Disease', 'OMIM:614456', (92, 120))	('SUMOylation', 'biological_process', 'GO:0016925', ('23', '34'))	('SENP1', 'Gene', '29843', (173, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('MITF', 'Gene', (45, 49))	('predisposes', 'Reg', (68, 79))	('SUMOylation-defective', 'MPA', (23, 44))	('renal carcinoma', 'Phenotype', 'HP:0005584', (105, 120))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('MITF', 'Gene', '4286', (45, 49))	('renal cell carcinoma', 'Disease', (182, 202))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (182, 202))	('SENP1', 'Gene', (173, 178))
128484	27741516	In this study, we found knockdown of SENP1 inhibits the proliferation of RCC4/VHL cells under hypoxic conditions, and SENP1 expression is positively associated with tumor grade in ccRCC, suggesting it as a potential biomarker for tumor differentiation and aggressiveness.	('VHL', 'Gene', (78, 81))	('proliferation', 'CPA', (56, 69))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('aggressiveness', 'Disease', (256, 270))	('aggressiveness', 'Phenotype', 'HP:0000718', (256, 270))	('RCC4', 'Gene', (73, 77))	('associated', 'Reg', (149, 159))	('VHL', 'Gene', '7428', (78, 81))	('aggressiveness', 'Disease', 'MESH:D001523', (256, 270))	('hypoxic conditions', 'Disease', 'MESH:D009135', (94, 112))	('tumor', 'Disease', (230, 235))	('RCC', 'Disease', (73, 76))	('RCC4', 'Gene', '84925', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('RCC', 'Disease', (182, 185))	('knockdown', 'Var', (24, 33))	('inhibits', 'NegReg', (43, 51))	('tumor', 'Disease', (165, 170))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('SENP1', 'Gene', '29843', (37, 42))	('SENP1', 'Gene', '29843', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('hypoxic conditions', 'Disease', (94, 112))	('expression', 'MPA', (124, 134))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('SENP1', 'Gene', (37, 42))	('SENP1', 'Gene', (118, 123))
128485	27741516	In addition, we found that patients with high SENP1 expression level have shorter overall survival (OS) and time to progression (TTP) than patients with low SENP1 expression level, and are prone to advanced disease progression.	('shorter', 'NegReg', (74, 81))	('SENP1', 'Gene', (157, 162))	('time', 'MPA', (108, 112))	('advanced disease', 'Disease', 'MESH:D020178', (198, 214))	('SENP1', 'Gene', '29843', (46, 51))	('patients', 'Species', '9606', (139, 147))	('high', 'Var', (41, 45))	('patients', 'Species', '9606', (27, 35))	('overall survival', 'MPA', (82, 98))	('SENP1', 'Gene', '29843', (157, 162))	('SENP1', 'Gene', (46, 51))	('advanced disease', 'Disease', (198, 214))
128487	27741516	VHL is biallelically inactivated via point mutation, deletion, or methylation in most sporadic ccRCC.	('RCC', 'Disease', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('deletion', 'Var', (53, 61))	('methylation', 'biological_process', 'GO:0032259', ('66', '77'))	('methylation', 'Var', (66, 77))	('VHL', 'Gene', (0, 3))	('point mutation', 'Var', (37, 51))	('VHL', 'Gene', '7428', (0, 3))
128488	27741516	The reported incidence of somatic VHL mutations in sporadic ccRCC varies up to 91%.	('VHL', 'Gene', '7428', (34, 37))	('VHL', 'Gene', (34, 37))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('mutations', 'Var', (38, 47))
128489	27741516	However, some mutant VHL variants do not affect stabilization of HIF alpha.	('stabilization', 'MPA', (48, 61))	('variants', 'Var', (25, 33))	('VHL', 'Gene', '7428', (21, 24))	('VHL', 'Gene', (21, 24))
128490	27741516	Previous studies suggest that inactivation of the VHL gene is an early step in the development of ccRCC, that most VHL-negative ccRCCs never metastasize, and that VHL mutation status does not provide useful prognostic information for patients with ccRCC as yet.	('VHL', 'Gene', (115, 118))	('VHL', 'Gene', (163, 166))	('VHL', 'Gene', '7428', (163, 166))	('VHL', 'Gene', (50, 53))	('inactivation', 'Var', (30, 42))	('VHL', 'Gene', '7428', (115, 118))	('VHL', 'Gene', '7428', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (250, 253))	('RCC', 'Disease', (250, 253))	('patients', 'Species', '9606', (234, 242))	('RCC', 'Disease', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))
128512	27741516	To explore the function of HIF-1alpha in SENP1 mediated glycolysis, wild type or SUMO dysfunctional HIF-1alpha mutant (K391R and K477R) was transfected into the stable SENP1 knockdown RCC4/VHL cells with lipofectamine 2000.	('glycolysis', 'biological_process', 'GO:0006096', ('56', '66'))	('HIF-1alpha', 'Gene', '3091', (27, 37))	('K391R', 'Var', (119, 124))	('VHL', 'Gene', (189, 192))	('dysfunctional HIF-1alpha', 'Disease', 'MESH:D006331', (86, 110))	('HIF-1alpha', 'Gene', (100, 110))	('RCC4', 'Gene', (184, 188))	('SENP1', 'Gene', '29843', (168, 173))	('VHL', 'Gene', '7428', (189, 192))	('SENP1', 'Gene', '29843', (41, 46))	('HIF-1alpha', 'Gene', (27, 37))	('SENP1', 'Gene', (168, 173))	('SENP1', 'Gene', (41, 46))	('dysfunctional HIF-1alpha', 'Disease', (86, 110))	('lipofectamine 2000', 'Chemical', 'MESH:C086724', (204, 222))	('RCC4', 'Gene', '84925', (184, 188))	('K477R', 'Mutation', 'p.K477R', (129, 134))	('K477R', 'Var', (129, 134))	('HIF-1alpha', 'Gene', '3091', (100, 110))	('K391R', 'Mutation', 'p.K391R', (119, 124))
128519	27741516	Western blots were performed using 20~50 mug of lysate protein, and membranes were incubated with antibodies against HIF-1alpha (1:500; NB 100-105, Novus, CO, USA) or HIF-2alpha (1:1000; NB 100-132, Novus, CO, USA).	('1:500; NB 100-105', 'Var', (129, 146))	('mug', 'molecular_function', 'GO:0043739', ('41', '44'))	('1:1000; NB 100-132', 'Var', (179, 197))	('HIF-2alpha', 'Gene', (167, 177))	('HIF-1alpha', 'Gene', '3091', (117, 127))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('HIF-2alpha', 'Gene', '2034', (167, 177))	('HIF-1alpha', 'Gene', (117, 127))
128526	27741516	RCC4/VHL cells with or without SENP1 knockdown were plated into 12 well plates (5 x 104 cells/well) in DMEM medium supplemented with 10% FBS, the medium was changed every two days.	('RCC4', 'Gene', (0, 4))	('SENP1', 'Gene', '29843', (31, 36))	('FBS', 'Disease', 'MESH:D005198', (137, 140))	('RCC4', 'Gene', '84925', (0, 4))	('VHL', 'Gene', (5, 8))	('knockdown', 'Var', (37, 46))	('DMEM medium', 'Chemical', '-', (103, 114))	('VHL', 'Gene', '7428', (5, 8))	('SENP1', 'Gene', (31, 36))	('FBS', 'Disease', (137, 140))
128535	31528228	Conclusion: We are the first to demonstrate that LND at CN is associated with poor CSS and OS in metastatic patients with ccRCC and non-ccRCC.	('RCC', 'Disease', (124, 127))	('RCC', 'Disease', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('CSS', 'Chemical', '-', (83, 86))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('poor', 'NegReg', (78, 82))	('OS', 'Chemical', '-', (91, 93))	('patients', 'Species', '9606', (108, 116))	('LND at CN', 'Var', (49, 58))
128545	31528228	Based on this consideration, we evaluated whether LND at cytoreductive nephrectomy in mRCC patients might be associated with oncologic outcomes, compared with no LND.	('associated', 'Reg', (109, 119))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('patients', 'Species', '9606', (91, 99))	('RCC', 'Disease', (87, 90))	('LND', 'Var', (50, 53))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
128555	31528228	Based on International Classification of Diseases for oncology, 3rd Edition (ICD-O-3), clear cell RCC (ccRCC) (8310, 8320 and 8316) was distinguished from non-ccRCC.	('8310', 'Var', (111, 115))	('oncology', 'Phenotype', 'HP:0002664', (54, 62))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('RCC', 'Disease', (161, 164))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('RCC', 'Disease', 'MESH:C538614', (161, 164))
128601	31528228	To the best of our knowledge, we are the first to demonstrate that LND at cytoreductive nephrectomy was associated with lower CSS and OS relative to non-LND in metastatic patients with ccRCC and non-ccRCC.	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('lower', 'NegReg', (120, 125))	('RCC', 'Disease', (201, 204))	('LND', 'Var', (67, 70))	('RCC', 'Disease', (187, 190))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('RCC', 'Phenotype', 'HP:0005584', (187, 190))	('RCC', 'Disease', 'MESH:C538614', (187, 190))	('patients', 'Species', '9606', (171, 179))	('CSS', 'MPA', (126, 129))	('OS', 'Chemical', '-', (134, 136))	('CSS', 'Chemical', '-', (126, 129))
128641	32217761	Cell suspensions were stained with fluorochrome-labeled antibodies specific for human CD3 (344 818 Biolegend), CD8 (301 006 Biolegend), PD1 (560 795 BD), CTLA4 (369610, Biolegend), TIM3 (345032, Biolegend) and TIGIT (372710, Biolegend).	('301', 'Var', (116, 119))	('372710', 'Var', (217, 223))	('TIGIT', 'Gene', (210, 215))	('CD8', 'Gene', (111, 114))	('human', 'Species', '9606', (80, 85))	('369610', 'Var', (161, 167))	('345032', 'Var', (187, 193))	('CD8', 'Gene', '925', (111, 114))	('560 795 BD', 'Var', (141, 151))	('TIM3', 'Gene', (181, 185))	('TIGIT', 'Gene', '201633', (210, 215))	('TIM3', 'Gene', '84868', (181, 185))
128659	32217761	TMEcluster-B cases had higher risk of overall mortality compared with TMEcluster-A (p<0.001; HR 2.629, 95% CI: 1.630 to 4.241) (figure 1F).	('mortality', 'Disease', (46, 55))	('mortality', 'Disease', 'MESH:D003643', (46, 55))	('TMEcluster-B', 'Var', (0, 12))
128664	32217761	Immune deconvolution analysis via ssGSEA showed TMEcluster-B had higher immune suppression (p<0.001) score (figure 2F).	('immune suppression', 'CPA', (72, 90))	('higher', 'PosReg', (65, 71))	('TMEcluster-B', 'Var', (48, 60))	('GSEA', 'Chemical', '-', (36, 40))
128670	32217761	Somatic SETD2 mutations were more frequent in TMEcluster-B with borderline statistical significance (p=0.054) (figure 3A).	('SETD2', 'Gene', (8, 13))	('TMEcluster-B', 'Disease', (46, 58))	('frequent', 'Reg', (34, 42))	('mutations', 'Var', (14, 23))	('SETD2', 'Gene', '29072', (8, 13))
128673	32217761	TMEcluster-B had lower overall tumor mutation burden compared with TMEcluster-A (p=0.008) (figure 3A), in accordance with a previous study showing that most immune signatures were upregulated in low-TMB subtype in ccRCC.	('upregulated', 'PosReg', (180, 191))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('TMB', 'Chemical', '-', (199, 202))	('lower', 'NegReg', (17, 22))	('tumor', 'Disease', (31, 36))	('low-TMB', 'Var', (195, 202))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('RCC', 'Disease', (216, 219))	('RCC', 'Phenotype', 'HP:0005584', (216, 219))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (214, 219))
128679	32217761	We further explored the correlation in Zhongshan metastatic ccRCC validation cohort and found that TMEcluster-B had significant worse treatment response compared with TMEcluster-A (p=0.009) (figure 4A).	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('treatment response', 'CPA', (134, 152))	('worse', 'NegReg', (128, 133))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('TMEcluster-B', 'Var', (99, 111))
128697	32217761	A high number of tumor mutations are expected to drive tumor immune-infiltration.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('mutations', 'Var', (23, 32))	('drive', 'PosReg', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
128698	32217761	However, we found higher TMB in the more immune-infiltrated subtype, TMEcluster-B, in accordance with a previous study showing that most immune signatures were upregulated in low-TMB subtype in ccRCC, which is different from other immunotherapy responsive solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('RCC', 'Phenotype', 'HP:0005584', (196, 199))	('TMB', 'Chemical', '-', (25, 28))	('TMB', 'Chemical', '-', (179, 182))	('upregulated', 'PosReg', (160, 171))	('tumors', 'Disease', (262, 268))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('low-TMB', 'Var', (175, 182))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('RCC', 'Disease', 'MESH:C538614', (196, 199))	('TMB', 'MPA', (25, 28))	('RCC', 'Disease', (196, 199))	('higher', 'PosReg', (18, 24))	('ccRCC', 'Phenotype', 'HP:0006770', (194, 199))	('immune signatures', 'MPA', (137, 154))
128728	32668608	Although metastases and primary tumors share standard histological features, this study highlighted chromosomal differences specific to metastases, which could be involved in ccRCC metastatic evolution.	('metastases', 'Disease', (9, 19))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('RCC', 'Disease', (177, 180))	('tumors', 'Disease', (32, 38))	('metastases', 'Disease', 'MESH:D009362', (9, 19))	('chromosomal differences', 'Var', (100, 123))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('metastases', 'Disease', (136, 146))	('involved', 'Reg', (163, 171))	('metastases', 'Disease', 'MESH:D009362', (136, 146))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
128739	32668608	Its mutations and deletion within primary tumors have been associated with an increased risk of metastasis, and new targeting of PTEN may prevent metastasis.	('metastasis', 'CPA', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('PTEN', 'Gene', (129, 133))	('associated', 'Reg', (59, 69))	('PTEN', 'Gene', '5728', (129, 133))	('mutations', 'Var', (4, 13))	('deletion', 'Var', (18, 26))
128745	32668608	Endothelin receptor type B, phos-S6 and CD44 are variously expressed in primary ccRCCs and their metastases and have effect on clinical outcome.	('effect', 'Reg', (117, 123))	('CD44', 'Gene', (40, 44))	('Endothelin receptor type B', 'Gene', '1910', (0, 26))	('metastases', 'Disease', (97, 107))	('Endothelin receptor type B', 'Gene', (0, 26))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('metastases', 'Disease', 'MESH:D009362', (97, 107))	('phos-S6', 'Var', (28, 35))	('CD44', 'Gene', '960', (40, 44))
128768	32668608	The membrane was incubated in a 1:2500 dilution of monoclonal mouse anti-human phospho-PTEN (Ser380), AKT (pan), phospho -AKT (T308), phospho-GSK-3-beta (Ser9), phospho-PDK1 (Ser241), phospho-c-Raf (Ser259), m-TOR, phospho-mTOR (Ser2448), phospho-p70 S6 (Ser371) and phospho-4E-BP1 (Thr37/46) (Cell Signaling, Beverly, MA, USA) at 4  C overnight.	('Signaling', 'biological_process', 'GO:0023052', ('299', '308'))	('PTEN', 'Gene', '5728', (87, 91))	('Ser', 'cellular_component', 'GO:0005790', ('255', '258'))	('AKT', 'Gene', '207', (122, 125))	('PDK1', 'Gene', '5163', (169, 173))	('c-Raf', 'Gene', (192, 197))	('AKT', 'Gene', (102, 105))	('GSK', 'molecular_function', 'GO:0050321', ('142', '145'))	('TOR', 'Gene', (210, 213))	('TOR', 'Gene', '6097', (224, 227))	('Ser', 'cellular_component', 'GO:0005790', ('199', '202'))	('Ser', 'cellular_component', 'GO:0005790', ('229', '232'))	('GSK-3-beta', 'Gene', '2931', (142, 152))	('c-Raf', 'Gene', '5894', (192, 197))	('Ser', 'cellular_component', 'GO:0005790', ('93', '96'))	('membrane', 'cellular_component', 'GO:0016020', ('4', '12'))	('phospho-p70 S6 (Ser371', 'Var', (239, 261))	('Ser2448', 'Var', (229, 236))	('mTOR', 'Gene', (223, 227))	('TOR', 'Gene', (224, 227))	('phospho-4E-BP1', 'Var', (267, 281))	('Ser', 'cellular_component', 'GO:0005790', ('154', '157'))	('AKT', 'Gene', '207', (102, 105))	('Ser', 'cellular_component', 'GO:0005790', ('175', '178'))	('GSK-3-beta', 'Gene', (142, 152))	('PDK1', 'Gene', (169, 173))	('AKT', 'Gene', (122, 125))	('mTOR', 'Gene', '2475', (223, 227))	('PTEN', 'Gene', (87, 91))	('PDK1', 'molecular_function', 'GO:0004740', ('169', '173'))	('TOR', 'Gene', '6097', (210, 213))
128773	32668608	The most aggressive course is the disseminated form of the disease, in the tissue of the primary tumor of which there is an increase in the content of NF-kB p50 (1.6 times), NF-kB p65 (1.4 times), HIF-1 (5.5 times) and HIF-2 (1.3 times) compared with normal renal parenchyma.	('increase', 'PosReg', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('NF-kB', 'Gene', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('p65', 'Gene', '5970', (180, 183))	('content', 'MPA', (140, 147))	('p50', 'Gene', (157, 160))	('HIF-1', 'Gene', '3091', (197, 202))	('tumor', 'Disease', (97, 102))	('disseminated', 'Disease', (34, 46))	('p50', 'Gene', '4790', (157, 160))	('HIF-1', 'Gene', (197, 202))	('HIF-2', 'Var', (219, 224))	('p65', 'Gene', (180, 183))
128828	32668608	Overactivation of angiogenic factors governing HIF-1 leads to the increase in VEGFR2 content in metastatic sites, accompanied by the growth in m-TOR protein level.	('increase', 'PosReg', (66, 74))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('VEGFR2', 'Gene', (78, 84))	('TOR', 'Gene', (145, 148))	('content', 'MPA', (85, 92))	('HIF-1', 'Gene', '3091', (47, 52))	('VEGFR2', 'Gene', '3791', (78, 84))	('TOR', 'Gene', '6097', (145, 148))	('HIF-1', 'Gene', (47, 52))	('growth', 'PosReg', (133, 139))	('Overactivation', 'Var', (0, 14))
128835	31277104	The results showed that the expression of PVT1 was closely related to the overall survival rate of cancers (HR = 1.64, 95% confidence interval [CI]: 1.50-1.78, P < .000001).	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('PVT1', 'Gene', (42, 46))	('cancers', 'Disease', (99, 106))	('expression', 'Var', (28, 38))	('related', 'Reg', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
128837	31277104	In addition, the high expression of PVT1 was positively correlated with tumor size (OR = 1.50, 95% CI: 1.14-1.96, P = .004), TNM stage (OR = 3.39, 95% CI: 2.73-4.20, P < .00001), lymph node metastasis (OR = 2.60, 95% CI: 1.76-3.84, P < .00001), and distant metastasis (OR = 2.94, 95% CI: 1.90-4.56, P < .00001).	('TNM stage', 'CPA', (125, 134))	('distant metastasis', 'CPA', (249, 267))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('high', 'Var', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('lymph node metastasis', 'CPA', (179, 200))	('PVT1', 'Gene', (36, 40))	('correlated', 'Reg', (56, 66))
128840	31277104	Abnormal lncRNA expression is believed to be closely related to the occurrence of a variety of human diseases, including various cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('human', 'Species', '9606', (95, 100))	('related', 'Reg', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('lncRNA expression', 'Protein', (9, 26))	('cancers', 'Disease', (129, 136))	('Abnormal', 'Var', (0, 8))
128847	31277104	It is reported that the high expression of PVT1 increased the expression of autophagy related 7 (Atg7) and Beclin1 (BECN1) by targeting miRNA-186, thereby inducing the protective autophagy of glioma cells and promoting the proliferation, migration and angiogenesis of vascular endothelial cells.	('angiogenesis of vascular endothelial cells', 'CPA', (252, 294))	('Atg7', 'Gene', (97, 101))	('proliferation', 'CPA', (223, 236))	('BECN1', 'Gene', (116, 121))	('protective autophagy', 'CPA', (168, 188))	('migration', 'CPA', (238, 247))	('Atg7', 'Gene', '10533', (97, 101))	('autophagy', 'biological_process', 'GO:0006914', ('179', '188'))	('Beclin1', 'Gene', (107, 114))	('autophagy', 'biological_process', 'GO:0016236', ('76', '85'))	('autophagy related 7', 'Gene', (76, 95))	('glioma', 'Disease', (192, 198))	('promoting', 'PosReg', (209, 218))	('glioma', 'Disease', 'MESH:D005910', (192, 198))	('autophagy related 7', 'Gene', '10533', (76, 95))	('targeting', 'Var', (126, 135))	('expression', 'MPA', (62, 72))	('miR', 'Gene', '220972', (136, 139))	('autophagy', 'biological_process', 'GO:0006914', ('76', '85'))	('angiogenesis', 'biological_process', 'GO:0001525', ('252', '264'))	('increased', 'PosReg', (48, 57))	('Beclin1', 'Gene', '8678', (107, 114))	('inducing', 'PosReg', (155, 163))	('PVT1', 'Gene', (43, 47))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('autophagy', 'biological_process', 'GO:0016236', ('179', '188'))	('miR', 'Gene', (136, 139))	('BECN1', 'Gene', '8678', (116, 121))
128883	31277104	The subgroup analysis based on different tumor types showed that the high expression of PVT1 was related to the poor overall survival rate of patients with clear cell renal cell carcinoma, breast cancer, cervical cancer, colon cancer, epithelial ovarian cancer, gastric cancer, lung cancer, osteosarcoma and others (including: bladder cancer, nasopharyngeal carcinoma, pancreatic cancer, melanoma, prostate cancer) respectively.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (369, 386))	('colon cancer', 'Disease', (221, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('lung cancer', 'Disease', (278, 289))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (343, 367))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (156, 187))	('gastric cancer', 'Disease', 'MESH:D013274', (262, 276))	('prostate cancer', 'Disease', 'MESH:D011471', (398, 413))	('osteosarcoma', 'Disease', (291, 303))	('cervical cancer', 'Disease', (204, 219))	('cervical cancer', 'Disease', 'MESH:D002583', (204, 219))	('prostate cancer', 'Phenotype', 'HP:0012125', (398, 413))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('osteosarcoma', 'Disease', 'MESH:D012516', (291, 303))	('bladder cancer', 'Disease', (327, 341))	('melanoma', 'Disease', 'MESH:D008545', (388, 396))	('bladder cancer', 'Disease', 'MESH:D001749', (327, 341))	('carcinoma', 'Phenotype', 'HP:0030731', (358, 367))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (235, 260))	('breast cancer', 'Disease', (189, 202))	('prostate cancer', 'Disease', (398, 413))	('high', 'Var', (69, 73))	('pancreatic cancer', 'Disease', 'MESH:D010190', (369, 386))	('melanoma', 'Phenotype', 'HP:0002861', (388, 396))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('melanoma', 'Disease', (388, 396))	('colon cancer', 'Phenotype', 'HP:0003003', (221, 233))	('bladder cancer', 'Phenotype', 'HP:0009725', (327, 341))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (343, 367))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('lung cancer', 'Disease', 'MESH:D008175', (278, 289))	('gastric cancer', 'Phenotype', 'HP:0012126', (262, 276))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (156, 187))	('tumor', 'Disease', (41, 46))	('epithelial ovarian cancer', 'Disease', (235, 260))	('pancreatic cancer', 'Disease', (369, 386))	('lung cancer', 'Phenotype', 'HP:0100526', (278, 289))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (167, 187))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('osteosarcoma', 'Phenotype', 'HP:0002669', (291, 303))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('colon cancer', 'Disease', 'MESH:D015179', (221, 233))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (235, 260))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('clear cell renal cell carcinoma', 'Disease', (156, 187))	('gastric cancer', 'Disease', (262, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('nasopharyngeal carcinoma', 'Disease', (343, 367))	('patients', 'Species', '9606', (142, 150))	('ovarian cancer', 'Phenotype', 'HP:0100615', (246, 260))	('PVT1', 'Gene', (88, 92))
128886	31277104	Although no significant association was found, patients exhibiting high PVT1 expression levels demonstrated a trend for poor prognoses.	('PVT1', 'Gene', (72, 76))	('expression', 'MPA', (77, 87))	('high', 'Var', (67, 71))	('patients', 'Species', '9606', (47, 55))
128902	31277104	To sum up, although there are some limitations, our meta-analysis showed that high expression of PVT1 was significantly associated with tumor size, TNM stage, lymph node metastasis, distant metastasis, and overall survival time and so on, especially in breast cancer, liver cancer, lung cancer, indicating meaning is more apparent, but in bladder cancer, renal cell carcinoma and nasopharyngeal carcinoma, the indication is relatively weak as the fewer samples.	('breast cancer', 'Phenotype', 'HP:0003002', (253, 266))	('associated', 'Reg', (120, 130))	('renal cell carcinoma', 'Disease', (355, 375))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (355, 375))	('lung cancer', 'Disease', 'MESH:D008175', (282, 293))	('liver cancer', 'Phenotype', 'HP:0002896', (268, 280))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (366, 375))	('liver cancer', 'Disease', (268, 280))	('breast cancer', 'Disease', 'MESH:D001943', (253, 266))	('lung cancer', 'Phenotype', 'HP:0100526', (282, 293))	('nasopharyngeal carcinoma', 'Disease', (380, 404))	('breast cancer', 'Disease', (253, 266))	('high', 'Var', (78, 82))	('lymph node metastasis', 'CPA', (159, 180))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (380, 404))	('distant metastasis', 'CPA', (182, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (395, 404))	('tumor', 'Disease', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (355, 375))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('lung cancer', 'Disease', (282, 293))	('bladder cancer', 'Disease', (339, 353))	('bladder cancer', 'Disease', 'MESH:D001749', (339, 353))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (380, 404))	('bladder cancer', 'Phenotype', 'HP:0009725', (339, 353))	('liver cancer', 'Disease', 'MESH:D006528', (268, 280))	('PVT1', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
128907	28598434	We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 x 10-10), 3p22.1 (rs67311347, P=2.5 x 10-8), 3q26.2 (rs10936602, P=8.8 x 10-9), 8p21.3 (rs2241261, P=5.8 x 10-9), 10q24.33-q25.1 (rs11813268, P=3.9 x 10-8), 11q22.3 (rs74911261, P=2.1 x 10-10) and 14q24.2 (rs4903064, P=2.2 x 10-24).	('rs74911261', 'Mutation', 'rs74911261', (261, 271))	('rs2241261', 'Var', (183, 192))	('rs4381241', 'Var', (78, 87))	('rs10936602', 'Mutation', 'rs10936602', (148, 158))	('rs4381241', 'Mutation', 'rs4381241', (78, 87))	('P=3.1', 'Var', (89, 94))	('rs67311347', 'Var', (113, 123))	('rs67311347', 'Mutation', 'rs67311347', (113, 123))	('rs11813268', 'Mutation', 'rs11813268', (225, 235))	('rs2241261', 'Mutation', 'rs2241261', (183, 192))	('rs74911261', 'Var', (261, 271))	('rs11813268', 'Var', (225, 235))	('rs10936602', 'Var', (148, 158))	('rs4903064', 'Mutation', 'rs4903064', (301, 310))	('rs4903064', 'Var', (301, 310))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('RCC', 'Disease', (25, 28))
128913	28598434	Direct evidence for inherited predisposition to RCC is provided by a number of rare cancer syndromes with defined germline mutations in 11 genes (BAP1, FLCN, FH, MET, PTEN, SDHB, SDHC, SDHD, TSC1, TSC2 and VHL), that are associated with the development of different RCC subtypes.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('RCC', 'Disease', (266, 269))	('TSC2', 'Gene', '7249', (197, 201))	('SDHD', 'Gene', (185, 189))	('VHL', 'Gene', '7428', (206, 209))	('SDHC', 'Gene', (179, 183))	('men', 'Species', '9606', (248, 251))	('SDHB', 'Gene', '6390', (173, 177))	('RCC', 'Disease', 'MESH:C538614', (266, 269))	('TSC2', 'Gene', (197, 201))	('TSC1', 'Gene', (191, 195))	('BAP1', 'Gene', '8314', (146, 150))	('cancer', 'Disease', (84, 90))	('SDHB', 'Gene', (173, 177))	('PTEN', 'Gene', (167, 171))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TSC1', 'Gene', '7248', (191, 195))	('FLCN', 'Gene', '201163', (152, 156))	('RCC', 'Disease', (48, 51))	('FH', 'Disease', 'MESH:D006938', (158, 160))	('SDHC', 'Gene', '6391', (179, 183))	('FLCN', 'Gene', (152, 156))	('BAP1', 'Gene', (146, 150))	('VHL', 'Gene', (206, 209))	('SDHD', 'Gene', '6392', (185, 189))	('PTEN', 'Gene', '5728', (167, 171))	('MET', 'Gene', (162, 165))	('mutations', 'Var', (123, 132))
128915	28598434	Support for polygenic susceptibility to RCC has come from genome-wide association studies (GWAS) that have identified single-nucleotide polymorphisms (SNPs) at six loci influencing RCC risk in populations of European ancestry at chromosome bands 2p21, 2q22.3, 8q24.21, 11q13.3, 12p11.23 and 12q24.31 (refs).	('single-nucleotide polymorphisms', 'Var', (118, 149))	('RCC', 'Disease', (40, 43))	('chromosome', 'cellular_component', 'GO:0005694', ('229', '239'))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('influencing', 'Reg', (169, 180))	('RCC', 'Disease', 'MESH:C538614', (181, 184))	('RCC', 'Disease', (181, 184))
128928	28598434	In the combined analysis, SNPs at seven loci showed evidence for an association with RCC which was genome-wide significant: 1p32.3 (rs4381241, P=3.1 x 10-10), 3p22.1 (rs67311347, P=2.5 x 10-8), 3q26.2 (rs10936602, P=8.8 x 10-9), 8p21.3 (rs2241261, P=5.8 x 10-9), 10q24.33-q25.1 (rs11813268, P=3.9 x 10-8), 11q22.3 (rs74911261, P=2.1 x 10-10) and 14q24.2 (rs4903064, P=2.2 x 10-24) (Table 1, Supplementary Data 1).	('rs4381241', 'Mutation', 'rs4381241', (132, 141))	('rs4381241', 'Var', (132, 141))	('rs11813268', 'Mutation', 'rs11813268', (279, 289))	('rs11813268', 'Var', (279, 289))	('rs74911261', 'Var', (315, 325))	('rs67311347', 'Mutation', 'rs67311347', (167, 177))	('men', 'Species', '9606', (397, 400))	('rs10936602', 'Var', (202, 212))	('rs4903064', 'Mutation', 'rs4903064', (355, 364))	('rs4903064', 'Var', (355, 364))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', (85, 88))	('rs67311347', 'Var', (167, 177))	('rs10936602', 'Mutation', 'rs10936602', (202, 212))	('rs74911261', 'Mutation', 'rs74911261', (315, 325))	('rs2241261', 'Var', (237, 246))	('rs2241261', 'Mutation', 'rs2241261', (237, 246))
128932	28598434	The most notable difference in risk was observed for the 14q24 variants that had a stronger effect in women than in men [for rs4903064, odds ratios: ORs (95% confidence interval: CI) of 1.36 (1.28-1.45) and 1.13 (1.08-1.19), respectively; heterogeneity P=7.4 x 10-6].	('14q24', 'Gene', (57, 62))	('men', 'Species', '9606', (104, 107))	('rs4903064', 'Var', (125, 134))	('women', 'Species', '9606', (102, 107))	('rs4903064', 'Mutation', 'rs4903064', (125, 134))	('men', 'Species', '9606', (116, 119))
128935	28598434	For SNP rs76912165, which was not genome-wide significant overall, a trend for higher risk associated with stage 1 cases was observed (Supplementary Data 2).	('rs76912165', 'Mutation', 'rs76912165', (8, 18))	('men', 'Species', '9606', (141, 144))	('SNP rs76912165', 'Var', (4, 18))	('stage 1 cases', 'Disease', (107, 120))
128936	28598434	We investigated whether rs6706003 and rs6755594 defined independent signals at the previously reported 2p21 locus.	('rs6755594', 'Var', (38, 47))	('rs6706003', 'Mutation', 'rs6706003', (24, 33))	('rs6755594', 'Mutation', 'rs6755594', (38, 47))	('rs6706003', 'Var', (24, 33))
128937	28598434	rs6706003 is minimally correlated with rs7579899 (r2=0.11 in CEU) that was identified in the initial GWAS, and moderately correlated with rs12617313 (r2=0.61), which was identified in a previous fine-mapping analysis.	('rs12617313', 'Mutation', 'rs12617313', (138, 148))	('rs6706003', 'Mutation', 'rs6706003', (0, 9))	('rs7579899', 'Mutation', 'rs7579899', (39, 48))	('rs7579899', 'Var', (39, 48))	('rs12617313', 'Var', (138, 148))	('rs6706003', 'Var', (0, 9))
128938	28598434	By comparison, the correlation of rs6755594 with both of these sites is notably weaker (r2=0.04 and 0.08, respectively).	('rs6755594', 'Mutation', 'rs6755594', (34, 43))	('correlation', 'Interaction', (19, 30))	('rs6755594', 'Var', (34, 43))	('weaker', 'NegReg', (80, 86))
128939	28598434	In conditional analyses of the GWAS data adjusting for rs7579899 and rs12617313, the rs6706003 signal was substantially reduced (OR 1.07, P=0.05), while the rs6755594 signal was partially attenuated (OR 1.07, P=4.0 x 10-4).	('rs6706003', 'Var', (85, 94))	('rs7579899', 'Mutation', 'rs7579899', (55, 64))	('rs7579899', 'Var', (55, 64))	('rs6706003', 'Mutation', 'rs6706003', (85, 94))	('rs12617313', 'Var', (69, 79))	('rs6755594', 'Mutation', 'rs6755594', (157, 166))	('reduced', 'NegReg', (120, 127))	('rs12617313', 'Mutation', 'rs12617313', (69, 79))
128943	28598434	to identify possible functional variants, primarily in cells of non-kidney origin but also in BC_kidney_01-11002 and BC_kidney_H12817N cell lines (Supplementary Data 3); and (3) performed expression quantitative trait locus (eQTL) analyses with genes located up to 3 Mb around the newly identified risk markers (or highly correlated proxies) using ccRCC and normal kidney tissue data from the Cancer Genome Atlas [Kidney Renal Clear Cell Carcinoma (KIRC) collection; 481 tumour and 71 normal tissue samples] and IARC (555 tumour and 234 normal tissue samples) (Supplementary Data 4).	('tumour', 'Phenotype', 'HP:0002664', (471, 477))	('Kidney Renal Clear Cell Carcinoma', 'Disease', (414, 447))	('men', 'Species', '9606', (567, 570))	('tumour', 'Phenotype', 'HP:0002664', (522, 528))	('H12817N', 'Mutation', 'p.H12817N', (127, 134))	('tumour', 'Disease', 'MESH:D009369', (522, 528))	('tumour', 'Disease', 'MESH:D009369', (471, 477))	('men', 'Species', '9606', (153, 156))	('Carcinoma', 'Phenotype', 'HP:0030731', (438, 447))	('variants', 'Var', (32, 40))	('tumour', 'Disease', (471, 477))	('Cancer', 'Phenotype', 'HP:0002664', (393, 399))	('tumour', 'Disease', (522, 528))	('RCC', 'Disease', 'MESH:C538614', (350, 353))	('Kidney Renal Clear Cell Carcinoma', 'Disease', 'MESH:C538614', (414, 447))	('RCC', 'Disease', (350, 353))
128944	28598434	The new highly significant locus marked by rs4903064 at 14q24 maps to the double PHD fingers 3 gene (DPF3), which encodes a histone acetylation and methylation reader of the BAF and PBAF chromatin remodelling complexes.	('chromatin remodelling', 'biological_process', 'GO:0006338', ('187', '208'))	('BAF', 'Gene', (174, 177))	('histone acetylation', 'biological_process', 'GO:0016573', ('124', '143'))	('BAF', 'Gene', '8815', (183, 186))	('PHD', 'molecular_function', 'GO:0050175', ('81', '84'))	('methylation', 'biological_process', 'GO:0032259', ('148', '159'))	('DPF3', 'Gene', (101, 105))	('BAF', 'Gene', (183, 186))	('BAF', 'Gene', '8815', (174, 177))	('chromatin', 'cellular_component', 'GO:0000785', ('187', '196'))	('rs4903064', 'Mutation', 'rs4903064', (43, 52))	('rs4903064', 'Var', (43, 52))	('DPF3', 'Gene', '8110', (101, 105))
128945	28598434	This locus contains a set of correlated SNPs (r2>0.8 in 1000G EUR) that reside within the introns of DPF3 (Supplementary Data 3), of which only rs4903064 itself is annotated as likely to disrupt transcription factor binding (RegulomeDB score <4).	('transcription', 'biological_process', 'GO:0006351', ('195', '208'))	('rs4903064', 'Mutation', 'rs4903064', (144, 153))	('rs4903064', 'Var', (144, 153))	('transcription', 'MPA', (195, 208))	('disrupt', 'Reg', (187, 194))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('195', '223'))	('DPF3', 'Gene', (101, 105))	('men', 'Species', '9606', (113, 116))	('DPF3', 'Gene', '8110', (101, 105))
128946	28598434	This variant is located within a region annotated as an enhancer in multiple tissues by the RoadMap project and is predicted to alter IRX2/IRX5 binding motifs.	('alter', 'Reg', (128, 133))	('IRX2', 'Gene', (134, 138))	('enhancer', 'PosReg', (56, 64))	('IRX2', 'Gene', '153572', (134, 138))	('binding', 'Interaction', (144, 151))	('binding', 'molecular_function', 'GO:0005488', ('144', '151'))	('variant', 'Var', (5, 12))	('IRX5', 'Gene', '10265', (139, 143))	('IRX5', 'Gene', (139, 143))
128947	28598434	In an eQTL analysis, we observed a consistent pattern of increased DPF3 expression associated with the rs49030604 risk allele in both the KIRC and IARC data sets (P=5.5 x 10-8 and 3.8 x 10-9, respectively, Fig.	('DPF3', 'Gene', (67, 71))	('DPF3', 'Gene', '8110', (67, 71))	('rs49030604', 'Mutation', 'rs49030604', (103, 113))	('rs49030604', 'Var', (103, 113))	('expression', 'MPA', (72, 82))	('increased', 'PosReg', (57, 66))
128950	28598434	While DPF3 mutation is rare in RCC, somatic alterations of BAP1 and PBRM1, components of the BAF and PBAF complexes, respectively, are commonly seen in ccRCC.	('BAF', 'Gene', '8815', (93, 96))	('BAP1', 'Gene', (59, 63))	('PBRM1', 'Gene', (68, 73))	('DPF3', 'Gene', (6, 10))	('BAF', 'Gene', (93, 96))	('alterations', 'Var', (44, 55))	('RCC', 'Disease', (154, 157))	('PBRM1', 'Gene', '55193', (68, 73))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('DPF3', 'Gene', '8110', (6, 10))	('BAF', 'Gene', '8815', (102, 105))	('BAP1', 'Gene', '8314', (59, 63))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('seen', 'Reg', (144, 148))	('RCC', 'Disease', (31, 34))	('BAF', 'Gene', (102, 105))
128951	28598434	In this regard, deregulation of this pathway is a common feature of RCC, and these data suggest that rs4903064 may play a role in RCC development through dysregulation of the DPF3 expression.	('men', 'Species', '9606', (141, 144))	('play', 'Reg', (115, 119))	('dysregulation', 'Var', (154, 167))	('DPF3', 'Gene', (175, 179))	('expression', 'MPA', (180, 190))	('rs4903064', 'Var', (101, 110))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('DPF3', 'Gene', '8110', (175, 179))	('RCC', 'Disease', (68, 71))	('RCC', 'Disease', (130, 133))	('rs4903064', 'Mutation', 'rs4903064', (101, 110))	('RCC', 'Disease', 'MESH:C538614', (130, 133))
128952	28598434	For the 1p32.3 locus marked by rs4381241, an intronic SNP within FAS-associated factor 1 (FAF1) that encodes a protein that can initiate or enhance FAS-mediated apoptosis, we identified several promising correlated variants with RegulomeDB scores, suggesting alteration of transcription factor binding (Supplementary Data 3) but did not observe a strong effect on expression (Supplementary Data 4).	('transcription', 'biological_process', 'GO:0006351', ('273', '286'))	('FAS-associated factor 1', 'Gene', '11124', (65, 88))	('enhance', 'PosReg', (140, 147))	('men', 'Species', '9606', (309, 312))	('apoptosis', 'biological_process', 'GO:0097194', ('161', '170'))	('FAS-associated factor 1', 'Gene', (65, 88))	('alteration', 'Reg', (259, 269))	('FAF1', 'Gene', '11124', (90, 94))	('men', 'Species', '9606', (382, 385))	('apoptosis', 'biological_process', 'GO:0006915', ('161', '170'))	('rs4381241', 'Mutation', 'rs4381241', (31, 40))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('273', '301'))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('variants', 'Var', (215, 223))	('rs4381241', 'Var', (31, 40))	('FAF1', 'Gene', (90, 94))	('binding', 'Interaction', (294, 301))	('transcription', 'MPA', (273, 286))
128954	28598434	Constitutively activated beta-catenin, induced by VHL inactivation, is an important pathway in ccRCC oncogenesis.	('oncogenesis', 'biological_process', 'GO:0007048', ('101', '112'))	('RCC', 'Disease', (97, 100))	('VHL', 'Gene', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('beta-catenin', 'Gene', '1499', (25, 37))	('VHL', 'Gene', '7428', (50, 53))	('beta-catenin', 'Gene', (25, 37))	('inactivation', 'Var', (54, 66))
128955	28598434	The rs4381241 risk allele is weakly correlated (r2=0.12 in CEU) with the allele of another FAF1 variant (rs17106184) associated with reduced risk of type-2 diabetes and lower serum insulin post oral glucose challenge.	('FAF1', 'Gene', '11124', (91, 95))	('insulin post oral glucose challenge', 'Disease', 'MESH:D020820', (181, 216))	('FAF1', 'Gene', (91, 95))	('diabetes', 'Disease', (156, 164))	('rs4381241', 'Var', (4, 13))	('rs4381241', 'Mutation', 'rs4381241', (4, 13))	('insulin post oral glucose challenge', 'Disease', (181, 216))	('insulin', 'molecular_function', 'GO:0016088', ('181', '188'))	('2 diabetes', 'Phenotype', 'HP:0005978', (154, 164))	('rs17106184', 'Mutation', 'rs17106184', (105, 115))	('rs17106184', 'Var', (105, 115))	('diabetes', 'Disease', 'MESH:D003920', (156, 164))	('lower', 'NegReg', (169, 174))	('reduced', 'NegReg', (133, 140))
128957	28598434	Within the KIRC tumour tissue data, the risk-associated allele of the surrogate SNP rs9821249 (r2=0.97 with rs67311347 in CEU) was weakly associated with higher expression of CTNNB1 (P=0.03).	('rs67311347', 'Mutation', 'rs67311347', (108, 118))	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('rs9821249', 'Var', (84, 93))	('tumour', 'Disease', (16, 22))	('rs67311347', 'Var', (108, 118))	('CTNNB1', 'Gene', (175, 181))	('expression', 'MPA', (161, 171))	('higher', 'PosReg', (154, 160))	('rs9821249', 'Mutation', 'rs9821249', (84, 93))	('CTNNB1', 'Gene', '1499', (175, 181))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))
128959	28598434	In both normal tissue data sets, the risk-associated allele of rs67311347 was associated with a higher expression of ZNF620 (P=0.03 and 0.02).	('ZNF620', 'Gene', '253639', (117, 123))	('higher', 'PosReg', (96, 102))	('rs67311347', 'Var', (63, 73))	('expression', 'MPA', (103, 113))	('rs67311347', 'Mutation', 'rs67311347', (63, 73))	('ZNF620', 'Gene', (117, 123))
128961	28598434	The 8p21.3 risk variants rs2241261 and rs2889 (used as proxy for rs2241260, P=1.6 x 10-9, r2=0.61 with rs2241261 in CEU; Supplementary Data 1) are located 0.9 and 1.7 kb respectively from TNFRSF10B, a tumour suppressor gene encoding a mediator of apoptosis signalling.	('TNFRSF10B', 'Gene', (188, 197))	('rs2241261', 'Var', (25, 34))	('tumour', 'Disease', (201, 207))	('rs2241261', 'Mutation', 'rs2241261', (103, 112))	('rs2241261', 'Mutation', 'rs2241261', (25, 34))	('signalling', 'biological_process', 'GO:0023052', ('257', '267'))	('rs2241260', 'Mutation', 'rs2241260', (65, 74))	('apoptosis', 'biological_process', 'GO:0097194', ('247', '256'))	('rs2889', 'Var', (39, 45))	('TNFRSF10B', 'Gene', '8795', (188, 197))	('apoptosis', 'biological_process', 'GO:0006915', ('247', '256'))	('rs2889', 'Mutation', 'rs2889', (39, 45))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('men', 'Species', '9606', (127, 130))	('tumour', 'Disease', 'MESH:D009369', (201, 207))
128962	28598434	In both the KIRC and IARC tumour tissue data (P=0.002 and 0.03, respectively), the rs2241261 risk allele was associated with a decreased expression of GFRA2, which encodes for cell-surface receptor for glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN), and mediates activation of the RET tyrosine kinase receptor (Glial cell line-derived neurotrophic factor (Supplementary Data 4).	('cell-surface', 'cellular_component', 'GO:0009986', ('176', '188'))	('GFRA2', 'Gene', (151, 156))	('GFRA2', 'Gene', '2675', (151, 156))	('neurturin', 'Gene', '4902', (257, 266))	('rs2241261', 'Mutation', 'rs2241261', (83, 92))	('expression', 'MPA', (137, 147))	('activation', 'PosReg', (287, 297))	('glial cell line-derived neurotrophic factor', 'Gene', '2668', (202, 245))	('rs2241261', 'Var', (83, 92))	('GDNF', 'Gene', (247, 251))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('cell-surface receptor', 'Gene', '57126', (176, 197))	('GDNF', 'Gene', '2668', (247, 251))	('decreased', 'NegReg', (127, 136))	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('tumour', 'Disease', (26, 32))	('Glial cell line-derived neurotrophic factor', 'Gene', (335, 378))	('Glial cell line-derived neurotrophic factor', 'Gene', '2668', (335, 378))	('men', 'Species', '9606', (386, 389))	('NTN', 'Gene', (268, 271))	('glial cell line-derived neurotrophic factor', 'Gene', (202, 245))	('NTN', 'Gene', '4902', (268, 271))	('cell-surface receptor', 'Gene', (176, 197))	('neurturin', 'Gene', (257, 266))
128963	28598434	Of the variants in strong LD with either rs2241261 or rs2889 (r2>0.8 in 1000G EUR), only rs2889 is annotated as a strong regulatory candidate by RegulomeDB, predicted to be in a strong enhancer region and altering motifs for FOX family members of transcription factors (Supplementary Data 3).	('transcription', 'biological_process', 'GO:0006351', ('247', '260'))	('rs2241261', 'Mutation', 'rs2241261', (41, 50))	('men', 'Species', '9606', (276, 279))	('altering', 'Reg', (205, 213))	('rs2889', 'Var', (54, 60))	('rs2889', 'Var', (89, 95))	('rs2889', 'Mutation', 'rs2889', (54, 60))	('rs2241261', 'Var', (41, 50))	('rs2889', 'Mutation', 'rs2889', (89, 95))
128964	28598434	SNPs rs74911261 and rs1800057 are located 214 kb apart on 11q22.3 and are highly correlated (r2=0.83 in CEU) non-synonymous variants, but for separate genes; rs74911261 (P144L) maps to KDELC2, which encodes a protein localizing to the endoplasmic reticulum, while rs1800057 (P1054R) maps to the DNA repair gene ATM.	('rs1800057', 'Mutation', 'rs1800057', (20, 29))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('235', '256'))	('ATM', 'Gene', (311, 314))	('rs1800057', 'Mutation', 'rs1800057', (264, 273))	('DNA repair', 'biological_process', 'GO:0006281', ('295', '305'))	('DNA', 'cellular_component', 'GO:0005574', ('295', '298'))	('ATM', 'Gene', '472', (311, 314))	('P1054R', 'Mutation', 'rs1800057', (275, 281))	('KDELC2', 'Gene', (185, 191))	('rs74911261 (P144L', 'Var', (158, 175))	('rs74911261', 'Mutation', 'rs74911261', (5, 15))	('KDELC2', 'Gene', '143888', (185, 191))	('protein', 'cellular_component', 'GO:0003675', ('209', '216'))	('P144L', 'Mutation', 'rs74911261', (170, 175))	('rs74911261', 'Mutation', 'rs74911261', (158, 168))	('rs1800057 (P1054R', 'Var', (264, 281))
128966	28598434	Only one of the five variants with strong LD to rs74911261 (r2>0.8 in 1000G EUR) has a RegulomeDB score suggesting likely disruption of transcription factor binding (score<4), rs141379009, and is located within a region annotated as an enhancer by the Roadmap project and predicted to alter a consensus Zfp105/ZNF35 binding motif (Supplementary Data 3).	('rs141379009', 'Mutation', 'rs141379009', (176, 187))	('transcription factor', 'MPA', (136, 156))	('men', 'Species', '9606', (337, 340))	('rs74911261', 'Var', (48, 58))	('disruption', 'NegReg', (122, 132))	('rs141379009', 'Var', (176, 187))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('136', '164'))	('transcription', 'biological_process', 'GO:0006351', ('136', '149'))	('alter', 'Reg', (285, 290))	('binding', 'molecular_function', 'GO:0005488', ('316', '323'))	('rs74911261', 'Mutation', 'rs74911261', (48, 58))
128967	28598434	ATM mutations in RCC are uncommon, and ataxia telangiectasia patients, though at markedly elevated cancer risk, have not been reported to frequently develop RCC, questioning a direct role of ATM in RCC susceptibility.	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('ataxia telangiectasia', 'Disease', (39, 60))	('ATM', 'Gene', (191, 194))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('patients', 'Species', '9606', (61, 69))	('ATM', 'Gene', (0, 3))	('RCC', 'Disease', (17, 20))	('telangiectasia', 'Phenotype', 'HP:0001009', (46, 60))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (39, 60))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('ataxia', 'Phenotype', 'HP:0001251', (39, 45))	('mutations', 'Var', (4, 13))	('ATM', 'Gene', '472', (191, 194))	('cancer', 'Disease', (99, 105))	('RCC', 'Disease', (198, 201))	('RCC', 'Disease', (157, 160))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('ATM', 'Gene', '472', (0, 3))
128970	28598434	The marker SNP rs10936602 maps to 3q26.2, a region amplified in 15% of ccRCC tumours in KIRC; several notable nearby genes could represent possible candidate genes, including MECOM, a transcriptional regulator frequently amplified in RCC, and TERC, encoding a component of telomerase, in which mutations cause autosomal dominant dyskeratosis congenita and aplastic anaemia.	('aplastic anaemia', 'Disease', (356, 372))	('MECOM', 'Gene', (175, 180))	('MECOM', 'Gene', '2122', (175, 180))	('RCC', 'Disease', (234, 237))	('TERC', 'Gene', '7012', (243, 247))	('mutations', 'Var', (294, 303))	('RCC', 'Disease', 'MESH:C538614', (234, 237))	('rs10936602', 'Mutation', 'rs10936602', (15, 25))	('RCC', 'Disease', (73, 76))	('TERC', 'Gene', (243, 247))	('tumours', 'Disease', (77, 84))	('aplastic anaemia', 'Disease', 'MESH:D000741', (356, 372))	('autosomal dominant dyskeratosis congenita', 'Disease', (310, 351))	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('cause', 'Reg', (304, 309))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('aplastic anaemia', 'Phenotype', 'HP:0001915', (356, 372))	('anaemia', 'Phenotype', 'HP:0001903', (365, 372))	('autosomal dominant dyskeratosis congenita', 'Disease', 'MESH:D019871', (310, 351))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
128971	28598434	This risk variant is moderately correlated with variants previously associated with telomere length and risk of several malignancies, including multiple myeloma, chronic lymphocytic leukaemia, bladder cancer, glioma and colorectal cancer (rs10936599, rs12696304, rs1920116; r2=0.66, 0.58 and 0.80, respectively).	('multiple myeloma', 'Disease', 'MESH:D009101', (144, 160))	('colorectal cancer', 'Phenotype', 'HP:0003003', (220, 237))	('bladder cancer', 'Disease', 'MESH:D001749', (193, 207))	('bladder cancer', 'Disease', (193, 207))	('rs1920116', 'Mutation', 'rs1920116', (263, 272))	('rs10936599', 'Mutation', 'rs10936599', (239, 249))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('glioma', 'Disease', (209, 215))	('bladder cancer', 'Phenotype', 'HP:0009725', (193, 207))	('telomere', 'cellular_component', 'GO:0000781', ('84', '92'))	('malignancies', 'Disease', 'MESH:D009369', (120, 132))	('telomere', 'cellular_component', 'GO:0005696', ('84', '92'))	('multiple myeloma', 'Disease', (144, 160))	('glioma', 'Disease', 'MESH:D005910', (209, 215))	('chronic lymphocytic leukaemia', 'Disease', 'MESH:D015451', (162, 191))	('malignancies', 'Disease', (120, 132))	('rs12696304', 'Mutation', 'rs12696304', (251, 261))	('colorectal cancer', 'Disease', 'MESH:D015179', (220, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('colorectal cancer', 'Disease', (220, 237))	('multiple myeloma', 'Phenotype', 'HP:0006775', (144, 160))	('rs1920116', 'Var', (263, 272))	('rs12696304', 'Var', (251, 261))	('chronic lymphocytic leukaemia', 'Disease', (162, 191))	('rs10936599', 'Var', (239, 249))
128972	28598434	The 10q24 risk variant rs11813268 is located 4 kb upstream of OBFC1, a gene identified in GWAS and laboratory investigation as a regulator of human telomere length.	('OBFC1', 'Gene', '79991', (62, 67))	('telomere', 'cellular_component', 'GO:0000781', ('148', '156'))	('human', 'Species', '9606', (142, 147))	('telomere', 'cellular_component', 'GO:0005696', ('148', '156'))	('rs11813268', 'Mutation', 'rs11813268', (23, 33))	('rs11813268', 'Var', (23, 33))	('OBFC1', 'Gene', (62, 67))
128973	28598434	This risk variant is highly correlated with SNPs associated with leucocyte telomere length (rs4387287, rs9419958 and rs9420907; r2=0.99, 0.82 and 0.82, respectively), and to a lesser degree with melanoma (rs2995264, r2=0.52), suggesting the underlying basis for RCC risk may be mediated through a common pathway.	('RCC', 'Disease', 'MESH:C538614', (262, 265))	('rs4387287', 'Mutation', 'rs4387287', (92, 101))	('rs9419958', 'Mutation', 'rs9419958', (103, 112))	('telomere', 'cellular_component', 'GO:0005696', ('75', '83'))	('rs4387287', 'Var', (92, 101))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('leucocyte telomere', 'MPA', (65, 83))	('rs9420907', 'Mutation', 'rs9420907', (117, 126))	('telomere', 'cellular_component', 'GO:0000781', ('75', '83'))	('rs9420907', 'Var', (117, 126))	('rs9419958', 'Var', (103, 112))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('rs2995264', 'Mutation', 'rs2995264', (205, 214))	('RCC', 'Disease', (262, 265))	('rs2995264', 'Var', (205, 214))
128976	28598434	Stratifying by histological subtypes, the PRS was most strongly associated with clear cell RCC (per unit increase: OR 3.24, 95% CI 2.91-3.62; P=3.4 x 10-100), with a weaker association for chromophobe RCC (OR 2.34, 95% CI 1.58-3.46; P=3.4 x 10-5) and papillary RCC (OR 1.83, 95% CI 1.44-2.32; P=5.3 x 10-7).	('RCC', 'Disease', 'MESH:C538614', (261, 264))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('chromophobe RCC', 'Disease', 'MESH:C538614', (189, 204))	('papillary RCC', 'Disease', 'MESH:C538614', (251, 264))	('associated', 'Interaction', (64, 74))	('chromophobe RCC', 'Disease', (189, 204))	('RCC', 'Disease', (91, 94))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('papillary RCC', 'Disease', (251, 264))	('RCC', 'Disease', (261, 264))	('PRS', 'Var', (42, 45))
128978	28598434	Using Genome-Wide Complex Trait Analysis (GCTA), we estimate that the heritability and familial relative risk of RCC attributable to all common variation were 14.2% (SE=0.023) and 1.52 (SE=0.10), respectively.	('variation', 'Var', (144, 153))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))
128983	28598434	By implication, variants with such profiles probably represent a much larger class of susceptibility loci for RCC and hence a large number of variants remain to be discovered.	('RCC', 'Disease', (110, 113))	('variants', 'Var', (16, 24))	('RCC', 'Disease', 'MESH:C538614', (110, 113))
128984	28598434	In parallel, whole-exome and whole-genome sequencing of genetically enriched cases selected according to early age of onset or family history would provide new opportunities to discover rare variants associated with RCC.	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('RCC', 'Disease', (216, 219))	('variants', 'Var', (191, 199))
128985	28598434	As more RCC susceptibility alleles are discovered, deciphering the biological basis of risk variants should provide new insights into the biology of RCC that may lead to new approaches to prevention, early detection and therapeutic intervention.	('RCC', 'Disease', (149, 152))	('RCC', 'Disease', (8, 11))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('variants', 'Var', (92, 100))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
129004	28598434	PRS was calculated for 13 SNPs, one from each of the six previously identified loci and seven newly identified RCC risk loci (rs7105934, rs4765623, rs718314, rs11894252, rs12105918, rs6470588, rs4381241, rs67311347, rs10936602, rs2241261, rs11813268, rs74911261 and rs4903064), as follows: where PRSi is the risk score for individual i, xij is the number of risk alleles for the jth variant and wj is the weight [ln(OR)] of the jth variant.	('rs4381241', 'Var', (193, 202))	('rs67311347', 'Mutation', 'rs67311347', (204, 214))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('PRSi', 'Gene', (296, 300))	('rs11894252', 'Var', (158, 168))	('rs2241261', 'Mutation', 'rs2241261', (228, 237))	('rs11894252', 'Mutation', 'rs11894252', (158, 168))	('rs11813268', 'Var', (239, 249))	('rs4903064', 'Mutation', 'rs4903064', (266, 275))	('rs4903064', 'Var', (266, 275))	('rs74911261', 'Mutation', 'rs74911261', (251, 261))	('rs4381241', 'Mutation', 'rs4381241', (193, 202))	('rs4765623', 'Mutation', 'rs4765623', (137, 146))	('rs67311347', 'Var', (204, 214))	('rs2241261', 'Var', (228, 237))	('rs74911261', 'Var', (251, 261))	('rs10936602', 'Var', (216, 226))	('jth', 'Disease', (379, 382))	('rs12105918', 'Var', (170, 180))	('rs10936602', 'Mutation', 'rs10936602', (216, 226))	('rs718314', 'Var', (148, 156))	('rs7105934', 'Var', (126, 135))	('rs718314', 'Mutation', 'rs718314', (148, 156))	('rs6470588', 'Var', (182, 191))	('rs6470588', 'Mutation', 'rs6470588', (182, 191))	('rs4765623', 'Var', (137, 146))	('RCC', 'Disease', (111, 114))	('rs12105918', 'Mutation', 'rs12105918', (170, 180))	('PRSi', 'Gene', '5631', (296, 300))	('rs11813268', 'Mutation', 'rs11813268', (239, 249))	('rs7105934', 'Mutation', 'rs7105934', (126, 135))
129028	27612417	Remarkably, nearly 60% incidence of ccRCC owed to the defect in the von Hippel-Lindau (VHL) gene.	('VHL', 'Gene', '7428', (87, 90))	('RCC', 'Disease', (38, 41))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('von Hippel-Lindau', 'Gene', '7428', (68, 85))	('defect', 'Var', (54, 60))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('VHL', 'Gene', (87, 90))	('von Hippel-Lindau', 'Gene', (68, 85))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
129066	27612417	Patients with JIH score 3 had a 58.3% 6-year survival rate for OS and 58.0% for RFS while JIH score 0 patients had a much better 96.7% 6-year survival rate for OS and 91.6% for RFS.	('RFS', 'Chemical', '-', (80, 83))	('patients', 'Species', '9606', (102, 110))	('JIH score 3', 'Var', (14, 25))	('Patients', 'Species', '9606', (0, 8))	('RFS', 'Chemical', '-', (177, 180))	('RFS', 'Disease', (80, 83))
129111	27612417	The author constructed a 5-biomarker panel composed of PI3K, PTEN, p-mTOR, p-4EBP1 and p-S6, which were all sprinkled throughout the mTOR pathway.	('mTOR', 'Gene', (69, 73))	('p-S6', 'Gene', (87, 91))	('PI3K', 'Var', (55, 59))	('mTOR', 'Gene', '2475', (133, 137))	('PI3K', 'molecular_function', 'GO:0016303', ('55', '59'))	('PTEN', 'Gene', (61, 65))	('p-S6', 'Gene', '338413', (87, 91))	('mTOR', 'Gene', (133, 137))	('PTEN', 'Gene', '5728', (61, 65))	('p-4EBP1', 'Var', (75, 82))	('mTOR', 'Gene', '2475', (69, 73))
129158	27906674	Inactivation of the VHL tumor suppressor gene is observed in all inherited forms of RCC and in many of the sporadically occurring tumors.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor suppressor', 'biological_process', 'GO:0051726', ('24', '40'))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('VHL tumor', 'Disease', (20, 29))	('RCC', 'Disease', (84, 87))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('24', '40'))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('VHL tumor', 'Disease', 'MESH:D006623', (20, 29))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('observed', 'Reg', (49, 57))	('Inactivation', 'Var', (0, 12))
129166	27906674	In a previous study we could show that high mRNA expression of CK2alpha was associated with poor prognosis in ccRCC.	('high mRNA', 'Var', (39, 48))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('CK2alpha', 'Gene', '1459', (63, 71))	('CK2alpha', 'Gene', (63, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))
129177	27906674	The correlation of mRNA expression of the different CK2 subunits in ccRCC to Fuhrman grade, tumor stage and metastasis showed a significant higher CK2alpha expression in high Fuhrman grade (p=0.001), high tumor stage (p=0.007) and a tendency towards a higher rate of metastasis (p=0.07), Figure 2A.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('high tumor', 'Disease', (200, 210))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('metastasis', 'CPA', (267, 277))	('higher', 'PosReg', (140, 146))	('tumor', 'Disease', (92, 97))	('high Fuhrman grade', 'Var', (170, 188))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('CK2alpha', 'Gene', '1459', (147, 155))	('high tumor', 'Disease', 'MESH:D009369', (200, 210))	('CK2alpha', 'Gene', (147, 155))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('expression', 'MPA', (156, 166))
129188	27906674	There was a statistically significant correlation between the Nuc+ expression group (log-rank, p=0.02, HR = 8.11) and poor PFS and a tendency toward a correlation with DSS (log rank p=0.06, HR = 5.6) (Figure 4).	('DSS', 'Chemical', '-', (168, 171))	('DSS', 'Disease', (168, 171))	('Nuc', 'Gene', '4924', (62, 65))	('S', 'Chemical', 'MESH:D013455', (170, 171))	('S', 'Chemical', 'MESH:D013455', (125, 126))	('S', 'Chemical', 'MESH:D013455', (169, 170))	('Nuc', 'Gene', (62, 65))	('poor', 'Var', (118, 122))
129189	27906674	In a multivariate cox regression analysis including the 40 patients with high stage ccRCC and the variables CK2alpha nuclear expression, Fuhrman grade G1-G2/G3-G4, tumor size <7/>=7 cm, VHL mutation and gender, nuclear expression of CK2alpha lost its prognostic value (Table 4).	('cox', 'Gene', (18, 21))	('mutation', 'Var', (190, 198))	('CK2alpha', 'Gene', (108, 116))	('tumor', 'Disease', (164, 169))	('VHL', 'Gene', (186, 189))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('VHL', 'Gene', '7428', (186, 189))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('cox', 'Gene', '1351', (18, 21))	('patients', 'Species', '9606', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('CK2alpha', 'Gene', '1459', (233, 241))	('CK2alpha', 'Gene', (233, 241))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('lost', 'NegReg', (242, 246))	('RCC', 'Disease', (86, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('CK2alpha', 'Gene', '1459', (108, 116))
129194	27906674	However, CX-4945 significantly inhibited the proliferation of Caki-2 cells compared to vehicle-treated controls (Figure 6A and 6C, 49 % of control at confluence (*indicates p<0.01 vs. vehicle)).	('Caki-2', 'CellLine', 'CVCL:0235', (62, 68))	('proliferation', 'CPA', (45, 58))	('CX-4945', 'Var', (9, 16))	('CX-4945', 'Chemical', 'MESH:C555142', (9, 16))	('inhibited', 'NegReg', (31, 40))
129215	27906674	Several functions of CK2 have been identified through which high CK2 activity favors neoplastic growth; it enhances the transforming potential of oncogenes, it supports neovascularization, it potentiates the multi-drug resistance phenotype, and it generates abnormal pro-survival and anti-apoptotic signals.	('enhances', 'PosReg', (107, 115))	('supports', 'PosReg', (160, 168))	('neovascularization', 'CPA', (169, 187))	('CK2', 'Protein', (65, 68))	('transforming potential', 'CPA', (120, 142))	('drug resistance', 'biological_process', 'GO:0009315', ('214', '229'))	('drug resistance', 'biological_process', 'GO:0042493', ('214', '229'))	('activity', 'MPA', (69, 77))	('high', 'Var', (60, 64))	('drug resistance', 'Phenotype', 'HP:0020174', (214, 229))	('multi-drug resistance phenotype', 'MPA', (208, 239))	('pro-survival', 'CPA', (267, 279))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('anti-apoptotic signals', 'CPA', (284, 306))	('favors', 'PosReg', (78, 84))	('neoplastic growth', 'CPA', (85, 102))	('pro-survival', 'biological_process', 'GO:0043066', ('267', '279'))	('CK2', 'Gene', (21, 24))	('potentiates', 'PosReg', (192, 203))
129218	27906674	PI3K/Akt signaling is known to regulate the response of endothelial cells to growth factor signaling including proliferation, migration and tube formation and represents thereby a molecular mechanism through, which CK2 can drive angiogenesis.	('angiogenesis', 'biological_process', 'GO:0001525', ('229', '241'))	('tube formation', 'CPA', (140, 154))	('Akt', 'Gene', '207', (5, 8))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('tube formation', 'biological_process', 'GO:0035148', ('140', '154'))	('angiogenesis', 'CPA', (229, 241))	('proliferation', 'CPA', (111, 124))	('Akt signaling', 'biological_process', 'GO:0043491', ('5', '18'))	('drive', 'PosReg', (223, 228))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('Akt', 'Gene', (5, 8))	('migration', 'CPA', (126, 135))	('CK2', 'Var', (215, 218))
129220	27906674	HIF-1alpha is often highly active in renal cell carcinoma due to mutations in VHL and subsequently accumulation of HIF-1alpha.	('HIF-1alpha', 'Gene', (115, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('VHL', 'Gene', (78, 81))	('renal cell carcinoma', 'Disease', (37, 57))	('HIF-1alpha', 'Gene', '3091', (0, 10))	('VHL', 'Gene', '7428', (78, 81))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (37, 57))	('HIF-1alpha', 'Gene', '3091', (115, 125))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (37, 57))	('accumulation', 'PosReg', (99, 111))	('mutations', 'Var', (65, 74))	('HIF-1alpha', 'Gene', (0, 10))
129226	27906674	However, Roelants et al did show that CX-4945 inhibited phosphorylation of AKT, p21 and alpha-catenin in renal cancer cell lines and moreover, they could show that CX-4945-induced p38MAPK activation correlated with increased p53 expression.	('p53', 'Gene', (225, 228))	('CX-4945-induced', 'Var', (164, 179))	('CX-4945', 'Chemical', 'MESH:C555142', (164, 171))	('CX-4945', 'Chemical', 'MESH:C555142', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('renal cancer', 'Disease', (105, 117))	('AKT', 'Gene', (75, 78))	('p21', 'Gene', (80, 83))	('phosphorylation', 'MPA', (56, 71))	('renal cancer', 'Phenotype', 'HP:0009726', (105, 117))	('p21', 'Gene', '644914', (80, 83))	('MAPK', 'molecular_function', 'GO:0004707', ('183', '187'))	('phosphorylation', 'biological_process', 'GO:0016310', ('56', '71'))	('alpha-catenin', 'Protein', (88, 101))	('inhibited', 'NegReg', (46, 55))	('renal cancer', 'Disease', 'MESH:D007680', (105, 117))	('expression', 'MPA', (229, 239))	('CX-4945', 'Var', (38, 45))	('AKT', 'Gene', '207', (75, 78))	('MAPK activation', 'biological_process', 'GO:0000187', ('183', '198'))	('p38MAPK', 'Enzyme', (180, 187))	('p53', 'Gene', '7157', (225, 228))	('increased', 'PosReg', (215, 224))	('activation', 'PosReg', (188, 198))
129232	27906674	The CK2 inhibitor CX-4945 exhibits anticancer activity by down-regulation of PI3K/Akt, p21 and HIF-1alpha and by that affects the transcriptional regulation of factors involved in cancer proliferation, angiogenesis and pro-inflammatory cytokine production.	('affects', 'Reg', (118, 125))	('regulation', 'biological_process', 'GO:0065007', ('63', '73'))	('PI3K', 'molecular_function', 'GO:0016303', ('77', '81'))	('CX-4945', 'Var', (18, 25))	('cancer', 'Disease', (39, 45))	('p21', 'Gene', (87, 90))	('p21', 'Gene', '644914', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', (180, 186))	('HIF-1alpha', 'Gene', '3091', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('Akt', 'Gene', (82, 85))	('down-regulation', 'NegReg', (58, 73))	('angiogenesis', 'biological_process', 'GO:0001525', ('202', '214'))	('transcriptional regulation', 'MPA', (130, 156))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('Akt', 'Gene', '207', (82, 85))	('CX-4945', 'Chemical', 'MESH:C555142', (18, 25))	('angiogenesis', 'CPA', (202, 214))	('HIF-1alpha', 'Gene', (95, 105))	('cytokine production', 'biological_process', 'GO:0001816', ('236', '255'))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('regulation', 'biological_process', 'GO:0065007', ('146', '156'))
129235	27906674	In our study we observed a significant reduced proliferation of the cells treated with CX-4945 compared to vehicle (reduced to 49% of control), whereas the cells treated with E9 grew in almost same density as vehicle.	('proliferation', 'CPA', (47, 60))	('CX-4945', 'Var', (87, 94))	('reduced', 'NegReg', (39, 46))	('CX-4945', 'Chemical', 'MESH:C555142', (87, 94))
129239	27906674	The different response in cell proliferation by treatment with CX-4945 and E9 in our study might be caused by distinct and/or unrelated intracellular targets of the two inhibitors.	('intracellular', 'cellular_component', 'GO:0005622', ('136', '149'))	('CX-4945', 'Var', (63, 70))	('cell proliferation', 'CPA', (26, 44))	('CX-4945', 'Chemical', 'MESH:C555142', (63, 70))	('cell proliferation', 'biological_process', 'GO:0008283', ('26', '44'))
129244	27906674	Thus, inhibition of CK2 is a promising approach for ccRCC treatment in combination with other treatment modalities.	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('CK2', 'Protein', (20, 23))	('inhibition', 'Var', (6, 16))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))
129306	32411604	Analysis from The Human Protein Atlas dataset shows that high collagen 1 or 4A2, fibronectin, entactin, or syndecan 3 expression is associated with poor prognosis whereas high collagen 4A3, syndecan 4, or glypican 4 expression is associated with increased patient survival.	('glypican 4', 'Gene', (205, 215))	('syndecan', 'molecular_function', 'GO:0015023', ('107', '115'))	('fibronectin', 'Gene', '2335', (81, 92))	('high', 'Var', (57, 61))	('collagen', 'molecular_function', 'GO:0005202', ('176', '184'))	('syndecan', 'molecular_function', 'GO:0015023', ('190', '198'))	('syndecan 4', 'Gene', (190, 200))	('syndecan 3', 'Gene', '9672', (107, 117))	('Human', 'Species', '9606', (18, 23))	('glypican', 'molecular_function', 'GO:0015017', ('205', '213'))	('syndecan 4', 'Gene', '6385', (190, 200))	('fibronectin', 'Gene', (81, 92))	('increased', 'PosReg', (246, 255))	('syndecan 3', 'Gene', (107, 117))	('glypican 4', 'Gene', '2239', (205, 215))	('collagen', 'molecular_function', 'GO:0005202', ('62', '70'))	('patient', 'Species', '9606', (256, 263))
129318	32411604	Loss of VHL deregulates and constitutively activates hypoxia-inducible factor HIF1alpha and HIF2alpha.	('HIF2alpha', 'Gene', '2034', (92, 101))	('hypoxia', 'Disease', (53, 60))	('hypoxia', 'Disease', 'MESH:D000860', (53, 60))	('HIF1alpha', 'Gene', '3091', (78, 87))	('deregulates', 'Reg', (12, 23))	('HIF2alpha', 'Gene', (92, 101))	('activates', 'PosReg', (43, 52))	('HIF1alpha', 'Gene', (78, 87))	('Loss', 'Var', (0, 4))	('VHL', 'Gene', (8, 11))
129321	32411604	Nevertheless, a recent meta-analysis study from Kim and colleagues found no correlation between VHL inactivation and patient survival in ccRCC.	('inactivation', 'Var', (100, 112))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('VHL', 'Gene', (96, 99))	('patient', 'Species', '9606', (117, 124))
129342	32411604	RCC cells expressed FN1 and silencing its expression inhibits cell proliferation and invasion in vitro.	('cell proliferation', 'biological_process', 'GO:0008283', ('62', '80'))	('expression', 'MPA', (42, 52))	('FN1', 'Gene', (20, 23))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('inhibits', 'NegReg', (53, 61))	('silencing', 'Var', (28, 37))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('RCC', 'Disease', (0, 3))
129350	32411604	The human 786-O cell line is derived from ccRCC mutated on the VHL gene.	('human', 'Species', '9606', (4, 9))	('mutated', 'Var', (48, 55))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('VHL', 'Gene', (63, 66))
129389	32411604	Furthermore, patients with high Col 4A3 expression have better survival rate in ccRCC (Table 2).	('Col 4A3', 'Gene', '1285', (32, 39))	('patients', 'Species', '9606', (13, 21))	('survival', 'CPA', (63, 71))	('Col 4A3', 'Gene', (32, 39))	('high', 'Var', (27, 31))	('better', 'PosReg', (56, 62))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))
129393	32411604	However, high Col 4A3, syndecan 4, and glypican 4 expression is of good prognosis in RCC (Table 2).	('Col 4A3', 'Gene', '1285', (14, 21))	('glypican 4', 'Gene', (39, 49))	('Col 4A3', 'Gene', (14, 21))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('glypican', 'molecular_function', 'GO:0015017', ('39', '47'))	('syndecan 4', 'Gene', '6385', (23, 33))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', (85, 88))	('syndecan 4', 'Gene', (23, 33))	('glypican 4', 'Gene', '2239', (39, 49))	('syndecan', 'molecular_function', 'GO:0015023', ('23', '31'))	('high', 'Var', (9, 13))
129418	32411604	Analysis of the 5-year patient survival in the The Human Protein Atlas reveals a negative correlation between ccRCC and pRCC and high Col 1 expression.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('negative', 'NegReg', (81, 89))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('high', 'Var', (129, 133))	('RCC', 'Disease', (121, 124))	('expression', 'MPA', (140, 150))	('Human', 'Species', '9606', (51, 56))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('pRCC', 'Phenotype', 'HP:0006766', (120, 124))	('patient', 'Species', '9606', (23, 30))
129457	29187877	CKAP4 silencing also significantly increased cell population at G2/M phase, while not influencing cell apoptosis.	('cell population at G2/M phase', 'CPA', (45, 74))	('increased', 'PosReg', (35, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('M phase', 'biological_process', 'GO:0000279', ('67', '74'))	('CKAP4', 'Gene', (0, 5))	('silencing', 'Var', (6, 15))	('CKAP4', 'Gene', '10970', (0, 5))
129458	29187877	Silencing or upregulation of CKAP4 resulted in decreased or increased CCNB1/2 expressions, respectively.	('CCNB1/2', 'Gene', (70, 77))	('expressions', 'MPA', (78, 89))	('CKAP4', 'Gene', (29, 34))	('CCNB1/2', 'Gene', '891;9133', (70, 77))	('CKAP4', 'Gene', '10970', (29, 34))	('upregulation', 'PosReg', (13, 25))	('Silencing', 'Var', (0, 9))	('increased', 'PosReg', (60, 69))
129466	29187877	Genetic alterations at a much lower frequency that are usually overlooked could in fact impact drastically on prognosis and patients with such genotype, despite receiving a variety of anti-VEGF regimes, still succumb soon after diagnosis.	('Genetic alterations', 'Var', (0, 19))	('impact', 'Reg', (88, 94))	('VEGF', 'Gene', '7422', (189, 193))	('VEGF', 'Gene', (189, 193))	('patients', 'Species', '9606', (124, 132))
129509	29187877	Patients with overexpressed CKAP4 had significantly worsened overall survival and shorter progression-free period (Fig 1D).	('overexpressed', 'Var', (14, 27))	('CKAP4', 'Gene', '10970', (28, 33))	('progression-free period', 'CPA', (90, 113))	('Patients', 'Species', '9606', (0, 8))	('CKAP4', 'Gene', (28, 33))	('overall', 'MPA', (61, 68))	('worsened', 'NegReg', (52, 60))	('shorter', 'NegReg', (82, 89))
129511	29187877	CKAP4 silencing significantly inhibited cell proliferation of ccRCC cells (Fig 2D).	('inhibited', 'NegReg', (30, 39))	('cell proliferation of', 'CPA', (40, 61))	('CKAP4', 'Gene', (0, 5))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('RCC', 'Disease', (64, 67))	('cell proliferation', 'biological_process', 'GO:0008283', ('40', '58'))	('silencing', 'Var', (6, 15))	('CKAP4', 'Gene', '10970', (0, 5))
129513	29187877	Silencing of CKAP4 also significantly inhibited invasion and migration of ccRCC cells (Fig 2E).	('CKAP4', 'Gene', '10970', (13, 18))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('inhibited', 'NegReg', (38, 47))	('CKAP4', 'Gene', (13, 18))	('Silencing', 'Var', (0, 9))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))
129515	29187877	Inhibition of CKAP4 significantly induced increased cell population at G2/M phase of cell cycle of ccRCC cells (Fig 3A).	('increased', 'PosReg', (42, 51))	('CKAP4', 'Gene', '10970', (14, 19))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('M phase', 'biological_process', 'GO:0000279', ('74', '81'))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('RCC', 'Disease', (101, 104))	('cell cycle', 'biological_process', 'GO:0007049', ('85', '95'))	('Inhibition', 'Var', (0, 10))	('cell population at G2/M phase of cell cycle', 'CPA', (52, 95))	('CKAP4', 'Gene', (14, 19))
129518	29187877	In apoptosis assay, neither silencing nor upregulation of CKAP4 showed significant alteration in apoptotic profile (Fig 3B).	('CKAP4', 'Gene', '10970', (58, 63))	('apoptotic', 'MPA', (97, 106))	('apoptosis', 'biological_process', 'GO:0097194', ('3', '12'))	('apoptosis', 'biological_process', 'GO:0006915', ('3', '12'))	('CKAP4', 'Gene', (58, 63))	('silencing', 'Var', (28, 37))	('upregulation', 'PosReg', (42, 54))
129519	29187877	CKAP4 silencing induced apparent decreased levels of Cyclin B1, Cyclin B2, and CDK1, while having no impact on PARP cleavage, which indicated cell apoptosis (Fig 3C).	('CDK', 'molecular_function', 'GO:0004693', ('79', '82'))	('Cyclin B2', 'Gene', '9133', (64, 73))	('Cyclin B2', 'Gene', (64, 73))	('Cyclin B1', 'Gene', '891', (53, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('147', '156'))	('CKAP4', 'Gene', (0, 5))	('PARP', 'Gene', '1302', (111, 115))	('Cyclin', 'molecular_function', 'GO:0016538', ('64', '70'))	('PARP', 'Gene', (111, 115))	('CDK1', 'Gene', '983', (79, 83))	('apoptosis', 'biological_process', 'GO:0006915', ('147', '156'))	('decreased', 'NegReg', (33, 42))	('CDK1', 'Gene', (79, 83))	('Cyclin', 'molecular_function', 'GO:0016538', ('53', '59'))	('silencing', 'Var', (6, 15))	('CKAP4', 'Gene', '10970', (0, 5))	('Cyclin B1', 'Gene', (53, 62))
129521	29187877	Using the CDK/CCNB inhibitor (RO-3306), we demonstrated that RO-3306 significantly inhibited anchorage-independent growth in terms of colony formation in ccRCC cells (Fig 4A).	('CCNB', 'Gene', (14, 18))	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('ccRCC', 'Phenotype', 'HP:0006770', (154, 159))	('RCC', 'Disease', (156, 159))	('RO-3306', 'Chemical', 'MESH:C512984', (61, 68))	('RO-3306', 'Chemical', 'MESH:C512984', (30, 37))	('formation', 'biological_process', 'GO:0009058', ('141', '150'))	('RO-3306', 'Var', (61, 68))	('inhibited', 'NegReg', (83, 92))	('CDK', 'molecular_function', 'GO:0004693', ('10', '13'))	('colony formation', 'CPA', (134, 150))	('anchorage-independent growth', 'CPA', (93, 121))	('CCNB', 'Gene', '891', (14, 18))
129522	29187877	Also, administration of RO-3306 to 786-O xenograft mice significantly inhibited tumor growth (Fig 4B).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('mice', 'Species', '10090', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('RO-3306', 'Chemical', 'MESH:C512984', (24, 31))	('inhibited', 'NegReg', (70, 79))	('RO-3306', 'Var', (24, 31))
129525	29187877	Indeed, overexpressed CKAP4, though only in 5% of cases, was significantly associated worsened prognosis and shorter disease-free period.	('disease-free period', 'CPA', (117, 136))	('CKAP4', 'Gene', (22, 27))	('overexpressed', 'Var', (8, 21))	('prognosis', 'CPA', (95, 104))	('CKAP4', 'Gene', '10970', (22, 27))	('shorter', 'NegReg', (109, 116))	('worsened', 'NegReg', (86, 94))
129526	29187877	In particular, patients with CKAP4 overexpression showed a drastically fall of overall survival, indicating a strong pro-tumorigenic role.	('fall', 'Phenotype', 'HP:0002527', (71, 75))	('patients', 'Species', '9606', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('CKAP4', 'Gene', (29, 34))	('overexpression', 'Var', (35, 49))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('CKAP4', 'Gene', '10970', (29, 34))	('fall', 'NegReg', (71, 75))	('overall survival', 'MPA', (79, 95))
129539	29187877	Dysregulation of G2/M phase in ccRCC has been reported in many studies, indicating the role G2/M checkpoint could have been underestimated.	('G2/M', 'CPA', (17, 21))	('G2/M checkpoint', 'biological_process', 'GO:0000075', ('92', '107'))	('Dysregulation', 'Var', (0, 13))	('M phase', 'biological_process', 'GO:0000279', ('20', '27'))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (31, 36))
129540	29187877	Pan et al show that EIF3D silencing suppresses renal cell carcinoma tumorigenesis via inducing G2/M arrest through downregulation of Cyclin B1/CDK1 signaling.	('CDK', 'molecular_function', 'GO:0004693', ('143', '146'))	('G2/M arrest', 'MPA', (95, 106))	('suppresses', 'NegReg', (36, 46))	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('downregulation', 'NegReg', (115, 129))	('Cyclin B1', 'Gene', (133, 142))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (47, 67))	('CDK1', 'Gene', '983', (143, 147))	('CDK1', 'Gene', (143, 147))	('Cyclin B1', 'Gene', '891', (133, 142))	('EIF3D', 'Gene', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('EIF3', 'cellular_component', 'GO:0005852', ('20', '24'))	('inducing', 'PosReg', (86, 94))	('EIF3D', 'Gene', '8664', (20, 25))	('signaling', 'biological_process', 'GO:0023052', ('148', '157'))	('renal cell carcinoma', 'Disease', (47, 67))	('Cyclin', 'molecular_function', 'GO:0016538', ('133', '139'))	('silencing', 'Var', (26, 35))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (47, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
129542	29187877	Li et al report inhibition of gamma-secretase by retinoic acid chalcone (RAC) induces G2/M arrest and triggers apoptosis in renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (124, 144))	('G2/M', 'MPA', (86, 90))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (124, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('triggers', 'Reg', (102, 110))	('RAC', 'Chemical', '-', (73, 76))	('gamma-secretase', 'Protein', (30, 45))	('retinoic acid chalcone', 'Chemical', '-', (49, 71))	('renal cell carcinoma', 'Disease', (124, 144))	('apoptosis', 'CPA', (111, 120))	('inhibition', 'Var', (16, 26))
129546	29187877	Wu et al report that inhibition of gamma-secretase induces G2/M arrest and triggers apoptosis in renal cell carcinoma.	('G2/M arrest', 'CPA', (59, 70))	('gamma-secretase', 'Protein', (35, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (97, 117))	('apoptosis', 'CPA', (84, 93))	('triggers', 'Reg', (75, 83))	('induces', 'Reg', (51, 58))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (97, 117))	('inhibition', 'Var', (21, 31))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('renal cell carcinoma', 'Disease', (97, 117))
129565	29088295	In this malignancy, high levels of LRP1 mRNA were associated with worsened patient survival.	('patient survival', 'CPA', (75, 91))	('high levels', 'Var', (20, 31))	('mRNA', 'MPA', (40, 44))	('patient', 'Species', '9606', (75, 82))	('malignancy', 'Disease', 'MESH:D009369', (8, 18))	('malignancy', 'Disease', (8, 18))	('LRP1', 'Protein', (35, 39))	('worsened', 'NegReg', (66, 74))
129568	29088295	LRP2 was the only LRP for which high levels of mRNA expression correlated with improved patient survival.	('high', 'Var', (32, 36))	('LRP', 'Gene', '4035', (18, 21))	('patient', 'Species', '9606', (88, 95))	('improved', 'PosReg', (79, 87))	('LRP', 'Gene', (0, 3))	('LRP', 'Gene', (18, 21))	('mRNA expression', 'MPA', (47, 62))	('LRP2', 'Gene', (0, 4))	('LRP2', 'Gene', '4036', (0, 4))	('patient survival', 'CPA', (88, 104))	('LRP', 'Gene', '4035', (0, 3))
129599	29088295	The CVs were 0.095, 0.106, and 0.109 for TARDP, HNRNPK, and WDR33, respectively, reflecting variability in gene expression across different categories of cancer that was no greater than the variability observed in different specimens of the same malignancy.	('HNRNPK', 'Gene', (48, 54))	('HNRNPK', 'Gene', '3190', (48, 54))	('gene expression', 'biological_process', 'GO:0010467', ('107', '122'))	('0.109', 'Var', (31, 36))	('WDR33', 'Gene', '55339', (60, 65))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('malignancy', 'Disease', 'MESH:D009369', (246, 256))	('malignancy', 'Disease', (246, 256))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('WDR33', 'Gene', (60, 65))
129623	29088295	In this cancer, high levels of LRP1 mRNA expression were associated with decreased survival in the 50%/50% comparison (p<0.0001) and in the 25%/25% comparison (p<0.0005) (Fig 3).	('mRNA expression', 'MPA', (36, 51))	('cancer', 'Disease', (8, 14))	('decreased', 'NegReg', (73, 82))	('high', 'Var', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('LRP1', 'Protein', (31, 35))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('survival', 'MPA', (83, 91))
129626	29088295	This is the only cancer in which we detected a correlation between high levels of expression of an LRP and increased patient survival.	('LRP', 'Gene', (99, 102))	('high levels of expression', 'Var', (67, 92))	('increased', 'PosReg', (107, 116))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('patient survival', 'CPA', (117, 133))	('cancer', 'Disease', (17, 23))	('LRP', 'Gene', '4035', (99, 102))	('patient', 'Species', '9606', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
129631	29088295	LDLR mRNA expression was associated with decreased patient survival in pancreatic adenocarcinoma.	('LDLR', 'Gene', (0, 4))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (71, 96))	('decreased', 'NegReg', (41, 50))	('mRNA expression', 'Var', (5, 20))	('patient', 'Species', '9606', (51, 58))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (71, 96))	('pancreatic adenocarcinoma', 'Disease', (71, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
129634	29088295	We did not consider somatic or germline mutations in LRPs that may alter LRP structure and/or function.	('alter', 'Reg', (67, 72))	('LRP', 'Gene', '4035', (73, 76))	('LRP', 'Gene', '4035', (53, 56))	('LRP', 'Gene', (73, 76))	('function', 'MPA', (94, 102))	('germline mutations', 'Var', (31, 49))	('structure', 'MPA', (77, 86))	('LRP', 'Gene', (53, 56))
129641	29088295	As a result, when the effects of LRP1 mRNA abundance on patient survival were examined, considering all gliomas comprehensively (grades 2+3+4), high levels of LRP1 mRNA were significantly associated with improved patient survival.	('gliomas', 'Disease', (104, 111))	('patient survival', 'CPA', (213, 229))	('patient', 'Species', '9606', (213, 220))	('high', 'Var', (144, 148))	('LRP1', 'Gene', (159, 163))	('improved', 'PosReg', (204, 212))	('mRNA', 'MPA', (164, 168))	('patient', 'Species', '9606', (56, 63))	('gliomas', 'Disease', 'MESH:D005910', (104, 111))	('gliomas', 'Phenotype', 'HP:0009733', (104, 111))
129647	29088295	Germ-line polymorphisms in the LRP2 gene may be associated with increased risk for recurrence in prostate cancer and somatic mutations in LRP2 have been identified in gastric cancer.	('mutations', 'Var', (125, 134))	('LRP2', 'Gene', '4036', (138, 142))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('gastric cancer', 'Disease', (167, 181))	('associated', 'Reg', (48, 58))	('prostate cancer', 'Disease', 'MESH:D011471', (97, 112))	('identified', 'Reg', (153, 163))	('gastric cancer', 'Disease', 'MESH:D013274', (167, 181))	('polymorphisms', 'Var', (10, 23))	('prostate cancer', 'Phenotype', 'HP:0012125', (97, 112))	('LRP2', 'Gene', (138, 142))	('gastric cancer', 'Phenotype', 'HP:0012126', (167, 181))	('LRP2', 'Gene', (31, 35))	('prostate cancer', 'Disease', (97, 112))	('LRP2', 'Gene', '4036', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
129653	29088295	Other members of this signaling pathway are well-characterized oncogenes and tumor suppressors, which when mutated in the germline or in cancer tissue, regulate carcinogenesis and cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('mutated', 'Var', (107, 114))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('signaling pathway', 'biological_process', 'GO:0007165', ('22', '39'))	('carcinogenesis', 'Disease', 'MESH:D063646', (161, 175))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('carcinogenesis', 'Disease', (161, 175))	('regulate', 'Reg', (152, 160))	('tumor', 'Disease', (77, 82))	('cancer', 'Disease', (180, 186))
129663	29088295	In patients with adenocarcinoma of the pancreas, high levels of LDLR mRNA expression were associated with worsened patient survival.	('high levels of LDLR', 'Phenotype', 'HP:0003141', (49, 68))	('adenocarcinoma of the pancreas', 'Disease', 'MESH:D010190', (17, 47))	('adenocarcinoma of the pancreas', 'Disease', (17, 47))	('high levels', 'Var', (49, 60))	('patient', 'Species', '9606', (3, 10))	('patient survival', 'CPA', (115, 131))	('adenocarcinoma of the pancreas', 'Phenotype', 'HP:0002894', (17, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('worsened', 'NegReg', (106, 114))	('patients', 'Species', '9606', (3, 11))	('patient', 'Species', '9606', (115, 122))	('LDLR', 'Protein', (64, 68))
129699	29970967	To further clarify the prognostic and clinicopathological value of sarcomatoid differentiation in RCC, we conducted a systematic review and meta-analysis to evaluate whether the presence of sarcomatoid differentiation has a prognostic impact on cancer-specific survival (CSS), overall survival (OS), recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific mortality (CSM).	('progression-free survival', 'CPA', (332, 357))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('impact', 'Reg', (235, 241))	('sarcomatoid differentiation', 'Disease', (190, 217))	('overall survival', 'CPA', (277, 293))	('OS', 'Chemical', '-', (295, 297))	('cancer', 'Disease', 'MESH:D009369', (369, 375))	('RCC', 'Disease', (98, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('sarcomatoid differentiation', 'Disease', 'MESH:C538614', (190, 217))	('CSS', 'Chemical', '-', (271, 274))	('cancer', 'Disease', (245, 251))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('presence', 'Var', (178, 186))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('sarcomatoid differentiation', 'Disease', (67, 94))	('recurrence-free', 'Disease', (300, 315))	('cancer', 'Disease', (369, 375))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('sarcomatoid differentiation', 'Disease', 'MESH:C538614', (67, 94))
129809	31824846	Long Non-coding RNA SNHG12 Functions as a Competing Endogenous RNA to Regulate MDM4 Expression by Sponging miR-129-5p in Clear Cell Renal Cell Carcinoma Clear cell renal cell carcinoma (ccRCC), the most common histological subtype of kidney cancer, shows poor prognosis, and non-sensitivity to radiotherapy or chemotherapy.	('Clear cell renal cell carcinoma', 'Disease', (153, 184))	('miR-129-5p', 'Gene', (107, 117))	('kidney cancer', 'Phenotype', 'HP:0009726', (234, 247))	('RNA', 'cellular_component', 'GO:0005562', ('63', '66'))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('kidney cancer', 'Disease', (234, 247))	('Carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('SNHG12', 'Gene', (20, 26))	('miR-129-5p', 'Gene', '100302178', (107, 117))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (164, 184))	('MDM4', 'Gene', '4194', (79, 83))	('MDM4', 'Gene', (79, 83))	('Sponging', 'Var', (98, 106))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (121, 152))	('SNHG12', 'Gene', '85028', (20, 26))	('ccRCC', 'Disease', 'MESH:D002292', (186, 191))	('Clear Cell Renal Cell Carcinoma', 'Disease', (121, 152))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:D002292', (121, 152))	('kidney cancer', 'Disease', 'MESH:D007680', (234, 247))	('ccRCC', 'Disease', (186, 191))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (132, 152))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (153, 184))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('ccRCC', 'Phenotype', 'HP:0006770', (186, 191))	('RNA', 'cellular_component', 'GO:0005562', ('16', '19'))
129825	31824846	Besides, cellular behaviors of tumor cells and different stages of tumor progression are closely correlated with abnormally expressed lncRNAs.	('abnormally expressed', 'Var', (113, 133))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('correlated', 'Reg', (97, 107))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('cellular behaviors', 'CPA', (9, 27))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
129867	31824846	Compared with HK2, the expression of SNHG12 was increased in 786-O, Caki-1 and 769-P, but did not change in ACHN (Figure 2A).	('increased', 'PosReg', (48, 57))	('786-O', 'Chemical', 'MESH:C002925', (61, 66))	('HK2', 'molecular_function', 'GO:0008256', ('14', '17'))	('SNHG12', 'Gene', (37, 43))	('expression', 'MPA', (23, 33))	('Caki-1', 'CellLine', 'CVCL:0234', (68, 74))	('769-P', 'Var', (79, 84))	('SNHG12', 'Gene', '85028', (37, 43))	('HK2', 'Gene', '3099', (14, 17))	('HK2', 'Gene', (14, 17))
129868	31824846	786-O and 769-P were then subjected to experiments in vitro.	('786-O', 'Chemical', 'MESH:C002925', (0, 5))	('786-O', 'Var', (0, 5))	('769-P', 'Var', (10, 15))
129875	31824846	Collectively, knockdown of SNHG12 inhibited the viability and mobility of ccRCC in vitro.	('SNHG12', 'Gene', (27, 33))	('ccRCC', 'Disease', (74, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('ccRCC', 'Disease', 'MESH:D002292', (74, 79))	('SNHG12', 'Gene', '85028', (27, 33))	('viability', 'CPA', (48, 57))	('inhibited', 'NegReg', (34, 43))	('mobility', 'CPA', (62, 70))	('knockdown', 'Var', (14, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))
129905	31824846	Silencing SNHG12 inhibited the proliferation, migration and invasion of ccRCC cells.	('SNHG12', 'Gene', (10, 16))	('invasion', 'CPA', (60, 68))	('proliferation', 'CPA', (31, 44))	('migration', 'CPA', (46, 55))	('SNHG12', 'Gene', '85028', (10, 16))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('inhibited', 'NegReg', (17, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('ccRCC', 'Disease', (72, 77))	('Silencing', 'Var', (0, 9))	('ccRCC', 'Disease', 'MESH:D002292', (72, 77))
129943	29707153	Finally, the kallikreins can activate one another, and cross-activation of kallikreins may be related to malignancies.	('malignancies', 'Disease', (105, 117))	('kallikrein', 'Gene', (75, 85))	('kallikrein', 'Gene', (13, 23))	('kallikrein', 'Gene', '9622', (75, 85))	('kallikrein', 'Gene', '9622', (13, 23))	('cross-activation', 'Var', (55, 71))	('malignancies', 'Disease', 'MESH:D009369', (105, 117))	('activate', 'PosReg', (29, 37))	('related', 'Reg', (94, 101))
130017	29707153	Thyroid hormones regulate kallikrein levels, and the dysfunction of thyroid hormones during thyroid carcinoma may lead to the dramatic changes in the kallikreins' expression.	('changes', 'Reg', (135, 142))	('kallikrein', 'molecular_function', 'GO:0004293', ('26', '36'))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (92, 109))	('kallikrein', 'Gene', (26, 36))	('kallikrein', 'Gene', '9622', (150, 160))	('dysfunction of thyroid hormones', 'Phenotype', 'HP:0002930', (53, 84))	('kallikrein', 'Gene', (150, 160))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (92, 109))	('kallikrein', 'Gene', '9622', (26, 36))	('expression', 'MPA', (163, 173))	('thyroid carcinoma', 'Disease', (92, 109))	('dysfunction', 'Var', (53, 64))	('kallikrein', 'molecular_function', 'GO:0003807', ('26', '36'))	('lead to', 'Reg', (114, 121))
130024	29707153	Increased KLK8 has been associated with a favorable clinical outcome in lung adenocarcinoma by suppressing tumor invasiveness through inhibition of integrin signaling and cell adhesion; however we could not confirm this finding in our study.	('lung adenocarcinoma', 'Disease', (72, 91))	('tumor invasiveness', 'Disease', (107, 125))	('suppressing', 'NegReg', (95, 106))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (72, 91))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('cell adhesion', 'biological_process', 'GO:0007155', ('171', '184'))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('inhibition', 'NegReg', (134, 144))	('tumor invasiveness', 'Disease', 'MESH:D009369', (107, 125))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))	('KLK8', 'Gene', '11202', (10, 14))	('integrin signaling', 'MPA', (148, 166))	('KLK8', 'Gene', (10, 14))	('cell adhesion', 'CPA', (171, 184))	('signaling', 'biological_process', 'GO:0023052', ('157', '166'))	('Increased', 'Var', (0, 9))
130101	32469992	It is known that variations in tumor-infiltrating leukocyte populations can dramatically alter CPI outcomes, regardless of host obesity status.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('variations', 'Var', (17, 27))	('host obesity status', 'Disease', 'MESH:D009765', (123, 142))	('tumor', 'Disease', (31, 36))	('CPI', 'Disease', (95, 98))	('alter', 'Reg', (89, 94))	('obesity', 'Phenotype', 'HP:0001513', (128, 135))	('CPI', 'Chemical', '-', (95, 98))	('host obesity status', 'Disease', (123, 142))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
130177	32469992	Plasma IDO activity was not altered (P = 0.9324) in a subset of ccRCC subjects (n = 37) by obesity status, suggesting that the IDO1 alteration is specific to the tumor microenvironment (Fig 5C).	('tumor', 'Disease', (162, 167))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('alteration', 'Var', (132, 142))	('IDO', 'molecular_function', 'GO:0047719', ('7', '10'))	('IDO1', 'Gene', '3620', (127, 131))	('IDO', 'Gene', (7, 10))	('IDO', 'Gene', (127, 130))	('IDO', 'molecular_function', 'GO:0033754', ('127', '130'))	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('obesity status', 'Disease', (91, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('obesity', 'Phenotype', 'HP:0001513', (91, 98))	('IDO1', 'Gene', (127, 131))	('IDO', 'molecular_function', 'GO:0047719', ('127', '130'))	('IDO', 'Gene', '3620', (127, 130))	('IDO', 'Gene', '3620', (7, 10))	('men', 'Species', '9606', (180, 183))	('IDO', 'molecular_function', 'GO:0033754', ('7', '10'))	('obesity status', 'Disease', 'MESH:D009765', (91, 105))
130200	32469992	IL-1beta is clinically relevant in RCC, because high intratumoral IL-1beta in human renal tumors has been associated with increased MDSC accumulation and poor survival (thehumanproteinatlas.org, p <0.001).	('MDSC accumulation', 'MPA', (132, 149))	('renal tumors', 'Disease', (84, 96))	('IL-1beta', 'Gene', '3552', (66, 74))	('high', 'Var', (48, 52))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('RCC', 'Disease', (35, 38))	('tumor', 'Disease', (58, 63))	('renal tumors', 'Disease', 'MESH:D007674', (84, 96))	('tumor', 'Disease', (90, 95))	('IL-1beta', 'Gene', '3552', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('increased', 'PosReg', (122, 131))	('renal tumors', 'Phenotype', 'HP:0009726', (84, 96))	('human', 'Species', '9606', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('IL-1', 'molecular_function', 'GO:0005149', ('0', '4'))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('IL-1', 'molecular_function', 'GO:0005149', ('66', '70'))	('renal tumor', 'Phenotype', 'HP:0009726', (84, 95))	('IL-1beta', 'Gene', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('human', 'Species', '9606', (172, 177))	('IL-1beta', 'Gene', (0, 8))
130214	32469992	CCL21 (also known as Secondary Lymphoid-tissue chemokine or "SLC") is a chemoattractant for activated T cells and one study linked low expression of this chemokine to decreased OS and PFS in patients with metastatic RCC.	('low', 'Var', (131, 134))	('CCL', 'molecular_function', 'GO:0044101', ('0', '3'))	('patients', 'Species', '9606', (191, 199))	('PFS', 'Disease', (184, 187))	('CCL21', 'Gene', '6366', (0, 5))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('RCC', 'Disease', (216, 219))	('RCC', 'Phenotype', 'HP:0005584', (216, 219))	('CCL21', 'Gene', (0, 5))	('decreased', 'NegReg', (167, 176))
130300	32236633	Furthermore, the functional involvement of USP19 in ccRCC was examined using Cell Counting Kit-8, soft agar, Transwell and wound healing assays in vitro following overexpression or knockdown of USP19 in the Caki-1 cell line.	('Caki-1', 'CellLine', 'CVCL:0234', (207, 213))	('USP', 'molecular_function', 'GO:0051748', ('43', '46'))	('RCC', 'Disease', (54, 57))	('USP19', 'Gene', (194, 199))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('Kit', 'Gene', (91, 94))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('Kit', 'Gene', '3815', (91, 94))	('knockdown', 'Var', (181, 190))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('USP', 'molecular_function', 'GO:0051748', ('194', '197'))	('wound healing', 'biological_process', 'GO:0042060', ('123', '136'))
130301	32236633	USP19 overexpression inhibited ccRCC proliferation and migration, whereas USP19 knockdown promoted ccRCC proliferation and migration in vitro.	('knockdown', 'Var', (80, 89))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('USP19', 'Gene', (74, 79))	('RCC', 'Disease', (101, 104))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('RCC', 'Disease', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (31, 36))	('overexpression', 'PosReg', (6, 20))	('inhibited', 'NegReg', (21, 30))	('USP', 'molecular_function', 'GO:0051748', ('74', '77'))	('promoted', 'PosReg', (90, 98))	('migration', 'CPA', (123, 132))	('USP19', 'Gene', (0, 5))	('USP', 'molecular_function', 'GO:0051748', ('0', '3'))
130303	32236633	Mechanistically, it was found that USP19 exerted its inhibitory effect on ccRCC proliferation and migration by suppressing the activation of ERK.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('ERK', 'Protein', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('USP', 'molecular_function', 'GO:0051748', ('35', '38'))	('activation', 'MPA', (127, 137))	('ERK', 'molecular_function', 'GO:0004707', ('141', '144'))	('migration', 'CPA', (98, 107))	('USP19', 'Var', (35, 40))	('suppressing', 'NegReg', (111, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))
130315	32236633	In addition, BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene important to the development and prognosis of numerous cancers; Shahriyari et al found that USP19 was highly positively associated with BAP1 expression in breast and uveal melanoma.	('tumor', 'Disease', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('BAP1', 'Gene', (41, 45))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('numerous cancers', 'Disease', (120, 136))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('associated', 'Interaction', (194, 204))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('positively', 'PosReg', (183, 193))	('BRCA1-associated protein 1', 'Gene', (13, 39))	('melanoma', 'Phenotype', 'HP:0002861', (246, 254))	('melanoma', 'Disease', (246, 254))	('BAP1', 'Gene', '8314', (210, 214))	('USP19', 'Var', (166, 171))	('expression', 'MPA', (215, 225))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('52', '68'))	('BAP1', 'Gene', '8314', (41, 45))	('uveal melanoma', 'Phenotype', 'HP:0007716', (240, 254))	('BAP1', 'Gene', (210, 214))	('numerous cancers', 'Disease', 'MESH:D009369', (120, 136))	('melanoma', 'Disease', 'MESH:D008545', (246, 254))	('USP', 'molecular_function', 'GO:0051748', ('166', '169'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('52', '68'))	('BRCA1-associated protein 1', 'Gene', '8314', (13, 39))
130321	32236633	GSE76207 and GSE102101 were obtained from the GEO database , and respectively contained 16 and 10 paired tumor and normal kidney tissues.	('GSE76207', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('GSE102101', 'Var', (13, 22))	('tumor', 'Disease', (105, 110))
130325	32236633	Gene Expression Profiling Interactive Analysis  was used to analyze the overall survival (OS) and disease-free survival (DFS) differences between patients with high or low expression levels of USP19.	('high', 'Var', (160, 164))	('expression levels', 'MPA', (172, 189))	('Gene Expression', 'biological_process', 'GO:0010467', ('0', '15'))	('low', 'NegReg', (168, 171))	('USP19', 'Gene', (193, 198))	('USP', 'molecular_function', 'GO:0051748', ('193', '196'))	('patients', 'Species', '9606', (146, 154))
130330	32236633	Two short hairpin RNAs (shRNAs) targeting different regions of USP19 mRNA (shUSP19#1 and shUSP19#2) were inserted into the pLKO.1 vector (OligoEngine) and confirmed by sequencing.	('OligoEngine', 'Chemical', '-', (138, 149))	('shUSP19', 'Var', (89, 96))	('USP', 'molecular_function', 'GO:0051748', ('63', '66'))	('USP19', 'Gene', (63, 68))
130364	32236633	RNA-seq data from the samples of 539 patients with ccRCC from TCGA database and 26 patients with ccRCC from GEO (GSE76207 and GSE102101) were employed.	('patients', 'Species', '9606', (37, 45))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('RCC', 'Disease', (99, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))	('GSE102101', 'Var', (126, 135))	('patients', 'Species', '9606', (83, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('GSE76207', 'Var', (113, 121))
130377	32236633	The results showed that mRNA levels of PCNA and cyclin D1 were downregulated when USP19 was overexpressed, whereas p27 was upregulated (all P<0.05; Fig.	('cyclin D1', 'Gene', (48, 57))	('USP', 'molecular_function', 'GO:0051748', ('82', '85'))	('PCNA', 'Gene', (39, 43))	('upregulated', 'PosReg', (123, 134))	('USP19', 'Var', (82, 87))	('p27', 'Gene', '10671', (115, 118))	('PCNA', 'Gene', '5111', (39, 43))	('downregulated', 'NegReg', (63, 76))	('cyclin', 'molecular_function', 'GO:0016538', ('48', '54'))	('overexpressed', 'PosReg', (92, 105))	('PCNA', 'molecular_function', 'GO:0003892', ('39', '43'))	('cyclin D1', 'Gene', '595', (48, 57))	('mRNA levels', 'MPA', (24, 35))	('p27', 'Gene', (115, 118))
130379	32236633	Taken together, the above results indicated that USP19 inhibits ccRCC cell proliferation.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('cell proliferation', 'biological_process', 'GO:0008283', ('70', '88'))	('inhibits', 'NegReg', (55, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('USP19', 'Var', (49, 54))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('USP', 'molecular_function', 'GO:0051748', ('49', '52'))
130380	32236633	To examine whether USP19 knockdown promotes ccRCC cell proliferation, lentivirus-mediated shRNA constructs targeting different USP19 mRNA regions were applied to generate two stable USP19 knockdown cell lines.	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('RCC', 'Disease', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('USP19', 'Gene', (19, 24))	('USP', 'molecular_function', 'GO:0051748', ('182', '185'))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('USP', 'molecular_function', 'GO:0051748', ('127', '130'))	('USP', 'molecular_function', 'GO:0051748', ('19', '22'))	('knockdown', 'Var', (25, 34))
130381	32236633	USP19 mRNA and protein levels were significantly reduced in stable USP19 knockdown Caki-1 cell lines compared with in shctrl Caki-1 cell lines (all P<0.05; Fig.	('Caki-1', 'CellLine', 'CVCL:0234', (83, 89))	('reduced', 'NegReg', (49, 56))	('USP', 'molecular_function', 'GO:0051748', ('67', '70'))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('Caki-1', 'CellLine', 'CVCL:0234', (125, 131))	('USP19', 'Gene', (67, 72))	('USP19', 'Gene', (0, 5))	('USP', 'molecular_function', 'GO:0051748', ('0', '3'))	('knockdown', 'Var', (73, 82))
130382	32236633	CCK-8 and soft agar assays also showed that Caki-1 cell proliferation was increased following USP19 knockdown (all P<0.05; Fig.	('knockdown', 'Var', (100, 109))	('cell proliferation', 'biological_process', 'GO:0008283', ('51', '69'))	('USP19', 'Gene', (94, 99))	('Caki-1', 'CellLine', 'CVCL:0234', (44, 50))	('increased', 'PosReg', (74, 83))	('USP', 'molecular_function', 'GO:0051748', ('94', '97'))	('Caki-1 cell proliferation', 'CPA', (44, 69))
130383	32236633	Accordingly, the mRNA levels of PCNA and cyclin D1 were higher, and those of p27 were lower in the USP19 knockdown group compared with in the shctrl group (all P<0.05; Fig.	('PCNA', 'Gene', (32, 36))	('cyclin D1', 'Gene', (41, 50))	('PCNA', 'molecular_function', 'GO:0003892', ('32', '36'))	('PCNA', 'Gene', '5111', (32, 36))	('USP19', 'Gene', (99, 104))	('USP', 'molecular_function', 'GO:0051748', ('99', '102'))	('knockdown', 'Var', (105, 114))	('lower', 'NegReg', (86, 91))	('cyclin', 'molecular_function', 'GO:0016538', ('41', '47'))	('p27', 'Gene', '10671', (77, 80))	('higher', 'PosReg', (56, 62))	('mRNA levels', 'MPA', (17, 28))	('cyclin D1', 'Gene', '595', (41, 50))	('p27', 'Gene', (77, 80))
130384	32236633	Similarly, the protein levels of PCNA and cyclin D1 were increased, while those of p27 were decreased by USP19 knockdown (all P<0.05; Fig.	('PCNA', 'Gene', (33, 37))	('knockdown', 'Var', (111, 120))	('USP', 'molecular_function', 'GO:0051748', ('105', '108'))	('protein levels', 'MPA', (15, 29))	('p27', 'Gene', '10671', (83, 86))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('PCNA', 'Gene', '5111', (33, 37))	('USP19', 'Gene', (105, 110))	('p27', 'Gene', (83, 86))	('cyclin', 'molecular_function', 'GO:0016538', ('42', '48'))	('PCNA', 'molecular_function', 'GO:0003892', ('33', '37'))	('increased', 'PosReg', (57, 66))	('decreased', 'NegReg', (92, 101))	('cyclin D1', 'Gene', '595', (42, 51))	('cyclin D1', 'Gene', (42, 51))
130385	32236633	These results indicated that USP19 knockdown promotes ccRCC cell proliferation.	('knockdown', 'Var', (35, 44))	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('cell proliferation', 'biological_process', 'GO:0008283', ('60', '78'))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('USP19', 'Gene', (29, 34))	('promotes', 'PosReg', (45, 53))	('USP', 'molecular_function', 'GO:0051748', ('29', '32'))
130386	32236633	Transwell assays showed that cell migration was impaired in USP19-overexpressing Caki-1 cells, whereas it was promoted in USP19 knockdown Caki-1 cells compared with the respective negative controls (all P<0.01; Fig.	('impaired', 'NegReg', (48, 56))	('cell migration', 'biological_process', 'GO:0016477', ('29', '43'))	('USP', 'molecular_function', 'GO:0051748', ('60', '63'))	('USP', 'molecular_function', 'GO:0051748', ('122', '125'))	('Caki-1', 'CellLine', 'CVCL:0234', (81, 87))	('USP19-overexpressing', 'Var', (60, 80))	('cell migration', 'CPA', (29, 43))	('promoted', 'PosReg', (110, 118))	('Caki-1', 'CellLine', 'CVCL:0234', (138, 144))
130388	32236633	RT-qPCR and western blot data showed that the expression levels of MMP2 and MMP9 were lower in USP19-overexpressing cells and higher in USP19-knockdown cells than in control cells (all P<0.05; Fig.	('USP', 'molecular_function', 'GO:0051748', ('95', '98'))	('MMP2', 'Gene', '4313', (67, 71))	('MMP9', 'Gene', (76, 80))	('higher', 'PosReg', (126, 132))	('expression levels', 'MPA', (46, 63))	('lower', 'NegReg', (86, 91))	('MMP9', 'Gene', '4318', (76, 80))	('MMP9', 'molecular_function', 'GO:0004229', ('76', '80'))	('MMP2', 'molecular_function', 'GO:0004228', ('67', '71'))	('USP', 'molecular_function', 'GO:0051748', ('136', '139'))	('USP19-overexpressing', 'Var', (95, 115))	('MMP2', 'Gene', (67, 71))
130395	32236633	As the CCK-8 assay showed, U0126 significantly rescued the increased Caki-1 cell proliferation induced by USP19 knockdown (all P<0.01; Fig.	('Caki-1', 'CellLine', 'CVCL:0234', (69, 75))	('Caki-1 cell proliferation', 'CPA', (69, 94))	('U0126', 'Chemical', 'MESH:C113580', (27, 32))	('cell proliferation', 'biological_process', 'GO:0008283', ('76', '94'))	('knockdown', 'Var', (112, 121))	('USP19', 'Gene', (106, 111))	('increased', 'PosReg', (59, 68))	('USP', 'molecular_function', 'GO:0051748', ('106', '109'))
130396	32236633	Transwell assays also indicated that the promoting effects of USP19 knockdown on Caki-1 cell migration were reversed by U0126 (all P<0.05; Fig.	('promoting', 'PosReg', (41, 50))	('USP19', 'Gene', (62, 67))	('Caki-1', 'CellLine', 'CVCL:0234', (81, 87))	('cell migration', 'biological_process', 'GO:0016477', ('88', '102'))	('Caki-1 cell migration', 'CPA', (81, 102))	('knockdown', 'Var', (68, 77))	('U0126', 'Chemical', 'MESH:C113580', (120, 125))	('USP', 'molecular_function', 'GO:0051748', ('62', '65'))
130397	32236633	Treatment of U0126 led to a significant decrease in p-ERK levels, whilst not notably affecting the total ERK protein levels (all P<0.01; Fig.	('ERK', 'molecular_function', 'GO:0004707', ('105', '108'))	('decrease', 'NegReg', (40, 48))	('ERK', 'molecular_function', 'GO:0004707', ('54', '57'))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('p-ERK levels', 'MPA', (52, 64))	('U0126', 'Var', (13, 18))	('U0126', 'Chemical', 'MESH:C113580', (13, 18))
130401	32236633	Consistently, the tumor weights at 60 days were significantly heavier in the shUSP19#1 group than the shctrl group (P<0.05; Fig.	('heavier', 'PosReg', (62, 69))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('shUSP19#1', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
130403	32236633	7D) Then, western blot experiments revealed notably increased p-ERK levels in the tumor tissues derived from the shUSP19#1 group compared with those derived from the shctrl group (Fig.	('shUSP19#1', 'Var', (113, 122))	('increased', 'PosReg', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('p-ERK levels', 'MPA', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('ERK', 'molecular_function', 'GO:0004707', ('64', '67'))
130408	32236633	In the present study, by analyzing CNV data from TCGA database, it was revealed that the copy number of USP19 was notably reduced in ccRCC tissues, suggesting that USP19 loss may be due to copy number loss, which requires further investigation.	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('USP19', 'Gene', (104, 109))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('loss', 'NegReg', (170, 174))	('RCC', 'Disease', (135, 138))	('USP', 'molecular_function', 'GO:0051748', ('164', '167'))	('USP', 'molecular_function', 'GO:0051748', ('104', '107'))	('copy number', 'MPA', (89, 100))	('USP19', 'Gene', (164, 169))	('reduced', 'NegReg', (122, 129))	('copy number loss', 'Var', (189, 205))
130412	32236633	Aberrant ERK-MAPK pathway signaling contributes to cell proliferation and migration in various types of cancer.	('contributes', 'Reg', (36, 47))	('ERK', 'molecular_function', 'GO:0004707', ('9', '12'))	('ERK-MAPK pathway signaling', 'Pathway', (9, 35))	('cell proliferation', 'biological_process', 'GO:0008283', ('51', '69'))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('MAPK', 'molecular_function', 'GO:0004707', ('13', '17'))	('migration', 'CPA', (74, 83))	('signaling', 'biological_process', 'GO:0023052', ('26', '35'))	('cell proliferation', 'CPA', (51, 69))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
130413	32236633	Moreover, USP19 knockdown promoted ERK phosphorylation, as well as promoting ccRCC proliferation in vitro and in vivo.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('ERK', 'molecular_function', 'GO:0004707', ('35', '38'))	('USP', 'molecular_function', 'GO:0051748', ('10', '13'))	('phosphorylation', 'MPA', (39, 54))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('ERK', 'Protein', (35, 38))	('USP19', 'Gene', (10, 15))	('phosphorylation', 'biological_process', 'GO:0016310', ('39', '54'))	('promoted', 'PosReg', (26, 34))	('knockdown', 'Var', (16, 25))	('promoting', 'PosReg', (67, 76))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
130419	32236633	Conversely, the present study demonstrated that USP19 overexpression inhibited ccRCC cell proliferation and migration in vitro; conversely, USP19 knockdown promoted proliferation and migration in vitro, as well as promoting tumor growth in vivo.	('knockdown', 'Var', (146, 155))	('USP', 'molecular_function', 'GO:0051748', ('48', '51'))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('cell proliferation', 'biological_process', 'GO:0008283', ('85', '103'))	('USP', 'molecular_function', 'GO:0051748', ('140', '143'))	('migration', 'CPA', (183, 192))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('tumor', 'Disease', (224, 229))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('promoting', 'PosReg', (214, 223))	('USP19', 'Gene', (140, 145))	('inhibited', 'NegReg', (69, 78))	('proliferation', 'CPA', (165, 178))	('promoted', 'PosReg', (156, 164))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
130444	32194783	The current exploitation of high-throughput gene microarray to analyze normal and tumor tissue samples from patients confers us an opportunity to detect and explore the comprehensive molecular landscapes of tumors at multiple levels ranging from somatic mutations and copy number alteration at the genome level to gene expression changes at transcriptome level.	('copy number', 'Var', (268, 279))	('gene expression', 'biological_process', 'GO:0010467', ('314', '329'))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', (207, 213))	('patients', 'Species', '9606', (108, 116))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (82, 87))
130499	32194783	Patients with high AURKB expression exhibited worse OS and DFS (Figure 3c, Figure 4d).	('DFS', 'CPA', (59, 62))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('AURKB', 'Gene', '9212', (19, 24))	('AURKB', 'Gene', (19, 24))
130505	32194783	This result shown that high expression of AURKB was enriched in JAEGER_METASTASIS_UP gene set (NES=1.868261, p=0.001957, FDR=0.059234), LIAO_METASTASIS_UP gene set (NES=1.687044, p=0.013619, FDR=0.130064), RAMASWAMY_METASTASIS_UP (NES=1.670244, p=0.009862, FDR=0.136635) and ZUCCHI_METASTASIS_UP (NES=1.6955399, p=0.009881, FDR=0.124113).	('LIAO', 'Disease', '-', (136, 140))	('AURKB', 'Gene', '9212', (42, 47))	('AURKB', 'Gene', (42, 47))	('expression', 'MPA', (28, 38))	('NES=1.6955399', 'Var', (297, 310))	('LIAO', 'Disease', (136, 140))
130506	32194783	Other gene sets which were important pathway for ccRCC progression and metastasis were also associated with AURKB mRNA expression.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('ccRCC', 'Disease', 'MESH:C538614', (49, 54))	('mRNA', 'Var', (114, 118))	('AURKB', 'Gene', '9212', (108, 113))	('AURKB', 'Gene', (108, 113))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('ccRCC', 'Disease', (49, 54))
130510	32194783	As the Figure 9c showed, AURKB knockdown significantly decreased the capacity of migration and invasion of ACHN cells.	('invasion of ACHN cells', 'CPA', (95, 117))	('AURKB', 'Gene', '9212', (25, 30))	('AURKB', 'Gene', (25, 30))	('decreased', 'NegReg', (55, 64))	('knockdown', 'Var', (31, 40))
130550	32194783	Pervious study has reported that inhibition of Aurora kinases induced apoptosis and autophagy in leukemia cells via AURKB/p70S6K/RPL15 axis with the involvement of PI3K/Akt/mTOR, AMPK, and p38 MAPK signaling pathways.	('p38', 'Gene', (189, 192))	('MAPK', 'molecular_function', 'GO:0004707', ('193', '197'))	('RPL15', 'Gene', (129, 134))	('apoptosis', 'biological_process', 'GO:0097194', ('70', '79'))	('RPL15', 'Gene', '6138', (129, 134))	('mTOR', 'Gene', '2475', (173, 177))	('leukemia', 'Disease', (97, 105))	('apoptosis', 'biological_process', 'GO:0006915', ('70', '79'))	('leukemia', 'Disease', 'MESH:D007938', (97, 105))	('AMPK', 'molecular_function', 'GO:0050405', ('179', '183'))	('apoptosis', 'CPA', (70, 79))	('MAPK', 'Gene', (193, 197))	('AURKB', 'Gene', '9212', (116, 121))	('p38 MAPK signaling', 'biological_process', 'GO:0051403', ('189', '207'))	('inhibition', 'Var', (33, 43))	('autophagy', 'biological_process', 'GO:0006914', ('84', '93'))	('p70S6K', 'Gene', '6198', (122, 128))	('MAPK', 'Gene', '5594', (193, 197))	('autophagy', 'CPA', (84, 93))	('p38', 'Gene', '5594', (189, 192))	('AMPK', 'molecular_function', 'GO:0004691', ('179', '183'))	('Akt', 'Gene', (169, 172))	('PI3K', 'molecular_function', 'GO:0016303', ('164', '168'))	('Akt', 'Gene', '207', (169, 172))	('AMPK', 'molecular_function', 'GO:0047322', ('179', '183'))	('p70S6K', 'Gene', (122, 128))	('AURKB', 'Gene', (116, 121))	('Aurora', 'Protein', (47, 53))	('mTOR', 'Gene', (173, 177))	('leukemia', 'Phenotype', 'HP:0001909', (97, 105))	('autophagy', 'biological_process', 'GO:0016236', ('84', '93'))
130650	30442178	The rationale behind such molecular reclassifications is that genetic alterations underlying cancer pathology predict response to therapy and may therefore offer a more precise view on cancer than histology.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('predict', 'Reg', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('response to therapy', 'MPA', (118, 137))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))	('genetic alterations', 'Var', (62, 81))
130651	30442178	The use of individual actionable mutations to select cancers for treatment across histotypes is already being tested in the so-called basket trials with variable success rates.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
130653	30442178	To determine effects of oncogenic mutations on protein profiles, we used the energy distance, which compares the Euclidean distances of protein profiles in tumors with an oncogenic mutation (inner distance) to that in tumors without the mutation (outer distance) and performed Monte Carlo simulations for the significance analysis.	('tumors', 'Disease', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('mutation', 'Var', (181, 189))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
130659	30442178	Next-generation sequencing has facilitated comprehensive mutational profiling of all major cancers and has led to the discovery of oncogenic driver mutations, many of which can be targeted therapeutically.	('mutations', 'Var', (148, 157))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Disease', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
130661	30442178	However, sequencing data has shown that actionable mutations, albeit with different frequencies, occur across cancers, which has raised the question about histotype-independent therapies and novel ways of tumor classifications no longer relying on histology but on genetic profiles.	('cancers', 'Disease', (110, 117))	('mutations', 'Var', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
130664	30442178	That targeted therapies against the same single molecular alteration can be effective across cancers, as shown, for instance, by the efficacy of anti-Her2 therapy in both gastric and breast cancers or the clinical benefit from inhibition of mutated cKIT in gastrointestinal stromal tumors (GIST) and melanoma or mastocytosis.	('gastric and breast cancers', 'Disease', 'MESH:D013274', (171, 197))	('melanoma or mastocytosis', 'Disease', (300, 324))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('Her2', 'Gene', '2064', (150, 154))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('gastrointestinal stromal tumors', 'Disease', (257, 288))	('GIST', 'Phenotype', 'HP:0100723', (290, 294))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('Her2', 'Gene', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('mutated', 'Var', (241, 248))	('melanoma', 'Phenotype', 'HP:0002861', (300, 308))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cKIT', 'Gene', '3815', (249, 253))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('cancers', 'Disease', (190, 197))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancers', 'Disease', (93, 100))	('melanoma or mastocytosis', 'Disease', 'MESH:D008415', (300, 324))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (257, 288))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (257, 288))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancers', 'Phenotype', 'HP:0003002', (183, 197))	('inhibition', 'Var', (227, 237))	('mastocytosis', 'Phenotype', 'HP:0100495', (312, 324))	('cKIT', 'Gene', (249, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
130665	30442178	However, the fact that inhibition of BRAF mutated at V600 is effective in melanoma but not in colorectal cancer is a prominent example against the general transferability of knowledge on a single actionable mutation from one histological tumor type to another.	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('BRAF', 'Gene', '673', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('rectal cancer', 'Phenotype', 'HP:0100743', (98, 111))	('BRAF', 'Gene', (37, 41))	('mutated at V600', 'Var', (42, 57))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Disease', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('tumor', 'Disease', (238, 243))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancer', 'Disease', (94, 111))	('ran', 'Gene', (156, 159))	('ran', 'Gene', '5901', (156, 159))
130667	30442178	Using mutational profiles or just single genetic aberrations, as is the case in the current basket trials, is unlikely to cover the full scope of (tissue-specific) molecular effects including epigenetic mechanisms and downstream regulation such as post-translational modifications.	('mutational', 'Var', (6, 16))	('regulation', 'biological_process', 'GO:0065007', ('229', '239'))	('ran', 'Gene', (254, 257))	('ran', 'Gene', '5901', (254, 257))
130682	30442178	To address the question of how mutational differences between two classes affect protein expressions in more than one histotype in the same way, we performed a cross-cancer effect analysis.	('mutational', 'Var', (31, 41))	('affect', 'Reg', (74, 80))	('protein expressions', 'MPA', (81, 100))	('cross-cancer', 'Disease', (160, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('cross-cancer', 'Disease', 'MESH:C537866', (160, 172))
130697	30442178	At this point, it is unclear whether the reason for this inconsistency between genetic and protein profiles is the differential translation of genetic profiles into protein levels in different cancer types, or organ- and tissue-specific protein base levels that are modulated by mutations:or a combination of both.	('ran', 'Gene', (129, 132))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('ran', 'Gene', '5901', (129, 132))	('mutations', 'Var', (279, 288))	('protein', 'cellular_component', 'GO:0003675', ('237', '244'))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('translation', 'biological_process', 'GO:0006412', ('128', '139'))	('cancer', 'Disease', (193, 199))	('modulated', 'Reg', (266, 275))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))
130711	30442178	In the proposal by Ciriello et al., tumors are classified by the presence of somatic mutations and copy number alterations in cancer-related pathways.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('copy number alterations', 'Var', (99, 122))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
130723	30442178	The least pronounced but still significant class discriminability is achieved for classes C12 and C5 in breast cancer (sdis = - 0.31, p = 4.4e-3; srand = - 8.0e-5).	('ran', 'Gene', (147, 150))	('sdis', 'Chemical', '-', (119, 123))	('ran', 'Gene', '5901', (147, 150))	('C12', 'Var', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))
130742	30442178	With CES = 2%, the overall classification effectivity score of this classification is the lowest among all tested classifications indicating that global comparisons based on somatic mutations only are not effective in classifying tumors in a meaningful way if the available protein profiles are considered relevant.	('CES', 'Chemical', '-', (5, 8))	('tumors', 'Disease', (230, 236))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('CES', 'Var', (5, 8))	('lowest', 'NegReg', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('protein', 'cellular_component', 'GO:0003675', ('274', '281'))
130745	30442178	For this classification, class discriminability sdis is highest between class toLGG (cases that are most similar to low-grade glioma cases by their mutation profile) and class toPRAD for low-grade glioma (LGG) (sdis = - 3.26; p = 0.0; srand = - 6.1e-5; characteristic protein profiles increased in toLGG: p70S6K_pT389; increased in ToPRAD: YAP_pS127, HER2_pY1248, HER2, EGFR_pY1068, EGFR_pY1173, Src_pY416, and Cyclin_D1).	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('EGFR', 'Gene', (370, 374))	('HER2', 'Gene', '2064', (351, 355))	('increased', 'PosReg', (285, 294))	('sdis', 'Chemical', '-', (48, 52))	('EGFR', 'molecular_function', 'GO:0005006', ('370', '374'))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))	('p70S6K', 'Gene', '6198', (305, 311))	('Cyclin_D1', 'Gene', (411, 420))	('EGFR', 'Gene', (383, 387))	('sdis', 'Chemical', '-', (211, 215))	('EGFR', 'Gene', '1956', (370, 374))	('HER2', 'Gene', '2064', (364, 368))	('HER2', 'Gene', (351, 355))	('EGFR', 'molecular_function', 'GO:0005006', ('383', '387'))	('ran', 'Gene', (236, 239))	('glioma', 'Disease', (126, 132))	('ran', 'Gene', '5901', (236, 239))	('increased', 'PosReg', (319, 328))	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('Cyclin', 'molecular_function', 'GO:0016538', ('411', '417'))	('p70S6K', 'Gene', (305, 311))	('protein', 'cellular_component', 'GO:0003675', ('268', '275'))	('EGFR', 'Gene', '1956', (383, 387))	('glioma', 'Disease', (197, 203))	('Src_pY416', 'Var', (396, 405))	('HER2', 'Gene', (364, 368))	('Cyclin_D1', 'Gene', '595', (411, 420))	('glioma', 'Disease', 'MESH:D005910', (197, 203))
130768	30442178	Using the same approach as above, we are systematically evaluating all major actionable somatic mutations and copy number alterations against which drugs are approved for clinical use or which are currently tested in clinical trials with respect to their effects on proteins across cancers.	('cancers', 'Disease', (282, 289))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('cancers', 'Disease', 'MESH:D009369', (282, 289))	('copy number alterations', 'Var', (110, 133))	('cancers', 'Phenotype', 'HP:0002664', (282, 289))	('mutations', 'Var', (96, 105))
130773	30442178	Overall, our analysis showed for all analyzed 12 actionable genes (OncoKB evidence levels 1-3) that the mutational status is associated with significant differences in protein profiles in histotypes for which the respective targeted drugs are approved or currently being clinically tested and showed additional mutation-associated protein profiles in 9 histological tumor types.	('tumor', 'Disease', (366, 371))	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('mutational', 'Var', (104, 114))	('associated', 'Reg', (125, 135))	('protein profiles', 'MPA', (168, 184))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('protein', 'cellular_component', 'GO:0003675', ('331', '338'))	('differences', 'Reg', (153, 164))
130775	30442178	Only KRAS/NRAS mutations in colorectal cancer do not result in discriminable protein profiles comparing wild-type and mutated cases, whereas an effect can be observed for thyroid cancer and melanoma.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('KRAS', 'Gene', (5, 9))	('NRAS', 'Gene', (10, 14))	('thyroid cancer', 'Disease', 'MESH:D013964', (171, 185))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', (190, 198))	('rectal cancer', 'Phenotype', 'HP:0100743', (32, 45))	('mutations', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('thyroid cancer', 'Phenotype', 'HP:0002890', (171, 185))	('result', 'Reg', (53, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('NRAS', 'Gene', '4893', (10, 14))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('colorectal cancer', 'Disease', (28, 45))	('KRAS', 'Gene', '3845', (5, 9))	('thyroid cancer', 'Disease', (171, 185))
130778	30442178	Our results demonstrate that in addition to confirming known druggable genes in the available cell line data, protein profile discriminability in between presence or absence of oncogenic mutations is predictive of drug response in cell line data across cancers (p = 0.048, Table 2).	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('cancers', 'Disease', (253, 260))	('cancers', 'Disease', 'MESH:D009369', (253, 260))	('mutations', 'Var', (187, 196))	('protein', 'MPA', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
130779	30442178	BRAF mutations are actionable in melanomas (OncoKB level 1).	('melanomas', 'Disease', 'MESH:D008545', (33, 42))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('melanomas', 'Disease', (33, 42))
130780	30442178	Mutations of BRAF are frequent enough in our data for melanoma (46% cases with mutation) and thyroid carcinoma (not yet reported by OncoKB, 56% cases with mutation) for further analysis.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (93, 110))	('thyroid carcinoma', 'Disease', (93, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('BRAF', 'Gene', '673', (13, 17))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('BRAF', 'Gene', (13, 17))	('melanoma', 'Disease', (54, 62))	('Mutations', 'Var', (0, 9))	('mutation', 'Var', (79, 87))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (93, 110))
130781	30442178	The actionable mutations create discriminable groups of cases for thyroid carcinoma (sdis = - 2.07; p = 0.0; srand = - 1.0e-4) and melanoma (sdis = - 0.10; p = 4.7e-3; srand = - 1.1e-4).	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (66, 83))	('melanoma', 'Disease', (131, 139))	('thyroid carcinoma', 'Disease', (66, 83))	('sdis', 'Chemical', '-', (85, 89))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('mutations', 'Var', (15, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('ran', 'Gene', (110, 113))	('ran', 'Gene', '5901', (110, 113))	('sdis', 'Chemical', '-', (141, 145))	('ran', 'Gene', (169, 172))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (66, 83))	('ran', 'Gene', '5901', (169, 172))
130785	30442178	CDK4 amplification is actionable for differentiated sarcomas (OncoKB level 2).	('sarcomas', 'Disease', 'MESH:D012509', (52, 60))	('amplification', 'Var', (5, 18))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('CDK', 'molecular_function', 'GO:0004693', ('0', '3'))	('sarcomas', 'Disease', (52, 60))	('CDK4', 'Gene', (0, 4))	('CDK4', 'Gene', '1019', (0, 4))
130787	30442178	For sarcoma, 36% of the cases show CDK4 amplification and protein profiles are discriminable (sdis = - 0.34; p = 0.0; srand = - 6.0e-5) with E-Cadherin, Caveolin-1, Akt_pS473, Cyclin_B1, ER-alpha, Akt_pT308, YAP_pS127, S6_pS240_S244, and Cyclin_E1 decreased and HSP70, Syk, Lck, Src_pY416, and Src_pY527 increased in CDK4 amplified cases.	('CDK4', 'Gene', '1019', (317, 321))	('Cyclin_B1', 'Gene', (176, 185))	('decreased', 'NegReg', (248, 257))	('Lck', 'Gene', (274, 277))	('Cyclin', 'molecular_function', 'GO:0016538', ('176', '182'))	('ER-alpha', 'Gene', (187, 195))	('E-Cadherin', 'Gene', '999', (141, 151))	('ER-alpha', 'Gene', '2099', (187, 195))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('increased', 'PosReg', (304, 313))	('sdis', 'Chemical', '-', (94, 98))	('Syk', 'Gene', '6850', (269, 272))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))	('Cyclin_B1', 'Gene', '891', (176, 185))	('CDK4', 'Gene', (35, 39))	('HSP70', 'Gene', (262, 267))	('ran', 'Gene', (119, 122))	('sarcoma', 'Disease', (4, 11))	('ran', 'Gene', '5901', (119, 122))	('Syk', 'Gene', (269, 272))	('Cadherin', 'molecular_function', 'GO:0008014', ('143', '151'))	('Cyclin_E1', 'Gene', '898', (238, 247))	('E-Cadherin', 'Gene', (141, 151))	('Caveolin-1', 'Gene', (153, 163))	('CDK4', 'Gene', (317, 321))	('CDK4', 'Gene', '1019', (35, 39))	('CDK', 'molecular_function', 'GO:0004693', ('317', '320'))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('CDK', 'molecular_function', 'GO:0004693', ('35', '38'))	('Src_pY416', 'Var', (279, 288))	('Caveolin-1', 'Gene', '857', (153, 163))	('Src_pY527', 'Var', (294, 303))	('Cyclin_E1', 'Gene', (238, 247))	('HSP70', 'Gene', '3308', (262, 267))	('Cyclin', 'molecular_function', 'GO:0016538', ('238', '244'))	('Lck', 'Gene', '3932', (274, 277))
130789	30442178	EGFR mutations are actionable in non-small cell lung cancer (OncoKB level 1).	('EGFR', 'Gene', (0, 4))	('non-small cell lung cancer', 'Disease', (33, 59))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (37, 59))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (33, 59))	('EGFR', 'Gene', '1956', (0, 4))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (33, 59))
130791	30442178	Lung adenocarcinoma (LUAD) cases with actionable mutation of EGFR are discriminable from those without by protein profile (sdis = - 0.44; p = 5.9e-4; srand = 3.1e-5).	('sdis', 'Chemical', '-', (123, 127))	('LUAD', 'Phenotype', 'HP:0030078', (21, 25))	('ran', 'Gene', (151, 154))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('ran', 'Gene', '5901', (151, 154))	('mutation', 'Var', (49, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('EGFR', 'molecular_function', 'GO:0005006', ('61', '65'))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('Lung adenocarcinoma', 'Disease', (0, 19))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
130792	30442178	EGFR_pY1068 levels are increased for cases with the respective mutations, and Claudin-7 levels are decreased among those cases.	('mutations', 'Var', (63, 72))	('decreased', 'NegReg', (99, 108))	('EGFR', 'Gene', (0, 4))	('Claudin-7', 'Gene', '1366', (78, 87))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('increased', 'PosReg', (23, 32))	('EGFR', 'Gene', '1956', (0, 4))	('Claudin-7', 'Gene', (78, 87))
130793	30442178	ERBB2/HER2 amplification is actionable in breast cancer and gastric cancer (level 1 evidence, FDA-approved).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ERBB2', 'Gene', '2064', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ERBB2', 'Gene', (0, 5))	('gastric cancer', 'Disease', (60, 74))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('breast cancer', 'Disease', (42, 55))	('HER2', 'Gene', (6, 10))	('HER2', 'Gene', '2064', (6, 10))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))	('amplification', 'Var', (11, 24))
130803	30442178	Two histological tumor types in which ERBB2 amplification has a similar impact on proteins are breast (BRCA) and gastric (STAD) cancers (p = 2.3e-3).	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('tumor', 'Disease', (17, 22))	('BRCA', 'Gene', '672', (103, 107))	('BRCA', 'Gene', (103, 107))	('gastric (STAD) cancers', 'Disease', 'MESH:D013274', (113, 135))	('amplification', 'Var', (44, 57))	('ERBB2', 'Gene', (38, 43))	('proteins', 'MPA', (82, 90))	('ERBB2', 'Gene', '2064', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('impact', 'Reg', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
130808	30442178	For FGFR1 amplification, clinical evidence (OncoKB level 3) exists on its actionability in lung squamous cell carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('FGFR1', 'Gene', (4, 9))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('lung squamous cell carcinomas', 'Disease', (91, 120))	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('FGFR1', 'Gene', '2260', (4, 9))	('amplification', 'Var', (10, 23))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (96, 120))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (91, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))
130809	30442178	Our analysis shows that besides lung squamous cell carcinoma, protein expression of amplified cases is discriminable from non-amplified cases in renal clear cell carcinoma, testicular germ cell tumors, lung adenocarcinoma, endometrial carcinoma, breast cancer, and thymoma (all currently not reported by OncoKB).	('endometrial carcinoma', 'Disease', 'MESH:D016889', (223, 244))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (145, 171))	('renal clear cell carcinoma', 'Disease', (145, 171))	('thymoma', 'Disease', (265, 272))	('thymoma', 'Phenotype', 'HP:0100522', (265, 272))	('breast cancer', 'Disease', 'MESH:D001943', (246, 259))	('breast cancer', 'Disease', (246, 259))	('lung adenocarcinoma', 'Disease', (202, 221))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (32, 60))	('lung squamous cell carcinoma', 'Disease', (32, 60))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (202, 221))	('endometrial carcinoma', 'Disease', (223, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (202, 221))	('tumors', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))	('protein expression', 'MPA', (62, 80))	('thymoma', 'Disease', 'MESH:D013945', (265, 272))	('testicular', 'Disease', (173, 183))	('amplified', 'Var', (84, 93))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (223, 244))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
130812	30442178	A cross-cancer effect is found between breast cancer and lung adenocarcinoma with HER2, HER2_pY1248, and EGFR_pY1068 levels decrease and 4E-BP1 levels increase associated with FGFR1 amplification for both histological tumor types.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('A cross-cancer', 'Disease', 'MESH:C537866', (0, 14))	('increase', 'PosReg', (151, 159))	('HER2', 'Gene', '2064', (88, 92))	('4E-BP1', 'Gene', (137, 143))	('EGFR', 'Gene', (105, 109))	('decrease', 'NegReg', (124, 132))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('tumor', 'Disease', (218, 223))	('breast cancer', 'Disease', (39, 52))	('A cross-cancer', 'Disease', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('lung adenocarcinoma', 'Disease', (57, 76))	('EGFR', 'molecular_function', 'GO:0005006', ('105', '109'))	('HER2', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('FGFR1', 'Gene', '2260', (176, 181))	('HER2', 'Gene', (88, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('176', '180'))	('EGFR', 'Gene', '1956', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (57, 76))	('4E-BP1', 'Gene', '1978', (137, 143))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (57, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('FGFR1', 'Gene', (176, 181))	('HER2', 'Gene', '2064', (82, 86))	('levels', 'MPA', (144, 150))	('amplification', 'Var', (182, 195))
130813	30442178	Certain FGFR3 mutations are actionable in bladder cancer (OncoKB level 3).	('bladder cancer', 'Phenotype', 'HP:0009725', (42, 56))	('FGFR3', 'Gene', '2261', (8, 13))	('FGFR', 'molecular_function', 'GO:0005007', ('8', '12'))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('actionable', 'Reg', (28, 38))	('bladder cancer', 'Disease', 'MESH:D001749', (42, 56))	('bladder cancer', 'Disease', (42, 56))	('mutations', 'Var', (14, 23))	('FGFR3', 'Gene', (8, 13))
130814	30442178	Targetable FGFR3 mutations are only frequent enough in urothelial and bladder carcinoma for our analysis.	('frequent', 'Reg', (36, 44))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (70, 87))	('FGFR3', 'Gene', '2261', (11, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('bladder carcinoma', 'Disease', 'MESH:D001749', (70, 87))	('FGFR3', 'Gene', (11, 16))	('bladder carcinoma', 'Disease', (70, 87))	('urothelial', 'Disease', (55, 65))	('FGFR', 'molecular_function', 'GO:0005007', ('11', '15'))	('mutations', 'Var', (17, 26))
130815	30442178	The protein profiles of cases with at least one of these mutations are discriminable from the profiles of those without (sdis = - 0.76; p = 2.7e-3; srand = - 1.3e-5).	('ran', 'Gene', (149, 152))	('ran', 'Gene', '5901', (149, 152))	('mutations', 'Var', (57, 66))	('sdis', 'Chemical', '-', (121, 125))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
130816	30442178	E-Cadherin, beta-Catenin, HER2, Ku80, PTEN, IRS1, and 53BP1 are increased among cases having one or more specific FGF3 mutation.	('53BP1', 'Gene', '7158', (54, 59))	('Ku80', 'Gene', '7520', (32, 36))	('HER2', 'Gene', '2064', (26, 30))	('IRS1', 'Gene', '3667', (44, 48))	('IRS1', 'Gene', (44, 48))	('E-Cadherin', 'Gene', '999', (0, 10))	('53BP1', 'Gene', (54, 59))	('PTEN', 'Gene', '5728', (38, 42))	('FGF3', 'Gene', (114, 118))	('Ku80', 'Gene', (32, 36))	('FGF3', 'Gene', '2248', (114, 118))	('beta-Catenin', 'Gene', '1499', (12, 24))	('mutation', 'Var', (119, 127))	('HER2', 'Gene', (26, 30))	('E-Cadherin', 'Gene', (0, 10))	('beta-Catenin', 'Gene', (12, 24))	('increased', 'PosReg', (64, 73))	('Cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('PTEN', 'Gene', (38, 42))
130817	30442178	IDH1 mutations are actionable in acute myeloid leukemia, cholangiocarcinoma, and glioma (OncoKB level 3).	('leukemia', 'Phenotype', 'HP:0001909', (47, 55))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (57, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (57, 75))	('acute myeloid leukemia', 'Disease', (33, 55))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (39, 55))	('mutations', 'Var', (5, 14))	('glioma', 'Disease', (81, 87))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (33, 55))	('glioma', 'Disease', 'MESH:D005910', (81, 87))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (33, 55))	('IDH1', 'Gene', (0, 4))	('cholangiocarcinoma', 'Disease', (57, 75))	('IDH1', 'Gene', '3417', (0, 4))
130818	30442178	Specific IDH1 mutations lead to discriminable protein profiles for low-grade glioma (sdis = - 0.47; p = 0.0; srand = - 3.1e-6) and glioblastoma (sdis = - 1.59; p = 5.0e-4; srand = - 1.0e-5).	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('IDH1', 'Gene', (9, 13))	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('sdis', 'Chemical', '-', (85, 89))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('IDH1', 'Gene', '3417', (9, 13))	('ran', 'Gene', (110, 113))	('ran', 'Gene', '5901', (110, 113))	('ran', 'Gene', (173, 176))	('glioma', 'Disease', (77, 83))	('protein profiles', 'MPA', (46, 62))	('ran', 'Gene', '5901', (173, 176))	('sdis', 'Chemical', '-', (145, 149))	('mutations', 'Var', (14, 23))	('glioblastoma', 'Disease', (131, 143))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('glioblastoma', 'Disease', 'MESH:D005909', (131, 143))
130820	30442178	For glioblastoma IGFBP2, EGFR_pY1068, HER2_pY1248, Caveolin-1, Akt_pT308, Fibronectin, Collagen_VI, and EGFR_pY1173 are decreased in the group of mutated cases.	('glioblastoma', 'Disease', 'MESH:D005909', (4, 16))	('Collagen', 'molecular_function', 'GO:0005202', ('87', '95'))	('IGFBP2', 'Gene', (17, 23))	('Fibronectin', 'Gene', '2335', (74, 85))	('decreased', 'NegReg', (120, 129))	('EGFR', 'Gene', (25, 29))	('EGFR', 'Gene', (104, 108))	('glioblastoma', 'Disease', (4, 16))	('glioblastoma', 'Phenotype', 'HP:0012174', (4, 16))	('HER2', 'Gene', '2064', (38, 42))	('Fibronectin', 'Gene', (74, 85))	('mutated', 'Var', (146, 153))	('Caveolin-1', 'Gene', (51, 61))	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'Gene', '1956', (104, 108))	('Caveolin-1', 'Gene', '857', (51, 61))	('IGFBP2', 'Gene', '3485', (17, 23))	('HER2', 'Gene', (38, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('104', '108'))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))
130821	30442178	Therefore, IGFBP2, EGFR_pY1068, HER2_pY1248, and EGFR_pY1173 are affected in the same way by IDH1 mutations in low-grade glioma and glioblastoma, and we report a cross-cancer effect for those groups.	('HER2', 'Gene', '2064', (32, 36))	('EGFR', 'Gene', (19, 23))	('glioblastoma', 'Disease', (132, 144))	('glioma', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('EGFR', 'Gene', (49, 53))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('cross-cancer', 'Disease', 'MESH:C537866', (162, 174))	('IDH1', 'Gene', (93, 97))	('HER2', 'Gene', (32, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('19', '23'))	('EGFR', 'Gene', '1956', (19, 23))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('cross-cancer', 'Disease', (162, 174))	('IGFBP2', 'Gene', '3485', (11, 17))	('EGFR', 'Gene', '1956', (49, 53))	('IDH1', 'Gene', '3417', (93, 97))	('mutations', 'Var', (98, 107))	('affected', 'Reg', (65, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (132, 144))	('IGFBP2', 'Gene', (11, 17))
130822	30442178	KIT mutations are actionable in gastrointestinal stromal tumors (OncoKB level 1).	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('gastrointestinal stromal tumors', 'Disease', (32, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (4, 13))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (32, 63))	('KIT', 'Gene', (0, 3))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (32, 63))
130823	30442178	For the tested KIT mutations, only testicular germ cell tumors (TGCT) had enough mutated cases sufficient for our analysis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('KIT', 'Gene', (15, 18))	('mutations', 'Var', (19, 28))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('KIT', 'molecular_function', 'GO:0005020', ('15', '18'))
130824	30442178	The protein profiles of the mutated and wild-type cases are discriminable (sdis = - 0.90; p = 4.5e-3; srand = - 2.6e-4) with decreased E-Cadherin and Fibronectin expression in wildtype cases and increased c-Kit, STAT5-alpha, and Syk expression levels.	('c-Kit', 'Gene', '3815', (205, 210))	('E-Cadherin', 'Gene', '999', (135, 145))	('increased', 'PosReg', (195, 204))	('c-Kit', 'Gene', (205, 210))	('E-Cadherin', 'Gene', (135, 145))	('Fibronectin', 'Gene', '2335', (150, 161))	('mutated', 'Var', (28, 35))	('Syk', 'Gene', '6850', (229, 232))	('decreased', 'NegReg', (125, 134))	('STAT5-alpha', 'Gene', '6776', (212, 223))	('ran', 'Gene', (103, 106))	('ran', 'Gene', '5901', (103, 106))	('Syk', 'Gene', (229, 232))	('STAT5-alpha', 'Gene', (212, 223))	('Cadherin', 'molecular_function', 'GO:0008014', ('137', '145'))	('Fibronectin', 'Gene', (150, 161))	('sdis', 'Chemical', '-', (75, 79))	('expression levels', 'MPA', (233, 250))	('expression', 'MPA', (162, 172))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
130826	30442178	KRAS/NRAS mutations are therapeutically relevant for melanomas, colorectal cancer, and thyroid cancer (OncoKB level 3).	('melanomas', 'Disease', (53, 62))	('KRAS', 'Gene', '3845', (0, 4))	('colorectal cancer', 'Disease', (64, 81))	('NRAS', 'Gene', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('thyroid cancer', 'Disease', 'MESH:D013964', (87, 101))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('NRAS', 'Gene', '4893', (5, 9))	('melanomas', 'Disease', 'MESH:D008545', (53, 62))	('rectal cancer', 'Phenotype', 'HP:0100743', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutations', 'Var', (10, 19))	('KRAS', 'Gene', (0, 4))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('thyroid cancer', 'Phenotype', 'HP:0002890', (87, 101))	('thyroid cancer', 'Disease', (87, 101))
130827	30442178	Specific KRAS/NRAS mutations are correlated with differences in protein profiles for melanomas and thyroid cancer and also for testicular germ cell tumors, endometrial carcinoma, and lung adenocarcinoma (in conformity with OncoKB level 4 data).	('melanomas', 'Disease', (85, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('thyroid cancer', 'Disease', (99, 113))	('differences', 'Reg', (49, 60))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (156, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('NRAS', 'Gene', '4893', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (156, 177))	('KRAS', 'Gene', '3845', (9, 13))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('thyroid cancer', 'Disease', 'MESH:D013964', (99, 113))	('protein profiles', 'MPA', (64, 80))	('lung adenocarcinoma', 'Disease', (183, 202))	('KRAS', 'Gene', (9, 13))	('thyroid cancer', 'Phenotype', 'HP:0002890', (99, 113))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('tumors', 'Disease', (148, 154))	('NRAS', 'Gene', (14, 18))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (183, 202))	('mutations', 'Var', (19, 28))	('melanomas', 'Disease', 'MESH:D008545', (85, 94))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('endometrial carcinoma', 'Disease', (156, 177))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (183, 202))
130830	30442178	For melanoma (sdis = - 0.16; p = 1.0e-3; and = 5.2e-6) E-Cadherin, Caveolin-1, and c-Kit expression levels are decreased for mutated cases, and MAPK_pT202_Y204 is increased.	('E-Cadherin', 'Gene', '999', (55, 65))	('Caveolin-1', 'Gene', (67, 77))	('MAPK', 'molecular_function', 'GO:0004707', ('144', '148'))	('Cadherin', 'molecular_function', 'GO:0008014', ('57', '65'))	('mutated', 'Var', (125, 132))	('MAPK_pT202_Y204', 'Var', (144, 159))	('decreased', 'NegReg', (111, 120))	('sdis', 'Chemical', '-', (14, 18))	('Caveolin-1', 'Gene', '857', (67, 77))	('c-Kit', 'Gene', (83, 88))	('c-Kit', 'Gene', '3815', (83, 88))	('E-Cadherin', 'Gene', (55, 65))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('melanoma', 'Disease', (4, 12))	('expression levels', 'MPA', (89, 106))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))
130831	30442178	For thyroid carcinoma (sdis = - 1.53; p = 0.0; srand = - 3.0e-4), the level of Fibronectin is decreased in mutated cases.	('sdis', 'Chemical', '-', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('ran', 'Gene', (48, 51))	('mutated', 'Var', (107, 114))	('ran', 'Gene', '5901', (48, 51))	('Fibronectin', 'Gene', '2335', (79, 90))	('decreased', 'NegReg', (94, 103))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (4, 21))	('Fibronectin', 'Gene', (79, 90))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (4, 21))	('thyroid carcinoma', 'Disease', (4, 21))
130832	30442178	For lung adenocarcinoma and endometrial carcinoma, we observed a cross-cancer effect for KRAS/NRAS-mutated cases as ATM levels are decreased, and MAPK_pT202_Y204, Claudin-7, S6_pS235_S236, and MEK1_pS217_S221 are increased in both histological tumor types consistently.	('S6_pS235_S236', 'Var', (174, 187))	('endometrial carcinoma', 'Disease', (28, 49))	('Claudin-7', 'Gene', '1366', (163, 172))	('lung adenocarcinoma', 'Disease', (4, 23))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (28, 49))	('NRAS', 'Gene', '4893', (94, 98))	('MAPK', 'molecular_function', 'GO:0004707', ('146', '150'))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('MEK', 'Gene', '5609', (193, 196))	('ATM', 'Gene', '472', (116, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('KRAS', 'Gene', '3845', (89, 93))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (28, 49))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (4, 23))	('cross-cancer', 'Disease', 'MESH:C537866', (65, 77))	('MEK', 'Gene', (193, 196))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (4, 23))	('MAPK_pT202_Y204', 'Var', (146, 161))	('KRAS', 'Gene', (89, 93))	('NRAS', 'Gene', (94, 98))	('MEK1', 'molecular_function', 'GO:0004708', ('193', '197'))	('tumor', 'Disease', (244, 249))	('cross-cancer', 'Disease', (65, 77))	('decreased', 'NegReg', (131, 140))	('ATM', 'Gene', (116, 119))	('Claudin-7', 'Gene', (163, 172))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('increased', 'PosReg', (213, 222))
130833	30442178	MDM2 amplification is actionable in liposarcoma (OncoKB level 3).	('liposarcoma', 'Disease', (36, 47))	('amplification', 'Var', (5, 18))	('liposarcoma', 'Phenotype', 'HP:0012034', (36, 47))	('liposarcoma', 'Disease', 'MESH:D008080', (36, 47))	('MDM2', 'Gene', '4193', (0, 4))	('MDM2', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))
130834	30442178	Besides sarcoma, the protein profiles of cases with MDM2 amplification are discriminable from those with normal copy numbers for renal clear cell carcinoma, lung adenocarcinoma, thyroid carcinoma, breast cancer, ovarian carcinoma, and low-grade glioma (all currently not reported by OncoKB).	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('MDM2', 'Gene', (52, 56))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (129, 155))	('glioma', 'Phenotype', 'HP:0009733', (245, 251))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (157, 176))	('renal clear cell carcinoma', 'Disease', (129, 155))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (157, 176))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (178, 195))	('MDM2', 'Gene', '4193', (52, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('thyroid carcinoma', 'Disease', (178, 195))	('breast cancer', 'Disease', (197, 210))	('amplification', 'Var', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (212, 229))	('ovarian carcinoma', 'Disease', (212, 229))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (178, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('sarcoma', 'Disease', (8, 15))	('glioma', 'Disease', (245, 251))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (212, 229))	('lung adenocarcinoma', 'Disease', (157, 176))	('glioma', 'Disease', 'MESH:D005910', (245, 251))
130835	30442178	Protein levels of sarcoma cases with MDM2 amplifications are discriminable from those without, with a dissimilarity score of sdis = - 0.41 (p = 0.0; srand = - 8.9e-5).	('sarcoma', 'Disease', 'MESH:D012509', (18, 25))	('ran', 'Gene', '5901', (150, 153))	('sarcoma', 'Disease', (18, 25))	('MDM2', 'Gene', '4193', (37, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('MDM2', 'Gene', (37, 41))	('amplifications', 'Var', (42, 56))	('sdis', 'Chemical', '-', (125, 129))	('ran', 'Gene', (150, 153))	('Protein levels', 'MPA', (0, 14))
130836	30442178	Amplified cases show decreased levels of E-Cadherin, Akt_pS473, Akt_pT308, ER-alpha, Caveolin-1, S6_pS240_S244, S6_pS235_S236, and Cyclin_B1 and increased levels of HSP70, Syk, and Lck.	('Lck', 'Gene', (181, 184))	('Akt_pT308', 'Gene', (64, 73))	('HSP70', 'Gene', '3308', (165, 170))	('Cyclin_B1', 'Gene', '891', (131, 140))	('Cyclin', 'molecular_function', 'GO:0016538', ('131', '137'))	('Caveolin-1', 'Gene', (85, 95))	('E-Cadherin', 'Gene', (41, 51))	('Caveolin-1', 'Gene', '857', (85, 95))	('S6_pS240_S244', 'Var', (97, 110))	('levels', 'MPA', (155, 161))	('Cadherin', 'molecular_function', 'GO:0008014', ('43', '51'))	('ER-alpha', 'Gene', (75, 83))	('increased', 'PosReg', (145, 154))	('ER-alpha', 'Gene', '2099', (75, 83))	('Syk', 'Gene', '6850', (172, 175))	('HSP70', 'Gene', (165, 170))	('S6_pS235_S236', 'Var', (112, 125))	('Syk', 'Gene', (172, 175))	('decreased', 'NegReg', (21, 30))	('Cyclin_B1', 'Gene', (131, 140))	('Lck', 'Gene', '3932', (181, 184))	('Akt_pS473', 'Protein', (53, 62))	('E-Cadherin', 'Gene', '999', (41, 51))
130839	30442178	In addition to these histotypes, we found 11 other histological tumor types (renal clear cell carcinoma, low-grade glioma, renal papillary cell carcinoma, colon carcinoma, thyroid carcinoma, thymoma, sarcoma, lung adenocarcinoma, testicular germ cell tumors, prostate adenocarcinoma, glioblastoma, breast and ovarian carcinoma) where MET amplification is associated with a significant change in protein expression.	('tumor', 'Disease', (251, 256))	('glioma', 'Disease', (115, 121))	('breast and ovarian carcinoma', 'Disease', 'MESH:D001943', (298, 326))	('glioblastoma', 'Phenotype', 'HP:0012174', (284, 296))	('protein expression', 'MPA', (395, 413))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('MET amplification', 'Var', (334, 351))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('lung adenocarcinoma', 'Disease', (209, 228))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (172, 189))	('thymoma', 'Disease', 'MESH:D013945', (191, 198))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('thyroid carcinoma', 'Disease', (172, 189))	('renal papillary cell carcinoma', 'Disease', (123, 153))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (209, 228))	('thymoma', 'Disease', (191, 198))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (172, 189))	('thymoma', 'Phenotype', 'HP:0100522', (191, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (209, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('prostate adenocarcinoma', 'Disease', (259, 282))	('tumors', 'Disease', (251, 257))	('colon carcinoma', 'Disease', (155, 170))	('change', 'Reg', (385, 391))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (77, 103))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (309, 326))	('renal clear cell carcinoma', 'Disease', (77, 103))	('renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (123, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('tumor', 'Disease', (64, 69))	('glioblastoma', 'Disease', 'MESH:D005909', (284, 296))	('sarcoma', 'Disease', 'MESH:D012509', (200, 207))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('colon carcinoma', 'Disease', 'MESH:D015179', (155, 170))	('sarcoma', 'Disease', (200, 207))	('protein', 'cellular_component', 'GO:0003675', ('395', '402'))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (259, 282))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('glioblastoma', 'Disease', (284, 296))
130842	30442178	MET amplification is present in renal clear cell carcinoma cases, and protein profiles of amplified and non-amplified cases can be discriminated (sdis = - 0.18; p = 0.0; srand = - 2.0e-5; Src_pY527, Bcl-2, beta-Catenin, PTEN, MAPK_pT202_Y204 are decreased in amplified cases and ACC1, Cyclin_B1, ASNS, ACC_pS79, and Transglutaminase are increased).	('Cyclin_B1', 'Gene', '891', (285, 294))	('ran', 'Gene', (171, 174))	('ran', 'Gene', '5901', (171, 174))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('beta-Catenin', 'Gene', '1499', (206, 218))	('ASNS', 'Gene', (296, 300))	('Src_pY527', 'Var', (188, 197))	('MAPK', 'molecular_function', 'GO:0004707', ('226', '230'))	('PTEN', 'Gene', '5728', (220, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('Cyclin', 'molecular_function', 'GO:0016538', ('285', '291'))	('increased', 'PosReg', (337, 346))	('ACC_pS79', 'MPA', (302, 310))	('ACC1', 'Gene', (279, 283))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (32, 58))	('beta-Catenin', 'Gene', (206, 218))	('MAPK_pT202_Y204', 'Gene', (226, 241))	('renal clear cell carcinoma', 'Disease', (32, 58))	('decreased', 'NegReg', (246, 255))	('ACC1', 'Gene', '597', (279, 283))	('Cyclin_B1', 'Gene', (285, 294))	('ran', 'Gene', (317, 320))	('ran', 'Gene', '5901', (317, 320))	('sdis', 'Chemical', '-', (146, 150))	('Bcl-2', 'Gene', (199, 204))	('Bcl-2', 'molecular_function', 'GO:0015283', ('199', '204'))	('ASNS', 'Gene', '440', (296, 300))	('PTEN', 'Gene', (220, 224))	('Bcl-2', 'Gene', '596', (199, 204))
130844	30442178	PIK3CA activating mutations are actionable for breast cancer (OncoKB evidence level 3).	('breast cancer', 'Disease', (47, 60))	('activating', 'PosReg', (7, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('mutations', 'Var', (18, 27))
130846	30442178	OncoKB level 4 data lists all available histological tumor types as possibly actionable for PIK3CA activating mutations.	('mutations', 'Var', (110, 119))	('PIK3CA', 'Gene', '5290', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('PIK3CA', 'Gene', (92, 98))
130848	30442178	Breast cancer cases with PIK3CA-activating mutations are discriminable from those without (sdis = - 0.52; p = 0.0; srand = 6.2e-6) with specific proteins (increased levels) PR, ER-alpha, MAPK_pT202_Y204, Fibronectin, AR, and GATA3 in mutated cases and Cyclin_B1, Cyclin_E1, ASNS, and HER2 being decreased.	('ran', 'Gene', (116, 119))	('ran', 'Gene', '5901', (116, 119))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Cyclin_B1', 'Gene', '891', (252, 261))	('PIK3CA', 'Gene', '5290', (25, 31))	('increased', 'PosReg', (155, 164))	('HER2', 'Gene', '2064', (284, 288))	('Cyclin_E1', 'Gene', '898', (263, 272))	('ASNS', 'Gene', '440', (274, 278))	('Cyclin', 'molecular_function', 'GO:0016538', ('263', '269'))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('mutated', 'Var', (234, 241))	('GATA3', 'Gene', '2625', (225, 230))	('PIK3CA', 'Gene', (25, 31))	('Cyclin_E1', 'Gene', (263, 272))	('Fibronectin', 'Gene', '2335', (204, 215))	('Cyclin_B1', 'Gene', (252, 261))	('sdis', 'Chemical', '-', (91, 95))	('ASNS', 'Gene', (274, 278))	('HER2', 'Gene', (284, 288))	('GATA3', 'Gene', (225, 230))	('ER-alpha', 'Gene', (177, 185))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('mutations', 'Var', (43, 52))	('ER-alpha', 'Gene', '2099', (177, 185))	('Cyclin', 'molecular_function', 'GO:0016538', ('252', '258'))	('Breast cancer', 'Disease', (0, 13))	('Fibronectin', 'Gene', (204, 215))	('MAPK', 'molecular_function', 'GO:0004707', ('187', '191'))
130852	30442178	However, many open questions remain because apart from mutations with unknown functional effects, it is often not possible even for oncogenic mutations with established clinical relevance in one cancer type to transfer knowledge of actionability to another cancer type.	('mutations', 'Var', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('ran', 'Gene', (211, 214))	('ran', 'Gene', '5901', (211, 214))	('cancer', 'Disease', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
130858	30442178	This indicates that identical genetic alterations are not translated into protein profiles in the same way in different histotypes.	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('ran', 'Gene', '5901', (59, 62))	('ran', 'Gene', (59, 62))	('genetic alterations', 'Var', (30, 49))
130862	30442178	In addition to showing that our analysis identifies protein-level effects for known actionable genes and corresponding cancer types, our approach also identified protein-level alterations indicative of potential novel actionable gene:cancer combinations that are so far unknown according to OncoKB including level 4 evidence (biological information).	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('combinations', 'Var', (241, 253))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
130863	30442178	This includes ERBB2/HER2 amplification in endometrial carcinoma, renal papillary carcinoma, testicular germ cell tumors, urothelial carcinoma, renal clear cell carcinoma, colon carcinoma, ovarian carcinoma, thymoma, thyroid carcinoma, cervical carcinoma, and head and neck squamous cell carcinoma.	('colon carcinoma', 'Disease', 'MESH:D015179', (171, 186))	('tumors', 'Disease', (113, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('HER2', 'Gene', (20, 24))	('thymoma', 'Disease', 'MESH:D013945', (207, 214))	('renal papillary carcinoma', 'Disease', (65, 90))	('cervical carcinoma', 'Disease', (235, 253))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('endometrial carcinoma', 'Disease', (42, 63))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (216, 233))	('ERBB2', 'Gene', (14, 19))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (121, 141))	('thyroid carcinoma', 'Disease', (216, 233))	('thymoma', 'Disease', (207, 214))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (143, 169))	('cervical carcinoma', 'Disease', 'MESH:D002575', (235, 253))	('renal clear cell carcinoma', 'Disease', (143, 169))	('thymoma', 'Phenotype', 'HP:0100522', (207, 214))	('neck squamous cell carcinoma', 'Disease', (268, 296))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (188, 205))	('ERBB2', 'Gene', '2064', (14, 19))	('ovarian carcinoma', 'Disease', (188, 205))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (42, 63))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (268, 296))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (216, 233))	('HER2', 'Gene', '2064', (20, 24))	('amplification', 'Var', (25, 38))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('renal papillary carcinoma', 'Disease', 'MESH:D007681', (65, 90))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (42, 63))	('colon carcinoma', 'Disease', (171, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('neck', 'cellular_component', 'GO:0044326', ('268', '272'))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (188, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (273, 296))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('urothelial carcinoma', 'Disease', (121, 141))
130867	30442178	Interestingly, actionable genes with copy number alterations showed effects on protein expression for more histotypes than those with simple somatic mutations (10.2 affected tumor types on average for amplifications vs. 2.14 for simple somatic mutations).	('tumor', 'Disease', (174, 179))	('protein expression', 'MPA', (79, 97))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('effects', 'Reg', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('copy number alterations', 'Var', (37, 60))
130871	30442178	With respect to the actionable gene analysis, our approach may underestimate the number of potentially druggable genes, but the fact that it readily identifies many well-established actionable gene, cancer combinations, such as, for instance, HER2 amplification in breast and gastric cancer, indicates its validity.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('cancer', 'Disease', (284, 290))	('HER2', 'Gene', (243, 247))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('HER2', 'Gene', '2064', (243, 247))	('cancer', 'Disease', (199, 205))	('gastric cancer', 'Phenotype', 'HP:0012126', (276, 290))	('breast and gastric cancer', 'Disease', 'MESH:D013274', (265, 290))	('amplification', 'Var', (248, 261))
130878	30442178	By evaluating protein-level effects of genetic aberrations, our approach facilitates the identification of functionally relevant mutations and may therefore contribute to predicting actionable mutations across cancers and to guide basket trial design.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('mutations', 'Var', (129, 138))	('facilitates', 'PosReg', (73, 84))	('cancers', 'Disease', 'MESH:D009369', (210, 217))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('cancers', 'Disease', (210, 217))
130879	29959988	Genetic and metabolic hallmarks of clear cell renal cell carcinoma Clear cell renal cell carcinoma (ccRCC) is a malignancy characterized by deregulated hypoxia-inducible factor signaling, mutation of several key chromatin modifying enzymes, and numerous alterations in cellular metabolism.	('hypoxia-inducible factor signaling', 'biological_process', 'GO:0097411', ('152', '186'))	('deregulated', 'PosReg', (140, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (67, 98))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('cellular metabolism', 'biological_process', 'GO:0044237', ('269', '288'))	('hypoxia', 'Disease', (152, 159))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (35, 66))	('cellular metabolism', 'MPA', (269, 288))	('chromatin', 'cellular_component', 'GO:0000785', ('212', '221'))	('hypoxia', 'Disease', 'MESH:D000860', (152, 159))	('malignancy', 'Disease', 'MESH:D009369', (112, 122))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (67, 98))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (35, 66))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (46, 66))	('Clear cell renal cell carcinoma', 'Disease', (67, 98))	('mutation', 'Var', (188, 196))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (78, 98))	('RCC', 'Disease', (102, 105))	('alterations', 'Reg', (254, 265))	('malignancy', 'Disease', (112, 122))	('clear cell renal cell carcinoma', 'Disease', (35, 66))
130889	29959988	Genetic hallmarks include biallelic inactivation of the VHL tumor suppressor gene, the negative regulator of hypoxia-inducible factor (HIF) proteins, as well as copy number alterations of chromosome 3p, 5q, and 14q genes, and high frequency of mutation in chromatin modifying enzymes (e.g., PBRM1, SETD2, and BAP1).	('BAP1', 'Gene', '8314', (309, 313))	('chromosome', 'cellular_component', 'GO:0005694', ('188', '198'))	('PBRM1', 'Gene', (291, 296))	('VHL tumor', 'Disease', 'MESH:D006623', (56, 65))	('chromatin', 'cellular_component', 'GO:0000785', ('256', '265'))	('hypoxia', 'Disease', (109, 116))	('hypoxia', 'Disease', 'MESH:D000860', (109, 116))	('copy number alterations', 'Var', (161, 184))	('BAP1', 'Gene', (309, 313))	('PBRM1', 'Gene', '55193', (291, 296))	('SETD2', 'Gene', '29072', (298, 303))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('60', '76'))	('biallelic', 'Var', (26, 35))	('SETD2', 'Gene', (298, 303))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mutation', 'Var', (244, 252))	('VHL tumor', 'Disease', (56, 65))	('tumor suppressor', 'biological_process', 'GO:0051726', ('60', '76'))
130891	29959988	The most common genetic event of ccRCC is copy number deletion, inactivating mutation, and/or epigenetic silencing of VHL (encoding pVHL), the recognition component of an E3-ubiquitin ligase complex responsible for targeting HIF-1alpha and HIF-2alpha for proteasomal degradation under normoxic conditions (Figure 1).	('inactivating mutation', 'Var', (64, 85))	('RCC', 'Disease', (35, 38))	('VHL', 'Gene', (118, 121))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (225, 250))	('epigenetic silencing', 'Var', (94, 114))	('ubiquitin', 'molecular_function', 'GO:0031386', ('174', '183'))	('copy number deletion', 'Var', (42, 62))	('degradation', 'biological_process', 'GO:0009056', ('267', '278'))	('ubiquitin ligase complex', 'cellular_component', 'GO:0000151', ('174', '198'))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
130901	29959988	Recent sequencing studies involving large cohorts of ccRCC patients have revealed signatures of copy number amplification and deletion across the tumor genome,.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('copy number amplification', 'Var', (96, 121))	('RCC', 'Disease', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('deletion', 'Var', (126, 134))	('patients', 'Species', '9606', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
130903	29959988	On a genome-wide scale, copy number variation of the following regions are most abundant in ccRCC tumors: chromosome 3p loss (91%), 5q gain (67%), and 14q loss (49%).	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (94, 97))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('chromosome', 'cellular_component', 'GO:0005694', ('106', '116'))	('abundant', 'Reg', (80, 88))	('copy number variation', 'Var', (24, 45))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('14q loss', 'Disease', 'MESH:C538031', (151, 159))	('14q loss', 'Disease', (151, 159))	('gain', 'PosReg', (135, 139))	('loss', 'NegReg', (120, 124))	('chromosome', 'Var', (106, 116))
130904	29959988	While chromosome 3p and 14q genes are generally associated with having tumor suppressive functions in ccRCC, copy number amplification of a ~60 gene region of chromosome 5q35 harbors candidate oncogenes,.	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('chromosome', 'cellular_component', 'GO:0005694', ('6', '16'))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('copy number amplification', 'Var', (109, 134))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('159', '169'))	('tumor', 'Disease', (71, 76))	('RCC', 'Disease', (104, 107))
130910	29959988	A 2017 study identified seven new susceptibility loci, including a single nucleotide polymorphism (SNP) within a predicted intronic enhancer of DPF3, a histone acetylation and methylation reader protein of the BRG1-associated factor (BAF) 180 and polybromo-BAF (PBAF) chromatin remodeling complexes.	('chromatin remodeling', 'biological_process', 'GO:0006338', ('268', '288'))	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))	('BRG1-associated factor (BAF) 180', 'Gene', '55193', (210, 242))	('BAF', 'Gene', (234, 237))	('BAF', 'Gene', (257, 260))	('DPF3', 'Gene', (144, 148))	('methylation', 'MPA', (176, 187))	('methylation', 'biological_process', 'GO:0032259', ('176', '187'))	('BAF', 'Gene', '8815', (263, 266))	('chromatin', 'cellular_component', 'GO:0000785', ('268', '277'))	('DPF3', 'Gene', '8110', (144, 148))	('BAF', 'Gene', '8815', (257, 260))	('BAF', 'Gene', '8815', (234, 237))	('N', 'Chemical', 'MESH:D009584', (100, 101))	('histone acetylation', 'biological_process', 'GO:0016573', ('152', '171'))	('single nucleotide polymorphism', 'Var', (67, 97))	('BAF', 'Gene', (263, 266))
130911	29959988	Interestingly, the location of this SNP (14q24) is deleted in one quarter to half of patients, and dysregulation of other components of BAF and PBAF complexes are common features of ccRCC.	('N', 'Chemical', 'MESH:D009584', (37, 38))	('BAF', 'Gene', '8815', (145, 148))	('BAF', 'Gene', (136, 139))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('RCC', 'Disease', (184, 187))	('dysregulation', 'Var', (99, 112))	('BAF', 'Gene', (145, 148))	('patients', 'Species', '9606', (85, 93))	('BAF', 'Gene', '8815', (136, 139))
130913	29959988	The ccRCC risk allele associated with this gene increased its expression, and the authors provided functional evidence that ectopic expression of BHLHE41 increased xenograft tumor growth.	('tumor', 'Disease', (174, 179))	('increased', 'PosReg', (48, 57))	('ectopic expression', 'Var', (124, 142))	('expression', 'MPA', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('BHLHE41', 'Gene', (146, 153))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('increased', 'PosReg', (154, 163))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('BHLHE41', 'Gene', '79365', (146, 153))	('RCC', 'Disease', (6, 9))
130916	29959988	The variants within EPAS1 are also notable as HIF-2alpha inhibition has been repeatedly demonstrated to reduce ccRCC growth,,).	('EPAS1', 'Gene', '2034', (20, 25))	('variants', 'Var', (4, 12))	('EPAS1', 'Gene', (20, 25))	('HIF-2alpha', 'Gene', (46, 56))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('reduce', 'NegReg', (104, 110))	('HIF-2alpha', 'Gene', '2034', (46, 56))
130918	29959988	A study of familial renal cell carcinoma identified mutations in the CDKN2B gene through exon sequencing as predisposing individuals to tumor development.	('mutations', 'Var', (52, 61))	('CDKN2B', 'Gene', (69, 75))	('familial renal cell carcinoma', 'Disease', 'MESH:C536851', (11, 40))	('CDKN2B', 'Gene', '1030', (69, 75))	('predisposing', 'Reg', (108, 120))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (20, 40))	('familial renal cell carcinoma', 'Disease', (11, 40))	('tumor', 'Disease', (136, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
130920	29959988	These mutations, which germline-inactivated CDKN2B in 5% of patients, were predicted to destabilize the interaction between p15INK4B and the CDKs.	('p15INK4B', 'Gene', (124, 132))	('destabilize', 'NegReg', (88, 99))	('interaction', 'Interaction', (104, 115))	('patients', 'Species', '9606', (60, 68))	('p15INK4B', 'Gene', '1030', (124, 132))	('CDKN2B', 'Gene', (44, 50))	('CDKN2B', 'Gene', '1030', (44, 50))	('mutations', 'Var', (6, 15))	('CDKs', 'Protein', (141, 145))
130925	29959988	Nevertheless, additional studies on copy number and single nucleotide variation may help elucidate the etiology of ccRCC, as well as identify new therapeutic targets of interest.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('single nucleotide variation', 'Var', (52, 79))
130926	29959988	After mutation of VHL (53% of patients), PBRM1, SETD2, and BAP1 are the most commonly mutated genes in ccRCC at 40%, 13%, and 10% of patients, respectively.	('BAP1', 'Gene', (59, 63))	('patients', 'Species', '9606', (133, 141))	('mutation', 'Var', (6, 14))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('patients', 'Species', '9606', (30, 38))	('SETD2', 'Gene', '29072', (48, 53))	('PBRM1', 'Gene', (41, 46))	('PBRM1', 'Gene', '55193', (41, 46))	('SETD2', 'Gene', (48, 53))	('BAP1', 'Gene', '8314', (59, 63))	('VHL', 'Gene', (18, 21))
130930	29959988	Inactivating or truncating mutations in JARID1C (also known as KDM5C), a histone H3 lysine 4 demethylase, and UTX (KMD6A) a histone H3 lysine 27 demethylase were identified in another study as positively selected for in ccRCC compared to other cancers,.	('JARID1C', 'Gene', '8242', (40, 47))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))	('UTX', 'Gene', (110, 113))	('lysine', 'Chemical', 'MESH:D008239', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('UTX', 'Gene', '7403', (110, 113))	('lysine', 'Chemical', 'MESH:D008239', (84, 90))	('Inactivating', 'Var', (0, 12))	('selected', 'Reg', (204, 212))	('JARID1C', 'Gene', (40, 47))	('RCC', 'Disease', 'MESH:C538614', (222, 225))	('RCC', 'Disease', (222, 225))	('KDM5C', 'Gene', (63, 68))	('cancers', 'Disease', 'MESH:D009369', (244, 251))	('KDM5C', 'Gene', '8242', (63, 68))	('cancers', 'Disease', (244, 251))	('truncating mutations', 'Var', (16, 36))
130934	29959988	How hypermethylation of enhancer and promoter CpG regions affects ccRCC progression is an ongoing area of investigation in the field.	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('hypermethylation', 'Var', (4, 20))	('affects', 'Reg', (58, 65))
130935	29959988	As VHL deletion is insufficient to drive ccRCC tumorigenesis, conditional knockout mice have been generated in several laboratories combining deletion of candidate tumor suppressor genes based on large-scale patient sequencing data,.	('patient', 'Species', '9606', (208, 215))	('tumor', 'Disease', (164, 169))	('tumor suppressor', 'biological_process', 'GO:0051726', ('164', '180'))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('mice', 'Species', '10090', (83, 87))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('164', '180'))	('RCC', 'Disease', (43, 46))	('VHL', 'Gene', (3, 6))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('deletion', 'Var', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('deletion', 'Var', (7, 15))	('tumor', 'Disease', (47, 52))	('insufficient', 'Disease', (19, 31))	('insufficient', 'Disease', 'MESH:D000309', (19, 31))
130936	29959988	A recent report combined Vhl and Pbrm1 deletion throughout renal tubules, collecting ducts, and thick ascending limbs using Ksp-Cre, and found that 67% of these mice first developed polycystic kidney disease (PKD) within 10-14 months of age.	('kidney disease', 'Phenotype', 'HP:0000112', (193, 207))	('mice', 'Species', '10090', (161, 165))	('PKD', 'Disease', (209, 212))	('Pbrm1', 'Gene', (33, 38))	('polycystic kidney disease', 'Disease', (182, 207))	('PKD', 'Disease', 'MESH:C537180', (209, 212))	('deletion', 'Var', (39, 47))	('polycystic kidney', 'Phenotype', 'HP:0000113', (182, 199))	('developed', 'Reg', (172, 181))	('polycystic kidney disease', 'Disease', 'MESH:D007690', (182, 207))	('Vhl', 'Gene', (25, 28))
130937	29959988	While deletion of either gene alone did not result in PKD or ccRCC, 50% of the double knockout (Vhl-/-, Pbrm1-/-) mice showed signs of tumor incidence after 10 months of age, with clear cell morphology, activated mTOR signaling, and reduction in oxidative phosphorylation gene signatures reported.	('RCC', 'Disease', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('oxidative phosphorylation gene signatures', 'MPA', (246, 287))	('RCC', 'Disease', 'MESH:C538614', (63, 66))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('signaling', 'biological_process', 'GO:0023052', ('218', '227'))	('deletion', 'Var', (6, 14))	('mice', 'Species', '10090', (114, 118))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('246', '271'))	('reduction', 'NegReg', (233, 242))	('activated', 'PosReg', (203, 212))	('mTOR signaling', 'MPA', (213, 227))	('PKD', 'Disease', 'MESH:C537180', (54, 57))	('PKD', 'Disease', (54, 57))
130941	29959988	Further analyses of a larger cohort suggested 82% of Vhl-/-, Trp53-/-, Rb1-/- mice developed tumors within 15 months of gene deletion, the majority of which were classified as grade 3 or 4 tumors growing in acinar or pseudo-papillary patterns.	('developed', 'PosReg', (83, 92))	('gene deletion', 'Var', (120, 133))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('papillary patterns', 'Phenotype', 'HP:0007482', (224, 242))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('Vhl-/-', 'Gene', (53, 59))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('Rb1-/-', 'Gene', (71, 77))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('Trp53-/-', 'Gene', (61, 69))	('mice', 'Species', '10090', (78, 82))
130946	29959988	Consistent with chromosome 3p genes displaying tumor suppressive functions in ccRCC, the effect of Bap1 deletion in combination with either Vhl or Pbrm1 loss has been examined in several publications from the Brugarolas group.	('Bap1', 'Gene', (99, 103))	('RCC', 'Disease', (80, 83))	('loss', 'NegReg', (153, 157))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('chromosome', 'cellular_component', 'GO:0005694', ('16', '26'))	('deletion', 'Var', (104, 112))	('tumor', 'Disease', (47, 52))
130947	29959988	Under the control of Six2-Cre driver, which is expressed in multipotent nephron progenitor cells of the kidney during development, the authors first generated Vhl-/-, Bap+/- mice (deletion of both alleles of Vhl and one of Bap1).	('Bap', 'Gene', (223, 226))	('multipotent nephron', 'Disease', (60, 79))	('deletion', 'Var', (180, 188))	('mice', 'Species', '10090', (174, 178))	('Vhl', 'Gene', (208, 211))	('Bap', 'Gene', '12034', (167, 170))	('multipotent nephron', 'Disease', 'MESH:D007683', (60, 79))	('Bap', 'Gene', (167, 170))	('Bap', 'Gene', '12034', (223, 226))
130949	29959988	Some of the lesions observed were similar to early-stage ccRCC tumors by cytoplasmic clearing, Ki67 expression, and phospho-S6 positivity as a marker of mTOR activity, yet tumors remained small overall.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('phospho-S6 positivity', 'Var', (116, 137))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))
130951	29959988	Pax8-Cre was used to delete Vhl and Bap1 or Pbrm1 within the proximal and distal renal tubules, loops of Henle, collecting ducts, and parietal cells of the Bowman capsule.	('Pax8', 'Gene', '7849', (0, 4))	('Pbrm1', 'Gene', (44, 49))	('Pax8', 'Gene', (0, 4))	('Bap1', 'Gene', (36, 40))	('capsule', 'cellular_component', 'GO:0042603', ('163', '170'))	('delete', 'Var', (21, 27))	('Vhl', 'Gene', (28, 31))
130952	29959988	Sglt2- and Villin-Cre were also used for more specific deletion within proximal tubule epithelial cells.	('Sglt2', 'Gene', (0, 5))	('Sglt2', 'Gene', '6524', (0, 5))	('deletion', 'Var', (55, 63))
130954	29959988	Interestingly, deletion of both alleles of Vhl along with a single allele of either Pbrm1 or Bap1 using Sglt2- and Villin-Cre drivers did not result in ccRCC formation.	('deletion', 'Var', (15, 23))	('Vhl', 'Gene', (43, 46))	('Sglt2', 'Gene', '6524', (104, 109))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('RCC', 'Disease', (154, 157))	('Sglt2', 'Gene', (104, 109))	('result in', 'Reg', (142, 151))	('formation', 'biological_process', 'GO:0009058', ('158', '167'))
130956	29959988	The authors also found that activation of mTORC1 signaling through inactivation of one allele of Tsc2 caused the formation of higher grade ccRCC specifically in Pbrm1-deficient kidneys.	('RCC', 'Disease', (141, 144))	('inactivation', 'Var', (67, 79))	('Pbrm1-deficient kidneys', 'Disease', (161, 184))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('mTORC1', 'cellular_component', 'GO:0031931', ('42', '48'))	('mTORC1', 'Gene', '382056', (42, 48))	('RCC', 'Disease', 'MESH:C538614', (141, 144))	('deficient kidneys', 'Phenotype', 'HP:0000089', (167, 184))	('Pbrm1-deficient kidneys', 'Disease', 'MESH:D007674', (161, 184))	('mTORC1', 'Gene', (42, 48))	('activation', 'PosReg', (28, 38))	('formation', 'biological_process', 'GO:0009058', ('113', '122'))	('Tsc2', 'Gene', (97, 101))	('Tsc2', 'Gene', '7249', (97, 101))
130957	29959988	Notably, patients with PBRM1 and BAP1 mutations have distinct gene expression patterns and clinical outcomes, and these alterations are largely mutually exclusive.	('PBRM1', 'Gene', (23, 28))	('patients', 'Species', '9606', (9, 17))	('PBRM1', 'Gene', '55193', (23, 28))	('gene expression', 'biological_process', 'GO:0010467', ('62', '77'))	('BAP1', 'Gene', '8314', (33, 37))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('BAP1', 'Gene', (33, 37))	('mutations', 'Var', (38, 47))
130958	29959988	While BAP1-deficient tumors are higher in grade and portend worse prognosis than PBRM1-deficient tumors, it is believed that BAP1 mutations are secondary to PBRM1 loss in the pathogenesis of ccRCC,.	('PBRM1', 'Gene', '55193', (81, 86))	('PBRM1-deficient tumors', 'Disease', (81, 103))	('BAP1-deficient tumors', 'Disease', 'MESH:D009369', (6, 27))	('BAP1', 'Gene', '8314', (6, 10))	('RCC', 'Disease', (193, 196))	('PBRM1', 'Gene', (81, 86))	('BAP1', 'Gene', '8314', (125, 129))	('loss', 'NegReg', (163, 167))	('PBRM1', 'Gene', '55193', (157, 162))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('pathogenesis', 'biological_process', 'GO:0009405', ('175', '187'))	('BAP1-deficient tumors', 'Disease', (6, 27))	('PBRM1-deficient tumors', 'Disease', 'MESH:D009369', (81, 103))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('BAP1', 'Gene', (6, 10))	('PBRM1', 'Gene', (157, 162))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('BAP1', 'Gene', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mutations', 'Var', (130, 139))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))
130971	29959988	In another report, the combination of MYC overexpression along with further deletion of Vhl and/or Cdkn2a (encoding Ink4/Arf) was investigated for the ability to induce papillary or clear cell renal cell carcinoma.	('deletion', 'Var', (76, 84))	('Ink4', 'Gene', (116, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('Vhl', 'Gene', (88, 91))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (193, 213))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (182, 213))	('papillary', 'Disease', (169, 178))	('Cdkn2a', 'Gene', (99, 105))	('induce', 'Reg', (162, 168))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (182, 213))	('Ink4', 'Gene', '1029', (116, 120))	('clear cell renal cell carcinoma', 'Disease', (182, 213))
130973	29959988	When MYC was overexpressed without deletion of either Vhl or Cdkn2a, the mice developed tumors histologically consistent with papillary RCC.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('papillary RCC', 'Disease', 'MESH:C538614', (126, 139))	('Vhl', 'Gene', (54, 57))	('papillary RCC', 'Disease', (126, 139))	('mice', 'Species', '10090', (73, 77))	('Cdkn2a', 'Gene', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('deletion', 'Var', (35, 43))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('developed', 'PosReg', (78, 87))
130974	29959988	However, Vhl deletion in combination with MYC overexpression ("VM") mice generated tumors more similar to ccRCC based on cytoplasmic clearing, necrosis, and hemorrhage.	('hemorrhage', 'Disease', (157, 167))	('mice', 'Species', '10090', (68, 72))	('RCC', 'Disease', (108, 111))	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('Vhl', 'Gene', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('necrosis', 'biological_process', 'GO:0019835', ('141', '149'))	('necrosis', 'biological_process', 'GO:0070265', ('141', '149'))	('necrosis', 'biological_process', 'GO:0008219', ('141', '149'))	('necrosis', 'biological_process', 'GO:0008220', ('141', '149'))	('hemorrhage', 'Disease', 'MESH:D006470', (157, 167))	('necrosis', 'Disease', 'MESH:D009336', (143, 151))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('necrosis', 'biological_process', 'GO:0001906', ('141', '149'))	('deletion', 'Var', (13, 21))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('necrosis', 'Disease', (143, 151))
130975	29959988	Addition of Cdkn2a deletion to this model ("VIM") further potentiated ccRCC formation compared with Vhl deletion alone, increasing tumor volume and decreasing median survival time.	('decreasing', 'NegReg', (148, 158))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('median survival time', 'CPA', (159, 179))	('increasing', 'PosReg', (120, 130))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('Cdkn2a', 'Gene', (12, 18))	('deletion', 'Var', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('potentiated', 'PosReg', (58, 69))	('formation', 'biological_process', 'GO:0009058', ('74', '83'))
130979	29959988	As evidenced by the publications described above, the various methods used to either delete tumor suppressors and/or express oncogenes in distinct kidney lineages result in different propensities for ccRCC development.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('delete', 'Var', (85, 91))	('tumor', 'Disease', (92, 97))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('RCC', 'Disease', (202, 205))	('oncogenes', 'Gene', (125, 134))
130995	29959988	Additionally, our group demonstrated that the gene encoding the gluconeogenic enzyme fructose-1,6-bisphosphatase 1, FBP1, is uniformly silenced or deleted in ccRCC patients.	('deleted', 'Var', (147, 154))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('FBP1', 'Gene', (116, 120))	('RCC', 'Disease', (160, 163))	('patients', 'Species', '9606', (164, 172))	('FBP1', 'Gene', '2203', (116, 120))
130996	29959988	Loss of FBP1 promotes ccRCC progression by two distinct mechanisms; first, by promoting glycolytic flux in renal epithelial cells, and secondly, by dissociation with the HIF-alpha inhibitory domain, facilitating constitutive HIF activity at the chromatin-level.	('RCC', 'Disease', (24, 27))	('chromatin', 'cellular_component', 'GO:0000785', ('245', '254'))	('FBP1', 'Gene', (8, 12))	('promotes', 'PosReg', (13, 21))	('glycolytic flux', 'MPA', (88, 103))	('dissociation', 'NegReg', (148, 160))	('promoting', 'PosReg', (78, 87))	('FBP1', 'Gene', '2203', (8, 12))	('Loss', 'Var', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
130998	29959988	The phosphoinositide 3-kinase (PI3K) signaling pathway is activated by copy number variation or mutation of its positive effectors PIK3CA, MTOR, and negative regulators PTEN and TSC1/2 in 28% of patients in ccRCC,.	('phosphoinositide 3-kinase', 'Gene', '5290', (4, 29))	('PI3K) signaling', 'biological_process', 'GO:0014065', ('31', '46'))	('MTOR', 'Gene', (139, 143))	('signaling pathway', 'biological_process', 'GO:0007165', ('37', '54'))	('TSC1/2', 'Gene', '7248;7249', (178, 184))	('MTOR', 'Gene', '2475', (139, 143))	('PIK3CA', 'Gene', (131, 137))	('RCC', 'Disease', (209, 212))	('phosphoinositide 3-kinase', 'Gene', (4, 29))	('mutation', 'Var', (96, 104))	('patients', 'Species', '9606', (195, 203))	('RCC', 'Disease', 'MESH:C538614', (209, 212))	('activated', 'PosReg', (58, 67))	('PI3K', 'molecular_function', 'GO:0016303', ('31', '35'))	('TSC1/2', 'Gene', (178, 184))	('copy number variation', 'Var', (71, 92))	('PTEN', 'Gene', (169, 173))	('PIK3CA', 'Gene', '5290', (131, 137))	('PTEN', 'Gene', '5728', (169, 173))
130999	29959988	PI3K activation activates Akt, also known as protein kinase B, by phosphorylation at the cell surface.	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('PI3K', 'Var', (0, 4))	('Akt', 'Gene', '207', (26, 29))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('phosphorylation', 'MPA', (66, 81))	('Akt', 'Gene', (26, 29))	('activates', 'PosReg', (16, 25))	('cell surface', 'cellular_component', 'GO:0009986', ('89', '101'))	('phosphorylation', 'biological_process', 'GO:0016310', ('66', '81'))
131001	29959988	Inactivation of the negative regulators of mTORC1, TSC1 and TSC2, has been associated with increased risk of ccRCC development, which presents at an earlier age than sporadic disease.	('mTORC1', 'Gene', '382056', (43, 49))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('mTORC1', 'Gene', (43, 49))	('RCC', 'Disease', (111, 114))	('TSC1', 'Gene', '7248', (51, 55))	('mTORC1', 'cellular_component', 'GO:0031931', ('43', '49'))	('TSC2', 'Gene', '7249', (60, 64))	('TSC1', 'Gene', (51, 55))	('TSC2', 'Gene', (60, 64))	('associated', 'Reg', (75, 85))	('Inactivation', 'Var', (0, 12))
131009	29959988	Ectopic expression of PGC-1alpha increased oxidative stress and slowed tumor growth in a subcutaneous xenograft model.	('PGC-1alpha', 'Gene', (22, 32))	('slowed', 'NegReg', (64, 70))	('oxidative stress', 'Phenotype', 'HP:0025464', (43, 59))	('PGC-1alpha', 'Gene', '10891', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('Ectopic expression', 'Var', (0, 18))	('oxidative stress', 'MPA', (43, 59))	('increased', 'PosReg', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (33, 59))	('tumor', 'Disease', (71, 76))
131012	29959988	A recent report found that pVHL reconstitution in several ccRCC cell lines reduced lipid droplet (LD) accumulation in a CPT1A dependent manner (i.e., knockdown of CPT1A in pVHL-reconstituted cells partially increased lipid accumulation).	('CPT', 'molecular_function', 'GO:0004142', ('120', '123'))	('CPT1A', 'Gene', '1374', (120, 125))	('increased lipid', 'Phenotype', 'HP:0003077', (207, 222))	('CPT', 'molecular_function', 'GO:0004142', ('163', '166'))	('CPT', 'molecular_function', 'GO:0004095', ('120', '123'))	('lipid', 'Chemical', 'MESH:D008055', (83, 88))	('lipid', 'Chemical', 'MESH:D008055', (217, 222))	('RCC', 'Disease', (60, 63))	('increased', 'PosReg', (207, 216))	('knockdown', 'Var', (150, 159))	('reduced', 'NegReg', (75, 82))	('CPT', 'molecular_function', 'GO:0004095', ('163', '166'))	('CPT1A', 'Gene', (163, 168))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('lipid droplet', 'cellular_component', 'GO:0005811', ('83', '96'))	('CPT1A', 'Gene', '1374', (163, 168))	('CPT1A', 'Gene', (120, 125))
131014	29959988	Ectopic expression of CPT1A increased oxygen consumption rate, decreased LD abundance, and decreased xenograft tumor growth.	('increased', 'PosReg', (28, 37))	('CPT', 'molecular_function', 'GO:0004095', ('22', '25'))	('CPT1A', 'Gene', '1374', (22, 27))	('LD abundance', 'CPA', (73, 85))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('decreased', 'NegReg', (63, 72))	('oxygen', 'Chemical', 'MESH:D010100', (38, 44))	('Ectopic expression', 'Var', (0, 18))	('decreased xenograft tumor', 'Disease', 'MESH:D009369', (91, 116))	('decreased xenograft tumor', 'Disease', (91, 116))	('oxygen consumption rate', 'MPA', (38, 61))	('CPT1A', 'Gene', (22, 27))	('CPT', 'molecular_function', 'GO:0004142', ('22', '25'))
131022	29959988	FASN levels correlate positively with tumor aggressiveness and poor survival in ccRCC, and genetic and pharmacologic inhibition of SCD1 induces apoptosis in ccRCC cell lines both in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('apoptosis', 'biological_process', 'GO:0006915', ('144', '153'))	('induces', 'Reg', (136, 143))	('SCD1', 'Gene', (131, 135))	('tumor aggressiveness', 'Disease', (38, 58))	('FASN', 'Gene', (0, 4))	('aggressiveness', 'Phenotype', 'HP:0000718', (44, 58))	('FASN', 'Gene', '2194', (0, 4))	('apoptosis', 'CPA', (144, 153))	('SCD1', 'Gene', '6319', (131, 135))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('inhibition', 'Var', (117, 127))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (38, 58))	('apoptosis', 'biological_process', 'GO:0097194', ('144', '153'))	('RCC', 'Disease', (159, 162))
131023	29959988	Treatment with ACC inhibitor reduces total phospholipid and triglyceride content, as predicted, and also increases sensitivity to oxidative stress-induced cell death.	('oxidative stress', 'Phenotype', 'HP:0025464', (130, 146))	('phospholipid', 'Chemical', 'MESH:D010743', (43, 55))	('triglyceride', 'Chemical', 'MESH:D014280', (60, 72))	('sensitivity to oxidative stress-induced cell death', 'MPA', (115, 165))	('cell death', 'biological_process', 'GO:0008219', ('155', '165'))	('reduces', 'NegReg', (29, 36))	('ACC', 'Gene', (15, 18))	('inhibitor', 'Var', (19, 28))	('increases', 'PosReg', (105, 114))
131024	29959988	Other work has demonstrated that lipid uptake protects against endoplasmic reticulum (ER) stress in ccRCC and other cancers, particularly under hypoxia when cells cannot desaturate fatty acids due to the inactivation of SCD1,.	('SCD1', 'Gene', '6319', (220, 224))	('lipid uptake', 'biological_process', 'GO:0140354', ('33', '45'))	('hypoxia', 'Disease', (144, 151))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('inactivation', 'Var', (204, 216))	('hypoxia', 'Disease', 'MESH:D000860', (144, 151))	('cancers', 'Disease', (116, 123))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('SCD1', 'Gene', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('63', '84'))	('lipid', 'Chemical', 'MESH:D008055', (33, 38))	('fatty acids', 'Chemical', 'MESH:D005227', (181, 192))
131025	29959988	The protective effect of LD accumulation in cancer cells is incompletely understood, although recent studies suggest several mechanisms by which LDs can enhance tumorigenesis and cell viability.	('cell viability', 'CPA', (179, 193))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('enhance', 'PosReg', (153, 160))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('LDs', 'Var', (145, 148))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
131027	29959988	Inhibition of the LD coat protein perilipin 2 in ccRCC, a highly-expressed HIF-2alpha target gene, reduced neutral lipid accumulation, tumor growth, and increased ER stress both in vitro and in vivo.	('ER stress', 'MPA', (163, 172))	('perilipin 2', 'Gene', '123', (34, 45))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('increased', 'PosReg', (153, 162))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('HIF-2alpha', 'Gene', (75, 85))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('Inhibition', 'Var', (0, 10))	('lipid', 'Chemical', 'MESH:D008055', (115, 120))	('HIF-2alpha', 'Gene', '2034', (75, 85))	('reduced', 'NegReg', (99, 106))	('neutral lipid accumulation', 'MPA', (107, 133))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('perilipin 2', 'Gene', (34, 45))	('RCC', 'Disease', (51, 54))
131051	29959988	PT2399 blocks the interaction between HIF-2alpha and HIF-1beta/ARNT by binding to a pocket within the PAS-B domain of HIF-2alpha, thereby eliminating DNA binding.	('PAS', 'cellular_component', 'GO:0000407', ('102', '105'))	('HIF-2alpha', 'Gene', (118, 128))	('ARNT', 'Gene', (63, 67))	('eliminating', 'NegReg', (138, 149))	('PT2399', 'Var', (0, 6))	('HIF-2alpha', 'Gene', '2034', (38, 48))	('HIF-2alpha and HIF-1beta', 'Disease', 'None', (38, 62))	('DNA binding', 'molecular_function', 'GO:0003677', ('150', '161'))	('binding', 'Interaction', (71, 78))	('HIF-2alpha', 'Gene', '2034', (118, 128))	('N', 'Chemical', 'MESH:D009584', (65, 66))	('DNA binding', 'Interaction', (150, 161))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))	('PT2399', 'Chemical', 'MESH:C000614278', (0, 6))	('interaction', 'Interaction', (18, 29))	('blocks', 'NegReg', (7, 13))	('DNA', 'cellular_component', 'GO:0005574', ('150', '153'))	('N', 'Chemical', 'MESH:D009584', (151, 152))	('ARNT', 'Gene', '405', (63, 67))	('HIF-2alpha', 'Gene', (38, 48))
131052	29959988	Importantly, PT2399 reduces HIF-2alpha target gene expression without affecting HIF-1alpha targets.	('gene expression', 'biological_process', 'GO:0010467', ('46', '61'))	('HIF-2alpha', 'Gene', '2034', (28, 38))	('reduces', 'NegReg', (20, 27))	('PT2399', 'Var', (13, 19))	('PT2399', 'Chemical', 'MESH:C000614278', (13, 19))	('HIF-2alpha', 'Gene', (28, 38))
131053	29959988	When tested alongside sunitinib, PT2399 decreased tumorgraft growth by 60% across all samples tested compared with 40% for sunitinib treatment, without causing a reduction in body weight as seen with the latter drug.	('sunitinib', 'Chemical', 'MESH:D000077210', (123, 132))	('reduction in body weight', 'Phenotype', 'HP:0004325', (162, 186))	('PT2399', 'Var', (33, 39))	('PT2399', 'Chemical', 'MESH:C000614278', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('sunitinib', 'Chemical', 'MESH:D000077210', (22, 31))	('decreased', 'NegReg', (40, 49))	('tumor', 'Disease', (50, 55))
131054	29959988	Resistance mechanisms were observed in tumors initially sensitive to PT2399, which were characterized by increased tumor vascularity and VEGF production despite dissociation between HIF-2alpha and ARNT.	('PT2399', 'Chemical', 'MESH:C000614278', (69, 75))	('tumor', 'Disease', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('VEGF', 'Gene', '7422', (137, 141))	('ARNT', 'Gene', '405', (197, 201))	('VEGF', 'Gene', (137, 141))	('ARNT', 'Gene', (197, 201))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('HIF-2alpha', 'Gene', '2034', (182, 192))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (39, 44))	('increased', 'PosReg', (105, 114))	('PT2399', 'Var', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('VEGF production', 'biological_process', 'GO:0010573', ('137', '152'))	('HIF-2alpha', 'Gene', (182, 192))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
131066	29959988	Clinical work comparing nivolumab, a monoclonal antibody targeting PD-1, to everolimus, found that nivolumab extended median survival to 25 months compared with 19.6 months for everolimus treatment in patients with advanced ccRCC.	('PD-1', 'Gene', (67, 71))	('patients', 'Species', '9606', (201, 209))	('antibody', 'molecular_function', 'GO:0003823', ('48', '56'))	('PD-1', 'Gene', '5133', (67, 71))	('extended', 'PosReg', (109, 117))	('nivolumab', 'Chemical', 'MESH:D000077594', (99, 108))	('everolimus', 'Chemical', 'MESH:D000068338', (177, 187))	('antibody', 'cellular_component', 'GO:0042571', ('48', '56'))	('nivolumab', 'Chemical', 'MESH:D000077594', (24, 33))	('nivolumab', 'Var', (99, 108))	('RCC', 'Disease', (226, 229))	('median survival', 'MPA', (118, 133))	('antibody', 'cellular_component', 'GO:0019814', ('48', '56'))	('antibody', 'cellular_component', 'GO:0019815', ('48', '56'))	('RCC', 'Disease', 'MESH:C538614', (226, 229))	('everolimus', 'Chemical', 'MESH:D000068338', (76, 86))
131107	30185225	Mechanistically, drug failure could be a consequence of: i) compensatory feedback signaling loops following mTOR inhibition; ii) activation of alternative as well as synergistic pathways such as TGF-beta after anti-angiogenesis therapy, and MAPKs/Ras signaling, respectively; iii) de novo somatic lesions, like mTORC-1 point mutations.	('drug failure', 'Disease', 'MESH:D017093', (17, 29))	('mTORC-1', 'cellular_component', 'GO:0031931', ('311', '318'))	('mTORC-1', 'Gene', (311, 318))	('mTOR', 'Gene', (108, 112))	('angiogenesis', 'biological_process', 'GO:0001525', ('215', '227'))	('mTOR', 'Gene', '2475', (108, 112))	('point mutations', 'Var', (319, 334))	('compensatory feedback signaling loops', 'MPA', (60, 97))	('signaling', 'biological_process', 'GO:0023052', ('82', '91'))	('drug failure', 'Phenotype', 'HP:0020174', (17, 29))	('activation', 'PosReg', (129, 139))	('TGF-beta', 'Pathway', (195, 203))	('mTOR', 'Gene', (311, 315))	('mTOR', 'Gene', '2475', (311, 315))	('signaling', 'biological_process', 'GO:0023052', ('251', '260'))	('drug failure', 'Disease', (17, 29))	('mTORC-1', 'Gene', '382056', (311, 318))
131137	30185225	Antibodies used were V450 Mouse Anti-Human CD44 (561292), PE-Cy7 Mouse Anti-Human CD45 (557748), PE Mouse Anti- Human CD146 (550315), PE-Mouse Anti-Human CD24 (555428), FITC Mouse Anti-Human CD90 (561969), FITC-Mouse Anti-Human EpCAM (347197), APC-Mouse Anti-Human CD10 (332777), (all from BD Bioscience Bedford, Franklin Lakes, NJ) and Mouse monoclonal antibody [5D3] to Cytokeratin 8 + 18 (Abcam Cambridge,UK, 17139).	('CD44', 'Gene', '960', (43, 47))	('CD44', 'Gene', (43, 47))	('CD24', 'Gene', '100133941', (154, 158))	('CD45', 'Gene', (82, 86))	('332777', 'Var', (271, 277))	('Mouse', 'Species', '10090', (174, 179))	('antibody', 'cellular_component', 'GO:0019815', ('354', '362'))	('561969', 'Var', (197, 203))	('Human', 'Species', '9606', (222, 227))	('CD45', 'Gene', '5788', (82, 86))	('CD10', 'Gene', '4311', (265, 269))	('Human', 'Species', '9606', (148, 153))	('347197', 'Var', (235, 241))	('Human', 'Species', '9606', (259, 264))	('Mouse', 'Species', '10090', (337, 342))	('Human', 'Species', '9606', (37, 42))	('antibody', 'cellular_component', 'GO:0019814', ('354', '362'))	('Mouse', 'Species', '10090', (100, 105))	('CD10', 'Gene', (265, 269))	('CD90', 'Gene', (191, 195))	('EpCAM', 'Gene', (228, 233))	('Mouse', 'Species', '10090', (211, 216))	('APC', 'cellular_component', 'GO:0005680', ('244', '247'))	('CD24', 'Gene', (154, 158))	('Mouse', 'Species', '10090', (65, 70))	('EpCAM', 'Gene', '4072', (228, 233))	('Human', 'Species', '9606', (76, 81))	('Mouse', 'Species', '10090', (248, 253))	('antibody', 'molecular_function', 'GO:0003823', ('354', '362'))	('Human', 'Species', '9606', (185, 190))	('CD90', 'Gene', '7070', (191, 195))	('CD10', 'molecular_function', 'GO:0004245', ('265', '269'))	('antibody', 'cellular_component', 'GO:0042571', ('354', '362'))	('Mouse', 'Species', '10090', (26, 31))	('CD146', 'Gene', '4162', (118, 123))	('CD146', 'Gene', (118, 123))	('Mouse', 'Species', '10090', (137, 142))	('Human', 'Species', '9606', (112, 117))
131164	30185225	Six weeks old male of 20 g NOD Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were purchased from Charles River Laboratories (Calco, LC, Italy) and were used for the injection of the clinical tumor samples depending on patient gender.	('tumor', 'Disease', (185, 190))	('Prkdc', 'Gene', (34, 39))	('Il2', 'molecular_function', 'GO:0005134', ('44', '47'))	('patient', 'Species', '9606', (212, 219))	('mice', 'Species', '10090', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('Prkdc', 'Gene', '19090', (34, 39))	('Il2rgtm1Wjl/SzJ', 'Var', (44, 59))
131201	30185225	EpCAM+/CD146+ cell percentage (ranging from 2 to 10% of total tissue population) seems increase with grading (Fig.	('EpCAM', 'Gene', '4072', (0, 5))	('increase', 'PosReg', (87, 95))	('CD146', 'Gene', (7, 12))	('grading', 'Var', (101, 108))	('EpCAM', 'Gene', (0, 5))	('CD146', 'Gene', '4162', (7, 12))
131213	30185225	In particular, DMEM cultures had a less clonogenic activity than cells maintained in stem serum-free medium, and produced a larger percentage of monolayer bidimensional colonies unable to form tridimensional spherical structures (Additional file 5: Figure S4B-D).	('less', 'NegReg', (35, 39))	('men', 'Species', '9606', (159, 162))	('monolayer bidimensional colonies', 'CPA', (145, 177))	('clonogenic activity', 'CPA', (40, 59))	('DMEM', 'Var', (15, 19))	('DMEM', 'Chemical', '-', (15, 19))	('men', 'Species', '9606', (198, 201))
131252	30185225	G3/G4 tumors demonstrated higher engrafting capacity (75%) and increased mass sizes when compared to low grade G1/G2 cases (Fig.	('increased', 'PosReg', (63, 72))	('G3/G4', 'Var', (0, 5))	('higher', 'PosReg', (26, 32))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('engrafting capacity', 'CPA', (33, 52))	('tumors', 'Disease', (6, 12))	('mass sizes', 'CPA', (73, 83))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
131282	30185225	In line with sarcomatoid phenotype, the bulk cell population showed elevated expression of CD44, coupled to moderate levels of CD146, EpCAM, CD24 and CD90 (Additional file 14: Figure S10B).	('CD146', 'Gene', '4162', (127, 132))	('CD90', 'Gene', (150, 154))	('CD146', 'Gene', (127, 132))	('expression', 'MPA', (77, 87))	('CD90', 'Gene', '7070', (150, 154))	('sarcomatoid', 'Disease', 'MESH:C538614', (13, 24))	('S10B', 'SUBSTITUTION', 'None', (183, 187))	('CD44', 'Gene', '960', (91, 95))	('CD24', 'Gene', '100133941', (141, 145))	('elevated', 'PosReg', (68, 76))	('CD44', 'Gene', (91, 95))	('EpCAM', 'Gene', (134, 139))	('S10B', 'Var', (183, 187))	('sarcomatoid', 'Disease', (13, 24))	('CD24', 'Gene', (141, 145))	('EpCAM', 'Gene', '4072', (134, 139))
131342	30988807	Kyoto Encyclopedia of Genes Genomes pathway analysis revealed that the DEGs were mainly involved in the 'cell cycle' (hsa04110), 'collecting duct acid secretion' (hsa04966), 'complement and coagulation cascades' (hsa04610) and 'aldosterone-regulated sodium reabsorption' (hsa04960) pathways.	('hsa04110', 'Var', (118, 126))	('hsa04966', 'Var', (163, 171))	('sodium', 'Chemical', 'MESH:D012964', (250, 256))	("'collecting duct", 'Phenotype', 'HP:0000081', (129, 145))	('coagulation', 'biological_process', 'GO:0050817', ('190', '201'))	('hsa04610', 'Var', (213, 221))	('acid secretion', 'biological_process', 'GO:0046717', ('146', '160'))	("'collecting duct acid secretion'", 'MPA', (129, 161))	("'cell", 'Pathway', (104, 109))	('cell cycle', 'biological_process', 'GO:0007049', ('105', '115'))	("'aldosterone-regulated sodium reabsorption'", 'Pathway', (227, 270))	('hsa04960', 'Var', (272, 280))	('men', 'Species', '9606', (181, 184))	('involved', 'Reg', (88, 96))
131383	30988807	GO enrichment analysis revealed that DEGs were mainly associated with 'cell transmembrane movement' and 'mitotic cell cycle process'.	('mitotic cell cycle process', 'biological_process', 'GO:1903047', ('105', '131'))	('men', 'Species', '9606', (94, 97))	('men', 'Species', '9606', (9, 12))	('DEGs', 'Var', (37, 41))	("'cell transmembrane movement'", 'CPA', (70, 99))	('transmembrane', 'cellular_component', 'GO:0044214', ('76', '89'))	('transmembrane', 'cellular_component', 'GO:0016021', ('76', '89'))	("'mitotic cell cycle process'", 'CPA', (104, 132))	('associated', 'Reg', (54, 64))
131394	30988807	These results suggest DEGs between the groups may also be associated with locally advanced tumors.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('associated', 'Reg', (58, 68))	('DEGs', 'Var', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))
131396	30988807	From a biological point of view, genes that promote tumor metastasis are likely to be genes that promote tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('promote', 'PosReg', (44, 51))	('genes', 'Var', (33, 38))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (105, 110))	('promote', 'PosReg', (97, 104))
131397	30988807	Therefore, it is reasonable that there were more T3/T4 or G3/G4 patients in the metastasis group as compared with the non-metastasis group, as the present study data shows.	('T3/T4', 'Var', (49, 54))	('patients', 'Species', '9606', (64, 72))	('G3/G4', 'Var', (58, 63))
131400	30988807	Another limitation is the difference in the proportion of patients with T3/T4 or G3/G4 in the two groups.	('patients', 'Species', '9606', (58, 66))	('T3/T4', 'Var', (72, 77))	('G3/G4', 'Var', (81, 86))
131408	33547392	In ccRCC patients, high expression of Plk1 was correlated to poor disease-free survival and overall survival.	('patients', 'Species', '9606', (9, 17))	('high', 'Var', (19, 23))	('expression', 'MPA', (24, 34))	('disease-free survival', 'CPA', (66, 87))	('poor', 'NegReg', (61, 65))	('ccRCC', 'Disease', (3, 8))	('Plk1', 'Gene', (38, 42))	('overall survival', 'CPA', (92, 108))
131409	33547392	High Plk1 expression conferred a resistant phenotype of ccRCC to targeted therapeutics such as sunitinib, in vitro, in vivo, and in metastatic ccRCC patients.	('patients', 'Species', '9606', (149, 157))	('High', 'Var', (0, 4))	('Plk1', 'Gene', (5, 9))	('resistant', 'MPA', (33, 42))	('sunitinib', 'Chemical', 'MESH:D000077210', (95, 104))	('ccRCC', 'Disease', (56, 61))
131417	33547392	Consequently, ccRCC is a hypervascularized tumor that carries frequent mutations in chromosome 3p, which affects an array of chromatin-remodeling genes, including Polybromo 1 (PBRM1), SET Domain Containing 2 (SETD2), and BRCA1 Associated Protein 1 (BAP1).	('hypervascularized tumor', 'Disease', 'MESH:D009369', (25, 48))	('SET Domain Containing 2', 'Gene', (184, 207))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('Polybromo 1', 'Gene', '55193', (163, 174))	('SETD2', 'Gene', (209, 214))	('PBRM1', 'Gene', (176, 181))	('SET Domain Containing 2', 'Gene', '29072', (184, 207))	('chromatin', 'cellular_component', 'GO:0000785', ('125', '134'))	('BRCA1 Associated Protein 1', 'Gene', (221, 247))	('SETD2', 'Gene', '29072', (209, 214))	('mutations', 'Var', (71, 80))	('ccRCC', 'Disease', (14, 19))	('affects', 'Reg', (105, 112))	('BAP1', 'Gene', '8314', (249, 253))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('BRCA1 Associated Protein 1', 'Gene', '8314', (221, 247))	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('125', '145'))	('hypervascularized tumor', 'Disease', (25, 48))	('Polybromo 1', 'Gene', (163, 174))	('BAP1', 'Gene', (249, 253))	('PBRM1', 'Gene', '55193', (176, 181))	('hypervascularized tumor', 'Phenotype', 'HP:0100742', (25, 48))
131444	33547392	Because of VHL inactivation, ccRCC represents a paradigm to assess the relationship between Plk1 and HIFs-alpha, and the impact of Plk1 on ccRCC aggressiveness.	('VHL', 'Gene', (11, 14))	('ccRCC aggressiveness', 'Disease', 'MESH:D001523', (139, 159))	('ccRCC aggressiveness', 'Disease', (139, 159))	('VHL', 'Gene', '7428', (11, 14))	('aggressiveness', 'Phenotype', 'HP:0000718', (145, 159))	('inactivation', 'Var', (15, 27))
131447	33547392	In 43 tumors out of 111 of the French cohort, the two alleles of the VHL gene were either deleted, mutated, or the VHL promoter was methylated resulting in transcriptional inhibition.	('VHL', 'Gene', (115, 118))	('VHL', 'Gene', '7428', (115, 118))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('transcriptional', 'MPA', (156, 171))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('mutated', 'Var', (99, 106))	('methylated', 'Var', (132, 142))	('VHL', 'Gene', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('VHL', 'Gene', '7428', (69, 72))
131448	33547392	Tumors with inactivation of the two alleles and/or promoter methylation presented higher Plk1 mRNA levels as compared to tumors with normal or with only one inactivated VHL allele (p = 0.05, Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('VHL', 'Gene', '7428', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('higher', 'PosReg', (82, 88))	('Plk1 mRNA levels', 'MPA', (89, 105))	('Tumors', 'Disease', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('inactivation', 'Var', (12, 24))	('VHL', 'Gene', (169, 172))	('promoter methylation', 'Var', (51, 71))
131456	33547392	The correlation between high Plk1 mRNA level and shorter OS of 70 M1 ccRCC patients was confirmed on samples of the TCGA cohort (Supplementary Fig.	('shorter', 'Disease', (49, 56))	('patients', 'Species', '9606', (75, 83))	('ccRCC', 'Disease', (69, 74))	('high', 'Var', (24, 28))	('Plk1 mRNA level', 'MPA', (29, 44))
131465	33547392	These results suggest a direct regulation of Plk1 transcription by HIF-2 but not by HIF-1 in ccRCC cells.	('HIF-1', 'Gene', '3091', (84, 89))	('transcription', 'biological_process', 'GO:0006351', ('50', '63'))	('HIF-2', 'Var', (67, 72))	('HIF-1', 'Gene', (84, 89))	('transcription', 'MPA', (50, 63))	('Plk1', 'Gene', (45, 49))	('regulation', 'biological_process', 'GO:0065007', ('31', '41'))
131473	33547392	In these cells, siH1 had no significant effect on promoter activity and Plk1 mRNA levels, and no additive inhibition was obtained by combining siH1 and siH2 (CC, Supplementary Fig.	('Plk1', 'Protein', (72, 76))	('promoter activity', 'MPA', (50, 67))	('mRNA levels', 'MPA', (77, 88))	('siH2', 'Chemical', '-', (152, 156))	('siH1', 'Chemical', '-', (16, 20))	('siH1', 'Chemical', '-', (143, 147))	('siH2', 'Var', (152, 156))	('siH1', 'Var', (143, 147))
131482	33547392	Hence, hypoxia or VHL inactivation drives Plk1 protein expression via a transcriptional program involving a HIF-2alpha-dependent stimulation of its promoter.	('inactivation', 'Var', (22, 34))	('protein', 'Protein', (47, 54))	('Plk1', 'Gene', (42, 46))	('HIF-2alpha', 'Gene', (108, 118))	('VHL', 'Gene', '7428', (18, 21))	('promoter', 'MPA', (148, 156))	('hypoxia', 'Disease', 'MESH:D000860', (7, 14))	('expression', 'MPA', (55, 65))	('hypoxia', 'Disease', (7, 14))	('drives', 'PosReg', (35, 41))	('HIF-2alpha', 'Gene', '2034', (108, 118))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('VHL', 'Gene', (18, 21))
131483	33547392	In all, 80% of ccRCC are inactivated for VHL but chromatin-remodeling genes (PBRM1, BAP1, and SETD2) are also frequently mutated.	('PBRM1', 'Gene', (77, 82))	('ccRCC', 'Disease', (15, 20))	('SETD2', 'Gene', (94, 99))	('SETD2', 'Gene', '29072', (94, 99))	('PBRM1', 'Gene', '55193', (77, 82))	('mutated', 'Var', (121, 128))	('BAP1', 'Gene', '8314', (84, 88))	('chromatin', 'cellular_component', 'GO:0000785', ('49', '58'))	('VHL', 'Gene', (41, 44))	('BAP1', 'Gene', (84, 88))	('VHL', 'Gene', '7428', (41, 44))	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('49', '69'))
131484	33547392	Mutations in PBRM1 and/or BAP1 did not modify Plk1 expression.	('BAP1', 'Gene', (26, 30))	('PBRM1', 'Gene', (13, 18))	('Plk1', 'Gene', (46, 50))	('Mutations', 'Var', (0, 9))	('expression', 'MPA', (51, 61))	('PBRM1', 'Gene', '55193', (13, 18))	('BAP1', 'Gene', '8314', (26, 30))
131486	33547392	Tumors with the wild-type (WT) or the mutated forms of SETD2 expressed equivalent Plk1 mRNA levels in a VHL-WT context (Fig.	('mutated', 'Var', (38, 45))	('VHL', 'Gene', '7428', (104, 107))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Plk1 mRNA levels', 'MPA', (82, 98))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('SETD2', 'Gene', '29072', (55, 60))	('VHL', 'Gene', (104, 107))	('SETD2', 'Gene', (55, 60))
131488	33547392	The 786, A, and C2 cells express normal SETD2, and 498 cells present an inactivating mutation that does not affect its expression (SETD2 V2536Efs*9; TCGA and CCLE data).	('SETD2', 'Gene', '29072', (40, 45))	('SETD2', 'Gene', (40, 45))	('SETD2', 'Gene', '29072', (131, 136))	('V2536Efs*9', 'Var', (137, 147))	('SETD2', 'Gene', (131, 136))
131492	33547392	Inactivation of SETD2 further stimulates Plk1 expression in cells presenting a constitutive expression of HIF-2alpha.	('SETD2', 'Gene', '29072', (16, 21))	('stimulates', 'PosReg', (30, 40))	('HIF-2alpha', 'Gene', '2034', (106, 116))	('SETD2', 'Gene', (16, 21))	('Plk1', 'Gene', (41, 45))	('expression', 'MPA', (46, 56))	('Inactivation', 'Var', (0, 12))	('HIF-2alpha', 'Gene', (106, 116))
131494	33547392	siH2 or VHL-WT increased SETD2 mRNA and protein levels in 786 cells (VHL-i, constitutive HIF-2alpha; Fig.	('HIF-2alpha', 'Gene', '2034', (89, 99))	('siH2', 'Chemical', '-', (0, 4))	('VHL', 'Gene', '7428', (8, 11))	('VHL-i', 'Gene', (69, 74))	('siH2', 'Var', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('increased', 'PosReg', (15, 24))	('VHL', 'Gene', (69, 72))	('HIF-2alpha', 'Gene', (89, 99))	('SETD2', 'Gene', '29072', (25, 30))	('VHL-i', 'Gene', '7428', (69, 74))	('VHL', 'Gene', '7428', (69, 72))	('VHL', 'Gene', (8, 11))	('SETD2', 'Gene', (25, 30))
131497	33547392	Hence, an enhanced aggressiveness program involves Plk1 upregulation through SETD2 inactivation and HIF-2alpha stabilization.	('SETD2', 'Gene', '29072', (77, 82))	('HIF-2alpha', 'Gene', (100, 110))	('upregulation', 'PosReg', (56, 68))	('aggressiveness', 'Phenotype', 'HP:0000718', (19, 33))	('SETD2', 'Gene', (77, 82))	('enhanced', 'PosReg', (10, 18))	('inactivation', 'Var', (83, 95))	('HIF-2alpha', 'Gene', '2034', (100, 110))	('aggressiveness', 'Disease', 'MESH:D001523', (19, 33))	('Plk1', 'Gene', (51, 55))	('aggressiveness', 'Disease', (19, 33))
131499	33547392	A volcano plot showed 933 upregulated (4.3%) and 316 downregulated (1.5%) genes in tumors expressing high or low levels of Plk1 (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('low', 'NegReg', (109, 112))	('upregulated', 'PosReg', (26, 37))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('Plk1', 'Gene', (123, 127))	('high', 'Var', (101, 105))	('downregulated', 'NegReg', (53, 66))
131502	33547392	The role of Plk1 in the aggressiveness of ccRCC was assessed by two strategies: inactivation/downregulation or over-expression of Plk1.	('aggressiveness', 'Disease', 'MESH:D001523', (24, 38))	('aggressiveness', 'Disease', (24, 38))	('Plk1', 'Gene', (130, 134))	('aggressiveness', 'Phenotype', 'HP:0000718', (24, 38))	('over-expression', 'PosReg', (111, 126))	('ccRCC', 'Disease', (42, 47))	('inactivation/downregulation', 'Var', (80, 107))
131515	33547392	At low concentrations, volasertib decreased the proliferation and induced the death of naive and sunitinib-resistant ccRCC cells (R10, R10R, 786, 786R, and 498; Supplementary Fig.	('death', 'Disease', 'MESH:D003643', (78, 83))	('R10R', 'Mutation', 'rs747908432', (135, 139))	('death', 'Disease', (78, 83))	('decreased', 'NegReg', (34, 43))	('proliferation', 'CPA', (48, 61))	('sunitinib', 'Chemical', 'MESH:D000077210', (97, 106))	('volasertib', 'Chemical', 'MESH:C541363', (23, 33))	('R10R', 'Var', (135, 139))
131533	33547392	In this model, 786R had a strong ability to metastasize in the tails of zebrafishes.	('metastasize', 'CPA', (44, 55))	('zebrafish', 'Species', '7955', (72, 81))	('786R', 'Var', (15, 19))
131539	33547392	Analysis of the TCGA database and the Cancer Immunome Atlas (TCIA) showed that M1 ccRCC patients with a low expression level of Plk1 and PDL1 had the longest OS, patients with a high expression level of PDL1 had an intermediate OS, and patients with high Plk1 and low PDL1 had the shortest OS (Supplementary Fig.	('Plk1', 'Gene', (128, 132))	('patients', 'Species', '9606', (162, 170))	('expression level', 'MPA', (108, 124))	('low', 'NegReg', (104, 107))	('PDL1', 'Gene', (137, 141))	('PDL1', 'Gene', '29126', (203, 207))	('high', 'Var', (250, 254))	('patients', 'Species', '9606', (88, 96))	('patients', 'Species', '9606', (236, 244))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('Cancer', 'Disease', (38, 44))	('PDL1', 'Gene', '29126', (268, 272))	('PDL1', 'Gene', (203, 207))	('Cancer', 'Disease', 'MESH:D009369', (38, 44))	('PDL1', 'Gene', (268, 272))	('PDL1', 'Gene', '29126', (137, 141))
131553	33547392	SETD2 mutations are mostly present in the ccrcc1 subtype (Supplementary Figure S7 in).	('present', 'Reg', (27, 34))	('SETD2', 'Gene', '29072', (0, 5))	('SETD2', 'Gene', (0, 5))	('ccrcc1', 'Disease', (42, 48))	('mutations', 'Var', (6, 15))
131554	33547392	Thus, SETD2 mutations and Plk1 appear as frequently represented in ccrcc1-subtype tumors.	('ccrcc1-subtype', 'Disease', (67, 81))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('mutations', 'Var', (12, 21))	('SETD2', 'Gene', '29072', (6, 11))	('Plk1', 'Gene', (26, 30))	('represented', 'Reg', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('SETD2', 'Gene', (6, 11))
131567	33547392	In addition to environmental hypoxia, mutations also trigger a similar hypoxia-like response in cancer cells.	('hypoxia', 'Disease', (29, 36))	('trigger', 'Reg', (53, 60))	('hypoxia', 'Disease', (71, 78))	('hypoxia', 'Disease', 'MESH:D000860', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', (96, 102))	('hypoxia', 'Disease', 'MESH:D000860', (71, 78))
131572	33547392	We showed that hypoxia-dependent upregulation of Plk1 depends on increased transcription dependent on HIF-2 but not HIF1, and on mutation of SETD2 in human ccRCC.	('human', 'Species', '9606', (150, 155))	('increased', 'PosReg', (65, 74))	('hypoxia', 'Disease', (15, 22))	('hypoxia', 'Disease', 'MESH:D000860', (15, 22))	('mutation', 'Var', (129, 137))	('HIF1', 'Gene', (116, 120))	('SETD2', 'Gene', (141, 146))	('upregulation', 'PosReg', (33, 45))	('transcription dependent', 'MPA', (75, 98))	('SETD2', 'Gene', '29072', (141, 146))	('transcription', 'biological_process', 'GO:0006351', ('75', '88'))	('HIF-2', 'Gene', (102, 107))	('Plk1', 'Gene', (49, 53))	('HIF1', 'Gene', '3091', (116, 120))
131573	33547392	At an advanced stage of tumor development, the hypoxia-like response triggered by genetic alterations and/or environmental hypoxia play a dual role in driving cancer progression.	('cancer', 'Disease', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('tumor', 'Disease', (24, 29))	('hypoxia', 'Disease', 'MESH:D000860', (123, 130))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('hypoxia', 'Disease', (47, 54))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('hypoxia', 'Disease', (123, 130))	('genetic alterations', 'Var', (82, 101))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
131574	33547392	We provide clinical evidences supporting this hypothesis by showing that high Plk1 expression in hypoxic/necrotic zones are correlated to a poor prognosis.	('hypoxic/necrotic zones', 'Disease', (97, 119))	('Plk1', 'Gene', (78, 82))	('hypoxic/necrotic zones', 'Disease', 'MESH:D020179', (97, 119))	('expression', 'MPA', (83, 93))	('high', 'Var', (73, 77))
131581	33547392	Thus, Plk1 blockade represents an attractive and alternative therapeutic solution for treating sunitinib-resistant ccRCC patients.	('blockade', 'Var', (11, 19))	('sunitinib', 'Chemical', 'MESH:D000077210', (95, 104))	('Plk1', 'Gene', (6, 10))	('patients', 'Species', '9606', (121, 129))	('ccRCC', 'Disease', (115, 120))
131585	33547392	Over-expression of Plk1 blocked p53 activation, resulting in the inhibition of sunitinib-induced senescence.	('inhibition', 'NegReg', (65, 75))	('sunitinib', 'Chemical', 'MESH:D000077210', (79, 88))	('Plk1', 'Gene', (19, 23))	('activation', 'PosReg', (36, 46))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('sunitinib-induced senescence', 'MPA', (79, 107))	('senescence', 'biological_process', 'GO:0010149', ('97', '107'))	('Over-expression', 'Var', (0, 15))
131597	33547392	These experiments are key to convince clinicians about the relevance to test Plk1 inhibitors in early-phase clinical trials, especially for patients experiencing relapses on angiogenic or immune checkpoint inhibitors.	('inhibitors', 'Var', (82, 92))	('Plk1', 'Gene', (77, 81))	('patients', 'Species', '9606', (140, 148))
131604	33547392	We also showed that aggressive ccRCC cells metastasized in zebrafish tails without genetic modification beforehand, and Plk1 inhibition prevented this metastatic spreading.	('aggressive ccRCC', 'Disease', (20, 36))	('zebrafish', 'Species', '7955', (59, 68))	('prevented', 'NegReg', (136, 145))	('aggressive ccRCC', 'Disease', 'MESH:D001523', (20, 36))	('Plk1', 'Gene', (120, 124))	('inhibition', 'Var', (125, 135))
131677	31293642	Silencing of CCNC mimicked overexpression of miR-25 inducing cell cycle progression passing G1 phase and less apoptosis in ccRCC cells treated by sunitinib.	('CCNC', 'Gene', (13, 17))	('cell cycle progression passing G1 phase', 'CPA', (61, 100))	('cell cycle', 'biological_process', 'GO:0007049', ('61', '71'))	('apoptosis', 'biological_process', 'GO:0097194', ('110', '119'))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('sunitinib', 'Chemical', 'MESH:D000077210', (146, 155))	('RCC', 'Disease', (125, 128))	('less', 'NegReg', (105, 109))	('Silencing', 'Var', (0, 9))	('G1 phase', 'biological_process', 'GO:0051318', ('92', '100'))	('inducing', 'Reg', (52, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('miR-25', 'Gene', '407014', (45, 51))	('apoptosis', 'biological_process', 'GO:0006915', ('110', '119'))	('miR-25', 'Gene', (45, 51))	('CCNC', 'Gene', '892', (13, 17))	('apoptosis', 'CPA', (110, 119))
131680	31293642	Conclusion: We here show miR-15b as a possible culprit for sunitinib resistance in ccRCC.	('miR-15b', 'Var', (25, 32))	('sunitinib', 'Chemical', 'MESH:D000077210', (59, 68))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('RCC', 'Disease', (85, 88))
131682	31293642	The clear cell renal cell carcinoma (ccRCC) is the most common subtype of it and therefore studied and known most clearly in biologically molecular mechanisms such as gene mutation, epigenetic modification and the influence of non-coding RNA.	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (4, 35))	('gene mutation', 'Var', (167, 180))	('epigenetic modification', 'Var', (182, 205))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (15, 35))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('non-coding RNA', 'Var', (227, 241))	('RNA', 'cellular_component', 'GO:0005562', ('238', '241'))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (4, 35))	('clear cell renal cell carcinoma', 'Disease', (4, 35))
131684	31293642	The loss of protein encoded by this gene can induce the overexpression of HIF1, promoting the proportion of VEGF, EGFR and TGF-a, all of which can stimulate the cell proliferation and angiogenesis.	('VEGF', 'Gene', (108, 112))	('cell proliferation', 'biological_process', 'GO:0008283', ('161', '179'))	('loss of', 'Var', (4, 11))	('overexpression', 'MPA', (56, 70))	('protein', 'cellular_component', 'GO:0003675', ('12', '19'))	('angiogenesis', 'CPA', (184, 196))	('cell proliferation', 'CPA', (161, 179))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('EGFR', 'Gene', (114, 118))	('TGF-a', 'Gene', '7039', (123, 128))	('protein', 'Protein', (12, 19))	('HIF1', 'Gene', '3091', (74, 78))	('TGF-a', 'Gene', (123, 128))	('HIF1', 'Gene', (74, 78))	('promoting', 'PosReg', (80, 89))	('proportion', 'MPA', (94, 104))	('VEGF', 'Gene', '7422', (108, 112))	('EGFR', 'Gene', '1956', (114, 118))	('stimulate', 'PosReg', (147, 156))	('angiogenesis', 'biological_process', 'GO:0001525', ('184', '196'))
131701	31293642	Overexpression of miR-15b was realized with transfection of miR-15-5p with Lipofectamine system when cells reached 70% confluence for 6 h before medium was refreshed (pmiR-15b).	('transfection', 'Var', (44, 56))	('miR', 'Gene', '220972', (60, 63))	('miR', 'Gene', (60, 63))	('miR', 'Gene', '220972', (168, 171))	('miR', 'Gene', (168, 171))	('pmiR-15b', 'Chemical', '-', (167, 175))	('5p', 'Chemical', '-', (67, 69))	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (18, 21))	('Lipofectamine', 'Chemical', 'MESH:C086724', (75, 88))
131728	31293642	We then investigated Cyclin C related proteins in 2 ccRCC cell lines treated with sunitinib and found that supplement of miR-15 notably decreased levels of CDK19, CDK8 and apoptotic indicator cleaved PARP (Fig 5A).	('CDK19', 'Gene', (156, 161))	('Cyclin C', 'Gene', (21, 29))	('CDK8', 'Gene', '1024', (163, 167))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('CDK', 'molecular_function', 'GO:0004693', ('163', '166'))	('decreased', 'NegReg', (136, 145))	('PARP', 'Gene', '1302', (200, 204))	('miR', 'Gene', '220972', (121, 124))	('supplement', 'Var', (107, 117))	('CDK19', 'Gene', '23097', (156, 161))	('CDK', 'molecular_function', 'GO:0004693', ('156', '159'))	('sunitinib', 'Chemical', 'MESH:D000077210', (82, 91))	('Cyclin', 'molecular_function', 'GO:0016538', ('21', '27'))	('miR', 'Gene', (121, 124))	('PARP', 'Gene', (200, 204))	('Cyclin C', 'Gene', '892', (21, 29))	('CDK8', 'Gene', (163, 167))	('RCC', 'Disease', (54, 57))	('levels', 'MPA', (146, 152))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))
131729	31293642	By silencing CCNC, cells displayed similar alterations in cell cycle population to miR-15b overexpression, showing less population in G1 phase following sunitinib treatment (Fig 5C-D).	('CCNC', 'Gene', (13, 17))	('silencing', 'Var', (3, 12))	('miR-15b', 'Gene', (83, 90))	('G1 phase', 'CPA', (134, 142))	('cell cycle', 'biological_process', 'GO:0007049', ('58', '68'))	('sunitinib', 'Chemical', 'MESH:D000077210', (153, 162))	('CCNC', 'Gene', '892', (13, 17))	('G1 phase', 'biological_process', 'GO:0051318', ('134', '142'))
131730	31293642	Sunitinib treatment with CCNC silencing also induced less apoptotic cells compared with sunitinib alone in both ccRCC cell lines (Fig 5E-F).	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('apoptotic cells', 'CPA', (58, 73))	('RCC', 'Disease', (114, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('CCNC', 'Gene', (25, 29))	('less', 'NegReg', (53, 57))	('Sunitinib', 'Chemical', 'MESH:D000077210', (0, 9))	('sunitinib', 'Chemical', 'MESH:D000077210', (88, 97))	('CCNC', 'Gene', '892', (25, 29))	('silencing', 'Var', (30, 39))
131731	31293642	We next studied cell motility and found that miR-15b restored cell migration of 786-O and ACHN cell lines treated with sunitinib (Fig 6A).	('miR-15b', 'Var', (45, 52))	('cell migration', 'biological_process', 'GO:0016477', ('62', '76'))	('cell migration', 'CPA', (62, 76))	('ACHN', 'Gene', (90, 94))	('cell motility', 'biological_process', 'GO:0048870', ('16', '29'))	('ACHN', 'Gene', '55323', (90, 94))	('restored', 'PosReg', (53, 61))	('sunitinib', 'Chemical', 'MESH:D000077210', (119, 128))
131732	31293642	We found that inhibitory effect by sunitinib was effaced by supplement of miR-15b (Fig 6B).	('sunitinib', 'Chemical', 'MESH:D000077210', (35, 44))	('supplement', 'Var', (60, 70))	('miR-15b', 'Gene', (74, 81))
131734	31293642	We found tumors with both sunitinib and miR-15b showed restored growth as control (Fig 6C).	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('growth', 'MPA', (64, 70))	('miR-15b', 'Var', (40, 47))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('sunitinib', 'Chemical', 'MESH:D000077210', (26, 35))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
131736	31293642	In the current study, we show that miR-15b is associated with sunitinib resistance in ccRCC.	('sunitinib', 'Chemical', 'MESH:D000077210', (62, 71))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('sunitinib resistance', 'MPA', (62, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('associated', 'Reg', (46, 56))	('miR-15b', 'Var', (35, 42))
131742	31293642	report that miR-15b-5p facilitates the tumorigenicity by targeting RECK and predicts tumour recurrence in prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('predicts', 'Reg', (76, 84))	('RECK', 'Gene', (67, 71))	('miR-15b-5p', 'Var', (12, 22))	('targeting', 'Reg', (57, 66))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumour', 'Disease', (85, 91))	('RECK', 'Gene', '8434', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('prostate cancer', 'Disease', (106, 121))	('5p', 'Chemical', '-', (20, 22))	('tumor', 'Disease', (39, 44))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('prostate cancer', 'Disease', 'MESH:D011471', (106, 121))	('facilitates', 'PosReg', (23, 34))
131746	31293642	report that MicroRNA-15b-5p targets ERK1 to regulate proliferation and apoptosis in rat PC12 cells.	('ERK1', 'Gene', (36, 40))	('MicroRNA-15b-5p', 'Var', (12, 27))	('apoptosis', 'CPA', (71, 80))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('ERK1', 'Gene', '50689', (36, 40))	('ERK1', 'molecular_function', 'GO:0004707', ('36', '40'))	('rat PC12', 'CellLine', 'CVCL:4695', (84, 92))	('5p', 'Chemical', '-', (25, 27))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('regulate', 'PosReg', (44, 52))
131747	31293642	report that Overexpression of miR-15b-5p promotes gastric cancer metastasis by regulating PAQR3.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('miR-15b-5p', 'Var', (30, 40))	('gastric cancer', 'Disease', (50, 64))	('PAQR3', 'Gene', '152559', (90, 95))	('gastric cancer', 'Disease', 'MESH:D013274', (50, 64))	('promotes', 'PosReg', (41, 49))	('PAQR3', 'Gene', (90, 95))	('5p', 'Chemical', '-', (38, 40))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))
131749	31293642	report that OIP5, a target of miR-15b-5p, regulates hepatocellular carcinoma growth and metastasis through the AKT/mTORC1 and beta-catenin signaling pathways.	('AKT', 'Gene', '207', (111, 114))	('mTORC1', 'Gene', (115, 121))	('beta-catenin', 'Gene', '1499', (126, 138))	('hepatocellular carcinoma growth', 'Disease', (52, 83))	('OIP5', 'Gene', (12, 16))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (52, 76))	('miR-15b-5p', 'Var', (30, 40))	('metastasis', 'CPA', (88, 98))	('hepatocellular carcinoma growth', 'Disease', 'MESH:D006528', (52, 83))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('mTORC1', 'Gene', '382056', (115, 121))	('AKT', 'Gene', (111, 114))	('OIP5', 'Gene', '11339', (12, 16))	('regulates', 'Reg', (42, 51))	('5p', 'Chemical', '-', (38, 40))	('mTORC1', 'cellular_component', 'GO:0031931', ('115', '121'))	('beta-catenin', 'Gene', (126, 138))
131751	31293642	report that multidrug resistance in osteosarcoma is associated with downregulation of miR-15b, and miR-15b reconstitution can reverse chemotherapy resistance in osteosarcoma.	('osteosarcoma', 'Disease', (161, 173))	('chemotherapy resistance', 'MPA', (134, 157))	('osteosarcoma', 'Phenotype', 'HP:0002669', (161, 173))	('drug resistance', 'Phenotype', 'HP:0020174', (17, 32))	('osteosarcoma', 'Disease', 'MESH:D012516', (161, 173))	('downregulation', 'NegReg', (68, 82))	('miR-15b', 'Var', (99, 106))	('multidrug', 'MPA', (12, 21))	('osteosarcoma', 'Phenotype', 'HP:0002669', (36, 48))	('osteosarcoma', 'Disease', (36, 48))	('osteosarcoma', 'Disease', 'MESH:D012516', (36, 48))	('miR-15b', 'Gene', (86, 93))
131752	31293642	report that miR-15b-5p resensitizes colon cancer cells to 5-fluorouracil by promoting apoptosis via the NF-kappaB/XIAP axis.	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('miR-15b-5p', 'Var', (12, 22))	('colon cancer', 'Disease', 'MESH:D015179', (36, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('colon cancer', 'Disease', (36, 48))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('promoting', 'PosReg', (76, 85))	('XIAP', 'Gene', (114, 118))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (58, 72))	('5p', 'Chemical', '-', (20, 22))	('XIAP', 'Gene', '331', (114, 118))	('apoptosis', 'CPA', (86, 95))	('colon cancer', 'Phenotype', 'HP:0003003', (36, 48))
131766	31293642	In all, we here show for the first time that miR-15b is associated with sunitinib resistance in RCC.	('RCC', 'Disease', (96, 99))	('miR-15b', 'Var', (45, 52))	('sunitinib', 'Chemical', 'MESH:D000077210', (72, 81))	('associated', 'Reg', (56, 66))	('sunitinib resistance', 'MPA', (72, 92))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
131781	29128526	Given that there are seven lysine residues located in the ubiquitin polypeptide itself (Lys6, Lys11, Lys27, Lys29, Lys33, Lys48, and Lys63, respectively), a variety of linkages can be formed in the poly-ubiquitin chain.	('Lys63', 'Chemical', '-', (133, 138))	('Lys29', 'Chemical', '-', (108, 113))	('Lys6', 'Var', (88, 92))	('ubiquitin', 'molecular_function', 'GO:0031386', ('203', '212'))	('Lys27', 'Chemical', '-', (101, 106))	('linkages', 'Interaction', (168, 176))	('Lys29', 'Var', (108, 113))	('ubiquitin', 'molecular_function', 'GO:0031386', ('58', '67'))	('lysine', 'Chemical', 'MESH:D008239', (27, 33))	('Lys11', 'Var', (94, 99))	('Lys48', 'Chemical', '-', (122, 127))	('Lys11', 'Chemical', '-', (94, 99))	('Lys6', 'Chemical', '-', (88, 92))	('Lys33', 'Var', (115, 120))	('Lys33', 'Chemical', '-', (115, 120))	('Lys63', 'Var', (133, 138))	('Lys27', 'Var', (101, 106))	('Lys48', 'Var', (122, 127))	('Lys6', 'Chemical', '-', (133, 137))
131789	29128526	Furthermore, activation of the Cullin scaffold is essential for its subsequent function on ubiquitin transfer, which is carried out by the Neddylation [attachment of NEDD8 (neural precursor cell expressed, developmentally down-regulated 8)] modification on a lysine residue near the C-terminus of the Cullin protein.	('lysine', 'Chemical', 'MESH:D008239', (259, 265))	('ubiquitin transfer', 'MPA', (91, 109))	('NEDD8', 'Gene', '18002', (166, 171))	('protein', 'cellular_component', 'GO:0003675', ('308', '315'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('91', '100'))	('NEDD8', 'Gene', (166, 171))	('modification', 'Var', (241, 253))
131798	29128526	Phenotypically mimicking Cul1-null mice, constitutive deletion of Cul3 causes embryonic lethality, which also may be due to dysregulation in cyclin E degradation, revealing the global significances of CRL3 in cellular division and differentiation.	('Cul1', 'Gene', (25, 29))	('embryonic lethality', 'Disease', 'MESH:D020964', (78, 97))	('embryonic lethality', 'Disease', (78, 97))	('Cul3', 'Gene', (66, 70))	('deletion', 'Var', (54, 62))	('Cul1', 'Gene', '26965', (25, 29))	('cyclin E degradation', 'MPA', (141, 161))	('CRL3', 'Gene', '218624', (201, 205))	('Cul3', 'Gene', '26554', (66, 70))	('cyclin', 'molecular_function', 'GO:0016538', ('141', '147'))	('mice', 'Species', '10090', (35, 39))	('CRL3', 'Gene', (201, 205))	('dysregulation', 'MPA', (124, 137))	('causes', 'Reg', (71, 77))	('degradation', 'biological_process', 'GO:0009056', ('150', '161'))
131799	29128526	Similarly, the morphological consequences following conditional Cul3 deletion in various organs and cell types may also be due to cyclin E, the elevated level of which induces renal fibrosis and functional maintenance of hepatic progenitors, thus verifying the regulatory interplay between CRL3-mediated ubiquitination and stemness/inflammatory pathways.	('functional maintenance', 'CPA', (195, 217))	('induces', 'Reg', (168, 175))	('cyclin', 'molecular_function', 'GO:0016538', ('130', '136'))	('renal fibrosis', 'Disease', 'MESH:D005355', (176, 190))	('due', 'Reg', (123, 126))	('Cul3', 'Gene', '26554', (64, 68))	('renal fibrosis', 'Disease', (176, 190))	('hepatic', 'MPA', (221, 228))	('renal fibrosis', 'Phenotype', 'HP:0030760', (176, 190))	('cyclin E', 'MPA', (130, 138))	('stemness', 'Disease', 'MESH:D020295', (323, 331))	('Cul3', 'Gene', (64, 68))	('deletion', 'Var', (69, 77))	('CRL3', 'Gene', '218624', (290, 294))	('stemness', 'Disease', (323, 331))	('CRL3', 'Gene', (290, 294))
131800	29128526	Furthermore, loss of Cul3 in lymphocytes leads to dysregulated production of NKT (natural killer T cell) and marginal-zone B cells, although the underlying mechanisms are not fully understood yet.	('Cul3', 'Gene', (21, 25))	('marginal-zone B cells', 'CPA', (109, 130))	('NKT', 'Protein', (77, 80))	('dysregulated production', 'MPA', (50, 73))	('Cul3', 'Gene', '26554', (21, 25))	('loss', 'Var', (13, 17))
131802	29128526	The constitutive ablation of Cul4a has given conflicting results in relation to embryonic fate.	('Cul4a', 'Gene', '99375', (29, 34))	('ablation', 'Var', (17, 25))	('Cul4a', 'Gene', (29, 34))
131803	29128526	Li and colleagues reported a Cul4a knockout in 2002, which exhibited embryonic lethality.	('Cul4a', 'Gene', '99375', (29, 34))	('embryonic lethality', 'Disease', 'MESH:D020964', (69, 88))	('Cul4a', 'Gene', (29, 34))	('embryonic lethality', 'Disease', (69, 88))	('knockout', 'Var', (35, 43))
131809	29128526	Unlike its homologous counterpart Cul4a, constitutive deletion of Cul4b results in embryonic lethality.	('Cul4a', 'Gene', (34, 39))	('Cul4b', 'Gene', '72584', (66, 71))	('Cul4b', 'Gene', (66, 71))	('deletion', 'Var', (54, 62))	('embryonic lethality', 'Disease', 'MESH:D020964', (83, 102))	('Cul4a', 'Gene', '99375', (34, 39))	('embryonic lethality', 'Disease', (83, 102))	('results in', 'Reg', (72, 82))
131811	29128526	Moreover, conditional deletion of Cul4b in different organ or cell types leads to various abnormalities, For instance, targeted deletion of Cul4b in the epiblast, germ cells, adipose tissue, and hematopoietic progenitors results in mice carrying phenotypes such as XLMR-relevant symptoms, male infertility, severe obesity, and tumor progression, respectively.	('male infertility', 'Disease', 'MESH:D007248', (289, 305))	('Cul4b', 'Gene', '72584', (34, 39))	('obesity', 'Disease', (314, 321))	('tumor', 'Disease', (327, 332))	('obesity', 'Disease', 'MESH:D009765', (314, 321))	('tumor', 'Disease', 'MESH:D009369', (327, 332))	('deletion', 'Var', (22, 30))	('male infertility', 'Phenotype', 'HP:0003251', (289, 305))	('Cul4b', 'Gene', (140, 145))	('infertility', 'Phenotype', 'HP:0000789', (294, 305))	('male infertility', 'Disease', (289, 305))	('XLMR-relevant symptoms', 'Disease', (265, 287))	('mice', 'Species', '10090', (232, 236))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('results in', 'Reg', (221, 231))	('obesity', 'Phenotype', 'HP:0001513', (314, 321))	('Cul4b', 'Gene', '72584', (140, 145))	('Cul4b', 'Gene', (34, 39))	('deletion', 'Var', (128, 136))
131812	29128526	However, under certain circumstances, loss of Cul4b displays beneficial effects such as regulating inflammatory restriction, suggesting that Cullin 4B might be a potential target against inflammatory diseases.	('loss', 'Var', (38, 42))	('Cul4b', 'Gene', '72584', (46, 51))	('Cul4b', 'Gene', (46, 51))	('Cullin 4B', 'Gene', (141, 150))	('beneficial', 'PosReg', (61, 71))	('regulating inflammatory restriction', 'MPA', (88, 123))	('Cullin 4B', 'Gene', '72584', (141, 150))
131819	29128526	Systemic depletion of Cul9 in mice is nonlethal and these mice carry no obvious phenotypic malformations, suggesting that CRL9 might not be necessary for core events during embryogenesis.	('mice', 'Species', '10090', (30, 34))	('Systemic depletion', 'Var', (0, 18))	('Cul9', 'Gene', (22, 26))	('CRL', 'Gene', (122, 125))	('Cul9', 'Gene', '78309', (22, 26))	('embryogenesis', 'biological_process', 'GO:0009792', ('173', '186'))	('mice', 'Species', '10090', (58, 62))	('CRL', 'Gene', '133396', (122, 125))	('embryogenesis', 'biological_process', 'GO:0009790', ('173', '186'))	('core', 'cellular_component', 'GO:0019013', ('154', '158'))	('malformations', 'Disease', 'MESH:D000014', (91, 104))	('malformations', 'Disease', (91, 104))	('embryogenesis', 'biological_process', 'GO:0009793', ('173', '186'))
131820	29128526	However, loss of Cul9 in the adult may increase the development of spontaneous tumors and lead to aneuploidy in multiple systems by degrading Survivin or interacting with p53-mediated pathway(s), indicating that CRL9 may be involved in controlling genomic stability and neoplastic events.	('p53', 'Gene', '22060', (171, 174))	('CRL', 'Gene', (212, 215))	('Survivin', 'Gene', '11799', (142, 150))	('interacting', 'Reg', (154, 165))	('increase', 'PosReg', (39, 47))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('Survivin', 'Gene', (142, 150))	('aneuploidy', 'Disease', (98, 108))	('tumors', 'Disease', (79, 85))	('CRL', 'Gene', '133396', (212, 215))	('lead to', 'Reg', (90, 97))	('degrading', 'NegReg', (132, 141))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('aneuploidy', 'Disease', 'MESH:D000782', (98, 108))	('Cul9', 'Gene', (17, 21))	('Cul9', 'Gene', '78309', (17, 21))	('loss', 'Var', (9, 13))	('development', 'CPA', (52, 63))	('p53', 'Gene', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
131832	29128526	As described above, Cullin 3 ligases carry out fundamentally essential processes exemplified by the observation that deletion of Cullin 3 causes early embryonic lethality in mice (Table 2).	('Cullin 3', 'Gene', (20, 28))	('mice', 'Species', '10090', (174, 178))	('Cullin 3', 'Gene', '26554', (20, 28))	('embryonic lethality', 'Disease', 'MESH:D020964', (151, 170))	('embryonic lethality', 'Disease', (151, 170))	('causes', 'Reg', (138, 144))	('Cullin 3', 'Gene', (129, 137))	('Cullin 3', 'Gene', '26554', (129, 137))	('deletion', 'Var', (117, 125))
131834	29128526	Furthermore, mutations within Cullin 3 subunits have been observed in relation to their role in regulating metabolic disturbance, muscle atrophy, and neurodegeneration.	('muscle atrophy', 'Phenotype', 'HP:0003202', (130, 144))	('Cullin 3', 'Gene', '26554', (30, 38))	('muscle atrophy', 'Disease', 'MESH:D009133', (130, 144))	('neurodegeneration', 'Phenotype', 'HP:0002180', (150, 167))	('muscle atrophy', 'biological_process', 'GO:0014889', ('130', '144'))	('muscle atrophy', 'Disease', (130, 144))	('neurodegeneration', 'Disease', (150, 167))	('mutations', 'Var', (13, 22))	('neurodegeneration', 'Disease', 'MESH:D019636', (150, 167))	('observed', 'Reg', (58, 66))	('metabolic disturbance', 'Phenotype', 'HP:0001939', (107, 128))	('Cullin 3', 'Gene', (30, 38))	('regulating', 'MPA', (96, 106))
131838	29128526	Systemic knockout of Keap1 induces early embryonic lethality, implicating it in regulating prenatal development.	('Keap1', 'Gene', '50868', (21, 26))	('knockout', 'Var', (9, 17))	('Keap1', 'Gene', (21, 26))	('embryonic lethality', 'Disease', 'MESH:D020964', (41, 60))	('embryonic lethality', 'Disease', (41, 60))	('prenatal development', 'CPA', (91, 111))
131839	29128526	However, deletion of Keap1 attenuates inflammatory injury developed following endogenous and exogenous damage in the airway epithelium, restores insulin sensitivity within skeletal muscle and pancreatic beta cells, as well as protects hepatocytes against various liver toxins.	('Keap1', 'Gene', '50868', (21, 26))	('hepatocytes', 'MPA', (235, 246))	('inflammatory injury', 'Disease', (38, 57))	('inflammatory injury', 'Disease', 'MESH:D001930', (38, 57))	('deletion', 'Var', (9, 17))	('insulin', 'molecular_function', 'GO:0016088', ('145', '152'))	('Keap1', 'Gene', (21, 26))	('attenuates', 'NegReg', (27, 37))	('restores', 'PosReg', (136, 144))	('insulin sensitivity', 'MPA', (145, 164))	('pancreatic', 'Disease', 'MESH:D010195', (192, 202))	('pancreatic', 'Disease', (192, 202))	('protects', 'Reg', (226, 234))
131840	29128526	Each of these phenotypes have the common feature of regulating inflammation, indicating a broad regulatory role of Keap1 in controlling inflammatory networks as its depletion dramatically stabilizes the activity of NRF2, which serves as a powerful anti-oxidative and anti-inflammatory factor.	('activity', 'MPA', (203, 211))	('inflammation', 'biological_process', 'GO:0006954', ('63', '75'))	('Keap1', 'Gene', '50868', (115, 120))	('depletion', 'Var', (165, 174))	('Keap1', 'Gene', (115, 120))	('NRF2', 'Gene', (215, 219))	('stabilizes', 'NegReg', (188, 198))	('inflammation', 'Disease', 'MESH:D007249', (63, 75))	('inflammation', 'Disease', (63, 75))
131843	29128526	Loss-of-function mutations in Keap1 has been detected in certain types of malignancies such as lung carcinoma, hinting that Keap1 might exert a tumor suppressive role against tumorigenesis.	('Loss-of-function', 'NegReg', (0, 16))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', (175, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('Keap1', 'Gene', '50868', (124, 129))	('malignancies', 'Disease', (74, 86))	('lung carcinoma', 'Disease', 'MESH:D008175', (95, 109))	('Keap1', 'Gene', (124, 129))	('lung carcinoma', 'Disease', (95, 109))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('Keap1', 'Gene', '50868', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('mutations', 'Var', (17, 26))	('malignancies', 'Disease', 'MESH:D009369', (74, 86))	('Keap1', 'Gene', (30, 35))
131850	29128526	Oxidative stress triggered loss-of-function mutations on tumor suppressor genes or gain-of-function mutations on oncogenes act as an important cause of malignant transformation in somatic cells.	('mutations', 'Var', (100, 109))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('57', '73'))	('loss-of-function', 'NegReg', (27, 43))	('malignant transformation', 'CPA', (152, 176))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('oncogenes', 'Gene', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('mutations', 'Var', (44, 53))	('gain-of-function', 'PosReg', (83, 99))	('tumor', 'Disease', (57, 62))	('tumor suppressor', 'biological_process', 'GO:0051726', ('57', '73'))
131852	29128526	Moreover, genetic ablation of NRF2 increases susceptibility to cancer formation in rodent models, suggesting an important tumor suppressive role for the NRF2-ARE axis.	('NRF2', 'Gene', (30, 34))	('AR', 'Gene', '11835', (158, 160))	('increases', 'PosReg', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('susceptibility', 'MPA', (45, 59))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('genetic ablation', 'Var', (10, 26))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('formation', 'biological_process', 'GO:0009058', ('70', '79'))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Disease', (122, 127))	('cancer', 'Disease', (63, 69))
131857	29128526	Consistent with this mechanism, gain-of-function mutations of NRF2 have been identified within dermatological, esophageal, and laryngeal carcinoma, while loss-of-function mutations in Keap1 have been observed in gastric, hepatic, mammary, pulmonary, and ovary malignancies.	('NRF2', 'Gene', (62, 66))	('Keap1', 'Gene', '50868', (184, 189))	('laryngeal carcinoma', 'Disease', (127, 146))	('ovary malignancies', 'Phenotype', 'HP:0100615', (254, 272))	('hepatic', 'Disease', (221, 228))	('mutations', 'Var', (49, 58))	('loss-of-function', 'NegReg', (154, 170))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (127, 146))	('ovary malignancies', 'Disease', 'MESH:D009369', (254, 272))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (127, 146))	('gastric', 'Disease', (212, 219))	('pulmonary', 'Disease', (239, 248))	('gain-of-function', 'PosReg', (32, 48))	('mammary', 'Disease', (230, 237))	('dermatological', 'Disease', (95, 109))	('ovary malignancies', 'Disease', (254, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('Keap1', 'Gene', (184, 189))	('esophageal', 'Disease', (111, 121))
131860	29128526	Knockout of Klhl6 in mice leads to defects in B cell maturation and impairment of transitional B cell survival and differentiation, primarily due to dysregulation of antigen receptor signaling in B lymphocytes and defects in germinal center formation.	('B cell maturation', 'CPA', (46, 63))	('germinal center formation', 'biological_process', 'GO:0002467', ('225', '250'))	('impairment', 'NegReg', (68, 78))	('antigen receptor signaling', 'MPA', (166, 192))	('mice', 'Species', '10090', (21, 25))	('signaling', 'biological_process', 'GO:0023052', ('183', '192'))	('germinal center formation', 'CPA', (225, 250))	('differentiation', 'CPA', (115, 130))	('transitional B cell survival', 'CPA', (82, 110))	('defects', 'NegReg', (214, 221))	('cell maturation', 'biological_process', 'GO:0048469', ('48', '63'))	('Klhl6', 'Gene', '239743', (12, 17))	('dysregulation', 'Var', (149, 162))	('defects', 'NegReg', (35, 42))	('Klhl6', 'Gene', (12, 17))
131862	29128526	In B cell lymphomas, KLHL6 loss-of-function mutations contribute to oncogenic transformation of germinal center B cells following overexpression of multiple pro-proliferation genes.	('lymphomas', 'Disease', 'MESH:D008223', (10, 19))	('KLHL6', 'Gene', (21, 26))	('oncogenic transformation', 'CPA', (68, 92))	('lymphomas', 'Phenotype', 'HP:0002665', (10, 19))	('loss-of-function', 'NegReg', (27, 43))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (3, 19))	('cell lymphoma', 'Phenotype', 'HP:0012191', (5, 18))	('KLHL6', 'Gene', '239743', (21, 26))	('mutations', 'Var', (44, 53))	('lymphoma', 'Phenotype', 'HP:0002665', (10, 18))	('lymphomas', 'Disease', (10, 19))
131866	29128526	KCTD10, a member of the potassium channel tetramerization domain containing proteins and an adaptor protein for CRL3, is critical for prenatal development demonstrated by its deletion in mice resulting in early embryonic lethality, while heterozygous knockouts are viable with no effects on fertility.	('CRL3', 'Gene', (112, 116))	('deletion', 'Var', (175, 183))	('mice', 'Species', '10090', (187, 191))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('CRL3', 'Gene', '218624', (112, 116))	('embryonic lethality', 'Disease', 'MESH:D020964', (211, 230))	('KCTD10', 'Gene', (0, 6))	('embryonic lethality', 'Disease', (211, 230))
131880	29128526	First, loss-of-function mutations, epigenetic silencing, or homozygous deletion of RhoBTB2 are commonly observed in nearly half of breast cancer, lung cancer, and bladder cancer tissues.	('bladder cancer', 'Disease', 'MESH:D001749', (163, 177))	('RhoBTB2', 'Gene', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('bladder cancer', 'Disease', (163, 177))	('loss-of-function', 'NegReg', (7, 23))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('epigenetic silencing', 'Var', (35, 55))	('RhoBTB2', 'Gene', '246710', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('lung cancer', 'Disease', (146, 157))	('bladder cancer', 'Phenotype', 'HP:0009725', (163, 177))	('breast cancer', 'Disease', (131, 144))	('mutations', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
131883	29128526	In addition to the adaptors described above, diminished expression or loss-of-function mutations have also been identified in other CRL3 adaptors including KLHL9, KLHL16, KCTD6, KCTD21, RhoBTB3 and LZTR1, suggesting their roles as putative tumor suppressors potentially mediated by their function within CRL3 complexes (Table 4).	('KCTD21', 'Gene', '622320', (178, 184))	('CRL3', 'Gene', '218624', (304, 308))	('mutations', 'Var', (87, 96))	('CRL3', 'Gene', (304, 308))	('RhoBTB3', 'Gene', (186, 193))	('tumor', 'Disease', (240, 245))	('KLHL16', 'Gene', (163, 169))	('KLHL9', 'Gene', '242521', (156, 161))	('expression', 'MPA', (56, 66))	('LZTR1', 'Gene', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('KCTD6', 'Gene', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('RhoBTB3', 'Gene', '73296', (186, 193))	('CRL3', 'Gene', '218624', (132, 136))	('KLHL16', 'Gene', '8139', (163, 169))	('LZTR1', 'Gene', '66863', (198, 203))	('CRL3', 'Gene', (132, 136))	('loss-of-function', 'NegReg', (70, 86))	('KCTD6', 'Gene', '71393', (171, 176))	('KCTD21', 'Gene', (178, 184))	('diminished', 'NegReg', (45, 55))	('KLHL9', 'Gene', (156, 161))
131892	29128526	Abrogating Cul3-KLHL20-mediated PML degradation appears to, at least in part, trigger metastasis of colon cancer and proliferation of renal cancer cells.	('Cul3', 'Gene', '26554', (11, 15))	('PML', 'Gene', (32, 35))	('PML', 'Gene', '18854', (32, 35))	('metastasis of colon cancer', 'Disease', 'MESH:D009362', (86, 112))	('Cul3', 'Gene', (11, 15))	('trigger', 'Reg', (78, 85))	('Abrogating', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('renal cancer', 'Phenotype', 'HP:0009726', (134, 146))	('colon cancer', 'Phenotype', 'HP:0003003', (100, 112))	('degradation', 'biological_process', 'GO:0009056', ('36', '47'))	('proliferation of renal cancer', 'Disease', 'MESH:D007680', (117, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('proliferation of renal cancer', 'Disease', (117, 146))	('metastasis of colon cancer', 'Disease', (86, 112))
131899	29128526	Furthermore, KBTBD2 is a BTB-domain adaptor involved in activation of PI3K signaling and insulin sensitivity, the systemic depletion of which results in diabetes, lipodystrophy, and hepatic steatosis.	('PI3K signaling', 'biological_process', 'GO:0014065', ('70', '84'))	('PI3K signaling', 'Pathway', (70, 84))	('diabetes', 'Disease', (153, 161))	('insulin', 'molecular_function', 'GO:0016088', ('89', '96'))	('BTB', 'Chemical', '-', (14, 17))	('lipodystrophy', 'Phenotype', 'HP:0009125', (163, 176))	('KBTBD2', 'Gene', '210973', (13, 19))	('depletion', 'Var', (123, 132))	('insulin', 'Disease', (89, 96))	('activation', 'PosReg', (56, 66))	('hepatic steatosis', 'Disease', (182, 199))	('BTB', 'Chemical', '-', (25, 28))	('hepatic steatosis', 'Phenotype', 'HP:0001397', (182, 199))	('diabetes', 'Disease', 'MESH:D003920', (153, 161))	('KBTBD2', 'Gene', (13, 19))	('results in', 'Reg', (142, 152))	('hepatic steatosis', 'Disease', 'MESH:D005234', (182, 199))	('BTB-domain', 'molecular_function', 'GO:0031208', ('25', '35'))	('lipodystrophy', 'Disease', (163, 176))	('PI3K', 'molecular_function', 'GO:0016303', ('70', '74'))
131902	29128526	KCTD2 is a CRL3 substrate recognition adaptor that functions in the nervous system, dysregulation of which contributes to neurodegeneration, sleep disorders, and synaptic malfunction.	('dysregulation', 'Var', (84, 97))	('KCTD2', 'Gene', '70382', (0, 5))	('sleep', 'biological_process', 'GO:0030431', ('141', '146'))	('CRL3', 'Gene', '218624', (11, 15))	('sleep disorders', 'Disease', 'MESH:D012893', (141, 156))	('CRL3', 'Gene', (11, 15))	('synaptic malfunction', 'Disease', (162, 182))	('neurodegeneration', 'Phenotype', 'HP:0002180', (122, 139))	('sleep disorders', 'Phenotype', 'HP:0002360', (141, 156))	('contributes', 'Reg', (107, 118))	('neurodegeneration', 'Disease', (122, 139))	('neurodegeneration', 'Disease', 'MESH:D019636', (122, 139))	('sleep disorders', 'Disease', (141, 156))	('KCTD2', 'Gene', (0, 5))
131915	29128526	Particularly, an II-x-E motif (consisting of M233, E234 and E235 residues) inside the 10-amino-acid alpha3-beta4 loop structure of the BTB domain essentially accounts for the connection with Cullin 3.	('BTB', 'Chemical', '-', (135, 138))	('E235 residues', 'Var', (60, 73))	('M233', 'Var', (45, 49))	('BTB domain', 'molecular_function', 'GO:0031208', ('135', '145'))	('Cullin 3', 'Gene', (191, 199))	('E235', 'Chemical', 'MESH:D010866', (60, 64))	('Cullin 3', 'Gene', '26554', (191, 199))	('E234', 'Var', (51, 55))
131922	29128526	In the cardio-vascular system, loss of SPOP stabilizes its substrate DAXX in umbilical vein endothelial cells, which disrupts the expression of VEGFR2 (vascular endothelial cell growth factor receptor 2) influencing endothelial homeostasis.	('cell growth', 'biological_process', 'GO:0016049', ('173', '184'))	('expression', 'MPA', (130, 140))	('homeostasis', 'biological_process', 'GO:0042592', ('228', '239'))	('VEGFR2', 'Gene', (144, 150))	('loss', 'Var', (31, 35))	('DAXX', 'Gene', (69, 73))	('influencing', 'Reg', (204, 215))	('DAXX', 'Gene', '13163', (69, 73))	('endothelial homeostasis', 'MPA', (216, 239))	('disrupts', 'NegReg', (117, 125))	('VEGFR2', 'Gene', '16542', (144, 150))	('SPOP', 'Gene', (39, 43))
131930	29128526	Spontaneous development of prostatic intraepithelial neoplasia occurs in mice with conditional SPOP knockout in the prostate epithelium.	('conditional', 'Var', (83, 94))	('prostatic intraepithelial neoplasia', 'Disease', (27, 62))	('mice', 'Species', '10090', (73, 77))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (37, 62))	('prostatic intraepithelial neoplasia', 'Disease', 'MESH:D019048', (27, 62))	('neoplasia', 'Phenotype', 'HP:0002664', (53, 62))	('SPOP', 'Gene', (95, 99))
131935	29128526	Further silencing of c-Myc successfully reverses the susceptibility of prostate cancer transformation due to loss of function of SPOP.	('loss of function', 'NegReg', (109, 125))	('SPOP', 'Protein', (129, 133))	('prostate cancer', 'Disease', (71, 86))	('c-Myc', 'Gene', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('silencing', 'Var', (8, 17))	('prostate cancer', 'Disease', 'MESH:D011471', (71, 86))	('prostate cancer', 'Phenotype', 'HP:0012125', (71, 86))	('c-Myc', 'Gene', '4609', (21, 26))
131941	29128526	Mutant SPOP fails to promote the ubiquitination of substrates, such as AR, thus allowing propagation of prostate cells even in the setting of low androgen.	('SPOP', 'Gene', (7, 11))	('ubiquitination', 'MPA', (33, 47))	('allowing', 'Reg', (80, 88))	('low androgen', 'Phenotype', 'HP:0008226', (142, 154))	('Mutant', 'Var', (0, 6))	('propagation', 'CPA', (89, 100))	('AR', 'Gene', '11835', (71, 73))
131944	29128526	An anti-androgen regimen has become the classical first-line strategy due to the close association between aberrant androgen pathway activation and prostate carcinogenesis.	('prostate carcinogenesis', 'Disease', 'MESH:D063646', (148, 171))	('androgen pathway', 'Pathway', (116, 132))	('aberrant', 'Var', (107, 115))	('activation', 'PosReg', (133, 143))	('prostate carcinogenesis', 'Disease', (148, 171))
131945	29128526	SPOP mutations that abrogate the degradation of AR or AR activators promote the formation of castration-resistant prostate cancer and anti-androgen refractoriness.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('SPOP', 'Gene', (0, 4))	('degradation', 'biological_process', 'GO:0009056', ('33', '44'))	('promote', 'PosReg', (68, 75))	('prostate cancer', 'Disease', 'MESH:D011471', (114, 129))	('mutations', 'Var', (5, 14))	('AR', 'Gene', '11835', (48, 50))	('prostate cancer', 'Phenotype', 'HP:0012125', (114, 129))	('formation', 'biological_process', 'GO:0009058', ('80', '89'))	('AR', 'Gene', '11835', (54, 56))	('anti-androgen refractoriness', 'CPA', (134, 162))	('prostate cancer', 'Disease', (114, 129))
131946	29128526	Recent findings have clarified that SPOP mutations confer resistance to BET inhibitors by reducing BRD2/3/4 degradation.	('mutations', 'Var', (41, 50))	('BET', 'Gene', (72, 75))	('degradation', 'biological_process', 'GO:0009056', ('108', '119'))	('BET', 'Gene', '227325', (72, 75))	('SPOP', 'Gene', (36, 40))	('reducing', 'NegReg', (90, 98))	('BRD2', 'Gene', '14312', (99, 103))	('BRD2', 'Gene', (99, 103))
131947	29128526	Moreover, therapeutic resistance to other targeted drugs such as a CDC20 inhibitor is also reported to rely on the presence of SPOP mutations.	('SPOP', 'Gene', (127, 131))	('CDC20', 'Gene', '107995', (67, 72))	('therapeutic', 'MPA', (10, 21))	('rely', 'Reg', (103, 107))	('mutations', 'Var', (132, 141))	('CDC20', 'Gene', (67, 72))
131952	29128526	found that more than 50% of ovarian cancer samples carried loss-of-function mutations of SPOP compared to 0% in adjacent tissues.	('SPOP', 'Gene', (89, 93))	('mutations', 'Var', (76, 85))	('ovarian cancer', 'Phenotype', 'HP:0100615', (28, 42))	('loss-of-function', 'NegReg', (59, 75))	('ovarian cancer', 'Disease', 'MESH:D010051', (28, 42))	('ovarian cancer', 'Disease', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
131959	29128526	Dysregulation of ERalpha turnover by mutant SPOP appears to promote endometrial tumorigenesis, consistent with the classical association between estrogen dysregulation and onset of endometrial cancer.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('promote', 'PosReg', (60, 67))	('endometrial cancer', 'Disease', 'MESH:D016889', (181, 199))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ERalpha', 'Gene', (17, 24))	('tumor', 'Disease', (80, 85))	('mutant', 'Var', (37, 43))	('ERalpha', 'Gene', '13982', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('endometrial cancer', 'Disease', (181, 199))	('SPOP', 'Gene', (44, 48))	('endometrial cancer', 'Phenotype', 'HP:0012114', (181, 199))
131971	29128526	These unexpected findings may actually reveal a probability of upstream mechanisms down-regulating SPOP activity rather than its own loss-of-function mutations that eventually contributes to pro-tumorigenic transformations.	('down-regulating', 'NegReg', (83, 98))	('tumor', 'Disease', (195, 200))	('loss-of-function', 'NegReg', (133, 149))	('SPOP activity', 'Protein', (99, 112))	('mutations', 'Var', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
131972	29128526	However, the specific mechanisms in digestive cancer cells that initiate and sustain epigenetic silencing remains unclear.	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('epigenetic silencing', 'Var', (85, 105))
131985	29128526	Moreover, the loss of SPOP activity enables the activation of the beta-catenin/TCF4/ZEB1 axis, consequently enhancing the transcriptional activities of epithelial-mesenchymal transition (EMT)-related genes that contribute to the dissemination of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (246, 251))	('ccRCC', 'Disease', (246, 251))	('transcriptional activities', 'MPA', (122, 148))	('loss', 'Var', (14, 18))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('152', '185'))	('beta-catenin', 'Gene', (66, 78))	('TCF4', 'Gene', (79, 83))	('ZEB1', 'Gene', (84, 88))	('TCF4', 'Gene', '21413', (79, 83))	('ccRCC', 'Disease', 'MESH:C538614', (246, 251))	('EMT', 'biological_process', 'GO:0001837', ('187', '190'))	('SPOP activity', 'Gene', (22, 35))	('activation', 'PosReg', (48, 58))	('beta-catenin', 'Gene', '12387', (66, 78))	('ZEB1', 'Gene', '21417', (84, 88))	('enhancing', 'PosReg', (108, 117))
131998	29128526	Taken together, targeted therapy on specific Cullin 3 adaptors seems promising in cancer treatment, thus more effort is needed for its broader clinical applications.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Cullin 3', 'Gene', (45, 53))	('Cullin 3', 'Gene', '26554', (45, 53))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', (82, 88))	('targeted', 'Var', (16, 24))
132112	28938681	Accumulating evidence suggests that the alteration of many kinds of biomarkers and corresponding downstream pathways are involved in the initiation and progression of tumor.	('alteration', 'Var', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('involved', 'Reg', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))
132124	28938681	Increasing studies have suggested that abnormal expression of MUC5AC is associated with inflammation or the development and progression of malignant diseases, which may be induced by the activation of signaling pathways in response to several factors, for example growth factors, inflammatory cytokines, and bacterial products.	('MUC5AC', 'Gene', (62, 68))	('malignant diseases', 'Disease', (139, 157))	('signaling', 'biological_process', 'GO:0023052', ('201', '210'))	('inflammation', 'Disease', 'MESH:D007249', (88, 100))	('associated', 'Reg', (72, 82))	('inflammation', 'biological_process', 'GO:0006954', ('88', '100'))	('MUC5AC', 'Gene', '4586', (62, 68))	('inflammation', 'Disease', (88, 100))	('abnormal', 'Var', (39, 47))	('progression', 'CPA', (124, 135))	('malignant diseases', 'Disease', 'MESH:D009369', (139, 157))	('signaling pathways', 'Pathway', (201, 219))	('development', 'CPA', (108, 119))
132152	28938681	As shown in Figure 1B, patients with high MUC5AC expression level presented a poorer OS comparing with those with a low MUC5AC expression (P < 0.001).	('MUC5AC', 'Gene', (42, 48))	('high', 'Var', (37, 41))	('patients', 'Species', '9606', (23, 31))	('MUC5AC', 'Gene', '4586', (120, 126))	('MUC5AC', 'Gene', '4586', (42, 48))	('MUC5AC', 'Gene', (120, 126))	('poorer', 'NegReg', (78, 84))
132164	28938681	No significant correlation was found between MUC5AC expression and OS or RFS in the cohort of patients with Fuhrman grade 1 (Figure 3A or 3F) or grade 2 (Figure 3B or 3G).	('MUC5AC', 'Gene', (45, 51))	('grade 2', 'Var', (145, 152))	('patients', 'Species', '9606', (94, 102))	('MUC5AC', 'Gene', '4586', (45, 51))	('RFS', 'Disease', (73, 76))
132187	28938681	The alteration of MUC5AC expression was found to be involved in chronic inflammation and malignant transformation in several diseases.	('malignant transformation', 'CPA', (89, 113))	('inflammation', 'Disease', (72, 84))	('expression', 'MPA', (25, 35))	('MUC5AC', 'Gene', (18, 24))	('alteration', 'Var', (4, 14))	('involved', 'Reg', (52, 60))	('inflammation', 'biological_process', 'GO:0006954', ('72', '84'))	('MUC5AC', 'Gene', '4586', (18, 24))	('inflammation', 'Disease', 'MESH:D007249', (72, 84))
132195	28938681	MUC5AC was proved to interact with integrin beta4 that mediates phosphorylation of FAK at Y397, resulting in lung cancer migration.	('MUC5AC', 'Gene', (0, 6))	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('integrin beta4', 'Gene', (35, 49))	('phosphorylation', 'biological_process', 'GO:0016310', ('64', '79'))	('resulting in', 'Reg', (96, 108))	('MUC5AC', 'Gene', '4586', (0, 6))	('FAK', 'molecular_function', 'GO:0004717', ('83', '86'))	('integrin beta4', 'Gene', '3691', (35, 49))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('FAK', 'Gene', '5747', (83, 86))	('at Y397', 'Var', (87, 94))	('FAK', 'Gene', (83, 86))
132197	28938681	Therefore, modulation of these MUC5AC-associated pathways may suggest a promising strategy for inflammatory and malignant diseases.	('MUC5AC', 'Gene', (31, 37))	('modulation', 'Var', (11, 21))	('malignant diseases', 'Disease', 'MESH:D009369', (112, 130))	('malignant diseases', 'Disease', (112, 130))	('MUC5AC', 'Gene', '4586', (31, 37))
132204	28938681	MUC5AC hypomethylation was an independently predictor of microsatellite instability associated with colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (100, 117))	('MUC5AC', 'Gene', (0, 6))	('hypomethylation', 'Var', (7, 22))	('colorectal cancer', 'Phenotype', 'HP:0003003', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('MUC5AC', 'Gene', '4586', (0, 6))	('colorectal cancer', 'Disease', (100, 117))	('associated', 'Reg', (84, 94))	('microsatellite instability', 'MPA', (57, 83))
132244	33540838	Most ccRCC have somatic mutations of both alleles of pVHL (von Hippel-Lindau), a component of an E3 ubiquitin ligase complex, which targets the hypoxia-inducible factors (HIF), HIF-1alpha and HIF-2alpha, for degradation.	('HIF-1alpha', 'Gene', '3091', (177, 187))	('ubiquitin ligase complex', 'cellular_component', 'GO:0000151', ('100', '124'))	('degradation', 'biological_process', 'GO:0009056', ('208', '219'))	('RCC', 'Disease', 'MESH:C538614', (7, 10))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (59, 76))	('HIF-1alpha', 'Gene', (177, 187))	('hypoxia', 'Disease', (144, 151))	('pVHL', 'Gene', '7428', (53, 57))	('hypoxia', 'Disease', 'MESH:D000860', (144, 151))	('ubiquitin', 'molecular_function', 'GO:0031386', ('100', '109'))	('HIF-2alpha', 'Gene', (192, 202))	('ccRCC', 'Phenotype', 'HP:0006770', (5, 10))	('pVHL', 'Gene', (53, 57))	('mutations', 'Var', (24, 33))	('von Hippel-Lindau', 'Disease', (59, 76))	('RCC', 'Phenotype', 'HP:0005584', (7, 10))	('RCC', 'Disease', (7, 10))	('HIF-2alpha', 'Gene', '2034', (192, 202))
132245	33540838	Inactivation of pVHL in ccRCC leads to the accumulation of HIF-2alpha, and reintroduction of a pVHL protein in VHL-deficient ccRCC cells downregulates HIF-2alpha and suppresses their ability to form tumors.	('tumors', 'Disease', (199, 205))	('HIF-2alpha', 'Gene', '2034', (59, 69))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('pVHL', 'Gene', '7428', (16, 20))	('pVHL', 'Gene', '7428', (95, 99))	('pVHL', 'Gene', (16, 20))	('VHL-deficient ccRCC', 'Disease', 'MESH:D006623', (111, 130))	('pVHL', 'Gene', (95, 99))	('accumulation', 'PosReg', (43, 55))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('downregulates', 'NegReg', (137, 150))	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('ccRCC', 'Phenotype', 'HP:0006770', (24, 29))	('Inactivation', 'Var', (0, 12))	('HIF-2alpha', 'Gene', (59, 69))	('HIF-2alpha', 'Gene', '2034', (151, 161))	('VHL-deficient ccRCC', 'Disease', (111, 130))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('ccRCC', 'Phenotype', 'HP:0006770', (125, 130))	('RCC', 'Disease', (127, 130))	('suppresses', 'NegReg', (166, 176))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('reintroduction', 'Var', (75, 89))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('HIF-2alpha', 'Gene', (151, 161))
132255	33540838	This screening strategy revealed that renal cancer cells deficient in VHL were more vulnerable to the dual inhibition of the CK2 (casein kinase 2) and ATM (Ataxia telengestasia mutated) kinases than cells with wild-type VHL, establishing a lethal situation wherein both drug treatment and VHL deficiency led to lethality.	('VHL', 'Gene', (70, 73))	('ATM', 'Gene', '472', (151, 154))	('deficient', 'Var', (57, 66))	('Ataxia', 'Phenotype', 'HP:0001251', (156, 162))	('renal cancer', 'Disease', (38, 50))	('Ataxia telengestasia', 'Disease', (156, 176))	('VHL deficiency', 'Disease', 'MESH:D006623', (289, 303))	('renal cancer', 'Phenotype', 'HP:0009726', (38, 50))	('Ataxia telengestasia', 'Disease', 'MESH:D001259', (156, 176))	('renal cancer', 'Disease', 'MESH:D007680', (38, 50))	('ATM', 'Gene', (151, 154))	('VHL deficiency', 'Disease', (289, 303))	('inhibition', 'NegReg', (107, 117))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
132259	33540838	Consequently, CK2 has emerged as a relevant therapeutic target being dysregulated in various cancers, including renal cancers.	('cancers', 'Disease', (93, 100))	('cancers', 'Disease', (118, 125))	('dysregulated', 'Var', (69, 81))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('renal cancer', 'Phenotype', 'HP:0009726', (112, 124))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('renal cancers', 'Disease', 'MESH:D007680', (112, 125))	('renal cancers', 'Disease', (112, 125))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('CK2', 'Gene', (14, 17))
132260	33540838	Here, we demonstrated that inhibiting CK2 with the clinically relevant inhibitor CX-4945 in VHL-deficient renal cancer cells triggered a strong activation of phospho-ATM (Ser1982), suggesting that the benefit resulting from the combination of CK2 and ATM inhibition may be synergistic.	('ATM', 'Gene', (166, 169))	('VHL-deficient renal cancer', 'Disease', (92, 118))	('inhibiting', 'Var', (27, 37))	('CX-4945', 'Chemical', 'MESH:C555142', (81, 88))	('VHL-deficient renal cancer', 'Disease', 'MESH:D007680', (92, 118))	('renal cancer', 'Phenotype', 'HP:0009726', (106, 118))	('Ser', 'cellular_component', 'GO:0005790', ('171', '174'))	('ATM', 'Gene', '472', (166, 169))	('ATM', 'Gene', (251, 254))	('activation', 'PosReg', (144, 154))	('CK2', 'Protein', (38, 41))	('Ser1982', 'Chemical', '-', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('ATM', 'Gene', '472', (251, 254))
132261	33540838	Mechanistic investigations showed that the ATM inhibitor KU-60019 in combination with CX-4945 induced a strong inhibition of tumor cell proliferation, reduction of cell migration and reactive oxygen species (ROS)-dependent apoptosis in HIF-2alpha-expressing VHL-deficient cells.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('cell migration', 'CPA', (164, 178))	('ATM', 'Gene', (43, 46))	('CX-4945', 'Chemical', 'MESH:C555142', (86, 93))	('HIF-2alpha', 'Gene', (236, 246))	('KU-60019', 'Var', (57, 65))	('ROS', 'Chemical', 'MESH:D017382', (208, 211))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (183, 206))	('cell proliferation', 'biological_process', 'GO:0008283', ('131', '149'))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('KU-60019', 'Chemical', 'MESH:C546193', (57, 65))	('ATM', 'Gene', '472', (43, 46))	('HIF-2alpha', 'Gene', '2034', (236, 246))	('cell migration', 'biological_process', 'GO:0016477', ('164', '178'))	('tumor', 'Disease', (125, 130))	('reduction', 'NegReg', (151, 160))	('apoptosis', 'biological_process', 'GO:0097194', ('223', '232'))	('inhibition', 'NegReg', (111, 121))	('apoptosis', 'biological_process', 'GO:0006915', ('223', '232'))
132272	33540838	The parental VHL null cell line was used to generate its derivative lines containing either the empty expression vector HA-pBABE or a functional VHL construct HA-VHL (VHL+ cells).	('HA-pBABE', 'Disease', (120, 128))	('HA-pBABE', 'Disease', 'MESH:C537629', (120, 128))	('HA-VHL', 'Var', (159, 165))
132321	33540838	The status of the VHL gene was determined as wild type (WT) and mutated (E160fs14aa (chr3-10191481-G->GA-frameshift insertion)) for RCC43B and RCC10B, respectively.	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('E160fs14aa', 'Var', (73, 83))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', (143, 146))	('VHL', 'Gene', (18, 21))
132332	33540838	The 786-O cells display a VHL frameshift deletion and a consequent increased HIF-2alpha and VEGF protein expression, making this cell line a workhorse for RCC research.	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('RCC', 'Disease', (155, 158))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('VHL', 'Gene', (26, 29))	('HIF-2alpha', 'Gene', (77, 87))	('VEGF', 'Gene', (92, 96))	('frameshift deletion', 'Var', (30, 49))	('increased', 'PosReg', (67, 76))	('HIF-2alpha', 'Gene', '2034', (77, 87))	('expression', 'MPA', (105, 115))	('VEGF', 'Gene', '7422', (92, 96))	('RCC', 'Disease', 'MESH:C538614', (155, 158))
132337	33540838	Importantly, the potentiation of cell lethality was also observed when the cells were treated with a combination of KU-60019 and CX-4945, a specific CK2 inhibitor (Figure 1B).	('potentiation', 'PosReg', (17, 29))	('CX-4945', 'Var', (129, 136))	('KU-60019', 'Chemical', 'MESH:C546193', (116, 124))	('KU-60019', 'Var', (116, 124))	('cell lethality', 'CPA', (33, 47))	('CX-4945', 'Chemical', 'MESH:C555142', (129, 136))
132340	33540838	ATM was clearly inhibited by KU-60019, as evidenced by a reduction in the canonical ATM auto-phosphorylation at Ser1981.	('inhibited', 'NegReg', (16, 25))	('ATM', 'Gene', (84, 87))	('phosphorylation', 'biological_process', 'GO:0016310', ('93', '108'))	('reduction', 'NegReg', (57, 66))	('KU-60019', 'Chemical', 'MESH:C546193', (29, 37))	('KU-60019', 'Var', (29, 37))	('ATM', 'Gene', (0, 3))	('ATM', 'Gene', '472', (84, 87))	('Ser', 'cellular_component', 'GO:0005790', ('112', '115'))	('Ser1981', 'Chemical', '-', (112, 119))	('ATM', 'Gene', '472', (0, 3))
132341	33540838	Likewise, CK2 was inhibited by CX-4945 as assessed by the reduction of P-AKT Ser 129.	('CK2', 'Enzyme', (10, 13))	('CX-4945', 'Var', (31, 38))	('AKT', 'Gene', (73, 76))	('Ser', 'Chemical', 'MESH:D012694', (77, 80))	('CX-4945', 'Chemical', 'MESH:C555142', (31, 38))	('Ser', 'cellular_component', 'GO:0005790', ('77', '80'))	('inhibited', 'NegReg', (18, 27))	('reduction', 'NegReg', (58, 67))	('AKT', 'Gene', '207', (73, 76))
132343	33540838	Surprisingly, CK2 inhibition led to a significant ATM activation, suggesting that combined inhibition of ATM and CK2 likely exerts its effect by affecting complementary signaling pathways that compromise cell viability.	('ATM', 'Gene', (105, 108))	('ATM', 'Gene', (50, 53))	('CK2', 'Gene', (113, 116))	('ATM', 'Gene', '472', (105, 108))	('inhibition', 'NegReg', (91, 101))	('activation', 'PosReg', (54, 64))	('ATM', 'Gene', '472', (50, 53))	('signaling', 'biological_process', 'GO:0023052', ('169', '178'))	('affecting', 'Reg', (145, 154))	('inhibition', 'Var', (18, 28))	('CK2', 'Gene', (14, 17))
132344	33540838	We next investigated whether the effect of this drug combination could also be observed in the Caki-2 cells, which express a mutated form of the VHL protein.	('mutated', 'Var', (125, 132))	('Caki-2', 'CellLine', 'CVCL:0235', (95, 101))	('VHL', 'Gene', (145, 148))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))
132345	33540838	In hypoxic conditions, the viability of these cells was also altered by the drug combination (Figure 1E), whereas no significant effect was observed in RPTEC cells, which represent normal renal proximal tubule epithelial cells (Supplementary Figure S2C).	('drug combination', 'Var', (76, 92))	('altered', 'Reg', (61, 68))	('RPTEC', 'CellLine', 'CVCL:K278', (152, 157))	('viability', 'CPA', (27, 36))
132352	33540838	Furthermore, cell death induction was also observed in MCTS generated from parental VHL- 786-O cells treated with KU-60019, CX-4945 alone or in combination (Figure 2C).	('KU-60019', 'Chemical', 'MESH:C546193', (114, 122))	('CX-4945', 'Var', (124, 131))	('MCTS', 'Chemical', '-', (55, 59))	('KU-60019', 'Var', (114, 122))	('cell death', 'CPA', (13, 23))	('cell death', 'biological_process', 'GO:0008219', ('13', '23'))	('CX-4945', 'Chemical', 'MESH:C555142', (124, 131))
132358	33540838	As shown in Figure 2E,F, after 5 days of culture, there was a statistically significant decrease in cell spreading after CX-4945/KU-60019 combination regimen, as compared with single treatments, indicating a synergistic effect of this drug combination.	('CX-4945/KU-60019', 'Var', (121, 137))	('decrease', 'NegReg', (88, 96))	('KU-60019', 'Chemical', 'MESH:C546193', (129, 137))	('CX-4945', 'Chemical', 'MESH:C555142', (121, 128))	('cell spreading', 'CPA', (100, 114))
132362	33540838	Similarly, IncuCyte  real-time imaging showed that the presence of Z-VAD completely thwarted the strong Caspase 3/7 activation observed in response to CX-4945/KU-60019 treatment (Figure 3C).	('presence', 'Var', (55, 63))	('KU-60019', 'Chemical', 'MESH:C546193', (159, 167))	('thwarted', 'NegReg', (84, 92))	('CX-4945', 'Chemical', 'MESH:C555142', (151, 158))	('Z-VAD', 'Chemical', '-', (67, 72))	('Caspase 3/7', 'Gene', '836;840', (104, 115))	('Caspase 3/7', 'Gene', (104, 115))	('activation', 'MPA', (116, 126))
132363	33540838	Therefore, these results indicate that apoptosis induction by the CX-4945/KU-60019 combination strongly compromises the viability of 786-O cells inside the MCTS.	('apoptosis', 'CPA', (39, 48))	('CX-4945/KU-60019', 'Var', (66, 82))	('apoptosis', 'biological_process', 'GO:0097194', ('39', '48'))	('CX-4945', 'Chemical', 'MESH:C555142', (66, 73))	('MCTS', 'Chemical', '-', (156, 160))	('apoptosis', 'biological_process', 'GO:0006915', ('39', '48'))	('KU-60019', 'Chemical', 'MESH:C546193', (74, 82))	('compromises', 'NegReg', (104, 115))	('viability', 'CPA', (120, 129))
132369	33540838	Strikingly, as shown in Figure 4C, the capacity of KU-60019 alone or in combination with CX-4945 to induce cell death in these MCTS was impeded in an on-target manner by CAS9-mediated loss of HIF-2alpha, suggesting that the vulnerability to combined inhibition of ATM and CK2 in VHL-deficient ccRCC is positively correlated with HIF-2alpha expression levels.	('HIF-2alpha', 'Gene', '2034', (329, 339))	('CX-4945', 'Chemical', 'MESH:C555142', (89, 96))	('ATM', 'Gene', '472', (264, 267))	('VHL-deficient ccRCC', 'Disease', (279, 298))	('KU-60019', 'Var', (51, 59))	('cell death', 'biological_process', 'GO:0008219', ('107', '117'))	('expression', 'MPA', (340, 350))	('loss', 'NegReg', (184, 188))	('CAS', 'cellular_component', 'GO:0005650', ('170', '173'))	('HIF-2alpha', 'Gene', (329, 339))	('VHL-deficient ccRCC', 'Disease', 'MESH:D006623', (279, 298))	('HIF-2alpha', 'Gene', (192, 202))	('RCC', 'Phenotype', 'HP:0005584', (295, 298))	('MCTS', 'Chemical', '-', (127, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (293, 298))	('ATM', 'Gene', (264, 267))	('KU-60019', 'Chemical', 'MESH:C546193', (51, 59))	('HIF-2alpha', 'Gene', '2034', (192, 202))
132372	33540838	Phosphorylation of HIF-1alpha and HIF-2alpha subunits have been demonstrated to enhance transactivation of target genes by either disrupting HIFalpha interaction with VHL and thereby stabilizing HIFalpha, or by increasing the affinity of HIFalpha for transcriptional coactivators.	('HIF-2alpha', 'Gene', '2034', (34, 44))	('HIFalpha', 'MPA', (195, 203))	('transcriptional', 'Interaction', (251, 266))	('increasing', 'PosReg', (211, 221))	('HIF-1alpha', 'Gene', '3091', (19, 29))	('disrupting', 'NegReg', (130, 140))	('Phosphorylation', 'Var', (0, 15))	('VHL', 'Protein', (167, 170))	('transactivation', 'MPA', (88, 103))	('enhance', 'PosReg', (80, 87))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('affinity', 'Interaction', (226, 234))	('stabilizing', 'Reg', (183, 194))	('HIFalpha', 'Protein', (141, 149))	('HIF-2alpha', 'Gene', (34, 44))	('interaction', 'Interaction', (150, 161))	('transactivation', 'biological_process', 'GO:2000144', ('88', '103'))	('HIF-1alpha', 'Gene', (19, 29))
132373	33540838	CK2 was described as a regulator of HIF-1alpha transcriptional activity and hypoxia-induced phosphorylation by CK2 has been demonstrated in the C-TAD domain at conserved threonine residues (Thr796 for HIF-1alpha and Thr840 for HIF-2alpha).	('Thr796', 'Var', (190, 196))	('CK2', 'Gene', (111, 114))	('hypoxia', 'Disease', (76, 83))	('threonine', 'Chemical', 'MESH:D013912', (170, 179))	('HIF-1alpha', 'Gene', '3091', (36, 46))	('HIF-2alpha', 'Gene', '2034', (227, 237))	('phosphorylation', 'biological_process', 'GO:0016310', ('92', '107'))	('Thr796', 'Chemical', '-', (190, 196))	('HIF-1alpha', 'Gene', (201, 211))	('Thr840', 'Var', (216, 222))	('HIF-1alpha', 'Gene', (36, 46))	('des', 'Chemical', 'MESH:D004054', (8, 11))	('HIF-2alpha', 'Gene', (227, 237))	('Thr840', 'Chemical', '-', (216, 222))	('hypoxia', 'Disease', 'MESH:D000860', (76, 83))	('HIF-1alpha', 'Gene', '3091', (201, 211))
132388	33540838	As mitochondria are known to play a central role to elicit apoptosis in response to many stresses, we investigated whether mitochondria are involved in KU-60019/CX-4945-induced apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('59', '68'))	('apoptosis', 'biological_process', 'GO:0006915', ('59', '68'))	('KU-60019', 'Chemical', 'MESH:C546193', (152, 160))	('CX-4945', 'Chemical', 'MESH:C555142', (161, 168))	('mitochondria', 'cellular_component', 'GO:0005739', ('3', '15'))	('elicit', 'Reg', (52, 58))	('apoptosis', 'MPA', (59, 68))	('mitochondria', 'cellular_component', 'GO:0005739', ('123', '135'))	('apoptosis', 'biological_process', 'GO:0097194', ('177', '186'))	('apoptosis', 'biological_process', 'GO:0006915', ('177', '186'))	('KU-60019/CX-4945-induced', 'Var', (152, 176))
132390	33540838	We found that the KU-60019/CX-4945 combination triggers a much stronger and more sustained ROS generation than the drugs alone in VHL- 786-O MCTS.	('ROS generation', 'MPA', (91, 105))	('ROS generation', 'biological_process', 'GO:1903409', ('91', '105'))	('MCTS', 'Chemical', '-', (141, 145))	('CX-4945', 'Chemical', 'MESH:C555142', (27, 34))	('stronger', 'PosReg', (63, 71))	('KU-60019/CX-4945', 'Var', (18, 34))	('ROS', 'Chemical', 'MESH:D017382', (91, 94))	('KU-60019', 'Chemical', 'MESH:C546193', (18, 26))
132392	33540838	To interrogate the causal relationship between ROS increase and cell death upon combined treatment, we hypothesized that counteracting ROS generation with Tiron would prevent apoptosis.	('Tiron', 'Chemical', 'MESH:D014013', (155, 160))	('cell death', 'biological_process', 'GO:0008219', ('64', '74'))	('apoptosis', 'CPA', (175, 184))	('prevent', 'NegReg', (167, 174))	('counteracting', 'Var', (121, 134))	('ROS increase', 'Phenotype', 'HP:0025464', (47, 59))	('ROS', 'Var', (135, 138))	('ROS generation', 'biological_process', 'GO:1903409', ('135', '149'))	('ROS', 'Chemical', 'MESH:D017382', (135, 138))	('apoptosis', 'biological_process', 'GO:0097194', ('175', '184'))	('apoptosis', 'biological_process', 'GO:0006915', ('175', '184'))	('ROS', 'Chemical', 'MESH:D017382', (47, 50))
132394	33540838	These results strongly suggest that mitochondrial ROS overproduction is critical in KU-60019/CX4945-induced apoptosis.	('KU-60019/CX4945-induced', 'Var', (84, 107))	('ROS', 'Chemical', 'MESH:D017382', (50, 53))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('mitochondrial ROS', 'Protein', (36, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('KU-60019', 'Chemical', 'MESH:C546193', (84, 92))	('overproduction', 'PosReg', (54, 68))
132402	33540838	MDC1 expression was diminished and its localization in nuclear foci was lost upon MCTS drug treatments with either KU-60019 alone or in association with CX-64945 (Figure 5E,F).	('expression', 'MPA', (5, 15))	('diminished', 'NegReg', (20, 30))	('localization', 'biological_process', 'GO:0051179', ('39', '51'))	('KU-60019', 'Chemical', 'MESH:C546193', (115, 123))	('KU-60019', 'Var', (115, 123))	('localization', 'MPA', (39, 51))	('lost', 'NegReg', (72, 76))	('MCTS', 'Chemical', '-', (82, 86))	('MDC1', 'Gene', (0, 4))	('MDC1', 'Gene', '9656', (0, 4))
132406	33540838	NOX4 was then knocked down in 786-O cells to evaluate its role in mitochondrial ROS production and cell death (Supplementary Figure S5).	('ROS', 'Chemical', 'MESH:D017382', (80, 83))	('NOX4', 'Gene', (0, 4))	('knocked down', 'Var', (14, 26))	('cell death', 'biological_process', 'GO:0008219', ('99', '109'))	('NOX4', 'Gene', '50507', (0, 4))	('mitochondrial ROS production', 'MPA', (66, 94))
132408	33540838	Likewise, PI incorporation in response to drug treatments was strongly reduced in NOX4-knockdown 786-O cells treated with CX-4945 or the KU-60019/CX-4945 combination (Figure 5H).	('response to drug', 'biological_process', 'GO:0042493', ('30', '46'))	('KU-60019/CX-4945', 'Var', (137, 153))	('CX-4945', 'Chemical', 'MESH:C555142', (122, 129))	('NOX4', 'Gene', '50507', (82, 86))	('CX-4945', 'Chemical', 'MESH:C555142', (146, 153))	('reduced', 'NegReg', (71, 78))	('PI incorporation', 'MPA', (10, 26))	('KU-60019', 'Chemical', 'MESH:C546193', (137, 145))	('CX-4945', 'Var', (122, 129))	('NOX4', 'Gene', (82, 86))
132412	33540838	To explore the overall impact of our drug combination on renal tumor cell biology, we performed transcriptome profiling of MCTS generated from 786-O cells treated with vehicle only (DMSO), KU-60019, CX-4945 or their combination.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('KU-60019', 'Chemical', 'MESH:C546193', (189, 197))	('KU-60019', 'Var', (189, 197))	('CX-4945', 'Chemical', 'MESH:C555142', (199, 206))	('renal tumor', 'Disease', 'MESH:D007674', (57, 68))	('MCTS', 'Chemical', '-', (123, 127))	('renal tumor', 'Phenotype', 'HP:0009726', (57, 68))	('DMSO', 'Chemical', 'MESH:D004121', (182, 186))	('CX-4945', 'Var', (199, 206))	('renal tumor', 'Disease', (57, 68))
132413	33540838	Classification of the transcriptomes by principal component analysis (PCA) showed that MCTS treated with CX-4945 or the KU-60019/CX-4945 combination were clearly separated from the control MCTS treated with DMSO (Supplementary Figure S6A).	('MCTS', 'Chemical', '-', (189, 193))	('MCTS', 'Chemical', '-', (87, 91))	('KU-60019/CX-4945', 'Var', (120, 136))	('CX-4945', 'Var', (105, 112))	('KU-60019', 'Chemical', 'MESH:C546193', (120, 128))	('CX-4945', 'Chemical', 'MESH:C555142', (129, 136))	('CX-4945', 'Chemical', 'MESH:C555142', (105, 112))	('DMSO', 'Chemical', 'MESH:D004121', (207, 211))
132414	33540838	On the other hand, the transcriptome for the KU-60019 condition was much closer to the control, suggesting a weaker impact of KU-60019 on the overall deregulation of the MCTS transcriptome.	('KU-60019', 'Var', (45, 53))	('KU-60019', 'Var', (126, 134))	('MCTS', 'Chemical', '-', (170, 174))	('MCTS transcriptome', 'MPA', (170, 188))	('KU-60019', 'Chemical', 'MESH:C546193', (45, 53))	('KU-60019', 'Chemical', 'MESH:C546193', (126, 134))
132415	33540838	Detection of genes deregulated for each treatment relative to the DMSO condition (Log2(gene expression fold change) > 0.3) showed a greater number of deregulated genes for KU-60019/CX-4945 (271 genes) compared to KU-60019 (193 genes) or CX-4945 (254 genes) (Supplementary Figures S6B and S7A,B).	('KU-60019', 'Chemical', 'MESH:C546193', (172, 180))	('gene expression', 'biological_process', 'GO:0010467', ('87', '102'))	('CX-4945', 'Chemical', 'MESH:C555142', (181, 188))	('CX-4945', 'Chemical', 'MESH:C555142', (237, 244))	('deregulated genes', 'MPA', (150, 167))	('KU-60019/CX-4945', 'Var', (172, 188))	('DMSO', 'Chemical', 'MESH:D004121', (66, 70))	('KU-60019', 'Chemical', 'MESH:C546193', (213, 221))
132417	33540838	A greater number of biological processes (BP) and molecular functions (MF) were identified as significantly enriched following treatment with KU-60019/CX-4945, compared to CX-4945 alone.	('KU-60019', 'Chemical', 'MESH:C546193', (142, 150))	('CX-4945', 'Chemical', 'MESH:C555142', (172, 179))	('CX-4945', 'Chemical', 'MESH:C555142', (151, 158))	('biological processes', 'CPA', (20, 40))	('enriched', 'PosReg', (108, 116))	('molecular functions', 'CPA', (50, 69))	('KU-60019/CX-4945', 'Var', (142, 158))
132419	33540838	This visualization, which clusters together sets of mutually overlapping genes, identified two major functional modules: one module, repressed by KU-60019/CX-4945, associated with mitochondrial energy production and metabolism, and another module, activated by the combination, associated with the cell cycle.	('metabolism', 'biological_process', 'GO:0008152', ('216', '226'))	('KU-60019', 'Chemical', 'MESH:C546193', (146, 154))	('cell cycle', 'biological_process', 'GO:0007049', ('298', '308'))	('CX-4945', 'Chemical', 'MESH:C555142', (155, 162))	('KU-60019/CX-4945', 'Var', (146, 162))	('mitochondrial energy production', 'MPA', (180, 211))
132421	33540838	Furthermore, a comparison of the levels of deregulation of the major biological processes, defined by the Normalized Enriched Score (NES), showed that they were overall more deregulated in the KU-60019/CX-4945 condition than with CX-4945 alone (Supplementary Figure S6E).	('CX-4945', 'Chemical', 'MESH:C555142', (230, 237))	('KU-60019', 'Chemical', 'MESH:C546193', (193, 201))	('CX-4945', 'Chemical', 'MESH:C555142', (202, 209))	('deregulation', 'MPA', (43, 55))	('deregulated', 'Reg', (174, 185))	('KU-60019/CX-4945', 'Var', (193, 209))	('more', 'PosReg', (169, 173))
132422	33540838	Regarding the MF terms enriched by GSEA, we found that two major repressed functional modules were shared by KU-60019/CX-4945 and CX-4945 treatments: a module associated with oxidation-reduction and another module involved in ionic transport (Supplementary Figures S7C and S8B).	('GSEA', 'Chemical', '-', (35, 39))	('oxidation-reduction', 'biological_process', 'GO:0055114', ('175', '194'))	('transport', 'biological_process', 'GO:0006810', ('232', '241'))	('KU-60019', 'Chemical', 'MESH:C546193', (109, 117))	('CX-4945', 'Var', (130, 137))	('CX-4945', 'Chemical', 'MESH:C555142', (118, 125))	('KU-60019/CX-4945', 'Var', (109, 125))	('CX-4945', 'Chemical', 'MESH:C555142', (130, 137))
132423	33540838	Again, the deregulation levels of these shared MF terms showed that they tended to be more repressed by the KU-60019/CX-4945 combination than with CX-4945 alone (Supplementary Figure S7D).	('KU-60019', 'Chemical', 'MESH:C546193', (108, 116))	('CX-4945', 'Chemical', 'MESH:C555142', (147, 154))	('CX-4945', 'Chemical', 'MESH:C555142', (117, 124))	('deregulation levels', 'MPA', (11, 30))	('KU-60019/CX-4945', 'Var', (108, 124))	('more', 'PosReg', (86, 90))
132424	33540838	Therefore, this first cartography shows that the stronger transcriptome deregulation in response to KU-60019/CX-4945 compared to drugs alone may compromise cell viability in MCTS.	('KU-60019', 'Chemical', 'MESH:C546193', (100, 108))	('KU-60019/CX-4945', 'Var', (100, 116))	('MCTS', 'Disease', (174, 178))	('CX-4945', 'Chemical', 'MESH:C555142', (109, 116))	('cell viability', 'CPA', (156, 170))	('compromise', 'NegReg', (145, 155))	('transcriptome deregulation', 'MPA', (58, 84))	('MCTS', 'Chemical', '-', (174, 178))
132436	33540838	As illustrated in Figure 7C.1,C.2, KU-60019 induced a significant cell death in both models, whereas the combination was only effective in the VHL- tumor samples (Figure 7C.2).	('KU-60019', 'Chemical', 'MESH:C546193', (35, 43))	('C.2', 'Var', (30, 33))	('KU-60019', 'Var', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('cell death', 'CPA', (66, 76))	('cell death', 'biological_process', 'GO:0008219', ('66', '76'))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
132437	33540838	To get even closer to a preclinical patient-relevant setting for predicting patient response to drugs, the effect of the KU-60019/CX-4945 combination was compared to the current standard of care sunitinib treatment in tumor tissue slices derived from six ccRCC patients (Figure 7D).	('patients', 'Species', '9606', (261, 269))	('KU-60019', 'Chemical', 'MESH:C546193', (121, 129))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('RCC', 'Phenotype', 'HP:0005584', (257, 260))	('patient', 'Species', '9606', (261, 268))	('patient', 'Species', '9606', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('ccRCC', 'Phenotype', 'HP:0006770', (255, 260))	('RCC', 'Disease', 'MESH:C538614', (257, 260))	('RCC', 'Disease', (257, 260))	('tumor', 'Disease', (218, 223))	('KU-60019/CX-4945', 'Var', (121, 137))	('sunitinib', 'Chemical', 'MESH:D000077210', (195, 204))	('patient', 'Species', '9606', (36, 43))	('CX-4945', 'Chemical', 'MESH:C555142', (130, 137))
132438	33540838	Although patient tissue slices responded to sunitinib with increased cell death, the KU-60019/CX-4945 combination was more efficient than sunitinib in all patient tissue slices except for patient D.  Altogether, these data illustrate the therapeutic predictive value of the tumor tissue slice models and demonstrate the significant therapeutic potential of the KU-60019/CX-4945 combination in patients with ccRCC.	('CX-4945', 'Chemical', 'MESH:C555142', (94, 101))	('KU-60019', 'Chemical', 'MESH:C546193', (361, 369))	('patient', 'Species', '9606', (9, 16))	('tumor', 'Disease', (274, 279))	('RCC', 'Disease', (409, 412))	('RCC', 'Phenotype', 'HP:0005584', (409, 412))	('ccRCC', 'Phenotype', 'HP:0006770', (407, 412))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('RCC', 'Disease', 'MESH:C538614', (409, 412))	('cell death', 'biological_process', 'GO:0008219', ('69', '79'))	('CX-4945', 'Chemical', 'MESH:C555142', (370, 377))	('patient', 'Species', '9606', (188, 195))	('patients', 'Species', '9606', (393, 401))	('sunitinib', 'Chemical', 'MESH:D000077210', (138, 147))	('patient', 'Species', '9606', (155, 162))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('patient', 'Species', '9606', (393, 400))	('KU-60019/CX-4945', 'Var', (361, 377))	('sunitinib', 'Chemical', 'MESH:D000077210', (44, 53))	('KU-60019', 'Chemical', 'MESH:C546193', (85, 93))
132439	33540838	The most common type of renal cell carcinoma (ccRCC) is characterized by inactivation of VHL leading to HIF stabilization and increased transcription of HIF target genes.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (24, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('transcription', 'MPA', (136, 149))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('VHL', 'Gene', (89, 92))	('inactivation', 'Var', (73, 85))	('transcription', 'biological_process', 'GO:0006351', ('136', '149'))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('renal cell carcinoma', 'Disease', (24, 44))	('HIF stabilization', 'MPA', (104, 121))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (24, 44))	('increased', 'PosReg', (126, 135))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
132450	33540838	Consequently, the association of aberrant CK2alpha expression with decreased patient disease-free and overall patient survival in many cancers make this enzyme a promising theranostic target for cancer therapy.	('cancer', 'Disease', (135, 141))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('CK2alpha', 'Gene', '1459', (42, 50))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('expression', 'MPA', (51, 61))	('patient', 'Species', '9606', (110, 117))	('patient disease-free', 'CPA', (77, 97))	('decreased', 'NegReg', (67, 76))	('aberrant', 'Var', (33, 41))	('patient', 'Species', '9606', (77, 84))	('CK2alpha', 'Gene', (42, 50))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
132456	33540838	On one hand, ROS production can lead to carcinogenesis, either by activation of several oncogenic pathways or through oncogenic mutations in DNA.	('lead to', 'Reg', (32, 39))	('carcinogenesis', 'Disease', 'MESH:D063646', (40, 54))	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('mutations', 'Var', (128, 137))	('ROS production', 'Var', (13, 27))	('carcinogenesis', 'Disease', (40, 54))	('DNA', 'Gene', (141, 144))	('ROS', 'Chemical', 'MESH:D017382', (13, 16))	('oncogenic pathways', 'Pathway', (88, 106))	('activation', 'PosReg', (66, 76))
132460	33540838	Here, we describe that as a single agent, CX-4945 moderately induced cell death in VHL-deficient renal cancer cells but unexpectedly, triggered a strong ATM upregulation, providing a potential link between CK2 and ATM pro-survival pathways.	('cell death', 'biological_process', 'GO:0008219', ('69', '79'))	('CX-4945', 'Var', (42, 49))	('ATM', 'Gene', (153, 156))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('pro-survival', 'biological_process', 'GO:0043066', ('218', '230'))	('ATM', 'Gene', (214, 217))	('des', 'Chemical', 'MESH:D004054', (9, 12))	('VHL-deficient renal cancer', 'Disease', (83, 109))	('CX-4945', 'Chemical', 'MESH:C555142', (42, 49))	('cell', 'CPA', (69, 73))	('ATM', 'Gene', '472', (153, 156))	('upregulation', 'PosReg', (157, 169))	('renal cancer', 'Phenotype', 'HP:0009726', (97, 109))	('ATM', 'Gene', '472', (214, 217))	('VHL-deficient renal cancer', 'Disease', 'MESH:D007680', (83, 109))
132465	33540838	For instance, ATM inhibition was shown to increase NOX4 expression in normal fibroblasts.	('ATM', 'Gene', '472', (14, 17))	('NOX4', 'Gene', (51, 55))	('expression', 'MPA', (56, 66))	('inhibition', 'Var', (18, 28))	('ATM', 'Gene', (14, 17))	('NOX4', 'Gene', '50507', (51, 55))	('increase', 'PosReg', (42, 50))
132466	33540838	Moreover, CK2 was described as a negative modulator of NOX4.	('NOX4', 'Gene', '50507', (55, 59))	('des', 'Chemical', 'MESH:D004054', (18, 21))	('NOX4', 'Gene', (55, 59))	('CK2', 'Var', (10, 13))
132471	33540838	Importantly, the sensitivity of 786-O VHL- MCTS was strongly affected by genetic disruption of HIF-2alpha.	('sensitivity', 'MPA', (17, 28))	('genetic disruption', 'Var', (73, 91))	('affected', 'Reg', (61, 69))	('HIF-2alpha', 'Gene', (95, 105))	('MCTS', 'Chemical', '-', (43, 47))	('HIF-2alpha', 'Gene', '2034', (95, 105))
132477	33540838	Mechanistically, phosphorylation of HIF-1alpha has been demonstrated to enhance transactivation of target genes by either disrupting its interaction with VHL and thereby stabilizing HIF-1alpha, or by increasing the affinity of HIF-1alpha for transcriptional coactivators.	('phosphorylation', 'biological_process', 'GO:0016310', ('17', '32'))	('HIF-1alpha', 'Gene', (227, 237))	('transactivation', 'MPA', (80, 95))	('enhance', 'PosReg', (72, 79))	('VHL', 'Protein', (154, 157))	('affinity', 'Interaction', (215, 223))	('disrupting', 'NegReg', (122, 132))	('HIF-1alpha', 'Gene', '3091', (36, 46))	('HIF-1alpha', 'Gene', '3091', (182, 192))	('transactivation', 'biological_process', 'GO:2000144', ('80', '95'))	('transcriptional', 'Interaction', (242, 257))	('HIF-1alpha', 'Gene', (36, 46))	('phosphorylation', 'Var', (17, 32))	('HIF-1alpha', 'Gene', '3091', (227, 237))	('stabilizing', 'Reg', (170, 181))	('HIF-1alpha', 'Gene', (182, 192))	('interaction', 'Interaction', (137, 148))	('increasing', 'PosReg', (200, 210))
132479	33540838	Hypoxia-induced phosphorylation by CK2 has been reported in the c-TAD domain of HIF-2alpha (Thr844) and mutation of this residue decreased reporter activity, possibly by increasing HIF affinity for an enzyme known as Factor Inhibiting HIF (FIH).	('Factor Inhibiting HIF', 'Disease', 'MESH:C565433', (217, 238))	('HIF-2alpha', 'Gene', (80, 90))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('increasing', 'PosReg', (170, 180))	('Hypoxia', 'Disease', (0, 7))	('reporter activity', 'MPA', (139, 156))	('phosphorylation', 'biological_process', 'GO:0016310', ('16', '31'))	('HIF-2alpha', 'Gene', '2034', (80, 90))	('mutation', 'Var', (104, 112))	('CK2', 'Protein', (35, 38))	('Factor Inhibiting HIF', 'Disease', (217, 238))	('Thr844', 'Chemical', '-', (92, 98))	('decreased', 'NegReg', (129, 138))
132531	30747736	Patients with high preoperative MTV and TLG had shorter overall survival.	('overall survival', 'MPA', (56, 72))	('TLG', 'Chemical', '-', (40, 43))	('shorter', 'NegReg', (48, 55))	('Patients', 'Species', '9606', (0, 8))	('MTV', 'Var', (32, 35))
132537	30747736	In this study, PET/CT results influenced patient management in 43% and were prognostic in that positive scans were associated with an inferior overall survival (OS) at 5 years and progression free survival (PFS) at 3 years compared to patients with negative scans.	('patient', 'Species', '9606', (235, 242))	('men', 'Species', '9606', (55, 58))	('patients', 'Species', '9606', (235, 243))	('inferior', 'NegReg', (134, 142))	('influenced', 'Reg', (30, 40))	('patient', 'Species', '9606', (41, 48))	('overall survival', 'MPA', (143, 159))	('progression free survival', 'CPA', (180, 205))	('positive scans', 'Var', (95, 109))
132564	30747736	In one study with 195 patients scheduled for resection of a renal mass, 124I geruntuximab demonstrated a sensitivity of 86% and specificity of 86% compared to a sensitivity of 76% and a specificity of 47% for contrast enhanced CT. Focal radiotracer uptake was noted mainly in ccRCC, but some benign and indolent tumors also accumulated radioactivity.	('RCC', 'Disease', 'MESH:C538614', (278, 281))	('RCC', 'Disease', (278, 281))	('tumors', 'Disease', (312, 318))	('tumors', 'Phenotype', 'HP:0002664', (312, 318))	('tumors', 'Disease', 'MESH:D009369', (312, 318))	('radiotracer', 'Chemical', '-', (237, 248))	('patients', 'Species', '9606', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('uptake', 'biological_process', 'GO:0098739', ('249', '255'))	('geruntuximab', 'Chemical', '-', (77, 89))	('uptake', 'biological_process', 'GO:0098657', ('249', '255'))	('RCC', 'Phenotype', 'HP:0005584', (278, 281))	('124I', 'Var', (72, 76))
132583	30747736	Sawicki et al studied 68Ga HBED-CC PSMA (68Ga PSMA) in 6 patients with primary or metastatic RCC and observed that 68Ga PSMA uptake in primary tumors was overshadowed by normal parenchymal activity and therefore was of limited value.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('RCC', 'Disease', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('68Ga', 'Var', (115, 119))	('PSMA', 'Gene', '2346', (35, 39))	('tumors', 'Disease', (143, 149))	('PSMA', 'molecular_function', 'GO:0043275', ('35', '39'))	('PSMA', 'Gene', '2346', (120, 124))	('PSMA', 'molecular_function', 'GO:0043275', ('46', '50'))	('PSMA', 'Gene', (35, 39))	('PSMA', 'molecular_function', 'GO:0043275', ('120', '124'))	('PSMA', 'Gene', (120, 124))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('uptake', 'biological_process', 'GO:0098657', ('125', '131'))	('PSMA', 'Gene', '2346', (46, 50))	('PSMA', 'Gene', (46, 50))	('patients', 'Species', '9606', (57, 65))	('uptake', 'biological_process', 'GO:0098739', ('125', '131'))
132601	30747736	Nakanishi et al reported the use of 11C Choline and FDG in 28 RCC patients with primary and metastatic disease and showed that 11C choline performed better than FDG with a sensitivity of 88% compared to 56% for FDG.	('FDG', 'Chemical', 'MESH:D019788', (161, 164))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('FDG', 'Chemical', 'MESH:D019788', (52, 55))	('11C choline', 'Chemical', '-', (127, 138))	('FDG', 'Chemical', 'MESH:D019788', (211, 214))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('11C Choline', 'Chemical', '-', (36, 47))	('11C', 'Var', (127, 130))	('patients', 'Species', '9606', (66, 74))
132637	33591636	Extensive studies have revealed that hyperactivation of HIF2alpha signaling is a central module of cell survival and metastasis in ccRCC [5].	('signaling', 'biological_process', 'GO:0023052', ('66', '75'))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('hyperactivation', 'Var', (37, 52))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('HIF2alpha signaling', 'MPA', (56, 75))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))
132643	33591636	Due to the fundamental role of HIF2alpha in ccRCC, structure-based drug design and rational modification has led to the development of a novel series of drugs, such as PT2385, PT2399, and PT2977, which can disrupt HIF2alpha/aryl hydrocarbon receptor nuclear translocator (ARNT) heterodimerization and inhibit HIF2alpha target gene expression [17, 18, 19].	('disrupt', 'NegReg', (206, 213))	('PT2399', 'Var', (176, 182))	('ARNT', 'Gene', '405', (272, 276))	('PT2385', 'Var', (168, 174))	('inhibit', 'NegReg', (301, 308))	('RCC', 'Disease', (46, 49))	('PT2385', 'Chemical', 'MESH:C000614279', (168, 174))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('HIF2alpha/aryl hydrocarbon receptor', 'Protein', (214, 249))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('ARNT', 'Gene', (272, 276))	('gene expression', 'biological_process', 'GO:0010467', ('326', '341'))	('PT2977', 'Var', (188, 194))	('heterodimerization', 'Interaction', (278, 296))	('expression', 'MPA', (331, 341))
132644	33591636	Additionally, a phase I trial showed PT2385 had a favorable safety profile and was active in patients with advanced ccRCC who had previously taken a tyrosine kinase inhibitor [20].	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('RCC', 'Disease', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('PT2385', 'Var', (37, 43))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('158', '174'))	('PT2385', 'Chemical', 'MESH:C000614279', (37, 43))	('patients', 'Species', '9606', (93, 101))
132651	33591636	The following antibodies were used in the experiments: mouse anti-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (G8795, 1:10,000) and anti-Flag (F3165, 1:2000) from Sigma-Aldrich (St. Louis, MO, USA); mouse anti-Myc (11667149001, 1:2000) and mouse anti-hemagglutinin (HA) antibody (11583816001, 1:2000) from Roche Applied Science (Penzberg, Germany); rabbit anti-Myc (562, 1:2000), rabbit anti-HA antibody (561, 1:2000), and anti-Strep-tag II (M211-3, 1:3000) from MBL Life Science (MBL, Nagoya, Japan); anti-HIF2alpha (NB100-122, 1:1000) from Novus Biologicals (Centennial, CO, USA); anti-histone H3 (acetyl K27) (H3K27ac, 1:100 for ChIP) (ab4729) from Abcam (Cambridge, MA, USA); anti-HDAC1 (GTX100513) from GeneTex (Irvine, CA, USA); rabbit anti-junction plakoglobin (JUP) (#75550, 1:1000) and anti-p300 (#86377, 1:100 for ChIP) from Cell Signaling Technology (Danvers, MA, USA); mouse anti-JUP (#MA5-15905, 1:1000), goat anti-mouse IgG secondary antibody (31430, 1:20,000), and goat anti-rabbit IgG-horseradish peroxidase (HRP) secondary antibody (31460, 1:20,000) from Thermo Fisher Scientific (Waltham, MA, USA).	('antibody', 'cellular_component', 'GO:0019814', ('1045', '1053'))	('GAPDH', 'Gene', (108, 113))	('mouse', 'Species', '10090', (245, 250))	('MBL', 'Gene', '17195', (486, 489))	('antibody', 'cellular_component', 'GO:0019814', ('400', '408'))	('antibody', 'molecular_function', 'GO:0003823', ('275', '283'))	('antibody', 'cellular_component', 'GO:0019815', ('953', '961'))	('MBL', 'Gene', (486, 489))	('31460', 'Var', (1055, 1060))	('GAPDH', 'Gene', '14433', (108, 113))	('antibody', 'cellular_component', 'GO:0042571', ('275', '283'))	('horseradish peroxidase (HRP', 'molecular_function', 'GO:0004601', ('1006', '1033'))	('antibody', 'molecular_function', 'GO:0003823', ('1045', '1053'))	('mouse', 'Species', '10090', (55, 60))	('mouse', 'Species', '10090', (204, 209))	('antibody', 'molecular_function', 'GO:0003823', ('400', '408'))	('antibody', 'cellular_component', 'GO:0042571', ('1045', '1053'))	('anti-junction plakoglobin', 'Gene', '16480', (747, 772))	('anti-glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '14433', (61, 106))	('anti-junction plakoglobin', 'Gene', (747, 772))	('antibody', 'cellular_component', 'GO:0042571', ('400', '408'))	('MBL', 'Gene', '17195', (468, 471))	('mouse', 'Species', '10090', (886, 891))	('antibody', 'cellular_component', 'GO:0019814', ('953', '961'))	('antibody', 'cellular_component', 'GO:0019815', ('275', '283'))	('MBL', 'Gene', (468, 471))	('mouse', 'Species', '10090', (933, 938))	('antibody', 'cellular_component', 'GO:0019815', ('1045', '1053'))	('antibody', 'cellular_component', 'GO:0019815', ('400', '408'))	('antibody', 'molecular_function', 'GO:0003823', ('953', '961'))	('Signaling', 'biological_process', 'GO:0023052', ('845', '854'))	('anti-glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (61, 106))	('antibody', 'cellular_component', 'GO:0042571', ('953', '961'))	('antibody', 'cellular_component', 'GO:0019814', ('275', '283'))
132664	33591636	The 12xHis-tag sequence was synthesized and cloned into PCDH-StrepII-GST-C1 to obtain PCDH-12xHis.	('PCDH-StrepII-GST-C1', 'Disease', (56, 75))	('PCDH-12xHis', 'Var', (86, 97))	('PCDH-StrepII-GST-C1', 'Disease', 'MESH:C565170', (56, 75))
132667	33591636	Mammalian expression plasmids for human ARNT, HDAC1, HDAC2, and deletion mutants of HIF2alpha and JUP were constructed using standard molecular biology techniques.	('HDAC2', 'Gene', (53, 58))	('HDAC2', 'Gene', '3066', (53, 58))	('human', 'Species', '9606', (34, 39))	('Mammalian', 'Species', '9606', (0, 9))	('deletion mutants', 'Var', (64, 80))	('ARNT', 'Gene', '405', (40, 44))	('HIF2alpha', 'Gene', (84, 93))	('ARNT', 'Gene', (40, 44))
132678	33591636	The ChIP assay was performed using antibodies against human JUP, HDAC1, HIF2alpha, p300, and H3K27ac as previously described [21].	('H3K27ac', 'Var', (93, 100))	('HDAC1', 'Gene', (65, 70))	('human', 'Species', '9606', (54, 59))	('p300', 'Var', (83, 87))
132708	33591636	Furthermore, Kaplan-Meier survival analysis demonstrated patients with low JUP expression had significantly poorer OS, disease-specific survival, and progression-free survival compared to those with high JUP expression (Figure 2F), indicating JUP might be an independent prognostic factor for ccRCC survival.	('low', 'Var', (71, 74))	('progression-free survival', 'CPA', (150, 175))	('patients', 'Species', '9606', (57, 65))	('poorer', 'NegReg', (108, 114))	('JUP', 'Protein', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (295, 298))	('RCC', 'Disease', (295, 298))	('RCC', 'Phenotype', 'HP:0005584', (295, 298))	('ccRCC', 'Phenotype', 'HP:0006770', (293, 298))	('disease-specific survival', 'CPA', (119, 144))
132711	33591636	Next, we determined whether JUP depletion could promote tumor growth in a xenograft mouse model.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('depletion', 'Var', (32, 41))	('tumor', 'Disease', (56, 61))	('mouse', 'Species', '10090', (84, 89))	('promote', 'PosReg', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
132712	33591636	S2), tumors from subcutaneously transplanted ACHN cells with stable knockdown of JUP grew more rapidly compared with the controls (Figure 3D-F).	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('knockdown', 'Var', (68, 77))	('grew', 'CPA', (85, 89))	('JUP', 'Gene', (81, 84))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
132715	33591636	In intravenous injection assay with EGFP quantitative imaging, we noticed that the mice injected with JUP-KD cells had a marked increase in fluorescence signal compared with those injected with control cells.	('JUP-KD cells', 'Var', (102, 114))	('fluorescence signal', 'MPA', (140, 159))	('increase', 'PosReg', (128, 136))	('mice', 'Species', '10090', (83, 87))
132719	33591636	Using 6xHRE-driven luciferase reporter, our results showed JUP decreased the transcriptional activity of both transfected and endogenous HIF2alpha in HEK293T and 786-O cells, respectively (Figure 4A and B).	('HEK293T', 'CellLine', 'CVCL:0063', (150, 157))	('decreased', 'NegReg', (63, 72))	('HIF2alpha', 'Gene', (137, 146))	('transcriptional activity', 'MPA', (77, 101))	('JUP', 'Var', (59, 62))
132720	33591636	We also observed JUP-KD resulted in upregulation of HIF2alpha target genes in both 786-O and OSRC-2 cells (Figure 4D and E).	('OSRC-2', 'CellLine', 'CVCL:1901', (93, 99))	('upregulation', 'PosReg', (36, 48))	('HIF2alpha target genes', 'Gene', (52, 74))	('JUP-KD', 'Var', (17, 23))
132733	33591636	Consistent with this observation, overexpression of JUP had little effect on exogenously produced hydroxylation-defective mutant HIF2alpha (P405A/P531A) levels (Supplementary Fig.	('hydroxylation-defective', 'MPA', (98, 121))	('HIF2alpha', 'Gene', (129, 138))	('P405A', 'SUBSTITUTION', 'None', (140, 145))	('P405A', 'Var', (140, 145))	('P531A', 'Mutation', 'p.P531A', (146, 151))
132742	33591636	Ectopically expressed JUP was found to strengthen VHL-HIF2alpha interaction (Figure 5N).	('VHL', 'Gene', (50, 53))	('VHL', 'Gene', '7428', (50, 53))	('Ectopically expressed', 'Var', (0, 21))	('JUP', 'Gene', (22, 25))	('strengthen', 'PosReg', (39, 49))
132750	33591636	Overexpression of JUP still repressed the transcriptional activity of the HRE reporter induced by HIF2alpha mutant (P405A and P531A double mutant [DM]) (Supplementary Fig.	('P531A', 'Mutation', 'p.P531A', (126, 131))	('transcriptional activity', 'MPA', (42, 66))	('HRE', 'Gene', (74, 77))	('P531A', 'Var', (126, 131))	('DM', 'Disease', 'MESH:D009223', (147, 149))	('HIF2alpha', 'Gene', (98, 107))	('P405A', 'Var', (116, 121))	('P405A', 'Mutation', 'p.P405A', (116, 121))
132759	33591636	Flag-HDAC1/2 proteins were observed after incubation with GST-JUP (Figure 6D), indicating JUP can recruit HDAC1/2 without HIF2alpha.	('HDAC1/2', 'Gene', (5, 12))	('GST', 'Gene', '373156', (58, 61))	('HDAC1/2', 'Gene', (106, 113))	('HDAC1/2', 'Gene', '3065;3066', (5, 12))	('HDAC1/2', 'Gene', '3065;3066', (106, 113))	('GST', 'Gene', (58, 61))	('JUP', 'Var', (90, 93))
132762	33591636	ChIP analysis indicated that the binding of JUP and HDAC1 to the VEGFA promoter and ZNF395 enhancer were decreased by HIF2alpha depletion (Figure 6F and G); this interaction is likely HIF2alpha-dependent.	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('HIF2alpha', 'Protein', (118, 127))	('VEGFA', 'Gene', '7422', (65, 70))	('ZNF395', 'Gene', '55893', (84, 90))	('depletion', 'Var', (128, 137))	('HDAC1', 'Gene', (52, 57))	('ZNF395', 'Gene', (84, 90))	('binding', 'Interaction', (33, 40))	('JUP', 'Gene', (44, 47))	('decreased', 'NegReg', (105, 114))	('VEGFA', 'Gene', (65, 70))
132763	33591636	Given that p300/CBP-mediated H3K27ac is a well-defined marker of active enhancers and promoters, we next tested whether JUP can regulate localization of p300 and H3K27Ac at these sites.	('tested', 'Reg', (105, 111))	('CBP', 'molecular_function', 'GO:0008140', ('16', '19'))	('CBP', 'Gene', (16, 19))	('CBP', 'Gene', '1387', (16, 19))	('p300', 'Var', (153, 157))	('localization', 'biological_process', 'GO:0051179', ('137', '149'))	('localization', 'MPA', (137, 149))	('H3K27Ac', 'Var', (162, 169))
132764	33591636	In addition, cell migratory and invasive abilities were increased in HIF2alpha-overexpressing cells, and further enhanced by JUP-KD (Figure 7D and E), again suggesting JUP is a potent tumor suppressor that inhibits HIF2alpha function.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('JUP-KD', 'Var', (125, 131))	('increased', 'PosReg', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('HIF2alpha-overexpressing', 'Gene', (69, 93))	('HIF2alpha-overexpressing', 'PosReg', (69, 93))	('tumor', 'Disease', (184, 189))	('tumor suppressor', 'biological_process', 'GO:0051726', ('184', '200'))	('enhanced', 'PosReg', (113, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('184', '200'))
132765	33591636	Together, these data show JUP inhibits the HIF2alpha-enhanced migration and invasion of RCC cells.	('migration', 'CPA', (62, 71))	('JUP', 'Var', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('HIF2alpha-enhanced', 'PosReg', (43, 61))	('HIF2alpha-enhanced', 'Protein', (43, 61))	('inhibits', 'NegReg', (30, 38))
132771	33591636	The opposite effects of HIF1alpha and HIF2alpha on beta-catenin signaling may be caused by the different domains of beta-catenin responsible for the interactions with HIF1alpha and HIF2alpha [15, 39].	('HIF1alpha', 'Gene', (167, 176))	('beta-catenin', 'Gene', '1499', (51, 63))	('HIF1alpha', 'Gene', (24, 33))	('HIF1alpha', 'Gene', '3091', (167, 176))	('signaling', 'biological_process', 'GO:0023052', ('64', '73'))	('HIF1alpha', 'Gene', '3091', (24, 33))	('HIF2alpha', 'Var', (181, 190))	('beta-catenin', 'Gene', (116, 128))	('interactions', 'Interaction', (149, 161))	('beta-catenin', 'Gene', (51, 63))	('beta-catenin', 'Gene', '1499', (116, 128))
132775	33591636	In addition to interacting with HIF2alpha, in the present study, JUP was found to associate with VHL and HDAC1/2 and to decrease the stability and transactivity of HIF2alpha.	('stability', 'MPA', (133, 142))	('JUP', 'Var', (65, 68))	('VHL', 'Gene', '7428', (97, 100))	('HDAC1/2', 'Gene', '3065;3066', (105, 112))	('decrease', 'NegReg', (120, 128))	('HIF2alpha', 'Protein', (164, 173))	('VHL', 'Gene', (97, 100))	('transactivity', 'MPA', (147, 160))	('HDAC1/2', 'Gene', (105, 112))	('associate', 'Interaction', (82, 91))
132777	33591636	Given JUP facilitates the pVHL-HIF2alpha interaction, JUP is likely to directly recruit the pVHL E3 ligase complex to ubiquitinate HIF2alpha.	('interaction', 'Interaction', (41, 52))	('facilitates', 'PosReg', (10, 21))	('pVHL', 'Gene', '7428', (92, 96))	('pVHL', 'Gene', '7428', (26, 30))	('pVHL', 'Gene', (92, 96))	('pVHL', 'Gene', (26, 30))	('JUP', 'Var', (6, 9))
132779	33591636	However, we found that JUP associated with the PAS/PAC and IH domains of HIF2alpha, indicating JUP may be sufficient to promote HIF2alpha ubiquination under both normoxic and hypoxic conditions.	('PAS', 'cellular_component', 'GO:0000407', ('47', '50'))	('HIF2alpha', 'Gene', (128, 137))	('JUP', 'Var', (95, 98))	('PAC', 'Phenotype', 'HP:0006699', (51, 54))	('promote', 'PosReg', (120, 127))	('PAS', 'Chemical', '-', (47, 50))	('hypoxic conditions', 'Disease', 'MESH:D000071069', (175, 193))	('ubiquination', 'MPA', (138, 150))	('hypoxic conditions', 'Disease', (175, 193))
132787	33591636	[46] demonstrated HIF1alpha can be acetylated by p300 at Lys-709, which increases its protein stability.	('increases', 'PosReg', (72, 81))	('protein stability', 'MPA', (86, 103))	('p300', 'Var', (49, 53))	('Lys-709', 'Var', (57, 64))	('HIF1alpha', 'Gene', (18, 27))	('Lys', 'Chemical', 'MESH:D008239', (57, 60))	('HIF1alpha', 'Gene', '3091', (18, 27))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))
132788	33591636	They also showed HIF1alpha can be deacetylated at Lys-709 by HDAC1.	('HIF1alpha', 'Gene', (17, 26))	('Lys', 'Chemical', 'MESH:D008239', (50, 53))	('HIF1alpha', 'Gene', '3091', (17, 26))	('Lys-709', 'Var', (50, 57))
132815	32309427	Although smoking, hypertension, and obesity are considered risk factors, genetic variation also plays a critical role during the tumorigenesis process.	('plays', 'Reg', (96, 101))	('genetic variation', 'Var', (73, 90))	('obesity', 'Disease', 'MESH:D009765', (36, 43))	('obesity', 'Phenotype', 'HP:0001513', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('obesity', 'Disease', (36, 43))	('hypertension', 'Disease', 'MESH:D006973', (18, 30))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('hypertension', 'Disease', (18, 30))	('tumor', 'Disease', (129, 134))	('hypertension', 'Phenotype', 'HP:0000822', (18, 30))
132816	32309427	Nearly 90% of ccRCC is characterized by the aberration of VHL, while PBRM1 is considered the second major tumor suppressor gene in ccRCC.	('aberration', 'Var', (44, 54))	('ccRCC', 'Phenotype', 'HP:0006770', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('PBRM1', 'Gene', (69, 74))	('VHL', 'Gene', (58, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('tumor suppressor', 'biological_process', 'GO:0051726', ('106', '122'))	('ccRCC', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('VHL', 'Gene', '7428', (58, 61))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('106', '122'))	('PBRM1', 'Gene', '55193', (69, 74))	('tumor', 'Disease', (106, 111))
132818	32309427	BAP1 is another tumor suppressor in ccRCC, the low expression of which is significantly associated with high grade but not survival.	('high grade', 'Disease', (104, 114))	('BAP1', 'Gene', (0, 4))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('ccRCC', 'Disease', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor suppressor', 'biological_process', 'GO:0051726', ('16', '32'))	('low', 'Var', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('16', '32'))	('associated', 'Reg', (88, 98))	('BAP1', 'Gene', '8314', (0, 4))
132842	32309427	On the GPL570 ([HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array) platform, we screened out two data sets (GSE53757 and GSE73731) with pathological stage information.	('GSE73731', 'Var', (131, 139))	('Human', 'Species', '9606', (43, 48))	('GSE53757', 'Var', (118, 126))
132872	32309427	For instance, overexpressed RRM2 was experimentally confirmed to be associated with a trend toward the advanced pathological stage, high Fuhrman grade, and poor prognosis.	('overexpressed', 'Var', (14, 27))	('RRM2', 'Gene', '6241', (28, 32))	('associated', 'Reg', (68, 78))	('RRM2', 'Gene', (28, 32))
132873	32309427	In addition, a recent study reported that miR-99a-3p could regulate RRM2 in sunitinib-resistant ccRCC, showing a potential antitumor effect.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('miR-99a-3p', 'Var', (42, 52))	('sunitinib', 'Chemical', 'MESH:D000077210', (76, 85))	('regulate', 'Reg', (59, 67))	('sunitinib-resistant ccRCC', 'Disease', (76, 101))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('RRM2', 'Gene', '6241', (68, 72))	('RRM2', 'Gene', (68, 72))
132890	30466410	In metastatic pRCC with a MET amplification, crizotinib maybe a potential met-inhibitory therapeutic option.	('MET amplification', 'Var', (26, 43))	('pRCC', 'Gene', '5546', (14, 18))	('pRCC', 'Phenotype', 'HP:0006766', (14, 18))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('pRCC', 'Gene', (14, 18))	('crizotinib', 'Chemical', 'MESH:D000077547', (45, 55))
132899	30466410	Histopathological examination revealed a tubulo-papillary renal cell carcinoma, type 1, grade 2 of Fuhrman, 20% of necrosis, without vascular embolus or peri-renal infiltration, R0, pT1bNx, vimentin +, CD 10+.	('necrosis', 'biological_process', 'GO:0008219', ('115', '123'))	('vimentin', 'cellular_component', 'GO:0045099', ('190', '198'))	('pT1bNx', 'Var', (182, 188))	('papillary renal cell carcinoma', 'Disease', (48, 78))	('CD 10', 'molecular_function', 'GO:0004245', ('202', '207'))	('necrosis', 'biological_process', 'GO:0008220', ('115', '123'))	('man', 'Species', '9606', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (58, 78))	('necrosis', 'biological_process', 'GO:0070265', ('115', '123'))	('vimentin', 'Gene', '7431', (190, 198))	('necrosis', 'biological_process', 'GO:0019835', ('115', '123'))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (48, 78))	('necrosis', 'biological_process', 'GO:0001906', ('115', '123'))	('vimentin', 'cellular_component', 'GO:0045098', ('190', '198'))	('vimentin', 'Gene', (190, 198))	('necrosis', 'Disease', 'MESH:D009336', (115, 123))	('vascular embolus', 'Disease', (133, 149))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (48, 78))	('necrosis', 'Disease', (115, 123))	('vascular embolus', 'Disease', 'MESH:D004617', (133, 149))
132901	30466410	1) confirmed the morphology of papillary renal cell carcinoma, with papillary and foamy macrophages (A, B, C) and a positivity of CK7 (D), Racemase/P504S (E) with immunohistochemistry (IHC).	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('Racemase/P504S', 'Var', (139, 153))	('papillary', 'CPA', (68, 77))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (31, 61))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (31, 61))	('foamy macrophages', 'Phenotype', 'HP:0003651', (82, 99))	('CK7', 'Gene', (130, 133))	('P504S', 'Mutation', 'p.P504S', (148, 153))	('CK7', 'Gene', '3855', (130, 133))	('papillary renal cell carcinoma', 'Disease', (31, 61))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (41, 61))
132931	30466410	described a pRCC patient with an activating MET gene mutation, pretreated by sunitinib and everolimus, with a long response to a tyrosine kinase inhibitor (TKI: PF-04217903).	('mutation', 'Var', (53, 61))	('tyrosine kinase', 'Gene', (129, 144))	('patient', 'Species', '9606', (17, 24))	('everolimus', 'Chemical', 'MESH:D000068338', (91, 101))	('pRCC', 'Phenotype', 'HP:0006766', (12, 16))	('pRCC', 'Gene', '5546', (12, 16))	('MET gene', 'Gene', (44, 52))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('activating', 'PosReg', (33, 43))	('sunitinib', 'Chemical', 'MESH:D000077210', (77, 86))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('138', '154'))	('tyrosine kinase', 'Gene', '7294', (129, 144))	('pRCC', 'Gene', (12, 16))
132933	30466410	Biologically, the proof of MET implication in pRCC was made in 1997 with the discovery that hereditary pRCC patients had a germline missense mutation in the MET proto-oncogene (7q3 locus), leading to constitutive activation of the MET protein.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('pRCC', 'Phenotype', 'HP:0006766', (103, 107))	('pRCC', 'Gene', '5546', (103, 107))	('protein', 'cellular_component', 'GO:0003675', ('235', '242'))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('pRCC', 'Phenotype', 'HP:0006766', (46, 50))	('pRCC', 'Gene', '5546', (46, 50))	('missense mutation', 'Var', (132, 149))	('constitutive activation', 'MPA', (200, 223))	('pRCC', 'Gene', (103, 107))	('protein', 'Protein', (235, 242))	('patients', 'Species', '9606', (108, 116))	('MET protein', 'Protein', (231, 242))	('pRCC', 'Gene', (46, 50))
132935	30466410	Another large series of pRCC (n = 164) described MET mutations in 17 tumors, mainly in type 1 pRCC and in the tyrosine kinase domain (14/17), and discovered an alternate MET RNA transcript leading to a constitutive activation of MET in a ligand-independent manner.	('tyrosine kinase', 'Gene', '7294', (110, 125))	('MET', 'Gene', (49, 52))	('pRCC', 'Gene', '5546', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('MET', 'MPA', (229, 232))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('pRCC', 'Phenotype', 'HP:0006766', (24, 28))	('pRCC', 'Gene', '5546', (94, 98))	('activation', 'PosReg', (215, 225))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('pRCC', 'Gene', (24, 28))	('mutations', 'Var', (53, 62))	('tumors', 'Disease', (69, 75))	('ligand', 'molecular_function', 'GO:0005488', ('238', '244'))	('RNA', 'cellular_component', 'GO:0005562', ('174', '177'))	('man', 'Species', '9606', (257, 260))	('pRCC', 'Phenotype', 'HP:0006766', (94, 98))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('pRCC', 'Gene', (94, 98))	('tyrosine kinase', 'Gene', (110, 125))
132937	30466410	First, foretinib (MET/VEGFR2 inhibitor) was examined in a phase II including 74 patients with mpRCC: the median PFS was 9.3 months and patients with a germline mutation were significantly more likely to respond.	('foretinib', 'Chemical', 'MESH:C544831', (7, 16))	('patients', 'Species', '9606', (135, 143))	('patients', 'Species', '9606', (80, 88))	('more', 'PosReg', (188, 192))	('respond', 'MPA', (203, 210))	('pRCC', 'Gene', (95, 99))	('VEGFR2', 'Gene', '3791', (22, 28))	('germline mutation', 'Var', (151, 168))	('pRCC', 'Gene', '5546', (95, 99))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('pRCC', 'Phenotype', 'HP:0006766', (95, 99))	('VEGFR2', 'Gene', (22, 28))
132941	30466410	Interestingly, if the response rate was 0% in MET-independent pRCC, it was of 18% in patients with a MET-driven pRCC (chromosome 7 copy gain, focal MET or HGF gene amplification, or MET kinase domain mutations).	('copy gain', 'Var', (131, 140))	('pRCC', 'Phenotype', 'HP:0006766', (62, 66))	('pRCC', 'Gene', '5546', (62, 66))	('HGF', 'Gene', '3082', (155, 158))	('pRCC', 'Gene', (112, 116))	('MET kinase domain mutations', 'Var', (182, 209))	('chromosome', 'cellular_component', 'GO:0005694', ('118', '128'))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('patients', 'Species', '9606', (85, 93))	('HGF', 'Gene', (155, 158))	('pRCC', 'Phenotype', 'HP:0006766', (112, 116))	('pRCC', 'Gene', (62, 66))	('pRCC', 'Gene', '5546', (112, 116))	('MET', 'Gene', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))
132946	30466410	Only a previous case report described a MET-mutated pRCC patient pre-treated with sunitinib and tivantinib; however this mutation (missense base substitution MET H1094L) is rare compared to MET amplification, and the patient only remained on crizotinib therapy for 5 months (versus 19 months in our patient).	('H1094L', 'Mutation', 'p.H1094L', (162, 168))	('pRCC', 'Phenotype', 'HP:0006766', (52, 56))	('pRCC', 'Gene', '5546', (52, 56))	('patient', 'Species', '9606', (57, 64))	('crizotinib', 'Chemical', 'MESH:D000077547', (242, 252))	('patient', 'Species', '9606', (217, 224))	('MET H1094L', 'Var', (158, 168))	('tivantinib', 'Chemical', 'MESH:C551661', (96, 106))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('pre', 'molecular_function', 'GO:0003904', ('65', '68'))	('pRCC', 'Gene', (52, 56))	('patient', 'Species', '9606', (299, 306))	('sunitinib', 'Chemical', 'MESH:D000077210', (82, 91))
132948	30466410	Interestingly, in November 2017 were published the results of pRCC1 patients included in the CREATE trial (EORTC 90101), a multicentric prospective phase II clinical trial including patients with tumors harboring specific alterations leading to ALK and/or MET activation and treated with crizotinib.	('pRCC', 'Phenotype', 'HP:0006766', (62, 66))	('pRCC', 'Gene', '5546', (62, 66))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumors', 'Disease', (196, 202))	('crizotinib', 'Chemical', 'MESH:D000077547', (288, 298))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('leading to', 'Reg', (234, 244))	('patients', 'Species', '9606', (68, 76))	('ALK', 'Gene', '238', (245, 248))	('patients', 'Species', '9606', (182, 190))	('pRCC', 'Gene', (62, 66))	('alterations', 'Var', (222, 233))	('MET activation', 'MPA', (256, 270))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('ALK', 'Gene', (245, 248))
132950	30466410	This study demonstrated that crizotinib is active in pRCC, achieving long-lasting disease control in patients with MET mutations or amplification.	('pRCC', 'Gene', (53, 57))	('patients', 'Species', '9606', (101, 109))	('crizotinib', 'Chemical', 'MESH:D000077547', (29, 39))	('amplification', 'Var', (132, 145))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('MET mutations', 'Var', (115, 128))	('pRCC', 'Phenotype', 'HP:0006766', (53, 57))	('pRCC', 'Gene', '5546', (53, 57))
132952	30466410	This precision treatment (crizotinib) was possible thanks to an original biology-driven national French program (AcSe crizotinib NCT02034981), giving access to crizotinib for patients with identified activating genomic alterations in the crizotinib target genes, with a safe monitoring.	('crizotinib', 'Chemical', 'MESH:D000077547', (238, 248))	('crizotinib', 'Chemical', 'MESH:D000077547', (118, 128))	('crizotinib', 'Chemical', 'MESH:D000077547', (26, 36))	('crizotinib', 'Chemical', 'MESH:D000077547', (160, 170))	('patients', 'Species', '9606', (175, 183))	('genomic alterations', 'Var', (211, 230))	('activating', 'PosReg', (200, 210))
132975	29805645	However, the VHL mutant alone was inadequate for ccRCC development.	('men', 'Species', '9606', (62, 65))	('VHL', 'Gene', (13, 16))	('VHL', 'Gene', '7428', (13, 16))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('mutant', 'Var', (17, 23))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
133001	29805645	6, indicating that altered MME, CDH1 and ICAM1 were associated with the prognosis of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('MME', 'Gene', (27, 30))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('CDH1', 'Gene', (32, 36))	('MME', 'Gene', '4311', (27, 30))	('ICAM1', 'Gene', '3383', (41, 46))	('altered', 'Var', (19, 26))	('associated with', 'Reg', (52, 67))	('CDH1', 'Gene', '999', (32, 36))	('ICAM1', 'Gene', (41, 46))
133036	29805645	Although our study shows that the seven Hub genes were associated with the occurrence or development of ccRCC, the survival analysis by OncoLnc database showed that altered MME, CDH1 and ICAM1 were associated with the prognosis of ccRCC, but CXCL12, PROM1, ALB and PTPRC were not.	('ICAM1', 'Gene', (187, 192))	('PTPRC', 'Gene', (265, 270))	('associated', 'Reg', (198, 208))	('ccRCC', 'Phenotype', 'HP:0006770', (231, 236))	('CXCL12', 'Gene', '6387', (242, 248))	('RCC', 'Disease', (233, 236))	('ALB', 'Gene', '213', (257, 260))	('ICAM1', 'Gene', '3383', (187, 192))	('altered', 'Var', (165, 172))	('men', 'Species', '9606', (96, 99))	('ALB', 'Gene', (257, 260))	('Hub', 'Gene', (40, 43))	('associated', 'Reg', (55, 65))	('CXCL12', 'Gene', (242, 248))	('RCC', 'Disease', (106, 109))	('MME', 'Gene', '4311', (173, 176))	('RCC', 'Disease', 'MESH:C538614', (233, 236))	('PTPRC', 'Gene', '5788', (265, 270))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))	('CDH1', 'Gene', '999', (178, 182))	('Hub', 'Gene', '1993', (40, 43))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('CDH1', 'Gene', (178, 182))	('PROM1', 'Gene', (250, 255))	('PROM1', 'Gene', '8842', (250, 255))	('MME', 'Gene', (173, 176))
133048	28662726	A two-gene methylation panel comprising OXR1 and MST1R identified malignancy with 98% sensitivity and 100% specificity, and clear cell renal cell carcinoma with 90% sensitivity and 98% specificity.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('malignancy', 'Disease', 'MESH:D009369', (66, 76))	('clear cell renal cell carcinoma', 'Disease', (124, 155))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (135, 155))	('methylation', 'biological_process', 'GO:0032259', ('11', '22'))	('MST1R', 'Gene', (49, 54))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (124, 155))	('malignancy', 'Disease', (66, 76))	('methylation', 'Var', (11, 22))	('OXR1', 'Gene', (40, 44))	('MST1R', 'Gene', '4486', (49, 54))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (124, 155))	('OXR1', 'Gene', '55074', (40, 44))
133050	28662726	Significantly higher OXR1 promoter methylation levels (p = 0.005) were associated with high nuclear grade in ccRCC.	('OXR1', 'Gene', (21, 25))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('RCC', 'Disease', (111, 114))	('OXR1', 'Gene', '55074', (21, 25))	('high nuclear', 'Var', (87, 99))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))	('higher', 'PosReg', (14, 20))
133053	28662726	Epigenetic deregulation is a frequent finding in renal cell tumors (RCT).	('Epigenetic deregulation', 'Var', (0, 23))	('renal cell tumors', 'Disease', (49, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('renal cell tumors', 'Disease', 'MESH:C538614', (49, 66))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
133060	28662726	Among epigenetic alterations, aberrant promoter methylation, which generally entails gene silencing, has emerged as a promising class of biomarkers in urologic neoplasms, including RCTs.	('RCTs', 'Disease', (181, 185))	('neoplasms', 'Phenotype', 'HP:0002664', (160, 169))	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('gene silencing', 'biological_process', 'GO:0016458', ('85', '99'))	('urologic neoplasms', 'Disease', (151, 169))	('urologic neoplasms', 'Disease', 'MESH:D014571', (151, 169))	('neoplasm', 'Phenotype', 'HP:0002664', (160, 168))	('aberrant promoter methylation', 'Var', (30, 59))
133062	28662726	Among genes with consistently high (>70%) methylation frequency in RCC, APAF1, MDR1, and PTGS2, should be highlighted (97-100, 86 and 94%, respectively).	('APAF1', 'Gene', (72, 77))	('PTGS2', 'Gene', '5743', (89, 94))	('PTGS2', 'Gene', (89, 94))	('APAF1', 'Gene', '317', (72, 77))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('MDR', 'molecular_function', 'GO:0004745', ('79', '82'))	('MDR1', 'Gene', (79, 83))	('methylation', 'biological_process', 'GO:0032259', ('42', '53'))	('methylation', 'Var', (42, 53))	('MDR1', 'Gene', '5243', (79, 83))	('PTGS', 'biological_process', 'GO:0016441', ('89', '93'))
133063	28662726	Recently, we showed that MST1R was also frequently methylated in RCC, and promoter methylation levels discriminated ccRCC from the remaining RCT subtypes with high specificity.	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('MST1R', 'Gene', (25, 30))	('RCC', 'Disease', (118, 121))	('methylated', 'Var', (51, 61))	('MST1R', 'Gene', '4486', (25, 30))	('methylation', 'biological_process', 'GO:0032259', ('83', '94'))	('promoter methylation levels', 'MPA', (74, 101))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
133064	28662726	Nevertheless, over the last years, several high-throughput studies on RCC promoter methylation using an array-based approach, identified several other hypermethylated genes in RCC, which might be useful as diagnostic biomarkers.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (176, 179))	('RCC', 'Disease', (70, 73))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('methylation', 'biological_process', 'GO:0032259', ('83', '94'))	('hypermethylated', 'Var', (151, 166))
133075	28662726	MST1R, the gene with the highest percent of hypermethylated DNA (representing the fraction of input DNA containing at least two methylated CpG sites in the targeted region) was selected for further analysis, and proved to be a specific ccRCC biomarker.	('RCC', 'Disease', 'MESH:C538614', (238, 241))	('MST1R', 'Gene', '4486', (0, 5))	('RCC', 'Disease', (238, 241))	('hypermethylated', 'Var', (44, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (236, 241))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('MST1R', 'Gene', (0, 5))
133087	28662726	Tumor samples were categorized as HOXA9 or OXR1 methylated using the respective highest methylation ratio value observed in normal/control samples as cutoff (14.11 for HOXA9 and 1577.45 for OXR1).	('HOXA9', 'Gene', '3205', (34, 39))	('HOXA9', 'Gene', '3205', (168, 173))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('OXR1', 'Gene', '55074', (43, 47))	('1577.45', 'Var', (178, 185))	('HOXA9', 'Gene', (34, 39))	('HOXA9', 'Gene', (168, 173))	('OXR1', 'Gene', (190, 194))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('OXR1', 'Gene', (43, 47))	('OXR1', 'Gene', '55074', (190, 194))
133116	28662726	Using robust methylation-specific primers for each gene promoter and performing quantitative methylation-specific PCR, we found that OXR1 and MST1R promoter methylation discriminated between normal renal tissue and renal cell tumours with high specificity.	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('MST1R', 'Gene', (142, 147))	('methylation', 'biological_process', 'GO:0032259', ('157', '168'))	('OXR1', 'Gene', '55074', (133, 137))	('renal cell tumours', 'Disease', (215, 233))	('tumours', 'Phenotype', 'HP:0002664', (226, 233))	('discriminated', 'Reg', (169, 182))	('methylation', 'Var', (157, 168))	('methylation', 'biological_process', 'GO:0032259', ('93', '104'))	('MST1R', 'Gene', '4486', (142, 147))	('renal cell tumours', 'Disease', 'MESH:C538614', (215, 233))	('OXR1', 'Gene', (133, 137))
133121	28662726	PCDH17 and TCF21 promoter methylation identified renal cell tumours with 67% sensitivity and 100% specificity, but OXR1 and MST1R were equally specific (100%) but more sensitive (98%) in the distinction between RCT and normal renal tissue.	('methylation', 'Var', (26, 37))	('PCDH17', 'Gene', '27253', (0, 6))	('MST1R', 'Gene', (124, 129))	('TCF21', 'Gene', (11, 16))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('PCDH17', 'Gene', (0, 6))	('renal cell tumours', 'Disease', 'MESH:C538614', (49, 67))	('MST1R', 'Gene', '4486', (124, 129))	('OXR1', 'Gene', (115, 119))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))	('renal cell tumours', 'Disease', (49, 67))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('RCT', 'Disease', (211, 214))	('TCF21', 'Gene', '6943', (11, 16))	('OXR1', 'Gene', '55074', (115, 119))
133123	28662726	Moreover, RASSF1A hypermethylation was shown to discriminate pRCC from normal renal tissue with 87.5% sensitivity and 73.3% specificity, although comparison with other RCT subtypes was not undertaken.	('discriminate', 'Reg', (48, 60))	('hypermethylation', 'Var', (18, 34))	('pRCC', 'Gene', (61, 65))	('RASSF1A', 'Gene', (10, 17))	('pRCC', 'Gene', '5546', (61, 65))	('RASSF1A', 'Gene', '11186', (10, 17))	('pRCC', 'Phenotype', 'HP:0006766', (61, 65))
133143	29872221	Moreover, silencing of enzymes of the GSH biosynthesis pathway or glutathione peroxidases, which depend on GSH for the removal of cellular hydroperoxides, selectively reduced viability of ccRCC cells but did not affect the growth of non-malignant renal epithelial cells.	('viability', 'CPA', (175, 184))	('hydroperoxides', 'Chemical', 'MESH:D006861', (139, 153))	('biosynthesis', 'biological_process', 'GO:0009058', ('42', '54'))	('GSH', 'Chemical', 'MESH:D005978', (38, 41))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Disease', (190, 193))	('glutathione', 'Chemical', 'MESH:D005978', (66, 77))	('GSH', 'Chemical', 'MESH:D005978', (107, 110))	('glutathione peroxidases', 'Enzyme', (66, 89))	('reduced', 'NegReg', (167, 174))	('silencing', 'Var', (10, 19))
133144	29872221	Inhibition of GSH synthesis triggered ferroptosis, an iron-dependent form of cell death associated with enhanced lipid peroxidation.	('lipid', 'Chemical', 'MESH:D008055', (113, 118))	('ferroptosis', 'biological_process', 'GO:0097707', ('38', '49'))	('GSH synthesis', 'Gene', (14, 27))	('GSH', 'Chemical', 'MESH:D005978', (14, 17))	('ferroptosis', 'Disease', (38, 49))	('enhanced', 'PosReg', (104, 112))	('enhanced lipid peroxidation', 'Phenotype', 'HP:0025464', (104, 131))	('lipid peroxidation', 'MPA', (113, 131))	('Inhibition', 'Var', (0, 10))	('iron', 'Chemical', 'MESH:D007501', (54, 58))	('cell death', 'biological_process', 'GO:0008219', ('77', '87'))	('synthesis', 'biological_process', 'GO:0009058', ('18', '27'))
133145	29872221	VHL is a major tumour suppressor in ccRCC and loss of VHL leads to stabilisation of hypoxia inducible factors HIF-1alpha and HIF-2alpha.	('hypoxia', 'Disease', (84, 91))	('RCC', 'Disease', (38, 41))	('hypoxia', 'Disease', 'MESH:D000860', (84, 91))	('stabilisation', 'MPA', (67, 80))	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('VHL', 'Gene', (54, 57))	('tumour', 'Disease', (15, 21))	('loss', 'Var', (46, 50))	('VHL', 'Gene', '7428', (54, 57))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (110, 135))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
133148	29872221	Importantly, inhibition of beta-oxidation or mitochondrial ATP-synthesis restored ferroptosis sensitivity in VHL reconstituted cells.	('ferroptosis sensitivity', 'MPA', (82, 105))	('ATP-synthesis', 'biological_process', 'GO:0006754', ('59', '72'))	('inhibition', 'Var', (13, 23))	('ATP', 'Chemical', 'MESH:D000255', (59, 62))	('VHL', 'Gene', (109, 112))	('restored', 'PosReg', (73, 81))	('VHL', 'Gene', '7428', (109, 112))	('ferroptosis', 'biological_process', 'GO:0097707', ('82', '93'))
133149	29872221	We also found that inhibition of GSH synthesis blocked tumour growth in a MYC-dependent mouse model of renal cancer.	('inhibition', 'Var', (19, 29))	('renal cancer', 'Disease', (103, 115))	('renal cancer', 'Phenotype', 'HP:0009726', (103, 115))	('GSH', 'Protein', (33, 36))	('blocked', 'NegReg', (47, 54))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour growth', 'Disease', (55, 68))	('renal cancer', 'Disease', 'MESH:D007680', (103, 115))	('GSH', 'Chemical', 'MESH:D005978', (33, 36))	('mouse', 'Species', '10090', (88, 93))	('tumour growth', 'Disease', 'MESH:D006130', (55, 68))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('synthesis', 'biological_process', 'GO:0009058', ('37', '46'))
133152	29872221	Clear cell renal cell carcinoma (ccRCC) is the most common type of RCC and both hereditary and sporadic ccRCC are strongly associated with mutations in the von Hippel Lindau (VHL) gene that lead to the stabilisation of the hypoxia inducible factors (HIF-1alpha and HIF-2alpha).	('RCC', 'Disease', (67, 70))	('stabilisation', 'MPA', (202, 215))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('VHL', 'Gene', '7428', (175, 178))	('von Hippel Lindau', 'Disease', (156, 173))	('RCC', 'Disease', (35, 38))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('RCC', 'Disease', (106, 109))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (250, 275))	('hypoxia', 'Disease', (223, 230))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('von Hippel Lindau', 'Disease', 'MESH:D006623', (156, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('hypoxia', 'Disease', 'MESH:D000860', (223, 230))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('associated', 'Reg', (123, 133))	('mutations', 'Var', (139, 148))	('VHL', 'Gene', (175, 178))
133156	29872221	There is now substantial evidence that oncogene activation provokes oxidative stress but also induces anti-oxidant pathways to prevent the accumulation of ROS and avoid cell damage.	('anti-oxidant pathways', 'Pathway', (102, 123))	('oxidative stress', 'Phenotype', 'HP:0025464', (68, 84))	('oncogene', 'Protein', (39, 47))	('prevent', 'NegReg', (127, 134))	('activation', 'Var', (48, 58))	('ROS', 'Chemical', 'MESH:D017382', (155, 158))	('oxidative stress', 'MPA', (68, 84))	('induces', 'Reg', (94, 101))	('accumulation', 'MPA', (139, 151))	('ROS', 'MPA', (155, 158))
133160	29872221	Impaired GSH synthesis or inhibition of GPX4 activity has been linked to the induction of ferroptosis, an iron-mediated form of cell death caused by the accumulation of lipid peroxides.	('activity', 'MPA', (45, 53))	('iron', 'Chemical', 'MESH:D007501', (106, 110))	('GPX4', 'Gene', '2879', (40, 44))	('lipid peroxides', 'Chemical', 'MESH:D008054', (169, 184))	('GSH', 'Protein', (9, 12))	('inhibition', 'NegReg', (26, 36))	('GSH', 'Chemical', 'MESH:D005978', (9, 12))	('ferroptosis', 'Disease', (90, 101))	('synthesis', 'biological_process', 'GO:0009058', ('13', '22'))	('ferroptosis', 'biological_process', 'GO:0097707', ('90', '101'))	('cell death', 'biological_process', 'GO:0008219', ('128', '138'))	('Impaired', 'Var', (0, 8))	('GPX4', 'Gene', (40, 44))
133163	29872221	Moreover, reconstitution of functional VHL prevented the induction of ferroptosis in response to inhibition of GSH synthesis in ccRCC cells, by reverting cells back to an oxidative metabolism and increasing fatty acid degradation through beta-oxidation.	('synthesis', 'biological_process', 'GO:0009058', ('115', '124'))	('inhibition', 'NegReg', (97, 107))	('VHL', 'Gene', (39, 42))	('oxidative metabolism', 'MPA', (171, 191))	('GSH', 'Chemical', 'MESH:D005978', (111, 114))	('fatty acid degradation', 'biological_process', 'GO:0009062', ('207', '229'))	('beta-oxidation', 'MPA', (238, 252))	('VHL', 'Gene', '7428', (39, 42))	('RCC', 'Disease', (130, 133))	('increasing', 'PosReg', (196, 206))	('oxidative metabolism', 'biological_process', 'GO:0045333', ('171', '191'))	('reverting', 'Reg', (144, 153))	('GSH', 'Protein', (111, 114))	('fatty acid', 'Chemical', 'MESH:D005227', (207, 217))	('ferroptosis', 'Disease', (70, 81))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('prevented', 'NegReg', (43, 52))	('reconstitution', 'Var', (10, 24))	('ferroptosis', 'biological_process', 'GO:0097707', ('70', '81'))	('fatty acid degradation', 'MPA', (207, 229))
133164	29872221	We also found that inhibition of GSH biosynthesis efficiently blocked tumour growth in a mouse model of renal cancer.	('inhibition', 'Var', (19, 29))	('renal cancer', 'Disease', (104, 116))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('biosynthesis', 'biological_process', 'GO:0009058', ('37', '49'))	('tumour growth', 'Disease', (70, 83))	('GSH', 'Protein', (33, 36))	('renal cancer', 'Disease', 'MESH:D007680', (104, 116))	('renal cancer', 'Phenotype', 'HP:0009726', (104, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumour growth', 'Disease', 'MESH:D006130', (70, 83))	('GSH', 'Chemical', 'MESH:D005978', (33, 36))	('blocked', 'NegReg', (62, 69))	('mouse', 'Species', '10090', (89, 94))
133180	29872221	Interestingly, silencing of SLC1A5, SLC7A11, glutathione reductase (GSR), glutaminase (GLS), GCLC and glutathione synthase (GSS) resulted in a strong reduction in cell number in several ccRCC cell lines (Fig.	('GCLC', 'Gene', (93, 97))	('glutaminase', 'Gene', (74, 85))	('silencing', 'Var', (15, 24))	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('glutathione reductase', 'Gene', (45, 66))	('SLC1A5', 'Gene', (28, 34))	('GLS', 'Gene', (87, 90))	('GSS', 'Gene', (124, 127))	('glutathione synthase', 'Gene', '2937', (102, 122))	('cell number', 'CPA', (163, 174))	('glutathione reductase', 'Gene', '2936', (45, 66))	('GCLC', 'Gene', '2729', (93, 97))	('SLC7A11', 'Gene', (36, 43))	('glutaminase', 'Gene', '2744', (74, 85))	('SLC1A5', 'Gene', '6510', (28, 34))	('RCC', 'Disease', (188, 191))	('reduction', 'NegReg', (150, 159))	('GSS', 'Gene', '2937', (124, 127))	('GLS', 'Gene', '2744', (87, 90))	('glutathione synthase', 'Gene', (102, 122))
133187	29872221	In addition, we found that silencing of DHCR24, the gene coding for an enzyme in the cholesterol biosynthesis pathway, also reduced cell numbers in renal cancer cells (Fig.	('DHCR24', 'Gene', '1718', (40, 46))	('silencing', 'Var', (27, 36))	('reduced', 'NegReg', (124, 131))	('cholesterol', 'Chemical', 'MESH:D002784', (85, 96))	('cell numbers in', 'CPA', (132, 147))	('cholesterol biosynthesis', 'biological_process', 'GO:0006695', ('85', '109'))	('renal cancer', 'Disease', (148, 160))	('renal cancer', 'Disease', 'MESH:D007680', (148, 160))	('renal cancer', 'Phenotype', 'HP:0009726', (148, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('DHCR24', 'Gene', (40, 46))
133193	29872221	Finally, silencing of G6PD, the gene coding for the first NADPH producing enzyme within the pentose phosphate pathway (PPP), was also detrimental to most ccRCC cell lines (Fig.	('G6PD', 'Gene', (22, 26))	('silencing', 'Var', (9, 18))	('NADPH', 'Chemical', 'MESH:D009249', (58, 63))	('RCC', 'Disease', (156, 159))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('detrimental', 'NegReg', (134, 145))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('92', '117'))	('pentose phosphate', 'Chemical', 'MESH:D010428', (92, 109))	('G6PD', 'Gene', '2539', (22, 26))
133196	29872221	We also confirmed the screen results by showing that individual silencing of MYC, G6PD, DHCR24, GPX3 and GPX4 significantly reduces cell numbers in several renal cancer cell lines (Fig.	('GPX4', 'Gene', '2879', (105, 109))	('G6PD', 'Gene', '2539', (82, 86))	('cell numbers in several', 'CPA', (132, 155))	('G6PD', 'Gene', (82, 86))	('reduces', 'NegReg', (124, 131))	('GPX3', 'Gene', (96, 100))	('GPX3', 'Gene', '2878', (96, 100))	('MYC', 'Gene', (77, 80))	('DHCR24', 'Gene', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('renal cancer', 'Disease', (156, 168))	('silencing', 'Var', (64, 73))	('renal cancer', 'Disease', 'MESH:D007680', (156, 168))	('renal cancer', 'Phenotype', 'HP:0009726', (156, 168))	('DHCR24', 'Gene', '1718', (88, 94))	('GPX4', 'Gene', (105, 109))
133199	29872221	The results obtained so far indicate that ccRCC cells are highly sensitive to the disruption of the GSH biosynthesis and regeneration pathway or depletion of specific GPX enzymes.	('GSH', 'Chemical', 'MESH:D005978', (100, 103))	('GSH', 'Pathway', (100, 103))	('depletion', 'MPA', (145, 154))	('disruption', 'Var', (82, 92))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('RCC', 'Disease', (44, 47))	('regeneration', 'biological_process', 'GO:0031099', ('121', '133'))	('GPX enzymes', 'Enzyme', (167, 178))	('biosynthesis', 'biological_process', 'GO:0009058', ('104', '116'))
133200	29872221	Inhibition of cystine uptake or inhibition of GPX4 has been linked to ferroptosis, caused by the accumulation of lipid hydroperoxides ( and Fig.	('cystine uptake', 'MPA', (14, 28))	('cystine', 'Chemical', 'MESH:D003553', (14, 21))	('inhibition', 'NegReg', (32, 42))	('uptake', 'biological_process', 'GO:0098739', ('22', '28'))	('ferroptosis', 'biological_process', 'GO:0097707', ('70', '81'))	('accumulation', 'PosReg', (97, 109))	('lipid hydroperoxides', 'Chemical', 'MESH:D008054', (113, 133))	('uptake', 'biological_process', 'GO:0098657', ('22', '28'))	('ferroptosis', 'Disease', (70, 81))	('Inhibition', 'Var', (0, 10))	('GPX4', 'Gene', (46, 50))	('lipid hydroperoxides', 'MPA', (113, 133))	('GPX4', 'Gene', '2879', (46, 50))	('linked', 'Reg', (60, 66))
133216	29872221	We also observed a strong upregulation of basal and maximal respiration as well as enhanced spare capacity and mitochondrial ATP production, which is consistent with a reversal of the glycolytic phenotype that is established by HIF and AKT activation in VHL mutant renal cancer cells (Fig.	('maximal respiration', 'MPA', (52, 71))	('upregulation', 'PosReg', (26, 38))	('AKT', 'Gene', (236, 239))	('ATP', 'Chemical', 'MESH:D000255', (125, 128))	('VHL', 'Gene', '7428', (254, 257))	('renal cancer', 'Disease', (265, 277))	('respiration', 'biological_process', 'GO:0007585', ('60', '71'))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('renal cancer', 'Phenotype', 'HP:0009726', (265, 277))	('respiration', 'biological_process', 'GO:0045333', ('60', '71'))	('activation', 'PosReg', (240, 250))	('AKT', 'Gene', '207', (236, 239))	('renal cancer', 'Disease', 'MESH:D007680', (265, 277))	('spare capacity', 'MPA', (92, 106))	('mutant', 'Var', (258, 264))	('enhanced', 'PosReg', (83, 91))	('basal', 'MPA', (42, 47))	('mitochondrial ATP production', 'MPA', (111, 139))	('VHL', 'Gene', (254, 257))
133256	29872221	Inactivation of VHL is a crucial event in the development of sporadic ccRCC.	('VHL', 'Gene', (16, 19))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('VHL', 'Gene', '7428', (16, 19))	('Inactivation', 'Var', (0, 12))
133258	29872221	We therefore expanded our panel of renal cancer cell lines to include three additional VHL mutant cell lines as well as four lines that retain functional VHL.	('VHL', 'Gene', '7428', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('renal cancer', 'Disease', (35, 47))	('renal cancer', 'Phenotype', 'HP:0009726', (35, 47))	('VHL', 'Gene', (154, 157))	('mutant', 'Var', (91, 97))	('renal cancer', 'Disease', 'MESH:D007680', (35, 47))	('VHL', 'Gene', '7428', (154, 157))	('VHL', 'Gene', (87, 90))
133260	29872221	As expected, VHL mutant cell lines showed high normoxic levels of either HIF-2alpha alone (786-O and 769-P) or both HIF-1alpha and HIF-2alpha, while VHL wild type cells display low to undetectable levels of these proteins (Fig.	('VHL', 'Gene', '7428', (149, 152))	('HIF-2alpha', 'Gene', (131, 141))	('HIF-2alpha', 'Gene', (73, 83))	('normoxic levels', 'MPA', (47, 62))	('HIF-2alpha', 'Gene', '2034', (131, 141))	('HIF-2alpha', 'Gene', '2034', (73, 83))	('VHL', 'Gene', (13, 16))	('VHL', 'Gene', (149, 152))	('VHL', 'Gene', '7428', (13, 16))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (116, 141))	('mutant', 'Var', (17, 23))
133261	29872221	VHL mutant cells also showed higher levels of AKT phosphorylation compared to wild type cells.	('higher', 'PosReg', (29, 35))	('AKT', 'Gene', '207', (46, 49))	('mutant', 'Var', (4, 10))	('AKT', 'Gene', (46, 49))	('VHL', 'Gene', (0, 3))	('phosphorylation', 'biological_process', 'GO:0016310', ('50', '65'))	('VHL', 'Gene', '7428', (0, 3))
133262	29872221	In contrast, VHL wild type cells expressed higher levels of the MYC oncoprotein compared to VHL mutant lines while non-malignant HK-2 cells showed high levels of HIF-1alpha, MYC and phospho-AKT, most likely due to the culture medium containing added growth factors (Fig.	('HK-2', 'molecular_function', 'GO:0008256', ('129', '133'))	('mutant', 'Var', (96, 102))	('higher', 'PosReg', (43, 49))	('HIF-1alpha', 'Gene', (162, 172))	('AKT', 'Gene', '207', (190, 193))	('HIF-1alpha', 'Gene', '3091', (162, 172))	('VHL', 'Gene', (92, 95))	('VHL', 'Gene', (13, 16))	('MYC oncoprotein', 'MPA', (64, 79))	('levels', 'MPA', (50, 56))	('HK-2', 'CellLine', 'CVCL:0302', (129, 133))	('VHL', 'Gene', '7428', (92, 95))	('AKT', 'Gene', (190, 193))	('VHL', 'Gene', '7428', (13, 16))	('MYC', 'MPA', (174, 177))
133264	29872221	Moreover, no difference in the sensitivity between VHL wild type and mutant cell lines towards inhibitors of glutaminolysis (BPTES) or GSH synthesis (BSO) was detected (Fig.	('VHL', 'Gene', '7428', (51, 54))	('glutaminolysis', 'Protein', (109, 123))	('mutant', 'Var', (69, 75))	('GSH synthesis', 'MPA', (135, 148))	('BSO', 'Chemical', '-', (150, 153))	('GSH', 'Chemical', 'MESH:D005978', (135, 138))	('BPTES', 'Chemical', '-', (125, 130))	('VHL', 'Gene', (51, 54))	('synthesis', 'biological_process', 'GO:0009058', ('139', '148'))
133265	29872221	In addition, silencing of components of the GSH synthesis pathway as well as MYC, DHCR24, GPX3 or GPX4 also reduced the viability of most ccRCC cells (Fig.	('GPX4', 'Gene', (98, 102))	('GPX4', 'Gene', '2879', (98, 102))	('DHCR24', 'Gene', (82, 88))	('reduced', 'NegReg', (108, 115))	('DHCR24', 'Gene', '1718', (82, 88))	('RCC', 'Disease', (140, 143))	('MYC', 'Gene', (77, 80))	('GPX3', 'Gene', '2878', (90, 94))	('GSH', 'Chemical', 'MESH:D005978', (44, 47))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('GPX3', 'Gene', (90, 94))	('synthesis', 'biological_process', 'GO:0009058', ('48', '57'))	('silencing', 'Var', (13, 22))
133267	29872221	These results also suggest that this dependency represents a general metabolic liability in this tumour type and can be induced not only through inactivation of VHL but also as a consequence of other oncogenic pathways, such as MYC activation.	('tumour type', 'Disease', 'MESH:D009369', (97, 108))	('VHL', 'Gene', (161, 164))	('inactivation', 'Var', (145, 157))	('VHL', 'Gene', '7428', (161, 164))	('tumour type', 'Disease', (97, 108))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))
133275	29872221	Moreover, we found that inhibition of GSH synthesis interferes with renal tumour growth and restores normal renal tissue morphology.	('GSH', 'Protein', (38, 41))	('renal', 'MPA', (108, 113))	('GSH', 'Chemical', 'MESH:D005978', (38, 41))	('interferes', 'NegReg', (52, 62))	('synthesis', 'biological_process', 'GO:0009058', ('42', '51'))	('renal tumour growth', 'Disease', (68, 87))	('renal tumour growth', 'Disease', 'MESH:D007680', (68, 87))	('restores', 'PosReg', (92, 100))	('inhibition', 'Var', (24, 34))	('renal tumour', 'Phenotype', 'HP:0009726', (68, 80))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
133277	29872221	Here we show that ccRCC cells are highly susceptible to disruption of the GSH/GPX pathway, which prevents the accumulation of ROS, including lipid peroxides.	('lipid peroxides', 'Chemical', 'MESH:D008054', (141, 156))	('lipid peroxides', 'MPA', (141, 156))	('ROS', 'Chemical', 'MESH:D017382', (126, 129))	('GSH', 'Chemical', 'MESH:D005978', (74, 77))	('accumulation', 'MPA', (110, 122))	('disruption', 'Var', (56, 66))	('GSH/GPX pathway', 'Pathway', (74, 89))	('ROS', 'MPA', (126, 129))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('prevents', 'NegReg', (97, 105))	('RCC', 'Disease', (20, 23))
133283	29872221	Moreover, molecular characterisation of genetic and transcriptional alterations in ccRCC confirmed the strong association between deregulated glycolysis and patient survival in this disease.	('patient', 'Species', '9606', (157, 164))	('deregulated glycolysis', 'MPA', (130, 152))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', (85, 88))	('alterations', 'Var', (68, 79))	('glycolysis', 'biological_process', 'GO:0006096', ('142', '152'))
133293	29872221	We found that the lipid-antioxidant ferrostatin protected VHL-deficient renal cancer cells over a range of different doses of Erastin or BSO treatment, confirming that cell death induced by inhibition of GSH biosynthesis involves a ferroptotic mechanism.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('lipid', 'Chemical', 'MESH:D008055', (18, 23))	('ferrostatin', 'Chemical', '-', (36, 47))	('VHL-deficient renal cancer', 'Disease', (58, 84))	('GSH', 'Chemical', 'MESH:D005978', (204, 207))	('renal cancer', 'Phenotype', 'HP:0009726', (72, 84))	('biosynthesis', 'biological_process', 'GO:0009058', ('208', '220'))	('Erastin', 'Chemical', 'MESH:C477224', (126, 133))	('BSO', 'Chemical', '-', (137, 140))	('cell death', 'biological_process', 'GO:0008219', ('168', '178'))	('VHL-deficient renal cancer', 'Disease', 'MESH:D007680', (58, 84))	('inhibition', 'Var', (190, 200))
133301	29872221	Although we did not observe major differences in fatty acid composition between VHL-mutant and VHL-restored cells, we found that pVHL expression reduced the amount of LDs, the major storage organelle for neutral lipids, including triacylglycerides and cholesterol.	('reduced', 'NegReg', (145, 152))	('VHL', 'Gene', (80, 83))	('VHL', 'Gene', '7428', (95, 98))	('lipids', 'Chemical', 'MESH:D008055', (212, 218))	('storage', 'biological_process', 'GO:0051235', ('182', '189'))	('LDs', 'MPA', (167, 170))	('VHL', 'Gene', '7428', (80, 83))	('triacylglycerides', 'Chemical', '-', (230, 247))	('fatty acid', 'Chemical', 'MESH:D005227', (49, 59))	('triacylglycerides', 'MPA', (230, 247))	('cholesterol', 'Chemical', 'MESH:D002784', (252, 263))	('VHL', 'Gene', (130, 133))	('pVHL', 'Gene', '7428', (129, 133))	('pVHL', 'Gene', (129, 133))	('cholesterol', 'MPA', (252, 263))	('amount', 'MPA', (157, 163))	('VHL', 'Gene', (95, 98))	('organelle', 'cellular_component', 'GO:0043226', ('190', '199'))	('expression', 'Var', (134, 144))	('VHL', 'Gene', '7428', (130, 133))
133304	29872221	Induction of ALOX5 in renal cancer would increase the production of pro-inflammatory leukotrienes.	('renal cancer', 'Phenotype', 'HP:0009726', (22, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('renal cancer', 'Disease', 'MESH:D007680', (22, 34))	('production of pro-inflammatory leukotrienes', 'MPA', (54, 97))	('ALOX5', 'Gene', (13, 18))	('leukotrienes', 'Chemical', 'MESH:D015289', (85, 97))	('ALOX5', 'Gene', '240', (13, 18))	('renal cancer', 'Disease', (22, 34))	('increase', 'PosReg', (41, 49))	('Induction', 'Var', (0, 9))
133306	29872221	Somewhat surprisingly, we did not observe major differences in the sensitivity towards nutrient restriction or inhibition of GSH synthesis between VHL wild type and mutant ccRCC cell lines.	('mutant', 'Var', (165, 171))	('GSH', 'Chemical', 'MESH:D005978', (125, 128))	('VHL', 'Gene', (147, 150))	('RCC', 'Disease', (174, 177))	('VHL', 'Gene', '7428', (147, 150))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('synthesis', 'biological_process', 'GO:0009058', ('129', '138'))
133309	29872221	MYC also induces widespread metabolic reprogramming in cancer cells, including activation of glucose and glutamine metabolism and increased lipid synthesis.	('lipid', 'Chemical', 'MESH:D008055', (140, 145))	('MYC', 'Var', (0, 3))	('glucose', 'Chemical', 'MESH:D005947', (93, 100))	('increased lipid', 'Phenotype', 'HP:0003077', (130, 145))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lipid synthesis', 'MPA', (140, 155))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('105', '125'))	('lipid synthesis', 'biological_process', 'GO:0008610', ('140', '155'))	('glutamine', 'Chemical', 'MESH:D005973', (105, 114))	('activation', 'PosReg', (79, 89))	('increased', 'PosReg', (130, 139))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('induces', 'Reg', (9, 16))	('metabolic reprogramming', 'CPA', (28, 51))	('cancer', 'Disease', (55, 61))
133316	29872221	Finally, our study demonstrates that inhibition of GSH biosynthesis by the gamma-cysteine synthetase inhibitor BSO attenuates tumour formation in a MYC-dependent mouse model of renal carcinogenesis.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('inhibition', 'Var', (37, 47))	('GSH', 'Chemical', 'MESH:D005978', (51, 54))	('formation', 'biological_process', 'GO:0009058', ('133', '142'))	('BSO', 'Chemical', '-', (111, 114))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('mouse', 'Species', '10090', (162, 167))	('attenuates', 'NegReg', (115, 125))	('tumour', 'Disease', (126, 132))	('cysteine', 'Chemical', 'MESH:D003545', (81, 89))	('renal carcinogenesis', 'Disease', (177, 197))	('biosynthesis', 'biological_process', 'GO:0009058', ('55', '67'))	('renal carcinogenesis', 'Disease', 'MESH:D007674', (177, 197))
133317	29872221	Interestingly, we found that BSO caused a reduction in tumour growth when delivered before tumour onset.	('tumour', 'Disease', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('tumour', 'Disease', (91, 97))	('BSO', 'Chemical', '-', (29, 32))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour growth', 'Disease', (55, 68))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('tumour growth', 'Disease', 'MESH:D006130', (55, 68))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('reduction', 'NegReg', (42, 51))	('BSO', 'Var', (29, 32))
133319	29872221	Overall, the results presented here demonstrate that renal cancer cells are highly dependent on the GSH pathway for the detoxification of reactive oxygen radicals, including lipid peroxides, and suggest that targeting components of this pathway could be an effective strategy for the treatment of this disease.	('targeting', 'Var', (208, 217))	('renal cancer', 'Disease', 'MESH:D007680', (53, 65))	('GSH', 'Chemical', 'MESH:D005978', (100, 103))	('reactive oxygen radicals', 'Chemical', '-', (138, 162))	('detoxification', 'biological_process', 'GO:0098754', ('120', '134'))	('detoxification of reactive oxygen radicals', 'MPA', (120, 162))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('lipid peroxides', 'Chemical', 'MESH:D008054', (174, 189))	('renal cancer', 'Disease', (53, 65))	('GSH pathway', 'Pathway', (100, 111))	('renal cancer', 'Phenotype', 'HP:0009726', (53, 65))
133320	29872221	RCC4, UMRC2, A498, 786-O, 769-P, CAKI1, CAKI2, TK10, A704, UMRC3, ACHN and UO31 cells as well as the non-tumorigenic proximal tubular HK-2 cell line were obtained from Cell Services (CRUK-LRI).	('RCC4', 'Gene', (0, 4))	('RCC4', 'Gene', '84925', (0, 4))	('A704', 'Var', (53, 57))	('UO31', 'CellLine', 'CVCL:1911', (75, 79))	('HK-2', 'molecular_function', 'GO:0008256', ('134', '138'))	('UMRC2', 'CellLine', 'CVCL:2739', (6, 11))	('HK-2', 'CellLine', 'CVCL:0302', (134, 138))
133329	29872221	The next day, cells were washed with PBS before adding full medium or medium lacking glutamine or cystine, containing either solvent or GSH, NAC, L-cysteine or TEMPO, as indicated.	('glutamine', 'MPA', (85, 94))	('GSH', 'Chemical', 'MESH:D005978', (136, 139))	('PBS', 'Chemical', 'MESH:D007854', (37, 40))	('L-cysteine', 'Var', (146, 156))	('L-cysteine', 'Chemical', 'MESH:D003545', (146, 156))	('TEMPO', 'Chemical', '-', (160, 165))	('NAC', 'cellular_component', 'GO:0005854', ('141', '144'))	('glutamine', 'Chemical', 'MESH:D005973', (85, 94))	('cystine', 'Chemical', 'MESH:D003553', (98, 105))	('NAC', 'Chemical', 'MESH:D000111', (141, 144))
133377	28242813	Recent evidence suggests that VCAN is an important target of chromosomal 5q gain, one of the most prevalent genetic abnormalities in ccRCC.	('genetic abnormalities', 'Disease', (108, 129))	('chromosomal 5q', 'Var', (61, 75))	('VCAN', 'Gene', (30, 34))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))	('gain', 'PosReg', (76, 80))	('VCAN', 'Gene', '1462', (30, 34))	('genetic abnormalities', 'Disease', 'MESH:D030342', (108, 129))
133384	28242813	In vitro, VCAN knockdown significantly decreased cell proliferation and increased apoptosis in Caki-2 and 786-O cells, and this was associated with alteration of several TNF signaling-related genes such as TNF-alpha, BID, and BAK.	('TNF-alpha', 'Gene', '7124', (206, 215))	('VCAN', 'Gene', (10, 14))	('BID', 'Gene', (217, 220))	('TNF-alpha', 'Gene', (206, 215))	('TNF', 'Gene', (170, 173))	('BID', 'Gene', '637', (217, 220))	('alteration', 'Reg', (148, 158))	('cell proliferation', 'CPA', (49, 67))	('decreased', 'NegReg', (39, 48))	('TNF', 'Gene', '7124', (170, 173))	('TNF', 'Gene', (206, 209))	('apoptosis', 'CPA', (82, 91))	('signaling', 'biological_process', 'GO:0023052', ('174', '183'))	('BAK', 'Gene', (226, 229))	('increased', 'PosReg', (72, 81))	('knockdown', 'Var', (15, 24))	('TNF', 'Gene', '7124', (206, 209))	('BAK', 'Gene', '578', (226, 229))	('cell proliferation', 'biological_process', 'GO:0008283', ('49', '67'))	('VCAN', 'Gene', '1462', (10, 14))	('apoptosis', 'biological_process', 'GO:0097194', ('82', '91'))	('apoptosis', 'biological_process', 'GO:0006915', ('82', '91'))
133385	28242813	Furthermore, VCAN depletion markedly decreased cell migration and invasion which correlated with reduction of MMP7 and CXCR4.	('reduction', 'NegReg', (97, 106))	('VCAN', 'Gene', (13, 17))	('cell migration', 'biological_process', 'GO:0016477', ('47', '61'))	('CXCR4', 'Gene', '7852', (119, 124))	('VCAN', 'Gene', '1462', (13, 17))	('MMP7', 'molecular_function', 'GO:0004235', ('110', '114'))	('MMP7', 'Gene', (110, 114))	('depletion', 'Var', (18, 27))	('CXCR4', 'Gene', (119, 124))	('MMP7', 'Gene', '4316', (110, 114))	('decreased', 'NegReg', (37, 46))	('CXCR4', 'molecular_function', 'GO:0038147', ('119', '124'))
133390	28242813	The discovery that somatic mutations of tumor suppressor von-Hippel Lindau (VHL) gene, located at 3p25.3, occur in about 90% of sporadic ccRCCs led to the development of new therapies targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) genes against advanced ccRCC.	('mutations', 'Var', (27, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (304, 309))	('von-Hippel Lindau', 'Disease', 'MESH:D006623', (57, 74))	('vascular endothelial growth factor', 'Gene', '7422', (198, 232))	('VEGF', 'Gene', '7422', (234, 238))	('von-Hippel Lindau', 'Disease', (57, 74))	('mammalian target of rapamycin', 'Gene', '2475', (244, 273))	('VHL', 'Disease', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('VEGF', 'Gene', (234, 238))	('vascular endothelial growth factor', 'Gene', (198, 232))	('RCC', 'Phenotype', 'HP:0005584', (306, 309))	('RCC', 'Disease', (306, 309))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('198', '232'))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('RCC', 'Disease', (139, 142))	('mammalian target of rapamycin', 'Gene', (244, 273))	('RCC', 'Disease', 'MESH:C538614', (306, 309))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('VHL', 'Disease', 'MESH:D006623', (76, 79))	('tumor', 'Disease', (40, 45))	('mTOR', 'Gene', (275, 279))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor suppressor', 'biological_process', 'GO:0051726', ('40', '56'))	('mTOR', 'Gene', '2475', (275, 279))
133392	28242813	Cytogenetic studies have revealed that sporadic ccRCC has characteristic chromosomal losses and gains such as loss of 3p (60%) and gain of 5q (33%) that are the most prevalent genetic abnormalities for this cancer.	('gains', 'PosReg', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('loss', 'Var', (110, 114))	('cancer', 'Disease', (207, 213))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('RCC', 'Disease', (50, 53))	('losses', 'NegReg', (85, 91))	('gain', 'PosReg', (131, 135))	('genetic abnormalities', 'Disease', 'MESH:D030342', (176, 197))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('genetic abnormalities', 'Disease', (176, 197))
133459	28242813	Forty-two patients with high VCAN expression among the 84 patients with ccRCC had a significantly worse 5-year OS probability than those with low expression (P=0.0139).	('VCAN', 'Gene', '1462', (29, 33))	('5-year OS probability', 'CPA', (104, 125))	('RCC', 'Disease', (74, 77))	('expression', 'Var', (34, 44))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('VCAN', 'Gene', (29, 33))	('high', 'Var', (24, 28))	('patients', 'Species', '9606', (10, 18))	('patients', 'Species', '9606', (58, 66))	('worse', 'NegReg', (98, 103))
133465	28242813	We thus examined whether VCAN knockdown affects the growth of ccRCC cells using two different VCAN siRNAs.	('VCAN', 'Gene', (25, 29))	('RCC', 'Disease', (64, 67))	('VCAN', 'Gene', (94, 98))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('VCAN', 'Gene', '1462', (25, 29))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('growth', 'MPA', (52, 58))	('knockdown', 'Var', (30, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('VCAN', 'Gene', '1462', (94, 98))
133467	28242813	As shown in Figure 2A, significant reduction of VCAN protein was observed in both cell lines after transfection with VCAN siRNAs.	('transfection', 'Var', (99, 111))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('VCAN', 'Gene', (48, 52))	('VCAN', 'Gene', (117, 121))	('VCAN', 'Gene', '1462', (117, 121))	('VCAN', 'Gene', '1462', (48, 52))	('reduction', 'NegReg', (35, 44))
133468	28242813	MTS assay showed that knockdown of VCAN caused significant inhibition of cell proliferation in both cell lines in a time-dependent manner as compared with controls (Figure 2B).	('inhibition', 'NegReg', (59, 69))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('59', '91'))	('cell proliferation in', 'CPA', (73, 94))	('knockdown', 'Var', (22, 31))	('VCAN', 'Gene', (35, 39))	('VCAN', 'Gene', '1462', (35, 39))
133470	28242813	As shown in Figure 2C, the early apoptotic and apoptotic fractions (lower right and upper right quadrants of biparametric histograms, respectively) were significantly greater in VCAN-depleted Caki-2 (2.35% + 5.36%) and 786-O (3.26% + 5.54%) cells compared to control Caki-2 (1.27% + 2.36%) and 786-O (0.94% + 0.90%) cells after 72 hours of treatment (total apoptosis, P<0.001 for both cell lines).	('greater', 'PosReg', (167, 174))	('apoptotic fractions', 'CPA', (47, 66))	('VCAN', 'Gene', (178, 182))	('apoptosis', 'biological_process', 'GO:0097194', ('357', '366'))	('apoptosis', 'biological_process', 'GO:0006915', ('357', '366'))	('Caki-2', 'Var', (192, 198))	('VCAN', 'Gene', '1462', (178, 182))
133475	28242813	In addition, matrigel invasion assay demonstrated that the number of invading cells was significantly decreased in VCAN siRNA transfectants compared with their control counterparts (Figure 3B).	('VCAN', 'Gene', '1462', (115, 119))	('matrigel invasion assay', 'CPA', (13, 36))	('transfectants', 'Var', (126, 139))	('VCAN', 'Gene', (115, 119))	('decreased', 'NegReg', (102, 111))
133482	28242813	As shown in Figure 4C, VCAN knockdown also caused an increase in cleaved Caspase-8, 9, 3, and cleaved BID in both Caki-2 and 786-O cells.	('Caspase-8', 'Gene', (73, 82))	('VCAN', 'Gene', '1462', (23, 27))	('BID', 'Gene', '637', (102, 105))	('increase', 'PosReg', (53, 61))	('cleaved', 'MPA', (65, 72))	('knockdown', 'Var', (28, 37))	('VCAN', 'Gene', (23, 27))	('BID', 'Gene', (102, 105))	('Caspase-8', 'Gene', '841', (73, 82))
133483	28242813	Our data thus indicates that attenuation of VCAN expression inhibits cell viability via induction of TNF signaling-mediated apoptosis in ccRCC.	('VCAN', 'Gene', '1462', (44, 48))	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('TNF', 'Gene', (101, 104))	('attenuation', 'Var', (29, 40))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('RCC', 'Disease', (139, 142))	('cell viability', 'CPA', (69, 83))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('inhibits', 'NegReg', (60, 68))	('TNF', 'Gene', '7124', (101, 104))	('VCAN', 'Gene', (44, 48))
133485	28242813	Figure 5A shows genes that were diminished two-fold or greater after VCAN knockdown using a tumor metastasis-related gene array.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('VCAN', 'Gene', (69, 73))	('tumor', 'Disease', (92, 97))	('knockdown', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('VCAN', 'Gene', '1462', (69, 73))	('diminished', 'NegReg', (32, 42))
133487	28242813	Thus these data indicate that attenuation of VCAN inhibits ccRCC cell migration and invasion via downregulation of MMP7 and CXCR4.	('MMP7', 'Gene', '4316', (115, 119))	('invasion', 'CPA', (84, 92))	('MMP7', 'molecular_function', 'GO:0004235', ('115', '119'))	('VCAN', 'Gene', (45, 49))	('CXCR4', 'Gene', (124, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('attenuation', 'Var', (30, 41))	('VCAN', 'Gene', '1462', (45, 49))	('inhibits', 'NegReg', (50, 58))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('cell migration', 'biological_process', 'GO:0016477', ('65', '79'))	('MMP7', 'Gene', (115, 119))	('CXCR4', 'Gene', '7852', (124, 129))	('downregulation', 'NegReg', (97, 111))	('CXCR4', 'molecular_function', 'GO:0038147', ('124', '129'))
133496	28242813	Dysregulation of the balance between cellular proliferation and apoptosis is a major factor that leads to tumorigenesis.	('Dysregulation', 'Var', (0, 13))	('apoptosis', 'CPA', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('leads', 'Reg', (97, 102))	('apoptosis', 'biological_process', 'GO:0006915', ('64', '73'))	('apoptosis', 'biological_process', 'GO:0097194', ('64', '73'))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
133498	28242813	We show here that knocking VCAN expression down strongly inhibited cell proliferation via induction of apoptosis in Caki-2 and 786-O cells.	('induction of apoptosis', 'biological_process', 'GO:0006915', ('90', '112'))	('down', 'NegReg', (43, 47))	('VCAN', 'Gene', (27, 31))	('inhibited', 'NegReg', (57, 66))	('knocking', 'Var', (18, 26))	('expression', 'Protein', (32, 42))	('VCAN', 'Gene', '1462', (27, 31))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('apoptosis', 'CPA', (103, 112))	('cell proliferation', 'CPA', (67, 85))
133499	28242813	Also, we found that VCAN attenuation affected the expression of several apoptosis-related genes and among them, TNF-alpha was confirmed to be significantly affected.	('affected', 'Reg', (37, 45))	('VCAN', 'Gene', (20, 24))	('apoptosis', 'biological_process', 'GO:0097194', ('72', '81'))	('VCAN', 'Gene', '1462', (20, 24))	('apoptosis', 'biological_process', 'GO:0006915', ('72', '81'))	('apoptosis-related genes', 'Gene', (72, 95))	('attenuation', 'Var', (25, 36))	('TNF-alpha', 'Gene', '7124', (112, 121))	('TNF-alpha', 'Gene', (112, 121))	('expression', 'MPA', (50, 60))
133504	28242813	Cleaved BID has the capacity to either block BCL-2 or activate BAK/BAX that induces the release of cytochrome C from mitochondria which ultimately leads to cell death via downstream caspases such as Caspase-9 and -3.	('BID', 'Gene', (8, 11))	('caspases', 'Gene', (182, 190))	('release of cytochrome C from mitochondria', 'biological_process', 'GO:0001836', ('88', '129'))	('BID', 'Gene', '637', (8, 11))	('cytochrome C', 'molecular_function', 'GO:0009461', ('99', '111'))	('caspases', 'Gene', '841;842', (182, 190))	('cytochrome C', 'Gene', (99, 111))	('BAK', 'Gene', (63, 66))	('BAK', 'Gene', '578', (63, 66))	('cell death', 'biological_process', 'GO:0008219', ('156', '166'))	('Cleaved', 'Var', (0, 7))	('BCL-2', 'molecular_function', 'GO:0015283', ('45', '50'))	('cytochrome C', 'Gene', '54205', (99, 111))	('BAX', 'Gene', (67, 70))	('BAX', 'Gene', '581', (67, 70))	('Caspase-9 and -3', 'Gene', '842;836', (199, 215))	('mitochondria', 'cellular_component', 'GO:0005739', ('117', '129'))	('leads to', 'Reg', (147, 155))	('BCL-2', 'Gene', '596', (45, 50))	('cytochrome C', 'molecular_function', 'GO:0045155', ('99', '111'))	('block', 'NegReg', (39, 44))	('BCL-2', 'Gene', (45, 50))	('activate', 'PosReg', (54, 62))	('cell death', 'CPA', (156, 166))
133506	28242813	Our results thus suggest that VCAN is critical for RCC tumorigenesis and by silencing this gene, growth of cancer cells may be abrogated by activation of the TNF signaling pathway.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('VCAN', 'Gene', (30, 34))	('TNF', 'Gene', '7124', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('silencing', 'Var', (76, 85))	('growth', 'CPA', (97, 103))	('signaling pathway', 'biological_process', 'GO:0007165', ('162', '179'))	('activation', 'PosReg', (140, 150))	('tumor', 'Disease', (55, 60))	('VCAN', 'Gene', '1462', (30, 34))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('abrogated', 'NegReg', (127, 136))	('TNF', 'Gene', (158, 161))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
133526	30173145	Scavenger receptor BI promotes cytoplasmic accumulation of lipoproteins in clear-cell renal cell carcinoma[S] Clear-cell renal cell carcinomas (ccRCCs) are characterized by inactivation of the von Hippel-Lindau (VHL) gene and intracellular lipid accumulation by unknown pathomechanisms.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('von Hippel-Lindau', 'Gene', '7428', (193, 210))	('intracellular', 'cellular_component', 'GO:0005622', ('226', '239'))	('VHL', 'Gene', (212, 215))	('inactivation', 'Var', (173, 185))	('RCC', 'Disease', (146, 149))	('Clear-cell renal cell carcinomas', 'Disease', (110, 142))	('lipid', 'Chemical', 'MESH:D008055', (240, 245))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (75, 106))	('Clear-cell renal cell carcinomas', 'Disease', 'MESH:C538614', (110, 142))	('VHL', 'Gene', '7428', (212, 215))	('cytoplasmic accumulation', 'MPA', (31, 55))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (121, 141))	('clear-cell renal cell carcinoma', 'Disease', (75, 106))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (121, 142))	('von Hippel-Lindau', 'Gene', (193, 210))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (86, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('Scavenger receptor BI', 'Gene', (0, 21))	('Scavenger receptor BI', 'Gene', '949', (0, 21))	('Clear-cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (110, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (75, 106))	('ccRCCs', 'Phenotype', 'HP:0006770', (144, 150))
133531	30173145	Uptake of 125I-HDL and 125I-LDL by patient-derived normal kidney epithelial cells as well as the VHL-reexpressing ccRCC cell lines, 786-O-VHL and RCC4-O-VHL cells, was strongly enhanced by VEGF treatment.	('VHL', 'Gene', '7428', (97, 100))	('VHL', 'Gene', '7428', (153, 156))	('RCC4', 'Gene', (146, 150))	('125I-LDL', 'Var', (23, 31))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('RCC', 'Disease', (116, 119))	('enhanced', 'PosReg', (177, 185))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('RCC4', 'Gene', '84925', (146, 150))	('Uptake', 'biological_process', 'GO:0098657', ('0', '6'))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('VHL', 'Gene', (138, 141))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('Uptake', 'MPA', (0, 6))	('125I-LDL', 'Chemical', '-', (23, 31))	('VHL', 'Gene', (97, 100))	('VHL', 'Gene', '7428', (138, 141))	('VHL', 'Gene', (153, 156))	('Uptake', 'biological_process', 'GO:0098739', ('0', '6'))	('patient', 'Species', '9606', (35, 42))	('VEGF', 'Gene', '7422', (189, 193))	('HDL', 'molecular_function', 'GO:0005321', ('15', '18'))	('VEGF', 'Gene', (189, 193))	('LDL', 'molecular_function', 'GO:0005322', ('28', '31'))
133546	30173145	Thus, the loss of VHL function leads to HIF-1alpha stabilization despite an adequately oxygenated tissue microenvironment, which in turn results in uncontrolled activation of HIF-target genes that regulate erythropoiesis (erythropoietin), angiogenesis (VEGF), glycolysis (glucose transporters and glycolytic pathway enzymes), and apoptosis (BNIP3).	('VHL', 'Gene', '7428', (18, 21))	('angiogenesis', 'CPA', (239, 251))	('activation', 'PosReg', (161, 171))	('apoptosis', 'CPA', (330, 339))	('erythropoiesis', 'biological_process', 'GO:0030218', ('206', '220'))	('HIF-1alpha', 'Gene', '3091', (40, 50))	('erythropoiesis', 'CPA', (206, 220))	('BNIP3', 'Gene', (341, 346))	('angiogenesis', 'biological_process', 'GO:0001525', ('239', '251'))	('VEGF', 'Gene', '7422', (253, 257))	('VHL', 'Gene', (18, 21))	('glycolysis', 'biological_process', 'GO:0006096', ('260', '270'))	('loss', 'Var', (10, 14))	('erythropoietin', 'molecular_function', 'GO:0005128', ('222', '236'))	('erythropoietin', 'Gene', (222, 236))	('VEGF', 'Gene', (253, 257))	('apoptosis', 'biological_process', 'GO:0097194', ('330', '339'))	('apoptosis', 'biological_process', 'GO:0006915', ('330', '339'))	('HIF-1alpha', 'Gene', (40, 50))	('erythropoietin', 'Gene', '2056', (222, 236))	('BNIP3', 'Gene', '664', (341, 346))
133559	30173145	Sanger sequencing was employed to assess the mutation status of the VHL gene (c.341-1G>C) for the ccRCC primary tumor and the corresponding cell culture.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('c.341-1G>C', 'Mutation', 'rs5030817', (78, 88))	('VHL', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('VHL', 'Gene', '7428', (68, 71))	('tumor', 'Disease', (112, 117))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('c.341-1G>C', 'Var', (78, 88))
133574	30173145	For the pulse-chase experiments, 50,000 cells were seeded in 24-well plates and cultured for 48 h. Then the cells were pulsed for 1 h with 10 mug/ml of 125I-HDL or 125I-LDL at 37 C in the presence or absence of the respective unlabeled lipoprotein for competition and determination of specific interactions.	('HDL', 'molecular_function', 'GO:0005321', ('157', '160'))	('125I-LDL', 'Chemical', '-', (164, 172))	('LDL', 'molecular_function', 'GO:0005322', ('169', '172'))	('mug', 'molecular_function', 'GO:0043739', ('142', '145'))	('125I-HDL', 'Var', (152, 160))	('interactions', 'Interaction', (294, 306))
133577	30173145	The 786-O and 786-O-VHL cells were reverse transfected with siRNA (Ambion Silencer Select; Life Technologies) targeted to LDLR (s224006, s224007, s4), VLDLR [siGENOME SMARTpool siRNA D-003721-02; ON-TARGET plus human VLDLR (7436), Dharmacon], neuropilin-1 (NRP1) (s16844, s16843), or nonsilencing control (4390843, silencer select or siGENOME control siRNA D-001220-01-20, Dharmacon or ON-TARGET control siRNA D-01810-10-20, Dharmacon) at a final concentration of 5 nmol/l using Lipofectamine RNA iMAX transfection reagent (Invitrogen; 13778150) in an antibiotic-free medium.	('VLDLR', 'Gene', (151, 156))	('s224006', 'Var', (128, 135))	('RNA', 'cellular_component', 'GO:0005562', ('493', '496'))	('LDLR', 'Gene', (218, 222))	('neuropilin-1', 'Gene', (243, 255))	('LDLR', 'Gene', (122, 126))	('VHL', 'Gene', (20, 23))	('LDLR', 'Gene', (152, 156))	('VLDLR', 'Gene', '7436', (151, 156))	('VLDLR', 'Gene', (217, 222))	('LDLR', 'Gene', '3949', (218, 222))	('s16844', 'Var', (264, 270))	('LDLR', 'Gene', '3949', (122, 126))	('VHL', 'Gene', '7428', (20, 23))	('LDLR', 'Gene', '3949', (152, 156))	('NRP', 'biological_process', 'GO:0085015', ('257', '260'))	('neuropilin-1', 'Gene', '8829', (243, 255))	('NRP1', 'Gene', '8829', (257, 261))	('NRP1', 'Gene', (257, 261))	('VLDLR', 'Gene', '7436', (217, 222))	('human', 'Species', '9606', (211, 216))
133581	30173145	The expression of LDLR (1:1,000, ab30532; Abcam), VLDLR (1:1,000, NBP1-78162; Novus), SR-BI (1:1,000, NB400-131; Novus), and NRP1 (1:1,000, ab81321; Abcam) were evaluated and compared with the expression of TATA binding protein (TBP) (1:1,000, ab51841; Abcam), which was used as a loading control.	('LDLR', 'Gene', (51, 55))	('VLDLR', 'Gene', '7436', (50, 55))	('ab30532', 'Var', (33, 40))	('protein', 'cellular_component', 'GO:0003675', ('220', '227'))	('TBP', 'Gene', (229, 232))	('SR-BI', 'Gene', '949', (86, 91))	('NBP1', 'Gene', (66, 70))	('LDLR', 'Gene', (18, 22))	('LDLR', 'Gene', '3949', (51, 55))	('TBP', 'Gene', '6908', (229, 232))	('NRP', 'biological_process', 'GO:0085015', ('125', '128'))	('NBP1', 'Gene', '4682', (66, 70))	('TATA binding protein', 'Gene', (207, 227))	('VLDLR', 'Gene', (50, 55))	('LDLR', 'Gene', '3949', (18, 22))	('NRP1', 'Gene', '8829', (125, 129))	('NRP1', 'Gene', (125, 129))	('TATA binding protein', 'Gene', '6908', (207, 227))	('binding', 'molecular_function', 'GO:0005488', ('212', '219'))	('SR-BI', 'Gene', (86, 91))
133607	30173145	To unravel the origin of lipoprotein accumulation in ccRCC, we performed in vitro assays in two ccRCC cell lines that lack functional VHL (786-O and RCC4) and their stably transfected VHL wild-type counterparts (786-O-VHL, RCC4-O-VHL).	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', 'MESH:C538614', (223, 226))	('VHL', 'Gene', '7428', (184, 187))	('RCC4', 'Gene', '84925', (149, 153))	('VHL', 'Gene', (134, 137))	('VHL', 'Gene', '7428', (230, 233))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('VHL', 'Gene', '7428', (134, 137))	('RCC4', 'Gene', (223, 227))	('VHL', 'Gene', (218, 221))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('RCC', 'Phenotype', 'HP:0005584', (223, 226))	('RCC', 'Disease', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('RCC', 'Disease', (55, 58))	('RCC', 'Disease', (223, 226))	('VHL', 'Gene', (184, 187))	('786-O', 'Var', (139, 144))	('RCC4', 'Gene', '84925', (223, 227))	('VHL', 'Gene', '7428', (218, 221))	('VHL', 'Gene', (230, 233))	('RCC4', 'Gene', (149, 153))	('lack', 'NegReg', (118, 122))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
133611	30173145	Importantly, the ccRCC-derived cell culture retained the VHL driver mutation of the primary human tumor.	('mutation', 'Var', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('VHL', 'Gene', (57, 60))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('VHL', 'Gene', '7428', (57, 60))	('tumor', 'Disease', (98, 103))	('human', 'Species', '9606', (92, 97))
133620	30173145	To investigate whether the increased cellular association of 125I-HDL and 125I-LDL by VHL-deficient cells is caused by impaired degradation or resecretion of the cell-associated lipoproteins, a combination of pulse-chase and degradation experiments were performed with 125I-HDL and 125I-LDL.	('125I-HDL', 'Var', (61, 69))	('VHL-deficient', 'Disease', (86, 99))	('increased', 'PosReg', (27, 36))	('degradation', 'biological_process', 'GO:0009056', ('225', '236'))	('cellular association', 'MPA', (37, 57))	('cell-associated', 'cellular_component', 'GO:0009986', ('162', '177'))	('125I-LDL', 'Var', (74, 82))	('HDL', 'molecular_function', 'GO:0005321', ('66', '69'))	('125I-LDL', 'Chemical', '-', (282, 290))	('degradation', 'biological_process', 'GO:0009056', ('128', '139'))	('resecretion', 'MPA', (143, 154))	('impaired degradation', 'Disease', (119, 139))	('impaired degradation', 'Disease', 'MESH:D009422', (119, 139))	('LDL', 'molecular_function', 'GO:0005322', ('79', '82'))	('125I-LDL', 'Chemical', '-', (74, 82))	('LDL', 'molecular_function', 'GO:0005322', ('287', '290'))	('HDL', 'molecular_function', 'GO:0005321', ('274', '277'))	('VHL-deficient', 'Disease', 'MESH:D006623', (86, 99))
133622	30173145	Very strikingly, in the patient-derived ccRCC cell culture, the percentage of cell-associated 125I-HDL was as high as 70% after 1 h chase and did not decrease significantly over prolonged chase.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('HDL', 'molecular_function', 'GO:0005321', ('99', '102'))	('patient', 'Species', '9606', (24, 31))	('125I-HDL', 'Var', (94, 102))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('cell-associated', 'cellular_component', 'GO:0009986', ('78', '93'))
133628	30173145	In principle, the same observations were made for the kinetics of 125I-HDL and 125I-LDL in a pulse chase experiment in the ccRCC cell lines, 786-O and 786-O-VHL (Fig.	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('125I-LDL', 'Chemical', '-', (79, 87))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('VHL', 'Gene', (157, 160))	('HDL', 'molecular_function', 'GO:0005321', ('71', '74'))	('125I-HDL', 'Var', (66, 74))	('VHL', 'Gene', '7428', (157, 160))	('LDL', 'molecular_function', 'GO:0005322', ('84', '87'))	('125I-LDL', 'Var', (79, 87))
133630	30173145	Together, these results indicate that the loss of VHL function in ccRCC cells increases lipoprotein uptake into a nondegrading nonsecretory compartment.	('loss', 'Var', (42, 46))	('VHL', 'Gene', (50, 53))	('VHL', 'Gene', '7428', (50, 53))	('uptake', 'biological_process', 'GO:0098657', ('100', '106'))	('uptake', 'biological_process', 'GO:0098739', ('100', '106'))	('increases lipoprotein', 'Phenotype', 'HP:0003141', (78, 99))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('increases', 'PosReg', (78, 87))
133632	30173145	Pretreatment with VEGF for 1 h increased the cellular association of both 125I-HDL and 125I-LDL in patient-derived normal epithelial kidney cells, but not in ccRCC-derived cells (Fig.	('patient', 'Species', '9606', (99, 106))	('125I-LDL', 'Var', (87, 95))	('increased', 'PosReg', (31, 40))	('HDL', 'molecular_function', 'GO:0005321', ('79', '82'))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('VEGF', 'Gene', '7422', (18, 22))	('RCC', 'Disease', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('125I-LDL', 'Chemical', '-', (87, 95))	('cellular association', 'MPA', (45, 65))	('125I-HDL', 'Var', (74, 82))	('LDL', 'molecular_function', 'GO:0005322', ('92', '95'))	('VEGF', 'Gene', (18, 22))
133633	30173145	Similar observations were made in the ccRCC cell lines: The significantly lower cellular association of both 125I-HDL and 125I-LDL by 786-O-VHL and RCC4-O-VHL cells was increased by pretreatment with VEGF for 1 h to the same level as observed in 786-O (Fig.	('RCC', 'Disease', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('cellular association', 'MPA', (80, 100))	('RCC4', 'Gene', '84925', (148, 152))	('lower', 'NegReg', (74, 79))	('VHL', 'Gene', (155, 158))	('HDL', 'molecular_function', 'GO:0005321', ('114', '117'))	('125I-LDL', 'Chemical', '-', (122, 130))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('VHL', 'Gene', (140, 143))	('VEGF', 'Gene', '7422', (200, 204))	('VHL', 'Gene', '7428', (155, 158))	('VEGF', 'Gene', (200, 204))	('RCC', 'Disease', (40, 43))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('125I-LDL', 'Var', (122, 130))	('LDL', 'molecular_function', 'GO:0005322', ('127', '130'))	('VHL', 'Gene', '7428', (140, 143))	('RCC4', 'Gene', (148, 152))	('RCC', 'Disease', 'MESH:C538614', (40, 43))
133636	30173145	Further, supporting the crucial role of VEGF, pretreatment of 786-O cells with VEGF receptor (VEGFR) inhibitors for 30 min decreased specific cellular association of both 125I-HDL and 125I-LDL, but had no effect in 786-O-VHL cells (supplemental Fig.	('VHL', 'Gene', (221, 224))	('HDL', 'molecular_function', 'GO:0005321', ('176', '179'))	('specific cellular association', 'MPA', (133, 162))	('VEGF', 'Gene', (94, 98))	('decreased', 'NegReg', (123, 132))	('VEGFR', 'Gene', '3791', (94, 99))	('VEGFR', 'Gene', (94, 99))	('VHL', 'Gene', '7428', (221, 224))	('VEGF receptor', 'Gene', (79, 92))	('125I-LDL', 'Chemical', '-', (184, 192))	('VEGF', 'Gene', '7422', (40, 44))	('125I-HDL', 'Var', (171, 179))	('VEGF receptor', 'Gene', '3791', (79, 92))	('VEGF', 'Gene', (40, 44))	('VEGF', 'Gene', '7422', (79, 83))	('VEGF', 'Gene', (79, 83))	('LDL', 'molecular_function', 'GO:0005322', ('189', '192'))	('125I-LDL', 'Var', (184, 192))	('VEGF', 'Gene', '7422', (94, 98))
133639	30173145	Silencing of NRP1 led to decreased specific cellular association of 125I-HDL as well as 125I-LDL in both 786-O and 786-O-VHL cells.	('VHL', 'Gene', '7428', (121, 124))	('HDL', 'molecular_function', 'GO:0005321', ('73', '76'))	('NRP', 'biological_process', 'GO:0085015', ('13', '16'))	('NRP1', 'Gene', '8829', (13, 17))	('NRP1', 'Gene', (13, 17))	('125I-LDL', 'Chemical', '-', (88, 96))	('decreased', 'NegReg', (25, 34))	('LDL', 'molecular_function', 'GO:0005322', ('93', '96'))	('specific cellular association', 'MPA', (35, 64))	('Silencing', 'Var', (0, 9))	('VHL', 'Gene', (121, 124))
133641	30173145	In conclusion, VEGF/NRP1-mediated signaling stimulates the uptake of 125I-HDL as well as 125I-LDL in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('HDL', 'molecular_function', 'GO:0005321', ('74', '77'))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('stimulates', 'PosReg', (44, 54))	('125I-LDL', 'Chemical', '-', (89, 97))	('NRP', 'biological_process', 'GO:0085015', ('20', '23'))	('VEGF', 'Gene', (15, 19))	('NRP1', 'Gene', '8829', (20, 24))	('125I-HDL', 'Var', (69, 77))	('uptake', 'biological_process', 'GO:0098739', ('59', '65'))	('uptake', 'biological_process', 'GO:0098657', ('59', '65'))	('NRP1', 'Gene', (20, 24))	('LDL', 'molecular_function', 'GO:0005322', ('94', '97'))	('VEGF', 'Gene', '7422', (15, 19))	('uptake', 'MPA', (59, 65))
133648	30173145	By contrast, in both 786-O and 786-O-VHL cells, the specific cellular association of 125I-HDL as well as 125I-LDL was significantly decreased in the presence of a neutralizing anti-SR-BI-antibody (Fig.	('antibody', 'cellular_component', 'GO:0019815', ('187', '195'))	('VHL', 'Gene', (37, 40))	('antibody', 'cellular_component', 'GO:0019814', ('187', '195'))	('125I-HDL', 'Var', (85, 93))	('VHL', 'Gene', '7428', (37, 40))	('LDL', 'molecular_function', 'GO:0005322', ('110', '113'))	('HDL', 'molecular_function', 'GO:0005321', ('90', '93'))	('SR-BI', 'Gene', (181, 186))	('antibody', 'molecular_function', 'GO:0003823', ('187', '195'))	('specific cellular association', 'MPA', (52, 81))	('decreased', 'NegReg', (132, 141))	('125I-LDL', 'Chemical', '-', (105, 113))	('antibody', 'cellular_component', 'GO:0042571', ('187', '195'))	('SR-BI', 'Gene', '949', (181, 186))
133653	30173145	We found higher proliferation of 786-O cells compared with 786-O-VHL cells, indicating that loss of VHL function increases proliferation in ccRCC cells (Fig.	('proliferation', 'CPA', (123, 136))	('VHL', 'Gene', '7428', (65, 68))	('RCC', 'Disease', (142, 145))	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('increases', 'PosReg', (113, 122))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('loss', 'Var', (92, 96))	('VHL', 'Gene', (100, 103))	('VHL', 'Gene', (65, 68))	('VHL', 'Gene', '7428', (100, 103))
133655	30173145	Basal as well as lipoprotein-stimulated proliferation was reduced in both 786-O and 786-O-VHL cells by knockdown of NRP1 (Fig.	('VHL', 'Gene', '7428', (90, 93))	('lipoprotein-stimulated', 'MPA', (17, 39))	('NRP1', 'Gene', '8829', (116, 120))	('NRP1', 'Gene', (116, 120))	('NRP', 'biological_process', 'GO:0085015', ('116', '119'))	('reduced', 'NegReg', (58, 65))	('VHL', 'Gene', (90, 93))	('knockdown', 'Var', (103, 112))
133657	30173145	S14b-d), the proliferation was significantly decreased by the neutralization of SR-BI (Fig.	('proliferation', 'CPA', (13, 26))	('SR-BI', 'Gene', '949', (80, 85))	('decreased', 'NegReg', (45, 54))	('neutralization', 'Var', (62, 76))	('SR-BI', 'Gene', (80, 85))
133667	30173145	LDL is then trafficked into an endosomal/lysosomal route, depending on the presence or absence of PCSK9 either together with or separated from the receptor.	('PCSK9', 'Gene', (98, 103))	('PCSK9', 'Gene', '255738', (98, 103))	('presence', 'Var', (75, 83))	('absence', 'NegReg', (87, 94))	('LDL', 'molecular_function', 'GO:0005322', ('0', '3'))
133682	30173145	However, several examples have been reported where ablation or blockage of SR-BI also inhibited the uptake of lipoprotein particles.	('uptake of lipoprotein particles', 'MPA', (100, 131))	('SR-BI', 'Gene', (75, 80))	('uptake', 'biological_process', 'GO:0098657', ('100', '106'))	('uptake', 'biological_process', 'GO:0098739', ('100', '106'))	('inhibited', 'NegReg', (86, 95))	('SR-BI', 'Gene', '949', (75, 80))	('ablation', 'Var', (51, 59))	('blockage', 'Var', (63, 71))
133692	30173145	Conversely, lipoprotein uptake was lowered in 786-O cells by VEGFR inhibitors (supplemental Fig.	('inhibitors', 'Var', (67, 77))	('VEGFR', 'Gene', (61, 66))	('lipoprotein uptake', 'MPA', (12, 30))	('uptake', 'biological_process', 'GO:0098739', ('24', '30'))	('lowered', 'NegReg', (35, 42))	('uptake', 'biological_process', 'GO:0098657', ('24', '30'))	('VEGFR', 'Gene', '3791', (61, 66))
133706	30173145	In line with this, immunoreactivity for apoA-I, apoB, or SR-BI was associated with the differentiation of renal carcinomas into ccRCC as well as with tumor grade (apoA-I and apoB) or tumor stage (apoB).	('apoA-I', 'Gene', '335', (40, 46))	('renal carcinomas', 'Disease', 'MESH:C538614', (106, 122))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('apoB', 'Gene', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('apoB', 'Gene', (196, 200))	('immunoreactivity', 'Var', (19, 35))	('apoB', 'Gene', (174, 178))	('RCC', 'Disease', (130, 133))	('renal carcinomas', 'Disease', (106, 122))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('apoA-I', 'Gene', '335', (163, 169))	('renal carcinomas', 'Phenotype', 'HP:0005584', (106, 122))	('apoA-I', 'Gene', (40, 46))	('SR-BI', 'Gene', (57, 62))	('associated', 'Reg', (67, 77))	('tumor', 'Disease', (183, 188))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('tumor', 'Disease', (150, 155))	('apoB', 'Gene', '338', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('SR-BI', 'Gene', '949', (57, 62))	('apoB', 'Gene', '338', (174, 178))	('apoB', 'Gene', '338', (196, 200))	('apoA-I', 'Gene', (163, 169))
133713	30173145	Interestingly, genome-wide association studies identified a borderline significant association of the rs4765623 polymorphism in SCARB1 with ccRCC susceptibility, indicating a pathogenic role of SR-BI in ccRCC.	('SR-BI', 'Gene', (194, 199))	('rs4765623', 'Var', (102, 111))	('RCC', 'Disease', (142, 145))	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('RCC', 'Disease', (205, 208))	('RCC', 'Phenotype', 'HP:0005584', (205, 208))	('SCARB1', 'Gene', (128, 134))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('rs4765623', 'Mutation', 'rs4765623', (102, 111))	('SR-BI', 'Gene', '949', (194, 199))	('SCARB1', 'Gene', '949', (128, 134))
133714	30173145	In line with an oncogenic role, knockdown of SR-BI was found to inhibit proliferation (Fig.	('SR-BI', 'Gene', '949', (45, 50))	('proliferation', 'CPA', (72, 85))	('knockdown', 'Var', (32, 41))	('inhibit', 'NegReg', (64, 71))	('SR-BI', 'Gene', (45, 50))
133719	29046731	Promoter methylation inhibits expression of tumor suppressor KIBRA in human clear cell renal cell carcinoma KIBRA has been suggested as a key regulator of the Hippo signaling pathway, regulating organ size, cell contact inhibition, tissue regeneration as well as tumorigenesis and cystogenesis.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (76, 107))	('Promoter methylation', 'Var', (0, 20))	('tissue regeneration', 'biological_process', 'GO:0042246', ('232', '251'))	('tumor', 'Disease', (44, 49))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('44', '60'))	('inhibits', 'NegReg', (21, 29))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('159', '182'))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (263, 268))	('Hippo', 'Gene', (159, 164))	('tumor suppressor', 'biological_process', 'GO:0051726', ('44', '60'))	('Hippo', 'Gene', '37247', (159, 164))	('cystogenesis', 'CPA', (281, 293))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (76, 107))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('human', 'Species', '9606', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('KIBRA', 'Gene', (61, 66))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('regulating', 'Reg', (184, 194))	('KIBRA', 'Gene', '23286', (61, 66))	('expression', 'MPA', (30, 40))	('clear cell renal cell carcinoma', 'Disease', (76, 107))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (87, 107))	('KIBRA', 'Gene', (108, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tissue regeneration', 'CPA', (232, 251))	('KIBRA', 'Gene', '23286', (108, 113))	('contact inhibition', 'biological_process', 'GO:0060242', ('212', '230'))
133725	29046731	Furthermore, SP1 transactivation of KIBRA transcription was largely prevented by methylation of KIBRA regulatory elements (p < 0.001).	('KIBRA', 'Gene', '23286', (36, 41))	('methylation', 'biological_process', 'GO:0032259', ('81', '92'))	('KIBRA', 'Gene', (96, 101))	('methylation', 'Var', (81, 92))	('prevented', 'NegReg', (68, 77))	('transcription', 'biological_process', 'GO:0006351', ('42', '55'))	('KIBRA', 'Gene', '23286', (96, 101))	('KIBRA', 'Gene', (36, 41))	('SP1', 'Var', (13, 16))	('transactivation', 'biological_process', 'GO:2000144', ('17', '32'))	('men', 'Species', '9606', (116, 119))
133728	29046731	We conclude that epigenetic downregulation of tumor suppressor KIBRA may involve impaired SP1 binding to functional methylation-sensitive KIBRA promoter elements as observed in human kidney clear cell carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (183, 210))	('human', 'Species', '9606', (177, 182))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('46', '62'))	('KIBRA', 'Gene', (63, 68))	('binding', 'molecular_function', 'GO:0005488', ('94', '101'))	('KIBRA', 'Gene', '23286', (63, 68))	('tumor suppressor', 'biological_process', 'GO:0051726', ('46', '62'))	('downregulation', 'NegReg', (28, 42))	('epigenetic', 'Var', (17, 27))	('tumor', 'Disease', (46, 51))	('impaired', 'NegReg', (81, 89))	('methylation', 'biological_process', 'GO:0032259', ('116', '127'))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('KIBRA', 'Gene', (138, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('SP1', 'Protein', (90, 93))	('kidney clear cell carcinoma', 'Disease', (183, 210))	('binding', 'Interaction', (94, 101))	('men', 'Species', '9606', (156, 159))	('KIBRA', 'Gene', '23286', (138, 143))
133733	29046731	The inactivation of Hippo genes including Warts (Wts), Hippo (Hpo), Salvador (Sav), and Mats as well as Merlin (Mer) and Expanded (Ex) resulted in a comparable phenotype with considerable tissue overgrowth.	('Sav', 'Gene', '60485', (78, 81))	('Wts', 'Gene', '9113', (49, 52))	('Wts', 'Phenotype', 'HP:0200043', (49, 52))	('Warts', 'Phenotype', 'HP:0200043', (42, 47))	('inactivation', 'Var', (4, 16))	('Salvador', 'Gene', '60485', (68, 76))	('overgrowth', 'Phenotype', 'HP:0001548', (195, 205))	('Mer', 'Gene', (104, 107))	('Sav', 'Gene', (78, 81))	('Merlin', 'Gene', '4771', (104, 110))	('Wts', 'Gene', (49, 52))	('Mer', 'Gene', (112, 115))	('Mer', 'Gene', '4771', (104, 107))	('Hippo', 'Gene', (55, 60))	('Salvador', 'Gene', (68, 76))	('Mer', 'Gene', '4771', (112, 115))	('tissue overgrowth', 'CPA', (188, 205))	('Hippo', 'Gene', '37247', (55, 60))	('Hippo', 'Gene', (20, 25))	('Hippo', 'Gene', '37247', (20, 25))	('Merlin', 'Gene', (104, 110))
133738	29046731	In humans, impaired Hippo signaling has been reported in a variety of different cancers, linking deregulated Hippo signaling to tumor initiation and progression.	('Hippo signaling', 'biological_process', 'GO:0035329', ('109', '124'))	('Hippo', 'Gene', (109, 114))	('Hippo', 'Gene', (20, 25))	('tumor initiation', 'Disease', 'MESH:D009369', (128, 144))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('impaired', 'NegReg', (11, 19))	('Hippo signaling', 'biological_process', 'GO:0035329', ('20', '35'))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('Hippo', 'Gene', '37247', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor initiation', 'Disease', (128, 144))	('humans', 'Species', '9606', (3, 9))	('Hippo', 'Gene', '37247', (20, 25))	('deregulated', 'Var', (97, 108))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
133739	29046731	Components of the Hippo pathway have, therefore, been suggested to be the target of aberrant gene methylation and epigenetic silencing in humans as already reported for LATS1/2 (large tumor suppressor kinases 1 and 2; human Warts homolog), MST1/2 (serin/threonine protein kinase 4/3; human Hippo homolog), and KIBRA.	('Hippo', 'Gene', (290, 295))	('Hippo', 'Gene', (18, 23))	('Hippo', 'Gene', '37247', (290, 295))	('Hippo', 'Gene', '37247', (18, 23))	('large tumor suppressor kinases 1 and 2', 'Gene', '9113;26524', (178, 216))	('KIBRA', 'Gene', (310, 315))	('LATS1/2', 'Gene', '9113;26524', (169, 176))	('KIBRA', 'Gene', '23286', (310, 315))	('LATS1/2', 'Gene', (169, 176))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('184', '200'))	('Warts', 'Phenotype', 'HP:0200043', (224, 229))	('epigenetic silencing', 'Var', (114, 134))	('MST1/2', 'Gene', '4485;6788', (240, 246))	('MST1/2', 'Gene', (240, 246))	('tumor suppressor', 'biological_process', 'GO:0051726', ('184', '200'))	('human', 'Species', '9606', (284, 289))	('aberrant', 'Var', (84, 92))	('humans', 'Species', '9606', (138, 144))	('protein', 'cellular_component', 'GO:0003675', ('264', '271'))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('methylation', 'biological_process', 'GO:0032259', ('98', '109'))	('human', 'Species', '9606', (138, 143))	('human', 'Species', '9606', (218, 223))
133751	29046731	Bisulfite sequencing and dichotomous analysis revealed that KIBRA CpG methylation occurred significantly more often in ccRCC samples (methylation level 73/504 [14.5%]) compared to control samples (methylation level 76/1008 [7.5%]; p = 0.0001, OR = 1.921, [CI 95%] = 1.369-2.695).	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('KIBRA', 'Gene', '23286', (60, 65))	('RCC', 'Disease', (121, 124))	('methylation', 'biological_process', 'GO:0032259', ('70', '81'))	('methylation', 'biological_process', 'GO:0032259', ('197', '208'))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('methylation', 'Var', (70, 81))	('methylation', 'biological_process', 'GO:0032259', ('134', '145'))	('KIBRA', 'Gene', (60, 65))	('Bisulfite', 'Chemical', 'MESH:C042345', (0, 9))
133758	29046731	In vitro methylation of CpG I by methyltransferase SssI (methylation of all CG-dinucleotides) led to total abrogation of P1aI and P1aII transcriptional activity compared to the unmethylated promoter in renal IHKE cells (Fig.	('methylation', 'Var', (9, 20))	('P1a', 'Gene', '7739', (121, 124))	('abrogation', 'NegReg', (107, 117))	('CG-dinucleotides', 'Chemical', 'MESH:C015772', (76, 92))	('P1a', 'Gene', (130, 133))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('methylation', 'biological_process', 'GO:0032259', ('57', '68'))	('P1a', 'Gene', '7739', (130, 133))	('P1a', 'Gene', (121, 124))
133761	29046731	Methylation of distal CpG II also led to a significant reduction of P1bI transcriptional activity compared to the active unmethylated promoter (p < 0.001).	('CpG II', 'Gene', (22, 28))	('reduction', 'NegReg', (55, 64))	('Methylation', 'Var', (0, 11))	('P1b', 'Gene', '7033', (68, 71))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('P1b', 'Gene', (68, 71))
133764	29046731	Treatment of SH-SY5Y cells with 5-azacytidine (Aza), alone or in combination with trichostatin A (TSA), an inhibitor of histone deacetylases, resulted in a significant ~3-fold increase in KIBRA mRNA levels compared to untreated cells (Fig.	('5-azacytidine', 'Chemical', 'MESH:D001374', (32, 45))	('5-azacytidine', 'Var', (32, 45))	('TSA', 'Chemical', 'MESH:C012589', (98, 101))	('increase', 'PosReg', (176, 184))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (13, 20))	('KIBRA', 'Gene', '23286', (188, 193))	('trichostatin A', 'Chemical', 'MESH:C012589', (82, 96))	('Aza', 'Chemical', 'MESH:D001374', (47, 50))	('TSA', 'molecular_function', 'GO:0033984', ('98', '101'))	('men', 'Species', '9606', (5, 8))	('KIBRA', 'Gene', (188, 193))
133766	29046731	4b; all p < 0.01 compared to control), suggesting that promoter demethylation restores KIBRA expression.	('KIBRA', 'Gene', (87, 92))	('restores', 'PosReg', (78, 86))	('promoter demethylation', 'Var', (55, 77))	('KIBRA', 'Gene', '23286', (87, 92))	('demethylation', 'biological_process', 'GO:0070988', ('64', '77'))
133771	29046731	This observation suggests that SP1 recruitment to KIBRA promoter regions is prevented by CpG methylation.	('KIBRA', 'Gene', '23286', (50, 55))	('men', 'Species', '9606', (42, 45))	('CpG', 'Var', (89, 92))	('methylation', 'biological_process', 'GO:0032259', ('93', '104'))	('KIBRA', 'Gene', (50, 55))	('methylation', 'Var', (93, 104))	('SP1 recruitment', 'MPA', (31, 46))
133774	29046731	The goal of this study was to elucidate epigenetic effects on KIBRA expression regulation in vitro and in human ccRCC.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('human', 'Species', '9606', (106, 111))	('RCC', 'Disease', (114, 117))	('KIBRA', 'Gene', (62, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('epigenetic effects', 'Var', (40, 58))	('KIBRA', 'Gene', '23286', (62, 67))	('regulation', 'biological_process', 'GO:0065007', ('79', '89'))
133779	29046731	In this respect, methylation at the CG dinucleotide of a specific transcription factor binding element such as SP1 consensus sites may sterically interfere with binding of the transcription factor to DNA, inhibiting transcription.	('inhibiting', 'NegReg', (205, 215))	('binding', 'Interaction', (161, 168))	('transcription', 'MPA', (216, 229))	('transcription', 'biological_process', 'GO:0006351', ('66', '79'))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('66', '94'))	('methylation', 'Var', (17, 28))	('DNA', 'Protein', (200, 203))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('interfere', 'NegReg', (146, 155))	('transcription', 'biological_process', 'GO:0006351', ('176', '189'))	('men', 'Species', '9606', (98, 101))	('DNA', 'cellular_component', 'GO:0005574', ('200', '203'))	('binding', 'molecular_function', 'GO:0005488', ('161', '168'))	('transcription factor', 'molecular_function', 'GO:0000981', ('176', '196'))	('CG dinucleotide', 'Chemical', 'MESH:C015772', (36, 51))	('transcription', 'biological_process', 'GO:0006351', ('216', '229'))
133780	29046731	With regard to KIBRA methylation, the group of Latif and colleagues recently identified frequent epigenetic inactivation of KIBRA in B cell acute lymphocytic leukemia and unfavorable prognostic parameters in chronic lymphocytic leukemia.	('chronic lymphocytic leukemia', 'Disease', (208, 236))	('KIBRA', 'Gene', '23286', (124, 129))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (216, 236))	('methylation', 'biological_process', 'GO:0032259', ('21', '32'))	('lymphocytic leukemia', 'Disease', (146, 166))	('KIBRA', 'Gene', (124, 129))	('leukemia', 'Phenotype', 'HP:0001909', (158, 166))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (146, 166))	('KIBRA', 'Gene', (15, 20))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (208, 236))	('epigenetic inactivation', 'Var', (97, 120))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (140, 166))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (208, 236))	('KIBRA', 'Gene', '23286', (15, 20))	('leukemia', 'Phenotype', 'HP:0001909', (228, 236))
133782	29046731	Our in vitro methylation experiments revealed that KIBRA expression is significantly affected by methylation patterns of at least two CpG islands located within functional promoters P1a and P1b.	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('methylation patterns', 'Var', (97, 117))	('men', 'Species', '9606', (31, 34))	('P1b', 'Gene', '7033', (190, 193))	('KIBRA', 'Gene', (51, 56))	('P1a', 'Gene', (182, 185))	('affected', 'Reg', (85, 93))	('KIBRA', 'Gene', '23286', (51, 56))	('methylation', 'biological_process', 'GO:0032259', ('97', '108'))	('CpG', 'Gene', (134, 137))	('P1b', 'Gene', (190, 193))	('P1a', 'Gene', '7739', (182, 185))
133783	29046731	Transcription factor analysis revealed that SP1 is a strong activator of KIBRA promoter activity, and KIBRA protein levels were significantly elevated by SP1 overexpression.	('overexpression', 'Var', (158, 172))	('elevated', 'PosReg', (142, 150))	('KIBRA', 'Gene', '23286', (102, 107))	('KIBRA', 'Gene', (73, 78))	('SP1', 'Gene', (154, 157))	('KIBRA', 'Gene', '23286', (73, 78))	('KIBRA', 'Gene', (102, 107))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
133784	29046731	Upon methylation of P1a promoter elements, the activating effect of SP1was lost.	('lost', 'NegReg', (75, 79))	('methylation', 'Var', (5, 16))	('activating effect', 'MPA', (47, 64))	('men', 'Species', '9606', (36, 39))	('P1a', 'Gene', (20, 23))	('methylation', 'biological_process', 'GO:0032259', ('5', '16'))	('P1a', 'Gene', '7739', (20, 23))
133785	29046731	Our results, therefore, suggest that in vivo methylation at KIBRA CG dinucleotides of SP1 consensus sites may reduce the ability of SP1 to bind its DNA recognition element potentially impairing transactivation (Fig.	('men', 'Species', '9606', (167, 170))	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('KIBRA', 'Gene', '23286', (60, 65))	('bind', 'Interaction', (139, 143))	('impairing', 'NegReg', (184, 193))	('transactivation', 'biological_process', 'GO:2000144', ('194', '209'))	('CG dinucleotides', 'Chemical', 'MESH:C015772', (66, 82))	('transactivation', 'MPA', (194, 209))	('methylation', 'Var', (45, 56))	('DNA recognition element', 'Interaction', (148, 171))	('KIBRA', 'Gene', (60, 65))	('SP1', 'Gene', (86, 89))	('reduce', 'NegReg', (110, 116))	('ability', 'MPA', (121, 128))
133795	29046731	If aberrant KIBRA methylation or reduced KIBRA expression can also be detected in blood or cells isolated from urine of ccRCC patients is currently unclear and further studies are needed to investigate these potential correlations.	('KIBRA', 'Gene', (41, 46))	('aberrant', 'Var', (3, 11))	('ccRCC', 'Phenotype', 'HP:0006770', (120, 125))	('KIBRA', 'Gene', (12, 17))	('KIBRA', 'Gene', '23286', (41, 46))	('reduced', 'NegReg', (33, 40))	('patients', 'Species', '9606', (126, 134))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))	('KIBRA', 'Gene', '23286', (12, 17))
133800	29046731	KIBRA expression levels are reduced in ccRCC and alterations in the balance of KIBRA/SP1 binding by promoter methylation may be involved in the onset and/or progression of ccRCC.	('binding', 'Interaction', (89, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('reduced', 'NegReg', (28, 35))	('alterations', 'Var', (49, 60))	('binding', 'molecular_function', 'GO:0005488', ('89', '96'))	('KIBRA', 'Gene', '23286', (0, 5))	('KIBRA', 'Gene', '23286', (79, 84))	('methylation', 'biological_process', 'GO:0032259', ('109', '120'))	('ccRCC', 'Phenotype', 'HP:0006770', (172, 177))	('RCC', 'Disease', (174, 177))	('involved', 'Reg', (128, 136))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))	('KIBRA', 'Gene', (0, 5))	('KIBRA', 'Gene', (79, 84))
133816	29046731	Trichostatin A (TSA, 250 nmol/l; Sigma-Aldrich) was applied for 24 h. Deletion constructs of the KIBRA 5'-flanking region have been described elsewhere.	('TSA', 'molecular_function', 'GO:0033984', ('16', '19'))	('KIBRA', 'Gene', (97, 102))	('Deletion constructs', 'Var', (70, 89))	('KIBRA', 'Gene', '23286', (97, 102))	('Trichostatin A', 'Chemical', 'MESH:C012589', (0, 14))	('TSA', 'Chemical', 'MESH:C012589', (16, 19))
133831	29046731	Oligonucleotides had an amplification efficiency of >= 90% (Additional file 1: Table S2).	('Oligonucleotides', 'Chemical', 'MESH:D009841', (0, 16))	('amplification', 'MPA', (24, 37))	('Oligonucleotides', 'Var', (0, 16))
133893	31046666	Then, the optimal values of lambda1 and lambda2 were the values corresponding to the PE that was two standard error (SE) greater than the minimum PE, and were greater than lambda1 min and lambda2 min, respectively.	('SE', 'Disease', 'None', (117, 119))	('lambda2', 'Var', (40, 47))	('lambda1', 'Var', (28, 35))
133941	31046666	The 460 genes were ranked according to the number of changed edges that these genes are involved in, and the top 10 genes are NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex 4-Like 2 (NDUFA4L2), Uromodulin (UMOD), Angiopoietin-Like 4 (ANGPTL4), Nicotinamide N-methyltransferase (NNMT), Carbonic anhydrase 9 (CA9), Insulin-like growth factor binding protein 3 (IGFBP3), Apolipoprotein E/C1 (APOE/C1), complement component 3 (C3), vimentin (VIM), and complement C4A.	('vimentin', 'Gene', (432, 440))	('complement C4A', 'Gene', (452, 466))	('Nicotinamide N-methyltransferase', 'Gene', '4837', (248, 280))	('APOE/C1', 'Gene', (393, 400))	('E/C1', 'Var', (396, 400))	('Uromodulin', 'Gene', (198, 208))	('UMOD', 'Gene', '7369', (210, 214))	('VIM', 'Gene', (442, 445))	('APOE/C1', 'Gene', '341;348;6966', (393, 400))	('NNMT', 'Gene', '4837', (282, 286))	('Angiopoietin-Like 4', 'Gene', '51129', (217, 236))	('CA9', 'Gene', '768', (311, 314))	('E/C1', 'Var', (387, 391))	('NDUFA4L2', 'Gene', '56901', (187, 195))	('vimentin', 'cellular_component', 'GO:0045098', ('432', '440'))	('NNMT', 'Gene', (282, 286))	('Apolipoprotein', 'molecular_function', 'GO:0005320', ('372', '386'))	('ANGPTL4', 'Gene', (238, 245))	('E/C1', 'SUBSTITUTION', 'None', (396, 400))	('Nicotinamide N-methyltransferase', 'Gene', (248, 280))	('Apolipoprotein', 'molecular_function', 'GO:0005319', ('372', '386'))	('complement C4A', 'Gene', '720', (452, 466))	('IGFBP3', 'Gene', (363, 369))	('C3', 'Gene', '718', (427, 429))	('Carbonic anhydrase 9', 'Gene', (289, 309))	('VIM', 'Gene', '7431', (442, 445))	('UMOD', 'Gene', (210, 214))	('E/C1', 'SUBSTITUTION', 'None', (387, 391))	('NDUFA4L2', 'Gene', (187, 195))	('Insulin-like growth factor binding protein 3', 'Gene', (317, 361))	('Carbonic anhydrase 9', 'Gene', '768', (289, 309))	('ANGPTL4', 'Gene', '51129', (238, 245))	('NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex 4-Like 2', 'Gene', '56901', (126, 185))	('Insulin-like growth factor binding protein', 'cellular_component', 'GO:0017052', ('317', '359'))	('vimentin', 'cellular_component', 'GO:0045099', ('432', '440'))	('IGFBP3', 'Gene', '3486', (363, 369))	('Angiopoietin-Like 4', 'Gene', (217, 236))	('CA9', 'Gene', (311, 314))	('vimentin', 'Gene', '7431', (432, 440))	('Insulin-like growth factor binding', 'molecular_function', 'GO:0005520', ('317', '351'))	('Uromodulin', 'Gene', '7369', (198, 208))	('Insulin-like growth factor binding protein 3', 'Gene', '3486', (317, 361))
133957	31046666	Single nucleotide polymorphisms (SNPs) at the APOE/C1 locus are found to be associated with RCC risk.	('Single nucleotide polymorphisms', 'Var', (0, 31))	('RCC', 'Disease', (92, 95))	('associated', 'Reg', (76, 86))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('APOE/C1', 'Gene', (46, 53))	('APOE/C1', 'Gene', '341;348;6966', (46, 53))
133984	30987368	These tumours are driven by inactivation of the von Hippel Lindau (VHL) tumour suppressor gene.	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('von Hippel Lindau (VHL) tumour', 'Disease', 'MESH:D006623', (48, 78))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('inactivation', 'Var', (28, 40))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('tumours', 'Disease', (6, 13))
133992	30987368	Recently, other common molecular drivers have been identified with mutations commonly involving chromatin-remodelling genes (PBRM1, KDM5C, SETD2, and BAP1).	('chromatin-remodelling', 'biological_process', 'GO:0006338', ('96', '117'))	('BAP1', 'Gene', (150, 154))	('SETD2', 'Gene', (139, 144))	('KDM5C', 'Gene', (132, 137))	('KDM5C', 'Gene', '8242', (132, 137))	('mutations', 'Var', (67, 76))	('chromatin', 'cellular_component', 'GO:0000785', ('96', '105'))	('PBRM1', 'Gene', (125, 130))	('BAP1', 'Gene', '8314', (150, 154))	('PBRM1', 'Gene', '55193', (125, 130))	('SETD2', 'Gene', '29072', (139, 144))
133995	30987368	Type 1 papillary renal cell carcinomas are enriched in MET alterations, mainly mutations and gains in chromosome 7 involving the MET locus.	('gains', 'PosReg', (93, 98))	('papillary renal cell carcinomas', 'Disease', 'MESH:C538614', (7, 38))	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (17, 37))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (17, 38))	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (7, 38))	('Type 1 papillary renal cell carcinomas', 'Phenotype', 'HP:0011797', (0, 38))	('chromosome', 'cellular_component', 'GO:0005694', ('102', '112'))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('papillary renal cell carcinomas', 'Disease', (7, 38))	('mutations', 'Var', (79, 88))
133996	30987368	However, MET copy number gain is also found in up to 50% of type 2 pRCC.	('pRCC', 'Gene', (67, 71))	('copy number gain', 'Var', (13, 29))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('pRCC', 'Phenotype', 'HP:0006766', (67, 71))	('pRCC', 'Gene', '5546', (67, 71))
133997	30987368	Recurrent alterations of SETD2, EGFR, CDKN2A, NF2, TERT, and FH were also described and occurred more frequently in type 2 pRCC, suggesting deregulation of chromatin remodelling and activation of the cell cycle and MAP kinases pathway.	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('pRCC', 'Gene', (123, 127))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('156', '177'))	('NF2', 'Gene', '4771', (46, 49))	('occurred', 'Reg', (88, 96))	('TERT', 'Gene', (51, 55))	('MAP', 'molecular_function', 'GO:0004239', ('215', '218'))	('NF2', 'Gene', (46, 49))	('TERT', 'Gene', '7015', (51, 55))	('EGFR', 'Gene', (32, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('32', '36'))	('SETD2', 'Gene', (25, 30))	('alterations', 'Var', (10, 21))	('deregulation', 'Reg', (140, 152))	('chromatin', 'cellular_component', 'GO:0000785', ('156', '165'))	('cell cycle', 'biological_process', 'GO:0007049', ('200', '210'))	('CDKN2A', 'Gene', (38, 44))	('pRCC', 'Gene', '5546', (123, 127))	('SETD2', 'Gene', '29072', (25, 30))	('EGFR', 'Gene', '1956', (32, 36))	('pRCC', 'Phenotype', 'HP:0006766', (123, 127))	('FH', 'Disease', 'MESH:D006938', (61, 63))	('CDKN2A', 'Gene', '1029', (38, 44))
133998	30987368	Chromophobe renal cell carcinoma (cRCC) is an eosinophilic tumour (Figure 1C) derived from the distal nephron, characterized by mitochondrial alterations with increased mitochondria count, expression of genes involved the in citric acid cycle, and mutations in mitochondrial DNA copies.	('mutations', 'Var', (248, 257))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (12, 32))	('Chromophobe renal cell carcinoma', 'Disease', (0, 32))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('261', '278'))	('eosinophilic tumour', 'Disease', (46, 65))	('citric acid cycle', 'biological_process', 'GO:0006099', ('225', '242'))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('mitochondrial alterations', 'Phenotype', 'HP:0012103', (128, 153))	('RCC', 'Disease', (35, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('mitochondria', 'cellular_component', 'GO:0005739', ('169', '181'))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('Chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 32))	('mitochondrial', 'Gene', (261, 274))	('citric acid', 'Chemical', 'MESH:D019343', (225, 236))	('increased', 'PosReg', (159, 168))	('eosinophilic tumour', 'Disease', 'MESH:D004802', (46, 65))	('increased mitochondria', 'Phenotype', 'HP:0041045', (159, 181))	('mitochondria count', 'MPA', (169, 187))
134009	30987368	Mutations of NF2, SETD2, and SMARCB1 were also reported.	('NF2', 'Gene', '4771', (13, 16))	('SMARCB1', 'Gene', '6598', (29, 36))	('SETD2', 'Gene', '29072', (18, 23))	('SMARCB1', 'Gene', (29, 36))	('Mutations', 'Var', (0, 9))	('SETD2', 'Gene', (18, 23))	('NF2', 'Gene', (13, 16))
134012	30987368	Sarcomatoid features can occur in each histologic subtype (Figure 1F) and in the sarcomatoid component, demonstrate an increased mutational burden along with a higher frequency of TP53, CDKN2A, and NF2 mutations and chromatin remodelling genes, BAP1 and ARID1A.	('chromatin', 'cellular_component', 'GO:0000785', ('216', '225'))	('Sarcomatoid', 'Disease', 'MESH:C538614', (0, 11))	('BAP1', 'Gene', '8314', (245, 249))	('TP53', 'Gene', (180, 184))	('NF2', 'Gene', '4771', (198, 201))	('CDKN2A', 'Gene', '1029', (186, 192))	('ARID1A', 'Gene', (254, 260))	('NF2', 'Gene', (198, 201))	('BAP1', 'Gene', (245, 249))	('ARID1A', 'Gene', '8289', (254, 260))	('mutational burden', 'MPA', (129, 146))	('Sarcomatoid', 'Disease', (0, 11))	('TP53', 'Gene', '7157', (180, 184))	('sarcomatoid component', 'Disease', (81, 102))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('216', '237'))	('sarcomatoid component', 'Disease', 'MESH:C538614', (81, 102))	('CDKN2A', 'Gene', (186, 192))	('increased', 'PosReg', (119, 128))	('mutations', 'Var', (202, 211))
134025	30987368	Biological rationale encouraged the synergy of CTLA-4 inhibition, which favours the development of an active immune response at the level of T-cell proliferation, with PD-1 inhibition, which modulates the immune response at the level of the tumour micro-environment.	('inhibition', 'Var', (54, 64))	('CTLA-4', 'Gene', '1493', (47, 53))	('CTLA-4', 'Gene', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (241, 247))	('T-cell proliferation', 'biological_process', 'GO:0042098', ('141', '161'))	('tumour', 'Disease', 'MESH:D009369', (241, 247))	('favours', 'PosReg', (72, 79))	('immune response', 'biological_process', 'GO:0006955', ('205', '220'))	('immune response', 'biological_process', 'GO:0006955', ('109', '124'))	('tumour', 'Disease', (241, 247))	('active immune', 'MPA', (102, 115))
134026	30987368	In ccRCC, the inactivation of VHL results in an increase of growth factors, such as VEGF, that favour the proliferation and migration of endothelial cells.	('VHL', 'Gene', (30, 33))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('favour', 'PosReg', (95, 101))	('RCC', 'Disease', (5, 8))	('VEGF', 'Gene', (84, 88))	('inactivation', 'Var', (14, 26))	('VHL', 'Gene', '7428', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('migration of endothelial cells', 'CPA', (124, 154))	('growth factors', 'MPA', (60, 74))	('proliferation', 'CPA', (106, 119))	('VEGF', 'Gene', '7422', (84, 88))	('increase', 'PosReg', (48, 56))
134031	30987368	Interestingly, VEGF inhibitors are able to reverse these effects by improving dendritic cell function and antigen presentation, vasculature normalization with greater trafficking of immune cells, increased cytotoxic T cell infiltration, and decreased MDSC and T-regulatory cells that could potentially reduce the immunosuppressive effect in the tumour micro-environment.	('tumour', 'Disease', (345, 351))	('increased', 'PosReg', (196, 205))	('trafficking', 'CPA', (167, 178))	('cytotoxic T cell infiltration', 'CPA', (206, 235))	('antigen presentation', 'biological_process', 'GO:0019882', ('106', '126'))	('decreased', 'NegReg', (241, 250))	('vasculature', 'CPA', (128, 139))	('antigen presentation', 'MPA', (106, 126))	('VEGF', 'Gene', (15, 19))	('inhibitors', 'Var', (20, 30))	('greater', 'PosReg', (159, 166))	('tumour', 'Phenotype', 'HP:0002664', (345, 351))	('improving', 'PosReg', (68, 77))	('tumour', 'Disease', 'MESH:D009369', (345, 351))	('VEGF', 'Gene', '7422', (15, 19))	('dendritic cell function', 'CPA', (78, 101))
134056	30987368	Pembrolizumab and atezolizumab are currently being evaluated in the phase III trials, IMmotion010 (NCT03024996) and Keynote 564 (NCT03142334), respectively.	('NCT03024996', 'Var', (99, 110))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (0, 13))	('atezolizumab', 'Chemical', 'MESH:C000594389', (18, 30))	('NCT03142334', 'Var', (129, 140))
134062	30987368	The coprimary endpoints were PFS in PD-L1+ patients and OS in intention-to-treat (ITT) patients.	('patients', 'Species', '9606', (43, 51))	('PD-L1+', 'Var', (36, 42))	('PFS', 'Disease', (29, 32))	('patients', 'Species', '9606', (87, 95))
134094	30987368	In concordance with the results on ccRCC, the expression of PD-L1 on tumour cells was associated with worse outcomes in nccRCC.	('tumour', 'Disease', (69, 75))	('expression', 'Var', (46, 56))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('associated', 'Reg', (86, 96))	('PD-L1', 'Gene', (60, 65))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (123, 126))	('RCC', 'Disease', (37, 40))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('RCC', 'Disease', 'MESH:C538614', (123, 126))
134102	30987368	Among mutations, insertions/deletions, a rich source of immunogenic neoantigens, are more frequently observed in RCC.	('insertions/deletions', 'Var', (17, 37))	('observed', 'Reg', (101, 109))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))
134103	30987368	One hypothesis is that RCC with the worst clinical prognosis better responds to ICI due to a higher mutational load.	('better', 'PosReg', (61, 67))	('clinical', 'Species', '191496', (42, 50))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('ICI', 'Chemical', '-', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('responds to ICI', 'MPA', (68, 83))	('mutational', 'Var', (100, 110))
134118	30987368	The clinical utility of mutational burden has not yet been demonstrated in RCC studies and is still under evaluation and the proportion of insertions and deletions could be more relevant in RCC.	('clinical', 'Species', '191496', (4, 12))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', (190, 193))	('RCC', 'Phenotype', 'HP:0005584', (190, 193))	('deletions', 'Var', (154, 163))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))
134121	30269473	Loss of Nuclear BAP1 Expression Is Associated with High WHO/ISUP Grade in Clear Cell Renal Cell Carcinoma BRCA1-associated protein 1 (BAP1) mutations are frequently reported in clear cell renal cell carcinoma (ccRCC); however, very few studies have evaluated the role of these mutations in other renal cell carcinoma (RCC) subtypes.	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (74, 105))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (85, 105))	('clear cell renal cell carcinoma', 'Disease', (177, 208))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (296, 316))	('BAP1', 'Gene', '8314', (16, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (210, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('BAP1', 'Gene', '8314', (134, 138))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('BRCA1-associated protein 1', 'Gene', '8314', (106, 132))	('Loss', 'NegReg', (0, 4))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (177, 208))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (74, 105))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (188, 208))	('BAP1', 'Gene', (16, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (307, 316))	('renal cell carcinoma', 'Disease', (296, 316))	('BRCA1-associated protein 1', 'Gene', (106, 132))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (296, 316))	('BAP1', 'Gene', (134, 138))	('RCC', 'Disease', (318, 321))	('RCC', 'Phenotype', 'HP:0005584', (318, 321))	('mutations', 'Var', (140, 149))	('Clear Cell Renal Cell Carcinoma', 'Disease', (74, 105))	('reported', 'Reg', (165, 173))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (177, 208))	('RCC', 'Disease', 'MESH:C538614', (318, 321))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (188, 208))	('Carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('RCC', 'Disease', (212, 215))	('RCC', 'Phenotype', 'HP:0005584', (212, 215))
134131	30269473	Clear cell renal cell carcinoma (ccRCC) is the most common renal tumor subtype and is closely associated with von Hippel Lindau (VHL) tumor suppressor gene mutations that lead to the stabilization of hypoxia-inducible factors in both sporadic and familial forms.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('134', '150'))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('tumor suppressor', 'biological_process', 'GO:0051726', ('134', '150'))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('hypoxia', 'Disease', (200, 207))	('RCC', 'Disease', (35, 38))	('stabilization', 'MPA', (183, 196))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('hypoxia', 'Disease', 'MESH:D000860', (200, 207))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('mutations', 'Var', (156, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('renal tumor', 'Disease', 'MESH:D007674', (59, 70))	('renal tumor', 'Phenotype', 'HP:0009726', (59, 70))	('von Hippel Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (110, 139))	('renal tumor', 'Disease', (59, 70))
134133	30269473	Studies have reported BAP1 mutation in about 10%-15% of ccRCC cases.	('mutation', 'Var', (27, 35))	('BAP1', 'Gene', '8314', (22, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('reported', 'Reg', (13, 21))	('BAP1', 'Gene', (22, 26))
134136	30269473	Inactivation mutations of the BAP1 gene, including insertion, deletion, frameshift, nonsense, and missense mutations, have also been reported.	('frameshift', 'Var', (72, 82))	('BAP1', 'Gene', (30, 34))	('nonsense', 'Var', (84, 92))	('missense mutations', 'Var', (98, 116))	('insertion', 'Var', (51, 60))	('BAP1', 'Gene', '8314', (30, 34))	('deletion', 'Var', (62, 70))
134137	30269473	The germline mutation in the BAP1 gene is inherited in an autosomal dominant pattern.	('BAP1', 'Gene', '8314', (29, 33))	('BAP1', 'Gene', (29, 33))	('germline mutation', 'Var', (4, 21))
134140	30269473	BAP1 germline mutations are associated with poor prognosis in uveal melanoma, cutaneous melanoma, and ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('uveal melanoma', 'Disease', (62, 76))	('BAP1', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('germline mutations', 'Var', (5, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (78, 96))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('cutaneous melanoma', 'Disease', (78, 96))	('BAP1', 'Gene', '8314', (0, 4))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (78, 96))	('uveal melanoma', 'Phenotype', 'HP:0007716', (62, 76))	('uveal melanoma', 'Disease', 'MESH:C536494', (62, 76))	('RCC', 'Disease', (104, 107))
134141	30269473	Sporadic BAP1 mutations have also been identified in several tumors, including uveal melanoma, malignant mesothelioma, and ccRCC.	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (95, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('BAP1', 'Gene', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('identified', 'Reg', (39, 49))	('malignant mesothelioma', 'Disease', (95, 117))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mutations', 'Var', (14, 23))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))	('uveal melanoma', 'Disease', (79, 93))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (95, 117))	('tumors', 'Disease', (61, 67))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('BAP1', 'Gene', '8314', (9, 13))
134143	30269473	Nearly half of the investigated uveal melanoma tumors harbor an inactivating BAP1 mutation, which was strongly associated with the loss of BAP1 nuclear staining and other aggressive prognostic features.	('uveal melanoma', 'Phenotype', 'HP:0007716', (32, 46))	('loss', 'NegReg', (131, 135))	('associated', 'Reg', (111, 121))	('inactivating', 'Var', (64, 76))	('BAP1', 'Gene', '8314', (139, 143))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (32, 53))	('BAP1', 'Gene', '8314', (77, 81))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('uveal melanoma tumors', 'Disease', (32, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('BAP1', 'Gene', (139, 143))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('BAP1', 'Gene', (77, 81))
134144	30269473	Furthermore, several studies have revealed the association between inactivating BAP1 mutation and high grade ccRCC, sarcomatoid transformation, and poor prognosis in patients with ccRCC, especially in those with low-grade RCC.	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('sarcomatoid transformation', 'Disease', (116, 142))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('BAP1', 'Gene', '8314', (80, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('inactivating', 'Var', (67, 79))	('mutation', 'Var', (85, 93))	('RCC', 'Phenotype', 'HP:0005584', (222, 225))	('RCC', 'Disease', 'MESH:C538614', (222, 225))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('RCC', 'Disease', (222, 225))	('BAP1', 'Gene', (80, 84))	('RCC', 'Disease', (182, 185))	('sarcomatoid transformation', 'Disease', 'MESH:C538614', (116, 142))	('patients', 'Species', '9606', (166, 174))
134145	30269473	The loss of BAP1 expression in immunohistochemical staining has been reported as a highly reliable method for the detection of BAP1 mutation.	('BAP1', 'Gene', (127, 131))	('mutation', 'Var', (132, 140))	('expression', 'MPA', (17, 27))	('BAP1', 'Gene', '8314', (12, 16))	('BAP1', 'Gene', '8314', (127, 131))	('BAP1', 'Gene', (12, 16))	('loss', 'NegReg', (4, 8))
134146	30269473	Although BAP1 mutations are frequently observed in ccRCC, limited data are available on the expression of BAP1 in other RCC types.	('BAP1', 'Gene', (106, 110))	('observed', 'Reg', (39, 47))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('BAP1', 'Gene', '8314', (9, 13))	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('BAP1', 'Gene', '8314', (106, 110))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
134181	30269473	BAP1 mutation, a chromatin remodeling gene mutation, was reported in ccRCC (11.0%) and papillary RCC (5.6%) but not in chromophobe RCC.	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('BAP1', 'Gene', (0, 4))	('chromophobe RCC', 'Disease', (119, 134))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('17', '37'))	('RCC', 'Disease', (131, 134))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('chromatin', 'cellular_component', 'GO:0000785', ('17', '26'))	('ccRCC', 'Phenotype', 'HP:0006770', (69, 74))	('chromophobe RCC', 'Disease', 'MESH:C538614', (119, 134))	('BAP1', 'Gene', '8314', (0, 4))	('mutation', 'Var', (5, 13))
134182	30269473	BAP1 mutation was also shown to be correlated with decreased survival in ccRCC.	('BAP1', 'Gene', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('decreased', 'NegReg', (51, 60))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('survival', 'MPA', (61, 69))	('BAP1', 'Gene', '8314', (0, 4))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))	('mutation', 'Var', (5, 13))
134185	30269473	BAP1 mutation was more frequent in female patients as per TCGA data.	('BAP1', 'Gene', (0, 4))	('frequent', 'Reg', (23, 31))	('BAP1', 'Gene', '8314', (0, 4))	('patients', 'Species', '9606', (42, 50))	('mutation', 'Var', (5, 13))
134187	30269473	In several studies, loss of BAP1 expression served as an independent marker of prognosis in patients with ccRCC and low-grade ccRCC.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (108, 111))	('RCC', 'Disease', (128, 131))	('loss', 'Var', (20, 24))	('BAP1', 'Gene', '8314', (28, 32))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('BAP1', 'Gene', (28, 32))	('patients', 'Species', '9606', (92, 100))	('expression', 'MPA', (33, 43))
134195	30269473	An additional analysis is needed to further elucidate the role of BAP1 and the relationship between loss of BAP1 expression in IHC and BAP1 mutation in chromophobe RCC and clear cell papillary RCC.	('expression', 'MPA', (113, 123))	('RCC', 'Disease', (193, 196))	('BAP1', 'Gene', '8314', (66, 70))	('BAP1', 'Gene', '8314', (108, 112))	('RCC', 'Phenotype', 'HP:0005584', (193, 196))	('chromophobe RCC', 'Disease', 'MESH:C538614', (152, 167))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('BAP1', 'Gene', '8314', (135, 139))	('mutation', 'Var', (140, 148))	('BAP1', 'Gene', (66, 70))	('BAP1', 'Gene', (108, 112))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('BAP1', 'Gene', (135, 139))	('RCC', 'Disease', (164, 167))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))	('chromophobe RCC', 'Disease', (152, 167))	('loss', 'NegReg', (100, 104))
134196	30269473	In conclusion, we revealed that BAP1 expression is associated with high WHO/ISUP grade in patients with ccRCC and that BAP1 expression loss is also observed in chromophobe RCC and clear cell papillary RCC.	('expression', 'Var', (37, 47))	('chromophobe RCC', 'Disease', 'MESH:C538614', (160, 175))	('BAP1', 'Gene', (32, 36))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('BAP1', 'Gene', (119, 123))	('RCC', 'Disease', (201, 204))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))	('chromophobe RCC', 'Disease', (160, 175))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('patients', 'Species', '9606', (90, 98))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('loss', 'NegReg', (135, 139))	('BAP1', 'Gene', '8314', (32, 36))	('associated', 'Reg', (51, 61))	('BAP1', 'Gene', '8314', (119, 123))	('expression', 'MPA', (124, 134))	('RCC', 'Disease', (172, 175))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))
134199	29301960	We found that clinical benefit was associated with loss-of-function mutations in the PBRM1 gene (p=0.012), which encodes a subunit of a SWI/SNF chromatin remodeling complex (the PBAF subtype).	('clinical benefit', 'CPA', (14, 30))	('PBRM1', 'Gene', (85, 90))	('loss-of-function', 'NegReg', (51, 67))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('144', '164'))	('mutations', 'Var', (68, 77))	('BAF', 'Chemical', 'MESH:C012071', (179, 182))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('144', '172'))
134205	29301960	Melanoma and NSCLC typically harbor 10 to 400 mutations per megabase (Mb) and these genetic variants can generate tumor-specific antigens (neoantigens) that stimulate a strong anti-tumor immune response.	('NSCLC', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('tumor', 'Disease', (181, 186))	('mutations', 'Var', (46, 55))	('NSCLC', 'Disease', 'MESH:D002289', (13, 18))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('stimulate', 'PosReg', (157, 166))	('Melanoma', 'Disease', (0, 8))	('immune response', 'biological_process', 'GO:0006955', ('187', '202'))	('tumor', 'Disease', (114, 119))	('NSCLC', 'Phenotype', 'HP:0030358', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('variants', 'Var', (92, 100))
134224	29301960	Mutations and copy number alterations affecting antigen presentation machinery and HLA class I alleles were uncommon and were present in tumors of both CB and NCB patients (fig.	('present', 'Reg', (126, 133))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('patients', 'Species', '9606', (163, 171))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('antigen presentation', 'biological_process', 'GO:0019882', ('48', '68'))	('copy number alterations', 'Var', (14, 37))	('NCB', 'Disease', (159, 162))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
134225	29301960	2A and table S1E), PBRM1 was the only gene in which truncating, or loss-of-function (LOF), mutations were enriched in tumors from patients in the CB vs. NCB group (9/11 vs. 3/13; Fisher's exact p=0.012, q=0.086, odds ratio for CB=12.93, 95% C.I.	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('patients', 'Species', '9606', (130, 138))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('mutations', 'Var', (91, 100))	('tumors', 'Disease', (118, 124))	('loss-of-function', 'NegReg', (67, 83))	('truncating', 'MPA', (52, 62))	('PBRM1', 'Gene', (19, 24))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
134226	29301960	2A), resulting in complete LOF of PBRM1, and most of the mutations were predicted to be clonal (present in all tumor cells) (table S1F).	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('PBRM1', 'Gene', (34, 39))	('tumor', 'Disease', (111, 116))	('mutations', 'Var', (57, 66))	('LOF', 'NegReg', (27, 30))
134227	29301960	Prior large-scale sequencing studies have shown that PBRM1 LOF alterations occur in up to 41% of ccRCC tumors and are commonly clonal events present in all or nearly all tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('alterations', 'Var', (63, 74))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (103, 108))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Disease', (170, 175))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('LOF', 'NegReg', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('PBRM1', 'Gene', (53, 58))
134234	29301960	Notably, one of the four NCB patients whose tumor showed a PBRM1 LOF mutation also had an alteration in B2M, which codes for a protein important in antigen presentation.	('patients', 'Species', '9606', (29, 37))	('alteration', 'Reg', (90, 100))	('antigen presentation', 'biological_process', 'GO:0019882', ('148', '168'))	('PBRM1', 'Gene', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('mutation', 'Var', (69, 77))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('LOF', 'NegReg', (65, 68))	('tumor', 'Disease', (44, 49))	('B2M', 'MPA', (104, 107))
134235	29301960	This provides a potential explanation for the patient's lack of clinical benefit from immune checkpoint blockade therapy despite having a truncating PBRM1 mutation.	('patient', 'Species', '9606', (46, 53))	('PBRM1', 'Gene', (149, 154))	('mutation', 'Var', (155, 163))	('truncating', 'MPA', (138, 148))
134236	29301960	While primary analyses excluded patients with intermediate benefit (IB) due to the unclear effect of immune checkpoint blockade therapy on patient outcomes in this group, the observed trend between PBRM1 mutation status and clinical benefit persisted with the inclusion of these patients as an intermediate phenotype.	('PBRM1', 'Gene', (198, 203))	('mutation', 'Var', (204, 212))	('patients', 'Species', '9606', (32, 40))	('patient', 'Species', '9606', (279, 286))	('patients', 'Species', '9606', (279, 287))	('patient', 'Species', '9606', (32, 39))	('patient', 'Species', '9606', (139, 146))
134242	29301960	To explore the potential impact of this complex on the immunophenotype of ccRCC, we analyzed previously reported whole transcriptome sequencing (RNA-seq) data from A704 ccRCC cell lines with perturbations in the PBAF complex.	('perturbations', 'Var', (191, 204))	('BAF', 'Chemical', 'MESH:C012071', (213, 216))	('PBAF', 'Gene', (212, 216))	('PBAF complex', 'cellular_component', 'GO:0016586', ('212', '224'))	('RNA', 'cellular_component', 'GO:0005562', ('145', '148'))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))
134243	29301960	Loss of BAF180 or the related PBAF subunit BRG1, encoded by the gene SMARCA4, prevent formation of the intact PBAF complex.	('BAF', 'Chemical', 'MESH:C012071', (31, 34))	('prevent', 'NegReg', (78, 85))	('BAF180', 'Gene', (8, 14))	('BAF', 'Chemical', 'MESH:C012071', (8, 11))	('PBAF complex', 'cellular_component', 'GO:0016586', ('110', '122'))	('BAF180', 'Gene', '55193', (8, 14))	('BAF', 'Chemical', 'MESH:C012071', (111, 114))	('formation', 'biological_process', 'GO:0009058', ('86', '95'))	('SMARCA4', 'Gene', (69, 76))	('BRG1', 'Gene', (43, 47))	('SMARCA4', 'Gene', '6597', (69, 76))	('BRG1', 'Gene', '6597', (43, 47))	('Loss', 'Var', (0, 4))
134254	29301960	Previously reported GSEA analysis of untreated ccRCC from The Cancer Genome Atlas (TCGA) and a murine model of PBRM1 loss also show amplified transcriptional outputs of HIF1 and STAT3, involved in hypoxia response and JAK-STAT signaling respectively, in PBRM1-mutant vs. PBRM1-wildtype states.	('loss', 'NegReg', (117, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('STAT3', 'MPA', (178, 183))	('PBRM1-mutant', 'Gene', (254, 266))	('signaling', 'biological_process', 'GO:0023052', ('227', '236'))	('hypoxia', 'Disease', (197, 204))	('hypoxia', 'Disease', 'MESH:D000860', (197, 204))	('Cancer Genome Atlas', 'Disease', (62, 81))	('murine', 'Species', '10090', (95, 101))	('amplified', 'PosReg', (132, 141))	('Cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (62, 81))	('JAK', 'molecular_function', 'GO:0004713', ('218', '221'))	('PBRM1', 'Gene', (111, 116))	('GSEA', 'Chemical', '-', (20, 24))	('PBRM1-mutant', 'Var', (254, 266))	('transcriptional outputs', 'MPA', (142, 165))
134259	29301960	In all three cohorts, tumors harboring LOF mutations in PBRM1 showed lower expression of immune inhibitory ligands (e.g., CD276 and BTLA) than those without PBRM1 mutations.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('CD276', 'Gene', (122, 127))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('LOF', 'NegReg', (39, 42))	('lower', 'NegReg', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('CD276', 'Gene', '80381', (122, 127))	('mutations', 'Var', (43, 52))	('PBRM1', 'Gene', (56, 61))	('BTLA', 'Gene', (132, 136))	('BTLA', 'Gene', '151888', (132, 136))	('tumors', 'Disease', (22, 28))	('expression', 'MPA', (75, 85))
134260	29301960	This finding was somewhat unexpected, as high PD-L1 staining is associated with increased responsiveness to anti-PD-1 and anti-PD-L1 agents in other cancer types.	('PD-L1', 'Gene', (46, 51))	('PD-1', 'Gene', '5133', (113, 117))	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('staining', 'Var', (52, 60))	('increased', 'PosReg', (80, 89))	('PD-L1', 'Gene', '29126', (46, 51))	('high', 'Var', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('PD-L1', 'Gene', (127, 132))	('responsiveness to', 'MPA', (90, 107))	('PD-1', 'Gene', (113, 117))	('PD-L1', 'Gene', '29126', (127, 132))
134262	29301960	We also examined LOF mutations in VHL, the most commonly-mutated gene in the TCGA ccRCC cohort.	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('VHL', 'Gene', (34, 37))	('LOF', 'NegReg', (17, 20))	('VHL', 'Gene', '7428', (34, 37))	('mutations', 'Var', (21, 30))
134264	29301960	In summary, we have shown that patients with metastatic ccRCC harboring truncating mutations in PBRM1 experienced increased clinical benefit from immune checkpoint therapy.	('patients', 'Species', '9606', (31, 39))	('PBRM1', 'Gene', (96, 101))	('metastatic ccRCC', 'Disease', (45, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('truncating mutations', 'Var', (72, 92))	('benefit', 'PosReg', (133, 140))
134266	29301960	Given the high prevalence of PBRM1 LOF in ccRCC and of SWI/SNF alterations across all cancer types (more than 20%), this finding has important implications as a molecular tool for considering immunotherapy-responsiveness in ccRCC and across cancer types.	('alterations', 'Var', (63, 74))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (42, 47))	('SWI/SNF', 'Gene', (55, 62))	('ccRCC', 'Disease', (42, 47))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('ccRCC', 'Phenotype', 'HP:0006770', (224, 229))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('PBRM1', 'Gene', (29, 34))	('LOF', 'NegReg', (35, 38))	('cancer', 'Disease', (86, 92))
134267	29301960	In vivo studies of mice harboring tumor clones with inactivation of PBRM1 - or the related essential PBAF complex components ARID2 or BRD7 - show that cells with PBAF loss are more sensitive to T-cell-mediated cytotoxicity compared to their PBAF-intact counterparts.	('cytotoxicity', 'Disease', 'MESH:D064420', (210, 222))	('PBAF complex', 'cellular_component', 'GO:0016586', ('101', '113'))	('PBRM1 -', 'Gene', (68, 75))	('BRD7', 'Gene', '26992', (134, 138))	('BAF', 'Chemical', 'MESH:C012071', (102, 105))	('ARID2', 'Gene', '77044', (125, 130))	('tumor', 'Disease', (34, 39))	('BAF', 'Chemical', 'MESH:C012071', (163, 166))	('BAF', 'Chemical', 'MESH:C012071', (242, 245))	('inactivation', 'Var', (52, 64))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('mice', 'Species', '10090', (19, 23))	('BRD7', 'Gene', (134, 138))	('PBAF loss', 'Disease', 'MESH:D015431', (162, 171))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('sensitive', 'Reg', (181, 190))	('ARID2', 'Gene', (125, 130))	('cytotoxicity', 'Disease', (210, 222))	('T-cell-mediated cytotoxicity', 'biological_process', 'GO:0001913', ('194', '222'))	('PBAF loss', 'Disease', (162, 171))
134271	33187526	Combining epigenetic and clinicopathological variables improves specificity in prognostic prediction in clear cell renal cell carcinoma Metastasized clear cell renal cell carcinoma (ccRCC) is associated with a poor prognosis.	('specificity', 'MPA', (64, 75))	('epigenetic', 'Var', (10, 20))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (104, 135))	('clear cell renal cell carcinoma', 'Disease', (104, 135))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (149, 180))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (115, 135))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('RCC', 'Disease', (184, 187))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (104, 135))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (160, 180))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (149, 180))	('Metastasized clear cell renal cell carcinoma', 'Disease', (136, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('improves', 'PosReg', (55, 63))	('Metastasized clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (136, 180))
134291	33187526	Altered DNA methylation has been identified as a prognostic marker in several malignancies including ccRCC, and has been suggested as a potential target for therapy.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('malignancies', 'Disease', (78, 90))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('methylation', 'Var', (12, 23))	('malignancies', 'Disease', 'MESH:D009369', (78, 90))	('Altered DNA methylation', 'Var', (0, 23))	('DNA methylation', 'biological_process', 'GO:0006306', ('8', '23'))
134296	33187526	performed a systematic review summarizing prognostic DNA methylation biomarkers in ccRCC, and identified nine genes with strong evidence as prognostic biomarkers in ccRCC.	('methylation', 'Var', (57, 68))	('DNA methylation', 'biological_process', 'GO:0006306', ('53', '68'))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('RCC', 'Disease', (85, 88))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))
134346	33187526	The tumor diameter was significantly larger in the M0-P group than in the M0-PF group at diagnosis (p < 0.001), 95.0 mm and 56.5 mm, respectively.	('tumor', 'Disease', (4, 9))	('larger', 'PosReg', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('M0-P', 'Var', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
134348	33187526	The hemoglobin value was significantly higher (p = 0.002) in M0-PF (mean 137.6 g/l) than in M0-P (mean 121.1 g/l) patients at diagnosis.	('patients', 'Species', '9606', (114, 122))	('M0-PF', 'Var', (61, 66))	('higher', 'PosReg', (39, 45))	('hemoglobin value', 'MPA', (4, 20))
134349	33187526	For the 64 previously identified sites (PI-CpGs), 15 (23.4%) sites were significantly more methylated in the M0-P group compared to the M0-PF group (Additional file 3: Table S3).	('methylated', 'MPA', (91, 101))	('M0-P', 'Var', (109, 113))	('PI-CpGs', 'Chemical', '-', (40, 47))	('more', 'PosReg', (86, 90))
134379	33187526	DNA methylation alterations are early events in tumor progression and has appeared as a molecular biomarker candidate for improved risk classification.	('tumor', 'Disease', (48, 53))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'Gene', (0, 3))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('methylation alterations', 'Var', (4, 27))
134394	33187526	Their study supports our conclusion that methylation analysis has the potential to improve risk classification in ccRCC.	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('improve', 'PosReg', (83, 90))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('methylation analysis', 'Var', (41, 61))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))
134398	33187526	Although methylation analyses have shown prognostic value in ccRCC they are still not used in clinical diagnosis.	('methylation', 'Var', (9, 20))	('RCC', 'Disease', (63, 66))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
134411	33187526	RCC Renal cell carcinoma ccRCC Clear cell renal cell carcinoma CpG Cytosine-phosphate-Guanine CIMP CpG island methylator phenotype PI-CpG Previously identified CpG DCA Directed cluster analysis HRP High risk for progress LRP Low risk for progress TNM Tumor-node metastasis M0 Non-metastatic (TNM I-III) M1 Metastatic TSS Transcription start site DM-CpG Differently methylated CpG TCGA-KIRC Tumor Cancer Genome Atlas Kidney Renal Cell Carcinoma mQTLs Methylation quantitative trait loci M0-PF Non metastatic without tumor progression within five year M0-P Non-metastatic tumor with progress within five year PC Principal components CIP Cumulative incidence of progress Supplementary information accompanies this paper at 10.1186/s12967-020-02608-1.	('tumor', 'Disease', 'MESH:D009369', (515, 520))	('PC', 'Gene', '5091', (607, 609))	('tumor', 'Phenotype', 'HP:0002664', (570, 575))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('Tumor', 'Phenotype', 'HP:0002664', (390, 395))	('Carcinoma', 'Phenotype', 'HP:0030731', (434, 443))	('CIMP', 'Chemical', '-', (94, 98))	('CIP', 'Disease', 'MESH:D010259', (631, 634))	('tumor', 'Phenotype', 'HP:0002664', (515, 520))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (31, 62))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (423, 443))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('Clear cell renal cell carcinoma', 'Disease', (31, 62))	('mQTLs', 'Disease', (444, 449))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (42, 62))	('Renal cell carcinoma', 'Disease', (4, 24))	('CIP', 'Disease', (631, 634))	('men', 'Species', '9606', (674, 677))	('M0-PF', 'Var', (486, 491))	('Tumor', 'Phenotype', 'HP:0002664', (251, 256))	('DCA', 'Chemical', '-', (164, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('tumor', 'Disease', (570, 575))	('RCC', 'Disease', (0, 3))	('Cancer', 'Phenotype', 'HP:0002664', (396, 402))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (31, 62))	('Renal cell carcinoma', 'Disease', 'MESH:C538614', (4, 24))	('Methylation', 'biological_process', 'GO:0032259', ('450', '461'))	('mQTLs', 'Disease', 'None', (444, 449))	('tumor', 'Disease', 'MESH:D009369', (570, 575))	('Tumor Cancer Genome Atlas Kidney Renal Cell Carcinoma', 'Disease', 'MESH:D007680', (390, 443))	('tumor', 'Disease', (515, 520))	('Renal cell carcinoma', 'Phenotype', 'HP:0005584', (4, 24))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('Cytosine-phosphate-Guanine', 'Chemical', '-', (67, 93))
134428	29534467	Over 50% of kidney cancers are of the clear cell renal cell carcinoma (ccRCC) subtype, which is often characterized by an inactivation of the von Hippel-Lindau gene and arises from the epithelium of the proximal tubule.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (38, 69))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (49, 69))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('inactivation', 'Var', (122, 134))	('von Hippel-Lindau', 'Disease', (142, 159))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('kidney cancers', 'Disease', 'MESH:D007680', (12, 26))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (142, 159))	('kidney cancers', 'Disease', (12, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('kidney cancers', 'Phenotype', 'HP:0009726', (12, 26))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (38, 69))	('clear cell renal cell carcinoma', 'Disease', (38, 69))
134455	29534467	Similarly, a log2CPM cut-off of 1 for miR-184 (Figure 2B) resulted in one normal sample being classified incorrectly, while all others were correctly classified as either tumour or normal tissue.	('miR-184', 'Gene', (38, 45))	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('miR-184', 'Gene', '406960', (38, 45))	('tumour', 'Disease', 'MESH:D009369', (171, 177))	('tumour', 'Disease', (171, 177))	('log2CPM', 'Var', (13, 20))
134554	27555084	Aristolochic Acid in the Etiology of Renal Cell Carcinoma Aristolochia species used in the practice of traditional herbal medicine contains aristolochic acid (AA), an established human carcinogen contributing to urothelial carcinomas of the upper urinary tract.	('carcinomas', 'Phenotype', 'HP:0030731', (223, 233))	('Aristolochia', 'Species', '158538', (58, 70))	('human', 'Species', '9606', (179, 184))	('urothelial carcinomas', 'Disease', (212, 233))	('aristolochic acid', 'Chemical', 'MESH:C000228', (140, 157))	('Aristolochic Acid', 'Chemical', 'MESH:C000228', (0, 17))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (212, 233))	('Renal Cell Carcinoma', 'Disease', (37, 57))	('urothelial carcinomas of the upper urinary', 'Phenotype', 'HP:0010935', (212, 254))	('aristolochic', 'Var', (140, 152))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (37, 57))	('Carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('herbal medicine', 'Species', '1407750', (115, 130))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (37, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))
134565	27555084	A recent bioinformatics survey of tumor types occurring primarily in Western populations identified at least 21 mutational signatures.	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('mutational', 'Var', (112, 122))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
134567	27555084	These tumors harbor a high content of A-to-T transversions, affecting adenines genome wide within a set of specific trinucleotide sequences.	('adenines', 'Chemical', 'MESH:D000225', (70, 78))	('affecting', 'Reg', (60, 69))	('A-to-T', 'Var', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('adenines', 'MPA', (70, 78))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('trinucleotide', 'Chemical', '-', (116, 129))
134613	27555084	For each tumor, any mutation in the VHL and PBRM1 genes, and six to nine randomly chosen mutations, were selected for validation by Sanger sequencing (Supplementary Table S3).	('PBRM1', 'Gene', (44, 49))	('VHL', 'Gene', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('VHL', 'Gene', '7428', (36, 39))	('mutation', 'Var', (20, 28))	('PBRM1', 'Gene', '55193', (44, 49))	('tumor', 'Disease', (9, 14))	('men', 'Species', '9606', (157, 160))
134614	27555084	Nonsynonymous mutations (protein altering) accounted for 78.9% of total mutations with a median of 65 nonsynonymous mutations per tumor (range, 14-278).	('mutations', 'Var', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('Nonsynonymous mutations', 'Var', (0, 23))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('tumor', 'Disease', (130, 135))
134616	27555084	Nonsynonymous mutations were found in 853 genes, including several genes found to be significantly mutated in prior studies of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('Nonsynonymous mutations', 'Var', (0, 23))	('RCC', 'Disease', (129, 132))
134618	27555084	The second most frequent was PBRM1, with inactivating mutations in 2 of 10 tumors.	('inactivating mutations', 'Var', (41, 63))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('PBRM1', 'Gene', '55193', (29, 34))	('tumors', 'Disease', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('PBRM1', 'Gene', (29, 34))
134620	27555084	We also observed mutations in other known ccRCC driver genes, including the tumor suppressors SETD2, BAP1, GNB2L1, and EPAS1, as well as an oncogenic mutation in PIK3CA (Supplementary Table S2).	('PIK3CA', 'Gene', '5290', (162, 168))	('SETD2', 'Gene', (94, 99))	('EPAS1', 'Gene', '2034', (119, 124))	('BAP1', 'Gene', '8314', (101, 105))	('SETD2', 'Gene', '29072', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('EPAS1', 'Gene', (119, 124))	('RCC', 'Disease', (44, 47))	('men', 'Species', '9606', (176, 179))	('ccRCC', 'Phenotype', 'HP:0006770', (42, 47))	('GNB2L1', 'Gene', '10399', (107, 113))	('BAP1', 'Gene', (101, 105))	('GNB2L1', 'Gene', (107, 113))	('mutations', 'Var', (17, 26))	('PIK3CA', 'Gene', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
134622	27555084	Loss of chromosome 3p is the most frequent somatic alteration in ccRCC, as this region contains a number of driver genes, including VHL.	('VHL', 'Gene', (132, 135))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('VHL', 'Gene', '7428', (132, 135))	('RCC', 'Disease', (67, 70))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('Loss', 'Var', (0, 4))
134623	27555084	Indeed, we detected chromosome 3p arm loss in 6 of 10 tumors (Supplementary Fig.	('chromosome', 'cellular_component', 'GO:0005694', ('20', '30'))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('chromosome', 'Var', (20, 30))	('tumors', 'Disease', (54, 60))	('men', 'Species', '9606', (68, 71))	('loss', 'NegReg', (38, 42))	('tumors', 'Disease', 'MESH:D009369', (54, 60))
134626	27555084	Indeed, the fraction of A-to-T transversion mutations in the 10 AA-exposed ccRCC was significantly higher (33 +- 23%, mean +- SD) than in the TCGA ccRCCs (10.7 +- 4.4%; P < 0.0001, two-tailed t test; Fig.	('RCC', 'Disease', (149, 152))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('higher', 'PosReg', (99, 105))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('ccRCC', 'Phenotype', 'HP:0006770', (147, 152))	('A-to-T transversion mutations', 'Var', (24, 53))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
134635	27555084	We examined 488 A-to-T mutations compiled from the 6 ccRCC cases with an excess fraction of A-to-T transversions for key features of the AA mutational signature observed in AA-associated UTUC.	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('transversions', 'Var', (99, 112))	('mutations', 'Var', (23, 32))
134639	27555084	The A>T strand biases in AA-associated ccRCCs and AA-associated UTUCs were 2.1-fold and 2.6-fold, respectively.	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('AA-associated', 'Disease', (25, 38))	('A>T', 'Var', (4, 7))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))
134641	27555084	Figure 4B shows the frequencies of the 16 potential trinucleotides in which a dA residue in the central position is mutated to form an A-to-T transversion.	('trinucleotides', 'Chemical', '-', (52, 66))	('mutated', 'Var', (116, 123))	('A-to-T transversion', 'MPA', (135, 154))	('dA', 'Chemical', 'MESH:C058118', (78, 80))
134642	27555084	The 5'CpApG trinucleotide includes 29% of the A-to-T mutations (141 A>T in CpApG of 488 XpApX) in the Taiwanese ccRCCs compared with only 11% (273/2,575) in the TCGA dataset (P = 2.3-27, two-sided chi2).	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('CpApG', 'Chemical', '-', (6, 11))	('RCC', 'Disease', (114, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('141 A>T', 'Mutation', 'rs876660821', (64, 71))	('CpApG', 'Gene', (75, 80))	('CpApG', 'Chemical', '-', (75, 80))	('trinucleotide', 'Chemical', '-', (12, 25))	('141 A>T', 'Var', (64, 71))
134645	27555084	Consistent with an increased A-to-T preference for the CpApG context, the frequency of mutations in the splice acceptor was elevated in ccRCC compared with TCGA (2.8% vs. 1.0% of substitutions, respectively; Fig.	('RCC', 'Disease', (138, 141))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('CpApG', 'Chemical', '-', (55, 60))	('mutations', 'Var', (87, 96))	('elevated', 'PosReg', (124, 132))
134646	27555084	The ratio of the number of mutations at splice acceptor to splice donor sites was 3.4-fold (24/7) in the Taiwanese ccRCCs.	('mutations', 'Var', (27, 36))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('donor', 'Species', '9606', (66, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))
134671	27555084	The mutation spectrum in RCCs from England, Russia, and the Czech Republic resembled that seen in the TCGA RCC study (drawn from an American population); however, the AA mutational signature predominated a majority of the Romanian RCCs (12/14) and 4 of 8 Croatian RCCs.	('RCC', 'Disease', 'MESH:C538614', (264, 267))	('RCC', 'Disease', (264, 267))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('RCC', 'Disease', (107, 110))	('RCC', 'Disease', (231, 234))	('RCC', 'Disease', 'MESH:C538614', (231, 234))	('AA mutational signature', 'Var', (167, 190))	('Romania', 'Disease', 'None', (222, 229))	('Romania', 'Disease', (222, 229))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('RCC', 'Disease', (25, 28))
134676	27555084	Also, the number of A-to-T transversions per exome is higher in UTUC with the AA mutational signature than AA-related RCC (median = 188 per exome in UTUC and 46 per exome in RCC).	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('higher', 'PosReg', (54, 60))	('A-to-T', 'Var', (20, 26))	('RCC', 'Disease', (118, 121))	('mutational signature', 'Var', (81, 101))	('RCC', 'Disease', (174, 177))	('transversions', 'Var', (27, 40))	('RCC', 'Disease', 'MESH:C538614', (174, 177))
134685	32197306	Germline mutations in DNA damage repair genes and the transcription factor HOXB13 are associated with prostate cancer and may be targeted therapeutically.	('Germline mutations', 'Var', (0, 18))	('transcription', 'biological_process', 'GO:0006351', ('54', '67'))	('HOXB13', 'Gene', '10481', (75, 81))	('transcription factor', 'molecular_function', 'GO:0000981', ('54', '74'))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('HOXB13', 'Gene', (75, 81))	('associated', 'Reg', (86, 96))	('prostate cancer', 'Disease', (102, 117))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('DNA damage repair genes', 'Gene', (22, 45))	('prostate cancer', 'Disease', 'MESH:D011471', (102, 117))	('prostate cancer', 'Phenotype', 'HP:0012125', (102, 117))
134687	32197306	Much of what is known about genitourinary (GU) cancers derives from the well-characterized genetic alterations in various hereditary syndromes (Figure 1).	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('genetic alterations', 'Var', (91, 110))	('genitourinary', 'Disease', (28, 41))	('cancers', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
134690	32197306	Clear cell RCC (ccRCC), the most common form of RCC, is associated with alterations in the VHL gene causing a cascade of events, ultimately increasing the expression of vascular growth factors (VEGF).	('RCC', 'Disease', (18, 21))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('alterations', 'Var', (72, 83))	('increasing', 'PosReg', (140, 150))	('causing', 'Reg', (100, 107))	('VHL', 'Gene', (91, 94))	('VEGF', 'Gene', (194, 198))	('expression', 'MPA', (155, 165))	('RCC', 'Disease', 'MESH:C538614', (18, 21))	('VHL', 'Gene', '7428', (91, 94))	('VEGF', 'Gene', '7422', (194, 198))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))	('RCC', 'Disease', (48, 51))
134694	32197306	Mutations in FGFR3 or HRAS are found in 65%-80% of low-grade cases and are less frequent in high-grade tumors, which are more likely to harbor mutations in TP53 or Rb.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('FGFR3', 'Gene', '2261', (13, 18))	('FGFR3', 'Gene', (13, 18))	('tumors', 'Disease', (103, 109))	('TP53', 'Gene', (156, 160))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('HRAS', 'Gene', '3265', (22, 26))	('TP53', 'Gene', '7157', (156, 160))	('HRAS', 'Gene', (22, 26))	('found', 'Reg', (31, 36))	('low-grade', 'Disease', (51, 60))	('mutations', 'Var', (143, 152))
134698	32197306	Recently, the first targeted therapy for urothelial carcinomas, erdafitinib, was approved by the FDA for the treatment of tumors harboring FGFR2 and FGFR3 alterations.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('erdafitinib', 'Chemical', 'MESH:C000604580', (64, 75))	('alterations', 'Var', (155, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('FGFR', 'molecular_function', 'GO:0005007', ('149', '153'))	('urothelial carcinomas', 'Disease', (41, 62))	('men', 'Species', '9606', (114, 117))	('FGFR2', 'Gene', (139, 144))	('FGFR3', 'Gene', '2261', (149, 154))	('FGFR2', 'Gene', '2263', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (41, 62))	('FGFR3', 'Gene', (149, 154))	('FGFR', 'molecular_function', 'GO:0005007', ('139', '143'))
134700	32197306	For patients with BRCA1, BRCA2, and ATM alterations, there is now an FDA breakthrough designation for the use of olaparib, a poly ADP-ribose polymerase (PARP) inhibitor, in metastatic castration-resistant prostate cancer (mCRPC).	('BRCA2', 'Gene', (25, 30))	('prostate cancer', 'Disease', (205, 220))	('ATM', 'Gene', (36, 39))	('BRCA1', 'Gene', '672', (18, 23))	('PARP', 'Gene', '142', (153, 157))	('poly ADP-ribose polymerase', 'Gene', '142', (125, 151))	('BRCA1', 'Gene', (18, 23))	('BRCA2', 'Gene', '675', (25, 30))	('alterations', 'Var', (40, 51))	('prostate cancer', 'Disease', 'MESH:D011471', (205, 220))	('ATM', 'Gene', '472', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('patients', 'Species', '9606', (4, 12))	('prostate cancer', 'Phenotype', 'HP:0012125', (205, 220))	('PARP', 'Gene', (153, 157))	('olaparib', 'Chemical', 'MESH:C531550', (113, 121))	('poly ADP-ribose polymerase', 'Gene', (125, 151))
134704	32197306	In TGCT, there is growing evidence that DNAAF1 mutations can also play a significant role in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('TGCT', 'Disease', (3, 7))	('tumor', 'Disease', (93, 98))	('mutations', 'Var', (47, 56))	('DNAAF1', 'Gene', (40, 46))	('DNAAF1', 'Gene', '123872', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
134708	32197306	In the context of hereditary papillary RCC (HPRCC), the defining MET mutation has informed the design of various trials in sporadic papillary RCC with MET inhibitors.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('hereditary papillary RCC', 'Disease', (18, 42))	('RCC', 'Disease', (46, 49))	('hereditary papillary RCC', 'Disease', 'MESH:C538614', (18, 42))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('mutation', 'Var', (69, 77))	('RCC', 'Disease', (39, 42))	('sporadic papillary RCC', 'Disease', 'MESH:C538614', (123, 145))	('sporadic papillary RCC', 'Disease', (123, 145))
134711	32197306	In Birt-Hogg-Dube (BHD) syndrome, individuals are often afflicted with skin tumors, lung disease, and chromophobe RCC due to mutations in FLCN leading to the downstream activation of mTOR, via the loss of negative inhibition by the BHD protein, similarly to how TSC1 and TSC2 complexes downregulate mTOR activity.	('BHD', 'Disease', (19, 22))	('mTOR', 'Gene', '2475', (299, 303))	('loss', 'NegReg', (197, 201))	('protein', 'cellular_component', 'GO:0003675', ('236', '243'))	('skin tumors', 'Disease', 'MESH:D012878', (71, 82))	('mTOR', 'Gene', (183, 187))	('skin tumors', 'Phenotype', 'HP:0008069', (71, 82))	('activation', 'PosReg', (169, 179))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('FLCN', 'Gene', '201163', (138, 142))	('chromophobe RCC', 'Disease', 'MESH:C538614', (102, 117))	('mutations', 'Var', (125, 134))	('TSC2', 'Gene', '7249', (271, 275))	('mTOR', 'Gene', '2475', (183, 187))	('FLCN', 'Gene', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('Birt-Hogg-Dube (BHD) syndrome', 'Disease', 'MESH:D058249', (3, 32))	('TSC1', 'Gene', (262, 266))	('mTOR', 'Gene', (299, 303))	('BHD', 'Disease', 'MESH:C564185', (232, 235))	('TSC2', 'Gene', (271, 275))	('chromophobe RCC', 'Disease', (102, 117))	('lung disease', 'Disease', (84, 96))	('BHD', 'Disease', 'MESH:C564185', (19, 22))	('lung disease', 'Phenotype', 'HP:0002088', (84, 96))	('skin tumors', 'Disease', (71, 82))	('negative inhibition', 'MPA', (205, 224))	('lung disease', 'Disease', 'MESH:D008171', (84, 96))	('TSC1', 'Gene', '7248', (262, 266))	('BHD', 'Disease', (232, 235))
134712	32197306	Patients with FLCN mutations and subsequent BHD, can provide valuable clinical insights on how chromophobe RCC will respond to the inhibition of the Akt-mTOR pathway.	('BHD', 'Disease', (44, 47))	('chromophobe RCC', 'Disease', (95, 110))	('FLCN', 'Gene', (14, 18))	('Akt', 'Gene', (149, 152))	('mTOR', 'Gene', (153, 157))	('BHD', 'Disease', 'MESH:C564185', (44, 47))	('mTOR', 'Gene', '2475', (153, 157))	('mutations', 'Var', (19, 28))	('Patients', 'Species', '9606', (0, 8))	('FLCN', 'Gene', '201163', (14, 18))	('chromophobe RCC', 'Disease', 'MESH:C538614', (95, 110))	('Akt', 'Gene', '207', (149, 152))	('inhibition', 'NegReg', (131, 141))
134717	32197306	The same group found by analyzing 575 primary and 335 metastatic RCC samples that 87% of clonal variants in metastases are the same as in the primary tissue.	('metastases', 'Disease', (108, 118))	('variants', 'Var', (96, 104))	('metastases', 'Disease', 'MESH:D009362', (108, 118))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
134718	32197306	Of the variants found in metastatic sites, only 5.4% were de novo mutations in driver genes such as VHL, BAP1, and mTOR.	('mTOR', 'Gene', '2475', (115, 119))	('BAP1', 'Gene', '8314', (105, 109))	('mTOR', 'Gene', (115, 119))	('variants', 'Var', (7, 15))	('VHL', 'Gene', (100, 103))	('BAP1', 'Gene', (105, 109))	('VHL', 'Gene', '7428', (100, 103))
134719	32197306	Metastatic sites demonstrated different characteristics based on whether they harbored mutations in either BAP1 or PBRM1.	('BAP1', 'Gene', '8314', (107, 111))	('mutations', 'Var', (87, 96))	('BAP1', 'Gene', (107, 111))	('PBRM1', 'Gene', (115, 120))	('PBRM1', 'Gene', '55193', (115, 120))
134722	32197306	Germline mutations in the BAP1 gene have also been associated with BAP1-tumor predisposition syndrome which carries an increased risk of developing uveal melanoma, cutaneous melanoma, malignant mesothelioma, RCC, meningioma, and cholangiocarcinoma.	('Germline mutations', 'Var', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (229, 247))	('malignant mesothelioma', 'Disease', (184, 206))	('uveal melanoma', 'Disease', 'MESH:C536494', (148, 162))	('BAP1-tumor', 'Disease', 'MESH:D009369', (67, 77))	('uveal melanoma', 'Disease', (148, 162))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (184, 206))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('BAP1', 'Gene', (26, 30))	('BAP1-tumor', 'Disease', (67, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (148, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('cutaneous melanoma', 'Disease', (164, 182))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (164, 182))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (164, 182))	('meningioma', 'Disease', (213, 223))	('RCC', 'Disease', (208, 211))	('BAP1', 'Gene', '8314', (67, 71))	('meningioma', 'Phenotype', 'HP:0002858', (213, 223))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (184, 206))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (229, 247))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('associated', 'Reg', (51, 61))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('BAP1', 'Gene', '8314', (26, 30))	('cholangiocarcinoma', 'Disease', (229, 247))	('meningioma', 'Disease', 'MESH:D008577', (213, 223))	('BAP1', 'Gene', (67, 71))
134723	32197306	Some groups recommend that, in patients who develop RCC at <46 years old, germline testing for BAP1 mutations may identify earlier BAP1-tumor predisposition syndrome patients and offer better surveillance.	('mutations', 'Var', (100, 109))	('BAP1-tumor', 'Disease', (131, 141))	('BAP1', 'Gene', (95, 99))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('BAP1-tumor', 'Disease', 'MESH:D009369', (131, 141))	('BAP1', 'Gene', '8314', (131, 135))	('BAP1', 'Gene', '8314', (95, 99))	('patients', 'Species', '9606', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('BAP1', 'Gene', (131, 135))	('patients', 'Species', '9606', (166, 174))	('men', 'Species', '9606', (17, 20))
134724	32197306	Another study found that among 181 families afflicted with BAP1-tumor predisposition syndrome, there were 140 unique germline variants in the BAP1 gene.	('BAP1-tumor', 'Disease', 'MESH:D009369', (59, 69))	('variants', 'Var', (126, 134))	('BAP1', 'Gene', (59, 63))	('BAP1', 'Gene', '8314', (142, 146))	('BAP1', 'Gene', (142, 146))	('BAP1', 'Gene', '8314', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('BAP1-tumor', 'Disease', (59, 69))
134725	32197306	This study found that 97.5% of missense variant carriers developed a BAP1-associated tumor, of which ~12% were RCC.	('tumor', 'Disease', (85, 90))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('BAP1', 'Gene', (69, 73))	('missense variant', 'Var', (31, 47))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('developed', 'PosReg', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('BAP1', 'Gene', '8314', (69, 73))
134728	32197306	RMC is a very aggressive form of RCC with poor overall survival following diagnosis, and shares some similarities to pediatric malignant rhabdoid tumors, which are also caused by SMARCB1 inactivation.	('malignant rhabdoid tumors', 'Disease', (127, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('caused by', 'Reg', (169, 178))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('inactivation', 'Var', (187, 199))	('RCC', 'Disease', (33, 36))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (127, 152))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('RMC', 'Disease', (0, 3))	('SMARCB1', 'Gene', (179, 186))
134729	32197306	A common mechanism of SMARCB1 loss is inactivating translocations, and a recently proposed mechanism of RMC pathogenesis postulates that regional ischemia induced by red blood cell sickling in the renal medulla of individuals with sickle cell trait or other sickle hemoglobinopathies can activate aberrant DNA damage repair mechanisms that can drive deletions and translocations in SMARCB1, which is located within a highly fragile region of chromosome 22.	('DNA', 'cellular_component', 'GO:0005574', ('306', '309'))	('regional ischemia induced by red blood cell', 'Phenotype', 'HP:0002637', (137, 180))	('ischemia', 'Disease', 'MESH:D007511', (146, 154))	('deletions', 'Var', (350, 359))	('SMARCB1', 'Gene', (382, 389))	('blood cell sickling in the renal medulla', 'Phenotype', 'HP:0008659', (170, 210))	('pathogenesis', 'biological_process', 'GO:0009405', ('108', '120'))	('SMARCB1', 'Gene', (22, 29))	('chromosome', 'cellular_component', 'GO:0005694', ('442', '452'))	('translocations', 'Var', (364, 378))	('aberrant DNA damage repair', 'Phenotype', 'HP:0003254', (297, 323))	('drive', 'Reg', (344, 349))	('activate', 'PosReg', (288, 296))	('red blood cell sickling', 'Phenotype', 'HP:0008346', (166, 189))	('ischemia', 'Disease', (146, 154))
134733	32197306	Fumarate hydratase (FH) mutations are associated with aggressive papillary type 2 renal cell carcinoma termed FH-deficient renal cell carcinoma (FH-RCC).	('FH', 'Gene', '2271', (110, 112))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (123, 143))	('papillary type', 'Phenotype', 'HP:0007482', (65, 79))	('mutations', 'Var', (24, 33))	('FH', 'Gene', '2271', (20, 22))	('FH-RCC', 'Disease', 'MESH:C538614', (145, 151))	('associated', 'Reg', (38, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (82, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('Fumarate hydratase', 'Gene', (0, 18))	('FH', 'Gene', '2271', (145, 147))	('papillary type 2 renal cell carcinoma', 'Phenotype', 'HP:0006732', (65, 102))	('FH-deficient renal cell carcinoma', 'Disease', (110, 143))	('aggressive papillary type 2 renal cell carcinoma', 'Disease', 'MESH:C538614', (54, 102))	('Fumarate hydratase', 'Gene', '2271', (0, 18))	('FH-deficient renal cell carcinoma', 'Disease', 'MESH:C538614', (110, 143))	('FH-RCC', 'Disease', (145, 151))	('aggressive papillary type 2 renal cell carcinoma', 'Disease', (54, 102))
134734	32197306	The majority of FH-RCC cases are associated with germline FH mutations as part of the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome characterized by cutaneous and uterine leiomyomas and increased risk of FH-RCC.	('FH', 'Gene', '2271', (226, 228))	('hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome', 'Disease', 'MESH:C538614', (86, 153))	('FH-RCC', 'Disease', 'MESH:C538614', (16, 22))	('FH-RCC', 'Disease', (226, 232))	('leiomyomas', 'Disease', 'MESH:D007889', (193, 203))	('germline', 'Var', (49, 57))	('leiomyomas', 'Disease', (193, 203))	('associated', 'Reg', (33, 43))	('FH-RCC', 'Disease', 'MESH:C538614', (226, 232))	('FH', 'Gene', '2271', (16, 18))	('uterine leiomyomas', 'Phenotype', 'HP:0000131', (185, 203))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (116, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('cutaneous and uterine leiomyomas', 'Phenotype', 'HP:0007620', (171, 203))	('FH-RCC', 'Disease', (16, 22))	('FH', 'Gene', '2271', (58, 60))
134741	32197306	Furthermore, female patients with non-invasive bladder cancer are approximately two-fold more likely than men (74% vs. 42%) to harbor KDM6A mutations.	('KDM6A', 'Gene', (134, 139))	('non-invasive bladder cancer', 'Disease', (34, 61))	('KDM6A', 'Gene', '7403', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('invasive bladder', 'Phenotype', 'HP:0100645', (38, 54))	('non-invasive bladder cancer', 'Disease', 'MESH:D001749', (34, 61))	('patients', 'Species', '9606', (20, 28))	('mutations', 'Var', (140, 149))	('bladder cancer', 'Phenotype', 'HP:0009725', (47, 61))	('men', 'Species', '9606', (106, 109))
134743	32197306	The male paralogue of KDM6A is the UTY gene located on Yq11 and is mutated in approximately 9% of male non-invasive bladder cancers.	('invasive bladder cancers', 'Disease', (107, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (116, 130))	('KDM6A', 'Gene', '7403', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('non-invasive bladder cancer', 'Disease', (103, 130))	('mutated', 'Var', (67, 74))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('UTY', 'Gene', (35, 38))	('UTY', 'Gene', '7404', (35, 38))	('invasive bladder cancers', 'Disease', 'MESH:D001749', (107, 131))	('KDM6A', 'Gene', (22, 27))	('non-invasive bladder cancer', 'Disease', 'MESH:D001749', (103, 130))	('invasive bladder', 'Phenotype', 'HP:0100645', (107, 123))	('bladder cancers', 'Phenotype', 'HP:0009725', (116, 131))
134745	32197306	Up to 40% of primary UC have FGFR3 mutations.	('primary UC', 'Disease', (13, 23))	('FGFR3', 'Gene', (29, 34))	('FGFR', 'molecular_function', 'GO:0005007', ('29', '33'))	('FGFR3', 'Gene', '2261', (29, 34))	('mutations', 'Var', (35, 44))
134746	32197306	Patients with metastatic UC harboring FGFR3 mutations, have shown to have minimal to modest responses to IO.	('FGFR3', 'Gene', '2261', (38, 43))	('metastatic UC', 'Disease', (14, 27))	('FGFR3', 'Gene', (38, 43))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (44, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))
134747	32197306	However, patients can have meaningful benefit when particular FGFR3 alterations are targeted with an inhibitor.	('patients', 'Species', '9606', (9, 17))	('FGFR', 'molecular_function', 'GO:0005007', ('62', '66'))	('FGFR3', 'Gene', '2261', (62, 67))	('FGFR3', 'Gene', (62, 67))	('alterations', 'Var', (68, 79))
134749	32197306	Erdafitinib recently became the first targeted therapy approved for metastatic UC harboring FGFR3 or FGFR2 mutations.	('Erdafitinib', 'Chemical', 'MESH:C000604580', (0, 11))	('metastatic UC', 'Disease', (68, 81))	('mutations', 'Var', (107, 116))	('FGFR3', 'Gene', (92, 97))	('FGFR2', 'Gene', (101, 106))	('FGFR2', 'Gene', '2263', (101, 106))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('FGFR3', 'Gene', '2261', (92, 97))	('FGFR', 'molecular_function', 'GO:0005007', ('101', '105'))
134751	32197306	Mutations in FGFR3 and Ras can occur in UC but are likely mutually exclusive events in carcinogenesis, with Ras mutations noted in about 11% of UC cases.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('carcinogenesis', 'Disease', 'MESH:D063646', (87, 101))	('FGFR3', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('carcinogenesis', 'Disease', (87, 101))	('FGFR3', 'Gene', '2261', (13, 18))
134752	32197306	Mutations in PIK3CA have been found in 24% of UC cases and can co-exist with FGFR3 mutations in 15% of UC cases, making combined targeted therapy an attractive approach.	('FGFR3', 'Gene', (77, 82))	('PIK3CA', 'Gene', (13, 19))	('FGFR', 'molecular_function', 'GO:0005007', ('77', '81'))	('found', 'Reg', (30, 35))	('PIK3CA', 'Gene', '5290', (13, 19))	('Mutations', 'Var', (0, 9))	('FGFR3', 'Gene', '2261', (77, 82))
134757	32197306	There continue to be ongoing trials investigating the role of HER2-directed treatments for patients with HER2 mutations, but as of yet the utility of this mutation as a biomarker of benefit to directed therapy remains unknown.	('HER2', 'Gene', '2064', (62, 66))	('patients', 'Species', '9606', (91, 99))	('mutations', 'Var', (110, 119))	('HER2', 'Gene', (105, 109))	('HER2', 'Gene', '2064', (105, 109))	('men', 'Species', '9606', (81, 84))	('HER2', 'Gene', (62, 66))
134761	32197306	Mutations in DNA repair genes such as BRCA1, BRCA2, ATM, CHEK2, and PALB2 are of importance in prostate cancer.	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('BRCA2', 'Gene', (45, 50))	('prostate cancer', 'Disease', (95, 110))	('BRCA2', 'Gene', '675', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('BRCA1', 'Gene', '672', (38, 43))	('ATM', 'Gene', '472', (52, 55))	('BRCA1', 'Gene', (38, 43))	('PALB2', 'Gene', '79728', (68, 73))	('DNA repair', 'biological_process', 'GO:0006281', ('13', '23'))	('Mutations', 'Var', (0, 9))	('PALB2', 'Gene', (68, 73))	('CHEK2', 'Gene', '11200', (57, 62))	('prostate cancer', 'Disease', 'MESH:D011471', (95, 110))	('prostate cancer', 'Phenotype', 'HP:0012125', (95, 110))	('ATM', 'Gene', (52, 55))	('CHEK2', 'Gene', (57, 62))
134762	32197306	In a study of 82 patients, 11.8% had germline mutations in DNA repair genes namely BRCA2 (5.3%), ATM (1.6%), CHEK2 (1.9%), BRCA1 (0.9%), and PALB2 (0.4%).	('DNA repair', 'biological_process', 'GO:0006281', ('59', '69'))	('CHEK2', 'Gene', (109, 114))	('BRCA1', 'Gene', '672', (123, 128))	('germline mutations', 'Var', (37, 55))	('BRCA2', 'Gene', '675', (83, 88))	('ATM', 'Gene', '472', (97, 100))	('DNA repair genes', 'Gene', (59, 75))	('BRCA1', 'Gene', (123, 128))	('CHEK2', 'Gene', '11200', (109, 114))	('PALB2', 'Gene', '79728', (141, 146))	('patients', 'Species', '9606', (17, 25))	('BRCA2', 'Gene', (83, 88))	('PALB2', 'Gene', (141, 146))	('ATM', 'Gene', (97, 100))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))
134764	32197306	Other studies have found that individuals with germline BRCA2 mutations are three-fold to 8.6-fold more likely to develop high risk prostate cancer.	('prostate cancer', 'Disease', (132, 147))	('germline', 'Var', (47, 55))	('BRCA2', 'Gene', '675', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('prostate cancer', 'Disease', 'MESH:D011471', (132, 147))	('develop', 'PosReg', (114, 121))	('prostate cancer', 'Phenotype', 'HP:0012125', (132, 147))	('BRCA2', 'Gene', (56, 61))	('mutations', 'Var', (62, 71))
134765	32197306	Looking into BRCA1, a study of 813 cases of prostate cancer found that having BRCA1 germline mutations resulted in a 3.75-fold relative risk for developing prostate cancer and in a cumulative risk of 8.6% of developing prostate cancer by 65 years old.	('BRCA1', 'Gene', '672', (13, 18))	('mutations', 'Var', (93, 102))	('prostate cancer', 'Disease', (156, 171))	('BRCA1', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('prostate cancer', 'Disease', (44, 59))	('prostate cancer', 'Disease', (219, 234))	('prostate cancer', 'Disease', 'MESH:D011471', (156, 171))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('BRCA1', 'Gene', '672', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (156, 171))	('prostate cancer', 'Disease', 'MESH:D011471', (44, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (44, 59))	('prostate cancer', 'Disease', 'MESH:D011471', (219, 234))	('BRCA1', 'Gene', (78, 83))	('prostate cancer', 'Phenotype', 'HP:0012125', (219, 234))
134768	32197306	Mutations in BRCA1/2 and ATM can be targeted with PARP inhibitors.	('BRCA1/2', 'Gene', '672;675', (13, 20))	('PARP', 'Gene', '142', (50, 54))	('ATM', 'Gene', (25, 28))	('Mutations', 'Var', (0, 9))	('BRCA1/2', 'Gene', (13, 20))	('PARP', 'Gene', (50, 54))	('ATM', 'Gene', '472', (25, 28))
134771	32197306	Analysis of familial risk models has revealed the importance of HOXB13 G84E mutations in the development of early-onset prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('prostate cancer', 'Phenotype', 'HP:0012125', (120, 135))	('men', 'Species', '9606', (100, 103))	('HOXB13', 'Gene', '10481', (64, 70))	('G84E', 'Mutation', 'rs138213197', (71, 75))	('G84E', 'Var', (71, 75))	('prostate cancer', 'Disease', (120, 135))	('HOXB13', 'Gene', (64, 70))	('prostate cancer', 'Disease', 'MESH:D011471', (120, 135))
134772	32197306	A study in over 6000 patients, found that HOXB13 gene mutations were significantly more likely in individuals with prostate cancer compared to those without (OR 20.1; 95% CI, 3.5-803.3).	('prostate cancer', 'Disease', (115, 130))	('mutations', 'Var', (54, 63))	('HOXB13', 'Gene', '10481', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('patients', 'Species', '9606', (21, 29))	('prostate cancer', 'Disease', 'MESH:D011471', (115, 130))	('prostate cancer', 'Phenotype', 'HP:0012125', (115, 130))	('HOXB13', 'Gene', (42, 48))
134776	32197306	A study including over 86,000 patients found that heterozygotes with CHEK2 mutations, were significantly more likely to develop prostate cancer than noncarriers (OR 1.60; 95% CI, 1.00-2.56).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('develop', 'PosReg', (120, 127))	('CHEK2', 'Gene', '11200', (69, 74))	('prostate cancer', 'Disease', 'MESH:D011471', (128, 143))	('CHEK2', 'Gene', (69, 74))	('prostate cancer', 'Phenotype', 'HP:0012125', (128, 143))	('patients', 'Species', '9606', (30, 38))	('mutations', 'Var', (75, 84))	('prostate cancer', 'Disease', (128, 143))
134777	32197306	In familial cases, CHEK2 mutations are associated with an increased risk of prostate cancer (OR 3.39; 95% CI, 1.78-6.47).	('mutations', 'Var', (25, 34))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('CHEK2', 'Gene', '11200', (19, 24))	('CHEK2', 'Gene', (19, 24))	('prostate cancer', 'Disease', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
134778	32197306	Additionally, a 45,000-patient case-control study on specific subset populations found that African men and European men with CHEK2 mutations has increased risk for developing prostate cancer (OR 3.03; 95% CI, 1.53-6.03; p = 0.0006 and OR 2.21; 95% CI, 1.06-4.63; p = 0.030, respectively).	('CHEK2', 'Gene', (126, 131))	('men', 'Species', '9606', (100, 103))	('prostate cancer', 'Disease', (176, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('mutations', 'Var', (132, 141))	('prostate cancer', 'Disease', 'MESH:D011471', (176, 191))	('men', 'Species', '9606', (117, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (176, 191))	('CHEK2', 'Gene', '11200', (126, 131))	('patient', 'Species', '9606', (23, 30))
134779	32197306	A study of 205 patients with TGCT found that 9.8% of patients had CHEK2 mutations and, compared to historical controls, patients with TGCT were significantly more likely to carry germline CHEK2 alteration (OR > 1.4; p = 0.03).	('mutations', 'Var', (72, 81))	('patients', 'Species', '9606', (15, 23))	('CHEK2', 'Gene', (188, 193))	('CHEK2', 'Gene', '11200', (66, 71))	('patients', 'Species', '9606', (53, 61))	('CHEK2', 'Gene', (66, 71))	('patients', 'Species', '9606', (120, 128))	('CHEK2', 'Gene', '11200', (188, 193))
134780	32197306	Additionally, carriers of CHEK2 mutations developed TGCTs almost six years earlier than those with TGCTs and wild-type CHEK2 (5.95 years; 95% CI, 1.48-10.42; p = 0.009.	('CHEK2', 'Gene', (119, 124))	('mutations', 'Var', (32, 41))	('CHEK2', 'Gene', '11200', (26, 31))	('CHEK2', 'Gene', (26, 31))	('TGCTs', 'Disease', (52, 57))	('CHEK2', 'Gene', '11200', (119, 124))
134784	32197306	Further, one study found that there were more mutations in KIT in patients with bilateral TGCT compared with unilateral disease (93% vs 1.3%).	('mutations', 'Var', (46, 55))	('KIT', 'molecular_function', 'GO:0005020', ('59', '62'))	('bilateral TGCT', 'Disease', (80, 94))	('KIT', 'Gene', '3815', (59, 62))	('KIT', 'Gene', (59, 62))	('patients', 'Species', '9606', (66, 74))
134788	32197306	In this study, one patient had a progression-free survival of 17 months and was found to have RET amplification, PTEN loss, EGFR and KRAS amplifications.	('PTEN loss', 'Disease', (113, 122))	('patient', 'Species', '9606', (19, 26))	('RET', 'Gene', '5979', (94, 97))	('EGFR', 'Gene', '1956', (124, 128))	('EGFR', 'Gene', (124, 128))	('EGFR', 'molecular_function', 'GO:0005006', ('124', '128'))	('KRAS', 'Gene', (133, 137))	('RET', 'Gene', (94, 97))	('amplifications', 'Var', (138, 152))	('PTEN loss', 'Disease', 'MESH:D006223', (113, 122))	('KRAS', 'Gene', '3845', (133, 137))
134790	32197306	c-KIT mutations in TGCT may confer response to imatinib, but the clinical utility of this therapy for TGCT remains controversial.	('c-KIT', 'Gene', (0, 5))	('c-KIT', 'Gene', '3815', (0, 5))	('TGCT', 'Gene', (19, 23))	('imatinib', 'Chemical', 'MESH:D000068877', (47, 55))	('response to imatinib', 'MPA', (35, 55))	('KIT', 'molecular_function', 'GO:0005020', ('2', '5'))	('mutations', 'Var', (6, 15))
134793	32197306	Patients with prostate adenocarcinoma had a higher frequency of mutations in genes related to DNA repair: BRCA2 (5%), CHEK2 (1.6%), ATM (6%), as well as mutations in cell cycle regulating genes: RB1 (10%) and TP53 (16%).	('mutations', 'Var', (153, 162))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (14, 37))	('CHEK2', 'Gene', '11200', (118, 123))	('BRCA2', 'Gene', '675', (106, 111))	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('ATM', 'Gene', '472', (132, 135))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (64, 73))	('RB1', 'Gene', (195, 198))	('TP53', 'Gene', (209, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('ATM', 'Gene', (132, 135))	('prostate adenocarcinoma', 'Disease', (14, 37))	('DNA repair', 'biological_process', 'GO:0006281', ('94', '104'))	('RB1', 'Gene', '5925', (195, 198))	('cell cycle', 'biological_process', 'GO:0007049', ('166', '176'))	('CHEK2', 'Gene', (118, 123))	('BRCA2', 'Gene', (106, 111))	('TP53', 'Gene', '7157', (209, 213))
134794	32197306	The papillary RCC dataset showed high mutation rates in the MET gene (10%), which is targeted with MET inhibitors like cabozantinib as well as mutations in PBRM1 (5%) which can affect responses to immunotherapy.	('papillary RCC', 'Disease', 'MESH:C538614', (4, 17))	('papillary RCC', 'Disease', (4, 17))	('PBRM1', 'Gene', '55193', (156, 161))	('cabozantinib', 'Chemical', 'MESH:C558660', (119, 131))	('MET gene', 'Gene', (60, 68))	('affect', 'Reg', (177, 183))	('mutation', 'Var', (38, 46))	('responses to immunotherapy', 'CPA', (184, 210))	('mutations', 'Var', (143, 152))	('PBRM1', 'Gene', (156, 161))
134795	32197306	The urothelial carcinoma dataset showed mutations in targetable genes such as FGFR3 (19%), ATM (14%), BRCA2 (13%), PIK3CA (25%), and ERBB2 (17%) which may provide insight into future therapeutic strategies.	('ERBB2', 'Gene', (133, 138))	('FGFR3', 'Gene', (78, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('78', '82'))	('ATM', 'Gene', (91, 94))	('PIK3CA', 'Gene', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('ATM', 'Gene', '472', (91, 94))	('mutations', 'Var', (40, 49))	('ERBB2', 'Gene', '2064', (133, 138))	('BRCA2', 'Gene', (102, 107))	('urothelial carcinoma', 'Disease', (4, 24))	('FGFR3', 'Gene', '2261', (78, 83))	('PIK3CA', 'Gene', '5290', (115, 121))	('BRCA2', 'Gene', '675', (102, 107))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (4, 24))
134796	32197306	The most commonly found mutation in the TCGT sample was KRAS (17%) followed by KIT (15%), which are both targetable and may affect platinum chemosensitivity and disease progression.	('platinum', 'Chemical', 'MESH:D010984', (131, 139))	('affect', 'Reg', (124, 130))	('KRAS', 'Gene', (56, 60))	('KRAS', 'Gene', '3845', (56, 60))	('TCGT', 'Gene', (40, 44))	('disease progression', 'CPA', (161, 180))	('KIT', 'Gene', '3815', (79, 82))	('mutation', 'Var', (24, 32))	('found', 'Reg', (18, 23))	('platinum chemosensitivity', 'CPA', (131, 156))	('KIT', 'Gene', (79, 82))	('KIT', 'molecular_function', 'GO:0005020', ('79', '82'))
134797	32197306	While it has been well established that there are a number of germline mutations associated with an increased risk of urologic malignancy, genetic counseling is an often-underutilized component of the work-up for cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('patients', 'Species', '9606', (220, 228))	('urologic malignancy', 'Disease', 'MESH:D014571', (118, 137))	('cancer', 'Disease', (213, 219))	('germline mutations', 'Var', (62, 80))	('associated', 'Reg', (81, 91))	('urologic malignancy', 'Disease', (118, 137))
134805	32197306	This arrangement was recently assessed during the ENGAGE (Evaluating Streamlined Onco-genetic BRCA Testing and Counseling Model Among Patients with Ovarian Cancer) study where patients with ovarian cancer underwent BRCA mutation testing.	('patients', 'Species', '9606', (176, 184))	('ovarian cancer', 'Disease', (190, 204))	('Cancer', 'Disease', 'MESH:D009369', (156, 162))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (148, 162))	('Cancer', 'Phenotype', 'HP:0002664', (156, 162))	('BRCA', 'Gene', '672', (94, 98))	('men', 'Species', '9606', (12, 15))	('BRCA', 'Gene', (94, 98))	('Patients', 'Species', '9606', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('BRCA', 'Gene', '672', (215, 219))	('ovarian cancer', 'Phenotype', 'HP:0100615', (190, 204))	('mutation testing', 'Var', (220, 236))	('BRCA', 'Gene', (215, 219))	('ovarian cancer', 'Disease', 'MESH:D010051', (190, 204))	('Cancer', 'Disease', (156, 162))
134810	32197306	This is significant because a number of the patients with VUS underwent bilateral mastectomy, even though the procedure has only shown a survival benefit for those with a known pathogenic variant of the BRCA gene.	('underwent', 'Reg', (62, 71))	('patients', 'Species', '9606', (44, 52))	('BRCA', 'Gene', '672', (203, 207))	('BRCA', 'Gene', (203, 207))	('bilateral mastectomy', 'Disease', (72, 92))	('variant', 'Var', (188, 195))
134812	32197306	Of the urologic malignancies, genetic testing is likely to impact the management of prostate cancer more than others, namely due to the potential use of targeted therapies for patients with known germline mutations.	('patients', 'Species', '9606', (176, 184))	('genetic testing', 'Var', (30, 45))	('prostate cancer', 'Disease', (84, 99))	('men', 'Species', '9606', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('malignancies', 'Disease', 'MESH:D009369', (16, 28))	('prostate cancer', 'Disease', 'MESH:D011471', (84, 99))	('impact', 'Reg', (59, 65))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))	('malignancies', 'Disease', (16, 28))
134816	32197306	As to how the discovery of a pathogenic mutation can impact prostate cancer screening, the NCCN Prostate Cancer Early Detection Guidelines state men with known BRCA1/2 mutations should consider PSA screening at age 40, as opposed to age 45 for average-risk men, following a discussion of risk and benefits.	('impact', 'Reg', (53, 59))	('men', 'Species', '9606', (257, 260))	('NCCN Prostate Cancer', 'Disease', (91, 111))	('men', 'Species', '9606', (145, 148))	('NCCN Prostate Cancer', 'Disease', 'MESH:D011471', (91, 111))	('Cancer', 'Phenotype', 'HP:0002664', (105, 111))	('prostate cancer', 'Disease', (60, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('BRCA1/2', 'Gene', (160, 167))	('PSA', 'Disease', (194, 197))	('Prostate Cancer', 'Phenotype', 'HP:0012125', (96, 111))	('prostate cancer', 'Disease', 'MESH:D011471', (60, 75))	('BRCA1/2', 'Gene', '672;675', (160, 167))	('mutations', 'Var', (168, 177))	('prostate cancer', 'Phenotype', 'HP:0012125', (60, 75))
134819	32197306	Currently, the IMPACT study is being conducted to aid the development of early detection guidelines for prostate cancer in men with BRCA1/2 germline mutations.	('BRCA1/2', 'Gene', (132, 139))	('prostate cancer', 'Disease', 'MESH:D011471', (104, 119))	('germline', 'Var', (140, 148))	('men', 'Species', '9606', (65, 68))	('prostate cancer', 'Phenotype', 'HP:0012125', (104, 119))	('BRCA1/2', 'Gene', '672;675', (132, 139))	('men', 'Species', '9606', (123, 126))	('prostate cancer', 'Disease', (104, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
134820	32197306	Following the first round of screening, it has shown no difference between BRCA1/2 mutation carriers and controls in the rate of detection of prostate cancer or the positive predictive value of prostate biopsy in men with a PSA >= 3 ng/mL.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('prostate cancer', 'Disease', 'MESH:D011471', (142, 157))	('BRCA1/2', 'Gene', (75, 82))	('prostate cancer', 'Phenotype', 'HP:0012125', (142, 157))	('mutation', 'Var', (83, 91))	('BRCA1/2', 'Gene', '672;675', (75, 82))	('men', 'Species', '9606', (213, 216))	('prostate cancer', 'Disease', (142, 157))
134830	32197306	In addition to prostate and renal cancer, upper tract urothelial carcinoma (UTUC) can be linked to germline alterations.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('prostate', 'Disease', (15, 23))	('renal cancer', 'Disease', (28, 40))	('upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (42, 74))	('renal cancer', 'Disease', 'MESH:D007680', (28, 40))	('renal cancer', 'Phenotype', 'HP:0009726', (28, 40))	('upper tract urothelial carcinoma', 'Disease', (42, 74))	('germline alterations', 'Var', (99, 119))	('linked', 'Reg', (89, 95))
134832	32197306	Lynch syndrome occurs due to defects in the DNA mismatch repair (MMR) system resulting in microsatellite instability (MSI), and ultimately leading to various types of cancer.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('leading to', 'Reg', (139, 149))	('MMR', 'biological_process', 'GO:0006298', ('65', '68'))	('microsatellite instability', 'MPA', (90, 116))	('cancer', 'Disease', (167, 173))	('defects', 'Var', (29, 36))	('Lynch syndrome', 'Disease', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))	('mismatch repair', 'biological_process', 'GO:0006298', ('48', '63'))
134841	32197306	The key driver mutations in familial syndromic cancers have informed studies of key biological pathways.	('familial syndromic cancers', 'Disease', (28, 54))	('mutations', 'Var', (15, 24))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('familial syndromic cancers', 'Disease', 'MESH:D009369', (28, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
134843	32197306	Common bladder cancer genetic mutations can be targeted by rationally designed therapies.	('bladder cancer', 'Phenotype', 'HP:0009725', (7, 21))	('bladder cancer', 'Disease', 'MESH:D001749', (7, 21))	('mutations', 'Var', (30, 39))	('bladder cancer', 'Disease', (7, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
134861	31878355	However, there have been only a few reports about chromosomal aberrations, mutations in CDCs, and RNA expression changes.	('RNA', 'cellular_component', 'GO:0005562', ('98', '101'))	('CDCs', 'Gene', (88, 92))	('CDCs', 'Chemical', 'MESH:C027616', (88, 92))	('mutations', 'Var', (75, 84))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (50, 73))
134862	31878355	identified clinically relevant genomic alterations mostly in genes NF2, SETD2, SMARCH1, and CDKN2A (29% to 12%) but also in 6% of genes PIK3CA, PIK3R2, FBXW7, BAP1, DNMT3A, VHL, and HRAS.	('VHL', 'Gene', (173, 176))	('clinical', 'Species', '191496', (11, 19))	('BAP1', 'Gene', '8314', (159, 163))	('CDKN2A', 'Gene', '1029', (92, 98))	('HRAS', 'Gene', (182, 186))	('PIK3CA', 'Gene', '5290', (136, 142))	('DNMT3A', 'Gene', (165, 171))	('SMARCH1', 'Gene', (79, 86))	('PIK3R2', 'Gene', '5296', (144, 150))	('VHL', 'Gene', '7428', (173, 176))	('FBXW7', 'Gene', '55294', (152, 157))	('BAP1', 'Gene', (159, 163))	('NF2', 'Gene', '4771', (67, 70))	('SETD2', 'Gene', (72, 77))	('PIK3CA', 'Gene', (136, 142))	('NF2', 'Gene', (67, 70))	('DNMT3A', 'Gene', '1788', (165, 171))	('SETD2', 'Gene', '29072', (72, 77))	('CDKN2A', 'Gene', (92, 98))	('alterations', 'Var', (39, 50))	('FBXW7', 'Gene', (152, 157))	('HRAS', 'Gene', '3265', (182, 186))	('PIK3R2', 'Gene', (144, 150))
134863	31878355	Furthermore, amplifications of ERBB2 and genomic alterations of SMARCB1 have been described.	('amplifications', 'Var', (13, 27))	('genomic alterations', 'Var', (41, 60))	('SMARCB1', 'Gene', '6598', (64, 71))	('ERBB2', 'Gene', '2064', (31, 36))	('SMARCB1', 'Gene', (64, 71))	('ERBB2', 'Gene', (31, 36))
134866	31878355	reported in a combined whole-exome sequencing and transcriptome sequencing study of CDC that many single nucleotide variations in cancer census genes, but also deletions of CDKN2A.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('CDKN2A', 'Gene', (173, 179))	('single nucleotide variations', 'Var', (98, 126))	('cancer', 'Disease', (130, 136))	('CDKN2A', 'Gene', '1029', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('deletions', 'Var', (160, 169))
134886	31878355	To define the potential clinical relevance, every identified variant was queried against the NCBI ClinVar database to check whether the variations were pathogenic, likely pathogenic, or confer sensitivity or drug response.	('variations', 'Var', (136, 146))	('clinical', 'Species', '191496', (24, 32))	('variant', 'Var', (61, 68))
134902	31878355	Significant associations of low PPARGC1A, low ALDH6A1, and high SLC7A11 gene expression with poor outcomes in ccRCC patients have been reported.	('ccRCC', 'Disease', 'MESH:D002292', (110, 115))	('ALDH6A1', 'Gene', (46, 53))	('expression', 'MPA', (77, 87))	('SLC7A11', 'Gene', (64, 71))	('PPARGC1A', 'Gene', (32, 40))	('ALDH', 'molecular_function', 'GO:0004030', ('46', '50'))	('patients', 'Species', '9606', (116, 124))	('low', 'NegReg', (28, 31))	('high', 'Var', (59, 63))	('low', 'NegReg', (42, 45))	('gene expression', 'biological_process', 'GO:0010467', ('72', '87'))	('ccRCC', 'Disease', (110, 115))
134920	31878355	In our study, we observed a significant association between high KRT17 gene expression and shorter overall survival in ccRCC patients in the KIRC dataset.	('KRT17', 'Gene', (65, 70))	('high', 'Var', (60, 64))	('ccRCC', 'Disease', (119, 124))	('overall survival', 'MPA', (99, 115))	('gene expression', 'biological_process', 'GO:0010467', ('71', '86'))	('ccRCC', 'Disease', 'MESH:D002292', (119, 124))	('KRT17', 'Gene', '3872', (65, 70))	('shorter', 'NegReg', (91, 98))	('patients', 'Species', '9606', (125, 133))
134929	31878355	In addition, the SLC47A gene may affect renal excretion of substrate drugs, such as metformin.	('renal excretion of substrate drugs', 'MPA', (40, 74))	('metformin', 'Disease', (84, 93))	('metformin', 'Chemical', 'MESH:D008687', (84, 93))	('gene', 'Var', (24, 28))	('SLC47A', 'Gene', (17, 23))	('affect', 'Reg', (33, 39))	('excretion', 'biological_process', 'GO:0007588', ('46', '55'))
134930	31878355	It is tempting to speculate that treatment of tumors with a downregulated SLC47A gene, e.g., CDCs, with metformin could have toxic effects; however, polymorphisms in the SLC47A gene may affect renal excretion of substrate drugs such as metformin, resulting in inadequate pharmacotherapy or toxic effects.	('affect', 'Reg', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('metformin', 'Chemical', 'MESH:D008687', (236, 245))	('renal excretion of', 'MPA', (193, 211))	('polymorphisms', 'Var', (149, 162))	('CDCs', 'Chemical', 'MESH:C027616', (93, 97))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('excretion', 'biological_process', 'GO:0007588', ('199', '208'))	('tumors', 'Disease', (46, 52))	('SLC47A', 'Gene', (170, 176))	('downregulated', 'NegReg', (60, 73))	('metformin', 'Chemical', 'MESH:D008687', (104, 113))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
134932	31878355	Notably, our two CDC patients did not possess single nucleotide variants in the SLC47A gene.	('patients', 'Species', '9606', (21, 29))	('single nucleotide variants', 'Var', (46, 72))	('SLC47A', 'Gene', (80, 86))	('CDC', 'Disease', (17, 20))
134942	31878355	In line with this, RCC patients with low levels of PGC-1alpha expression displayed a poor outcome in the TCGA ccRCC dataset.	('ccRCC', 'Disease', 'MESH:D002292', (110, 115))	('patients', 'Species', '9606', (23, 31))	('PGC-1alpha', 'Gene', '10891', (51, 61))	('RCC', 'Disease', 'MESH:D002292', (19, 22))	('RCC', 'Disease', (19, 22))	('RCC', 'Disease', (112, 115))	('RCC', 'Disease', 'MESH:D002292', (112, 115))	('PGC-1alpha', 'Gene', (51, 61))	('low levels', 'Var', (37, 47))	('ccRCC', 'Disease', (110, 115))
134970	31878355	The RNA sequencing analysis of CDCs in comparison to normal tissues revealed a large number of dysregulated protein-coding genes with a predominance of solute carrier transporters, potential miRNA-target interactions and prognostic markers that could be associated with CDC.	('miRNA-target', 'Var', (191, 203))	('protein-coding', 'Protein', (108, 122))	('CDCs', 'Chemical', 'MESH:C027616', (31, 35))	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('CDC', 'Disease', (270, 273))	('dysregulated', 'Gene', (95, 107))	('solute carrier transporters', 'MPA', (152, 179))	('interactions', 'Interaction', (204, 216))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('carrier', 'molecular_function', 'GO:0005215', ('159', '166'))
134973	31878355	X.L., J.V., H.T., M.K., D.M., S.H.	('H.T', 'Disease', 'MESH:D000848', (12, 15))	('D.M.', 'Var', (24, 28))	('M.K.', 'Var', (18, 22))	('H.T', 'Disease', (12, 15))
134982	29391527	High SMARCA4 expression was associated with poor prognosis in many types of tumors, including liver hepatocellular carcinoma (LIHC), and kidney renal clear cell carcinoma (KIRC).	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (137, 170))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (100, 124))	('High', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('expression', 'MPA', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('LIHC', 'Disease', 'None', (126, 130))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (94, 124))	('liver hepatocellular carcinoma', 'Disease', (94, 124))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('LIHC', 'Disease', (126, 130))	('SMARCA4', 'Gene', (5, 12))	('SMARCA4', 'Gene', '6597', (5, 12))	('kidney renal clear cell carcinoma', 'Disease', (137, 170))
134983	29391527	In contrast, high SMARCA2 expression was associated with good prognosis.	('expression', 'MPA', (26, 36))	('high', 'Var', (13, 17))	('SMARCA2', 'Gene', '6595', (18, 25))	('SMARCA2', 'Gene', (18, 25))
134993	29391527	The mechanisms by which loss-of-function mutations in SWI/SNF complex subunits trigger tumor formation or affect tumor cell behavior is still a highly debated issue.	('mutations', 'Var', (41, 50))	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('loss-of-function', 'NegReg', (24, 40))	('formation', 'biological_process', 'GO:0009058', ('93', '102'))	('trigger', 'PosReg', (79, 86))	('tumor', 'Disease', (87, 92))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('54', '69'))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('SWI/SNF', 'Gene', (54, 61))	('affect', 'Reg', (106, 112))
134994	29391527	Several data point to the pathological effects of aberrant residual SWI/SNF complexes as the cause of the potential selective advantage of SWI/SNF mutant cancer cells.	('mutant', 'Var', (147, 153))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('SWI/SNF complexes', 'Protein', (68, 85))	('SWI/SNF', 'Gene', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('aberrant', 'Var', (50, 58))
134997	29391527	In addition, SMARCA4 has been found to be silenced or mutated in a number of cancer cell lines.	('SMARCA4', 'Gene', (13, 20))	('SMARCA4', 'Gene', '6597', (13, 20))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('mutated', 'Var', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
134998	29391527	Brg1 homozygous knockout mice die early during development; however, heterozygote mice or conditional inactivation of Brg1 in some adult tissues display increased tumor formation.	('mice', 'Species', '10090', (82, 86))	('Brg1', 'Gene', '20586', (0, 4))	('Brg1', 'Gene', (118, 122))	('mice', 'Species', '10090', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('increased', 'PosReg', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('formation', 'biological_process', 'GO:0009058', ('169', '178'))	('Brg1', 'Gene', '20586', (118, 122))	('conditional inactivation', 'Var', (90, 114))	('tumor', 'Disease', (163, 168))	('Brg1', 'Gene', (0, 4))
135001	29391527	Furthermore, heterozygote and homozygote Brm mutants treated with carcinogens display increased tumor development.	('mutants', 'Var', (45, 52))	('increased', 'PosReg', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('Brm', 'Gene', (41, 44))	('carcinogens', 'Disease', 'MESH:D063646', (66, 77))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('carcinogens', 'Disease', (66, 77))
135007	29391527	A meta-analysis of prognosis data indicated that tumors with high SMARCA4 expression are mostly associated with poor prognosis, while tumors with high SMARCA2 expression are mostly associated with good prognosis.	('expression', 'MPA', (74, 84))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('SMARCA4', 'Gene', (66, 73))	('SMARCA4', 'Gene', '6597', (66, 73))	('high', 'Var', (61, 65))	('SMARCA2', 'Gene', (151, 158))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('SMARCA2', 'Gene', '6595', (151, 158))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
135021	29391527	We next investigated whether SMARCA4 overexpression occurs predominantly in tumors harboring SMARCA4 mutations as a possible consequence of a putative negative autoregulation.	('SMARCA4', 'Gene', '6597', (29, 36))	('overexpression', 'PosReg', (37, 51))	('mutations', 'Var', (101, 110))	('negative', 'NegReg', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('SMARCA4', 'Gene', (93, 100))	('autoregulation', 'MPA', (160, 174))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('SMARCA4', 'Gene', '6597', (93, 100))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('SMARCA4', 'Gene', (29, 36))
135022	29391527	Using data on SMARCA4 mutations in 18 types of tumors obtained from TCGA through cBioPortal, we found SMARCA4 to be mutated in either none or up to 8.5% of the samples, depending on the tumor type.	('SMARCA4', 'Gene', (102, 109))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('SMARCA4', 'Gene', (14, 21))	('SMARCA4', 'Gene', '6597', (102, 109))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('SMARCA4', 'Gene', '6597', (14, 21))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mutated', 'Var', (116, 123))	('tumor', 'Disease', (47, 52))
135023	29391527	SMARCA4 mutated tumors displayed similar level of accumulation of SMARCA4 mRNA as tumors harboring non-mutated SMARCA4 (Supplementary Fig.	('SMARCA4', 'Gene', (0, 7))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('SMARCA4', 'Gene', (66, 73))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('mutated', 'Var', (8, 15))	('SMARCA4', 'Gene', '6597', (66, 73))	('SMARCA4', 'Gene', '6597', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('SMARCA4', 'Gene', (111, 118))	('SMARCA4', 'Gene', '6597', (111, 118))	('accumulation', 'PosReg', (50, 62))	('tumors', 'Disease', (16, 22))
135025	29391527	Taken together, these data demonstrate that SMARCA4 expression is upregulated and SMARCA2 is downregulated in most types of tumors irrespectively of the presence of mutations in the gene.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('SMARCA2', 'Gene', (82, 89))	('SMARCA2', 'Gene', '6595', (82, 89))	('upregulated', 'PosReg', (66, 77))	('expression', 'MPA', (52, 62))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('downregulated', 'NegReg', (93, 106))	('mutations', 'Var', (165, 174))	('SMARCA4', 'Gene', (44, 51))	('SMARCA4', 'Gene', '6597', (44, 51))
135029	29391527	High expression of SMARCA4 was significantly associated (COX P <= 0.01) with a poor prognosis in breast and ovarian cancer, lung adenocarcinoma, liposarcoma and uveal melanoma datasets (Fig.	('liposarcoma', 'Disease', (145, 156))	('uveal melanoma', 'Phenotype', 'HP:0007716', (161, 175))	('uveal melanoma', 'Disease', (161, 175))	('liposarcoma', 'Disease', 'MESH:D008080', (145, 156))	('High', 'Var', (0, 4))	('lung adenocarcinoma', 'Disease', (124, 143))	('liposarcoma', 'Phenotype', 'HP:0012034', (145, 156))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (124, 143))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (97, 122))	('uveal melanoma', 'Disease', 'MESH:C536494', (161, 175))	('associated', 'Reg', (45, 55))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (124, 143))	('SMARCA4', 'Gene', (19, 26))	('SMARCA4', 'Gene', '6597', (19, 26))
135030	29391527	In contrast, high expression of SMARCA2 was associated to good prognosis in breast and ovarian cancer, lung adenocarcinoma, and liposarcoma datasets (Fig.	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (76, 101))	('liposarcoma', 'Phenotype', 'HP:0012034', (128, 139))	('high', 'Var', (13, 17))	('liposarcoma', 'Disease', 'MESH:D008080', (128, 139))	('lung adenocarcinoma', 'Disease', (103, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (103, 122))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (103, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('SMARCA2', 'Gene', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('liposarcoma', 'Disease', (128, 139))	('SMARCA2', 'Gene', '6595', (32, 39))
135031	29391527	In fact, high expression of SMARCA2 was associated with poor prognosis only in colon carcinoma.	('colon carcinoma', 'Disease', 'MESH:D015179', (79, 94))	('colon carcinoma', 'Disease', (79, 94))	('SMARCA2', 'Gene', (28, 35))	('SMARCA2', 'Gene', '6595', (28, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('high', 'Var', (9, 13))
135039	29391527	Analysis of these plots indicates that high expression of SMARCA4 is associated with poor prognosis in LIHC, BLCA, SKCM and KIRC (Fig.	('SMARCA4', 'Gene', (58, 65))	('BLCA', 'Disease', (109, 113))	('LIHC', 'Disease', 'None', (103, 107))	('high expression', 'Var', (39, 54))	('SKCM', 'Disease', (115, 119))	('SMARCA4', 'Gene', '6597', (58, 65))	('KIRC', 'Disease', (124, 128))	('LIHC', 'Disease', (103, 107))
135040	29391527	In clear contrast, high expression of SMARCA2 is associated with good prognosis in LIHC and KIRC (Fig.	('LIHC', 'Disease', 'None', (83, 87))	('high expression', 'Var', (19, 34))	('KIRC', 'Disease', (92, 96))	('SMARCA2', 'Gene', (38, 45))	('SMARCA2', 'Gene', '6595', (38, 45))	('LIHC', 'Disease', (83, 87))
135041	29391527	Taken together, these data suggest that in most of the cohorts analyzed, high expression of SMARCA4 is associated with poor prognosis, while high expression of SMARCA2 is associated with good prognosis.	('SMARCA2', 'Gene', (160, 167))	('SMARCA2', 'Gene', '6595', (160, 167))	('SMARCA4', 'Gene', '6597', (92, 99))	('high', 'Var', (73, 77))	('SMARCA4', 'Gene', (92, 99))
135044	29391527	Consistently with the prognosis results, LIHC tumors with high levels of SMARCA4 expression (upper decile) presented a significant increased proportion of advanced stages, and poorly differentiated histology with respect to the rest of the LIHC tumors analyzed (Table 1).	('high levels', 'Var', (58, 69))	('LIHC tumors', 'Disease', 'MESH:D009369', (240, 251))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('LIHC tumors', 'Disease', (41, 52))	('increased', 'PosReg', (131, 140))	('LIHC tumors', 'Disease', 'MESH:D009369', (41, 52))	('LIHC tumors', 'Disease', (240, 251))	('advanced stages', 'CPA', (155, 170))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('SMARCA4', 'Gene', (73, 80))	('SMARCA4', 'Gene', '6597', (73, 80))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('expression', 'MPA', (81, 91))
135045	29391527	In contrast, tumors with high levels of SMARCA2 transcript (upper decile) presented increased proportion of well-differentiated tumors (Table 1).	('SMARCA2', 'Gene', (40, 47))	('SMARCA2', 'Gene', '6595', (40, 47))	('high levels', 'Var', (25, 36))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
135047	29391527	Similarly, in KIRC tumors, high expression of SMARCA4 is associated with increased undifferentiated histological grade (Fig.	('increased', 'PosReg', (73, 82))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Disease', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('high expression', 'Var', (27, 42))	('SMARCA4', 'Gene', (46, 53))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('SMARCA4', 'Gene', '6597', (46, 53))
135049	29391527	In addition, in KIRC tumors, high expression of SMARCA4 was strongly associated with the presence of metastasis (high proportion of N1, P = 0.035, and M1, P = 0.0009) (Table 2).	('high', 'Var', (29, 33))	('associated', 'Reg', (69, 79))	('tumors', 'Disease', (21, 27))	('metastasis', 'CPA', (101, 111))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('SMARCA4', 'Gene', (48, 55))	('SMARCA4', 'Gene', '6597', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
135073	29391527	5j; Supplementary Figs S3d and S4b), and often presented E2F (P = 1.05x10-26), MYC (P = 3.9x10-16) and ELK1 (P = 1.2 x 10-11) binding sites, suggesting a reduced proliferation of these tumor cells.	('tumor', 'Disease', (185, 190))	('ELK1', 'Gene', (103, 107))	('E2F', 'Protein', (57, 60))	('MYC', 'Gene', (79, 82))	('ELK1', 'Gene', '2002', (103, 107))	('S3d', 'Var', (23, 26))	('S4b', 'Var', (31, 34))	('binding', 'Interaction', (126, 133))	('proliferation', 'CPA', (162, 175))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('MYC', 'Gene', '4609', (79, 82))	('reduced', 'NegReg', (154, 161))	('binding', 'molecular_function', 'GO:0005488', ('126', '133'))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
135081	29391527	In contrast, genes positively coexpressed with SMARCA2 and negatively coexpressed with SMARCA4 (Supplementary Table S7) were enriched in liver metabolism functions, such as lipid metabolism (ACADL, ACSL1, LIPG), amino acid metabolism (TAT, BCKDHB, PAH, IDH1), xenobiotic detoxification (CYP3A4, CYP4V2, CYP8B1), and blood coagulation (F8, F11) categories.	('xenobiotic detoxification', 'Disease', 'MESH:C565043', (260, 285))	('BCKDHB', 'Gene', (240, 246))	('TAT', 'Disease', 'None', (235, 238))	('SMARCA2', 'Gene', (47, 54))	('SMARCA2', 'Gene', '6595', (47, 54))	('ACADL', 'Gene', (191, 196))	('ACADL', 'Gene', '33', (191, 196))	('LIPG', 'Gene', (205, 209))	('CYP3A4', 'Var', (287, 293))	('CYP4V2', 'Gene', (295, 301))	('lipid metabolism', 'MPA', (173, 189))	('metabolism', 'biological_process', 'GO:0008152', ('223', '233'))	('PAH', 'molecular_function', 'GO:0033972', ('248', '251'))	('IDH1', 'Gene', (253, 257))	('liver metabolism functions', 'MPA', (137, 163))	('SMARCA4', 'Gene', (87, 94))	('PAH', 'Gene', (248, 251))	('CYP8B1', 'Gene', '1582', (303, 309))	('amino acid metabolism', 'MPA', (212, 233))	('blood coagulation', 'Disease', 'MESH:D001778', (316, 333))	('detoxification', 'biological_process', 'GO:0098754', ('271', '285'))	('BCKDHB', 'Gene', '594', (240, 246))	('TAT', 'Disease', (235, 238))	('ACSL1', 'Gene', '2180', (198, 203))	('IDH1', 'Gene', '3417', (253, 257))	('metabolism', 'biological_process', 'GO:0008152', ('143', '153'))	('CYP8B1', 'molecular_function', 'GO:0033779', ('303', '309'))	('LIPG', 'Gene', '9388', (205, 209))	('lipid metabolism', 'biological_process', 'GO:0006629', ('173', '189'))	('ACSL1', 'Gene', (198, 203))	('CYP8B1', 'Gene', (303, 309))	('xenobiotic detoxification', 'Disease', (260, 285))	('CYP3A4', 'molecular_function', 'GO:0033780', ('287', '293'))	('SMARCA4', 'Gene', '6597', (87, 94))	('blood coagulation', 'Disease', (316, 333))	('PAH', 'Gene', '5053', (248, 251))	('blood coagulation', 'biological_process', 'GO:0007596', ('316', '333'))	('lipid', 'Chemical', 'MESH:D008055', (173, 178))	('CYP4V2', 'Gene', '285440', (295, 301))
135114	29391527	A role of SWI/SNF complexes as tumor suppressors is widely accepted, mostly based on the fact that genes encoding SWI/SNF subunits are mutated in a wide-ranging proportion of tumors.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Disease', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('mutated', 'Var', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
135115	29391527	Thus, SMARCA4 is frequently mutated (more than 90% of the cases) in ovarian small cell carcinoma of the hypercalcemic type.	('SMARCA4', 'Gene', (6, 13))	('mutated', 'Var', (28, 35))	('SMARCA4', 'Gene', '6597', (6, 13))	('ovarian small cell carcinoma of the hypercalcemic type', 'Disease', 'MESH:D018288', (68, 122))	('ovarian small', 'Phenotype', 'HP:0008724', (68, 81))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (76, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
135116	29391527	However, several studies and inspection of the TCGA data indicate that, in most of the tumor types SMARCA4 mutations vary between 0% and 15% of the cases.	('SMARCA4', 'Gene', (99, 106))	('SMARCA4', 'Gene', '6597', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mutations', 'Var', (107, 116))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
135123	29391527	Furthermore, we find that high levels of SMARCA4 expression are associated with an advanced tumor stage and histological grade in LIHC, and with increased metastasis in KIRC.	('associated', 'Reg', (64, 74))	('metastasis', 'CPA', (155, 165))	('high', 'Var', (26, 30))	('SMARCA4', 'Gene', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('increased', 'PosReg', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('SMARCA4', 'Gene', '6597', (41, 48))	('LIHC', 'Disease', (130, 134))	('LIHC', 'Disease', 'None', (130, 134))	('tumor', 'Disease', (92, 97))	('histological grade', 'CPA', (108, 126))
135124	29391527	Taken together, these data suggest that, at least for several types of cancers, high expression of SMARCA4 confers a selective advantage to tumor cells.	('SMARCA4', 'Gene', (99, 106))	('SMARCA4', 'Gene', '6597', (99, 106))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('high expression', 'Var', (80, 95))	('tumor', 'Disease', (140, 145))
135138	29391527	Consistently, Kaufmann et al., recently showed that knockdown of SMARCA4 impairs proliferation and decreases cyclin B and cyclin E expression in hepatocellular carcinoma cell lines.	('decreases', 'NegReg', (99, 108))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (145, 169))	('cyclin', 'molecular_function', 'GO:0016538', ('109', '115'))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('hepatocellular carcinoma', 'Disease', (145, 169))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (145, 169))	('SMARCA4', 'Gene', (65, 72))	('SMARCA4', 'Gene', '6597', (65, 72))	('impairs', 'NegReg', (73, 80))	('proliferation', 'CPA', (81, 94))	('knockdown', 'Var', (52, 61))	('cyclin', 'molecular_function', 'GO:0016538', ('122', '128'))
135144	29391527	Interestingly, RhoA signaling activation was reported upon SMARCA4 re-expression in SMARCA4-deficient human adrenal adenocarcinoma SW13 cells.	('SMARCA4-deficient human adrenal adenocarcinoma', 'Disease', 'MESH:D000310', (84, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('re-expression', 'Var', (67, 80))	('SMARCA4', 'Gene', (59, 66))	('RhoA', 'Gene', (15, 19))	('SMARCA4-deficient human adrenal adenocarcinoma', 'Disease', (84, 130))	('activation', 'PosReg', (30, 40))	('SMARCA4', 'Gene', '6597', (59, 66))	('signaling', 'biological_process', 'GO:0023052', ('20', '29'))	('RhoA', 'Gene', '387', (15, 19))	('SW13', 'CellLine', 'CVCL:0542', (131, 135))	('SMARCA4', 'Gene', (84, 91))	('adrenal adenocarcinoma', 'Phenotype', 'HP:0006744', (108, 130))	('SMARCA4', 'Gene', '6597', (84, 91))
135147	29391527	In addition, high levels of SMARCA2 expression were associated with a low tumor stage and well-differentiated tumors in LIHC and KIRC.	('low tumor', 'Disease', 'MESH:D009800', (70, 79))	('high', 'Var', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('low tumor', 'Disease', (70, 79))	('LIHC', 'Disease', (120, 124))	('SMARCA2', 'Gene', (28, 35))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('SMARCA2', 'Gene', '6595', (28, 35))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('LIHC', 'Disease', 'None', (120, 124))	('expression', 'MPA', (36, 46))
135188	29520901	Both cytosine and thymine, corresponding to methylated and unmethylated cytosine after bisulfite modification, respectively, are captured by electrostatic interaction and then discriminated from each other by their hydrophobic interactions.	('methylated', 'Var', (44, 54))	('cytosine', 'Chemical', 'MESH:D003596', (5, 13))	('electrostatic interaction', 'MPA', (141, 166))	('bisulfite', 'Chemical', 'MESH:C042345', (87, 96))	('thymine', 'Chemical', 'MESH:D013941', (18, 25))	('cytosine', 'Chemical', 'MESH:D003596', (72, 80))
135190	29520901	When the DNA methylation status of the FAM150A gene, a marker of the CpG island methylator phenotype specific to clear cell renal cell carcinoma (ccRCC), was examined in 98 patients with ccRCC, bulk specimens of tumorous tissue including cancer cells showing DNA methylation of the FAM150A gene were easily identifiable by simply viewing the differentiated chromatograms, even when the cancer cell content was low.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (124, 144))	('FAM150A', 'Gene', '389658', (39, 46))	('clear cell renal cell carcinoma', 'Disease', (113, 144))	('DNA methylation', 'Var', (259, 274))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('FAM150A', 'Gene', (282, 289))	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (386, 392))	('patients', 'Species', '9606', (173, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('DNA methylation', 'biological_process', 'GO:0006306', ('259', '274'))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (113, 144))	('FAM150A', 'Gene', '389658', (282, 289))	('DNA', 'cellular_component', 'GO:0005574', ('259', '262'))	('tumorous', 'Disease', 'MESH:D009369', (212, 220))	('ccRCC', 'Disease', (187, 192))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('FAM150A', 'Gene', (39, 46))	('cancer', 'Disease', (386, 392))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (113, 144))	('men', 'Species', '9606', (204, 207))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('ccRCC', 'Phenotype', 'HP:0006770', (187, 192))	('tumorous', 'Disease', (212, 220))
135191	29520901	Sixteen ccRCC showing DNA methylation more frequently exhibited clinicopathological parameters reflecting tumor aggressiveness (ie, a larger diameter, higher histological grade, vascular involvement, renal vein tumor thrombi, infiltrating growth, tumor necrosis, renal pelvis invasion and higher pathological TNM stage), and had significantly lower recurrence-free and overall survival rates.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('necrosis', 'biological_process', 'GO:0070265', ('253', '261'))	('men', 'Species', '9606', (194, 197))	('larger', 'PosReg', (134, 140))	('necrosis', 'biological_process', 'GO:0019835', ('253', '261'))	('higher', 'PosReg', (151, 157))	('infiltrating growth', 'CPA', (226, 245))	('necrosis', 'biological_process', 'GO:0001906', ('253', '261'))	('renal vein tumor thrombi', 'Disease', (200, 224))	('ccRCC', 'Disease', (8, 13))	('aggressiveness', 'Phenotype', 'HP:0000718', (112, 126))	('renal vein tumor thrombi', 'Disease', 'MESH:D007674', (200, 224))	('renal pelvis invasion', 'Disease', 'MESH:D007674', (263, 284))	('ccRCC', 'Phenotype', 'HP:0006770', (8, 13))	('tumor aggressiveness', 'Disease', (106, 126))	('vascular involvement', 'CPA', (178, 198))	('renal pelvis invasion', 'Disease', (263, 284))	('lower', 'NegReg', (343, 348))	('vein tumor thrombi', 'Phenotype', 'HP:0004936', (206, 224))	('exhibited', 'Reg', (54, 63))	('necrosis', 'biological_process', 'GO:0008219', ('253', '261'))	('DNA methylation', 'biological_process', 'GO:0006306', ('22', '37'))	('overall survival rates', 'CPA', (369, 391))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('tumor necrosis', 'Disease', 'MESH:D009336', (247, 261))	('methylation', 'Var', (26, 37))	('tumor necrosis', 'Disease', (247, 261))	('necrosis', 'biological_process', 'GO:0008220', ('253', '261'))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (106, 126))	('renal pelvis', 'Phenotype', 'HP:0000125', (263, 275))
135193	29520901	DNA methylation alterations are known to occur during multistage human carcinogenesis,1, 2 even from the early and precancerous stage.	('human', 'Species', '9606', (65, 70))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('cancerous', 'Disease', (118, 127))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('carcinogenesis', 'Disease', (71, 85))	('alterations', 'Var', (16, 27))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancerous', 'Disease', 'MESH:D009369', (118, 127))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))	('methylation alterations', 'Var', (4, 27))
135246	29520901	Thereafter, the hydrophobicity of the polymer particles plays a role in discrimination between cytosine derived from methylated CpG and thymine derived from unmethylated CpG within the PCR products.	('cytosine', 'Chemical', 'MESH:D003596', (95, 103))	('thymine', 'Chemical', 'MESH:D013941', (136, 143))	('methylated', 'Var', (117, 127))	('hydrophobicity', 'MPA', (16, 30))	('polymer', 'Chemical', 'MESH:D011108', (38, 45))	('discrimination', 'MPA', (72, 86))	('cytosine', 'MPA', (95, 103))	('thymine', 'MPA', (136, 143))
135247	29520901	Although the amounts of negative charge from the phosphate groups in cytosine and thymine are the same, hydrophobic interaction between the polymer particles and the PCR products containing thymine is stronger due to the methyl group at the 5' position of the pyrimidine ring in comparison with that between the polymer particles and the PCR products containing cytosine.	('methyl group', 'Var', (221, 233))	('polymer', 'Chemical', 'MESH:D011108', (312, 319))	('phosphate', 'Chemical', 'MESH:D010710', (49, 58))	('pyrimidine', 'Chemical', 'MESH:C030986', (260, 270))	('thymine', 'Chemical', 'MESH:D013941', (82, 89))	('polymer', 'Chemical', 'MESH:D011108', (140, 147))	('cytosine', 'Chemical', 'MESH:D003596', (69, 77))	('stronger', 'PosReg', (201, 209))	('thymine', 'Var', (190, 197))	('hydrophobic interaction', 'MPA', (104, 127))	('cytosine', 'Chemical', 'MESH:D003596', (362, 370))	('thymine', 'Chemical', 'MESH:D013941', (190, 197))
135255	29520901	In the "bimodal peak" pattern where the DNA methylation level of the target region in cancer cells is high, as shown in Case 91 in Figure 3A (close to the fully methylated control DNA), we can identify the presence of cancer cells having methylated DNA even if the content of such cells is low.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('methylated', 'Var', (238, 248))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
135258	29520901	Simple viewing of the differential curves (Figure 3B) made it possible to identify tissue samples including cancer cells having methylated DNA and showing the "two upward convex pattern," allowing discrimination from tissue samples lacking methylated DNA and showing the "one upward convex pattern," even if the content of cancer cells showing DNA methylation and the DNA methylation level of the target region were low.	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('cancer', 'Disease', (323, 329))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('methylated', 'Var', (128, 138))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
135259	29520901	In comparison to ordinary methods, such as MassARRAY and pyrosequencing, for which the reliability of measured values of less than 10% is restricted, simple and reliable detection of only a small number of cancer cells having methylated DNA using our HPLC system would be advantageous for analysis of clinical specimens.	('men', 'Species', '9606', (315, 318))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('methylated', 'Var', (226, 236))	('DNA', 'cellular_component', 'GO:0005574', ('237', '240'))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
135260	29520901	These 16 ccRCC including cancer cells showing various degree of DNA methylation of the FAM150A gene showed a significantly higher incidence of clinicopathological features reflecting tumor aggressiveness (Table 2) and shorter recurrence-free and overall survival times than 82 ccRCC showing a "one upward convex pattern" (Figure 4).	('ccRCC', 'Phenotype', 'HP:0006770', (277, 282))	('FAM150A', 'Gene', '389658', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('higher', 'PosReg', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('overall survival times', 'CPA', (246, 268))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('tumor aggressiveness', 'Disease', (183, 203))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('DNA', 'Var', (64, 67))	('aggressiveness', 'Phenotype', 'HP:0000718', (189, 203))	('DNA methylation', 'biological_process', 'GO:0006306', ('64', '79'))	('FAM150A', 'Gene', (87, 94))	('cancer', 'Disease', (25, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (9, 14))	('shorter', 'NegReg', (218, 225))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (183, 203))
135265	29520901	Because our HPLC method is able to detect 5% DNA methylation (Figure S5), 16%-58% of cancer cells in liquid biopsy samples would be detectable using our system.	('DNA methylation', 'Var', (45, 60))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('cancer', 'Disease', (85, 91))	('DNA methylation', 'biological_process', 'GO:0006306', ('45', '60'))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
135268	29520901	DNA methylation alterations accumulate upon exposure to carcinogenetic factors, even in precancerous conditions, and generally precede genetic alterations revealed by clinical sequencing.	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'Gene', (0, 3))	('alterations accumulate', 'Reg', (16, 38))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('precancerous conditions', 'Disease', 'MESH:D011230', (88, 111))	('methylation', 'Var', (4, 15))	('precancerous conditions', 'Disease', (88, 111))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
135269	29520901	DNA methylation profiles generally reflect each of the steps of multistage carcinogenesis and are frequently correlated with the clinicopathological features of individual cancers.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('carcinogenesis', 'Disease', (75, 89))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('reflect', 'Reg', (35, 42))	('methylation', 'Var', (4, 15))	('correlated', 'Reg', (109, 119))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))	('carcinogenesis', 'Disease', 'MESH:D063646', (75, 89))
135270	29520901	In addition, unlike alterations of mRNA and/or protein expression and metabolomic features, which can be easily affected by the microenvironment of cancer cells, DNA methylation alterations are stably preserved on DNA double strands by covalent bonds.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('men', 'Species', '9606', (140, 143))	('methylation alterations', 'Var', (166, 189))	('DNA', 'cellular_component', 'GO:0005574', ('162', '165'))	('DNA', 'cellular_component', 'GO:0005574', ('214', '217'))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('DNA methylation', 'biological_process', 'GO:0006306', ('162', '177'))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('DNA', 'MPA', (162, 165))
135276	29088846	In the univariate analysis CDHR5 expression was significantly associated with a longer overall survival of RCC patients at the protein (p = 0.026, HR = 0.56) and transcript levels (TCGA-cohort: p = 0.0002, HR = 0.55).	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('RCC', 'Disease', (107, 110))	('expression', 'Var', (33, 43))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('CDHR5', 'Gene', '53841', (27, 32))	('longer', 'PosReg', (80, 86))	('CDHR5', 'Gene', (27, 32))	('overall survival', 'MPA', (87, 103))	('patients', 'Species', '9606', (111, 119))
135294	29088846	Aberrations in this region are also associated with the Beckwith-Wiedmann syndrome and show as a second locus, a loss of heterozygosity in Wilms tumors.	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('Aberrations', 'Var', (0, 11))	('Wilms tumors', 'Phenotype', 'HP:0002667', (139, 151))	('Beckwith-Wiedmann syndrome', 'Disease', (56, 82))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('Wilms tumors', 'Disease', (139, 151))	('Beckwith-Wiedmann syndrome', 'Disease', 'MESH:D001506', (56, 82))	('associated', 'Reg', (36, 46))	('Wilms tumors', 'Disease', 'MESH:D009396', (139, 151))
135322	29088846	In univariate Cox proportional hazards analysis high CDHR5 mRNA expression (as assessed by RNASeq) showed a significantly lower risk of earlier death compared to patients with low CDHR5 mRNA expression (p = 0.0002, HR = 0.55, 95% CI [0.40-0.75]; Table 3).	('lower', 'NegReg', (122, 127))	('patients', 'Species', '9606', (162, 170))	('CDHR5', 'Gene', (180, 185))	('CDHR5', 'Gene', '53841', (53, 58))	('death', 'Disease', 'MESH:D003643', (144, 149))	('CDHR5', 'Gene', (53, 58))	('death', 'Disease', (144, 149))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('CDHR5', 'Gene', '53841', (180, 185))	('high', 'Var', (48, 52))
135326	29088846	CDHR5 positivity is significantly associated with a longer overall survival time.	('positivity', 'Var', (6, 16))	('CDHR5', 'Gene', '53841', (0, 5))	('CDHR5', 'Gene', (0, 5))	('longer', 'PosReg', (52, 58))
135339	29088846	In CRC cell lines, expression of CDHR5 leads to a reduction of colonies and a disbanding of established colonies.	('CDHR5', 'Gene', '53841', (33, 38))	('reduction', 'NegReg', (50, 59))	('colonies', 'CPA', (63, 71))	('CDHR5', 'Gene', (33, 38))	('expression', 'Var', (19, 29))	('disbanding of established colonies', 'CPA', (78, 112))
135344	29088846	Especially, the dysregulation of beta-catenin in ccRCC is a predictor of a lower tumor mortality and a potential target for therapy.	('lower', 'NegReg', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('beta-catenin', 'Gene', (33, 45))	('dysregulation', 'Var', (16, 29))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('beta-catenin', 'Gene', '1499', (33, 45))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('tumor', 'Disease', (81, 86))	('RCC', 'Disease', (51, 54))
135380	29088846	Secondly, we have performed the additional investigations for top 100 genes with differential expression (50 upregulated and 50 downregulated) between samples with high and low CDHR5 mRNA expression using the cut-off for transcript number from our prognostic studies (Supplementary Table 3), which proved to have the highest prognostic value with regard to survival and statistical significance (Cut-off = 2580.166).	('upregulated', 'PosReg', (109, 120))	('CDHR5', 'Gene', '53841', (177, 182))	('high', 'Var', (164, 168))	('CDHR5', 'Gene', (177, 182))	('men', 'Species', '9606', (274, 277))	('mRNA expression', 'MPA', (183, 198))	('low', 'NegReg', (173, 176))
135389	28358873	Elaborating on previous results on MET, we find a germline SNP (rs11762213) in this gene predicting prognosis.	('predicting', 'Reg', (89, 99))	('rs11762213', 'Mutation', 'rs11762213', (64, 74))	('rs11762213', 'Var', (64, 74))
135390	28358873	We also notice an elevation of mutations in the long noncoding RNA NEAT1, and these mutations are associated with increased expression and unfavorable outcome.	('NEAT1', 'Gene', (67, 72))	('mutations', 'Var', (31, 40))	('RNA', 'cellular_component', 'GO:0005562', ('63', '66'))	('increased', 'PosReg', (114, 123))	('expression', 'MPA', (124, 134))	('elevation', 'PosReg', (18, 27))	('NEAT1', 'Gene', '283131', (67, 72))
135392	28358873	First, we investigate genome-wide mutational patterns, finding they are governed mostly by methylation-associated C-to-T transitions.	('methylation-associated', 'Var', (91, 113))	('C-to-T transitions', 'Disease', (114, 132))	('C', 'Chemical', 'MESH:D002244', (114, 115))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))
135393	28358873	We also observe significantly more mutations in open chromatin and early-replicating regions in tumors with chromatin-modifier alterations.	('chromatin', 'cellular_component', 'GO:0000785', ('108', '117'))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('more', 'PosReg', (30, 34))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('chromatin', 'cellular_component', 'GO:0000785', ('53', '62'))	('alterations', 'Var', (127, 138))	('open', 'Protein', (48, 52))	('early-replicating regions', 'CPA', (67, 92))	('mutations', 'Var', (35, 44))
135408	28358873	An amino acid substitution that leads to constitutive activation and/or overexpression are two mechanisms of dysfunction of MET in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('activation', 'PosReg', (54, 64))	('tumor', 'Disease', (131, 136))	('amino acid substitution', 'Var', (3, 26))	('overexpression', 'MPA', (72, 86))
135421	28358873	We found rs11762213, a germline exonic single nucleotide polymorphism (SNP) inside MET, predicted cancer-specific survival (CSS) in type II pRCC.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('pRCC', 'Phenotype', 'HP:0006766', (140, 144))	('C', 'Chemical', 'MESH:D002244', (143, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('C', 'Chemical', 'MESH:D002244', (124, 125))	('pRCC', 'Gene', (140, 144))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('rs11762213', 'Mutation', 'rs11762213', (9, 19))	('predicted', 'Reg', (88, 97))	('rs11762213', 'Var', (9, 19))	('pRCC', 'Gene', '5546', (140, 144))	('C', 'Chemical', 'MESH:D002244', (142, 143))
135428	28358873	V1110I and M1268T were two recurrent mutations in this extra set.	('V1110I', 'Var', (0, 6))	('M1268T', 'Var', (11, 17))	('V1110I', 'Mutation', 'p.V1110I', (0, 6))	('M1268T', 'Mutation', 'p.M1268T', (11, 17))
135430	28358873	Additionally, we found two samples carrying H112Y and Y1248C respectively.	('H112Y', 'Mutation', 'p.H112Y', (44, 49))	('H112Y', 'Var', (44, 49))	('Y1248C', 'Var', (54, 60))	('Y1248C', 'Mutation', 'rs771116500', (54, 60))
135431	28358873	H1112Y has been observed in two patients in the original TCGA study cohort and H1118R is a long-known germline mutation associated with hereditary papillary renal carcinoma (HPRC).	('associated', 'Reg', (120, 130))	('patients', 'Species', '9606', (32, 40))	('H1118R', 'Mutation', 'p.H1118R', (79, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('H1112Y', 'Mutation', 'p.H1112Y', (0, 6))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (147, 172))	('C', 'Chemical', 'MESH:D002244', (177, 178))	('renal carcinoma', 'Phenotype', 'HP:0005584', (157, 172))	('H1112Y', 'Var', (0, 6))	('H1118R', 'Var', (79, 85))	('hereditary papillary renal carcinoma', 'Disease', 'MESH:D007681', (136, 172))	('hereditary papillary renal carcinoma', 'Disease', (136, 172))	('C', 'Chemical', 'MESH:D002244', (58, 59))
135432	28358873	Y1248C has been observed in type I pRCC before and the TCGA cohort has a case carrying Y1248H.	('Y1248C', 'Mutation', 'rs771116500', (0, 6))	('Y1248H', 'Var', (87, 93))	('C', 'Chemical', 'MESH:D002244', (56, 57))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('Y1248H', 'Mutation', 'p.Y1248H', (87, 93))	('pRCC', 'Phenotype', 'HP:0006766', (35, 39))	('pRCC', 'Gene', '5546', (35, 39))	('C', 'Chemical', 'MESH:D002244', (37, 38))	('C', 'Chemical', 'MESH:D002244', (5, 6))	('Y1248C', 'Var', (0, 6))	('pRCC', 'Gene', (35, 39))	('C', 'Chemical', 'MESH:D002244', (38, 39))
135434	28358873	Although many MET somatic mutations are believed to play a central role in pRCC, some germline MET mutations have also been associated with the disease.	('MET', 'Gene', (95, 98))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('pRCC', 'Gene', (75, 79))	('associated', 'Reg', (124, 134))	('mutations', 'Var', (99, 108))	('pRCC', 'Gene', '5546', (75, 79))	('pRCC', 'Phenotype', 'HP:0006766', (75, 79))
135435	28358873	In particular, a germline SNP, rs11762213 (Fig 1A), has been discovered to predict recurrence and survival in a mixed RCC cohort.	('survival', 'CPA', (98, 106))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('rs11762213', 'Mutation', 'rs11762213', (31, 41))	('predict', 'Reg', (75, 82))	('rs11762213', 'Var', (31, 41))	('recurrence', 'CPA', (83, 93))
135441	28358873	Cancer-speccific survival was significantly worse in type II patients carrying the risk allele of rs11762213 (p = 0.034, Fig 1B).	('worse', 'NegReg', (44, 49))	('rs11762213', 'Var', (98, 108))	('patients', 'Species', '9606', (61, 69))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('rs11762213', 'Mutation', 'rs11762213', (98, 108))	('Cancer-speccific survival', 'CPA', (0, 25))
135443	28358873	We did not observe statistically significant correlation of rs11762213 with MET RNA expression in either tumor samples or normal controls (p > 0.1, two-sided rank-sum test).	('rs11762213', 'Mutation', 'rs11762213', (60, 70))	('rs11762213', 'Var', (60, 70))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('MET', 'Protein', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('RNA', 'cellular_component', 'GO:0005562', ('80', '83'))
135450	28358873	We further expanded our scope and ran FunSeq to identify potentially high-impact, noncoding variants in pRCC.	('pRCC', 'Phenotype', 'HP:0006766', (104, 108))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('pRCC', 'Gene', (104, 108))	('variants', 'Var', (92, 100))	('pRCC', 'Gene', '5546', (104, 108))
135457	28358873	Mutations we found all fell into a putative promoter and its flanking region of NEAT1.	('NEAT1', 'Gene', '283131', (80, 85))	('NEAT1', 'Gene', (80, 85))	('Mutations', 'Var', (0, 9))	('fell', 'Reg', (23, 27))
135458	28358873	We noticed NEAT1 mutations were associated with higher NEAT1 expression (Fig 2C, S2A Fig, p < 0.032, two-sided rank sum test).	('NEAT1', 'Gene', '283131', (11, 16))	('higher', 'PosReg', (48, 54))	('NEAT1', 'Gene', '283131', (55, 60))	('NEAT1', 'Gene', (11, 16))	('C', 'Chemical', 'MESH:D002244', (78, 79))	('NEAT1', 'Gene', (55, 60))	('mutations', 'Var', (17, 26))	('expression', 'MPA', (61, 71))
135459	28358873	We also found NEAT1 mutations were associated with worse prognosis (Fig 2D, p < 0.041, log-rank test).	('mutations', 'Var', (20, 29))	('NEAT1', 'Gene', (14, 19))	('NEAT1', 'Gene', '283131', (14, 19))
135463	28358873	The Catalogue of Somatic Mutations in Cancer (COSMIC) annotates MALAT1 as a cancer consensus gene, associating it with pediatric RCC and lung cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('C', 'Chemical', 'MESH:D002244', (131, 132))	('C', 'Chemical', 'MESH:D002244', (130, 131))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('MALAT1', 'Gene', (64, 70))	('C', 'Chemical', 'MESH:D002244', (51, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('MALAT1', 'Gene', '378938', (64, 70))	('Mutations', 'Var', (25, 34))	('cancer', 'Disease', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (76, 82))	('C', 'Chemical', 'MESH:D002244', (38, 39))	('lung cancer', 'Disease', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('C', 'Chemical', 'MESH:D002244', (46, 47))	('pediatric RCC', 'Disease', (119, 132))	('C', 'Chemical', 'MESH:D002244', (4, 5))
135472	28358873	We found two cases with deletions in SDHB.	('SDHB', 'Gene', '6390', (37, 41))	('SDHB', 'Gene', (37, 41))	('deletions', 'Var', (24, 33))
135474	28358873	We validated the deletions affecting SDHB with another SV caller, Lumpy-SV.	('Lumpy-SV', 'Disease', 'MESH:D008166', (66, 74))	('SDHB', 'Gene', '6390', (37, 41))	('deletions', 'Var', (17, 26))	('SDHB', 'Gene', (37, 41))	('Lumpy-SV', 'Disease', (66, 74))
135475	28358873	Besides, we confirmed three cases carrying deletions affecting CDKN2A called by the TCGA array-based method but not the other two cases.	('deletions', 'Var', (43, 52))	('CDKN2A', 'Gene', '1029', (63, 69))	('C', 'Chemical', 'MESH:D002244', (85, 86))	('CDKN2A', 'Gene', (63, 69))	('C', 'Chemical', 'MESH:D002244', (63, 64))
135478	28358873	Lastly, we observed several high-impact sporadic events, including duplications in EGFR and HIF1A, and deletions in DNMT3A and STAG2 (S2C Fig).	('EGFR', 'Gene', '1956', (83, 87))	('STAG2', 'Gene', '10735', (127, 132))	('DNMT3A', 'Gene', (116, 122))	('duplications', 'Var', (67, 79))	('DNMT3A', 'Gene', '1788', (116, 122))	('EGFR', 'Gene', (83, 87))	('deletions', 'Var', (103, 112))	('HIF1A', 'Gene', '3091', (92, 97))	('EGFR', 'molecular_function', 'GO:0005006', ('83', '87'))	('C', 'Chemical', 'MESH:D002244', (136, 137))	('HIF1A', 'Gene', (92, 97))	('STAG2', 'Gene', (127, 132))
135480	28358873	C-to-T in CpGs showed the highest mutation rates, which were roughly three to six-fold higher than mutation rates of other nucleotide contexts.	('CpGs', 'Gene', (10, 14))	('mutation', 'MPA', (34, 42))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('CpGs', 'Chemical', 'MESH:C015772', (10, 14))	('C', 'Chemical', 'MESH:D002244', (10, 11))	('C-to-T', 'Var', (0, 6))
135483	28358873	C-to-T in CpGs is highly associated with methylation.	('methylation', 'MPA', (41, 52))	('associated', 'Reg', (25, 35))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('CpGs', 'Chemical', 'MESH:C015772', (10, 14))	('C', 'Chemical', 'MESH:D002244', (10, 11))	('C-to-T', 'Var', (0, 6))
135487	28358873	We confirmed this association by showing samples from methylation cluster 1 had higher PC1 scores as well as higher C-to-T mutation counts and mutation percentages in CpGs (Fig 3C).	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('PC1', 'Gene', (87, 90))	('methylation', 'Var', (54, 65))	('higher', 'PosReg', (109, 115))	('mutation', 'Var', (143, 151))	('CpGs', 'Chemical', 'MESH:C015772', (167, 171))	('C', 'Chemical', 'MESH:D002244', (88, 89))	('C-to-T mutation counts', 'CPA', (116, 138))	('CpGs', 'Disease', (167, 171))	('C', 'Chemical', 'MESH:D002244', (116, 117))	('PC1', 'Gene', '3868', (87, 90))	('C', 'Chemical', 'MESH:D002244', (167, 168))	('higher', 'PosReg', (80, 86))	('C', 'Chemical', 'MESH:D002244', (178, 179))
135490	28358873	C-to-T mutations in CpGs we observed in pRCCs were more likely to be in the coding region (OR = 1.54, 95%CI: 1.27-1.85, p<0.0001) and nonsynonymous (OR = 1.47, 95%CI: 1.17-1.84, p<0.001), which indicated they tended to be high-impact mutations.	('C', 'Chemical', 'MESH:D002244', (42, 43))	('CpGs', 'Gene', (20, 24))	('nonsynonymous', 'Var', (134, 147))	('C', 'Chemical', 'MESH:D002244', (163, 164))	('pRCC', 'Gene', '5546', (40, 44))	('C', 'Chemical', 'MESH:D002244', (43, 44))	('pRCC', 'Phenotype', 'HP:0006766', (40, 44))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('C', 'Chemical', 'MESH:D002244', (105, 106))	('CpGs', 'Chemical', 'MESH:C015772', (20, 24))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C', 'Chemical', 'MESH:D002244', (20, 21))	('C-to-T mutations', 'Var', (0, 16))	('pRCC', 'Gene', (40, 44))	('mutations', 'Var', (7, 16))
135491	28358873	However, C-to-T mutations in CpGs did not show functional bias between the two methylation clusters in noncoding regions (based on FunSeq score distribution).	('CpGs', 'Chemical', 'MESH:C015772', (29, 33))	('C', 'Chemical', 'MESH:D002244', (9, 10))	('C', 'Chemical', 'MESH:D002244', (29, 30))	('C-to-T mutations', 'Var', (9, 25))	('CpGs', 'Gene', (29, 33))	('methylation', 'biological_process', 'GO:0032259', ('79', '90'))
135493	28358873	Interestingly, we found one type II pRCC case out of 155 somatic WXS sequenced samples exhibited APOBEC-associated mutation signatures 2 and 13.	('APOBEC', 'cellular_component', 'GO:0030895', ('97', '103'))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('pRCC', 'Phenotype', 'HP:0006766', (36, 40))	('pRCC', 'Gene', '5546', (36, 40))	('mutation signatures', 'Var', (115, 134))	('C', 'Chemical', 'MESH:D002244', (39, 40))	('C', 'Chemical', 'MESH:D002244', (102, 103))	('APOBEC-associated', 'Gene', (97, 114))	('pRCC', 'Gene', (36, 40))	('C', 'Chemical', 'MESH:D002244', (38, 39))
135495	28358873	This sample was statistically enriched of APOBEC-induced mutations (adjusted p-value < 0.0003).	('C', 'Chemical', 'MESH:D002244', (47, 48))	('mutations', 'Var', (57, 66))	('APOBEC', 'cellular_component', 'GO:0030895', ('42', '48'))	('APOBEC-induced', 'Gene', (42, 56))
135497	28358873	UC often carries APOBEC associated mutation signatures and our result is consistent with the TCGA bladder urothelial cancer study.	('bladder urothelial cancer', 'Disease', (98, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('APOBEC associated', 'Gene', (17, 34))	('C', 'Chemical', 'MESH:D002244', (94, 95))	('C', 'Chemical', 'MESH:D002244', (1, 2))	('bladder urothelial cancer', 'Disease', 'MESH:D001749', (98, 123))	('APOBEC', 'cellular_component', 'GO:0030895', ('17', '23'))	('C', 'Chemical', 'MESH:D002244', (22, 23))	('mutation', 'Var', (35, 43))
135506	28358873	Chromatin remodeling genes are frequently mutated in pRCC and many other cancers, including ccRCC.	('pRCC', 'Gene', (53, 57))	('Chromatin', 'cellular_component', 'GO:0000785', ('0', '9'))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('Chromatin remodeling genes', 'Gene', (0, 26))	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('Chromatin remodeling', 'biological_process', 'GO:0006338', ('0', '20'))	('C', 'Chemical', 'MESH:D002244', (96, 97))	('C', 'Chemical', 'MESH:D002244', (56, 57))	('ccRCC', 'Disease', (92, 97))	('C', 'Chemical', 'MESH:D002244', (95, 96))	('pRCC', 'Gene', '5546', (53, 57))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('mutated', 'Var', (42, 49))	('C', 'Chemical', 'MESH:D002244', (55, 56))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('pRCC', 'Phenotype', 'HP:0006766', (53, 57))
135507	28358873	To test this, we tallied the number of mutations inside DNase I hypersensitive sites (DHS) inferred from 11 normal fetal kidney cortex samples (The NIH Roadmap Epigenomics Mapping Consortium), which represent normal tissues under physiological conditions.	('C', 'Chemical', 'MESH:D002244', (180, 181))	('DNase I', 'molecular_function', 'GO:0004530', ('56', '63'))	('mutations', 'Var', (39, 48))	('hypersensitive', 'Disease', 'MESH:D004342', (64, 78))	('DNase', 'Gene', (56, 61))	('hypersensitive', 'Disease', (64, 78))	('DHS', 'Chemical', '-', (86, 89))
135508	28358873	9/35 samples with disruptive mutations in ten chromatin remodeling genes, cancer-associated genes showed higher genome-wide mutation counts (p < 0.021, one-sided rank-sum test;), partially driven by higher mutation counts in the DHS regions (p < 0.0023, one-sided rank-sum test).	('genome-wide mutation counts', 'MPA', (112, 139))	('DHS', 'Chemical', '-', (229, 232))	('higher', 'PosReg', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('mutations', 'Var', (29, 38))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('46', '66'))	('higher', 'PosReg', (199, 205))	('cancer', 'Disease', (74, 80))	('chromatin', 'cellular_component', 'GO:0000785', ('46', '55'))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
135509	28358873	The median number of mutations in DHS regions considerably increased by 60% (67.5 versus 108) in samples carrying chromatin remodeling defects.	('chromatin', 'cellular_component', 'GO:0000785', ('114', '123'))	('DHS', 'Chemical', '-', (34, 37))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('114', '134'))	('increased', 'PosReg', (59, 68))	('DHS regions', 'Gene', (34, 45))	('mutations', 'Var', (21, 30))
135519	28358873	Beyond traditionally driver events, we suggested several novel noncoding alterations potentially drive tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('noncoding alterations', 'Var', (63, 84))	('drive', 'Reg', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
135522	28358873	Then we found an exonic SNP in MET, rs11762213, to be a prognostic germline variance in type II pRCC.	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('pRCC', 'Gene', '5546', (96, 100))	('rs11762213', 'Var', (36, 46))	('pRCC', 'Gene', (96, 100))	('pRCC', 'Phenotype', 'HP:0006766', (96, 100))	('rs11762213', 'Mutation', 'rs11762213', (36, 46))
135523	28358873	Previously, rs11762213 was found to predict outcome in a mixed RCC samples, predominated by ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('rs11762213', 'Var', (12, 22))	('ccRCC', 'Disease', (92, 97))	('predict', 'Reg', (36, 43))	('rs11762213', 'Mutation', 'rs11762213', (12, 22))
135525	28358873	However, it was never clear whether rs11762213 only predicts the outcome in ccRCC or other histological types as well.	('rs11762213', 'Var', (36, 46))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('ccRCC', 'Disease', (76, 81))	('rs11762213', 'Mutation', 'rs11762213', (36, 46))
135526	28358873	In this study, we concluded that the minor alternative allele of rs11762213 also forecasts unfavorable outcome in type II pRCC patients.	('pRCC', 'Gene', (122, 126))	('rs11762213', 'Mutation', 'rs11762213', (65, 75))	('patients', 'Species', '9606', (127, 135))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('rs11762213', 'Var', (65, 75))	('pRCC', 'Phenotype', 'HP:0006766', (122, 126))	('pRCC', 'Gene', '5546', (122, 126))
135528	28358873	Given the significant role of MET in pRCC, we think rs11762213 is affecting survival through MET, although the mechanism unknown.	('pRCC', 'Gene', (37, 41))	('pRCC', 'Gene', '5546', (37, 41))	('rs11762213', 'Mutation', 'rs11762213', (52, 62))	('MET', 'Disease', (93, 96))	('rs11762213', 'Var', (52, 62))	('affecting', 'Reg', (66, 75))	('pRCC', 'Phenotype', 'HP:0006766', (37, 41))	('survival', 'CPA', (76, 84))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))
135531	28358873	Our finding on rs11762213 is potentially meaningful in the clinical management of patients with the more aggressive type II pRCC.	('pRCC', 'Phenotype', 'HP:0006766', (124, 128))	('pRCC', 'Gene', '5546', (124, 128))	('patients', 'Species', '9606', (82, 90))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('pRCC', 'Gene', (124, 128))	('rs11762213', 'Mutation', 'rs11762213', (15, 25))	('rs11762213', 'Var', (15, 25))
135536	28358873	This implies a possible effect of rs11762213 on pRCC incidence among African Americans that is worth further investigation.	('pRCC', 'Phenotype', 'HP:0006766', (48, 52))	('pRCC', 'Gene', '5546', (48, 52))	('rs11762213', 'Mutation', 'rs11762213', (34, 44))	('rs11762213', 'Var', (34, 44))	('pRCC', 'Gene', (48, 52))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))
135538	28358873	Methylation is a major source of silencing retrotransposon activities in the human genome.	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('Methylation', 'Var', (0, 11))	('silencing', 'MPA', (33, 42))	('human', 'Species', '9606', (77, 82))
135543	28358873	These mutations potentially disrupt regulatory elements of ERRFI1 and thus play a role in tumorigenesis.	('regulatory elements', 'MPA', (36, 55))	('disrupt', 'NegReg', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('play', 'Reg', (75, 79))	('ERRFI1', 'Gene', '54206', (59, 65))	('role', 'Reg', (82, 86))	('ERRFI1', 'Gene', (59, 65))	('mutations', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
135546	28358873	Patients carrying mutations in NEAT1 had significantly higher NEAT1 expression and worse prognosis.	('expression', 'MPA', (68, 78))	('NEAT1', 'Gene', '283131', (31, 36))	('NEAT1', 'Gene', '283131', (62, 67))	('Patients', 'Species', '9606', (0, 8))	('NEAT1', 'Gene', (31, 36))	('NEAT1', 'Gene', (62, 67))	('higher', 'PosReg', (55, 61))	('mutations', 'Var', (18, 27))
135547	28358873	High expression of NEAT1 predicted significantly worse survival in ccRCC as well.	('NEAT1', 'Gene', (19, 24))	('High expression', 'Var', (0, 15))	('ccRCC', 'Disease', (67, 72))	('worse', 'NegReg', (49, 54))	('NEAT1', 'Gene', '283131', (19, 24))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
135548	28358873	NEAT1 has been shown to be hypermutated in other cancers and some studies also linked high NEAT1 association with unfavorable prognosis.	('NEAT1', 'Gene', (91, 96))	('NEAT1', 'Gene', (0, 5))	('NEAT1', 'Gene', '283131', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('high', 'Var', (86, 90))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))	('NEAT1', 'Gene', '283131', (91, 96))
135552	28358873	In fact, we confirmed the well-known deletion of CDKN2A and found that we predicted its down-regulate expression better than the copy number variation analysis in TCGA study.	('CDKN2A', 'Gene', '1029', (49, 55))	('C', 'Chemical', 'MESH:D002244', (49, 50))	('deletion', 'Var', (37, 45))	('down-regulate expression', 'MPA', (88, 112))	('CDKN2A', 'Gene', (49, 55))	('C', 'Chemical', 'MESH:D002244', (164, 165))
135555	28358873	Our SV study also discovered recurrent cases of SDHB deletion and expression data supported our finding.	('SDHB', 'Gene', '6390', (48, 52))	('deletion', 'Var', (53, 61))	('SDHB', 'Gene', (48, 52))
135562	28358873	We identified mutation rate dispersion of C-to-T transitions in CpGs motifs contributed the most to the inter-sample mutation spectra variation.	('C', 'Chemical', 'MESH:D002244', (42, 43))	('C-to-T transitions', 'Var', (42, 60))	('CpGs', 'Chemical', 'MESH:C015772', (64, 68))	('C', 'Chemical', 'MESH:D002244', (64, 65))	('CpGs', 'Gene', (64, 68))
135563	28358873	We further pinned down the cause of dispersion by showing the hypermethylated cluster, identified in the previous TCGA study, had a higher C-to-T rate in CpGs.	('higher', 'PosReg', (132, 138))	('C-to-T rate', 'CPA', (139, 150))	('hypermethylated', 'Var', (62, 77))	('C', 'Chemical', 'MESH:D002244', (115, 116))	('C', 'Chemical', 'MESH:D002244', (139, 140))	('CpGs', 'Disease', (154, 158))	('CpGs', 'Chemical', 'MESH:C015772', (154, 158))	('C', 'Chemical', 'MESH:D002244', (154, 155))
135564	28358873	Although increased C-to-T in CpGs is likely the result of hypermethylation, we cannot rule out the possibility the change of mutation landscape plays a role in cancer development.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('CpGs', 'Chemical', 'MESH:C015772', (29, 33))	('C', 'Chemical', 'MESH:D002244', (29, 30))	('cancer', 'Disease', (160, 166))	('C-to-T', 'Var', (19, 25))	('C', 'Chemical', 'MESH:D002244', (19, 20))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
135565	28358873	For example, C-to-T in methylated CpGs causes loss of methylation, which could have effects on local chromatin environment, trans-elements recruitment and gene expression regulation.	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('loss', 'NegReg', (46, 50))	('gene expression', 'biological_process', 'GO:0010467', ('155', '170'))	('methylation', 'MPA', (54, 65))	('chromatin', 'cellular_component', 'GO:0000785', ('101', '110'))	('C', 'Chemical', 'MESH:D002244', (13, 14))	('effects', 'Reg', (84, 91))	('CpGs', 'Chemical', 'MESH:C015772', (34, 38))	('C', 'Chemical', 'MESH:D002244', (34, 35))	('C-to-T', 'Var', (13, 19))	('regulation', 'biological_process', 'GO:0065007', ('171', '181'))
135566	28358873	In our study, we observed C-to-Ts in CpGs were enriched in coding regions, which suggested they might have a higher functional impact in the cancer genome.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('CpGs', 'Chemical', 'MESH:C015772', (37, 41))	('C', 'Chemical', 'MESH:D002244', (37, 38))	('CpGs', 'Gene', (37, 41))	('C', 'Chemical', 'MESH:D002244', (26, 27))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('C-to-Ts', 'Var', (26, 33))	('cancer', 'Disease', (141, 147))
135571	28358873	APOBEC mutation signature was also found in a small percentage of chromophobe renal cell carcinoma, although they are believed to have a different cellular origin.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (78, 98))	('APOBEC', 'Gene', (0, 6))	('C', 'Chemical', 'MESH:D002244', (5, 6))	('chromophobe renal cell carcinoma', 'Disease', (66, 98))	('mutation', 'Var', (7, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('APOBEC', 'cellular_component', 'GO:0030895', ('0', '6'))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (66, 98))	('found', 'Reg', (35, 40))
135577	28358873	We demonstrated pRCCs with defects in chromatin remodeling genes showed higher mutation rate in general, driven by an even stronger mutation rate increase in putative open chromatin regions in normal kidney tissues.	('defects', 'Var', (27, 34))	('pRCC', 'Gene', (16, 20))	('increase', 'PosReg', (146, 154))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('chromatin', 'cellular_component', 'GO:0000785', ('38', '47'))	('chromatin remodeling genes', 'Gene', (38, 64))	('pRCC', 'Phenotype', 'HP:0006766', (16, 20))	('pRCC', 'Gene', '5546', (16, 20))	('chromatin', 'cellular_component', 'GO:0000785', ('172', '181'))	('higher', 'PosReg', (72, 78))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('38', '58'))	('mutation rate', 'MPA', (79, 92))
135579	28358873	Yet, high mutation burden in functional important open chromatin regions also raises the chance that tumor antigens activate the host immune system.	('chromatin', 'cellular_component', 'GO:0000785', ('55', '64'))	('mutation burden', 'Var', (10, 25))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
135580	28358873	Researchers found tumors with DNA mismatch repair deficiency responded better to PD-1 blockage.	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('better', 'PosReg', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('mismatch repair', 'biological_process', 'GO:0006298', ('34', '49'))	('deficiency', 'Var', (50, 60))
135581	28358873	These tumors also accumulate more mutations in early replicating regions.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('accumulate', 'Reg', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('mutations', 'Var', (34, 43))
135586	28358873	In this first whole genome study of pRCC, we found several novel noncoding alterations that might drive tumor development and we explored the mutational landscape and evolutionary trees to better understand tumor heterogeneity.	('drive', 'Reg', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('noncoding alterations', 'Var', (65, 86))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('pRCC', 'Gene', '5546', (36, 40))	('pRCC', 'Phenotype', 'HP:0006766', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))	('pRCC', 'Gene', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
135620	28358873	However, adding BAP1 into the list did not change the significance of our key tests (p<0.0115 for mutation counts in DHS and p<0.020 for mutation percentage in DHS).	('mutation', 'Var', (98, 106))	('DHS', 'Chemical', '-', (160, 163))	('BAP1', 'Gene', '8314', (16, 20))	('DHS', 'Disease', (117, 120))	('BAP1', 'Gene', (16, 20))	('DHS', 'Chemical', '-', (117, 120))
135630	33255938	We therefore hypothesized that single nucleotide polymorphisms (SNPs) (located in regulatory regions involved in regulation of expression and alternative splicing as well as SNPs introducing changes to the protein sequence) in genes encoding PD-1 and PD-L1 molecules may be associated with the development and outcome of renal cell carcinoma (RCC).	('single nucleotide polymorphisms', 'Var', (31, 62))	('renal cell carcinoma', 'Disease', (321, 341))	('protein', 'cellular_component', 'GO:0003675', ('206', '213'))	('regulation', 'biological_process', 'GO:0065007', ('113', '123'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (321, 341))	('RCC', 'Disease', 'MESH:C538614', (343, 346))	('RCC', 'Disease', (343, 346))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (321, 341))	('SNPs', 'Var', (174, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (332, 341))	('splicing', 'biological_process', 'GO:0045292', ('154', '162'))	('PD-L1', 'Gene', (251, 256))	('PD-1', 'Gene', (242, 246))	('x', 'Mutation', 'x', (128, 129))	('associated with', 'Reg', (274, 289))
135631	33255938	We genotyped nine SNPs in PD-1/PD-L1 axis genes, with application of TaqMan allelic discrimination assays, and found that two of them taken together (rs10815225xrs7421861) may be considered to be potential risk factor for clear cell RCC.	('x', 'Mutation', 'x', (160, 161))	('PD-1/PD-L1 axis', 'Gene', (26, 41))	('x', 'Mutation', 'x', (38, 39))	('rs10815225xrs7421861', 'Var', (150, 170))	('RCC', 'Disease', 'MESH:C538614', (233, 236))	('RCC', 'Disease', (233, 236))
135633	33255938	We therefore hypothesized that single nucleotide polymorphisms (SNPs) in genes encoding PD-1 and PD-L1 molecules are associated with the development and outcome of renal cell carcinoma (RCC).	('renal cell carcinoma', 'Disease', 'MESH:C538614', (164, 184))	('single nucleotide polymorphisms', 'Var', (31, 62))	('associated with', 'Reg', (117, 132))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('RCC', 'Disease', (186, 189))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (164, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('renal cell carcinoma', 'Disease', (164, 184))	('PD-L1', 'Gene', (97, 102))	('PD-1', 'Gene', (88, 92))
135634	33255938	Here we genotyped nine polymorphisms: five of PDCD1: rs36084323G>A, rs11568821G>A, rs2227981C>T, rs10204525G>A, rs7421861T>C and four of PD-L1: rs822335C>T, rs4143815G>C, rs4742098A>G, rs10815225G>C in 237 RCC patients (including 208 with clear cell RCC (ccRCC)) and 256 controls, with application of allelic discrimination method with use of TaqMan Assays.	('rs11568821G>A', 'DBSNP_MENTION', 'None', (68, 81))	('rs822335C>T', 'DBSNP_MENTION', 'None', (144, 155))	('rs822335C>T', 'Var', (144, 155))	('RCC', 'Disease', (250, 253))	('RCC', 'Disease', (257, 260))	('rs10815225G>C', 'DBSNP_MENTION', 'None', (185, 198))	('rs7421861T>C', 'Var', (112, 124))	('rs2227981C>T', 'DBSNP_MENTION', 'None', (83, 95))	('RCC', 'Disease', 'MESH:C538614', (250, 253))	('rs10204525G>A', 'Var', (97, 110))	('rs4742098A>G', 'DBSNP_MENTION', 'None', (171, 183))	('rs10204525G>A', 'DBSNP_MENTION', 'None', (97, 110))	('patients', 'Species', '9606', (210, 218))	('rs36084323G>A', 'Var', (53, 66))	('RCC', 'Disease', 'MESH:C538614', (257, 260))	('rs2227981C>T', 'Var', (83, 95))	('rs4742098A>G', 'Var', (171, 183))	('rs36084323G>A', 'DBSNP_MENTION', 'None', (53, 66))	('rs4143815G>C', 'DBSNP_MENTION', 'None', (157, 169))	('RCC', 'Disease', (206, 209))	('rs11568821G>A', 'Var', (68, 81))	('rs4143815G>C', 'Var', (157, 169))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (112, 124))	('PDCD1', 'Gene', '5133', (46, 51))	('rs10815225G>C', 'Var', (185, 198))	('PDCD1', 'Gene', (46, 51))	('RCC', 'Disease', 'MESH:C538614', (206, 209))
135635	33255938	Interestingly, we found the SNP-SNP interaction between rs10815225 and rs7421861 polymorphisms associated with ccRCC risk.	('rs7421861', 'Var', (71, 80))	('rs7421861', 'Mutation', 'rs7421861', (71, 80))	('rs10815225', 'Mutation', 'rs10815225', (56, 66))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('rs10815225', 'Var', (56, 66))	('associated', 'Reg', (95, 105))
135636	33255938	The rs7421861 TC genotype decreased the risk of ccRCC development compared to TT and CC genotypes in the group of rs10815225 GC + CC individuals (OR = 0.21, CI95% = 0.08; 0.54).	('rs10815225', 'Var', (114, 124))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('rs7421861', 'Var', (4, 13))	('RCC', 'Disease', (50, 53))	('rs10815225', 'Mutation', 'rs10815225', (114, 124))	('TC', 'Chemical', 'MESH:D013667', (14, 16))	('rs7421861', 'Mutation', 'rs7421861', (4, 13))	('decreased', 'NegReg', (26, 35))
135637	33255938	While possessing of rs10815225 GC or CC genotype increased susceptibility to ccRCC when compared to rs10815225 GG genotype in individuals with rs7421861 TT or CC genotype (OR = 2.40, CI95% = 1.25; 4.61).	('rs10815225 GC', 'Var', (20, 33))	('RCC', 'Disease', (79, 82))	('rs10815225', 'Mutation', 'rs10815225', (100, 110))	('rs7421861', 'Mutation', 'rs7421861', (143, 152))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('rs10815225', 'Mutation', 'rs10815225', (20, 30))
135638	33255938	In conclusion, genetic variants in PDCD1 and PD-L1 genes, especially taken together as SNP-SNP interactions, can be considered to be ccRCC risk factors.	('genetic variants', 'Var', (15, 31))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))	('PDCD1', 'Gene', (35, 40))	('PDCD1', 'Gene', '5133', (35, 40))	('PD-L1', 'Gene', (45, 50))
135649	33255938	To prevent this process, in recent years, highly efficacious immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1, alone or in combination), whose role is to enhance immune response against cancer cells, were introduced into clinical practice and they revolutionized cancer immunotherapy.	('CTLA-4', 'Gene', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('enhance', 'PosReg', (161, 168))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('immune response', 'biological_process', 'GO:0006955', ('169', '184'))	('anti-PD-1', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('CTLA-4', 'Gene', '1493', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('immune', 'MPA', (169, 175))
135655	33255938	It is well established that the mRNA and protein expression level can be regulated, among others, by the presence of genetic variants that can affect epigenetic modifications (methylation, microRNA binding), transcription factors binding sites and the formation of protein isoforms.	('microRNA binding', 'molecular_function', 'GO:0035198', ('189', '205'))	('binding', 'molecular_function', 'GO:0005488', ('230', '237'))	('epigenetic modifications', 'MPA', (150, 174))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('protein', 'Protein', (265, 272))	('variants', 'Var', (125, 133))	('methylation', 'MPA', (176, 187))	('formation', 'biological_process', 'GO:0009058', ('252', '261'))	('methylation', 'biological_process', 'GO:0032259', ('176', '187'))	('formation of', 'MPA', (252, 264))	('transcription', 'MPA', (208, 221))	('transcription', 'biological_process', 'GO:0006351', ('208', '221'))	('protein', 'cellular_component', 'GO:0003675', ('265', '272'))	('regulated', 'Reg', (73, 82))	('affect', 'Reg', (143, 149))	('x', 'Mutation', 'x', (50, 51))	('binding sites', 'Interaction', (230, 243))
135656	33255938	Therefore, we put forward the hypothesis that single nucleotide polymorphisms (SNPs) located within genes encoding PD-1 and PD-L1 molecules as well as SNP-SNP interactions (between variations in genes encoding receptor and ligand) are associated with RCC risk and outcomes.	('PD-L1', 'Gene', (124, 129))	('associated with', 'Reg', (235, 250))	('SNP-SNP', 'Var', (151, 158))	('RCC', 'Disease', (251, 254))	('interactions', 'Interaction', (159, 171))	('single nucleotide polymorphisms', 'Var', (46, 77))	('PD-1', 'Gene', (115, 119))	('RCC', 'Disease', 'MESH:C538614', (251, 254))	('ligand', 'molecular_function', 'GO:0005488', ('223', '229'))
135657	33255938	In the present study, we investigated nine polymorphisms:five of which were located in PDCD1 gene (encoding PD-1 molecule): rs36084323G>A (PD-1.1), rs11568821G>A (PD-1.3), rs2227981C>T (PD-1.5), rs10204525G>A (PD-1.6), rs7421861T>C and four in PD-L1 gene: rs822335C>T, rs4143815G>C, rs4742098A>G, rs10815225G>C.	('rs10204525G>A', 'DBSNP_MENTION', 'None', (195, 208))	('rs822335C>T', 'Var', (256, 267))	('rs10204525G>A', 'Var', (195, 208))	('rs10815225G>C', 'DBSNP_MENTION', 'None', (297, 310))	('rs4742098A>G', 'DBSNP_MENTION', 'None', (283, 295))	('rs2227981C>T', 'DBSNP_MENTION', 'None', (172, 184))	('rs36084323G>A', 'Var', (124, 137))	('rs11568821G>A', 'Var', (148, 161))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (219, 231))	('rs4143815G>C', 'DBSNP_MENTION', 'None', (269, 281))	('rs2227981C>T', 'Var', (172, 184))	('rs11568821G>A', 'DBSNP_MENTION', 'None', (148, 161))	('rs36084323G>A', 'DBSNP_MENTION', 'None', (124, 137))	('rs4742098A>G', 'Var', (283, 295))	('rs4143815G>C', 'Var', (269, 281))	('rs10815225G>C', 'Var', (297, 310))	('rs7421861T>C', 'Var', (219, 231))	('PDCD1', 'Gene', '5133', (87, 92))	('PDCD1', 'Gene', (87, 92))	('rs822335C>T', 'DBSNP_MENTION', 'None', (256, 267))
135660	33255938	For all SNPs except three (rs10204525G>A, rs11568821G>A and rs7421861T>C) the genotype distribution was in Hardy-Weinberg Equilibrium (HWE) (Table 1).	('rs11568821G>A', 'DBSNP_MENTION', 'None', (42, 55))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (60, 72))	('rs11568821G>A', 'Var', (42, 55))	('rs10204525G>A', 'DBSNP_MENTION', 'None', (27, 40))	('rs10204525G>A', 'Var', (27, 40))	('x', 'Mutation', 'x', (14, 15))	('rs7421861T>C', 'Var', (60, 72))
135661	33255938	For rs10204525G>A we found deviation from HWE in controls, resulting from the deficiency of rs10204525 GA heterozygotes (p = 0.037, f = 0.131).	('rs10204525', 'Mutation', 'rs10204525', (4, 14))	('rs10204525G>A', 'DBSNP_MENTION', 'None', (4, 17))	('rs10204525G>A', 'Var', (4, 17))	('rs10204525', 'Mutation', 'rs10204525', (92, 102))	('rs10204525', 'Var', (92, 102))
135662	33255938	Departures from HWE were also observed for rs7421861T>C and rs11568821G>A polymorphisms in the group of ccRCC patients (p = 0.048, f = 0.137 and p = 0.050, f = 0.136, respectively).	('rs7421861T>C', 'Var', (43, 55))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (43, 55))	('rs11568821G>A', 'DBSNP_MENTION', 'None', (60, 73))	('RCC', 'Disease', (106, 109))	('rs11568821G>A', 'Var', (60, 73))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('patients', 'Species', '9606', (110, 118))
135664	33255938	As can be seen in these tables, PDCD1 and PD-L1 polymorphisms, selected for examination, were not in LD with each other, except for rs4143815G>C and rs4742098A>G in PD-L1 gene, for which the weak LD was observed (r2 = 0.537 and r2 = 0.558 for controls and ccRCC patients, respectively) (Table S3).	('rs4742098A>G', 'Var', (149, 161))	('RCC', 'Disease', (258, 261))	('rs4742098A>G', 'DBSNP_MENTION', 'None', (149, 161))	('x', 'Mutation', 'x', (77, 78))	('x', 'Mutation', 'x', (122, 123))	('rs4143815G>C', 'DBSNP_MENTION', 'None', (132, 144))	('PDCD1', 'Gene', '5133', (32, 37))	('PD-L1', 'Gene', (165, 170))	('PD-L1', 'Gene', (42, 47))	('rs4143815G>C', 'Var', (132, 144))	('patients', 'Species', '9606', (262, 270))	('PDCD1', 'Gene', (32, 37))	('RCC', 'Disease', 'MESH:C538614', (258, 261))
135666	33255938	Significant difference in genotype distribution between cases and controls was observed inter alia for rs7421861T>C in PDCD1 (chi2 = 6.272; p = 0.043).	('rs7421861T>C', 'DBSNP_MENTION', 'None', (103, 115))	('PDCD1', 'Gene', '5133', (119, 124))	('PDCD1', 'Gene', (119, 124))	('rs7421861T>C', 'Var', (103, 115))
135667	33255938	In detail, individuals with rs7421861 TC genotype had 1.5-fold lower risk of ccRCC development in comparison to rs7421861 TT homozygotes (OR = 0.65, CI95% = 0.44; 0.96) while for rare homozygotes (rs7421861 CC) the risk was similar as in the case of individuals with rs7421861 TT genotype (OR = 1.14, CI95% = 0.64; 2.08).	('lower', 'NegReg', (63, 68))	('rs7421861', 'Mutation', 'rs7421861', (197, 206))	('TC', 'Chemical', 'MESH:D013667', (38, 40))	('rs7421861', 'Var', (28, 37))	('rs7421861', 'Mutation', 'rs7421861', (267, 276))	('rs7421861', 'Mutation', 'rs7421861', (112, 121))	('rs7421861 CC', 'Var', (197, 209))	('rs7421861', 'Mutation', 'rs7421861', (28, 37))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
135668	33255938	Therefore the results suggested the lower risk of ccRCC for rs7421861 TC heterozygotes in comparison to combined group of both homozygotes (TC vs. TT + CC; chi2 = 6.058; p = 0.014; OR = 0.63, CI95% = 0.43; 0.91).	('lower', 'NegReg', (36, 41))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('rs7421861', 'Var', (60, 69))	('RCC', 'Disease', (52, 55))	('TC', 'Chemical', 'MESH:D013667', (140, 142))	('rs7421861', 'Mutation', 'rs7421861', (60, 69))	('TT + CC', 'Chemical', '-', (147, 154))	('TC', 'Chemical', 'MESH:D013667', (70, 72))
135669	33255938	The second polymorphism for which the association with the risk of ccRCC development was observed was rs10815225G>C in PD-L1 gene (chi2 = 6.981; p = 0.031).	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('PD-L1', 'Gene', (119, 124))	('rs10815225G>C', 'Var', (102, 115))	('rs10815225G>C', 'DBSNP_MENTION', 'None', (102, 115))
135670	33255938	In the case of this polymorphism, rs10815225 GC genotype was more frequent in the ccRCC patient group as compared to controls (20.5% vs. 13.5%).	('patient', 'Species', '9606', (88, 95))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('rs10815225', 'Var', (34, 44))	('rs10815225', 'Mutation', 'rs10815225', (34, 44))
135676	33255938	Namely the C C G A (rs822335 rs10815225 rs4143815 rs4742098) haplotype was more frequent in ccRCC patients than in control group (6.3 vs. 3.1%) and increased the risk of developing ccRCC (OR = 2.03, CI95% = 1.07; 3.86).	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (94, 97))	('6.3', 'Gene', '55558', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('RCC', 'Disease', (183, 186))	('rs4143815', 'Mutation', 'rs4143815', (40, 49))	('6.3', 'Gene', (130, 133))	('patients', 'Species', '9606', (98, 106))	('rs10815225', 'Mutation', 'rs10815225', (29, 39))	('rs822335', 'Mutation', 'rs822335', (20, 28))	('rs822335 rs10815225 rs4143815 rs4742098', 'Var', (20, 59))	('rs4742098', 'Mutation', 'rs4742098', (50, 59))
135677	33255938	It is worth noting that this haplotype differed from the wild haplotype (most frequent in both groups C G G A) only in the second position corresponding to rs10815225G>C (which was shown to be associated with ccRCC development in our study).	('rs10815225G>C', 'Var', (156, 169))	('rs10815225G>C', 'DBSNP_MENTION', 'None', (156, 169))	('RCC', 'Disease', (211, 214))	('RCC', 'Disease', 'MESH:C538614', (211, 214))	('associated', 'Reg', (193, 203))
135678	33255938	The opposite effect:the decreased susceptibility to ccRCC was observed for T G G A (OR = 0.64, CI95% = 0.46; 0.89) as well as for C G C G (OR = 0.55, CI9% = 0.33; 0.93) haplotypes (with common G allele in the second position:rs10815225).	('decreased', 'NegReg', (24, 33))	('RCC', 'Disease', (54, 57))	('rs10815225', 'Var', (225, 235))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('rs10815225', 'Mutation', 'rs10815225', (225, 235))	('susceptibility', 'MPA', (34, 48))
135680	33255938	This analysis revealed an interesting relationship-it indicated that the association of rs7421861T>C with ccRCC risk (described above) should be analyzed with the simultaneous consideration of the genotype at rs10815225G>C polymorphic site (and vice versa) (p = 0.009) (please see Table S5).	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (88, 100))	('rs10815225G>C', 'Var', (209, 222))	('rs10815225G>C', 'DBSNP_MENTION', 'None', (209, 222))	('rs7421861T>C', 'Var', (88, 100))
135681	33255938	It turned out that although the effect of rs7421861 TC genotype was observed in the whole group, this genotype decreased the risk of ccRCC development in individuals with C allele carriers (GC + CC) at rs10815225 polymorphic site (rs7421861 TC vs. TT + CC: chi2 = 11.180, p = 0.0009, OR = 0.21, CI95% = 0.08; 0.54, in rs10815225 (GC + CC) group) (Table 3).	('rs7421861', 'Mutation', 'rs7421861', (231, 240))	('rs10815225', 'Var', (318, 328))	('rs10815225', 'Mutation', 'rs10815225', (202, 212))	('decreased', 'NegReg', (111, 120))	('rs7421861', 'Var', (231, 240))	('RCC', 'Disease', (135, 138))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('TC', 'Chemical', 'MESH:D013667', (241, 243))	('TC', 'Chemical', 'MESH:D013667', (52, 54))	('rs7421861', 'Var', (42, 51))	('TT + CC', 'Chemical', '-', (248, 255))	('rs7421861', 'Mutation', 'rs7421861', (42, 51))	('rs10815225', 'Mutation', 'rs10815225', (318, 328))	('rs10815225', 'Var', (202, 212))
135682	33255938	Moreover, in the group of subjects possessing TT or CC genotype at rs7421861 polymorphic site, those who were rs10815225 C allele carriers had higher risk of ccRCC development (GC + CC vs. GG: chi2 = 7.306, p = 0.007, OR = 2.40, CI95% = 1.25, 4.61) (Table 4).	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('rs7421861', 'Mutation', 'rs7421861', (67, 76))	('RCC', 'Disease', (160, 163))	('rs10815225', 'Mutation', 'rs10815225', (110, 120))	('rs10815225 C', 'Var', (110, 122))	('rs7421861', 'Gene', (67, 76))
135684	33255938	However, we did not find any associations between variations in PDCD1 and PD-L1 genes and overall survival in patients with ccRCC as well as in the group of RCC patients.	('PDCD1', 'Gene', '5133', (64, 69))	('PDCD1', 'Gene', (64, 69))	('PD-L1', 'Gene', (74, 79))	('associations', 'Interaction', (29, 41))	('patients', 'Species', '9606', (161, 169))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', (126, 129))	('RCC', 'Disease', (157, 160))	('variations', 'Var', (50, 60))	('patients', 'Species', '9606', (110, 118))
135690	33255938	The chosen SNPs cover large linkage disequilibrium (LD) blocks, therefore they may serve as TagSNPs (on the basis of which the conclusion can be drawn for other SNPs included in LD block) (PDCD1: rs36084323G>A, rs2227981C>T, rs10204525G>A, PD-L1: rs4742098A>G) (Figures S1 and S2).	('rs36084323G>A', 'DBSNP_MENTION', 'None', (196, 209))	('PDCD1', 'Gene', (189, 194))	('rs36084323G>A', 'Var', (196, 209))	('rs4742098A>G', 'DBSNP_MENTION', 'None', (247, 259))	('PDCD1', 'Gene', '5133', (189, 194))	('rs4742098A>G', 'Var', (247, 259))	('rs2227981C>T', 'Var', (211, 223))	('rs10204525G>A', 'DBSNP_MENTION', 'None', (225, 238))	('rs10204525G>A', 'Var', (225, 238))	('rs2227981C>T', 'DBSNP_MENTION', 'None', (211, 223))
135691	33255938	The other ones are located in key regulatory regions (5' flanking regions or promoters) where transcription factors may bind (PDCD1: rs36084323G>A, rs7421861T >, PD-L1: rs822335C>T, rs10815225G>C) or in 3'UTR miRNAs binding sites (PDCD1: 10204525G>A, PD-L1: rs4143815G>C, rs4742098A>G).	('PDCD1', 'Gene', (126, 131))	('rs4143815G>C', 'DBSNP_MENTION', 'None', (258, 270))	('PDCD1', 'Gene', '5133', (126, 131))	('rs7421861T >', 'Var', (148, 160))	('rs4143815G>C', 'Var', (258, 270))	('rs36084323G>A', 'Var', (133, 146))	('transcription', 'biological_process', 'GO:0006351', ('94', '107'))	('rs36084323G>A', 'DBSNP_MENTION', 'None', (133, 146))	('binding', 'molecular_function', 'GO:0005488', ('216', '223'))	('rs10815225G>C', 'Var', (182, 195))	('rs4742098A>G', 'DBSNP_MENTION', 'None', (272, 284))	('PDCD1', 'Gene', '5133', (231, 236))	('PDCD1', 'Gene', (231, 236))	('rs10815225G>C', 'DBSNP_MENTION', 'None', (182, 195))	('rs7421861', 'Mutation', 'rs7421861', (148, 157))	('rs822335C>T', 'DBSNP_MENTION', 'None', (169, 180))	('rs4742098A>G', 'Var', (272, 284))	('10204525G>A', 'Mutation', 'g.10204525G>A', (238, 249))	('rs822335C>T', 'Var', (169, 180))
135692	33255938	For three polymorphisms of PDCD1 gene: rs10204525G>A, rs11568821G>A and rs7421861T>C we observed deviation from HWE.	('rs7421861T>C', 'DBSNP_MENTION', 'None', (72, 84))	('PDCD1', 'Gene', (27, 32))	('PDCD1', 'Gene', '5133', (27, 32))	('rs7421861T>C', 'Var', (72, 84))	('rs11568821G>A', 'DBSNP_MENTION', 'None', (54, 67))	('rs11568821G>A', 'Var', (54, 67))	('rs10204525G>A', 'DBSNP_MENTION', 'None', (39, 52))	('rs10204525G>A', 'Var', (39, 52))
135694	33255938	Since according to literature data in the presence of an association, the deviations from HWE in patients can be treated as a confirmation of the gene-disease association, the results of our HWE analysis may suggest an association of rs11568821G>A and rs7421861T>C with ccRCC risk.	('RCC', 'Disease', (272, 275))	('rs11568821G>A', 'Var', (234, 247))	('rs7421861T>C', 'Var', (252, 264))	('RCC', 'Disease', 'MESH:C538614', (272, 275))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (252, 264))	('rs11568821G>A', 'DBSNP_MENTION', 'None', (234, 247))	('patients', 'Species', '9606', (97, 105))
135695	33255938	Indeed, from our study came the observation that individuals with rs7421861 TC genotype in PDCD1 gene had decreased risk of ccRCC development in comparison to individuals possessing homozygous genotypes.	('decreased', 'NegReg', (106, 115))	('PDCD1', 'Gene', '5133', (91, 96))	('rs7421861', 'Var', (66, 75))	('TC', 'Chemical', 'MESH:D013667', (76, 78))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('RCC', 'Disease', (126, 129))	('rs7421861', 'Mutation', 'rs7421861', (66, 75))	('PDCD1', 'Gene', (91, 96))
135696	33255938	The effect of this genetic variant was observed in the whole group of studied individuals (TC vs. TT + CC, OR = 0.63, CI95% = 0.43, 0.91); however the detailed analysis showed that rs7421861 TC genotype decreased risk of ccRCC in rs10815225 C allele carriers (TC vs. TT + CC OR = 0.21, CI95% = 0.08; 0.54).	('RCC', 'Disease', 'MESH:C538614', (223, 226))	('RCC', 'Disease', (223, 226))	('decreased', 'NegReg', (203, 212))	('TC', 'Chemical', 'MESH:D013667', (91, 93))	('rs10815225', 'Mutation', 'rs10815225', (230, 240))	('TC', 'Chemical', 'MESH:D013667', (260, 262))	('rs7421861', 'Var', (181, 190))	('TT + CC', 'Chemical', '-', (98, 105))	('TT + CC', 'Chemical', '-', (267, 274))	('rs7421861', 'Mutation', 'rs7421861', (181, 190))	('rs10815225 C', 'Var', (230, 242))	('TC', 'Chemical', 'MESH:D013667', (191, 193))
135697	33255938	The substantial effect size of rs7421861 TC genotype OR = 0.21 (5-fold decrease) is the reason this effect is observable in the whole group.	('rs7421861', 'Mutation', 'rs7421861', (31, 40))	('decrease', 'NegReg', (71, 79))	('rs7421861', 'Var', (31, 40))	('TC', 'Chemical', 'MESH:D013667', (41, 43))
135698	33255938	performed a meta-analysis of studies concerning association between PDCD1 and PD-L1 polymorphisms and overall cancer risk.	('cancer', 'Disease', (110, 116))	('PDCD1', 'Gene', '5133', (68, 73))	('PDCD1', 'Gene', (68, 73))	('PD-L1', 'Gene', (78, 83))	('association', 'Interaction', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('polymorphisms', 'Var', (84, 97))
135699	33255938	In the case of rs7421861T>C SNP the authors summarized seven studies on different types of cancer and found out that, in contrast to our observation, rs7421861 TC genotype was associated with increased overall cancer risk.	('TC', 'Chemical', 'MESH:D013667', (160, 162))	('rs7421861', 'Mutation', 'rs7421861', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (15, 27))	('rs7421861', 'Mutation', 'rs7421861', (150, 159))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('rs7421861T>C', 'Var', (15, 27))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (210, 216))	('rs7421861 TC', 'Var', (150, 162))
135700	33255938	However, all the studies included in this meta-analysis were conducted on other than ccRCC types of cancer and on Chinese population with a different genotype distribution at rs7421861 polymorphic site compared to European populations.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('rs7421861', 'Var', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('rs7421861', 'Mutation', 'rs7421861', (175, 184))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
135702	33255938	Since, according to our best knowledge, our study is the first that analyzed PDCD1 and PD-L1 gene polymorphisms in the context of renal cell cancer, further studies will be needed in order to determine whether rs7421861T>C polymorphism may be considered to be a risk factor for this type of cancer.	('PDCD1', 'Gene', '5133', (77, 82))	('renal cell cancer', 'Phenotype', 'HP:0005584', (130, 147))	('cancer', 'Disease', (291, 297))	('PDCD1', 'Gene', (77, 82))	('rs7421861T>C', 'Var', (210, 222))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('x', 'Mutation', 'x', (124, 125))	('renal cell cancer', 'Disease', 'MESH:C538614', (130, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('PD-L1', 'Gene', (87, 92))	('renal cell cancer', 'Disease', (130, 147))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (210, 222))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('cancer', 'Disease', (141, 147))
135703	33255938	Rs7421861T>C is located in intron 1 of PDCD1 gene, where potential splicing control components and regulatory elements may be located.	('Rs7421861', 'Mutation', 'Rs7421861', (0, 9))	('Rs7421861T>C', 'Var', (0, 12))	('splicing', 'biological_process', 'GO:0045292', ('67', '75'))	('PDCD1', 'Gene', (39, 44))	('PDCD1', 'Gene', '5133', (39, 44))
135705	33255938	With regard to our results, it can be supposed that rs7421861 TC genotype that was more frequent in controls, might be associated with decreased expression of PD-1.	('rs7421861', 'Var', (52, 61))	('expression', 'MPA', (145, 155))	('PD-1', 'Gene', (159, 163))	('x', 'Mutation', 'x', (146, 147))	('decreased', 'NegReg', (135, 144))	('TC', 'Chemical', 'MESH:D013667', (62, 64))	('rs7421861', 'Mutation', 'rs7421861', (52, 61))
135707	33255938	Additionally, in our study we observed the increased risk of ccRCC in case of individuals with rs10815225 GC genotype.	('rs10815225', 'Mutation', 'rs10815225', (95, 105))	('RCC', 'Disease', (63, 66))	('rs10815225 GC', 'Var', (95, 108))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
135709	33255938	In the literature there is one report concerning rs10815225G>C SNP in the context of gastric adenocarcinoma; however Tao et al.	('rs10815225G>C', 'Var', (49, 62))	('rs10815225G>C', 'DBSNP_MENTION', 'None', (49, 62))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (85, 107))	('gastric adenocarcinoma', 'Disease', (85, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('x', 'Mutation', 'x', (79, 80))
135710	33255938	Namely the authors noticed lower risk of gastric cancer for individuals with rs10815255 GC as compared to rs10815225 GG.	('rs10815225', 'Mutation', 'rs10815225', (106, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('rs10815255 GC', 'Var', (77, 90))	('lower', 'NegReg', (27, 32))	('rs10815255', 'Mutation', 'rs10815255', (77, 87))	('gastric cancer', 'Disease', (41, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (41, 55))
135711	33255938	The rs10815225G>C polymorphism was also investigated in the context of colorectal cancer; however, no evidence of association was found by Catalano et al.	('colorectal cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('x', 'Mutation', 'x', (65, 66))	('rs10815225G>C', 'Var', (4, 17))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('rs10815225G>C', 'DBSNP_MENTION', 'None', (4, 17))
135712	33255938	It would be interesting to verify in further studies whether rs10815225 SNP may be considered to be a risk factor for cancer development and whether the discrepancy between published studies may result from different mechanism underlying these types of cancer.	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('rs10815225', 'Var', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (253, 259))	('rs10815225', 'Mutation', 'rs10815225', (61, 71))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
135713	33255938	It is worth recalling here that due to the SNP-SNP interaction the effect of rs10815225G>C polymorphism should be considered together with rs7421861T>C.	('rs10815225G>C', 'Var', (77, 90))	('rs10815225G>C', 'DBSNP_MENTION', 'None', (77, 90))	('rs7421861T>C', 'Var', (139, 151))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (139, 151))
135715	33255938	The rs10815225 polymorphism seemed to be associated with PD-L1 expression (Meta-Analysis RE2 P-Value: 2.8e-40).	('x', 'Mutation', 'x', (64, 65))	('associated', 'Reg', (41, 51))	('rs10815225', 'Mutation', 'rs10815225', (4, 14))	('PD-L1 expression', 'Gene', (57, 73))	('rs10815225', 'Var', (4, 14))
135716	33255938	The minor allele at rs10815225 polymorphic site (C allele) was associated with higher PD-L1 expression in some tissues e.g., esophagus - mucosa, testis, while for other tissues (e.g., artery-aorta, spleen) the same allele showed association with lower PD-L1 expression.	('expression', 'MPA', (258, 268))	('x', 'Mutation', 'x', (93, 94))	('rs10815225', 'Var', (20, 30))	('x', 'Mutation', 'x', (259, 260))	('higher', 'PosReg', (79, 85))	('PD-L1', 'Gene', (86, 91))	('expression', 'MPA', (92, 102))	('rs10815225', 'Mutation', 'rs10815225', (20, 30))
135718	33255938	This observation suggests that rs10815225G>C may be associated with tissue-specific regulation of PD-L1 expression.	('rs10815225G>C', 'Var', (31, 44))	('rs10815225G>C', 'DBSNP_MENTION', 'None', (31, 44))	('x', 'Mutation', 'x', (105, 106))	('regulation', 'biological_process', 'GO:0065007', ('84', '94'))	('PD-L1', 'Gene', (98, 103))	('associated', 'Reg', (52, 62))	('expression', 'MPA', (104, 114))
135719	33255938	In line with that, the in silico analysis of functional relevance of specific gene regions carried out using ENCODE data (Figure 2) indicated that this SNP is located in a candidate cis-regulatory element (cCRE) EH38E2679714 (hg38), which is predicted to have promoter-like signature inter alia in HEK293 cell line (established from primary embryonic human kidney) as well as high DNase signal (characteristics of active gene regulatory elements) in renal cell carcinoma (other data are not available for RCC).	('renal cell carcinoma', 'Disease', 'MESH:C538614', (450, 470))	('carcinoma', 'Phenotype', 'HP:0030731', (461, 470))	('EH38E2679714', 'Var', (212, 224))	('hg38', 'Gene', '8549', (226, 230))	('HEK293', 'CellLine', 'CVCL:0045', (298, 304))	('human', 'Species', '9606', (351, 356))	('high DNase signal', 'MPA', (376, 393))	('renal cell carcinoma', 'Disease', (450, 470))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (450, 470))	('RCC', 'Disease', 'MESH:C538614', (505, 508))	('hg38', 'Gene', (226, 230))	('RCC', 'Disease', (505, 508))
135721	33255938	It was also shown that the examined TF bound to construct with rs10815225 G allele but not to construct with C allele and that the up-regulation or silencing of SP1 resulted respectively in elevated or decreased PD-L1 expression on mRNA and protein level in SGC-7901 cells (gastric cancer cell line).	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('rs10815225', 'Mutation', 'rs10815225', (63, 73))	('decreased', 'NegReg', (202, 211))	('up-regulation', 'PosReg', (131, 144))	('x', 'Mutation', 'x', (219, 220))	('gastric cancer', 'Disease', (274, 288))	('rs10815225 G', 'Var', (63, 75))	('SGC-7901', 'CellLine', 'CVCL:0520', (258, 266))	('x', 'Mutation', 'x', (28, 29))	('gastric cancer', 'Disease', 'MESH:D013274', (274, 288))	('PD-L1', 'Gene', (212, 217))	('decreased PD', 'Phenotype', 'HP:0032198', (202, 214))	('protein', 'cellular_component', 'GO:0003675', ('241', '248'))	('regulation', 'biological_process', 'GO:0065007', ('134', '144'))	('SP1', 'Gene', (161, 164))	('expression', 'MPA', (218, 228))	('gastric cancer', 'Phenotype', 'HP:0012126', (274, 288))	('silencing', 'NegReg', (148, 157))
135722	33255938	described higher mRNA expression of PD-L1 in gastric adenocarcinoma patients with rs10815225 GG genotype than in those with rs10815225 GC genotype.	('x', 'Mutation', 'x', (23, 24))	('rs10815225', 'Mutation', 'rs10815225', (82, 92))	('PD-L1', 'Gene', (36, 41))	('rs10815225', 'Mutation', 'rs10815225', (124, 134))	('patients', 'Species', '9606', (68, 76))	('mRNA expression', 'MPA', (17, 32))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (45, 67))	('higher', 'PosReg', (10, 16))	('gastric adenocarcinoma', 'Disease', (45, 67))	('rs10815225 GG', 'Var', (82, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
135723	33255938	However, it would be worth determining in further studies whether the difference in mRNA expression between individuals with different genotypes at the rs10815225 polymorphic site obtained in gastric cancer patients and that generated from 1000 Genomes (both presented by Tao et al.)	('patients', 'Species', '9606', (207, 215))	('mRNA expression', 'MPA', (84, 99))	('gastric cancer', 'Phenotype', 'HP:0012126', (192, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('rs10815225', 'Var', (152, 162))	('x', 'Mutation', 'x', (90, 91))	('rs10815225', 'Mutation', 'rs10815225', (152, 162))	('gastric cancer', 'Disease', (192, 206))	('gastric cancer', 'Disease', 'MESH:D013274', (192, 206))
135724	33255938	did not show any difference in expression of PD-L1 (on protein level) between gastric cancer patients with different genotypes at the rs10815225 polymorphic site.	('x', 'Mutation', 'x', (32, 33))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('rs10815225', 'Var', (134, 144))	('gastric cancer', 'Disease', (78, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (78, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (78, 92))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('patients', 'Species', '9606', (93, 101))	('PD-L1', 'Gene', (45, 50))	('rs10815225', 'Mutation', 'rs10815225', (134, 144))
135726	33255938	Therefore, it can be assumed that the genotype rs10815225 GC, which were more frequent in ccRCC patients than in controls and increased the risk of ccRCC, might be associated with increased expression of PD-L1.	('increased', 'PosReg', (180, 189))	('rs10815225', 'Var', (47, 57))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('RCC', 'Disease', (150, 153))	('RCC', 'Disease', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('patients', 'Species', '9606', (96, 104))	('x', 'Mutation', 'x', (191, 192))	('rs10815225', 'Mutation', 'rs10815225', (47, 57))	('increased', 'PosReg', (126, 135))	('PD-L1', 'Gene', (204, 209))
135728	33255938	showing higher risk and increased PD-L1 expression for rs10815225 GG genotype, our observation seems to be unexpected.	('expression', 'MPA', (40, 50))	('rs10815225', 'Mutation', 'rs10815225', (55, 65))	('x', 'Mutation', 'x', (41, 42))	('increased PD', 'Phenotype', 'HP:0008151', (24, 36))	('PD-L1', 'Gene', (34, 39))	('x', 'Mutation', 'x', (110, 111))	('increased', 'PosReg', (24, 33))	('rs10815225', 'Var', (55, 65))
135731	33255938	With regard to in silico analysis (Figure 2), not only SP1, but also other transcription factors (that can be expressed in a tissue-specific manner) can bind, possibly with different affinities for the C and G alleles, to the promoter region where rs10815225 polymorphism is located (e.g., TAF1, EGR1).	('rs10815225 polymorphism', 'Var', (248, 271))	('EGR1', 'Gene', (296, 300))	('bind', 'Interaction', (153, 157))	('TAF1', 'Gene', (290, 294))	('TAF1', 'Gene', '6872', (290, 294))	('rs10815225', 'Mutation', 'rs10815225', (248, 258))	('EGR1', 'Gene', '1958', (296, 300))	('x', 'Mutation', 'x', (111, 112))	('transcription', 'biological_process', 'GO:0006351', ('75', '88'))
135733	33255938	It is also worth noting that this SNP is located in CG dinucleotide within CpG island (Figure 2); however a G>C substitution removes one CG dinucleotide but creates another (CCTCCGGGCC).	('CG dinucleotide', 'Chemical', 'MESH:C015772', (137, 152))	('TC', 'Chemical', 'MESH:D013667', (176, 178))	('CG dinucleotide', 'Chemical', 'MESH:C015772', (52, 67))	('CG dinucleotide', 'MPA', (137, 152))	('G>C substitution', 'Var', (108, 124))	('removes', 'NegReg', (125, 132))
135734	33255938	It seems worthwhile to investigate whether the PD-L1 methylation status (and in consequence mRNA expression) may be different depending on the genotype at the rs10815225 polymorphic site.	('rs10815225', 'Var', (159, 169))	('mRNA expression', 'MPA', (92, 107))	('rs10815225', 'Mutation', 'rs10815225', (159, 169))	('methylation', 'biological_process', 'GO:0032259', ('53', '64'))	('x', 'Mutation', 'x', (98, 99))
135735	33255938	Interestingly, as was mentioned earlier, the analysis of SNP-SNP interaction (between SNPs in receptor/ligand encoding genes) indicated that polymorphisms rs7421861T>C of PDCD1 and rs10815225G>C of PD-L1, should be considered together in relation to ccRCC risk.	('PDCD1', 'Gene', (171, 176))	('PD-L1', 'Gene', (198, 203))	('rs7421861T>C', 'Var', (155, 167))	('RCC', 'Disease', 'MESH:C538614', (252, 255))	('RCC', 'Disease', (252, 255))	('rs10815225G>C', 'Var', (181, 194))	('rs10815225G>C', 'DBSNP_MENTION', 'None', (181, 194))	('receptor/ligand', 'molecular_function', 'GO:0005102', ('94', '109'))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (155, 167))	('PDCD1', 'Gene', '5133', (171, 176))
135736	33255938	To explain the potential biological relevance of detected interaction in relation to ccRCC development, two earlier justified assumptions were made: 1) increased expression of PD-L1 on tumor cells in individuals with C allele in rs10815225 (GC + CC) as compared to those with rs10815225 GG and 2) decreased expression of PD-1 on T cells in individuals with rs7421861 TC genotype in comparison to subjects with rs7421861 TT or CC genotype.	('x', 'Mutation', 'x', (308, 309))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('rs10815225', 'Var', (229, 239))	('tumor', 'Disease', (185, 190))	('x', 'Mutation', 'x', (4, 5))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('x', 'Mutation', 'x', (163, 164))	('C allele', 'Var', (217, 225))	('increased', 'PosReg', (152, 161))	('rs7421861', 'Var', (357, 366))	('rs7421861', 'Mutation', 'rs7421861', (357, 366))	('rs10815225', 'Mutation', 'rs10815225', (276, 286))	('rs10815225', 'Mutation', 'rs10815225', (229, 239))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('RCC', 'Disease', (87, 90))	('rs7421861', 'Mutation', 'rs7421861', (410, 419))	('TC', 'Chemical', 'MESH:D013667', (367, 369))	('expression', 'MPA', (162, 172))	('decreased', 'NegReg', (297, 306))	('expression', 'MPA', (307, 317))	('PD-L1', 'Gene', (176, 181))
135737	33255938	As described above, our analysis showed that the C allele in rs10815225 (GC or CC genotype) increased (more than twice, OR = 2.4) the risk of ccRCC development in individuals with rs7421861 TT or CC genotype (Table 4).	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('rs7421861', 'Mutation', 'rs7421861', (180, 189))	('rs10815225', 'Var', (61, 71))	('increased', 'PosReg', (92, 101))	('rs7421861', 'Var', (180, 189))	('rs10815225', 'Mutation', 'rs10815225', (61, 71))	('RCC', 'Disease', (144, 147))
135741	33255938	In contrast, rs7421861 TC genotype was associated with lower risk of ccRCC development in rs10815225 C allele carriers (Table 3).	('rs10815225 C', 'Var', (90, 102))	('TC', 'Chemical', 'MESH:D013667', (23, 25))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('rs10815225', 'Mutation', 'rs10815225', (90, 100))	('rs7421861', 'Var', (13, 22))	('lower', 'NegReg', (55, 60))	('rs7421861', 'Mutation', 'rs7421861', (13, 22))
135744	33255938	In the next step it would be necessary to investigate PD-1 and PD-L1 expression (on mRNA and protein level) in relation to genotype at rs7421861 and rs10815225 polymorphic sites, respectively, in order to verify that the assumptions described above can be considered true.	('rs7421861', 'Mutation', 'rs7421861', (135, 144))	('rs10815225', 'Var', (149, 159))	('PD-1', 'Gene', (54, 58))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('rs10815225', 'Mutation', 'rs10815225', (149, 159))	('x', 'Mutation', 'x', (70, 71))	('PD-L1', 'Gene', (63, 68))	('x', 'Mutation', 'x', (9, 10))	('rs7421861', 'Var', (135, 144))	('investigate', 'Reg', (42, 53))
135747	33255938	Our study revealed that genetic variants of PDCD1 and PD-L1 may be associated with the risk of ccRCC development and that in association studies it is worth considering the interactions between variants in the genes encoding molecules belonging to the receptor/ligand axis.	('RCC', 'Disease', (97, 100))	('PDCD1', 'Gene', '5133', (44, 49))	('receptor/ligand', 'molecular_function', 'GO:0005102', ('252', '267'))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('PD-L1', 'Gene', (54, 59))	('variants', 'Var', (32, 40))	('associated', 'Reg', (67, 77))	('x', 'Mutation', 'x', (269, 270))	('interactions', 'Interaction', (173, 185))	('PDCD1', 'Gene', (44, 49))
135748	33255938	Since this is the first study of PDCD1 and PD-L1 polymorphisms in the context of ccRCC, we believe that our research will broaden current knowledge of the genetic basis of this type of cancer.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('x', 'Mutation', 'x', (75, 76))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('PDCD1', 'Gene', '5133', (33, 38))	('PD-L1', 'Gene', (43, 48))	('polymorphisms', 'Var', (49, 62))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('PDCD1', 'Gene', (33, 38))	('cancer', 'Disease', (185, 191))
135754	33255938	The following single nucleotide polymorphisms (SNPs) in PDCD1 gene: rs36084323G>A (PD-1.1), rs11568821G>A (PD-1.3), rs2227981C>T (PD-1.5), rs10204525G>A (PD-1.6), rs7421861T>C as well as in PD-L1 gene: rs822335C>T, rs4143815G>C, rs4742098A>G, rs10815225G>C:were genotyped with the use of appropriate TaqMan SNP Genotyping Assays (in detail presented in Table S6).	('rs10204525G>A', 'DBSNP_MENTION', 'None', (139, 152))	('rs10204525G>A', 'Var', (139, 152))	('rs2227981C>T', 'DBSNP_MENTION', 'None', (116, 128))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (163, 175))	('rs4742098A>G', 'Var', (229, 241))	('rs4143815G>C', 'DBSNP_MENTION', 'None', (215, 227))	('rs2227981C>T', 'Var', (116, 128))	('rs11568821G>A', 'Var', (92, 105))	('rs4143815G>C', 'Var', (215, 227))	('rs10815225G>C', 'Var', (243, 256))	('rs7421861T>C', 'Var', (163, 175))	('rs11568821G>A', 'DBSNP_MENTION', 'None', (92, 105))	('rs36084323G>A', 'Var', (68, 81))	('rs822335C>T', 'DBSNP_MENTION', 'None', (202, 213))	('PDCD1', 'Gene', (56, 61))	('rs822335C>T', 'Var', (202, 213))	('rs10815225G>C', 'DBSNP_MENTION', 'None', (243, 256))	('PDCD1', 'Gene', '5133', (56, 61))	('rs36084323G>A', 'DBSNP_MENTION', 'None', (68, 81))	('rs4742098A>G', 'DBSNP_MENTION', 'None', (229, 241))
135760	33255938	In conclusion, the results of our study suggest that polymorphisms of PD-1/PD-L1 axis genes may be associated with the risk of ccRCC development.	('x', 'Mutation', 'x', (82, 83))	('associated with', 'Reg', (99, 114))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('RCC', 'Disease', (129, 132))	('PD-1/PD-L1 axis', 'Gene', (70, 85))	('polymorphisms', 'Var', (53, 66))
135761	33255938	Since PD-1 and PD-L1 genetic variants have not been examined in the context of ccRCC so far, further studies are necessary to validate observed by us associations.	('PD-L1', 'Gene', (15, 20))	('PD-1', 'Gene', (6, 10))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('variants', 'Var', (29, 37))	('x', 'Mutation', 'x', (73, 74))	('x', 'Mutation', 'x', (53, 54))
135762	33255938	The next key step that must be taken is to quantify the expression of PD-1 and PD-L1 (on mRNA and protein level) in relation to rs7421861 and rs10815225 genotype, respectively.	('x', 'Mutation', 'x', (57, 58))	('rs7421861', 'Mutation', 'rs7421861', (128, 137))	('x', 'Mutation', 'x', (6, 7))	('rs10815225', 'Var', (142, 152))	('rs10815225', 'Mutation', 'rs10815225', (142, 152))	('PD-L1', 'Gene', (79, 84))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('PD-1', 'Gene', (70, 74))	('rs7421861', 'Var', (128, 137))
135763	33255938	It would also be interesting to investigate the possible effect of rs7421861 SNP on the level of PD-1 isoforms (generated by alternative splicing), as well as the effect of rs10815225 polymorphism on PD-L1 methylation status.	('rs10815225', 'Var', (173, 183))	('splicing', 'biological_process', 'GO:0045292', ('137', '145'))	('rs7421861', 'Mutation', 'rs7421861', (67, 76))	('rs10815225', 'Mutation', 'rs10815225', (173, 183))	('methylation', 'biological_process', 'GO:0032259', ('206', '217'))	('rs7421861', 'Var', (67, 76))
135764	33255938	Importantly, our research showed that in order to find possible risk factors for renal cell carcinoma (and possibly other types of cancer), it is worth investigating SNP-SNP interactions between variants in the genes encoding the receptor/ligand.	('cancer', 'Disease', (131, 137))	('variants', 'Var', (195, 203))	('receptor/ligand', 'molecular_function', 'GO:0005102', ('230', '245'))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('renal cell carcinoma', 'Disease', (81, 101))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (81, 101))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (81, 101))
135767	33255938	The following are available online at , Table S1: Genotype distribution of investigated PDCD1 and PD-L1 polymorphisms in renal cell carcinoma (RCC) patients and controls.	('patients', 'Species', '9606', (148, 156))	('renal cell carcinoma', 'Disease', (121, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (121, 141))	('PD-L1', 'Gene', (98, 103))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (121, 141))	('PDCD1', 'Gene', '5133', (88, 93))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', (143, 146))	('polymorphisms', 'Var', (104, 117))	('PDCD1', 'Gene', (88, 93))
135768	33255938	Table S2: Analysis of linkage disequilibrium (r2) between genetic variants located in PDCD1 gene.	('PDCD1', 'Gene', (86, 91))	('variants', 'Var', (66, 74))	('PDCD1', 'Gene', '5133', (86, 91))
135770	33255938	Rs7421861 x rs10815225 interaction-observed and expected genotype distributions in ccRCC patients and control subjects.	('x', 'Mutation', 'x', (10, 11))	('rs10815225', 'Var', (12, 22))	('Rs7421861', 'Mutation', 'Rs7421861', (0, 9))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('rs10815225', 'Mutation', 'rs10815225', (12, 22))	('RCC', 'Disease', (85, 88))	('patients', 'Species', '9606', (89, 97))	('x', 'Mutation', 'x', (49, 50))	('Rs7421861', 'Var', (0, 9))
135772	33255938	Figure S1: Linkage disequilibrium (LD) blocks generated with application of HaploReg v4.1 presenting SNPs being in strong LD (r2 > 0.8) with (A) rs36084323G>A (PD-1.1), (B) rs11568821G>A (PD-1.3), (C) rs2227981C>T (PD-1.5), (D) rs10204525G>A (PD-1.6), (E) rs7421861T>C.	('rs7421861T>C', 'Var', (256, 268))	('v4.1', 'Gene', (85, 89))	('rs2227981C>T', 'Var', (201, 213))	('v4.1', 'Gene', '28783', (85, 89))	('rs36084323G>A', 'DBSNP_MENTION', 'None', (145, 158))	('rs11568821G>A', 'DBSNP_MENTION', 'None', (173, 186))	('rs2227981C>T', 'DBSNP_MENTION', 'None', (201, 213))	('rs36084323G>A', 'Var', (145, 158))	('rs7421861T>C', 'DBSNP_MENTION', 'None', (256, 268))	('rs10204525G>A', 'DBSNP_MENTION', 'None', (228, 241))	('rs11568821G>A', 'Var', (173, 186))	('rs10204525G>A', 'Var', (228, 241))
135773	33255938	Figure S2: Linkage disequilibrium (LD) blocks generated with application of HaploReg v4.1 presenting SNPs being in strong LD (r2 > 0.8) with rs822335C>T, rs4143815G>C, rs4742098A>G, rs10815225G>C.	('rs4143815G>C', 'DBSNP_MENTION', 'None', (154, 166))	('v4.1', 'Gene', (85, 89))	('rs822335C>T', 'DBSNP_MENTION', 'None', (141, 152))	('rs4143815G>C', 'Var', (154, 166))	('rs4742098A>G', 'Var', (168, 180))	('rs4742098A>G', 'DBSNP_MENTION', 'None', (168, 180))	('rs822335C>T', 'Var', (141, 152))	('v4.1', 'Gene', '28783', (85, 89))	('rs10815225G>C', 'Var', (182, 195))	('rs10815225G>C', 'DBSNP_MENTION', 'None', (182, 195))
135780	31342628	Additionally, the overexpression of miR-30c-5p inhibited ccRCC progression in vitro and in vivo.	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('inhibited', 'NegReg', (47, 56))	('ccRCC', 'Disease', (57, 62))	('ccRCC', 'Disease', 'MESH:D002292', (57, 62))	('miR-30c-5p', 'Var', (36, 46))	('overexpression', 'PosReg', (18, 32))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
135781	31342628	The depletion of HSPA5 caused by miR-30c-5p inhibition reversed the promoting effect of ccRCC growth.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('ccRCC', 'Disease', (88, 93))	('ccRCC', 'Disease', 'MESH:D002292', (88, 93))	('miR-30c-5p inhibition', 'Var', (33, 54))	('HSPA5', 'Protein', (17, 22))	('depletion', 'MPA', (4, 13))
135782	31342628	In conclusion, urinary exosomal miR-30c-5p acts as a potential diagnostic biomarker of early-stage ccRCC and may be able to modulate the expression of HSPA5, which is correlated with the progression of ccRCC.	('expression', 'MPA', (137, 147))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('ccRCC', 'Disease', (99, 104))	('RCC', 'Phenotype', 'HP:0005584', (204, 207))	('miR-30c-5p', 'Var', (32, 42))	('correlated', 'Reg', (167, 177))	('ccRCC', 'Phenotype', 'HP:0006770', (202, 207))	('ccRCC', 'Disease', 'MESH:D002292', (99, 104))	('ccRCC', 'Disease', (202, 207))	('HSPA5', 'Protein', (151, 156))	('ccRCC', 'Disease', 'MESH:D002292', (202, 207))	('modulate', 'Reg', (124, 132))
135821	31342628	The tumour formation ability of the RCC cells overexpressing miR-30c-5p was evaluated by injecting cell suspensions into BALB/c nude male mice.	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('RCC', 'Disease', 'MESH:D002292', (36, 39))	('RCC', 'Disease', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('mice', 'Species', '10090', (138, 142))	('miR-30c-5p', 'Var', (61, 71))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('formation', 'biological_process', 'GO:0009058', ('11', '20'))	('tumour', 'Disease', (4, 10))
135833	31342628	From the two groups of candidate, 16 miRNAs showed dramatically different expression in urinary exosome and 49 miRNAs showed similar different expression trend both in urinary and in cellular exosomes, in which 5 overlapped miRNAs, miR-30c-5p, miR-27b-3p, miR-26a-5p and miR-194-5p, which were down-regulated, and miR-122-5p, which was up-regulated, were screened.	('expression', 'MPA', (74, 84))	('miR-194-5p', 'Var', (271, 281))	('down-regulated', 'NegReg', (294, 308))	('miR-26a-5p', 'Var', (256, 266))	('miR-30c-5p', 'Var', (232, 242))	('miR-122-5p', 'Gene', (314, 324))	('miR-27b', 'Gene', '407019', (244, 251))	('exosome', 'cellular_component', 'GO:0070062', ('96', '103'))	('up-regulated', 'PosReg', (336, 348))	('miR-122-5p', 'Gene', '100188847', (314, 324))	('miR-27b', 'Gene', (244, 251))
135835	31342628	Among them, miR-194-5p and miR-26a-5p were barely detectable and the expression levels of miR-30c-5p, miR-122-5p and miR-27b-3p were stably amplified (data not shown).	('miR-27b', 'Gene', (117, 124))	('miR-30c-5p', 'Var', (90, 100))	('miR-122-5p', 'Gene', '100188847', (102, 112))	('expression', 'MPA', (69, 79))	('miR-27b', 'Gene', '407019', (117, 124))	('miR-122-5p', 'Gene', (102, 112))
135837	31342628	Although miR-30c-5p (3'-CGACUCUCACAUCCUACAAAUGU-5') was stably amplified in urine exosomes of prostate cancer and bladder cancer patients as well, there was no significant difference between its expression in these patients and healthy individuals.	('patients', 'Species', '9606', (215, 223))	('bladder cancer', 'Disease', 'MESH:D001749', (114, 128))	('bladder cancer', 'Disease', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('miR-30c-5p', 'Var', (9, 19))	('patients', 'Species', '9606', (129, 137))	('prostate cancer', 'Disease', 'MESH:D011471', (94, 109))	('prostate cancer', 'Phenotype', 'HP:0012125', (94, 109))	("(3'-CGACUCUCACAUCCUACAAAUGU-5')", 'Chemical', 'MESH:C068492', (20, 51))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('bladder cancer', 'Phenotype', 'HP:0009725', (114, 128))	('prostate cancer', 'Disease', (94, 109))
135838	31342628	However, the expression level of miR-30c-5p in the urinary exosomes of ccRCC patients was significantly lower than that of normal individuals (Figure 3A), which implies that miR-30c-5p might be a potential urinary exosomal ccRCC biomarker.	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('ccRCC', 'Disease', (71, 76))	('RCC', 'Phenotype', 'HP:0005584', (225, 228))	('ccRCC', 'Disease', 'MESH:D002292', (71, 76))	('lower', 'NegReg', (104, 109))	('miR-30c-5p', 'Var', (33, 43))	('patients', 'Species', '9606', (77, 85))	('expression level', 'MPA', (13, 29))	('ccRCC', 'Disease', (223, 228))	('ccRCC', 'Phenotype', 'HP:0006770', (223, 228))	('ccRCC', 'Disease', 'MESH:D002292', (223, 228))	('miR-30c-5p', 'Var', (174, 184))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
135842	31342628	miR-30c-5p overexpression inhibited the tumorigenicity of nude mice with ACHN xenografts (Figure 4G).	('inhibited', 'NegReg', (26, 35))	('tumorigenicity of nude mice', 'CPA', (40, 67))	('overexpression', 'PosReg', (11, 25))	('nude mice', 'Species', '10090', (58, 67))	('miR-30c-5p', 'Var', (0, 10))
135843	31342628	The results above suggest that miR-30c-5p inhibits ccRCC progression both in vitro and in vivo.	('ccRCC', 'Disease', 'MESH:D002292', (51, 56))	('inhibits', 'NegReg', (42, 50))	('miR-30c-5p', 'Var', (31, 41))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))	('ccRCC', 'Disease', (51, 56))
135848	31342628	In order to confirm whether HSPA5 or HSPD1 would be the direct target gene of miR-30c-5p, luciferase activity assay was performed with ccRCC cells, which were transfected with luciferase constructs containing WT-3'-UTR and Mut-3'-UTR of HSPA5 (Figure 5A).	('ccRCC', 'Disease', 'MESH:D002292', (135, 140))	('luciferase activity', 'molecular_function', 'GO:0050397', ('90', '109'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('90', '109'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('90', '109'))	("Mut-3'-UTR", 'Var', (223, 233))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('ccRCC', 'Disease', (135, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('luciferase activity', 'molecular_function', 'GO:0045289', ('90', '109'))	('HSPD1', 'Gene', (37, 42))	('luciferase activity', 'molecular_function', 'GO:0050248', ('90', '109'))	('HSPD1', 'Gene', '3329', (37, 42))
135849	31342628	Furthermore, dual-luciferase assays showed that while miR-30c-5p suppressed the luciferase activity of the reporter containing wt-3'-UTRs of HSPA5 in both 786-O and ACHN cells, the effect was obviously abrogated with the mutated reporter (Figure 5C,D), whereas there was no effect on HSPD1 wt-3'-UTRs (data not shown), indicating that miR-30c-5p suppressed the expression of HSPA5 by directly binding to target sites in 3'-UTRs.	('luciferase', 'Enzyme', (80, 90))	('HSPD1', 'Gene', '3329', (284, 289))	('suppressed', 'NegReg', (346, 356))	('luciferase activity', 'molecular_function', 'GO:0047077', ('80', '99'))	('binding', 'Interaction', (393, 400))	('luciferase activity', 'molecular_function', 'GO:0047712', ('80', '99'))	('activity', 'MPA', (91, 99))	('suppressed', 'NegReg', (65, 75))	('HSPA5', 'Gene', (375, 380))	('luciferase activity', 'molecular_function', 'GO:0045289', ('80', '99'))	('miR-30c-5p', 'Var', (54, 64))	('expression', 'MPA', (361, 371))	('luciferase activity', 'molecular_function', 'GO:0050397', ('80', '99'))	('binding', 'molecular_function', 'GO:0005488', ('393', '400'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('80', '99'))	('miR-30c-5p', 'Var', (335, 345))	('HSPD1', 'Gene', (284, 289))	('abrogated', 'NegReg', (202, 211))
135850	31342628	These results support the bioinformatics predictions and demonstrate that miR-30c-5p directly targets HSPA5 and inhibits its expression in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (139, 144))	('ccRCC', 'Disease', (139, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('ccRCC', 'Disease', 'MESH:D002292', (139, 144))	('HSPA5', 'Protein', (102, 107))	('expression', 'MPA', (125, 135))	('miR-30c-5p', 'Var', (74, 84))	('inhibits', 'NegReg', (112, 120))	('targets', 'Reg', (94, 101))
135851	31342628	Numerous studies have reported that HSPA5 performs an important role in the progression of various cancers.20, 21, 22, 23 Thus, we speculate that HSPA5 might be a direct target of miR-30c-5p in regulating the progression of ccRCC.	('ccRCC', 'Disease', 'MESH:D002292', (224, 229))	('miR-30c-5p', 'Var', (180, 190))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (224, 229))	('ccRCC', 'Disease', (224, 229))	('RCC', 'Phenotype', 'HP:0005584', (226, 229))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
135854	31342628	Various studies have focused on the association between miRNA and cancers, while increasing evidence has shown a close connection between the dysregulated expression of miRNAs and the occurrence and progression of cancers.	('miRNAs', 'Gene', (169, 175))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Disease', (214, 221))	('dysregulated', 'Var', (142, 154))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('expression', 'MPA', (155, 165))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('association', 'Interaction', (36, 47))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
135858	31342628	Moreover, the expression level of miR-30c-5p in urinary exosomes of ccRCC patients was lower than that of normal individuals, and a ROC curve revealed that the AUC value was 0.8192 (95% confidence interval was 0.7388-0.8996, P < .01).	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('lower', 'NegReg', (87, 92))	('patients', 'Species', '9606', (74, 82))	('ccRCC', 'Disease', (68, 73))	('ccRCC', 'Disease', 'MESH:D002292', (68, 73))	('miR-30c-5p', 'Var', (34, 44))	('expression level', 'MPA', (14, 30))
135859	31342628	Thus, we propose miR-30c-5p to be a potential candidate for a ccRCC biomarker.	('ccRCC', 'Disease', 'MESH:D002292', (62, 67))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('ccRCC', 'Disease', (62, 67))	('miR-30c-5p', 'Var', (17, 27))
135860	31342628	To our knowledge, this is the first time the correlation between miR-30c-5p and kidney cancer has been studied.	('miR-30c-5p', 'Var', (65, 75))	('kidney cancer', 'Disease', 'MESH:D007680', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('kidney cancer', 'Phenotype', 'HP:0009726', (80, 93))	('kidney cancer', 'Disease', (80, 93))
135862	31342628	From the result that miR-30c-5p in urinary exosome of ccRCC patients was lower than healthy individuals, we then speculated that miR-30c-5p might act as a suppressor in ccRCC progression.	('miR-30c-5p', 'MPA', (21, 31))	('exosome', 'cellular_component', 'GO:0070062', ('43', '50'))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('ccRCC', 'Disease', 'MESH:D002292', (169, 174))	('ccRCC', 'Disease', (54, 59))	('patients', 'Species', '9606', (60, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('ccRCC', 'Disease', 'MESH:D002292', (54, 59))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('lower', 'NegReg', (73, 78))	('miR-30c-5p', 'Var', (129, 139))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))	('ccRCC', 'Disease', (169, 174))
135863	31342628	As expected, overexpression of miR-30c-5p was found to inhibit the growth of RCC cells in vitro, indicating its association with the development and progression of ccRCC.	('miR-30c-5p', 'Var', (31, 41))	('RCC', 'Disease', (166, 169))	('RCC', 'Disease', 'MESH:D002292', (166, 169))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('ccRCC', 'Phenotype', 'HP:0006770', (164, 169))	('RCC', 'Disease', 'MESH:D002292', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('association', 'Reg', (112, 123))	('overexpression', 'PosReg', (13, 27))	('growth', 'CPA', (67, 73))	('ccRCC', 'Disease', (164, 169))	('ccRCC', 'Disease', 'MESH:D002292', (164, 169))	('inhibit', 'NegReg', (55, 62))
135864	31342628	Moreover, miR-30c-5p overexpression inhibited tumorigenicity in nude mice.	('inhibited', 'NegReg', (36, 45))	('miR-30c-5p', 'Var', (10, 20))	('nude mice', 'Species', '10090', (64, 73))	('overexpression', 'PosReg', (21, 35))	('tumorigenicity', 'CPA', (46, 60))
135866	31342628	Cao24 reported that miR-30c-5p suppressed tumorigenesis and metastasis via MTA1 (metastasis-associated protein 1) in gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('metastasis-associated protein 1', 'Gene', (81, 112))	('metastasis-associated protein 1', 'Gene', '9112', (81, 112))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('MTA1', 'Gene', (75, 79))	('tumorigenesis', 'CPA', (42, 55))	('metastasis', 'CPA', (60, 70))	('suppressed', 'NegReg', (31, 41))	('gastric cancer', 'Disease', (117, 131))	('miR-30c-5p', 'Var', (20, 30))	('MTA1', 'Gene', '9112', (75, 79))
135867	31342628	However, in the present study, HSPA5, also called GRP78/BiP, was confirmed to be a direct target of miR-30c-5p, as HSPA5 down-regulation caused by miR-30c-5p inhibition reversed the promoting effect of ccRCC growth.	('GRP78', 'Gene', '3309', (50, 55))	('RCC', 'Phenotype', 'HP:0005584', (204, 207))	('regulation', 'biological_process', 'GO:0065007', ('126', '136'))	('ccRCC', 'Phenotype', 'HP:0006770', (202, 207))	('GRP78', 'Gene', (50, 55))	('miR-30c-5p inhibition', 'Var', (147, 168))	('HSPA5', 'Gene', (115, 120))	('ccRCC', 'Disease', (202, 207))	('BiP', 'Gene', (56, 59))	('ccRCC', 'Disease', 'MESH:D002292', (202, 207))	('down-regulation', 'NegReg', (121, 136))	('BiP', 'Gene', '3309', (56, 59))
135871	31342628	In conclusion, miR-30c-5p-HSPA5 signalling pathway may be correlated with the progression of ccRCC, which indicates that urinary exosomal miR-30c-5p may act as a specific and sensitive biomarker for diagnosing and monitoring the progression of ccRCC.	('ccRCC', 'Disease', 'MESH:D002292', (93, 98))	('RCC', 'Phenotype', 'HP:0005584', (246, 249))	('miR-30c-5p', 'Var', (138, 148))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (244, 249))	('ccRCC', 'Disease', (244, 249))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('ccRCC', 'Disease', (93, 98))	('ccRCC', 'Disease', 'MESH:D002292', (244, 249))	('signalling pathway', 'biological_process', 'GO:0007165', ('32', '50'))
135899	31481981	suggested that CASZ1 inhibits the MAPK/ERK signaling pathway by downregulating RAF1 in HCC.	('HCC', 'Phenotype', 'HP:0001402', (87, 90))	('MAPK', 'molecular_function', 'GO:0004707', ('34', '38'))	('RAF1', 'Gene', '5894', (79, 83))	('inhibits', 'NegReg', (21, 29))	('ERK', 'Gene', '5594', (39, 42))	('CASZ1', 'Var', (15, 20))	('ERK', 'Gene', (39, 42))	('signaling pathway', 'biological_process', 'GO:0007165', ('43', '60'))	('ERK', 'molecular_function', 'GO:0004707', ('39', '42'))	('RAF1', 'Gene', (79, 83))	('downregulating', 'NegReg', (64, 78))
135969	30538212	Finally, we showed that silencing of NDUFA4L2 affects cell viability, increases mitochondrial mass, and induces ROS generation in hypoxia.	('ROS', 'Chemical', 'MESH:D017382', (112, 115))	('ROS generation', 'biological_process', 'GO:1903409', ('112', '126'))	('ROS generation', 'MPA', (112, 126))	('hypoxia', 'Disease', (130, 137))	('hypoxia', 'Disease', 'MESH:D000860', (130, 137))	('affects', 'Reg', (46, 53))	('NDUFA4L2', 'Gene', '56901', (37, 45))	('increases', 'PosReg', (70, 79))	('mitochondrial mass', 'MPA', (80, 98))	('induces', 'Reg', (104, 111))	('NDUFA4L2', 'Gene', (37, 45))	('cell viability', 'CPA', (54, 68))	('silencing', 'Var', (24, 33))
135975	30538212	The recent comprehensive molecular characterization of clear cell RCC (ccRCC) by the cancer genome atlas (TCGA) research network has confirmed that a reprogrammed metabolism and DNA epigenetic changes, associated with mutations of chromatin remodeling genes, are two major features in this cancer.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('DNA epigenetic changes', 'CPA', (178, 200))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('cancer genome atlas', 'Disease', 'MESH:D009369', (85, 104))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('cancer genome atlas', 'Disease', (85, 104))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('RCC', 'Disease', (73, 76))	('metabolism', 'biological_process', 'GO:0008152', ('163', '173'))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('DNA', 'cellular_component', 'GO:0005574', ('178', '181'))	('mutations', 'Var', (218, 227))	('cancer', 'Disease', (290, 296))	('reprogrammed metabolism', 'CPA', (150, 173))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('231', '251'))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('chromatin', 'cellular_component', 'GO:0000785', ('231', '240'))
135978	30538212	Recently we showed that in ccRCC a metabolic reprogramming occurs, involving the glucose metabolism and the pentose phosphate pathway, and that patients with high levels of glycolytic enzymes had reduced progression-free and cancer-specific survival rates as compared to subjects with low levels.	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('glucose metabolism', 'Disease', (81, 99))	('cancer', 'Disease', (225, 231))	('RCC', 'Disease', (29, 32))	('pentose', 'Enzyme', (108, 115))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('glycolytic', 'MPA', (173, 183))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('pentose phosphate', 'Chemical', 'MESH:D010428', (108, 125))	('glucose metabolism', 'Disease', 'MESH:D044882', (81, 99))	('patients', 'Species', '9606', (144, 152))	('ccRCC', 'Phenotype', 'HP:0006770', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('metabolic reprogramming', 'CPA', (35, 58))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('108', '133'))	('high levels', 'Var', (158, 169))	('glucose metabolism', 'biological_process', 'GO:0006006', ('81', '99'))	('reduced', 'NegReg', (196, 203))
136048	30538212	Moreover, NDUFA4L2 silencing increased the membrane potential and reactive oxygen species (ROS) production in cancer cells, as shown by increased signals of the fluorescence probe TMRE and the mitochondrial superoxide indicator MitoSOX (Figure 4E).	('NDUFA4L2', 'Gene', (10, 18))	('MitoSOX', 'MPA', (228, 235))	('cancer', 'Disease', (110, 116))	('superoxide', 'Chemical', 'MESH:D013481', (207, 217))	('silencing', 'Var', (19, 28))	('Mito', 'Species', '262676', (228, 232))	('increased', 'PosReg', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('membrane', 'cellular_component', 'GO:0016020', ('43', '51'))	('membrane potential', 'MPA', (43, 61))	('signals', 'MPA', (146, 153))	('TMRE', 'Chemical', 'MESH:C110932', (180, 184))	('increased', 'PosReg', (136, 145))	('ROS', 'Chemical', 'MESH:D017382', (91, 94))	('NDUFA4L2', 'Gene', '56901', (10, 18))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (66, 89))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
136060	30538212	Both CSS and PFS were significantly decreased in patients with high levels of NDUFA4L2.	('high levels', 'Var', (63, 74))	('PFS', 'CPA', (13, 16))	('NDUFA4L2', 'Gene', '56901', (78, 86))	('CSS', 'Chemical', '-', (5, 8))	('NDUFA4L2', 'Gene', (78, 86))	('patients', 'Species', '9606', (49, 57))	('CSS', 'CPA', (5, 8))	('decreased', 'NegReg', (36, 45))
136061	30538212	Univariate analysis for the predefined variables showed that the pathological stage, presence of nodal and visceral metastases, Fuhrman grade, presence of necrosis, tumor size, and high levels of NDUFA4L2, were significantly associated with the risk of death (Table 1) and progression (Table 2).	('necrosis', 'biological_process', 'GO:0008220', ('155', '163'))	('NDUFA4L2', 'Gene', '56901', (196, 204))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('death', 'Disease', (253, 258))	('necrosis', 'biological_process', 'GO:0070265', ('155', '163'))	('necrosis', 'biological_process', 'GO:0019835', ('155', '163'))	('high', 'Var', (181, 185))	('necrosis', 'biological_process', 'GO:0001906', ('155', '163'))	('necrosis', 'Disease', 'MESH:D009336', (155, 163))	('visceral metastases', 'Disease', (107, 126))	('NDUFA4L2', 'Gene', (196, 204))	('necrosis', 'Disease', (155, 163))	('death', 'Disease', 'MESH:D003643', (253, 258))	('tumor', 'Disease', (165, 170))	('necrosis', 'biological_process', 'GO:0008219', ('155', '163'))	('visceral metastases', 'Disease', 'MESH:D009362', (107, 126))	('nodal', 'CPA', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('associated', 'Reg', (225, 235))
136070	30538212	In addition, after cisplatin treatment, the death rate of tumor cells treated with siNDUFA4L2 was significantly greater than that of untreated cancer cells (p < 0.001, Figure 5C).	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('death', 'Disease', 'MESH:D003643', (44, 49))	('siNDUFA4L2', 'Var', (83, 93))	('death', 'Disease', (44, 49))	('siNDUFA4L2', 'Chemical', '-', (83, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('greater', 'PosReg', (112, 119))
136071	30538212	The MTT assay confirmed these findings, demonstrating a decreased cell viability when tumor cells were pre-treated with siNDUAFA4L2 before cisplatin incubation (Figure 5C).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('siNDUAFA4L2', 'Var', (120, 131))	('cell viability', 'CPA', (66, 80))	('tumor', 'Disease', (86, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('decreased', 'NegReg', (56, 65))	('pre', 'molecular_function', 'GO:0003904', ('103', '106'))	('siNDUAFA4L2', 'Chemical', '-', (120, 131))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
136073	30538212	In normoxic conditions, the silencing of NDUFA4L2 impaired cell proliferation, led to an inhibition of the autophagic machine, and increased the mitochondrial mass, as suggested by higher levels of the mitochondrial protein TOM20 (Figure 8A).	('NDUFA4L2', 'Gene', (41, 49))	('increased', 'PosReg', (131, 140))	('impaired', 'NegReg', (50, 58))	('cell proliferation', 'CPA', (59, 77))	('higher', 'PosReg', (181, 187))	('TOM20', 'Gene', (224, 229))	('inhibition', 'NegReg', (89, 99))	('autophagic machine', 'CPA', (107, 125))	('NDUFA4L2', 'Gene', '56901', (41, 49))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('protein', 'cellular_component', 'GO:0003675', ('216', '223'))	('TOM20', 'Gene', '9804', (224, 229))	('silencing', 'Var', (28, 37))	('levels', 'MPA', (188, 194))	('mitochondrial mass', 'CPA', (145, 163))
136078	30538212	These findings were also in accordance with the increased levels of H2AX histone phosphorylation observed in silenced human renal cancer cells, suggesting that the lack of NDUFA4L2 induces cell stress.	('NDUFA4L2', 'Gene', (172, 180))	('cell stress', 'CPA', (189, 200))	('H2AX histone', 'Gene', (68, 80))	('renal cancer', 'Disease', (124, 136))	('lack', 'Var', (164, 168))	('renal cancer', 'Disease', 'MESH:D007680', (124, 136))	('renal cancer', 'Phenotype', 'HP:0009726', (124, 136))	('H2AX histone', 'Gene', '3014', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('human', 'Species', '9606', (118, 123))	('NDUFA4L2', 'Gene', '56901', (172, 180))	('histone phosphorylation', 'biological_process', 'GO:0016572', ('73', '96'))
136090	30538212	Interestingly, NDUFA4L2 knockdown decreased cell viability, and improved cisplatin susceptibility, suggesting that this protein can regulate chemotherapy resistance in RCC.	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('regulate', 'Reg', (132, 140))	('NDUFA4L2', 'Gene', '56901', (15, 23))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('decreased', 'NegReg', (34, 43))	('cisplatin susceptibility', 'MPA', (73, 97))	('chemotherapy resistance', 'MPA', (141, 164))	('NDUFA4L2', 'Gene', (15, 23))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('RCC', 'Disease', (168, 171))	('improved', 'PosReg', (64, 72))	('knockdown', 'Var', (24, 33))	('cell viability', 'CPA', (44, 58))
136091	30538212	Moreover, NDUFA4L2 silencing led to an inhibition of the autophagic machine, increased mitochondrial mass, and induced an overproduction of ROS, especially in hypoxic conditions.	('NDUFA4L2', 'Gene', (10, 18))	('ROS', 'Chemical', 'MESH:D017382', (140, 143))	('increased mitochondrial mass', 'Phenotype', 'HP:0040014', (77, 105))	('ROS', 'Protein', (140, 143))	('silencing', 'Var', (19, 28))	('hypoxic conditions', 'Disease', (159, 177))	('inhibition', 'NegReg', (39, 49))	('increased', 'PosReg', (77, 86))	('mitochondrial mass', 'CPA', (87, 105))	('NDUFA4L2', 'Gene', '56901', (10, 18))	('hypoxic conditions', 'Disease', 'MESH:D009135', (159, 177))	('overproduction', 'PosReg', (122, 136))	('autophagic machine', 'CPA', (57, 75))
136093	30538212	In accordance with these findings, renal cancer cells treated with siNDUFA4L2, exhibited increased levels of mitochondrial DNA, and increased fluorescence intensity of mitochondrial dye MitoTracker.	('levels of mitochondrial DNA', 'MPA', (99, 126))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('109', '126'))	('renal cancer', 'Disease', (35, 47))	('Mito', 'Species', '262676', (186, 190))	('siNDUFA4L2', 'Var', (67, 77))	('renal cancer', 'Phenotype', 'HP:0009726', (35, 47))	('increased', 'PosReg', (132, 141))	('renal cancer', 'Disease', 'MESH:D007680', (35, 47))	('siNDUFA4L2', 'Chemical', '-', (67, 77))	('increased', 'PosReg', (89, 98))
136123	30538212	After transfection, normal and tumor renal cells were incubated for 24h and 72h at 37 C in 5% CO2 and used for total RNA extraction, immunofluorescence, wound healing and cell viability assays, respectively.	('CO2', 'Chemical', '-', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('transfection', 'Var', (6, 18))	('2h', 'Chemical', 'MESH:D003903', (77, 79))	('tumor', 'Disease', (31, 36))	('RNA', 'cellular_component', 'GO:0005562', ('117', '120'))	('wound healing', 'biological_process', 'GO:0042060', ('153', '166'))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
136188	30158581	Firstly, we showed that RASAL2 was frequently epigenetically silenced in RCC, and its loss was negatively correlated with overall survival of RCC patients.	('RASAL2', 'Gene', (24, 30))	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('loss', 'NegReg', (86, 90))	('RCC', 'Disease', (73, 76))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('epigenetically silenced', 'Var', (46, 69))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('negatively', 'NegReg', (95, 105))	('patients', 'Species', '9606', (146, 154))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
136190	30158581	Mechanistically, we identified that RASAL2 could activate GSK3beta by reducing Ser9 phosphorylation and subsequently decrease the expression of c-FOS and vascular endothelial growth factor A (VEGFA).	('GSK3beta', 'Protein', (58, 66))	('expression', 'MPA', (130, 140))	('Ser9 phosphorylation', 'MPA', (79, 99))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('154', '188'))	('activate', 'PosReg', (49, 57))	('GSK', 'molecular_function', 'GO:0050321', ('58', '61'))	('c-FOS', 'Gene', '2353', (144, 149))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('RASAL2', 'Var', (36, 42))	('vascular endothelial growth factor A', 'Gene', '7422', (154, 190))	('reducing', 'NegReg', (70, 78))	('Ser', 'cellular_component', 'GO:0005790', ('79', '82'))	('c-FOS', 'Gene', (144, 149))	('decrease', 'NegReg', (117, 125))	('vascular endothelial growth factor A', 'Gene', (154, 190))	('Ser9', 'Chemical', '-', (79, 83))
136191	30158581	Interruption of the p-GSK3beta/c-FOS pathway with the specific inhibitor or small interfering RNA could reverse the expression of VEGFA, which may provide a new insight to prevent RCC from resistance to antivascular therapy.	('c-FOS', 'Gene', (31, 36))	('expression', 'MPA', (116, 126))	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('RCC', 'Disease', (180, 183))	('Interruption', 'Var', (0, 12))	('RCC', 'Phenotype', 'HP:0005584', (180, 183))	('GSK', 'molecular_function', 'GO:0050321', ('22', '25'))	('c-FOS', 'Gene', '2353', (31, 36))	('RNA', 'cellular_component', 'GO:0005562', ('94', '97'))	('VEGFA', 'Gene', (130, 135))
136214	30158581	Moreover, RASAL2 hypermethylation was associated with higher stages and grades in RCC patients (Figure S1D).	('higher', 'PosReg', (54, 60))	('grades', 'CPA', (72, 78))	('RASAL2', 'Gene', (10, 16))	('stages', 'CPA', (61, 67))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('hypermethylation', 'Var', (17, 33))	('patients', 'Species', '9606', (86, 94))
136217	30158581	Indeed, we found that RASAL2 mRNA significantly increased in OSRC-2 cells treated with 5-Aza (Figure S1F).	('increased', 'PosReg', (48, 57))	('mRNA', 'MPA', (29, 33))	('5-Aza', 'Chemical', 'MESH:D001374', (87, 92))	('5-Aza', 'Var', (87, 92))	('OSRC-2', 'CellLine', 'CVCL:1901', (61, 67))	('RASAL2', 'Gene', (22, 28))
136218	30158581	These results suggested that DNA promoter methylation might contribute to the downregulation of RASAL2 in RCC.	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('downregulation', 'NegReg', (78, 92))	('RASAL2', 'Gene', (96, 102))	('methylation', 'biological_process', 'GO:0032259', ('42', '53'))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('methylation', 'Var', (42, 53))	('RCC', 'Disease', 'MESH:C538614', (106, 109))
136219	30158581	To examine the effect of RASAL2 on RCC angiogenesis, we successfully established the stable ACHN sublines with endogenous RASAL2 knockdown (KD) and 786O sublines with ectopic RASAL2 overexpression (Fig.	('RCC', 'Disease', (35, 38))	('angiogenesis', 'biological_process', 'GO:0001525', ('39', '51'))	('knockdown', 'Var', (129, 138))	('overexpression', 'PosReg', (182, 196))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
136228	30158581	Since VHL mutations occurred in 60-70% ccRCC cases and hypoxia-inducible factor (HIF) activated by VHL mutations could induce VEGFA expression for RCC angiogenesis, we explored the association between RASAL2 and VHL status.	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('mutations', 'Var', (103, 112))	('VHL', 'Gene', '7428', (212, 215))	('VHL', 'Gene', (99, 102))	('hypoxia', 'Disease', 'MESH:D000860', (55, 62))	('angiogenesis', 'biological_process', 'GO:0001525', ('151', '163'))	('VHL', 'Gene', '7428', (99, 102))	('VHL', 'Gene', (6, 9))	('VEGFA expression', 'Protein', (126, 142))	('RCC', 'Disease', (147, 150))	('VHL', 'Gene', (212, 215))	('VHL', 'Gene', '7428', (6, 9))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('hypoxia', 'Disease', (55, 62))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('RCC', 'Disease', (41, 44))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('induce', 'Reg', (119, 125))
136229	30158581	Based on the analyses of VHL gene mutation data in RCC patients from TCGA database, we found a slight significant difference in terms of RASAL2 mRNA expression between VHL wild-type and mutation patients, whereas there was no significant difference in different mutation subtypes or mutation sublocations (Figs.	('VHL', 'Gene', '7428', (25, 28))	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('mutation', 'Var', (34, 42))	('VHL', 'Gene', (168, 171))	('VHL', 'Gene', (25, 28))	('RASAL2 mRNA expression', 'MPA', (137, 159))	('VHL', 'Gene', '7428', (168, 171))	('patients', 'Species', '9606', (195, 203))	('patients', 'Species', '9606', (55, 63))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('mutation', 'Var', (186, 194))	('RCC', 'Disease', (51, 54))
136230	30158581	Moreover, HIF-1alpha level was detected with no difference between 786O/NC and 786O/RASAL2 sublines (Figure S4A).	('HIF-1alpha', 'Gene', '3091', (10, 20))	('HIF-1alpha', 'Gene', (10, 20))	('786O/NC', 'Var', (67, 74))	('786O/RASAL2', 'Var', (79, 90))
136237	30158581	Indeed, wnt pathway inhibitor XAV-939 could abolish the elevation of c-FOS and VEGFA after RASAL2-KD in ACHN cells (Fig.	('RASAL2-KD', 'Var', (91, 100))	('XAV-939', 'Chemical', 'MESH:C544261', (30, 37))	('c-FOS', 'Gene', '2353', (69, 74))	('abolish', 'NegReg', (44, 51))	('elevation', 'PosReg', (56, 65))	('VEGFA', 'Protein', (79, 84))	('c-FOS', 'Gene', (69, 74))
136238	30158581	Consistently, the downregulation of c-FOS and VEGFA were rescued by GSK3beta kinase inhibitor CT99021 in 786O/RASAL2 sublines or OSRC-2/RASAL2 sublines (Fig.	('CT99021', 'Var', (94, 101))	('GSK', 'molecular_function', 'GO:0050321', ('68', '71'))	('c-FOS', 'Gene', '2353', (36, 41))	('VEGFA', 'Protein', (46, 51))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('77', '93'))	('c-FOS', 'Gene', (36, 41))	('OSRC-2', 'CellLine', 'CVCL:1901', (129, 135))	('downregulation', 'NegReg', (18, 32))
136260	30158581	However, in hepatocellular carcinoma, RASAL2 promoter was hypomethylated with an elevated expression of RASAL2.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('RASAL2', 'Gene', (38, 44))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (12, 36))	('RASAL2', 'Gene', (104, 110))	('elevated', 'PosReg', (81, 89))	('hepatocellular carcinoma', 'Disease', (12, 36))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (12, 36))	('expression', 'MPA', (90, 100))	('hypomethylated', 'Var', (58, 72))
136262	30158581	Similarly, DAB2IP, another member of the RAS-GAP family, was also downregulated due to DNA promotor hypermethylation in RCC.	('RAS-GAP', 'Gene', (41, 48))	('hypermethylation', 'Var', (100, 116))	('DAB2IP', 'Gene', '153090', (11, 17))	('RAS-GAP', 'Gene', '5921', (41, 48))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('downregulated', 'NegReg', (66, 79))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('DAB2IP', 'Gene', (11, 17))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('DNA', 'MPA', (87, 90))
136268	30158581	In ccRCC, there was another important molecular mechanism of angiogenesis, in which the inactivation of the VHL gene could result in the failure of HIF protein degradation and then induce VEGF expression.	('protein degradation', 'biological_process', 'GO:0030163', ('152', '171'))	('VHL', 'Gene', '7428', (108, 111))	('induce', 'Reg', (181, 187))	('HIF protein degradation', 'Disease', (148, 171))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('failure', 'NegReg', (137, 144))	('VEGF', 'Gene', (188, 192))	('VEGF', 'Gene', '7422', (188, 192))	('HIF protein degradation', 'Disease', 'MESH:D055959', (148, 171))	('angiogenesis', 'biological_process', 'GO:0001525', ('61', '73'))	('inactivation', 'Var', (88, 100))	('VHL', 'Gene', (108, 111))
136276	30158581	Taken together, the findings in our study revealed a novel mechanism of RCC angiogenesis contributing to progression and metastasis, in which loss of RASAL2 could facilitate RCC angiogenesis.	('angiogenesis', 'biological_process', 'GO:0001525', ('76', '88'))	('RASAL2', 'Gene', (150, 156))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('loss', 'Var', (142, 146))	('facilitate', 'PosReg', (163, 173))	('RCC', 'Disease', (174, 177))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('angiogenesis', 'biological_process', 'GO:0001525', ('178', '190'))	('RCC', 'Disease', 'MESH:C538614', (174, 177))
136283	30158581	The antibodies used were as follows: RASAL2 (Rabbit, GeneTex, Inc., Irvine, CA, USA), GAPDH (mouse, KangChen Bio-tech, Shanghai, China), VEGFA (Rabbit, abcam, Inc., Cambridge, Britain), c-FOS (Rabbit, Santa Cruz Biotechnology, Dallas, TX, USA), GSK3beta (Rabbit, Cell Signaling Technology, Danvers, MA, USA), p-GSK3betaSer9 (Rabbit, Cell Signaling Technology, Danvers, MA, USA).	('GSK', 'molecular_function', 'GO:0050321', ('311', '314'))	('c-FOS', 'Gene', (186, 191))	('Rabbit', 'Species', '9986', (193, 199))	('mouse', 'Species', '10090', (93, 98))	('GSK', 'molecular_function', 'GO:0050321', ('245', '248'))	('Rabbit', 'Species', '9986', (325, 331))	('Signaling', 'biological_process', 'GO:0023052', ('338', '347'))	('Signaling', 'biological_process', 'GO:0023052', ('268', '277'))	('Rabbit', 'Species', '9986', (144, 150))	('c-FOS', 'Gene', '2353', (186, 191))	('Rabbit', 'Species', '9986', (45, 51))	('Rabbit', 'Species', '9986', (255, 261))	('p-GSK3betaSer9', 'Var', (309, 323))
136311	33946584	High circEHD2 and low circNETO2 levels were an independent predictor of a shortened progression-free survival, cancer-specific survival, and overall survival in patients with ccRCC undergoing nephrectomy.	('circNETO2', 'Chemical', '-', (22, 31))	('circNETO2 levels', 'MPA', (22, 38))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('High', 'Var', (0, 4))	('RCC', 'Disease', (177, 180))	('overall survival', 'CPA', (141, 157))	('RCC', 'Phenotype', 'HP:0005584', (177, 180))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (175, 180))	('patients', 'Species', '9606', (161, 169))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('progression-free survival', 'CPA', (84, 109))	('shortened', 'NegReg', (74, 83))	('low', 'NegReg', (18, 21))
136354	33946584	High circEHD2 levels were associated with a significantly shortened progression-free survival (p = 0.002) and cancer-specific survival (p = 0.032).	('cancer', 'Disease', (110, 116))	('High', 'Var', (0, 4))	('shortened', 'NegReg', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('progression-free survival', 'CPA', (68, 93))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
136356	33946584	Furthermore, univariate and multivariate Cox regression analyses demonstrated that low circNETO2 and high circEHD2 were correlated with progression-free survival (see Table 2), overall-survival (see Table 3), and cancer-specific (see Table 4) survival.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('overall-survival', 'CPA', (177, 193))	('progression-free survival', 'CPA', (136, 161))	('high circEHD2', 'Var', (101, 114))	('circNETO2', 'Gene', (87, 96))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('circNETO2', 'Chemical', '-', (87, 96))	('cancer', 'Disease', (213, 219))	('low', 'NegReg', (83, 86))
136366	33946584	Furthermore, high circEHD2 expression was an independent predictor of progression-free and cancer-specific survival in patients undergoing radical or partial nephrectomy.	('high', 'Var', (13, 17))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('patients', 'Species', '9606', (119, 127))	('expression', 'MPA', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('progression-free', 'CPA', (70, 86))	('circEHD2', 'Gene', (18, 26))
136379	33946584	It was shown that circEGLN3 acts as an oncogene through upregulating IRF7 via sponging miR-1299 in ccRCC.	('IRF7', 'Gene', (69, 73))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('IRF7', 'Gene', '3665', (69, 73))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('circEGLN3', 'Gene', (18, 27))	('RCC', 'Disease', (101, 104))	('circEGLN3', 'Gene', '112399', (18, 27))	('upregulating', 'PosReg', (56, 68))	('miR-1299', 'Gene', (87, 95))	('sponging', 'Var', (78, 86))	('miR-1299', 'Gene', '100302167', (87, 95))
136382	33946584	Furthermore, survival analyses demonstrated that circNETO2 was a predictor of progression-free, cancer-specific and overall survival independent from clinicopathological parameters.	('progression-free', 'CPA', (78, 94))	('overall survival', 'CPA', (116, 132))	('circNETO2', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('circNETO2', 'Chemical', '-', (49, 58))	('cancer', 'Disease', (96, 102))
136385	33946584	Although we could not confirm a diagnostic relevance for any of these circRNA, they have been associated with oncogenic functions in cancer in former studies: circSCARB1 promoted RCC progression by sequestering miR-510-5p and indirectly up-regulating SDC3 expression, and circCOL5A1 acted as a miR-1224-5p sponge, thereby activating CREB1 expression and promoting cellular proliferation in bladder cancer.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (398, 404))	('cellular proliferation', 'CPA', (364, 386))	('SDC3', 'Gene', '9672', (251, 255))	('RCC', 'Phenotype', 'HP:0005584', (179, 182))	('CREB1', 'Gene', (333, 338))	('expression', 'MPA', (256, 266))	('RCC', 'Disease', (179, 182))	('sequestering', 'biological_process', 'GO:0051235', ('198', '210'))	('cancer', 'Phenotype', 'HP:0002664', (398, 404))	('bladder cancer', 'Disease', 'MESH:D001749', (390, 404))	('bladder cancer', 'Disease', (390, 404))	('promoting', 'PosReg', (354, 363))	('miR-1224', 'Gene', '100187716', (294, 302))	('CREB1', 'Gene', '1385', (333, 338))	('miR-510', 'Gene', (211, 218))	('activating', 'PosReg', (322, 332))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('bladder cancer', 'Phenotype', 'HP:0009725', (390, 404))	('miR-510', 'Gene', '574515', (211, 218))	('cancer', 'Disease', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (398, 404))	('up-regulating', 'PosReg', (237, 250))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('promoted', 'PosReg', (170, 178))	('circSCARB1', 'Var', (159, 169))	('expression', 'MPA', (339, 349))	('SDC3', 'Gene', (251, 255))	('miR-1224', 'Gene', (294, 302))
136386	33946584	circSOD2 expression enhanced cancer cell growth, cell migration, cell cycle progression, and in vivo tumor growth in hepatocellular cancer; circSOD2 inhibited miR-502-5p expression, thereby upregulating DNMT3A expression.	('cell migration', 'biological_process', 'GO:0016477', ('49', '63'))	('cell growth', 'biological_process', 'GO:0016049', ('36', '47'))	('DNMT3A', 'Gene', (203, 209))	('expression', 'MPA', (210, 220))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cell cycle', 'biological_process', 'GO:0007049', ('65', '75'))	('miR-502-5p expression', 'MPA', (159, 180))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('circSOD2', 'Var', (140, 148))	('tumor growth in hepatocellular cancer', 'Disease', (101, 138))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (117, 138))	('cancer', 'Disease', (29, 35))	('cell migration', 'CPA', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('DNMT3A', 'Gene', '1788', (203, 209))	('upregulating', 'PosReg', (190, 202))	('cancer', 'Disease', (132, 138))	('cell cycle progression', 'CPA', (65, 87))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('inhibited', 'NegReg', (149, 158))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('tumor growth in hepatocellular cancer', 'Disease', 'MESH:D006528', (101, 138))
136390	33946584	In fact, EIF4A3 induced circMMP9 expression in glioblastoma and circSEPT9 in breast cancer cells.	('EIF4A3', 'Gene', '9775', (9, 15))	('induced', 'Reg', (16, 23))	('breast cancer', 'Disease', (77, 90))	('circMMP9 expression', 'MPA', (24, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('EIF4', 'cellular_component', 'GO:0008304', ('9', '13'))	('glioblastoma', 'Disease', (47, 59))	('glioblastoma', 'Disease', 'MESH:D005909', (47, 59))	('circSEPT9', 'Var', (64, 73))	('EIF4A3', 'Gene', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('glioblastoma', 'Phenotype', 'HP:0012174', (47, 59))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
136402	33031058	SYNE1 mutation may enhance the response to immune checkpoint blockade therapy in clear cell renal cell carcinoma patients As one of the 10 most common cancers in men, the incidence of renal cell carcinoma (RCC) has been increasing in recent years.	('SYNE1', 'Gene', (0, 5))	('men', 'Species', '9606', (162, 165))	('clear cell renal cell carcinoma', 'Disease', (81, 112))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (92, 112))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (184, 204))	('SYNE1', 'Gene', '23345', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (81, 112))	('response to immune checkpoint blockade therapy', 'MPA', (31, 77))	('cancers', 'Disease', (151, 158))	('renal cell carcinoma', 'Disease', (184, 204))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (184, 204))	('RCC', 'Phenotype', 'HP:0005584', (206, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('enhance', 'PosReg', (19, 26))	('RCC', 'Disease', (206, 209))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (92, 112))	('mutation', 'Var', (6, 14))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (81, 112))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('RCC', 'Disease', 'MESH:C538614', (206, 209))
136408	33031058	To further investigate the relationship between SYNE1 mutation and the immune system, we used Gene Set Enrichment Analysis and the CIBERSORT algorithm.	('men', 'Species', '9606', (109, 112))	('SYNE1', 'Gene', (48, 53))	('mutation', 'Var', (54, 62))	('SYNE1', 'Gene', '23345', (48, 53))
136409	33031058	They showed that SYNE1 mutations correlate with immune system pathways and immune cell tumor infiltration.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('immune', 'CPA', (48, 54))	('SYNE1', 'Gene', (17, 22))	('tumor', 'Disease', (87, 92))	('mutations', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('SYNE1', 'Gene', '23345', (17, 22))
136410	33031058	We also found that SYNE1 mutation correlated with a better response to ICB therapy.	('mutation', 'Var', (25, 33))	('SYNE1', 'Gene', '23345', (19, 24))	('SYNE1', 'Gene', (19, 24))	('better', 'PosReg', (52, 58))
136411	33031058	Thus, mutation of SYNE1 correlates with a higher TMB and a poorer outcome in ccRCC, but may mediate better responses to ICB therapy.	('SYNE1', 'Gene', '23345', (18, 23))	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('SYNE1', 'Gene', (18, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('mutation', 'Var', (6, 14))	('TMB', 'Chemical', '-', (49, 52))	('better', 'PosReg', (100, 106))	('higher', 'PosReg', (42, 48))	('TMB', 'MPA', (49, 52))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
136425	33031058	The frequently mutated gene, SYNE1, encodes a series of spectrin structural proteins, which play key roles in cytoskeletal, nuclear and vesicular anchoring, and its mutation is associated with a form of cerebellar ataxia.	('spectrin', 'cellular_component', 'GO:0008091', ('56', '64'))	('cerebellar ataxia', 'Disease', 'MESH:D002524', (203, 220))	('cerebellar ataxia', 'Phenotype', 'HP:0001251', (203, 220))	('SYNE1', 'Gene', '23345', (29, 34))	('mutation', 'Var', (165, 173))	('cerebellar ataxia', 'Disease', (203, 220))	('SYNE1', 'Gene', (29, 34))	('associated with', 'Reg', (177, 192))	('anchoring', 'molecular_function', 'GO:0043495', ('146', '155'))
136426	33031058	In addition, recent evidence suggests changes in SYNE1 expression levels, somatic mutations, and single nucleotide polymorphisms are related to the occurrence and development of lung cancer, oral cancer, hepatocellular carcinoma, and gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (234, 248))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('SYNE1', 'Gene', (49, 54))	('related', 'Reg', (133, 140))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (204, 228))	('men', 'Species', '9606', (170, 173))	('SYNE1', 'Gene', '23345', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('oral cancer', 'Disease', 'MESH:D009369', (191, 202))	('gastric cancer', 'Phenotype', 'HP:0012126', (234, 248))	('expression levels', 'MPA', (55, 72))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (204, 228))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('changes', 'Reg', (38, 45))	('lung cancer', 'Disease', (178, 189))	('single nucleotide polymorphisms', 'Var', (97, 128))	('hepatocellular carcinoma', 'Disease', (204, 228))	('oral cancer', 'Disease', (191, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('gastric cancer', 'Disease', (234, 248))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('mutations', 'Var', (82, 91))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))
136429	33031058	We also compared immune cell infiltration between those with SYNE1 mutation type (mt) and those with wild type (wt), and evaluated the utility of SYNE1 mutation as a ICB biomarker using the tumor immune dysfunction and exclusion (TIDE) algorithm.	('mutation', 'Var', (67, 75))	('SYNE1', 'Gene', '23345', (146, 151))	('tumor immune dysfunction', 'Disease', 'MESH:D007154', (190, 214))	('SYNE1', 'Gene', (146, 151))	('tumor immune dysfunction', 'Disease', (190, 214))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('SYNE1', 'Gene', '23345', (61, 66))	('SYNE1', 'Gene', (61, 66))	('mutation', 'Var', (152, 160))
136432	33031058	The genes and percentages of patients carrying the mutations are as follows: VHL (26%), PBRM1 (18%), TTN (15%), SETD2 (8%), MTOR (7%), BAP1 (6%), MUC16 (6%), DNAH9 (5%), LRP2 (4%), SPEN (4%), HMCN1 (4%), CSMD3 (3%), KMT2C (3%), ANK3 (3%), DNAH2 (3%), DST(3%), FBN2 (3%), RYR3 (3%), MARCA4 (3%), AKAP9 (3%), ATM (3%), BRCA2 (3%), ERBB4 (3%), FLG (3%), KDM5C (3%), MACF1 (3%), PCLO (3%), ROS1 (3%), SYNE1 (3%), USH2A (3%).	('mutations', 'Var', (51, 60))	('USH2A', 'Gene', '7399', (409, 414))	('SPEN', 'Gene', '23013', (181, 185))	('PBRM1', 'Gene', '55193', (88, 93))	('MACF1', 'Gene', '23499', (363, 368))	('HMCN1', 'Gene', '83872', (192, 197))	('DNAH2', 'Gene', (239, 244))	('VHL', 'Gene', (77, 80))	('BAP1', 'Gene', '8314', (135, 139))	('CSMD3', 'Gene', '114788', (204, 209))	('RYR', 'cellular_component', 'GO:1990425', ('271', '274'))	('SYNE1', 'Gene', (397, 402))	('KMT2C', 'Gene', '58508', (216, 221))	('KMT2C', 'Gene', (216, 221))	('FLG', 'Gene', '2312', (341, 344))	('BRCA2', 'Gene', (317, 322))	('DNAH9', 'Gene', (158, 163))	('LRP2', 'Gene', (170, 174))	('FBN2', 'Gene', (260, 264))	('MUC16', 'Gene', (146, 151))	('patients', 'Species', '9606', (29, 37))	('PBRM1', 'Gene', (88, 93))	('KDM5C', 'Gene', '8242', (351, 356))	('MACF1', 'Gene', (363, 368))	('DNAH2', 'Gene', '146754', (239, 244))	('ATM', 'Gene', '472', (307, 310))	('RYR3', 'Gene', '6263', (271, 275))	('CSMD3', 'Gene', (204, 209))	('ANK3', 'Gene', (228, 232))	('SETD2', 'Gene', (112, 117))	('SYNE1', 'Gene', '23345', (397, 402))	('VHL', 'Gene', '7428', (77, 80))	('BAP1', 'Gene', (135, 139))	('ROS1', 'Gene', (386, 390))	('SPEN', 'Gene', (181, 185))	('FBN2', 'Gene', '2201', (260, 264))	('DNAH9', 'Gene', '1770', (158, 163))	('TTN', 'Gene', '7273', (101, 104))	('AKAP9', 'Gene', '10142', (295, 300))	('ANK3', 'Gene', '288', (228, 232))	('AKAP9', 'Gene', (295, 300))	('BRCA2', 'Gene', '675', (317, 322))	('SETD2', 'Gene', '29072', (112, 117))	('HMCN1', 'Gene', (192, 197))	('RYR3', 'Gene', (271, 275))	('TTN', 'Gene', (101, 104))	('USH2A', 'Gene', (409, 414))	('MTOR', 'Gene', (124, 128))	('KDM5C', 'Gene', (351, 356))	('ATM', 'Gene', (307, 310))	('ERBB4', 'Gene', '2066', (329, 334))	('LRP2', 'Gene', '4036', (170, 174))	('MTOR', 'Gene', '2475', (124, 128))	('MUC16', 'Gene', '94025', (146, 151))	('ERBB4', 'Gene', (329, 334))	('FLG', 'Gene', (341, 344))	('ROS1', 'Gene', '6098', (386, 390))
136438	33031058	We detected the SYNE1 mutation in a Venn diagram at the intersection of the top 30 somatic mutations, survival-related mutations, and TMB-related mutations in ccRCC (Figure 2A).	('TMB', 'Chemical', '-', (134, 137))	('mutation', 'Var', (22, 30))	('ccRCC', 'Phenotype', 'HP:0006770', (159, 164))	('SYNE1', 'Gene', '23345', (16, 21))	('RCC', 'Disease', (161, 164))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('SYNE1', 'Gene', (16, 21))	('RCC', 'Disease', 'MESH:C538614', (161, 164))
136439	33031058	Patients with SYNE1 mutation (mt) had poorer survival outcomes, irrespective of DFS (p<0.0001) or OS (p=0.0017) status (Figure 2B).	('SYNE1', 'Gene', (14, 19))	('poorer', 'NegReg', (38, 44))	('mutation', 'Var', (20, 28))	('Patients', 'Species', '9606', (0, 8))	('survival', 'MPA', (45, 53))	('SYNE1', 'Gene', '23345', (14, 19))
136440	33031058	In addition, a higher TMB correlated with SYNE1 mutation (p<0.0001) (Figure 2C).	('higher', 'PosReg', (15, 21))	('SYNE1', 'Gene', (42, 47))	('TMB', 'MPA', (22, 25))	('mutation', 'Var', (48, 56))	('TMB', 'Chemical', '-', (22, 25))	('SYNE1', 'Gene', '23345', (42, 47))
136442	33031058	COX survival analysis revealed that SYNE1 mutation was a risk factor affecting prognosis (HR=0.978; 95% CI, 1.156-6.114; P=0.021).	('SYNE1', 'Gene', (36, 41))	('mutation', 'Var', (42, 50))	('prognosis', 'MPA', (79, 88))	('SYNE1', 'Gene', '23345', (36, 41))
136443	33031058	In a multivariate analysis, however, SYNE1 mutation did not remain a significant factor affecting prognosis (Table 1), suggesting SYNE1 mutation may not be an independent risk factor affecting prognosis in ccRCC patients.	('RCC', 'Phenotype', 'HP:0005584', (208, 211))	('mutation', 'Var', (136, 144))	('SYNE1', 'Gene', '23345', (37, 42))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('patients', 'Species', '9606', (212, 220))	('RCC', 'Disease', (208, 211))	('ccRCC', 'Phenotype', 'HP:0006770', (206, 211))	('SYNE1', 'Gene', '23345', (130, 135))	('SYNE1', 'Gene', (37, 42))	('SYNE1', 'Gene', (130, 135))
136445	33031058	To further compare the differential profiles of immune fractions between SYNE1 mt and wt groups, we used the CIBERSORT algorithm to evaluate the association between SYNE1 mutation and tumor-infiltrating immune cells.	('SYNE1', 'Gene', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('mutation', 'Var', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('SYNE1', 'Gene', '23345', (73, 78))	('SYNE1', 'Gene', (73, 78))	('tumor', 'Disease', (184, 189))	('association', 'Interaction', (145, 156))	('SYNE1', 'Gene', '23345', (165, 170))
136449	33031058	To evaluate the ability of SYNE1 mutation to served as a biomarker predictive of the clinical response to ICB therapy, we analyzed datasets from patients with stage 4 ccRCC using the TIDE algorithm.	('patients', 'Species', '9606', (145, 153))	('SYNE1', 'Gene', '23345', (27, 32))	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('mutation', 'Var', (33, 41))	('SYNE1', 'Gene', (27, 32))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('ccRCC', 'Phenotype', 'HP:0006770', (167, 172))	('RCC', 'Disease', (169, 172))
136450	33031058	To evaluate its utility as a biomarker, we compared SYNE1 mutation to other existing biomarkers.	('mutation', 'Var', (58, 66))	('SYNE1', 'Gene', '23345', (52, 57))	('SYNE1', 'Gene', (52, 57))
136457	33031058	We found that SYNE1 was frequently mutated in TCGA cohorts.	('SYNE1', 'Gene', (14, 19))	('mutated', 'Var', (35, 42))	('SYNE1', 'Gene', '23345', (14, 19))
136458	33031058	In contrast to outcomes in patients with other tumors, where higher TMBs correlated with more favorable clinical prognoses, SYNE1 mutation was reportedly associated with higher TMB and poorer clinical prognoses.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('higher', 'PosReg', (170, 176))	('SYNE1', 'Gene', '23345', (124, 129))	('TMB', 'MPA', (177, 180))	('mutation', 'Var', (130, 138))	('TMBs', 'Disease', (68, 72))	('SYNE1', 'Gene', (124, 129))	('TMB', 'Chemical', '-', (177, 180))	('patients', 'Species', '9606', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('TMB', 'Chemical', '-', (68, 71))	('TMBs', 'Disease', 'None', (68, 72))
136459	33031058	GSEA enrichment analysis showed that SYNE1 mutation correlates negatively with T cell activation and cytokine secretion, and correlates positively with neutrophil degranulation and T cell receptor (TCR) signaling.	('TCR', 'biological_process', 'GO:0006283', ('198', '201'))	('positively', 'Reg', (136, 146))	('T cell receptor', 'Gene', (181, 196))	('T cell receptor', 'Gene', '6962', (181, 196))	('neutrophil degranulation', 'MPA', (152, 176))	('TCR', 'Gene', '6962', (198, 201))	('T cell activation', 'biological_process', 'GO:0042110', ('79', '96'))	('mutation', 'Var', (43, 51))	('SYNE1', 'Gene', (37, 42))	('cytokine secretion', 'biological_process', 'GO:0050663', ('101', '119'))	('GSEA', 'Chemical', '-', (0, 4))	('cytokine secretion', 'MPA', (101, 119))	('T cell activation', 'MPA', (79, 96))	('SYNE1', 'Gene', '23345', (37, 42))	('signaling', 'biological_process', 'GO:0023052', ('203', '212'))	('TCR', 'Gene', (198, 201))	('neutrophil degranulation', 'biological_process', 'GO:0043312', ('152', '176'))	('negatively', 'NegReg', (63, 73))	('TCR', 'cellular_component', 'GO:0042101', ('198', '201'))	('men', 'Species', '9606', (11, 14))
136463	33031058	It is reported, however, that only 0.3%-1.3% of tumor gene mutations induce T cell responses via TCR signaling.	('tumor', 'Disease', (48, 53))	('TCR', 'Gene', (97, 100))	('induce', 'Reg', (69, 75))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))	('TCR', 'cellular_component', 'GO:0042101', ('97', '100'))	('TCR', 'biological_process', 'GO:0006283', ('97', '100'))	('TCR', 'Gene', '6962', (97, 100))	('T cell responses', 'CPA', (76, 92))	('mutations', 'Var', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
136464	33031058	Secondly, proteasome cleavage of mutation-containing protein can destroy TCR-recognized peptide epitopes.	('destroy', 'NegReg', (65, 72))	('cleavage', 'Var', (21, 29))	('TCR', 'Gene', (73, 76))	('TCR', 'cellular_component', 'GO:0042101', ('73', '76'))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('TCR', 'biological_process', 'GO:0006283', ('73', '76'))	('protein', 'Protein', (53, 60))	('TCR', 'Gene', '6962', (73, 76))	('proteasome', 'molecular_function', 'GO:0004299', ('10', '20'))	('proteasome', 'cellular_component', 'GO:0000502', ('10', '20'))
136465	33031058	Samples with SYNE1 mutations were correlated with signaling pathways involved in immune responses and alterations in the profiles of infiltrating immune cells.	('signaling pathways', 'Pathway', (50, 68))	('SYNE1', 'Gene', (13, 18))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('mutations', 'Var', (19, 28))	('profiles of infiltrating immune cells', 'MPA', (121, 158))	('alterations', 'Reg', (102, 113))	('SYNE1', 'Gene', '23345', (13, 18))
136470	33031058	This may explain the results of our GSEA enrichment pathways analysis, which indicated that SYNE1 mutations correlate positively with TCR signaling but correlate negatively with T cell activation.	('T cell activation', 'CPA', (178, 195))	('TCR', 'cellular_component', 'GO:0042101', ('134', '137'))	('negatively', 'NegReg', (162, 172))	('TCR', 'Gene', '6962', (134, 137))	('T cell activation', 'biological_process', 'GO:0042110', ('178', '195'))	('TCR', 'Gene', (134, 137))	('GSEA', 'Chemical', '-', (36, 40))	('mutations', 'Var', (98, 107))	('SYNE1', 'Gene', '23345', (92, 97))	('TCR', 'biological_process', 'GO:0006283', ('134', '137'))	('men', 'Species', '9606', (47, 50))	('signaling', 'biological_process', 'GO:0023052', ('138', '147'))	('SYNE1', 'Gene', (92, 97))
136471	33031058	We evaluated the ability of SYNE1 mutation to serve as a biomarker.	('SYNE1', 'Gene', (28, 33))	('mutation', 'Var', (34, 42))	('SYNE1', 'Gene', '23345', (28, 33))
136473	33031058	And compared with existing biomarkers, SYNE1 mutation exhibited good prediction ability.	('SYNE1', 'Gene', '23345', (39, 44))	('mutation', 'Var', (45, 53))	('SYNE1', 'Gene', (39, 44))
136474	33031058	These findings suggest SYNE1 mutations may play a role in ICB therapy in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('SYNE1', 'Gene', '23345', (23, 28))	('mutations', 'Var', (29, 38))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('SYNE1', 'Gene', (23, 28))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))
136482	33031058	Gene expression data were downloaded from TCGA and divided into two groups based on SYNE1 mutation status.	('SYNE1', 'Gene', '23345', (84, 89))	('mutation', 'Var', (90, 98))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('SYNE1', 'Gene', (84, 89))
136484	33031058	The CIBERSORT algorithm was used to evaluate the fractions of 22 tumor-infiltrating lymphocyte subsets and were compared based on SYNE1 mutation status.	('tumor', 'Disease', (65, 70))	('mutation', 'Var', (136, 144))	('SYNE1', 'Gene', '23345', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('SYNE1', 'Gene', (130, 135))
136486	33031058	The Kaplan-Meier method was used to analyze the correlation between SYNE1 mutation, TMB and patient survival, and the log-rank test was used to compare survival curves.	('mutation', 'Var', (74, 82))	('patient', 'Species', '9606', (92, 99))	('SYNE1', 'Gene', (68, 73))	('SYNE1', 'Gene', '23345', (68, 73))	('TMB', 'Chemical', '-', (84, 87))
136492	32256811	Similar to patients with RCC, neoplastic tissue showed high levels of p65, one of the predominant subunits of NF-kappaB in ccRCC and of EGFR (protein and mRNA), as well as a decrease in the levels of NF-kappaB's main inhibitor, IkappaBalpha, resulting in a classic oncogenic combination.	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('levels', 'MPA', (190, 196))	('RCC', 'Disease', (25, 28))	('decrease', 'NegReg', (174, 182))	('RCC', 'Disease', (125, 128))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('oncogenic', 'Disease', (265, 274))	('p65', 'Var', (70, 73))	('neoplastic tissue', 'Phenotype', 'HP:0002664', (30, 47))	('NF-kappaB', 'Gene', '4790', (110, 119))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('NF-kappaB', 'Gene', '4790', (200, 209))	('patients', 'Species', '9606', (11, 19))	('NF-kappaB', 'Gene', (110, 119))	('EGFR', 'molecular_function', 'GO:0005006', ('136', '140'))	('NF-kappaB', 'Gene', (200, 209))
136514	32256811	However, dysregulation of EGFR has been associated with progressive fibrotic renal damage, polycystic renal disease and RCC.	('EGFR', 'Gene', (26, 30))	('renal disease', 'Phenotype', 'HP:0000112', (102, 115))	('polycystic renal disease', 'Phenotype', 'HP:0000113', (91, 115))	('EGFR', 'molecular_function', 'GO:0005006', ('26', '30'))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('fibrotic renal damage, polycystic renal disease', 'Disease', 'MESH:D007674', (68, 115))	('dysregulation', 'Var', (9, 22))	('associated', 'Reg', (40, 50))
136521	32256811	PK-6101 and PK 6102) and the peroxidase substrate kit DAB (cat.	('DAB', 'Chemical', 'MESH:C000469', (54, 57))	('PK-6101', 'Var', (0, 7))	('cat', 'molecular_function', 'GO:0004096', ('59', '62'))	('PK 6102', 'Var', (12, 19))	('rat', 'Species', '10116', (45, 48))
136532	32256811	Euthanasia was executed by carbon dioxide inhalation when rats showed signs of health deterioration such as loosing 20% of weight, or exhibiting prostration, mobility impairment and/or difficulty eating, urinating or defecating.	('mobility impairment', 'CPA', (158, 177))	('urinating', 'CPA', (204, 213))	('defecating', 'CPA', (217, 227))	('rats', 'Species', '10116', (58, 62))	('rat', 'Species', '10116', (150, 153))	('carbon dioxide', 'Chemical', 'MESH:D002245', (27, 41))	('rat', 'Species', '10116', (58, 61))	('loosing', 'Var', (108, 115))	('eating', 'biological_process', 'GO:0007631', ('196', '202'))	('rat', 'Species', '10116', (93, 96))
136581	32256811	Finally, the authors reported in a previous study that no primary tumors were developed in liver or lungs using the scheme of FeNTA-exposure followed in the present investigation; thus, in order to determine if the alterations observed in p65, IkappaBalpha and EGFR behavior were particularly associated with the kidney, and was not a generalized response, the status of these proteins was determined in hepatic and lung tissues, finding no differences between C and DF groups (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('FeNTA', 'Chemical', 'MESH:C020326', (126, 131))	('EGFR', 'Protein', (261, 265))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('EGFR', 'molecular_function', 'GO:0005006', ('261', '265'))	('rat', 'Species', '10116', (219, 222))	('associated', 'Reg', (293, 303))	('kidney', 'Disease', (313, 319))	('p65', 'Var', (239, 242))	('IkappaBalpha', 'Protein', (244, 256))
136585	32256811	The present study found an overexpression of p65 in FeNTA-induced renal tumors, in agreement with previous observations for NF-kappaB in rat kidney after long term of FeNTA-exposure and similar to what happens in patients' clear cell subtype tumors, as well as in some RCC human cell lines.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('p65', 'Var', (45, 48))	('tumors', 'Disease', (72, 78))	('patients', 'Species', '9606', (213, 221))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('overexpression', 'PosReg', (27, 41))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('renal tumors', 'Disease', (66, 78))	('FeNTA', 'Chemical', 'MESH:C020326', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('tumors', 'Disease', (242, 248))	('NF-kappaB', 'Gene', (124, 133))	('renal tumors', 'Disease', 'MESH:D007674', (66, 78))	('RCC', 'Disease', (269, 272))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('renal tumors', 'Phenotype', 'HP:0009726', (66, 78))	('rat', 'Species', '10116', (137, 140))	('NF-kappaB', 'Gene', '4790', (124, 133))	('human', 'Species', '9606', (273, 278))	('FeNTA', 'Chemical', 'MESH:C020326', (167, 172))	('RCC', 'Disease', 'MESH:C538614', (269, 272))
136593	32256811	This could be explained by p65 posttranslational modifications which have been reported to increase the affinity of the transcription factor for its target sequence or to promote its association with some co-activators and thus, IkappaBalpha might be playing other roles than regulating NF-kappaB.	('NF-kappaB', 'Gene', '4790', (287, 296))	('NF-kappaB', 'Gene', (287, 296))	('transcription factor', 'molecular_function', 'GO:0000981', ('120', '140'))	('promote', 'PosReg', (171, 178))	('increase', 'PosReg', (91, 99))	('p65', 'Gene', (27, 30))	('association', 'Interaction', (183, 194))	('posttranslational modifications', 'Var', (31, 62))	('transcription', 'biological_process', 'GO:0006351', ('120', '133'))	('affinity', 'Interaction', (104, 112))
136596	32256811	On the other hand, it has been established that, besides preventing NF-kappaB translocation into the nucleus, IkappaBalpha is able to retain p53 in the cytoplasm, thereby counteracting the tumor-suppressive functions of p53 in other neoplasias.	('p53', 'Gene', (220, 223))	('p53', 'Gene', '7157', (220, 223))	('tumor', 'Disease', (189, 194))	('p53', 'Gene', (141, 144))	('p53', 'Gene', '7157', (141, 144))	('neoplasias', 'Phenotype', 'HP:0002664', (233, 243))	('translocation into the nucleus', 'MPA', (78, 108))	('NF-kappaB', 'Gene', '4790', (68, 77))	('cytoplasm', 'cellular_component', 'GO:0005737', ('152', '161'))	('neoplasias', 'Disease', 'MESH:D009369', (233, 243))	('NF-kappaB', 'Gene', (68, 77))	('neoplasias', 'Disease', (233, 243))	('preventing', 'NegReg', (57, 67))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('IkappaBalpha', 'Var', (110, 122))	('nucleus', 'cellular_component', 'GO:0005634', ('101', '108'))
136599	32256811	It may therefore indicate that the carcinogen provokes IkappaBalpha renal accumulation due to the inhibition of the 26S proteasome, effect that has been demonstrated by Okada et al.	('26S proteasome', 'cellular_component', 'GO:0005837', ('116', '130'))	('26S proteasome', 'cellular_component', 'GO:0000504', ('116', '130'))	('rat', 'Species', '10116', (160, 163))	('inhibition', 'NegReg', (98, 108))	('proteasome', 'molecular_function', 'GO:0004299', ('120', '130'))	('26S proteasome', 'cellular_component', 'GO:0000502', ('116', '130'))	('26S proteasome', 'Protein', (116, 130))	('carcinogen', 'Var', (35, 45))	('IkappaBalpha renal accumulation', 'MPA', (55, 86))
136600	32256811	IkappaBalpha accretion may then be an early alteration that leads to promotion of the pro-carcinogenic mechanisms described above.	('promotion', 'PosReg', (69, 78))	('IkappaBalpha', 'Var', (0, 12))	('carcinogenic', 'Disease', 'MESH:D063646', (90, 102))	('carcinogenic', 'Disease', (90, 102))	('rat', 'Species', '10116', (48, 51))
136642	32123314	The most prevalent type, clear cell renal cell carcinoma (ccRCC), is characterized by genetic mutations in factors governing the hypoxia signaling pathway, resulting in metabolic dysregulation, heightened angiogenesis, intratumoral heterogeneity, and deleterious tumor microenvironmental (TME) crosstalk.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('hypoxia', 'Disease', (129, 136))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (36, 56))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('clear cell renal cell carcinoma', 'Disease', (25, 56))	('hypoxia', 'Disease', 'MESH:D000860', (129, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('signaling pathway', 'biological_process', 'GO:0007165', ('137', '154'))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('tumor', 'Disease', (263, 268))	('angiogenesis', 'CPA', (205, 217))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('mutations', 'Var', (94, 103))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (25, 56))	('tumor', 'Disease', (224, 229))	('heightened', 'PosReg', (194, 204))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('metabolic dysregulation', 'MPA', (169, 192))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('angiogenesis', 'biological_process', 'GO:0001525', ('205', '217'))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (25, 56))
136654	32123314	ccRCC is characterized by loss or mutation of the von Hippel Lindau (VHL) gene, which is responsible for encoding the oxygen sensing mediator protein VHL (pVHL).	('VHL', 'Gene', '7428', (150, 153))	('oxygen', 'Chemical', 'MESH:D010100', (118, 124))	('VHL', 'Gene', (69, 72))	('VHL', 'Gene', (156, 159))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('mutation', 'Var', (34, 42))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('VHL', 'Gene', '7428', (69, 72))	('von Hippel Lindau', 'Disease', (50, 67))	('pVHL', 'Gene', '7428', (155, 159))	('VHL', 'Gene', '7428', (156, 159))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('pVHL', 'Gene', (155, 159))	('loss', 'NegReg', (26, 30))	('protein VHL', 'Gene', (142, 153))	('von Hippel Lindau', 'Disease', 'MESH:D006623', (50, 67))	('VHL', 'Gene', (150, 153))	('protein VHL', 'Gene', '7428', (142, 153))
136660	32123314	Results indicated that deletion of chromosome 3p typically occurs decades before diagnosis, usually during childhood or adolescence; this event is the projected 'first-hit' to VHL and the initial driver of sporadic ccRCC types.	('VHL', 'Gene', (176, 179))	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('ccRCC', 'Phenotype', 'HP:0006770', (215, 220))	('RCC', 'Disease', (217, 220))	('VHL', 'Gene', '7428', (176, 179))	('deletion', 'Var', (23, 31))	('chromosome', 'cellular_component', 'GO:0005694', ('35', '45'))	('RCC', 'Phenotype', 'HP:0005584', (217, 220))
136661	32123314	A subsequent 'second-hit' occurs as the result of a somatic intragenic mutation or gene silencing event, in the remaining VHL allele.	('gene silencing', 'biological_process', 'GO:0016458', ('83', '97'))	('mutation', 'Var', (71, 79))	('gene silencing', 'NegReg', (83, 97))	('VHL', 'Gene', (122, 125))	('VHL', 'Gene', '7428', (122, 125))
136669	32123314	ccRCC biology can be subdivided based on recurrent mutations in the chromatin modifying co-driver genes (PBRM1, SETD2, BAP1, KDM5C, KDM6A, and MLL2) believed to contribute to intratumoral heterogeneity in ccRCC and serve as a potential etiology of drug resistance.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('drug resistance', 'biological_process', 'GO:0042493', ('248', '263'))	('mutations', 'Var', (51, 60))	('PBRM1', 'Gene', '55193', (105, 110))	('chromatin', 'cellular_component', 'GO:0000785', ('68', '77'))	('MLL2', 'Gene', (143, 147))	('KDM5C', 'Gene', (125, 130))	('BAP1', 'Gene', (119, 123))	('PBRM1', 'Gene', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('SETD2', 'Gene', (112, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('KDM6A', 'Gene', '7403', (132, 137))	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('RCC', 'Disease', (207, 210))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('drug resistance', 'Phenotype', 'HP:0020174', (248, 263))	('contribute', 'Reg', (161, 171))	('KDM5C', 'Gene', '8242', (125, 130))	('ccRCC', 'Phenotype', 'HP:0006770', (205, 210))	('MLL2', 'Gene', '9757', (143, 147))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('tumor', 'Disease', (180, 185))	('BAP1', 'Gene', '8314', (119, 123))	('KDM6A', 'Gene', (132, 137))	('drug resistance', 'biological_process', 'GO:0009315', ('248', '263'))
136671	32123314	Phylogenetic analyses of multiple unique regions within the same ccRCC tumor determined that only VHL mutations were similar and abundant across all regions and additional mutations in co-driver genes varied across these tumor regions.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('ccRCC tumor', 'Disease', (65, 76))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('VHL', 'Gene', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mutations', 'Var', (102, 111))	('VHL', 'Gene', '7428', (98, 101))	('ccRCC tumor', 'Disease', 'MESH:D009369', (65, 76))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
136680	32123314	Based on expression of the 34 gene signature, ClearCode34 classifies tumors as either indolent (ccA) or aggressive (ccB).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('indolent', 'Disease', (86, 94))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('ClearCode34', 'Var', (46, 57))	('aggressive', 'Disease', (104, 114))
136706	32123314	The COSMIC Cell Lines Project (CCLP) and Broad Novartis Cell Line Encyclopedia (CCLE) report a p.G104fs VHL frameshift deletion in 786-Os, and consistently, 786-O cells display increased HIF-2alpha and VEGF protein expression, making this cell line a workhorse for ccRCC research.	('protein', 'cellular_component', 'GO:0003675', ('207', '214'))	('VHL', 'Gene', '7428', (104, 107))	('p.G104fs', 'Mutation', 'rs869025628', (95, 103))	('VEGF', 'Gene', '7422', (202, 206))	('p.G104fs', 'Var', (95, 103))	('RCC', 'Disease', 'MESH:C538614', (267, 270))	('RCC', 'Disease', (267, 270))	('increased', 'PosReg', (177, 186))	('RCC', 'Phenotype', 'HP:0005584', (267, 270))	('ccRCC', 'Phenotype', 'HP:0006770', (265, 270))	('VEGF', 'Gene', (202, 206))	('VHL', 'Gene', (104, 107))	('expression', 'MPA', (215, 225))
136714	32123314	The second most highly cited RCC line, A-498, is classified as ccRCC based on VHL mutation status.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('mutation', 'Var', (82, 90))	('VHL', 'Gene', (78, 81))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('VHL', 'Gene', '7428', (78, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
136715	32123314	The CCLP and CCLE report p.G144fs*14 and p.V142fs VHL mutations, respectively.	('p.V142fs', 'Var', (41, 49))	('VHL', 'Gene', (50, 53))	('VHL', 'Gene', '7428', (50, 53))	('p.V142fs', 'Mutation', 'p.V142fsX', (41, 49))	('p.G144fs*14', 'Var', (25, 36))	('p.G144fs*14', 'Mutation', 'rs869025651', (25, 36))
136720	32123314	When HIF-1alpha and HIF-2alpha are both present and functional, VEGF is preferentially expressed by HIF-1alpha; however, when HIF-1alpha is deleted or nonfunctional, HIF-2alpha is upregulated and VEGF levels remain unchanged.	('upregulated', 'PosReg', (180, 191))	('VEGF', 'Gene', '7422', (196, 200))	('deleted', 'Var', (140, 147))	('VEGF', 'Gene', (64, 68))	('HIF-2alpha', 'MPA', (166, 176))	('VEGF', 'Gene', (196, 200))	('HIF-1alpha', 'Gene', (126, 136))	('VEGF', 'Gene', '7422', (64, 68))
136722	32123314	ACHN cells harbor a pRCC specific mutation in c-MET and do not have classical VHL mutations.	('c-MET', 'Gene', (46, 51))	('VHL', 'Gene', (78, 81))	('mutation', 'Var', (34, 42))	('pRCC', 'Gene', (20, 24))	('VHL', 'Gene', '7428', (78, 81))	('c-MET', 'Gene', '4233', (46, 51))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('pRCC', 'Gene', '5546', (20, 24))
136723	32123314	Though not representative of the ccRCC genetic phenotype, ACHN cells were exploited to demonstrate VHL deficient sensitization to mTOR inhibition by shRNA knockdown.	('RCC', 'Disease', (35, 38))	('knockdown', 'Var', (155, 164))	('deficient sensitization', 'Phenotype', 'HP:0002972', (103, 126))	('VHL deficient sensitization', 'Disease', 'MESH:D006623', (99, 126))	('sensitization', 'biological_process', 'GO:0046960', ('113', '126'))	('VHL deficient sensitization', 'Disease', (99, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('shRNA', 'Gene', (149, 154))	('mTOR', 'Gene', (130, 134))	('mTOR', 'Gene', '2475', (130, 134))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
136724	32123314	Increased uptake of the glucose tracer fluorodeoxyglucose (FDG) was decreased in VHL knockdown tumors treated with the mTOR inhibitor, CCI-779, compared to the vehicle treated control tumors by positron emission tomography (PET).	('decreased', 'NegReg', (68, 77))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('knockdown', 'Var', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('uptake', 'biological_process', 'GO:0098657', ('10', '16'))	('tumors', 'Disease', (95, 101))	('mTOR', 'Gene', (119, 123))	('uptake', 'biological_process', 'GO:0098739', ('10', '16'))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('VHL', 'Gene', (81, 84))	('glucose tracer fluorodeoxyglucose', 'Disease', (24, 57))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('mTOR', 'Gene', '2475', (119, 123))	('FDG', 'Chemical', 'MESH:D019788', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('VHL', 'Gene', '7428', (81, 84))	('tumors', 'Disease', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('CCI-779', 'Chemical', 'MESH:C401859', (135, 142))	('glucose tracer fluorodeoxyglucose', 'Disease', 'MESH:D044882', (24, 57))
136733	32123314	New developments in genetically engineered mouse models (GEMMs) have allowed for kidney-specific conditional knockout of Vhl with at least one other ccRCC associated co-driver gene.	('knockout', 'Var', (109, 117))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (151, 154))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('mouse', 'Species', '10090', (43, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (149, 154))	('Vhl', 'Gene', (121, 124))
136734	32123314	VHL bi-allelic inactivation is thought to occur during early stages of ccRCC development in humans with additional co-drivers leading to enhanced tumor progression at a later stage.	('enhanced', 'PosReg', (137, 145))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('bi-allelic inactivation', 'Var', (4, 27))	('RCC', 'Disease', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('tumor', 'Disease', (146, 151))	('humans', 'Species', '9606', (92, 98))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
136740	32123314	Xenograft models have been shown to maintain patient tumor histology, gene expression, DNA copy number alterations, mutagenic profiles, and general drug responsiveness.	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('DNA', 'Gene', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('gene expression', 'MPA', (70, 85))	('patient', 'Species', '9606', (45, 52))	('gene expression', 'biological_process', 'GO:0010467', ('70', '85'))	('tumor', 'Disease', (53, 58))	('copy number alterations', 'Var', (91, 114))
136748	32123314	Overall, changes in blood flow intensity provided valuable diagnostic and mechanistic information at earlier timepoints than previously assessed, thereby highlighting the potential for measuring functional tumor activity, in addition to gross anatomical quantification.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('changes', 'Var', (9, 16))	('tumor', 'Disease', (206, 211))	('blood flow intensity', 'MPA', (20, 40))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
136752	32123314	Patient tumors harboring BAP1 mutations have since been shown to associate with worse cancer specific survival and exhibit aggressive tumor features.	('aggressive tumor', 'Disease', 'MESH:D001523', (123, 139))	('BAP1', 'Gene', (25, 29))	('aggressive tumor', 'Disease', (123, 139))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('worse', 'NegReg', (80, 85))	('mutations', 'Var', (30, 39))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('BAP1', 'Gene', '8314', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('Patient', 'Species', '9606', (0, 7))	('cancer', 'Disease', (86, 92))
136755	32123314	Though Renca cells do not fully mimic the genetic profile observed in human ccRCC, Vhl deletion in Renca cells leads to HIF-1alpha stabilization and epithelial-mesenchymal transition (EMT), both of which classically define human ccRCC.	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('149', '182'))	('Renca', 'Phenotype', 'HP:0005584', (99, 104))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('deletion', 'Var', (87, 95))	('human', 'Species', '9606', (223, 228))	('HIF-1alpha', 'Protein', (120, 130))	('Vhl', 'Gene', (83, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (229, 234))	('RCC', 'Disease', (231, 234))	('RCC', 'Phenotype', 'HP:0005584', (231, 234))	('EMT', 'biological_process', 'GO:0001837', ('184', '187'))	('human', 'Species', '9606', (70, 75))	('Renca', 'Phenotype', 'HP:0005584', (7, 12))	('stabilization', 'NegReg', (131, 144))	('RCC', 'Disease', 'MESH:C538614', (231, 234))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('epithelial-mesenchymal transition', 'CPA', (149, 182))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))
136761	32123314	Reproducing common mutational events in genetically engineered mouse models (GEMMs) under kidney epithelial specific Cre drivers of deletion has proven challenging in ccRCC for several reasons (Figure 3).	('deletion', 'Var', (132, 140))	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('mouse', 'Species', '10090', (63, 68))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('ccRCC', 'Phenotype', 'HP:0006770', (167, 172))	('RCC', 'Disease', (169, 172))
136762	32123314	Contrary to human disease, Vhl heterozygosity has not been shown to predispose mice to ccRCC tumor development.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('ccRCC tumor', 'Disease', (87, 98))	('mice', 'Species', '10090', (79, 83))	('heterozygosity', 'Var', (31, 45))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('Vhl', 'Gene', (27, 30))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('human', 'Species', '9606', (12, 17))	('ccRCC tumor', 'Disease', 'MESH:D009369', (87, 98))
136764	32123314	In humans, an initial 'first-hit' VHL mutagenic event is thought to occur when chromosome arm 3p is lost in near entirety; a subsequent 'second-hit' occurs when the remaining VHL allele is mutated, resulting in loss of function of VHL.	('mutated', 'Var', (189, 196))	('VHL', 'Gene', (231, 234))	('VHL', 'Gene', '7428', (231, 234))	('VHL', 'Gene', (175, 178))	('VHL', 'Gene', (34, 37))	('VHL', 'Gene', '7428', (175, 178))	('humans', 'Species', '9606', (3, 9))	('loss of function', 'NegReg', (211, 227))	('VHL', 'Gene', '7428', (34, 37))	('chromosome', 'cellular_component', 'GO:0005694', ('79', '89'))
136773	32123314	Two independent groups have published their attempts to recapitulate human ccRCC in mice by deletion of both Vhl and Pbrm1, the 1st and 2nd most commonly altered genes observed in ccRCC, respectively.	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('Vhl', 'Gene', (109, 112))	('deletion', 'Var', (92, 100))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('human', 'Species', '9606', (69, 74))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('Pbrm1', 'Gene', (117, 122))	('RCC', 'Disease', (182, 185))	('mice', 'Species', '10090', (84, 88))
136774	32123314	PBRM1, a tumor suppressor subunit of the SWI/SNF chromatin remodeling complex, located on chromosome 3p, is mutated in 45% of human ccRCC cases.	('mutated', 'Var', (108, 115))	('human', 'Species', '9606', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('9', '25'))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('49', '69'))	('tumor', 'Disease', (9, 14))	('chromosome', 'cellular_component', 'GO:0005694', ('90', '100'))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('RCC', 'Disease', (134, 137))	('RCC', 'Phenotype', 'HP:0005584', (134, 137))	('ccRCC', 'Phenotype', 'HP:0006770', (132, 137))	('tumor suppressor', 'biological_process', 'GO:0051726', ('9', '25'))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('49', '77'))
136779	32123314	The author's described the Vhl, Pbrm1 deleted tumors as low-grade, based on aggression and histologic analysis; a result consistent with loss of PBRM1 in human ccRCC.	('Pbrm1', 'Gene', (32, 37))	('aggression', 'Disease', 'MESH:D001523', (76, 86))	('human', 'Species', '9606', (154, 159))	('RCC', 'Disease', (162, 165))	('RCC', 'Phenotype', 'HP:0005584', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('ccRCC', 'Phenotype', 'HP:0006770', (160, 165))	('aggression', 'Disease', (76, 86))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('aggression', 'Phenotype', 'HP:0000718', (76, 86))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('loss', 'Var', (137, 141))	('tumors', 'Disease', (46, 52))	('PBRM1', 'Gene', (145, 150))	('PBRM1', 'Gene', '55193', (145, 150))	('aggression', 'biological_process', 'GO:0002118', ('76', '86'))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
136780	32123314	Based on immunohistochemical (IHC) staining and gene expression analysis of specialized nephric regions, the proximal convoluted tubule (PCT), consisting of at least 13 distinct epithelial cell types, has been recognized as the most likely site of origin of human ccRCC mutations.	('gene expression', 'biological_process', 'GO:0010467', ('48', '63'))	('human', 'Species', '9606', (258, 263))	('RCC', 'Disease', 'MESH:C538614', (266, 269))	('proximal convoluted tubule', 'Phenotype', 'HP:0000114', (109, 135))	('RCC', 'Disease', (266, 269))	('mutations', 'Var', (270, 279))	('RCC', 'Phenotype', 'HP:0005584', (266, 269))	('ccRCC', 'Phenotype', 'HP:0006770', (264, 269))	('PCT', 'Phenotype', 'HP:0000114', (137, 140))
136781	32123314	However, Gu and colleagues found that Vhl and Pbrm1 deletion in a murine system using a Pax8 Cre promoted tumorigenesis, where the Cre driver expression was limited to the parietal cells of Bowman's capsule.	('deletion', 'Var', (52, 60))	('capsule', 'cellular_component', 'GO:0042603', ('199', '206'))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('murine', 'Species', '10090', (66, 72))	('Pbrm1', 'Gene', (46, 51))	('promoted', 'PosReg', (97, 105))	('tumor', 'Disease', (106, 111))	('Vhl', 'Gene', (38, 41))
136785	32123314	Importantly, both investigations targeting Vhl and Pbrm1 for deletion confirm the tumor suppressive role of Pbrm1 in vivo and will be valuable tools moving forward in ccRCC tumor therapeutic investigations.	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('ccRCC tumor', 'Disease', 'MESH:D009369', (167, 178))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('ccRCC', 'Phenotype', 'HP:0006770', (167, 172))	('deletion', 'Var', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('Pbrm1', 'Gene', (51, 56))	('tumor', 'Disease', (82, 87))	('ccRCC tumor', 'Disease', (167, 178))	('Pbrm1', 'Gene', (108, 113))
136787	32123314	BAP1 deletion or mutation occurs in 10-15% of ccRCC tumors.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('deletion', 'Var', (5, 13))	('BAP1', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('mutation', 'Var', (17, 25))	('ccRCC tumors', 'Disease', 'MESH:D009369', (46, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('BAP1', 'Gene', '8314', (0, 4))	('ccRCC tumors', 'Disease', (46, 58))
136788	32123314	BAP1 mutations were identified through next generation sequencing as strongly associated with high grade tumors and increased risk of tumor recurrence following surgical resection.	('tumors', 'Disease', (105, 111))	('associated', 'Reg', (78, 88))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('BAP1', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('BAP1', 'Gene', '8314', (0, 4))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', (134, 139))
136789	32123314	Combined targeting of Bap1 and Vhl, using the nephron progenitor transcription regulator, Six2, as a Cre driver, resulted in ccRCC development; however, pups only survived up to one month.	('resulted in', 'Reg', (113, 124))	('Six2', 'Gene', '10736', (90, 94))	('Six2', 'Gene', (90, 94))	('transcription', 'biological_process', 'GO:0006351', ('65', '78'))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('Vhl', 'Gene', (31, 34))	('ccRCC', 'Phenotype', 'HP:0006770', (125, 130))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('Bap1', 'Gene', (22, 26))	('targeting', 'Var', (9, 18))
136790	32123314	When the same group utilized the nephric specific transcription factor, Pax8, as the Cre driver of complete Vhl deletion and heterozygous manipulation of Bap1, features reminiscent of ccRCC were observed.	('Bap1', 'Gene', (154, 158))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('transcription', 'biological_process', 'GO:0006351', ('50', '63'))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('deletion', 'Var', (112, 120))	('RCC', 'Disease', (186, 189))	('transcription factor', 'molecular_function', 'GO:0000981', ('50', '70'))	('ccRCC', 'Phenotype', 'HP:0006770', (184, 189))	('Vhl', 'Gene', (108, 111))
136797	32123314	Bailey and colleagues exploited a previously described doxycycline inducible c-Myc transgenic mouse to explore Myc activation alone, and with Ksp-Cre promotor driven Vhl and Cdkn2a deletion in renal tubular cells, thus generating three useful models.	('doxycycline', 'Chemical', 'MESH:D004318', (55, 66))	('Cdkn2a', 'Gene', '12578', (174, 180))	('mouse', 'Species', '10090', (94, 99))	('Cdkn2a', 'Gene', (174, 180))	('Myc', 'Gene', (79, 82))	('Myc', 'Gene', '17869', (79, 82))	('deletion', 'Var', (181, 189))	('Myc', 'Gene', (111, 114))	('Myc', 'Gene', '17869', (111, 114))
136799	32123314	c-Myc overexpression plus Vhl deletion resulted in tumors demonstrating some ccRCC pathological features, such as cytoplasmic clearing, necrosis, and intratumor hemorrhaging.	('necrosis', 'Disease', 'MESH:D009336', (136, 144))	('necrosis', 'biological_process', 'GO:0008219', ('136', '144'))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('necrosis', 'Disease', (136, 144))	('necrosis', 'biological_process', 'GO:0008220', ('136', '144'))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('Myc', 'Gene', '17869', (2, 5))	('necrosis', 'biological_process', 'GO:0070265', ('136', '144'))	('Vhl', 'Gene', (26, 29))	('necrosis', 'biological_process', 'GO:0019835', ('136', '144'))	('deletion', 'Var', (30, 38))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('necrosis', 'biological_process', 'GO:0001906', ('136', '144'))	('cytoplasmic clearing', 'CPA', (114, 134))	('Myc', 'Gene', (2, 5))	('RCC', 'Disease', (79, 82))	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('intratumor hemorrhaging', 'Disease', (150, 173))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('tumors', 'Disease', (51, 57))	('intratumor hemorrhaging', 'Disease', 'MESH:D006470', (150, 173))	('RCC', 'Disease', 'MESH:C538614', (79, 82))
136800	32123314	Deletion of Cdkn2a, in addition to Vhl deletion and c-Myc overexpression, gave rise to an aggressive ccRCC phenotype, exhibiting liver metastasis in 30% of mice.	('Myc', 'Gene', '17869', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('Cdkn2a', 'Gene', '12578', (12, 18))	('aggressive ccRCC', 'Disease', (90, 106))	('Cdkn2a', 'Gene', (12, 18))	('Deletion', 'Var', (0, 8))	('mice', 'Species', '10090', (156, 160))	('aggressive ccRCC', 'Disease', 'MESH:D001523', (90, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('Myc', 'Gene', (54, 57))
136803	32123314	Single nucleotide alterations affecting the function of tumor suppressor genes, RB and TP53, during the G1-S cell cycle transition, are relatively infrequent in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('56', '72'))	('TP53', 'Gene', '7157', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('RB', 'Disease', 'MESH:D012175', (80, 82))	('RCC', 'Disease', (163, 166))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (161, 166))	('tumor', 'Disease', (56, 61))	('TP53', 'Gene', (87, 91))	('cell cycle transition', 'biological_process', 'GO:0044770', ('109', '130'))	('cell cycle transition', 'biological_process', 'GO:0044771', ('109', '130'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('56', '72'))	('function', 'MPA', (44, 52))	('Single nucleotide alterations', 'Var', (0, 29))
136804	32123314	However, copy number gains or losses in RB and TP53 are common, and TCGA patient data demonstrates independent evolution in these regulators from those occurring in VHL, PBRM1, BAP1, and SETD2.	('PBRM1', 'Gene', '55193', (170, 175))	('copy number gains', 'Var', (9, 26))	('BAP1', 'Gene', '8314', (177, 181))	('patient', 'Species', '9606', (73, 80))	('losses', 'NegReg', (30, 36))	('VHL', 'Gene', (165, 168))	('TP53', 'Gene', '7157', (47, 51))	('RB', 'Disease', 'MESH:D012175', (40, 42))	('PBRM1', 'Gene', (170, 175))	('VHL', 'Gene', '7428', (165, 168))	('BAP1', 'Gene', (177, 181))	('TP53', 'Gene', (47, 51))
136805	32123314	Hence, the conditional triple-mutant GEMM model, inactivating Vhl, Trp53, and Rb1, was predicted to confer the evolution of genetically distinct tumors overtime.	('Trp53', 'Gene', '7157', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('confer', 'Reg', (100, 106))	('tumors', 'Disease', (145, 151))	('Rb1', 'Gene', (78, 81))	('Vhl', 'Gene', (62, 65))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('inactivating', 'Var', (49, 61))	('Trp53', 'Gene', (67, 72))	('Rb1', 'Gene', '5925', (78, 81))
136809	32123314	Greater than 80% of the triple-mutant mice developed tumors within 25-61 weeks, with each mouse averaging five tumors.	('mice', 'Species', '10090', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('mouse', 'Species', '10090', (90, 95))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('developed', 'PosReg', (43, 52))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('triple-mutant', 'Var', (24, 37))	('tumors', 'Disease', (53, 59))
136815	32123314	Most current RCC GEMMs rely on simultaneous deletion of target genes during early embryogenesis, rather than promoting sequential loss of function.	('embryogenesis', 'biological_process', 'GO:0009792', ('82', '95'))	('deletion', 'Var', (44, 52))	('embryogenesis', 'biological_process', 'GO:0009790', ('82', '95'))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', (13, 16))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('embryogenesis', 'biological_process', 'GO:0009793', ('82', '95'))
136816	32123314	Thus, future GEMMs in ccRCC should attempt to alter or delete genes of interest sequentially in an attempt to mimic clonal selection.	('RCC', 'Disease', (24, 27))	('delete', 'Var', (55, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (22, 27))	('genes', 'Gene', (62, 67))	('alter', 'Reg', (46, 51))	('RCC', 'Phenotype', 'HP:0005584', (24, 27))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
136818	32123314	For many genes residing on human 3p, notably SETD2, the 'first-hit' mutation results in a haploinsufficiency phenotype that is not yet technically feasible to recapitulate in a murine setting.	('SETD2', 'Gene', (45, 50))	('haploinsufficiency', 'Disease', (90, 108))	('murine', 'Species', '10090', (177, 183))	('mutation', 'Var', (68, 76))	('human', 'Species', '9606', (27, 32))	('results in', 'Reg', (77, 87))	('haploinsufficiency', 'Disease', 'MESH:D058495', (90, 108))
136819	32123314	Indeed, heterozygosity phenotypes for SETD2 have been implicated in tumorigenic processes as an early driver of genomic and microtubule instability.	('tumor', 'Disease', (68, 73))	('heterozygosity phenotypes', 'Var', (8, 33))	('microtubule', 'cellular_component', 'GO:0005874', ('124', '135'))	('implicated', 'Reg', (54, 64))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('SETD2', 'Gene', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
136820	32123314	Additionally, complete gene deletion, as opposed to mutation, limits investigations aimed at examining adverse interactions conferred by truncated or nonfunctional proteins, which may contribute to tumor progression in human ccRCC.	('RCC', 'Disease', (227, 230))	('contribute', 'Reg', (184, 194))	('complete gene deletion', 'Var', (14, 36))	('RCC', 'Phenotype', 'HP:0005584', (227, 230))	('RCC', 'Disease', 'MESH:C538614', (227, 230))	('human', 'Species', '9606', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('interactions', 'Interaction', (111, 123))	('tumor', 'Disease', (198, 203))	('limits', 'NegReg', (62, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (225, 230))
136837	32123314	In addition, immune checkpoint blockade therapy with PD1 and PD-L1 propagated expansion of TILs and production of granzyme b cytotoxic CD8 T cells, thereby killing tumor cells and recapitulating immune checkpoint functionality in a 3D system.	('CD8', 'Gene', '925', (135, 138))	('tumor', 'Disease', (164, 169))	('immune', 'MPA', (195, 201))	('PD-L1', 'Gene', (61, 66))	('PD1', 'Var', (53, 56))	('TILs', 'CPA', (91, 95))	('granzyme b', 'Gene', '3002', (114, 124))	('PD-L1', 'Gene', '29126', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('CD8', 'Gene', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('granzyme b', 'Gene', (114, 124))
136858	29050225	HCaRG accelerates tubular repair by facilitating re-differentiation of injured proximal tubular epithelial cells, thus improving mouse survival after acute kidney injury.	('tubular repair', 'CPA', (18, 32))	('rat', 'Species', '10116', (12, 15))	('acute kidney', 'Phenotype', 'HP:0001919', (150, 162))	('HCaRG', 'Var', (0, 5))	('accelerates', 'PosReg', (6, 17))	('improving', 'PosReg', (119, 128))	('kidney injury', 'Disease', (156, 169))	('re-differentiation', 'CPA', (49, 67))	('mouse', 'Species', '10090', (129, 134))	('kidney injury', 'Disease', 'MESH:D058186', (156, 169))	('mouse survival', 'CPA', (129, 143))
136862	29050225	Mechanistically, HCaRG promotes de-phosphorylation of the proto-oncogene erythroblastosis oncogene B (ErbB)2/HER2 and epigenetic gene silencing of epidermal growth factor receptor and ErbB3 via promoter methylation.	('erythroblastosis oncogene B', 'Gene', '1956', (73, 100))	('phosphorylation', 'biological_process', 'GO:0016310', ('35', '50'))	('gene silencing', 'biological_process', 'GO:0016458', ('129', '143'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('147', '170'))	('de-phosphorylation', 'MPA', (32, 50))	('epigenetic gene', 'Var', (118, 133))	('ErbB', 'Gene', (102, 106))	('methylation', 'biological_process', 'GO:0032259', ('203', '214'))	('epidermal', 'Protein', (147, 156))	('ErbB3', 'Gene', (184, 189))	('erythroblastosis oncogene B', 'Gene', (73, 100))
136870	29050225	HCaRG accelerates RPT repair after injury by facilitating re-differentiation and controlling proliferation of injured RPT cells, resulting in a higher mice survival.	('RPT repair', 'CPA', (18, 28))	('mice survival', 'CPA', (151, 164))	('rat', 'Species', '10116', (12, 15))	('mice', 'Species', '10090', (151, 155))	('higher', 'PosReg', (144, 150))	('re-differentiation', 'CPA', (58, 76))	('accelerates', 'PosReg', (6, 17))	('HCaRG', 'Var', (0, 5))	('rat', 'Species', '10116', (100, 103))
136922	29050225	Oncogene amplification and overexpression of ErbB receptors have been observed in many human tumors of epithelial origin, and have been linked to cancer development and progression.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('amplification', 'Var', (9, 22))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('human', 'Species', '9606', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('linked to', 'Reg', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ErbB receptors', 'Protein', (45, 59))	('tumors', 'Disease', (93, 99))	('overexpression', 'PosReg', (27, 41))	('observed', 'Reg', (70, 78))
136934	29050225	Promoter activities of EGFR and ErbB3 but not of ErbB2 were significantly lower in HCaRG-Renca cells than in Neo-controls while their mRNA degradation was not different (Figure 4F), suggesting that HCaRG effects occur at the transcriptional level.	('ErbB3', 'Gene', (32, 37))	('Promoter activities', 'MPA', (0, 19))	('mRNA degradation', 'biological_process', 'GO:0006402', ('134', '150'))	('HCaRG-Renca', 'Var', (83, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('23', '27'))	('lower', 'NegReg', (74, 79))	('EGFR', 'Gene', (23, 27))	('HCaRG-Renca', 'CellLine', 'CVCL:2174', (83, 94))
136937	29050225	These data indicate that a hyper-methylated state in EGFR and ErbB3 promoters could result in their transcriptional gene silencing observed in HCaRG-Renca cells.	('transcriptional gene silencing', 'biological_process', 'GO:0006342', ('100', '130'))	('ErbB3', 'Gene', (62, 67))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('HCaRG-Renca', 'CellLine', 'CVCL:2174', (143, 154))	('transcriptional gene', 'MPA', (100, 120))	('hyper-methylated', 'Var', (27, 43))	('EGFR', 'Gene', (53, 57))
136947	29050225	As expected, both intracellular and secreted HCaRG protein levels were higher in HCaRG-TCMK-1 cells than in Neo-TCMK-1 cells (Figure 6D).	('higher', 'PosReg', (71, 77))	('secreted HCaRG protein levels', 'MPA', (36, 65))	('intracellular', 'cellular_component', 'GO:0005622', ('18', '31'))	('HCaRG-TCMK-1', 'Var', (81, 93))	('HCaRG-TCMK-1', 'CellLine', 'CVCL:2772', (81, 93))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
136952	29050225	We report here that HCaRG reduced tumor enlargement and facilitated differentiation in RCC through the inactivation of the ErbB receptor tyrosine kinase family.	('facilitated', 'PosReg', (56, 67))	('ErbB receptor tyrosine kinase family', 'Enzyme', (123, 159))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('inactivation', 'Var', (103, 115))	('tumor enlargement', 'Disease', (34, 51))	('reduced', 'NegReg', (26, 33))	('tumor enlargement', 'Disease', 'MESH:D006332', (34, 51))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('differentiation', 'CPA', (68, 83))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
136954	29050225	Widespread DNA hyper- or hypo-methylation are associated with underlying gene mutations of the PI3K/AKT/mTOR signaling pathway in ccRCC.	('PI3K/AKT/mTOR signaling pathway', 'Pathway', (95, 126))	('hypo-methylation', 'Var', (25, 41))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('signaling pathway', 'biological_process', 'GO:0007165', ('109', '126'))	('hyper-', 'Var', (15, 21))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('mutations', 'Var', (78, 87))	('associated', 'Reg', (46, 56))	('PI3K', 'molecular_function', 'GO:0016303', ('95', '99'))
136969	29050225	On the other hand, a high level of autophagy can cause necrotic cell death that is not associated to necroptosis and inactivation of autophagy is related to tumorigenesis.	('tumor', 'Disease', (157, 162))	('autophagy', 'CPA', (133, 142))	('autophagy', 'CPA', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('autophagy', 'biological_process', 'GO:0016236', ('133', '142'))	('inactivation', 'Var', (117, 129))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('autophagy', 'biological_process', 'GO:0016236', ('35', '44'))	('necrotic cell death', 'Disease', 'MESH:D003643', (55, 74))	('necroptosis', 'biological_process', 'GO:0097528', ('101', '112'))	('necrotic cell death', 'biological_process', 'GO:0070265', ('55', '74'))	('autophagy', 'biological_process', 'GO:0006914', ('133', '142'))	('necrotic cell death', 'Disease', (55, 74))	('autophagy', 'biological_process', 'GO:0006914', ('35', '44'))	('cause', 'Reg', (49, 54))	('necroptosis', 'biological_process', 'GO:0070266', ('101', '112'))
136970	29050225	The induction of autophagosome/autolysosome formation was observed only in HCaRG-Renca cells and HCaRG overexpression was associated with a 3-fold increase in the percentage of necrotic cells that was not diminished by the necroptosis inhibitor, Necrostatin-1.	('necrotic', 'Disease', 'MESH:D009336', (177, 185))	('formation', 'biological_process', 'GO:0009058', ('44', '53'))	('autolysosome', 'cellular_component', 'GO:0044754', ('31', '43'))	('overexpression', 'Var', (103, 117))	('HCaRG-Renca', 'CellLine', 'CVCL:2174', (75, 86))	('necroptosis', 'biological_process', 'GO:0070266', ('223', '234'))	('necrotic', 'Disease', (177, 185))	('increase', 'PosReg', (147, 155))	('necroptosis', 'biological_process', 'GO:0097528', ('223', '234'))	('autophagosome/autolysosome formation', 'CPA', (17, 53))	('autophagosome', 'cellular_component', 'GO:0005776', ('17', '30'))	('HCaRG', 'Gene', (97, 102))
136979	29050225	Our data suggest that higher HCaRG levels in normal tissue around the tumors could favor controlled cell proliferation and differentiation, thus inhibiting tumor growth and that the screening for HCaRG expression levels and somatic mutations of HCaRG not only in ccRCC but also in normal tissues could be a marker for renal cancerization, progression and prognosis of ccRCC.	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('mutations', 'Var', (232, 241))	('rat', 'Species', '10116', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (370, 373))	('tumor', 'Disease', (156, 161))	('differentiation', 'CPA', (123, 138))	('RCC', 'Disease', (370, 373))	('RCC', 'Disease', (265, 268))	('RCC', 'Phenotype', 'HP:0005584', (265, 268))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumors', 'Disease', (70, 76))	('inhibiting', 'NegReg', (145, 155))	('controlled cell proliferation', 'CPA', (89, 118))	('RCC', 'Disease', 'MESH:C538614', (370, 373))	('RCC', 'Disease', 'MESH:C538614', (265, 268))	('favor', 'PosReg', (83, 88))	('cancer', 'Disease', (324, 330))	('HCaRG', 'Gene', (245, 250))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('cell proliferation', 'biological_process', 'GO:0008283', ('100', '118'))	('tumor', 'Disease', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (324, 330))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
136981	29050225	COMMD1 was shown to inhibit HIF-mediated gene expression, resulting in reduction of tumor metastases.	('COMMD1', 'Var', (0, 6))	('tumor metastases', 'Disease', (84, 100))	('gene expression', 'biological_process', 'GO:0010467', ('41', '56'))	('tumor metastases', 'Disease', 'MESH:D009362', (84, 100))	('reduction', 'NegReg', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('HIF-mediated', 'Protein', (28, 40))	('inhibit', 'NegReg', (20, 27))
136984	29050225	Our data demonstrate that overexpression of HCaRG inhibits RCC development and tumor angiogenesis by inactivating the proto-oncogene, ErbB2, and gene silencing of EGFR and ErbB3.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('ErbB2', 'Gene', (134, 139))	('rat', 'Species', '10116', (16, 19))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))	('angiogenesis', 'biological_process', 'GO:0001525', ('85', '97'))	('ErbB3', 'Gene', (172, 177))	('EGFR', 'Gene', (163, 167))	('gene silencing', 'Var', (145, 159))	('gene silencing', 'biological_process', 'GO:0016458', ('145', '159'))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('inhibits', 'NegReg', (50, 58))	('EGFR', 'molecular_function', 'GO:0005006', ('163', '167'))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('inactivating', 'NegReg', (101, 113))
136995	29050225	In some experiments, the cells were serum deprived in Roswell Park Memorial Institute medium (RPMI)-1640 medium or Dulbecco's modified Eagle's medium (DMEM) (Thermo Fisher Scientific) in the presence or absence of CQ (036-17972; Wako Pure Chemical Industries, Ltd., Osaka, Japan), Necrostatin-1 (ab141053; abcam, Cambridge, MA, USA), 10 microg/ml of alpha-amanitin (A2263; Sigma-Aldrich, St. Louis, MO, USA) or 5-Aza-CdR (A3656; Sigma-Aldrich).	('A2263', 'Var', (366, 371))	('5-Aza-CdR', 'Var', (411, 420))	('CQ', 'Chemical', '-', (214, 216))	('Pure', 'molecular_function', 'GO:0034023', ('234', '238'))
137041	32220885	Associations between molecular features and outcomes were evaluated using non-parametric testing Copy-number aberrant tRCCs were associated with poor overall survival (p=0.03).	('poor', 'NegReg', (145, 149))	('Copy-number aberrant', 'Var', (97, 117))	('overall survival', 'MPA', (150, 166))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))
137044	32220885	TERT promoter mutations were found exclusively in high-stage tumors.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('found', 'Reg', (29, 34))	('TERT promoter', 'Gene', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (14, 23))
137053	32220885	The most frequent CNVs in this cohort were 17q gain and 9p loss, the latter also representing a known prognostic feature of clear cell RCC (ccRCC),.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))	('gain', 'PosReg', (47, 51))	('17q', 'Var', (43, 46))
137055	32220885	In a recent retrospective, multi-institutional study of 24 patients undergoing immune-checkpoint blockade (ICB) therapy, to date the largest report on outcomes to systemic therapy in tRCC, the authors reported a benefit in patients harboring mutations in bromodomain-containing genes.	('benefit', 'PosReg', (212, 219))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('RCC', 'Disease', (184, 187))	('mutations', 'Var', (242, 251))	('patients', 'Species', '9606', (59, 67))	('patients', 'Species', '9606', (223, 231))	('bromodomain-containing genes', 'Gene', (255, 283))
137058	32220885	We further carried out neoantigen prediction of mutations and fusion-generated peptides and investigated the tumor microenvironment using RNA sequencing data.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('RNA', 'cellular_component', 'GO:0005562', ('138', '141'))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mutations', 'Var', (48, 57))	('tumor', 'Disease', (109, 114))
137066	32220885	These filters included a base coverage of a minimum of 10 reads in the tumor, at least 5 reads supporting the mutation and an allelic frequency below 2% in the matched-blood sample.	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('mutation', 'Var', (110, 118))
137069	32220885	Copy number-aberrant tumors were classified as such when they satisfied at least one of the following criteria: (1) 9p loss/focal loss of CDKN2A/2B, (2) 17q gain, (3) FCNAg greater than the median in the relevant cohort.	('gain', 'PosReg', (157, 161))	('Copy number-aberrant', 'Var', (0, 20))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('loss/focal', 'NegReg', (119, 129))	('loss', 'NegReg', (130, 134))	('CDKN2A/2B', 'Gene', (138, 147))	('FCNAg', 'Chemical', '-', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
137072	32220885	Mutations with a cancer cell fraction (CCF) of >= 0.9 were defined as clonal, and all other mutations were considered subclonal.	('cell fraction', 'cellular_component', 'GO:0000267', ('24', '37'))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
137084	32220885	Additionally, we identified an independent cohort from the pan-kidney (KIPAN) TCGA cohort of 14 primary tumors with a confirmed MiTF gene fusion and WES data (Supplementary Table 2), TFE3 and TFEB rearrangements were identified in 13 and 1 cases, respectively.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('MiTF', 'Gene', (128, 132))	('TFEB', 'Gene', (192, 196))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('rearrangements', 'Var', (197, 211))	('TFE3', 'Gene', (183, 187))
137087	32220885	After excluding TFE fusions and copy number alterations, 15/22 (68.2%) patients demonstrated somatic single nucleotide variations or indels, with putatively oncogenic driver mutations in SWI/SNF and DNA damage repair (DDR) pathways in 5/22 (22.7%) samples.	('patients', 'Species', '9606', (71, 79))	('DNA', 'cellular_component', 'GO:0005574', ('199', '202'))	('indels', 'Var', (133, 139))	('mutations', 'Var', (174, 183))	('single nucleotide variations', 'Var', (101, 129))
137088	32220885	We identified activating TERT promoter mutations (C228T) in three patients, all of which occurred in high AJCC stages, suggesting that activation of TERT may be a novel marker of aggressive tRCC.	('C228T', 'Mutation', 'c.228C>T', (50, 55))	('activating', 'PosReg', (14, 24))	('aggressive tRCC', 'Disease', 'MESH:D001523', (179, 194))	('aggressive tRCC', 'Disease', (179, 194))	('TERT promoter', 'Gene', (25, 38))	('C228T', 'Var', (50, 55))	('patients', 'Species', '9606', (66, 74))
137097	32220885	The median ITH-index across all tRCC exome samples considering all mutations was 0.82 (IQR 0.55-1.36), indicating a higher rate of clonal events relative to subclonal events.	('ITH-index', 'MPA', (11, 20))	('clonal events', 'CPA', (131, 144))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('mutations', 'Var', (67, 76))
137099	32220885	Taken together, these results indicate that, from a mutational perspective, tRCC tumors exhibit (1) relatively low mutation burden, (2) relatively few canonically oncogenic mutational events aside from MiTF translocation, and (3) in cases with loss-of-function mutations to tumor suppressors, the wild-type allele infrequently undergoes concomitant loss-of-heterozygosity (LOH).	('mutations', 'Var', (261, 270))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('loss-of-function', 'NegReg', (244, 260))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tRCC tumors', 'Disease', 'MESH:D009369', (76, 87))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', (274, 279))	('tRCC tumors', 'Disease', (76, 87))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('loss-of-heterozygosity', 'NegReg', (349, 371))
137104	32220885	In prior analyses of tRCC, loss of chromosome arm 9p and gain of arm 17q were identified as common and, in the case of 17q gain, potential prognostic biomarkers.	('loss', 'Var', (27, 31))	('RCC', 'Disease', (22, 25))	('RCC', 'Disease', 'MESH:C538614', (22, 25))	('chromosome', 'cellular_component', 'GO:0005694', ('35', '45'))	('gain', 'PosReg', (123, 127))	('gain', 'PosReg', (57, 61))
137105	32220885	We therefore set out to evaluate the association between gross copy number events and both clinical features and OS in tRCC.	('gross copy number events', 'Var', (57, 81))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))
137109	32220885	The most common arm-level copy number alterations observed in the MSK-IMPACT cohort were loss of 9p in 9/22 (41%) patients, gain of 17q in 8/22 (36%) patients, and gain of 6p in 8/22 (36%) patients.	('gain', 'PosReg', (164, 168))	('copy number', 'Var', (26, 37))	('gain', 'PosReg', (124, 128))	('patients', 'Species', '9606', (150, 158))	('patients', 'Species', '9606', (114, 122))	('patients', 'Species', '9606', (189, 197))	('loss', 'NegReg', (89, 93))
137111	32220885	Based on the relatively low TMB of tRCC and the comparatively high frequency of copy number alterations, we sought to evaluate the association between clinical outcomes and a summary measure of copy number changes.	('TMB', 'Chemical', '-', (28, 31))	('RCC', 'Disease', (36, 39))	('copy number', 'Var', (80, 91))	('RCC', 'Disease', 'MESH:C538614', (36, 39))
137113	32220885	In the MSK-IMPACT cohort, the 15 patients with copy number-aberrant (CNA) tumors demonstrated worse overall survival (5-year OS 34.9% vs 100%, log-rank p=0.03).	('patients', 'Species', '9606', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('copy number-aberrant', 'Var', (47, 67))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('worse', 'NegReg', (94, 99))	('overall survival', 'MPA', (100, 116))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
137114	32220885	Two tumors in the MSK-IMPACT cohort and two tumors in the TCGA cohort exhibited bi-allelic loss of CDKN2A/B; treating these tumors as a separate group for the purposes of survival analysis did not meaningfully affect our findings, suggesting that bi-allelic loss of this gene is not the sole driver of poor prognosis in CNA tumors.	('CDKN2A/B', 'Gene', (99, 107))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('tumors', 'Disease', (324, 330))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('loss', 'NegReg', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('bi-allelic', 'Var', (247, 257))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumors', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumors', 'Disease', 'MESH:D009369', (324, 330))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('CNA', 'Disease', (320, 323))
137120	32220885	This local kidney recurrence was found to have concordant morphologic features when compared to the previous specimen, as well as a TFE3 gene rearrangement; prompting a change in the original diagnosis to MiTF-family tRCC.	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('rearrangement', 'Var', (142, 155))	('RCC', 'Disease', (218, 221))	('change', 'Reg', (169, 175))	('TFE3', 'Gene', (132, 136))
137126	32220885	To understand the clonal relatedness of these tumors, we completed exome sequencing on the nodal metastasis, and compared copy number aberrations and mutations between MSK-RP-5887 and TCGA-BQ-5887.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('TCGA-BQ-5887', 'Gene', (184, 196))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('MSK-RP-5887', 'Gene', (168, 179))	('mutations', 'Var', (150, 159))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
137127	32220885	Interestingly, we noted that both samples exhibited whole-genome doubling (WGD) and extensive copy number alterations across the entire genome and therefore an aberrantly high FCNAg compared to other tRCC tumors.	('FCNAg', 'Chemical', '-', (176, 181))	('copy number alterations', 'Var', (94, 117))	('tRCC tumors', 'Disease', 'MESH:D009369', (200, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tRCC tumors', 'Disease', (200, 211))
137131	32220885	Together, this suggests that in this particular tRCC tumor, copy number alterations occurred early during tumor evolution, whereas the acquisition of the bulk of the somatic mutations occurred later (Figure 4).	('copy number alterations', 'Var', (60, 83))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tRCC tumor', 'Disease', 'MESH:D009369', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (53, 58))	('tRCC tumor', 'Disease', (48, 58))	('tumor', 'Disease', (106, 111))
137138	32220885	Two patients had undergone prior chemotherapy: one for retinoblastoma, who also had evidence of a germline RB1 mutation (P-0025629-T02-IM6, germline status identified from sequencing of matched normal blood per standard MSK-IMPACT sequencing), and the other for neuroblastoma (P-0024809-T02-IM6).	('retinoblastoma', 'Disease', 'MESH:D012175', (55, 69))	('retinoblastoma', 'Disease', (55, 69))	('neuroblastoma', 'Phenotype', 'HP:0003006', (262, 275))	('P-0025629-T02-IM6', 'Var', (121, 138))	('P-0024809-T02-IM6', 'Var', (277, 294))	('RB1', 'Gene', (107, 110))	('patients', 'Species', '9606', (4, 12))	('neuroblastoma', 'Disease', 'MESH:D009447', (262, 275))	('retinoblastoma', 'Phenotype', 'HP:0009919', (55, 69))	('neuroblastoma', 'Disease', (262, 275))
137139	32220885	None of the pediatric cases showed 9p loss or 17q gain and, consistently, they were also found to have a significantly lower FCNAg when compared to their older counterparts (Mann-Whitney U, p=0.02) (see Supplementary Table 3).	('FCNAg', 'CPA', (125, 130))	('lower', 'NegReg', (119, 124))	('FCNAg', 'Chemical', '-', (125, 130))	('gain', 'PosReg', (50, 54))	('9p loss', 'Var', (35, 42))	('17q', 'CPA', (46, 49))
137142	32220885	Our results suggest that tRCCs are driven primarily by copy number aberrations, rather than by somatic mutations in tumor suppressors and oncogenes.	('copy number aberrations', 'Var', (55, 78))	('driven', 'Reg', (35, 41))	('RCC', 'Disease', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
137144	32220885	The smaller proportion of non-diploid genome in pediatric tRCC cases, compared to adults, is in line with a less aggressive tumor biology.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('aggressive tumor', 'Disease', (113, 129))	('non-diploid genome', 'Var', (26, 44))	('aggressive tumor', 'Disease', 'MESH:D001523', (113, 129))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))
137145	32220885	Gene rearrangements are the key oncogenic event in tRCC, and prior work has associated certain fusion partners with worse outcomes.	('Gene rearrangements', 'Var', (0, 19))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))
137147	32220885	An earlier genomic study in 16 patients with tRCC found heterogeneous molecular profiles, with 17q gain and 9p loss identified as the most frequent CNVs.	('loss', 'NegReg', (111, 115))	('RCC', 'Disease', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('patients', 'Species', '9606', (31, 39))	('17q', 'Var', (95, 98))	('gain', 'PosReg', (99, 103))
137148	32220885	These results are partially consistent with our own findings, which, however, showed a significant association in the MSK-IMPACT cohort between poor outcome in a copy number-aberrant group of tumors defined by the presence of either 9p loss, 17q gain, or elevated FCNAg.	('FCNAg', 'Chemical', '-', (264, 269))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('9p loss', 'Var', (233, 240))	('FCNAg', 'MPA', (264, 269))	('gain', 'PosReg', (246, 250))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('17q', 'CPA', (242, 245))
137150	32220885	TERT promoter mutations have also previously been associated with an aggressive disease course in more common variants of RCC, but the implications of these mutations in tRCC have not been described.	('associated with', 'Reg', (50, 65))	('mutations', 'Var', (14, 23))	('variants', 'Var', (110, 118))	('aggressive disease', 'Disease', 'MESH:D001523', (69, 87))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('RCC', 'Disease', (171, 174))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))	('aggressive disease', 'Disease', (69, 87))
137151	32220885	In the MSK-IMPACT cohort, we detected clonal activating hotspot mutations in the TERT promoter of three tumors.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('activating hotspot', 'PosReg', (45, 63))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('TERT promoter', 'Gene', (81, 94))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('mutations', 'Var', (64, 73))
137161	32220885	In light of recent data describing the immunogenicity of fusion-derived neoantigens in head and neck cancers, this suggests that neoantigens produced by TFE3/TFEB translocation may be clinically meaningful.	('neck cancers', 'Disease', (96, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('head and neck cancer', 'Phenotype', 'HP:0012288', (87, 107))	('TFE3/TFEB', 'Gene', (153, 162))	('neck cancers', 'Disease', 'MESH:D006258', (96, 108))	('translocation', 'Var', (163, 176))	('head and neck cancers', 'Phenotype', 'HP:0012288', (87, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('neck', 'cellular_component', 'GO:0044326', ('96', '100'))	('head and neck cancer', 'Disease', 'MESH:D006258', (87, 107))
137163	32220885	An immunogenic effect of SMARCA4 mutations, via PD-L1 upregulation, has previously been postulated for small cell ovarian cancer.	('SMARCA4', 'Gene', (25, 32))	('small cell ovarian cancer', 'Disease', 'MESH:D015451', (103, 128))	('upregulation', 'PosReg', (54, 66))	('mutations', 'Var', (33, 42))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('small cell ovarian cancer', 'Phenotype', 'HP:0030357', (103, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('PD-L1', 'Gene', (48, 53))	('small cell ovarian cancer', 'Disease', (103, 128))
137164	32220885	PBRM1 mutations were recently reported to have an increased clinical benefit in metastatic ccRCC patients undergoing ICB.	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Disease', (93, 96))	('benefit', 'PosReg', (69, 76))	('PBRM1', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('patients', 'Species', '9606', (97, 105))
137173	32220885	Notably, patient P-0025629-T02-IM6 is, to our knowledge, the first described case of an RCC following a diagnosis of retinoblastoma, however, the remaining RB1 copy was found to be unaffected in the tRCC sample.	('retinoblastoma', 'Disease', 'MESH:D012175', (117, 131))	('retinoblastoma', 'Disease', (117, 131))	('RCC', 'Disease', (200, 203))	('P-0025629-T02-IM6', 'Var', (17, 34))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('RCC', 'Disease', 'MESH:C538614', (200, 203))	('retinoblastoma', 'Phenotype', 'HP:0009919', (117, 131))
137185	32220885	This is particularly interesting with regards to a recently opened multi-institutional prospective trial of an ICB/TKI combination therapy in tRCC patients (NCT03595124), a study of an ICB/anti-VEGF combination regimen including tRCC patients (NCT02724878) as well as potential trials involving neoantigen vaccines.	('NCT03595124', 'Var', (157, 168))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (234, 242))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', 'MESH:C538614', (230, 233))	('RCC', 'Disease', (143, 146))	('RCC', 'Disease', (230, 233))
137187	32220885	Copy number aberrations are pervasive in tRCC, and appear to condition poor outcomes.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('RCC', 'Disease', (42, 45))	('Copy number aberrations', 'Var', (0, 23))
137188	32220885	The presence of TERT hotspot mutations in cases of advanced disease suggests an association with molecular progression in tRCC.	('mutations', 'Var', (29, 38))	('RCC', 'Disease', (123, 126))	('association', 'Interaction', (80, 91))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('TERT hotspot', 'Gene', (16, 28))
137192	32220885	Our study found that certain copy number variations (CNVs) were associated with disease aggressiveness in tRCC.	('associated with', 'Reg', (64, 79))	('copy number variations', 'Var', (29, 51))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('RCC', 'Disease', (107, 110))	('aggressiveness', 'Phenotype', 'HP:0000718', (88, 102))	('aggressiveness', 'Disease', 'MESH:D001523', (88, 102))	('aggressiveness', 'Disease', (88, 102))
137203	32712616	The hsa04110: cell cycle and hsa04510: focal adhesion were the significant pathways associated with ccRCC overlapped with enrichment analysis.	('cell cycle', 'CPA', (14, 24))	('focal adhesion', 'cellular_component', 'GO:0005925', ('39', '53'))	('cell cycle', 'biological_process', 'GO:0007049', ('14', '24'))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('hsa04110', 'Var', (4, 12))	('RCC', 'Disease', (102, 105))	('focal adhesion', 'CPA', (39, 53))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('hsa04510', 'Var', (29, 37))
137205	32712616	CCND2 and CCNA2 were cell-cycle-associated genes, which were regulated by hsa-miR-324-3p, hsa-miR-146a and hsa-miR-145.	('CCNA2', 'Gene', (10, 15))	('hsa-miR-324-3p', 'Var', (74, 88))	('hsa-miR-146a', 'Gene', (90, 102))	('regulated', 'Reg', (61, 70))	('hsa-miR-145', 'Gene', '406937', (107, 118))	('CCNA2', 'Gene', '890', (10, 15))	('CCND2', 'Gene', (0, 5))	('hsa-miR-146a', 'Gene', '406938', (90, 102))	('CCND2', 'Gene', '894', (0, 5))	('hsa-miR-145', 'Gene', (107, 118))	('cell-cycle', 'biological_process', 'GO:0007049', ('21', '31'))
137207	32712616	The deregulation of pathways and associated genes may provide insights to ccRCC research and therapy.	('deregulation', 'Var', (4, 16))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))
137229	32712616	Three microarray datasets related to ccRCC were retrieved from the publicly available Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/) at the National Center for Biotechnology Information (NCBI), including GSE6344, GSE781, and GSE53000.	('GSE53000', 'Var', (252, 260))	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('GSE6344', 'Chemical', '-', (231, 238))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('Gene Expression', 'biological_process', 'GO:0010467', ('86', '101'))
137240	32712616	The overrepresented pathways of downregulated genes mainly included hsa00020: citrate cycle (TCA cycle), hsa03320: peroxisome proliferator-activated receptor (PPAR) signaling pathway, and hsa00071: fatty acid metabolism.	('hsa03320', 'Var', (105, 113))	('downregulated', 'NegReg', (32, 45))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('198', '219'))	('PPAR) signaling pathway', 'biological_process', 'GO:0035357', ('159', '182'))	('fatty acid', 'Chemical', 'MESH:D005227', (198, 208))	('PPAR', 'Gene', (159, 163))	('TCA cycle', 'biological_process', 'GO:0006099', ('93', '102'))	('peroxisome', 'cellular_component', 'GO:0005777', ('115', '125'))	('citrate', 'Chemical', 'MESH:D019343', (78, 85))	('TCA', 'Chemical', 'MESH:D014238', (93, 96))	('PPAR', 'Gene', '5465', (159, 163))	('peroxisome proliferator-activated receptor', 'Gene', (115, 157))	('peroxisome proliferator-activated receptor', 'Gene', '5465', (115, 157))
137243	32712616	There were 191 ccRCC-related pathways in the CTD database, among which focal adhesion (hsa04510) and cell cycle (hsa04110) were overrepresented by miRNA-target genes including CCND2, ITGB4, KDR, and CCNA2.	('CTD', 'Gene', '1283', (45, 48))	('ITGB4', 'Gene', '3691', (183, 188))	('overrepresented', 'PosReg', (128, 143))	('CCND2', 'Gene', (176, 181))	('KDR', 'Gene', '3791', (190, 193))	('cell cycle', 'biological_process', 'GO:0007049', ('101', '111'))	('CCND2', 'Gene', '894', (176, 181))	('CCNA2', 'Gene', '890', (199, 204))	('focal adhesion', 'cellular_component', 'GO:0005925', ('71', '85'))	('ITGB4', 'Gene', (183, 188))	('focal adhesion', 'Pathway', (71, 85))	('RCC', 'Disease', (17, 20))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (15, 20))	('CTD', 'Gene', (45, 48))	('hsa04110', 'Var', (113, 121))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('cell cycle', 'CPA', (101, 111))	('KDR', 'Gene', (190, 193))	('CCNA2', 'Gene', (199, 204))
137245	32712616	Has-miR-424 targeting KDR, has-miR-204 targeting ITGB4, and has-miR-324-3p targeting CCND2 were involved in the focal adhesion pathway.	('miR-424', 'Gene', (4, 11))	('has-miR-324-3p', 'Var', (60, 74))	('miR-204', 'Gene', '406987', (31, 38))	('ITGB4', 'Gene', (49, 54))	('miR-424', 'Gene', '494336', (4, 11))	('involved', 'Reg', (96, 104))	('ITGB4', 'Gene', '3691', (49, 54))	('focal adhesion', 'cellular_component', 'GO:0005925', ('112', '126'))	('CCND2', 'Gene', (85, 90))	('miR-204', 'Gene', (31, 38))	('KDR', 'Gene', (22, 25))	('focal adhesion pathway', 'Pathway', (112, 134))	('CCND2', 'Gene', '894', (85, 90))	('KDR', 'Gene', '3791', (22, 25))
137246	32712616	CCND2 regulated by hsa-miR-324-3p and CCNA2 regulated by has-miR-146a and hsa-miR-145 were enriched in the cell cycle pathway.	('CCNA2', 'Gene', (38, 43))	('hsa-miR-145', 'Gene', (74, 85))	('miR-146a', 'Gene', (61, 69))	('CCNA2', 'Gene', '890', (38, 43))	('CCND2', 'Gene', (0, 5))	('miR-146a', 'Gene', '406938', (61, 69))	('cell cycle pathway', 'Pathway', (107, 125))	('hsa-miR-324-3p', 'Var', (19, 33))	('cell cycle', 'biological_process', 'GO:0007049', ('107', '117'))	('CCND2', 'Gene', '894', (0, 5))	('hsa-miR-145', 'Gene', '406937', (74, 85))
137252	32712616	The pathway analysis showed that hsa00020: citrate cycle (TCA cycle), hsa03320: PPAR signaling pathway, and hsa04110: cell cycle were the significant pathways dysregulated by DEGs in ccRCC.	('RCC', 'Disease', (185, 188))	('ccRCC', 'Phenotype', 'HP:0006770', (183, 188))	('citrate cycle', 'MPA', (43, 56))	('PPAR signaling pathway', 'biological_process', 'GO:0035357', ('80', '102'))	('PPAR', 'Gene', (80, 84))	('TCA', 'Chemical', 'MESH:D014238', (58, 61))	('DEGs', 'Var', (175, 179))	('cell cycle', 'biological_process', 'GO:0007049', ('118', '128'))	('cell cycle', 'CPA', (118, 128))	('citrate', 'Chemical', 'MESH:D019343', (43, 50))	('TCA cycle', 'biological_process', 'GO:0006099', ('58', '67'))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('PPAR', 'Gene', '5465', (80, 84))	('hsa04110', 'Var', (108, 116))	('RCC', 'Disease', 'MESH:C538614', (185, 188))
137257	32712616	Moreover, hsa04110: cell cycle and hsa04510: focal adhesions were found to be the ccRCC-related pathways that overlapped with the enrichment pathways of GO categories.	('cell cycle', 'CPA', (20, 30))	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('cell cycle', 'biological_process', 'GO:0007049', ('20', '30'))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('hsa04510', 'Var', (35, 43))	('hsa04110', 'Var', (10, 18))	('focal adhesions', 'CPA', (45, 60))
137270	32712616	It is reported that hsa-miR-324-3p is a specific miRNA in ccRCC relative to papillary RCC by miRNA profiling analysis.	('hsa-miR-324-3p', 'Var', (20, 34))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))
137325	28003924	Paragangliomas will show positivity for synaptophysin, chromogramin, and S100 protein stains in sustenticular cells with negativity for PTH.	('Paragangliomas', 'Disease', 'MESH:D010235', (0, 14))	('positivity', 'Var', (25, 35))	('PTH', 'Gene', (136, 139))	('synaptophysin', 'Gene', (40, 53))	('S100', 'Gene', (73, 77))	('Paragangliomas', 'Phenotype', 'HP:0002668', (0, 14))	('synaptophysin', 'Gene', '6855', (40, 53))	('PTH', 'Gene', '5741', (136, 139))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('S100', 'Gene', '6271', (73, 77))	('Paragangliomas', 'Disease', (0, 14))
137335	28003924	Negativity for TTF1 and thyroglobulin ruled out thyroid neoplasm.	('thyroid neoplasm', 'Disease', (48, 64))	('TTF1', 'Gene', '7270', (15, 19))	('thyroglobulin', 'Gene', '7038', (24, 37))	('thyroid neoplasm', 'Phenotype', 'HP:0100031', (48, 64))	('thyroglobulin', 'Gene', (24, 37))	('Negativity', 'Var', (0, 10))	('neoplasm', 'Phenotype', 'HP:0002664', (56, 64))	('TTF1', 'Gene', (15, 19))	('thyroid neoplasm', 'Disease', 'MESH:D013959', (48, 64))
137357	27713405	Here we perform a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, single-nucleotide polymorphism array, fluorescence in situ hybridization, immunohistochemistry and cell-based assays.	('uRCC', 'Gene', (62, 66))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('uRCC', 'Gene', '54894', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RNA', 'cellular_component', 'GO:0005562', ('115', '118'))	('single-nucleotide', 'Var', (131, 148))
137359	27713405	Integrated analysis reveals a subset of 26% uRCC characterized by NF2 loss, dysregulated Hippo-YAP pathway and worse survival, whereas 21% uRCC with mutations of MTOR, TSC1, TSC2 or PTEN and hyperactive mTORC1 signalling are associated with better clinical outcome.	('MTOR', 'Gene', (162, 166))	('mTORC1', 'Gene', '382056', (203, 209))	('loss', 'NegReg', (70, 74))	('MTOR', 'Gene', '2475', (162, 166))	('TSC2', 'Gene', '7249', (174, 178))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('PTEN', 'Gene', '5728', (182, 186))	('TSC2', 'Gene', (174, 178))	('mTORC1', 'cellular_component', 'GO:0031931', ('203', '209'))	('mutations', 'Var', (149, 158))	('uRCC', 'Gene', '54894', (44, 48))	('TSC1', 'Gene', (168, 172))	('hyperactive', 'Disease', 'MESH:D006948', (191, 202))	('uRCC', 'Gene', (44, 48))	('hyperactive', 'Disease', (191, 202))	('signalling', 'biological_process', 'GO:0023052', ('210', '220'))	('uRCC', 'Gene', '54894', (139, 143))	('dysregulated', 'Reg', (76, 88))	('NF2', 'Gene', (66, 69))	('TSC1', 'Gene', '7248', (168, 172))	('mTORC1', 'Gene', (203, 209))	('uRCC', 'Gene', (139, 143))	('Hippo-YAP pathway', 'Pathway', (89, 106))	('PTEN', 'Gene', (182, 186))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
137372	27713405	We find recurrent somatic mutations in 29 genes, and identify distinct molecular subsets that are characterized by NF2 loss, hyperactive mTORC1 signalling, FH deficiency, chromatin/DNA damage regulator mutations or ALK translocation and associated with varying clinical outcomes.	('ALK', 'Gene', (215, 218))	('DNA', 'cellular_component', 'GO:0005574', ('181', '184'))	('mTORC1', 'Gene', '382056', (137, 143))	('FH deficiency', 'Disease', (156, 169))	('mTORC1', 'cellular_component', 'GO:0031931', ('137', '143'))	('ALK', 'Gene', '238', (215, 218))	('signalling', 'biological_process', 'GO:0023052', ('144', '154'))	('mutations', 'Var', (26, 35))	('NF2', 'Gene', (115, 118))	('mTORC1', 'Gene', (137, 143))	('FH deficiency', 'Disease', 'MESH:D006938', (156, 169))	('hyperactive', 'Disease', (125, 136))	('loss', 'NegReg', (119, 123))	('hyperactive', 'Disease', 'MESH:D006948', (125, 136))	('chromatin', 'cellular_component', 'GO:0000785', ('171', '180'))	('mutations', 'Var', (202, 211))
137377	27713405	We identified 29 recurrently mutated genes with an average of 2.6 (0-8) protein-coding somatic mutations per patient tumour (Fig.	('patient', 'Species', '9606', (109, 116))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('mutations', 'Var', (95, 104))	('tumour', 'Disease', (117, 123))
137379	27713405	The incidence of NF2 mutations in our cohort is markedly higher than what is reported in ccRCC (0-1%), pRCC (0-6%) and chRCC (0%).	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', (104, 107))	('pRCC', 'Gene', '5546', (103, 107))	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('higher', 'PosReg', (57, 63))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('pRCC', 'Gene', (103, 107))	('NF2', 'Gene', (17, 20))	('mutations', 'Var', (21, 30))
137380	27713405	In ccRCC, VHL mutations occur at ~75%, and SETD2 and BAP1 at 10-20% frequencies, whereas in our uRCC cohort, only a single VHL mutation was detected in one case (T08).	('VHL', 'Gene', '7428', (10, 13))	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('uRCC', 'Gene', (96, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('SETD2', 'Gene', '29072', (43, 48))	('VHL', 'Gene', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('SETD2', 'Gene', (43, 48))	('RCC', 'Disease', (5, 8))	('uRCC', 'Gene', '54894', (96, 100))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('VHL', 'Gene', '7428', (123, 126))	('BAP1', 'Gene', '8314', (53, 57))	('VHL', 'Gene', (10, 13))	('mutations', 'Var', (14, 23))	('BAP1', 'Gene', (53, 57))
137382	27713405	The enrichment of cases with NF2 mutations (11 of 62) discovered in our uRCC cohort suggests that NF2 loss could potentially define a molecular subset of uRCC.	('uRCC', 'Gene', (154, 158))	('uRCC', 'Gene', (72, 76))	('mutations', 'Var', (33, 42))	('uRCC', 'Gene', '54894', (154, 158))	('uRCC', 'Gene', '54894', (72, 76))	('loss', 'NegReg', (102, 106))	('NF2', 'Gene', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('NF2', 'Gene', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
137383	27713405	To assess the NF2 status in uRCC beyond mutations, we next assessed the status of chromosome 22q12 where NF2 resides.	('chromosome', 'cellular_component', 'GO:0005694', ('82', '92'))	('uRCC', 'Gene', (28, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('mutations', 'Var', (40, 49))	('uRCC', 'Gene', '54894', (28, 32))
137384	27713405	High-resolution, genome-wide SNP array analysis was performed for 15 of the 16 uRCC cases carrying NF2 mutations and/or exhibiting 22q12 copy-number loss (referred to as the 'NF2 loss' subset from here onwards; Fig.	('mutations', 'Var', (103, 112))	('uRCC', 'Gene', (79, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('uRCC', 'Gene', '54894', (79, 83))	('NF2', 'Gene', (99, 102))
137385	27713405	Thirteen cases were confirmed to exhibit hemizygous loss of 22q and the remaining two tumours (T22 and T64), known to carry NF2 somatic mutations, showed copy-neutral loss of heterozygosity (LOH) of 22q (Supplementary Fig.	('hemizygous loss', 'Disease', 'MESH:C564097', (41, 56))	('NF2', 'Gene', (124, 127))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('hemizygous loss', 'Disease', (41, 56))	('mutations', 'Var', (136, 145))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumours', 'Disease', (86, 93))	('loss of', 'NegReg', (167, 174))
137389	27713405	Germline mutation of NF2 is the principal genetic event underlying the human neurofibromatosis type 2 cancer predisposition syndrome.	('NF2', 'Gene', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('neurofibromatosis type 2 cancer', 'Disease', (77, 108))	('neurofibromatosis type 2 cancer', 'Disease', 'MESH:D009369', (77, 108))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (77, 94))	('Germline mutation', 'Var', (0, 17))	('human', 'Species', '9606', (71, 76))
137390	27713405	The role of NF2 as a tumour suppressor gene is further demonstrated by mouse models in which genetic loss of Nf2 results in various cancers.	('cancers', 'Disease', (132, 139))	('Nf2', 'Gene', (109, 112))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('Nf2', 'Gene', '18016', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('results in', 'Reg', (113, 123))	('tumour', 'Disease', (21, 27))	('mouse', 'Species', '10090', (71, 76))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('genetic loss', 'Var', (93, 105))
137391	27713405	We first focused on the NF2-Hippo tumour suppressor network, which was highlighted by a series of reports showing that NF2 enforces the Hippo tumour suppression signalling pathway by phosphorylating, sequestering, degrading and suppressing YAP/TAZ nuclear translocation, thereby disrupting oncogenic transcription.	('tumour', 'Disease', (142, 148))	('signalling pathway', 'biological_process', 'GO:0007165', ('161', '179'))	('transcription', 'biological_process', 'GO:0006351', ('300', '313'))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('degrading', 'NegReg', (214, 223))	('sequestering', 'MPA', (200, 212))	('NF2', 'Var', (119, 122))	('tumour', 'Disease', (34, 40))	('enforces', 'PosReg', (123, 131))	('YAP/TAZ', 'MPA', (240, 247))	('disrupting', 'NegReg', (279, 289))	('phosphorylating', 'MPA', (183, 198))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('oncogenic transcription', 'CPA', (290, 313))	('sequestering', 'biological_process', 'GO:0051235', ('200', '212'))	('suppressing', 'NegReg', (228, 239))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
137402	27713405	Furthermore, the occurrence of SETD2 (3p21) mutation was significantly higher in the NF2 loss than in the remaining uRCC tumours (44% versus 9%, Fisher's exact test, P=0.004).	('higher', 'PosReg', (71, 77))	('SETD2', 'Gene', (31, 36))	('uRCC tumours', 'Disease', 'MESH:D009369', (116, 128))	('mutation', 'Var', (44, 52))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('uRCC tumours', 'Disease', (116, 128))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))	('SETD2', 'Gene', '29072', (31, 36))	('NF2', 'Gene', (85, 88))	('loss', 'NegReg', (89, 93))
137406	27713405	Recurrent mutations of the other chromatin modulating genes including BAP1 did not show significant enrichment in the NF2 loss subset.	('chromatin', 'cellular_component', 'GO:0000785', ('33', '42'))	('BAP1', 'Gene', '8314', (70, 74))	('NF2', 'Gene', (118, 121))	('BAP1', 'Gene', (70, 74))	('loss', 'NegReg', (122, 126))	('mutations', 'Var', (10, 19))
137409	27713405	Nevertheless, as small number of RCC with NF2 mutations have been recently reported in pRCC and collecting duct RCC, it remains to be determined whether these tumours were distinct from or overlapped with our NF2 loss uRCC.	('NF2', 'Gene', (42, 45))	('loss uRCC', 'Disease', (213, 222))	('RCC', 'Disease', (219, 222))	('RCC', 'Phenotype', 'HP:0005584', (219, 222))	('reported', 'Reg', (75, 83))	('tumours', 'Disease', (159, 166))	('pRCC', 'Gene', '5546', (87, 91))	('mutations', 'Var', (46, 55))	('tumours', 'Phenotype', 'HP:0002664', (159, 166))	('tumours', 'Disease', 'MESH:D009369', (159, 166))	('RCC', 'Disease', 'MESH:C538614', (219, 222))	('loss uRCC', 'Disease', 'MESH:D014786', (213, 222))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('RCC', 'Disease', (33, 36))	('pRCC', 'Gene', (87, 91))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', 'MESH:C538614', (112, 115))
137410	27713405	Somatic mutation analysis of our uRCC cohort demonstrated that potentially mTORC1 pathway activating mutations comprising MTOR (5), TSC1 (4), TSC2 (3) and PTEN (4) occurred mutually exclusively in 16 (26%) cases, which might indicate another distinct subset (Fig.	('mutations', 'Var', (101, 110))	('PTEN', 'Gene', (155, 159))	('TSC2', 'Gene', '7249', (142, 146))	('PTEN', 'Gene', '5728', (155, 159))	('uRCC', 'Gene', '54894', (33, 37))	('mTORC1', 'cellular_component', 'GO:0031931', ('75', '81'))	('mTORC1', 'Gene', (75, 81))	('TSC2', 'Gene', (142, 146))	('MTOR', 'Gene', (122, 126))	('uRCC', 'Gene', (33, 37))	('activating', 'PosReg', (90, 100))	('TSC1', 'Gene', '7248', (132, 136))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('mTORC1', 'Gene', '382056', (75, 81))	('MTOR', 'Gene', '2475', (122, 126))	('TSC1', 'Gene', (132, 136))
137411	27713405	Mutations of these genes have been described in ccRCC (12%), pRCC (8%) and chRCC (9%).	('described', 'Reg', (35, 44))	('pRCC', 'Gene', (61, 65))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('Mutations', 'Var', (0, 9))	('pRCC', 'Gene', '5546', (61, 65))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))
137412	27713405	Of the MTOR mutations seen in this cohort (Fig.	('mutations', 'Var', (12, 21))	('MTOR', 'Gene', (7, 11))	('MTOR', 'Gene', '2475', (7, 11))
137413	27713405	3b), I1973F has been described and shown to be hyperactive in cell-based assays, whereas L2427R (recurred three times in our uRCC cohort) and V2475M mutations have not yet been reported.	('V2475M', 'SUBSTITUTION', 'None', (142, 148))	('hyperactive', 'Disease', (47, 58))	('hyperactive', 'Disease', 'MESH:D006948', (47, 58))	('uRCC', 'Gene', (125, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('L2427R', 'Var', (89, 95))	('L2427R', 'SUBSTITUTION', 'None', (89, 95))	('I1973F', 'Var', (5, 11))	('I1973F', 'SUBSTITUTION', 'None', (5, 11))	('uRCC', 'Gene', '54894', (125, 129))	('V2475M', 'Var', (142, 148))
137414	27713405	To interrogate the functional impact of individual MTOR mutations, we generated MTOR L2427R and V2475M mutants, and assessed the mTORC1 activity by phosphorylation of S6K and 4EBP1, two key mTORC1 downstream substrates.	('mTORC1', 'Gene', (190, 196))	('MTOR', 'Gene', '2475', (51, 55))	('V2475M', 'SUBSTITUTION', 'None', (96, 102))	('MTOR', 'Gene', (80, 84))	('mTORC1', 'cellular_component', 'GO:0031931', ('129', '135'))	('mTORC1', 'Gene', (129, 135))	('L2427R', 'Var', (85, 91))	('L2427R', 'SUBSTITUTION', 'None', (85, 91))	('mTORC1', 'Gene', '382056', (190, 196))	('MTOR', 'Gene', '2475', (80, 84))	('mTORC1', 'Gene', '382056', (129, 135))	('S6K and 4EBP1', 'Gene', '6198', (167, 180))	('phosphorylation', 'biological_process', 'GO:0016310', ('148', '163'))	('mTORC1', 'cellular_component', 'GO:0031931', ('190', '196'))	('MTOR', 'Gene', (51, 55))	('V2475M', 'Var', (96, 102))	('activity', 'MPA', (136, 144))
137415	27713405	When the MTOR mutant was co-expressed with HA-S6K in 293T human embryonic kidney cells, L2427R exhibited higher activity, whereas V2475M showed baseline mTORC1 kinase activity comparable to the wild-type MTOR (Fig.	('L2427R', 'Var', (88, 94))	('embryonic kidney', 'Disease', 'MESH:D007674', (64, 80))	('mTORC1', 'Gene', (153, 159))	('MTOR', 'Gene', (9, 13))	('higher', 'PosReg', (105, 111))	('MTOR', 'Gene', (204, 208))	('V2475M', 'Var', (130, 136))	('human', 'Species', '9606', (58, 63))	('V2475M', 'SUBSTITUTION', 'None', (130, 136))	('L2427R', 'SUBSTITUTION', 'None', (88, 94))	('MTOR', 'Gene', '2475', (9, 13))	('MTOR', 'Gene', '2475', (204, 208))	('293T', 'CellLine', 'CVCL:0063', (53, 57))	('mTORC1', 'Gene', '382056', (153, 159))	('activity', 'MPA', (112, 120))	('embryonic kidney', 'Disease', (64, 80))	('mTORC1', 'cellular_component', 'GO:0031931', ('153', '159'))	('kinase activity', 'molecular_function', 'GO:0016301', ('160', '175'))
137416	27713405	Consistent with cell-based assays, immunohistochemistry of the uRCC with L2427R mutation displayed strong p-4EBP1 and p-S6 staining, whereas that of V2475M did not (Fig.	('4EBP1', 'Gene', '1978', (108, 113))	('V2475M', 'Var', (149, 155))	('uRCC', 'Gene', (63, 67))	('L2427R', 'SUBSTITUTION', 'None', (73, 79))	('4EBP1', 'Gene', (108, 113))	('uRCC', 'Gene', '54894', (63, 67))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('V2475M', 'SUBSTITUTION', 'None', (149, 155))	('L2427R', 'Var', (73, 79))
137417	27713405	These findings suggest that the recurrent I1973F and L2427R MTOR mutations are likely pathogenic, whereas V2475M could be a passenger mutation.	('I1973F', 'Var', (42, 48))	('L2427R', 'Var', (53, 59))	('MTOR', 'Gene', (60, 64))	('L2427R', 'SUBSTITUTION', 'None', (53, 59))	('V2475M', 'Var', (106, 112))	('V2475M', 'SUBSTITUTION', 'None', (106, 112))	('MTOR', 'Gene', '2475', (60, 64))	('I1973F', 'SUBSTITUTION', 'None', (42, 48))
137418	27713405	Notably, all seven tumours with TSC1 or TSC2 mutations had high level of p-4EBP1 (H score=300), whereas only two of four tumours with PTEN mutations exhibited such staining (Fig.	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('mutations', 'Var', (45, 54))	('tumours', 'Disease', 'MESH:D009369', (121, 128))	('tumours', 'Disease', (121, 128))	('TSC1', 'Gene', (32, 36))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumours', 'Disease', (19, 26))	('TSC2', 'Gene', '7249', (40, 44))	('4EBP1', 'Gene', '1978', (75, 80))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))	('4EBP1', 'Gene', (75, 80))	('TSC2', 'Gene', (40, 44))	('PTEN', 'Gene', (134, 138))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('PTEN', 'Gene', '5728', (134, 138))	('TSC1', 'Gene', '7248', (32, 36))
137419	27713405	Altogether, our integrated analysis demonstrated that 13 of the 16 uRCC tumours with MTOR, TSC1, TSC2 or PTEN mutations exhibited hyperactive mTORC1 signals (Fig.	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('hyperactive', 'Disease', (130, 141))	('hyperactive', 'Disease', 'MESH:D006948', (130, 141))	('uRCC tumours', 'Disease', (67, 79))	('PTEN', 'Gene', (105, 109))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('TSC1', 'Gene', (91, 95))	('uRCC tumours', 'Disease', 'MESH:D009369', (67, 79))	('mutations', 'Var', (110, 119))	('TSC1', 'Gene', '7248', (91, 95))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('TSC2', 'Gene', '7249', (97, 101))	('PTEN', 'Gene', '5728', (105, 109))	('mTORC1', 'Gene', (142, 148))	('TSC2', 'Gene', (97, 101))	('mTORC1', 'Gene', '382056', (142, 148))	('mTORC1', 'cellular_component', 'GO:0031931', ('142', '148'))	('MTOR', 'Gene', (85, 89))	('MTOR', 'Gene', '2475', (85, 89))
137422	27713405	As germline and somatic mutations of FH have been described in hereditary leiomyomatosis RCC (HLRCC) and a small number of sporadic type II pRCC, we performed 2SC (2-succino-cystein) and FH immunohistochemistry to investigate the recurrent FH somatic mutations observed in three of our uRCC cases (Fig.	('pRCC', 'Gene', (140, 144))	('hereditary leiomyomatosis RCC', 'Disease', 'MESH:C538614', (63, 92))	('uRCC', 'Gene', '54894', (286, 290))	('mutations', 'Var', (24, 33))	('uRCC', 'Gene', (286, 290))	('RCC', 'Disease', (89, 92))	('described', 'Reg', (50, 59))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RCC', 'Disease', (96, 99))	('RCC', 'Phenotype', 'HP:0005584', (287, 290))	('2-succino-cystein', 'Chemical', '-', (164, 181))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('RCC', 'Disease', (287, 290))	('pRCC', 'Gene', '5546', (140, 144))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('RCC', 'Disease', 'MESH:C538614', (287, 290))	('hereditary leiomyomatosis RCC', 'Disease', (63, 92))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
137426	27713405	The remaining FH-negative/2SC-positive tumour (T41) harboured somatic homozygous deletion of the FH gene, revealing a somatic mechanism that can lead to FH functional loss (Supplementary Fig.	('tumour', 'Disease', (39, 45))	('deletion', 'Var', (81, 89))	('FH functional loss', 'Disease', (153, 171))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('FH functional loss', 'Disease', 'MESH:D006938', (153, 171))
137427	27713405	On the other hand, one tumour (T71) with FH G401V somatic mutation was found to be FH positive/2SC negative, and lacked histologic features of HLRCC or FH-deficient RCC, suggesting that FH G401V might be better categorized as a passenger mutation (Fig.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('FH-deficient RCC', 'Disease', 'MESH:C538614', (152, 168))	('RCC', 'Disease', (145, 148))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('tumour', 'Disease', (23, 29))	('G401V', 'SUBSTITUTION', 'None', (44, 49))	('G401V', 'Var', (44, 49))	('G401V', 'SUBSTITUTION', 'None', (189, 194))	('G401V', 'Var', (189, 194))	('FH-deficient RCC', 'Disease', (152, 168))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('RCC', 'Disease', (165, 168))
137432	27713405	Of the remaining 28 (45%) uRCC, 8 cases carried mutations of genes involved in chromatin modulation (SETD2, BAP1, KMT2A/C/D and PBRM1); 5 in DNA damage response (TP53, CHEK2 and BRCA2); and 15 without recurrent molecular features based on our analyses (Fig.	('uRCC', 'Gene', '54894', (26, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('uRCC', 'Gene', (26, 30))	('mutations', 'Var', (48, 57))	('BRCA2', 'Gene', '675', (178, 183))	('PBRM1', 'Gene', '55193', (128, 133))	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('BAP1', 'Gene', '8314', (108, 112))	('TP53', 'Gene', (162, 166))	('PBRM1', 'Gene', (128, 133))	('chromatin', 'cellular_component', 'GO:0000785', ('79', '88'))	('DNA damage response', 'biological_process', 'GO:0006974', ('141', '160'))	('CHEK2', 'Gene', (168, 173))	('KMT2A/C/D', 'Gene', '4297', (114, 123))	('KMT2A/C/D', 'Gene', (114, 123))	('BAP1', 'Gene', (108, 112))	('SETD2', 'Gene', (101, 106))	('CHEK2', 'Gene', '11200', (168, 173))	('TP53', 'Gene', '7157', (162, 166))	('BRCA2', 'Gene', (178, 183))	('SETD2', 'Gene', '29072', (101, 106))
137433	27713405	The possibility of these tumours representing other RCC subtypes (for example, TFE3/TFEB translocation or SDHB deficiency) was also excluded by established diagnostic assays.	('translocation', 'Var', (89, 102))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('TFEB', 'Gene', '7942', (84, 88))	('TFE3', 'Gene', '7030', (79, 83))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('TFEB', 'Gene', (84, 88))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('tumours', 'Disease', 'MESH:D009369', (25, 32))	('SDHB deficiency', 'Disease', (106, 121))	('TFE3', 'Gene', (79, 83))	('SDHB deficiency', 'Disease', 'MESH:D007153', (106, 121))	('tumours', 'Disease', (25, 32))
137434	27713405	Commonly mutated in VHL-deficient ccRCC, chromatin modulators PBRM1, SETD2 and BAP1 were recurrently mutated in uRCC that lacked VHL mutations.	('BAP1', 'Gene', '8314', (79, 83))	('VHL-deficient ccRCC', 'Disease', (20, 39))	('uRCC', 'Gene', '54894', (112, 116))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('uRCC', 'Gene', (112, 116))	('chromatin', 'cellular_component', 'GO:0000785', ('41', '50'))	('mutated', 'Var', (101, 108))	('BAP1', 'Gene', (79, 83))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('VHL', 'Gene', (20, 23))	('PBRM1', 'Gene', '55193', (62, 67))	('VHL', 'Gene', (129, 132))	('VHL-deficient ccRCC', 'Disease', 'MESH:D006623', (20, 39))	('PBRM1', 'Gene', (62, 67))	('SETD2', 'Gene', (69, 74))	('VHL', 'Gene', '7428', (20, 23))	('mutated', 'Var', (9, 16))	('SETD2', 'Gene', '29072', (69, 74))	('VHL', 'Gene', '7428', (129, 132))
137435	27713405	Our finding that these mutations also recur in nccRCC is in line with the recently reported mutations of SWI/SNF and chromatin modifier pathways in type 1 and type 2 pRCC.	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('chromatin modifier pathways', 'Pathway', (117, 144))	('pRCC', 'Gene', '5546', (166, 170))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('mutations', 'Var', (92, 101))	('RCC', 'Disease', (50, 53))	('mutations', 'Var', (23, 32))	('chromatin', 'cellular_component', 'GO:0000785', ('117', '126'))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('pRCC', 'Gene', (166, 170))	('SWI/SNF', 'Gene', (105, 112))
137436	27713405	Given the presence of mutations of chromatin modulation or DNA damage response genes in a wide variety of cancers and their known implications in tumorigenesis, we tentatively grouped together the uRCC cases with mutations in these pathways and lacking other apparent driver alterations.	('uRCC', 'Gene', '54894', (197, 201))	('DNA damage response genes', 'Gene', (59, 84))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('chromatin modulation', 'Gene', (35, 55))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('cancers', 'Disease', (106, 113))	('DNA damage response', 'biological_process', 'GO:0006974', ('59', '78'))	('mutations', 'Var', (22, 31))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('mutations', 'Var', (213, 222))	('uRCC', 'Gene', (197, 201))	('chromatin', 'cellular_component', 'GO:0000785', ('35', '44'))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
137437	27713405	Among the 15 cases lacking recurrent features ('other' group), T62 and T69 had non-recurrent MET (H1094Y) or BRAF (Y472C) pathogenic mutations, respectively (Supplementary Data 2).	('H1094Y', 'Var', (98, 104))	('Y472C', 'Var', (115, 120))	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('MET', 'Gene', '79811', (93, 96))	('MET', 'Gene', (93, 96))	('H1094Y', 'SUBSTITUTION', 'None', (98, 104))	('Y472C', 'SUBSTITUTION', 'None', (115, 120))
137438	27713405	Together, there were seven cases in which no mutation or other significant molecular alteration was detected by our panel of analyses, but the clinicopathologic features of these cases (for example, high-grade nuclear features, necrosis and so on) excluded the possibility of them being reclassified as renal oncocytomas.	('necrosis', 'Disease', 'MESH:D009336', (228, 236))	('renal oncocytomas', 'Disease', (303, 320))	('necrosis', 'biological_process', 'GO:0001906', ('228', '236'))	('renal oncocytomas', 'Disease', 'MESH:C537750', (303, 320))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (303, 320))	('necrosis', 'biological_process', 'GO:0070265', ('228', '236'))	('necrosis', 'biological_process', 'GO:0008219', ('228', '236'))	('necrosis', 'Disease', (228, 236))	('necrosis', 'biological_process', 'GO:0019835', ('228', '236'))	('high-grade', 'Var', (199, 209))	('necrosis', 'biological_process', 'GO:0008220', ('228', '236'))
137439	27713405	In addition, three uRCC tumours with somatic SMARCB1 mutations (T23, T38 and T41) retained the INI1 protein expression (encoded by SMARCB1), and were histologically distinct from renal medullary carcinoma that exhibits characteristic INI1 loss and occurs in individuals with sickle cell trait or other hemoglobinopathies (Supplementary Fig.	('T38', 'Var', (69, 72))	('carcinoma', 'Disease', 'MESH:D009369', (195, 204))	('T23', 'Var', (64, 67))	('INI1', 'Gene', (234, 238))	('INI1', 'Gene', '6598', (234, 238))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('SMARCB1', 'Gene', '6598', (131, 138))	('sickle cell trait', 'Disease', (275, 292))	('SMARCB1', 'Gene', (131, 138))	('uRCC tumours', 'Disease', (19, 31))	('uRCC tumours', 'Disease', 'MESH:D009369', (19, 31))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('loss', 'NegReg', (239, 243))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('hemoglobinopathies', 'Disease', 'MESH:D006453', (302, 320))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('carcinoma', 'Disease', (195, 204))	('INI1', 'Gene', (95, 99))	('INI1', 'Gene', '6598', (95, 99))	('T41', 'Var', (77, 80))	('hemoglobinopathies', 'Disease', (302, 320))	('SMARCB1', 'Gene', '6598', (45, 52))	('SMARCB1', 'Gene', (45, 52))
137447	27713405	Although some of these mutations are present in certain established subtypes of RCC, the overall mutation profiles, the frequencies of mutations in specific genes and a lack of characteristic molecular features of established RCC subtypes support the notion that these uRCC tumours are largely distinct from the established RCC subtypes and harbour their unique oncogenic pathways.	('RCC', 'Phenotype', 'HP:0005584', (324, 327))	('tumour', 'Phenotype', 'HP:0002664', (274, 280))	('RCC', 'Disease', 'MESH:C538614', (324, 327))	('tumours', 'Phenotype', 'HP:0002664', (274, 281))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (270, 273))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (270, 273))	('RCC', 'Disease', (270, 273))	('mutations', 'Var', (23, 32))	('uRCC tumours', 'Disease', 'MESH:D009369', (269, 281))	('RCC', 'Disease', 'MESH:C538614', (226, 229))	('RCC', 'Disease', (226, 229))	('RCC', 'Phenotype', 'HP:0005584', (226, 229))	('uRCC tumours', 'Disease', (269, 281))	('RCC', 'Disease', (324, 327))
137448	27713405	This study identifies a subset of uRCC that is characterized by NF2 loss, dysregulated Hippo-YAP signalling and aggressive clinical behaviour (Figs 2 and 4).	('uRCC', 'Gene', (34, 38))	('behaviour', 'biological_process', 'GO:0007610', ('132', '141'))	('uRCC', 'Gene', '54894', (34, 38))	('signalling', 'biological_process', 'GO:0023052', ('97', '107'))	('Hippo-YAP signalling', 'MPA', (87, 107))	('loss', 'NegReg', (68, 72))	('dysregulated', 'Var', (74, 86))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('NF2', 'Gene', (64, 67))	('aggressive clinical behaviour', 'Phenotype', 'HP:0000718', (112, 141))
137449	27713405	The majority (69%) of this subset demonstrates biallelic inactivation of NF2 with concurrent NF2 mutation and LOH, a molecular feature that has not been reported in RCC.	('LOH', 'MPA', (110, 113))	('NF2', 'Gene', (73, 76))	('NF2', 'Gene', (93, 96))	('mutation', 'Var', (97, 105))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('biallelic inactivation', 'Var', (47, 69))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('RCC', 'Disease', (165, 168))
137451	27713405	As the regulation of Hippo signalling could differ based on organ or cellular contexts, the YAP activation we observed predominantly in the NF2 loss subset of uRCC suggests that NF2 inactivation is an essential mechanism dysregulating Hippo signalling in RCC.	('inactivation', 'Var', (182, 194))	('Hippo signalling', 'MPA', (235, 251))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('signalling', 'biological_process', 'GO:0023052', ('27', '37'))	('RCC', 'Disease', (160, 163))	('uRCC', 'Gene', (159, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('signalling', 'biological_process', 'GO:0023052', ('241', '251'))	('uRCC', 'Gene', '54894', (159, 163))	('RCC', 'Disease', 'MESH:C538614', (255, 258))	('RCC', 'Disease', (255, 258))	('RCC', 'Phenotype', 'HP:0005584', (255, 258))	('loss', 'NegReg', (144, 148))	('activation', 'PosReg', (96, 106))	('NF2', 'Gene', (140, 143))	('regulation', 'biological_process', 'GO:0065007', ('7', '17'))
137453	27713405	Other molecular features found in this subset of tumours include the enrichment of SETD2 mutations, frequent 1p and 3p losses and aberrant histone methylation (absence of H3K36me3) in cases with concurrent 3p loss and SETD2 mutation.	('tumours', 'Disease', (49, 56))	('SETD2', 'Gene', '29072', (218, 223))	('aberrant', 'Var', (130, 138))	('SETD2', 'Gene', (218, 223))	('H3K36me3', 'Protein', (171, 179))	('mutation', 'Var', (224, 232))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('SETD2', 'Gene', '29072', (83, 88))	('losses', 'NegReg', (119, 125))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('mutations', 'Var', (89, 98))	('tumours', 'Disease', 'MESH:D009369', (49, 56))	('SETD2', 'Gene', (83, 88))	('loss', 'NegReg', (209, 213))	('histone methylation', 'biological_process', 'GO:0016571', ('139', '158'))	('histone methylation', 'MPA', (139, 158))
137463	27713405	Similar to what have been described in ccRCC and pRCC, mutations in chromatin modulation genes are relatively frequent in uRCC, although none of which (for example, SETD2 and BAP1) was found to be significantly associated with clinical outcomes in this cohort.	('uRCC', 'Gene', (122, 126))	('pRCC', 'Gene', '5546', (49, 53))	('chromatin', 'cellular_component', 'GO:0000785', ('68', '77'))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('BAP1', 'Gene', (175, 179))	('chromatin modulation genes', 'Gene', (68, 94))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('RCC', 'Disease', (50, 53))	('pRCC', 'Gene', (49, 53))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('frequent', 'Reg', (110, 118))	('RCC', 'Disease', (41, 44))	('mutations', 'Var', (55, 64))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('SETD2', 'Gene', (165, 170))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('associated', 'Reg', (211, 221))	('uRCC', 'Gene', '54894', (122, 126))	('SETD2', 'Gene', '29072', (165, 170))	('BAP1', 'Gene', '8314', (175, 179))
137464	27713405	We did not observe specific patterns of distribution for these mutations, except for the enrichment of SETD2 mutations in the NF2 loss subset.	('SETD2', 'Gene', '29072', (103, 108))	('mutations', 'Var', (109, 118))	('loss', 'NegReg', (130, 134))	('SETD2', 'Gene', (103, 108))	('NF2', 'Gene', (126, 129))
137465	27713405	Further validation studies are needed to clarify the roles of these mutations in the oncogenesis of various types of RCC.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('oncogenesis', 'biological_process', 'GO:0007048', ('85', '96'))	('mutations', 'Var', (68, 77))
137466	27713405	MET mutations have been predominantly, but not exclusively detected in pRCC based on the recent genomic studies of RCC.	('MET', 'Gene', '79811', (0, 3))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('pRCC', 'Gene', (71, 75))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('MET', 'Gene', (0, 3))	('pRCC', 'Gene', '5546', (71, 75))	('mutations', 'Var', (4, 13))
137467	27713405	While the discovery of MET H1094Y mutation in one uRCC may suggest it represents a pRCC with atypical histologic features, more importantly it provides a potential therapeutic option for this patient.	('uRCC', 'Gene', '54894', (50, 54))	('MET', 'Gene', (23, 26))	('pRCC', 'Gene', '5546', (83, 87))	('patient', 'Species', '9606', (192, 199))	('H1094Y', 'SUBSTITUTION', 'None', (27, 33))	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('H1094Y', 'Var', (27, 33))	('uRCC', 'Gene', (50, 54))	('pRCC', 'Gene', (83, 87))	('MET', 'Gene', '79811', (23, 26))
137480	27713405	Copy number was computed using tumour:normal ratios of normalized coverage data to determine amplifications and deletions except for data on chromosome X.	('deletions', 'Var', (112, 121))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('chromosome', 'cellular_component', 'GO:0005694', ('141', '151'))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('tumour', 'Disease', (31, 37))
137489	27713405	of South Carolina), FH (1:1,000, Clone J-13, Santa Cruz Biotechnology), INI1 (1:100, BAF47, BD Bioscience) and H3K36me3 (1:200, MABI-0333, Active Motif).	('H3K36me3', 'Var', (111, 119))	('INI1', 'Gene', '6598', (72, 76))	('INI1', 'Gene', (72, 76))
137499	27713405	Signals for ALK gene rearrangement are either 'broken apart' signal or 'single orange' signal (deleted green signal for 5'ALK).	('ALK', 'Gene', (12, 15))	('ALK', 'Gene', '238', (12, 15))	('rearrangement', 'Var', (21, 34))	('ALK', 'Gene', (122, 125))	("'broken apart", 'Phenotype', 'HP:0001061', (46, 59))	('ALK', 'Gene', '238', (122, 125))
137503	27713405	The mTOR single mutations were generated by introducing corresponding nucleotide changes into pcDNA3-Flag-mTOR using QuikChange II XL site-directed mutagenesis kit (Agilent).	('mutagenesis', 'biological_process', 'GO:0006280', ('148', '159'))	('mTOR', 'Gene', '2475', (106, 110))	('nucleotide changes', 'Var', (70, 88))	('mTOR', 'Gene', (106, 110))	('mTOR', 'Gene', (4, 8))	('mTOR', 'Gene', '2475', (4, 8))	('introducing', 'Reg', (44, 55))
137504	27713405	The primers for site-directed mutagenesis are as follows: mTOR L2427R, 5'-CATCAGCCTCCAGTTCCGCAAGGGGTCATAGAC-3'; mTOR V2475M, 5'-AATAGATTCTGGCATTGTGGTCCCCGTTTTCTTATGGG-3'.	('mTOR', 'Gene', (58, 62))	('L2427R', 'SUBSTITUTION', 'None', (63, 69))	('mTOR', 'Gene', '2475', (112, 116))	('mTOR', 'Gene', (112, 116))	('V2475M', 'Var', (117, 123))	('L2427R', 'Var', (63, 69))	('V2475M', 'SUBSTITUTION', 'None', (117, 123))	('mTOR', 'Gene', '2475', (58, 62))	('mutagenesis', 'biological_process', 'GO:0006280', ('30', '41'))
137516	27713405	For mTORC1 signalling experiments, 293T cells were seeded in 6-well plates (1.8 x 106 cells per well) 24 h before transfection by 1.5 mug of vectors expressing wild type or mutant mTOR and 50 ng of vector expressing S6K using Lipofectamine 2000 (Invitrogen).	('mTORC1', 'cellular_component', 'GO:0031931', ('4', '10'))	('mTOR', 'Gene', (180, 184))	('mTOR', 'Gene', '2475', (180, 184))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (226, 244))	('mTORC1', 'Gene', '382056', (4, 10))	('293T', 'CellLine', 'CVCL:0063', (35, 39))	('mug', 'molecular_function', 'GO:0043739', ('134', '137'))	('mutant', 'Var', (173, 179))	('signalling', 'biological_process', 'GO:0023052', ('11', '21'))	('mTOR', 'Gene', '2475', (4, 8))	('mTOR', 'Gene', (4, 8))	('mTORC1', 'Gene', (4, 10))
137519	27713405	Antibodies used for immunoblot analysis are as follows: anti-NF2 (ab88957, Abcam), anti-YAP1 (no.	('anti-NF2', 'Var', (56, 64))	('YAP1', 'Gene', (88, 92))	('YAP1', 'Gene', '10413', (88, 92))
137520	27713405	12395, Cell Signaling Technology), anti-pSer-127 YAP1 (no.	('anti-pSer-127', 'Var', (35, 48))	('YAP1', 'Gene', (49, 53))	('Signaling', 'biological_process', 'GO:0023052', ('12', '21'))	('YAP1', 'Gene', '10413', (49, 53))
137522	27713405	2217, Cell Signaling Technology), anti-Flag (F1804, Sigma), anti-RAPTOR (no.	('Signaling', 'biological_process', 'GO:0023052', ('11', '20'))	('RAPTOR', 'Gene', (65, 71))	('F1804', 'Var', (45, 50))	('RAPTOR', 'Gene', '57521', (65, 71))
137537	30380599	Both primary and metastatic ccRCC tumors are uniquely characterized by the expression of altered biomarkers associated with increased angiogenesis, metastasis, and drug resistance, including deletion and/or mutation of the von Hippel-Lindau (VHL) tumor suppressor gene in the majority of ccRCC tumors, resulting in the stable expression of hypoxia-inducible factors 1alpha and 2alpha (HIFs), and vascular endothelial growth factor (VEGF).	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('deletion', 'Var', (191, 199))	('drug resistance', 'Phenotype', 'HP:0020174', (164, 179))	('vascular endothelial growth factor', 'Gene', (396, 430))	('angiogenesis', 'biological_process', 'GO:0001525', ('134', '146'))	('ccRCC tumors', 'Disease', (28, 40))	('tumor suppressor', 'biological_process', 'GO:0051726', ('247', '263'))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('expression', 'MPA', (326, 336))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (223, 252))	('ccRCC tumors', 'Disease', (288, 300))	('ccRCC tumors', 'Disease', 'MESH:D009369', (28, 40))	('mutation', 'Var', (207, 215))	('ccRCC tumors', 'Disease', 'MESH:D009369', (288, 300))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('drug resistance', 'biological_process', 'GO:0009315', ('164', '179'))	('drug resistance', 'biological_process', 'GO:0042493', ('164', '179'))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('hypoxia-inducible factors 1alpha and 2alpha', 'Gene', '3091;2034', (340, 383))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('396', '430'))	('vascular endothelial growth factor', 'Gene', '7422', (396, 430))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('247', '263'))	('tumors', 'Phenotype', 'HP:0002664', (294, 300))
137543	30380599	PD-L1 was expressed in 69 out of 98 (70.9%) ccRCC tumors expressing mutant VHL.	('VHL', 'Gene', (75, 78))	('ccRCC tumors', 'Disease', (44, 56))	('VHL', 'Gene', '7428', (75, 78))	('PD-L1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('ccRCC tumors', 'Disease', 'MESH:D009369', (44, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('PD-L1', 'Gene', '29126', (0, 5))	('mutant', 'Var', (68, 74))
137558	30380599	Recent published reports indicated that ccRCC tumor cells expressing mutant VHL and the stable expression of HIFs participate in lipid deposition.	('participate', 'Reg', (114, 125))	('VHL', 'Gene', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('mutant', 'Var', (69, 75))	('VHL', 'Gene', '7428', (76, 79))	('ccRCC', 'Disease', (40, 45))	('tumor', 'Disease', (46, 51))	('lipid deposition', 'MPA', (129, 145))	('lipid', 'Chemical', 'MESH:D008055', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
137561	30380599	Since both HIFs are involved in the regulation of lipid droplets in ccRCC, agents that target HIF2alpha, but not HIF1alpha, may express limited antitumor activity.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('HIF1alpha', 'Gene', (113, 122))	('HIF2alpha', 'Var', (94, 103))	('involved', 'Reg', (20, 28))	('HIF1alpha', 'Gene', '3091', (113, 122))	('tumor', 'Disease', (148, 153))	('ccRCC', 'Disease', (68, 73))	('lipid droplets', 'MPA', (50, 64))	('regulation', 'biological_process', 'GO:0065007', ('36', '46'))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('lipid', 'Chemical', 'MESH:D008055', (50, 55))
137566	30380599	The data in Figure 2 show that the inhibition of constitutively expressed HIF1alpha and HIF2alpha in RC2 and 786.0 Clear-cell RCC cells, and HIF1alpha in FaDu head and neck, A548 lung carcinoma cells, and HT29 colorectal tumor cells is selenium dose-dependent and independent of the disease site/cell type.	('HT29', 'CellLine', 'CVCL:0320', (205, 209))	('HIF1alpha', 'Gene', '3091', (74, 83))	('colorectal tumor', 'Disease', 'MESH:D015179', (210, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('neck', 'cellular_component', 'GO:0044326', ('168', '172'))	('HIF2alpha', 'Var', (88, 97))	('selenium', 'Chemical', 'MESH:D012643', (236, 244))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('lung carcinoma', 'Disease', 'MESH:D008175', (179, 193))	('HIF1alpha', 'Gene', (141, 150))	('lung carcinoma', 'Disease', (179, 193))	('colorectal tumor', 'Disease', (210, 226))	('HIF1alpha', 'Gene', '3091', (141, 150))	('HIF1alpha', 'Gene', (74, 83))
137579	30380599	Oncogenic miRNA-155 and miRNA-210 are highly overexpressed in ccRCC tumors expressing HIF1alpha, HIF2alpha, VEGF, and PD-L1.	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('PD-L1', 'Gene', (118, 123))	('HIF2alpha', 'Var', (97, 106))	('miRNA-155', 'Gene', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('overexpressed', 'PosReg', (45, 58))	('ccRCC tumors', 'Disease', 'MESH:D009369', (62, 74))	('PD-L1', 'Gene', '29126', (118, 123))	('miR', 'Gene', '220972', (10, 13))	('miR', 'Gene', '220972', (24, 27))	('HIF1alpha', 'Gene', (86, 95))	('miR', 'Gene', (10, 13))	('miR', 'Gene', (24, 27))	('ccRCC tumors', 'Disease', (62, 74))	('miRNA-155', 'Gene', '406947', (10, 19))	('HIF1alpha', 'Gene', '3091', (86, 95))
137590	30380599	Collectively, MSC was found to significantly enhance the therapeutic efficacy of chemotherapy and radiation in different human cancer xenografts from different disease sites.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('therapeutic efficacy', 'CPA', (57, 77))	('enhance', 'PosReg', (45, 52))	('human', 'Species', '9606', (121, 126))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('MSC', 'Var', (14, 17))
137599	30380599	MSC potentiates the antitumor activity of topotecan, a topoisomerase 1 poison which targets HIF synthesis, as well as that of Avastin, axitinib, and sunitinib, which target VEGF/VEGFR.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('Avastin', 'Chemical', 'MESH:D000068258', (126, 133))	('axitinib', 'Chemical', 'MESH:D000077784', (135, 143))	('topoisomerase', 'molecular_function', 'GO:0003918', ('55', '68'))	('VEGFR', 'Gene', '3791', (178, 183))	('tumor', 'Disease', (24, 29))	('topotecan', 'Chemical', 'MESH:D019772', (42, 51))	('sunitinib', 'Chemical', 'MESH:D000077210', (149, 158))	('synthesis', 'biological_process', 'GO:0009058', ('96', '105'))	('VEGFR', 'Gene', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('potentiates', 'PosReg', (4, 15))	('topoisomerase', 'molecular_function', 'GO:0003917', ('55', '68'))	('MSC', 'Var', (0, 3))
137606	30380599	Loss of VHL in ccRCC tumors may mimic the upregulation of HIFs by hypoxia.	('ccRCC tumors', 'Disease', 'MESH:D009369', (15, 27))	('VHL', 'Gene', '7428', (8, 11))	('ccRCC tumors', 'Disease', (15, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('hypoxia', 'Disease', (66, 73))	('hypoxia', 'Disease', 'MESH:D000860', (66, 73))	('Loss', 'Var', (0, 4))	('VHL', 'Gene', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
137608	30380599	Similarly, recognizing that HIFs are upregulated by hypoxia-dependent and -independent pathways and that they are critical therapeutic targets, a number of HIF inhibitors are presently under preclinical and clinical development.	('hypoxia', 'Disease', (52, 59))	('inhibitors', 'Var', (160, 170))	('upregulated', 'PosReg', (37, 48))	('hypoxia', 'Disease', 'MESH:D000860', (52, 59))
137613	30380599	It is possible that the inhibition of one HIF isoform may induce the activation of the other in support of tumor growth.	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('inhibition', 'Var', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))
137624	30380599	Molecularly, the majority of ccRCC tumors express high incidence and intensity of HIF1alpha, HIF2alpha, and oncogenic miRNA-155 and -210, which target genes involved in ccRCC tumorigenesis, including VEGF and PD-L.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', (175, 180))	('HIF2alpha', 'Var', (93, 102))	('ccRCC tumors', 'Disease', (29, 41))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('HIF1alpha', 'Gene', '3091', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('ccRCC tumors', 'Disease', 'MESH:D009369', (29, 41))	('VEGF', 'Disease', (200, 204))	('miRNA-155 and -210', 'Gene', '406947', (118, 136))	('HIF1alpha', 'Gene', (82, 91))	('ccRCC', 'Disease', (169, 174))
137638	30380599	The antitumor activity of VEFG/VEGFR-targeted therapies alone and in combination with topotecan and S-1 can be further enhanced by MSC in mice bearing VHL-deficient 786.0 ccRCC tumors expressing HIF2alpha, VEGF, miRNA-155, and miRNA-210.	('ccRCC tumors', 'Disease', (171, 183))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('VEGFR', 'Gene', '3791', (31, 36))	('miR', 'Gene', (212, 215))	('HIF2alpha', 'Var', (195, 204))	('miR', 'Gene', '220972', (227, 230))	('miRNA-155', 'Gene', (212, 221))	('enhanced', 'PosReg', (119, 127))	('VEGFR', 'Gene', (31, 36))	('ccRCC tumors', 'Disease', 'MESH:D009369', (171, 183))	('mice', 'Species', '10090', (138, 142))	('VHL-deficient', 'Disease', 'MESH:D006623', (151, 164))	('miR', 'Gene', (227, 230))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('topotecan', 'Chemical', 'MESH:D019772', (86, 95))	('miR', 'Gene', '220972', (212, 215))	('miRNA-155', 'Gene', '406947', (212, 221))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('VHL-deficient', 'Disease', (151, 164))
137653	30380599	Unlike the 200 mug/day SLM dose used in prevention clinical trials, the SLM doses used in combination therapy were 10 mg/kg in nude mice, and 8000 mug/day in ccRCC patients, which was the dose recommended for the ongoing phase 2 clinical trial for efficacy assessment and for the monitoring of the effects of SLM on relevant biomarkers.	('mug', 'molecular_function', 'GO:0043739', ('15', '18'))	('8000 mug/day', 'Var', (142, 154))	('nude mice', 'Species', '10090', (127, 136))	('ccRCC', 'Disease', (158, 163))	('patients', 'Species', '9606', (164, 172))	('mug', 'molecular_function', 'GO:0043739', ('147', '150'))
137701	28934212	Accordingly, RCC histopathology classification has been confirmed by (cyto)genetic analyses, with pRCC showing trisomy of chromosomes 7 and 17 and loss of chromosome Y, whereas clear cell RCC (ccRCC) frequently displays deletion of chromosome 3p and mutation of VHL gene.	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('VHL', 'Disease', 'MESH:D006623', (262, 265))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', (99, 102))	('loss', 'NegReg', (147, 151))	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (195, 198))	('chromosome', 'Gene', (155, 165))	('RCC', 'Disease', (195, 198))	('mutation', 'Var', (250, 258))	('pRCC', 'Gene', (98, 102))	('trisomy', 'Var', (111, 118))	('deletion', 'Var', (220, 228))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('VHL', 'Disease', (262, 265))	('chromosome', 'cellular_component', 'GO:0005694', ('155', '165'))	('chromosome', 'cellular_component', 'GO:0005694', ('232', '242'))	('RCC', 'Disease', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('RCC', 'Disease', (13, 16))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('pRCC', 'Gene', '5546', (98, 102))
137722	28934212	Approval of the study was obtained from the ethics committee of the State Medical Board Brandenburg, Germany, the ethics committee of the University Hospital Frankfurt, Goethe-University, Germany (#4/09), the local ethics committee of the Faculty Hospital Plzen and Faculty of Medicine Plzen, Charles University, Prague, Czech Republic, the Medical Ethics Committee II of the Faculty of Medicine Mannheim, University of Heidelberg, Germany (#2014-811R-MA), the ethics committee of the State Medical Board Westfalen-Lippe and the Faculty of Medicine University of Muenster, Germany (#2015-506-f-S), San Raffaele Ethics Committee, University Vita-Salute San Raffaele, Milan, Italy (#2007/29082007/V3), the ethical committee of the University of Heidelberg, Germany (#206/2005), the local human research ethics committee of the Medical Faculty of the University of Wuerzburg, Germany, the institutional review board of Weill Cornell Medical College, New York, NY, USA (#1007011131), UT Southwestern Institutional Review Board, Dallas, TX, USA, the Washington University in St. Louis Institutional Review Board, St. Louis, MO, USA (#201102423), the ethics committee of the Technical University of Dresden, Germany (EK 269072014), the ethics committee of the Medical University of Vienna and Vienna General Hospital, Austria, and the ethics committee of the Medical University of Graz, Austria.	('#201102423', 'Var', (1128, 1138))	('human', 'Species', '9606', (786, 791))	('EK 269072014', 'Var', (1211, 1223))
137784	28934212	Given mutations of the mesenchymal-epithelial transition (MET) oncogene in pRCC type 1 and of fumarate hydratase (FH) in pRCC type 2, targeted agents assigning MET (e.g.	('pRCC', 'Gene', '5546', (121, 125))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('pRCC', 'Gene', (75, 79))	('MET', 'Gene', (58, 61))	('FH', 'Gene', '2271', (114, 116))	('mesenchymal-epithelial transition', 'biological_process', 'GO:0060231', ('23', '56'))	('pRCC', 'Gene', '5546', (75, 79))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('pRCC', 'Gene', (121, 125))	('fumarate hydratase', 'Gene', '2271', (94, 112))	('fumarate hydratase', 'Gene', (94, 112))	('mutations', 'Var', (6, 15))
137799	32024997	Truncating mutations are markedly enriched in kidney, colorectal and thyroid cancers, suggesting oncogenic effects with the activation of signaling pathways.	('Truncating mutations', 'Var', (0, 20))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('thyroid cancer', 'Phenotype', 'HP:0002890', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colorectal and thyroid cancers', 'Disease', 'MESH:D015179', (54, 84))	('signaling', 'biological_process', 'GO:0023052', ('138', '147'))	('kidney', 'Disease', (46, 52))
137800	32024997	Mitochondrial copy number varies greatly within and across cancers and correlates with clinical variables.	('correlates', 'Reg', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('Mitochondrial copy number', 'Var', (0, 25))	('cancers', 'Disease', (59, 66))
137815	32024997	The high reliability of the mutations was confirmed by long-range PCR-based validation (Supplementary Table 2) and by inspection of the mutational spectrum of the very low-VAF mutation candidates (Supplementary Fig.	('low-VAF', 'NegReg', (168, 175))	('VAF', 'Chemical', '-', (172, 175))	('mutation', 'Var', (176, 184))	('mutations', 'Var', (28, 37))
137817	32024997	Overall, mtDNA mutations located in the transcribed regions were also found in RNA-seq with similar VAFs, except for a fraction of transfer RNA (tRNA) mutations showing much higher VAFs in transcripts due to the accumulation of unprocessed tRNA precursors during the processing of polycistronic mitochondrial transcripts (Supplementary Fig.	('transfer RNA', 'molecular_function', 'GO:0005563', ('131', '143'))	('RNA', 'cellular_component', 'GO:0005562', ('140', '143'))	('transfer RNA', 'molecular_function', 'GO:0030533', ('131', '143'))	('mutations', 'Var', (15, 24))	('VAF', 'Chemical', '-', (100, 103))	('VAF', 'Chemical', '-', (181, 184))	('RNA', 'cellular_component', 'GO:0005562', ('79', '82'))	('tRNA', 'molecular_function', 'GO:0030533', ('145', '149'))	('mtDNA', 'cellular_component', 'GO:0000262', ('9', '14'))	('mutations', 'Var', (151, 160))	('tRNA', 'molecular_function', 'GO:0030533', ('240', '244'))
137818	32024997	Across all of the cancer samples, we observed several mutational hotspots in the regulatory D-loop region and the ND4 gene (Fig.	('ND4', 'Gene', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('mutational', 'Var', (54, 64))	('ND4', 'Gene', '4538', (114, 117))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
137819	32024997	Of the 13 protein-coding genes, ND5 was the most frequently mutated in most cancer types, while ND4 was most frequently mutated in prostate and lung cancers, and COX1 was most frequently mutated in breast, cervical and bladder cancers (Supplementary Fig.	('bladder cancers', 'Disease', 'MESH:D001749', (219, 234))	('COX1', 'Gene', '4512', (162, 166))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('bladder cancers', 'Disease', (219, 234))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('mutated', 'Var', (187, 194))	('mutated', 'Reg', (60, 67))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('cancer', 'Disease', (149, 155))	('cervical', 'Disease', (206, 214))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Disease', (227, 233))	('lung cancers', 'Phenotype', 'HP:0100526', (144, 156))	('ND4', 'Gene', '4538', (96, 99))	('cancer', 'Disease', (76, 82))	('ND4', 'Gene', (96, 99))	('ND5', 'Gene', (32, 35))	('bladder cancers', 'Phenotype', 'HP:0009725', (219, 234))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('COX1', 'Gene', (162, 166))	('breast', 'Disease', (198, 204))	('ND5', 'Gene', '4540', (32, 35))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('prostate and lung cancers', 'Disease', 'MESH:D011471', (131, 156))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('mutated', 'Var', (120, 127))
137820	32024997	We identified that cancer type and gene identity were associated with the mutation status of the 13 coding genes (log-linear model, Pcancer type < 2.2 x 10-16; Pgene < 2.2 x 10-16), but the effect of their interaction was not significant (Pcancer type x gene = 0.12).	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('mutation status', 'Var', (74, 89))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('Pgene', 'Chemical', '-', (160, 165))	('cancer', 'Disease', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('associated', 'Reg', (54, 64))
137821	32024997	In contrast with somatic mutations in nuclear genomes (where cancer type-specific mutational signatures are observed), mtDNA mutational signatures were very similar across tumor types, with C:G>T:A (58.3%) and T:A>C:G (34.2%) substitutions being the most and second most frequent mutation types, respectively (Fig.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('T:A>C:G', 'Var', (210, 217))	('mtDNA', 'cellular_component', 'GO:0000262', ('119', '124'))	('tumor', 'Disease', (172, 177))	('C:G>T:A', 'Var', (190, 197))	('cancer', 'Disease', (61, 67))	('frequent', 'Reg', (271, 279))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
137824	32024997	Instead, the vast majority of mtDNA mutations were manifesting extreme replicational mtDNA strand bias; that is, predominant G>A and T>C substitutions and deficient complementary C>T and A>G substitutions on the light (L) strand of the mtDNA genome sequence (+strand of the revised Cambridge Reference Sequence) despite the relative depletion of guanines and thymines on the L strand (Supplementary Fig.	('A>G substitutions', 'Var', (187, 204))	('G>A', 'Var', (125, 128))	('deficient complementary C>T', 'Disease', (155, 182))	('deficient complementary C>T', 'Disease', 'MESH:C537418', (155, 182))	('mutations', 'Var', (36, 45))	('substitutions', 'Var', (191, 204))	('mtDNA', 'cellular_component', 'GO:0000262', ('30', '35'))	('mtDNA', 'cellular_component', 'GO:0000262', ('85', '90'))	('substitutions', 'Var', (137, 150))	('guanines', 'Chemical', 'MESH:D006147', (346, 354))	('thymines', 'Chemical', 'MESH:D013941', (359, 367))	('thymines', 'MPA', (359, 367))	('depletion', 'MPA', (333, 342))	('mtDNA', 'Gene', (30, 35))	('mtDNA', 'cellular_component', 'GO:0000262', ('236', '241'))	('T>C substitutions', 'Var', (133, 150))	('guanines', 'MPA', (346, 354))
137825	32024997	These mutational signatures suggest that mitochondria-specific, replication-coupled mutational processes (such as mtDNA polymerase gamma error or other replication-coupled DNA damage mechanisms) are dominantly responsible for somatic mtDNA mutations in cancer.	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('mtDNA', 'cellular_component', 'GO:0000262', ('114', '119'))	('mitochondria', 'cellular_component', 'GO:0005739', ('41', '53'))	('DNA', 'cellular_component', 'GO:0005574', ('172', '175'))	('cancer', 'Disease', (253, 259))	('mtDNA', 'cellular_component', 'GO:0000262', ('234', '239'))	('mtDNA', 'Gene', (234, 239))	('responsible', 'Reg', (210, 221))	('mutations', 'Var', (240, 249))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
137826	32024997	The number of mtDNA mutations in our study was largely proportional to the age of the patient at the time of tissue sampling (Supplementary Fig.	('mtDNA', 'Gene', (14, 19))	('mtDNA', 'cellular_component', 'GO:0000262', ('14', '19'))	('mutations', 'Var', (20, 29))	('patient', 'Species', '9606', (86, 93))
137828	32024997	We observed significantly positive correlations between the mutation burdens of mitochondrial and nuclear genomes in several cancer types, with the highest correlations observed in kidney chromophobe and thyroid cancers (magenta bars in Fig.	('mutation', 'Var', (60, 68))	('thyroid cancer', 'Phenotype', 'HP:0002890', (204, 218))	('kidney chromophobe and thyroid cancers', 'Disease', 'MESH:D013964', (181, 219))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('cancer', 'Disease', (212, 218))	('mitochondrial', 'Protein', (80, 93))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
137829	32024997	Some of these correlations may be explained by the age effect, as the mutation numbers in both mitochondrial and nuclear genomes were significantly correlated with patient age in the corresponding cancer types (bars marked with an asterisk in Fig.	('nuclear genomes', 'Gene', (113, 128))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('patient', 'Species', '9606', (164, 171))	('cancer', 'Disease', (197, 203))	('correlated', 'Reg', (148, 158))	('mutation numbers', 'Var', (70, 86))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('mitochondrial', 'Gene', (95, 108))
137830	32024997	Although nuclear driver alterations exist in the majority of patients in most cancer types, a notable proportion of patients (22.2% with kidney chromophobe cancer and 18.8% with thyroid cancer) bear non-silent mtDNA mutations but no known nuclear drivers, suggesting a potential functional contribution of mtDNA mutations in the absence of nuclear drivers in these cancer types (Fig.	('mtDNA', 'cellular_component', 'GO:0000262', ('306', '311'))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('kidney chromophobe cancer', 'Disease', (137, 162))	('thyroid cancer', 'Disease', (178, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('cancer', 'Disease', (365, 371))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('mtDNA', 'cellular_component', 'GO:0000262', ('210', '215'))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('thyroid cancer', 'Disease', 'MESH:D013964', (178, 192))	('cancer', 'Disease', (78, 84))	('thyroid cancer', 'Phenotype', 'HP:0002890', (178, 192))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (365, 371))	('cancer', 'Disease', (186, 192))	('mtDNA', 'Gene', (210, 215))	('cancer', 'Disease', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('kidney chromophobe cancer', 'Disease', 'MESH:D007680', (137, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('mutations', 'Var', (216, 225))
137833	32024997	The most striking case was a breast cancer sample (sample ID: SP6730) harboring 33 mutations, 30 of which were localized in a 2-kb region (Fig.	('mutations', 'Var', (83, 92))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', (29, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
137835	32024997	The mutated mtDNA copy is then likely to shift to appreciable VAF (~7% frequency) by a series of replications throughout the cell lineages, despite the low probability of causation of a defective phenotype.	('mutated', 'Var', (4, 11))	('shift', 'PosReg', (41, 46))	('mtDNA', 'Gene', (12, 17))	('mtDNA', 'cellular_component', 'GO:0000262', ('12', '17'))	('VAF', 'Chemical', '-', (62, 65))
137836	32024997	We found that dN/dS was overall close to 1 for missense mutations at different VAFs across cancer types, suggesting that overall selection for mtDNA missense mutations is nearly neutral (Supplementary Fig.	('mtDNA', 'cellular_component', 'GO:0000262', ('143', '148'))	('missense mutations', 'Var', (47, 65))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('missense mutations', 'Var', (149, 167))	('VAF', 'Chemical', '-', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('mtDNA', 'Gene', (143, 148))
137837	32024997	For truncating mutations on the 13 mtDNA genes, we found evidence of negative selection in most cancer types, suggesting the importance of intact mitochondrial function in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('truncating mutations', 'Var', (4, 24))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('mtDNA genes', 'Gene', (35, 46))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (172, 178))	('mtDNA', 'cellular_component', 'GO:0000262', ('35', '40'))	('cancer', 'Disease', (96, 102))
137838	32024997	For example, the VAFs of mtDNA truncating mutations were notably more suppressed than those of missense or silent mutations (Fig.	('mtDNA', 'cellular_component', 'GO:0000262', ('25', '30'))	('VAF', 'Chemical', '-', (17, 20))	('truncating mutations', 'Var', (31, 51))	('suppressed', 'NegReg', (70, 80))	('VAFs', 'CPA', (17, 21))	('mtDNA', 'Gene', (25, 30))
137840	32024997	The enrichment of nearly homoplasmic (>60% VAF) truncating mutations was very striking in kidney cancers, especially in chromophobe and papillary types, suggesting that the inactivation of the normal mitochondrial function is an important step in tumorigenesis (Fig.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Disease', (247, 252))	('VAF', 'Chemical', '-', (43, 46))	('kidney cancer', 'Phenotype', 'HP:0009726', (90, 103))	('truncating', 'Var', (48, 58))	('kidney cancers', 'Disease', (90, 104))	('kidney cancers', 'Phenotype', 'HP:0009726', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('kidney cancers', 'Disease', 'MESH:D007680', (90, 104))	('tumor', 'Disease', 'MESH:D009369', (247, 252))
137844	32024997	Moreover, samples with mtDNA truncating mutations showed upregulation of gene expression in cancer-related pathways, such as mammalian target of rapamycin signaling, tumor necrosis factor-alpha signaling, oxidative phosphorylation and protein secretion (false discovery rate (FDR) < 0.05; Fig.	('false', 'biological_process', 'GO:0071878', ('254', '259'))	('truncating mutations', 'Var', (29, 49))	('necrosis', 'biological_process', 'GO:0008220', ('172', '180'))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('166', '187'))	('mtDNA', 'cellular_component', 'GO:0000262', ('23', '28'))	('mtDNA', 'Gene', (23, 28))	('upregulation', 'PosReg', (57, 69))	('protein', 'cellular_component', 'GO:0003675', ('235', '242'))	('necrosis', 'biological_process', 'GO:0070265', ('172', '180'))	('necrosis', 'biological_process', 'GO:0019835', ('172', '180'))	('mammalian target of rapamycin signaling', 'MPA', (125, 164))	('necrosis', 'biological_process', 'GO:0001906', ('172', '180'))	('protein secretion', 'MPA', (235, 252))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('205', '230'))	('cancer', 'Disease', (92, 98))	('signaling', 'biological_process', 'GO:0023052', ('194', '203'))	('oxidative phosphorylation', 'MPA', (205, 230))	('false', 'biological_process', 'GO:0071877', ('254', '259'))	('gene expression', 'biological_process', 'GO:0010467', ('73', '88'))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('necrosis', 'biological_process', 'GO:0008219', ('172', '180'))	('tumor necrosis', 'Disease', 'MESH:D009336', (166, 180))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('protein secretion', 'biological_process', 'GO:0009306', ('235', '252'))	('tumor necrosis', 'Disease', (166, 180))	('gene expression', 'MPA', (73, 88))
137845	32024997	Collectively, these results strongly suggest functional oncogenic impacts of mitochondrial truncating mutations in the initiation and clonal evolution of the specific cancer types.	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('mitochondrial truncating mutations', 'Var', (77, 111))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (167, 173))
137864	32024997	For the cancer samples with WGS data from matched normal tissues (n = 507), we observed increased mtDNA copy numbers in cancer samples in patients with chronic lymphocytic leukemia, lung squamous cell carcinoma and pancreatic adenocarcinoma, but decreased copy numbers in cancer samples in patients with kidney clear cell carcinoma, hepatocellular carcinoma and myeloproliferative neoplasm (Fig.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('cancer', 'Disease', (120, 126))	('hepatocellular carcinoma and myeloproliferative neoplasm', 'Disease', 'MESH:D006528', (333, 389))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (215, 240))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (152, 180))	('pancreatic adenocarcinoma', 'Disease', (215, 240))	('chronic lymphocytic leukemia', 'Disease', (152, 180))	('copy numbers', 'Var', (104, 116))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (8, 14))	('patients', 'Species', '9606', (290, 298))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (152, 180))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('patients', 'Species', '9606', (138, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (187, 210))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (182, 210))	('lung squamous cell carcinoma', 'Disease', (182, 210))	('leukemia', 'Phenotype', 'HP:0001909', (172, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (348, 357))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('increased', 'PosReg', (88, 97))	('kidney clear cell carcinoma', 'Disease', (304, 331))	('mtDNA', 'Gene', (98, 103))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (333, 357))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (215, 240))	('neoplasm', 'Phenotype', 'HP:0002664', (381, 389))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('mtDNA', 'cellular_component', 'GO:0000262', ('98', '103'))	('myeloproliferative neoplasm', 'Phenotype', 'HP:0005547', (362, 389))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (304, 331))	('cancer', 'Disease', (272, 278))
137871	32024997	We further observed correlations between mtDNA copy number and tumor stage in multiple cancer types (Fig.	('tumor', 'Disease', (63, 68))	('mtDNA', 'Gene', (41, 46))	('multiple cancer', 'Disease', (78, 93))	('copy number', 'Var', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mtDNA', 'cellular_component', 'GO:0000262', ('41', '46'))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('correlations', 'Interaction', (20, 32))	('multiple cancer', 'Disease', 'MESH:D009369', (78, 93))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
137873	32024997	Of the 2,658 cancer samples, three (0.11%) showed notable structural variants in the mtDNA (Fig.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('mtDNA', 'cellular_component', 'GO:0000262', ('85', '90'))	('mtDNA', 'Gene', (85, 90))	('structural variants', 'Var', (58, 77))
137874	32024997	For example, a pancreatic cancer case (sample ID: SP76017) harbored a ~3.4-kb-long mtDNA loss that truncated ribosomal RNA and ND1 genes.	('ND1', 'Gene', (127, 130))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (15, 32))	('mtDNA', 'cellular_component', 'GO:0000262', ('83', '88'))	('ribosomal RNA', 'molecular_function', 'GO:0005566', ('109', '122'))	('ribosomal RNA', 'Protein', (109, 122))	('ribosomal RNA', 'molecular_function', 'GO:0003735', ('109', '122'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (15, 32))	('pancreatic cancer', 'Disease', (15, 32))	('ND1', 'Gene', '4535', (127, 130))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('ribosomal RNA', 'cellular_component', 'GO:0005840', ('109', '122'))	('truncated', 'Var', (99, 108))
137876	32024997	Similarly, a melanoma case (sample ID: SP127680) showed tandem duplication of an mtDNA segment of ~4 kb, with 100% VAF.	('VAF', 'Chemical', '-', (115, 118))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanoma', 'Disease', (13, 21))	('mtDNA', 'Gene', (81, 86))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))	('mtDNA', 'cellular_component', 'GO:0000262', ('81', '86'))	('tandem duplication', 'Var', (56, 74))
137880	32024997	This observation was partially due to the relative abundance of mtDNA copy number across cancer types and is consistent with a study of normal tissues.	('mtDNA', 'Gene', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('mtDNA', 'cellular_component', 'GO:0000262', ('64', '69'))	('cancer', 'Disease', (89, 95))	('copy number', 'Var', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
137891	32024997	This work characterizes the cancer mitochondrial genome in a comprehensive manner, including somatic mutations, nuclear transfer, copy number, structural variants and mtDNA gene expression.	('copy number', 'Var', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('gene expression', 'biological_process', 'GO:0010467', ('173', '188'))	('mtDNA gene', 'Gene', (167, 177))	('mitochondrial genome', 'cellular_component', 'GO:0000262', ('35', '55'))	('mtDNA', 'cellular_component', 'GO:0000262', ('167', '172'))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))
137893	32024997	Second, our systemic analysis of mitochondrial genomes has firmly shown that several cancer types are enriched for high-allele-frequency truncating mutations, including previously reported kidney chromophobe as well as newly identified kidney papillary, and thyroid and colorectal cancers.	('kidney chromophobe', 'Disease', 'MESH:D000238', (189, 207))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('truncating mutations', 'Var', (137, 157))	('colorectal cancers', 'Disease', (270, 288))	('thyroid', 'Disease', (258, 265))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (281, 287))	('cancer', 'Disease', (85, 91))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('kidney papillary', 'Disease', (236, 252))	('colorectal cancers', 'Disease', 'MESH:D015179', (270, 288))	('kidney chromophobe', 'Disease', (189, 207))
137895	32024997	Third, in contrast with the diversified mutational signatures observed in the nuclear genomes of different cancers, mtDNAs show very similar mutational signatures regardless of cancer tissue origins: predominantly G>A and T>C substitutions on the L strand.	('cancers', 'Disease', (107, 114))	('cancer', 'Disease', (177, 183))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('G>A', 'Var', (214, 217))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('cancer', 'Disease', (107, 113))	('T>C substitutions', 'Var', (222, 239))
137897	32024997	We found that: (1) high-allele-frequency truncating mtDNA mutations are mutually exclusive to mutated cancer genes in kidney cancer; (2) mtDNA nuclear transfers are associated with increased numbers of structural variants in the nuclear genome; and (3) mtDNA co-expressed nuclear genes are enriched in several processes critical for tumor development.	('mutations', 'Var', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('mtDNA', 'cellular_component', 'GO:0000262', ('137', '142'))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('structural variants', 'MPA', (202, 221))	('cancer', 'Disease', (125, 131))	('mtDNA', 'Gene', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (102, 108))	('kidney cancer', 'Disease', 'MESH:D007680', (118, 131))	('tumor', 'Disease', (333, 338))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mtDNA', 'cellular_component', 'GO:0000262', ('52', '57'))	('mtDNA', 'cellular_component', 'GO:0000262', ('253', '258'))	('kidney cancer', 'Phenotype', 'HP:0009726', (118, 131))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('nuclear transfers', 'CPA', (143, 160))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('kidney cancer', 'Disease', (118, 131))
137900	32024997	Our analyses have provided essentially complete catalogs of somatic mtDNA alterations in cancers, including substitutions, indels, copy-number alterations and structural variants.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('mtDNA', 'cellular_component', 'GO:0000262', ('68', '73'))	('substitutions', 'Var', (108, 121))	('copy-number alterations', 'Var', (131, 154))	('indels', 'Var', (123, 129))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('alterations', 'Var', (74, 85))	('mtDNA', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
137910	32024997	To remove these false positive calls, we applied two statistical tests of: (1) whether the VAF of a mutation candidate in the matched normal sequences was within the normal range (<0.0024; the cutoff is determined by the median VAF of all mutation candidates +2x the interquartile range); and (2) whether:was within the normal range (<0.0357; the cutoff is determined by the median VAF of all mutation candidates +2x the interquartile range), where Nmut is the mutation allele count, RD is the average read depth for the nuclear genome, and nor and tum are normal and matched tumor tissues, respectively.	('VAF', 'Chemical', '-', (382, 385))	('VAF', 'Chemical', '-', (91, 94))	('false', 'biological_process', 'GO:0071878', ('16', '21'))	('false', 'biological_process', 'GO:0071877', ('16', '21'))	('tumor', 'Disease', 'MESH:D009369', (576, 581))	('mutation', 'Var', (100, 108))	('tumor', 'Phenotype', 'HP:0002664', (576, 581))	('tumor', 'Disease', (576, 581))	('VAF', 'Chemical', '-', (228, 231))
137914	32024997	Because of the ultra-high depth, even 1% VAF mutations were considered to be specific, and were supported by a high number (n = ~80) of mutation alleles.	('mutations', 'Var', (45, 54))	('VAF', 'Chemical', '-', (41, 44))	('VAF', 'Gene', (41, 44))
137915	32024997	We confirmed the high specificity of these mutations using the unique mtDNA mutational signatures robustly observed even from these low-VAF mutations: (1) the mutational spectrum is generally consistent with those from higher heteroplasmic levels of mutations (that is, VAFs from 3-10% and 10-100%); (2) we observed the absolute dominance of C>T and T>C substitutions in the expected trinucleotide contexts (NpCpG for C>T and NpTpC for T>C substitutions); and (3) we also observed extreme replication strand bias (Supplementary Fig.	('C>T', 'Var', (342, 345))	('T>C substitutions', 'Var', (350, 367))	('C>T', 'Var', (418, 421))	('VAF', 'Chemical', '-', (270, 273))	('VAF', 'Chemical', '-', (136, 139))	('replication strand bias', 'CPA', (489, 512))	('mtDNA', 'cellular_component', 'GO:0000262', ('70', '75'))
137918	32024997	We defined truncating mutations as those that lead to truncated protein products (that is, nonsense mutations and frameshift indels), and accordingly categorized the samples into the truncating group (bearing at least one truncating mutation with VAF >= 60%).	('lead to', 'Reg', (46, 53))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('VAF', 'Chemical', '-', (247, 250))	('mutations', 'Var', (22, 31))	('frameshift indels', 'Var', (114, 131))	('truncated protein products', 'MPA', (54, 80))
137943	32024997	In addition, to access somatic single-nucleotide variants derived from TCGA donors, researchers will also need to obtain Database of Genotypes and Phenotypes authorization.	('donor', 'Species', '9606', (76, 81))	('single-nucleotide variants', 'Var', (31, 57))	('TCGA', 'Gene', (71, 75))
137950	31963743	Among cancer-associated alterations, changes in protein N-glycosylation have recently received attention as one of the key events that are able to influence the onset of neoplasia and its consequent spreading.	('neoplasia', 'Disease', (170, 179))	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('alterations', 'Var', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('protein', 'Protein', (48, 55))	('neoplasia', 'Phenotype', 'HP:0002664', (170, 179))	('changes', 'Reg', (37, 44))	('glycosylation', 'biological_process', 'GO:0070085', ('58', '71'))	('neoplasia', 'Disease', 'MESH:D009369', (170, 179))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('influence', 'Reg', (147, 156))	('cancer', 'Disease', (6, 12))	('N', 'Chemical', 'MESH:D009584', (56, 57))
137951	31963743	N-glycosylation represents one of the most prominent protein post-translational modification (PTMs) and play a role in determining several protein properties, defining its correct tertiary structure, specific function as well as its cellular localisation.	('post-translational modification', 'biological_process', 'GO:0043687', ('61', '92'))	('specific', 'MPA', (200, 208))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('tertiary structure', 'MPA', (180, 198))	('N-glycosylation', 'Var', (0, 15))	('cellular localisation', 'biological_process', 'GO:0051641', ('233', '254'))	('glycosylation', 'biological_process', 'GO:0070085', ('2', '15'))
137952	31963743	Under physiological conditions, N-glycosylated proteins have various biological functions, including folding and quality control, cell adhesion and motility, molecular trafficking, cell signalling, immune recognition and clearance.	('cell signalling', 'CPA', (181, 196))	('N', 'Chemical', 'MESH:D009584', (32, 33))	('cell adhesion', 'biological_process', 'GO:0007155', ('130', '143'))	('N-glycosylated', 'Var', (32, 46))	('motility', 'CPA', (148, 156))	('signalling', 'biological_process', 'GO:0023052', ('186', '196'))	('molecular trafficking', 'CPA', (158, 179))	('cell adhesion', 'CPA', (130, 143))
137953	31963743	In fact, high levels of altered N-glycosylated proteins are demonstrated to promote tumour invasiveness as well as being correlated with a high frequency of tumour recurrence and metastasis.	('correlated', 'Reg', (121, 131))	('promote', 'PosReg', (76, 83))	('tumour', 'Disease', (84, 90))	('N', 'Chemical', 'MESH:D009584', (32, 33))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('N-glycosylated proteins', 'Protein', (32, 55))	('altered', 'Var', (24, 31))	('tumour', 'Disease', 'MESH:D009369', (157, 163))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('metastasis', 'CPA', (179, 189))	('tumour invasiveness', 'Disease', (84, 103))	('tumour', 'Disease', (157, 163))	('tumour', 'Disease', 'MESH:D009369', (84, 90))	('tumour invasiveness', 'Disease', 'MESH:D009361', (84, 103))
137979	31963743	Considering that the canonical N-glycosylation motif of proteins is N-x-S/T (where x are all the amino acids, with the exception of proline), we observed a variation of the glycosylated sites between the CTRL and ccRCC patients (Table 2a).	('patients', 'Species', '9606', (219, 227))	('glycosylated sites', 'MPA', (173, 191))	('N-x-S', 'Chemical', '-', (68, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (213, 218))	('glycosylation', 'biological_process', 'GO:0070085', ('33', '46'))	('N', 'Chemical', 'MESH:D009584', (68, 69))	('ccRCC', 'Disease', (213, 218))	('variation', 'Reg', (156, 165))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('ccRCC', 'Disease', 'MESH:D002292', (213, 218))	('proline', 'Chemical', 'MESH:D011392', (132, 139))	('CTRL', 'Gene', '1506', (204, 208))	('N-x-S/T', 'Var', (68, 75))	('CTRL', 'Gene', (204, 208))
137983	31963743	Moreover, N-glycosites that matched with N-x-T (88% CTRL, 82% ccRCC) occurred more frequently than those that matched with N-x-S (71% CTRL, 69% ccRCC) (Table 2a).	('ccRCC', 'Disease', 'MESH:D002292', (62, 67))	('CTRL', 'Gene', '1506', (134, 138))	('N-glycosites', 'MPA', (10, 22))	('CTRL', 'Gene', (134, 138))	('N-x-S', 'Chemical', '-', (123, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('CTRL', 'Gene', '1506', (52, 56))	('CTRL', 'Gene', (52, 56))	('ccRCC', 'Disease', (144, 149))	('N-x-T', 'Var', (41, 46))	('N-glycosites', 'Chemical', '-', (10, 22))	('ccRCC', 'Disease', (62, 67))	('ccRCC', 'Disease', 'MESH:D002292', (144, 149))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('N-x-T', 'Chemical', '-', (41, 46))
137990	31963743	We also detected a decrease of glycosylation frequency for the motif N-x-T (-7%) in pT3, despite an overall increment of the total modified asparagine on all the sequences (9%) (Table 2b, Figure S1a).	('decrease', 'NegReg', (19, 27))	('modified asparagine', 'MPA', (131, 150))	('glycosylation', 'biological_process', 'GO:0070085', ('31', '44'))	('N-x-T', 'Chemical', '-', (69, 74))	('asparagine', 'Chemical', 'MESH:D001216', (140, 150))	('N-x-T', 'Var', (69, 74))	('increment', 'PosReg', (108, 117))	('pT3', 'Gene', '7694', (84, 87))	('S', 'Chemical', 'MESH:D012694', (195, 196))	('pT3', 'Gene', (84, 87))	('glycosylation frequency', 'MPA', (31, 54))
138016	31963743	These nine proteins were differently expressed in the comparisons pT1 vs. CTRL and pT3 vs. CTRL; three of them showed an increasing pattern (CD97, COCH and P3IP1), whilst six presented a decreasing trend (APOB, FINC, CERU, HPT, CFAH and PLTP).	('P3IP1', 'Var', (156, 161))	('COCH', 'Gene', '1690', (147, 151))	('PLTP', 'Gene', '5360', (237, 241))	('CFAH', 'Gene', (228, 232))	('PLTP', 'Gene', (237, 241))	('pT3', 'Gene', (83, 86))	('pT1', 'Gene', '58492', (66, 69))	('FINC', 'Gene', '2335', (211, 215))	('CD97', 'Gene', '976', (141, 145))	('pT1', 'Gene', (66, 69))	('CTRL', 'Gene', '1506', (74, 78))	('APOB', 'Gene', '338', (205, 209))	('CTRL', 'Gene', (74, 78))	('CTRL', 'Gene', '1506', (91, 95))	('CD97', 'Gene', (141, 145))	('CTRL', 'Gene', (91, 95))	('CERU', 'Chemical', '-', (217, 221))	('COCH', 'Gene', (147, 151))	('HPT', 'Gene', (223, 226))	('pT3', 'Gene', '7694', (83, 86))	('HPT', 'Gene', '3240', (223, 226))	('FINC', 'Gene', (211, 215))	('CFAH', 'Gene', '3075', (228, 232))	('APOB', 'Gene', (205, 209))
138036	31963743	Among them, HPT is one of the proteins that is most reported to be affected by oligosaccharide modifications in human malignancies, including ovarian, liver, colon and pancreatic cancers, and its N-glycosylation status is different from one type of cancer to another.	('colon and pancreatic cancers', 'Disease', 'MESH:D015179', (158, 186))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', (249, 255))	('N', 'Chemical', 'MESH:D009584', (196, 197))	('liver', 'Disease', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('oligosaccharide', 'Chemical', 'MESH:D009844', (79, 94))	('human', 'Species', '9606', (112, 117))	('glycosylation', 'biological_process', 'GO:0070085', ('198', '211'))	('ovarian', 'Disease', 'MESH:D010049', (142, 149))	('malignancies', 'Disease', 'MESH:D009369', (118, 130))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (168, 185))	('modifications', 'Var', (95, 108))	('malignancies', 'Disease', (118, 130))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('oligosaccharide', 'Protein', (79, 94))	('affected', 'Reg', (67, 75))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (168, 186))	('ovarian', 'Disease', (142, 149))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('HPT', 'Gene', (12, 15))	('cancer', 'Disease', (179, 185))	('HPT', 'Gene', '3240', (12, 15))
138061	31963743	Moreover, increasing evidence shows that high concentrations of plasma APOB are also associated with poor prognosis in patients with hepatocellular carcinoma and breast cancer.	('APOB', 'Gene', '338', (71, 75))	('APOB', 'Gene', (71, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('hepatocellular carcinoma', 'Disease', (133, 157))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (133, 157))	('breast cancer', 'Disease', (162, 175))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (133, 157))	('high concentrations', 'Var', (41, 60))	('associated', 'Reg', (85, 95))
138074	31963743	Given its role, CFAH alterations can have serious implications and cause various diseases, including several cancers, such as non-small cell lung cancer, ovarian cancer, and colon cancer.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (126, 152))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('ovarian cancer', 'Disease', 'MESH:D010051', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (130, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (126, 152))	('colon cancer', 'Phenotype', 'HP:0003003', (174, 186))	('diseases', 'Disease', (81, 89))	('ovarian cancer', 'Disease', (154, 168))	('ovarian cancer', 'Phenotype', 'HP:0100615', (154, 168))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('colon cancer', 'Disease', 'MESH:D015179', (174, 186))	('cancers', 'Disease', (109, 116))	('CFAH', 'Gene', '3075', (16, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('non-small cell lung cancer', 'Disease', (126, 152))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cause', 'Reg', (67, 72))	('CFAH', 'Gene', (16, 20))	('colon cancer', 'Disease', (174, 186))	('alterations', 'Var', (21, 32))
138147	30924768	For example, loss of fumarate hydratase (FH), succinate dehydrogenase (SDH), or isocitrate dehydrogenase (IDH) induces pathological accumulation of metabolites which potently inhibit alpha-ketoglutarate-dependent enzymes, inducing hypermethylation of the genome and a fundamental reprogramming of cellular identity.	('SDH', 'Gene', '6390', (71, 74))	('fumarate hydratase', 'Gene', (21, 39))	('inhibit', 'NegReg', (175, 182))	('induces', 'Reg', (111, 118))	('succinate dehydrogenase', 'Gene', '6390', (46, 69))	('loss', 'Var', (13, 17))	('isocitrate dehydrogenase', 'Gene', (80, 104))	('IDH', 'Gene', '3417', (106, 109))	('metabolites', 'MPA', (148, 159))	('hypermethylation', 'CPA', (231, 247))	('accumulation', 'MPA', (132, 144))	('inducing', 'Reg', (222, 230))	('SDH', 'Gene', (71, 74))	('fumarate hydratase', 'Gene', '2271', (21, 39))	('succinate dehydrogenase', 'Gene', (46, 69))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (183, 202))	('FH', 'Gene', '2271', (41, 43))	('isocitrate dehydrogenase', 'Gene', '3417', (80, 104))	('IDH', 'Gene', (106, 109))	('alpha-ketoglutarate-dependent enzymes', 'Enzyme', (183, 220))
138150	30924768	Data from tumor genomics, imaging and metabolomics have now demonstrated that not all tumors exhibit signatures of aerobic glycolysis, and that alterations both intrinsic to mitochondria (e.g.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('aerobic glycolysis', 'MPA', (115, 133))	('mitochondria', 'cellular_component', 'GO:0005739', ('174', '186'))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', (86, 91))	('glycolysis', 'biological_process', 'GO:0006096', ('123', '133'))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('alterations', 'Var', (144, 155))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
138152	30924768	While disruption of mitochondrial respiration is generally not viewed as a driver of oncogenesis, a handful of individual cancer types are peculiarly enriched for mitochondrial dysfunction.	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (163, 188))	('oncogenesis', 'biological_process', 'GO:0007048', ('85', '96'))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (163, 188))	('respiration', 'biological_process', 'GO:0045333', ('34', '45'))	('disruption', 'Var', (6, 16))	('mitochondrial dysfunction', 'Disease', (163, 188))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('respiration', 'biological_process', 'GO:0007585', ('34', '45'))
138156	30924768	Similarly, chRCCs and renal oncocytomas are characterized by loss-of-function mutations in the mitochondrial genome resulting in accumulation of respiration-defective mitochondria.	('mitochondria', 'cellular_component', 'GO:0005739', ('167', '179'))	('mutations', 'Var', (78, 87))	('renal oncocytomas', 'Disease', (22, 39))	('mitochondrial genome', 'Gene', (95, 115))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('respiration', 'biological_process', 'GO:0007585', ('145', '156'))	('RCC', 'Disease', (13, 16))	('respiration', 'biological_process', 'GO:0045333', ('145', '156'))	('respiration-defective mitochondria', 'MPA', (145, 179))	('mitochondrial genome', 'cellular_component', 'GO:0000262', ('95', '115'))	('accumulation', 'PosReg', (129, 141))	('renal oncocytomas', 'Disease', 'MESH:C537750', (22, 39))	('loss-of-function', 'NegReg', (61, 77))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (22, 39))
138163	30924768	A handful of molecular studies have reported that cytogenetically, CCPAP tumors show neither deletion of chromosome 3p nor mutation of VHL, the characteristic molecular features of ccRCC.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('VHL', 'Gene', (135, 138))	('mutation', 'Var', (123, 131))	('CCPAP', 'Chemical', '-', (67, 72))	('CCPAP', 'Disease', (67, 72))	('RCC', 'Disease', (183, 186))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('VHL', 'Gene', '7428', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('chromosome', 'cellular_component', 'GO:0005694', ('105', '115'))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('deletion', 'Var', (93, 101))
138179	30924768	We observed that high-sorbitol ccRCC tumors clustered with other ccRCC tumors and not with CCPAP samples.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('high-sorbitol', 'Var', (17, 30))	('ccRCC tumors', 'Disease', 'MESH:D009369', (31, 43))	('ccRCC tumors', 'Disease', 'MESH:D009369', (65, 77))	('CCPAP', 'Chemical', '-', (91, 96))	('ccRCC tumors', 'Disease', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('sorbitol', 'Chemical', 'MESH:D013012', (22, 30))	('ccRCC tumors', 'Disease', (31, 43))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))
138214	30924768	Five suspected cases of CCPAP (BP-4760, BP-4784, BP-4795, DV-5567, BP-4177) were identified during re-review by the TCGA panel pathologists, including two at our institution as part of the TCGA effort and excluded from the final TCGA manuscript (Figure 3:figure supplement 1).	('BP-4795', 'Var', (49, 56))	('BP-4784', 'Var', (40, 47))	('BP-4177', 'Var', (67, 74))	('CCPAP', 'Chemical', '-', (24, 29))	('DV-5567', 'Var', (58, 65))	('CCPAP', 'Disease', (24, 29))	('BP-4760', 'Var', (31, 38))
138224	30924768	In prior work, our group estimated mtDNA copy number across ~322 ccRCC samples profiled by the TCGA, including 2 CCPAP samples misclassified as ccRCC.	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('CCPAP', 'Chemical', '-', (113, 118))	('RCC', 'Disease', (67, 70))	('copy', 'Var', (41, 45))	('mtDNA', 'cellular_component', 'GO:0000262', ('35', '40'))
138226	30924768	Depletion of mtDNA copy number in a tumor cell may lead to a drop in mtRNA, and a consequent drop in the capacity of the cell to conduct oxygen-dependent mitochondrial respiration.	('respiration', 'biological_process', 'GO:0045333', ('168', '179'))	('oxygen', 'Chemical', 'MESH:D010100', (137, 143))	('drop', 'NegReg', (93, 97))	('Depletion', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('mtDNA', 'cellular_component', 'GO:0000262', ('13', '18'))	('conduct oxygen-dependent mitochondrial respiration', 'MPA', (129, 179))	('capacity', 'MPA', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mtDNA', 'Gene', (13, 18))	('respiration', 'biological_process', 'GO:0007585', ('168', '179'))	('mtRNA', 'MPA', (69, 74))	('tumor', 'Disease', (36, 41))	('drop', 'NegReg', (61, 65))
138233	30924768	Given the distinct landscape of metabolic and transcriptomic alterations characterizing CCPAP, we sought to determine if CCPAP tumors were driven by genetic alterations similar to those driving more common kidney cancer types, for example ccRCC or pRCC.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('CCPAP', 'Chemical', '-', (88, 93))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('kidney cancer', 'Phenotype', 'HP:0009726', (206, 219))	('CCPAP', 'Chemical', '-', (121, 126))	('kidney cancer', 'Disease', 'MESH:D007680', (206, 219))	('alterations', 'Var', (157, 168))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('RCC', 'Disease', 'MESH:C538614', (249, 252))	('kidney cancer', 'Disease', (206, 219))	('RCC', 'Disease', (249, 252))	('RCC', 'Disease', 'MESH:C538614', (241, 244))	('RCC', 'Disease', (241, 244))	('driven by', 'Reg', (139, 148))
138235	30924768	Identified somatic variants were pooled with 3 CCPAP tumors profiled by exome sequencing in the TCGA.	('CCPAP', 'Chemical', '-', (47, 52))	('CCPAP', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('variants', 'Var', (19, 27))	('tumors', 'Disease', (53, 59))
138237	30924768	Notably, several of the non-synonymous mutations in CCPAP tumors were in genes previously associated with oncogenesis (e.g.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('oncogenesis', 'biological_process', 'GO:0007048', ('106', '117'))	('non-synonymous mutations', 'Var', (24, 48))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('associated', 'Reg', (90, 100))	('CCPAP', 'Chemical', '-', (52, 57))	('oncogenesis', 'Disease', (106, 117))	('CCPAP', 'Gene', (52, 57))
138238	30924768	GNAQ), but these mutations were not enriched in genes of any particular pathway or gene set.	('GNAQ', 'Gene', (0, 4))	('mutations', 'Var', (17, 26))	('GNAQ', 'Gene', '2776', (0, 4))
138247	30924768	by truncating or otherwise loss-of-function mutations) in CCPAP tumors.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('loss-of-function', 'NegReg', (27, 43))	('truncating', 'Var', (3, 13))	('CCPAP', 'Chemical', '-', (58, 63))	('CCPAP', 'Disease', (58, 63))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
138252	30924768	As shown in Figure 4E, we observed a handful of non-synonymous mtDNA mutations, with a frequency of <1 non-synonymous somatic mutation per sequenced tumor.	('mutations', 'Var', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mtDNA', 'cellular_component', 'GO:0000262', ('63', '68'))	('tumor', 'Disease', (149, 154))	('mtDNA', 'Gene', (63, 68))
138253	30924768	Finally, to evaluate if DNA methylation changes may underlie CCPAP pathogenesis, we examined TCGA data on DNA methylation from 4 CCPAP cases (BP-4784, BP-4795, DV-5567, BP-4177, see Materials and methods, Figure 5:figure supplement 1B).	('BP-4795', 'Var', (151, 158))	('BP-4784', 'Var', (142, 149))	('CCPAP', 'Disease', (129, 134))	('CCPAP', 'Chemical', '-', (129, 134))	('BP-4177', 'Var', (169, 176))	('CCPAP', 'Chemical', '-', (61, 66))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('DV-5567', 'Var', (160, 167))	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('DNA methylation', 'biological_process', 'GO:0006306', ('24', '39'))	('pathogenesis', 'biological_process', 'GO:0009405', ('67', '79'))	('DNA methylation', 'biological_process', 'GO:0006306', ('106', '121'))
138257	30924768	Our failure to identify recurrent mutations or copy number alterations is not atypical in the context of our institution's clinical sequencing experience; in fact,~8% of all tumors prospectively deep sequenced for alterations in 341 cancer-associated genes fail to show a single mutation.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumors', 'Disease', (174, 180))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('alterations', 'Var', (214, 225))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
138259	30924768	We sought to validate that CCPAP-specific depletion of respiratory genes is not an artifact of TCGA profiling, and to confirm that the depletion of the mitochondrial genome is specific to CCPAP tumor cells, as opposed to other cells in the tumor microenvironment.	('tumor', 'Disease', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('depletion', 'MPA', (135, 144))	('CCPAP', 'Chemical', '-', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('CCPAP', 'Chemical', '-', (188, 193))	('mitochondrial genome', 'cellular_component', 'GO:0000262', ('152', '172'))	('tumor', 'Disease', (194, 199))	('mitochondrial genome', 'MPA', (152, 172))	('CCPAP', 'Var', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
138269	30924768	A more comprehensive quantification using tissue array samples comprised of different subtypes of renal cell carcinoma also showed CCPAP has the highest 8-oxo-dG H-score (Figure 5D, Figure 5:source data 1).	('CCPAP', 'Var', (131, 136))	('renal cell carcinoma', 'Disease', (98, 118))	('8-oxo-dG H-score', 'MPA', (153, 169))	('8-oxo-dG', 'Chemical', 'MESH:C067134', (153, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (98, 118))	('CCPAP', 'Chemical', '-', (131, 136))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (98, 118))
138273	30924768	Specifically, oxidation of guanine bases is associated with a high prevalence of C:G > A:T transversions, typically associated with Signature 18 in the COSMIC database of mutation signatures.	('C:G > A:T transversions', 'Var', (81, 104))	('guanine', 'Chemical', 'MESH:D006147', (27, 34))	('oxidation', 'Var', (14, 23))
138290	30924768	While genetic/epigenetic alterations are certainly the drivers of all (or nearly all) cancers, our data reinforces the notion that such driver alterations need not be the distinguishing molecular feature of the tumor itself.	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('genetic/epigenetic alterations', 'Var', (6, 36))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
138294	30924768	As described earlier, each of the common types of RCC are characterized in part by mitochondrial dysfunction: HIF activation and suppression of mitochondrial biogenesis in clear cell RCC, FH mutations in HLRCC, and mtDNA mutations in chromophobe RCC.	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (83, 108))	('mitochondrial dysfunction', 'Disease', (83, 108))	('chromophobe RCC', 'Disease', (234, 249))	('FH', 'Gene', '2271', (188, 190))	('activation', 'PosReg', (114, 124))	('mutations', 'Var', (221, 230))	('mutations', 'Var', (191, 200))	('RCC', 'Disease', (50, 53))	('RCC', 'Disease', (183, 186))	('mtDNA', 'cellular_component', 'GO:0000262', ('215', '220'))	('RCC', 'Disease', (246, 249))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (206, 209))	('chromophobe RCC', 'Disease', 'MESH:C538614', (234, 249))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (83, 108))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('RCC', 'Disease', 'MESH:C538614', (246, 249))	('mitochondrial biogenesis', 'MPA', (144, 168))	('RCC', 'Disease', 'MESH:C538614', (206, 209))	('suppression', 'NegReg', (129, 140))
138295	30924768	Rare subtypes of RCC further support the recurring theme of mitochondrial dysfunction: mitochondrial Complex II dysfunction in SDH-mutant RCC, and loss-of-function mtDNA mutations in renal oncocytomas.	('loss-of-function', 'NegReg', (147, 163))	('Complex II dysfunction', 'Disease', 'MESH:C565375', (101, 123))	('SDH', 'Gene', '6390', (127, 130))	('RCC', 'Disease', (138, 141))	('mtDNA', 'cellular_component', 'GO:0000262', ('164', '169'))	('renal oncocytomas', 'Disease', 'MESH:C537750', (183, 200))	('RCC', 'Disease', (17, 20))	('mtDNA', 'Gene', (164, 169))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('SDH', 'Gene', (127, 130))	('Complex II dysfunction', 'Disease', (101, 123))	('mitochondrial dysfunction', 'Disease', (60, 85))	('renal oncocytomas', 'Disease', (183, 200))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (60, 85))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('Complex II dysfunction', 'Phenotype', 'HP:0008314', (101, 123))	('mutations', 'Var', (170, 179))	('Complex II', 'molecular_function', 'GO:0008177', ('101', '111'))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (60, 85))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (183, 200))
138336	30924768	Without application of the Battenberg algorithm, the resolution of subclonal copy number states is not possible, so copy number segments are called as single integer values (corresponding to the copy number state of the dominant cancer clone) on chromosome X. Mutational signature analysis of the substitutions was performed using the R package DeconstructSigs.	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('chromosome', 'cellular_component', 'GO:0005694', ('246', '256'))	('substitutions', 'Var', (297, 310))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
138361	30924768	Controlled access for TCGA sequencing data (RNA-sequencing and whole exome sequencing of CCPAP tumors) are available via GDC commons data portal (https://gdc.cancer.gov/) by querying the 5 CCPAP sample IDs (BP-4760, BP-4784, BP-4795, DV-5567, BP-4177).	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('CCPAP', 'Chemical', '-', (89, 94))	('CCPAP', 'Disease', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('RNA', 'cellular_component', 'GO:0005562', ('44', '47'))	('BP-4795', 'Var', (225, 232))	('cancer', 'Disease', (158, 164))	('CCPAP', 'Chemical', '-', (189, 194))	('DV-5567', 'Var', (234, 241))	('BP-4177', 'Var', (243, 250))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('BP-4784', 'Var', (216, 223))	('tumors', 'Disease', (95, 101))	('BP-4760', 'Var', (207, 214))
138367	30924768	In some forms of kidney cancer, these alterations result from recurrent driver mutations such as the loss of VHL, fumarate hydratase, or components of the succinate dehydrogenase complex.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('kidney cancer', 'Phenotype', 'HP:0009726', (17, 30))	('result from', 'Reg', (50, 61))	('kidney cancer', 'Disease', 'MESH:D007680', (17, 30))	('succinate dehydrogenase complex', 'cellular_component', 'GO:0045282', ('155', '186'))	('succinate dehydrogenase complex', 'cellular_component', 'GO:0045281', ('155', '186'))	('loss', 'Var', (101, 105))	('succinate dehydrogenase', 'Gene', (155, 178))	('VHL', 'Gene', (109, 112))	('kidney cancer', 'Disease', (17, 30))	('succinate dehydrogenase', 'Gene', '6390', (155, 178))	('VHL', 'Gene', '7428', (109, 112))	('fumarate hydratase', 'Gene', '2271', (114, 132))	('fumarate hydratase', 'Gene', (114, 132))
138396	30924768	a) Using a distinct metabolomic platform (RC15, see Materials and methods) we ran a standard curve with sorbitol to determine the absolute concentration of sorbitol in several CCPAP tumor samples, including both high- and low sorbitol CCPAP tumors (Figure 2:figure supplement 1B).	('high-', 'Var', (212, 217))	('CCPAP', 'Chemical', '-', (235, 240))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', (241, 246))	('sorbitol', 'Chemical', 'MESH:D013012', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('sorbitol', 'Chemical', 'MESH:D013012', (156, 164))	('tumors', 'Disease', (241, 247))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('low sorbitol', 'Var', (222, 234))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('CCPAP', 'Chemical', '-', (176, 181))	('sorbitol', 'Chemical', 'MESH:D013012', (226, 234))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
138416	30924768	We performed experiments by using more cells (from 10 cm dishes instead of 6 well dish), labeling with either U13C-fructose or U13C-glucose, and harvesting at 5 additional time points (0h, 2h, 4h, 8h, 24h).	('2h', 'Chemical', 'MESH:D003903', (189, 191))	('4h', 'Chemical', '-', (202, 204))	('4h', 'Chemical', '-', (193, 195))	('U13C-glucose', 'Var', (127, 139))	('0h', 'Chemical', '-', (185, 187))	('U13C-fructose', 'Var', (110, 123))	('U13C-fructose', 'Chemical', '-', (110, 123))	('24h', 'Chemical', '-', (201, 204))	('8h', 'Chemical', '-', (197, 199))	('U13C-glucose', 'Chemical', '-', (127, 139))
138430	30924768	the preference for C>A mutations at TpCpT trinucleotides in POLE-mutated tumors.	('trinucleotides', 'Chemical', '-', (42, 56))	('C>A mutations', 'Var', (19, 32))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('TpCpT', 'Gene', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
138432	30924768	We observed that the majority of mutations were C>T, which is not consistent with the expected bias towards C>A mutations in conditions of high oxidative stress (subsection "Immunohistochemical Validation of the Molecular Phenotype of CCPAP", third paragraph, Figure 5:figure supplement 2).	('CCPAP', 'Chemical', '-', (235, 240))	('C>T', 'Var', (48, 51))	('oxidative stress', 'Phenotype', 'HP:0025464', (144, 160))	('mutations', 'Var', (33, 42))
138461	28815885	Moreover, the alternative exon selection might produce new protein variants that might potentially redefine cell fate and cancer progression.	('protein', 'Protein', (59, 66))	('cancer', 'Disease', (122, 128))	('cell fate', 'CPA', (108, 117))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('variants', 'Var', (67, 75))	('redefine', 'Reg', (99, 107))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
138513	28815885	The tumor sections of the eight patients studied above were amplified with the well-known G257F and G526R primers (Paul et al., 2000b) schematically represented in Fig.	('tumor', 'Disease', (4, 9))	('patients', 'Species', '9606', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('G257F', 'Mutation', 'p.G257F', (90, 95))	('G257F', 'Var', (90, 95))	('G526R', 'Var', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('G526R', 'Mutation', 'p.G526R', (100, 105))
138528	28815885	In view of this result, we further amplified tumor samples using primers Int1F and G257R.	('G257R', 'Var', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('Int1F', 'Var', (73, 78))	('G257R', 'Mutation', 'p.G257R', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
138537	28815885	The results demonstrated a high degree of similarity with HLA-G except for a deletion of 106-bp fragment.	('deletion', 'Var', (77, 85))	('HLA-G', 'Gene', (58, 63))	('HLA-G', 'Gene', '3135', (58, 63))
138540	28815885	When RT-PCR was performed with primer G963R, whose sequence is complementary to a region of exon 6, no amplification products could be obtained in combination with the forward primer G257F (exon 3) or G256F (exon 4).	('G256F', 'Mutation', 'p.G256F', (201, 206))	('G963R', 'Var', (38, 43))	('G256F', 'Var', (201, 206))	('G257F', 'Var', (183, 188))	('G963R', 'Mutation', 'p.G963R', (38, 43))	('G257F', 'Mutation', 'p.G257F', (183, 188))
138563	28815885	Even though other peptides that differ in length and sequence might also allow the expression of HLA-E at the surface of the cell, these peptides may prevent HLA-E interaction with its inhibitory receptor NKG2A, resulting in high increase in target cell lysis (Hoare et al., 2008).	('interaction', 'Interaction', (164, 175))	('prevent', 'NegReg', (150, 157))	('HLA-E', 'Gene', '3133', (158, 163))	('lysis', 'biological_process', 'GO:0019835', ('254', '259'))	('HLA-E', 'Gene', (97, 102))	('peptides', 'Var', (137, 145))	('target cell lysis', 'CPA', (242, 259))	('HLA-E', 'Gene', '3133', (97, 102))	('NKG2A', 'Gene', '3821', (205, 210))	('NKG2A', 'Gene', (205, 210))	('increase', 'PosReg', (230, 238))	('HLA-E', 'Gene', (158, 163))
138569	28815885	These molecules might have diverse functions, as is the case for vascular endothelial growth factor (VEGF), for which the only presence of six amino acids at the C-terminal end yields a protein that moves from a proapoptotic level to an antiapoptotic stage (Nowak et al., 2010).	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('65', '99'))	('VEGF', 'Gene', (101, 105))	('moves', 'MPA', (199, 204))	('vascular endothelial growth factor', 'Gene', (65, 99))	('protein', 'cellular_component', 'GO:0003675', ('186', '193'))	('VEGF', 'Gene', '7422', (101, 105))	('vascular endothelial growth factor', 'Gene', '7422', (65, 99))	('presence', 'Var', (127, 135))
138572	28815885	Alternatively, conserving the signal peptide in the absence of the alpha1 domain might result in a modified spatial configuration of the alpha2alpha3 molecule in which the Cys147 located in the alpha2 domain may interact together to form homodimers at the surface of the cell.	('form', 'Reg', (233, 237))	('interact together', 'Interaction', (212, 229))	('homodimers', 'MPA', (238, 248))	('spatial configuration', 'MPA', (108, 129))	('modified', 'Reg', (99, 107))	('Cys147', 'Chemical', '-', (172, 178))	('Cys147', 'Var', (172, 178))
138573	28815885	It was previously shown that the Cys42 present in the alpha 1 domain of HLA-G1 can form Cys42-Cys42 or Cys42-Cys147 disulfide bonds, but not Cys147-Cys147 bonds (Gonen-Gross et al., 2003).	('HLA-G1', 'Gene', (72, 78))	('alpha 1', 'Gene', '146', (54, 61))	('alpha 1', 'Gene', (54, 61))	('Cys147', 'Chemical', '-', (141, 147))	('Cys42', 'Chemical', '-', (103, 108))	('form', 'Reg', (83, 87))	('Cys42', 'Chemical', '-', (94, 99))	('Cys42', 'Var', (33, 38))	('Cys147', 'Chemical', '-', (148, 154))	('Cys42', 'Chemical', '-', (33, 38))	('Cys42-Cys147 disulfide bonds', 'MPA', (103, 131))	('Cys147', 'Chemical', '-', (109, 115))	('HLA-G1', 'Gene', '3135', (72, 78))	('Cys42', 'Chemical', '-', (88, 93))	('Cys42-Cys42', 'MPA', (88, 99))	('disulfide', 'Chemical', 'MESH:D004220', (116, 125))
138574	28815885	The Cys147-Cys147 homodimers that might be formed in the alpha1-deleted alpha2alpha3 molecules would possess two receptor binding sites which may affect the specificity or modulate the affinity of such HLA-G isoforms for their receptors.	('Cys147', 'Chemical', '-', (4, 10))	('HLA-G', 'Gene', (202, 207))	('HLA-G', 'Gene', '3135', (202, 207))	('specificity', 'MPA', (157, 168))	('affect', 'Reg', (146, 152))	('receptor binding', 'molecular_function', 'GO:0005102', ('113', '129'))	('Cys147-Cys147', 'Var', (4, 17))	('modulate', 'Reg', (172, 180))	('affinity', 'Interaction', (185, 193))	('Cys147', 'Chemical', '-', (11, 17))
138578	28815885	Importantly, no detection of any of these proteins, possessing only the alpha2alpha3 domains or only the alpha3 domain, has been possible for now, either by immunochemistry or by cytometry as most of the antibodies currently available (87G, G233, MEMG, 4H84) recognize an epitope located in the alpha 1 domain.	('recognize', 'Reg', (259, 268))	('G233', 'Var', (241, 245))	('alpha 1', 'Gene', '146', (295, 302))	('alpha 1', 'Gene', (295, 302))
138582	28815885	For instance, the human TP53 gene encodes at least 12 isoforms, which are produced in normal tissues or stress conditions through alternative initiation of translation, usage of alternative promoters, and alternative splicing (Aoubala et al., 2011; Khoury and Bourdon, 2010, 2011).	('alternative splicing', 'Var', (205, 225))	('TP53', 'Gene', (24, 28))	('human', 'Species', '9606', (18, 23))	('splicing', 'biological_process', 'GO:0045292', ('217', '225'))	('translation', 'biological_process', 'GO:0006412', ('156', '167'))	('TP53', 'Gene', '7157', (24, 28))
138617	32521645	reported significantly (p = 0.004) lower mean ADC in malignant HNT (1.071 +- 0.293 x 10-3 mm2/s) than in benign (1.505 +- 0.487 x 10-3 mm2/s).	('malignant', 'Var', (53, 62))	('lower', 'NegReg', (35, 40))	('ADC', 'MPA', (46, 49))	('ADC', 'Chemical', '-', (46, 49))
138625	32521645	According to most studies, pre-treatment low ADC seems to be a positive predictor in HNSCC, being associated with good local control and treatment response.	('pre', 'molecular_function', 'GO:0003904', ('27', '30'))	('HNSCC', 'Disease', (85, 90))	('low ADC', 'Var', (41, 48))	('ADC', 'Chemical', '-', (45, 48))
138646	32521645	In this setting, a high b-value (b = 900/1000) improves the discrimination of breast lesions from the neighboring soft tissue, although the best choice of b-values to be used in breast DWI is still debated.	('breast lesions', 'Disease', 'MESH:D001943', (78, 92))	('b = 900/1000', 'Var', (33, 45))	('discrimination', 'MPA', (60, 74))	('improves', 'PosReg', (47, 55))	('breast lesions', 'Disease', (78, 92))
138667	32521645	found significantly lower ADC in tumoral viable tissue after radiofrequency ablation than in the ablation zone and normal parenchyma (1.02 x 10-3 mm2/s vs. 1.31 x 10-3 mm2/s).	('tumoral', 'Disease', (33, 40))	('tumoral', 'Disease', 'MESH:D009369', (33, 40))	('lower', 'NegReg', (20, 25))	('radiofrequency', 'Var', (61, 75))	('ADC', 'MPA', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('ADC', 'Chemical', '-', (26, 29))
138695	32521645	DWI can be helpful in primary staging of rectal cancer in adjunction to conventional sequences, applying at least two b values and with b = 1000 generally being used as the highest b-value.	('b = 1000', 'Var', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('rectal cancer', 'Phenotype', 'HP:0100743', (41, 54))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
138705	32521645	However, DWI has been shown to improve small cancers' detection after biopsy, since post-procedure inflammatory changes may alter the normal anatomy.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('small cancers', 'Disease', (39, 52))	('small cancers', 'Disease', 'MESH:D009369', (39, 52))	('improve', 'PosReg', (31, 38))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('DWI', 'Var', (9, 12))	('alter', 'Reg', (124, 129))
138709	32521645	DWI seems also to increase the diagnostic performance of MRI in the diagnosis of ovarian cancer when it is added to conventional sequences.	('increase', 'PosReg', (18, 26))	('diagnostic', 'MPA', (31, 41))	('DWI', 'Var', (0, 3))	('ovarian cancer', 'Disease', 'MESH:D010051', (81, 95))	('ovarian cancer', 'Disease', (81, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('ovarian cancer', 'Phenotype', 'HP:0100615', (81, 95))
138711	32521645	Further, the presence of a solid component within an adnexal mass that is hypointense both on T2-weighted and high-b-value DWI is highly specific for benignity, while a solid component with intermediate T2 signal and high b1000-DWI signal is associated with a positive likelihood ratio of 4.5 for a malignant adnexal tumor.	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('benignity', 'Disease', (150, 159))	('malignant adnexal tumor', 'Disease', (299, 322))	('malignant adnexal tumor', 'Disease', 'MESH:D000292', (299, 322))	('b1000-DWI', 'Var', (222, 231))
138764	32521645	As a general rule, malignant BTs show lower ADC compared to benign BTs.	('malignant BTs', 'Var', (19, 32))	('ADC', 'Chemical', '-', (44, 47))	('lower', 'NegReg', (38, 43))	('ADC', 'MPA', (44, 47))
138814	29805741	However, in hypoxic conditions or in cancer cells lacking pVHL due to mutational loss, HIFalpha dimerizes with HIFbeta.	('mutational', 'Var', (70, 80))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('pVHL', 'Gene', '7428', (58, 62))	('cancer', 'Disease', (37, 43))	('dimerizes', 'MPA', (96, 105))	('pVHL', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('hypoxic conditions', 'Disease', (12, 30))	('loss', 'NegReg', (81, 85))	('hypoxic conditions', 'Disease', 'MESH:D009135', (12, 30))
138816	29805741	Given that VHL inactivation leads to inappropriate angiogenesis in both sporadic and germline VHL-disease associated lesions, tyrosine kinase inhibitors against the VEGF pathway, such as sunitinib and pazopanib, are approved treatment approaches for metastatic ccRCC and are just some of the inhibitors being actively investigated for treatment of VHL disease.	('metastatic ccRCC', 'Disease', (250, 266))	('VHL-disease', 'Disease', 'MESH:D006623', (94, 105))	('VHL', 'Disease', 'MESH:D006623', (11, 14))	('VHL disease', 'Disease', 'MESH:D006623', (348, 359))	('angiogenesis', 'biological_process', 'GO:0001525', ('51', '63'))	('VHL', 'Disease', (11, 14))	('VHL disease', 'Disease', (348, 359))	('VHL-disease', 'Disease', (94, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (261, 266))	('VHL', 'Disease', (94, 97))	('pazopanib', 'Chemical', 'MESH:C516667', (201, 210))	('VHL', 'Disease', 'MESH:D006623', (94, 97))	('sunitinib', 'Chemical', 'MESH:D000077210', (187, 196))	('VHL', 'Disease', 'MESH:D006623', (348, 351))	('angiogenesis', 'CPA', (51, 63))	('VHL', 'Disease', (348, 351))	('inactivation', 'Var', (15, 27))
138817	29805741	A pilot study of sunitinib in 15 patients with germline VHL mutations with measurable VHL-associated lesions showed that the drug had manageable toxicity and that 33% (6/18) of RCC lesions showed partial response; however, 0/21 HB lesions showed response.	('patients', 'Species', '9606', (33, 41))	('RCC', 'Disease', (177, 180))	('VHL', 'Disease', (86, 89))	('VHL', 'Disease', 'MESH:D006623', (86, 89))	('VHL', 'Disease', (56, 59))	('toxicity', 'Disease', 'MESH:D064420', (145, 153))	('VHL', 'Disease', 'MESH:D006623', (56, 59))	('toxicity', 'Disease', (145, 153))	('mutations', 'Var', (60, 69))	('sunitinib', 'Chemical', 'MESH:D000077210', (17, 26))
138921	29556139	Mutations in the FBP1 gene cause FBP1 deficiency, an inherited autosomal recessive disorder, which leads to the impairment of glucose synthesis from all gluconeogenic precursors.	('impairment', 'MPA', (112, 122))	('FBP1 deficiency', 'Disease', (33, 48))	('FBP1', 'Gene', (17, 21))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (63, 91))	('Mutations', 'Var', (0, 9))	('cause', 'Reg', (27, 32))	('FBP1 deficiency', 'Disease', 'MESH:D007153', (33, 48))	('glucose', 'Chemical', 'MESH:D005947', (126, 133))	('synthesis', 'biological_process', 'GO:0009058', ('134', '143'))	('autosomal recessive disorder', 'Disease', (63, 91))
138930	29556139	Downregulation of FBP1 in mouse pancreatic beta-cells by small interfering RNA enhanced glucose utilization and GSIS, whereas overexpression of FBP1 decreased GSIS.	('pancreatic', 'Disease', 'MESH:D010195', (32, 42))	('small interfering', 'Var', (57, 74))	('Downregulation', 'NegReg', (0, 14))	('pancreatic', 'Disease', (32, 42))	('enhanced', 'PosReg', (79, 87))	('mouse', 'Species', '10090', (26, 31))	('glucose', 'Chemical', 'MESH:D005947', (88, 95))	('FBP1', 'Gene', (18, 22))	('glucose utilization', 'MPA', (88, 107))	('GSIS', 'MPA', (112, 116))	('RNA', 'cellular_component', 'GO:0005562', ('75', '78'))
138940	29556139	Expression of FBP1 and FBP2 was significantly downregulated in gastric cancer cell lines and gastric carcinomas (GCs) due to promoter hypermethylation.	('gastric cancer', 'Disease', (63, 77))	('promoter hypermethylation', 'Var', (125, 150))	('gastric cancer', 'Disease', 'MESH:D013274', (63, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('Expression', 'MPA', (0, 10))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (63, 77))	('FBP2', 'Gene', '8789', (23, 27))	('downregulated', 'NegReg', (46, 59))	('FBP1', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('gastric carcinomas', 'Disease', 'MESH:D013274', (93, 111))	('gastric carcinomas', 'Disease', (93, 111))	('FBP2', 'Gene', (23, 27))
138941	29556139	Ectopic expression of FBPase in GC cells led to significant inhibition of proliferation in vitro, as well as xenograft tumour growth in vivo.	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumour growth', 'Disease', (119, 132))	('FBPase', 'Gene', (22, 28))	('tumour growth', 'Disease', 'MESH:D006130', (119, 132))	('Ectopic expression', 'Var', (0, 18))	('inhibition', 'NegReg', (60, 70))	('proliferation', 'CPA', (74, 87))	('FBPase', 'Gene', '114508', (22, 28))
138942	29556139	Absent or low FBP2 expression and FBP1 promoter methylation in GC tissues was correlated with the poor survival of GC patients.	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('expression', 'MPA', (19, 29))	('FBP2', 'Gene', (14, 18))	('FBP2', 'Gene', '8789', (14, 18))	('Absent', 'NegReg', (0, 6))	('low', 'NegReg', (10, 13))	('FBP1', 'Gene', (34, 38))	('methylation', 'Var', (48, 59))	('patients', 'Species', '9606', (118, 126))
138954	29556139	Ectopic FBP1 expression in several ccRCC cell lines significantly inhibited their growth, while FBP1 depletion promoted the growth of kidney proximal tubule cells, the presumptive cells-of-origin for ccRCC.	('FBP1', 'Gene', (8, 12))	('growth', 'MPA', (82, 88))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('ccRCC', 'Phenotype', 'HP:0006770', (200, 205))	('RCC', 'Disease', (37, 40))	('Ectopic', 'Var', (0, 7))	('inhibited', 'NegReg', (66, 75))	('ccRCC', 'Phenotype', 'HP:0006770', (35, 40))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('depletion', 'Var', (101, 110))	('RCC', 'Disease', (202, 205))	('growth', 'MPA', (124, 130))	('promoted', 'PosReg', (111, 119))
138958	29556139	Downregulation of FBP1 was also observed in HT29, SW480, SW620, HCT116, LoVo and RKO colon cancer cell lines when compared to human normal adult colon tissue, and this downregulation correlated well with the promoter methylation status of FBP1.	('HCT116', 'CellLine', 'CVCL:0291', (64, 70))	('human', 'Species', '9606', (126, 131))	('SW620', 'CellLine', 'CVCL:0547', (57, 62))	('SW620', 'Var', (57, 62))	('Downregulation', 'NegReg', (0, 14))	('colon cancer', 'Phenotype', 'HP:0003003', (85, 97))	('HT29', 'CellLine', 'CVCL:0320', (44, 48))	('colon cancer', 'Disease', 'MESH:D015179', (85, 97))	('methylation', 'biological_process', 'GO:0032259', ('217', '228'))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('FBP1', 'Gene', (18, 22))	('colon cancer', 'Disease', (85, 97))	('SW480', 'CellLine', 'CVCL:0546', (50, 55))
138959	29556139	FBP1 overexpression reduced the colony formation abilities of cancer cells and inhibited their growth.	('reduced', 'NegReg', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('formation', 'biological_process', 'GO:0009058', ('39', '48'))	('inhibited', 'NegReg', (79, 88))	('FBP1', 'Gene', (0, 4))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('overexpression', 'Var', (5, 19))	('growth', 'CPA', (95, 101))
138968	29556139	Upon FBPase silencing, glucose uptake and lactate secretion were significantly increased in various cancer cells (BLBC, ccRCC, gastric cancer, HCC, lung cancer, and pancreatic cancer cell lines).	('lactate secretion', 'biological_process', 'GO:0046722', ('42', '59'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (165, 182))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('glucose', 'Chemical', 'MESH:D005947', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('gastric cancer', 'Disease', (127, 141))	('HCC', 'Gene', '619501', (143, 146))	('HCC', 'Phenotype', 'HP:0001402', (143, 146))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('pancreatic cancer', 'Disease', (165, 182))	('cancer', 'Disease', (135, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (120, 125))	('HCC', 'Gene', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', (148, 159))	('gastric cancer', 'Disease', 'MESH:D013274', (127, 141))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('RCC', 'Disease', (122, 125))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('glucose uptake', 'biological_process', 'GO:0046323', ('23', '37'))	('silencing', 'Var', (12, 21))	('lactate secretion', 'MPA', (42, 59))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (165, 182))	('cancer', 'Disease', (100, 106))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('glucose uptake', 'MPA', (23, 37))	('increased', 'PosReg', (79, 88))	('gastric cancer', 'Phenotype', 'HP:0012126', (127, 141))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('FBPase', 'Gene', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lactate', 'Chemical', 'MESH:D019344', (42, 49))	('FBPase', 'Gene', '114508', (5, 11))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('cancer', 'Disease', (176, 182))
138970	29556139	FBP1 expression decreased glucose uptake, TXNIP induction and insulin sensitivities, whereas the loss of FBP1 enhanced glucose uptake, TXNIP induction and insulin sensitivities.	('insulin', 'molecular_function', 'GO:0016088', ('155', '162'))	('glucose uptake', 'biological_process', 'GO:0046323', ('26', '40'))	('insulin', 'molecular_function', 'GO:0016088', ('62', '69'))	('TXNIP', 'Gene', '10628', (42, 47))	('insulin', 'Gene', (155, 162))	('TXNIP', 'Gene', (135, 140))	('enhanced', 'PosReg', (110, 118))	('insulin', 'Gene', '3630', (62, 69))	('glucose uptake', 'biological_process', 'GO:0046323', ('119', '133'))	('decreased', 'NegReg', (16, 25))	('TXNIP', 'Gene', '10628', (135, 140))	('FBP1', 'Gene', (105, 109))	('glucose uptake', 'MPA', (26, 40))	('glucose', 'Chemical', 'MESH:D005947', (26, 33))	('insulin', 'Gene', '3630', (155, 162))	('loss', 'Var', (97, 101))	('glucose uptake', 'MPA', (119, 133))	('FBP1', 'Gene', (0, 4))	('insulin', 'Gene', (62, 69))	('glucose', 'Chemical', 'MESH:D005947', (119, 126))	('TXNIP', 'Gene', (42, 47))
138986	29556139	The basal oxygen consumption rate (OCR) was found to be significantly decreased in FBP1-knockdown cells, whereas it was significantly increased in FBP1-expressing cells.	('FBP1-knockdown', 'Gene', (83, 97))	('decreased', 'NegReg', (70, 79))	('oxygen', 'Chemical', 'MESH:D010100', (10, 16))	('oxygen consumption rate', 'MPA', (10, 33))	('increased', 'PosReg', (134, 143))	('FBP1-knockdown', 'Var', (83, 97))
138988	29556139	FBPase silencing helped maintain energy homeostasis in cancer cells.	('energy homeostasis', 'biological_process', 'GO:0097009', ('33', '51'))	('FBPase', 'Gene', '114508', (0, 6))	('energy homeostasis', 'MPA', (33, 51))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('FBPase', 'Gene', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('silencing', 'Var', (7, 16))	('cancer', 'Disease', (55, 61))
138990	29556139	Under normoxic conditions, expression or knockdown of FBP1 did not alter the steady-state level of ATP in BLBC or luminal cells.	('ATP', 'Chemical', 'MESH:D000255', (99, 102))	('knockdown', 'Var', (41, 50))	('FBP1', 'Gene', (54, 58))
138991	29556139	However, under hypoxia, knockdown of FBP1 helped maintain ATP production, whereas expression of FBP1 significantly decreased ATP production in BCLC and HCC.	('HCC', 'Gene', '619501', (152, 155))	('ATP production', 'MPA', (58, 72))	('hypoxia', 'Disease', (15, 22))	('HCC', 'Gene', (152, 155))	('hypoxia', 'Disease', 'MESH:D000860', (15, 22))	('HCC', 'Phenotype', 'HP:0001402', (152, 155))	('ATP production', 'MPA', (125, 139))	('FBP1', 'Gene', (37, 41))	('ATP', 'Chemical', 'MESH:D000255', (58, 61))	('decreased', 'NegReg', (115, 124))	('ATP', 'Chemical', 'MESH:D000255', (125, 128))	('FBP1', 'Gene', (96, 100))	('knockdown', 'Var', (24, 33))
138992	29556139	In gastric cancer cells, studies have found that FBP2 overexpression significantly reduces the levels of ATP and lactate through interference of the Akt-mTOR pathway.	('interference', 'NegReg', (129, 141))	('Akt', 'Gene', (149, 152))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('mTOR', 'Gene', (153, 157))	('FBP2', 'Gene', (49, 53))	('mTOR', 'Gene', '2475', (153, 157))	('reduces', 'NegReg', (83, 90))	('gastric cancer', 'Disease', (3, 17))	('lactate', 'Chemical', 'MESH:D019344', (113, 120))	('FBP2', 'Gene', '8789', (49, 53))	('Akt', 'Gene', '207', (149, 152))	('overexpression', 'Var', (54, 68))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('ATP', 'Chemical', 'MESH:D000255', (105, 108))
138995	29556139	Ectopic FBP1 tended to inhibit M2 enrichment of TCA cycle intermediates, such as succinate, fumarate and malate, as well as M4 enrichment of citrate.	('fumarate', 'Chemical', 'MESH:D005650', (92, 100))	('citrate', 'Chemical', 'MESH:D019343', (141, 148))	('malate', 'MPA', (105, 111))	('M4 enrichment of citrate', 'MPA', (124, 148))	('FBP1', 'Gene', (8, 12))	('M2 enrichment of', 'MPA', (31, 47))	('malate', 'Chemical', 'MESH:C030298', (105, 111))	('inhibit', 'NegReg', (23, 30))	('fumarate', 'MPA', (92, 100))	('succinate', 'MPA', (81, 90))	('TCA cycle', 'biological_process', 'GO:0006099', ('48', '57'))	('TCA', 'Enzyme', (48, 51))	('TCA', 'Chemical', 'MESH:D014233', (48, 51))	('Ectopic', 'Var', (0, 7))	('succinate', 'Chemical', 'MESH:D019802', (81, 90))
138996	29556139	Furthermore, FBP1 expression reduced M5 enrichment of the ribosyl unit of ribonucleotides and their derivatives (i.e., NAD+, and UDPG), suggesting that FBP1 suppressed de novo nucleic acid synthesis through the pentose phosphate pathway.	('FBP1', 'Var', (152, 156))	('de novo nucleic acid synthesis', 'MPA', (168, 198))	('UDPG', 'Gene', (129, 133))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('211', '236'))	('NAD+', 'Chemical', 'MESH:D009243', (119, 123))	('suppressed', 'NegReg', (157, 167))	('FBP1', 'Gene', (13, 17))	('UDPG', 'Gene', '7360', (129, 133))	('nucleic acid', 'cellular_component', 'GO:0005561', ('176', '188'))	('reduced', 'NegReg', (29, 36))	('pentose phosphate', 'Chemical', 'MESH:D010428', (211, 228))	('pentose phosphate pathway', 'Pathway', (211, 236))	('synthesis', 'biological_process', 'GO:0009058', ('189', '198'))
139001	29556139	All these data imply that loss of FBPase facilitates glycolytic flux and decreases OXPHOS in cancer cells.	('FBPase', 'Gene', '114508', (34, 40))	('glycolytic flux', 'MPA', (53, 68))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('decreases', 'NegReg', (73, 82))	('OXPHOS', 'biological_process', 'GO:0002082', ('83', '89'))	('facilitates', 'PosReg', (41, 52))	('OXPHOS', 'MPA', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('FBPase', 'Gene', (34, 40))	('loss', 'Var', (26, 30))
139003	29556139	In HCC, FBP1 expression was found to significantly decrease the levels of glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA).	('LDHA', 'Gene', '3939', (133, 137))	('glucose transporter 1', 'Gene', (74, 95))	('FBP1', 'Gene', (8, 12))	('HCC', 'Gene', (3, 6))	('lactate dehydrogenase A', 'Gene', (108, 131))	('glucose transporter 1', 'Gene', '6513', (74, 95))	('lactate dehydrogenase A', 'Gene', '3939', (108, 131))	('expression', 'Var', (13, 23))	('HCC', 'Gene', '619501', (3, 6))	('decrease', 'NegReg', (51, 59))	('GLUT1', 'Gene', (97, 102))	('HCC', 'Phenotype', 'HP:0001402', (3, 6))	('LDHA', 'Gene', (133, 137))	('GLUT1', 'Gene', '6513', (97, 102))
139006	29556139	FBP1 expression significantly decreased the tetrameric PKM2, whereas knockdown of FBP1 increased the formation of tetrameric PKM2.	('increased', 'PosReg', (87, 96))	('FBP1', 'Gene', (82, 86))	('PKM2', 'Gene', (125, 129))	('PKM2', 'Gene', (55, 59))	('PKM2', 'Gene', '5315', (55, 59))	('tetrameric', 'MPA', (44, 54))	('FBP1', 'Gene', (0, 4))	('formation', 'biological_process', 'GO:0009058', ('101', '110'))	('PKM2', 'Gene', '5315', (125, 129))	('knockdown', 'Var', (69, 78))	('decreased', 'NegReg', (30, 39))
139007	29556139	In addition, FBP1 expression was found to significantly decrease the HK2 and PFK1 levels in HCC.	('HCC', 'Gene', (92, 95))	('PFK', 'molecular_function', 'GO:0003872', ('77', '80'))	('HCC', 'Gene', '619501', (92, 95))	('FBP1', 'Gene', (13, 17))	('PFK1', 'Gene', '5213', (77, 81))	('HK2', 'molecular_function', 'GO:0008256', ('69', '72'))	('expression', 'Var', (18, 28))	('HCC', 'Phenotype', 'HP:0001402', (92, 95))	('HK2', 'Gene', '3099', (69, 72))	('decrease', 'NegReg', (56, 64))	('PFK1', 'Gene', (77, 81))	('HK2', 'Gene', (69, 72))
139008	29556139	All these results indicated that the loss of FBP1 activated GLUT1, PKM2, HK2, PFK1 and LDHA, which facilitated glucose uptake and lactate production and triggered the switch to aerobic glycolysis.	('HK2', 'molecular_function', 'GO:0008256', ('73', '76'))	('glucose', 'Chemical', 'MESH:D005947', (111, 118))	('facilitated', 'PosReg', (99, 110))	('lactate production', 'MPA', (130, 148))	('triggered', 'Reg', (153, 162))	('glycolysis', 'biological_process', 'GO:0006096', ('185', '195'))	('FBP1', 'Gene', (45, 49))	('PFK1', 'Gene', '5213', (78, 82))	('HK2', 'Gene', (73, 76))	('HK2', 'Gene', '3099', (73, 76))	('LDHA', 'Gene', (87, 91))	('GLUT1', 'Gene', (60, 65))	('loss', 'Var', (37, 41))	('lactate', 'Chemical', 'MESH:D019344', (130, 137))	('glucose uptake', 'MPA', (111, 125))	('PKM2', 'Gene', (67, 71))	('glucose uptake', 'biological_process', 'GO:0046323', ('111', '125'))	('PKM2', 'Gene', '5315', (67, 71))	('LDHA', 'Gene', '3939', (87, 91))	('GLUT1', 'Gene', '6513', (60, 65))	('switch', 'MPA', (167, 173))	('PFK1', 'Gene', (78, 82))	('PFK', 'molecular_function', 'GO:0003872', ('78', '81'))
139016	29556139	Moreover, ROS induces mitochondrial apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('36', '45'))	('ROS', 'Var', (10, 13))	('ROS', 'Chemical', 'MESH:D017382', (10, 13))	('apoptosis', 'biological_process', 'GO:0006915', ('36', '45'))	('induces', 'Reg', (14, 21))	('mitochondrial apoptosis', 'CPA', (22, 45))
139021	29556139	In brain metastatic breast cancer cells, knocking down FBP2 resulted in a significant amount of apoptotic cell death (as indicated by the increase incleaved PARP), whereas exogenous FBP2 significantly rescued cell death.	('increase', 'PosReg', (138, 146))	('cell death', 'biological_process', 'GO:0008219', ('209', '219'))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('96', '116'))	('FBP2', 'Gene', (182, 186))	('PARP', 'Gene', (157, 161))	('breast cancer', 'Disease', (20, 33))	('FBP2', 'Gene', (55, 59))	('FBP2', 'Gene', '8789', (55, 59))	('FBP2', 'Gene', '8789', (182, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('apoptotic cell death', 'CPA', (96, 116))	('PARP', 'Gene', '142', (157, 161))	('knocking down', 'Var', (41, 54))
139025	29556139	In hepatocellular carcinoma and colon cancer, forced FBP1 expression was found to increase the number of G2-M phase cells but decrease the number of S phase cells.	('colon cancer', 'Phenotype', 'HP:0003003', (32, 44))	('hepatocellular carcinoma', 'Disease', (3, 27))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('S phase cells', 'CPA', (149, 162))	('G2-M phase cells', 'CPA', (105, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('colon cancer', 'Disease', (32, 44))	('FBP1', 'Gene', (53, 57))	('S phase', 'biological_process', 'GO:0051320', ('149', '156'))	('forced', 'Var', (46, 52))	('decrease', 'NegReg', (126, 134))	('M phase', 'biological_process', 'GO:0000279', ('108', '115'))	('increase', 'PosReg', (82, 90))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('colon cancer', 'Disease', 'MESH:D015179', (32, 44))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))
139027	29556139	All these data indicated that the growth suppression induced by forced FBP1 expression might be partly due to cell cycle arrest.	('arrest', 'Disease', 'MESH:D006323', (121, 127))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('110', '127'))	('growth suppression', 'CPA', (34, 52))	('arrest', 'Disease', (121, 127))	('FBP1', 'Gene', (71, 75))	('forced', 'Var', (64, 70))
139031	29556139	Under conditions of persistent hypoxia, the induction of HIF1 leads to adaptive mechanisms for the reduction of ROS and re-establishment of homeostasis.	('induction', 'Var', (44, 53))	('ROS', 'Chemical', 'MESH:D017382', (112, 115))	('ROS', 'Protein', (112, 115))	('homeostasis', 'biological_process', 'GO:0042592', ('140', '151'))	('HIF1', 'Gene', (57, 61))	('homeostasis', 'MPA', (140, 151))	('reduction', 'NegReg', (99, 108))	('hypoxia', 'Disease', (31, 38))	('hypoxia', 'Disease', 'MESH:D000860', (31, 38))	('HIF1', 'Gene', '3091', (57, 61))
139042	29556139	In pancreatic cancer, FBP1 expression impeded gemcitabine-induced ERK activation through inhibition of the IQGAP1-ERK1/2 signalling axis in a manner independent of its enzymatic activity.	('ERK1', 'molecular_function', 'GO:0004707', ('114', '118'))	('ERK1/2', 'Gene', (114, 120))	('ERK1/2', 'Gene', '5595;5594', (114, 120))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('ERK', 'Gene', (66, 69))	('ERK', 'Gene', (114, 117))	('FBP1', 'Gene', (22, 26))	('expression', 'Var', (27, 37))	('IQGAP1', 'Gene', '8826', (107, 113))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('signalling', 'biological_process', 'GO:0023052', ('121', '131'))	('impeded', 'NegReg', (38, 45))	('gemcitabine', 'Chemical', 'MESH:C056507', (46, 57))	('activation', 'PosReg', (70, 80))	('ERK', 'molecular_function', 'GO:0004707', ('66', '69'))	('pancreatic cancer', 'Disease', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('inhibition', 'NegReg', (89, 99))	('ERK', 'Gene', '5594', (66, 69))	('gemcitabine-induced', 'MPA', (46, 65))	('ERK', 'Gene', '5594', (114, 117))	('IQGAP1', 'Gene', (107, 113))
139046	29556139	However, recently, ubiquitin-mediated degradation and copy number loss of FBP1 were also shown to explain the loss of FBPase in cancer (Table 2).	('FBPase', 'Gene', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('ubiquitin-mediated degradation', 'MPA', (19, 49))	('loss', 'NegReg', (110, 114))	('FBP1', 'Gene', (74, 78))	('ubiquitin', 'molecular_function', 'GO:0031386', ('19', '28'))	('copy number loss', 'Var', (54, 70))	('FBPase', 'Gene', '114508', (118, 124))	('degradation', 'biological_process', 'GO:0009056', ('38', '49'))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (128, 134))
139047	29556139	Epigenetic changes, including DNA methylation and histone modifications, have been shown to alter patterns of gene expression and to be involved in carcinogenesis.	('carcinogenesis', 'Disease', (148, 162))	('DNA', 'MPA', (30, 33))	('alter', 'Reg', (92, 97))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('involved', 'Reg', (136, 144))	('histone modifications', 'Var', (50, 71))	('DNA methylation', 'biological_process', 'GO:0006306', ('30', '45'))	('carcinogenesis', 'Disease', 'MESH:D063646', (148, 162))	('patterns of gene expression', 'MPA', (98, 125))	('gene expression', 'biological_process', 'GO:0010467', ('110', '125'))
139051	29556139	Lysine (K)-specificdemethylase 1A (LSD1)-mediated demethylation of H3K4me2 at FBP1 promoters suppressed FBP1 expression in HepG2 cells.	('demethylation', 'Var', (50, 63))	('expression', 'MPA', (109, 119))	('HepG2', 'CellLine', 'CVCL:0027', (123, 128))	('LSD1', 'Gene', (35, 39))	('demethylation', 'biological_process', 'GO:0070988', ('50', '63'))	('LSD1', 'Gene', '23028', (35, 39))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))	('H3K4me2', 'Protein', (67, 74))	('FBP1', 'Gene', (104, 108))	('suppressed', 'NegReg', (93, 103))
139057	29556139	Treatment with HDAC inhibitors or knockdown of HDAC1 and/or HDAC2 restored FBP1 expression.	('HDAC2', 'Gene', '3066', (60, 65))	('HDAC2', 'Gene', (60, 65))	('HDAC1', 'Gene', (47, 52))	('FBP1', 'Gene', (75, 79))	('HDAC', 'Gene', (15, 19))	('HDAC', 'Gene', (60, 64))	('HDAC1', 'Gene', '3065', (47, 52))	('HDAC', 'Gene', (47, 51))	('HDAC', 'Gene', '9734', (15, 19))	('restored', 'PosReg', (66, 74))	('HDAC', 'Gene', '9734', (60, 64))	('expression', 'MPA', (80, 90))	('HDAC', 'Gene', '9734', (47, 51))	('knockdown', 'Var', (34, 43))
139058	29556139	Copy number loss of FBP1 was observed in ccRCC cases.	('observed', 'Reg', (29, 37))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('FBP1', 'Gene', (20, 24))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('Copy number loss', 'Var', (0, 16))
139059	29556139	Copy number loss of FBP1 was significantly associated with lower FBP1 expression in HCC.	('HCC', 'Gene', '619501', (84, 87))	('lower', 'NegReg', (59, 64))	('HCC', 'Phenotype', 'HP:0001402', (84, 87))	('expression', 'MPA', (70, 80))	('FBP1', 'Gene', (20, 24))	('FBP1', 'Gene', (65, 69))	('HCC', 'Gene', (84, 87))	('Copy number loss', 'Var', (0, 16))
139066	29556139	Treatment of cells with 5AZA resulted in a significant increase in the expression of FBPase mRNA in breast cancer, gastric cancer and lung cancer, while treatment with sodium butyrate, SAHA and LBH589 upregulated FBP1 protein and mRNA expression in HCC.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung cancer', 'Disease', (134, 145))	('5AZA', 'Chemical', 'MESH:D000077209', (24, 28))	('increase', 'PosReg', (55, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('LBH589', 'Chemical', 'MESH:D000077767', (194, 200))	('SAHA', 'Disease', (185, 189))	('FBP1', 'Gene', (213, 217))	('LBH589', 'Var', (194, 200))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('upregulated', 'PosReg', (201, 212))	('gastric cancer', 'Disease', (115, 129))	('expression', 'MPA', (71, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('HCC', 'Gene', (249, 252))	('SAHA', 'Disease', 'None', (185, 189))	('FBPase', 'Gene', (85, 91))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('mRNA expression', 'MPA', (230, 245))	('breast cancer', 'Disease', (100, 113))	('FBPase', 'Gene', '114508', (85, 91))	('gastric cancer', 'Disease', 'MESH:D013274', (115, 129))	('HCC', 'Gene', '619501', (249, 252))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('mRNA', 'Protein', (92, 96))	('HCC', 'Phenotype', 'HP:0001402', (249, 252))	('protein', 'cellular_component', 'GO:0003675', ('218', '225'))	('sodium butyrate', 'Chemical', 'MESH:D020148', (168, 183))	('protein', 'Protein', (218, 225))
139068	29556139	All these data indicated that the silencing of FBP1 can be a target of methyltransferase inhibitors and HDAC inhibitors for the potential treatment of cancer.	('HDAC', 'Gene', (104, 108))	('HDAC', 'Gene', '9734', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('FBP1', 'Gene', (47, 51))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('silencing', 'Var', (34, 43))
139071	29556139	Meanwhile, LSD1 also converts the inactive H3K9me3 into the less repressive H3K9me1 or H3K9me2 marks, thereby leading to gene derepression.	('LSD1', 'Gene', (11, 15))	('LSD1', 'Gene', '23028', (11, 15))	('H3K9me2', 'Var', (87, 94))	('gene derepression', 'MPA', (121, 138))
139072	29556139	Thus, the functional outcome of LSD1 activity depends on the balance between the modification of H3K4me2/3 or H3K9me3.	('LSD1', 'Gene', '23028', (32, 36))	('H3K9me3', 'Var', (110, 117))	('LSD1', 'Gene', (32, 36))	('H3K4me2/3', 'Protein', (97, 106))
139078	29556139	Meanwhile, bortezomib-induced decreases in glucose consumption, lactate levels and cell growth inhibition were largely diminished by the knockdown of FBP1.	('glucose consumption', 'Disease', (43, 62))	('decreases', 'NegReg', (30, 39))	('cell growth', 'biological_process', 'GO:0016049', ('83', '94'))	('diminished', 'NegReg', (119, 129))	('bortezomib', 'Chemical', 'MESH:D000069286', (11, 21))	('lactate levels', 'MPA', (64, 78))	('lactate', 'Chemical', 'MESH:D019344', (64, 71))	('knockdown', 'Var', (137, 146))	('cell growth inhibition', 'CPA', (83, 105))	('FBP1', 'Gene', (150, 154))	('glucose consumption', 'Disease', 'MESH:D014397', (43, 62))
139089	29556139	To overcome all these unfavourable growth conditions, cancer cells have to reprogram their metabolic and epigenetic phenotypes through the activation of oncogenes and inactivation of tumour-suppressor genes, altering the pattern of epigenetic modification and leading to the aberrant expression of numerous genes, including those involved in metabolic rate-limiting, metastasis or differentiation.	('inactivation', 'Var', (167, 179))	('oncogenes', 'Gene', (153, 162))	('tumour', 'Disease', (183, 189))	('activation', 'PosReg', (139, 149))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('leading to', 'Reg', (260, 270))	('tumour', 'Disease', 'MESH:D009369', (183, 189))	('epigenetic modification', 'MPA', (232, 255))	('pattern', 'MPA', (221, 228))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('altering', 'Reg', (208, 216))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('expression', 'MPA', (284, 294))
139090	29556139	Therefore, it is not surprising to find an aberrant epigenetic modification of FBPase in cancer.	('FBPase', 'Gene', '114508', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('epigenetic modification', 'Var', (52, 75))	('cancer', 'Disease', (89, 95))	('FBPase', 'Gene', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
139094	29556139	What is the meaning and intrinsic mechanism of the interplay between aberrant FBPase and other cancer hallmarks?	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('FBPase', 'Gene', (78, 84))	('aberrant', 'Var', (69, 77))	('cancer', 'Disease', (95, 101))	('FBPase', 'Gene', '114508', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
139097	29556139	One main obstacle is the identification of distinct regulatory markers exclusive to aberrant FBPase.	('FBPase', 'Gene', (93, 99))	('aberrant', 'Var', (84, 92))	('FBPase', 'Gene', '114508', (93, 99))
139098	29556139	Without this knowledge, drugs targeting aberrant FBPase with higher specificity but fewer side effects can't be found or designed.	('FBPase', 'Gene', '114508', (49, 55))	('FBPase', 'Gene', (49, 55))	('aberrant', 'Var', (40, 48))
139101	29556139	Co-treatment of drugs targeting FBPase with conventional chemotherapy is promising, as expression of FBPase promotes differentiation and apoptosis and inhibits the chemoresistance of cancer cells.	('differentiation', 'CPA', (117, 132))	('expression', 'Var', (87, 97))	('inhibits', 'NegReg', (151, 159))	('cancer', 'Disease', (183, 189))	('apoptosis', 'CPA', (137, 146))	('FBPase', 'Gene', (101, 107))	('FBPase', 'Gene', (32, 38))	('apoptosis', 'biological_process', 'GO:0097194', ('137', '146'))	('apoptosis', 'biological_process', 'GO:0006915', ('137', '146'))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('FBPase', 'Gene', '114508', (101, 107))	('promotes', 'PosReg', (108, 116))	('FBPase', 'Gene', '114508', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
139104	28626293	CD146 Promoter Polymorphism (rs3923594) Is Associated with Recurrence of Clear Cell Renal Cell Carcinoma in Chinese Population CD146 is a membrane signal receptor in tumor-induced angiogenesis.	('CD146', 'Gene', '4162', (127, 132))	('rs3923594', 'Var', (29, 38))	('CD146', 'Gene', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('membrane', 'cellular_component', 'GO:0016020', ('138', '146'))	('angiogenesis', 'biological_process', 'GO:0001525', ('180', '192'))	('Carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (73, 104))	('Associated', 'Reg', (43, 53))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (73, 104))	('CD146', 'Gene', '4162', (0, 5))	('Clear Cell Renal Cell Carcinoma', 'Disease', (73, 104))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (84, 104))	('rs3923594', 'Mutation', 'rs3923594', (29, 38))	('CD146', 'Gene', (0, 5))
139105	28626293	However, limited studies have focused on the CD146 promoter polymorphisms in clear cell renal cell carcinoma (ccRCC).	('polymorphisms', 'Var', (60, 73))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (77, 108))	('clear cell renal cell carcinoma', 'Disease', (77, 108))	('CD146', 'Gene', (45, 50))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (88, 108))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (77, 108))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))
139107	28626293	The rs3923594 was associated with stage and metastasis (300 cases) and recurrence (263 cases) of ccRCC in Chinese population.	('stage', 'CPA', (34, 39))	('recurrence', 'CPA', (71, 81))	('rs3923594', 'DBSNP_MENTION', 'None', (4, 13))	('rs3923594', 'Var', (4, 13))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('associated', 'Reg', (18, 28))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('ccRCC', 'Disease', (97, 102))
139108	28626293	A significant association was also observed between the rs3923594 and CD146 expression (227 cases) in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('CD146', 'Gene', (70, 75))	('ccRCC', 'Disease', (102, 107))	('rs3923594', 'Var', (56, 65))	('rs3923594', 'DBSNP_MENTION', 'None', (56, 65))
139109	28626293	The rs3923594 was an independent predictor of recurrence in Chinese patients with localized ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('rs3923594', 'DBSNP_MENTION', 'None', (4, 13))	('rs3923594', 'Var', (4, 13))	('localized ccRCC', 'Disease', (82, 97))
139123	28626293	CD146 gene expression was defined as a ratio of CD146 mRNA to beta-actin mRNA and then multiplied by 1000 for easier tabulation.	('beta-actin', 'Gene', (62, 72))	('gene expression', 'biological_process', 'GO:0010467', ('6', '21'))	('beta-actin', 'Gene', '728378', (62, 72))	('CD146', 'Var', (48, 53))
139125	28626293	Significant associations were found between rs3923594 and stage (P = 0.030), metastasis in lymph node (P = 0.007), and distant metastasis (P = 0.005) (Table 4).	('stage', 'CPA', (58, 63))	('rs3923594', 'DBSNP_MENTION', 'None', (44, 53))	('rs3923594', 'Var', (44, 53))	('distant metastasis', 'CPA', (119, 137))	('metastasis in lymph node', 'CPA', (77, 101))
139126	28626293	As shown in Table 5, the rs3923594 was significantly associated with recurrence of localized ccRCC (HR, 2.788; 95% CI, 1.186-6.586; P = 0.021) by the univariate analysis.	('localized ccRCC', 'Disease', (83, 98))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('rs3923594', 'DBSNP_MENTION', 'None', (25, 34))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('rs3923594', 'Var', (25, 34))	('associated with', 'Reg', (53, 68))
139127	28626293	A multivariate Cox proportional hazard model indicated that tumor size, stage, grade, presence of necrosis, and rs3923594 (all P < 0.05) were independent predictors of recurrence of localized ccRCC.	('rs3923594', 'DBSNP_MENTION', 'None', (112, 121))	('rs3923594', 'Var', (112, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (192, 197))	('RCC', 'Phenotype', 'HP:0005584', (194, 197))	('necrosis', 'biological_process', 'GO:0070265', ('98', '106'))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('necrosis', 'biological_process', 'GO:0008219', ('98', '106'))	('necrosis', 'biological_process', 'GO:0001906', ('98', '106'))	('necrosis', 'biological_process', 'GO:0019835', ('98', '106'))	('necrosis', 'biological_process', 'GO:0008220', ('98', '106'))	('localized ccRCC', 'Disease', (182, 197))
139129	28626293	None of significant associations were found between five SNPs with CD146 gene expression, whereas rs3923594 was associated with CD146 gene expression at mRNA level in 227 specimens.	('rs3923594', 'DBSNP_MENTION', 'None', (98, 107))	('rs3923594', 'Var', (98, 107))	('gene expression', 'biological_process', 'GO:0010467', ('73', '88'))	('CD146', 'Gene', (67, 72))	('gene expression', 'biological_process', 'GO:0010467', ('134', '149'))	('associated', 'Reg', (112, 122))
139130	28626293	The mean of CD146 gene expression in patients with genotype TT of rs3923594 (4.84 +- 1.22) was significantly higher than that in those with genotype GG (3.96 +- 0.85, P = 0.014).	('higher', 'PosReg', (109, 115))	('rs3923594', 'DBSNP_MENTION', 'None', (66, 75))	('CD146 gene', 'Gene', (12, 22))	('rs3923594', 'Var', (66, 75))	('gene expression', 'biological_process', 'GO:0010467', ('18', '33'))	('expression', 'MPA', (23, 33))
139131	28626293	The mean of CD146 gene expression in patients with genotype GT of rs3923594 (4.26 +- 1.14) was also higher than that in those with genotype GG, but the difference did not reach statistical significance (P = 0.119) (Figure 2).	('rs3923594', 'DBSNP_MENTION', 'None', (66, 75))	('CD146 gene', 'Gene', (12, 22))	('rs3923594', 'Var', (66, 75))	('higher', 'PosReg', (100, 106))	('gene expression', 'biological_process', 'GO:0010467', ('18', '33'))	('expression', 'MPA', (23, 33))
139132	28626293	Currently, many studies have reported that polymorphism of NFKB1, PTPRD, CASP8, GSTM3, and BTLA is related to the risk of RCC.	('GSTM3', 'Gene', (80, 85))	('NFKB1', 'Gene', (59, 64))	('BTLA', 'Gene', '151888', (91, 95))	('related', 'Reg', (99, 106))	('GSTM3', 'Gene', '2947', (80, 85))	('BTLA', 'Gene', (91, 95))	('PTPRD', 'Gene', '5789', (66, 71))	('PTPRD', 'Gene', (66, 71))	('NFKB1', 'Gene', '4790', (59, 64))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('polymorphism', 'Var', (43, 55))	('CASP8', 'Gene', (73, 78))	('CASP8', 'Gene', '841', (73, 78))	('RCC', 'Disease', (122, 125))
139133	28626293	Some researchers have further presented the associations between survival of RCC and polymorphism of IL-4, VEGF, CYP3A5, and ABCB1.	('IL-4', 'Gene', '3565', (101, 105))	('VEGF', 'Gene', (107, 111))	('CYP3A5', 'Gene', '1577', (113, 119))	('IL-4', 'molecular_function', 'GO:0005136', ('101', '105'))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('VEGF', 'Gene', '7422', (107, 111))	('CYP3A5', 'Gene', (113, 119))	('associations', 'Interaction', (44, 56))	('ABCB1', 'Gene', (125, 130))	('ABCB1', 'Gene', '5243', (125, 130))	('IL-4', 'Gene', (101, 105))	('polymorphism', 'Var', (85, 97))
139134	28626293	However, the rs543070476, new 1, new 2, new 3, and new 4 were not associated with clinicopathological characteristics of ccRCC.	('rs543070476', 'Mutation', 'rs543070476', (13, 24))	('rs543070476', 'Var', (13, 24))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (121, 126))	('ccRCC', 'Disease', (121, 126))
139135	28626293	The significant associations were found between rs3923594 and stage, lymph node metastasis, and distant metastasis.	('stage', 'CPA', (62, 67))	('rs3923594', 'DBSNP_MENTION', 'None', (48, 57))	('rs3923594', 'Var', (48, 57))	('distant metastasis', 'CPA', (96, 114))	('lymph node metastasis', 'CPA', (69, 90))
139136	28626293	These results suggested that the rs3923594 was associated with tumor stage and metastasis of ccRCC in Chinese population.	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('tumor stage', 'CPA', (63, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('ccRCC', 'Disease', (93, 98))	('rs3923594', 'DBSNP_MENTION', 'None', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('associated', 'Reg', (47, 57))	('metastasis', 'CPA', (79, 89))	('rs3923594', 'Var', (33, 42))
139138	28626293	We also investigated the associations between rs3923594 and recurrence of localized ccRCC in Chinese population.	('localized ccRCC', 'Disease', (74, 89))	('rs3923594', 'DBSNP_MENTION', 'None', (46, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('rs3923594', 'Var', (46, 55))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))
139139	28626293	Univariate analysis demonstrated that the rs3923594 was significantly associated with recurrence of localized ccRCC.	('localized ccRCC', 'Disease', (100, 115))	('rs3923594', 'DBSNP_MENTION', 'None', (42, 51))	('associated', 'Reg', (70, 80))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('rs3923594', 'Var', (42, 51))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))
139140	28626293	Furthermore, multivariate analysis reconfirmed the independence of rs3923594 in predicting recurrence, just like tumor size, stage, grade, and presence of necrosis.	('rs3923594', 'DBSNP_MENTION', 'None', (67, 76))	('rs3923594', 'Var', (67, 76))	('necrosis', 'biological_process', 'GO:0070265', ('155', '163'))	('necrosis', 'biological_process', 'GO:0008219', ('155', '163'))	('necrosis', 'biological_process', 'GO:0019835', ('155', '163'))	('necrosis', 'biological_process', 'GO:0008220', ('155', '163'))	('necrosis', 'biological_process', 'GO:0001906', ('155', '163'))	('recurrence', 'Disease', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
139141	28626293	Thus, rs3923594 may serve as a valuable predictor of recurrence in patients with localized ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('rs3923594', 'Var', (6, 15))	('rs3923594', 'DBSNP_MENTION', 'None', (6, 15))	('localized ccRCC', 'Disease', (81, 96))
139142	28626293	We had found the association between the rs3923594 and CD146 gene expression at mRNA level in patients with ccRCC.	('ccRCC', 'Disease', (108, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('association', 'Interaction', (17, 28))	('CD146', 'Gene', (55, 60))	('rs3923594', 'DBSNP_MENTION', 'None', (41, 50))	('rs3923594', 'Var', (41, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('gene expression', 'biological_process', 'GO:0010467', ('61', '76'))
139144	28626293	We had also found that the mean of CD146 gene expression at mRNA level in patients with genotype GG of rs3923594 was lowest.	('gene expression', 'biological_process', 'GO:0010467', ('41', '56'))	('CD146 gene', 'Gene', (35, 45))	('rs3923594', 'DBSNP_MENTION', 'None', (103, 112))	('rs3923594', 'Var', (103, 112))	('lowest', 'NegReg', (117, 123))
139147	29181278	Inhibition of CA IX enzymatic activity with selective inhibitors, antibodies or labeled probes has been shown to reverse the acidic environment of solid tumors and reduce the tumor growth establishing the significant role of CA IX in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', (234, 239))	('solid tumors', 'Disease', (147, 159))	('reduce', 'NegReg', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('Inhibition', 'Var', (0, 10))	('solid tumors', 'Disease', 'MESH:D009369', (147, 159))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('acidic environment', 'MPA', (125, 143))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
139160	29181278	Thus, HIF is critically essential for cancer cells to survive and metastasize in the hostile tumor environment due to the HIF-dependent activation of oncogenes and inactivation of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('hostile tumor', 'Disease', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor suppressor', 'biological_process', 'GO:0051726', ('180', '196'))	('inactivation', 'Var', (164, 176))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (180, 185))	('oncogenes', 'Gene', (150, 159))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('activation', 'PosReg', (136, 146))	('cancer', 'Disease', (38, 44))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('180', '196'))	('hostile tumor', 'Disease', 'MESH:D009369', (85, 98))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
139177	29181278	Thus, CA IX targeting compounds have shown to significantly diminish the cancer stem cell population, inhibit the growth of primary tumors, and reduce metastatic burden.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('compounds', 'Var', (22, 31))	('primary tumors', 'Disease', 'MESH:D009369', (124, 138))	('reduce', 'NegReg', (144, 150))	('diminish', 'NegReg', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('primary tumors', 'Disease', (124, 138))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('inhibit', 'NegReg', (102, 109))	('metastatic burden', 'CPA', (151, 168))
139182	29181278	At the core of alpha-CA active site, the metal ion, Zn (II), is tetrahedrally coordinated to three imidazole rings from His94, 96, and 119 (numbering according to CA II) and a water/hydroxide anion.	('alpha-CA', 'Chemical', '-', (15, 23))	('CA II', 'Gene', (163, 168))	('core', 'cellular_component', 'GO:0019013', ('7', '11'))	('metal', 'Chemical', 'MESH:D008670', (41, 46))	('imidazole', 'Chemical', 'MESH:C029899', (99, 108))	('hydroxide anion', 'Chemical', 'MESH:C031356', (182, 197))	('CA II', 'Gene', '760', (163, 168))	('Zn (II)', 'Chemical', 'MESH:D015032', (52, 59))	('water', 'Chemical', 'MESH:D014867', (176, 181))	('His94', 'Var', (120, 125))
139183	29181278	The catalytic site is located at approximately 15 A  depth conical cavity which consists of hydrophobic (Val121, Val143, Leu198, Val207, Trp209) as well as hydrophilic (Tyr7, Asn62, His64, Asn67, Thr199, Thr200) regions and provides the accessibility to the solvent.	('Val207', 'Var', (129, 135))	('Val143', 'Var', (113, 119))	('His64', 'Chemical', '-', (182, 187))	('Val121', 'Chemical', '-', (105, 111))	('Trp209', 'Var', (137, 143))	('Leu198', 'Var', (121, 127))	('Thr200', 'Chemical', '-', (204, 210))	('Val207', 'Chemical', '-', (129, 135))	('Leu198', 'Chemical', '-', (121, 127))	('Tyr7', 'Chemical', '-', (169, 173))	('Val121', 'Var', (105, 111))	('Thr199', 'Chemical', '-', (196, 202))	('Val143', 'Chemical', '-', (113, 119))	('Asn67', 'Chemical', '-', (189, 194))	('Asn62', 'Chemical', '-', (175, 180))	('Trp209', 'Chemical', '-', (137, 143))
139246	29181278	In the recent past, this mAb under the name of girentuximab, has been assessed as an adjuvant in Phase III ARISER trial in RCC patients and showed that the patients expressing CA IX benefited more than ones without or minimal expression of CA IX.	('patients', 'Species', '9606', (156, 164))	('girentuximab', 'Chemical', 'MESH:C106533', (47, 59))	('CA IX', 'Var', (176, 181))	('RCC', 'Disease', (123, 126))	('patients', 'Species', '9606', (127, 135))	('benefited', 'PosReg', (182, 191))	('RCC', 'Disease', 'MESH:C538614', (123, 126))
139261	29181278	U-104 significantly decreased the growth of pancreatic cells in hypoxia but not in normoxia and reduced the tumor growth in mice emphasizing the potential of the compound as a therapeutic agent against CA IX.	('U-104', 'Chemical', 'MESH:C585353', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('hypoxia', 'Disease', (64, 71))	('decreased', 'NegReg', (20, 29))	('hypoxia', 'Disease', 'MESH:D000860', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('U-104', 'Var', (0, 5))	('growth', 'MPA', (34, 40))	('pancreatic', 'Disease', 'MESH:D010195', (44, 54))	('mice', 'Species', '10090', (124, 128))	('tumor', 'Disease', (108, 113))	('pancreatic', 'Disease', (44, 54))	('reduced', 'NegReg', (96, 103))
139270	29181278	By using nontoxic doses of DH348, the hypoxia-induced extracellular acidification was significantly reduced and the tumor growth was decreased.	('acidification', 'biological_process', 'GO:0045851', ('68', '81'))	('reduced', 'NegReg', (100, 107))	('extracellular', 'cellular_component', 'GO:0005576', ('54', '67'))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('DH348', 'Chemical', '-', (27, 32))	('hypoxia', 'Disease', 'MESH:D000860', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('hypoxia', 'Disease', (38, 45))	('tumor', 'Disease', (116, 121))	('DH348', 'Var', (27, 32))	('decreased', 'NegReg', (133, 142))
139271	29181278	DH348 also sensitized the tumor to irradiation and the effect was CA IX-dependent.	('sensitized', 'Reg', (11, 21))	('DH348', 'Chemical', '-', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('DH348', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
139312	29181278	However, the mAbs (G250 and M75) bind to the PG domain, and therefore they cannot affect its catalytic activity.	('G250', 'Var', (19, 23))	('catalytic activity', 'molecular_function', 'GO:0003824', ('93', '111'))	('bind', 'Interaction', (33, 37))	('mAbs', 'Gene', (13, 17))	('M75', 'Var', (28, 31))	('mAbs', 'Gene', '72935', (13, 17))
139344	29368112	For familial type II papillary cancers, the proto-oncogene MET is frequently mutated usually in the tyrosine kinase domain resulting in possible efficacy of multikinase inhibitors such as vascular endothelial growth factor inhibitors and MET inhibitors.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('familial type II papillary cancers', 'Disease', 'MESH:D009369', (4, 38))	('familial type II papillary cancers', 'Disease', (4, 38))	('MET', 'Gene', (59, 62))	('mutated', 'Var', (77, 84))	('efficacy', 'PosReg', (145, 153))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('188', '222'))	('tyrosine', 'Chemical', 'None', (100, 108))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))
139358	29368112	If CN is done in patients with suboptimal PS or bulky metastases, it is likely that the window of opportunity to treat with systemic therapy and achieve significant palliation is lost.	('suboptimal', 'Var', (31, 41))	('metastases', 'Disease', (54, 64))	('patients', 'Species', '9606', (17, 25))	('metastases', 'Disease', 'MESH:D009362', (54, 64))
139379	29368112	Forty-four patients (40%) had MET-driven papillary renal cancer (PRCC), defined by the presence of chromosome 7, MET copy number gain, focal MET, or HGF gene amplification, or MET kinase domain mutations in their tumor samples.	('tumor', 'Disease', (213, 218))	('chromosome', 'cellular_component', 'GO:0005694', ('99', '109'))	('papillary renal cancer', 'Disease', (41, 63))	('papillary renal cancer', 'Phenotype', 'HP:0006766', (41, 63))	('renal cancer', 'Phenotype', 'HP:0009726', (51, 63))	('HGF', 'Gene', '3082', (149, 152))	('MET kinase domain mutations', 'Var', (176, 203))	('HGF', 'Gene', (149, 152))	('MET copy number', 'Var', (113, 128))	('gain', 'PosReg', (129, 133))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('PRCC', 'Disease', (65, 69))	('patients', 'Species', '9606', (11, 19))	('papillary renal cancer', 'Disease', 'MESH:D007680', (41, 63))	('PRCC', 'Phenotype', 'HP:0006766', (65, 69))	('PRCC', 'Disease', 'MESH:D007680', (65, 69))
139380	29368112	The median PFS were 6.2 and 1.4 months, respectively, a difference that was statistically significant and showed a hazard ratio of 0.33 in favor of MET-driven PRCC as compared to the non-MET-driven disease.	('PRCC', 'Disease', 'MESH:D007680', (159, 163))	('PRCC', 'Disease', (159, 163))	('MET-driven', 'Var', (148, 158))	('PRCC', 'Phenotype', 'HP:0006766', (159, 163))
139389	29368112	Combinations of PD-1 inhibitors with ipilimumab, epacadostat, or other Ido-1 inhibitors are worthy of evaluation.	('Ido-1', 'Gene', (71, 76))	('Ido-1', 'Gene', '3620', (71, 76))	('Ido', 'molecular_function', 'GO:0033754', ('71', '74'))	('inhibitors', 'Var', (21, 31))	('Ido', 'molecular_function', 'GO:0047719', ('71', '74'))	('PD-1', 'Gene', (16, 20))
139394	29368112	The c-Met mutations are being explored in clinical trials as a therapeutic target, and clinical trials in metastatic papillary renal cancer are selecting patients with MET mutations to be randomized to sunitinib therapy or the c-Met inhibitor savolitinib.	('mutations', 'Var', (172, 181))	('c-Met', 'Gene', (227, 232))	('papillary renal cancer', 'Phenotype', 'HP:0006766', (117, 139))	('c-Met', 'Gene', '4233', (227, 232))	('savolitinib', 'Chemical', 'None', (243, 254))	('renal cancer', 'Phenotype', 'HP:0009726', (127, 139))	('papillary renal cancer', 'Disease', (117, 139))	('patients', 'Species', '9606', (154, 162))	('sunitinib', 'Chemical', 'MESH:C473478', (202, 211))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('c-Met', 'Gene', (4, 9))	('papillary renal cancer', 'Disease', 'MESH:D007680', (117, 139))	('c-Met', 'Gene', '4233', (4, 9))
139396	29368112	In type 2 papillary renal cell carcinomas, alterations such as CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element pathway were frequently noted.	('fusions', 'Var', (103, 110))	('CDKN2A', 'Gene', '1029', (63, 69))	('silencing', 'NegReg', (70, 79))	('TFE3', 'Gene', (98, 102))	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (10, 41))	('increased', 'PosReg', (116, 125))	('TFE3', 'Gene', '7030', (98, 102))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (20, 40))	('mutations', 'Var', (87, 96))	('SETD2', 'Gene', (81, 86))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (20, 41))	('NRF2', 'Gene', '4780', (144, 148))	('papillary renal cell carcinomas', 'Disease', 'MESH:D002292', (10, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('papillary renal cell carcinomas', 'Disease', (10, 41))	('SETD2', 'Gene', '29072', (81, 86))	('expression', 'MPA', (126, 136))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('CDKN2A', 'Gene', (63, 69))	('NRF2', 'Gene', (144, 148))
139397	29368112	Mutation of the gene encoding fumarate hydratase was observed in a distinct subgroup of type 2 characterized by poor prognosis.	('type 2', 'Disease', (88, 94))	('fumarate hydratase', 'Gene', '2271', (30, 48))	('observed', 'Reg', (53, 61))	('fumarate hydratase', 'Gene', (30, 48))	('Mutation', 'Var', (0, 8))
139399	29368112	Chromophobe RCC is typically associated with folliculin gene mutations but has also been associated with Cowden syndrome characterized by PTEN mutations.	('associated', 'Reg', (89, 99))	('Cowden syndrome', 'Disease', 'MESH:D006223', (105, 120))	('PTEN', 'Gene', (138, 142))	('Cowden syndrome', 'Disease', (105, 120))	('PTEN', 'Gene', '5728', (138, 142))	('RCC', 'Disease', 'MESH:D002292', (12, 15))	('RCC', 'Disease', (12, 15))	('folliculin', 'Gene', '201163', (45, 55))	('mutations', 'Var', (61, 70))	('associated', 'Reg', (29, 39))	('folliculin', 'Gene', (45, 55))	('mutations', 'Var', (143, 152))
139400	29368112	InTSC1/2 mutations, mTOR inhibition should be the therapy of choice.	('InTSC1/2', 'Gene', (0, 8))	('mutations', 'Var', (9, 18))	('mTOR', 'Gene', '2475', (20, 24))	('mTOR', 'Gene', (20, 24))
139407	31624646	Our results indicated significant associations between the overexpression of Snail, under expression of E-cadherin and high Fuhrman grade.	('Snail', 'Gene', '6615', (77, 82))	('Snail', 'Gene', (77, 82))	('under', 'Var', (84, 89))	('high Fuhrman grade', 'CPA', (119, 137))	('overexpression', 'PosReg', (59, 73))	('cadherin', 'molecular_function', 'GO:0008014', ('106', '114'))	('E-cadherin', 'Gene', (104, 114))	('E-cadherin', 'Gene', '999', (104, 114))
139425	31624646	Through statistical analysis of the analyzed parameters, we have shown significant associations between high CS of Snail and high Fuhrman grade (p=0.007) (Fig.1.E) and fat tissue invasion (p=0.03).	('high CS', 'Var', (104, 111))	('fat tissue invasion', 'CPA', (168, 187))	('tissue invasion', 'biological_process', 'GO:0001404', ('172', '187'))	('Snail', 'Gene', (115, 120))	('Snail', 'Gene', '6615', (115, 120))	('high Fuhrman grade', 'CPA', (125, 143))
139428	31624646	The statistical analysis indicated significant associations between high CS, E-cadherin and low Fuhrman grade (p=0.000) (Fig.1.H) and the absence of vascular invasion (p=0.031).	('cadherin', 'molecular_function', 'GO:0008014', ('79', '87'))	('high', 'Var', (68, 72))	('low', 'NegReg', (92, 95))	('E-cadherin', 'Gene', (77, 87))	('E-cadherin', 'Gene', '999', (77, 87))	('vascular invasion', 'CPA', (149, 166))
139441	31624646	They noticed that ccRCC with low Snail expression show relatively high percentage of E-cadherin marked tumor cells compared to tumors with high Snail immunoexpression, but the difference was not statistically significant.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('low', 'Var', (29, 32))	('Snail', 'Gene', '6615', (144, 149))	('cadherin', 'molecular_function', 'GO:0008014', ('87', '95'))	('ccRCC', 'Phenotype', 'HP:0006770', (18, 23))	('E-cadherin', 'Gene', (85, 95))	('E-cadherin', 'Gene', '999', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('Snail', 'Gene', (33, 38))	('tumor', 'Disease', (103, 108))	('Snail', 'Gene', (144, 149))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (127, 132))	('ccRCC', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('Snail', 'Gene', '6615', (33, 38))
139460	31455359	Ectopic expression of CR-1 significantly promoted cell proliferation, migration, invasion and angiogenesis whereas knockdown of CR-1 inhibited these activities both in vitro and in vivo.	('angiogenesis', 'CPA', (94, 106))	('angiogenesis', 'biological_process', 'GO:0001525', ('94', '106'))	('CR-1', 'Gene', (22, 26))	('migration', 'CPA', (70, 79))	('CR-1', 'Gene', '21667', (22, 26))	('invasion', 'CPA', (81, 89))	('promoted', 'PosReg', (41, 49))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('CR-1', 'Gene', (128, 132))	('cell proliferation', 'CPA', (50, 68))	('CR-1', 'Gene', '21667', (128, 132))	('knockdown', 'Var', (115, 124))
139475	31455359	More importantly, the atypical expression of CR-1 has been shown to be connected with clinically aggressive behaviour and patients' survival in these cancers.	('clinically', 'CPA', (86, 96))	('connected', 'Reg', (71, 80))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('clinical', 'Species', '191496', (86, 94))	('cancers', 'Disease', (150, 157))	('CR-1', 'Gene', (45, 49))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('behaviour', 'biological_process', 'GO:0007610', ('108', '117'))	('CR-1', 'Gene', '21667', (45, 49))	('patients', 'Species', '9606', (122, 130))	('atypical expression', 'Var', (22, 41))	('aggressive behaviour', 'Phenotype', 'HP:0000718', (97, 117))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
139485	31455359	Conversely, ectopic expression of CR-1 in ccRCC cells noticeably enhanced these effects.	('ectopic expression', 'Var', (12, 30))	('CR-1', 'Gene', (34, 38))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('enhanced', 'PosReg', (65, 73))	('RCC', 'Disease', (44, 47))	('CR-1', 'Gene', '21667', (34, 38))
139559	31455359	The Kaplan-Meier survival analysis showed that patients with high expression of CR-1 had significantly shorter OS and RFS than those with low expression of CR-1 (both P <  0.001; Fig.	('high expression', 'Var', (61, 76))	('CR-1', 'Gene', '21667', (80, 84))	('CR-1', 'Gene', '21667', (156, 160))	('patients', 'Species', '9606', (47, 55))	('shorter', 'NegReg', (103, 110))	('OS', 'Chemical', '-', (111, 113))	('CR-1', 'Gene', (80, 84))	('CR-1', 'Gene', (156, 160))
139560	31455359	This results were further confirmed by the univariate analysis, in which high expression of CR-1 was significantly related to poor patient survival (OS, HR, 7.031, 95% CI, 4.068-12.152, P <  0.001; RFS, HR, 5.133, 95% CI, 3.058-8.616, P <  0.001; Table 2A and B).	('CR-1', 'Gene', '21667', (92, 96))	('OS', 'Chemical', '-', (149, 151))	('patient survival', 'CPA', (131, 147))	('poor', 'NegReg', (126, 130))	('high expression', 'Var', (73, 88))	('patient', 'Species', '9606', (131, 138))	('CR-1', 'Gene', (92, 96))
139561	31455359	Furthermore, multivariate analysis revealed that high expression of CR-1 was an independent predictor for both OS and RFS (OS, HR, 6.518, 95% CI, 3.689-11.516, P <  0.001; RFS, HR, 5.638, 95% CI, 3.274-9.711, P <  0.001).	('CR-1', 'Gene', (68, 72))	('CR-1', 'Gene', '21667', (68, 72))	('OS', 'Chemical', '-', (111, 113))	('high expression', 'Var', (49, 64))	('RFS', 'Disease', (118, 121))	('OS', 'Chemical', '-', (123, 125))
139575	31455359	The efficacy of ectopic expression or knockdown of CR-1 in cells was verified by Western blot (Fig.	('CR-1', 'Gene', '21667', (51, 55))	('knockdown', 'Var', (38, 47))	('ectopic expression', 'Var', (16, 34))	('CR-1', 'Gene', (51, 55))
139576	31455359	MTT assay demonstrated that CR-1 ectopic expression could significantly facilitate the proliferative capacity in Caki-2 cells as compared to control cells (P <  0.01; Fig.	('ectopic expression', 'Var', (33, 51))	('facilitate', 'PosReg', (72, 82))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('CR-1', 'Gene', (28, 32))	('proliferative capacity', 'CPA', (87, 109))	('CR-1', 'Gene', '21667', (28, 32))	('Caki-2', 'CellLine', 'CVCL:0235', (113, 119))
139578	31455359	In contrast, knockdown of CR-1 impeded the growth ability of 786-O and Caki-1 cells as indicated by the MTT and colony formation assays (P <  0.01; Fig.	('CR-1', 'Gene', (26, 30))	('MTT', 'CPA', (104, 107))	('CR-1', 'Gene', '21667', (26, 30))	('impeded', 'NegReg', (31, 38))	('growth ability', 'CPA', (43, 57))	('MTT', 'Chemical', 'MESH:C070243', (104, 107))	('formation', 'biological_process', 'GO:0009058', ('119', '128'))	('colony formation assays', 'CPA', (112, 135))	('knockdown', 'Var', (13, 22))
139580	31455359	Our data showed that 786-O and Caki-1 cells with CR-1 knockdown exhibited a significant accumulation in G1 phase and a remarkable decrease in S phases as compared with those in the matched controls, whereas CR-1 overexpression significantly decreased the percentage of Caki-2 cells in G1 phase and increased that in S phase (P <  0.01; Fig.	('CR-1', 'Gene', '21667', (49, 53))	('S phase', 'biological_process', 'GO:0051320', ('316', '323'))	('knockdown', 'Var', (54, 63))	('G1 phase', 'biological_process', 'GO:0051318', ('285', '293'))	('decreased', 'NegReg', (241, 250))	('decrease', 'NegReg', (130, 138))	('Caki-2', 'CellLine', 'CVCL:0235', (269, 275))	('CR-1', 'Gene', (49, 53))	('S phases', 'CPA', (142, 150))	('S phase', 'CPA', (316, 323))	('G1 phase', 'biological_process', 'GO:0051318', ('104', '112'))	('G1 phase', 'CPA', (104, 112))	('increased', 'PosReg', (298, 307))	('CR-1', 'Gene', (207, 211))	('accumulation', 'PosReg', (88, 100))	('CR-1', 'Gene', '21667', (207, 211))
139586	31455359	Conversely, knockdown of CR-1 could restrict the migration and invasion of 786-O and caki-1 cells apparently (P <  0.01; Fig.	('migration', 'CPA', (49, 58))	('CR-1', 'Gene', (25, 29))	('knockdown', 'Var', (12, 21))	('CR-1', 'Gene', '21667', (25, 29))	('restrict', 'NegReg', (36, 44))
139589	31455359	5c), whereas CR-1 knockdown inhibited the migration of 786-O and Caki-1 cells (P <  0.01; Fig.	('knockdown', 'Var', (18, 27))	('CR-1', 'Gene', (13, 17))	('CR-1', 'Gene', '21667', (13, 17))	('inhibited', 'NegReg', (28, 37))	('migration of 786-O', 'CPA', (42, 60))
139593	31455359	Besides, when VEGF neutralizing antibody was used to neutralize VEGF in the culture supernatants of HUVEC cells, the tube formation of the cell induced by CR-1 were markedly abolished in vitro (P <  0.01; Fig.	('tube formation of the cell induced', 'CPA', (117, 151))	('abolished', 'NegReg', (174, 183))	('antibody', 'cellular_component', 'GO:0042571', ('32', '40'))	('VEGF', 'Gene', '7422', (14, 18))	('HUVEC', 'CellLine', 'CVCL:2959', (100, 105))	('antibody', 'cellular_component', 'GO:0019815', ('32', '40'))	('VEGF', 'Gene', '7422', (64, 68))	('VEGF', 'Gene', (64, 68))	('antibody', 'cellular_component', 'GO:0019814', ('32', '40'))	('tube formation', 'biological_process', 'GO:0035148', ('117', '131'))	('antibody', 'molecular_function', 'GO:0003823', ('32', '40'))	('CR-1', 'Gene', (155, 159))	('CR-1', 'Gene', '21667', (155, 159))	('VEGF', 'Gene', (14, 18))	('neutralize', 'Var', (53, 63))
139595	31455359	5e) while knockdown of CR-1 could reduce the blood vessels formation in Caki-1 and 786-O cells (P <  0.01; Fig.	('CR-1', 'Gene', (23, 27))	('formation', 'biological_process', 'GO:0009058', ('59', '68'))	('blood vessels formation', 'CPA', (45, 68))	('CR-1', 'Gene', '21667', (23, 27))	('reduce', 'NegReg', (34, 40))	('knockdown', 'Var', (10, 19))
139596	31455359	Moreover, we found that the expression of VEGF was significantly decreased when knocking down CR-1 in Caki-1 and 786-O cells (Fig.	('CR-1', 'Gene', '21667', (94, 98))	('decreased', 'NegReg', (65, 74))	('knocking down', 'Var', (80, 93))	('expression', 'MPA', (28, 38))	('VEGF', 'Gene', '7422', (42, 46))	('CR-1', 'Gene', (94, 98))	('VEGF', 'Gene', (42, 46))
139598	31455359	We also detected noticeably reduced VEGF protein expression in Caki-1 cells xenografts with knockdown of CR-1 by IHC (Fig.	('reduced', 'NegReg', (28, 35))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('CR-1', 'Gene', '21667', (105, 109))	('VEGF', 'Gene', (36, 40))	('knockdown', 'Var', (92, 101))	('VEGF', 'Gene', '7422', (36, 40))	('CR-1', 'Gene', (105, 109))
139599	31455359	In addition, the CD31-postive microvascular was greatly decreased with the knockdown of CR-1 in the xenograft tissues (Fig.	('CR-1', 'Gene', (88, 92))	('CR-1', 'Gene', '21667', (88, 92))	('CD31', 'Gene', (17, 21))	('decreased', 'NegReg', (56, 65))	('knockdown', 'Var', (75, 84))	('CD31', 'Gene', '5175', (17, 21))
139614	31455359	Accumulating evidence has demonstrated that high expression of CR-1 might be a key alteration contributing to the invasion and metastasis of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('high', 'Var', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('CR-1', 'Gene', (63, 67))	('expression', 'MPA', (49, 59))	('contributing', 'Reg', (94, 106))	('CR-1', 'Gene', '21667', (63, 67))	('invasion', 'CPA', (114, 122))
139628	31455359	Reactivation of CR-1 in adult tissues has been associated with various cancer types.	('CR-1', 'Gene', (16, 20))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('CR-1', 'Gene', '21667', (16, 20))	('cancer', 'Disease', (71, 77))	('Reactivation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('associated', 'Reg', (47, 57))
139630	31455359	This phenomenon may be a representation of the so called "field cancerization" of theory, suggesting a cumulative process of carcinogenesis in which genetic alterations are acquired step-wise, leaving the adjacent non-tumor tissue in an intermediate, pre-neoplastic state composed of morphologically normal but molecularly altered cells.	('genetic alterations', 'Var', (149, 168))	('carcinogenesis', 'Disease', (125, 139))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('leaving', 'Reg', (193, 200))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('carcinogenesis', 'Disease', 'MESH:D063646', (125, 139))	('neoplastic state', 'Phenotype', 'HP:0002664', (255, 271))	('tumor', 'Disease', (218, 223))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
139632	31455359	In our IHC analysis, high CR-1 expression is associated significantly with aggressive tumor phenotype, which suggest that CR-1 expression may be vital for the acquisition of malignant potential in ccRCCs.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('aggressive tumor', 'Disease', 'MESH:D001523', (75, 91))	('CR-1', 'Gene', (26, 30))	('aggressive tumor', 'Disease', (75, 91))	('CR-1', 'Gene', (122, 126))	('CR-1', 'Gene', '21667', (26, 30))	('high', 'Var', (21, 25))	('CR-1', 'Gene', '21667', (122, 126))	('expression', 'MPA', (31, 41))	('RCC', 'Disease', (199, 202))	('RCC', 'Disease', 'MESH:C538614', (199, 202))
139639	31455359	Further analysis of the prognostic significance of CR-1 in clinical subgroups indicated that the OS and RFS of CR-1 high expression patients who had TNM stage I or II were dramatically worse than CR-1 low expression patients in the same stage.	('RFS', 'MPA', (104, 107))	('worse', 'NegReg', (185, 190))	('CR-1', 'Gene', (196, 200))	('CR-1', 'Gene', '21667', (196, 200))	('high expression', 'Var', (116, 131))	('CR-1', 'Gene', (51, 55))	('TNM', 'Gene', '10178', (149, 152))	('OS', 'Chemical', '-', (97, 99))	('patients', 'Species', '9606', (216, 224))	('CR-1', 'Gene', '21667', (51, 55))	('CR-1', 'Gene', (111, 115))	('TNM', 'Gene', (149, 152))	('CR-1', 'Gene', '21667', (111, 115))	('patients', 'Species', '9606', (132, 140))	('clinical', 'Species', '191496', (59, 67))
139652	31455359	In the present study, we demonstrated that CR-1 knockdown cells were arrested in the G1 phase and thus inhibited ccRCC cell proliferation.	('CR-1', 'Gene', (43, 47))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('cell proliferation', 'biological_process', 'GO:0008283', ('119', '137'))	('RCC', 'Disease', (115, 118))	('CR-1', 'Gene', '21667', (43, 47))	('inhibited', 'NegReg', (103, 112))	('G1 phase', 'biological_process', 'GO:0051318', ('85', '93'))	('knockdown', 'Var', (48, 57))
139654	31455359	has suggested that CR-1 knockdown does not influence the cell cycle in nasopharyngeal carcinoma cells.	('CR-1', 'Gene', '21667', (19, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (71, 95))	('nasopharyngeal carcinoma', 'Disease', (71, 95))	('cell cycle', 'biological_process', 'GO:0007049', ('57', '67'))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (71, 95))	('knockdown', 'Var', (24, 33))	('CR-1', 'Gene', (19, 23))
139660	31455359	The expression levels of Snail and ZEB-1 were repressed significantly after CR-1 knockdown in 786-O and Caki-1 cells, while the epithelial marker E-cadherin was upregulated.	('expression levels', 'MPA', (4, 21))	('E-cadherin', 'Gene', (146, 156))	('E-cadherin', 'Gene', '999', (146, 156))	('cadherin', 'molecular_function', 'GO:0008014', ('148', '156'))	('upregulated', 'PosReg', (161, 172))	('knockdown', 'Var', (81, 90))	('Snail', 'Gene', '6615', (25, 30))	('Snail', 'Gene', (25, 30))	('ZEB-1', 'Gene', (35, 40))	('ZEB-1', 'Gene', '6935', (35, 40))	('CR-1', 'Gene', (76, 80))	('CR-1', 'Gene', '21667', (76, 80))
139667	31455359	In the current study, we found that CR-1 knockdown suppressed microtubule assembly in vitro and decreased microvascular density in vivo.	('CR-1', 'Gene', '21667', (36, 40))	('decreased', 'NegReg', (96, 105))	('microvascular density', 'CPA', (106, 127))	('microtubule', 'cellular_component', 'GO:0005874', ('62', '73'))	('suppressed', 'NegReg', (51, 61))	('microtubule assembly', 'MPA', (62, 82))	('microtubule assembly', 'biological_process', 'GO:0046785', ('62', '82'))	('knockdown', 'Var', (41, 50))	('CR-1', 'Gene', (36, 40))
139668	31455359	Moreover, neutralizing VEGF could block CR-1 overexpressed culture medium stimulated angiogenesis in tube formation assay, which suggested an indirect effect of CR-1 on angiogenesis.	('CR-1', 'Gene', '21667', (40, 44))	('angiogenesis in tube formation assay', 'CPA', (85, 121))	('CR-1', 'Gene', (161, 165))	('angiogenesis', 'biological_process', 'GO:0001525', ('85', '97'))	('CR-1', 'Gene', '21667', (161, 165))	('tube formation', 'biological_process', 'GO:0035148', ('101', '115'))	('VEGF', 'Gene', (23, 27))	('neutralizing', 'Var', (10, 22))	('angiogenesis', 'biological_process', 'GO:0001525', ('169', '181'))	('CR-1', 'Gene', (40, 44))	('VEGF', 'Gene', '7422', (23, 27))
139669	31455359	These results implied that CR-1 knockdown attenuated ccRCC angiogenesis.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('attenuated', 'NegReg', (42, 52))	('CR-1', 'Gene', (27, 31))	('knockdown', 'Var', (32, 41))	('angiogenesis', 'biological_process', 'GO:0001525', ('59', '71'))	('CR-1', 'Gene', '21667', (27, 31))
139672	31455359	Dysregulation of Wnt/beta-catenin signaling pathway is believed to enhance the malignancy in various types of human cancers, including ccRCC.	('malignancy', 'Disease', 'MESH:D009369', (79, 89))	('signaling pathway', 'biological_process', 'GO:0007165', ('34', '51'))	('malignancy', 'Disease', (79, 89))	('beta-catenin', 'Gene', '1499', (21, 33))	('Dysregulation', 'Var', (0, 13))	('human', 'Species', '9606', (110, 115))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('enhance', 'PosReg', (67, 74))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('cancers', 'Disease', (116, 123))	('RCC', 'Disease', (137, 140))	('beta-catenin', 'Gene', (21, 33))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
139704	28467794	Although great insight into the epigenetics of RCC has been made, for instance, DNA methylation, histone modification, as well as noncoding RNA.	('methylation', 'Var', (84, 95))	('RNA', 'cellular_component', 'GO:0005562', ('140', '143'))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('DNA', 'Var', (80, 83))	('histone modification', 'biological_process', 'GO:0016570', ('97', '117'))	('histone modification', 'MPA', (97, 117))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('DNA methylation', 'biological_process', 'GO:0006306', ('80', '95'))
139718	28467794	In addition, lncRNAs deregulated in RCC are shown in Table 2A and Table 2B; the functions, targeted genes/signaling, and the mechanisms involved are also indicated.	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('deregulated', 'Var', (21, 32))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))
139723	28467794	Many studies of determining aberrant lncRNAs expression for diagnostic purpose and the identification of novel deregulated lncRNAs as biomarkers for RCC have been carried out.	('RCC', 'Disease', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('RCC', 'Disease', 'MESH:C538614', (149, 152))	('aberrant', 'Var', (28, 36))
139724	28467794	A recent study found that the expression level of CYP4A22-2/3 can discriminate ccRCCs from normal kidney tissues.	('expression', 'MPA', (30, 40))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('CYP4A22-2/3', 'Var', (50, 61))
139734	28467794	The expression level of lncRNA NONHSAT123350 was closely associated with OS and DFS in patients without distant metastasis; the median values of OS and DFS were significantly higher among patients with high NONHSAT123350 expression when compared to the patients whose expression of NONHSAT123350 were low.	('higher', 'PosReg', (175, 181))	('patients', 'Species', '9606', (87, 95))	('high NONHSAT123350', 'Var', (202, 220))	('patients', 'Species', '9606', (253, 261))	('patients', 'Species', '9606', (188, 196))	('NONHSAT123350', 'Var', (207, 220))
139752	28467794	Through RNAi technology, HOTAIR knockdown can affect cell cycle in G0/G1 phase and decrease cell proliferation and invasion of RCC cells.	('HOTAIR', 'Gene', '100124700', (25, 31))	('RNAi', 'biological_process', 'GO:0016246', ('8', '12'))	('G1 phase', 'biological_process', 'GO:0051318', ('70', '78'))	('knockdown', 'Var', (32, 41))	('affect', 'Reg', (46, 52))	('cell cycle in G0/G1 phase', 'CPA', (53, 78))	('decrease', 'NegReg', (83, 91))	('cell proliferation', 'biological_process', 'GO:0008283', ('92', '110'))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('HOTAIR', 'Gene', (25, 31))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('cell cycle', 'biological_process', 'GO:0007049', ('53', '63'))
139753	28467794	The inhibiton of HOTAIR also suppressed tumor formation in the xenograft experiments in vivo.	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('HOTAIR', 'Gene', (17, 23))	('inhibiton', 'Var', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('formation', 'biological_process', 'GO:0009058', ('46', '55'))	('HOTAIR', 'Gene', '100124700', (17, 23))	('suppressed', 'NegReg', (29, 39))
139757	28467794	The knockdown of RCCRT1 by RNAi technique can suppress migration and invasion in RCC cell lines.	('suppress', 'NegReg', (46, 54))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('RNAi', 'biological_process', 'GO:0016246', ('27', '31'))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('knockdown', 'Var', (4, 13))
139761	28467794	In vitro experiments found that the inhibition of MALAT1 not only suppressed cell proliferation, promoted apoptosis, but also inhibited migration, and invasion of RCC cells.	('migration', 'CPA', (136, 145))	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('cell proliferation', 'biological_process', 'GO:0008283', ('77', '95'))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('inhibition', 'Var', (36, 46))	('RCC', 'Disease', (163, 166))	('apoptosis', 'CPA', (106, 115))	('inhibited', 'NegReg', (126, 135))	('MALAT1', 'Gene', '378938', (50, 56))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('suppressed', 'NegReg', (66, 76))	('MALAT1', 'Gene', (50, 56))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('cell proliferation', 'CPA', (77, 95))	('promoted', 'PosReg', (97, 105))
139762	28467794	Thus, inhibition of MALAT1 may become a promising strategy for RCC therapy.	('MALAT1', 'Gene', (20, 26))	('RCC', 'Disease', (63, 66))	('inhibition', 'Var', (6, 16))	('MALAT1', 'Gene', '378938', (20, 26))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
139766	28467794	Moreover, inhibition of H19 can suppress proliferation, invasion, and migration of RCC cells.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('H19', 'Gene', (24, 27))	('H19', 'Gene', '283120', (24, 27))	('suppress', 'NegReg', (32, 40))	('inhibition', 'Var', (10, 20))	('invasion', 'CPA', (56, 64))	('proliferation', 'CPA', (41, 54))
139770	28467794	Over-expression of CADM1-AS1 can significantly decrease cell growth and migration, as well as increase apoptosis in RCC cells.	('CADM1', 'Gene', '23705', (19, 24))	('decrease cell growth', 'Phenotype', 'HP:0001510', (47, 67))	('cell growth', 'biological_process', 'GO:0016049', ('56', '67'))	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('cell growth', 'CPA', (56, 67))	('increase', 'PosReg', (94, 102))	('decrease', 'NegReg', (47, 55))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('apoptosis', 'CPA', (103, 112))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('CADM1', 'Gene', (19, 24))	('Over-expression', 'Var', (0, 15))	('AS1', 'Gene', '5729', (25, 28))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('AS1', 'Gene', (25, 28))	('RCC', 'Disease', (116, 119))
139775	28467794	Interestingly, lncRNA-SRLR knockdown sensitized nonresponsive RCC cells to sorafenib treatment, whereas the overexpression of lncRNA-SRLR conferred sorafenib resistance to responsive RCC cells.	('conferred', 'Reg', (138, 147))	('knockdown', 'Var', (27, 36))	('RCC', 'Phenotype', 'HP:0005584', (183, 186))	('sorafenib', 'Chemical', 'MESH:D000077157', (148, 157))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('RCC', 'Disease', (183, 186))	('sorafenib', 'MPA', (148, 157))	('RCC', 'Disease', (62, 65))	('lncRNA-SRLR', 'Gene', (15, 26))	('sorafenib', 'Chemical', 'MESH:D000077157', (75, 84))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('sensitized', 'Reg', (37, 47))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))
139791	28467794	LncRNA-SARCC suppresses hypoxic cell cycle progression in VHL mutant type of RCC cells and de-represses it in VHL restored type of RCC cells.	('cell cycle', 'biological_process', 'GO:0007049', ('32', '42'))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('hypoxic', 'MPA', (24, 31))	('VHL', 'Gene', '7428', (110, 113))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('VHL', 'Gene', (58, 61))	('mutant', 'Var', (62, 68))	('AR', 'Gene', '367', (8, 10))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (9, 12))	('RCC', 'Phenotype', 'HP:0005584', (9, 12))	('VHL', 'Gene', '7428', (58, 61))	('de-represses', 'NegReg', (91, 103))	('RCC', 'Disease', 'MESH:C538614', (9, 12))	('RCC', 'Disease', (77, 80))	('suppresses', 'NegReg', (13, 23))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('VHL', 'Gene', (110, 113))
139804	32784396	Then, the YRNA molecule is bound to the polyuridine tail of the La protein responsible for both its nuclear retention and protection from degradation.	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('polyuridine', 'Chemical', '-', (40, 51))	('bound', 'Interaction', (27, 32))	('degradation', 'biological_process', 'GO:0009056', ('138', '149'))	('nuclear retention', 'CPA', (100, 117))	('polyuridine', 'Var', (40, 51))	('retention', 'biological_process', 'GO:0051235', ('108', '117'))
139820	32784396	Interestingly, YRNA3 may enter an alternative transport pathway by way of binding to zipcode-binding protein 1 (ZBP1) and enabling export through Exportin-1.	('YRNA3', 'Var', (15, 20))	('enter', 'Reg', (25, 30))	('ZBP1', 'Gene', '10642', (112, 116))	('transport', 'biological_process', 'GO:0006810', ('46', '55'))	('Exportin', 'cellular_component', 'GO:0005651', ('146', '154'))	('binding', 'molecular_function', 'GO:0005488', ('93', '100'))	('ZBP1', 'Gene', (112, 116))	('binding', 'molecular_function', 'GO:0005488', ('74', '81'))	('Exportin-1', 'Gene', (146, 156))	('Exportin-1', 'Gene', '7514', (146, 156))	('zipcode-binding protein 1', 'Gene', (85, 110))	('export', 'MPA', (131, 137))	('zipcode-binding protein 1', 'Gene', '10642', (85, 110))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('binding', 'Interaction', (74, 81))	('enabling', 'PosReg', (122, 130))
139827	32784396	YsRNAs may also be formed by enzyme RNAse L in response to UV exposure or by poly I:C-mediated activation of the innate immune system.	('response to UV', 'biological_process', 'GO:0009411', ('47', '61'))	('RNAse L', 'Gene', (36, 43))	('poly I:C-mediated', 'Var', (77, 94))	('poly I:C', 'Chemical', 'MESH:D011070', (77, 85))	('RNAse L', 'Gene', '6041', (36, 43))
139831	32784396	Interestingly, YsRNAs derived from YRNA3 and YRNA5 are present in solid tumor samples at a similar rate as the cancer-associated miRNA-21.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('miRNA-21', 'Gene', '406991', (129, 137))	('tumor', 'Disease', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('miRNA-21', 'Gene', (129, 137))	('YRNA3', 'Var', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('YRNA5', 'Var', (45, 50))
139852	32784396	Additionally, Ro60 binds miss-folded or aberrant non-coding RNAs, such as U2snRNA or 5S rRNA.	('Ro60', 'Gene', '6738', (14, 18))	('miss-folded', 'Var', (25, 36))	('Ro60', 'Gene', (14, 18))	('aberrant non-coding', 'Var', (40, 59))	('binds', 'Interaction', (19, 24))
139876	32784396	Due to the fact that pseudogenes may play an important role in diseases including cancer, it is very important to take a closer look at this issue and dispel any doubts or discrepancies.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('role', 'Reg', (55, 59))	('play', 'Reg', (37, 41))	('pseudogenes', 'Var', (21, 32))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))
139877	32784396	Although the exact role of YRNAs has not yet been fully discovered, short non-coding RNAs definitely play an important role in human tumorigenesis.	('play', 'Reg', (101, 105))	('human', 'Species', '9606', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('short non-coding RNAs', 'Var', (68, 89))
139878	32784396	Up till now, the dysregulated expression of YRNAs has been described in several tumor types including bladder cancer, clear cell renal cell carcinoma, prostate cancer, head and neck cancer, triple-negative breast cancer and lung cancer (Figure 4).	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('head and neck cancer', 'Disease', 'MESH:D006258', (168, 188))	('described', 'Reg', (59, 68))	('lung cancer', 'Disease', 'MESH:D008175', (224, 235))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (118, 149))	('breast cancer', 'Disease', 'MESH:D001943', (206, 219))	('bladder cancer', 'Disease', 'MESH:D001749', (102, 116))	('bladder cancer', 'Disease', (102, 116))	('breast cancer', 'Disease', (206, 219))	('lung cancer', 'Phenotype', 'HP:0100526', (224, 235))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (129, 149))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('dysregulated', 'Var', (17, 29))	('prostate cancer', 'Disease', 'MESH:D011471', (151, 166))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('prostate cancer', 'Phenotype', 'HP:0012125', (151, 166))	('bladder cancer', 'Phenotype', 'HP:0009725', (102, 116))	('clear cell renal cell carcinoma', 'Disease', (118, 149))	('YRNAs', 'Gene', (44, 49))	('neck', 'cellular_component', 'GO:0044326', ('177', '181'))	('tumor', 'Disease', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('prostate cancer', 'Disease', (151, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('expression', 'MPA', (30, 40))	('head and neck cancer', 'Phenotype', 'HP:0012288', (168, 188))	('lung cancer', 'Disease', (224, 235))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (118, 149))
139916	32784396	It was also indicated that in HeLa cells the expression of YRNA5 fragments was significantly higher with poly(I:C) treatment.	('higher', 'PosReg', (93, 99))	('poly(I:C) treatment', 'Var', (105, 124))	('YRNA5 fragments', 'MPA', (59, 74))	('HeLa', 'CellLine', 'CVCL:0030', (30, 34))	('expression', 'MPA', (45, 55))	('poly(I:C)', 'Chemical', 'MESH:D011070', (105, 114))
139920	32784396	What is more, in a study based on blood serum derived from rectal cancer patients, YRNA4 was found to be highly expressed in multiple variants.	('variants', 'Var', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('YRNA4', 'Gene', (83, 88))	('rectal cancer', 'Phenotype', 'HP:0100743', (59, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('patients', 'Species', '9606', (73, 81))	('cancer', 'Disease', (66, 72))
139923	32784396	The knockdown of Ro60 resulted in a significant decrease in cell proliferation and invasion, making YRNAs a promising possible target for silencing Ro60 in PDAC.	('cell proliferation', 'CPA', (60, 78))	('silencing', 'Var', (138, 147))	('Ro60', 'Gene', '6738', (17, 21))	('cell proliferation', 'biological_process', 'GO:0008283', ('60', '78'))	('Ro60', 'Gene', (17, 21))	('Ro60', 'Gene', '6738', (148, 152))	('decrease', 'NegReg', (48, 56))	('Ro60', 'Gene', (148, 152))	('invasion', 'CPA', (83, 91))	('knockdown', 'Var', (4, 13))	('PDAC', 'Disease', (156, 160))	('PDAC', 'Phenotype', 'HP:0006725', (156, 160))
139983	33292053	PTPN12 relative mRNA expression levels were higher in patients aged <=60 years compared with those aged >60 years, and higher in men than in women, but the differences were not significant.	('women', 'Species', '9606', (141, 146))	('PTPN12', 'Gene', (0, 6))	('mRNA expression levels', 'MPA', (16, 38))	('higher', 'PosReg', (44, 50))	('patients', 'Species', '9606', (54, 62))	('higher', 'PosReg', (119, 125))	('<=60 years', 'Var', (68, 78))	('men', 'Species', '9606', (129, 132))	('PTPN12', 'Gene', '5782', (0, 6))	('men', 'Species', '9606', (143, 146))
139984	33292053	Relative expression levels were significantly higher in patients with a tumor diameter <=7 cm compared with >7 cm (P = 0.012), and expression was significantly higher in patients with clinical stage I or II compared with clinical stage III or IV (P = 0.047) (Table 3).	('patients', 'Species', '9606', (170, 178))	('patients', 'Species', '9606', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('higher', 'PosReg', (160, 166))	('higher', 'PosReg', (46, 52))	('tumor', 'Disease', (72, 77))	('expression', 'MPA', (131, 141))	('Relative expression levels', 'MPA', (0, 26))	('<=7', 'Var', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
139991	33292053	analyzed the expression of PTPN12 using immunohistochemistry and western blotting and found that high PTPN12 expression levels were associated with a favorable survival duration in patients with non-small cell lung cancer (NSCLC), suggesting that PTPN12 expression may be a valuable prognostic biomarker for NSCLC.	('NSCLC', 'Disease', (223, 228))	('PTPN12', 'Gene', '5782', (247, 253))	('lung cancer', 'Phenotype', 'HP:0100526', (210, 221))	('NSCLC', 'Disease', (308, 313))	('patients', 'Species', '9606', (181, 189))	('NSCLC', 'Phenotype', 'HP:0030358', (223, 228))	('expression levels', 'MPA', (109, 126))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (195, 221))	('PTPN12', 'Gene', (27, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (308, 313))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (199, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('PTPN12', 'Gene', (247, 253))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (195, 221))	('PTPN12', 'Gene', '5782', (102, 108))	('associated', 'Reg', (132, 142))	('NSCLC', 'Disease', 'MESH:D002289', (223, 228))	('non-small cell lung cancer', 'Disease', (195, 221))	('PTPN12', 'Gene', '5782', (27, 33))	('NSCLC', 'Disease', 'MESH:D002289', (308, 313))	('PTPN12', 'Gene', (102, 108))	('high', 'Var', (97, 101))
139998	33292053	This may be the molecular mechanism by which low PTPN12 expression could promote ccRCC.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('PTPN12', 'Gene', (49, 55))	('promote', 'PosReg', (73, 80))	('PTPN12', 'Gene', '5782', (49, 55))	('low', 'Var', (45, 48))
140029	31956361	Although they are very similar, PPT2 cannot rescue the neural inclusion phenotypes associated with loss of PPT1, which suggests distinct functions and substrates for these two thioesterases.	('PPT2', 'Gene', (32, 36))	('PPT', 'molecular_function', 'GO:0043751', ('32', '35'))	('PPT2', 'Gene', '9374', (32, 36))	('PPT', 'molecular_function', 'GO:0015121', ('107', '110'))	('PPT1', 'Gene', (107, 111))	('thioester', 'Chemical', 'MESH:C474517', (176, 185))	('PPT', 'molecular_function', 'GO:0043751', ('107', '110'))	('loss', 'Var', (99, 103))	('PPT', 'molecular_function', 'GO:0015121', ('32', '35'))
140031	31956361	Studies have shown that, PPT1 promotes tumor progression and serves as the molecular target of drugs in cancer, targeting PPT1 blocks mTOR signaling and concurrently inhibits autophagy in a different way from catalytic inhibitors, thus provides a new strategy for cancer treatment.	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('inhibits', 'NegReg', (166, 174))	('PPT', 'molecular_function', 'GO:0043751', ('122', '125'))	('mTOR signaling', 'MPA', (134, 148))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', (264, 270))	('autophagy', 'biological_process', 'GO:0016236', ('175', '184'))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('promotes', 'PosReg', (30, 38))	('PPT', 'molecular_function', 'GO:0015121', ('122', '125'))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('targeting', 'Var', (112, 121))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('autophagy', 'biological_process', 'GO:0006914', ('175', '184'))	('PPT', 'molecular_function', 'GO:0043751', ('25', '28'))	('tumor', 'Disease', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('PPT1', 'Gene', (122, 126))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('PPT', 'molecular_function', 'GO:0015121', ('25', '28'))	('blocks', 'NegReg', (127, 133))	('autophagy', 'CPA', (175, 184))
140055	31956361	The primary antibodies used included anti-PPT2, anti-E-cadherin, anti-Vimentin, anti-beta-actin and anti-Snail1.	('anti-Vimentin', 'Var', (65, 78))	('PPT', 'molecular_function', 'GO:0043751', ('42', '45'))	('PPT2', 'Gene', '9374', (42, 46))	('anti-Snail1', 'Var', (100, 111))	('Vimentin', 'cellular_component', 'GO:0045098', ('70', '78'))	('cadherin', 'molecular_function', 'GO:0008014', ('55', '63'))	('PPT', 'molecular_function', 'GO:0015121', ('42', '45'))	('anti-beta-actin', 'Var', (80, 95))	('PPT2', 'Gene', (42, 46))	('Vimentin', 'cellular_component', 'GO:0045099', ('70', '78'))	('anti-E-cadherin', 'Var', (48, 63))
140063	31956361	PPT1 promotes tumor progression and serves as the molecular target of drugs in cancer, targeting PPT1 blocks mTOR signaling and concurrently inhibits autophagy in a different way from catalytic inhibitors.	('PPT', 'molecular_function', 'GO:0043751', ('0', '3'))	('blocks', 'NegReg', (102, 108))	('autophagy', 'CPA', (150, 159))	('PPT', 'molecular_function', 'GO:0015121', ('0', '3'))	('promotes', 'PosReg', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('PPT', 'molecular_function', 'GO:0043751', ('97', '100'))	('mTOR signaling', 'Pathway', (109, 123))	('inhibits', 'NegReg', (141, 149))	('targeting', 'Var', (87, 96))	('PPT', 'molecular_function', 'GO:0015121', ('97', '100'))	('autophagy', 'biological_process', 'GO:0016236', ('150', '159'))	('cancer', 'Disease', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('autophagy', 'biological_process', 'GO:0006914', ('150', '159'))	('signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('tumor', 'Disease', (14, 19))	('PPT1', 'Gene', (97, 101))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
140081	31956361	The results showed that PPT2 mRNA expression is of significance in differentiating ccRCC from normal tissues with an area under the curve (AUC) of 0.6435 (95% CI: 0.5539 to 0.7332, P<0.01) (Figure 3A), patients with metastasis from those without metastasis with an AUC of 0.6271 (95% CI: 0.5583 to 0.6958, P<0.001) (Figure 3B), G1+G2 from G3+G4 with an AUC of 0.6166 (95% CI: 0.5686 to 0.6647, P<0.0001) (Figure 3C), T1+T2 from T3+T4 with an AUC of 0.6123 (95% CI: 0.5629 to 0.6618, P<0.0001) (Figure 3D), TNM stage I+II from TNM stage III+IV with an AUC of 0.6188(95% CI: 0.5700 to 0.6675, P<0.0001) (Figure 3E), the recurred/progressed from the disease-free with an AUC of 0.6033 (95% CI: 0.5457 to 0.6609, P<0.001) (Figure 3F).	('PPT2', 'Gene', '9374', (24, 28))	('TNM', 'Gene', '10178', (526, 529))	('PPT', 'molecular_function', 'GO:0043751', ('24', '27'))	('recurred/progressed', 'PosReg', (618, 637))	('G4 with an AUC', 'Mutation', 'c.4G>AUC', (342, 356))	('TNM', 'Gene', '10178', (506, 509))	('ccRCC', 'Disease', 'MESH:D002292', (83, 88))	('patients', 'Species', '9606', (202, 210))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('ccRCC', 'Disease', (83, 88))	('TNM', 'Gene', (526, 529))	('PPT', 'molecular_function', 'GO:0015121', ('24', '27'))	('PPT2', 'Gene', (24, 28))	('TNM', 'Gene', (506, 509))	('T4 with an AUC', 'Mutation', 'c.4T>AUC', (431, 445))	('0.6033', 'Var', (675, 681))	('expression', 'Species', '29278', (34, 44))
140088	31956361	The dysregulation of PPT2 in ccRCC may have a potential impact on the progression of ccRCC.	('PPT', 'molecular_function', 'GO:0015121', ('21', '24'))	('ccRCC', 'Disease', (29, 34))	('ccRCC', 'Disease', 'MESH:D002292', (29, 34))	('PPT', 'molecular_function', 'GO:0043751', ('21', '24'))	('dysregulation', 'Var', (4, 17))	('ccRCC', 'Disease', (85, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('PPT2', 'Gene', (21, 25))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))	('ccRCC', 'Disease', 'MESH:D002292', (85, 90))	('PPT2', 'Gene', '9374', (21, 25))	('impact', 'Reg', (56, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
140112	31956361	To date, the consensus seems to be that the mutation of von Hippel-Lindau (VHL) tumor suppressor gene and subsequent inactivation of hypoxia-inducible factor (HIF) lead to the occurrence of tumors.	('mutation', 'Var', (44, 52))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (56, 85))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('inactivation', 'NegReg', (117, 129))	('lead to', 'Reg', (164, 171))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('hypoxia', 'Disease', (133, 140))	('hypoxia', 'Disease', 'MESH:D000860', (133, 140))	('occurrence', 'Reg', (176, 186))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('tumors', 'Disease', (190, 196))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
140133	31886201	Bioinformatic analysis showed the probable processes and pathways involved in altered IGFBP5 expression, including blood vessel development, the cellular response to growth factor stimulus, the response to transforming growth factor beta (TGF-beta), and extracellular matrix organization.	('response to transforming growth factor beta', 'biological_process', 'GO:0071559', ('194', '237'))	('blood vessel development', 'CPA', (115, 139))	('extracellular matrix organization', 'biological_process', 'GO:0030198', ('254', '287'))	('blood vessel development', 'biological_process', 'GO:0001568', ('115', '139'))	('transforming growth factor beta', 'Gene', (206, 237))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('254', '274'))	('cellular response to growth factor stimulus', 'biological_process', 'GO:0071363', ('145', '188'))	('altered', 'Var', (78, 85))	('transforming growth factor beta', 'Gene', '7124', (206, 237))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('206', '237'))	('IGFBP5', 'Gene', (86, 92))
140164	31886201	A First Strand cDNA Synthesis Kit (New England Biolabs, E6560S) was used for cDNA synthesis with a standard protocol.	('synthesis', 'biological_process', 'GO:0009058', ('82', '91'))	('Kit', 'Gene', (30, 33))	('E6560S', 'SUBSTITUTION', 'None', (56, 62))	('E6560S', 'Var', (56, 62))	('Kit', 'Gene', '3815', (30, 33))
140186	31886201	The best cutoff value in Kaplan-Meier survival curve analysis was 36.07, and 72 patients were classified as exhibiting high IGFBP5 expression, while 215 patients were classified as exhibiting low IGFBP5 expression (data from three participants were lost).	('IGFBP5', 'Gene', (124, 130))	('participants', 'Species', '9606', (231, 243))	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (153, 161))	('high', 'Var', (119, 123))
140187	31886201	The median fragments per kilobase of transcript per million mapped reads (FPKM) in patients with low and high levels of IGFBP5 were 10.85 vs 56.1, respectively.	('patients', 'Species', '9606', (83, 91))	('fragments', 'MPA', (11, 20))	('IGFBP5', 'Gene', (120, 126))	('high levels', 'Var', (105, 116))
140196	31886201	Many studies have shown that excessive expression of TGF-beta can promote the development and metastasis of carcinoma via stimulating the formation of peripheral blood vessels, inhibiting the immune system, forming the extracellular matrix, and promoting epithelial to mesenchymal transition (EMT).	('inhibiting', 'NegReg', (177, 187))	('metastasis of carcinoma', 'Disease', 'MESH:D009362', (94, 117))	('development', 'CPA', (78, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('excessive', 'Var', (29, 38))	('formation of peripheral blood vessels', 'CPA', (138, 175))	('stimulating', 'Reg', (122, 133))	('promote', 'PosReg', (66, 73))	('immune system', 'CPA', (192, 205))	('promoting', 'PosReg', (245, 254))	('metastasis of carcinoma', 'Disease', (94, 117))	('epithelial to mesenchymal transition', 'CPA', (255, 291))	('formation', 'biological_process', 'GO:0009058', ('138', '147'))	('expression', 'MPA', (39, 49))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('255', '291'))	('TGF-beta', 'Gene', (53, 61))	('EMT', 'biological_process', 'GO:0001837', ('293', '296'))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('219', '239'))
140232	29285183	Targeting microRNA/UHRF1 pathways as a novel strategy for cancer therapy Ubiquitin-like containing plant homeodomain and RING finger domains 1 (UHRF1) is an anti-apoptotic protein involved in the silencing of several tumor suppressor genes (TSGs) through epigenetic modifications including DNA methylation and histone post-translational alterations, and also epigenetic-independent mechanisms.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('TSG', 'Gene', '57045', (241, 244))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('DNA methylation', 'Var', (290, 305))	('tumor suppressor', 'biological_process', 'GO:0051726', ('217', '233'))	('silencing', 'NegReg', (196, 205))	('DNA', 'cellular_component', 'GO:0005574', ('290', '293'))	('TSG', 'Gene', (241, 244))	('UHRF1', 'Gene', '29128', (19, 24))	('histone', 'Protein', (310, 317))	('tumor', 'Disease', (217, 222))	('RING finger domains 1', 'Gene', '29128', (121, 142))	('DNA methylation', 'biological_process', 'GO:0006306', ('290', '305'))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('UHRF1', 'Gene', (19, 24))	('UHRF1', 'Gene', '29128', (144, 149))	('post-translational alterations', 'Var', (318, 348))	('Ubiquitin', 'molecular_function', 'GO:0031386', ('73', '82'))	('RING finger domains 1', 'Gene', (121, 142))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('UHRF1', 'Gene', (144, 149))	('epigenetic modifications', 'Var', (255, 279))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('217', '233'))	('cancer', 'Disease', (58, 64))
140238	29285183	Epigenetic silencing of tumor suppressor genes (TSGs) including breast cancer susceptibility gene 1 (BRCA1), human MutL homolog 1 (hMLH1), p16INK4A and p14ARF involves DNA methylation maintained by DNA methyltransferase 1 (DNMT1), histone deacetylation and methylation through histone deacetylase 1 (HDAC1) and histone H3K9 methyltransferase G9a respectively.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('p16INK4A', 'Gene', (139, 147))	('DNA methylation', 'MPA', (168, 183))	('DNA methylation', 'biological_process', 'GO:0006306', ('168', '183'))	('p16INK4A', 'Gene', '1029', (139, 147))	('methyltransferase 1', 'molecular_function', 'GO:0047152', ('202', '221'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('24', '40'))	('HDAC1', 'Gene', (300, 305))	('tumor suppressor', 'biological_process', 'GO:0051726', ('24', '40'))	('histone deacetylase 1', 'Gene', (277, 298))	('DNMT1', 'Gene', (223, 228))	('histone deacetylation', 'biological_process', 'GO:0016575', ('231', '252'))	('hMLH1', 'Gene', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('DNA', 'cellular_component', 'GO:0005574', ('168', '171'))	('DNA methyltransferase 1', 'Gene', (198, 221))	('hMLH1', 'Gene', '4292', (131, 136))	('Epigenetic', 'MPA', (0, 10))	('MutL homolog 1', 'Gene', '4292', (115, 129))	('DNMT1', 'Gene', '1786', (223, 228))	('DNA methyltransferase 1', 'Gene', '1786', (198, 221))	('HDAC1', 'Gene', '3065', (300, 305))	('tumor', 'Disease', (24, 29))	('DNA', 'cellular_component', 'GO:0005574', ('198', '201'))	('TSG', 'Gene', '57045', (48, 51))	('methylation', 'Var', (257, 268))	('p14ARF', 'Gene', '1029', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('TSG', 'Gene', (48, 51))	('histone deacetylase 1', 'Gene', '3065', (277, 298))	('human', 'Species', '9606', (109, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('BRCA1', 'Gene', '672', (101, 106))	('BRCA1', 'Gene', (101, 106))	('methylation', 'biological_process', 'GO:0032259', ('257', '268'))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('p14ARF', 'Gene', (152, 158))	('MutL homolog 1', 'Gene', (115, 129))	('breast cancer', 'Disease', (64, 77))
140240	29285183	UHRF1-mediated epigenetic silencing of TSG is primarily due to the presence of the SET- and RING-associated (SRA) domain.	('SRA', 'Gene', (109, 112))	('UHRF1', 'Gene', '29128', (0, 5))	('UHRF1', 'Gene', (0, 5))	('TSG', 'Gene', (39, 42))	('epigenetic silencing', 'Var', (15, 35))	('SRA', 'Gene', '4481', (109, 112))	('TSG', 'Gene', '57045', (39, 42))
140248	29285183	Although overexpression of wild-type UHRF1 induced p16INK4A downregulation, such an effect was not demonstrated when the TTD-mutated UHRF1 variant was overexpressed, thus indicating that UHRF1 binding to H3K9me3 through the TTD domain is involved in the silencing of p16INK4A.	('UHRF1', 'Gene', (133, 138))	('UHRF1', 'Gene', '29128', (133, 138))	('UHRF1', 'Gene', (37, 42))	('UHRF1', 'Gene', '29128', (37, 42))	('binding', 'molecular_function', 'GO:0005488', ('193', '200'))	('p16INK4A', 'Gene', (267, 275))	('variant', 'Var', (139, 146))	('downregulation', 'NegReg', (60, 74))	('p16INK4A', 'Gene', '1029', (267, 275))	('silencing', 'NegReg', (254, 263))	('UHRF1', 'Gene', '29128', (187, 192))	('binding', 'Interaction', (193, 200))	('p16INK4A', 'Gene', (51, 59))	('H3K9me3', 'Protein', (204, 211))	('UHRF1', 'Gene', (187, 192))	('p16INK4A', 'Gene', '1029', (51, 59))
140262	29285183	The second is associated with the maintenance of DNA methylation patterns, particularly the hypermethylation of the TSG promoters and genome-wide hypomethylation.	('TSG', 'Gene', '57045', (116, 119))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('hypermethylation', 'MPA', (92, 108))	('hypomethylation', 'Var', (146, 161))	('maintenance of DNA methylation', 'biological_process', 'GO:0010216', ('34', '64'))	('TSG', 'Gene', (116, 119))
140267	29285183	Considering that cancer cells overexpress UHRF1, deciphering the upstream pathways involved in UHRF1 may shed light on the underlying molecular mechanisms involved in the silencing of TSGs in tumorigenesis.	('tumor', 'Disease', (192, 197))	('UHRF1', 'Gene', (95, 100))	('UHRF1', 'Gene', '29128', (95, 100))	('TSG', 'Gene', (184, 187))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('UHRF1', 'Gene', (42, 47))	('UHRF1', 'Gene', '29128', (42, 47))	('cancer', 'Disease', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('silencing', 'Var', (171, 180))	('TSG', 'Gene', '57045', (184, 187))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('overexpress', 'PosReg', (30, 41))
140269	29285183	A number of non-coding RNAs have potential transcriptional, post-transcriptional and epigenetic regulatory functions, and are often dysregulated in many types of disease including cancer.	('RNAs', 'Protein', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('non-coding', 'Var', (12, 22))	('transcriptional', 'MPA', (43, 58))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('dysregulated', 'Reg', (132, 144))	('cancer', 'Disease', (180, 186))
140273	29285183	Aberrant levels of miRNAs contribute to cancer formation and progression by regulating expression levels of key genes involved in tumorigenesis pathways which are responsible for cell proliferation, tumor migration, invasion, integrin-mediated adhesion, EMT and resistance to cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('formation', 'biological_process', 'GO:0009058', ('47', '56'))	('expression levels', 'MPA', (87, 104))	('tumor', 'Disease', (130, 135))	('miR', 'Gene', '220972', (19, 22))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('cancer', 'Disease', (40, 46))	('invasion', 'CPA', (216, 224))	('regulating', 'Reg', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Disease', (199, 204))	('miR', 'Gene', (19, 22))	('EMT', 'biological_process', 'GO:0001837', ('254', '257'))	('cancer', 'Disease', (276, 282))	('contribute', 'Reg', (26, 36))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cell proliferation', 'biological_process', 'GO:0008283', ('179', '197'))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
140289	29285183	Of note, UHRF1 depletion decreased GC migration and metastasis; however, overexpression significantly promoted these effects.	('depletion', 'Var', (15, 24))	('GC migration', 'CPA', (35, 47))	('metastasis', 'CPA', (52, 62))	('GC', 'Phenotype', 'HP:0012126', (35, 37))	('UHRF1', 'Gene', '29128', (9, 14))	('decreased', 'NegReg', (25, 34))	('UHRF1', 'Gene', (9, 14))
140302	29285183	UHRF1 was demonstrated to promote the invasion of BC through epigenetic silencing of the tumor suppressor kisspeptin (KiSS1) and the regulator of G-protein signaling 2.	('promote', 'PosReg', (26, 33))	('epigenetic silencing', 'Var', (61, 81))	('KiSS1', 'Gene', '3814', (118, 123))	('tumor suppressor', 'biological_process', 'GO:0051726', ('89', '105'))	('KiSS1', 'Gene', (118, 123))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('89', '105'))	('BC', 'Phenotype', 'HP:0009725', (50, 52))	('UHRF1', 'Gene', (0, 5))	('UHRF1', 'Gene', '29128', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('invasion', 'CPA', (38, 46))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
140335	29285183	Notably, UHRF1 depletion induced a promoter demethylation-dependent reactivation of CDKN2A and RASSF1 with subsequent inhibition of cell proliferation and metastasis.	('depletion', 'Var', (15, 24))	('RASSF1', 'Gene', '11186', (95, 101))	('metastasis', 'CPA', (155, 165))	('CDKN2A', 'Gene', (84, 90))	('CDKN2A', 'Gene', '1029', (84, 90))	('promoter', 'MPA', (35, 43))	('inhibition', 'NegReg', (118, 128))	('UHRF1', 'Gene', '29128', (9, 14))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('118', '150'))	('RASSF1', 'Gene', (95, 101))	('demethylation', 'biological_process', 'GO:0070988', ('44', '57'))	('reactivation', 'MPA', (68, 80))	('cell proliferation', 'CPA', (132, 150))	('UHRF1', 'Gene', (9, 14))
140344	29285183	Considering the fact that abnormalities in miRNA expression may be a potent cause of cancer development, exploring the direct association between UHRF1 and miRNAs will increase our understanding of tumor pathology, and may also allow the development of novel therapeutic strategies based on specific targeting of the miRNA/UHRF1 pathways in several types of tumor (Fig.	('increase', 'PosReg', (168, 176))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (358, 363))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('UHRF1', 'Gene', (323, 328))	('UHRF1', 'Gene', '29128', (146, 151))	('miR', 'Gene', (156, 159))	('miR', 'Gene', '220972', (43, 46))	('UHRF1', 'Gene', (146, 151))	('miR', 'Gene', (43, 46))	('abnormalities', 'Var', (26, 39))	('cancer', 'Disease', (85, 91))	('miR', 'Gene', '220972', (317, 320))	('tumor', 'Disease', (358, 363))	('cause', 'Reg', (76, 81))	('tumor', 'Disease', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (358, 363))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('miR', 'Gene', (317, 320))	('UHRF1', 'Gene', '29128', (323, 328))	('miR', 'Gene', '220972', (156, 159))
140379	32340156	Thus, we sought to uncover the effect of lactate in epigenetic modulation of RCC aggressiveness, as well as the ability to epigenetically modulate adjacent normal cells.	('RCC aggressiveness', 'Disease', (77, 95))	('RCC aggressiveness', 'Disease', 'MESH:C538614', (77, 95))	('aggressiveness', 'Phenotype', 'HP:0000718', (81, 95))	('lactate', 'Chemical', 'MESH:D019344', (41, 48))	('epigenetic', 'Var', (52, 62))
140455	32340156	In addition, NAM promoted a decrease on global sirtuin activity in RCC, except for Caki2 cell line and normal kidney cells (Figure S2C).	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('decrease', 'NegReg', (28, 36))	('NAM', 'Var', (13, 16))	('NAM', 'Chemical', 'MESH:D009536', (13, 16))	('global sirtuin activity', 'MPA', (40, 63))
140493	32340156	In fact, it has been demonstrated that high lactate levels are associated with higher incidence of distant metastasis in different cancer types, although the mechanism is not completely understood.	('cancer', 'Disease', (131, 137))	('high', 'Var', (39, 43))	('lactate', 'Chemical', 'MESH:D019344', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lactate levels', 'MPA', (44, 58))	('distant metastasis', 'CPA', (99, 117))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
140517	32340156	Conversely, SIRT1 loss of expression promoted SMAD4 hyperacetylation; increased MMP7 levels; and, consequently, caused reduction of E-cadherin expression, and SIRT1 knockdown (KD) prevented beta-catenin degradation by promoting its translocation to the nucleus (a mesenchymal feature).	('increased', 'PosReg', (70, 79))	('cadherin', 'molecular_function', 'GO:0008014', ('134', '142'))	('translocation to the nucleus', 'MPA', (232, 260))	('E-cadherin', 'Gene', (132, 142))	('SIRT1', 'Gene', (12, 17))	('E-cadherin', 'Gene', '999', (132, 142))	('hyperacetylation', 'MPA', (52, 68))	('loss of expression', 'NegReg', (18, 36))	('SMAD4', 'Gene', '4089', (46, 51))	('beta-catenin', 'Gene', (190, 202))	('promoting', 'PosReg', (218, 227))	('MMP7', 'Gene', (80, 84))	('beta-catenin', 'Gene', '1499', (190, 202))	('prevented', 'NegReg', (180, 189))	('MMP7', 'molecular_function', 'GO:0004235', ('80', '84'))	('promoted', 'PosReg', (37, 45))	('expression', 'MPA', (143, 153))	('degradation', 'biological_process', 'GO:0009056', ('203', '214'))	('SIRT1', 'Gene', (159, 164))	('nucleus', 'cellular_component', 'GO:0005634', ('253', '260'))	('KD', 'Disease', 'MESH:C537017', (176, 178))	('knockdown', 'Var', (165, 174))	('reduction', 'NegReg', (119, 128))	('SMAD4', 'Gene', (46, 51))	('MMP7', 'Gene', '4316', (80, 84))
140524	32340156	Because CHC also inhibits lactate efflux with consequent reduction of glycolytic metabolism, NAD+ availability is augmented allowing for SIRT1 reactivation.	('inhibits', 'NegReg', (17, 25))	('reduction of glycolytic metabolism', 'Disease', 'MESH:D007022', (57, 91))	('lactate', 'Chemical', 'MESH:D019344', (26, 33))	('lactate efflux', 'MPA', (26, 40))	('metabolism', 'biological_process', 'GO:0008152', ('81', '91'))	('efflux', 'biological_process', 'GO:0140115', ('34', '40'))	('CHC', 'Var', (8, 11))	('efflux', 'biological_process', 'GO:0140352', ('34', '40'))	('NAD+', 'Chemical', 'MESH:D009243', (93, 97))	('reduction of glycolytic metabolism', 'Disease', (57, 91))
140572	28871275	Type I tumors consist of low-grade serous, low-grade endometrioid, clear cell carcinomas, and mucinous carcinomas and are characterized by mutations in KRAS, BRAF, PTEN, PIK3CA, CTNNB1, ARID1A, and PPP2R1A.	('PIK3CA', 'Gene', '5290', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('clear cell carcinomas', 'Disease', (67, 88))	('ARID1A', 'Gene', '8289', (186, 192))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (67, 88))	('PTEN', 'Gene', (164, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (94, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('CTNNB1', 'Gene', (178, 184))	('BRAF', 'Gene', '673', (158, 162))	('KRAS', 'Gene', '3845', (152, 156))	('BRAF', 'Gene', (158, 162))	('PPP2R1A', 'Gene', '5518', (198, 205))	('PIK3CA', 'Gene', (170, 176))	('PTEN', 'Gene', '5728', (164, 168))	('KRAS', 'Gene', (152, 156))	('Type I tumors', 'Disease', (0, 13))	('PPP2R1A', 'Gene', (198, 205))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('mutations', 'Var', (139, 148))	('Type I tumors', 'Disease', 'MESH:D005776', (0, 13))	('mucinous carcinomas', 'Disease', (94, 113))	('ARID1A', 'Gene', (186, 192))	('CTNNB1', 'Gene', '1499', (178, 184))
140575	28871275	Type II tumors are defined by TP53 mutations, which are rare in Type I cancers.	('TP53', 'Gene', (30, 34))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('Type I cancers', 'Disease', (64, 78))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Type I cancers', 'Disease', 'MESH:D009369', (64, 78))	('Type II tumors', 'Disease', (0, 14))	('TP53', 'Gene', '7157', (30, 34))	('Type II tumors', 'Disease', 'MESH:D009369', (0, 14))	('mutations', 'Var', (35, 44))
140591	28871275	The first reported clinical application of 32P was in the 1930s and other intraperitoneal radioactive isotypes were investigated in the 1950s and 1960s most notably 198Au, but for reasons of safety and toxicity, 32P became the agent of choice for the treatment of ovarian cancer and the palliation of malignant ascites in the 1960s.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('ascites', 'Phenotype', 'HP:0001541', (311, 318))	('32P', 'Var', (212, 215))	('toxicity', 'Disease', 'MESH:D064420', (202, 210))	('toxicity', 'Disease', (202, 210))	('ovarian cancer', 'Phenotype', 'HP:0100615', (264, 278))	('malignant ascites', 'Disease', (301, 318))	('ovarian cancer', 'Disease', 'MESH:D010051', (264, 278))	('32P', 'Chemical', 'MESH:C000615311', (43, 46))	('malignant ascites', 'Disease', 'MESH:D001201', (301, 318))	('ovarian cancer', 'Disease', (264, 278))	('32P', 'Chemical', 'MESH:C000615311', (212, 215))
140695	28871275	Poly(ADP-ribose) polymerase (PARP) is an important family of enzymes activated in response to single-strand damage of DNA.	('DNA', 'cellular_component', 'GO:0005574', ('118', '121'))	('single-strand damage', 'Var', (94, 114))	('Poly(ADP-ribose) polymerase', 'Gene', (0, 27))	('Poly(ADP-ribose) polymerase', 'Gene', '142', (0, 27))
140698	28871275	Although cancer cells with defective homologous recombination (e.g., BRCA mutated or platinum sensitive) are noted to have enhanced sensitivity to PARP inhibition, homologous recombination deficiency is not always an accurate predictive biomarker of PARP inhibitor activity.	('enhanced', 'PosReg', (123, 131))	('cancer', 'Disease', (9, 15))	('homologous recombination', 'biological_process', 'GO:0035825', ('37', '61'))	('BRCA', 'Gene', '672', (69, 73))	('homologous recombination', 'biological_process', 'GO:0035825', ('164', '188'))	('BRCA', 'Gene', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('sensitivity', 'MPA', (132, 143))	('defective', 'Var', (27, 36))	('mutated', 'Var', (74, 81))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('platinum', 'Chemical', 'MESH:D010984', (85, 93))
140700	28871275	In a preclinical model of the combination of PARP inhibition and radiation, significant cell death in vitro was demonstrated as well as inhibition of tumor growth in a pancreatic cancer mouse xenograft model.	('pancreatic cancer', 'Disease', 'MESH:D010190', (168, 185))	('cell death', 'biological_process', 'GO:0008219', ('88', '98'))	('pancreatic cancer', 'Disease', (168, 185))	('inhibition', 'Var', (50, 60))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('PARP', 'Gene', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('mouse', 'Species', '10090', (186, 191))	('inhibition', 'NegReg', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (168, 185))	('tumor', 'Disease', (150, 155))	('cell death', 'CPA', (88, 98))
140702	28871275	Patients with gynecologic malignancy had the best responses and a platinum sensitive ovarian cancer patient with a germline BRCA mutation was an exceptional responder with a response of several years.	('ovarian cancer', 'Phenotype', 'HP:0100615', (85, 99))	('platinum', 'Chemical', 'MESH:D010984', (66, 74))	('ovarian cancer', 'Disease', 'MESH:D010051', (85, 99))	('mutation', 'Var', (129, 137))	('BRCA', 'Gene', '672', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('BRCA', 'Gene', (124, 128))	('Patients', 'Species', '9606', (0, 8))	('ovarian cancer', 'Disease', (85, 99))	('patient', 'Species', '9606', (100, 107))	('malignancy', 'Disease', 'MESH:D009369', (26, 36))	('platinum sensitive ovarian cancer', 'Phenotype', 'HP:0025318', (66, 99))	('malignancy', 'Disease', (26, 36))
140707	28871275	Enhanced radiation response with inhibitors of NHEJ has been demonstrated in pancreatic cancer cell lines and may be rational in ovarian cancer as well.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('ovarian cancer', 'Phenotype', 'HP:0100615', (129, 143))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))	('Enhanced', 'PosReg', (0, 8))	('ovarian cancer', 'Disease', 'MESH:D010051', (129, 143))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('NHEJ', 'biological_process', 'GO:0006303', ('47', '51'))	('ovarian cancer', 'Disease', (129, 143))	('NHEJ', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('radiation response', 'CPA', (9, 27))	('pancreatic cancer', 'Disease', (77, 94))	('inhibitors', 'Var', (33, 43))
140724	27659536	Notably, RG7112 significantly suppressed cell viability in clear cell carcinoma cell lines with wild type TP53.	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('suppressed', 'NegReg', (30, 40))	('clear cell carcinoma', 'Disease', (59, 79))	('RG7112', 'Var', (9, 15))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (59, 79))
140725	27659536	Finally, RG7112 significantly reduced the tumor volume of xenografted RMG-I clear cell carcinoma cells (P = 0.033), and the density of microvessels (P = 0.011).	('tumor', 'Disease', (42, 47))	('RG7112', 'Var', (9, 15))	('clear cell carcinoma', 'Disease', (76, 96))	('reduced', 'NegReg', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (76, 96))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('density of microvessels', 'CPA', (124, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
140734	27659536	TP53 mutations are characteristically infrequent, and are present in only 10% of ovarian clear cell carcinomas, with loss of heterozygosity in < 20%.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('TP53', 'Gene', (0, 4))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (81, 110))	('ovarian clear cell carcinomas', 'Disease', (81, 110))	('mutations', 'Var', (5, 14))
140735	27659536	In contrast, TP53 mutations are present in 96% of high-grade serous tumors.	('TP53', 'Gene', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('serous tumors', 'Disease', 'MESH:D018284', (61, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('serous tumors', 'Disease', (61, 74))	('mutations', 'Var', (18, 27))
140751	27659536	TP53 mutations were detected by Sanger sequencing in 4 (5.6%) clear cell carcinomas (Supplementary Figure 1B), all of which were MDM2-low or intermediate (Supplementary Table 1).	('TP53', 'Gene', (0, 4))	('MDM2-low', 'Disease', (129, 137))	('Supplementary Figure 1B', 'Disease', (85, 108))	('Supplementary Figure 1B', 'Disease', 'MESH:D017034', (85, 108))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (62, 83))	('mutations', 'Var', (5, 14))	('MDM2-low', 'Disease', 'MESH:D009800', (129, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('clear cell carcinomas', 'Disease', (62, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
140752	27659536	In clear cell carcinomas without TP53 mutations, high MDM2 expression was significantly associated with poor progression-free survival (PFS) (P = 0.0002 by log-rank test, Figure 1C), as was advanced stage (P = 0.0002 by log-rank test, Supplementary Figure 1C), but not age (Supplementary Figure 1D).	('MDM2', 'Gene', (54, 58))	('Supplementary Figure 1D', 'Disease', (274, 297))	('advanced stage', 'CPA', (190, 204))	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (3, 24))	('expression', 'MPA', (59, 69))	('poor', 'NegReg', (104, 108))	('high', 'Var', (49, 53))	('Supplementary Figure 1D', 'Disease', 'MESH:D017034', (274, 297))	('progression-free survival', 'CPA', (109, 134))	('clear cell carcinomas', 'Disease', (3, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
140753	27659536	Similarly, univariate analysis demonstrated that advanced stage (HR = 5.05, 95% CI = 1.84-12.91, P = 0.0025) and high MDM2 expression (HR = 5.48, 95% CI = 2.10-15.97, P = 0.0005) were significantly associated with poor PFS (Table 1: upper rows) and with poor OS (Table 1: lower rows).	('high', 'Var', (113, 117))	('poor', 'Disease', (254, 258))	('MDM2', 'Gene', (118, 122))	('poor', 'NegReg', (214, 218))	('expression', 'MPA', (123, 133))	('PFS', 'CPA', (219, 222))	('rat', 'Species', '10116', (38, 41))
140754	27659536	In addition, multivariate analysis indicated that high MDM2 expression was a poor prognostic factor for PFS (HR = 5.61, 95% CI = 2.11-16.62, P = 0.0005) and OS (HR = 6.14, 95% CI = 1.85-24.32, P = 0.0028, independent of age and cancer stage (Table 1).	('expression', 'MPA', (60, 70))	('cancer', 'Disease', (228, 234))	('PFS', 'Disease', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('MDM2', 'Gene', (55, 59))	('high', 'Var', (50, 54))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
140756	27659536	MDM2 expression was assessed by immunoblotting in 7 clear cell carcinoma cell lines with wild-type (OVISE, OVTOKO, JHOC-7, and RMG-I) or mutated (SKOV3, JHOC-9, and ES-2) TP53 (Supplementary Figure 4).	('TP53', 'Gene', (171, 175))	('VT', 'Disease', 'MESH:D017180', (108, 110))	('JHOC-9', 'CellLine', 'CVCL:4643', (153, 159))	('JHOC-7', 'CellLine', 'CVCL:4641', (115, 121))	('clear cell carcinoma', 'Disease', (52, 72))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (52, 72))	('mutated', 'Var', (137, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('SKOV3', 'CellLine', 'CVCL:0532', (146, 151))
140758	27659536	RG7112 suppressed cell proliferation in dose-dependent fashion only in cells with wild type TP53, with half maximal inhibitory concentration (IC50) between 1.0 and 2.2 muM (Figure 2A).	('muM', 'Gene', (168, 171))	('RG7112', 'Var', (0, 6))	('suppressed', 'NegReg', (7, 17))	('cell proliferation', 'biological_process', 'GO:0008283', ('18', '36'))	('rat', 'Species', '10116', (30, 33))	('cell proliferation', 'CPA', (18, 36))	('rat', 'Species', '10116', (134, 137))	('muM', 'Gene', '56925', (168, 171))
140759	27659536	On the other hand, IC50 was > 10 muM in cell lines with mutant TP53 (Figure 2B).	('TP53', 'Gene', (63, 67))	('mutant', 'Var', (56, 62))	('muM', 'Gene', (33, 36))	('muM', 'Gene', '56925', (33, 36))
140760	27659536	Indeed, differences in cell viability were statistically significant between tumors with wild type and mutated TP53 (P < 0.001 by paired t-test, Figure 2C).	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('mutated', 'Var', (103, 110))	('significant', 'Reg', (57, 68))	('TP53', 'Gene', (111, 115))	('cell viability', 'CPA', (23, 37))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('differences', 'Reg', (8, 19))
140762	27659536	RG7112 increased the abundance of MDM2 and TP53 in OVTOKO cells in a time-dependent (at 2.5 muM) and dose-dependent fashion (Figure 2D and 2E), suggesting that interference with MDM2-TP53 binding resulted in accumulation of both proteins.	('VT', 'Disease', 'MESH:D017180', (52, 54))	('binding', 'Interaction', (188, 195))	('increased', 'PosReg', (7, 16))	('muM', 'Gene', (92, 95))	('binding', 'molecular_function', 'GO:0005488', ('188', '195'))	('accumulation', 'PosReg', (208, 220))	('RG7112', 'Var', (0, 6))	('muM', 'Gene', '56925', (92, 95))	('abundance', 'MPA', (21, 30))	('interference', 'NegReg', (160, 172))
140764	27659536	RG7112 also stimulated TP53-dependent apoptotic signaling in OVISE, RMG-I, and OVTOKO cells, as indicated by increased TP53 phosphorylation at Ser-46 and Ser-15, increased expression of the proapoptotic gene PUMA, and suppression of the antiapoptotic protein survivin (Figure 2F).	('VT', 'Disease', 'MESH:D017180', (80, 82))	('stimulated', 'PosReg', (12, 22))	('TP53', 'Protein', (119, 123))	('increased', 'PosReg', (162, 171))	('TP53-dependent apoptotic signaling', 'MPA', (23, 57))	('RG7112', 'Var', (0, 6))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('expression', 'MPA', (172, 182))	('Ser', 'cellular_component', 'GO:0005790', ('154', '157'))	('phosphorylation', 'MPA', (124, 139))	('protein', 'cellular_component', 'GO:0003675', ('251', '258'))	('Ser', 'Chemical', 'MESH:D012694', (154, 157))	('Ser', 'cellular_component', 'GO:0005790', ('143', '146'))	('increased', 'PosReg', (109, 118))	('phosphorylation', 'biological_process', 'GO:0016310', ('124', '139'))	('suppression', 'NegReg', (218, 229))	('Ser', 'Chemical', 'MESH:D012694', (143, 146))
140765	27659536	Consequently, cleaved PARP accumulated following exposure to 2.5 or 5 muM RG7112 in OVISE cells (Figure 2F).	('PARP', 'Gene', (22, 26))	('PARP', 'Gene', '1302', (22, 26))	('muM', 'Gene', '56925', (70, 73))	('accumulated', 'PosReg', (27, 38))	('muM', 'Gene', (70, 73))	('cleaved', 'MPA', (14, 21))	('RG7112', 'Var', (74, 80))
140767	27659536	In particular, the proportion of cells in sub-G1 increased to 14-59% in cells treated with 5 muM RG7112, while the S phase population contracted.	('S phase', 'biological_process', 'GO:0051320', ('115', '122'))	('increased', 'PosReg', (49, 58))	('muM', 'Gene', '56925', (93, 96))	('muM', 'Gene', (93, 96))	('RG7112', 'Var', (97, 103))
140768	27659536	In addition, exposure to 2.5 muM or 5 muM RG7112 significantly increased the ratio of apoptotic cells by 12-22%, as measured by annexin V staining (Figure 3B).	('muM', 'Gene', (29, 32))	('muM', 'Gene', '56925', (38, 41))	('increased', 'PosReg', (63, 72))	('rat', 'Species', '10116', (77, 80))	('RG7112', 'Var', (42, 48))	('annexin V', 'Gene', '308', (128, 137))	('muM', 'Gene', (38, 41))	('annexin V', 'Gene', (128, 137))	('muM', 'Gene', '56925', (29, 32))
140773	27659536	Western blotting of three tumors from RG7112-treated mice showed upregulation of MDM2, TP53, and TP53 phosphorylation at Ser15 and Ser46 (Figure 4D and 4E, and Supplementary Figure 6B and 6C).	('mice', 'Species', '10090', (53, 57))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('Ser46', 'Var', (131, 136))	('Ser', 'cellular_component', 'GO:0005790', ('131', '134'))	('RG7112-treated', 'Var', (38, 52))	('phosphorylation', 'MPA', (102, 117))	('MDM2', 'Gene', (81, 85))	('TP53', 'Gene', (97, 101))	('Supplementary Figure 6B', 'Disease', 'MESH:D017034', (160, 183))	('Ser15', 'Var', (121, 126))	('Ser', 'cellular_component', 'GO:0005790', ('121', '124'))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('phosphorylation', 'biological_process', 'GO:0016310', ('102', '117'))	('Supplementary Figure 6B', 'Disease', (160, 183))	('TP53', 'Gene', (87, 91))	('Ser15', 'Chemical', '-', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('upregulation', 'PosReg', (65, 77))	('Ser46', 'Chemical', '-', (131, 136))	('tumors', 'Disease', (26, 32))
140776	27659536	Exposure to RG7112 (Figure 5A) and MDM2 siRNA (Supplementary Figure 7A) suppressed hypoxia (1% O2)-induced expression of HIF-1alpha in two cell lines with wild type TP53.	('HIF-1alpha', 'Gene', (121, 131))	('hypoxia', 'Disease', 'MESH:D000860', (83, 90))	('O2', 'Chemical', '-', (95, 97))	('expression', 'MPA', (107, 117))	('MDM2', 'Var', (35, 39))	('HIF-1alpha', 'Gene', '3091', (121, 131))	('suppressed', 'NegReg', (72, 82))	('RG7112', 'Var', (12, 18))	('hypoxia', 'Disease', (83, 90))
140778	27659536	Indeed, the number of microvessels in RMG-I and OVISE tumors was significantly reduced in RG7112-treated mice (P = 0.011 and P = 0.016, respectively), indicating that RG7112 inhibits angiogenesis (Figure 5C and Supplementary Figure 7C).	('angiogenesis', 'CPA', (183, 195))	('reduced', 'NegReg', (79, 86))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('angiogenesis', 'biological_process', 'GO:0001525', ('183', '195'))	('RG7112-treated', 'Gene', (90, 104))	('RG7112', 'Var', (167, 173))	('mice', 'Species', '10090', (105, 109))	('inhibits', 'NegReg', (174, 182))	('tumors', 'Disease', (54, 60))
140781	27659536	MDM2 is negatively regulated by specific microRNAs such as miR-1827 and miR-340, and overexpression via multiple mechanisms is observed in various types of human malignancies, including sarcomas, gliomas, hematological malignancies, and breast cancer.	('overexpression', 'PosReg', (85, 99))	('hematological malignancies', 'Phenotype', 'HP:0004377', (205, 231))	('observed', 'Reg', (127, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('gliomas', 'Disease', 'MESH:D005910', (196, 203))	('miR-340', 'Gene', (72, 79))	('miR-340', 'Gene', '442908', (72, 79))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('breast cancer', 'Disease', (237, 250))	('gliomas', 'Phenotype', 'HP:0009733', (196, 203))	('hematological malignancies', 'Disease', (205, 231))	('malignancies', 'Disease', (162, 174))	('negatively', 'NegReg', (8, 18))	('sarcomas', 'Disease', 'MESH:D012509', (186, 194))	('sarcomas', 'Phenotype', 'HP:0100242', (186, 194))	('sarcomas', 'Disease', (186, 194))	('MDM2', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('malignancies', 'Disease', 'MESH:D009369', (219, 231))	('malignancies', 'Disease', 'MESH:D009369', (162, 174))	('miR-1827', 'Var', (59, 67))	('malignancies', 'Disease', (219, 231))	('gliomas', 'Disease', (196, 203))	('human', 'Species', '9606', (156, 161))	('hematological malignancies', 'Disease', 'MESH:D019337', (205, 231))
140783	27659536	Accordingly, MDM2 expression was significantly lower in high-grade serous and clear cell carcinomas with mutated TP53.	('lower', 'NegReg', (47, 52))	('high-grade serous', 'Disease', (56, 73))	('MDM2', 'Gene', (13, 17))	('clear cell carcinomas', 'Disease', (78, 99))	('expression', 'MPA', (18, 28))	('mutated', 'Var', (105, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (78, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('TP53', 'Gene', (113, 117))
140787	27659536	We found that RG7112 has antitumor activity exclusively in clear cell tumors with wild type TP53.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('RG7112', 'Var', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', (29, 34))	('clear cell tumors', 'Disease', 'MESH:D008649', (59, 76))	('clear cell tumors', 'Disease', (59, 76))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
140789	27659536	We previously demonstrated that phosphorylation at Ser-46 is required for TP53-dependent apoptosis, and is induced by either overexpression of TP53 or by severe DNA damage.	('phosphorylation', 'biological_process', 'GO:0016310', ('32', '47'))	('phosphorylation', 'Var', (32, 47))	('Ser', 'Chemical', 'MESH:D012694', (51, 54))	('damage', 'Disease', (165, 171))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('TP53', 'Var', (143, 147))	('damage', 'Disease', 'MESH:D004194', (165, 171))	('rat', 'Species', '10116', (21, 24))	('Ser', 'cellular_component', 'GO:0005790', ('51', '54'))	('apoptosis', 'biological_process', 'GO:0097194', ('89', '98'))	('apoptosis', 'biological_process', 'GO:0006915', ('89', '98'))	('induced', 'Reg', (107, 114))
140790	27659536	Recently, inhibition of MDM2 was reported to induce p53-induced senescence or quiescence in cells with activation of the mTOR (mammalian target of rapamycin) pathway.	('mTOR', 'Gene', '2475', (121, 125))	('quiescence', 'biological_process', 'GO:0044838', ('78', '88'))	('mTOR', 'Gene', (121, 125))	('induce', 'PosReg', (45, 51))	('p53', 'Gene', (52, 55))	('mammalian target of rapamycin', 'Gene', (127, 156))	('mammalian target of rapamycin', 'Gene', '2475', (127, 156))	('p53', 'Gene', '7157', (52, 55))	('MDM2', 'Gene', (24, 28))	('senescence', 'biological_process', 'GO:0010149', ('64', '74'))	('quiescence', 'MPA', (78, 88))	('inhibition', 'Var', (10, 20))
140794	27659536	In this study, RG7112 inhibited tumor vascularization by stabilization of TP53, which is known to prevent angiogenesis via suppression of HIF-1alpha.	('stabilization', 'Var', (57, 70))	('inhibited', 'NegReg', (22, 31))	('angiogenesis', 'biological_process', 'GO:0001525', ('106', '118'))	('HIF-1alpha', 'Gene', (138, 148))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('RG7112', 'Var', (15, 21))	('HIF-1alpha', 'Gene', '3091', (138, 148))	('tumor', 'Disease', (32, 37))	('TP53', 'Gene', (74, 78))
140801	27659536	RG7112 might prove to be particularly promising against clear cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('clear cell carcinoma', 'Disease', (56, 76))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (56, 76))	('RG7112', 'Var', (0, 6))
140804	27659536	Furthermore, RG7112 elicited apoptotic cell death via phosphorylation of TP53 at Ser-46, and via induction of proapoptotic TP53 target genes.	('apoptotic cell death', 'CPA', (29, 49))	('Ser', 'cellular_component', 'GO:0005790', ('81', '84'))	('elicited', 'Reg', (20, 28))	('RG7112', 'Var', (13, 19))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('29', '49'))	('induction', 'PosReg', (97, 106))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('TP53', 'Protein', (73, 77))	('Ser', 'Chemical', 'MESH:D012694', (81, 84))	('phosphorylation', 'MPA', (54, 69))
140812	27659536	Genomic DNA was extracted from 72 of 75 clear cell carcinomas, and TP53 mutations (all exons) were determined by Sanger sequencing.	('mutations', 'Var', (72, 81))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (40, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('clear cell carcinomas', 'Disease', (40, 61))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('TP53', 'Gene', (67, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
140835	27659536	Sections were then probed at 4 C overnight with 1:500 anti-CD31 (PECAM-1; BD Biosciences; Franklin Lakes, NJ), washed in Tris-buffered saline, and labeled at room temperature for 45 min with 1:400 biotinylated rabbit anti-rat (DAKO), and then at room temperature for 45 min with LSAB (DAKO).	('PECAM-1', 'Gene', '5175', (65, 72))	('DAKO', 'Chemical', '-', (285, 289))	('rat', 'Species', '10116', (256, 259))	('DAKO', 'Chemical', '-', (227, 231))	('rat', 'Species', '10116', (222, 225))	('rat', 'Species', '10116', (168, 171))	('Tris-buffered saline', 'Chemical', '-', (121, 141))	('anti-CD31', 'Var', (54, 63))	('rabbit', 'Species', '9986', (210, 216))	('PECAM-1', 'Gene', (65, 72))
140840	32461965	Solute carriers (SLCs) are important in the transport of small molecules in humans, and defects in SLC transporters can lead to serious diseases.	('SLC', 'Gene', (17, 20))	('serious diseases', 'Disease', (128, 144))	('lead to', 'Reg', (120, 127))	('defects', 'Var', (88, 95))	('SLC', 'Gene', '6366', (99, 102))	('transport', 'biological_process', 'GO:0006810', ('44', '53'))	('SLC', 'Gene', (99, 102))	('humans', 'Species', '9606', (76, 82))	('SLC', 'Gene', '6366', (17, 20))
140859	32461965	Epigenetic changes in ccRCC may be related to its prognosis and treatment.	('RCC', 'Disease', (24, 27))	('men', 'Species', '9606', (69, 72))	('related', 'Reg', (35, 42))	('RCC', 'Phenotype', 'HP:0005584', (24, 27))	('Epigenetic changes', 'Var', (0, 18))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
140860	32461965	Genetic markers of ccRCC include biallelic inactivation of Von Hippel-Lindau (VHL) tumor suppressor genes; negative regulators of hypoxia-inducible factor (HIF) protein; copy number changes of chromosome 3p, 5q, and 14q genes; and chromatin-modifying enzyme high mutation frequencies, such as protein polybromo-1 (PBRM1), SET domain containing 2 (SETD2), and BRCA1-associated protein-1 (BAP1).	('tumor suppressor', 'biological_process', 'GO:0051726', ('83', '99'))	('biallelic', 'Var', (33, 42))	('hypoxia', 'Disease', 'MESH:D000860', (130, 137))	('BRCA1-associated protein-1', 'Gene', '8314', (359, 385))	('copy number changes', 'Var', (170, 189))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('BAP1', 'Gene', '8314', (387, 391))	('BRCA1-associated protein-1', 'Gene', (359, 385))	('chromosome', 'cellular_component', 'GO:0005694', ('193', '203'))	('protein polybromo-1', 'Gene', (293, 312))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('protein', 'cellular_component', 'GO:0003675', ('293', '300'))	('BAP1', 'Gene', (387, 391))	('protein', 'cellular_component', 'GO:0003675', ('376', '383'))	('protein polybromo-1', 'Gene', '55193', (293, 312))	('SETD2', 'Gene', (347, 352))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))	('PBRM1', 'Gene', '55193', (314, 319))	('hypoxia', 'Disease', (130, 137))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('83', '99'))	('SETD2', 'Gene', '29072', (347, 352))	('PBRM1', 'Gene', (314, 319))	('RCC', 'Disease', (21, 24))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('chromatin', 'cellular_component', 'GO:0000785', ('231', '240'))	('Von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (59, 88))
140872	32461965	High SLC10A2 expression was associated with good prognosis of ccRCC.	('High', 'Var', (0, 4))	('expression', 'MPA', (13, 23))	('SLC10A2', 'Gene', (5, 12))	('SLC10A2', 'Gene', '6555', (5, 12))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))
140886	32461965	The genomic profiles included mutations, putative copy number alterations from the Genomic Identification of Significant Targets in Cancer (GISTIC), mRNA expression Z-scores (RNASeq V2 RSEM), and protein expression Z-scores (RPPA).	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))	('protein expression', 'MPA', (196, 214))	('mutations', 'Var', (30, 39))	('copy number alterations', 'Var', (50, 73))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Cancer', 'Disease', (132, 138))	('mRNA expression', 'MPA', (149, 164))	('Cancer', 'Disease', 'MESH:D009369', (132, 138))
140927	32461965	As shown in Figures 6, genetic alterations in SLC22A6, SLC22A7, SLC22A13, SLC25A4, SLC34A1, and SLC44A4 occurred in 42.2% of ccRCC patients, with SLC22A6 in 3%, SLC22A7 in 2.2%, SLC22A13 in 12%, SLC25A4 in 3%, SLC34A1 in 18%, and SLC44A4 in 4%.	('SLC25A4', 'Gene', (74, 81))	('SLC44A4', 'Gene', '80736', (96, 103))	('SLC44A4', 'Gene', (230, 237))	('SLC22A6', 'Gene', (46, 53))	('SLC34A1', 'Gene', (210, 217))	('SLC22A6', 'Gene', '9356', (146, 153))	('SLC34A1', 'Gene', (83, 90))	('SLC22A13', 'Gene', (178, 186))	('SLC25A4', 'Gene', '291', (74, 81))	('occurred', 'Reg', (104, 112))	('SLC22A7', 'Gene', (161, 168))	('SLC22A13', 'Gene', '9390', (178, 186))	('SLC34A1', 'Gene', '6569', (210, 217))	('SLC44A4', 'Gene', '80736', (230, 237))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('SLC34A1', 'Gene', '6569', (83, 90))	('patients', 'Species', '9606', (131, 139))	('SLC22A7', 'Gene', '10864', (161, 168))	('SLC22A7', 'Gene', (55, 62))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('SLC22A6', 'Gene', (146, 153))	('SLC22A13', 'Gene', (64, 72))	('RCC', 'Disease', (127, 130))	('alterations', 'Var', (31, 42))	('SLC25A4', 'Gene', '291', (195, 202))	('SLC22A6', 'Gene', '9356', (46, 53))	('SLC22A7', 'Gene', '10864', (55, 62))	('SLC22A13', 'Gene', '9390', (64, 72))	('SLC25A4', 'Gene', (195, 202))	('SLC44A4', 'Gene', (96, 103))
140928	32461965	SLC22A6, SLC22A7, SLC25A4, and SLC44A4 were mainly altered by mRNA high, SLC22A13 was mainly altered by a deep deletion, and SLC34A1 was mainly altered by an amplification.	('SLC34A1', 'Gene', (125, 132))	('altered', 'Reg', (51, 58))	('SLC25A4', 'Gene', (18, 25))	('SLC34A1', 'Gene', '6569', (125, 132))	('SLC22A13', 'Gene', '9390', (73, 81))	('altered', 'Reg', (93, 100))	('SLC25A4', 'Gene', '291', (18, 25))	('SLC22A6', 'Gene', (0, 7))	('SLC22A13', 'Gene', (73, 81))	('SLC22A7', 'Gene', '10864', (9, 16))	('SLC22A6', 'Gene', '9356', (0, 7))	('SLC22A7', 'Gene', (9, 16))	('deep deletion', 'Var', (106, 119))	('mRNA', 'Var', (62, 66))	('SLC44A4', 'Gene', (31, 38))	('SLC44A4', 'Gene', '80736', (31, 38))
140934	32461965	The functions of the SLC family genes and the genes significantly associated with SLC family gene alterations were predicted by GO and KEGG analyses with Metascape (Figure 8).	('SLC', 'Gene', (21, 24))	('SLC', 'Gene', '6366', (82, 85))	('SLC', 'Gene', '6366', (21, 24))	('alterations', 'Var', (98, 109))	('functions', 'MPA', (4, 13))	('SLC', 'Gene', (82, 85))
140936	32461965	The biological process terms mainly included GO: 0007005 (mitochondrion organization), GO: 0006820 (anion transport), GO: 0007006 (mitochondrial membrane organization), GO: 0015672 (monovalent inorganic cation transport), and GO: 0015893 (drug transport); the cellular component terms mainly included GO: 0005740 (mitochondrial envelope), GO: 0005758 (mitochondrial intermembrane space), GO: 0005744 (TIM23 mitochondrial import inner membrane translocase complex), GO: 0005759 (mitochondrial matrix), and GO: 0005742 (mitochondrial outer membrane translocase complex); and the molecular function terms mainly included GO: 0022804 (active transmembrane transporter activity), GO: 0008509 (anion transmembrane transporter activity), GO: 1904680 (peptide transmembrane transporter activity), GO: 0015238 (drug transmembrane transporter activity), and GO: 0015288 (porin activity).	('active transmembrane transporter activity', 'molecular_function', 'GO:0022804', ('631', '672'))	('transmembrane', 'cellular_component', 'GO:0044214', ('752', '765'))	('anion transmembrane transporter activity', 'molecular_function', 'GO:0008509', ('688', '728'))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('131', '153'))	('transmembrane', 'cellular_component', 'GO:0044214', ('807', '820'))	('mitochondrial outer membrane translocase complex', 'cellular_component', 'GO:0005742', ('518', '566'))	('GO: 0015238', 'Var', (789, 800))	('transmembrane', 'cellular_component', 'GO:0016021', ('638', '651'))	('GO: 1904680', 'Var', (731, 742))	('TIM23', 'Gene', '100287932', (401, 406))	('mitochondrial intermembrane space', 'cellular_component', 'GO:0005758', ('352', '385'))	('porin', 'Gene', '7416', (861, 866))	('transmembrane', 'cellular_component', 'GO:0044214', ('638', '651'))	('mitochondrial envelope', 'cellular_component', 'GO:0005740', ('314', '336'))	('mitochondrion organization', 'biological_process', 'GO:0007005', ('58', '84'))	('peptide transmembrane transporter activity', 'molecular_function', 'GO:1904680', ('744', '786'))	('transmembrane', 'cellular_component', 'GO:0016021', ('694', '707'))	('mitochondrion', 'cellular_component', 'GO:0005739', ('58', '71'))	('porin activity', 'molecular_function', 'GO:0015288', ('861', '875'))	('mitochondrial matrix', 'cellular_component', 'GO:0005759', ('478', '498'))	('porin', 'Gene', (861, 866))	('GO: 0015288', 'Var', (848, 859))	('molecular function', 'molecular_function', 'GO:0003674', ('577', '595'))	('anion transport', 'biological_process', 'GO:0006820', ('100', '115'))	('mitochondrial membrane organization', 'biological_process', 'GO:0007006', ('131', '166'))	('monovalent inorganic cation transport', 'biological_process', 'GO:0015672', ('182', '219'))	('transmembrane', 'cellular_component', 'GO:0044214', ('694', '707'))	('cellular component', 'cellular_component', 'GO:0005575', ('260', '278'))	('drug transmembrane transporter activity', 'molecular_function', 'GO:0042910', ('802', '841'))	('GO: 0022804', 'Var', (618, 629))	('biological process', 'biological_process', 'GO:0008150', ('4', '22'))	('transmembrane', 'cellular_component', 'GO:0016021', ('752', '765'))	('transmembrane', 'cellular_component', 'GO:0016021', ('807', '820'))	('TIM23', 'Gene', (401, 406))	('GO: 0008509', 'Var', (675, 686))	('drug transport', 'biological_process', 'GO:0015893', ('239', '253'))	('TIM23 mitochondrial import inner membrane translocase complex', 'cellular_component', 'GO:0005744', ('401', '462'))
140938	32461965	The relevant signaling pathways were hsa05012 (Parkinson's disease), M00009 (citrate cycle (TCA cycle, Krebs cycle)), hsa00190 (oxidative phosphorylation), and hsa04976 (bile secretion).	('TCA', 'Chemical', 'MESH:D014233', (92, 95))	('hsa05012', 'Var', (37, 45))	('hsa00190', 'Var', (118, 126))	('Krebs cycle', 'biological_process', 'GO:0006099', ('103', '114'))	('TCA cycle', 'biological_process', 'GO:0006099', ('92', '101'))	('signaling', 'biological_process', 'GO:0023052', ('13', '22'))	('hsa04976', 'Var', (160, 168))	("Parkinson's disease", 'Disease', (47, 66))	('citrate', 'Chemical', 'MESH:D019343', (77, 84))	('Krebs', 'Chemical', '-', (103, 108))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('128', '153'))	("Parkinson's disease", 'Disease', 'MESH:D010300', (47, 66))	('M00009', 'Var', (69, 75))	('secretion', 'biological_process', 'GO:0046903', ('175', '184'))
140952	32461965	As a metabolic disease, many mutated genes, such as VHL, fumarate hydratase (FH), and succinate dehydrogenase (SDH), are involved in cellular respiration and energy metabolism.	('VHL', 'Gene', '7428', (52, 55))	('fumarate hydratase', 'Gene', (57, 75))	('SDH', 'Gene', '6390', (111, 114))	('succinate dehydrogenase', 'Gene', (86, 109))	('succinate dehydrogenase', 'Gene', '6390', (86, 109))	('involved', 'Reg', (121, 129))	('FH', 'Gene', '2271', (77, 79))	('mutated', 'Var', (29, 36))	('metabolism', 'biological_process', 'GO:0008152', ('165', '175'))	('cellular respiration', 'biological_process', 'GO:0045333', ('133', '153'))	('SDH', 'Gene', (111, 114))	('VHL', 'Gene', (52, 55))	('fumarate hydratase', 'Gene', '2271', (57, 75))
140953	32461965	HIF-1-induced genetic reprogramming promotes a classic Warburg phenotype in RCC through VHL or mechanisms dependent on metabolic enzymes.	('HIF-1', 'Gene', (0, 5))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('VHL', 'Gene', (88, 91))	('genetic', 'Var', (14, 21))	('HIF-1', 'Gene', '3091', (0, 5))	('classic Warburg', 'MPA', (47, 62))	('promotes', 'PosReg', (36, 44))
140955	32461965	The loss of VHL leads to a HIF-1-dependent reprogramming of energy metabolism that includes elevated glucose uptake, glycolysis, and lactate production accompanied by a reciprocal decrease in respiration under aerobic conditions.	('elevated glucose', 'Phenotype', 'HP:0003074', (92, 108))	('HIF-1', 'Gene', (27, 32))	('elevated', 'PosReg', (92, 100))	('glycolysis', 'biological_process', 'GO:0006096', ('117', '127'))	('HIF-1', 'Gene', '29072', (27, 32))	('glycolysis', 'MPA', (117, 127))	('decrease', 'NegReg', (180, 188))	('VHL', 'Gene', (12, 15))	('glucose uptake', 'MPA', (101, 115))	('glucose uptake', 'biological_process', 'GO:0046323', ('101', '115'))	('respiration', 'biological_process', 'GO:0007585', ('192', '203'))	('metabolism', 'biological_process', 'GO:0008152', ('67', '77'))	('glucose', 'Chemical', 'MESH:D005947', (101, 108))	('lactate', 'Chemical', 'MESH:D019344', (133, 140))	('respiration', 'biological_process', 'GO:0045333', ('192', '203'))	('reprogramming of energy metabolism', 'MPA', (43, 77))	('loss', 'Var', (4, 8))	('VHL', 'Gene', '7428', (12, 15))	('respiration under aerobic conditions', 'MPA', (192, 228))	('lactate production', 'MPA', (133, 151))
141015	28165361	Mutations affecting hypoxia inducible factor (HIF), succinate dehydrogenase and fumarate hydratase are known to alter cellular metabolism and contribute to cellular growth.	('cellular growth', 'CPA', (156, 171))	('alter', 'Reg', (112, 117))	('cellular metabolism', 'biological_process', 'GO:0044237', ('118', '137'))	('cellular metabolism', 'MPA', (118, 137))	('Mutations', 'Var', (0, 9))	('fumarate hydratase', 'Gene', '2271', (80, 98))	('hypoxia', 'Disease', (20, 27))	('hypoxia', 'Disease', 'MESH:D000860', (20, 27))	('cellular growth', 'biological_process', 'GO:0016049', ('156', '171'))	('fumarate hydratase', 'Gene', (80, 98))	('succinate', 'Chemical', 'MESH:D019802', (52, 61))	('contribute', 'Reg', (142, 152))
141068	28165361	The inactivation or loss of the VHL tumour suppressor is the main molecular trigger for altered metabolism in ccRCC.	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('metabolism', 'biological_process', 'GO:0008152', ('96', '106'))	('inactivation', 'Var', (4, 16))	('metabolism', 'MPA', (96, 106))	('loss of the VHL tumour', 'Disease', 'MESH:D006623', (20, 42))	('loss of the VHL tumour', 'Disease', (20, 42))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('altered', 'Reg', (88, 95))
141071	28165361	With the loss of VHL in ccRCC, hydroxylated HIF-alpha "escapes" degradation, becomes stabilized and translocates to the nucleus where it dimerizes with HIF-beta.	('nucleus', 'cellular_component', 'GO:0005634', ('118', '125'))	('degradation', 'biological_process', 'GO:0009056', ('62', '73'))	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('loss', 'Var', (9, 13))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('VHL', 'Gene', (17, 20))	('degradation', 'MPA', (64, 75))	('HIF-beta', 'Disease', (152, 160))	('VHL', 'Gene', '7428', (17, 20))	('HIF-beta', 'Disease', 'MESH:D012497', (152, 160))
141075	28165361	Cross-platform molecular analyses of mRNA, miRNA, DNA methylation and protein conducted on ccRCC nephrectomy samples have shown that alteration in molecular metabolism, which stem from the diversion of intermediates towards pentose phosphate pathway, downregulated Krebs cycle enzymes and reduced AMPK along with the upregulation of glutamine flux was associated with unfavorable prognostic outcome in ccRCC patients.	('Krebs cycle enzymes', 'Enzyme', (265, 284))	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('AMPK', 'molecular_function', 'GO:0050405', ('297', '301'))	('RCC', 'Disease', (93, 96))	('reduced', 'NegReg', (289, 296))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('alteration', 'Var', (133, 143))	('RCC', 'Disease', 'MESH:C538614', (404, 407))	('glutamine flux', 'MPA', (333, 347))	('Krebs cycle', 'biological_process', 'GO:0006099', ('265', '276'))	('molecular metabolism', 'MPA', (147, 167))	('upregulation', 'PosReg', (317, 329))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('AMPK', 'molecular_function', 'GO:0004691', ('297', '301'))	('AMPK', 'Gene', (297, 301))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('224', '249'))	('patients', 'Species', '9606', (408, 416))	('Krebs', 'Chemical', '-', (265, 270))	('pentose phosphate', 'Chemical', 'MESH:D010428', (224, 241))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('metabolism', 'biological_process', 'GO:0008152', ('157', '167'))	('AMPK', 'molecular_function', 'GO:0047322', ('297', '301'))	('glutamine', 'Chemical', 'MESH:D005973', (333, 342))	('AMPK', 'Gene', '5562', (297, 301))	('RCC', 'Disease', (404, 407))	('RCC', 'Phenotype', 'HP:0005584', (404, 407))	('downregulated', 'NegReg', (251, 264))	('DNA methylation', 'biological_process', 'GO:0006306', ('50', '65'))
141099	28165361	The filtrates (volume ranging from 100-150 muL) were then transferred to clean microcentrifuge tubes and the final volume brought to 400 muL by the addition of 80 muL of phosphate buffer (0.5 M NaH2PO4 buffer solution at pH 7.0) containing 2.5 mM 2,2-dimethyl-2- silapentane-5-sulfonate (DSS, final concentration 0.5 mM), 10 muL of 1M sodium azide to prevent bacterial growth, and D2O.	('bacterial growth', 'CPA', (359, 375))	('phosphate', 'Chemical', 'MESH:D010710', (170, 179))	('D2O', 'Chemical', 'MESH:D017666', (381, 384))	('NaH2PO4', 'Chemical', 'MESH:C018279', (194, 201))	('sodium azide', 'Chemical', 'MESH:D019810', (335, 347))	('D2O', 'Var', (381, 384))	('2,2-dimethyl-2- silapentane-5-sulfonate', 'Chemical', 'MESH:C009580', (247, 286))	('DSS', 'Chemical', 'MESH:C009580', (288, 291))
141130	32316112	The ancestral disparities in Ov-CCA prevalence suggests the presence of Ov-CCA-specific genetic alterations and may provide an opportunity to identify the novel genes associated with Ov-CCA tumorigenesis.	('Ov-CCA', 'Disease', (29, 35))	('Ov-CCA', 'Disease', (183, 189))	('alterations', 'Var', (96, 107))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('Ov-CCA', 'Phenotype', 'HP:0031522', (72, 78))	('Ov-CCA', 'Phenotype', 'HP:0031522', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('Ov-CCA', 'Phenotype', 'HP:0031522', (183, 189))	('tumor', 'Disease', (190, 195))	('Ov-CCA-specific', 'Disease', (72, 87))
141131	32316112	Four single-nucleotide polymorphisms (SNPs) (rs4873815, rs12976454, rs11136002, and rs13259097) that had different allele frequencies in the Japanese ancestry and seven genes associated in cis (APBA3, C8orf58, KIAA1967, NAPRT1, RHOBTB2, TNFRSF10B, and ZNF707) were identified.	('rs4873815', 'Mutation', 'rs4873815', (45, 54))	('rs4873815', 'Var', (45, 54))	('APBA3', 'Gene', (194, 199))	('rs13259097', 'Var', (84, 94))	('APBA3', 'Gene', '9546', (194, 199))	('rs12976454', 'Var', (56, 66))	('KIAA1967', 'Gene', (210, 218))	('NAPRT1', 'Gene', '93100', (220, 226))	('NAPRT1', 'Gene', (220, 226))	('RHOBTB2', 'Gene', (228, 235))	('TNFRSF10B', 'Gene', (237, 246))	('rs13259097', 'Mutation', 'rs13259097', (84, 94))	('KIAA1967', 'Gene', '57805', (210, 218))	('TNFRSF10B', 'Gene', '8795', (237, 246))	('C8orf58', 'Gene', '541565', (201, 208))	('ZNF707', 'Gene', '286075', (252, 258))	('rs12976454', 'Mutation', 'rs12976454', (56, 66))	('ZNF707', 'Gene', (252, 258))	('C8orf58', 'Gene', (201, 208))	('RHOBTB2', 'Gene', '23221', (228, 235))	('rs11136002', 'Var', (68, 78))	('rs11136002', 'Mutation', 'rs11136002', (68, 78))
141132	32316112	In silico functional annotation analysis and in vitro promoter assay validated the regulatory effect of rs4873815-TT on ZNF707 and rs11136002-TT on TNFRSF10B.	('ZNF707', 'Gene', '286075', (120, 126))	('rs4873815', 'Mutation', 'rs4873815', (104, 113))	('rs11136002-TT', 'Var', (131, 144))	('TNFRSF10B', 'Gene', (148, 157))	('rs11136002', 'Mutation', 'rs11136002', (131, 141))	('ZNF707', 'Gene', (120, 126))	('rs4873815-TT', 'Var', (104, 116))	('TNFRSF10B', 'Gene', '8795', (148, 157))
141137	32316112	Identifying causal variants located outside of the protein coding region is an ingenious and perceptive way to discover the genetic landscape of complex diseases, including cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('variants', 'Var', (19, 27))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
141146	32316112	Four SNPs (rs4873815, rs12976454, rs11136002, and rs13259097) fit these criteria (Figure 1B).	('rs4873815', 'Mutation', 'rs4873815', (11, 20))	('rs11136002', 'Mutation', 'rs11136002', (34, 44))	('rs12976454', 'Var', (22, 32))	('rs12976454', 'Mutation', 'rs12976454', (22, 32))	('rs13259097', 'Mutation', 'rs13259097', (50, 60))	('rs4873815', 'Var', (11, 20))	('rs11136002', 'Var', (34, 44))	('rs13259097', 'Var', (50, 60))
141149	32316112	In addition, because rs11136002 was associated in cis with four genes among the seven identified genes, rs11136002/TNFRSF10B was also selected for promoter assay as representative.	('rs11136002', 'Mutation', 'rs11136002', (21, 31))	('rs11136002', 'Mutation', 'rs11136002', (104, 114))	('TNFRSF10B', 'Gene', (115, 124))	('rs11136002', 'Var', (21, 31))	('TNFRSF10B', 'Gene', '8795', (115, 124))
141150	32316112	In the multistep eQTL analysis of this study, alleles TT of rs4873815 and rs11136002 were most frequently expressed in Japanese ancestry.	('rs4873815', 'Mutation', 'rs4873815', (60, 69))	('rs11136002', 'Mutation', 'rs11136002', (74, 84))	('rs11136002', 'Var', (74, 84))	('rs4873815', 'Var', (60, 69))
141151	32316112	Accordingly, promoter assay was performed with the alleles TT of rs4873815 and rs11136002, which were expected to have regulatory effects on ZNF707 and TNFRSF10B, respectively.	('rs11136002', 'Mutation', 'rs11136002', (79, 89))	('ZNF707', 'Gene', '286075', (141, 147))	('TNFRSF10B', 'Gene', (152, 161))	('rs4873815', 'Var', (65, 74))	('rs11136002', 'Var', (79, 89))	('TNFRSF10B', 'Gene', '8795', (152, 161))	('rs4873815', 'Mutation', 'rs4873815', (65, 74))	('ZNF707', 'Gene', (141, 147))
141154	32316112	We conducted dual-luciferase reporter assays to investigate whether the promoter activity of ZNF707 and TNFRSF10B was regulated by rs4873815 and rs11136002, respectively.	('promoter activity', 'MPA', (72, 89))	('rs4873815', 'Mutation', 'rs4873815', (131, 140))	('rs11136002', 'Var', (145, 155))	('regulated', 'Reg', (118, 127))	('ZNF707', 'Gene', (93, 99))	('TNFRSF10B', 'Gene', (104, 113))	('rs11136002', 'Mutation', 'rs11136002', (145, 155))	('ZNF707', 'Gene', '286075', (93, 99))	('rs4873815', 'Var', (131, 140))	('TNFRSF10B', 'Gene', '8795', (104, 113))
141157	32316112	About 500 base pairs around the SNP region in rs11136002 and rs4873815 were amplified by PCR with genomic DNA isolated from the RMG-2 ovarian clear cell carcinoma cell line.	('rs4873815', 'Var', (61, 70))	('RMG-2 ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (128, 162))	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('rs4873815', 'Mutation', 'rs4873815', (61, 70))	('rs11136002', 'Var', (46, 56))	('rs11136002', 'Mutation', 'rs11136002', (46, 56))	('RMG-2 ovarian clear cell carcinoma', 'Disease', (128, 162))
141160	32316112	Each primer used for PCR reactions (described above) were used for sequencing of rs11136002 and rs4873815 genes.	('rs11136002', 'Var', (81, 91))	('rs4873815', 'Var', (96, 105))	('rs11136002', 'Mutation', 'rs11136002', (81, 91))	('rs4873815', 'Mutation', 'rs4873815', (96, 105))
141170	32316112	Of the 935 identified cis-eQTLs, four SNPs (rs4873815, rs12976454, rs11136002, and rs13259097) had significantly different frequencies of alternative alleles among CEU, CHB, and JPT populations (x2 = 61.79, 108.50, 47.21, and 36.87, all of p < 0.001, respectively) (Figure 1B).	('rs12976454', 'Mutation', 'rs12976454', (55, 65))	('rs4873815', 'Var', (44, 53))	('rs11136002', 'Var', (67, 77))	('rs13259097', 'Mutation', 'rs13259097', (83, 93))	('CHB', 'Disease', (169, 172))	('eQTLs', 'Disease', 'None', (26, 31))	('rs4873815', 'Mutation', 'rs4873815', (44, 53))	('rs13259097', 'Var', (83, 93))	('eQTLs', 'Disease', (26, 31))	('rs11136002', 'Mutation', 'rs11136002', (67, 77))	('CHB', 'Disease', 'None', (169, 172))	('rs12976454', 'Var', (55, 65))
141172	32316112	As shown in Table 1, rs4873815 was located on chromosome 8q24.3 and identified as a cis-eQTL for genes ZNF707 (p = 8.92e-4) and NAPRT1 (p = 4.41e-4).	('ZNF707', 'Gene', (103, 109))	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('rs4873815', 'Var', (21, 30))	('ZNF707', 'Gene', '286075', (103, 109))	('NAPRT1', 'Gene', '93100', (128, 134))	('NAPRT1', 'Gene', (128, 134))	('rs4873815', 'Mutation', 'rs4873815', (21, 30))
141173	32316112	rs11136002 was located on chromosome 8p21.3 and identified as a cis-eQTL for C8orf58 (p = 5.53e-4), KIAA1967 (p = 9.19e-4), RHOBTB2 (p = 3.12e-4), and TNFRSF10B (p = 4.03e-4).	('rs11136002', 'Var', (0, 10))	('rs11136002', 'Mutation', 'rs11136002', (0, 10))	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('TNFRSF10B', 'Gene', (151, 160))	('RHOBTB2', 'Gene', '23221', (124, 131))	('RHOBTB2', 'Gene', (124, 131))	('KIAA1967', 'Gene', '57805', (100, 108))	('TNFRSF10B', 'Gene', '8795', (151, 160))	('C8orf58', 'Gene', (77, 84))	('C8orf58', 'Gene', '541565', (77, 84))	('KIAA1967', 'Gene', (100, 108))
141174	32316112	rs12976454 was located on chromosome 19p13.3 and identified as a cis-eQTL for APBA3 (p = 3.40e-4).	('APBA3', 'Gene', '9546', (78, 83))	('rs12976454', 'Mutation', 'rs12976454', (0, 10))	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('rs12976454', 'Var', (0, 10))	('APBA3', 'Gene', (78, 83))
141175	32316112	rs13259097 was located on chromosome 8p21.3 and identified as a cis-eQTL for RHOBTB2 (p = 3.87e-4).	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('rs13259097', 'Var', (0, 10))	('RHOBTB2', 'Gene', '23221', (77, 84))	('RHOBTB2', 'Gene', (77, 84))	('rs13259097', 'Mutation', 'rs13259097', (0, 10))
141178	32316112	As shown in Figure S1, rs4873815 had a 12.08 CADD Phred score and 0.627 LoFtool score for the ZNF623 gene located near the ZNF707 gene, indicating that it is a possibly deleterious and phenotypically functional variant in an individual.	('ZNF707', 'Gene', '286075', (123, 129))	('ZNF623', 'Gene', (94, 100))	('ZNF623', 'Gene', '9831', (94, 100))	('rs4873815', 'Mutation', 'rs4873815', (23, 32))	('ZNF707', 'Gene', (123, 129))	('rs4873815', 'Var', (23, 32))
141179	32316112	In addition, because rs11136002 was associated in cis with four genes among seven identified genes, rs11136002/TNFRSF10B was selected for the promoter assay as representative.	('rs11136002', 'Mutation', 'rs11136002', (21, 31))	('rs11136002', 'Mutation', 'rs11136002', (100, 110))	('TNFRSF10B', 'Gene', (111, 120))	('rs11136002', 'Var', (21, 31))	('TNFRSF10B', 'Gene', '8795', (111, 120))
141180	32316112	To verify whether identified susceptibility loci affect promoter activity of associate genes, luciferase reporter assays were performed in HEK293T cells using rs4873815 and its candidate gene ZNF707 or rs11136002 and TNFRSF10B.	('rs11136002', 'Var', (202, 212))	('TNFRSF10B', 'Gene', (217, 226))	('affect', 'Reg', (49, 55))	('rs11136002', 'Mutation', 'rs11136002', (202, 212))	('ZNF707', 'Gene', '286075', (192, 198))	('HEK293T', 'CellLine', 'CVCL:0063', (139, 146))	('rs4873815', 'Mutation', 'rs4873815', (159, 168))	('rs4873815', 'Var', (159, 168))	('TNFRSF10B', 'Gene', '8795', (217, 226))	('ZNF707', 'Gene', (192, 198))	('promoter activity', 'MPA', (56, 73))
141181	32316112	As shown in Figure 2, transcriptional activity with the T allele of rs4873815 (rs4873815-TT), which showed a high frequency in JPT, was significantly higher than that with the C allele of rs4873815 (rs4873815-CC, high frequency in CEU) of ZNF707 (p < 0.01).	('higher', 'PosReg', (150, 156))	('rs4873815', 'Var', (68, 77))	('rs4873815', 'Mutation', 'rs4873815', (199, 208))	('rs4873815', 'Mutation', 'rs4873815', (188, 197))	('ZNF707', 'Gene', (239, 245))	('transcriptional activity', 'MPA', (22, 46))	('rs4873815', 'Mutation', 'rs4873815', (68, 77))	('rs4873815', 'Mutation', 'rs4873815', (79, 88))	('ZNF707', 'Gene', '286075', (239, 245))
141182	32316112	Moreover, rs11136002-TT (high frequency in JPT) increased the transcriptional activity of TNFRSF10B compared to CC (high frequency in CEU) (p < 0.05).	('increased', 'PosReg', (48, 57))	('TNFRSF10B', 'Gene', '8795', (90, 99))	('transcriptional activity', 'MPA', (62, 86))	('rs11136002', 'Mutation', 'rs11136002', (10, 20))	('TNFRSF10B', 'Gene', (90, 99))	('rs11136002-TT', 'Var', (10, 23))
141183	32316112	This significantly increased transcriptional activity demonstrates that TT, which showed a high frequency in JPT in both rs4873815 and rs11136002, may induce the expression of ZNF707 or TNFRSF10B, respectively, by regulating promoter activity.	('regulating', 'Reg', (214, 224))	('promoter activity', 'MPA', (225, 242))	('ZNF707', 'Gene', (176, 182))	('rs4873815', 'Mutation', 'rs4873815', (121, 130))	('rs11136002', 'Var', (135, 145))	('JPT', 'Gene', (109, 112))	('induce', 'PosReg', (151, 157))	('transcriptional', 'MPA', (29, 44))	('rs11136002', 'Mutation', 'rs11136002', (135, 145))	('ZNF707', 'Gene', '286075', (176, 182))	('TNFRSF10B', 'Gene', (186, 195))	('increased', 'PosReg', (19, 28))	('rs4873815', 'Var', (121, 130))	('expression', 'MPA', (162, 172))	('TNFRSF10B', 'Gene', '8795', (186, 195))
141192	32316112	Through multistep cis-eQTL analyses using HapMap3 dataset, four SNPs (rs4873815, rs12976454, rs11136002, and rs13259097) and seven associated genes (APBA3, C8orf58, KIAA1967, NAPRT1, RHOBTB2, TNFRSF10B, and ZNF707) were identified by differences in disease prevalence of Japanese ancestry.	('rs12976454', 'Var', (81, 91))	('RHOBTB2', 'Gene', (183, 190))	('TNFRSF10B', 'Gene', (192, 201))	('rs13259097', 'Var', (109, 119))	('KIAA1967', 'Gene', '57805', (165, 173))	('ZNF707', 'Gene', '286075', (207, 213))	('TNFRSF10B', 'Gene', '8795', (192, 201))	('C8orf58', 'Gene', '541565', (156, 163))	('ZNF707', 'Gene', (207, 213))	('rs13259097', 'Mutation', 'rs13259097', (109, 119))	('rs12976454', 'Mutation', 'rs12976454', (81, 91))	('RHOBTB2', 'Gene', '23221', (183, 190))	('C8orf58', 'Gene', (156, 163))	('NAPRT1', 'Gene', '93100', (175, 181))	('rs4873815', 'Mutation', 'rs4873815', (70, 79))	('NAPRT1', 'Gene', (175, 181))	('rs11136002', 'Var', (93, 103))	('APBA3', 'Gene', (149, 154))	('rs11136002', 'Mutation', 'rs11136002', (93, 103))	('APBA3', 'Gene', '9546', (149, 154))	('rs4873815', 'Var', (70, 79))	('KIAA1967', 'Gene', (165, 173))
141194	32316112	rs4873815-TT, which demonstrated enrichment in the Japanese ancestry compared to European and Chinese ancestries, induced promoter activity on ZNF707 compared to rs4873815-CC.	('rs4873815', 'Mutation', 'rs4873815', (162, 171))	('ZNF707', 'Gene', '286075', (143, 149))	('rs4873815-TT', 'Var', (0, 12))	('promoter activity', 'MPA', (122, 139))	('rs4873815', 'Mutation', 'rs4873815', (0, 9))	('ZNF707', 'Gene', (143, 149))
141195	32316112	In addition, rs11136002-TT, which was also enriched in the Japanese ancestry in comparison to the others, induced more promoter activity on the TNFRSF10B gene in comparison to rs11136002-CC.	('TNFRSF10B', 'Gene', (144, 153))	('more', 'PosReg', (114, 118))	('rs11136002', 'Mutation', 'rs11136002', (176, 186))	('TNFRSF10B', 'Gene', '8795', (144, 153))	('promoter activity', 'MPA', (119, 136))	('rs11136002-TT', 'Var', (13, 26))	('rs11136002', 'Mutation', 'rs11136002', (13, 23))
141198	32316112	In survival analyses of our Ov-CCA cohort, only high expression of ZNF707 was associated with poor prognosis in Ov-CCA disease recurrence.	('Ov-CCA', 'Phenotype', 'HP:0031522', (28, 34))	('ZNF707', 'Gene', (67, 73))	('Ov-CCA disease', 'Disease', (112, 126))	('high expression', 'Var', (48, 63))	('Ov-CCA', 'Phenotype', 'HP:0031522', (112, 118))	('ZNF707', 'Gene', '286075', (67, 73))	('Ov-CCA disease', 'Disease', 'MESH:C536211', (112, 126))
141201	32316112	Moreover, high expression of ZNF707 may have prognostic power in clear cell histology regardless of tissue origin.	('ZNF707', 'Gene', (29, 35))	('clear cell histology', 'Disease', (65, 85))	('high', 'Var', (10, 14))	('ZNF707', 'Gene', '286075', (29, 35))	('prognostic', 'Reg', (45, 55))
141203	32316112	reported that ZNF707 is hypermethylated in ovarian endometrioma in comparison to eutopic endometrium (fold: 1.884).	('ZNF707', 'Gene', (14, 20))	('ovarian endometrioma', 'Disease', (43, 63))	('ovarian endometrioma', 'Disease', 'MESH:D004715', (43, 63))	('ZNF707', 'Gene', '286075', (14, 20))	('hypermethylated', 'Var', (24, 39))
141209	32316112	Several polymorphisms and mutations of the TRAIL and TRAIL receptor genes have been suggested as risk or prognostic factors in lymphoid malignancies as well as breast, colon, liver, lung, and prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (192, 207))	('lymphoid malignancies', 'Phenotype', 'HP:0002665', (127, 148))	('lung', 'Disease', (182, 186))	('TRAIL', 'Gene', (43, 48))	('prostate cancer', 'Disease', 'MESH:D011471', (192, 207))	('colon', 'Disease', (168, 173))	('liver', 'Disease', (175, 180))	('mutations', 'Var', (26, 35))	('breast', 'Disease', (160, 166))	('prostate cancer', 'Disease', (192, 207))	('TRAIL', 'Gene', '8743', (53, 58))	('TRAIL', 'Gene', '8743', (43, 48))	('lymphoid malignancies', 'Disease', 'MESH:D008223', (127, 148))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('lymphoid malignancies', 'Disease', (127, 148))	('TRAIL', 'Gene', (53, 58))	('polymorphisms', 'Var', (8, 21))
141210	32316112	Specifically, loss of TNFRSF10B expression is a frequent event in hepatocellular carcinoma (HCC) and lung and testicular cancers.	('loss', 'Var', (14, 18))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (66, 90))	('testicular cancers', 'Disease', 'MESH:D013736', (110, 128))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('hepatocellular carcinoma', 'Disease', (66, 90))	('TNFRSF10B', 'Gene', '8795', (22, 31))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (66, 90))	('testicular cancers', 'Phenotype', 'HP:0010788', (110, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('lung', 'Disease', (101, 105))	('HCC', 'Phenotype', 'HP:0001402', (92, 95))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('testicular cancers', 'Disease', (110, 128))	('TNFRSF10B', 'Gene', (22, 31))
141213	32316112	In addition, APBA3 promotes aerobic glycolysis by activating hypoxia-inducible factor 1 (HIF-1) in macrophages; therefore, inhibition of APBA3 in macrophages contributes to suppression of cancer cell metastasis.	('APBA3', 'Gene', (137, 142))	('HIF-1', 'Gene', (89, 94))	('promotes', 'PosReg', (19, 27))	('APBA3', 'Gene', (13, 18))	('hypoxia-inducible factor 1', 'Gene', (61, 87))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('inhibition', 'Var', (123, 133))	('APBA3', 'Gene', '9546', (137, 142))	('hypoxia-inducible factor 1', 'Gene', '3091', (61, 87))	('APBA3', 'Gene', '9546', (13, 18))	('glycolysis', 'biological_process', 'GO:0006096', ('36', '46'))	('suppression', 'NegReg', (173, 184))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('HIF-1', 'Gene', '3091', (89, 94))	('cancer', 'Disease', (188, 194))	('activating', 'Reg', (50, 60))	('aerobic glycolysis', 'MPA', (28, 46))
141223	32316112	This study suggests that cis-eQTL analysis using publicly available datasets may facilitate the discovery of novel genetic alterations in Ov-CCA and provide the basis for understanding its tumorigenesis.	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('Ov-CCA', 'Phenotype', 'HP:0031522', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('Ov-CCA', 'Disease', (138, 144))	('alterations', 'Var', (123, 134))
141329	32218839	KM survival curves indicated that GLDC may inhibit tumor development and ENO2 may promote tumor progression (Fig.	('GLDC', 'Var', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('promote', 'PosReg', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (51, 56))	('inhibit', 'NegReg', (43, 50))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('ENO2', 'Gene', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
141331	32218839	Analyses of ENO2 revealed that high expression levels of ENO2 was associated with poor prognosis (GEPIA, P=0.02; UCSC Xena, P=0.01375).	('si', 'Chemical', 'MESH:D012825', (93, 95))	('ENO2', 'Gene', (57, 61))	('high', 'Var', (31, 35))	('si', 'Chemical', 'MESH:D012825', (42, 44))	('UCSC Xena', 'Disease', (113, 122))
141339	32218839	saRNA was used to induce GLDC overexpression in 786-O cells and siRNA was used to knockdown ENO2 expression (Fig.	('ENO2', 'Gene', (92, 96))	('knockdown', 'Var', (82, 91))	('si', 'Chemical', 'MESH:D012825', (40, 42))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('sa', 'Chemical', 'MESH:C012546', (0, 2))
141342	32218839	The number of apoptotic 786-O cells was increased in sa-GLDC-786-O cells and si-ENO2-786-O cells compared to control group (Fig.	('si', 'Chemical', 'MESH:D012825', (77, 79))	('sa', 'Chemical', 'MESH:C012546', (53, 55))	('apoptotic 786-O cells', 'CPA', (14, 35))	('increased', 'PosReg', (40, 49))	('sa-GLDC-786-O cells', 'Var', (53, 72))
141348	32218839	The reasons for this may be the activation of one or more proto-oncogenes and mutations of or deletions in tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('activation', 'PosReg', (32, 42))	('mutations', 'Var', (78, 87))	('deletions', 'Var', (94, 103))	('tumor suppressor', 'biological_process', 'GO:0051726', ('107', '123'))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('107', '123'))
141368	32218839	In gastric cancer, GLDC promoter hypermethylation regulates transcriptional silencing inhibiting tumor development, whereas GLDC was reported as a putative tumor suppressor gene involved in tumor progression.	('GLDC', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('156', '172'))	('tumor', 'Disease', (156, 161))	('promoter hypermethylation', 'Var', (24, 49))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('transcriptional silencing', 'MPA', (60, 85))	('tumor suppressor', 'biological_process', 'GO:0051726', ('156', '172'))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (190, 195))	('gastric cancer', 'Disease', (3, 17))	('si', 'Chemical', 'MESH:D012825', (203, 205))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('inhibiting', 'NegReg', (86, 96))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
141377	32218839	The mechanism of ENO2 was initially demonstrated in the present study, also demonstrating that high ENO2 expression may be a promising prognostic and diagnostic marker for patients with RCC.	('si', 'Chemical', 'MESH:D012825', (111, 113))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('high', 'Var', (95, 99))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('RCC', 'Disease', (186, 189))	('ENO2', 'Gene', (100, 104))	('patients', 'Species', '9606', (172, 180))	('expression', 'MPA', (105, 115))
141378	32218839	DEGs are candidate diagnostic markers of RCC, with some well-established genes, such as EGFR and VEGF already associated with this disease.	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('EGFR', 'molecular_function', 'GO:0005006', ('88', '92'))	('VEGF', 'Gene', (97, 101))	('associated', 'Reg', (110, 120))	('EGFR', 'Gene', '1956', (88, 92))	('VEGF', 'Gene', '7422', (97, 101))	('DEGs', 'Var', (0, 4))	('RCC', 'Disease', (41, 44))	('EGFR', 'Gene', (88, 92))
141383	32218839	UMOD gene is associated with more aggressive clinical and pathological characteristics in RCC.	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('UMOD', 'Gene', (0, 4))	('UMOD', 'Gene', '7369', (0, 4))	('si', 'Chemical', 'MESH:D012825', (40, 42))	('gene', 'Var', (5, 9))	('RCC', 'Disease', (90, 93))
141399	32021423	The statistical results indicated that patients with total piecemeal spondylectomy (TPS), targeted therapy, NLR < 3.8 and PLR < 206.9 had a significantly longer OS rate.	('targeted therapy', 'Var', (90, 106))	('OS rate', 'CPA', (161, 168))	('longer', 'PosReg', (154, 160))	('patients', 'Species', '9606', (39, 47))	('PLR < 206.9', 'Var', (122, 133))	('NLR < 3.8', 'Var', (108, 117))
141447	32021423	However, statistical analysis revealed that TPS could prolong the OS of patients compared with TES.	('prolong', 'PosReg', (54, 61))	('TPS', 'Var', (44, 47))	('patients', 'Species', '9606', (72, 80))
141448	32021423	With the development of targeted agents that inhibit the vascular endothelial grow factor (VEGF) and the mammalian target of rapamycin (mTOR) signal transduction pathways (7, 8), patients administered with targeted therapy had longer OS than those without it.	('targeted therapy', 'Var', (206, 222))	('VEGF', 'Gene', '7422', (91, 95))	('signal transduction', 'biological_process', 'GO:0007165', ('142', '161'))	('vascular endothelial grow factor', 'Gene', (57, 89))	('longer', 'PosReg', (227, 233))	('mTOR', 'Gene', '2475', (136, 140))	('vascular endothelial grow factor', 'Gene', '7422', (57, 89))	('VEGF', 'Gene', (91, 95))	('patients', 'Species', '9606', (179, 187))	('mTOR', 'Gene', (136, 140))	('inhibit', 'NegReg', (45, 52))	('mammalian target of rapamycin', 'Gene', '2475', (105, 134))	('mammalian target of rapamycin', 'Gene', (105, 134))
141491	33711273	Whole-exome sequencing (WES) data generated from tumor and adjacent normal tissue DNA revealed the detection of genomic alterations typical for ccRCC, including >90% of tumors with loss of regions of chromosome 3p and >60% with mutations in VHL (Figure 1B).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('chromosome', 'cellular_component', 'GO:0005694', ('200', '210'))	('regions of chromosome 3p', 'Protein', (189, 213))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (49, 54))	('mutations', 'Var', (228, 237))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('ccRCC', 'Disease', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Disease', (169, 174))	('VHL', 'Gene', (241, 244))	('loss', 'NegReg', (181, 185))	('tumors', 'Disease', (169, 175))	('VHL', 'Gene', '7428', (241, 244))
141506	33711273	The first group (two clusters) expressed CD69 and CD40LG/CD40L, consistent with an activated phenotype.	('CD40LG', 'Gene', '959', (50, 56))	('CD69', 'Var', (41, 45))	('CD40LG', 'Gene', (50, 56))	('CD40L', 'Gene', '959', (57, 62))	('CD40L', 'Gene', '959', (50, 55))	('CD40L', 'Gene', (57, 62))	('CD40L', 'Gene', (50, 55))
141556	33711273	The final group contained a cluster of proliferating cells of mixed lineage (high MKI67 and TOP2A expression) and a cluster with low expression of most marker genes.	('MKI67', 'Gene', (82, 87))	('MKI67', 'Gene', '4288', (82, 87))	('high', 'Var', (77, 81))	('TOP2A', 'Gene', '7153', (92, 97))	('TOP2A', 'Gene', (92, 97))	('expression', 'MPA', (98, 108))
141561	33711273	The resulting trajectory begins with classical monocytes (expressing CD14), and then bifurcates to a non-classical monocyte population on one side (expressing FCGR3A/CD16) and a macrophage population on the other side (expressing, for example, the macrophage scavenger receptor MSR1/CD204).	('CD204', 'Gene', '4481', (283, 288))	('CD204', 'Gene', (283, 288))	('MSR1', 'Gene', (278, 282))	('FCGR3A', 'Gene', (159, 165))	('CD14', 'Var', (69, 73))	('FCGR3A', 'Gene', '2214', (159, 165))	('MSR1', 'Gene', '4481', (278, 282))
141586	33711273	We confirmed the presence of terminally exhausted CD8+ T cells (expressing CD8, CD137/4-1BB, PD-1, and TIM-3, and lacking expression of CD4 or KI-67, matching the phenotype from our scRNA-seq analysis; Figure S7A) and M2-like macrophages (expressing high levels of CD163; Figure S7B).	('CD8', 'Gene', (50, 53))	('TIM-3', 'Gene', (103, 108))	('CD137', 'Gene', (80, 85))	('CD8', 'Gene', '925', (75, 78))	('CD8', 'Gene', '925', (50, 53))	('CD4', 'Gene', '920', (136, 139))	('TIM-3', 'Gene', '84868', (103, 108))	('CD137', 'Gene', '3604', (80, 85))	('CD163', 'Gene', '9332', (265, 270))	('CD163', 'Gene', (265, 270))	('PD-1', 'Var', (93, 97))	('CD8', 'Gene', (75, 78))	('CD4', 'Gene', (136, 139))
141639	33711273	For mutation analysis, we performed a comparative analysis of whole-exome sequencing data of tumor and matched germline samples using the Mutect2 tool in GATK4 (v2.7.0) to identify somatic mutations, insertions and deletions in patients.	('v2.7', 'Gene', '28803', (161, 165))	('deletions', 'Var', (215, 224))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('patients', 'Species', '9606', (228, 236))	('tumor', 'Disease', (93, 98))	('insertions', 'Var', (200, 210))	('mutations', 'Var', (189, 198))	('v2.7', 'Gene', (161, 165))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
141641	33711273	Significantly recurrent mutations in the cohort were identified using the MutSig2CV tool (v1.3) using a nominal p-value threshold of 0.05.	('v1.3', 'Gene', (90, 94))	('mutations', 'Var', (24, 33))	('v1.3', 'Gene', '28816', (90, 94))
141677	33711273	The anti-CD163 (1:7,500, EPR19518 rabbit monoclonal antibody, Abcam) was detected using the Alexa 555 fluorophore (1:100, FITC).	('antibody', 'cellular_component', 'GO:0042571', ('52', '60'))	('antibody', 'cellular_component', 'GO:0019815', ('52', '60'))	('CD163', 'Gene', '9332', (9, 14))	('antibody', 'cellular_component', 'GO:0019814', ('52', '60'))	('FITC', 'Chemical', 'MESH:D016650', (122, 126))	('antibody', 'molecular_function', 'GO:0003823', ('52', '60'))	('EPR19518', 'Var', (25, 33))	('CD163', 'Gene', (9, 14))	('Alexa 555 fluorophore', 'Chemical', '-', (92, 113))
141681	33711273	The immune cells were similarly phenotyped in the hotspots images using the 4 channels dedicated to the 4 antibodies of interest (FITC, Cy3, Texas Red, Cy5).	('Cy3', 'Var', (136, 139))	('Cy5', 'Chemical', 'MESH:C085321', (152, 155))	('Texas Red', 'Chemical', 'MESH:C034657', (141, 150))	('FITC', 'Chemical', 'MESH:D016650', (130, 134))	('Cy3', 'Chemical', '-', (136, 139))	('FITC', 'Var', (130, 134))	('Cy5', 'Var', (152, 155))
141686	33711273	For the T cell panel, CD3+ cells were selected (clusters 7, 8, 10, 11, 14, 15, 16, 18) and subclustered using FlowSOM on all markers except CD15, CD86, CD20, CD7, CD68, and CD206, which were also excluded in the original analysis of the dataset by Chevrier et al.	('CD15', 'Var', (140, 144))	('CD7', 'Gene', '924', (158, 161))	('CD206', 'Gene', (173, 178))	('CD206', 'Gene', '4360', (173, 178))	('CD8', 'Gene', (146, 149))	('CD8', 'Gene', '925', (146, 149))	('CD7', 'Gene', (158, 161))	('CD68', 'Var', (163, 167))
141696	29523820	Recently, alterations of KIBRA expression caused by promotor methylation have been reported for several types of cancer.	('methylation', 'Var', (61, 72))	('KIBRA', 'Gene', (25, 30))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('KIBRA', 'Gene', '23286', (25, 30))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('alterations', 'Reg', (10, 21))
141700	29523820	ZFP226 showed nuclear localization in human immortalized kidney epithelial cells and activated the KIBRA core promoter (p < 0.001) resulting in significantly increased KIBRA mRNA and protein levels (p < 0.001).	('ZFP226', 'Chemical', '-', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('human', 'Species', '9606', (38, 43))	('KIBRA', 'Gene', '23286', (99, 104))	('KIBRA', 'Gene', (168, 173))	('KIBRA', 'Gene', '23286', (168, 173))	('ZFP226', 'Var', (0, 6))	('localization', 'biological_process', 'GO:0051179', ('22', '34'))	('core', 'cellular_component', 'GO:0019013', ('105', '109'))	('activated', 'PosReg', (85, 94))	('KIBRA', 'Gene', (99, 104))	('increased', 'PosReg', (158, 167))
141701	29523820	Furthermore, ZFP226 led to activation of hippo signaling marked by elevated YAP and LATS phosphorylation.	('ZFP226', 'Chemical', '-', (13, 19))	('hippo', 'Gene', (41, 46))	('ZFP226', 'Var', (13, 19))	('YAP', 'Gene', '10413', (76, 79))	('elevated', 'PosReg', (67, 75))	('YAP', 'Gene', (76, 79))	('hippo signaling', 'biological_process', 'GO:0035329', ('41', '56'))	('LATS phosphorylation', 'CPA', (84, 104))	('activation', 'PosReg', (27, 37))	('hippo', 'Gene', '37247', (41, 46))	('phosphorylation', 'biological_process', 'GO:0016310', ('89', '104'))
141711	29523820	In humans, impaired hippo signaling has been reported in a variety of different cancers, such as renal cell carcinoma, hepatocellular carcinoma and breast cancer, linking dysregulated hippo signaling to tumor initiation and progression.	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('hippo signaling', 'biological_process', 'GO:0035329', ('184', '199'))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (97, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('hepatocellular carcinoma', 'Disease', (119, 143))	('dysregulated', 'Var', (171, 183))	('tumor initiation', 'Disease', 'MESH:D009369', (203, 219))	('tumor initiation', 'Disease', (203, 219))	('hippo', 'Gene', (184, 189))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('hippo', 'Gene', '37247', (20, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('breast cancer', 'Disease', (148, 161))	('impaired', 'NegReg', (11, 19))	('renal cell carcinoma', 'Disease', (97, 117))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (97, 117))	('cancers', 'Disease', (80, 87))	('humans', 'Species', '9606', (3, 9))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (119, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('hippo', 'Gene', '37247', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('hippo signaling', 'biological_process', 'GO:0035329', ('20', '35'))	('hippo', 'Gene', (20, 25))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (119, 143))
141712	29523820	Components of the hippo pathway are target of aberrant gene methylation and epigenetic silencing in humans as already reported for LATS1/2 (large tumor suppressor kinases 1 and 2; human Warts homologue), MST1/2 (serine/threonine protein kinase 4/3; human hippo homologue).	('hippo', 'Gene', '37247', (255, 260))	('large tumor suppressor kinases 1 and 2', 'Gene', '9113;26524', (140, 178))	('Warts', 'Phenotype', 'HP:0200043', (186, 191))	('hippo', 'Gene', (18, 23))	('LATS1/2', 'Gene', '9113;26524', (131, 138))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('LATS1/2', 'Gene', (131, 138))	('humans', 'Species', '9606', (100, 106))	('hippo', 'Gene', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('human', 'Species', '9606', (180, 185))	('aberrant gene methylation', 'Var', (46, 71))	('epigenetic silencing', 'Var', (76, 96))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('146', '162'))	('hippo', 'Gene', '37247', (18, 23))	('MST1/2 (serine/threonine protein kinase 4/3', 'Gene', '4485;6788;6789', (204, 247))	('tumor suppressor', 'biological_process', 'GO:0051726', ('146', '162'))	('human', 'Species', '9606', (100, 105))	('human', 'Species', '9606', (249, 254))	('protein', 'cellular_component', 'GO:0003675', ('229', '236'))
141713	29523820	KIBRA promoter methylation resulting in reduced KIBRA protein levels has been identified in chronic and acute lymphocytic leukemia.	('methylation', 'Var', (15, 26))	('KIBRA', 'Gene', (48, 53))	('chronic', 'Disease', (92, 99))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('KIBRA', 'Gene', '23286', (0, 5))	('KIBRA', 'Gene', '23286', (48, 53))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (104, 130))	('reduced', 'NegReg', (40, 47))	('acute lymphocytic leukemia', 'Disease', (104, 130))	('KIBRA', 'Gene', (0, 5))	('acute lymphocytic leukemia', 'Disease', 'MESH:D054198', (104, 130))
141716	29523820	Since aberrant epigenetic silencing of tumor suppressor genes (TSGs) plays a major role during tumorigenesis, regaining expression and effective normalization of function offers a unique opportunity for targeted therapies.	('expression', 'MPA', (120, 130))	('aberrant epigenetic silencing', 'Var', (6, 35))	('regaining', 'PosReg', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('TSG', 'Gene', '57045', (63, 66))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('39', '55'))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor suppressor', 'biological_process', 'GO:0051726', ('39', '55'))	('function', 'MPA', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (39, 44))	('TSG', 'Gene', (63, 66))	('tumor', 'Disease', (95, 100))
141721	29523820	Furthermore, ZFP226 was capable of reducing the viability of MCF-7 breast cancer cells.	('ZFP226', 'Chemical', '-', (13, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('ZFP226', 'Var', (13, 19))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (61, 80))	('MCF-7 breast cancer', 'Disease', (61, 80))	('reducing', 'NegReg', (35, 43))	('viability', 'CPA', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
141722	29523820	KIBRA, a hippo pathway regulator, has been identified as a central TSG, which is frequently affected by epigenetic silencing in different types of cancer.	('epigenetic', 'Var', (104, 114))	('hippo', 'Gene', '37247', (9, 14))	('hippo', 'Gene', (9, 14))	('TSG', 'Gene', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('KIBRA', 'Gene', '23286', (0, 5))	('TSG', 'Gene', '57045', (67, 70))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('KIBRA', 'Gene', (0, 5))
141730	29523820	In brief, the structural stability of the Cys2-His2 zinc finger betabetaalpha-fold is based on hydrophobic interactions and chelation of a zinc ion by the Cys2-His2 residues.	('Cys2', 'Chemical', '-', (155, 159))	('chelation', 'MPA', (124, 133))	('2-His', 'molecular_function', 'GO:0033770', ('45', '50'))	('Cys2-His2', 'Var', (42, 51))	('structural', 'MPA', (14, 24))	('Cys2', 'Chemical', '-', (42, 46))	('His2', 'Chemical', '-', (160, 164))	('hydrophobic interactions', 'MPA', (95, 119))	('2-His', 'molecular_function', 'GO:0033770', ('158', '163'))	('His2', 'Chemical', '-', (47, 51))
141735	29523820	Consistently, ZFP226 binding-site mutation prevented the activating effect of ZFP226 (p = 0.0731, Fig.	('binding-site', 'Interaction', (21, 33))	('ZFP226', 'Chemical', '-', (14, 20))	('activating effect', 'MPA', (57, 74))	('mutation', 'Var', (34, 42))	('ZFP226', 'Gene', (78, 84))	('binding', 'molecular_function', 'GO:0005488', ('21', '28'))	('ZFP226', 'Gene', (14, 20))	('prevented', 'NegReg', (43, 52))	('ZFP226', 'Chemical', '-', (78, 84))
141738	29523820	Real-time PCR analysis revealed significantly increased KIBRA mRNA expression levels 48 hrs after ZFP226 transfection compared to shuttle vector control (all p < 0.001, Fig.	('transfection', 'Var', (105, 117))	('KIBRA', 'Gene', (56, 61))	('increased', 'PosReg', (46, 55))	('ZFP226', 'Gene', (98, 104))	('KIBRA', 'Gene', '23286', (56, 61))	('shuttle vector', 'Species', '45197', (130, 144))	('ZFP226', 'Chemical', '-', (98, 104))
141741	29523820	KIBRA protein was significantly increased by SP1 and ZFP226 compared to shuttle vector control (p < 0.001, Fig.	('SP1', 'Var', (45, 48))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('shuttle vector', 'Species', '45197', (72, 86))	('KIBRA', 'Gene', '23286', (0, 5))	('increased', 'PosReg', (32, 41))	('ZFP226', 'Chemical', '-', (53, 59))	('ZFP226', 'Var', (53, 59))	('KIBRA', 'Gene', (0, 5))
141744	29523820	We were able to show that relative levels of pLATS1 and most importantly pYAP were significantly increased 48 hrs after ZFP226 transfection in IHKE cells (both p < 0.001, Fig.	('increased', 'PosReg', (97, 106))	('transfection', 'Var', (127, 139))	('YAP', 'Gene', '10413', (74, 77))	('ZFP226', 'Gene', (120, 126))	('YAP', 'Gene', (74, 77))	('LATS1', 'Gene', (46, 51))	('ZFP226', 'Chemical', '-', (120, 126))	('LATS1', 'Gene', '9113', (46, 51))
141746	29523820	Of Note, YAP expression was unaffected by pZFP226 transfection.	('YAP', 'Gene', '10413', (9, 12))	('YAP', 'Gene', (9, 12))	('ZFP226', 'Chemical', '-', (43, 49))	('transfection', 'Var', (50, 62))	('pZFP226 transfection', 'Var', (42, 62))
141747	29523820	In cancer, defects in different apoptotic pathways can disturb the balance between cell proliferation and apoptosis, and thus allow the survival of cells with genetic abnormalities.	('defects', 'Var', (11, 18))	('genetic abnormalities', 'Disease', (159, 180))	('allow', 'Reg', (126, 131))	('balance', 'MPA', (67, 74))	('cell proliferation', 'CPA', (83, 101))	('apoptosis', 'CPA', (106, 115))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('cell proliferation', 'biological_process', 'GO:0008283', ('83', '101'))	('cancer', 'Disease', (3, 9))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('genetic abnormalities', 'Disease', 'MESH:D030342', (159, 180))	('disturb', 'NegReg', (55, 62))	('apoptotic pathways', 'Pathway', (32, 50))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
141749	29523820	Furthermore, impaired hippo signaling has been reported in a variety of different cancers, including breast cancer, linking dysregulated hippo signaling to tumor initiation and progression.	('dysregulated', 'Var', (124, 136))	('hippo signaling', 'biological_process', 'GO:0035329', ('137', '152'))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('tumor initiation', 'Disease', 'MESH:D009369', (156, 172))	('cancers', 'Disease', (82, 89))	('tumor initiation', 'Disease', (156, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('hippo', 'Gene', '37247', (22, 27))	('hippo signaling', 'biological_process', 'GO:0035329', ('22', '37'))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('hippo', 'Gene', (137, 142))	('breast cancer', 'Disease', (101, 114))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('impaired', 'NegReg', (13, 21))	('hippo', 'Gene', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('hippo', 'Gene', '37247', (137, 142))
141750	29523820	Therefore, we hypothesized that ZFP226 may induce apoptosis in human MCF-7 breast adenocarcinoma cells by activating hippo signaling.	('apoptosis', 'biological_process', 'GO:0006915', ('50', '59'))	('human', 'Species', '9606', (63, 68))	('apoptosis', 'biological_process', 'GO:0097194', ('50', '59'))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (75, 96))	('activating', 'PosReg', (106, 116))	('hippo', 'Gene', (117, 122))	('MCF-7', 'CellLine', 'CVCL:0031', (69, 74))	('ZFP226', 'Chemical', '-', (32, 38))	('breast adenocarcinoma', 'Disease', (75, 96))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (75, 96))	('hippo signaling', 'biological_process', 'GO:0035329', ('117', '132'))	('induce', 'PosReg', (43, 49))	('ZFP226', 'Var', (32, 38))	('hippo', 'Gene', '37247', (117, 122))	('apoptosis', 'CPA', (50, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
141753	29523820	The number of apoptotic cells within quadrant Q2 (early-apoptotic cells) and quadrant Q3 (late-apoptotic/necrotic cells) was significantly increased after ZFP226 transfection in MCF-7 cells compared to shuttle vector control (pQ2 < 0.05, pQ3 < 0.01; Fig.	('shuttle vector', 'Species', '45197', (202, 216))	('MCF-7', 'CellLine', 'CVCL:0031', (178, 183))	('increased', 'PosReg', (139, 148))	('ZFP226', 'Chemical', '-', (155, 161))	('transfection', 'Var', (162, 174))	('ZFP226', 'Gene', (155, 161))
141754	29523820	Additionally, real-time PCR analysis of apoptotic markers revealed significantly increased pro-apoptotic BAX as well as decreased anti-apoptotic BCL-2 expression after ZFP226 transfection compared to shuttle vector control (pBAX < 0.01, pBCL-2 < 0.001; Fig.	('decreased', 'NegReg', (120, 129))	('ZFP226', 'Chemical', '-', (168, 174))	('ZFP226 transfection', 'Var', (168, 187))	('BAX', 'Gene', '581', (225, 228))	('increased', 'PosReg', (81, 90))	('shuttle vector', 'Species', '45197', (200, 214))	('expression', 'MPA', (151, 161))	('BCL-2', 'molecular_function', 'GO:0015283', ('145', '150'))	('transfection', 'Var', (175, 187))	('BCL-2', 'Gene', '596', (145, 150))	('BCL-2', 'Gene', '596', (238, 243))	('BCL-2', 'Gene', (145, 150))	('BAX', 'Gene', (105, 108))	('BAX', 'Gene', (225, 228))	('BAX', 'Gene', '581', (105, 108))	('BCL-2', 'Gene', (238, 243))
141756	29523820	ZFP226 was capable to (1) activate the KIBRA core promoter, a tumor suppressor and upstream regulator of the hippo pathway, resulting in (2) significantly increased KIBRA mRNA as well as protein levels, (3) activation of hippo signaling marked by elevated LATS1 and YAP phosphorylation and (4) reduced viability of breast cancer cells.	('ZFP226', 'Chemical', '-', (0, 6))	('hippo', 'Gene', '37247', (221, 226))	('viability', 'CPA', (302, 311))	('phosphorylation', 'biological_process', 'GO:0016310', ('270', '285'))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (315, 328))	('increased', 'PosReg', (155, 164))	('ZFP226', 'Var', (0, 6))	('LATS1', 'Gene', (256, 261))	('hippo signaling', 'biological_process', 'GO:0035329', ('221', '236'))	('LATS1', 'Gene', '9113', (256, 261))	('KIBRA', 'Gene', (39, 44))	('hippo', 'Gene', '37247', (109, 114))	('elevated', 'PosReg', (247, 255))	('YAP', 'Gene', (266, 269))	('reduced', 'NegReg', (294, 301))	('KIBRA', 'Gene', '23286', (39, 44))	('KIBRA', 'Gene', (165, 170))	('breast cancer', 'Disease', 'MESH:D001943', (315, 328))	('breast cancer', 'Disease', (315, 328))	('hippo', 'Gene', (221, 226))	('activation', 'PosReg', (207, 217))	('KIBRA', 'Gene', '23286', (165, 170))	('protein levels', 'MPA', (187, 201))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('62', '78'))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('core', 'cellular_component', 'GO:0019013', ('45', '49'))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))	('activate', 'PosReg', (26, 34))	('YAP', 'Gene', '10413', (266, 269))	('tumor', 'Disease', (62, 67))	('tumor suppressor', 'biological_process', 'GO:0051726', ('62', '78'))	('hippo', 'Gene', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
141758	29523820	In line with this observation, components of the hippo pathway are target of aberrant gene methylation and epigenetic silencing also in humans as already reported for LATS1/2, MST1/2 and KIBRA.	('hippo', 'Gene', '37247', (49, 54))	('hippo', 'Gene', (49, 54))	('LATS1/2', 'Gene', (167, 174))	('epigenetic silencing', 'Var', (107, 127))	('MST1/2', 'Gene', '4485;6788', (176, 182))	('KIBRA', 'Gene', (187, 192))	('humans', 'Species', '9606', (136, 142))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))	('KIBRA', 'Gene', '23286', (187, 192))	('LATS1/2', 'Gene', '9113;26524', (167, 174))	('MST1/2', 'Gene', (176, 182))	('aberrant gene methylation', 'Var', (77, 102))
141759	29523820	We recently reported that human KIBRA expression depends on a complex alternative CpG-rich promoter system with inactivated KIBRA expression induced by promoter methylation in ccRCC.	('promoter methylation', 'Var', (152, 172))	('methylation', 'biological_process', 'GO:0032259', ('161', '172'))	('KIBRA', 'Gene', (124, 129))	('KIBRA', 'Gene', (32, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (176, 181))	('KIBRA', 'Gene', '23286', (124, 129))	('ccRCC', 'Disease', (176, 181))	('human', 'Species', '9606', (26, 31))	('KIBRA', 'Gene', '23286', (32, 37))
141766	29523820	Even if we were able to demonstrate the ability of ZFP226 to activate the KIBRA core promoter resulting in significantly increased KIBRA mRNA and protein levels, further improvement of ZFP226 specificity by target sequence extension is mandatory.	('activate', 'PosReg', (61, 69))	('ZFP226', 'Chemical', '-', (185, 191))	('increased', 'PosReg', (121, 130))	('KIBRA', 'Gene', (131, 136))	('ZFP226', 'Chemical', '-', (51, 57))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('ZFP226', 'Var', (51, 57))	('men', 'Species', '9606', (177, 180))	('core', 'cellular_component', 'GO:0019013', ('80', '84'))	('KIBRA', 'Gene', (74, 79))	('KIBRA', 'Gene', '23286', (131, 136))	('KIBRA', 'Gene', '23286', (74, 79))
141768	29523820	YAP and TAZ are inactivated by phosphorylation through LATS kinases with subsequent inhibition of proliferation.	('YAP', 'Gene', (0, 3))	('TAZ', 'Gene', (8, 11))	('inhibition', 'NegReg', (84, 94))	('LATS kinases', 'Enzyme', (55, 67))	('YAP', 'Gene', '10413', (0, 3))	('TAZ', 'Gene', '6901', (8, 11))	('phosphorylation', 'Var', (31, 46))	('proliferation', 'CPA', (98, 111))	('phosphorylation', 'biological_process', 'GO:0016310', ('31', '46'))
141773	29523820	In our experiments, we detected a significant activation of hippo signaling in ZFP226-transfected cells marked by elevated LATS1 and YAP phosphorylation.	('phosphorylation', 'biological_process', 'GO:0016310', ('137', '152'))	('activation', 'PosReg', (46, 56))	('ZFP226', 'Chemical', '-', (79, 85))	('hippo', 'Gene', '37247', (60, 65))	('YAP', 'Gene', '10413', (133, 136))	('LATS1', 'Gene', (123, 128))	('hippo', 'Gene', (60, 65))	('hippo signaling', 'biological_process', 'GO:0035329', ('60', '75'))	('LATS1', 'Gene', '9113', (123, 128))	('elevated', 'PosReg', (114, 122))	('YAP', 'Gene', (133, 136))	('men', 'Species', '9606', (13, 16))	('ZFP226-transfected', 'Var', (79, 97))
141776	29523820	Most importantly, we found that ZFP226 was able to induce apoptosis by activating hippo signaling in human breast adenocarcinoma cells as we observed a significantly increased number of early- and late-apoptotic cells after transfection with ZPF226.	('breast adenocarcinoma', 'Disease', (107, 128))	('ZPF226', 'Chemical', '-', (242, 248))	('hippo signaling', 'biological_process', 'GO:0035329', ('82', '97'))	('increased', 'PosReg', (166, 175))	('hippo', 'Gene', '37247', (82, 87))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (107, 128))	('human', 'Species', '9606', (101, 106))	('apoptosis', 'biological_process', 'GO:0097194', ('58', '67'))	('ZFP226', 'Chemical', '-', (32, 38))	('apoptosis', 'biological_process', 'GO:0006915', ('58', '67'))	('hippo', 'Gene', (82, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (107, 128))	('activating', 'PosReg', (71, 81))	('ZFP226', 'Var', (32, 38))
141778	29523820	ZFP226 is a novel artificial TF, which was capable to activate the KIBRA core promoter, to significantly increase KIBRA mRNA as well as protein levels, thereby activating hippo signaling marked by elevated LATS1 and YAP phosphorylation.	('ZFP226', 'Chemical', '-', (0, 6))	('KIBRA', 'Gene', '23286', (67, 72))	('KIBRA', 'Gene', (114, 119))	('KIBRA', 'Gene', '23286', (114, 119))	('hippo signaling', 'biological_process', 'GO:0035329', ('171', '186'))	('YAP', 'Gene', '10413', (216, 219))	('activating', 'PosReg', (160, 170))	('ZFP226', 'Var', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('hippo', 'Gene', '37247', (171, 176))	('increase', 'PosReg', (105, 113))	('LATS1', 'Gene', (206, 211))	('core', 'cellular_component', 'GO:0019013', ('73', '77'))	('LATS1', 'Gene', '9113', (206, 211))	('YAP', 'Gene', (216, 219))	('elevated', 'PosReg', (197, 205))	('protein levels', 'MPA', (136, 150))	('hippo', 'Gene', (171, 176))	('KIBRA', 'Gene', (67, 72))	('phosphorylation', 'biological_process', 'GO:0016310', ('220', '235'))
141789	29523820	In brief, ZFP226 or SP1 expression vector or the appropriate shuttle vector control and KIBRA reporter gene plasmids for promoter P1a (-361/+186 and -730/+186) were transfected in a 1:1 ratio.	('ZFP226', 'Chemical', '-', (10, 16))	('-361/+186', 'Var', (135, 144))	('P1a', 'Gene', (130, 133))	('KIBRA', 'Gene', (88, 93))	('shuttle vector', 'Species', '45197', (61, 75))	('P1a', 'Gene', '7739', (130, 133))	('KIBRA', 'Gene', '23286', (88, 93))
141796	29523820	A total of 2 x 105 IHKE cells per 24-well were seeded on coverslips, transfected with pZFP226 and incubated for 48 hrs.	('transfected', 'Var', (69, 80))	('ZFP226', 'Chemical', '-', (87, 93))	('pZFP226', 'Gene', (86, 93))
141810	29523820	Live cells; (Q1 Annexin V-/DAPI-), early-apoptotic cells; (Q2 Annexin V+/DAPI-), late-apoptotic/necrotic cells; (Q3 Annexin V+/DAPI+) and cell debris (Q4 Annexin V-/DAPI+).	('Annexin V', 'Gene', (116, 125))	('DAPI', 'Chemical', 'MESH:C007293', (165, 169))	('Annexin V', 'Gene', '308', (154, 163))	('Annexin V', 'Gene', (154, 163))	('DAPI', 'Chemical', 'MESH:C007293', (27, 31))	('DAPI', 'Chemical', 'MESH:C007293', (73, 77))	('Annexin V', 'Gene', '308', (62, 71))	('Annexin V', 'Gene', (62, 71))	('Q4', 'Var', (151, 153))	('Annexin V', 'Gene', '308', (116, 125))	('Annexin V', 'Gene', '308', (16, 25))	('Annexin V', 'Gene', (16, 25))	('DAPI', 'Chemical', 'MESH:C007293', (127, 131))
141812	28715484	Multiple renal cancer susceptibility polymorphisms modulate the HIF pathway Un-physiological activation of hypoxia inducible factor (HIF) is an early event in most renal cell cancers (RCC) following inactivation of the von Hippel-Lindau tumor suppressor.	('activation', 'PosReg', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('modulate', 'Reg', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('hypoxia', 'Disease', 'MESH:D000860', (107, 114))	('HIF pathway', 'Pathway', (64, 75))	('von Hippel-Lindau tumor', 'Disease', (219, 242))	('renal cell cancers', 'Disease', 'MESH:C538614', (164, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('237', '253'))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('renal cancer', 'Phenotype', 'HP:0009726', (9, 21))	('renal cell cancers', 'Disease', (164, 182))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('von Hippel-Lindau tumor', 'Disease', 'MESH:D006623', (219, 242))	('tumor suppressor', 'biological_process', 'GO:0051726', ('237', '253'))	('inactivation', 'Var', (199, 211))	('renal cell cancer', 'Phenotype', 'HP:0005584', (164, 181))	('Multiple renal cancer', 'Disease', 'MESH:D007680', (0, 21))	('Multiple renal cancer', 'Disease', (0, 21))	('hypoxia', 'Disease', (107, 114))
141816	28715484	This defined a novel stage-specific mechanism in which the risk polymorphism, rs12814794, directly creates a new HIF-binding site that mediates HIF-1alpha isoform specific upregulation of its target BHLHE41.	('upregulation', 'PosReg', (172, 184))	('BHLHE41', 'Gene', (199, 206))	('rs12814794', 'Mutation', 'rs12814794', (78, 88))	('HIF-1alpha', 'Gene', '3091', (144, 154))	('BHLHE41', 'Gene', '79365', (199, 206))	('rs12814794', 'Var', (78, 88))	('binding', 'molecular_function', 'GO:0005488', ('117', '124'))	('HIF-binding', 'MPA', (113, 124))	('HIF-1alpha', 'Gene', (144, 154))
141820	28715484	Our study has provided new insights into renal specific oncogenesis, revealing multiple mechanisms by which modulation of specific aspects of HIF signalling impact on this form of cancer.	('modulation', 'Var', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('signalling', 'biological_process', 'GO:0023052', ('146', '156'))	('impact', 'Reg', (157, 163))	('oncogenesis', 'biological_process', 'GO:0007048', ('56', '67'))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))
141826	28715484	Following inactivation of VHL in clear cell (cc)RCC, the HIF pathway is constitutively activated.	('VHL', 'Gene', (26, 29))	('inactivation', 'Var', (10, 22))	('VHL', 'Gene', '7428', (26, 29))	('HIF pathway', 'Pathway', (57, 68))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
141828	28715484	Therefore its activation in the kidney tubule, as an early event in the pathogenesis of ccRCC, provides a framework for testing for the extent of alignment between extragenic polymorphism influencing RCC-susceptibility and a pre-defined biological pathway that is relevant to that cancer.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('polymorphism', 'Var', (175, 187))	('activation', 'PosReg', (14, 24))	('ccRCC', 'Disease', (88, 93))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('RCC', 'Phenotype', 'HP:0005584', (200, 203))	('cancer', 'Disease', (281, 287))	('pre', 'molecular_function', 'GO:0003904', ('225', '228'))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('pathogenesis', 'biological_process', 'GO:0009405', ('72', '84'))
141831	28715484	Allele-specific studies of this polymorphism in renal tubular cells, ccRCC cell lines, and human ccRCC material, suggests a novel stage-specific mechanism by which polymorphism tunes the output of the HIF pathway.	('polymorphism', 'Var', (164, 176))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('HIF pathway', 'Pathway', (201, 212))	('output', 'MPA', (187, 193))	('human', 'Species', '9606', (91, 96))
141832	28715484	For each locus, the single nucleotide polymorphism (SNP) that showed the most significant association with renal cancer was considered as the index SNP.	('single nucleotide polymorphism', 'Var', (20, 50))	('renal cancer', 'Disease', (107, 119))	('renal cancer', 'Phenotype', 'HP:0009726', (107, 119))	('renal cancer', 'Disease', 'MESH:D007680', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
141855	28715484	Inspection of the RCC-associated haplotype block revealed that the index SNP rs718314 is in high LD (r2 = 0.956) with rs12814794, which overlies the HIF ChIP-seq signal (Fig 3A).	('rs12814794', 'Mutation', 'rs12814794', (118, 128))	('RCC', 'Phenotype', 'HP:0005584', (18, 21))	('rs718314', 'Mutation', 'rs718314', (77, 85))	('rs12814794', 'Var', (118, 128))	('rs718314', 'Var', (77, 85))
141857	28715484	Both HIF-binding and (following re-expression) HIF-1alpha dependent BHLHE41 gene expression, was observed in 786-O cells that were homozygous for the A allele at rs12814794 (Fig 2A and 2C), suggesting that this second HRE can be functional, at least in specific settings.	('BHLHE41', 'Gene', (68, 75))	('rs12814794', 'Var', (162, 172))	('HIF-1alpha', 'Gene', '3091', (47, 57))	('BHLHE41', 'Gene', '79365', (68, 75))	('gene expression', 'biological_process', 'GO:0010467', ('76', '91'))	('HIF-1alpha', 'Gene', (47, 57))	('binding', 'molecular_function', 'GO:0005488', ('9', '16'))	('rs12814794', 'Mutation', 'rs12814794', (162, 172))	('expression', 'MPA', (81, 91))
141858	28715484	Therefore, it was unclear to what extent the totality of HIF-binding to the chr 12p12.1 enhancer might be affected by the rs12814794 polymorphism that affects just one of the HREs.	('chr', 'Gene', (76, 79))	('rs12814794', 'Mutation', 'rs12814794', (122, 132))	('affected', 'Reg', (106, 114))	('rs12814794', 'Var', (122, 132))	('binding', 'molecular_function', 'GO:0005488', ('61', '68'))
141859	28715484	To determine the effect of the rs12814794 polymorphism on HIF-binding and BHLHE41 gene expression, we identified four individuals who are heterozygous for the rs12814794 SNP.	('rs12814794', 'Var', (159, 169))	('BHLHE41', 'Gene', (74, 81))	('BHLHE41', 'Gene', '79365', (74, 81))	('gene expression', 'biological_process', 'GO:0010467', ('82', '97'))	('rs12814794', 'Mutation', 'rs12814794', (159, 169))	('rs12814794', 'Mutation', 'rs12814794', (31, 41))	('binding', 'molecular_function', 'GO:0005488', ('62', '69'))
141861	28715484	Taken together these results indicate that RCC-associated polymorphisms, which include those at rs12814794, affect binding of HIF at the chr 12p12.1 enhancer in primary renal tubular cells.	('RCC-associated', 'Gene', (43, 57))	('affect', 'Reg', (108, 114))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('rs12814794', 'Mutation', 'rs12814794', (96, 106))	('binding', 'Interaction', (115, 122))	('binding', 'molecular_function', 'GO:0005488', ('115', '122'))	('rs12814794', 'Var', (96, 106))
141862	28715484	We then examined for allele-specific HIF-binding in RCC cells using the VHL-defective RCC L13 cell line, which is heterozygous for rs12814794.	('rs12814794', 'Var', (131, 141))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('binding', 'molecular_function', 'GO:0005488', ('41', '48'))	('VHL-defective RCC L13', 'Disease', 'MESH:C538614', (72, 93))	('VHL-defective RCC L13', 'Disease', (72, 93))	('rs12814794', 'Mutation', 'rs12814794', (131, 141))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))
141865	28715484	Having shown that the RCC-associated polymorphism underlying the chr 12p12.1 HIF-binding site influences binding of HIF, we next tested for effects on expression of the transcriptional target, BHLHE41.	('binding', 'molecular_function', 'GO:0005488', ('105', '112'))	('binding', 'molecular_function', 'GO:0005488', ('81', '88'))	('BHLHE41', 'Gene', '79365', (193, 200))	('RCC', 'Phenotype', 'HP:0005584', (22, 25))	('influences', 'Reg', (94, 104))	('tested', 'Reg', (129, 135))	('polymorphism', 'Var', (37, 49))	('BHLHE41', 'Gene', (193, 200))	('binding', 'Interaction', (105, 112))
141866	28715484	We first identified individuals who were heterozygous for a SNP (rs1048155) in the 3' UTR of the BHLHE41 gene (Fig 5A).	('BHLHE41', 'Gene', '79365', (97, 104))	('rs1048155', 'Mutation', 'rs1048155', (65, 74))	('rs1048155', 'Var', (65, 74))	('BHLHE41', 'Gene', (97, 104))
141868	28715484	Cells from individuals who were homozygous for either the A allele or the G allele at rs12814794 did not show any allelic imbalance in transcript abundance for the heterozygous rs104155 transcribed polymorphism (Fig 5B-5E, S4 and S5 Figs).	('rs104155', 'Var', (177, 185))	('rs12814794', 'Var', (86, 96))	('imbalance', 'Phenotype', 'HP:0002172', (122, 131))	('rs12814794', 'Mutation', 'rs12814794', (86, 96))	('rs104155', 'Mutation', 'rs104155', (177, 185))
141870	28715484	Furthermore, cDNA from un-stimulated cells that were heterozygous for the RCC-associated polymorphism (rs12814794) did not show any allelic imbalance in expression of the rs104155 polymorphism either.	('rs104155', 'Mutation', 'rs104155', (171, 179))	('rs104155', 'Var', (171, 179))	('RCC-associated', 'Gene', (74, 88))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('rs12814794', 'Mutation', 'rs12814794', (103, 113))	('rs12814794', 'Var', (103, 113))	('imbalance', 'Phenotype', 'HP:0002172', (140, 149))
141871	28715484	However, when HIF was induced in these heterozygous cells using DMOG, preferential expression of one rs104155 allele over the other was observed (Fig 5F and 5G, S4 and S5 Figs).	('DMOG', 'Chemical', 'MESH:C040947', (64, 68))	('preferential', 'PosReg', (70, 82))	('expression', 'MPA', (83, 93))	('rs104155', 'Mutation', 'rs104155', (101, 109))	('rs104155', 'Var', (101, 109))
141873	28715484	No difference in BHLHE41 expression was observed between each of the three different rs12814794 genotypes under basal, non-stimulated conditions (S6 Fig).	('rs12814794', 'Var', (85, 95))	('BHLHE41', 'Gene', (17, 24))	('rs12814794', 'Mutation', 'rs12814794', (85, 95))	('BHLHE41', 'Gene', '79365', (17, 24))
141874	28715484	However, following HIF induction by DMOG, a significant increase in BHLHE41 mRNA was observed in cells that carried at least one RCC-risk allele at the rs12814794 SNP, whilst the expression and induction of an control HIF target gene at an independent locus (EGLN3) was unaffected by the rs12814794 genotype (Fig 6A and 6B).	('BHLHE41', 'Gene', (68, 75))	('rs12814794', 'Mutation', 'rs12814794', (152, 162))	('DMOG', 'Chemical', 'MESH:C040947', (36, 40))	('increase', 'PosReg', (56, 64))	('rs12814794 SNP', 'Var', (152, 166))	('mRNA', 'MPA', (76, 80))	('rs12814794', 'Mutation', 'rs12814794', (288, 298))	('BHLHE41', 'Gene', '79365', (68, 75))	('DMOG', 'Var', (36, 40))	('rs12814794', 'Var', (288, 298))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('EGLN3', 'Gene', '112399', (259, 264))	('EGLN3', 'Gene', (259, 264))
141875	28715484	As has been previously reported, we observed an effect of RCC-associated polymorphisms (including rs12814794) at this locus on the expression of BHLHE41 mRNA in ccRCC tumor samples analyzed by The Cancer Genome Atlas (TCGA).	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('effect', 'Reg', (48, 54))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (197, 216))	('Cancer', 'Phenotype', 'HP:0002664', (197, 203))	('rs12814794', 'Mutation', 'rs12814794', (98, 108))	('RCC tumor', 'Disease', (163, 172))	('BHLHE41', 'Gene', (145, 152))	('rs12814794', 'Var', (98, 108))	('expression', 'MPA', (131, 141))	('BHLHE41', 'Gene', '79365', (145, 152))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC tumor', 'Disease', 'MESH:C538614', (163, 172))	('Cancer Genome Atlas', 'Disease', (197, 216))
141876	28715484	However, in our analysis of cell lines heterozygous for rs12814794, the effect of the polymorphism on gene expression required the presence of HIF-1alpha.	('gene expression', 'biological_process', 'GO:0010467', ('102', '117'))	('HIF-1alpha', 'Gene', (143, 153))	('gene expression', 'MPA', (102, 117))	('HIF-1alpha', 'Gene', '3091', (143, 153))	('rs12814794', 'Mutation', 'rs12814794', (56, 66))	('rs12814794', 'Var', (56, 66))
141879	28715484	We used these to stratify the TCGA ccRCCs according to low or high activity of HIF-1alpha or HIF-2alpha and re-examined for association between polymorphism at the chr 12p12.1 RCC-associated locus and the expression of BHLHE41 (Fig 6C-6F).	('polymorphism', 'Var', (144, 156))	('BHLHE41', 'Gene', (219, 226))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('BHLHE41', 'Gene', '79365', (219, 226))	('HIF-1alpha or HIF-2alpha', 'Disease', (79, 103))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('association', 'Interaction', (124, 135))	('HIF-1alpha or HIF-2alpha', 'Disease', 'None', (79, 103))
141881	28715484	Taken together, these analyses indicate that the RCC-associated polymorphism is capable of driving differential expression of BHLHE41, and that this action is at least in part dependent on the function of HIF-1alpha.	('HIF-1alpha', 'Gene', '3091', (205, 215))	('BHLHE41', 'Gene', (126, 133))	('BHLHE41', 'Gene', '79365', (126, 133))	('HIF-1alpha', 'Gene', (205, 215))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('polymorphism', 'Var', (64, 76))	('expression', 'MPA', (112, 122))
141883	28715484	At three loci, which coincide with intergenic enhancers of CCND1, MYC and BHLHE41 expression, we have performed detailed functional analyses that reveal mechanisms by which polymorphisms affect the expression of specific HIF target genes.	('BHLHE41', 'Gene', (74, 81))	('MYC', 'Gene', (66, 69))	('BHLHE41', 'Gene', '79365', (74, 81))	('affect', 'Reg', (187, 193))	('MYC', 'Gene', '4609', (66, 69))	('CCND1', 'Gene', (59, 64))	('expression', 'MPA', (198, 208))	('CCND1', 'Gene', '595', (59, 64))	('polymorphisms', 'Var', (173, 186))
141886	28715484	For instance, RCC-associated polymorphisms might operate on the HIF system in 'trans', as is suggested by one of RCC-associated GWAS signals that does not overlap the HIF ChIP-sequences, but lies within the EPAS1 (HIF-2alpha) locus itself.	('EPAS1', 'Gene', (207, 212))	('operate', 'Reg', (49, 56))	('HIF-2alpha', 'Gene', (214, 224))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))	('HIF-2alpha', 'Gene', '2034', (214, 224))	('polymorphisms', 'Var', (29, 42))	('EPAS1', 'Gene', '2034', (207, 212))
141890	28715484	Taken together with the functional studies on specific loci in this and previous work, these findings suggest a remarkable coincidence between loci at which extra-genic human polymorphism influences risk of RCC, and loci at which such polymorphism modulates the output of the HIF pathway.	('polymorphism', 'Var', (175, 187))	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('influences', 'Reg', (188, 198))	('modulates', 'Reg', (248, 257))	('RCC', 'Disease', (207, 210))	('human', 'Species', '9606', (169, 174))	('HIF pathway', 'Pathway', (276, 287))	('extra-genic human', 'Protein', (157, 174))
141892	28715484	Nevertheless, the work suggests that multiple polymorphisms with small quantitative effects on the output of the HIF system have effects on RCC that are clearly discernible at the level of clinical cancer development.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('effects', 'Reg', (129, 136))	('RCC', 'Disease', (140, 143))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('polymorphisms', 'Var', (46, 59))
141898	28715484	This suggests that this RCC-associated polymorphism acts early during ccRCC development and cannot operate by this mechanism once mature ccRCC has extinguished HIF-1alpha.	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('HIF-1alpha', 'Gene', '3091', (160, 170))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('RCC-associated', 'Gene', (24, 38))	('polymorphism', 'Var', (39, 51))	('ccRCC', 'Disease', (70, 75))	('HIF-1alpha', 'Gene', (160, 170))	('RCC', 'Phenotype', 'HP:0005584', (24, 27))
141899	28715484	That there is such pressure to modulate the output of HIF system at an early stage in ccRCC development is consistent first with evidence that VHL-inactivation itself (and hence general un-physiological up-regulation of HIF) is an early event in ccRCC development, and secondly with the existence of changes in HIF-alpha isoform expression associated with ccRCC development.	('RCC', 'Phenotype', 'HP:0005584', (358, 361))	('ccRCC', 'Disease', (246, 251))	('VHL', 'Gene', '7428', (143, 146))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('regulation', 'biological_process', 'GO:0065007', ('206', '216'))	('VHL', 'Gene', (143, 146))	('ccRCC', 'Disease', (86, 91))	('modulate', 'Var', (31, 39))	('up-regulation', 'PosReg', (203, 216))	('RCC', 'Phenotype', 'HP:0005584', (248, 251))
141901	28715484	Therefore, the observation that the enhancer-promoter interaction persists in a HIF-1 defective cell (786-O), whilst BHLHE41 gene induction and the eQTL require HIF-1 is consistent with these findings.	('HIF-1', 'Gene', '3091', (80, 85))	('HIF-1', 'Gene', (80, 85))	('BHLHE41', 'Gene', '79365', (117, 124))	('HIF-1', 'Gene', '3091', (161, 166))	('BHLHE41', 'Gene', (117, 124))	('defective', 'Var', (86, 95))	('HIF-1', 'Gene', (161, 166))	('enhancer-promoter interaction', 'MPA', (36, 65))
141906	28715484	It clearly reveals that a specific polymorphism within that haplotype creates a new, functional, HIF-1alpha binding motif that is physically associated with and directly activates the BHLHE41 target gene at the risk locus.	('BHLHE41', 'Gene', '79365', (184, 191))	('HIF-1alpha', 'Gene', '3091', (97, 107))	('polymorphism', 'Var', (35, 47))	('activates', 'PosReg', (170, 179))	('HIF-1alpha', 'Gene', (97, 107))	('associated', 'Interaction', (141, 151))	('BHLHE41', 'Gene', (184, 191))	('binding', 'molecular_function', 'GO:0005488', ('108', '115'))
141921	28715484	The identity of RCC4 and 786-O cells was confirmed through the presence in RNA-seq data sets of unique mutations in the coding region of the VHL gene (chr3: 10,183,725 C>G and chr3:10,183,841 G>del) that have been previously been described for each cell line.	('mutations', 'Var', (103, 112))	('VHL', 'Gene', '7428', (141, 144))	('725 C>G', 'Mutation', 'c.725C>G', (164, 171))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('RCC4', 'Gene', '84925', (16, 20))	('RNA', 'cellular_component', 'GO:0005562', ('75', '78'))	('VHL', 'Gene', (141, 144))	('RCC4', 'Gene', (16, 20))
141933	28715484	Chromatin immunoprecipitation (ChIP) experiments were performed as previously described using antibodies directed against HIF-1alpha (rabbit polyclonal, PM14 or Cayman Chemicals, Cay10006421), HIF-2alpha (rabbit polyclonal, PM9 or PM8), HIF-1beta (rabbit polyclonal, Novus Biologicals, NB100-110), H3K4me1 (rabbit polyclonal, Millipore, #07-436), H3K4me3 (rabbit monoclonal, Cell Signaling Technology, #9751) or H3K27ac (rabbit polyclonal, Abcam, #ab4729).	('Chromatin', 'cellular_component', 'GO:0000785', ('0', '9'))	('HIF-1alpha', 'Gene', '3091', (122, 132))	('rabbit', 'Species', '9986', (307, 313))	('HIF-2alpha', 'Gene', '2034', (193, 203))	('HIF-1', 'Gene', (122, 127))	('Cay10006421', 'Var', (179, 190))	('HIF-1', 'Gene', '3091', (237, 242))	('HIF-1alpha', 'Gene', (122, 132))	('H3K4me3', 'Var', (347, 354))	('PM8', 'Species', '1214577', (231, 234))	('rabbit', 'Species', '9986', (248, 254))	('HIF-1', 'Gene', (237, 242))	('rabbit', 'Species', '9986', (421, 427))	('HIF-2alpha', 'Gene', (193, 203))	('rabbit', 'Species', '9986', (356, 362))	('rabbit', 'Species', '9986', (134, 140))	('H3K27ac', 'Var', (412, 419))	('rabbit', 'Species', '9986', (205, 211))	('HIF-1', 'Gene', '3091', (122, 127))	('Signaling', 'biological_process', 'GO:0023052', ('380', '389'))	('H3K4me1', 'Var', (298, 305))
141940	28715484	ChIP-seq data are available from the Gene Expression Omnibus: GSE67237 (HIF-2alpha and HIF-1beta ChIP-seq in 786-O cells); GSE78113 (histone modifications in 786-O cells); GSM1011120 (FAIRE-seq in 786-O cells) and GSE101064 (FAIRE and ChIP-seq in human primary tubular cells).	('human', 'Species', '9606', (247, 252))	('GSE78113', 'Var', (123, 131))	('GSM1011120', 'Var', (172, 182))	('HIF-2alpha and HIF-1beta', 'Disease', 'None', (72, 96))	('Gene Expression', 'biological_process', 'GO:0010467', ('37', '52'))	('GSE101064', 'Var', (214, 223))
141941	28715484	TCGA level 3 RNA-Seq expression data for 450 clear cell Renal Cell Carcinoma patients was associated with Affymetrix Genome-Wide Human SNP Array 6.0 level 2 data on the same tumors, which included genotyping data for rs12814794.	('clear cell Renal Cell Carcinoma', 'Disease', (45, 76))	('tumors', 'Disease', (174, 180))	('clear cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (45, 76))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (56, 76))	('clear cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (45, 76))	('rs12814794', 'Mutation', 'rs12814794', (217, 227))	('patients', 'Species', '9606', (77, 85))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('TCGA', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('rs12814794', 'Var', (217, 227))	('Human', 'Species', '9606', (129, 134))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('Carcinoma', 'Phenotype', 'HP:0030731', (67, 76))
141944	28715484	To identify samples heterozygous for the common and rare alleles at rs1048155 and rs12814794 DNA from cell lines and primary tubular cells was genotyped using TaqMan assays (S1 Table, Life Technologies).	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('rs12814794 DNA', 'Var', (82, 96))	('rs12814794', 'Mutation', 'rs12814794', (82, 92))	('rs1048155', 'Mutation', 'rs1048155', (68, 77))	('rs1048155', 'Var', (68, 77))
141984	31597249	This therapy is composed by a carrier molecule (SSA), a radionuclide isotope (111In, 90Y and 177Lu), and a chelator [Tetra-azacyclododecane-tetra-acetic acid (DOTA) and diethylenetriamine penta-acetic acid (DTPA)] that binds and stabilizes the complex.	('SSA', 'Gene', '6737', (48, 51))	('diethylenetriamine penta-acetic acid', 'Chemical', 'MESH:C583865', (169, 205))	('DTPA', 'Chemical', 'MESH:C583865', (207, 211))	('carrier', 'molecular_function', 'GO:0005215', ('30', '37'))	('binds', 'Interaction', (219, 224))	('90Y', 'Var', (85, 88))	('111In', 'Var', (78, 83))	('SSA', 'Gene', (48, 51))	('Tetra', 'Species', '42554', (117, 122))	('DOTA', 'Chemical', 'MESH:C071349', (159, 163))	('tetra', 'Species', '42554', (140, 145))	('177Lu', 'Chemical', 'MESH:C575017', (93, 98))
141985	31597249	So far, the most satisfactory results have been obtained with 177Lu-based radiolabelled SSAs, based on the phase III trial NETTER 1.	('SSA', 'Gene', '6737', (88, 91))	('SSA', 'Gene', (88, 91))	('177Lu', 'Chemical', 'MESH:C575017', (62, 67))	('177Lu-based radiolabelled', 'Var', (62, 87))
142012	31597249	In a cohort involving 59% of early stage and 41% of metastatic P-NETs, mutations were identified in genes involved in chromatin remodelling such as MEN1, DAXX and ATRX as well as those implicated in mTOR pathway (PTEN and TSC2).	('PTEN', 'Gene', '5728', (213, 217))	('mTOR', 'Gene', (199, 203))	('NETs', 'Disease', 'MESH:D018358', (65, 69))	('ATRX', 'Gene', '546', (163, 167))	('DAXX', 'Gene', (154, 158))	('MEN1', 'Gene', '4221', (148, 152))	('chromatin', 'cellular_component', 'GO:0000785', ('118', '127'))	('MEN1', 'Gene', (148, 152))	('DAXX', 'Gene', '1616', (154, 158))	('mutations', 'Var', (71, 80))	('NETs', 'Disease', (65, 69))	('ATRX', 'Gene', (163, 167))	('TSC2', 'Gene', '7249', (222, 226))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('118', '139'))	('TSC2', 'Gene', (222, 226))	('mTOR', 'Gene', '2475', (199, 203))	('PTEN', 'Gene', (213, 217))
142013	31597249	It was noticed that tumors that have mutations in both MEN1 and either ATRX or DAXX have a 100% OS at 10 years, whilst in the absence of this mutation, 60% die within 5 years.	('DAXX', 'Gene', '1616', (79, 83))	('tumors', 'Disease', (20, 26))	('MEN1', 'Gene', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('MEN1', 'Gene', '4221', (55, 59))	('ATRX', 'Gene', '546', (71, 75))	('DAXX', 'Gene', (79, 83))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('ATRX', 'Gene', (71, 75))
142016	31597249	Four molecular pathways were found to be involved in the development of these tumors: (1) DNA damage repair: Germline mutations seem to have an important role in the development of P-NETs; several germline-damaging variants of the base-excision-repair MUTYH gene and the homologous recombination genes BRCA2 and CHEK2 have been reported.	('homologous recombination', 'biological_process', 'GO:0035825', ('271', '295'))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('NETs', 'Disease', 'MESH:D018358', (183, 187))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('base-excision-repair', 'biological_process', 'GO:0006284', ('231', '251'))	('MUTYH', 'Gene', (252, 257))	('MUTYH', 'Gene', '4595', (252, 257))	('BRCA2', 'Gene', '675', (302, 307))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('variants', 'Var', (215, 223))	('CHEK2', 'Gene', '11200', (312, 317))	('NETs', 'Disease', (183, 187))	('CHEK2', 'Gene', (312, 317))	('BRCA2', 'Gene', (302, 307))
142017	31597249	(2) Chromatin remodelling: Inactivating mutations of MEN1, SETD2, ARID1A, and MLL3 lead to widespread transcriptional dysregulation.	('MLL3', 'Gene', (78, 82))	('widespread transcriptional dysregulation', 'MPA', (91, 131))	('SETD2', 'Gene', '29072', (59, 64))	('ARID1A', 'Gene', '8289', (66, 72))	('Chromatin remodelling', 'biological_process', 'GO:0006338', ('4', '25'))	('ARID1A', 'Gene', (66, 72))	('Inactivating mutations', 'Var', (27, 49))	('SETD2', 'Gene', (59, 64))	('Chromatin', 'cellular_component', 'GO:0000785', ('4', '13'))	('lead to', 'Reg', (83, 90))	('MEN1', 'Gene', '4221', (53, 57))	('MLL3', 'Gene', '58508', (78, 82))	('MEN1', 'Gene', (53, 57))
142018	31597249	(3) Telomere maintenance: Approximately one third of P-NETs express inactivating mutations in DAXX or ATRX, which correlates with telomere length and repeat content, hence resulting in a poorer prognosis, (4) mTOR signalling activation: Several inactivating mutations have been described in inhibitors of the mTOR signalling pathway, such as PTEN, TSC1, TSC2, EWSR1, and DEPDC5.	('ATRX', 'Gene', (102, 106))	('TSC2', 'Gene', '7249', (354, 358))	('TSC1', 'Gene', (348, 352))	('EWSR1', 'Gene', '2130', (360, 365))	('ATRX', 'Gene', '546', (102, 106))	('DAXX', 'Gene', (94, 98))	('DEPDC5', 'Gene', '9681', (371, 377))	('mutations', 'Var', (81, 90))	('mTOR', 'Gene', (209, 213))	('Telomere', 'cellular_component', 'GO:0000781', ('4', '12'))	('DEPDC5', 'Gene', (371, 377))	('TSC1', 'Gene', '7248', (348, 352))	('Telomere', 'cellular_component', 'GO:0005696', ('4', '12'))	('Telomere maintenance', 'biological_process', 'GO:0000723', ('4', '24'))	('TSC2', 'Gene', (354, 358))	('DAXX', 'Gene', '1616', (94, 98))	('telomere', 'cellular_component', 'GO:0000781', ('130', '138'))	('mTOR', 'Gene', '2475', (209, 213))	('telomere', 'cellular_component', 'GO:0005696', ('130', '138'))	('NETs', 'Disease', 'MESH:D018358', (55, 59))	('EWSR1', 'Gene', (360, 365))	('mTOR', 'Gene', (309, 313))	('signalling', 'biological_process', 'GO:0023052', ('214', '224'))	('signalling pathway', 'biological_process', 'GO:0007165', ('314', '332'))	('PTEN', 'Gene', (342, 346))	('mTOR', 'Gene', '2475', (309, 313))	('NETs', 'Disease', (55, 59))	('PTEN', 'Gene', '5728', (342, 346))
142032	31597249	The activation of HIF1alpha is driven by genetic inactivation of VHL protein and the stimulating hypoxic conditions that are typically present in P-NET cellular environment.	('hypoxic conditions', 'Disease', 'MESH:D009135', (97, 115))	('VHL', 'Gene', '7428', (65, 68))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('genetic inactivation', 'Var', (41, 61))	('hypoxic conditions', 'Disease', (97, 115))	('HIF1alpha', 'Gene', (18, 27))	('HIF1alpha', 'Gene', '3091', (18, 27))	('VHL', 'Gene', (65, 68))	('activation', 'PosReg', (4, 14))
142033	31597249	Chromogranin A (CgA) is a protein that is commonly expressed and secreted by P-NETs and its positivity on IHQ is a diagnostic hallmark of GEP-NETs, while serum CgA is used for follow up.	('Chromogranin A', 'Gene', (0, 14))	('NETs', 'Disease', 'MESH:D018358', (79, 83))	('Chromogranin A', 'Gene', '1113', (0, 14))	('NETs', 'Disease', 'MESH:D018358', (142, 146))	('CgA', 'Gene', (160, 163))	('GEP', 'Gene', '2896', (138, 141))	('CgA', 'Gene', (16, 19))	('GEP', 'Gene', (138, 141))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('NETs', 'Disease', (79, 83))	('CgA', 'Gene', '1113', (16, 19))	('NETs', 'Disease', (142, 146))	('CgA', 'Gene', '1113', (160, 163))	('positivity', 'Var', (92, 102))
142039	31597249	Later on, the phase III clinical trial SUN1111 comparing sunitinib with placebo, showed an improvement in PFS (11.4 vs. 5.5 months) and OS (median not reached, but the observed HR favoured sunitinib), being then approved by the regulatory agencies for the treatment of P-NETs.	('sunitinib', 'Chemical', 'MESH:C473478', (57, 66))	('PFS', 'MPA', (106, 109))	('SUN1111', 'Chemical', 'MESH:C004377', (39, 46))	('NETs', 'Disease', (271, 275))	('sunitinib', 'Chemical', 'MESH:C473478', (189, 198))	('SUN1111', 'Var', (39, 46))	('NETs', 'Disease', 'MESH:D018358', (271, 275))
142048	31597249	Firstly, the VHL gene can be inactivated by genetic or epigenetic alterations, either because of germline mutations as part of VHL disease or because of somatic mutations in sporadic P-NETs.	('epigenetic alterations', 'Var', (55, 77))	('rat', 'Species', '10116', (70, 73))	('VHL', 'Gene', (13, 16))	('VHL', 'Gene', (127, 130))	('NETs', 'Disease', (185, 189))	('mutations', 'Var', (161, 170))	('mutations', 'Var', (106, 115))	('inactivated', 'NegReg', (29, 40))	('VHL', 'Gene', '7428', (127, 130))	('VHL', 'Gene', '7428', (13, 16))	('NETs', 'Disease', 'MESH:D018358', (185, 189))
142060	31597249	Moreover, thanks to its vascular normalizing activity, Sema3A ameliorates blood vessel function and improves cancer tissue oxygenation through its ability to induce normoxia, thus counteracting the TME hypoxia created by sunitinib-induced activation of HIF-1alpha, EMT, and c-MET.	('c-MET', 'Gene', '4233', (274, 279))	('EMT', 'biological_process', 'GO:0001837', ('265', '268'))	('normoxia', 'MPA', (165, 173))	('blood vessel function', 'CPA', (74, 95))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('HIF-1alpha', 'Gene', '3091', (253, 263))	('oxygen', 'Chemical', 'MESH:D010100', (123, 129))	('cancer', 'Disease', (109, 115))	('ameliorates', 'PosReg', (62, 73))	('Sema3A', 'Var', (55, 61))	('hypoxia', 'Disease', (202, 209))	('hypoxia', 'Disease', 'MESH:D000860', (202, 209))	('rat', 'Species', '10116', (68, 71))	('improves', 'PosReg', (100, 108))	('c-MET', 'Gene', (274, 279))	('HIF-1alpha', 'Gene', (253, 263))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('sunitinib', 'Chemical', 'MESH:C473478', (221, 230))
142102	31597249	In ccRCC, VHL inactivation induces overexpression and activation of c-MET and AXL.	('c-MET', 'Gene', '4233', (68, 73))	('AXL', 'Gene', '558', (78, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('inactivation', 'Var', (14, 26))	('ccRCC', 'Disease', 'MESH:D002292', (3, 8))	('activation', 'PosReg', (54, 64))	('AXL', 'Gene', (78, 81))	('ccRCC', 'Disease', (3, 8))	('VHL', 'Gene', (10, 13))	('c-MET', 'Gene', (68, 73))	('overexpression', 'PosReg', (35, 49))	('VHL', 'Gene', '7428', (10, 13))
142112	31597249	The expression of Ang2 seems to be the principal regulator of this process: The absence of VEGF facilitates vessel regression but its presence favours angiogenesis.	('absence', 'Var', (80, 87))	('Ang2', 'Gene', (18, 22))	('Ang2', 'Gene', '285', (18, 22))	('favours', 'PosReg', (143, 150))	('facilitates', 'PosReg', (96, 107))	('vessel regression', 'CPA', (108, 125))	('presence', 'Var', (134, 142))	('angiogenesis', 'CPA', (151, 163))	('angiogenesis', 'biological_process', 'GO:0001525', ('151', '163'))	('VEGF', 'Protein', (91, 95))
142136	31597249	Similarly, poor differentiation (G3 neuroendocrine carcinomas) was associated to a higher TAM infiltration when compared to well-differentiated tumors (p < 0.0001).	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('poor differentiation', 'Var', (11, 31))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (36, 61))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('neuroendocrine carcinomas', 'Disease', (36, 61))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (36, 61))	('TAM infiltration', 'CPA', (90, 106))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (36, 60))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('higher', 'PosReg', (83, 89))	('rat', 'Species', '10116', (100, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
142151	31597249	It has been found that using PDGFRbeta inhibitors to target tumor-associated pericytes, along with standard antiangiogenic therapies, reduces pericyte coverage of blood vessels, showing a synergic efficacy.	('pericyte coverage of blood vessels', 'CPA', (142, 176))	('inhibitors', 'Var', (39, 49))	('PDGFRbeta', 'Gene', '5159', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('PDGFRbeta', 'Gene', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('reduces', 'NegReg', (134, 141))	('tumor', 'Disease', (60, 65))
142164	31597249	Furthermore, high ATX expression was associated with higher tumor grade, TNM staging and lymph node metastasis.	('ATX', 'Gene', '5168', (18, 21))	('high', 'Var', (13, 17))	('TNM', 'Gene', '10178', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('lymph node metastasis', 'CPA', (89, 110))	('TNM', 'Gene', (73, 76))	('tumor', 'Disease', (60, 65))	('expression', 'MPA', (22, 32))	('ATX', 'Gene', (18, 21))
142168	31597249	Recently, a pathologic analysis of 144 non-metastatic primary GEP-NETs who underwent curative-intent resection showed that high STAT3 expression is associated with an increased Ki67 index, presence of lymphovascular invasion, and worse 3 years relapse-free survival.	('STAT3', 'Gene', '6774', (128, 133))	('expression', 'MPA', (134, 144))	('NETs', 'Disease', 'MESH:D018358', (66, 70))	('Ki67 index', 'CPA', (177, 187))	('GEP', 'Gene', (62, 65))	('lymphovascular invasion', 'CPA', (201, 224))	('high', 'Var', (123, 127))	('STAT3', 'Gene', (128, 133))	('increased', 'PosReg', (167, 176))	('NETs', 'Disease', (66, 70))	('GEP', 'Gene', '2896', (62, 65))	('rat', 'Species', '10116', (87, 90))
142179	31597249	Also, using an inhibitor of EZH2 has been shown to increase the activation of tumor suppressor and re-establish sensitivity to sunitinib in both cell lines and PDX models.	('increase', 'PosReg', (51, 59))	('sensitivity to sunitinib', 'MPA', (112, 136))	('re-establish', 'MPA', (99, 111))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('EZH2', 'Gene', '2146', (28, 32))	('tumor suppressor', 'biological_process', 'GO:0051726', ('78', '94'))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('EZH2', 'Gene', (28, 32))	('sunitinib', 'Chemical', 'MESH:C473478', (127, 136))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('78', '94'))	('activation', 'PosReg', (64, 74))	('inhibitor', 'Var', (15, 24))
142195	31597249	Its importance relays on the fact that high PlGF levels are associated with reduced tumor-related survival and/or shorter time-to-progression.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('high', 'Var', (39, 43))	('PlGF', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('reduced', 'NegReg', (76, 83))	('PlGF', 'Gene', '5228', (44, 48))
142207	31597249	Several multi-TKIs with combined anti-VEGF and anti-MET activity have shown increased angiogenesis inhibition and suppressed tumor invasion and metastasis in P-NET models.	('angiogenesis', 'biological_process', 'GO:0001525', ('86', '98'))	('tumor invasion', 'Disease', (125, 139))	('increased', 'PosReg', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('anti-MET', 'Var', (47, 55))	('angiogenesis inhibition', 'CPA', (86, 109))	('tumor invasion', 'Disease', 'MESH:D009361', (125, 139))	('suppressed', 'NegReg', (114, 124))
142215	31597249	For instance, the molecular compound CVM-1118 is a potent anti-cancer agent that inhibits vascular mimicry formation, and is currently being tested in a phase II clinical trial, which results have to be awaited.	('inhibits', 'NegReg', (81, 89))	('vascular mimicry formation', 'CPA', (90, 116))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('CVM-1118', 'Var', (37, 45))	('formation', 'biological_process', 'GO:0009058', ('107', '116'))	('CVM-1118', 'Chemical', 'MESH:C553487', (37, 45))	('cancer', 'Disease', (63, 69))
142250	27701871	These subtypes are (I) mutant BRAF, (II) mutant NRAS, (III) mutant NF1, and (IV) triple wild-type.	('NF1', 'Gene', (67, 70))	('NRAS', 'Gene', '4893', (48, 52))	('mutant', 'Var', (41, 47))	('NF1', 'Gene', '4763', (67, 70))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('mutant', 'Var', (60, 66))	('NRAS', 'Gene', (48, 52))	('mutant', 'Var', (23, 29))
142251	27701871	About 50% of cutaneous melanomas (but only a very small percentage of acral-lentiginous, desmoplastic, uveal and mucosal melanomas) fall into the first subtype as they harbor BRAF mutations.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('mucosal melanomas', 'Disease', (113, 130))	('melanomas', 'Phenotype', 'HP:0002861', (121, 130))	('mucosal melanomas', 'Disease', 'MESH:D008545', (113, 130))	('mutations', 'Var', (180, 189))	('cutaneous melanomas', 'Disease', (13, 32))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanomas', 'Phenotype', 'HP:0002861', (23, 32))	('BRAF', 'Gene', (175, 179))	('BRAF', 'Gene', '673', (175, 179))	('fall', 'Phenotype', 'HP:0002527', (132, 136))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (13, 31))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (13, 32))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (13, 32))
142252	27701871	BRAF mutations lead to activation of the mitogen-activated protein kinases (MAPK) pathway.	('MAPK', 'molecular_function', 'GO:0004707', ('76', '80'))	('mutations', 'Var', (5, 14))	('activation', 'PosReg', (23, 33))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
142253	27701871	Many patients with BRAF mutant metastatic melanoma first receive treatment with BRAF inhibitors alone or with MEK inhibitors and some are then treated with anti-PD-1 therapy after they develop resistance to MAPK-targeted therapy.	('mutant', 'Var', (24, 30))	('melanoma', 'Disease', (42, 50))	('BRAF', 'Gene', (80, 84))	('BRAF', 'Gene', '673', (19, 23))	('patients', 'Species', '9606', (5, 13))	('MAPK', 'molecular_function', 'GO:0004707', ('207', '211'))	('BRAF', 'Gene', (19, 23))	('MEK', 'Gene', (110, 113))	('MEK', 'Gene', '5609', (110, 113))	('BRAF', 'Gene', '673', (80, 84))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
142264	27701871	Malignant tumors all have mutations in their somatic DNA that are not present in the patient's germline DNA.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('patient', 'Species', '9606', (85, 92))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('Malignant tumors', 'Disease', 'MESH:D009369', (0, 16))	('mutations', 'Var', (26, 35))	('Malignant tumors', 'Disease', (0, 16))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))
142268	27701871	Tumor specimens obtained from melanoma patients responding to anti-PD-1 therapy harbored more nsSNV mutations and more human leukocyte antigen (HLA) class I and class II neoepitopes compared to the non-responding patients, but this association did not reach statistical significance.	('mutations', 'Var', (100, 109))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('patients', 'Species', '9606', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('patients', 'Species', '9606', (213, 221))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanoma', 'Disease', (30, 38))	('nsSNV', 'Gene', (94, 99))	('more', 'PosReg', (114, 118))	('human', 'Species', '9606', (119, 124))
142273	27701871	BRCA2 mutations are frequently observed within the tumor specimens of melanoma patients responding to anti-PD-1 therapy.	('melanoma', 'Disease', (70, 78))	('BRCA2', 'Gene', '675', (0, 5))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('BRCA2', 'Gene', (0, 5))	('patients', 'Species', '9606', (79, 87))	('observed', 'Reg', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('mutations', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
142274	27701871	then went on to analyze the genetic variations (nsSNVs, small insertions and deletions, copy number changes) in tumors prior to treatment, and then looked for differences between responding and non-responding patients on anti-PD-1 therapy.	('deletions', 'Var', (77, 86))	('tumors', 'Disease', (112, 118))	('copy number changes', 'Var', (88, 107))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('patients', 'Species', '9606', (209, 217))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
142276	27701871	BRCA2 copy number changes, nsSNV, mutations resulting in the net change in the number of nucleotides resulting from the insertion and deletions of nucleotides (INDEL) or mutant allele copy number gain were significantly more frequently found in tumors from patients responding to treatment.	('BRCA2', 'Gene', '675', (0, 5))	('gain', 'PosReg', (196, 200))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('insertion', 'Var', (120, 129))	('number of nucleotides', 'MPA', (79, 100))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('found', 'Reg', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('deletions', 'NegReg', (134, 143))	('change', 'Reg', (65, 71))	('BRCA2', 'Gene', (0, 5))	('patients', 'Species', '9606', (257, 265))	('mutant allele copy number', 'Var', (170, 195))	('tumors', 'Disease', (245, 251))	('mutations', 'Var', (34, 43))
142277	27701871	The pattern of BRCA2 mutations suggested that they were loss of function mutations.	('BRCA2', 'Gene', '675', (15, 20))	('BRCA2', 'Gene', (15, 20))	('loss of function', 'NegReg', (56, 72))	('mutations', 'Var', (21, 30))
142278	27701871	Loss of function mutations in BRCA2 are known to lead to defects in homologous recombination and double-strand break repair.	('homologous recombination', 'MPA', (68, 92))	('Loss of function', 'NegReg', (0, 16))	('double-strand break repair', 'biological_process', 'GO:0006302', ('97', '123'))	('defects', 'NegReg', (57, 64))	('BRCA2', 'Gene', (30, 35))	('homologous recombination', 'biological_process', 'GO:0035825', ('68', '92'))	('double-strand', 'CPA', (97, 110))	('mutations', 'Var', (17, 26))	('BRCA2', 'Gene', '675', (30, 35))
142279	27701871	Therefore, it is possible that the loss of BRCA2 leads to an environment where the cancer cell may undergo apoptosis or has preferential selection of mutations that lead to anti-PD-1 responsiveness.	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('leads to', 'Reg', (49, 57))	('loss', 'Var', (35, 39))	('lead to', 'Reg', (165, 172))	('BRCA2', 'Gene', (43, 48))	('mutations', 'Var', (150, 159))	('anti-PD-1 responsiveness', 'MPA', (173, 197))	('BRCA2', 'Gene', '675', (43, 48))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
142297	27701871	BRCA2 loss of function mutations were found to be associated with anti-PD-1 responsiveness.	('BRCA2', 'Gene', '675', (0, 5))	('loss of function', 'NegReg', (6, 22))	('mutations', 'Var', (23, 32))	('anti-PD-1 responsiveness', 'MPA', (66, 90))	('BRCA2', 'Gene', (0, 5))
142298	27701871	The mutational load of melanoma may be associated with overall survival, but there is insufficient evidence to predict responsiveness to anti-PD-1 therapy based on this paper.	('mutational load', 'Var', (4, 19))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('overall', 'MPA', (55, 62))	('melanoma', 'Disease', (23, 31))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('associated', 'Reg', (39, 49))
142322	33772065	Classically, STAT3 activation relies on the phosphorylation of its tyrosine 705 (Y705), nonetheless, recent reports described the phosphorylation of its serine 727 (S727) as a novel and non-canonical mechanism of STAT3 activation.	('phosphorylation', 'biological_process', 'GO:0016310', ('44', '59'))	('S727', 'Var', (165, 169))	('phosphorylation', 'biological_process', 'GO:0016310', ('130', '145'))	('tyrosine', 'Chemical', 'MESH:D014443', (67, 75))	('STAT3', 'Gene', '6774', (213, 218))	('Y705', 'Var', (81, 85))	('STAT3', 'Gene', '6774', (13, 18))	('serine', 'Chemical', 'MESH:D012694', (153, 159))	('STAT3', 'Gene', (213, 218))	('STAT3', 'Gene', (13, 18))
142323	33772065	Previously, and in order to establish the role of STAT3 in the ccRCC, our group analyzed the expression of both phosphorylated residues (pY705 and pS727) on localized tumor samples from 98 ccRCC patients who had not undergone chemo- or immunotherapy before or after nephrectomy.	('pY705', 'Chemical', '-', (137, 142))	('pY705', 'Var', (137, 142))	('RCC', 'Disease', (191, 194))	('STAT3', 'Gene', '6774', (50, 55))	('RCC', 'Disease', 'MESH:C538614', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('STAT3', 'Gene', (50, 55))	('patients', 'Species', '9606', (195, 203))	('pS727', 'Var', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('tumor', 'Disease', (167, 172))	('RCC', 'Disease', (65, 68))
142341	33772065	Conventionally, an activated STAT3, either by Y705 or S727 phosphorylation, is predominantly located within the nucleus regulating gene expression; however, recent studies have demonstrated that STAT3 phosphorylated at its S727 also exerts non-genomic functions in the mitochondria and the endoplasmic reticulum (ER).	('STAT3', 'Gene', '6774', (29, 34))	('S727', 'Var', (223, 227))	('nucleus', 'cellular_component', 'GO:0005634', ('112', '119'))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('290', '311'))	('Y705', 'Var', (46, 50))	('mitochondria', 'cellular_component', 'GO:0005739', ('269', '281'))	('gene expression', 'biological_process', 'GO:0010467', ('131', '146'))	('STAT3', 'Gene', (29, 34))	('phosphorylation', 'biological_process', 'GO:0016310', ('59', '74'))	('exerts', 'Reg', (233, 239))	('STAT3', 'Gene', '6774', (195, 200))	('non-genomic functions', 'CPA', (240, 261))	('STAT3', 'Gene', (195, 200))
142356	33772065	In that scenario, a previous study from our group pointed out the role of STAT3 in ccRCC by demonstrating, for the first time, that nuclear presence of its phosphorylated form (at S727) correlated with the overall survival of ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (228, 231))	('patients', 'Species', '9606', (232, 240))	('RCC', 'Disease', (228, 231))	('STAT3', 'Gene', '6774', (74, 79))	('STAT3', 'Gene', (74, 79))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', (85, 88))	('at S727', 'Var', (177, 184))	('correlated with', 'Reg', (186, 201))
142357	33772065	Accordingly, over the past years, it has been extensively confirmed that abnormal activation of STAT3:either by Y705 or S727 phosphorylation:is a key event that contributes to oncogenesis in several tumors other than ccRCC.	('STAT3', 'Gene', (96, 101))	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('STAT3', 'Gene', '6774', (96, 101))	('contributes', 'Reg', (161, 172))	('activation', 'PosReg', (82, 92))	('oncogenesis', 'biological_process', 'GO:0007048', ('176', '187'))	('Y705', 'Var', (112, 116))	('S727 phosphorylation', 'Var', (120, 140))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('phosphorylation', 'biological_process', 'GO:0016310', ('125', '140'))	('RCC', 'Disease', (219, 222))	('oncogenesis', 'CPA', (176, 187))	('RCC', 'Disease', 'MESH:C538614', (219, 222))
142360	33772065	Aligned with our results, other studies evaluating STAT3 activation (via pY705 or pS727) on tissue samples of other cancer types such as cervical intraepithelial neoplasia (CIN) and prostate cancer, have also reported a significant correlation of pS727-STAT3 levels to the clinical outcome of those patients.	('STAT3', 'Gene', '6774', (51, 56))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('neoplasia', 'Phenotype', 'HP:0002664', (162, 171))	('pS727', 'Var', (82, 87))	('STAT3', 'Gene', (253, 258))	('patients', 'Species', '9606', (299, 307))	('cancer', 'Disease', (191, 197))	('activation', 'PosReg', (57, 67))	('STAT3', 'Gene', '6774', (253, 258))	('pY705', 'Chemical', '-', (73, 78))	('pY705', 'Var', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cervical intraepithelial neoplasia', 'Phenotype', 'HP:0032242', (137, 171))	('prostate cancer', 'Phenotype', 'HP:0012125', (182, 197))	('cancer', 'Disease', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (146, 171))	('neoplasia (CIN) and prostate cancer', 'Disease', 'MESH:D011471', (162, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('STAT3', 'Gene', (51, 56))
142368	33772065	Since both pY705- and pS727-STAT3 localize to the ER and MAMs, phosphoablative mutants (Y705F and S727A) were used to evaluate their effect on IP3R3-mediated Ca2+ release founding that only pSer727-STAT3 inhibited Ca2+ release by interacting with IP3R3 and facilitating its degradation via the proteasome, thus, avoiding apoptosis.	('inhibited', 'NegReg', (204, 213))	('Y705F', 'Var', (88, 93))	('S727A', 'Var', (98, 103))	('pY705', 'Chemical', '-', (11, 16))	('IP3R3', 'Gene', '3710', (247, 252))	('STAT3', 'Gene', (198, 203))	('pY705-', 'Var', (11, 17))	('STAT3', 'Gene', '6774', (198, 203))	('S727A', 'Mutation', 'p.S727A', (98, 103))	('IP3R3', 'Gene', '3710', (143, 148))	('degradation', 'MPA', (274, 285))	('degradation', 'biological_process', 'GO:0009056', ('274', '285'))	('interacting', 'Interaction', (230, 241))	('facilitating', 'NegReg', (257, 269))	('STAT3', 'Gene', (28, 33))	('Y705F', 'Mutation', 'p.Y705F', (88, 93))	('Ca2+ release', 'MPA', (214, 226))	('proteasome', 'molecular_function', 'GO:0004299', ('294', '304'))	('apoptosis', 'CPA', (321, 330))	('avoiding', 'NegReg', (312, 320))	('IP3R3', 'Gene', (247, 252))	('STAT3', 'Gene', '6774', (28, 33))	('Ca2+', 'Chemical', 'MESH:D000069285', (214, 218))	('apoptosis', 'biological_process', 'GO:0097194', ('321', '330'))	('apoptosis', 'biological_process', 'GO:0006915', ('321', '330'))	('Ca2+', 'Chemical', 'MESH:D000069285', (158, 162))	('proteasome', 'cellular_component', 'GO:0000502', ('294', '304'))	('IP3R3', 'Gene', (143, 148))
142380	33772065	Based on this study and our observation that ccRCC patients with a high pS727-STAT3 expression which undergone TKIs treatment experienced a significant stabilization of the disease (~ 20 months), we postulated that determination of pS727-STAT3 levels at the time of surgery could indicate that patients with localized tumors might benefit from adjuvant treatment versus those that only will suffer the adverse effects.	('high', 'Var', (67, 71))	('localized tumors', 'Disease', (308, 324))	('STAT3', 'Gene', '6774', (238, 243))	('men', 'Species', '9606', (358, 361))	('men', 'Species', '9606', (121, 124))	('patients', 'Species', '9606', (294, 302))	('STAT3', 'Gene', '6774', (78, 83))	('localized tumors', 'Disease', 'MESH:D009364', (308, 324))	('STAT3', 'Gene', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('STAT3', 'Gene', (78, 83))	('benefit', 'PosReg', (331, 338))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('patients', 'Species', '9606', (51, 59))	('tumors', 'Phenotype', 'HP:0002664', (318, 324))
142458	33413672	Interestingly, the same authors reported that near-complete ablation of SR-B2/CD36 mRNA reduced free fatty acid uptake by only 35% in PC-3 prostate cancer cells.	('uptake', 'biological_process', 'GO:0098739', ('112', '118'))	('PC-3 prostate cancer', 'Disease', (134, 154))	('ablation', 'Var', (60, 68))	('free fatty acid', 'Chemical', 'MESH:D005230', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('free fatty acid uptake', 'MPA', (96, 118))	('mRNA', 'Var', (83, 87))	('SR-B', 'Gene', '10575', (72, 76))	('PC-3 prostate cancer', 'Disease', 'MESH:D011471', (134, 154))	('reduced', 'NegReg', (88, 95))	('prostate cancer', 'Phenotype', 'HP:0012125', (139, 154))	('SR-B', 'Gene', (72, 76))	('uptake', 'biological_process', 'GO:0098657', ('112', '118'))
142459	33413672	This is consistent with knockdown of SR-B2/CD36 in SKOV3ip1 ovarian cancer cells which attenuated fatty acid uptake by ~ 40%.	('uptake', 'biological_process', 'GO:0098739', ('109', '115'))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (60, 74))	('SR-B', 'Gene', (37, 41))	('SR-B', 'Gene', '10575', (37, 41))	('SKOV3ip1', 'CellLine', 'CVCL:0C84', (51, 59))	('ovarian cancer', 'Disease', 'MESH:D010051', (60, 74))	('attenuated', 'NegReg', (87, 97))	('fatty acid', 'Chemical', 'MESH:D005227', (98, 108))	('ovarian cancer', 'Disease', (60, 74))	('uptake', 'biological_process', 'GO:0098657', ('109', '115'))	('fatty acid uptake', 'MPA', (98, 115))	('knockdown', 'Var', (24, 33))
142460	33413672	In vivo, ablation of SR-B2/CD36 in the prostate tissue of Pten-deficient mice reduced fatty acid uptake by ~ 55%, while treating mice harboring PDXs of localized high-risk prostate cancer with a SR-B2/CD36 mAb reduced fatty acid uptake by 22%.	('SR-B', 'Gene', '10575', (195, 199))	('fatty acid', 'Chemical', 'MESH:D005227', (218, 228))	('fatty acid uptake', 'MPA', (218, 235))	('SR-B', 'Gene', (21, 25))	('uptake', 'biological_process', 'GO:0098657', ('97', '103'))	('n-', 'Chemical', 'MESH:D009584', (61, 63))	('SR-B', 'Gene', (195, 199))	('uptake', 'biological_process', 'GO:0098739', ('97', '103'))	('mice', 'Species', '10090', (129, 133))	('Pten', 'Gene', '5728', (58, 62))	('Pten', 'Gene', (58, 62))	('ablation', 'Var', (9, 17))	('mice', 'Species', '10090', (73, 77))	('reduced', 'NegReg', (78, 85))	('uptake', 'biological_process', 'GO:0098657', ('229', '235'))	('fatty acid', 'Chemical', 'MESH:D005227', (86, 96))	('prostate cancer', 'Disease', 'MESH:D011471', (172, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('prostate cancer', 'Phenotype', 'HP:0012125', (172, 187))	('fatty acid uptake', 'MPA', (86, 103))	('SR-B', 'Gene', '10575', (21, 25))	('prostate cancer', 'Disease', (172, 187))	('uptake', 'biological_process', 'GO:0098739', ('229', '235'))
142463	33413672	For example, prostate-specific deletion of SR-B2/CD36 of cancer-susceptible Pten-/- mice slowed cancer progression, while SR-B2/CD36 antibody therapy reduced cancer severity in patient-derived xenografts.	('cancer', 'Disease', (57, 63))	('deletion', 'Var', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', (96, 102))	('Pten', 'Gene', '5728', (76, 80))	('mice', 'Species', '10090', (84, 88))	('Pten', 'Gene', (76, 80))	('antibody', 'cellular_component', 'GO:0019815', ('133', '141'))	('n-', 'Chemical', 'MESH:D009584', (79, 81))	('SR-B', 'Gene', '10575', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('SR-B', 'Gene', '10575', (122, 126))	('slowed', 'NegReg', (89, 95))	('cancer', 'Disease', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('SR-B', 'Gene', (43, 47))	('antibody', 'cellular_component', 'GO:0019814', ('133', '141'))	('SR-B', 'Gene', (122, 126))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('antibody', 'molecular_function', 'GO:0003823', ('133', '141'))	('antibody', 'cellular_component', 'GO:0042571', ('133', '141'))	('patient', 'Species', '9606', (177, 184))
142493	33413672	Recent examples include knockdown of ACLY impairing pancreatic tumor formation and knockdown of FASN blocking tumor development in mTOR-driven liver cancer, while pharmacological inhibition of FAS reduced tumor growth in preclinical models of castration-resistant prostate cancer.	('impairing', 'NegReg', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('mTOR', 'Gene', (131, 135))	('tumor growth', 'Disease', 'MESH:D006130', (205, 217))	('FASN', 'Gene', '2194', (96, 100))	('knockdown', 'Var', (83, 92))	('formation', 'biological_process', 'GO:0009058', ('69', '78'))	('FAS', 'Gene', '2194', (193, 196))	('prostate cancer', 'Disease', 'MESH:D011471', (264, 279))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('mTOR', 'Gene', '2475', (131, 135))	('prostate cancer', 'Phenotype', 'HP:0012125', (264, 279))	('n-', 'Chemical', 'MESH:D009584', (252, 254))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (52, 68))	('FAS', 'Gene', '2194', (96, 99))	('prostate cancer', 'Disease', (264, 279))	('tumor', 'Disease', (63, 68))	('liver cancer', 'Disease', 'MESH:D006528', (143, 155))	('FASN', 'Gene', (96, 100))	('FAS', 'Gene', (193, 196))	('tumor growth', 'Disease', (205, 217))	('reduced', 'NegReg', (197, 204))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('ACLY', 'Gene', '47', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('pancreatic tumor', 'Disease', (52, 68))	('ACLY', 'Gene', (37, 41))	('knockdown', 'Var', (24, 33))	('liver cancer', 'Phenotype', 'HP:0002896', (143, 155))	('FAS', 'Gene', (96, 99))	('pancreatic tumor', 'Disease', 'MESH:D010190', (52, 68))	('liver cancer', 'Disease', (143, 155))	('blocking', 'NegReg', (101, 109))	('tumor', 'Disease', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
142509	33413672	The authors also reported the incorporation of these labeled non-lipid substrates into C18:0 and C18:1, including m+16 and m+18 isotopologues, indicating that a fraction of de novo synthesized palmitate is modified before being incorporation into lipids (discussed in greater detail in the "Modification of free fatty acids: fatty acid elongation" section).	('C18', 'Gene', (87, 90))	('C18', 'Gene', (97, 100))	('C18', 'Gene', '27241', (87, 90))	('C18', 'Gene', '27241', (97, 100))	('modified', 'Var', (206, 214))	('fatty acid', 'Chemical', 'MESH:D005227', (325, 335))	('fatty acid', 'Chemical', 'MESH:D005227', (312, 322))	('free fatty acids', 'Chemical', 'MESH:D005230', (307, 323))	('lipids', 'Chemical', 'MESH:D008055', (247, 253))	('palmitate', 'Chemical', 'MESH:D010168', (193, 202))
142519	33413672	One of the other aspects of palmitate metabolism that remains to be resolved, especially in terms of its requirement for cell viability, is the fact that palmitate supplementation of cell culture media leads to lipotoxicity and activation of apoptosis.	('apoptosis', 'CPA', (242, 251))	('palmitate', 'Chemical', 'MESH:D010168', (154, 163))	('activation', 'PosReg', (228, 238))	('palmitate', 'Chemical', 'MESH:D010168', (28, 37))	('lipotoxicity', 'Disease', 'None', (211, 223))	('activation of apoptosis', 'biological_process', 'GO:0043065', ('228', '251'))	('palmitate', 'Var', (154, 163))	('metabolism', 'biological_process', 'GO:0008152', ('38', '48'))	('activation of apoptosis', 'biological_process', 'GO:0006915', ('228', '251'))	('lipotoxicity', 'Disease', (211, 223))
142521	33413672	We recently demonstrated that the higher rates of fatty acid oxidation in C4-2B prostate cancer cells and MCF-7 breast cancer cells protect from palmitate-induced apoptosis, and inhibition of mitochondrial fatty acid oxidation sensitized these cells and lead to increased cell death.	('inhibition', 'Var', (178, 188))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('206', '226'))	('cell death', 'CPA', (272, 282))	('mitochondrial', 'MPA', (192, 205))	('palmitate-induced', 'MPA', (145, 162))	('C4-2B prostate cancer', 'Disease', (74, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('prostate cancer', 'Phenotype', 'HP:0012125', (80, 95))	('fatty acid', 'Chemical', 'MESH:D005227', (50, 60))	('palmitate', 'Chemical', 'MESH:D010168', (145, 154))	('apoptosis', 'biological_process', 'GO:0097194', ('163', '172'))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('apoptosis', 'biological_process', 'GO:0006915', ('163', '172'))	('apoptosis', 'CPA', (163, 172))	('higher', 'PosReg', (34, 40))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (106, 125))	('MCF-7 breast cancer', 'Disease', (106, 125))	('cell death', 'biological_process', 'GO:0008219', ('272', '282'))	('C4-2B prostate cancer', 'Disease', 'MESH:D011471', (74, 95))	('fatty acid', 'Chemical', 'MESH:D005227', (206, 216))	('increased', 'PosReg', (262, 271))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('rates', 'MPA', (41, 46))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('50', '70'))	('fatty acid oxidation', 'MPA', (50, 70))
142537	33413672	Conversely, LYPLA1 plays a tumor-promotor role in non-small cell lung cancer cells, which is unlikely to be linked to the liberation of fatty acids from lysophospholipids contributing to the free fatty acid pool, but through changes in lysophospholipid levels which can regulate several signaling pathways including MAPK and ERK or via depalmitoylation of the alpha-subunit of G-proteins and proto-oncogene H-Ras products.	('signaling pathways', 'Pathway', (287, 305))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (50, 76))	('ERK', 'molecular_function', 'GO:0004707', ('325', '328'))	('lysophospholipid', 'Chemical', 'MESH:D008246', (153, 169))	('H-Ras', 'Gene', '3265', (407, 412))	('fatty acids', 'Chemical', 'MESH:D005227', (136, 147))	('depalmitoylation', 'Var', (336, 352))	('LYPLA1', 'Gene', '10434', (12, 18))	('lysophospholipid', 'MPA', (236, 252))	('MAPK', 'molecular_function', 'GO:0004707', ('316', '320'))	('tumor', 'Disease', (27, 32))	('LYPLA1', 'Gene', (12, 18))	('ERK', 'Gene', '5594', (325, 328))	('non-small cell lung cancer', 'Disease', (50, 76))	('H-Ras', 'Gene', (407, 412))	('G-proteins', 'Protein', (377, 387))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('MAPK', 'Pathway', (316, 320))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('lysophospholipid', 'Chemical', 'MESH:D008246', (236, 252))	('ERK', 'Gene', (325, 328))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (50, 76))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('changes', 'Reg', (225, 232))	('regulate', 'Reg', (270, 278))	('signaling', 'biological_process', 'GO:0023052', ('287', '296'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (54, 76))	('free fatty acid', 'Chemical', 'MESH:D005230', (191, 206))	('lysophospholipids', 'Chemical', 'MESH:D008246', (153, 170))
142568	33413672	Overall, reduced ATGL activity, via knockdown of ATGL or ABHD5, has similar effects on cancer cell proliferation and viability as increased ATGL activity, via overexpression of ATGL or knockdown of HILPDA.	('ATGL', 'Gene', (177, 181))	('ATGL', 'Gene', '57104', (17, 21))	('ABHD5', 'Gene', '51099', (57, 62))	('ATGL', 'Gene', '57104', (49, 53))	('ABHD5', 'Gene', (57, 62))	('HILPDA', 'Gene', (198, 204))	('ATGL', 'Gene', '57104', (177, 181))	('knockdown', 'Var', (36, 45))	('reduced', 'NegReg', (9, 16))	('HILPDA', 'Gene', '29923', (198, 204))	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ATGL', 'Gene', (140, 144))	('activity', 'MPA', (22, 30))	('cell proliferation', 'biological_process', 'GO:0008283', ('94', '112'))	('ATGL', 'Gene', (17, 21))	('ATGL', 'Gene', '57104', (140, 144))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('ATGL', 'Gene', (49, 53))
142575	33413672	Recently, ABHD6 has been reported to be the primary MG lipase in NSCLC and blockade of ABHD6 significantly reduced the migration, invasion, and in vivo tumor growth of NSCLC.	('ABHD6', 'Gene', (10, 15))	('MG', 'Chemical', 'MESH:D008274', (52, 54))	('ABHD6', 'Gene', (87, 92))	('tumor growth', 'Disease', (152, 164))	('migration', 'CPA', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('blockade', 'Var', (75, 83))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('reduced', 'NegReg', (107, 114))	('invasion', 'CPA', (130, 138))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('tumor growth', 'Disease', 'MESH:D006130', (152, 164))	('NSCLC', 'Disease', (168, 173))	('ABHD6', 'Gene', '57406', (87, 92))	('NSCLC', 'Disease', (65, 70))	('ABHD6', 'Gene', '57406', (10, 15))
142601	33413672	For example, ACSL4 has been regularly reported to be overexpressed in multiple cancer types but downregulated in others, whereas high expression of ACSLs 1, 3, and 5 associate with a favorable prognosis in patients with lung cancer.	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('ACSLs 1, 3, and 5', 'Gene', '2180;2181;51703', (148, 165))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('high expression', 'Var', (129, 144))	('cancer', 'Disease', (225, 231))	('lung cancer', 'Disease', (220, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('patients', 'Species', '9606', (206, 214))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('ACSL4', 'Gene', '2182', (13, 18))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('ACSL4', 'Gene', (13, 18))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))
142602	33413672	It is also conceivable that the altered fatty acyl-species profile of cancer cells and tumor (i.e., altered MUFA/PUFA ratio; see below) drives a change in ACSL expression and localization.	('expression', 'MPA', (160, 170))	('localization', 'MPA', (175, 187))	('altered', 'Var', (100, 107))	('fatty', 'Chemical', '-', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('localization', 'biological_process', 'GO:0051179', ('175', '187'))	('fatty acyl-species profile', 'MPA', (40, 66))	('tumor', 'Disease', (87, 92))	('altered', 'Reg', (32, 39))	('change', 'Reg', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('PUFA', 'Gene', '9933', (113, 117))	('cancer', 'Disease', (70, 76))	('ACSL', 'Protein', (155, 159))	('PUFA', 'Gene', (113, 117))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
142603	33413672	An interesting advance was the identification that the transmembrane glycoprotein, CUB-domain containing protein 1 (CDCP1), a driver of migration and invasion in multiple forms of carcinoma, interacts with many members of the ASCL family in breast cancer, and loss-of-function of CDCP1 increases ASCL activity and lipid droplet abundance and reduces fatty acid oxidation and impairs cell migration.	('CDCP1', 'Gene', '64866', (280, 285))	('CDCP1', 'Gene', (280, 285))	('ASCL activity', 'MPA', (296, 309))	('lipid', 'Chemical', 'MESH:D008055', (314, 319))	('CUB-domain containing protein 1', 'Gene', '64866', (83, 114))	('fatty acid oxidation', 'MPA', (350, 370))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('transmembrane', 'cellular_component', 'GO:0016021', ('55', '68'))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('350', '370'))	('cell migration', 'CPA', (383, 397))	('fatty acid', 'Chemical', 'MESH:D005227', (350, 360))	('impairs', 'NegReg', (375, 382))	('CUB-domain containing protein 1', 'Gene', (83, 114))	('loss-of-function', 'Var', (260, 276))	('reduces', 'NegReg', (342, 349))	('cell migration', 'biological_process', 'GO:0016477', ('383', '397'))	('transmembrane', 'cellular_component', 'GO:0044214', ('55', '68'))	('CDCP1', 'Gene', (116, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('increases', 'PosReg', (286, 295))	('CDCP1', 'Gene', '64866', (116, 121))	('carcinoma', 'Disease', (180, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (241, 254))	('breast cancer', 'Disease', 'MESH:D001943', (241, 254))	('lipid droplet abundance', 'MPA', (314, 337))	('breast cancer', 'Disease', (241, 254))	('lipid droplet', 'cellular_component', 'GO:0005811', ('314', '327'))	('carcinoma', 'Disease', 'MESH:D009369', (180, 189))
142610	33413672	These changes in ACOT expression reported in clinical cancer tissues would be predicted to change the tumor lipidome and thereby behavior.	('COT', 'Gene', (18, 21))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Disease', (54, 60))	('changes', 'Var', (6, 13))	('lipid', 'Chemical', 'MESH:D008055', (108, 113))	('behavior', 'MPA', (129, 137))	('COT', 'Gene', '54677', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('change', 'Reg', (91, 97))
142625	33413672	Many of these recent studies have demonstrated that inhibiting SCD leads to accumulation of palmitate and stearate saturated fatty acids and reduced palmitoleate and oleate monounsaturated fatty acids.	('reduced', 'NegReg', (141, 148))	('oleate monounsaturated fatty acids', 'Chemical', '-', (166, 200))	('inhibiting', 'Var', (52, 62))	('stearate saturated fatty acids', 'Chemical', '-', (106, 136))	('stearate saturated fatty acids', 'MPA', (106, 136))	('palmitate', 'MPA', (92, 101))	('accumulation', 'PosReg', (76, 88))	('SCD', 'Disease', (63, 66))	('reduced palmitoleate', 'Chemical', '-', (141, 161))	('palmitate', 'Chemical', 'MESH:D010168', (92, 101))
142627	33413672	However, deletion of SCD in the intestinal epithelium of mice resulted in more and larger tumors.	('mice', 'Species', '10090', (57, 61))	('more', 'PosReg', (74, 78))	('deletion', 'Var', (9, 17))	('SCD', 'Gene', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))
142630	33413672	The same authors demonstrated that inhibition of de novo ceramide synthesis reversed the tumor shrinkage that arose from SCD inhibition.	('ceramide synthesis', 'biological_process', 'GO:0046513', ('57', '75'))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('inhibition', 'Var', (35, 45))	('ceramide', 'Chemical', 'MESH:D002518', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
142640	33413672	Further, this altered MUFA/PUFA ratio is advantageous for cancer cells as it results in fewer peroxidation susceptible targets and reduced susceptibility to ferroptosis (i.e., iron-dependent cell death).	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('altered', 'Var', (14, 21))	('PUFA', 'Gene', '9933', (27, 31))	('PUFA', 'Gene', (27, 31))	('iron', 'Chemical', 'MESH:D007501', (176, 180))	('susceptibility', 'MPA', (139, 153))	('fewer', 'NegReg', (88, 93))	('reduced', 'NegReg', (131, 138))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cell death', 'biological_process', 'GO:0008219', ('191', '201'))	('ferroptosis', 'biological_process', 'GO:0097707', ('157', '168'))	('cancer', 'Disease', (58, 64))	('n-', 'Chemical', 'MESH:D009584', (179, 181))	('peroxidation susceptible targets', 'MPA', (94, 126))
142647	33413672	Membrane lipid elongation and/or enhanced ELOVL expression is a common feature in cancer when compared to matched normal tissue and, as targeting ELOVLs is efficacious in cancer models, membrane lipid elongation appears to promote cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('lipid', 'Chemical', 'MESH:D008055', (195, 200))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (231, 237))	('expression', 'MPA', (48, 58))	('cancer', 'Disease', (171, 177))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('membrane lipid', 'Var', (186, 200))	('ELOVL', 'Protein', (42, 47))	('lipid', 'Chemical', 'MESH:D008055', (9, 14))	('membrane', 'cellular_component', 'GO:0016020', ('186', '194'))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('promote', 'PosReg', (223, 230))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('enhanced', 'PosReg', (33, 41))
142650	33413672	Mutation of p53 in pancreatic cancer cell lines reduced acyl chain lengths of PI-based glycerophospholipids, but had no effect on chain length in PC species which, like PI, are derived from the same precursor, phosphatidate.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (19, 36))	('reduced', 'NegReg', (48, 55))	('Mutation', 'Var', (0, 8))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('pancreatic cancer', 'Disease', (19, 36))	('acyl chain lengths', 'MPA', (56, 74))	('glycerophospholipids', 'Chemical', 'MESH:D020404', (87, 107))	('pancreatic cancer', 'Disease', 'MESH:D010190', (19, 36))	('phosphatidate', 'Chemical', '-', (210, 223))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
142651	33413672	As PI lipids form the scaffold for PI3K signaling at the plasma membrane, it is possible that specific oncogenic alterations may act via regulating the production of the second messengers that control cancer cell growth and survival.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cell growth', 'biological_process', 'GO:0016049', ('208', '219'))	('cancer', 'Disease', (201, 207))	('lipids', 'Chemical', 'MESH:D008055', (6, 12))	('regulating', 'Reg', (137, 147))	('plasma membrane', 'cellular_component', 'GO:0005886', ('57', '72'))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('alterations', 'Var', (113, 124))	('production', 'MPA', (152, 162))	('PI3K signaling', 'biological_process', 'GO:0014065', ('35', '49'))	('PI3K', 'molecular_function', 'GO:0016303', ('35', '39'))
142652	33413672	In prostate cancer, knockdown of ELOVL7 reduced saturated fatty acids in membrane glycerophospholipids but also reduced the levels of cholesterol, the critical precursor of the androgen hormones that drive prostate cancer growth.	('saturated fatty acids', 'Chemical', 'MESH:D005227', (48, 69))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (206, 221))	('ELOVL7', 'Gene', (33, 39))	('prostate cancer', 'Phenotype', 'HP:0012125', (206, 221))	('cholesterol', 'Chemical', 'MESH:D002784', (134, 145))	('membrane', 'cellular_component', 'GO:0016020', ('73', '81'))	('levels of cholesterol', 'MPA', (124, 145))	('glycerophospholipids', 'Chemical', 'MESH:D020404', (82, 102))	('knockdown', 'Var', (20, 29))	('reduced', 'NegReg', (40, 47))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('reduced', 'NegReg', (112, 119))	('prostate cancer', 'Disease', (206, 221))	('ELOVL7', 'Gene', '79993', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
142688	33413672	Our approach is based upon the assumption that changes in gene/protein levels will result in changes in lipid levels and thereby affect cell biology.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('cell', 'MPA', (136, 140))	('lipid levels', 'MPA', (104, 116))	('gene/protein levels', 'MPA', (58, 77))	('changes', 'Var', (47, 54))	('affect', 'Reg', (129, 135))	('lipid', 'Chemical', 'MESH:D008055', (104, 109))	('result', 'Reg', (83, 89))	('changes', 'Reg', (93, 100))
142694	33413672	In fact, knockdown of GPAT1 in breast and ovarian cancer cells, which reduced lysophosphatidate levels, slowed cell growth and migration and was rescued by lysophosphatidate supplementation.	('GPAT1', 'Gene', (22, 27))	('reduced', 'NegReg', (70, 77))	('knockdown', 'Var', (9, 18))	('cell growth', 'CPA', (111, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (42, 56))	('slowed cell growth', 'Phenotype', 'HP:0001510', (104, 122))	('lysophosphatidate', 'Chemical', '-', (78, 95))	('cell growth', 'biological_process', 'GO:0016049', ('111', '122'))	('GPAT1', 'Gene', '57678', (22, 27))	('slowed', 'NegReg', (104, 110))	('lysophosphatidate levels', 'MPA', (78, 102))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (31, 56))	('lysophosphatidate', 'Chemical', '-', (156, 173))
142698	33413672	However, LPIN1, one of three members of the LPIN family, is highly expressed in ovarian cancer, hepatocellular carcinoma, and breast cancer, and therefore causing an increased conversion of phosphatidate to DG and resulting in no accumulation of PA. Knockdown of LPIN1 reduced incorporation of extracellular palmitate into glycerophospholipids, indicating reduced synthesis and remodeling, which resulted in impaired basal-like triple-negative breast cancer cell viability and orthotopic xenograft growth.	('hepatocellular carcinoma', 'Disease', (96, 120))	('LPIN1', 'Gene', (9, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('LPIN1', 'Gene', (263, 268))	('PA', 'Chemical', 'MESH:D011478', (246, 248))	('remodeling', 'CPA', (378, 388))	('impaired', 'NegReg', (408, 416))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancer', 'Disease', (444, 457))	('breast cancer', 'Disease', 'MESH:D001943', (444, 457))	('glycerophospholipids', 'Chemical', 'MESH:D020404', (323, 343))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Disease', (126, 139))	('LPIN', 'Chemical', '-', (44, 48))	('ovarian cancer', 'Disease', 'MESH:D010051', (80, 94))	('LPIN1', 'Gene', '23175', (9, 14))	('Knockdown', 'Var', (250, 259))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (96, 120))	('phosphatidate', 'Chemical', '-', (190, 203))	('LPIN1', 'Gene', '23175', (263, 268))	('reduced', 'NegReg', (269, 276))	('synthesis', 'biological_process', 'GO:0009058', ('364', '373'))	('cancer', 'Phenotype', 'HP:0002664', (451, 457))	('palmitate', 'Chemical', 'MESH:D010168', (308, 317))	('reduced', 'NegReg', (356, 363))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('synthesis', 'CPA', (364, 373))	('ovarian cancer', 'Disease', (80, 94))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (96, 120))	('extracellular', 'cellular_component', 'GO:0005576', ('294', '307'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (80, 94))	('LPIN', 'Chemical', '-', (9, 13))	('LPIN', 'Chemical', '-', (263, 267))	('breast cancer', 'Phenotype', 'HP:0003002', (444, 457))
142701	33413672	In fact, overexpression of DGKalpha, one of ten isoforms, enhanced cancer cell proliferation and tumor growth, whereas knockdown of DGKalpha reduced cell viability in a range of cancer types.	('DGKalpha', 'Gene', (27, 35))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('overexpression', 'PosReg', (9, 23))	('DGKalpha', 'Gene', '1606', (132, 140))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor growth', 'Disease', (97, 109))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('enhanced', 'PosReg', (58, 66))	('tumor growth', 'Disease', 'MESH:D006130', (97, 109))	('DGKalpha', 'Gene', (132, 140))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('knockdown', 'Var', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('DGKalpha', 'Gene', '1606', (27, 35))	('cell proliferation', 'biological_process', 'GO:0008283', ('74', '92'))
142709	33413672	Likewise, knockdown of DGAT1 reduced lipid droplet number and cell proliferation and invasion of prostate cancer cells and glioblastoma.	('glioblastoma', 'Disease', (123, 135))	('DGAT1', 'Gene', (23, 28))	('cell proliferation', 'biological_process', 'GO:0008283', ('62', '80'))	('DGAT1', 'Gene', '8694', (23, 28))	('lipid', 'Chemical', 'MESH:D008055', (37, 42))	('glioblastoma', 'Disease', 'MESH:D005909', (123, 135))	('cell proliferation', 'CPA', (62, 80))	('invasion of prostate cancer', 'Disease', (85, 112))	('lipid droplet number', 'MPA', (37, 57))	('reduced', 'NegReg', (29, 36))	('invasion of prostate cancer', 'Disease', 'MESH:D011471', (85, 112))	('prostate cancer', 'Phenotype', 'HP:0012125', (97, 112))	('glioblastoma', 'Phenotype', 'HP:0012174', (123, 135))	('lipid droplet', 'cellular_component', 'GO:0005811', ('37', '50'))	('knockdown', 'Var', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
142719	33413672	Accumulation of cholesteryl ester in lipid droplets has been reported in pancreatic and prostate cancer as recent examples, and that inhibiting SOAT1 blocked cholesteryl ester synthesis and suppress tumor growth or cancer cell proliferation.	('tumor growth', 'Disease', 'MESH:D006130', (199, 211))	('cell proliferation', 'biological_process', 'GO:0008283', ('222', '240'))	('cholesteryl ester synthesis', 'MPA', (158, 185))	('cholesteryl ester', 'Chemical', 'MESH:D002788', (16, 33))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', (215, 221))	('cholesteryl ester', 'Chemical', 'MESH:D002788', (158, 175))	('SOAT1', 'Gene', '6646', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('inhibiting', 'Var', (133, 143))	('tumor growth', 'Disease', (199, 211))	('SOAT1', 'Gene', (144, 149))	('SOAT', 'molecular_function', 'GO:0043825', ('144', '148'))	('suppress', 'NegReg', (190, 198))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('Accumulation', 'PosReg', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('blocked', 'NegReg', (150, 157))	('cholesteryl ester in', 'MPA', (16, 36))	('synthesis', 'biological_process', 'GO:0009058', ('176', '185'))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('lipid', 'Chemical', 'MESH:D008055', (37, 42))	('pancreatic and prostate cancer', 'Disease', 'MESH:D011471', (73, 103))
142732	33413672	Tumor tissues and cancer cells with high LPCAT1 expression had increased PC and decreased LPC levels, and loss-of-function impaired cell growth and survival.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cell growth', 'CPA', (132, 143))	('increased', 'PosReg', (63, 72))	('LPC', 'Chemical', '-', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('LPC levels', 'MPA', (90, 100))	('LPCAT1', 'Gene', '79888', (41, 47))	('cell growth', 'biological_process', 'GO:0016049', ('132', '143'))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('decreased', 'NegReg', (80, 89))	('LPCAT1', 'Gene', (41, 47))	('impaired', 'NegReg', (123, 131))	('survival', 'CPA', (148, 156))	('LPC', 'Chemical', '-', (41, 44))	('cancer', 'Disease', (18, 24))	('high', 'Var', (36, 40))
142733	33413672	Other members of the LPLAT family have also been implicated in tumor biology, including increased LPCAT2 supporting chemoresistance in colorectal cancer, increased protein levels in breast and cervical cancer tissue, loss of LPCAT3 enhancing intestinal tumor formation via a cholesterol synthesis mechanism, and lysophosphatidylinositol-acyltransferase 1 (LPIAT1) mediated prostaglandin production and non-small cell lung cancer cell growth.	('cancer', 'Disease', (146, 152))	('enhancing', 'PosReg', (232, 241))	('intestinal tumor', 'Disease', (242, 258))	('prostaglandin', 'Enzyme', (373, 386))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('LPCAT3', 'Gene', (225, 231))	('LPCAT2', 'Gene', (98, 104))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', (422, 428))	('cancer', 'Phenotype', 'HP:0002664', (422, 428))	('colorectal cancer', 'Disease', 'MESH:D015179', (135, 152))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (406, 428))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (402, 428))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('chemoresistance', 'CPA', (116, 131))	('protein levels', 'MPA', (164, 178))	('increased', 'PosReg', (154, 163))	('colorectal cancer', 'Disease', (135, 152))	('LPCAT3', 'Gene', '10162', (225, 231))	('tumor', 'Disease', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('prostaglandin', 'Chemical', 'MESH:D011453', (373, 386))	('increased', 'PosReg', (88, 97))	('cancer', 'Disease', 'MESH:D009369', (422, 428))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('cholesterol', 'Chemical', 'MESH:D002784', (275, 286))	('tumor', 'Disease', (253, 258))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (402, 428))	('intestinal tumor', 'Disease', 'MESH:D007414', (242, 258))	('loss', 'Var', (217, 221))	('cell growth', 'biological_process', 'GO:0016049', ('429', '440'))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('formation', 'biological_process', 'GO:0009058', ('259', '268'))	('cholesterol synthesis', 'biological_process', 'GO:0006695', ('275', '296'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (135, 152))	('cancer', 'Disease', (202, 208))	('LPCAT2', 'Gene', '54947', (98, 104))	('LPLAT', 'Gene', '154141', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (417, 428))	('non-small cell lung cancer', 'Disease', (402, 428))	('LPLAT', 'Gene', (21, 26))
142740	33413672	Inhibition of protein acylation has been shown to be a potential therapeutic strategy for many cancers; for example, small molecules that inhibit the acyltransferase Porcupine and thereby O-palmiteoylation of Wnt are efficacious in Wnt-dependent cancers.	('acyltransferase Porcupine', 'Enzyme', (150, 175))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('O-palmiteoylation', 'Var', (188, 205))	('cancers', 'Disease', (246, 253))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (246, 253))	('cancers', 'Disease', (95, 102))	('protein acylation', 'biological_process', 'GO:0043543', ('14', '31'))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('inhibit', 'NegReg', (138, 145))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))
142753	33413672	CPT1 levels are increased in many cancers and targeting CPT1 impairs cancer cell growth and viability (see reviews).	('impairs cancer', 'Disease', (61, 75))	('targeting', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('CPT1', 'Gene', (56, 60))	('CPT1', 'Gene', '1374', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cell growth', 'biological_process', 'GO:0016049', ('76', '87'))	('CPT', 'molecular_function', 'GO:0004142', ('56', '59'))	('impairs cancer', 'Disease', 'MESH:D009369', (61, 75))	('CPT1', 'Gene', '1374', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('CPT', 'molecular_function', 'GO:0004142', ('0', '3'))	('cancers', 'Disease', (34, 41))	('CPT', 'molecular_function', 'GO:0004095', ('0', '3'))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('CPT', 'molecular_function', 'GO:0004095', ('56', '59'))	('CPT1', 'Gene', (0, 4))
142756	33413672	Conversely, others have reported that CPT1 expression is elevated in triple-negative breast cancer cells that overexpress c-Myc, leading to increased fatty acid oxidation, and that inhibition of CPT1 reduced growth of Myc-driven triple-negative breast cancer tumors.	('CPT', 'molecular_function', 'GO:0004095', ('38', '41'))	('CPT1', 'Gene', '1374', (195, 199))	('growth', 'CPA', (208, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (245, 258))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('c-Myc', 'Gene', '4609', (122, 127))	('breast cancer', 'Disease', 'MESH:D001943', (245, 258))	('CPT1', 'Gene', (195, 199))	('fatty acid oxidation', 'MPA', (150, 170))	('increased', 'PosReg', (140, 149))	('Myc', 'Gene', '4609', (218, 221))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('150', '170'))	('CPT', 'molecular_function', 'GO:0004142', ('195', '198'))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('reduced', 'NegReg', (200, 207))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('Myc', 'Gene', (124, 127))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('CPT', 'molecular_function', 'GO:0004142', ('38', '41'))	('breast cancer', 'Disease', (85, 98))	('elevated', 'PosReg', (57, 65))	('inhibition', 'Var', (181, 191))	('fatty acid', 'Chemical', 'MESH:D005227', (150, 160))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('breast cancer tumors', 'Disease', 'MESH:D001943', (245, 265))	('Myc', 'Gene', (218, 221))	('breast cancer tumors', 'Disease', (245, 265))	('CPT', 'molecular_function', 'GO:0004095', ('195', '198'))	('Myc', 'Gene', '4609', (124, 127))	('CPT1', 'Gene', '1374', (38, 42))	('expression', 'MPA', (43, 53))	('CPT1', 'Gene', (38, 42))	('c-Myc', 'Gene', (122, 127))
142762	33413672	Several mechanisms have been proposed to explain how the inhibition of CPT1 activity, to reduce fatty acid oxidation, slows cell proliferation.	('inhibition', 'Var', (57, 67))	('fatty acid oxidation', 'MPA', (96, 116))	('activity', 'MPA', (76, 84))	('CPT1', 'Gene', '1374', (71, 75))	('CPT', 'molecular_function', 'GO:0004142', ('71', '74'))	('reduce', 'NegReg', (89, 95))	('cell proliferation', 'biological_process', 'GO:0008283', ('124', '142'))	('slows', 'NegReg', (118, 123))	('CPT', 'molecular_function', 'GO:0004095', ('71', '74'))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('96', '116'))	('CPT1', 'Gene', (71, 75))	('cell proliferation', 'CPA', (124, 142))	('fatty acid', 'Chemical', 'MESH:D005227', (96, 106))
142764	33413672	More recently, it has been shown that inhibition of CPT1 and fatty acid oxidation reduces the activation of the proto-oncogene SRC, including mitochondrially-localized SRC, to result in reduced in vitro and in vivo triple-negative breast cancer cell and tumor growth.	('tumor growth', 'Disease', 'MESH:D006130', (254, 266))	('reduced', 'NegReg', (186, 193))	('SRC', 'Gene', '6714', (127, 130))	('SRC', 'Gene', (168, 171))	('activation', 'MPA', (94, 104))	('CPT1', 'Gene', '1374', (52, 56))	('CPT', 'molecular_function', 'GO:0004142', ('52', '55'))	('reduces', 'NegReg', (82, 89))	('CPT1', 'Gene', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('SRC', 'Gene', (127, 130))	('tumor growth', 'Disease', (254, 266))	('inhibition', 'Var', (38, 48))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('61', '81'))	('breast cancer', 'Phenotype', 'HP:0003002', (231, 244))	('CPT', 'molecular_function', 'GO:0004095', ('52', '55'))	('SRC', 'Gene', '6714', (168, 171))	('fatty acid', 'Chemical', 'MESH:D005227', (61, 71))	('breast cancer', 'Disease', 'MESH:D001943', (231, 244))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('breast cancer', 'Disease', (231, 244))
142783	33413672	The presence of one or more double bond introduces complexity into the oxidation of these monounsaturated or polyunsaturated fatty acyl-CoAs (Fig.	('complexity', 'Reg', (51, 61))	('polyunsaturated', 'Var', (109, 124))	('oxidation', 'MPA', (71, 80))	('monounsaturated or polyunsaturated fatty acyl-CoAs', 'Chemical', '-', (90, 140))
142796	33413672	Alterations in the genes encoding key enzymes that regulate the levels or oxidation status of PUFAs have been reported, and are often closely linked to ferroptosis, as PUFA oxidation is the major cellular stimulus for this iron-dependent form of programmed cell death.	('PUFAs', 'Chemical', 'MESH:D005231', (94, 99))	('iron', 'Chemical', 'MESH:D007501', (223, 227))	('programmed cell death', 'biological_process', 'GO:0012501', ('246', '267'))	('Alterations', 'Var', (0, 11))	('linked', 'Reg', (142, 148))	('PUFA', 'Gene', '9933', (168, 172))	('PUFA', 'Gene', (168, 172))	('ferroptosis', 'biological_process', 'GO:0097707', ('152', '163'))	('PUFA', 'Gene', '9933', (94, 98))	('PUFA', 'Gene', (94, 98))	('n-', 'Chemical', 'MESH:D009584', (226, 228))
142800	33413672	Selective knockdown of these enzymes impacts growth and tumorigenicity of prostate cancer cells, but not non-malignant lines, coincident with an accumulation of cellular PUFAs, resulting in increased lipid peroxidation and induction of ferroptosis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumorigenicity of prostate cancer', 'Disease', 'MESH:D011471', (56, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('impacts', 'Reg', (37, 44))	('prostate cancer', 'Phenotype', 'HP:0012125', (74, 89))	('ferroptosis', 'biological_process', 'GO:0097707', ('236', '247'))	('increased lipid', 'Phenotype', 'HP:0003077', (190, 205))	('induction', 'Reg', (223, 232))	('accumulation', 'PosReg', (145, 157))	('ferroptosis', 'CPA', (236, 247))	('lipid', 'Chemical', 'MESH:D008055', (200, 205))	('knockdown', 'Var', (10, 19))	('increased lipid peroxidation', 'Phenotype', 'HP:0025464', (190, 218))	('n-', 'Chemical', 'MESH:D009584', (107, 109))	('lipid peroxidation', 'MPA', (200, 218))	('PUFAs', 'Chemical', 'MESH:D005231', (170, 175))	('growth', 'CPA', (45, 51))	('increased', 'PosReg', (190, 199))	('tumorigenicity of prostate cancer', 'Disease', (56, 89))
142802	33413672	These effects, however, appear to be cancer type-specific, with DECR1 shown to be decreased in mouse models of breast cancer and in clinical breast tumors compared to normal mammary gland, and ectopic expression of DECR1 in HER2/neu-transformed breast cancer cells reducing tumorigenesis:an effect linked to reduced de novo lipogenesis.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('neu', 'Gene', (229, 232))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Disease', (111, 124))	('breast cancer', 'Disease', 'MESH:D001943', (245, 258))	('tumor', 'Disease', (274, 279))	('breast cancer', 'Disease', (245, 258))	('mouse', 'Species', '10090', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('DECR1', 'Gene', (215, 220))	('DECR1', 'Gene', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('breast tumors', 'Disease', 'MESH:D001943', (141, 154))	('cancer', 'Disease', (118, 124))	('breast tumors', 'Disease', (141, 154))	('neu', 'Gene', '13866', (229, 232))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', (252, 258))	('ectopic expression', 'Var', (193, 211))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('de novo lipogenesis', 'MPA', (316, 335))	('breast tumors', 'Phenotype', 'HP:0100013', (141, 154))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('reduced', 'NegReg', (308, 315))	('lipogenesis', 'biological_process', 'GO:0008610', ('324', '335'))	('tumor', 'Disease', (148, 153))	('reducing', 'NegReg', (265, 273))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (245, 258))	('decreased', 'NegReg', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
142810	33413672	For example, many studies report reduced peroxisomal protein abundance or enzymatic activities in colon, breast, and hepatocellular carcinoma, whereas others have reported PEX2 mRNA, which encodes peroxisomal biogenesis factor 2 that is required for peroxisome biogenesis, is increased in hepatocellular carcinoma and that knockdown of PEX2 reduced tumor formation (see review).	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (117, 141))	('knockdown', 'Var', (323, 332))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('enzymatic', 'MPA', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('peroxisomal protein abundance', 'MPA', (41, 70))	('PEX2', 'Gene', (172, 176))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (117, 141))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (289, 313))	('peroxisomal', 'cellular_component', 'GO:0005777', ('41', '52'))	('reduced', 'NegReg', (33, 40))	('PEX2', 'Gene', '5828', (172, 176))	('PEX2', 'Gene', (336, 340))	('hepatocellular carcinoma', 'Disease', (117, 141))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (289, 313))	('PEX2', 'Gene', '5828', (336, 340))	('reduced', 'NegReg', (341, 348))	('peroxisomal', 'cellular_component', 'GO:0005777', ('197', '208'))	('peroxisome', 'cellular_component', 'GO:0005777', ('250', '260'))	('tumor', 'Disease', (349, 354))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('factor 2', 'Gene', '8458', (220, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (304, 313))	('increased', 'PosReg', (276, 285))	('hepatocellular carcinoma', 'Disease', (289, 313))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('formation', 'biological_process', 'GO:0009058', ('355', '364'))	('factor 2', 'Gene', (220, 228))
142832	33413672	These recent observations, in combination with lipidomic studies described above, point to important roles for specific fatty acid species, beyond eicosanoid production, where changes in the MUFA/PUFA and saturated/MUFA ratios can have profound effects on cell function, including activation of ferroptosis, ceramide synthesis, ER stress, and apoptosis as well as increased sensitivity to chemotherapeutic agents.	('ferroptosis', 'biological_process', 'GO:0097707', ('295', '306'))	('activation', 'PosReg', (281, 291))	('stress', 'Disease', 'MESH:D000079225', (331, 337))	('apoptosis', 'biological_process', 'GO:0097194', ('343', '352'))	('PUFA', 'Gene', '9933', (196, 200))	('apoptosis', 'biological_process', 'GO:0006915', ('343', '352'))	('effects', 'Reg', (245, 252))	('fatty acid', 'Chemical', 'MESH:D005227', (120, 130))	('stress', 'Disease', (331, 337))	('ceramide synthesis', 'biological_process', 'GO:0046513', ('308', '326'))	('cell function', 'CPA', (256, 269))	('ceramide', 'Chemical', 'MESH:D002518', (308, 316))	('changes', 'Var', (176, 183))	('lipid', 'Chemical', 'MESH:D008055', (47, 52))	('ferroptosis', 'MPA', (295, 306))	('PUFA', 'Gene', (196, 200))	('apoptosis', 'CPA', (343, 352))	('ceramide synthesis', 'MPA', (308, 326))	('eicosanoid', 'Chemical', 'MESH:D015777', (147, 157))	('increased', 'PosReg', (364, 373))
142857	33413672	A recent example is that the rate of de novo fatty acid synthesis is upregulated in response to SR-B2/CD36 inhibition to reduce the uptake of extracellular fatty acids.	('fatty acid synthesis', 'biological_process', 'GO:0006633', ('45', '65'))	('uptake', 'biological_process', 'GO:0098657', ('132', '138'))	('fatty acid', 'Chemical', 'MESH:D005227', (45, 55))	('uptake', 'biological_process', 'GO:0098739', ('132', '138'))	('extracellular', 'cellular_component', 'GO:0005576', ('142', '155'))	('uptake of extracellular fatty acids', 'MPA', (132, 167))	('fatty acid', 'Chemical', 'MESH:D005227', (156, 166))	('de novo fatty acid synthesis', 'MPA', (37, 65))	('SR-B', 'Gene', '10575', (96, 100))	('SR-B', 'Gene', (96, 100))	('upregulated', 'PosReg', (69, 80))	('fatty acids', 'Chemical', 'MESH:D005227', (156, 167))	('reduce', 'NegReg', (121, 127))	('inhibition', 'Var', (107, 117))
142867	33413672	It has been long appreciated that the various endpoints of fatty acid metabolism, including energy production (beta-oxidation), synthesis of signaling lipids, altered protein function via acylation, and membrane lipid synthesis and modification to alter fluidity and permeability, can profoundly influence tumor progression, including treatment resistance.	('lipids', 'Chemical', 'MESH:D008055', (151, 157))	('altered', 'Reg', (159, 166))	('treatment resistance', 'CPA', (335, 355))	('alter', 'Reg', (248, 253))	('tumor', 'Disease', (306, 311))	('membrane', 'cellular_component', 'GO:0016020', ('203', '211'))	('protein', 'Protein', (167, 174))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('fatty acid', 'Chemical', 'MESH:D005227', (59, 69))	('synthesis', 'biological_process', 'GO:0009058', ('128', '137'))	('protein', 'cellular_component', 'GO:0003675', ('167', '174'))	('permeability', 'MPA', (267, 279))	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('membrane lipid synthesis', 'biological_process', 'GO:0046467', ('203', '227'))	('fluidity', 'MPA', (254, 262))	('modification', 'Var', (232, 244))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('59', '80'))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('lipid', 'Chemical', 'MESH:D008055', (212, 217))	('acylation', 'MPA', (188, 197))	('lipid', 'Chemical', 'MESH:D008055', (151, 156))	('influence', 'Reg', (296, 305))	('energy production', 'MPA', (92, 109))
142911	32104247	There were many CTLs in component #1, whereas CD8-positive CTLs were few in component #2, suggesting that component #1 RCC was an inflamed tumor, and component #2 RCC was an immune desert tumor.	('tumor', 'Disease', (188, 193))	('CD8', 'Gene', '925', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('RCC', 'Disease', 'MESH:D002292', (163, 166))	('RCC', 'Disease', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('RCC', 'Disease', 'MESH:D002292', (119, 122))	('RCC', 'Disease', (119, 122))	('component #1', 'Var', (106, 118))	('CD8', 'Gene', (46, 49))
142913	32104247	Several prognostic markers have been reported in RCCs, and high C-reactive protein (CRP), low hemoglobin, and thrombocythemia were also reported to be related to poorer prognosis in RCCs.	('RCC', 'Disease', 'MESH:D002292', (49, 52))	('RCC', 'Disease', (49, 52))	('low hemoglobin', 'Phenotype', 'HP:0001903', (90, 104))	('thrombocythemia', 'Disease', (110, 125))	('thrombocythemia', 'Phenotype', 'HP:0001894', (110, 125))	('CRP', 'Gene', (84, 87))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('C-reactive protein', 'Gene', (64, 82))	('low hemoglobin', 'MPA', (90, 104))	('high', 'Var', (59, 63))	('CRP', 'Gene', '1401', (84, 87))	('C-reactive protein', 'Gene', '1401', (64, 82))	('RCC', 'Disease', 'MESH:D002292', (182, 185))	('RCC', 'Disease', (182, 185))	('thrombocythemia', 'Disease', 'MESH:D013922', (110, 125))
142916	32104247	High CRP has also been shown to be related to poorer prognosis in melanoma patients treated by cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (95, 138))	('High', 'Var', (0, 4))	('CRP', 'Gene', (5, 8))	('CTLA-4', 'Gene', (140, 146))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', (95, 138))	('patients', 'Species', '9606', (75, 83))	('CTLA-4', 'Gene', '1493', (140, 146))	('CRP', 'Gene', '1401', (5, 8))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('poorer', 'NegReg', (46, 52))
142952	31015843	In this study, we further interrogated the role of CD105 in EMT and metastasis by short hairpin RNA- (shRNA-) mediated knockdown of this gene.	('RNA', 'cellular_component', 'GO:0005562', ('96', '99'))	('CD105', 'Gene', (51, 56))	('knockdown', 'Var', (119, 128))	('EMT', 'CPA', (60, 63))	('CD105', 'Gene', '13805', (51, 56))	('EMT', 'biological_process', 'GO:0001837', ('60', '63'))
142990	31015843	To further solidify the role of CD105 in EMT, we used two short hairpin RNAs (shRNA), denoted as shENG-1 and shENG-2, to knock down CD105 expression.	('CD105', 'Gene', (32, 37))	('CD105', 'Gene', '13805', (32, 37))	('EMT', 'biological_process', 'GO:0001837', ('41', '44'))	('CD105', 'Gene', (132, 137))	('knock', 'Var', (121, 126))	('CD105', 'Gene', '13805', (132, 137))
142995	31015843	As expected, the motility and invasiveness of the CD105 knocked down cells were significantly depressed in our 2D migration assay (Figure 2(c)) and modified 3D assay (Figure 2(d)), respectively.	('depressed', 'Disease', 'MESH:D000275', (94, 103))	('motility', 'CPA', (17, 25))	('CD105', 'Gene', '13805', (50, 55))	('CD105', 'Gene', (50, 55))	('knocked down', 'Var', (56, 68))	('depressed', 'Disease', (94, 103))	('invasiveness', 'CPA', (30, 42))
142999	31015843	Consistent with our previous report, knockdown of CD105 by shENG-1 reduced MYC protein expression (Figure 3(a)).	('MYC', 'Gene', '4609', (75, 78))	('CD105', 'Gene', '13805', (50, 55))	('CD105', 'Gene', (50, 55))	('knockdown', 'Var', (37, 46))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('reduced', 'NegReg', (67, 74))	('MYC', 'Gene', (75, 78))
143003	31015843	Also, in order to confirm the effect of TGF-beta on the EMT changes, a TGF-beta type I receptor kinase inhibitor LY-364947 was applied on the CD105(+) cells and was found to inhibit the EMT markers including TWIST-1 significantly (Figure 3(e)).	('EMT', 'biological_process', 'GO:0001837', ('186', '189'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('96', '112'))	('TGF-beta', 'Gene', '7040', (40, 48))	('LY-364947', 'Var', (113, 122))	('inhibit', 'NegReg', (174, 181))	('EMT', 'biological_process', 'GO:0001837', ('56', '59'))	('CD105', 'Gene', (142, 147))	('TGF-beta', 'Gene', '7040', (71, 79))	('TWIST-1', 'Gene', '7291', (208, 215))	('TGF-beta', 'Gene', (40, 48))	('CD105', 'Gene', '13805', (142, 147))	('TGF-beta', 'Gene', (71, 79))	('TWIST-1', 'Gene', (208, 215))	('LY-364947', 'Chemical', 'MESH:C520284', (113, 122))	('EMT markers', 'CPA', (186, 197))
143005	31015843	The knockdown of CD105 in CD105(+)-shENG cells significantly decreased their growth potential as renal xenograft compared to CD105(+) cells in serial dilution tumorigenicity assay.	('CD105', 'Gene', '13805', (26, 31))	('CD105', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('growth potential as renal xenograft', 'CPA', (77, 112))	('CD105', 'Gene', (17, 22))	('CD105', 'Gene', '13805', (17, 22))	('tumor', 'Disease', (159, 164))	('CD105', 'Gene', '13805', (125, 130))	('CD105', 'Gene', (125, 130))	('decreased', 'NegReg', (61, 70))	('knockdown', 'Var', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
143036	31856414	The proliferation and migration of ccRCC cell lines were suppressed by siRNA knockdown of MAPK14, however, that could be partially reversed by the overexpression of CDC25B.	('ccRCC', 'Disease', 'MESH:D002292', (35, 40))	('proliferation', 'CPA', (4, 17))	('MAPK', 'molecular_function', 'GO:0004707', ('90', '94'))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('MAPK14', 'Gene', (90, 96))	('knockdown', 'Var', (77, 86))	('migration', 'CPA', (22, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (35, 40))	('ccRCC', 'Disease', (35, 40))	('suppressed', 'NegReg', (57, 67))
143037	31856414	These results suggest that downregulation of MAPK14 and P-MAPK14 could inhibit the proliferation and migration of ccRCC by downregulating CDC25B.	('ccRCC', 'Disease', (114, 119))	('P-MAPK14', 'Var', (56, 64))	('ccRCC', 'Disease', 'MESH:D002292', (114, 119))	('proliferation', 'CPA', (83, 96))	('inhibit', 'NegReg', (71, 78))	('MAPK14', 'Gene', (45, 51))	('MAPK', 'molecular_function', 'GO:0004707', ('58', '62'))	('CDC25B', 'Protein', (138, 144))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('downregulation', 'NegReg', (27, 41))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('MAPK', 'molecular_function', 'GO:0004707', ('45', '49'))	('downregulating', 'NegReg', (123, 137))
143039	31856414	We affirm that our results reveal that phosphorylated MAPK14 (P-MAPK14) and CDC25B are highly expressed in ccRCC tissue, and that P-MAPK14 binds to CDC25B, potentially stabilizing it.	('MAPK', 'molecular_function', 'GO:0004707', ('54', '58'))	('binds', 'Interaction', (139, 144))	('CDC25B', 'Gene', (76, 82))	('MAPK', 'molecular_function', 'GO:0004707', ('132', '136'))	('MAPK', 'molecular_function', 'GO:0004707', ('64', '68'))	('P-MAPK14', 'Var', (130, 138))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('CDC25B', 'Gene', (148, 154))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('ccRCC', 'Disease', (107, 112))	('ccRCC', 'Disease', 'MESH:D002292', (107, 112))
143040	31856414	Additionally, MAPK14 knockdown inhibits the proliferation and migration of ccRCC cells, an effect that is partially reversed by CDC25B overexpression, suggesting that downregulation of MAPK14 and P-MAPK14 inhibits the proliferation and migration of ccRCC by downregulating CDC25B.	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('inhibits', 'NegReg', (31, 39))	('inhibits', 'NegReg', (205, 213))	('knockdown', 'Var', (21, 30))	('downregulating', 'NegReg', (258, 272))	('MAPK', 'molecular_function', 'GO:0004707', ('198', '202'))	('MAPK', 'molecular_function', 'GO:0004707', ('14', '18'))	('P-MAPK14', 'Var', (196, 204))	('MAPK14', 'Gene', (14, 20))	('ccRCC', 'Disease', 'MESH:D002292', (249, 254))	('ccRCC', 'Disease', 'MESH:D002292', (75, 80))	('CDC25B', 'Protein', (273, 279))	('proliferation', 'CPA', (218, 231))	('MAPK', 'molecular_function', 'GO:0004707', ('185', '189'))	('proliferation', 'CPA', (44, 57))	('ccRCC', 'Disease', (249, 254))	('downregulation', 'NegReg', (167, 181))	('ccRCC', 'Disease', (75, 80))	('MAPK14', 'Gene', (185, 191))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (251, 254))	('ccRCC', 'Phenotype', 'HP:0006770', (249, 254))
143047	31856414	In this study, it was revealed that phosphorylated MAPK14 (P-MAPK14, Thr180, and Tyr182) and CDC25B were overexpressed in ccRCC, and P-MAPK14 might affect the stability of CDC25B.	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('affect', 'Reg', (148, 154))	('Tyr182', 'Var', (81, 87))	('Thr180', 'Chemical', 'MESH:C055175', (69, 75))	('MAPK', 'molecular_function', 'GO:0004707', ('135', '139'))	('P-MAPK14', 'Var', (133, 141))	('ccRCC', 'Disease', (122, 127))	('Tyr182', 'Chemical', 'MESH:C096583', (81, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (122, 127))	('ccRCC', 'Disease', 'MESH:D002292', (122, 127))	('MAPK', 'molecular_function', 'GO:0004707', ('51', '55'))	('stability', 'MPA', (159, 168))	('MAPK', 'molecular_function', 'GO:0004707', ('61', '65'))	('CDC25B', 'Gene', (93, 99))	('Thr180', 'Var', (69, 75))
143059	31856414	Total RNA was extracted from ACHN and CAKI-1 cells 48 hours after siRNA transfection.	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('ACHN', 'Gene', (29, 33))	('CAKI-1', 'CellLine', 'CVCL:0234', (38, 44))	('transfection', 'Var', (72, 84))	('ACHN', 'Gene', '55323', (29, 33))
143064	31856414	The membrane was incubated overnight with the primary antibody in 5% fat-free milk at 4 C. The primary antibodies were as follows: anti-MAPK14 (1;1000, 9218, CST), anti-P-MAPK14 (1;1000, 4511, CST), anti-CDC25B (1;100, ab70927, abcam), anti-P-CDC2 (1:1000, ab47594, abcam), anti-E-Cadherin (1:10 000, ab40772, abcam), anti-N-Cadherin (1:5000, ab76011, abcam), and anti-beta-tubulin (1:1000, 2128S, CST).	('Cadherin', 'molecular_function', 'GO:0008014', ('325', '333'))	('antibody', 'cellular_component', 'GO:0019815', ('54', '62'))	('2128S', 'Chemical', 'MESH:C482070', (391, 396))	('CST', 'Gene', '106478911', (158, 161))	('CST', 'Gene', (193, 196))	('CDC2', 'Gene', (204, 208))	('CDC2', 'Gene', '983', (204, 208))	('CDC2', 'Gene', '983', (243, 247))	('CDC2', 'Gene', (243, 247))	('ab76011', 'Var', (343, 350))	('anti-beta-tubulin', 'Protein', (364, 381))	('CST', 'Gene', (398, 401))	('antibody', 'cellular_component', 'GO:0019814', ('54', '62'))	('E-Cadherin', 'Gene', (279, 289))	('membrane', 'cellular_component', 'GO:0016020', ('4', '12'))	('1:5000', 'Var', (335, 341))	('CST', 'Gene', (158, 161))	('Cadherin', 'molecular_function', 'GO:0008014', ('281', '289'))	('antibody', 'molecular_function', 'GO:0003823', ('54', '62'))	('MAPK', 'molecular_function', 'GO:0004707', ('136', '140'))	('antibody', 'cellular_component', 'GO:0042571', ('54', '62'))	('MAPK', 'molecular_function', 'GO:0004707', ('171', '175'))	('1:10 000', 'Var', (291, 299))	('CST', 'Gene', '106478911', (193, 196))	('CST', 'Gene', '106478911', (398, 401))	('N-Cadherin', 'Gene', (323, 333))	('N-Cadherin', 'Gene', '1000', (323, 333))	('E-Cadherin', 'Gene', '999', (279, 289))
143077	31856414	Our results revealed that there was a significant increase in the expression of P-MAPK14 protein in ccRCC tissues in comparison to healthy tissues (P < .001) (Figure 1C,D).	('P-MAPK14', 'Var', (80, 88))	('expression', 'MPA', (66, 76))	('increase', 'PosReg', (50, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('MAPK', 'molecular_function', 'GO:0004707', ('82', '86'))	('ccRCC', 'Disease', (100, 105))	('protein', 'Protein', (89, 96))	('ccRCC', 'Disease', 'MESH:D002292', (100, 105))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
143088	31856414	To determine whether the increased P-CDC2 was caused by the downregulation of P-MAPK14 and CDC25B, siRNAs were used to knockdown CDC25B, and the concordant results were revealed by Western blot (P < .05) (Figure 2E,F).	('CDC2', 'Gene', (91, 95))	('CDC2', 'Gene', '983', (91, 95))	('CDC2', 'Gene', '983', (129, 133))	('increased', 'PosReg', (25, 34))	('downregulation', 'NegReg', (60, 74))	('MAPK', 'molecular_function', 'GO:0004707', ('80', '84'))	('knockdown', 'Var', (119, 128))	('CDC2', 'Gene', (129, 133))	('P-MAPK14', 'Gene', (78, 86))	('CDC2', 'Gene', '983', (37, 41))	('CDC2', 'Gene', (37, 41))
143090	31856414	These results showed that P-MAPK14 might directly interact with CDC25B, but not with P-CDC2 (Figure 2G).	('CDC2', 'Gene', (87, 91))	('CDC2', 'Gene', '983', (87, 91))	('MAPK', 'molecular_function', 'GO:0004707', ('28', '32'))	('interact', 'Interaction', (50, 58))	('P-MAPK14', 'Var', (26, 34))	('CDC2', 'Gene', '983', (64, 68))	('CDC2', 'Gene', (64, 68))
143093	31856414	The results revealed that after transfection with MAPK14 siRNAs for 72 hours, the activity of ACHN and CAKI-1 cells was significantly reduced compared with the siNC group (P < .01) (Figure 3A).	('MAPK14 siRNAs', 'Var', (50, 63))	('ACHN', 'Gene', (94, 98))	('CAKI-1', 'CellLine', 'CVCL:0234', (103, 109))	('activity', 'MPA', (82, 90))	('reduced', 'NegReg', (134, 141))	('ACHN', 'Gene', '55323', (94, 98))	('MAPK', 'molecular_function', 'GO:0004707', ('50', '54'))
143094	31856414	These results suggest that knockdown of MAPK14 could inhibit the activity and proliferation ability of ccRCC cells in vitro.	('MAPK14', 'Gene', (40, 46))	('knockdown', 'Var', (27, 36))	('inhibit', 'NegReg', (53, 60))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('MAPK', 'molecular_function', 'GO:0004707', ('40', '44'))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('ccRCC', 'Disease', (103, 108))	('ccRCC', 'Disease', 'MESH:D002292', (103, 108))
143096	31856414	After 48 hours of transfection with siMAPK14-1# and siMAPK14-2#, the migration ability of ACHN and CAKI-1 cells was significantly decreased (P < .05) (Figure 3C).	('CAKI-1', 'CellLine', 'CVCL:0234', (99, 105))	('ACHN', 'Gene', (90, 94))	('siMAPK14-1#', 'Var', (36, 47))	('ACHN', 'Gene', '55323', (90, 94))	('siMAPK14-2#', 'Var', (52, 63))	('decreased', 'NegReg', (130, 139))
143103	31856414	After 4 weeks, it was found that the tumor size and weight in MAPK14 knockdown group were significantly lower than those of vector group, while in CDC25B overexpression group, the tumor size and weight were significantly higher than those of the vector group (P < .05) (Figure 5A,B).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('MAPK14', 'Gene', (62, 68))	('tumor', 'Disease', (180, 185))	('MAPK', 'molecular_function', 'GO:0004707', ('62', '66'))	('lower', 'NegReg', (104, 109))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('knockdown', 'Var', (69, 78))	('higher', 'PosReg', (221, 227))
143105	31856414	The selected genes include those that phosphorylate both Thr180 and Tyr182, and unlabeled sites.	('Thr180', 'Chemical', 'MESH:C055175', (57, 63))	('Tyr182', 'Chemical', 'MESH:C096583', (68, 74))	('Thr180', 'Var', (57, 63))	('Tyr182', 'Var', (68, 74))
143108	31856414	Therefore, it could infer that in ccRCC, the selected genes may be involved in phosphorylation of MAPK14, and P-MAPK14 may regulate cell migration and proliferation by binding to CDC25B and affecting its protein stability (Figure 6B).	('involved', 'Reg', (67, 75))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (34, 39))	('protein', 'cellular_component', 'GO:0003675', ('204', '211'))	('cell migration', 'CPA', (132, 146))	('P-MAPK14', 'Var', (110, 118))	('regulate', 'Reg', (123, 131))	('phosphorylation', 'biological_process', 'GO:0016310', ('79', '94'))	('cell migration', 'biological_process', 'GO:0016477', ('132', '146'))	('phosphorylation', 'MPA', (79, 94))	('binding', 'molecular_function', 'GO:0005488', ('168', '175'))	('binding', 'Interaction', (168, 175))	('protein stability', 'MPA', (204, 221))	('MAPK', 'molecular_function', 'GO:0004707', ('98', '102'))	('ccRCC', 'Disease', 'MESH:D002292', (34, 39))	('MAPK14', 'Gene', (98, 104))	('CDC25B', 'Protein', (179, 185))	('ccRCC', 'Disease', (34, 39))	('affecting', 'Reg', (190, 199))	('MAPK', 'molecular_function', 'GO:0004707', ('112', '116'))
143114	31856414	Furthermore, phosphorylation of MAPK14 has been reported to stimulate the progression or recurrence of lung, pancreatic, and colon cancers.34, 35, 36 However, none of these studies has directly targeted MAPK14 or P-MAPK14 in ccRCC.	('ccRCC', 'Disease', (225, 230))	('colon cancers', 'Disease', (125, 138))	('RCC', 'Phenotype', 'HP:0005584', (227, 230))	('ccRCC', 'Disease', 'MESH:D002292', (225, 230))	('MAPK14', 'Gene', (203, 209))	('MAPK', 'molecular_function', 'GO:0004707', ('203', '207'))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('MAPK', 'molecular_function', 'GO:0004707', ('215', '219'))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('pancreatic', 'Disease', 'MESH:D010195', (109, 119))	('pancreatic', 'Disease', (109, 119))	('colon cancers', 'Disease', 'MESH:D015179', (125, 138))	('MAPK', 'molecular_function', 'GO:0004707', ('32', '36'))	('P-MAPK14', 'Var', (213, 221))	('ccRCC', 'Phenotype', 'HP:0006770', (225, 230))
143120	31856414	This was confirmed by the results of Co-IP experiments, which showed that P-MAPK14 could directly bind with CDC25B.	('Co-IP', 'Chemical', 'MESH:C062616', (37, 42))	('P-MAPK14', 'Var', (74, 82))	('CDC25B', 'Protein', (108, 114))	('MAPK', 'molecular_function', 'GO:0004707', ('76', '80'))	('bind', 'Interaction', (98, 102))
143121	31856414	It has been demonstrated that p38 can bind to and phosphorylate CDC25B,21 and activation of p38 might phosphorylate CDC25B at Ser101, leading to the rapid degradation of CDC25B and cell cycle arrest.37 Here, it was found that the level of MAPK14 phosphorylation in ccRCC tissues was higher than that of the healthy tissues, and P-MAPK14 could affect the stability of CDC25B.	('MAPK14', 'Gene', (239, 245))	('RCC', 'Phenotype', 'HP:0005584', (267, 270))	('stability', 'MPA', (354, 363))	('p38', 'Gene', (92, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (265, 270))	('phosphorylation', 'MPA', (246, 261))	('higher', 'PosReg', (283, 289))	('phosphorylation', 'biological_process', 'GO:0016310', ('246', '261'))	('Ser', 'cellular_component', 'GO:0005790', ('126', '129'))	('p38', 'Gene', '1432', (30, 33))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('181', '198'))	('Ser', 'Chemical', 'MESH:C530429', (126, 129))	('p38', 'Gene', '1432', (92, 95))	('affect', 'Reg', (343, 349))	('degradation', 'biological_process', 'GO:0009056', ('155', '166'))	('ccRCC', 'Disease', 'MESH:D002292', (265, 270))	('MAPK', 'molecular_function', 'GO:0004707', ('330', '334'))	('MAPK', 'molecular_function', 'GO:0004707', ('239', '243'))	('P-MAPK14', 'Var', (328, 336))	('p38', 'Gene', (30, 33))	('ccRCC', 'Disease', (265, 270))
143122	31856414	These results suggest that MAPK14 and P-MAPK14 might facilitate the proliferation and metastasis of ccRCC.	('proliferation', 'CPA', (68, 81))	('MAPK', 'molecular_function', 'GO:0004707', ('40', '44'))	('MAPK', 'molecular_function', 'GO:0004707', ('27', '31'))	('facilitate', 'PosReg', (53, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('ccRCC', 'Disease', (100, 105))	('ccRCC', 'Disease', 'MESH:D002292', (100, 105))	('metastasis', 'CPA', (86, 96))	('P-MAPK14', 'Var', (38, 46))
143123	31856414	It has been reported that barbaloin treatment can inhibit the levels of P-MAPK14 and CDC25B in non-small cell lung carcinoma, and suppress cell proliferation and migration consequently.38 In this study, it was demonstrated that P-MAPK14 and CDC25B expressions in ccRCC were significantly higher than those in adjacent healthy tissues.	('non-small cell lung carcinoma', 'Disease', (95, 124))	('ccRCC', 'Disease', (263, 268))	('MAPK', 'molecular_function', 'GO:0004707', ('230', '234'))	('higher', 'PosReg', (288, 294))	('ccRCC', 'Disease', 'MESH:D002292', (263, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (99, 124))	('CDC25B', 'Gene', (241, 247))	('barbaloin', 'Chemical', 'MESH:C045601', (26, 35))	('MAPK', 'molecular_function', 'GO:0004707', ('74', '78'))	('P-MAPK14', 'Var', (228, 236))	('expressions', 'MPA', (248, 259))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (95, 124))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (95, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (263, 268))	('cell proliferation', 'biological_process', 'GO:0008283', ('139', '157'))	('RCC', 'Phenotype', 'HP:0005584', (265, 268))
143124	31856414	Both P-MAPK14 and CDC25B could stimulate cell proliferation and metastasis in ccRCC in vitro and in vivo.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('MAPK', 'molecular_function', 'GO:0004707', ('7', '11'))	('ccRCC', 'Disease', (78, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('cell proliferation', 'CPA', (41, 59))	('ccRCC', 'Disease', 'MESH:D002292', (78, 83))	('P-MAPK14', 'Var', (5, 13))	('stimulate', 'PosReg', (31, 40))	('CDC25B', 'Gene', (18, 24))	('metastasis', 'CPA', (64, 74))	('cell proliferation', 'biological_process', 'GO:0008283', ('41', '59'))
143128	31856414	P-MAPK14 could promote tumor proliferation and migration through binding to and affecting the stability of CDC25B.	('promote', 'PosReg', (15, 22))	('binding', 'Interaction', (65, 72))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('CDC25B', 'Gene', (107, 113))	('stability', 'MPA', (94, 103))	('migration', 'CPA', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('P-MAPK14', 'Var', (0, 8))	('affecting', 'Reg', (80, 89))	('MAPK', 'molecular_function', 'GO:0004707', ('2', '6'))	('binding', 'molecular_function', 'GO:0005488', ('65', '72'))	('tumor', 'Disease', (23, 28))
143136	31165139	In addition, we used ccRCC datasets from Gene Expression Omnibus (IDs: GSE6344, GSE15641, GSE14994, GSE11024).	('GSE15641', 'Var', (80, 88))	('GSE6344', 'Chemical', 'MESH:C081303', (71, 78))	('ccRCC', 'Disease', (21, 26))	('ccRCC', 'Disease', 'MESH:D002292', (21, 26))	('Gene Expression', 'biological_process', 'GO:0010467', ('41', '56'))
143138	31165139	For this, we used six ccRCC datasets (GSE14762, GSE781, GSE6344, GSE15641, GSE14994, GSE11024).	('ccRCC', 'Disease', (22, 27))	('ccRCC', 'Disease', 'MESH:D002292', (22, 27))	('GSE14762', 'Var', (38, 46))	('GSE6344', 'Var', (56, 63))	('GSE11024', 'Var', (85, 93))	('GSE15641', 'Var', (65, 73))	('GSE14994', 'Var', (75, 83))	('GSE6344', 'Chemical', 'MESH:C081303', (56, 63))	('GSE781', 'Var', (48, 54))
143188	33542901	To search the potential differential expression genes (DEGs) and differential expression miRNAs (DE-miRNAs) in metastatic ccRCC tissues compared with primary ccRCC tissues, we conducted a data mining in Gene Expression Omnibus (GEO) database and two datasets (GSE22541 for mRNAs, GSE37989 for miRNAs) were finally included in our study.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('RCC', 'Disease', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('Gene Expression', 'biological_process', 'GO:0010467', ('203', '218'))	('GSE22541', 'Var', (260, 268))
143217	33542901	COL6A3 gene silencing inhibits gastric cancer cell proliferation, migration, and invasion while promoting apoptosis through the PI3K-Akt signaling pathway.	('Akt', 'Gene', (133, 136))	('gastric cancer', 'Disease', (31, 45))	('Akt signaling', 'biological_process', 'GO:0043491', ('133', '146'))	('Akt', 'Gene', '207', (133, 136))	('signaling pathway', 'biological_process', 'GO:0007165', ('137', '154'))	('PI3K', 'molecular_function', 'GO:0016303', ('128', '132'))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('inhibits', 'NegReg', (22, 30))	('gastric cancer', 'Disease', 'MESH:D013274', (31, 45))	('gene silencing', 'biological_process', 'GO:0016458', ('7', '21'))	('invasion', 'CPA', (81, 89))	('apoptosis', 'CPA', (106, 115))	('silencing', 'Var', (12, 21))	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))	('COL6A3', 'Gene', (0, 6))	('migration', 'CPA', (66, 75))	('promoting', 'PosReg', (96, 105))	('gastric cancer', 'Phenotype', 'HP:0012126', (31, 45))	('COL6A3', 'Gene', '1293', (0, 6))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))
143226	33542901	MiRNAs not only play the role of proto-oncogenes in tumor cells by promoting the occurrence and development of tumors, but also play a role of anti-cancer via inhibiting the oncogenesis and metastasis of cancers.	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('development', 'CPA', (96, 107))	('metastasis of cancers', 'Disease', (190, 211))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('oncogenesis', 'biological_process', 'GO:0007048', ('174', '185'))	('metastasis of cancers', 'Disease', 'MESH:D009362', (190, 211))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('promoting', 'PosReg', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cancer', 'Disease', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Disease', (111, 116))	('inhibiting', 'NegReg', (159, 169))	('cancer', 'Disease', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('MiRNAs', 'Var', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('occurrence', 'CPA', (81, 91))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))
143231	33542901	A recent study showed that knock down of histone methyltransferase SET8, a target gene of miR-502, led to the inhibition of cell proliferation, colony formation, cellular migration, and invasion in RCC cells, implying the anti-cancer activity of miR-502.	('formation', 'biological_process', 'GO:0009058', ('151', '160'))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('SET8', 'Gene', '387893', (67, 71))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('miR-502', 'Gene', (90, 97))	('invasion', 'CPA', (186, 194))	('inhibition', 'NegReg', (110, 120))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('110', '142'))	('histone methyltransferase', 'Gene', (41, 66))	('miR-502', 'Gene', (246, 253))	('miR-502', 'Gene', '574504', (90, 97))	('SET8', 'Gene', (67, 71))	('cancer', 'Disease', (227, 233))	('knock down', 'Var', (27, 37))	('cellular migration', 'CPA', (162, 180))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('RCC', 'Disease', (198, 201))	('histone methyltransferase', 'Gene', '56979', (41, 66))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('cell proliferation', 'CPA', (124, 142))	('colony formation', 'CPA', (144, 160))	('miR-502', 'Gene', '574504', (246, 253))
143257	32850445	Canonical correlation (CC) analysis was applied and four CCs (CC32, CC20, CC9, and CC7) have an AUC > 0.65 in our dataset with similar predictive power in the TCGA-KIRC dataset.	('CC20', 'Var', (68, 72))	('CC7', 'Var', (83, 86))	('CCs', 'molecular_function', 'GO:0052727', ('57', '60'))	('CC9', 'Chemical', '-', (74, 77))	('CCs', 'molecular_function', 'GO:0052728', ('57', '60'))	('CC9', 'Var', (74, 77))	('CC32', 'Var', (62, 66))	('AUC', 'MPA', (96, 99))	('CCs', 'molecular_function', 'GO:0034019', ('57', '60'))
143259	32850445	In a multivariate Cox model, the four CCs were able to identify high/low risk groups for metastases in the TCGA-KIRC (p < 0.05) with odds ratios of CC32 = 5.7, CC20 = 4.4, CC9 = 3.6, and CC7 = 2.7.	('CC7', 'Var', (187, 190))	('CC9', 'Chemical', '-', (172, 175))	('CCs', 'molecular_function', 'GO:0052728', ('38', '41'))	('CCs', 'molecular_function', 'GO:0052727', ('38', '41'))	('CC32', 'Var', (148, 152))	('metastases', 'Disease', (89, 99))	('CC20', 'Var', (160, 164))	('CC9', 'Var', (172, 175))	('metastases', 'Disease', 'MESH:D009362', (89, 99))	('CCs', 'molecular_function', 'GO:0034019', ('38', '41'))
143308	32850445	CC32 was enriched in GO terms related to RNA binding and spindle function, CC20 was enriched in oxidative-phosphorylation genes, CC9 was enriched in kidney development while CC7 was enriched in immune terms.	('oxidative-phosphorylation genes', 'MPA', (96, 127))	('RNA', 'Interaction', (41, 44))	('spindle', 'MPA', (57, 64))	('CC20', 'Var', (75, 79))	('RNA', 'cellular_component', 'GO:0005562', ('41', '44'))	('men', 'Species', '9606', (163, 166))	('spindle', 'cellular_component', 'GO:0005819', ('57', '64'))	('oxidative-phosphorylation', 'biological_process', 'GO:0006119', ('96', '121'))	('kidney development', 'biological_process', 'GO:0001822', ('149', '167'))	('CC9', 'Var', (129, 132))	('RNA binding', 'molecular_function', 'GO:0003723', ('41', '52'))	('kidney development', 'CPA', (149, 167))	('CC9', 'Chemical', '-', (129, 132))
143310	32850445	These thresholds were applied to TCGA-KIRC to separate them; thresholds for high risk were CC9 <0.02, CC20>0.52, CC32>0.23 and CC7 < -0.04.	('CC9', 'Chemical', '-', (91, 94))	('CC32>0.23', 'Var', (113, 122))	('CC20>0.52', 'Var', (102, 111))	('CC7 < -0.04', 'Var', (127, 138))	('CC9 <0.02', 'Var', (91, 100))
143311	32850445	All cox regression analyses were found to be significant (p-values CC9 = 6.8E-3, CC20 = 9.4E-4, CC32 = 1.5E-4, and CC7 = 0.021, see Figure 3) with an odds ratio >2.5 (OR CC32 = 5.7, CC20 = 4.4, CC9 = 3.6, and CC7 = 2.7).	('CC20', 'Var', (81, 85))	('CC7', 'Var', (115, 118))	('CC32', 'Var', (96, 100))	('CC20', 'Var', (182, 186))	('CC9', 'Chemical', '-', (67, 70))	('CC32', 'Var', (170, 174))	('CC9', 'Chemical', '-', (194, 197))
143346	32850445	Some studies have examined mutational differences between men and women in ccRCC, showing that stratification by gender showed BAP1 mutations have a female-specific poorer outcome.	('BAP1', 'Gene', (127, 131))	('poorer', 'NegReg', (165, 171))	('mutations', 'Var', (132, 141))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('BAP1', 'Gene', '8314', (127, 131))	('women', 'Species', '9606', (66, 71))	('men', 'Species', '9606', (68, 71))	('men', 'Species', '9606', (58, 61))
143350	32850445	CTHRC1 knockdown has been shown to reduce proliferation and epithelial-to-mesenchymal transition and increased expression is associated with a poorer prognosis.	('CTHRC1', 'Gene', (0, 6))	('proliferation', 'CPA', (42, 55))	('increased', 'PosReg', (101, 110))	('expression', 'MPA', (111, 121))	('reduce', 'NegReg', (35, 41))	('knockdown', 'Var', (7, 16))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('60', '96'))	('CTHRC1', 'Gene', '115908', (0, 6))
143356	32850445	Using TCGA-KIRC for validation may have been limited due to the fact that the TCGA-KIRC has local and distant recurrence of disease in their dataset when our cohort consisted only of distant metastases.	('TCGA-KIRC', 'Var', (78, 87))	('metastases', 'Disease', (191, 201))	('metastases', 'Disease', 'MESH:D009362', (191, 201))
143398	32667929	According to data from The Cancer Genome Atlas, NPL4 mRNA expression was significantly upregulated in clinical ccRCC samples compared with that in normal kidney samples, and patients with high NPL4 expression had poor overall survival compared with patients with low NPL4 expression.	('NPL', 'molecular_function', 'GO:0008747', ('267', '270'))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('high', 'Var', (188, 192))	('NPL', 'molecular_function', 'GO:0008747', ('193', '196'))	('Cancer', 'Disease', (27, 33))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('NPL', 'molecular_function', 'GO:0008747', ('48', '51'))	('RCC', 'Disease', (113, 116))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('NPL4', 'Gene', (193, 197))	('patients', 'Species', '9606', (249, 257))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('overall survival', 'CPA', (218, 234))	('Cancer', 'Disease', 'MESH:D009369', (27, 33))	('upregulated', 'PosReg', (87, 98))	('mRNA expression', 'MPA', (53, 68))	('patients', 'Species', '9606', (174, 182))	('poor', 'NegReg', (213, 217))	('NPL4', 'Gene', (48, 52))
143399	32667929	Disulfiram and NPL4 siRNA inhibited ccRCC cell proliferation in vitro, and disulfiram inhibited ccRCC tumor growth in a xenograft model.	('RCC', 'Disease', (38, 41))	('ccRCC tumor', 'Disease', (96, 107))	('inhibited', 'NegReg', (26, 35))	('disulfiram', 'Chemical', 'MESH:D004221', (75, 85))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('ccRCC tumor', 'Disease', 'MESH:D009369', (96, 107))	('disulfiram', 'Var', (75, 85))	('NPL', 'molecular_function', 'GO:0008747', ('15', '18'))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('cell proliferation', 'biological_process', 'GO:0008283', ('42', '60'))	('Disulfiram', 'Chemical', 'MESH:D004221', (0, 10))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('inhibited', 'NegReg', (86, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
143412	32667929	In both studies, in vivo and in vitro analyses showed antitumor effects in RCCs using PHGDH or BRD4 inhibitors, which exhibit mechanisms different from those of RTK and mTOR inhibitors or anti-PD-1 antibodies.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('RTK', 'Gene', '5979', (161, 164))	('mTOR', 'Gene', '2475', (169, 173))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('PHGDH', 'Gene', '26227', (86, 91))	('BRD4', 'Gene', (95, 99))	('RTK', 'Gene', (161, 164))	('RCC', 'Disease', (75, 78))	('mTOR', 'Gene', (169, 173))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('PD-1', 'Gene', (193, 197))	('PD-1', 'Gene', '5133', (193, 197))	('PHGDH', 'Gene', (86, 91))	('inhibitors', 'Var', (100, 110))	('BRD4', 'Gene', '23476', (95, 99))
143431	32667929	Western blot analysis was carried out as previously described with diluted (1:1,000) anti-NPL4 antibodies (Novus bio, CO, USA), anti-AKR1B1 antibodies (GTX113381; Gene Tex, Inc., Irvine CA, USA), anti-PSAT1 antibodies (GTX633623; Gene Tex), and anti-b-actin antibodies (bs-0061R; Bioss).	('AKR1B1', 'Gene', (133, 139))	('GTX633623;', 'Var', (219, 229))	('PSAT1', 'Gene', '29968', (201, 206))	('AKR1B1', 'Gene', '231', (133, 139))	('PSAT1', 'Gene', (201, 206))	('NPL', 'molecular_function', 'GO:0008747', ('90', '93'))
143447	32667929	Cell proliferation was inhibited by transfection of RCC cells with siNPL4 compared with that in mock or siControl transfection (P < 0.0001; Fig 2A).	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('inhibited', 'NegReg', (23, 32))	('RCC', 'Disease', (52, 55))	('siNPL4', 'Var', (67, 73))	('transfection', 'Var', (36, 48))	('Cell proliferation', 'CPA', (0, 18))
143448	32667929	Cell migration and invasion were also inhibited by transfection of RCC cells with siNPL4 compared with that in mock or siControl transfection (P < 0.0001; Fig 2B).	('Cell migration', 'biological_process', 'GO:0016477', ('0', '14'))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('Cell migration', 'CPA', (0, 14))	('invasion', 'CPA', (19, 27))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('inhibited', 'NegReg', (38, 47))	('transfection', 'Var', (51, 63))	('siNPL4', 'Var', (82, 88))
143449	32667929	Furthermore, cell proliferation was inhibited by disulfiram in a concentration-dependent manner (Fig 2C).	('disulfiram', 'Var', (49, 59))	('inhibited', 'NegReg', (36, 45))	('cell proliferation', 'CPA', (13, 31))	('disulfiram', 'Chemical', 'MESH:D004221', (49, 59))	('cell proliferation', 'biological_process', 'GO:0008283', ('13', '31'))
143456	32667929	The results showed that tumor growth was significantly suppressed in mice treated with disulfiram compared with that in vehicle-treated mice (P = 0.02).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mice', 'Species', '10090', (136, 140))	('disulfiram', 'Var', (87, 97))	('tumor', 'Disease', (24, 29))	('mice', 'Species', '10090', (69, 73))	('suppressed', 'NegReg', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('disulfiram', 'Chemical', 'MESH:D004221', (87, 97))
143479	32667929	reported that dysfunction of the p97 pathway owing to NPL4 aggregate formation in response to disulfiram causes cell death through inhibition of protein degradation with its increased intensity.	('cell death', 'CPA', (112, 122))	('NPL', 'molecular_function', 'GO:0008747', ('54', '57'))	('NPL4 aggregate', 'Protein', (54, 68))	('formation', 'biological_process', 'GO:0009058', ('69', '78'))	('p97', 'Gene', '7415', (33, 36))	('protein degradation', 'MPA', (145, 164))	('disulfiram', 'MPA', (94, 104))	('dysfunction', 'Var', (14, 25))	('disulfiram', 'Chemical', 'MESH:D004221', (94, 104))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('protein degradation', 'biological_process', 'GO:0030163', ('145', '164'))	('cell death', 'biological_process', 'GO:0008219', ('112', '122'))	('p97', 'Gene', (33, 36))	('inhibition', 'NegReg', (131, 141))
143481	32667929	showed that NPL4 was upregulated in bladder cancer tissue and was correlated with poor prognosis; NPL4 knockdown was found to decrease bladder cancer cell proliferation by reduction of cyclin D1 expression.	('decrease', 'NegReg', (126, 134))	('cell proliferation', 'biological_process', 'GO:0008283', ('150', '168'))	('cyclin D1', 'Gene', '595', (185, 194))	('reduction', 'NegReg', (172, 181))	('bladder cancer', 'Disease', 'MESH:D001749', (135, 149))	('bladder cancer', 'Disease', (135, 149))	('bladder cancer', 'Phenotype', 'HP:0009725', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cyclin', 'molecular_function', 'GO:0016538', ('185', '191'))	('NPL4', 'Gene', (98, 102))	('decrease bladder', 'Phenotype', 'HP:0005343', (126, 142))	('knockdown', 'Var', (103, 112))	('NPL', 'molecular_function', 'GO:0008747', ('98', '101'))	('NPL', 'molecular_function', 'GO:0008747', ('12', '15'))	('expression', 'MPA', (195, 205))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('bladder cancer', 'Disease', 'MESH:D001749', (36, 50))	('bladder cancer', 'Disease', (36, 50))	('cyclin D1', 'Gene', (185, 194))	('bladder cancer', 'Phenotype', 'HP:0009725', (36, 50))
143496	32667929	Interestingly, disulfiram inhibits PHGDH; although PHGDH was not detected in this proteomics analysis, the serine biosynthetic pathway can be inhibited by disulfiram through PSAT1 inhibition.	('serine biosynthetic pathway', 'Pathway', (107, 134))	('PHGDH', 'Gene', '26227', (51, 56))	('serine', 'Chemical', 'MESH:D012694', (107, 113))	('PHGDH', 'Gene', '26227', (35, 40))	('PSAT1', 'Gene', '29968', (174, 179))	('PSAT1', 'Gene', (174, 179))	('inhibited', 'NegReg', (142, 151))	('disulfiram', 'Chemical', 'MESH:D004221', (155, 165))	('PHGDH', 'Gene', (51, 56))	('inhibition', 'NegReg', (180, 190))	('PHGDH', 'Gene', (35, 40))	('disulfiram', 'Chemical', 'MESH:D004221', (15, 25))	('disulfiram', 'Var', (155, 165))
143499	32667929	Although it is unclear whether AKR1B1 expression is a biomarker for cancer or a potential target for cancer treatment, several studies have shown that AKR proteins play central roles in the cellular response to osmotic, electrophilic, and oxidative stress, suggesting potential applications in cancer therapy.	('oxidative stress', 'Phenotype', 'HP:0025464', (239, 255))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cellular response to osmotic', 'MPA', (190, 218))	('cancer', 'Disease', (101, 107))	('AKR1B1', 'Gene', (31, 37))	('AKR', 'Var', (151, 154))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('AKR1B1', 'Gene', '231', (31, 37))	('cancer', 'Disease', (294, 300))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))
143510	31151999	Of note, GGT1 inhibition also impairs ccRCC cell migration.	('impairs', 'NegReg', (30, 37))	('cell migration', 'biological_process', 'GO:0016477', ('44', '58'))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('ccRCC', 'Disease', (38, 43))	('GGT1', 'Gene', (9, 13))	('ccRCC', 'Disease', 'MESH:D002292', (38, 43))	('inhibition', 'Var', (14, 24))
143511	31151999	Finally, pharmacological GSH pathway inhibition decreases ccRCC cell proliferation and increases sensitivity to standard chemotherapy.	('sensitivity to standard chemotherapy', 'MPA', (97, 133))	('inhibition', 'Var', (37, 47))	('increases', 'PosReg', (87, 96))	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('decreases', 'NegReg', (48, 57))	('GSH pathway', 'Pathway', (25, 36))	('ccRCC', 'Disease', (58, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('ccRCC', 'Disease', 'MESH:D002292', (58, 63))	('GSH', 'Chemical', '-', (25, 28))
143512	31151999	Our results suggest that GGT1/GSH pathway inhibition represents a new strategy to overcome ccRCC chemoresistance.	('GGT1/GSH', 'Gene', (25, 33))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('ccRCC', 'Disease', (91, 96))	('inhibition', 'Var', (42, 52))	('ccRCC', 'Disease', 'MESH:D002292', (91, 96))	('GSH', 'Chemical', '-', (30, 33))
143538	31151999	Therefore, modulation of the GSH-based antioxidant system, particularly through GGT1 activity, represents a promising therapeutic strategy to overcome chemoresistance and inhibit progression of ccRCC tumors.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('modulation', 'Var', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('ccRCC', 'Disease', 'MESH:D002292', (194, 199))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('progression', 'CPA', (179, 190))	('tumor', 'Disease', (200, 205))	('GGT1', 'Gene', (80, 84))	('inhibit', 'NegReg', (171, 178))	('GSH', 'Chemical', '-', (29, 32))	('chemoresistance', 'CPA', (151, 166))	('ccRCC', 'Phenotype', 'HP:0006770', (194, 199))	('ccRCC', 'Disease', (194, 199))
143559	31151999	hs01060665_G1) and TBP (hs00427620_m1).	('hs01060665_G1', 'Var', (0, 13))	('hs00427620_m1', 'Var', (24, 37))	('TBP', 'Gene', (19, 22))	('TBP', 'Gene', '6908', (19, 22))
143607	31151999	Ab15580), and 1:400 Cleaved Caspase 3 (Cell Signaling Technology, cat.	('cat', 'molecular_function', 'GO:0004096', ('66', '69'))	('Cleaved', 'Var', (20, 27))	('Caspase 3', 'Protein', (28, 37))	('S', 'Chemical', 'MESH:D013455', (44, 45))	('Signaling', 'biological_process', 'GO:0023052', ('44', '53'))
143632	31151999	To determine the functions of GGT1 in ccRCC, we used two different shRNAs with varied efficacy (shGGT1_1 and shGGT1_2) to knockdown (KD) GGT1 in 786O and RCC10 ccRCC cells and confirmed decreased protein abundance by Western blot (Figure 2B).	('ccRCC', 'Phenotype', 'HP:0006770', (160, 165))	('ccRCC', 'Disease', (160, 165))	('ccRCC', 'Disease', 'MESH:D002292', (160, 165))	('knockdown', 'Var', (122, 131))	('protein abundance', 'MPA', (196, 213))	('decreased', 'NegReg', (186, 195))	('ccRCC', 'Disease', (38, 43))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('ccRCC', 'Disease', 'MESH:D002292', (38, 43))	('GGT1', 'Gene', (137, 141))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))
143636	31151999	Glutathione levels also correlated with efficacy of GGT1 knockdown in 786O and RCC10 cells (Figure S2C).	('Glutathione', 'Chemical', 'MESH:D005978', (0, 11))	('Glutathione levels', 'MPA', (0, 18))	('GGT1', 'Gene', (52, 56))	('knockdown', 'Var', (57, 66))	('S', 'Chemical', 'MESH:D013455', (99, 100))
143643	31151999	Since it has also been reported that GSH levels correlate with tumor stage and recurrence of the disease, we determined if GGT1 ablation affected the migration capacity of ccRCC cells in vitro.	('tumor', 'Disease', (63, 68))	('GSH', 'MPA', (37, 40))	('S', 'Chemical', 'MESH:D013455', (38, 39))	('migration capacity', 'CPA', (150, 168))	('affected', 'Reg', (137, 145))	('GSH', 'Chemical', '-', (37, 40))	('ccRCC', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('ccRCC', 'Disease', 'MESH:D002292', (172, 177))	('ccRCC', 'Phenotype', 'HP:0006770', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('GGT1', 'Gene', (123, 127))	('ablation', 'Var', (128, 136))	('S', 'Chemical', 'MESH:D013455', (0, 1))
143644	31151999	We observed a significant difference in the percentage of wound healing between control and GGT1 deficient cells for both ccRCC lines (Figure 3A, 3B).	('wound healing', 'CPA', (58, 71))	('wound healing', 'biological_process', 'GO:0042060', ('58', '71'))	('ccRCC', 'Phenotype', 'HP:0006770', (122, 127))	('ccRCC', 'Disease', (122, 127))	('ccRCC', 'Disease', 'MESH:D002292', (122, 127))	('deficient', 'Var', (97, 106))	('GGT1', 'Gene', (92, 96))
143650	31151999	As expected, GSH/GSSG ratios were reduced in GGT1 KD tumors compared to controls (Figure S5A).	('GGT1 KD', 'Var', (45, 52))	('GSSG', 'Chemical', 'MESH:D019803', (17, 21))	('S', 'Chemical', 'MESH:D013455', (18, 19))	('reduced', 'NegReg', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('S', 'Chemical', 'MESH:D013455', (19, 20))	('GSH/GSSG ratios', 'MPA', (13, 28))	('S', 'Chemical', 'MESH:D013455', (14, 15))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (53, 58))	('GSH', 'Chemical', '-', (13, 16))	('S', 'Chemical', 'MESH:D013455', (89, 90))
143651	31151999	We concluded that GGT1 inhibition results in significant reduction in ccRCC cell proliferation in vivo.	('inhibition', 'Var', (23, 33))	('GGT1', 'Gene', (18, 22))	('reduction', 'NegReg', (57, 66))	('cell proliferation', 'biological_process', 'GO:0008283', ('76', '94'))	('ccRCC', 'Phenotype', 'HP:0006770', (70, 75))	('ccRCC', 'Disease', (70, 75))	('ccRCC', 'Disease', 'MESH:D002292', (70, 75))
143658	31151999	We therefore tested the combination of GGT1 inhibition and cisplatin treatment in 786O and RCC10 cells, and determined that cells with reduced GSH due to GGT1 depletion exhibit enhanced sensitivity to cisplatin, particularly those with more efficient GGT1 knockdown (shGGT1_2).	('GGT1', 'Gene', (154, 158))	('cisplatin', 'Chemical', 'MESH:D002945', (201, 210))	('GSH', 'MPA', (143, 146))	('sensitivity to cisplatin', 'MPA', (186, 210))	('reduced', 'NegReg', (135, 142))	('men', 'Species', '9606', (74, 77))	('GSH', 'Chemical', '-', (143, 146))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('enhanced', 'PosReg', (177, 185))	('depletion', 'Var', (159, 168))
143659	31151999	This could be attributed to the levels of GSH reduction achieved by each knockdown and indicates that only cells with very low GSH levels respond to chemotherapeutics (Figure 5B).	('reduction', 'NegReg', (46, 55))	('GSH', 'Chemical', '-', (42, 45))	('GSH', 'MPA', (42, 45))	('GSH', 'Chemical', '-', (127, 130))	('knockdown', 'Var', (73, 82))
143666	31151999	Of note, cisplatin and BSO - CIS treatments showed significant toxicity and mice experienced weight loss (Figure 6C), necessitating the experiment to be terminated 3 weeks after treatments began.	('cisplatin', 'Var', (9, 18))	('men', 'Species', '9606', (38, 41))	('men', 'Species', '9606', (142, 145))	('S', 'Chemical', 'MESH:D013455', (31, 32))	('men', 'Species', '9606', (183, 186))	('weight loss', 'Disease', 'MESH:D015431', (93, 104))	('toxicity', 'Disease', 'MESH:D064420', (63, 71))	('cisplatin', 'Chemical', 'MESH:D002945', (9, 18))	('toxicity', 'Disease', (63, 71))	('BSO', 'Chemical', '-', (23, 26))	('mice', 'Species', '10090', (76, 80))	('weight loss', 'Disease', (93, 104))	('weight loss', 'Phenotype', 'HP:0001824', (93, 104))	('S', 'Chemical', 'MESH:D013455', (24, 25))
143677	31151999	Nevertheless, GGT1 inhibition also enhances ChRCC cell sensitivity to oxidative stress, as well as in normal kidney cells.	('inhibition', 'Var', (19, 29))	('GGT1', 'Gene', (14, 18))	('ChRCC', 'Disease', (44, 49))	('ChRCC', 'Disease', 'MESH:D002292', (44, 49))	('oxidative stress', 'Phenotype', 'HP:0025464', (70, 86))	('enhances', 'PosReg', (35, 43))
143687	31151999	Furthermore, high GGT1 levels correlate with poor patient survival in those suffering from lung, prostate, and ovarian cancers.	('ovarian cancers', 'Phenotype', 'HP:0100615', (111, 126))	('lung', 'Disease', (91, 95))	('ovarian cancers', 'Disease', (111, 126))	('high', 'Var', (13, 17))	('ovarian cancers', 'Disease', 'MESH:D010051', (111, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('ovarian cancer', 'Phenotype', 'HP:0100615', (111, 125))	('GGT1', 'Protein', (18, 22))	('poor', 'NegReg', (45, 49))	('patient survival', 'CPA', (50, 66))	('prostate', 'Disease', (97, 105))	('patient', 'Species', '9606', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
143690	31151999	Indeed, GGT1 depletion induces a significant decrease in ccRCC cell growth and colony forming properties.	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('cell growth', 'biological_process', 'GO:0016049', ('63', '74'))	('ccRCC', 'Disease', (57, 62))	('depletion', 'Var', (13, 22))	('ccRCC', 'Disease', 'MESH:D002292', (57, 62))	('GGT1', 'Gene', (8, 12))	('decrease', 'NegReg', (45, 53))	('colony forming properties', 'CPA', (79, 104))
143692	31151999	However, we cannot exclude other forms of cell death, as inhibition of cystine uptake and GSH depletion have already been described to result in ccRCC cell death through ferroptotic processes.	('cystine uptake', 'MPA', (71, 85))	('GSH depletion', 'MPA', (90, 103))	('inhibition', 'Var', (57, 67))	('ccRCC', 'Disease', 'MESH:D002292', (145, 150))	('GSH', 'Chemical', '-', (90, 93))	('cell death', 'biological_process', 'GO:0008219', ('42', '52'))	('cell death', 'biological_process', 'GO:0008219', ('151', '161'))	('ccRCC', 'Phenotype', 'HP:0006770', (145, 150))	('uptake', 'biological_process', 'GO:0098657', ('79', '85'))	('cystine', 'Chemical', 'MESH:D003553', (71, 78))	('uptake', 'biological_process', 'GO:0098739', ('79', '85'))	('ferroptotic processes', 'CPA', (170, 191))	('ccRCC', 'Disease', (145, 150))
143696	31151999	Moreover, GGT1 inhibition only slightly impacts GSH/GSSG ratios, an indicator of oxidative stress in cells, especially for cells treated with shGGT1.	('GGT1', 'Gene', (10, 14))	('GSH', 'Chemical', '-', (48, 51))	('impacts', 'Reg', (40, 47))	('oxidative stress', 'Phenotype', 'HP:0025464', (81, 97))	('GSSG', 'Chemical', 'MESH:D019803', (52, 56))	('GSH/GSSG ratios', 'MPA', (48, 63))	('inhibition', 'Var', (15, 25))
143701	31151999	These in vitro observations correlate with our findings in vivo, where GGT1 deficiency significantly decreases the number of Ki67-positive cells, resulting in impaired tumor growth.	('impaired tumor', 'Disease', (159, 173))	('decreases', 'NegReg', (101, 110))	('impaired tumor', 'Disease', 'MESH:D009369', (159, 173))	('Ki67', 'Chemical', '-', (125, 129))	('deficiency', 'Var', (76, 86))	('GGT1', 'Gene', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
143704	31151999	Here, we report that GGT1 inhibition significantly decreases ccRCC cell migration, suggesting that GGT1 could be of therapeutic interest for advanced-stage patients.	('patients', 'Species', '9606', (156, 164))	('GGT1', 'Gene', (21, 25))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('ccRCC', 'Disease', (61, 66))	('inhibition', 'Var', (26, 36))	('decreases', 'NegReg', (51, 60))	('ccRCC', 'Disease', 'MESH:D002292', (61, 66))	('cell migration', 'biological_process', 'GO:0016477', ('67', '81'))
143705	31151999	Most importantly, GGT1/GSH pathway inhibition enhances the efficacy of standard chemotherapeutic agents such as cisplatin.	('enhances', 'PosReg', (46, 54))	('GSH', 'Chemical', '-', (23, 26))	('efficacy', 'MPA', (59, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('GGT1/GSH pathway', 'Pathway', (18, 34))	('inhibition', 'Var', (35, 45))
143707	31151999	Additionally, ovarian cancer cells overexpressing GGT1 are more resistant to chemotherapies, particularly cisplatin, and 5-fluorouracil.	('overexpressing', 'Var', (35, 49))	('ovarian cancer', 'Disease', (14, 28))	('ovarian cancer', 'Phenotype', 'HP:0100615', (14, 28))	('resistant to', 'MPA', (64, 76))	('GGT1', 'Gene', (50, 54))	('5-fluorouracil', 'MPA', (121, 135))	('ovarian cancer', 'Disease', 'MESH:D010051', (14, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (121, 135))
143708	31151999	In line with these data, we show that GGT1 depletion or pharmacological inhibition can improve the sensitivity of ccRCC cells to chemotherapeutics, and the development of a potent inhibitor of GGT1 represents a new therapeutic strategy.	('ccRCC', 'Disease', (114, 119))	('GGT1', 'Gene', (38, 42))	('ccRCC', 'Disease', 'MESH:D002292', (114, 119))	('depletion', 'Var', (43, 52))	('men', 'Species', '9606', (163, 166))	('GGT1', 'Gene', (193, 197))	('inhibition', 'Var', (72, 82))	('improve', 'PosReg', (87, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('sensitivity', 'MPA', (99, 110))
143710	31151999	GGT1/GSH pathway inhibition represents a promising therapeutic strategy to overcome chemoresistance and inhibit progression of ccRCC tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('GGT1/GSH', 'Gene', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('progression', 'CPA', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('inhibition', 'Var', (17, 27))	('chemoresistance', 'CPA', (84, 99))	('ccRCC', 'Disease', (127, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('tumor', 'Disease', (133, 138))	('GSH', 'Chemical', '-', (5, 8))	('ccRCC', 'Disease', 'MESH:D002292', (127, 132))	('inhibit', 'NegReg', (104, 111))
143742	31061809	Immunohistochemically, the tumor cells were positive for Ki67, epidermal growth factor receptor (EGFR), cytokeratins 8 (CK8), cluster of differentiation 10 (CD10), but negative for, cytokeratins 7 (CK7), cytokeratins 20 (CK20), p53 and caudal-related home-odomain transcription-2 (CDX-2).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('Ki67', 'Var', (57, 61))	('tumor', 'Disease', (27, 32))	('epidermal growth factor receptor', 'Gene', (63, 95))	('EGFR', 'Gene', '1956', (97, 101))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('63', '86'))	('p53', 'Gene', (228, 231))	('p53', 'Gene', '7157', (228, 231))	('EGFR', 'Gene', (97, 101))	('transcription', 'biological_process', 'GO:0006351', ('264', '277'))	('epidermal growth factor receptor', 'Gene', '1956', (63, 95))	('CD10', 'molecular_function', 'GO:0004245', ('157', '161'))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('CDX-2', 'Gene', '1045', (281, 286))	('CDX-2', 'Gene', (281, 286))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))
143803	29915025	However, ROS production is significantly increased in cancer cells because of mitochondrial dysfunction, altered metabolism, and frequent genetic mutations, resulting in an accumulation of large amounts of oxidized protein, DNA, and lipids.	('metabolism', 'biological_process', 'GO:0008152', ('113', '123'))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('DNA', 'MPA', (224, 227))	('ROS', 'Chemical', 'MESH:D017382', (9, 12))	('N', 'Chemical', 'MESH:D009584', (225, 226))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (78, 103))	('metabolism', 'MPA', (113, 123))	('lipids', 'Chemical', 'MESH:D008055', (233, 239))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('cancer', 'Disease', (54, 60))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (78, 103))	('ROS production', 'MPA', (9, 23))	('mitochondrial dysfunction', 'Disease', (78, 103))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('increased', 'PosReg', (41, 50))	('mutations', 'Var', (146, 155))	('DNA', 'cellular_component', 'GO:0005574', ('224', '227'))	('altered', 'Reg', (105, 112))	('accumulation', 'PosReg', (173, 185))
143819	29915025	As a result, disturbances in GSH homeostasis are often found in multiple pathologies, e.g., neurodegenerative disorders, cancer, cystic fibrosis, liver disorders, and diabetes.	('diabetes', 'Disease', (167, 175))	('found', 'Reg', (55, 60))	('neurodegenerative disorders', 'Disease', (92, 119))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (92, 119))	('liver disorders', 'Phenotype', 'HP:0001392', (146, 161))	('diabetes', 'Disease', 'MESH:D003920', (167, 175))	('cystic fibrosis', 'Disease', (129, 144))	('GSH homeostasis', 'MPA', (29, 44))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('homeostasis', 'biological_process', 'GO:0042592', ('33', '44'))	('disturbances', 'Var', (13, 25))	('cystic fibrosis', 'Disease', 'MESH:D003550', (129, 144))	('GSH', 'Chemical', '-', (29, 32))	('liver disorders', 'Disease', 'MESH:D008107', (146, 161))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('liver disorders', 'Disease', (146, 161))	('cancer', 'Disease', (121, 127))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (92, 119))
143827	29915025	Data supporting this indicated that elevated GSH promotes metastasis in both melanoma and liver cancer.	('GSH', 'Chemical', '-', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('GSH', 'Protein', (45, 48))	('promotes', 'PosReg', (49, 57))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('liver cancer', 'Phenotype', 'HP:0002896', (90, 102))	('elevated', 'Var', (36, 44))	('melanoma and liver cancer', 'Disease', 'MESH:D006528', (77, 102))	('metastasis', 'CPA', (58, 68))
143842	29915025	In contrast, high GCLM expression has been found to be associated with therapeutic resistance in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('high', 'Var', (13, 17))	('associated', 'Reg', (55, 65))	('GCLM', 'Protein', (18, 22))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('therapeutic resistance', 'CPA', (71, 93))	('breast cancer', 'Disease', (97, 110))	('expression', 'MPA', (23, 33))
143843	29915025	Additionally, GCLM mutations result in delayed tumor onset in sarcoma, mammary, and lymphoma mouse models, making GCLM an effective pharmacologic target to combat chemotherapeutic resistance in these cancers.	('delayed', 'NegReg', (39, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('lymphoma', 'Disease', 'MESH:D008223', (84, 92))	('tumor', 'Disease', (47, 52))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('mouse', 'Species', '10090', (93, 98))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('lymphoma', 'Phenotype', 'HP:0002665', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('mutations', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('GCLM', 'Gene', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('sarcoma', 'Disease', 'MESH:D012509', (62, 69))	('lymphoma', 'Disease', (84, 92))	('sarcoma', 'Disease', (62, 69))
143856	29915025	Additionally, although increased GSS and GCLC are found in colon cancer patients, GSS variants are also correlated with the recurrence of bladder cancer and small cell lung cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (138, 152))	('bladder cancer', 'Disease', (138, 152))	('bladder cancer', 'Phenotype', 'HP:0009725', (138, 152))	('small cell lung cancer', 'Disease', 'MESH:D055752', (157, 179))	('correlated with', 'Reg', (104, 119))	('colon cancer', 'Disease', 'MESH:D015179', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('small cell lung cancer', 'Disease', (157, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('GSS', 'Gene', '2937', (82, 85))	('GCLC', 'Gene', (41, 45))	('colon cancer', 'Disease', (59, 71))	('GSS', 'Gene', '2937', (33, 36))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (157, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('GSS', 'Gene', (82, 85))	('recurrence of bladder', 'Phenotype', 'HP:0012786', (124, 145))	('colon cancer', 'Phenotype', 'HP:0003003', (59, 71))	('variants', 'Var', (86, 94))	('GSS', 'Gene', (33, 36))	('GCLC', 'Gene', '2729', (41, 45))	('increased', 'PosReg', (23, 32))	('patients', 'Species', '9606', (72, 80))
143859	29915025	Oncogenic PI3K signaling has been recently shown to stimulate GSH production in breast cancer cells specifically for tumor samples with mutations in this pathway.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('PI3K', 'molecular_function', 'GO:0016303', ('10', '14'))	('tumor', 'Disease', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('mutations', 'Var', (136, 145))	('PI3K signaling', 'biological_process', 'GO:0014065', ('10', '24'))	('breast cancer', 'Disease', (80, 93))	('stimulate', 'PosReg', (52, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('GSH production', 'MPA', (62, 76))	('GSH', 'Chemical', '-', (62, 65))
143863	29915025	Here GSH acts as a cofactor of GPX4; therefore, modulation of amino acid availability and in turn GSH production becomes an important factor for this form of cell death.	('modulation', 'Var', (48, 58))	('amino acid availability', 'MPA', (62, 85))	('GPX4', 'Gene', (31, 35))	('GSH', 'Chemical', '-', (5, 8))	('cell death', 'biological_process', 'GO:0008219', ('158', '168'))	('GPX4', 'Gene', '2879', (31, 35))	('GSH', 'Chemical', '-', (98, 101))
143867	29915025	Several other drugs known to reduce cellular GSH levels are currently being used in clinical trials to improve efficacy of targeted therapy; for example, disulfiram induces melanoma cell apoptosis by shifting the ratio of GSH/GSSG toward its oxidized state and is now being used in phase I/II clinical research in metastatic melanoma.	('GSSG', 'Chemical', 'MESH:D019803', (226, 230))	('induces', 'PosReg', (165, 172))	('apoptosis', 'biological_process', 'GO:0006915', ('187', '196'))	('ratio', 'MPA', (213, 218))	('GSH', 'Chemical', '-', (45, 48))	('melanoma', 'Phenotype', 'HP:0002861', (325, 333))	('melanoma', 'Disease', (325, 333))	('disulfiram', 'Chemical', 'MESH:D004221', (154, 164))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', (173, 181))	('melanoma', 'Disease', 'MESH:D008545', (325, 333))	('disulfiram', 'Var', (154, 164))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('GSH', 'Chemical', '-', (222, 225))	('shifting', 'Reg', (200, 208))	('apoptosis', 'biological_process', 'GO:0097194', ('187', '196'))	('GSH/GSSG', 'MPA', (222, 230))
143869	29915025	Therefore, modulating levels of GSH by inhibiting different steps of its de novo biosynthesis is a viable option either to increase the sensitivity of tumor cells to chemotherapeutics or for other targeted therapy.	('GSH', 'Gene', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('GSH', 'Chemical', '-', (32, 35))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('biosynthesis', 'biological_process', 'GO:0009058', ('81', '93'))	('increase', 'PosReg', (123, 131))	('sensitivity', 'MPA', (136, 147))	('modulating', 'Var', (11, 21))	('inhibiting', 'NegReg', (39, 49))	('de novo biosynthesis', 'MPA', (73, 93))
143873	29915025	GGT depletion in mice results in glutathionuria and cysteine deficiency because of decreased tissue GSH.	('GSH', 'Chemical', '-', (100, 103))	('mice', 'Species', '10090', (17, 21))	('GGT', 'Gene', (0, 3))	('decreased', 'NegReg', (83, 92))	('depletion', 'Var', (4, 13))	('glutathionuria and cysteine deficiency', 'Disease', 'MESH:C536836', (33, 71))	('tissue GSH', 'CPA', (93, 103))	('GGT', 'Gene', '2678', (0, 3))
143882	29915025	Therefore, high GGT levels also correlate with therapeutic resistance and worse prognosis in breast cancer and sarcoma patients.	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('sarcoma', 'Disease', (111, 118))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('GGT', 'Gene', '2678', (16, 19))	('therapeutic resistance', 'CPA', (47, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('breast cancer', 'Disease', (93, 106))	('correlate with', 'Reg', (32, 46))	('high', 'Var', (11, 15))	('GGT', 'Gene', (16, 19))
143887	29915025	GGT inhibition represents a novel approach to reduce intracellular GSH levels as a means of sensitizing them to different chemotherapeutics.	('reduce', 'NegReg', (46, 52))	('intracellular', 'cellular_component', 'GO:0005622', ('53', '66'))	('GGT', 'Gene', (0, 3))	('GSH', 'Chemical', '-', (67, 70))	('inhibition', 'Var', (4, 14))	('intracellular GSH levels', 'MPA', (53, 77))	('GGT', 'Gene', '2678', (0, 3))
143890	29915025	Novel classes of noncompetitive inhibitors like OU749, which have low toxicity, can also be used to make the cancer cells sensitive to therapy by lowering the GSH and cysteine availability.	('GSH', 'Chemical', '-', (159, 162))	('low toxicity', 'Disease', (66, 78))	('low toxicity', 'Disease', 'MESH:D009800', (66, 78))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('OU749', 'Var', (48, 53))	('cysteine', 'Chemical', 'MESH:D003545', (167, 175))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('lowering', 'NegReg', (146, 154))
143905	29915025	Moreover, perturbation of xCT levels in these cancers increases their sensitivity to chemotherapeutics, making it an appealing target for combinatorial therapy.	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('xCT', 'Gene', '23657', (26, 29))	('cancers', 'Disease', (46, 53))	('sensitivity to chemotherapeutics', 'MPA', (70, 102))	('increases', 'PosReg', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('perturbation', 'Var', (10, 22))	('xCT', 'Gene', (26, 29))
143909	29915025	Suppression of cysteine desulfurase (NFS1) induces an iron starvation response, which can trigger this kind of cell death when exposed to ROS.	('induces', 'Reg', (43, 50))	('sulfur', 'Chemical', 'MESH:D013455', (26, 32))	('cell death', 'biological_process', 'GO:0008219', ('111', '121'))	('NFS1', 'Gene', (37, 41))	('Suppression', 'Var', (0, 11))	('cysteine', 'Chemical', 'MESH:D003545', (15, 23))	('ROS', 'Chemical', 'MESH:D017382', (138, 141))	('NFS1', 'Gene', '9054', (37, 41))	('iron starvation response', 'MPA', (54, 78))	('iron', 'Chemical', 'MESH:D007501', (54, 58))
143942	29915025	Mutations in KEAP1 or NRF2 lead to metabolic rewiring of tumors toward increased glutamine consumption for GSH synthesis.	('glutamine consumption for GSH synthesis', 'MPA', (81, 120))	('KEAP1', 'Gene', '9817', (13, 18))	('GSH', 'Chemical', '-', (107, 110))	('metabolic', 'MPA', (35, 44))	('increased glutamine', 'Phenotype', 'HP:0003217', (71, 90))	('KEAP1', 'Gene', (13, 18))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('NRF2', 'Gene', '4780', (22, 26))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('lead to', 'Reg', (27, 34))	('increased', 'PosReg', (71, 80))	('glutamine', 'Chemical', 'MESH:D005973', (81, 90))	('tumors', 'Disease', (57, 63))	('synthesis', 'biological_process', 'GO:0009058', ('111', '120'))	('NRF2', 'Gene', (22, 26))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
143943	29915025	Several mechanisms appear to be responsible for increased NRF2 activity in cancers: somatic mutations in KEAP1, CUL3, or NRF2; epigenetic silencing of KEAP; transcriptional NRF2 up-regulation through oncogene-dependent signaling and modification of KEAP1 by metabolic alterations; and cysteine modification of KEAP1, leading to NRF2 accumulation.	('epigenetic silencing', 'Var', (127, 147))	('KEAP', 'Chemical', '-', (249, 253))	('KEAP', 'Chemical', '-', (105, 109))	('CUL3', 'Gene', '8452', (112, 116))	('NRF2', 'Gene', '4780', (328, 332))	('KEAP1', 'Gene', '9817', (105, 110))	('NRF2', 'Gene', (173, 177))	('cysteine modification', 'Var', (285, 306))	('NRF2', 'Gene', '4780', (58, 62))	('KEAP1', 'Gene', (105, 110))	('cysteine', 'Chemical', 'MESH:D003545', (285, 293))	('NRF2', 'Gene', '4780', (121, 125))	('activity', 'MPA', (63, 71))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('KEAP1', 'Gene', '9817', (310, 315))	('KEAP', 'Chemical', '-', (151, 155))	('KEAP1', 'Gene', (310, 315))	('NRF2', 'Gene', (328, 332))	('accumulation', 'PosReg', (333, 345))	('KEAP', 'Chemical', '-', (310, 314))	('signaling', 'biological_process', 'GO:0023052', ('219', '228'))	('NRF2', 'Gene', (58, 62))	('CUL3', 'Gene', (112, 116))	('NRF2', 'Gene', (121, 125))	('mutations', 'Var', (92, 101))	('increased', 'PosReg', (48, 57))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('regulation', 'biological_process', 'GO:0065007', ('181', '191'))	('cancers', 'Disease', (75, 82))	('NRF2', 'Gene', '4780', (173, 177))	('KEAP1', 'Gene', '9817', (249, 254))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('up-regulation', 'PosReg', (178, 191))	('KEAP1', 'Gene', (249, 254))
143958	29915025	Collectively, a combination of inhibitors of GSH synthesis and/or its utilization with either chemotherapeutics or targeted treatment might increase the sensitivity of such drugs and provide viable options for patients suffering from therapy-resistant tumors.	('GSH', 'Chemical', '-', (45, 48))	('synthesis', 'biological_process', 'GO:0009058', ('49', '58'))	('tumors', 'Disease', 'MESH:D009369', (252, 258))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('sensitivity', 'MPA', (153, 164))	('patients', 'Species', '9606', (210, 218))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('increase', 'PosReg', (140, 148))	('inhibitors', 'Var', (31, 41))	('GSH', 'Protein', (45, 48))	('tumors', 'Disease', (252, 258))
143963	29915025	A better understanding of these pathways and the role of GSH in them should aid the development of mechanism-based GSH inhibitors, which can then be combinatorically used with other drugs to effectively limit tumor growth.	('GSH', 'Gene', (115, 118))	('tumor', 'Disease', (209, 214))	('inhibitors', 'Var', (119, 129))	('GSH', 'Chemical', '-', (115, 118))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('GSH', 'Chemical', '-', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
143969	32641718	Furthermore, in vivo experiments showed that SNHG12 increased tumour growth and that knocking down SNHG12 could reverse RCC sunitinib resistance.	('increased', 'PosReg', (52, 61))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('tumour growth', 'Disease', (62, 75))	('tumour growth', 'Disease', 'MESH:D006130', (62, 75))	('sunitinib', 'Chemical', 'MESH:D000077210', (124, 133))	('SNHG12', 'Var', (45, 51))	('SNHG12', 'Gene', (99, 105))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('knocking down', 'Var', (85, 98))
143985	32641718	By further exploration, we determined that SNHG12 could upregulate CDCA3 by stabilising the transcription factor SP1.	('SNHG12', 'Var', (43, 49))	('stabilising', 'MPA', (76, 87))	('CDCA3', 'Gene', '83461', (67, 72))	('transcription', 'biological_process', 'GO:0006351', ('92', '105'))	('CDCA3', 'Gene', (67, 72))	('transcription factor', 'molecular_function', 'GO:0000981', ('92', '112'))	('upregulate', 'PosReg', (56, 66))	('transcription factor SP1', 'MPA', (92, 116))
143993	32641718	Univariate and multivariate analyses were performed demonstrating that SNHG12 was one of the independent prognostic markers of ccRCC (Table 2).	('SNHG12', 'Var', (71, 77))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('RCC', 'Disease', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))
143994	32641718	SNHG12 was expressed at a higher level in tumour tissues than in normal tissues, and the receiver operating characteristic (ROC) curve showed that SNHG12 could be used as a diagnostic biomarker for ccRCC (Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (198, 203))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('RCC', 'Disease', (200, 203))	('RCC', 'Phenotype', 'HP:0005584', (200, 203))	('RCC', 'Disease', 'MESH:C538614', (200, 203))	('SNHG12', 'Var', (147, 153))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('tumour', 'Disease', (42, 48))
144000	32641718	CCK8 assays showed that knocking down SNHG12 expression significantly reduced the proliferation ability of 786-O cells and ACHN cells; conversely, overexpressing SNHG12 increased cell proliferation (Fig.	('cell proliferation', 'CPA', (179, 197))	('knocking down', 'Var', (24, 37))	('reduced', 'NegReg', (70, 77))	('increased', 'PosReg', (169, 178))	('SNHG12', 'Gene', (162, 168))	('cell proliferation', 'biological_process', 'GO:0008283', ('179', '197'))	('CCK8', 'Chemical', 'MESH:D012844', (0, 4))	('SNHG12', 'Gene', (38, 44))	('proliferation ability of 786-O cells and ACHN cells', 'CPA', (82, 133))
144001	32641718	In summary, SNHG12 increased the proliferation, invasion and migration of RCC cells.	('SNHG12', 'Var', (12, 18))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('migration', 'CPA', (61, 70))	('proliferation', 'CPA', (33, 46))	('increased', 'PosReg', (19, 28))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('invasion', 'CPA', (48, 56))
144007	32641718	Western blotting showed that at the protein level, SNHG12 could regulate CDCA3 expression (Fig.	('regulate', 'Reg', (64, 72))	('CDCA3', 'Gene', '83461', (73, 78))	('expression', 'MPA', (79, 89))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('CDCA3', 'Gene', (73, 78))	('SNHG12', 'Var', (51, 57))
144016	32641718	Furthermore, after knocking down or overexpressing CDCA3 (Supplementary Fig.	('CDCA3', 'Gene', '83461', (51, 56))	('CDCA3', 'Gene', (51, 56))	('overexpressing', 'PosReg', (36, 50))	('knocking down', 'Var', (19, 32))
144026	32641718	Knocking down CDCA3 could also weaken the positive effect of SNHG12 on RCC cell migration and invasion.	('invasion', 'CPA', (94, 102))	('CDCA3', 'Gene', (14, 19))	('Knocking down', 'Var', (0, 13))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('SNHG12', 'Gene', (61, 67))	('weaken', 'NegReg', (31, 37))	('cell migration', 'biological_process', 'GO:0016477', ('75', '89'))	('CDCA3', 'Gene', '83461', (14, 19))
144027	32641718	Overall, we found that SNHG12 promoted tumour progression via CDCA3 in RCC cells.	('CDCA3', 'Gene', (62, 67))	('tumour', 'Disease', (39, 45))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('SNHG12', 'Var', (23, 29))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('promoted', 'PosReg', (30, 38))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('CDCA3', 'Gene', '83461', (62, 67))
144028	32641718	The differential expression analysis of lncRNA from GSE64052 already showed that SNHG12 was highly expressed in sunitinib-resistant RCC cells (Supplementary Fig.	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('SNHG12', 'Gene', (81, 87))	('GSE64052', 'Var', (52, 60))	('sunitinib', 'Chemical', 'MESH:D000077210', (112, 121))
144033	32641718	Then, the sunitinib sensitivity of ACHN-R was evaluated after SNHG12 knockdown or overexpression.	('sunitinib', 'Chemical', 'MESH:D000077210', (10, 19))	('knockdown', 'Var', (69, 78))	('SNHG12', 'Gene', (62, 68))
144034	32641718	Similarly, we also found that high expression of CDCA3 promoted ACHN-R cell sunitinib resistance (Fig.	('CDCA3', 'Gene', '83461', (49, 54))	('CDCA3', 'Gene', (49, 54))	('high expression', 'Var', (30, 45))	('ACHN-R cell', 'CPA', (64, 75))	('sunitinib', 'Chemical', 'MESH:D000077210', (76, 85))	('promoted', 'PosReg', (55, 63))	('sunitinib resistance', 'MPA', (76, 96))
144036	32641718	However, when SNHG12 or CDCA3 was knocked down, cell viability decreased in the presence of sunitinib (Fig.	('CDCA3', 'Gene', (24, 29))	('SNHG12', 'Gene', (14, 20))	('cell viability', 'CPA', (48, 62))	('decreased', 'NegReg', (63, 72))	('knocked down', 'Var', (34, 46))	('sunitinib', 'Chemical', 'MESH:D000077210', (92, 101))	('CDCA3', 'Gene', '83461', (24, 29))
144037	32641718	These results revealed that knocking down SNHG12 or CDCA3 might increase the sensitivity of drug-resistant RCC to sunitinib.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('CDCA3', 'Gene', '83461', (52, 57))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('knocking down', 'Var', (28, 41))	('RCC', 'Disease', (107, 110))	('CDCA3', 'Gene', (52, 57))	('increase', 'PosReg', (64, 72))	('sunitinib', 'Chemical', 'MESH:D000077210', (114, 123))	('drug-resistant', 'MPA', (92, 106))	('SNHG12', 'Gene', (42, 48))	('sensitivity', 'MPA', (77, 88))
144039	32641718	Similarly, in SNHG12-overexpressing cells, when CDCA3 was knocked down with siRNA, the enhanced drug tolerance could be reversed (Fig.	('CDCA3', 'Gene', (48, 53))	('knocked', 'Var', (58, 65))	('drug tolerance', 'CPA', (96, 110))	('enhanced', 'PosReg', (87, 95))	('CDCA3', 'Gene', '83461', (48, 53))
144040	32641718	From these findings, we concluded that SNHG12 increased sunitinib resistance in RCC cells through CDCA3.	('SNHG12', 'Var', (39, 45))	('sunitinib', 'Chemical', 'MESH:D000077210', (56, 65))	('RCC', 'Disease', (80, 83))	('increased', 'PosReg', (46, 55))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('CDCA3', 'Gene', '83461', (98, 103))	('sunitinib resistance', 'MPA', (56, 76))	('CDCA3', 'Gene', (98, 103))
144047	32641718	Based on this mechanism, cycloheximide (CHX), a protein synthesis inhibitor, was used to investigate whether SNHG12 regulates SP1 stability.	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('cycloheximide', 'Chemical', 'MESH:D003513', (25, 38))	('SNHG12', 'Var', (109, 115))	('regulates', 'Reg', (116, 125))	('CHX', 'Chemical', 'MESH:D003513', (40, 43))	('protein synthesis', 'biological_process', 'GO:0006412', ('48', '65'))
144050	32641718	6j, when MG132 was added, SP1 remained stable even if SNHG12 was knocked down in RCC cells.	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('knocked down', 'Var', (65, 77))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('MG132', 'Chemical', 'MESH:C072553', (9, 14))	('SNHG12', 'Gene', (54, 60))
144057	32641718	From the results, we observed that knocking down SNHG12 inhibited tumour growth (Fig.	('SNHG12', 'Gene', (49, 55))	('knocking down', 'Var', (35, 48))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('tumour growth', 'Disease', (66, 79))	('tumour growth', 'Disease', 'MESH:D006130', (66, 79))	('inhibited', 'NegReg', (56, 65))
144058	32641718	Moreover, in the sh SNHG12 group, both the volume and weight of tumours from mice fed sunitinib were obviously decreased, which revealed that low SNHG12 expression increased RCC sensitivity to sunitinib (Fig.	('mice', 'Species', '10090', (77, 81))	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('decreased', 'NegReg', (111, 120))	('sunitinib', 'Chemical', 'MESH:D000077210', (86, 95))	('SNHG12', 'Gene', (146, 152))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('RCC', 'Disease', (174, 177))	('sunitinib', 'Chemical', 'MESH:D000077210', (193, 202))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('low', 'Var', (142, 145))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('increased', 'PosReg', (164, 173))
144061	32641718	SNHG12 could bind to SP1 and inhibit its ubiquitination and degradation in RCC.	('degradation', 'MPA', (60, 71))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('ubiquitination', 'MPA', (41, 55))	('inhibit', 'NegReg', (29, 36))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('bind', 'Interaction', (13, 17))	('degradation', 'biological_process', 'GO:0009056', ('60', '71'))	('SNHG12', 'Var', (0, 6))	('SP1', 'Protein', (21, 24))
144066	32641718	Next, functional experiments showed that SNHG12 could promote RCC cell proliferation, migration, invasion and sunitinib resistance.	('promote', 'PosReg', (54, 61))	('migration', 'CPA', (86, 95))	('sunitinib resistance', 'CPA', (110, 130))	('sunitinib', 'Chemical', 'MESH:D000077210', (110, 119))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('SNHG12', 'Var', (41, 47))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('invasion', 'CPA', (97, 105))
144074	32641718	Hence, we found that SNHG12 could inhibit SP1 ubiquitin-mediated proteolysis in RCC cells, which was a completely different regulatory mechanism of SNHG12 from previous studies.	('ubiquitin', 'molecular_function', 'GO:0031386', ('46', '55'))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('SP1 ubiquitin-mediated proteolysis', 'MPA', (42, 76))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('SNHG12', 'Var', (21, 27))	('proteolysis', 'biological_process', 'GO:0006508', ('65', '76'))	('inhibit', 'NegReg', (34, 41))
144078	32641718	In our research, we found for the first time that CDCA3 upregulated by SNHG12/SP1 was related to RCC and was involved in sunitinib resistance.	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('SNHG12/SP1', 'Var', (71, 81))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('sunitinib', 'Chemical', 'MESH:D000077210', (121, 130))	('CDCA3', 'Gene', '83461', (50, 55))	('CDCA3', 'Gene', (50, 55))	('sunitinib resistance', 'MPA', (121, 141))	('involved', 'Reg', (109, 117))	('upregulated', 'PosReg', (56, 67))
144091	32641718	In summary, we demonstrated for the first time that long noncoding RNA SNHG12 could upregulate the expression of CDCA3 by stabilising the transcription factor SP1 and thereby promoting tumour progression and sunitinib resistance in RCC.	('expression', 'MPA', (99, 109))	('sunitinib', 'MPA', (208, 217))	('transcription factor SP1', 'MPA', (138, 162))	('long noncoding RNA SNHG12', 'Var', (52, 77))	('CDCA3', 'Gene', '83461', (113, 118))	('transcription factor', 'molecular_function', 'GO:0000981', ('138', '158'))	('CDCA3', 'Gene', (113, 118))	('upregulate', 'PosReg', (84, 94))	('RNA', 'cellular_component', 'GO:0005562', ('67', '70'))	('RCC', 'Phenotype', 'HP:0005584', (232, 235))	('RCC', 'Disease', (232, 235))	('transcription', 'biological_process', 'GO:0006351', ('138', '151'))	('stabilising', 'MPA', (122, 133))	('RCC', 'Disease', 'MESH:C538614', (232, 235))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('tumour', 'Disease', 'MESH:D009369', (185, 191))	('tumour', 'Disease', (185, 191))	('promoting', 'PosReg', (175, 184))	('sunitinib', 'Chemical', 'MESH:D000077210', (208, 217))
144097	32641718	In addition, the pcDNA3.1 vector (Vigene Biology) containing the full-length cDNA sequence of SNHG12, CDCA3 or SP1 was used to overexpress SNHG12, CDCA3 or SP1, respectively.	('CDCA3', 'Gene', (147, 152))	('overexpress', 'PosReg', (127, 138))	('SNHG12', 'Gene', (94, 100))	('CDCA3', 'Gene', '83461', (102, 107))	('CDCA3', 'Gene', (102, 107))	('CDCA3', 'Gene', '83461', (147, 152))	('SNHG12', 'Var', (139, 145))
144140	32113161	Ectopic expression of KLF6 or disruption of CBX4-HDAC1 interaction attenuates CBX4-mediated cell growth and migration.	('HDAC1', 'Gene', '3065', (49, 54))	('KLF6', 'Gene', '1316', (22, 26))	('cell growth', 'biological_process', 'GO:0016049', ('92', '103'))	('disruption', 'Var', (30, 40))	('interaction', 'Interaction', (55, 66))	('Ectopic expression', 'Var', (0, 18))	('attenuates', 'NegReg', (67, 77))	('KLF6', 'Gene', (22, 26))	('HDAC1', 'Gene', (49, 54))
144141	32113161	Furthermore, CBX4 depletion markedly enhances the histone deacetylase inhibitor (HDACi)-induced cell apoptosis and suppression of tumor growth.	('enhances', 'PosReg', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('suppression', 'NegReg', (115, 126))	('apoptosis', 'biological_process', 'GO:0097194', ('101', '110'))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('depletion', 'Var', (18, 27))	('apoptosis', 'biological_process', 'GO:0006915', ('101', '110'))	('HDAC', 'Gene', (81, 85))	('tumor', 'Disease', (130, 135))	('CBX4', 'Gene', (13, 17))	('HDAC', 'Gene', '9734', (81, 85))
144148	32113161	Patients with high expression of CBX4 were likely to survived shorter.	('survived shorter', 'CPA', (53, 69))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('CBX4', 'Gene', (33, 37))
144150	32113161	Combinative treatment of CBX4 knockdown and HDAC inhibitor is of great lethal effect on ccRCC cell survival.	('CBX4', 'Gene', (25, 29))	('ccRCC', 'Disease', (88, 93))	('ccRCC', 'Disease', 'MESH:D002292', (88, 93))	('HDAC', 'Gene', (44, 48))	('HDAC', 'Gene', '9734', (44, 48))	('knockdown', 'Var', (30, 39))
144164	32113161	Overexpression of CBX4 has also been found in breast cancer and osteosarcoma.	('osteosarcoma', 'Disease', 'MESH:D012516', (64, 76))	('CBX4', 'Gene', (18, 22))	('breast cancer', 'Disease', (46, 59))	('found', 'Reg', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Overexpression', 'Var', (0, 14))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('osteosarcoma', 'Disease', (64, 76))	('osteosarcoma', 'Phenotype', 'HP:0002669', (64, 76))
144170	32113161	Inhibition of CBX4 was able to increase cell apoptosis induced by the treatment of HDAC inhibitor Trichostatin A (TSA).	('CBX4', 'Gene', (14, 18))	('HDAC', 'Gene', (83, 87))	('cell apoptosis', 'CPA', (40, 54))	('HDAC', 'Gene', '9734', (83, 87))	('TSA', 'Chemical', 'MESH:C012589', (114, 117))	('Trichostatin A', 'Chemical', 'MESH:C012589', (98, 112))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('Inhibition', 'Var', (0, 10))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('TSA', 'molecular_function', 'GO:0033984', ('114', '117'))	('increase', 'PosReg', (31, 39))
144200	32113161	High expression of CBX4 was closely associated with higher Fuhrman grade, tumor sarcomatoid differentiation and lymph node invasion in SYSUCC cohort (Supplementary Table 2).	('lymph node invasion', 'CPA', (112, 131))	('High', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('Fuhrman grade', 'CPA', (59, 72))	('higher', 'PosReg', (52, 58))	('tumor sarcomatoid', 'Disease', 'MESH:D002292', (74, 91))	('CBX4', 'Gene', (19, 23))	('tumor sarcomatoid', 'Phenotype', 'HP:0100242', (74, 91))	('associated', 'Reg', (36, 46))	('tumor sarcomatoid', 'Disease', (74, 91))
144203	32113161	Compared with those with low CBX4, patients with high CBX4 expression were likely to survive shorter and experience tumor progression in SYSUCC cohort (Fig.	('experience', 'Reg', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('shorter', 'NegReg', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('CBX4', 'Gene', (54, 58))	('high', 'Var', (49, 53))	('patients', 'Species', '9606', (35, 43))	('tumor', 'Disease', (116, 121))
144206	32113161	Patients with high CBX4 expression were frequently with tumor lymph node and distant metastasis (Fig.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('expression', 'MPA', (24, 34))	('tumor', 'Disease', (56, 61))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('CBX4', 'Gene', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
144210	32113161	MTT assays showed that ectopic expression of CBX4 increased, whereas knockdown of CBX4 decreased the cell viabilities of ccRCC cells (Fig.	('ectopic expression', 'MPA', (23, 41))	('ccRCC', 'Disease', 'MESH:D002292', (121, 126))	('decreased', 'NegReg', (87, 96))	('cell viabilities', 'CPA', (101, 117))	('increased', 'PosReg', (50, 59))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('CBX4', 'Gene', (82, 86))	('knockdown', 'Var', (69, 78))	('ccRCC', 'Disease', (121, 126))	('CBX4', 'Gene', (45, 49))
144215	32113161	Overexpression of CBX4 significantly promoted, whereas knockdown of CBX4 attenuated tumor growth (Fig.	('knockdown', 'Var', (55, 64))	('attenuated tumor', 'Disease', (73, 89))	('promoted', 'PosReg', (37, 45))	('CBX4', 'Gene', (18, 22))	('attenuated tumor', 'Disease', 'MESH:C538265', (73, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('CBX4', 'Gene', (68, 72))
144220	32113161	Western blot showed that the expression of mesenchymal markers Vimentin, N-cadherin and MMP2 was induced by CBX4, but reduced by CBX4 shRNAs in ccRCC cells.	('Vimentin', 'cellular_component', 'GO:0045099', ('63', '71'))	('Vimentin', 'Gene', (63, 71))	('MMP2', 'Gene', '4313', (88, 92))	('MMP2', 'molecular_function', 'GO:0004228', ('88', '92'))	('Vimentin', 'Gene', '7431', (63, 71))	('N-cadherin', 'Gene', '1000', (73, 83))	('CBX4', 'Var', (108, 112))	('reduced', 'NegReg', (118, 125))	('cadherin', 'molecular_function', 'GO:0008014', ('75', '83'))	('N-cadherin', 'Gene', (73, 83))	('induced', 'PosReg', (97, 104))	('ccRCC', 'Disease', (144, 149))	('ccRCC', 'Disease', 'MESH:D002292', (144, 149))	('Vimentin', 'cellular_component', 'GO:0045098', ('63', '71'))	('MMP2', 'Gene', (88, 92))	('expression', 'MPA', (29, 39))
144223	32113161	Injection of ACHN and RCC4 cells with CBX4 overexpression formed more nodules in the lung, compared with the control cells.	('nodules in the lung', 'CPA', (70, 89))	('CBX4', 'Gene', (38, 42))	('ACHN', 'Gene', '55323', (13, 17))	('RCC', 'Disease', (22, 25))	('RCC', 'Disease', 'MESH:D002292', (22, 25))	('ACHN', 'Gene', (13, 17))	('overexpression', 'Var', (43, 57))
144227	32113161	In another study, treatment of CBX4 shRNAs resulted in increased expression of KLF6 (Supplementary figure 4B).	('KLF6', 'Gene', (79, 83))	('CBX4 shRNAs', 'Var', (31, 42))	('KLF6', 'Gene', '1316', (79, 83))	('increased', 'PosReg', (55, 64))	('expression', 'MPA', (65, 75))
144230	32113161	In SYSUCC cohort, patients with high CBX4 expression frequently expressed less KLF6 (Fig.	('KLF6', 'Gene', (79, 83))	('high', 'Var', (32, 36))	('less', 'NegReg', (74, 78))	('KLF6', 'Gene', '1316', (79, 83))	('patients', 'Species', '9606', (18, 26))	('CBX4', 'Gene', (37, 41))
144242	32113161	According to a previous study, deletion mutant of SUMO interacting motifs (CBX4DeltaSIM1/2) and chromodomain mutant (CBX4F11A/W35L) containing both CBX4F11A and CBX4W35L mutations were constructed.	('W35L', 'SUBSTITUTION', 'None', (126, 130))	('W35L', 'SUBSTITUTION', 'None', (165, 169))	('W35L', 'Var', (165, 169))	('W35L', 'Var', (126, 130))	('CBX4DeltaSIM1/2', 'Gene', '6492;6493', (75, 90))	('CBX4F11A', 'Var', (148, 156))	('CBX4DeltaSIM1/2', 'Gene', (75, 90))
144243	32113161	After transfection of CBX4F11A/W35L or CBX4DeltaSIM1/2 in ACHN and RCC4 cells for 36 h, KLF6 mRNA was determined by qRT-PCR.	('KLF6', 'Gene', '1316', (88, 92))	('ACHN', 'Gene', (58, 62))	('CBX4DeltaSIM1/2', 'Gene', (39, 54))	('W35L', 'SUBSTITUTION', 'None', (31, 35))	('RCC', 'Disease', 'MESH:D002292', (67, 70))	('RCC', 'Disease', (67, 70))	('KLF6', 'Gene', (88, 92))	('ACHN', 'Gene', '55323', (58, 62))	('CBX4DeltaSIM1/2', 'Gene', '6492;6493', (39, 54))	('W35L', 'Var', (31, 35))
144244	32113161	Results showed that both mutants were capable of suppressing KLF6 expression (Fig.	('suppressing', 'NegReg', (49, 60))	('mutants', 'Var', (25, 32))	('KLF6', 'Gene', '1316', (61, 65))	('KLF6', 'Gene', (61, 65))
144248	32113161	The enrichment of CBX4 on the KLF6 promoter was induced by CBX4 overexpression but reduced by CBX4 siRNAs (Fig.	('CBX4', 'Gene', (18, 22))	('reduced', 'NegReg', (83, 90))	('KLF6', 'Gene', '1316', (30, 34))	('enrichment', 'MPA', (4, 14))	('induced', 'PosReg', (48, 55))	('overexpression', 'Var', (64, 78))	('KLF6', 'Gene', (30, 34))	('CBX4', 'Gene', (59, 63))
144250	32113161	KLF6 expression was restored to the basal line in cells with CBX4 overexpression or depletion.	('expression', 'MPA', (5, 15))	('depletion', 'Var', (84, 93))	('KLF6', 'Gene', '1316', (0, 4))	('CBX4', 'Gene', (61, 65))	('overexpression', 'PosReg', (66, 80))	('KLF6', 'Gene', (0, 4))
144258	32113161	Strikingly, knockdown of HDAC1 almost fully restored the inhibitory effect of CBX4 on KLF6 promoter (Fig.	('HDAC1', 'Gene', '3065', (25, 30))	('KLF6', 'Gene', (86, 90))	('knockdown', 'Var', (12, 21))	('inhibitory effect', 'MPA', (57, 74))	('KLF6', 'Gene', '1316', (86, 90))	('HDAC1', 'Gene', (25, 30))	('CBX4', 'Gene', (78, 82))
144267	32113161	CBX4 knockdown markedly weakened the binding of HDAC1 to KLF6 promoter (Supplementary figure 14).	('binding', 'molecular_function', 'GO:0005488', ('37', '44'))	('binding', 'Interaction', (37, 44))	('CBX4', 'Gene', (0, 4))	('Supplementary figure 14', 'Disease', (72, 95))	('knockdown', 'Var', (5, 14))	('Supplementary figure 14', 'Disease', 'MESH:D017034', (72, 95))	('KLF6', 'Gene', '1316', (57, 61))	('HDAC1', 'Gene', (48, 53))	('weakened', 'NegReg', (24, 32))	('KLF6', 'Gene', (57, 61))	('HDAC1', 'Gene', '3065', (48, 53))
144268	32113161	When HDAC1 was knocked down in ACHN and RCC4 cells, the binding of CBX4 onto KLF6 promoter was markedly decreased (Fig.	('KLF6', 'Gene', '1316', (77, 81))	('knocked down', 'Var', (15, 27))	('HDAC1', 'Gene', (5, 10))	('ACHN', 'Gene', (31, 35))	('RCC', 'Disease', (40, 43))	('decreased', 'NegReg', (104, 113))	('HDAC1', 'Gene', '3065', (5, 10))	('RCC', 'Disease', 'MESH:D002292', (40, 43))	('binding', 'Interaction', (56, 63))	('KLF6', 'Gene', (77, 81))	('ACHN', 'Gene', '55323', (31, 35))	('binding', 'molecular_function', 'GO:0005488', ('56', '63'))	('CBX4', 'Gene', (67, 71))
144280	32113161	The therapeutic effect of combinative treatment was partially attenuated by the knockdown of KLF6 in 786-O cells (Supplementary figure 16).	('therapeutic effect', 'CPA', (4, 22))	('knockdown', 'Var', (80, 89))	('attenuated', 'NegReg', (62, 72))	('KLF6', 'Gene', (93, 97))	('KLF6', 'Gene', '1316', (93, 97))
144286	32113161	As expected, the combination of TSA and CBX4 shRNA significantly reduced the weights of xenograft tumor, compared with other groups (Fig.	('TSA', 'molecular_function', 'GO:0033984', ('32', '35'))	('reduced', 'NegReg', (65, 72))	('CBX4 shRNA', 'Var', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('TSA', 'Chemical', 'MESH:C012589', (32, 35))
144290	32113161	Dysregulation of PcG proteins have been implicated in ccRCC.	('Dysregulation', 'Var', (0, 13))	('PcG proteins', 'Protein', (17, 29))	('ccRCC', 'Disease', (54, 59))	('ccRCC', 'Disease', 'MESH:D002292', (54, 59))	('implicated', 'Reg', (40, 50))
144295	32113161	Overexpression of CBX2 in leukemia, high grade serous ovarian carcinoma and prostate cancer was associated with poor survivals.	('leukemia', 'Phenotype', 'HP:0001909', (26, 34))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (54, 71))	('leukemia', 'Disease', 'MESH:D007938', (26, 34))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (54, 71))	('leukemia', 'Disease', (26, 34))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('ovarian carcinoma', 'Disease', (54, 71))	('Overexpression', 'Var', (0, 14))	('CBX2', 'Gene', '84733', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('prostate cancer', 'Disease', (76, 91))	('CBX2', 'Gene', (18, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
144296	32113161	High CBX6 expression was linked to worse overall survival in hepatocellular carcinoma, but better recurrence-free survival in breast carcinoma.	('High', 'Var', (0, 4))	('CBX6', 'Gene', (5, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('CBX6', 'Gene', '23466', (5, 9))	('breast carcinoma', 'Disease', (126, 142))	('expression', 'MPA', (10, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('breast carcinoma', 'Disease', 'MESH:D001943', (126, 142))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (61, 85))	('breast carcinoma', 'Phenotype', 'HP:0003002', (126, 142))	('hepatocellular carcinoma', 'Disease', (61, 85))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (61, 85))
144302	32113161	Patients with high expression of CBX4 were accompanied with worse overall and disease-free survivals.	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('disease-free survivals', 'CPA', (78, 100))	('CBX4', 'Gene', (33, 37))
144312	32113161	Collectively, our data suggest that the effect of gene repress of CBX proteins in human cancers does not depend on catalytic activities.	('CBX', 'Gene', '10951', (66, 69))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('CBX', 'Gene', (66, 69))	('gene', 'Var', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('human', 'Species', '9606', (82, 87))
144318	32113161	High expression of KLF6 mRNA was associated with better overall and disease-free survivals of ccRCC patients in TCGA dataset, which may finely support the tumor suppressor role of KLF6 in ccRCC.	('ccRCC', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('155', '171'))	('ccRCC', 'Disease', 'MESH:D002292', (94, 99))	('High', 'Var', (0, 4))	('disease-free survivals', 'CPA', (68, 90))	('KLF6', 'Gene', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('KLF6', 'Gene', (19, 23))	('ccRCC', 'Disease', (188, 193))	('patients', 'Species', '9606', (100, 108))	('KLF6', 'Gene', '1316', (180, 184))	('better', 'PosReg', (49, 55))	('ccRCC', 'Disease', 'MESH:D002292', (188, 193))	('tumor suppressor', 'biological_process', 'GO:0051726', ('155', '171'))	('KLF6', 'Gene', '1316', (19, 23))
144320	32113161	Furthermore, in rescue experiments using two KLF6 shRNAs, our data showed KLF6 knockdown markedly attenuated the CBX4 shRNA-induced suppression of cell proliferation and migration.	('knockdown', 'Var', (79, 88))	('KLF6', 'Gene', '1316', (74, 78))	('cell proliferation', 'biological_process', 'GO:0008283', ('147', '165'))	('suppression', 'NegReg', (132, 143))	('KLF6', 'Gene', '1316', (45, 49))	('CBX4', 'Gene', (113, 117))	('KLF6', 'Gene', (74, 78))	('attenuated', 'NegReg', (98, 108))	('KLF6', 'Gene', (45, 49))
144329	32113161	A single lysine-to-arginine point mutation (K209R) reduces acetylation of KLF6 and abrogates its capacity to modulate gene expression.	('KLF6', 'Gene', '1316', (74, 78))	('arginine', 'Chemical', 'MESH:D001120', (19, 27))	('lysine', 'Chemical', 'MESH:D008239', (9, 15))	('modulate', 'Reg', (109, 117))	('capacity', 'MPA', (97, 105))	('reduces', 'NegReg', (51, 58))	('KLF6', 'Gene', (74, 78))	('abrogates', 'NegReg', (83, 92))	('gene expression', 'biological_process', 'GO:0010467', ('118', '133'))	('K209R', 'SUBSTITUTION', 'None', (44, 49))	('K209R', 'Var', (44, 49))
144333	32113161	Combinative treatment of HDACi and CBX4 knockdown should be more powerful to reduce the ccRCC cell growth.	('reduce', 'NegReg', (77, 83))	('ccRCC', 'Disease', (88, 93))	('ccRCC', 'Disease', 'MESH:D002292', (88, 93))	('knockdown', 'Var', (40, 49))	('CBX4', 'Gene', (35, 39))	('cell growth', 'biological_process', 'GO:0016049', ('94', '105'))	('HDAC', 'Gene', (25, 29))	('HDAC', 'Gene', '9734', (25, 29))
144334	32113161	Since HDACis have potential in clinical management of human cancers, targeting CBX4 represents an adjuvant strategy to improve the efficacy of chemotherapy in ccRCC.	('HDAC', 'Gene', (6, 10))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('HDAC', 'Gene', '9734', (6, 10))	('CBX4', 'Gene', (79, 83))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('ccRCC', 'Disease', 'MESH:D002292', (159, 164))	('targeting', 'Var', (69, 78))	('ccRCC', 'Disease', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('human', 'Species', '9606', (54, 59))	('clinical', 'Species', '191496', (31, 39))
144353	30099580	The high frequency of A:T-to-T:A transversions consistent with mutational damage as a result of aristolochic acid exposure was detected via sequencing of patients from Eastern Europe and has directly influenced primary prevention strategies.	('aristolochic acid', 'Chemical', 'MESH:C000228', (96, 113))	('influenced', 'Reg', (200, 210))	('transversions', 'Var', (33, 46))	('patients', 'Species', '9606', (154, 162))
144356	30099580	The two correlated variants on 2p21 map to EPAS1, a transcription factor previously implicated in RCC, whereas the variant on 11q13.3 contains no characterised genes.	('EPAS1', 'Gene', (43, 48))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('transcription', 'biological_process', 'GO:0006351', ('52', '65'))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('variants', 'Var', (19, 27))	('transcription factor', 'molecular_function', 'GO:0000981', ('52', '72'))	('EPAS1', 'Gene', '2034', (43, 48))
144357	30099580	An additional susceptibility locus on 12p11.23 was later discovered containing two variants in the ITPR2 gene, though direct functional evidence between ITPR2 and oncogenesis is lacking.	('variants', 'Var', (83, 91))	('ITPR2', 'Gene', (99, 104))	('ITPR2', 'Gene', '3709', (153, 158))	('oncogenesis', 'biological_process', 'GO:0007048', ('163', '174'))	('ITPR2', 'Gene', '3709', (99, 104))	('ITPR2', 'Gene', (153, 158))
144361	30099580	The second copy of VHL is lost, usually much later in life, by either non-synonymous mutation or epigenetic down-regulation.	('VHL', 'Gene', (19, 22))	('epigenetic down-regulation', 'Var', (97, 123))	('non-synonymous mutation', 'Var', (70, 93))	('VHL', 'Gene', '7428', (19, 22))	('regulation', 'biological_process', 'GO:0065007', ('113', '123'))
144362	30099580	VHL inactivation prevents the ubiquitination of hypoxia-inducible factor (HIF) for degradation.	('inactivation', 'Var', (4, 16))	('degradation', 'MPA', (83, 94))	('prevents', 'NegReg', (17, 25))	('VHL', 'Gene', (0, 3))	('degradation', 'biological_process', 'GO:0009056', ('83', '94'))	('hypoxia', 'Disease', 'MESH:D000860', (48, 55))	('VHL', 'Gene', '7428', (0, 3))	('hypoxia', 'Disease', (48, 55))	('ubiquitination', 'MPA', (30, 44))
144367	30099580	The first three of these genes are also co-located with VHL on chromosome 3p, meaning that after 3p loss, any further non-synonymous mutation will result in complete inactivation of these haploinsufficient genes.	('VHL', 'Gene', (56, 59))	('haploinsufficient', 'Disease', 'MESH:D058495', (188, 205))	('mutation', 'Var', (133, 141))	('VHL', 'Gene', '7428', (56, 59))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('haploinsufficient', 'Disease', (188, 205))	('inactivation', 'NegReg', (166, 178))	('loss', 'NegReg', (100, 104))
144369	30099580	PBRM1's inactivation could lead to loss of DNA methylation via reduction of H3K36me3.	('DNA methylation', 'MPA', (43, 58))	('loss', 'NegReg', (35, 39))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('inactivation', 'Var', (8, 20))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('DNA methylation', 'biological_process', 'GO:0006306', ('43', '58'))	('reduction', 'NegReg', (63, 72))	('H3K36me3', 'Protein', (76, 84))
144370	30099580	SETD2 is mutated in 10-30% of ccRCCs.	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('SETD2', 'Gene', '29072', (0, 5))	('mutated', 'Var', (9, 16))	('RCC', 'Disease', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCCs', 'Phenotype', 'HP:0005584', (32, 36))	('SETD2', 'Gene', (0, 5))
144371	30099580	SETD2's intracellular roles are numerous, including the regulation of transcription elongation, RNA processing, and double-stranded DNA break repair that may then activate the p53-mediated checkpoint in the absence of specific p53 mutations.	('p53', 'Gene', (227, 230))	('RNA', 'cellular_component', 'GO:0005562', ('96', '99'))	('p53', 'Gene', (176, 179))	('mutations', 'Var', (231, 240))	('regulation', 'biological_process', 'GO:0065007', ('56', '66'))	('p53', 'Gene', '7157', (227, 230))	('SETD2', 'Gene', '29072', (0, 5))	('RNA processing', 'biological_process', 'GO:0006396', ('96', '110'))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('p53', 'Gene', '7157', (176, 179))	('SETD2', 'Gene', (0, 5))	('activate', 'PosReg', (163, 171))	('intracellular', 'cellular_component', 'GO:0005622', ('8', '21'))	('transcription', 'biological_process', 'GO:0006351', ('70', '83'))
144372	30099580	BAP1, a histone deubiquitinase, is mutated in up to 5-15% of ccRCCs.	('mutated', 'Var', (35, 42))	('RCC', 'Disease', (63, 66))	('RCCs', 'Phenotype', 'HP:0005584', (63, 67))	('BAP1', 'Gene', (0, 4))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('16', '30'))	('BAP1', 'Gene', '8314', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
144375	30099580	A retrospective, validated analysis found that tumours with BAP1 mutations conferred a worse prognosis, higher grade, and worse overall survival when compared to those with PBRM1 mutations or when compared to those without BAP1 mutations.	('PBRM1', 'Gene', (173, 178))	('BAP1', 'Gene', '8314', (223, 227))	('PBRM1', 'Gene', '55193', (173, 178))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('BAP1', 'Gene', (223, 227))	('tumours', 'Disease', 'MESH:D009369', (47, 54))	('BAP1', 'Gene', '8314', (60, 64))	('grade', 'CPA', (111, 116))	('tumours', 'Disease', (47, 54))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('higher', 'PosReg', (104, 110))	('BAP1', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
144376	30099580	The presence of BAP1 and PBRM1 mutants appeared anti-correlated, though when co-existing, their presence conferred the worst overall survival.	('mutants', 'Var', (31, 38))	('PBRM1', 'Gene', (25, 30))	('BAP1', 'Gene', '8314', (16, 20))	('worst', 'NegReg', (119, 124))	('PBRM1', 'Gene', '55193', (25, 30))	('BAP1', 'Gene', (16, 20))
144377	30099580	Similarly, the presence of SETD2 confers worse overall survival by a hazard ratio of 1.7.	('presence', 'Var', (15, 23))	('worse', 'NegReg', (41, 46))	('SETD2', 'Gene', '29072', (27, 32))	('overall survival', 'MPA', (47, 63))	('SETD2', 'Gene', (27, 32))
144378	30099580	Genomic profiling of tumours from patients with ccRCC is beginning to illustrate how the presence of mutations in chromatin-modifying genes may aid systemic treatment stratification.	('aid', 'Reg', (144, 147))	('mutations', 'Var', (101, 110))	('chromatin-modifying genes', 'Gene', (114, 139))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('tumours', 'Phenotype', 'HP:0002664', (21, 28))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('tumours', 'Disease', 'MESH:D009369', (21, 28))	('chromatin', 'cellular_component', 'GO:0000785', ('114', '123'))	('patients', 'Species', '9606', (34, 42))	('tumours', 'Disease', (21, 28))	('systemic treatment stratification', 'CPA', (148, 181))
144380	30099580	Immuno-oncological agents are now showing increasing promise in metastatic ccRCC settings, where PBRM1 mutations appear to confer clinical benefit after treatment with these agents.	('mutations', 'Var', (103, 112))	('clinical', 'MPA', (130, 138))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('benefit', 'PosReg', (139, 146))	('PBRM1', 'Gene', (97, 102))	('PBRM1', 'Gene', '55193', (97, 102))
144381	30099580	Somatic mutations have been detected within the core promoter and 5'UTR of telomerase reverse transcriptase (TERT) in 6-14% of ccRCCs.	('core', 'cellular_component', 'GO:0019013', ('48', '52'))	('TERT', 'Gene', '7015', (109, 113))	('detected', 'Reg', (28, 36))	('mutations', 'Var', (8, 17))	('RCCs', 'Phenotype', 'HP:0005584', (129, 133))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('transcriptase', 'molecular_function', 'GO:0003899', ('94', '107'))	('RCC', 'Disease', (129, 132))	('telomerase reverse transcriptase', 'Gene', (75, 107))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('transcriptase', 'molecular_function', 'GO:0003968', ('94', '107'))	('telomerase reverse transcriptase', 'Gene', '7015', (75, 107))	('TERT', 'Gene', (109, 113))	('transcriptase', 'molecular_function', 'GO:0034062', ('94', '107'))
144382	30099580	Furthermore, the presence of TERT promoter mutations has been shown to decrease cancer-specific survival and increased disease stage.	('TERT', 'Gene', '7015', (29, 33))	('cancer', 'Disease', (80, 86))	('decrease', 'NegReg', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('disease stage', 'CPA', (119, 132))	('mutations', 'Var', (43, 52))	('presence', 'Var', (17, 25))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('increased', 'PosReg', (109, 118))	('TERT', 'Gene', (29, 33))
144383	30099580	The PTEN gene undergoes both recurrent point mutations (2-12% of samples) and focal deletions (approximately 7% of samples) in ccRCC.	('PTEN', 'Gene', '5728', (4, 8))	('point mutations', 'Var', (39, 54))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('RCC', 'Disease', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('PTEN', 'Gene', (4, 8))	('deletions', 'Var', (84, 93))
144385	30099580	An interrogation of the TCGA data set revealed that bi-allelic loss of PTEN was uncommon but conferred worse overall survival.	('worse', 'NegReg', (103, 108))	('PTEN', 'Gene', (71, 75))	('overall survival', 'MPA', (109, 125))	('PTEN', 'Gene', '5728', (71, 75))	('bi-allelic', 'Var', (52, 62))	('loss', 'NegReg', (63, 67))
144386	30099580	Tumours with mutant PTEN status showed a non-significant increase in rates of progression when compared to non-PTEN mutant tumours after either VEGFR or MTOR inhibition in metastatic patients in the RECORD-3 trial.	('mutant', 'Var', (13, 19))	('PTEN', 'Gene', '5728', (20, 24))	('MTOR', 'Gene', (153, 157))	('PTEN', 'Gene', (111, 115))	('VEGFR', 'Gene', '3791', (144, 149))	('PTEN', 'Gene', '5728', (111, 115))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('tumours', 'Disease', 'MESH:D009369', (123, 130))	('MTOR', 'Gene', '2475', (153, 157))	('increase', 'PosReg', (57, 65))	('VEGFR', 'Gene', (144, 149))	('tumours', 'Disease', (123, 130))	('PTEN', 'Gene', (20, 24))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('patients', 'Species', '9606', (183, 191))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
144387	30099580	The PI3K-AKT-mTOR signalling axis is directly augmented via MTOR mutations, observed in 4-9% of ccRCC neoplasms.	('AKT', 'Gene', '207', (9, 12))	('MTOR', 'Gene', (60, 64))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('mTOR', 'Gene', '2475', (13, 17))	('neoplasms', 'Phenotype', 'HP:0002664', (102, 111))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('AKT', 'Gene', (9, 12))	('augmented', 'PosReg', (46, 55))	('mTOR', 'Gene', (13, 17))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('MTOR', 'Gene', '2475', (60, 64))	('signalling', 'biological_process', 'GO:0023052', ('18', '28'))	('neoplasms', 'Disease', 'MESH:D009369', (102, 111))	('mutations', 'Var', (65, 74))	('neoplasms', 'Disease', (102, 111))
144393	30099580	There is some evidence that tumours with mutations in MTOR/TSC1/2 have a better response to rapalogs, although statistical significance has not been reached.	('mutations', 'Var', (41, 50))	('response', 'MPA', (80, 88))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('MTOR', 'Gene', (54, 58))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('MTOR', 'Gene', '2475', (54, 58))	('better', 'PosReg', (73, 79))	('TSC1/2', 'Gene', '7248;7249', (59, 65))	('tumours', 'Disease', 'MESH:D009369', (28, 35))	('tumours', 'Disease', (28, 35))	('TSC1/2', 'Gene', (59, 65))
144395	30099580	However, aberrations in genes involved in the P53 pathway are relatively common implying that the p53 pathway and cell-cycle checkpoint inhibition play significant roles in ccRCC.	('P53', 'Gene', '7157', (46, 49))	('aberrations', 'Var', (9, 20))	('p53', 'Gene', '7157', (98, 101))	('p53', 'Gene', (98, 101))	('RCC', 'Disease', (175, 178))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('cell-cycle checkpoint', 'biological_process', 'GO:0000075', ('114', '135'))	('RCC', 'Disease', 'MESH:C538614', (175, 178))	('P53', 'Gene', (46, 49))
144396	30099580	TP53 appears to be more frequently mutated in metastases and on survival analysis, confers a worse cancer-specific survival than any other single mutation.	('mutated', 'Var', (35, 42))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('metastases', 'Disease', (46, 56))	('worse', 'NegReg', (93, 98))	('cancer', 'Disease', (99, 105))	('metastases', 'Disease', 'MESH:D009362', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
144397	30099580	Aside from translocation renal cell carcinoma, gene fusions are uncommon in renal cell cancer.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (25, 45))	('renal cell cancer', 'Disease', 'MESH:C538614', (76, 93))	('renal cell cancer', 'Disease', (76, 93))	('translocation', 'Var', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('renal cell carcinoma', 'Disease', (25, 45))	('renal cell cancer', 'Phenotype', 'HP:0005584', (76, 93))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (25, 45))
144401	30099580	In bladder cancer amongst others, mutational burden as a surrogate for neoantigen levels has been associated with enhanced response to targeted immunotherapy.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('mutational burden', 'Var', (34, 51))	('response', 'MPA', (123, 131))	('enhanced', 'PosReg', (114, 122))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))
144408	30099580	Somatic mutations that are found in all sampled tumour regions present in the trunk of the phylogenetic tree, including VHL mutations and 3p loss.	('mutations', 'Var', (124, 133))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('VHL', 'Gene', (120, 123))	('trunk', 'cellular_component', 'GO:0043198', ('78', '83'))	('tumour', 'Disease', (48, 54))	('VHL', 'Gene', '7428', (120, 123))
144409	30099580	This finding supports the Knudson two-hit hypothesis, where two 'hits' (i.e., bi-allelic inactivation of VHL) are required for clonal expansion to yield a clone large enough to stochastically acquire independent branches.	('VHL', 'Gene', '7428', (105, 108))	('VHL', 'Gene', (105, 108))	('bi-allelic inactivation', 'Var', (78, 101))
144415	30099580	Papillary RCC (pRCC) represents approximately 20% of all kidney cancers and accumulates mutations at a similar rate to ccRCC, again with a predominance of a clock-like process.	('mutations', 'Var', (88, 97))	('Papillary RCC', 'Disease', (0, 13))	('kidney cancers', 'Disease', 'MESH:D007680', (57, 71))	('kidney cancers', 'Disease', (57, 71))	('pRCC', 'Gene', '5546', (15, 19))	('Papillary RCC', 'Disease', 'MESH:C538614', (0, 13))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('kidney cancer', 'Phenotype', 'HP:0009726', (57, 70))	('RCC', 'Disease', (10, 13))	('RCC', 'Phenotype', 'HP:0005584', (10, 13))	('kidney cancers', 'Phenotype', 'HP:0009726', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', (121, 124))	('RCC', 'Disease', (16, 19))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('pRCC', 'Gene', (15, 19))	('RCC', 'Disease', 'MESH:C538614', (10, 13))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (16, 19))
144419	30099580	Some of the shared genomic features, such as gene fusions involving TFE3 or TFEB, are present in approximately 10% of samples and show no particular disposition to type I or type II cancers.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('type II cancers', 'Disease', (174, 189))	('gene fusions', 'Var', (45, 57))	('TFE3', 'Gene', (68, 72))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('type I', 'Disease', (164, 170))	('TFEB', 'Gene', '7942', (76, 80))	('TFE3', 'Gene', '7030', (68, 72))	('TFEB', 'Gene', (76, 80))	('type II cancers', 'Disease', 'MESH:D009369', (174, 189))
144420	30099580	Hereditary papillary renal cancer (HPRC) predisposes to type I pRCC via autosomal dominant inheritance of a mutation in the MET proto-oncogene.	('pRCC', 'Gene', '5546', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('papillary renal cancer', 'Phenotype', 'HP:0006766', (11, 33))	('renal cancer', 'Phenotype', 'HP:0009726', (21, 33))	('Hereditary papillary renal cancer', 'Disease', (0, 33))	('MET proto-oncogene', 'Gene', (124, 142))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('pRCC', 'Gene', (63, 67))	('mutation', 'Var', (108, 116))	('Hereditary papillary renal cancer', 'Disease', 'MESH:D007681', (0, 33))
144426	30099580	Despite widening the net to discover other candidate driver mutations through known-cancer associated genes, one-third of tumours had no clearly discernible driver, other than trisomy of broad copy number alterations, most commonly chromosome 7.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('trisomy', 'Var', (176, 183))	('tumours', 'Disease', 'MESH:D009369', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('chromosome', 'cellular_component', 'GO:0005694', ('232', '242'))	('chromosome 7', 'Var', (232, 244))	('mutations', 'Var', (60, 69))	('tumours', 'Disease', (122, 129))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
144428	30099580	Sporadic FH mutations are rarely found; however, mutations of genes in the downstream NRF2-antioxidant response element (ARE) pathway such as NFE2L2 are recurrently detected.	('NRF2', 'Gene', '4780', (86, 90))	('mutations', 'Var', (49, 58))	('NRF2', 'Gene', (86, 90))	('NFE2L2', 'Gene', '4780', (142, 148))	('FH', 'Gene', '2271', (9, 11))	('NFE2L2', 'Gene', (142, 148))
144429	30099580	CDKN2A alterations are present in 25% of type II pRCC tumours when loss of heterogeneity, promoter hypermethylation, and somatic mutations are considered together.	('type II pRCC tumours', 'Disease', 'MESH:D009369', (41, 61))	('alterations', 'Var', (7, 18))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('type II pRCC tumours', 'Disease', (41, 61))	('CDKN2A', 'Gene', (0, 6))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('present', 'Reg', (23, 30))	('CDKN2A', 'Gene', '1029', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
144431	30099580	The presence of CDKN2A alterations was also adversely associated survival in univariate analysis of the whole cohort and when limited to the more aggressive type II phenotype.	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('alterations', 'Var', (23, 34))	('presence', 'Var', (4, 12))	('associated', 'Reg', (54, 64))
144432	30099580	A small subset of type II pRCC; CpG island methylator phenotype (CIMP) had universal hypermethylation of the CDKN2A promoter and also a high prevalence of germline or somatic mutations in FH.	('pRCC', 'Gene', (26, 30))	('CDKN2A', 'Gene', (109, 115))	('germline', 'Var', (155, 163))	('hypermethylation', 'MPA', (85, 101))	('CDKN2A', 'Gene', '1029', (109, 115))	('pRCC', 'Gene', '5546', (26, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('FH', 'Gene', '2271', (188, 190))
144438	30099580	These tumours derived from the distal nephron accumulate mutations at a low rate (~ 0.4 per Mb).	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('mutations', 'Var', (57, 66))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('tumours', 'Disease', (6, 13))
144440	30099580	Recurrent aberrations in the TERT gene were also detected with some harbouring the canonical 228T mutations, but mainly via structural variants that correlated strongly with increased TERT expression.	('TERT', 'Gene', '7015', (29, 33))	('TERT', 'Gene', '7015', (184, 188))	('increased', 'PosReg', (174, 183))	('mutations', 'Var', (98, 107))	('variants', 'Var', (135, 143))	('228T', 'Gene', (93, 97))	('TERT', 'Gene', (184, 188))	('TERT', 'Gene', (29, 33))
144441	30099580	The eosinophilic subtype, describing an eosinophilic cytoplasm with densely packed mitochondria, harboured cases that were devoid of copy number aberrations and some that were enriched for the mitochondrial MT-ND5 gene mutations.	('mitochondria', 'cellular_component', 'GO:0005739', ('83', '95'))	('MT-ND5', 'Gene', '4540', (207, 213))	('cytoplasm', 'cellular_component', 'GO:0005737', ('53', '62'))	('mutations', 'Var', (219, 228))	('eosinophilic subtype', 'Disease', 'MESH:D004802', (4, 24))	('MT-ND5', 'Gene', (207, 213))	('eosinophilic subtype', 'Disease', (4, 24))
144444	30099580	TP53 mutations were found in 33% of tumours, while loss of HNF1B was seen in 88%.	('HNF1B', 'Gene', (59, 64))	('TP53', 'Gene', '7157', (0, 4))	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('TP53', 'Gene', (0, 4))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('mutations', 'Var', (5, 14))	('tumours', 'Disease', (36, 43))	('HNF1B', 'Gene', '6928', (59, 64))	('found', 'Reg', (20, 25))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('loss', 'NegReg', (51, 55))
144445	30099580	Prevalence of both TP53 mutations and loss of HNF1b increased with tumour stage and were linked with poor survival.	('HNF1b', 'Gene', '6928', (46, 51))	('increased', 'PosReg', (52, 61))	('tumour', 'Disease', (67, 73))	('TP53', 'Gene', '7157', (19, 23))	('HNF1b', 'Gene', (46, 51))	('TP53', 'Gene', (19, 23))	('tumour', 'Disease', 'MESH:D009369', (67, 73))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (24, 33))	('loss', 'NegReg', (38, 42))	('linked', 'Reg', (89, 95))
144447	30099580	TP53 mutations (58%), PTEN mutations (24%), and imbalanced chromosome duplication (duplication of >= 3 chromosomes, 25%) were enriched in patients with metastatic disease.	('mutations', 'Var', (27, 36))	('metastatic disease', 'Disease', (152, 170))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('imbalanced chromosome duplication', 'Var', (48, 81))	('mutations', 'Var', (5, 14))	('PTEN', 'Gene', (22, 26))	('PTEN', 'Gene', '5728', (22, 26))	('patients', 'Species', '9606', (138, 146))	('chromosome', 'cellular_component', 'GO:0005694', ('59', '69'))
144448	30099580	Oncocytomas are benign tumours that share many features with eosinophilic chRCCs, including derivation from the distal tubule and recurrent mutations in mitochondria-encoded proteins.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('RCC', 'Disease', (76, 79))	('benign tumours', 'Disease', (16, 30))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('RCCs', 'Phenotype', 'HP:0005584', (76, 80))	('mitochondria-encoded', 'Gene', (153, 173))	('eosinophilic', 'Disease', (61, 73))	('benign tumours', 'Disease', 'MESH:D009369', (16, 30))	('Oncocytomas', 'Disease', 'MESH:D018249', (0, 11))	('mitochondria', 'cellular_component', 'GO:0005739', ('153', '165'))	('Oncocytomas', 'Disease', (0, 11))	('mutations', 'Var', (140, 149))
144450	30099580	The absence of PT53 mutations and activation of the p53 pathway in oncocytomas highlights p53 as a barrier to oncocytoma progression.	('p53', 'Gene', (90, 93))	('oncocytomas', 'Disease', 'MESH:D018249', (67, 78))	('p53', 'Gene', '7157', (90, 93))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('activation', 'PosReg', (34, 44))	('PT53', 'Gene', (15, 19))	('oncocytomas', 'Disease', (67, 78))	('mutations', 'Var', (20, 29))
144461	33800656	In this retrospective analysis we present dysregulated miRNA in ccRCC, which are associated with bone metastasis.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('miRNA', 'MPA', (55, 60))	('RCC', 'Disease', (66, 69))	('dysregulated', 'Var', (42, 54))
144462	33800656	In particular, miR-23a-3p, miR-27a-3p, miR-20a-5p, and miR-335-3p specifically correlated with the earlier appearance of bone metastasis, compared to metastasis in other organs.	('miR-335-3p', 'Var', (55, 65))	('miR-23a-3p', 'Var', (15, 25))	('miR-335-3p', 'Chemical', '-', (55, 65))	('miR-27a-3p', 'Var', (27, 37))	('bone metastasis', 'CPA', (121, 136))	('miR-20a-5p', 'Chemical', '-', (39, 49))	('miR-20a-5p', 'Var', (39, 49))	('miR-27a-3p', 'Chemical', '-', (27, 37))	('miR-23a-3p', 'Chemical', '-', (15, 25))
144463	33800656	In contrast, miR-30b-3p and miR-139-3p were correlated with less occurrence of bone metastasis.	('miR-139-3p', 'Gene', '406931', (28, 38))	('miR-30b-3p', 'Var', (13, 23))	('bone metastasis', 'CPA', (79, 94))	('miR-30b-3p', 'Chemical', '-', (13, 23))	('miR-139-3p', 'Gene', (28, 38))
144472	33800656	Dysregulation of miRNAs is frequently associated with cell proliferation, metastasis and apoptosis in various cancers.	('cell proliferation', 'CPA', (54, 72))	('cancers', 'Disease', (110, 117))	('associated', 'Reg', (38, 48))	('Dysregulation', 'Var', (0, 13))	('apoptosis', 'CPA', (89, 98))	('metastasis', 'CPA', (74, 84))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('miRNAs', 'Gene', (17, 23))	('cell proliferation', 'biological_process', 'GO:0008283', ('54', '72'))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('apoptosis', 'biological_process', 'GO:0097194', ('89', '98'))	('apoptosis', 'biological_process', 'GO:0006915', ('89', '98'))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
144505	33800656	A total of 4 out of 78 miRNA were significantly associated with longer TTBM: miR-204-5p, miR-30b-3p, miR-542-5p, and miR-139-3p.	('miR-139-3p', 'Gene', (117, 127))	('TTBM', 'Chemical', '-', (71, 75))	('associated', 'Reg', (48, 58))	('miR-204-5p', 'Chemical', '-', (77, 87))	('miR-204-5p', 'Var', (77, 87))	('miR-30b-3p', 'Var', (89, 99))	('miR-139-3p', 'Gene', '406931', (117, 127))	('miR-542-5p', 'Var', (101, 111))	('miR-542-5p', 'Chemical', '-', (101, 111))	('miR-30b-3p', 'Chemical', '-', (89, 99))
144506	33800656	miR-204-5p and miR-542-5p were also correlated to TTMOTB, thus their effect might not be specific for BM.	('TTMOTB', 'Gene', (50, 56))	('miR-542-5p', 'Var', (15, 25))	('correlated', 'Reg', (36, 46))	('miR-542-5p', 'Chemical', '-', (15, 25))	('miR-204-5p', 'Chemical', '-', (0, 10))	('TTMOTB', 'Chemical', '-', (50, 56))	('miR-204-5p', 'Var', (0, 10))
144507	33800656	miR-30b-3p and miR-139-3p were not correlated with TTMOTB, thus their effect might be specific for BM.	('miR-30b-3p', 'Chemical', '-', (0, 10))	('TTMOTB', 'Chemical', '-', (51, 57))	('miR-139-3p', 'Gene', (15, 25))	('miR-30b-3p', 'Var', (0, 10))	('miR-139-3p', 'Gene', '406931', (15, 25))
144508	33800656	Nine miRNAs were found to be significantly associated with shorter TTBM: miR-21-5p, miR-21-3p, miR-28-3p, miR-34c-5p, miR-23a-3p, miR-20a-5p, miR-335-3p, miR-182-5p, and miR-27a-3p.	('miR-27a-3p', 'Chemical', '-', (170, 180))	('miR-23a-3p', 'Chemical', '-', (118, 128))	('miR-34c-5p', 'Chemical', '-', (106, 116))	('miR-34c-5p', 'Var', (106, 116))	('miR-335-3p', 'Chemical', '-', (142, 152))	('miR-21-3p', 'Gene', '406995', (84, 93))	('miR-28', 'Gene', '407020', (95, 101))	('miR-23a-3p', 'Var', (118, 128))	('miR-20a-5p', 'Var', (130, 140))	('TTBM', 'Chemical', '-', (67, 71))	('miR-27a-3p', 'Var', (170, 180))	('miR-182', 'Gene', (154, 161))	('miR-182', 'Gene', '406958', (154, 161))	('miR-20a-5p', 'Chemical', '-', (130, 140))	('miR-21-5p', 'Gene', (73, 82))	('miR-28', 'Gene', (95, 101))	('miR-21-3p', 'Gene', (84, 93))	('miR-21-5p', 'Gene', '406997', (73, 82))	('miR-335-3p', 'Var', (142, 152))	('-182-5p', 'Chemical', '-', (157, 164))
144509	33800656	However, miR-21-5p, miR-34c-5p, miR-28-3p, and miR-21-3p were also correlated to TTMOTB, thus their effect might not be specific for BM.	('miR-28', 'Gene', (32, 38))	('miR-34c-5p', 'Chemical', '-', (20, 30))	('miR-34c-5p', 'Var', (20, 30))	('miR-21-3p', 'Gene', '406995', (47, 56))	('correlated', 'Reg', (67, 77))	('miR-21-3p', 'Gene', (47, 56))	('miR-21-5p', 'Gene', (9, 18))	('miR-21-5p', 'Gene', '406997', (9, 18))	('TTMOTB', 'Chemical', '-', (81, 87))	('TTMOTB', 'MPA', (81, 87))	('miR-28', 'Gene', '407020', (32, 38))
144511	33800656	miR-20a-5p, miR-335-3p, miR-27a-3p, and miR-23a-3p were clearly not correlated to TTMOTB, thus their effect might be specific for the development of BM.	('miR-20a-5p', 'Chemical', '-', (0, 10))	('miR-20a-5p', 'Var', (0, 10))	('TTMOTB', 'Chemical', '-', (82, 88))	('miR-23a-3p', 'Chemical', '-', (40, 50))	('miR-335-3p', 'Var', (12, 22))	('miR-27a-3p', 'Var', (24, 34))	('miR-27a-3p', 'Chemical', '-', (24, 34))	('miR-335-3p', 'Chemical', '-', (12, 22))	('miR-23a-3p', 'Var', (40, 50))
144514	33800656	Among the miRNAs associated with longer TTBM, miR-204-5p was inversely correlated with RUNX2 and TGFB1.	('miR-204-5p', 'Chemical', '-', (46, 56))	('miR-204-5p', 'Var', (46, 56))	('RUNX2', 'Gene', (87, 92))	('TGFB1', 'Gene', (97, 102))	('correlated', 'Interaction', (71, 81))	('TTBM', 'Chemical', '-', (40, 44))	('RUNX2', 'Gene', '860', (87, 92))
144516	33800656	miR-30b-3p was inversely correlated with the mRNA expression levels of CXCL8.	('CXCL8', 'Gene', '3576', (71, 76))	('CXCL8', 'Gene', (71, 76))	('miR-30b-3p', 'Chemical', '-', (0, 10))	('miR-30b-3p', 'Var', (0, 10))
144519	33800656	miR-34c-5p was correlated with reduced SATB2 levels.	('miR-34c-5p', 'Var', (0, 10))	('reduced', 'NegReg', (31, 38))	('SATB2 levels', 'MPA', (39, 51))	('miR-34c-5p', 'Chemical', '-', (0, 10))
144523	33800656	miR-204-5p, associated with longer TTBM, is significantly correlated with longer OS.	('longer OS', 'Disease', (74, 83))	('TTBM', 'Chemical', '-', (35, 39))	('miR-204-5p', 'Chemical', '-', (0, 10))	('correlated', 'Reg', (58, 68))	('miR-204-5p', 'Var', (0, 10))
144524	33800656	miR-21-5p, miR-21-3p, miR-34c-5p, miR-335-3p, and miR-182-5p, associated with shorter TTBM, were significantly correlated with shorter OS.	('-182-5p', 'Chemical', '-', (53, 60))	('miR-182', 'Gene', (50, 57))	('correlated', 'Reg', (111, 121))	('TTBM', 'Chemical', '-', (86, 90))	('miR-21-5p', 'Gene', (0, 9))	('miR-182', 'Gene', '406958', (50, 57))	('miR-21-3p', 'Gene', '406995', (11, 20))	('miR-21-5p', 'Gene', '406997', (0, 9))	('miR-335-3p', 'Var', (34, 44))	('miR-34c-5p', 'Chemical', '-', (22, 32))	('miR-21-3p', 'Gene', (11, 20))	('shorter OS', 'Disease', (127, 137))	('miR-34c-5p', 'Var', (22, 32))	('miR-335-3p', 'Chemical', '-', (34, 44))
144526	33800656	miR-204-5p, correlated with longer TTBM, was also correlated with longer PFS and OS on VEGFR-TKIs.	('VEGFR', 'Gene', '3791', (87, 92))	('TTBM', 'MPA', (35, 39))	('correlated', 'Reg', (50, 60))	('TTBM', 'Chemical', '-', (35, 39))	('miR-204-5p', 'Chemical', '-', (0, 10))	('VEGFR', 'Gene', (87, 92))	('miR-204-5p', 'Var', (0, 10))
144527	33800656	miR-21-3p and miR-34c-5p, correlated with shorter TTBM, were also correlated with shorter PFS and OS on VEGFR-TKIs.	('VEGFR', 'Gene', (104, 109))	('shorter', 'NegReg', (42, 49))	('miR-34c-5p', 'Chemical', '-', (14, 24))	('miR-21-3p', 'Gene', '406995', (0, 9))	('TTBM', 'Chemical', '-', (50, 54))	('VEGFR', 'Gene', '3791', (104, 109))	('PFS', 'CPA', (90, 93))	('miR-21-3p', 'Gene', (0, 9))	('TTBM', 'MPA', (50, 54))	('miR-34c-5p', 'Var', (14, 24))	('shorter', 'NegReg', (82, 89))
144529	33800656	miR-204-5p was associated with increased RR (p = 0.03) and miR-34c-5p with decreased RR (p = 0.003).	('increased', 'PosReg', (31, 40))	('miR-34c-5p', 'Chemical', '-', (59, 69))	('miR-34c-5p', 'Var', (59, 69))	('miR-204-5p', 'Chemical', '-', (0, 10))	('miR-204-5p', 'Var', (0, 10))	('decreased', 'NegReg', (75, 84))
144546	33800656	In this study, we identified four miRNA associated with longer TTBM (miR-30b-3p, miR-139-3p, miR-204-5p and miR-542-5p).	('miR-204-5p', 'Chemical', '-', (93, 103))	('miR-204-5p', 'Var', (93, 103))	('miR-139-3p', 'Gene', '406931', (81, 91))	('miR-30b-3p', 'Chemical', '-', (69, 79))	('miR-542-5p', 'Var', (108, 118))	('TTBM', 'Chemical', '-', (63, 67))	('miR-542-5p', 'Chemical', '-', (108, 118))	('miR-139-3p', 'Gene', (81, 91))	('miR-30b-3p', 'Var', (69, 79))
144547	33800656	miR-30b-3p and miR-139-3p were not significantly associated with TTMOTB and might thus be specific for the development of BM.	('miR-30b-3p', 'Chemical', '-', (0, 10))	('TTMOTB', 'Chemical', '-', (65, 71))	('TTMOTB', 'Disease', (65, 71))	('miR-139-3p', 'Gene', (15, 25))	('miR-30b-3p', 'Var', (0, 10))	('miR-139-3p', 'Gene', '406931', (15, 25))
144549	33800656	In our series, miR-30b-3p was associated with longer TTBM and inversely correlated to mRNA expression of several genes involved in BM (CD44, ITGA3, TCF7, RANKL and CXLC8).	('TCF7', 'Gene', (148, 152))	('longer', 'PosReg', (46, 52))	('TTBM', 'Chemical', '-', (53, 57))	('TCF7', 'Gene', '6932', (148, 152))	('RANKL', 'Gene', '8600', (154, 159))	('RANKL', 'Gene', (154, 159))	('miR-30b-3p', 'Chemical', '-', (15, 25))	('TTBM', 'MPA', (53, 57))	('mRNA expression', 'MPA', (86, 101))	('miR-30b-3p', 'Var', (15, 25))
144550	33800656	The miR-30 family, to which miR-30b-3p belongs, suppresses BM in BC and PC.	('miR-30', 'Chemical', '-', (28, 34))	('miR-30b-3p', 'Chemical', '-', (28, 38))	('miR-30', 'Chemical', '-', (4, 10))	('PC', 'Phenotype', 'HP:0012125', (72, 74))	('suppresses', 'NegReg', (48, 58))	('BC', 'Phenotype', 'HP:0003002', (65, 67))	('miR-30', 'Gene', (4, 10))	('miR-30b-3p', 'Var', (28, 38))	('BM in BC', 'CPA', (59, 67))
144553	33800656	In BC, miR-30b-3p suppresses BM by targeting CXCL8, IL11, DKK1, RUNX2, CDH11, CTGF, ITGA5, and ITGB3.	('miR-30b-3p', 'Chemical', '-', (7, 17))	('ITGB3', 'Gene', '3690', (95, 100))	('ITGB3', 'Gene', (95, 100))	('BC', 'Phenotype', 'HP:0003002', (3, 5))	('IL11', 'molecular_function', 'GO:0005142', ('52', '56'))	('ITGA5', 'Gene', (84, 89))	('targeting', 'Reg', (35, 44))	('ITGA5', 'Gene', '3678', (84, 89))	('suppresses', 'NegReg', (18, 28))	('RUNX2', 'Gene', (64, 69))	('CXCL8', 'Gene', '3576', (45, 50))	('CXCL8', 'Gene', (45, 50))	('DKK1', 'Gene', '22943', (58, 62))	('DKK1', 'Gene', (58, 62))	('CTGF', 'Gene', '1490', (78, 82))	('RUNX2', 'Gene', '860', (64, 69))	('miR-30b-3p', 'Var', (7, 17))	('CTGF', 'Gene', (78, 82))	('IL11', 'Gene', (52, 56))	('CDH11', 'Gene', '1009', (71, 76))	('IL11', 'Gene', '3589', (52, 56))	('CDH11', 'Gene', (71, 76))
144554	33800656	Finally, in multiple myeloma, an osteolytic disease, miR-30b-3p has a tumor suppressor role targeting the Wnt/b-Catenin/BCL9 Pathway.	('miR-30b-3p', 'Var', (53, 63))	('BC', 'Phenotype', 'HP:0003002', (120, 122))	('b-Catenin', 'Gene', (110, 119))	('osteolytic disease', 'Disease', (33, 51))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('osteolytic disease', 'Phenotype', 'HP:0002797', (33, 51))	('tumor', 'Disease', (70, 75))	('osteolytic disease', 'Disease', 'MESH:D030981', (33, 51))	('multiple myeloma', 'Disease', 'MESH:D009101', (12, 28))	('multiple myeloma', 'Phenotype', 'HP:0006775', (12, 28))	('multiple myeloma', 'Disease', (12, 28))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('miR-30b-3p', 'Chemical', '-', (53, 63))	('b-Catenin', 'Gene', '1499', (110, 119))	('BCL9', 'Gene', '607', (120, 124))	('BCL9', 'Gene', (120, 124))
144555	33800656	We have found that miR-542-5p was associated with longer TTBM and TTMOTB, inversely correlated with the mRNA expression of genes involved in BM (CD44, CXCR4, RUNX2 and TCF7) and positively correlated with the mRNA expression of genes protective against BM (SATB2 and SMAD2).	('TCF7', 'Gene', '6932', (168, 172))	('correlated', 'Reg', (189, 199))	('mRNA expression', 'MPA', (209, 224))	('CXCR4', 'Gene', '7852', (151, 156))	('CXCR4', 'Gene', (151, 156))	('TTMOTB', 'Chemical', '-', (66, 72))	('mRNA expression', 'MPA', (104, 119))	('RUNX2', 'Gene', (158, 163))	('TTMOTB', 'Gene', (66, 72))	('SMAD2', 'Gene', '4087', (267, 272))	('RUNX2', 'Gene', '860', (158, 163))	('TCF7', 'Gene', (168, 172))	('TTBM', 'Chemical', '-', (57, 61))	('CXCR4', 'molecular_function', 'GO:0038147', ('151', '156'))	('correlated', 'Reg', (84, 94))	('TTBM', 'Gene', (57, 61))	('miR-542-5p', 'Var', (19, 29))	('SMAD2', 'Gene', (267, 272))	('miR-542-5p', 'Chemical', '-', (19, 29))
144556	33800656	miR-542-5p acts as a tumor suppressor in non-small cell lung cancer (NSCLC), neuroblastoma, osteosarcoma, CRC, BC, and hepatocellular carcinoma (HCC), though contradictory evidence exists.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (45, 67))	('tumor', 'Disease', (21, 26))	('tumor suppressor', 'biological_process', 'GO:0051726', ('21', '37'))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('hepatocellular carcinoma', 'Disease', (119, 143))	('osteosarcoma', 'Disease', (92, 104))	('lung cancer', 'Disease', (56, 67))	('osteosarcoma', 'Disease', 'MESH:D012516', (92, 104))	('miR-542-5p', 'Var', (0, 10))	('NSCLC', 'Disease', (69, 74))	('miR-542-5p', 'Chemical', '-', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('CRC', 'Disease', (106, 109))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('CRC', 'Phenotype', 'HP:0003003', (106, 109))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (119, 143))	('neuroblastoma', 'Disease', (77, 90))	('neuroblastoma', 'Phenotype', 'HP:0003006', (77, 90))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('BC', 'Phenotype', 'HP:0003002', (111, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('HCC', 'Phenotype', 'HP:0001402', (145, 148))	('osteosarcoma', 'Phenotype', 'HP:0002669', (92, 104))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (41, 67))	('neuroblastoma', 'Disease', 'MESH:D009447', (77, 90))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('21', '37'))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (119, 143))
144558	33800656	miR-542-5p has been shown to increase expression levels of SMAD2 in other diseases.	('expression levels', 'MPA', (38, 55))	('miR-542-5p', 'Var', (0, 10))	('SMAD2', 'Gene', (59, 64))	('SMAD2', 'Gene', '4087', (59, 64))	('increase', 'PosReg', (29, 37))	('miR-542-5p', 'Chemical', '-', (0, 10))
144560	33800656	miR-139-3p and its guide strand miR-139-5p are involved in ccRCC pathogenesis and expression levels of both miRNA and several of their target genes are correlated with clinical outcomes.	('miR-139-5p', 'Chemical', '-', (32, 42))	('miR-139-3p', 'Gene', (0, 10))	('correlated', 'Reg', (152, 162))	('involved', 'Reg', (47, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('miR-139-3p', 'Gene', '406931', (0, 10))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('pathogenesis', 'biological_process', 'GO:0009405', ('65', '77'))	('miR-139-5p', 'Var', (32, 42))
144563	33800656	miR-139-5p is a regulator of osteoblast differentiation and apoptosis by targeting ELK1 and ODSM.	('ELK1', 'Gene', '2002', (83, 87))	('osteoblast differentiation', 'biological_process', 'GO:0001649', ('29', '55'))	('miR-139-5p', 'Var', (0, 10))	('ODSM', 'CPA', (92, 96))	('targeting', 'Reg', (73, 82))	('miR-139-5p', 'Chemical', '-', (0, 10))	('apoptosis', 'biological_process', 'GO:0006915', ('60', '69'))	('apoptosis', 'biological_process', 'GO:0097194', ('60', '69'))	('ELK1', 'Gene', (83, 87))
144565	33800656	Increased expression of miR-139-5p enhances osteogenic differentiation of mesenchymal stem cells (MSC) through NOTCH1 signaling.	('miR-139-5p', 'Var', (24, 34))	('miR-139-5p', 'Chemical', '-', (24, 34))	('NOTCH1', 'Gene', '4851', (111, 117))	('signaling', 'biological_process', 'GO:0023052', ('118', '127'))	('enhances', 'PosReg', (35, 43))	('NOTCH1', 'Gene', (111, 117))
144569	33800656	Finally, miR-204-5p was associated with longer TTBM and TTMOTB, inversely correlated with the expression of genes involved in BM (CD44, RANKL, ITGA3, RUNX2, CDH11, TCF7, ITGA5, TGFB1, CXCL8 and CTGF), correlated with the expression of genes protective for BM (FOS, BMPR2, SATB2 and SMAD4) and correlated with longer OS.	('miR-204-5p', 'Chemical', '-', (9, 19))	('miR-204-5p', 'Var', (9, 19))	('TTBM', 'Chemical', '-', (47, 51))	('BMPR2', 'Gene', (265, 270))	('CTGF', 'Gene', '1490', (194, 198))	('TCF7', 'Gene', (164, 168))	('correlated', 'Reg', (201, 211))	('RANKL', 'Gene', (136, 141))	('CTGF', 'Gene', (194, 198))	('TCF7', 'Gene', '6932', (164, 168))	('SMAD4', 'Gene', (282, 287))	('longer OS', 'Disease', (309, 318))	('RUNX2', 'Gene', (150, 155))	('ITGA5', 'Gene', (170, 175))	('TTMOTB', 'Chemical', '-', (56, 62))	('BMPR2', 'Gene', '659', (265, 270))	('ITGA5', 'Gene', '3678', (170, 175))	('RUNX2', 'Gene', '860', (150, 155))	('expression', 'MPA', (94, 104))	('expression', 'MPA', (221, 231))	('TGFB1', 'Gene', (177, 182))	('correlated', 'Reg', (293, 303))	('SMAD4', 'Gene', '4089', (282, 287))	('RANKL', 'Gene', '8600', (136, 141))	('CXCL8', 'Gene', '3576', (184, 189))	('CXCL8', 'Gene', (184, 189))	('TTMOTB', 'Gene', (56, 62))	('CDH11', 'Gene', '1009', (157, 162))	('CDH11', 'Gene', (157, 162))
144570	33800656	miR-204-5p is usually downregulated in ccRCC tumor tissues and seems protective for the development of BM.	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('ccRCC tumor', 'Disease', 'MESH:D009369', (39, 50))	('ccRCC tumor', 'Disease', (39, 50))	('miR-204-5p', 'Chemical', '-', (0, 10))	('miR-204-5p', 'Var', (0, 10))	('downregulated', 'NegReg', (22, 35))
144571	33800656	Moreover, miR-204-5p is lower in the more aggressive ccrcc1+4 molecular ccRCC subtypes compared to the less aggressive ccrcc2+3 subtypes.	('miR-204-5p', 'Var', (10, 20))	('ccrcc1+4', 'Disease', (53, 61))	('RCC', 'Disease', (74, 77))	('lower', 'NegReg', (24, 29))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('miR-204-5p', 'Chemical', '-', (10, 20))
144572	33800656	In bone metastatic BC cells, miR-204-5p inhibits TGF-beta-induced IL11 production.	('BC', 'Phenotype', 'HP:0003002', (19, 21))	('TGF-beta', 'Gene', (49, 57))	('miR-204-5p', 'Var', (29, 39))	('miR-204-5p', 'Chemical', '-', (29, 39))	('IL11', 'molecular_function', 'GO:0005142', ('66', '70'))	('TGF-beta', 'Gene', '7039', (49, 57))	('inhibits', 'NegReg', (40, 48))	('IL11 production', 'biological_process', 'GO:0032614', ('66', '81'))	('IL11', 'Gene', (66, 70))	('IL11', 'Gene', '3589', (66, 70))
144573	33800656	In laryngeal SCC, miR-204-5p inhibits cell proliferation, invasion, and metastasis.	('miR-204-5p', 'Var', (18, 28))	('miR-204-5p', 'Chemical', '-', (18, 28))	('cell proliferation', 'CPA', (38, 56))	('SCC', 'Phenotype', 'HP:0002860', (13, 16))	('laryngeal SCC', 'Disease', (3, 16))	('invasion', 'CPA', (58, 66))	('inhibits', 'NegReg', (29, 37))	('cell proliferation', 'biological_process', 'GO:0008283', ('38', '56'))
144574	33800656	In BC cells, miR-204-5p inhibits viability, proliferation and migration.	('migration', 'CPA', (62, 71))	('inhibits', 'NegReg', (24, 32))	('miR-204-5p', 'Chemical', '-', (13, 23))	('BC', 'Phenotype', 'HP:0003002', (3, 5))	('miR-204-5p', 'Var', (13, 23))	('viability', 'CPA', (33, 42))
144576	33800656	Finally, miR-204-5p was shown to inhibit osteogenic differentiation of MSC.	('miR-204-5p', 'Chemical', '-', (9, 19))	('inhibit', 'NegReg', (33, 40))	('osteogenic differentiation', 'CPA', (41, 67))	('miR-204-5p', 'Var', (9, 19))
144578	33800656	Of these, most were also associated with shorter TTMOTB, however miR-23a-3p, miR-20a-5p, miR-335-3p, and miR-27a-3p were not and might therefore be specifically involved in the development of BM.	('miR-27a-3p', 'Var', (105, 115))	('miR-27a-3p', 'Chemical', '-', (105, 115))	('involved', 'Reg', (161, 169))	('shorter', 'NegReg', (41, 48))	('miR-23a-3p', 'Var', (65, 75))	('TTMOTB', 'Chemical', '-', (49, 55))	('TTMOTB', 'MPA', (49, 55))	('miR-20a-5p', 'Chemical', '-', (77, 87))	('miR-20a-5p', 'Var', (77, 87))	('miR-335-3p', 'Var', (89, 99))	('miR-335-3p', 'Chemical', '-', (89, 99))	('miR-23a-3p', 'Chemical', '-', (65, 75))
144580	33800656	The oncogenic properties of miR-23a-3p have been previously demonstrated.	('miR-23a-3p', 'Var', (28, 38))	('oncogenic properties', 'CPA', (4, 24))	('miR-23a-3p', 'Chemical', '-', (28, 38))
144585	33800656	Inhibition of miR-23a-3p promotes osteoblast proliferation and differentiation.	('differentiation', 'CPA', (63, 78))	('promotes', 'PosReg', (25, 33))	('osteoblast proliferation', 'Phenotype', 'HP:0011846', (34, 58))	('osteoblast proliferation', 'CPA', (34, 58))	('osteoblast proliferation', 'biological_process', 'GO:0033687', ('34', '58'))	('miR-23a-3p', 'Gene', (14, 24))	('Inhibition', 'Var', (0, 10))	('miR-23a-3p', 'Chemical', '-', (14, 24))
144586	33800656	miR-23a-3p also inhibits osteogenic differentiation of human MSC.	('miR-23a-3p', 'Var', (0, 10))	('osteogenic differentiation of human MSC', 'CPA', (25, 64))	('human', 'Species', '9606', (55, 60))	('miR-23a-3p', 'Chemical', '-', (0, 10))	('inhibits', 'NegReg', (16, 24))
144595	33800656	The inverse correlation with OPG, a protein which acts as a decoy receptor for RANK and neutralizes its role in osteoclastogenesis, seems biologically consistent with the association of miR-20a-5p with shorter TTBM.	('OPG', 'Gene', '4982', (29, 32))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('miR-20a-5p', 'Chemical', '-', (186, 196))	('miR-20a-5p', 'Var', (186, 196))	('TTBM', 'Chemical', '-', (210, 214))	('decoy receptor', 'molecular_function', 'GO:0140319', ('60', '74'))	('OPG', 'Gene', (29, 32))
144599	33800656	We observed that miR-27a-3p was associated with TTBM and inversely correlated with expression of the bone protective gene BMP7.	('TTBM', 'Disease', (48, 52))	('miR-27a-3p', 'Chemical', '-', (17, 27))	('miR-27a-3p', 'Var', (17, 27))	('BMP7', 'Gene', '655', (122, 126))	('TTBM', 'Chemical', '-', (48, 52))	('expression', 'MPA', (83, 93))	('associated', 'Reg', (32, 42))	('BMP7', 'Gene', (122, 126))
144600	33800656	In ccRCC, miR-27a-3p promotes proliferation and metastasis.	('promotes', 'PosReg', (21, 29))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('RCC', 'Disease', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('miR-27a-3p', 'Var', (10, 20))	('miR-27a-3p', 'Chemical', '-', (10, 20))	('metastasis', 'CPA', (48, 58))	('proliferation', 'CPA', (30, 43))
144602	33800656	Serum levels of miR-27a-3p are elevated in pancreatic cancer, CRC, and PC, demonstrating its potential as a non-invasive biomarker.	('miR-27a-3p', 'Var', (16, 26))	('Serum levels', 'MPA', (0, 12))	('miR-27a-3p', 'Chemical', '-', (16, 26))	('CRC', 'Phenotype', 'HP:0003003', (62, 65))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (43, 60))	('CRC', 'Disease', (62, 65))	('elevated', 'PosReg', (31, 39))	('pancreatic cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('PC', 'Phenotype', 'HP:0012125', (71, 73))	('pancreatic cancer', 'Disease', 'MESH:D010190', (43, 60))
144603	33800656	miR-27a-3p is involved in bone metabolism and negatively regulates osteogenic differentiation.	('osteogenic differentiation', 'CPA', (67, 93))	('regulates', 'Reg', (57, 66))	('metabolism', 'biological_process', 'GO:0008152', ('31', '41'))	('negatively', 'NegReg', (46, 56))	('miR-27a-3p', 'Var', (0, 10))	('miR-27a-3p', 'Chemical', '-', (0, 10))
144605	33800656	Surprisingly, miR-27a-3p was also inversely correlated with CXCL8, promotor of osteoclastogenesis, and positively correlated with PDCD4 expression.	('expression', 'MPA', (136, 146))	('correlated', 'Reg', (114, 124))	('CXCL8', 'Gene', (60, 65))	('PDCD4', 'Gene', (130, 135))	('CXCL8', 'Gene', '3576', (60, 65))	('PDCD4', 'Gene', '27250', (130, 135))	('inversely', 'NegReg', (34, 43))	('miR-27a-3p', 'Var', (14, 24))	('miR-27a-3p', 'Chemical', '-', (14, 24))	('correlated', 'Interaction', (44, 54))
144614	33800656	Exosomal miR-21 from NSCLC cells facilitates osteoclastogenesis by targeting PDCD4 and inhibition of miR-21 impairs osteoclast activity in multiple myeloma by targeting OPG and PIAS3.	('osteoclastogenesis', 'CPA', (45, 63))	('miR-21', 'Gene', '406991', (101, 107))	('PDCD4', 'Gene', '27250', (77, 82))	('PIAS3', 'Gene', '10401', (177, 182))	('impairs', 'NegReg', (108, 115))	('miR-21', 'Gene', '406991', (9, 15))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('multiple myeloma', 'Phenotype', 'HP:0006775', (139, 155))	('OPG', 'Gene', '4982', (169, 172))	('miR-21', 'Gene', (101, 107))	('NSCLC', 'Disease', (21, 26))	('OPG', 'Gene', (169, 172))	('multiple myeloma', 'Disease', 'MESH:D009101', (139, 155))	('NSCLC', 'Phenotype', 'HP:0030358', (21, 26))	('miR-21', 'Gene', (9, 15))	('facilitates', 'PosReg', (33, 44))	('inhibition', 'Var', (87, 97))	('PIAS3', 'Gene', (177, 182))	('targeting', 'Reg', (159, 168))	('PDCD4', 'Gene', (77, 82))	('multiple myeloma', 'Disease', (139, 155))	('osteoclast activity', 'CPA', (116, 135))
144615	33800656	In our samples, miR-34c-5p was associated with shorter TTBM and TTMOTB, correlated with the expression of genes involved in BM (RANK, TGFB1, CD44 and ITGA3), inversely correlated with the expression of genes protective for BM (FOS and SATB2) and significantly correlated with shorter OS.	('shorter', 'NegReg', (47, 54))	('miR-34c-5p', 'Chemical', '-', (16, 26))	('TGFB1', 'Gene', (134, 139))	('TTMOTB', 'Gene', (64, 70))	('shorter OS', 'Disease', (276, 286))	('TTBM', 'Chemical', '-', (55, 59))	('correlated', 'Reg', (260, 270))	('correlated', 'Reg', (168, 178))	('TTMOTB', 'Chemical', '-', (64, 70))	('miR-34c-5p', 'Var', (16, 26))	('TTBM', 'Gene', (55, 59))	('CD44', 'Gene', (141, 145))
144617	33800656	In bladder cancer, miR-34c-5p enhances proliferation and migration of bladder cancer cells through targeting of NOTCH1.	('miR-34c-5p', 'Chemical', '-', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('miR-34c-5p', 'Var', (19, 29))	('NOTCH1', 'Gene', '4851', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('NOTCH1', 'Gene', (112, 118))	('enhances', 'PosReg', (30, 38))	('migration', 'CPA', (57, 66))	('proliferation', 'CPA', (39, 52))	('bladder cancer', 'Phenotype', 'HP:0009725', (70, 84))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('bladder cancer', 'Disease', 'MESH:D001749', (70, 84))	('bladder cancer', 'Disease', (70, 84))
144619	33800656	In our previous study, miR-34c-5p was correlated with the more aggressive ccrcc1+4 molecular subtypes.	('ccrcc1+4', 'Disease', (74, 82))	('correlated', 'Reg', (38, 48))	('miR-34c-5p', 'Chemical', '-', (23, 33))	('miR-34c-5p', 'Var', (23, 33))
144620	33800656	We found that miR-335-3p was correlated with shorter TTBM, inversely associated with OPG expression, positively associated with the expression of genes involved in BM (RANKL, ITGA3, ITGA5, TGFB1, RUNX2, CD44, TCF7 and CDH11), and associated with shorter OS.	('miR-335-3p', 'Var', (14, 24))	('shorter', 'NegReg', (45, 52))	('TGFB1', 'Gene', (189, 194))	('associated', 'Reg', (112, 122))	('OPG', 'Gene', (85, 88))	('TTBM', 'Chemical', '-', (53, 57))	('ITGA5', 'Gene', (182, 187))	('expression', 'MPA', (89, 99))	('ITGA5', 'Gene', '3678', (182, 187))	('miR-335-3p', 'Chemical', '-', (14, 24))	('TTBM', 'Gene', (53, 57))	('RANKL', 'Gene', (168, 173))	('TCF7', 'Gene', (209, 213))	('CDH11', 'Gene', '1009', (218, 223))	('CDH11', 'Gene', (218, 223))	('TCF7', 'Gene', '6932', (209, 213))	('positively', 'PosReg', (101, 111))	('RUNX2', 'Gene', (196, 201))	('RANKL', 'Gene', '8600', (168, 173))	('expression', 'MPA', (132, 142))	('CD44', 'Gene', (203, 207))	('OPG', 'Gene', '4982', (85, 88))	('RUNX2', 'Gene', '860', (196, 201))
144622	33800656	In our previous study, miR-335-3p was correlated with the more aggressive ccrcc1+4 molecular subtypes, but evidence on its prognostic effects remains conflicting.	('ccrcc1+4', 'Disease', (74, 82))	('correlated', 'Reg', (38, 48))	('miR-335-3p', 'Var', (23, 33))	('miR-335-3p', 'Chemical', '-', (23, 33))
144632	33800656	A total of five miRNA associated with shorter TTBM (miR-21-3p, miR-21-5p, miR-28-3p, miR-34c-5p and miR-128-5p) were associated with lower SATB2 levels.	('miR-21-3p', 'Gene', (52, 61))	('miR-21-3p', 'Gene', '406995', (52, 61))	('miR-21-5p', 'Gene', (63, 72))	('SATB2 levels', 'MPA', (139, 151))	('miR-28', 'Gene', '407020', (74, 80))	('miR-28', 'Gene', (74, 80))	('miR-21-5p', 'Gene', '406997', (63, 72))	('miR-34c-5p', 'Var', (85, 95))	('shorter', 'NegReg', (38, 45))	('TTBM', 'MPA', (46, 50))	('miR-128-5p', 'Var', (100, 110))	('lower', 'NegReg', (133, 138))	('TTBM', 'Chemical', '-', (46, 50))	('miR-34c-5p', 'Chemical', '-', (85, 95))
144633	33800656	A total of two miRNA associated with longer TTBM (miR-204-5p, miR-542-5p) were associated with higher SATB2 expression and could therefore potentially target suppressors of SATB2.	('miR-542-5p', 'Var', (62, 72))	('higher', 'PosReg', (95, 101))	('miR-204-5p', 'Chemical', '-', (50, 60))	('SATB2', 'Gene', (102, 107))	('miR-542-5p', 'Chemical', '-', (62, 72))	('miR-204-5p', 'Var', (50, 60))	('expression', 'MPA', (108, 118))	('TTBM', 'Chemical', '-', (44, 48))
144668	33324675	IGFLR1 was expressed on the surface of T cells of mouse, and its high expression enhances inflammatory infiltration and activation.	('IGFLR1', 'Gene', (0, 6))	('activation', 'CPA', (120, 130))	('enhances', 'PosReg', (81, 89))	('high', 'Var', (65, 69))	('mouse', 'Species', '10090', (50, 55))
144707	33324675	Figure 2E showed the correlation between IGFLR1 expression level and DNA methylation, copy number and clinical data in ccRCC in detail.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('IGFLR1', 'Gene', (41, 47))	('RCC', 'Disease', (121, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('DNA methylation', 'biological_process', 'GO:0006306', ('69', '84'))	('copy', 'Var', (86, 90))
144715	33324675	The expression level of IGFL1 was higher in ccRCC samples with IGFLR1-high-expression than that with IGFLR1-low-expression (0.025 vs. 0.008, p < 0.001) (Supplementary Figure S2B).	('expression level', 'MPA', (4, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('RCC', 'Disease', (46, 49))	('IGFL1', 'Gene', '374918', (24, 29))	('higher', 'PosReg', (34, 40))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('IGFLR1-high-expression', 'Var', (63, 85))	('IGFL1', 'Gene', (24, 29))
144736	33324675	Survival analysis and Cox regression analysis indicated that expression of IGFLR1 was a prognostic factor in ccRCC patients, rather than an independent prognostic factor.	('patients', 'Species', '9606', (115, 123))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('RCC', 'Disease', (111, 114))	('expression', 'Var', (61, 71))	('IGFLR1', 'Gene', (75, 81))
144737	33324675	In the present study, we carefully examined the prognostic value of IGFLR1 in ccRCC patients using TCGA-KIRC cohort, and confirmed that the expression of IGFLR1 was an independent prognostic factor for ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('patients', 'Species', '9606', (84, 92))	('RCC', 'Disease', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('RCC', 'Disease', (204, 207))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('expression', 'Var', (140, 150))	('ccRCC', 'Phenotype', 'HP:0006770', (202, 207))	('IGFLR1', 'Gene', (154, 160))
144747	33324675	In addition to angiogenesis, MDSC also promoted tumor development through immunosuppression, targeting T cells primarily.	('promoted', 'PosReg', (39, 47))	('tumor', 'Disease', (48, 53))	('MDSC', 'Var', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('angiogenesis', 'biological_process', 'GO:0001525', ('15', '27'))
144756	33324675	Regarding the therapeutic value of IGFLR1, firstly, IGFLR1 can be used as a potential target, and inhibiting the expression of IGFLR1 may slow the progression of RCC tumors.	('expression', 'MPA', (113, 123))	('IGFLR1', 'Gene', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('progression', 'CPA', (147, 158))	('RCC tumors', 'Disease', 'MESH:C538614', (162, 172))	('slow', 'NegReg', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('inhibiting', 'Var', (98, 108))	('RCC tumors', 'Disease', (162, 172))
144757	33324675	Besides, IGFLR1 expression was significantly positively correlated with CD8+T cell and MDSC infiltration, suggesting that inhibition of CD8+T cell and MDSC activation may also slow down the progression of RCC.	('inhibition', 'Var', (122, 132))	('CD8', 'Gene', (136, 139))	('RCC', 'Disease', (205, 208))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('slow down', 'NegReg', (176, 185))	('IGFLR1', 'Gene', (9, 15))	('CD8', 'Gene', '925', (136, 139))	('CD8', 'Gene', (72, 75))	('CD8', 'Gene', '925', (72, 75))
144759	33324675	In addition, K-M survival curve showed that, patients with high IGFLR1 expression had significantly shorter survival time and worse prognosis.	('expression', 'MPA', (71, 81))	('IGFLR1', 'Gene', (64, 70))	('shorter', 'NegReg', (100, 107))	('high', 'Var', (59, 63))	('patients', 'Species', '9606', (45, 53))	('survival time', 'CPA', (108, 121))	('high IGFLR1 expression', 'Phenotype', 'HP:0030269', (59, 81))
144794	31963500	Moreover, monitoring the size of the spheroids after 36 h of treatment showed that the GDC/SRC combination induces a significant reduction of the spheroid size (35%) while the effects of the other drugs were weaker compared to DMSO for which spheroid area declined by 15%, probably due to the maturation of the organoids that were under culture condition for five days (Figure 1C).	('GDC/SRC combination', 'Var', (87, 106))	('spheroid size', 'CPA', (146, 159))	('reduction', 'NegReg', (129, 138))	('GDC', 'Chemical', '-', (87, 90))	('DMSO', 'Chemical', 'MESH:D004121', (227, 231))	('combination', 'Var', (95, 106))
144813	31963500	We found that the GDC/SRC combination caused a significant decrease in PCNA staining, while temsirolimus, sunitinib, and pazopanib were less efficient (Figure 3C).	('GDC', 'Chemical', '-', (18, 21))	('PCNA', 'Gene', (71, 75))	('pazopanib', 'Chemical', 'MESH:C516667', (121, 130))	('PCNA', 'Gene', '5111', (71, 75))	('decrease', 'NegReg', (59, 67))	('PCNA', 'molecular_function', 'GO:0003892', ('71', '75'))	('temsirolimus', 'Chemical', 'MESH:C401859', (92, 104))	('sunitinib', 'Chemical', 'MESH:D000077210', (106, 115))	('combination', 'Var', (26, 37))
144824	31963500	PCNA staining was detected in DMSO-treated slices (11.9%), whereas very few cells were stained in sunitinib-treated slices (0.2%).	('DMSO-treated', 'Var', (30, 42))	('DMSO', 'Chemical', 'MESH:D004121', (30, 34))	('PCNA', 'Gene', (0, 4))	('sunitinib', 'Chemical', 'MESH:D000077210', (98, 107))	('PCNA', 'molecular_function', 'GO:0003892', ('0', '4'))	('PCNA', 'Gene', '5111', (0, 4))
144830	31963500	For example, pazopanib was completely inactive on NB029, YL024 and MD034, whereas it was the most efficient on NM014.	('MD034', 'Var', (67, 72))	('NB029', 'Var', (50, 55))	('YL024', 'Chemical', '-', (57, 62))	('YL024', 'Var', (57, 62))	('pazopanib', 'Chemical', 'MESH:C516667', (13, 22))	('inactive', 'NegReg', (38, 46))
144832	31963500	Inactivation of the Von Hippel-Lindau (VHL) tumor suppressor gene has been shown to play an important role in the process of angiogenesis in RCC.	('RCC', 'Disease', 'MESH:D002292', (141, 144))	('RCC', 'Disease', (141, 144))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('44', '60'))	('angiogenesis', 'biological_process', 'GO:0001525', ('125', '137'))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor suppressor', 'biological_process', 'GO:0051726', ('44', '60'))	('Inactivation', 'Var', (0, 12))	('Von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (20, 49))
144834	31963500	Loss of VHL function in ccRCC leads to the constitutive stabilization of these transcription factors, leading to a highly angiogenic environment and HIF2alpha has recently emerged as a therapeutic target in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (207, 212))	('HIF2alpha', 'Gene', (149, 158))	('ccRCC', 'Disease', (207, 212))	('VHL', 'Gene', '7428', (8, 11))	('transcription', 'biological_process', 'GO:0006351', ('79', '92'))	('ccRCC', 'Disease', 'MESH:D002292', (207, 212))	('constitutive', 'MPA', (43, 55))	('Loss', 'NegReg', (0, 4))	('leading to', 'Reg', (102, 112))	('function', 'Var', (12, 20))	('ccRCC', 'Disease', (24, 29))	('ccRCC', 'Phenotype', 'HP:0006770', (24, 29))	('ccRCC', 'Disease', 'MESH:D002292', (24, 29))	('HIF2alpha', 'Gene', '2034', (149, 158))	('highly angiogenic environment', 'MPA', (115, 144))	('VHL', 'Gene', (8, 11))
144841	31963500	Tumor slice DP027 was infiltrated with fewer cytotoxic CD8+ T cells than the tumor slice ML025.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('fewer', 'NegReg', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CD8', 'Gene', (55, 58))	('CD8', 'Gene', '925', (55, 58))	('DP027', 'Var', (12, 17))	('tumor', 'Disease', (77, 82))
144852	31963500	CD45+ cells were abundant in DP027 tumor and localized in close proximity with microvessels and red blood cells.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('CD45', 'Gene', '5788', (0, 4))	('tumor', 'Disease', (35, 40))	('CD45', 'Gene', (0, 4))	('DP027', 'Var', (29, 34))
144854	31963500	One mechanism implies the aberrant expression of programmed death-ligand 1 (PD-L1) that targets the neutralization of activated CD8 T cells.	('ligand', 'molecular_function', 'GO:0005488', ('66', '72'))	('programmed death-ligand 1', 'Gene', (49, 74))	('aberrant', 'Var', (26, 34))	('programmed death-ligand 1', 'Gene', '29126', (49, 74))	('neutralization', 'MPA', (100, 114))	('PD-L1', 'Gene', '29126', (76, 81))	('CD8', 'Gene', (128, 131))	('CD8', 'Gene', '925', (128, 131))	('PD-L1', 'Gene', (76, 81))
144912	32854260	Targeting beta2-Adrenergic Receptors Shows Therapeutical Benefits in Clear Cell Renal Cell Carcinoma from Von Hippel-Lindau Disease Von Hippel-Lindau (VHL), is a rare autosomal dominant inherited cancer in which the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HB), CNS-HB, and clear cell renal cell carcinoma (ccRCC).	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('VHL', 'Gene', '7428', (224, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (359, 368))	('RCC', 'Disease', 'MESH:C538614', (372, 375))	('multisystemic tumors', 'Disease', 'MESH:D012791', (264, 284))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (337, 368))	('triggers', 'Reg', (236, 244))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (69, 100))	('Von Hippel-Lindau Disease', 'Disease', (106, 131))	('retinal hemangioblastomas', 'Phenotype', 'HP:0009711', (293, 318))	('multisystemic tumors', 'Disease', (264, 284))	('VHL', 'Gene', '7428', (151, 154))	('CNS-HB', 'Disease', (325, 331))	('protein', 'cellular_component', 'GO:0003675', ('228', '235'))	('Von Hippel-Lindau', 'Disease', 'MESH:D006623', (106, 123))	('Clear Cell Renal Cell Carcinoma', 'Disease', (69, 100))	('Von Hippel-Lindau Disease', 'Disease', 'MESH:D006623', (106, 131))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (337, 368))	('retinal hemangioblastomas', 'Disease', (293, 318))	('Carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('autosomal dominant inherited cancer', 'Disease', (167, 202))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (69, 100))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (80, 100))	('VHL', 'Gene', (224, 227))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('clear cell renal cell carcinoma', 'Disease', (337, 368))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (348, 368))	('Von Hippel-Lindau', 'Disease', (132, 149))	('autosomal dominant inherited cancer', 'Disease', 'MESH:D009369', (167, 202))	('retinal hemangioblastomas', 'Disease', 'MESH:D018325', (293, 318))	('RCC', 'Disease', (372, 375))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('lack', 'Var', (216, 220))	('VHL', 'Gene', (151, 154))	('Von Hippel-Lindau', 'Disease', 'MESH:D006623', (132, 149))
144915	32854260	Targeting of beta2-adrenergic receptor (ADRB) has shown therapeutic antitumor benefits on VHL-retinal HB (clinical trial) and VHL-CNS HB (in vitro).	('VHL', 'Gene', '7428', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('Targeting', 'Var', (0, 9))	('beta2-adrenergic receptor', 'Gene', (13, 38))	('VHL-retinal HB', 'Disease', 'MESH:D006623', (90, 104))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('VHL', 'Gene', (126, 129))	('ADRB', 'Gene', (40, 44))	('beta2-adrenergic receptor', 'Gene', '154', (13, 38))	('VHL-retinal HB', 'Disease', (90, 104))	('VHL', 'Gene', '7428', (126, 129))	('VHL', 'Gene', (90, 93))
144920	32854260	In summary, propranolol and ICI-118,551 have shown antitumor benefits in VHL-derived ccRCC, and since ccRCCs comprise 63% of the total RCCs, targeting ADRB2 becomes a promising drug for VHL and other non-VHL tumors.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('VHL', 'Gene', '7428', (73, 76))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('VHL', 'Gene', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (208, 213))	('RCC', 'Disease', (104, 107))	('VHL', 'Gene', (186, 189))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('VHL', 'Gene', '7428', (204, 207))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('ADRB2', 'Gene', '154', (151, 156))	('targeting', 'Var', (141, 150))	('ADRB2', 'Gene', (151, 156))	('VHL', 'Gene', (73, 76))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('RCC', 'Disease', (87, 90))	('VHL', 'Gene', '7428', (186, 189))	('propranolol', 'Chemical', 'MESH:D011433', (12, 23))	('VHL tumors', 'Disease', (204, 214))	('RCC', 'Disease', (135, 138))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('VHL tumors', 'Disease', 'MESH:D006623', (204, 214))
144931	32854260	In the kidney, VHL is presumed as an early tumor suppressor gene where genetic and epigenetic events (either by mutation, loss of heterozygosity or hypermethylation of the promoter) are required for tumorigenesis and it has been documented in up to 80% of the sporadic ccRCC.	('tumor', 'Disease', (199, 204))	('loss of heterozygosity', 'Var', (122, 144))	('mutation', 'Var', (112, 120))	('VHL', 'Gene', (15, 18))	('hypermethylation', 'Var', (148, 164))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('VHL', 'Gene', '7428', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor suppressor', 'biological_process', 'GO:0051726', ('43', '59'))	('RCC', 'Disease', 'MESH:C538614', (271, 274))	('RCC', 'Disease', (271, 274))	('tumor', 'Disease', (43, 48))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('43', '59'))
144985	32854260	Interestingly and in agreement with the result observed in CNS-HBs, ADRB-2 expression was also significantly downregulated by the ADRB antagonists, as shown in Figure 2C (p = 0.003 for propranolol and p = 0.021 for ICI).	('propranolol', 'Chemical', 'MESH:D011433', (185, 196))	('ADRB', 'Gene', (130, 134))	('downregulated', 'NegReg', (109, 122))	('ADRB-2', 'Gene', (68, 74))	('ADRB-2', 'Gene', '154', (68, 74))	('antagonists', 'Var', (135, 146))	('expression', 'MPA', (75, 85))
144988	32854260	As observed, the blockage of ADBR-2 significantly decreased CAIX expression in all the cells tested.	('ADBR-2', 'Gene', (29, 35))	('decreased', 'NegReg', (50, 59))	('ADBR-2', 'Chemical', '-', (29, 35))	('CAIX', 'Protein', (60, 64))	('blockage', 'Var', (17, 25))
144992	32854260	Lack of VHL protein prevents HIF degradation, allowing its accumulation even under normoxic conditions (pseudo-hypoxic state), therefore triggering their downstream signaling pathways.	('protein', 'cellular_component', 'GO:0003675', ('12', '19'))	('degradation', 'biological_process', 'GO:0009056', ('33', '44'))	('VHL', 'Gene', '7428', (8, 11))	('accumulation', 'MPA', (59, 71))	('Lack', 'Var', (0, 4))	('triggering', 'Reg', (137, 147))	('protein', 'Protein', (12, 19))	('degradation', 'MPA', (33, 44))	('signaling', 'biological_process', 'GO:0023052', ('165', '174'))	('VHL', 'Gene', (8, 11))
145004	32854260	The free unbound NFkappaB protein, p65, can then translocate to the nucleus and activate transcription of target genes.	('transcription', 'MPA', (89, 102))	('p65', 'Var', (35, 38))	('NFkappaB', 'Gene', (17, 25))	('translocate', 'MPA', (49, 60))	('NFkappaB', 'Gene', '4790', (17, 25))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('activate', 'PosReg', (80, 88))	('transcription', 'biological_process', 'GO:0006351', ('89', '102'))	('nucleus', 'cellular_component', 'GO:0005634', ('68', '75'))
145054	32854260	In VHL patients, a second stochastic event (e.g., missense/nonsense mutation of the VHL gene) ends in a defect or absence of pVHL.	('VHL', 'Gene', (84, 87))	('missense/nonsense mutation', 'Var', (50, 76))	('pVHL', 'Gene', '7428', (125, 129))	('VHL', 'Gene', '7428', (84, 87))	('pVHL', 'Gene', (125, 129))	('VHL', 'Gene', (3, 6))	('VHL', 'Gene', (126, 129))	('defect', 'Disease', (104, 110))	('VHL', 'Gene', '7428', (3, 6))	('VHL', 'Gene', '7428', (126, 129))	('defect', 'Disease', 'MESH:D000014', (104, 110))	('patients', 'Species', '9606', (7, 15))	('absence', 'NegReg', (114, 121))
145055	32854260	Hence, the lack of functional pVHL in VHL patients triggers the initiation of multiple highly vascularized tumors alongside their life span (resulting in an average life expectancy of 59.4 years for males and 48.4 years for females).	('VHL', 'Gene', '7428', (31, 34))	('pVHL', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('VHL', 'Gene', (38, 41))	('lack', 'Var', (11, 15))	('patients', 'Species', '9606', (42, 50))	('VHL', 'Gene', (31, 34))	('VHL', 'Gene', '7428', (38, 41))	('pVHL', 'Gene', '7428', (30, 34))
145067	32854260	In this regard, few of the recent trials target HIF-2alpha (PT2799), Hsp90 (17AAG), or beta-adrenergic receptor (propranolol) are aiming to open new strategies for VHL treatment (Table 1).	('PT2799', 'Chemical', '-', (60, 66))	('PT2799', 'Var', (60, 66))	('Hsp90', 'Gene', (69, 74))	('HIF-2alpha', 'Protein', (48, 58))	('Hsp90', 'Gene', '3320', (69, 74))	('VHL', 'Gene', (164, 167))	('propranolol', 'Chemical', 'MESH:D011433', (113, 124))	('VHL', 'Gene', '7428', (164, 167))
145072	32854260	Moreover, some papers have shown in vitro the therapeutic benefits of ADRB-2 blockers, counteracting the activation of the receptor.	('ADRB-2', 'Gene', (70, 76))	('ADRB-2', 'Gene', '154', (70, 76))	('therapeutic', 'MPA', (46, 57))	('blockers', 'Var', (77, 85))
145100	32854260	Considering that ADRB-2 antagonists reduced HIF levels, and significantly inhibited HIF target genes (such as VEGF, AQP-1, and CAIX), HIF-2alpha subcellular distribution had to be addressed.	('inhibited', 'NegReg', (74, 83))	('antagonists', 'Var', (24, 35))	('AQP-1', 'Gene', '358', (116, 121))	('ADRB-2', 'Gene', (17, 23))	('HIF levels', 'MPA', (44, 54))	('CAIX', 'Gene', (127, 131))	('ADRB-2', 'Gene', '154', (17, 23))	('AQP-1', 'Gene', (116, 121))	('reduced', 'NegReg', (36, 43))	('VEGF', 'Gene', (110, 114))
145114	32854260	Altogether, ADRB-2 antagonists have proven to be able to reduce the translocation of HIF-2alpha and p65, master transcription regulatory keys of both pathways.	('HIF-2alpha', 'Protein', (85, 95))	('reduce', 'NegReg', (57, 63))	('translocation', 'MPA', (68, 81))	('p65', 'Protein', (100, 103))	('antagonists', 'Var', (19, 30))	('transcription', 'biological_process', 'GO:0006351', ('112', '125'))	('ADRB-2', 'Gene', (12, 18))	('ADRB-2', 'Gene', '154', (12, 18))
145115	32854260	IL-1beta, IL-6, and TNFAIP6 are known targets of p65, the inflammatory program led by NFkB.	('TNFAIP6', 'Gene', '7130', (20, 27))	('IL-6', 'molecular_function', 'GO:0005138', ('10', '14'))	('IL-1beta', 'Gene', '3552', (0, 8))	('p65', 'Var', (49, 52))	('IL-1', 'molecular_function', 'GO:0005149', ('0', '4'))	('IL-1beta', 'Gene', (0, 8))	('IL-6', 'Gene', (10, 14))	('IL-6', 'Gene', '3569', (10, 14))	('TNFAIP6', 'Gene', (20, 27))
145133	32854260	Despite this, it seems that the lesions tend to have a slower growth, especially in patient 1, sharing a mutation that provoked a total bilateral nephrectomy for her mother but no tumor growth for her, and in patient 3 who has a history of several and fast growth lesions in the past.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('mutation', 'Var', (105, 113))	('patient', 'Species', '9606', (209, 216))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('fast growth', 'Phenotype', 'HP:0001510', (252, 263))	('tumor', 'Disease', (180, 185))	('patient', 'Species', '9606', (84, 91))
145151	32854260	In summary, these findings demonstrate for the first time that ADRB-2 antagonists could be used as promising therapeutic agents to treat RCCs, acting through inhibition of cancer cell proliferation, tumor angiogenesis, and inflammation (Figure 7).	('antagonists', 'Var', (70, 81))	('inflammation', 'Disease', (223, 235))	('tumor', 'Disease', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('angiogenesis', 'biological_process', 'GO:0001525', ('205', '217'))	('inflammation', 'biological_process', 'GO:0006954', ('223', '235'))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('ADRB-2', 'Gene', (63, 69))	('ADRB-2', 'Gene', '154', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('inhibition', 'NegReg', (158, 168))	('cancer', 'Disease', (172, 178))	('inflammation', 'Disease', 'MESH:D007249', (223, 235))	('RCC', 'Disease', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('cell proliferation', 'biological_process', 'GO:0008283', ('179', '197'))
145234	33665156	A recent study showed that ccRCCs have the largest number of pan-cancer-based indel mutations, which can produce a higher amount of neoantigens and cause robust adaptive immune response.	('indel mutations', 'Var', (78, 93))	('neoantigens', 'MPA', (132, 143))	('RCC', 'Disease', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('adaptive immune response', 'biological_process', 'GO:0002250', ('161', '185'))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (27, 32))	('cause', 'Reg', (148, 153))	('higher', 'PosReg', (115, 121))	('adaptive immune response', 'CPA', (161, 185))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
145243	33665156	The study used 19 cohorts of samples from patients with RCC for this study: GSE781, GSE46699, GSE53000, GSE6344, GSE53757, GSE11151, GSE68417, GSE15641, GSE16449, GSE16441, GSE105261, GSE36895, GSE40911, GSE40435, GSE85285, GSE73731, GSE79449, GSE68748, and TCGA-KIRC.	('GSE105261', 'Var', (173, 182))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('GSE15641', 'Var', (143, 151))	('GSE79449', 'Var', (234, 242))	('GSE46699', 'Var', (84, 92))	('GSE68748', 'Var', (244, 252))	('GSE40435', 'Var', (204, 212))	('GSE40911', 'Var', (194, 202))	('GSE85285', 'Var', (214, 222))	('GSE68417', 'Var', (133, 141))	('GSE6344', 'Var', (104, 111))	('GSE53000', 'Var', (94, 102))	('patients', 'Species', '9606', (42, 50))	('GSE36895', 'Var', (184, 192))	('GSE16441', 'Var', (163, 171))	('GSE53757', 'Var', (113, 121))	('GSE781', 'Var', (76, 82))	('RCC', 'Disease', (56, 59))	('GSE16449', 'Var', (153, 161))	('GSE11151', 'Var', (123, 131))	('GSE73731', 'Var', (224, 232))
145259	33665156	Analyses were also conducted separately for the VHL wildtype and mutant, which elucidate the fundamental difference in the most remarkable RCC mutant gene subgroup.	('VHL', 'Gene', '7428', (48, 51))	('mutant', 'Var', (65, 71))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('VHL', 'Gene', (48, 51))
145276	33665156	The researchers found that patients with P <0.01 were more closely associated with deteriorating overall survival and PFS ( Figure 5C ).	('P <0.01', 'Var', (41, 48))	('deteriorating', 'NegReg', (83, 96))	('overall survival', 'CPA', (97, 113))	('patients', 'Species', '9606', (27, 35))	('PFS', 'CPA', (118, 121))
145299	33665156	Up to 92 percent of clear cell carcinoma patients were characteristic of VHL gene mutant, which leads to overproduction of VEGF and then contributes to angiogenesis of ccRCC.	('angiogenesis', 'CPA', (152, 164))	('VHL', 'Gene', (73, 76))	('VEGF', 'Gene', '7422', (123, 127))	('VHL', 'Gene', '7428', (73, 76))	('contributes', 'Reg', (137, 148))	('RCC', 'Disease', (170, 173))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (20, 40))	('clear cell carcinoma', 'Disease', (20, 40))	('angiogenesis', 'biological_process', 'GO:0001525', ('152', '164'))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('VEGF', 'Gene', (123, 127))	('patients', 'Species', '9606', (41, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (168, 173))	('overproduction', 'PosReg', (105, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('mutant', 'Var', (82, 88))
145301	33665156	It is commonly accepted that VHL inactivation is a marker of ccRCC following target immunotherapy.	('RCC', 'Disease', (63, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('VHL', 'Gene', (29, 32))	('VHL', 'Gene', '7428', (29, 32))	('inactivation', 'Var', (33, 45))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
145303	33665156	We performed an exploratory subgroup analysis of the prognosis of the 22 immune cell subsets using molecular subtype defined by VHL mutant ( Figures 7A, B ).	('mutant', 'Var', (132, 138))	('VHL', 'Gene', '7428', (128, 131))	('VHL', 'Gene', (128, 131))
145304	33665156	Most strikingly, macrophages M1n have the opposite effect in VHL-related patients, with the favorable outcome in the mutant subgroup (HR = 0.45, 95% CI 0.217-0.935) and unfavorable outcome in the wildtype subgroup (HR = 1.882, 95% CI 1.129-3.828).	('VHL', 'Gene', '7428', (61, 64))	('mutant', 'Var', (117, 123))	('VHL', 'Gene', (61, 64))	('patients', 'Species', '9606', (73, 81))
145333	33665156	Cytotoxic T-lymphocyte antigen-4 (CTLA-4) blockage weakens the function of Tregs, resulting in a stronger anti-tumor response.	('weakens', 'NegReg', (51, 58))	('blockage', 'Var', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Tregs', 'Chemical', '-', (75, 80))	('Cytotoxic T-lymphocyte antigen-4', 'Gene', (0, 32))	('CTLA-4', 'Gene', '1493', (34, 40))	('function', 'MPA', (63, 71))	('tumor', 'Disease', (111, 116))	('stronger', 'PosReg', (97, 105))	('lymphocyte antigen', 'molecular_function', 'GO:0005557', ('12', '30'))	('Cytotoxic T-lymphocyte antigen-4', 'Gene', '1493', (0, 32))	('CTLA-4', 'Gene', (34, 40))
145334	33665156	Inhibition of mTOR promotes the expansion of immunosuppressive Tregs that can strengthen the effect of anti-tumor immune responses in ccRCC.	('mTOR', 'Gene', '2475', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('strengthen', 'PosReg', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('tumor', 'Disease', (108, 113))	('Inhibition', 'Var', (0, 10))	('Tregs', 'Chemical', '-', (63, 68))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))	('mTOR', 'Gene', (14, 18))
145346	33665156	VHL loss is the most common genetic characteristic of ccRCC, with 92% of ccRCC showing VHL mutant.	('VHL', 'Gene', '7428', (87, 90))	('RCC', 'Disease', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('mutant', 'Var', (91, 97))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', (87, 90))	('loss', 'NegReg', (4, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))
145347	33665156	Inactivation of the VHL leads to overproduction of VEGF, which contributes to the angiogenesis of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('VEGF', 'Gene', '7422', (51, 55))	('angiogenesis', 'CPA', (82, 94))	('angiogenesis', 'biological_process', 'GO:0001525', ('82', '94'))	('overproduction', 'PosReg', (33, 47))	('contributes', 'Reg', (63, 74))	('VHL', 'Gene', (20, 23))	('VHL', 'Gene', '7428', (20, 23))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('Inactivation', 'Var', (0, 12))	('VEGF', 'Gene', (51, 55))
145348	33665156	The absence of VHL exerts a significant effect on ccRCC progression and affecting the responsiveness of immune checkpoint therapy.	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (50, 55))	('VHL', 'Gene', (15, 18))	('RCC', 'Disease', (52, 55))	('responsiveness of immune checkpoint therapy', 'MPA', (86, 129))	('VHL', 'Gene', '7428', (15, 18))	('effect', 'Reg', (40, 46))	('affecting', 'Reg', (72, 81))	('absence', 'Var', (4, 11))
145352	33665156	We analyzed the absent and wild-type of VHL in ccRCC and found that alterations of a variety of immune cells, including memory B cells, activated memory CD4 T cells, Tregs, M1 macrophages, M2 macrophages, and activated dendritic cells in two groups.	('RCC', 'Disease', (49, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('memory', 'biological_process', 'GO:0007613', ('120', '126'))	('VHL', 'Gene', (40, 43))	('activated', 'PosReg', (136, 145))	('VHL', 'Gene', '7428', (40, 43))	('CD4', 'Gene', (153, 156))	('CD4', 'Gene', '920', (153, 156))	('alterations', 'Var', (68, 79))	('memory', 'biological_process', 'GO:0007613', ('146', '152'))	('Tregs', 'Chemical', '-', (166, 171))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
145358	33665156	There are also some potential therapeutic agents such as Epacadostat, an inhibitor targeting indoleamine 2, 3-dioxidase (IDO), Galunisertib, which is an inhibitor of transforming growth factor-beta (TGF-beta) related with immune tolerance and bms-986016, which is an inhibitor targeting t-cell function anti-lymphocyte-activated gene 3 (LAG-3).	('TGF-beta', 'Gene', (199, 207))	('IDO', 'Gene', '3620', (121, 124))	('transforming growth factor-beta', 'molecular_function', 'GO:0005160', ('166', '197'))	('Epacadostat', 'Chemical', 'MESH:C000613752', (57, 68))	('indoleamine 2, 3-dioxidase', 'Gene', '3620', (93, 119))	('IDO', 'molecular_function', 'GO:0047719', ('121', '124'))	('transforming growth factor-beta', 'Gene', (166, 197))	('bms-986016', 'Var', (243, 253))	('TGF-beta', 'Gene', '7039', (199, 207))	('transforming growth factor-beta', 'Gene', '7124', (166, 197))	('Galunisertib', 'Chemical', 'MESH:C557799', (127, 139))	('LAG-3', 'Gene', (337, 342))	('LAG-3', 'Gene', '3902', (337, 342))	('IDO', 'molecular_function', 'GO:0033754', ('121', '124'))	('IDO', 'Gene', (121, 124))
145363	33665156	The datasets generated for this study can be found in the The Cancer Genome Atlas (TCGA)  database: GSE781, GSE6344, GSE11151, GSE36895, GSE40435, GSE46699, GSE53000, GSE53757, GSE68417, GSE16449, GSE105261, GSE15641, GSE16441, GSE40911, GSE68784, GSE85258, SE73731, GSE79449.	('GSE15641', 'Var', (208, 216))	('GSE53757', 'Var', (167, 175))	('GSE79449', 'Var', (267, 275))	('GSE105261', 'Var', (197, 206))	('GSE6344', 'Var', (108, 115))	('Cancer', 'Disease', 'MESH:D009369', (62, 68))	('GSE40911', 'Var', (228, 236))	('GSE85258', 'Var', (248, 256))	('GSE46699', 'Var', (147, 155))	('GSE16449', 'Var', (187, 195))	('GSE68417', 'Var', (177, 185))	('GSE53000', 'Var', (157, 165))	('GSE40435', 'Var', (137, 145))	('Cancer', 'Phenotype', 'HP:0002664', (62, 68))	('GSE781', 'Var', (100, 106))	('GSE36895', 'Var', (127, 135))	('GSE11151', 'Var', (117, 125))	('Cancer', 'Disease', (62, 68))	('GSE16441', 'Var', (218, 226))	('SE73731', 'Var', (258, 265))	('GSE68784', 'Var', (238, 246))
145371	31576249	Kaplan-Meier survival analysis suggested that high AURKB expression patients had a worse prognosis than patients with low AURKB expression levels.	('high', 'Var', (46, 50))	('AURKB', 'Gene', (122, 127))	('AURKB', 'Gene', '9212', (51, 56))	('patients', 'Species', '9606', (68, 76))	('AURKB', 'Gene', (51, 56))	('AURKB', 'Gene', '9212', (122, 127))	('patients', 'Species', '9606', (104, 112))
145380	31576249	Previous researches have reported that aberrant AURKB expression is related to tumorigenesis and progression of tumors.	('expression', 'MPA', (54, 64))	('AURKB', 'Gene', '9212', (48, 53))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('AURKB', 'Gene', (48, 53))	('related', 'Reg', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('aberrant', 'Var', (39, 47))	('tumors', 'Disease', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
145381	31576249	Single nucleotide polymorphisms (SNPs) of AURKB were associated with occurrence of gastric cancer (GC).	('AURKB', 'Gene', '9212', (42, 47))	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('GC', 'Phenotype', 'HP:0012126', (99, 101))	('AURKB', 'Gene', (42, 47))	('GC', 'Disease', 'MESH:D013274', (99, 101))	('associated', 'Reg', (53, 63))	('gastric cancer', 'Disease', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))
145382	31576249	rs2289590 in AURKB might contribute to susceptibility for the development of gastric cancer.	('AURKB', 'Gene', '9212', (13, 18))	('AURKB', 'Gene', (13, 18))	('gastric cancer', 'Disease', (77, 91))	('gastric cancer', 'Disease', 'MESH:D013274', (77, 91))	('rs2289590', 'Mutation', 'rs2289590', (0, 9))	('contribute', 'Reg', (25, 35))	('gastric cancer', 'Phenotype', 'HP:0012126', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('susceptibility', 'Reg', (39, 53))	('rs2289590', 'Var', (0, 9))
145384	31576249	Further experiments indicated that silencing AURKB can obviously inhibit the growth of thyroid carcinoma cells.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (87, 104))	('silencing', 'Var', (35, 44))	('thyroid carcinoma', 'Disease', (87, 104))	('AURKB', 'Gene', '9212', (45, 50))	('AURKB', 'Gene', (45, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (87, 104))	('inhibit', 'NegReg', (65, 72))
145388	31576249	Over-expression of AURKB can decrease glycolytic activities, conferring to the occurrence and progression of asthenozoospermia.	('asthenozoospermia', 'Disease', 'MESH:D053627', (109, 126))	('glycolytic activities', 'MPA', (38, 59))	('AURKB', 'Gene', '9212', (19, 24))	('Over-expression', 'Var', (0, 15))	('decrease', 'NegReg', (29, 37))	('AURKB', 'Gene', (19, 24))	('asthenozoospermia', 'Disease', (109, 126))
145394	31576249	Results indicated that patients with high AURKB expression have poorer prognosis than patients with low AURKB expression.	('AURKB', 'Gene', '9212', (42, 47))	('high', 'Var', (37, 41))	('patients', 'Species', '9606', (23, 31))	('AURKB', 'Gene', (42, 47))	('AURKB', 'Gene', '9212', (104, 109))	('AURKB', 'Gene', (104, 109))	('patients', 'Species', '9606', (86, 94))
145424	31576249	The univariate analysis indicated that high AURKB expression was associated with poorer OS and DFS (p <0.05).	('AURKB', 'Gene', (44, 49))	('high', 'Var', (39, 43))	('poorer OS', 'CPA', (81, 90))	('DFS', 'CPA', (95, 98))	('AURKB', 'Gene', '9212', (44, 49))	('expression', 'MPA', (50, 60))
145433	31576249	These results suggested that ccRCC cell lines were more sensitive to Genentech Cpd 10 than Cabozantinib and Axitinib (p < 0.05), and AURKB probably become a promising target to treat ccRCC.	('AURKB', 'Gene', (133, 138))	('Genentech', 'Var', (69, 78))	('ccRCC', 'Disease', (29, 34))	('Cabozantinib', 'Chemical', 'MESH:C558660', (91, 103))	('ccRCC', 'Disease', 'MESH:D002292', (29, 34))	('ccRCC', 'Disease', 'MESH:D002292', (183, 188))	('Axitinib', 'Chemical', 'MESH:C503983', (108, 116))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))	('AURKB', 'Gene', '9212', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('sensitive', 'MPA', (56, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('ccRCC', 'Phenotype', 'HP:0006770', (183, 188))	('ccRCC', 'Disease', (183, 188))
145441	31576249	In addition, expression of AURKB has also been associated with drug resistance in NSCLC.	('NSCLC', 'Disease', (82, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('associated with', 'Reg', (47, 62))	('AURKB', 'Gene', '9212', (27, 32))	('drug resistance', 'biological_process', 'GO:0009315', ('63', '78'))	('drug resistance', 'Phenotype', 'HP:0020174', (63, 78))	('drug resistance', 'biological_process', 'GO:0042493', ('63', '78'))	('AURKB', 'Gene', (27, 32))	('expression', 'Var', (13, 23))	('drug resistance', 'MPA', (63, 78))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
145442	31576249	Overexpression of AURKB increased drug resistance in NSCLC cells, whereas AURKB knockdown re-sensitized NSCLC cells to chemotherapeutic drugs.	('drug resistance', 'Phenotype', 'HP:0020174', (34, 49))	('knockdown', 'Var', (80, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('drug resistance', 'biological_process', 'GO:0009315', ('34', '49'))	('AURKB', 'Gene', '9212', (18, 23))	('NSCLC', 'Disease', (104, 109))	('drug resistance', 'biological_process', 'GO:0042493', ('34', '49'))	('AURKB', 'Gene', (18, 23))	('drug resistance', 'MPA', (34, 49))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('AURKB', 'Gene', '9212', (74, 79))	('NSCLC', 'Disease', (53, 58))	('AURKB', 'Gene', (74, 79))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))	('increased', 'PosReg', (24, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))
145472	31086581	Bioinformatics analysis revealed that CD105 is overexpressed in ccRCC tumor tissue vs. normal renal tissue, and a higher CD105 copy number in ccRCC tissues was significantly associated with longer patient survival.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('RCC tumor', 'Disease', 'MESH:C538614', (66, 75))	('RCC', 'Disease', (66, 69))	('CD105', 'Gene', '13805', (38, 43))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('CD105', 'Gene', (38, 43))	('copy number', 'Var', (127, 138))	('CD105', 'Gene', (121, 126))	('CD105', 'Gene', '13805', (121, 126))	('longer', 'PosReg', (190, 196))	('RCC tumor', 'Disease', (66, 75))	('RCC', 'Disease', (144, 147))	('patient', 'Species', '9606', (197, 204))	('higher', 'PosReg', (114, 120))	('overexpressed', 'PosReg', (47, 60))
145478	31086581	The exact influence of CD105 mRNA expression and copy number in RCC tumors on patient survival and the underlying mechanisms require further elucidation.	('CD105', 'Gene', (23, 28))	('RCC tumors', 'Disease', 'MESH:C538614', (64, 74))	('patient', 'Species', '9606', (78, 85))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('copy number', 'Var', (49, 60))	('RCC tumors', 'Disease', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CD105', 'Gene', '13805', (23, 28))
145487	31086581	RCC exhibits a poor response to chemotherapy and radiotherapy due to the survival of CSCs, and it is important to identify molecular markers to isolate and characterize the CSCs among the tumor cells; of note, targeting of CSCs in RCC has provided a novel treatment strategy, particularly for metastatic RCC.	('tumor', 'Disease', (188, 193))	('men', 'Species', '9606', (261, 264))	('RCC', 'Disease', (231, 234))	('CSCs', 'Protein', (223, 227))	('RCC', 'Phenotype', 'HP:0005584', (231, 234))	('RCC', 'Phenotype', 'HP:0005584', (304, 307))	('RCC', 'Disease', 'MESH:C538614', (231, 234))	('RCC', 'Disease', 'MESH:C538614', (304, 307))	('RCC', 'Disease', (304, 307))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('targeting', 'Var', (210, 219))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('RCC', 'Disease', (0, 3))
145510	31086581	Patients were stratified into two groups (high and low) based on the mean levels of CD105 mRNA expression or copy number.	('CD105', 'Gene', (84, 89))	('Patients', 'Species', '9606', (0, 8))	('CD105', 'Gene', '13805', (84, 89))	('copy number', 'Var', (109, 120))
145543	31086581	Time to death was plotted in a Kaplan-Meier curve for those cases with a CD105 copy number above the median (n=265) and equal to or below the median (n=267).	('CD105', 'Gene', '13805', (73, 78))	('CD105', 'Gene', (73, 78))	('copy number', 'Var', (79, 90))	('above', 'PosReg', (91, 96))
145546	31086581	However, in pRCC and chRCC, no significant impact of the CD105 copy number on survival was noted, but there was a trend, with those pRCC cases with a lower copy number of CD105 surviving for longer (Fig.	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('pRCC', 'Gene', (12, 16))	('CD105', 'Gene', '13805', (57, 62))	('CD105', 'Gene', (171, 176))	('pRCC', 'Gene', '5546', (132, 136))	('longer', 'PosReg', (191, 197))	('CD105', 'Gene', (57, 62))	('lower', 'NegReg', (150, 155))	('copy number', 'Var', (156, 167))	('CD105', 'Gene', '13805', (171, 176))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('pRCC', 'Gene', '5546', (12, 16))	('RCC', 'Disease', (23, 26))	('RCC', 'Disease', (13, 16))	('RCC', 'Disease', (133, 136))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('pRCC', 'Gene', (132, 136))
145580	31086581	Of note, the association of CD105 mRNA expression and copy number with various types of RCC, their association with patient survival and the underlying mechanisms require further study.	('association', 'Interaction', (13, 24))	('copy number', 'Var', (54, 65))	('patient', 'Species', '9606', (116, 123))	('CD105', 'Gene', (28, 33))	('mRNA expression', 'MPA', (34, 49))	('RCC', 'Disease', (88, 91))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('CD105', 'Gene', '13805', (28, 33))
145620	33324563	Additionally, it was found the OS and DFS patients in the high-risk group were corresponded to more death cases, and high expression of APCDD1L-DT, LINC01559, AC063948.1, THUMPD3-AS1, and CD27-AS1, whereas, more alive cases and high expression level of LINC00957, LINC01507, LINC02532, AL357140.2, DOCK9-DT and AC002070.1 were reported in the low-risk group ( Figure S1 ).	('AC002070.1', 'Var', (311, 321))	('LINC00957', 'Gene', (253, 262))	('AS1', 'Gene', '5729', (193, 196))	('APCDD1L', 'Gene', '164284', (136, 143))	('PC', 'Phenotype', 'HP:0002894', (137, 139))	('THUMPD3', 'Gene', '25917', (171, 178))	('DOCK9', 'Gene', '23348', (298, 303))	('LINC01507', 'Gene', (264, 273))	('AL357140.2', 'Var', (286, 296))	('APCDD1L', 'Gene', (136, 143))	('LINC01507', 'Gene', '101927477', (264, 273))	('LINC00957', 'Gene', '255031', (253, 262))	('AS1', 'Gene', (179, 182))	('AS1', 'Gene', (193, 196))	('CD27', 'Gene', (188, 192))	('THUMPD3', 'Gene', (171, 178))	('AC063948.1', 'Var', (159, 169))	('patients', 'Species', '9606', (42, 50))	('LINC01559', 'Gene', '283422', (148, 157))	('LINC01559', 'Gene', (148, 157))	('CD27', 'Gene', '939', (188, 192))	('DOCK9', 'Gene', (298, 303))	('AS1', 'Gene', '5729', (179, 182))
145640	33324563	In addition, the overall expression levels of known immune checkpoints including IL6, CXCR4, CD276, TGFB1, CCL2, CTLA4, LAG3, CD274, and CD 4 were relatively higher in subtype C2 compared to subtype C1 and subtype C3 ( Figure 11 ).	('CD 4', 'Gene', '920', (137, 141))	('CTLA4', 'Gene', (113, 118))	('expression levels', 'MPA', (25, 42))	('higher', 'PosReg', (158, 164))	('CD274', 'Gene', (126, 131))	('CXCR4', 'Gene', '7852', (86, 91))	('IL6', 'Gene', (81, 84))	('CXCR4', 'Gene', (86, 91))	('TGFB1', 'Gene', '7040', (100, 105))	('subtype', 'Var', (168, 175))	('TGFB1', 'Gene', (100, 105))	('CCL', 'molecular_function', 'GO:0044101', ('107', '110'))	('CCL2', 'Gene', (107, 111))	('CXCR4', 'molecular_function', 'GO:0038147', ('86', '91'))	('IL6', 'molecular_function', 'GO:0005138', ('81', '84'))	('CD 4', 'Gene', (137, 141))	('LAG3', 'Gene', '3902', (120, 124))	('CD276', 'Gene', (93, 98))	('CD276', 'Gene', '80381', (93, 98))	('CTLA4', 'Gene', '1493', (113, 118))	('CCL2', 'Gene', '6347', (107, 111))	('CD274', 'Gene', '29126', (126, 131))	('LAG3', 'Gene', (120, 124))	('IL6', 'Gene', '3569', (81, 84))
145653	33324563	For instance, LINC00957 was proved to be a potential biomarker and therapeutic target for colorectal cancer patients; LINC02532 was demonstrated to act as an oncogene in gastric cancer (GC) and promoted the GC cell proliferation, migration, and invasion; DOCK9-DT was revealed to play a protective role in the prognosis of thyroid carcinoma; THUMPD3-AS1 regulated non-small cell lung cancer cell self-renewal via the expression of miR-543 and ONECUT2, and THUMPD3-AS1 can serve as a potential biomarker or therapeutic target in non-small cell lung cancer.	('thyroid carcinoma', 'Disease', (323, 340))	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (364, 390))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('gastric cancer', 'Phenotype', 'HP:0012126', (170, 184))	('LINC00957', 'Gene', (14, 23))	('miR-543', 'Gene', '100126335', (431, 438))	('GC', 'Phenotype', 'HP:0012126', (207, 209))	('lung cancer', 'Disease', (379, 390))	('lung cancer', 'Phenotype', 'HP:0100526', (543, 554))	('patients', 'Species', '9606', (108, 116))	('DOCK9', 'Gene', (255, 260))	('colorectal cancer', 'Disease', (90, 107))	('THUMPD3', 'Gene', (342, 349))	('LINC02532', 'Var', (118, 127))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (323, 340))	('THUMPD3', 'Gene', '25917', (456, 463))	('cell proliferation', 'biological_process', 'GO:0008283', ('210', '228'))	('cancer', 'Phenotype', 'HP:0002664', (384, 390))	('AS1', 'Gene', (464, 467))	('AS1', 'Gene', '5729', (350, 353))	('ONECUT2', 'Gene', (443, 450))	('gastric cancer', 'Disease', (170, 184))	('cancer', 'Phenotype', 'HP:0002664', (548, 554))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (528, 554))	('carcinoma', 'Phenotype', 'HP:0030731', (331, 340))	('lung cancer', 'Disease', 'MESH:D008175', (379, 390))	('ONECUT2', 'Gene', '9480', (443, 450))	('LINC00957', 'Gene', '255031', (14, 23))	('GC', 'Phenotype', 'HP:0012126', (186, 188))	('DOCK9', 'Gene', '23348', (255, 260))	('miR-543', 'Gene', (431, 438))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('lung cancer', 'Disease', (543, 554))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (532, 554))	('lung cancer', 'Phenotype', 'HP:0100526', (379, 390))	('THUMPD3', 'Gene', '25917', (342, 349))	('THUMPD3', 'Gene', (456, 463))	('gastric cancer', 'Disease', 'MESH:D013274', (170, 184))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('AS1', 'Gene', '5729', (464, 467))	('AS1', 'Gene', (350, 353))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (323, 340))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (368, 390))	('lung cancer', 'Disease', 'MESH:D008175', (543, 554))
145657	33324563	Currently, the molecular mechanism or prognostic value of other lncRNAs including LINC01507, AL357140.2, AC063948.1, CD27-AS1, and AC002070.1 are elusive.	('CD27', 'Gene', '939', (117, 121))	('LINC01507', 'Gene', (82, 91))	('LINC01507', 'Gene', '101927477', (82, 91))	('AL357140.2', 'Var', (93, 103))	('AS1', 'Gene', '5729', (122, 125))	('AS1', 'Gene', (122, 125))	('CD27', 'Gene', (117, 121))
145661	33324563	Furthermore, the K-M curve result suggested that subtype C1 was was associated with better survival outcomes and in a majority of early-stage patients, whereas subtype C2 was associated with worse survival outcomes and in more advanced-stage patients.	('survival outcomes', 'CPA', (91, 108))	('subtype C1', 'Var', (49, 59))	('better', 'PosReg', (84, 90))	('patients', 'Species', '9606', (142, 150))	('patients', 'Species', '9606', (242, 250))
145678	32273759	High expression of CASC19 was closely associated with unfavorable clinicopathological parameters and predicted negative clinical outcomes in patients with ccRCC.	('CASC19', 'Gene', (19, 25))	('associated', 'Reg', (38, 48))	('High', 'Var', (0, 4))	('CASC19', 'Gene', '103021165', (19, 25))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('negative', 'NegReg', (111, 119))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', (157, 160))	('patients', 'Species', '9606', (141, 149))	('ccRCC', 'Phenotype', 'HP:0006770', (155, 160))
145681	32273759	Furthermore, rescue assays revealed that inhibiting miR-532 or restoring ETS1 expression partially abolished the impacts of CASC19 knockdown on ccRCC cells.	('abolished', 'NegReg', (99, 108))	('knockdown', 'Var', (131, 140))	('expression', 'MPA', (78, 88))	('RCC', 'Disease', (146, 149))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('ETS1', 'Gene', '2113', (73, 77))	('ETS1', 'Gene', (73, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('inhibiting', 'NegReg', (41, 51))	('CASC19', 'Gene', '103021165', (124, 130))	('miR-532', 'Gene', '693124', (52, 59))	('CASC19', 'Gene', (124, 130))	('impacts', 'MPA', (113, 120))	('miR-532', 'Gene', (52, 59))
145694	32273759	An increasing number of studies report that dysregulation of miRNAs affects various aspects of tumorigenesis and tumor development in almost all human tumor types.	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('dysregulation', 'Var', (44, 57))	('miRNAs', 'Gene', (61, 67))	('tumor', 'Disease', (151, 156))	('affects', 'Reg', (68, 75))	('human', 'Species', '9606', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (95, 100))
145755	32273759	Correlation analyses demonstrated that ccRCC patients with high CASC19 expression tended to have larger tumor sizes (P = 0.045), more advanced TNM stage (P = 0.012), and more frequently have lymph node metastasis (P = 0.003) (Table 1).	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('CASC19', 'Gene', (64, 70))	('larger', 'PosReg', (97, 103))	('lymph node metastasis', 'CPA', (191, 212))	('tumor', 'Disease', (104, 109))	('TNM', 'Gene', (143, 146))	('high', 'Var', (59, 63))	('patients', 'Species', '9606', (45, 53))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('CASC19', 'Gene', '103021165', (64, 70))	('RCC', 'Disease', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('TNM', 'Gene', '10178', (143, 146))
145756	32273759	In addition, patients with ccRCC having high CASC19 expression exhibited much lower overall survival rate than those with low CASC19 expression (Figure 1C; P = 0.038).	('high', 'Var', (40, 44))	('CASC19', 'Gene', (126, 132))	('CASC19', 'Gene', '103021165', (45, 51))	('patients', 'Species', '9606', (13, 21))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('overall survival', 'MPA', (84, 100))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('CASC19', 'Gene', (45, 51))	('ccRCC', 'Phenotype', 'HP:0006770', (27, 32))	('CASC19', 'Gene', '103021165', (126, 132))	('lower', 'NegReg', (78, 83))
145762	32273759	By using the MTT and colony formation assays, we observed that CASC19 knockdown impaired the proliferative (Figure 2B) and colony-forming abilities (Figure 2C) of 786-O and A498 cells.	('MTT', 'Chemical', 'MESH:C070243', (13, 16))	('knockdown', 'Var', (70, 79))	('impaired', 'NegReg', (80, 88))	('CASC19', 'Gene', '103021165', (63, 69))	('formation', 'biological_process', 'GO:0009058', ('28', '37'))	('colony-forming abilities', 'CPA', (123, 147))	('CASC19', 'Gene', (63, 69))	('A498', 'CellLine', 'CVCL:1056', (173, 177))
145763	32273759	Furthermore, the migration (Figure 2D) and invasiveness (Figure 2E) of 786-O and A498 cells was markedly attenuated by CASC19 silencing, as suggested by the results of the cell migration and invasion assays.	('migration', 'CPA', (17, 26))	('cell migration', 'biological_process', 'GO:0016477', ('172', '186'))	('CASC19', 'Gene', (119, 125))	('attenuated', 'NegReg', (105, 115))	('invasiveness', 'CPA', (43, 55))	('CASC19', 'Gene', '103021165', (119, 125))	('silencing', 'Var', (126, 135))	('A498', 'CellLine', 'CVCL:1056', (81, 85))
145786	32273759	ETS1 mRNA (Figure 4G) and protein (Figure 4H) levels, which were decreased by CASC19 knockdown, were almost fully recovered in 786-O and A498 cells after their co-transfection with the miR-532 inhibitor.	('A498', 'CellLine', 'CVCL:1056', (137, 141))	('CASC19', 'Gene', (78, 84))	('ETS1', 'Gene', '2113', (0, 4))	('ETS1', 'Gene', (0, 4))	('miR-532', 'Gene', '693124', (185, 192))	('miR-532', 'Gene', (185, 192))	('knockdown', 'Var', (85, 94))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('CASC19', 'Gene', '103021165', (78, 84))
145789	32273759	First, a combination of si-GASC19, plus miR-532 inhibitor or NC inhibitor was co-transfected into 786-O and A498 cells, and changes in the proliferation, migration, and invasiveness were evaluated.	('miR-532', 'Gene', (40, 47))	('A498', 'CellLine', 'CVCL:1056', (108, 112))	('invasiveness', 'CPA', (169, 181))	('miR-532', 'Gene', '693124', (40, 47))	('si-GASC19', 'Var', (24, 33))	('migration', 'CPA', (154, 163))
145790	32273759	Inhibition of miR-532 expression abrogated the inhibitory effects of CASC19 knockdown on the proliferation (Figure 5A), colony formation (Figure 5B), migration (Figure 5C), and invasiveness (Figure 5D) of 786-O and A498 cells.	('knockdown', 'Var', (76, 85))	('CASC19', 'Gene', '103021165', (69, 75))	('abrogated', 'NegReg', (33, 42))	('miR-532', 'Gene', '693124', (14, 21))	('colony formation', 'CPA', (120, 136))	('invasiveness', 'CPA', (177, 189))	('miR-532', 'Gene', (14, 21))	('CASC19', 'Gene', (69, 75))	('migration', 'CPA', (150, 159))	('A498', 'CellLine', 'CVCL:1056', (215, 219))	('formation', 'biological_process', 'GO:0009058', ('127', '136'))
145793	32273759	Functional experiments showed that the impacts of CASC19 knockdown on the proliferation (Figure 6B), colony formation (Figure 6C), migration (Figure 6D), and invasiveness (Figure 6E) of 786-O and A498 cells were eliminated by means of pcDNA3.1-ETS1 restoration.	('invasiveness', 'CPA', (158, 170))	('colony formation', 'CPA', (101, 117))	('A498', 'CellLine', 'CVCL:1056', (196, 200))	('migration', 'CPA', (131, 140))	('ETS1', 'Gene', '2113', (244, 248))	('knockdown', 'Var', (57, 66))	('ETS1', 'Gene', (244, 248))	('formation', 'biological_process', 'GO:0009058', ('108', '117'))	('CASC19', 'Gene', '103021165', (50, 56))	('CASC19', 'Gene', (50, 56))
145802	32273759	Collectively, silenced CASC19 expression impaired tumor growth of ccRCC cells in vivo.	('impaired tumor', 'Disease', (41, 55))	('CASC19', 'Gene', (23, 29))	('silenced', 'Var', (14, 22))	('impaired tumor', 'Disease', 'MESH:D060825', (41, 55))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('CASC19', 'Gene', '103021165', (23, 29))
145805	32273759	Therefore, detailed elucidation of lncRNA roles and mechanisms underlying dysregulation of lncRNAs in ccRCC may be instrumental for the development of promising novel therapeutic approaches for patients with this disease.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('patients', 'Species', '9606', (194, 202))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('dysregulation', 'Var', (74, 87))	('RCC', 'Disease', (104, 107))
145816	32273759	Notably, ccRCC patients with high CASC19 expression had shorter overall survival than patients with low CASC19 expression.	('high', 'Var', (29, 33))	('CASC19', 'Gene', '103021165', (34, 40))	('patients', 'Species', '9606', (15, 23))	('CASC19', 'Gene', (34, 40))	('ccRCC', 'Phenotype', 'HP:0006770', (9, 14))	('CASC19', 'Gene', '103021165', (104, 110))	('shorter', 'NegReg', (56, 63))	('overall survival', 'MPA', (64, 80))	('CASC19', 'Gene', (104, 110))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('expression', 'Var', (41, 51))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))	('patients', 'Species', '9606', (86, 94))
145818	32273759	For example, interference with CASC19 expression restricted colorectal cancer cell proliferation, migration, invasiveness and epithelial-mesenchymal transition in vitro.	('restricted', 'NegReg', (49, 59))	('cell proliferation', 'biological_process', 'GO:0008283', ('78', '96'))	('epithelial-mesenchymal transition', 'CPA', (126, 159))	('CASC19', 'Gene', '103021165', (31, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (60, 77))	('invasiveness', 'CPA', (109, 121))	('interference', 'Var', (13, 25))	('colorectal cancer', 'Phenotype', 'HP:0003003', (60, 77))	('CASC19', 'Gene', (31, 37))	('migration', 'CPA', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('126', '159'))	('colorectal cancer', 'Disease', (60, 77))
145866	28939740	There is increasing evidence that epigenetic modulation may have immunostimulatory activity in addition to a direct antitumor effect.	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('immunostimulatory activity', 'MPA', (65, 91))	('epigenetic modulation', 'Var', (34, 55))	('tumor', 'Disease', (120, 125))
145889	28939740	For activated antigen presenting cells, we used the following antibodies (BD): CD86 BB515, CD14 PE, Lin Dump FL3 PC5, HLADr PECy7, CD11c APC, CD45 APCH7, CD80 BV421, CD123 BV510.	('CD123 BV510', 'Var', (166, 177))	('CD45', 'Gene', (142, 146))	('CD80', 'Gene', (154, 158))	('CD14', 'Gene', (91, 95))	('APC', 'Disease', 'MESH:D011125', (137, 140))	('APC', 'Disease', 'MESH:D011125', (147, 150))	('CD86', 'Gene', '942', (79, 83))	('CD14', 'Gene', '929', (91, 95))	('APC', 'Disease', (137, 140))	('CD80', 'Gene', '941', (154, 158))	('CD45', 'Gene', '5788', (142, 146))	('APC', 'Disease', (147, 150))	('CD86', 'Gene', (79, 83))	('Dump', 'Chemical', 'MESH:C007267', (104, 108))	('APC', 'cellular_component', 'GO:0005680', ('137', '140'))	('CD11c', 'Gene', '3687', (131, 136))	('CD11c', 'Gene', (131, 136))
145890	28939740	For Treg we used the following antibodies (BD and Bioscience): FOXP3 PE, CD4 PcP, CD3PC7, CD127 APC, CD45 APCH7, CD25 BV421.	('PcP', 'molecular_function', 'GO:1904091', ('77', '80'))	('CD4', 'Gene', '920', (101, 104))	('CD25', 'Gene', (113, 117))	('CD4', 'Gene', (101, 104))	('PC7', 'CellLine', 'CVCL:A786', (85, 88))	('APC', 'cellular_component', 'GO:0005680', ('96', '99'))	('FOXP3', 'Gene', (63, 68))	('PcP', 'molecular_function', 'GO:0004188', ('77', '80'))	('CD25', 'Gene', '3559', (113, 117))	('CD4', 'Gene', '920', (73, 76))	('CD45', 'Gene', (101, 105))	('APC', 'Disease', 'MESH:D011125', (106, 109))	('APC', 'Disease', (106, 109))	('CD4', 'Gene', (73, 76))	('FOXP3', 'Gene', '50943', (63, 68))	('Treg', 'Chemical', '-', (4, 8))	('APC', 'Disease', 'MESH:D011125', (96, 99))	('CD45', 'Gene', '5788', (101, 105))	('APC', 'Disease', (96, 99))	('CD3PC7', 'Var', (82, 88))
145892	28939740	Formalin-fixed paraffin sections of tumor biopsies were stained for FOXP3 (Clone 236A/E7, Abcam; catalog #ab20034) and CD8 staining (Clone C8/144B, Dako; catalog# M7103).	('FOXP3', 'Gene', (68, 73))	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('CD8', 'Gene', (119, 122))	('CD8', 'Gene', '925', (119, 122))	('FOXP3', 'Gene', '50943', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('paraffin', 'Chemical', 'MESH:D010232', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Clone C8/144B', 'Var', (133, 146))	('tumor', 'Disease', (36, 41))
145934	28939740	Values for responders were likely to be higher for APC at C1 D-7 (p=0.0095) and APC at C1D1 (p=0.0121).	('APC', 'cellular_component', 'GO:0005680', ('51', '54'))	('APC', 'Disease', (80, 83))	('higher', 'PosReg', (40, 46))	('APC', 'cellular_component', 'GO:0005680', ('80', '83'))	('C1 D-7', 'Var', (58, 64))	('APC', 'Disease', 'MESH:D011125', (51, 54))	('APC', 'Disease', (51, 54))	('APC', 'Disease', 'MESH:D011125', (80, 83))
145941	28939740	For example, HDAC inhibitors have been reported to enhance the effect of vaccine strategies .	('enhance', 'PosReg', (51, 58))	('HDAC', 'Gene', '9734', (13, 17))	('inhibitors', 'Var', (18, 28))	('HDAC', 'Gene', (13, 17))
145961	28939740	Interestingly, HDAC inhibition has been shown to increase PD-L1 expression in preclinical models, including in combination with a demethylating agent .	('PD-L1', 'Gene', '29126', (58, 63))	('increase', 'PosReg', (49, 57))	('expression', 'MPA', (64, 74))	('inhibition', 'Var', (20, 30))	('increase PD', 'Phenotype', 'HP:0008151', (49, 60))	('HDAC', 'Gene', (15, 19))	('HDAC', 'Gene', '9734', (15, 19))	('PD-L1', 'Gene', (58, 63))
145965	28939740	These findings represent the first evidence, to our knowledge, of improved benefit through immunotherapy combination with an epigenetic agent in the first-line setting treatment for ccRCC, and provide the rationale for a prospective validation of this therapeutic strategy.	('epigenetic', 'Var', (125, 135))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('RCC', 'Disease', (184, 187))	('improved', 'PosReg', (66, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (182, 187))	('benefit', 'MPA', (75, 82))
145970	33233657	While many different genes have been found to be mutated and to drive the initiation and progression of these lethal cancers, a fine molecular understanding of the process is still lacking.	('mutated', 'Var', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('drive', 'PosReg', (64, 69))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
145973	33233657	In the kidney, its function is essential in appropriate cellular response to oxidative stress, however its aberrant activation supports progression, metastasis, and resistance to therapies in renal cell carcinoma, similarly to what happens in other nonrenal cancers.	('metastasis', 'CPA', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('renal cancer', 'Phenotype', 'HP:0009726', (252, 264))	('progression', 'CPA', (136, 147))	('oxidative stress', 'Phenotype', 'HP:0025464', (77, 93))	('resistance', 'CPA', (165, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('renal cancers', 'Disease', 'MESH:D007680', (252, 265))	('aberrant', 'Var', (107, 115))	('activation', 'PosReg', (116, 126))	('renal cell carcinoma', 'Disease', (192, 212))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (192, 212))	('renal cancers', 'Disease', (252, 265))	('cancers', 'Phenotype', 'HP:0002664', (258, 265))	('cellular response to oxidative stress', 'biological_process', 'GO:0034599', ('56', '93'))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (192, 212))
145991	33233657	Although activators of NRF2 are opening new perspectives in the treatment of different renal pathologies, underlying its protective role in kidney tissue, its aberrant hyperactivation is becoming a central driver of progression of different cancer types, such as renal cell carcinoma.	('renal cell carcinoma', 'Disease', (263, 283))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (263, 283))	('aberrant', 'Var', (159, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('NRF2', 'Gene', (23, 27))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (263, 283))
146007	33233657	Indeed, several pathways potentially involved in RCC subtypes progression were found to be altered by somatic mutations, genomic rearrangements, or epigenetic modifications targeting newly found or already known key genes.	('RCC', 'Disease', (49, 52))	('pathways', 'Pathway', (16, 24))	('altered', 'Reg', (91, 98))	('genomic rearrangements', 'Var', (121, 143))	('epigenetic modifications', 'Var', (148, 172))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
146008	33233657	ccRCC is mainly characterized by genomic alteration in the short arm of chromosome 3 that encodes for the Von Hippel Lindau tumor suppressor gene VHL, reported in almost 90% of the cases.	('VHL', 'Gene', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('chromosome', 'cellular_component', 'GO:0005694', ('72', '82'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('124', '140'))	('RCC', 'Disease', (2, 5))	('VHL', 'Gene', '7428', (146, 149))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('124', '140'))	('short arm', 'Phenotype', 'HP:0009824', (59, 68))	('alteration', 'Var', (41, 51))	('Von Hippel Lindau tumor suppressor', 'Gene', '7428', (106, 140))	('Von Hippel Lindau tumor suppressor', 'Gene', (106, 140))
146011	33233657	Loss of VHL stabilizes HIF1alpha and HIF2alpha in normal oxygen conditions, leading to a state of pseudohypoxia.	('VHL', 'Gene', '7428', (8, 11))	('HIF1alpha', 'Gene', '3091', (23, 32))	('pseudohypoxia', 'Disease', (98, 111))	('oxygen', 'Chemical', 'MESH:D010100', (57, 63))	('HIF2alpha', 'Gene', (37, 46))	('HIF2alpha', 'Gene', '2034', (37, 46))	('pseudohypoxia', 'Disease', 'None', (98, 111))	('Loss', 'Var', (0, 4))	('leading to', 'Reg', (76, 86))	('HIF1alpha', 'Gene', (23, 32))	('VHL', 'Gene', (8, 11))
146013	33233657	ccRCCs that are not mutated in VHL carry mutations mainly in the PI3K/AKT/mTOR pathway, with an upregulation of mTORC1 signaling observed in about 80% of the cases, in the chromatin remodeling and histone modifying pathways.	('mutations', 'Var', (41, 50))	('VHL', 'Gene', '7428', (31, 34))	('AKT', 'Gene', '207', (70, 73))	('mTORC1', 'Gene', (112, 118))	('RCC', 'Disease', (2, 5))	('PI3K', 'molecular_function', 'GO:0016303', ('65', '69'))	('upregulation', 'PosReg', (96, 108))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('histone modifying pathways', 'Pathway', (197, 223))	('AKT', 'Gene', (70, 73))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('172', '192'))	('chromatin', 'cellular_component', 'GO:0000785', ('172', '181'))	('mTORC1', 'cellular_component', 'GO:0031931', ('112', '118'))	('VHL', 'Gene', (31, 34))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))	('mTORC1', 'Gene', '382056', (112, 118))
146017	33233657	Among them, activating mutations or alterations in the MET signature have been reported in 81% of cases, with a prevalence of somatic or germline mutations in the MET gene (18.6%), which results in the upregulation of cell survival, proliferation, and migration pathways.	('proliferation', 'CPA', (233, 246))	('mutations', 'Var', (146, 155))	('MET', 'Gene', '79811', (55, 58))	('MET', 'Gene', '79811', (163, 166))	('alterations', 'Var', (36, 47))	('mutations', 'Var', (23, 32))	('MET', 'Gene', (55, 58))	('MET', 'Gene', (163, 166))	('cell survival', 'CPA', (218, 231))	('activating', 'PosReg', (12, 22))	('migration pathways', 'CPA', (252, 270))	('upregulation', 'PosReg', (202, 214))
146019	33233657	While sporadic type II pRCC mainly displays mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A), histone lysine methyltransferase (SETD2), and transcription factor E3 (TFE3), hereditary type II pRCC is triggered by germ line mutations in the fumarate hydratase gene (FH), an enzyme of the tricarboxylic acid cycle (TCA), which causes an intracellular accumulation of the oncometabolite fumarate.	('transcription factor E3', 'Gene', (150, 173))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (57, 93))	('triggered by', 'Reg', (209, 221))	('pRCC', 'Phenotype', 'HP:0006766', (201, 205))	('SETD2', 'Gene', '29072', (138, 143))	('mutations', 'Var', (232, 241))	('transcription factor', 'molecular_function', 'GO:0000981', ('150', '170'))	('pRCC', 'Gene', (201, 205))	('TCA', 'Gene', (322, 325))	('fumarate hydratase', 'Gene', (249, 267))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (57, 93))	('intracellular', 'cellular_component', 'GO:0005622', ('344', '357'))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('57', '90'))	('tricarboxylic acid cycle', 'biological_process', 'GO:0006099', ('296', '320'))	('pRCC', 'Gene', '5546', (23, 27))	('TFE3', 'Gene', (175, 179))	('FH', 'Gene', '2271', (274, 276))	('TFE3', 'Gene', '7030', (175, 179))	('hereditary type II pRCC', 'Disease', 'MESH:D020176', (182, 205))	('CDKN2A', 'Gene', (95, 101))	('fumarate hydratase', 'Gene', '2271', (249, 267))	('pRCC', 'Phenotype', 'HP:0006766', (23, 27))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('74', '90'))	('fumarate', 'Chemical', 'MESH:D005650', (393, 401))	('fumarate', 'Chemical', 'MESH:D005650', (249, 257))	('transcription', 'biological_process', 'GO:0006351', ('150', '163'))	('pRCC', 'Gene', (23, 27))	('pRCC', 'Gene', '5546', (201, 205))	('hereditary type II pRCC', 'Disease', (182, 205))	('transcription factor E3', 'Gene', '7030', (150, 173))	('CDKN2A', 'Gene', '1029', (95, 101))	('mutations', 'Var', (44, 53))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (296, 314))	('SETD2', 'Gene', (138, 143))
146021	33233657	This group of tumors features both somatic and germline mutations in the FH gene, resulting in fumarate accumulation, as described for HLRCC patients.	('FH', 'Gene', '2271', (73, 75))	('germline mutations', 'Var', (47, 65))	('fumarate', 'Chemical', 'MESH:D005650', (95, 103))	('tumors', 'Disease', (14, 20))	('fumarate accumulation', 'MPA', (95, 116))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('patients', 'Species', '9606', (141, 149))
146026	33233657	Mutations involving the major players of the NRF2 pathway are generally mutually exclusive, even if they can co-occur in tumors with known association to exposure to carcinogenic factors.	('NRF2 pathway', 'Pathway', (45, 57))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('carcinogenic', 'Disease', 'MESH:D063646', (166, 178))	('carcinogenic', 'Disease', (166, 178))
146027	33233657	These mutations involve directly the NRF2 coding gene NFE2L2, but also genes encoding for the regulatory proteins KEAP1 and CUL3, and NRF2 transcriptional targets (Table 1).	('involve', 'Reg', (16, 23))	('NFE2L2', 'Gene', '4780', (54, 60))	('NFE2L2', 'Gene', (54, 60))	('KEAP1', 'Gene', '9817', (114, 119))	('NRF2', 'Gene', (37, 41))	('CUL3', 'Gene', '8452', (124, 128))	('CUL3', 'Gene', (124, 128))	('KEAP1', 'Gene', (114, 119))	('mutations', 'Var', (6, 15))
146033	33233657	Despite activating hotspots in NFE2L2 and inactivating mutations in its negative regulators, KEAP1, CUL3, and SIRT1 have been reported, they do not justify themselves the overexpression of NRF2 transcriptional signature in the different tumor types.	('SIRT1', 'Gene', (110, 115))	('tumor', 'Disease', (237, 242))	('inactivating mutations', 'Var', (42, 64))	('KEAP1', 'Gene', '9817', (93, 98))	('NFE2L2', 'Gene', '4780', (31, 37))	('activating', 'MPA', (8, 18))	('KEAP1', 'Gene', (93, 98))	('CUL3', 'Gene', '8452', (100, 104))	('CUL3', 'Gene', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('NFE2L2', 'Gene', (31, 37))	('SIRT1', 'Gene', '23411', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
146035	33233657	However, as described for ccRCC, hyperactivation of the NRF2 signature associates with tumor progression and decreased survival.	('decreased', 'NegReg', (109, 118))	('survival', 'CPA', (119, 127))	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('NRF2', 'Gene', (56, 60))	('tumor', 'Disease', (87, 92))	('hyperactivation', 'Var', (33, 48))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('RCC', 'Disease', (28, 31))
146049	33233657	Indeed, NRF2 activators were reported to reduce cisplatin cytotoxicity in kidney epithelial cells, thus allowing to think about a combinatory treatment to prevent chemotherapy side effects, even if their effect is still contradictory in in vivo experiments because of biodistribution and bioavailability.	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('reduce', 'NegReg', (41, 47))	('cytotoxicity', 'Disease', (58, 70))	('activators', 'Var', (13, 23))	('NRF2', 'Gene', (8, 12))	('cytotoxicity', 'Disease', 'MESH:D064420', (58, 70))
146059	33233657	This occurs also in metastatic RCC, where the EMT process is activated by different mechanisms, such as chronic oxidative stress, loss of VHL, and stabilization of HIF-1 alpha and activation of Wilm's tumor transcription factor 1, that induces an epithelial-to-mesenchymal hybrid transition in which the cells retain both epithelial and mesenchymal features.	('VHL', 'Gene', '7428', (138, 141))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('EMT', 'biological_process', 'GO:0001837', ('46', '49'))	('HIF-1 alpha', 'Gene', '3091', (164, 175))	('oxidative stress', 'Phenotype', 'HP:0025464', (112, 128))	("Wilm's tumor", 'Phenotype', 'HP:0002667', (194, 206))	('epithelial-to-mesenchymal hybrid transition', 'CPA', (247, 290))	('HIF-1 alpha', 'Gene', (164, 175))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('transcription factor', 'molecular_function', 'GO:0000981', ('207', '227'))	('RCC', 'Disease', (31, 34))	('transcription', 'biological_process', 'GO:0006351', ('207', '220'))	("Wilm's tumor", 'Disease', 'MESH:D009396', (194, 206))	('loss', 'Var', (130, 134))	('VHL', 'Gene', (138, 141))	('induces', 'Reg', (236, 243))	('activation', 'PosReg', (180, 190))	("Wilm's tumor", 'Disease', (194, 206))
146063	33233657	Indeed, cancers harboring mutations in the NFE2L2 gene and featuring NRF2 constitutive activation show increased proliferation, anchorage-independent growth, and metastatic potential, dependent on mTORC1 activation.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('increased', 'PosReg', (103, 112))	('metastatic potential', 'CPA', (162, 182))	('NRF2', 'Gene', (69, 73))	('NFE2L2', 'Gene', (43, 49))	('mTORC1', 'Gene', (197, 203))	('mTORC1', 'cellular_component', 'GO:0031931', ('197', '203'))	('mutations', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('anchorage-independent growth', 'CPA', (128, 156))	('mTORC1', 'Gene', '382056', (197, 203))	('NFE2L2', 'Gene', '4780', (43, 49))
146064	33233657	Moreover, expression of mutant NRF2 gene in human embryonic kidney (HEK)-293 cells is sufficient to confer them an oncogenic and metastatic phenotype.	('mutant', 'Var', (24, 30))	('human', 'Species', '9606', (44, 49))	('NRF2', 'Gene', (31, 35))	('HEK)-293', 'CellLine', 'CVCL:0045', (68, 76))	('embryonic kidney', 'Disease', (50, 66))	('embryonic kidney', 'Disease', 'MESH:D007674', (50, 66))
146074	33233657	In order to understand how genetic alterations in the KEAP1-NRF2 axis can impact on cancer progression in the kidney, it is helpful to describe the major animal models that feature NRF2 hyperactivation with implications in this tissue.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('NRF2', 'Gene', (181, 185))	('KEAP1', 'Gene', (54, 59))	('cancer', 'Disease', (84, 90))	('impact', 'Reg', (74, 80))	('hyperactivation', 'PosReg', (186, 201))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('KEAP1', 'Gene', '9817', (54, 59))	('genetic alterations', 'Var', (27, 46))
146075	33233657	Keap1 knockout mice feature postnatal lethality, due to hyperkeratosis in the upper digestive tract, which is corrected by local deletion of the Nrf2 gene.	('hyperkeratosis', 'Disease', 'MESH:D017488', (56, 70))	('Nrf2', 'Gene', (145, 149))	('local deletion', 'Var', (123, 137))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (56, 70))	('mice', 'Species', '10090', (15, 19))	('hyperkeratosis', 'Disease', (56, 70))
146076	33233657	Interestingly, these mice show polyuria and kidney damage, probably due to downregulation of aquaporin 2 and reduced water resorption, as demonstrated in mice with Keap1 specific deletion in renal tubules.	('aquaporin 2', 'Gene', (93, 104))	('aquaporin', 'molecular_function', 'GO:0015250', ('93', '102'))	('downregulation', 'NegReg', (75, 89))	('mice', 'Species', '10090', (154, 158))	('reduced', 'NegReg', (109, 116))	('mice', 'Species', '10090', (21, 25))	('polyuria', 'Disease', 'MESH:D011141', (31, 39))	('downregulation of aquaporin', 'biological_process', 'GO:1902428', ('75', '102'))	('kidney damage', 'Disease', (44, 57))	('kidney damage', 'Phenotype', 'HP:0000112', (44, 57))	('aquaporin 2', 'Gene', '11827', (93, 104))	('polyuria', 'Phenotype', 'HP:0000103', (31, 39))	('deletion', 'Var', (179, 187))	('water', 'Chemical', 'MESH:D014867', (117, 122))	('water', 'MPA', (117, 122))	('kidney damage', 'Disease', 'MESH:D007674', (44, 57))	('polyuria', 'Disease', (31, 39))
146078	33233657	However, systemic or kidney-specific deletion of the Keap1 gene is not sufficient to cause an aggressive tumor formation, suggesting that NRF2 plays a role in supporting tumor growth and drug resistance, but not in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('deletion', 'Var', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('cause', 'Reg', (85, 90))	('formation', 'biological_process', 'GO:0009058', ('111', '120'))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (170, 175))	('drug resistance', 'CPA', (187, 202))	('drug resistance', 'Phenotype', 'HP:0020174', (187, 202))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('drug resistance', 'biological_process', 'GO:0009315', ('187', '202'))	('drug resistance', 'biological_process', 'GO:0042493', ('187', '202'))	('tumor', 'Disease', (215, 220))	('Keap1', 'Gene', (53, 58))	('tumor', 'Disease', (105, 110))	('supporting', 'PosReg', (159, 169))
146079	33233657	This is further sustained by the observation that human germline loss of function mutations in the KEAP1 gene are not associated with cancer formation, even if it predisposes to multinodular goiters.	('multinodular goiters', 'Disease', (178, 198))	('KEAP1', 'Gene', (99, 104))	('multinodular goiters', 'Phenotype', 'HP:0005987', (178, 198))	('goiters', 'Phenotype', 'HP:0000853', (191, 198))	('formation', 'biological_process', 'GO:0009058', ('141', '150'))	('cancer', 'Disease', (134, 140))	('loss of function', 'NegReg', (65, 81))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('mutations', 'Var', (82, 91))	('KEAP1', 'Gene', '9817', (99, 104))	('human', 'Species', '9606', (50, 55))	('multinodular goiters', 'Disease', 'MESH:C564546', (178, 198))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
146081	33233657	Several mutations involve directly the NFE2L2 gene and are highly conserved among different cancer types.	('involve', 'Reg', (18, 25))	('NFE2L2', 'Gene', (39, 45))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutations', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('NFE2L2', 'Gene', '4780', (39, 45))
146082	33233657	The analysis of TCGA catalogue has identified almost 2% of unique NRF2-mutant tumors among all cases reported, with the 63% of tumor type harboring NLE2L2 mutations.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('NRF2-mutant', 'Gene', (66, 77))	('tumors', 'Disease', (78, 84))	('NRF2-mutant', 'Var', (66, 77))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
146083	33233657	These mutations localize mainly in ETGE and DLG motives of the Neh2 domain, which determine KEAP1 ability to bind NRF2 and direct its CUL3-dependent degradation.	('KEAP1', 'Gene', (92, 97))	('degradation', 'biological_process', 'GO:0009056', ('149', '160'))	('Neh2', 'Gene', (63, 67))	('CUL3', 'Gene', '8452', (134, 138))	('direct', 'Reg', (123, 129))	('bind', 'Interaction', (109, 113))	('CUL3', 'Gene', (134, 138))	('Neh2', 'Gene', '252969', (63, 67))	('KEAP1', 'Gene', '9817', (92, 97))	('NRF2', 'Protein', (114, 118))	('mutations', 'Var', (6, 15))
146084	33233657	In RCCs, NFE2L2 is among the 20 aberrant genes, harboring mainly missense mutations in activating hotspots, prevalently reported in PRCC (Table 2).	('activating hotspots', 'MPA', (87, 106))	('PRCC', 'Gene', '5546', (132, 136))	('PRCC', 'Gene', (132, 136))	('missense mutations', 'Var', (65, 83))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('NFE2L2', 'Gene', '4780', (9, 15))	('RCC', 'Disease', (3, 6))	('RCC', 'Disease', 'MESH:C538614', (3, 6))	('NFE2L2', 'Gene', (9, 15))
146085	33233657	However, NRF2 signature harbors mutations also in 3.2% of ccRCCs, with 2% of mutations involving directly NFE2L2 and copy number alteration in position 2q31.2 (Table 1).	('NFE2L2', 'Gene', '4780', (106, 112))	('RCC', 'Disease', (60, 63))	('NFE2L2', 'Gene', (106, 112))	('NRF2', 'Gene', (9, 13))	('mutations', 'Var', (32, 41))	('RCC', 'Disease', 'MESH:C538614', (60, 63))
146086	33233657	Indeed, rs6721961 single nucleotide polymorphism (SNP) in the promoter of NFE2L2 gene has been described to support carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (116, 130))	('carcinogenesis', 'Disease', (116, 130))	('NFE2L2', 'Gene', (74, 80))	('rs6721961', 'Mutation', 'rs6721961', (8, 17))	('NFE2L2', 'Gene', '4780', (74, 80))	('rs6721961 single nucleotide polymorphism', 'Var', (8, 48))	('support', 'PosReg', (108, 115))
146087	33233657	However, NFE2L2 gene alterations in the primary tumor, both in homo- and in heterozygosity, impact not only on tumor progression, but also on the clinical outcome and in the response to therapy, with patients developing chronic kidney disease after partial nephrectomy and reduced response of metastasis to vascular endothelial growth factor-targeting therapy.	('alterations', 'Var', (21, 32))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('chronic kidney disease', 'Disease', 'MESH:D051436', (220, 242))	('vascular endothelial growth factor', 'Gene', '7422', (307, 341))	('kidney disease', 'Phenotype', 'HP:0000112', (228, 242))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (220, 242))	('vascular endothelial growth factor', 'Gene', (307, 341))	('NFE2L2', 'Gene', '4780', (9, 15))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', (111, 116))	('chronic kidney disease', 'Disease', (220, 242))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('NFE2L2', 'Gene', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('patients', 'Species', '9606', (200, 208))	('impact', 'Reg', (92, 98))	('developing', 'Reg', (209, 219))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('307', '341'))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
146088	33233657	However, the described NFE2L2 alterations are not the only cause of the hyperactivation of NRF2-ARE signatures reported in RCCs.	('NFE2L2', 'Gene', '4780', (23, 29))	('NFE2L2', 'Gene', (23, 29))	('RCC', 'Disease', (123, 126))	('alterations', 'Var', (30, 41))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('NRF2-ARE', 'Gene', (91, 99))
146089	33233657	Indeed, a plethora of mutations involving genes encoding for the regulatory interactors of NRF2 have been reported in different types of RCC (Table 1).	('reported', 'Reg', (106, 114))	('mutations', 'Var', (22, 31))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('plethora', 'Phenotype', 'HP:0001050', (10, 18))	('RCC', 'Disease', (137, 140))	('NRF2', 'Gene', (91, 95))
146090	33233657	Mutations in KEAP1 and CUL3 genes are mutually exclusive with the one in the NFE2L2 gene present in 6.6% of ccRCCs; indeed 10.4% of the tumor analyzed presented a deletion in the CUL3 locus 2q36.	('RCC', 'Disease', (110, 113))	('KEAP1', 'Gene', '9817', (13, 18))	('deletion', 'Var', (163, 171))	('CUL3', 'Gene', '8452', (23, 27))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('NFE2L2', 'Gene', (77, 83))	('CUL3', 'Gene', (23, 27))	('KEAP1', 'Gene', (13, 18))	('CUL3', 'Gene', '8452', (179, 183))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('CUL3', 'Gene', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('NFE2L2', 'Gene', '4780', (77, 83))
146091	33233657	Inactivating mutations in the same genes are described also in PRCCs.	('PRCC', 'Gene', '5546', (63, 67))	('PRCC', 'Gene', (63, 67))	('Inactivating mutations', 'Var', (0, 22))
146092	33233657	In addition, a dominant negative mutation in the SIRT1 gene has been described in co-occurance with NFE2L2 mutation in one case of sporadic type II PRCC.	('SIRT1', 'Gene', (49, 54))	('PRCC', 'Gene', '5546', (148, 152))	('NFE2L2', 'Gene', '4780', (100, 106))	('negative', 'NegReg', (24, 32))	('SIRT1', 'Gene', '23411', (49, 54))	('NFE2L2', 'Gene', (100, 106))	('PRCC', 'Gene', (148, 152))	('mutation', 'Var', (107, 115))
146095	33233657	Mutations in the key genes of the NRF2 pathway are not always sufficient to justify its aberrantly increased transcriptional activity in different solid tumors, such as lung cancer and PRCC.	('lung cancer', 'Disease', 'MESH:D008175', (169, 180))	('NRF2', 'Gene', (34, 38))	('solid tumors', 'Disease', (147, 159))	('PRCC', 'Gene', '5546', (185, 189))	('PRCC', 'Gene', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('Mutations', 'Var', (0, 9))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('solid tumors', 'Disease', 'MESH:D009369', (147, 159))	('increased', 'PosReg', (99, 108))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('lung cancer', 'Disease', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('transcriptional activity', 'MPA', (109, 133))
146096	33233657	The NRF2 axis is subjected to epigenetic regulation, which is the most frequent mechanism of downregulation of KEAP1 in solid tumors, caused by the methylation of CpGs located in the P1 region of the promoter, near the transcriptional starting site.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('solid tumors', 'Disease', (120, 132))	('KEAP1', 'Gene', '9817', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('regulation', 'biological_process', 'GO:0065007', ('41', '51'))	('CpGs', 'Gene', (163, 167))	('methylation', 'biological_process', 'GO:0032259', ('148', '159'))	('KEAP1', 'Gene', (111, 116))	('solid tumors', 'Disease', 'MESH:D009369', (120, 132))	('methylation', 'Var', (148, 159))	('downregulation', 'NegReg', (93, 107))
146097	33233657	This is relevant in RCC, since DNA methylation and epigenetic modifications have been extensively investigated in this set of tumors, resulting in the characterization of a new type II PRCC (CIMP-PRCC) associated with hypermethylation of CpG islands.	('CIMP-PRCC', 'Gene', '5546', (191, 200))	('PRCC', 'Gene', '5546', (185, 189))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('PRCC', 'Gene', (196, 200))	('RCC', 'Disease', 'MESH:C538614', (197, 200))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('RCC', 'Disease', (20, 23))	('tumors', 'Disease', (126, 132))	('RCC', 'Disease', (186, 189))	('DNA methylation', 'biological_process', 'GO:0006306', ('31', '46'))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('PRCC', 'Gene', '5546', (196, 200))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('PRCC', 'Gene', (185, 189))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('associated', 'Reg', (202, 212))	('RCC', 'Disease', (197, 200))	('CIMP-PRCC', 'Gene', (191, 200))	('hypermethylation', 'Var', (218, 234))
146100	33233657	Indeed, it is known that also the NFE2L2 promoter is subjected to epigenetic modifications in some kinds of cancer.	('NFE2L2', 'Gene', '4780', (34, 40))	('subjected', 'Reg', (53, 62))	('NFE2L2', 'Gene', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('epigenetic', 'Var', (66, 76))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
146102	33233657	Colorectal cancer featuring hypomethylation of the NFE2L2 promoter and consequent hyperactivation of the NRF2 axis shows resistance to different chemotherapeutic drugs.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('hypomethylation', 'Var', (28, 43))	('NFE2L2', 'Gene', '4780', (51, 57))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('NRF2', 'Gene', (105, 109))	('Colorectal cancer', 'Disease', (0, 17))	('NFE2L2', 'Gene', (51, 57))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))
146109	33233657	Indeed, miR-200c, through the downregulation of HMOX1, a target gene of NRF2, sensitizes ccRCC to chemotherapeutic agents, suggesting that miRNAs regulation of the NRF2-ARE signature can impact on different features of RCC.	('miR-200c', 'Gene', (8, 16))	('impact', 'Reg', (187, 193))	('miR-200c', 'Gene', '406985', (8, 16))	('miRNAs', 'Var', (139, 145))	('downregulation', 'NegReg', (30, 44))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))	('sensitizes', 'Reg', (78, 88))	('HMOX1', 'Gene', (48, 53))	('RCC', 'Disease', 'MESH:C538614', (219, 222))	('RCC', 'Disease', (219, 222))	('regulation', 'biological_process', 'GO:0065007', ('146', '156'))	('HMOX1', 'Gene', '3162', (48, 53))
146113	33233657	Curiously, miR-101 is downregulated in ccRCC and the consequent overexpression of its targets (e.g., DONSON) associates with resistance to Sunitinib treatment, while its restoration inhibits the invasive behavior of RCC cells.	('DONSON', 'Gene', '29980', (101, 107))	('miR-101', 'Chemical', '-', (11, 18))	('Sunitinib', 'Chemical', 'MESH:D000077210', (139, 148))	('inhibits', 'NegReg', (182, 190))	('overexpression', 'PosReg', (64, 78))	('restoration', 'Var', (170, 181))	('miR-101', 'Gene', (11, 18))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (216, 219))	('RCC', 'Disease', (41, 44))	('DONSON', 'Gene', (101, 107))	('resistance to Sunitinib treatment', 'MPA', (125, 158))	('downregulated', 'NegReg', (22, 35))
146115	33233657	Thus, even if a precise definition of which specific miRNAs impact on the NRF2-ARE signature in the different types of RCC is lacking, multiple lines of evidence suggest that they can play a crucial role in supporting NRF2 aberrant activation in cancer.	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Disease', (246, 252))	('impact', 'Reg', (60, 66))	('aberrant', 'Var', (223, 231))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('RCC', 'Disease', (119, 122))	('NRF2', 'Gene', (218, 222))
146123	33233657	On the other hand, despite the fact that amplification of KRAS was described in RCC, as reported for c-MYC, mutations in RAS and BRAF are extremely rare in kidney tumors (almost 1%).	('KRAS', 'Gene', (58, 62))	('KRAS', 'Gene', '3845', (58, 62))	('BRAF', 'Gene', (129, 133))	('mutations', 'Var', (108, 117))	('RCC', 'Disease', (80, 83))	('c-MYC', 'Gene', (101, 106))	('BRAF', 'Gene', '673', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('RAS', 'Gene', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('described', 'Reg', (67, 76))	('kidney tumors', 'Disease', (156, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('kidney tumors', 'Disease', 'MESH:D007680', (156, 169))	('c-MYC', 'Gene', '4609', (101, 106))	('kidney tumors', 'Phenotype', 'HP:0009726', (156, 169))
146124	33233657	While some studies outlined a different incidence of mutations among the RAS isoforms in RCC samples, with 0-16% of KRAS mutation and very rare events in NRAS and HRAS, others did not detect any mutation of KRAS, such as BRAF, neither in primary nor in metastatic ccRCC or PRCC.	('RCC', 'Disease', (274, 277))	('RCC', 'Disease', (266, 269))	('KRAS', 'Gene', (116, 120))	('NRAS', 'Gene', (154, 158))	('BRAF', 'Gene', '673', (221, 225))	('BRAF', 'Gene', (221, 225))	('RCC', 'Disease', 'MESH:C538614', (266, 269))	('HRAS', 'Gene', '3265', (163, 167))	('KRAS', 'Gene', '3845', (207, 211))	('RCC', 'Disease', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (274, 277))	('HRAS', 'Gene', (163, 167))	('mutation', 'Var', (121, 129))	('PRCC', 'Gene', (273, 277))	('KRAS', 'Gene', (207, 211))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('NRAS', 'Gene', '4893', (154, 158))	('PRCC', 'Gene', '5546', (273, 277))	('KRAS', 'Gene', '3845', (116, 120))
146142	33233657	Curiously, co-occurrence between mutations in PI3K/AKT and NRF2 pathways have been reported in different kind of tumors, and activation of PI3K was described to induce NRF2 accumulation and metabolic rewiring with the aim to support cell proliferation and protection from oxidative stress, suggesting a direct interaction among the two pathways.	('support', 'PosReg', (225, 232))	('tumors', 'Disease', (113, 119))	('cell proliferation', 'CPA', (233, 251))	('mutations', 'Var', (33, 42))	('PI3K', 'Var', (139, 143))	('NRF2', 'Gene', (59, 63))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('induce', 'PosReg', (161, 167))	('NRF2', 'Protein', (168, 172))	('cell proliferation', 'biological_process', 'GO:0008283', ('233', '251'))	('PI3K', 'molecular_function', 'GO:0016303', ('46', '50'))	('accumulation', 'PosReg', (173, 185))	('AKT', 'Gene', (51, 54))	('PI3K', 'molecular_function', 'GO:0016303', ('139', '143'))	('metabolic rewiring', 'CPA', (190, 208))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('oxidative stress', 'Phenotype', 'HP:0025464', (272, 288))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('AKT', 'Gene', '207', (51, 54))
146151	33233657	However, the role of NRF2 post-translational modification in promoting its nuclear accumulation and protumorigenic activity in RCC has been reported by different studies.	('NRF2', 'Gene', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('nuclear accumulation', 'CPA', (75, 95))	('tumor', 'Disease', (103, 108))	('post-translational modification', 'biological_process', 'GO:0043687', ('26', '57'))	('post-translational modification', 'Var', (26, 57))	('promoting', 'PosReg', (61, 70))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
146166	33233657	For example, it was demonstrated that the hyperactivation of mTORC1 and p62 triggers renal carcinogenesis in models of tuberous sclerosis characterized by inactivation of the tuberous sclerosis complex 2 (TSC2), but in this case it does not rely on the consequent hyperactivation of Nrf2.	('triggers', 'Reg', (76, 84))	('tuberous sclerosis complex 2', 'Gene', (175, 203))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (119, 137))	('renal carcinogenesis', 'Disease', (85, 105))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (175, 193))	('mTORC1', 'cellular_component', 'GO:0031931', ('61', '67'))	('TSC2', 'Gene', '7249', (205, 209))	('inactivation', 'Var', (155, 167))	('mTORC1', 'Gene', (61, 67))	('renal carcinogenesis', 'Disease', 'MESH:D063646', (85, 105))	('tuberous sclerosis complex 2', 'Gene', '7249', (175, 203))	('p62', 'Gene', '8878', (72, 75))	('TSC2', 'Gene', (205, 209))	('p62', 'Gene', (72, 75))	('tuberous sclerosis', 'Disease', (119, 137))	('mTORC1', 'Gene', '382056', (61, 67))	('hyperactivation', 'Var', (42, 57))	('tuberous sclerosis complex', 'cellular_component', 'GO:0033596', ('175', '201'))
146167	33233657	On the other hand, ccRCC features copy number gains on chromosome 5q, which contains the SQSTM1 gene, in 70% of the cases with consequent overexpression of p62.	('copy number gains', 'Var', (34, 51))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('SQSTM1', 'Gene', (89, 95))	('p62', 'Gene', '8878', (156, 159))	('p62', 'Gene', (156, 159))	('SQSTM1', 'Gene', '8878', (89, 95))	('RCC', 'Disease', (21, 24))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))
146181	33233657	Moreover, fumarate accumulation is involved in a process called succination, in which there is nucleophilic addition of fumarate on cysteine residues (Michael addition type reaction) forming adducts of S-2-succynil cysteine (2SC), that have been proposed as marker for HLRCC and PRCC type II featuring FH mutations that are not detected as changes in the protein levels.	('FH', 'Gene', '2271', (302, 304))	('S-2-succynil cysteine', 'Chemical', '-', (202, 223))	('cysteine', 'Chemical', 'MESH:D003545', (132, 140))	('PRCC', 'Gene', '5546', (279, 283))	('fumarate', 'Chemical', 'MESH:D005650', (120, 128))	('RCC', 'Disease', 'MESH:C538614', (280, 283))	('cysteine', 'Chemical', 'MESH:D003545', (215, 223))	('RCC', 'Disease', (280, 283))	('fumarate', 'Chemical', 'MESH:D005650', (10, 18))	('PRCC', 'Gene', (279, 283))	('mutations', 'Var', (305, 314))	('RCC', 'Disease', 'MESH:C538614', (271, 274))	('RCC', 'Disease', (271, 274))	('protein', 'cellular_component', 'GO:0003675', ('355', '362'))
146182	33233657	Through this mechanism, fumarate interacts with Cys151 and Cys288 in KEAP1, inducing the release of NRF2, which can translocate into the nucleus and support target genes production.	('Cys151', 'Var', (48, 54))	('NRF2', 'Gene', (100, 104))	('translocate', 'MPA', (116, 127))	('KEAP1', 'Gene', '9817', (69, 74))	('release', 'MPA', (89, 96))	('Cys151', 'Chemical', '-', (48, 54))	('Cys288', 'Var', (59, 65))	('KEAP1', 'Gene', (69, 74))	('inducing', 'Reg', (76, 84))	('Cys288', 'Chemical', '-', (59, 65))	('fumarate', 'Chemical', 'MESH:D005650', (24, 32))	('nucleus', 'cellular_component', 'GO:0005634', ('137', '144'))
146185	33233657	Indeed, our group described a new murine model of PRCC type II, in which mice feature slowly progressive transformation of cystic epithelium into carcinomas, in consequence of inactivation of a single gene Tsc1, and mTORC1 hyperactivation.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('mTORC1', 'cellular_component', 'GO:0031931', ('216', '222'))	('hyperactivation', 'PosReg', (223, 238))	('carcinomas', 'Disease', 'MESH:D009369', (146, 156))	('mice', 'Species', '10090', (73, 77))	('mTORC1', 'Gene', '382056', (216, 222))	('murine', 'Species', '10090', (34, 40))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('carcinomas', 'Disease', (146, 156))	('Tsc1', 'Gene', (206, 210))	('PRCC', 'Gene', '5546', (50, 54))	('inactivation', 'Var', (176, 188))	('mTORC1', 'Gene', (216, 222))	('Tsc1', 'Gene', '64930', (206, 210))	('PRCC', 'Gene', (50, 54))
146192	33233657	What is particularly interestingly is that modulation of the concentration of DMF can differentially regulate the activation of NRF2 signaling.	('NRF2 signaling', 'Pathway', (128, 142))	('DMF', 'Chemical', 'MESH:D000069462', (78, 81))	('signaling', 'biological_process', 'GO:0023052', ('133', '142'))	('DMF', 'Var', (78, 81))	('activation', 'MPA', (114, 124))	('regulate', 'Reg', (101, 109))
146193	33233657	have reported that low doses of DMF in cancer cells promote activation of NRF2 antioxidant pathway, impairing KEAP1 binding and resulting in cytoprotective effects and tumor progression.	('DMF', 'Var', (32, 35))	('binding', 'molecular_function', 'GO:0005488', ('116', '123'))	('cytoprotective effects', 'CPA', (141, 163))	('tumor', 'Disease', (168, 173))	('cancer', 'Disease', (39, 45))	('impairing', 'NegReg', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('KEAP1', 'Gene', '9817', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('activation', 'PosReg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('DMF', 'Chemical', 'MESH:D000069462', (32, 35))	('KEAP1', 'Gene', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('NRF2 antioxidant pathway', 'Pathway', (74, 98))
146194	33233657	On the other hand, high doses of DMF not only result in succination of KEAP1, but also DJ-1, an NRF2 binding protein encoded by the PARK7 gene and necessary for NRF2 nuclear translocation.	('PARK7', 'Gene', '11315', (132, 137))	('result', 'Reg', (46, 52))	('KEAP1', 'Gene', (71, 76))	('DMF', 'Var', (33, 36))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('succination', 'MPA', (56, 67))	('PARK7', 'Gene', (132, 137))	('KEAP1', 'Gene', '9817', (71, 76))	('DJ-1', 'Gene', (87, 91))	('DJ-1', 'Gene', '11315', (87, 91))	('binding', 'molecular_function', 'GO:0005488', ('101', '108'))	('DMF', 'Chemical', 'MESH:D000069462', (33, 36))
146195	33233657	This modification on Cys106 accounts for a reduction of nuclear NRF2 and consequent tumor cell sensitization to cell death.	('Cys106', 'Chemical', '-', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('nuclear NRF2', 'Protein', (56, 68))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('reduction', 'NegReg', (43, 52))	('tumor', 'Disease', (84, 89))	('death', 'Disease', 'MESH:D003643', (117, 122))	('sensitization', 'biological_process', 'GO:0046960', ('95', '108'))	('death', 'Disease', (117, 122))	('cell death', 'biological_process', 'GO:0008219', ('112', '122'))	('Cys106', 'Var', (21, 27))
146196	33233657	This effect is not evident in normal cells, where the expression of DJ-1 is very low, while it is further exacerbated in KRAS mutated cells, as some kind of RCC.	('expression', 'MPA', (54, 64))	('low', 'NegReg', (81, 84))	('KRAS', 'Gene', (121, 125))	('DJ-1', 'Gene', (68, 72))	('DJ-1', 'Gene', '11315', (68, 72))	('KRAS', 'Gene', '3845', (121, 125))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', (157, 160))	('exacerbated', 'PosReg', (106, 117))	('mutated', 'Var', (126, 133))
146203	33233657	In a first stage, the inability to produce fumarate near the nucleus impairs DNA damage repair and accounts for accumulation of mutations, then the proliferation of FH deficient cells leads to accumulation of fumarate that supports tumor progression.	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('DNA damage repair', 'MPA', (77, 94))	('nucleus', 'cellular_component', 'GO:0005634', ('61', '68'))	('fumarate', 'Chemical', 'MESH:D005650', (43, 51))	('mutations', 'Var', (128, 137))	('FH deficient', 'Disease', 'MESH:D006938', (165, 177))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('FH deficient', 'Disease', (165, 177))	('fumarate', 'Chemical', 'MESH:D005650', (209, 217))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('fumarate', 'MPA', (209, 217))	('supports', 'PosReg', (223, 231))	('accumulation', 'PosReg', (193, 205))	('impairs', 'NegReg', (69, 76))	('tumor', 'Disease', (232, 237))
146207	33233657	As previously reported, ccRCC features mutations mainly in VHL/HIF and PI3K/AKT/mTOR pathways, thus the currently approved therapeutical approaches involve VEGF or mTOR inhibitors (such as Tensirolimus or Everolimus), for advanced RCC.	('VHL', 'Gene', '7428', (59, 62))	('AKT', 'Gene', '207', (76, 79))	('RCC', 'Disease', (231, 234))	('VEGF', 'Gene', (156, 160))	('Tensirolimus', 'Chemical', '-', (189, 201))	('RCC', 'Disease', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (231, 234))	('AKT', 'Gene', (76, 79))	('mutations', 'Var', (39, 48))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('Everolimus', 'Chemical', 'MESH:D000068338', (205, 215))	('VEGF', 'Gene', '7422', (156, 160))	('VHL', 'Gene', (59, 62))	('PI3K', 'molecular_function', 'GO:0016303', ('71', '75'))
146209	33233657	On the other hand, PRCC is mainly characterized by mutations in the MET gene or loss of the FH gene that characterize type I and type II, respectively.	('MET', 'Gene', (68, 71))	('mutations', 'Var', (51, 60))	('loss', 'NegReg', (80, 84))	('PRCC', 'Gene', '5546', (19, 23))	('FH', 'Gene', '2271', (92, 94))	('PRCC', 'Gene', (19, 23))	('MET', 'Gene', '79811', (68, 71))
146211	33233657	Alterations in NRF2 signature are one of the targets initially related to PRCC type II, but that is becoming a common feature among the principal RCC types.	('PRCC', 'Gene', (74, 78))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('Alterations', 'Var', (0, 11))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('NRF2', 'Gene', (15, 19))	('PRCC', 'Gene', '5546', (74, 78))
146216	33233657	Thus, understanding the different pathways and players that cooperate in sustaining the aberrant activation of NRF2 in cancers such as RCC represents a good opportunity to identify indirect targeted strategies.	('activation', 'PosReg', (97, 107))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('RCC', 'Disease', (135, 138))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('NRF2', 'Gene', (111, 115))	('cancers', 'Disease', (119, 126))	('aberrant', 'Var', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
146227	33233657	Interestingly, dimethyl fumarate, which is approved by FDA as an NRF2 activator, displays some anticancer activities, and indeed at high concentrations it appears to behave as a NRF2 inhibitor.	('dimethyl', 'Var', (15, 23))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('dimethyl fumarate', 'Chemical', 'MESH:D000069462', (15, 32))
146232	33233657	This study supports the idea that a combinatory targeted therapy, modulating NRF2-ARE signature directly or indirectly, can be a promising opportunity for the treatment of RCCs featuring NRF2 hyperactivation.	('modulating', 'Var', (66, 76))	('NRF2', 'Gene', (187, 191))	('hyperactivation', 'Var', (192, 207))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('RCC', 'Disease', (172, 175))	('NRF2-ARE', 'Gene', (77, 85))
146251	31880322	Clear cell RCC (ccRCC) represents about 70% of all cases 9 and is characterized by inactivating mutations in the von Hippel-Lindau gene (VHL) 10, 11.	('von Hippel-Lindau gene', 'Gene', (113, 135))	('RCC', 'Disease', (18, 21))	('inactivating mutations', 'Var', (83, 105))	('RCC', 'Phenotype', 'HP:0005584', (18, 21))	('von Hippel-Lindau gene', 'Gene', '7428', (113, 135))	('VHL', 'Gene', (137, 140))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('VHL', 'Gene', '7428', (137, 140))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (18, 21))
146253	31880322	In tumors with VHL mutations, HIF is constitutively stable, promoting the expression of a wide range of genes.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('VHL', 'Gene', (15, 18))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('mutations', 'Var', (19, 28))	('VHL', 'Gene', '7428', (15, 18))	('IF', 'Chemical', '-', (31, 33))	('promoting', 'PosReg', (60, 69))	('expression of a wide range of genes', 'MPA', (74, 109))
146260	31880322	We recently demonstrated that VEGFR2/NRP1 complexes are formed in human pancreatic ductal adenocarcinoma, and the presence of VEGFR2/NRP1 trans complexes was identified as an independent marker of improved overall survival 22.	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (72, 104))	('overall', 'MPA', (206, 213))	('VEGFR2/NRP1', 'Gene', (126, 137))	('presence', 'Var', (114, 122))	('NRP', 'biological_process', 'GO:0085015', ('133', '136'))	('NRP', 'biological_process', 'GO:0085015', ('37', '40'))	('human', 'Species', '9606', (66, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('improved', 'PosReg', (197, 205))	('pancreatic ductal adenocarcinoma', 'Disease', (72, 104))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (72, 104))
146314	31880322	We have shown recently that the presence of VEGFR2/NRP1 trans complexes correlates with altered vessel parameters, including reduced total vessel area and vessel size in pancreatic adenocarcinoma (PDAC) 22.	('total vessel area', 'MPA', (133, 150))	('NRP', 'biological_process', 'GO:0085015', ('51', '54'))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('PDAC', 'Phenotype', 'HP:0006725', (197, 201))	('presence', 'Var', (32, 40))	('reduced', 'NegReg', (125, 132))	('vessel size', 'CPA', (155, 166))	('vessel parameters', 'MPA', (96, 113))	('pancreatic adenocarcinoma', 'Disease', (170, 195))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (170, 195))	('altered', 'Reg', (88, 95))	('VEGFR2/NRP1', 'Gene', (44, 55))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (170, 195))
146316	31880322	In concordance with results from the previous study, vessel area and size were significantly smaller in RCC samples that were positive for VEGFR2/NRP1 complexes in trans, as compared to samples lacking trans complexes (Figure 2A).	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('complexes', 'Var', (151, 160))	('positive', 'Reg', (126, 134))	('NRP', 'biological_process', 'GO:0085015', ('146', '149'))	('VEGFR2/NRP1', 'Gene', (139, 150))	('smaller', 'NegReg', (93, 100))	('RCC', 'Disease', (104, 107))
146318	31880322	There was a significant association between the presence of trans complexes and NRP1 expression in perivascular tumor cells (p-value = 0.004), and between trans complexes and general NRP1 expression in tumor cells (p-value = 0.036).	('expression', 'MPA', (85, 95))	('trans complexes', 'Var', (60, 75))	('presence', 'Var', (48, 56))	('tumor', 'Disease', (202, 207))	('expression', 'MPA', (188, 198))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('NRP', 'biological_process', 'GO:0085015', ('183', '186'))	('NRP', 'biological_process', 'GO:0085015', ('80', '83'))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('trans complexes', 'Var', (155, 170))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('NRP1', 'Gene', (80, 84))	('NRP1', 'Protein', (183, 187))
146321	31880322	Moreover, samples with VEGFR2/NRP1 trans complexes, detected by PLA, or alternatively, NRP1 expression on perivascular or tumor cells, detected by IF staining, exhibited decreased overall vessel area and reduced vessel size.	('NRP', 'biological_process', 'GO:0085015', ('30', '33'))	('vessel size', 'CPA', (212, 223))	('NRP', 'biological_process', 'GO:0085015', ('87', '90'))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('vessel area', 'CPA', (188, 199))	('reduced', 'NegReg', (204, 211))	('IF', 'Chemical', '-', (147, 149))	('decreased', 'NegReg', (170, 179))	('NRP1', 'Gene', (87, 91))	('VEGFR2/NRP1', 'Gene', (23, 34))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('trans complexes', 'Var', (35, 50))	('tumor', 'Disease', (122, 127))
146332	31880322	Kaplan-Meier analysis demonstrated significantly improved overall survival for patients with high NRP1 transcript levels (Figure 3C, Log rank test, p-value <0.001).	('overall survival', 'MPA', (58, 74))	('improved', 'PosReg', (49, 57))	('NRP1', 'Gene', (98, 102))	('patients', 'Species', '9606', (79, 87))	('NRP', 'biological_process', 'GO:0085015', ('98', '101'))	('high', 'Var', (93, 97))	('transcript levels', 'MPA', (103, 120))
146335	31880322	This observation of worse overall survival for patients with NRP1 expression in the tumor vessels is supported by previous findings that VEGFR2/NRP1 cis-complexes promote tumor angiogenesis in mouse models 21.	('NRP', 'biological_process', 'GO:0085015', ('144', '147'))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('NRP1', 'Gene', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('patients', 'Species', '9606', (47, 55))	('angiogenesis', 'biological_process', 'GO:0001525', ('177', '189'))	('NRP', 'biological_process', 'GO:0085015', ('61', '64'))	('tumor', 'Disease', (84, 89))	('expression', 'Var', (66, 76))	('tumor', 'Disease', (171, 176))	('mouse', 'Species', '10090', (193, 198))	('promote', 'PosReg', (163, 170))
146337	31880322	These results indicate that the negative effect of the VEGFR2/NRP1 trans configuration dominates the positive cis effects in regulating angiogenesis, in congruence with mechanistic data from murine tumor models 21.	('murine', 'Species', '10090', (191, 197))	('VEGFR2/NRP1', 'Gene', (55, 66))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('angiogenesis', 'biological_process', 'GO:0001525', ('136', '148'))	('NRP', 'biological_process', 'GO:0085015', ('62', '65'))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('trans', 'Var', (67, 72))
146342	31880322	In addition, for the validation cohort, there was decreased risk of cancer-related death with NRP1 expression in tumor cells (HR = 0.3, 95% CI = 0.2-0.5, p-value <0.001) and perivascular NRP1 (HR = 0.3, 95% CI = 0.2-0.4, p-value <0.001).	('tumor', 'Disease', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('NRP', 'biological_process', 'GO:0085015', ('94', '97'))	('NRP', 'biological_process', 'GO:0085015', ('187', '190'))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('expression', 'Var', (99, 109))	('decreased', 'NegReg', (50, 59))	('death', 'Disease', 'MESH:D003643', (83, 88))	('death', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('cancer', 'Disease', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('NRP1', 'Gene', (94, 98))
146358	31880322	Patients with tumors that were positive for perivascular NRP1 expression in the validation cohort and high levels of NRP1 mRNA in KIRC showed reduced metastatic spread.	('NRP', 'biological_process', 'GO:0085015', ('117', '120'))	('NRP1', 'Gene', (57, 61))	('reduced', 'NegReg', (142, 149))	('high', 'Var', (102, 106))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('metastatic spread', 'CPA', (150, 167))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('NRP1', 'Gene', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('NRP', 'biological_process', 'GO:0085015', ('57', '60'))
146366	27583351	Analysis of various potential prognostic markers and survival data in clear cell renal cell carcinoma Clear cell renal cell cancers frequently harbor Von Hippel-Lindau gene mutations, leading to stabilization of the hypoxia-inducible factors (HIFs) and their target genes.	('carcinoma', 'Disease', 'MESH:D002277', (92, 101))	('hypoxia', 'Disease', (216, 223))	('harbor', 'Reg', (143, 149))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (70, 101))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (81, 101))	('Clear cell renal cell cancers', 'Disease', 'MESH:C538614', (102, 131))	('hypoxia', 'Disease', 'MESH:D000860', (216, 223))	('clear cell renal cell carcinoma', 'Disease', (70, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('mutations', 'Var', (173, 182))	('stabilization', 'MPA', (195, 208))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (81, 101))	('carcinoma', 'Disease', (92, 101))	('cancer', 'Disease', (124, 130))	('Clear cell renal cell cancers', 'Disease', (102, 131))	('Von Hippel-Lindau', 'Gene', '7428', (150, 167))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (70, 101))	('Von Hippel-Lindau', 'Gene', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))
146370	27583351	Patients with high expression of VEGF, HIF-1alpha and HIF-2alpha positivity, a high Ki-67 proliferation index, and a high microvessel density evaluation score had a shorter survival time (p<0.05).	('shorter', 'NegReg', (165, 172))	('VEGF', 'Protein', (33, 37))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('HIF-2alpha', 'Gene', (54, 64))	('HIF-1alpha', 'Gene', (39, 49))	('survival time', 'CPA', (173, 186))
146374	27583351	Sporadic ccRCC is caused by Von Hippel-Lindau (VHL) tumor suppressor gene mutations located on chromosome 3p in up to 90% of cases.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (28, 57))	('caused', 'Reg', (18, 24))	('mutations', 'Var', (74, 83))	('chromosome', 'cellular_component', 'GO:0005694', ('95', '105'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('52', '68'))	('VHL', 'Gene', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('VHL', 'Gene', '7428', (47, 50))	('ccRCC', 'Disease', (9, 14))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('52', '68'))
146385	27583351	We observed that VEGF and HIF-1alpha proteins that play an important role in tumor angiogenesis, p53 gene mutation related to apoptosis, the Ki-67 proliferation index, prognostic properties of the tumor (FNG, stage, SD) related to each other or independently affect patient's survival may lead to poor prognosis.	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('p53', 'Gene', (97, 100))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('HIF-1alpha proteins', 'Disease', (26, 45))	('mutation', 'Var', (106, 114))	('affect', 'Reg', (259, 265))	('angiogenesis', 'biological_process', 'GO:0001525', ('83', '95'))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('HIF-1alpha proteins', 'Disease', 'MESH:D011488', (26, 45))	('lead to', 'Reg', (289, 296))
146388	27583351	According to their study on RCC tumors, with VHL mutations, while the HIF-2alpha level is high, HIF-1alpha is not.	('HIF-2alpha level', 'MPA', (70, 86))	('mutations', 'Var', (49, 58))	('RCC tumors', 'Disease', 'MESH:C538614', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('RCC tumors', 'Disease', (28, 38))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('VHL', 'Gene', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (28, 31))
146390	27583351	Raval et al., in a study of the effects of HIF subgroups in VHL-related RCC, emphasized that HIF-2alpha has a tumor-growing effect and HIF1-alpha stops tumor growth.	('HIF-2alpha', 'Var', (93, 103))	('HIF1-alpha', 'Gene', (135, 145))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('HIF1-alpha', 'Gene', '3091', (135, 145))	('VHL-related', 'Gene', (60, 71))	('tumor-growing effect', 'CPA', (110, 130))	('tumor growth', 'CPA', (152, 164))
146391	27583351	Some studies have shown that staining patterns differ between tumors and non-tumor tissues or in VHL mutant or non-mutant samples.	('non-tumor', 'Disease', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('non-tumor', 'Disease', 'MESH:D009369', (73, 82))	('mutant', 'Var', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('differ', 'Reg', (47, 53))	('VHL', 'Gene', (97, 100))
146404	33207686	A high expression of FAP and low levels sFAP are significantly associated with high tumour diameter, high grade, and high pT stage, lymph node invasion, development of early metastases, and worse 5-year cancer specific survival of CCRCC patients.	('high grade', 'CPA', (101, 111))	('high pT stage', 'CPA', (117, 130))	('FAP', 'Gene', '2191', (21, 24))	('FAP', 'Gene', (41, 44))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('RCC', 'Phenotype', 'HP:0005584', (233, 236))	('patients', 'Species', '9606', (237, 245))	('RCC', 'Disease', (233, 236))	('associated', 'Reg', (63, 73))	('RCC', 'Disease', 'MESH:C538614', (233, 236))	('low levels', 'Var', (29, 39))	('metastases', 'Disease', 'MESH:D009362', (174, 184))	('FAP', 'Gene', '2191', (41, 44))	('cancer', 'Disease', (203, 209))	('FAP', 'Gene', (21, 24))	('metastases', 'Disease', (174, 184))	('CCRCC', 'Phenotype', 'HP:0006770', (231, 236))	('high tumour', 'Disease', 'MESH:D009369', (79, 90))	('high tumour', 'Disease', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('lymph node invasion', 'CPA', (132, 151))	('worse', 'NegReg', (190, 195))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))
146416	33207686	The identification of alterations that may influence this unpredictable tumour behaviour and clinical outcome both in primary tumour tissues and in liquid biopsies is needed to improve the management of these patients.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('influence', 'Reg', (43, 52))	('behaviour', 'biological_process', 'GO:0007610', ('79', '88'))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (126, 132))	('alterations', 'Var', (22, 33))	('patients', 'Species', '9606', (209, 217))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))
146422	33207686	Regarding renal cancer, in vitro studies have demonstrated that the crosstalk communication between CAFs and tumour cells induces pro-invasive properties in RCC cell lines.	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('renal cancer', 'Disease', (10, 22))	('induces', 'Reg', (122, 129))	('renal cancer', 'Phenotype', 'HP:0009726', (10, 22))	('tumour', 'Disease', (109, 115))	('pro-invasive properties', 'CPA', (130, 153))	('CAF', 'Gene', (100, 103))	('renal cancer', 'Disease', 'MESH:D007680', (10, 22))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('crosstalk', 'Var', (68, 77))	('RCC', 'Disease', (157, 160))	('CAF', 'Gene', '8850', (100, 103))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
146499	33207686	We validated previous results in a new series of CCRCCs, and the association between FAP positivity and worse prognosis was confirmed, regardless of the area of the tumour in which the protein was expressed.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('positivity', 'Var', (89, 99))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('FAP', 'Gene', (85, 88))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('FAP', 'Gene', '2191', (85, 88))	('tumour', 'Disease', (165, 171))	('CCRCC', 'Phenotype', 'HP:0006770', (49, 54))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
146532	33207686	Some of these stromal targets are being evaluated in pancreatic cancer, either by depleting CAFs using CAF-related cell-surface markers, such as alpha-SMA or FAP, reprogramming CAFs into quiescent fibroblasts, or targeting interactions between CAFs and their surrounding microenvironment.	('CAF', 'Gene', '8850', (244, 247))	('CAF', 'Gene', '8850', (92, 95))	('CAF', 'Gene', (244, 247))	('pancreatic cancer', 'Disease', 'MESH:D010190', (53, 70))	('CAF', 'Gene', (92, 95))	('CAF', 'Gene', '8850', (177, 180))	('FAP', 'Gene', (158, 161))	('depleting', 'NegReg', (82, 91))	('pancreatic cancer', 'Disease', (53, 70))	('CAF', 'Gene', (177, 180))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('alpha-SMA', 'Gene', (145, 154))	('interactions', 'Interaction', (223, 235))	('cell-surface', 'cellular_component', 'GO:0009986', ('115', '127'))	('alpha-SMA', 'Gene', '58', (145, 154))	('FAP', 'Gene', '2191', (158, 161))	('CAF', 'Gene', '8850', (103, 106))	('reprogramming', 'Var', (163, 176))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (53, 70))	('targeting', 'Reg', (213, 222))	('CAF', 'Gene', (103, 106))
146564	33207686	At the infiltrating front of these non-organ-confined tumours, FAP positive cases almost duplicated the expression of pT1 tumours, although it did not reach statistical significance, and pT2 tumours had higher FAP expression than pT1 ones.	('tumours', 'Disease', (122, 129))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('FAP', 'Gene', '2191', (210, 213))	('tumours', 'Disease', (191, 198))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('higher', 'PosReg', (203, 209))	('tumours', 'Disease', 'MESH:D009369', (122, 129))	('tumours', 'Phenotype', 'HP:0002664', (191, 198))	('FAP', 'Gene', (63, 66))	('tumours', 'Disease', 'MESH:D009369', (191, 198))	('tumours', 'Disease', (54, 61))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('pT1', 'Gene', '58492', (230, 233))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('pT1', 'Gene', '58492', (118, 121))	('pT1', 'Gene', (230, 233))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('FAP', 'Gene', '2191', (63, 66))	('pT1', 'Gene', (118, 121))	('FAP', 'Gene', (210, 213))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('pT2', 'Var', (187, 190))
146755	27621699	However, loss of VHL function alone is not sufficient for ccRCC initiation, and a higher number of genetic or epigenetic events are required.	('RCC', 'Disease', (60, 63))	('loss', 'Var', (9, 13))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('VHL', 'Gene', (17, 20))	('VHL', 'Gene', '7428', (17, 20))
146787	27621699	A more recent study investigated genetic alterations of 20 representative PI3K/AKT pathway components in ccRCC, such as PIK3CA amplifications or mutations (5%), PTEN deletions or mutations (5%), or mTOR mutations (6%), reiterating the critical role of the PI3K/AKT pathway in this cancer.	('PI3K/AKT', 'Gene', '5290;207', (256, 264))	('mutations', 'Var', (145, 154))	('PIK3CA', 'Gene', '5290', (120, 126))	('RCC', 'Disease', (107, 110))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('PTEN', 'Gene', (161, 165))	('PIK3CA', 'Gene', (120, 126))	('PI3K/AKT', 'Gene', (74, 82))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('PI3K', 'molecular_function', 'GO:0016303', ('256', '260'))	('mTOR', 'Gene', (198, 202))	('mutations', 'Var', (179, 188))	('PI3K', 'molecular_function', 'GO:0016303', ('74', '78'))	('mutations', 'Var', (203, 212))	('PTEN', 'Gene', '5728', (161, 165))	('deletions', 'Var', (166, 175))	('PI3K/AKT', 'Gene', '5290;207', (74, 82))	('cancer', 'Disease', (281, 287))	('PI3K/AKT', 'Gene', (256, 264))	('mTOR', 'Gene', '2475', (198, 202))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))
146790	27621699	Mutations in FH, associated with type 2 pRCC, result in the accumulation of fumarate, which leads to the upregulation of HIF-1alpha and activation of mTOR pathway through the mechanism described earlier.	('mTOR', 'Gene', '2475', (150, 154))	('fumarate', 'MPA', (76, 84))	('HIF-1alpha', 'Gene', (121, 131))	('upregulation', 'PosReg', (105, 117))	('pRCC', 'Gene', '5546', (40, 44))	('Mutations', 'Var', (0, 9))	('activation', 'PosReg', (136, 146))	('HIF-1alpha', 'Gene', '3091', (121, 131))	('fumarate', 'Chemical', 'MESH:D005650', (76, 84))	('accumulation', 'PosReg', (60, 72))	('mTOR', 'Gene', (150, 154))	('pRCC', 'Gene', (40, 44))
146799	27621699	The disruption of p-S6K1 and 4EBP1 function, the two main downstream effectors of mTORC1, interferes with mRNA translation of genes involved in cell cycle regulation and cellular response to hypoxia.	('cell cycle', 'CPA', (144, 154))	('p-S6K1', 'Gene', '6198', (18, 24))	('mTORC1', 'Gene', '382056', (82, 88))	('4EBP1', 'Gene', '1978', (29, 34))	('translation', 'biological_process', 'GO:0006412', ('111', '122'))	('interferes', 'NegReg', (90, 100))	('mTORC1', 'cellular_component', 'GO:0031931', ('82', '88'))	('mTORC1', 'Gene', (82, 88))	('4EBP1', 'Gene', (29, 34))	('mRNA translation of genes', 'MPA', (106, 131))	('hypoxia', 'Disease', 'MESH:D000860', (191, 198))	('cellular response to hypoxia', 'biological_process', 'GO:0071456', ('170', '198'))	('disruption', 'Var', (4, 14))	('p-S6K1', 'Gene', (18, 24))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('144', '165'))	('hypoxia', 'Disease', (191, 198))
146862	27621699	The rationale of associating two different agents in the treatment of RCC results from the notion that blocking the VEGF pathway can lead to hypoxia, and inhibiting the mTOR response to hypoxia may block the cellular response to the hypoxic stress.	('VEGF', 'Gene', '7422', (116, 120))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('hypoxia', 'Disease', (186, 193))	('RCC', 'Disease', (70, 73))	('inhibiting', 'NegReg', (154, 164))	('hypoxia', 'Disease', 'MESH:D000860', (186, 193))	('response to hypoxia', 'biological_process', 'GO:0001666', ('174', '193'))	('lead to', 'Reg', (133, 140))	('mTOR', 'Gene', '2475', (169, 173))	('cellular response', 'CPA', (208, 225))	('mTOR', 'Gene', (169, 173))	('hypoxia', 'Disease', 'MESH:D000860', (141, 148))	('blocking', 'Var', (103, 111))	('VEGF', 'Gene', (116, 120))	('block', 'NegReg', (198, 203))	('hypoxic stress', 'Disease', 'MESH:D004194', (233, 247))	('hypoxia', 'Disease', (141, 148))	('hypoxic stress', 'Disease', (233, 247))
146871	27621699	One hundred and fifty-three enrolled patients progressive to first-line VEGFR-TKI were randomly assigned to receive lenvatinib plus everolimus, single-agent lenvatinib, or single-agent everolimus.	('patients', 'Species', '9606', (37, 45))	('lenvatinib', 'Var', (116, 126))	('lenvatinib', 'Chemical', 'MESH:C531958', (116, 126))	('everolimus', 'Chemical', 'MESH:D000068338', (132, 142))	('VEGFR', 'Gene', '3791', (72, 77))	('lenvatinib', 'Chemical', 'MESH:C531958', (157, 167))	('everolimus', 'Chemical', 'MESH:D000068338', (185, 195))	('VEGFR', 'Gene', (72, 77))
146884	27621699	In support to this hypothesis, a large Phase III trial explored the efficacy of temsirolimus, an mTOR inhibitor, in 626 patients with previously untreated poor-prognosis mRCC: in this study, temsirolimus showed a better outcome compared to IFN in patients with non-clear cell histotype (n=73).	('mTOR', 'Gene', '2475', (97, 101))	('mTOR', 'Gene', (97, 101))	('temsirolimus', 'Chemical', 'MESH:C401859', (191, 203))	('temsirolimus', 'Chemical', 'MESH:C401859', (80, 92))	('IFN', 'Gene', '3439', (240, 243))	('patients', 'Species', '9606', (247, 255))	('patients', 'Species', '9606', (120, 128))	('temsirolimus', 'Var', (191, 203))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('RCC', 'Disease', (171, 174))	('IFN', 'Gene', (240, 243))
146890	27621699	Interestingly, patients with chromophobe histology tended to have longer PFS than those with other nccRCC subtypes (13.1 vs 3.4 months, P=0.084).	('patients', 'Species', '9606', (15, 23))	('chromophobe histology', 'Var', (29, 50))	('PFS', 'MPA', (73, 76))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('longer', 'PosReg', (66, 72))
146891	27621699	In a post hoc subgroup analysis of metastatic nccRCC patients (n=66) enrolled in the RECORD-3 trial, mPFS was shorter for patients treated with everolimus compared to those treated with sunitinib in first-line setting (5.1 vs 7.2 months; HR 1.5, 95% CI 0.9-2.8).	('RCC', 'Disease', (49, 52))	('patients', 'Species', '9606', (53, 61))	('everolimus', 'Var', (144, 154))	('shorter', 'NegReg', (110, 117))	('sunitinib', 'Chemical', 'MESH:D000077210', (186, 195))	('patients', 'Species', '9606', (122, 130))	('mPFS', 'MPA', (101, 105))	('everolimus', 'Chemical', 'MESH:D000068338', (144, 154))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
146910	27621699	After TKI failure in Chinese RCC patients, a Phase Ib trial of everolimus explored the expression of p-AKT, p-mTOR, p-4EBP1, and p-S6RP by immunohistochemistry in paraffin-embedded tumor tissue specimens derived from 18 RCC patients.	('mTOR', 'Gene', (110, 114))	('AKT', 'Gene', '207', (103, 106))	('mTOR', 'Gene', '2475', (110, 114))	('tumor', 'Disease', (181, 186))	('patients', 'Species', '9606', (33, 41))	('4EBP1', 'Gene', '1978', (118, 123))	('everolimus', 'Chemical', 'MESH:D000068338', (63, 73))	('p-S6RP', 'Var', (129, 135))	('RCC', 'Disease', (29, 32))	('AKT', 'Gene', (103, 106))	('paraffin', 'Chemical', 'MESH:D010232', (163, 171))	('4EBP1', 'Gene', (118, 123))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('patients', 'Species', '9606', (224, 232))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('RCC', 'Disease', (220, 223))
146911	27621699	In this study, patients with the expression of p-mTOR or p-S6RP on the primary tumor had longer mPFS compared to patients with no expression (11.3 vs 3.7 months for p-mTOR, P=0.001; 11.3 vs 3.7 months for p-S6RP, P=0.002); co-expression of these two targets with p-4EBP1 was also associated with a longer PFS.	('PFS', 'CPA', (305, 308))	('mTOR', 'Gene', (49, 53))	('patients', 'Species', '9606', (15, 23))	('mTOR', 'Gene', '2475', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('4EBP1', 'Gene', (265, 270))	('patients', 'Species', '9606', (113, 121))	('longer', 'PosReg', (89, 95))	('mTOR', 'Gene', '2475', (167, 171))	('4EBP1', 'Gene', '1978', (265, 270))	('mTOR', 'Gene', (167, 171))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('p-S6RP', 'Var', (57, 63))
146912	27621699	Moreover, none of the patients without expression of p-mTOR or p-S6RP experienced benefits with everolimus.	('everolimus', 'Chemical', 'MESH:D000068338', (96, 106))	('mTOR', 'Gene', (55, 59))	('mTOR', 'Gene', '2475', (55, 59))	('patients', 'Species', '9606', (22, 30))	('benefits', 'PosReg', (82, 90))	('p-S6RP', 'Var', (63, 69))
146913	27621699	According to the results of this study, it could be supposed that expression status of p-mTOR and p-S6RP (that could imply a hyperactivation of mTOR pathway) may be applied as a potential predictive biomarker for everolimus efficacy in patients with mRCC, and a potential indicator for selection of patients.	('mTOR', 'Gene', '2475', (89, 93))	('hyperactivation', 'PosReg', (125, 140))	('RCC', 'Disease', 'MESH:C538614', (251, 254))	('p-S6RP', 'Var', (98, 104))	('patients', 'Species', '9606', (236, 244))	('patients', 'Species', '9606', (299, 307))	('RCC', 'Disease', (251, 254))	('everolimus', 'Chemical', 'MESH:D000068338', (213, 223))	('mTOR', 'Gene', (144, 148))	('mTOR', 'Gene', '2475', (144, 148))	('mTOR', 'Gene', (89, 93))
146914	27621699	However, these data may have been confounded by a bias, since the detection of p-mTOR and p-S6RP has been assessed on tissue available after nephrectomy at baseline, before TKI treatment, and not just before everolimus therapy.	('mTOR', 'Gene', (81, 85))	('mTOR', 'Gene', '2475', (81, 85))	('everolimus', 'Chemical', 'MESH:D000068338', (208, 218))	('p-S6RP', 'Var', (90, 96))
146915	27621699	A more recent study by Knoll et al explored the role of p-S6RP, the major mediator of antitumoral effects exerted by everolimus, in vitro and in a novel ex vivo tissue slice model using fresh vital human RCC tissue, and then incubating the tissue with everolimus.	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('RCC', 'Disease', (204, 207))	('tumor', 'Disease', (90, 95))	('everolimus', 'Chemical', 'MESH:D000068338', (252, 262))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('human', 'Species', '9606', (198, 203))	('p-S6RP', 'Var', (56, 62))	('everolimus', 'Chemical', 'MESH:D000068338', (117, 127))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
146919	27621699	Until now, there is no prospectively validated predictive biomarker to monitor everolimus response or to apply a useful selection of patient candidate to mTOR inhibition; S6RP, a main downstream effector of the cascade, and its phosphorylated form p-S6RP are promising for this role, but their clinical use should be further validated.	('patient', 'Species', '9606', (133, 140))	('S6RP', 'Var', (171, 175))	('mTOR', 'Gene', (154, 158))	('mTOR', 'Gene', '2475', (154, 158))	('everolimus', 'Chemical', 'MESH:D000068338', (79, 89))
146929	27621699	mTOR pathway has been implicated in insulin resistance: mTOR inhibitors are known to be associated with hyperglycemia because of their effects on inhibition of glucose uptake and insulin synthesis.	('insulin', 'Gene', (36, 43))	('insulin resistance', 'Phenotype', 'HP:0000855', (36, 54))	('hyperglycemia', 'Phenotype', 'HP:0003074', (104, 117))	('insulin', 'Gene', (179, 186))	('mTOR', 'Gene', (0, 4))	('mTOR', 'Gene', (56, 60))	('inhibitors', 'Var', (61, 71))	('glucose uptake', 'biological_process', 'GO:0046323', ('160', '174'))	('mTOR', 'Gene', '2475', (0, 4))	('hyperglycemia', 'Disease', (104, 117))	('mTOR', 'Gene', '2475', (56, 60))	('inhibition', 'NegReg', (146, 156))	('glucose uptake', 'MPA', (160, 174))	('insulin', 'Gene', '3630', (36, 43))	('glucose', 'Chemical', 'MESH:D005947', (160, 167))	('insulin synthesis', 'biological_process', 'GO:1901144', ('179', '196'))	('insulin', 'molecular_function', 'GO:0016088', ('179', '186'))	('hyperglycemia', 'Disease', 'MESH:D006943', (104, 117))	('associated', 'Reg', (88, 98))	('insulin', 'molecular_function', 'GO:0016088', ('36', '43'))	('insulin', 'Gene', '3630', (179, 186))
146930	27621699	Moreover, inhibition of mTOR interferes with cell metabolism, leading to dyslipidemia.	('dyslipidemia', 'Disease', (73, 85))	('cell metabolism', 'MPA', (45, 60))	('interferes', 'NegReg', (29, 39))	('dyslipidemia', 'Disease', 'MESH:D050171', (73, 85))	('metabolism', 'biological_process', 'GO:0008152', ('50', '60'))	('inhibition', 'Var', (10, 20))	('dyslipidemia', 'Phenotype', 'HP:0003119', (73, 85))	('mTOR', 'Gene', (24, 28))	('leading to', 'Reg', (62, 72))	('mTOR', 'Gene', '2475', (24, 28))
147016	27574806	Additionally, a preclinical study reported a potential role for GSG2 inhibitors in multiple malignancies.	('malignancies', 'Disease', (92, 104))	('GSG2', 'Gene', '83903', (64, 68))	('inhibitors', 'Var', (69, 79))	('malignancies', 'Disease', 'MESH:D009369', (92, 104))	('GSG2', 'Gene', (64, 68))
147087	32456352	Next, several novel biomarkers are currently being evaluated to assess the prognostic and predictive value for different response of renal malignancies treated with antiangiogenic-TKI and immunotherapy.	('renal malignancies', 'Disease', 'MESH:D007680', (133, 151))	('renal malignancies', 'Disease', (133, 151))	('renal malignancies', 'Phenotype', 'HP:0009726', (133, 151))	('antiangiogenic-TKI', 'Var', (165, 183))
147099	32456352	Ancillary, emerging evidences uncovered nucleotide polymorphisms (SNPs) of IL-8, HIF-1alpha and VEGF axes to significantly impact the therapeutic outcome in RCC as in several TKI sensitive tumors; however, no validation has been achieved in statistically powered clinical studies.	('HIF-1alpha', 'Gene', '3091', (81, 91))	('IL-8', 'Gene', '3576', (75, 79))	('therapeutic outcome', 'MPA', (134, 153))	('VEGF', 'Gene', '7422', (96, 100))	('tumors', 'Disease', (189, 195))	('IL-8', 'Gene', (75, 79))	('impact', 'Reg', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('HIF-1alpha', 'Gene', (81, 91))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('IL-8', 'molecular_function', 'GO:0005153', ('75', '79'))	('RCC', 'Disease', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('nucleotide polymorphisms', 'Var', (40, 64))	('VEGF', 'Gene', (96, 100))
147110	32456352	However, several data and meta-analyses revealed that VHL gene alteration holds neither prognostic, nor predictive value in subjects suffering from ccRCC.	('VHL', 'Gene', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('VHL', 'Gene', '7428', (54, 57))	('RCC', 'Disease', (150, 153))	('alteration', 'Var', (63, 73))
147112	32456352	Indeed, several additional genetic alterations were also frequent in ccRCC, such as somatic mutation of chromatin remodeling genes including PBRM1, SETD2 and BAP1 (38%, 13% and 11% of cases, respectively), mutation of PI3K-AKT-mTOR pathway genes (occurring in 16% of patients) comprising PTEN, MTOR and PIK3CA, loss of CDKN2A, and mutation of TP53 (16.2% and 2.6%, of subjects, respectively).	('mutation', 'Var', (92, 100))	('AKT', 'Gene', (223, 226))	('mTOR', 'Gene', (227, 231))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('104', '124'))	('BAP1', 'Gene', '8314', (158, 162))	('PIK3CA', 'Gene', '5290', (303, 309))	('mTOR', 'Gene', '2475', (227, 231))	('patients', 'Species', '9606', (267, 275))	('MTOR', 'Gene', (294, 298))	('CDKN2A', 'Gene', (319, 325))	('PTEN', 'Gene', (288, 292))	('MTOR', 'Gene', '2475', (294, 298))	('AKT', 'Gene', '207', (223, 226))	('PBRM1', 'Gene', '55193', (141, 146))	('TP53', 'Gene', (343, 347))	('BAP1', 'Gene', (158, 162))	('RCC', 'Disease', (71, 74))	('mutation', 'Var', (206, 214))	('PTEN', 'Gene', '5728', (288, 292))	('PIK3CA', 'Gene', (303, 309))	('CDKN2A', 'Gene', '1029', (319, 325))	('loss', 'NegReg', (311, 315))	('PBRM1', 'Gene', (141, 146))	('SETD2', 'Gene', (148, 153))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('TP53', 'Gene', '7157', (343, 347))	('SETD2', 'Gene', '29072', (148, 153))	('chromatin', 'cellular_component', 'GO:0000785', ('104', '113'))	('PI3K', 'molecular_function', 'GO:0016303', ('218', '222'))	('mutation', 'Var', (331, 339))
147113	32456352	CDKN2A loss, BAP-1 and TP53 mutation are associated with poorer survival in ccRCC.	('loss', 'NegReg', (7, 11))	('BAP-1', 'Gene', '8314', (13, 18))	('BAP-1', 'Gene', (13, 18))	('RCC', 'Disease', (78, 81))	('TP53', 'Gene', '7157', (23, 27))	('mutation', 'Var', (28, 36))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('CDKN2A', 'Gene', (0, 6))	('TP53', 'Gene', (23, 27))	('poorer', 'NegReg', (57, 63))	('CDKN2A', 'Gene', '1029', (0, 6))
147115	32456352	Conversely, PBRM1 loss-of-function mutations correlated with less aggressive behavior and with better PFS and OS in advanced patients.	('patients', 'Species', '9606', (125, 133))	('PBRM1', 'Gene', (12, 17))	('PBRM1', 'Gene', '55193', (12, 17))	('loss-of-function', 'NegReg', (18, 34))	('less', 'NegReg', (61, 65))	('aggressive behavior', 'Disease', (66, 85))	('aggressive behavior', 'biological_process', 'GO:0002118', ('66', '85'))	('aggressive behavior', 'Disease', 'MESH:D001523', (66, 85))	('aggressive behavior', 'Phenotype', 'HP:0000718', (66, 85))	('mutations', 'Var', (35, 44))
147118	32456352	Consistently, data from TCGA confirmed the UTSW cohort by showing median OS of 5.4 and 1.9 years for PBRM1 vs. BAP1 mutated cases, respectively.	('mutated', 'Var', (116, 123))	('BAP1', 'Gene', '8314', (111, 115))	('BAP1', 'Gene', (111, 115))	('PBRM1', 'Gene', (101, 106))	('PBRM1', 'Gene', '55193', (101, 106))
147119	32456352	Next, genomic annotation-model based uncovered the independent prognostic value harbored by any TP53, BAP1 and PBRM1 mutation to be relevant in improving the MSKCC model in patients treated with first-line TKI.	('BAP1', 'Gene', (102, 106))	('TP53', 'Gene', (96, 100))	('patients', 'Species', '9606', (173, 181))	('improving', 'PosReg', (144, 153))	('PBRM1', 'Gene', (111, 116))	('PBRM1', 'Gene', '55193', (111, 116))	('mutation', 'Var', (117, 125))	('BAP1', 'Gene', '8314', (102, 106))	('TP53', 'Gene', '7157', (96, 100))
147120	32456352	Likewise, the IMmotion150 trial, which compared, in a three-arm fashion, sunitinib over atezolizumab monotherapy and atezolizumab plus bevacizumab in treatment-naive RCC, revealed PBRM1 mutations to be correlated with improved survival in the sunitinib arm.	('atezolizumab', 'Chemical', 'MESH:C000594389', (88, 100))	('survival', 'MPA', (227, 235))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('mutations', 'Var', (186, 195))	('RCC', 'Disease', (166, 169))	('sunitinib', 'Chemical', 'MESH:D000077210', (73, 82))	('atezolizumab', 'Chemical', 'MESH:C000594389', (117, 129))	('sunitinib', 'Chemical', 'MESH:D000077210', (243, 252))	('PBRM1', 'Gene', (180, 185))	('PBRM1', 'Gene', '55193', (180, 185))	('atezolizumab plus bevacizumab', 'Disease', (117, 146))	('atezolizumab plus bevacizumab', 'Disease', 'MESH:D007625', (117, 146))	('improved', 'PosReg', (218, 226))
147121	32456352	Additionally, the ICI response prediction to anti-PD1 identified by PBRM1 mutational status apparently parallels the behavior reported in TKI-treated patients, warranting further statistically powered trials aimed to clarify the predictive value of PBRM1.	('PBRM1', 'Gene', '55193', (249, 254))	('PBRM1', 'Gene', (68, 73))	('PD1', 'Gene', '5133', (50, 53))	('ICI response', 'MPA', (18, 30))	('PBRM1', 'Gene', '55193', (68, 73))	('patients', 'Species', '9606', (150, 158))	('PD1', 'Gene', (50, 53))	('mutational status', 'Var', (74, 91))	('PBRM1', 'Gene', (249, 254))
147124	32456352	Moreover, the combination of the singular subtypes can dissect three different clinical behaviors: (1) good prognosis group (cluster ccA, CC-e.2, and m1), involved chromatin modifier genes mutations, such as PBRM1; (2) poor prognosis group (cluster ccB, CC-e.3, m3), associated with higher expression of CDKN2A and hypoxia-related genes, chromatin remodeling genes mutation including SETD2 or BAP1, PI3K/AKT/mTOR pathway genes mutations, epithelial-mesenchymal transition, hypermethylation, and a metabolic shift with higher glutathione and dipeptide levels; (3) intermediate prognosis group (cluster 3, CC-e.1, m2, and m4) associated with BAP1 mutations and base-excision repair.	('PBRM1', 'Gene', '55193', (208, 213))	('SETD2', 'Gene', (384, 389))	('AKT', 'Gene', (404, 407))	('chromatin', 'cellular_component', 'GO:0000785', ('164', '173'))	('PBRM1', 'Gene', (208, 213))	('mTOR', 'Gene', (408, 412))	('SETD2', 'Gene', '29072', (384, 389))	('CDKN2A', 'Gene', (304, 310))	('BAP1', 'Gene', '8314', (640, 644))	('chromatin', 'cellular_component', 'GO:0000785', ('338', '347'))	('mTOR', 'Gene', '2475', (408, 412))	('BAP1', 'Gene', (393, 397))	('BAP1', 'Gene', '8314', (393, 397))	('hypoxia', 'Disease', (315, 322))	('AKT', 'Gene', '207', (404, 407))	('CDKN2A', 'Gene', '1029', (304, 310))	('PI3K', 'molecular_function', 'GO:0016303', ('399', '403'))	('BAP1', 'Gene', (640, 644))	('hypoxia', 'Disease', 'MESH:D000860', (315, 322))	('higher', 'PosReg', (518, 524))	('base-excision repair', 'biological_process', 'GO:0006284', ('659', '679'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('438', '471'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('338', '358'))	('mutations', 'Var', (645, 654))
147127	32456352	Characteristically, the ccrcc4 subtype had a strong inflammation, BAP1 mutation, sarcomatoid dedifferentiation and decreased angiogenesis dependency, and significantly poor survival and response to sunitinib and pazopanib.	('ccrcc4', 'Disease', (24, 30))	('sarcomatoid', 'Disease', 'MESH:C538614', (81, 92))	('inflammation', 'Disease', (52, 64))	('pazopanib', 'Chemical', 'MESH:C516667', (212, 221))	('BAP1', 'Gene', '8314', (66, 70))	('mutation', 'Var', (71, 79))	('angiogenesis', 'biological_process', 'GO:0001525', ('125', '137'))	('decreased', 'NegReg', (115, 124))	('BAP1', 'Gene', (66, 70))	('dedifferentiation', 'biological_process', 'GO:0043696', ('93', '110'))	('sarcomatoid', 'Disease', (81, 92))	('angiogenesis dependency', 'CPA', (125, 148))	('sunitinib', 'Chemical', 'MESH:D000077210', (198, 207))	('inflammation', 'Disease', 'MESH:D007249', (52, 64))	('inflammation', 'biological_process', 'GO:0006954', ('52', '64'))	('poor', 'NegReg', (168, 172))	('survival', 'CPA', (173, 181))
147128	32456352	Remarkably, PBRM1 mutational status and boosted angiogenesis in ccrcc2-3 seem to have more interactions among themselves than would be expected for a random set of molecular interactions.	('PBRM1', 'Gene', (12, 17))	('PBRM1', 'Gene', '55193', (12, 17))	('mutational status', 'Var', (18, 35))	('interactions', 'Interaction', (91, 103))	('angiogenesis', 'biological_process', 'GO:0001525', ('48', '60'))	('boosted', 'PosReg', (40, 47))	('angiogenesis', 'CPA', (48, 60))
147170	31215499	Recent reports have shown that FAM83H is also involved in the progression of human cancers in conjunction with tumor-associated molecules, such as MYC and beta-catenin.	('MYC', 'Gene', (147, 150))	('beta-catenin', 'Gene', (155, 167))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('FAM83H', 'Var', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('beta-catenin', 'Gene', '1499', (155, 167))	('MYC', 'Gene', '4609', (147, 150))	('tumor', 'Disease', (111, 116))	('involved', 'Reg', (46, 54))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))	('human', 'Species', '9606', (77, 82))
147173	31215499	The expression of nuclear FAM83H, cytoplasmic FAM83H, and beta-catenin were significantly associated with each other and significantly associated with shorter survival of osteosarcoma patients by univariate analysis.	('survival', 'MPA', (159, 167))	('beta-catenin', 'Gene', (58, 70))	('nuclear FAM83H', 'Var', (18, 32))	('osteosarcoma', 'Phenotype', 'HP:0002669', (171, 183))	('osteosarcoma', 'Disease', 'MESH:D012516', (171, 183))	('cytoplasmic FAM83H', 'Var', (34, 52))	('patients', 'Species', '9606', (184, 192))	('expression', 'Species', '29278', (4, 14))	('shorter', 'NegReg', (151, 158))	('beta-catenin', 'Gene', '1499', (58, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('associated', 'Reg', (90, 100))	('associated', 'Reg', (135, 145))	('osteosarcoma', 'Disease', (171, 183))
147174	31215499	In multivariate analysis, cytoplasmic expression of FAM83H was an independent indicator of shorter survival of osteosarcoma patients (overall survival; P <  0.001, relapse-free survival; P <  0.001).	('expression', 'Species', '29278', (38, 48))	('FAM83H', 'Var', (52, 58))	('osteosarcoma', 'Phenotype', 'HP:0002669', (111, 123))	('osteosarcoma', 'Disease', (111, 123))	('osteosarcoma', 'Disease', 'MESH:D012516', (111, 123))	('survival', 'MPA', (99, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (116, 123))	('shorter', 'NegReg', (91, 98))	('patients', 'Species', '9606', (124, 132))
147175	31215499	In U2OS, MG63, and KHOS/NP osteosarcoma cells, the knock-down of FAM83H decreased proliferation and invasion activity and overexpression of FAM83H increased proliferation and invasion activity.	('expression', 'Species', '29278', (126, 136))	('osteosarcoma', 'Phenotype', 'HP:0002669', (27, 39))	('KHOS/NP osteosarcoma', 'Disease', (19, 39))	('increased', 'PosReg', (147, 156))	('KHOS/NP osteosarcoma', 'Disease', 'MESH:D012516', (19, 39))	('U2OS', 'CellLine', 'CVCL:0042', (3, 7))	('FAM83H', 'Var', (65, 71))	('decreased', 'NegReg', (72, 81))	('invasion activity', 'CPA', (175, 192))	('knock-down', 'Var', (51, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('proliferation', 'CPA', (82, 95))	('MG63', 'CellLine', 'CVCL:0426', (9, 13))	('invasion activity', 'CPA', (100, 117))	('proliferation', 'CPA', (157, 170))
147176	31215499	In KHOS/NP cells, knock-down of FAM83H significantly inhibited, and overexpression of FAM83H significantly increased in vivo growth of cells.	('KHOS', 'Chemical', '-', (3, 7))	('FAM83H', 'Var', (32, 38))	('inhibited', 'NegReg', (53, 62))	('FAM83H', 'Var', (86, 92))	('increased', 'PosReg', (107, 116))	('expression', 'Species', '29278', (72, 82))	('overexpression', 'PosReg', (68, 82))	('knock-down', 'Var', (18, 28))
147177	31215499	In addition, the knock-down of FAM83H decreased protein expression of beta-catenin, active beta-catenin, cyclin D1, vimentin, and snail.	('cyclin', 'molecular_function', 'GO:0016538', ('105', '111'))	('active', 'MPA', (84, 90))	('cyclin D1', 'Gene', (105, 114))	('vimentin', 'cellular_component', 'GO:0045098', ('116', '124'))	('snail', 'Gene', '6615', (130, 135))	('cyclin D1', 'Gene', '595', (105, 114))	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('decreased', 'NegReg', (38, 47))	('protein expression', 'MPA', (48, 66))	('FAM83H', 'Var', (31, 37))	('beta-catenin', 'Gene', (70, 82))	('beta-catenin', 'Gene', (91, 103))	('beta-catenin', 'Gene', '1499', (70, 82))	('snail', 'Gene', (130, 135))	('beta-catenin', 'Gene', '1499', (91, 103))	('vimentin', 'cellular_component', 'GO:0045099', ('116', '124'))	('expression', 'Species', '29278', (56, 66))	('knock-down', 'Var', (17, 27))	('vimentin', 'Gene', '7431', (116, 124))	('vimentin', 'Gene', (116, 124))
147178	31215499	Overexpression of FAM83H increased protein expression of beta-catenin, active beta-catenin, cyclin D1, vimentin, and snail.	('vimentin', 'cellular_component', 'GO:0045099', ('103', '111'))	('beta-catenin', 'Gene', (57, 69))	('snail', 'Gene', (117, 122))	('beta-catenin', 'Gene', '1499', (57, 69))	('FAM83H', 'Var', (18, 24))	('protein expression', 'MPA', (35, 53))	('expression', 'Species', '29278', (43, 53))	('beta-catenin', 'Gene', (78, 90))	('beta-catenin', 'Gene', '1499', (78, 90))	('vimentin', 'Gene', '7431', (103, 111))	('vimentin', 'Gene', (103, 111))	('expression', 'Species', '29278', (4, 14))	('cyclin', 'molecular_function', 'GO:0016538', ('92', '98'))	('vimentin', 'cellular_component', 'GO:0045098', ('103', '111'))	('cyclin D1', 'Gene', (92, 101))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('cyclin D1', 'Gene', '595', (92, 101))	('increased', 'PosReg', (25, 34))	('snail', 'Gene', '6615', (117, 122))
147179	31215499	However, the expression of beta-catenin mRNA was not significantly altered with knock-down or overexpression of FAM83H.	('expression', 'Species', '29278', (13, 23))	('beta-catenin', 'Gene', '1499', (27, 39))	('expression', 'MPA', (13, 23))	('FAM83H', 'Var', (112, 118))	('expression', 'Species', '29278', (98, 108))	('beta-catenin', 'Gene', (27, 39))
147180	31215499	In addition, FAM83H and beta-catenin shown to directly interact via immunoprecipitation and nuclear and cytoplasmic localization of beta-catenin was decreased with knock-down of FAM83H.	('FAM83H', 'Var', (178, 184))	('beta-catenin', 'Gene', (24, 36))	('localization', 'biological_process', 'GO:0051179', ('116', '128'))	('knock-down', 'Var', (164, 174))	('beta-catenin', 'Gene', (132, 144))	('beta-catenin', 'Gene', '1499', (24, 36))	('beta-catenin', 'Gene', '1499', (132, 144))	('decreased', 'NegReg', (149, 158))
147181	31215499	Moreover, the ubiquitination and proteasomal degradation of beta-catenin was increased with knock-down of FAM83H.	('FAM83H', 'Var', (106, 112))	('degradation', 'biological_process', 'GO:0009056', ('45', '56'))	('ubiquitination', 'MPA', (14, 28))	('proteasomal degradation', 'MPA', (33, 56))	('beta-catenin', 'Gene', (60, 72))	('increased', 'PosReg', (77, 86))	('beta-catenin', 'Gene', '1499', (60, 72))	('knock-down', 'Var', (92, 102))
147182	31215499	This study suggests that FAM83H is involved in the progression of osteosarcomas via a mechanism involving the stabilization of beta-catenin and the promotion of proliferation and invasiveness of osteosarcomas.	('invasiveness of osteosarcomas', 'Disease', 'MESH:D012516', (179, 208))	('osteosarcomas', 'Disease', (195, 208))	('osteosarcoma', 'Phenotype', 'HP:0002669', (66, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('osteosarcomas', 'Disease', 'MESH:D012516', (66, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('beta-catenin', 'Gene', (127, 139))	('sarcomas', 'Phenotype', 'HP:0100242', (71, 79))	('beta-catenin', 'Gene', '1499', (127, 139))	('FAM83H', 'Var', (25, 31))	('osteosarcomas', 'Phenotype', 'HP:0002669', (195, 208))	('osteosarcomas', 'Disease', (66, 79))	('stabilization', 'MPA', (110, 123))	('promotion', 'PosReg', (148, 157))	('osteosarcomas', 'Phenotype', 'HP:0002669', (66, 79))	('proliferation', 'CPA', (161, 174))	('osteosarcoma', 'Phenotype', 'HP:0002669', (195, 207))	('involved', 'Reg', (35, 43))	('osteosarcomas', 'Disease', 'MESH:D012516', (195, 208))	('sarcomas', 'Phenotype', 'HP:0100242', (200, 208))	('invasiveness of osteosarcomas', 'Disease', (179, 208))
147184	31215499	Mutation of FAM83H is the main etiological factor for human autosomal dominant hypocalcified amelogenesis imperfecta.	('amelogenesis', 'biological_process', 'GO:0097186', ('93', '105'))	('Mutation', 'Var', (0, 8))	('autosomal dominant hypocalcified amelogenesis imperfecta', 'Disease', 'MESH:D000567', (60, 116))	('FAM83H', 'Gene', (12, 18))	('etiological', 'Reg', (31, 42))	('amelogenesis imperfecta', 'Phenotype', 'HP:0000705', (93, 116))	('human', 'Species', '9606', (54, 59))
147186	31215499	However, there are controversial reports for the role of FAM83H in human cancers.	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('FAM83H', 'Var', (57, 63))	('human', 'Species', '9606', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
147189	31215499	The roles of FAM83H in the progression of human cancers involve changes in the proliferation and invasiveness of cancer cells.	('cancers', 'Disease', (48, 55))	('invasiveness of cancer', 'Disease', 'MESH:D009362', (97, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('invasiveness of cancer', 'Disease', (97, 119))	('human', 'Species', '9606', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('changes', 'Reg', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('FAM83H', 'Var', (13, 19))
147190	31215499	In colon cancer cells, overexpression of FAM83H is suggested to be involved in the progression of cancer cells by disorganizing keratin cytoskeleton structures.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', (9, 15))	('involved', 'Reg', (67, 75))	('disorganizing', 'NegReg', (114, 127))	('overexpression', 'PosReg', (23, 37))	('FAM83H', 'Var', (41, 47))	('expression', 'Species', '29278', (27, 37))	('keratin cytoskeleton structures', 'MPA', (128, 159))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('136', '148'))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('cancer', 'Disease', (98, 104))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('colon cancer', 'Disease', (3, 15))
147191	31215499	In addition, FAM83H increases proliferation of prostatic cancer cells, hepatocellular carcinoma cells, and clear cell renal cell carcinoma cells.	('hepatocellular carcinoma cells', 'Disease', 'MESH:D006528', (71, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (107, 138))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (118, 138))	('prostatic cancer', 'Disease', 'MESH:D011471', (47, 63))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (107, 138))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (71, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('prostatic cancer', 'Phenotype', 'HP:0012125', (47, 63))	('prostatic cancer', 'Disease', (47, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('proliferation', 'CPA', (30, 43))	('hepatocellular carcinoma cells', 'Disease', (71, 101))	('clear cell renal cell carcinoma', 'Disease', (107, 138))	('FAM83H', 'Var', (13, 19))	('increases', 'PosReg', (20, 29))
147193	31215499	Moreover, higher expression of FAM83H is associated with an increased recurrence rate of prostatic cancer patients and shorter survival of uterine cancer, hepatocellular carcinoma, and clear cell renal cell carcinoma patients.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (155, 179))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('clear cell renal cell carcinoma', 'Disease', (185, 216))	('prostatic cancer', 'Disease', (89, 105))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (155, 179))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('expression', 'MPA', (17, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('hepatocellular carcinoma', 'Disease', (155, 179))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (185, 216))	('FAM83H', 'Var', (31, 37))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (217, 225))	('shorter', 'NegReg', (119, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('expression', 'Species', '29278', (17, 27))	('uterine cancer', 'Phenotype', 'HP:0010784', (139, 153))	('prostatic cancer', 'Disease', 'MESH:D011471', (89, 105))	('prostatic cancer', 'Phenotype', 'HP:0012125', (89, 105))	('cancer', 'Disease', (99, 105))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (196, 216))	('higher', 'PosReg', (10, 16))	('cancer', 'Disease', (147, 153))	('recurrence', 'CPA', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (185, 216))
147194	31215499	These findings suggest that FAM83H has a vital role in tumorigenesis and progression of human malignant tumors, and might be involved in the progression of various types of human cancers.	('FAM83H', 'Var', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('malignant tumors', 'Disease', 'MESH:D018198', (94, 110))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('malignant tumors', 'Disease', (94, 110))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', (55, 60))	('progression', 'CPA', (73, 84))	('human', 'Species', '9606', (173, 178))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('human', 'Species', '9606', (88, 93))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('involved', 'Reg', (125, 133))	('cancers', 'Disease', (179, 186))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
147195	31215499	However, the expression of FAM83H is down-regulated in astrocytoma and oligodendroglioma of the brain, and higher expression of FAM83H is associated with favorable prognosis of glioma and head and neck cancer patients.	('head and neck cancer', 'Phenotype', 'HP:0012288', (188, 208))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('FAM83H', 'Gene', (27, 33))	('astrocytoma', 'Disease', 'MESH:D001254', (55, 66))	('astrocytoma', 'Disease', (55, 66))	('neck cancer', 'Disease', 'MESH:D006258', (197, 208))	('neck cancer', 'Disease', (197, 208))	('expression', 'MPA', (114, 124))	('expression', 'Species', '29278', (13, 23))	('glioma', 'Disease', (177, 183))	('FAM83H', 'Var', (128, 134))	('oligodendroglioma of the brain', 'Disease', 'MESH:D009837', (71, 101))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('glioma', 'Disease', (82, 88))	('higher', 'PosReg', (107, 113))	('oligodendroglioma of the brain', 'Disease', (71, 101))	('down-regulated', 'NegReg', (37, 51))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('expression', 'Species', '29278', (114, 124))	('patients', 'Species', '9606', (209, 217))	('astrocytoma', 'Phenotype', 'HP:0009592', (55, 66))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('neck', 'cellular_component', 'GO:0044326', ('197', '201'))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('expression', 'MPA', (13, 23))
147200	31215499	Therefore, new therapeutic approaches are needed to improve therapeutic efficacy in osteosarcoma patients, and we hypothesize that the FAM83H might be involved in the oncogenesis of the osteosarcoma based on the role of FAM83H in cancer progression in conjunction with MYC and the beta-catenin pathway.	('beta-catenin', 'Gene', '1499', (281, 293))	('oncogenesis', 'biological_process', 'GO:0007048', ('167', '178'))	('sarcoma', 'Phenotype', 'HP:0100242', (191, 198))	('osteosarcoma', 'Disease', (84, 96))	('osteosarcoma', 'Disease', 'MESH:D012516', (84, 96))	('involved', 'Reg', (151, 159))	('osteosarcoma', 'Disease', (186, 198))	('cancer', 'Disease', (230, 236))	('osteosarcoma', 'Disease', 'MESH:D012516', (186, 198))	('osteosarcoma', 'Phenotype', 'HP:0002669', (186, 198))	('MYC', 'Gene', (269, 272))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('osteosarcoma', 'Phenotype', 'HP:0002669', (84, 96))	('patients', 'Species', '9606', (97, 105))	('FAM83H', 'Var', (220, 226))	('beta-catenin', 'Gene', (281, 293))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('MYC', 'Gene', '4609', (269, 272))
147203	31215499	Therefore, when considering p27 and cyclin D1 as down-stream signaling molecules of the beta-catenin pathway, there might be an association between FAM83H and the beta-catenin pathway.	('beta-catenin', 'Gene', (163, 175))	('signaling', 'biological_process', 'GO:0023052', ('61', '70'))	('cyclin D1', 'Gene', '595', (36, 45))	('p27', 'Gene', '3429', (28, 31))	('p27', 'Gene', (28, 31))	('FAM83H', 'Var', (148, 154))	('cyclin D1', 'Gene', (36, 45))	('association', 'Interaction', (128, 139))	('beta-catenin', 'Gene', (88, 100))	('beta-catenin', 'Gene', '1499', (163, 175))	('cyclin', 'molecular_function', 'GO:0016538', ('36', '42'))	('beta-catenin', 'Gene', '1499', (88, 100))
147205	31215499	Therefore, FAM83H and the beta-catenin pathway might have roles in the progression of osteosarcomas.	('beta-catenin', 'Gene', '1499', (26, 38))	('FAM83H', 'Var', (11, 17))	('osteosarcomas', 'Disease', (86, 99))	('osteosarcomas', 'Phenotype', 'HP:0002669', (86, 99))	('roles', 'Reg', (58, 63))	('osteosarcoma', 'Phenotype', 'HP:0002669', (86, 98))	('osteosarcomas', 'Disease', 'MESH:D012516', (86, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('beta-catenin', 'Gene', (26, 38))
147211	31215499	The osteosarcomas were grouped according to age (< 30 y versus >= 30 y), sex (male versus female), tumor size (<= 8 cm versus > 8 cm), tumor stage (I versus II-IV), histologic grade (1 and 2 versus 3 and 4), lymph node metastasis (absence versus presence), and distant metastasis (absence versus presence).	('<=', 'Var', (111, 113))	('tumor', 'Disease', (99, 104))	('osteosarcoma', 'Phenotype', 'HP:0002669', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('osteosarcomas', 'Disease', (4, 17))	('osteosarcomas', 'Phenotype', 'HP:0002669', (4, 17))	('lymph node metastasis', 'CPA', (208, 229))	('osteosarcomas', 'Disease', 'MESH:D012516', (4, 17))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('sarcomas', 'Phenotype', 'HP:0100242', (9, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('distant metastasis', 'CPA', (261, 279))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
147217	31215499	The nuclear and cytoplasmic expression of FAM83H were separately evaluated, and the expression of beta-catenin was evaluated by overall cellular level.	('FAM83H', 'Var', (42, 48))	('expression', 'Species', '29278', (28, 38))	('expression', 'Species', '29278', (84, 94))	('beta-catenin', 'Gene', (98, 110))	('beta-catenin', 'Gene', '1499', (98, 110))
147221	31215499	Therefore, because we have used two TMA cores in each case, the final immunohistochemical staining score for Cy-FAM83H, Nu-FAM83H, and beta-catenin was ranged from zero to sixteen.	('Cy-FAM83H', 'Chemical', '-', (109, 118))	('beta-catenin', 'Gene', (135, 147))	('Cy-FAM83H', 'Var', (109, 118))	('Nu-FAM83H', 'Chemical', '-', (120, 129))	('beta-catenin', 'Gene', '1499', (135, 147))	('TMA', 'Chemical', '-', (36, 39))
147242	31215499	Thereafter, the eluted proteins were immunoblotted with anti-FAM83H, anti-beta-catenin, anti-ubiquitin, and anti-actin antibodies.	('ubiquitin', 'molecular_function', 'GO:0031386', ('93', '102'))	('anti-FAM83H', 'Var', (56, 67))	('beta-catenin', 'Gene', (74, 86))	('anti-ubiquitin', 'Var', (88, 102))	('beta-catenin', 'Gene', '1499', (74, 86))
147248	31215499	To determine positivity for the immunohistochemical staining for FAM83H and beta-catenin, receiver operating characteristic curve analysis was preformed, and the cut-off points were determined at the points with the highest positive likelihood ratio point for the estimation of the death of osteosarcoma patients.	('sarcoma', 'Phenotype', 'HP:0100242', (296, 303))	('patients', 'Species', '9606', (304, 312))	('death of osteosarcoma', 'Disease', 'MESH:D012516', (282, 303))	('FAM83H', 'Var', (65, 71))	('beta-catenin', 'Gene', (76, 88))	('death of osteosarcoma', 'Disease', (282, 303))	('beta-catenin', 'Gene', '1499', (76, 88))	('osteosarcoma', 'Phenotype', 'HP:0002669', (291, 303))
147255	31215499	When we compared FAM83H protein expression in normal human osteoblast cells and human osteosarcoma cells, U2OS, MG63, and KHOS/NP osteosarcoma cells showed higher expression of FAM83H compared with normal osteoblast cells (Fig.	('U2OS', 'CellLine', 'CVCL:0042', (106, 110))	('osteosarcoma', 'Phenotype', 'HP:0002669', (130, 142))	('osteosarcoma', 'Disease', (86, 98))	('FAM83H', 'Var', (177, 183))	('KHOS/NP osteosarcoma', 'Disease', (122, 142))	('osteosarcoma', 'Disease', 'MESH:D012516', (86, 98))	('expression', 'Species', '29278', (163, 173))	('human', 'Species', '9606', (80, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('MG63', 'CellLine', 'CVCL:0426', (112, 116))	('osteosarcoma', 'Disease', (130, 142))	('higher', 'PosReg', (156, 162))	('osteosarcoma', 'Disease', 'MESH:D012516', (130, 142))	('KHOS/NP osteosarcoma', 'Disease', 'MESH:D012516', (122, 142))	('osteosarcoma', 'Phenotype', 'HP:0002669', (86, 98))	('human', 'Species', '9606', (53, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('expression', 'MPA', (163, 173))	('expression', 'Species', '29278', (32, 42))
147256	31215499	In human osteosarcoma tissue, immunohistochemical expression of FAM83H and beta-catenin were observed in both the cytoplasm and nuclei of osteosarcoma cells (Fig.	('cytoplasm', 'cellular_component', 'GO:0005737', ('114', '123'))	('beta-catenin', 'Gene', '1499', (75, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('human', 'Species', '9606', (3, 8))	('osteosarcoma', 'Phenotype', 'HP:0002669', (138, 150))	('osteosarcoma', 'Disease', (138, 150))	('osteosarcoma', 'Disease', 'MESH:D012516', (9, 21))	('osteosarcoma', 'Disease', 'MESH:D012516', (138, 150))	('osteosarcoma', 'Phenotype', 'HP:0002669', (9, 21))	('beta-catenin', 'Gene', (75, 87))	('osteosarcoma', 'Disease', (9, 21))	('expression', 'Species', '29278', (50, 60))	('FAM83H', 'Var', (64, 70))
147257	31215499	Although, previous reports have presented very rare expression of FAM83H in the nuclei of cells, cytoplasmic and nuclear expression of FAM83H have been presented in human cancers.	('human', 'Species', '9606', (165, 170))	('expression', 'Species', '29278', (121, 131))	('expression', 'Species', '29278', (52, 62))	('FAM83H', 'Var', (66, 72))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('FAM83H', 'Var', (135, 141))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cancers', 'Disease', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
147260	31215499	The cut-off values for the positivity of cytoplasmic expression of FAM83H (Cy-FAM83H), nuclear expression of FAM83H (Nu-FAM83H), and beta-catenin expression were determined with receiver operating character curve analysis to predict the death of osteosarcoma patients.	('beta-catenin', 'Gene', '1499', (133, 145))	('Cy-FAM83H', 'Chemical', '-', (75, 84))	('sarcoma', 'Phenotype', 'HP:0100242', (251, 258))	('death of osteosarcoma', 'Disease', 'MESH:D012516', (237, 258))	('death of osteosarcoma', 'Disease', (237, 258))	('patients', 'Species', '9606', (259, 267))	('expression', 'Species', '29278', (53, 63))	('FAM83H', 'Var', (67, 73))	('beta-catenin', 'Gene', (133, 145))	('expression', 'Species', '29278', (146, 156))	('osteosarcoma', 'Phenotype', 'HP:0002669', (246, 258))	('expression', 'Species', '29278', (95, 105))	('FAM83H', 'Var', (109, 115))	('Nu-FAM83H', 'Chemical', '-', (117, 126))
147261	31215499	The cut-off points for the expression of Cy-FAM83H, Nu-FAM83H, and beta-catenin were eight, twelve, and eleven, respectively (Fig.	('expression', 'Species', '29278', (27, 37))	('beta-catenin', 'Gene', '1499', (67, 79))	('Cy-FAM83H', 'Chemical', '-', (41, 50))	('beta-catenin', 'Gene', (67, 79))	('Cy-FAM83H', 'Var', (41, 50))	('Nu-FAM83H', 'Chemical', '-', (52, 61))	('Nu-FAM83H', 'Var', (52, 61))
147262	31215499	With these cut-off values, the positive expression of Cy-FAM83H, Nu-FAM83H, and beta-catenin were seen in 47.1% (16 of 34), 44.1% (15 of 34), and 38.2% (13 of 34) of osteosarcomas, respectively.	('Nu-FAM83H', 'Chemical', '-', (65, 74))	('Cy-FAM83H', 'Var', (54, 63))	('beta-catenin', 'Gene', (80, 92))	('osteosarcomas', 'Disease', (166, 179))	('osteosarcoma', 'Phenotype', 'HP:0002669', (166, 178))	('beta-catenin', 'Gene', '1499', (80, 92))	('osteosarcomas', 'Phenotype', 'HP:0002669', (166, 179))	('Cy-FAM83H', 'Chemical', '-', (54, 63))	('sarcomas', 'Phenotype', 'HP:0100242', (171, 179))	('osteosarcomas', 'Disease', 'MESH:D012516', (166, 179))	('expression', 'Species', '29278', (40, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('positive expression', 'PosReg', (31, 50))	('Nu-FAM83H', 'Var', (65, 74))
147263	31215499	Cy-FAM83H positivity was significantly associated with age of the patients (P = 0.013), larger tumor size (P = 0.039), higher tumor stage (P = 0.002), and higher histologic grade (P = 0.002).	('Cy-FAM83H', 'Chemical', '-', (0, 9))	('Cy-FAM83H positivity', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('patients', 'Species', '9606', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('associated', 'Reg', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (95, 100))	('tumor', 'Disease', (126, 131))
147264	31215499	Nu-FAM83H positivity was significantly associated with larger tumor size (P = 0.016), higher tumor stage (P <  0.001), and higher histologic grade (P <  0.001).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (93, 98))	('positivity', 'Var', (10, 20))	('Nu-FAM83H positivity', 'Var', (0, 20))	('Nu-FAM83H', 'Chemical', '-', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
147265	31215499	In addition, there was significant association between Cy-FAM83H, Nu-FAM83H, and beta-catenin expression (Cy-FAM83H versus Nu-FAM83H; P <  0.001, Cy-FAM83H versus beta-catenin; P = 0.042, Nu-FAM83H versus beta-catenin; P = 0.002) (Table 2).	('beta-catenin', 'Gene', '1499', (81, 93))	('Cy-FAM83H', 'Chemical', '-', (106, 115))	('beta-catenin', 'Gene', (163, 175))	('beta-catenin', 'Gene', (205, 217))	('expression', 'Species', '29278', (94, 104))	('Cy-FAM83H', 'Chemical', '-', (146, 155))	('beta-catenin', 'Gene', '1499', (163, 175))	('Nu-FAM83H', 'Chemical', '-', (188, 197))	('Cy-FAM83H', 'Chemical', '-', (55, 64))	('beta-catenin', 'Gene', '1499', (205, 217))	('beta-catenin', 'Gene', (81, 93))	('Nu-FAM83H', 'Chemical', '-', (123, 132))	('Nu-FAM83H', 'Chemical', '-', (66, 75))	('Cy-FAM83H', 'Var', (55, 64))
147266	31215499	In univariate survival analysis, age of the patients (OS; P = 0.048, RFS; P = 0.027), tumor size (OS; P = 0.012, RFS; P = 0.012), tumor stage (OS; P = 0.023, RFS; P = 0.020), histologic grade (OS; P = 0.023, RFS; P = 0.020), distant metastasis (OS; P = 0.006, RFS; P = 0.009), Cy-FAM83H expression (OS; P = 0.001, RFS; P <  0.001), Nu-FAM83H expression (OS; P = 0.002, RFS; P = 0.001), and beta-catenin (OS; P = 0.006, RFS; P = 0.012) were significantly associated with both OS and RFS of osteosarcoma patients (Table 3).	('RFS of osteosarcoma', 'Disease', (482, 501))	('Nu-FAM83H expression', 'Var', (332, 352))	('distant metastasis', 'CPA', (225, 243))	('Nu-FAM83H', 'Chemical', '-', (332, 341))	('associated', 'Reg', (454, 464))	('beta-catenin', 'Gene', (390, 402))	('OS', 'Chemical', '-', (193, 195))	('beta-catenin', 'Gene', '1499', (390, 402))	('OS', 'Chemical', '-', (98, 100))	('tumor', 'Disease', (130, 135))	('Cy-FAM83H', 'Chemical', '-', (277, 286))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('patients', 'Species', '9606', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('OS', 'Chemical', '-', (143, 145))	('OS', 'Chemical', '-', (475, 477))	('RFS of osteosarcoma', 'Disease', 'MESH:D005198', (482, 501))	('OS', 'Chemical', '-', (404, 406))	('OS', 'Chemical', '-', (54, 56))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('osteosarcoma', 'Phenotype', 'HP:0002669', (489, 501))	('expression', 'Species', '29278', (342, 352))	('OS', 'Chemical', '-', (245, 247))	('expression', 'Species', '29278', (287, 297))	('patients', 'Species', '9606', (502, 510))	('Cy-FAM83H expression', 'Var', (277, 297))	('OS', 'Chemical', '-', (299, 301))	('tumor', 'Disease', (86, 91))	('OS', 'Chemical', '-', (354, 356))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (494, 501))
147267	31215499	Cy-FAM83H positivity predicted a 12.106-fold (95% confidence interval [95% CI]; 2.736-53.563) greater risk of shorter OS and a 14.253-fold (95% CI; 3.225-62.994) greater risk of shorter RFS in osteosarcoma patients.	('shorter OS', 'Disease', (110, 120))	('Cy-FAM83H', 'Chemical', '-', (0, 9))	('Cy-FAM83H positivity', 'Var', (0, 20))	('OS', 'Chemical', '-', (118, 120))	('patients', 'Species', '9606', (206, 214))	('osteosarcoma', 'Phenotype', 'HP:0002669', (193, 205))	('osteosarcoma', 'Disease', (193, 205))	('osteosarcoma', 'Disease', 'MESH:D012516', (193, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (198, 205))
147268	31215499	Nu-FAM83H positivity predicted a 5.865-fold (95% CI; 1.874-18.355) greater risk of shorter OS and a 6.294-fold (95% CI; 2.038-19.431) greater risk of shorter RFS in osteosarcoma patients.	('osteosarcoma', 'Disease', (165, 177))	('shorter OS', 'Disease', (83, 93))	('osteosarcoma', 'Phenotype', 'HP:0002669', (165, 177))	('osteosarcoma', 'Disease', 'MESH:D012516', (165, 177))	('patients', 'Species', '9606', (178, 186))	('Nu-FAM83H', 'Chemical', '-', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('Nu-FAM83H', 'Var', (0, 9))	('OS', 'Chemical', '-', (91, 93))	('RFS', 'MPA', (158, 161))	('shorter', 'NegReg', (150, 157))
147270	31215499	The Kaplan-Meier survival curves according to the expressions of Cy-FAM83H, Nu-FAM83H, and beta-catenin are presented in Fig.	('Cy-FAM83H', 'Chemical', '-', (65, 74))	('beta-catenin', 'Gene', (91, 103))	('Cy-FAM83H', 'Var', (65, 74))	('expression', 'Species', '29278', (50, 60))	('beta-catenin', 'Gene', '1499', (91, 103))	('Nu-FAM83H', 'Chemical', '-', (76, 85))
147271	31215499	Multivariate analysis was performed with the factors significantly associated with OS or RFS by univariate analysis: the age of patients, tumor size, tumor stage, lymph node metastasis, distant metastasis, histologic grade, Cy-FAM83H expression, Nu-FAM83H expression, and beta-catenin expression.	('beta-catenin', 'Gene', (272, 284))	('tumor', 'Disease', (138, 143))	('OS', 'Chemical', '-', (83, 85))	('Nu-FAM83H', 'Chemical', '-', (246, 255))	('beta-catenin', 'Gene', '1499', (272, 284))	('expression', 'Species', '29278', (285, 295))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('Cy-FAM83H expression', 'Var', (224, 244))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('expression', 'Species', '29278', (234, 244))	('expression', 'MPA', (285, 295))	('patients', 'Species', '9606', (128, 136))	('tumor', 'Disease', (150, 155))	('Nu-FAM83H expression', 'Var', (246, 266))	('expression', 'Species', '29278', (256, 266))	('distant metastasis', 'CPA', (186, 204))	('lymph node metastasis', 'CPA', (163, 184))	('Cy-FAM83H', 'Chemical', '-', (224, 233))	('tumor', 'Disease', 'MESH:D009369', (150, 155))
147272	31215499	Multivariate analysis revealed presence of distant metastasis (OS; P = 0.005, RFS; P = 0.012) and Cy-FAM83H expression (OS; P <  0.001, RFS; P <  0.001) as independent indicators of poor prognostic of OS and RFS in osteosarcoma patients.	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('OS', 'Chemical', '-', (63, 65))	('distant metastasis', 'CPA', (43, 61))	('patients', 'Species', '9606', (228, 236))	('expression', 'Species', '29278', (108, 118))	('OS', 'Chemical', '-', (201, 203))	('Cy-FAM83H expression', 'Var', (98, 118))	('osteosarcoma', 'Disease', (215, 227))	('OS', 'Chemical', '-', (120, 122))	('osteosarcoma', 'Phenotype', 'HP:0002669', (215, 227))	('Cy-FAM83H', 'Chemical', '-', (98, 107))	('osteosarcoma', 'Disease', 'MESH:D012516', (215, 227))
147273	31215499	Cy-FAM83H expression indicated a 15.463-fold (95% CI; 3.196-74.809) greater risk of death and a 15.825-fold (95% CI; 3.461-72.358) greater risk of relapse or death of osteosarcoma patients (Table 4).	('relapse', 'Disease', (147, 154))	('Cy-FAM83H', 'Chemical', '-', (0, 9))	('death of osteosarcoma', 'Disease', (158, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('Cy-FAM83H expression', 'Var', (0, 20))	('death of osteosarcoma', 'Disease', 'MESH:D012516', (158, 179))	('death', 'Disease', 'MESH:D003643', (158, 163))	('death', 'Disease', (158, 163))	('expression', 'Species', '29278', (10, 20))	('death', 'Disease', 'MESH:D003643', (84, 89))	('death', 'Disease', (84, 89))	('patients', 'Species', '9606', (180, 188))	('osteosarcoma', 'Phenotype', 'HP:0002669', (167, 179))	('greater', 'PosReg', (68, 75))
147274	31215499	As the expression of FAM83H was significantly associated with advanced clinicopathological factors such as larger tumor size, higher tumor stage, and higher histologic grade, we evaluated the effect of the FAM83H on the proliferation and invasiveness of osteosarcoma cells.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('FAM83H', 'Var', (21, 27))	('osteosarcoma', 'Phenotype', 'HP:0002669', (254, 266))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('expression', 'Species', '29278', (7, 17))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', (133, 138))	('associated', 'Reg', (46, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (259, 266))	('invasiveness of osteosarcoma', 'Disease', 'MESH:D012516', (238, 266))	('invasiveness of osteosarcoma', 'Disease', (238, 266))
147275	31215499	As expected, the knock-down of FAM83H with shRNA for FAM83H inhibited proliferation, and overexpression of FAM83H increased the proliferation of U2OS and MG63 osteosarcoma cells (Fig.	('U2OS', 'CPA', (145, 149))	('MG63', 'CellLine', 'CVCL:0426', (154, 158))	('osteosarcoma', 'Disease', (159, 171))	('FAM83H', 'Var', (107, 113))	('increased', 'PosReg', (114, 123))	('expression', 'Species', '29278', (93, 103))	('knock-down', 'Var', (17, 27))	('proliferation', 'CPA', (70, 83))	('overexpression', 'PosReg', (89, 103))	('inhibited', 'NegReg', (60, 69))	('osteosarcoma', 'Disease', 'MESH:D012516', (159, 171))	('proliferation', 'CPA', (128, 141))	('osteosarcoma', 'Phenotype', 'HP:0002669', (159, 171))	('U2OS', 'CellLine', 'CVCL:0042', (145, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))
147276	31215499	In addition, the migration and invasion activities of osteosarcoma cells were significantly inhibited with knock-down of FAM83H and increased with overexpression of FAM83H in U2OS and MG63 cells (Fig.	('U2OS', 'CellLine', 'CVCL:0042', (175, 179))	('FAM83H', 'Var', (165, 171))	('inhibited', 'NegReg', (92, 101))	('expression', 'Species', '29278', (151, 161))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('FAM83H', 'Var', (121, 127))	('increased', 'PosReg', (132, 141))	('knock-down', 'Var', (107, 117))	('MG63', 'CellLine', 'CVCL:0426', (184, 188))	('overexpression', 'PosReg', (147, 161))	('osteosarcoma', 'Disease', (54, 66))	('osteosarcoma', 'Phenotype', 'HP:0002669', (54, 66))	('osteosarcoma', 'Disease', 'MESH:D012516', (54, 66))
147277	31215499	Moreover, overexpression of FAM83H significantly increased in vivo growth of KHOS/NP cells, and knock-down of FAM83H significantly inhibited in vivo growth of KHOS/NP cells (Fig.	('FAM83H', 'Var', (28, 34))	('KHOS', 'Chemical', '-', (159, 163))	('inhibited', 'NegReg', (131, 140))	('increased', 'PosReg', (49, 58))	('expression', 'Species', '29278', (14, 24))	('KHOS', 'Chemical', '-', (77, 81))	('knock-down', 'Var', (96, 106))	('FAM83H', 'Var', (110, 116))	('overexpression', 'PosReg', (10, 24))
147278	31215499	Furthermore, overexpression of FAM83H was significantly associated with increased pulmonary metastases (Fig.	('increased pulmonary metastases', 'Disease', 'MESH:D009362', (72, 102))	('expression', 'Species', '29278', (17, 27))	('increased pulmonary metastases', 'Disease', (72, 102))	('FAM83H', 'Var', (31, 37))	('overexpression', 'PosReg', (13, 27))
147279	31215499	The five mice with FAM83H-overexpressing KHOS/NP cells showed grossly visible pulmonary metastatic nodules, but no grossly visible metastatic pulmonary nodule in neither cells transfected with control vectors nor shRNA for FAM83H.	('FAM83H-overexpressing', 'Var', (19, 40))	('mice', 'Species', '10090', (9, 13))	('KHOS', 'Chemical', '-', (41, 45))	('pulmonary metastatic nodules', 'CPA', (78, 106))
147280	31215499	Microscopically, FAM83H-overexpressing cells showed more pulmonary metastasis compared with cells transfected with control vectors or shRNA for FAM83H (mean number of metastatic nodule per mice: FAM83H-overexpression; 9.4, control vectors; 1.6, shFAM83H; 0.8) (Fig.	('expression', 'Species', '29278', (206, 216))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (57, 77))	('mice', 'Species', '10090', (189, 193))	('FAM83H-overexpressing', 'Var', (17, 38))	('FAM83H-overexpression', 'Var', (195, 216))	('pulmonary metastasis', 'Disease', (57, 77))
147282	31215499	The expression of mRNA and protein of cyclin D1, snail, and vimentin were decreased with the knock-down of FAM83H and increased with the overexpression of FAM83H in both U2OS and MG63 cells (Fig.	('snail', 'Gene', (49, 54))	('MG63', 'CellLine', 'CVCL:0426', (179, 183))	('expression', 'MPA', (4, 14))	('increased', 'PosReg', (118, 127))	('expression', 'Species', '29278', (141, 151))	('vimentin', 'cellular_component', 'GO:0045099', ('60', '68'))	('cyclin', 'molecular_function', 'GO:0016538', ('38', '44'))	('knock-down', 'Var', (93, 103))	('cyclin D1', 'Gene', (38, 47))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))	('expression', 'Species', '29278', (4, 14))	('overexpression', 'PosReg', (137, 151))	('snail', 'Gene', '6615', (49, 54))	('cyclin D1', 'Gene', '595', (38, 47))	('FAM83H', 'Var', (107, 113))	('FAM83H', 'Var', (155, 161))	('vimentin', 'Gene', '7431', (60, 68))	('vimentin', 'cellular_component', 'GO:0045098', ('60', '68'))	('U2OS', 'CellLine', 'CVCL:0042', (170, 174))	('decreased', 'NegReg', (74, 83))	('vimentin', 'Gene', (60, 68))
147283	31215499	The expression of p27 protein and mRNA were increased with knockdown of FAM83H and decreased with FAM83H overexpression (Fig.	('expression', 'Species', '29278', (4, 14))	('decreased', 'NegReg', (83, 92))	('expression', 'MPA', (4, 14))	('FAM83H', 'Var', (72, 78))	('p27', 'Gene', '3429', (18, 21))	('p27', 'Gene', (18, 21))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('knockdown', 'Var', (59, 68))	('increased', 'PosReg', (44, 53))	('mRNA', 'MPA', (34, 38))	('expression', 'Species', '29278', (109, 119))
147284	31215499	However, despite no significant change in expression of mRNA of beta-catenin with the knock-down or overexpression of FAM83H, the protein expression of beta-catenin and active beta-catenin were decreased with the knock-down of FAM83H and increased with the overexpression of FAM83H (Fig.	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('FAM83H', 'Var', (227, 233))	('expression', 'Species', '29278', (42, 52))	('expression', 'Species', '29278', (261, 271))	('beta-catenin', 'Gene', (176, 188))	('knock-down', 'Var', (213, 223))	('FAM83H', 'Var', (275, 281))	('beta-catenin', 'Gene', (152, 164))	('expression', 'Species', '29278', (104, 114))	('increased', 'PosReg', (238, 247))	('beta-catenin', 'Gene', '1499', (176, 188))	('expression', 'Species', '29278', (138, 148))	('beta-catenin', 'Gene', '1499', (152, 164))	('beta-catenin', 'Gene', (64, 76))	('decreased', 'NegReg', (194, 203))	('beta-catenin', 'Gene', '1499', (64, 76))	('protein expression', 'MPA', (130, 148))
147285	31215499	5, FAM83H did not affect the mRNA expression of beta-catenin, but the expression of total beta-catenin and active beta-catenin were associated with FAM83H expression.	('beta-catenin', 'Gene', (114, 126))	('beta-catenin', 'Gene', (48, 60))	('active', 'MPA', (107, 113))	('expression', 'Species', '29278', (155, 165))	('FAM83H expression', 'Var', (148, 165))	('beta-catenin', 'Gene', (90, 102))	('expression', 'Species', '29278', (70, 80))	('beta-catenin', 'Gene', '1499', (114, 126))	('beta-catenin', 'Gene', '1499', (48, 60))	('expression', 'MPA', (70, 80))	('beta-catenin', 'Gene', '1499', (90, 102))	('associated', 'Reg', (132, 142))	('expression', 'Species', '29278', (34, 44))
147287	31215499	Immunoprecipitation for FAM83H or beta-catenin in MG63 cells showed complex formation of FAM83H and beta-catenin.	('formation', 'biological_process', 'GO:0009058', ('76', '85'))	('FAM83H', 'Var', (89, 95))	('beta-catenin', 'Gene', (100, 112))	('beta-catenin', 'Gene', '1499', (100, 112))	('beta-catenin', 'Gene', '1499', (34, 46))	('MG63', 'CellLine', 'CVCL:0426', (50, 54))	('beta-catenin', 'Gene', (34, 46))
147288	31215499	After immunoprecipitation with FAM83H, immunoblot bands for beta-catenin was detected and vice versa (Fig.	('FAM83H', 'Var', (31, 37))	('beta-catenin', 'Gene', (60, 72))	('beta-catenin', 'Gene', '1499', (60, 72))
147289	31215499	In addition, when we performed fractionation of cell lysates of MG63 cells after knock-down of FAM83H, cytoplasmic and nuclear expression of beta-catenin was low compared with the cells transfected with control shRNA (Fig.	('knock-down', 'Var', (81, 91))	('expression', 'Species', '29278', (127, 137))	('low', 'NegReg', (158, 161))	('beta-catenin', 'Gene', (141, 153))	('beta-catenin', 'Gene', '1499', (141, 153))	('FAM83H', 'Var', (95, 101))	('MG63', 'CellLine', 'CVCL:0426', (64, 68))
147291	31215499	Because FAM83H influenced the expression and subcellular localization of beta-catenin, we investigated whether FAM83H is involved in post-translational protein stabilization of beta-catenin.	('expression', 'MPA', (30, 40))	('beta-catenin', 'Gene', (73, 85))	('influenced', 'Reg', (15, 25))	('subcellular localization', 'MPA', (45, 69))	('protein stabilization', 'biological_process', 'GO:0050821', ('152', '173'))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('beta-catenin', 'Gene', '1499', (73, 85))	('beta-catenin', 'Gene', (177, 189))	('FAM83H', 'Var', (8, 14))	('localization', 'biological_process', 'GO:0051179', ('57', '69'))	('expression', 'Species', '29278', (30, 40))	('beta-catenin', 'Gene', '1499', (177, 189))
147292	31215499	For this purpose, we examined the protein stability of beta-catenin in MG63 cells via treatment with cycloheximide after transfection with either control shRNA or FAM83H shRNA.	('beta-catenin', 'Gene', (55, 67))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('examined', 'Reg', (21, 29))	('FAM83H', 'Var', (163, 169))	('cycloheximide', 'Chemical', 'MESH:D003513', (101, 114))	('beta-catenin', 'Gene', '1499', (55, 67))	('MG63', 'CellLine', 'CVCL:0426', (71, 75))
147293	31215499	5d, the protein stability of beta-catenin in MG63 cells transfected with FAM83H shRNA was greatly reduced (as indicated by more rapid depletion) than in MG63 cells transfected with control shRNA.	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('MG63', 'CellLine', 'CVCL:0426', (45, 49))	('FAM83H', 'Var', (73, 79))	('beta-catenin', 'Gene', (29, 41))	('depletion', 'MPA', (134, 143))	('MG63', 'CellLine', 'CVCL:0426', (153, 157))	('reduced', 'NegReg', (98, 105))	('protein stability', 'MPA', (8, 25))	('beta-catenin', 'Gene', '1499', (29, 41))
147294	31215499	Furthermore, the protein expression of beta-catenin in MG63 cells transfected with FAM83H shRNA decreased within one-hour of treatment of MG132, but the protein expression of beta-catenin in MG63 cells transfected with control shRNA did not decrease after up to two hours (Fig.	('expression', 'Species', '29278', (161, 171))	('expression', 'Species', '29278', (25, 35))	('protein expression', 'MPA', (17, 35))	('beta-catenin', 'Gene', '1499', (175, 187))	('decreased', 'NegReg', (96, 105))	('MG132', 'Chemical', 'MESH:C072553', (138, 143))	('MG63', 'CellLine', 'CVCL:0426', (55, 59))	('MG132', 'Var', (138, 143))	('FAM83H', 'Var', (83, 89))	('protein', 'cellular_component', 'GO:0003675', ('153', '160'))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('MG63', 'CellLine', 'CVCL:0426', (191, 195))	('beta-catenin', 'Gene', (39, 51))	('beta-catenin', 'Gene', (175, 187))	('beta-catenin', 'Gene', '1499', (39, 51))
147295	31215499	These results suggest that the decreased expression level of beta-catenin with knock-down of FAM83H depends on proteasome-mediated protein degradation.	('beta-catenin', 'Gene', '1499', (61, 73))	('expression', 'Species', '29278', (41, 51))	('proteasome', 'molecular_function', 'GO:0004299', ('111', '121'))	('protein degradation', 'biological_process', 'GO:0030163', ('131', '150'))	('knock-down', 'Var', (79, 89))	('decreased', 'NegReg', (31, 40))	('FAM83H', 'Gene', (93, 99))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('beta-catenin', 'Gene', (61, 73))	('expression level', 'MPA', (41, 57))	('proteasome', 'cellular_component', 'GO:0000502', ('111', '121'))	('proteasome-mediated protein degradation', 'MPA', (111, 150))
147299	31215499	6e, immunoprecipitated beta-catenin MG63 cells transfected with FAM83H shRNA clearly showed the poly-ubiquitination pattern of beta-catenin compared to MG63 cells transfected with control shRNA.	('poly-ubiquitination pattern', 'MPA', (96, 123))	('beta-catenin', 'Gene', (23, 35))	('beta-catenin', 'Gene', (127, 139))	('MG63', 'CellLine', 'CVCL:0426', (152, 156))	('MG63', 'CellLine', 'CVCL:0426', (36, 40))	('FAM83H', 'Var', (64, 70))	('beta-catenin', 'Gene', '1499', (23, 35))	('beta-catenin', 'Gene', '1499', (127, 139))
147300	31215499	In this study, we investigate the roles and relationship of FAM83H and beta-catenin in osteosarcomas and show that the expression of FAM83H and beta-catenin are closely associated, and their expression are involved in the progression of osteosarcomas.	('osteosarcomas', 'Phenotype', 'HP:0002669', (237, 250))	('beta-catenin', 'Gene', (144, 156))	('beta-catenin', 'Gene', '1499', (144, 156))	('osteosarcoma', 'Phenotype', 'HP:0002669', (87, 99))	('involved', 'Reg', (206, 214))	('sarcomas', 'Phenotype', 'HP:0100242', (242, 250))	('osteosarcomas', 'Disease', 'MESH:D012516', (87, 100))	('sarcomas', 'Phenotype', 'HP:0100242', (92, 100))	('beta-catenin', 'Gene', (71, 83))	('expression', 'MPA', (191, 201))	('beta-catenin', 'Gene', '1499', (71, 83))	('osteosarcomas', 'Disease', (87, 100))	('osteosarcoma', 'Phenotype', 'HP:0002669', (237, 249))	('osteosarcomas', 'Disease', 'MESH:D012516', (237, 250))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('FAM83H', 'Var', (133, 139))	('osteosarcomas', 'Disease', (237, 250))	('osteosarcomas', 'Phenotype', 'HP:0002669', (87, 100))	('associated', 'Reg', (169, 179))	('expression', 'Species', '29278', (191, 201))	('expression', 'Species', '29278', (119, 129))
147301	31215499	In human osteosarcoma tissue samples, the expression of Cy-FAM83H and Nu-FAM83H were associated with advanced clinicopathologic factors such as larger tumor size, higher tumor stage, and higher histologic grade of osteosarcomas.	('osteosarcoma', 'Disease', 'MESH:D012516', (214, 226))	('human', 'Species', '9606', (3, 8))	('Cy-FAM83H', 'Chemical', '-', (56, 65))	('tumor', 'Disease', (170, 175))	('osteosarcoma', 'Phenotype', 'HP:0002669', (9, 21))	('Cy-FAM83H', 'Var', (56, 65))	('Nu-FAM83H', 'Chemical', '-', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('associated', 'Reg', (85, 95))	('osteosarcoma', 'Phenotype', 'HP:0002669', (214, 226))	('osteosarcomas', 'Disease', 'MESH:D012516', (214, 227))	('sarcomas', 'Phenotype', 'HP:0100242', (219, 227))	('sarcoma', 'Phenotype', 'HP:0100242', (219, 226))	('expression', 'Species', '29278', (42, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('osteosarcomas', 'Disease', (214, 227))	('osteosarcoma', 'Disease', 'MESH:D012516', (9, 21))	('osteosarcoma', 'Disease', (9, 21))	('Nu-FAM83H', 'Var', (70, 79))	('tumor', 'Disease', (151, 156))	('osteosarcomas', 'Phenotype', 'HP:0002669', (214, 227))	('osteosarcoma', 'Disease', (214, 226))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
147302	31215499	Moreover, both Cy-FAM83H and Nu-FAM83H positivity were significantly associated with shorter OS and RFS of osteosarcoma patients by univariate analysis.	('RFS of osteosarcoma', 'Disease', (100, 119))	('Cy-FAM83H', 'Var', (15, 24))	('Nu-FAM83H', 'Chemical', '-', (29, 38))	('Nu-FAM83H', 'Var', (29, 38))	('OS', 'Chemical', '-', (93, 95))	('osteosarcoma', 'Phenotype', 'HP:0002669', (107, 119))	('patients', 'Species', '9606', (120, 128))	('shorter OS', 'Disease', (85, 95))	('RFS of osteosarcoma', 'Disease', 'MESH:D005198', (100, 119))	('Cy-FAM83H', 'Chemical', '-', (15, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))
147303	31215499	Despite the limited number of cases of osteosarcomas, higher expression of Cy-FAM83H was an independent indicator of poor prognosis and shorter OS and RFS of osteosarcoma patients in multivariate analysis.	('expression', 'Species', '29278', (61, 71))	('Cy-FAM83H', 'Chemical', '-', (75, 84))	('osteosarcomas', 'Disease', 'MESH:D012516', (39, 52))	('osteosarcoma', 'Phenotype', 'HP:0002669', (39, 51))	('osteosarcoma', 'Phenotype', 'HP:0002669', (158, 170))	('higher', 'PosReg', (54, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('Cy-FAM83H', 'Var', (75, 84))	('sarcomas', 'Phenotype', 'HP:0100242', (44, 52))	('patients', 'Species', '9606', (171, 179))	('RFS of osteosarcoma', 'Disease', 'MESH:D005198', (151, 170))	('osteosarcomas', 'Disease', (39, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('OS', 'Chemical', '-', (144, 146))	('RFS of osteosarcoma', 'Disease', (151, 170))	('expression', 'MPA', (61, 71))	('osteosarcomas', 'Phenotype', 'HP:0002669', (39, 52))
147304	31215499	In line with these results, higher expression of FAM83H was significantly associated with higher tumor stage and shorter survival of hepatocellular carcinomas and clear cell renal cell carcinoma patients.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (163, 194))	('expression', 'MPA', (35, 45))	('survival', 'MPA', (121, 129))	('FAM83H', 'Var', (49, 55))	('tumor', 'Disease', (97, 102))	('higher', 'PosReg', (28, 34))	('patients', 'Species', '9606', (195, 203))	('shorter', 'NegReg', (113, 120))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (133, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (163, 194))	('expression', 'Species', '29278', (35, 45))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (133, 158))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (174, 194))	('higher', 'PosReg', (90, 96))	('hepatocellular carcinomas', 'Disease', (133, 158))	('clear cell renal cell carcinoma', 'Disease', (163, 194))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (133, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
147305	31215499	In addition, the expression of FAM83H gene was consistently overexpressed in various human cancers such as lung, breast, colon, liver, ovary, pancreas, and stomach cancers, and higher expression of FAM83H gene was associated with shorter survival of uterine cancer patients.	('liver', 'Disease', (128, 133))	('stomach cancers', 'Disease', (156, 171))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('stomach cancers', 'Phenotype', 'HP:0012126', (156, 171))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('expression', 'MPA', (184, 194))	('pancreas', 'Disease', 'MESH:D010190', (142, 150))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('colon', 'Disease', (121, 126))	('ovary', 'Disease', (135, 140))	('FAM83H', 'Var', (198, 204))	('patients', 'Species', '9606', (265, 273))	('FAM83H', 'Gene', (31, 37))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancer', 'Disease', (164, 170))	('cancers', 'Disease', (164, 171))	('expression', 'Species', '29278', (184, 194))	('cancer', 'Disease', (258, 264))	('human', 'Species', '9606', (85, 90))	('breast', 'Disease', (113, 119))	('higher', 'PosReg', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('expression', 'Species', '29278', (17, 27))	('shorter', 'NegReg', (230, 237))	('stomach cancers', 'Disease', 'MESH:D013274', (156, 171))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Disease', (91, 98))	('cancer', 'Disease', (91, 97))	('lung', 'Disease', (107, 111))	('uterine cancer', 'Phenotype', 'HP:0010784', (250, 264))	('pancreas', 'Disease', (142, 150))	('overexpressed', 'PosReg', (60, 73))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
147306	31215499	However, in contrast, gene expression of FAM83H lower in brain astrocytoma and brain oligodendroglioma, and lower expression of FAM83H in these tumors was associated with shorter disease-free survival of patients.	('tumors', 'Disease', (144, 150))	('lower', 'NegReg', (108, 113))	('expression', 'MPA', (114, 124))	('brain astrocytoma', 'Disease', 'MESH:D001254', (57, 74))	('patients', 'Species', '9606', (204, 212))	('FAM83H', 'Var', (41, 47))	('shorter', 'NegReg', (171, 178))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('FAM83H', 'Var', (128, 134))	('brain oligodendroglioma', 'Disease', (79, 102))	('disease-free survival', 'CPA', (179, 200))	('expression', 'Species', '29278', (27, 37))	('lower', 'NegReg', (48, 53))	('expression', 'Species', '29278', (114, 124))	('astrocytoma', 'Phenotype', 'HP:0009592', (63, 74))	('gene expression', 'biological_process', 'GO:0010467', ('22', '37'))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('brain oligodendroglioma', 'Disease', 'MESH:D009837', (79, 102))	('brain astrocytoma', 'Disease', (57, 74))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
147307	31215499	Therefore, there is a possibility that the role of FAM83H in tumorigenesis might differ according to cancer types.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('FAM83H', 'Var', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
147310	31215499	However, despite a difference in the prognostic role of FAM83H according to the type of cancer and the limited number of cases of osteosarcoma used in this study, our results suggest that FAM83H expression might be used as a prognostic marker for osteosarcoma patients.	('cancer', 'Disease', (88, 94))	('FAM83H', 'Var', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('osteosarcoma', 'Phenotype', 'HP:0002669', (130, 142))	('osteosarcoma', 'Disease', 'MESH:D012516', (247, 259))	('osteosarcoma', 'Disease', 'MESH:D012516', (130, 142))	('osteosarcoma', 'Phenotype', 'HP:0002669', (247, 259))	('patients', 'Species', '9606', (260, 268))	('osteosarcoma', 'Disease', (247, 259))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('sarcoma', 'Phenotype', 'HP:0100242', (135, 142))	('expression', 'Species', '29278', (195, 205))	('osteosarcoma', 'Disease', (130, 142))
147312	31215499	Supportively, in this study, in addition to the prognostic significance of Cy-FAM83H and Nu-FAM83H expression in osteosarcoma patients, overexpression of FAM83H increased proliferation of osteosarcoma cells, and knock-down of FAM83H inhibited proliferation of osteosarcoma cells both in vitro and in vivo.	('osteosarcoma', 'Disease', 'MESH:D012516', (188, 200))	('patients', 'Species', '9606', (126, 134))	('expression', 'Species', '29278', (140, 150))	('osteosarcoma', 'Disease', (260, 272))	('osteosarcoma', 'Disease', 'MESH:D012516', (260, 272))	('knock-down', 'Var', (212, 222))	('inhibited', 'NegReg', (233, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (118, 125))	('proliferation', 'CPA', (243, 256))	('increased', 'PosReg', (161, 170))	('osteosarcoma', 'Disease', (113, 125))	('expression', 'Species', '29278', (99, 109))	('proliferation', 'CPA', (171, 184))	('osteosarcoma', 'Phenotype', 'HP:0002669', (188, 200))	('osteosarcoma', 'Disease', 'MESH:D012516', (113, 125))	('Cy-FAM83H', 'Chemical', '-', (75, 84))	('osteosarcoma', 'Phenotype', 'HP:0002669', (260, 272))	('sarcoma', 'Phenotype', 'HP:0100242', (265, 272))	('osteosarcoma', 'Phenotype', 'HP:0002669', (113, 125))	('Nu-FAM83H', 'Chemical', '-', (89, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('FAM83H', 'Var', (154, 160))	('osteosarcoma', 'Disease', (188, 200))
147313	31215499	Moreover, overexpression of FAM83H increased expression of beta-catenin, active beta-catenin, and cyclin D1, and decreased expression of p27.	('FAM83H', 'Var', (28, 34))	('p27', 'Gene', '3429', (137, 140))	('increased', 'PosReg', (35, 44))	('expression', 'MPA', (123, 133))	('p27', 'Gene', (137, 140))	('beta-catenin', 'Gene', '1499', (59, 71))	('expression', 'Species', '29278', (14, 24))	('expression', 'Species', '29278', (45, 55))	('active', 'MPA', (73, 79))	('beta-catenin', 'Gene', (80, 92))	('cyclin D1', 'Gene', '595', (98, 107))	('expression', 'MPA', (45, 55))	('cyclin D1', 'Gene', (98, 107))	('beta-catenin', 'Gene', '1499', (80, 92))	('cyclin', 'molecular_function', 'GO:0016538', ('98', '104'))	('decreased', 'NegReg', (113, 122))	('beta-catenin', 'Gene', (59, 71))	('expression', 'Species', '29278', (123, 133))
147314	31215499	In line with our results, knock-down of FAM83H inhibited proliferation of prostate cancer cells and clear cell renal cell carcinoma cells.	('clear cell renal cell carcinoma', 'Disease', (100, 131))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (111, 131))	('knock-down', 'Var', (26, 36))	('inhibited', 'NegReg', (47, 56))	('prostate cancer', 'Disease', (74, 89))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (100, 131))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('prostate cancer', 'Disease', 'MESH:D011471', (74, 89))	('proliferation', 'CPA', (57, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('prostate cancer', 'Phenotype', 'HP:0012125', (74, 89))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (100, 131))	('FAM83H', 'Var', (40, 46))
147315	31215499	In hepatocellular carcinomas, overexpression of FAM83H increased proliferation of cancer cells in vitro and in vivo.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('FAM83H', 'Var', (48, 54))	('proliferation', 'CPA', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (3, 28))	('hepatocellular carcinomas', 'Disease', (3, 28))	('carcinomas', 'Phenotype', 'HP:0030731', (18, 28))	('increased', 'PosReg', (55, 64))	('overexpression', 'PosReg', (30, 44))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (3, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('expression', 'Species', '29278', (34, 44))
147317	31215499	In addition to the role of FAM83H in the proliferation of cancer cells, FAM83H was involved in the invasiveness of cancer cells.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('involved', 'Reg', (83, 91))	('FAM83H', 'Var', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('invasiveness of cancer', 'Disease', (99, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('invasiveness of cancer', 'Disease', 'MESH:D009362', (99, 121))
147318	31215499	Overexpression of FAM83H increased the migration and invasion activity of osteosarcoma cells, which was associated with increased expression of vimentin and snail.	('osteosarcoma', 'Disease', 'MESH:D012516', (74, 86))	('invasion activity', 'CPA', (53, 70))	('expression', 'MPA', (130, 140))	('snail', 'Gene', '6615', (157, 162))	('osteosarcoma', 'Phenotype', 'HP:0002669', (74, 86))	('increased', 'PosReg', (25, 34))	('expression', 'Species', '29278', (4, 14))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('vimentin', 'cellular_component', 'GO:0045099', ('144', '152'))	('FAM83H', 'Var', (18, 24))	('vimentin', 'cellular_component', 'GO:0045098', ('144', '152'))	('snail', 'Gene', (157, 162))	('migration', 'CPA', (39, 48))	('vimentin', 'Gene', '7431', (144, 152))	('increased', 'PosReg', (120, 129))	('expression', 'Species', '29278', (130, 140))	('vimentin', 'Gene', (144, 152))	('osteosarcoma', 'Disease', (74, 86))
147319	31215499	Moreover, overexpression of FAM83H was associated with more pulmonary metastasis of KHOS/NP cells in vivo (Fig.	('FAM83H', 'Var', (28, 34))	('KHOS', 'Chemical', '-', (84, 88))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (60, 80))	('expression', 'Species', '29278', (14, 24))	('more', 'PosReg', (55, 59))	('overexpression', 'PosReg', (10, 24))	('pulmonary metastasis', 'Disease', (60, 80))
147322	31215499	In human breast cancers, the expression of snail was associated with shorter survival of patients.	('expression', 'Var', (29, 39))	('survival', 'CPA', (77, 85))	('human', 'Species', '9606', (3, 8))	('breast cancers', 'Phenotype', 'HP:0003002', (9, 23))	('shorter', 'NegReg', (69, 76))	('snail', 'Gene', (43, 48))	('expression', 'Species', '29278', (29, 39))	('patients', 'Species', '9606', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('breast cancers', 'Disease', 'MESH:D001943', (9, 23))	('breast cancers', 'Disease', (9, 23))	('snail', 'Gene', '6615', (43, 48))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))
147323	31215499	Therefore, when considering the roles of FAM83H in the expression of vimentin and snail, FAM83H-mediated EMT, which enhances invasiveness of osteosarcomas, might explain how FAM83H is involved in the progression of osteosarcoma.	('expression', 'Species', '29278', (55, 65))	('osteosarcoma', 'Disease', (141, 153))	('osteosarcoma', 'Disease', 'MESH:D012516', (141, 153))	('vimentin', 'cellular_component', 'GO:0045099', ('69', '77'))	('osteosarcomas', 'Phenotype', 'HP:0002669', (141, 154))	('osteosarcoma', 'Phenotype', 'HP:0002669', (215, 227))	('snail', 'Gene', '6615', (82, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (220, 227))	('sarcomas', 'Phenotype', 'HP:0100242', (146, 154))	('osteosarcoma', 'Phenotype', 'HP:0002669', (141, 153))	('snail', 'Gene', (82, 87))	('osteosarcoma', 'Disease', (215, 227))	('vimentin', 'cellular_component', 'GO:0045098', ('69', '77'))	('osteosarcoma', 'Disease', 'MESH:D012516', (215, 227))	('vimentin', 'Gene', '7431', (69, 77))	('invasiveness of osteosarcomas', 'Disease', (125, 154))	('vimentin', 'Gene', (69, 77))	('enhances', 'PosReg', (116, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('FAM83H-mediated', 'Var', (89, 104))	('invasiveness of osteosarcomas', 'Disease', 'MESH:D012516', (125, 154))	('EMT', 'biological_process', 'GO:0001837', ('105', '108'))
147324	31215499	Consistently, knock-down of FAM83H disrupted keratin cytoskeleton organization and inhibited the migration activity of colon cancer cells.	('FAM83H', 'Gene', (28, 34))	('colon cancer', 'Phenotype', 'HP:0003003', (119, 131))	('cytoskeleton organization', 'biological_process', 'GO:0007010', ('53', '78'))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colon cancer', 'Disease', 'MESH:D015179', (119, 131))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('53', '65'))	('colon cancer', 'Disease', (119, 131))	('inhibited', 'NegReg', (83, 92))	('knock-down', 'Var', (14, 24))	('keratin', 'Protein', (45, 52))	('disrupted', 'NegReg', (35, 44))
147331	31215499	Especially, the expressions of both FAM83H and beta-catenin were associated with shorter survival of osteosarcoma patients.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('beta-catenin', 'Gene', '1499', (47, 59))	('expressions', 'Var', (16, 27))	('osteosarcoma', 'Disease', (101, 113))	('FAM83H', 'Var', (36, 42))	('osteosarcoma', 'Phenotype', 'HP:0002669', (101, 113))	('beta-catenin', 'Gene', (47, 59))	('expression', 'Species', '29278', (16, 26))	('osteosarcoma', 'Disease', 'MESH:D012516', (101, 113))	('patients', 'Species', '9606', (114, 122))	('survival', 'MPA', (89, 97))	('shorter', 'NegReg', (81, 88))
147332	31215499	These findings suggest that both FAM83H and beta-catenin are closely associated and involved in the progression of osteosarcomas.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('associated', 'Reg', (69, 79))	('beta-catenin', 'Gene', (44, 56))	('osteosarcomas', 'Disease', (115, 128))	('FAM83H', 'Var', (33, 39))	('osteosarcomas', 'Phenotype', 'HP:0002669', (115, 128))	('osteosarcoma', 'Phenotype', 'HP:0002669', (115, 127))	('osteosarcomas', 'Disease', 'MESH:D012516', (115, 128))	('beta-catenin', 'Gene', '1499', (44, 56))	('involved', 'Reg', (84, 92))	('sarcomas', 'Phenotype', 'HP:0100242', (120, 128))
147337	31215499	In MG63 osteosarcoma cells, knock-down or overexpression of FAM83H did not significantly affect the level of beta-catenin mRNA, but the protein level of beta-catenin decreased with knock-down of FAM83H and increased with overexpression of FAM83H.	('increased', 'PosReg', (206, 215))	('knock-down', 'Var', (181, 191))	('MG63', 'CellLine', 'CVCL:0426', (3, 7))	('beta-catenin', 'Gene', (153, 165))	('decreased', 'NegReg', (166, 175))	('beta-catenin', 'Gene', (109, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('osteosarcoma', 'Phenotype', 'HP:0002669', (8, 20))	('osteosarcoma', 'Disease', (8, 20))	('expression', 'Species', '29278', (46, 56))	('expression', 'Species', '29278', (225, 235))	('osteosarcoma', 'Disease', 'MESH:D012516', (8, 20))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('FAM83H', 'Var', (195, 201))	('beta-catenin', 'Gene', '1499', (153, 165))	('beta-catenin', 'Gene', '1499', (109, 121))	('protein level', 'MPA', (136, 149))
147338	31215499	In addition, FAM83H directly bound to beta-catenin and retarded proteasomal degradation of beta-catenin.	('beta-catenin', 'Gene', (38, 50))	('beta-catenin', 'Gene', '1499', (38, 50))	('beta-catenin', 'Gene', (91, 103))	('retarded', 'Disease', (55, 63))	('degradation', 'biological_process', 'GO:0009056', ('76', '87'))	('bound', 'Interaction', (29, 34))	('retarded', 'Disease', 'MESH:D008607', (55, 63))	('beta-catenin', 'Gene', '1499', (91, 103))	('FAM83H', 'Var', (13, 19))
147339	31215499	When we induced knock-down of FAM83H, ubiquitination of beta-catenin increased which subsequently increased its degradation.	('degradation', 'biological_process', 'GO:0009056', ('112', '123'))	('ubiquitination', 'MPA', (38, 52))	('increased', 'PosReg', (69, 78))	('beta-catenin', 'Gene', (56, 68))	('beta-catenin', 'Gene', '1499', (56, 68))	('increased', 'PosReg', (98, 107))	('FAM83H', 'Var', (30, 36))	('degradation', 'MPA', (112, 123))	('knock-down', 'Var', (16, 26))
147341	31215499	Consistently, FAM83H-mediated stabilization of beta-catenin has been suggested in colorectal cancers.	('beta-catenin', 'Gene', '1499', (47, 59))	('colorectal cancers', 'Disease', 'MESH:D015179', (82, 100))	('stabilization', 'MPA', (30, 43))	('colorectal cancers', 'Disease', (82, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('beta-catenin', 'Gene', (47, 59))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('FAM83H-mediated', 'Var', (14, 29))
147342	31215499	Overexpression of FAM83H suppressed cytoplasmic CK1alpha and thereby supported nuclear localization of beta-catenin with de-phosphorylation mediated stabilization.	('stabilization', 'MPA', (149, 162))	('de-phosphorylation', 'MPA', (121, 139))	('localization', 'biological_process', 'GO:0051179', ('87', '99'))	('nuclear localization', 'MPA', (79, 99))	('expression', 'Species', '29278', (4, 14))	('beta-catenin', 'Gene', (103, 115))	('FAM83H', 'Var', (18, 24))	('CK1', 'Species', '2498238', (48, 51))	('beta-catenin', 'Gene', '1499', (103, 115))	('suppressed', 'NegReg', (25, 35))	('phosphorylation', 'biological_process', 'GO:0016310', ('124', '139'))	('CK1alpha', 'Protein', (48, 56))	('cytoplasmic', 'MPA', (36, 47))	('supported', 'PosReg', (69, 78))
147343	31215499	In liver and kidney cancer, FAM83H expression was associated with the expression of cyclin D1, cyclin E1, and downstream signaling of the Wnt/beta-catenin pathway.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('kidney cancer', 'Phenotype', 'HP:0009726', (13, 26))	('FAM83H expression', 'Var', (28, 45))	('signaling', 'biological_process', 'GO:0023052', ('121', '130'))	('cyclin', 'molecular_function', 'GO:0016538', ('95', '101'))	('cyclin D1', 'Gene', '595', (84, 93))	('liver and kidney cancer', 'Disease', 'MESH:D006528', (3, 26))	('expression', 'Species', '29278', (35, 45))	('beta-catenin', 'Gene', (142, 154))	('cyclin', 'molecular_function', 'GO:0016538', ('84', '90'))	('cyclin D1', 'Gene', (84, 93))	('expression', 'Species', '29278', (70, 80))	('beta-catenin', 'Gene', '1499', (142, 154))	('expression', 'MPA', (70, 80))	('cyclin E1', 'Gene', (95, 104))	('associated', 'Reg', (50, 60))
147344	31215499	Therefore, these findings suggest that FAM83H is involved in the progression of osteosarcoma by mediating stabilization of beta-catenin from its proteasomal degradation.	('beta-catenin', 'Gene', '1499', (123, 135))	('osteosarcoma', 'Phenotype', 'HP:0002669', (80, 92))	('degradation', 'biological_process', 'GO:0009056', ('157', '168'))	('stabilization', 'MPA', (106, 119))	('involved', 'Reg', (49, 57))	('osteosarcoma', 'Disease', (80, 92))	('FAM83H', 'Var', (39, 45))	('beta-catenin', 'Gene', (123, 135))	('osteosarcoma', 'Disease', 'MESH:D012516', (80, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))
147346	31215499	In addition, in our results, the expression of beta-catenin was significantly associated with shorter OS and RFS of osteosarcoma patients in univariate analysis.	('beta-catenin', 'Gene', '1499', (47, 59))	('OS', 'Chemical', '-', (102, 104))	('shorter OS', 'Disease', (94, 104))	('osteosarcoma', 'Phenotype', 'HP:0002669', (116, 128))	('expression', 'Var', (33, 43))	('patients', 'Species', '9606', (129, 137))	('RFS of osteosarcoma', 'Disease', 'MESH:D005198', (109, 128))	('RFS of osteosarcoma', 'Disease', (109, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('expression', 'Species', '29278', (33, 43))	('beta-catenin', 'Gene', (47, 59))
147347	31215499	Although there is one controversial report, the expression of beta-catenin has been reported to be associated with poor prognosis of cancer patients including those with soft-tissue sarcomas.	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (170, 190))	('sarcomas', 'Disease', 'MESH:D012509', (182, 190))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('beta-catenin', 'Gene', (62, 74))	('expression', 'Species', '29278', (48, 58))	('sarcomas', 'Phenotype', 'HP:0100242', (182, 190))	('sarcomas', 'Disease', (182, 190))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('beta-catenin', 'Gene', '1499', (62, 74))	('cancer', 'Disease', (133, 139))	('expression', 'Var', (48, 58))	('patients', 'Species', '9606', (140, 148))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (170, 189))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('associated', 'Reg', (99, 109))
147349	31215499	However, as we have shown in human osteosarcoma tissue samples, western blotting of subcellular fractionated protein and confocal microscopic images indicate that FAM83H expression was observed in the cytoplasmic membrane, cytoplasm, and nuclei.	('osteosarcoma', 'Phenotype', 'HP:0002669', (35, 47))	('FAM83H', 'Var', (163, 169))	('cytoplasmic membrane', 'cellular_component', 'GO:0005886', ('201', '221'))	('osteosarcoma', 'Disease', (35, 47))	('osteosarcoma', 'Disease', 'MESH:D012516', (35, 47))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('human', 'Species', '9606', (29, 34))	('expression', 'Species', '29278', (170, 180))	('cytoplasmic membrane', 'cellular_component', 'GO:0009280', ('201', '221'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('223', '232'))
147350	31215499	In addition, both Cy-FAM83H and Nu-FAM83H expression were significantly associated with higher stage, larger tumor size, and higher histologic grade of osteosarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (157, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (157, 164))	('expression', 'Species', '29278', (42, 52))	('Nu-FAM83H', 'Var', (32, 41))	('Cy-FAM83H', 'Chemical', '-', (18, 27))	('associated', 'Reg', (72, 82))	('osteosarcomas', 'Disease', (152, 165))	('Nu-FAM83H', 'Chemical', '-', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('osteosarcoma', 'Phenotype', 'HP:0002669', (152, 164))	('osteosarcomas', 'Phenotype', 'HP:0002669', (152, 165))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('Cy-FAM83H', 'Var', (18, 27))	('osteosarcomas', 'Disease', 'MESH:D012516', (152, 165))	('tumor', 'Disease', (109, 114))
147351	31215499	Moreover, both Cy-FAM83H and Nu-FAM83H expression was significantly associated with shorter survival of osteosarcoma patients in univariate analysis.	('Cy-FAM83H', 'Var', (15, 24))	('Nu-FAM83H', 'Chemical', '-', (29, 38))	('osteosarcoma', 'Disease', (104, 116))	('osteosarcoma', 'Phenotype', 'HP:0002669', (104, 116))	('osteosarcoma', 'Disease', 'MESH:D012516', (104, 116))	('survival', 'MPA', (92, 100))	('shorter', 'NegReg', (84, 91))	('Cy-FAM83H', 'Chemical', '-', (15, 24))	('expression', 'Species', '29278', (39, 49))	('patients', 'Species', '9606', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('Nu-FAM83H expression', 'Var', (29, 49))
147352	31215499	Consistently, both Cy-FAM83H and Nu-FAM83H expression were associated with shorter survival of hepatocellular carcinoma and clear cell renal cell carcinoma patients.	('patients', 'Species', '9606', (156, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('clear cell renal cell carcinoma', 'Disease', (124, 155))	('Cy-FAM83H', 'Var', (19, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (135, 155))	('Nu-FAM83H', 'Chemical', '-', (33, 42))	('Nu-FAM83H expression', 'Var', (33, 53))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (124, 155))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (95, 119))	('expression', 'Species', '29278', (43, 53))	('shorter', 'NegReg', (75, 82))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (95, 119))	('Cy-FAM83H', 'Chemical', '-', (19, 28))	('hepatocellular carcinoma', 'Disease', (95, 119))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (124, 155))	('survival', 'MPA', (83, 91))
147353	31215499	In multivariate analysis, Nu-FAM83H expression was an independent indicator of shorter survival of hepatocellular carcinoma and clear cell renal cell carcinoma patients.	('survival', 'MPA', (87, 95))	('patients', 'Species', '9606', (160, 168))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (128, 159))	('clear cell renal cell carcinoma', 'Disease', (128, 159))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (139, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('shorter', 'NegReg', (79, 86))	('Nu-FAM83H', 'Chemical', '-', (26, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (128, 159))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (99, 123))	('expression', 'Species', '29278', (36, 46))	('hepatocellular carcinoma', 'Disease', (99, 123))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (99, 123))	('Nu-FAM83H expression', 'Var', (26, 46))
147354	31215499	Therefore, nuclear localization of FAM83H was suggested as an important indicator of cancer progression.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('FAM83H', 'Var', (35, 41))	('cancer', 'Disease', (85, 91))	('localization', 'biological_process', 'GO:0051179', ('19', '31'))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
147355	31215499	However, in osteosarcoma, the statistical prognostic significance of Cy-FAM83H expression was potent in comparison to Nu-FAM83H expression in multivariate analysis.	('expression', 'Species', '29278', (79, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('Nu-FAM83H', 'Chemical', '-', (118, 127))	('Cy-FAM83H', 'Chemical', '-', (69, 78))	('Cy-FAM83H expression', 'Var', (69, 89))	('osteosarcoma', 'Disease', (12, 24))	('expression', 'Species', '29278', (128, 138))	('osteosarcoma', 'Phenotype', 'HP:0002669', (12, 24))	('osteosarcoma', 'Disease', 'MESH:D012516', (12, 24))
147357	31215499	However, despite this limitation, knock-down or overexpression of FAM83H influenced proliferation and/or invasiveness of various human cancers such as osteosarcoma, prostate cancer, hepatocellular carcinoma, and clear cell renal cell carcinoma patients.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (212, 243))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('invasiveness', 'CPA', (105, 117))	('FAM83H', 'Var', (66, 72))	('patients', 'Species', '9606', (244, 252))	('hepatocellular carcinoma', 'Disease', (182, 206))	('influenced', 'Reg', (73, 83))	('osteosarcoma', 'Phenotype', 'HP:0002669', (151, 163))	('expression', 'Species', '29278', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('proliferation', 'CPA', (84, 97))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (212, 243))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('knock-down', 'Var', (34, 44))	('cancers', 'Disease', (135, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('overexpression', 'PosReg', (48, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('clear cell renal cell carcinoma', 'Disease', (212, 243))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (182, 206))	('osteosarcoma', 'Disease', (151, 163))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (223, 243))	('prostate cancer', 'Disease', 'MESH:D011471', (165, 180))	('prostate cancer', 'Phenotype', 'HP:0012125', (165, 180))	('osteosarcoma', 'Disease', 'MESH:D012516', (151, 163))	('prostate cancer', 'Disease', (165, 180))	('human', 'Species', '9606', (129, 134))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (182, 206))
147358	31215499	Therefore, it is suggested that the overall expression of FAM83H is important in the progression of FAM83H and higher expression of FAM83H might promote tumor progression.	('FAM83H', 'Disease', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('higher expression', 'PosReg', (111, 128))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('FAM83H', 'Var', (132, 138))	('expression', 'Species', '29278', (118, 128))	('promote', 'PosReg', (145, 152))	('expression', 'Species', '29278', (44, 54))
147359	31215499	In conclusion, we showed that FAM38H expression is important for the proliferation and invasiveness of osteosarcoma cells and suggest that stabilizing beta-catenin protein by FAM38H can be a biochemical mechanism to explain the significant association between FAM38H expression and shorter survival of osteosarcoma patients.	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('expression', 'Species', '29278', (37, 47))	('FAM38H', 'Chemical', '-', (175, 181))	('expression', 'Species', '29278', (267, 277))	('beta-catenin', 'Gene', (151, 163))	('beta-catenin', 'Gene', '1499', (151, 163))	('osteosarcoma', 'Phenotype', 'HP:0002669', (103, 115))	('osteosarcoma', 'Phenotype', 'HP:0002669', (302, 314))	('shorter', 'NegReg', (282, 289))	('FAM38H', 'Var', (175, 181))	('patients', 'Species', '9606', (315, 323))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('sarcoma', 'Phenotype', 'HP:0100242', (307, 314))	('FAM38H', 'Chemical', '-', (260, 266))	('FAM38H', 'Chemical', '-', (30, 36))	('invasiveness of osteosarcoma', 'Disease', (87, 115))	('osteosarcoma', 'Disease', (103, 115))	('osteosarcoma', 'Disease', 'MESH:D012516', (103, 115))	('osteosarcoma', 'Disease', (302, 314))	('osteosarcoma', 'Disease', 'MESH:D012516', (302, 314))	('FAM38H', 'Var', (260, 266))	('invasiveness of osteosarcoma', 'Disease', 'MESH:D012516', (87, 115))
147370	32244557	LTF overexpression suppresses migration ability in A498 ccRCC cells with high metastatic potential, whereas LTF knockdown fosters cellular migration in poorly metastatic ccRCC cells.	('migration ability', 'CPA', (30, 47))	('fosters', 'PosReg', (122, 129))	('A498', 'CellLine', 'CVCL:1056', (51, 55))	('suppresses', 'NegReg', (19, 29))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('LTF', 'Gene', (0, 3))	('LTF', 'Gene', '4057', (0, 3))	('LTF', 'Gene', (108, 111))	('knockdown', 'Var', (112, 121))	('LTF', 'Gene', '4057', (108, 111))	('RCC', 'Disease', (58, 61))	('RCC', 'Disease', (172, 175))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('cellular migration', 'CPA', (130, 148))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))
147412	32244557	Specifically, patients with ccRCC expressing a low level of LTF transcript had the shortest overall survival time (Figure 1E).	('LTF', 'Gene', (60, 63))	('LTF', 'Gene', '4057', (60, 63))	('shortest', 'NegReg', (83, 91))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('RCC', 'Disease', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('low level', 'Var', (47, 56))	('patients', 'Species', '9606', (14, 22))	('overall', 'MPA', (92, 99))
147413	32244557	We further found that TCGA ccRCC patients with primary tumors expressing a high level of LTF transcript had a 72.2% 5-year survival rate, while patients with primary tumors harboring a low level of LTF transcript had a 23.1% 5-year survival rate (Figure 2A).	('LTF', 'Gene', (198, 201))	('LTF', 'Gene', '4057', (198, 201))	('primary tumors', 'Disease', 'MESH:D001932', (47, 61))	('primary tumors', 'Disease', (158, 172))	('patients', 'Species', '9606', (33, 41))	('LTF', 'Gene', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('LTF', 'Gene', '4057', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('primary tumors', 'Disease', 'MESH:D001932', (158, 172))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('high level', 'Var', (75, 85))	('patients', 'Species', '9606', (144, 152))	('primary tumors', 'Disease', (47, 61))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
147422	32244557	While the overexpression of the exogenous LTF gene in ACHN cells dramatically suppressed cellular migration ability (Figure 3D-F), the gene knockdown of endogenous LTF using two independent shRNA clones predominantly enhanced the migration ability of A498 cells (Figure 3G-I).	('ACHN', 'Gene', '55323', (54, 58))	('LTF', 'Gene', (164, 167))	('A498', 'CellLine', 'CVCL:1056', (251, 255))	('LTF', 'Gene', '4057', (164, 167))	('suppressed', 'NegReg', (78, 88))	('gene knockdown', 'Var', (135, 149))	('enhanced', 'PosReg', (217, 225))	('ACHN', 'Gene', (54, 58))	('migration ability of A498 cells', 'CPA', (230, 261))	('LTF', 'Gene', (42, 45))	('LTF', 'Gene', '4057', (42, 45))	('cellular migration ability', 'CPA', (89, 115))
147431	32244557	While the enforced expression of the exogenous LTF gene in ACHN cells reduced ENO2 mRNA and protein expression but increased CDH6 mRNA and protein expression (Figure 4F and Figure S2B), silencing endogenous LTF expression in A498 cells enhanced ENO2 mRNA and protein expression but reduced CDH6 mRNA and protein expression (Figure 4G and Figure S2C).	('protein', 'cellular_component', 'GO:0003675', ('259', '266'))	('LTF', 'Gene', (47, 50))	('LTF', 'Gene', '4057', (47, 50))	('reduced', 'NegReg', (282, 289))	('ENO2', 'Gene', '2026', (245, 249))	('ENO2', 'Gene', '2026', (78, 82))	('ENO2', 'Gene', (78, 82))	('ENO2', 'Gene', (245, 249))	('increased', 'PosReg', (115, 124))	('ACHN', 'Gene', '55323', (59, 63))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('reduced', 'NegReg', (70, 77))	('protein', 'cellular_component', 'GO:0003675', ('304', '311'))	('silencing', 'Var', (186, 195))	('endogenous', 'Gene', (196, 206))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('CDH6', 'Gene', '1004', (125, 129))	('LTF', 'Gene', (207, 210))	('enhanced', 'PosReg', (236, 244))	('CDH6', 'Gene', '1004', (290, 294))	('LTF', 'Gene', '4057', (207, 210))	('ACHN', 'Gene', (59, 63))	('CDH6', 'Gene', (125, 129))	('A498', 'CellLine', 'CVCL:1056', (225, 229))	('CDH6', 'Gene', (290, 294))
147435	32244557	The data showed that LTF knockdown in A498 cells enhanced E2F DNA-binding activity, which was suppressed by adding recombinant LTF (recLTF) protein into the cell culture (Figure S3A).	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('62', '73'))	('LTF', 'Gene', (21, 24))	('LTF', 'Gene', (127, 130))	('E2F', 'Protein', (58, 61))	('enhanced', 'PosReg', (49, 57))	('LTF', 'Gene', '4057', (21, 24))	('LTF', 'Gene', '4057', (127, 130))	('A498', 'CellLine', 'CVCL:1056', (38, 42))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('LTF', 'Gene', (135, 138))	('knockdown', 'Var', (25, 34))	('LTF', 'Gene', '4057', (135, 138))
147445	32244557	LRP1 knockdown appeared to compromise the recLTF protein-mediated suppression of cellular migration ability in ACHN cells (Figure 6B,C).	('ACHN', 'Gene', (111, 115))	('LRP1', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('LTF', 'Gene', (45, 48))	('LTF', 'Gene', '4057', (45, 48))	('compromise', 'NegReg', (27, 37))	('LRP1', 'Gene', '4035', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('ACHN', 'Gene', '55323', (111, 115))	('suppression', 'NegReg', (66, 77))
147448	32244557	Kaplan-Meier analyses demonstrated that LRP1 acts as a poor prognostic marker, and the signature of combining high LRP1 level with low LTF expression predicts a poor overall survival rate in ccRCC patients (Figure 6H).	('LRP1', 'Gene', '4035', (115, 119))	('LRP1', 'Gene', '4035', (40, 44))	('RCC', 'Disease', (193, 196))	('patients', 'Species', '9606', (197, 205))	('RCC', 'Phenotype', 'HP:0005584', (193, 196))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('poor', 'NegReg', (161, 165))	('LRP1', 'Gene', (115, 119))	('high', 'Var', (110, 114))	('LRP1', 'Gene', (40, 44))	('LTF', 'Gene', (135, 138))	('LTF', 'Gene', '4057', (135, 138))
147476	32244557	We found that nine signaling pathways were significantly predicted to be activated in metastatic ccRCC with low LTF expression but inhibited in nonmetastatic ccRCC with high LTF expression (Figure 4B).	('low', 'Var', (108, 111))	('LTF', 'Gene', (112, 115))	('LTF', 'Gene', (174, 177))	('LTF', 'Gene', '4057', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('LTF', 'Gene', '4057', (174, 177))	('RCC', 'Disease', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('inhibited', 'NegReg', (131, 140))	('signaling pathways', 'Pathway', (19, 37))	('activated', 'PosReg', (73, 82))
147483	32244557	Recent evidence from a multivariate analysis showed that high ENO2 expression was an independent prognostic factor for acute lymphoblastic leukemia patients.	('patients', 'Species', '9606', (148, 156))	('acute lymphoblastic leukemia', 'Disease', (119, 147))	('high', 'Var', (57, 61))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (119, 147))	('ENO2', 'Gene', '2026', (62, 66))	('expression', 'MPA', (67, 77))	('leukemia', 'Phenotype', 'HP:0001909', (139, 147))	('ENO2', 'Gene', (62, 66))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (119, 147))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (125, 147))
147484	32244557	Another recent study concluded that high ENO2 expression was associated with poor overall survival in ccRCC patients.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('poor', 'NegReg', (77, 81))	('ENO2', 'Gene', '2026', (41, 45))	('ENO2', 'Gene', (41, 45))	('overall survival', 'MPA', (82, 98))	('patients', 'Species', '9606', (108, 116))	('expression', 'MPA', (46, 56))	('high', 'Var', (36, 40))	('RCC', 'Disease', (104, 107))
147496	32244557	In this study, silencing LRP1 inhibited the recLTF protein-suppressed cellular migration ability and failed to alter the gene expression of ENO2 and CDH6 in ccRCC cells (Figure 6B-D).	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('LRP1', 'Gene', (25, 29))	('LTF', 'Gene', (47, 50))	('LTF', 'Gene', '4057', (47, 50))	('inhibited', 'NegReg', (30, 39))	('LRP1', 'Gene', '4035', (25, 29))	('ENO2', 'Gene', '2026', (140, 144))	('ENO2', 'Gene', (140, 144))	('RCC', 'Disease', (159, 162))	('silencing', 'Var', (15, 24))	('protein-suppressed', 'NegReg', (51, 69))	('CDH6', 'Gene', (149, 153))	('CDH6', 'Gene', '1004', (149, 153))	('gene expression', 'biological_process', 'GO:0010467', ('121', '136'))	('cellular migration ability', 'CPA', (70, 96))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
147507	32244557	Cells (50% confluent) grown on 6-well plates were cultured in fresh media containing 5 mug/mL polybrene (SantaCruz, Dallas, TX, USA) before infection overnight with a lentiviral particle-driven control or candidate gene shRNA at 2-10 multiplicity of infection (MOI).	('polybrene', 'Chemical', 'MESH:D006583', (94, 103))	('infection', 'Disease', (140, 149))	('polybrene', 'Var', (94, 103))	('infection', 'Disease', 'MESH:D007239', (140, 149))	('infection', 'Disease', (250, 259))	('mug', 'molecular_function', 'GO:0043739', ('87', '90'))	('infection', 'Disease', 'MESH:D007239', (250, 259))
147529	29451900	Endometrioid ovarian carcinomas showed negative staining for ARID1A (a) and p21 (b), aberrant expression of p53 (c) and p16 (d) and ss-Catenin positive nuclear expression (e) respectively in 19% (a), 100% (b), 28.6% (c), 52.4% (d) and 4.8% (e) of all cases.	('carcinomas', 'Phenotype', 'HP:0030731', (21, 31))	('aberrant', 'Var', (85, 93))	('p53', 'Gene', (108, 111))	('Endometrioid ovarian carcinomas', 'Disease', 'MESH:D016889', (0, 31))	('ss-Catenin', 'Chemical', '-', (132, 142))	('p53', 'Gene', '7157', (108, 111))	('p21', 'Gene', '1026', (76, 79))	('p16', 'Gene', (120, 123))	('p21', 'Gene', (76, 79))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (13, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (13, 30))	('Endometrioid ovarian carcinomas', 'Disease', (0, 31))	('p16', 'Gene', '1029', (120, 123))	('negative', 'NegReg', (39, 47))	('ARID1A', 'Protein', (61, 67))
147532	29451900	Survival analysis showed that negative expression of ARID1A, p53 aberrant expression and ss-Catenin nuclear positive staining are independent negative prognosticators in both, clear cell and endometrioid carcinoma, regardless of ovarian or uterine origin.	('endometrioid carcinoma', 'Disease', (191, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('negative', 'NegReg', (30, 38))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (191, 213))	('regardless of ovarian', 'Disease', (215, 236))	('aberrant expression', 'Var', (65, 84))	('negative', 'NegReg', (142, 150))	('clear cell', 'Disease', (176, 186))	('ss-Catenin', 'Chemical', '-', (89, 99))	('regardless of ovarian', 'Disease', 'MESH:D010051', (215, 236))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (191, 213))	('ARID1A', 'Gene', (53, 59))
147541	29451900	Type II carcinomas include high-grade serous, which show typically a p53 mutation and, at least for patients with a BRCA mutation frequently arise from the fimbriated end of the fallopian tube via serous tubar intraepithelial carcinoma (STIC).	('high-grade serous', 'Disease', (27, 44))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('Type II carcinomas', 'Disease', (0, 18))	('Type II carcinomas', 'Disease', 'MESH:D016532', (0, 18))	('fallopian tube via serous tubar intraepithelial carcinoma', 'Disease', 'MESH:D005185', (178, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('carcinomas', 'Phenotype', 'HP:0030731', (8, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('patients', 'Species', '9606', (100, 108))	('mutation', 'Var', (121, 129))	('mutation', 'Var', (73, 81))	('arise', 'Reg', (141, 146))	('BRCA', 'Gene', (116, 120))	('BRCA', 'Gene', '672', (116, 120))
147608	29451900	Patients with n-m- staining for ss-Catenin in their tumors had a 5-year survival rate of 44.4% and patients with n+m+ staining had a 5-year survival rate of 40,0% compared to 78.5% survival for those with n-m+ expression.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('ss-Catenin', 'Chemical', '-', (32, 42))	('n-m- staining', 'Var', (14, 27))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('patients', 'Species', '9606', (99, 107))	('Patients', 'Species', '9606', (0, 8))	('ss-Catenin', 'Protein', (32, 42))
147615	29451900	This staining combination was found to be mostly in tumors with grading G3 and FIGO staging IV.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('FIGO staging', 'Disease', (79, 91))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('grading G3', 'Var', (64, 74))
147627	29451900	These findings confirm the results of various studies, which indicate that most of the ovarian clear cell tumors show p53 mutations, while most of endometrioid tumors do not.	('ovarian clear cell tumors', 'Disease', (87, 112))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('endometrioid tumors', 'Disease', (147, 166))	('p53', 'Gene', (118, 121))	('endometrioid tumors', 'Disease', 'MESH:D016889', (147, 166))	('ovarian clear cell tumors', 'Disease', 'MESH:D008649', (87, 112))	('p53', 'Gene', '7157', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('mutations', 'Var', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))
147632	29451900	In several studies, the p53 mutation prevalence among clear cell uterine carcinoma ranges from 28.5% to 76.9%.	('p53', 'Gene', '7157', (24, 27))	('p53', 'Gene', (24, 27))	('carcinoma', 'Disease', (73, 82))	('uterine carcinoma', 'Phenotype', 'HP:0010784', (65, 82))	('clear cell uterine carcinoma', 'Phenotype', 'HP:0031522', (54, 82))	('mutation', 'Var', (28, 36))	('carcinoma', 'Disease', 'MESH:D002277', (73, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
147633	29451900	For endometrioid uterine carcinoma however, most of the tumors appear to have no p53 mutation, which is in agreement with our results.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('carcinoma', 'Disease', (25, 34))	('mutation', 'Var', (85, 93))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('uterine carcinoma', 'Phenotype', 'HP:0010784', (17, 34))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('p53', 'Gene', '7157', (81, 84))	('p53', 'Gene', (81, 84))	('carcinoma', 'Disease', 'MESH:D002277', (25, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))
147641	29451900	ss-Catenin mutations are particularly common in endometrioid ovarian and uterine cancer.	('ss-Catenin', 'Gene', (0, 10))	('mutations', 'Var', (11, 20))	('uterine cancer', 'Phenotype', 'HP:0010784', (73, 87))	('endometrioid ovarian', 'Disease', 'MESH:D016889', (48, 68))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('ss-Catenin', 'Chemical', '-', (0, 10))	('endometrioid ovarian', 'Disease', (48, 68))	('common', 'Reg', (38, 44))
147644	29451900	ARID1A mutations are frequently in various tumors including gastric cancer, colorectal cancer, breast cancer, lung cancer and gynaecological cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('lung cancer', 'Disease', (110, 121))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))	('breast cancer', 'Disease', (95, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', (141, 147))	('mutations', 'Var', (7, 16))	('cancer', 'Disease', (87, 93))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('gastric cancer', 'Disease', (60, 74))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (102, 108))	('ARID1A', 'Gene', (0, 6))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('cancer', 'Disease', (115, 121))	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('colorectal cancer', 'Disease', (76, 93))	('cancer', 'Disease', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
147645	29451900	High rates of ARID1A mutations were observed in 46-57% of ovarian clear cell carcinomas, 30% of ovarian endometrioid carcinomas and 40% of uterine endometrioid carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (104, 126))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (104, 127))	('ovarian endometrioid carcinomas', 'Disease', 'MESH:D016889', (96, 127))	('endometrioid carcinomas', 'Disease', (147, 170))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('observed', 'Reg', (36, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (147, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('ovarian clear cell carcinomas', 'Disease', (58, 87))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('mutations', 'Var', (21, 30))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (147, 169))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (58, 87))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (147, 170))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (104, 127))	('ARID1A', 'Gene', (14, 20))	('ovarian endometrioid carcinomas', 'Disease', (96, 127))
147649	29451900	ARID1A silencing seems to be inducing a subcellular redistribution of beta-catenin from the plasma membrane to the cytoplasm and nucleus in gastric cancer, which was found to be significantly associated with worse clinical prognosis.	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('plasma membrane', 'cellular_component', 'GO:0005886', ('92', '107'))	('beta-catenin', 'Gene', (70, 82))	('cytoplasm', 'cellular_component', 'GO:0005737', ('115', '124'))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('beta-catenin', 'Gene', '1499', (70, 82))	('gastric cancer', 'Disease', (140, 154))	('ARID1A', 'Gene', (0, 6))	('nucleus', 'cellular_component', 'GO:0005634', ('129', '136'))	('gastric cancer', 'Disease', 'MESH:D013274', (140, 154))	('silencing', 'Var', (7, 16))
147654	29451900	In a multivariate Cox Regression analysis this staining combination of ARID1A and ss-Catenin meant a 2.209 fold increased risk for tumor-related death.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('Cox', 'Gene', '1351', (18, 21))	('tumor', 'Disease', (131, 136))	('Cox', 'Gene', (18, 21))	('ss-Catenin', 'Chemical', '-', (82, 92))	('staining', 'Var', (47, 55))	('ARID1A', 'Gene', (71, 77))
147656	29451900	It could already be demonstrated that ARID1A loss and ss-Catenin mutation, each seen individually, are important in progression of different types of human cancer.	('human', 'Species', '9606', (150, 155))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('ARID1A', 'Gene', (38, 44))	('ss-Catenin', 'Chemical', '-', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('mutation', 'Var', (65, 73))	('ss-Catenin', 'Gene', (54, 64))	('loss', 'NegReg', (45, 49))
147673	33178496	High TNFRSF9+ CD8+ T cells infiltration was associated with inferior overall survival in ZS cohort (p = .0016) and TCGA-KIRC cohort (p = .018).	('overall survival', 'MPA', (69, 85))	('inferior', 'NegReg', (60, 68))	('High', 'Var', (0, 4))	('TNFRSF9+', 'Gene', (5, 13))	('CD8', 'Gene', (14, 17))	('CD8', 'Gene', '925', (14, 17))
147674	33178496	TNFRSF9+ CD8+ T cells expressed higher exhaustion markers (PD-1, TIM-3, CTLA-4, and TIGIT), and effector markers (IFN-gamma, GZMB, CD107a, and Ki-67), than their TNFRSF9 negative counterparts.	('TIM-3', 'Gene', (65, 70))	('CD8', 'Gene', '925', (9, 12))	('TIGIT', 'Gene', '201633', (84, 89))	('CTLA-4', 'Gene', (72, 78))	('TIM-3', 'Gene', '84868', (65, 70))	('higher', 'PosReg', (32, 38))	('TIGIT', 'Gene', (84, 89))	('GZMB', 'Gene', '3002', (125, 129))	('TNFRSF9+', 'Var', (0, 8))	('IFN-gamma', 'Gene', '3458', (114, 123))	('IFN-gamma', 'Gene', (114, 123))	('CD107a', 'Gene', '3916', (131, 137))	('CTLA-4', 'Gene', '1493', (72, 78))	('GZMB', 'Gene', (125, 129))	('CD107a', 'Gene', (131, 137))	('CD8', 'Gene', (9, 12))
147684	33178496	Intuitively and experimentally, high CD8+ T cells infiltration is associated with a favorable prognosis in patients with cancer.	('high', 'Var', (32, 36))	('CD8', 'Gene', (37, 40))	('CD8', 'Gene', '925', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('patients', 'Species', '9606', (107, 115))
147735	33178496	The co-expression between TNFRSF9 and CD8A was further been validated by the detection of TNFRSF9+ CD8+ T cells in tumor tissue both by immunohistochemistry and immunofluorescence (Figure 1(c,e)).	('CD8A', 'Gene', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('CD8', 'Gene', (99, 102))	('CD8', 'Gene', '925', (99, 102))	('tumor', 'Disease', (115, 120))	('TNFRSF9', 'Gene', (26, 33))	('CD8', 'Gene', (38, 41))	('CD8', 'Gene', '925', (38, 41))	('CD8A', 'Gene', '925', (38, 42))	('TNFRSF9+', 'Var', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
147737	33178496	Correspondingly, the percentage of TNFRSF9+ CD8+ T cells in CD8+ T cells was significantly higher in tumor samples compared with that in peritumoral and blood samples (Figure 1(d,g)).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('CD8', 'Gene', (44, 47))	('CD8', 'Gene', '925', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('higher', 'PosReg', (91, 97))	('CD8', 'Gene', '925', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', (141, 146))	('TNFRSF9+', 'Var', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('CD8', 'Gene', (60, 63))
147738	33178496	These results indicated that TNFRSF9+ CD8+ T cells were enriched in ccRCC tissues.	('ccRCC', 'Disease', (68, 73))	('CD8', 'Gene', (38, 41))	('TNFRSF9+', 'Var', (29, 37))	('CD8', 'Gene', '925', (38, 41))
147741	33178496	However, the high TNFRSF9+ CD8+ T cells were associated with worse OS or RFS (Figure 2(b), p= .0016 and p= .0069, respectively).	('high', 'Var', (13, 17))	('CD8', 'Gene', (27, 30))	('CD8', 'Gene', '925', (27, 30))	('RFS', 'Disease', (73, 76))	('TNFRSF9+', 'Gene', (18, 26))	('RFS', 'Disease', 'MESH:D005198', (73, 76))
147742	33178496	Multivariate Cox regression analysis suggested that high TNFRSF9+ CD8+ T cells infiltration was still associated with inferior OS after adjusted for sex, ECOG score, nuclear grade, age, necrosis, and TNM stage (Figure 2(c), HR = 1.609, 95% CI = 1.032-2.507 & p= .036 in OS, and HR = 1.592, 95% CI = 0.978-2.591 & p= .061 in RFS).	('necrosis', 'biological_process', 'GO:0008220', ('186', '194'))	('TNM', 'Gene', (200, 203))	('inferior', 'Disease', (118, 126))	('necrosis', 'biological_process', 'GO:0001906', ('186', '194'))	('necrosis', 'biological_process', 'GO:0070265', ('186', '194'))	('necrosis', 'Disease', (186, 194))	('CD8', 'Gene', (66, 69))	('TNFRSF9+', 'Gene', (57, 65))	('CD8', 'Gene', '925', (66, 69))	('RFS', 'Disease', (324, 327))	('high', 'Var', (52, 56))	('TNM', 'Gene', '10178', (200, 203))	('RFS', 'Disease', 'MESH:D005198', (324, 327))	('necrosis', 'biological_process', 'GO:0008219', ('186', '194'))	('necrosis', 'Disease', 'MESH:D009336', (186, 194))	('necrosis', 'biological_process', 'GO:0019835', ('186', '194'))
147743	33178496	In addition, high TNFRSF9+ CD8+ T cells infiltration were associated with higher T stage or TNM stage, which indicated a potential relationship between TNFRSF9+ CD8+ T cells and disease progression (Figure 2(d)).	('T stage', 'CPA', (81, 88))	('higher', 'PosReg', (74, 80))	('CD8', 'Gene', (161, 164))	('high', 'Var', (13, 17))	('TNM', 'Gene', (92, 95))	('CD8', 'Gene', (27, 30))	('TNM', 'Gene', '10178', (92, 95))	('CD8', 'Gene', '925', (27, 30))	('CD8', 'Gene', '925', (161, 164))	('TNFRSF9+', 'Gene', (18, 26))
147745	33178496	Furthermore, in TCGA-KIRC cohort, high TNFRSF9+ CD8+ T cells signature was also more frequently present in high T stage or TNM stage (Supplement Figure 2C).	('TNM', 'Gene', (123, 126))	('TNFRSF9+', 'Gene', (39, 47))	('CD8', 'Gene', (48, 51))	('high', 'Var', (34, 38))	('CD8', 'Gene', '925', (48, 51))	('high T stage', 'CPA', (107, 119))	('TNM', 'Gene', '10178', (123, 126))
147746	33178496	As described above, the expression of TNFRSF9 was significantly associated with exhaustion markers and effector phenotype markers in TCGA-KIRC cohort, which delineated a distinct and complicated role of TNFRSF9 in anti-tumor immune response.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('associated', 'Reg', (64, 74))	('immune response', 'biological_process', 'GO:0006955', ('225', '240'))	('tumor', 'Disease', (219, 224))	('expression', 'Var', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('TNFRSF9', 'Gene', (38, 45))
147748	33178496	TNFRSF9+ CD8+ T cells expressed more exhaustion makers (PD-1, TIGIT, TIM-3, and CTLA-4) than TNFRSF9- CD8+ T cells (Figure 3(a)).	('CD8', 'Gene', '925', (9, 12))	('CD8', 'Gene', (102, 105))	('CD8', 'Gene', '925', (102, 105))	('CTLA-4', 'Gene', (80, 86))	('TIM-3', 'Gene', (69, 74))	('TIM-3', 'Gene', '84868', (69, 74))	('TNFRSF9+', 'Var', (0, 8))	('TIGIT', 'Gene', '201633', (62, 67))	('CTLA-4', 'Gene', '1493', (80, 86))	('TIGIT', 'Gene', (62, 67))	('more', 'PosReg', (32, 36))	('CD8', 'Gene', (9, 12))
147759	33178496	Interestingly, the TNFRSF9+ CD8+ T cells were also correlated with Exhausted CD8+ T cells and Activated CD8+ T cells, which further supported the "dual phenotype" of TNFRSF9+ CD8+ T cells.	('CD8', 'Gene', (77, 80))	('CD8', 'Gene', '925', (77, 80))	('TNFRSF9+', 'Var', (19, 27))	('CD8', 'Gene', (175, 178))	('CD8', 'Gene', (28, 31))	('CD8', 'Gene', (104, 107))	('CD8', 'Gene', '925', (175, 178))	('CD8', 'Gene', '925', (28, 31))	('CD8', 'Gene', '925', (104, 107))
147766	33178496	Higher TNFRSF9+ CD8+ T cells signature was also associated with better progression-free survival (Supplement Figure 5B, log rank p = .040).	('better', 'PosReg', (64, 70))	('TNFRSF9+', 'Var', (7, 15))	('CD8', 'Gene', (16, 19))	('progression-free survival', 'CPA', (71, 96))	('CD8', 'Gene', '925', (16, 19))
147782	33178496	High TNFRSF9+ CD8+ T cells infiltration was found to be associated with higher T stage, TNM stage, and poor prognosis.	('High', 'Var', (0, 4))	('TNM', 'Gene', (88, 91))	('TNFRSF9+', 'Gene', (5, 13))	('CD8', 'Gene', (14, 17))	('T stage', 'CPA', (79, 86))	('CD8', 'Gene', '925', (14, 17))	('TNM', 'Gene', '10178', (88, 91))
147790	33178496	Dysfunctional T cells, or at least, some of them are not totally inert, but still retain suboptimal function of cytotoxicity and proliferation and might be required for tumor control.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('cytotoxicity', 'Disease', (112, 124))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cytotoxicity', 'Disease', 'MESH:D064420', (112, 124))	('tumor', 'Disease', (169, 174))	('Dysfunctional', 'Var', (0, 13))
147794	33178496	Furthermore, a scRNA sequencing study on melanoma revealed that CD8+ T cells with PD1 and TIM3 expression are the most proliferative T cell populations with high levels of effector molecules.	('CD8', 'Gene', (64, 67))	('TIM3', 'Gene', (90, 94))	('CD8', 'Gene', '925', (64, 67))	('TIM3', 'Gene', '84868', (90, 94))	('expression', 'Var', (95, 105))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('PD1', 'Gene', (82, 85))
147795	33178496	These findings implied that TNFRSF9+ CD8+ T cells in ccRCC with "dual phenotype" may play a distinct and important role in immune response.	('ccRCC', 'Disease', (53, 58))	('CD8', 'Gene', '925', (37, 40))	('TNFRSF9+', 'Var', (28, 36))	('CD8', 'Gene', (37, 40))
147798	33178496	In addition, it was found that TNFRSF9 could be a marker of tumor-reactive CD8+ T cells and TNFRSF9+ T cells mediated superior antitumor effects than TNFRSF9- T cells.	('superior', 'PosReg', (118, 126))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('CD8', 'Gene', '925', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('TNFRSF9+ T', 'Var', (92, 102))	('tumor', 'Disease', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('CD8', 'Gene', (75, 78))
147799	33178496	This "dual phenotypes" of TNFRSF9+ CD8+ T cells indicated that these cells may be not terminally exhausted, but could respond to ICB.	('TNFRSF9+', 'Var', (26, 34))	('CD8', 'Gene', (35, 38))	('respond to ICB', 'MPA', (118, 132))	('CD8', 'Gene', '925', (35, 38))
147800	33178496	A study focused on hepatocellular carcinoma also revealed that TNFRSF9 was a distinct activation status marker of highly exhausted CD8+ T cells and TNFRSF9+ PD1high CD8+ T cells exhibited higher activation markers than their TNFRSF9- counterparts.	('activation markers', 'MPA', (195, 213))	('higher', 'PosReg', (188, 194))	('CD8', 'Gene', (165, 168))	('CD8', 'Gene', '925', (165, 168))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (19, 43))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (19, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('hepatocellular carcinoma', 'Disease', (19, 43))	('TNFRSF9+ PD1high', 'Var', (148, 164))	('CD8', 'Gene', (131, 134))	('CD8', 'Gene', '925', (131, 134))
147802	33178496	This could be partly explained by the high expression of both PD-1 and effector phenotype markers in TNFRSF9+ CD8+ T cells.	('PD-1', 'Gene', (62, 66))	('CD8', 'Gene', (110, 113))	('high', 'PosReg', (38, 42))	('expression', 'MPA', (43, 53))	('TNFRSF9+', 'Var', (101, 109))	('CD8', 'Gene', '925', (110, 113))
147803	33178496	Furthermore, the observation that high tumor shrinkage was correlated with high TNFRSF9+ CD8+ T cells signature in nivolumab treatment arm but not everolimus treatment arm further suggested a potential role of TNFRSF9+ CD8+ T cells and its predictive value in response of ICB in ccRCC.	('CD8', 'Gene', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('high', 'Var', (75, 79))	('CD8', 'Gene', (219, 222))	('CD8', 'Gene', '925', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('everolimus', 'Chemical', 'MESH:D000068338', (147, 157))	('CD8', 'Gene', '925', (219, 222))	('tumor', 'Disease', (39, 44))	('nivolumab', 'Chemical', 'MESH:D000077594', (115, 124))	('ccRCC', 'Disease', (279, 284))
147804	33178496	Since exhausted T cells were thought to be maintained by persistent antigen stimulation and TNFRSF9 expression could be prolonged if the antigen persists, TNFRSF9 may thus promote the maintenance of dysfunctional T cells.	('TNFRSF9', 'Var', (155, 162))	('expression', 'MPA', (100, 110))	('promote', 'PosReg', (172, 179))	('dysfunctional T', 'Disease', 'MESH:D009461', (199, 214))	('TNFRSF9', 'Gene', (92, 99))	('dysfunctional T', 'Disease', (199, 214))
147806	33178496	Furthermore, it was found that activation of TNFRSF9 could reverse the dysfunctional state of CD8+ T cells.	('activation', 'Var', (31, 41))	('CD8', 'Gene', (94, 97))	('CD8', 'Gene', '925', (94, 97))	('dysfunctional state', 'MPA', (71, 90))	('TNFRSF9', 'Gene', (45, 52))
147819	29749470	In addition, the expression levels of PLIN2 were significantly associated with various clinicopathological factors, and high PLIN2 expression was associated with a good prognosis.	('expression levels', 'MPA', (17, 34))	('PLIN2', 'Gene', '123', (38, 43))	('high', 'Var', (120, 124))	('associated', 'Reg', (63, 73))	('PLIN2', 'Gene', '123', (125, 130))	('expression', 'MPA', (131, 141))	('PLIN2', 'Gene', (38, 43))	('associated', 'Reg', (146, 156))	('PLIN2', 'Gene', (125, 130))
147820	29749470	The results of a multivariate analysis demonstrated that high PLIN2 expression was an independent prognostic indicator of overall survival (hazard ratio, 0.586; P=0.001).	('expression', 'MPA', (68, 78))	('PLIN2', 'Gene', '123', (62, 67))	('PLIN2', 'Gene', (62, 67))	('high', 'Var', (57, 61))
147821	29749470	Furthermore, PLIN2 knockdown promoted proliferation of ccRCC cells, and enhanced cell invasion and migration.	('promoted', 'PosReg', (29, 37))	('proliferation', 'CPA', (38, 51))	('PLIN2', 'Gene', '123', (13, 18))	('knockdown', 'Var', (19, 28))	('PLIN2', 'Gene', (13, 18))	('enhanced', 'PosReg', (72, 80))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('ccRCC', 'Disease', (55, 60))	('cell invasion', 'CPA', (81, 94))
147832	29749470	In cervical cancer, high PLIN3 expression is correlated with advanced tumor stages and poor patient prognosis.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('patient', 'Species', '9606', (92, 99))	('cancer', 'Disease', (12, 18))	('tumor', 'Disease', (70, 75))	('expression', 'MPA', (31, 41))	('high', 'Var', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('PLIN3', 'Gene', (25, 30))	('PLIN3', 'Gene', '10226', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
147850	29749470	Subsequently, IHC was conducted by incubating tissue sections (4 microm) with a primary rabbit PLIN2 polyclonal antibody (1:100; A6276; ABclonal Biotech Co., Ltd., Wuhan, China) overnight at 4 C. Subsequently, after washing three times with PBS, the sections were incubated with goat anti-rabbit secondary antibody (1:200; GB23303; Servicebio, Inc., Woburn, MA, USA) at room temperature for 2 h. A-498 cells were transfected with si-PLIN2 or si-NC.	('PLIN2', 'Gene', '123', (95, 100))	('PLIN2', 'Gene', '123', (433, 438))	('rabbit', 'Species', '9986', (289, 295))	('antibody', 'cellular_component', 'GO:0019814', ('112', '120'))	('antibody', 'cellular_component', 'GO:0042571', ('306', '314'))	('antibody', 'cellular_component', 'GO:0042571', ('112', '120'))	('PLIN2', 'Gene', (95, 100))	('rabbit', 'Species', '9986', (88, 94))	('antibody', 'molecular_function', 'GO:0003823', ('112', '120'))	('PBS', 'Chemical', 'MESH:D007854', (241, 244))	('antibody', 'cellular_component', 'GO:0019815', ('306', '314'))	('PLIN2', 'Gene', (433, 438))	('goat', 'Species', '9925', (279, 283))	('A-498', 'CellLine', 'CVCL:1056', (396, 401))	('antibody', 'cellular_component', 'GO:0019814', ('306', '314'))	('antibody', 'molecular_function', 'GO:0003823', ('306', '314'))	('si-NC', 'Var', (442, 447))	('antibody', 'cellular_component', 'GO:0019815', ('112', '120'))
147869	29749470	Furthermore, TCGA dataset revealed that PLIN2 expression was increased in patients >=60 years old compared with in those <60 years old (Fig.	('patients', 'Species', '9606', (74, 82))	('PLIN2', 'Gene', (40, 45))	('increased', 'PosReg', (61, 70))	('>=60 years', 'Var', (83, 93))	('expression', 'MPA', (46, 56))	('PLIN2', 'Gene', '123', (40, 45))
147873	29749470	There was a significant association between high PLIN2 expression and age or sex, which is consistent with the aforementioned results.	('PLIN2', 'Gene', '123', (49, 54))	('PLIN2', 'Gene', (49, 54))	('high', 'Var', (44, 48))	('expression', 'MPA', (55, 65))
147876	29749470	Patients with high PLIN2 expression exhibited better OS (P<0.0001) (Fig.	('PLIN2', 'Gene', (19, 24))	('high', 'Var', (14, 18))	('PLIN2', 'Gene', '123', (19, 24))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (46, 52))
147885	29749470	As expected, the results demonstrated that high PLIN2 expression was a potential prognostic indicator for patients with ccRCC with the following characteristics: Female (Fig.	('expression', 'MPA', (54, 64))	('high', 'Var', (43, 47))	('PLIN2', 'Gene', '123', (48, 53))	('ccRCC', 'Disease', (120, 125))	('PLIN2', 'Gene', (48, 53))	('patients', 'Species', '9606', (106, 114))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))
147896	29749470	To evaluate the functional role of PLIN2 in ccRCC, ccRCC cell lines with PLIN2 knockdown were generated.	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('PLIN2', 'Gene', '123', (35, 40))	('ccRCC', 'Disease', (44, 49))	('PLIN2', 'Gene', '123', (73, 78))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('knockdown', 'Var', (79, 88))	('PLIN2', 'Gene', (35, 40))	('PLIN2', 'Gene', (73, 78))
147899	29749470	Furthermore, Transwell assays were conducted to assess the migration and invasion of ccRCC cells; downregulation of PLIN2 significantly promoted migration and invasion ability compared with in the si-NC group (Fig.	('PLIN2', 'Gene', (116, 121))	('migration', 'CPA', (145, 154))	('promoted', 'PosReg', (136, 144))	('invasion ability', 'CPA', (159, 175))	('downregulation', 'Var', (98, 112))	('PLIN2', 'Gene', '123', (116, 121))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
147903	29749470	Furthermore, the results demonstrated that knockdown of PLIN2 enhanced proliferation, migration and invasion of ccRCC cells.	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('migration', 'CPA', (86, 95))	('ccRCC', 'Disease', (112, 117))	('knockdown', 'Var', (43, 52))	('enhanced', 'PosReg', (62, 70))	('PLIN2', 'Gene', '123', (56, 61))	('invasion', 'CPA', (100, 108))	('proliferation', 'CPA', (71, 84))	('PLIN2', 'Gene', (56, 61))
147920	29749470	Age is a risk factor for numerous types of cancer, including ccRCC; however, the present study demonstrated that PLIN2 expression was increased in patients >=60 years group compared with in those <60 years old.	('expression', 'MPA', (119, 129))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('ccRCC', 'Disease', (61, 66))	('cancer', 'Disease', (43, 49))	('PLIN2', 'Gene', (113, 118))	('patients', 'Species', '9606', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('increased', 'PosReg', (134, 143))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('PLIN2', 'Gene', '123', (113, 118))	('>=60 years group', 'Var', (156, 172))
147921	29749470	These findings indicated that high PLIN2 expression is associated with poor prognosis, which is in contradiction with the follow-up results.	('expression', 'MPA', (41, 51))	('PLIN2', 'Gene', '123', (35, 40))	('PLIN2', 'Gene', (35, 40))	('high', 'Var', (30, 34))
147925	29749470	The present results revealed that high PLIN2 expression was associated with good OS (P<0.001) and DFS (P=0.0006), and may be considered a diagnostic biomarker in patients with ccRCC with various clinicopathological characteristics.	('patients', 'Species', '9606', (162, 170))	('PLIN2', 'Gene', (39, 44))	('good OS', 'Disease', (76, 83))	('expression', 'MPA', (45, 55))	('high', 'Var', (34, 38))	('PLIN2', 'Gene', '123', (39, 44))	('DFS', 'CPA', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('ccRCC', 'Disease', (176, 181))	('good OS', 'Disease', 'MESH:C567932', (76, 83))
147927	29749470	Notably, the present study demonstrated that knockdown of PLIN2 promoted ccRCC cell invasion and migration in vitro.	('promoted', 'PosReg', (64, 72))	('migration', 'CPA', (97, 106))	('PLIN2', 'Gene', '123', (58, 63))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('PLIN2', 'Gene', (58, 63))	('ccRCC', 'Disease', (73, 78))	('knockdown', 'Var', (45, 54))
147928	29749470	Furthermore, PLIN2 inhibited ccRCC cell proliferation; 4 days following PLIN2 knockdown, the proliferative capacity of A-498 cells was significantly elevated compared with in cells in the control group.	('elevated', 'PosReg', (149, 157))	('inhibited', 'NegReg', (19, 28))	('A-498', 'CellLine', 'CVCL:1056', (119, 124))	('PLIN2', 'Gene', '123', (13, 18))	('knockdown', 'Var', (78, 87))	('PLIN2', 'Gene', '123', (72, 77))	('PLIN2', 'Gene', (13, 18))	('PLIN2', 'Gene', (72, 77))	('proliferative capacity', 'CPA', (93, 115))	('cell proliferation', 'biological_process', 'GO:0008283', ('35', '53'))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
147933	29749470	Yao et al revealed that overexpression of PLIN2 may be induced by disruption of the VHL/HIF pathway in ccRCC.	('VHL', 'Gene', (84, 87))	('PLIN2', 'Gene', '123', (42, 47))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('VHL', 'Gene', '7428', (84, 87))	('PLIN2', 'Gene', (42, 47))	('overexpression', 'PosReg', (24, 38))	('ccRCC', 'Disease', (103, 108))	('disruption', 'Var', (66, 76))
147935	29749470	The present study demonstrated that VHL alteration-positive ccRCC was associated with increased PLIN2 expression.	('increased', 'PosReg', (86, 95))	('alteration-positive', 'Var', (40, 59))	('VHL', 'Gene', (36, 39))	('expression', 'MPA', (102, 112))	('PLIN2', 'Gene', '123', (96, 101))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('ccRCC', 'Disease', (60, 65))	('VHL', 'Gene', '7428', (36, 39))	('PLIN2', 'Gene', (96, 101))
147937	29749470	It may be hypothesized that inactivation of VHL, which activates downstream HIF expression, contributes to increased expression of PLIN2 in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('ccRCC', 'Disease', (140, 145))	('increased', 'PosReg', (107, 116))	('expression', 'MPA', (117, 127))	('VHL', 'Gene', (44, 47))	('PLIN2', 'Gene', '123', (131, 136))	('inactivation', 'Var', (28, 40))	('VHL', 'Gene', '7428', (44, 47))	('PLIN2', 'Gene', (131, 136))
147946	29749470	In vitro experiments also indicated that PLIN2 knockdown may enhance proliferation, migration and invasion of RCC cells.	('enhance', 'PosReg', (61, 68))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('proliferation', 'CPA', (69, 82))	('PLIN2', 'Gene', '123', (41, 46))	('migration', 'CPA', (84, 93))	('knockdown', 'Var', (47, 56))	('invasion of RCC cells', 'CPA', (98, 119))	('PLIN2', 'Gene', (41, 46))
147975	29632619	In colon adenocarcinoma, CPTH2 lowers cancer growth, decreasing GCN5 activity regulated by cMyc/E2F1.	('cMyc', 'Gene', (91, 95))	('decreasing', 'NegReg', (53, 63))	('cMyc', 'Gene', '4609', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('GCN5', 'Gene', (64, 68))	('lowers', 'NegReg', (31, 37))	('CPTH2', 'Chemical', '-', (25, 30))	('GCN5', 'Gene', '2648', (64, 68))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('colon adenocarcinoma', 'Disease', (3, 23))	('cancer', 'Disease', (38, 44))	('CPTH2', 'Var', (25, 30))	('E2F1', 'Gene', '1869', (96, 100))	('E2F1', 'Gene', (96, 100))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (3, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
147979	29632619	The results obtained by treating the cells with CPTH2 were comparable with the effects induced by silencing KAT3B, thus confirming the inhibitory selectivity of CPTH2 for KAT3B in 786-O cell line.	('KAT3B', 'Gene', '2033', (171, 176))	('CPTH2', 'Chemical', '-', (48, 53))	('KAT3B', 'Gene', (108, 113))	('silencing', 'Var', (98, 107))	('KAT', 'molecular_function', 'GO:0003988', ('108', '111'))	('KAT3B', 'Gene', '2033', (108, 113))	('KAT3B', 'Gene', (171, 176))	('KAT', 'molecular_function', 'GO:0003988', ('171', '174'))	('CPTH2', 'Chemical', '-', (161, 166))
148009	29632619	Each sample assayed in triplicate was performed with PCR cycles: (10 min) at 95  C and 60 cycles of (15 s) at 95  C and a final (1 min) at 60  C. The primers and probes of the following transcripts were EP300 (Hs00914223_m1), AKT-1 (Hs00178289_m1), TGF-b2 (Hs00234244_m1), HIF-1a (Hs00153153_m1), CD44 (Hs01075864_m1), ITGb1 (Hs01127536_m1), ITGb3 (Hs01001469_m1), ITGa5 (Hs01547673_m1), and ITGa6 (Hs01041011_m1) (Applied Biosystems).	('ITGa6', 'Gene', (392, 397))	('Hs00914223_m1', 'Var', (210, 223))	('TGF-b2', 'Gene', (249, 255))	('CD44', 'Gene', '960', (297, 301))	('ITGa6', 'Gene', '3655', (392, 397))	('Hs01547673_m1', 'Var', (372, 385))	('TGF-b2', 'Gene', '7042', (249, 255))	('ITGa5', 'Gene', '3678', (365, 370))	('Hs01041011_m1', 'Var', (399, 412))	('CD44', 'Gene', (297, 301))	('EP300', 'Gene', '2033', (203, 208))	('AKT-1', 'Gene', '207', (226, 231))	('ITGb3', 'Gene', (342, 347))	('Hs00178289_m1', 'Var', (233, 246))	('ITGb1', 'Gene', '3688', (319, 324))	('EP300', 'Gene', (203, 208))	('HIF-1a', 'Gene', '3091', (273, 279))	('ITGa5', 'Gene', (365, 370))	('Hs01001469_m1', 'Var', (349, 362))	('ITGb3', 'Gene', '3690', (342, 347))	('Hs01127536_m1', 'Var', (326, 339))	('ITGb1', 'Gene', (319, 324))	('AKT-1', 'Gene', (226, 231))	('Hs00234244_m1', 'Var', (257, 270))	('HIF-1a', 'Gene', (273, 279))	('Hs01075864_m1', 'Var', (303, 316))	('Hs00153153_m1', 'Var', (281, 294))
148012	29632619	Total protein extracts were resuspended in Laemmli buffer (Bio-Rad, CA) and heated 5 min at 90  C. Protein extracts were run on 15% SDS-PAGE, blotted onto nitrocellulose (GE Healthcare Life Sciences, UK) and hybridized with anti-H3AcK18 (Abcam, UK), anti-H3Ac (Merck, Germany), and anti-GAPDH (Santa-Cruz, TX) antibodies.	('Rad', 'Gene', (63, 66))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('Rad', 'biological_process', 'GO:1990116', ('63', '66'))	('anti-H3AcK18', 'Var', (224, 236))	('GAPDH', 'Gene', '2597', (287, 292))	('Laemmli buffer', 'Chemical', 'MESH:C088816', (43, 57))	('GAPDH', 'Gene', (287, 292))	('anti-H3Ac', 'Protein', (250, 259))	('Rad', 'Gene', '6236', (63, 66))	('SDS', 'Chemical', 'MESH:D012967', (132, 135))
148018	29632619	Endogenous peroxidase was blocked for 10 min in 3% hydrogen peroxide in methanol, incubated 1 h RT with primary antibody diluted to anti-p300 rabbit polyclonal antibody 1:1000 (Bethyl Laboratories), anti-H3AcK18 1:2000 (Abcam), and anti-H3AcK14 1:2000 (Abcam).	('methanol', 'Chemical', 'MESH:D000432', (72, 80))	('H3AcK14', 'Chemical', '-', (237, 244))	('rabbit', 'Species', '9986', (142, 148))	('anti-H3AcK14 1:2000', 'Var', (232, 251))	('antibody', 'cellular_component', 'GO:0019814', ('112', '120'))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (51, 68))	('p300', 'Gene', '2033', (137, 141))	('antibody', 'cellular_component', 'GO:0042571', ('160', '168'))	('Endogenous peroxidase', 'Enzyme', (0, 21))	('anti-H3AcK18', 'Var', (199, 211))	('antibody', 'molecular_function', 'GO:0003823', ('112', '120'))	('antibody', 'cellular_component', 'GO:0019815', ('160', '168'))	('antibody', 'cellular_component', 'GO:0019814', ('160', '168'))	('antibody', 'cellular_component', 'GO:0042571', ('112', '120'))	('antibody', 'molecular_function', 'GO:0003823', ('160', '168'))	('p300', 'Gene', (137, 141))	('antibody', 'cellular_component', 'GO:0019815', ('112', '120'))
148024	29632619	The variables considered for entry into the model included age, p300, H3AcK14, and H3AcK18.	('H3AcK14', 'Chemical', '-', (70, 77))	('H3AcK14', 'Var', (70, 77))	('p300', 'Gene', '2033', (64, 68))	('p300', 'Gene', (64, 68))	('H3AcK18', 'Var', (83, 90))
148029	29632619	CPTH2 treatment caused a decrease in cell proliferation after as early as 12 h with a further significant reduction after 48 h stimulation.	('cell proliferation', 'biological_process', 'GO:0008283', ('37', '55'))	('CPTH2', 'Chemical', '-', (0, 5))	('decrease', 'NegReg', (25, 33))	('reduction', 'NegReg', (106, 115))	('treatment', 'Var', (6, 15))	('CPTH2', 'Gene', (0, 5))	('cell proliferation', 'CPA', (37, 55))
148030	29632619	K1 cell line, which is derived from papillary thyroid carcinoma and is responsive to chemotherapy and apoptotic drugs, showed a reduction of 80% after 48 h. ccRCC-786-O, which is from renal clear cell carcinoma and is much less sensitive to anti-proliferative drugs, presented a significant, but less pronounced, decrease, 40% (Fig.	('ccRCC-786-O', 'Var', (157, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('papillary thyroid carcinoma', 'Disease', (36, 63))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (46, 63))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (184, 210))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (36, 63))	('renal clear cell carcinoma', 'Disease', (184, 210))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (36, 63))
148034	29632619	Annexin-V FACS analysis of K1 and 786-O cell lines showed in addition that CPTH2 treatment produced a drastic increase in apoptotic/dead cell population after 48 h quantified as a percentage of total apoptotic cells (Fig.	('increase', 'PosReg', (110, 118))	('treatment', 'Var', (81, 90))	('Annexin-V', 'Gene', (0, 9))	('CPTH2', 'Gene', (75, 80))	('Annexin-V', 'Gene', '308', (0, 9))	('apoptotic/dead cell population', 'CPA', (122, 152))	('CPTH2', 'Chemical', '-', (75, 80))
148035	29632619	1d and Additional file 1), suggesting that CPTH2 treatment leads to cell death rather than cell cycle arrest.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('91', '108'))	('cell death', 'CPA', (68, 78))	('cell death', 'biological_process', 'GO:0008219', ('68', '78'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (91, 108))	('CPTH2', 'Gene', (43, 48))	('treatment', 'Var', (49, 58))	('CPTH2', 'Chemical', '-', (43, 48))
148040	29632619	We next assayed the adhesion capabilities of 786-O cells grown on different substrates treated with CPTH2 for 12 and 24 h. Interestingly, CPTH2 was able to modulate cell adhesion only when 786-O cells were plated on the complex synthetic matrix Matrigel, while on single components such as fibronectin and collagen, it was substantially unaffected (Fig.	('modulate', 'Reg', (156, 164))	('CPTH2', 'Chemical', '-', (138, 143))	('CPTH2', 'Chemical', '-', (100, 105))	('collagen', 'molecular_function', 'GO:0005202', ('306', '314'))	('cell adhesion', 'biological_process', 'GO:0007155', ('165', '178'))	('CPTH2', 'Var', (138, 143))	('cell adhesion', 'CPA', (165, 178))
148046	29632619	Results indicate that after 48 h, it is clearly seen that while cells in DMSO were actively migrating and able to fill the gap in the presence of CPTH2 migration was severely inhibited.	('migration', 'CPA', (152, 161))	('CPTH2', 'Gene', (146, 151))	('inhibited', 'NegReg', (175, 184))	('CPTH2', 'Chemical', '-', (146, 151))	('presence', 'Var', (134, 142))	('DMSO', 'Chemical', 'MESH:D004121', (73, 77))
148065	29632619	We found that cell proliferation, number of stress fibers, and migration showed the same values in controls and si-p300 cells, thus demonstrating full overlap between CPTH2 activity and silencing of p300.	('p300', 'Gene', '2033', (115, 119))	('p300', 'Gene', (199, 203))	('silencing', 'Var', (186, 195))	('cell proliferation', 'CPA', (14, 32))	('cell proliferation', 'biological_process', 'GO:0008283', ('14', '32'))	('p300', 'Gene', '2033', (199, 203))	('p300', 'Gene', (115, 119))	('migration', 'CPA', (63, 72))	('CPTH2', 'Chemical', '-', (167, 172))
148070	29632619	Western blot analysis of bulk histone preparations from 786-O cells were serially hybridized with anti-AcH3 and anti-H3AcK18 antibodies after a 48-h time course incubation with CPTH2 showing a reduced acetylation of both global AcH3 histone and H3AcK18 (Fig.	('acetylation', 'MPA', (201, 212))	('anti-H3AcK18', 'Var', (112, 124))	('H3AcK18', 'Gene', (245, 252))	('reduced', 'NegReg', (193, 200))	('global AcH3 histone', 'Protein', (221, 240))	('CPTH2', 'Chemical', '-', (177, 182))
148074	29632619	The immunohistochemical analysis on p300si 786-O cells with anti-p300, as a control, anti-H3AcK14, and H3AcK18 compared to untreated nc cells (Fig.	('p300', 'Gene', '2033', (36, 40))	('p300', 'Gene', (65, 69))	('H3AcK14', 'Chemical', '-', (90, 97))	('p300', 'Gene', (36, 40))	('p300', 'Gene', '2033', (65, 69))	('H3AcK18', 'Var', (103, 110))
148075	29632619	This unbiased result confirms that silencing of p300 and CPTH2 treatment induce similar effects lowering the degree of global histone H3AcK18 in a p300 dependent way.	('silencing', 'Var', (35, 44))	('p300', 'Gene', (147, 151))	('p300', 'Gene', '2033', (147, 151))	('p300', 'Gene', (48, 52))	('lowering', 'NegReg', (96, 104))	('CPTH2', 'Gene', (57, 62))	('global histone H3AcK18', 'MPA', (119, 141))	('p300', 'Gene', '2033', (48, 52))	('CPTH2', 'Chemical', '-', (57, 62))
148076	29632619	We then added a control experiment by comparing the activity of the previously described specific KAT3B inhibitor, C646 with CPTH2.	('C646', 'Chemical', '-', (115, 119))	('activity', 'MPA', (52, 60))	('CPTH2', 'Chemical', '-', (125, 130))	('KAT3B', 'Gene', (98, 103))	('C646', 'Var', (115, 119))	('KAT3B', 'Gene', '2033', (98, 103))	('KAT', 'molecular_function', 'GO:0003988', ('98', '101'))
148077	29632619	Western blot analysis showed that the effects of C646 and CPTH2 on inhibition of bulk AcH3, H3AcK14, and H3AcK18 were fully comparable at increasing times (Fig.	('CPTH2', 'Chemical', '-', (58, 63))	('C646', 'Var', (49, 53))	('inhibition', 'MPA', (67, 77))	('CPTH2', 'Gene', (58, 63))	('C646', 'Chemical', '-', (49, 53))	('H3AcK14', 'Chemical', '-', (92, 99))
148080	29632619	As shown, the amount of H3AcK18 was generally much lower than H3AcK14, and overall, the acetylation of both was extremely variable among cases.	('lower', 'NegReg', (51, 56))	('acetylation', 'MPA', (88, 99))	('H3AcK14', 'Chemical', '-', (62, 69))	('H3AcK18', 'Var', (24, 31))
148081	29632619	Interestingly, however, the respective acetylation of tumor versus normal paired tissue was higher for H3AcK18 and lower for H3AcK14.	('higher', 'PosReg', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('acetylation', 'MPA', (39, 50))	('H3AcK14', 'Chemical', '-', (125, 132))	('lower', 'NegReg', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('H3AcK18', 'Var', (103, 110))
148083	29632619	Taken together, these data evidenced a global heterogeneity in the levels of H3AcK14 and H3AcK18 among individuals but hinted of an opposite influence of H3AcK18 and H3AcK14 residues on tumor growth.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('H3AcK18', 'Gene', (89, 96))	('tumor', 'Disease', (186, 191))	('H3AcK14', 'Chemical', '-', (77, 84))	('H3AcK14', 'Chemical', '-', (166, 173))	('H3AcK14', 'Var', (77, 84))
148088	29632619	As expected, expression of H3AcK18 and H3AcK14 was limited to the cell nucleus of both clear renal cell carcinoma and epithelial cells of normal kidney (podocytes and epithelial cells of the proximal and distal tubules), whereas KAT3B-p300 antibody stained both the nucleus and the cytoplasm in 42/70 ccRCC cases and 67/69 epithelial cell of the peritumoral normal kidneys.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (93, 113))	('KAT3B', 'Gene', (229, 234))	('antibody', 'cellular_component', 'GO:0019815', ('240', '248'))	('KAT', 'molecular_function', 'GO:0003988', ('229', '232'))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('clear renal cell carcinoma', 'Disease', 'MESH:C538614', (87, 113))	('ccRCC', 'Disease', (301, 306))	('tumor', 'Disease', (350, 355))	('H3AcK18', 'Var', (27, 34))	('antibody', 'cellular_component', 'GO:0019814', ('240', '248'))	('H3AcK14', 'Chemical', '-', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (350, 355))	('p300', 'Gene', (235, 239))	('cell nucleus', 'cellular_component', 'GO:0005634', ('66', '78'))	('nucleus', 'cellular_component', 'GO:0005634', ('266', '273'))	('clear renal cell carcinoma', 'Disease', (87, 113))	('H3AcK14', 'Var', (39, 46))	('antibody', 'molecular_function', 'GO:0003823', ('240', '248'))	('p300', 'Gene', '2033', (235, 239))	('cytoplasm', 'cellular_component', 'GO:0005737', ('282', '291'))	('antibody', 'cellular_component', 'GO:0042571', ('240', '248'))	('tumor', 'Phenotype', 'HP:0002664', (350, 355))	('KAT3B', 'Gene', '2033', (229, 234))
148090	29632619	Patients' characteristics according to p300, H3AcK14, and H3AcK18 expression are summarized in Table 2.	('H3AcK14', 'Chemical', '-', (45, 52))	('p300', 'Gene', '2033', (39, 43))	('H3AcK14', 'Var', (45, 52))	('Patients', 'Species', '9606', (0, 8))	('H3AcK18', 'Var', (58, 65))	('p300', 'Gene', (39, 43))
148092	29632619	The frequency of H3AcK18, H3AcK14, and p300 positive epithelial cells in normal tissues, although different among cases, showed similar mean + SD values independently from the sex, age, grade, and stage of the hosted tumor.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('p300', 'Gene', '2033', (39, 43))	('H3AcK18', 'Var', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('H3AcK14', 'Chemical', '-', (26, 33))	('p300', 'Gene', (39, 43))	('H3AcK14', 'Var', (26, 33))
148094	29632619	5b and Table 2, G2-G3 ccRCC presented a significant higher expression of p300 and H3AcK18 and a lower expression of H3AcK14 compared to G1 ccRCC (p < 0.001).	('H3AcK14', 'Chemical', '-', (116, 123))	('H3AcK18', 'Protein', (82, 89))	('G2-G3', 'Var', (16, 21))	('expression', 'MPA', (102, 112))	('lower', 'NegReg', (96, 101))	('p300', 'Gene', (73, 77))	('expression', 'MPA', (59, 69))	('higher', 'PosReg', (52, 58))	('p300', 'Gene', '2033', (73, 77))
148097	29632619	On the multivariable analysis, H3AcK14 and p300 were found to be independent predictors of high-grade ccRCC (Table 3).	('H3AcK14', 'Chemical', '-', (31, 38))	('high-grade ccRCC', 'Disease', (91, 107))	('p300', 'Gene', '2033', (43, 47))	('H3AcK14', 'Var', (31, 38))	('p300', 'Gene', (43, 47))
148098	29632619	Particularly, p300 increased the risk of high-grade ccRCC by 7.6% per unit (OR 1.076, IC 1.029-1.236, p = 0.001) and H3AcK14 reduced the risk of high-grade ccRCC by 3% per unit (OR 0.971, IC 0.943-0.999, p = 0.0041).	('p300', 'Gene', (14, 18))	('high-grade ccRCC', 'Disease', (145, 161))	('H3AcK14', 'Chemical', '-', (117, 124))	('reduced', 'NegReg', (125, 132))	('H3AcK14', 'Var', (117, 124))	('p300', 'Gene', '2033', (14, 18))	('high-grade ccRCC', 'Disease', (41, 57))
148099	29632619	H3AcK14 was also independent predictors of high-stage ccRCC.	('H3AcK14', 'Var', (0, 7))	('H3AcK14', 'Chemical', '-', (0, 7))	('high-stage ccRCC', 'Disease', (43, 59))
148102	29632619	Overall, epigenetic regulation tuning cell differentiation in response to environmental stimuli can be considered a driving alteration of tumor progression and a response sign to therapy.	('regulation', 'biological_process', 'GO:0065007', ('20', '30'))	('cell differentiation', 'biological_process', 'GO:0030154', ('38', '58'))	('tumor', 'Disease', (138, 143))	('epigenetic regulation', 'Var', (9, 30))	('cell', 'CPA', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
148116	29632619	Administration of CPTH2 and silencing of p300 showed identical effects in treated cells.	('CPTH2', 'Chemical', '-', (18, 23))	('silencing', 'Var', (28, 37))	('p300', 'Gene', '2033', (41, 45))	('p300', 'Gene', (41, 45))
148119	29632619	Hypoacetylation of H3AcK18 is associated to prostate carcinoma with poor prognosis, and increase of H3AcK18 caused by absence of SIRT7 at sites of DNA damage affects the maintenance of genome integrity.	('associated', 'Reg', (30, 40))	('maintenance of genome integrity', 'biological_process', 'GO:0051276', ('170', '201'))	('prostate carcinoma', 'Disease', 'MESH:D011472', (44, 62))	('H3AcK18', 'Gene', (19, 26))	('SIRT7', 'Gene', '51547', (129, 134))	('DNA', 'cellular_component', 'GO:0005574', ('147', '150'))	('maintenance', 'MPA', (170, 181))	('increase', 'PosReg', (88, 96))	('affects', 'Reg', (158, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('Hypoacetylation', 'Var', (0, 15))	('SIRT7', 'Gene', (129, 134))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (44, 62))	('prostate carcinoma', 'Disease', (44, 62))	('H3AcK18', 'Gene', (100, 107))	('absence', 'Var', (118, 125))
148120	29632619	Lower levels of H3K3me2 and H3AcK18 are in fact predictive for higher recurrence in prostate, lung, and kidney cancer patients and can be used for distinguishing clinical outcomes of patients with substantially similar clinico-pathological variables.	('prostate', 'Disease', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('kidney cancer', 'Phenotype', 'HP:0009726', (104, 117))	('kidney cancer', 'Disease', 'MESH:D007680', (104, 117))	('lung', 'Disease', (94, 98))	('Lower', 'NegReg', (0, 5))	('kidney cancer', 'Disease', (104, 117))	('patients', 'Species', '9606', (183, 191))	('H3K3me2', 'Protein', (16, 23))	('patients', 'Species', '9606', (118, 126))	('higher recurrence', 'CPA', (63, 80))	('H3AcK18', 'Var', (28, 35))
148121	29632619	On the basis of the effects of CPTH2 in lowering p300 and H3AcK18 and the vast literature on the relevance of this histone mark as prognosticator in cancer patients, we wanted to extend the analysis of histone H3 acetylation at K18 and K14 along with p300 in 70 cases of ccRCC tumor patients (listed in Table 1).	('patients', 'Species', '9606', (156, 164))	('p300', 'Gene', (251, 255))	('lowering', 'NegReg', (40, 48))	('cancer', 'Disease', (149, 155))	('CPTH2', 'Gene', (31, 36))	('patients', 'Species', '9606', (283, 291))	('p300', 'Gene', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('CPTH2', 'Chemical', '-', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('histone H3 acetylation at K18', 'biological_process', 'GO:0043971', ('202', '231'))	('p300', 'Gene', '2033', (251, 255))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('H3AcK18', 'Var', (58, 65))	('tumor', 'Disease', (277, 282))	('p300', 'Gene', '2033', (49, 53))	('K14', 'Var', (236, 239))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
148125	29632619	Statistical analysis of our collected results showed that p300 and H3AcK18 levels gave identical profiles supporting selectivity of p300 for H3AcK18 also in ccRCC specimens.	('p300', 'Gene', '2033', (132, 136))	('ccRCC', 'Disease', (157, 162))	('p300', 'Gene', (58, 62))	('p300', 'Gene', (132, 136))	('H3AcK18', 'Var', (141, 148))	('p300', 'Gene', '2033', (58, 62))
148126	29632619	Importantly, the analysis showed an identical pattern of p300, H3AcK18, and H3AcK14 in the normal peritumoral tissue of all patients confirming the relevance of analyzing normal epithelium in our screening.	('p300', 'Gene', '2033', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('H3AcK18', 'Var', (63, 70))	('H3AcK14', 'Chemical', '-', (76, 83))	('H3AcK14', 'Var', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('patients', 'Species', '9606', (124, 132))	('p300', 'Gene', (57, 61))
148128	29632619	In addition, with tumor worsening to G2-G3 grade, while p300/H3AcK18 come back to levels found in normal tissues, H3AcK14 showed a significant, progressive decrease (Fig.	('tumor', 'Disease', (18, 23))	('p300', 'Gene', (56, 60))	('H3AcK14', 'Chemical', '-', (114, 121))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('H3AcK14', 'Var', (114, 121))	('decrease', 'NegReg', (156, 164))	('p300', 'Gene', '2033', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
148129	29632619	The opposed degree of H3AcK14 vs H3AcK18/p300 expression is significatively restricted to G1 tumors and may therefore represent an important epigenetic signature of low-grade ccRCC.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('p300', 'Gene', (41, 45))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('low-grade ccRCC', 'Disease', (165, 180))	('p300', 'Gene', '2033', (41, 45))	('H3AcK14', 'Chemical', '-', (22, 29))	('tumors', 'Disease', (93, 99))	('H3AcK14', 'Var', (22, 29))
148130	29632619	Notably, conflicting results have been reported on the expression levels of histone H3 acetylation and specific H3AcK18 and H3AcK14 in cancer.	('cancer', 'Disease', (135, 141))	('H3AcK18', 'Protein', (112, 119))	('H3AcK14', 'Chemical', '-', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('histone H3 acetylation', 'biological_process', 'GO:0043966', ('76', '98'))	('histone', 'MPA', (76, 83))	('H3AcK14', 'Var', (124, 131))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
148132	29632619	Further molecular analysis for cancer markers such as expression of oncogenes and oncosuppressors or noncoding RNAs can be developed to identify additional characterizing features for the classification of high- or low-H3K18/K14 ratio found in ccRCC low-grade G1 tumors.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('high-', 'Var', (206, 211))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('low-H3K18/K14 ratio', 'Var', (215, 234))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('tumors', 'Disease', (263, 269))	('cancer', 'Disease', (31, 37))	('ccRCC low-grade G1', 'Disease', (244, 262))
148134	29632619	It is a promising compound for counteracting the increase of p300 and H3AcK18 found in higher grade G2, G3 ccRCC tumor tissues.	('tumor', 'Disease', (113, 118))	('p300', 'Gene', (61, 65))	('p300', 'Gene', '2033', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('H3AcK18', 'Var', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('G3 ccRCC', 'Disease', (104, 112))
148161	29158991	Furthermore, knockdown of NDUFA4L2 impaired cell proliferation in hypoxia by increasing mitochondrial reactive oxygen species (ROS) generation in cultured RCC cells.	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('RCC', 'Disease', (155, 158))	('increasing', 'PosReg', (77, 87))	('ROS', 'Chemical', 'MESH:D017382', (127, 130))	('cell proliferation', 'CPA', (44, 62))	('ROS) generation', 'biological_process', 'GO:1903409', ('127', '142'))	('RCC', 'Disease', 'MESH:C538614', (155, 158))	('hypoxia', 'Disease', (66, 73))	('NDUFA4L2', 'Gene', '56901', (26, 34))	('hypoxia', 'Disease', 'MESH:D000860', (66, 73))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (102, 125))	('knockdown', 'Var', (13, 22))	('impaired', 'NegReg', (35, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('44', '62'))	('NDUFA4L2', 'Gene', (26, 34))
148164	29158991	The aberrant expression of tumor-related genes is triggered at multiple levels including copy number variation, gene mutation, abnormal levels of methylation, miRNAs, transcription factors and post-translational modification, etc.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('expression', 'MPA', (13, 23))	('post-translational modification', 'biological_process', 'GO:0043687', ('193', '224'))	('triggered', 'Reg', (50, 59))	('transcription', 'biological_process', 'GO:0006351', ('167', '180'))	('mutation', 'Var', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('methylation', 'biological_process', 'GO:0032259', ('146', '157'))
148173	29158991	GSEA calculates a gene set Enrichment Score (ES) that estimates whether genes from pre-defined gene set (obtained from the Molecular Signatures Database, MSigDB) are enriched in the NDUFA4L2 high/low expression group or distributed randomly.	('high/low', 'Var', (191, 199))	('NDUFA4L2', 'Gene', (182, 190))	('pre', 'molecular_function', 'GO:0003904', ('83', '86'))	('NDUFA4L2', 'Gene', '56901', (182, 190))	('GSEA', 'Chemical', '-', (0, 4))
148193	29158991	The KM curve revealed that patients with a high NDUFA4L2 expression level presented lower overall survival probability than those with a low NDUFA4L2 expression level.	('NDUFA4L2', 'Gene', '56901', (141, 149))	('NDUFA4L2', 'Gene', (48, 56))	('high', 'Var', (43, 47))	('NDUFA4L2', 'Gene', (141, 149))	('patients', 'Species', '9606', (27, 35))	('lower', 'NegReg', (84, 89))	('overall', 'CPA', (90, 97))	('NDUFA4L2', 'Gene', '56901', (48, 56))
148197	29158991	Gene sets of cell proliferation and negative regulation of apoptotic signaling pathway were highly enriched in the high NDUFA4L2 expression group (Figs.	('high', 'Var', (115, 119))	('cell proliferation', 'CPA', (13, 31))	('NDUFA4L2', 'Gene', '56901', (120, 128))	('negative regulation of apoptotic signaling pathway', 'biological_process', 'GO:2001234', ('36', '86'))	('apoptotic signaling pathway', 'Pathway', (59, 86))	('negative', 'NegReg', (36, 44))	('NDUFA4L2', 'Gene', (120, 128))	('cell proliferation', 'biological_process', 'GO:0008283', ('13', '31'))
148207	29158991	However, bioinformatics analysis results revealed that copy number variation and mutation for NDUFA4L2 gene were not the reasons for NDUFA4L2 level upregulation in ccRCC (Fig.	('upregulation', 'PosReg', (148, 160))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('RCC', 'Disease', (166, 169))	('NDUFA4L2', 'Gene', '56901', (94, 102))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('mutation', 'Var', (81, 89))	('ccRCC', 'Phenotype', 'HP:0006770', (164, 169))	('NDUFA4L2', 'Gene', (94, 102))	('NDUFA4L2', 'Gene', '56901', (133, 141))	('NDUFA4L2', 'Gene', (133, 141))
148216	29158991	Since the correlation between the expression of NDUFA4L2 and ELK1 is very weak, we further performed the knockdown of ELK1 and detected the levels of NDUFA4L2 in ccRCC cells 786-O and ACHN to elucidate the direct regulatory role of ELK1 on NDUFA4L2 expression.	('NDUFA4L2', 'Gene', (240, 248))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('NDUFA4L2', 'Gene', '56901', (150, 158))	('NDUFA4L2', 'Gene', (48, 56))	('ACHN', 'Gene', (184, 188))	('ELK1', 'Gene', '2002', (118, 122))	('ELK1', 'Gene', (232, 236))	('ELK1', 'Gene', '2002', (61, 65))	('NDUFA4L2', 'Gene', (150, 158))	('knockdown', 'Var', (105, 114))	('NDUFA4L2', 'Gene', '56901', (240, 248))	('ACHN', 'Gene', '55323', (184, 188))	('ELK1', 'Gene', (118, 122))	('ELK1', 'Gene', '2002', (232, 236))	('ELK1', 'Gene', (61, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (162, 167))	('RCC', 'Disease', (164, 167))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))	('NDUFA4L2', 'Gene', '56901', (48, 56))
148217	29158991	Results showed that with the knockdown of ELK1, the protein level of NDUFA4L2 was downregulated, verifying that the levels of NDUFA4L2 could be regulated by ELK1 expression (Figs.	('NDUFA4L2', 'Gene', (69, 77))	('downregulated', 'NegReg', (82, 95))	('ELK1', 'Gene', (42, 46))	('ELK1', 'Gene', '2002', (42, 46))	('knockdown', 'Var', (29, 38))	('protein level', 'MPA', (52, 65))	('NDUFA4L2', 'Gene', '56901', (126, 134))	('ELK1', 'Gene', (157, 161))	('ELK1', 'Gene', '2002', (157, 161))	('NDUFA4L2', 'Gene', '56901', (69, 77))	('NDUFA4L2', 'Gene', (126, 134))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
148225	29158991	Inactivation of NDUFA4L2 increased mitochondrial activity and oxygen consumption, resulting in ROS accumulation and apoptosis in hepatocellular carcinoma.	('increased', 'PosReg', (25, 34))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (129, 153))	('apoptosis', 'CPA', (116, 125))	('ROS', 'Chemical', 'MESH:D017382', (95, 98))	('oxygen', 'Chemical', 'MESH:D010100', (62, 68))	('NDUFA4L2', 'Gene', '56901', (16, 24))	('apoptosis', 'biological_process', 'GO:0097194', ('116', '125'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (129, 153))	('NDUFA4L2', 'Gene', (16, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('oxygen consumption', 'MPA', (62, 80))	('hepatocellular carcinoma', 'Disease', (129, 153))	('mitochondrial activity', 'MPA', (35, 57))	('Inactivation', 'Var', (0, 12))	('ROS accumulation', 'MPA', (95, 111))	('apoptosis', 'biological_process', 'GO:0006915', ('116', '125'))
148227	29158991	Overexpression of NDUFA4L2 was also reported to be associated with poor prognosis in colorectal cancer patients.	('NDUFA4L2', 'Gene', (18, 26))	('NDUFA4L2', 'Gene', '56901', (18, 26))	('colorectal cancer', 'Disease', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Overexpression', 'Var', (0, 14))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('patients', 'Species', '9606', (103, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
148228	29158991	In ccRCC cell lines, NDUFA4L2 knockdown impaired cell proliferation and colony formation.	('NDUFA4L2', 'Gene', (21, 29))	('colony formation', 'CPA', (72, 88))	('cell proliferation', 'biological_process', 'GO:0008283', ('49', '67'))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('impaired', 'NegReg', (40, 48))	('RCC', 'Disease', (5, 8))	('cell proliferation', 'CPA', (49, 67))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('NDUFA4L2', 'Gene', '56901', (21, 29))	('formation', 'biological_process', 'GO:0009058', ('79', '88'))	('knockdown', 'Var', (30, 39))
148250	28548943	Significant anti-tumour activity was found in KI2367 treated with Sorafenib/Sunitinib monotherapy, combined Sorafenib/Sunitinib, and alternating therapy of Sorafenib/Sunitinib (P<0.05) but not in that treated with Axitinib monotherapy.	('Sunitinib', 'Chemical', 'MESH:D000077210', (76, 85))	('KI2367', 'Chemical', '-', (46, 52))	('Sorafenib', 'Chemical', 'MESH:D000077157', (66, 75))	('Sorafenib', 'Chemical', 'MESH:D000077157', (108, 117))	('Sorafenib', 'Chemical', 'MESH:D000077157', (156, 165))	('Sunitinib', 'Chemical', 'MESH:D000077210', (166, 175))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('Sunitinib', 'Chemical', 'MESH:D000077210', (118, 127))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('Axitinib', 'Chemical', 'MESH:D000077784', (214, 222))	('tumour', 'Disease', (17, 23))	('KI2367', 'Var', (46, 52))
148251	28548943	In contrast, KI2368 was significantly responsive to Sunitinib monotherapy, combined Sorafenib/Sunitinib therapy and alternating therapy of Sorafenib/Sunitinib but not responsive to Sorafenib and Axitinib monotherapy (P<0.05).	('Sunitinib', 'Chemical', 'MESH:D000077210', (149, 158))	('Sunitinib', 'Chemical', 'MESH:D000077210', (94, 103))	('KI2368', 'Var', (13, 19))	('Sorafenib', 'Chemical', 'MESH:D000077157', (139, 148))	('Sorafenib', 'Chemical', 'MESH:D000077157', (84, 93))	('KI2368', 'Chemical', '-', (13, 19))	('responsive', 'MPA', (38, 48))	('Sorafenib', 'Chemical', 'MESH:D000077157', (181, 190))	('Axitinib', 'Chemical', 'MESH:D000077784', (195, 203))	('Sunitinib', 'Chemical', 'MESH:D000077210', (52, 61))
148252	28548943	RNAseq of the two models demonstrated that the expression levels of 1,725 genes including the drug targeted genes of PDGFA, PDGFB and PDGFRA were >5-fold higher in KI2367 than in KI2368 and the expression levels of 994 genes were > 5-fold higher in KI2368 than in KI2367.	('PDGFRA', 'Gene', '5156', (134, 140))	('KI2368', 'Chemical', '-', (249, 255))	('PDGFB', 'Gene', '5155', (124, 129))	('higher', 'PosReg', (239, 245))	('PDGFB', 'Gene', (124, 129))	('higher', 'PosReg', (154, 160))	('KI2367', 'Var', (164, 170))	('KI2368', 'Chemical', '-', (179, 185))	('KI2367', 'Chemical', '-', (164, 170))	('PDGFA', 'Gene', (117, 122))	('expression levels', 'MPA', (194, 211))	('PDGFA', 'Gene', '5154', (117, 122))	('expression levels', 'MPA', (47, 64))	('KI2367', 'Chemical', '-', (264, 270))	('PDGFRA', 'Gene', (134, 140))
148261	28548943	Several malignant tumours have recently achieved personalized cancer treatment in clinical practice, such as anti-HER2 antibody for HER2-positive breast cancer, anti-EGFR therapy for KRAS wild-type colon cancer, and BRAF inhibitor for BRAF mutant melanoma.	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('HER2-positive breast cancer', 'Disease', (132, 159))	('cancer', 'Disease', (153, 159))	('malignant tumours', 'Disease', 'MESH:D009369', (8, 25))	('malignant tumours', 'Disease', (8, 25))	('HER2', 'Gene', '2064', (114, 118))	('EGFR', 'Gene', '1956', (166, 170))	('antibody', 'molecular_function', 'GO:0003823', ('119', '127'))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('colon cancer', 'Disease', (198, 210))	('antibody', 'cellular_component', 'GO:0042571', ('119', '127'))	('mutant', 'Var', (240, 246))	('KRAS', 'Gene', '3845', (183, 187))	('cancer', 'Disease', (62, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('tumours', 'Phenotype', 'HP:0002664', (18, 25))	('melanoma', 'Disease', 'MESH:D008545', (247, 255))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (204, 210))	('HER2', 'Gene', '2064', (132, 136))	('BRAF', 'Gene', '673', (235, 239))	('KRAS', 'Gene', (183, 187))	('BRAF', 'Gene', (235, 239))	('HER2', 'Gene', (114, 118))	('colon cancer', 'Phenotype', 'HP:0003003', (198, 210))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('antibody', 'cellular_component', 'GO:0019815', ('119', '127'))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('EGFR', 'Gene', (166, 170))	('EGFR', 'molecular_function', 'GO:0005006', ('166', '170'))	('colon cancer', 'Disease', 'MESH:D015179', (198, 210))	('BRAF', 'Gene', '673', (216, 220))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (132, 159))	('antibody', 'cellular_component', 'GO:0019814', ('119', '127'))	('BRAF', 'Gene', (216, 220))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('melanoma', 'Disease', (247, 255))	('melanoma', 'Phenotype', 'HP:0002861', (247, 255))	('HER2', 'Gene', (132, 136))
148270	28548943	Genome-wide studies have confirmed significant genetic diversity among RCCs and found several important driver mutations and multiple of passenger changes in RCCs, which partially explain the heterogeneous clinical outcomes of patients with similar histopathological type.	('mutations', 'Var', (111, 120))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))	('patients', 'Species', '9606', (227, 235))
148294	28548943	We found 1,725 genes with > 5-fold higher expression levels in KI2367 than in KI2368; these genes included drug target-related genes such as PDGFA, PDGFB and PDGFRA (Supplementary Table 1).	('PDGFA', 'Gene', '5154', (141, 146))	('PDGFRA', 'Gene', '5156', (158, 164))	('expression levels', 'MPA', (42, 59))	('PDGFB', 'Gene', (148, 153))	('PDGFB', 'Gene', '5155', (148, 153))	('KI2368', 'Chemical', '-', (78, 84))	('KI2367', 'Var', (63, 69))	('PDGFA', 'Gene', (141, 146))	('higher', 'PosReg', (35, 41))	('PDGFRA', 'Gene', (158, 164))	('KI2367', 'Chemical', '-', (63, 69))
148295	28548943	A total of 994 genes had > 5-fold higher expression levels in KI2368 than in KI2367 (Supplementary Table 2).	('expression levels', 'MPA', (41, 58))	('KI2367', 'Chemical', '-', (77, 83))	('KI2368', 'Var', (62, 68))	('higher', 'PosReg', (34, 40))	('KI2368', 'Chemical', '-', (62, 68))
148296	28548943	In addition, 5,539 and 5,827 mRNA changes predicted to result in protein variants were found in KI2367 and KI2368 respectively, and 4,023 mRNA changes predicted to result in protein variants were found both in KI2367 and KI2368.	('protein', 'Protein', (65, 72))	('variants', 'Var', (73, 81))	('KI2368', 'Chemical', '-', (107, 113))	('KI2367', 'Chemical', '-', (210, 216))	('KI2367', 'Chemical', '-', (96, 102))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('result', 'Reg', (55, 61))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))	('KI2368', 'Chemical', '-', (221, 227))
148297	28548943	We also found 20 and 4 in-frame gene fusions in KI2367 and KI2368, respectively, but no common in-frame fusion was detected (Table 3; see Supplementary Figure 1-5 for validation).	('KI2367', 'Var', (48, 54))	('KI2367', 'Chemical', '-', (48, 54))	('KI2368', 'Var', (59, 65))	('KI2368', 'Chemical', '-', (59, 65))
148298	28548943	PDGFRA was highly expressed in KI2367, but not expressed in KI2368.	('PDGFRA', 'Gene', (0, 6))	('KI2368', 'Chemical', '-', (60, 66))	('PDGFRA', 'Gene', '5156', (0, 6))	('KI2367', 'Var', (31, 37))	('KI2367', 'Chemical', '-', (31, 37))
148299	28548943	The expression level of PDGFRB was higher in KI2367 than in KI2368 (Table 4).	('expression level', 'MPA', (4, 20))	('PDGFRB', 'Gene', (24, 30))	('KI2368', 'Chemical', '-', (60, 66))	('KI2367', 'Var', (45, 51))	('KI2367', 'Chemical', '-', (45, 51))	('PDGFRB', 'Gene', '5159', (24, 30))	('higher', 'PosReg', (35, 41))
148300	28548943	The frameshift insertion in the HIF1A gene was observed in KI2368, which may impact the expression of PDGFRB and other genes (Table 5; Supplementary Figure 6).	('PDGFRB', 'Gene', (102, 108))	('frameshift insertion', 'Var', (4, 24))	('HIF1A', 'Gene', '3091', (32, 37))	('impact', 'Reg', (77, 83))	('PDGFRB', 'Gene', '5159', (102, 108))	('KI2368', 'Chemical', '-', (59, 65))	('HIF1A', 'Gene', (32, 37))	('expression', 'MPA', (88, 98))
148301	28548943	Moreover, a frameshift mutation in RICTOR that may affect HIF1A function and subsequently PDGFR expression was found in KI2368, and a frameshift mutation in VEGFB was detected in KI2368 but not in KI2367 (Table 5; Supplementary Figure 7).	('PDGFR', 'Gene', (90, 95))	('VEGFB', 'Gene', '7423', (157, 162))	('KI2368', 'Var', (120, 126))	('KI2367', 'Chemical', '-', (197, 203))	('PDGFR', 'Gene', '5159', (90, 95))	('affect', 'Reg', (51, 57))	('HIF1A', 'Gene', (58, 63))	('KI2368', 'Chemical', '-', (120, 126))	('VEGFB', 'Gene', (157, 162))	('HIF1A', 'Gene', '3091', (58, 63))	('expression', 'MPA', (96, 106))	('RICTOR', 'Gene', '253260', (35, 41))	('frameshift mutation', 'Var', (12, 31))	('KI2368', 'Chemical', '-', (179, 185))	('KI2368', 'Var', (179, 185))	('frameshift mutation', 'Var', (134, 153))	('function', 'MPA', (64, 72))	('RICTOR', 'Gene', (35, 41))
148317	28548943	The high-throughput sequencing have identified significant genetic diversity and screened out several important driver mutations and multiple of passenger changes in RCC.	('mutations', 'Var', (119, 128))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('RCC', 'Disease', (166, 169))
148332	28548943	The PDX models of KI2367 and KI2368 showed different responses to Sorafenib monotherapy (in group 2), also indicating that metastases in different locations may have different molecular changes that may relate to the diverse responses to targeted therapies.	('Sorafenib', 'Chemical', 'MESH:D000077157', (66, 75))	('relate', 'Reg', (203, 209))	('KI2367', 'Var', (18, 24))	('metastases', 'Disease', (123, 133))	('KI2368', 'Chemical', '-', (29, 35))	('KI2368', 'Var', (29, 35))	('metastases', 'Disease', 'MESH:D009362', (123, 133))	('KI2367', 'Chemical', '-', (18, 24))
148334	28548943	We observed that KI2367 and KI2368 had different response to the TKIs, indicating that primary and metastatic tumours have different genomic profiles.	('KI2368', 'Var', (28, 34))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('KI2367', 'Var', (17, 23))	('KI2368', 'Chemical', '-', (28, 34))	('tumours', 'Phenotype', 'HP:0002664', (110, 117))	('KI2367', 'Chemical', '-', (17, 23))	('response', 'MPA', (49, 57))	('tumours', 'Disease', 'MESH:D009369', (110, 117))	('tumours', 'Disease', (110, 117))
148335	28548943	RNAseq analysis reveals that PDGFRA is highly expressed in KI2367 but not expressed in KI2368.	('KI2367', 'Var', (59, 65))	('PDGFRA', 'Gene', (29, 35))	('PDGFRA', 'Gene', '5156', (29, 35))	('KI2368', 'Chemical', '-', (87, 93))	('KI2367', 'Chemical', '-', (59, 65))
148336	28548943	The expression of PDGFRB is higher in KI2367 than in KI2368.	('KI2368', 'Chemical', '-', (53, 59))	('PDGFRB', 'Gene', '5159', (18, 24))	('PDGFRB', 'Gene', (18, 24))	('KI2367', 'Var', (38, 44))	('expression', 'MPA', (4, 14))	('KI2367', 'Chemical', '-', (38, 44))	('higher', 'PosReg', (28, 34))
148337	28548943	Conversely, KIT is expressed in KI2368 but not expressed in KI2367.	('KI2368', 'Var', (32, 38))	('KI2367', 'Chemical', '-', (60, 66))	('KIT', 'Gene', (12, 15))	('KIT', 'molecular_function', 'GO:0005020', ('12', '15'))	('KI2368', 'Chemical', '-', (32, 38))
148339	28548943	The frameshift insertion in HIF1A may impact on the expression of PDGFRB and other genes in KI2368.	('PDGFRB', 'Gene', '5159', (66, 72))	('KI2368', 'Chemical', '-', (92, 98))	('frameshift insertion', 'Var', (4, 24))	('PDGFRB', 'Gene', (66, 72))	('HIF1A', 'Gene', (28, 33))	('HIF1A', 'Gene', '3091', (28, 33))	('expression', 'MPA', (52, 62))	('impact', 'Reg', (38, 44))
148340	28548943	The frameshift mutation of RICTOR in KI2368 may also affect the function of HIF1A and subsequently PDGFR expression.	('frameshift mutation', 'Var', (4, 23))	('RICTOR', 'Gene', '253260', (27, 33))	('KI2368', 'Chemical', '-', (37, 43))	('affect', 'Reg', (53, 59))	('PDGFR', 'Gene', (99, 104))	('HIF1A', 'Gene', (76, 81))	('HIF1A', 'Gene', '3091', (76, 81))	('RICTOR', 'Gene', (27, 33))	('PDGFR', 'Gene', '5159', (99, 104))	('expression', 'MPA', (105, 115))	('function', 'MPA', (64, 72))	('KI2368', 'Var', (37, 43))
148342	28548943	We also found a VEGFB frameshift mutation in KI2368 but not in KI2367.	('VEGFB', 'Gene', (16, 21))	('KI2368', 'Chemical', '-', (45, 51))	('frameshift mutation', 'Var', (22, 41))	('KI2367', 'Chemical', '-', (63, 69))	('VEGFB', 'Gene', '7423', (16, 21))
148344	28548943	The VEGFB mutation may reduce the effectiveness of drugs such as Axitinib on VEGF receptors.	('VEGF', 'Gene', '7422', (77, 81))	('VEGFB', 'Gene', '7423', (4, 9))	('Axitinib', 'Chemical', 'MESH:D000077784', (65, 73))	('reduce', 'NegReg', (23, 29))	('VEGF', 'Gene', '7422', (4, 8))	('mutation', 'Var', (10, 18))	('VEGFB', 'Gene', (4, 9))	('VEGF', 'Gene', (77, 81))	('effectiveness', 'MPA', (34, 47))	('VEGF', 'Gene', (4, 8))
148375	28548943	The established PDX models were KI2367 from the primary tumour and KI2368 from the subcutaneous metastatic tumour of the chest wall.	('primary tumour', 'Disease', 'MESH:D009369', (48, 62))	('KI2367', 'Chemical', '-', (32, 38))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('KI2368', 'Chemical', '-', (67, 73))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('primary tumour', 'Disease', (48, 62))	('tumour', 'Disease', (56, 62))	('KI2368', 'Var', (67, 73))	('tumour', 'Disease', (107, 113))
148391	28548943	The sequencing was performed at PE125 on an Illumina HiSeq2500 platform (KI2367) and PE100 on an Illumina HiSeq2500 platform (KI2368) by certified Illumina service providers.	('KI2367', 'Chemical', '-', (73, 79))	('PE125', 'Var', (32, 37))	('KI2368', 'Chemical', '-', (126, 132))	('PE100', 'Var', (85, 90))
148398	31616061	In vitro, V2R antagonists OPC31260 and Tolvaptan, or V2R gene silencing reduced wound closure and cell viability of 786-O and Caki-1 human ccRCC cell lines.	('RCC', 'Disease', (141, 144))	('reduced', 'NegReg', (72, 79))	('wound closure', 'CPA', (80, 93))	('OPC31260', 'Chemical', 'MESH:C076251', (26, 34))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('gene silencing', 'Var', (57, 71))	('Tolvaptan', 'Chemical', 'MESH:D000077602', (39, 48))	('gene silencing', 'biological_process', 'GO:0016458', ('57', '71'))	('human', 'Species', '9606', (133, 138))	('V2R', 'Gene', (53, 56))	('Caki-1', 'CellLine', 'CVCL:0234', (126, 132))	('cell viability', 'CPA', (98, 112))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
148403	31616061	V2R gene silencing in Caki-1 cells also reduced cAMP and ERK1/2 activation.	('activation', 'MPA', (64, 74))	('Caki-1', 'CellLine', 'CVCL:0234', (22, 28))	('cAMP', 'MPA', (48, 52))	('ERK1/2', 'Gene', (57, 63))	('gene silencing', 'biological_process', 'GO:0016458', ('4', '18'))	('reduced', 'NegReg', (40, 47))	('ERK1', 'molecular_function', 'GO:0004707', ('57', '61'))	('V2R', 'Gene', (0, 3))	('ERK1/2', 'Gene', '5595;5594', (57, 63))	('cAMP', 'Chemical', '-', (48, 52))	('gene silencing', 'Var', (4, 18))
148442	31616061	Cells incubated with OPC31260 for 24h were washed in cold PBS, resuspended in calcium containing binding buffer (10 mM HEPES, 140mM NaCl, 5mM CaCl2; pH 7.4) at 1X106 cells/ml and stained for 15min, with 5mul Annexin V-FITC and 5mul PI at 1 mug/ml.	('binding', 'molecular_function', 'GO:0005488', ('97', '104'))	('OPC31260', 'Chemical', 'MESH:C076251', (21, 29))	('cold PBS', 'Disease', 'MESH:D011535', (53, 61))	('FITC', 'Chemical', 'MESH:D016650', (218, 222))	('HEPES', 'Chemical', 'MESH:D006531', (119, 124))	('calcium', 'Chemical', 'MESH:D002118', (78, 85))	('Annexin V', 'Gene', '308', (208, 217))	('mug', 'molecular_function', 'GO:0043739', ('240', '243'))	('NaCl', 'Chemical', 'MESH:D012965', (132, 136))	('OPC31260', 'Var', (21, 29))	('CaCl2', 'Chemical', 'MESH:D002122', (142, 147))	('Annexin V', 'Gene', (208, 217))	('cold PBS', 'Disease', (53, 61))
148486	31616061	These results suggest that inhibition of V2R in ccRCC cells reduces clonogenicity and is cytostatic, and that inhibition of cell proliferation occurs by inducing G2/M cell cycle arrest rather than lytic death.	('inhibition', 'NegReg', (110, 120))	('arrest', 'Disease', (178, 184))	('clonogenicity', 'CPA', (68, 81))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (167, 184))	('RCC', 'Disease', (50, 53))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('167', '184'))	('inhibition', 'Var', (27, 37))	('rat', 'Species', '10116', (185, 188))	('rat', 'Species', '10116', (136, 139))	('cell proliferation', 'CPA', (124, 142))	('inducing', 'Reg', (153, 161))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('110', '142'))	('reduces', 'NegReg', (60, 67))	('V2R', 'Protein', (41, 44))	('arrest', 'Disease', 'MESH:D006323', (178, 184))
148490	31616061	Treatment of Caki-1 cells with dDAVP, a V2R agonist showed a trend towards increased cell viability and wound closure when compared to vehicle treatment, but the values were not significantly different (Fig-2I, J).	('dDAVP', 'Var', (31, 36))	('Caki-1', 'CellLine', 'CVCL:0234', (13, 19))	('wound closure', 'CPA', (104, 117))	('increased', 'PosReg', (75, 84))	('cell viability', 'CPA', (85, 99))
148496	31616061	Mice carrying tumors of approximately 80-100mm3 size were randomized into three groups for treatment with vehicle, OPC31260 (30mg/Kg) or OPC31260 (60mg/Kg) for 28 days by daily intraperitoneal injections.	('OPC31260', 'Chemical', 'MESH:C076251', (137, 145))	('OPC31260', 'Var', (115, 123))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('OPC31260', 'Chemical', 'MESH:C076251', (115, 123))	('Mice', 'Species', '10090', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
148498	31616061	At sacrifice, the tumors in the OPC31260 treatment groups were smaller and weighed significantly less than in the vehicle treatment group (Fig-3B, C).	('OPC31260', 'Var', (32, 40))	('smaller', 'NegReg', (63, 70))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('weighed', 'CPA', (75, 82))	('OPC31260', 'Chemical', 'MESH:C076251', (32, 40))	('less', 'NegReg', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
148501	31616061	OPC31260 treatment did not significantly affect the body weight of the mice, but reduced urine osmolality, as expected, in a dose-dependent manner (Supplemental-4B, C), suggesting that OPC31260 at these doses is well tolerated, but inhibits the V2R-regulated urine concentrating ability in these mice.	('mice', 'Species', '10090', (71, 75))	('reduced urine osmolality', 'Phenotype', 'HP:0003158', (81, 105))	('rat', 'Species', '10116', (221, 224))	('urine concentrating ability', 'Phenotype', 'HP:0004727', (259, 286))	('OPC31260', 'Chemical', 'MESH:C076251', (0, 8))	('OPC31260', 'Chemical', 'MESH:C076251', (185, 193))	('urine osmolality', 'MPA', (89, 105))	('mice', 'Species', '10090', (296, 300))	('reduced urine', 'Phenotype', 'HP:0011037', (81, 94))	('V2R-regulated urine concentrating ability', 'MPA', (245, 286))	('reduced', 'NegReg', (81, 88))	('rat', 'Species', '10116', (272, 275))	('inhibits', 'NegReg', (232, 240))	('OPC31260', 'Var', (185, 193))
148506	31616061	By comparison, tumor volumes in dDAVP treatment group significantly increased starting on day 21, and by day 28 were 14-fold higher than on day 1 (Fig-4A).	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('dDAVP', 'Var', (32, 37))	('tumor', 'Disease', (15, 20))	('higher', 'PosReg', (125, 131))	('increased', 'PosReg', (68, 77))
148510	31616061	In both the OPC31260 and Tolvaptan groups, the tumors showed significantly reduced Ki-67 staining (Fig-5A,B), and increased TUNEL staining (Fig-5A,C) compared to vehicle treatment.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('TUNEL staining', 'MPA', (124, 138))	('Ki-67', 'Gene', (83, 88))	('OPC31260', 'Var', (12, 20))	('increased', 'PosReg', (114, 123))	('reduced', 'NegReg', (75, 82))	('staining', 'MPA', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('OPC31260', 'Chemical', 'MESH:C076251', (12, 20))	('Tolvaptan', 'Chemical', 'MESH:D000077602', (25, 34))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('Ki-67', 'Gene', '17345', (83, 88))
148511	31616061	In contrast, tumors in the dDAVP group showed a significant increase in Ki-67 staining and reduced TUNEL staining compared to the vehicle group (Fig-5A, B, C).	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('staining', 'MPA', (78, 86))	('Ki-67', 'Gene', (72, 77))	('increase', 'PosReg', (60, 68))	('reduced', 'NegReg', (91, 98))	('TUNEL staining', 'MPA', (99, 113))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('dDAVP', 'Var', (27, 32))	('Ki-67', 'Gene', '17345', (72, 77))
148514	31616061	However, OPC31260 and Tolvaptan significantly reduced vascular endothelial growth factor (VEGF) protein levels, an important angiogenic growth factor in the tumors compared to vehicle treatment (Fig-5E, F), while dDAVP did not affect VEGF levels.	('vascular endothelial growth factor', 'Gene', '7422', (54, 88))	('VEGF', 'Gene', (90, 94))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('OPC31260', 'Var', (9, 17))	('VEGF', 'Gene', '7422', (234, 238))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('Tolvaptan', 'Chemical', 'MESH:D000077602', (22, 31))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('VEGF', 'Gene', '7422', (90, 94))	('reduced', 'NegReg', (46, 53))	('OPC31260', 'Chemical', 'MESH:C076251', (9, 17))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('54', '88'))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('vascular endothelial growth factor', 'Gene', (54, 88))	('VEGF', 'Gene', (234, 238))
148515	31616061	These results suggest that V2R inhibition can reduce angiogenesis and tumor cell proliferation, and increase apoptosis in ccRCC tumors.	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('rat', 'Species', '10116', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('increase', 'PosReg', (100, 108))	('reduce', 'NegReg', (46, 52))	('V2R', 'Protein', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('angiogenesis', 'biological_process', 'GO:0001525', ('53', '65'))	('apoptosis', 'CPA', (109, 118))	('cell proliferation', 'biological_process', 'GO:0008283', ('76', '94'))	('ccRCC tumors', 'Disease', (122, 134))	('ccRCC tumors', 'Disease', 'MESH:D009369', (122, 134))	('inhibition', 'Var', (31, 41))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('angiogenesis', 'CPA', (53, 65))	('tumor', 'Disease', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
148519	31616061	In ccRCC tissue, high levels of pERK1/2 (Thr202/Tyr204), ERK1/2, pCREB (Ser133) and CREB were observed (Fig-6A and Supplemental-6A,B), as well as high intracellular cAMP levels (Fig-6B).	('Thr202', 'Chemical', '-', (41, 47))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('RCC', 'Disease', (5, 8))	('ERK1/2', 'Gene', (57, 63))	('Tyr204', 'Chemical', '-', (48, 54))	('ERK1/2', 'Gene', (33, 39))	('cAMP', 'Chemical', '-', (165, 169))	('Thr202/Tyr204', 'Var', (41, 54))	('ERK1/2', 'Gene', '5595;5594', (33, 39))	('ERK1/2', 'Gene', '5595;5594', (57, 63))	('intracellular cAMP levels', 'MPA', (151, 176))	('Ser133', 'Chemical', '-', (72, 78))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('Ser', 'cellular_component', 'GO:0005790', ('72', '75'))	('ERK1', 'molecular_function', 'GO:0004707', ('57', '61'))	('intracellular', 'cellular_component', 'GO:0005622', ('151', '164'))
148521	31616061	In mouse xenograft tumor tissue lysates, a significant reduction in pERK1/2 was observed in the OPC31260 and Tolvaptan groups, compared to the vehicle treatment groups (Fig-6C,D,E,F).	('mouse', 'Species', '10090', (3, 8))	('reduction', 'NegReg', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('OPC31260', 'Chemical', 'MESH:C076251', (96, 104))	('ERK1/2', 'Gene', (69, 75))	('ERK1/2', 'Gene', '5595;5594', (69, 75))	('Tolvaptan', 'Chemical', 'MESH:D000077602', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('OPC31260', 'Var', (96, 104))
148522	31616061	We next measured intracellular cAMP generation in vitro, since (unlike V1R) activation of V2R induces Gs-mediated adenylate cyclase stimulation resulting in increased intracellular cAMP levels and CREB activity.	('Gs-mediated adenylate cyclase', 'MPA', (102, 131))	('intracellular', 'cellular_component', 'GO:0005622', ('167', '180'))	('increased intracellular cAMP levels', 'Phenotype', 'HP:0003575', (157, 192))	('CREB', 'Enzyme', (197, 201))	('intracellular', 'cellular_component', 'GO:0005622', ('17', '30'))	('rat', 'Species', '10116', (40, 43))	('activation', 'Var', (76, 86))	('cAMP', 'Chemical', '-', (181, 185))	('increased', 'PosReg', (157, 166))	('intracellular cAMP levels', 'MPA', (167, 192))	('stimulation', 'PosReg', (132, 143))	('activity', 'MPA', (202, 210))	('cAMP', 'Chemical', '-', (31, 35))	('V2R', 'Gene', (90, 93))
148524	31616061	Consistently, dDAVP increased pERK1/2 and pCREB levels in Caki-1 cells within 5-30 minutes after treatment (Fig-6H), while OPC31260 and Tolvaptan reduced the pERK1/2 and pCREB levels (Fig-6I).	('increased', 'PosReg', (20, 29))	('OPC31260', 'Chemical', 'MESH:C076251', (123, 131))	('ERK1/2', 'Gene', (159, 165))	('ERK1/2', 'Gene', (31, 37))	('pCREB levels', 'MPA', (42, 54))	('ERK1/2', 'Gene', '5595;5594', (31, 37))	('Tolvaptan', 'Chemical', 'MESH:D000077602', (136, 145))	('reduced', 'NegReg', (146, 153))	('ERK1/2', 'Gene', '5595;5594', (159, 165))	('Caki-1', 'CellLine', 'CVCL:0234', (58, 64))	('dDAVP', 'Var', (14, 19))
148525	31616061	In this study, the V1R antagonist SR49059 showed no effect on pERK1/2 and pCREB levels (Fig-6I).	('SR49059', 'Chemical', 'MESH:C082134', (34, 41))	('ERK1/2', 'Gene', '5595;5594', (63, 69))	('ERK1/2', 'Gene', (63, 69))	('SR49059', 'Var', (34, 41))	('pCREB levels', 'MPA', (74, 86))
148528	31616061	Caki-1 cells were treated with forskolin, a direct activator of adenylate cyclase, that increases intracellular cAMP, or 8-Br-cAMP, a cell permeable cAMP analog.	('cAMP', 'Chemical', '-', (149, 153))	('cAMP', 'Chemical', '-', (112, 116))	('intracellular', 'cellular_component', 'GO:0005622', ('98', '111'))	('forskolin', 'Chemical', 'MESH:D005576', (31, 40))	('cAMP', 'Chemical', '-', (126, 130))	('increases', 'PosReg', (88, 97))	('8-Br-cAMP', 'Var', (121, 130))	('8-Br-cAMP', 'Chemical', '-', (121, 130))	('Caki-1', 'CellLine', 'CVCL:0234', (0, 6))	('intracellular cAMP', 'MPA', (98, 116))
148531	31616061	When compared scrambled-siRNA group, V2R-siRNA or did not show cell cycle arrest (Fig-6J, K), but showed significantly reduced cell viability (Fig-6L) and wound closure (Fig-6M).	('cell viability', 'CPA', (127, 141))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('63', '80'))	('arrest', 'Disease', 'MESH:D006323', (74, 80))	('wound closure', 'CPA', (155, 168))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (63, 80))	('reduced', 'NegReg', (119, 126))	('arrest', 'Disease', (74, 80))	('V2R-siRNA', 'Var', (37, 46))
148532	31616061	Importantly, OPC31260 treatment caused G2/M cell cycle arrest, reduced cell viability and wound closure in the scrambled-siRNA group, it failed to do so in the V2R-siRNA group (Fig-6K, L, M) consistent with the effect of OPC31260 being through inhibition of V2R.	('arrest', 'Disease', 'MESH:D006323', (55, 61))	('reduced', 'NegReg', (63, 70))	('OPC31260', 'Var', (221, 229))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('44', '61'))	('arrest', 'Disease', (55, 61))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (44, 61))	('wound closure', 'CPA', (90, 103))	('OPC31260', 'Chemical', 'MESH:C076251', (221, 229))	('OPC31260', 'Var', (13, 21))	('cell viability', 'CPA', (71, 85))	('OPC31260', 'Chemical', 'MESH:C076251', (13, 21))
148535	31616061	V2R antagonists were found to reduce cell viability, clonogenicity, and wound closure, and to induce cell cycle arrest of ccRCC cell lines in vitro.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('antagonists', 'Var', (4, 15))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (101, 118))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('reduce', 'NegReg', (30, 36))	('induce', 'Reg', (94, 100))	('arrest', 'Disease', 'MESH:D006323', (112, 118))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('101', '118'))	('V2R', 'Gene', (0, 3))	('clonogenicity', 'CPA', (53, 66))	('wound closure', 'CPA', (72, 85))	('arrest', 'Disease', (112, 118))	('cell viability', 'CPA', (37, 51))
148536	31616061	Moreover, V2R antagonists suppressed ccRCC tumor growth in a mouse RCC xenograft model by reducing tumor cell proliferation and increasing apoptosis, while a V2R selective agonist had the reverse effect.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('suppressed', 'NegReg', (26, 36))	('RCC', 'Disease', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('reducing', 'NegReg', (90, 98))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (99, 104))	('apoptosis', 'biological_process', 'GO:0097194', ('139', '148'))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('apoptosis', 'biological_process', 'GO:0006915', ('139', '148'))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('mouse', 'Species', '10090', (61, 66))	('ccRCC tumor', 'Disease', (37, 48))	('apoptosis', 'CPA', (139, 148))	('rat', 'Species', '10116', (117, 120))	('antagonists', 'Var', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('ccRCC tumor', 'Disease', 'MESH:D009369', (37, 48))	('cell proliferation', 'biological_process', 'GO:0008283', ('105', '123'))	('RCC', 'Disease', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('increasing', 'PosReg', (128, 138))	('V2R', 'Gene', (10, 13))
148537	31616061	V2R inhibition was found to reduce cAMP levels, and ERK and CREB activity in ccRCC cell lines or mouse xenograft tumors.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('activity', 'MPA', (65, 73))	('cAMP', 'Chemical', '-', (35, 39))	('ERK', 'molecular_function', 'GO:0004707', ('52', '55'))	('tumors', 'Disease', (113, 119))	('RCC', 'Disease', (79, 82))	('CREB', 'Enzyme', (60, 64))	('cAMP levels', 'MPA', (35, 46))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('inhibition', 'Var', (4, 14))	('mouse', 'Species', '10090', (97, 102))	('ERK', 'Enzyme', (52, 55))	('reduce', 'NegReg', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('V2R', 'Protein', (0, 3))
148541	31616061	Mutations in the tumor suppressor PTEN correlates with poor survival in the majority of cancer patients.	('tumor suppressor', 'biological_process', 'GO:0051726', ('17', '33'))	('cancer', 'Disease', (88, 94))	('tumor', 'Disease', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('patients', 'Species', '9606', (95, 103))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('17', '33'))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('poor', 'NegReg', (55, 59))	('PTEN', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('PTEN', 'Gene', '5728', (34, 38))
148542	31616061	However, mutant PTEN in ccRCC samples in the TCGA database do not correlate with poor survival.	('mutant', 'Var', (9, 15))	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('PTEN', 'Gene', (16, 20))	('PTEN', 'Gene', '5728', (16, 20))
148550	31616061	Thus, ectopic expression of V2R as well as its ligand could provide a survival and growth advantage to ccRCC tumor cells.	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('ccRCC tumor', 'Disease', (103, 114))	('ccRCC tumor', 'Disease', 'MESH:D009369', (103, 114))	('ectopic expression', 'Var', (6, 24))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('survival', 'CPA', (70, 78))	('ligand', 'molecular_function', 'GO:0005488', ('47', '53'))	('growth advantage', 'CPA', (83, 99))	('V2R', 'Gene', (28, 31))
148553	31616061	Based on prior studies, the effect of AVP on tumor growth appears to be dependent on the following: (A) Type of cancer: AVP promotes growth of SCLC and breast cancer cell lines in vitro.	('Type of cancer', 'Disease', (104, 118))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Type of cancer', 'Disease', 'MESH:D009369', (104, 118))	('growth', 'MPA', (133, 139))	('tumor', 'Disease', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('SCLC', 'Disease', 'MESH:D018288', (143, 147))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('SCLC', 'Disease', (143, 147))	('promotes', 'PosReg', (124, 132))	('breast cancer', 'Disease', (152, 165))	('AVP', 'Var', (120, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
148554	31616061	In vivo, transgenic AVP overexpression increased mammary tumor growth, while antibody- mediated targeting of pro- vasopressin impaired SCLC and breast cancer tumor growth in mice.	('transgenic', 'Var', (9, 19))	('mice', 'Species', '10090', (174, 178))	('antibody', 'cellular_component', 'GO:0019815', ('77', '85'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('impaired SCLC and breast cancer tumor', 'Disease', 'MESH:D001943', (126, 163))	('transgenic', 'Species', '10090', (9, 19))	('vasopressin', 'Gene', '551', (114, 125))	('AVP', 'Gene', (20, 23))	('breast cancer tumor', 'Phenotype', 'HP:0100013', (144, 163))	('antibody', 'cellular_component', 'GO:0019814', ('77', '85'))	('tumor', 'Disease', (57, 62))	('overexpression', 'Var', (24, 38))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('antibody', 'molecular_function', 'GO:0003823', ('77', '85'))	('tumor', 'Disease', (158, 163))	('vasopressin', 'Gene', (114, 125))	('antibody', 'cellular_component', 'GO:0042571', ('77', '85'))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('increased', 'PosReg', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (158, 163))
148561	31616061	Our in vivo studies showed that dDAVP can stimulate increases in tumor cell proliferation and tumor growth, and a reduction in tumor cell apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('rat', 'Species', '10116', (83, 86))	('cell proliferation', 'biological_process', 'GO:0008283', ('71', '89'))	('tumor', 'Disease', (65, 70))	('reduction', 'NegReg', (114, 123))	('tumor', 'Disease', (127, 132))	('increases', 'PosReg', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('apoptosis', 'biological_process', 'GO:0097194', ('138', '147'))	('dDAVP', 'Var', (32, 37))	('tumor', 'Disease', (94, 99))	('apoptosis', 'biological_process', 'GO:0006915', ('138', '147'))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
148564	31616061	Since dDAVP has greater selectivity for V2R compared to V1R, these studies concluded that the effect of dDAVP could be via V2R, and protective in these cancers.	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('dDAVP', 'Var', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('V2R', 'Protein', (123, 126))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
148572	31616061	However, SR49059, a V1R inhibitor, failed to reduce pERK1/2 levels in Caki-1 cells, unlike V2R antagonists which did so.	('ERK1/2', 'Gene', (53, 59))	('ERK1/2', 'Gene', '5595;5594', (53, 59))	('SR49059', 'Chemical', 'MESH:C082134', (9, 16))	('SR49059', 'Var', (9, 16))	('Caki-1', 'CellLine', 'CVCL:0234', (70, 76))
148573	31616061	Importantly, V2R gene silencing in Caki-1 cells not only reduced cell viability and wound closure, but abolished the ability of OPC31260 to induce cell cycle arrest or further reduce cell viability and wound closure.	('Caki-1', 'CellLine', 'CVCL:0234', (35, 41))	('wound closure', 'CPA', (84, 97))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('147', '164'))	('abolished', 'NegReg', (103, 112))	('cell viability', 'CPA', (65, 79))	('OPC31260', 'Chemical', 'MESH:C076251', (128, 136))	('gene silencing', 'Var', (17, 31))	('gene silencing', 'biological_process', 'GO:0016458', ('17', '31'))	('reduce', 'NegReg', (176, 182))	('V2R', 'Gene', (13, 16))	('arrest', 'Disease', 'MESH:D006323', (158, 164))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (147, 164))	('reduced', 'NegReg', (57, 64))	('arrest', 'Disease', (158, 164))
148576	31616061	In fact, dDAVP suppresses cell proliferation related gene expression in normal mouse kidneys, because cAMP via PKA inhibits RAF-1, and hence the RAS-RAF-MEK-ERK signaling pathway, which inhibits cell proliferation.	('mouse', 'Species', '10090', (79, 84))	('dDAVP', 'Var', (9, 14))	('rat', 'Species', '10116', (207, 210))	('PKA', 'cellular_component', 'GO:0005952', ('111', '114'))	('RAF', 'Gene', '673;5894;110157', (124, 127))	('signaling pathway', 'biological_process', 'GO:0007165', ('161', '178'))	('gene expression', 'biological_process', 'GO:0010467', ('53', '68'))	('PKA', 'molecular_function', 'GO:0004691', ('111', '114'))	('rat', 'Species', '10116', (38, 41))	('cell', 'Gene', (26, 30))	('suppresses', 'NegReg', (15, 25))	('cell proliferation', 'biological_process', 'GO:0008283', ('195', '213'))	('RAF', 'Gene', (149, 152))	('inhibits', 'NegReg', (186, 194))	('inhibits', 'NegReg', (115, 123))	('cell proliferation', 'biological_process', 'GO:0008283', ('26', '44'))	('ERK', 'molecular_function', 'GO:0004707', ('157', '160'))	('cell proliferation', 'CPA', (195, 213))	('RAF', 'Gene', (124, 127))	('cAMP', 'Chemical', '-', (102, 106))	('RAF', 'Gene', '673;5894;110157', (149, 152))
148581	31616061	OPC31260 is about 100 times more selectivity for V2R than for V1aR, while Tolvaptan has 29-fold greater selectivity for human V2R than V1aR.	('V1aR', 'Gene', (62, 66))	('human', 'Species', '9606', (120, 125))	('OPC31260', 'Chemical', 'MESH:C076251', (0, 8))	('V1aR', 'Gene', '552', (62, 66))	('V1aR', 'Gene', (135, 139))	('Tolvaptan', 'Chemical', 'MESH:D000077602', (74, 83))	('V2R', 'MPA', (49, 52))	('V1aR', 'Gene', '552', (135, 139))	('OPC31260', 'Var', (0, 8))
148584	31616061	OPC31260 was also more effective in causing cell cycle arrest, reducing cell viability and wound closure than Tolvaptan.	('arrest', 'Disease', 'MESH:D006323', (55, 61))	('wound closure', 'CPA', (91, 104))	('OPC31260', 'Chemical', 'MESH:C076251', (0, 8))	('cell viability', 'CPA', (72, 86))	('reducing', 'NegReg', (63, 71))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('44', '61'))	('arrest', 'Disease', (55, 61))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (44, 61))	('OPC31260', 'Var', (0, 8))	('Tolvaptan', 'Chemical', 'MESH:D000077602', (110, 119))
148591	31616061	Although OPC31260 was found to have an IC50 value of 1.2muM for V2R in vitro in isolated rat kidney plasma membranes , in our studies, a dose range of 5-10muM was required to significantly inhibit migration and colony formation and cell viability, and induce cell cycle arrest of Caki-1 and 786-O cells in vitro.	('arrest', 'Disease', (270, 276))	('colon', 'Disease', (211, 216))	('Caki-1', 'CellLine', 'CVCL:0234', (280, 286))	('formation', 'biological_process', 'GO:0009058', ('218', '227'))	('rat', 'Species', '10116', (200, 203))	('OPC31260', 'Var', (9, 17))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (259, 276))	('V2R', 'Gene', (64, 67))	('migration', 'CPA', (197, 206))	('arrest', 'Disease', 'MESH:D006323', (270, 276))	('cell viability', 'CPA', (232, 246))	('rat', 'Species', '10116', (89, 92))	('OPC31260', 'Chemical', 'MESH:C076251', (9, 17))	('induce', 'Reg', (252, 258))	('colon', 'Disease', 'MESH:D003110', (211, 216))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('259', '276'))	('inhibit', 'NegReg', (189, 196))
148593	31616061	In our in vitro studies, both OPC31260 and Tolvaptan reduced cell viability and wound closure in unstimulated ccRCC cells and reduced tumor growth in vivo.	('reduced', 'NegReg', (126, 133))	('OPC31260', 'Chemical', 'MESH:C076251', (30, 38))	('Tolvaptan', 'Chemical', 'MESH:D000077602', (43, 52))	('reduced', 'NegReg', (53, 60))	('RCC', 'Disease', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('cell viability', 'CPA', (61, 75))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('wound closure', 'CPA', (80, 93))	('OPC31260', 'Var', (30, 38))	('tumor', 'Disease', (134, 139))
148594	31616061	In addition, OPC31260 and Tolvaptan also significantly increased tumor cell death by apoptosis, while dDVAP treatment reduced apoptosis compared to vehicle treatment in mouse xenograft tumors.	('Tolvaptan', 'Chemical', 'MESH:D000077602', (26, 35))	('increased', 'PosReg', (55, 64))	('tumors', 'Disease', (185, 191))	('apoptosis', 'biological_process', 'GO:0097194', ('85', '94'))	('OPC31260', 'Var', (13, 21))	('apoptosis', 'biological_process', 'GO:0006915', ('85', '94'))	('OPC31260', 'Chemical', 'MESH:C076251', (13, 21))	('tumor', 'Disease', (185, 190))	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('tumor', 'Disease', (65, 70))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('apoptosis', 'CPA', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('cell death', 'biological_process', 'GO:0008219', ('71', '81'))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('dDVAP', 'Chemical', '-', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('mouse', 'Species', '10090', (169, 174))
148597	31616061	Thus, while ectopic expression of V2R by ccRCC tumor cells could be an adaptation that gives them a survival and pathogenic advantage, it also makes V2R a potentially useful target of inhibition for ccRCC therapy.	('ccRCC tumor', 'Disease', (41, 52))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('ccRCC tumor', 'Disease', 'MESH:D009369', (41, 52))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('V2R', 'Gene', (34, 37))	('ectopic', 'Var', (12, 19))
148605	31616061	Although OPC31260 was found to be more effective compared to Tolvaptan, the later is an FDA approved drug for the treatment of hyponatremia and PKD, and could be repurposed for use in ccRCC therapy.	('OPC31260', 'Var', (9, 17))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('Tolvaptan', 'Chemical', 'MESH:D000077602', (61, 70))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('PKD', 'Disease', (144, 147))	('RCC', 'Disease', (186, 189))	('hyponatremia', 'Phenotype', 'HP:0002902', (127, 139))	('PKD', 'Disease', 'MESH:C537180', (144, 147))	('OPC31260', 'Chemical', 'MESH:C076251', (9, 17))	('hyponatremia', 'Disease', 'MESH:D007010', (127, 139))	('hyponatremia', 'Disease', (127, 139))
148634	27494883	EpCAM was only positively expressed in 18.6% of cases with a range of 6.3-27.6% in each clinical stage, and there was a declining trend of EpCAM positivity in patients with advanced-stage RCC (III and IV) compared to early-stage cases (I and II) (Figure 1A and Table 2).	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('EpCAM', 'Gene', '4072', (0, 5))	('EpCAM', 'Gene', (139, 144))	('positivity', 'Var', (145, 155))	('RCC', 'Disease', (188, 191))	('EpCAM', 'Gene', '4072', (139, 144))	('declining', 'NegReg', (120, 129))	('EpCAM', 'Gene', (0, 5))	('patients', 'Species', '9606', (159, 167))
148675	27494883	High expression of CA9 in tumors is associated with increased aggressiveness and poor prognosis.	('CA9', 'Gene', '768', (19, 22))	('increased', 'PosReg', (52, 61))	('High', 'Var', (0, 4))	('aggressiveness', 'Disease', 'MESH:D001523', (62, 76))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('aggressiveness', 'Disease', (62, 76))	('aggressiveness', 'Phenotype', 'HP:0000718', (62, 76))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('CA9', 'Gene', (19, 22))	('tumors', 'Disease', (26, 32))
148725	32284789	Although HIF promotes the progression of ccRCC, the precise mechanism by which the loss of VHL leads to tumor initiation remains unclear.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('loss', 'Var', (83, 87))	('VHL', 'Gene', (91, 94))	('tumor', 'Disease', (104, 109))	('ccRCC', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
148727	32284789	Through the mutant analysis, we found that the role of pVHL in DNA repair is conserved in zebrafish Vll.	('DNA repair', 'biological_process', 'GO:0006281', ('63', '73'))	('pVHL', 'Gene', (55, 59))	('zebrafish', 'Species', '7955', (90, 99))	('mutant', 'Var', (12, 18))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))
148728	32284789	Interestingly, we also discovered that Hif activation strongly suppressed genotoxic stress induced DNA repair defects and apoptosis in vll and brca2 mutants and in embryos lacking ATM activity.	('apoptosis', 'biological_process', 'GO:0097194', ('122', '131'))	('apoptosis', 'biological_process', 'GO:0006915', ('122', '131'))	('apoptosis', 'CPA', (122, 131))	('DNA repair', 'MPA', (99, 109))	('brca2', 'Gene', '675', (143, 148))	('mutants', 'Var', (149, 156))	('vll', 'Gene', (135, 138))	('suppressed', 'NegReg', (63, 73))	('brca2', 'Gene', (143, 148))	('genotoxic stress', 'Disease', 'MESH:D000079225', (74, 90))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))	('genotoxic stress', 'Disease', (74, 90))	('DNA repair', 'biological_process', 'GO:0006281', ('99', '109'))
148730	32284789	In humans, mutations in the pVHL protein, a tumor suppressor protein, predispose patients to Von Hippel Lindau (VHL) disease, a rare form of dominantly inherited cancer syndrome.	('dominantly inherited cancer syndrome', 'Disease', (141, 177))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('44', '60'))	('mutations', 'Var', (11, 20))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('predispose', 'Reg', (70, 80))	('pVHL', 'Gene', (28, 32))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('humans', 'Species', '9606', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Von Hippel Lindau (VHL) disease', 'Disease', 'MESH:D006623', (93, 124))	('tumor suppressor', 'biological_process', 'GO:0051726', ('44', '60'))	('tumor', 'Disease', (44, 49))	('dominantly inherited cancer syndrome', 'Disease', 'MESH:D009386', (141, 177))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
148740	32284789	However, when cells are exposed to hypoxia, the inactivation of PHD enzymes lead to HIFalpha stabilization, its translocation into the nuclei and the formation of functional heterodimers with HIF1beta subunit.	('formation of', 'Reg', (150, 162))	('PHD', 'Disease', 'MESH:D011547', (64, 67))	('PHD', 'Disease', (64, 67))	('formation', 'biological_process', 'GO:0009058', ('150', '159'))	('HIFalpha', 'Gene', (84, 92))	('inactivation', 'Var', (48, 60))	('hypoxia', 'Disease', 'MESH:D000860', (35, 42))	('HIF1beta', 'Gene', (192, 200))	('PHD', 'molecular_function', 'GO:0050175', ('64', '67'))	('functional', 'MPA', (163, 173))	('heterodimers', 'Interaction', (174, 186))	('hypoxia', 'Disease', (35, 42))	('stabilization', 'MPA', (93, 106))	('HIF1beta', 'Gene', '3091', (192, 200))	('translocation into the', 'MPA', (112, 134))
148744	32284789	The mutations in pVHL that cause pheochromocytoma retain the ability to regulate HIF degradation, indicating that HIF independent roles of pVHL are important for tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('ability', 'MPA', (61, 68))	('pheochromocytoma', 'Disease', (33, 49))	('degradation', 'biological_process', 'GO:0009056', ('85', '96'))	('tumor', 'Disease', (162, 167))	('pheochromocytoma', 'Disease', 'MESH:D010673', (33, 49))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (33, 49))	('rad', 'Gene', '6236', (88, 91))	('cause', 'Reg', (27, 32))	('rad', 'Gene', (88, 91))	('mutations', 'Var', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('pVHL', 'Gene', (17, 21))
148748	32284789	Indeed, inherited mutations in the genes that play important roles in the DNA repair pathways predispose patients to cancer development or premature aging.	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('premature aging', 'CPA', (139, 154))	('patients', 'Species', '9606', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('predispose', 'Reg', (94, 104))	('DNA repair', 'biological_process', 'GO:0006281', ('74', '84'))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('genes', 'Gene', (35, 40))	('cancer', 'Disease', (117, 123))	('aging', 'biological_process', 'GO:0007568', ('149', '154'))	('mutations', 'Var', (18, 27))
148749	32284789	For example, mutations in one allele of the BRCA2 gene that promotes double strand break repair (DSB) by homologous recombination (HR), increase susceptibility to breast and ovarian cancer, and mutations in ATM that is crucial for DNA repair and cell cycle control upon DNA damage, cause Ataxia -Telangiectasia (A-T) syndrome that is characterized by the very high risk of malignancy, radiosensitivity and progressive ataxia.	('ovarian cancer', 'Phenotype', 'HP:0100615', (174, 188))	('progressive ataxia', 'Phenotype', 'HP:0002073', (406, 424))	('ataxia', 'Phenotype', 'HP:0001251', (418, 424))	('Ataxia', 'Phenotype', 'HP:0001251', (288, 294))	('DNA', 'cellular_component', 'GO:0005574', ('270', '273'))	('Telangiectasia', 'Phenotype', 'HP:0001009', (296, 310))	('BRCA2', 'Gene', '675', (44, 49))	('rad', 'Gene', '6236', (385, 388))	('rad', 'Gene', (385, 388))	('promotes', 'PosReg', (60, 68))	('ATM', 'Gene', (207, 210))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (163, 188))	('double strand break repair', 'biological_process', 'GO:0006302', ('69', '95'))	('homologous recombination', 'biological_process', 'GO:0035825', ('105', '129'))	('ataxia', 'Disease', (418, 424))	('malignancy', 'Disease', (373, 383))	('ataxia', 'Disease', 'MESH:D001259', (418, 424))	('susceptibility', 'Reg', (145, 159))	('Ataxia -Telangiectasia (A-T) syndrome', 'Disease', 'MESH:D001260', (288, 325))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('DNA', 'cellular_component', 'GO:0005574', ('231', '234'))	('cell cycle control', 'biological_process', 'GO:1901987', ('246', '264'))	('cause', 'Reg', (282, 287))	('mutations', 'Var', (13, 22))	('double strand break', 'MPA', (69, 88))	('mutations', 'Var', (194, 203))	('BRCA2', 'Gene', (44, 49))	('increase', 'PosReg', (136, 144))	('DNA repair', 'biological_process', 'GO:0006281', ('231', '241'))	('malignancy', 'Disease', 'MESH:D009369', (373, 383))
148751	32284789	The authors suggest that the VHL deficient cells activate processes that are similar to those in the cells exposed to hypoxia.	('hypoxia', 'Disease', (118, 125))	('activate', 'PosReg', (49, 57))	('VHL', 'Gene', (29, 32))	('hypoxia', 'Disease', 'MESH:D000860', (118, 125))	('deficient', 'Var', (33, 42))
148752	32284789	It was speculated that the downregulation of DNA repair genes in ccRCC cell lines is due to the activation of HIF2 rather than HIF1, since ccRCC cells expressing only HIF2 exhibit the same gene expression profile as that of the cells expressing both HIF transcription factors, i. e. downregulated DNA repair genes.	('DNA', 'cellular_component', 'GO:0005574', ('297', '300'))	('downregulation of DNA repair', 'biological_process', 'GO:0045738', ('27', '55'))	('HIF1', 'Gene', (127, 131))	('HIF2', 'Var', (167, 171))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('DNA repair', 'biological_process', 'GO:0006281', ('297', '307'))	('downregulation', 'NegReg', (27, 41))	('transcription', 'biological_process', 'GO:0006351', ('254', '267'))	('gene expression', 'biological_process', 'GO:0010467', ('189', '204'))	('DNA repair genes', 'Gene', (297, 313))	('downregulated', 'NegReg', (283, 296))	('HIF1', 'Gene', '3091', (127, 131))
148755	32284789	suggested that the defects in the DNA repair in the vhl mutant cells are similar to those in the cells exposed to hypoxia and they are likely to involve HIF2 transcription factor.	('DNA repair', 'biological_process', 'GO:0006281', ('34', '44'))	('DNA repair', 'MPA', (34, 44))	('mutant', 'Var', (56, 62))	('vhl', 'Gene', (52, 55))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('transcription', 'biological_process', 'GO:0006351', ('158', '171'))	('hypoxia', 'Disease', (114, 121))	('transcription factor', 'molecular_function', 'GO:0000981', ('158', '178'))	('hypoxia', 'Disease', 'MESH:D000860', (114, 121))
148756	32284789	This is the limitation of the studies using isolated cells: the cells accumulate mutations in the adaptation process and become different from the tumours they are originated from, although cell lines have certainly been extremely valuable in identifying cancer drugs (e. g., PARP inhibitors).	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('tumours', 'Phenotype', 'HP:0002664', (147, 154))	('PARP', 'Gene', '142', (276, 280))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumours', 'Disease', 'MESH:D009369', (147, 154))	('tumours', 'Disease', (147, 154))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('cancer', 'Disease', (255, 261))	('PARP', 'Gene', (276, 280))
148761	32284789	Similarly, HIF1alpha was shown to provide the radioresistance in hypoxic mice mesenchymal stromal cells by upregulating DNA repair proteins.	('DNA repair proteins', 'Protein', (120, 139))	('rad', 'Gene', '6236', (46, 49))	('rad', 'Gene', (46, 49))	('mice', 'Species', '10090', (73, 77))	('upregulating', 'PosReg', (107, 119))	('HIF1alpha', 'Var', (11, 20))	('DNA', 'cellular_component', 'GO:0005574', ('120', '123'))	('DNA repair', 'biological_process', 'GO:0006281', ('120', '130'))
148762	32284789	pVHL is also known to regulate p53 that is another crucial transcription factor in the adaptation of cells in response to genotoxic stress and its malfunction provides various tumours with resistance to chemo and radio therapies.	('genotoxic stress', 'Disease', 'MESH:D000079225', (122, 138))	('p53', 'Gene', (31, 34))	('tumours', 'Disease', 'MESH:D009369', (176, 183))	('tumours', 'Disease', (176, 183))	('genotoxic stress', 'Disease', (122, 138))	('response to genotoxic stress', 'biological_process', 'GO:0006974', ('110', '138'))	('transcription', 'biological_process', 'GO:0006351', ('59', '72'))	('transcription factor', 'molecular_function', 'GO:0000981', ('59', '79'))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('provides', 'Reg', (159, 167))	('rad', 'Gene', '6236', (213, 216))	('rad', 'Gene', (213, 216))	('tumours', 'Phenotype', 'HP:0002664', (176, 183))	('malfunction', 'Var', (147, 158))
148768	32284789	Previously we reported the role of vhl in the HIF regulation and the null zebrafish vhl mutant mimics Chuvash polycythemia in human.	('human', 'Species', '9606', (126, 131))	('Chuvash polycythemia', 'Disease', (102, 122))	('regulation', 'biological_process', 'GO:0065007', ('50', '60'))	('mutant', 'Var', (88, 94))	('zebrafish', 'Species', '7955', (74, 83))	('vhl', 'Gene', (84, 87))	('polycythemia', 'Phenotype', 'HP:0001901', (110, 122))	('Chuvash polycythemia', 'Disease', 'MESH:C563918', (102, 122))	('HIF regulation', 'MPA', (46, 60))
148771	32284789	Upregulated Hif suppresses not only the DNA repair defects in the vll mutants but also the defects in the brca2 mutants and the embryos in which ATM function is inhibited.	('brca2', 'Gene', '675', (106, 111))	('suppresses', 'NegReg', (16, 26))	('mutants', 'Var', (70, 77))	('DNA repair', 'biological_process', 'GO:0006281', ('40', '50'))	('DNA repair', 'MPA', (40, 50))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('brca2', 'Gene', (106, 111))	('mutants', 'Var', (112, 119))	('defects', 'NegReg', (51, 58))	('vll', 'Gene', (66, 69))
148775	32284789	Therefore, to fully appreciate the function of Vhl in zebrafish, we created a genetic knock-out of vll by a zinc finger nuclease.	('vll', 'Gene', (99, 102))	('knock-out', 'Var', (86, 95))	('zebrafish', 'Species', '7955', (54, 63))
148777	32284789	As we previously reported, vhl mutant embryos can survive up to 9dpf, and the mutant embryos show typical hypoxic responses such as increased blood vessel formation, upregulated erythropoiesis and hyperventilation.	('upregulated', 'PosReg', (166, 177))	('blood vessel formation', 'CPA', (142, 164))	('mutant', 'Var', (31, 37))	('erythropoiesis', 'biological_process', 'GO:0030218', ('178', '192'))	('vhl', 'Gene', (27, 30))	('hyperventilation', 'CPA', (197, 213))	('formation', 'biological_process', 'GO:0009058', ('155', '164'))	('increased', 'PosReg', (132, 141))	('erythropoiesis', 'CPA', (178, 192))	('to 9', 'Species', '1214577', (61, 65))	('hyperventilation', 'Phenotype', 'HP:0002883', (197, 213))	('mutant', 'Var', (78, 84))
148778	32284789	When we repeated qPCR with rps29 as a reference gene instead of previous beta-actin, the modest upregulation of phd3 expression was no longer observed in vll-/-; Tg (phd3:: EGFP)i144 mutant embryos (Supplementary Table 1).	('phd', 'molecular_function', 'GO:0050175', ('112', '115'))	('rps29', 'Gene', (27, 32))	('phd', 'molecular_function', 'GO:0050175', ('166', '169'))	('mutant', 'Var', (183, 189))	('phd3', 'Gene', (112, 116))	('rps29', 'Gene', '6235', (27, 32))
148781	32284789	Using Tg (phd3:: EGFP)i144 as a tool to study the genomic instability, we treated vll-/- mutant embryos with a high level of X-ray to introduce DSBs.	('DSBs', 'Chemical', 'MESH:C007563', (144, 148))	('mutant', 'Var', (89, 95))	('phd', 'molecular_function', 'GO:0050175', ('10', '13'))	('vll-/-', 'Gene', (82, 88))
148786	32284789	We injected guide RNAs targeting AR /vhl into vll-/- mutants and wild type embryos to quantify mutagenesis rates in the vll-/- mutants in comparison to wild type embryos.	('mutants', 'Var', (53, 60))	('mutagenesis', 'biological_process', 'GO:0006280', ('95', '106'))	('vll-/-', 'Gene', (120, 126))	('AR', 'Gene', '367', (33, 35))
148787	32284789	This revealed that there was no significant increase in the mutation frequencies, or in the size of indels in the vll-/- mutants in both AR and vhl targeting CRISPR injected embryos (Supplementary Figure 1).	('mutants', 'Var', (121, 128))	('AR', 'Gene', '367', (137, 139))	('vll-/-', 'Gene', (114, 120))
148789	32284789	We irradiated vhl+/- and vhl+/-; vll-/- embryos at 1dpf and fixed them immediately after the X-ray treatment.	('rad', 'Gene', '6236', (5, 8))	('rad', 'Gene', (5, 8))	('vhl+/-', 'Var', (25, 31))
148808	32284789	Since we observed reduced apoptosis in the vhl-/-; vll-/- mutants and Hif activated embryos in response to genotoxic stress, we questioned whether the reduction in apoptosis in these embryos is due to the downregulation in p53 expression.	('downregulation', 'NegReg', (205, 219))	('apoptosis', 'CPA', (26, 35))	('p53', 'Gene', (223, 226))	('vhl-/-', 'Gene', (43, 49))	('vll-/-', 'Gene', (51, 57))	('reduced', 'NegReg', (18, 25))	('apoptosis', 'biological_process', 'GO:0097194', ('26', '35'))	('apoptosis', 'biological_process', 'GO:0006915', ('26', '35'))	('genotoxic stress', 'Disease', 'MESH:D000079225', (107, 123))	('genotoxic stress', 'Disease', (107, 123))	('apoptosis', 'biological_process', 'GO:0097194', ('164', '173'))	('apoptosis', 'biological_process', 'GO:0006915', ('164', '173'))	('mutants', 'Var', (58, 65))	('response to genotoxic stress', 'biological_process', 'GO:0006974', ('95', '123'))
148813	32284789	These data are consistent with the idea that double mutants can be protected from genotoxic stress due to a low level of p53 expression.	('genotoxic stress', 'Disease', (82, 98))	('p53', 'Protein', (121, 124))	('expression', 'MPA', (125, 135))	('double mutants', 'Var', (45, 59))	('genotoxic stress', 'Disease', 'MESH:D000079225', (82, 98))
148815	32284789	Similarly, p53 knock down enhanced the Hif activation provided protection in response to CPT treatment, suggesting that Hif suppresses the p53 induction but does not fully eliminate its function (Supplementary Figure 5).	('p53', 'Gene', (11, 14))	('suppresses', 'NegReg', (124, 134))	('CPT', 'molecular_function', 'GO:0004142', ('89', '92'))	('knock down', 'Var', (15, 25))	('CPT', 'molecular_function', 'GO:0004095', ('89', '92'))	('induction', 'MPA', (143, 152))	('p53', 'Gene', (139, 142))	('CPT', 'Chemical', 'MESH:D002166', (89, 92))	('response to CPT', 'biological_process', 'GO:1901563', ('77', '92'))
148821	32284789	Firstly, we created a brca2 mutant allele using the CRISPR/Cas9 system.	('brca2', 'Gene', '675', (22, 27))	('mutant', 'Var', (28, 34))	('Cas', 'cellular_component', 'GO:0005650', ('59', '62'))	('brca2', 'Gene', (22, 27))
148822	32284789	The brca2 mutant allele for this experiment contained an 83 bp insertion at the amino acid 445 (exon 10) position introducing premature stop.	('brca2', 'Gene', (4, 9))	('brca2', 'Gene', '675', (4, 9))	('premature stop', 'MPA', (126, 140))	('mutant', 'Var', (10, 16))
148826	32284789	We then proceeded to check whether elevated Hif activation seen in the vhl-/-; vll-/- mutants can also suppress the increased sensitivity of brca2-/- embryos to genotoxic stress.	('mutants', 'Var', (86, 93))	('genotoxic stress', 'Disease', (161, 177))	('brca2', 'Gene', (141, 146))	('suppress', 'NegReg', (103, 111))	('vhl-/-', 'Gene', (71, 77))	('sensitivity', 'MPA', (126, 137))	('genotoxic stress', 'Disease', 'MESH:D000079225', (161, 177))	('vll-/-', 'Gene', (79, 85))	('Hif', 'CPA', (44, 47))	('brca2', 'Gene', '675', (141, 146))	('activation', 'PosReg', (48, 58))
148829	32284789	This revealed that the increased apoptosis in the brca2-/- mutant was suppressed by the presence of vhl-/-; vll-/- and that in this background, brca2-/- embryos were indistinguishable from their siblings, suggesting that the elevated Hif can strongly suppress the sensitivity of brca2-/- embryos to X-ray induced apoptosis (Figure 10D).	('brca2', 'Gene', '675', (50, 55))	('apoptosis', 'biological_process', 'GO:0097194', ('33', '42'))	('apoptosis', 'biological_process', 'GO:0006915', ('313', '322'))	('apoptosis', 'CPA', (33, 42))	('brca2', 'Gene', (279, 284))	('brca2', 'Gene', '675', (144, 149))	('mutant', 'Var', (59, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('33', '42'))	('brca2', 'Gene', (50, 55))	('brca2', 'Gene', '675', (279, 284))	('suppressed', 'NegReg', (70, 80))	('sensitivity', 'MPA', (264, 275))	('apoptosis', 'biological_process', 'GO:0097194', ('313', '322'))	('suppress', 'NegReg', (251, 259))	('brca2', 'Gene', (144, 149))
148836	32284789	Patients with mutations in ATM develop A-T syndrome that are characterised by progressive neurodegeneration, increased risk of cancer development, radiosensitivity and immune system impairment.	('immune system impairment', 'Phenotype', 'HP:0002721', (168, 192))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('A-T syndrome', 'Disease', (39, 51))	('A-T syndrome', 'Disease', 'MESH:D001260', (39, 51))	('neurodegeneration', 'Disease', (90, 107))	('develop', 'Reg', (31, 38))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('neurodegeneration', 'Disease', 'MESH:D019636', (90, 107))	('progressive neurodegeneration', 'Phenotype', 'HP:0002344', (78, 107))	('ATM', 'Gene', (27, 30))	('cancer', 'Disease', (127, 133))	('rad', 'Gene', '6236', (147, 150))	('rad', 'Gene', (147, 150))	('mutations', 'Var', (14, 23))	('neurodegeneration', 'Phenotype', 'HP:0002180', (90, 107))
148859	32284789	According to the mutator phenotype theory in cancer, the rate of random mutations cannot explain the frequency of mutations in cancer, and the mutations in the genes that are essential for the maintenance of genomic stability, including genes that are involved in DNA repair, have been speculated to increase the mutation rates and drive cancer development.	('cancer', 'Disease', (338, 344))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mutation rates', 'MPA', (313, 327))	('drive', 'PosReg', (332, 337))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('increase', 'PosReg', (300, 308))	('DNA repair', 'biological_process', 'GO:0006281', ('264', '274'))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('DNA', 'cellular_component', 'GO:0005574', ('264', '267'))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (338, 344))	('mutations', 'Var', (143, 152))
148863	32284789	We found that, consistent with the studies in the ccRCC cell lines, vll mutant embryos were more susceptible to genotoxic stress and induced increased LOH in our assay with Tg (phd3:: EGFP)i144 reporter line, indicating the role of VHL in DNA repair is conserved in Vll in zebrafish.	('LOH', 'MPA', (151, 154))	('DNA', 'cellular_component', 'GO:0005574', ('239', '242'))	('DNA repair', 'biological_process', 'GO:0006281', ('239', '249'))	('mutant', 'Var', (72, 78))	('increased', 'PosReg', (141, 150))	('susceptible', 'MPA', (97, 108))	('vll', 'Gene', (68, 71))	('phd', 'molecular_function', 'GO:0050175', ('177', '180'))	('zebrafish', 'Species', '7955', (273, 282))	('genotoxic stress', 'Disease', 'MESH:D000079225', (112, 128))	('genotoxic stress', 'Disease', (112, 128))
148864	32284789	However, when we performed deep sequencing around the target sites of CRISPRs against AR and Vhl, the rate of mutation frequencies generated in vll mutants was not significantly different from vll wild type embryos.	('AR', 'Gene', '367', (86, 88))	('mutants', 'Var', (148, 155))	('Vhl', 'Gene', (93, 96))
148869	32284789	Considering the prominent upregulation of Hif in the vhl-/-; vll-/- double mutants, we then tested whether the elevated Hif in double mutants is responsible for the protection of embryos from the genotoxic stress induced cell death.	('genotoxic stress', 'Disease', 'MESH:D000079225', (196, 212))	('cell death', 'biological_process', 'GO:0008219', ('221', '231'))	('genotoxic stress', 'Disease', (196, 212))	('tested', 'Reg', (92, 98))	('vhl-/-', 'Gene', (53, 59))	('mutants', 'Var', (75, 82))	('upregulation', 'PosReg', (26, 38))	('vll-/-', 'Gene', (61, 67))
148872	32284789	On the contrary, the weak upregulation of Hif in the vll single mutants was not sufficient to suppress the DNA repair defect caused by the lack of Vll function in DNA repair, manifesting the increased LOH in the vhl locus in response to ionizing irradiation.	('rad', 'Gene', '6236', (248, 251))	('rad', 'Gene', (248, 251))	('DNA repair defect', 'MPA', (107, 124))	('DNA repair', 'biological_process', 'GO:0006281', ('107', '117'))	('increased', 'PosReg', (191, 200))	('vll', 'Gene', (53, 56))	('mutants', 'Var', (64, 71))	('DNA', 'cellular_component', 'GO:0005574', ('163', '166'))	('Vll', 'Gene', (147, 150))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))	('lack', 'Var', (139, 143))	('DNA repair', 'biological_process', 'GO:0006281', ('163', '173'))
148876	32284789	We propose zebrafish vhl-/-; vll-/- mutants as an excellent platform for the screening for drugs that can interfere with the protection that is conferred by Hif, and therefore overcome resistance.	('zebrafish', 'Species', '7955', (11, 20))	('interfere', 'NegReg', (106, 115))	('resistance', 'MPA', (185, 195))	('mutants', 'Var', (36, 43))	('protection', 'MPA', (125, 135))
148878	32284789	In addition, when we injected embryos with p53 morpholino, the injected embryos were all protected from CPT induced apoptosis even in the presence of intact vhl, suggesting that the decreased level of p53 is responsible for the protection of embryos from apoptosis in the vhl mutants, at least partially.	('apoptosis', 'biological_process', 'GO:0097194', ('255', '264'))	('CPT', 'molecular_function', 'GO:0004142', ('104', '107'))	('apoptosis', 'biological_process', 'GO:0006915', ('255', '264'))	('CPT', 'Chemical', 'MESH:D002166', (104, 107))	('CPT', 'molecular_function', 'GO:0004095', ('104', '107'))	('decreased', 'NegReg', (182, 191))	('vhl', 'Gene', (272, 275))	('apoptosis', 'biological_process', 'GO:0097194', ('116', '125'))	('mutants', 'Var', (276, 283))	('apoptosis', 'biological_process', 'GO:0006915', ('116', '125'))	('morpholino', 'Chemical', 'MESH:D060172', (47, 57))
148879	32284789	However, we propose that the downregulated p53 level in the zebrafish vhl mutants is due to the elevated Hif, rather than by the Hif independent role of Vhl in regulation of p53.	('zebrafish', 'Species', '7955', (60, 69))	('regulation', 'biological_process', 'GO:0065007', ('160', '170'))	('elevated', 'PosReg', (96, 104))	('p53 level', 'MPA', (43, 52))	('vhl', 'Gene', (70, 73))	('Hif', 'MPA', (105, 108))	('mutants', 'Var', (74, 81))	('downregulated', 'NegReg', (29, 42))
148880	32284789	Most interestingly, Hif activation also suppressed the increased apoptosis and DNA damage induced by X-ray and CPT treatment in the brca2 mutant and in the embryos with deficient ATM function.	('suppressed', 'NegReg', (40, 50))	('CPT', 'Chemical', 'MESH:D002166', (111, 114))	('brca2', 'Gene', (132, 137))	('mutant', 'Var', (138, 144))	('apoptosis', 'biological_process', 'GO:0006915', ('65', '74'))	('apoptosis', 'CPA', (65, 74))	('CPT', 'molecular_function', 'GO:0004142', ('111', '114'))	('brca2', 'Gene', '675', (132, 137))	('apoptosis', 'biological_process', 'GO:0097194', ('65', '74'))	('DNA damage', 'MPA', (79, 89))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))	('CPT', 'molecular_function', 'GO:0004095', ('111', '114'))
148881	32284789	Both BRCA2 and ATM play important roles in the DNA repair pathways in human and their mutations increase the risk of cancer development.	('mutations', 'Var', (86, 95))	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('DNA repair', 'biological_process', 'GO:0006281', ('47', '57'))	('BRCA2', 'Gene', (5, 10))	('increase', 'Reg', (96, 104))	('human', 'Species', '9606', (70, 75))	('BRCA2', 'Gene', '675', (5, 10))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('DNA repair pathways', 'Pathway', (47, 66))
148882	32284789	In addition, one of the distinctive features of A-T syndrome caused by the deficient ATM function is the defective movement and coordination due to neurodegeneration in cerebellum.	('deficient', 'Var', (75, 84))	('neurodegeneration', 'Disease', (148, 165))	('defective', 'NegReg', (105, 114))	('neurodegeneration', 'Disease', 'MESH:D019636', (148, 165))	('caused', 'Reg', (61, 67))	('A-T syndrome', 'Disease', (48, 60))	('A-T syndrome', 'Disease', 'MESH:D001260', (48, 60))	('ATM function', 'Gene', (85, 97))	('neurodegeneration', 'Phenotype', 'HP:0002180', (148, 165))	('defective movement', 'Phenotype', 'HP:0100022', (105, 123))
148883	32284789	Similarly, the mutations in genes that encode proteins in the DNA repair machineries often lead to congenital neurodegenerative disorders in human, highlighting the importance of maintaining the genomic stability in the nervous system.	('lead to', 'Reg', (91, 98))	('congenital neurodegenerative disorders', 'Disease', 'MESH:D020271', (99, 137))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('mutations', 'Var', (15, 24))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (110, 137))	('human', 'Species', '9606', (141, 146))	('DNA repair', 'biological_process', 'GO:0006281', ('62', '72'))	('congenital neurodegenerative disorders', 'Disease', (99, 137))
148884	32284789	For example, mutations in MRE11, TDP1 and aprataxin (APTX) result in neurodegenerative disorders such as A-T like disease (ATLD), spinocerebellar ataxia with axonal neuropathy (SCAN1), and ataxia-oculomotor apraxia-1 respectively.	('ATLD', 'Gene', (123, 127))	('spinocerebellar ataxia with axonal neuropathy', 'Disease', 'MESH:C537308', (130, 175))	('ataxia-oculomotor apraxia-1', 'Disease', 'MESH:C538013', (189, 216))	('ataxia', 'Phenotype', 'HP:0001251', (189, 195))	('A-T like disease', 'Disease', 'MESH:C565779', (105, 121))	('result in', 'Reg', (59, 68))	('apraxia', 'Phenotype', 'HP:0002186', (207, 214))	('aprataxin', 'Gene', '54840', (42, 51))	('APTX', 'Gene', (53, 57))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (69, 96))	('ataxia-oculomotor apraxia-1', 'Disease', (189, 216))	('TDP1', 'Gene', '55775', (33, 37))	('TDP1', 'Gene', (33, 37))	('ataxia', 'Phenotype', 'HP:0001251', (146, 152))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (69, 96))	('ATLD', 'Gene', '4361', (123, 127))	('neuropathy', 'Phenotype', 'HP:0009830', (165, 175))	('axonal neuropathy', 'Phenotype', 'HP:0003477', (158, 175))	('SCAN1', 'Gene', (177, 182))	('mutations', 'Var', (13, 22))	('MRE11', 'Gene', (26, 31))	('oculomotor apraxia', 'Phenotype', 'HP:0000657', (196, 214))	('APTX', 'Gene', '54840', (53, 57))	('aprataxin', 'Gene', (42, 51))	('A-T like disease', 'Disease', (105, 121))	('neurodegenerative disorders', 'Disease', (69, 96))	('spinocerebellar ataxia with axonal neuropathy', 'Disease', (130, 175))	('MRE11', 'Gene', '4361', (26, 31))	('SCAN1', 'Gene', '124583', (177, 182))
148885	32284789	The efficacy of Hif activators for the suppression of DNA damage and apoptosis in brca2 mutants and ATM inhibitor treated embryos in our study suggests that HIF activators might provide a possible intervention to slow the progression of such congenital neurodegenerative disorders.	('congenital neurodegenerative disorders', 'Disease', 'MESH:D020271', (242, 280))	('apoptosis', 'biological_process', 'GO:0006915', ('69', '78'))	('DNA damage', 'MPA', (54, 64))	('brca2', 'Gene', (82, 87))	('congenital neurodegenerative disorders', 'Disease', (242, 280))	('apoptosis', 'CPA', (69, 78))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (253, 280))	('mutants', 'Var', (88, 95))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('brca2', 'Gene', '675', (82, 87))	('apoptosis', 'biological_process', 'GO:0097194', ('69', '78'))
148888	32284789	Given time, we could use mutants and treatments that lead to defects in various DNA repair pathways, and study how Hif activation can modulate the response such genotoxic stressors.	('genotoxic stress', 'Disease', (161, 177))	('mutants', 'Var', (25, 32))	('genotoxic stress', 'Disease', 'MESH:D000079225', (161, 177))	('DNA repair', 'biological_process', 'GO:0006281', ('80', '90'))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('DNA repair pathways', 'Pathway', (80, 99))	('defects', 'NegReg', (61, 68))	('modulate', 'Reg', (134, 142))
148890	32284789	The activated Hif in the vhl; vll mutants strongly suppresses DNA damage and apoptosis induced by genotoxic stress.	('DNA damage', 'MPA', (62, 72))	('genotoxic stress', 'Disease', 'MESH:D000079225', (98, 114))	('mutants', 'Var', (34, 41))	('apoptosis', 'CPA', (77, 86))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('vhl; vll', 'Gene', (25, 33))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('suppresses', 'NegReg', (51, 61))	('genotoxic stress', 'Disease', (98, 114))
148892	32284789	We found Hif activation suppresses the DNA damage in the brca2 and vll mutants and ATM deficient embryos and also prevents apoptosis.	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('apoptosis', 'biological_process', 'GO:0006915', ('123', '132'))	('DNA damage', 'MPA', (39, 49))	('vll', 'Gene', (67, 70))	('brca2', 'Gene', (57, 62))	('mutants', 'Var', (71, 78))	('apoptosis', 'CPA', (123, 132))	('suppresses', 'NegReg', (24, 34))	('apoptosis', 'biological_process', 'GO:0097194', ('123', '132'))	('prevents', 'NegReg', (114, 122))	('brca2', 'Gene', '675', (57, 62))
148896	32284789	caCAGCTCATCCATGGtgcaGAGCATCTGATGGAGct brca2 mutants were induced by CRISPR/Cas9 system.	('brca2', 'Gene', (38, 43))	('Cas', 'cellular_component', 'GO:0005650', ('75', '78'))	('brca2', 'Gene', '675', (38, 43))	('mutants', 'Var', (44, 51))
148932	33026261	Herein, we report an adult case of Xp11.2 translocation RCC, and review the relevant literature to improve our understanding of the pathogenesis, epidemiology, clinical manifestations, diagnosis, differential diagnosis, treatment, and other aspects of the disease.	('RCC', 'Disease', (56, 59))	('p11', 'Gene', '6281', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('translocation', 'Var', (42, 55))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('pathogenesis', 'biological_process', 'GO:0009405', ('132', '144'))	('p11', 'Gene', (36, 39))
148935	33026261	The origin of the name of this disease reflects the fact that it is characterized by fusions involving the TFE3 gene, located on chromosome Xp11.2, which leads to overexpression of the TFE3 protein in the nucleus of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('TFE3', 'Gene', '7030', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('TFE3', 'Gene', '7030', (107, 111))	('nucleus', 'cellular_component', 'GO:0005634', ('205', '212'))	('protein', 'cellular_component', 'GO:0003675', ('190', '197'))	('p11', 'Gene', (141, 144))	('fusions', 'Var', (85, 92))	('cancer', 'Disease', (216, 222))	('TFE3', 'Gene', (185, 189))	('protein', 'Protein', (190, 197))	('p11', 'Gene', '6281', (141, 144))	('TFE3', 'Gene', (107, 111))	('overexpression', 'PosReg', (163, 177))	('chromosome', 'cellular_component', 'GO:0005694', ('129', '139'))
148956	33026261	Immunohistochemical features are shown in Figure 3, with positive staining for TFE3, vimentin, CD10, P504S, PAX8, CK-pan (scattered) and negative staining for CK7 and carbonic anhydrase IX.	('CK-pan', 'Chemical', '-', (114, 120))	('PAX8', 'Gene', '7849', (108, 112))	('carbonic anhydrase IX', 'Gene', (167, 188))	('P504S', 'Mutation', 'p.P504S', (101, 106))	('CK7', 'Gene', (159, 162))	('P504S', 'Var', (101, 106))	('vimentin', 'cellular_component', 'GO:0045098', ('85', '93'))	('TFE3', 'Gene', (79, 83))	('CK7', 'Gene', '3855', (159, 162))	('TFE3', 'Gene', '7030', (79, 83))	('CD10', 'Gene', '4311', (95, 99))	('CD10', 'molecular_function', 'GO:0004245', ('95', '99'))	('vimentin', 'cellular_component', 'GO:0045099', ('85', '93'))	('PAX8', 'Gene', (108, 112))	('carbonic anhydrase IX', 'Gene', '768', (167, 188))	('CD10', 'Gene', (95, 99))	('vimentin', 'Gene', '7431', (85, 93))	('vimentin', 'Gene', (85, 93))	('CK-pan', 'Gene', (114, 120))
148960	33026261	This genetic disease is caused by increased TFE3 expression as a result of translocation of the TFE3 gene on chromosome Xp11.2, and it is associated with cytotoxic chemotherapy in pediatric patients.	('translocation', 'Var', (75, 88))	('genetic disease', 'Disease', (5, 20))	('p11', 'Gene', '6281', (121, 124))	('TFE3', 'Gene', (44, 48))	('TFE3', 'Gene', '7030', (96, 100))	('patients', 'Species', '9606', (190, 198))	('expression', 'MPA', (49, 59))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))	('p11', 'Gene', (121, 124))	('TFE3', 'Gene', '7030', (44, 48))	('TFE3', 'Gene', (96, 100))	('increased', 'PosReg', (34, 43))	('genetic disease', 'Disease', 'MESH:D030342', (5, 20))
148962	33026261	Clinically, the most common types of gene fusions are the first three: t(X;1)(p11.2;q21.2), with the PRCC gene; t(X;17)(p11.2;q25) with the ASPL gene (also called ASPSCR1); and t(X;1)(p11.2;p34) with the SFPQ gene (also called PSF).	('PSF', 'Gene', '6421', (227, 230))	('t(X;17)(p11.2;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (112, 130))	('t(X;17)(p11.2;q25', 'Var', (112, 129))	('t(X;1)(p11.2;p34)', 'STRUCTURAL_ABNORMALITY', 'None', (177, 194))	('ASPSCR1', 'Gene', '79058', (163, 170))	('PSF', 'Gene', (227, 230))	('SFPQ', 'Gene', '6421', (204, 208))	('SFPQ', 'Gene', (204, 208))	('ASPL', 'Gene', '79058', (140, 144))	('PRCC', 'Gene', '5546', (101, 105))	('ASPSCR1', 'Gene', (163, 170))	('ASPL', 'Gene', (140, 144))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('t(X;1)(p11.2;q21.2', 'Var', (71, 89))	('PRCC', 'Gene', (101, 105))	('t(X;1)(p11.2;q21.2)', 'STRUCTURAL_ABNORMALITY', 'None', (71, 90))
148978	33026261	Xp11.2/TFE3-related RCC usually has the following immunohistochemical characteristics: PAX8+, vimentin+, P504S+, CK7-, carbonic anhydrase IX-, and CD10+.	('CD10', 'molecular_function', 'GO:0004245', ('147', '151'))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('CD10', 'Gene', (147, 151))	('P504S+', 'Var', (105, 111))	('RCC', 'Disease', (20, 23))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('vimentin', 'cellular_component', 'GO:0045098', ('94', '102'))	('p11', 'Gene', '6281', (1, 4))	('PAX8', 'Gene', (87, 91))	('TFE3', 'Gene', (7, 11))	('p11', 'Gene', (1, 4))	('CK7-, carbonic anhydrase IX', 'Gene', '3855;768', (113, 140))	('P504S', 'Mutation', 'p.P504S', (105, 110))	('vimentin', 'Gene', '7431', (94, 102))	('TFE3', 'Gene', '7030', (7, 11))	('PAX8', 'Gene', '7849', (87, 91))	('vimentin', 'Gene', (94, 102))	('vimentin', 'cellular_component', 'GO:0045099', ('94', '102'))	('CD10', 'Gene', '4311', (147, 151))
148981	33026261	Because of common false-positive or false-negative results in TFE3 immunostaining, the diagnosis of the TFE3 gene rearrangement by FISH is now the gold standard for Xp11 translocation RCC.	('p11', 'Gene', '6281', (166, 169))	('TFE3', 'Gene', '7030', (62, 66))	('TFE3', 'Gene', '7030', (104, 108))	('false', 'biological_process', 'GO:0071877', ('36', '41'))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('false', 'biological_process', 'GO:0071877', ('18', '23'))	('RCC', 'Disease', (184, 187))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('rearrangement', 'Var', (114, 127))	('TFE3', 'Gene', (104, 108))	('p11', 'Gene', (166, 169))	('false', 'biological_process', 'GO:0071878', ('36', '41'))	('false', 'biological_process', 'GO:0071878', ('18', '23'))	('TFE3', 'Gene', (62, 66))
148992	33026261	In addition, RCC associated with Xp11.2 translocation/TFE3 gene fusions can be differentiated from PRCC by alpha-methylacyl COA racemase (AMACR) and CK7.	('alpha-methylacyl COA racemase', 'Gene', '23600', (107, 136))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('AMACR', 'Gene', '23600', (138, 143))	('PRCC', 'Gene', '5546', (99, 103))	('p11', 'Gene', '6281', (34, 37))	('CK7', 'Gene', (149, 152))	('PRCC', 'Gene', (99, 103))	('TFE3', 'Gene', (54, 58))	('p11', 'Gene', (34, 37))	('TFE3', 'Gene', '7030', (54, 58))	('CK7', 'Gene', '3855', (149, 152))	('alpha-methylacyl COA racemase', 'Gene', (107, 136))	('fusions', 'Var', (64, 71))	('RCC', 'Disease', (13, 16))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('AMACR', 'Gene', (138, 143))
148995	33026261	All of these characteristics help differentiate RCC with TFE3 gene fusions from common types of RCC.	('RCC', 'Disease', (96, 99))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('gene fusions', 'Var', (62, 74))	('TFE3', 'Gene', (57, 61))	('TFE3', 'Gene', '7030', (57, 61))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
149007	33026261	For patients with metastatic Xp11.2 translocation RCC, adjuvant therapies such as targeted therapy and immunotherapy are being tested.	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('p11', 'Gene', '6281', (30, 33))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('patients', 'Species', '9606', (4, 12))	('translocation', 'Var', (36, 49))	('p11', 'Gene', (30, 33))
149009	33026261	Overall, the incidence of Xp11.2 translocation RCC is relatively low, especially in adults, and the clinical features and underlying mechanisms of the disease have not been fully clarified.	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('p11', 'Gene', (27, 30))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('p11', 'Gene', '6281', (27, 30))	('translocation', 'Var', (33, 46))
149021	28565840	Inhibition of miR-155 significantly suppressed the proliferation, colony formation, migration and invasion, and induced G1 arrest and apoptosis of ccRCC cells in vitro.	('apoptosis', 'CPA', (134, 143))	('ccRCC', 'Phenotype', 'HP:0006770', (147, 152))	('invasion', 'CPA', (98, 106))	('induced', 'Reg', (112, 119))	('formation', 'biological_process', 'GO:0009058', ('73', '82'))	('migration', 'CPA', (84, 93))	('miR-155', 'Gene', (14, 21))	('arrest', 'Disease', (123, 129))	('miR-155', 'Gene', '406947', (14, 21))	('Inhibition', 'Var', (0, 10))	('colony formation', 'CPA', (66, 82))	('apoptosis', 'biological_process', 'GO:0097194', ('134', '143'))	('RCC', 'Disease', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('suppressed', 'NegReg', (36, 46))	('apoptosis', 'biological_process', 'GO:0006915', ('134', '143'))	('proliferation', 'CPA', (51, 64))	('arrest', 'Disease', 'MESH:D006323', (123, 129))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
149022	28565840	Moreover, inhibition of miR-155 significantly upregulated FOXO3a expression, and miR-155 expression was inversely correlated with FOXO3a expression in ccRCC tissues.	('FOXO3a', 'Gene', (130, 136))	('expression', 'MPA', (89, 99))	('miR-155', 'Gene', '406947', (24, 31))	('miR-155', 'Gene', (81, 88))	('FOXO3a', 'Gene', '2309', (58, 64))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('RCC', 'Disease', (153, 156))	('miR-155', 'Gene', (24, 31))	('FOXO3a', 'Gene', (58, 64))	('expression', 'MPA', (65, 75))	('miR-155', 'Gene', '406947', (81, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (151, 156))	('inhibition', 'Var', (10, 20))	('FOXO3a', 'Gene', '2309', (130, 136))	('upregulated', 'PosReg', (46, 57))
149028	28565840	However, increasing evidence has indicated that dysregulation of certain microRNAs (miRNAs) is also closely associated with the pathogenesis of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('miR', 'Gene', (84, 87))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('miR', 'Gene', '22877', (84, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('dysregulation', 'Var', (48, 61))	('pathogenesis', 'biological_process', 'GO:0009405', ('128', '140'))	('associated', 'Reg', (108, 118))
149034	28565840	In addition, apoptosis was induced in cancer cells subjected to overexpression of tumor suppressor miRNAs or silencing of oncogenic miRNAs.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('13', '22'))	('apoptosis', 'biological_process', 'GO:0006915', ('13', '22'))	('miR', 'Gene', (99, 102))	('miR', 'Gene', '22877', (132, 135))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('overexpression', 'PosReg', (64, 78))	('apoptosis', 'CPA', (13, 22))	('miR', 'Gene', '22877', (99, 102))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor suppressor', 'biological_process', 'GO:0051726', ('82', '98'))	('induced', 'Reg', (27, 34))	('silencing', 'Var', (109, 118))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('82', '98'))	('cancer', 'Disease', (38, 44))	('miR', 'Gene', (132, 135))	('tumor', 'Disease', (82, 87))
149096	28565840	Taken together, inhibition of miR-155 caused apoptosis in ccRCC cells.	('miR-155', 'Gene', (30, 37))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('miR-155', 'Gene', '406947', (30, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('inhibition', 'Var', (16, 26))
149099	28565840	Collectively, these results indicated that inhibition of miR-155 resulted in G1/G0 arrest and suppressed ccRCC cell proliferation in vitro.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('arrest', 'Disease', 'MESH:D006323', (83, 89))	('inhibition', 'Var', (43, 53))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('RCC', 'Disease', (107, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (105, 110))	('cell proliferation', 'biological_process', 'GO:0008283', ('111', '129'))	('miR-155', 'Gene', (57, 64))	('arrest', 'Disease', (83, 89))	('suppressed', 'NegReg', (94, 104))	('miR-155', 'Gene', '406947', (57, 64))
149100	28565840	Inhibition of miR-155 reduces migration and invasion of ccRCC cells.	('miR-155', 'Gene', '406947', (14, 21))	('miR-155', 'Gene', (14, 21))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('reduces', 'NegReg', (22, 29))	('Inhibition', 'Var', (0, 10))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
149102	28565840	The wound healing assay demonstrated that inhibition of miR-155 reduced the migratory capacity of the ANCH cells (Fig.	('miR-155', 'Gene', '406947', (56, 63))	('inhibition', 'Var', (42, 52))	('reduced', 'NegReg', (64, 71))	('miR-155', 'Gene', (56, 63))	('wound healing', 'biological_process', 'GO:0042060', ('4', '17'))	('migratory capacity of the ANCH cells', 'CPA', (76, 112))
149120	28565840	The results demonstrated that inhibition of miR-155 significantly decreased ccRCC cell proliferation, colony formation, and induced G1 arrest and apoptosis in vitro.	('formation', 'biological_process', 'GO:0009058', ('109', '118'))	('inhibition', 'Var', (30, 40))	('cell proliferation', 'biological_process', 'GO:0008283', ('82', '100'))	('arrest', 'Disease', 'MESH:D006323', (135, 141))	('decreased', 'NegReg', (66, 75))	('colony formation', 'CPA', (102, 118))	('RCC', 'Disease', (78, 81))	('arrest', 'Disease', (135, 141))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('miR-155', 'Gene', '406947', (44, 51))	('apoptosis', 'biological_process', 'GO:0097194', ('146', '155'))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('apoptosis', 'biological_process', 'GO:0006915', ('146', '155'))	('induced', 'Reg', (124, 131))	('apoptosis', 'CPA', (146, 155))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('miR-155', 'Gene', (44, 51))
149123	28565840	Lao et al demonstrated that inhibition of miR-155 promoted apoptosis of the cervical cancer cell lines Hela and SiHa and increased the percentage of cells in G1 phase.	('apoptosis', 'biological_process', 'GO:0097194', ('59', '68'))	('miR-155', 'Gene', '406947', (42, 49))	('SiHa', 'CellLine', 'CVCL:0032', (112, 116))	('Hela', 'CellLine', 'CVCL:0030', (103, 107))	('promoted', 'PosReg', (50, 58))	('apoptosis', 'biological_process', 'GO:0006915', ('59', '68'))	('G1 phase', 'biological_process', 'GO:0051318', ('158', '166'))	('Lao', 'Gene', '259307', (0, 3))	('increased', 'PosReg', (121, 130))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('inhibition', 'Var', (28, 38))	('cancer', 'Disease', (85, 91))	('apoptosis', 'CPA', (59, 68))	('miR-155', 'Gene', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Lao', 'Gene', (0, 3))
149139	28565840	Activation of FOXO3a has a tumor suppressor effect, promoting cell-cycle arrest and apoptosis in RCC cell lines.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('RCC', 'Disease', (97, 100))	('promoting', 'PosReg', (52, 61))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('apoptosis', 'CPA', (84, 93))	('arrest', 'Disease', 'MESH:D006323', (73, 79))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('tumor', 'Disease', (27, 32))	('FOXO3a', 'Gene', '2309', (14, 20))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('62', '79'))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('Activation', 'Var', (0, 10))	('arrest', 'Disease', (73, 79))	('tumor suppressor', 'biological_process', 'GO:0051726', ('27', '43'))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('FOXO3a', 'Gene', (14, 20))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('27', '43'))
149244	33392088	It has a strong expression in CCRCC, papillary RCC, and Xp11 translocation RCC.	('papillary RCC', 'Disease', (37, 50))	('CCRCC', 'Phenotype', 'HP:0006770', (30, 35))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('Xp11 translocation', 'Var', (56, 74))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('papillary RCC', 'Disease', 'MESH:C538614', (37, 50))
149388	31322247	Notably, the bevacizumab-induced decrease in MVD was significantly enhanced by PEGylated liposomal doxorubicin (Fig.	('MVD', 'MPA', (45, 48))	('decrease', 'NegReg', (33, 41))	('doxorubicin', 'Chemical', 'MESH:D004317', (99, 110))	('bevacizumab', 'Chemical', 'MESH:D000068258', (13, 24))	('PEGylated liposomal', 'Var', (79, 98))	('enhanced', 'PosReg', (67, 75))
149393	31322247	Although PEGylated liposomal doxorubicin alone and bevacizumab alone did not affect human IGFBP-3 expression, PEGylated liposomal doxorubicin plus bevacizumab treatment resulted in levels of human IGFBP-3 being significantly lower, compared with levels following PEGylated liposomal doxorubicin alone or bevacizumab alone treatment (Fig.	('doxorubicin', 'Chemical', 'MESH:D004317', (283, 294))	('bevacizumab', 'Chemical', 'MESH:D000068258', (51, 62))	('doxorubicin', 'Chemical', 'MESH:D004317', (29, 40))	('doxorubicin', 'Chemical', 'MESH:D004317', (130, 141))	('IGFBP-3', 'Gene', (90, 97))	('bevacizumab', 'Chemical', 'MESH:D000068258', (304, 315))	('IGFBP-3', 'Gene', '3486', (197, 204))	('IGFBP-3', 'Gene', (197, 204))	('lower', 'NegReg', (225, 230))	('human', 'Species', '9606', (84, 89))	('bevacizumab', 'Chemical', 'MESH:D000068258', (147, 158))	('human', 'Species', '9606', (191, 196))	('PEGylated liposomal doxorubicin', 'Var', (110, 141))	('IGFBP-3', 'Gene', '3486', (90, 97))
149399	31322247	The precise mechanism by which the PEGylated liposomal doxorubicin plus bevacizumab combination reduces the IGFBP-3 level and its general contribution to tumor angiogenesis remains to be elucidated.	('tumor', 'Disease', (154, 159))	('reduces', 'NegReg', (96, 103))	('IGFBP-3', 'Gene', (108, 115))	('PEGylated', 'Var', (35, 44))	('angiogenesis', 'biological_process', 'GO:0001525', ('160', '172'))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('doxorubicin', 'Chemical', 'MESH:D004317', (55, 66))	('bevacizumab', 'Chemical', 'MESH:D000068258', (72, 83))	('IGFBP-3', 'Gene', '3486', (108, 115))
149406	27491826	ccRCC is known to be strongly associated with silencing of the von Hippel Lindau (VHL) tumor suppressor gene, yet VHL deficiency alone does not seem to be sufficient to drive the oncogenic transformation of normal renal epithelium and induce renal tumorigenesis.	('associated', 'Reg', (30, 40))	('tumor', 'Disease', (248, 253))	('induce', 'Reg', (235, 241))	('von Hippel Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (63, 92))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('oncogenic transformation', 'CPA', (179, 203))	('silencing', 'Var', (46, 55))	('VHL deficiency', 'Disease', 'MESH:D006623', (114, 128))	('tumor', 'Disease', (87, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('ccRCC', 'Disease', (0, 5))	('tumor suppressor', 'biological_process', 'GO:0051726', ('87', '103'))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('87', '103'))	('VHL deficiency', 'Disease', (114, 128))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('drive', 'PosReg', (169, 174))
149409	27491826	To explore the consequences of the elevated Notch1 signaling observed in ccRCC patient material, we made use of a conditional mouse model based on concurrent ectopic expression of constitutively active Notch1 (NICD1) and deletion of the Vhl gene.	('mouse', 'Species', '10090', (126, 131))	('deletion', 'Var', (221, 229))	('Vhl', 'Gene', '22346', (237, 240))	('patient', 'Species', '9606', (79, 86))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('Vhl', 'Gene', (237, 240))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))
149415	27491826	The vast majority of sporadic ccRCCs are associated with somatic biallelic inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) and the consequent stabilization of hypoxia-inducible factor (HIF) alpha subunits, and hence a constitutively activated hypoxic response.	('stabilization', 'MPA', (160, 173))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('95', '111'))	('VHL', 'Disease', 'MESH:D006623', (136, 139))	('tumor', 'Disease', (95, 100))	('von Hippel-Lindau', 'Gene', (117, 134))	('VHL', 'Disease', (136, 139))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('von Hippel-Lindau', 'Gene', '22346', (117, 134))	('biallelic', 'Var', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('hypoxia', 'Disease', 'MESH:D000860', (177, 184))	('ccRCCs', 'Disease', (30, 36))	('hypoxia', 'Disease', (177, 184))	('tumor suppressor', 'biological_process', 'GO:0051726', ('95', '111'))
149416	27491826	Although the absence of functional VHL protein (pVHL) and the resulting accumulation of HIF-alpha is crucial to ccRCC pathogenesis, kidney-restricted ablation of Vhl in transgenic mice has repeatedly been shown to be insufficient to induce renal tumorigenesis.	('induce', 'Reg', (233, 239))	('ccRCC', 'Disease', (112, 117))	('insufficient', 'Disease', 'MESH:D000309', (217, 229))	('pVHL', 'Gene', (48, 52))	('VHL', 'Disease', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('pVHL', 'Gene', '22346', (48, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('absence', 'NegReg', (13, 20))	('VHL', 'Disease', (49, 52))	('pathogenesis', 'biological_process', 'GO:0009405', ('118', '130'))	('Vhl', 'Gene', (162, 165))	('VHL', 'Disease', 'MESH:D006623', (35, 38))	('accumulation', 'PosReg', (72, 84))	('insufficient', 'Disease', (217, 229))	('tumor', 'Disease', (246, 251))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('transgenic mice', 'Species', '10090', (169, 184))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('VHL', 'Disease', 'MESH:D006623', (49, 52))	('ablation', 'Var', (150, 158))	('Vhl', 'Gene', '22346', (162, 165))
149417	27491826	Moreover, germline inactivation of the VHL gene, associated with the von Hippel-Lindau syndrome, is accompanied by a high frequency of renal cysts, which only occasionally develop into ccRCC.	('VHL', 'Disease', (39, 42))	('VHL', 'Disease', 'MESH:D006623', (39, 42))	('renal cysts', 'Phenotype', 'HP:0000107', (135, 146))	('von Hippel-Lindau syndrome', 'Disease', (69, 95))	('associated', 'Reg', (49, 59))	('von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (69, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (185, 190))	('ccRCC', 'Disease', (185, 190))	('renal cysts', 'Disease', 'MESH:D007674', (135, 146))	('renal cysts', 'Disease', (135, 146))	('accompanied by', 'Reg', (100, 114))	('germline inactivation', 'Var', (10, 31))
149419	27491826	This statement was further supported by recent major sequencing efforts that indicate that chromatin modifying genes often are mutated in ccRCC in conjunction with loss of pVHL, thus representing a major cooperating pathway.	('chromatin', 'cellular_component', 'GO:0000785', ('91', '100'))	('pVHL', 'Gene', (172, 176))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('chromatin modifying genes', 'Gene', (91, 116))	('pVHL', 'Gene', '22346', (172, 176))	('ccRCC', 'Disease', (138, 143))	('mutated', 'Var', (127, 134))
149421	27491826	Aberrant Notch signaling has been associated with multiple human disorders, particularly a wide range of cancers in which Notch, depending on the affected tissue and cell type, act as a tumor suppressor or, when overactive, a potent oncogene.	('overactive', 'PosReg', (212, 222))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('associated', 'Reg', (34, 44))	('Notch', 'Gene', (122, 127))	('human', 'Species', '9606', (59, 64))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('186', '202'))	('signaling', 'biological_process', 'GO:0023052', ('15', '24'))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('tumor', 'Disease', (186, 191))	('Notch', 'Gene', '31293', (122, 127))	('Notch', 'Gene', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumor suppressor', 'biological_process', 'GO:0051726', ('186', '202'))	('Notch', 'Gene', '31293', (9, 14))
149427	27491826	To determine whether Notch signaling could induce an oncogenic switch in renal proximal tubular epithelial cells (PTECs) in vivo, we used a conditional mouse model based on the ectopic expression of constitutively active intracellular domain of Notch1 (NICD1) and the disruption of the Vhl-gene.	('Vhl', 'Gene', (286, 289))	('signaling', 'biological_process', 'GO:0023052', ('27', '36'))	('Notch', 'Gene', '31293', (245, 250))	('intracellular', 'cellular_component', 'GO:0005622', ('221', '234'))	('Notch', 'Gene', (21, 26))	('mouse', 'Species', '10090', (152, 157))	('Notch', 'Gene', (245, 250))	('Notch', 'Gene', '31293', (21, 26))	('induce', 'Reg', (43, 49))	('disruption', 'Var', (268, 278))	('Vhl', 'Gene', '22346', (286, 289))
149444	27491826	Carbonic anhydrase IX (CAIX) is a well-accepted surrogate marker of hypoxia that is known to be up-regulated upon loss of Vhl.	('hypoxia', 'Disease', (68, 75))	('CAIX', 'Gene', (23, 27))	('hypoxia', 'Disease', 'MESH:D000860', (68, 75))	('Vhl', 'Gene', '22346', (122, 125))	('Carbonic anhydrase IX', 'Gene', '230099', (0, 21))	('loss', 'Var', (114, 118))	('Carbonic anhydrase IX', 'Gene', (0, 21))	('Vhl', 'Gene', (122, 125))	('CAIX', 'Gene', '230099', (23, 27))	('up-regulated', 'PosReg', (96, 108))
149446	27491826	Immunofluorescent co-staining of CAIX and the PTEC marker Lotus tetragonolobus agglutinin (LTA) confirmed that the Vhl was deleted specifically in the proximal tubules (Fig.	('Vhl', 'Gene', (115, 118))	('CAIX', 'Gene', (33, 37))	('Lotus tetragonolobus', 'Species', '3868', (58, 78))	('CAIX', 'Gene', '230099', (33, 37))	('Vhl', 'Gene', '22346', (115, 118))	('deleted', 'Var', (123, 130))
149452	27491826	It has been reported that Vhl deletion might lead to increased renal fibrosis.	('Vhl', 'Gene', '22346', (26, 29))	('Vhl', 'Gene', (26, 29))	('fibrosis', 'Disease', 'MESH:D005355', (69, 77))	('fibrosis', 'Disease', (69, 77))	('deletion', 'Var', (30, 38))	('renal fibrosis', 'Phenotype', 'HP:0030760', (63, 77))	('increased', 'PosReg', (53, 62))
149455	27491826	Further, podocalyxin staining showed that silencing of Vhl and ectopic expression of NICD1 did not confer any changes in the renal vascular structure (Figure S1C).	('silencing', 'Var', (42, 51))	('NICD1', 'Gene', (85, 90))	('renal vascular structure', 'CPA', (125, 149))	('podocalyxin', 'Gene', (9, 20))	('Vhl', 'Gene', '22346', (55, 58))	('podocalyxin', 'Gene', '27205', (9, 20))	('Vhl', 'Gene', (55, 58))
149465	27491826	Together, this data suggest that the clear cell phenotype is induced by the activation of NICD1 in the context of Vhl deletion.	('induced', 'Reg', (61, 68))	('Vhl', 'Gene', '22346', (114, 117))	('activation', 'PosReg', (76, 86))	('NICD1', 'Gene', (90, 95))	('clear', 'Disease', (37, 42))	('deletion', 'Var', (118, 126))	('Vhl', 'Gene', (114, 117))
149480	27491826	As loss of VHL is so strongly associated with initiation of ccRCC, several efforts have been made to target this tumor suppressor gene in mice.	('associated', 'Reg', (30, 40))	('tumor', 'Disease', (113, 118))	('loss', 'Var', (3, 7))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('113', '129'))	('VHL', 'Disease', 'MESH:D006623', (11, 14))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('ccRCC', 'Disease', (60, 65))	('VHL', 'Disease', (11, 14))	('mice', 'Species', '10090', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor suppressor', 'biological_process', 'GO:0051726', ('113', '129'))
149483	27491826	Similarly, conditional inactivation of Vhl in the distal tubule and ascending loop of Henle failed to give rise to any renal structural abnormalities.	('renal structural abnormalities', 'Disease', 'MESH:D007674', (119, 149))	('Vhl', 'Gene', (39, 42))	('renal structural abnormalities', 'Phenotype', 'HP:0012210', (119, 149))	('inactivation', 'Var', (23, 35))	('Vhl', 'Gene', '22346', (39, 42))	('renal structural abnormalities', 'Disease', (119, 149))
149484	27491826	Elimination of functional pVHL in the kidney proximal tubule epithelial cells increased the number of renal cysts, but only after long latency and with a low penetrance.	('renal cysts', 'Disease', 'MESH:D007674', (102, 113))	('renal cysts', 'Disease', (102, 113))	('pVHL', 'Gene', '22346', (26, 30))	('Elimination', 'Var', (0, 11))	('renal cysts', 'Phenotype', 'HP:0000107', (102, 113))	('increased', 'PosReg', (78, 87))	('pVHL', 'Gene', (26, 30))
149486	27491826	In accordance with this theory, researchers have combined kidney specific deletion of Vhl with the deletion of other tumor suppressor genes such as PTEN p53 or Bap1 The two latter, but not the first, do show signs of renal neoplasms.	('PTEN', 'Gene', (148, 152))	('Bap1', 'Gene', '104416', (160, 164))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('117', '133'))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('Vhl', 'Gene', '22346', (86, 89))	('tumor suppressor', 'biological_process', 'GO:0051726', ('117', '133'))	('combined kidney', 'Phenotype', 'HP:0000085', (49, 64))	('p53', 'Gene', (153, 156))	('Bap1', 'Gene', (160, 164))	('renal neoplasm', 'Phenotype', 'HP:0009726', (217, 231))	('PTEN', 'Gene', '19211', (148, 152))	('renal neoplasms', 'Disease', 'MESH:D007680', (217, 232))	('neoplasms', 'Phenotype', 'HP:0002664', (223, 232))	('deletion', 'Var', (74, 82))	('tumor', 'Disease', (117, 122))	('neoplasm', 'Phenotype', 'HP:0002664', (223, 231))	('renal neoplasms', 'Disease', (217, 232))	('renal neoplasms', 'Phenotype', 'HP:0009726', (217, 232))	('p53', 'Gene', '22059', (153, 156))	('Vhl', 'Gene', (86, 89))	('deletion', 'Var', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
149493	27491826	The oncogenic role of aberrant Notch signaling has been established in several tumors including T-cell Acute Lymphoid Leukemia (T-ALL), brain tumors, melanoma, lung carcinoma, pancreatic cancer, and epithelial tumors such as breast cancer.	('Acute Lymphoid Leukemia', 'Phenotype', 'HP:0006721', (103, 126))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (176, 193))	('T-ALL', 'Phenotype', 'HP:0006727', (128, 133))	('lung carcinoma', 'Disease', 'MESH:D008175', (160, 174))	('Lymphoid Leukemia', 'Phenotype', 'HP:0005526', (109, 126))	('brain tumors', 'Phenotype', 'HP:0030692', (136, 148))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', (142, 148))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('Leukemia', 'Phenotype', 'HP:0001909', (118, 126))	('Notch', 'Gene', '31293', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('pancreatic cancer', 'Disease', 'MESH:D010190', (176, 193))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('signaling', 'biological_process', 'GO:0023052', ('37', '46'))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('breast cancer', 'Disease', (225, 238))	('aberrant', 'Var', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumors', 'Disease', (210, 216))	('pancreatic cancer', 'Disease', (176, 193))	('lung carcinoma', 'Disease', (160, 174))	('T-cell Acute Lymphoid Leukemia (T-ALL), brain tumors', 'Disease', 'MESH:D054218', (96, 148))	('epithelial tumors', 'Disease', (199, 216))	('Notch', 'Gene', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('epithelial tumors', 'Disease', 'MESH:D002277', (199, 216))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
149510	27491826	In our model system, where we combined deletion of Vhl with ectopic expression of NICD1, we observed several dysplastic nests of cells with a clear cell phenotype, but only one overt neoplasm.	('dysplastic', 'Disease', (109, 119))	('deletion', 'Var', (39, 47))	('neoplasm', 'Disease', (183, 191))	('Vhl', 'Gene', '22346', (51, 54))	('neoplasm', 'Disease', 'MESH:D009369', (183, 191))	('neoplasm', 'Phenotype', 'HP:0002664', (183, 191))	('Vhl', 'Gene', (51, 54))	('dysplastic', 'Disease', 'MESH:D004416', (109, 119))
149513	27491826	R26R-YFP, Vhlfl/fl 52, CALSL-NICD and Kap2-iCre mice strains were purchased from the Jackson Laboratory (Bar Harbor, ME) and were kept under pathogen free conditions.	('Kap', 'Gene', (38, 41))	('Vhl', 'Gene', '22346', (10, 13))	('mice', 'Species', '10090', (48, 52))	('Vhl', 'Gene', (10, 13))	('Kap', 'Gene', '16483', (38, 41))	('R26R', 'Mutation', 'rs139200646', (0, 4))	('R26R-YFP', 'Var', (0, 8))
149514	27491826	The mice were crossed to generate R26RYFPtg/+/Kap2-iCretg/+, R26RYFPtg/+, Vhlfl/fl/CALSL-NICDtg/+/Kap2-iCretg/+, Vhlfl/fl/Kap2-iCre and Vhlfl/fl/CALSL-NICDtg/+; mice and were maintained on a mixed C57BL6/129S background.	('Kap', 'Gene', (122, 125))	('mice', 'Species', '10090', (161, 165))	('Vhl', 'Gene', '22346', (113, 116))	('Vhl', 'Gene', (74, 77))	('mice', 'Species', '10090', (4, 8))	('Kap', 'Gene', '16483', (98, 101))	('Vhl', 'Gene', '22346', (136, 139))	('Vhl', 'Gene', (113, 116))	('Kap', 'Gene', '16483', (122, 125))	('R26R', 'Mutation', 'rs139200646', (61, 65))	('Kap', 'Gene', (46, 49))	('Vhl', 'Gene', (136, 139))	('R26R', 'Mutation', 'rs139200646', (34, 38))	('R26RYFPtg/+', 'Var', (61, 72))	('Vhl', 'Gene', '22346', (74, 77))	('Kap', 'Gene', (98, 101))	('Kap', 'Gene', '16483', (46, 49))
149527	27491826	The TMA was stained with Notch 1 antibody (3E12, Sigma Aldrich Saint Louis, MO).	('antibody', 'cellular_component', 'GO:0019815', ('33', '41'))	('Notch 1', 'Gene', '18128', (25, 32))	('3E12', 'Var', (43, 47))	('antibody', 'cellular_component', 'GO:0019814', ('33', '41'))	('antibody', 'molecular_function', 'GO:0003823', ('33', '41'))	('Notch 1', 'Gene', (25, 32))	('antibody', 'cellular_component', 'GO:0042571', ('33', '41'))
149600	32123862	Wild-type (wt)TNF or R2TNF but not R1TNF (TNF muteins that selectively bind to TNFR2 and TNFR1) induces phosphorylation of signal transducer and activator of transcription 3 (STAT3) on serine727 but not tyrosine705, resulting in pSTAT3Ser727 translocation to and colocalization with TNFR2 in mitochondria.	('mitochondria', 'cellular_component', 'GO:0005739', ('292', '304'))	('pSTAT3Ser727 translocation', 'MPA', (229, 255))	('TNFR2', 'Gene', (79, 84))	('serine727', 'Chemical', '-', (185, 194))	('phosphorylation', 'biological_process', 'GO:0016310', ('104', '119'))	('induces', 'Reg', (96, 103))	('tyrosine705', 'Chemical', '-', (203, 214))	('transcription', 'biological_process', 'GO:0006351', ('158', '171'))	('colocalization', 'MPA', (263, 277))	('phosphorylation', 'MPA', (104, 119))	('TNFR1', 'Gene', '7132', (89, 94))	('R2TNF', 'Var', (21, 26))	('signal transducer and activator of transcription 3', 'Gene', '6774', (123, 173))	('Ser', 'cellular_component', 'GO:0005790', ('235', '238'))	('TNFR1', 'Gene', (89, 94))
149602	32123862	Inhibition of any of the kinases or siRNA knockdown of TNFR2 or STAT3 promotes cell death associated with mitochondrial morphological changes, cytochrome c release, generation of reactive oxygen species, and TUNEL+cells expressing phosphorylated mixed lineage kinase-like (MLKL).	('cytochrome c', 'molecular_function', 'GO:0045155', ('143', '155'))	('rat', 'Species', '10116', (169, 172))	('cytochrome c', 'Gene', '54205', (143, 155))	('knockdown', 'Var', (42, 51))	('mitochondrial morphological changes', 'CPA', (106, 141))	('mixed lineage kinase-like', 'Gene', '197259', (246, 271))	('cell death', 'CPA', (79, 89))	('TNFR2', 'Gene', (55, 60))	('cell death', 'biological_process', 'GO:0008219', ('79', '89'))	('cytochrome c', 'molecular_function', 'GO:0009461', ('143', '155'))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (179, 202))	('cytochrome c', 'Gene', (143, 155))	('promotes', 'PosReg', (70, 78))	('STAT3', 'Gene', (64, 69))	('MLKL', 'Gene', (273, 277))	('MLKL', 'Gene', '197259', (273, 277))	('mixed lineage kinase-like', 'Gene', (246, 271))	('generation of reactive oxygen species', 'MPA', (165, 202))
149613	32123862	Disruption of this pathway results in mitochondrial instability, mitochondrial outer membrane permeabilization, generation of ROS, and necroptotic cell death.	('mitochondrial outer membrane', 'cellular_component', 'GO:0005741', ('65', '93'))	('ROS', 'Chemical', 'MESH:D017382', (126, 129))	('ROS', 'Protein', (126, 129))	('mitochondrial outer membrane permeabilization', 'biological_process', 'GO:0097345', ('65', '110'))	('necroptotic cell death', 'CPA', (135, 157))	('rat', 'Species', '10116', (116, 119))	('cell death', 'biological_process', 'GO:0008219', ('147', '157'))	('results in', 'Reg', (27, 37))	('mitochondrial', 'MPA', (38, 51))	('mitochondrial outer membrane permeabilization', 'MPA', (65, 110))	('Disruption', 'Var', (0, 10))
149614	32123862	Antibodies and reagents used were anti-CD133/1-W6B3C1 (cat~130-092-395) (Miltenyi Biotec Ltd, Surrey, UK), anti-CD133 (cat~E90032)(Source Bioscience, Nottingham, UK), anti-STAT3 (phospho-Ty705) [EP2147Y] (ab76315), anti-STAT3 (phospho-Ser727) (ab131103), anti-PI-3K-p110beta [epr5515(2)](cat~ab151549), anti-Akt (phospho-Thr308) (cat~ab8933), anti-Akt (phospho-Ser473)[EP2109Y](cat~ab81283), anti-mTOR (phospho-Ser2448)(cat~ab118815), anti-VEGFR2 (phospho-Y1054-1059)(cat~ab5473), anti-human TNF Receptor II [EPR1653] (cat~ab109322), anti-phospho-Histone H3S10 antibodies (cat~ab14955 and cat~ab5176), anti-phospho-MLKLSer358 (cat~ab187091) and N-Acetyl-L-Cysteine (NAC, cat~ab143032), and phosphorylated JAK-1, -2, and -3 (cat~ab32101, ab61102; ab138005; Abcam).	('Ser727', 'Chemical', '-', (235, 241))	('p110beta', 'Gene', (266, 274))	('cat', 'molecular_function', 'GO:0004096', ('468', '471'))	('cat', 'molecular_function', 'GO:0004096', ('671', '674'))	('human', 'Species', '9606', (486, 491))	('p110beta', 'Gene', '5291', (266, 274))	('cat', 'molecular_function', 'GO:0004096', ('119', '122'))	('cat', 'molecular_function', 'GO:0004096', ('55', '58'))	('NAC', 'cellular_component', 'GO:0005854', ('666', '669'))	('cat', 'molecular_function', 'GO:0004096', ('378', '381'))	('PI-3K', 'molecular_function', 'GO:0016303', ('260', '265'))	('cat', 'molecular_function', 'GO:0004096', ('420', '423'))	('ab138005', 'Var', (746, 754))	('cat', 'molecular_function', 'GO:0004096', ('288', '291'))	('cat', 'molecular_function', 'GO:0004096', ('589', '592'))	('MLKL', 'Gene', (615, 619))	('JAK-1, -2, and -3', 'Gene', '3716;3717;3718', (705, 722))	('Ser', 'cellular_component', 'GO:0005790', ('361', '364'))	('cat', 'molecular_function', 'GO:0004096', ('724', '727'))	('cat', 'molecular_function', 'GO:0004096', ('519', '522'))	('mTOR', 'Gene', (397, 401))	('Ser', 'cellular_component', 'GO:0005790', ('235', '238'))	('cat', 'molecular_function', 'GO:0004096', ('573', '576'))	('ab61102; ab138005', 'Var', (737, 754))	('cat', 'molecular_function', 'GO:0004096', ('330', '333'))	('Ser', 'cellular_component', 'GO:0005790', ('411', '414'))	('Biotec', 'Chemical', '-', (82, 88))	('cat', 'molecular_function', 'GO:0004096', ('627', '630'))	('JAK', 'molecular_function', 'GO:0004713', ('705', '708'))	('MLKL', 'Gene', '197259', (615, 619))	('mTOR', 'Gene', '2475', (397, 401))	('NAC', 'Chemical', 'MESH:D000111', (666, 669))
149616	32123862	Anti-STAT3 (cat~9132), Anti-phospho-STAT3 Ser727 [M9C6] (cat~4113), anti-VDAC [D73D12] (cat~4661) and anti-cleaved caspase-3Asp175 (cat~9661), and phycoerythrin (PE)-conjugated anti-cleaved caspase-3p175 [5A1E] (cat~9978) (Cell Signaling Technology).	('cat', 'molecular_function', 'GO:0004096', ('132', '135'))	('caspase-3', 'Gene', (190, 199))	('cat', 'molecular_function', 'GO:0004096', ('88', '91'))	('Ser727', 'Chemical', '-', (42, 48))	('Signaling', 'biological_process', 'GO:0023052', ('228', '237'))	('caspase-3', 'Gene', '836', (190, 199))	('caspase-3', 'Gene', '836', (115, 124))	('cat', 'molecular_function', 'GO:0004096', ('212', '215'))	('cat', 'molecular_function', 'GO:0004096', ('12', '15'))	('cat', 'molecular_function', 'GO:0004096', ('57', '60'))	('Ser', 'cellular_component', 'GO:0005790', ('42', '45'))	('Ser727 [M9C6]', 'Var', (42, 55))	('caspase-3', 'Gene', (115, 124))
149619	32123862	Anti-cytochrome c (cat~556432), PE-conjugated: anti-phospho-STAT3S727 (cat~558557), anti-mTORSer2448 (cat~563489) and anti-phospho-AktThreonine308 (cat~558275)(BD Pharmingen).	('mTOR', 'Gene', '2475', (89, 93))	('cat', 'molecular_function', 'GO:0004096', ('148', '151'))	('cat~563489', 'Var', (102, 112))	('cat~558557', 'Var', (71, 81))	('cytochrome c', 'molecular_function', 'GO:0045155', ('5', '17'))	('cat~558275', 'Var', (148, 158))	('cytochrome c', 'Gene', (5, 17))	('cytochrome c', 'molecular_function', 'GO:0009461', ('5', '17'))	('cat', 'molecular_function', 'GO:0004096', ('71', '74'))	('cat', 'molecular_function', 'GO:0004096', ('102', '105'))	('cat', 'molecular_function', 'GO:0004096', ('19', '22'))	('cytochrome c', 'Gene', '54205', (5, 17))	('cat~556432', 'Var', (19, 29))	('mTOR', 'Gene', (89, 93))
149620	32123862	MitoTracker Red CMXRos (cat~M7512), Hoechst-33342 (cat~62249), 8-well Nunc  Lab-Tek  II Chamber Slides  System (cat~154526PK), Gibco  Opti-MEM  I Reduced Serum Medium (cat~31985062), CellROX Green (cat~C10492), BD Cytofix  (cat~554655), and BD Phosflow Perm Buffer II (cat~558050) (Thermofisher Scientific).	('CellROX Green', 'Chemical', '-', (183, 196))	('cat~31985062', 'Var', (168, 180))	('cat', 'molecular_function', 'GO:0004096', ('198', '201'))	('Opti-MEM', 'Chemical', '-', (134, 142))	('cat~C10492', 'Var', (198, 208))	('cat', 'molecular_function', 'GO:0004096', ('168', '171'))	('cat', 'molecular_function', 'GO:0004096', ('224', '227'))	('cat', 'molecular_function', 'GO:0004096', ('269', '272'))	('cat', 'molecular_function', 'GO:0004096', ('51', '54'))	('cat~554655', 'Var', (224, 234))	('cat', 'molecular_function', 'GO:0004096', ('112', '115'))	('Tek', 'Gene', (80, 83))	('Tek', 'Gene', '7010', (80, 83))	('cat~M7512', 'Var', (24, 33))	('cat~558050', 'Var', (269, 279))	('cat', 'molecular_function', 'GO:0004096', ('24', '27'))
149621	32123862	Tissue Dissociation Kit (cat~130-095-929), MS columns (cat~130-042-201), and C-Tubes (cat~130-093-237) (Miltenyi Biotec).	('Biotec', 'Chemical', '-', (113, 119))	('C-Tubes', 'CPA', (77, 84))	('cat', 'molecular_function', 'GO:0004096', ('86', '89'))	('cat', 'molecular_function', 'GO:0004096', ('25', '28'))	('cat', 'molecular_function', 'GO:0004096', ('55', '58'))	('cat~130-042-201', 'Var', (55, 70))	('MS columns', 'CPA', (43, 53))	('cat~130-093-237', 'Var', (86, 101))
149623	32123862	VEGFR2 Kinase Inhibitor I (SU5408, cat~ab145888), Ku-0063794 (mTORC1/2 inhibitor) (cat~13597) (Cayman Chemical), Akt inhibitor (AZD5363) (cat~S8019), and PI-3K inhibitor (BMK120, Buparlisib) (cat~S2247)( Selleckchem).	('cat', 'molecular_function', 'GO:0004096', ('138', '141'))	('mTORC1/2', 'Gene', '74343;382056', (62, 70))	('SU5408', 'Chemical', '-', (27, 33))	('AZD5363', 'Chemical', 'MESH:C575618', (128, 135))	('cat', 'molecular_function', 'GO:0004096', ('35', '38'))	('Kinase Inhibitor', 'biological_process', 'GO:0033673', ('7', '23'))	('mTORC1', 'cellular_component', 'GO:0031931', ('62', '68'))	('Ku-0063794', 'Chemical', 'MESH:C541932', (50, 60))	('Buparlisib', 'Chemical', 'MESH:C571178', (179, 189))	('cat', 'molecular_function', 'GO:0004096', ('83', '86'))	('ab145888', 'Chemical', '-', (39, 47))	('SU5408', 'Var', (27, 33))	('mTORC1/2', 'Gene', (62, 70))	('BMK120', 'Chemical', '-', (171, 177))	('PI-3K', 'molecular_function', 'GO:0016303', ('154', '159'))	('cat', 'molecular_function', 'GO:0004096', ('192', '195'))	('cat~13597', 'Var', (83, 92))	('Ku-0063794', 'Var', (50, 60))
149625	32123862	For TNFR1 the point mutation is R32W and for TNFR2 is D143N.22 Necrostatin-1 (Nec-1, cat~N9037) (Sigma-Aldrich, Dorset, UK), TUNEL-label (dUTP-FITC) (cat~11767291910), Terminal transferase enzyme (TdT) (cat~03333566001), Cell Counting Kit-8 (cat~96992), and trypan blue dye (cat~T6146) (Sigma-Aldrich, Dorset, UK).	('TNFR1', 'Gene', (4, 9))	('cat~T6146', 'Var', (275, 284))	('cat~11767291910', 'Var', (150, 165))	('cat', 'molecular_function', 'GO:0004096', ('150', '153'))	('cat', 'molecular_function', 'GO:0004096', ('275', '278'))	('TNFR1', 'Gene', '7132', (4, 9))	('cat', 'molecular_function', 'GO:0004096', ('242', '245'))	('TdT', 'Gene', (197, 200))	('cat~03333566001', 'Var', (203, 218))	('R32W', 'Var', (32, 36))	('R32W', 'Mutation', 'p.R32W', (32, 36))	('TdT', 'molecular_function', 'GO:0003912', ('197', '200'))	('TdT', 'Gene', '1791', (197, 200))	('cat', 'molecular_function', 'GO:0004096', ('85', '88'))	('cat', 'molecular_function', 'GO:0004096', ('203', '206'))	('dUTP', 'Chemical', 'MESH:C027078', (138, 142))	('D143N', 'Mutation', 'p.D143N', (54, 59))
149631	32123862	These included human ON-TARGETplus  TNFRSF1B siRNAs (10 nMol-set of four individual, cat~J-003934-05-0002, J-003934-06-0002, J-003934-07-0002, J-003934-08-0002), human ON-TARGETplus TNFRSF1A (10 nMol-set of four individual, cat~L-005197-00-0005), and ON-TARGETplus  nontargeting human siRNA (NTsiRNA; cat~D-001810-01-05), which does not target any known mammalian genes, as negative control, set of three human individual Stealth STAT3siRNAs (20nMol, cat~HSS110279, HSS186130, HSS186131) (Invitrogen).	('HSS186131', 'Var', (477, 486))	('cat', 'molecular_function', 'GO:0004096', ('224', '227'))	('human', 'Species', '9606', (405, 410))	('cat~HSS110279', 'Var', (451, 464))	('mammalian', 'Species', '9606', (354, 363))	('TNFRSF1A', 'Gene', (182, 190))	('human', 'Species', '9606', (162, 167))	('human', 'Species', '9606', (279, 284))	('TNFRSF1B', 'Gene', '7133', (36, 44))	('20nMol', 'Var', (443, 449))	('TNFRSF1A', 'Gene', '7132', (182, 190))	('TNFRSF1B', 'Gene', (36, 44))	('cat', 'molecular_function', 'GO:0004096', ('85', '88'))	('human', 'Species', '9606', (15, 20))	('cat', 'molecular_function', 'GO:0004096', ('301', '304'))	('cat', 'molecular_function', 'GO:0004096', ('451', '454'))	('HSS186130', 'Var', (466, 475))
149633	32123862	For cells, 8-well slide chambers were permeabilized at -20 C in cold methanol (4 minutes) before incubation with anti-CD133 alone or -anti-SSAE and -Nanog (1:100 dilution) overnight (4 C).	('Nanog', 'Gene', (149, 154))	('anti-CD133', 'Var', (113, 123))	('methanol', 'Chemical', 'MESH:D000432', (69, 77))	('Nanog', 'Gene', '79923', (149, 154))
149634	32123862	In parallel, cells treated with wtTNF (10 ng/mL), R1TNF, R2TNF (1 mug/mL) or left UT for 30 minutes (37 C) were incubation with anti-pSTAT3Ser727 and -CD133 or -TNFR2; anti-CD133 and phosphorylated-VEGFR2Y1059, -PI-3K110beta, -AktThr308 or -mTORSer2448.	('mTOR', 'Gene', (241, 245))	('mTOR', 'Gene', '2475', (241, 245))	('mug', 'molecular_function', 'GO:0043739', ('66', '69'))	('Ser', 'cellular_component', 'GO:0005790', ('139', '142'))	('Ser727', 'Chemical', '-', (139, 145))	('PI-3K', 'molecular_function', 'GO:0016303', ('212', '217'))	('anti-CD133', 'Var', (168, 178))
149646	32123862	Following siRNA transfection, some cells were posttreated with wtTNF, R1TNF, and R2TNF for 30 minutes (37 C) then CCK-8 reagent (10 muL) was added to each well for 4h (37 C) and the absorbance (OD) was measured at 450nm on Infinite M200 PRO Microplate Reader (Tecan).	('4h', 'Chemical', '-', (164, 166))	('transfection', 'Var', (16, 28))	('R2TNF', 'Var', (81, 86))	('siRNA', 'Gene', (10, 15))
149654	32123862	As we were unable to obtain sufficient mitochondria fraction for immunoblotting from ccRCC-CD133+CSCs, we used a human RCC immortalized cell line (RCC-26; derived from a patient with stage I disease) 32 Equal amount of protein (50microg) from mitochondria and cytosolic fraction were probed with anti- TNFR2, -total STAT3 or -pSTAT3Ser727 followed by specific HRP-conjugated secondary antibodies prior to visualization.	('mitochondria', 'cellular_component', 'GO:0005739', ('39', '51'))	('Ser', 'cellular_component', 'GO:0005790', ('332', '335'))	('RCC-26', 'CellLine', 'CVCL:5886', (147, 153))	('patient', 'Species', '9606', (170, 177))	('HRP-conjugated', 'Protein', (360, 374))	('mitochondria', 'cellular_component', 'GO:0005739', ('243', '255'))	('anti-', 'Var', (296, 301))	('protein', 'cellular_component', 'GO:0003675', ('219', '226'))	('human', 'Species', '9606', (113, 118))
149661	32123862	pSTAT3Ty705 associated with nuclear translocation is seen in many stem cells and malignancies and may play a role in cell proliferation.	('malignancies', 'Disease', 'MESH:D009369', (81, 93))	('nuclear translocation', 'MPA', (28, 49))	('rat', 'Species', '10116', (129, 132))	('malignancies', 'Disease', (81, 93))	('play', 'Reg', (102, 106))	('cell proliferation', 'biological_process', 'GO:0008283', ('117', '135'))	('pSTAT3Ty705', 'Var', (0, 11))
149662	32123862	To further confirm the absence of pSTAT3Ty705 expression after TNF-treatment, organ cultures were immunostained for phosphorylated JAK-1, -2, and -3.	('JAK', 'molecular_function', 'GO:0004713', ('131', '134'))	('pSTAT3Ty705', 'Var', (34, 45))	('absence', 'NegReg', (23, 30))	('JAK-1, -2, and -3', 'Gene', '3716;3717;3718', (131, 148))
149664	32123862	To further study the effect of TNF, we isolated CD133+cells from ccRCC-(ccRCCCD133+CSCs).21 Isolated cells were strongly positive for CD133 and exhibited a stem-cell phenotype evidenced by strong immunostaining for SSEA-4 and Nanog (Figure 1E,F), as previously reported.21 To test whether TNF phosphorylates STAT3 in ccRCC-CD133+CSCs, cells were treated with wtTNF, R1TNF, and R2TNF or left UT for 30 minutes (37 C).	('Nanog', 'Gene', '79923', (226, 231))	('Nanog', 'Gene', (226, 231))	('R2TNF', 'Var', (377, 382))	('R1TNF', 'Var', (366, 371))
149665	32123862	As in ccRCC organ cultures, R2TNF-induced TNFR2 expression, which colocalized with pSTAT3Ser727 in ~68% of the cells showing a cytoplasmic/granular pattern of staining (Figure 2E,F).	('Ser727', 'Chemical', '-', (89, 95))	('TNFR2', 'Gene', (42, 47))	('expression', 'MPA', (48, 58))	('R2TNF-induced', 'Var', (28, 41))	('Ser', 'cellular_component', 'GO:0005790', ('89', '92'))
149672	32123862	Flow cytometry and IF analysis confirmed that wtTNF and R2TNF (not R1TNF), induce pVEGFR2Y1059, AktThr308, mToRSer2448, and PI-3Kp110beta in ccRCC-CD133+ CSCs compared to UT controls (Figure 3A-D).	('R2TNF', 'Var', (56, 61))	('ccRCC-CD133+', 'Disease', (141, 153))	('p110beta', 'Gene', '5291', (129, 137))	('AktThr308', 'Var', (96, 105))	('p110beta', 'Gene', (129, 137))	('pVEGFR2Y1059', 'Var', (82, 94))	('induce', 'PosReg', (75, 81))	('mToRSer2448', 'Var', (107, 118))
149673	32123862	To determine the relevance of this pathway for TNFR2-mediated pSTAT3Ser727 signaling, cells were pretreated with specific inhibitors to these kinases--SU5408, BMK120, AZ5363 or Ku0063794 (VEGFR2, PI-3K, Akt, and mTOR, respectively) and each decreased R2TNF-induced pSTAT3Ser727 formation by ~4-fold in ccRCC-CD133+CSCs (Figure 4A, quantified in B).	('Ku0063794', 'Var', (177, 186))	('BMK120', 'Chemical', '-', (159, 165))	('decreased', 'NegReg', (241, 250))	('pSTAT3Ser727 formation', 'MPA', (265, 287))	('BMK120', 'Var', (159, 165))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('Ser', 'cellular_component', 'GO:0005790', ('271', '274'))	('SU5408', 'Var', (151, 157))	('AZ5363', 'Var', (167, 173))	('formation', 'biological_process', 'GO:0009058', ('278', '287'))	('PI-3K', 'molecular_function', 'GO:0016303', ('196', '201'))	('mTOR', 'Gene', (212, 216))	('mTOR', 'Gene', '2475', (212, 216))	('Ser', 'cellular_component', 'GO:0005790', ('68', '71'))	('SU5408', 'Chemical', '-', (151, 157))
149674	32123862	These data indicate a role for the ETK/VEGFR2/PI-3K/Akt/mTORC pathway in TNFR2-mediated pSTAT3Ser727 in ccRCC-CD133+CSCs.	('TNFR2-mediated', 'Gene', (73, 87))	('mTOR', 'Gene', (56, 60))	('ETK', 'Gene', (35, 38))	('mTOR', 'Gene', '2475', (56, 60))	('PI-3K', 'molecular_function', 'GO:0016303', ('46', '51'))	('pSTAT3Ser727', 'Var', (88, 100))	('ccRCC-CD133+CSCs', 'Disease', (104, 120))	('ETK', 'Gene', '660', (35, 38))	('Ser', 'cellular_component', 'GO:0005790', ('94', '97'))
149678	32123862	While pSTAT3Ty705 is known to translocate to and act in the nucleus as a transcription factor, pSTAT3Ser727 exerts biological effects in mitochondria.16, 18, 19, 20 Since ligation of TNFR2 increases the expression of TNFR2 and pSTAT3Ser727, we wondered if these proteins are expressed and associated with mitochondria in ccRCC-CD133+CSCs.	('ccRCC-CD133+CSCs', 'Disease', (321, 337))	('Ser', 'cellular_component', 'GO:0005790', ('101', '104'))	('increases', 'PosReg', (189, 198))	('Ser', 'cellular_component', 'GO:0005790', ('233', '236'))	('TNFR2', 'Gene', (217, 222))	('expression', 'MPA', (203, 213))	('Ser727', 'Chemical', '-', (233, 239))	('nucleus', 'cellular_component', 'GO:0005634', ('60', '67'))	('transcription', 'biological_process', 'GO:0006351', ('73', '86'))	('mitochondria', 'cellular_component', 'GO:0005739', ('137', '149'))	('ligation', 'Var', (171, 179))	('TNFR2', 'Gene', (183, 188))	('mitochondria', 'cellular_component', 'GO:0005739', ('305', '317'))	('transcription factor', 'molecular_function', 'GO:0000981', ('73', '93'))	('Ser727', 'Chemical', '-', (101, 107))
149679	32123862	As we were unable to obtain a sufficient number of ccRCC-CD133+CSCs for immunoblotting isolated mitochondria, we isolated mitochondria from a ccRCC immortalized cell line (RCC-26) treated with R2TNF or left UT and observed that R2TNF induced the expression of TNFR2 and pSTAT3Ser727 (Figure 4E).	('mitochondria', 'cellular_component', 'GO:0005739', ('96', '108'))	('R2TNF', 'Var', (228, 233))	('pSTAT3Ser727', 'Gene', (270, 282))	('Ser', 'cellular_component', 'GO:0005790', ('276', '279'))	('RCC-26', 'CellLine', 'CVCL:5886', (172, 178))	('mitochondria', 'cellular_component', 'GO:0005739', ('122', '134'))	('expression', 'MPA', (246, 256))	('Ser727', 'Chemical', '-', (276, 282))	('TNFR2', 'Gene', (260, 265))
149688	32123862	Some protection was conferred with the knockdown expression of TNFR1 in the absence of either TNFR2 or STAT3 signals alone (x P < 0.0001) but not in combination (Psi P < .001).	('knockdown expression', 'Var', (39, 59))	('TNFR1', 'Gene', (63, 68))	('TNFR1', 'Gene', '7132', (63, 68))
149689	32123862	The degree of cell death induced by the absence of TNFR1, TNFR2, and STAT3 either alone or in combination compared to control groups is illustrated in phase contrast micrographs (Figure S1D).	('absence', 'Var', (40, 47))	('STAT3', 'Gene', (69, 74))	('TNFR2', 'Gene', (58, 63))	('TNFR1', 'Gene', (51, 56))	('cell death', 'CPA', (14, 24))	('TNFR1', 'Gene', '7132', (51, 56))	('rat', 'Species', '10116', (142, 145))	('cell death', 'biological_process', 'GO:0008219', ('14', '24'))
149691	32123862	The other is mediated by pathological increases in ROS generation through dysregulation of the mitochondrial ETC.	('increases', 'PosReg', (38, 47))	('ROS generation', 'biological_process', 'GO:1903409', ('51', '65'))	('ROS', 'Chemical', 'MESH:D017382', (51, 54))	('mitochondrial ETC', 'Pathway', (95, 112))	('rat', 'Species', '10116', (59, 62))	('ROS generation', 'MPA', (51, 65))	('dysregulation', 'Var', (74, 87))
149709	32123862	However, in contrast to ccRCC-CD133+CSCs, activation of the kinase cascade appears to predominantly involve Akt and mTOR, with less activation of VEGFR2 and PI3K (Figure S5A-D) and specific inhibition of Akt and mTOR resulted in a diminished R2TNF-mediated pSTAT3Ser727 induction (Figure S6A,B) and cell death but significantly less (~2-fold) compared to that observed in ccRCC-CD133+CSCs (Table S1).	('diminished', 'NegReg', (231, 241))	('mTOR', 'Gene', '2475', (212, 216))	('R2TNF-mediated pSTAT3Ser727 induction', 'MPA', (242, 279))	('cell death', 'biological_process', 'GO:0008219', ('299', '309'))	('PI3K', 'molecular_function', 'GO:0016303', ('157', '161'))	('Ser727', 'Chemical', '-', (263, 269))	('Ser', 'cellular_component', 'GO:0005790', ('263', '266'))	('mTOR', 'Gene', (116, 120))	('mTOR', 'Gene', '2475', (116, 120))	('mTOR', 'Gene', (212, 216))	('VEGFR2', 'Gene', (146, 152))	('cell death', 'CPA', (299, 309))	('inhibition', 'Var', (190, 200))
149710	32123862	Knockdown of TNFR1 signals also induced a small degree of cell death in NK-CD133+cells and as in ccRCC-CD133+CSCs, absence of all three signals induced an even higher level of cell death but significantly less(~2-fold) than in ccRCC-CD133+CSCs (Figure S7C).	('TNFR1', 'Gene', (13, 18))	('absence', 'Var', (115, 122))	('less', 'NegReg', (205, 209))	('cell death', 'biological_process', 'GO:0008219', ('176', '186'))	('TNFR1', 'Gene', '7132', (13, 18))	('cell death', 'CPA', (58, 68))	('cell death', 'biological_process', 'GO:0008219', ('58', '68'))	('cell death', 'CPA', (176, 186))
149712	32123862	Cell death in NK-CD133+cells was also associated with cytochrome c release in the cytosol and generation of ROS but the frequency/intensity of these factors was notably less than in ccRCC-CD133+CSCs (Figures S8B-D, quantified in Table 5).	('Cell death', 'biological_process', 'GO:0008219', ('0', '10'))	('Cell death', 'CPA', (0, 10))	('NK-CD133+cells', 'Var', (14, 28))	('ROS', 'Chemical', 'MESH:D017382', (108, 111))	('cytochrome c', 'molecular_function', 'GO:0045155', ('54', '66'))	('cytochrome c', 'Gene', (54, 66))	('rat', 'Species', '10116', (98, 101))	('cytochrome c', 'Gene', '54205', (54, 66))	('cytosol', 'cellular_component', 'GO:0005829', ('82', '89'))	('cytochrome c', 'molecular_function', 'GO:0009461', ('54', '66'))	('ROS', 'MPA', (108, 111))
149713	32123862	The percentage of NK-CD133+cells that respond by colocalization of TNFR2 and pSTAT3Ser727 is significantly less and activation of the kinase cascade appears to predominantly involve Akt and mTOR, with less activation of VEGFR2 and PI-3K than in ccRCC-CD133+CSCs (Figure 2).	('less', 'NegReg', (107, 111))	('PI-3K', 'molecular_function', 'GO:0016303', ('231', '236'))	('respond', 'MPA', (38, 45))	('mTOR', 'Gene', '2475', (190, 194))	('Ser', 'cellular_component', 'GO:0005790', ('83', '86'))	('mTOR', 'Gene', (190, 194))	('colocalization', 'MPA', (49, 63))	('pSTAT3Ser727', 'Var', (77, 89))	('Akt', 'Pathway', (182, 185))	('TNFR2', 'Gene', (67, 72))
149717	32123862	The putative anti-tumor activity of infliximab (anti-TNF antibody) was demonstrated in advanced RCC,42 but a subsequent phase I/II trial using a combination of infliximab and the multi-kinase inhibitor sorafenib showed adverse events with lack of efficacy.43 Our data indicate that blocking TNFR2 may account for adverse outcomes and suggest that a TNFR2 agonist combined with standard chemotherapy regimens may offer greater efficacy.	('TNFR2', 'Gene', (291, 296))	('antibody', 'cellular_component', 'GO:0042571', ('57', '65'))	('sorafenib', 'Chemical', 'MESH:D000077157', (202, 211))	('antibody', 'cellular_component', 'GO:0019815', ('57', '65'))	('tumor', 'Disease', (18, 23))	('infliximab', 'Chemical', 'MESH:D000069285', (160, 170))	('antibody', 'cellular_component', 'GO:0019814', ('57', '65'))	('infliximab', 'Chemical', 'MESH:D000069285', (36, 46))	('rat', 'Species', '10116', (78, 81))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('185', '201'))	('blocking', 'Var', (282, 290))	('antibody', 'molecular_function', 'GO:0003823', ('57', '65'))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
149722	32123862	Similar to in situ CD133+cells, selective ligation of TNFR2 by R2TNF and wtTNF (but not R1TNF) induced pSTAT3Ser727 but not pSTAT3Ty705 in vitro in isolated CD133+cells from both ccRCC and NK, but the expression was more pronounced in ccRCC-CD133+CSCs.	('Ser727', 'Chemical', '-', (109, 115))	('R2TNF', 'Var', (63, 68))	('pSTAT3Ser727', 'MPA', (103, 115))	('Ser', 'cellular_component', 'GO:0005790', ('109', '112'))	('ligation', 'Var', (42, 50))	('TNFR2', 'Gene', (54, 59))
149723	32123862	Our data indicate that TNFR2-mediated pSTAT3Ser727 involves the activation of VEGFR2/PI-3K/Akt/mTORC1/2 pathway in ccRCC-CD133+CSCs.	('mTORC1/2', 'Gene', (95, 103))	('PI-3K', 'molecular_function', 'GO:0016303', ('85', '90'))	('mTORC1/2', 'Gene', '74343;382056', (95, 103))	('Ser', 'cellular_component', 'GO:0005790', ('44', '47'))	('activation', 'PosReg', (64, 74))	('pSTAT3Ser727', 'Var', (38, 50))	('mTORC1', 'cellular_component', 'GO:0031931', ('95', '101'))	('ccRCC-CD133+CSCs', 'Disease', (115, 131))
149734	32123862	Importantly, we show that blocking TNFR1 signals confers only partial protection from cell death induced by the absence of TNFR2/STAT3 signals, suggesting the involvement of an unknown mechanism, perhaps similar to that reported by Lacerda et al, where TNF's effect on mitochondria is independent of its cell surface receptors and occur via ROS generation.50 Unexpectedly, the absence of TNFR1 signals alone induced cytotoxic effect, albeit small compared to that induced by the absence of TNFR2/STAT3 signals either alone or in combination.	('TNFR1', 'Gene', (388, 393))	('cell death', 'biological_process', 'GO:0008219', ('86', '96'))	('cytotoxic effect', 'CPA', (416, 432))	('ROS generation', 'biological_process', 'GO:1903409', ('341', '355'))	('TNFR1', 'Gene', (35, 40))	('rat', 'Species', '10116', (349, 352))	('cell surface', 'cellular_component', 'GO:0009986', ('304', '316'))	('TNFR1', 'Gene', '7132', (388, 393))	('ROS', 'Chemical', 'MESH:D017382', (341, 344))	('absence', 'Var', (377, 384))	('mitochondria', 'cellular_component', 'GO:0005739', ('269', '281'))	('TNFR1', 'Gene', '7132', (35, 40))
149738	32123862	The absence of TNFR2/STAT3 increases cell death triggering changes in mitochondrial ultrastructure, release of cytochrome c, activation of cleaved caspase 3p175, phosphorylation of MLKLSer358, and generation of ROS.	('caspase', 'Gene', (147, 154))	('cytochrome c', 'molecular_function', 'GO:0009461', ('111', '123'))	('cell death', 'biological_process', 'GO:0008219', ('37', '47'))	('phosphorylation', 'biological_process', 'GO:0016310', ('162', '177'))	('MLKL', 'Gene', (181, 185))	('cytochrome c', 'Gene', '54205', (111, 123))	('ROS', 'Protein', (211, 214))	('TNFR2/STAT3', 'Gene', (15, 26))	('MLKL', 'Gene', '197259', (181, 185))	('changes', 'Reg', (59, 66))	('caspase', 'Gene', '842', (147, 154))	('mitochondrial ultrastructure', 'CPA', (70, 98))	('ROS', 'Chemical', 'MESH:D017382', (211, 214))	('activation', 'PosReg', (125, 135))	('cell death', 'CPA', (37, 47))	('rat', 'Species', '10116', (201, 204))	('cytochrome c', 'molecular_function', 'GO:0045155', ('111', '123'))	('cytochrome c', 'Gene', (111, 123))	('cleaved', 'MPA', (139, 146))	('phosphorylation', 'MPA', (162, 177))	('absence', 'Var', (4, 11))
149768	27617248	Although the exact cause or pathogenesis has not yet been clarified, multiple risk factors have been suggested including DES use during pregnancy, genetic predisposing factors, instability of microsatellite repeat sequences, human papilloma virus infection, overexpression of B-cell lymphoma 2 (Bcl-2) protein, variation of the p53 gene, and external or environmental factors.	('variation', 'Var', (311, 320))	('papilloma virus infection', 'Disease', (231, 256))	('papilloma virus infection', 'Disease', 'MESH:D010212', (231, 256))	('instability', 'Var', (177, 188))	('DES', 'Chemical', 'MESH:D004054', (121, 124))	('papilloma', 'Phenotype', 'HP:0012740', (231, 240))	('lymphoma', 'Phenotype', 'HP:0002665', (283, 291))	('protein', 'cellular_component', 'GO:0003675', ('302', '309'))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (276, 291))	('overexpression', 'PosReg', (258, 272))	('pathogenesis', 'biological_process', 'GO:0009405', ('28', '40'))	('p53', 'Gene', (328, 331))	('Bcl-2', 'Gene', (295, 300))	('Bcl-2', 'molecular_function', 'GO:0015283', ('295', '300'))
149793	31130475	Interestingly, ectopic expression of miR-200b in the Caki-1 and OSRC-2 cell lines suppresses cell migration and invasion in vitro as well as tumor metastases in vivo.	('ectopic expression', 'Var', (15, 33))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('miR-200b', 'Gene', (37, 45))	('suppresses', 'NegReg', (82, 92))	('OSRC-2', 'CellLine', 'CVCL:1901', (64, 70))	('cell migration', 'biological_process', 'GO:0016477', ('93', '107'))	('tumor metastases', 'Disease', (141, 157))	('tumor metastases', 'Disease', 'MESH:D009362', (141, 157))
149795	31130475	In addition, bioinformatics target predication and RNA-seq results reveals that Laminin subunit alpha 4 (LAMA4) is one target of miR-200b and significantly inhibited by miR-200b in vitro and in vivo.	('miR-200b', 'Var', (169, 177))	('Laminin subunit alpha 4', 'Gene', '3910', (80, 103))	('miR-200b', 'Var', (129, 137))	('Laminin subunit alpha 4', 'Gene', (80, 103))	('RNA', 'cellular_component', 'GO:0005562', ('51', '54'))	('LAMA4', 'Gene', (105, 110))	('inhibited', 'NegReg', (156, 165))
149796	31130475	These results demonstrate a previously undescribed role of miR-200b as a suppressor of tumor metastasis in RCC by directly destabilizing LAMA4 mRNA.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('RCC', 'Disease', (107, 110))	('destabilizing', 'NegReg', (123, 136))	('tumor metastasis', 'Disease', 'MESH:D009362', (87, 103))	('miR-200b', 'Var', (59, 67))	('tumor metastasis', 'Disease', (87, 103))	('LAMA4 mRNA', 'MPA', (137, 147))
149805	31130475	Dysregulation of miR-200b-LAMA4 axis may serve as early metastatic biomarker in RCC.	('Dysregulation', 'Var', (0, 13))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('miR-200b-LAMA4', 'Gene', (17, 31))
149806	31130475	Moreover, targeting metastasis in RCC through epigenetically regulates LAMA4 expression could be achieved by miR-200b.	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('expression', 'MPA', (77, 87))	('miR-200b', 'Var', (109, 117))	('LAMA4', 'Gene', (71, 76))	('epigenetically regulates', 'Var', (46, 70))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('RCC', 'Disease', (34, 37))
149824	31130475	In all, 70 normal kidney and 241 ccRCC tissues were determined to express hsa-miR-200b (MIMAT0000318) and LAMA4 mRNA.	('RCC', 'Disease', (35, 38))	('hsa-miR-200b', 'Gene', (74, 86))	('MIMAT0000318', 'Var', (88, 100))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
149845	31130475	The relative expression (RQ) was calculated as the fold change relative to internal reference, which was based on the following equation: RQ = 2-DeltaDeltaCt, DeltaDeltaCt = (meanCtcancer - meanCtreference) - (meanCtnormal - meanCtreference).	('cancer', 'Disease', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('DeltaDeltaCt', 'Var', (159, 171))
149869	31130475	The 3'-UTRs of LAMA4 carrying the putative miR-200b binding sites and the mutant binding sites were amplified by PCR using XbaI/EcoRI restriction sites and were inserted immediately downstream of the firefly luciferase cDNA in the pGL3-control vector (Promega, Madison, WI, USA) to construct pGL3-LAMA4 WT and pGL3-LAMA4 MUT.	('binding', 'molecular_function', 'GO:0005488', ('81', '88'))	('binding', 'molecular_function', 'GO:0005488', ('52', '59'))	('pGL3', 'Gene', (292, 296))	('pGL3', 'Gene', (310, 314))	('miR-200b', 'Gene', (43, 51))	('pGL3', 'Gene', (231, 235))	('pGL3', 'Gene', '6391', (292, 296))	('pGL', 'molecular_function', 'GO:0004598', ('292', '295'))	('pGL', 'molecular_function', 'GO:0004598', ('231', '234'))	('pGL3', 'Gene', '6391', (310, 314))	('mutant', 'Var', (74, 80))	('pGL', 'molecular_function', 'GO:0004598', ('310', '313'))	('pGL3', 'Gene', '6391', (231, 235))
149902	31130475	Next, we infected the cell lines Caki-1 and OSRC-2 with miR-200b and knock down miR-200b in 786-O cells using lentivirus system.	('miR-200b', 'Gene', (56, 64))	('OSRC-2', 'CellLine', 'CVCL:1901', (44, 50))	('knock down miR-200b', 'Var', (69, 88))	('miR-200b', 'Var', (80, 88))
149903	31130475	S4a the expression levels of miR-200b were increased about 3.1 and 5.7 folds in miR-200b infected Caki-1 and OSRC-2 cells, respectively, and reduced to 13% in 786-OmiR-200b TUD cells.	('miR-200b', 'Gene', (29, 37))	('miR-200b', 'Var', (80, 88))	('OSRC-2', 'CellLine', 'CVCL:1901', (109, 115))	('increased', 'PosReg', (43, 52))	('expression levels', 'MPA', (8, 25))
149904	31130475	Consistent with the increase of miR-200b expression, the migration ability of Caki-1 and OSRC-2cells infected with miR-200b into the wound was attenuated (58.9% and 56.2%, respectively) compared with the control cells, revealing by wound-healing assay (Fig.	('attenuated', 'NegReg', (143, 153))	('migration ability', 'CPA', (57, 74))	('miR-200b', 'Var', (115, 123))	('miR-200b', 'Gene', (32, 40))	('wound-healing', 'biological_process', 'GO:0042060', ('232', '245'))	('OSRC-2cells infected', 'Disease', 'MESH:D012516', (89, 109))	('expression', 'MPA', (41, 51))	('OSRC-2cells infected', 'Disease', (89, 109))	('increase', 'PosReg', (20, 28))
149905	31130475	Boyden chamber assays shown that while Caki-1 and OSRC-2 cells was infected with miR-200b mimics, the number of migratory cells was significantly decreased (56.3% and 72.9%, respectively) compared with the controls (Fig.	('mimics', 'Var', (90, 96))	('miR-200b', 'Gene', (81, 89))	('OSRC-2', 'CellLine', 'CVCL:1901', (50, 56))	('decreased', 'NegReg', (146, 155))
149909	31130475	To understand the underlying mechanisms that are involved in the suppression of tumor metastasis by miR-200b in RCC, we first performed a RNA sequencing assay using Caki-1miR-200b and control cells.	('miR-200b', 'Var', (100, 108))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('RNA', 'cellular_component', 'GO:0005562', ('138', '141'))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('tumor metastasis', 'Disease', 'MESH:D009362', (80, 96))	('tumor metastasis', 'Disease', (80, 96))
149921	31130475	We then analyzed the expression of miR-200b and the mRNA level of LAMA4 in the same set of 80 primary RCC tissues by qRT-PCR and found a statistically significant inverse correlation between miR-200b and LAMA4 mRNA levels (r = -0.6425, p < .0001, Pearson correlation test) (Fig.	('miR-200b', 'Var', (191, 199))	('LAMA4 mRNA levels', 'MPA', (204, 221))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('inverse', 'NegReg', (163, 170))
149929	31130475	Moreover, no significant difference was observed among CDXs derived from 786-O control, 786-O miR-200b TUD and 786-O miR-200b TUD + shLAMA4 cells (Fig.	('miR-200b', 'Var', (117, 125))	('miR-200b', 'Var', (94, 102))	('CDXs', 'Chemical', '-', (55, 59))
149930	31130475	It is suggested that miR-200b had no effect on RCC cells' proliferation in vivo.	('miR-200b', 'Var', (21, 29))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))
149934	31130475	To further demonstrate the contribution of miR-200b to RCC treatment, a patient-derived xenograft (PDX) model was established to determine the effects of miR-200b.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('patient', 'Species', '9606', (72, 79))	('miR-200b', 'Var', (154, 162))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
149939	31130475	Nevertheless, the quantification of human-specific Alu-sequences, which was measured by qRT-PCR, showed that transfection of cells with miR-200b in vivo could suppress lung metastasis in mice with tail vein transplanted tumor cells (Fig.	('suppress', 'NegReg', (159, 167))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (220, 225))	('mice', 'Species', '10090', (187, 191))	('miR-200b', 'Var', (136, 144))	('lung metastasis', 'CPA', (168, 183))	('human', 'Species', '9606', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
149944	31130475	Although miR-200b has no influence on tumor growth as shown in Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('miR-200b', 'Var', (9, 17))
149945	31130475	6h, according to Alu-PCR, the intratumor injection of miR-200b mimics decreased the extent of lung metastases in the PDX model compared with the control and PBS (Fig.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('lung metastases', 'Disease', (94, 109))	('miR-200b', 'Gene', (54, 62))	('lung metastases', 'Disease', 'MESH:D009362', (94, 109))	('decreased', 'NegReg', (70, 79))	('tumor', 'Disease', (35, 40))	('mimics', 'Var', (63, 69))	('PBS', 'Chemical', '-', (157, 160))
149963	31130475	Phosphorylation of ILK, FAK and ERK were markedly reduced upon ILK inhibition, while ERK phosphorylation decreased after ERK inhibition.	('inhibition', 'Var', (67, 77))	('FAK', 'molecular_function', 'GO:0004717', ('24', '27'))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('reduced', 'NegReg', (50, 57))	('ERK', 'Gene', '5594', (32, 35))	('ERK', 'Gene', '5594', (121, 124))	('ILK', 'Gene', (19, 22))	('ILK', 'Gene', '3611', (19, 22))	('ERK', 'molecular_function', 'GO:0004707', ('85', '88'))	('ERK', 'molecular_function', 'GO:0004707', ('32', '35'))	('ERK', 'Gene', (121, 124))	('ERK', 'Gene', (32, 35))	('ERK', 'Gene', '5594', (85, 88))	('FAK', 'Gene', (24, 27))	('ERK', 'molecular_function', 'GO:0004707', ('121', '124'))	('ILK', 'Gene', (63, 66))	('ILK', 'Gene', '3611', (63, 66))	('phosphorylation', 'biological_process', 'GO:0016310', ('89', '104'))	('Phosphorylation', 'MPA', (0, 15))	('ERK', 'Gene', (85, 88))	('FAK', 'Gene', '5747', (24, 27))
149971	31130475	In our study, the overexpression of miR-200b not only impeded cell spreading and migration in Caki-1 and OSRC-2 cells but also inhibited the metastasis of patient- derived xenografts and cell-derived xenografts in nude mice.	('impeded', 'NegReg', (54, 61))	('miR-200b', 'Var', (36, 44))	('nude mice', 'Species', '10090', (214, 223))	('metastasis of', 'CPA', (141, 154))	('inhibited', 'NegReg', (127, 136))	('patient', 'Species', '9606', (155, 162))	('OSRC-2', 'CellLine', 'CVCL:1901', (105, 111))	('cell spreading', 'CPA', (62, 76))	('overexpression', 'PosReg', (18, 32))
149974	31130475	Evidences have suggested that miR-200b behave as a tumor suppressor in various cancer by inhibiting cell proliferation.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cell proliferation', 'biological_process', 'GO:0008283', ('100', '118'))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('51', '67'))	('inhibiting', 'NegReg', (89, 99))	('tumor', 'Disease', (51, 56))	('miR-200b', 'Var', (30, 38))	('cell proliferation', 'CPA', (100, 118))	('tumor suppressor', 'biological_process', 'GO:0051726', ('51', '67'))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
149975	31130475	On the contrary, miR-200b have been demonstrated as a promoter of cell proliferation in several other malignancies, such as acute lymphoblastic leukemia and colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('leukemia', 'Phenotype', 'HP:0001909', (144, 152))	('malignancies', 'Disease', 'MESH:D009369', (102, 114))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (124, 152))	('colorectal cancer', 'Disease', (157, 174))	('cell proliferation', 'CPA', (66, 84))	('acute lymphoblastic leukemia', 'Disease', (124, 152))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (130, 152))	('colorectal cancer', 'Disease', 'MESH:D015179', (157, 174))	('malignancies', 'Disease', (102, 114))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('miR-200b', 'Var', (17, 25))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (124, 152))	('colorectal cancer', 'Phenotype', 'HP:0003003', (157, 174))	('promoter', 'PosReg', (54, 62))
149977	31130475	That lower expression of miR-200b in RCC specimen correlated with higher tumor stage in our study, suggested that miR-200b could possibly execute antiproliferative function in RCC.	('RCC', 'Disease', (176, 179))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('expression', 'MPA', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('tumor', 'Disease', (73, 78))	('miR-200b', 'Var', (114, 122))	('lower', 'NegReg', (5, 10))
149987	31130475	In this study, we found that co-expression of LAMA4 with integrin alpha5beta1, and LAMA4 increased integrin alpha5beta1 expression and induced RCC cell migration by activating ILK/FAK/ERK pathway.	('FAK', 'Gene', (180, 183))	('ILK', 'Gene', (176, 179))	('ERK', 'Gene', '5594', (184, 187))	('expression', 'MPA', (120, 130))	('ILK', 'Gene', '3611', (176, 179))	('ERK', 'molecular_function', 'GO:0004707', ('184', '187'))	('activating', 'PosReg', (165, 175))	('ERK', 'Gene', (184, 187))	('increased', 'PosReg', (89, 98))	('FAK', 'molecular_function', 'GO:0004717', ('180', '183'))	('integrin alpha5beta1', 'Protein', (99, 119))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('cell migration', 'biological_process', 'GO:0016477', ('147', '161'))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('induced', 'PosReg', (135, 142))	('RCC', 'Disease', (143, 146))	('LAMA4', 'Var', (83, 88))	('FAK', 'Gene', '5747', (180, 183))
149990	31130475	In vitro and in vivo models suggest that miR-200b-LAMA4 axis plays a functional role in RCC progression.	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('miR-200b-LAMA4', 'Var', (41, 55))
149992	31130475	Our findings revealed for the first time a potential tumor suppressive role for miR-200b in RCC progression and it may serve as a biomarker or even a therapeutic target for RCC through epigenetically regulates LAMA4 expression.	('miR-200b', 'Gene', (80, 88))	('LAMA4', 'Protein', (210, 215))	('RCC', 'Disease', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('epigenetically regulates', 'Var', (185, 209))	('expression', 'MPA', (216, 226))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('tumor', 'Disease', (53, 58))
150000	31175280	The low CDH1 or high TKTL1-induced accumulation of ribose-5-phosphate facilitates nucleotide and DNA synthesis as well as cell cycle progression in a ribose-5-phosphate-saturable manner.	('DNA synthesis', 'biological_process', 'GO:0071897', ('97', '110'))	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('TKTL1', 'Gene', (21, 26))	('accumulation', 'PosReg', (35, 47))	('facilitates', 'PosReg', (70, 81))	('cell cycle', 'biological_process', 'GO:0007049', ('122', '132'))	('ribose-5-phosphate', 'Chemical', 'MESH:C031626', (51, 69))	('CDH1', 'Gene', (8, 12))	('low', 'Var', (4, 7))	('CDH1', 'Chemical', '-', (8, 12))	('TKTL1', 'Gene', '8277', (21, 26))	('cell cycle progression', 'CPA', (122, 144))	('ribose-5-phosphate', 'Chemical', 'MESH:C031626', (150, 168))
150014	31175280	In fact, proactive R5P-accumulating mechanisms may also induce consequences such as PRPS activation and nucleotide increases from late G1 to S phase.	('induce', 'Reg', (56, 62))	('R5P', 'Chemical', 'MESH:C031626', (19, 22))	('nucleotide increases', 'MPA', (104, 124))	('S phase', 'biological_process', 'GO:0051320', ('141', '148'))	('activation', 'PosReg', (89, 99))	('R5P-accumulating', 'Var', (19, 35))	('PRPS', 'Gene', (84, 88))
150016	31175280	For example, enhanced PPP by either p53 or TAp73 led to accelerated DNA synthesis.	('enhanced', 'PosReg', (13, 21))	('TAp73', 'Var', (43, 48))	('DNA synthesis', 'biological_process', 'GO:0071897', ('68', '81'))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('DNA synthesis', 'MPA', (68, 81))	('PPP', 'MPA', (22, 25))	('accelerated', 'PosReg', (56, 67))
150027	31175280	Structural studies found that TKT proteins harboring this deletion lack TKT activity, suggesting that TKTL1 lacks TKT activity, while a biochemical study detected certain levels of TKT activity for TKTL1.	('activity', 'MPA', (185, 193))	('TKT', 'Gene', '7086', (72, 75))	('TKT', 'Gene', (72, 75))	('TKT', 'Gene', '7086', (30, 33))	('TKT', 'Gene', '7086', (198, 201))	('TKTL1', 'Gene', (198, 203))	('TKT', 'Gene', '7086', (102, 105))	('TKT', 'Gene', (30, 33))	('TKT', 'Gene', (198, 201))	('lack', 'NegReg', (67, 71))	('TKT', 'Gene', (102, 105))	('TKT', 'Gene', '7086', (181, 184))	('TKTL1', 'Gene', (102, 107))	('TKT', 'Gene', (181, 184))	('TKT', 'Gene', '7086', (114, 117))	('TKT', 'Gene', (114, 117))	('lacks', 'NegReg', (108, 113))	('TKTL1', 'Gene', '8277', (198, 203))	('TKTL1', 'Gene', '8277', (102, 107))	('deletion', 'Var', (58, 66))
150037	31175280	Meanwhile, endogenous levels of TKTL1, but not TKT and TKTL2, decreased in HeLa cells synchronized to G2/M phase by RO3306 (Supplementary Fig.	('RO3306', 'Chemical', 'MESH:C512984', (116, 122))	('RO3306', 'Var', (116, 122))	('TKT', 'Gene', '7086', (47, 50))	('decreased', 'NegReg', (62, 71))	('TKT', 'Gene', '7086', (32, 35))	('TKTL2', 'Gene', (55, 60))	('TKT', 'Gene', (55, 58))	('endogenous levels', 'MPA', (11, 28))	('TKTL1', 'Gene', '8277', (32, 37))	('TKTL2', 'Gene', '84076', (55, 60))	('HeLa', 'CellLine', 'CVCL:0030', (75, 79))	('TKT', 'Gene', (32, 35))	('M phase', 'biological_process', 'GO:0000279', ('105', '112'))	('TKTL1', 'Gene', (32, 37))	('TKT', 'Gene', '7086', (55, 58))	('TKT', 'Gene', (47, 50))
150040	31175280	TKTL1 protein levels also increased after RO3306-synchronized G2/M phase HeLa cells entered G1 phase (Fig.	('TKTL1', 'Gene', (0, 5))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('G1 phase', 'biological_process', 'GO:0051318', ('92', '100'))	('RO3306-synchronized', 'Var', (42, 61))	('M phase', 'biological_process', 'GO:0000279', ('65', '72'))	('RO3306', 'Chemical', 'MESH:C512984', (42, 48))	('increased', 'PosReg', (26, 35))	('TKTL1', 'Gene', '8277', (0, 5))	('HeLa', 'CellLine', 'CVCL:0030', (73, 77))
150049	31175280	Conversely, TKTL1 knockdown led to a 35% and 40% decrease in cellular R5P levels in HEK293T and HeLa cells, respectively (Fig.	('knockdown', 'Var', (18, 27))	('R5P', 'Chemical', 'MESH:C031626', (70, 73))	('HEK293T', 'CellLine', 'CVCL:0063', (84, 91))	('TKTL1', 'Gene', '8277', (12, 17))	('cellular R5P levels', 'MPA', (61, 80))	('decrease', 'NegReg', (49, 57))	('TKTL1', 'Gene', (12, 17))	('HeLa', 'CellLine', 'CVCL:0030', (96, 100))
150070	31175280	5a), while CDH1 knockdown increased it (Supplementary Fig.	('CDH1', 'Gene', (11, 15))	('increased', 'PosReg', (26, 35))	('CDH1', 'Chemical', '-', (11, 15))	('knockdown', 'Var', (16, 25))
150073	31175280	2h), whereas CDH1 knockdown by small interfering (si) RNA decreased ubiquitination levels (Fig.	('knockdown', 'Var', (18, 27))	('decreased', 'NegReg', (58, 67))	('RNA', 'cellular_component', 'GO:0005562', ('54', '57'))	('ubiquitination levels', 'MPA', (68, 89))	('small interfering', 'Var', (31, 48))	('CDH1', 'Gene', (13, 17))	('CDH1', 'Chemical', '-', (13, 17))
150074	31175280	2i) of ectopically expressed TKTL1 and stabilized endogenous TKTL1 (Fig.	('ectopically expressed', 'Var', (7, 28))	('TKTL1', 'Gene', '8277', (29, 34))	('TKTL1', 'Gene', '8277', (61, 66))	('TKTL1', 'Gene', (29, 34))	('TKTL1', 'Gene', (61, 66))	('endogenous', 'MPA', (50, 60))
150079	31175280	Endogenous mutant TKTL1 levels in Crispr/Cas9-mediated TKTL1 D-box mutant knock-in cells (TKTL1DeltaD-box-knockin) did not respond to CDH1 overexpression (Fig.	('CDH1', 'Chemical', '-', (134, 138))	('TKTL1', 'Gene', '8277', (55, 60))	('TKTL1', 'Gene', '8277', (18, 23))	('TKTL1', 'Gene', (18, 23))	('TKTL1', 'Gene', '8277', (90, 95))	('Cas', 'cellular_component', 'GO:0005650', ('41', '44'))	('TKTL1', 'Gene', (55, 60))	('TKTL1', 'Gene', (90, 95))	('mutant', 'Var', (67, 73))
150115	31175280	1b) in HeLa cells, removal of ectopically expressed TKTL1 from the cell lysates by affinity purification dose-dependently decreased their TKT levels (Fig.	('ectopically expressed', 'Var', (30, 51))	('TKTL1', 'Gene', '8277', (52, 57))	('TKT', 'Gene', '7086', (138, 141))	('TKT', 'Gene', '7086', (52, 55))	('TKT', 'Gene', (138, 141))	('TKTL1', 'Gene', (52, 57))	('TKT', 'Gene', (52, 55))	('removal', 'Var', (19, 26))	('HeLa', 'CellLine', 'CVCL:0030', (7, 11))	('decreased', 'NegReg', (122, 131))
150136	31175280	Compared with TKTL1 wild-type cells, TKTL1 D-box mutant cells with elevated TKTL1 protein levels led to increased non-oxidative PPP-derived M2 R5P and total R5P concentrations (Fig.	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('mutant', 'Var', (49, 55))	('TKTL1', 'Gene', '8277', (76, 81))	('increased', 'PosReg', (104, 113))	('total R5P concentrations', 'MPA', (151, 175))	('TKTL1', 'Gene', (14, 19))	('TKTL1', 'Gene', '8277', (37, 42))	('R5P', 'Chemical', 'MESH:C031626', (143, 146))	('TKTL1', 'Gene', (76, 81))	('non-oxidative PPP-derived M2 R5P', 'MPA', (114, 146))	('R5P', 'Chemical', 'MESH:C031626', (157, 160))	('TKTL1', 'Gene', (37, 42))	('TKTL1', 'Gene', '8277', (14, 19))
150142	31175280	Furthermore, knockout of the key glycolytic enzyme PFKFB3:also regulated by APC/CCDH1 and a limiting factor in providing the G3P that links glycolysis with non-oxidative PPP:led to decreased total R5P and M2 R5P production in cells (Fig.	('R5P', 'Chemical', 'MESH:C031626', (208, 211))	('R5P', 'Chemical', 'MESH:C031626', (197, 200))	('glycolysis', 'biological_process', 'GO:0006096', ('140', '150'))	('knockout', 'Var', (13, 21))	('PFKFB3', 'Gene', '5209', (51, 57))	('PFKFB3', 'Gene', (51, 57))	('APC/CCDH1', 'Gene', '324', (76, 85))	('APC', 'cellular_component', 'GO:0005680', ('76', '79'))	('APC/CCDH1', 'Gene', (76, 85))	('G3P', 'Chemical', 'MESH:D005986', (125, 128))	('M2 R5P production', 'MPA', (205, 222))	('decreased', 'NegReg', (181, 190))
150146	31175280	TKTL1 overexpression in HeLa cells increased total levels and percentage of M2-form R5P-containing molecules but did not alter the percentage of M1-form R5P-containing molecules (Fig.	('TKTL1', 'Gene', (0, 5))	('increased', 'PosReg', (35, 44))	('R5P', 'Chemical', 'MESH:C031626', (153, 156))	('overexpression', 'Var', (6, 20))	('R5P', 'Chemical', 'MESH:C031626', (84, 87))	('HeLa', 'CellLine', 'CVCL:0030', (24, 28))	('M2-form R5P-containing molecules', 'MPA', (76, 108))	('TKTL1', 'Gene', '8277', (0, 5))	('percentage', 'MPA', (62, 72))
150149	31175280	Notably, CDH1 knockdown phenocopied the effects of TKTL1 overexpression in regulating R5P-containing molecule levels (Fig.	('regulating R5P-containing molecule levels', 'MPA', (75, 116))	('overexpression', 'PosReg', (57, 71))	('TKTL1', 'Gene', '8277', (51, 56))	('TKTL1', 'Gene', (51, 56))	('CDH1', 'Gene', (9, 13))	('CDH1', 'Chemical', '-', (9, 13))	('knockdown', 'Var', (14, 23))	('R5P', 'Chemical', 'MESH:C031626', (86, 89))
150150	31175280	6b), consistent with the observation that CDH1 knockdown increased TKTL1 levels (Fig.	('CDH1', 'Gene', (42, 46))	('CDH1', 'Chemical', '-', (42, 46))	('knockdown', 'Var', (47, 56))	('TKTL1', 'Gene', '8277', (67, 72))	('increased', 'PosReg', (57, 66))	('TKTL1', 'Gene', (67, 72))
150151	31175280	Moreover, CDH1 knockdown in HeLa cells elevated R5P levels but decreased the variations of R5P among G1/S, G2/M, and the following G1 phase (Fig.	('CDH1', 'Gene', (10, 14))	('CDH1', 'Chemical', '-', (10, 14))	('knockdown', 'Var', (15, 24))	('R5P', 'Chemical', 'MESH:C031626', (91, 94))	('R5P levels', 'MPA', (48, 58))	('decreased', 'NegReg', (63, 72))	('G1 phase', 'biological_process', 'GO:0051318', ('131', '139'))	('elevated', 'PosReg', (39, 47))	('variations', 'MPA', (77, 87))	('HeLa', 'CellLine', 'CVCL:0030', (28, 32))	('R5P', 'Chemical', 'MESH:C031626', (48, 51))	('R5P', 'MPA', (91, 94))
150154	31175280	Together with the finding that both CDH1 overexpression and knockdown did not alter R5P levels in TKTL1DeltaD-box-knockin HeLa cells (Supplementary Fig.	('R5P', 'Chemical', 'MESH:C031626', (84, 87))	('CDH1', 'Gene', (36, 40))	('HeLa', 'CellLine', 'CVCL:0030', (122, 126))	('TKTL1', 'Gene', '8277', (98, 103))	('knockdown', 'Var', (60, 69))	('CDH1', 'Chemical', '-', (36, 40))	('R5P levels', 'MPA', (84, 94))	('TKTL1', 'Gene', (98, 103))
150156	31175280	TKTL1 knockdown not only lowered the levels of R5P-containing molecules, but also abolished the effects of CDH1 overexpression in HEK293T cells (Fig.	('TKTL1', 'Gene', (0, 5))	('HEK293T', 'CellLine', 'CVCL:0063', (130, 137))	('CDH1', 'Gene', (107, 111))	('overexpression', 'PosReg', (112, 126))	('TKTL1', 'Gene', '8277', (0, 5))	('lowered', 'NegReg', (25, 32))	('R5P', 'Chemical', 'MESH:C031626', (47, 50))	('CDH1', 'Chemical', '-', (107, 111))	('levels of R5P-containing molecules', 'MPA', (37, 71))	('knockdown', 'Var', (6, 15))	('abolished', 'NegReg', (82, 91))
150157	31175280	6e) and CDH1 knockdown in HeLa cells (Fig.	('CDH1', 'Gene', (8, 12))	('CDH1', 'Chemical', '-', (8, 12))	('knockdown', 'Var', (13, 22))	('HeLa', 'CellLine', 'CVCL:0030', (26, 30))
150159	31175280	Moreover, the regulating effects of CDH1 knockdown (Fig.	('CDH1', 'Gene', (36, 40))	('knockdown', 'Var', (41, 50))	('CDH1', 'Chemical', '-', (36, 40))
150160	31175280	6h) were also diminished by TKTL1 knockdown.	('knockdown', 'Var', (34, 43))	('TKTL1', 'Gene', (28, 33))	('diminished', 'NegReg', (14, 24))	('TKTL1', 'Gene', '8277', (28, 33))
150165	31175280	By utilizing 5-ethynyl-2'-deoxyuridine (EDU) staining to monitor DNA synthesis, we found that CDH1 knockdown increased while CDH1 overexpression decreased DNA synthesis in HEK293T cells.	('DNA', 'cellular_component', 'GO:0005574', ('155', '158'))	('EDU', 'Chemical', 'MESH:C031086', (40, 43))	('CDH1', 'Gene', (94, 98))	('CDH1', 'Gene', (125, 129))	('overexpression', 'PosReg', (130, 144))	('CDH1', 'Chemical', '-', (125, 129))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('DNA synthesis', 'biological_process', 'GO:0071897', ('65', '78'))	('decreased', 'NegReg', (145, 154))	('knockdown', 'Var', (99, 108))	('HEK293T', 'CellLine', 'CVCL:0063', (172, 179))	('CDH1', 'Chemical', '-', (94, 98))	('DNA synthesis', 'biological_process', 'GO:0071897', ('155', '168'))	('increased', 'PosReg', (109, 118))	('DNA synthesis', 'MPA', (155, 168))	("5-ethynyl-2'-deoxyuridine", 'Chemical', 'MESH:C031086', (13, 38))
150166	31175280	However, CDH1 exerted DNA synthesis regulating effects only when TKTL1 was present in the cells; depleting TKTL1 abrogated CDH1 ability to regulate DNA synthesis (Fig.	('DNA synthesis', 'biological_process', 'GO:0071897', ('22', '35'))	('TKTL1', 'Gene', '8277', (107, 112))	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('TKTL1', 'Gene', (65, 70))	('TKTL1', 'Gene', (107, 112))	('depleting', 'Var', (97, 106))	('regulate DNA synthesis', 'MPA', (139, 161))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('CDH1', 'Chemical', '-', (9, 13))	('abrogated', 'NegReg', (113, 122))	('TKTL1', 'Gene', '8277', (65, 70))	('ability', 'MPA', (128, 135))	('CDH1', 'Chemical', '-', (123, 127))	('DNA synthesis', 'biological_process', 'GO:0071897', ('148', '161'))	('CDH1', 'Gene', (123, 127))
150168	31175280	Moreover, TKTL1 knockdown and TKTL1 overexpression decreased and increased DNA synthesis, respectively, in HEK293T cells (Fig.	('increased', 'PosReg', (65, 74))	('TKTL1', 'Gene', (10, 15))	('DNA synthesis', 'MPA', (75, 88))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('decreased', 'NegReg', (51, 60))	('knockdown', 'Var', (16, 25))	('TKTL1', 'Gene', '8277', (30, 35))	('DNA synthesis', 'biological_process', 'GO:0071897', ('75', '88'))	('TKTL1', 'Gene', (30, 35))	('TKTL1', 'Gene', '8277', (10, 15))	('HEK293T', 'CellLine', 'CVCL:0063', (107, 114))
150170	31175280	Furthermore, supplementation with 10 mM R5P promoted DNA synthesis and saturated the DNA synthesis-promoting effects of CDH1 knockdown or TKTL1 overexpression (Fig.	('CDH1', 'Chemical', '-', (120, 124))	('knockdown', 'Var', (125, 134))	('promoted', 'PosReg', (44, 52))	('DNA synthesis', 'MPA', (53, 66))	('DNA synthesis-promoting', 'MPA', (85, 108))	('TKTL1', 'Gene', (138, 143))	('TKTL1', 'Gene', '8277', (138, 143))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('R5P', 'Chemical', 'MESH:C031626', (40, 43))	('overexpression', 'PosReg', (144, 158))	('CDH1', 'Gene', (120, 124))	('DNA synthesis', 'biological_process', 'GO:0071897', ('53', '66'))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('DNA synthesis', 'biological_process', 'GO:0071897', ('85', '98'))
150171	31175280	7a, b), confirming that both CDH1 knockdown and TKTL1 overexpression promoted DNA synthesis by increasing R5P levels.	('TKTL1', 'Gene', '8277', (48, 53))	('DNA synthesis', 'MPA', (78, 91))	('increasing', 'PosReg', (95, 105))	('R5P levels', 'MPA', (106, 116))	('TKTL1', 'Gene', (48, 53))	('CDH1', 'Gene', (29, 33))	('CDH1', 'Chemical', '-', (29, 33))	('promoted', 'PosReg', (69, 77))	('R5P', 'Chemical', 'MESH:C031626', (106, 109))	('knockdown', 'Var', (34, 43))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))	('DNA synthesis', 'biological_process', 'GO:0071897', ('78', '91'))
150172	31175280	In addition, PFKFB3 knockout decreased DNA synthesis and weakened the influence of CDH1 on DNA synthesis (Supplementary Fig.	('weakened', 'NegReg', (57, 65))	('DNA synthesis', 'MPA', (39, 52))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('DNA synthesis', 'biological_process', 'GO:0071897', ('39', '52'))	('PFKFB3', 'Gene', (13, 19))	('DNA synthesis', 'MPA', (91, 104))	('DNA synthesis', 'biological_process', 'GO:0071897', ('91', '104'))	('CDH1', 'MPA', (83, 87))	('CDH1', 'Chemical', '-', (83, 87))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('PFKFB3', 'Gene', '5209', (13, 19))	('influence', 'MPA', (70, 79))	('decreased', 'NegReg', (29, 38))	('knockout', 'Var', (20, 28))
150173	31175280	The S phase content (the percentage of S-phase cells), a readout for proliferation activity and cell cycle progression, was increased by CDH1 knockdown in HEK293T cells in a R5P saturable manner (Fig.	('cell cycle', 'biological_process', 'GO:0007049', ('96', '106'))	('cell cycle progression', 'CPA', (96, 118))	('increased', 'PosReg', (124, 133))	('S phase', 'biological_process', 'GO:0051320', ('4', '11'))	('S-phase', 'biological_process', 'GO:0051320', ('39', '46'))	('R5P', 'Chemical', 'MESH:C031626', (174, 177))	('S phase content', 'MPA', (4, 19))	('HEK293T', 'CellLine', 'CVCL:0063', (155, 162))	('CDH1', 'Gene', (137, 141))	('proliferation activity', 'CPA', (69, 91))	('CDH1', 'Chemical', '-', (137, 141))	('knockdown', 'Var', (142, 151))
150175	31175280	Additionally, TKTL1 overexpression and knockdown in HEK293T cells increased and decreased the percentage of cells in S phase, respectively (Fig.	('increased', 'PosReg', (66, 75))	('TKTL1', 'Gene', (14, 19))	('knockdown', 'Var', (39, 48))	('HEK293T', 'CellLine', 'CVCL:0063', (52, 59))	('overexpression', 'PosReg', (20, 34))	('decreased', 'NegReg', (80, 89))	('S phase', 'biological_process', 'GO:0051320', ('117', '124'))	('TKTL1', 'Gene', '8277', (14, 19))
150177	31175280	Furthermore, TKTL1 knockdown in HEK293T cells abrogated the effects of CDH1 knockdown and CDH1 overexpression in decreasing and increasing S phase content, respectively (Fig.	('TKTL1', 'Gene', (13, 18))	('HEK293T', 'CellLine', 'CVCL:0063', (32, 39))	('knockdown', 'Var', (76, 85))	('S phase', 'biological_process', 'GO:0051320', ('139', '146'))	('knockdown', 'Var', (19, 28))	('abrogated', 'NegReg', (46, 55))	('CDH1', 'Gene', (90, 94))	('S phase content', 'MPA', (139, 154))	('overexpression', 'PosReg', (95, 109))	('CDH1', 'Chemical', '-', (90, 94))	('CDH1', 'Gene', (71, 75))	('increasing', 'PosReg', (128, 138))	('TKTL1', 'Gene', '8277', (13, 18))	('CDH1', 'Chemical', '-', (71, 75))
150178	31175280	7c, d), whereas CDH1 knockdown in HEK293T cells failed to affect the inhibition and promotion of S phase content by TKTL1 overexpression and knockdown, respectively (Fig.	('TKTL1', 'Gene', (116, 121))	('knockdown', 'Var', (141, 150))	('overexpression', 'PosReg', (122, 136))	('S phase', 'biological_process', 'GO:0051320', ('97', '104'))	('promotion', 'PosReg', (84, 93))	('HEK293T', 'CellLine', 'CVCL:0063', (34, 41))	('TKTL1', 'Gene', '8277', (116, 121))	('CDH1', 'Chemical', '-', (16, 20))	('S phase content', 'MPA', (97, 112))
150180	31175280	Notably, TKT knockdown, in which R5P levels were unresponsive to cell cycle progression (Fig.	('R5P', 'Chemical', 'MESH:C031626', (33, 36))	('TKT', 'Gene', '7086', (9, 12))	('TKT', 'Gene', (9, 12))	('knockdown', 'Var', (13, 22))	('cell cycle', 'biological_process', 'GO:0007049', ('65', '75'))
150181	31175280	5j), rendered the S phase content of HeLa cells unresponsive to both TKTL1 overexpression and CDH1 knockdown (Fig.	('TKTL1', 'Gene', '8277', (69, 74))	('S phase', 'biological_process', 'GO:0051320', ('18', '25'))	('TKTL1', 'Gene', (69, 74))	('CDH1', 'Gene', (94, 98))	('HeLa', 'CellLine', 'CVCL:0030', (37, 41))	('CDH1', 'Chemical', '-', (94, 98))	('knockdown', 'Var', (99, 108))	('S phase content', 'MPA', (18, 33))
150184	31175280	HeLa, HEK293T, and breast cancer MCF7 cell growth was enhanced by CDH1 knockdown and TKTL1 overexpression, and exhibited inhibited growth after CDH1 overexpression and TKTL1 knockdown (Fig.	('TKTL1', 'Gene', (168, 173))	('CDH1', 'Chemical', '-', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('TKTL1', 'Gene', '8277', (85, 90))	('overexpression', 'PosReg', (91, 105))	('cell growth', 'biological_process', 'GO:0016049', ('38', '49'))	('HEK293T', 'CellLine', 'CVCL:0063', (6, 13))	('HeLa', 'CellLine', 'CVCL:0030', (0, 4))	('enhanced', 'PosReg', (54, 62))	('TKTL1', 'Gene', (85, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('MCF7', 'CellLine', 'CVCL:0031', (33, 37))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('TKTL1', 'Gene', '8277', (168, 173))	('breast cancer', 'Disease', (19, 32))	('HEK293T', 'CPA', (6, 13))	('CDH1', 'Gene', (66, 70))	('CDH1', 'Chemical', '-', (66, 70))	('knockdown', 'Var', (71, 80))
150190	31175280	In late G1 and early S phase when DNA synthesis begins, the absence of CDH1 results in increased levels of TKTL1; this reprograms R5P metabolism by forming TKTL1-TKT heterodimers, which produce R5P from the non-oxidative branch of PPP and inhibits R5P removal.	('R5P', 'Chemical', 'MESH:C031626', (194, 197))	('S phase', 'biological_process', 'GO:0051320', ('21', '28'))	('levels', 'MPA', (97, 103))	('R5P', 'Chemical', 'MESH:C031626', (130, 133))	('CDH1', 'Gene', (71, 75))	('R5P metabolism', 'MPA', (130, 144))	('R5P', 'Chemical', 'MESH:C031626', (248, 251))	('CDH1', 'Chemical', '-', (71, 75))	('TKTL1', 'Gene', '8277', (107, 112))	('TKT', 'Gene', '7086', (156, 159))	('R5P removal', 'MPA', (248, 259))	('TKTL1', 'Gene', '8277', (156, 161))	('TKT', 'Gene', (156, 159))	('metabolism', 'biological_process', 'GO:0008152', ('134', '144'))	('reprograms', 'Reg', (119, 129))	('TKT', 'Gene', '7086', (107, 110))	('TKT', 'Gene', '7086', (162, 165))	('TKTL1', 'Gene', (107, 112))	('TKT', 'Gene', (107, 110))	('TKT', 'Gene', (162, 165))	('TKTL1', 'Gene', (156, 161))	('increased', 'PosReg', (87, 96))	('absence', 'Var', (60, 67))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('DNA synthesis', 'biological_process', 'GO:0071897', ('34', '47'))	('inhibits', 'NegReg', (239, 247))
150193	31175280	Our findings are consistent with and explain previous findings where CDH1 knockdown and overexpression elevated and decreased the percentage of S phase content in MCF7 cells, respectively, and where TKTL1 overexpression increased S phase content of melanoma LM-MEL-59 cells.	('CDH1', 'Gene', (69, 73))	('overexpression', 'PosReg', (88, 102))	('TKTL1', 'Gene', (199, 204))	('S phase', 'biological_process', 'GO:0051320', ('230', '237'))	('MCF7', 'CellLine', 'CVCL:0031', (163, 167))	('S phase content', 'MPA', (144, 159))	('melanoma', 'Disease', 'MESH:D008545', (249, 257))	('CDH1', 'Chemical', '-', (69, 73))	('knockdown', 'Var', (74, 83))	('melanoma', 'Disease', (249, 257))	('melanoma', 'Phenotype', 'HP:0002861', (249, 257))	('S phase', 'biological_process', 'GO:0051320', ('144', '151'))	('overexpression increased', 'PosReg', (205, 229))	('LM-MEL-59', 'CellLine', 'CVCL:5998', (258, 267))	('S phase content', 'MPA', (230, 245))	('elevated', 'PosReg', (103, 111))	('TKTL1', 'Gene', '8277', (199, 204))	('decreased', 'NegReg', (116, 125))
150195	31175280	These results indicate a direct control of PPP and glycolysis by APC/CCDH1 and suggest a possibility that activation of APC/CCDH1 may help inhibiting cancer cell progression by prohibiting R5P generation through the inhibition of PPP and early steps of glycolysis.	('APC/CCDH1', 'Gene', (120, 129))	('APC/CCDH1', 'Gene', '324', (65, 74))	('APC', 'cellular_component', 'GO:0005680', ('120', '123'))	('glycolysis', 'biological_process', 'GO:0006096', ('253', '263'))	('inhibiting', 'NegReg', (139, 149))	('APC/CCDH1', 'Gene', '324', (120, 129))	('R5P generation', 'MPA', (189, 203))	('activation', 'Var', (106, 116))	('APC', 'cellular_component', 'GO:0005680', ('65', '68'))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('prohibiting', 'NegReg', (177, 188))	('R5P', 'Chemical', 'MESH:C031626', (189, 192))	('glycolysis', 'MPA', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('APC/CCDH1', 'Gene', (65, 74))	('PPP', 'Enzyme', (230, 233))	('inhibition', 'NegReg', (216, 226))	('glycolysis', 'biological_process', 'GO:0006096', ('51', '61'))
150201	31175280	If the oxidative branch of PPP is employed to produce R5P prior to and during S phase, an increase in oxidative PPP activity will cause an increase in NADPH production, which may activate NADPH oxidases and accumulate reactive oxygen species, exerting deleterious effects on DNA replication.	('activate', 'PosReg', (179, 187))	('increase', 'PosReg', (90, 98))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (218, 241))	('NADPH oxidases', 'Enzyme', (188, 202))	('NADPH', 'Chemical', 'MESH:D009249', (188, 193))	('R5P', 'Chemical', 'MESH:C031626', (54, 57))	('NADPH', 'Chemical', 'MESH:D009249', (151, 156))	('DNA replication', 'biological_process', 'GO:0006260', ('275', '290'))	('increase', 'PosReg', (139, 147))	('NADPH production', 'MPA', (151, 167))	('accumulate', 'PosReg', (207, 217))	('oxidative', 'Var', (102, 111))	('activity', 'MPA', (116, 124))	('DNA', 'cellular_component', 'GO:0005574', ('275', '278'))	('reactive oxygen species', 'MPA', (218, 241))	('PPP', 'Gene', (112, 115))	('S phase', 'biological_process', 'GO:0051320', ('78', '85'))
150203	31175280	In addition, overexpressed TKTL1 leads to acetyl-CoA accumulation which is an energy rich building block for lipid and amino acid synthesis.	('lipid', 'Chemical', 'MESH:D008055', (109, 114))	('TKTL1', 'Gene', '8277', (27, 32))	('TKTL1', 'Gene', (27, 32))	('acetyl-CoA accumulation', 'MPA', (42, 65))	('synthesis', 'biological_process', 'GO:0009058', ('130', '139'))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (42, 52))	('overexpressed', 'Var', (13, 26))
150218	31175280	The CDC20 (#4823, dilution 1:3000), SKP2 (#4358, dilution 1:1000) antibody was from Cell Signaling Technology.	('antibody', 'cellular_component', 'GO:0042571', ('66', '74'))	('antibody', 'cellular_component', 'GO:0019814', ('66', '74'))	('SKP2', 'Gene', (36, 40))	('#4358', 'Var', (42, 47))	('antibody', 'cellular_component', 'GO:0019815', ('66', '74'))	('Signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('CDC20', 'Gene', (4, 9))	('CDC20', 'Gene', '991', (4, 9))	('antibody', 'molecular_function', 'GO:0003823', ('66', '74'))	('SKP2', 'Gene', '6502', (36, 40))
150223	31175280	Anti-Flag (#M20008, dilution 1:5000), Anti-Myc (#M20003, dilution 1:5000), and anti-HA (#M20002, dilution 1:5000) antibodies were obtained from Abmart.	('Myc', 'Gene', (43, 46))	('#M20002', 'Var', (88, 95))	('#M20003', 'Var', (48, 55))	('#M20008', 'Var', (11, 18))	('Myc', 'Gene', '4609', (43, 46))
150225	31175280	EdU (#A10044) and Azide Alexa Fluor(#A10266) were purchased from Invitrogen.	('#A10044', 'Var', (5, 12))	('Azide Alexa Fluor', 'Chemical', '-', (18, 35))	('#A10266', 'Var', (36, 43))
150226	31175280	HEK293T (ATCC Number: CRL-11268), HeLa (ATCC Number: CCL-2) and MCF7 (ATCC Number: HTB-22) were purchased from Shanghai Cell Bank and tested negative for mycoplasma contamination.	('CCL', 'molecular_function', 'GO:0044101', ('53', '56'))	('HEK293T', 'Var', (0, 7))	('CCL-2', 'Gene', '6347', (53, 58))	('MCF7', 'CellLine', 'CVCL:0031', (64, 68))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('CCL-2', 'Gene', (53, 58))	('HeLa', 'CellLine', 'CVCL:0030', (34, 38))	('mycoplasma', 'Disease', (154, 164))	('mycoplasma', 'Disease', 'MESH:D009175', (154, 164))
150274	31175280	Approximately 106 treated cells were suspended in cold 70% ethanol for 3 h, and incubated for 1 h at 37  C in PBS with DNase-free RNase A (100 mg mL-1) and propidium iodide (50 mg mL-1).	('RNase A', 'Gene', '6035', (130, 137))	('mL-1', 'Gene', (146, 150))	('propidium iodide', 'Chemical', 'MESH:D011419', (156, 172))	('mL-1', 'Gene', (180, 184))	('100', 'Var', (139, 142))	('mL-1', 'Gene', '23961', (180, 184))	('mL-1', 'Gene', '23961', (146, 150))	('RNase A', 'Gene', (130, 137))	('PBS', 'Chemical', 'MESH:D007854', (110, 113))	('ethanol', 'Chemical', 'MESH:D000431', (59, 66))
150309	32460168	We found that LATS1 interacted with Cullin3, and depletion of Cullin 3 upregulated the abundance of LATS1 largely via prolonging LATS1 protein half-life.	('abundance', 'MPA', (87, 96))	('LATS1 protein', 'Protein', (129, 142))	('Cullin 3', 'Gene', (62, 70))	('prolonging', 'PosReg', (118, 128))	('Cullin3', 'Gene', (36, 43))	('Cullin3', 'Gene', '8452', (36, 43))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('LATS1', 'Gene', (100, 105))	('Cullin 3', 'Gene', '8452', (62, 70))	('depletion', 'Var', (49, 58))	('upregulated', 'PosReg', (71, 82))
150311	32460168	Furthermore, SPOP also promoted kidney cancer cell invasion via degrading LATS1.	('SPOP', 'Var', (13, 17))	('kidney cancer', 'Disease', (32, 45))	('promoted', 'PosReg', (23, 31))	('LATS1', 'MPA', (74, 79))	('degrading', 'NegReg', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('kidney cancer', 'Disease', 'MESH:D007680', (32, 45))	('kidney cancer', 'Phenotype', 'HP:0009726', (32, 45))
150386	32460168	Firstly, we detected that proteasome inhibitor MG132 could stabilize the endogenous LATS1 protein level (Fig.	('stabilize', 'MPA', (59, 68))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('proteasome', 'cellular_component', 'GO:0000502', ('26', '36'))	('proteasome', 'molecular_function', 'GO:0004299', ('26', '36'))	('endogenous LATS1 protein level', 'MPA', (73, 103))	('MG132', 'Var', (47, 52))	('MG132', 'Chemical', 'MESH:C072553', (47, 52))
150396	32460168	Moreover, either loss of MATH or BTB domain of SPOP prevented the degradation of LATS1 (Supplementary Fig.	('BTB', 'Chemical', '-', (33, 36))	('BTB domain', 'molecular_function', 'GO:0031208', ('33', '43'))	('degradation', 'biological_process', 'GO:0009056', ('66', '77'))	('prevented', 'NegReg', (52, 61))	('BTB domain', 'Var', (33, 43))	('SPOP', 'Gene', (47, 51))	('loss', 'Var', (17, 21))	('degradation', 'MPA', (66, 77))	('LATS1', 'Protein', (81, 86))
150397	32460168	Mutagenesis studies demonstrated that the serine 336-to alanine mutation (S336A) in DeltaDeg1 rarely attenuated the interaction of LATS1 with SPOP, but mutating Ser334, Ser335, Ser336 to alanine (LATS1-3A) dramatically attenuated the interaction of LATS1 with SPOP in cells (Fig.	('Ser336 to alanine', 'SUBSTITUTION', 'None', (177, 194))	('attenuated', 'NegReg', (219, 229))	('Mutagenesis', 'biological_process', 'GO:0006280', ('0', '11'))	('Ser', 'cellular_component', 'GO:0005790', ('177', '180'))	('serine 336-to alanine', 'Mutation', 'p.S336A', (42, 63))	('Ser', 'cellular_component', 'GO:0005790', ('161', '164'))	('interaction', 'Interaction', (234, 245))	('Ser', 'cellular_component', 'GO:0005790', ('169', '172'))	('S336A', 'Mutation', 'p.S336A', (74, 79))	('DeltaDeg1', 'Gene', (84, 93))	('mutating Ser334', 'Var', (152, 167))	('Ser336 to alanine', 'Var', (177, 194))	('attenuated', 'NegReg', (101, 111))	('Ser334', 'Chemical', '-', (161, 167))	('Ser334', 'Var', (161, 167))	('interaction', 'Interaction', (116, 127))
150402	32460168	Moreover, depletion of CKIotadelta with its siRNA or inhibitors, D4476 and IC261, dramatically elevated the protein level of LATS1 in cells (Fig.	('CKIotadelta', 'Chemical', '-', (23, 34))	('LATS1', 'MPA', (125, 130))	('elevated', 'PosReg', (95, 103))	('protein level', 'MPA', (108, 121))	('depletion', 'MPA', (10, 19))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('D4476', 'Var', (65, 70))	('D4476', 'Chemical', 'MESH:C493177', (65, 70))	('IC261', 'Var', (75, 80))
150404	32460168	Moreover, the LATS1-DeltaDeg1+2 and LATS1-3A mutant, but not the LATS1-S336A, exhibited resistance to CKIotadelta-mediated LATS1 degradation (Fig.	('CKIotadelta', 'Chemical', '-', (102, 113))	('CKIotadelta-mediated LATS1 degradation', 'MPA', (102, 140))	('resistance', 'MPA', (88, 98))	('S336A', 'Mutation', 'p.S336A', (71, 76))	('LATS1-3A', 'Gene', (36, 44))	('LATS1-DeltaDeg1+2', 'Var', (14, 31))	('degradation', 'biological_process', 'GO:0009056', ('129', '140'))
150413	32460168	It has been previously reported that ectopic expression of LATS1 induced cells at G2/M arrest.	('ectopic expression', 'Var', (37, 55))	('M arrest', 'Disease', (85, 93))	('M arrest', 'Disease', 'MESH:D006323', (85, 93))	('LATS1', 'Gene', (59, 64))	('induced', 'Reg', (65, 72))
150415	32460168	In keeping with a possible role of SPOP in regulating cell cycle via LATS1, we found that co-expression with CKIotadelta suppressed LATS1-WT-mediated G2/M arrest (Supplementary Fig.	('M arrest', 'Disease', 'MESH:D006323', (153, 161))	('CKIotadelta', 'Var', (109, 120))	('cell cycle', 'biological_process', 'GO:0007049', ('54', '64'))	('M arrest', 'Disease', (153, 161))	('suppressed', 'NegReg', (121, 131))	('CKIotadelta', 'Chemical', '-', (109, 120))
150416	32460168	Moreover, co-expression with SPOP suppressed LATS1-WT, but not DeltaDeg1+2, -mediated G2/M arrest (Supplementary Fig.	('suppressed', 'NegReg', (34, 44))	('co-expression', 'Var', (10, 23))	('SPOP', 'Gene', (29, 33))	('M arrest', 'Disease', 'MESH:D006323', (89, 97))	('LATS1-WT', 'MPA', (45, 53))	('M arrest', 'Disease', (89, 97))
150417	32460168	These findings are consistent with the expression of LATS1 and its downstream targets, YAP and TAZ in cells after dysregulation of SPOP and LATS1 (Supplementary Fig.	('LATS1', 'Gene', (53, 58))	('YAP', 'Gene', (87, 90))	('LATS1', 'Gene', (140, 145))	('dysregulation', 'Var', (114, 127))	('YAP', 'Gene', '10413', (87, 90))
150430	32460168	Another study revealed that lncRNA01638 impeded SPOP-involved c-Myc degradation in breast cancer.	('c-Myc', 'Gene', '4609', (62, 67))	('impeded', 'NegReg', (40, 47))	('c-Myc', 'Gene', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('lncRNA01638', 'Chemical', '-', (28, 39))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('lncRNA01638', 'Var', (28, 39))	('breast cancer', 'Disease', (83, 96))	('degradation', 'biological_process', 'GO:0009056', ('68', '79'))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))
150478	29805765	One of the characteristic features of ccRCC is the frequently mutated von Hippel-Lindau (VHL) gene, found within ~50% of ccRCC tumors, or loss of the short arm of chromosome 3.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('chromosome', 'cellular_component', 'GO:0005694', ('163', '173'))	('RCC tumors', 'Disease', 'MESH:C538614', (123, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('von Hippel-Lindau', 'Gene', (70, 87))	('VHL', 'Gene', (89, 92))	('RCC', 'Disease', (40, 43))	('short arm', 'Phenotype', 'HP:0009824', (150, 159))	('RCC', 'Disease', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('VHL', 'Gene', '7428', (89, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('RCC tumors', 'Disease', (123, 133))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (121, 126))	('von Hippel-Lindau', 'Gene', '7428', (70, 87))	('mutated', 'Var', (62, 69))
150484	29805765	Aberrant transcript isoforms from altered transcription initiation, termination and RNA processing (including altered alternative splicing) are well-documented phenomena found within many cancers.	('splicing', 'biological_process', 'GO:0045292', ('130', '138'))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('altered', 'Var', (34, 41))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('transcription', 'biological_process', 'GO:0006351', ('42', '55'))	('cancers', 'Disease', (188, 195))	('transcription initiation', 'MPA', (42, 66))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('RNA processing', 'MPA', (84, 98))	('termination', 'MPA', (68, 79))	('RNA', 'cellular_component', 'GO:0005562', ('84', '87'))	('RNA processing', 'biological_process', 'GO:0006396', ('84', '98'))
150485	29805765	In a recent example, inactivation of a histone methyltransferase, known as SET domain containing 2 (SETD2), was discovered to be one of the inciting causes of widespread transcriptional read-through and abnormal RNA chimera production found in ccRCC.	('read-through', 'PosReg', (186, 198))	('inactivation', 'Var', (21, 33))	('transcriptional', 'MPA', (170, 185))	('RCC', 'Disease', 'MESH:C538614', (246, 249))	('RCC', 'Disease', (246, 249))	('ccRCC', 'Phenotype', 'HP:0006770', (244, 249))	('RNA', 'cellular_component', 'GO:0005562', ('212', '215'))	('SETD2', 'Gene', '29072', (100, 105))	('RNA chimera', 'CPA', (212, 223))	('SETD2', 'Gene', (100, 105))
150489	29805765	For example, DTU can frequently result in isoform-switching, in which the major isoform (most abundant) "switches" with an alternative transcript, and thereby that isoform is longer the major isoform of that particular gene.	('isoform-switching', 'Disease', (42, 59))	('DTU', 'Chemical', '-', (13, 16))	('result', 'Reg', (32, 38))	('DTU', 'Var', (13, 16))
150504	29805765	As mutations in key epigenetic modifiers, such as SETD2, PBRM1 and BAP1, among ccRCCs have demonstrated to have significant effects on the epigenetic landscape and consequently splicing events, we compared the DETs observed in the current study against 6,207 RefSeq transcripts previously found to have defects in splicing and intron retention.	('PBRM1', 'Gene', (57, 62))	('effects', 'Reg', (124, 131))	('SETD2', 'Gene', '29072', (50, 55))	('splicing', 'biological_process', 'GO:0045292', ('177', '185'))	('SETD2', 'Gene', (50, 55))	('PBRM1', 'Gene', '55193', (57, 62))	('epigenetic', 'MPA', (139, 149))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('BAP1', 'Gene', '8314', (67, 71))	('retention', 'biological_process', 'GO:0051235', ('334', '343'))	('splicing', 'biological_process', 'GO:0045292', ('314', '322'))	('mutations', 'Var', (3, 12))	('BAP1', 'Gene', (67, 71))
150508	29805765	PHLDB2 encodes for 18 putative transcripts, and two transcripts ENST00000393923.7 and ENST00000431670.6 are downregulated in ccRCC (Supplementary Table 1).	('PHLDB2', 'Gene', '90102', (0, 6))	('ccRCC', 'Phenotype', 'HP:0006770', (125, 130))	('ENST00000393923.7', 'Var', (64, 81))	('downregulated', 'NegReg', (108, 121))	('PHLDB2', 'Gene', (0, 6))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('ENST00000431670.6', 'Var', (86, 103))
150510	29805765	ENST00000393925.7 is a slightly less abundant PHLDB2 transcript, and it is unaffected in ccRCC.	('less', 'NegReg', (32, 36))	('PHLDB2', 'Gene', (46, 52))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (89, 94))	('RCC', 'Disease', (91, 94))	('PHLDB2', 'Gene', '90102', (46, 52))	('ENST00000393925.7', 'Var', (0, 17))
150514	29805765	Using a Wilcoxon signed-rank test, ENST00000393923.7 was found to be significantly downregulated in ccRCC with a median downregulation of ~6.3 fold change.	('ENST00000393923.7', 'Var', (35, 52))	('downregulation', 'NegReg', (120, 134))	('downregulated', 'NegReg', (83, 96))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('RCC', 'Disease', (102, 105))
150538	29805765	ENST00000393676.4 has an alternative 5' end and is the most abundant FOLR1 transcript in normal renal tissue (Figure 4D); however, ENST00000393681.6 switches with ENST00000393676.4 becoming the most abundant or primary FOLR1 transcript in ccRCC.	('ENST00000393681.6', 'Var', (131, 148))	('FOLR1', 'Gene', '2348', (219, 224))	('FOLR1', 'Gene', '2348', (69, 74))	('FOLR1', 'Gene', (219, 224))	('FOLR1', 'Gene', (69, 74))	('RCC', 'Disease', 'MESH:C538614', (241, 244))	('ENST00000393676.4', 'Var', (163, 180))	('RCC', 'Disease', (241, 244))	('ccRCC', 'Phenotype', 'HP:0006770', (239, 244))
150550	29805765	As only 12 ccRCC tumors had a mutated SETD2, in the current study, our findings largely reflect SETD2-independent isoform-specific changes.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('RCC tumors', 'Disease', 'MESH:C538614', (13, 23))	('mutated', 'Var', (30, 37))	('SETD2', 'Gene', '29072', (38, 43))	('RCC tumors', 'Disease', (13, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (11, 16))	('SETD2', 'Gene', '29072', (96, 101))	('SETD2', 'Gene', (38, 43))	('SETD2', 'Gene', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
150559	29805765	While our findings show that the majority of isoform switching events involves non-primary isoforms, which is consistent with a previous result, alterations in the expression of non-primary isoforms could still be clinically relevant, as supported by the survival analyses seen with the non-primary SLC37A3 and HDLBP deregulated transcripts.	('SLC37A3', 'Gene', '84255', (299, 306))	('HDLBP', 'Gene', (311, 316))	('alterations', 'Var', (145, 156))	('HDLBP', 'Gene', '3069', (311, 316))	('SLC37A3', 'Gene', (299, 306))
150560	29805765	Recent studies have illustrated how isoform-specific alterations could be highly influential in ccRCC and other cancers.	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('alterations', 'Var', (53, 64))	('influential', 'Reg', (81, 92))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('RCC', 'Disease', (98, 101))	('cancers', 'Disease', (112, 119))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
150635	31326218	Several autosomal dominant hereditary RCC syndromes have been described, including those related to germline pathogenic variants in VHL, MET, FH, TSC1/TSC2, FLCN, SDHA/B/C/D, BAP1, CDC73, and MITF.	('autosomal dominant hereditary RCC syndromes', 'Disease', 'MESH:C538614', (8, 51))	('SDHA/B/C/D', 'Gene', (163, 173))	('TSC2', 'Gene', (151, 155))	('MET', 'Gene', (137, 140))	('FH', 'Gene', '2271', (142, 144))	('MITF', 'Gene', (192, 196))	('FLCN', 'Gene', '201163', (157, 161))	('CDC73', 'Gene', '79577', (181, 186))	('CDC73', 'Gene', (181, 186))	('FLCN', 'Gene', (157, 161))	('TSC1', 'Gene', (146, 150))	('VHL', 'Gene', (132, 135))	('BAP1', 'Gene', (175, 179))	('TSC1', 'Gene', '7248', (146, 150))	('MET', 'Gene', '79811', (137, 140))	('variants', 'Var', (120, 128))	('related', 'Reg', (89, 96))	('TSC2', 'Gene', '7249', (151, 155))	('autosomal dominant hereditary RCC syndromes', 'Disease', (8, 51))	('SDHA/B/C/D', 'Gene', '6389;285440', (163, 173))	('MITF', 'Gene', '4286', (192, 196))	('BAP1', 'Gene', '8314', (175, 179))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))
150653	31326218	Until recently, there were no large-scale studies analysing the prevalence of germline, likely pathogenic or pathogenic, variants (henceforth, referred together as "pathogenic variants") in RCC cases.	('RCC', 'Phenotype', 'HP:0005584', (190, 193))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Disease', (190, 193))	('variants', 'Var', (121, 129))
150657	31326218	In the ccRCC TCGA cohort, BAP1 germline mutations were the second most common, found in 0.8% of cases, and associated with an inherited tumour syndrome not described until 2011.	('BAP1', 'Gene', (26, 30))	('inherited tumour syndrome', 'Disease', (126, 151))	('RCC', 'Disease', 'MESH:C538614', (9, 12))	('inherited tumour syndrome', 'Disease', 'MESH:D009386', (126, 151))	('RCC', 'Disease', (9, 12))	('RCC', 'Phenotype', 'HP:0005584', (9, 12))	('associated with', 'Reg', (107, 122))	('germline mutations', 'Var', (31, 49))	('BAP1', 'Gene', '8314', (26, 30))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
150663	31326218	Another study examined the prevalence of germline pathogenic variants in patients with advanced RCC unselected for a suspicion of hereditary syndromes.	('RCC', 'Disease', (96, 99))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('patients', 'Species', '9606', (73, 81))	('variants', 'Var', (61, 69))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
150664	31326218	Of patients with non-ccRCC, 12% had a germline pathogenic variant in an RCC-associated gene.	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('pathogenic', 'Reg', (47, 57))	('variant', 'Var', (58, 65))	('patients', 'Species', '9606', (3, 11))
150673	31326218	Inactivation of VHL leads to accumulation of HIF-1 and HIF-2 and their downstream targets, which include vascular endothelial growth factor (VEGF), glucose transporter-1, platelet-derived growth factor-b, and transforming growth factor-a, which likely leads to the development of RCC.	('vascular endothelial growth factor', 'Gene', (105, 139))	('VHL', 'Gene', (16, 19))	('glucose', 'Chemical', 'MESH:D005947', (148, 155))	('VEGF', 'Gene', (141, 145))	('vascular endothelial growth factor', 'Gene', '7422', (105, 139))	('RCC', 'Disease', 'MESH:C538614', (280, 283))	('transforming growth factor-a', 'Gene', (209, 237))	('RCC', 'Disease', (280, 283))	('RCC', 'Phenotype', 'HP:0005584', (280, 283))	('VEGF', 'Gene', '7422', (141, 145))	('HIF-1 and HIF-2', 'Disease', 'MESH:C000657245', (45, 60))	('glucose transporter-1', 'MPA', (148, 169))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('171', '201'))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('105', '139'))	('accumulation', 'PosReg', (29, 41))	('Inactivation', 'Var', (0, 12))	('transforming growth factor-a', 'Gene', '7124', (209, 237))
150677	31326218	Genotype-phenotype studies have shown that the risk of pheochromocytomas is associated with missense mutations, while there are earlier age of onset of RCC, and higher risks of RCC and retinal angiomas with nonsense or frameshift mutations rather than with deletions or missense mutations.	('pheochromocytomas', 'Phenotype', 'HP:0002666', (55, 72))	('retinal angiomas', 'Disease', (185, 201))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('RCC', 'Disease', (152, 155))	('RCC', 'Disease', (177, 180))	('RCC', 'Phenotype', 'HP:0005584', (177, 180))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('pheochromocytomas', 'Disease', 'MESH:D010673', (55, 72))	('associated', 'Reg', (76, 86))	('pheochromocytomas', 'Disease', (55, 72))	('retinal angiomas', 'Disease', 'MESH:D006391', (185, 201))	('nonsense or frameshift mutations', 'Var', (207, 239))	('missense mutations', 'Var', (92, 110))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (55, 71))
150694	31326218	HLRCC is caused by mutations in FH, which encodes the Krebs cycle enzyme fumarate hydratase (FH), which catalyses the hydration of fumarate to malate.	('Krebs', 'Chemical', '-', (54, 59))	('caused by', 'Reg', (9, 18))	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('mutations', 'Var', (19, 28))	('FH', 'Gene', '2271', (93, 95))	('Krebs cycle', 'biological_process', 'GO:0006099', ('54', '65'))	('malate', 'Chemical', 'MESH:C030298', (143, 149))	('fumarate hydratase', 'Gene', '2271', (73, 91))	('FH', 'Gene', '2271', (32, 34))	('fumarate', 'Chemical', 'MESH:D005650', (73, 81))	('fumarate hydratase', 'Gene', (73, 91))	('fumarate', 'Chemical', 'MESH:D005650', (131, 139))
150696	31326218	FH inactivation leads to a pseudohypoxic state via stabilization of HIF-1 alpha through inhibition of prolyl hydroxylase.	('FH', 'Gene', '2271', (0, 2))	('inhibition', 'NegReg', (88, 98))	('HIF-1 alpha', 'Gene', (68, 79))	('pseudohypoxic state', 'MPA', (27, 46))	('inactivation', 'Var', (3, 15))	('HIF-1 alpha', 'Gene', '3091', (68, 79))	('prolyl', 'Protein', (102, 108))	('stabilization', 'MPA', (51, 64))
150708	31326218	Germline FH mutations may also be detected rarely in patients with paraganglioma/pheochromocytoma.	('paraganglioma/pheochromocytoma', 'Disease', 'MESH:D010673', (67, 97))	('patients', 'Species', '9606', (53, 61))	('mutations', 'Var', (12, 21))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (81, 97))	('FH', 'Gene', '2271', (9, 11))	('paraganglioma', 'Phenotype', 'HP:0002668', (67, 80))	('paraganglioma/pheochromocytoma', 'Disease', (67, 97))
150721	31326218	BHD is caused by mutations in the FLCN tumour suppressor gene; concomitant LOH or somatic mutations in the wild-type allele are frequently observed.	('FLCN tumour', 'Disease', 'MESH:D009369', (34, 45))	('BHD', 'Disease', (0, 3))	('FLCN tumour', 'Disease', (34, 45))	('BHD', 'Disease', 'MESH:C564185', (0, 3))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('caused by', 'Reg', (7, 16))	('mutations', 'Var', (17, 26))
150722	31326218	FLCN mutations in sporadic chromophobe RCC have not been observed to our knowledge.	('FLCN', 'Gene', (0, 4))	('FLCN', 'Gene', '201163', (0, 4))	('chromophobe RCC', 'Disease', (27, 42))	('mutations', 'Var', (5, 14))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('chromophobe RCC', 'Disease', 'MESH:C538614', (27, 42))
150735	31326218	HPRC is caused by pathogenic activating variants in the MET protooncogene, located in chromosome 7, which encodes for a receptor tyrosine kinase.	('HPRC', 'Disease', (0, 4))	('tyrosine kinase', 'Gene', (129, 144))	('MET', 'Gene', '79811', (56, 59))	('chromosome', 'cellular_component', 'GO:0005694', ('86', '96'))	('MET', 'Gene', (56, 59))	('variants', 'Var', (40, 48))	('activating', 'PosReg', (29, 39))	('tyrosine kinase', 'Gene', '7294', (129, 144))
150745	31326218	For advanced disease, the identification of activating MET mutations in patients with HPRC and sporadic papillary type 1 RCC has led to trials of MET pathway inhibitors.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('activating', 'PosReg', (44, 54))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('MET', 'Gene', '79811', (55, 58))	('MET', 'Gene', (55, 58))	('HPRC', 'Disease', (86, 90))	('MET', 'Gene', '79811', (146, 149))	('MET', 'Gene', (146, 149))	('mutations', 'Var', (59, 68))	('papillary type', 'Phenotype', 'HP:0007482', (104, 118))	('patients', 'Species', '9606', (72, 80))
150748	31326218	Pathogenic variants in the SDH genes (SDHA, SDHB, SDHC, SDHD, and SDHAF2) are associated with the development of paragangliomas, pheochromocytomas, gastrointestinal stromal tumours, and RCCs.	('paragangliomas', 'Disease', 'MESH:D010235', (113, 127))	('SDH', 'Gene', (44, 47))	('paragangliomas', 'Phenotype', 'HP:0002668', (113, 127))	('SDHAF2', 'Gene', (66, 72))	('paraganglioma', 'Phenotype', 'HP:0002668', (113, 126))	('SDHAF2', 'Gene', '54949', (66, 72))	('SDHA', 'Gene', (66, 70))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (129, 146))	('SDH', 'Gene', (27, 30))	('SDH', 'Gene', (66, 69))	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (148, 180))	('SDH', 'Gene', (50, 53))	('SDHA', 'Gene', '6389', (66, 70))	('SDHD', 'Gene', '6392', (56, 60))	('SDHB', 'Gene', '6390', (44, 48))	('variants', 'Var', (11, 19))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('SDH', 'Gene', '6390', (56, 59))	('RCC', 'Disease', (186, 189))	('SDHC', 'Gene', (50, 54))	('SDHD', 'Gene', (56, 60))	('paragangliomas', 'Disease', (113, 127))	('SDH', 'Gene', '6390', (38, 41))	('SDHA', 'Gene', (38, 42))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('SDHB', 'Gene', (44, 48))	('SDH', 'Gene', '6390', (44, 47))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (129, 145))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('SDH', 'Gene', (56, 59))	('pheochromocytomas', 'Disease', 'MESH:D010673', (129, 146))	('gastrointestinal stromal tumours', 'Disease', (148, 180))	('SDHA', 'Gene', '6389', (38, 42))	('pheochromocytomas', 'Disease', (129, 146))	('SDH', 'Gene', '6390', (27, 30))	('associated with', 'Reg', (78, 93))	('SDH', 'Gene', '6390', (66, 69))	('SDH', 'Gene', '6390', (50, 53))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('SDH', 'Gene', (38, 41))	('SDHC', 'Gene', '6391', (50, 54))
150751	31326218	Patients with SDH-deficient RCC most often have a mutation in SDHB, but mutations have also been reported in the other SDH genes.	('SDH', 'Gene', '6390', (62, 65))	('SDH', 'Gene', (119, 122))	('SDH', 'Gene', '6390', (14, 17))	('SDH', 'Gene', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (28, 31))	('SDH', 'Gene', (14, 17))	('SDH-deficient RCC', 'Disease', 'MESH:C538614', (14, 31))	('Patients', 'Species', '9606', (0, 8))	('SDH', 'Gene', '6390', (119, 122))	('SDHB', 'Gene', (62, 66))	('SDH-deficient RCC', 'Disease', (14, 31))	('SDHB', 'Gene', '6390', (62, 66))	('mutation', 'Var', (50, 58))
150754	31326218	Mutations in Krebs cycle enzymes shift the cells towards increased glucose uptake, aerobic glycolysis, and fatty acid synthesis.	('glycolysis', 'biological_process', 'GO:0006096', ('91', '101'))	('glucose uptake', 'MPA', (67, 81))	('Krebs', 'Chemical', '-', (13, 18))	('glucose', 'Chemical', 'MESH:D005947', (67, 74))	('fatty acid synthesis', 'biological_process', 'GO:0006633', ('107', '127'))	('fatty acid synthesis', 'MPA', (107, 127))	('Krebs cycle', 'biological_process', 'GO:0006099', ('13', '24'))	('Mutations', 'Var', (0, 9))	('increased glucose', 'Phenotype', 'HP:0003074', (57, 74))	('increased', 'PosReg', (57, 66))	('aerobic glycolysis', 'MPA', (83, 101))	('glucose uptake', 'biological_process', 'GO:0046323', ('67', '81'))	('fatty acid', 'Chemical', 'MESH:D005227', (107, 117))
150758	31326218	estimated the lifetime risk of developing RCC at about 5% in SDHB mutation carriers.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('SDHB', 'Gene', '6390', (61, 65))	('SDHB', 'Gene', (61, 65))	('mutation', 'Var', (66, 74))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))
150762	31326218	Loss of SDHB on IHC is a sensitive and specific marker for these neoplasms, and should prompt genetic assessment.	('SDHB', 'Gene', '6390', (8, 12))	('neoplasms', 'Disease', 'MESH:D009369', (65, 74))	('neoplasms', 'Disease', (65, 74))	('SDHB', 'Gene', (8, 12))	('neoplasms', 'Phenotype', 'HP:0002664', (65, 74))	('Loss', 'Var', (0, 4))
150763	31326218	Given the possibility of metastasis even with small tumours, RCCs in patients with SDH germline pathogenic variants should be treated similarly to HLRCC, with aggressive wide excision.	('RCC', 'Disease', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('small tumours', 'Disease', 'MESH:D009369', (46, 59))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('SDH', 'Gene', '6390', (83, 86))	('variants', 'Var', (107, 115))	('small tumours', 'Disease', (46, 59))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('SDH', 'Gene', (83, 86))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('patients', 'Species', '9606', (69, 77))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
150770	31326218	BAP1 alterations are seen in about 10-15% of sporadic ccRCCs.	('RCC', 'Disease', (56, 59))	('BAP1', 'Gene', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('alterations', 'Var', (5, 16))	('BAP1', 'Gene', '8314', (0, 4))
150771	31326218	Germline mutations in BAP1 were first linked to cancer in 2011, when studies identified increased risks of melanoma and mesothelioma.	('Germline mutations', 'Var', (0, 18))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('linked', 'Reg', (38, 44))	('melanoma', 'Disease', (107, 115))	('mesothelioma', 'Disease', (120, 132))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('mesothelioma', 'Disease', 'MESH:D008654', (120, 132))	('BAP1', 'Gene', '8314', (22, 26))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('BAP1', 'Gene', (22, 26))
150772	31326218	In 2013, several groups identified germline BAP1 mutations that cosegregated in families with multiple cases of ccRCC, showing that RCC is one of the core tumours of the syndrome.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('tumours of the syndrome', 'Disease', 'MESH:D009369', (155, 178))	('mutations', 'Var', (49, 58))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('core', 'cellular_component', 'GO:0019013', ('150', '154'))	('tumours of the syndrome', 'Disease', (155, 178))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('BAP1', 'Gene', '8314', (44, 48))	('tumours', 'Phenotype', 'HP:0002664', (155, 162))	('BAP1', 'Gene', (44, 48))
150774	31326218	The risk of RCC in BAP1 carriers is estimated at 10%, but this number may be inflated due to an ascertainment bias.	('carriers', 'Var', (24, 32))	('RCC', 'Phenotype', 'HP:0005584', (12, 15))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('BAP1', 'Gene', '8314', (19, 23))	('RCC', 'Disease', (12, 15))	('BAP1', 'Gene', (19, 23))
150778	31326218	Somatic ccRCC with BAP1 mutations is associated with a higher tumour grade and decreased survival, but whether this also applies to germline BAP1-associated RCC needs further study.	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('BAP1', 'Gene', '8314', (141, 145))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('decreased', 'NegReg', (79, 88))	('survival', 'CPA', (89, 97))	('BAP1', 'Gene', '8314', (19, 23))	('BAP1', 'Gene', (141, 145))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('mutations', 'Var', (24, 33))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('tumour', 'Disease', (62, 68))	('BAP1', 'Gene', (19, 23))	('RCC', 'Disease', (157, 160))	('RCC', 'Disease', (10, 13))	('RCC', 'Phenotype', 'HP:0005584', (10, 13))	('higher', 'PosReg', (55, 61))	('RCC', 'Disease', 'MESH:C538614', (10, 13))
150780	31326218	Although there are no evidence-based guidelines for cancer screening in individuals with germline BAP1 pathogenic variants, consensus recommendations suggest annual abdominal imaging to screen for RCC.	('BAP1', 'Gene', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('RCC', 'Phenotype', 'HP:0005584', (197, 200))	('RCC', 'Disease', 'MESH:C538614', (197, 200))	('RCC', 'Disease', (197, 200))	('variants', 'Var', (114, 122))	('BAP1', 'Gene', '8314', (98, 102))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
150782	31326218	TSC is caused by heterozygous germline pathogenic variants in TSC1 or TSC2, which act as tumour suppressors.	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('TSC2', 'Gene', '7249', (70, 74))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('TSC1', 'Gene', '7248', (62, 66))	('tumour', 'Disease', (89, 95))	('TSC2', 'Gene', (70, 74))	('variants', 'Var', (50, 58))	('TSC', 'Disease', (0, 3))	('caused by', 'Reg', (7, 16))	('TSC1', 'Gene', (62, 66))
150792	31326218	Patients with de novo disease or TSC2 mutations may be at higher risks of AML and renal cysts.	('renal cysts', 'Disease', 'MESH:D007674', (82, 93))	('AML', 'Disease', 'MESH:D015470', (74, 77))	('renal cysts', 'Disease', (82, 93))	('Patients', 'Species', '9606', (0, 8))	('TSC2', 'Gene', '7249', (33, 37))	('renal cysts', 'Phenotype', 'HP:0000107', (82, 93))	('TSC2', 'Gene', (33, 37))	('AML', 'Disease', (74, 77))	('mutations', 'Var', (38, 47))
150799	31326218	Recently reported sporadic RCCs characterised by somatic TSC1/TSC2/MTOR mutations show a morphological overlap with tumours in TSC patients.	('patients', 'Species', '9606', (131, 139))	('mutations', 'Var', (72, 81))	('MTOR', 'Gene', '2475', (67, 71))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('TSC1', 'Gene', '7248', (57, 61))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('TSC2', 'Gene', '7249', (62, 66))	('TSC2', 'Gene', (62, 66))	('MTOR', 'Gene', (67, 71))	('TSC1', 'Gene', (57, 61))	('tumours', 'Disease', 'MESH:D009369', (116, 123))	('tumours', 'Disease', (116, 123))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))
150801	31326218	In cases of lipid-rich or biopsy-proven lipid-poor AML, surveillance is the preferred method until the largest tumour reaches about 4 cm, at which point selective angioembolisation is considered.	('AML', 'Disease', (51, 54))	('lipid', 'Chemical', 'MESH:D008055', (40, 45))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('lipid-poor', 'Var', (40, 50))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('AML', 'Disease', 'MESH:D015470', (51, 54))	('tumour', 'Disease', (111, 117))	('lipid', 'Chemical', 'MESH:D008055', (12, 17))
150812	31326218	In a series of 219 prospectively accrued individuals with PTEN mutations, nine (4%) had RCC; patients with papillary RCC, chromophobe RCC, and ccRCC have been described.	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('papillary RCC', 'Disease', 'MESH:C538614', (107, 120))	('papillary RCC', 'Disease', (107, 120))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('patients', 'Species', '9606', (93, 101))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('mutations', 'Var', (63, 72))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (145, 148))	('chromophobe RCC', 'Disease', (122, 137))	('PTEN', 'Gene', (58, 62))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('PTEN', 'Gene', '5728', (58, 62))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (134, 137))	('RCC', 'Phenotype', 'HP:0005584', (134, 137))	('chromophobe RCC', 'Disease', 'MESH:C538614', (122, 137))
150813	31326218	Hereditary hyperparathyroidism jaw tumour syndrome (OMIM 145001) is an inherited autosomal dominant disorder caused by mutations in CDC73 and characterised by susceptibility to parathyroid adenomas, ossifying jaw fibromas, and renal abnormalities, most commonly renal cysts, but also ccRCC and Wilms' tumour.	('ossifying jaw fibromas', 'Disease', 'MESH:D018214', (199, 221))	('fibromas', 'Phenotype', 'HP:0010614', (213, 221))	('renal abnormalities', 'Disease', (227, 246))	('RCC', 'Disease', 'MESH:C538614', (286, 289))	('Hereditary hyperparathyroidism jaw tumour syndrome', 'Disease', 'MESH:C563273', (0, 50))	('renal cysts', 'Disease', 'MESH:D007674', (262, 273))	('parathyroid adenomas', 'Disease', (177, 197))	('parathyroid adenomas', 'Disease', 'MESH:D010282', (177, 197))	('renal cysts', 'Phenotype', 'HP:0000107', (262, 273))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (81, 108))	("Wilms' tumour", 'Disease', 'MESH:D009396', (294, 307))	('renal abnormalities', 'Phenotype', 'HP:0000077', (227, 246))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (11, 30))	('mutations', 'Var', (119, 128))	('jaw tumour', 'Phenotype', 'HP:0030792', (31, 41))	("Wilms' tumour", 'Disease', (294, 307))	('CDC73', 'Gene', (132, 137))	('parathyroid adenomas', 'Phenotype', 'HP:0002897', (177, 197))	('ossifying jaw', 'Phenotype', 'HP:0004472', (199, 212))	('CDC73', 'Gene', '79577', (132, 137))	('tumour', 'Phenotype', 'HP:0002664', (301, 307))	('autosomal dominant disorder', 'Disease', (81, 108))	('renal abnormalities', 'Disease', 'MESH:D007674', (227, 246))	('RCC', 'Phenotype', 'HP:0005584', (286, 289))	('RCC', 'Disease', (286, 289))	('renal cysts', 'Disease', (262, 273))	('caused by', 'Reg', (109, 118))	('Hereditary hyperparathyroidism jaw tumour syndrome', 'Disease', (0, 50))	('ossifying jaw fibromas', 'Disease', (199, 221))
150814	31326218	The MITF E318K variant has been linked to a fivefold increased risk of melanoma or RCC or both cancers.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('MITF', 'Gene', '4286', (4, 8))	('MITF', 'Gene', (4, 8))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('E318K', 'Mutation', 'rs149617956', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('E318K', 'Var', (9, 14))
150824	32033228	Along with the conventional treatment, such as chemotherapy and radiotherapy, targeted therapy has greater impact in cancer management.	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('targeted', 'Var', (78, 86))
150831	32033228	Aberrant post-translational modifications such as phosphorylation may drive numerous fundamental biological processes which may lead to tumor initiation and progression.	('tumor initiation', 'Disease', (136, 152))	('phosphorylation', 'MPA', (50, 65))	('Aberrant', 'Var', (0, 8))	('drive', 'Reg', (70, 75))	('phosphorylation', 'biological_process', 'GO:0016310', ('50', '65'))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor initiation', 'Disease', 'MESH:D009369', (136, 152))	('lead to', 'Reg', (128, 135))
150876	32033228	Mutations in these kinases often lead to the constitutive kinase activity followed by cellular aberrations and tumorigenesis.	('cellular aberrations', 'CPA', (86, 106))	('lead to', 'Reg', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('constitutive kinase activity', 'MPA', (45, 73))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('Mutations', 'Var', (0, 9))	('kinase activity', 'molecular_function', 'GO:0016301', ('58', '73'))
150881	32033228	With a combined integrative and bioinformatics approach, we identified the dysregulation in the cell cycle pathway and predicted the activation of NEK2 and AURKA across breast cancer, colon cancer, LUAD, ovarian cancer, and UCEC.	('cell cycle', 'biological_process', 'GO:0007049', ('96', '106'))	('ovarian cancer', 'Disease', (204, 218))	('NEK2', 'Gene', (147, 151))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('AURKA', 'Gene', '6790', (156, 161))	('ovarian cancer', 'Phenotype', 'HP:0100615', (204, 218))	('AURKA', 'Gene', (156, 161))	('colon cancer', 'Phenotype', 'HP:0003003', (184, 196))	('LUAD', 'Disease', 'MESH:D000077192', (198, 202))	('dysregulation', 'Var', (75, 88))	('NEK2', 'Gene', '4751', (147, 151))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cell cycle pathway', 'Pathway', (96, 114))	('colon cancer', 'Disease', 'MESH:D015179', (184, 196))	('UCEC', 'Disease', (224, 228))	('LUAD', 'Disease', (198, 202))	('ovarian cancer', 'Disease', 'MESH:D010051', (204, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('colon cancer', 'Disease', (184, 196))	('activation', 'PosReg', (133, 143))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('breast cancer', 'Disease', (169, 182))
150898	32033228	We also identified the dysregulation of RNA metabolism pathway across five cancer types.	('RNA metabolism', 'biological_process', 'GO:0016070', ('40', '54'))	('dysregulation', 'Var', (23, 36))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('RNA metabolism pathway', 'Pathway', (40, 62))
150906	32033228	The activation of NEK2 is through the phosphorylation on its auto-phosphorylation sites such as (T170/S171 and T175).	('T170/S171', 'Var', (97, 106))	('phosphorylation', 'MPA', (38, 53))	('NEK2', 'Gene', (18, 22))	('phosphorylation', 'biological_process', 'GO:0016310', ('66', '81'))	('NEK2', 'Gene', '4751', (18, 22))	('phosphorylation', 'biological_process', 'GO:0016310', ('38', '53'))	('T175', 'Var', (111, 115))	('activation', 'PosReg', (4, 14))
150911	32033228	Moreover, we observed that high grade breast cancer patients and lung adenocarcinoma patients with a high AURKA and NEK2 gene expression had a significant poor overall survival.	('AURKA', 'Gene', (106, 111))	('NEK2', 'Gene', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (65, 84))	('NEK2', 'Gene', '4751', (116, 120))	('breast cancer', 'Disease', (38, 51))	('patients', 'Species', '9606', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (65, 84))	('AURKA', 'Gene', '6790', (106, 111))	('high', 'Var', (101, 105))	('gene expression', 'biological_process', 'GO:0010467', ('121', '136'))	('poor', 'NegReg', (155, 159))	('patients', 'Species', '9606', (52, 60))	('lung adenocarcinoma', 'Disease', (65, 84))
150945	30093597	Furthermore, we studied the earliest precursor lesions of ccRCC: CA9+ proximal tubular cells residing in morphologically normal kidney, predisposed to ccRCC through pathogenic germline mutation of VHL.	('VHL', 'Disease', 'MESH:D006623', (197, 200))	('germline mutation', 'Var', (176, 193))	('ccRCC', 'Disease', (151, 156))	('VHL', 'Disease', (197, 200))
150953	30093597	S18A) exhibited lymphangiogenic VEGFC and FLT1.	('VEGFC', 'Gene', '7424', (32, 37))	('S18A', 'Var', (0, 4))	('S18A', 'SUBSTITUTION', 'None', (0, 4))	('VEGFC', 'Gene', (32, 37))
150992	28414866	To determine the utility of the International mRCC Database Consortium (IMDC) prognostic model in pRCC, patients were stratified into risk groups based on the IMDC prognostic factors: hemoglobin below the lower limit of normal (LLN), corrected calcium greater than the upper limit of normal (ULN), neutrophils above ULN, platelets above ULN, Karnofsky performance status (KPS) below 80%, and time from diagnosis to treatment of <1 year 12.	('below', 'NegReg', (195, 200))	('below', 'NegReg', (377, 382))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('hemoglobin', 'MPA', (184, 194))	('pRCC', 'Gene', (98, 102))	('Karnofsky performance status', 'CPA', (342, 370))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('platelets', 'CPA', (321, 330))	('RCC', 'Disease', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('pRCC', 'Gene', '5546', (98, 102))	('pRCC', 'Phenotype', 'HP:0006766', (98, 102))	('calcium', 'Chemical', 'MESH:D002118', (244, 251))	('corrected calcium', 'MPA', (234, 251))	('patients', 'Species', '9606', (104, 112))	('neutrophils', 'Var', (298, 309))
151020	28414866	Only two clinical trials, SUPAP (NCT00541008) and RAPTOR (NCT00688753), have enrolled pRCC patients by subtype, but each enrolled only 15 and 13 type I patients, respectively 19, 20.	('NCT00541008', 'Var', (33, 44))	('patients', 'Species', '9606', (91, 99))	('pRCC', 'Phenotype', 'HP:0006766', (86, 90))	('pRCC', 'Gene', '5546', (86, 90))	('RAPTOR', 'Gene', (50, 56))	('RAPTOR', 'Gene', '57521', (50, 56))	('NCT00688753', 'Var', (58, 69))	('pRCC', 'Gene', (86, 90))	('patients', 'Species', '9606', (152, 160))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
151032	28414866	ASPEN included 70 pRCC patients and found sunitinib to have a higher ORR (24% vs. 5%) and a longer median PFS (8.1 months vs. 5.5 months) than everolimus, but reported no difference in OS 27.	('sunitinib', 'Var', (42, 51))	('pRCC', 'Gene', '5546', (18, 22))	('sunitinib', 'Chemical', 'MESH:D000077210', (42, 51))	('patients', 'Species', '9606', (23, 31))	('pRCC', 'Phenotype', 'HP:0006766', (18, 22))	('PFS', 'MPA', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('ORR', 'MPA', (69, 72))	('pRCC', 'Gene', (18, 22))	('higher', 'PosReg', (62, 68))	('everolimus', 'Chemical', 'MESH:D000068338', (143, 153))
151044	28414866	MET pathway alterations were traditionally associated with type I pRCC, however recent studies have identified that type II pRCCs can also display high-MET expression 4, 5.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('pRCC', 'Phenotype', 'HP:0006766', (124, 128))	('pRCC', 'Gene', '5546', (124, 128))	('pRCC', 'Gene', '5546', (66, 70))	('alterations', 'Var', (12, 23))	('pRCC', 'Phenotype', 'HP:0006766', (66, 70))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('type', 'Disease', (116, 120))	('pRCC', 'Gene', (124, 128))	('pRCC', 'Gene', (66, 70))	('MET pathway', 'Pathway', (0, 11))	('high-MET expression', 'MPA', (147, 166))
151062	32021450	NSD2 expression could discriminate ccRCC samples from normal samples, and moreover, high NSD2 expression was characterized with a short overall survival (OS) time.	('ccRCC', 'Disease', 'MESH:D002292', (35, 40))	('high', 'Var', (84, 88))	('NSD2', 'Gene', (89, 93))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('expression', 'MPA', (94, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (35, 40))	('ccRCC', 'Disease', (35, 40))	('overall survival', 'CPA', (136, 152))
151063	32021450	Additionally, knockdown of NSD2 suppressed proliferation and induced apoptosis of cancer cells by inhibiting Akt/Erk signaling and regulating Bcl-2 and Bax expression.	('Bcl-2', 'Gene', '596', (142, 147))	('cancer', 'Disease', (82, 88))	('Erk', 'Gene', (113, 116))	('apoptosis', 'CPA', (69, 78))	('Akt', 'Gene', (109, 112))	('Bcl-2', 'molecular_function', 'GO:0015283', ('142', '147'))	('Erk', 'Gene', '5594', (113, 116))	('inhibiting', 'NegReg', (98, 108))	('suppressed', 'NegReg', (32, 42))	('apoptosis', 'biological_process', 'GO:0097194', ('69', '78'))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Bax', 'Gene', (152, 155))	('Akt', 'Gene', '207', (109, 112))	('expression', 'MPA', (156, 166))	('apoptosis', 'biological_process', 'GO:0006915', ('69', '78'))	('Erk', 'molecular_function', 'GO:0004707', ('113', '116'))	('Bax', 'Gene', '581', (152, 155))	('regulating', 'Reg', (131, 141))	('NSD2', 'Gene', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('proliferation', 'CPA', (43, 56))	('Bcl-2', 'Gene', (142, 147))	('induced', 'Reg', (61, 68))	('knockdown', 'Var', (14, 23))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))
151064	32021450	Silencing of NSD2 reduced xenograft tumor growth in vivo.	('NSD2', 'Gene', (13, 17))	('reduced', 'NegReg', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', (36, 41))
151069	32021450	Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cancers, which is often characterized by 3p loss that harbors mutational inactivation or hypermethylation of the tumor suppressor gene VHL.	('ccRCC', 'Disease', (33, 38))	('renal cancers', 'Disease', (83, 96))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('202', '218'))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (0, 31))	('tumor', 'Disease', (202, 207))	('VHL', 'Disease', (224, 227))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('renal cancer', 'Phenotype', 'HP:0009726', (83, 95))	('tumor suppressor', 'biological_process', 'GO:0051726', ('202', '218'))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('renal cancers', 'Disease', 'MESH:D007680', (83, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('mutational inactivation', 'Var', (151, 174))	('hypermethylation', 'Var', (178, 194))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('ccRCC', 'Disease', 'MESH:D002292', (33, 38))	('VHL', 'Disease', 'MESH:D006623', (224, 227))
151072	32021450	Over the past decades, the protein members have been reported to be involved in chromatin integrity and gene expression through mono- or di-methylating lysine 36 of histone H3 (H3K36).	('mono-', 'Var', (128, 133))	('lysine', 'Chemical', 'MESH:C114808', (152, 158))	('involved', 'Reg', (68, 76))	('di-methylating', 'Var', (137, 151))	('chromatin', 'cellular_component', 'GO:0000785', ('80', '89'))	('gene expression', 'biological_process', 'GO:0010467', ('104', '119'))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))
151124	32021450	Here, Western blot analysis revealed that silencing of NSD2 could repress the expression of p-Akt, p-Erk1/2, Bcl-2, and enhance Bax at protein level, but not alter total Akt and Erk1/2 expression in 786-O and ACHN cells (Figure 5A).	('enhance', 'PosReg', (120, 127))	('Akt', 'Gene', (94, 97))	('NSD2', 'Gene', (55, 59))	('Erk1/2', 'Gene', '5595;5594', (101, 107))	('ACHN', 'Gene', (209, 213))	('Akt', 'Gene', '207', (94, 97))	('Bcl-2', 'Gene', (109, 114))	('Bcl-2', 'molecular_function', 'GO:0015283', ('109', '114'))	('Bax', 'Gene', (128, 131))	('Erk1/2', 'Gene', '5595;5594', (178, 184))	('repress', 'NegReg', (66, 73))	('Bax', 'Gene', '581', (128, 131))	('Erk1', 'molecular_function', 'GO:0004707', ('101', '105'))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('Bcl-2', 'Gene', '596', (109, 114))	('ACHN', 'Gene', '55323', (209, 213))	('Akt', 'Gene', (170, 173))	('Akt', 'Gene', '207', (170, 173))	('Erk1/2', 'Gene', (101, 107))	('silencing', 'Var', (42, 51))	('expression', 'MPA', (78, 88))	('Erk1/2', 'Gene', (178, 184))	('Erk1', 'molecular_function', 'GO:0004707', ('178', '182'))
151129	32021450	The results showed that knockdown of NSD2 would reduce tumor growth in vivo, compared with control group (Figure 6B), as manifested by decreased tumor volume and weight (Figure 6C and D).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', (145, 150))	('reduce', 'NegReg', (48, 54))	('decreased', 'NegReg', (135, 144))	('knockdown', 'Var', (24, 33))	('NSD2', 'Gene', (37, 41))
151147	32021450	Thus, the results demonstrated that NSD2 would facilitate ccRCC carcinogenesis via stimulation of Akt/Erk signaling and regulation of Bcl-2 and Bax expression.	('Erk', 'molecular_function', 'GO:0004707', ('102', '105'))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('Bcl-2', 'Gene', '596', (134, 139))	('Bcl-2', 'molecular_function', 'GO:0015283', ('134', '139'))	('Bax', 'Gene', (144, 147))	('regulation', 'biological_process', 'GO:0065007', ('120', '130'))	('Bax', 'Gene', '581', (144, 147))	('NSD2', 'Var', (36, 40))	('Akt', 'Gene', (98, 101))	('facilitate', 'PosReg', (47, 57))	('ccRCC', 'Disease', 'MESH:D002292', (58, 63))	('Erk', 'Gene', (102, 105))	('Erk', 'Gene', '5594', (102, 105))	('Akt', 'Gene', '207', (98, 101))	('ccRCC', 'Disease', (58, 63))	('stimulation', 'PosReg', (83, 94))	('expression', 'MPA', (148, 158))	('Bcl-2', 'Gene', (134, 139))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))
151156	31402955	High Lamin-B1 expression was associated with poor clinical outcomes and multivariate Cox regression analyses revealed that Lamin-B1 was an independent prognostic factor for cancer-specific survival.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('High', 'Var', (0, 4))	('Cox', 'Gene', (85, 88))	('cancer', 'Disease', (173, 179))	('Lamin-B1', 'Gene', (5, 13))	('Lamin-B1', 'Gene', '4001', (5, 13))	('Lamin-B1', 'Gene', '4001', (123, 131))	('expression', 'MPA', (14, 24))	('Lamin-B1', 'Gene', (123, 131))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('Cox', 'Gene', '1351', (85, 88))
151158	31402955	In conclusion, patients affected by ccRCC with high Lamin-B1 expression exhibit poor prognosis.	('RCC', 'Disease', (38, 41))	('patients', 'Species', '9606', (15, 23))	('Lamin-B1', 'Gene', (52, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('high', 'Var', (47, 51))	('Lamin-B1', 'Gene', '4001', (52, 60))	('expression', 'MPA', (61, 71))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
151160	31402955	Clear-cell renal cell carcinoma (ccRCC) comprises the majority of malignant tumors in the kidneys and inactivation of the von Hippel-Lindau (VHL) gene is the driving force in ccRCC tumorigenesis.	('inactivation', 'Var', (102, 114))	('tumor', 'Disease', (76, 81))	('Clear-cell renal cell carcinoma', 'Disease', (0, 31))	('Clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('RCC', 'Disease', (35, 38))	('VHL', 'Gene', '7428', (141, 144))	('RCC', 'Disease', (177, 180))	('ccRCC', 'Phenotype', 'HP:0006770', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('malignant tumors', 'Disease', 'MESH:D018198', (66, 82))	('von Hippel-Lindau', 'Gene', (122, 139))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('malignant tumors', 'Disease', (66, 82))	('Clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('tumor', 'Disease', (181, 186))	('von Hippel-Lindau', 'Gene', '7428', (122, 139))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('malignant tumors in the kidneys', 'Phenotype', 'HP:0009726', (66, 97))	('VHL', 'Gene', (141, 144))
151162	31402955	VHL inactivation results in stabilization of hypoxia-inducible factor (HIF), which activates many downstream hypoxia-driven genes, including vascular endothelial growth factor and other genes involved in angiogenesis.	('activates', 'PosReg', (83, 92))	('angiogenesis', 'biological_process', 'GO:0001525', ('204', '216'))	('inactivation', 'Var', (4, 16))	('hypoxia', 'Disease', (109, 116))	('hypoxia', 'Disease', 'MESH:D000860', (109, 116))	('VHL', 'Gene', (0, 3))	('vascular endothelial growth factor', 'Gene', (141, 175))	('hypoxia', 'Disease', (45, 52))	('hypoxia', 'Disease', 'MESH:D000860', (45, 52))	('stabilization', 'MPA', (28, 41))	('VHL', 'Gene', '7428', (0, 3))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('141', '175'))	('vascular endothelial growth factor', 'Gene', '7422', (141, 175))
151166	31402955	The induction of senescence via the inactivation of tumor-suppressor genes has also been shown for neurofibromin 1 and PTEN, and also via the activation of oncogenes such as RAS and BRAF.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('RAS', 'Gene', (174, 177))	('activation', 'PosReg', (142, 152))	('tumor', 'Disease', (52, 57))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('52', '68'))	('senescence', 'MPA', (17, 27))	('senescence', 'biological_process', 'GO:0010149', ('17', '27'))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('52', '68'))	('PTEN', 'Gene', (119, 123))	('neurofibromin 1', 'Gene', '4763', (99, 114))	('BRAF', 'Gene', '673', (182, 186))	('PTEN', 'Gene', '5728', (119, 123))	('inactivation', 'Var', (36, 48))	('BRAF', 'Gene', (182, 186))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('neurofibromin 1', 'Gene', (99, 114))
151171	31402955	In addition, silencing LMNB1 expression decreases proliferation and induces premature senescence in human diploid fibroblasts.	('induces', 'Reg', (68, 75))	('LMNB1', 'Gene', (23, 28))	('proliferation', 'CPA', (50, 63))	('human', 'Species', '9606', (100, 105))	('LMNB1', 'Gene', '4001', (23, 28))	('premature', 'MPA', (76, 85))	('decreases', 'NegReg', (40, 49))	('silencing', 'Var', (13, 22))	('senescence', 'biological_process', 'GO:0010149', ('86', '96'))
151172	31402955	Furthermore, adult-onset autosomal dominant leukodystrophy, a slow progressive neurological disorder characterized by symmetrical widespread myelin loss in the central nervous system, is caused by LMNB1 duplications resulting in increased gene expression in brain tissue.	('gene expression', 'biological_process', 'GO:0010467', ('239', '254'))	('autosomal dominant leukodystrophy', 'Disease', (25, 58))	('LMNB1', 'Gene', (197, 202))	('loss in the central nervous system', 'Phenotype', 'HP:0002529', (148, 182))	('loss', 'NegReg', (148, 152))	('gene expression', 'MPA', (239, 254))	('caused by', 'Reg', (187, 196))	('progressive neurological disorder', 'Phenotype', 'HP:0002180', (67, 100))	('increased', 'PosReg', (229, 238))	('leukodystrophy', 'Phenotype', 'HP:0002415', (44, 58))	('duplications', 'Var', (203, 215))	('LMNB1', 'Gene', '4001', (197, 202))	('neurological disorder', 'Phenotype', 'HP:0000707', (79, 100))	('autosomal dominant leukodystrophy', 'Disease', 'MESH:D007966', (25, 58))	('neurological disorder', 'Disease', (79, 100))	('neurological disorder', 'Disease', 'MESH:D009422', (79, 100))
151199	31402955	LMNB1 protein expression was dichotomized utilizing the Charite Cut-off finder functions to provide a significant distinction between the high and low LMNB1 protein expression levels based on survival outcome.	('LMNB1', 'Gene', '4001', (151, 156))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('LMNB1', 'Gene', '4001', (0, 5))	('LMNB1', 'Gene', (0, 5))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('low', 'NegReg', (147, 150))	('LMNB1', 'Gene', (151, 156))	('high', 'Var', (138, 142))
151229	31402955	In agreement with this biological function, the present study identified high LMNB1 expression as an unfavorable prognostic marker in ccRCC patients.	('LMNB1', 'Gene', (78, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('patients', 'Species', '9606', (140, 148))	('LMNB1', 'Gene', '4001', (78, 83))	('high', 'Var', (73, 77))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))
151233	31402955	RCCs with high LMNB1 expression predominantly exhibited higher proliferation rates when compared with those with low LMNB1 expression (Fig.	('LMNB1', 'Gene', '4001', (117, 122))	('LMNB1', 'Gene', (15, 20))	('proliferation rates', 'CPA', (63, 82))	('LMNB1', 'Gene', '4001', (15, 20))	('LMNB1', 'Gene', (117, 122))	('high', 'Var', (10, 14))	('expression', 'Var', (21, 31))	('higher', 'PosReg', (56, 62))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('RCC', 'Disease', (0, 3))
151236	31402955	In recent years, therapeutic approaches such as p53 reactivation, inhibition of c-MYC in p53- or c-MYC-driven tumors, or treatment with cyclin-dependent kinase inhibitors have proven effective by invoking a senescence response.	('p53', 'Gene', (48, 51))	('senescence', 'biological_process', 'GO:0010149', ('207', '217'))	('c-MYC', 'Gene', '4609', (80, 85))	('cyclin', 'molecular_function', 'GO:0016538', ('136', '142'))	('p53', 'Gene', '7157', (48, 51))	('c-MYC', 'Gene', (80, 85))	('c-MYC', 'Gene', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('inhibition', 'Var', (66, 76))	('p53', 'Gene', (89, 92))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('invoking', 'Reg', (196, 204))	('c-MYC', 'Gene', '4609', (97, 102))	('senescence', 'MPA', (207, 217))	('p53', 'Gene', '7157', (89, 92))
151239	31402955	Thus, reinforcing a therapy-induced senescence therapy by adding a novel synthetic compound such as STK899704, which suppresses the proliferation of a broad range of cancer cell types, may offer a novel therapeutic strategy for patients with advanced RCC.	('cancer', 'Disease', (166, 172))	('STK899704', 'Var', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('STK', 'molecular_function', 'GO:0050359', ('100', '103'))	('patients', 'Species', '9606', (228, 236))	('senescence', 'biological_process', 'GO:0010149', ('36', '46'))	('suppresses', 'NegReg', (117, 127))	('proliferation', 'CPA', (132, 145))	('STK899704', 'CellLine', 'CVCL:8513', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('RCC', 'Disease', (251, 254))	('RCC', 'Disease', 'MESH:C538614', (251, 254))
151254	33778158	In this review, we provide evidence that pharmacological inhibition of lipid desaturation in renal cancer patients is not without risk, and that the presence of unsaturated fatty acids may be a beneficial factor in patient outcomes.	('patient', 'Species', '9606', (106, 113))	('renal cancer', 'Disease', (93, 105))	('presence', 'Var', (149, 157))	('renal cancer', 'Phenotype', 'HP:0009726', (93, 105))	('patients', 'Species', '9606', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('renal cancer', 'Disease', 'MESH:D007680', (93, 105))	('lipid', 'Chemical', 'MESH:D008055', (71, 76))	('unsaturated fatty acids', 'Chemical', 'MESH:D005231', (161, 184))	('patient', 'Species', '9606', (215, 222))
151277	33778158	However, there is still no clear evidence that the presence or absence of VHL, or mutation in the gene influences disease outcome.	('mutation', 'Var', (82, 90))	('VHL', 'Gene', (74, 77))	('influences', 'Reg', (103, 113))	('VHL', 'Gene', '7428', (74, 77))	('absence', 'NegReg', (63, 70))	('presence', 'Var', (51, 59))
151278	33778158	Studies have shown that the VHL gene (located on chromosome 3p) is mutated in 50% of early-stage and some advanced ccRCC tumors.	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('chromosome', 'cellular_component', 'GO:0005694', ('49', '59'))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('mutated', 'Var', (67, 74))	('ccRCC tumors', 'Disease', 'MESH:D009369', (115, 127))	('VHL', 'Gene', (28, 31))	('early-stage', 'Disease', (85, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('ccRCC tumors', 'Disease', (115, 127))	('VHL', 'Gene', '7428', (28, 31))
151279	33778158	Additionally, mutations have been observed across all 3 of VHL's exons, with varying degrees of association with ccRCC development.	('VHL', 'Gene', '7428', (59, 62))	('men', 'Species', '9606', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (113, 118))	('RCC', 'Disease', (115, 118))	('association', 'Interaction', (96, 107))	('VHL', 'Gene', (59, 62))	('mutations', 'Var', (14, 23))
151280	33778158	VHL gene can also be subjected to frameshift mutations (c.439del) which further implicates VHL in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('c.439del', 'Mutation', 'c.439del', (56, 64))	('VHL', 'Gene', (91, 94))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('VHL', 'Gene', '7428', (91, 94))	('c.439del', 'Var', (56, 64))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('implicates', 'Reg', (80, 90))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
151281	33778158	Early-stage ccRCC tumors with loss of heterozygosity (LOH) in the VHL gene had no other obvious chromosomal deletions which led to the conclusion that VHL mutations must occur at the primary stage of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('ccRCC', 'Phenotype', 'HP:0006770', (12, 17))	('RCC', 'Disease', (14, 17))	('mutations', 'Var', (155, 164))	('VHL', 'Gene', '7428', (151, 154))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))	('ccRCC', 'Phenotype', 'HP:0006770', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('VHL', 'Gene', (151, 154))	('ccRCC tumors', 'Disease', 'MESH:D009369', (12, 24))	('loss', 'NegReg', (30, 34))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('RCC', 'Disease', (202, 205))	('RCC', 'Phenotype', 'HP:0005584', (202, 205))	('VHL', 'Gene', '7428', (66, 69))	('VHL', 'Gene', (66, 69))	('ccRCC tumors', 'Disease', (12, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
151282	33778158	The most notable consequence of possessing deficient, or mutant, VHL proteins is the dysregulated expression of the oxygen-sensitive transcription factors HIF1alpha and HIF2 alpha, in conjunction with other transcription factors.	('VHL', 'Gene', '7428', (65, 68))	('HIF2 alpha', 'Gene', '2034', (169, 179))	('transcription', 'biological_process', 'GO:0006351', ('133', '146'))	('HIF2 alpha', 'Gene', (169, 179))	('dysregulated expression', 'MPA', (85, 108))	('HIF1alpha', 'Gene', (155, 164))	('mutant', 'Var', (57, 63))	('transcription', 'biological_process', 'GO:0006351', ('207', '220'))	('VHL', 'Gene', (65, 68))	('HIF1alpha', 'Gene', '3091', (155, 164))	('oxygen', 'Chemical', 'MESH:D010100', (116, 122))	('deficient', 'NegReg', (43, 52))
151283	33778158	This is because mutant VHL is unable to ubiquitylate HIF proteins, allowing abnormally high expression of HIF-target genes, which drive cell growth and proliferation in ccRCC.	('VHL', 'Gene', (23, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))	('drive', 'PosReg', (130, 135))	('proliferation', 'CPA', (152, 165))	('cell growth', 'CPA', (136, 147))	('cell growth', 'biological_process', 'GO:0016049', ('136', '147'))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('mutant', 'Var', (16, 22))	('VHL', 'Gene', '7428', (23, 26))	('high', 'PosReg', (87, 91))	('RCC', 'Disease', (171, 174))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('expression', 'MPA', (92, 102))
151284	33778158	Furthermore, studies show that the expression of HIF transcription factors increases the expression of lipogenic genes, which in turn increases the ability of ccRCC cells to produce fat.	('expression', 'MPA', (89, 99))	('ccRCC', 'Phenotype', 'HP:0006770', (159, 164))	('lipogenic genes', 'Gene', (103, 118))	('expression', 'Var', (35, 45))	('RCC', 'Disease', (161, 164))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('transcription', 'biological_process', 'GO:0006351', ('53', '66'))	('increases', 'PosReg', (134, 143))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('increases', 'PosReg', (75, 84))
151330	33778158	From our analysis, we found that patients with high levels of SCD1 protein have better overall survival.	('SCD1', 'Gene', (62, 66))	('patients', 'Species', '9606', (33, 41))	('overall survival', 'CPA', (87, 103))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('SCD1', 'Gene', '6319', (62, 66))	('better', 'PosReg', (80, 86))	('high levels', 'Var', (47, 58))
151365	33778158	In another study, YB-1 was expressed in immature and anaplastic multiple myeloma (MM) cells and the subsequent knockdown of YB-1, by siRNA, leading to growth arrest and induction of apoptosis in MM cell lines.	('growth arrest', 'Phenotype', 'HP:0001510', (151, 164))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('169', '191'))	('knockdown', 'Var', (111, 120))	('MM', 'Disease', 'MESH:D009101', (195, 197))	('MM', 'Disease', 'MESH:D009101', (82, 84))	('anaplastic multiple myeloma', 'Disease', 'MESH:D009101', (53, 80))	('anaplastic multiple myeloma', 'Disease', (53, 80))	('induction', 'Reg', (169, 178))	('apoptosis', 'CPA', (182, 191))	('multiple myeloma', 'Phenotype', 'HP:0006775', (64, 80))	('arrest', 'Disease', 'MESH:D006323', (158, 164))	('YB-1', 'Gene', (124, 128))	('arrest', 'Disease', (158, 164))
151377	33778158	It has also been shown to interact with other proteins of the serine/arginine (SR)-rich proteins that work in concert to process pre-mRNAs through alternative splicing.	('serine', 'Chemical', 'MESH:D012694', (62, 68))	('pre', 'molecular_function', 'GO:0003904', ('129', '132'))	('arginine', 'Chemical', 'MESH:D001120', (69, 77))	('alternative splicing', 'Var', (147, 167))	('interact', 'Interaction', (26, 34))	('splicing', 'biological_process', 'GO:0045292', ('159', '167'))
151396	33778158	Without targeted therapy directed at the tumor, the off-target effects of shutting down SCD-1 are likely going to lead to deleterious outcomes in the patient.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('patient', 'Species', '9606', (150, 157))	('tumor', 'Disease', (41, 46))	('SCD-1', 'Gene', (88, 93))	('shutting down', 'Var', (74, 87))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
151398	29137305	miR-93-3p inhibition suppresses clear cell renal cell carcinoma proliferation, metastasis and invasion miRNA dysregulation is associated with many human diseases, including cancer.	('invasion miRNA', 'CPA', (94, 108))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('human', 'Species', '9606', (147, 152))	('cancer', 'Disease', (173, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('miR-93-3p', 'Gene', (0, 9))	('miR-93-3p', 'Gene', '100126350', (0, 9))	('renal cell carcinoma', 'Disease', (43, 63))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (32, 63))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('suppresses', 'NegReg', (21, 31))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (43, 63))	('inhibition', 'Var', (10, 20))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (43, 63))	('metastasis', 'CPA', (79, 89))
151404	29137305	Like miR-93-3p inhibition, PEDF overexpression induced cell apoptosis and inhibited migration and invasion.	('inhibited', 'NegReg', (74, 83))	('miR-93-3p', 'Gene', (5, 14))	('miR-93-3p', 'Gene', '100126350', (5, 14))	('PEDF', 'Gene', '5176', (27, 31))	('overexpression', 'Var', (32, 46))	('apoptosis', 'biological_process', 'GO:0097194', ('60', '69'))	('apoptosis', 'biological_process', 'GO:0006915', ('60', '69'))	('cell apoptosis', 'CPA', (55, 69))	('PEDF', 'Gene', (27, 31))
151415	29137305	MicroRNAs (miRNAs) are a class of endogenous, small noncoding RNAs that regulate gene expression by directly degrading or inhibiting translation of target mRNAs through base pairing to partially complementary sites.	('inhibiting', 'NegReg', (122, 132))	('base', 'Var', (169, 173))	('degrading', 'NegReg', (109, 118))	('men', 'Species', '9606', (201, 204))	('translation', 'MPA', (133, 144))	('translation', 'biological_process', 'GO:0006412', ('133', '144'))	('gene expression', 'biological_process', 'GO:0010467', ('81', '96'))	('base pairing', 'molecular_function', 'GO:0003676', ('169', '181'))
151416	29137305	Dysregulation of miRNA expression and activity is associated with a variety of human diseases, and many miRNAs are potential ccRCC prognostic markers and therapeutic targets.	('human', 'Species', '9606', (79, 84))	('activity', 'MPA', (38, 46))	('Dysregulation', 'Var', (0, 13))	('ccRCC', 'Phenotype', 'HP:0006770', (125, 130))	('associated', 'Reg', (50, 60))	('miRNA', 'Protein', (17, 22))
151432	29137305	miR-93-3p transfection increased treated cell viability 1.5-2-fold over controls (H2O2 + NC), while anti-miR-93-3p again inhibited viability (Figure 2C).	('miR-93-3p', 'Gene', (105, 114))	('miR-93-3p', 'Gene', '100126350', (105, 114))	('miR-93-3p', 'Gene', (0, 9))	('miR-93-3p', 'Gene', '100126350', (0, 9))	('H2O2', 'Chemical', 'MESH:D006861', (82, 86))	('transfection', 'Var', (10, 22))	('increased', 'PosReg', (23, 32))	('treated cell viability', 'CPA', (33, 55))	('inhibited', 'NegReg', (121, 130))
151443	29137305	While 69.5+-4.0 ACHN cells and 122.8+-19.3 786-O cells traversed the matrigel-coated membrane under control conditions, anti-miR-93-3p transfection decreased these numbers to 42.5+-2.5 and 58.0+-6.4 cells, respectively (Figure 3E).	('ACHN', 'Chemical', '-', (16, 20))	('decreased', 'NegReg', (148, 157))	('coated membrane', 'cellular_component', 'GO:0048475', ('78', '93'))	('miR-93-3p', 'Gene', '100126350', (125, 134))	('miR-93-3p', 'Gene', (125, 134))	('transfection', 'Var', (135, 147))
151450	29137305	To determine whether there was a direct interaction between miR-93-3p and PEDF, the wild type or mutant PEDF 3'-UTR was inserted into the dual-luciferase reporter plasmid.	('PEDF', 'Gene', '5176', (74, 78))	('PEDF', 'Gene', (104, 108))	('miR-93-3p', 'Gene', '100126350', (60, 69))	('mutant', 'Var', (97, 103))	('miR-93-3p', 'Gene', (60, 69))	('PEDF', 'Gene', '5176', (104, 108))	('PEDF', 'Gene', (74, 78))
151452	29137305	miR-93-3p inhibited relative luciferase activity in the reporter plasmid containing the wild type, but not mutants, PEDF 3'-UTR, demonstrating that miR-93-3p directly targets PEDF (Figure 4E).	('PEDF', 'Gene', (175, 179))	('luciferase', 'Enzyme', (29, 39))	('luciferase activity', 'molecular_function', 'GO:0047077', ('29', '48'))	('PEDF', 'Gene', '5176', (116, 120))	('PEDF', 'Gene', '5176', (175, 179))	('mutants', 'Var', (107, 114))	('miR-93-3p', 'Gene', (0, 9))	('miR-93-3p', 'Gene', '100126350', (0, 9))	('inhibited', 'NegReg', (10, 19))	('luciferase activity', 'molecular_function', 'GO:0047712', ('29', '48'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('29', '48'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('29', '48'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('29', '48'))	('activity', 'MPA', (40, 48))	('miR-93-3p', 'Gene', '100126350', (148, 157))	('miR-93-3p', 'Gene', (148, 157))	('PEDF', 'Gene', (116, 120))
151454	29137305	Similar to the effects of anti-miR-93-3p, PEDF overexpression induced cell apoptosis (Figure 5A) and inhibited migration and invasion (Figure 5B-5C).	('apoptosis', 'biological_process', 'GO:0006915', ('75', '84'))	('PEDF', 'Gene', (42, 46))	('PEDF', 'Gene', '5176', (42, 46))	('miR-93-3p', 'Gene', '100126350', (31, 40))	('miR-93-3p', 'Gene', (31, 40))	('cell apoptosis', 'CPA', (70, 84))	('inhibited', 'NegReg', (101, 110))	('overexpression', 'Var', (47, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('75', '84'))
151471	29137305	The effects of miR-93-3p knockdown in ccRCC cells were abrogated by PEDF siRNA.	('miR-93-3p', 'Gene', '100126350', (15, 24))	('miR-93-3p', 'Gene', (15, 24))	('PEDF', 'Gene', '5176', (68, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('PEDF', 'Gene', (68, 72))	('knockdown', 'Var', (25, 34))
151474	29137305	Many ectopically expressed miRNAs have been shown to promote carcinogenesis by regulating tumor cell proliferation, apoptosis, and metastasis.	('carcinogenesis', 'Disease', 'MESH:D063646', (61, 75))	('apoptosis', 'biological_process', 'GO:0006915', ('116', '125'))	('metastasis', 'CPA', (131, 141))	('apoptosis', 'CPA', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('carcinogenesis', 'Disease', (61, 75))	('apoptosis', 'biological_process', 'GO:0097194', ('116', '125'))	('regulating', 'Reg', (79, 89))	('miRNAs', 'Var', (27, 33))	('cell proliferation', 'biological_process', 'GO:0008283', ('96', '114'))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('promote', 'PosReg', (53, 60))
151475	29137305	Inhibition of these miRNAs represents a new avenue for anti-cancer treatments.	('men', 'Species', '9606', (72, 75))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
151478	29137305	miRNAs also modulate renal carcinoma tumorigenesis and their expression patterns can distinguish between renal carcinoma subtypes.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('renal carcinoma subtypes', 'Disease', (105, 129))	('modulate', 'Reg', (12, 20))	('renal carcinoma', 'Disease', 'MESH:C538614', (21, 36))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('renal carcinoma', 'Phenotype', 'HP:0005584', (105, 120))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('renal carcinoma', 'Disease', (21, 36))	('renal carcinoma subtypes', 'Disease', 'MESH:C538614', (105, 129))	('miRNAs', 'Var', (0, 6))	('renal carcinoma', 'Disease', 'MESH:C538614', (105, 120))	('renal carcinoma', 'Phenotype', 'HP:0005584', (21, 36))
151518	29137305	Mutations were introduced by site-directed mutagenesis into putative binding sites in the 3'-UTR of PEDF gene for miR-93-3p using the TaKaRa MutanBEST Kit (Takara, Japan).	('PEDF', 'Gene', (100, 104))	('PEDF', 'Gene', '5176', (100, 104))	('Mutations', 'Var', (0, 9))	('mutagenesis', 'biological_process', 'GO:0006280', ('43', '54'))	('binding', 'molecular_function', 'GO:0005488', ('69', '76'))	('miR-93-3p', 'Gene', (114, 123))	('miR-93-3p', 'Gene', '100126350', (114, 123))
151543	32443497	Notably, retroperitoneal LN dissection in all cases or optimally debulked cases reduced risks of recurrence/persistence and mortality, and prolonged PFS and OS significantly (all p < 0.05).	('mortality', 'Disease', (124, 133))	('recurrence/persistence', 'MPA', (97, 119))	('retroperitoneal', 'Var', (9, 24))	('reduced', 'NegReg', (80, 87))	('PFS', 'CPA', (149, 152))	('mortality', 'Disease', 'MESH:D003643', (124, 133))
151578	32443497	In risk of mortality, it shows that LN dissection actually decreased the risk of mortality.	('mortality', 'Disease', 'MESH:D003643', (81, 90))	('decreased', 'NegReg', (59, 68))	('mortality', 'Disease', 'MESH:D003643', (11, 20))	('mortality', 'Disease', (81, 90))	('LN dissection', 'Var', (36, 49))	('mortality', 'Disease', (11, 20))
151585	32443497	However, intraperitoneal chemotherapy from GOG-172 in an optimal debulking group reduced the risk of mortality when compared with chemotherapy from GOG-158 (HR = 0.233, 95% CI = 0.057-0.95, p = 0.0421).	('mortality', 'Disease', (101, 110))	('GOG-172', 'Var', (43, 50))	('GOG-172', 'Chemical', '-', (43, 50))	('GOG-158', 'Chemical', '-', (148, 155))	('mortality', 'Disease', 'MESH:D003643', (101, 110))	('reduced', 'NegReg', (81, 88))
151637	30508956	Immunologic dysfunction has frequently accused of oncogenesis and progression of RCC as a quite proportion of patients with ccRCC harbor mutations of Janus Kinase (JAK3) gene which mediates cytokine signaling and T-cell function.	('JAK', 'molecular_function', 'GO:0004713', ('164', '167'))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('oncogenesis', 'biological_process', 'GO:0007048', ('50', '61'))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('mutations', 'Var', (137, 146))	('RCC', 'Disease', (81, 84))	('signaling', 'biological_process', 'GO:0023052', ('199', '208'))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('JAK3', 'Gene', (164, 168))	('patients', 'Species', '9606', (110, 118))	('JAK3', 'Gene', '3718', (164, 168))
151638	30508956	Besides, the cancer associated imbalance in antigen-presenting cells (i.e., dendritic cells) which normally play an antitumor effect by capturing tumor-specific antigen to regional lymphatics where tumor-specific T-cells become ready for action.	('imbalance', 'Phenotype', 'HP:0002172', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', (120, 125))	('cancer', 'Disease', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (198, 203))	('imbalance', 'Var', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
151656	30508956	However, patients with MLR >=0.21 tended to have a greater nuclear grade (P = .064).	('patients', 'Species', '9606', (9, 17))	('nuclear grade', 'CPA', (59, 72))	('greater', 'PosReg', (51, 58))	('MLR', 'Var', (23, 26))
151657	30508956	In univariate analyses, MLR >=0.21 was associated with 2.4-fold increased risk or recurrence (P = .003) and with 4.4-fold increased risk of death from the disease (P = .002).	('death', 'Disease', 'MESH:D003643', (140, 145))	('death', 'Disease', (140, 145))	('MLR >=0.21', 'Var', (24, 34))	('recurrence', 'CPA', (82, 92))
151659	30508956	MLR >=0.21 was an independent predictor of RFS (HR 2.17, P = .012), among other predictors such as CCI score (HR 2.58, P = .004), greater clinical tumor size (HR 3.92, P < .001) and greater pathological T stage (HR 4.78, P < .001), while other factors like age, Fuhrman grade, and Preoperative aspects and dimensions used for anatomic classification (PADUA) score were excluded at earlier steps in the backward variable selection (Table 2).	('MLR', 'Var', (0, 3))	('tumor', 'Disease', (147, 152))	('RFS', 'Disease', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('pathological T stage', 'CPA', (190, 210))	('men', 'Species', '9606', (308, 311))	('greater', 'PosReg', (130, 137))
151664	30508956	The RFS rates in patients with MLR <0.21 was 97.2% at 5 years and 94.9% at 10 years, significantly higher than the 93.7% at 5 years and 90.2% at 10 years in patients with MLR >=0.21 (log-rank, P = .002; Fig.	('MLR <0.21', 'Var', (31, 40))	('higher', 'PosReg', (99, 105))	('patients', 'Species', '9606', (157, 165))	('patients', 'Species', '9606', (17, 25))	('RFS', 'MPA', (4, 7))
151665	30508956	The 5 years and 10 years for CSS rates were significantly higher in MLR <0.21 than in MLR >=0.21 (96.9% and 90.8%) versus (93.7% and 79.7%) (Logrank, P = .001; Fig.	('CSS', 'CPA', (29, 32))	('MLR <0.21', 'Var', (68, 77))	('CSS', 'Chemical', '-', (29, 32))	('higher', 'PosReg', (58, 64))
151673	30508956	Moreover in RCC, there are associated poor quality of CD8+ T as well as defects in JAK3/STAT5/6 intracellular cytokine mediated signaling pathway leads to arrest of T-lymphocytes towards their terminal differentiation.	('defects', 'Var', (72, 79))	('CD8', 'Gene', '925', (54, 57))	('terminal differentiation', 'biological_process', 'GO:0048468', ('193', '217'))	('JAK3', 'Gene', '3718', (83, 87))	('RCC', 'Phenotype', 'HP:0005584', (12, 15))	('cytokine mediated signaling pathway', 'biological_process', 'GO:0019221', ('110', '145'))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('RCC', 'Disease', (12, 15))	('STAT5', 'Gene', '6776', (88, 93))	('T-lymphocytes towards', 'CPA', (165, 186))	('arrest', 'CPA', (155, 161))	('intracellular', 'cellular_component', 'GO:0005622', ('96', '109'))	('STAT5', 'Gene', (88, 93))	('JAK3', 'Gene', (83, 87))	('JAK', 'molecular_function', 'GO:0004713', ('83', '86'))	('CD8', 'Gene', (54, 57))
151693	28276433	Although somatic VHL mutations have been described for some time, more-recent cancer genomic studies have identified mutations in epigenetics regulatory genes and demonstrated marked intratumour heterogeneity, which could have prognostic, predictive and therapeutic relevance.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('mutations', 'Var', (117, 126))	('cancer', 'Disease', (78, 84))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('tumour', 'Disease', (188, 194))	('VHL', 'Gene', (17, 20))	('epigenetics regulatory genes', 'Gene', (130, 158))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mutations', 'Var', (21, 30))
151729	28276433	Investigations into familial RCC have uncovered mutations in at least 11 genes (namely BAP1, FLCN, FH, MET, PTEN, SDHB, SDHC, SDHD, TSC1, TSC2, and VHL), some of which have also been implicated in sporadic RCC development.	('BAP1', 'Gene', '8314', (87, 91))	('PTEN', 'Gene', (108, 112))	('SDHB', 'Gene', (114, 118))	('RCC', 'Disease', (29, 32))	('TSC1', 'Gene', '7248', (132, 136))	('FLCN', 'Gene', '201163', (93, 97))	('FH', 'Disease', 'MESH:D006938', (99, 101))	('mutations', 'Var', (48, 57))	('VHL', 'Gene', (148, 151))	('men', 'Species', '9606', (217, 220))	('PTEN', 'Gene', '5728', (108, 112))	('TSC2', 'Gene', '7249', (138, 142))	('SDHC', 'Gene', '6391', (120, 124))	('FLCN', 'Gene', (93, 97))	('BAP1', 'Gene', (87, 91))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('MET', 'Gene', (103, 106))	('SDHD', 'Gene', '6392', (126, 130))	('implicated', 'Reg', (183, 193))	('TSC2', 'Gene', (138, 142))	('SDHD', 'Gene', (126, 130))	('RCC', 'Disease', (206, 209))	('SDHC', 'Gene', (120, 124))	('SDHB', 'Gene', '6390', (114, 118))	('RCC', 'Disease', 'MESH:C538614', (206, 209))	('TSC1', 'Gene', (132, 136))
151730	28276433	A notable example is VHL, the mutated gene underlying von Hippel-Lindau disease, which is characterized by a high risk of developing ccRCC; inactivation of the VHL protein, leading to unchecked expression of oncogenic hypoxia-inducible factors (HIF-1 and HIF-2), is also a hallmark of sporadic ccRCC tumours (see Mechanisms, below).	('inactivation', 'Var', (140, 152))	('VHL', 'Gene', (160, 163))	('hypoxia', 'Disease', (218, 225))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('hypoxia', 'Disease', 'MESH:D000860', (218, 225))	('RCC', 'Disease', (135, 138))	('tumour', 'Phenotype', 'HP:0002664', (300, 306))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('von Hippel-Lindau disease', 'Disease', (54, 79))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (54, 79))	('expression', 'MPA', (194, 204))	('tumours', 'Phenotype', 'HP:0002664', (300, 307))	('hallmark of sporadic ccRCC tumours', 'Disease', 'MESH:D009369', (273, 307))	('hallmark of sporadic ccRCC tumours', 'Disease', (273, 307))	('RCC', 'Disease', 'MESH:C538614', (296, 299))	('HIF-1 and HIF-2', 'Disease', 'MESH:D003924', (245, 260))	('RCC', 'Disease', (296, 299))
151733	28276433	The locus 12p11.23 probably maps to changes in BHLHE41 (encoding basic helix-loop-helix family member e41, which is thought to have a role in regulation of the circadian rhythm).	('BHLHE41', 'Gene', (47, 54))	('regulation', 'biological_process', 'GO:0065007', ('142', '152'))	('changes', 'Var', (36, 43))	('BHLHE41', 'Gene', '79365', (47, 54))	('circadian rhythm', 'biological_process', 'GO:0007623', ('160', '176'))
151734	28276433	In ccRCC, the VHL tumour suppressor gene is the most frequently mutated gene, and its complete loss through genetic (point mutations, indels and 3p25 loss) and/or epigenetic (promoter methylation) mechanisms constitutes the earliest, truncal oncogenic driving event.	('epigenetic', 'Var', (163, 173))	('indels', 'Var', (134, 140))	('VHL tumour', 'Disease', (14, 24))	('RCC', 'Disease', (5, 8))	('point mutations', 'Var', (117, 132))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('VHL tumour', 'Disease', 'MESH:D006623', (14, 24))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('methylation', 'biological_process', 'GO:0032259', ('184', '195'))	('loss', 'NegReg', (150, 154))	('loss', 'NegReg', (95, 99))
151736	28276433	Loss of VHL, therefore, leads to aberrant accumulation of HIF proteins despite an adequately oxygenated tissue microenvironment, which in turn results in uncontrolled activation of HIF target genes that regulate angiogenesis, glycolysis and apoptosis (FIG.	('HIF proteins', 'Disease', 'MESH:D011488', (58, 70))	('HIF proteins', 'Disease', (58, 70))	('apoptosis', 'biological_process', 'GO:0097194', ('241', '250'))	('accumulation', 'PosReg', (42, 54))	('activation', 'PosReg', (167, 177))	('apoptosis', 'biological_process', 'GO:0006915', ('241', '250'))	('apoptosis', 'CPA', (241, 250))	('glycolysis', 'biological_process', 'GO:0006096', ('226', '236'))	('angiogenesis', 'biological_process', 'GO:0001525', ('212', '224'))	('men', 'Species', '9606', (123, 126))	('Loss', 'Var', (0, 4))	('VHL', 'Gene', (8, 11))
151738	28276433	However, VHL loss alone is insufficient to induce ccRCC as evidenced by the long latency (>30 years) in individuals who harbour VHL germline mutations to develop ccRCC and by the observation that Vhl loss in mice is unable to induce ccRCC.	('mutations', 'Var', (141, 150))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('insufficient', 'Disease', (27, 39))	('mice', 'Species', '10090', (208, 212))	('insufficient', 'Disease', 'MESH:D000309', (27, 39))	('RCC', 'Disease', 'MESH:C538614', (235, 238))	('VHL loss', 'Disease', 'MESH:D006623', (9, 17))	('RCC', 'Disease', (235, 238))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('RCC', 'Disease', (164, 167))	('Vhl loss', 'Disease', (196, 204))	('Vhl loss', 'Disease', 'MESH:D015431', (196, 204))	('VHL loss', 'Disease', (9, 17))	('develop', 'PosReg', (154, 161))	('VHL', 'Gene', (128, 131))
151739	28276433	These results suggest that additional genetic and/or epigenetic events are probably needed for ccRCC to develop.	('RCC', 'Disease', (97, 100))	('epigenetic', 'Var', (53, 63))	('RCC', 'Disease', 'MESH:C538614', (97, 100))
151740	28276433	To identify these events, large-scale cancer genomic projects have been undertaken, and have revealed several novel prevalent mutations in ccRCC, including PBRM1 (29-41% of tumour samples), SETD2 (8-12%), BAP1 (6-10%), KDM5C (4-7%) and MTOR (5-6%).	('tumour', 'Disease', (173, 179))	('PBRM1', 'Gene', (156, 161))	('BAP1', 'Gene', '8314', (205, 209))	('KDM5C', 'Gene', (219, 224))	('BAP1', 'Gene', (205, 209))	('mutations', 'Var', (126, 135))	('cancer', 'Disease', (38, 44))	('SETD2', 'Gene', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('SETD2', 'Gene', '29072', (190, 195))	('RCC', 'Disease', (141, 144))	('PBRM1', 'Gene', '55193', (156, 161))	('MTOR', 'Gene', (236, 240))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('MTOR', 'Gene', '2475', (236, 240))	('KDM5C', 'Gene', '8242', (219, 224))	('tumour', 'Disease', 'MESH:D009369', (173, 179))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
151743	28276433	By contrast, MTOR mutations in ccRCC are generally missense and functionally activating, which could explain the reason mTOR pathway inhibitors, including everolimus and temsirolimus, are effective.	('everolimus', 'Chemical', 'MESH:D000068338', (155, 165))	('missense', 'Var', (51, 59))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('MTOR', 'Gene', (13, 17))	('temsirolimus', 'Chemical', 'MESH:C401859', (170, 182))	('mTOR', 'Gene', (120, 124))	('mTOR', 'Gene', '2475', (120, 124))	('activating', 'PosReg', (77, 87))	('MTOR', 'Gene', '2475', (13, 17))	('mutations', 'Var', (18, 27))
151745	28276433	As inactivation of VHL is the founding event of ccRCC, its mutation status has no effect on clinical outcome, whereas mutations involved in disease progression such as PBRM1, SETD2 and BAP1 as well as KDM5C (which is also involved in chromatin modification) were shown to associate with aggressive clinical features.	('associate with', 'Reg', (272, 286))	('KDM5C', 'Gene', (201, 206))	('BAP1', 'Gene', '8314', (185, 189))	('chromatin modification', 'biological_process', 'GO:0006325', ('234', '256'))	('BAP1', 'Gene', (185, 189))	('SETD2', 'Gene', '29072', (175, 180))	('VHL', 'Gene', (19, 22))	('mutations', 'Var', (118, 127))	('KDM5C', 'Gene', '8242', (201, 206))	('PBRM1', 'Gene', (168, 173))	('inactivation', 'Var', (3, 15))	('RCC', 'Disease', (50, 53))	('SETD2', 'Gene', (175, 180))	('PBRM1', 'Gene', '55193', (168, 173))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('chromatin modification', 'biological_process', 'GO:0016569', ('234', '256'))	('chromatin', 'cellular_component', 'GO:0000785', ('234', '243'))	('aggressive clinical', 'Disease', (287, 306))
151746	28276433	Small renal masses harbouring PBRM1 mutations were associated with stage III pathological features (that is, extrarenal growth but not extending beyond Gerota's fascia see below), whereas BAP1 mutations were associated with larger tumour sizes, higher Fuhrman nuclear grade (large nucleus with prominent nucleolus) and worse cancer-specific survival.	('BAP1', 'Gene', '8314', (188, 192))	('mutations', 'Var', (193, 202))	('renal masses', 'Phenotype', 'HP:0009726', (6, 18))	('extrarenal growth', 'CPA', (109, 126))	('cancer', 'Disease', (325, 331))	('Fuhrman nuclear grade', 'CPA', (252, 273))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('nucleolus', 'cellular_component', 'GO:0005730', ('304', '313'))	('BAP1', 'Gene', (188, 192))	("Gerota's fascia", 'Disease', (152, 167))	('PBRM1', 'Gene', '55193', (30, 35))	('tumour', 'Phenotype', 'HP:0002664', (231, 237))	('tumour', 'Disease', 'MESH:D009369', (231, 237))	('PBRM1', 'Gene', (30, 35))	("Gerota's fascia", 'Disease', 'MESH:D010300', (152, 167))	('tumour', 'Disease', (231, 237))	('cancer', 'Disease', 'MESH:D009369', (325, 331))	('mutations', 'Var', (36, 45))	('associated', 'Reg', (51, 61))	('Small renal', 'Phenotype', 'HP:0000089', (0, 11))	('nucleus', 'cellular_component', 'GO:0005634', ('281', '288'))
151747	28276433	Interestingly, mutations in BAP1 and PBRM1 or KDM5C seem to occur mutually exclusively in ccRCC, offering a molecular subclassification of ccRCC.	('RCC', 'Disease', (141, 144))	('KDM5C', 'Gene', (46, 51))	('PBRM1', 'Gene', (37, 42))	('PBRM1', 'Gene', '55193', (37, 42))	('BAP1', 'Gene', '8314', (28, 32))	('KDM5C', 'Gene', '8242', (46, 51))	('mutations', 'Var', (15, 24))	('BAP1', 'Gene', (28, 32))	('RCC', 'Disease', 'MESH:C538614', (141, 144))	('RCC', 'Disease', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('occur', 'Reg', (60, 65))
151748	28276433	Furthermore, mutations of KDM5C, which is located at Xp.11, were predominantly detected in male patients and correlated with long-term therapeutic benefit from sunitinib; and mutations of SETD2 were associated with reduced relapse-free survival.	('KDM5C', 'Gene', (26, 31))	('SETD2', 'Gene', '29072', (188, 193))	('sunitinib', 'Chemical', 'MESH:D000077210', (160, 169))	('reduced', 'NegReg', (215, 222))	('KDM5C', 'Gene', '8242', (26, 31))	('mutations', 'Var', (175, 184))	('SETD2', 'Gene', (188, 193))	('patients', 'Species', '9606', (96, 104))	('relapse-free survival', 'CPA', (223, 244))	('mutations', 'Var', (13, 22))
151751	28276433	For example, in a study of four patients with ccRCC who had multiple tumours were subjected to multi-region genetic analysis, VHL mutation and 3p loss of heterozygosity were found to be ubiquitous events across all regions sampled.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('patients', 'Species', '9606', (32, 40))	('RCC', 'Disease', (48, 51))	('multiple tumours', 'Disease', 'MESH:D009369', (60, 76))	('mutation', 'Var', (130, 138))	('loss of', 'NegReg', (146, 153))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('VHL', 'Gene', (126, 129))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('multiple tumours', 'Disease', (60, 76))
151752	28276433	By contrast, common driver events such as SETD2, PBRM1, MTOR, PIK3CA, PTEN and KDM5C mutations were present heterogeneously within the primary tumour and metastatic sites : in some regions but not others.	('MTOR', 'Gene', (56, 60))	('primary tumour', 'Disease', (135, 149))	('PTEN', 'Gene', (70, 74))	('KDM5C', 'Gene', '8242', (79, 84))	('PIK3CA', 'Gene', (62, 68))	('PTEN', 'Gene', '5728', (70, 74))	('primary tumour', 'Disease', 'MESH:D009369', (135, 149))	('MTOR', 'Gene', '2475', (56, 60))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('mutations', 'Var', (85, 94))	('KDM5C', 'Gene', (79, 84))	('SETD2', 'Gene', '29072', (42, 47))	('PIK3CA', 'Gene', '5290', (62, 68))	('PBRM1', 'Gene', (49, 54))	('PBRM1', 'Gene', '55193', (49, 54))	('SETD2', 'Gene', (42, 47))
151753	28276433	Such genetic characteristics enable the construction of tumour phylogenies, whereby the 'trunk' of the evolutionary tree depicts mutations found in the most recent common ancestor (MRCA) that are present in every tumour cell.	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('mutations', 'Var', (129, 138))	('tumour', 'Disease', 'MESH:D009369', (213, 219))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumour', 'Disease', (213, 219))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('trunk', 'cellular_component', 'GO:0043198', ('89', '94'))	('tumour', 'Disease', (56, 62))
151754	28276433	'Branched' mutations are found in some subclones but not others; these mutations may be regionally distributed across the tumour, occupying distinct regional niches within the primary tumour or different niches between the primary and metastatic sites of disease.	('primary tumour', 'Disease', 'MESH:D009369', (176, 190))	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('tumour', 'Disease', (122, 128))	('mutations', 'Var', (71, 80))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('tumour', 'Disease', (184, 190))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('primary tumour', 'Disease', (176, 190))
151755	28276433	In some cases : such as BAP1, PBRM1 and SETD2 mutations : such recurrent but distinct alterations can be readily explained as the 'second hit' event in the evolution of the tumour.	('mutations ', 'Var', (46, 56))	('tumour', 'Disease', (173, 179))	('PBRM1', 'Gene', (30, 35))	('SETD2', 'Gene', '29072', (40, 45))	('BAP1', 'Gene', (24, 28))	('PBRM1', 'Gene', '55193', (30, 35))	('SETD2', 'Gene', (40, 45))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumour', 'Disease', 'MESH:D009369', (173, 179))	('BAP1', 'Gene', '8314', (24, 28))
151756	28276433	Additionally, convergence of genetic characteristics has been noted in several studies of ccRCC, whereby mutations in genes occur at different time points but result in similar overall genomic and phenotypic profiles; a 'braided river' model has been conceived to illustrate this phenomenon (FIG.	('RCC', 'Disease', (92, 95))	('mutations', 'Var', (105, 114))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('men', 'Species', '9606', (285, 288))
151757	28276433	Regardless of the modality, a follow up study of ccRCC samples for eight patients demonstrated evidence for branched evolution in which 73-75% of driver alterations were found to be subclonal.	('patients', 'Species', '9606', (73, 81))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('alterations', 'Var', (153, 164))	('RCC', 'Disease', (51, 54))
151759	28276433	For example, it has been shown that patients who responded well to mTOR inhibition harbour recurrent regionally separated aberrations in components of the mTOR pathway.	('mTOR', 'Gene', '2475', (155, 159))	('patients', 'Species', '9606', (36, 44))	('mTOR', 'Gene', (155, 159))	('mTOR', 'Gene', (67, 71))	('mTOR', 'Gene', '2475', (67, 71))	('aberrations', 'Var', (122, 133))
151770	28276433	At the same time, efforts to develop mouse models that truly reflect human ccRCC genomics and morphology have been hampered by the fact that homozygous inactivation of the Vhl gene in mice does not result in ccRCC.	('result in', 'Reg', (198, 207))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('human', 'Species', '9606', (69, 74))	('RCC', 'Disease', (77, 80))	('inactivation', 'Var', (152, 164))	('mouse', 'Species', '10090', (37, 42))	('Vhl', 'Gene', (172, 175))	('mice', 'Species', '10090', (184, 188))	('RCC', 'Disease', (210, 213))	('RCC', 'Disease', 'MESH:C538614', (210, 213))
151771	28276433	However, the identification of additional recurrent, prevalent mutations in human ccRCC have rekindled efforts to generate such models.	('mutations', 'Var', (63, 72))	('RCC', 'Disease', (84, 87))	('human', 'Species', '9606', (76, 81))	('RCC', 'Disease', 'MESH:C538614', (84, 87))
151772	28276433	For example, homozygous deletion of Vhl and Pbrm1 in a mouse model resulted in multifocal, lipid-rich, glycogen-rich, transplantable ccRCC (J.J.H., unpublished data).	('resulted in', 'Reg', (67, 78))	('Vhl', 'Gene', (36, 39))	('Pbrm1', 'Gene', (44, 49))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('glycogen', 'Chemical', 'MESH:D006003', (103, 111))	('RCC', 'Disease', (135, 138))	('Pbrm1', 'Gene', '66923', (44, 49))	('mouse', 'Species', '10090', (55, 60))	('deletion', 'Var', (24, 32))	('J.J.H', 'CellLine', 'CVCL:M891', (140, 145))	('lipid', 'Chemical', 'MESH:D008055', (91, 96))
151773	28276433	Interestingly, homozygous deletion of Vhl and Bap1 in a mouse model resulted in early lethality (<1 month), and some mice (within a cohort of 7) carrying homozygous deletion of Vhl and heterozygous deletion of Bap1 developed tumour micronodules (0.25-1.8mm) with unknown tumour incidence and molecular characteristics .	('Bap1', 'Gene', (210, 214))	('mouse', 'Species', '10090', (56, 61))	('deletion', 'Var', (26, 34))	('mice', 'Species', '10090', (117, 121))	('unknown tumour', 'Disease', (263, 277))	('developed', 'PosReg', (215, 224))	('Vhl', 'Gene', (38, 41))	('deletion', 'Var', (198, 206))	('Bap1', 'Gene', '104416', (46, 50))	('deletion', 'Var', (165, 173))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('Vhl', 'Gene', (177, 180))	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('tumour', 'Disease', (225, 231))	('tumour', 'Phenotype', 'HP:0002664', (271, 277))	('tumour', 'Disease', 'MESH:D009369', (271, 277))	('Bap1', 'Gene', (46, 50))	('tumour', 'Disease', (271, 277))	('Bap1', 'Gene', '104416', (210, 214))	('unknown tumour', 'Disease', 'MESH:D009382', (263, 277))
151794	28276433	For instance, the presence of clear cells is not unique to ccRCC but can be observed in pRCC, chRCC and MiT family translocation RCC (tRCC).	('RCC', 'Disease', (96, 99))	('MiT family translocation', 'Var', (104, 128))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))	('RCC', 'Disease', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('RCC', 'Disease', (129, 132))	('pRCC', 'Gene', '5546', (88, 92))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('RCC', 'Disease', (61, 64))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('pRCC', 'Gene', (88, 92))
151797	28276433	Nevertheless, a recent molecular characterization of 62 aggressive uRCC revealed distinct subsets including NF2 loss (26%), mTORC1 pathway activation (21%) and mutations in chromatin and DNA damage regulators (21%).	('mTORC1', 'Gene', (124, 130))	('mutations', 'Var', (160, 169))	('activation', 'PosReg', (139, 149))	('DNA', 'cellular_component', 'GO:0005574', ('187', '190'))	('mTORC1', 'cellular_component', 'GO:0031931', ('124', '130'))	('chromatin', 'cellular_component', 'GO:0000785', ('173', '182'))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('mTORC1', 'Gene', '382056', (124, 130))	('NF2 loss', 'Disease', 'MESH:C537392', (108, 116))	('NF2 loss', 'Disease', (108, 116))
151805	28276433	Of note, recent genomic insights from sequencing matched sarcomatous and carcinomatous RCC demonstrated enrichment in TP53 and CDKN2A mutations, implicating these genetic defects as underlying causes of sarcomatoid differentiation in RCC.	('carcinomatous RCC', 'Disease', (73, 90))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('sarcomatous', 'Disease', 'MESH:D018316', (57, 68))	('sarcomatous', 'Disease', (57, 68))	('TP53', 'Gene', (118, 122))	('RCC', 'Disease', (234, 237))	('carcinomatous RCC', 'Disease', 'MESH:C538614', (73, 90))	('mutations', 'Var', (134, 143))	('RCC', 'Disease', 'MESH:C538614', (234, 237))	('genetic defects', 'Disease', 'MESH:D030342', (163, 178))	('genetic defects', 'Disease', (163, 178))	('sarcomatoid', 'Disease', (203, 214))	('men', 'Species', '9606', (110, 113))	('TP53', 'Gene', '7157', (118, 122))	('CDKN2A', 'Gene', (127, 133))	('RCC', 'Disease', (87, 90))	('sarcomatoid', 'Disease', 'MESH:C538614', (203, 214))	('CDKN2A', 'Gene', '1029', (127, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
151889	28276433	PD1 negatively regulates T cell function and its ligand PDL1 is highly expressed by cancer cells; accordingly, blockade of the PD1-PDL1 axis promotes T cell activation and immune killing of the cancer.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', (84, 90))	('T cell activation', 'biological_process', 'GO:0042110', ('150', '167'))	('ligand', 'molecular_function', 'GO:0005488', ('49', '55'))	('immune killing', 'CPA', (172, 186))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('T cell function', 'CPA', (25, 40))	('PD1-PDL1', 'Gene', (127, 135))	('blockade', 'Var', (111, 119))	('T cell activation', 'CPA', (150, 167))	('promotes', 'PosReg', (141, 149))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
151909	28276433	Improved quality of life scores were observed in those patients taking pazopanib versus those taking sunitinib.	('pazopanib', 'Chemical', 'MESH:C516667', (71, 80))	('pazopanib', 'Var', (71, 80))	('sunitinib', 'Chemical', 'MESH:D000077210', (101, 110))	('quality', 'MPA', (9, 16))	('patients', 'Species', '9606', (55, 63))	('Improved', 'PosReg', (0, 8))
151911	28276433	Median time to health-related quality of life improvement was shorter in patients given nivolumab (4.7 months, 95% CI 3.7-7.5) than in patients given everolimus (median not reached).	('patients', 'Species', '9606', (135, 143))	('shorter', 'NegReg', (62, 69))	('nivolumab', 'Chemical', 'MESH:D000077594', (88, 97))	('improvement', 'PosReg', (46, 57))	('health-related quality of life', 'CPA', (15, 45))	('nivolumab', 'Var', (88, 97))	('everolimus', 'Chemical', 'MESH:D000068338', (150, 160))	('men', 'Species', '9606', (53, 56))	('patients', 'Species', '9606', (73, 81))
151919	28276433	For example, as an on-target clinical biomarker, hypertension (systolic blood pressure >=140mmHg) in patients receiving VEGF inhibitors has been shown to be associated with longer progression free survival and overall survival.	('overall survival', 'CPA', (210, 226))	('patients', 'Species', '9606', (101, 109))	('VEGF', 'Gene', '7422', (120, 124))	('hypertension', 'Disease', 'MESH:D006973', (49, 61))	('hypertension', 'Phenotype', 'HP:0000822', (49, 61))	('VEGF', 'Gene', (120, 124))	('progression free survival', 'CPA', (180, 205))	('hypertension', 'Disease', (49, 61))	('inhibitors', 'Var', (125, 135))	('longer', 'PosReg', (173, 179))
151920	28276433	Additionally, many studies have looked into circulating biomarkers, among which high levels of IL-6, IL-8, hepatocyte growth factor and osteopontin were associated with shorter progression free survival in patients receiving pazopanib and sunitinib whereas high levels of lactate dehydrogenase were associated with better overall survival in those receiving temsirolimus but not interferon-alpha.	('progression', 'MPA', (177, 188))	('pazopanib', 'Chemical', 'MESH:C516667', (225, 234))	('pazopanib', 'Var', (225, 234))	('IL-6', 'molecular_function', 'GO:0005138', ('95', '99'))	('temsirolimus', 'Chemical', 'MESH:C401859', (358, 370))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('107', '131'))	('IL-6', 'Gene', (95, 99))	('hepatocyte growth factor', 'Gene', (107, 131))	('IL-6', 'Gene', '3569', (95, 99))	('sunitinib', 'Chemical', 'MESH:D000077210', (239, 248))	('patients', 'Species', '9606', (206, 214))	('shorter', 'NegReg', (169, 176))	('IL-8', 'molecular_function', 'GO:0005153', ('101', '105'))	('IL-8', 'Gene', '3576', (101, 105))	('hepatocyte growth factor', 'Gene', '3082', (107, 131))	('IL-8', 'Gene', (101, 105))
151923	28276433	Interestingly, genomic biomarker analysis of patients enrolled in RECORD-3 showed that BAP1 mutations were associated with 8.1 month progression free survival with first line sunitinib but 5.5 month with first-line everolimus : a significant difference.	('BAP1', 'Gene', '8314', (87, 91))	('BAP1', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('everolimus', 'Chemical', 'MESH:D000068338', (215, 225))	('patients', 'Species', '9606', (45, 53))	('sunitinib', 'Chemical', 'MESH:D000077210', (175, 184))
151924	28276433	By contrast PBRM1 mutations showed no such association, which is consistent with a VEGF inhibitor outlier study and warrants further validation.	('PBRM1', 'Gene', (12, 17))	('VEGF', 'Gene', (83, 87))	('PBRM1', 'Gene', '55193', (12, 17))	('VEGF', 'Gene', '7422', (83, 87))	('mutations', 'Var', (18, 27))
151925	28276433	That BAP1 mutations were associated with inferior outcomes on everolimus is surprising given their reported higher mTORC1 activity than PBMR1 mutant tumours.	('mTORC1', 'Gene', (115, 121))	('tumours', 'Disease', (149, 156))	('BAP1', 'Gene', '8314', (5, 9))	('tumours', 'Phenotype', 'HP:0002664', (149, 156))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('mTORC1', 'Gene', '382056', (115, 121))	('mTORC1', 'cellular_component', 'GO:0031931', ('115', '121'))	('BAP1', 'Gene', (5, 9))	('mutations', 'Var', (10, 19))	('higher', 'PosReg', (108, 114))	('tumours', 'Disease', 'MESH:D009369', (149, 156))	('everolimus', 'Chemical', 'MESH:D000068338', (62, 72))
151926	28276433	Furthermore, patients with KDM5C mutations were associated with a much longer first-line progression-free survival with sunitinib (20.6 months) than everolimus (9.8 months).	('longer', 'PosReg', (71, 77))	('everolimus', 'Chemical', 'MESH:D000068338', (149, 159))	('patients', 'Species', '9606', (13, 21))	('mutations', 'Var', (33, 42))	('KDM5C', 'Gene', (27, 32))	('sunitinib', 'Chemical', 'MESH:D000077210', (120, 129))	('KDM5C', 'Gene', '8242', (27, 32))
151927	28276433	As mutual exclusivity was detected between mutations of BAP1 and PBRM1 or KDM5C, molecular subgrouping of metastatic ccRCC based on these three genes could be of clinical value in the future.	('KDM5C', 'Gene', (74, 79))	('BAP1', 'Gene', '8314', (56, 60))	('PBRM1', 'Gene', (65, 70))	('KDM5C', 'Gene', '8242', (74, 79))	('PBRM1', 'Gene', '55193', (65, 70))	('mutations', 'Var', (43, 52))	('BAP1', 'Gene', (56, 60))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))
151928	28276433	In addition, case-based mTOR inhibitor outlier studies recognized activation mutations of MTOR and bi-allelic inactivation of TSC1 or TSC2 as potential biomarkers for long-term responders.	('MTOR', 'Gene', (90, 94))	('TSC2', 'Gene', (134, 138))	('MTOR', 'Gene', '2475', (90, 94))	('TSC1', 'Gene', (126, 130))	('TSC1', 'Gene', '7248', (126, 130))	('mutations', 'Var', (77, 86))	('bi-allelic inactivation', 'Var', (99, 122))	('TSC2', 'Gene', '7249', (134, 138))	('mTOR', 'Gene', (24, 28))	('mTOR', 'Gene', '2475', (24, 28))	('activation', 'PosReg', (66, 76))
151951	33543019	However, in murine models, the depletion of fibroblasts, the main ExtraCellular Matrix (ECM)-producing cells, led to more aggressive tumors even though they were more susceptible to anti-angiogenic and immuno-modulators.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('murine', 'Species', '10090', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('ExtraCellular Matrix', 'cellular_component', 'GO:0031012', ('66', '86'))	('depletion', 'Var', (31, 40))	('aggressive tumors', 'Disease', 'MESH:D001523', (122, 139))	('more', 'PosReg', (117, 121))	('aggressive tumors', 'Disease', (122, 139))
151957	33543019	We thus demonstrated that, in most cancers, TNX expression is significantly downregulated during cancer progression and we also highlighted, when data were available, that high TNXB mRNA expression in cancer is correlated with a good survival prognosis.	('cancer', 'Disease', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancers', 'Disease', (35, 42))	('cancer', 'Disease', (97, 103))	('expression', 'MPA', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('TNX', 'Gene', '7148', (44, 47))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('TNXB', 'Gene', '7148', (177, 181))	('TNX', 'Gene', (44, 47))	('mRNA expression', 'MPA', (182, 197))	('TNX', 'Gene', '7148', (177, 180))	('high', 'Var', (172, 176))	('TNXB', 'Gene', (177, 181))	('TNX', 'Gene', (177, 180))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('downregulated', 'NegReg', (76, 89))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancer', 'Disease', (35, 41))
151958	33543019	Tumor development is a multi-step process initially involving (1) chronic inflammation and viral and bacterial infections and/or (2) the genetic alteration of critical genes thus allowing the selection of the malignant cells with the highest proliferative potential.	('bacterial infections', 'Disease', 'MESH:D001424', (101, 121))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('genetic alteration', 'Var', (137, 155))	('bacterial infections', 'Disease', (101, 121))	('inflammation', 'Disease', 'MESH:D007249', (74, 86))	('inflammation', 'Disease', (74, 86))	('bacterial infections', 'Phenotype', 'HP:0002718', (101, 121))	('allowing', 'Reg', (179, 187))	('inflammation', 'biological_process', 'GO:0006954', ('74', '86'))
151992	33543019	Collectively, our results demonstrated (1) TNX is downregulated in most cancers, except gliomas, and (2) high TNXB mRNA expression in tumoral samples is correlated with a good survival prognosis in the 2 cancers with the highest incidence and mortality worldwide, i.e.	('tumoral', 'Disease', (134, 141))	('tumoral', 'Disease', 'MESH:D009369', (134, 141))	('mortality', 'Disease', (243, 252))	('TNX', 'Gene', '7148', (110, 113))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('TNX', 'Gene', (110, 113))	('cancers', 'Disease', (72, 79))	('mRNA expression', 'MPA', (115, 130))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mortality', 'Disease', 'MESH:D003643', (243, 252))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('gliomas', 'Disease', (88, 95))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('TNXB', 'Gene', '7148', (110, 114))	('TNX', 'Gene', '7148', (43, 46))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('high', 'Var', (105, 109))	('TNX', 'Gene', (43, 46))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('TNXB', 'Gene', (110, 114))	('gliomas', 'Disease', 'MESH:D005910', (88, 95))	('downregulated', 'NegReg', (50, 63))
152044	33543019	Altogether, these data clearly demonstrated that TNXB expression is correlated with tumor progression and that high level of TNXB mRNA is a good survival marker in carcinomas and could thus be used as a novel survival prognosis marker.	('carcinomas', 'Disease', (164, 174))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('high level', 'Var', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('TNXB', 'Gene', '7148', (125, 129))	('mRNA', 'MPA', (130, 134))	('TNXB', 'Gene', (49, 53))	('TNXB', 'Gene', (125, 129))	('tumor', 'Disease', (84, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('carcinomas', 'Disease', 'MESH:D009369', (164, 174))	('TNXB', 'Gene', '7148', (49, 53))	('correlated', 'Reg', (68, 78))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
152051	33543019	Our results are reinforced by the data recently published by Chakravarthy et al., in which they examined TCGA database and analyzed the pan-cancer landscape of ECM gene dysregulation in 8043 malignant tissues from 15 different tumor types and 704 corresponding normal tissues.	('tumor', 'Disease', (227, 232))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('ECM gene', 'Gene', (160, 168))	('dysregulation', 'Var', (169, 182))
152094	33543019	This promoter was shown to be activated by hypoxia and subsequent histone deacetylase 1 (HDAC1) dissociation from Sp1/HDAC1 complex resulting in a transcript encoding an N-terminally truncated and shorter TNXB (TNXB-S) protein with cytoplasmic localization.	('HDAC1', 'Gene', (118, 123))	('TNXB', 'Gene', '7148', (211, 215))	('dissociation', 'Var', (96, 108))	('histone deacetylase 1', 'Gene', (66, 87))	('HDAC1', 'Gene', (89, 94))	('hypoxia', 'Disease', (43, 50))	('hypoxia', 'Disease', 'MESH:D000860', (43, 50))	('HDAC1', 'Gene', '3065', (118, 123))	('TNXB-S', 'Gene', '7148', (211, 217))	('histone deacetylase 1', 'Gene', '3065', (66, 87))	('localization', 'biological_process', 'GO:0051179', ('244', '256'))	('TNXB', 'Gene', (205, 209))	('TNXB', 'Gene', (211, 215))	('TNXB-S', 'Gene', (211, 217))	('protein', 'cellular_component', 'GO:0003675', ('219', '226'))	('HDAC1', 'Gene', '3065', (89, 94))	('TNXB', 'Gene', '7148', (205, 209))
152098	33543019	By analyzing the GEO datasets used for TNXB mRNA expression (GSE31210 for lung cancer and GSE37751 for breast cancer), we demonstrated that HDAC1 mRNA expression was significantly upregulated in lung (Fc = 0.401; p = 1.30 10-4) and breast (Fc = 0.457; p = 4.90 10-6) carcinomas compared to non-tumoral tissues.	('tumoral', 'Disease', (294, 301))	('tumoral', 'Disease', 'MESH:D009369', (294, 301))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('breast cancer', 'Disease', (103, 116))	('carcinomas', 'Disease', (267, 277))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('mRNA expression', 'MPA', (146, 161))	('upregulated', 'PosReg', (180, 191))	('GSE31210', 'Var', (61, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('HDAC1', 'Gene', (140, 145))	('GSE37751', 'Var', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('carcinomas', 'Disease', 'MESH:D009369', (267, 277))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('carcinomas', 'Phenotype', 'HP:0030731', (267, 277))	('breast', 'Disease', (232, 238))	('HDAC1', 'Gene', '3065', (140, 145))	('lung', 'Disease', (195, 199))	('lung cancer', 'Disease', (74, 85))	('TNXB', 'Gene', '7148', (39, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('TNXB', 'Gene', (39, 43))
152107	33543019	These results thus suggest that high TNXB expression could limit metastasis formation and thus could be a good prognosis factor during cancer progression.	('formation', 'biological_process', 'GO:0009058', ('76', '85'))	('high', 'Var', (32, 36))	('TNXB', 'Gene', (37, 41))	('cancer', 'Disease', (135, 141))	('TNXB', 'Gene', '7148', (37, 41))	('expression', 'MPA', (42, 52))	('limit', 'NegReg', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('metastasis formation', 'CPA', (65, 85))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
152108	33543019	Indeed, in our study, we observed that high TNXB expression is correlated with a good survival rate in breast and lung carcinomas.	('high', 'Var', (39, 43))	('TNXB', 'Gene', '7148', (44, 48))	('TNXB', 'Gene', (44, 48))	('expression', 'MPA', (49, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('breast and lung carcinomas', 'Disease', 'MESH:D001943', (103, 129))
152120	33543019	Briefly, after deparaffinization and rehydration, epitopes retrieval step was performed in sodium citrate buffer pH 6 for 20 min at 98  C. Endogenous peroxidases were then quenched by 3% H2O2 (v/v) in phosphate Buffered Saline (PBS) and non-specific sites were blocked with 2.5% (v/v) normal horse serum in Tris-buffered saline (TBS).	('sodium citrate', 'Chemical', 'MESH:D000077559', (91, 105))	('PBS', 'Chemical', '-', (228, 231))	('H2O2', 'Chemical', 'MESH:D006861', (187, 191))	('H2O2', 'Var', (187, 191))	('TBS', 'Chemical', '-', (329, 332))	('Tris-buffered saline', 'Chemical', '-', (307, 327))	('quenched', 'NegReg', (172, 180))	('phosphate Buffered Saline', 'Chemical', '-', (201, 226))
152124	33543019	TNX labelling was first assessed on human skin sections with different antibodies (sc-271594 (1/100) from Santa Cruz, AF6999 (1/100) from R&D Systems and two home-made antibodies provided by Joost SCHALKWIJK (1/100) and Manuel KOCH (1/1000)) (Supplementary Fig.	('TNX', 'Gene', '7148', (0, 3))	('sc-271594', 'Var', (83, 92))	('TNX', 'Gene', (0, 3))	('ALK', 'Gene', '238', (200, 203))	('human', 'Species', '9606', (36, 41))	('ALK', 'Gene', (200, 203))
152136	33453148	We also found that circPVT1 directly binds to miRNA-145-5p via the Biotin-labelled miRNA pulldown assay and dual-luciferase reporter assay, and miR-145-5p inhibitor significantly attenuated the effect of circPVT1 knockdown on ccRCC cells.	('attenuated', 'NegReg', (179, 189))	('miR-145-5p', 'Chemical', '-', (144, 154))	('circPVT1', 'Gene', '5820', (204, 212))	('5p', 'Chemical', '-', (152, 154))	('Biotin', 'Chemical', 'MESH:D001710', (67, 73))	('RCC', 'Phenotype', 'HP:0005584', (228, 231))	('circPVT1', 'Gene', '5820', (19, 27))	('ccRCC', 'Phenotype', 'HP:0006770', (226, 231))	('ccRCC', 'Disease', (226, 231))	('binds', 'Interaction', (37, 42))	('miR-145-5p', 'Var', (144, 154))	('circPVT1', 'Gene', (204, 212))	('miRNA-145', 'Gene', '406937', (46, 55))	('5p', 'Chemical', '-', (56, 58))	('circPVT1', 'Gene', (19, 27))	('miRNA-145', 'Gene', (46, 55))
152141	33453148	circPVT1 directly bound to miR-145-5p and subsequently inhibited its suppressing capability on TBX15.	('suppressing', 'MPA', (69, 80))	('circPVT1', 'Gene', (0, 8))	('bound', 'Interaction', (18, 23))	('TBX15', 'Gene', (95, 100))	('TBX15', 'Gene', '6913', (95, 100))	('circPVT1', 'Gene', '5820', (0, 8))	('miR-145-5p', 'Chemical', '-', (27, 37))	('miR-145-5p', 'Var', (27, 37))	('inhibited', 'NegReg', (55, 64))
152148	33453148	Emerging evidence revealed that the dysregulation of circRNAs may be involved in the development and progression of many cancers, including breast cancer, lung cancer, and prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('dysregulation', 'Var', (36, 49))	('cancers', 'Disease', (121, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('lung cancer', 'Disease', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('breast cancer', 'Disease', (140, 153))	('involved', 'Reg', (69, 77))	('circRNAs', 'Gene', (53, 61))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))	('prostate cancer', 'Disease', 'MESH:D011471', (172, 187))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('prostate cancer', 'Phenotype', 'HP:0012125', (172, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('prostate cancer', 'Disease', (172, 187))
152155	33453148	Our in vivo study showed that circPVT1 overexpression significantly promoted ccRCC growth and metastasis.	('circPVT1', 'Gene', (30, 38))	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('metastasis', 'CPA', (94, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('promoted', 'PosReg', (68, 76))	('ccRCC', 'Disease', (77, 82))	('circPVT1', 'Gene', '5820', (30, 38))	('overexpression', 'Var', (39, 53))
152163	33453148	The circPVT1 siRNA target sequences were as follows: Si#1 for circPVT1, 5'-UGGGCUUGAGGCCUGAUCU-3'; Si#2 for circPVT1, 5'-GCUUGAGGCCUGAUCUUUU-3'.	('circPVT1', 'Gene', (4, 12))	('Si#', 'Var', (99, 102))	('circPVT1', 'Gene', (62, 70))	('circPVT1', 'Gene', (108, 116))	('circPVT1', 'Gene', '5820', (4, 12))	('circPVT1', 'Gene', '5820', (62, 70))	('circPVT1', 'Gene', '5820', (108, 116))
152179	33453148	Luciferase reporter plasmids psicheck2 with the wild type or mutant sequence of circPVT1 or 3'-UTR of TBX15 were constructed.	('circPVT1', 'Gene', '5820', (80, 88))	('TBX15', 'Gene', (102, 107))	('TBX15', 'Gene', '6913', (102, 107))	('circPVT1', 'Gene', (80, 88))	('mutant', 'Var', (61, 67))
152222	33453148	The results revealed that circPVT1 knockdown significantly reduced the proliferation ability in ccRCC cells (Caki-1, ACHN, and 786O) (Figure 3B,C).	('knockdown', 'Var', (35, 44))	('reduced', 'NegReg', (59, 66))	('circPVT1', 'Gene', (26, 34))	('circPVT1', 'Gene', '5820', (26, 34))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('ccRCC', 'Disease', (96, 101))	('proliferation ability', 'CPA', (71, 92))
152228	33453148	These results indicated that circPVT1 knockdown suppressed migration and invasion in ccRCC cells (Caki-1, ACHN, and 786O) (Figure 3E).	('circPVT1', 'Gene', '5820', (29, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('ccRCC', 'Disease', (85, 90))	('suppressed', 'NegReg', (48, 58))	('circPVT1', 'Gene', (29, 37))	('migration', 'CPA', (59, 68))	('knockdown', 'Var', (38, 47))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
152232	33453148	Transwell assays revealed that the number of migratory and invasive cells was significantly increased in circPVT1 overexpression ccRCC cells compared with the negative control (Figure 4C,D).	('ccRCC', 'Phenotype', 'HP:0006770', (129, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('circPVT1', 'Gene', '5820', (105, 113))	('overexpression', 'Var', (114, 128))	('increased', 'PosReg', (92, 101))	('circPVT1', 'Gene', (105, 113))
152244	33453148	Subsequently, RNA interference assays revealed that, among these candidate miRNAs, miR-145-5p expression was significantly upregulated after circPVT1 knockdown in ccRCC cells (Caki-1, ACHN, and 786O) (Figure 5B-D and Figure S1).	('circPVT1', 'Gene', '5820', (141, 149))	('miR-145-5p', 'Chemical', '-', (83, 93))	('RNA interference', 'biological_process', 'GO:0016246', ('14', '30'))	('upregulated', 'PosReg', (123, 134))	('miR-145-5p', 'Gene', (83, 93))	('RNA', 'cellular_component', 'GO:0005562', ('14', '17'))	('knockdown', 'Var', (150, 159))	('circPVT1', 'Gene', (141, 149))	('expression', 'MPA', (94, 104))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('ccRCC', 'Phenotype', 'HP:0006770', (163, 168))
152245	33453148	Then, we focused on miR-145-5p and performed biotin-labeled miRNA pulldown assay to further confirm the direct binding of circPVT1 and miR-145-5p.	('circPVT1', 'Gene', (122, 130))	('miR-145-5p', 'Chemical', '-', (135, 145))	('biotin', 'Chemical', 'MESH:D001710', (45, 51))	('binding', 'Interaction', (111, 118))	('miR-145-5p', 'Chemical', '-', (20, 30))	('circPVT1', 'Gene', '5820', (122, 130))	('binding', 'molecular_function', 'GO:0005488', ('111', '118'))	('miR-145-5p', 'Var', (135, 145))
152246	33453148	The result showed that circPVT1 was abundantly pulled down by biotin-labeled miR-145-5p in ccRCC cells compared with biotin-labeled negative control (Figure 5E).	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('miR-145-5p', 'Var', (77, 87))	('biotin', 'Chemical', 'MESH:D001710', (117, 123))	('biotin', 'Chemical', 'MESH:D001710', (62, 68))	('circPVT1', 'Gene', '5820', (23, 31))	('miR-145-5p', 'Chemical', '-', (77, 87))	('pulled down', 'NegReg', (47, 58))	('circPVT1', 'Gene', (23, 31))
152248	33453148	The result showed that the luciferase intensity of 293T cells cotransfected with circPVT1-wt and miR-145-5p mimics significantly reduced, while the luciferase intensity of 293T cells transfected with circPVT1-mut or miRNA mimics showed no significant changes (Figure 5F).	('circPVT1', 'Gene', (81, 89))	('circPVT1', 'Gene', '5820', (200, 208))	('293T', 'CellLine', 'CVCL:0063', (51, 55))	('293T', 'CellLine', 'CVCL:0063', (172, 176))	('miR-145-5p', 'Chemical', '-', (97, 107))	('circPVT1', 'Gene', (200, 208))	('circPVT1', 'Gene', '5820', (81, 89))	('miR-145-5p mimics', 'Var', (97, 114))	('luciferase', 'Enzyme', (27, 37))	('reduced', 'NegReg', (129, 136))
152249	33453148	These results demonstrated that circPVT1 directly binds to miR-145-5p in ccRCC cells.	('miR-145-5p', 'Chemical', '-', (59, 69))	('circPVT1', 'Gene', '5820', (32, 40))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('circPVT1', 'Gene', (32, 40))	('miR-145-5p', 'Var', (59, 69))	('binds', 'Interaction', (50, 55))	('ccRCC', 'Disease', (73, 78))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))
152250	33453148	To further demonstrate that the circPVT1/mir-145-5p axis promotes the progression of ccRCC, we first transfected miR-145-5p or miR-145-5p inhibitor into ccRCC cells.	('ccRCC', 'Phenotype', 'HP:0006770', (153, 158))	('circPVT1', 'Gene', '5820', (32, 40))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('ccRCC', 'Disease', (85, 90))	('miR-145-5p', 'Chemical', '-', (113, 123))	('miR-145-5p', 'Var', (113, 123))	('circPVT1', 'Gene', (32, 40))	('mir-145-5p', 'Chemical', '-', (41, 51))	('miR-145-5p', 'Chemical', '-', (127, 137))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
152252	33453148	EdU assay revealed that miR-145-5p mimics could inhibit the proliferative ability of ccRCC cells, and miR-145-5p inhibitor could promote the proliferative ability of ccRCC cells (Figure 6A,B).	('proliferative ability of ccRCC cells', 'CPA', (60, 96))	('promote', 'PosReg', (129, 136))	('ccRCC', 'Phenotype', 'HP:0006770', (166, 171))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('proliferative ability', 'CPA', (141, 162))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('miR-145-5p', 'Chemical', '-', (24, 34))	('miR-145-5p', 'Chemical', '-', (102, 112))	('ccRCC', 'Disease', (166, 171))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))	('miR-145-5p inhibitor', 'Var', (102, 122))	('inhibit', 'NegReg', (48, 55))
152253	33453148	Transwell assays revealed that miR-145-5p mimics could inhibit the migratory ability of ccRCC cells, and miR-145-5p inhibitor could promote the migratory ability of ccRCC cells (Figure 6C,D).	('migratory ability of ccRCC cells', 'CPA', (67, 99))	('miR-145-5p', 'Chemical', '-', (31, 41))	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (165, 170))	('ccRCC', 'Disease', (165, 170))	('migratory ability', 'CPA', (144, 161))	('miR-145-5p', 'Chemical', '-', (105, 115))	('miR-145-5p inhibitor', 'Var', (105, 125))	('promote', 'PosReg', (132, 139))	('inhibit', 'NegReg', (55, 62))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))
152255	33453148	Cell proliferation assay revealed that miR-145-5p inhibitor could attenuate the effect of circPVT1 knockdown on the proliferative ability of ccRCC cells (Figure 6E).	('circPVT1', 'Gene', '5820', (90, 98))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('miR-145-5p', 'Chemical', '-', (39, 49))	('attenuate', 'NegReg', (66, 75))	('proliferative ability', 'CPA', (116, 137))	('circPVT1', 'Gene', (90, 98))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('knockdown', 'Var', (99, 108))	('ccRCC', 'Phenotype', 'HP:0006770', (141, 146))	('ccRCC', 'Disease', (141, 146))
152256	33453148	Transwell assays revealed that miR-145-5p inhibitor could attenuate the effect of circPVT1 knockdown on the migratory ability of ccRCC cells (Figure 6F).	('miR-145-5p', 'Chemical', '-', (31, 41))	('ccRCC', 'Phenotype', 'HP:0006770', (129, 134))	('ccRCC', 'Disease', (129, 134))	('attenuate', 'NegReg', (58, 67))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('knockdown', 'Var', (91, 100))	('circPVT1', 'Gene', '5820', (82, 90))	('migratory ability', 'CPA', (108, 125))	('circPVT1', 'Gene', (82, 90))
152258	33453148	Then, we aimed to found out the target genes circPVT1 regulated through miR-145-5p in ccRCC.	('circPVT1', 'Gene', (45, 53))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('miR-145-5p', 'Var', (72, 82))	('ccRCC', 'Disease', (86, 91))	('circPVT1', 'Gene', '5820', (45, 53))	('miR-145-5p', 'Chemical', '-', (72, 82))
152273	33453148	The results showed that transfection of miR-145-5p mimic could significantly reduce the luciferase intensity of the 293T cell cotransfected with wild-type TBX15-3'UTR compared with mimic-NC, while no significant changes were observed in the mutant TBX15-3'UTR group.	('luciferase', 'Enzyme', (88, 98))	('intensity', 'MPA', (99, 108))	('reduce', 'NegReg', (77, 83))	('miR-145-5p mimic', 'Var', (40, 56))	('miR-145-5p', 'Chemical', '-', (40, 50))	('TBX15', 'Gene', (248, 253))	('TBX15', 'Gene', '6913', (248, 253))	('TBX15', 'Gene', (155, 160))	('TBX15', 'Gene', '6913', (155, 160))	('293T', 'CellLine', 'CVCL:0063', (116, 120))
152274	33453148	We also found that TBX15 mRNA expression was significantly decreased in circPVT1-knockdown cells compared with the negative control, and miR-145-5p mimic could significantly downregulate TBX15 mRNA expression compared with mimic-NC (Figure 7I,J).	('TBX15', 'Gene', (19, 24))	('TBX15', 'Gene', (187, 192))	('TBX15', 'Gene', '6913', (187, 192))	('decreased', 'NegReg', (59, 68))	('TBX15', 'Gene', '6913', (19, 24))	('downregulate', 'NegReg', (174, 186))	('circPVT1', 'Gene', (72, 80))	('mRNA expression', 'MPA', (25, 40))	('miR-145-5p mimic', 'Var', (137, 153))	('circPVT1', 'Gene', '5820', (72, 80))	('miR-145-5p', 'Chemical', '-', (137, 147))	('mRNA expression', 'MPA', (193, 208))
152275	33453148	Western blot analysis also confirmed that knockdown of circPVT1 and miR-145-5p mimic could suppress the expression of TBX15 (Figure 7K).	('TBX15', 'Gene', (118, 123))	('TBX15', 'Gene', '6913', (118, 123))	('suppress', 'NegReg', (91, 99))	('circPVT1', 'Gene', (55, 63))	('miR-145-5p', 'Var', (68, 78))	('expression', 'MPA', (104, 114))	('miR-145-5p', 'Chemical', '-', (68, 78))	('circPVT1', 'Gene', '5820', (55, 63))
152286	33453148	Loss-of-function and gain-of-function experiments showed that circPVT1 knockdown suppressed proliferation and invasion in ccRCC cells, which could be attenuated by miR-145-5p inhibitor.	('Loss-of-function', 'NegReg', (0, 16))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('suppressed', 'NegReg', (81, 91))	('circPVT1', 'Gene', (62, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (122, 127))	('ccRCC', 'Disease', (122, 127))	('knockdown', 'Var', (71, 80))	('gain-of-function', 'PosReg', (21, 37))	('miR-145-5p', 'Chemical', '-', (164, 174))	('circPVT1', 'Gene', '5820', (62, 70))
152287	33453148	circPVT1 overexpression significantly promoted growth in ccRCC, which was also verified by xenograft experiments in vivo.	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('circPVT1', 'Gene', (0, 8))	('ccRCC', 'Disease', (57, 62))	('growth', 'MPA', (47, 53))	('overexpression', 'Var', (9, 23))	('circPVT1', 'Gene', '5820', (0, 8))	('promoted', 'PosReg', (38, 46))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
152290	33453148	circRNA circHIPK3 regulated autophagy through miR-124-3p-STAT3-PRKAA/AMPKalpha signaling in STK11 mutant lung cancer.	('autophagy', 'CPA', (28, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('STK11', 'Gene', '6794', (92, 97))	('miR-124-3p', 'Gene', '406909', (46, 56))	('STAT3', 'Gene', '6774', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('lung cancer', 'Disease', (105, 116))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('miR-124-3p', 'Gene', (46, 56))	('autophagy', 'biological_process', 'GO:0016236', ('28', '37'))	('STAT3', 'Gene', (57, 62))	('STK11', 'molecular_function', 'GO:0033868', ('92', '97'))	('PRKAA', 'Gene', (63, 68))	('autophagy', 'biological_process', 'GO:0006914', ('28', '37'))	('mutant', 'Var', (98, 104))	('STK11', 'Gene', (92, 97))	('PRKAA', 'Gene', '5563', (63, 68))
152294	33453148	Biotin-labeled miRNA pulldown assay and dual-luciferase reporter assay were performed to demonstrate the direct binding of circPVT1 and miR-145-5p.	('binding', 'Interaction', (112, 119))	('miR-145-5p', 'Var', (136, 146))	('circPVT1', 'Gene', '5820', (123, 131))	('miR-145-5p', 'Chemical', '-', (136, 146))	('binding', 'molecular_function', 'GO:0005488', ('112', '119'))	('Biotin', 'Chemical', 'MESH:D001710', (0, 6))	('circPVT1', 'Gene', (123, 131))
152295	33453148	Rescue experiments revealed circPVT1 knockdown suppressed ccRCC proliferation and invasion dependently on miR-145-5p.	('suppressed', 'NegReg', (47, 57))	('circPVT1', 'Gene', (28, 36))	('knockdown', 'Var', (37, 46))	('invasion', 'CPA', (82, 90))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('ccRCC', 'Disease', (58, 63))	('miR-145-5p', 'Chemical', '-', (106, 116))	('circPVT1', 'Gene', '5820', (28, 36))
152298	33453148	Consistently, miR-145-5p mimic increased and miR-145-5p inhibitor reduced the TBX15 expression in ccRCC cells.	('miR-145-5p', 'Chemical', '-', (45, 55))	('reduced', 'NegReg', (66, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('TBX15', 'Gene', (78, 83))	('TBX15', 'Gene', '6913', (78, 83))	('expression', 'MPA', (84, 94))	('miR-145-5p', 'Var', (45, 55))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('miR-145-5p', 'Chemical', '-', (14, 24))
152304	31980715	The loss of the von Hippel-Lindau tumour suppressor gene (VHL) in these tumours favours stabilization of the Hypoxia Inducible Factors (HIF), which in turn contribute to adapt tumour cells to hostile environments promoting tumour progression.	('stabilization', 'MPA', (88, 101))	('tumours', 'Disease', (72, 79))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('contribute', 'Reg', (156, 166))	('von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (16, 40))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('tumour', 'Disease', (34, 40))	('VHL', 'Gene', (58, 61))	('tumour', 'Disease', 'MESH:D009369', (176, 182))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('tumour', 'Disease', (176, 182))	('loss', 'Var', (4, 8))	('favours', 'PosReg', (80, 87))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('adapt', 'CPA', (170, 175))	('tumour', 'Disease', (223, 229))	('Hypoxia', 'Disease', 'MESH:D000860', (109, 116))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))	('Hypoxia', 'Disease', (109, 116))	('von Hippel-Lindau tumour', 'Disease', (16, 40))
152306	31980715	Our results proved that pVHL loss or mutation in its alpha or beta domain significantly decreased TSP-1 levels in ccRCC in a HIF-independent manner.	('TSP-1', 'Gene', '7057', (98, 103))	('TSP-1', 'molecular_function', 'GO:0004277', ('98', '103'))	('pVHL loss', 'Disease', 'MESH:D016388', (24, 33))	('mutation in', 'Var', (37, 48))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('decreased', 'NegReg', (88, 97))	('pVHL loss', 'Disease', (24, 33))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('RCC', 'Disease', 'MESH:D002292', (116, 119))	('RCC', 'Disease', (116, 119))	('TSP-1', 'Gene', (98, 103))
152309	31980715	Dysregulation of the von Hippel-Lindau (VHL) gene is closely associated with clear cell renal cell carcinoma (ccRCC), being this one of the most common features in patients with the Von Hippel-Lindau disease.	('VHL', 'Gene', (40, 43))	('von Hippel-Lindau', 'Gene', (21, 38))	('Dysregulation', 'Var', (0, 13))	('clear cell renal cell carcinoma', 'Disease', (77, 108))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (88, 108))	('RCC', 'Disease', (112, 115))	('Von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (182, 207))	('von Hippel-Lindau', 'Gene', '7428', (21, 38))	('Von Hippel-Lindau disease', 'Disease', (182, 207))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('RCC', 'Disease', 'MESH:D002292', (112, 115))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (77, 108))	('patients', 'Species', '9606', (164, 172))	('associated', 'Reg', (61, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (77, 108))
152310	31980715	This disease is an autosomal dominant hereditary cancer syndrome caused by germ line mutations or deletions in the VHL tumour suppressor gene.	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('autosomal dominant hereditary cancer syndrome', 'Disease', 'MESH:D009386', (19, 64))	('autosomal dominant hereditary cancer syndrome', 'Disease', (19, 64))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('caused', 'Reg', (65, 71))	('This disease', 'Disease', (0, 12))	('VHL tumour', 'Disease', (115, 125))	('VHL tumour', 'Disease', 'MESH:D006623', (115, 125))	('deletions', 'Var', (98, 107))
152311	31980715	Several pieces of evidence have implicated this gene as a gatekeeper gene in the pathogenesis of RCC, these including VHL gene mutations in most primary sporadic renal cell carcinomas (RCCs) and the development of renal cysts in Vhl conditional knockout mice.	('RCCs', 'Phenotype', 'HP:0005584', (185, 189))	('Vhl', 'Gene', (229, 232))	('renal cysts', 'Phenotype', 'HP:0000107', (214, 225))	('sporadic renal cell carcinomas', 'Disease', (153, 183))	('sporadic renal cell carcinomas', 'Disease', 'MESH:D002292', (153, 183))	('VHL gene', 'Gene', (118, 126))	('renal cysts', 'Disease', 'MESH:D007674', (214, 225))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (162, 182))	('pathogenesis', 'biological_process', 'GO:0009405', ('81', '93'))	('RCCs', 'Disease', (185, 189))	('gatekeeper', 'Species', '111938', (58, 68))	('mutations', 'Var', (127, 136))	('Vhl', 'Gene', '7428', (229, 232))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (162, 183))	('RCC', 'Disease', (185, 188))	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (173, 183))	('RCCs', 'Disease', 'MESH:D002292', (185, 189))	('RCC', 'Disease', 'MESH:D002292', (185, 188))	('RCC', 'Disease', 'MESH:D002292', (97, 100))	('mice', 'Species', '10090', (254, 258))	('renal cysts', 'Disease', (214, 225))
152313	31980715	Therefore, VHL loss or certain mutations in this tumour suppressor gene lead to the stabilization of HIF in normoxia which in turn promotes the transcription of HIF target genes, these including angiogenic factors like vascular endothelial growth factor A (VEGF A).	('transcription', 'MPA', (144, 157))	('mutations', 'Var', (31, 40))	('stabilization', 'MPA', (84, 97))	('transcription', 'biological_process', 'GO:0006351', ('144', '157'))	('VEGF', 'Gene', '7422', (257, 261))	('loss', 'NegReg', (15, 19))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('219', '253'))	('VHL', 'Gene', (11, 14))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('VEGF', 'Gene', (257, 261))	('promotes', 'PosReg', (131, 139))	('tumour', 'Disease', (49, 55))
152315	31980715	In this respect, other pVHL HIF-independent functions have been shown to be required and help to explain why loss of pVHL leads to renal cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('leads to', 'Reg', (122, 130))	('pVHL', 'Gene', (117, 121))	('renal cancer', 'Disease', (131, 143))	('loss', 'Var', (109, 113))	('renal cancer', 'Phenotype', 'HP:0009726', (131, 143))	('renal cancer', 'Disease', 'MESH:D007680', (131, 143))
152321	31980715	Additionally, TSP-1 expression is frequently lost during malignant transformation due to regulation of its expression by oncogenes, tumour suppressor genes and hypermethylation.	('tumour', 'Disease', (132, 138))	('expression', 'MPA', (20, 30))	('TSP-1', 'molecular_function', 'GO:0004277', ('14', '19'))	('expression', 'Species', '29278', (107, 117))	('TSP-1', 'Gene', (14, 19))	('lost', 'NegReg', (45, 49))	('expression', 'MPA', (107, 117))	('TSP-1', 'Gene', '7057', (14, 19))	('regulation', 'biological_process', 'GO:0065007', ('89', '99'))	('hypermethylation', 'Var', (160, 176))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('regulation', 'Reg', (89, 99))	('expression', 'Species', '29278', (20, 30))
152335	31980715	VHL interference led to a marked decrease of TSP-1 protein levels, similar to those in pVHL negative cells (Fig.	('decrease', 'NegReg', (33, 41))	('TSP-1', 'Gene', (45, 50))	('VHL', 'Gene', (0, 3))	('TSP-1', 'Gene', '7057', (45, 50))	('interference', 'Var', (4, 16))	('TSP-1', 'molecular_function', 'GO:0004277', ('45', '50'))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
152336	31980715	In order to gain further proof of the role of pVHL in TSP-1 regulation we also used 786-O sublines stably transfected with well-characterized naturally occurring mutant forms of pVHL in its alpha (L188V) or its beta domain (Y112H).	('Y112H', 'Var', (224, 229))	('TSP-1', 'Gene', '7057', (54, 59))	('pVHL', 'Gene', (178, 182))	('Y112H', 'Mutation', 'rs104893824', (224, 229))	('L188V', 'Mutation', 'rs5030824', (197, 202))	('regulation', 'biological_process', 'GO:0065007', ('60', '70'))	('TSP-1', 'molecular_function', 'GO:0004277', ('54', '59'))	('TSP-1', 'Gene', (54, 59))
152337	31980715	Our results indicated that TSP-1 protein levels were decreased in both mutants to levels resembling those in pVHL negative cells (Fig.	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('TSP-1', 'Gene', (27, 32))	('TSP-1', 'molecular_function', 'GO:0004277', ('27', '32'))	('TSP-1', 'Gene', '7057', (27, 32))	('mutants', 'Var', (71, 78))	('decreased', 'NegReg', (53, 62))	('protein', 'Protein', (33, 40))
152338	31980715	Additionally, we generated different pVHL mutations that produced other truncated forms in its alpha domain (1-161, 1-164 and 1-171) and tested for VHL transcripts expression (Fig.	('expression', 'Species', '29278', (164, 174))	('1-161', 'Var', (109, 114))	('1-171', 'Var', (126, 131))	('tested', 'Reg', (137, 143))	('pVHL', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('1-164', 'Var', (116, 121))
152339	31980715	TSP-1 levels were similarly decrease with all these mutants compared with the wild type pVHL (Fig.	('TSP-1', 'Gene', (0, 5))	('TSP-1', 'Gene', '7057', (0, 5))	('mutants', 'Var', (52, 59))	('decrease', 'NegReg', (28, 36))	('TSP-1', 'molecular_function', 'GO:0004277', ('0', '5'))
152350	31980715	Interestingly, when we knocked down them in both pVHL positive and negative cells we only observed a slight decrease but never a TSP-1 protein recovery (Fig.	('TSP-1', 'Gene', '7057', (129, 134))	('knocked', 'Var', (23, 30))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('TSP-1', 'molecular_function', 'GO:0004277', ('129', '134'))	('TSP-1', 'Gene', (129, 134))	('decrease', 'NegReg', (108, 116))
152351	31980715	Additionally, HIF-independent regulation of TSP-1 in ccRCC cells was also confirmed in cells expressing the L188V or the Y112H mutant forms of pVHL, the first reported to regulate HIF normally although it is defective in promoting the assembly of fibronectin extracellular matrix.	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('pVHL', 'Gene', (143, 147))	('TSP-1', 'Gene', (44, 49))	('Y112H', 'Var', (121, 126))	('RCC', 'Disease', (55, 58))	('TSP-1', 'Gene', '7057', (44, 49))	('RCC', 'Disease', 'MESH:D002292', (55, 58))	('Y112H', 'Mutation', 'rs104893824', (121, 126))	('regulation', 'biological_process', 'GO:0065007', ('30', '40'))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('TSP-1', 'molecular_function', 'GO:0004277', ('44', '49'))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('259', '279'))	('L188V', 'Mutation', 'rs5030824', (108, 113))	('assembly', 'MPA', (235, 243))	('L188V', 'Var', (108, 113))
152352	31980715	Our results demonstrated that despite HIF-2alpha levels were low in normoxia in this mutant cells, TSP-1 levels were similarly decreased in normoxia or hypoxia in both, the pVHL L188V and Y112H mutants to levels resembling those in pVHL negative cells (Fig.	('decreased', 'NegReg', (127, 136))	('HIF-2alpha', 'Gene', '2034', (38, 48))	('TSP-1', 'molecular_function', 'GO:0004277', ('99', '104'))	('normoxia or hypoxia', 'Disease', 'MESH:D000860', (140, 159))	('TSP-1', 'Gene', '7057', (99, 104))	('pVHL L188V', 'Var', (173, 183))	('L188V', 'Mutation', 'rs5030824', (178, 183))	('normoxia or hypoxia', 'Disease', (140, 159))	('Y112H', 'Mutation', 'rs104893824', (188, 193))	('HIF-2alpha', 'Gene', (38, 48))	('Y112H', 'Var', (188, 193))	('TSP-1', 'Gene', (99, 104))
152366	31980715	However, when stimulated with serum, pVHL positive cells transfected with siRNA to TSP-1 showed a significant increase of cell migration/invasion compared to cells transfected with scramble siRNA.	('increase', 'PosReg', (110, 118))	('TSP-1', 'molecular_function', 'GO:0004277', ('83', '88'))	('TSP-1', 'Gene', (83, 88))	('siRNA to', 'Var', (74, 82))	('TSP-1', 'Gene', '7057', (83, 88))	('cell migration', 'biological_process', 'GO:0016477', ('122', '136'))	('cell migration/invasion', 'CPA', (122, 145))
152367	31980715	Taken together these results indicated that the lack of pVHL in ccRCC promotes an increase of cell migration through decreasing TSP-1 levels.	('TSP-1', 'Gene', '7057', (128, 133))	('RCC', 'Disease', 'MESH:D002292', (66, 69))	('TSP-1', 'molecular_function', 'GO:0004277', ('128', '133'))	('pVHL', 'Gene', (56, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('cell migration', 'CPA', (94, 108))	('decreasing', 'NegReg', (117, 127))	('TSP-1', 'Gene', (128, 133))	('increase', 'PosReg', (82, 90))	('lack', 'Var', (48, 52))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('cell migration', 'biological_process', 'GO:0016477', ('94', '108'))
152386	31980715	However, p53 protein levels were significantly decreased in all the analysed pVHL negative and in the pVHL mutants L188V and Y112H (Supplementary Fig.	('Y112H', 'Var', (125, 130))	('Y112H', 'Mutation', 'rs104893824', (125, 130))	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', (9, 12))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('L188V', 'Var', (115, 120))	('L188V', 'Mutation', 'rs5030824', (115, 120))	('decreased', 'NegReg', (47, 56))
152395	31980715	Interestingly, we observed a higher molecular weight band in p53 blots that is likely to correspond to a phosphorylated form of this protein, especially in 786-O pRV cells and Y112H mutant (Supplementary Fig.	('Y112H', 'Var', (176, 181))	('Y112H', 'Mutation', 'rs104893824', (176, 181))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))
152399	31980715	Other mechanisms such as epigenetic changes, these including hypermethylation of CpG islands around the transcription start site are also involved in the silencing of TSP-1 expression in cancer.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('TSP-1', 'Gene', '7057', (167, 172))	('cancer', 'Disease', (187, 193))	('TSP-1', 'molecular_function', 'GO:0004277', ('167', '172'))	('silencing', 'NegReg', (154, 163))	('involved', 'Reg', (138, 146))	('expression', 'Species', '29278', (173, 183))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('hypermethylation', 'Var', (61, 77))	('expression', 'MPA', (173, 183))	('TSP-1', 'Gene', (167, 172))	('transcription', 'biological_process', 'GO:0006351', ('104', '117'))
152413	31980715	Additionally, we used 786-O expressing the naturally occurring type 2 C pVHL mutant L188V, or type 2 A pVHL mutant Y112H, that affect its alpha (L188V) or beta domain (Y112H).	('L188V', 'Var', (84, 89))	('L188V', 'Mutation', 'rs5030824', (84, 89))	('Y112H', 'Mutation', 'rs104893824', (115, 120))	('Y112H', 'Var', (115, 120))	('pVHL', 'Gene', (72, 76))	('beta domain', 'MPA', (155, 166))	('Y112H', 'Var', (168, 173))	('L188V', 'Mutation', 'rs5030824', (145, 150))	('Y112H', 'Mutation', 'rs104893824', (168, 173))
152414	31980715	Furthermore, to assess the role of HIF in the regulation of TSP-1, retroviral vectors encoding the constitutively active mutated form of HIF-2alpha [HIF-2alpha P405A;P531A (P-A)2], a mutant lacking transcriptional activity [HIF-2alpha (P-A)2] P405A;P531A;bHLH] or the empty vector pBabe were used.	('P531A', 'Var', (249, 254))	('HIF-2alpha', 'Gene', (224, 234))	('HIF-2alpha', 'Gene', '2034', (137, 147))	('TSP-1', 'Gene', '7057', (60, 65))	('regulation', 'biological_process', 'GO:0065007', ('46', '56'))	('P405A', 'Mutation', 'p.P405A', (243, 248))	('HIF-2alpha', 'Gene', (149, 159))	('HIF-2alpha', 'Gene', '2034', (224, 234))	('TSP-1', 'molecular_function', 'GO:0004277', ('60', '65'))	('HIF-2alpha', 'Gene', '2034', (149, 159))	('P531A', 'Mutation', 'p.P531A', (166, 171))	('HIF-2alpha', 'Gene', (137, 147))	('P405A', 'Mutation', 'p.P405A', (160, 165))	('P531A', 'Mutation', 'p.P531A', (249, 254))	('TSP-1', 'Gene', (60, 65))
152420	31980715	Stable pVHL-mutants were maintained in RPMI 1640 medium with GLUTAMAX-I supplemented with 10% FBS, penicillin/streptomycin and 1 mug/mL puromycin (Thermo Fisher Scientific).	('streptomycin', 'Chemical', 'MESH:D013307', (110, 122))	('pVHL-mutants', 'Gene', (7, 19))	('pVHL-mutants', 'Var', (7, 19))	('mug', 'molecular_function', 'GO:0043739', ('129', '132'))	('penicillin', 'Chemical', 'MESH:D010406', (99, 109))	('puromycin', 'Chemical', 'MESH:D011691', (136, 145))
152437	31717694	The functional role of PKM2 in human renal cancer cells following small-interfering RNA-mediated PKM2 knockdown, which retarded 786-O cell growth was examined.	('renal cancer', 'Disease', 'MESH:D007680', (37, 49))	('PKM2', 'Gene', '5315', (23, 27))	('cell growth', 'biological_process', 'GO:0016049', ('134', '145'))	('PKM2', 'Gene', (97, 101))	('knockdown', 'Var', (102, 111))	('human', 'Species', '9606', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('renal cancer', 'Disease', (37, 49))	('small-interfering', 'Var', (66, 83))	('PKM2', 'Gene', '5315', (97, 101))	('RNA', 'cellular_component', 'GO:0005562', ('84', '87'))	('renal cancer', 'Phenotype', 'HP:0009726', (37, 49))	('PKM2', 'Gene', (23, 27))
152439	31717694	PKM2 knockdown changed glycolytic metabolism, mitochondrial function, adenosine triphosphate (ATP) level, and intracellular metabolite formation and significantly reduced 786-O cell migration and invasion.	('mitochondrial function', 'MPA', (46, 68))	('glycolytic metabolism', 'MPA', (23, 44))	('formation', 'biological_process', 'GO:0009058', ('135', '144'))	('intracellular metabolite formation', 'MPA', (110, 144))	('knockdown', 'Var', (5, 14))	('PKM2', 'Gene', (0, 4))	('invasion', 'CPA', (196, 204))	('mito', 'Species', '262676', (46, 50))	('reduced', 'NegReg', (163, 170))	('PKM2', 'Gene', '5315', (0, 4))	('metabolism', 'biological_process', 'GO:0008152', ('34', '44'))	('intracellular', 'cellular_component', 'GO:0005622', ('110', '123'))	('cell migration', 'biological_process', 'GO:0016477', ('177', '191'))	('changed', 'Reg', (15, 22))	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (70, 92))	('ATP', 'Chemical', 'MESH:D000255', (94, 97))
152440	31717694	Acridine orange and monodansylcadaverine staining, immunocytochemistry, and immunoblotting analyses revealed the induction of autophagy in renal cancer cells following PKM2 knockdown.	('renal cancer', 'Disease', 'MESH:D007680', (139, 151))	('renal cancer', 'Phenotype', 'HP:0009726', (139, 151))	('monodansylcadaverine', 'Chemical', 'MESH:C008542', (20, 40))	('knockdown', 'Var', (173, 182))	('PKM2', 'Gene', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('autophagy', 'biological_process', 'GO:0016236', ('126', '135'))	('PKM2', 'Gene', '5315', (168, 172))	('renal cancer', 'Disease', (139, 151))	('autophagy', 'biological_process', 'GO:0006914', ('126', '135'))	('autophagy', 'CPA', (126, 135))	('Acridine', 'Chemical', 'MESH:D000166', (0, 8))
152459	31717694	Our data clearly demonstrate that PKM2 is overexpressed in RCC tissues as compared with normal renal tissues and that PKM2 knockdown decreases the production of major glycolytic metabolites (pyruvate and lactate).	('pyruvate', 'Chemical', 'MESH:D011773', (191, 199))	('lactate', 'Chemical', 'MESH:D019344', (204, 211))	('PKM2', 'Gene', (34, 38))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))	('PKM2', 'Gene', '5315', (34, 38))	('PKM2', 'Gene', (118, 122))	('knockdown', 'Var', (123, 132))	('decreases', 'NegReg', (133, 142))	('RCC', 'Disease', 'MESH:D002292', (59, 62))	('RCC', 'Disease', (59, 62))	('PKM2', 'Gene', '5315', (118, 122))
152460	31717694	Furthermore, PKM2 knockdown significantly reduces cell viability and induces autophagy via the protein kinase B (AKT)/mTOR pathway.	('PKM2', 'Gene', (13, 17))	('knockdown', 'Var', (18, 27))	('autophagy', 'biological_process', 'GO:0006914', ('77', '86'))	('PKM2', 'Gene', '5315', (13, 17))	('reduces', 'NegReg', (42, 49))	('AKT', 'Gene', '207', (113, 116))	('autophagy', 'CPA', (77, 86))	('protein kinase B', 'Gene', (95, 111))	('mTOR', 'Gene', (118, 122))	('induces', 'Reg', (69, 76))	('mTOR', 'Gene', '2475', (118, 122))	('AKT', 'Gene', (113, 116))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('cell viability', 'CPA', (50, 64))	('autophagy', 'biological_process', 'GO:0016236', ('77', '86'))	('protein kinase B', 'Gene', '2185', (95, 111))
152461	31717694	Our findings clearly indicate that PKM2 regulates the viability of 786-O cells and that targeting PKM2 could reduce the Warburg effect and serve as a potential therapeutic strategy for RCC.	('RCC', 'Disease', (185, 188))	('targeting', 'Var', (88, 97))	('reduce', 'NegReg', (109, 115))	('PKM2', 'Gene', '5315', (98, 102))	('Warburg effect', 'CPA', (120, 134))	('PKM2', 'Gene', (35, 39))	('PKM2', 'Gene', '5315', (35, 39))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('PKM2', 'Gene', (98, 102))	('RCC', 'Disease', 'MESH:D002292', (185, 188))
152468	31717694	As shown in Figure 2, si156 treatment (100 nM for 72 h) significantly decreased PKM2 protein expression, without any effect on PKM1 expression level, as compared with cells from normal and negative control groups (Figure 2A,B).	('PKM', 'Gene', (127, 130))	('si156', 'Var', (22, 27))	('PKM', 'Gene', '5315', (127, 130))	('decreased', 'NegReg', (70, 79))	('PKM2', 'Gene', (80, 84))	('PKM', 'Gene', (80, 83))	('PKM', 'Gene', '5315', (80, 83))	('PKM2', 'Gene', '5315', (80, 84))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
152469	31717694	PKM2 expression was significantly downregulated in the cytoplasmic and nuclear extracts following si156 treatment, consistent with the above observations (Figure 2C).	('expression', 'MPA', (5, 15))	('downregulated', 'NegReg', (34, 47))	('si156 treatment', 'Var', (98, 113))	('PKM2', 'Gene', (0, 4))	('PKM2', 'Gene', '5315', (0, 4))
152472	31717694	The significant knockdown of PKM2 expression mediated by si156 in 786-O cells was further confirmed with immunocytochemistry (Figure 2D).	('si156', 'Var', (57, 62))	('PKM2', 'Gene', (29, 33))	('knockdown', 'NegReg', (16, 25))	('PKM2', 'Gene', '5315', (29, 33))
152476	31717694	Furthermore, si156-mediated knockdown of PKM2 expression not only reduced viability but also induced remarkable morphological changes in 786-O cells (Figure 3B).	('reduced', 'NegReg', (66, 73))	('morphological changes', 'CPA', (112, 133))	('PKM2', 'Gene', (41, 45))	('PKM2', 'Gene', '5315', (41, 45))	('knockdown', 'Var', (28, 37))	('viability', 'CPA', (74, 83))	('induced', 'Reg', (93, 100))
152479	31717694	We also confirmed that PKM2 knockdown altered the migratory and invasive properties of 786-O cells, as confirmed by the in vitro wound healing assay results.	('invasive properties of 786-O cells', 'CPA', (64, 98))	('PKM2', 'Gene', '5315', (23, 27))	('altered', 'Reg', (38, 45))	('wound healing', 'biological_process', 'GO:0042060', ('129', '142'))	('knockdown', 'Var', (28, 37))	('PKM2', 'Gene', (23, 27))
152480	31717694	We performed Western blotting for matrix metalloproteinase (MMP)-2/9 and found that PKM2 knockdown altered the expression of these proteins (Figure 4E,F).	('PKM2', 'Gene', '5315', (84, 88))	('matrix metalloproteinase (MMP)-2', 'Gene', '4313', (34, 66))	('expression', 'MPA', (111, 121))	('altered', 'Reg', (99, 106))	('knockdown', 'Var', (89, 98))	('PKM2', 'Gene', (84, 88))	('MMP)-2', 'molecular_function', 'GO:0004228', ('60', '66'))
152482	31717694	Here, to investigate the role of PKM2 on EMT in kidney cancer cells, we examined the expression level of classical epithelial (E-cadherin) and mesenchymal (N-cadherin and vimentin) cells after PKM2 knockdown.	('PKM2', 'Gene', '5315', (33, 37))	('N-cadherin', 'Gene', (156, 166))	('vimentin', 'cellular_component', 'GO:0045098', ('171', '179'))	('N-cadherin', 'Gene', '1000', (156, 166))	('EMT', 'Gene', (41, 44))	('kidney cancer', 'Disease', 'MESH:D007680', (48, 61))	('EMT', 'Gene', '3702', (41, 44))	('cadherin', 'molecular_function', 'GO:0008014', ('129', '137'))	('kidney cancer', 'Phenotype', 'HP:0009726', (48, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('PKM2', 'Gene', (193, 197))	('kidney cancer', 'Disease', (48, 61))	('vimentin', 'cellular_component', 'GO:0045099', ('171', '179'))	('PKM2', 'Gene', '5315', (193, 197))	('knockdown', 'Var', (198, 207))	('cadherin', 'molecular_function', 'GO:0008014', ('158', '166'))	('E-cadherin', 'Gene', (127, 137))	('EMT', 'biological_process', 'GO:0001837', ('41', '44'))	('vimentin', 'Gene', '7431', (171, 179))	('E-cadherin', 'Gene', '999', (127, 137))	('PKM2', 'Gene', (33, 37))	('vimentin', 'Gene', (171, 179))
152485	31717694	Our results show that PKM2 knockdown may inhibit the EMT in kidney cancer cells.	('EMT', 'biological_process', 'GO:0001837', ('53', '56'))	('knockdown', 'Var', (27, 36))	('PKM2', 'Gene', (22, 26))	('kidney cancer', 'Disease', (60, 73))	('PKM2', 'Gene', '5315', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('kidney cancer', 'Phenotype', 'HP:0009726', (60, 73))	('inhibit', 'NegReg', (41, 48))	('kidney cancer', 'Disease', 'MESH:D007680', (60, 73))	('EMT', 'Gene', (53, 56))	('EMT', 'Gene', '3702', (53, 56))
152487	31717694	To investigate whether PKM2 exerts any role in autophagy of 786-O cells, we performed acridine orange and MDC staining and found that the si156-mediated PKM2 expression knockdown significantly induced acidic and autophagic vacuole formation, as confirmed by the staining results with two acidotropic dyes, acridine orange and MDC, respectively (Figure 5A,B).	('autophagic vacuole formation', 'biological_process', 'GO:0000045', ('212', '240'))	('PKM2', 'Gene', '5315', (23, 27))	('autophagy', 'biological_process', 'GO:0006914', ('47', '56'))	('knockdown', 'Var', (169, 178))	('autophagic vacuole', 'cellular_component', 'GO:0005776', ('212', '230'))	('acridine orange', 'Chemical', 'MESH:D000165', (306, 321))	('acridine orange', 'Chemical', 'MESH:D000165', (86, 101))	('autophagy', 'biological_process', 'GO:0016236', ('47', '56'))	('PKM2', 'Gene', (153, 157))	('induced', 'PosReg', (193, 200))	('autophagic vacuole', 'Phenotype', 'HP:0003736', (212, 230))	('PKM2', 'Gene', '5315', (153, 157))	('PKM2', 'Gene', (23, 27))
152488	31717694	We also performed Western blot analysis for autophagy-related proteins and found that PKM2 knockdown upregulated beclin 1 and ATG7 expression and LC3 I/II conversion (Figure 5C,D).	('PKM2', 'Gene', '5315', (86, 90))	('ATG7', 'Gene', '10533', (126, 130))	('beclin 1', 'Gene', '8678', (113, 121))	('LC3 I/II conversion', 'CPA', (146, 165))	('autophagy', 'biological_process', 'GO:0016236', ('44', '53'))	('knockdown', 'Var', (91, 100))	('beclin 1', 'Gene', (113, 121))	('expression', 'MPA', (131, 141))	('PKM2', 'Gene', (86, 90))	('autophagy', 'biological_process', 'GO:0006914', ('44', '53'))	('ATG7', 'Gene', (126, 130))	('upregulated', 'PosReg', (101, 112))
152490	31717694	Expression of the autophagy marker light chain 3 B (LC3B) was detected in si156-mediated PKM2 knockdown examined by ICC, consistent with the results of immunoblotting (Figure 5E).	('detected', 'Reg', (62, 70))	('knockdown', 'Var', (94, 103))	('PKM2', 'Gene', (89, 93))	('autophagy', 'biological_process', 'GO:0016236', ('18', '27'))	('LC3B', 'Gene', (52, 56))	('PKM2', 'Gene', '5315', (89, 93))	('autophagy', 'biological_process', 'GO:0006914', ('18', '27'))	('LC3B', 'Gene', '81631', (52, 56))
152491	31717694	To elucidate the regulatory pathways implicated in the effect of PKM2 knockdown on RCC cell metabolism, we examined the AMP-activated protein kinase (AMPK) signaling pathway.	('RCC', 'Disease', 'MESH:D002292', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('AMPK', 'molecular_function', 'GO:0050405', ('150', '154'))	('knockdown', 'Var', (70, 79))	('AMPK', 'molecular_function', 'GO:0004691', ('150', '154'))	('PKM2', 'Gene', (65, 69))	('AMPK', 'molecular_function', 'GO:0047322', ('150', '154'))	('AMP', 'Chemical', 'MESH:D000249', (150, 153))	('PKM2', 'Gene', '5315', (65, 69))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('metabolism', 'biological_process', 'GO:0008152', ('92', '102'))	('AMP', 'Chemical', 'MESH:D000249', (120, 123))	('signaling pathway', 'biological_process', 'GO:0007165', ('156', '173'))
152494	31717694	As a result, we found that si156-mediated PKM2 knockdown significantly downregulated the expression of p-AKT, p-mTOR, and other related proteins (HIF-1alpha, c-Myc, p-P70s6K, p-glycogen synthase kinase 3 beta (GSK3beta), p-ERK1/2, and Glut-1) without affecting the corresponding total protein levels (Figure 6A-D).	('si156-mediated', 'Var', (27, 41))	('AKT', 'Gene', '207', (105, 108))	('protein', 'cellular_component', 'GO:0003675', ('285', '292'))	('P70s6K', 'Gene', '6198', (167, 173))	('HIF-1alpha', 'Gene', '3091', (146, 156))	('ERK1/2', 'Gene', (223, 229))	('glycogen synthase kinase 3 beta', 'Gene', (177, 208))	('Glut-1', 'Gene', '6513', (235, 241))	('expression', 'MPA', (89, 99))	('ERK1/2', 'Gene', '5595;5594', (223, 229))	('mTOR', 'Gene', (112, 116))	('GSK3beta', 'Gene', '2932', (210, 218))	('downregulated', 'NegReg', (71, 84))	('c-Myc', 'Gene', (158, 163))	('P70s6K', 'Gene', (167, 173))	('HIF-1alpha', 'Gene', (146, 156))	('AKT', 'Gene', (105, 108))	('mTOR', 'Gene', '2475', (112, 116))	('c-Myc', 'Gene', '4609', (158, 163))	('GSK', 'molecular_function', 'GO:0050321', ('210', '213'))	('Glut-1', 'Gene', (235, 241))	('PKM2', 'Gene', (42, 46))	('knockdown', 'Var', (47, 56))	('PKM2', 'Gene', '5315', (42, 46))	('glycogen synthase kinase 3 beta', 'Gene', '2932', (177, 208))	('ERK1', 'molecular_function', 'GO:0004707', ('223', '227'))	('GSK3beta', 'Gene', (210, 218))
152497	31717694	To understand the mechanism underlying the tumorigenic functions of PKM2, we examined whether PKM2 knockdown affects aerobic glycolysis.	('affects', 'Reg', (109, 116))	('PKM2', 'Gene', '5315', (68, 72))	('PKM2', 'Gene', '5315', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('glycolysis', 'biological_process', 'GO:0006096', ('125', '135'))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('knockdown', 'Var', (99, 108))	('PKM2', 'Gene', (94, 98))	('aerobic glycolysis', 'MPA', (117, 135))	('tumor', 'Disease', (43, 48))	('PKM2', 'Gene', (68, 72))
152498	31717694	PKM2 silencing in 786-O cells attenuated glucose uptake (reduced Glut-1 expression, as shown in Figure 6C,D) and pyruvate and lactate production in cell lysates and media as compared with cells from normal and negative control groups (Figure 7A,B).	('PKM2', 'Gene', (0, 4))	('silencing', 'Var', (5, 14))	('PKM2', 'Gene', '5315', (0, 4))	('glucose uptake', 'biological_process', 'GO:0046323', ('41', '55'))	('expression', 'MPA', (72, 82))	('lactate', 'Chemical', 'MESH:D019344', (126, 133))	('Glut-1', 'Gene', '6513', (65, 71))	('Glut-1', 'Gene', (65, 71))	('glucose', 'MPA', (41, 48))	('reduced', 'NegReg', (57, 64))	('glucose', 'Chemical', 'MESH:D005947', (41, 48))	('attenuated', 'NegReg', (30, 40))	('pyruvate', 'Chemical', 'MESH:D011773', (113, 121))
152499	31717694	As seen with immunoblotting, PKM2 expression knockdown significantly downregulated the protein levels of LDHA and MCT4 (Figure 6A-D).	('MCT4', 'Gene', (114, 118))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('LDHA', 'Gene', '3939', (105, 109))	('MCT4', 'Gene', '9123', (114, 118))	('downregulated', 'NegReg', (69, 82))	('LDHA', 'Gene', (105, 109))	('PKM2', 'Gene', (29, 33))	('MCT', 'biological_process', 'GO:0120197', ('114', '117'))	('protein levels', 'MPA', (87, 101))	('PKM2', 'Gene', '5315', (29, 33))	('knockdown', 'Var', (45, 54))
152500	31717694	Therefore, we determined the concentrations of lactate and pyruvate in the cell media and intact cell lysates to investigate whether PKM2 knockdown changes the intermediate concentration.	('knockdown', 'Var', (138, 147))	('PKM2', 'Gene', (133, 137))	('PKM2', 'Gene', '5315', (133, 137))	('pyruvate', 'Chemical', 'MESH:D011773', (59, 67))	('lactate', 'Chemical', 'MESH:D019344', (47, 54))	('changes', 'Reg', (148, 155))
152502	31717694	PKM2 knockdown had a little inhibitory effect on oxygen consumption rate (OCR) (Figure 8A) and basal respiration, indicating that their energy may be mainly generated by mitochondrial oxidative phosphorylation.	('respiration', 'biological_process', 'GO:0045333', ('101', '112'))	('basal', 'CPA', (95, 100))	('mito', 'Species', '262676', (170, 174))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('184', '209'))	('knockdown', 'Var', (5, 14))	('PKM2', 'Gene', (0, 4))	('PKM2', 'Gene', '5315', (0, 4))	('oxygen', 'Chemical', 'MESH:D010100', (49, 55))	('respiration', 'biological_process', 'GO:0007585', ('101', '112'))	('oxygen consumption rate', 'MPA', (49, 72))
152503	31717694	On the other hand, PKM2 knockdown in 786-O cells resulted in a decrease in total proton efflux rate (PER) and glycolytic proton efflux rate (glycoPER; Figure 8B,C) and caused a decline in glycolysis under basal conditions and compensatory glycolysis, an indicator of decreased aerobic glycolytic rates.	('PKM2', 'Gene', '5315', (19, 23))	('efflux', 'biological_process', 'GO:0140115', ('128', '134'))	('efflux', 'biological_process', 'GO:0140352', ('128', '134'))	('compensatory', 'MPA', (226, 238))	('efflux', 'biological_process', 'GO:0140115', ('88', '94'))	('decline', 'NegReg', (177, 184))	('efflux', 'biological_process', 'GO:0140352', ('88', '94'))	('decrease', 'NegReg', (63, 71))	('glycolysis', 'MPA', (188, 198))	('glycolysis', 'biological_process', 'GO:0006096', ('188', '198'))	('PKM2', 'Gene', (19, 23))	('glycolysis', 'biological_process', 'GO:0006096', ('239', '249'))	('knockdown', 'Var', (24, 33))	('glycolytic proton efflux rate (glycoPER', 'MPA', (110, 149))
152523	31717694	Based on these results, we used siRNA for PKM2 expression knockdown in 786-O renal cancer cells.	('renal cancer', 'Disease', 'MESH:D007680', (77, 89))	('renal cancer', 'Phenotype', 'HP:0009726', (77, 89))	('PKM2', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('PKM2', 'Gene', '5315', (42, 46))	('renal cancer', 'Disease', (77, 89))	('knockdown', 'Var', (58, 67))
152527	31717694	In this direction, we investigated the consequences of PKM2 knockdown to the mTOR pathway in renal cancer cells.	('renal cancer', 'Disease', (93, 105))	('PKM2', 'Gene', (55, 59))	('mTOR', 'Gene', '2475', (77, 81))	('renal cancer', 'Phenotype', 'HP:0009726', (93, 105))	('PKM2', 'Gene', '5315', (55, 59))	('knockdown', 'Var', (60, 69))	('mTOR', 'Gene', (77, 81))	('renal cancer', 'Disease', 'MESH:D007680', (93, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
152536	31717694	Our results indicate that PKM2 knockdown could attenuate the phosphorylation of AKT and subsequently downregulate mTOR phosphorylation and induce autophagy.	('phosphorylation', 'CPA', (61, 76))	('PKM2', 'Gene', '5315', (26, 30))	('autophagy', 'biological_process', 'GO:0006914', ('146', '155'))	('AKT', 'Gene', '207', (80, 83))	('autophagy', 'CPA', (146, 155))	('mTOR', 'Gene', '2475', (114, 118))	('phosphorylation', 'biological_process', 'GO:0016310', ('119', '134'))	('mTOR', 'Gene', (114, 118))	('knockdown', 'Var', (31, 40))	('AKT', 'Gene', (80, 83))	('autophagy', 'biological_process', 'GO:0016236', ('146', '155'))	('induce', 'PosReg', (139, 145))	('attenuate', 'NegReg', (47, 56))	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))	('PKM2', 'Gene', (26, 30))	('downregulate', 'NegReg', (101, 113))
152539	31717694	Furthermore, the expression of other autophagy-specific proteins was upregulated after PKM2 knockdown.	('knockdown', 'Var', (92, 101))	('expression', 'MPA', (17, 27))	('autophagy-specific proteins', 'Protein', (37, 64))	('PKM2', 'Gene', (87, 91))	('autophagy', 'biological_process', 'GO:0016236', ('37', '46'))	('upregulated', 'PosReg', (69, 80))	('PKM2', 'Gene', '5315', (87, 91))	('autophagy', 'biological_process', 'GO:0006914', ('37', '46'))
152540	31717694	The roles of 3-MA and knockdown of PKM2 in autophagy are contradictory.	('autophagy', 'biological_process', 'GO:0006914', ('43', '52'))	('knockdown', 'Var', (22, 31))	('PKM2', 'Gene', (35, 39))	('PKM2', 'Gene', '5315', (35, 39))	('autophagy', 'biological_process', 'GO:0016236', ('43', '52'))
152543	31717694	On the other hand, upregulation in the expression of autophagy-related proteins after PKM2 knockdown was reversed after 3-MA treatment.	('autophagy', 'biological_process', 'GO:0016236', ('53', '62'))	('autophagy', 'biological_process', 'GO:0006914', ('53', '62'))	('knockdown', 'Var', (91, 100))	('upregulation', 'PosReg', (19, 31))	('PKM2', 'Gene', (86, 90))	('expression', 'MPA', (39, 49))	('PKM2', 'Gene', '5315', (86, 90))
152544	31717694	The compound 3-MA inhibits autophagy induction through the suppression of class III PI3K activity; however, activation of class I PI3K may lead to induction of the AKT/mTOR signaling pathway, which also inhibits autophagy.	('PI3K', 'molecular_function', 'GO:0016303', ('130', '134'))	('autophagy', 'biological_process', 'GO:0016236', ('27', '36'))	('induction', 'Reg', (147, 156))	('PI3K', 'molecular_function', 'GO:0016303', ('84', '88'))	('autophagy', 'CPA', (212, 221))	('activity', 'MPA', (89, 97))	('AKT', 'Gene', (164, 167))	('PI3K', 'Var', (130, 134))	('class', 'Protein', (74, 79))	('autophagy', 'biological_process', 'GO:0016236', ('212', '221'))	('autophagy', 'biological_process', 'GO:0006914', ('27', '36'))	('mTOR', 'Gene', (168, 172))	('inhibits', 'NegReg', (203, 211))	('autophagy', 'biological_process', 'GO:0006914', ('212', '221'))	('AKT', 'Gene', '207', (164, 167))	('suppression', 'NegReg', (59, 70))	('mTOR', 'Gene', '2475', (168, 172))	('inhibits', 'NegReg', (18, 26))	('signaling pathway', 'biological_process', 'GO:0007165', ('173', '190'))	('autophagy induction', 'CPA', (27, 46))	('activation', 'PosReg', (108, 118))
152545	31717694	Here, we hypothesized that PKM2 knockdown may suppress the activity of class I PI3K without affecting class III PI3K activity, indicating that the AKT/mTOR pathway is crucial for induction of autophagy in PKM2-knockdown cells.	('activity', 'MPA', (59, 67))	('autophagy', 'biological_process', 'GO:0006914', ('192', '201'))	('PKM2', 'Gene', (27, 31))	('PI3K', 'molecular_function', 'GO:0016303', ('79', '83'))	('suppress', 'NegReg', (46, 54))	('PKM2', 'Gene', '5315', (27, 31))	('knockdown', 'Var', (32, 41))	('PI3K', 'molecular_function', 'GO:0016303', ('112', '116'))	('PKM2', 'Gene', (205, 209))	('AKT', 'Gene', '207', (147, 150))	('PKM2', 'Gene', '5315', (205, 209))	('mTOR', 'Gene', (151, 155))	('mTOR', 'Gene', '2475', (151, 155))	('autophagy', 'biological_process', 'GO:0016236', ('192', '201'))	('class I', 'Enzyme', (71, 78))	('AKT', 'Gene', (147, 150))
152551	31717694	Thus, si156-treated cells showed significant dysregulation in their glycolytic capacity and inhibited mito-acidification after PKM2 knockdown.	('PKM2', 'Gene', (127, 131))	('si156-treated', 'Var', (6, 19))	('glycolytic capacity', 'MPA', (68, 87))	('inhibited', 'NegReg', (92, 101))	('knockdown', 'Var', (132, 141))	('PKM2', 'Gene', '5315', (127, 131))	('acidification', 'biological_process', 'GO:0045851', ('107', '120'))	('dysregulation', 'Reg', (45, 58))	('mito-acidification', 'MPA', (102, 120))	('mito', 'Species', '262676', (102, 106))
152553	31717694	Moreover, the significant reduction in basal and compensatory glycolysis observed after PKM2 knockdown reveals the strong association with maintenance of the glycolytic pathway in 786-O cells.	('knockdown', 'Var', (93, 102))	('reduction', 'NegReg', (26, 35))	('glycolysis', 'biological_process', 'GO:0006096', ('62', '72'))	('PKM2', 'Gene', (88, 92))	('PKM2', 'Gene', '5315', (88, 92))	('glycolytic pathway', 'Pathway', (158, 176))
152555	31717694	PKM2 knockdown had minor effects on OCR; however, the OCR/PER ratio increased in si156-treated cells as compared to normal and negative control cells (data not shown), suggesting a partial metabolic switch to oxidative phosphorylation upon PKM2 inhibition.	('PKM2', 'Gene', (0, 4))	('PKM2', 'Gene', (240, 244))	('PKM2', 'Gene', '5315', (0, 4))	('PKM2', 'Gene', '5315', (240, 244))	('increased', 'PosReg', (68, 77))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('209', '234'))	('si156-treated', 'Var', (81, 94))	('OCR/PER ratio', 'MPA', (54, 67))
152559	31717694	In 786-O cells, total ATP production was inhibited after PKM2 knockdown.	('PKM2', 'Gene', '5315', (57, 61))	('total ATP production', 'MPA', (16, 36))	('knockdown', 'Var', (62, 71))	('inhibited', 'NegReg', (41, 50))	('ATP', 'Chemical', 'MESH:D000255', (22, 25))	('PKM2', 'Gene', (57, 61))
152563	31717694	Thus, the cells become more oxidative or less glycolytic after PKM2 knockdown.	('more', 'PosReg', (23, 27))	('oxidative', 'MPA', (28, 37))	('PKM2', 'Gene', (63, 67))	('PKM2', 'Gene', '5315', (63, 67))	('knockdown', 'Var', (68, 77))	('glycolytic', 'MPA', (46, 56))	('less', 'NegReg', (41, 45))
152564	31717694	High-performance liquid chromatography (HPLC) analysis also revealed that the levels of glycolytic metabolites pyruvate and lactate were significantly decreased in si156-treated cells, suggesting that PKM2 plays an important role in maintaining glycolysis in 786-O cells.	('glycolysis', 'MPA', (245, 255))	('glycolysis', 'biological_process', 'GO:0006096', ('245', '255'))	('si156-treated', 'Var', (164, 177))	('decreased', 'NegReg', (151, 160))	('PKM2', 'Gene', (201, 205))	('pyruvate', 'Chemical', 'MESH:D011773', (111, 119))	('PKM2', 'Gene', '5315', (201, 205))	('lactate', 'Chemical', 'MESH:D019344', (124, 131))
152570	31717694	In the present study, si156-transfected 786-O cells lost their migratory and invasive property after 72 h of transfection as compared with negative and normal control cells, reflecting the functional role of PKM2 in tumor migration and invasion.	('tumor', 'Disease', (216, 221))	('si156-transfected', 'Var', (22, 39))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('lost', 'NegReg', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('PKM2', 'Gene', (208, 212))	('PKM2', 'Gene', '5315', (208, 212))
152573	31717694	Moreover, the expression of other EMT-relevant proteins was also altered after PKM2 knockdown.	('EMT', 'Gene', (34, 37))	('altered', 'Reg', (65, 72))	('EMT', 'Gene', '3702', (34, 37))	('PKM2', 'Gene', (79, 83))	('knockdown', 'Var', (84, 93))	('expression of', 'MPA', (14, 27))	('PKM2', 'Gene', '5315', (79, 83))	('EMT', 'biological_process', 'GO:0001837', ('34', '37'))
152574	31717694	As a result, the wound-healing capability of 786-O cells was significantly decreased after knockdown of si156-mediated PKM2 expression.	('PKM2', 'Gene', (119, 123))	('wound-healing', 'biological_process', 'GO:0042060', ('17', '30'))	('PKM2', 'Gene', '5315', (119, 123))	('knockdown', 'Var', (91, 100))	('wound-healing capability of 786-O cells', 'CPA', (17, 56))	('decreased', 'NegReg', (75, 84))
152578	31717694	As a result, alteration of glycolysis or other growth or signaling factors makes them more highly sensitized by the 786-O cells to form colonies than in the cell survival assay (where the number of cells is high) after PKM2 knockdown.	('PKM2', 'Gene', (219, 223))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('PKM2', 'Gene', '5315', (219, 223))	('glycolysis', 'biological_process', 'GO:0006096', ('27', '37'))	('glycolysis', 'MPA', (27, 37))	('knockdown', 'Var', (224, 233))	('alteration', 'Reg', (13, 23))
152619	31717694	SC-13515), MMP-2 (sc-10736), MMP-9 (sc-10737), and MCT-4 (cat.	('sc-10737', 'Var', (36, 44))	('MMP-2', 'molecular_function', 'GO:0004228', ('11', '16'))	('MMP-9', 'molecular_function', 'GO:0004229', ('29', '34'))	('cat', 'molecular_function', 'GO:0004096', ('58', '61'))	('MMP-2', 'Gene', (11, 16))	('MCT', 'biological_process', 'GO:0120197', ('51', '54'))	('MMP-9', 'Gene', '4318', (29, 34))	('MCT-4', 'Gene', (51, 56))	('MMP-9', 'Gene', (29, 34))	('MMP-2', 'Gene', '4313', (11, 16))	('MCT-4', 'Gene', '9123', (51, 56))
152631	31717694	The slides were blocked and sequentially incubated with a primary antibody against PKM2 (1:1000) and a horseradish peroxidase (HRP)-conjugated secondary antibody (1:10,000), as per the standard protocol.	('1:1000', 'Var', (89, 95))	('horseradish', 'Species', '3704', (103, 114))	('horseradish peroxidase (HRP', 'molecular_function', 'GO:0004601', ('103', '130'))	('antibody', 'cellular_component', 'GO:0042571', ('66', '74'))	('antibody', 'cellular_component', 'GO:0042571', ('153', '161'))	('PKM2', 'Gene', (83, 87))	('PKM2', 'Gene', '5315', (83, 87))	('antibody', 'cellular_component', 'GO:0019815', ('66', '74'))	('antibody', 'cellular_component', 'GO:0019815', ('153', '161'))	('antibody', 'cellular_component', 'GO:0019814', ('66', '74'))	('antibody', 'molecular_function', 'GO:0003823', ('66', '74'))	('antibody', 'cellular_component', 'GO:0019814', ('153', '161'))	('antibody', 'molecular_function', 'GO:0003823', ('153', '161'))
152635	31717694	The small-interfering RNA (siRNA) sequences targeting PKM2 isoform (si27, si155, and si156) were used to knock down the expression of human PKM2 mRNA, as previously described (Table 2).	('human', 'Species', '9606', (134, 139))	('RNA', 'cellular_component', 'GO:0005562', ('22', '25'))	('PKM2', 'Gene', (140, 144))	('expression', 'MPA', (120, 130))	('PKM2', 'Gene', (54, 58))	('PKM2', 'Gene', '5315', (54, 58))	('PKM2', 'Gene', '5315', (140, 144))	('si156', 'Var', (85, 90))	('si155', 'Var', (74, 79))	('knock', 'Reg', (105, 110))	('si27', 'Var', (68, 72))
152640	31717694	Transfected 786-O cells were fixed with acetone and incubated with primary antibodies against PKM2 (1:100) and LC3B (1:400), followed by treatment with Alexa Fluor-conjugated secondary antibodies (1:200) and DAPI (0.1 mug/mL), as per the standard protocols.	('mug', 'molecular_function', 'GO:0043739', ('218', '221'))	('acetone', 'Chemical', 'MESH:D000096', (40, 47))	('LC3B', 'Gene', (111, 115))	('PKM2', 'Gene', (94, 98))	('Alexa Fluor', 'Chemical', 'MESH:C569686', (152, 163))	('PKM2', 'Gene', '5315', (94, 98))	('1:100', 'Var', (100, 105))	('1:400', 'Var', (117, 122))	('LC3B', 'Gene', '81631', (111, 115))
152658	31717694	Here, we successfully identified the glycolytic metabolic profile of PKM2 in kidney cancer cells and found that PKM2 inhibition not only suppressed 786-O cell energy metabolism (glycolysis) but also inhibited kidney cancer cell proliferation, survival, migration, and invasion.	('kidney cancer', 'Disease', (77, 90))	('PKM2', 'Gene', '5315', (112, 116))	('suppressed', 'NegReg', (137, 147))	('glycolysis', 'biological_process', 'GO:0006096', ('178', '188'))	('metabolism', 'biological_process', 'GO:0008152', ('166', '176'))	('migration', 'CPA', (253, 262))	('kidney cancer', 'Phenotype', 'HP:0009726', (209, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('kidney cancer', 'Disease', (209, 222))	('PKM2', 'Gene', (69, 73))	('PKM2', 'Gene', '5315', (69, 73))	('cell proliferation', 'biological_process', 'GO:0008283', ('223', '241'))	('survival', 'CPA', (243, 251))	('inhibited', 'NegReg', (199, 208))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('inhibition', 'Var', (117, 127))	('kidney cancer', 'Disease', 'MESH:D007680', (77, 90))	('invasion', 'CPA', (268, 276))	('kidney cancer', 'Phenotype', 'HP:0009726', (77, 90))	('PKM2', 'Gene', (112, 116))	('kidney cancer', 'Disease', 'MESH:D007680', (209, 222))
152659	31717694	This is the first report to demonstrate that knockdown of PKM2 expression promotes autophagy, probably mediated by the AKT/mTOR pathway (Figure 9).	('promotes', 'PosReg', (74, 82))	('autophagy', 'CPA', (83, 92))	('AKT', 'Gene', '207', (119, 122))	('PKM2', 'Gene', (58, 62))	('autophagy', 'biological_process', 'GO:0016236', ('83', '92'))	('PKM2', 'Gene', '5315', (58, 62))	('mTOR', 'Gene', '2475', (123, 127))	('AKT', 'Gene', (119, 122))	('mTOR', 'Gene', (123, 127))	('autophagy', 'biological_process', 'GO:0006914', ('83', '92'))	('knockdown', 'Var', (45, 54))
152664	32765803	used comparative genomic hybridization assays to demonstrate that partial deletion of chromosome 3 encompassing the BAP1 locus was associated with strikingly worse 5-year metastasis-free and overall survival.	('BAP1', 'Gene', (116, 120))	('worse', 'NegReg', (158, 163))	('partial deletion', 'Var', (66, 82))	('overall survival', 'CPA', (191, 207))	('chromosome', 'cellular_component', 'GO:0005694', ('86', '96'))	('BAP1', 'Gene', '8314', (116, 120))	('metastasis-free', 'CPA', (171, 186))
152667	32765803	In line with Knudson's two-hit hypothesis, the most common driver mutations found in ccRCC involve the tumor suppressor genes found within a short stretch on chromosome 3p, including the histone deubiquitinase gene BAP1 in up to 15% of sporadic cases.	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('chromosome', 'cellular_component', 'GO:0005694', ('158', '168'))	('tumor', 'Disease', (103, 108))	('ccRCC', 'Disease', (85, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('BAP1', 'Gene', '8314', (215, 219))	('tumor suppressor', 'biological_process', 'GO:0051726', ('103', '119'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('103', '119'))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('195', '209'))	('BAP1', 'Gene', (215, 219))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
152668	32765803	As in the case of UM, loss of the BAP1 protein has been consistently associated with more aggressive forms of disease and worse prognostic outcomes in ccRCC patients, leading further to the development of distinct molecular subclassifications of ccRCC.	('aggressive forms of disease', 'Disease', (90, 117))	('ccRCC', 'Disease', (246, 251))	('BAP1', 'Gene', '8314', (34, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (246, 251))	('BAP1', 'Gene', (34, 38))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('UM', 'Phenotype', 'HP:0007716', (18, 20))	('associated', 'Reg', (69, 79))	('patients', 'Species', '9606', (157, 165))	('ccRCC', 'Phenotype', 'HP:0006770', (151, 156))	('ccRCC', 'Disease', (151, 156))	('aggressive forms of disease', 'Disease', 'MESH:D006527', (90, 117))	('protein', 'Protein', (39, 46))	('loss', 'Var', (22, 26))
152669	32765803	speculate on different prognostic subtypes of UM defined by the presence of BAP1 alterations and/or chromosome 8q gains.	('chromosome 8q gains', 'Var', (100, 119))	('BAP1', 'Gene', '8314', (76, 80))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('BAP1', 'Gene', (76, 80))	('alterations', 'Var', (81, 92))	('chromosome', 'cellular_component', 'GO:0005694', ('100', '110'))
152684	28278333	clinicaltrials.gov Identifier: NCT00326898 We recently reported no improvement in disease-free survival (DFS) in our primary analysis of the first and largest adjuvant vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) trial in primary resected renal cell carcinoma (RCC), E2805/ASSURE.	('carcinoma', 'Phenotype', 'HP:0030731', (279, 288))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('168', '202'))	('RCC', 'Phenotype', 'HP:0005584', (290, 293))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (268, 288))	('VEGF', 'Gene', (231, 235))	('E2805/ASSURE', 'Var', (296, 308))	('RCC', 'Disease', (290, 293))	('RCC', 'Disease', 'MESH:C538614', (290, 293))	('men', 'Species', '9606', (74, 77))	('renal cell carcinoma', 'Disease', (268, 288))	('VEGF', 'Gene', '7422', (231, 235))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (268, 288))
152708	28278333	The 5-year DFS rate in high-risk patients with clear cell histology for sunitinib was 47.7%, for sorafenib was 49.9%, and for placebo was 50.0%.	('patients', 'Species', '9606', (33, 41))	('sunitinib', 'Var', (72, 81))	('sorafenib', 'Chemical', 'MESH:D000077157', (97, 106))	('sunitinib', 'Chemical', 'MESH:D000077210', (72, 81))	('DFS', 'MPA', (11, 14))
152719	28278333	Consistent with the primary analysis, our analysis of E2805 patients with ccRCC and high-risk (pT3 and higher or node-positive) disease showed no statistically significant benefit from these agents vs placebo.	('E2805', 'Var', (54, 59))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('patients', 'Species', '9606', (60, 68))	('pT3', 'Gene', '7694', (95, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))	('pT3', 'Gene', (95, 98))
152736	28789379	Epigenetic modifications that alter classical tumor suppressor genes are typical in inherited and sporadic RCC.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('RCC', 'Disease', (107, 110))	('tumor', 'Disease', (46, 51))	('tumor suppressor', 'biological_process', 'GO:0051726', ('46', '62'))	('Epigenetic modifications', 'Var', (0, 24))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('46', '62'))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
152740	28789379	H3K27 methylation has been demonstrated to serve oncogenic functions through the inactivation of tumor suppressor genes in a number of types of human carcinoma, including renal cell carcinoma, and overexpression of EZH2 has been reported to contribute to tumor cell migration and invasion through epigenetic repression of E-cadherin in RCC.	('epigenetic repression', 'Var', (297, 318))	('E-cadherin', 'Gene', (322, 332))	('overexpression', 'PosReg', (197, 211))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('E-cadherin', 'Gene', '999', (322, 332))	('methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('renal cell carcinoma', 'Disease', (171, 191))	('EZH2', 'Gene', (215, 219))	('EZH2', 'Gene', '2146', (215, 219))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (171, 191))	('invasion', 'CPA', (280, 288))	('human', 'Species', '9606', (144, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('tumor', 'Disease', (97, 102))	('methylation', 'Var', (6, 17))	('RCC', 'Phenotype', 'HP:0005584', (336, 339))	('contribute', 'Reg', (241, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('RCC', 'Disease', (336, 339))	('inactivation', 'NegReg', (81, 93))	('carcinoma', 'Disease', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', (255, 260))	('carcinoma', 'Disease', (182, 191))	('cell migration', 'biological_process', 'GO:0016477', ('261', '275'))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('RCC', 'Disease', 'MESH:C538614', (336, 339))	('H3', 'Chemical', 'MESH:C012616', (0, 2))	('cadherin', 'molecular_function', 'GO:0008014', ('324', '332'))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (171, 191))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('97', '113'))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('carcinoma', 'Disease', 'MESH:D002277', (150, 159))	('H3K27', 'Protein', (0, 5))	('carcinoma', 'Disease', 'MESH:D002277', (182, 191))	('tumor suppressor', 'biological_process', 'GO:0051726', ('97', '113'))
152743	28789379	In addition, deregulation of JMJD3 may contribute to gliomagenesis via inhibition of the tumor protein p53 (p53) signaling pathway, which results in the inhibition of terminal differentiation.	('p53', 'Gene', (108, 111))	('gliomagenesis', 'Disease', (53, 66))	('p53', 'Gene', (103, 106))	('JMJD3', 'Gene', (29, 34))	('contribute', 'Reg', (39, 49))	('inhibition', 'NegReg', (153, 163))	('p53', 'Gene', '7157', (108, 111))	('p53', 'Gene', '7157', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('inhibition', 'NegReg', (71, 81))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('JMJD3', 'Gene', '23135', (29, 34))	('p53) signaling pathway', 'biological_process', 'GO:0030330', ('108', '130'))	('terminal differentiation', 'CPA', (167, 191))	('terminal differentiation', 'biological_process', 'GO:0048468', ('167', '191'))	('deregulation', 'Var', (13, 25))	('tumor', 'Disease', (89, 94))
152803	28789379	Together with UTX, it forms the KDM6 subfamily, whose primary function is to reverse gene silencing induced by H3K27 methylation through the demethylation of H3K27me3 and H3K27me2.	('UTX', 'Gene', (14, 17))	('gene silencing', 'biological_process', 'GO:0016458', ('85', '99'))	('H3K27', 'Protein', (111, 116))	('H3', 'Chemical', 'MESH:C012616', (111, 113))	('UTX', 'Gene', '7403', (14, 17))	('H3K27me3', 'Protein', (158, 166))	('reverse', 'NegReg', (77, 84))	('methylation', 'Var', (117, 128))	('H3K27me2', 'Var', (171, 179))	('H3', 'Chemical', 'MESH:C012616', (158, 160))	('H3', 'Chemical', 'MESH:C012616', (171, 173))	('gene', 'MPA', (85, 89))	('methylation', 'biological_process', 'GO:0032259', ('117', '128'))	('demethylation', 'biological_process', 'GO:0070988', ('141', '154'))	('demethylation', 'MPA', (141, 154))
152804	28789379	H3K27 methylation, primarily catalyzed by EZH2, has been demonstrated to serve oncogenic functions in a number of human carcinomas, including renal cell carcinoma.	('renal cell carcinoma', 'Disease', (142, 162))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (142, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (142, 162))	('EZH2', 'Gene', '2146', (42, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('EZH2', 'Gene', (42, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('H3K27', 'Protein', (0, 5))	('methylation', 'Var', (6, 17))	('human', 'Species', '9606', (114, 119))	('H3', 'Chemical', 'MESH:C012616', (0, 2))	('carcinomas', 'Disease', (120, 130))	('carcinomas', 'Disease', 'MESH:D002277', (120, 130))
152819	28789379	OIS acts as a tumor suppressor mechanism by driving stable growth arrest of cancer progenitor cells harboring the initial oncogenic mutation.	('growth arrest', 'Phenotype', 'HP:0001510', (59, 72))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('14', '30'))	('tumor', 'Disease', (14, 19))	('growth arrest of cancer', 'Disease', (59, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('OIS', 'biological_process', 'GO:0090402', ('0', '3'))	('mutation', 'Var', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor suppressor', 'biological_process', 'GO:0051726', ('14', '30'))	('growth arrest of cancer', 'Disease', 'MESH:D006323', (59, 82))
152860	31825950	Overexpression of SPINK1 predicts poor outcomes of several cancers.	('SPINK1', 'Gene', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('SPINK1', 'Gene', '6690', (18, 24))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('Overexpression', 'Var', (0, 14))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))
152916	31825950	Multivariate Cox regression analysis indicated that SPINK13 amplification was significantly correlated with poor PFS (HR, 2.506; p=0.029) and OS (HR, 2.244; p<0.001) for patients with CCRCC in the TCGA-CCRCC cohort (Tables 2, 3).	('PFS', 'MPA', (113, 116))	('patients', 'Species', '9606', (170, 178))	('SPINK13', 'Gene', '153218', (52, 59))	('amplification', 'Var', (60, 73))	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('RCC', 'Disease', (204, 207))	('RCC', 'Phenotype', 'HP:0005584', (204, 207))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('RCC', 'Disease', (186, 189))	('CCRCC', 'Phenotype', 'HP:0006770', (202, 207))	('SPINK13', 'Gene', (52, 59))	('CCRCC', 'Phenotype', 'HP:0006770', (184, 189))	('poor', 'NegReg', (108, 112))
152919	31825950	Also, SPINK13 expression was significantly associated with unfavorable prognosis in terms of PFS (HR, 2.295; p<0.001) and OS (HR, 1.513; p=0.046) for patients with CCRCC.	('expression', 'Var', (14, 24))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('RCC', 'Disease', (166, 169))	('SPINK13', 'Gene', (6, 13))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('CCRCC', 'Phenotype', 'HP:0006770', (164, 169))	('PFS', 'MPA', (93, 96))	('patients', 'Species', '9606', (150, 158))	('associated', 'Reg', (43, 53))	('SPINK13', 'Gene', '153218', (6, 13))
152927	31825950	Cancer genetics and abnormal epigenetic regulation, participate in the development and progression of clear cell renal cell carcinoma (CCRCC).	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (102, 133))	('epigenetic', 'Var', (29, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('regulation', 'biological_process', 'GO:0065007', ('40', '50'))	('men', 'Species', '9606', (78, 81))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (113, 133))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))	('clear cell renal cell carcinoma', 'Disease', (102, 133))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (102, 133))	('CCRCC', 'Phenotype', 'HP:0006770', (135, 140))	('participate', 'Reg', (52, 63))
152948	31825950	HIF pathways in renal cell carcinoma (RCC) are upregulated by inactivation of the von-Hippel-Lindau tumor suppressor.	('RCC', 'Disease', (38, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('100', '116'))	('von-Hippel-Lindau tumor suppressor', 'Gene', (82, 116))	('renal cell carcinoma', 'Disease', (16, 36))	('upregulated', 'PosReg', (47, 58))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (16, 36))	('inactivation', 'Var', (62, 74))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (16, 36))	('tumor suppressor', 'biological_process', 'GO:0051726', ('100', '116'))	('von-Hippel-Lindau tumor suppressor', 'Gene', '7428', (82, 116))	('HIF pathways', 'Pathway', (0, 12))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
152949	31825950	Clinically targeted inhibition of the STAT5 signaling pathway has been proposed as a therapeutic strategy for renal cancer.	('signaling pathway', 'biological_process', 'GO:0007165', ('44', '61'))	('STAT5', 'Gene', (38, 43))	('inhibition', 'Var', (20, 30))	('renal cancer', 'Disease', (110, 122))	('renal cancer', 'Disease', 'MESH:D007680', (110, 122))	('renal cancer', 'Phenotype', 'HP:0009726', (110, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('STAT5', 'Gene', '6776', (38, 43))
152964	32487141	Under the course of this study, it was discovered that this patient carries a mutation for a second rare disease, Neuronal Ceroid Lipofuscinosis (NCL or CNL).	('patient', 'Species', '9606', (60, 67))	('Neuronal Ceroid Lipofuscinosis', 'Disease', (114, 144))	('mutation', 'Var', (78, 86))	('NCL', 'Gene', '4691', (146, 149))	('NCL', 'Gene', (146, 149))	('Neuronal Ceroid Lipofuscinosis', 'Disease', 'MESH:D009472', (114, 144))
152965	32487141	We hypothesize that the CLN mutation she carries offers a protective effect, preventing tumor development in the cells potentially suffering a VHL second hit mutation.	('VHL', 'Gene', '7428', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('preventing', 'NegReg', (77, 87))	('CLN mutation', 'Var', (24, 36))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('VHL', 'Gene', (143, 146))	('tumor', 'Disease', (88, 93))
152969	32487141	In this case report we present a unique and, to the best of our knowledge, unprecedented combination of two rare diseases segregating in a family, leading to an unexpected clinical picture: a 72 year old woman carrying mutations in heterozygosis for both Neural Ceroid Lipofuscinosis (NCL or CNL) and Von Hippel Lindau disease (VHL), with no development of any pathology.	('Neural Ceroid Lipofuscinosis', 'Disease', 'MESH:D009472', (255, 283))	('NCL', 'Gene', (285, 288))	('Neural Ceroid Lipofuscinosis', 'Disease', (255, 283))	('NCL', 'Gene', '4691', (285, 288))	('VHL', 'Gene', (328, 331))	('VHL', 'Gene', '7428', (328, 331))	('mutations', 'Var', (219, 228))	('Von Hippel Lindau disease', 'Disease', (301, 326))	('Von Hippel Lindau disease', 'Disease', 'MESH:D006623', (301, 326))	('woman', 'Species', '9606', (204, 209))
152975	32487141	These develop after a second hit mutation in VHL - a tumor suppressor gene - causes the loss of functional VHL protein.	('VHL', 'Gene', '7428', (45, 48))	('VHL', 'Gene', '7428', (107, 110))	('mutation', 'Var', (33, 41))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('53', '69'))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('loss of functional', 'NegReg', (88, 106))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('tumor', 'Disease', (53, 58))	('VHL', 'Gene', (45, 48))	('VHL', 'Gene', (107, 110))	('tumor suppressor', 'biological_process', 'GO:0051726', ('53', '69'))
152977	32487141	Tissues suffering a stochastic VHL second hit mutation unfold a lack of functional VHL protein, which induces a state of pseudo-hypoxia, promoting tumor growth in these tissues where cells have lost heterozygosis.	('VHL', 'Gene', '7428', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('VHL', 'Gene', '7428', (83, 86))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('promoting', 'PosReg', (137, 146))	('protein', 'Protein', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('hypoxia', 'Disease', (128, 135))	('hypoxia', 'Disease', 'MESH:D000860', (128, 135))	('VHL', 'Gene', (31, 34))	('mutation', 'Var', (46, 54))	('lack', 'NegReg', (64, 68))	('VHL', 'Gene', (83, 86))
152979	32487141	However, her son inherited her mutation and developed bilateral suprarenal tumors in his thirties.	('developed', 'Reg', (44, 53))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('mutation', 'Var', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumors', 'Disease', (75, 81))
152982	32487141	The combination of our in vitro results and the clinical data gathered from the studied family points towards a protective effect by NCL in this patient regarding tumor development: VHL cells that suffer a second hit mutation in VHL cannot divide and progress to develop a tumor, due to the lower viability caused by NCL haplo-insufficiency, interfering in some way with the process of tumorigenesis.	('NCL', 'Gene', '4691', (133, 136))	('VHL', 'Gene', (229, 232))	('viability', 'MPA', (297, 306))	('NCL', 'Gene', (317, 320))	('NCL haplo-insufficiency', 'Disease', (317, 340))	('tumor', 'Disease', (163, 168))	('VHL', 'Gene', '7428', (182, 185))	('NCL haplo-insufficiency', 'Disease', 'MESH:D000309', (317, 340))	('tumor', 'Disease', (273, 278))	('tumor', 'Disease', (386, 391))	('died', 'Disease', (83, 87))	('NCL', 'Gene', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('VHL', 'Gene', '7428', (229, 232))	('tumor', 'Disease', 'MESH:D009369', (386, 391))	('mutation', 'Var', (217, 225))	('not', 'NegReg', (236, 239))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (386, 391))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('died', 'Disease', 'MESH:D003643', (83, 87))	('VHL', 'Gene', (182, 185))	('NCL', 'Gene', '4691', (317, 320))	('patient', 'Species', '9606', (145, 152))	('lower', 'NegReg', (291, 296))
152987	32487141	Upon genetic screening of the immediate relatives, it was discovered that subject A carried the same VHL mutation as subject E, and thus had been maternally transmitted to him.	('VHL', 'Gene', (101, 104))	('mutation', 'Var', (105, 113))	('VHL', 'Gene', '7428', (101, 104))	('carried', 'Reg', (84, 91))
152988	32487141	Intriguingly, subject A remains completely healthy at the age of 72, despite her VHL mutation.	('VHL', 'Gene', '7428', (81, 84))	('VHL', 'Gene', (81, 84))	('mutation', 'Var', (85, 93))
153018	32487141	In addition to this, and according to our in vitro results, because of her VHL mutation, her cells would be further reduced at CLN5 protein levels.	('VHL', 'Gene', (75, 78))	('CLN5', 'Gene', '1203', (127, 131))	('VHL', 'Gene', '7428', (75, 78))	('CLN5', 'Gene', (127, 131))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('mutation', 'Var', (79, 87))	('reduced', 'NegReg', (116, 123))
153021	32487141	Thus, the cells suffering a VHL second hit mutation will not expand, preventing tumor development.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('preventing', 'NegReg', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mutation', 'Var', (43, 51))	('tumor', 'Disease', (80, 85))	('VHL', 'Gene', (28, 31))	('VHL', 'Gene', '7428', (28, 31))
153022	32487141	This hypothesis has been supported by an observation made in our lab: BOECs obtained from subject A are not susceptible to VHL silencing.	('VHL', 'Gene', '7428', (123, 126))	('VHL', 'Gene', (123, 126))	('silencing', 'Var', (127, 136))
153023	32487141	After siRNA VHL transfection, most of the cells die, and the few remaining have no silenced VHL, according to qPCR (data not shown).	('VHL', 'Gene', (12, 15))	('VHL', 'Gene', '7428', (12, 15))	('VHL', 'Gene', (92, 95))	('VHL', 'Gene', '7428', (92, 95))	('transfection', 'Var', (16, 28))
153024	32487141	Overall, our work suggests that a second hit mutation in VHL is incompatible with a CLN5 heterozygosis cellular background.	('CLN5', 'Gene', '1203', (84, 88))	('VHL', 'Gene', (57, 60))	('CLN5', 'Gene', (84, 88))	('mutation', 'Var', (45, 53))	('VHL', 'Gene', '7428', (57, 60))
153030	32487141	The following siRNAs were used: Scrambled (#SIC001) from Sigma-Aldrich (Saint Louis, MO, USA) for control, and a combination of 1-CLN5 (#8149), 2-CLN5 (#18061) and 3-CLN5 (#146678) from Ambion/Thermo Scientific for CLN5 silencing.	('CLN5', 'Gene', '1203', (215, 219))	('CLN5', 'Gene', (146, 150))	('CLN5', 'Gene', (166, 170))	('#SIC001', 'Var', (43, 50))	('CLN5', 'Gene', '1203', (146, 150))	('CLN5', 'Gene', (215, 219))	('CLN5', 'Gene', '1203', (130, 134))	('#8149', 'Var', (136, 141))	('CLN5', 'Gene', (130, 134))	('#18061', 'Var', (152, 158))	('#146678', 'Var', (172, 179))	('CLN5', 'Gene', '1203', (166, 170))
153052	31816951	Moreover, ectopic MCPIP expression increased PERK expression in Human embryonic kidney (HEK)293 cells.	('increased', 'PosReg', (35, 44))	('Human', 'Species', '9606', (64, 69))	('embryonic kidney', 'Disease', (70, 86))	('HEK)293', 'CellLine', 'CVCL:0045', (88, 95))	('ectopic', 'Var', (10, 17))	('embryonic kidney', 'Disease', 'MESH:D007674', (70, 86))	('PERK', 'Gene', (45, 49))	('expression', 'MPA', (50, 60))
153053	31816951	Our meta-analysis revealed that low MCP-1 levels reduce 1-year post-nephrectomy survival in patients with RCC.	('low', 'Var', (32, 35))	('reduce', 'NegReg', (49, 55))	('1-year', 'MPA', (56, 62))	('MCP-1 levels', 'MPA', (36, 48))	('patients', 'Species', '9606', (92, 100))	('MCP', 'molecular_function', 'GO:0004298', ('36', '39'))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('low MCP', 'Phenotype', 'HP:0025066', (32, 39))
153078	31816951	In addition to monocyte recruitment, studies have shown that MCP-1 causes cell death by induction of MCP-1-induced protein (MCPIP)-1.	('cell death', 'CPA', (74, 84))	('cell death', 'biological_process', 'GO:0008219', ('74', '84'))	('men', 'Species', '9606', (31, 34))	('MCP', 'molecular_function', 'GO:0004298', ('101', '104'))	('MCP', 'molecular_function', 'GO:0004298', ('61', '64'))	('MCP-1-induced protein (MCPIP)-1', 'Gene', '230738', (101, 132))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('MCP-1', 'Var', (61, 66))
153104	31816951	These results indicate that IL-1beta induces the production of MCP-1; MCP-1 then enhances MCPIP-1 expression in RCC cells in an autocrine manner.	('MCP-1', 'Var', (70, 75))	('MCP', 'molecular_function', 'GO:0004298', ('70', '73'))	('IL-1', 'molecular_function', 'GO:0005149', ('28', '32'))	('RCC', 'Disease', (112, 115))	('enhances', 'PosReg', (81, 89))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('MCPIP-1', 'Gene', (90, 97))	('MCP', 'molecular_function', 'GO:0004298', ('63', '66'))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('expression', 'MPA', (98, 108))
153120	31816951	To examine whether that MCPIP-1 was involved in PERK or CNX induction by MCP-1, a human embryonic kidney cell line HEK293 was transfected with plasmids expressing either MCPIP-1-Emerald Green Fluorescent Protein (EmGFP) (ZC3H12A-EmGFP) or EmGFP.	('embryonic kidney', 'Disease', 'MESH:D007674', (88, 104))	('ZC3H12A', 'Gene', (221, 228))	('MCP', 'molecular_function', 'GO:0004298', ('73', '76'))	('HEK293', 'CellLine', 'CVCL:0045', (115, 121))	('ZC3H12A', 'Gene', '80149', (221, 228))	('embryonic kidney', 'Disease', (88, 104))	('MCPIP-1-Emerald', 'Var', (170, 185))	('human', 'Species', '9606', (82, 87))
153132	31816951	Zhao's array data showed that more ccRCC patients with high MCP-1 expression (n = 132) survive than those who with low MCP-1 expression (n = 38) at 1 year after nephrectomy (p = 0.025, t-test; Figure 6A).	('MCP', 'molecular_function', 'GO:0004298', ('119', '122'))	('high MCP-1 expression', 'Var', (55, 76))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('patients', 'Species', '9606', (41, 49))	('RCC', 'Disease', (37, 40))	('MCP', 'molecular_function', 'GO:0004298', ('60', '63'))	('low MCP', 'Phenotype', 'HP:0025066', (115, 122))
153152	31816951	In RCC, the blockage of MCP-1/CCR2 signaling inhibits cell proliferation, but MCP-1 treatment does not affect cell growth.	('cell proliferation', 'CPA', (54, 72))	('MCP', 'molecular_function', 'GO:0004298', ('24', '27'))	('inhibits', 'NegReg', (45, 53))	('blockage', 'Var', (12, 20))	('signaling', 'biological_process', 'GO:0023052', ('35', '44'))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('CCR', 'molecular_function', 'GO:0043880', ('30', '33'))	('cell growth', 'biological_process', 'GO:0016049', ('110', '121'))	('cell proliferation', 'biological_process', 'GO:0008283', ('54', '72'))	('RCC', 'Disease', (3, 6))	('men', 'Species', '9606', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (3, 6))	('MCP', 'molecular_function', 'GO:0004298', ('78', '81'))
153153	31816951	Research on heart failure has discovered that MCP-1 causes cell death by inducing MCPIP-1.	('MCP', 'molecular_function', 'GO:0004298', ('46', '49'))	('inducing', 'PosReg', (73, 81))	('MCPIP-1', 'Gene', (82, 89))	('heart failure', 'Phenotype', 'HP:0001635', (12, 25))	('heart failure', 'Disease', 'MESH:D006333', (12, 25))	('MCP-1', 'Var', (46, 51))	('cell death', 'biological_process', 'GO:0008219', ('59', '69'))	('heart failure', 'Disease', (12, 25))
153154	31816951	MCPIP-1 has transcriptional activity, and its expression induces the expression of genes involved in oxidative and ER stress as well as apoptosis in both HEK 293 cells and the cardiomyoblast cells H9c2.	('expression', 'Var', (46, 56))	('MCPIP-1', 'Gene', (0, 7))	('apoptosis', 'biological_process', 'GO:0097194', ('136', '145'))	('expression', 'MPA', (69, 79))	('HEK 293', 'CellLine', 'CVCL:0045', (154, 161))	('apoptosis', 'biological_process', 'GO:0006915', ('136', '145'))	('induces', 'PosReg', (57, 64))
153156	31816951	Notably, proteins being important for ER stress-induced apoptosis, such as PERK, CHOP, and CNX were also induced by MCP-1 or MCPIP-1 in RCC cells and RCC xenograft tumors.	('ER stress-induced apoptosis', 'biological_process', 'GO:0070059', ('38', '65'))	('induced', 'Reg', (105, 112))	('PERK', 'Disease', (75, 79))	('CNX', 'Gene', (91, 94))	('CHOP', 'Disease', (81, 85))	('MCP', 'molecular_function', 'GO:0004298', ('116', '119'))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('RCC xenograft tumors', 'Disease', (150, 170))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('MCP-1', 'Var', (116, 121))	('proteins', 'Protein', (9, 17))	('RCC', 'Disease', (150, 153))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('RCC', 'Disease', (136, 139))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('MCPIP-1', 'Var', (125, 132))	('RCC xenograft tumors', 'Disease', 'MESH:C538614', (150, 170))	('RCC', 'Disease', 'MESH:C538614', (136, 139))
153166	31816951	Therefore, accumulating FA leads to excessive ROS; in turn, ROS interferes with the redox status of ER lumen and thus inhibit protein-folding as well as induce ER stress and the UPR.	('inhibit', 'NegReg', (118, 125))	('ER stress', 'MPA', (160, 169))	('protein-folding', 'biological_process', 'GO:0006457', ('126', '141'))	('UPR', 'PosReg', (178, 181))	('ER lumen', 'cellular_component', 'GO:0005788', ('100', '108'))	('men', 'Species', '9606', (105, 108))	('induce', 'Reg', (153, 159))	('ROS', 'Chemical', 'MESH:D017382', (46, 49))	('redox status of ER lumen', 'MPA', (84, 108))	('ROS', 'Var', (60, 63))	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))	('interferes', 'NegReg', (64, 74))	('ROS', 'Chemical', 'MESH:D017382', (60, 63))	('protein-folding', 'MPA', (126, 141))
153177	31816951	Aberrations in either the composition or number of MAMs lead to an alteration in inter-organellar calcium dynamics and causes increased oxidative stress and metabolic disturbance.	('increased oxidative stress', 'Phenotype', 'HP:0025464', (126, 152))	('MAM', 'Gene', '6445', (51, 54))	('inter-organellar calcium dynamics', 'MPA', (81, 114))	('metabolic disturbance', 'Phenotype', 'HP:0001939', (157, 178))	('alteration', 'Reg', (67, 77))	('calcium', 'Chemical', 'MESH:D002118', (98, 105))	('metabolic disturbance', 'MPA', (157, 178))	('MAM', 'Gene', (51, 54))	('oxidative stress', 'MPA', (136, 152))	('Aberrations', 'Var', (0, 11))	('increased', 'PosReg', (126, 135))
153183	31816951	Along with MCPIP-1 induction, the up-regulation of PERK and CNX in RCC cells and xenograft tumors by MCP-1 treatment may sensitize RCC cells to ER stress-induced apoptosis by facilitating the propagation of ROS signals through enhancing MAMs and by forming Bap31-containing pro-apoptosis complex, respectively.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('pro-apoptosis', 'biological_process', 'GO:0043065', ('274', '287'))	('regulation', 'biological_process', 'GO:0065007', ('37', '47'))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', (67, 70))	('ROS', 'Chemical', 'MESH:D017382', (207, 210))	('propagation', 'MPA', (192, 203))	('CNX', 'Gene', (60, 63))	('PERK', 'Gene', (51, 55))	('sensitize', 'Reg', (121, 130))	('ROS signals', 'MPA', (207, 218))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('MAM', 'Gene', (237, 240))	('MCP-1', 'Var', (101, 106))	('men', 'Species', '9606', (112, 115))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('MCP', 'molecular_function', 'GO:0004298', ('101', '104'))	('ER stress-induced apoptosis', 'biological_process', 'GO:0070059', ('144', '171'))	('enhancing', 'PosReg', (227, 236))	('facilitating', 'PosReg', (175, 187))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('MAM', 'Gene', '6445', (237, 240))	('tumors', 'Disease', (91, 97))	('up-regulation', 'PosReg', (34, 47))
153252	31404170	Abnormal expressions of lncRNAs are frequent biological phenomena in tumor and closely associated with prognosis of tumor patients.	('Abnormal expressions', 'Phenotype', 'HP:0100022', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('associated', 'Reg', (87, 97))	('patients', 'Species', '9606', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('Abnormal', 'Var', (0, 8))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
153280	31404170	Then, survival analysis was performed for the 9 lncRNAs, among these lncRNAs, 6 lncRNAs (RP13-463N16.6, CTD-2201E18.5, RP11-430G17.3, AC005785.2, RP11-2E11.9 and TFAP2A-AS1) were associated with worse prognosis, and the remaining 3 lncRNAs (RP11-133F8.2, RP11-297L17.2 and RP11-348J24.2) were associated with better prognosis (Fig.	('RP13', 'Gene', '10594', (89, 93))	('TFAP2A-AS1', 'Gene', (162, 172))	('RP11', 'Gene', (146, 150))	('RP11', 'Gene', '26121', (255, 259))	('RP11', 'Gene', '26121', (146, 150))	('RP11', 'Gene', '26121', (241, 245))	('RP13', 'Gene', (89, 93))	('RP11', 'Gene', (273, 277))	('RP11', 'Gene', (119, 123))	('AC005785.2', 'Var', (134, 144))	('CTD-2201E18.5', 'Var', (104, 117))	('RP11', 'Gene', (255, 259))	('RP11', 'Gene', '26121', (119, 123))	('RP11', 'Gene', '26121', (273, 277))	('TFAP2A-AS1', 'Gene', '100130275;7020;5729', (162, 172))	('RP11', 'Gene', (241, 245))
153344	33390830	Furthermore, high ACE2 expression group in decreased CD4 Naive, enriched CD4 Naive and enriched CD4 memory cohort had favorable prognosis.	('CD4', 'Gene', (96, 99))	('high', 'Var', (13, 17))	('CD4', 'Gene', '920', (96, 99))	('CD4', 'Gene', (73, 76))	('CD4', 'Gene', '920', (73, 76))	('ACE2', 'Gene', (18, 22))	('memory', 'biological_process', 'GO:0007613', ('100', '106'))	('CD4', 'Gene', (53, 56))	('CD4', 'Gene', '920', (53, 56))	('ACE2', 'Gene', '59272', (18, 22))	('expression', 'MPA', (23, 33))
153395	33390830	The log-rank test results showed that high ACE2 expression groups was associated with longer OS in T3/T4, Grade 3/4, Stage III/IV and Metastasis subgroups (Figure 4A), and it was also correlated with longer RFS in T3/T4, Grade 3/4 and Stage III/IV subgroups (Figure 4B).	('S', 'Gene', '43740568', (117, 118))	('S', 'Gene', '43740568', (94, 95))	('ACE2', 'Gene', '59272', (43, 47))	('high', 'Var', (38, 42))	('Grade 3/4', 'Disease', (106, 115))	('Metastasis', 'CPA', (134, 144))	('T3/T4', 'Disease', (99, 104))	('S', 'Gene', '43740568', (235, 236))	('S', 'Gene', '43740568', (209, 210))	('ACE2', 'Gene', (43, 47))
153403	33390830	Moreover, T3/T4, G3/G4, Stage III/IV, and Metastasis (M1) groups had lower CD4 Naive and higher CD4 Memory and DC infiltration levels (Figure 6B).	('CD4', 'Gene', (96, 99))	('CD4', 'Gene', '920', (96, 99))	('G3/G4', 'Var', (17, 22))	('lower', 'NegReg', (69, 74))	('higher', 'PosReg', (89, 95))	('CD4', 'Gene', (75, 78))	('Metastasis', 'CPA', (42, 52))	('S', 'Gene', '43740568', (24, 25))	('CD4', 'Gene', '920', (75, 78))
153418	33390830	Using the RNA-sequencing and clinical data from TCGA, survival analysis results showed that the high ACE2 expression group had remarkably longer OS and RFS than the low ACE2 expression group, and the multivariate Cox regression analysis results indicated that increased ACE2 expression independently predicted longer OS and RFS of ccRCC patients.	('RNA', 'cellular_component', 'GO:0005562', ('10', '13'))	('ACE2', 'Gene', '59272', (101, 105))	('ACE2', 'Gene', '59272', (169, 173))	('S', 'Gene', '43740568', (146, 147))	('ACE2', 'Gene', '59272', (270, 274))	('S', 'Gene', '43740568', (318, 319))	('S', 'Gene', '43740568', (154, 155))	('expression', 'MPA', (275, 285))	('S', 'Gene', '43740568', (326, 327))	('RCC', 'Disease', 'MESH:C538614', (333, 336))	('high', 'Var', (96, 100))	('RCC', 'Disease', (333, 336))	('longer', 'PosReg', (138, 144))	('ACE2', 'Gene', (101, 105))	('ACE2', 'Gene', (169, 173))	('ACE2', 'Gene', (270, 274))	('increased', 'PosReg', (260, 269))	('patients', 'Species', '9606', (337, 345))
153421	33390830	Moreover, our immunohistochemistry results confirmed that T3/T4, Grade 3/4 and M1 groups had lower ACE2 protein expression than that in T1/T2, Grade 1/2 and M0 groups, respectively.	('ACE2', 'Gene', (99, 103))	('ACE2', 'Gene', '59272', (99, 103))	('lower', 'NegReg', (93, 98))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('T3/T4', 'Var', (58, 63))
153463	33194661	In addition, mutations in RCC-associated genes are thought to be involved in pathways such as the tricarboxylic acid (TCA) cycle and tumor energetics.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (98, 116))	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('involved', 'Reg', (65, 73))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('tumor', 'Disease', (133, 138))	('TCA', 'Chemical', 'MESH:D014233', (118, 121))	('mutations', 'Var', (13, 22))	('TCA) cycle', 'biological_process', 'GO:0006099', ('118', '128'))
153464	33194661	studied the relationships of metabolism-associated genes deregulation in ccRCC and Luo et al.	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('metabolism', 'biological_process', 'GO:0008152', ('29', '39'))	('deregulation', 'Var', (57, 69))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))
153485	33194661	Through the application of "glmnet" and "survival" packages in R software, a three-gene-RS model was calculated (Figure 3A), which was presented as "(-0.00958307120509029) * (CPT2 expression) + (-0.00609212290247052) * (ALDH3A2 expression) + 0.0187929890446235 * (B3GAT3expression).	('CPT2', 'Gene', '1376', (175, 179))	('ALDH3A2', 'Gene', '224', (220, 227))	('B3GAT3', 'Gene', '26229', (264, 270))	('ALDH3A2', 'Gene', (220, 227))	('B3GAT3', 'Gene', (264, 270))	('-0.00609212290247052', 'Var', (195, 215))	('CPT2', 'Gene', (175, 179))
153507	33194661	Our study showed that low levels of ALDH3A2 were associated with decreased survival.	('survival', 'CPA', (75, 83))	('decreased', 'NegReg', (65, 74))	('ALDH3A2', 'Gene', (36, 43))	('ALDH3A2', 'Gene', '224', (36, 43))	('low levels', 'Var', (22, 32))	('ALDH', 'molecular_function', 'GO:0004030', ('36', '40'))
153547	30146487	The major genetic driver in ccRCC is loss of the von Hippel-Lindau (VHL) tumor suppressor gene through somatic mutations, epigenetic silencing or loss of heterozygosity.	('epigenetic silencing', 'Var', (122, 142))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (49, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor suppressor', 'biological_process', 'GO:0051726', ('73', '89'))	('loss', 'NegReg', (37, 41))	('ccRCC', 'Disease', (28, 33))	('loss of heterozygosity', 'Var', (146, 168))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('73', '89'))	('ccRCC', 'Disease', 'MESH:D002292', (28, 33))
153550	30146487	Consequently, loss of VHL leads to a pseudo-hypoxic state in the cell stemming from aberrant accumulation of HIF-1alpha and -2alpha, and HIFalpha transcriptionally controlled downstream pathways are permutated.	('loss', 'Var', (14, 18))	('leads to', 'Reg', (26, 34))	('VHL', 'Gene', (22, 25))	('VHL', 'Gene', '7428', (22, 25))	('accumulation', 'PosReg', (93, 105))	('HIF-1alpha', 'Protein', (109, 119))	('pseudo-hypoxic state', 'MPA', (37, 57))
153601	30146487	In cell culture models, PDK1 is a transcriptional target of HIF1alpha and its expression is enhanced upon VHL loss.	('expression', 'MPA', (78, 88))	('HIF1alpha', 'Gene', (60, 69))	('loss', 'Var', (110, 114))	('PDK1', 'Gene', '5163', (24, 28))	('HIF1alpha', 'Gene', '3091', (60, 69))	('PDK1', 'Gene', (24, 28))	('PDK1', 'molecular_function', 'GO:0004740', ('24', '28'))	('VHL', 'Gene', (106, 109))	('VHL', 'Gene', '7428', (106, 109))	('enhanced', 'PosReg', (92, 100))
153602	30146487	Expression of PDK1 and suppression of PDH is predicted to result in reduced enrichment of the citrate m+2 isotopologue compared to pyruvate m+3 as shown in Figure 3D, and subsequent decrease in glucose derived intermediates contributing to the TCA cycle.	('Expression', 'Var', (0, 10))	('decrease', 'NegReg', (182, 190))	('PDK1', 'Gene', (14, 18))	('citrate', 'Chemical', 'MESH:C102006', (94, 101))	('TCA cycle', 'biological_process', 'GO:0006099', ('244', '253'))	('glucose derived intermediates contributing', 'MPA', (194, 236))	('PDH', 'molecular_function', 'GO:0004246', ('38', '41'))	('PDH', 'Gene', (38, 41))	('PDK1', 'molecular_function', 'GO:0004740', ('14', '18'))	('suppression', 'NegReg', (23, 34))	('PDH', 'molecular_function', 'GO:0033718', ('38', '41'))	('PDK1', 'Gene', '5163', (14, 18))	('glucose', 'Chemical', 'MESH:D005947', (194, 201))	('enrichment of the citrate m+2 isotopologue', 'MPA', (76, 118))	('pyruvate m', 'Chemical', 'MESH:D011773', (131, 141))	('PDH', 'molecular_function', 'GO:0004739', ('38', '41'))	('TCA', 'Enzyme', (244, 247))	('TCA', 'Chemical', 'MESH:D014233', (244, 247))	('reduced', 'NegReg', (68, 75))	('PDH', 'Gene', '54704', (38, 41))
153606	30146487	If [U-13C]glucose is converted to [U-13C]lactate outside the tumor, this labeled lactate can enter the circulation and eventually contribute to 13C labeling in tumor lactate and other metabolites.	('lactate', 'Chemical', 'MESH:D019344', (166, 173))	('13C', 'Chemical', 'MESH:C513342', (144, 147))	('[U-13C', 'Var', (34, 40))	('13C', 'Chemical', 'MESH:C513342', (6, 9))	('contribute', 'Reg', (130, 140))	('lactate', 'Chemical', 'MESH:D019344', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('[U-13C]glucose', 'Chemical', 'MESH:D005947', (3, 17))	('13C', 'Chemical', 'MESH:C513342', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('lactate', 'Chemical', 'MESH:D019344', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('13C labeling', 'MPA', (144, 156))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', (61, 66))	('[U-13C]lactate', 'Chemical', 'MESH:D019344', (34, 48))
153625	30146487	VHL inactivation through mutation, epigenetic silencing, or loss of heterozygosity occurs in up to 90% of ccRCCs.	('mutation', 'Var', (25, 33))	('epigenetic silencing', 'Var', (35, 55))	('ccRCC', 'Disease', (106, 111))	('VHL', 'Gene', (0, 3))	('loss', 'Var', (60, 64))	('ccRCC', 'Disease', 'MESH:D002292', (106, 111))	('VHL', 'Gene', '7428', (0, 3))	('inactivation', 'NegReg', (4, 16))
153668	30046388	Combined inhibition of PI3K and Src kinases demonstrates synergistic therapeutic efficacy in clear-cell renal carcinoma Potent inhibitors of PI3K (GDC-0941) and Src (Saracatinib) exhibit as individual agents, excellent oral anticancer activity in preclinical models and have entered phase II clinical trials in various cancers.	('cancers', 'Phenotype', 'HP:0002664', (319, 326))	('cancer', 'Disease', (319, 325))	('cancers', 'Disease', (319, 326))	('GDC-0941', 'Chemical', 'MESH:C532162', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('inhibitors', 'Var', (127, 137))	('clear-cell renal carcinoma', 'Phenotype', 'HP:0006770', (93, 119))	('PI3K', 'molecular_function', 'GO:0016303', ('23', '27'))	('clinical', 'Species', '191496', (292, 300))	('cancer', 'Disease', (228, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('cancers', 'Disease', 'MESH:D009369', (319, 326))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('Saracatinib', 'Chemical', 'MESH:C515233', (166, 177))	('PI3K', 'Gene', (141, 145))	('renal carcinoma', 'Phenotype', 'HP:0005584', (104, 119))	('clear-cell renal carcinoma', 'Disease', 'MESH:C538614', (93, 119))	('clear-cell renal carcinoma', 'Disease', (93, 119))	('clinical', 'Species', '191496', (250, 258))	('PI3K', 'molecular_function', 'GO:0016303', ('141', '145'))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
153679	30046388	Indeed, PI3K activation in tumor cells is often accompanied by concurrent activation of other oncogenic pathways, explaining the de novo treatment resistance.	('oncogenic pathways', 'Pathway', (94, 112))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('PI3K', 'molecular_function', 'GO:0016303', ('8', '12'))	('activation', 'PosReg', (13, 23))	('activation', 'PosReg', (74, 84))	('PI3K', 'Var', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
153684	30046388	Accumulating evidence suggest that Src interacts with and stimulates the PI3K/Akt pathway in cancer cells and knockdown of PI3K was shown to inhibit Src activation suggesting a potential bidirectional crosstalk.	('knockdown', 'Var', (110, 119))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('Src activation', 'MPA', (149, 163))	('PI3K', 'molecular_function', 'GO:0016303', ('73', '77'))	('Akt', 'Gene', '207', (78, 81))	('interacts', 'Interaction', (39, 48))	('stimulates', 'PosReg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Akt', 'Gene', (78, 81))	('PI3K', 'molecular_function', 'GO:0016303', ('123', '127'))	('inhibit', 'NegReg', (141, 148))	('PI3K', 'Var', (123, 127))
153700	30046388	As single agent, GDC-0941 and Saracatinib inhibited ccRCC cell growth in a dose dependent manner (Figure 1B).	('cell growth', 'biological_process', 'GO:0016049', ('58', '69'))	('inhibited', 'NegReg', (42, 51))	('GDC-0941', 'Var', (17, 25))	('ccRCC', 'Disease', (52, 57))	('GDC-0941', 'Chemical', 'MESH:C532162', (17, 25))	('Saracatinib', 'Chemical', 'MESH:C515233', (30, 41))
153701	30046388	786-O VHL+ cells displayed higher sensitivity to GDC-0941 than 786-O VHL- cells (GI25: 1.0 and 1.6muM respectively).	('GDC-0941', 'Var', (49, 57))	('sensitivity', 'MPA', (34, 45))	('muM', 'Gene', (98, 101))	('VHL', 'Disease', 'MESH:D006623', (6, 9))	('VHL', 'Disease', 'MESH:D006623', (69, 72))	('VHL', 'Disease', (6, 9))	('VHL+', 'Gene', (6, 10))	('VHL+', 'Gene', '7428', (6, 10))	('VHL', 'Disease', (69, 72))	('muM', 'Gene', '56925', (98, 101))	('GDC-0941', 'Chemical', 'MESH:C532162', (49, 57))
153705	30046388	As expected, Src phosphorylation was also inhibited in a dose-dependent manner by Saracatinib (Supplementary Figure 4A).	('Saracatinib', 'Chemical', 'MESH:C515233', (82, 93))	('phosphorylation', 'biological_process', 'GO:0016310', ('17', '32'))	('Saracatinib', 'Var', (82, 93))	('inhibited', 'NegReg', (42, 51))	('Src phosphorylation', 'MPA', (13, 32))
153706	30046388	Unexpectedly, in both cell lines, Akt and Src expression levels, were upregulated in response to either GDC-0941 or Saracatinib treatment respectively, suggesting a potential crosstalk between the PI3K/Akt and Src signaling pathways (Supplementary Figure 4A and 4B).	('Saracatinib', 'Chemical', 'MESH:C515233', (116, 127))	('crosstalk', 'Reg', (175, 184))	('GDC-0941', 'Chemical', 'MESH:C532162', (104, 112))	('Src expression levels', 'MPA', (42, 63))	('Src signaling pathways', 'Pathway', (210, 232))	('PI3K', 'molecular_function', 'GO:0016303', ('197', '201'))	('Akt', 'Gene', '207', (202, 205))	('Akt', 'Gene', (202, 205))	('Akt', 'Gene', '207', (34, 37))	('signaling', 'biological_process', 'GO:0023052', ('214', '223'))	('upregulated', 'PosReg', (70, 81))	('Akt', 'Gene', (34, 37))	('GDC-0941', 'Var', (104, 112))
153708	30046388	When used as a single agent, GDC-0941 inhibited viability of 786-O VHL- and VHL+ cells with IC50s equal to 4 and 1.6 muM respectively.	('50s', 'Species', '1214577', (94, 97))	('GDC-0941', 'Chemical', 'MESH:C532162', (29, 37))	('GDC-0941', 'Var', (29, 37))	('viability', 'CPA', (48, 57))	('muM', 'Gene', '56925', (117, 120))	('inhibited', 'NegReg', (38, 47))	('VHL+', 'Gene', '7428', (76, 80))	('VHL', 'Disease', (76, 79))	('VHL+', 'Gene', (76, 80))	('muM', 'Gene', (117, 120))	('VHL', 'Disease', 'MESH:D006623', (76, 79))	('VHL', 'Disease', 'MESH:D006623', (67, 70))	('VHL', 'Disease', (67, 70))
153710	30046388	Interestingly, a GDC-0941/ Saracatinib combination was highly synergistic in killing 786-O cells in the lower, clinically relevant dose range, reaching up to 40% more inhibition than predicted by Bliss additivity (Figure 1C).	('Saracatinib', 'Chemical', 'MESH:C515233', (27, 38))	('clinical', 'Species', '191496', (111, 119))	('GDC-0941/', 'Var', (17, 26))	('inhibition', 'MPA', (167, 177))	('GDC-0941', 'Chemical', 'MESH:C532162', (17, 25))
153712	30046388	The results show that Akt2 that is selectively inhibited by CCT128930, might not be involved as it had a low impact on 786-O cell mortality, and importantly, no synergistic effect in combination with Saracatinib (Supplementary Figure 5A).	('inhibited', 'NegReg', (47, 56))	('786-O cell mortality', 'CPA', (119, 139))	('Saracatinib', 'Chemical', 'MESH:C515233', (200, 211))	('Akt2', 'Gene', (22, 26))	('Akt2', 'Gene', '208', (22, 26))	('CCT128930', 'Var', (60, 69))
153714	30046388	Immunoblotting of lysates prepared from VHL- or VHL+ 786-O-treated cells showed that GDC-0941caused a marked induction of cleaved-PARP, a key substrate of activated caspases and an early indicator of apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('200', '209'))	('PARP', 'Gene', (130, 134))	('induction', 'PosReg', (109, 118))	('VHL', 'Disease', 'MESH:D006623', (40, 43))	('apoptosis', 'biological_process', 'GO:0006915', ('200', '209'))	('PARP', 'Gene', '1302', (130, 134))	('VHL', 'Disease', (48, 51))	('VHL', 'Disease', 'MESH:D006623', (48, 51))	('VHL+', 'Gene', (48, 52))	('VHL+', 'Gene', '7428', (48, 52))	('GDC-0941caused', 'Var', (85, 99))	('VHL', 'Disease', (40, 43))	('GDC-0941caused', 'Chemical', '-', (85, 99))
153719	30046388	Accordingly, cell motility signaling components were differentially activated in 786-O VHL-, 786-O VHL+ and RPTEC cells as evidenced by phosphorylation of FAK (Y576/577), Paxillin (Y118) and p130Cas (Y410) (Figure 2B, left panel).	('phosphorylation', 'MPA', (136, 151))	('VHL', 'Disease', (99, 102))	('VHL', 'Disease', 'MESH:D006623', (87, 90))	('cell motility', 'biological_process', 'GO:0048870', ('13', '26'))	('Cas', 'cellular_component', 'GO:0005650', ('195', '198'))	('FAK', 'Gene', '5747', (155, 158))	('Paxillin', 'Gene', '5829', (171, 179))	('VHL+', 'Gene', '7428', (99, 103))	('activated', 'PosReg', (68, 77))	('VHL', 'Disease', 'MESH:D006623', (99, 102))	('signaling', 'biological_process', 'GO:0023052', ('27', '36'))	('p130Cas', 'Gene', (191, 198))	('VHL+', 'Gene', (99, 103))	('Paxillin', 'Gene', (171, 179))	('VHL', 'Disease', (87, 90))	('cell motility signaling components', 'MPA', (13, 47))	('Y576/577', 'Var', (160, 168))	('FAK', 'molecular_function', 'GO:0004717', ('155', '158'))	('p130Cas', 'Gene', '9564', (191, 198))	('Y118', 'Var', (181, 185))	('FAK', 'Gene', (155, 158))	('phosphorylation', 'biological_process', 'GO:0016310', ('136', '151'))
153721	30046388	However, combined inhibition of PI3K and Src led to a significant synergistic inhibition of migration of 786-O VHL- cells, whereas migration of 786-O VHL+ cells was weakly affected (Figure 2A, right panel).	('VHL', 'Disease', 'MESH:D006623', (150, 153))	('inhibition', 'NegReg', (18, 28))	('PI3K', 'molecular_function', 'GO:0016303', ('32', '36'))	('VHL+', 'Gene', (150, 154))	('Src', 'Gene', (41, 44))	('VHL+', 'Gene', '7428', (150, 154))	('inhibition', 'NegReg', (78, 88))	('migration', 'CPA', (92, 101))	('PI3K', 'Var', (32, 36))	('VHL', 'Disease', 'MESH:D006623', (111, 114))	('VHL', 'Disease', (111, 114))	('VHL', 'Disease', (150, 153))
153722	30046388	Single treatment of 786-O VHL- cells with Saracatinib resulted in efficient suppression of Src autophosphorylation at Y418 (Supplementary Figure 4B) together with a strong decrease in the phosphorylation of FAK, Paxillin and p130Cas, which are signaling proteins required for efficient integrin-mediated focal adhesion formation (Figure 2B, right panel).	('Paxillin', 'Gene', '5829', (212, 220))	('Src autophosphorylation', 'MPA', (91, 114))	('VHL', 'Disease', (26, 29))	('p130Cas', 'Gene', (225, 232))	('signaling', 'biological_process', 'GO:0023052', ('244', '253'))	('Cas', 'cellular_component', 'GO:0005650', ('229', '232'))	('Saracatinib', 'Chemical', 'MESH:C515233', (42, 53))	('Paxillin', 'Gene', (212, 220))	('decrease', 'NegReg', (172, 180))	('FAK', 'Gene', (207, 210))	('phosphorylation', 'MPA', (188, 203))	('suppression', 'NegReg', (76, 87))	('focal adhesion formation', 'biological_process', 'GO:0048041', ('304', '328'))	('phosphorylation', 'biological_process', 'GO:0016310', ('188', '203'))	('p130Cas', 'Gene', '9564', (225, 232))	('VHL', 'Disease', 'MESH:D006623', (26, 29))	('focal adhesion', 'cellular_component', 'GO:0005925', ('304', '318'))	('FAK', 'Gene', '5747', (207, 210))	('FAK', 'molecular_function', 'GO:0004717', ('207', '210'))	('Saracatinib', 'Var', (42, 53))
153726	30046388	Single agent treatment with GDC-0941 or Saracatinib at a concentration of 0.75muM or 1muM respectively, had a significant inhibitory effect on the invasion of 786-O cells.	('GDC-0941', 'Chemical', 'MESH:C532162', (28, 36))	('muM', 'Gene', (78, 81))	('muM', 'Gene', '56925', (86, 89))	('inhibitory effect', 'NegReg', (122, 139))	('invasion of 786-O cells', 'CPA', (147, 170))	('Saracatinib', 'Gene', (40, 51))	('muM', 'Gene', (86, 89))	('Saracatinib', 'Chemical', 'MESH:C515233', (40, 51))	('muM', 'Gene', '56925', (78, 81))	('GDC-0941', 'Var', (28, 36))
153727	30046388	Interestingly, invasion of both cell lines was almost completely suppressed by the GDC-0941/Saracatinib combination (Figure 2C, right panel).	('GDC-0941/Saracatinib', 'Var', (83, 103))	('suppressed', 'NegReg', (65, 75))	('Saracatinib', 'Chemical', 'MESH:C515233', (92, 103))	('invasion of', 'CPA', (15, 26))	('GDC-0941', 'Chemical', 'MESH:C532162', (83, 91))
153729	30046388	We found that GDC-0941 caused in both VHL- or VHL+ 786-O cells, a dramatic decrease in expression of MMP-9 in its cleaved and hence active form, whereas MMP-2 was not affected (Figure 2D).	('GDC-0941', 'Chemical', 'MESH:C532162', (14, 22))	('cleaved', 'MPA', (114, 121))	('MMP-2', 'molecular_function', 'GO:0004228', ('153', '158'))	('MMP-9', 'molecular_function', 'GO:0004229', ('101', '106'))	('decrease', 'NegReg', (75, 83))	('MMP-9', 'Gene', '4318', (101, 106))	('MMP-2', 'Gene', '4313', (153, 158))	('VHL+', 'Gene', (46, 50))	('VHL', 'Disease', 'MESH:D006623', (38, 41))	('MMP-9', 'Gene', (101, 106))	('VHL', 'Disease', (38, 41))	('expression', 'MPA', (87, 97))	('MMP-2', 'Gene', (153, 158))	('VHL', 'Disease', 'MESH:D006623', (46, 49))	('VHL', 'Disease', (46, 49))	('GDC-0941', 'Var', (14, 22))	('VHL+', 'Gene', '7428', (46, 50))
153733	30046388	After 72h of treatment with GDC-0941 or Saracatinib alone, a decrease in the size of the spheroids could be observed and this effect was more pronounced in response to the drug combination (Figure 3A).	('GDC-0941', 'Chemical', 'MESH:C532162', (28, 36))	('decrease', 'NegReg', (61, 69))	('Saracatinib', 'Chemical', 'MESH:C515233', (40, 51))	('size of the spheroids', 'CPA', (77, 98))	('GDC-0941', 'Var', (28, 36))
153734	30046388	Western blot and immunochemistry analyses of these MCTSs showed that both GDC-0941 and Saracatinib were able to dampen the Akt and Src phosphorylation (Figure 3B, left panel).	('phosphorylation', 'biological_process', 'GO:0016310', ('135', '150'))	('Saracatinib', 'Chemical', 'MESH:C515233', (87, 98))	('Akt', 'Gene', '207', (123, 126))	('GDC-0941', 'Var', (74, 82))	('GDC-0941', 'Chemical', 'MESH:C532162', (74, 82))	('dampen', 'NegReg', (112, 118))	('Akt', 'Gene', (123, 126))
153735	30046388	Consistent with findings obtained with 2D cultures of 786-O cells, Akt and Src expression levels were upregulated in response to either GDC-0941 or Saracatinib treatment respectively, suggesting again a potential crosstalk between these two signaling pathways.	('crosstalk', 'Reg', (213, 222))	('Akt', 'Gene', (67, 70))	('upregulated', 'PosReg', (102, 113))	('Saracatinib', 'Chemical', 'MESH:C515233', (148, 159))	('GDC-0941', 'Var', (136, 144))	('signaling', 'biological_process', 'GO:0023052', ('241', '250'))	('Src expression levels', 'MPA', (75, 96))	('GDC-0941', 'Chemical', 'MESH:C532162', (136, 144))	('Akt', 'Gene', '207', (67, 70))
153737	30046388	GDC-0941 or Saracatinib as single agent induced significant levels of apoptosis visualized by cleavage of effector caspases-3/7 and PARP together with an inhibition of proliferation (PCNA staining).	('PCNA', 'molecular_function', 'GO:0003892', ('183', '187'))	('proliferation', 'CPA', (168, 181))	('apoptosis', 'biological_process', 'GO:0097194', ('70', '79'))	('caspases-3/7', 'Protein', (115, 127))	('PARP', 'Gene', '1302', (132, 136))	('PARP', 'Gene', (132, 136))	('Saracatinib', 'Chemical', 'MESH:C515233', (12, 23))	('apoptosis', 'biological_process', 'GO:0006915', ('70', '79'))	('inhibition', 'NegReg', (154, 164))	('PCNA', 'Gene', (183, 187))	('GDC-0941', 'Var', (0, 8))	('cleavage', 'MPA', (94, 102))	('GDC-0941', 'Chemical', 'MESH:C532162', (0, 8))	('PCNA', 'Gene', '5111', (183, 187))
153739	30046388	As illustrated in Figure 4A, left panel, Saracatinib and GDC-0941 to a lower extent, induced a detectable cell death that was strikingly enhanced by the drug combination.	('enhanced', 'PosReg', (137, 145))	('Saracatinib', 'Chemical', 'MESH:C515233', (41, 52))	('cell death', 'CPA', (106, 116))	('induced', 'Reg', (85, 92))	('combination', 'Interaction', (158, 169))	('GDC-0941', 'Chemical', 'MESH:C532162', (57, 65))	('Saracatinib', 'Var', (41, 52))	('GDC-0941', 'Gene', (57, 65))	('cell death', 'biological_process', 'GO:0008219', ('106', '116'))
153740	30046388	Taken together, these results demonstrate that combined inhibition of PI3K and Src induces a massive cell death in tumor slice cultures derived from a PDX model.	('inhibition', 'NegReg', (56, 66))	('cell death', 'CPA', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('Src', 'Gene', (79, 82))	('PI3K', 'Var', (70, 74))	('cell death', 'biological_process', 'GO:0008219', ('101', '111'))	('PI3K', 'molecular_function', 'GO:0016303', ('70', '74'))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
153754	30046388	All the three Akt isoforms possess a Serine at position 473 that should be phosphorylated by PI3K.	('Akt', 'Gene', (14, 17))	('Serine at', 'Var', (37, 46))	('Serine', 'Chemical', 'MESH:D012694', (37, 43))	('PI3K', 'molecular_function', 'GO:0016303', ('93', '97'))	('Akt', 'Gene', '207', (14, 17))
153766	30046388	Antibodies against P-FAK (Y576/577) (#3281), P-Paxillin (Y118) (#2541), P-p130Cas (Y410) (#4011), PARP (#9542), Akt (#9272), Src (#2109), Active-Caspase-3 (#9664), P-Akt (S473) (#4051), Caspase 7 (D2Q3L) (#12827), VHL (#2738), MMP2 (#4022), MMP9 (#3852) and HSP90 (#4874) were from Cell Signaling Technologies (Danvers, MA).	('Paxillin', 'Gene', '5829', (47, 55))	('#2738', 'Var', (219, 224))	('FAK', 'molecular_function', 'GO:0004717', ('21', '24'))	('Akt', 'Gene', (166, 169))	('#3852', 'Var', (247, 252))	('Caspase-3', 'Gene', (145, 154))	('MMP2', 'Gene', (227, 231))	('Akt', 'Gene', '207', (112, 115))	('FAK', 'Gene', '5747', (21, 24))	('Signaling', 'biological_process', 'GO:0023052', ('287', '296'))	('Akt', 'Gene', '207', (166, 169))	('PARP', 'Gene', '1302', (98, 102))	('VHL', 'Disease', 'MESH:D006623', (214, 217))	('#4874', 'Var', (265, 270))	('Caspase 7', 'Gene', (186, 195))	('Paxillin', 'Gene', (47, 55))	('p130Cas', 'Gene', (74, 81))	('Cas', 'cellular_component', 'GO:0005650', ('78', '81'))	('Caspase 7', 'Gene', '840', (186, 195))	('#9664', 'Var', (156, 161))	('MMP2', 'Gene', '4313', (227, 231))	('PARP', 'Gene', (98, 102))	('#4022', 'Var', (233, 238))	('Y118', 'Var', (57, 61))	('#4051', 'Var', (178, 183))	('HSP90', 'Gene', (258, 263))	('Caspase-3', 'Gene', '836', (145, 154))	('#2541', 'Var', (64, 69))	('p130Cas', 'Gene', '9564', (74, 81))	('#12827', 'Var', (205, 211))	('VHL', 'Disease', (214, 217))	('MMP9', 'Gene', (241, 245))	('MMP9', 'Gene', '4318', (241, 245))	('MMP2', 'molecular_function', 'GO:0004228', ('227', '231'))	('FAK', 'Gene', (21, 24))	('HSP90', 'Gene', '3320', (258, 263))	('Akt', 'Gene', (112, 115))	('MMP9', 'molecular_function', 'GO:0004229', ('241', '245'))
153767	30046388	Antibodies against Paxillin (610052), FAK (610088) and p130Cas (610271) were from BD Biosciences (San Jose, CA).	('Paxillin', 'Gene', (19, 27))	('p130Cas', 'Gene', '9564', (55, 62))	('610271', 'Var', (64, 70))	('FAK', 'molecular_function', 'GO:0004717', ('38', '41'))	('Cas', 'cellular_component', 'GO:0005650', ('59', '62'))	('FAK', 'Gene', (38, 41))	('610052', 'Var', (29, 35))	('FAK', 'Gene', '5747', (38, 41))	('Paxillin', 'Gene', '5829', (19, 27))	('p130Cas', 'Gene', (55, 62))
153787	30046388	Cell pellets were suspended in 150mul of lysis buffer (RIPA buffer: Tris HCl pH 7.4 10mM, NaCl 150mM, SDS 0.1%, Na Deoxycholate 0.5%, EDTA 1mM, Triton X100 1%, Protease and phosphatase inhibitor cocktails (P8340 and P5726, Sigma, St Louis)).	('HCl', 'Chemical', '-', (73, 76))	('P8340', 'Var', (206, 211))	('P5726', 'Chemical', '-', (216, 221))	('phosphatase', 'molecular_function', 'GO:0016791', ('173', '184'))	('Triton X100', 'Chemical', 'MESH:D017830', (144, 155))	('SDS', 'Chemical', 'MESH:D012967', (102, 105))	('EDTA', 'Chemical', 'MESH:D004492', (134, 138))	('P5726', 'Var', (216, 221))	('NaCl', 'Chemical', 'MESH:D012965', (90, 94))	('lysis', 'biological_process', 'GO:0019835', ('41', '46'))	('Deoxycholate', 'Chemical', 'MESH:D003840', (115, 127))	('RIPA buffer', 'Chemical', '-', (55, 66))	('Tris', 'Chemical', '-', (68, 72))
153803	30046388	The status of VHL gene was determined as mutated (E160fs14aa (chr3-10191481-G->GA- (frameshift insertion) for RCC10B.	('VHL', 'Disease', (14, 17))	('E160fs14aa', 'Var', (50, 60))	('RCC10B', 'Gene', (110, 116))	('VHL', 'Disease', 'MESH:D006623', (14, 17))
153826	28969078	Epigenetic and genetic changes are identified to be significantly associated with cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('associated', 'Reg', (66, 76))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('Epigenetic', 'Var', (0, 10))	('genetic changes', 'Var', (15, 30))
153827	28969078	DNA methylation is an important mechanism of epigenetic alterations involved in gene expression, which is closely associated with the carcinogenesis and progression of various carcinomas.	('carcinogenesis', 'Disease', 'MESH:D063646', (134, 148))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('carcinomas', 'Disease', (176, 186))	('carcinomas', 'Disease', 'MESH:D002277', (176, 186))	('gene expression', 'biological_process', 'GO:0010467', ('80', '95'))	('carcinogenesis', 'Disease', (134, 148))	('associated', 'Reg', (114, 124))	('epigenetic alterations', 'Var', (45, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
153858	28969078	2004 reported that p14ARF methylation was not significantly associated with the prognosis in OS (Table 1).	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('methylation', 'Var', (26, 37))	('p14ARF', 'Gene', (19, 25))	('p14ARF', 'Gene', '1029', (19, 25))
153863	28969078	The silencing of p16INK4A and p14ARF can result in uncontrollable cell proliferation and tumor growth.	('p14ARF', 'Gene', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('p16INK4A', 'Gene', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('p14ARF', 'Gene', '1029', (30, 36))	('uncontrollable', 'MPA', (51, 65))	('result in', 'Reg', (41, 50))	('p16INK4A', 'Gene', '1029', (17, 25))	('tumor', 'Disease', (89, 94))	('silencing', 'Var', (4, 13))
153864	28969078	Methylated p16INK4A and p14ARF have been investigated in various cancers, including RCC, esophageal squamous cell carcinoma, melanoma, and gliomas.	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('RCC', 'Disease', (84, 87))	('p16INK4A', 'Gene', (11, 19))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))	('p16INK4A', 'Gene', '1029', (11, 19))	('esophageal squamous cell carcinoma', 'Disease', (89, 123))	('gliomas', 'Disease', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('Methylated', 'Var', (0, 10))	('p14ARF', 'Gene', '1029', (24, 30))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (89, 123))	('investigated', 'Reg', (41, 53))	('p14ARF', 'Gene', (24, 30))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))
153877	28969078	Methylated p14ARF was significantly associated with gender, in which it was lower in males than in females, suggesting that female RCC patients can be more susceptible to p14ARF promoter methylation, whereas methylated p16INK4A had a similar frequency in males and females.	('patients', 'Species', '9606', (135, 143))	('p14ARF', 'Gene', '1029', (11, 17))	('susceptible', 'Reg', (156, 167))	('p14ARF', 'Gene', (171, 177))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (131, 134))	('methylation', 'biological_process', 'GO:0032259', ('187', '198'))	('p14ARF', 'Gene', (11, 17))	('p16INK4A', 'Gene', (219, 227))	('p14ARF', 'Gene', '1029', (171, 177))	('methylation', 'Var', (187, 198))	('p16INK4A', 'Gene', '1029', (219, 227))
153878	28969078	Methylated p16INK4A was significantly associated with tumor size, in which it was higher in pT2-4 patients than in pT1 patients, suggesting that p16INK4A promoter methylation may play a key role in the pathogenesis of T2-4, whereas methylated p14ARF was not significantly correlated with tumor size.	('T2-4', 'Gene', '292', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('p16INK4A', 'Gene', (11, 19))	('p14ARF', 'Gene', '1029', (243, 249))	('p16INK4A', 'Gene', (145, 153))	('p16INK4A', 'Gene', '1029', (11, 19))	('pT1', 'Gene', '58492', (115, 118))	('p16INK4A', 'Gene', '1029', (145, 153))	('T2-4', 'Gene', (93, 97))	('T2-4', 'Gene', '292', (218, 222))	('pT1', 'Gene', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('methylation', 'biological_process', 'GO:0032259', ('163', '174'))	('Methylated', 'Var', (0, 10))	('tumor', 'Disease', (288, 293))	('p14ARF', 'Gene', (243, 249))	('patients', 'Species', '9606', (98, 106))	('T2-4', 'Gene', (218, 222))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('play', 'Reg', (179, 183))	('pathogenesis', 'biological_process', 'GO:0009405', ('202', '214'))	('patients', 'Species', '9606', (119, 127))	('higher', 'PosReg', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('tumor', 'Disease', (54, 59))
153887	28969078	We used the following free text and their combinations: (kidney OR renal) AND (cancer OR tumor OR neoplasm OR carcinoma) AND (CDKN2A OR MTS1 OR P16 OR INK4A OR P14 OR ARF) AND (methylation OR epigene*) up to September 20, 2016.	('INK4A', 'Gene', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('ARF', 'Disease', (167, 170))	('P16', 'Gene', '1029', (144, 147))	('P14', 'Gene', (160, 163))	('P16', 'Gene', (144, 147))	('epigene*', 'Var', (192, 200))	('MTS1', 'Gene', (136, 140))	('tumor', 'Disease', (89, 94))	('methylation', 'biological_process', 'GO:0032259', ('177', '188'))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('neoplasm OR carcinoma', 'Disease', (98, 119))	('CDKN2A', 'Gene', (126, 132))	('ARF', 'Disease', 'MESH:D058186', (167, 170))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('neoplasm OR carcinoma', 'Disease', 'MESH:D009369', (98, 119))	('INK4A', 'Gene', '1029', (151, 156))	('kidney OR renal) AND (cancer', 'Disease', 'MESH:D007680', (57, 85))	('CDKN2A', 'Gene', '1029', (126, 132))	('P14', 'Gene', '1029', (160, 163))	('MTS1', 'Gene', '1029', (136, 140))
153899	28775317	VHL mutations were also found in sporadic renal cell carcinoma and account for approximately 50% of sporadic ccRCC cases.	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('sporadic renal cell carcinoma', 'Disease', 'MESH:C538614', (33, 62))	('ccRCC', 'Disease', (109, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('VHL', 'Gene', (0, 3))	('sporadic renal cell carcinoma', 'Disease', (33, 62))	('mutations', 'Var', (4, 13))	('found', 'Reg', (24, 29))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (42, 62))	('VHL', 'Gene', '7428', (0, 3))
153905	28775317	From studies using genetically modified mice, HIF-1alpha mainly regulates glucose metabolism by activating the expression of glycolytic enzymes, whereas HIF-2alpha regulates fatty acid metabolism by suppressing the expression of enzymes for lipogenesis and beta-oxidation.	('glycolytic enzymes', 'MPA', (125, 143))	('enzymes for lipogenesis', 'MPA', (229, 252))	('glucose metabolism', 'biological_process', 'GO:0006006', ('74', '92'))	('regulates', 'Reg', (164, 173))	('activating', 'PosReg', (96, 106))	('regulates', 'Reg', (64, 73))	('fatty acid metabolism', 'MPA', (174, 195))	('expression', 'MPA', (111, 121))	('suppressing', 'NegReg', (199, 210))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('174', '195'))	('glucose', 'Chemical', 'MESH:D005947', (74, 81))	('lipogenesis', 'biological_process', 'GO:0008610', ('241', '252'))	('glucose metabolism', 'MPA', (74, 92))	('mice', 'Species', '10090', (40, 44))	('fatty acid', 'Chemical', 'MESH:D005227', (174, 184))	('HIF-2alpha', 'Var', (153, 163))	('beta-oxidation', 'MPA', (257, 271))	('expression', 'MPA', (215, 225))
153922	28775317	WCEs from HCT116 stably expressing Flag-tagged wild-type or mutant pVHL were prepared and tested for interactions by immunoprecipitation and western blot analyses (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (10, 16))	('interactions', 'Interaction', (101, 113))	('pVHL', 'Gene', (67, 71))	('mutant', 'Var', (60, 66))	('tested', 'Reg', (90, 96))
153923	28775317	In agreement with previous reports, the mutants pVHL-W88S, pVHL-H115Q, and pVHL-L158P showed a dramatic decrease in binding to HIF-1alpha whereas the mutants pVHL-L158P and pVHL-L184P almost completely lost binding to Elongin C and CUL2.	('L158P', 'Mutation', 'rs121913346', (163, 168))	('binding', 'molecular_function', 'GO:0005488', ('116', '123'))	('L158P', 'Mutation', 'rs121913346', (80, 85))	('binding', 'Interaction', (116, 123))	('W88S', 'Mutation', 'rs119103277', (53, 57))	('lost', 'NegReg', (202, 206))	('Elongin C', 'Protein', (218, 227))	('pVHL-L158P', 'Var', (75, 85))	('pVHL-L184P', 'Var', (173, 183))	('pVHL-L158P', 'Var', (158, 168))	('H115Q', 'Mutation', 'rs864622646', (64, 69))	('L184P', 'Mutation', 'rs1064793878', (178, 183))	('pVHL-W88S', 'Var', (48, 57))	('decrease', 'NegReg', (104, 112))	('binding', 'Interaction', (207, 214))	('HIF-1alpha', 'Protein', (127, 137))	('pVHL-H115Q', 'Var', (59, 69))	('binding', 'molecular_function', 'GO:0005488', ('207', '214'))
153924	28775317	pVHL-R167Q retained binding strongly to HIF-1alpha and weakly but significantly to HIF-2alpha and the E3 ligase components, which could reflect weakened HIF-2alpha degradation activity in pVHL-negative 786-O renal cancer cells (Supplementary Fig.	('renal cancer', 'Phenotype', 'HP:0009726', (208, 220))	('binding', 'Interaction', (20, 27))	('degradation', 'biological_process', 'GO:0009056', ('164', '175'))	('degradation activity', 'MPA', (164, 184))	('weakened', 'NegReg', (144, 152))	('R167Q', 'Mutation', 'rs5030821', (5, 10))	('HIF-1alpha', 'Protein', (40, 50))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('binding', 'molecular_function', 'GO:0005488', ('20', '27'))	('renal cancer', 'Disease', (208, 220))	('pVHL-R167Q', 'Var', (0, 10))	('renal cancer', 'Disease', 'MESH:D007680', (208, 220))
153925	28775317	pVHL-Y112H showed binding to both HIF-alpha proteins and Elongin C which was indistinguishable from pVHL-WT (Fig.	('binding', 'molecular_function', 'GO:0005488', ('18', '25'))	('HIF-alpha proteins', 'Protein', (34, 52))	('pVHL-Y112H', 'Var', (0, 10))	('Y112H', 'Mutation', 'rs104893824', (5, 10))	('binding', 'Interaction', (18, 25))	('Elongin C', 'Protein', (57, 66))
153926	28775317	In control experiments, pVHL-Y112H was able to strongly downregulate HIF-2alpha levels.	('Y112H', 'Mutation', 'rs104893824', (29, 34))	('pVHL-Y112H', 'Var', (24, 34))	('HIF-2alpha levels', 'MPA', (69, 86))	('downregulate', 'NegReg', (56, 68))
153927	28775317	The specific interactions between mutant pVHLs and E3 ligase components were further confirmed by silver staining (Fig.	('pVHLs', 'Gene', (41, 46))	('silver', 'Chemical', 'MESH:D012834', (98, 104))	('interactions', 'Interaction', (13, 25))	('mutant', 'Var', (34, 40))
153928	28775317	The precipitated pVHL mutant proteins were next tested for binding to FASN and CAD as well as a previously reported pVHL-interacting protein the large subunit of RNA polymerase II (RPB1) (Fig.	('binding', 'molecular_function', 'GO:0005488', ('59', '66'))	('binding', 'Interaction', (59, 66))	('CAD', 'Gene', '730249', (79, 82))	('proteins', 'Protein', (29, 37))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('mutant', 'Var', (22, 28))	('tested', 'Reg', (48, 54))	('RPB1', 'Gene', '5430', (181, 185))	('RNA', 'cellular_component', 'GO:0005562', ('162', '165'))	('CAD', 'Gene', (79, 82))	('RPB1', 'Gene', (181, 185))	('pVHL', 'Gene', (17, 21))
153929	28775317	Strikingly, pVHL-W88S and pVHL-Y112H showed greatly reduced binding to FASN and CAD, and moderately to RPB1.	('pVHL-W88S', 'Var', (12, 21))	('RPB1', 'Gene', (103, 107))	('RPB1', 'Gene', '5430', (103, 107))	('Y112H', 'Mutation', 'rs104893824', (31, 36))	('reduced', 'NegReg', (52, 59))	('binding', 'molecular_function', 'GO:0005488', ('60', '67'))	('W88S', 'Mutation', 'rs119103277', (17, 21))	('CAD', 'Gene', (80, 83))	('CAD', 'Gene', '730249', (80, 83))	('FASN', 'Protein', (71, 75))	('binding', 'Interaction', (60, 67))	('pVHL-Y112H', 'Var', (26, 36))
153930	28775317	Intriguingly, we found by IF staining that the majority of pVHL-Y112H and pVHL-W88S proteins were localized in the nucleus, whereas pVHL-WT and pVHL-H115Q were co-localized in the cytoplasm (Fig.	('H115Q', 'Mutation', 'rs864622646', (149, 154))	('pVHL-W88S', 'Var', (74, 83))	('pVHL-Y112H', 'Var', (59, 69))	('cytoplasm', 'cellular_component', 'GO:0005737', ('180', '189'))	('proteins', 'Protein', (84, 92))	('W88S', 'Mutation', 'rs119103277', (79, 83))	('nucleus', 'cellular_component', 'GO:0005634', ('115', '122'))	('Y112H', 'Mutation', 'rs104893824', (64, 69))
153931	28775317	This nuclear localization could be due to loss of binding of pVHL-W88S and pVHL-Y112H to FASN.	('pVHL-W88S', 'Var', (61, 70))	('FASN', 'Protein', (89, 93))	('Y112H', 'Mutation', 'rs104893824', (80, 85))	('localization', 'biological_process', 'GO:0051179', ('13', '25'))	('binding', 'molecular_function', 'GO:0005488', ('50', '57'))	('W88S', 'Mutation', 'rs119103277', (66, 70))	('binding', 'Interaction', (50, 57))	('pVHL-Y112H', 'Var', (75, 85))	('loss', 'NegReg', (42, 46))
153932	28775317	To investigate functional importance of the interaction, we tested the effects of siRNA-mediated knockdown of FASN expression on HIF-alpha protein levels in HeLa, HCT116 and cultured human primary renal epithelial cells (PREC).	('knockdown', 'Var', (97, 106))	('tested', 'Reg', (60, 66))	('FASN', 'Gene', (110, 114))	('human', 'Species', '9606', (183, 188))	('HeLa', 'CellLine', 'CVCL:0030', (157, 161))	('HIF-alpha protein levels', 'MPA', (129, 153))	('HCT116', 'CellLine', 'CVCL:0291', (163, 169))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))
153947	28775317	Ectopic expression of pVHL-WT and pVHL-Y112H was able to suppress HIF-1alpha and HIF-2alpha levels in normoxia.	('pVHL-Y112H', 'Var', (34, 44))	('pVHL-WT', 'Var', (22, 29))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (66, 91))	('suppress', 'NegReg', (57, 65))	('Y112H', 'Mutation', 'rs104893824', (39, 44))
153971	28775317	Suppressed Fasn expression was reversed by further disruption of the Hif-2alpha but not the Hif-1alpha locus, suggesting that Hif-2alpha is a major negative regulator of Fasn.	('Hif-2alpha', 'Gene', (69, 79))	('Hif-2alpha', 'Gene', '2034', (126, 136))	('Hif-2alpha', 'Gene', (126, 136))	('Fasn', 'Gene', (11, 15))	('disruption', 'Var', (51, 61))	('Hif-2alpha', 'Gene', '2034', (69, 79))
153980	28775317	Full length human cDNAs for wild-type or mutant pVHL (213 amino acids), HIF-1alpha, and HIF-2alpha were inserted into pCSGW, CSII-CMV-MCS-IRES2-Venus (RIKEN) or a derivative vector carrying a minimal HIV promoter with TATA and Sp1 binding sequences.	('MCS', 'cellular_component', 'GO:0044232', ('134', '137'))	('mutant', 'Var', (41, 47))	('pVHL', 'Gene', (48, 52))	('human', 'Species', '9606', (12, 17))	('binding', 'molecular_function', 'GO:0005488', ('231', '238'))
153982	28775317	The VHL cDNA sequence was mutagenized using the QuickChange II XL Site-directed Mutagenesis Kit (Stratagene) according to the manufacturer's instructions.	('Mutagenesis', 'biological_process', 'GO:0006280', ('80', '91'))	('VHL', 'Gene', '7428', (4, 7))	('VHL', 'Gene', (4, 7))	('mutagenized', 'Var', (26, 37))
153993	28775317	Antibodies used for western blot analysis are as follows: HIF-1alpha (GTX127309) from GeneTex; HIF-1alpha (NB100-479) and HIF-2alpha (NB100-122) from Novus Biologicals; HIF-2alpha (#7096), pVHL (#2738), FASN (#3180) and ubiquitin (#3936) from Cell Signaling; Elongin C (sc-135895), CUL2 (sc-166506), ARNT (sc-5580), SREBP1 (sc-366), and normal mouse and rabbit IgG (sc-2025 and sc-2027 respectively) from Santa Cruz Biotechnology; CAD (ab40800), RNA polymerase II large subunit CTD (ab5408), and CA9 (ab107257) from Abcam; beta-actin (A5441) and anti-Flag M2 (F1804) from Sigma-Aldrich; p65 (610869) from Becton Dickinson (BD) and REDD1 (A500-001A) from Bethyl Laboratories.	('CA9', 'Gene', '230099', (496, 499))	('rabbit', 'Species', '9986', (354, 360))	('p65 (610869', 'Var', (587, 598))	('CAD', 'Gene', (431, 434))	('mouse', 'Species', '10090', (344, 349))	('ubiquitin', 'molecular_function', 'GO:0031386', ('220', '229'))	('Signaling', 'biological_process', 'GO:0023052', ('248', '257'))	('CA9', 'Gene', (496, 499))	('RNA', 'cellular_component', 'GO:0005562', ('446', '449'))	('CAD', 'Gene', '730249', (431, 434))	('ab40800', 'Var', (436, 443))
154002	28775317	3T3-L1 cells (ATCC, CL-173) were cultured in DMEM and differentiated with insulin, dexamethasone, and 3-isobutyl-1-methylxanthine (Sigma-Aldrich, I-6634, D-4902, and I-5879 respectively), and stained with Oil Red O (Sigma-Aldrich, O-0625) as previously reported.	('DMEM', 'Chemical', '-', (45, 49))	('insulin', 'molecular_function', 'GO:0016088', ('74', '81'))	('insulin', 'Gene', (74, 81))	('3-isobutyl-1-methylxanthine', 'Chemical', 'MESH:D015056', (102, 129))	('dexamethasone', 'Chemical', 'MESH:D003907', (83, 96))	('Oil Red O', 'Chemical', 'MESH:C011049', (205, 214))	('insulin', 'Gene', '3630', (74, 81))	('-L1', 'CellLine', 'CVCL:S918', (3, 6))	('D-4902', 'Var', (154, 160))
154031	31655611	Deregulated gene expression, especially that related to epigenetic control mechanisms clearly contributes to the development of renal tumors.	('renal tumors', 'Disease', (128, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('Deregulated', 'Var', (0, 11))	('renal tumor', 'Phenotype', 'HP:0009726', (128, 139))	('contributes', 'Reg', (94, 105))	('renal tumors', 'Phenotype', 'HP:0009726', (128, 140))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('gene expression', 'biological_process', 'GO:0010467', ('12', '27'))	('renal tumors', 'Disease', 'MESH:D007680', (128, 140))
154037	31655611	EMT is partially regulated by Wnt/beta-catenin signaling pathway, whose hallmark is membrane dissociation of ss-catenin and its translocation into the cytoplasm or nucleus, which then leads to N-cadherin overexpression and reduced E-cadherin expression.	('N-cadherin', 'Gene', '1000', (193, 203))	('ss-catenin', 'Var', (109, 119))	('cadherin', 'molecular_function', 'GO:0008014', ('195', '203'))	('E-cadherin', 'Gene', (231, 241))	('E-cadherin', 'Gene', '999', (231, 241))	('beta-catenin', 'Gene', '1499', (34, 46))	('reduced', 'NegReg', (223, 230))	('EMT', 'biological_process', 'GO:0001837', ('0', '3'))	('signaling pathway', 'biological_process', 'GO:0007165', ('47', '64'))	('cadherin', 'molecular_function', 'GO:0008014', ('233', '241'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('151', '160'))	('nucleus', 'cellular_component', 'GO:0005634', ('164', '171'))	('beta-catenin', 'Gene', (34, 46))	('membrane', 'cellular_component', 'GO:0016020', ('84', '92'))	('N-cadherin', 'Gene', (193, 203))	('translocation', 'MPA', (128, 141))	('overexpression', 'PosReg', (204, 218))	('expression', 'MPA', (242, 252))
154039	31655611	Furthermore, it was shown that PRMT1 directly methylates Runt-related transcription factor 1 (RUNX1) and functions as a co-activator for RUNX1-dependent transcriptional activation in different hematopoietic cell lineages.	('activation', 'PosReg', (169, 179))	('RUNX1', 'Gene', (94, 99))	('RUNX1', 'Gene', '861', (94, 99))	('transcriptional', 'MPA', (153, 168))	('PRMT1', 'Gene', '3276', (31, 36))	('Runt-related transcription factor 1', 'Gene', (57, 92))	('PRMT1', 'Gene', (31, 36))	('Runt-related transcription factor 1', 'Gene', '861', (57, 92))	('transcription factor', 'molecular_function', 'GO:0000981', ('70', '90'))	('RUNX1', 'Gene', (137, 142))	('transcription', 'biological_process', 'GO:0006351', ('70', '83'))	('methylates', 'Var', (46, 56))	('RUNX1', 'Gene', '861', (137, 142))
154124	31655611	Among analyzed RCT types, aberrant ss-catenin cytoplasmic immunoreactivity was observed in 147 (71.7%) of cases, without nuclear positivity.	('aberrant', 'Var', (26, 34))	('ss-catenin', 'Protein', (35, 45))	('RCT', 'Disease', 'MESH:D002292', (15, 18))	('observed', 'Reg', (79, 87))	('RCT', 'Disease', (15, 18))
154129	31655611	E-cadherin loss was less frequent in RUNX1 positive than in RUNX1 negative ccRCC (p = 0.019).	('positive', 'Var', (43, 51))	('loss', 'NegReg', (11, 15))	('ccRCC', 'Disease', (75, 80))	('RUNX1', 'Gene', (37, 42))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('ccRCC', 'Disease', 'MESH:D002292', (75, 80))	('RUNX1', 'Gene', (60, 65))	('RUNX1', 'Gene', '861', (37, 42))	('E-cadherin', 'Gene', (0, 10))	('RUNX1', 'Gene', '861', (60, 65))	('E-cadherin', 'Gene', '999', (0, 10))
154134	31655611	In particular, the expression of PRMT1 and ZEB1 in ccRCC, as well as low-nuclear tumor grade and low-tumor stage were significantly associated with better cancer-specific survival (p = 0.029, p = 0.009, p < 0.001 and p < 0.001, respectively) (Fig.	('low-tumor', 'Disease', (97, 106))	('ZEB1', 'Gene', '6935', (43, 47))	('PRMT1', 'Gene', '3276', (33, 38))	('better', 'PosReg', (148, 154))	('low-tumor', 'Disease', 'MESH:D009800', (97, 106))	('PRMT1', 'Gene', (33, 38))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (81, 86))	('ZEB1', 'Gene', (43, 47))	('expression', 'Var', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('low-nuclear', 'Var', (69, 80))	('cancer', 'Disease', (155, 161))	('ccRCC', 'Disease', 'MESH:D002292', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('ccRCC', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
154151	31655611	Furthermore, it has been widely accepted that epigenetic regulation plays an important role in many biological processes, including tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('epigenetic regulation', 'Var', (46, 67))	('regulation', 'biological_process', 'GO:0065007', ('57', '67'))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))
154180	31655611	Thus, in breast carcinoma, PRMT1 methylates ZEB1 promoter, which then induces EMT and therefore implies ZEB1 as a negative prognostic parameter.	('PRMT1', 'Gene', '3276', (27, 32))	('induces', 'PosReg', (70, 77))	('breast carcinoma', 'Phenotype', 'HP:0003002', (9, 25))	('ZEB1', 'Gene', '6935', (44, 48))	('ZEB1', 'Gene', '6935', (104, 108))	('PRMT1', 'Gene', (27, 32))	('ZEB1', 'Gene', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('methylates', 'Var', (33, 43))	('EMT', 'CPA', (78, 81))	('breast carcinoma', 'Disease', 'MESH:D001943', (9, 25))	('breast carcinoma', 'Disease', (9, 25))	('ZEB1', 'Gene', (104, 108))	('EMT', 'biological_process', 'GO:0001837', ('78', '81'))
154182	31655611	Finally, in non-small lung carcinoma, PRMT1 methylates TWIST1 and induces EMT related aggressive cancer behavior.	('small lung carcinoma', 'Phenotype', 'HP:0030357', (16, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('PRMT1', 'Gene', '3276', (38, 43))	('cancer', 'Disease', (97, 103))	('EMT', 'biological_process', 'GO:0001837', ('74', '77'))	('methylates', 'Var', (44, 54))	('induces', 'Reg', (66, 73))	('non-small lung carcinoma', 'Disease', 'MESH:D002289', (12, 36))	('TWIST1', 'Gene', (55, 61))	('TWIST1', 'Gene', '7291', (55, 61))	('PRMT1', 'Gene', (38, 43))	('small lung', 'Phenotype', 'HP:0002089', (16, 26))	('EMT', 'CPA', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('non-small lung carcinoma', 'Disease', (12, 36))	('non-small lung carcinoma', 'Phenotype', 'HP:0030358', (12, 36))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
154189	31655611	This may suggest that PRMT1/ZEB1 co-expression may be significant in RO tumorigenesis and may serve as a helpful IHC tool in the diagnosis of RO.	('co-expression', 'Var', (33, 46))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('RO', 'Disease', 'MESH:C537750', (69, 71))	('RO', 'Disease', 'MESH:C537750', (142, 144))	('tumor', 'Disease', (72, 77))	('significant', 'Reg', (54, 65))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('PRMT1', 'Gene', '3276', (22, 27))	('PRMT1', 'Gene', (22, 27))	('ZEB1', 'Gene', (28, 32))	('ZEB1', 'Gene', '6935', (28, 32))
154194	31655611	Therefore, we suggest that loss of PRMT1 in ccRCC could lead to TWIST1 cytoplasmic expression and more aggressive behavior.	('TWIST1', 'Gene', (64, 70))	('loss', 'Var', (27, 31))	('TWIST1', 'Gene', '7291', (64, 70))	('aggressive behavior', 'Phenotype', 'HP:0000718', (103, 122))	('more', 'PosReg', (98, 102))	('aggressive behavior', 'biological_process', 'GO:0002118', ('103', '122'))	('PRMT1', 'Gene', '3276', (35, 40))	('ccRCC', 'Disease', (44, 49))	('ccRCC', 'Disease', 'MESH:D002292', (44, 49))	('PRMT1', 'Gene', (35, 40))	('aggressive behavior', 'CPA', (103, 122))	('lead to', 'Reg', (56, 63))
154204	31655611	Heterogenous PRMT1 IHC expression may emphasize intratumor heterogeneity which should be extensively examined in further studies.	('PRMT1', 'Gene', '3276', (13, 18))	('PRMT1', 'Gene', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('Heterogenous', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
154261	31860772	Glycans in the fibrillar capsule were primarily represented by a biantennary core fucosylated N-glycan (Hex5HexNAc4Fuc1) and a mono-sialylated version (Hex5HexNAc4Fuc1NeuAc1).	('capsule', 'cellular_component', 'GO:0042603', ('25', '32'))	('Hex5HexNAc4Fuc1NeuAc1', 'Var', (152, 173))	('core', 'cellular_component', 'GO:0019013', ('77', '81'))	('N-glycan', 'Chemical', '-', (94, 102))	('Glycans', 'Chemical', 'MESH:D011134', (0, 7))	('Hex5HexNAc4Fuc1', 'Var', (104, 119))
154267	31860772	Although not detected as intensely, there were also clear glomeruli specific glycans that had tetra-antennary structures, Hex7HexNAc6Fuc1 and Hex7HexNAc6Fuc1NeuAc1 (Figure 2D,E).	('Hex7HexNAc6Fuc1NeuAc1', 'Var', (142, 163))	('glycans', 'Chemical', 'MESH:D011134', (77, 84))	('Hex7HexNAc6Fuc1', 'Var', (122, 137))
154281	31860772	Glycan images in Figure 4C highlight the differential detection of the fucosylated bisecting GlcNAc tubule glycans in the nontumor sections with minimal to no detection in the tumor tissue.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('glycans', 'Chemical', 'MESH:D011134', (107, 114))	('Glycan', 'Chemical', 'MESH:D011134', (0, 6))	('fucosylated', 'Var', (71, 82))	('GlcNAc', 'Chemical', '-', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
154282	31860772	The majority of the glycans detected above m/z = 2500 are tumor associated (in purple, Figure 4B), and these are noted in a column in Figure S1.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('glycans', 'Protein', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('m/z = 2500', 'Var', (43, 53))	('glycans', 'Chemical', 'MESH:D011134', (20, 27))
154290	31860772	An example glycan image from a stage 1 ccRCC TMA of the most abundant tetra-antennary tumor glycan (Hex7HexNAc6Fuc1, in red) overlaid with a fucosylated bisecting GlcNAc glycan (Hex6HexNAc6Fuc2, in green) is shown in Figure 6A.	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('tetra-antennary tumor', 'Disease', (70, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('glycan', 'Chemical', 'MESH:D011134', (11, 17))	('glycan', 'Chemical', 'MESH:D011134', (170, 176))	('tetra-antennary tumor', 'Disease', 'MESH:C536498', (70, 91))	('GlcNAc glycan', 'Chemical', '-', (163, 176))	('ccRCC TMA', 'Disease', (39, 48))	('ccRCC TMA', 'Disease', 'MESH:D000783', (39, 48))	('glycan', 'Chemical', 'MESH:D011134', (92, 98))	('Hex7HexNAc6Fuc1', 'Var', (100, 115))
154372	29067547	The patient's lung lesion was visible with both imaging modalities; however, 18F-FDG PET/CT provided for superior image quality and a higher SUVmax relative to 18F-DCFPyL (4.6 versus 1.5).	('lung lesion', 'Disease', (14, 25))	('SUVmax', 'MPA', (141, 147))	('superior', 'PosReg', (105, 113))	('18F-FDG PET/CT', 'Var', (77, 91))	('higher', 'PosReg', (134, 140))	('patient', 'Species', '9606', (4, 11))	('18F-DCFPyL', 'Chemical', 'MESH:C572626', (160, 170))	('lung lesion', 'Disease', 'MESH:D008171', (14, 25))	('image quality', 'MPA', (114, 127))	('18F-FDG', 'Chemical', 'MESH:D019788', (77, 84))
154391	29247567	When two clear cell carcinoma cell lines (RMG-I and TOV21G cells) with ADAM9m expression were treated with cisplatin, viability was significantly reduced and apoptosis increased in ADAM9m knockdown cells compared with mock transfectants.	('ADAM9', 'Gene', (181, 186))	('ADAM9', 'Gene', '8754', (181, 186))	('increased', 'PosReg', (168, 177))	('apoptosis', 'biological_process', 'GO:0006915', ('158', '167'))	('carcinoma cell', 'Disease', 'MESH:C538614', (20, 34))	('apoptosis', 'biological_process', 'GO:0097194', ('158', '167'))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('reduced', 'NegReg', (146, 153))	('carcinoma cell', 'Disease', (20, 34))	('apoptosis', 'CPA', (158, 167))	('knockdown', 'Var', (188, 197))	('ADAM9', 'Gene', '8754', (71, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('clear cell carcinoma', 'Disease', (9, 29))	('viability', 'CPA', (118, 127))	('expression', 'Species', '29278', (78, 88))	('ADAM9', 'Gene', (71, 76))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (9, 29))
154421	29247567	mRNA expression of ADAM8, ADAM9m, ADAM9s, ADAM10, ADAM12m, ADAM12s, ADAM15, ADAM17, ADAM19, ADAM20, ADAM21, ADAM28m, ADAM28s, ADAM30, ADAM33 and ADAMDEC1 was screened by RT-PCR in serous (n = 4), endometrioid (n = 3), mucinous (n = 3) and clear cell carcinomas (n = 4), and control non-neoplastic ovarian tissues (n = 3).	('ADAM9', 'Gene', '8754', (34, 39))	('ADAM28', 'Gene', (108, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (250, 260))	('ADAM9', 'Gene', (34, 39))	('ADAM20', 'Var', (92, 98))	('ADAM9', 'Gene', (26, 31))	('non-neoplastic ovarian tissues', 'Disease', (282, 312))	('ADAM9', 'Gene', '8754', (26, 31))	('clear cell carcinomas', 'Disease', (239, 260))	('non-neoplastic ovarian tissues', 'Disease', 'MESH:D010051', (282, 312))	('ADAM28', 'Gene', '10863', (117, 123))	('clear cell carcinomas', 'Disease', 'MESH:C538614', (239, 260))	('expression', 'Species', '29278', (5, 15))	('neoplastic ovarian tissue', 'Phenotype', 'HP:0100615', (286, 311))	('ADAM12', 'Gene', '8038', (59, 65))	('ADAM12', 'Gene', (59, 65))	('ADAM12', 'Gene', '8038', (50, 56))	('ADAM12', 'Gene', (50, 56))	('ADAM28', 'Gene', '10863', (108, 114))	('ADAM15', 'Var', (68, 74))	('ADAM28', 'Gene', (117, 123))	('ADAM8', 'Var', (19, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('ADAM10', 'Var', (42, 48))	('ADAM17', 'Var', (76, 82))	('ADAM19', 'Var', (84, 90))	('ADAM21', 'Var', (100, 106))
154422	29247567	There was no or negligible expression of ADAM9s, ADAM12s, ADAM33 and ADAMDEC1 in the carcinoma or the non-neoplastic tissues, and expression of ADAM8, ADAM12m, ADAM19, ADAM20, ADAM21 and ADAM30 was observed in less than ~50% of the carcinoma samples (Figure 1).	('ADAM12', 'Gene', (151, 157))	('carcinoma', 'Disease', (85, 94))	('ADAM33', 'Gene', (58, 64))	('ADAM9', 'Gene', '8754', (41, 46))	('ADAMDEC1', 'Gene', (69, 77))	('ADAM12', 'Gene', '8038', (49, 55))	('expression', 'Species', '29278', (27, 37))	('ADAM12', 'Gene', (49, 55))	('ADAM9', 'Gene', (41, 46))	('carcinoma', 'Disease', 'MESH:D002277', (232, 241))	('ADAM8', 'Var', (144, 149))	('carcinoma', 'Disease', 'MESH:D002277', (85, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('carcinoma', 'Disease', (232, 241))	('expression', 'Species', '29278', (130, 140))	('ADAM12', 'Gene', '8038', (151, 157))
154423	29247567	In contrast, ADAM9m, ADAM10, ADAM15, ADAM17, ADAM28m and ADAM28s were expressed in more than 70% of the carcinoma tissues, and the expression of these ADAM species appeared to be high in the carcinomas and only weak in the non-neoplastic ovarian tissues (Figure 1).	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('expression', 'Species', '29278', (131, 141))	('ADAM28', 'Gene', (57, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('ADAM15', 'Var', (29, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (191, 201))	('carcinomas', 'Disease', 'MESH:D002277', (191, 201))	('carcinoma tissues', 'Disease', 'MESH:D009380', (104, 121))	('carcinoma tissues', 'Disease', (104, 121))	('carcinomas', 'Disease', (191, 201))	('non-neoplastic ovarian tissues', 'Disease', (223, 253))	('ADAM10', 'Var', (21, 27))	('ADAM28', 'Gene', '10863', (45, 51))	('ADAM9', 'Gene', '8754', (13, 18))	('ADAM17', 'Var', (37, 43))	('ADAM9', 'Gene', (13, 18))	('expression', 'MPA', (131, 141))	('non-neoplastic ovarian tissues', 'Disease', 'MESH:D010051', (223, 253))	('neoplastic ovarian tissue', 'Phenotype', 'HP:0100615', (227, 252))	('ADAM28', 'Gene', '10863', (57, 63))	('ADAM28', 'Gene', (45, 51))
154425	29247567	Expression levels of ADAM9m, ADAM10, ADAM15, ADAM17, ADAM28m and ADAM28s were compared by setting the average level in the control samples as 1.0.	('ADAM28', 'Gene', (65, 71))	('ADAM10', 'Var', (29, 35))	('ADAM28', 'Gene', '10863', (53, 59))	('ADAM9', 'Gene', '8754', (21, 26))	('ADAM9', 'Gene', (21, 26))	('ADAM28', 'Gene', (53, 59))	('ADAM15', 'Var', (37, 43))	('Expression', 'Species', '29278', (0, 10))	('ADAM28', 'Gene', '10863', (65, 71))
154428	29247567	Expression levels of ADAM10, ADAM15, ADAM17 and ADAM28s were almost similar between the carcinoma and the control non-neoplastic samples (Figure 2A).	('ADAM28', 'Gene', (48, 54))	('carcinoma', 'Disease', 'MESH:D002277', (88, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('ADAM15', 'Var', (29, 35))	('ADAM28', 'Gene', '10863', (48, 54))	('Expression', 'Species', '29278', (0, 10))	('ADAM10', 'Var', (21, 27))	('carcinoma', 'Disease', (88, 97))	('ADAM17', 'Var', (37, 43))
154450	29247567	They expressed ADAM9m, ADAM10 and ADAM17, but not ADAM9s (Figure 5A).	('ADAM17', 'Var', (34, 40))	('ADAM10', 'Var', (23, 29))	('ADAM9', 'Gene', '8754', (15, 20))	('ADAM9', 'Gene', (15, 20))	('ADAM9', 'Gene', (50, 55))	('ADAM9', 'Gene', '8754', (50, 55))
154451	29247567	When the expression of ADAM9m was knocked down by shRNAs for ADAM9 (sh1 and sh2), ADAM9m protein expression was effectively reduced in RMG-Ish1 (44.7% +- 12.2%), RMG-Ish2 (49.4% +- 9.0%), TOV21Gsh1 (10.7% +- 8.8%) and TOV21Gsh2 (47.6% +- 22.8%) cells as compared to their mock transfectants (Figure 5B), although no changes in the expression of ADAM10 or ADAM17 were seen (Figure 5A).	('RMG-Ish2', 'Chemical', '-', (162, 170))	('expression', 'Species', '29278', (97, 107))	('expression', 'MPA', (9, 19))	('TOV21Gsh2', 'Gene', (218, 227))	('TOV21Gsh2', 'Gene', '170825', (218, 227))	('ADAM9', 'Gene', (23, 28))	('ADAM9', 'Gene', '8754', (23, 28))	('expression', 'Species', '29278', (331, 341))	('knocked', 'Var', (34, 41))	('ADAM17', 'Gene', (355, 361))	('TOV21Gsh1', 'Gene', '219409', (188, 197))	('expression', 'Species', '29278', (9, 19))	('ADAM9', 'Gene', (61, 66))	('ADAM9', 'Gene', '8754', (61, 66))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))	('reduced', 'NegReg', (124, 131))	('TOV21Gsh1', 'Gene', (188, 197))	('ADAM9', 'Gene', '8754', (82, 87))	('protein', 'Protein', (89, 96))	('ADAM9', 'Gene', (82, 87))
154452	29247567	We first examined cell migration and EGFR phosphorylation, and found that cell migration activity was significantly increased in shRNA transfectants of both RMG-I and TOV21G cells compared with Mock transfectants (Figure 5C).	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('RMG-I', 'Gene', (157, 162))	('cell migration', 'biological_process', 'GO:0016477', ('74', '88'))	('cell migration', 'biological_process', 'GO:0016477', ('18', '32'))	('cell migration', 'CPA', (18, 32))	('EGFR', 'Gene', '1956', (37, 41))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))	('increased', 'PosReg', (116, 125))	('EGFR', 'Gene', (37, 41))	('cell migration activity', 'CPA', (74, 97))	('transfectants', 'Var', (135, 148))
154453	29247567	In contrast, EGFR phosphorylation was significantly decreased in RMG-Ish1 and RMG-Ish2 cells compared with Mock transfectants (Figure 5D).	('decreased', 'NegReg', (52, 61))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('phosphorylation', 'MPA', (18, 33))	('RMG-Ish2', 'Chemical', '-', (78, 86))	('EGFR', 'Gene', '1956', (13, 17))	('RMG-Ish1', 'Var', (65, 73))	('EGFR', 'Gene', (13, 17))	('phosphorylation', 'biological_process', 'GO:0016310', ('18', '33'))
154455	29247567	When these cells were treated with cisplatin at LD50 concentrations for each cell line, cell viability by MTT assay was significantly decreased in RMG-Ish1 (21.2% +- 9.4%) and RMG-Ish2 (31.4% +- 6.3%) compared with RMG-IMock (51.5% +- 6.4%) (P < .001) (Figure 6A).	('decreased', 'NegReg', (134, 143))	('RMG-Ish2', 'Var', (176, 184))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('RMG-Ish2', 'Chemical', '-', (176, 184))	('MTT', 'Chemical', 'MESH:C070243', (106, 109))	('RMG-IMock', 'Chemical', '-', (215, 224))	('RMG-Ish1', 'Var', (147, 155))	('cell viability', 'CPA', (88, 102))
154457	29247567	Flow cytometric analysis indicated that numbers of Annexin V-positive and PI-positive cells (apoptotic cells) after cisplatin treatment were significantly increased in RMG-Ish1 (43.8% +- 6.2%) and RMG-Ish2 (40.9% +- 2.7%) cells compared to RMG-IMock cells (25.0% +- 2.6%) (P < .001) (Figure 6B).	('PI-positive cells', 'CPA', (74, 91))	('increased', 'PosReg', (155, 164))	('RMG-Ish2', 'Var', (197, 205))	('RMG-Ish2', 'Chemical', '-', (197, 205))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('Annexin V-positive', 'Protein', (51, 69))	('RMG-Ish1', 'Var', (168, 176))	('RMG-IMock', 'Chemical', '-', (240, 249))
154469	29247567	However, our previous study on oncogene-transformed MDCK cells has shown that gene expression of ADAM9, ADAM10, ADAM12 and ADAM28 is induced by oncogene-modulated transformation.26 As type I ovarian carcinomas are characterized by specific mutations such as ARID1A, PIK3CA, KRAS, BRAF and PTEN, which target several cell signaling pathways, and develop in a stepwise way from precursor lesions,25 it is possible to speculate that the cell signaling pathways caused by these mutations may trigger ADAM9m gene expression after transformation to type I ovarian carcinomas.	('signaling', 'biological_process', 'GO:0023052', ('439', '448'))	('carcinoma', 'Phenotype', 'HP:0030731', (558, 567))	('carcinomas', 'Phenotype', 'HP:0030731', (558, 568))	('ADAM9', 'Gene', '8754', (97, 102))	('ADAM9', 'Gene', (97, 102))	('ADAM28', 'Gene', (123, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))	('type I ovarian carcinomas', 'Disease', 'MESH:D010051', (543, 568))	('type I ovarian carcinomas', 'Disease', (543, 568))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (550, 568))	('gene expression', 'biological_process', 'GO:0010467', ('503', '518'))	('trigger', 'Reg', (488, 495))	('mutations', 'Var', (474, 483))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (550, 567))	('type I ovarian carcinomas', 'Disease', 'MESH:D010051', (184, 209))	('expression', 'Species', '29278', (83, 93))	('ADAM12', 'Gene', '8038', (112, 118))	('ADAM12', 'Gene', (112, 118))	('type I ovarian carcinomas', 'Disease', (184, 209))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (191, 209))	('expression', 'Species', '29278', (508, 518))	('ADAM28', 'Gene', '10863', (123, 129))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (191, 208))	('signaling', 'biological_process', 'GO:0023052', ('321', '330'))	('gene expression', 'biological_process', 'GO:0010467', ('78', '93'))	('MDCK', 'CellLine', 'CVCL:0422', (52, 56))	('ADAM9', 'Gene', (496, 501))	('ADAM9', 'Gene', '8754', (496, 501))
154477	29247567	Therefore, we then examined the effect on cell viability in cisplatin-treated clear cell carcinoma cells and showed that knock-down of ADAM9m or inhibition of ADAM9m activity increases apoptotic cells, indicating enhancement of sensitivity to cisplatin in clear cell carcinoma cells.	('clear cell carcinoma', 'Disease', 'MESH:C538614', (78, 98))	('carcinoma cell', 'Disease', 'MESH:C538614', (89, 103))	('enhancement', 'PosReg', (213, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('inhibition', 'Var', (145, 155))	('clear cell carcinoma', 'Disease', (256, 276))	('activity', 'MPA', (166, 174))	('ADAM9', 'Gene', '8754', (135, 140))	('ADAM9', 'Gene', (159, 164))	('ADAM9', 'Gene', '8754', (159, 164))	('ADAM9', 'Gene', (135, 140))	('carcinoma cell', 'Disease', 'MESH:C538614', (267, 281))	('increases', 'PosReg', (175, 184))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (256, 276))	('carcinoma cell', 'Disease', (89, 103))	('knock-down', 'Var', (121, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('sensitivity', 'MPA', (228, 239))	('cisplatin', 'Chemical', 'MESH:D002945', (243, 252))	('clear cell carcinoma', 'Disease', (78, 98))	('apoptotic cells', 'CPA', (185, 200))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))	('carcinoma cell', 'Disease', (267, 281))
154478	29247567	Similar effect of ADAM9 on resistance to chemotherapeutic drugs and radiation has been reported by siRNA-driven ADAM9 knock-down experiments in prostate carcinoma cells.44 The authors in the study suggested that ADAM9 plays a role in therapeutic resistance by altering E-cadherin and integrin expression.44 In colorectal carcinoma cell lines, chemotherapy-induced activation of ADAM17 is known to contribute to chemoresistance to 5-fluorouracil by transactivation of EGF receptor (EGFR) through shedding of EGFR ligands such as transforming growth factor-alpha.45 Shedding of HB-EGF by ADAM17, ADAM9 and/or ADAM10 is also suggested to be related to resistance to doxorubicin in bladder and lung carcinoma cells.46 In addition, a recent study on stomach carcinoma cell lines provided evidence that ADAM9 plays a role in EGFR transactivation through shedding of EGFR ligands.47 In the present study, we provided data that EGFR activation is down-regulated by knock-down of ADAM9m expression.	('EGFR', 'molecular_function', 'GO:0005006', ('507', '511'))	('ADAM9', 'Gene', '8754', (18, 23))	('colorectal carcinoma', 'Disease', (310, 330))	('EGFR', 'Gene', '1956', (920, 924))	('ADAM9', 'Gene', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('activation', 'PosReg', (925, 935))	('EGFR', 'Gene', (481, 485))	('EGFR', 'Gene', (860, 864))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (310, 330))	('expression', 'Species', '29278', (293, 303))	('ADAM9', 'Gene', '8754', (112, 117))	('EGFR', 'Gene', '1956', (507, 511))	('transforming growth factor-alpha', 'molecular_function', 'GO:0005154', ('528', '560'))	('ADAM9', 'Gene', (112, 117))	('transactivation', 'biological_process', 'GO:2000144', ('448', '463'))	('carcinoma cell', 'Disease', (321, 335))	('cadherin', 'molecular_function', 'GO:0008014', ('271', '279'))	('carcinoma cell', 'Disease', (695, 709))	('bladder and lung carcinoma', 'Disease', 'MESH:D001749', (678, 704))	('EGF', 'molecular_function', 'GO:0005154', ('467', '470'))	('EGFR', 'Gene', (819, 823))	('carcinoma cell', 'Disease', (153, 167))	('carcinoma cell', 'Disease', 'MESH:C538614', (753, 767))	('ADAM9', 'Gene', '8754', (971, 976))	('ADAM9', 'Gene', '8754', (212, 217))	('EGFR', 'molecular_function', 'GO:0005006', ('920', '924'))	('EGF', 'molecular_function', 'GO:0005154', ('579', '582'))	('ADAM9', 'Gene', (212, 217))	('ADAM9', 'Gene', (594, 599))	('prostate carcinoma', 'Disease', 'MESH:D011472', (144, 162))	('ADAM9', 'Gene', '8754', (594, 599))	('EGFR', 'molecular_function', 'GO:0005006', ('860', '864'))	('transactivation', 'biological_process', 'GO:2000144', ('824', '839'))	('carcinoma', 'Phenotype', 'HP:0030731', (695, 704))	('EGFR', 'molecular_function', 'GO:0005006', ('819', '823'))	('knock-down', 'Var', (957, 967))	('stomach carcinoma', 'Disease', 'MESH:D013274', (745, 762))	('carcinoma', 'Phenotype', 'HP:0030731', (753, 762))	('EGFR', 'Gene', (920, 924))	('EGFR', 'Gene', '1956', (481, 485))	('EGFR', 'Gene', '1956', (860, 864))	('down-regulated', 'NegReg', (939, 953))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (144, 162))	('EGFR', 'Gene', (507, 511))	('expression', 'Species', '29278', (978, 988))	('carcinoma cell', 'Disease', 'MESH:C538614', (321, 335))	('carcinoma cell', 'Disease', 'MESH:C538614', (695, 709))	('stomach carcinoma', 'Phenotype', 'HP:0012126', (745, 762))	('ADAM9', 'Gene', '8754', (797, 802))	('EGFR', 'Gene', '1956', (819, 823))	('ADAM9', 'Gene', (797, 802))	('EGFR', 'molecular_function', 'GO:0005006', ('481', '485'))	('carcinoma', 'Phenotype', 'HP:0030731', (321, 330))	('carcinoma cell', 'Disease', 'MESH:C538614', (153, 167))	('carcinoma cell', 'Disease', (753, 767))	('stomach carcinoma', 'Disease', (745, 762))	('ADAM9', 'Gene', (971, 976))	('prostate carcinoma', 'Disease', (144, 162))
154479	29247567	We also showed that ADAM9m exists on clear cell carcinoma cell membranes in an activated form and showed that knock-down of ADAM9m with shRNAs or inhibition of the activity with neutralizing anti-ADAM9m antibody enhances chemosensitivity to cisplatin and ADAM9m over-expression increases chemoresistance in ovarian clear cell carcinoma cells.	('clear cell carcinoma', 'Disease', (37, 57))	('antibody', 'cellular_component', 'GO:0042571', ('203', '211'))	('cisplatin', 'Chemical', 'MESH:D002945', (241, 250))	('carcinoma cell', 'Disease', 'MESH:C538614', (48, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (326, 335))	('knock-down', 'Var', (110, 120))	('expression', 'Species', '29278', (267, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('chemosensitivity to cisplatin', 'MPA', (221, 250))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (37, 57))	('ADAM9', 'Gene', (255, 260))	('ADAM9', 'Gene', '8754', (255, 260))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (315, 335))	('antibody', 'cellular_component', 'GO:0019815', ('203', '211'))	('over-expression increases', 'PosReg', (262, 287))	('carcinoma cell', 'Disease', (326, 340))	('chemoresistance', 'CPA', (288, 303))	('enhances', 'PosReg', (212, 220))	('antibody', 'cellular_component', 'GO:0019814', ('203', '211'))	('carcinoma cell', 'Disease', (48, 62))	('ovarian clear cell carcinoma', 'Disease', (307, 335))	('ADAM9', 'Gene', '8754', (20, 25))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (307, 335))	('ADAM9', 'Gene', (20, 25))	('ADAM9', 'Gene', '8754', (196, 201))	('ADAM9', 'Gene', (196, 201))	('ADAM9', 'Gene', '8754', (124, 129))	('ADAM9', 'Gene', (124, 129))	('antibody', 'molecular_function', 'GO:0003823', ('203', '211'))	('carcinoma cell', 'Disease', 'MESH:C538614', (326, 340))
154486	28985012	Importantly, aberrant CXCL7 expression was confirmed even in peripheral blood cells obtained from early stage (pT1a) RCC patients, and the expression level of CXCL7 in peripheral blood cells was a potential independent biomarker for the diagnosis of RCC by receiver operating characteristic curve analysis (sensitivity, 70.0%; specificity, 64.0%; area under the curve = 0.722; multiple logistic regression analysis: odds ratio, 1.07; 95% confidence interval, 1.03-1.11; P = 0.0004).	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (250, 253))	('RCC', 'Disease', 'MESH:C538614', (250, 253))	('RCC', 'Disease', (250, 253))	('CXCL7 expression', 'MPA', (22, 38))	('patients', 'Species', '9606', (121, 129))	('aberrant', 'Var', (13, 21))
154490	28985012	These results suggest that aberrant CXCL7 expression in peripheral blood cells is induced by RCC cells and may serve as a novel biomarker in the diagnosis of RCC.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('aberrant', 'Var', (27, 35))	('RCC', 'Disease', (93, 96))	('induced', 'Reg', (82, 89))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('CXCL7 expression', 'MPA', (36, 52))
154552	31975504	MicroRNA-92b-3p is a prognostic oncomiR that targets TSC1 in clear cell renal cell carcinoma Although several studies have reported that microRNA (miR)-92b-3p is involved in various cellular processes related to carcinogenesis, its physiological role in clear cell renal cell carcinoma (ccRCC) remains unclear.	('TSC1', 'Gene', (53, 57))	('carcinogenesis', 'Disease', (212, 226))	('clear cell renal cell carcinoma', 'Disease', (254, 285))	('microRNA (miR)-92b-3p', 'Var', (137, 158))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (265, 285))	('RCC', 'Disease', (289, 292))	('TSC1', 'Gene', '7248', (53, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('ccRCC', 'Phenotype', 'HP:0006770', (287, 292))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (61, 92))	('carcinogenesis', 'Disease', 'MESH:D063646', (212, 226))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (254, 285))	('RCC', 'Disease', 'MESH:C538614', (289, 292))	('clear cell renal cell carcinoma', 'Disease', (61, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (72, 92))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (254, 285))	('involved', 'Reg', (162, 170))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (61, 92))
154554	31975504	Significant upregulation of miR-92b-3p was observed in ccRCC tissues.	('upregulation', 'PosReg', (12, 24))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('miR-92b-3p', 'Var', (28, 38))	('RCC', 'Disease', (57, 60))	('miR-92b-3p', 'Chemical', '-', (28, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))
154557	31975504	Mechanistically, it was found that miR-92b-3p directly targeted the TSC1 gene, a known upstream regulator of mTOR.	('TSC1 gene', 'Gene', (68, 77))	('targeted', 'Reg', (55, 63))	('miR-92b-3p', 'Var', (35, 45))	('miR-92b-3p', 'Chemical', '-', (35, 45))
154558	31975504	Overexpression of miR-92b-3p decreased the protein expression of TSC1 and enhanced the downstream phosphorylation of p70S6 kinase, suggesting that the mTOR signaling pathway was activated by miR-92b-3p in RCC cells.	('mTOR signaling pathway', 'Pathway', (151, 173))	('miR-92b-3p', 'Var', (191, 201))	('phosphorylation', 'biological_process', 'GO:0016310', ('98', '113'))	('RCC', 'Disease', (205, 208))	('miR-92b-3p', 'Chemical', '-', (191, 201))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('protein expression', 'MPA', (43, 61))	('p70S6 kinase', 'MPA', (117, 129))	('activated', 'PosReg', (178, 187))	('downstream phosphorylation', 'MPA', (87, 113))	('decreased', 'NegReg', (29, 38))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('TSC1', 'Gene', (65, 69))	('signaling pathway', 'biological_process', 'GO:0007165', ('156', '173'))	('miR-92b-3p', 'Var', (18, 28))	('enhanced', 'PosReg', (74, 82))	('miR-92b-3p', 'Chemical', '-', (18, 28))
154559	31975504	Importantly, a multivariate Cox proportion hazard model, based on TNM staging and high levels of miR-92b-3p, revealed that miR-92b-3p expression (high vs. low hazard ratio, 2.86; 95% confidence interval, 1.20-6.83; P = .018) was a significant prognostic factor for overall survival of ccRCC patients with surgical management.	('miR-92b-3p', 'Chemical', '-', (97, 107))	('TNM', 'Gene', '10178', (66, 69))	('miR-92b-3p', 'Var', (123, 133))	('miR-92b-3p', 'Chemical', '-', (123, 133))	('prognostic', 'Reg', (243, 253))	('patients', 'Species', '9606', (291, 299))	('RCC', 'Disease', 'MESH:C538614', (287, 290))	('TNM', 'Gene', (66, 69))	('RCC', 'Disease', (287, 290))	('ccRCC', 'Phenotype', 'HP:0006770', (285, 290))
154560	31975504	Taken together, miR-92b-3p was found to act as an oncomiR, promoting cell proliferation by downregulating TSC1 in ccRCC.	('promoting', 'PosReg', (59, 68))	('miR-92b-3p', 'Var', (16, 26))	('miR-92b-3p', 'Chemical', '-', (16, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('TSC1', 'Gene', (106, 110))	('cell proliferation', 'CPA', (69, 87))	('downregulating', 'NegReg', (91, 105))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))	('cell proliferation', 'biological_process', 'GO:0008283', ('69', '87'))	('oncomiR', 'Chemical', '-', (50, 57))
154561	31975504	MicroRNA-92b-3p was found to act as an oncomiR, promoting cell proliferation by downregulating TSC1 in clear cell renal cell carcinoma, and predicts poor patient overall survival.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (103, 134))	('poor', 'NegReg', (149, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (114, 134))	('patient', 'Species', '9606', (154, 161))	('MicroRNA-92b-3p', 'Var', (0, 15))	('promoting', 'PosReg', (48, 57))	('oncomiR', 'Chemical', '-', (39, 46))	('cell proliferation', 'CPA', (58, 76))	('downregulating', 'NegReg', (80, 94))	('TSC1', 'Gene', (95, 99))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (103, 134))	('clear cell renal cell carcinoma', 'Disease', (103, 134))	('cell proliferation', 'biological_process', 'GO:0008283', ('58', '76'))
154568	31975504	Our data showed for the first time that miR-92b-3p functions as an oncomiR by regulating TSC1 as the direct target gene in RCC cell lines and influences cell proliferation by regulating the TSC1-mTOR signaling pathway.	('oncomiR', 'Chemical', '-', (67, 74))	('regulating', 'Reg', (175, 185))	('miR-92b-3p', 'Var', (40, 50))	('regulating', 'Reg', (78, 88))	('miR-92b-3p', 'Chemical', '-', (40, 50))	('signaling pathway', 'biological_process', 'GO:0007165', ('200', '217'))	('RCC', 'Disease', (123, 126))	('cell proliferation', 'CPA', (153, 171))	('TSC1', 'Gene', (89, 93))	('influences', 'Reg', (142, 152))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('TSC1-mTOR signaling pathway', 'Pathway', (190, 217))	('cell proliferation', 'biological_process', 'GO:0008283', ('153', '171'))
154569	31975504	Collectively, our findings suggest that miR-92b-3p is a promising target for RCC treatment and a potential prognostic marker in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('miR-92b-3p', 'Var', (40, 50))	('miR-92b-3p', 'Chemical', '-', (40, 50))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Disease', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (130, 133))
154585	31975504	ACHN cells were cotransfected with 50 nmol/L miR-92b-3p (or control mimic) and luciferase reporter constructs, and Caki-2 cells were cotransfected with 50 nmol/L miR-92b-3p (or control inhibitor) and luciferase reporter constructs using Lipofectamine 2000 (Thermo Fisher Scientific).	('miR-92b-3p', 'Chemical', '-', (45, 55))	('Caki-2', 'CellLine', 'CVCL:0235', (115, 121))	('ACHN', 'Gene', '55323', (0, 4))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (237, 255))	('ACHN', 'Gene', (0, 4))	('miR-92b-3p', 'Var', (45, 55))	('miR-92b-3p', 'Chemical', '-', (162, 172))
154593	31975504	ACHN cells transfected with the miR-92b-3p mimic or a negative control miRNA mimic for 24 hours were reseeded in a 96-well plate and incubated for another 24 hours.	('miR-92b-3p', 'Chemical', '-', (32, 42))	('ACHN', 'Gene', '55323', (0, 4))	('miR-92b-3p mimic', 'Var', (32, 48))	('ACHN', 'Gene', (0, 4))
154601	31975504	To confirm the miRNA expression signature of miR-92b-3p in ccRCC, we performed quantitative real-time PCR analysis to compare the expression of miR-92b-3p in ccRCC tissues with normal renal tissues (Table 1).	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('ccRCC', 'Phenotype', 'HP:0006770', (158, 163))	('RCC', 'Disease', (160, 163))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('miR-92b-3p', 'Var', (144, 154))	('miR-92b-3p', 'Chemical', '-', (144, 154))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('miR-92b-3p', 'Chemical', '-', (45, 55))
154605	31975504	Kaplan-Meier survival analysis revealed that levels of miR-92b-3p were significantly correlated with OS rate (Figure 1B; high vs. low, P = .005).	('miR-92b-3p', 'Chemical', '-', (55, 65))	('correlated', 'Reg', (85, 95))	('miR-92b-3p', 'Var', (55, 65))	('OS rate', 'Disease', (101, 108))
154608	31975504	To further validate the correlation between the miR-92b-3p expression level and OS, we used the SurvMicro tool, which assesses miRNA signatures from publicly available miRNA profiles.17 We found that miR-92b-3p was also associated with OS in ccRCC patients from TCGA database.	('RCC', 'Disease', (244, 247))	('associated', 'Reg', (220, 230))	('ccRCC', 'Phenotype', 'HP:0006770', (242, 247))	('RCC', 'Disease', 'MESH:C538614', (244, 247))	('miR-92b-3p', 'Chemical', '-', (48, 58))	('patients', 'Species', '9606', (248, 256))	('miR-92b-3p', 'Var', (200, 210))	('miR-92b-3p', 'Chemical', '-', (200, 210))
154609	31975504	Altogether, these data demonstrated that the transcriptional level of miR-92b-3p is upregulated in ccRCC and can be a significant prognostic factor to predict prognosis in ccRCC.	('upregulated', 'PosReg', (84, 95))	('transcriptional level', 'MPA', (45, 66))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('RCC', 'Disease', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (172, 177))	('RCC', 'Disease', (174, 177))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('miR-92b-3p', 'Var', (70, 80))	('miR-92b-3p', 'Chemical', '-', (70, 80))
154610	31975504	To investigate the role of miR-92b-3p in ccRCC, we first examined the expression levels of miR-92b-3p in RCC cell lines (Caki-1, Caki-2, 786-O, and ACHN cells).	('miR-92b-3p', 'Var', (91, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('ACHN', 'Gene', (148, 152))	('Caki-1', 'CellLine', 'CVCL:0234', (121, 127))	('miR-92b-3p', 'Chemical', '-', (91, 101))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('ACHN', 'Gene', '55323', (148, 152))	('miR-92b-3p', 'Chemical', '-', (27, 37))	('Caki-2', 'CellLine', 'CVCL:0235', (129, 135))
154613	31975504	The miR-92b-3p mimic significantly increased the cell growth (P < .01, Figure 2B), migration (P < .01, Figure 2C), and invasion ability (P < .05, Figure 2D).	('increased', 'PosReg', (35, 44))	('invasion ability', 'CPA', (119, 135))	('cell growth', 'biological_process', 'GO:0016049', ('49', '60'))	('migration', 'CPA', (83, 92))	('miR-92b-3p', 'Chemical', '-', (4, 14))	('cell growth', 'CPA', (49, 60))	('miR-92b-3p mimic', 'Var', (4, 20))
154616	31975504	These results indicate that miR-92b-3p is involved in regulating the expression of crucial molecules in RCC cell lines.	('regulating', 'Reg', (54, 64))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('expression of crucial', 'MPA', (69, 90))	('miR-92b-3p', 'Var', (28, 38))	('miR-92b-3p', 'Chemical', '-', (28, 38))	('RCC', 'Disease', (104, 107))
154621	31975504	Conversely, in Caki-2 cells cotransfected with the miR-92b-3p inhibitor, the luciferase activity of the TSC1 3'-UTR construct increased when compared to that cotransfected with a negative control inhibitor (Figure 4C).	('luciferase activity', 'molecular_function', 'GO:0050397', ('77', '96'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('77', '96'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('77', '96'))	('luciferase', 'Enzyme', (77, 87))	('luciferase activity', 'molecular_function', 'GO:0047077', ('77', '96'))	('activity', 'MPA', (88, 96))	('miR-92b-3p inhibitor', 'Var', (51, 71))	('Caki-2', 'CellLine', 'CVCL:0235', (15, 21))	('luciferase activity', 'molecular_function', 'GO:0045289', ('77', '96'))	('increased', 'PosReg', (126, 135))	('miR-92b-3p', 'Chemical', '-', (51, 61))
154622	31975504	These results indicated that TSC1 is a direct target of miR-92b-3p in RCC cells.	('miR-92b-3p', 'Var', (56, 66))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('miR-92b-3p', 'Chemical', '-', (56, 66))	('RCC', 'Disease', (70, 73))
154625	31975504	When miR-92b-3p was overexpressed in ACHN cells, phosphorylation of S6K was upregulated.	('ACHN', 'Gene', '55323', (37, 41))	('S6K', 'Gene', '6198', (68, 71))	('miR-92b-3p', 'Var', (5, 15))	('miR-92b-3p', 'Chemical', '-', (5, 15))	('ACHN', 'Gene', (37, 41))	('phosphorylation', 'biological_process', 'GO:0016310', ('49', '64'))	('phosphorylation', 'MPA', (49, 64))	('upregulated', 'PosReg', (76, 87))	('S6K', 'Gene', (68, 71))	('overexpressed', 'PosReg', (20, 33))
154626	31975504	In contrast, inhibition of miR-92b-3p decreased phosphorylation of S6K in Caki-2 cells (Figure 5A).	('decreased', 'NegReg', (38, 47))	('S6K', 'Gene', '6198', (67, 70))	('inhibition', 'Var', (13, 23))	('phosphorylation', 'MPA', (48, 63))	('S6K', 'Gene', (67, 70))	('Caki-2', 'CellLine', 'CVCL:0235', (74, 80))	('miR-92b-3p', 'Protein', (27, 37))	('miR-92b-3p', 'Chemical', '-', (27, 37))	('phosphorylation', 'biological_process', 'GO:0016310', ('48', '63'))
154627	31975504	To examine whether the malignant phenotypes upregulated by the miR-92b-3p in RCC cells were due to the decrease in TSC1 expression, we undertook cell proliferation assays using ACHN cells treated with mTORC1 inhibitor everolimus (RAD001).	('mTORC1', 'cellular_component', 'GO:0031931', ('201', '207'))	('expression', 'MPA', (120, 130))	('TSC1', 'Gene', (115, 119))	('mTORC1', 'Gene', (201, 207))	('upregulated', 'PosReg', (44, 55))	('ACHN', 'Gene', '55323', (177, 181))	('RAD', 'biological_process', 'GO:1990116', ('230', '233'))	('cell proliferation', 'biological_process', 'GO:0008283', ('145', '163'))	('everolimus', 'Chemical', 'MESH:D000068338', (218, 228))	('ACHN', 'Gene', (177, 181))	('RCC', 'Disease', (77, 80))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('miR-92b-3p', 'Var', (63, 73))	('mTORC1', 'Gene', '382056', (201, 207))	('decrease', 'NegReg', (103, 111))	('miR-92b-3p', 'Chemical', '-', (63, 73))
154628	31975504	As expected, the result showed that ACHN cells transfected with miR-92b-3p mimic were more sensitive to everolimus than ACHN cells transfected with negative control mimic (Figure 5B), suggesting that miR-92b-3p upregulates the mTOR signaling pathway by targeting TSC1 in RCC cells.	('ACHN', 'Gene', '55323', (36, 40))	('mTOR signaling pathway', 'Pathway', (227, 249))	('targeting', 'Reg', (253, 262))	('everolimus', 'Chemical', 'MESH:D000068338', (104, 114))	('ACHN', 'Gene', '55323', (120, 124))	('ACHN', 'Gene', (36, 40))	('upregulates', 'PosReg', (211, 222))	('TSC1', 'Gene', (263, 267))	('miR-92b-3p', 'Chemical', '-', (64, 74))	('RCC', 'Disease', 'MESH:C538614', (271, 274))	('ACHN', 'Gene', (120, 124))	('RCC', 'Disease', (271, 274))	('signaling pathway', 'biological_process', 'GO:0007165', ('232', '249'))	('miR-92b-3p', 'Var', (200, 210))	('miR-92b-3p', 'Chemical', '-', (200, 210))
154633	31975504	These results are consistent with the upregulated expression levels of miR-92b-3p observed in ccRCC tissues compared with paired normal tissues (Figure 1A).	('RCC', 'Disease', (96, 99))	('miR-92b-3p', 'Var', (71, 81))	('miR-92b-3p', 'Chemical', '-', (71, 81))	('upregulated', 'PosReg', (38, 49))	('expression levels', 'MPA', (50, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
154634	31975504	There have been several reports showing that miR-92b-3p functions as an oncomiR in several types of cancer.10, 11 Wu et al reported that miR-92b-3p functions as a potential oncogenic miRNA in glioblastomas by targeting SMAD3.20 In nonsmall-cell lung cancer, miR-92b-3p directly targets PTEN, promotes cell growth, and induces cisplatin chemosensitivity.21 However, miR-92b-3p has also been reported to act as a tumor suppressor miRNA.12 The present study shows for the first time that miR-92b-3p functions as an oncomiR in both RCC cell lines and ccRCC clinical specimens.	('PTEN', 'Gene', '5728', (286, 290))	('SMAD3', 'Gene', (219, 224))	('nonsmall-cell lung cancer', 'Disease', (231, 256))	('RCC', 'Disease', (528, 531))	('glioblastomas', 'Disease', 'MESH:D005909', (192, 205))	('oncomiR', 'Chemical', '-', (512, 519))	('miR-92b-3p', 'Chemical', '-', (258, 268))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('miR-92b-3p', 'Chemical', '-', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (411, 416))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('ccRCC', 'Phenotype', 'HP:0006770', (547, 552))	('RCC', 'Disease', (549, 552))	('oncomiR', 'Chemical', '-', (72, 79))	('RCC', 'Disease', 'MESH:C538614', (528, 531))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('411', '427'))	('nonsmall-cell lung cancer', 'Disease', 'MESH:D002289', (231, 256))	('glioblastomas', 'Phenotype', 'HP:0012174', (192, 205))	('RCC', 'Disease', 'MESH:C538614', (549, 552))	('tumor suppressor', 'biological_process', 'GO:0051726', ('411', '427'))	('miR-92b-3p', 'Var', (485, 495))	('miR-92b-3p', 'Chemical', '-', (137, 147))	('cancer', 'Disease', (100, 106))	('miR-92b-3p', 'Chemical', '-', (485, 495))	('tumor', 'Disease', (411, 416))	('miR-92b-3p', 'Chemical', '-', (365, 375))	('lung cancer', 'Phenotype', 'HP:0100526', (245, 256))	('PTEN', 'Gene', (286, 290))	('SMAD3', 'Gene', '4088', (219, 224))	('cancer', 'Disease', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cell growth', 'biological_process', 'GO:0016049', ('301', '312'))	('tumor', 'Disease', 'MESH:D009369', (411, 416))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('glioblastomas', 'Disease', (192, 205))
154638	31975504	In the present study, we identified miR-92b-3p as a suppressor of TSC1 expression and an activator of the mTOR signaling pathway by upregulating phosphorylated S6K levels in RCC cells.	('S6K', 'Gene', '6198', (160, 163))	('miR-92b-3p', 'Var', (36, 46))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('miR-92b-3p', 'Chemical', '-', (36, 46))	('RCC', 'Disease', (174, 177))	('upregulating', 'PosReg', (132, 144))	('S6K', 'Gene', (160, 163))	('signaling pathway', 'biological_process', 'GO:0007165', ('111', '128'))	('TSC1', 'Gene', (66, 70))	('mTOR signaling pathway', 'Pathway', (106, 128))
154640	31975504	The TSC1 gene was previously reported to be mutated in only approximately 4% of ccRCC, and no correlations were found between mutations and mTORC activation in tumors.24 Given the low frequency of TSC1 mutations in ccRCC, other mechanisms might exist to account for the relative low protein expression of TSC1 in ccRCC tumor tissues compared to normal counterparts.	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('RCC', 'Disease', (217, 220))	('ccRCC', 'Phenotype', 'HP:0006770', (215, 220))	('ccRCC tumor', 'Disease', (313, 324))	('TSC1', 'Gene', (197, 201))	('RCC', 'Disease', 'MESH:C538614', (315, 318))	('ccRCC', 'Phenotype', 'HP:0006770', (313, 318))	('RCC', 'Disease', (315, 318))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('ccRCC tumor', 'Disease', 'MESH:D009369', (313, 324))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('protein', 'cellular_component', 'GO:0003675', ('283', '290'))	('tumors', 'Disease', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('mutations', 'Var', (202, 211))
154642	31975504	Although we have shown that miR-92b-3p regulated not only cell growth (Figures 2, 2 and S5), but also cell invasion in RCC cells (Figures 2 and 2), it is not clear whether the described cellular phenotypic changes were caused directly by the variation in TSC1 expression.	('cell growth', 'biological_process', 'GO:0016049', ('58', '69'))	('regulated', 'Reg', (39, 48))	('miR-92b-3p', 'Var', (28, 38))	('TSC1', 'Gene', (255, 259))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))	('miR-92b-3p', 'Chemical', '-', (28, 38))	('cell growth', 'CPA', (58, 69))	('cell invasion', 'CPA', (102, 115))	('variation', 'Var', (242, 251))
154643	31975504	It should also be noted that the target prediction programs predicted miR-92b-3p-putative binding sequences in other genes involved in the invasion in RCC: PTE 25 and Dickkopf-related protein-3 (DKK-3).26 As a single miRNA can regulate multiple protein-coding and noncoding RNA transcripts in cells, miR-92b-3p could also mediate RCC cell invasion activities through other target molecules.	('RCC', 'Disease', (330, 333))	('mediate', 'Reg', (322, 329))	('binding', 'molecular_function', 'GO:0005488', ('90', '97'))	('DKK-3', 'Gene', (195, 200))	('protein', 'cellular_component', 'GO:0003675', ('245', '252'))	('RNA', 'cellular_component', 'GO:0005562', ('274', '277'))	('miR-92b-3p', 'Chemical', '-', (300, 310))	('protein', 'cellular_component', 'GO:0003675', ('184', '191'))	('Dickkopf-related protein-3', 'Gene', (167, 193))	('Dickkopf-related protein-3', 'Gene', '27122', (167, 193))	('regulate', 'MPA', (227, 235))	('DKK-3', 'Gene', '27122', (195, 200))	('miR-92b-3p', 'Var', (300, 310))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (151, 154))	('miR-92b-3p', 'Chemical', '-', (70, 80))	('RCC', 'Disease', 'MESH:C538614', (330, 333))
154645	31975504	Taken together, our study indicates that miR-92b-3p plays an important role in ccRCC progression and predicts poor patient OS.	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('miR-92b-3p', 'Var', (41, 51))	('RCC', 'Disease', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('miR-92b-3p', 'Chemical', '-', (41, 51))	('patient', 'Species', '9606', (115, 122))
154653	31070059	Inclusion of HIF-1/2 inhibitors to the current chemotherapy regimens has been proven advantageous in numerous reported preclinical studies.	('inhibitors', 'Var', (21, 31))	('HIF-1', 'Gene', '3091', (13, 18))	('HIF-1', 'Gene', (13, 18))
154654	31070059	The combination therapy ideally should be personalized based on the type of mutations involved in the specific cancers and it might be better to include two drugs that inhibit HIF-1/2 activity by synergistic molecular mechanisms.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('mutations', 'Var', (76, 85))	('cancers', 'Disease', (111, 118))	('HIF-1', 'Gene', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('activity', 'MPA', (184, 192))	('inhibit', 'NegReg', (168, 175))	('HIF-1', 'Gene', '3091', (176, 181))
154667	31070059	The unfavorable effects of hypoxia extend beyond its negative impact on the effectiveness of radiotherapy and chemotherapy, as hypoxic microenvironment is linked with genomic instability, genetic alterations, mutagenesis, and poor prognosis.	('genomic', 'MPA', (167, 174))	('rat', 'Species', '10116', (200, 203))	('mutagenesis', 'biological_process', 'GO:0006280', ('209', '220'))	('hypoxia', 'Disease', (27, 34))	('genetic alterations', 'Var', (188, 207))	('linked with', 'Reg', (155, 166))	('hypoxia', 'Disease', 'MESH:D000860', (27, 34))	('mutagenesis', 'Var', (209, 220))	('iron', 'Chemical', 'MESH:D007501', (143, 147))
154668	31070059	For instance, hypoxia is able to select for cells expressing mutations in both p53, a tumor suppressor gene, and Bcl-2, an apoptosis-inhibiting protein, in oncogenically transformed cells.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('p53', 'Gene', (79, 82))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('tumor', 'Disease', (86, 91))	('tumor suppressor', 'biological_process', 'GO:0051726', ('86', '102'))	('mutations', 'Var', (61, 70))	('hypoxia', 'Disease', (14, 21))	('hypoxia', 'Disease', 'MESH:D000860', (14, 21))	('Bcl-2', 'Gene', (113, 118))	('apoptosis', 'biological_process', 'GO:0097194', ('123', '132'))	('Bcl-2', 'Gene', '596', (113, 118))	('Bcl-2', 'molecular_function', 'GO:0015283', ('113', '118'))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('apoptosis', 'biological_process', 'GO:0006915', ('123', '132'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('86', '102'))
154711	31070059	Other multiple splice variants of the human HIF-3alpha have also been reported, however; it was evident that all human HIF-3alpha variants are induced by hypoxia and the induction is mediated by HIF-1alpha but not by HIF-2alpha.	('variants', 'Var', (130, 138))	('human', 'Species', '9606', (38, 43))	('HIF-3alpha', 'Gene', (119, 129))	('hypoxia', 'Disease', (154, 161))	('hypoxia', 'Disease', 'MESH:D000860', (154, 161))	('induced', 'Reg', (143, 150))	('human', 'Species', '9606', (113, 118))
154715	31070059	Conversely, Hypoxia stabilizes HIF-1/2alpha via inactivation of pVHL, thus decreases HIF-alpha ubiquitination and proteasomal degradation (Figure 2).	('HIF-alpha ubiquitination', 'Disease', 'MESH:C563003', (85, 109))	('degradation', 'biological_process', 'GO:0009056', ('126', '137'))	('HIF-1', 'Gene', (31, 36))	('inactivation', 'Var', (48, 60))	('Hypoxia', 'Disease', 'MESH:D000860', (12, 19))	('HIF-alpha ubiquitination', 'Disease', (85, 109))	('proteasomal degradation', 'MPA', (114, 137))	('Hypoxia', 'Disease', (12, 19))	('pVHL', 'Gene', (64, 68))	('decreases', 'NegReg', (75, 84))	('HIF-1', 'Gene', '3091', (31, 36))
154717	31070059	However, this ubiquitination step requires a posttranslational hydroxylation step of two separate consensus proline residues (P402 and P564) within the ODDD of the human HIF-1alpha and (P405 and P531) with in the ODDD of human HIF-2alpha subunits.	('P405', 'Var', (186, 190))	('human', 'Species', '9606', (164, 169))	('human', 'Species', '9606', (221, 226))	('P402', 'Var', (126, 130))	('P531', 'Var', (195, 199))	('proline', 'Chemical', 'MESH:D011392', (108, 115))	('P564', 'Var', (135, 139))	('rat', 'Species', '10116', (93, 96))
154731	31070059	Multiple sites of the HIF-1alpha protein can be modified by lysine acetylation leading to different downstream effects.	('modified', 'Reg', (48, 56))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('HIF-1alpha', 'Gene', (22, 32))	('lysine', 'Chemical', 'MESH:D008239', (60, 66))	('lysine acetylation', 'Var', (60, 78))
154733	31070059	However, the acetylation function of ARD1 is counteracted by the action of Metastasis-associated protein 1 (MTA1), where MTA1 induces the deacetylation of HIF-1alpha at K532R by increasing the expression of Histone deacetylase 1 (HDAC1) and thus enhances the transcriptional activity and stability of HIF-1alpha protein.	('ARD1', 'Gene', (37, 41))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('K532R', 'Var', (169, 174))	('HDAC1', 'Gene', '3065', (230, 235))	('expression', 'MPA', (193, 203))	('MTA1', 'Gene', (108, 112))	('transcriptional activity', 'MPA', (259, 283))	('MTA1', 'Gene', '9112', (108, 112))	('protein', 'cellular_component', 'GO:0003675', ('312', '319'))	('stability', 'MPA', (288, 297))	('deacetylation', 'MPA', (138, 151))	('Metastasis-associated protein 1', 'Gene', (75, 106))	('increasing', 'PosReg', (178, 188))	('enhances', 'PosReg', (246, 254))	('ARD1', 'molecular_function', 'GO:0010309', ('37', '41'))	('MTA1', 'Gene', (121, 125))	('Histone deacetylase 1', 'Gene', (207, 228))	('ARD1', 'Gene', '373', (37, 41))	('MTA1', 'Gene', '9112', (121, 125))	('Metastasis-associated protein 1', 'Gene', '9112', (75, 106))	('K532R', 'Mutation', 'p.K532R', (169, 174))	('HDAC1', 'Gene', (230, 235))	('Histone deacetylase 1', 'Gene', '3065', (207, 228))	('HIF-1alpha protein', 'Protein', (301, 319))
154737	31070059	reported that K532R mutation did not affect the interaction between the HIF-1alpha ODDD and human ARD1 (hARD1), and they concluded that hARD1 did not acetylate and destabilize HIF-1alpha.	('ARD1', 'Gene', (137, 141))	('ARD1', 'Gene', (98, 102))	('ARD1', 'Gene', '373', (105, 109))	('hARD1', 'Gene', '373', (104, 109))	('acetylate', 'MPA', (150, 159))	('hARD1', 'Gene', (104, 109))	('ARD1', 'Gene', '373', (137, 141))	('ARD1', 'Gene', '373', (98, 102))	('hARD1', 'Gene', '373', (136, 141))	('ARD1', 'molecular_function', 'GO:0010309', ('98', '102'))	('hARD1', 'Gene', (136, 141))	('human', 'Species', '9606', (92, 97))	('K532R', 'Var', (14, 19))	('ARD1', 'Gene', (105, 109))	('K532R', 'Mutation', 'p.K532R', (14, 19))
154739	31070059	Whereas, acetylations of lysine (K709) and lysine (K674) in the carboxy terminal region of HIF-1alpha are related to HIF-1alpha/p300 interaction and HIF-1 transactivation.	('K674', 'Var', (51, 55))	('HIF-1', 'Gene', '3091', (117, 122))	('HIF-1', 'Gene', '3091', (149, 154))	('HIF-1', 'Gene', (117, 122))	('p300', 'Gene', (128, 132))	('lysine', 'Chemical', 'MESH:D008239', (43, 49))	('HIF-1', 'Gene', '3091', (91, 96))	('acetylations', 'MPA', (9, 21))	('HIF-1', 'Gene', (149, 154))	('related', 'Reg', (106, 113))	('K709', 'Chemical', '-', (33, 37))	('p300', 'Gene', '2033', (128, 132))	('HIF-1', 'Gene', (91, 96))	('transactivation', 'biological_process', 'GO:2000144', ('155', '170'))	('K709', 'Var', (33, 37))	('lysine', 'Chemical', 'MESH:D008239', (25, 31))
154741	31070059	However, K674 in HIF-1alpha was shown to be acetylated primarily by the CBP/p300 -associated factor (PCAF) leading to the increase of HIF-1alpha protein levels and binding of p300.	('HIF-1alpha', 'Gene', (17, 27))	('CBP', 'molecular_function', 'GO:0008140', ('72', '75'))	('p300', 'Gene', (175, 179))	('CBP/p300 -associated factor', 'Gene', (72, 99))	('CBP/p300 -associated factor', 'Gene', '8850', (72, 99))	('PCAF', 'Gene', '8850', (101, 105))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('HIF-1alpha protein levels', 'MPA', (134, 159))	('p300', 'Gene', '2033', (175, 179))	('p300', 'Gene', (76, 80))	('binding', 'molecular_function', 'GO:0005488', ('164', '171'))	('K674', 'Var', (9, 13))	('PCAF', 'Gene', (101, 105))	('p300', 'Gene', '2033', (76, 80))	('increase', 'PosReg', (122, 130))	('binding', 'Interaction', (164, 171))
154742	31070059	showed that Sirtuin 1 (SIRT1), a NAD-dependent deacetylase, binds to HIF-1alpha, deacetylates it at K674 position, blocks p300 recruitment and consequently represses HIF-1 target genes.	('p300', 'Gene', (122, 126))	('HIF-1', 'Gene', '3091', (166, 171))	('SIRT1', 'Gene', (23, 28))	('HIF-1', 'Gene', (69, 74))	('Sirtuin 1', 'Gene', '23411', (12, 21))	('HIF-1', 'Gene', (166, 171))	('p300', 'Gene', '2033', (122, 126))	('represses', 'NegReg', (156, 165))	('HIF-1', 'Gene', '3091', (69, 74))	('blocks', 'NegReg', (115, 121))	('binds', 'Interaction', (60, 65))	('Sirtuin 1', 'Gene', (12, 21))	('deacetylates', 'Var', (81, 93))	('SIRT1', 'Gene', '23411', (23, 28))
154743	31070059	demonstrated that HIF-2alpha can be acetylated at K385, K685, and K741 positions within its C terminus by CBP and selectively deacetylated by SIRT1 to augment HIF-2 signaling.	('HIF-2alpha', 'Gene', (18, 28))	('HIF-2 signaling', 'MPA', (159, 174))	('K385', 'Var', (50, 54))	('CBP', 'Gene', '1977', (106, 109))	('K741 positions', 'Var', (66, 80))	('CBP', 'molecular_function', 'GO:0008140', ('106', '109'))	('augment', 'PosReg', (151, 158))	('SIRT1', 'Gene', (142, 147))	('signaling', 'biological_process', 'GO:0023052', ('165', '174'))	('rat', 'Species', '10116', (7, 10))	('SIRT1', 'Gene', '23411', (142, 147))	('K685', 'Var', (56, 60))	('CBP', 'Gene', (106, 109))
154744	31070059	In non-hypoxic conditions, overexpression of HIF-1alpha could be achieved by growth factors stimulation where they are able to increase HIF-1alpha protein synthesis in a cell type-specific manner via activation of protein tyrosine kinases (PTKs) by mutation or ligand binding.	('ligand binding', 'Interaction', (261, 275))	('mutation', 'Var', (249, 257))	('ligand', 'molecular_function', 'GO:0005488', ('261', '267'))	('increase HIF-1', 'Phenotype', 'HP:0030269', (127, 141))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))	('hypoxic conditions', 'Disease', (7, 25))	('protein tyrosine kinases', 'Pathway', (214, 238))	('binding', 'molecular_function', 'GO:0005488', ('268', '275'))	('protein synthesis', 'MPA', (147, 164))	('protein', 'cellular_component', 'GO:0003675', ('214', '221'))	('increase', 'PosReg', (127, 135))	('HIF-1alpha', 'Gene', (136, 146))	('protein synthesis', 'biological_process', 'GO:0006412', ('147', '164'))	('hypoxic conditions', 'Disease', 'MESH:D000071069', (7, 25))	('activation', 'PosReg', (200, 210))
154746	31070059	The two pathways are affected by the tumor microenvironment favorable selection of cells with somatic mutations that activates oncogenes and inactivate tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('activates', 'PosReg', (117, 126))	('iron', 'Chemical', 'MESH:D007501', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor suppressor', 'biological_process', 'GO:0051726', ('152', '168'))	('tumor', 'Disease', (152, 157))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('152', '168'))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('mutations', 'Var', (102, 111))	('inactivate', 'NegReg', (141, 151))	('oncogenes', 'Protein', (127, 136))
154747	31070059	PI3K regulates HIF-1alpha protein synthesis via its target downstream serine threonine kinases, AKT and rapamycin-associated protein (FRAP/FKBP), which is also known as mammalian target of rapamycin (mTOR).	('regulates', 'Reg', (5, 14))	('FKBP', 'molecular_function', 'GO:0030051', ('139', '143'))	('protein synthesis', 'biological_process', 'GO:0006412', ('26', '43'))	('mTOR', 'Gene', (200, 204))	('threonine', 'Chemical', 'MESH:D013912', (77, 86))	('AKT', 'Pathway', (96, 99))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('rapamycin', 'Chemical', 'MESH:D020123', (104, 113))	('PI3K', 'Var', (0, 4))	('mTOR', 'Gene', '2475', (200, 204))	('rapamycin', 'Chemical', 'MESH:D020123', (189, 198))	('mammalian target of rapamycin', 'Gene', '2475', (169, 198))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('FRAP', 'Gene', (134, 138))	('HIF-1alpha', 'Gene', (15, 25))	('FRAP', 'Gene', '2475', (134, 138))	('serine', 'Chemical', 'MESH:D012694', (70, 76))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('mammalian target of rapamycin', 'Gene', (169, 198))
154757	31070059	In prostate carcinoma and glioblastoma, mutation and inactivation of the tumor suppressor PTEN, which acts as a negative regulator of the PI3K via dephosphorylating the 3 position of phosphoinositides, is evident with elevated HIF-1alpha protein expressions.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('73', '89'))	('prostate carcinoma', 'Disease', 'MESH:D011471', (3, 21))	('elevated', 'PosReg', (218, 226))	('phosphoinositides', 'Chemical', 'MESH:D010716', (183, 200))	('HIF-1alpha protein', 'Protein', (227, 245))	('tumor suppressor', 'biological_process', 'GO:0051726', ('73', '89'))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (3, 21))	('protein', 'cellular_component', 'GO:0003675', ('238', '245'))	('mutation', 'Var', (40, 48))	('glioblastoma', 'Disease', 'MESH:D005909', (26, 38))	('tumor', 'Disease', (73, 78))	('prostate carcinoma', 'Disease', (3, 21))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('glioblastoma', 'Disease', (26, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('glioblastoma', 'Phenotype', 'HP:0012174', (26, 38))	('inactivation', 'NegReg', (53, 65))	('PI3K', 'molecular_function', 'GO:0016303', ('138', '142'))
154758	31070059	In addition to PTEN, VHL and p53 are two tumor suppressor genes in which their loss of function mutations results in increased expression of HIF-1alpha.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('HIF-1alpha', 'Protein', (141, 151))	('increased', 'PosReg', (117, 126))	('tumor', 'Disease', (41, 46))	('expression', 'MPA', (127, 137))	('loss of function', 'NegReg', (79, 95))	('tumor suppressor', 'biological_process', 'GO:0051726', ('41', '57'))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('41', '57'))	('mutations', 'Var', (96, 105))
154762	31070059	However, activating mutations in oncogenes such as the previously mentioned MTA1 is associated with increased HIF-alpha protein level and VEGF protein level, progression and metastasis of the pancreatic cancer.	('metastasis of the pancreatic cancer', 'Disease', 'MESH:D010190', (174, 209))	('increased', 'PosReg', (100, 109))	('progression', 'CPA', (158, 169))	('activating mutations', 'Var', (9, 29))	('MTA1', 'Gene', '9112', (76, 80))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('metastasis of the pancreatic cancer', 'Disease', (174, 209))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('VEGF', 'Gene', (138, 142))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (192, 209))	('HIF-alpha protein level', 'MPA', (110, 133))	('VEGF', 'Gene', '7422', (138, 142))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('MTA1', 'Gene', (76, 80))
154765	31070059	Moreover, ERK2 was reported to directly phosphorylate the C-terminal domain of HIF-1alpha at two distinct serine residues (S641 and S643) and by doing so it blocks HIF-1alpha nuclear exclusion by Chromosomal maintenance 1 (CRM1 also known as Exportin 1, XPO1) and enhances the nuclear accumulation and activity of HIF-1alpha.	('ERK2', 'molecular_function', 'GO:0004707', ('10', '14'))	('CRM1', 'Gene', (223, 227))	('serine', 'Chemical', 'MESH:D012694', (106, 112))	('activity', 'MPA', (302, 310))	('HIF-1alpha nuclear exclusion', 'MPA', (164, 192))	('Exportin 1', 'Gene', (242, 252))	('Exportin', 'cellular_component', 'GO:0005651', ('242', '250'))	('XPO1', 'Gene', '7514', (254, 258))	('blocks', 'NegReg', (157, 163))	('XPO1', 'Gene', (254, 258))	('S641', 'Var', (123, 127))	('S643', 'Var', (132, 136))	('ERK2', 'Gene', (10, 14))	('nuclear accumulation', 'MPA', (277, 297))	('Exportin 1', 'Gene', '7514', (242, 252))	('CRM1', 'Gene', '7514', (223, 227))	('enhances', 'PosReg', (264, 272))	('ERK2', 'Gene', '5594', (10, 14))
154766	31070059	showed that HIF-1alpha and HIF-2alpha were phosphorylated at threonine 796 and threonine 844, respectively, under hypoxic conditions.	('threonine', 'Chemical', 'MESH:D013912', (79, 88))	('hypoxic conditions', 'Disease', 'MESH:D000071069', (114, 132))	('threonine 844', 'Var', (79, 92))	('hypoxic conditions', 'Disease', (114, 132))	('threonine', 'Chemical', 'MESH:D013912', (61, 70))	('threonine 796', 'Var', (61, 74))
154768	31070059	showed that phosphorylation of HIF-1alpha at threonine 796 prevented the hydroxylation of asparagine 803 by FIH.	('threonine 796', 'Var', (45, 58))	('HIF-1alpha', 'Protein', (31, 41))	('threonine', 'Chemical', 'MESH:D013912', (45, 54))	('prevented', 'NegReg', (59, 68))	('phosphorylation', 'Var', (12, 27))	('asparagine', 'Chemical', 'MESH:D001216', (90, 100))	('phosphorylation', 'biological_process', 'GO:0016310', ('12', '27'))	('hydroxylation of asparagine 803', 'MPA', (73, 104))
154769	31070059	However, HIF-1alpha can be phosphorylated at several threonine and serine residues including: threonine 63 and serine 692 by Protein kinase A (PKA), serine 696 by Ataxia telangiectasia mutated serine/threonine kinase (ATM), and serine 668 by Cyclin-dependent kinase 1 (CDK1).	('CDK1', 'Gene', (269, 273))	('ATM', 'Gene', (218, 221))	('serine', 'Chemical', 'MESH:D012694', (67, 73))	('Cyclin-dependent kinase 1', 'Gene', (242, 267))	('threonine', 'Chemical', 'MESH:D013912', (94, 103))	('threonine', 'Chemical', 'MESH:D013912', (53, 62))	('serine', 'Chemical', 'MESH:D012694', (193, 199))	('threonine 63', 'Var', (94, 106))	('CDK', 'molecular_function', 'GO:0004693', ('269', '272'))	('serine', 'Chemical', 'MESH:D012694', (111, 117))	('Cyclin-dependent kinase 1', 'Gene', '983', (242, 267))	('ATM', 'Gene', '472', (218, 221))	('serine 696', 'Var', (149, 159))	('serine 668', 'Var', (228, 238))	('Ataxia', 'Phenotype', 'HP:0001251', (163, 169))	('PKA', 'cellular_component', 'GO:0005952', ('143', '146'))	('telangiectasia', 'Phenotype', 'HP:0001009', (170, 184))	('serine 692', 'Var', (111, 121))	('Ataxia telangiectasia', 'Disease', (163, 184))	('Cyclin', 'molecular_function', 'GO:0016538', ('242', '248'))	('threonine', 'Chemical', 'MESH:D013912', (200, 209))	('serine', 'Chemical', 'MESH:D012694', (149, 155))	('Ataxia telangiectasia', 'Disease', 'MESH:D001260', (163, 184))	('serine', 'Chemical', 'MESH:D012694', (228, 234))	('PKA', 'molecular_function', 'GO:0004691', ('143', '146'))	('CDK1', 'Gene', '983', (269, 273))
154770	31070059	Whereas these modifications by PKA, ATM and CDK1 resulted in increased HIF-1alpha stability, phosphorylation by Glycogen synthase kinase 3beta (GSK3beta) at serine 551, threonine 555, and serine 589, or by polo-like kinase 3 (PLK3) at serine 576 and serine 657 increases HIF-1alpha degradation.	('PLK3', 'Gene', (226, 230))	('serine', 'Chemical', 'MESH:D012694', (188, 194))	('CDK1', 'Gene', '983', (44, 48))	('CDK1', 'Gene', (44, 48))	('serine', 'Chemical', 'MESH:D012694', (157, 163))	('PLK3', 'Gene', '1263', (226, 230))	('increased', 'PosReg', (61, 70))	('serine', 'Chemical', 'MESH:D012694', (250, 256))	('serine', 'Chemical', 'MESH:D012694', (235, 241))	('PKA', 'cellular_component', 'GO:0005952', ('31', '34'))	('polo-like kinase 3', 'Gene', '1263', (206, 224))	('Glycogen synthase kinase 3beta', 'Gene', '2932', (112, 142))	('ATM', 'Gene', '472', (36, 39))	('PKA', 'molecular_function', 'GO:0004691', ('31', '34'))	('GSK3beta', 'Gene', (144, 152))	('CDK', 'molecular_function', 'GO:0004693', ('44', '47'))	('serine 576', 'Var', (235, 245))	('modifications', 'Var', (14, 27))	('degradation', 'biological_process', 'GO:0009056', ('282', '293'))	('GSK', 'molecular_function', 'GO:0050321', ('144', '147'))	('serine 657', 'Var', (250, 260))	('phosphorylation', 'MPA', (93, 108))	('HIF-1alpha stability', 'MPA', (71, 91))	('ATM', 'Gene', (36, 39))	('phosphorylation', 'biological_process', 'GO:0016310', ('93', '108'))	('polo-like kinase 3', 'Gene', (206, 224))	('increases', 'PosReg', (261, 270))	('HIF-1alpha degradation', 'MPA', (271, 293))	('threonine', 'Chemical', 'MESH:D013912', (169, 178))	('increased HIF-1', 'Phenotype', 'HP:0030269', (61, 76))	('Glycogen synthase kinase 3beta', 'Gene', (112, 142))	('GSK3beta', 'Gene', '2931', (144, 152))	('serine', 'Var', (188, 194))
154771	31070059	HIF-2alpha is phosphorylated at by casein kinase 1delta (CK1delta) at serine 383 and threonine 528, and as a result, CK1delta enhances the nuclear accumulation of HIF-2alpha via blocking the CRM1-dependent export of HIF-2alpha from the nucleus.	('CK1', 'Species', '2498238', (57, 60))	('nucleus', 'cellular_component', 'GO:0005634', ('236', '243'))	('CRM1', 'Gene', '7514', (191, 195))	('CRM1', 'Gene', (191, 195))	('nuclear accumulation', 'MPA', (139, 159))	('serine', 'Chemical', 'MESH:D012694', (70, 76))	('CK1', 'Species', '2498238', (117, 120))	('enhances', 'PosReg', (126, 134))	('export', 'MPA', (206, 212))	('blocking', 'NegReg', (178, 186))	('threonine', 'Chemical', 'MESH:D013912', (85, 94))	('CK1delta', 'Var', (117, 125))
154772	31070059	On the contrary, CK1delta phosphorylates HIF-1alpha at serine 247 and inhibits its activity via inhibiting its ability to associate with HIF-1beta.	('activity', 'MPA', (83, 91))	('HIF-1beta', 'Protein', (137, 146))	('CK1', 'Species', '2498238', (17, 20))	('associate', 'Interaction', (122, 131))	('inhibits', 'NegReg', (70, 78))	('CK1delta', 'Var', (17, 25))	('serine', 'Chemical', 'MESH:D012694', (55, 61))	('inhibiting', 'NegReg', (96, 106))	('serine 247', 'MPA', (55, 65))	('ability', 'MPA', (111, 118))
154784	31070059	Hsp70 recruits the ubiquitin ligase, carboxyl terminus of Hsp70-interacting protein (CHIP) to selectively promote the ubiquitination and proteasomal degradation of HIF-1alpha but not HIF-2alpha.	('HIF-1alpha', 'Var', (164, 174))	('Hsp70', 'Gene', (58, 63))	('proteasomal degradation', 'MPA', (137, 160))	('degradation', 'biological_process', 'GO:0009056', ('149', '160'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('19', '28'))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('promote', 'PosReg', (106, 113))	('Hsp70', 'Gene', '3308', (0, 5))	('Hsp70', 'Gene', '3308', (58, 63))	('ubiquitin', 'Protein', (19, 28))	('ubiquitination', 'MPA', (118, 132))	('Hsp70', 'Gene', (0, 5))
154794	31070059	The function of EPO enhancer in hypoxic liver tissue is shown to be modulated by sequences lying 3' downstream of HREs which contains the HIF binding site.	('binding', 'molecular_function', 'GO:0005488', ('142', '149'))	('EPO', 'Gene', (16, 19))	('hypoxic liver', 'Disease', (32, 45))	('modulated', 'Reg', (68, 77))	('sequences', 'Var', (81, 90))	('hypoxic liver', 'Disease', 'MESH:D017093', (32, 45))	('EPO', 'Gene', '2056', (16, 19))
154816	31070059	Many of the synthesized HIF-1/2 inhibitors act on HIF-1alpha, or HIF-2alpha, or both through direct mechanisms, while many other compounds and approved drugs have been shown to indirectly inhibit HIF-1/2 activity due to the connection between HIF-1/2 signaling and other cellular pathways such as the upstream pathways: the PI3K/AKT/mTOR pathways or the downstream cellular pathways: anti-VEGF-therapy.	('HIF-1', 'Gene', '3091', (24, 29))	('PI3K', 'molecular_function', 'GO:0016303', ('324', '328'))	('inhibitors', 'Var', (32, 42))	('HIF-1', 'Gene', (196, 201))	('HIF-1', 'Gene', (243, 248))	('VEGF', 'Gene', (389, 393))	('HIF-1', 'Gene', (24, 29))	('HIF-1', 'Gene', '3091', (196, 201))	('signaling', 'biological_process', 'GO:0023052', ('251', '260'))	('inhibit', 'NegReg', (188, 195))	('activity', 'MPA', (204, 212))	('HIF-1', 'Gene', '3091', (50, 55))	('HIF-1', 'Gene', '3091', (243, 248))	('VEGF', 'Gene', '7422', (389, 393))	('HIF-1', 'Gene', (50, 55))	('connection', 'Reg', (224, 234))	('mTOR', 'Gene', (333, 337))	('mTOR', 'Gene', '2475', (333, 337))
154822	31070059	It has a synergistic effect with gefitinib, an Epidermal growth factor receptor (EGFR) inhibitor that is used clinically in lung and breast cancer with mutated and overactive EGFR, because the combination treatment inhibits tumor growth and angiogenesis in allograft model significantly.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('Epidermal growth factor receptor', 'Gene', '1956', (47, 79))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('breast cancer', 'Disease', (133, 146))	('EGFR', 'Gene', (81, 85))	('EGFR', 'Gene', (175, 179))	('Epidermal growth factor receptor', 'Gene', (47, 79))	('tumor', 'Disease', (224, 229))	('angiogenesis', 'biological_process', 'GO:0001525', ('241', '253'))	('overactive', 'PosReg', (164, 174))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('mutated', 'Var', (152, 159))	('Epidermal growth factor', 'molecular_function', 'GO:0005154', ('47', '70'))	('EGFR', 'molecular_function', 'GO:0005006', ('81', '85'))	('gefitinib', 'Chemical', 'MESH:D000077156', (33, 42))	('inhibits', 'NegReg', (215, 223))	('EGFR', 'molecular_function', 'GO:0005006', ('175', '179'))	('EGFR', 'Gene', '1956', (175, 179))	('EGFR', 'Gene', '1956', (81, 85))
154823	31070059	BIX01294 (2) is a diazepinquinazolin-amine derivative that was originally identified as an Euchromatic histone-lysine N-methyltransferase 2 (EHMT2)/G9a inhibitor during a chemical library screening of small molecules.	('BIX01294', 'Chemical', 'MESH:C518299', (0, 8))	('BIX01294', 'Var', (0, 8))	('G9a', 'Gene', (148, 151))	('G9a', 'Gene', '10919', (148, 151))	('EHMT2', 'Gene', '10919', (141, 146))	('-amine', 'Chemical', 'MESH:D000588', (36, 42))	('Euchromatic histone-lysine N-methyltransferase 2', 'Gene', '10919', (91, 139))	('EHMT2', 'Gene', (141, 146))	('methyltransferase 2', 'molecular_function', 'GO:0043851', ('120', '139'))	('Euchromatic histone-lysine N-methyltransferase 2', 'Gene', (91, 139))
154824	31070059	EHMT2 is an essential enzyme that catalyzes the methylation of histone H3 at lysine residue 9 to form H3K9me2, which is an epigenetic marker.	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('EHMT2', 'Gene', (0, 5))	('H3K9me2', 'Var', (102, 109))	('lysine', 'Chemical', 'MESH:D008239', (77, 83))	('EHMT2', 'Gene', '10919', (0, 5))
154825	31070059	EHMT2 is highly expressed in human cancer cells such as in neuroblastoma and glioblastoma brain cancers and BIX01294 was reported to decrease the proliferation of neuroblastoma cells.	('neuroblastoma', 'Disease', 'MESH:D009447', (163, 176))	('decrease', 'NegReg', (133, 141))	('EHMT2', 'Gene', (0, 5))	('rat', 'Species', '10116', (153, 156))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('EHMT2', 'Gene', '10919', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Disease', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('neuroblastoma and glioblastoma brain cancers', 'Disease', 'MESH:D001932', (59, 103))	('glioblastoma', 'Phenotype', 'HP:0012174', (77, 89))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('proliferation', 'CPA', (146, 159))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('human', 'Species', '9606', (29, 34))	('neuroblastoma', 'Disease', (59, 72))	('neuroblastoma', 'Phenotype', 'HP:0003006', (59, 72))	('BIX01294', 'Chemical', 'MESH:C518299', (108, 116))	('neuroblastoma', 'Disease', (163, 176))	('BIX01294', 'Var', (108, 116))	('neuroblastoma', 'Phenotype', 'HP:0003006', (163, 176))	('neuroblastoma', 'Disease', 'MESH:D009447', (59, 72))	('cancer', 'Disease', (35, 41))
154826	31070059	BIX01294 was also reported to decrease HIF-1 expression in HepG2 human hepatocellular carcinoma cells via increasing the hydroxylation of HIF-1alpha by increasing PHD2 and pVHL expressions and thus diminishing HIF-1alpha stability (at 1 muM range).	('HIF-1', 'Gene', '3091', (210, 215))	('increasing', 'PosReg', (152, 162))	('human', 'Species', '9606', (65, 70))	('HIF-1', 'Gene', (210, 215))	('hepatocellular carcinoma', 'Disease', (71, 95))	('hydroxylation', 'MPA', (121, 134))	('HIF-1', 'Gene', '3091', (39, 44))	('decrease', 'NegReg', (30, 38))	('HIF-1', 'Gene', (39, 44))	('BIX01294', 'Chemical', 'MESH:C518299', (0, 8))	('PHD2', 'Gene', (163, 167))	('BIX01294', 'Var', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('pVHL', 'Gene', (172, 176))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (71, 95))	('HepG2', 'CellLine', 'CVCL:0027', (59, 64))	('HIF-1', 'Gene', '3091', (138, 143))	('expressions', 'MPA', (177, 188))	('PHD2', 'Gene', '54583', (163, 167))	('HIF-1', 'Gene', (138, 143))	('expression', 'MPA', (45, 55))	('increasing', 'PosReg', (106, 116))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (71, 95))	('diminishing', 'NegReg', (198, 209))	('PHD', 'molecular_function', 'GO:0050175', ('163', '166'))
154843	31070059	SN38 (7-ethyl-10-hydroxy-camptothecin) is the active metabolite of CPT-11 and it has anti Topo-I activity.	('CPT', 'molecular_function', 'GO:0004095', ('67', '70'))	('SN38', 'Var', (0, 4))	('camptothecin', 'Chemical', 'MESH:D002166', (25, 37))	('CPT-11', 'Chemical', 'MESH:D000077146', (67, 73))	('CPT', 'molecular_function', 'GO:0004142', ('67', '70'))	('anti Topo-I activity', 'MPA', (85, 105))	('SN38', 'Chemical', 'MESH:D000077146', (0, 4))	('CPT-11', 'Gene', (67, 73))
154854	31070059	IDF-11774 (7) is another aryloxyacetylaminobenzoic acid analogue like LW6, which have been reported to inhibit the accumulation of HIF-1alpha via regulation of VHL expression.	('HIF-1alpha', 'Protein', (131, 141))	('LW6', 'Chemical', '-', (70, 73))	('aryloxyacetylaminobenzoic acid', 'Chemical', '-', (25, 55))	('VHL', 'Gene', (160, 163))	('IDF-11774', 'Var', (0, 9))	('accumulation', 'MPA', (115, 127))	('inhibit', 'NegReg', (103, 110))	('regulation', 'biological_process', 'GO:0065007', ('146', '156'))
154858	31070059	IDF-11774 promotes HIF-1alpha degradation and inhibits its accumulation in colorectal cancer cells in vitro and in vivo.	('colorectal cancer', 'Disease', (75, 92))	('accumulation', 'MPA', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('IDF-11774', 'Var', (0, 9))	('promotes', 'PosReg', (10, 18))	('inhibits', 'NegReg', (46, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('degradation', 'biological_process', 'GO:0009056', ('30', '41'))	('HIF-1alpha', 'Protein', (19, 29))	('degradation', 'MPA', (30, 41))	('rectal cancer', 'Phenotype', 'HP:0100743', (79, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))
154859	31070059	IDF-11774 was shown to significantly inhibit mitochondrial respiration and increase the intracellular oxygen tension, and thus promote the proteasomal degradation of HIF-1alpha.	('degradation', 'biological_process', 'GO:0009056', ('151', '162'))	('mitochondrial respiration', 'MPA', (45, 70))	('oxygen', 'Chemical', 'MESH:D010100', (102, 108))	('respiration', 'biological_process', 'GO:0007585', ('59', '70'))	('promote', 'PosReg', (127, 134))	('HIF-1alpha', 'Protein', (166, 176))	('proteasomal degradation', 'MPA', (139, 162))	('IDF-11774', 'Var', (0, 9))	('inhibit', 'NegReg', (37, 44))	('intracellular oxygen tension', 'MPA', (88, 116))	('rat', 'Species', '10116', (64, 67))	('respiration', 'biological_process', 'GO:0045333', ('59', '70'))	('intracellular', 'cellular_component', 'GO:0005622', ('88', '101'))	('increase', 'PosReg', (75, 83))
154860	31070059	Intriguingly, IDF-11774 was reported to act as Hsp70 inhibitor by binding to the allosteric pocket of Hsp70.	('binding', 'molecular_function', 'GO:0005488', ('66', '73'))	('Hsp70', 'Gene', '3308', (47, 52))	('binding', 'Interaction', (66, 73))	('Hsp70', 'Gene', '3308', (102, 107))	('IDF-11774', 'Var', (14, 23))	('Hsp70', 'Gene', (47, 52))	('Hsp70', 'Gene', (102, 107))
154861	31070059	Moreover, IDF-11774 suppresses the hypoxia-induced mRNA expression of hypoxia target genes including VEGF and EPO.	('VEGF', 'Gene', (101, 105))	('EPO', 'Gene', (110, 113))	('hypoxia', 'Disease', 'MESH:D000860', (70, 77))	('IDF-11774', 'Var', (10, 19))	('suppresses', 'NegReg', (20, 30))	('VEGF', 'Gene', '7422', (101, 105))	('hypoxia', 'Disease', 'MESH:D000860', (35, 42))	('hypoxia', 'Disease', (70, 77))	('EPO', 'Gene', '2056', (110, 113))	('hypoxia', 'Disease', (35, 42))
154864	31070059	Moreover, LBH589 showed anticancer activity against glioblastoma both in vitro and in vivo through interfering with HIF-1alpha stability and inducing its degradation.	('stability', 'MPA', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('LBH589', 'Chemical', 'MESH:D000077767', (10, 16))	('HIF-1alpha', 'Protein', (116, 126))	('degradation', 'biological_process', 'GO:0009056', ('154', '165'))	('inducing', 'Reg', (141, 149))	('glioblastoma', 'Disease', (52, 64))	('degradation', 'MPA', (154, 165))	('LBH589', 'Var', (10, 16))	('glioblastoma', 'Disease', 'MESH:D005909', (52, 64))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('interfering', 'NegReg', (99, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))
154865	31070059	LBH589 disrupts Hsp90/Histone deacetylase 6 (HDAC6) complex because Hsp90 chaperone activity is regulated by its interaction and reversible acetylation by HDAC6 and inactivation of HDAC6 leads to Hsp90 hyperacetylation, its dissociation from p23 co-chaperone, and a loss of Hsp90 activity.	('Hsp90', 'Gene', (68, 73))	('loss', 'NegReg', (266, 270))	('inactivation', 'Var', (165, 177))	('HDAC6', 'Gene', '10013', (45, 50))	('chaperone activity', 'biological_process', 'GO:0006457', ('74', '92'))	('Hsp90/Histone deacetylase 6', 'Gene', (16, 43))	('HDAC6', 'Gene', '10013', (155, 160))	('p23', 'Gene', '7178', (242, 245))	('hyperacetylation', 'MPA', (202, 218))	('Hsp90', 'Gene', '3320', (16, 21))	('p23', 'Gene', (242, 245))	('acetylation', 'MPA', (140, 151))	('HDAC6', 'Gene', (181, 186))	('Hsp90', 'Gene', (16, 21))	('chaperone activity', 'molecular_function', 'GO:0003754', ('74', '92'))	('dissociation', 'MPA', (224, 236))	('Hsp90/Histone deacetylase 6', 'Gene', '10013', (16, 43))	('Hsp90', 'Gene', '3320', (196, 201))	('chaperone activity', 'biological_process', 'GO:0051131', ('74', '92'))	('HDAC6', 'Gene', (45, 50))	('activity', 'MPA', (84, 92))	('HDAC6', 'Gene', (155, 160))	('chaperone activity', 'molecular_function', 'GO:0044183', ('74', '92'))	('interaction', 'Interaction', (113, 124))	('Hsp90', 'Gene', '3320', (274, 279))	('HDAC6', 'Gene', '10013', (181, 186))	('LBH589', 'Chemical', 'MESH:D000077767', (0, 6))	('Hsp90', 'Gene', (196, 201))	('Hsp90', 'Gene', '3320', (68, 73))	('activity', 'MPA', (280, 288))	('chaperone activity', 'molecular_function', 'GO:0051082', ('74', '92'))	('chaperone activity', 'biological_process', 'GO:0065003', ('74', '92'))	('Hsp90', 'Gene', (274, 279))
154866	31070059	However, the newly synthesized HIF-1alpha molecules need to interact with the chaperone Hsp90 to complete its maturation and LBH589 treatment causes disruption of Hsp90-mediated folding of HIF-1alpha leading to its subsequent degradation by proteasome However, LBH589 attenuates hypoxia in a much higher level of complexity due to its influence on multiple HDACs.	('rat', 'Species', '10116', (114, 117))	('HIF-1alpha', 'Gene', (189, 199))	('attenuates', 'NegReg', (268, 278))	('LBH589', 'Chemical', 'MESH:D000077767', (261, 267))	('LBH589', 'Chemical', 'MESH:D000077767', (125, 131))	('degradation by proteasome', 'MPA', (226, 251))	('Hsp90', 'Gene', (163, 168))	('LBH589', 'Var', (261, 267))	('Hsp90', 'Gene', '3320', (163, 168))	('HDAC', 'Gene', (357, 361))	('Hsp90', 'Gene', (88, 93))	('hypoxia', 'Disease', (279, 286))	('hypoxia', 'Disease', 'MESH:D000860', (279, 286))	('HDAC', 'Gene', '9734', (357, 361))	('proteasome', 'cellular_component', 'GO:0000502', ('241', '251'))	('Hsp90', 'Gene', '3320', (88, 93))	('proteasome', 'molecular_function', 'GO:0004299', ('241', '251'))	('degradation', 'biological_process', 'GO:0009056', ('226', '237'))
154871	31070059	MPT0G157 exerted potent inhibition against HDAC1, 2, 3 and 6 and subsequently resulted in hyper-acetylation of Hsp90 and of HIF-1alpha, leading to its subsequent degradation.	('inhibition', 'MPA', (24, 34))	('HIF-1alpha', 'Protein', (124, 134))	('MPT', 'biological_process', 'GO:0035794', ('0', '3'))	('degradation', 'MPA', (162, 173))	('HDAC1', 'Gene', (43, 48))	('Hsp90', 'Gene', (111, 116))	('Hsp90', 'Gene', '3320', (111, 116))	('HDAC1', 'Gene', '3065', (43, 48))	('MPT0G157', 'Var', (0, 8))	('hyper-acetylation', 'MPA', (90, 107))	('degradation', 'biological_process', 'GO:0009056', ('162', '173'))
154872	31070059	In addition to its anti-inflammatory effect, MPT0G157 showed anticancer activity in vitro and in vivo particularly in human colorectal cancer (HCT116) cells.	('anti-inflammatory', 'MPA', (19, 36))	('cancer', 'Disease', (135, 141))	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('rectal cancer', 'Phenotype', 'HP:0100743', (128, 141))	('HCT116', 'CellLine', 'CVCL:0291', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('colorectal cancer', 'Disease', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('MPT', 'biological_process', 'GO:0035794', ('45', '48'))	('MPT0G157', 'Var', (45, 53))	('human', 'Species', '9606', (118, 123))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('colorectal cancer', 'Disease', 'MESH:D015179', (124, 141))
154881	31070059	NNC 55-0396 was found to significantly suppress the hypoxia-induced mitochondrial ROS generation and thus blocks HIF-1 activation and tumor growth and angiogenesis in vitro and in vivo.	('rat', 'Species', '10116', (90, 93))	('ROS', 'Chemical', 'MESH:D017382', (82, 85))	('hypoxia', 'Disease', (52, 59))	('activation', 'MPA', (119, 129))	('hypoxia', 'Disease', 'MESH:D000860', (52, 59))	('ROS generation', 'biological_process', 'GO:1903409', ('82', '96'))	('blocks', 'NegReg', (106, 112))	('HIF-1', 'Gene', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('suppress', 'NegReg', (39, 47))	('HIF-1', 'Gene', '3091', (113, 118))	('angiogenesis', 'biological_process', 'GO:0001525', ('151', '163'))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('NNC 55-0396', 'Chemical', 'MESH:C484287', (0, 11))	('angiogenesis', 'CPA', (151, 163))	('mitochondrial ROS generation', 'MPA', (68, 96))	('tumor', 'Disease', (134, 139))	('NNC 55-0396', 'Var', (0, 11))
154885	31070059	In addition, NNC 55-0396 increased the hydroxylation of HIF-1alpha and its subsequent ubiquitination and degradation.	('HIF-1alpha', 'Protein', (56, 66))	('increased', 'PosReg', (25, 34))	('NNC 55-0396', 'Chemical', 'MESH:C484287', (13, 24))	('hydroxylation', 'MPA', (39, 52))	('degradation', 'MPA', (105, 116))	('ubiquitination', 'MPA', (86, 100))	('degradation', 'biological_process', 'GO:0009056', ('105', '116'))	('NNC 55-0396', 'Var', (13, 24))
154886	31070059	Moreover, NNC 55-0396 suppressed the de novo HIF-1 alpha synthesis via inhibition the phosphorylation of mTOR and p70S6K.	('HIF-1 alpha', 'Gene', '3091', (45, 56))	('suppressed', 'NegReg', (22, 32))	('phosphorylation', 'biological_process', 'GO:0016310', ('86', '101'))	('inhibition', 'NegReg', (71, 81))	('phosphorylation', 'MPA', (86, 101))	('mTOR', 'Gene', (105, 109))	('mTOR', 'Gene', '2475', (105, 109))	('NNC 55-0396', 'Chemical', 'MESH:C484287', (10, 21))	('p70S6K', 'Gene', (114, 120))	('HIF-1 alpha', 'Gene', (45, 56))	('synthesis', 'biological_process', 'GO:0009058', ('57', '66'))	('p70S6K', 'Gene', '6198', (114, 120))	('de novo', 'MPA', (37, 44))	('NNC 55-0396', 'Var', (10, 21))
154891	31070059	PT2385 (13) and PT2399 (14) are selective HIF-2alpha inhibitors that allosterically blocks its dimerization with HIF-1beta.	('PT2385', 'Var', (0, 6))	('PT2399', 'Var', (16, 22))	('PT2385', 'Chemical', 'MESH:C000614279', (0, 6))	('dimerization', 'MPA', (95, 107))	('PT2399', 'Chemical', 'MESH:C000614278', (16, 22))	('HIF-2alpha', 'Gene', (42, 52))	('blocks', 'NegReg', (84, 90))
154895	31070059	However, phase I clinical trial demonstrated that PT2385 has a favorable safety profile and is active in patients with heavily pretreated ccRCC.	('patients', 'Species', '9606', (105, 113))	('rat', 'Species', '10116', (39, 42))	('PT2385', 'Var', (50, 56))	('ccRCC', 'Disease', (138, 143))	('PT2385', 'Chemical', 'MESH:C000614279', (50, 56))
154917	31070059	For instances, large number of ccRCC show genetic mutation in VHL and TCEB1, which encodes Elongin C. These defects impair the classical regulation pathway of HIF-1/2, cause failure to degrade HIF-alpha subunits and result in its accumulation under normoxic conditions.	('defects', 'Var', (108, 115))	('HIF-1', 'Gene', '3091', (159, 164))	('Elongin C', 'Gene', (91, 100))	('classical regulation pathway', 'Pathway', (127, 155))	('accumulation', 'MPA', (230, 242))	('regulation', 'biological_process', 'GO:0065007', ('137', '147'))	('HIF-1', 'Gene', (159, 164))	('HIF-alpha subunits', 'Protein', (193, 211))	('TCEB1', 'Gene', '6921', (70, 75))	('TCEB1', 'Gene', (70, 75))	('VHL', 'Gene', (62, 65))	('degrade', 'NegReg', (185, 192))	('impair', 'NegReg', (116, 122))	('Elongin C', 'Gene', '6921', (91, 100))	('mutation', 'Var', (50, 58))
154920	31070059	PT2385 may particularly effective in the treatment of renal cell carcinomas especially with the positive results of its phase I clinical trial.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (54, 75))	('PT2385', 'Var', (0, 6))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('PT2385', 'Chemical', 'MESH:C000614279', (0, 6))	('renal cell carcinomas', 'Disease', (54, 75))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (54, 75))
154921	31070059	However, PT2399 prolonged treatment causes cross-resistance in xenograft models, probably due to mutations in the binding site in HIF-2alpha.	('PT2399', 'Var', (9, 15))	('mutations', 'Var', (97, 106))	('PT2399', 'Chemical', 'MESH:C000614278', (9, 15))	('binding', 'molecular_function', 'GO:0005488', ('114', '121'))	('cross-resistance', 'MPA', (43, 59))	('binding', 'Interaction', (114, 121))	('HIF-2alpha', 'Gene', (130, 140))
154929	31070059	HIF-1/2alpha is overexpressed in human cancers as a result of intratumoral hypoxia, low-molecular weight signaling molecules such as reactive oxygen species, gain-of-function mutations in oncogenes and loss-of-function mutations in tumor-suppressor genes.	('hypoxia', 'Disease', 'MESH:D000860', (75, 82))	('tumor-suppressor', 'Gene', '7248', (232, 248))	('loss-of-function', 'NegReg', (202, 218))	('low-molecular weight signaling molecules', 'MPA', (84, 124))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('HIF-1', 'Gene', '3091', (0, 5))	('gain-of-function', 'PosReg', (158, 174))	('human', 'Species', '9606', (33, 38))	('mutations', 'Var', (175, 184))	('tumor', 'Disease', (67, 72))	('HIF-1', 'Gene', (0, 5))	('reactive oxygen species', 'MPA', (133, 156))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('tumor-suppressor', 'Gene', (232, 248))	('tumor', 'Disease', (232, 237))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('cancers', 'Disease', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (133, 156))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('232', '248'))	('mutations', 'Var', (219, 228))	('hypoxia', 'Disease', (75, 82))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('232', '248'))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('oncogenes', 'Gene', (188, 197))	('rat', 'Species', '10116', (65, 68))
154933	31070059	In preclinical and clinical studies, inhibition of HIF-1/2 activity has marked effects on angiogenesis and tumor growth.	('activity', 'MPA', (59, 67))	('inhibition', 'Var', (37, 47))	('angiogenesis', 'biological_process', 'GO:0001525', ('90', '102'))	('angiogenesis', 'CPA', (90, 102))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('effects', 'Reg', (79, 86))	('HIF-1', 'Gene', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('HIF-1', 'Gene', '3091', (51, 56))
154957	29416873	The clonal evolution model or stochastic model implies the presence of a tumor cell population carrying different mutations which have accumulated over time and then selected under different selective pressures 14.	('mutations', 'Var', (114, 123))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))
154966	29416873	More recently, a unifying model of clonal evolution applied to CSCs was proposed by Kreso et al, whereby CSCs can acquire mutations and generate new stem cell branches and, at the same time, tumor cells in the non-CSC subpopulation can undergo epithelial-mesenchymal transition (EMT) and acquire CSC-like features contributing to tumor heterogeneity 17 (Figure 1).	('CSCs', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('epithelial-mesenchymal transition', 'CPA', (244, 277))	('tumor', 'Disease', (330, 335))	('undergo', 'PosReg', (236, 243))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('244', '277'))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('mutations', 'Var', (122, 131))	('tumor', 'Disease', (191, 196))	('EMT', 'biological_process', 'GO:0001837', ('279', '282'))	('tumor', 'Disease', 'MESH:D009369', (330, 335))
155002	29416873	CD133+ cancer cells were able to form spheres, gave rise to tumors in vivo and exhibited chemoresistance properties in colorectal carcinoma (CRC), HCC, lung cancer, glioblastoma, pancreatic cancer, and ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('glioblastoma', 'Disease', (165, 177))	('ovarian cancer', 'Disease', 'MESH:D010051', (202, 216))	('glioblastoma', 'Phenotype', 'HP:0012174', (165, 177))	('cancer cells', 'Disease', 'MESH:C538614', (7, 19))	('pancreatic cancer', 'Disease', 'MESH:D010190', (179, 196))	('lung cancer', 'Disease', 'MESH:D008175', (152, 163))	('gave rise', 'Reg', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('ovarian cancer', 'Disease', (202, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('CRC', 'Phenotype', 'HP:0030731', (141, 144))	('pancreatic cancer', 'Disease', (179, 196))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('ovarian cancer', 'Phenotype', 'HP:0100615', (202, 216))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('HCC', 'Disease', (147, 150))	('HCC', 'Phenotype', 'HP:0001402', (147, 150))	('chemoresistance properties', 'CPA', (89, 115))	('cancer cells', 'Disease', (7, 19))	('tumors', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('glioblastoma', 'Disease', 'MESH:D005909', (165, 177))	('CD133+', 'Var', (0, 6))	('colorectal carcinoma', 'Disease', (119, 139))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (179, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (119, 139))	('lung cancer', 'Disease', (152, 163))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
155004	29416873	When co-transplanted with renal carcinoma cells, CD133+ progenitors significantly enhanced tumor development and growth.	('renal carcinoma', 'Disease', 'MESH:C538614', (26, 41))	('enhanced', 'PosReg', (82, 90))	('renal carcinoma', 'Disease', (26, 41))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('renal carcinoma', 'Phenotype', 'HP:0005584', (26, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('CD133+', 'Var', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('growth', 'CPA', (113, 119))
155005	29416873	Of note, CD105+ cells did not express CD133, suggesting that CD133+ cells may represent renal resident adult progenitor cells rather than CSCs.	('CD105', 'Gene', (9, 14))	('CD133+', 'Var', (61, 67))	('CD105', 'Gene', '13805', (9, 14))
155010	29416873	Moreover, CD133- cells were also able to give rise to tumors in immunodeficient mice in glioblastoma and CRC 73, 74.	('glioblastoma', 'Disease', (88, 100))	('rise to tumors in immunodeficient', 'Disease', (46, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (88, 100))	('glioblastoma', 'Phenotype', 'HP:0012174', (88, 100))	('rise to tumors in immunodeficient', 'Disease', 'MESH:D009369', (46, 79))	('CRC', 'Phenotype', 'HP:0030731', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('CD133-', 'Var', (10, 16))	('mice', 'Species', '10090', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
155029	29416873	Monoclonal antibodies against CD44 are now in clinical trial for patients affected by AML, whereas knockdown of CD44 has been shown to increase sensitivity to chemotherapy in cell cultures derived from HCC, lung, breast and pancreatic cancers 80, 86.	('AML', 'Phenotype', 'HP:0004808', (86, 89))	('sensitivity to chemotherapy', 'MPA', (144, 171))	('AML', 'Disease', (86, 89))	('increase', 'PosReg', (135, 143))	('CD44', 'Gene', '960', (112, 116))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (224, 242))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('breast and pancreatic cancers', 'Disease', 'MESH:D010190', (213, 242))	('CD44', 'Gene', '960', (30, 34))	('CD44', 'Gene', (112, 116))	('AML', 'Disease', 'MESH:D015470', (86, 89))	('knockdown', 'Var', (99, 108))	('CD44', 'Gene', (30, 34))	('patients', 'Species', '9606', (65, 73))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (224, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('HCC', 'Phenotype', 'HP:0001402', (202, 205))
155049	29416873	Conversely, inhibition of CXCR4 by ADM3100 or small interfering RNA (siRNA) impaired tumor formation 44, 47.	('impaired tumor', 'Disease', (76, 90))	('CXCR4', 'Gene', '7852', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('formation', 'biological_process', 'GO:0009058', ('91', '100'))	('CXCR4', 'molecular_function', 'GO:0038147', ('26', '31'))	('CXCR4', 'Gene', (26, 31))	('small interfering', 'Var', (46, 63))	('ADM3100', 'Var', (35, 42))	('impaired tumor', 'Disease', 'MESH:D015417', (76, 90))	('RNA', 'cellular_component', 'GO:0005562', ('64', '67'))
155068	29416873	This protein is involved in the transport of small ions, sugar, peptides, and organic molecules across the plasma membrane against a concentration gradient by hydrolysis of ATP 108.	('involved', 'Reg', (16, 24))	('transport', 'MPA', (32, 41))	('plasma membrane', 'cellular_component', 'GO:0005886', ('107', '122'))	('protein', 'cellular_component', 'GO:0003675', ('5', '12'))	('transport', 'biological_process', 'GO:0006810', ('32', '41'))	('ATP', 'Chemical', 'MESH:D000255', (173, 176))	('hydrolysis', 'Var', (159, 169))	('sugar', 'Chemical', 'MESH:D000073893', (57, 62))
155081	29416873	Inhibition of miR17 resulted in enhanced sphere formation indicating that TGFbeta signalling plays an important role in renal CSCs and that miR17 impairs the signalling cascade by targeting the TGFbeta signalling pathway 40.	('miR17', 'Gene', '406952', (140, 145))	('formation', 'biological_process', 'GO:0009058', ('48', '57'))	('enhanced', 'PosReg', (32, 40))	('signalling pathway', 'biological_process', 'GO:0007165', ('202', '220'))	('signalling cascade', 'Pathway', (158, 176))	('sphere formation', 'CPA', (41, 57))	('impairs', 'NegReg', (146, 153))	('renal CSCs', 'Disease', (120, 130))	('miR17', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('TGFbeta', 'Gene', (194, 201))	('signalling', 'biological_process', 'GO:0023052', ('82', '92'))	('miR17', 'Gene', (140, 145))	('TGFbeta', 'Gene', (74, 81))	('miR17', 'Gene', '406952', (14, 19))	('TGFbeta', 'Gene', '7040', (194, 201))	('signalling cascade', 'biological_process', 'GO:0007165', ('158', '176'))	('TGFbeta', 'Gene', '7040', (74, 81))	('targeting', 'Reg', (180, 189))
155086	29416873	786O cells were stained with Rh123 and sorted by flow cytometry into two population: Rh123high and Rh123low.	('Rh123', 'Chemical', 'MESH:D020112', (29, 34))	('Rh123low', 'Var', (99, 107))	('Rh123', 'Chemical', 'MESH:D020112', (85, 90))	('Rh123', 'Chemical', 'MESH:D020112', (99, 104))	('Rh123high', 'Var', (85, 94))
155087	29416873	Rh123high exhibited high proliferative activity, differentiation, resistance to radiation, tumourigenic potential, and spheroid formation in soft agar, indicating Rh123 as an alternative method to isolate CSCs 37.	('tumourigenic potential', 'CPA', (91, 113))	('differentiation', 'CPA', (49, 64))	('Rh123', 'Chemical', 'MESH:D020112', (0, 5))	('resistance', 'CPA', (66, 76))	('agar', 'Chemical', 'MESH:D000362', (146, 150))	('proliferative activity', 'CPA', (25, 47))	('Rh123high', 'Var', (0, 9))	('formation', 'biological_process', 'GO:0009058', ('128', '137'))	('spheroid formation', 'CPA', (119, 137))	('Rh123', 'Chemical', 'MESH:D020112', (163, 168))
155141	29416873	Following BrdU staining, a subset of cells expressing CD133 and CD24 were isolated from the urinary pole of Bowman's capsule and from the proximal tubules, in particular in the S3 segment.	('CD24', 'Gene', '100133941', (64, 68))	('CD133', 'Var', (54, 59))	('BrdU', 'Chemical', 'MESH:D001973', (10, 14))	('CD24', 'Gene', (64, 68))	('capsule', 'cellular_component', 'GO:0042603', ('117', '124'))
155167	32884346	As treatment options for mRCC are rapidly expanding, immunotherapy combinations could potentially change the treatment paradigm, with the ultimate goal of prolonging life and eventually curing mRCC.	('combinations', 'Var', (67, 79))	('prolonging', 'PosReg', (155, 165))	('change', 'Reg', (98, 104))	('RCC', 'Disease', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (194, 197))	('RCC', 'Disease', (194, 197))	('RCC', 'Disease', 'MESH:C538614', (26, 29))
155183	32884346	In a phase III study comparing sunitinib and interferon-alfa (IFN-alpha), patients treated with sunitinib had significantly longer PFS (11 months vs 5 months) (HR=0.42, 95% CI 0.32-0.54; p<0.001).	('sunitinib', 'Chemical', 'MESH:D000077210', (31, 40))	('sunitinib', 'Var', (96, 105))	('sunitinib', 'Chemical', 'MESH:D000077210', (96, 105))	('patients', 'Species', '9606', (74, 82))	('PFS', 'MPA', (131, 134))	('longer', 'PosReg', (124, 130))
155197	32884346	In a phase III trial, pazopanib increased PFS over placebo (9.2 months vs 4.2 months, respectively; HR=0.46, 95% CI 0.34-0.62; p<0.0001).	('PFS', 'MPA', (42, 45))	('pazopanib', 'Chemical', 'MESH:C516667', (22, 31))	('pazopanib', 'Var', (22, 31))	('increased', 'PosReg', (32, 41))
155215	32884346	Anti-PD-1 and anti-CTLA4 antibodies improve T-cell responses and allow upregulation of anticancer activity by negative Treg regulation and increased IFN-gamma and IL-2 production.	('Treg regulation', 'CPA', (119, 134))	('IL-2', 'Gene', (163, 167))	('T-cell responses', 'CPA', (44, 60))	('IL-2', 'molecular_function', 'GO:0005134', ('163', '167'))	('IFN-gamma', 'Gene', '3458', (149, 158))	('IFN-gamma', 'Gene', (149, 158))	('increased', 'PosReg', (139, 148))	('IL-2 production', 'biological_process', 'GO:0032623', ('163', '178'))	('antibodies', 'Var', (25, 35))	('CTLA4', 'Gene', '1493', (19, 24))	('upregulation', 'PosReg', (71, 83))	('improve', 'PosReg', (36, 43))	('IL-2', 'Gene', '3558', (163, 167))	('Anti-PD-1', 'Var', (0, 9))	('CTLA4', 'Gene', (19, 24))	('anticancer activity', 'MPA', (87, 106))	('negative', 'NegReg', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('regulation', 'biological_process', 'GO:0065007', ('124', '134'))
155216	32884346	One of the key mechanisms of resistance to immune checkpoint inhibitors is MDSCs, which are known to accumulate in kidney tumors and inhibit activation of CD4+ and CD8+ T cells.	('CD8', 'Gene', (164, 167))	('CD4', 'Gene', (155, 158))	('CD8', 'Gene', '925', (164, 167))	('CD4', 'Gene', '920', (155, 158))	('inhibit', 'NegReg', (133, 140))	('activation', 'MPA', (141, 151))	('accumulate', 'PosReg', (101, 111))	('kidney tumors', 'Disease', (115, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('kidney tumors', 'Disease', 'MESH:D007680', (115, 128))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('MDSCs', 'Var', (75, 80))	('kidney tumors', 'Phenotype', 'HP:0009726', (115, 128))
155217	32884346	Pembrolizumab, a selective, fully humanized immunoglobulin G4-kappa monoclonal antibody against PD-1, is FDA-approved for the treatment of many cancers, including head and neck squamous cell carcinoma, melanoma, non-small cell and small cell lung cancer, gastric cancer, urothelial cancer, triple-negative breast cancer, microsatellite instability-high (MSI-high) colorectal cancer, and Hodgkin lymphoma.	('colorectal cancer', 'Phenotype', 'HP:0003003', (364, 381))	('small cell lung cancer', 'Disease', 'MESH:D055752', (231, 253))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('microsatellite instability-high', 'Var', (321, 352))	('small cell lung cancer', 'Disease', (231, 253))	('gastric cancer', 'Disease', 'MESH:D013274', (255, 269))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('antibody', 'molecular_function', 'GO:0003823', ('79', '87'))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('44', '58'))	('Hodgkin lymphoma', 'Disease', (387, 403))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('antibody', 'cellular_component', 'GO:0042571', ('79', '87'))	('PD-1', 'Gene', (96, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('urothelial cancer', 'Disease', 'MESH:D014523', (271, 288))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (0, 13))	('neck', 'cellular_component', 'GO:0044326', ('172', '176'))	('cancers', 'Disease', (144, 151))	('colorectal cancer', 'Disease', 'MESH:D015179', (364, 381))	('breast cancer', 'Phenotype', 'HP:0003002', (306, 319))	('neck squamous cell carcinoma', 'Disease', (172, 200))	('gastric cancer', 'Phenotype', 'HP:0012126', (255, 269))	('urothelial cancer', 'Disease', (271, 288))	('colorectal cancer', 'Disease', (364, 381))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (387, 403))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (387, 403))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (172, 200))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (231, 253))	('breast cancer', 'Disease', 'MESH:D001943', (306, 319))	('lymphoma', 'Phenotype', 'HP:0002665', (395, 403))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('antibody', 'cellular_component', 'GO:0019815', ('79', '87'))	('melanoma', 'Disease', (202, 210))	('breast cancer', 'Disease', (306, 319))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('antibody', 'cellular_component', 'GO:0019814', ('79', '87'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('gastric cancer', 'Disease', (255, 269))	('lung cancer', 'Phenotype', 'HP:0100526', (242, 253))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (163, 200))
155239	32884346	Most patients treated with VEGFR inhibitors will eventually develop resistance to therapy.	('patients', 'Species', '9606', (5, 13))	('VEGFR', 'Gene', '3791', (27, 32))	('resistance to therapy', 'MPA', (68, 89))	('VEGFR', 'Gene', (27, 32))	('develop', 'PosReg', (60, 67))	('inhibitors', 'Var', (33, 43))
155243	32884346	In a murine model of colon adenocarcinoma, treatment with anti-VEGFR-2 and anti-PD-1 monoclonal antibodies simultaneously inhibited tumor growth synergistically in vivo.	('anti-PD-1', 'Var', (75, 84))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (21, 41))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('inhibited', 'NegReg', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('murine', 'Species', '10090', (5, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('VEGFR-2', 'Gene', '16542', (63, 70))	('tumor', 'Disease', (132, 137))	('VEGFR-2', 'Gene', (63, 70))	('colon adenocarcinoma', 'Disease', (21, 41))
155245	32884346	These findings suggest that the combination of anti-VEGF and anti-PD-1 therapies may have immune-modulating functions and clinical benefits greater than either modality alone.	('VEGF', 'Gene', (52, 56))	('immune-modulating', 'CPA', (90, 107))	('VEGF', 'Gene', '7422', (52, 56))	('clinical benefits', 'CPA', (122, 139))	('anti-PD-1', 'Var', (61, 70))
155415	30532559	Immunohistochemistry almost showed reactions to antibodies against CK-7 in all cases, while showed no reactions to neuroendocrine markers such as CGA, SYN in all cases.	('CK-7', 'Gene', '3855', (67, 71))	('CK-7', 'Gene', (67, 71))	('CGA', 'Gene', (146, 149))	('showed reactions', 'Reg', (28, 44))	('antibodies', 'Var', (48, 58))	('SYN', 'Gene', '6855', (151, 154))	('SYN', 'Gene', (151, 154))	('CGA', 'Gene', '1113', (146, 149))
155416	30532559	Sequencing of the K-ras oncogene was analyzed in three cases, and a mutation at codon 12 in K-ras oncogene was detected in two cases, providing molecular evidence of ductal origin.	('K-ras', 'Gene', '3845', (18, 23))	('mutation at codon', 'Var', (68, 85))	('K-ras', 'Gene', (92, 97))	('K-ras', 'Gene', '3845', (92, 97))	('K-ras', 'Gene', (18, 23))
155427	30532559	Genetic analysis for detecting K-ras mutations and biomarker studies, such as HNF-1beta, would aid in the identification of this rare neoplasm, but it is not absolute.	('K-ras', 'Gene', (31, 36))	('neoplasm', 'Disease', 'MESH:D009369', (134, 142))	('K-ras', 'Gene', '3845', (31, 36))	('mutations', 'Var', (37, 46))	('HNF-1beta', 'Gene', (78, 87))	('HNF-1beta', 'Gene', '6928', (78, 87))	('neoplasm', 'Disease', (134, 142))	('neoplasm', 'Phenotype', 'HP:0002664', (134, 142))
155433	29973214	This S315-score was validated in 108 metastatic and non-metastatic ccRCC patients and ccRCC-derived metastases including in part several regions from one metastasis.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('metastases', 'Disease', (100, 110))	('S315-score', 'Var', (5, 15))	('RCC', 'Disease', (69, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('metastases', 'Disease', 'MESH:D009362', (100, 110))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('patients', 'Species', '9606', (73, 81))
155435	29973214	The S397-score was significantly associated with cancer-specific survival (CSS) in 52 ccRCC patients (HR 2.9, 95% Cl 1.0-8.0, PLog-rank = 3.3 x 10-2) as well as progression-free survival in sunitinib-treated patients (2.1, 1.1-4.2, PLog-rank = 2.2 x 10-2).	('patients', 'Species', '9606', (208, 216))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('sunitinib', 'Chemical', 'MESH:D000077210', (190, 199))	('patients', 'Species', '9606', (92, 100))	('CSS', 'Chemical', '-', (75, 78))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('S397-score', 'Var', (4, 14))	('cancer', 'Disease', (49, 55))	('associated with', 'Reg', (33, 48))
155436	29973214	The qRT-PCR based S315-score performed similarly to the S397-score, and was significantly associated with CSS in our extended cohort of 108 patients (5.0, 2.1-11.7, PLog-rank = 5.1 x 10-5) including metastatic (9.3, 1.8-50.0, PLog-rank = 2.3 x 10-3) and non-metastatic patients (4.4, 1.2-16.3, PLog-rank = 1.6 x 10-2), even in multivariate Cox regression, including clinicopathological parameters (7.3, 2.5-21.5, PWald = 3.3 x 10-4).	('Cox', 'Gene', '1351', (340, 343))	('Cox', 'Gene', (340, 343))	('CSS', 'Disease', (106, 109))	('associated', 'Reg', (90, 100))	('S315-score', 'Var', (18, 28))	('patients', 'Species', '9606', (140, 148))	('CSS', 'Chemical', '-', (106, 109))	('patients', 'Species', '9606', (269, 277))
155437	29973214	Matched primary tumors and metastases revealed similar S315-scores, thus allowing prediction of outcome from metastatic tissue.	('tumors', 'Disease', (16, 22))	('metastases', 'Disease', 'MESH:D009362', (27, 37))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('S315-scores', 'Var', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('metastases', 'Disease', (27, 37))	('tumors', 'Disease', 'MESH:D009369', (16, 22))
155438	29973214	The molecular-based qRT-PCR S315-score significantly improved prediction of CSS by the established clinicopathological-based SSIGN score (P = 1.6 x 10-3).	('CSS', 'Chemical', '-', (76, 79))	('improved', 'PosReg', (53, 61))	('S315-score', 'Var', (28, 38))	('CSS', 'Disease', (76, 79))
155475	29973214	patients with a high S397-score had an decreased risk for cancer-related death compared to patients with low S397-scores.	('patients', 'Species', '9606', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', (58, 64))	('decreased', 'NegReg', (39, 48))	('S397-score', 'Var', (21, 31))
155476	29973214	Furthermore, univariate Cox regression including evaluation of the predictive ability according to Harrell's c-index indicated a significant association of the S397-score with patient survival (HR 2.9, 95% Cl 1.0-8.0, PLog-rank = 3.3 x 10-2) (Additional file 1: Table S2).	('association', 'Interaction', (141, 152))	('Cox', 'Gene', '1351', (24, 27))	('S397-score', 'Var', (160, 170))	('patient survival', 'CPA', (176, 192))	('Cox', 'Gene', (24, 27))	('patient', 'Species', '9606', (176, 183))
155480	29973214	1b); i.e., patients with a high S397-score had increased progression-free survival probability after sunitinib treatment compared with patients with a low S397-score.	('patients', 'Species', '9606', (135, 143))	('sunitinib', 'Chemical', 'MESH:D000077210', (101, 110))	('S397-score', 'Var', (32, 42))	('high S397-score', 'Var', (27, 42))	('increased', 'PosReg', (47, 56))	('patients', 'Species', '9606', (11, 19))	('progression-free survival', 'CPA', (57, 82))
155481	29973214	Furthermore, univariate Cox regression including evaluation of the predictive ability according to Harrell's c-index, indicated a significant association of the S397-score with patient survival after treatment with sunitinib (HR 2.1, 95% CI 1.1-4.2, PLog-rank = 2.2 x 10-2) (Additional file 1: Table S2).	('Cox', 'Gene', '1351', (24, 27))	('Cox', 'Gene', (24, 27))	('S397-score', 'Var', (161, 171))	('patient survival', 'CPA', (177, 193))	('sunitinib', 'Chemical', 'MESH:D000077210', (215, 224))	('patient', 'Species', '9606', (177, 184))
155482	29973214	Based on our results, the S397-score has the ability to significantly predict not only CSS in ccRCC patients, but also the progression-free survival in sunitinib-treated individuals.	('RCC', 'Disease', (96, 99))	('CSS', 'Chemical', '-', (87, 90))	('predict', 'Reg', (70, 77))	('sunitinib', 'Chemical', 'MESH:D000077210', (152, 161))	('patients', 'Species', '9606', (100, 108))	('S397-score', 'Var', (26, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('CSS', 'Disease', (87, 90))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
155484	29973214	Univariate Cox regression indicated that the S315-score was significantly associated with CSS in our extended ccRCC cohort 2 (n = 108) (Table 2).	('CSS', 'Disease', (90, 93))	('CSS', 'Chemical', '-', (90, 93))	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('RCC', 'Disease', (112, 115))	('S315-score', 'Var', (45, 55))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))	('associated', 'Reg', (74, 84))
155486	29973214	Moreover, similarly to the 97 gene-based S397-score we could confirm the ability of the S315-score to predict CSS in non-metastatic (HR 4.4, 95% Cl 1.2-16.3, PLog-Rank = 1.6 x 10-2) as well as metastatic patients (HR 9.3, 95% Cl 1.8-50.0, PLog-rank = 2.3 x 10-3) (Fig.	('patients', 'Species', '9606', (204, 212))	('CSS', 'Chemical', '-', (110, 113))	('non-metastatic', 'Disease', (117, 131))	('CSS', 'Disease', (110, 113))	('S315-score', 'Var', (88, 98))
155487	29973214	As expected, a higher incidence of advanced stage tumors as well as metastatic tumors occurred in the S315-low group with poor survival (Additional file 1: Figure S5 and Table S4).	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('S315-low', 'Var', (102, 110))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('advanced stage tumors', 'Disease', 'MESH:D020178', (35, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('advanced stage tumors', 'Disease', (35, 56))
155488	29973214	Multivariate Cox regression indicated that the S315-score is able to significantly improve the predictive ability of the clinicopathological parameters (Table 3).	('improve', 'PosReg', (83, 90))	('Cox', 'Gene', '1351', (13, 16))	('S315-score', 'Var', (47, 57))	('Cox', 'Gene', (13, 16))
155490	29973214	Moreover, the S315-score significantly improved CSS prediction when added to the Cox model initially including only the clinicopathologic-based SSIGN score (Pchi2 = 1.6 x 10-3) (Fig.	('Cox', 'Gene', (81, 84))	('CSS', 'Chemical', '-', (48, 51))	('S315-score', 'Var', (14, 24))	('improved', 'PosReg', (39, 47))	('Cox', 'Gene', '1351', (81, 84))	('CSS', 'Disease', (48, 51))
155492	29973214	We now aimed to investigate the S397-score and S315-score in metastases in order to evaluate the concordance between primary tumors and metastases.	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('metastases', 'Disease', (61, 71))	('tumors', 'Disease', (125, 131))	('S397-score', 'Var', (32, 42))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('metastases', 'Disease', (136, 146))	('metastases', 'Disease', 'MESH:D009362', (136, 146))	('metastases', 'Disease', 'MESH:D009362', (61, 71))	('S315-score', 'Var', (47, 57))
155493	29973214	First, we analyzed the S397-score in metastases using microarray data.	('metastases', 'Disease', (37, 47))	('S397-score', 'Var', (23, 33))	('metastases', 'Disease', 'MESH:D009362', (37, 47))
155495	29973214	Calculation of the S397-score individually for tumor and metastases resulted in similar risk prediction (Fig.	('metastases', 'Disease', (57, 67))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('S397-score', 'Var', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('metastases', 'Disease', 'MESH:D009362', (57, 67))	('tumor', 'Disease', (47, 52))
155496	29973214	One patient (P4) was assigned to the high risk group (low S397-score) with worse prognosis using either metastases or tumor tissue (Additional file 1: Table S5).	('low S397-score', 'Var', (54, 68))	('metastases', 'Disease', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('metastases', 'Disease', 'MESH:D009362', (104, 114))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Disease', (118, 123))	('S397-score', 'Var', (58, 68))
155497	29973214	Three patients (P1, P3, P5) showed a high S397-score in tumor as well as metastasis tissue (Additional file 1: Table S5).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('patients', 'Species', '9606', (6, 14))	('S397-score', 'Var', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
155501	29973214	We additionally performed qRT-PCR quantification and calculation of the S315-score in a subset of metastases samples.	('metastases', 'Disease', (98, 108))	('metastases', 'Disease', 'MESH:D009362', (98, 108))	('S315-score', 'Var', (72, 82))
155502	29973214	Regarding the five metastatic patients from our ccRCC cohorts for whom primary tumors as well as metastases were available, we found that, except for one case, the S397-score tendency was preserved using the improved S315-score (Fig.	('metastases', 'Disease', (97, 107))	('S315-score', 'Var', (217, 227))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('RCC', 'Disease', (50, 53))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('patients', 'Species', '9606', (30, 38))	('metastases', 'Disease', 'MESH:D009362', (97, 107))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
155510	29973214	Here, we showed not only that a platform transfer to microarray data is possible, but also that the S397-score significantly predicts CSS in our cohort.	('predicts', 'Reg', (125, 133))	('CSS', 'Chemical', '-', (134, 137))	('S397-score', 'Var', (100, 110))	('CSS', 'Disease', (134, 137))
155517	29973214	In this cohort, the S397-score was significantly associated with progression-free survival of patients, indicating that our score enables even prediction of sunitinib outcome.	('patients', 'Species', '9606', (94, 102))	('progression-free survival', 'CPA', (65, 90))	('associated', 'Reg', (49, 59))	('S397-score', 'Var', (20, 30))	('sunitinib', 'Chemical', 'MESH:D000077210', (157, 166))
155520	29973214	To provide a more cost-effective approach for clinical application of the S3-score in individual patient samples, such as even formalin-fixed paraffin-embedded samples, we improved the S397-score by reducing the number of signature genes from 97 to 15 especially for expression analyses through RT-PCR.	('paraffin', 'Chemical', 'MESH:D010232', (142, 150))	('reducing', 'NegReg', (199, 207))	('formalin', 'Chemical', 'MESH:D005557', (127, 135))	('S397-score', 'Var', (185, 195))	('patient', 'Species', '9606', (97, 104))
155521	29973214	Our improved S315-score was validated using RT-PCR technology in a cohort of 108 ccRCC cases, clearly indicating that the S315-score was associated with CSS in the complete cohort, as well as non-metastatic and metastatic subsets.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('S315-score', 'Var', (122, 132))	('associated', 'Reg', (137, 147))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('CSS', 'Disease', (153, 156))	('CSS', 'Chemical', '-', (153, 156))
155522	29973214	Moreover, the S315-score improves prediction of CSS by the currently clinically applied SSIGN score, which is based on clinical parameters and pathologic features.	('S315-score', 'Var', (14, 24))	('CSS', 'Chemical', '-', (48, 51))	('CSS', 'Disease', (48, 51))	('improves', 'PosReg', (25, 33))
155523	29973214	Finally, the S315-score allows risk prediction in tumor and metastases tissue.	('S315-score', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('metastases', 'Disease', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('metastases', 'Disease', 'MESH:D009362', (60, 70))	('tumor', 'Disease', (50, 55))
155529	29973214	The 97 gene-based S397-score and a simplified 15-gene RT-PCR-based S315-score are significantly associated with CSS or progression-free survival in non-metastatic and metastatic ccRCC patients, as well as in TKI-treated patients.	('S397-score', 'Var', (18, 28))	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('RCC', 'Disease', (180, 183))	('patients', 'Species', '9606', (184, 192))	('associated with', 'Reg', (96, 111))	('CSS', 'Disease', (112, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (178, 183))	('patients', 'Species', '9606', (220, 228))	('CSS', 'Chemical', '-', (112, 115))	('S315-score', 'Var', (67, 77))	('non-metastatic', 'Disease', (148, 162))	('progression-free survival', 'CPA', (119, 144))
155540	29674707	We collected targeted next-generation sequencing mutation calls from two independent cohorts and described the metastases GA landscape and descriptively compared it to the GA landscape in primary tumours.	('metastases', 'Disease', (111, 121))	('primary tumours', 'Disease', 'MESH:D009369', (188, 203))	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('tumours', 'Phenotype', 'HP:0002664', (196, 203))	('primary tumours', 'Disease', (188, 203))	('metastases', 'Disease', 'MESH:D009362', (111, 121))	('mutation', 'Var', (49, 57))
155542	29674707	Overall, the most common mutations in the metastases were VHL (66.8%), PBRM1 (41.87%), and SETD2 (24.7%).	('metastases', 'Disease', 'MESH:D009362', (42, 52))	('mutations', 'Var', (25, 34))	('PBRM1', 'Gene', (71, 76))	('SETD2', 'Gene', '29072', (91, 96))	('SETD2', 'Gene', (91, 96))	('PBRM1', 'Gene', '55193', (71, 76))	('VHL', 'Gene', (58, 61))	('VHL', 'Gene', '7428', (58, 61))	('metastases', 'Disease', (42, 52))
155543	29674707	TP53 was more frequently mutated in metastases compared to primary tumours (14.85% versus 8.9%; p = 0.031).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('metastases', 'Disease', (36, 46))	('primary tumours', 'Disease', (59, 74))	('primary tumours', 'Disease', 'MESH:D009369', (59, 74))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('metastases', 'Disease', 'MESH:D009362', (36, 46))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))	('mutated', 'Var', (25, 32))
155554	29674707	Few RCC mutations have potentially actionable mutations.	('RCC', 'Disease', (4, 7))	('RCC', 'Disease', 'MESH:C538614', (4, 7))	('mutations', 'Var', (8, 17))
155580	29674707	Mutations in TP53 were more frequent in the metastases than in the primary tumours (14.85% versus 8.9%; p = 0.031), however this did not pass the false discovery rate (FDR; q = 0.21).	('TP53', 'Gene', (13, 17))	('false', 'biological_process', 'GO:0071877', ('146', '151'))	('metastases', 'Disease', (44, 54))	('Mutations', 'Var', (0, 9))	('primary tumours', 'Disease', 'MESH:D009369', (67, 82))	('frequent', 'Reg', (28, 36))	('false', 'biological_process', 'GO:0071878', ('146', '151'))	('TP53', 'Gene', '7157', (13, 17))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('primary tumours', 'Disease', (67, 82))	('metastases', 'Disease', 'MESH:D009362', (44, 54))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
155581	29674707	PBRM1 (39.2% versus 47.1%) and KDM5C (11.5% versus 15.6%) were numerically more frequently mutated in metastases, but differences were not statistically significant.	('KDM5C', 'Gene', '8242', (31, 36))	('PBRM1', 'Gene', (0, 5))	('mutated', 'Var', (91, 98))	('PBRM1', 'Gene', '55193', (0, 5))	('metastases', 'Disease', (102, 112))	('metastases', 'Disease', 'MESH:D009362', (102, 112))	('KDM5C', 'Gene', (31, 36))
155600	29674707	Multiple other studies have suggested non-mutation related reasons as to why a ccRCC tumour metastasises, including expression, protein, and epigenetic changes.	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('tumour metastasises', 'Disease', 'MESH:D009369', (85, 104))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('tumour metastasises', 'Disease', (85, 104))	('RCC', 'Disease', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('epigenetic changes', 'Var', (141, 159))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
155601	29674707	However, there is emerging evidence that specific mutations in advanced RCC may increase over subsequent lines of therapy.	('mutations', 'Var', (50, 59))	('RCC', 'Disease', (72, 75))	('increase', 'PosReg', (80, 88))	('RCC', 'Disease', 'MESH:C538614', (72, 75))
155608	29674707	Furthermore, the frequencies of mutations in most genes in both cohorts are higher than what was reported in the ccRCC cohort from TCGA, potentially due to germ line SNPs or higher clinical stage in our study.	('higher', 'Reg', (76, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (113, 118))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('mutations', 'Var', (32, 41))
155611	29674707	We demonstrate that there are no significant differences in frequencies of most common gene mutations between primary tumours and metastases from ccRCC using two different targeted gene panels.	('RCC', 'Disease', (148, 151))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))	('mutations', 'Var', (92, 101))	('primary tumours', 'Disease', 'MESH:D009369', (110, 125))	('metastases', 'Disease', (130, 140))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('metastases', 'Disease', 'MESH:D009362', (130, 140))	('primary tumours', 'Disease', (110, 125))
155644	31186699	Synonymous mutations were introduced an shKMT5A#1 (5'-CGCAGCAAAACCGTAAGCTCA-3', mutations underlined) (GENEWIZ, Suzhou, China) target sequences in KMT5A coding sequences to create the RNAi resistant shKMT5A-RES plasmid.	('KMT5A', 'Gene', '387893', (201, 206))	('mutations', 'Var', (11, 20))	('RNAi', 'biological_process', 'GO:0016246', ('184', '188'))	('KMT5A', 'Gene', (147, 152))	('KMT5A', 'Gene', '387893', (42, 47))	('KMT5A', 'Gene', (42, 47))	('KMT5A', 'Gene', '387893', (147, 152))	('KMT5A', 'Gene', (201, 206))
155669	31186699	The cells with silenced KMT5A expression displayed sharp declines in cell migration and invasiveness compared with the corresponding control groups, which was prevented by re-expression of KMT5A (Fig.	('KMT5A', 'Gene', (189, 194))	('expression', 'Var', (30, 40))	('KMT5A', 'Gene', (24, 29))	('KMT5A', 'Gene', '387893', (189, 194))	('cell migration', 'CPA', (69, 83))	('cell migration', 'biological_process', 'GO:0016477', ('69', '83'))	('KMT5A', 'Gene', '387893', (24, 29))	('invasiveness', 'CPA', (88, 100))	('silenced', 'Var', (15, 23))	('declines', 'NegReg', (57, 65))
155673	31186699	Western blot analysis was used to determine any effects on the CDH1 protein expression levels in the KMT5A-knockout and control cells, and revealed that knockdown of KMT5A expression markedly upregulated CDH1 protein levels in 786-O cells (Fig.	('CDH1', 'Gene', '999', (204, 208))	('CDH1', 'Gene', (63, 67))	('knockdown', 'Var', (153, 162))	('KMT5A', 'Gene', '387893', (166, 171))	('CDH1', 'Gene', '999', (63, 67))	('upregulated', 'PosReg', (192, 203))	('KMT5A', 'Gene', (166, 171))	('CDH1', 'Gene', (204, 208))	('protein levels', 'MPA', (209, 223))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('KMT5A', 'Gene', (101, 106))	('protein', 'cellular_component', 'GO:0003675', ('209', '216'))	('KMT5A', 'Gene', '387893', (101, 106))
155674	31186699	Next, the CDH1 mRNA levels were measured, demonstrating that the knockdown of KMT5A increased CDH1 transcription levels (P<0.01; Fig.	('CDH1', 'Gene', (10, 14))	('KMT5A', 'Gene', (78, 83))	('CDH1', 'Gene', '999', (10, 14))	('KMT5A', 'Gene', '387893', (78, 83))	('transcription levels', 'MPA', (99, 119))	('CDH1', 'Gene', (94, 98))	('transcription', 'biological_process', 'GO:0006351', ('99', '112'))	('increased', 'PosReg', (84, 93))	('CDH1', 'Gene', '999', (94, 98))	('knockdown', 'Var', (65, 74))
155675	31186699	Furthermore, the luciferase reporter assay revealed that silencing KMT5A in 786-O cells led to the activation of CDH1 promoter activity (P<0.01; Fig.	('KMT5A', 'Gene', (67, 72))	('KMT5A', 'Gene', '387893', (67, 72))	('silencing', 'Var', (57, 66))	('activation', 'PosReg', (99, 109))	('CDH1', 'Gene', (113, 117))	('CDH1', 'Gene', '999', (113, 117))
155679	31186699	Following the finding of upregulation in the expression level of CDH1 in the 786-O cells upon KMT5A knockdown, the correlation between the expression levels of KMT5A and CDH1 in the tumor tissues from the aforementioned patients with ccRCC was investigated.	('RCC', 'Disease', 'MESH:C538614', (236, 239))	('patients', 'Species', '9606', (220, 228))	('KMT5A', 'Gene', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('knockdown', 'Var', (100, 109))	('CDH1', 'Gene', '999', (170, 174))	('KMT5A', 'Gene', (94, 99))	('expression level', 'MPA', (45, 61))	('CDH1', 'Gene', (170, 174))	('CDH1', 'Gene', '999', (65, 69))	('KMT5A', 'Gene', '387893', (94, 99))	('KMT5A', 'Gene', '387893', (160, 165))	('tumor', 'Disease', (182, 187))	('CDH1', 'Gene', (65, 69))	('RCC', 'Disease', (236, 239))	('RCC', 'Phenotype', 'HP:0005584', (236, 239))	('ccRCC', 'Phenotype', 'HP:0006770', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('upregulation', 'PosReg', (25, 37))
155682	31186699	The patients whose samples expressed high CDH1 levels had longer OS times compared with those whose samples expressed low levels (Fig.	('OS times', 'MPA', (65, 73))	('CDH1', 'Gene', (42, 46))	('high', 'Var', (37, 41))	('CDH1', 'Gene', '999', (42, 46))	('longer', 'PosReg', (58, 64))	('patients', 'Species', '9606', (4, 12))
155684	31186699	The combination of KMT5A and CDH1 was demonstrated to be a promising independent prognostic indicator for OS time (P<0.001), more accurate than KMT5A or CDH1 alone.	('combination', 'Var', (4, 15))	('KMT5A', 'Gene', '387893', (144, 149))	('CDH1', 'Gene', (29, 33))	('KMT5A', 'Gene', (144, 149))	('CDH1', 'Gene', (153, 157))	('OS time', 'Disease', (106, 113))	('CDH1', 'Gene', '999', (153, 157))	('CDH1', 'Gene', '999', (29, 33))	('KMT5A', 'Gene', (19, 24))	('KMT5A', 'Gene', '387893', (19, 24))
155689	31186699	Consistent with these findings, ccRCC patients with high KMT5A expression levels were associated with shorter OS time.	('shorter', 'NegReg', (102, 109))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('KMT5A', 'Gene', '387893', (57, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (32, 37))	('expression', 'MPA', (63, 73))	('high', 'Var', (52, 56))	('patients', 'Species', '9606', (38, 46))	('OS time', 'CPA', (110, 117))	('KMT5A', 'Gene', (57, 62))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('RCC', 'Disease', (34, 37))
155698	31186699	The results of the present study demonstrated that the knockdown of KMT5A expression inhibits the migration and invasiveness of ccRCC 786-O cells.	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('knockdown', 'Var', (55, 64))	('inhibits', 'NegReg', (85, 93))	('KMT5A', 'Gene', (68, 73))	('KMT5A', 'Gene', '387893', (68, 73))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (130, 133))
155707	31186699	Patients with high KMT5A expression levels were revealed to be associated with shorter postoperative OS time.	('postoperative OS time', 'CPA', (87, 108))	('expression', 'MPA', (25, 35))	('shorter', 'NegReg', (79, 86))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('KMT5A', 'Gene', (19, 24))	('KMT5A', 'Gene', '387893', (19, 24))
155710	31186699	The combination of KMT5A and CDH1 was confirmed to be an independent prognostic indicator for OS (P<0.001), which was more accurate than monitoring KMT5A or CDH1 expression alone.	('CDH1', 'Gene', '999', (157, 161))	('CDH1', 'Gene', (157, 161))	('combination', 'Var', (4, 15))	('CDH1', 'Gene', (29, 33))	('KMT5A', 'Gene', (148, 153))	('CDH1', 'Gene', '999', (29, 33))	('KMT5A', 'Gene', (19, 24))	('KMT5A', 'Gene', '387893', (148, 153))	('KMT5A', 'Gene', '387893', (19, 24))
155717	30355451	Loss of HIF2alpha, PBRM1, or KDM5C in VHL-/-cells reduces the expression of interferon stimulated gene factor 3 (ISGF3), a transcription factor that regulates the interferon signature.	('KDM5C', 'Gene', (29, 34))	('transcription factor', 'molecular_function', 'GO:0000981', ('123', '143'))	('HIF2alpha', 'Gene', (8, 17))	('expression', 'MPA', (62, 72))	('KDM5C', 'Gene', '8242', (29, 34))	('ISGF3', 'Gene', (113, 118))	('interferon stimulated gene factor 3', 'Gene', (76, 111))	('reduces', 'NegReg', (50, 57))	('ISGF3', 'Gene', '6772', (113, 118))	('interferon stimulated gene factor 3', 'Gene', '6772', (76, 111))	('Loss', 'Var', (0, 4))	('transcription', 'biological_process', 'GO:0006351', ('123', '136'))	('PBRM1', 'Gene', (19, 24))
155718	30355451	Moreover, loss of SETD2 or BAP1 also reduces the ISGF3 level.	('loss', 'Var', (10, 14))	('ISGF3', 'Gene', '6772', (49, 54))	('BAP1', 'Gene', (27, 31))	('SETD2', 'Gene', '29072', (18, 23))	('SETD2', 'Gene', (18, 23))	('reduces', 'NegReg', (37, 44))	('ISGF3', 'Gene', (49, 54))
155720	30355451	Conversely, reactivation of ISGF3 retards tumor growth by PBRM1-deficient ccRCC cells.	('PBRM1-deficient', 'Gene', (58, 73))	('ISGF3', 'Gene', '6772', (28, 33))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('reactivation', 'Var', (12, 24))	('retards tumor', 'Disease', 'MESH:D009369', (34, 47))	('ISGF3', 'Gene', (28, 33))	('retards tumor', 'Disease', (34, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
155721	30355451	Thus after VHL inactivation, HIF induces ISGF3, which is reversed by the loss of secondary tumor suppressors, suggesting that this is a key negative feedback loop in ccRCC.	('RCC', 'Disease', (168, 171))	('ISGF3', 'Gene', '6772', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('VHL', 'Gene', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('ISGF3', 'Gene', (41, 46))	('tumor', 'Disease', (91, 96))	('inactivation', 'Var', (15, 27))
155723	30355451	Inactivation of the VHL tumor suppressor gene is a causal event in the pathogenesis of clear cell Renal Cell Carcinoma (ccRCC), the most frequent subtype of kidney cancer.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (98, 118))	('clear cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (87, 118))	('clear cell Renal Cell Carcinoma', 'Disease', (87, 118))	('clear cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (87, 118))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('Carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('kidney cancer', 'Disease', (157, 170))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('tumor suppressor', 'biological_process', 'GO:0051726', ('24', '40'))	('VHL tumor', 'Disease', (20, 29))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('24', '40'))	('VHL tumor', 'Disease', 'MESH:D006623', (20, 29))	('pathogenesis', 'biological_process', 'GO:0009405', ('71', '83'))	('kidney cancer', 'Disease', 'MESH:D007680', (157, 170))	('RCC', 'Disease', (122, 125))	('Inactivation', 'Var', (0, 12))	('kidney cancer', 'Phenotype', 'HP:0009726', (157, 170))
155724	30355451	Approximately 70 - 80% of ccRCC are sporadic tumors that harbor biallelic inactivation of VHL.	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('sporadic tumors', 'Disease', (36, 51))	('biallelic', 'Var', (64, 73))	('VHL', 'Gene', (90, 93))	('RCC', 'Disease', (28, 31))	('sporadic tumors', 'Disease', 'MESH:D009369', (36, 51))
155725	30355451	In the rare disease of hereditary kidney cancer, germline VHL mutation leads to early-onset bilateral kidney tumors.	('bilateral kidney tumors', 'Disease', (92, 115))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('kidney cancer', 'Phenotype', 'HP:0009726', (34, 47))	('bilateral kidney tumors', 'Disease', 'MESH:D007674', (92, 115))	('hereditary kidney cancer', 'Disease', (23, 47))	('hereditary kidney cancer', 'Disease', 'MESH:D007680', (23, 47))	('kidney tumors', 'Phenotype', 'HP:0009726', (102, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('germline VHL mutation', 'Var', (49, 70))	('leads to', 'Reg', (71, 79))
155736	30355451	Most types of solid tumors harbor multiple, sometimes dozens of mutations, in cancer genes to establish the hallmarks of cancer.	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (78, 84))	('solid tumors', 'Disease', (14, 26))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('mutations', 'Var', (64, 73))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (121, 127))	('solid tumors', 'Disease', 'MESH:D009369', (14, 26))
155738	30355451	reported that 41% of ccRCC tumors had inactivating mutations in the PBRM1 gene.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('inactivating mutations', 'Var', (38, 60))	('RCC tumors', 'Disease', 'MESH:C538614', (23, 33))	('PBRM1', 'Gene', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('RCC tumors', 'Disease', (23, 33))
155741	30355451	Like VHL mutations, many PBRM1 mutations occur early in tumorigenesis, unlike the other secondary mutations.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mutations', 'Var', (31, 40))	('tumor', 'Disease', (56, 61))	('PBRM1', 'Gene', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
155743	30355451	PBRM1 was also found to amplify a HIF signature and genetic ablation of both Vhl and Pbrm1 in mouse kidneys leads to ccRCC while single loss fails to do so.	('Vhl', 'Gene', (77, 80))	('leads to', 'Reg', (108, 116))	('Pbrm1', 'Gene', (85, 90))	('mouse', 'Species', '10090', (94, 99))	('genetic ablation', 'Var', (52, 68))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))	('HIF signature', 'MPA', (34, 47))
155745	30355451	KDM5C mutations occur in 3-7% of ccRCC tumors.	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('KDM5C', 'Gene', (0, 5))	('RCC tumors', 'Disease', 'MESH:C538614', (35, 45))	('KDM5C', 'Gene', '8242', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('mutations', 'Var', (6, 15))	('RCC tumors', 'Disease', (35, 45))
155751	30355451	SETD2 mutations are subclonalin ccRCC tumors, and are associated with worse patient survival.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('RCC tumors', 'Disease', 'MESH:C538614', (34, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('SETD2', 'Gene', '29072', (0, 5))	('SETD2', 'Gene', (0, 5))	('RCC tumors', 'Disease', (34, 44))	('patient', 'Species', '9606', (76, 83))	('mutations', 'Var', (6, 15))
155753	30355451	Indeed, SETD2 mutations in ccRCC tumors are associated with changes in chromatin accessibility and DNA methylation or widespread RNA processing defects.	('RNA', 'cellular_component', 'GO:0005562', ('129', '132'))	('widespread', 'MPA', (118, 128))	('SETD2', 'Gene', (8, 13))	('RCC tumors', 'Disease', (29, 39))	('RNA processing', 'biological_process', 'GO:0006396', ('129', '143'))	('changes', 'Reg', (60, 67))	('DNA methylation', 'MPA', (99, 114))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('DNA methylation', 'biological_process', 'GO:0006306', ('99', '114'))	('chromatin', 'cellular_component', 'GO:0000785', ('71', '80'))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('RCC tumors', 'Disease', 'MESH:C538614', (29, 39))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))	('chromatin accessibility', 'MPA', (71, 94))	('mutations', 'Var', (14, 23))	('SETD2', 'Gene', '29072', (8, 13))
155754	30355451	Recently, SETD2 was shown to regulate interferon signaling by methylating STAT1, and to maintain mitosis and cytokinesis through methylating alpha-tubulin.	('mitosis', 'biological_process', 'GO:0000278', ('97', '104'))	('methylating', 'Var', (129, 140))	('alpha-tubulin', 'Protein', (141, 154))	('mitosis', 'Disease', (97, 104))	('maintain', 'PosReg', (88, 96))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('mitosis', 'Disease', 'None', (97, 104))	('methylating', 'Var', (62, 73))	('STAT1', 'Gene', (74, 79))	('SETD2', 'Gene', '29072', (10, 15))	('cytokinesis', 'biological_process', 'GO:0000910', ('109', '120'))	('cytokinesis', 'MPA', (109, 120))	('SETD2', 'Gene', (10, 15))	('interferon signaling', 'MPA', (38, 58))	('regulate', 'Reg', (29, 37))
155758	30355451	As with VHL, PBRM1 and SETD2, biallelic inactivation of BAP1 via mutation and loss of heterozygosity fit a two-hit tumor suppressor profile.	('SETD2', 'Gene', '29072', (23, 28))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('115', '131'))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('SETD2', 'Gene', (23, 28))	('tumor', 'Disease', (115, 120))	('BAP1', 'Gene', (56, 60))	('mutation', 'Var', (65, 73))	('loss of', 'NegReg', (78, 85))	('biallelic inactivation', 'Var', (30, 52))	('tumor suppressor', 'biological_process', 'GO:0051726', ('115', '131'))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
155759	30355451	Germline mutations of BAP1 predispose patients to ccRCC, uveal melanomas, mesothelioma, lung adenocarcinoma, meningioma, breast carcinoma and paraganglioma.	('Germline mutations', 'Var', (0, 18))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (88, 107))	('paraganglioma', 'Phenotype', 'HP:0002668', (142, 155))	('meningioma', 'Disease', 'MESH:D008577', (109, 119))	('patients', 'Species', '9606', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('mesothelioma', 'Disease', (74, 86))	('predispose', 'Reg', (27, 37))	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('RCC', 'Disease', (52, 55))	('uveal melanomas', 'Disease', 'MESH:C536494', (57, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('breast carcinoma', 'Phenotype', 'HP:0003002', (121, 137))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('lung adenocarcinoma', 'Disease', (88, 107))	('BAP1', 'Gene', (22, 26))	('uveal melanomas', 'Phenotype', 'HP:0007716', (57, 72))	('uveal melanomas', 'Disease', (57, 72))	('meningioma', 'Disease', (109, 119))	('meningioma', 'Phenotype', 'HP:0002858', (109, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (88, 107))	('melanomas', 'Phenotype', 'HP:0002861', (63, 72))	('breast carcinoma and paraganglioma', 'Disease', 'MESH:D010235', (121, 155))
155767	30355451	To determine how the suppression of PBRM1 changes the transcriptome of ccRCC cells, we used shRNA to stably knock down the expression of PBRM1 in VHL+/+ and VHL-/- 786-O cells.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('knock down', 'Var', (108, 118))	('RCC', 'Disease', (73, 76))	('PBRM1', 'Gene', (137, 142))
155772	30355451	In order to learn how the loss of KDM5C impacts the transcriptome of ccRCC cells, we stably knocked down the expression of KDM5C in VHL+/+ and VHL-/- 786-O cells.	('impacts', 'Reg', (40, 47))	('KDM5C', 'Gene', '8242', (34, 39))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('transcriptome', 'MPA', (52, 65))	('KDM5C', 'Gene', (123, 128))	('KDM5C', 'Gene', (34, 39))	('KDM5C', 'Gene', '8242', (123, 128))	('loss', 'Var', (26, 30))	('knocked', 'Reg', (92, 99))
155785	30355451	Since loss of PBRM1 or KDM5C elicited very similar transcriptional responses, we examined whether these two proteins exist in one complex.	('loss', 'Var', (6, 10))	('KDM5C', 'Gene', (23, 28))	('PBRM1', 'Gene', (14, 19))	('KDM5C', 'Gene', '8242', (23, 28))	('elicited', 'Reg', (29, 37))	('transcriptional responses', 'MPA', (51, 76))
155792	30355451	Since loss of both PBRM1 and KDM5C triggered greater transcriptional responses in VHL-/- cells than that in VHL+/+ cells, and HIF transcriptionally interacts with PBRM1 and KDM5C, we wondered whether VHL-regulated genes overlapped with PBRM1 and KDM5C-regulated genes.	('loss', 'Var', (6, 10))	('KDM5C', 'Gene', (173, 178))	('KDM5C', 'Gene', (246, 251))	('KDM5C', 'Gene', (29, 34))	('greater', 'PosReg', (45, 52))	('transcriptional responses', 'MPA', (53, 78))	('KDM5C', 'Gene', '8242', (173, 178))	('KDM5C', 'Gene', '8242', (246, 251))	('KDM5C', 'Gene', '8242', (29, 34))	('PBRM1', 'Gene', (19, 24))
155800	30355451	Suppression of HIF1alpha did not reduce ISGF3 protein level or function in RCC4 cells (Figure 5:figure supplement 2).	('RCC4', 'Gene', '84925', (75, 79))	('HIF1alpha', 'Gene', '3091', (15, 24))	('RCC4', 'Gene', (75, 79))	('ISGF3', 'Gene', (40, 45))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('Suppression', 'Var', (0, 11))	('function', 'MPA', (63, 71))	('ISGF3', 'Gene', '6772', (40, 45))	('HIF1alpha', 'Gene', (15, 24))	('men', 'Species', '9606', (109, 112))	('reduce', 'NegReg', (33, 39))
155801	30355451	To test whether PBRM1 and KDM5C also had similar effects on ISGF3, we examined its components in 786-O cells with PBRM1 and KDM5C knocked down with various shRNA constructs.	('KDM5C', 'Gene', (124, 129))	('KDM5C', 'Gene', '8242', (124, 129))	('knocked down', 'Var', (130, 142))	('ISGF3', 'Gene', (60, 65))	('KDM5C', 'Gene', (26, 31))	('KDM5C', 'Gene', '8242', (26, 31))	('ISGF3', 'Gene', '6772', (60, 65))	('PBRM1', 'Gene', (114, 119))
155802	30355451	In PBRM1 knockdown cells, the protein levels of IRF9 and STAT2 were lower compared to control (Figure 5D).	('lower', 'NegReg', (68, 73))	('knockdown', 'Var', (9, 18))	('STAT2', 'Gene', (57, 62))	('PBRM1', 'Gene', (3, 8))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('STAT2', 'Gene', '6773', (57, 62))	('protein levels of IRF9', 'MPA', (30, 52))
155805	30355451	To ensure that this observation is not confined to just one ccRCC cell line, we knocked down HIF2alpha, PBRM1 or KDM5C in another VHL-deficient ccRCC cell line, Ren-02.	('Ren', 'Gene', (161, 164))	('HIF2alpha', 'Gene', (93, 102))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('Ren', 'Gene', '5972', (161, 164))	('VHL-deficient', 'Disease', 'MESH:D006623', (130, 143))	('VHL-deficient', 'Disease', (130, 143))	('KDM5C', 'Gene', (113, 118))	('PBRM1', 'Gene', (104, 109))	('KDM5C', 'Gene', '8242', (113, 118))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('knocked down', 'Var', (80, 92))
155812	30355451	A recent report suggested that SETD2 promotes ISGF3 activity through methylating STAT1 after interferon stimulation.	('SETD2', 'Gene', (31, 36))	('ISGF3', 'Gene', '6772', (46, 51))	('activity', 'MPA', (52, 60))	('ISGF3', 'Gene', (46, 51))	('methylating', 'Var', (69, 80))	('SETD2', 'Gene', '29072', (31, 36))	('STAT1', 'Gene', (81, 86))	('promotes', 'PosReg', (37, 45))
155816	30355451	BAP1 re-expression in a Ren-02 BAP1 knockdown (Figure 6B, left) or knockout clone (Figure 6B, right) generated by CRISPR/Cas9 increased the protein levels of STAT2, IRF9 and PLSCR1, suggesting that BAP1's impact on ISGF3 is specific.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('PLSCR1', 'Gene', '5359', (174, 180))	('STAT2', 'Gene', '6773', (158, 163))	('re-expression', 'Var', (5, 18))	('BAP1', 'Gene', (0, 4))	('Ren', 'Gene', (24, 27))	('IRF9', 'MPA', (165, 169))	('ISGF3', 'Gene', (215, 220))	('STAT2', 'Gene', (158, 163))	('BAP1', 'Gene', (31, 35))	('ISGF3', 'Gene', '6772', (215, 220))	('Ren', 'Gene', '5972', (24, 27))	('Cas', 'cellular_component', 'GO:0005650', ('121', '124'))	('PLSCR1', 'Gene', (174, 180))	('increased', 'PosReg', (126, 135))
155817	30355451	To ensure that this effect is not confined to one cell line, we knocked down the expression of BAP1 or SETD2 in RCC4 and BAP1 in A498 cells (A498 has an inactivating mutation in SETD2 so it is not suitable for SETD2 analysis), two additional VHL-deficient ccRCC cell lines.	('BAP1', 'Gene', (121, 125))	('SETD2', 'Gene', (178, 183))	('expression', 'MPA', (81, 91))	('RCC', 'Disease', (258, 261))	('SETD2', 'Gene', (210, 215))	('VHL-deficient', 'Disease', (242, 255))	('SETD2', 'Gene', '29072', (178, 183))	('SETD2', 'Gene', '29072', (210, 215))	('SETD2', 'Gene', (103, 108))	('knocked', 'Reg', (64, 71))	('RCC', 'Disease', 'MESH:C538614', (258, 261))	('RCC4', 'Gene', (112, 116))	('BAP1', 'Gene', (95, 99))	('RCC', 'Disease', (112, 115))	('SETD2', 'Gene', '29072', (103, 108))	('RCC4', 'Gene', '84925', (112, 116))	('VHL-deficient', 'Disease', 'MESH:D006623', (242, 255))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('inactivating mutation', 'Var', (153, 174))
155819	30355451	In order to further examine the impact of BAP1 on ISGF3 expression and activity, we expressed GFP, wild type BAP1, or BAP1 with tumor-derived mutations (N78S or G185R) in BAP1 null ccRCC cell lines UMRC2 and UMRC6.	('BAP1', 'Gene', (171, 175))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('UMRC2', 'CellLine', 'CVCL:2739', (198, 203))	('RCC', 'Disease', (183, 186))	('G185R', 'Var', (161, 166))	('N78S', 'Mutation', 'rs1319729011', (153, 157))	('ISGF3', 'Gene', (50, 55))	('N78S', 'Var', (153, 157))	('UMRC6', 'CellLine', 'CVCL:2741', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('ISGF3', 'Gene', '6772', (50, 55))	('tumor', 'Disease', (128, 133))	('G185R', 'Mutation', 'p.G185R', (161, 166))	('BAP1', 'Gene', (118, 122))
155820	30355451	Expression of wild type or N78S BAP1 clearly increased ISGF3 protein levels and its activity in these cells, while the G185R mutant failed to do so (Figure 6F and G).	('ISGF3', 'Gene', (55, 60))	('N78S', 'Var', (27, 31))	('ISGF3', 'Gene', '6772', (55, 60))	('increased', 'PosReg', (45, 54))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))	('activity', 'MPA', (84, 92))	('BAP1', 'Gene', (32, 36))	('N78S', 'Mutation', 'rs1319729011', (27, 31))	('G185R', 'Mutation', 'p.G185R', (119, 124))
155822	30355451	As a ccRCC tumor-derived mutation in BAP1 disrupted this function in both BAP1-null cells, it suggests that the regulation of ISGF3 is important to BAP1's tumor suppressor function.	('tumor', 'Disease', (155, 160))	('ISGF3', 'Gene', (126, 131))	("BAP1's tumor", 'Disease', (148, 160))	('disrupted', 'NegReg', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('function', 'MPA', (57, 65))	('tumor', 'Disease', (11, 16))	('mutation', 'Var', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('155', '171'))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor suppressor', 'biological_process', 'GO:0051726', ('155', '171'))	('BAP1', 'Gene', (37, 41))	('RCC', 'Disease', (7, 10))	('regulation', 'biological_process', 'GO:0065007', ('112', '122'))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	("BAP1's tumor", 'Disease', 'MESH:D009396', (148, 160))	('ISGF3', 'Gene', '6772', (126, 131))	('RCC', 'Disease', 'MESH:C538614', (7, 10))
155825	30355451	Since ISGF3 is activated by HIF and suppressed after the loss of PBRM1, KDM5C, SETD2 or BAP1, it may function as the executioner of a negative feedback loop that potently opposes tumor growth.	('activated', 'PosReg', (15, 24))	('suppressed', 'NegReg', (36, 46))	('KDM5C', 'Gene', '8242', (72, 77))	('SETD2', 'Gene', '29072', (79, 84))	('PBRM1', 'Gene', (65, 70))	('ISGF3', 'Gene', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('SETD2', 'Gene', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('loss', 'Var', (57, 61))	('ISGF3', 'Gene', '6772', (6, 11))	('BAP1', 'Gene', (88, 92))	('KDM5C', 'Gene', (72, 77))	('tumor', 'Disease', (179, 184))
155832	30355451	In order to learn the reason for enhanced tumor growth after IRF9 knockdown, we performed hematoxylin and eosin(H&E) and immunohistochemistry (IHC) staining on five pairs of 786-O SCR and IRF9-69 tumors.	('tumor', 'Disease', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('H&E', 'Chemical', 'MESH:D006371', (112, 115))	('hematoxylin', 'Chemical', 'MESH:D006416', (90, 101))	('eosin', 'Chemical', 'MESH:D004801', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('knockdown', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('enhanced', 'PosReg', (33, 41))
155833	30355451	The control tumors contained higher percentages of mouse stromal cells, while the IRF9 knockdown tumors were mostly comprised of cancer cells (Figure 7E and Figure 7:figure supplement 4).	('IRF9', 'Gene', (82, 86))	('men', 'Species', '9606', (179, 182))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mouse', 'Species', '10090', (51, 56))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('knockdown', 'Var', (87, 96))
155834	30355451	The cancer cells in tumors with IRF9 knockdown had a slight but insignificant increase in Ki67 staining, a marker for cell proliferation, over cancer cells in control tumors (Figure 7E).	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('knockdown', 'Var', (37, 46))	('increase', 'PosReg', (78, 86))	('cell proliferation', 'biological_process', 'GO:0008283', ('118', '136'))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (20, 26))	('Ki67', 'Protein', (90, 94))	('IRF9', 'Gene', (32, 36))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('tumors', 'Disease', (167, 173))	('cancer', 'Disease', (4, 10))
155837	30355451	Thus the lack of infiltrating host immune cells into the tumors formed by ccRCC cells depleted of IRF9, not changes in cell proliferation, apoptosis, or blood vessel growth, might be the primary reason of enhanced growth.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('apoptosis', 'biological_process', 'GO:0097194', ('139', '148'))	('apoptosis', 'biological_process', 'GO:0006915', ('139', '148'))	('cell proliferation', 'biological_process', 'GO:0008283', ('119', '137'))	('depleted', 'Var', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('enhanced', 'PosReg', (205, 213))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('IRF9', 'Gene', (98, 102))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
155842	30355451	The over-expression of STAT2 +IRF9 did not change cell growth in culture (Figure 8B), however, overexpression of these ISGF3 components strongly suppressed tumor growth by PBRM1-deficient 786-O cells in a xenograft model (Figure 8C and D).Thus depletion of ISGF3 greatly enhanced tumor growth while its activation very potently blocked it, suggesting that ISGF3 is a central player in ccRCC tumor growth that is targeted by most of the cancer genes.	('enhanced', 'PosReg', (271, 279))	('ISGF3', 'Gene', (356, 361))	('ISGF3', 'Gene', (119, 124))	('RCC', 'Disease', 'MESH:C538614', (387, 390))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', (391, 396))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (391, 396))	('tumor', 'Disease', (280, 285))	('STAT2', 'Gene', '6773', (23, 28))	('cancer', 'Disease', (436, 442))	('ISGF3', 'Gene', '6772', (257, 262))	('STAT2', 'Gene', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (436, 442))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('ISGF3', 'Gene', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))	('cell growth', 'biological_process', 'GO:0016049', ('50', '61'))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('cancer', 'Disease', 'MESH:D009369', (436, 442))	('depletion', 'Var', (244, 253))	('RCC', 'Disease', (387, 390))	('ISGF3', 'Gene', '6772', (119, 124))	('ISGF3', 'Gene', '6772', (356, 361))
155864	30355451	Consistent with this idea, the change of IRF9 protein in the TMA (Figure 9B) and in the cultured cells (Figures 5 and 6) tracked better with the changes of PBRM1, SETD2 or BAP1.	('SETD2', 'Gene', (163, 168))	('IRF9 protein', 'Protein', (41, 53))	('BAP1', 'Gene', (172, 176))	('TMA', 'Chemical', '-', (61, 64))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('changes', 'Var', (145, 152))	('SETD2', 'Gene', '29072', (163, 168))	('PBRM1', 'Gene', (156, 161))
155869	30355451	Consistent with this, Vhl conditional knockout in mouse kidneys alone is not sufficient to generate ccRCC despite fully activated HIF.	('Vhl', 'Gene', (22, 25))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('mouse', 'Species', '10090', (50, 55))	('knockout', 'Var', (38, 46))
155870	30355451	Only after combination with Pbrm1 or Bap1 conditional knockout can Vhl loss lead to kidney tumors.	('kidney tumors', 'Disease', (84, 97))	('kidney tumors', 'Disease', 'MESH:D007674', (84, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('Vhl', 'Gene', (67, 70))	('kidney tumors', 'Phenotype', 'HP:0009726', (84, 97))	('lead to', 'Reg', (76, 83))	('Pbrm1', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('loss', 'NegReg', (71, 75))	('Bap1', 'Gene', '8314', (37, 41))	('conditional knockout', 'Var', (42, 62))	('Bap1', 'Gene', (37, 41))
155872	30355451	Its inhibitory effect on tumor growth can be relieved by the loss of PBRM1, KDM5C, SETD2 or BAP1 to promote robust tumor growth (Figure 9E).	('KDM5C', 'Gene', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('KDM5C', 'Gene', '8242', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', (115, 120))	('SETD2', 'Gene', '29072', (83, 88))	('PBRM1', 'Gene', (69, 74))	('SETD2', 'Gene', (83, 88))	('promote', 'PosReg', (100, 107))	('loss', 'Var', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('BAP1', 'Gene', (92, 96))
155879	30355451	Loss-of-function mutations in PBRM1 were discovered to confer clinical benefit to ccRCC patients treated with anti-PD-1 alone or in combination with anti-CTLA-4 therapies.	('Loss-of-function', 'NegReg', (0, 16))	('PBRM1', 'Gene', (30, 35))	('patients', 'Species', '9606', (88, 96))	('CTLA-4', 'Gene', '1493', (154, 160))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('PD-1', 'Gene', (115, 119))	('PD-1', 'Gene', '5133', (115, 119))	('CTLA-4', 'Gene', (154, 160))	('mutations', 'Var', (17, 26))
155880	30355451	In addition, PBRM1 mutations were found to enhance T-cell-mediated killing in an unbiased, high-throughput screen in a melanoma model.	('PBRM1', 'Gene', (13, 18))	('mutations', 'Var', (19, 28))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', (119, 127))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('T-cell-mediated killing', 'CPA', (51, 74))	('enhance', 'PosReg', (43, 50))
155882	30355451	The fact that PBRM1 mutations, but not those of BAP1, SETD2, and KDM5C, are a predictive biomarker for response to immunotherapy is likely because PBRM1 and BAP1 mutations are truncal (root change) in many cases while the mutations of the other two are subclonal.	('mutations', 'Var', (162, 171))	('SETD2', 'Gene', '29072', (54, 59))	('BAP1', 'Gene', (157, 161))	('PBRM1', 'Gene', (14, 19))	('SETD2', 'Gene', (54, 59))	('PBRM1', 'Gene', (147, 152))	('KDM5C', 'Gene', (65, 70))	('KDM5C', 'Gene', '8242', (65, 70))	('mutations', 'Var', (20, 29))
155884	30355451	Inactivating mutations in PBRM1, SETD2, KDM5C and BAP1 tend to be focal in the tumors, so therapies that are designed to exploit the weakness induced by mutation of an individual gene could be problematic since it cannot treat the remaining cancer cells free of that mutation.	('SETD2', 'Gene', (33, 38))	('PBRM1', 'Gene', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('KDM5C', 'Gene', (40, 45))	('Inactivating mutations', 'Var', (0, 22))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('BAP1', 'Gene', (50, 54))	('KDM5C', 'Gene', '8242', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('weakness', 'Disease', (133, 141))	('weakness', 'Disease', 'MESH:D018908', (133, 141))	('SETD2', 'Gene', '29072', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
155889	30355451	In human T lymphoma cells or mouse cells, loss of STAT3 leads to prolonged activation of STAT1.	('loss', 'Var', (42, 46))	('human', 'Species', '9606', (3, 8))	('activation', 'PosReg', (75, 85))	('lymphoma', 'Phenotype', 'HP:0002665', (11, 19))	('STAT3', 'Gene', (50, 55))	('T lymphoma', 'Phenotype', 'HP:0012190', (9, 19))	('mouse', 'Species', '10090', (29, 34))	('T lymphoma', 'Disease', (9, 19))	('STAT1', 'MPA', (89, 94))	('T lymphoma', 'Disease', 'MESH:D016399', (9, 19))
155892	30355451	In a recent publication, SETD2 was shown to methylate STAT1 to promote ISGF3 function.	('function', 'MPA', (77, 85))	('ISGF3', 'Gene', (71, 76))	('ISGF3', 'Gene', '6772', (71, 76))	('methylate', 'Var', (44, 53))	('promote', 'PosReg', (63, 70))	('SETD2', 'Gene', '29072', (25, 30))	('SETD2', 'Gene', (25, 30))
155910	30355451	KDM5C mutations were reported to occur in the cells with PBRM1 mutations.	('mutations', 'Var', (63, 72))	('KDM5C', 'Gene', (0, 5))	('PBRM1', 'Gene', (57, 62))	('KDM5C', 'Gene', '8242', (0, 5))
155951	30355451	Summary: This paper describes the role of secondary mutations in ccRCC cells affecting PBRM1, KDM5C, BAP1 and SETD2; multiple tumor suppressors frequently mutated in ccRCC that converge on a HIF-dependent negative feedback loop through ISGF3.	('mutated', 'Var', (155, 162))	('SETD2', 'Gene', (110, 115))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('KDM5C', 'Gene', '8242', (94, 99))	('RCC', 'Disease', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('ISGF3', 'Gene', (236, 241))	('ISGF3', 'Gene', '6772', (236, 241))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('PBRM1', 'Gene', (87, 92))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('RCC', 'Disease', (168, 171))	('SETD2', 'Gene', '29072', (110, 115))	('KDM5C', 'Gene', (94, 99))	('tumor', 'Disease', (126, 131))
155952	30355451	ShRNA knockdown of these genes in ccRCC cells in vitro, taken as a surrogate for the normally observed inactivating mutations seen in human tumours, lowers the expression of the STAT1, STAT2 and/or IRF9 proteins that together form the ISGF3 transcription factor.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('RCC', 'Disease', (36, 39))	('STAT2', 'Gene', '6773', (185, 190))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('ISGF3', 'Gene', '6772', (235, 240))	('STAT2', 'Gene', (185, 190))	('tumours', 'Disease', 'MESH:D009369', (140, 147))	('IRF9 proteins', 'Protein', (198, 211))	('proteins', 'Protein', (203, 211))	('ISGF3', 'Gene', (235, 240))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('transcription factor', 'molecular_function', 'GO:0000981', ('241', '261'))	('expression', 'MPA', (160, 170))	('human', 'Species', '9606', (134, 139))	('mutations', 'Var', (116, 125))	('STAT1', 'Protein', (178, 183))	('transcription', 'biological_process', 'GO:0006351', ('241', '254'))	('lowers', 'NegReg', (149, 155))	('tumours', 'Disease', (140, 147))
155960	30355451	Figure 4 shows that expression of FLAG-PBRM1 can precipitate endogenous KDM5C, but the opposite has not been shown by transfecting FLAG-KDM5C to pull down endogenous PBRM1.	('KDM5C', 'Gene', '8242', (72, 77))	('FLAG-PBRM1', 'Gene', (34, 44))	('expression', 'Var', (20, 30))	('KDM5C', 'Gene', (136, 141))	('KDM5C', 'Gene', '8242', (136, 141))	('KDM5C', 'Gene', (72, 77))
155962	30355451	The authors should investigate whether tagged PBRM1 co-precipitates other subunits of the PBAF complex and they should verify whether tagged KDM5C can precipitate additional subunits of the PBAF complex.	('KDM5C', 'Gene', '8242', (141, 146))	('co-precipitates', 'Reg', (52, 67))	('tagged', 'Var', (39, 45))	('PBAF complex', 'cellular_component', 'GO:0016586', ('190', '202'))	('PBRM1', 'Gene', (46, 51))	('KDM5C', 'Gene', (141, 146))	('PBAF complex', 'cellular_component', 'GO:0016586', ('90', '102'))
155964	30355451	The authors should also comment on the fact that KDM5C mutations tend to occur under the PBRM1 mutated background (PMID 27751729).	('KDM5C', 'Gene', '8242', (49, 54))	('mutations', 'Var', (55, 64))	('occur', 'Reg', (73, 78))	('KDM5C', 'Gene', (49, 54))	('men', 'Species', '9606', (27, 30))
155965	30355451	The authors show that knockdown of IRF9 leads to much larger xenograft tumours than control cells.	('xenograft tumours', 'Disease', (61, 78))	('IRF9', 'Gene', (35, 39))	('xenograft tumours', 'Disease', 'MESH:D009369', (61, 78))	('knockdown', 'Var', (22, 31))	('larger', 'PosReg', (54, 60))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))
155967	30355451	If there is no caveat, they should also show that silencing of either STAT1 or STAT2 has the same tumour-promoting effect.	('STAT1', 'Gene', (70, 75))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('STAT2', 'Gene', '6773', (79, 84))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('silencing', 'Var', (50, 59))	('tumour', 'Disease', (98, 104))	('STAT2', 'Gene', (79, 84))
155974	30355451	We suggest to repeat the experiment in Figure 5:figure supplement 4 in KDM5C knock-down.	('men', 'Species', '9606', (31, 34))	('KDM5C', 'Gene', (71, 76))	('KDM5C', 'Gene', '8242', (71, 76))	('men', 'Species', '9606', (61, 64))	('knock-down', 'Var', (77, 87))
155991	30355451	As to the co-occurrence of mutations in PBRM1 and KDM5C, we stated that "undoubtedly each TSG has its own unique tumor suppressing functions so each carries different prognosis for the patients" in our Discussion.	('mutations', 'Var', (27, 36))	('tumor', 'Disease', (113, 118))	('TSG', 'Gene', (90, 93))	('PBRM1', 'Gene', (40, 45))	('KDM5C', 'Gene', (50, 55))	('TSG', 'Gene', '57045', (90, 93))	('KDM5C', 'Gene', '8242', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('patients', 'Species', '9606', (185, 193))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
156008	30355451	We added western blots of knockdown of KDM5C and PBRM1 to Figure 5F.	('KDM5C', 'Gene', '8242', (39, 44))	('knockdown', 'Var', (26, 35))	('KDM5C', 'Gene', (39, 44))	('PBRM1', 'Gene', (49, 54))
156009	30355451	We were able to detect SETD2 knockdown by western blot in 6A but not in 6C (probably due to low expression of SETD2 protein in RCC4 cells), and it was added as Figure 6:figure supplement 1.	('SETD2', 'Gene', '29072', (23, 28))	('SETD2', 'Gene', (110, 115))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('knockdown', 'Var', (29, 38))	('SETD2', 'Gene', (23, 28))	('men', 'Species', '9606', (182, 185))	('SETD2', 'Gene', '29072', (110, 115))	('RCC4', 'Gene', (127, 131))	('RCC4', 'Gene', '84925', (127, 131))
156017	33324547	High expression of FMNL1 is significantly correlated with advanced tumor stage, higher pathological tumor grade, tumor metastasis, and unfavorable prognosis in two independent cohorts containing over 800 patients with ccRCC.	('tumor', 'Disease', (113, 118))	('patients', 'Species', '9606', (204, 212))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (67, 72))	('tumor metastasis', 'Disease', (113, 129))	('High', 'Var', (0, 4))	('ccRCC', 'Phenotype', 'HP:0006770', (218, 223))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('FMNL1', 'Gene', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('correlated', 'Reg', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor metastasis', 'Disease', 'MESH:D009362', (113, 129))
156032	33324547	Functionally, FMNL1 was able to activate the epithelial to mesenchymal transition (EMT) to promote tumor progression.	('tumor', 'Disease', (99, 104))	('promote', 'PosReg', (91, 98))	('FMNL1', 'Var', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('activate', 'PosReg', (32, 40))	('EMT', 'biological_process', 'GO:0001837', ('83', '86'))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('epithelial to mesenchymal transition', 'CPA', (45, 81))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('45', '81'))
156042	33324547	The 786-O cells were infected with retroviruses carrying psi-LVRH1MP-FMNL1-shRNAs, according to the following sequence: shRNA-1: CATCGCGCCATCATGAACTAC; shRNA-2: GGAGAYGAAGTCGACTGACG.	('infected', 'Disease', (21, 29))	('infected', 'Disease', 'MESH:D007239', (21, 29))	('psi-LVRH1MP-FMNL1-shRNAs', 'Var', (57, 81))
156071	33324547	GSEA involves determining whether a predefined set of genes is significantly different between the two groups: high and low FMNL1.	('FMNL1', 'Gene', (124, 129))	('GSEA', 'Chemical', '-', (0, 4))	('low', 'Var', (120, 123))	('high', 'Var', (111, 115))
156077	33324547	In TCGA cohort, high FMNL1 expression was associated with tumor pathological grade, clinical stage and tumor metastasis ( Supplementary Figure 4 ).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('FMNL1', 'Gene', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('associated', 'Reg', (42, 52))	('high', 'Var', (16, 20))	('tumor', 'Disease', (103, 108))	('tumor metastasis', 'Disease', 'MESH:D009362', (103, 119))	('expression', 'MPA', (27, 37))	('clinical stage', 'CPA', (84, 98))	('tumor metastasis', 'Disease', (103, 119))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
156080	33324547	Patients expressing more FMNL1 in tumor tissues survival much shorter and experienced tumor relapse in a much shorter time.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('shorter', 'NegReg', (62, 69))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', (86, 91))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('FMNL1', 'Var', (25, 30))
156095	33324547	In contrast, FMNL1 knockdown substantially inhibited the tumor formation in the lung ( Figure 3D ).	('formation', 'biological_process', 'GO:0009058', ('63', '72'))	('inhibited', 'NegReg', (43, 52))	('knockdown', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('FMNL1', 'Gene', (13, 18))
156099	33324547	In A498 cells with FMNL1 depletion, CXCR2 was noticeably downregulated, compared with other factors involved in inflammation ( Figure 4D ).	('downregulated', 'NegReg', (57, 70))	('CXCR2', 'Gene', (36, 41))	('inflammation', 'Disease', 'MESH:D007249', (112, 124))	('inflammation', 'Disease', (112, 124))	('inflammation', 'biological_process', 'GO:0006954', ('112', '124'))	('FMNL1 depletion', 'Var', (19, 34))	('CXCR2', 'Gene', '3579', (36, 41))
156101	33324547	Transwell assays showed that knockdown of CXCR2 by siRNAs in A498 and RCC10 cells substantially attenuated the cell migration and invasion ( Figures 4E, F ).	('cell migration', 'biological_process', 'GO:0016477', ('111', '125'))	('CXCR2', 'Gene', '3579', (42, 47))	('knockdown', 'Var', (29, 38))	('attenuated', 'NegReg', (96, 106))	('CXCR2', 'Gene', (42, 47))	('siRNAs', 'Gene', (51, 57))
156104	33324547	However, this was rescued by the knockdown of CXCR2 ( Figure 4G ).	('knockdown', 'Var', (33, 42))	('CXCR2', 'Gene', (46, 51))	('CXCR2', 'Gene', '3579', (46, 51))
156108	33324547	In RCC10 and A498 stable cells with FMNL1 overexpression, the mRNA level of CXCR2 was markedly increased ( Figure 5A ).	('overexpression', 'Var', (42, 56))	('CXCR2', 'Gene', '3579', (76, 81))	('FMNL1', 'Gene', (36, 41))	('increased', 'PosReg', (95, 104))	('CXCR2', 'Gene', (76, 81))
156112	33324547	GDS2294 and GDS4813), CXCR2 mRNA expression was reduced by siRNA for HDAC1 ( Figure 5C ), but not HDAC2 and HDAC3 ( Figure 5D ).	('HDAC2', 'Gene', (98, 103))	('GDS4813', 'Var', (12, 19))	('HDAC1', 'Gene', '3065', (69, 74))	('HDAC2', 'Gene', '3066', (98, 103))	('GDS', 'molecular_function', 'GO:0005085', ('12', '15'))	('HDAC3', 'Gene', '8841', (108, 113))	('reduced', 'NegReg', (48, 55))	('HDAC3', 'Gene', (108, 113))	('HDAC1', 'Gene', (69, 74))	('CXCR2', 'Gene', '3579', (22, 27))	('GDS', 'molecular_function', 'GO:0005085', ('0', '3'))	('CXCR2', 'Gene', (22, 27))
156114	33324547	Results of qRT-PCR and western blot demonstrated that the FMNL1-mediated upregulation of CXCR2 was abolished by HDAC1 silencing ( Figures 5E, F ).	('abolished', 'NegReg', (99, 108))	('HDAC1', 'Gene', (112, 117))	('CXCR2', 'Gene', (89, 94))	('silencing', 'Var', (118, 127))	('HDAC1', 'Gene', '3065', (112, 117))	('FMNL1-mediated', 'Gene', (58, 72))	('CXCR2', 'Gene', '3579', (89, 94))	('upregulation', 'PosReg', (73, 85))
156121	33324547	Furthermore, worst prognosis was identified in ccRCC patients with high expression of FMNL1 and CXCR2 ( Figure 5J ).	('FMNL1', 'Gene', (86, 91))	('patients', 'Species', '9606', (53, 61))	('ccRCC', 'Disease', (47, 52))	('CXCR2', 'Gene', '3579', (96, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('CXCR2', 'Gene', (96, 101))	('high expression', 'Var', (67, 82))
156126	33324547	Here in our study, we found that FMNL1 was upregulated by the loss of GATA3 in ccRCC, and function as a prometastatic factor via HDAC1-mediated CXCR2 upregulation.	('CXCR2', 'Gene', '3579', (144, 149))	('loss', 'Var', (62, 66))	('upregulated', 'PosReg', (43, 54))	('HDAC1', 'Gene', (129, 134))	('GATA3', 'Gene', '2625', (70, 75))	('CXCR2', 'Gene', (144, 149))	('HDAC1', 'Gene', '3065', (129, 134))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('ccRCC', 'Disease', (79, 84))	('FMNL1', 'Gene', (33, 38))	('upregulation', 'PosReg', (150, 162))	('GATA3', 'Gene', (70, 75))
156130	33324547	Current literatures reported that FMNL1 was epigenetically modulated by microRNAs, such as miR-16 and miR-143.	('FMNL1', 'Gene', (34, 39))	('miR-16', 'Gene', '51573', (91, 97))	('miR-143', 'Gene', '406935', (102, 109))	('miR-143', 'Gene', (102, 109))	('epigenetically modulated', 'Var', (44, 68))	('miR-16', 'Gene', (91, 97))
156134	33324547	Gene silencing of GATA3 was documented in several cancers and re-expression of GATA3 was capable of inhibiting tumor metastasis.	('GATA3', 'Gene', '2625', (79, 84))	('GATA3', 'Gene', '2625', (18, 23))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Gene silencing', 'biological_process', 'GO:0016458', ('0', '14'))	('cancers', 'Disease', (50, 57))	('inhibiting', 'NegReg', (100, 110))	('tumor metastasis', 'Disease', 'MESH:D009362', (111, 127))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('GATA3', 'Gene', (79, 84))	('GATA3', 'Gene', (18, 23))	('tumor metastasis', 'Disease', (111, 127))	('re-expression', 'Var', (62, 75))
156136	33324547	In vitro and in vivo data demonstrated that FMNL1 overexpression was able to promote cell migration and tumor metastasis, which was in line with previous studies showing that RNAi-mediated silencing of FMNL1 markedly weakened the cell migration potent in human cancer cells.	('silencing', 'Var', (189, 198))	('cell migration', 'CPA', (85, 99))	('FMNL1', 'Gene', (202, 207))	('promote', 'PosReg', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('human', 'Species', '9606', (255, 260))	('tumor metastasis', 'Disease', 'MESH:D009362', (104, 120))	('tumor metastasis', 'Disease', (104, 120))	('weakened', 'NegReg', (217, 225))	('cell migration', 'biological_process', 'GO:0016477', ('85', '99'))	('cancer', 'Disease', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('cell migration', 'biological_process', 'GO:0016477', ('230', '244'))	('RNAi', 'biological_process', 'GO:0016246', ('175', '179'))
156262	28648142	Improved prognosis associated with elevated mTOR in NEAT suggests that tumours dependent upon mTOR have enhanced sensitivity to sunitinib.	('elevated', 'Var', (35, 43))	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('sensitivity to sunitinib', 'MPA', (113, 137))	('mTOR', 'Gene', (94, 98))	('mTOR', 'Gene', '2475', (94, 98))	('tumours', 'Disease', (71, 78))	('enhanced', 'PosReg', (104, 112))	('mTOR', 'Gene', (44, 48))	('sunitinib', 'Chemical', 'MESH:D000077210', (128, 137))	('mTOR', 'Gene', '2475', (44, 48))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('Improved', 'PosReg', (0, 8))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))
156289	27861513	In conclusion, high SCD1 expression is an independent prognostic factor for OS in patients with ccRCC.	('high', 'Var', (15, 19))	('OS', 'Chemical', '-', (76, 78))	('SCD1', 'Gene', '6319', (20, 24))	('patients', 'Species', '9606', (82, 90))	('expression', 'MPA', (25, 35))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('SCD1', 'Gene', (20, 24))
156299	27861513	Saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) constitute the majority of the fatty acids in mammalian cells, and the ratio of MUFAs/SFAs is strictly regulated by cells since alterations in this balance can significantly change the physiological functions of cells.	('change', 'Reg', (243, 249))	('fatty acids', 'Chemical', 'MESH:D005227', (49, 60))	('fatty acids', 'Chemical', 'MESH:D005227', (10, 21))	('fatty acids', 'Chemical', 'MESH:D005227', (100, 111))	('mammalian', 'Species', '9606', (115, 124))	('alterations', 'Var', (197, 208))	('physiological functions of cells', 'CPA', (254, 286))	('Saturated fatty acids', 'Chemical', 'MESH:D005227', (0, 21))	('monounsaturated fatty acids', 'Chemical', 'MESH:D005229', (33, 60))
156305	27861513	Furthermore, the prognostic significance of SCD1 expression was also revealed in many cancers, such as breast cancer, lung adenocarcinoma, colon cancer and soft tissue sarcomas, which showed that high expression of SCD1 was related to a poor outcome for patients with cancers.	('sarcomas', 'Phenotype', 'HP:0100242', (168, 176))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (118, 137))	('breast cancer', 'Disease', (103, 116))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))	('cancers', 'Disease', 'MESH:D009369', (268, 275))	('colon cancer', 'Disease', 'MESH:D015179', (139, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('SCD1', 'Gene', (44, 48))	('high', 'Var', (196, 200))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('SCD1', 'Gene', '6319', (215, 219))	('colon cancer', 'Disease', (139, 151))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('soft tissue sarcomas', 'Disease', (156, 176))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (268, 275))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (156, 176))	('cancers', 'Disease', (268, 275))	('related to', 'Reg', (224, 234))	('SCD1', 'Gene', (215, 219))	('lung adenocarcinoma', 'Disease', (118, 137))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (156, 176))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('patients', 'Species', '9606', (254, 262))	('SCD1', 'Gene', '6319', (44, 48))	('colon cancer', 'Phenotype', 'HP:0003003', (139, 151))
156308	27861513	It had also showed that knockdown of SCD1 gene expression in 786-O human ccRCC cells led to tumor cells apoptosis, significantly delays the formation of tumors, and reduces the growth rate of tumors formed.	('tumors', 'Disease', (192, 198))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', (75, 78))	('apoptosis', 'biological_process', 'GO:0097194', ('104', '113'))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('apoptosis', 'biological_process', 'GO:0006915', ('104', '113'))	('delays', 'NegReg', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('SCD1', 'Gene', (37, 41))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('gene expression', 'biological_process', 'GO:0010467', ('42', '57'))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('knockdown', 'Var', (24, 33))	('formation', 'biological_process', 'GO:0009058', ('140', '149'))	('reduces', 'NegReg', (165, 172))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('tumor', 'Disease', (92, 97))	('SCD1', 'Gene', '6319', (37, 41))	('human', 'Species', '9606', (67, 72))
156340	27861513	In univariate analysis, SCD1 expression was found to be significantly associated with the overall survival of ccRCC patients (p<0.001, Table 4).	('expression', 'Var', (29, 39))	('SCD1', 'Gene', '6319', (24, 28))	('patients', 'Species', '9606', (116, 124))	('associated with', 'Reg', (70, 85))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))	('SCD1', 'Gene', (24, 28))
156352	27861513	This study showed that there was a notable association between high SCD1 expression and poor outcome in patients with ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))	('SCD1', 'Gene', (68, 72))	('expression', 'MPA', (73, 83))	('high', 'Var', (63, 67))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('SCD1', 'Gene', '6319', (68, 72))	('patients', 'Species', '9606', (104, 112))
156362	27861513	The major mutations in kidney cancer genes result in dysregulation of metabolic pathways involved in oxygen, iron, energy and/or nutrient sensing suggesting that kidney cancer is a disease of cell metabolism.	('kidney cancer', 'Disease', (23, 36))	('metabolic pathways', 'Pathway', (70, 88))	('dysregulation', 'MPA', (53, 66))	('kidney cancer', 'Phenotype', 'HP:0009726', (162, 175))	('result in', 'Reg', (43, 52))	('kidney cancer', 'Disease', 'MESH:D007680', (162, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('metabolism', 'biological_process', 'GO:0008152', ('197', '207'))	('kidney cancer', 'Disease', 'MESH:D007680', (23, 36))	('iron', 'Chemical', 'MESH:D007501', (109, 113))	('nutrient sensing', 'biological_process', 'GO:0009594', ('129', '145'))	('kidney cancer', 'Phenotype', 'HP:0009726', (23, 36))	('mutations', 'Var', (10, 19))	('kidney cancer', 'Disease', (162, 175))	('oxygen', 'Chemical', 'MESH:D010100', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
156363	27861513	Therefore, the dysregulation of lipid metabolism may also participate in the progress of ccRCC.	('lipid metabolism', 'biological_process', 'GO:0006629', ('32', '48'))	('lipid metabolism', 'MPA', (32, 48))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (89, 94))	('RCC', 'Disease', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('participate', 'Reg', (58, 69))	('lipid', 'Chemical', 'MESH:D008055', (32, 37))	('dysregulation', 'Var', (15, 28))
156366	27861513	Similar to our study, Holder et al suggested that high levels of SCD1 expression are associated with significantly shorter RFS and OS in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('RFS', 'Disease', (123, 126))	('OS', 'Chemical', '-', (131, 133))	('RFS', 'Disease', 'MESH:D005198', (123, 126))	('SCD1', 'Gene', '6319', (65, 69))	('shorter', 'NegReg', (115, 122))	('high levels', 'Var', (50, 61))	('SCD1', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
156368	27861513	Huang et al reported that the pathological stage in patients with lung adenocarcinoma was associated with the SCD1 mutation, which is associated with poor prognosis.	('lung adenocarcinoma', 'Disease', (66, 85))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (66, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('SCD1', 'Gene', '6319', (110, 114))	('associated', 'Reg', (90, 100))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (66, 85))	('mutation', 'Var', (115, 123))	('SCD1', 'Gene', (110, 114))	('patients', 'Species', '9606', (52, 60))
156369	27861513	During the study, they observed that high expression of SCD1 in lung adenocarcinoma was required for the cell proliferation, migration and invasion, which suggested that high expression of SCD1 remarkably enhanced the ability of tumor formation and invasion.	('SCD1', 'Gene', (189, 193))	('cell proliferation', 'biological_process', 'GO:0008283', ('105', '123'))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('invasion', 'CPA', (249, 257))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (64, 83))	('SCD1', 'Gene', (56, 60))	('SCD1', 'Gene', '6319', (189, 193))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('tumor', 'Disease', (229, 234))	('SCD1', 'Gene', '6319', (56, 60))	('formation', 'biological_process', 'GO:0009058', ('235', '244'))	('enhanced', 'PosReg', (205, 213))	('lung adenocarcinoma', 'Disease', (64, 83))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (64, 83))	('high expression', 'Var', (170, 185))
156383	33619294	Immune classification of clear cell renal cell carcinoma Since the outcome of treatments, particularly immunotherapeutic interventions, depends on the tumor immune micro-environment (TIM), several experimental and computational tools such as flow cytometry, immunohistochemistry, and digital cytometry have been developed and utilized to classify TIM variations.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (36, 56))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (25, 56))	('tumor', 'Disease', (151, 156))	('variations', 'Var', (351, 361))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (25, 56))	('clear cell renal cell carcinoma', 'Disease', (25, 56))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
156406	33619294	are macrophages, CD8+ T-cells, CD4+ T-cells, NK cells, B cells, plasma cells, dendritic cells (DC), CD45+ T-cells, double positive T-cells (DP_T-cells), double negative T-cells (DN_T-cells).	('double positive T-cells', 'CPA', (115, 138))	('CD4', 'Gene', (100, 103))	('CD4', 'Gene', (31, 34))	('CD8', 'Gene', (17, 20))	('CD4', 'Gene', '920', (31, 34))	('CD8', 'Gene', '925', (17, 20))	('CD4', 'Gene', '920', (100, 103))	('double negative', 'Var', (153, 168))
156499	30854133	Overexpression of FZD1 is Associated with a Good Prognosis and Resistance of Sunitinib in Clear Cell Renal Cell Carcinoma Frizzled class receptor 1 (FZD1), a receptor for Wnt signaling pathway.	('FZD1', 'Gene', (149, 153))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('171', '192'))	('FZD1', 'Gene', '8321', (149, 153))	('Carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (90, 121))	('Sunitinib', 'Chemical', 'MESH:D000077210', (77, 86))	('Clear Cell Renal Cell Carcinoma', 'Disease', (90, 121))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (90, 121))	('Overexpression', 'Var', (0, 14))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (101, 121))	('FZD1', 'Gene', '8321', (18, 22))	('FZD1', 'Gene', (18, 22))
156500	30854133	Overexpression of FZD1 has been detected in many cancer tissues and cells resulting in tumor development and drug resistance.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('FZD1', 'Gene', '8321', (18, 22))	('drug resistance', 'biological_process', 'GO:0042493', ('109', '124'))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (87, 92))	('drug resistance', 'biological_process', 'GO:0009315', ('109', '124'))	('detected', 'Reg', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('drug resistance', 'CPA', (109, 124))	('drug resistance', 'Phenotype', 'HP:0020174', (109, 124))	('FZD1', 'Gene', (18, 22))	('cancer', 'Disease', (49, 55))	('resulting in', 'Reg', (74, 86))
156507	30854133	Both univariate and multivariate cox regression analysis indicated that high FZD1 level was an independent predictor of good prognosis for OS (HR 0.569, P=0.001) and DFS (HR 0.559, P=0.036) in ccRCC patients.	('cox', 'Gene', '1351', (33, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (193, 198))	('RCC', 'Disease', (195, 198))	('OS', 'Chemical', '-', (139, 141))	('FZD1', 'Gene', '8321', (77, 81))	('cox', 'Gene', (33, 36))	('FZD1', 'Gene', (77, 81))	('patients', 'Species', '9606', (199, 207))	('RCC', 'Phenotype', 'HP:0005584', (195, 198))	('DFS', 'Disease', (166, 169))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('high', 'Var', (72, 76))
156508	30854133	Using cBioportal program, less than 1% mutation in the patients with renal cancer was observed, the alterations in FZD1 were correlated with better OS (P=0.0404) in ccRCC patients.	('FZD1', 'Gene', '8321', (115, 119))	('renal cancer', 'Disease', (69, 81))	('FZD1', 'Gene', (115, 119))	('OS', 'Chemical', '-', (148, 150))	('patients', 'Species', '9606', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (165, 170))	('renal cancer', 'Disease', 'MESH:D007680', (69, 81))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('renal cancer', 'Phenotype', 'HP:0009726', (69, 81))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('patients', 'Species', '9606', (55, 63))	('alterations', 'Var', (100, 111))
156522	30854133	A previous report that ccRCC patients even within the same tumor stage may have different clinical features because mutation or dysregulation of different genes.	('patients', 'Species', '9606', (29, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (23, 28))	('tumor', 'Disease', (59, 64))	('mutation', 'Var', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('dysregulation', 'Var', (128, 141))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('RCC', 'Disease', (25, 28))
156563	30854133	The database query was based on mutation and altered expression of the FZD1 in ccRCC (U Tokyo, Nat Genet 2013; TCGA, Nature 2013; TCGA, Provisional), pRCC (TCGA, Provisional) and nccRCC (Genentech, Nat Genet 2014).	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('pRCC', 'Gene', '5546', (150, 154))	('mutation', 'Var', (32, 40))	('altered', 'Reg', (45, 52))	('FZD1', 'Gene', '8321', (71, 75))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('FZD1', 'Gene', (71, 75))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('expression', 'MPA', (53, 63))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('RCC', 'Disease', (151, 154))	('RCC', 'Disease', (182, 185))	('pRCC', 'Phenotype', 'HP:0006766', (150, 154))	('pRCC', 'Gene', (150, 154))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', 'MESH:C538614', (182, 185))
156564	30854133	Catalogue of Somatic Mutations in Cancer (COSMIC) database (http://www.sanger.ac.uk/cosmic/) was utilized for assessment of FZD1 mutations in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('mutations', 'Var', (129, 138))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('OS', 'Chemical', '-', (43, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('FZD1', 'Gene', '8321', (124, 128))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('FZD1', 'Gene', (124, 128))
156583	30854133	Overexpression of FZD1 significantly correlated with lower T stage (P<0.0001; Figure 2C), negative lymph node metastasis (P=0.0353; Figure 2D), negative distant metastasis (P=0.0068; Figure 2E), pathological stage (P<0.0001; Figure 2F), Grade stage (P=0.0001; Figure 2G) in ccRCC patients.	('patients', 'Species', '9606', (280, 288))	('negative', 'NegReg', (144, 152))	('RCC', 'Disease', 'MESH:C538614', (276, 279))	('ccRCC', 'Phenotype', 'HP:0006770', (274, 279))	('RCC', 'Disease', (276, 279))	('RCC', 'Phenotype', 'HP:0005584', (276, 279))	('pathological stage', 'CPA', (195, 213))	('negative lymph node metastasis', 'CPA', (90, 120))	('T stage', 'CPA', (59, 66))	('Overexpression', 'Var', (0, 14))	('FZD1', 'Gene', '8321', (18, 22))	('Grade', 'CPA', (237, 242))	('lower', 'NegReg', (53, 58))	('FZD1', 'Gene', (18, 22))
156595	30854133	Our results showed that upregulated FZD1 level could be a potential prognostic factor for ccRCC patients with Age<60 years (P=0.0021), Age>=60 years (P<0.0001), Female (P<0.0001), Male (P=0.0029), T3+T4 stage (P=0.0009), N0 stage (P<0.0001), Non-metastasis (P=0.0019), Metastasis (P=0.0011), Pathological (III+IV) stage (P=0.0006), G3+G4 stage (P<0.0001) and Non-neoadjuvant treatment (P<0.0001), which all were significantly related to better OS.	('Non-metastasis (P=0.0019), Metastasis', 'Disease', 'MESH:D009362', (242, 279))	('FZD1', 'Gene', '8321', (36, 40))	('FZD1', 'Gene', (36, 40))	('OS', 'Chemical', '-', (444, 446))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('upregulated', 'PosReg', (24, 35))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('patients', 'Species', '9606', (96, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('G3+G4 stage', 'Var', (332, 343))	('better OS', 'Disease', (437, 446))
156598	30854133	High expression of FZD1 had better DFS than low FZD1 expression group (log-rank test, P=0.0033; Figure 5A).	('High expression', 'Var', (0, 15))	('FZD1', 'Gene', '8321', (19, 23))	('better', 'PosReg', (28, 34))	('FZD1', 'Gene', (19, 23))	('DFS', 'MPA', (35, 38))	('FZD1', 'Gene', (48, 52))	('FZD1', 'Gene', '8321', (48, 52))
156606	30854133	We also found that FZD1 expression was a risk factor for DFS in the ccRCC patients by univariate cox regression analysis (HR 0.588; P=0.004).	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('FZD1', 'Gene', '8321', (19, 23))	('cox', 'Gene', (97, 100))	('patients', 'Species', '9606', (74, 82))	('DFS', 'Disease', (57, 60))	('FZD1', 'Gene', (19, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('risk', 'Reg', (41, 45))	('cox', 'Gene', '1351', (97, 100))	('expression', 'Var', (24, 34))
156607	30854133	By adjusting multivariate analysis, high FZD1 expression was still considered as an independent predictor of good prognosis for DFS in ccRCC (HR 0.559; P=0.036).	('FZD1', 'Gene', (41, 45))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('FZD1', 'Gene', '8321', (41, 45))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('RCC', 'Disease', (137, 140))	('high', 'Var', (36, 40))
156610	30854133	Univariate analysis indicated that FZD1 expression was identified as a risk factor for OS in pRCC patients (HR 0.424; P=0.008).	('risk', 'Reg', (71, 75))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('FZD1', 'Gene', (35, 39))	('pRCC', 'Gene', '5546', (93, 97))	('expression', 'Var', (40, 50))	('OS', 'Chemical', '-', (87, 89))	('pRCC', 'Phenotype', 'HP:0006766', (93, 97))	('patients', 'Species', '9606', (98, 106))	('pRCC', 'Gene', (93, 97))	('FZD1', 'Gene', '8321', (35, 39))
156613	30854133	Using COSMIC database, the pie chart described the mutations information including substitution nonsense, missense, synonymous, deletion frame and insertion frame shift.	('OS', 'Chemical', '-', (7, 9))	('missense', 'Var', (106, 114))	('deletion frame', 'Var', (128, 142))	('substitution nonsense', 'Var', (83, 104))	('synonymous', 'Var', (116, 126))	('insertion frame shift', 'Var', (147, 168))
156614	30854133	Substitution missense rate was 100% of mutation samples of ccRCC (Figure 6A).	('Substitution missense', 'Var', (0, 21))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))
156615	30854133	Alteration frequency of FZD1 mutation in renal cancer was analyzed by cBioportal program.	('mutation', 'Var', (29, 37))	('renal cancer', 'Disease', (41, 53))	('renal cancer', 'Disease', 'MESH:D007680', (41, 53))	('renal cancer', 'Phenotype', 'HP:0009726', (41, 53))	('FZD1', 'Gene', '8321', (24, 28))	('FZD1', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
156617	30854133	After analyzed by Kaplan-Meier plot and log-rank test, the alterations in FZD1 were associated with better OS in ccRCC patients (P=0.0404; Figure 6C).	('alterations', 'Var', (59, 70))	('FZD1', 'Gene', '8321', (74, 78))	('OS', 'Chemical', '-', (107, 109))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('FZD1', 'Gene', (74, 78))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('patients', 'Species', '9606', (119, 127))	('ccRCC', 'Phenotype', 'HP:0006770', (113, 118))	('better', 'PosReg', (100, 106))
156618	30854133	However, there was no significant difference between DFS in ccRCC patients with/without FZD1 alterations (P=0.328; Figure 6D).	('FZD1', 'Gene', '8321', (88, 92))	('alterations', 'Var', (93, 104))	('FZD1', 'Gene', (88, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('patients', 'Species', '9606', (66, 74))
156630	30854133	Overexpression of FZD1 in pancreatic cancer were associated with invasion, metastasis and shorter overall survival.	('FZD1', 'Gene', '8321', (18, 22))	('shorter', 'NegReg', (90, 97))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (26, 43))	('pancreatic cancer', 'Disease', 'MESH:D010190', (26, 43))	('metastasis', 'CPA', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Overexpression', 'Var', (0, 14))	('invasion', 'CPA', (65, 73))	('pancreatic cancer', 'Disease', (26, 43))	('overall', 'MPA', (98, 105))	('FZD1', 'Gene', (18, 22))
156633	30854133	The high FZD1 level was strongly associated with indolent and non-recurrent characteristics of ccRCC.	('RCC', 'Disease', (97, 100))	('FZD1', 'Gene', '8321', (9, 13))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('FZD1', 'Gene', (9, 13))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('associated', 'Reg', (33, 43))	('high', 'Var', (4, 8))
156634	30854133	Genetic mutations and epigenetic alterations are very important for tumorigenesis, also impose vital impact as independent prognostic markers on therapeutic strategies for cancer patients.	('tumor', 'Disease', (68, 73))	('Genetic mutations', 'Var', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('epigenetic alterations', 'Var', (22, 44))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('patients', 'Species', '9606', (179, 187))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cancer', 'Disease', (172, 178))
156635	30854133	In ccRCC, although somatic VHL mutations have been described for some time, more recent cancer genomic studies have identified new mutations in ccRCC, including PBRM1, SETD2, BAP1, MTOR and CKAP4 that were associated with aggressive clinical features.	('cancer', 'Disease', (88, 94))	('PBRM1', 'Gene', (161, 166))	('VHL', 'Disease', (27, 30))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('CKAP4', 'Gene', '10970', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('BAP1', 'Gene', (175, 179))	('RCC', 'Disease', (146, 149))	('associated', 'Reg', (206, 216))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('SETD2', 'Gene', (168, 173))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('CKAP4', 'Gene', (190, 195))	('VHL', 'Disease', 'MESH:D006623', (27, 30))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('SETD2', 'Gene', '29072', (168, 173))	('MTOR', 'Gene', (181, 185))	('MTOR', 'Gene', '2475', (181, 185))	('mutations', 'Var', (131, 140))	('PBRM1', 'Gene', '55193', (161, 166))	('BAP1', 'Gene', '8314', (175, 179))
156636	30854133	FZD1 was mutated at frequency ranged from 4% to 2%, involved in cell migration and invasion in neuroblastoma.	('neuroblastoma', 'Phenotype', 'HP:0003006', (95, 108))	('involved in', 'Reg', (52, 63))	('neuroblastoma', 'Disease', 'MESH:D009447', (95, 108))	('mutated', 'Var', (9, 16))	('neuroblastoma', 'Disease', (95, 108))	('invasion', 'CPA', (83, 91))	('FZD1', 'Gene', '8321', (0, 4))	('cell migration', 'biological_process', 'GO:0016477', ('64', '78'))	('FZD1', 'Gene', (0, 4))	('cell migration', 'CPA', (64, 78))
156637	30854133	FZD1 was also frequently methylated and whose methylation was associated with inactivation of gene expression in prostate cancer cell lines.	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('gene expression', 'biological_process', 'GO:0010467', ('94', '109'))	('associated', 'Reg', (62, 72))	('methylated', 'Var', (25, 35))	('prostate cancer', 'Disease', (113, 128))	('methylation', 'MPA', (46, 57))	('FZD1', 'Gene', '8321', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('FZD1', 'Gene', (0, 4))	('prostate cancer', 'Disease', 'MESH:D011471', (113, 128))	('inactivation', 'NegReg', (78, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (113, 128))
156638	30854133	We found less than 1% mutation in the patients with renal cancer was observed and the alterations in FZD1 were associated with better OS in ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('FZD1', 'Gene', (101, 105))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('renal cancer', 'Disease', (52, 64))	('associated', 'Reg', (111, 121))	('better OS', 'Disease', (127, 136))	('renal cancer', 'Phenotype', 'HP:0009726', (52, 64))	('OS', 'Chemical', '-', (134, 136))	('patients', 'Species', '9606', (38, 46))	('renal cancer', 'Disease', 'MESH:D007680', (52, 64))	('patients', 'Species', '9606', (146, 154))	('FZD1', 'Gene', '8321', (101, 105))	('alterations', 'Var', (86, 97))
156639	30854133	The exact mechanism of FZD1 alteration with longer OS in ccRCC patients needs more investigations.	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('OS', 'Chemical', '-', (51, 53))	('FZD1', 'Gene', '8321', (23, 27))	('alteration', 'Var', (28, 38))	('FZD1', 'Gene', (23, 27))	('patients', 'Species', '9606', (63, 71))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
156645	30854133	We also identified new mutated genes that are involved in the pathogenesis of ccRCC, which help identify clinic patients.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('patients', 'Species', '9606', (112, 120))	('pathogenesis', 'biological_process', 'GO:0009405', ('62', '74'))	('mutated', 'Var', (23, 30))
156652	30854133	FZD1 is overexpressed in the multidrug resistant breast cancer cell, when FZD1 silencing induced down-regulation of MDR1/P-gp through the Wnt/beta-catenin signaling, restored sensitivity to chemotherapy drugs.	('down-regulation', 'NegReg', (97, 112))	('MDR1', 'Gene', (116, 120))	('FZD1', 'Gene', '8321', (74, 78))	('MDR', 'molecular_function', 'GO:0004745', ('116', '119'))	('FZD1', 'Gene', (74, 78))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('beta-catenin', 'Gene', (142, 154))	('regulation', 'biological_process', 'GO:0065007', ('102', '112'))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('beta-catenin', 'Gene', '1499', (142, 154))	('P-gp', 'Gene', '283871', (121, 125))	('restored', 'PosReg', (166, 174))	('FZD1', 'Gene', '8321', (0, 4))	('sensitivity to chemotherapy drugs', 'MPA', (175, 208))	('P-gp', 'Gene', (121, 125))	('FZD1', 'Gene', (0, 4))	('MDR1', 'Gene', '5243', (116, 120))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('silencing', 'Var', (79, 88))
156654	30854133	Hippo signaling dysregulation underlies various human diseases including cancer.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('human', 'Species', '9606', (48, 53))	('Hippo signaling', 'MPA', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Hippo signaling', 'biological_process', 'GO:0035329', ('0', '15'))	('dysregulation', 'Var', (16, 29))
156694	27783999	IOD = 17138 was chosen as cutoff points according to minimum p value method with X-tile for clinical use and further analyses.	('X-tile', 'Disease', (81, 87))	('IOD = 17138', 'Var', (0, 11))	('X-tile', 'Disease', 'MESH:D005171', (81, 87))
156704	27783999	Patients with low CCL21 expression had significantly worse OS than those with high CCL21 expression as is shown in Figure 1A (P = 0.005).	('CCL', 'molecular_function', 'GO:0044101', ('83', '86'))	('CCL21', 'Gene', (18, 23))	('CCL21', 'Gene', (83, 88))	('CCL', 'molecular_function', 'GO:0044101', ('18', '21'))	('Patients', 'Species', '9606', (0, 8))	('low', 'NegReg', (14, 17))	('expression', 'Var', (24, 34))	('CCL21', 'Gene', '6366', (18, 23))	('CCL21', 'Gene', '6366', (83, 88))
156706	27783999	Multivariate analysis was further performed using CCL21 expression as a dichotomous variable and low CCL21 expression was still an adverse independent prognosticator for OS (HR, 2.106, 95% CI, 1.286-3.450, P = 0.003).	('low', 'Var', (97, 100))	('CCL21', 'Gene', '6366', (101, 106))	('CCL21', 'Gene', (101, 106))	('expression', 'MPA', (107, 117))	('CCL21', 'Gene', '6366', (50, 55))	('CCL', 'molecular_function', 'GO:0044101', ('50', '53'))	('CCL21', 'Gene', (50, 55))	('CCL', 'molecular_function', 'GO:0044101', ('101', '104'))
156709	27783999	Univariate subgroup analyses showed that CCL21 expression was a risk factor in ccRCC patients (P = 0.019), patients treated with sorafenib (P = 0.012), patients with one metastatic site (P = 0.044) and patients with no lymph node involvement (P = 0.019) (Table S2).	('CCL', 'molecular_function', 'GO:0044101', ('41', '44'))	('CCL21', 'Gene', (41, 46))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('expression', 'Var', (47, 57))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('patients', 'Species', '9606', (85, 93))	('RCC', 'Disease', (81, 84))	('patients', 'Species', '9606', (202, 210))	('sorafenib', 'Chemical', 'MESH:D000077157', (129, 138))	('patients', 'Species', '9606', (107, 115))	('patients', 'Species', '9606', (152, 160))	('CCL21', 'Gene', '6366', (41, 46))
156716	27783999	The objective response rate for patients with low and high CCL21 expression were 16.9% and 35.4% respectively.	('patients', 'Species', '9606', (32, 40))	('CCL21', 'Gene', (59, 64))	('high', 'Var', (54, 58))	('CCL', 'molecular_function', 'GO:0044101', ('59', '62'))	('expression', 'MPA', (65, 75))	('CCL21', 'Gene', '6366', (59, 64))
156771	31349573	Therefore, we launch the hypothesis that silencing the GMR may selectively kill the cancer cells from a tissue.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('silencing', 'Var', (41, 50))	('cancer', 'Disease', (84, 90))	('GMR', 'Chemical', '-', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('kill', 'CPA', (75, 79))
156797	31349573	The GMR targeting would be effective in selectively destroying the cancer cells from a tissue if: (1) cancer nuclei and surrounding quasi-normal tissues are governed by different GCH hierarchies, (2) expression manipulation of a gene has larger consequences in cells where that gene has higher GCH and (3) the GCH of the GMR is well above the GCHs of the next genes in the hierarchy.	('GCH', 'MPA', (294, 297))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('manipulation', 'Var', (211, 223))	('higher', 'PosReg', (287, 293))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (67, 73))	('GMR', 'Chemical', '-', (4, 7))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('expression manipulation', 'Var', (200, 223))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('GMR', 'Chemical', '-', (321, 324))	('man', 'Species', '9606', (211, 214))
156811	31349573	The BCPAP cell line is a papillary thyroid carcinoma cell line isolated from a female patient, with a TP53 mutation in the codon 278 in heterozygosity (Pro Leu).	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (25, 52))	('mutation in', 'Var', (107, 118))	('TP53', 'Gene', (102, 106))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (35, 52))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (25, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('patient', 'Species', '9606', (86, 93))	('papillary thyroid carcinoma', 'Disease', (25, 52))	('TP53', 'Gene', '7157', (102, 106))
156838	31349573	The theory is validated if the alterations of the same gene transfection are higher in the cells where that gene has a higher GCH.	('higher', 'PosReg', (119, 125))	('rat', 'Species', '10116', (35, 38))	('GCH', 'MPA', (126, 129))	('gene', 'Var', (108, 112))
156841	31349573	Data used in this report were from GSE72304 (a case of metastatic clear cell renal cell carcinoma (CCRCC), GSE97001 (a case of papillary thyroid cancer), GSE97002 (BCPAP papillary and 8505C anaplastic thyroid cancer cell lines) and from two cases of prostate cancer (GSE133891, GSE133906).	('clear cell renal cell carcinoma', 'Disease', (66, 97))	('prostate cancer', 'Disease', (250, 265))	('RCC', 'Disease', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('anaplastic thyroid cancer', 'Disease', (190, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (77, 97))	('GSE72304', 'Var', (35, 43))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (66, 97))	('papillary thyroid cancer', 'Disease', (127, 151))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('anaplastic thyroid cancer', 'Disease', 'MESH:D065646', (190, 215))	('GSE97002', 'Var', (154, 162))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('GSE97001', 'Var', (107, 115))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (127, 151))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (66, 97))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (190, 215))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (127, 151))	('thyroid cancer', 'Phenotype', 'HP:0002890', (201, 215))	('prostate cancer', 'Disease', 'MESH:D011471', (250, 265))	('thyroid cancer', 'Phenotype', 'HP:0002890', (137, 151))	('prostate cancer', 'Phenotype', 'HP:0012125', (250, 265))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
156842	31349573	Expression data for the GMR Theory validation on thyroid cancer cell lines BCPAP and 8505C were collected from GSE97031 (transfection with NEMP1), GSE97028 (DDX19B), GSE97030 (PANK2) and GSE97427 (UBALD1).	('thyroid cancer', 'Phenotype', 'HP:0002890', (49, 63))	('thyroid cancer', 'Disease', (49, 63))	('GSE97030', 'Var', (166, 174))	('PANK2', 'Gene', (176, 181))	('NEMP1', 'Gene', (139, 144))	('GMR', 'Chemical', '-', (24, 27))	('thyroid cancer', 'Disease', 'MESH:D013964', (49, 63))	('UBALD1', 'Gene', '124402', (197, 203))	('GSE97028', 'Var', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('UBALD1', 'Gene', (197, 203))	('DDX19B', 'Gene', '11269', (157, 163))	('DDX19B', 'Gene', (157, 163))	('NEMP1', 'Gene', '23306', (139, 144))	('GSE97031', 'Var', (111, 119))	('PANK2', 'Gene', '80025', (176, 181))
156843	31349573	Other expression data from cancer cell lines were collected from GSE72333 (DU145), GSE72414 (LNCaP) and GSE72415 (HL-60).	('GSE72415', 'Var', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('HL-60', 'CellLine', 'CVCL:0002', (114, 119))	('GSE72414', 'Var', (83, 91))	('GSE72333', 'Var', (65, 73))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('LNCaP', 'CellLine', 'CVCL:0395', (93, 98))
156850	31349573	HRAS is among the most documented genes whose mutations have been associated with thyroid cancer.	('HRAS', 'Gene', (0, 4))	('mutations', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('associated', 'Reg', (66, 76))	('thyroid cancer', 'Disease', (82, 96))	('thyroid cancer', 'Phenotype', 'HP:0002890', (82, 96))	('HRAS', 'Gene', '3265', (0, 4))	('men', 'Species', '9606', (27, 30))	('thyroid cancer', 'Disease', 'MESH:D013964', (82, 96))
156852	31349573	TFG-MET (MET proto-oncogene receptor tyrosine-kinase) translocation was reported in a follicular variant of the papillary thyroid carcinoma.	('MET proto-oncogene receptor tyrosine-kinase', 'Gene', '4233', (9, 52))	('TFG', 'Gene', (0, 3))	('papillary thyroid carcinoma', 'Disease', (112, 139))	('MET proto-oncogene receptor tyrosine-kinase', 'Gene', (9, 52))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (112, 139))	('reported', 'Reg', (72, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('translocation', 'Var', (54, 67))	('follicular variant', 'Disease', (86, 104))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (122, 139))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (112, 139))	('TFG', 'Gene', '10342', (0, 3))
156858	31349573	Note also that MIR1915HG, previous names: chromosome 10 open reading frame 114, cancer susceptibility candidate 10 and cancer susceptibility 10, is a long non-coding RNA.	('MIR1915HG', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('MIR1915HG', 'CellLine', 'CVCL:1505', (15, 24))	('RNA', 'cellular_component', 'GO:0005562', ('166', '169'))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('chromosome', 'cellular_component', 'GO:0005694', ('42', '52'))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Disease', (80, 86))
156862	31349573	Interestingly, SPINT2 a transmembrane protein that inhibits serine proteases implicated in cancer progression, acts as a putative tumor suppressor when hypermethylated.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('130', '146'))	('transmembrane', 'cellular_component', 'GO:0044214', ('24', '37'))	('transmembrane', 'cellular_component', 'GO:0016021', ('24', '37'))	('hypermethylated', 'Var', (152, 167))	('serine proteases', 'Enzyme', (60, 76))	('inhibits', 'NegReg', (51, 59))	('SPINT2', 'Gene', (15, 21))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('SPINT2', 'Gene', '10653', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor suppressor', 'biological_process', 'GO:0051726', ('130', '146'))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('tumor', 'Disease', (130, 135))
156865	31349573	To our knowledge, this is the first time that LOC145474 is reported as related to a prostate cancer.	('prostate cancer', 'Disease', (84, 99))	('related', 'Reg', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('prostate cancer', 'Disease', 'MESH:D011471', (84, 99))	('LOC145474', 'Var', (46, 55))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))
156866	31349573	Our experimental results (summarized in Figure 3) on the 8505C (anaplastic, 3A & 3C) and BCPAP (papillary, 3B & 3D) human thyroid cancer cell lines stably transfected with DDX19B, NEMP1, PANK2 or UBALD1 (characteristics in Figure 1) indicate that: We have also observed that transfections of NEMP1 and PANK2 significantly slowed down multiplication of BCPAP cells, while transfection of DDX19B or UBALD1 had little effect on these cells.	('observed', 'Var', (261, 269))	('DDX19B', 'Gene', (387, 393))	('thyroid cancer', 'Disease', (122, 136))	('UBALD1', 'Gene', '124402', (196, 202))	('DDX19B', 'Gene', (172, 178))	('men', 'Species', '9606', (10, 13))	('NEMP1', 'Gene', (292, 297))	('NEMP1', 'Gene', (180, 185))	('slowed', 'CPA', (322, 328))	('PANK2', 'Gene', (187, 192))	('transfections', 'Gene', (275, 288))	('UBALD1', 'Gene', (397, 403))	('thyroid cancer', 'Disease', 'MESH:D013964', (122, 136))	('PANK2', 'Gene', '80025', (187, 192))	('NEMP1', 'Gene', '23306', (292, 297))	('NEMP1', 'Gene', '23306', (180, 185))	('thyroid cancer', 'Phenotype', 'HP:0002890', (122, 136))	('human', 'Species', '9606', (116, 121))	('UBALD1', 'Gene', (196, 202))	('UBALD1', 'Gene', '124402', (397, 403))	('PANK2', 'Gene', (302, 307))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('PANK2', 'Gene', '80025', (302, 307))	('DDX19B', 'Gene', '11269', (172, 178))	('DDX19B', 'Gene', '11269', (387, 393))
156868	31349573	Together, these observations confirm that expression manipulation of a gene has larger consequences in cells where that gene has higher GCH.	('man', 'Species', '9606', (53, 56))	('higher', 'PosReg', (129, 135))	('gene', 'Var', (120, 124))	('GCH', 'CPA', (136, 139))
156902	31349573	Importantly, we found that the cancer nuclei and the surrounding normal tissues are governed by different GMRs and that manipulation of the expression of a gene has consequences in line with its Gene Commanding Height.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('GMR', 'Chemical', '-', (106, 109))	('man', 'Species', '9606', (120, 123))	('man', 'Species', '9606', (203, 206))	('manipulation', 'Var', (120, 132))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))
156903	31349573	Based on these findings, we provide the hypothesis that silencing the GMR (using CRISPR or shRNA) may selectively kill the cancer cells with little effect on the normal cells of the tissue.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('silencing', 'Var', (56, 65))	('GMR', 'Chemical', '-', (70, 73))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))
156906	31349573	If the GMR transcript is coding, then its forced alteration affects directly the encoded protein, although coding or non-coding, through the strong expression coordination and manipulation of the GMR should affect the levels of numerous proteins involved in major functional pathways.	('GMR', 'Chemical', '-', (196, 199))	('GMR', 'Chemical', '-', (7, 10))	('affects', 'Reg', (60, 67))	('levels of numerous proteins', 'MPA', (218, 245))	('affect', 'Reg', (207, 213))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))	('rat', 'Species', '10116', (53, 56))	('expression', 'MPA', (148, 158))	('man', 'Species', '9606', (176, 179))	('alteration', 'Var', (49, 59))
156907	31349573	At this moment, we do not know whether targeting cancer GMRs may improve the results of the chemo- or radiation therapy, but combining gene manipulation with traditional treatment (as suggested by one of the reviewers) appears to be a very interesting idea.	('men', 'Species', '9606', (10, 13))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('GMR', 'Chemical', '-', (56, 59))	('man', 'Species', '9606', (140, 143))	('gene manipulation', 'Var', (135, 152))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))	('men', 'Species', '9606', (175, 178))
156973	29967214	RCC is a complex disease characterized by mutations in many genes.	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('mutations', 'Var', (42, 51))	('RCC', 'Disease', (0, 3))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))
156974	29967214	Deactivation of the VHL gene is the most common mutation in RCC.	('Deactivation', 'Var', (0, 12))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('VHL', 'Gene', (20, 23))	('VHL', 'Gene', '7428', (20, 23))
156976	29967214	Epigenetic silencing of VHL was present in 7% of ccRCC tumors, which is consistent with the role of epigenetic changes in renal carcinogenesis.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('VHL', 'Gene', '7428', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('renal carcinogenesis', 'Disease', (122, 142))	('ccRCC tumors', 'Disease', 'MESH:D009369', (49, 61))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('ccRCC tumors', 'Disease', (49, 61))	('Epigenetic silencing', 'Var', (0, 20))	('renal carcinogenesis', 'Disease', 'MESH:D007674', (122, 142))	('VHL', 'Gene', (24, 27))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))
156980	29967214	VHL mutations may confer aberrant activation of AKT/mTOR signaling given that VHL inactivation subsequently activates mTOR, which in turn up-regulates HIF and jumpstarts other angiogenic pathways.	('mTOR', 'Gene', (52, 56))	('mTOR', 'Gene', '2475', (52, 56))	('activates', 'PosReg', (108, 117))	('up-regulates', 'PosReg', (138, 150))	('AKT', 'Gene', (48, 51))	('VHL', 'Gene', (78, 81))	('mTOR', 'Gene', (118, 122))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('mTOR', 'Gene', '2475', (118, 122))	('HIF', 'CPA', (151, 154))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (78, 81))	('activation', 'PosReg', (34, 44))	('mutations', 'Var', (4, 13))	('VHL', 'Gene', '7428', (0, 3))	('AKT', 'Gene', '207', (48, 51))	('inactivation', 'Var', (82, 94))	('jumpstarts', 'NegReg', (159, 169))
156983	29967214	A potential mechanism that accounts for resistance to everolimus and temsirolimus is mutation in FKBP-12 domain in mTOR, which reduces the binding affinity of mTOR inhibitors.	('reduces', 'NegReg', (127, 134))	('FKBP-12', 'Gene', (97, 104))	('FKBP', 'molecular_function', 'GO:0030051', ('97', '101'))	('mTOR', 'Gene', '2475', (115, 119))	('temsirolimus', 'Chemical', 'MESH:C401859', (69, 81))	('mTOR', 'Gene', (159, 163))	('mTOR', 'Gene', (115, 119))	('mTOR', 'Gene', '2475', (159, 163))	('mutation', 'Var', (85, 93))	('everolimus', 'Chemical', 'MESH:D000068338', (54, 64))	('binding', 'Interaction', (139, 146))	('binding', 'molecular_function', 'GO:0005488', ('139', '146'))
156984	29967214	The mutational status of the mTOR pathway genes TSC1, TSC2, and REDD1 could also predict response to everolimus or temsirolimus in RCC tumors.	('REDD1', 'Gene', (64, 69))	('RCC tumors', 'Disease', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('everolimus', 'Chemical', 'MESH:D000068338', (101, 111))	('mTOR', 'Gene', (29, 33))	('temsirolimus', 'Chemical', 'MESH:C401859', (115, 127))	('RCC tumors', 'Disease', 'MESH:C538614', (131, 141))	('mTOR', 'Gene', '2475', (29, 33))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('REDD1', 'Gene', '54541', (64, 69))	('predict', 'Reg', (81, 88))	('TSC1', 'Gene', '7248', (48, 52))	('TSC2', 'Gene', (54, 58))	('TSC2', 'Gene', '7249', (54, 58))	('response to everolimus', 'MPA', (89, 111))	('mutational', 'Var', (4, 14))	('TSC1', 'Gene', (48, 52))
156986	29967214	Alterations in TSC1, TSC2, or REDD1 therefore, prevent the inhibition of mTORC1.	('REDD1', 'Gene', (30, 35))	('mTORC1', 'Gene', (73, 79))	('TSC1', 'Gene', (15, 19))	('TSC2', 'Gene', (21, 25))	('prevent', 'NegReg', (47, 54))	('Alterations', 'Var', (0, 11))	('inhibition', 'MPA', (59, 69))	('mTORC1', 'Gene', '382056', (73, 79))	('REDD1', 'Gene', '54541', (30, 35))	('mTORC1', 'cellular_component', 'GO:0031931', ('73', '79'))	('TSC2', 'Gene', '7249', (21, 25))	('TSC1', 'Gene', '7248', (15, 19))
156987	29967214	Mutations in all these genes have been observed in RCC.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('observed', 'Reg', (39, 47))	('Mutations', 'Var', (0, 9))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
156988	29967214	The aberrant expression of proteins involved in the mTOR signaling pathway may also modulate sensitivity to mTOR inhibitors.	('mTOR', 'Gene', (52, 56))	('mTOR', 'Gene', (108, 112))	('mTOR', 'Gene', '2475', (52, 56))	('mTOR', 'Gene', '2475', (108, 112))	('modulate', 'Reg', (84, 92))	('expression', 'MPA', (13, 23))	('aberrant', 'Var', (4, 12))	('proteins', 'Protein', (27, 35))	('signaling pathway', 'biological_process', 'GO:0007165', ('57', '74'))
156993	29967214	demonstrated that the overexpression of the histone methyltransferase enhancer of zeste homologue 2 (EZH2) promotes tumor angiogenesis by inactivating anti-angiogenic factors via methylation at their promoter regions, causing resistance to sunitinib.	('sunitinib', 'Chemical', 'MESH:D000077210', (240, 249))	('anti-angiogenic factors', 'MPA', (151, 174))	('overexpression', 'PosReg', (22, 36))	('methylation', 'biological_process', 'GO:0032259', ('179', '190'))	('methylation', 'Var', (179, 190))	('resistance to sunitinib', 'MPA', (226, 249))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('EZH2', 'Gene', (101, 105))	('promotes', 'PosReg', (107, 115))	('EZH2', 'Gene', '2146', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('angiogenesis', 'biological_process', 'GO:0001525', ('122', '134'))	('causing', 'Reg', (218, 225))	('inactivating', 'NegReg', (138, 150))	('tumor', 'Disease', (116, 121))
156998	29967214	Accordingly, phosphorylated 4E-BP1 has recently been shown to be the single most accurate biomarker for predicting treatment response to mTOR inhibitors.	('4E-BP1', 'Gene', '1978', (28, 34))	('phosphorylated', 'Var', (13, 27))	('mTOR', 'Gene', (137, 141))	('mTOR', 'Gene', '2475', (137, 141))	('4E-BP1', 'Gene', (28, 34))	('men', 'Species', '9606', (120, 123))
156999	29967214	Inactivation of VHL in RCC cells lead to increased HIF-1 and HIF-2 activities.	('increased', 'PosReg', (41, 50))	('VHL', 'Gene', (16, 19))	('HIF-1', 'Gene', (51, 56))	('VHL', 'Gene', '7428', (16, 19))	('HIF-1', 'Gene', '3091', (51, 56))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('activities', 'MPA', (67, 77))	('increased HIF-1', 'Phenotype', 'HP:0030269', (41, 56))	('Inactivation', 'Var', (0, 12))	('HIF-2', 'CPA', (61, 66))
157000	29967214	Interestingly, HIF-2 antagonist PT2399 was more active than sunitinib (p=0.0126) and inhibited tumor growth in several sunitinib-resistant RCC xenograft tumors.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('RCC xenograft tumors', 'Disease', (139, 159))	('active', 'MPA', (48, 54))	('inhibited', 'NegReg', (85, 94))	('PT2399', 'Var', (32, 38))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('RCC xenograft tumors', 'Disease', 'MESH:C538614', (139, 159))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('PT2399', 'Chemical', 'MESH:C000614278', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('sunitinib', 'Chemical', 'MESH:D000077210', (60, 69))	('sunitinib', 'Chemical', 'MESH:D000077210', (119, 128))	('tumor', 'Disease', (95, 100))
157001	29967214	However, as discussed above, VHL mutation status by itself had little effect on patient responses to VEGF-targeted agents in metastatic ccRCC.	('RCC', 'Disease', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('mutation', 'Var', (33, 41))	('VEGF', 'Gene', (101, 105))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('VHL', 'Gene', (29, 32))	('VHL', 'Gene', '7428', (29, 32))	('VEGF', 'Gene', '7422', (101, 105))	('patient', 'Species', '9606', (80, 87))
157011	29967214	evaluated the predictive value of polymorphisms in IL-8 in sunitinib and pazopanib resistance.	('sunitinib', 'Chemical', 'MESH:D000077210', (59, 68))	('polymorphisms', 'Var', (34, 47))	('pazopanib', 'Chemical', 'MESH:C516667', (73, 82))	('IL-8', 'Gene', (51, 55))	('pazopanib resistance', 'MPA', (73, 93))	('IL-8', 'molecular_function', 'GO:0005153', ('51', '55'))
157012	29967214	These findings showed that variant alleles of IL-8 are associated with poorer survival outcomes in pazopanib- or sunitinib-treated patients with advanced RCC.	('patients', 'Species', '9606', (131, 139))	('pazopanib', 'Chemical', 'MESH:C516667', (99, 108))	('IL-8', 'Gene', (46, 50))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('RCC', 'Disease', (154, 157))	('RCC', 'Phenotype', 'HP:0005584', (154, 157))	('survival', 'MPA', (78, 86))	('variant', 'Var', (27, 34))	('IL-8', 'molecular_function', 'GO:0005153', ('46', '50'))	('poorer', 'NegReg', (71, 77))	('sunitinib', 'Chemical', 'MESH:D000077210', (113, 122))
157022	29967214	VHL inactivation in ccRCC induces overexpression and activation of the receptor tyrosine kinases MET and AXL.	('AXL', 'Gene', '558', (105, 108))	('inactivation', 'Var', (4, 16))	('activation', 'PosReg', (53, 63))	('RCC', 'Disease', (22, 25))	('RCC', 'Phenotype', 'HP:0005584', (22, 25))	('RCC', 'Disease', 'MESH:C538614', (22, 25))	('overexpression', 'PosReg', (34, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (20, 25))	('AXL', 'Gene', (105, 108))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('tyrosine kinases MET', 'Enzyme', (80, 100))
157034	29967214	PTEN mutations are rare in RCC.	('mutations', 'Var', (5, 14))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('PTEN', 'Gene', (0, 4))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('PTEN', 'Gene', '5728', (0, 4))
157055	29967214	Varying gene, microRNA, and protein expression signatures can be detected even within the same tumor specimen, and variations in the dysregulation of microRNA has been shown to impact ccRCC pathogenicity.	('impact', 'Reg', (177, 183))	('dysregulation', 'MPA', (133, 146))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('RCC', 'Disease', (186, 189))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('variations', 'Var', (115, 125))	('pathogenicity', 'CPA', (190, 203))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (184, 189))	('microRNA', 'Gene', (150, 158))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))	('tumor', 'Disease', (95, 100))	('men', 'Species', '9606', (106, 109))
157056	29967214	In one study, post-sunitinib metastatic lesions carried mutations in FLT4, KMT2D, and BMP5, which were not detected in the primary tumor.	('BMP5', 'Gene', (86, 90))	('mutations', 'Var', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('BMP5', 'Gene', '653', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('KMT2D', 'Gene', (75, 80))	('KMT2D', 'Gene', '8085', (75, 80))	('metastatic lesions', 'CPA', (29, 47))	('tumor', 'Disease', (131, 136))	('FLT4', 'Gene', (69, 73))	('sunitinib', 'Chemical', 'MESH:D000077210', (19, 28))	('FLT4', 'Gene', '2324', (69, 73))
157134	29925043	The genetic alterations of TSC1 or TSC2 are responsible for the development of TSC.	('genetic alterations', 'Var', (4, 23))	('responsible', 'Reg', (44, 55))	('TSC2', 'Gene', '7249', (35, 39))	('TSC1', 'Gene', '7248', (27, 31))	('TSC', 'Gene', (27, 30))	('TSC', 'Gene', '7248', (27, 30))	('TSC2', 'Gene', (35, 39))	('TSC', 'Gene', (79, 82))	('TSC1', 'Gene', (27, 31))	('TSC', 'Gene', (35, 38))	('TSC', 'Gene', '7248', (79, 82))	('TSC', 'Gene', '7248', (35, 38))
157139	29925043	The mTOR pathway activation and the germline mutations of TSC2 were identified in both TSC-RCC cases.	('TSC2', 'Gene', '7249', (58, 62))	('TSC2', 'Gene', (58, 62))	('germline mutations', 'Var', (36, 54))	('TSC', 'Gene', (58, 61))	('TSC', 'Gene', '7248', (58, 61))	('TSC', 'Gene', '7248', (87, 90))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('activation', 'PosReg', (17, 27))	('mTOR', 'Gene', (4, 8))	('mTOR', 'Gene', '2475', (4, 8))	('TSC', 'Gene', (87, 90))
157140	29925043	The WES revealed several cancer gene alterations.	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('alterations', 'Var', (37, 48))
157142	29925043	In Case 2, genetic alterations of IWS1 and TSC2 were identified.	('IWS1', 'Gene', '55677', (34, 38))	('TSC2', 'Gene', '7249', (43, 47))	('IWS1', 'Gene', (34, 38))	('genetic alterations', 'Var', (11, 30))	('TSC2', 'Gene', (43, 47))
157153	29925043	The disease is caused by alterations in TSC1 or TSC2 genes, which encode hamartin and tuberin, respectively.	('alterations', 'Var', (25, 36))	('tuberin', 'Gene', (86, 93))	('TSC1', 'Gene', (40, 44))	('caused by', 'Reg', (15, 24))	('TSC2', 'Gene', '7249', (48, 52))	('TSC2', 'Gene', (48, 52))	('hamartin', 'Gene', '7248', (73, 81))	('tuberin', 'Gene', '7249', (86, 93))	('hamartin', 'Gene', (73, 81))	('TSC1', 'Gene', '7248', (40, 44))
157162	29925043	In this study, we assessed the activation of the mTOR pathway and the genetic alterations in two cases of TSC-RCC by immunohistochemistry and whole exome sequencing (WES).	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('mTOR', 'Gene', (49, 53))	('mTOR', 'Gene', '2475', (49, 53))	('TSC', 'Gene', (106, 109))	('TSC', 'Gene', '7248', (106, 109))	('activation', 'PosReg', (31, 41))	('genetic alterations', 'Var', (70, 89))
157200	29925043	We regarded identical mutations on both normal and cancer tissues as germline mutations.	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('mutations', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))
157201	29925043	In Case 1, a TSC2 c.4707C > A (p.Tyr1569*) mutation was identified, and in Case 2, a TSC2 c.2548+ 2 T > G mutation was seen (Table 1 and Supplementary Figure 2), which were stop gained effect and a splice donor variant, respectively.	('TSC2', 'Gene', (13, 17))	('2 T > G', 'SUBSTITUTION', 'None', (98, 105))	('donor variant', 'Species', '9606', (205, 218))	('c.4707C > A', 'Mutation', 'rs397514999', (18, 29))	('p.Tyr1569*', 'Mutation', 'rs397514999', (31, 41))	('2 T > G', 'Var', (98, 105))	('TSC2', 'Gene', '7249', (13, 17))	('c.4707C > A', 'Var', (18, 29))	('TSC2', 'Gene', '7249', (85, 89))	('TSC2', 'Gene', (85, 89))
157210	29925043	In both TSC-RCCs, there were no megabase-scale amplification or deletion.	('TSC', 'Gene', '7248', (8, 11))	('deletion', 'Var', (64, 72))	('RCC', 'Phenotype', 'HP:0005584', (12, 15))	('TSC', 'Gene', (8, 11))
157227	29925043	The mTOR activation has been thought to be one of the pathogenic alterations in TSC-RCC because alterations of TSC1 or TSC2 genes were responsible for the development of TSC.	('TSC1', 'Gene', (111, 115))	('alterations', 'Var', (96, 107))	('TSC', 'Gene', '7248', (80, 83))	('TSC', 'Gene', '7248', (111, 114))	('responsible', 'Reg', (135, 146))	('TSC', 'Gene', (119, 122))	('TSC', 'Gene', '7248', (119, 122))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('TSC2', 'Gene', (119, 123))	('TSC', 'Gene', '7248', (170, 173))	('TSC2', 'Gene', '7249', (119, 123))	('mTOR', 'Gene', (4, 8))	('TSC1', 'Gene', '7248', (111, 115))	('mTOR', 'Gene', '2475', (4, 8))	('TSC', 'Gene', (80, 83))	('TSC', 'Gene', (111, 114))	('TSC', 'Gene', (170, 173))
157233	29925043	In TSC-associated papillary RCC cases, there were second-hit mutations (3 SNVs, 1 indel, and 1 LOH) in TSC2, and somatic mutations of PROS1, NPFFR2, TLL2, and RASA1 were identified.	('RASA1', 'Gene', '5921', (159, 164))	('PROS1', 'Gene', '5627', (134, 139))	('TSC2', 'Gene', '7249', (103, 107))	('TSC2', 'Gene', (103, 107))	('RASA1', 'Gene', (159, 164))	('TLL2', 'Gene', (149, 153))	('TSC', 'Gene', (3, 6))	('mutations', 'Var', (61, 70))	('TSC', 'Gene', '7248', (3, 6))	('TLL2', 'Gene', '7093', (149, 153))	('NPFFR2', 'Gene', '10886', (141, 147))	('PROS1', 'Gene', (134, 139))	('TSC', 'Gene', '7248', (103, 106))	('TSC', 'Gene', (103, 106))	('NPFFR2', 'Gene', (141, 147))	('RCC', 'Phenotype', 'HP:0005584', (28, 31))
157234	29925043	In sporadic cases of eosinophilic/macrocystic RCC, copy number gain of 16p-q, 7p-q, 13q, 19p, 1p, and 10q; copy number loss of Xp, 22q, 19p,19q, and Xq; and LOH in 16p, Xq, 11p, and 9q were identified.	('copy number loss', 'Var', (107, 123))	('eosinophilic/macrocystic RCC', 'Disease', (21, 49))	('gain', 'PosReg', (63, 67))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('eosinophilic/macrocystic RCC', 'Disease', 'MESH:D004802', (21, 49))	('copy number', 'Var', (51, 62))
157236	29925043	For the development of tumors related to TSC, biallelic TSC2 inactivation is needed.	('inactivation', 'Var', (61, 73))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('TSC', 'Gene', '7248', (56, 59))	('TSC2', 'Gene', '7249', (56, 60))	('TSC2', 'Gene', (56, 60))	('TSC', 'Gene', (41, 44))	('TSC', 'Gene', '7248', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('TSC', 'Gene', (56, 59))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
157237	29925043	However, we could not find additional TSC2 mutations or LOH in Case 1.	('mutations', 'Var', (43, 52))	('TSC2', 'Gene', '7249', (38, 42))	('TSC2', 'Gene', (38, 42))
157238	29925043	There is the possibility that other types of mutations (large indel or epigenetic alterations), not detected in WES, may exist in the Case 1 patient or TSC2 inactivation was not responsible for mTOR activation, and tumor progression as histopathologic feature of Case 1 was truly unclassifiable.	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('epigenetic alterations', 'Var', (71, 93))	('TSC2', 'Gene', '7249', (152, 156))	('patient', 'Species', '9606', (141, 148))	('mTOR', 'Gene', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('mTOR', 'Gene', '2475', (194, 198))	('TSC2', 'Gene', (152, 156))	('tumor', 'Disease', (215, 220))
157242	29925043	The USP34 and NDE1 alteration in TSC-associated papillary RCC was found in Case 1 and 2, respectively.	('TSC', 'Gene', (33, 36))	('TSC', 'Gene', '7248', (33, 36))	('alteration', 'Var', (19, 29))	('USP34', 'Gene', '9736', (4, 9))	('NDE1', 'Gene', '54820', (14, 18))	('USP34', 'Gene', (4, 9))	('USP', 'molecular_function', 'GO:0051748', ('4', '7'))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('NDE1', 'Gene', (14, 18))
157246	29925043	CHD8 c.2368C > T, p.R790C mutation was previously reported in malignant melanoma and is considered pathogenic based upon FATHMM.	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('malignant melanoma', 'Phenotype', 'HP:0002861', (62, 80))	('CHD8', 'Gene', (0, 4))	('CHD8', 'Gene', '57680', (0, 4))	('malignant melanoma', 'Disease', 'MESH:D008545', (62, 80))	('malignant melanoma', 'Disease', (62, 80))	('c.2368C > T', 'Mutation', 'rs776528619', (5, 16))	('reported', 'Reg', (50, 58))	('p.R790C', 'Mutation', 'rs776528619', (18, 25))	('p.R790C', 'Var', (18, 25))
157248	29925043	CRISPLD1 c.1363C > T, p.R455* was in LCCL domain and has not been previously reported.	('p.R455*', 'Mutation', 'p.R455*', (22, 29))	('p.R455*', 'Var', (22, 29))	('CRISPLD1', 'Gene', '83690', (0, 8))	('CRISPLD1', 'Gene', (0, 8))	('c.1363C > T', 'Mutation', 'rs149361480', (9, 20))	('c.1363C > T', 'Var', (9, 20))
157249	29925043	Also, EPB41L4A c.1618C > T, p.R540C mutation has not been previously reported.	('EPB41L4A', 'Gene', '64097', (6, 14))	('p.R540C', 'Mutation', 'rs774150056', (28, 35))	('p.R540C', 'Var', (28, 35))	('c.1618C > T', 'Var', (15, 26))	('c.1618C > T', 'Mutation', 'rs774150056', (15, 26))	('EPB41L4A', 'Gene', (6, 14))
157251	29925043	GNA11 c.604C > T, p.R202W mutation located in G-alpha domain has not been previously reported.	('GNA11', 'Gene', (0, 5))	('c.604C > T', 'Mutation', 'c.604C>T', (6, 16))	('GNA11', 'Gene', '2767', (0, 5))	('p.R202W', 'Var', (18, 25))	('p.R202W', 'Mutation', 'p.R202W', (18, 25))
157253	29925043	NOTCH3 c.1194C > T, p.G398G mutation in EGF_CA domain has previously been reported in urothelial carcinoma of urinary bladder, hepatocellular carcinoma, and cutaneous malignant melanoma.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (127, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('NOTCH3', 'Gene', (0, 6))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('malignant melanoma', 'Phenotype', 'HP:0002861', (167, 185))	('c.1194C > T', 'Mutation', 'rs140368657', (7, 18))	('cutaneous malignant melanoma', 'Disease', (157, 185))	('reported', 'Reg', (74, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('hepatocellular carcinoma', 'Disease', (127, 151))	('p.G398G', 'SUBSTITUTION', 'None', (20, 27))	('urothelial carcinoma of urinary bladder', 'Disease', (86, 125))	('p.G398G', 'Var', (20, 27))	('EGF', 'molecular_function', 'GO:0005154', ('40', '43'))	('EGF_CA domain', 'Gene', (40, 53))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (157, 185))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (127, 151))	('cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (157, 185))	('NOTCH3', 'Gene', '4854', (0, 6))	('urothelial carcinoma of urinary bladder', 'Disease', 'MESH:D001749', (86, 125))
157255	29925043	PBRM1 c.49G > A, p.G17R mutation was previously reported in prostate adenocarcinoma.	('c.49G > A', 'Mutation', 'rs764436452', (6, 15))	('p.G17R', 'Mutation', 'rs764436452', (17, 23))	('PBRM1', 'Gene', (0, 5))	('reported', 'Reg', (48, 56))	('c.49G > A', 'Var', (6, 15))	('PBRM1', 'Gene', '55193', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('prostate adenocarcinoma', 'Disease', (60, 83))	('p.G17R', 'Var', (17, 23))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (60, 83))
157257	29925043	PTPRU c.1412G > A, p.R471H mutation was not previously reported.	('p.R471H', 'Mutation', 'rs35745442', (19, 26))	('p.R471H', 'Var', (19, 26))	('PTPRU', 'Gene', (0, 5))	('c.1412G > A', 'Mutation', 'rs35745442', (6, 17))	('PTPRU', 'Gene', '10076', (0, 5))	('c.1412G > A', 'Var', (6, 17))
157259	29925043	RGS12 c.4073C > T, p.P1358L mutation was in RGS12_usC domain and was not previously reported.	('RGS12', 'Gene', '6002', (44, 49))	('RGS12', 'Gene', '6002', (0, 5))	('p.P1358L', 'Mutation', 'rs140022951', (19, 27))	('c.4073C > T', 'Mutation', 'rs140022951', (6, 17))	('RGS', 'molecular_function', 'GO:0016299', ('44', '47'))	('p.P1358L', 'Var', (19, 27))	('RGS12', 'Gene', (44, 49))	('RGS', 'molecular_function', 'GO:0016299', ('0', '3'))	('RGS12', 'Gene', (0, 5))
157261	29925043	SETBP1 c.2572G > A, p.E858K mutation was previously reported in esophageal carcinoma, cutaneous malignant melanoma, esophagus-stomach cancer, and hematopoietic neoplasm.	('p.E858K', 'Var', (20, 27))	('cutaneous malignant melanoma', 'Disease', (86, 114))	('reported', 'Reg', (52, 60))	('c.2572G > A', 'Mutation', 'rs1178702025', (7, 18))	('hematopoietic neoplasm', 'Disease', 'MESH:D019337', (146, 168))	('stomach cancer', 'Phenotype', 'HP:0012126', (126, 140))	('p.E858K', 'Mutation', 'rs1178702025', (20, 27))	('esophagus-stomach cancer', 'Disease', (116, 140))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (64, 84))	('hematopoietic neoplasm', 'Phenotype', 'HP:0004377', (146, 168))	('malignant melanoma', 'Phenotype', 'HP:0002861', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (86, 114))	('SETBP1', 'Gene', '26040', (0, 6))	('hematopoietic neoplasm', 'Disease', (146, 168))	('SETBP1', 'Gene', (0, 6))	('neoplasm', 'Phenotype', 'HP:0002664', (160, 168))	('cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (86, 114))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (64, 84))	('esophagus-stomach cancer', 'Disease', 'MESH:D004938', (116, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('c.2572G > A', 'Var', (7, 18))	('esophageal carcinoma', 'Disease', (64, 84))
157263	29925043	SMARCA4 c.3067G > A, p.E1023K mutation was in SNF2_N domain and previously reported in colorectal adenocarcinoma and lung cancer.	('SMARCA4', 'Gene', (0, 7))	('c.3067G > A', 'Mutation', 'c.3067G>A', (8, 19))	('SMARCA4', 'Gene', '6597', (0, 7))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('colorectal adenocarcinoma and lung cancer', 'Disease', 'MESH:D015179', (87, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('c.3067G > A', 'Var', (8, 19))	('p.E1023K', 'Var', (21, 29))	('reported', 'Reg', (75, 83))	('p.E1023K', 'Mutation', 'p.E1023K', (21, 29))
157265	29925043	STMN1 c.235G > A, p.E79K was in Stathmin domain and has not been reported previously.	('STMN1', 'Gene', (0, 5))	('p.E79K', 'Mutation', 'p.E79K', (18, 24))	('p.E79K', 'Var', (18, 24))	('c.235G > A', 'Mutation', 'c.235G>A', (6, 16))	('STMN1', 'Gene', '3925', (0, 5))	('c.235G > A', 'Var', (6, 16))
157267	29925043	ZNRF3 c.1361G > A, p.R454H has not been previously reported.	('c.1361G > A', 'Var', (6, 17))	('p.R454H', 'Mutation', 'rs761341292', (19, 26))	('ZNRF3', 'Gene', '84133', (0, 5))	('ZNRF3', 'Gene', (0, 5))	('c.1361G > A', 'Mutation', 'rs1210755528', (6, 17))
157270	29925043	IWS1 c.2048A > G, p.N683S mutation was in Med26 domain and was not previously reported.	('c.2048A > G', 'Var', (5, 16))	('IWS1', 'Gene', '55677', (0, 4))	('IWS1', 'Gene', (0, 4))	('p.N683S', 'Var', (18, 25))	('c.2048A > G', 'Mutation', 'c.2048A>G', (5, 16))	('p.N683S', 'Mutation', 'p.N683S', (18, 25))
157272	29925043	TSC2 c.1372C > T, p.R458* was in DUF3384 domain and was previously reported in sporadic pulmonary lymphangioleiomyomatosis.	('TSC2', 'Gene', '7249', (0, 4))	('c.1372C > T', 'Var', (5, 16))	('TSC2', 'Gene', (0, 4))	('c.1372C > T', 'Mutation', 'rs45517169', (5, 16))	('lymphangioleiomyomatosis', 'Phenotype', 'HP:0012798', (98, 122))	('p.R458*', 'Var', (18, 25))	('pulmonary lymphangioleiomyomatosis', 'Phenotype', 'HP:0012798', (88, 122))	('sporadic pulmonary lymphangioleiomyomatosis', 'Disease', 'MESH:D018192', (79, 122))	('sporadic pulmonary lymphangioleiomyomatosis', 'Disease', (79, 122))	('p.R458*', 'Mutation', 'p.R458*', (18, 25))
157280	29925043	The NOTCH3 mRNA expression with our mutation was 26 percentile in hepatocellular carcinoma and 56 percentile in melanoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (66, 90))	('hepatocellular carcinoma', 'Disease', (66, 90))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (66, 90))	('NOTCH3', 'Gene', (4, 10))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('NOTCH3', 'Gene', '4854', (4, 10))	('melanoma', 'Disease', (112, 120))	('mutation', 'Var', (36, 44))
157282	29925043	The SETBP1 mRNA expression with our mutation was 60 percentile in esophageal carcinoma and 97 percentile in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('melanoma', 'Disease', (108, 116))	('SETBP1', 'Gene', (4, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('mRNA expression', 'MPA', (11, 26))	('esophageal carcinoma', 'Disease', (66, 86))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (66, 86))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (66, 86))	('SETBP1', 'Gene', '26040', (4, 10))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('mutation', 'Var', (36, 44))
157313	27779101	For example, phosphatase and tensin homologue deletion on chromosome 10 (PTEN) is one of the most frequently mutated human tumor suppressor genes.	('deletion', 'Var', (46, 54))	('tumor', 'Disease', (123, 128))	('human', 'Species', '9606', (117, 122))	('tumor suppressor', 'biological_process', 'GO:0051726', ('123', '139'))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('phosphatase', 'molecular_function', 'GO:0016791', ('13', '24'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('123', '139'))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('chromosome', 'cellular_component', 'GO:0005694', ('58', '68'))
157316	27779101	In recent years, many studies have shown that PTEN often has an abnormal frequency of deletions, genetic mutations or methylation in a variety of cancers, such as prostate cancer and renal cell carcinoma.	('cancers', 'Disease', (146, 153))	('prostate cancer', 'Disease', (163, 178))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (183, 203))	('PTEN', 'Gene', (46, 50))	('prostate cancer', 'Disease', 'MESH:D011471', (163, 178))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (183, 203))	('methylation', 'biological_process', 'GO:0032259', ('118', '129'))	('prostate cancer', 'Phenotype', 'HP:0012125', (163, 178))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('deletions', 'Var', (86, 95))	('methylation', 'Var', (118, 129))	('genetic mutations', 'Var', (97, 114))	('renal cell carcinoma', 'Disease', (183, 203))
157318	27779101	Loss of PTEN can also result in abnormal activation of the Phosphatidyl Inositol 3-kinase/Protein Kinase B (PI3K/Akt) pathway, which regulates proliferation, apoptosis, survival, translation, differentiation and cellular metabolism.	('apoptosis', 'biological_process', 'GO:0006915', ('158', '167'))	('survival', 'CPA', (169, 177))	('Protein Kinase B', 'Gene', (90, 106))	('regulates', 'Reg', (133, 142))	('Akt', 'Gene', '207', (113, 116))	('PI3K', 'molecular_function', 'GO:0016303', ('108', '112'))	('PTEN', 'Gene', (8, 12))	('Protein Kinase B', 'Gene', '2185', (90, 106))	('apoptosis', 'CPA', (158, 167))	('Akt', 'Gene', (113, 116))	('cellular metabolism', 'biological_process', 'GO:0044237', ('212', '231'))	('translation', 'biological_process', 'GO:0006412', ('179', '190'))	('activation', 'PosReg', (41, 51))	('apoptosis', 'biological_process', 'GO:0097194', ('158', '167'))	('differentiation', 'CPA', (192, 207))	('Loss', 'Var', (0, 4))	('proliferation', 'CPA', (143, 156))
157373	27779101	identified a 4-microRNA (miR-10b, miR-139-5p, miR-130b and miR-199b-5p) signature and it was validated to be associated with ccRCC metastasis and prognosis.	('miR-10b', 'Gene', '406903', (25, 32))	('miR-130b', 'Gene', '406920', (46, 54))	('miR-139-5p', 'Var', (34, 44))	('miR-199b-5p', 'Var', (59, 70))	('miR-130b', 'Gene', (46, 54))	('miR-10b', 'Gene', (25, 32))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('associated with', 'Reg', (109, 124))	('RCC', 'Disease', (127, 130))
157445	30564062	Candidate hub genes were mapped to DEGs in GSE15641 to find the real hub genes.	('DEGs', 'Var', (35, 39))	('GS', 'Disease', 'MESH:D011125', (43, 45))	('hub', 'Gene', '1993', (10, 13))	('hub', 'Gene', '1993', (69, 72))	('hub', 'Gene', (10, 13))	('hub', 'Gene', (69, 72))
157455	30564062	All these results implied that dysfunctional mitotic cell cycle may contribute to tumorigeneses of ChRCC.	('mitotic cell cycle', 'biological_process', 'GO:0000278', ('45', '63'))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Disease', (101, 104))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('mitotic cell cycle', 'CPA', (45, 63))	('contribute', 'Reg', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('dysfunctional', 'Var', (31, 44))	('tumor', 'Disease', (82, 87))
157470	30564062	GO and KEGG analysis showed that dysregulation of cell cycle may be the underlying mechanism of tumorigeneses of ChRCC.	('dysregulation', 'Var', (33, 46))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('tumor', 'Disease', (96, 101))	('cell cycle', 'biological_process', 'GO:0007049', ('50', '60'))	('cell cycle', 'CPA', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
157480	30564062	Downregulation of ERCC6L decreased cell viability in RCC cell lines by blocking mitogen-activated protein kinase (MAPK) signaling pathway and interactions with protein PLK1.	('cell viability', 'CPA', (35, 49))	('RCC', 'Disease', (53, 56))	('ERCC6L', 'Gene', '54821', (18, 24))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('MAPK) signaling', 'biological_process', 'GO:0000165', ('114', '129'))	('decreased', 'NegReg', (25, 34))	('Downregulation', 'Var', (0, 14))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('MAPK', 'molecular_function', 'GO:0004707', ('114', '118'))	('PLK1', 'Gene', (168, 172))	('signaling pathway', 'biological_process', 'GO:0007165', ('120', '137'))	('protein', 'cellular_component', 'GO:0003675', ('160', '167'))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('interactions', 'Interaction', (142, 154))	('ERCC6L', 'Gene', (18, 24))	('blocking', 'NegReg', (71, 79))	('PLK1', 'Gene', '5347', (168, 172))
157484	30564062	Silencing GTSE-1 expression inhibits proliferation and invasion of hepatocellular carcinoma cells.	('inhibits', 'NegReg', (28, 36))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (67, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('hepatocellular carcinoma', 'Disease', (67, 91))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (67, 91))	('GTSE-1', 'Gene', (10, 16))	('invasion', 'CPA', (55, 63))	('GTSE-1', 'Gene', '51512', (10, 16))	('Silencing', 'Var', (0, 9))
157506	29530001	During embryonic development, RPs are expressed at different levels across tissue types, and loss of RPs due to mutation or targeted knockdown produces specific developmental abnormalities in plants, invertebrates, and vertebrates.	('RPs', 'Gene', (101, 104))	('mutation', 'Var', (112, 120))	('loss', 'NegReg', (93, 97))	('developmental abnormalities', 'Disease', (161, 188))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (161, 188))	('developmental abnormalities', 'Disease', 'MESH:D006130', (161, 188))
157511	29530001	Indeed, an entire class of diseases has been shown to be associated with haploinsufficient expression or mutation in individual RPs.	('mutation', 'Var', (105, 113))	('associated', 'Reg', (57, 67))	('haploinsufficient', 'Disease', 'MESH:D058495', (73, 90))	('haploinsufficient', 'Disease', (73, 90))	('RPs', 'Gene', (128, 131))
157515	29530001	The developmental abnormalities of the ribosomopathies are variable and associate with specific RP loss or mutation.	('developmental abnormalities of the ribosomopathies', 'Disease', 'MESH:D006130', (4, 54))	('RP loss', 'Disease', (96, 103))	('developmental abnormalities of the ribosomopathies', 'Disease', (4, 54))	('RP loss', 'Disease', 'MESH:C538365', (96, 103))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (4, 31))	('mutation', 'Var', (107, 115))
157518	29530001	We have recently shown that RP transcripts (RPTs) were dysregulated in two murine models of hepatoblastoma and hepatocellular carcinoma (HCC) in a tumor-specific manner and in patterns unrelated to tumor growth rates.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('dysregulated', 'Var', (55, 67))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (111, 135))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('murine', 'Species', '10090', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('hepatoblastoma and hepatocellular carcinoma', 'Disease', 'MESH:D018197', (92, 135))	('HCC', 'Phenotype', 'HP:0001402', (137, 140))	('tumor', 'Disease', (198, 203))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (92, 106))
157520	29530001	Perturbations of several individual RPs have been found in numerous human cancers, including those of the breast, pancreas, bladder, brain and many other tissues.	('bladder', 'Disease', (124, 131))	('breast', 'Disease', (106, 112))	('numerous human cancers', 'Disease', 'MESH:D009369', (59, 81))	('brain', 'Disease', (133, 138))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('found', 'Reg', (50, 55))	('RPs', 'Protein', (36, 39))	('pancreas', 'Disease', (114, 122))	('numerous human cancers', 'Disease', (59, 81))	('Perturbations', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
157521	29530001	Mutations and deletions of RP-encoding genes have also been found in endometrial cancer, colorectal cancer, glioma, and various hematopoietic malignancies.	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('endometrial cancer', 'Disease', (69, 87))	('glioma', 'Disease', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Disease', (89, 106))	('hematopoietic malignancies', 'Disease', (128, 154))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('endometrial cancer', 'Phenotype', 'HP:0012114', (69, 87))	('RP-encoding genes', 'Gene', (27, 44))	('Mutations', 'Var', (0, 9))	('deletions', 'Var', (14, 23))	('found', 'Reg', (60, 65))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('endometrial cancer', 'Disease', 'MESH:D016889', (69, 87))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (128, 154))
157522	29530001	5q- abnormality associated with myelodysplastic syndrome and the accompanying haploinsufficiency of RPS14 is considered one of the prototype "acquired" ribosomopathies that are often classified together with DBA, SDS and other inherited ribosomopathies.	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (32, 56))	('haploinsufficiency', 'Disease', 'MESH:D058495', (78, 96))	('SDS', 'Disease', 'MESH:D000081003', (213, 216))	('RPS14', 'Gene', (100, 105))	('myelodysplastic syndrome', 'Disease', (32, 56))	('haploinsufficiency', 'Disease', (78, 96))	('SDS', 'Disease', (213, 216))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (32, 56))	('inherited ribosomopathies', 'Disease', 'MESH:D030342', (227, 252))	('RPS14', 'Gene', '6208', (100, 105))	('inherited ribosomopathies', 'Disease', (227, 252))	('associated', 'Reg', (16, 26))	('5q- abnormality', 'Var', (0, 15))
157543	29530001	When comparing relative expression of other RPTs between these clusters and other tumors from the same cohorts, all five clusters with high RPL8 and RPL30 also displayed, on average, lower relative expression of RPL10 and higher relative expression of RPL7.	('high', 'Var', (135, 139))	('RPL7', 'Gene', '6129', (252, 256))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('RPL10', 'Gene', '6134', (212, 217))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('higher', 'PosReg', (222, 228))	('RPL7', 'Gene', (252, 256))	('RPL10', 'Gene', (212, 217))	('RPL8', 'Gene', '6132', (140, 144))	('RPL8', 'Gene', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('RPL30', 'Gene', '6156', (149, 154))	('lower', 'NegReg', (183, 188))	('expression', 'MPA', (198, 208))	('expression', 'MPA', (238, 248))	('RPL30', 'Gene', (149, 154))
157545	29530001	The frequency of amplifications and deletions in RP genes were compared between clusters of tumors in each TCGA cohort using chi-squared tests and adjusted for 5% false discovery rate.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('deletions', 'Var', (36, 45))	('false', 'biological_process', 'GO:0071878', ('163', '168'))	('RP genes', 'Gene', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (92, 98))	('false', 'biological_process', 'GO:0071877', ('163', '168'))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
157560	29530001	The first contained 143 tumors from 15 cohorts, 98% of which had amplification and relative up-regulation of RPL19, RPL23, and ERBB2 (Her2/Neu).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('Her2/Neu', 'Gene', (134, 142))	('RPL23', 'Gene', (116, 121))	('regulation', 'biological_process', 'GO:0065007', ('95', '105'))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('RPL23', 'Gene', '9349', (116, 121))	('up-regulation', 'PosReg', (92, 105))	('ERBB2', 'Gene', (127, 132))	('RPL19', 'Gene', '6143', (109, 114))	('ERBB2', 'Gene', '2064', (127, 132))	('Her2/Neu', 'Gene', '2064', (134, 142))	('amplification', 'Var', (65, 78))	('RPL19', 'Gene', (109, 114))
157577	29530001	Excluding thyroid cancers, all other tumor clusters with low RPL3 also shared 11 other similarly co-regulated RPTs.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('thyroid cancers', 'Disease', (10, 25))	('RPL3', 'Gene', (61, 65))	('thyroid cancers', 'Disease', 'MESH:D013964', (10, 25))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('low', 'Var', (57, 60))	('tumor', 'Disease', (37, 42))	('RPL3', 'Gene', '6122', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))
157584	29530001	For example, 48% of tumors in kidney clear cell carcinoma Cluster 3 possessed deletions of RPL12, RPL35, and RPL7A on 9q33-34.	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('RPL7A', 'Gene', (109, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('RPL35', 'Gene', (98, 103))	('tumors in kidney clear cell carcinoma Cluster', 'Disease', (20, 65))	('RPL12', 'Gene', (91, 96))	('RPL35', 'Gene', '11224', (98, 103))	('RPL12', 'Gene', '6136', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('RPL7A', 'Gene', '6130', (109, 114))	('deletions', 'Var', (78, 87))	('tumors in kidney clear cell carcinoma Cluster', 'Disease', 'MESH:C538614', (20, 65))
157585	29530001	Similarly, half of brain cancers in Cluster 1 possessed a 1p/19q13 co-deletion, compared to nearly 100% of tumors in Cluster 5 with this deletion (Table 2).	('brain cancer', 'Phenotype', 'HP:0030692', (19, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('brain cancers', 'Disease', (19, 32))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('brain cancers', 'Disease', 'MESH:D001932', (19, 32))	('1p/19q13 co-deletion', 'Var', (58, 78))
157604	29530001	In addition to their tissue-specific patterning, virtually all tumors showed perturbations of RPT expression that readily allowed them to be distinguished from the normal tissues from which they originated.	('perturbations', 'Var', (77, 90))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Disease', (63, 69))	('RPT', 'Gene', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('expression', 'MPA', (98, 108))
157608	29530001	Aside from potentially altering translation, the notion that altered RP expression might influence the behaviors of both normal tissues and tumors is not new.	('tumors', 'Disease', (140, 146))	('behaviors of', 'CPA', (103, 115))	('altered', 'Var', (61, 68))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('translation', 'MPA', (32, 43))	('influence', 'Reg', (89, 98))	('RP expression', 'Protein', (69, 82))	('translation', 'biological_process', 'GO:0006412', ('32', '43'))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('altering', 'Reg', (23, 31))
157610	29530001	It has been proposed that subsequent circumvention of this TP53-mediated senescence by mutation and/or dysregulation of the p19ARF/MDM2/TP53 pathway is responsible for the propensity for eventual neoplastic progression [.	('TP53', 'Gene', '7157', (59, 63))	('p19ARF', 'Gene', '1029', (124, 130))	('TP53', 'Gene', (59, 63))	('p19ARF', 'Gene', (124, 130))	('TP53', 'Gene', '7157', (136, 140))	('senescence', 'biological_process', 'GO:0010149', ('73', '83'))	('neoplastic progression [', 'CPA', (196, 220))	('dysregulation', 'Var', (103, 116))	('p19', 'cellular_component', 'GO:0070743', ('124', '127'))	('mutation', 'Var', (87, 95))	('TP53', 'Gene', (136, 140))
157627	29530001	As with RPL3, deregulated RPS4X has been previously associated with various tumors and tumor phenotypes, including subgroups of colorectal carcinoma, a myelodysplasia risk signature and poor prognosis in bladder cancer.	('RPS4X', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('RPL3', 'Gene', '6122', (8, 12))	('tumor', 'Disease', (76, 81))	('myelodysplasia', 'Phenotype', 'HP:0002863', (152, 166))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('myelodysplasia', 'Disease', 'MESH:D009190', (152, 166))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('bladder cancer', 'Disease', 'MESH:D001749', (204, 218))	('bladder cancer', 'Disease', (204, 218))	('RPS4X', 'Gene', '6191', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (87, 92))	('associated', 'Reg', (52, 62))	('tumors', 'Disease', (76, 82))	('bladder cancer', 'Phenotype', 'HP:0009725', (204, 218))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('RPL3', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('colorectal carcinoma', 'Disease', (128, 148))	('myelodysplasia', 'Disease', (152, 166))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (128, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('deregulated', 'Var', (14, 25))
157628	29530001	Interestingly, some of our tumor clusters with altered RPS4X expression were comprised of a greater proportion of females than males (Table 1 and Table 3), perhaps reflecting RPS4X's residence on the X chromosome.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('RPS4X', 'Gene', '6191', (175, 180))	('X chromosome', 'cellular_component', 'GO:0000805', ('200', '212'))	('RPS4X', 'Gene', (175, 180))	('RPS4X', 'Gene', '6191', (55, 60))	('RPS4X', 'Gene', (55, 60))	('expression', 'MPA', (61, 71))	('altered', 'Var', (47, 54))
157634	29530001	In contrast, kidney clear cell carcinomas with high RPL13 expression tended to be of higher pathologic grade and were associated with significantly poorer survival (Tables 1 and 3, and Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('kidney clear cell carcinomas', 'Disease', (13, 41))	('high', 'Var', (47, 51))	('kidney clear cell carcinomas', 'Disease', 'MESH:C538614', (13, 41))	('RPL13', 'Gene', (52, 57))	('RPL13', 'Gene', '6137', (52, 57))	('poorer', 'NegReg', (148, 154))	('survival', 'MPA', (155, 163))
157637	29530001	Virtually all tumors with this expression pattern possessed co-amplification of a region on 8q22-24 that includes RPL8, RPL30, and the oncogenes MYC and PVT1.	('RPL8', 'Gene', (114, 118))	('PVT1', 'Gene', '5820', (153, 157))	('MYC', 'Gene', (145, 148))	('co-amplification', 'Var', (60, 76))	('RPL30', 'Gene', '6156', (120, 125))	('RPL30', 'Gene', (120, 125))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('MYC', 'Gene', '4609', (145, 148))	('PVT1', 'Gene', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('RPL8', 'Gene', '6132', (114, 118))
157638	29530001	Amplification of this region has been previously described in breast cancers and correlates with chemoresistance and metastasis.	('chemoresistance', 'CPA', (97, 112))	('Amplification', 'Var', (0, 13))	('described', 'Reg', (49, 58))	('breast cancers', 'Phenotype', 'HP:0003002', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancers', 'Disease', 'MESH:D001943', (62, 76))	('breast cancers', 'Disease', (62, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('metastasis', 'CPA', (117, 127))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('correlates', 'Reg', (81, 91))
157643	29530001	Amplification of a region on 11q13 that contains RPS3, occurring in a cluster of breast cancers and HCCs, has been previously described in both cancers and is thought to confer unfavorable prognosis due to amplification of the adjacent oncogene EMS1.	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cluster of breast cancers', 'Disease', (70, 95))	('HCCs', 'Disease', (100, 104))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('HCC', 'Phenotype', 'HP:0001402', (100, 103))	('EMS1', 'Gene', '2017', (245, 249))	('RPS3', 'Gene', '6188', (49, 53))	('breast cancers', 'Phenotype', 'HP:0003002', (81, 95))	('RPS3', 'Gene', (49, 53))	('Amplification', 'Var', (0, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('EMS1', 'Gene', (245, 249))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cluster of breast cancers', 'Disease', 'MESH:D001943', (70, 95))	('amplification', 'Var', (206, 219))	('described', 'Reg', (126, 135))
157644	29530001	The co-deletion of 19q13 along with 1p, which together includes 12 RP genes, has been described in low-grade gliomas and confers a favorable prognosis.	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('co-deletion', 'Var', (4, 15))	('described', 'Reg', (86, 95))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('gliomas', 'Disease', (109, 116))	('19q13', 'Gene', (19, 24))
157650	29530001	Although the means by which altered RPT patterns influence the pathogenesis and/or behavior of tumors remain incompletely understood, several non-mutually exclusive mechanisms can be envisioned.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('altered', 'Var', (28, 35))	('pathogenesis', 'biological_process', 'GO:0009405', ('63', '75'))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('RPT', 'Protein', (36, 39))	('influence', 'Reg', (49, 58))	('tumors', 'Disease', (95, 101))
157654	29530001	In addition to their stabilization of TP53 mediated by binding to and inactivating MDM2, specific RPs have been shown to inactivate Myc; to inhibit the Myc target Lin28B; to activate NF-kappaB, cyclins, and cyclin-dependent kinases and to regulate a variety of other tumorigenic functions and immunogenic pathways.	('cyclin-dependent', 'Enzyme', (207, 223))	('TP53', 'Gene', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('Lin28B', 'Gene', '389421', (163, 169))	('MDM2', 'Gene', (83, 87))	('RPs', 'Var', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('Myc', 'Gene', '4609', (152, 155))	('inactivate', 'NegReg', (121, 131))	('binding', 'molecular_function', 'GO:0005488', ('55', '62'))	('Myc', 'Gene', (132, 135))	('inactivating', 'NegReg', (70, 82))	('TP53', 'Gene', '7157', (38, 42))	('cyclin', 'molecular_function', 'GO:0016538', ('207', '213'))	('cyclins', 'Enzyme', (194, 201))	('inhibit', 'NegReg', (140, 147))	('Lin28B', 'Gene', (163, 169))	('activate', 'PosReg', (174, 182))	('regulate', 'Reg', (239, 247))	('Myc', 'Gene', '4609', (132, 135))	('binding', 'Interaction', (55, 62))	('NF-kappaB', 'Pathway', (183, 192))	('immunogenic', 'CPA', (293, 304))	('tumor', 'Disease', (267, 272))	('Myc', 'Gene', (152, 155))
157659	29530001	As this is a cross-sectional study, we also recognize that causality cannot be inferred, and it remains unknown whether altered RPT expression is an early or late event in tumorigenesis despite its predictive value.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('RPT', 'Gene', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('altered', 'Var', (120, 127))
157661	29530001	Finally, additional molecular analyses of the identified t-SNE clusters with whole-transcriptome sequencing data, pathway analysis, whole-genome DNA mutation data, and DNA methylation patterning may offer additional insights into the biological mechanisms that link altered RPT expression with tumor phenotypes.	('RPT', 'Gene', (274, 277))	('tumor', 'Disease', (294, 299))	('DNA', 'cellular_component', 'GO:0005574', ('145', '148'))	('expression', 'MPA', (278, 288))	('DNA methylation', 'biological_process', 'GO:0006306', ('168', '183'))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('altered', 'Var', (266, 273))	('DNA', 'cellular_component', 'GO:0005574', ('168', '171'))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))
157697	33614703	In terms of the described effects of CKAP4 on the architecture of the ER and microtubule networks, there are predicted phosphorylation sites of serine 3, 17, and 19 on CKAP4 (Figure 1), which have shown negatively regulated microtubule and induced collapse of the ER around the nucleus.	('ER', 'Gene', '2069', (264, 266))	('collapse', 'MPA', (248, 256))	('microtubule', 'cellular_component', 'GO:0005874', ('224', '235'))	('serine', 'Chemical', 'MESH:D012694', (144, 150))	('CKAP4', 'Var', (168, 173))	('phosphorylation', 'biological_process', 'GO:0016310', ('119', '134'))	('microtubule', 'cellular_component', 'GO:0005874', ('77', '88'))	('nucleus', 'cellular_component', 'GO:0005634', ('278', '285'))	('regulated microtubule', 'MPA', (214, 235))	('ER', 'Gene', '2069', (70, 72))	('negatively', 'NegReg', (203, 213))
157703	33614703	Palmitoyl acyltransferase DHHC2, which is a putative tumor suppressor, modifies Cys100 of CKAP4 and contributes to the localization of CKAP4 on the plasma membrane.	('tumor suppressor', 'biological_process', 'GO:0051726', ('53', '69'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('53', '69'))	('Cys100', 'Chemical', '-', (80, 86))	('DHHC2', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('plasma membrane', 'cellular_component', 'GO:0005886', ('148', '163'))	('localization', 'MPA', (119, 131))	('modifies', 'Var', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('contributes', 'Reg', (100, 111))	('localization', 'biological_process', 'GO:0051179', ('119', '131'))	('tumor', 'Disease', (53, 58))	('Cys100', 'MPA', (80, 86))	('DHHC2', 'Gene', '51201', (26, 31))	('CKAP4', 'Gene', (90, 95))
157704	33614703	In the extracellular region, CKAP4 contains three coiled-coil regions, two shorter regions (AA 130-214 and AA 533-602) and one longer one (AA 256-460), and a leucine zipper (LZ) domain (AA 468-503) (Figure 1).	('leucine', 'Chemical', 'MESH:D007930', (158, 165))	('CKAP4', 'Gene', (29, 34))	('extracellular region', 'cellular_component', 'GO:0005576', ('7', '27'))	('AA 533-602', 'Var', (107, 117))	('coiled-coil regions', 'MPA', (50, 69))	('AA 130-214', 'Var', (92, 102))
157719	33614703	Transfection of the mutant's COS-1 cells led to an increase in tPA-catalyzed plasminogen activation, which confirmed the role of cell surface CKAP4 in tPA binding.	('increase', 'PosReg', (51, 59))	('tPA', 'Gene', (63, 66))	('mutant', 'Var', (20, 26))	('tPA', 'Gene', '100128998', (63, 66))	('binding', 'molecular_function', 'GO:0005488', ('155', '162'))	('plasminogen activation', 'biological_process', 'GO:0031639', ('77', '99'))	('cell surface', 'cellular_component', 'GO:0009986', ('129', '141'))	('tPA', 'molecular_function', 'GO:0031299', ('63', '66'))	('tPA', 'Gene', (151, 154))	('tPA', 'molecular_function', 'GO:0031299', ('151', '154'))	('tPA', 'Gene', '100128998', (151, 154))	('COS-1', 'CellLine', 'CVCL:0223', (29, 34))
157745	33614703	CKAP4 knockdown or CRD-1 deletion mutants of DKKs inhibited MDCK cellular proliferation (14).	('MDCK cellular proliferation', 'CPA', (60, 87))	('MDCK', 'CellLine', 'CVCL:0422', (60, 64))	('inhibited', 'NegReg', (50, 59))	('deletion mutants', 'Var', (25, 41))	('CRD-1', 'Gene', '1319', (19, 24))	('CRD-1', 'Gene', (19, 24))	('DKK', 'Gene', '22943', (45, 48))	('DKK', 'Gene', (45, 48))
157752	33614703	Following CKAP4 knockdown, the inhibition effect of APF on T24 cell proliferation was eliminated, indicating the important role of the receptor in mediating the antiproliferation activity of APF in bladder cancer cells.	('APF', 'Chemical', '-', (191, 194))	('bladder cancer', 'Disease', 'MESH:D001749', (198, 212))	('T24 cell proliferation', 'CPA', (59, 81))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))	('bladder cancer', 'Disease', (198, 212))	('knockdown', 'Var', (16, 25))	('eliminated', 'NegReg', (86, 96))	('CKAP4', 'Gene', (10, 15))	('bladder cancer', 'Phenotype', 'HP:0009725', (198, 212))	('APF', 'Chemical', '-', (52, 55))
157756	33614703	When CKAP4 was reduced with siRNA or anti-CKAP4 antibody, the upregulation of CCN2 during APF treatment was inhibited.	('antibody', 'molecular_function', 'GO:0003823', ('48', '56'))	('CCN2', 'Gene', '1490', (78, 82))	('CCN2', 'Gene', (78, 82))	('antibody', 'cellular_component', 'GO:0042571', ('48', '56'))	('reduced', 'NegReg', (15, 22))	('APF', 'Chemical', '-', (90, 93))	('anti-CKAP4 antibody', 'Var', (37, 56))	('antibody', 'cellular_component', 'GO:0019814', ('48', '56'))	('antibody', 'cellular_component', 'GO:0019815', ('48', '56'))	('anti-CKAP4', 'Gene', (37, 47))	('inhibited', 'NegReg', (108, 117))
157762	33614703	Further research demonstrated that CKAP4 phosphorylation of N-terminal serine residues (S3, S17, and S19) is necessary for translocation from the plasma membrane to the nucleus in Hela cell (Figure 2).	('S19', 'Var', (101, 104))	('phosphorylation', 'biological_process', 'GO:0016310', ('41', '56'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('146', '161'))	('translocation', 'MPA', (123, 136))	('S17', 'Gene', '6218', (92, 95))	('S3', 'Var', (88, 90))	('nucleus', 'cellular_component', 'GO:0005634', ('169', '176'))	('Hela cell', 'CellLine', 'CVCL:0030', (180, 189))	('serine', 'Chemical', 'MESH:D012694', (71, 77))	('S17', 'Gene', (92, 95))
157764	33614703	CKAP4 of palmitoylation site mutant (C100S) or phosphorylation site mutant does not cause relocalization and has APF-like activity inhibiting cell proliferation.	('APF', 'Chemical', '-', (113, 116))	('APF-like activity', 'MPA', (113, 130))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('cell proliferation', 'biological_process', 'GO:0008283', ('142', '160'))	('cell proliferation', 'CPA', (142, 160))	('inhibiting', 'NegReg', (131, 141))	('C100S', 'Mutation', 'p.C100S', (37, 42))	('C100S', 'Var', (37, 42))
157765	33614703	It suggests that the mutation of CKAP4 could be used to treat excessive proliferation diseases such as tumor.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('CKAP4', 'Gene', (33, 38))	('proliferation diseases', 'Disease', (72, 94))	('tumor', 'Disease', (103, 108))	('proliferation diseases', 'Disease', 'MESH:C565054', (72, 94))	('mutation', 'Var', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
157767	33614703	Moreover, high expression of CKAP4 inhibited the growth of xenograft tumor and the metastatic potential of HCC in nude mice.	('HCC', 'Phenotype', 'HP:0001402', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CKAP4', 'Gene', (29, 34))	('tumor', 'Disease', (69, 74))	('nude mice', 'Species', '10090', (114, 123))	('metastatic potential of HCC', 'CPA', (83, 110))	('high expression', 'Var', (10, 25))	('inhibited', 'NegReg', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
157776	33614703	Furthermore, in vivo experiments also showed that the low CKAP4 expression cells formed much smaller xenograft tumors than the control group.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('low', 'Var', (54, 57))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('smaller', 'NegReg', (93, 100))	('CKAP4', 'Gene', (58, 63))
157778	33614703	It is worth noting that knockdown of CKAP4 did not influence cell proliferation in cells with insufficient DKK1 and/or DKK3.	('CKAP4', 'Gene', (37, 42))	('cell proliferation', 'biological_process', 'GO:0008283', ('61', '79'))	('DKK1', 'Var', (107, 111))	('DKK3', 'Gene', '27122', (119, 123))	('knockdown', 'Var', (24, 33))	('DKK3', 'Gene', (119, 123))	('cell proliferation', 'CPA', (61, 79))
157786	33614703	It was noted that CKAP4 was not directly involved in alpha5beta1 integrin endocytosis but inhibited its recycling.	('beta1 integrin', 'Gene', '3688', (59, 73))	('endocytosis', 'biological_process', 'GO:0006897', ('74', '85'))	('beta1 integrin', 'Gene', (59, 73))	('CKAP4', 'Var', (18, 23))	('inhibited', 'NegReg', (90, 99))	('recycling', 'MPA', (104, 113))
157802	33614703	Prognosis was favorable in patients with high CKAP4 or high DHHC2 expression compared with those with low CKAP4 or low DHHC2 expression.	('DHHC2', 'Gene', '51201', (119, 124))	('DHHC2', 'Gene', (60, 65))	('high CKAP4', 'Var', (41, 51))	('DHHC2', 'Gene', (119, 124))	('expression', 'MPA', (66, 76))	('patients', 'Species', '9606', (27, 35))	('high', 'Var', (55, 59))	('DHHC2', 'Gene', '51201', (60, 65))
157807	33614703	Prognostic values of CKAP4 expression showed that the high-CKAP4 patients had a much longer overall survival and lower recurrence rate than the low-CKAP4 patients, and CKAP4 is an independent predictor for overall survival in ICC patients.	('longer', 'PosReg', (85, 91))	('lower', 'NegReg', (113, 118))	('recurrence rate', 'CPA', (119, 134))	('patients', 'Species', '9606', (154, 162))	('patients', 'Species', '9606', (230, 238))	('IC', 'Disease', 'MESH:C566126', (226, 228))	('patients', 'Species', '9606', (65, 73))	('overall survival', 'CPA', (92, 108))	('high-CKAP4', 'Var', (54, 64))
157812	33614703	The positive rates of CKAP4 and DKK1in lung adenocarcinoma were 74.6 and 79.1%, respectively, and in squamous cell carcinoma were 74.6 and 73.8%, respectively (Table 2).	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('CKAP4', 'Var', (22, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (39, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('DKK1in', 'Var', (32, 38))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (101, 124))	('squamous cell carcinoma', 'Disease', (101, 124))	('lung adenocarcinoma', 'Disease', (39, 58))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (39, 58))
157813	33614703	Patients positive for both CKAP4 and DKK1 showed a more shorter relapse-free survival than patients positive for either CKAP4 or DKK1 or negative for both (Table 2).	('DKK1', 'Var', (37, 41))	('patients', 'Species', '9606', (91, 99))	('relapse-free survival', 'CPA', (64, 85))	('CKAP4', 'Var', (27, 32))	('shorter', 'NegReg', (56, 63))	('Patients', 'Species', '9606', (0, 8))
157818	33614703	analyzed 119 cases and 72 cases of esophageal squamous cell carcinoma (ESCC) and showed that expression of CKAP4, along with DKK1 and/or DKK3, in ESCC was associated with poor prognosis (Table 2).	('DKK3', 'Gene', (137, 141))	('expression', 'Var', (93, 103))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (35, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('associated', 'Reg', (155, 165))	('esophageal squamous cell carcinoma', 'Disease', (35, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('CKAP4', 'Gene', (107, 112))	('DKK3', 'Gene', '27122', (137, 141))
157825	33614703	Patients positive for both CKAP4 and ligands (DKK1 and/or DKK3) showed unfavorable prognosis and shortened relapse-free survival than do patients positive for either CKAP4 or DKK1/DKK3 or negative for CKAP4 and DKK1/DKK3 (Table 2).	('relapse-free survival', 'CPA', (107, 128))	('DKK3', 'Gene', (216, 220))	('DKK3', 'Gene', '27122', (58, 62))	('DKK3', 'Gene', (58, 62))	('CKAP4', 'Var', (27, 32))	('patients', 'Species', '9606', (137, 145))	('Patients', 'Species', '9606', (0, 8))	('shortened', 'NegReg', (97, 106))	('DKK3', 'Gene', '27122', (180, 184))	('DKK3', 'Gene', (180, 184))	('DKK3', 'Gene', '27122', (216, 220))	('DKK1', 'Var', (46, 50))
157828	33614703	However, patients with high CKAP4 protein levels had unfavorable overall survival and relapse-free survival, and overexpression of CKAP4 was significantly associated with TNM stages and Fuhrman grades (Table 2).	('patients', 'Species', '9606', (9, 17))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('relapse-free survival', 'CPA', (86, 107))	('high', 'Var', (23, 27))	('overall survival', 'CPA', (65, 81))	('overexpression', 'PosReg', (113, 127))	('associated', 'Reg', (155, 165))	('TNM', 'Gene', (171, 174))	('CKAP4 protein', 'Protein', (28, 41))	('Fuhrman', 'Disease', (186, 193))	('CKAP4', 'Gene', (131, 136))	('TNM', 'Gene', '10178', (171, 174))
157832	33614703	In the cells with high CKAP4 but with little ligands, DKKs, CKAP4 did not affect cellular proliferation.	('DKK', 'Gene', '22943', (54, 57))	('DKK', 'Gene', (54, 57))	('high CKAP4', 'Var', (18, 28))	('CKAP4', 'Var', (23, 28))
157833	33614703	On the other hand, patients positive for both CKAP4 and DKKs show unfavorable prognosis and shorter relapse-free survival in pancreatic, lung, and esophageal tumors.	('DKK', 'Gene', '22943', (56, 59))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('pancreatic', 'Disease', (125, 135))	('relapse-free survival', 'CPA', (100, 121))	('patients', 'Species', '9606', (19, 27))	('esophageal tumors', 'Disease', 'MESH:D004938', (147, 164))	('DKK', 'Gene', (56, 59))	('esophageal tumors', 'Disease', (147, 164))	('esophageal tumors', 'Phenotype', 'HP:0100751', (147, 164))	('CKAP4', 'Var', (46, 51))	('pancreatic', 'Disease', 'MESH:D010195', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('shorter', 'NegReg', (92, 99))	('lung', 'Disease', (137, 141))
157834	33614703	However, high expression of CKAP4 showed a favorable overall survival and longer disease-free survival in HCC and ICC.	('high expression', 'Var', (9, 24))	('HCC', 'Disease', (106, 109))	('CKAP4', 'Gene', (28, 33))	('HCC', 'Phenotype', 'HP:0001402', (106, 109))	('IC', 'Disease', 'MESH:C566126', (114, 116))
157837	33614703	Palmitoylated CKAP4 translocates to the nucleus and then binds to CCN2 gene, which inhibits cell proliferation, adhesion, migration, differentiation, and survival.	('migration', 'CPA', (122, 131))	('inhibits', 'NegReg', (83, 91))	('survival', 'CPA', (154, 162))	('CCN2', 'Gene', (66, 70))	('Palmitoylated', 'Var', (0, 13))	('cell proliferation', 'biological_process', 'GO:0008283', ('92', '110'))	('differentiation', 'CPA', (133, 148))	('adhesion', 'CPA', (112, 120))	('binds', 'Interaction', (57, 62))	('cell proliferation', 'CPA', (92, 110))	('CCN2', 'Gene', '1490', (66, 70))	('nucleus', 'cellular_component', 'GO:0005634', ('40', '47'))
157853	33614703	The results showed that the sensitivity of the serum CKAP4 is 70% and the specificity is 67.5%, and detection of serum CKAP4 increased the diagnostic efficacy especially in HCC patients with low or negative alpha-fetoprotein (AFP).	('low', 'NegReg', (191, 194))	('HCC', 'Disease', (173, 176))	('serum CKAP4', 'Var', (113, 124))	('increased', 'PosReg', (125, 134))	('HCC', 'Phenotype', 'HP:0001402', (173, 176))	('patients', 'Species', '9606', (177, 185))	('alpha-fetoprotein', 'Gene', '174', (207, 224))	('AFP', 'Gene', (226, 229))	('AFP', 'Gene', '174', (226, 229))	('alpha-fetoprotein', 'Gene', (207, 224))	('negative', 'NegReg', (198, 206))
157855	33614703	The sensitivity and specificity for HCC diagnosis of CKAP4 alone had no advantage compared with AFP, but combined CKAP4 and AFP showed a better diagnostic accuracy (sensitivity = 0.8, specificity = 0.963), even in early HCC (sensitivity = 0.762, specificity = 0.963), which was similar to our results (Table 3).	('AFP', 'Gene', '174', (124, 127))	('AFP', 'Gene', '174', (96, 99))	('HCC', 'Phenotype', 'HP:0001402', (36, 39))	('AFP', 'Gene', (96, 99))	('CKAP4', 'Var', (114, 119))	('HCC', 'Phenotype', 'HP:0001402', (220, 223))	('AFP', 'Gene', (124, 127))	('early HCC', 'Disease', (214, 223))
157874	33614703	Furthermore, an anti-CKAP4 polyclonal antibody (pAb) can significantly reduce xenograft tumor volume and weight caused by these cancer cell lines, suggesting that CAKP4 represents a novel molecular target for cancer therapy.	('anti-CKAP4', 'Var', (16, 26))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('reduce', 'NegReg', (71, 77))	('antibody', 'cellular_component', 'GO:0019815', ('38', '46'))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('antibody', 'cellular_component', 'GO:0019814', ('38', '46'))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('antibody', 'molecular_function', 'GO:0003823', ('38', '46'))	('anti-CKAP4', 'Gene', (16, 26))	('tumor', 'Disease', (88, 93))	('antibody', 'cellular_component', 'GO:0042571', ('38', '46'))	('cancer', 'Disease', (128, 134))
157887	33614703	Mechanistically, TGF-beta was revealed to induce CKAP4 expression, and inhibition of CKAP4 increased the expression of markers for activated fibroblasts under TGF-beta treatment.	('TGF-beta', 'Gene', (17, 25))	('CKAP4', 'Gene', (49, 54))	('inhibition', 'Var', (71, 81))	('TGF-beta', 'Gene', (159, 167))	('TGF-beta', 'Gene', '7039', (17, 25))	('induce', 'PosReg', (42, 48))	('expression', 'MPA', (55, 65))	('CKAP4', 'Gene', (85, 90))	('TGF-beta', 'Gene', '7039', (159, 167))	('increased', 'PosReg', (91, 100))	('expression of', 'MPA', (105, 118))
157889	33614703	Another research showed that it is possible to establish a noninvasion diagnostic method for IC/PBS because the special domains of CKAP4 (AA127-360, AA361-524) could enhance the binding activity to APF, increasing detection efficiency to APF concentrations in urine.	('APF', 'Protein', (198, 201))	('APF concentrations', 'MPA', (238, 256))	('IC', 'Disease', 'MESH:C566126', (93, 95))	('APF', 'Chemical', '-', (198, 201))	('detection efficiency', 'MPA', (214, 234))	('CKAP4', 'Gene', (131, 136))	('PBS', 'Chemical', 'MESH:D007854', (96, 99))	('increasing', 'PosReg', (203, 213))	('enhance', 'PosReg', (166, 173))	('AA361-524', 'Var', (149, 158))	('binding', 'molecular_function', 'GO:0005488', ('178', '185'))	('APF', 'Chemical', '-', (238, 241))	('AA127-360', 'Var', (138, 147))	('binding', 'Interaction', (178, 185))
157905	33614703	81600593, 81770763, and 81500583), the State Key Project for Liver Cancer (2017ZX10203,2017ZX10203206), and the National Key Research and Development Program (2017YFC0906900).	('81770763', 'Var', (10, 18))	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Liver Cancer', 'Disease', 'MESH:D006528', (61, 73))	('Liver Cancer', 'Phenotype', 'HP:0002896', (61, 73))	('2017ZX10203,2017ZX10203206', 'Var', (75, 101))	('Liver Cancer', 'Disease', (61, 73))	('81500583', 'Var', (24, 32))	('81600593', 'Var', (0, 8))
157908	33033692	The clinician may choose from numerous available panels to assess the type of cancer based on the mutation or expression regulation ("transcriptomic signature") of "driver" genes.	('regulation', 'biological_process', 'GO:0065007', ('121', '131'))	('mutation', 'Var', (98, 106))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('expression regulation', 'MPA', (110, 131))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
157919	33033692	According to the 22.0 release of the NIH National Cancer Institute Genomic Data Commons Data Portal on July 5, 2020 there are now 3142246 certified mutations detected all over the 22872 genes sequenced from 84031 cases of cancers localized in 67 primary sites.	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('mutations', 'Var', (148, 157))	('Cancer', 'Disease', (50, 56))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('cancers', 'Disease', (222, 229))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))
157973	33033692	Expression data from surgically removed tumors are available from the  as GSE72304 (kidney cancer), GSE97001 (papillary thyroid cancer), and GSE133891 and GSE133906 (two cases of prostate cancer).	('kidney cancer', 'Disease', (84, 97))	('prostate cancer', 'Disease', 'MESH:D011471', (179, 194))	('prostate cancer', 'Phenotype', 'HP:0012125', (179, 194))	('prostate cancer', 'Disease', (179, 194))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('GSE97001', 'Var', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('papillary thyroid cancer', 'Disease', (110, 134))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('kidney cancer', 'Disease', 'MESH:D007680', (84, 97))	('GSE133906', 'Var', (155, 164))	('GSE133891', 'Var', (141, 150))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (110, 134))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('GSE97001', 'CellLine', 'CVCL:6F81', (100, 108))	('kidney cancer', 'Phenotype', 'HP:0009726', (84, 97))	('thyroid cancer', 'Phenotype', 'HP:0002890', (120, 134))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (110, 134))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
157998	33033692	Figure 1C presents the expression coordination in the normal kidney tissue of selected chemokine signaling genes with VHL (E3 ubiquitin protein ligase), a gene whose mutation allegedly causes von Hippel-Lindau disease and clear cell kidney tumors.	('clear cell kidney tumors', 'Disease', 'MESH:C538614', (222, 246))	('VHL', 'Gene', (118, 121))	('clear cell kidney tumors', 'Disease', (222, 246))	('VHL', 'Gene', '7428', (118, 121))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (192, 217))	('clear cell kidney tumors', 'Phenotype', 'HP:0006770', (222, 246))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('kidney tumors', 'Phenotype', 'HP:0009726', (233, 246))	('ubiquitin', 'molecular_function', 'GO:0031386', ('126', '135'))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('signaling', 'biological_process', 'GO:0023052', ('97', '106'))	('von Hippel-Lindau disease', 'Disease', (192, 217))	('causes', 'Reg', (185, 191))	('mutation', 'Var', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
158033	33033692	Third, there is enough evidence of the importance of the alternative transcription and alternative splicing in cancer.	('alternative splicing', 'Var', (87, 107))	('splicing', 'biological_process', 'GO:0045292', ('99', '107'))	('transcription', 'biological_process', 'GO:0006351', ('69', '82'))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('alternative transcription', 'Var', (57, 82))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
158034	33033692	We presented the coordination of two transcript variants of VEGFA with opposite functions (pro-angiogenic and anti-angiogenic) because of their distinct association with the cancer.	('association', 'Reg', (153, 164))	('VEGFA', 'Gene', '7422', (60, 65))	('variants', 'Var', (48, 56))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('VEGFA', 'Gene', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
158043	33033692	The examples are from the prostate cancer pathway in the cancer nodules of two patients (P1C and P2C) with respect to the corresponding cancer-free surrounding tissues (P1N, P2N, expression data from GSE133891 and GSE133906).	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('prostate cancer', 'Disease', (26, 41))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('prostate cancer', 'Phenotype', 'HP:0012125', (26, 41))	('P2', 'Chemical', 'MESH:C020845', (97, 99))	('cancer', 'Disease', (136, 142))	('patients', 'Species', '9606', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('P2', 'Chemical', 'MESH:C020845', (174, 176))	('prostate cancer', 'Disease', 'MESH:D011471', (26, 41))	('cancer', 'Disease', (35, 41))	('GSE133906', 'Var', (214, 223))	('GSE133891', 'Var', (200, 209))
158046	33033692	Thus, HSP90B1 with WIR = 69 in P1C and WIR = -141 in P2C was not only the most altered gene in both patients but its regulations were opposite.	('HSP90B1', 'Gene', (6, 13))	('HSP90B1', 'Gene', '7184', (6, 13))	('altered', 'Reg', (79, 86))	('WIR = -141', 'Var', (39, 49))	('P2', 'Chemical', 'MESH:C020845', (53, 55))	('patients', 'Species', '9606', (100, 108))	('WIR = 69', 'Var', (19, 27))
158057	33033692	For example, Figure 6 shows the regulation of genes included by KEGG in the prostate cancer pathway in the cancer nodules of two men with the same phenotype, prostate cancer Gleason score 4 + 5 = 9.	('prostate cancer', 'Phenotype', 'HP:0012125', (158, 173))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('cancer', 'Disease', (167, 173))	('regulation', 'biological_process', 'GO:0065007', ('32', '42'))	('cancer', 'Disease', (85, 91))	('KEGG', 'Var', (64, 68))	('prostate cancer', 'Disease', (158, 173))	('men', 'Species', '9606', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('prostate cancer', 'Disease', 'MESH:D011471', (158, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('prostate cancer', 'Disease', (76, 91))	('cancer', 'Disease', (107, 113))
158061	33033692	For instance, CREB3 is down-regulated with x = -1.43 in P1C (CUT = 1.35x), but not with x = 1.57 in P2C (CUT = 1.58x).	('P2', 'Chemical', 'MESH:C020845', (100, 102))	('x = -1.43', 'Var', (43, 52))	('P1C', 'Disease', (56, 59))	('CREB3', 'Gene', (14, 19))	('down-regulated', 'NegReg', (23, 37))	('CREB3', 'Gene', '10488', (14, 19))
158082	33033692	In recent publications, we proposed that the GMRs of cancer nodules could be the most legitimate targets for cancer gene therapy because: (1) The strict control of the expression level indicates that the right amount of GMR transcripts is critical for the cell survival; (2) The high coordination degree with expressions of many other genes shows how influential the GMR is for the cell physiology; and (3) The very low GCH scores of the cancer nodule GMR in the surrounding normal substance suggest that silencing the GMR may selectively kill the cancer cells from the tissue.	('cancer', 'Disease', (438, 444))	('silencing', 'Var', (505, 514))	('cancer', 'Disease', 'MESH:D009369', (438, 444))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cell physiology', 'biological_process', 'GO:0009987', ('382', '397'))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (438, 444))	('cancer', 'Disease', (548, 554))	('cancer', 'Disease', 'MESH:D009369', (548, 554))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (548, 554))
158084	33033692	We found that manipulating the expression of: NEMP1, PANK2, DDX19B and UBALD1 had transcriptomic consequences in line with their GCH in the untransfected cells.	('PANK2', 'Gene', '80025', (53, 58))	('NEMP1', 'Gene', (46, 51))	('UBALD1', 'Gene', '124402', (71, 77))	('DDX19B', 'Gene', '11269', (60, 66))	('DDX19B', 'Gene', (60, 66))	('PANK2', 'Gene', (53, 58))	('UBALD1', 'Gene', (71, 77))	('manipulating', 'Var', (14, 26))	('NEMP1', 'Gene', '23306', (46, 51))
158100	32440207	High expression of TTN-AS1 was closely associated with adverse clinicopathological characteristics of ccRCC patients.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('TTN-AS1', 'Gene', (19, 26))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('High', 'Var', (0, 4))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('associated', 'Reg', (39, 49))	('patients', 'Species', '9606', (108, 116))	('TTN-AS1', 'Gene', '100506866', (19, 26))	('RCC', 'Disease', (104, 107))
158103	32440207	Further, we showed that cyclin D1 is a direct target of miR-195 in ccRCC, and rescue assays verified that restoration of miR-195 expression partially blocked the oncogenic effects of TTN-AS1 in ccRCC cells.	('oncogenic effects', 'CPA', (162, 179))	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('RCC', 'Disease', (69, 72))	('RCC', 'Disease', 'MESH:C538614', (196, 199))	('cyclin D1', 'Gene', (24, 33))	('TTN-AS1', 'Gene', (183, 190))	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('miR-195', 'Gene', '406971', (121, 128))	('cyclin D1', 'Gene', '595', (24, 33))	('cyclin', 'molecular_function', 'GO:0016538', ('24', '30'))	('restoration', 'Var', (106, 117))	('TTN-AS1', 'Gene', '100506866', (183, 190))	('miR-195', 'Gene', (121, 128))	('miR-195', 'Gene', '406971', (56, 63))	('blocked', 'NegReg', (150, 157))	('miR-195', 'Gene', (56, 63))	('RCC', 'Disease', (196, 199))	('RCC', 'Phenotype', 'HP:0005584', (196, 199))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (194, 199))
158132	32440207	The binding sites were mutated by the Quick-change site-directed mutagenesis kit (Agilent Technologies, Santa Clara, CA, USA).	('mutagenesis', 'biological_process', 'GO:0006280', ('65', '76'))	('binding', 'Interaction', (4, 11))	('mutated', 'Var', (23, 30))	('kit', 'Gene', (77, 80))	('kit', 'Gene', '3815', (77, 80))	('binding', 'molecular_function', 'GO:0005488', ('4', '11'))
158141	32440207	As exhibited in Figure 2B, the proliferation rate of ACHN cells was tremendously impaired when TTN-AS1 was knocked down, whereas overexpression of TTN-AS1 could otherwise enhance the proliferation in 786-O cells.	('TTN-AS1', 'Gene', '100506866', (147, 154))	('ACHN', 'Gene', '55323', (53, 57))	('enhance', 'PosReg', (171, 178))	('TTN-AS1', 'Gene', (95, 102))	('proliferation rate', 'CPA', (31, 49))	('ACHN', 'Gene', (53, 57))	('TTN-AS1', 'Gene', (147, 154))	('impaired', 'NegReg', (81, 89))	('knocked down', 'Var', (107, 119))	('TTN-AS1', 'Gene', '100506866', (95, 102))
158142	32440207	Besides, cell cycle analysis confirmed that cell cycle progression was markedly suppressed by TTN-AS1 knockdown in ACHN cells, while 786-O cells with overexpressing TTN-AS1 had a decreased G0/G1 population (Figure 2C).	('decreased', 'NegReg', (179, 188))	('TTN-AS1', 'Gene', '100506866', (165, 172))	('ACHN', 'Gene', (115, 119))	('cell cycle', 'biological_process', 'GO:0007049', ('44', '54'))	('cell cycle', 'biological_process', 'GO:0007049', ('9', '19'))	('TTN-AS1', 'Gene', '100506866', (94, 101))	('knockdown', 'Var', (102, 111))	('TTN-AS1', 'Gene', (165, 172))	('TTN-AS1', 'Gene', (94, 101))	('cell cycle progression', 'CPA', (44, 66))	('suppressed', 'NegReg', (80, 90))	('G0/G1 population', 'CPA', (189, 205))	('ACHN', 'Gene', '55323', (115, 119))
158143	32440207	Western blot analysis further showed that the expression level of cyclin D1 protein was decreased by TTN-AS1 knockdown in ACHN cells, as well as increased by TTN-AS1 overexpression in786-O cells (Figure 2D).	('TTN-AS1', 'Gene', (101, 108))	('TTN-AS1', 'Gene', '100506866', (158, 165))	('cyclin', 'molecular_function', 'GO:0016538', ('66', '72'))	('cyclin D1', 'Gene', (66, 75))	('ACHN', 'Gene', '55323', (122, 126))	('TTN-AS1', 'Gene', (158, 165))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('increased', 'PosReg', (145, 154))	('expression level', 'MPA', (46, 62))	('protein', 'Protein', (76, 83))	('knockdown', 'Var', (109, 118))	('TTN-AS1', 'Gene', '100506866', (101, 108))	('ACHN', 'Gene', (122, 126))	('decreased', 'NegReg', (88, 97))	('cyclin D1', 'Gene', '595', (66, 75))
158147	32440207	In addition, as demonstrated in Figure 3F, miR-195 was upregulated by TTN-AS1 knockdown in ACHN cells, as well as downregulated by TTN-AS1 overexpression in 786-O cells.	('miR-195', 'Gene', (43, 50))	('miR-195', 'Gene', '406971', (43, 50))	('ACHN', 'Gene', '55323', (91, 95))	('TTN-AS1', 'Gene', '100506866', (70, 77))	('knockdown', 'Var', (78, 87))	('TTN-AS1', 'Gene', (70, 77))	('upregulated', 'PosReg', (55, 66))	('ACHN', 'Gene', (91, 95))	('TTN-AS1', 'Gene', '100506866', (131, 138))	('downregulated', 'NegReg', (114, 127))	('TTN-AS1', 'Gene', (131, 138))
158150	32440207	Dual-luciferase reporter assay showed that administration of miR-195 mimics significantly reduced the luciferase activity of cyclin D1-WT in both ACHN and 786-O cells (Figure 4B).	('cyclin D1', 'Gene', (125, 134))	('reduced', 'NegReg', (90, 97))	('luciferase activity', 'molecular_function', 'GO:0047077', ('102', '121'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('102', '121'))	('luciferase', 'Enzyme', (102, 112))	('cyclin D1', 'Gene', '595', (125, 134))	('mimics', 'Var', (69, 75))	('cyclin', 'molecular_function', 'GO:0016538', ('125', '131'))	('activity', 'MPA', (113, 121))	('ACHN', 'Gene', '55323', (146, 150))	('luciferase activity', 'molecular_function', 'GO:0045289', ('102', '121'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('102', '121'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('102', '121'))	('miR-195', 'Gene', (61, 68))	('miR-195', 'Gene', '406971', (61, 68))	('ACHN', 'Gene', (146, 150))
158152	32440207	MTT assay showed that restoration of miR-195 also abolished the enhanced proliferation of TTN-AS1-overexpressing 786-O cells (Figure 5C).	('miR-195', 'Gene', (37, 44))	('miR-195', 'Gene', '406971', (37, 44))	('TTN-AS1', 'Gene', '100506866', (90, 97))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('restoration', 'Var', (22, 33))	('abolished', 'NegReg', (50, 59))	('TTN-AS1', 'Gene', (90, 97))	('enhanced', 'PosReg', (64, 72))
158159	32440207	Through a series of functional experiments, we further observed the effects of TTN-AS1 on the biological behaviors of ccRCC cells, showing that TTN-AS1 knockdown suppressed ccRCC cell proliferation partly by inducing cell cycle arrest, a hallmark of restrained cell proliferation.	('arrest', 'Disease', (228, 234))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (217, 234))	('cell proliferation', 'biological_process', 'GO:0008283', ('261', '279'))	('TTN-AS1', 'Gene', (144, 151))	('TTN-AS1', 'Gene', (79, 86))	('knockdown', 'Var', (152, 161))	('arrest', 'Disease', 'MESH:D006323', (228, 234))	('RCC', 'Disease', (175, 178))	('inducing', 'NegReg', (208, 216))	('suppressed', 'NegReg', (162, 172))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))	('ccRCC', 'Phenotype', 'HP:0006770', (173, 178))	('TTN-AS1', 'Gene', '100506866', (144, 151))	('TTN-AS1', 'Gene', '100506866', (79, 86))	('cell proliferation', 'biological_process', 'GO:0008283', ('179', '197'))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', 'MESH:C538614', (175, 178))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('217', '234'))
158164	32440207	Moreover, rescue experiments showed that restoration of miR-195 expression blocked the oncogenic effects of TTN-AS1 in ccRCC cells.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('restoration', 'Var', (41, 52))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('blocked', 'NegReg', (75, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('TTN-AS1', 'Gene', '100506866', (108, 115))	('miR-195', 'Gene', (56, 63))	('miR-195', 'Gene', '406971', (56, 63))	('TTN-AS1', 'Gene', (108, 115))	('oncogenic effects', 'CPA', (87, 104))
158187	31905821	Thus, the most frequent genetic alteration in CCRCC involves chromosome 3p deletion, VHL mutation and/or VHL promoter methylation, leading to VHL inactivation, an early and crucial event in sporadic CCRCC and in the familial cancer syndrome von Hippel-Lindau disease.	('VHL', 'Gene', (85, 88))	('inactivation', 'NegReg', (146, 158))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('familial cancer syndrome von Hippel-Lindau disease', 'Disease', (216, 266))	('VHL', 'Gene', '7428', (142, 145))	('methylation', 'biological_process', 'GO:0032259', ('118', '129'))	('CCRCC', 'Disease', 'MESH:D002292', (199, 204))	('VHL', 'Gene', '7428', (85, 88))	('CCRCC', 'Disease', (199, 204))	('CCRCC', 'Disease', 'MESH:D002292', (46, 51))	('VHL', 'Gene', (105, 108))	('familial cancer syndrome von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (216, 266))	('mutation', 'Var', (89, 97))	('CCRCC', 'Disease', (46, 51))	('CCRCC', 'Phenotype', 'HP:0006770', (199, 204))	('VHL', 'Gene', '7428', (105, 108))	('CCRCC', 'Phenotype', 'HP:0006770', (46, 51))	('chromosome', 'cellular_component', 'GO:0005694', ('61', '71'))	('VHL', 'Gene', (142, 145))
158189	31905821	Application in routine practice: The presence of VHL mutation, chromosome 3p deletion or VHL promoter methylation is considered useful for the confirmation of CCRCC diagnosis in difficult cases (see following sections).	('methylation', 'biological_process', 'GO:0032259', ('102', '113'))	('mutation', 'Var', (53, 61))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('VHL', 'Gene', (89, 92))	('CCRCC', 'Disease', (159, 164))	('VHL', 'Gene', '7428', (89, 92))	('CCRCC', 'Phenotype', 'HP:0006770', (159, 164))	('VHL', 'Gene', (49, 52))	('VHL', 'Gene', '7428', (49, 52))	('CCRCC', 'Disease', 'MESH:D002292', (159, 164))
158193	31905821	The most frequent genetic alterations in MCRCNLMP are identical to chromosome 3p deletion in 74% (14/19) of cases and VHL mutation in 25% (3/12) of cases.	('VHL', 'Gene', (118, 121))	('chromosome', 'cellular_component', 'GO:0005694', ('67', '77'))	('VHL', 'Gene', '7428', (118, 121))	('mutation', 'Var', (122, 130))	('MCRCNLMP', 'Gene', (41, 49))
158196	31905821	Application in routine practice: Similar to CCRCC, chromosome 3p deletion and VHL mutation might be found in MCRCNLMP, but no specific genetic alterations have so far been identified.	('CCRCC', 'Phenotype', 'HP:0006770', (44, 49))	('mutation', 'Var', (82, 90))	('VHL', 'Gene', (78, 81))	('chromosome', 'cellular_component', 'GO:0005694', ('51', '61'))	('CCRCC', 'Disease', 'MESH:D002292', (44, 49))	('chromosome 3p deletion', 'Var', (51, 73))	('VHL', 'Gene', '7428', (78, 81))	('found', 'Reg', (100, 105))	('MCRCNLMP', 'Disease', (109, 117))	('CCRCC', 'Disease', (44, 49))
158204	31905821	While mutations of MET are rarely referred for sporadic type 1 PRCC, it is commonly associated with hereditary papillary RCC syndrome.	('PRCC', 'Gene', '5546', (63, 67))	('papillary RCC', 'Gene', '5546', (111, 124))	('PRCC', 'Gene', (63, 67))	('associated', 'Reg', (84, 94))	('PRCC', 'Phenotype', 'HP:0006766', (63, 67))	('papillary RCC', 'Gene', (111, 124))	('mutations', 'Var', (6, 15))	('MET', 'Gene', (19, 22))
158207	31905821	Although gains of chromosomes 7 and 17 were reported to be the most frequently listed CNV changes for this subtype, the recent literature show that trisomy/polysomy 7/17 is not commonly associated with type 2 PRCC.	('PRCC', 'Gene', '5546', (209, 213))	('PRCC', 'Gene', (209, 213))	('trisomy/polysomy 7/17', 'Var', (148, 169))	('associated', 'Reg', (186, 196))	('PRCC', 'Phenotype', 'HP:0006766', (209, 213))
158210	31905821	Such tumors showed CDKN2A silencing, SETD2 mutations, and increased expression of the NRF2 antioxidant response element pathway.	('SETD2', 'Gene', '29072', (37, 42))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('NRF2', 'Gene', '4780', (86, 90))	('increased', 'PosReg', (58, 67))	('expression', 'MPA', (68, 78))	('SETD2', 'Gene', (37, 42))	('CDKN2A', 'Gene', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('NRF2', 'Gene', (86, 90))	('CDKN2A', 'Gene', '1029', (19, 25))	('mutations', 'Var', (43, 52))	('silencing', 'NegReg', (26, 35))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
158214	31905821	Some these tumors have shown to have a copy number pattern identical to renal oncocytoma: disomic status of chromosomes 7 and 17, some with deletion of chromosome 14, deletion of 1p (locus 1p36).	('renal oncocytoma', 'Disease', 'MESH:C537750', (72, 88))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('chromosome', 'cellular_component', 'GO:0005694', ('152', '162'))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (72, 88))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('renal oncocytoma', 'Disease', (72, 88))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('deletion of', 'Var', (167, 178))
158217	31905821	Interestingly, this tumor is characterized by frequent KRAS mutations.	('KRAS', 'Gene', (55, 59))	('KRAS', 'Gene', '3845', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', (20, 25))
158219	31905821	It should be noted that all of these variants are defined mostly using morphologic features and that their molecular-genetic features are widely varied, as generally observed in papillary RCCs.	('observed', 'Reg', (166, 174))	('papillary RCC', 'Gene', '5546', (178, 191))	('RCCs', 'Disease', (188, 192))	('RCCs', 'Disease', 'MESH:D002292', (188, 192))	('papillary RCC', 'Gene', (178, 191))	('RCCs', 'Phenotype', 'HP:0005584', (188, 192))	('variants', 'Var', (37, 45))
158231	31905821	Testing germline mutations in the novel tumor suppressor gene FLCN (folliculin) can be used to support the diagnosis of Birt-Hogg-Dube syndrome, which predisposes to the so-called "hybrid" oncocytic/chromophobe tumors.	('germline mutations', 'Var', (8, 26))	('folliculin', 'Gene', '201163', (68, 78))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('FLCN', 'Gene', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('folliculin', 'Gene', (68, 78))	('Birt-Hogg-Dube syndrome', 'Disease', (120, 143))	('FLCN', 'Gene', '201163', (62, 66))	('Birt-Hogg-Dube syndrome', 'Disease', 'MESH:D058249', (120, 143))	('tumor', 'Disease', (211, 216))	('chromophobe tumors', 'Disease', (199, 217))	('chromophobe tumors', 'Disease', 'MESH:D000238', (199, 217))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor suppressor', 'biological_process', 'GO:0051726', ('40', '56'))
158236	31905821	There are 3 basic genetic patterns in ROs: (1) loss of chromosome 1 (in whole or in part) and loss of chromosome Y, (2) rearrangements of 11q13 (mostly translocation t(5;11)(q35;q13)), chromosome 14 deletion, and (3) a normal karyotype.	('rearrangements', 'Var', (120, 134))	('ROs', 'Chemical', '-', (38, 41))	('ROs', 'Gene', (38, 41))	('t(5;11)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (166, 182))	('chromosome', 'cellular_component', 'GO:0005694', ('185', '195'))	('translocation t(5;11)(q35;q13', 'Var', (152, 181))	('loss', 'NegReg', (94, 98))	('loss', 'NegReg', (47, 51))	('chromosome', 'cellular_component', 'GO:0005694', ('102', '112'))	('11q13', 'Gene', (138, 143))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))	('RO', 'Phenotype', 'HP:0011798', (38, 40))
158248	31905821	In fact, analysis of 3p25 loss and VHL gene alterations (mutations and methylation status) together with morphology and immunohistochemical profile would allow us to correctly diagnose almost all such cases.	('diagnose', 'Reg', (176, 184))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('alterations', 'Var', (44, 55))	('loss', 'NegReg', (26, 30))	('VHL', 'Gene', (35, 38))	('3p25', 'Protein', (21, 25))	('VHL', 'Gene', '7428', (35, 38))
158252	31905821	In challenging cases where the morphology and/or immunohistochemical profile are not typical of CCPRCC, genetic testing for VHL mutation/methylation and/or chromosome 3p loss are essential for rendering an accurate diagnosis of CCPRCC.	('chromosome', 'cellular_component', 'GO:0005694', ('156', '166'))	('methylation', 'biological_process', 'GO:0032259', ('137', '148'))	('VHL', 'Gene', '7428', (124, 127))	('CCPRCC', 'Disease', (96, 102))	('loss', 'NegReg', (170, 174))	('mutation/methylation', 'Var', (128, 148))	('PRCC', 'Phenotype', 'HP:0006766', (98, 102))	('CCPRCC', 'Disease', 'MESH:D002292', (96, 102))	('CCPRCC', 'Disease', (228, 234))	('PRCC', 'Phenotype', 'HP:0006766', (230, 234))	('CCPRCC', 'Disease', 'MESH:D002292', (228, 234))	('VHL', 'Gene', (124, 127))
158253	31905821	Renal tumors with TFE3, TFEB, and MiTF rearrangements are "classic" translocation-associated RCCs, being diagnosed based on a combination of morphologic, immunohistochemical, and molecular genetic analyses.	('RCCs', 'Disease', (93, 97))	('RCCs', 'Disease', 'MESH:D002292', (93, 97))	('Renal tumors', 'Disease', (0, 12))	('TFE3', 'Gene', '7030', (18, 22))	('RCCs', 'Phenotype', 'HP:0005584', (93, 97))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('MiTF', 'Gene', (34, 38))	('TFEB', 'Gene', '7942', (24, 28))	('TFEB', 'Gene', (24, 28))	('rearrangements', 'Var', (39, 53))	('Renal tumors', 'Phenotype', 'HP:0009726', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('MiTF', 'Gene', '4286', (34, 38))	('Renal tumors', 'Disease', 'MESH:D007680', (0, 12))	('TFE3', 'Gene', (18, 22))
158254	31905821	RCC with TFE3 rearrangements (Xp11.2) is the most common of all translocation-associated RCCs.	('RCCs', 'Phenotype', 'HP:0005584', (89, 93))	('TFE3', 'Gene', (9, 13))	('translocation-associated', 'Disease', (64, 88))	('rearrangements', 'Var', (14, 28))	('common', 'Reg', (50, 56))	('RCC', 'Disease', (89, 92))	('TFE3', 'Gene', '7030', (9, 13))	('RCC', 'Disease', 'MESH:D002292', (89, 92))	('RCCs', 'Disease', (89, 93))	('RCCs', 'Disease', 'MESH:D002292', (89, 93))	('RCC', 'Disease', 'MESH:D002292', (0, 3))	('RCC', 'Disease', (0, 3))
158259	31905821	Immunohistochemical analysis may not be sufficient to confirm the diagnosis of TFE3 translocation RCC, and that in some cases further molecular genetic testing maybe indicated.	('TFE3', 'Gene', '7030', (79, 83))	('RCC', 'Disease', (98, 101))	('translocation', 'Var', (84, 97))	('TFE3', 'Gene', (79, 83))	('RCC', 'Disease', 'MESH:D002292', (98, 101))
158265	31905821	However, even in the group of TFEB or t(6;11) translocation RCC, there is morphologic variability and that not all cases follow a "classic" morphologic pattern with biphasic morphology (Figure 1).	('TFEB', 'Gene', '7942', (30, 34))	('TFEB', 'Gene', (30, 34))	('RCC', 'Disease', (60, 63))	('translocation', 'Var', (46, 59))	('RCC', 'Disease', 'MESH:D002292', (60, 63))
158266	31905821	Recent studies have shown that amplification of the TFEB gene in TFEB or t(6;11) translocation RCCs can uncommonly occur and is associated with more aggressive clinical behavior with distant metastases (see RCC with TFEB amplification).	('RCCs', 'Disease', 'MESH:D002292', (95, 99))	('associated with', 'Reg', (128, 143))	('TFEB', 'Gene', (52, 56))	('metastases', 'Disease', 'MESH:D009362', (191, 201))	('RCCs', 'Phenotype', 'HP:0005584', (95, 99))	('t(6;11', 'Gene', (73, 79))	('metastases', 'Disease', (191, 201))	('RCC', 'Disease', (207, 210))	('RCC', 'Disease', (95, 98))	('TFEB', 'Gene', (216, 220))	('TFEB', 'Gene', '7942', (52, 56))	('TFEB', 'Gene', (65, 69))	('RCC', 'Disease', 'MESH:D002292', (207, 210))	('TFEB', 'Gene', '7942', (216, 220))	('RCC', 'Disease', 'MESH:D002292', (95, 98))	('TFEB', 'Gene', '7942', (65, 69))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (149, 177))	('RCCs', 'Disease', (95, 99))	('amplification', 'Var', (31, 44))
158271	31905821	In other words, when the morphology and/or immunohistochemical profile is suggestive of TFE3 translocation RCC, NGS analysis is recommended for confirmation.	('RCC', 'Disease', 'MESH:D002292', (107, 110))	('RCC', 'Disease', (107, 110))	('translocation', 'Var', (93, 106))	('TFE3', 'Gene', (88, 92))	('TFE3', 'Gene', '7030', (88, 92))
158272	31905821	Amplification of TFEB gene seems to be a strong adverse prognostic indicator in TFEB translocation RCCs, however such cases are rare and less frequently encountered comparing with TFEB amplified RCCs (without TFEB break) its occurrence is rather rare.	('Amplification', 'Var', (0, 13))	('TFEB', 'Gene', '7942', (209, 213))	('TFEB', 'Gene', '7942', (17, 21))	('TFEB', 'Gene', (209, 213))	('TFEB', 'Gene', (17, 21))	('RCCs', 'Disease', (99, 103))	('RCCs', 'Disease', (195, 199))	('RCCs', 'Phenotype', 'HP:0005584', (99, 103))	('RCCs', 'Disease', 'MESH:D002292', (99, 103))	('RCCs', 'Phenotype', 'HP:0005584', (195, 199))	('TFEB', 'Gene', '7942', (180, 184))	('TFEB', 'Gene', '7942', (80, 84))	('RCCs', 'Disease', 'MESH:D002292', (195, 199))	('translocation', 'Var', (85, 98))	('TFEB', 'Gene', (180, 184))	('TFEB', 'Gene', (80, 84))
158284	31905821	In fact, loss of chromosome 9 has been suggested as a characteristic feature of TC-RCC.	('loss', 'Var', (9, 13))	('chromosome', 'cellular_component', 'GO:0005694', ('17', '27'))	('TC-RCC', 'Disease', 'MESH:D002292', (80, 86))	('TC-RCC', 'Disease', (80, 86))
158290	31905821	RCCs with "Tubulocystic" features and high grade abrupt areas should raise the possibility of FH-deficient RCC and be further genetically tested for FH gene mutation/LOH.	('RCCs', 'Phenotype', 'HP:0005584', (0, 4))	('RCC', 'Disease', 'MESH:D002292', (107, 110))	('RCC', 'Disease', (107, 110))	('FH', 'Gene', '2271', (149, 151))	('FH', 'Gene', '2271', (94, 96))	('mutation/LOH', 'Var', (157, 169))	('RCCs', 'Disease', (0, 4))	('RCCs', 'Disease', 'MESH:D002292', (0, 4))	('RCC', 'Disease', 'MESH:D002292', (0, 3))	('RCC', 'Disease', (0, 3))
158296	31905821	In rare cases where alterations of SMARCB1 gene or abnormal negative staining for the protein is documented in the absence of sickle trait, the term "RCC unclassified with medullary phenotype" has been proposed.	('negative', 'NegReg', (60, 68))	('alterations', 'Var', (20, 31))	('RCC', 'Disease', 'MESH:D002292', (150, 153))	('RCC', 'Disease', (150, 153))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('SMARCB1', 'Gene', '6598', (35, 42))	('SMARCB1', 'Gene', (35, 42))
158312	31905821	SDH deficiency is almost always associated with germline SDH subunit mutation.	('SDH', 'Gene', (57, 60))	('SDH', 'Gene', (0, 3))	('deficiency', 'Var', (4, 14))	('associated', 'Reg', (32, 42))	('SDH', 'Gene', '6390', (57, 60))	('SDH', 'Gene', '6390', (0, 3))
158315	31905821	The vast majority of SDH-deficient RCCs are associated with germline mutation of the SDHB subunit.	('associated', 'Reg', (44, 54))	('RCCs', 'Disease', (35, 39))	('SDH', 'Gene', (85, 88))	('germline mutation', 'Var', (60, 77))	('RCCs', 'Phenotype', 'HP:0005584', (35, 39))	('RCCs', 'Disease', 'MESH:D002292', (35, 39))	('SDH', 'Gene', (21, 24))	('SDHB', 'Gene', '6390', (85, 89))	('SDHB', 'Gene', (85, 89))	('SDH', 'Gene', '6390', (85, 88))	('SDH', 'Gene', '6390', (21, 24))
158316	31905821	Genetic testing of SDH subunit mutation is not necessary, however in cases where the result of immunohistochemical examination is inconclusive, it is highly recommended.	('SDH', 'Gene', (19, 22))	('mutation', 'Var', (31, 39))	('SDH', 'Gene', '6390', (19, 22))
158324	31905821	For screening, immunohistochemical staining with FH is useful, however cases where staining interpretation is not convincing or in suspected clinical settings it would be better to test for FH mutation/LOH.	('FH', 'Gene', '2271', (190, 192))	('FH', 'Gene', '2271', (49, 51))	('test', 'Reg', (181, 185))	('mutation/LOH', 'Var', (193, 205))
158328	31905821	It is questionable whether all these variants will be regarded as established entities within future classifications or whether they will be reclassified as variants of some "traditional" renal tumors.	('renal tumors', 'Disease', 'MESH:D007680', (188, 200))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('renal tumors', 'Disease', (188, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('variants', 'Var', (37, 45))	('renal tumors', 'Phenotype', 'HP:0009726', (188, 200))	('renal tumor', 'Phenotype', 'HP:0009726', (188, 199))
158335	31905821	Both familiar and sporadic tumors have molecular alterations of TSC1 or TSC2.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('TSC1', 'Gene', '7248', (64, 68))	('molecular alterations', 'Var', (39, 60))	('TSC2', 'Gene', '7249', (72, 76))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('TSC2', 'Gene', (72, 76))	('TSC1', 'Gene', (64, 68))	('sporadic tumors', 'Disease', 'MESH:D020821', (18, 33))	('sporadic tumors', 'Disease', (18, 33))
158336	31905821	The molecular genetic revolution in the field of oncopathology has resulted in identifying more entities including a recently described subset of tumors harboring mutations of TSC1, TSC2, or MTOR, being recognized in sporadic patients as well as patients with tuberous sclerosis complex.	('TSC2', 'Gene', '7249', (182, 186))	('MTOR', 'Gene', (191, 195))	('TSC1', 'Gene', (176, 180))	('mutations', 'Var', (163, 172))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (260, 278))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('patients', 'Species', '9606', (246, 254))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('TSC2', 'Gene', (182, 186))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('MTOR', 'Gene', '2475', (191, 195))	('tuberous sclerosis', 'Disease', (260, 278))	('patients', 'Species', '9606', (226, 234))	('tuberous sclerosis complex', 'cellular_component', 'GO:0033596', ('260', '286'))	('tumors', 'Disease', (146, 152))	('TSC1', 'Gene', '7248', (176, 180))
158339	31905821	They are distinct from both CCRCC and CCPRCC, harboring mutations of TCEB1 but with no VHL gene abnormalities.	('VHL', 'Gene', '7428', (87, 90))	('PRCC', 'Phenotype', 'HP:0006766', (40, 44))	('mutations', 'Var', (56, 65))	('CCPRCC', 'Disease', (38, 44))	('CCRCC', 'Disease', (28, 33))	('CCPRCC', 'Disease', 'MESH:D002292', (38, 44))	('CCRCC', 'Phenotype', 'HP:0006770', (28, 33))	('TCEB1', 'Gene', '6921', (69, 74))	('TCEB1', 'Gene', (69, 74))	('CCRCC', 'Disease', 'MESH:D002292', (28, 33))	('VHL', 'Gene', (87, 90))
158346	31905821	Molecular genetics usually disclose amplification of TFEB/6p21/VEGFA, while rearrangement of TFEB is usually not present.	('VEGFA', 'Gene', (63, 68))	('TFEB', 'Gene', '7942', (53, 57))	('TFEB', 'Gene', (53, 57))	('amplification', 'Var', (36, 49))	('VEGFA', 'Gene', '7422', (63, 68))	('TFEB', 'Gene', '7942', (93, 97))	('disclose', 'Reg', (27, 35))	('TFEB', 'Gene', (93, 97))
158347	31905821	However, in one of the first cases authors pointed out that amplification of TFEB gene might be a marker of aggressive behavior showed both rearrangement and amplification (Figure 4).	('rearrangement', 'Var', (140, 153))	('amplification', 'Var', (60, 73))	('TFEB', 'Gene', '7942', (77, 81))	('TFEB', 'Gene', (77, 81))	('amplification', 'Var', (158, 171))	('aggressive behavior', 'Disease', (108, 127))	('aggressive behavior', 'Phenotype', 'HP:0000718', (108, 127))	('aggressive behavior', 'biological_process', 'GO:0002118', ('108', '127'))	('aggressive behavior', 'Disease', 'MESH:D001523', (108, 127))
158349	31905821	Rearrangement of ALK has been described in various tumors, mostly in lymphomas, lung carcinomas, and thyroid carcinomas.	('lymphomas', 'Disease', 'MESH:D008223', (69, 78))	('lymphomas', 'Phenotype', 'HP:0002665', (69, 78))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('lung carcinomas', 'Disease', 'MESH:D008175', (80, 95))	('described', 'Reg', (30, 39))	('lung carcinomas', 'Disease', (80, 95))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (101, 119))	('Rearrangement', 'Var', (0, 13))	('lymphomas', 'Disease', (69, 78))	('ALK', 'Gene', '238', (17, 20))	('thyroid carcinomas', 'Disease', (101, 119))	('ALK', 'Gene', (17, 20))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (101, 119))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumors', 'Disease', (51, 57))
158377	28078239	In ccRCC, the pathological inactivation of VHL in turn leads to the aberrant accumulation of HIFalpha despite an adequate oxygen supply.	('VHL', 'Disease', (43, 46))	('accumulation', 'PosReg', (77, 89))	('inactivation', 'Var', (27, 39))	('leads to', 'Reg', (55, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('ccRCC', 'Disease', (3, 8))	('VHL', 'Disease', 'MESH:D006623', (43, 46))	('oxygen', 'Chemical', 'MESH:D010100', (122, 128))
158390	28078239	Third, there was an increased usage of the one-carbon metabolic network in ccRCC based on elevated levels of serine, homocysteine, methionine, S-adenosyl methionine (SAM), and S-adenosyl homocysteine (SAH), which is consistent with an increased feed of one methyl group from serine into the tetrahydrofolate (THF) cycle for nucleotide synthesis.	('serine', 'Chemical', 'MESH:D012694', (109, 115))	('homocysteine', 'Chemical', 'MESH:D006710', (187, 199))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('THF', 'Chemical', 'MESH:C030371', (309, 312))	('serine', 'Chemical', 'MESH:D012694', (275, 281))	('homocysteine', 'MPA', (117, 129))	('methionine', 'Chemical', 'MESH:D008715', (131, 141))	('tetrahydrofolate', 'Chemical', 'MESH:C030371', (291, 307))	('nucleotide synthesis', 'biological_process', 'GO:0009165', ('324', '344'))	('increased', 'PosReg', (20, 29))	('methionine', 'Chemical', 'MESH:D008715', (154, 164))	('S-adenosyl homocysteine', 'Chemical', 'MESH:D012435', (176, 199))	('methionine', 'MPA', (131, 141))	('elevated', 'PosReg', (90, 98))	('SAM', 'Chemical', 'MESH:D012436', (166, 169))	('levels', 'MPA', (99, 105))	('S-adenosyl', 'Var', (176, 186))	('usage', 'MPA', (30, 35))	('serine', 'MPA', (109, 115))	('elevated levels of serine', 'Phenotype', 'HP:0500138', (90, 115))	('carbon', 'Chemical', 'MESH:D002244', (47, 53))	('homocysteine', 'Chemical', 'MESH:D006710', (117, 129))	('S-adenosyl methionine', 'Chemical', 'MESH:D012436', (143, 164))
158442	30603059	We also evaluated differential expression between high and low SSIGN score for 64 genes associated with ccRCC aggressiveness, recurrence, or survival identified in previous studies.	('SSIGN score', 'Gene', (63, 74))	('aggressiveness', 'Disease', 'MESH:D001523', (110, 124))	('aggressiveness', 'Phenotype', 'HP:0000718', (110, 124))	('low', 'Var', (59, 62))	('aggressiveness', 'Disease', (110, 124))	('RCC', 'Disease', (106, 109))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('high', 'Var', (50, 54))
158463	30603059	It was in the analysis of the association of differential gene expression with SSIGN score that we made our most significant observations and found 4 genes that were over-expressed in tumors with high SSIGN score as well as advanced stage and high grade ccRCC and ccRCC with necrosis.	('necrosis', 'Disease', (275, 283))	('necrosis', 'biological_process', 'GO:0070265', ('275', '283'))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('high SSIGN score', 'Var', (196, 212))	('RCC', 'Disease', 'MESH:C538614', (266, 269))	('necrosis', 'biological_process', 'GO:0008219', ('275', '283'))	('over-expressed', 'PosReg', (166, 180))	('RCC', 'Disease', (266, 269))	('tumors', 'Disease', (184, 190))	('RCC', 'Disease', (256, 259))	('necrosis', 'Disease', 'MESH:D009336', (275, 283))	('RCC', 'Disease', 'MESH:C538614', (256, 259))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('necrosis', 'biological_process', 'GO:0019835', ('275', '283'))	('necrosis', 'biological_process', 'GO:0008220', ('275', '283'))	('necrosis', 'biological_process', 'GO:0001906', ('275', '283'))	('gene expression', 'biological_process', 'GO:0010467', ('58', '73'))
158654	33740948	A mutant type vector was designed by mutating the binding sequence between miR-4429 and DLX1 mRNA.	('DLX1', 'Gene', '1745', (88, 92))	('DLX1', 'Gene', (88, 92))	('miR-4429', 'Gene', (75, 83))	('mutating', 'Var', (37, 45))	('binding', 'molecular_function', 'GO:0005488', ('50', '57'))	('binding', 'Interaction', (50, 57))	('miR-4429', 'Gene', '100616469', (75, 83))
158658	33740948	Primary antibodies included DLX1 (UniProt Entry ID: P56177) (1:2000, ab126054), beta-catenin (UniProt Entry ID: P35222) (1: 7500, ab32572) and GAPDH (1: 2500, ab9485) and secondary antibody was (1:50,000, ab205718) (Abcam, NY, USA).	('GAPDH', 'Gene', '2597', (143, 148))	('1:2000', 'Var', (61, 67))	('antibody', 'cellular_component', 'GO:0019815', ('181', '189'))	('1:50,000', 'Var', (195, 203))	('antibody', 'cellular_component', 'GO:0019814', ('181', '189'))	('GAPDH', 'Gene', (143, 148))	('antibody', 'molecular_function', 'GO:0003823', ('181', '189'))	('beta-catenin', 'Gene', (80, 92))	('1: 2500', 'Var', (150, 157))	('DLX1', 'Gene', '1745', (28, 32))	('beta-catenin', 'Gene', '1499', (80, 92))	('antibody', 'cellular_component', 'GO:0042571', ('181', '189'))	('1: 7500', 'Var', (121, 128))	('DLX1', 'Gene', (28, 32))
158694	33740948	Likewise, silencing of miR-4429 was also found to increase the viability of glioblastoma multiforme cells.	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (76, 99))	('viability', 'CPA', (63, 72))	('miR-4429', 'Gene', (23, 31))	('increase', 'PosReg', (50, 58))	('miR-4429', 'Gene', '100616469', (23, 31))	('glioblastoma multiforme', 'Disease', (76, 99))	('silencing', 'Var', (10, 19))
158704	33740948	Aberrant activation of the Wnt/beta-catenin is closely associated with onset and progression of multiple human cancers, leaving this signaling as a potential target for cancer therapy.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('human', 'Species', '9606', (105, 110))	('activation', 'PosReg', (9, 19))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('beta-catenin', 'Gene', (31, 43))	('cancers', 'Disease', (111, 118))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (169, 175))	('signaling', 'biological_process', 'GO:0023052', ('133', '142'))	('beta-catenin', 'Gene', '1499', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
158706	33740948	Wnt signaling aberrant activation is able to induce nuclear beta-catenin accumulation, contributing to transcriptional activation of proto-oncogenes that are associated with cell progression.	('proto-oncogenes', 'Gene', (133, 148))	('transcriptional', 'MPA', (103, 118))	('activation', 'PosReg', (23, 33))	('aberrant', 'Var', (14, 22))	('activation', 'PosReg', (119, 129))	('beta-catenin', 'Gene', (60, 72))	('beta-catenin', 'Gene', '1499', (60, 72))	('signaling', 'biological_process', 'GO:0023052', ('4', '13'))
158708	33740948	In addition to the finding that miR-4429 inactivated this pathway, overexpression of DLX1 was found to increase the protein level of beta-catenin, indicating that down-regulation of Wnt/beta-catenin was implicated in the miR-4429/DLX1-mediated events.	('beta-catenin', 'Gene', '1499', (133, 145))	('miR-4429', 'Gene', (32, 40))	('increase', 'PosReg', (103, 111))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('miR-4429', 'Gene', (221, 229))	('beta-catenin', 'Gene', (186, 198))	('miR-4429', 'Gene', '100616469', (221, 229))	('miR-4429', 'Gene', '100616469', (32, 40))	('beta-catenin', 'Gene', '1499', (186, 198))	('beta-catenin', 'Gene', (133, 145))	('overexpression', 'Var', (67, 81))	('DLX1', 'Gene', (85, 89))	('DLX1', 'Gene', '1745', (85, 89))	('DLX1', 'Gene', '1745', (230, 234))	('DLX1', 'Gene', (230, 234))	('regulation', 'biological_process', 'GO:0065007', ('168', '178'))
158722	30591082	Of the patients whose genomic alterations were analyzed, two patients with mutations in bromodomain-containing genes (PBRM1 and BRD8) had a clinical benefit.	('BRD8', 'Gene', (128, 132))	('PBRM1', 'Gene', '55193', (118, 123))	('benefit', 'PosReg', (149, 156))	('patients', 'Species', '9606', (61, 69))	('mutations', 'Var', (75, 84))	('PBRM1', 'Gene', (118, 123))	('patients', 'Species', '9606', (7, 15))	('BRD8', 'Gene', '10902', (128, 132))
158723	30591082	Resistant clones in a patient with exceptional response to ipilimumab showed loss of BRD8 mutations and increased mutational load driven by parallel evolution affecting 17 genes (median mutations per gene, 3), which were enriched mainly for O-glycan processing (29.4%, FDR = 9.7 x 10- 6).	('ipilimumab', 'Chemical', 'MESH:D000074324', (59, 69))	('mutations', 'Var', (90, 99))	('O-glycan processing', 'biological_process', 'GO:0016266', ('241', '260'))	('BRD8', 'Gene', '10902', (85, 89))	('BRD8', 'Gene', (85, 89))	('loss', 'NegReg', (77, 81))	('O-glycan', 'Chemical', '-', (241, 249))	('patient', 'Species', '9606', (22, 29))
158726	30591082	As tRCCs with TFE3 or TFEB mutations share clinical, histopathological and molecular features, the 2013 ISUP Vancouver classification grouped these entities as the "MiTF/TFE translocation carcinomas family".	('mutations', 'Var', (27, 36))	('TFEB', 'Gene', '7942', (22, 26))	('TFE3', 'Gene', '7030', (14, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))	('TFEB', 'Gene', (22, 26))	('MiTF', 'Gene', (165, 169))	('MiTF', 'Gene', '4286', (165, 169))	('TFE3', 'Gene', (14, 18))	('RCC', 'Disease', (4, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('RCC', 'Disease', 'MESH:C538614', (4, 7))	('carcinomas', 'Disease', (188, 198))	('carcinomas', 'Disease', 'MESH:D002277', (188, 198))
158778	30591082	Notably, SMARCA4 mutation was the sole recurrent mutation, identified in 2 cases.	('SMARCA4', 'Gene', '6597', (9, 16))	('mutation', 'Var', (17, 25))	('SMARCA4', 'Gene', (9, 16))
158779	30591082	The two patients which showed clinical benefit lasting for at least 6 months harbored mutations of bromodomain member genes (PBRM1 and BRD8) (Fig.	('mutations', 'Var', (86, 95))	('harbored', 'Reg', (77, 85))	('BRD8', 'Gene', '10902', (135, 139))	('BRD8', 'Gene', (135, 139))	('PBRM1', 'Gene', (125, 130))	('PBRM1', 'Gene', '55193', (125, 130))	('patients', 'Species', '9606', (8, 16))
158781	30591082	The number of somatic mutations in these 2 resistant clones was high, ranging from 120 to 136 mutations/50 Mb as compared to 30 mutations/50 Mb in the primary tumor (Fig.	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('mutations/50', 'Var', (94, 106))
158784	30591082	CDC27 was the most frequently mutated gene, involving 13 and 14 single-nucleotide polymorphisms in resistant clones 1 and 2, respectively (Fig.	('CDC27', 'Gene', '996', (0, 5))	('single-nucleotide polymorphisms', 'Var', (64, 95))	('CDC27', 'Gene', (0, 5))
158786	30591082	Although genetic assessment was available for limited number of samples, we discovered that tumors of patients with clinical benefit harbored mutations in bromodomain-containing genes.	('mutations', 'Var', (142, 151))	('harbored', 'Reg', (133, 141))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('bromodomain-containing genes', 'Gene', (155, 183))	('patients', 'Species', '9606', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))
158802	30591082	Higher tumor mutational load has been correlated with response to ICIs in several tumor types.	('mutational load', 'Var', (13, 28))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
158804	30591082	It is, however, important to highlight here that the two patients lasting clinical benefit harbored somatic mutations of bromodomain-containing genes PBRM1 and BRD8.	('BRD8', 'Gene', '10902', (160, 164))	('PBRM1', 'Gene', (150, 155))	('BRD8', 'Gene', (160, 164))	('mutations', 'Var', (108, 117))	('patients', 'Species', '9606', (57, 65))	('PBRM1', 'Gene', '55193', (150, 155))
158805	30591082	Recently, mutations of PBRM1 have been shown to be associated with benefit from nivolumab in patients with ccRCC.	('PBRM1', 'Gene', (23, 28))	('PBRM1', 'Gene', '55193', (23, 28))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('benefit', 'PosReg', (67, 74))	('mutations', 'Var', (10, 19))	('patients', 'Species', '9606', (93, 101))	('nivolumab', 'Chemical', 'MESH:D000077594', (80, 89))
158808	30591082	Notably, this is the first published report, to our knowledge, not only of a loss of BRD8 mutation in the 2 resistant clones in response to an ICI but also of an increase in mutational load and a phenomenon of parallel evolution affecting genes involved in O-glycosylation.	('increase', 'PosReg', (162, 170))	('response to an ICI', 'MPA', (128, 146))	('mutational load', 'MPA', (174, 189))	('BRD8', 'Gene', '10902', (85, 89))	('BRD8', 'Gene', (85, 89))	('glycosylation', 'biological_process', 'GO:0070085', ('259', '272'))	('loss', 'NegReg', (77, 81))	('mutation', 'Var', (90, 98))
158809	30591082	Furthermore, unbiased genomic screens showed recently that dysfunction of CDC27, a member of the anaphase-promoting complex/cyclosome, limits excessive instability of cancer chromosomes, allowing tumor cells to dynamically improve their fitness during cancer evolution.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('limits', 'NegReg', (135, 141))	('cancer', 'Disease', (167, 173))	('CDC27', 'Gene', (74, 79))	('improve', 'PosReg', (223, 230))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('allowing tumor', 'Disease', (187, 201))	('dysfunction', 'Var', (59, 70))	('allowing tumor', 'Disease', 'MESH:D009369', (187, 201))	('cyclosome', 'cellular_component', 'GO:0005680', ('124', '133'))	('anaphase-promoting complex', 'cellular_component', 'GO:0005680', ('97', '123'))	('fitness', 'Disease', 'MESH:D012640', (237, 244))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('fitness', 'Disease', (237, 244))	('CDC27', 'Gene', '996', (74, 79))	('instability', 'MPA', (152, 163))	('anaphase', 'biological_process', 'GO:0051322', ('97', '105'))
158811	30591082	For example, PTEN mutation and reduced expression of genes encoding neoantigens was recently identified as potential mediators of resistance to immune checkpoint therapy in one patient with metastatic uterine leiomyosarcoma who had experienced complete tumor remission for > 2 years on anti-PD-1 monotherapy.	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (201, 223))	('PD-1', 'Gene', (291, 295))	('reduced', 'NegReg', (31, 38))	('PD-1', 'Gene', '5133', (291, 295))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('leiomyosarcoma', 'Disease', (209, 223))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('PTEN', 'Gene', '5728', (13, 17))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (209, 223))	('mutation', 'Var', (18, 26))	('tumor', 'Disease', (253, 258))	('expression', 'MPA', (39, 49))	('PTEN', 'Gene', (13, 17))	('patient', 'Species', '9606', (177, 184))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (209, 223))
158812	30591082	In addition, long term responses to anti-PD1 immunotherapy was recently described in four patients with small cell carcinoma of the ovary, a highly aggressive monogenic cancer driven by SMARCA4 mutations; this was unexpected for a low mutation burden cancer, but the majority of the tumors demonstrated PD-L1 expression with strong associated T-cell infiltration.	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('PD1', 'Gene', '5133', (41, 44))	('tumors', 'Phenotype', 'HP:0002664', (283, 289))	('PD-L1', 'Gene', (303, 308))	('expression', 'MPA', (309, 319))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('PD-L1', 'Gene', '29126', (303, 308))	('tumors', 'Disease', (283, 289))	('SMARCA4', 'Gene', '6597', (186, 193))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('small cell carcinoma of the ovary', 'Disease', (104, 137))	('T-cell infiltration', 'CPA', (343, 362))	('tumors', 'Disease', 'MESH:D009369', (283, 289))	('cancer', 'Disease', (251, 257))	('patients', 'Species', '9606', (90, 98))	('PD1', 'Gene', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('mutations', 'Var', (194, 203))	('small cell carcinoma of the ovary', 'Disease', 'MESH:D018288', (104, 137))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (104, 124))	('SMARCA4', 'Gene', (186, 193))
158817	30591082	Although the small numbers of patients limit comparison, the earlier studies, which used TFE3 staining to confirm the diagnosis, may have included patients without a true translocation, whereas in this study the majority of cases (87.5%) were confirmed by FISH confirmation of translocation.	('TFE3', 'Gene', '7030', (89, 93))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (30, 38))	('TFE3', 'Gene', (89, 93))	('translocation', 'Var', (277, 290))
158824	30591082	Mutations in bromodomain-containing genes might predict response to ICIs as reported in other cancer subtypes, and this requires prospective exploration.	('bromodomain-containing genes', 'Gene', (13, 41))	('predict', 'Reg', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
158826	30591082	Given the early data showing high rates of response to combinations of an ICI and a VEGFR-targeted agent in patients with ccRCC, combinations are now being explored in clinical trials in non-ccRCC, including tRCC [NCT02724878, NCT02496208].	('RCC', 'Disease', (124, 127))	('RCC', 'Disease', (193, 196))	('VEGFR', 'Gene', (84, 89))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('NCT02496208]', 'Var', (227, 239))	('RCC', 'Disease', 'MESH:C538614', (209, 212))	('VEGFR', 'Gene', '3791', (84, 89))	('RCC', 'Disease', (209, 212))	('patients', 'Species', '9606', (108, 116))
158841	30386718	Implications of Programmed Death Ligand-1 Positivity in Non-Clear Cell Renal Cell Carcinoma The purpose of this study was to assess the prognostic value of programmed death ligand-1 (PD-L1) positivity in a non-clear cell renal cell carcinoma (non-ccRCC) cohort.	('PD-L1', 'Gene', (183, 188))	('Non-Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (56, 91))	('Carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('-Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (59, 91))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (216, 241))	('Non-Clear Cell Renal Cell Carcinoma', 'Disease', (56, 91))	('cell renal cell carcinoma', 'Disease', (216, 241))	('PD-L1', 'Gene', '29126', (183, 188))	('RCC', 'Phenotype', 'HP:0005584', (249, 252))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (221, 241))	('positivity', 'Var', (190, 200))	('RCC', 'Disease', 'MESH:C538614', (249, 252))	('RCC', 'Disease', (249, 252))	('-clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (209, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('ligand', 'molecular_function', 'GO:0005488', ('173', '179'))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (71, 91))
158846	30386718	Non-ccRCC subtypes included sarcomatoid (n = 9), rhabdoid (n = 6), medullary (n = 2), Xp11.2 translocation (n = 2), collecting duct (n = 1), papillary type I (n = 11), and papillary type II (n = 14).	('Xp11.2 translocation', 'Var', (86, 106))	('rhabdoid', 'Disease', (49, 57))	('papillary type I', 'Disease', (141, 157))	('papillary type II', 'Disease', (172, 189))	('sarcomatoid', 'Disease', (28, 39))	('medullary', 'Disease', (67, 76))	('papillary type II', 'Disease', 'MESH:D002291', (172, 189))	('collecting duct', 'Disease', (116, 131))	('papillary type', 'Phenotype', 'HP:0007482', (172, 186))	('rhabdoid', 'Disease', 'MESH:D018335', (49, 57))	('sarcomatoid', 'Disease', 'MESH:C538614', (28, 39))	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('papillary type', 'Phenotype', 'HP:0007482', (141, 155))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))
158848	30386718	PD-L1 positivity was significantly associated with higher Fuhrman nuclear grade (P = 0.048) and perineural invasion (P = 0.043).	('Fuhrman nuclear grade', 'CPA', (58, 79))	('positivity', 'Var', (6, 16))	('PD-L1', 'Gene', (0, 5))	('higher', 'PosReg', (51, 57))	('PD-L1', 'Gene', '29126', (0, 5))	('perineural invasion', 'CPA', (96, 115))
158850	30386718	Five-year RFS was 55.6 and 61.5% for PD-L1 positive and negative tumors, respectively (P = 0.58).	('positive', 'Var', (43, 51))	('PD-L1', 'Gene', (37, 42))	('PD-L1', 'Gene', '29126', (37, 42))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
158882	30386718	Histology subtypes included sarcomatoid RCC (n = 9), rhabdoid RCC (n = 6), medullary RCC (n = 2), Xp11.2 translocation RCC (n = 2), collecting duct RCC (n = 1), papillary type I RCC (n = 11), and papillary type II RCC (n = 14).	('RCC', 'Disease', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('sarcomatoid RCC', 'Disease', (28, 43))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('papillary type II RCC', 'Disease', 'MESH:C538614', (196, 217))	('RCC', 'Disease', 'MESH:C538614', (214, 217))	('papillary type', 'Phenotype', 'HP:0007482', (161, 175))	('RCC', 'Disease', (178, 181))	('sarcomatoid RCC', 'Disease', 'MESH:C538614', (28, 43))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('rhabdoid RCC', 'Disease', (53, 65))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('papillary type I RCC', 'Disease', (161, 181))	('RCC', 'Disease', (40, 43))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('papillary type II RCC', 'Disease', (196, 217))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('papillary type', 'Phenotype', 'HP:0007482', (196, 210))	('RCC', 'Disease', (119, 122))	('papillary type I RCC', 'Disease', 'MESH:C538614', (161, 181))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('Xp11.2 translocation', 'Var', (98, 118))	('rhabdoid RCC', 'Disease', 'MESH:C538614', (53, 65))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('RCC', 'Disease', (214, 217))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (85, 88))	('RCC', 'Disease', 'MESH:C538614', (62, 65))
158885	30386718	PD-L1 positivity on tumor cells was noted in nine (20%) patients (Figure 1), including two papillary type 2 (18%), three sarcomatoid (33%), three rhabdoid (50%), and one Xp11.2 translocation tumors (50%).	('sarcomatoid', 'Disease', (121, 132))	('patients', 'Species', '9606', (56, 64))	('translocation tumors', 'Disease', (177, 197))	('rhabdoid', 'Disease', (146, 154))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('papillary type', 'Phenotype', 'HP:0007482', (91, 105))	('translocation tumors', 'Disease', 'MESH:D014178', (177, 197))	('positivity', 'Var', (6, 16))	('rhabdoid', 'Disease', 'MESH:D018335', (146, 154))	('PD-L1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('sarcomatoid', 'Disease', 'MESH:C538614', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('PD-L1', 'Gene', '29126', (0, 5))	('tumor', 'Disease', (20, 25))
158886	30386718	PD-L1 positivity was significantly associated with higher Fuhrman nuclear grade (P = 0.048) and perineural invasion (P = 0.043) (Table 2).	('Fuhrman nuclear grade', 'CPA', (58, 79))	('positivity', 'Var', (6, 16))	('PD-L1', 'Gene', (0, 5))	('higher', 'PosReg', (51, 57))	('PD-L1', 'Gene', '29126', (0, 5))	('perineural invasion', 'CPA', (96, 115))
158896	30386718	were one of the first groups to demonstrate PD-L1 expression as a significant predictor of cancer progression and mortality in ccRCC.	('mortality', 'CPA', (114, 123))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('expression', 'Var', (50, 60))	('PD-L1', 'Gene', (44, 49))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('RCC', 'Disease', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('PD-L1', 'Gene', '29126', (44, 49))
158898	30386718	assessed PD-L1 expression in 101 non-ccRCC patients including chromophobe (n = 36), papillary (n = 50), collecting duct (n = 5), and Xp.11.2 translocation (n = 10) variants.	('chromophobe', 'Disease', (62, 73))	('variants', 'Var', (164, 172))	('patients', 'Species', '9606', (43, 51))	('PD-L1', 'Gene', '29126', (9, 14))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('PD-L1', 'Gene', (9, 14))
158899	30386718	PD-L1 positivity on tumor cells (11 cases, 10.9%) was significantly associated with higher stage and Fuhrman grade, and a worse overall survival.	('worse', 'NegReg', (122, 127))	('higher stage', 'CPA', (84, 96))	('associated', 'Reg', (68, 78))	('positivity', 'Var', (6, 16))	('overall', 'MPA', (128, 135))	('PD-L1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('Fuhrman grade', 'CPA', (101, 114))	('PD-L1', 'Gene', '29126', (0, 5))	('tumor', 'Disease', (20, 25))
158900	30386718	Similarly, our study revealed that PD-L1 positivity was associated with higher Fuhrman grade and perineural invasion, with a trend towards worse oncological outcomes.	('PD-L1', 'Gene', '29126', (35, 40))	('perineural invasion', 'CPA', (97, 116))	('positivity', 'Var', (41, 51))	('Fuhrman grade', 'CPA', (79, 92))	('higher', 'PosReg', (72, 78))	('PD-L1', 'Gene', (35, 40))
158908	30386718	Moreover, this study validates the findings of the only previous report showing a correlation between PD-L1 positivity and adverse histopathologic features in non-ccRCC.	('correlation', 'Interaction', (82, 93))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('positivity', 'Var', (108, 118))	('PD-L1', 'Gene', (102, 107))	('PD-L1', 'Gene', '29126', (102, 107))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('RCC', 'Disease', (165, 168))
158928	28109828	Moreover, PDZK1 knockdown in MCF-7 cells blocked estrogen receptor-dependent growth and reduced c-Myc expression.	('c-Myc', 'Gene', '4609', (96, 101))	('estrogen receptor-dependent', 'Protein', (49, 76))	('c-Myc', 'Gene', (96, 101))	('knockdown', 'Var', (16, 25))	('PDZK1', 'Gene', (10, 15))	('blocked', 'NegReg', (41, 48))	('MCF-7', 'CellLine', 'CVCL:0031', (29, 34))	('reduced', 'NegReg', (88, 95))	('PDZK1', 'Gene', '5174', (10, 15))
158942	32737216	Using orthogonal approaches including Mass Spectrometry on immune cell infiltrates, we report numerous alterations that provide new insight into the biology of treatment-naive ccRCC and identification of novel targets that may prove to be clinically impactful.	('alterations', 'Var', (103, 114))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('RCC', 'Disease', (178, 181))
158943	32737216	Highlights Using ExCYT, genomics, and Mass Spectrometry, we were able to uncover immune cell marker alterations that provide new insight into the biology of early stage ccRCC.	('RCC', 'Disease', (171, 174))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('alterations', 'Var', (100, 111))
158961	32737216	Genetic alterations that influence susceptibility to immunotherapy continue to be identified, further solidifying the impactful role of the immune system in ccRCC.	('Genetic alterations', 'Var', (0, 19))	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('RCC', 'Disease', (159, 162))
159006	32737216	Cluster 2 was defined by higher expression of CD15 and CD16, whereas cluster 3 was defined by relatively higher expression of CD11b, CD14, CD33, and HLA-DR. Taken together, these data provide evidence that the NAT may be characterized by CD15+CD16+ cells of potential granulocytic identity whereas the TME is characterized by CD11b+CD14+CD33+HLA-DR+ cells of potential monocytic/macrophage cellular identity.	('CD11b', 'Gene', (326, 331))	('CD11b', 'Gene', '3684', (326, 331))	('CD11b', 'Gene', '3684', (126, 131))	('CD15+CD16+', 'Var', (238, 248))	('CD11b', 'Gene', (126, 131))
159011	32737216	Given significant up-regulation of myeloid-related genes in CD45+ enriched fractions in the TME relative to patient-matched NAT, we sought to validate several top differentially expressed genes by quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR).	('up-regulation', 'PosReg', (18, 31))	('regulation', 'biological_process', 'GO:0065007', ('21', '31'))	('Reverse Transcription', 'biological_process', 'GO:0001171', ('210', '231'))	('myeloid-related genes', 'Gene', (35, 56))	('patient', 'Species', '9606', (108, 115))	('CD45+', 'Var', (60, 65))
159012	32737216	A total of 6 clinically localized ccRCC tissues and matched NAT underwent CD45+ enrichment as previously described (Fig.	('RCC', 'Disease', (36, 39))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('CD45+ enrichment', 'Var', (74, 90))
159024	32737216	Interestingly, we observed several proteins robustly detected in RCC-derived CD45+ cells, but not NAT-derived CD45+ cells including CD36, CXCL8 and VAV1, further supporting a disparate activated immune profile associated with of CD45+ cells in RCC tissues relative to CD45+ cells in NATs.	('RCC', 'Disease', (244, 247))	('CD45+ cells', 'Var', (229, 240))	('activated immune profile', 'MPA', (185, 209))	('CD36', 'Species', '42374', (132, 136))	('RCC', 'Disease', 'MESH:C538614', (244, 247))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
159048	32359397	We found that RMC was characterized by high replication stress and an abundance of focal copy number alterations associated with activation of the stimulator of the cyclic GMP-AMP synthase interferon genes (cGAS-STING) innate immune pathway.	('RMC', 'Disease', (14, 17))	('alterations', 'Var', (101, 112))	('cGAS-STING', 'Gene', (207, 217))	('RMC', 'Chemical', '-', (14, 17))	('activation', 'PosReg', (129, 139))
159051	32359397	These tumors harbor SMARCB1 mutations leading to high MYC expression and replicative stress that sensitize RMC cells to PARP inhibitors.	('leading', 'Reg', (38, 45))	('high MYC expression', 'MPA', (49, 68))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('RMC', 'Chemical', '-', (107, 110))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('SMARCB1', 'Gene', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('mutations', 'Var', (28, 37))
159060	32359397	Inactivation of SMARCB1 deregulates the activity of SWI/SNF, resulting in aggressive tumors.	('resulting in', 'Reg', (61, 73))	('aggressive tumors', 'Disease', 'MESH:D001523', (74, 91))	('deregulates', 'Reg', (24, 35))	('SMARCB1', 'Gene', (16, 23))	('aggressive tumors', 'Disease', (74, 91))	('activity', 'MPA', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Inactivation', 'Var', (0, 12))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
159061	32359397	In addition to RMC, inactivation of SMARCB1 occurs in the majority of malignant rhabdoid tumors (MRT), atypical teratoid/rhabdoid tumors (ATRT), and epithelioid sarcomas (ES).	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('occurs', 'Reg', (44, 50))	('sarcomas', 'Disease', (161, 169))	('inactivation', 'Var', (20, 32))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('malignant rhabdoid tumors', 'Disease', (70, 95))	('SMARCB1', 'Gene', (36, 43))	('rhabdoid tumors', 'Disease', (121, 136))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (121, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('sarcomas', 'Disease', 'MESH:D012509', (161, 169))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('RMC', 'Chemical', '-', (15, 18))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (80, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (161, 169))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (70, 95))
159066	32359397	Overall, rates of single nucleotide variants (SNVs) and insertion and deletion mutations (inDels) were very low for RMC.	('deletion mutations', 'Var', (70, 88))	('RMC', 'Chemical', '-', (116, 119))	('insertion', 'Var', (56, 65))	('low', 'NegReg', (108, 111))	('RMC', 'Disease', (116, 119))	('single nucleotide variants', 'Var', (18, 44))
159068	32359397	A total of 1332 SNVs and inDels in 1165 genes were identified by WES, with a median of 24 per patient (Figure 1 and Supplementary Table 1).	('inDels', 'Var', (25, 31))	('SNVs', 'Var', (16, 20))	('men', 'Species', '9606', (122, 125))	('patient', 'Species', '9606', (94, 101))
159069	32359397	Clinical targeted next-generation sequencing of 5/31 untreated primary tumor samples (Figure 1) did not detect additional SNVs and inDels.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('inDels', 'Var', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('SNVs', 'Var', (122, 126))	('tumor', 'Disease', (71, 76))
159072	32359397	Of the 1165 genes mutated in untreated primary RMC tumors from a total of 31 patients, only 22 were known tumor suppressors or oncogenes listed in the Catalogue of Somatic Mutations in Cancer (COSMIC) database (Figure S1B and Supplementary Table 1).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mutated', 'Var', (18, 25))	('tumor', 'Disease', (51, 56))	('RMC tumors', 'Disease', 'MESH:D009369', (47, 57))	('men', 'Species', '9606', (232, 235))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('patients', 'Species', '9606', (77, 85))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('Cancer', 'Disease', (185, 191))	('Cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('Cancer', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Disease', (106, 111))	('RMC tumors', 'Disease', (47, 57))
159076	32359397	SETD2 was mutated in 2/31 (6.5%) of RMC tumors and was the only established gene driver of other renal cell carcinomas to be altered in RMC (Figure 1 and Supplementary Table 1).	('mutated', 'Var', (10, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (97, 117))	('RMC', 'Chemical', '-', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('renal cell carcinomas', 'Disease', (97, 118))	('RMC tumors', 'Disease', 'MESH:D009369', (36, 46))	('SETD2', 'Gene', '29072', (0, 5))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('SETD2', 'Gene', (0, 5))	('men', 'Species', '9606', (160, 163))	('RMC', 'Chemical', '-', (36, 39))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (97, 118))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (97, 118))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('RMC tumors', 'Disease', (36, 46))
159078	32359397	Whereas other SMARCB1-deficient malignancies, such as the rhabdoid tumors MRT and ATRT, harbor a simple genome with very few CNAs other than 22q11.23 loss (Figure S1E), RMC had recurrent focal chromosomal amplifications and deletions in addition to 22q11.23 loss (Figures 2C, 2D, and S2).	('loss', 'NegReg', (258, 262))	('rhabdoid tumors MRT', 'Disease', (58, 77))	('deletions', 'Var', (224, 233))	('deficient malignancies', 'Disease', 'MESH:D009369', (22, 44))	('RMC', 'Chemical', '-', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('rhabdoid tumors MRT', 'Disease', 'MESH:D018335', (58, 77))	('deficient malignancies', 'Disease', (22, 44))
159086	32359397	The most common focal deletion in both RMC and rhabdoid tumors was in the SMARCB1 locus 22q11.23 found in 9/15 (60%) RMC tumors and in 28/35 (80%) rhabdoid tumors.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('deletion', 'Var', (22, 30))	('RMC tumors', 'Disease', (117, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('rhabdoid tumors', 'Disease', (147, 162))	('rhabdoid tumors', 'Disease', (47, 62))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (47, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('SMARCB1', 'Gene', (74, 81))	('RMC', 'Chemical', '-', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (147, 162))	('RMC tumors', 'Disease', 'MESH:D009369', (117, 127))	('RMC', 'Chemical', '-', (39, 42))
159089	32359397	Furthermore, we found amplification of NOTCH2 in 6/15 (40%) RMC tumors, with 4/15 (26.7%) demonstrating concurrent deletion of NOTCH1 and NOTCH3 and amplification of NOTCH2, a distinct pattern also found in the basal subtype of bladder urothelial carcinoma (BLCA) and associated with increased cell-cycle progression and epithelial-mesenchymal transition (EMT).	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('RMC tumors', 'Disease', (60, 70))	('amplification', 'Var', (149, 162))	('NOTCH2', 'Gene', (166, 172))	('amplification', 'Var', (22, 35))	('NOTCH1', 'Gene', (127, 133))	('EMT', 'biological_process', 'GO:0001837', ('356', '359'))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('cell-cycle', 'biological_process', 'GO:0007049', ('294', '304'))	('RMC tumors', 'Disease', 'MESH:D009369', (60, 70))	('bladder urothelial carcinoma', 'Disease', (228, 256))	('NOTCH1', 'Gene', '4851', (127, 133))	('NOTCH3', 'Gene', '4854', (138, 144))	('NOTCH2', 'Gene', '4853', (39, 45))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (228, 256))	('NOTCH3', 'Gene', (138, 144))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('321', '354'))	('deletion', 'Var', (115, 123))	('NOTCH2', 'Gene', '4853', (166, 172))	('cell-cycle progression', 'CPA', (294, 316))	('NOTCH2', 'Gene', (39, 45))	('increased', 'PosReg', (284, 293))	('epithelial-mesenchymal transition', 'CPA', (321, 354))
159091	32359397	By integrating our genomic and RNA-seq data we identified 341 genes (Supplementary Table 2) in areas of recurrent focal copy number gain or loss that were significantly (FDR < 0.1) upregulated or downregulated, respectively, in RMC tumors compared with adjacent normal kidney.	('focal copy number', 'Var', (114, 131))	('RMC tumors', 'Disease', 'MESH:D009369', (228, 238))	('RNA', 'cellular_component', 'GO:0005562', ('31', '34'))	('gain', 'PosReg', (132, 136))	('upregulated', 'PosReg', (181, 192))	('downregulated', 'NegReg', (196, 209))	('men', 'Species', '9606', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('RMC tumors', 'Disease', (228, 238))	('loss', 'NegReg', (140, 144))
159092	32359397	The reliability of our CNA analyses of WES data was confirmed in sample MED1T by array CGH (Figure 3A), which detected the presence of the focal amplification on chromosome 2p, large amplification of chromosome 8, monosomy of chromosomes 4 and 22, large deletions of chromosomes 15 and 16, and a focal deletion of chromosome 17p13.1 (TP53 gene region), which were also found by WES (Figure S2).	('chromosome', 'cellular_component', 'GO:0005694', ('314', '324'))	('MED1', 'Gene', (72, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('162', '172'))	('monosomy', 'Var', (214, 222))	('chromosome', 'cellular_component', 'GO:0005694', ('200', '210'))	('MED1', 'Gene', '5469', (72, 76))
159095	32359397	Less frequent were deletion of both SMARCB1 alleles (6/38 patients; 15.8%), deletion of one SMARCB1 allele and inDel of the second SMARCB1 allele (5/38 patients; 13.2%), and deletion of one SMARCB1 allele and truncating nonsense mutation of the second SMARCB1 allele (1/38 patients; 2.6%).	('deletion', 'Var', (76, 84))	('patients', 'Species', '9606', (273, 281))	('SMARCB1', 'Gene', (190, 197))	('SMARCB1', 'Gene', (252, 259))	('deletion', 'Var', (19, 27))	('truncating nonsense mutation', 'Var', (209, 237))	('SMARCB1', 'Gene', (36, 43))	('deletion', 'Var', (174, 182))	('SMARCB1', 'Gene', (92, 99))	('patients', 'Species', '9606', (58, 66))	('patients', 'Species', '9606', (152, 160))
159097	32359397	In addition, we determined that this pattern for SMARCB1 inactivation (inactivating translocation combined with hemizygous deletion) occurred not only in primary tumors but also in lymph node and liver mestastases of patients RMC38 and RMC32, respectively.	('inactivation', 'NegReg', (57, 69))	('liver mestastases', 'Disease', (196, 213))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('RMC', 'Chemical', '-', (226, 229))	('patients', 'Species', '9606', (217, 225))	('tumors', 'Disease', (162, 168))	('RMC', 'Chemical', '-', (236, 239))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('RMC38', 'Var', (226, 231))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('liver mestastases', 'Disease', 'MESH:D017093', (196, 213))	('SMARCB1', 'Gene', (49, 56))
159098	32359397	Sanger sequencing confirmed that both the primary kidney tumor and the liver metastasis of patient RMC32 harbored the same translocation between the SMARCB1 and MYOM1 genes (Figures 3E and 3F).	('translocation', 'Var', (123, 136))	('kidney tumor', 'Disease', 'MESH:D007680', (50, 62))	('SMARCB1', 'Gene', (149, 156))	('kidney tumor', 'Phenotype', 'HP:0009726', (50, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('kidney tumor', 'Disease', (50, 62))	('MYOM1', 'Gene', (161, 166))	('liver metastasis', 'CPA', (71, 87))	('patient', 'Species', '9606', (91, 98))	('RMC', 'Chemical', '-', (99, 102))	('MYOM1', 'Gene', '8736', (161, 166))
159101	32359397	RNA-seq (see below) of 5 samples (RMC32T, RMC36T1, MED1T, MED2T, MED5T) that harbored inactivating translocations identified SMARCB1 fusion transcripts in 2/5 cases (RMC32T and MED1T) as shown in Figure 3E.	('RMC36T1', 'CellLine', 'CVCL:5354', (42, 49))	('RMC', 'Chemical', '-', (34, 37))	('SMARCB1', 'Gene', (125, 132))	('MED1', 'Gene', (177, 181))	('MED1', 'Gene', '5469', (177, 181))	('RMC', 'Chemical', '-', (42, 45))	('MED1', 'Gene', '5469', (51, 55))	('RMC32T', 'Var', (166, 172))	('RMC', 'Chemical', '-', (166, 169))	('MED5T', 'CellLine', 'CVCL:M137', (65, 70))	('MED1', 'Gene', (51, 55))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('inactivating translocations', 'Var', (86, 113))
159105	32359397	The RMC36T1 sample that clustered within the CDC samples in our unsupervised analysis of protein-coding gene expression (Figure 4A) was confirmed to be RMC as the patient had sickle cell trait by hemoglobin electrophoresis (Figure 1) and the tumor was negative for SMARCB1 by immunohistochemistry (Figure S1A).	('sickle cell trait', 'Disease', (175, 192))	('RMC36T1', 'CellLine', 'CVCL:5354', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('RMC', 'Chemical', '-', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('gene expression', 'biological_process', 'GO:0010467', ('104', '119'))	('patient', 'Species', '9606', (163, 170))	('tumor', 'Disease', (242, 247))	('RMC', 'Chemical', '-', (152, 155))	('RMC36T1', 'Var', (4, 11))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
159108	32359397	The distinct gene expression profiles of RMC compared with kidney MRT, despite their common renal origin and shared etiology of SMARCB1 inactivation, led us to explore the nephron site of origin of these malignancies.	('malignancies', 'Disease', (204, 216))	('inactivation', 'Var', (136, 148))	('SMARCB1', 'Gene', (128, 135))	('gene expression', 'biological_process', 'GO:0010467', ('13', '28'))	('RMC', 'Chemical', '-', (41, 44))	('malignancies', 'Disease', 'MESH:D009369', (204, 216))	('RMC', 'Disease', (41, 44))
159142	32359397	In the mutational landscape of RMC we noted that the most common substitutions in most RMC tumors were C > T transitions (Figure 1), which are linked to the process of cytosine deamination often associated with age or DNA replication stress.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('RMC tumors', 'Disease', 'MESH:D009369', (87, 97))	('DNA replication', 'biological_process', 'GO:0006260', ('218', '233'))	('C > T transitions', 'Var', (103, 120))	('DNA', 'cellular_component', 'GO:0005574', ('218', '221'))	('RMC', 'Chemical', '-', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('RMC tumors', 'Disease', (87, 97))	('RMC', 'Chemical', '-', (87, 90))	('cytosine', 'Chemical', 'MESH:D003596', (168, 176))
159143	32359397	However, patient age did not strongly correlate with the number of C > T mutations (Spearman rank correlation = 0.395, p = 0.145), suggesting that they are instead caused by replication stress in the setting of high cell turnover.	('C > T mutations', 'Var', (67, 82))	('patient', 'Species', '9606', (9, 16))	('caused by', 'Reg', (164, 173))
159144	32359397	Furthermore, the predominant mutational signature pattern in RMC tumors was Signature 1 (Figure S1C), which consists mainly of C > T transitions at CpG dinucleotide motifs and is known to be associated with age and/or high number of mitoses.	('RMC tumors', 'Disease', 'MESH:D009369', (61, 71))	('C > T transitions', 'Var', (127, 144))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('dinucleotide', 'Chemical', 'MESH:D015226', (152, 164))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('RMC tumors', 'Disease', (61, 71))
159151	32359397	We additionally used a previously established established RMC cell line (RMC219), which is also negative for inactivating SMARCB1 translocations and harbors centromeric deletions of both SMARCB1 alleles (Supplementary Table 3 and Figure S6H).	('men', 'Species', '9606', (210, 213))	('RMC', 'Chemical', '-', (58, 61))	('SMARCB1', 'Gene', (187, 194))	('RMC219', 'Chemical', '-', (73, 79))	('RMC', 'Chemical', '-', (73, 76))	('translocations', 'Var', (130, 144))	('SMARCB1', 'Gene', (122, 129))
159155	32359397	As shown using our two RMC cell lines and two other SMARCB1-negative cell lines (MRT line G401 and epitheliod sarcoma line VA-ES-BJ) in Figure 6D, high c-MYC levels correlated with expression of the DNA damage marker gammaH2AX, expression of DNA damage repair enzymes Poly-(ADP-ribose) polymerase (PARP) and ataxia-telangiectasia and Rad3-related (ATR), ATR activation via phosphorylation at serine 428, upregulation and phosphorylation at serines 4 and 8 of the RPA32 subunit of human replication protein A (a marker of DNA damage response), upregulation of FANCD2 (which protects cells from replication stress), phosphorylation of CDK1 at tyrosine 15 (which regulates the G2-M checkpoint), as well as phosphorylation of TP53 at serine 15, a marker specific to DNA damage response and not to other stimuli such as hyper-proliferation.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('ataxia', 'Phenotype', 'HP:0001251', (308, 314))	('CDK1', 'Gene', (633, 637))	('sarcoma', 'Disease', (110, 117))	('DNA', 'cellular_component', 'GO:0005574', ('199', '202'))	('phosphorylation', 'Var', (614, 629))	('DNA damage response', 'biological_process', 'GO:0006974', ('521', '540'))	('DNA damage response', 'biological_process', 'GO:0006974', ('762', '781'))	('ataxia-telangiectasia and Rad3-related', 'Gene', '685055', (308, 346))	('FANCD2', 'Gene', (559, 565))	('Poly-(ADP-ribose) polymerase', 'Gene', '25591', (268, 296))	('replication protein A', 'cellular_component', 'GO:0005662', ('486', '507'))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('serine', 'Chemical', 'MESH:D012694', (440, 446))	('CDK', 'molecular_function', 'GO:0004693', ('633', '636'))	('serine', 'Chemical', 'MESH:D012694', (392, 398))	('G2-M checkpoint', 'biological_process', 'GO:0000075', ('674', '689'))	('RPA32', 'Gene', '108689', (463, 468))	('RMC', 'Chemical', '-', (23, 26))	('phosphorylation', 'biological_process', 'GO:0016310', ('373', '388'))	('gammaH2AX', 'Gene', (217, 226))	('DNA', 'cellular_component', 'GO:0005574', ('762', '765'))	('DNA', 'cellular_component', 'GO:0005574', ('242', '245'))	('Rad', 'biological_process', 'GO:1990116', ('334', '337'))	('RPA32', 'Gene', (463, 468))	('BJ', 'CellLine', 'CVCL:6573', (129, 131))	('Poly-(ADP-ribose) polymerase', 'Gene', (268, 296))	('phosphorylation', 'biological_process', 'GO:0016310', ('703', '718'))	('telangiectasia', 'Phenotype', 'HP:0001009', (315, 329))	('upregulation', 'PosReg', (543, 555))	('serine', 'Chemical', 'MESH:D012694', (730, 736))	('RPA', 'cellular_component', 'GO:0005662', ('463', '466'))	('phosphorylation', 'MPA', (703, 718))	('phosphorylation', 'biological_process', 'GO:0016310', ('614', '629'))	('DNA', 'cellular_component', 'GO:0005574', ('521', '524'))	('TP53', 'Gene', (722, 726))	('gammaH2AX', 'Gene', '15270', (217, 226))	('phosphorylation', 'biological_process', 'GO:0016310', ('421', '436'))	('human', 'Species', '9606', (480, 485))
159156	32359397	Conversely, SMARCB1 knockout by CRISPR/Cas9 in human embryonic kidney (HEK-293FT) cells increased c-MYC and the resulting replication stress (Figures S7B and S7C).	('S7C', 'Mutation', 'p.S7C', (158, 161))	('embryonic kidney', 'Disease', 'MESH:D007674', (53, 69))	('Cas', 'cellular_component', 'GO:0005650', ('39', '42'))	('SMARCB1', 'Gene', (12, 19))	('replication', 'MPA', (122, 133))	('increased', 'PosReg', (88, 97))	('HEK-293FT', 'CellLine', 'CVCL:6911', (71, 80))	('knockout', 'Var', (20, 28))	('human', 'Species', '9606', (47, 52))	('embryonic kidney', 'Disease', (53, 69))	('c-MYC', 'MPA', (98, 103))
159165	32359397	We also found that SMARCB1-negative cell lines are sensitive to the ATR inhibitors VX970 and AZD6738 and to the WEE1 inhibitor adavosertib (Figure 7B).	('AZD6738', 'Var', (93, 100))	('ATR', 'Gene', (68, 71))	('sensitive', 'Reg', (51, 60))	('AZD6738', 'Chemical', 'MESH:C000611951', (93, 100))	('VX970', 'Var', (83, 88))	('WEE1', 'Gene', (112, 116))	('WEE1', 'Gene', '7465', (112, 116))	('adavosertib', 'Chemical', 'MESH:C549567', (127, 138))
159171	32359397	Mice harboring RMC2X tumors (n = 5 per group; average tumor volume of 158 mm3 at treatment initiation) were randomly assigned to receive niraparib, AZD6738, the combination of niraparib with AZD6738, or vehicle control for a total of 25 days.	('men', 'Species', '9606', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('AZD6738', 'Chemical', 'MESH:C000611951', (148, 155))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('AZD6738', 'Var', (148, 155))	('AZD6738', 'Chemical', 'MESH:C000611951', (191, 198))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('niraparib', 'Chemical', 'MESH:C545685', (137, 146))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', (54, 59))	('RMC', 'Chemical', '-', (15, 18))	('niraparib', 'Chemical', 'MESH:C545685', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
159174	32359397	Conversely, treatment with AZD6738 did not significantly reduce tumor volume compared with vehicle control (p = 0.54), and its combination with niraparib did not produce a stronger antitumor effect compared with niraparib alone (p = 0.868).	('tumor', 'Disease', (185, 190))	('AZD6738', 'Chemical', 'MESH:C000611951', (27, 34))	('tumor', 'Disease', (64, 69))	('AZD6738', 'Var', (27, 34))	('combination', 'Interaction', (127, 138))	('niraparib', 'Chemical', 'MESH:C545685', (212, 221))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('niraparib', 'Chemical', 'MESH:C545685', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('men', 'Species', '9606', (17, 20))
159184	32359397	CNAs in chromosomal fragile sites such as those noted in RMC can be both a source and a consequence of DNA replication stress in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('RMC', 'Chemical', '-', (57, 60))	('DNA replication', 'biological_process', 'GO:0006260', ('103', '118'))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('chromosomal fragile sites', 'Phenotype', 'HP:0040012', (8, 33))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('CNAs', 'Var', (0, 4))
159235	32359397	Thus, although our WES had high sensitivity to detect dominant clonal or subclonal RMC tumor mutations, it would be less likely to detect more rare subclonal alterations.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('RMC tumor', 'Disease', (83, 92))	('RMC tumor', 'Disease', 'MESH:D009369', (83, 92))	('mutations', 'Var', (93, 102))
159242	32359397	The somatic status of a specific SNV/inDel was reported once the matched germline had wild allele-based homozygous genotype and the tumor had heterozygous or mutant allele-based homozygous genotype with a certain cutoff of genotype likelihood/p value of 0.99.	('mutant', 'Var', (158, 164))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))
159257	32359397	DNA was labeled by random priming with CY5-dCTPs (tumor DNA) and CY3-dCTPs (control DNA), and was hybridized to 4x180K whole-genome Agilent arrays (G4448A).	('CY3-dCTPs', 'Var', (65, 74))	('CY3-dCTPs', 'Chemical', '-', (65, 74))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('CY5-dCTPs', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('G4448A', 'Mutation', 'rs1249266779', (148, 154))	('CY5-dCTPs', 'Chemical', 'MESH:C544355', (39, 48))	('tumor', 'Disease', (50, 55))
159283	32359397	Samples with break-apart in >= 15% of tumor nuclei were considered positive for SMARCB1 translocation.	('positive', 'Reg', (67, 75))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('SMARCB1', 'Gene', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('translocation', 'Var', (88, 101))
159284	32359397	Partial SMARCB1 deletion was defined as loss of either green or orange probes in >= 15% of tumor nuclei.	('orange probes', 'MPA', (64, 77))	('SMARCB1', 'Gene', (8, 15))	('deletion', 'Var', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('loss', 'NegReg', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('green', 'MPA', (55, 60))	('Partial', 'Var', (0, 7))
159367	31975570	The Cancer Genome Atlas dataset shows that low expression of both strands of pre-miR-101 (miR-101-5p and miR-101-3p) significantly predicted poor prognosis in clear cell renal cell carcinoma (ccRCC).	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (159, 190))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('miR-101-3p', 'Var', (105, 115))	('pre', 'molecular_function', 'GO:0003904', ('77', '80'))	('clear cell renal cell carcinoma', 'Disease', (159, 190))	('miR-101', 'Chemical', '-', (90, 97))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (170, 190))	('ccRCC', 'Phenotype', 'HP:0006770', (192, 197))	('RCC', 'Disease', (194, 197))	('RCC', 'Phenotype', 'HP:0005584', (194, 197))	('Cancer', 'Disease', (4, 10))	('miR-101', 'Chemical', '-', (105, 112))	('miR-101', 'Chemical', '-', (81, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('miR-101-5p', 'Chemical', '-', (90, 100))	('pre-miR-101', 'Gene', (77, 88))	('expression', 'MPA', (47, 57))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (159, 190))	('RCC', 'Disease', 'MESH:C538614', (194, 197))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('miR-101-5p', 'Var', (90, 100))	('miR-101-3p', 'Chemical', '-', (105, 115))
159368	31975570	The functional significance of miR-101-5p in cancer cells is poorly understood.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('miR-101-5p', 'Chemical', '-', (31, 41))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('miR-101-5p', 'Var', (31, 41))
159372	31975570	Expression of miR-101-5p caused cell cycle arrest and apoptosis in ccRCC cells.	('miR-101-5p', 'Var', (14, 24))	('apoptosis', 'CPA', (54, 63))	('RCC', 'Disease', (69, 72))	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (32, 49))	('arrest', 'Disease', 'MESH:D006323', (43, 49))	('apoptosis', 'biological_process', 'GO:0097194', ('54', '63'))	('apoptosis', 'biological_process', 'GO:0006915', ('54', '63'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('32', '49'))	('arrest', 'Disease', (43, 49))	('miR-101-5p', 'Chemical', '-', (14, 24))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
159373	31975570	Downstream neighbor of son (DONSON) was directly regulated by miR-101-5p, and its aberrant expression was significantly associated with shorter survival in propensity score-matched analysis (P = .0001).	('regulated', 'Reg', (49, 58))	('DONSON', 'Gene', (28, 34))	('DONSON', 'Gene', '29980', (28, 34))	('miR-101-5p', 'Chemical', '-', (62, 72))	('shorter', 'NegReg', (136, 143))	('miR-101-5p', 'Var', (62, 72))	('aberrant', 'Var', (82, 90))
159383	31975570	Therefore, the analysis of aberrantly expressed miRNAs in human cancers provides us information about cancer-modulating molecular networks.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('human', 'Species', '9606', (58, 63))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancers', 'Disease', (64, 71))	('miR', 'Gene', '220972', (48, 51))	('aberrantly', 'Var', (27, 37))	('miR', 'Gene', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
159389	31975570	Here, we focused on miR-101-5p (the passenger strand) to elucidate the function of miR-101-5p and determine its target oncogenes as useful diagnostic markers in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('ccRCC', 'Phenotype', 'HP:0006770', (161, 166))	('RCC', 'Disease', (163, 166))	('miR-101-5p', 'Chemical', '-', (20, 30))	('miR-101-5p', 'Chemical', '-', (83, 93))	('miR-101-5p', 'Var', (83, 93))
159391	31975570	Ectopic expression of miR-101-5p attenuated the aggressive phenotype of ccRCC cells.	('miR-101-5p', 'Chemical', '-', (22, 32))	('miR-101-5p', 'Var', (22, 32))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('attenuated', 'NegReg', (33, 43))	('aggressive phenotype of', 'CPA', (48, 71))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))
159392	31975570	Downstream neighbor of son (DONSON) was directly regulated by miR-101-5p, and its aberrant expression was significantly associated with shorter survival in propensity score-matched analysis.	('regulated', 'Reg', (49, 58))	('DONSON', 'Gene', (28, 34))	('DONSON', 'Gene', '29980', (28, 34))	('miR-101-5p', 'Chemical', '-', (62, 72))	('shorter', 'NegReg', (136, 143))	('miR-101-5p', 'Var', (62, 72))	('aberrant', 'Var', (82, 90))
159403	31975570	The PCR quantification was carried out as previously described.19, 20  Cell proliferation, migration, and invasion were assessed as described previously.19, 20  Clear cell RCC cells were transfected with either the transfection reagents alone as a control or miR-101-5p, miR-101-3p, and si-DONSON in 6-well tissue culture plates.	('DONSON', 'Gene', (290, 296))	('DONSON', 'Gene', '29980', (290, 296))	('miR-101-5p', 'Var', (259, 269))	('miR-101-3p', 'Var', (271, 281))	('Cell proliferation', 'biological_process', 'GO:0008283', ('71', '89'))	('miR-101-3p', 'Chemical', '-', (271, 281))	('Clear cell RCC', 'Disease', (161, 175))	('Clear cell RCC', 'Disease', 'MESH:C538614', (161, 175))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))	('miR-101-5p', 'Chemical', '-', (259, 269))
159409	31975570	The method of measuring the amount of miR-101-5p incorporated into RISC was according to a previous study.14  Candidate target genes regulated by miR-101-5p or miR-101-3p were identified using in silico and genome-wide gene expression analyses and those obtained from the TargetScan database (http://www.targetscan.org/vert_70/).	('miR-101-5p', 'Var', (146, 156))	('miR-101-5p', 'Chemical', '-', (38, 48))	('gene expression', 'biological_process', 'GO:0010467', ('219', '234'))	('miR-101-3p', 'Var', (160, 170))	('miR-101-5p', 'Chemical', '-', (146, 156))	('miR-101-3p', 'Chemical', '-', (160, 170))
159420	31975570	The mature sequences of miR-101-5p and miR-101-3p are 5'-CAGUUAUCACAGUGCUGAUGCU-3' and 5'-UACAGUACUGUGAUAACUGAA-3', respectively.	('miR-101-3p', 'Chemical', '-', (39, 49))	('miR-101-3p', 'Var', (39, 49))	('miR-101-5p', 'Chemical', '-', (24, 34))	('miR-101-5p', 'Var', (24, 34))
159421	31975570	Both miR-101-5p and miR-101-3p expressions were significantly reduced in ccRCC tissues compared with those in adjacent noncancerous tissues (P = .027 and P = .0057, respectively; Figure 1A,B).	('miR-101-3p', 'Var', (20, 30))	('miR-101-3p', 'Chemical', '-', (20, 30))	('miR-101-5p', 'Chemical', '-', (5, 15))	('expressions', 'MPA', (31, 42))	('cancer', 'Disease', (122, 128))	('miR-101-5p', 'Var', (5, 15))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))	('reduced', 'NegReg', (62, 69))
159423	31975570	From a large cohort of TCGA database, low expressions of miR-101-5p and miR-101-3p were significantly associated with high pathological grade (both, P < .0001; Figure 1D,E) and poor clinical outcomes (disease-free survival, P = .0485 and P = .0457; overall survival, P = .0397 and P = .00271, respectively, Figure 1F-I) in ccRCC patients.	('high pathological grade', 'CPA', (118, 141))	('miR-101-5p', 'Chemical', '-', (57, 67))	('miR-101-5p', 'Var', (57, 67))	('miR-101-3p', 'Var', (72, 82))	('RCC', 'Disease', 'MESH:C538614', (325, 328))	('RCC', 'Disease', (325, 328))	('RCC', 'Phenotype', 'HP:0005584', (325, 328))	('expressions', 'MPA', (42, 53))	('miR-101-3p', 'Chemical', '-', (72, 82))	('low', 'NegReg', (38, 41))	('patients', 'Species', '9606', (329, 337))	('ccRCC', 'Phenotype', 'HP:0006770', (323, 328))
159425	31975570	Furthermore, the apoptotic rate was elevated in miR-101-5p and miR-101-3p transfected cells compared to controls (Figure 2B,C).	('apoptotic rate', 'CPA', (17, 31))	('elevated', 'PosReg', (36, 44))	('miR-101-3p', 'Var', (63, 73))	('miR-101-5p', 'Chemical', '-', (48, 58))	('miR-101-3p', 'Chemical', '-', (63, 73))	('miR-101-5p', 'Var', (48, 58))
159426	31975570	In addition, transfection of miR-101-3p apparently upregulated cleaved PARP expression (Figure 2D).	('PARP', 'Gene', '142', (71, 75))	('miR-101-3p', 'Var', (29, 39))	('upregulated', 'PosReg', (51, 62))	('cleaved', 'MPA', (63, 70))	('miR-101-3p', 'Chemical', '-', (29, 39))	('PARP', 'Gene', (71, 75))
159428	31975570	We analyzed the expression levels of cell cycle-related genes by ectopic expression of miR-101-5p and/or miR-101-3p in ccRCC cells (Table S4).	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('miR-101-5p', 'Var', (87, 97))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('cell cycle', 'biological_process', 'GO:0007049', ('37', '47'))	('miR-101-3p', 'Var', (105, 115))	('miR-101-5p', 'Chemical', '-', (87, 97))	('expression', 'MPA', (16, 26))	('miR-101-3p', 'Chemical', '-', (105, 115))
159430	31975570	Cell migration and invasive abilities were significantly inhibited by ectopic expression of miR-101-5p and miR-101-3p in ccRCC cells.	('invasive abilities', 'CPA', (19, 37))	('Cell migration', 'biological_process', 'GO:0016477', ('0', '14'))	('miR-101-5p', 'Var', (92, 102))	('Cell migration', 'CPA', (0, 14))	('miR-101-3p', 'Var', (107, 117))	('inhibited', 'NegReg', (57, 66))	('miR-101-3p', 'Chemical', '-', (107, 117))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (121, 126))	('miR-101-5p', 'Chemical', '-', (92, 102))
159431	31975570	The mRNA expression levels of CDH2, VIM, ZEB1, TWIST1, SNAI1, and FN1 were reduced by miR-101-5p and/or miR-101-3p transfection into ccRCC cells.	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('VIM', 'Gene', (36, 39))	('CDH2', 'Gene', '1000', (30, 34))	('ZEB1', 'Gene', '6935', (41, 45))	('miR-101-3p', 'Chemical', '-', (104, 114))	('miR-101-5p', 'Var', (86, 96))	('TWIST1', 'Gene', (47, 53))	('miR-101-3p', 'Var', (104, 114))	('TWIST1', 'Gene', '7291', (47, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('FN1', 'Gene', '2335', (66, 69))	('mRNA expression levels', 'MPA', (4, 26))	('ZEB1', 'Gene', (41, 45))	('SNAI1', 'Gene', '6615', (55, 60))	('SNAI1', 'Gene', (55, 60))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('CDH2', 'Gene', (30, 34))	('RCC', 'Disease', (135, 138))	('reduced', 'NegReg', (75, 82))	('FN1', 'Gene', (66, 69))	('miR-101-5p', 'Chemical', '-', (86, 96))	('VIM', 'Gene', '7431', (36, 39))
159432	31975570	Furthermore, we investigated the expression changes of EMT-related proteins (eg, E-cadherin, N-cadherin, SLUG, Vimentin, and TWIST) by ectopic expression of miR-101-5p and miR-101-3p in ccRCC cells (Figure S2).	('miR-101-5p', 'Chemical', '-', (157, 167))	('Vimentin', 'Gene', '7431', (111, 119))	('N-cadherin', 'Gene', (93, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (186, 191))	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('N-cadherin', 'Gene', '1000', (93, 103))	('Vimentin', 'Gene', (111, 119))	('TWIST', 'Gene', (125, 130))	('Vimentin', 'cellular_component', 'GO:0045098', ('111', '119'))	('miR-101-5p', 'Var', (157, 167))	('TWIST', 'Gene', '7291', (125, 130))	('cadherin', 'molecular_function', 'GO:0008014', ('83', '91'))	('E-cadherin', 'Gene', (81, 91))	('miR-101-3p', 'Chemical', '-', (172, 182))	('E-cadherin', 'Gene', '999', (81, 91))	('SLUG', 'Gene', '6591', (105, 109))	('SLUG', 'Gene', (105, 109))	('miR-101-3p', 'Var', (172, 182))	('RCC', 'Disease', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('Vimentin', 'cellular_component', 'GO:0045099', ('111', '119'))	('cadherin', 'molecular_function', 'GO:0008014', ('95', '103'))	('EMT', 'biological_process', 'GO:0001837', ('55', '58'))
159433	31975570	Notably, the expression levels of N-cadherin, SLUG, and Vimentin were suppressed by expressions of miR-101-5p and miR-101-3p in 2 RCC cell lines, 786-O and A498 (Figure S2).	('SLUG', 'Gene', (46, 50))	('expression levels', 'MPA', (13, 30))	('Vimentin', 'Gene', (56, 64))	('N-cadherin', 'Gene', (34, 44))	('miR-101-5p', 'Chemical', '-', (99, 109))	('Vimentin', 'cellular_component', 'GO:0045098', ('56', '64'))	('miR-101-3p', 'Var', (114, 124))	('N-cadherin', 'Gene', '1000', (34, 44))	('suppressed', 'NegReg', (70, 80))	('miR-101-5p', 'Var', (99, 109))	('Vimentin', 'Gene', '7431', (56, 64))	('miR-101-3p', 'Chemical', '-', (114, 124))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('SLUG', 'Gene', '6591', (46, 50))	('cadherin', 'molecular_function', 'GO:0008014', ('36', '44'))	('Vimentin', 'cellular_component', 'GO:0045099', ('56', '64'))	('RCC', 'Disease', 'MESH:C538614', (130, 133))
159434	31975570	Downregulation of TWIST was detected in 786-O cells by miR-101-5p expression.	('TWIST', 'Gene', (18, 23))	('Downregulation', 'NegReg', (0, 14))	('miR-101-5p expression', 'Var', (55, 76))	('miR-101-5p', 'Chemical', '-', (55, 65))	('TWIST', 'Gene', '7291', (18, 23))
159439	31975570	Immunoprecipitation using anti-Ago2 Abs was carried out after transfection of miR-101-5p into 786-O cells.	('Ago2', 'Gene', '27161', (31, 35))	('miR-101-5p', 'Chemical', '-', (78, 88))	('miR-101-5p', 'Var', (78, 88))	('Ago2', 'Gene', (31, 35))
159442	31975570	We identified genes that had putative target sites for miR-101 in their 3'-UTR and that showed downregulated expression in ccRCC cells transfected with miR-101 (log2 ratio less than -1.5) and upregulated expression levels (fold-change greater than 1.5) in RCC tissues from the GEO database (Figure 3A).	('expression', 'MPA', (109, 119))	('downregulated', 'NegReg', (95, 108))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('miR-101', 'Chemical', '-', (55, 62))	('miR-101', 'Var', (55, 62))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('miR-101', 'Chemical', '-', (152, 159))	('miR-101', 'Var', (152, 159))	('upregulated', 'PosReg', (192, 203))	('RCC', 'Disease', (256, 259))	('RCC', 'Disease', 'MESH:C538614', (256, 259))	('expression levels', 'MPA', (204, 221))	('RCC', 'Phenotype', 'HP:0005584', (256, 259))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))
159443	31975570	Using this search strategy, 38 and 47 genes were found as candidate target genes for miR-101-5p and miR-101-3p, respectively (Table 1).	('miR-101-5p', 'Var', (85, 95))	('miR-101-5p', 'Chemical', '-', (85, 95))	('miR-101-3p', 'Chemical', '-', (100, 110))	('miR-101-3p', 'Var', (100, 110))
159444	31975570	Among these genes, we focused on DONSON, which is targeted by miR-101-5p and had the strongest relation to the prognosis from TCGA database.	('DONSON', 'Gene', (33, 39))	('miR-101-5p', 'Var', (62, 72))	('DONSON', 'Gene', '29980', (33, 39))	('miR-101-5p', 'Chemical', '-', (62, 72))
159445	31975570	mRNA and protein levels of DONSON were significantly reduced after transfection of 786-0 and A498 cells with miR-101-5p compared to control cells (Figure 3B,C).	('miR-101-5p', 'Chemical', '-', (109, 119))	('DONSON', 'Gene', (27, 33))	('miR-101-5p', 'Var', (109, 119))	('DONSON', 'Gene', '29980', (27, 33))	('reduced', 'NegReg', (53, 60))	('protein', 'cellular_component', 'GO:0003675', ('9', '16'))
159446	31975570	The TargetScan Human database showed that there is a binding site for miR-101-5p (positions 219-225) in the DONSON 3'-UTR (Figure 3D).	('binding', 'Interaction', (53, 60))	('binding', 'molecular_function', 'GO:0005488', ('53', '60'))	('miR-101-5p', 'Chemical', '-', (70, 80))	('DONSON', 'Gene', '29980', (108, 114))	('Human', 'Species', '9606', (15, 20))	('DONSON', 'Gene', (108, 114))	('miR-101-5p', 'Var', (70, 80))
159448	31975570	Cotransfection of miR-101-5p with vectors significantly suppressed luciferase activity compared to control cells (P = .0012) (Figure 3E).	('luciferase', 'Enzyme', (67, 77))	('luciferase activity', 'molecular_function', 'GO:0047077', ('67', '86'))	('suppressed', 'NegReg', (56, 66))	('miR-101-5p', 'Chemical', '-', (18, 28))	('luciferase activity', 'molecular_function', 'GO:0045289', ('67', '86'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('67', '86'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('67', '86'))	('activity', 'MPA', (78, 86))	('luciferase activity', 'molecular_function', 'GO:0050397', ('67', '86'))	('miR-101-5p', 'Var', (18, 28))
159449	31975570	Conventional and propensity score-matched cohort analyses showed that patients with high DONSON expression showed poor prognosis (Figure 3F,G).	('patients', 'Species', '9606', (70, 78))	('DONSON', 'Gene', '29980', (89, 95))	('high', 'Var', (84, 88))	('DONSON', 'Gene', (89, 95))
159451	31975570	Combination analyses (miR-101-5p and DONSON) showed that patient group (low expression of miR-101-5p or high expression of DONSON) was a promising prognostic marker of patients with RCC (disease-free survival, P < .001; overall survival, P < .001) (Figure S5A,B).	('low', 'Var', (72, 75))	('DONSON', 'Gene', '29980', (37, 43))	('miR-101-5p', 'Chemical', '-', (22, 32))	('patient', 'Species', '9606', (57, 64))	('DONSON', 'Gene', (123, 129))	('DONSON', 'Gene', '29980', (123, 129))	('patient', 'Species', '9606', (168, 175))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('patients', 'Species', '9606', (168, 176))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('RCC', 'Disease', (182, 185))	('miR-101-5p', 'Chemical', '-', (90, 100))	('miR-101-5p', 'Var', (90, 100))	('DONSON', 'Gene', (37, 43))
159456	31975570	We confirmed that the expression levels of both DONSON mRNA and DONSON protein could be suppressed by si-DONSON transfection of ccRCC cells (Figure S6A,B).	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('DONSON', 'Gene', '29980', (105, 111))	('transfection', 'Var', (112, 124))	('DONSON', 'Gene', '29980', (64, 70))	('DONSON', 'Gene', (64, 70))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('DONSON', 'Gene', (48, 54))	('DONSON', 'Gene', '29980', (48, 54))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('expression levels', 'MPA', (22, 39))	('suppressed', 'NegReg', (88, 98))	('DONSON', 'Gene', (105, 111))
159458	31975570	In addition, introduction of both DONSON and miR-101-5p significantly restored cell proliferation, migration, and invasive activity, compared to cells transfected with miR-101-5p alone (Figure 4B-D).	('DONSON', 'Gene', (34, 40))	('cell proliferation', 'CPA', (79, 97))	('DONSON', 'Gene', '29980', (34, 40))	('miR-101-5p', 'Chemical', '-', (168, 178))	('cell proliferation', 'biological_process', 'GO:0008283', ('79', '97'))	('restored', 'PosReg', (70, 78))	('miR-101-5p', 'Chemical', '-', (45, 55))	('migration', 'CPA', (99, 108))	('miR-101-5p', 'Var', (45, 55))	('invasive activity', 'CPA', (114, 131))
159459	31975570	We confirmed that DONSON and miR-101-5p transfection restored DONSON protein expression (Figure S7).	('miR-101-5p transfection', 'Var', (29, 52))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('DONSON', 'Gene', (62, 68))	('DONSON', 'Gene', '29980', (62, 68))	('DONSON', 'Gene', (18, 24))	('miR-101-5p', 'Chemical', '-', (29, 39))	('DONSON', 'Gene', '29980', (18, 24))	('restored', 'PosReg', (53, 61))
159461	31975570	Transfection of si-DONSON did not apparently upregulate the level of cleaved PARP (Figure 4G).	('DONSON', 'Gene', '29980', (19, 25))	('PARP', 'Gene', (77, 81))	('Transfection', 'Var', (0, 12))	('PARP', 'Gene', '142', (77, 81))	('DONSON', 'Gene', (19, 25))
159468	31975570	DONSON expression was the most downregulated after si-DONSON transfection, indicating that these analyses were reliable and can be analyzed.	('DONSON', 'Gene', (54, 60))	('DONSON', 'Gene', '29980', (54, 60))	('transfection', 'Var', (61, 73))	('DONSON', 'Gene', (0, 6))	('expression', 'MPA', (7, 17))	('DONSON', 'Gene', '29980', (0, 6))	('downregulated', 'NegReg', (31, 44))
159472	31975570	In this study, we focused on miR-101-5p (the passenger strand of pre-miR-101) and investigated the associated regulatory RNA networks in ccRCC cells.	('miR-101-5p', 'Var', (29, 39))	('miR-101', 'Chemical', '-', (69, 76))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('RCC', 'Disease', (139, 142))	('miR-101', 'Chemical', '-', (29, 36))	('pre', 'molecular_function', 'GO:0003904', ('65', '68'))	('RNA', 'cellular_component', 'GO:0005562', ('121', '124'))	('miR-101-5p', 'Chemical', '-', (29, 39))
159476	31975570	miR-101-5p was shown to inhibit cell aggressiveness through targeting of C-X-C motif chemokine ligand 6 (CXCL6) in cervical cancer and nonsmall-cell lung carcinoma.27, 28 To our knowledge, the present study is the first report to show the antitumor functions of miR-101-5p in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (278, 281))	('nonsmall-cell lung carcinoma', 'Disease', (135, 163))	('C-X-C motif chemokine ligand 6', 'Gene', '6372', (73, 103))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Disease', (243, 248))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('CXCL6', 'Gene', (105, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (276, 281))	('CXCL6', 'Gene', '6372', (105, 110))	('miR-101-5p', 'Chemical', '-', (262, 272))	('RCC', 'Phenotype', 'HP:0005584', (278, 281))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('aggressiveness', 'Disease', (37, 51))	('RCC', 'Disease', (278, 281))	('cancer', 'Disease', (124, 130))	('aggressiveness', 'Phenotype', 'HP:0000718', (37, 51))	('C-X-C motif chemokine ligand 6', 'Gene', (73, 103))	('ligand', 'molecular_function', 'GO:0005488', ('95', '101'))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('miR-101-5p', 'Chemical', '-', (0, 10))	('miR-101-5p', 'Var', (262, 272))	('aggressiveness', 'Disease', 'MESH:D001523', (37, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('nonsmall-cell lung carcinoma', 'Disease', 'MESH:D002289', (135, 163))
159477	31975570	The elucidation of miR-101-5p-controlled novel oncogenic networks in ccRCC cells is particularly important.	('miR-101-5p', 'Chemical', '-', (19, 29))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('miR-101-5p-controlled', 'Var', (19, 40))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (69, 74))	('oncogenic networks', 'CPA', (47, 65))
159479	31975570	A total of 38 oncogenes was found to be regulated by miR-101-5p.	('miR-101-5p', 'Var', (53, 63))	('oncogenes', 'Gene', (14, 23))	('miR-101-5p', 'Chemical', '-', (53, 63))	('regulated', 'Reg', (40, 49))
159480	31975570	Of these oncogenic targets, the high expression of 13 genes was a significant prognostic factor for ccRCC.	('high', 'Var', (32, 36))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))
159481	31975570	We focused on DONSON because it was directly regulated by miR-101-5p and it was the best predictor of poor prognosis of patients.	('miR-101-5p', 'Chemical', '-', (58, 68))	('miR-101-5p', 'Var', (58, 68))	('patients', 'Species', '9606', (120, 128))	('DONSON', 'Gene', (14, 20))	('DONSON', 'Gene', '29980', (14, 20))	('regulated', 'Reg', (45, 54))
159485	31975570	They are often overexpressed in ccRCC tissues and could be useful prognostic markers in ccRCC patients.34, 35 Aberrant expression of DONSON was observed in sunitinib-treated ccRCC and silencing DONSON inhibited cell growth and induced apoptosis and cell cycle arrest in G2/M phase.	('DONSON', 'Gene', (133, 139))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (249, 266))	('DONSON', 'Gene', (194, 200))	('inhibited', 'NegReg', (201, 210))	('arrest', 'Disease', (260, 266))	('RCC', 'Disease', (90, 93))	('apoptosis', 'CPA', (235, 244))	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('249', '266'))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('patients', 'Species', '9606', (94, 102))	('DONSON', 'Gene', '29980', (133, 139))	('sunitinib', 'Chemical', 'MESH:D000077210', (156, 165))	('M phase', 'biological_process', 'GO:0000279', ('273', '280'))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('DONSON', 'Gene', '29980', (194, 200))	('RCC', 'Disease', (34, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (32, 37))	('RCC', 'Disease', (176, 179))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('ccRCC', 'Phenotype', 'HP:0006770', (174, 179))	('arrest', 'Disease', 'MESH:D006323', (260, 266))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('silencing', 'Var', (184, 193))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('cell growth', 'CPA', (211, 222))	('apoptosis', 'biological_process', 'GO:0097194', ('235', '244'))	('apoptosis', 'biological_process', 'GO:0006915', ('235', '244'))	('cell growth', 'biological_process', 'GO:0016049', ('211', '222'))	('induced', 'Reg', (227, 234))
159488	31975570	Also, our data showed that miR-101-5p regulated the expression of several EMT-related genes, indicating miR-101-5p might have a relation to resistance to TKI treatment.	('EMT', 'biological_process', 'GO:0001837', ('74', '77'))	('expression', 'MPA', (52, 62))	('miR-101-5p', 'Chemical', '-', (27, 37))	('EMT-related genes', 'Gene', (74, 91))	('relation', 'Reg', (128, 136))	('regulated', 'Reg', (38, 47))	('miR-101-5p', 'Chemical', '-', (104, 114))	('miR-101-5p', 'Var', (104, 114))
159490	31975570	Aberrant expression of DONSON has serious effects on the prognosis of patients with ccRCC.	('patients', 'Species', '9606', (70, 78))	('Aberrant expression', 'Var', (0, 19))	('DONSON', 'Gene', (23, 29))	('DONSON', 'Gene', '29980', (23, 29))	('effects', 'Reg', (42, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))
159497	31975570	The replisome is a complex molecular machine that comprises the DNA replication apparatus.39 The replisome unwinds double-stranded DNA into single strands.40 These findings suggest that aberrantly expressed genes involved in the replisome affected ccRCC pathogenesis.	('affected', 'Reg', (239, 247))	('pathogenesis', 'biological_process', 'GO:0009405', ('254', '266'))	('aberrantly expressed genes', 'Var', (186, 212))	('RCC', 'Phenotype', 'HP:0005584', (250, 253))	('RCC', 'Disease', 'MESH:C538614', (250, 253))	('ccRCC', 'Phenotype', 'HP:0006770', (248, 253))	('RCC', 'Disease', (250, 253))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('replisome', 'cellular_component', 'GO:0030894', ('97', '106'))	('DNA replication', 'biological_process', 'GO:0006260', ('64', '79'))	('DNA', 'cellular_component', 'GO:0005574', ('131', '134'))	('replisome', 'cellular_component', 'GO:0030894', ('229', '238'))	('replisome', 'cellular_component', 'GO:0030894', ('4', '13'))
159499	31975570	Several oncogenic targets regulated by miR-101-5p were closely involved with ccRCC pathogenesis.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('pathogenesis', 'biological_process', 'GO:0009405', ('83', '95'))	('miR-101-5p', 'Var', (39, 49))	('involved', 'Reg', (63, 71))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('miR-101-5p', 'Chemical', '-', (39, 49))	('RCC', 'Disease', (79, 82))
159508	28846080	The effects in the combination group were driven by the Akt/GSK-3beta/beta-catenin signaling pathway, and deregulation of beta-catenin expression was predictive of poor outcome in ccRCC patients.	('Akt', 'Gene', '207', (56, 59))	('beta-catenin', 'Gene', '1499', (122, 134))	('patients', 'Species', '9606', (186, 194))	('Akt', 'Gene', (56, 59))	('beta-catenin', 'Gene', (70, 82))	('beta-catenin', 'Gene', '1499', (70, 82))	('signaling pathway', 'biological_process', 'GO:0007165', ('83', '100'))	('GSK', 'molecular_function', 'GO:0050321', ('60', '63'))	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('ccRCC', 'Disease', (180, 185))	('beta-catenin', 'Gene', (122, 134))	('GSK-3beta', 'Gene', '2932', (60, 69))	('GSK-3beta', 'Gene', (60, 69))	('deregulation', 'Var', (106, 118))
159534	28846080	alpha-SMA (+) cells were present throughout the tissue in Fuhrman III-IV compared to Fuhrman I specimens (Figure 2a, 44.74+-5.7 and 18.91+-4.3 cells/field, respectively; P<0.0001).	('Fuhrman III-IV', 'Var', (58, 72))	('SMA', 'Gene', '6606', (6, 9))	('SMA', 'Gene', (6, 9))	('III-IV', 'Var', (66, 72))
159595	28846080	Meanwhile, treatment of cells in the four groups with the Akt inhibitor MK-2206, showed that signaling pathway was impaired by suppression of AKT expression (Figure 6e).	('MK-2206', 'Chemical', 'MESH:C548887', (72, 79))	('MK-2206', 'Var', (72, 79))	('impaired', 'NegReg', (115, 123))	('signaling pathway', 'Pathway', (93, 110))	('signaling pathway', 'biological_process', 'GO:0007165', ('93', '110'))	('AKT', 'Gene', (142, 145))	('Akt', 'Gene', '207', (58, 61))	('expression', 'MPA', (146, 156))	('Akt', 'Gene', (58, 61))	('AKT', 'Gene', '207', (142, 145))	('suppression', 'NegReg', (127, 138))
159600	28846080	In addition, high CD44 expression was correlated with Fuhrman grade (Figure 6g, top right, P=0.002, respectively) and metastasis in ccRCC tissues (Figure 6g, bottom left, P=0.003).	('ccRCC', 'Disease', (132, 137))	('metastasis', 'CPA', (118, 128))	('high', 'Var', (13, 17))	('expression', 'MPA', (23, 33))	('CD44', 'Gene', '960', (18, 22))	('Fuhrman', 'Disease', (54, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (132, 137))	('CD44', 'Gene', (18, 22))
159603	28846080	Based on our self-designed 'TME PCR Array' and immunohistochemistry, we found that in the stroma of high Fuhrman grade ccRCC, there are more alpha-SMA (+) cells compared with low Fuhrman grade ccRCC and these are correlated with progression and survival in ccRCC patients.	('SMA', 'Gene', '6606', (147, 150))	('SMA', 'Gene', (147, 150))	('ccRCC', 'Phenotype', 'HP:0006770', (193, 198))	('high Fuhrman grade', 'Var', (100, 118))	('patients', 'Species', '9606', (263, 271))	('more', 'PosReg', (136, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (257, 262))	('ccRCC', 'Disease', (257, 262))	('correlated', 'Reg', (213, 223))
159606	28846080	This result is consistent with studies suggesting that high serum IL-6 is a powerful predictor for poor prognosis in renal cell carcinoma and other cancers.	('renal cell carcinoma', 'Disease', (117, 137))	('IL-6', 'Gene', '3569', (66, 70))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (117, 137))	('cancers', 'Disease', (148, 155))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (117, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('IL-6', 'molecular_function', 'GO:0005138', ('66', '70'))	('high', 'Var', (55, 59))	('IL-6', 'Gene', (66, 70))
159611	28846080	Additionally, based on gene expression profiles, we revealed abnormalities in cytokines that have been reported to enhance tumor formation and progression (for example, CCL5, CXCL8 and CXCL12).	('CXCL8', 'Gene', '3576', (175, 180))	('gene expression', 'biological_process', 'GO:0010467', ('23', '38'))	('CXCL12', 'Gene', (185, 191))	('tumor', 'Disease', (123, 128))	('CXCL8', 'Gene', (175, 180))	('progression', 'CPA', (143, 154))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('CCL', 'molecular_function', 'GO:0044101', ('169', '172'))	('formation', 'biological_process', 'GO:0009058', ('129', '138'))	('CCL5', 'Gene', (169, 173))	('CXCL12', 'Gene', '6387', (185, 191))	('abnormalities', 'Var', (61, 74))	('enhance', 'PosReg', (115, 122))	('CCL5', 'Gene', '6352', (169, 173))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
159621	28846080	Force-induced changes in protein conformation and protein structural motifs transmit physical signals, and therefore compression combined with IL-6 activates Akt/GSK/beta-catenin signaling pathway and enhances the progression of ccRCC.	('activates', 'PosReg', (148, 157))	('ccRCC', 'Disease', (229, 234))	('ccRCC', 'Phenotype', 'HP:0006770', (229, 234))	('progression', 'CPA', (214, 225))	('beta-catenin', 'Gene', (166, 178))	('compression', 'Var', (117, 128))	('Akt', 'Gene', '207', (158, 161))	('signaling pathway', 'biological_process', 'GO:0007165', ('179', '196'))	('GSK', 'molecular_function', 'GO:0050321', ('162', '165'))	('IL-6', 'Gene', (143, 147))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('beta-catenin', 'Gene', '1499', (166, 178))	('IL-6', 'Gene', '3569', (143, 147))	('IL-6', 'molecular_function', 'GO:0005138', ('143', '147'))	('changes', 'Reg', (14, 21))	('Akt', 'Gene', (158, 161))	('enhances', 'PosReg', (201, 209))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))
159634	28846080	Next, sections were treated with primary antibodies as follows: alpha-SMA (cat.ab5694, 1:200 dilution, Abcam), Collagen I (cat.ab138492, 1:500 dilution, Abcam), CD4 (cat.ab133616, 1:500 dilution, Abcam), beta-catenin (cat.51067-2-AP, 1:100 dilution, Proteintech), CD44 (cat.	('cat.51067-2-AP', 'Var', (218, 232))	('cat', 'molecular_function', 'GO:0004096', ('270', '273'))	('CD44', 'Gene', '960', (264, 268))	('Collagen', 'molecular_function', 'GO:0005202', ('111', '119'))	('cat.ab133616', 'Var', (166, 178))	('cat', 'molecular_function', 'GO:0004096', ('123', '126'))	('CD44', 'Gene', (264, 268))	('cat', 'molecular_function', 'GO:0004096', ('218', '221'))	('SMA', 'Gene', '6606', (70, 73))	('cat', 'molecular_function', 'GO:0004096', ('166', '169'))	('cat', 'molecular_function', 'GO:0004096', ('75', '78'))	('CD4', 'Gene', '920', (161, 164))	('CD4', 'Gene', '920', (264, 267))	('beta-catenin', 'Gene', (204, 216))	('AP, 1', 'cellular_component', 'GO:0005907', ('230', '235'))	('beta-catenin', 'Gene', '1499', (204, 216))	('CD4', 'Gene', (161, 164))	('CD4', 'Gene', (264, 267))	('SMA', 'Gene', (70, 73))
159684	29891694	ccRCC is characterized by alterations at chromosome 3p, affecting the von Hippel-Lindau locus.	('von Hippel-Lindau', 'Disease', (70, 87))	('RCC', 'Disease', (2, 5))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('alterations', 'Var', (26, 37))	('affecting', 'Reg', (56, 65))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (70, 87))	('chromosome', 'cellular_component', 'GO:0005694', ('41', '51'))
159695	29891694	While mutations in TP53 and genes in the PIK3CA pathway were detected in some tumors, the overall mutational burden was remarkably low, and nearly half of the tumors in both studies seem to lack an obvious "driver" mutation.	('PIK3CA', 'Gene', '5290', (41, 47))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('PIK3CA', 'Gene', (41, 47))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('detected', 'Reg', (61, 69))	('mutations', 'Var', (6, 15))
159696	29891694	Interestingly, the TCGA identified elevated expression of mitochondrial genes and mutations of mitochondrial DNA as characteristic features of ChRCC, with 18% of the tumors carrying heteroplasmic mutations in the mitochondrial genes ND1 or ND5, leading to the hypothesis that mitochondrial-driven metabolic mechanisms may be critical in the pathogenesis of ChRCC.	('ND1', 'Gene', (233, 236))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('expression', 'MPA', (44, 54))	('RCC', 'Disease', (145, 148))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('RCC', 'Disease', 'MESH:C538614', (359, 362))	('RCC', 'Disease', (359, 362))	('ND5', 'Gene', (240, 243))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('95', '112'))	('mutations', 'Var', (82, 91))	('mitochondrial genes', 'Gene', (58, 77))	('pathogenesis', 'biological_process', 'GO:0009405', ('341', '353'))	('elevated', 'PosReg', (35, 43))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('mutations', 'Var', (196, 205))	('mitochondrial DNA', 'Gene', (95, 112))
159705	29891694	This highly specific defect in GGT1 suggests that impairment of the glutathione salvage pathway may act as an "Achilles' heel" of ChRCC, leading to increased sensitivity to oxidative stress, mitochondrial damage, and reprogramming of glutamine and glucose metabolism.	('reprogramming', 'CPA', (217, 230))	('sensitivity to oxidative stress', 'MPA', (158, 189))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('glutathione', 'Chemical', 'MESH:D005978', (68, 79))	('RCC', 'Disease', (132, 135))	('increased', 'PosReg', (148, 157))	('GGT1', 'Gene', '2678', (31, 35))	('glucose metabolism', 'Disease', 'MESH:D044882', (248, 266))	('mitochondrial damage', 'MPA', (191, 211))	('GGT1', 'Gene', (31, 35))	('impairment', 'Var', (50, 60))	('glutathione salvage', 'Enzyme', (68, 87))	('glucose metabolism', 'Disease', (248, 266))	('glutamine', 'Chemical', 'MESH:D005973', (234, 243))	('oxidative stress', 'Phenotype', 'HP:0025464', (173, 189))	('defect', 'Var', (21, 27))
159710	29891694	Whole-exome sequencing revealed a low somatic mutation rate (15-40 somatic mutations per tumor), including p53 mutations in three cases (c.524G > A; c.469G > T; c.672_splice) and mutations in components of the PI3-kinase pathway in two cases (PTEN, c.546_549delAAAG; c.591_593delGAT; and PIK3CA, c.3130A > T).	('c.546_549delAAAG', 'Var', (249, 265))	('p53', 'Gene', (107, 110))	('c.524G > A; c.469G > T; c.672_splice', 'Var', (137, 173))	('PIK3CA', 'Gene', '5290', (288, 294))	('c.469G > T', 'Mutation', 'rs121912654', (149, 159))	('PTEN', 'Gene', (243, 247))	('c.3130A > T', 'Var', (296, 307))	('mutations', 'Var', (111, 120))	('c.546_549delAAAG', 'Mutation', 'c.546_549delAAAG', (249, 265))	('PTEN', 'Gene', '5728', (243, 247))	('tumor', 'Disease', (89, 94))	('c.524G > A', 'Mutation', 'rs28934578', (137, 147))	('PIK3CA', 'Gene', (288, 294))	('c.3130A > T', 'Mutation', 'c.3130A>T', (296, 307))	('PI3-kinase pathway', 'Pathway', (210, 228))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('mutations', 'Var', (179, 188))	('c.591_593delGAT', 'Var', (267, 282))	('p53', 'Gene', '7157', (107, 110))	('c.591_593delGAT', 'Mutation', 'c.591_593delGAT', (267, 282))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
159711	29891694	Copy number inferred from whole-exome data revealed whole chromosome loss in most tumors (Fig.	('loss', 'NegReg', (69, 73))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('whole chromosome', 'Var', (52, 68))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('chromosome', 'cellular_component', 'GO:0005694', ('58', '68'))
159726	29891694	One of the main pathologic hallmarks of ChRCC is increased mitochondrial mass and aberrant mitochondrial morphology.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('aberrant mitochondrial morphology', 'Phenotype', 'HP:0008322', (82, 115))	('increased', 'PosReg', (49, 58))	('mitochondrial morphology', 'CPA', (91, 115))	('aberrant mitochondria', 'Phenotype', 'HP:0012103', (82, 103))	('increased mitochondrial mass', 'Phenotype', 'HP:0040014', (49, 77))	('RCC', 'Disease', (42, 45))	('aberrant', 'Var', (82, 90))	('mitochondrial mass', 'CPA', (59, 77))
159736	29891694	Oncocytomas have been shown to harbor mitochondrial mutations.	('mutations', 'Var', (52, 61))	('mitochondrial', 'Gene', (38, 51))	('Oncocytomas', 'Disease', 'MESH:D018249', (0, 11))	('Oncocytomas', 'Disease', (0, 11))	('harbor', 'Reg', (31, 37))
159761	29891694	Treatment with the combination of H2O2 and BSO for 48 h significantly suppressed ATP production in siGGT1 as measured by CellTiter-GLo luminescence (Fig.	('BSO', 'Chemical', 'MESH:D019328', (43, 46))	('GGT1', 'Gene', (101, 105))	('suppressed', 'NegReg', (70, 80))	('ATP production', 'MPA', (81, 95))	('GGT1', 'Gene', '2678', (101, 105))	('H2O2', 'Chemical', 'MESH:D006861', (34, 38))	('H2O2', 'Var', (34, 38))	('ATP', 'Chemical', 'MESH:D000255', (81, 84))
159762	29891694	S3 A-C), confirming that loss of GGT1 enhances susceptibility to oxidative stress.	('loss', 'Var', (25, 29))	('GGT1', 'Gene', '2678', (33, 37))	('oxidative stress', 'Phenotype', 'HP:0025464', (65, 81))	('GGT1', 'Gene', (33, 37))	('susceptibility to oxidative stress', 'MPA', (47, 81))	('enhances', 'PosReg', (38, 46))
159769	29891694	Both glutamine and glutamate decreased significantly in siGGT1 cells after challenge with H2O2, consistent with higher consumption in response to oxidative stress (Fig.	('glutamate', 'MPA', (19, 28))	('GGT1', 'Gene', (58, 62))	('higher', 'PosReg', (112, 118))	('response to oxidative stress', 'biological_process', 'GO:0006979', ('134', '162'))	('H2O2', 'Chemical', 'MESH:D006861', (90, 94))	('H2O2', 'Var', (90, 94))	('glutamine', 'Chemical', 'MESH:D005973', (5, 14))	('oxidative stress', 'Phenotype', 'HP:0025464', (146, 162))	('glutamine', 'MPA', (5, 14))	('decreased', 'NegReg', (29, 38))	('GGT1', 'Gene', '2678', (58, 62))	('glutamate', 'Chemical', 'MESH:D018698', (19, 28))	('glutamate decreased', 'Phenotype', 'HP:0500150', (19, 38))
159774	29891694	Significance analysis of microarray (SAM) revealed association of GGT1 overexpression with an increase in 5-oxoproline, consistent with enhanced gamma-glutamyl transferase activity, and a decrease in both GSH and GSSG (Fig.	('5-oxoproline', 'Chemical', 'MESH:D011761', (106, 118))	('activity', 'MPA', (172, 180))	('enhanced', 'PosReg', (136, 144))	('GSH', 'CPA', (205, 208))	('glutamyl', 'Chemical', '-', (151, 159))	('decrease', 'NegReg', (188, 196))	('increase', 'PosReg', (94, 102))	('5-oxoproline', 'MPA', (106, 118))	('GGT1', 'Gene', (66, 70))	('GSSG', 'Chemical', 'MESH:D019803', (213, 217))	('GSH', 'Chemical', '-', (205, 208))	('GGT1', 'Gene', '2678', (66, 70))	('overexpression', 'Var', (71, 85))	('GSSG', 'CPA', (213, 217))	('transferase activity', 'molecular_function', 'GO:0016740', ('160', '180'))	('gamma-glutamyl', 'MPA', (145, 159))
159792	29891694	The ChRCC TCGA found mutations in ETC complex 1 genes in 18% of cases, with MT-ND5 (essential for complex 1 activity) being the most frequently altered gene, but whether these mutations are a cause or an effect of the mitochondrial dysfunction is unclear.	('MT-ND5', 'Gene', '4540', (76, 82))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (218, 243))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (218, 243))	('MT-ND5', 'Gene', (76, 82))	('mitochondrial dysfunction', 'Disease', (218, 243))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))	('mutations', 'Var', (21, 30))
159795	29891694	Whether the accumulation of mitochondrial DNA mutations in a subset of ChRCC is a potential consequence of GGT1 deficiency is unknown.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('mutations', 'Var', (46, 55))	('mitochondrial DNA', 'Gene', (28, 45))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('28', '45'))	('GGT1 deficiency', 'Disease', (107, 122))	('GGT1 deficiency', 'Disease', 'MESH:D007153', (107, 122))	('accumulation', 'PosReg', (12, 24))
159796	29891694	Interestingly, the metabolite profile of oncocytomas, which are known to harbor mitochondrial DNA mutations impairing mitochondrial respiration, revealed similar changes in TCA cycle intermediates, supporting our hypothesis that mitochondria are dysfunctional in ChRCC.	('dysfunctional', 'Disease', 'MESH:D006331', (246, 259))	('mitochondrial respiration', 'MPA', (118, 143))	('RCC', 'Disease', (265, 268))	('respiration', 'biological_process', 'GO:0007585', ('132', '143'))	('mitochondrial DNA', 'Gene', (80, 97))	('respiration', 'biological_process', 'GO:0045333', ('132', '143'))	('metabolite profile', 'MPA', (19, 37))	('RCC', 'Disease', 'MESH:C538614', (265, 268))	('TCA cycle intermediates', 'MPA', (173, 196))	('oncocytomas', 'Disease', 'MESH:D018249', (41, 52))	('dysfunctional', 'Disease', (246, 259))	('TCA cycle', 'biological_process', 'GO:0006099', ('173', '182'))	('mitochondria', 'cellular_component', 'GO:0005739', ('229', '241'))	('changes', 'Reg', (162, 169))	('impairing', 'NegReg', (108, 117))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('80', '97'))	('mutations', 'Var', (98, 107))	('oncocytomas', 'Disease', (41, 52))	('TCA', 'Chemical', 'MESH:D014238', (173, 176))
159800	29891694	In oncocytoma, defective mitophagy leads to the accumulation of abnormal mitochondria, but in the setting of wild-type p53, tumorigenesis is suppressed, resulting in a benign phenotype.	('mitophagy', 'biological_process', 'GO:0000423', ('25', '34'))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('benign', 'MPA', (168, 174))	('accumulation', 'PosReg', (48, 60))	('tumor', 'Disease', (124, 129))	('p53', 'Gene', '7157', (119, 122))	('suppressed', 'NegReg', (141, 151))	('mitophagy', 'CPA', (25, 34))	('defective', 'Var', (15, 24))	('mitophagy', 'biological_process', 'GO:0000422', ('25', '34'))	('p53', 'Gene', (119, 122))	('oncocytoma', 'Disease', 'MESH:D018249', (3, 13))	('mitochondria', 'cellular_component', 'GO:0005739', ('73', '85'))	('oncocytoma', 'Disease', (3, 13))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
159801	29891694	Subsequent mutations in p53 are hypothesized to restore growth capacity and enable progression from oncocytoma toward chromophobe RCC; in this model, oncocytomas represent a precursor lesion for ChRCC.	('mutations', 'Var', (11, 20))	('p53', 'Gene', (24, 27))	('p53', 'Gene', '7157', (24, 27))	('oncocytomas', 'Disease', (150, 161))	('oncocytomas', 'Disease', 'MESH:D018249', (150, 161))	('RCC', 'Disease', 'MESH:C538614', (197, 200))	('oncocytoma toward chromophobe RCC', 'Disease', 'MESH:C538614', (100, 133))	('RCC', 'Disease', (197, 200))	('RCC', 'Disease', (130, 133))	('restore', 'PosReg', (48, 55))	('growth capacity', 'MPA', (56, 71))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('oncocytoma toward chromophobe RCC', 'Disease', (100, 133))
159821	29891694	For the siRNA experiments, HEK293T or 786-O cells were transfected for 72 h with GGT1 smart pool siRNA, individual siRNAs comprising the pool [all purchased from GE Dharmacon; target sequences: J-005884-18 (GCUCGAAGAUUGGGAGGGA), J-005884-19 (UACAACAGCACCACACGAA), J-005884-20 (ACGAGACGCUGGCCAUCGA), J-005884-21 (CUGUCUUGUGUGAGGUGUU)], or other individual siRNAs (Silencer Select siRNA s5724, Ambion; target sequences: s5724 (UGGUUGUCAGGUUCCUUGG).	('GGT1', 'Gene', (81, 85))	('GGT1', 'Gene', '2678', (81, 85))	('J-005884-20', 'Var', (264, 275))	('J-005884-21', 'Var', (299, 310))	('HEK293T', 'CellLine', 'CVCL:0063', (27, 34))
159839	28261513	Affected individuals carry germline mutations in the VHL tumour-suppressor gene with loss of the wild-type allele (normal gene copy) in a VHL disease-associated organ system leading to tumour formation.	('tumour', 'Disease', (57, 63))	('VHL tumour', 'Disease', 'MESH:D006623', (53, 63))	('VHL disease', 'Disease', (138, 149))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (185, 191))	('VHL tumour', 'Disease', (53, 63))	('loss', 'NegReg', (85, 89))	('formation', 'biological_process', 'GO:0009058', ('192', '201'))	('VHL disease', 'Disease', 'MESH:D006623', (138, 149))	('germline mutations', 'Var', (27, 45))	('tumour', 'Disease', (185, 191))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
159846	28261513	Molecular analysis had confirmed a germline VHL mutation in 2004.	('VHL', 'Disease', 'MESH:D006623', (44, 47))	('mutation', 'Var', (48, 56))	('VHL', 'Disease', (44, 47))
159866	28261513	Analysis of tumour DNA demonstrated no causative mutations; however, the tumour was heterozygous for an intron 1 polymorphism (c.341-50G>A), reducing the likelihood of LOH.	('tumour', 'Disease', (73, 79))	('c.341-50G>A', 'Var', (127, 138))	('tumour', 'Disease', (12, 18))	('c.341-50G>A', 'Mutation', 'rs1479846552', (127, 138))	('LOH', 'Disease', (168, 171))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('reducing', 'NegReg', (141, 149))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumour', 'Disease', 'MESH:D009369', (12, 18))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
159902	27413115	Recurrent mutations arise in genes encoding several BAF/PBAF subunits, including ARID1A, ARID2, PBRM1, SMARCA4, and SMARCB1.	('SMARCB1', 'Gene', (116, 123))	('ARID', 'Disease', (81, 85))	('SMARCB1', 'Gene', '20587', (116, 123))	('BRM', 'Gene', '6595', (97, 100))	('ARID', 'Disease', (89, 93))	('ARID1A', 'Gene', '93760', (81, 87))	('ARID', 'Disease', 'None', (81, 85))	('SMARCA4', 'Gene', (103, 110))	('SMARCA4', 'Gene', '6597', (103, 110))	('BRM', 'Gene', (97, 100))	('ARID', 'Disease', 'None', (89, 93))	('mutations', 'Var', (10, 19))	('ARID1A', 'Gene', (81, 87))
159912	27413115	As we discuss below, the mechanisms revealed by fundamental studies inform our understanding of how epigenetic dysfunction contributes to cancer.	('cancer', 'Disease', (138, 144))	('epigenetic dysfunction', 'Var', (100, 122))	('contributes', 'Reg', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
159913	27413115	ATP-dependent chromatin remodelers were independently discovered in yeast, by screening for mutations that disrupt the ability of yeast to switch mating type or activate sucrose fermentation pathways, both in response to extrinsic cues.	('activate', 'PosReg', (161, 169))	('sucrose fermentation pathways', 'Pathway', (170, 199))	('ATP', 'Chemical', 'MESH:D000255', (0, 3))	('yeast', 'Species', '4932', (130, 135))	('mating', 'biological_process', 'GO:0000747', ('146', '152'))	('mating', 'biological_process', 'GO:0007618', ('146', '152'))	('mutations', 'Var', (92, 101))	('yeast', 'Species', '4932', (68, 73))	('chromatin', 'cellular_component', 'GO:0000785', ('14', '23'))	('sucrose', 'Chemical', 'MESH:D013395', (170, 177))	('fermentation', 'biological_process', 'GO:0006113', ('178', '190'))	('mating', 'biological_process', 'GO:1990277', ('146', '152'))
159915	27413115	The observation that histone mutants were able to reverse the phenotypic defects associated with SWI/SNF mutation indicated that regulation of chromatin structure was the central function of the SWI/SNF complex.	('mutation', 'Var', (105, 113))	('SWI', 'Gene', (195, 198))	('SWI', 'Gene', '31120', (195, 198))	('SWI', 'Gene', '31120', (97, 100))	('SNF', 'Gene', (101, 104))	('chromatin', 'cellular_component', 'GO:0000785', ('143', '152'))	('SWI', 'Gene', (97, 100))	('SNF', 'Gene', '31442', (199, 202))	('regulation', 'biological_process', 'GO:0065007', ('129', '139'))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('195', '210'))	('SNF', 'Gene', (199, 202))	('SNF', 'Gene', '31442', (101, 104))
159921	27413115	Cells with SWI/SNF subunit mutations have disrupted chromatin structures, and fail to express many genes, leading to diverse phenotypic defects.	('mutations', 'Var', (27, 36))	('chromatin structures', 'MPA', (52, 72))	('SWI', 'Gene', '31120', (11, 14))	('SWI', 'Gene', (11, 14))	('SNF', 'Gene', (15, 18))	('chromatin', 'cellular_component', 'GO:0000785', ('52', '61'))	('disrupted', 'NegReg', (42, 51))	('leading to', 'Reg', (106, 116))	('SNF', 'Gene', '31442', (15, 18))
159928	27413115	SWI/SNF mutations also cause increased sensitivity to DNA-damaging agents, including hydroxyurea, cisplatin, methyl methanesulfonate, and UV-light.	('SWI', 'Gene', (0, 3))	('cisplatin', 'MPA', (98, 107))	('SWI', 'Gene', '31120', (0, 3))	('hydroxyurea', 'Chemical', 'MESH:D006918', (85, 96))	('hydroxyurea', 'MPA', (85, 96))	('increased', 'PosReg', (29, 38))	('mutations', 'Var', (8, 17))	('SNF', 'Gene', '31442', (4, 7))	('sensitivity to DNA-damaging agents', 'MPA', (39, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('methyl methanesulfonate', 'Chemical', 'MESH:D008741', (109, 132))	('methyl methanesulfonate', 'MPA', (109, 132))	('SNF', 'Gene', (4, 7))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))
159931	27413115	Because transcription, DNA repair, and chromatin modification domains are each influenced by the availability of accessible DNA, disruption of the nucleosome mobilization activity of SWI/SNF has distinct and pleiotropic effects.	('nucleosome', 'cellular_component', 'GO:0000786', ('147', '157'))	('nucleosome mobilization', 'biological_process', 'GO:0042766', ('147', '170'))	('SNF', 'Gene', (187, 190))	('chromatin modification', 'biological_process', 'GO:0006325', ('39', '61'))	('chromatin', 'cellular_component', 'GO:0000785', ('39', '48'))	('disruption', 'Var', (129, 139))	('transcription', 'biological_process', 'GO:0006351', ('8', '21'))	('DNA repair', 'biological_process', 'GO:0006281', ('23', '33'))	('DNA', 'cellular_component', 'GO:0005574', ('124', '127'))	('SWI', 'Gene', (183, 186))	('chromatin modification', 'biological_process', 'GO:0016569', ('39', '61'))	('influenced', 'Reg', (79, 89))	('SWI', 'Gene', '31120', (183, 186))	('nucleosome mobilization activity', 'MPA', (147, 179))	('SNF', 'Gene', '31442', (187, 190))	('DNA', 'cellular_component', 'GO:0005574', ('23', '26'))
159939	27413115	Rsc2 is required for insulator boundary function at the HMR locus, and its mutation leads to a loss of the nucleosome-depleted region encompassed by the insulator.	('mutation', 'Var', (75, 83))	('nucleosome-depleted region encompassed by the', 'MPA', (107, 152))	('Rsc2', 'Gene', '851071', (0, 4))	('nucleosome', 'cellular_component', 'GO:0000786', ('107', '117'))	('loss', 'NegReg', (95, 99))	('Rsc2', 'Gene', (0, 4))
159963	27413115	Some of the complexes' subunits are tissue-specific; for example, BAF53B (ACTL6B), BAF45B (DPF1), and SS18L1 (CREST, a Ca2+-responsive regulator), are found only in BAF complexes of mature, post-mitotic neurons.	('BAF45B', 'Var', (83, 89))	('SS18L1', 'Gene', (102, 108))	('SS18L1', 'Gene', '26039', (102, 108))	('BAF53B', 'Gene', (66, 72))	('Ca2+', 'Chemical', 'MESH:D000069285', (119, 123))
159964	27413115	BAF subunit composition is subject to tight regulation, as miRNA-based repression of BAF53A occurs immediately after the last mitotic division of neurons, and failure to express neural-specific subunits like BAF53B leads to defects in synaptogenesis and dendritic outgrowth.	('dendritic outgrowth', 'CPA', (254, 273))	('repression', 'NegReg', (71, 81))	('synaptogenesis', 'MPA', (235, 249))	('BAF53A', 'Gene', (85, 91))	('BAF53A', 'Gene', '86', (85, 91))	('regulation', 'biological_process', 'GO:0065007', ('44', '54'))	('failure', 'Var', (159, 166))	('defects', 'NegReg', (224, 231))	('synaptogenesis', 'biological_process', 'GO:0007416', ('235', '249'))
159966	27413115	Screening for BRG mutations revealed widespread defects in a number of different cancer cell lines, and ectopic expression of BRG in these lines often results in altered morphology.	('defects', 'NegReg', (48, 55))	('mutations', 'Var', (18, 27))	('BRG', 'Gene', (14, 17))	('results in altered', 'Reg', (151, 169))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('morphology', 'CPA', (170, 180))	('ectopic', 'Var', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('BRG', 'Gene', (126, 129))
159972	27413115	PBAF complexes also contain BRD7 in place of BRD9, BAF45A (PHF10) instead of BAF45B/C/D (DPF1/3/2), and lack SS18 (see Figure 1).	('lack', 'NegReg', (104, 108))	('BRD9', 'Gene', '65980', (45, 49))	('SS18', 'Gene', (109, 113))	('BAF45A', 'Var', (51, 57))	('SS18', 'Gene', '6760', (109, 113))	('BRD7', 'Var', (28, 32))	('BRD9', 'Gene', (45, 49))
159978	27413115	On account of their distinct biological activities, disruption of each of these remodelers is under different selection pressure in cancer, resulting in a wide range of mutation frequencies (Figure 2b).	('resulting in', 'Reg', (140, 152))	('cancer', 'Disease', (132, 138))	('mutation frequencies', 'MPA', (169, 189))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('disruption', 'Var', (52, 62))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
159982	27413115	Some of these subunits are among the most frequently mutated genes in cancer, and highly subunit-specific mutation patterns contribute to different cancer types (Figure 2c, 3).	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutation', 'Var', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('contribute', 'Reg', (124, 134))
159984	27413115	As defined by the overall number of truncating and high-functional-impact mutations, BRG is the most frequently mutated Snf2-like chromatin remodeling ATPase in cancer (Figure 2c).	('chromatin remodeling', 'biological_process', 'GO:0006338', ('130', '150'))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ATPase', 'Gene', '27429461', (151, 157))	('ATPase', 'Gene', (151, 157))	('Snf2', 'Gene', (120, 124))	('mutations', 'Var', (74, 83))	('Snf2', 'Gene', '854465', (120, 124))	('chromatin', 'cellular_component', 'GO:0000785', ('130', '139'))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('BRG', 'Gene', (85, 88))
159985	27413115	Unlike many other tumor suppressors, hypermethylation and silencing of BRG is reported to be relatively uncommon.	('tumor', 'Disease', (18, 23))	('silencing', 'MPA', (58, 67))	('BRG', 'Gene', (71, 74))	('hypermethylation', 'Var', (37, 53))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
159986	27413115	However, heterozygous and biallelic inactivation of BRG occurs in tumors of the breast, lung, stomach, bladder, colon, and in several other tumor types and cell lines.	('bladder', 'Disease', (103, 110))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('occurs', 'Reg', (56, 62))	('lung', 'Disease', (88, 92))	('tumors of the breast', 'Phenotype', 'HP:0100013', (66, 86))	('biallelic inactivation', 'Var', (26, 48))	('tumor', 'Disease', (66, 71))	('colon', 'Disease', 'MESH:D015179', (112, 117))	('BRG', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('colon', 'Disease', (112, 117))	('tumors of the breast', 'Disease', 'MESH:D001943', (66, 86))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('bladder', 'Disease', 'MESH:D001745', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('stomach', 'Disease', (94, 101))	('tumors of the breast', 'Disease', (66, 86))	('tumor', 'Disease', (140, 145))
159987	27413115	Disruption of BRG is especially common in small cell ovarian cancer (90-100%), cancers of the skin (up to 27%), diffuse large B-cell lymphoma (10%), and non-small cell lung cancers (~11%), where it has been reported as the fifth most frequently mutated gene.	('BRG', 'Gene', (14, 17))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (157, 180))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (153, 180))	('ovarian cancer', 'Phenotype', 'HP:0100615', (53, 67))	('Disruption', 'Var', (0, 10))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (126, 141))	('cancers of the skin', 'Phenotype', 'HP:0008069', (79, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('small cell ovarian cancer', 'Phenotype', 'HP:0030357', (42, 67))	('small cell ovarian cancer', 'Disease', (42, 67))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('B-cell lymphoma', 'Disease', (126, 141))	('non-small cell lung cancers', 'Disease', (153, 180))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('small cell ovarian cancer', 'Disease', 'MESH:D055752', (42, 67))	('lymphoma', 'Phenotype', 'HP:0002665', (133, 141))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (157, 179))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (153, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (153, 180))	('lung cancers', 'Phenotype', 'HP:0100526', (168, 180))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancers of the skin', 'Disease', 'MESH:D012878', (79, 98))	('cancers of the skin', 'Disease', (79, 98))	('common', 'Reg', (32, 38))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (126, 141))
159988	27413115	In some specific malignancies, such as certain thoracic sarcomas, biallelic inactivation of BRG occurs at elevated frequencies.	('malignancies', 'Disease', 'MESH:D009369', (17, 29))	('biallelic inactivation', 'Var', (66, 88))	('sarcomas', 'Disease', 'MESH:D012509', (56, 64))	('sarcomas', 'Disease', (56, 64))	('malignancies', 'Disease', (17, 29))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('BRG', 'Gene', (92, 95))
159989	27413115	Although it was initially thought that in most cancers BRG mutations were generally homozygous, it has since been determined that in many cancer types, a large number of mutations of BRG are heterozygous, with many mutations clustering at conserved motifs of the ATPase domain.	('mutations clustering', 'Reg', (215, 235))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('mutations', 'Var', (170, 179))	('cancer', 'Disease', (47, 53))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('BRG', 'Gene', (183, 186))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Disease', (47, 54))	('ATPase', 'Gene', '27429461', (263, 269))	('ATPase', 'Gene', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
159994	27413115	For example, K785R and T910M, respectively observed in melanoma, medulloblastoma and several cancer cell lines, have severely reduced ATPase activity, leading to anaphase bridges and failure of topoisomerase IIa to bind DNA, discussed in greater detail below.	('medulloblastoma', 'Disease', (65, 80))	('failure', 'NegReg', (183, 190))	('ATPase', 'Gene', '27429461', (134, 140))	('T910M', 'Mutation', 'p.T910M', (23, 28))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))	('topoisomerase', 'molecular_function', 'GO:0003918', ('194', '207'))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('bind', 'Interaction', (215, 219))	('ATPase activity', 'molecular_function', 'GO:0016887', ('134', '149'))	('ATPase', 'Gene', (134, 140))	('anaphase bridges', 'CPA', (162, 178))	('activity', 'MPA', (141, 149))	('reduced', 'NegReg', (126, 133))	('anaphase', 'biological_process', 'GO:0051322', ('162', '170'))	('cancer', 'Disease', (93, 99))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('DNA', 'cellular_component', 'GO:0005574', ('220', '223'))	('topoisomerase', 'Protein', (194, 207))	('medulloblastoma', 'Disease', 'MESH:D008527', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('T910M', 'Var', (23, 28))	('K785R', 'Var', (13, 18))	('medulloblastoma', 'Phenotype', 'HP:0002885', (65, 80))	('topoisomerase', 'molecular_function', 'GO:0003917', ('194', '207'))	('K785R', 'Mutation', 'rs562397332', (13, 18))
159996	27413115	In other ATP-dependent remodelers, dominant-negative mutations result in phenotypes distinct from subunit deletion, suggesting that the particular mechanisms of inactivation may lead to different downstream effects.	('ATP', 'Chemical', 'MESH:D000255', (9, 12))	('lead', 'Reg', (178, 182))	('mutations', 'Var', (53, 62))
159998	27413115	In the C-terminal ATPase subdomain of BRG, R1192 is recurrently mutated in cancer of the stomach, liver, lung, melanoma, esophagus, and breast, as well as in gliomas (Figures 3, 4).	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('esophagus', 'Disease', (121, 130))	('liver', 'Disease', (98, 103))	('cancer', 'Disease', (75, 81))	('ATPase', 'Gene', '27429461', (18, 24))	('ATPase', 'Gene', (18, 24))	('gliomas', 'Disease', 'MESH:D005910', (158, 165))	('lung', 'Disease', (105, 109))	('R1192', 'Var', (43, 48))	('gliomas', 'Disease', (158, 165))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('breast', 'Disease', (136, 142))	('cancer of the stomach', 'Phenotype', 'HP:0006753', (75, 96))
159999	27413115	Moreover, the homologous position is also mutated in BTAF1, CHD1, and ATRX in several different malignancies, suggesting this well-conserved position may be an Achilles' heel of Snf2-like remodelers.	('CHD1', 'Gene', (60, 64))	('BTAF1', 'Gene', (53, 58))	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('mutated', 'Var', (42, 49))	('malignancies', 'Disease', (96, 108))	('Snf2', 'Gene', (178, 182))	('Snf2', 'Gene', '854465', (178, 182))	('CHD1', 'Gene', '856911', (60, 64))
160000	27413115	Other nearby mutations at conserved residues in Motif V of the C-terminal subdomain severely compromise ATPase activity in the yeast SWI/SNF complex.	('mutations', 'Var', (13, 22))	('SNF', 'Gene', '31442', (137, 140))	('activity', 'MPA', (111, 119))	('ATPase activity', 'molecular_function', 'GO:0016887', ('104', '119'))	('ATPase', 'Gene', '27429461', (104, 110))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('133', '148'))	('ATPase', 'Gene', (104, 110))	('yeast', 'Species', '4932', (127, 132))	('SWI', 'Gene', '31120', (133, 136))	('SNF', 'Gene', (137, 140))	('SWI', 'Gene', (133, 136))	('compromise', 'NegReg', (93, 103))
160001	27413115	Although it is clear that commonly observed point mutations disrupt or completely abolish ATPase activity, a complete accounting of the downstream effects of these mutations in malignancy has not yet been performed.	('point mutations', 'Var', (44, 59))	('ATPase activity', 'molecular_function', 'GO:0016887', ('90', '105'))	('activity', 'MPA', (97, 105))	('ATPase', 'Gene', '27429461', (90, 96))	('ATPase', 'Gene', (90, 96))	('malignancy', 'Disease', 'MESH:D009369', (177, 187))	('disrupt', 'NegReg', (60, 67))	('abolish', 'NegReg', (82, 89))	('malignancy', 'Disease', (177, 187))
160002	27413115	BRM, the paralog of BRG that is not a subunit of the PBAF complex, also shows similar clustering of mutations at the N- and C-terminal helicase-like subdomains, but is much less frequently mutated in cancers (Figures 3, 4).	('mutations', 'Var', (100, 109))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('BRM', 'Gene', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('PBAF complex', 'cellular_component', 'GO:0016586', ('53', '65'))	('BRM', 'Gene', '6595', (0, 3))
160003	27413115	Interestingly, several in-frame deletions in the QLQ domain of BRM have been observed in primary tumors and several cancer cell lines.	('deletions', 'Var', (32, 41))	('primary tumors', 'Disease', 'MESH:D009369', (89, 103))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cancer', 'Disease', (116, 122))	('BRM', 'Gene', (63, 66))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('observed', 'Reg', (77, 85))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('BRM', 'Gene', '6595', (63, 66))	('primary tumors', 'Disease', (89, 103))
160008	27413115	Among the earliest reports of the complex's tumor suppressor role was the discovery that ~50% of ovarian clear cell carcinomas and endometriosis-associated ovarian carcinomas contain inactivating ARID1A mutations.	('tumor', 'Disease', (44, 49))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (156, 174))	('endometriosis-associated ovarian carcinomas', 'Disease', 'MESH:D004715', (131, 174))	('inactivating', 'Var', (183, 195))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('44', '60'))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('endometriosis-associated ovarian carcinomas', 'Disease', (131, 174))	('tumor suppressor', 'biological_process', 'GO:0051726', ('44', '60'))	('ovarian clear cell carcinomas', 'Disease', (97, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('endometriosis', 'Phenotype', 'HP:0030127', (131, 144))	('mutations', 'Var', (203, 212))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))	('ARID1A', 'Gene', (196, 202))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (97, 126))	('ARID1A', 'Gene', '93760', (196, 202))
160009	27413115	Mutations of ARID1A have since been observed at high frequency in a number of studies, including uterine endometrial carcinoma (34%), colorectal cancers (10%), as well as cancers of the bladder (29%), stomach (34%), cholangiocarcinomas (27%), neuroblastomas (11%), and pancreas (~5%).	('colorectal cancers', 'Disease', (134, 152))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('carcinomas', 'Phenotype', 'HP:0030731', (225, 235))	('pancreas', 'Disease', (269, 277))	('endometrial carcinoma', 'Disease', (105, 126))	('stomach', 'Disease', (201, 208))	('Mutations', 'Var', (0, 9))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (105, 126))	('cancers of the bladder', 'Disease', 'MESH:D001749', (171, 193))	('observed', 'Reg', (36, 44))	('colorectal cancers', 'Disease', 'MESH:D015179', (134, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (105, 126))	('neuroblastomas', 'Disease', (243, 257))	('cancers of the bladder', 'Phenotype', 'HP:0009725', (171, 193))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancers of the bladder', 'Disease', (171, 193))	('ARID1A', 'Gene', (13, 19))	('cholangiocarcinomas', 'Disease', 'MESH:D018281', (216, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('ARID1A', 'Gene', '93760', (13, 19))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('neuroblastomas', 'Disease', 'MESH:D009447', (243, 257))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('cholangiocarcinomas', 'Disease', (216, 235))
160010	27413115	These recurrent loss-of-function mutations make ARID1A the premier tumor-suppressor subunit of the BAF complex, however very little is known about the mechanisms of how this subunit contributes to malignancy.	('tumor', 'Disease', (67, 72))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('67', '83'))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('ARID1A', 'Gene', (48, 54))	('mutations', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('ARID1A', 'Gene', '93760', (48, 54))	('malignancy', 'Disease', 'MESH:D009369', (197, 207))	('loss-of-function', 'NegReg', (16, 32))	('malignancy', 'Disease', (197, 207))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('67', '83'))
160011	27413115	Mutations of ARID1A are most frequently truncating mutations (frameshifts and nonsense mutations (Figure 2c, 4), which may be degraded by nonsense-mediated decay.	('ARID1A', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('ARID1A', 'Gene', '93760', (13, 19))
160013	27413115	The hotspots of truncating mutations that occur are explained in part by frequent ARID1A mutations arising in tumors with mutated DNA polymerase epsilon (POLE).	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('ARID1A', 'Gene', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('ARID1A', 'Gene', '93760', (82, 88))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('mutations', 'Var', (89, 98))	('mutated', 'Var', (122, 129))
160016	27413115	However, hypermethylation of the ARID1A promoter has been observed in many breast cancers, hence epigenetic silencing mechanisms are also common.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ARID1A', 'Gene', '93760', (33, 39))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('hypermethylation', 'Var', (9, 25))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('breast cancers', 'Phenotype', 'HP:0003002', (75, 89))	('observed', 'Reg', (58, 66))	('ARID1A', 'Gene', (33, 39))
160017	27413115	In ovarian cancer, mutation of ARID1A frequently co-occurs with activating mutations of phosphatidylinositol 3-kinase (PI3K).	('co-occurs', 'Reg', (49, 58))	('mutation', 'Var', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('PI3K', 'molecular_function', 'GO:0016303', ('119', '123'))	('ARID1A', 'Gene', (31, 37))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('ovarian cancer', 'Disease', (3, 17))	('ARID1A', 'Gene', '93760', (31, 37))
160019	27413115	Binding of PIP2 by Brg regulates association of the complex with actin; therefore, activating mutations of PI3K may deplete PIP2, leading to altered BAF localization or function.	('PIP2', 'Gene', (11, 15))	('PIP2', 'Gene', '854545', (11, 15))	('altered', 'Reg', (141, 148))	('mutations', 'Var', (94, 103))	('PI3K', 'molecular_function', 'GO:0016303', ('107', '111'))	('localization', 'biological_process', 'GO:0051179', ('153', '165'))	('BAF', 'CPA', (149, 152))	('localization', 'MPA', (153, 165))	('PIP2', 'Gene', '854545', (124, 128))	('PI3K', 'Gene', (107, 111))	('deplete', 'NegReg', (116, 123))	('function', 'MPA', (169, 177))	('PIP2', 'Gene', (124, 128))
160022	27413115	However, ARID1B mutations are not as frequent as those of ARID1A (Figure 2c).	('ARID1A', 'Gene', (58, 64))	('mutations', 'Var', (16, 25))	('ARID1B', 'Gene', (9, 15))	('ARID1A', 'Gene', '93760', (58, 64))	('ARID1B', 'Gene', '57492', (9, 15))
160026	27413115	In renal clear cell carcinoma (ccRCC), mutation or loss of PBRM1 occurs in ~41% of cases, making it the second-most frequently mutated gene in ccRCC.	('mutation', 'Var', (39, 47))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (3, 29))	('renal clear cell carcinoma', 'Disease', (3, 29))	('BRM', 'Gene', '6595', (60, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('loss', 'NegReg', (51, 55))	('BRM', 'Gene', (60, 63))
160027	27413115	Like ARID1A in other cancers, the majority of mutations of PBRM1 in ccRCC are truncating mutations (Figures 2c, 4), which may not result in protein expression due to nonsense-mediated decay.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('ARID1A', 'Gene', (5, 11))	('mutations', 'Var', (46, 55))	('ARID1A', 'Gene', '93760', (5, 11))	('BRM', 'Gene', '6595', (60, 63))	('ccRCC', 'Disease', (68, 73))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('cancers', 'Disease', (21, 28))	('truncating', 'MPA', (78, 88))	('BRM', 'Gene', (60, 63))
160028	27413115	However, many ccRCC cases have biallelic inactivation of PBRM1, through loss of one allele via focal/chromosomal deletion at chromosome arm 3p, and an inactivating mutation on the remaining allele.	('chromosome', 'cellular_component', 'GO:0005694', ('125', '135'))	('loss', 'NegReg', (72, 76))	('BRM', 'Gene', (58, 61))	('focal/chromosomal deletion', 'Var', (95, 121))	('ccRCC', 'Disease', (14, 19))	('inactivating', 'Reg', (151, 163))	('BRM', 'Gene', '6595', (58, 61))
160029	27413115	Furthermore, hypermethylation of the PBRM1 promoter is generally absent in ccRCC, indicating that inactivation occurs primarily through mutation or deletion.	('deletion', 'Var', (148, 156))	('ccRCC', 'Disease', (75, 80))	('absent', 'NegReg', (65, 71))	('mutation', 'Var', (136, 144))	('hypermethylation', 'MPA', (13, 29))	('BRM', 'Gene', (38, 41))	('BRM', 'Gene', '6595', (38, 41))
160030	27413115	Some tumors do contain missense mutations, and although their functional impacts remain uncertain, their presence suggests a degree of non-redundancy between these domains.	('missense mutations', 'Var', (23, 41))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
160032	27413115	In ccRCC, PBRM1 inactivation frequently coincides with mutation of the VHL (von Hippel-Lindau) tumor suppressor.	('coincides', 'Reg', (40, 49))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('95', '111'))	('BRM', 'Gene', (11, 14))	('inactivation', 'Var', (16, 28))	('VHL (von Hippel-Lindau) tumor', 'Disease', 'MESH:D006623', (71, 100))	('ccRCC', 'Disease', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mutation', 'Var', (55, 63))	('BRM', 'Gene', '6595', (11, 14))	('tumor suppressor', 'biological_process', 'GO:0051726', ('95', '111'))
160033	27413115	However, the striking frequency of inactivating point mutations of PBRM1 alongside VHL and BAP1 mutations suggests that joint inactivation of these genes may potentiate the oncogenic nature of these defects.	('inactivation', 'Var', (126, 138))	('BAP1', 'Gene', (91, 95))	('BRM', 'Gene', (68, 71))	('potentiate', 'PosReg', (158, 168))	('BAP1', 'Gene', '852074', (91, 95))	('inactivating point mutations', 'Var', (35, 63))	('oncogenic nature', 'CPA', (173, 189))	('VHL', 'Disease', (83, 86))	('VHL', 'Disease', 'MESH:D006623', (83, 86))	('BRM', 'Gene', '6595', (68, 71))	('mutations', 'Var', (96, 105))
160037	27413115	ARID2 has been reported to contribute to repression, and is frequently mutated in melanoma, non-small cell lung cancer as well as in ~18% of hepatitis-associated hepatocellular carcinomas.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (92, 118))	('hepatitis-associated hepatocellular carcinomas', 'Disease', (141, 187))	('hepatitis-associated hepatocellular carcinomas', 'Disease', 'MESH:D056486', (141, 187))	('hepatitis', 'Phenotype', 'HP:0012115', (141, 150))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (162, 187))	('ARID', 'Disease', (0, 4))	('mutated', 'Var', (71, 78))	('non-small cell lung cancer', 'Disease', (92, 118))	('melanoma', 'Disease', (82, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('ARID', 'Disease', 'None', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (92, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (96, 118))
160040	27413115	MRTs are rare but highly lethal childhood cancers that are caused by biallelic inactivation of SMARCB1 (BAF47, SNF5, or INI1), which occurs in nearly all cases.	('cancers', 'Disease', (42, 49))	('SMARCB1', 'Gene', '20587', (95, 102))	('SNF5', 'Gene', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('SNF5', 'Gene', '852592', (111, 115))	('SMARCB1', 'Gene', (95, 102))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('MRTs', 'Disease', (0, 4))	('caused by', 'Reg', (59, 68))	('cancers', 'Disease', 'MESH:D009369', (42, 49))	('biallelic', 'Var', (69, 78))
160042	27413115	As a result of failure to oppose Polycomb, the repressive mark H3K27me3 accumulates at the tumor suppressor p16/INK4A (CDKN2A) locus.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('91', '107'))	('Polycomb', 'Gene', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('Polycomb', 'Gene', '40358', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('H3K27me3', 'Var', (63, 71))	('tumor', 'Disease', (91, 96))	('accumulates', 'PosReg', (72, 83))	('tumor suppressor', 'biological_process', 'GO:0051726', ('91', '107'))
160044	27413115	MRTs have remarkably stable diploid genomes except for deletions and mutations at chromosome 22q, where SMARCB1 is located.	('mutations', 'Var', (69, 78))	('chromosome', 'cellular_component', 'GO:0005694', ('82', '92'))	('SMARCB1', 'Gene', (104, 111))	('SMARCB1', 'Gene', '20587', (104, 111))	('deletions', 'Var', (55, 64))
160046	27413115	Finally, ectopic expression of SMARCB1 reverses Polycomb silencing at the tumor suppressor p16/INK4A locus, leading to cellular senescence, indicating that these tumors are driven exclusively by epigenetic regulation (except for the original genetic inactivation of SMARCB1).	('cellular senescence', 'biological_process', 'GO:0090398', ('119', '138'))	('tumor', 'Disease', (162, 167))	('SMARCB1', 'Gene', (266, 273))	('tumor', 'Disease', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('Polycomb', 'Gene', (48, 56))	('SMARCB1', 'Gene', '20587', (266, 273))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('Polycomb', 'Gene', '40358', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('74', '90'))	('epigenetic regulation', 'Var', (195, 216))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor suppressor', 'biological_process', 'GO:0051726', ('74', '90'))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('SMARCB1', 'Gene', (31, 38))	('leading to', 'Reg', (108, 118))	('cellular senescence', 'CPA', (119, 138))	('SMARCB1', 'Gene', '20587', (31, 38))	('tumors', 'Disease', (162, 168))	('regulation', 'biological_process', 'GO:0065007', ('206', '216'))
160048	27413115	Biallelic inactivation of SMARCB1 has also been reported in 7-10% of Ewing sarcomas.	('Ewing sarcomas', 'Disease', (69, 83))	('Ewing sarcomas', 'Disease', 'MESH:C563168', (69, 83))	('reported', 'Reg', (48, 56))	('Biallelic inactivation', 'Var', (0, 22))	('SMARCB1', 'Gene', (26, 33))	('Ewing sarcomas', 'Phenotype', 'HP:0012254', (69, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('SMARCB1', 'Gene', '20587', (26, 33))	('sarcomas', 'Phenotype', 'HP:0100242', (75, 83))
160049	27413115	In mouse models, conditional deletion of SMARCB1 leads to T cell lymphomas with short latency and 100% penetrance, suggesting that SMARCB1 inactivation can cause fast transformation alone without other genetic changes, as observed in MRTs.	('SMARCB1', 'Gene', (41, 48))	('mouse', 'Species', '10090', (3, 8))	('SMARCB1', 'Gene', (131, 138))	('SMARCB1', 'Gene', '20587', (41, 48))	('leads to', 'Reg', (49, 57))	('T cell lymphomas', 'Disease', 'MESH:D016399', (58, 74))	('T cell lymphomas', 'Disease', (58, 74))	('lymphomas', 'Phenotype', 'HP:0002665', (65, 74))	('SMARCB1', 'Gene', '20587', (131, 138))	('lymphoma', 'Phenotype', 'HP:0002665', (65, 73))	('T cell lymphomas', 'Phenotype', 'HP:0012190', (58, 74))	('inactivation', 'Var', (139, 151))
160050	27413115	Interestingly, rhabdoid tumors are not seen in mice with SMARCB1 inactivation, attesting to the tissue-specific and species-specific function of the complexes.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('SMARCB1', 'Gene', '20587', (57, 64))	('rhabdoid tumors', 'Disease', (15, 30))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (15, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('inactivation', 'Var', (65, 77))	('SMARCB1', 'Gene', (57, 64))	('mice', 'Species', '10090', (47, 51))
160051	27413115	Importantly, the pathogenesis of most human malignancies with BAF/PBAF mutations may be different from that of MRTs.	('human', 'Species', '9606', (38, 43))	('malignancies', 'Disease', (44, 56))	('BAF/PBAF', 'Gene', (62, 70))	('mutations', 'Var', (71, 80))	('pathogenesis', 'biological_process', 'GO:0009405', ('17', '29'))	('malignancies', 'Disease', 'MESH:D009369', (44, 56))
160052	27413115	With the exception of some noteworthy examples described below, the majority of cancers bearing BAF/PBAF subunit mutations are found in older age groups, where tumors have long latencies, are highly mutated, and are genomically unstable.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('mutations', 'Var', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('BAF/PBAF subunit', 'Gene', (96, 112))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
160054	27413115	The hallmark of synovial sarcoma is a highly characteristic translocation of chromosomes 18 and X, which fuses the dedicated BAF subunit SS18 to the SSX fusion partner on the X chromosome.	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (16, 32))	('synovial sarcoma', 'Disease', 'MESH:D013584', (16, 32))	('SS18', 'Gene', (137, 141))	('X chromosome', 'cellular_component', 'GO:0000805', ('175', '187'))	('translocation', 'Var', (60, 73))	('synovial sarcoma', 'Disease', (16, 32))	('SS18', 'Gene', '6760', (137, 141))
160056	27413115	BAF complexes containing the SS18-SSX fusion are retargeted to oncogenic loci such as SOX2 and PAX6, where removal of the repressive histone mark H3K27me3 results in transformation.	('results in', 'Reg', (155, 165))	('SS18', 'Gene', (29, 33))	('transformation', 'CPA', (166, 180))	('removal', 'Var', (107, 114))	('H3K27me3', 'Protein', (146, 154))	('SS18', 'Gene', '6760', (29, 33))
160057	27413115	Forced overexpression of wild-type SS18, or shRNA-mediated knockdown of the SS18-SSX fusion, is sufficient to reverse oncogenic BAF subunit composition.	('SS18', 'Gene', (76, 80))	('SS18', 'Gene', (35, 39))	('SS18', 'Gene', '6760', (76, 80))	('SS18', 'Gene', '6760', (35, 39))	('knockdown', 'Var', (59, 68))
160060	27413115	They are both childhood malignancies driven by a defining alteration of a single BAF subunit, and senescence can be achieved by repair of the affected subunit.	('malignancies', 'Disease', 'MESH:D009369', (24, 36))	('senescence', 'biological_process', 'GO:0010149', ('98', '108'))	('alteration', 'Var', (58, 68))	('BAF', 'Protein', (81, 84))	('malignancies', 'Disease', (24, 36))
160066	27413115	Recent work has also shown that BAF53A is a target of miR-206, a microRNA missing in rhabdomyosarcomas (RMS).	('rhabdomyosarcomas', 'Disease', (85, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('BAF53A', 'Gene', '86', (32, 38))	('BAF53A', 'Gene', (32, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (85, 102))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (85, 102))	('miR-206', 'Var', (54, 61))
160069	27413115	Ablation of the HSA domain from Sth1, the ATPase of RSC in yeast, causes the specific loss of ARPs from the complex, and a reduction in the activity of the ATPase.	('Sth1', 'Gene', (32, 36))	('RSC', 'Gene', '5656974', (52, 55))	('loss', 'NegReg', (86, 90))	('ATPase', 'Gene', '27429461', (42, 48))	('ATPase', 'Gene', (42, 48))	('Ablation', 'Var', (0, 8))	('ATPase', 'Gene', '27429461', (156, 162))	('yeast', 'Species', '4932', (59, 64))	('Sth1', 'Gene', '854680', (32, 36))	('reduction', 'NegReg', (123, 132))	('ARPs', 'Protein', (94, 98))	('activity', 'MPA', (140, 148))	('ATPase', 'Gene', (156, 162))	('RSC', 'Gene', (52, 55))
160082	27413115	PBRM1 plays a critical role in sister chromatid cohesion, where misregulation leads to genome instability, anaphase bridges, and aneuploidy.	('leads to', 'Reg', (78, 86))	('chromatid', 'cellular_component', 'GO:0005695', ('38', '47'))	('aneuploidy', 'Disease', 'MESH:D000782', (129, 139))	('BRM', 'Gene', '6595', (1, 4))	('anaphase bridges', 'CPA', (107, 123))	('chromatid', 'cellular_component', 'GO:0005694', ('38', '47'))	('aneuploidy', 'Disease', (129, 139))	('sister chromatid cohesion', 'biological_process', 'GO:0007062', ('31', '56'))	('anaphase', 'biological_process', 'GO:0051322', ('107', '115'))	('genome instability', 'CPA', (87, 105))	('misregulation', 'Var', (64, 77))	('BRM', 'Gene', (1, 4))
160086	27413115	Topoisomerases require nucleosome-free DNA, and mutants of BRG that impair ATPase activity induce loss of topoisomerase IIa (TOP2A) binding to DNA, leading to topological defects, anaphase bridges and partial arrest at the relatively uncharacterized decatenation checkpoint.	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('ATPase', 'Gene', (75, 81))	('topological', 'MPA', (159, 170))	('binding', 'molecular_function', 'GO:0005488', ('132', '139'))	('binding', 'Interaction', (132, 139))	('topoisomerase', 'molecular_function', 'GO:0003917', ('106', '119'))	('partial arrest', 'CPA', (201, 215))	('BRG', 'Gene', (59, 62))	('decatenation checkpoint', 'MPA', (250, 273))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('anaphase bridges', 'CPA', (180, 196))	('loss', 'NegReg', (98, 102))	('topoisomerase', 'molecular_function', 'GO:0003918', ('106', '119'))	('ATPase', 'Gene', '27429461', (75, 81))	('TOP2A', 'Gene', (125, 130))	('nucleosome', 'cellular_component', 'GO:0000786', ('23', '33'))	('ATPase activity', 'molecular_function', 'GO:0016887', ('75', '90'))	('anaphase', 'biological_process', 'GO:0051322', ('180', '188'))	('mutants', 'Var', (48, 55))
160087	27413115	Lung cancer cell lines with BRG mutations show increased sensitivity to topoisomerase II inhibitors when EZH2 is also inhibited, suggesting interplay between BAF, TOP2A, and PRC2 in the maintenance of chromatin topology.	('inhibited', 'NegReg', (118, 127))	('PRC2', 'Gene', (174, 178))	('PRC2', 'Gene', '852873', (174, 178))	('BRG', 'Gene', (28, 31))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Disease', (5, 11))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('topoisomerase II', 'molecular_function', 'GO:0003918', ('72', '88'))	('chromatin', 'cellular_component', 'GO:0000785', ('201', '210'))	('increased', 'PosReg', (47, 56))	('mutations', 'Var', (32, 41))	('interplay', 'Interaction', (140, 149))	('sensitivity', 'MPA', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
160090	27413115	In several tumor types, inactivation of one BAF/PBAF subunit induces dependency on the continued expression of that subunit's paralog.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('induces', 'Reg', (61, 68))	('dependency on the continued expression', 'MPA', (69, 107))	('tumor', 'Disease', (11, 16))	('inactivation', 'Var', (24, 36))	('BAF/PBAF', 'Gene', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
160091	27413115	For example, tumors with BRG mutations frequently depend on the expression of BRM, while tumors with ARID1A mutations often depend on ARID1B.	('ARID1A', 'Gene', (101, 107))	('tumors', 'Disease', (89, 95))	('BRM', 'Gene', (78, 81))	('expression', 'MPA', (64, 74))	('ARID1B', 'Gene', '57492', (134, 140))	('tumors', 'Disease', (13, 19))	('ARID1A', 'Gene', '93760', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (29, 38))	('BRM', 'Gene', '6595', (78, 81))	('ARID1B', 'Gene', (134, 140))	('depend', 'Reg', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('BRG', 'Gene', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
160096	27413115	While abundant evidence indicates that BAF and PBAF defects contribute to malignancy by altering the epigenetic landscape to regulate transcription, many lines of evidence indicate that these defects have pleiotropic effects, because complexes participate in a number of other important chromatin regulatory processes.	('malignancy', 'Disease', (74, 84))	('defects', 'Var', (52, 59))	('contribute', 'Reg', (60, 70))	('PBAF', 'Gene', (47, 51))	('epigenetic landscape to regulate transcription', 'MPA', (101, 147))	('malignancy', 'Disease', 'MESH:D009369', (74, 84))	('chromatin', 'cellular_component', 'GO:0000785', ('287', '296'))	('transcription', 'biological_process', 'GO:0006351', ('134', '147'))	('altering', 'Reg', (88, 96))	('BAF', 'Gene', (39, 42))	('participate', 'Reg', (244, 255))
160098	27413115	As a result, the fundamental role of any given BAF and PBAF alteration in cancer is likely to be unique to each cancer type, and may reflect the idiosyncratic processes that drive each malignancy (whether oncogene addiction, autocrine signaling, mutagen exposure, chromosomal instability, etc.).	('BAF', 'Gene', (47, 50))	('reflect', 'Reg', (133, 140))	('malignancy', 'Disease', 'MESH:D009369', (185, 195))	('alteration', 'Var', (60, 70))	('malignancy', 'Disease', (185, 195))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('autocrine signaling', 'biological_process', 'GO:0035425', ('225', '244'))	('cancer', 'Disease', (74, 80))	('chromosomal instability', 'Phenotype', 'HP:0040012', (264, 287))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('PBAF', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
160122	30386650	Nakada and co-authors reported that 43 microRNAs were differently expressed in conventional RCC and in healthy kidney tissues: 37 miRs were significantly under-expressed in conventional RCC and the other 6 were overexpressed; the most significantly down-regulated miRs were microRNA-141 and microRNA -200c.	('under-expressed', 'NegReg', (154, 169))	('microRNA-141', 'Gene', (274, 286))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('microRNA -200c', 'Var', (291, 305))	('miR', 'Gene', '220972', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('miR', 'Gene', (130, 133))	('RCC', 'Disease', (186, 189))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('microRNA-141', 'Gene', '406933', (274, 286))	('miR', 'Gene', '220972', (264, 267))	('miR', 'Gene', (264, 267))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('down-regulated', 'NegReg', (249, 263))
160131	30386650	assessed the expression of microRNA-129-3p and microRNA-129-5p in 69 cases of paired renal tumors, healthy tissues and conventional renal cancer cell lines.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('renal tumors', 'Phenotype', 'HP:0009726', (85, 97))	('renal cancer', 'Disease', (132, 144))	('microRNA-129-3p', 'Var', (27, 42))	('renal tumors', 'Disease', 'MESH:D007674', (85, 97))	('renal cancer', 'Phenotype', 'HP:0009726', (132, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('microRNA-129-5p', 'Var', (47, 62))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('renal cancer', 'Disease', 'MESH:D007680', (132, 144))	('renal tumors', 'Disease', (85, 97))
160157	30386650	Moreover, miR-451 knockdown improved drug susceptibility, reduced programmed cell death rate, and improved cell viability of ACHN cell line induced by ADM; however, ATF-2 suppression reversed the low rate of cell apoptosis and the high rate of cell viability induced by miR-451 knockdown.	('knockdown', 'Var', (18, 27))	('miR-451', 'Gene', (10, 17))	('programmed', 'MPA', (66, 76))	('cell viability of ACHN cell line', 'CPA', (107, 139))	('improved', 'PosReg', (28, 36))	('reduced', 'NegReg', (58, 65))	('ATF-2', 'Gene', (165, 170))	('miR-451', 'Gene', '574411', (10, 17))	('miR-451', 'Gene', (270, 277))	('apoptosis', 'biological_process', 'GO:0097194', ('213', '222'))	('ADM', 'Chemical', 'MESH:D004317', (151, 154))	('ATF-2', 'Gene', '1386', (165, 170))	('programmed cell death', 'biological_process', 'GO:0012501', ('66', '87'))	('drug susceptibility', 'MPA', (37, 56))	('improved', 'PosReg', (98, 106))	('apoptosis', 'biological_process', 'GO:0006915', ('213', '222'))	('miR-451', 'Gene', '574411', (270, 277))
160166	30386650	Furthermore, the new paracrine tract of up-regulation of matrix metallopeptidase 9 (MMP-9) and VEGF secretion through microRNA-942 expression and as a result enhancement in endothelial migration and resistance to sunitinib was depicted.	('men', 'Species', '9606', (165, 168))	('expression', 'Var', (131, 141))	('sunitinib', 'Chemical', 'MESH:D000077210', (213, 222))	('VEGF', 'Gene', '7422', (95, 99))	('regulation', 'biological_process', 'GO:0065007', ('43', '53'))	('matrix metallopeptidase 9', 'Gene', (57, 82))	('microRNA-942', 'Gene', '100126331', (118, 130))	('MMP-9', 'Gene', '4318', (84, 89))	('endothelial migration', 'CPA', (173, 194))	('microRNA-942', 'Gene', (118, 130))	('matrix metallopeptidase 9', 'Gene', '4318', (57, 82))	('MMP-9', 'Gene', (84, 89))	('secretion', 'biological_process', 'GO:0046903', ('100', '109'))	('VEGF', 'Gene', (95, 99))	('enhancement', 'PosReg', (158, 169))	('up-regulation', 'PosReg', (40, 53))	('MMP-9', 'molecular_function', 'GO:0004229', ('84', '89'))
160173	30386650	Significant shifts in expression of microRNA-15a, -16 and -145 under the impact of sunitinib and in expression levels of microRNA-15a, -145, BAX and BCL2 in everolimus application cohort were observed.	('everolimus', 'Chemical', 'MESH:D000068338', (157, 167))	('microRNA-15a', 'Gene', (36, 48))	('sunitinib', 'Chemical', 'MESH:D000077210', (83, 92))	('BCL2', 'molecular_function', 'GO:0015283', ('149', '153'))	('shifts', 'Reg', (12, 18))	('BCL2', 'Gene', '596', (149, 153))	('BAX', 'Gene', '581', (141, 144))	('BAX', 'Gene', (141, 144))	('microRNA-15a', 'Var', (121, 133))	('BCL2', 'Gene', (149, 153))	('expression', 'MPA', (22, 32))
160177	30386650	Conversely, a knockdown of microRNA-30a by means of exogenously expressed antagomiRNA-30a up-regulated expression of Beclin-1 and inhibited sorafenib-induced cytotoxicity in RCC cells.	('miR', 'Gene', '220972', (80, 83))	('miR', 'Gene', (80, 83))	('inhibited', 'NegReg', (130, 139))	('up-regulated', 'PosReg', (90, 102))	('expression', 'MPA', (103, 113))	('cytotoxicity', 'Disease', (158, 170))	('RCC', 'Disease', (174, 177))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('Beclin-1', 'Gene', (117, 125))	('knockdown', 'Var', (14, 23))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('Beclin-1', 'Gene', '8678', (117, 125))	('sorafenib', 'Chemical', 'MESH:D000077157', (140, 149))	('cytotoxicity', 'Disease', 'MESH:D064420', (158, 170))
160188	30386650	Furthermore, the transwell invasion assay disclosed that the potential of renal cancer invasiveness transfected with microRNA-506 mimics was considerably decreased.	('decreased', 'NegReg', (154, 163))	('renal cancer invasiveness', 'Disease', (74, 99))	('transfected', 'Var', (100, 111))	('microRNA-506', 'Gene', '574511', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('renal cancer invasiveness', 'Disease', 'MESH:D007680', (74, 99))	('microRNA-506', 'Gene', (117, 129))	('renal cancer', 'Phenotype', 'HP:0009726', (74, 86))
160192	30386650	In 46 cases of RCCs of stage III and IV overexpressed microRNA 486, which was associated with poor cancer specific mortality (CSM), independent of other covariates and TNM staging (P = 0.0064).	('microRNA 486', 'Var', (54, 66))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('TNM', 'Gene', (168, 171))	('RCC', 'Disease', (15, 18))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('cancer', 'Disease', (99, 105))	('overexpressed', 'PosReg', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('TNM', 'Gene', '10178', (168, 171))
160193	30386650	Besides, according to the Kaplan Meier analysis, microRNA 486 expression was associated with CSM in 14 patients with RCC (of III and IV stages) that were not treated with interferon alpha (P = 0.0574).	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('CSM', 'Disease', (93, 96))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('microRNA 486 expression', 'Var', (49, 72))	('patients', 'Species', '9606', (103, 111))	('associated', 'Reg', (77, 87))
160212	29559845	Many studies revealed that targeted therapies, such as multipotase inhibitors, anti-VEGF antibodies and mTOR, had been approved for clinical use.	('mTOR', 'Gene', (104, 108))	('mTOR', 'Gene', '2475', (104, 108))	('antibodies', 'Var', (89, 99))	('VEGF', 'Gene', (84, 88))	('VEGF', 'Gene', '7422', (84, 88))
160246	29559845	In this study, we investigated the gene expression profile of GSE53000, including 56 clear cell renal cell carcinoma samples (including 2 lymph node metastasis samples and 1 venous thrombus samples) and 6 normal kidney samples to explore the molecular mechanism of ccRCC and find some biomarkers, which might be helpful therapeutic targets by using bioinformatics analysis.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('venous thrombus', 'Disease', 'MESH:D013927', (174, 189))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (85, 116))	('venous thrombus', 'Disease', (174, 189))	('GSE53000', 'Var', (62, 70))	('RCC', 'Disease', 'MESH:C538614', (267, 270))	('RCC', 'Disease', (267, 270))	('RCC', 'Phenotype', 'HP:0005584', (267, 270))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (85, 116))	('clear cell renal cell carcinoma', 'Disease', (85, 116))	('ccRCC', 'Phenotype', 'HP:0006770', (265, 270))	('venous thrombus', 'Phenotype', 'HP:0004936', (174, 189))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (96, 116))	('gene expression', 'biological_process', 'GO:0010467', ('35', '50'))
160306	29357836	Aberrant metabolism not only supports the synthesis of macromolecules, including proteins, lipids and nucleic acids, but also fuels the growth, proliferation and invasion of cancer cells.	('supports', 'PosReg', (29, 37))	('synthesis of macromolecules', 'MPA', (42, 69))	('Aberrant', 'Var', (0, 8))	('synthesis', 'biological_process', 'GO:0009058', ('42', '51'))	('metabolism', 'MPA', (9, 19))	('si', 'Chemical', 'MESH:D012825', (166, 168))	('metabolism', 'biological_process', 'GO:0008152', ('9', '19'))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('lipids', 'Chemical', 'MESH:D008055', (91, 97))	('growth', 'CPA', (136, 142))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('invasion', 'CPA', (162, 170))	('proliferation', 'CPA', (144, 157))
160368	29357836	Cells transfected with si-NC or si-SR-BI for 48 h were plated into 6-well plates at a density of 1.0 x 103 cells per well and maintained in an incubator for 2 weeks with the medium replaced every 3 days.	('si-NC', 'Chemical', 'MESH:C052464', (23, 28))	('SR-BI', 'Gene', '949', (35, 40))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('SR-BI', 'Gene', (35, 40))	('si-NC', 'Var', (23, 28))
160373	29357836	Briefly, cells were seeded into 6-well plates and transfected with si-NC or si-SR-BI.	('SR-BI', 'Gene', '949', (79, 84))	('si-NC', 'Chemical', 'MESH:C052464', (67, 72))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('SR-BI', 'Gene', (79, 84))	('si-NC', 'Var', (67, 72))
160398	29357836	2a, the patients with tumors that expressed high levels of SR-BI had a shorter PFS survival (P = 0.0062).	('SR-BI', 'Gene', '949', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('PFS survival', 'CPA', (79, 91))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('SR-BI', 'Gene', (59, 64))	('shorter', 'NegReg', (71, 78))	('tumors', 'Disease', (22, 28))	('high levels', 'Var', (44, 55))	('patients', 'Species', '9606', (8, 16))
160407	29357836	The results showed that knockdown of SR-BI could significantly decrease the proliferative ability of ccRCC cells (Fig.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('proliferative ability of', 'CPA', (76, 100))	('decrease', 'NegReg', (63, 71))	('SR-BI', 'Gene', '949', (37, 42))	('knockdown', 'Var', (24, 33))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('si', 'Chemical', 'MESH:D012825', (49, 51))	('SR-BI', 'Gene', (37, 42))
160410	29357836	Next, we explored whether depletion of endogenous SR-BI could attenuate the invasion and migration of ccRCC cells in vitro.	('endogenous', 'Var', (39, 49))	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('SR-BI', 'Gene', (50, 55))	('attenuate', 'NegReg', (62, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('depletion', 'MPA', (26, 35))	('SR-BI', 'Gene', '949', (50, 55))	('si', 'Chemical', 'MESH:D012825', (80, 82))	('RCC', 'Disease', (104, 107))
160414	29357836	Accompanied by the results, wound healing assay proved that SR-BI knockdown closed the gap much slower (Fig.	('SR-BI', 'Gene', (60, 65))	('wound healing', 'biological_process', 'GO:0042060', ('28', '41'))	('closed', 'NegReg', (76, 82))	('slower', 'NegReg', (96, 102))	('knockdown', 'Var', (66, 75))	('SR-BI', 'Gene', '949', (60, 65))
160415	29357836	5a, ccRCC cells transfected with siRNA were stained by ORO, and we found that knockdown of SR-BI inhibited the proliferation of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('si', 'Chemical', 'MESH:D012825', (33, 35))	('SR-BI', 'Gene', (91, 96))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('knockdown', 'Var', (78, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('SR-BI', 'Gene', '949', (91, 96))	('inhibited', 'NegReg', (97, 106))	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('ORO', 'Chemical', 'MESH:C011049', (55, 58))	('RCC', 'Disease', (6, 9))	('cancer', 'Disease', (128, 134))
160416	29357836	More importantly, cells transfected with si-NC showed much fresher red color than cells treated with si-SR-BI, which meant that there was much lower HDL-cholesterol content in cells treated with si-SR-BI, when HDL receptor was knocked down.	('SR-BI', 'Gene', (198, 203))	('HDL', 'molecular_function', 'GO:0005321', ('149', '152'))	('lower HDL-cholesterol', 'Phenotype', 'HP:0003233', (143, 164))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('lower', 'NegReg', (143, 148))	('SR-BI', 'Gene', '949', (104, 109))	('si', 'Chemical', 'MESH:D012825', (195, 197))	('si-NC', 'Var', (41, 46))	('SR-BI', 'Gene', '949', (198, 203))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('SR-BI', 'Gene', (104, 109))	('si-NC', 'Chemical', 'MESH:C052464', (41, 46))	('cholesterol', 'Chemical', 'MESH:D002784', (153, 164))	('HDL-cholesterol content', 'MPA', (149, 172))	('HDL receptor', 'molecular_function', 'GO:0070506', ('210', '222'))
160421	29357836	Hence, we confirmed whether knockdown of SR-BI would influence the expression of AKT, p-AKT and MMP-2/9.	('MMP-2/9', 'Gene', '4313;4318', (96, 103))	('MMP-2/9', 'Gene', (96, 103))	('influence', 'Reg', (53, 62))	('si', 'Chemical', 'MESH:D012825', (73, 75))	('AKT', 'Gene', '207', (81, 84))	('SR-BI', 'Gene', '949', (41, 46))	('AKT', 'Gene', '207', (88, 91))	('AKT', 'Gene', (88, 91))	('AKT', 'Gene', (81, 84))	('SR-BI', 'Gene', (41, 46))	('MMP-2', 'molecular_function', 'GO:0004228', ('96', '101'))	('knockdown', 'Var', (28, 37))	('expression', 'MPA', (67, 77))
160424	29357836	As the most predominant subtype of RCC, ccRCC is featured by loss of heterozygosity (LOH) on chromosome 3p or direct deletion of chromosome 3p.	('direct deletion', 'Var', (110, 125))	('RCC', 'Disease', (35, 38))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('si', 'Chemical', 'MESH:D012825', (79, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('chromosome', 'cellular_component', 'GO:0005694', ('129', '139'))	('loss', 'NegReg', (61, 65))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
160425	29357836	Additionally, mutation or silencing of tumor suppressive genes such as VHL and PTEN, accompanied by the activation of oncogenes sometimes, contributes to the carcinogenesis of ccRCC.	('si', 'Chemical', 'MESH:D012825', (169, 171))	('carcinogenesis', 'Disease', 'MESH:D063646', (158, 172))	('VHL', 'Gene', '7428', (71, 74))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (176, 181))	('RCC', 'Disease', (178, 181))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('contributes', 'Reg', (139, 150))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('activation', 'PosReg', (104, 114))	('silencing', 'NegReg', (26, 35))	('tumor', 'Disease', (39, 44))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('PTEN', 'Gene', (79, 83))	('VHL', 'Gene', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('mutation', 'Var', (14, 22))	('carcinogenesis', 'Disease', (158, 172))	('PTEN', 'Gene', '5728', (79, 83))
160441	29357836	The result indicated that high expression of SR-BI may participate in the aggressiveness and metastasis of ccRCC, according to its expression pattern in other cancers.	('high', 'Var', (26, 30))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('si', 'Chemical', 'MESH:D012825', (137, 139))	('SR-BI', 'Gene', (45, 50))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('si', 'Chemical', 'MESH:D012825', (80, 82))	('cancers', 'Disease', (159, 166))	('aggressiveness', 'Disease', (74, 88))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('aggressiveness', 'Phenotype', 'HP:0000718', (74, 88))	('aggressiveness', 'Disease', 'MESH:D001523', (74, 88))	('participate', 'Reg', (55, 66))	('SR-BI', 'Gene', '949', (45, 50))	('metastasis', 'CPA', (93, 103))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('si', 'Chemical', 'MESH:D012825', (100, 102))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))
160443	29357836	Similarly, Schorghofer also reported that high SR-BI expression was significantly associated with Gleason score, an important clinical feature in prostate cancer.	('prostate cancer', 'Disease', (146, 161))	('associated', 'Reg', (82, 92))	('SR-BI', 'Gene', (47, 52))	('SR-BI', 'Gene', '949', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('Gleason score', 'Disease', (98, 111))	('prostate cancer', 'Disease', 'MESH:D011471', (146, 161))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('prostate cancer', 'Phenotype', 'HP:0012125', (146, 161))	('high', 'Var', (42, 46))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('clinical', 'Species', '191496', (126, 134))
160445	29357836	As a retrospective study, we obtained the PFS time of patients by follow-up, and we identified that high SR-BI mRNA expression was associated with shorter PFS.	('SR-BI', 'Gene', (105, 110))	('patients', 'Species', '9606', (54, 62))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('high', 'Var', (100, 104))	('SR-BI', 'Gene', '949', (105, 110))
160446	29357836	Univariate and multivariate analysis showed that high SR-BI mRNA level was an independent prognostic biomarker for PFS.	('si', 'Chemical', 'MESH:D012825', (33, 35))	('SR-BI', 'Gene', (54, 59))	('PFS', 'Disease', (115, 118))	('high', 'Var', (49, 53))	('SR-BI', 'Gene', '949', (54, 59))
160447	29357836	Then, we concluded that high expression of SR-BI meant an unfavorable outcome in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('SR-BI', 'Gene', (43, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('SR-BI', 'Gene', '949', (43, 48))	('high', 'Var', (24, 28))	('si', 'Chemical', 'MESH:D012825', (35, 37))
160453	29357836	Similar results were observed in previous studies that depletion of SR-BI either by RNA interfering or gene mutation critically reduce the growth of cancer cells.	('cancer', 'Disease', (149, 155))	('depletion', 'MPA', (55, 64))	('RNA interfering', 'MPA', (84, 99))	('SR-BI', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('RNA', 'cellular_component', 'GO:0005562', ('84', '87'))	('gene mutation', 'Var', (103, 116))	('reduce', 'NegReg', (128, 134))	('SR-BI', 'Gene', '949', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
160454	29357836	In addition, we confirmed that depletion of SR-BI significantly reduced cell invasion and migration.	('SR-BI', 'Gene', (44, 49))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('cell invasion', 'CPA', (72, 85))	('reduced', 'NegReg', (64, 71))	('SR-BI', 'Gene', '949', (44, 49))	('depletion', 'Var', (31, 40))
160455	29357836	Similarly, Danilo also demonstrated that knockdown of SR-BI vitally inhibited the invasion of breast cancer cells despite there was no difference in cell migration.	('invasion of', 'CPA', (82, 93))	('SR-BI', 'Gene', (54, 59))	('SR-BI', 'Gene', '949', (54, 59))	('inhibited', 'NegReg', (68, 77))	('cell migration', 'biological_process', 'GO:0016477', ('149', '163'))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('knockdown', 'Var', (41, 50))	('breast cancer', 'Disease', (94, 107))	('si', 'Chemical', 'MESH:D012825', (86, 88))
160460	29357836	reported that the PI3K/Akt signaling pathway played vital roles in CAL-1 (SR-BI) mediated breast cancer progression, mutant form of SR-BI impairs the proliferation of MCF-7 cells and the effect was induced by inactivation of PI3K/Akt pathway.	('Akt', 'Gene', '207', (230, 233))	('Akt', 'Gene', (23, 26))	('SR-BI', 'Gene', (132, 137))	('SR-BI', 'Gene', (74, 79))	('proliferation', 'CPA', (150, 163))	('Akt', 'Gene', '207', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('signaling pathway', 'biological_process', 'GO:0007165', ('27', '44'))	('impairs', 'NegReg', (138, 145))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('Akt signaling', 'biological_process', 'GO:0043491', ('23', '36'))	('mutant', 'Var', (117, 123))	('SR-BI', 'Gene', '949', (132, 137))	('SR-BI', 'Gene', '949', (74, 79))	('PI3K', 'molecular_function', 'GO:0016303', ('225', '229'))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('MCF-7', 'CellLine', 'CVCL:0031', (167, 172))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('PI3K', 'molecular_function', 'GO:0016303', ('18', '22'))	('breast cancer', 'Disease', (90, 103))	('si', 'Chemical', 'MESH:D012825', (27, 29))	('Akt', 'Gene', (230, 233))
160461	29357836	Danilo revealed that activation of Akt cascades was induced by SR-BI and knockdown of SR-BI impair the effects.	('SR-BI', 'Gene', '949', (63, 68))	('SR-BI', 'Gene', '949', (86, 91))	('SR-BI', 'Gene', (63, 68))	('SR-BI', 'Gene', (86, 91))	('Akt', 'Gene', '207', (35, 38))	('activation', 'PosReg', (21, 31))	('impair', 'NegReg', (92, 98))	('knockdown', 'Var', (73, 82))	('Akt', 'Gene', (35, 38))
160462	29357836	Fruhwurth also shed out direct link between mTOR pathway and SR-BI expression, inhibition of mTOR pathway decreased SR-BI expression and nitric oxide (NO) synthesis in human umbilical vein endothelial cells (HUVECs) and human coronary artery endothelial cells (HCAECs).	('decreased', 'NegReg', (106, 115))	('si', 'Chemical', 'MESH:D012825', (73, 75))	('human', 'Species', '9606', (168, 173))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('mTOR', 'Gene', (93, 97))	('SR-BI', 'Gene', (116, 121))	('SR-BI', 'Gene', (61, 66))	('human', 'Species', '9606', (220, 225))	('mTOR', 'Gene', '2475', (93, 97))	('mTOR', 'Gene', (44, 48))	('inhibition', 'Var', (79, 89))	('mTOR', 'Gene', '2475', (44, 48))	('nitric oxide', 'Chemical', 'MESH:D009569', (137, 149))	('si', 'Chemical', 'MESH:D012825', (161, 163))	('SR-BI', 'Gene', '949', (61, 66))	('synthesis', 'biological_process', 'GO:0009058', ('155', '164'))	('SR-BI', 'Gene', '949', (116, 121))
160468	29357836	High SR-BI expression correlated tightly with aggressive features of ccRCC and predicted an unfavorable clinical outcome.	('SR-BI', 'Gene', (5, 10))	('predicted', 'Reg', (79, 88))	('High', 'Var', (0, 4))	('clinical', 'Species', '191496', (104, 112))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('SR-BI', 'Gene', '949', (5, 10))	('ccRCC', 'Phenotype', 'HP:0006770', (69, 74))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('si', 'Chemical', 'MESH:D012825', (52, 54))
160469	29357836	We further identified that inhibition of SR-BI in ccRCC cell lines in vitro using specific siRNA successfully damaged the growth, colony formation, migration and invasion, as well as the up-take of HDL-cholesterol.	('SR-BI', 'Gene', '949', (41, 46))	('inhibition', 'Var', (27, 37))	('invasion', 'CPA', (162, 170))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (50, 55))	('migration', 'CPA', (148, 157))	('RCC', 'Disease', (52, 55))	('formation', 'biological_process', 'GO:0009058', ('137', '146'))	('HDL-cholesterol', 'MPA', (198, 213))	('HDL', 'molecular_function', 'GO:0005321', ('198', '201'))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('up-take', 'PosReg', (187, 194))	('si', 'Chemical', 'MESH:D012825', (166, 168))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('colony formation', 'CPA', (130, 146))	('SR-BI', 'Gene', (41, 46))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('cholesterol', 'Chemical', 'MESH:D002784', (202, 213))	('growth', 'CPA', (122, 128))	('damaged', 'NegReg', (110, 117))
160512	32495158	The CAL-54 cell line conforms with copy number amplifications (CNAs) in several key kidney cancer genes.	('kidney cancer', 'Disease', (84, 97))	('kidney cancer', 'Disease', 'MESH:D007680', (84, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('kidney cancer', 'Phenotype', 'HP:0009726', (84, 97))	('copy number amplifications', 'Var', (35, 61))	('CAL-54', 'CellLine', 'CVCL:1111', (4, 10))
160545	32495158	The more comprehensive gene set (gs-ifng-m14004) had the highest enrichment score (ES) in SKCM tissues (ES = 0.825, FDR, q value 0.0; FWER p value 0.0) (Fig.	('SKCM', 'Disease', (90, 94))	('ES', 'Chemical', '-', (104, 106))	('ES', 'Chemical', '-', (83, 85))	('gs-ifng-m14004', 'Var', (33, 47))
160558	32495158	In SKCM with low PD-L1-mRNA tissue levels, patient survival was significantly shorter than in those with high-level PD-L1-mRNA levels (OS: HR 1.984; p < 0.0001 and DFS: HR 1.436; p = 0.0046).	('patient', 'Species', '9606', (43, 50))	('low', 'Var', (13, 16))	('PD-L1-mRNA', 'MPA', (17, 27))	('shorter', 'NegReg', (78, 85))	('patient survival', 'CPA', (43, 59))
160571	32495158	In IFN-gamma-responsive tumors such as melanoma and ccRCC, patients with high PD-L1-mRNA tissue levels had longer OS and DFS than those with low PD-L1-mRNA levels.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('RCC', 'Disease', (54, 57))	('melanoma', 'Disease', (39, 47))	('PD-L1-mRNA', 'MPA', (78, 88))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('longer', 'PosReg', (107, 113))	('DFS', 'MPA', (121, 124))	('patients', 'Species', '9606', (59, 67))	('high', 'Var', (73, 77))
160583	32495158	Conversely, tandem amplification of PD-L1/PD-L2 and JAK2, causing enhanced IFN-gamma signaling, was associated with high responsiveness towards immune checkpoint blockade in Hodgkin's lymphoma.	('PD-L2', 'Gene', (42, 47))	('responsiveness', 'MPA', (121, 135))	('lymphoma', 'Phenotype', 'HP:0002665', (184, 192))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (174, 192))	("Hodgkin's lymphoma", 'Disease', (174, 192))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (174, 192))	('enhanced', 'PosReg', (66, 74))	('IFN-gamma signaling', 'MPA', (75, 94))	('PD-L2', 'Gene', '80380', (42, 47))	('tandem amplification', 'Var', (12, 32))	('JAK', 'molecular_function', 'GO:0004713', ('52', '55'))	('JAK2', 'Gene', (52, 56))
160586	32495158	In melanoma, a high PD-L1 protein score was associated with shorter survival.	('high', 'Var', (15, 19))	('PD-L1 protein', 'Protein', (20, 33))	('melanoma', 'Disease', (3, 11))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('survival', 'MPA', (68, 76))	('shorter', 'NegReg', (60, 67))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))
160587	32495158	In particular, a high PD-L1 score, considering PD-L1 in cancer cells or macrophages, predicted both worse outcome and, in a mouse model, the knockout of PD-L1 or of IFN-gamma signaling by STAT1-knockdown in tumor cells prolonged survival.	('PD-L1', 'Gene', (153, 158))	('prolonged', 'PosReg', (219, 228))	('signaling', 'biological_process', 'GO:0023052', ('175', '184'))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mouse', 'Species', '10090', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('survival', 'CPA', (229, 237))	('knockout', 'Var', (141, 149))
160588	32495158	Furthermore, in RCC, a high PD-L1 protein score was predictive of poor outcome in patients who received anti-angiogenic TKI treatment with sunitinib or pazopanib (COMPARZ trial).	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('high', 'Var', (23, 27))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('RCC', 'Disease', (16, 19))	('patients', 'Species', '9606', (82, 90))	('pazopanib', 'Chemical', 'MESH:C516667', (152, 161))	('sunitinib', 'Chemical', 'MESH:D000077210', (139, 148))	('PD-L1', 'Gene', (28, 33))
160616	30854124	demonstrated a 15% objective response rate in RCC patients who treated with high-dose IL-2, this lead the US Food and Drug Administration (FDA) to approve the use of IL-2.	('RCC', 'Disease', (46, 49))	('patients', 'Species', '9606', (50, 58))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('IL-2', 'molecular_function', 'GO:0005134', ('166', '170'))	('IL-2', 'Gene', '3558', (86, 90))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('IL-2', 'Gene', '3558', (166, 170))	('IL-2', 'Gene', (86, 90))	('IL-2', 'Gene', (166, 170))	('high-dose', 'Var', (76, 85))	('IL-2', 'molecular_function', 'GO:0005134', ('86', '90'))
160673	30854124	Univariate analysis revealed higher risks of death (HR, 2.519; P = 0.001) and disease relapse (HR, 2.285; P = 0.001) in patients with high levels of CD8+ TILs (Table 2).	('disease relapse', 'CPA', (78, 93))	('CD8', 'Gene', (149, 152))	('death', 'Disease', 'MESH:D003643', (45, 50))	('CD8', 'Gene', '925', (149, 152))	('death', 'Disease', (45, 50))	('patients', 'Species', '9606', (120, 128))	('high levels', 'Var', (134, 145))
160720	31652661	At the end of the six rounds of selection, the identified signature (called signature-H) included the following 15 genes: CD2 (Gene ID: 914), CD247 (Gene ID: 919), CD28 (Gene ID: 940), CD3D (Gene ID: 915), CD3G (Gene ID: 917), CD6 (Gene ID: 923), GPR171 (Gene ID: 29909), GZMK (Gene ID: 3003), ICOS (Gene ID: 29851), ITK (Gene ID: 3702), KLRB1 (Gene ID: 3820), PYHIN1 (Gene ID: 149628), TIGIT (Gene ID: 201633), TRAT1 (Gene ID: 50852), and TRBC1 (Gene ID: 28639).	('Gene ID: 149628', 'Var', (369, 384))	('CD2', 'Gene', (164, 167))	('CD2', 'Gene', '914', (164, 167))	('TRAT1', 'Gene', (412, 417))	('PYHIN1', 'Gene', '149628', (361, 367))	('TIGIT', 'Gene', '201633', (387, 392))	('CD6', 'Gene', (227, 230))	('PYHIN1', 'Gene', (361, 367))	('ITK', 'Gene', '3702', (317, 320))	('CD3G', 'Gene', (206, 210))	('CD28', 'Gene', '940', (164, 168))	('CD3D', 'Gene', (185, 189))	('TRAT1', 'Gene', '50852', (412, 417))	('CD6', 'Gene', '923', (227, 230))	('CD247', 'Gene', (142, 147))	('ICOS', 'Gene', '29851', (294, 298))	('CD247', 'Gene', '919', (142, 147))	('CD3D', 'Gene', '915', (185, 189))	('GPR171', 'Gene', '29909', (247, 253))	('GZMK', 'Gene', '3003', (272, 276))	('Gene', 'Var', (300, 304))	('CD2', 'Gene', (122, 125))	('TRBC1', 'Gene', (440, 445))	('CD2', 'Gene', '914', (122, 125))	('ICOS', 'Gene', (294, 298))	('KLRB1', 'Gene', (338, 343))	('TIGIT', 'Gene', (387, 392))	('Gene', 'Var', (394, 398))	('GPR171', 'Gene', (247, 253))	('GZMK', 'Gene', (272, 276))	('ITK', 'Gene', (317, 320))	('CD3G', 'Gene', '917', (206, 210))	('CD2', 'Gene', (142, 145))	('CD2', 'Gene', '914', (142, 145))	('CD28', 'Gene', (164, 168))	('Gene ID: 29909', 'Var', (255, 269))	('TRBC1', 'Gene', '28639', (440, 445))	('KLRB1', 'Gene', '3820', (338, 343))
160734	31652661	Interestingly, five "hot" cancers (some lung cancers, stomach, and pancreas cancers) resulted highly infiltrated with signature-H but not with signature-B and signature-C and cancers known to be infiltrated by T-cells (e.g., colon adenocarcinoma and brain neuroblastoma) resulted moderately infiltrated with signature-H but infiltrated at low levels (similar to HT) with signature-B and signature-C.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('neuroblastoma', 'Phenotype', 'HP:0003006', (256, 269))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('pancreas cancers', 'Disease', (67, 83))	('lung cancers', 'Disease', 'MESH:D008175', (40, 52))	('pancreas cancers', 'Disease', 'MESH:D010190', (67, 83))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('lung cancers', 'Disease', (40, 52))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('lung cancers', 'Phenotype', 'HP:0100526', (40, 52))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('colon adenocarcinoma and brain neuroblastoma', 'Disease', 'MESH:D009447', (225, 269))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('signature-H', 'Var', (118, 129))	('cancers', 'Disease', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('stomach', 'Disease', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('HT', 'Disease', 'MESH:D006973', (362, 364))	('cancers', 'Disease', 'MESH:D009369', (175, 182))
160736	31652661	Moreover, signature-H has a higher sensitivity in the evaluation of Tci of cancer as compared the other T cell signatures.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('signature-H', 'Var', (10, 21))	('cancer', 'Disease', (75, 81))	('sensitivity', 'MPA', (35, 46))	('Tc', 'Chemical', 'MESH:D013667', (68, 70))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
160738	31652661	On the contrary, the maximum difference in the Ts% of the tumors was three-fold (from 2.9 to 7.9) or about four-fold (from 2.4 to 9.2) when Ts% was calculated by signature-B or signature-C, respectively (Figure S6).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('signature-B', 'Var', (162, 173))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('to 9', 'Species', '1214577', (127, 131))	('to 7', 'Species', '1214577', (90, 94))	('signature-C', 'Var', (177, 188))
160759	31652661	Of note, patients with the lowest Tav-array (<0.125) had a death hazard ratio of 6.2 (95% CI, 2.5-9.1) as compared to patients with the highest Tav-array (>2).	('lowest', 'NegReg', (27, 33))	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (118, 126))	('<0.125', 'Var', (45, 51))
160760	31652661	Moreover, children classified into the COG high-risk group can be further ranked according to the Tav-array levels, so that patients with the lowest Tav-array (<0.125) had a death hazard ratio of 2.8 (95%CI, 1.1-4.6) as compared to patients with the highest Tav-array (>2) (Figure 5E).	('COG', 'Chemical', 'MESH:C530207', (39, 42))	('<0.125', 'Var', (160, 166))	('patients', 'Species', '9606', (232, 240))	('lowest', 'NegReg', (142, 148))	('patients', 'Species', '9606', (124, 132))	('children', 'Species', '9606', (10, 18))
160761	31652661	These results indicate that Tci determined with signature-H8 (i.e., an adapted signature-H) has prognostic value in cancers and its performance is similar to that of Tci determined by histological evaluation.	('Tc', 'Chemical', 'MESH:D013667', (166, 168))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('signature-H8', 'Var', (48, 60))	('cancers', 'Disease', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('Tc', 'Chemical', 'MESH:D013667', (28, 30))
160768	31652661	We found that a ligand/receptor ratio higher than 0.5 and lower than 10 was somehow predictive of the response (Table S12A and Figure S10).	('S12A', 'Var', (118, 122))	('ligand/receptor', 'MPA', (16, 31))	('S12A', 'SUBSTITUTION', 'None', (118, 122))	('S10', 'Gene', (134, 137))	('ligand', 'molecular_function', 'GO:0005488', ('16', '22'))	('lower', 'Var', (58, 63))	('S10', 'Gene', '3897', (134, 137))
160770	31652661	The patients with good signature-1 showed a complete response (CR), partial response (PR), or progressive disease (PD) (Figure S10A).	('signature-1', 'Gene', (23, 34))	('S10A', 'SUBSTITUTION', 'None', (127, 131))	('progressive', 'Disease', (94, 105))	('patients', 'Species', '9606', (4, 12))	('partial', 'Disease', (68, 75))	('S10A', 'Var', (127, 131))
160771	31652661	The patients with bad signature-1 showed PR or PD.	('signature-1', 'Gene', (22, 33))	('bad', 'Var', (18, 21))	('patients', 'Species', '9606', (4, 12))
160780	31652661	(1) signature-H describes brain and cerebellum as the least infiltrated tissues by T cells among the non-lymphoid HT whereas signature-B and signature-C do not, (2) the difference between T cell infiltration levels in the most and the least infiltrated non-lymphoid tissues results to be higher with signature-H than signature-B and signature-C.	('HT', 'Disease', 'MESH:D006973', (114, 116))	('signature-H', 'Var', (300, 311))	('T cell infiltration levels', 'MPA', (188, 214))	('higher', 'PosReg', (288, 294))
160848	33276608	CD147, also called Basignin/extracellular matrix metalloproteinase inducer (EMMPRIN), is a glycoprotein with versatile functional properties: it is indispensable for the exchange of lactate between cells, acts as a cell adhesion molecule, and induces matrix metalloproteases (MMPs).	('MMPs', 'Gene', '4318', (276, 280))	('cell adhesion', 'biological_process', 'GO:0007155', ('215', '228'))	('matrix', 'CPA', (251, 257))	('CD147', 'Var', (0, 5))	('exchange', 'MPA', (170, 178))	('lactate', 'Chemical', 'MESH:D019344', (182, 189))	('EMMPRIN', 'Gene', '682', (76, 83))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('215', '237'))	('EMMPRIN', 'Gene', (76, 83))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('28', '48'))	('Basignin/extracellular matrix metalloproteinase inducer', 'Gene', '682', (19, 74))	('induces', 'PosReg', (243, 250))	('MMPs', 'Gene', (276, 280))
160880	33276608	The tissue sections were incubated with primary antibodies (solved in 1% BSA in PBS, pH 7.2) against CD70 (monoclonal mouse, MAB2738, RD Systems), CD147 (monoclonal rabbit, ab108308, Abcam), CA9 (recombinant mouse, monoclonal from hybridoma, Integra), or EpCAM (monoclonal rabbit, D4K8R, Cell Signaling) for 1 h at 37  C and then washed four times with PBS.	('Signaling', 'biological_process', 'GO:0023052', ('293', '302'))	('CD70', 'Gene', (101, 105))	('PBS', 'Chemical', '-', (80, 83))	('PBS', 'Chemical', '-', (353, 356))	('mouse', 'Species', '10090', (118, 123))	('mouse', 'Species', '10090', (208, 213))	('CD147', 'Var', (147, 152))
160958	33276608	Upon CD27 binding, CD70 induces the proliferation of co-stimulated T-cells and triggers the generation of cytolytic T-cells.	('CD70', 'Var', (19, 23))	('induces', 'PosReg', (24, 31))	('CD27', 'Gene', '939', (5, 9))	('CD27', 'Gene', (5, 9))	('binding', 'Interaction', (10, 17))	('triggers', 'Reg', (79, 87))	('binding', 'molecular_function', 'GO:0005488', ('10', '17'))	('proliferation', 'CPA', (36, 49))	('cytolytic T-cells', 'MPA', (106, 123))
160972	31661791	Herein, we firstly identified eight potentially prognostic miRNAs (hsa-miR-144-5p, hsa-miR-223-3p, hsa-miR-365b-3p, hsa-miR-3613-5p, hsa-miR-9-5p, hsa-miR-183-5p, hsa-miR-335-3p, hsa-miR-1269a).	('hsa-miR-9-5p', 'Gene', '407052', (133, 145))	('hsa-miR-365b-3p', 'Var', (99, 114))	('hsa-miR-1269a', 'Gene', (179, 192))	('hsa-miR-3613', 'Gene', '100500908', (116, 128))	('hsa-miR-223-3p', 'Var', (83, 97))	('hsa-miR-335', 'Gene', '442904', (163, 174))	('hsa-miR-144', 'Gene', '406936', (67, 78))	('hsa-miR-1269a', 'Gene', '100302177', (179, 192))	('hsa-miR-335', 'Gene', (163, 174))	('hsa-miR-9-5p', 'Gene', (133, 145))	('miR-183', 'Gene', '406959', (151, 158))	('hsa-miR-144', 'Gene', (67, 78))	('miR-183', 'Gene', (151, 158))	('hsa-miR-3613', 'Gene', (116, 128))
160981	31661791	In recent years, many studies have revealed that miRNAs not only can act as oncogenes or tumor suppressor genes involve in tumorigenesis and progressions of various cancers, but can serve as valuable boimarkers for the detection and prognosis of cancer patients.	('patients', 'Species', '9606', (253, 261))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('tumor', 'Disease', (123, 128))	('cancer', 'Disease', (246, 252))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('89', '105'))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('miRNAs', 'Var', (49, 55))	('tumor', 'Disease', (89, 94))	('tumor suppressor', 'biological_process', 'GO:0051726', ('89', '105'))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('involve', 'Reg', (112, 119))	('cancer', 'Disease', (165, 171))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
160984	31661791	However, several studies have shown that some miRNAs may play complete contradictor roles in diagnosic and prognosic effects for ccRCC, such as miR-99a, miR-106a, miR-125b, miR-144, miR-203, and miR-378, which might greatly limit their applications into the clinical diagnosis and prognosis for ccRCC patients.	('miR-106a', 'Gene', '406899', (153, 161))	('ccRCC', 'Phenotype', 'HP:0006770', (129, 134))	('ccRCC', 'Disease', (129, 134))	('miR-106a', 'Gene', (153, 161))	('ccRCC', 'Phenotype', 'HP:0006770', (295, 300))	('miR-99a', 'Gene', '407055', (144, 151))	('patients', 'Species', '9606', (301, 309))	('ccRCC', 'Disease', (295, 300))	('miR-144', 'Gene', (173, 180))	('miR-378', 'Gene', '494327', (195, 202))	('miR-378', 'Gene', (195, 202))	('miR-203', 'Gene', (182, 189))	('miR-99a', 'Gene', (144, 151))	('miR-125b', 'Var', (163, 171))	('miR-203', 'Gene', '406986', (182, 189))	('miR-144', 'Gene', '406936', (173, 180))
160994	31661791	We finally obtained eight potential prognostic miRNAs, including four down-regulated miRNAs (hsa-miR-9-5p, hsa-miR-1269a, hsa-miR-183-5p, hsa-miR-335-3p) and four up-regulated miRNAs (hsa-miR-365b-3p, hsa-miR-223-3p, hsa-miR-144-5p, hsa-miR-3613-5p), which might be involved in the survival of ccRCC patients.	('hsa-miR-144', 'Gene', (217, 228))	('hsa-miR-9-5p', 'Gene', '407052', (93, 105))	('patients', 'Species', '9606', (300, 308))	('hsa-miR-3613', 'Gene', (233, 245))	('up-regulated', 'PosReg', (163, 175))	('ccRCC', 'Disease', (294, 299))	('hsa-miR-1269a', 'Gene', (107, 120))	('down-regulated', 'NegReg', (70, 84))	('hsa-miR-1269a', 'Gene', '100302177', (107, 120))	('hsa-miR-9-5p', 'Gene', (93, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (294, 299))	('hsa-miR-335', 'Gene', '442904', (138, 149))	('miR-183', 'Gene', '406959', (126, 133))	('hsa-miR-335', 'Gene', (138, 149))	('hsa-miR-3613', 'Gene', '100500908', (233, 245))	('involved', 'Reg', (266, 274))	('miR-183', 'Gene', (126, 133))	('hsa-miR-365b-3p', 'Var', (184, 199))	('hsa-miR-144', 'Gene', '406936', (217, 228))
161001	31661791	This result indicated that, in all eight independent miRNA cohorts, ccRCC patients with high-expression miRNA groups exhibited a worse overall survival rate than the low-expression miRNA groups, except for hsa-miR-144-5p (Figure 2).	('hsa-miR-144', 'Gene', '406936', (206, 217))	('high-expression miRNA', 'Var', (88, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('miRNA', 'Var', (104, 109))	('patients', 'Species', '9606', (74, 82))	('hsa-miR-144', 'Gene', (206, 217))	('ccRCC', 'Disease', (68, 73))	('overall', 'MPA', (135, 142))	('worse', 'NegReg', (129, 134))
161002	31661791	These results seemed to indicate that these highly expressed hsa-miR-9-5p, hsa-miR-1269a, hsa-miR-183-5p, hsa-miR-335-3p, hsa-miR-365b-3p, hsa-miR-223-3p, and hsa-miR-3613-5p might be associated with a poor prognosis for ccRCC patients.	('hsa-miR-9-5p', 'Gene', '407052', (61, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (221, 226))	('hsa-miR-365b-3p', 'Var', (122, 137))	('hsa-miR-3613', 'Gene', (159, 171))	('miR-183', 'Gene', '406959', (94, 101))	('hsa-miR-335', 'Gene', '442904', (106, 117))	('hsa-miR-335', 'Gene', (106, 117))	('patients', 'Species', '9606', (227, 235))	('hsa-miR-1269a', 'Gene', '100302177', (75, 88))	('hsa-miR-3613', 'Gene', '100500908', (159, 171))	('hsa-miR-9-5p', 'Gene', (61, 73))	('hsa-miR-223-3p', 'Var', (139, 153))	('hsa-miR-1269a', 'Gene', (75, 88))	('ccRCC', 'Disease', (221, 226))	('miR-183', 'Gene', (94, 101))
161028	31661791	Overall, we proposed a possibly functional mechanism that three highly expressed miRNAs (hsa-miR-365b-3p, hsa-miR-223-3p, and hsa-miR-3613-5p) might synergistically down-regulate the expression of many tumor suppressor genes to decrease the survival of ccRCC patients.	('hsa-miR-365b-3p', 'Var', (89, 104))	('hsa-miR-223-3p', 'Var', (106, 120))	('hsa-miR-3613', 'Gene', (126, 138))	('decrease', 'NegReg', (228, 236))	('patients', 'Species', '9606', (259, 267))	('ccRCC', 'Disease', (253, 258))	('tumor', 'Disease', (202, 207))	('down-regulate', 'NegReg', (165, 178))	('hsa-miR-3613', 'Gene', '100500908', (126, 138))	('survival', 'CPA', (241, 249))	('expression', 'MPA', (183, 193))	('tumor suppressor', 'biological_process', 'GO:0051726', ('202', '218'))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('202', '218'))	('ccRCC', 'Phenotype', 'HP:0006770', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
161066	31661791	At present, a few studies have reported that hsa-miR-183-5p can promote canceration by targeting SRSF2 in renal cancer, miR-335 could inhibit the proliferation and invasion of clear renal cells through suppressing Bcl-w, hsa-miR-365b-3p is poorly associated with ccRCC patient survival and hsa-miR-9-5p is associated with the development and risk of renal cancer recurrence.	('ccRCC', 'Disease', (263, 268))	('cancer', 'Disease', (112, 118))	('inhibit', 'NegReg', (134, 141))	('renal cancer', 'Disease', 'MESH:D007680', (350, 362))	('invasion', 'CPA', (164, 172))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('miR-183', 'Gene', '406959', (49, 56))	('ccRCC', 'Phenotype', 'HP:0006770', (263, 268))	('hsa-miR-9-5p', 'Gene', '407052', (290, 302))	('cancer', 'Disease', (72, 78))	('promote', 'PosReg', (64, 71))	('miR-335', 'Gene', '442904', (120, 127))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('suppressing', 'NegReg', (202, 213))	('targeting', 'Var', (87, 96))	('cancer', 'Disease', (356, 362))	('patient', 'Species', '9606', (269, 276))	('miR-183', 'Gene', (49, 56))	('Bcl-w', 'Gene', '599', (214, 219))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('renal cancer', 'Disease', (106, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('proliferation', 'CPA', (146, 159))	('SRSF2', 'Gene', '6427', (97, 102))	('renal cancer', 'Phenotype', 'HP:0009726', (106, 118))	('hsa-miR-9-5p', 'Gene', (290, 302))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('miR-335', 'Gene', (120, 127))	('SRSF2', 'Gene', (97, 102))	('renal cancer', 'Disease', (350, 362))	('renal cancer', 'Phenotype', 'HP:0009726', (350, 362))	('renal cancer', 'Disease', 'MESH:D007680', (106, 118))	('cancer', 'Disease', 'MESH:D009369', (356, 362))	('Bcl-w', 'Gene', (214, 219))
161069	31661791	Some recent studies have indicated that miR-223-3p could down-regulate aNHEJ expression to result in synthetic lethality in human BRCA1-deficient cancers, and also act as an oncogenic miRNA in colon cancer through regulating EMT and PRDM1.	('regulating', 'Reg', (214, 224))	('PRDM1', 'Gene', '639', (233, 238))	('BRCA1-deficient cancers', 'Disease', 'MESH:D001943', (130, 153))	('BRCA1-deficient cancers', 'Disease', (130, 153))	('PRDM1', 'Gene', (233, 238))	('EMT', 'Gene', (225, 228))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('colon cancer', 'Disease', 'MESH:D015179', (193, 205))	('result in', 'Reg', (91, 100))	('miR-223-3p', 'Var', (40, 50))	('colon cancer', 'Disease', (193, 205))	('aNHEJ', 'Gene', (71, 76))	('down-regulate', 'NegReg', (57, 70))	('expression', 'MPA', (77, 87))	('human', 'Species', '9606', (124, 129))	('EMT', 'biological_process', 'GO:0001837', ('225', '228'))	('colon cancer', 'Phenotype', 'HP:0003003', (193, 205))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
161082	31661791	Additionally, up-regulated MYC and IKZF1 can activate miR-223-3p and miR-365b-3p to down-regulate RPS6KA6, DEPTOR, and other tumor suppressor genes, whilst miR-223-3p and miR-365b-3p can also down-regulate TFAP2A and GATA2 to down-regulate miR-183-5p and miR-1269a to up-regulated FAS and VEGFA.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('activate', 'PosReg', (45, 53))	('VEGFA', 'Gene', (289, 294))	('RPS6KA6', 'Gene', '27330', (98, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('125', '141'))	('miR-183', 'Gene', '406959', (240, 247))	('down-regulate', 'NegReg', (84, 97))	('FAS', 'Protein', (281, 284))	('DEPTOR', 'Gene', (107, 113))	('RPS6KA6', 'Gene', (98, 105))	('up-regulated', 'PosReg', (14, 26))	('down-regulate', 'NegReg', (226, 239))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('up-regulated', 'PosReg', (268, 280))	('miR-365b-3p', 'Gene', (69, 80))	('tumor suppressor', 'biological_process', 'GO:0051726', ('125', '141'))	('MYC', 'Gene', '4609', (27, 30))	('miR-183', 'Gene', (240, 247))	('IKZF1', 'Gene', (35, 40))	('VEGFA', 'Gene', '7422', (289, 294))	('miR-223-3p', 'Gene', (54, 64))	('GATA2', 'Gene', '2624', (217, 222))	('TFAP2A', 'Gene', '7020', (206, 212))	('miR-1269a', 'Gene', (255, 264))	('miR-365b-3p', 'Var', (171, 182))	('miR-1269a', 'Gene', '100302177', (255, 264))	('DEPTOR', 'Gene', '64798', (107, 113))	('GATA2', 'Gene', (217, 222))	('down-regulate', 'NegReg', (192, 205))	('miR-223-3p', 'Var', (156, 166))	('TFAP2A', 'Gene', (206, 212))	('tumor', 'Disease', (125, 130))	('IKZF1', 'Gene', '10320', (35, 40))	('MYC', 'Gene', (27, 30))
161095	31661791	Among them, seven miRNAs (hsa-miR-223-3p, hsa-miR-365b-3p, hsa-miR-3613-5p hsa-miR-9-5p, hsa-miR-183-5p, hsa-miR-335-3p, hsa-miR-1269a) can serve as potential oncogenes, whereas hsa-miR-144-5p might act as a tumor suppressor gene for ccRCC diagnosis.	('hsa-miR-3613', 'Gene', (59, 71))	('miR-183', 'Gene', (93, 100))	('hsa-miR-144', 'Gene', (178, 189))	('hsa-miR-223-3p', 'Var', (26, 40))	('hsa-miR-3613', 'Gene', '100500908', (59, 71))	('tumor', 'Disease', (208, 213))	('hsa-miR-9-5p', 'Gene', '407052', (75, 87))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('hsa-miR-1269a', 'Gene', (121, 134))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('208', '224'))	('ccRCC', 'Disease', (234, 239))	('hsa-miR-335', 'Gene', '442904', (105, 116))	('hsa-miR-1269a', 'Gene', '100302177', (121, 134))	('miR-183', 'Gene', '406959', (93, 100))	('hsa-miR-335', 'Gene', (105, 116))	('tumor suppressor', 'biological_process', 'GO:0051726', ('208', '224'))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('ccRCC', 'Phenotype', 'HP:0006770', (234, 239))	('hsa-miR-9-5p', 'Gene', (75, 87))	('hsa-miR-144', 'Gene', '406936', (178, 189))
161228	31374051	To select the data of patients with ccRCC from SEER database, we combined 2 International Classification of Diseases for Oncology (ICD-O-3) codes: C649 (kidney) and 8310/3 (clear cell adenocarcinoma).	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('ccRCC', 'Disease', (36, 41))	('patients', 'Species', '9606', (22, 30))	('8310/3', 'Var', (165, 171))	('C649', 'Var', (147, 151))	('clear cell adenocarcinoma', 'Disease', 'MESH:D018262', (173, 198))	('ccRCC', 'Disease', 'MESH:D002292', (36, 41))	('Oncology', 'Phenotype', 'HP:0002664', (121, 129))	('clear cell adenocarcinoma', 'Disease', (173, 198))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('ICD-O-3', 'Chemical', 'MESH:C517075', (131, 138))	('C649', 'Chemical', 'MESH:C435505', (147, 151))
161300	33468140	RNA pull-down assay, luciferase reporter and fluorescent in situ hybridization assays were used to confirm the interactions between circSDHC, miR-127-3p and its target genes.	('SDHC', 'Gene', (136, 140))	('SDHC', 'Gene', '6391', (136, 140))	('miR-127-3p', 'Var', (142, 152))	('interactions', 'Interaction', (111, 123))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))
161304	33468140	Furthermore, knockdown of circSDHC caused decreased CDKN3 expression and E2F1 pathway inhibition, which could be rescued by treatment with an miR-127-3p inhibitor.	('SDHC', 'Gene', (30, 34))	('decreased', 'NegReg', (42, 51))	('expression', 'MPA', (58, 68))	('E2F1 pathway', 'Pathway', (73, 85))	('SDHC', 'Gene', '6391', (30, 34))	('CDKN3', 'Pathway', (52, 57))	('knockdown', 'Var', (13, 22))	('inhibition', 'NegReg', (86, 96))
161314	33468140	This process can mediate cancer progression; for example, circMAPK4 acts as a sponge for miR-125a-3p, which participates glioma progression via the MAPK signaling pathway.	('MAPK', 'molecular_function', 'GO:0004707', ('148', '152'))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('miR-125a-3p', 'Var', (89, 100))	('MAPK signaling', 'biological_process', 'GO:0000165', ('148', '162'))	('cancer', 'Disease', (25, 31))	('signaling pathway', 'biological_process', 'GO:0007165', ('153', '170'))	('participates', 'Reg', (108, 120))	('glioma', 'Disease', (121, 127))
161315	33468140	Further, circZNF609 can interact with and downregulate miR-138-5p, promoting RCC progression; however, the biological functions and clinical significance of circRNAs in RCC remain largely unknown, and require elucidation.	('circZNF609', 'Var', (9, 19))	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('miR-138-5p', 'Gene', (55, 65))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('RCC', 'Disease', (169, 172))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('promoting', 'PosReg', (67, 76))	('downregulate', 'NegReg', (42, 54))
161317	33468140	By performing in vitro and in vivo experiments, we demonstrate that circSDHC serves as a sponge for miRNA-127-3p, thereby regulating the CDKN3/E2F1 axis.	('regulating', 'Reg', (122, 132))	('miRNA-127-3p', 'Var', (100, 112))	('CDKN3/E2F1 axis', 'Pathway', (137, 152))	('SDHC', 'Gene', (72, 76))	('SDHC', 'Gene', '6391', (72, 76))
161330	33468140	Two datasets were retrieved: GSE100186, consisting of 4 tumors and matched adjacent normal tissue; and GSE137836, consisting of 3 primary tumors and 3 metastatic tumors.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumors', 'Disease', (56, 62))	('GSE137836', 'Var', (103, 112))	('tumors', 'Disease', (138, 144))	('GSE100186', 'Var', (29, 38))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
161368	33468140	Two GEO datasets (GSE137836 and GSE100186) from circRNA microarray chips analyzing human tissue samples were used to investigate the role of circRNA in RCC development and progression.	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('RCC', 'Disease', (152, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('human', 'Species', '9606', (83, 88))	('GSE137836', 'Var', (18, 27))	('GSE100186', 'Var', (32, 41))
161369	33468140	The GSE137836 dataset was from three primary and three metastatic tumors, while GSE100186 includes data from four tumors and matched adjacent normal tissue.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (66, 72))	('GSE137836', 'Var', (4, 13))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
161389	33468140	Further, proliferation of these cells was also suppressed on knockdown of circSDHC (Fig.	('knockdown', 'Var', (61, 70))	('suppressed', 'NegReg', (47, 57))	('SDHC', 'Gene', (78, 82))	('SDHC', 'Gene', '6391', (78, 82))
161396	33468140	Four miRNAs, including miR-3612, miR-650, miR-519a-3p, and miR-127-3p, were identified as potential targets of circSDHC in both databases (Fig.	('miR-3612', 'Gene', (23, 31))	('miR-3612', 'Gene', '100500817', (23, 31))	('miR-519a-3p', 'Var', (42, 53))	('miR-127-3p', 'Var', (59, 69))	('miR-650', 'Gene', (33, 40))	('SDHC', 'Gene', (115, 119))	('SDHC', 'Gene', '6391', (115, 119))	('miR-650', 'Gene', '723778', (33, 40))
161399	33468140	Subsequent qRT-PCR confirmed that miR-127-3p could bind to circSDHC in both 786-O and A498 cells (Fig.	('miR-127-3p', 'Var', (34, 44))	('SDHC', 'Gene', '6391', (63, 67))	('SDHC', 'Gene', (63, 67))	('bind', 'Interaction', (51, 55))
161400	33468140	Further, biotin-labeled miR-127-3p captured more circSDHC than a negative control probe (Fig.	('SDHC', 'Gene', '6391', (53, 57))	('biotin', 'Chemical', 'MESH:D001710', (9, 15))	('SDHC', 'Gene', (53, 57))	('miR-127-3p', 'Var', (24, 34))
161401	33468140	3f) and FISH analysis in 786-O cells showed that circSDHC and miR-127-3p were co-localized in the cytoplasm (Fig.	('miR-127-3p', 'Var', (62, 72))	('SDHC', 'Gene', '6391', (53, 57))	('cytoplasm', 'cellular_component', 'GO:0005737', ('98', '107'))	('SDHC', 'Gene', (53, 57))
161402	33468140	Furthermore, analysis of our ccRCC patient data showed a negative correlation between miR-127-3p and circSDHC (Fig.	('SDHC', 'Gene', '6391', (105, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('patient', 'Species', '9606', (35, 42))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))	('miR-127-3p', 'Var', (86, 96))	('SDHC', 'Gene', (105, 109))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))	('negative', 'NegReg', (57, 65))
161403	33468140	These results demonstrate that circSDHC can bind to miR-127-3p and act as a sponge for miR-127-3p.	('bind', 'Interaction', (44, 48))	('SDHC', 'Gene', (35, 39))	('miR-127-3p', 'Protein', (52, 62))	('miR-127-3p', 'Var', (87, 97))	('SDHC', 'Gene', '6391', (35, 39))
161404	33468140	According to TCGA ccRCC database, miR-127-3p expression is lower in tumor tissues of ccRCC, compared to normal tissue (Additional file 5: Fig.	('tumor', 'Disease', (68, 73))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('lower', 'NegReg', (59, 64))	('miR-127-3p', 'Var', (34, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('RCC', 'Disease', (20, 23))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
161405	33468140	Moreover, it has previously been reported that lower expression of miR-127-3p correlates with early relapse in patients with RCC following nephrectomy.	('lower', 'NegReg', (47, 52))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('early relapse', 'CPA', (94, 107))	('expression', 'MPA', (53, 63))	('miR-127-3p', 'Var', (67, 77))	('patients', 'Species', '9606', (111, 119))
161406	33468140	These data suggested that miR-127-3p may have an inhibitory role in RCC development and progression.	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('miR-127-3p', 'Var', (26, 36))
161407	33468140	We also had similar observations in our patient cohort, where lower miR-127-3p expression was detected in tumor tissues than in adjacent normal adjacent tissues (Additional file 5: Fig.	('patient', 'Species', '9606', (40, 47))	('miR-127-3p', 'Var', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('lower', 'NegReg', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
161409	33468140	Consistent with these findings, overexpression of miR-127-3p in 786-O and A498 cells resulted in decreases in both aggression and proliferation (Fig.	('miR-127-3p', 'Var', (50, 60))	('overexpression', 'PosReg', (32, 46))	('aggression', 'Disease', 'MESH:D001523', (115, 125))	('aggression', 'Disease', (115, 125))	('decreases', 'NegReg', (97, 106))	('proliferation', 'CPA', (130, 143))	('aggression', 'Phenotype', 'HP:0000718', (115, 125))	('aggression', 'biological_process', 'GO:0002118', ('115', '125'))
161410	33468140	Cyclin dependent kinase inhibitor 3 (CDKN3) was identified as a potential candidate gene regulated by miR-127-3p, with the binding classified as 7mer-m8 (Fig.	('binding', 'molecular_function', 'GO:0005488', ('123', '130'))	('miR-127-3p', 'Var', (102, 112))	('Cyclin dependent kinase inhibitor 3', 'Gene', (0, 35))	('regulated', 'Reg', (89, 98))	('CDKN3', 'Gene', (37, 42))	('Cyclin dependent kinase inhibitor 3', 'Gene', '1033', (0, 35))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('17', '33'))	('Cyclin dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('0', '33'))
161411	33468140	Moreover, in our patient cohort, we detected a negative relationship between miR-127-3p and CDKN3 expression levels (Additional file 6: Fig.	('miR-127-3p', 'Var', (77, 87))	('negative', 'NegReg', (47, 55))	('patient', 'Species', '9606', (17, 24))	('CDKN3 expression levels', 'MPA', (92, 115))
161412	33468140	These results indicate that miR-127-3p can inhibit RCC progression through downregulation of CDKN3.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('downregulation', 'NegReg', (75, 89))	('CDKN3', 'Gene', (93, 98))	('miR-127-3p', 'Var', (28, 38))	('inhibit', 'NegReg', (43, 50))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
161414	33468140	CDKN3 knockdown in RCC cells led to a lower proliferation rate and diminished migration and invasion abilities (Fig.	('diminished', 'NegReg', (67, 77))	('lower', 'NegReg', (38, 43))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('knockdown', 'Var', (6, 15))	('proliferation rate', 'CPA', (44, 62))	('CDKN3', 'Gene', (0, 5))
161416	33468140	E2F1 is a potent transcription regulator that participates in the development of many different types of cancer, and a previous paper reported that E2F1 is also involved in ccRCC progression.	('ccRCC', 'Phenotype', 'HP:0006770', (173, 178))	('E2F1', 'Var', (148, 152))	('involved', 'Reg', (161, 169))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('transcription', 'biological_process', 'GO:0006351', ('17', '30'))	('RCC', 'Disease', (175, 178))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('RCC', 'Disease', 'MESH:C538614', (175, 178))
161421	33468140	In contrast, the CDKN3/E2F1 pathway could be activated by transfection with the circSDHC overexpression vector and this effect was diminished by introduction of miR-127-3p mimic into 769P cells (Fig.	('SDHC', 'Gene', '6391', (84, 88))	('transfection', 'Var', (58, 70))	('CDKN3/E2F1 pathway', 'Pathway', (17, 35))	('activated', 'PosReg', (45, 54))	('SDHC', 'Gene', (84, 88))
161423	33468140	Our result proved that knockdown of circSDHC caused downregulation of CDKN3 and further decreased the expression of CDK1 and CDK2 (Additional file 6: Fig.	('CDKN3', 'Gene', (70, 75))	('expression', 'MPA', (102, 112))	('CDK', 'molecular_function', 'GO:0004693', ('116', '119'))	('knockdown', 'Var', (23, 32))	('CDK2', 'Gene', (125, 129))	('CDK1', 'Gene', (116, 120))	('CDK', 'molecular_function', 'GO:0004693', ('125', '128'))	('downregulation', 'NegReg', (52, 66))	('decreased', 'NegReg', (88, 97))	('SDHC', 'Gene', (40, 44))	('SDHC', 'Gene', '6391', (40, 44))
161427	33468140	On both gross and microscope examination, lungs from mice injected with circSDHC knockdown cancer cells had less metastatic foci than controls (Fig.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('knockdown', 'Var', (81, 90))	('SDHC', 'Gene', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('SDHC', 'Gene', '6391', (76, 80))	('mice', 'Species', '10090', (53, 57))	('less', 'NegReg', (108, 112))	('metastatic foci', 'CPA', (113, 128))
161431	33468140	These results demonstrate that knockdown of circSDHC inhibits RCC tumor progression in vivo.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('circSDHC inhibits RCC tumor', 'Disease', 'MESH:C538614', (44, 71))	('circSDHC inhibits RCC tumor', 'Disease', (44, 71))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('knockdown', 'Var', (31, 40))
161442	33468140	Subsequently, we used a biotin-labeled probe targeting circSDHC and luciferase reporter assays to confirm that miR-127-3p is a target of circSDHC.	('SDHC', 'Gene', (59, 63))	('biotin', 'Chemical', 'MESH:D001710', (24, 30))	('SDHC', 'Gene', '6391', (59, 63))	('SDHC', 'Gene', (141, 145))	('miR-127-3p', 'Var', (111, 121))	('SDHC', 'Gene', '6391', (141, 145))
161443	33468140	Further, analysis of TCGA dataset and data from our own patient cohort showed lower expression of miR-127-3p in tumor, compared with normal tissues.	('patient', 'Species', '9606', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('lower', 'NegReg', (78, 83))	('miR-127-3p', 'Var', (98, 108))	('expression', 'MPA', (84, 94))
161444	33468140	Our findings are consistent with previous studies, which proved that miR-127-3p functions as a tumor suppressor in several different cancers, including osteosarcoma, oral squamous cell carcinoma, and prostate cancer.	('tumor suppressor', 'Gene', (95, 111))	('prostate cancer', 'Disease', 'MESH:D011471', (200, 215))	('prostate cancer', 'Phenotype', 'HP:0012125', (200, 215))	('osteosarcoma', 'Phenotype', 'HP:0002669', (152, 164))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('miR-127-3p', 'Var', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor suppressor', 'biological_process', 'GO:0051726', ('95', '111'))	('prostate cancer', 'Disease', (200, 215))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (166, 194))	('tumor suppressor', 'Gene', '7248', (95, 111))	('oral squamous cell carcinoma', 'Disease', (166, 194))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('osteosarcoma', 'Disease', (152, 164))	('osteosarcoma', 'Disease', 'MESH:D012516', (152, 164))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (171, 194))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('95', '111'))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
161445	33468140	Despite the negative regulatory effects of CDKN3 on CDK1 and CDK2, an oncogenic role for aberrant overexpression of CDKN3 has been implicated in numerous types of human cancer, including prostate cancer, gastric cancer, nasopharyngeal carcinoma, and esophageal cancer.	('implicated', 'Reg', (131, 141))	('CDK2', 'Gene', (61, 65))	('carcinoma', 'Disease', 'MESH:D009369', (235, 244))	('cancer', 'Disease', (169, 175))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (220, 244))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('negative', 'NegReg', (12, 20))	('CDKN3', 'Gene', (116, 121))	('CDK1', 'Gene', (52, 56))	('gastric cancer', 'Disease', (204, 218))	('esophageal cancer', 'Disease', 'MESH:D004938', (250, 267))	('aberrant', 'Var', (89, 97))	('overexpression', 'PosReg', (98, 112))	('cancer', 'Disease', (261, 267))	('esophageal cancer', 'Disease', (250, 267))	('CDKN3', 'Gene', (43, 48))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('gastric cancer', 'Disease', 'MESH:D013274', (204, 218))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', (196, 202))	('regulatory', 'MPA', (21, 31))	('carcinoma', 'Disease', (235, 244))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('prostate cancer', 'Disease', 'MESH:D011471', (187, 202))	('gastric cancer', 'Phenotype', 'HP:0012126', (204, 218))	('CDK', 'molecular_function', 'GO:0004693', ('61', '64'))	('CDK', 'molecular_function', 'GO:0004693', ('52', '55'))	('human', 'Species', '9606', (163, 168))	('prostate cancer', 'Phenotype', 'HP:0012125', (187, 202))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('prostate cancer', 'Disease', (187, 202))
161449	33468140	Specifically, E2F1 promotes tumor malignancy and correlates with TNM stage in ccRCC.	('tumor malignancy', 'Disease', (28, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('promotes', 'PosReg', (19, 27))	('TNM', 'Gene', '10178', (65, 68))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('tumor malignancy', 'Disease', 'MESH:D009369', (28, 44))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('E2F1', 'Var', (14, 18))	('TNM', 'Gene', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
161450	33468140	Therefore, we predicted that the CDKN3/E2F1 pathway may be a target of circSDHC and miR-127-3p.	('SDHC', 'Gene', '6391', (75, 79))	('miR-127-3p', 'Var', (84, 94))	('CDKN3/E2F1 pathway', 'Pathway', (33, 51))	('SDHC', 'Gene', (75, 79))
161453	33468140	Further, circSDHC promotes ccRCC progression and metastasis by acting as a sponge for miR-127-3p, which is a tumor suppressor that downregulates the activity of CDKN3/E2F1 axis.	('SDHC', 'Gene', (13, 17))	('tumor suppressor', 'biological_process', 'GO:0051726', ('109', '125'))	('metastasis', 'CPA', (49, 59))	('SDHC', 'Gene', '6391', (13, 17))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('109', '125'))	('tumor suppressor', 'Gene', (109, 125))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('activity', 'MPA', (149, 157))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (27, 32))	('CDKN3/E2F1 axis', 'Pathway', (161, 176))	('promotes', 'PosReg', (18, 26))	('miR-127-3p', 'Var', (86, 96))	('tumor suppressor', 'Gene', '7248', (109, 125))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('downregulates', 'NegReg', (131, 144))
161462	31640193	As a result, pAMPK positivity, either in the cytoplasm or nuclei, was independently associated with improved ccRCC prognosis, after adjusting for TNM stage and WHO grade.	('TNM', 'Gene', (146, 149))	('positivity', 'Var', (19, 29))	('improved', 'PosReg', (100, 108))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('ccRCC', 'Disease', (109, 114))	('ccRCC', 'Disease', 'MESH:D002292', (109, 114))	('TNM', 'Gene', '10178', (146, 149))	('cytoplasm', 'cellular_component', 'GO:0005737', ('45', '54'))	('AMPK', 'Gene', (14, 18))	('AMPK', 'Gene', '5564', (14, 18))
161468	31640193	For example, accumulation of an oxygen-sensing protein, hypoxia-inducible factor (HIF)-alpha, by the mutational loss of the VHL tumor-suppressor gene supports ccRCC progression via angiogenesis and epithelial-mesenchymal transition (EMT).	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('198', '231'))	('EMT', 'biological_process', 'GO:0001837', ('233', '236'))	('mutational', 'Var', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('epithelial-mesenchymal', 'CPA', (198, 220))	('ccRCC', 'Disease', (159, 164))	('supports', 'PosReg', (150, 158))	('ccRCC', 'Phenotype', 'HP:0006770', (159, 164))	('hypoxia', 'Disease', (56, 63))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('128', '144'))	('loss', 'NegReg', (112, 116))	('angiogenesis', 'CPA', (181, 193))	('VHL tumor', 'Disease', (124, 133))	('hypoxia', 'Disease', 'MESH:D000860', (56, 63))	('accumulation', 'PosReg', (13, 25))	('VHL tumor', 'Disease', 'MESH:D006623', (124, 133))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('128', '144'))	('angiogenesis', 'biological_process', 'GO:0001525', ('181', '193'))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('oxygen', 'Chemical', 'MESH:D010100', (32, 38))	('ccRCC', 'Disease', 'MESH:D002292', (159, 164))
161482	31640193	Upon receptor-regulated phosphorylation by TGF-beta, pSMAD2/pSMAD3 forms a complex with SMAD4 and acts as a coactivator of numerous TGF-beta target promoters in the nuclei that contributes to either tumorigenesis or tumor progression, depending on the context.	('SMAD3', 'Gene', (61, 66))	('TGF-beta', 'Gene', '7040', (43, 51))	('TGF-beta', 'Gene', (132, 140))	('SMAD4', 'Gene', '4089', (88, 93))	('tumor', 'Disease', (216, 221))	('contributes to', 'Reg', (177, 191))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('TGF-beta', 'Gene', (43, 51))	('tumor', 'Disease', (199, 204))	('complex', 'Interaction', (75, 82))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('SMAD3', 'Gene', '4088', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('SMAD2', 'Gene', '4087', (54, 59))	('phosphorylation', 'Var', (24, 39))	('TGF-beta', 'Gene', '7040', (132, 140))	('SMAD4', 'Gene', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('SMAD2', 'Gene', (54, 59))	('phosphorylation', 'biological_process', 'GO:0016310', ('24', '39'))
161487	31640193	IHC staining revealed cytoplasmic (Figure 1A,B) and nuclear (Figure 1B,C) pAMPK positivity in 250 (55.2%) and 228 (50.3%) samples, respectively, of the discovery cohort, and in 242 (45.3%) and 231 (43.3%) patients, respectively, of the validation cohort (Table 1).	('patients', 'Species', '9606', (205, 213))	('AMPK', 'Gene', (75, 79))	('AMPK', 'Gene', '5564', (75, 79))	('positivity', 'Var', (80, 90))	('cytoplasmic', 'CPA', (22, 33))
161489	31640193	Both cytoplasmic and nuclear pAMPK positivity was significantly associated with small tumor size (p < 0.001), low TNM stage (p < 0.001), and low WHO grade (p < 0.001) in the discovery cohort, which was verified in the validation cohort (Table 1).	('small tumor', 'Disease', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('TNM', 'Gene', '10178', (114, 117))	('positivity', 'Var', (35, 45))	('low WHO grade', 'CPA', (141, 154))	('AMPK', 'Gene', (30, 34))	('AMPK', 'Gene', '5564', (30, 34))	('small tumor', 'Disease', 'MESH:D058405', (80, 91))	('TNM', 'Gene', (114, 117))
161492	31640193	A multivariate analysis incorporating TNM stage and WHO grade showed that pAMPK positivity is an independent prognostic factor for favorable PFS (cytoplasmic, hazard ratio [HR] = 0.260, p < 0.001; nuclear, HR = 0.308, p < 0.001), OS (cytoplasmic, HR = 0.656, p = 0.032), and CSS (cytoplasmic, HR = 0.374, p = 0.001; nuclear, HR = 0.232, p = 0.003) in the discovery cohort (Table 2).	('PFS', 'Disease', (141, 144))	('TNM', 'Gene', '10178', (38, 41))	('AMPK', 'Gene', (75, 79))	('AMPK', 'Gene', '5564', (75, 79))	('TNM', 'Gene', (38, 41))	('positivity', 'Var', (80, 90))
161496	31640193	Similarly, SMAD4 nuclear expression was observed in 20.0% (+-22.6) and 2.6% (+-5.9) (p < 0.001) of tumor cells with cytoplasmic pAMPK positivity and negativity, respectively, and in 19.0% (+-23.2) and 5.4% (+-10.5) (p < 0.001) of those with positive and negative nuclear pAMPK immunostaining, respectively (Figure 3B).	('tumor', 'Disease', (99, 104))	('AMPK', 'Gene', (129, 133))	('AMPK', 'Gene', '5564', (129, 133))	('SMAD4', 'Gene', '4089', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('AMPK', 'Gene', '5564', (272, 276))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('SMAD4', 'Gene', (11, 16))	('AMPK', 'Gene', (272, 276))	('positivity', 'Var', (134, 144))	('negativity', 'Var', (149, 159))
161505	31640193	pAMPK positivity was related to low-risk pathological traits of ccRCC, including small tumor size, early TNM stage, and low WHO grade, and was an independent favorable prognostic factor in ccRCC.	('TNM', 'Gene', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('AMPK', 'Gene', (1, 5))	('AMPK', 'Gene', '5564', (1, 5))	('positivity', 'Var', (6, 16))	('small tumor', 'Disease', 'MESH:D058405', (81, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (189, 194))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('ccRCC', 'Disease', (64, 69))	('small tumor', 'Disease', (81, 92))	('ccRCC', 'Disease', 'MESH:D002292', (64, 69))	('ccRCC', 'Disease', (189, 194))	('TNM', 'Gene', '10178', (105, 108))	('ccRCC', 'Disease', 'MESH:D002292', (189, 194))
161550	31640193	However, more detailed in vitro studies adopting a constitutively active mutant of AMPK or depletion of pAMPK using compound C or siRNA to AMPK would profoundly improve the understanding of the causal relationship between pAMPK and pSMAD2/SMAD4 activation.	('SMAD2', 'Gene', '4087', (233, 238))	('SMAD4', 'Gene', '4089', (239, 244))	('AMPK', 'Gene', '5564', (83, 87))	('AMPK', 'Gene', (83, 87))	('AMPK', 'Gene', (139, 143))	('AMPK', 'Gene', '5564', (105, 109))	('AMPK', 'molecular_function', 'GO:0050405', ('139', '143'))	('AMPK', 'Gene', '5564', (139, 143))	('AMPK', 'Gene', (105, 109))	('SMAD2', 'Gene', (233, 238))	('mutant', 'Var', (73, 79))	('AMPK', 'molecular_function', 'GO:0050405', ('83', '87'))	('AMPK', 'molecular_function', 'GO:0004691', ('139', '143'))	('AMPK', 'molecular_function', 'GO:0004691', ('83', '87'))	('AMPK', 'Gene', (223, 227))	('AMPK', 'Gene', '5564', (223, 227))	('SMAD4', 'Gene', (239, 244))	('improve', 'PosReg', (161, 168))	('AMPK', 'molecular_function', 'GO:0047322', ('139', '143'))	('AMPK', 'molecular_function', 'GO:0047322', ('83', '87'))
161590	31640193	pAMPK positivity is associated with nuclear overexpression of pSMAD2 and SMAD4, through stimulation of TGF-beta-independent phosphorylation of SMAD2, which is a novel antitumoral mechanism for pAMPK in ccRCC.	('SMAD4', 'Gene', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('ccRCC', 'Phenotype', 'HP:0006770', (202, 207))	('phosphorylation', 'biological_process', 'GO:0016310', ('124', '139'))	('stimulation', 'PosReg', (88, 99))	('SMAD2', 'Gene', '4087', (63, 68))	('AMPK', 'Gene', (194, 198))	('positivity', 'Var', (6, 16))	('AMPK', 'Gene', '5564', (194, 198))	('overexpression', 'PosReg', (44, 58))	('SMAD4', 'Gene', '4089', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('TGF-beta', 'Gene', '7040', (103, 111))	('SMAD2', 'Gene', (63, 68))	('AMPK', 'Gene', (1, 5))	('AMPK', 'Gene', '5564', (1, 5))	('SMAD2', 'Gene', '4087', (143, 148))	('ccRCC', 'Disease', 'MESH:D002292', (202, 207))	('SMAD2', 'Gene', (143, 148))	('TGF-beta', 'Gene', (103, 111))	('ccRCC', 'Disease', (202, 207))	('tumor', 'Disease', (171, 176))
161613	29416756	For instance, the eosinophilic variants of chRCC and ccRCC can exhibit similar cytological features.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('eosinophilic', 'Var', (18, 30))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('eosin', 'Chemical', 'MESH:D004801', (18, 23))
161701	29416756	RCC subtypes exhibit characteristic chromosomal aberrations, such as whole or partial chromosomal duplications and deletions.	('partial chromosomal duplications', 'Var', (78, 110))	('whole', 'Var', (69, 74))	('deletions', 'Var', (115, 124))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('RCC', 'Disease', (0, 3))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (36, 59))
161708	29416756	Interestingly, loss of chromosome 9p and 9q have also been reported in ccRCC, however this occurs at a later stage of disease progression.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('reported', 'Reg', (59, 67))	('RCC', 'Disease', (73, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('23', '33'))	('loss', 'Var', (15, 19))
161719	29416756	Frequent copy number gains in chromosome 12 have been reported in chRCC.	('copy number gains', 'Var', (9, 26))	('RCC', 'Disease', (68, 71))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('chromosome', 'cellular_component', 'GO:0005694', ('30', '40'))
161754	33649535	Phenotypically, we notice abundant cell surface PD-L1 in HuR-high cancer cells, which significantly inhibits immune activation of co-cultured T cells as indicated by IL-2 production.	('cell surface', 'cellular_component', 'GO:0009986', ('35', '47'))	('inhibits', 'NegReg', (100, 108))	('IL-2', 'molecular_function', 'GO:0005134', ('166', '170'))	('IL-2 production', 'MPA', (166, 181))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('IL-2 production', 'biological_process', 'GO:0032623', ('166', '181'))	('immune activation', 'MPA', (109, 126))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('PD-L1', 'Var', (48, 53))	('cancer', 'Disease', (66, 72))
161756	33649535	Ectopic HuR accelerates allograft tumor progression in vivo, which is greatly compromised by simultaneous administration with MS-444.	('Ectopic HuR', 'Var', (0, 11))	('tumor', 'Disease', (34, 39))	('MS-444', 'Chemical', 'MESH:C096620', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('accelerates', 'PosReg', (12, 23))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
161762	33649535	found shRNA-mediated depletion of CMTM6 down-regulated PD-L1 expression in SCC7 tongue squamous cancer cells, and consequently delayed allograft tumor growth and augmented CD8+ and CD4+ T-cell infiltration, which was accompanied by decrease of PD-1+, TIM-3+, VISTA+, LAG-3+, and B7-H3+ exhausted T cells.	('decrease of PD', 'Phenotype', 'HP:0032198', (232, 246))	('depletion', 'Var', (21, 30))	('B7-H3', 'Gene', '102657', (279, 284))	('CD4+ T-cell infiltration', 'Phenotype', 'HP:0005407', (181, 205))	('down-regulated', 'NegReg', (40, 54))	('PD-1+', 'CPA', (244, 249))	('squamous cancer', 'Phenotype', 'HP:0002860', (87, 102))	('CD4', 'Gene', (181, 184))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('TIM-3', 'Gene', '171285', (251, 256))	('tumor', 'Disease', (145, 150))	('CD8', 'Gene', '925', (172, 175))	('B7-H3', 'Gene', (279, 284))	('PD-L1', 'Gene', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('TIM-3', 'Gene', (251, 256))	('delayed', 'NegReg', (127, 134))	('LAG-3', 'Gene', '16768', (267, 272))	('VISTA', 'Gene', '74048', (259, 264))	('CD4', 'Gene', '12504', (181, 184))	('SCC7 tongue squamous cancer', 'Disease', (75, 102))	('expression', 'MPA', (61, 71))	('decrease', 'NegReg', (232, 240))	('LAG-3', 'Gene', (267, 272))	('SCC7 tongue squamous cancer', 'Disease', 'MESH:D014062', (75, 102))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('augmented', 'PosReg', (162, 171))	('CD8', 'Gene', (172, 175))	('tongue squamous cancer', 'Phenotype', 'HP:0030413', (80, 102))	('CMTM6', 'Var', (34, 39))	('VISTA', 'Gene', (259, 264))
161774	33649535	We further examined this at protein level with renal tumor tissues array, and IHC results clearly showed that CMTM6 was abundant in HuR-high samples (Fig.	('renal tumor', 'Phenotype', 'HP:0009726', (47, 58))	('CMTM6', 'Var', (110, 115))	('renal tumor', 'Disease', (47, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('renal tumor', 'Disease', 'MESH:D007674', (47, 58))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
161782	33649535	Consistent with previous reports, we noticed that ectopic HuR greatly suppressed the turnover rate of PD-L1 while HuR-deficiency significantly accelerated PD-L1 degradation in the presence of protein synthesis inhibitor cycloheximide (CHX, Fig.	('protein synthesis', 'biological_process', 'GO:0006412', ('192', '209'))	('PD-L1 while HuR-deficiency', 'Disease', 'MESH:D010300', (102, 128))	('ectopic', 'Var', (50, 57))	('degradation', 'biological_process', 'GO:0009056', ('161', '172'))	('accelerated', 'PosReg', (143, 154))	('PD-L1 while HuR-deficiency', 'Disease', (102, 128))	('suppressed', 'NegReg', (70, 80))	('accelerated PD', 'Phenotype', 'HP:0008151', (143, 157))	('turnover rate', 'MPA', (85, 98))	('CHX', 'Disease', 'None', (235, 238))	('protein', 'cellular_component', 'GO:0003675', ('192', '199'))	('cycloheximide', 'Chemical', 'MESH:D003513', (220, 233))	('CHX', 'Disease', (235, 238))	('PD-L1 degradation', 'MPA', (155, 172))
161785	33649535	S11) and found that treatment with MS-444 completely impaired enrichment of CMTM6 transcripts in HuR-immunoprecipitated complex in both 769-p and ACHN cells (Fig.	('CMTM6', 'Gene', (76, 81))	('impaired', 'NegReg', (53, 61))	('MS-444', 'Var', (35, 41))	('MS-444', 'Chemical', 'MESH:C096620', (35, 41))	('enrichment', 'MPA', (62, 72))
161786	33649535	In addition, HuR levels were significantly reduced in probe 660-1259-pulldowned protein species in the presence of MS-444 (Fig.	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('HuR levels', 'MPA', (13, 23))	('MS-444', 'Var', (115, 121))	('MS-444', 'Chemical', 'MESH:C096620', (115, 121))	('reduced', 'NegReg', (43, 50))
161788	33649535	The T1 luciferase reporter activities stimulated by HuR-overexpression were inhibited by co-treatment with MS-444 as well due to the disruption of association between HuR protein and luciferase mRNA (Figs.	('luciferase', 'Enzyme', (183, 193))	('association', 'Interaction', (147, 158))	('activities', 'MPA', (27, 37))	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('MS-444', 'Var', (107, 113))	('HuR protein', 'Protein', (167, 178))	('T1 luciferase reporter', 'Enzyme', (4, 26))	('MS-444', 'Chemical', 'MESH:C096620', (107, 113))	('stimulated', 'PosReg', (38, 48))	('disruption', 'NegReg', (133, 143))	('inhibited', 'NegReg', (76, 85))
161802	33649535	We noticed relative reduction of IL-2 production by PD-1High T cells upon addition of co-cultured tumor cells in comparison with PD-1Low, and HuR-proficiency in 786-0 cells significantly imposed suppressive effects on IL-2 production.	('IL-2 production', 'biological_process', 'GO:0032623', ('218', '233'))	('PD-1High T', 'CellLine', 'CVCL:C190', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('PD-1High T', 'Var', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('IL-2 production', 'MPA', (33, 48))	('IL-2 production', 'MPA', (218, 233))	('imposed', 'Reg', (187, 194))	('suppressive', 'NegReg', (195, 206))	('tumor', 'Disease', (98, 103))	('reduction', 'NegReg', (20, 29))	('IL-2', 'molecular_function', 'GO:0005134', ('218', '222'))	('IL-2', 'molecular_function', 'GO:0005134', ('33', '37'))	('IL-2 production', 'biological_process', 'GO:0032623', ('33', '48'))
161805	33649535	Allograft tumor progression was significantly accelerated in HuR-high group compared to control mice, while greatly suppressed by simultaneous administration of MS-444 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mice', 'Species', '10090', (96, 100))	('tumor', 'Disease', (10, 15))	('accelerated', 'PosReg', (46, 57))	('MS-444', 'Chemical', 'MESH:C096620', (161, 167))	('HuR-high group', 'Var', (61, 75))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
161815	33649535	Most importantly, via association with and stabilization of CMTM6, HuR was shown to upregulate cancer cell surface PD-L1 with exposure to IFN-gamma, which was potently blockaded by HuR-specific inhibitor.	('upregulate', 'PosReg', (84, 94))	('IFN-gamma', 'Gene', '3458', (138, 147))	('IFN-gamma', 'Gene', (138, 147))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('CMTM6', 'Var', (60, 65))	('cell surface', 'cellular_component', 'GO:0009986', ('102', '114'))	('association', 'Interaction', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
161832	33649535	Also, MS-444 has been shown to exhibit anti-tumor effects against thyroid cancer cells via downregulation of MAD2, and cytotoxicity toward human lung cancer cells via activation of cell cycle arrest and apoptosis.	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('MS-444', 'Var', (6, 12))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('arrest', 'Disease', 'MESH:D006323', (192, 198))	('thyroid cancer', 'Disease', (66, 80))	('tumor', 'Disease', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cytotoxicity', 'Disease', (119, 131))	('MS-444', 'Chemical', 'MESH:C096620', (6, 12))	('activation', 'PosReg', (167, 177))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('apoptosis', 'CPA', (203, 212))	('cytotoxicity', 'Disease', 'MESH:D064420', (119, 131))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('181', '198'))	('MAD', 'biological_process', 'GO:0072671', ('109', '112'))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('apoptosis', 'biological_process', 'GO:0097194', ('203', '212'))	('downregulation', 'NegReg', (91, 105))	('apoptosis', 'biological_process', 'GO:0006915', ('203', '212'))	('thyroid cancer', 'Disease', 'MESH:D013964', (66, 80))	('lung cancer', 'Disease', (145, 156))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('thyroid cancer', 'Phenotype', 'HP:0002890', (66, 80))	('MAD2', 'Gene', '4085', (109, 113))	('arrest', 'Disease', (192, 198))	('human', 'Species', '9606', (139, 144))	('MAD2', 'Gene', (109, 113))
161834	33649535	Human embryonic kidney cell line 293T, human ccRCC cell lines 786-0, 769-p, A498, A704, ACHN, Caki-1, Caki2, T lymphocyte cell Jurkat and murine renal carcinoma cell line Renca were obtained from ATCC (NY, USA).	('cell Jurkat', 'CellLine', 'CVCL:0065', (122, 133))	('Human', 'Species', '9606', (0, 5))	('renal carcinoma', 'Phenotype', 'HP:0005584', (145, 160))	('embryonic kidney', 'Disease', (6, 22))	('renal carcinoma', 'Disease', 'MESH:C538614', (145, 160))	('embryonic kidney', 'Disease', 'MESH:D007674', (6, 22))	('A704', 'Var', (82, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('293T', 'CellLine', 'CVCL:0063', (33, 37))	('human', 'Species', '9606', (39, 44))	('murine', 'Species', '10090', (138, 144))	('renal carcinoma', 'Disease', (145, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
161870	33649535	TILs were further enriched using Percoll gradient (17089102, Cytiva, MA, USA) following the manufacturer's instruction, and CD107a (APC labelled, sab4700417, Sigma, MO, USA) and GZMB (FITC-labelled, sab4700295, Sigma, MO, USA) subpopulation was analyzed by flow cytometry as previously described.	('FITC', 'Chemical', 'MESH:D016650', (184, 188))	('17089102', 'Var', (51, 59))	('CD107a', 'Gene', (124, 130))	('APC', 'cellular_component', 'GO:0005680', ('132', '135'))	('GZMB', 'Gene', '3002', (178, 182))	('GZMB', 'Gene', (178, 182))	('APC', 'Gene', (132, 135))	('CD107a', 'Gene', '3916', (124, 130))	('APC', 'Gene', '324', (132, 135))
161882	28710314	Notably, sarcomatoid clear cell RCC (SccRCC) showed significantly fewer deletions at 3p21-25, a lower rate of two-hit loss for VHL and PBRM1, and more mutations in PTEN, TP53, and RELN compared to clear cell RCC (ccRCC).	('3p21-25', 'Gene', (85, 92))	('sarcomatoid clear cell RCC', 'Disease', (9, 35))	('loss', 'NegReg', (118, 122))	('VHL', 'Gene', '7428', (127, 130))	('PTEN', 'Gene', (164, 168))	('PBRM1', 'Gene', '55193', (135, 140))	('sarcomatoid clear cell RCC', 'Disease', 'MESH:C538614', (9, 35))	('RELN', 'Gene', '5649', (180, 184))	('TP53', 'Gene', (170, 174))	('PBRM1', 'Gene', (135, 140))	('two-hit', 'CPA', (110, 117))	('mutations', 'Var', (151, 160))	('PTEN', 'Gene', '5728', (164, 168))	('fewer', 'NegReg', (66, 71))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('RCC', 'Phenotype', 'HP:0005584', (208, 211))	('RCC', 'Disease', (215, 218))	('RCC', 'Disease', (40, 43))	('RCC', 'Disease', (32, 35))	('RCC', 'Disease', (208, 211))	('lower', 'NegReg', (96, 101))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('RCC', 'Phenotype', 'HP:0005584', (215, 218))	('deletions', 'Var', (72, 81))	('RCC', 'Disease', 'MESH:C538614', (215, 218))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('TP53', 'Gene', '7157', (170, 174))	('VHL', 'Gene', (127, 130))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('more', 'PosReg', (146, 150))	('RELN', 'Gene', (180, 184))
161883	28710314	A two-hit loss involving VHL predicted for ccRCC and a better prognosis whereas mutations in PTEN, TP53, or RELN predicted for SccRCC and worse prognosis.	('VHL', 'Gene', '7428', (25, 28))	('TP53', 'Gene', (99, 103))	('PTEN', 'Gene', (93, 97))	('PTEN', 'Gene', '5728', (93, 97))	('mutations', 'Var', (80, 89))	('RELN', 'Gene', '5649', (108, 112))	('RELN', 'Gene', (108, 112))	('predicted', 'Reg', (29, 38))	('VHL', 'Gene', (25, 28))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('TP53', 'Gene', '7157', (99, 103))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('predicted', 'Reg', (113, 122))
161912	28710314	Potentially actionable mutations, involving pan-cancer T200 panel genes, were distributed across all SRCC subtypes (Table S2).	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('mutations', 'Var', (23, 32))	('T200 panel genes', 'Gene', (55, 71))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))
161913	28710314	However, mutations in 3p21-25 genes (VHL, PBRM1, SETD2, and BAP1) were only seen in SccRCC (Figure 2d).	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('VHL', 'Gene', (37, 40))	('mutations', 'Var', (9, 18))	('PBRM1', 'Gene', (42, 47))	('VHL', 'Gene', '7428', (37, 40))	('seen', 'Reg', (76, 80))	('BAP1', 'Gene', '8314', (60, 64))	('BAP1', 'Gene', (60, 64))	('PBRM1', 'Gene', '55193', (42, 47))	('SETD2', 'Gene', '29072', (49, 54))	('SETD2', 'Gene', (49, 54))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
161914	28710314	Despite the large number of non-synonymous mutations that were found in SRCC, relatively few genes were recurrently mutated.	('non-synonymous mutations', 'Var', (28, 52))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
161917	28710314	We next assessed whether mutations in the aforementioned genes were significantly enriched in sarcomatoid tumors compared to non-sarcomatoid tumors within the same parent RCC subtype using institutional and TCGA derived data (Table S3b).	('mutations', 'Var', (25, 34))	('non-sarcomatoid tumors', 'Disease', (125, 147))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('non-sarcomatoid tumors', 'Disease', 'MESH:C538614', (125, 147))	('enriched', 'Reg', (82, 90))	('sarcomatoid tumors', 'Disease', 'MESH:C538614', (129, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('sarcomatoid tumors', 'Phenotype', 'HP:0100242', (129, 147))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('sarcomatoid tumors', 'Disease', 'MESH:C538614', (94, 112))	('RCC', 'Disease', (171, 174))	('sarcomatoid tumors', 'Disease', (94, 112))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('sarcomatoid tumors', 'Phenotype', 'HP:0100242', (94, 112))
161918	28710314	PTEN was more frequently mutated in SccRCC versus ccRCC; TP53 mutations were associated with SccRCC and SPapRCC; and NF2 mutations were associated with SPapRCC only.	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('RCC', 'Disease', (156, 159))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('TP53', 'Gene', '7157', (57, 61))	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('RCC', 'Disease', (52, 55))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('NF2', 'Gene', '4771', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('mutations', 'Var', (62, 71))	('associated', 'Reg', (77, 87))	('RCC', 'Disease', (96, 99))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('NF2', 'Gene', (117, 120))	('PTEN', 'Gene', (0, 4))	('TP53', 'Gene', (57, 61))	('mutated', 'Var', (25, 32))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('RCC', 'Disease', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('PTEN', 'Gene', '5728', (0, 4))
161919	28710314	RELN mutations were significantly higher in SRCC across all subtypes.	('RELN', 'Gene', '5649', (0, 4))	('RELN', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('higher', 'Reg', (34, 40))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
161920	28710314	Biallelic loss of tumor suppressor genes at 3p21-25 is fundamental to the pathogenesis of ccRCC.	('pathogenesis', 'biological_process', 'GO:0009405', ('74', '86'))	('tumor', 'Disease', (18, 23))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('tumor suppressor', 'biological_process', 'GO:0051726', ('18', '34'))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('18', '34'))	('Biallelic', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('loss', 'NegReg', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
161921	28710314	Loss of VHL is thought to be the initiating event, followed by inactivation of other 3p21-25 genes, such as PBRM1 and BAP1.	('PBRM1', 'Gene', '55193', (108, 113))	('VHL', 'Gene', '7428', (8, 11))	('BAP1', 'Gene', '8314', (118, 122))	('PBRM1', 'Gene', (108, 113))	('Loss', 'Var', (0, 4))	('BAP1', 'Gene', (118, 122))	('VHL', 'Gene', (8, 11))
161922	28710314	Numerous additional chromosomal copy number alterations have been proposed as contributing to the progression of ccRCC.	('chromosomal copy number alterations', 'Var', (20, 55))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('contributing', 'Reg', (78, 90))
161923	28710314	In terms of arm-spanning copy number changes, fewer chromosomal losses at 3p were associated with high-grade and SccRCC (Table S4).	('associated', 'Reg', (82, 92))	('high-grade', 'Disease', (98, 108))	('fewer', 'NegReg', (46, 51))	('chromosomal losses', 'Var', (52, 70))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))
161929	28710314	Using FISH as the basis for copy number calls, SccRCC showed fewer VHL deletions compared to ccRCC (P= 0.001) and high grade ccRCC showed fewer VHL deletions compared to lower grade ccRCC tumors (P=0.000049).	('fewer', 'NegReg', (61, 66))	('VHL', 'Gene', '7428', (144, 147))	('VHL', 'Gene', (67, 70))	('RCC tumor', 'Disease', (184, 193))	('fewer', 'NegReg', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('RCC', 'Disease', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumors', 'Disease', (188, 194))	('VHL', 'Gene', '7428', (67, 70))	('RCC', 'Disease', (184, 187))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (95, 98))	('RCC tumor', 'Disease', 'MESH:C538614', (184, 193))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('RCC', 'Disease', (127, 130))	('deletions', 'Var', (71, 80))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('VHL', 'Gene', (144, 147))	('RCC', 'Disease', 'MESH:C538614', (127, 130))
161930	28710314	Our analysis of SNP data from TCGA showed copy neutral LOH to be an exceedingly rare event in ccRCC (~1%) and to involve only 1 case of SccRCC (Supplemental Methods 5 and Figures S3-S7).	('RCC', 'Disease', (96, 99))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('copy neutral', 'Var', (42, 54))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
161931	28710314	We assessed independent ccRCC samples assayed by SNP array (GSE12808, GSE14670, GSE11447 and GSE9469) and also found a low incidence of copy neutral LOH (~2%) that was not correlated to tumor grade.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('copy neutral LOH', 'Var', (136, 152))	('GSE12808', 'Var', (60, 68))	('GSE14670', 'Var', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('tumor', 'Disease', (186, 191))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('GSE11447', 'Var', (80, 88))	('GSE9469', 'Chemical', '-', (93, 100))	('GSE9469', 'Var', (93, 100))
161932	28710314	SccRCC exhibited less concurrent mutation and copy loss (i.e., two-hit loss) of the VHL and PBRM1 genes than did ccRCC across different histological grades (Table 1).	('mutation', 'Var', (33, 41))	('VHL', 'Gene', (84, 87))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('PBRM1', 'Gene', '55193', (92, 97))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('VHL', 'Gene', '7428', (84, 87))	('copy loss', 'Var', (46, 55))	('less', 'NegReg', (17, 21))	('loss', 'NegReg', (71, 75))	('RCC', 'Disease', (3, 6))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('RCC', 'Disease', 'MESH:C538614', (3, 6))	('PBRM1', 'Gene', (92, 97))
161933	28710314	Epigenetic silencing has been reported to be mutually exclusive with mutation for VHL in ccRCC, consistent with our data where VHL mutations and methylation did not overlap (Figure 1d).	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))	('VHL', 'Gene', (82, 85))	('mutation', 'Var', (69, 77))	('VHL', 'Gene', (127, 130))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('Epigenetic silencing', 'Var', (0, 20))	('VHL', 'Gene', '7428', (82, 85))	('VHL', 'Gene', '7428', (127, 130))	('methylation', 'biological_process', 'GO:0032259', ('145', '156'))
161934	28710314	We only found methylation of the VHL gene and not for the PBRM1, SETD2, or BAP1 genes (Figure S8).	('BAP1', 'Gene', (75, 79))	('found', 'Reg', (8, 13))	('VHL', 'Gene', (33, 36))	('SETD2', 'Gene', '29072', (65, 70))	('PBRM1', 'Gene', (58, 63))	('methylation', 'Var', (14, 25))	('PBRM1', 'Gene', '55193', (58, 63))	('SETD2', 'Gene', (65, 70))	('VHL', 'Gene', '7428', (33, 36))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))	('BAP1', 'Gene', '8314', (75, 79))
161935	28710314	Notably, after taking methylation status into account as well as mutation and loss of heterozygosity, SccRCC still showed fewer two-hit losses of VHL compared to ccRCC (P<0.001; OR: 0.22).	('two-hit', 'MPA', (128, 135))	('VHL', 'Gene', (146, 149))	('VHL', 'Gene', '7428', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('methylation', 'biological_process', 'GO:0032259', ('22', '33'))	('mutation', 'Var', (65, 73))	('losses', 'NegReg', (136, 142))	('RCC', 'Disease', (164, 167))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('fewer', 'NegReg', (122, 127))
161936	28710314	With respect to ccRCC, we found that mutations in TP53, PTEN, RELN, BAP1 and SETD2 were individually associated with or anti-correlated (PBRM1) with sarcomatoid change (Table 2).	('SETD2', 'Gene', '29072', (77, 82))	('PTEN', 'Gene', '5728', (56, 60))	('PBRM1', 'Gene', '55193', (137, 142))	('sarcomatoid change', 'Phenotype', 'HP:0100242', (149, 167))	('RELN', 'Gene', '5649', (62, 66))	('PBRM1', 'Gene', (137, 142))	('BAP1', 'Gene', '8314', (68, 72))	('TP53', 'Gene', (50, 54))	('RCC', 'Disease', (18, 21))	('RCC', 'Phenotype', 'HP:0005584', (18, 21))	('mutations', 'Var', (37, 46))	('associated', 'Reg', (101, 111))	('BAP1', 'Gene', (68, 72))	('RCC', 'Disease', 'MESH:C538614', (18, 21))	('sarcomatoid change', 'Disease', 'MESH:C538614', (149, 167))	('sarcomatoid change', 'Disease', (149, 167))	('PTEN', 'Gene', (56, 60))	('SETD2', 'Gene', (77, 82))	('RELN', 'Gene', (62, 66))	('TP53', 'Gene', '7157', (50, 54))	('anti-correlated', 'NegReg', (120, 135))
161937	28710314	A mutation in TP53, PTEN, or RELN was correlated with sarcomatoid change in ccRCC (P=1.64E-06, OR=6.53), including grade 4 (P=4.68E-02, OR=3.2) (Table S6).	('TP53', 'Gene', '7157', (14, 18))	('mutation', 'Var', (2, 10))	('TP53', 'Gene', (14, 18))	('correlated with', 'Reg', (38, 53))	('sarcomatoid change', 'Phenotype', 'HP:0100242', (54, 72))	('sarcomatoid change', 'Disease', 'MESH:C538614', (54, 72))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RELN', 'Gene', '5649', (29, 33))	('sarcomatoid change', 'Disease', (54, 72))	('RELN', 'Gene', (29, 33))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('PTEN', 'Gene', (20, 24))	('PTEN', 'Gene', '5728', (20, 24))
161938	28710314	Further, mutant allelic frequencies in TP53, PTEN, and RELN were lower than in VHL or BAP1 (P=0.035), suggesting they occurred later in the evolution of the tumor.	('tumor', 'Disease', (157, 162))	('VHL', 'Gene', '7428', (79, 82))	('BAP1', 'Gene', '8314', (86, 90))	('RELN', 'Gene', '5649', (55, 59))	('RELN', 'Gene', (55, 59))	('mutant', 'Var', (9, 15))	('lower', 'NegReg', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('PTEN', 'Gene', '5728', (45, 49))	('PTEN', 'Gene', (45, 49))	('BAP1', 'Gene', (86, 90))	('TP53', 'Gene', '7157', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('VHL', 'Gene', (79, 82))	('TP53', 'Gene', (39, 43))
161940	28710314	A survival analysis showed that a mutation in TP53, PTEN, or RELN was associated with reduced overall survival in ccRCC (Figure 3a, P=8.72E-07).	('reduced', 'NegReg', (86, 93))	('PTEN', 'Gene', (52, 56))	('overall survival', 'MPA', (94, 110))	('PTEN', 'Gene', '5728', (52, 56))	('TP53', 'Gene', '7157', (46, 50))	('mutation', 'Var', (34, 42))	('TP53', 'Gene', (46, 50))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))	('RELN', 'Gene', '5649', (61, 65))	('RELN', 'Gene', (61, 65))
161941	28710314	By contrast, deletion of 3p21-25 genes or a two-hit loss of VHL was associated with increased overall survival (Figures 3b and 3c).	('loss', 'NegReg', (52, 56))	('overall survival', 'MPA', (94, 110))	('VHL', 'Gene', (60, 63))	('VHL', 'Gene', '7428', (60, 63))	('deletion', 'Var', (13, 21))	('increased', 'PosReg', (84, 93))	('3p21-25 genes', 'Gene', (25, 38))
161948	28710314	The S- component showed a significantly higher overall mutational load than did the E- component across all RCC subtypes (P=0.0215) and in the ccRCC subtype (P=0.0199) (Figure S10a and S10b).	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (108, 111))	('RCC', 'Disease', (145, 148))	('mutational', 'Var', (55, 65))	('higher', 'PosReg', (40, 46))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))
161950	28710314	Interestingly, mutations in cancer related genes were more commonly shared among the E- and S- components as compared to all gene mutations: eg.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('shared', 'Reg', (68, 74))	('mutations', 'Var', (15, 24))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))
161951	28710314	66% shared cancer related mutations in SRCC vs 19% shared total mutations in RCC, P=1.15 E-09; and 62% shared cancer related mutations in SccRCC vs 19% shared total mutations in ccRCC, P= 3.57 E-05.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('RCC', 'Disease', (180, 183))	('RCC', 'Phenotype', 'HP:0005584', (180, 183))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('mutations', 'Var', (26, 35))	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (110, 116))	('RCC', 'Disease', (40, 43))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
161959	28710314	The signal molecular alteration in ccRCC is loss of VHL on 3p (through deletion, mutation, or methylation), leading to activation of HIF pathway molecules such as VEGF and CAIX.	('methylation', 'biological_process', 'GO:0032259', ('94', '105'))	('HIF pathway molecules', 'Pathway', (133, 154))	('VHL', 'Gene', '7428', (52, 55))	('CAIX', 'Gene', '768', (172, 176))	('VEGF', 'Gene', (163, 167))	('mutation', 'Var', (81, 89))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('deletion', 'Var', (71, 79))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('loss', 'NegReg', (44, 48))	('RCC', 'Disease', (37, 40))	('activation', 'PosReg', (119, 129))	('methylation', 'Var', (94, 105))	('VEGF', 'Gene', '7422', (163, 167))	('CAIX', 'Gene', (172, 176))	('VHL', 'Gene', (52, 55))
161961	28710314	The relationship between VHL's mutational status and tumor progression is controversial and we did not find a mutation in VHL to correlate with sarcomatoid features or with aggressive disease (Table 2).	('aggressive disease', 'Disease', (173, 191))	('sarcomatoid', 'Disease', 'MESH:C538614', (144, 155))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('VHL', 'Gene', (122, 125))	('VHL', 'Gene', (25, 28))	('VHL', 'Gene', '7428', (122, 125))	('mutation', 'Var', (110, 118))	('sarcomatoid', 'Disease', (144, 155))	('tumor', 'Disease', (53, 58))	('VHL', 'Gene', '7428', (25, 28))	('aggressive disease', 'Disease', 'MESH:D001523', (173, 191))
161962	28710314	However, sarcomatoid ccRCC differs from non-sarcomatoid ccRCC molecularly in that there is significantly less 3p21-25 deletion spanning the VHL, PBRM1, BAP1, and SETD2 genes and less two-copy loss of VHL and PBRM1.	('SETD2', 'Gene', (162, 167))	('PBRM1', 'Gene', '55193', (208, 213))	('less', 'NegReg', (105, 109))	('VHL', 'Gene', '7428', (200, 203))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (58, 61))	('BAP1', 'Gene', (152, 156))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('SETD2', 'Gene', '29072', (162, 167))	('PBRM1', 'Gene', (145, 150))	('sarcomatoid', 'Disease', 'MESH:C538614', (9, 20))	('PBRM1', 'Gene', (208, 213))	('non-sarcomatoid', 'Disease', 'MESH:C538614', (40, 55))	('non-sarcomatoid', 'Disease', (40, 55))	('VHL', 'Gene', (140, 143))	('sarcomatoid', 'Disease', (44, 55))	('loss', 'NegReg', (192, 196))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('3p21-25 deletion', 'Var', (110, 126))	('VHL', 'Gene', '7428', (140, 143))	('sarcomatoid', 'Disease', 'MESH:C538614', (44, 55))	('VHL', 'Gene', (200, 203))	('BAP1', 'Gene', '8314', (152, 156))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('RCC', 'Disease', (23, 26))	('sarcomatoid', 'Disease', (9, 20))	('PBRM1', 'Gene', '55193', (145, 150))
161963	28710314	This is consistent with historical cytogenetic studies that have shown the presence of 3p deletions to be associated with lower grade and lower stage disease, absence of sarcomatoid features and with improved survival outcomes in ccRCC.	('lower stage disease', 'CPA', (138, 157))	('absence of sarcomatoid features', 'Disease', 'MESH:D000013', (159, 190))	('RCC', 'Phenotype', 'HP:0005584', (232, 235))	('RCC', 'Disease', 'MESH:C538614', (232, 235))	('RCC', 'Disease', (232, 235))	('improved', 'PosReg', (200, 208))	('absence of sarcomatoid features', 'Disease', (159, 190))	('presence', 'Var', (75, 83))	('lower grade', 'CPA', (122, 133))
161964	28710314	More recent molecular evidence also supports our findings in that loss of heterozygosity at the VHL locus and two-hit loss of the VHL gene in ccRCC were associated with lower stage, lower grade disease and with absence of sarcomatoid features.	('absence of sarcomatoid features', 'Disease', (211, 242))	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('VHL', 'Gene', '7428', (96, 99))	('lower grade disease', 'CPA', (182, 201))	('loss', 'NegReg', (118, 122))	('VHL', 'Gene', (130, 133))	('absence of sarcomatoid features', 'Disease', 'MESH:D000013', (211, 242))	('loss of heterozygosity', 'Var', (66, 88))	('VHL', 'Gene', (96, 99))	('VHL', 'Gene', '7428', (130, 133))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('lower stage', 'CPA', (169, 180))
161965	28710314	Regulation of PBRM1 is postulated to be influenced by tumor differentiation, with fewer mutations in higher grade and more aggressive tumors.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('PBRM1', 'Gene', (14, 19))	('mutations', 'Var', (88, 97))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('aggressive tumors', 'Disease', 'MESH:D001523', (123, 140))	('PBRM1', 'Gene', '55193', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (54, 59))	('aggressive tumors', 'Disease', (123, 140))
161971	28710314	Consequently, diagnostic molecular assays that fail to demonstrate a 3p or VHL deletion in a suspected ccRCC case do not necessarily rule out a clear cell subtype of RCC, particularly when associated with higher grade or sarcomatoid features.	('VHL', 'Gene', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('RCC', 'Disease', (166, 169))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('VHL', 'Gene', '7428', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('sarcomatoid', 'Disease', (221, 232))	('RCC', 'Disease', (105, 108))	('deletion', 'Var', (79, 87))	('sarcomatoid', 'Disease', 'MESH:C538614', (221, 232))
161973	28710314	Although mutations in these genes occurred in all SRCC subtypes, their specific association with sarcomatoid change within a given subtype varied according to the gene.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('sarcomatoid change', 'Phenotype', 'HP:0100242', (97, 115))	('sarcomatoid change', 'Disease', 'MESH:C538614', (97, 115))	('sarcomatoid change', 'Disease', (97, 115))	('mutations', 'Var', (9, 18))	('occurred', 'Reg', (34, 42))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
161974	28710314	Among ccRCC, a mutation in PTEN, TP53, or RELN was predictive of sarcomatoid histological type, whereas a two-hit inactivation of VHL or PBRM1 was predictive of non-sarcomatoid ccRCC histologic type (Figure 5).	('non-sarcomatoid', 'Disease', 'MESH:C538614', (161, 176))	('TP53', 'Gene', '7157', (33, 37))	('PBRM1', 'Gene', '55193', (137, 142))	('sarcomatoid', 'Disease', 'MESH:C538614', (65, 76))	('PTEN', 'Gene', (27, 31))	('RCC', 'Phenotype', 'HP:0005584', (179, 182))	('non-sarcomatoid', 'Disease', (161, 176))	('RCC', 'Disease', (179, 182))	('sarcomatoid', 'Disease', (165, 176))	('sarcomatoid histological type', 'Phenotype', 'HP:0100242', (65, 94))	('RELN', 'Gene', (42, 46))	('PBRM1', 'Gene', (137, 142))	('PTEN', 'Gene', '5728', (27, 31))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('RCC', 'Disease', (8, 11))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('sarcomatoid', 'Disease', 'MESH:C538614', (165, 176))	('VHL', 'Gene', (130, 133))	('TP53', 'Gene', (33, 37))	('mutation', 'Var', (15, 23))	('sarcomatoid', 'Disease', (65, 76))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('RELN', 'Gene', '5649', (42, 46))	('VHL', 'Gene', '7428', (130, 133))	('predictive', 'Reg', (51, 61))
161978	28710314	However, the intratumoral mutational heterogeneity of ccRCC, resulting from a putative pattern of branched evolution, limits the utility of any mutational screen based on single biopsies because the majority of mutations are subclonal and therefore would not be detected by sampling a single region.	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('tumor', 'Disease', (18, 23))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('limits', 'NegReg', (118, 124))	('mutations', 'Var', (211, 220))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
161979	28710314	Nevertheless, VHL is considered as a clonal mutation, and PBRM1 is sometimes clonal and often shared among different regions; thus, assays for these mutations or deletions are less likely to be impacted by intratumoral heterogeneity than are assays for the other genes that we have proposed.	('mutations', 'Var', (149, 158))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('PBRM1', 'Gene', (58, 63))	('deletions', 'Var', (162, 171))	('PBRM1', 'Gene', '55193', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('VHL', 'Gene', (14, 17))	('VHL', 'Gene', '7428', (14, 17))
161982	28710314	TP53 mutations have been associated with decreased therapeutic response to antiangiogenic therapies and to PI3K pathway targeting agents.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('PI3K pathway', 'Pathway', (107, 119))	('therapeutic response', 'CPA', (51, 71))	('decreased', 'NegReg', (41, 50))	('decreased therapeutic response', 'Phenotype', 'HP:0020173', (41, 71))	('PI3K', 'molecular_function', 'GO:0016303', ('107', '111'))	('mutations', 'Var', (5, 14))
161983	28710314	Our recent publication testing the efficacy of PI3K pathway targeted agents, including MK-2206 and everolimus, demonstrated that mutations in TP53 were associated with reduced response to either agent.	('response', 'MPA', (176, 184))	('TP53', 'Gene', '7157', (142, 146))	('mutations', 'Var', (129, 138))	('TP53', 'Gene', (142, 146))	('MK-2206', 'Chemical', 'MESH:C548887', (87, 94))	('everolimus', 'Chemical', 'MESH:D000068338', (99, 109))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))	('reduced', 'NegReg', (168, 175))
161989	28710314	detected a high rate of TP53 mutations (64%) in the circulating tumor DNA of patients with clear-cell RCC treated with later lines of vascular endothelial growth factor inhibitors versus first-line treatment (31%).	('vascular endothelial growth factor', 'Gene', (134, 168))	('tumor', 'Disease', (64, 69))	('TP53', 'Gene', (24, 28))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('mutations', 'Var', (29, 38))	('vascular endothelial growth factor', 'Gene', '7422', (134, 168))	('patients', 'Species', '9606', (77, 85))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('134', '168'))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('TP53', 'Gene', '7157', (24, 28))
162026	31411994	This includes more frequent genetic mutations in MET and FH, rather than the VHL alterations seen in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('MET', 'Gene', '79811', (49, 52))	('VHL', 'Gene', (77, 80))	('MET', 'Gene', (49, 52))	('VHL', 'Gene', '7428', (77, 80))	('genetic mutations', 'Var', (28, 45))	('FH', 'Disease', 'MESH:D006938', (57, 59))
162216	32350988	For the ccRCC group, we tested for correlation between the 33 metabolites for early diagnosis (control vs cT1a) and clinicopathological factors by analyzing the following parameters: clinical T stage (cT1 vs cT2-4), pathological T stage (pT1 vs pT3), clinical M stage (cM0 vs cM1), Fuhrman grade (low vs high), and coagulation necrosis (absence vs presence).	('cT1', 'Gene', (201, 204))	('coagulation necrosis', 'Disease', (315, 335))	('cT1', 'Gene', '1489', (106, 109))	('necrosis', 'biological_process', 'GO:0070265', ('327', '335'))	('necrosis', 'biological_process', 'GO:0019835', ('327', '335'))	('pT3', 'Gene', '7694', (245, 248))	('necrosis', 'biological_process', 'GO:0001906', ('327', '335'))	('cT1', 'Gene', (106, 109))	('cM0', 'Var', (269, 272))	('cT2-4', 'Gene', '85317', (208, 213))	('RCC', 'Disease', (10, 13))	('RCC', 'Phenotype', 'HP:0005584', (10, 13))	('pT1', 'Gene', '58492', (238, 241))	('ccRCC', 'Phenotype', 'HP:0006770', (8, 13))	('pT1', 'Gene', (238, 241))	('necrosis', 'biological_process', 'GO:0008219', ('327', '335'))	('coagulation necrosis', 'Disease', 'MESH:D001778', (315, 335))	('cT2-4', 'Gene', (208, 213))	('pT3', 'Gene', (245, 248))	('RCC', 'Disease', 'MESH:C538614', (10, 13))	('coagulation', 'biological_process', 'GO:0050817', ('315', '326'))	('coagulation necrosis', 'Phenotype', 'HP:0010885', (315, 335))	('tested', 'Reg', (24, 30))	('Fuhrman grade', 'CPA', (282, 295))	('necrosis', 'biological_process', 'GO:0008220', ('327', '335'))	('cT1', 'Gene', '1489', (201, 204))
162220	32350988	l-Kynurenine levels were higher in cM1 than in cM0 (P = .009).	('cM1', 'Var', (35, 38))	('l-Kynurenine', 'Chemical', 'MESH:D007737', (0, 12))	('l-Kynurenine levels', 'MPA', (0, 19))	('higher', 'PosReg', (25, 31))
162244	32350988	The expression of kynurenine in RCC tissue previously has been shown to indicate poor prognostic outcome.	('kynurenine', 'Var', (18, 28))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('kynurenine', 'Chemical', 'MESH:D007737', (18, 28))
162272	32039517	We stratified SCNAs in the ccRCCs using a hierarchical cluster analysis based on SCNA types, including gain, loss of heterozygosity (LOH), copy neutral LOH, mosaic, and mixed types.	('mosaic', 'Disease', (157, 163))	('gain', 'PosReg', (103, 107))	('loss', 'NegReg', (109, 113))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('ccRCC', 'Disease', (27, 32))	('copy neutral LOH', 'Var', (139, 155))	('ccRCC', 'Disease', 'MESH:C538614', (27, 32))
162273	32039517	Among the 3p mixed type, we found that 3p24.3 mixed type was inversely correlated with the presence of metachronous metastasis in ccRCC.	('3p24.3', 'Var', (39, 45))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('inversely', 'NegReg', (61, 70))	('ccRCC', 'Disease', (130, 135))	('ccRCC', 'Disease', 'MESH:C538614', (130, 135))	('metachronous metastasis', 'CPA', (103, 126))
162274	32039517	We suggest that the 3p24.3 mixed type may be a novel marker to predict a favorable prognosis in ccRCC.	('ccRCC', 'Disease', 'MESH:C538614', (96, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('3p24.3', 'Var', (20, 26))	('ccRCC', 'Disease', (96, 101))
162282	32039517	9 ,  10  Several studies have demonstrated that the presence of multiple SCNAs is associated with overall patient survival, tumor stage, and development of metastasis.	('patient survival', 'CPA', (106, 122))	('associated', 'Reg', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('presence', 'Var', (52, 60))	('patient', 'Species', '9606', (106, 113))	('tumor', 'Disease', (124, 129))	('development of metastasis', 'CPA', (141, 166))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
162311	32039517	The median total number of chromosomal aberrations per patient was 113.5, with an average of 12.5 gains (range, 1-198), 21 LOHs (range, 6-64), and 18 copy-neutral LOHs (range, 5-98), 3 mosaic (0-279), and 31 mixed (0-162) types.	('LOHs', 'Var', (123, 127))	('copy-neutral LOHs', 'Var', (150, 167))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (27, 50))	('gains', 'PosReg', (98, 103))	('patient', 'Species', '9606', (55, 62))
162314	32039517	We identified two distinct subgroups (subgroup 1, 13 cases; subgroup 2, 17 cases) as shown in Figure 1A, in which the copy number alteration (CNA) marker in tumor tissue is indicated by the vertical line, and the horizontal lines denote "relatedness" between samples.	('tumor', 'Disease', (157, 162))	('copy number', 'Var', (118, 129))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
162321	32039517	We found that 3p24.3 mixed type was an independent factor for predicting good prognosis of ccRCC.	('3p24.3', 'Var', (14, 20))	('ccRCC', 'Disease', (91, 96))	('ccRCC', 'Disease', 'MESH:C538614', (91, 96))	('RCC', 'Phenotype', 'HP:0005584', (93, 96))
162322	32039517	In univariate analysis, two factors, including tumor size and 3p24.3 mixed type, were correlated with metachronous metastasis (Table 6a).	('correlated', 'Reg', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('metachronous metastasis', 'CPA', (102, 125))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('3p24.3', 'Var', (62, 68))	('tumor', 'Disease', (47, 52))
162323	32039517	The median total number of chromosomal aberrations per patient was 138, with averages of 23 gains (range, 23-187), 15 LOHs (range, 2-67), and 7 copy-neutral LOHs (range, 2-76), 3 mosaics (0-541), and 20 mixed (0-59) types.	('copy-neutral LOHs', 'Var', (144, 161))	('gains', 'PosReg', (92, 97))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (27, 50))	('patient', 'Species', '9606', (55, 62))	('LOHs', 'Var', (118, 122))
162325	32039517	Additionally, regions of LOH (more than 50% of ccRCC cases) and that of mosaic type were at 14q24.3, 6q23.31, 19q13.42 and 3p12.3, 3p13, 3p14.1, respectively.	('ccRCC', 'Disease', (47, 52))	('3p12.3', 'Var', (123, 129))	('6q23.31', 'Var', (101, 108))	('ccRCC', 'Disease', 'MESH:C538614', (47, 52))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))
162332	32039517	As a result, we found that although the 3p24.3 SCNA mixed type was not associated with overall survival, it was an independent factor to predict favorable prognosis of ccRCC.	('ccRCC', 'Disease', (168, 173))	('ccRCC', 'Disease', 'MESH:C538614', (168, 173))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('3p24.3', 'Var', (40, 46))
162346	32039517	Interestingly, we showed that 3p24.3 mixed type was an independent factor that predicted an excellent disease-free prognosis in ccRCC.	('ccRCC', 'Disease', (128, 133))	('3p24.3', 'Var', (30, 36))	('ccRCC', 'Disease', 'MESH:C538614', (128, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))
162348	32039517	Although we do not know why 3p24.3 mixed type (LOH + LOH mosaic) contributes to an excellent outcome in ccRCC, it is possible that the loss of oncogenic action located at 3p24.3 may be associated with a good prognosis for ccRCC (LOH and LOH mosaic pattern may cause loss of function).	('RCC', 'Phenotype', 'HP:0005584', (224, 227))	('ccRCC', 'Disease', (222, 227))	('ccRCC', 'Disease', 'MESH:C538614', (222, 227))	('LOH mosaic', 'Var', (237, 247))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('LOH', 'Var', (229, 232))	('ccRCC', 'Disease', (104, 109))	('ccRCC', 'Disease', 'MESH:C538614', (104, 109))
162351	32039517	We examined candidate oncogenes located at 3p24.3, given that loss of oncogenic function due to LOH and LOH mosaic pattern may contributes to a good prognosis of ccRCC.	('loss', 'NegReg', (62, 66))	('LOH', 'Var', (96, 99))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))	('LOH mosaic pattern', 'Var', (104, 122))	('oncogenic function', 'CPA', (70, 88))	('ccRCC', 'Disease', (162, 167))	('ccRCC', 'Disease', 'MESH:C538614', (162, 167))
162356	32039517	One report showed that high expression of RFTN1 was closely associated with poor prognosis of ccRCC, compared with low expression (The Human Genome Atlas).	('ccRCC', 'Disease', (94, 99))	('ccRCC', 'Disease', 'MESH:C538614', (94, 99))	('high expression', 'Var', (23, 38))	('RFTN1', 'Gene', (42, 47))	('Human', 'Species', '9606', (135, 140))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RFTN1', 'Gene', '23180', (42, 47))	('associated', 'Reg', (60, 70))
162362	32039517	Third, a previous study provided new evidence that RPL24 expression is common in human breast tumors, but that depletion or structural alteration of RPL24 can significantly impair human breast cancer cell viability.	('breast tumors', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('RPL24', 'Gene', '6152', (51, 56))	('RPL24', 'Gene', '6152', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('breast tumors', 'Disease', 'MESH:D001943', (87, 100))	('human', 'Species', '9606', (180, 185))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('breast tumors', 'Phenotype', 'HP:0100013', (87, 100))	('structural alteration', 'Var', (124, 145))	('human', 'Species', '9606', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (186, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('impair', 'NegReg', (173, 179))	('RPL24', 'Gene', (51, 56))	('RPL24', 'Gene', (149, 154))	('depletion', 'MPA', (111, 120))
162365	32039517	RPL31 knockdown could mediate extraribosomal functions and regulate the function of tumor suppressor p53.	('RPL31', 'Gene', '6160', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor suppressor', 'biological_process', 'GO:0051726', ('84', '100'))	('RPL31', 'Gene', (0, 5))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('regulate', 'Reg', (59, 67))	('tumor', 'Disease', (84, 89))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('84', '100'))	('knockdown', 'Var', (6, 15))	('function', 'MPA', (72, 80))	('extraribosomal', 'MPA', (30, 44))	('mediate', 'Reg', (22, 29))
162380	30962421	CCCs are distinguished by aberrant lipid and glycogen accumulation and are refractory to a broad range of anti-cancer therapies.	('aberrant', 'Var', (26, 34))	('glycogen', 'Chemical', 'MESH:D006003', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('CCCs', 'Disease', (0, 4))	('lipid', 'Chemical', 'MESH:D008055', (35, 40))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('glycogen accumulation', 'MPA', (45, 66))
162389	30962421	While these metabolic alterations support cancer progression and promote resistance to immune surveillance and therapies, directly targeting the primary metabolic liabilities remains challenging due to complications from metabolic plasticity and systemic toxicity of currently available compounds.	('toxicity', 'Disease', 'MESH:D064420', (255, 263))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('toxicity', 'Disease', (255, 263))	('alterations', 'Var', (22, 33))	('promote', 'PosReg', (65, 72))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('support', 'PosReg', (34, 41))
162394	30962421	Though the developmental role of ferroptosis has not yet been identified, ferroptotic death is associated with various pathological conditions, including acute kidney injury, hepatocellular degeneration and hemochromatosis, traumatic brain injury, and neurodegeneration.	('ferroptotic', 'Var', (74, 85))	('hemochromatosis', 'Disease', 'MESH:D006432', (207, 222))	('neurodegeneration', 'Phenotype', 'HP:0002180', (252, 269))	('traumatic brain injury', 'Disease', (224, 246))	('associated', 'Reg', (95, 105))	('ferroptosis', 'biological_process', 'GO:0097707', ('33', '44'))	('hepatocellular degeneration', 'Disease', 'MESH:D006528', (175, 202))	('hepatocellular degeneration', 'Phenotype', 'HP:0001404', (175, 202))	('traumatic brain injury', 'Disease', 'MESH:D000070642', (224, 246))	('neurodegeneration', 'Disease', (252, 269))	('acute kidney', 'Phenotype', 'HP:0001919', (154, 166))	('neurodegeneration', 'Disease', 'MESH:D019636', (252, 269))	('kidney injury', 'Disease', 'MESH:D058186', (160, 173))	('kidney injury', 'Disease', (160, 173))	('hemochromatosis', 'Disease', (207, 222))	('hepatocellular degeneration', 'Disease', (175, 202))
162402	30962421	In contrast to the low efficacy of conventional chemotherapies such as paclitaxel, three GPX4 inhibitors emerged as the most potent and selective compounds for killing CCC cells: (1S, 3R)-RSL3 (RSL3), ML210 and, ML162 (Fig.	('ML210', 'Var', (201, 206))	('RSL3', 'Chemical', '-', (188, 192))	('pac', 'Phenotype', 'HP:0006699', (71, 74))	('RSL3', 'Chemical', '-', (194, 198))	('paclitaxel', 'Chemical', 'MESH:D017239', (71, 81))	('ML162', 'Var', (212, 217))	('CCC', 'cellular_component', 'GO:0030896', ('168', '171'))	('1S', 'Var', (180, 182))	('CCC', 'Disease', (168, 171))
162408	30962421	Moreover, ML210-treatment induced rapid accumulation of lipid radicals in ccRCC but not BFTC909 cells, as reported by BODIPY-C11, confirming the involvement of ferroptotic cell death (Fig.	('C11', 'Gene', '1109', (125, 128))	('lipid radicals', 'Chemical', '-', (56, 70))	('cell death', 'biological_process', 'GO:0008219', ('172', '182'))	('BFTC909', 'CellLine', 'CVCL:1084', (88, 95))	('C11', 'Gene', (125, 128))	('ML210-treatment', 'Var', (10, 25))	('lipid radicals', 'MPA', (56, 70))	('accumulation', 'PosReg', (40, 52))
162412	30962421	Lip-1 treatment rescued OCCC cells from ML210 or RSL3-induced cell death (Supplementary Fig.	('ML210', 'Var', (40, 45))	('Lip-1', 'Disease', 'MESH:D002971', (0, 5))	('Lip-1', 'Disease', (0, 5))	('cell death', 'biological_process', 'GO:0008219', ('62', '72'))	('RSL3', 'Chemical', '-', (49, 53))
162421	30962421	4g), HIF-2alpha ablation significantly reduced lipid peroxidation levels (Supplementary Fig.	('lipid', 'Chemical', 'MESH:D008055', (47, 52))	('ablation', 'Var', (16, 24))	('lipid peroxidation levels', 'MPA', (47, 72))	('reduced', 'NegReg', (39, 46))	('HIF-2alpha', 'Gene', (5, 15))	('HIF-2alpha', 'Gene', '2034', (5, 15))
162423	30962421	Notably, cancer cells with VHL mutations exhibited greater dependence on GPX4 than VHL wildtype cells in a pan-cancer DepMap analysis (Supplementary Fig.	('dependence', 'MPA', (59, 69))	('cancer', 'Disease', (9, 15))	('mutations', 'Var', (31, 40))	('VHL', 'Gene', '7428', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('VHL', 'Gene', (27, 30))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('VHL', 'Gene', '7428', (27, 30))	('VHL', 'Gene', (83, 86))
162427	30962421	Ferroptosis is executed by peroxidized membrane phospholipids, particularly phosphatidylethanolamines (PEs) that contain polyunsaturated fatty acyl (PUFA) chains including arachidonic acid (C20:4) and docosahexaenoic acid (C22:6).	('phospholipids', 'Chemical', 'MESH:D010743', (48, 61))	('arachidonic acid', 'Chemical', 'MESH:D016718', (172, 188))	('C20:4', 'Var', (190, 195))	('membrane', 'cellular_component', 'GO:0016020', ('39', '47'))	('polyunsaturated fatty acyl', 'Chemical', '-', (121, 147))	('PUFA', 'Chemical', '-', (149, 153))	('PEs', 'Chemical', 'MESH:D010714', (103, 106))	('Ferroptosis', 'Disease', (0, 11))	('docosahexaenoic acid', 'Chemical', 'MESH:D004281', (201, 221))	('phosphatidylethanolamines', 'Chemical', 'MESH:D010714', (76, 101))	('Ferroptosis', 'biological_process', 'GO:0097707', ('0', '11'))
162433	30962421	Moreover, most PEs and PE-plasmalogens (ePEs), including the ferroptosis-relevant C36:4, C38:4/5/6 and C40:6 PEs and C36:5, C38:5 and C40:7 ePEs, were significantly reduced in EPAS1-/- cells (Fig.	('C38:4/5/6', 'Var', (89, 98))	('C40:6', 'Var', (103, 108))	('PEs', 'Chemical', 'MESH:D010714', (109, 112))	('C36:4', 'Var', (82, 87))	('C36:5', 'Var', (117, 122))	('PEs', 'Chemical', 'MESH:D010714', (41, 44))	('EPAS1', 'Gene', '2034', (176, 181))	('PEs', 'CPA', (15, 18))	('PEs', 'Chemical', 'MESH:D010714', (141, 144))	('C40:7', 'Var', (134, 139))	('C38:5', 'Var', (124, 129))	('ferroptosis', 'biological_process', 'GO:0097707', ('61', '72'))	('EPAS1', 'Gene', (176, 181))	('PEs', 'Chemical', 'MESH:D010714', (15, 18))	('reduced', 'NegReg', (165, 172))
162460	30962421	Remarkably, HILPDA expression in EPAS1-/- cells selectively restored the levels of most PUFA-PE/ePEs and PUFA-TAGs, but barely impacted SFA/MUFA-lipids (Fig.	('impacted', 'Reg', (127, 135))	('EPAS1', 'Gene', (33, 38))	('SFA/MUFA-lipids', 'MPA', (136, 151))	('levels', 'MPA', (73, 79))	('PUFA-PE/ePEs', 'MPA', (88, 100))	('expression', 'Var', (19, 29))	('PUFA', 'Chemical', '-', (105, 109))	('HILPDA', 'Gene', (12, 18))	('lipids', 'Chemical', 'MESH:D008055', (145, 151))	('PEs', 'Chemical', 'MESH:D010714', (97, 100))	('PUFA', 'Chemical', '-', (88, 92))	('pac', 'Phenotype', 'HP:0006699', (129, 132))	('PUFA-TAGs', 'MPA', (105, 114))	('restored', 'PosReg', (60, 68))	('EPAS1', 'Gene', '2034', (33, 38))	('expression', 'Species', '29278', (19, 29))
162471	30962421	PCPGs are two rare, hard-to-treat neuroendocrine malignancies that display frequent mutations in the VHL/HIF pathway.	('VHL', 'Gene', (101, 104))	('neuroendocrine malignancies', 'Phenotype', 'HP:0100634', (34, 61))	('VHL', 'Gene', '7428', (101, 104))	('mutations', 'Var', (84, 93))	('neuroendocrine malignancies', 'Disease', (34, 61))	('PCPGs', 'Disease', (0, 5))	('neuroendocrine malignancies', 'Disease', 'MESH:D018358', (34, 61))
162474	30962421	First, while lipid droplets (LDs) in CCCs have been considered labile organelles that protect cells from lipotoxicity, our data imply that PUFA-TAGs in LDs of CCCs contribute to ferroptosis susceptibility.	('lipid', 'Chemical', 'MESH:D008055', (13, 18))	('PUFA-TAGs', 'Var', (139, 148))	('ferroptosis', 'biological_process', 'GO:0097707', ('178', '189'))	('ferroptosis', 'Disease', (178, 189))	('PUFA', 'Chemical', '-', (139, 143))	('contribute', 'Reg', (164, 174))	('toxicity', 'Disease', 'MESH:D064420', (109, 117))	('toxicity', 'Disease', (109, 117))
162475	30962421	Of note, our PLIN2-overexpressing EPAS1-/- 786-O cells demonstrated that aberrant LD accumulation is not sufficient to drive ferroptosis susceptibility (Fig.	('PLIN2', 'Gene', '123', (13, 18))	('EPAS1', 'Gene', '2034', (34, 39))	('PLIN2', 'Gene', (13, 18))	('ferroptosis', 'biological_process', 'GO:0097707', ('125', '136'))	('aberrant', 'Var', (73, 81))	('EPAS1', 'Gene', (34, 39))	('ferroptosis susceptibility', 'Disease', (125, 151))
162483	30962421	Recently, a mutant allele of PNPLA3, the closest homolog of ATGL (PNPLA2), was reported to convert selectively PUFA-TAGs to PUFA-phospholipids in non-alcoholic fatty liver disease.	('non-alcoholic fatty liver disease', 'Disease', 'MESH:D065626', (146, 179))	('liver disease', 'Phenotype', 'HP:0001392', (166, 179))	('PUFA', 'Chemical', '-', (124, 128))	('convert', 'Reg', (91, 98))	('PUFA', 'Chemical', '-', (111, 115))	('PNPLA2', 'Gene', '57104', (66, 72))	('non-alcoholic fatty liver disease', 'Disease', (146, 179))	('fatty liver', 'Phenotype', 'HP:0001397', (160, 171))	('ATGL', 'Gene', (60, 64))	('ATGL', 'Gene', '57104', (60, 64))	('mutant', 'Var', (12, 18))	('PUFA-phospholipids', 'MPA', (124, 142))	('phospholipids', 'Chemical', 'MESH:D010743', (129, 142))	('PNPLA2', 'Gene', (66, 72))	('PUFA-TAGs', 'Protein', (111, 120))	('alcoholic fatty liver', 'Phenotype', 'HP:0006573', (150, 171))	('PUFA-phospholipid', 'Chemical', '-', (124, 141))
162498	30962421	The concentration range for ML210 was 0.01953-20 muM in 11-concentration experiments and 0.07813-5 muM in 7-concentration experiments unless otherwise indicated.	('0.07813-5', 'Var', (89, 98))	('muM', 'Gene', (99, 102))	('muM', 'Gene', '56925', (49, 52))	('muM', 'Gene', (49, 52))	('0.01953-20', 'Var', (38, 48))	('muM', 'Gene', '56925', (99, 102))
162499	30962421	The concentration range for RSL3 is 0.001953-2 muM in 11-concentration experiments and 0.01563-1 muM in 7-concentration experiments unless otherwise indicated.	('0.001953-2', 'Var', (36, 46))	('RSL3', 'Chemical', '-', (28, 32))	('muM', 'Gene', (47, 50))	('muM', 'Gene', '56925', (97, 100))	('0.01563-1', 'Var', (87, 96))	('muM', 'Gene', (97, 100))	('muM', 'Gene', '56925', (47, 50))
162506	30962421	Membranes were blocked with 50% Odyssey blocking buffer (LiCor) diluted with 0.1% Tween-20-containing TBS and immunoblotted with antibodies from Abcam, including GPX4 (Ab41787), HIF-1alpha (Ab51608), HILPDA (Ab78349), ACSL4 (Ab155282), and from Cell Signaling Technologies, including V5-tag (D3H8Q, #13202), HIF-1beta/ARNT (D28F3, #5537), HIF-2alpha (D9E3, #7096), KEAP1 (D6B12, #8047), NRF2 (D1Z9C, #12721), beta-Actin (8H10D10, #3700 and 13E5, #4970).	('HIF-1alpha', 'Gene', '3091', (178, 188))	('HIF-2alpha', 'Gene', (339, 349))	('D1Z9C', 'Var', (393, 398))	('D9E3', 'Var', (351, 355))	('ACSL4', 'Gene', '2182', (218, 223))	('KEAP1', 'Gene', '9817', (365, 370))	('KEAP1', 'Gene', (365, 370))	('HIF-1alpha', 'Gene', (178, 188))	('D6B12', 'Var', (372, 377))	('Signaling', 'biological_process', 'GO:0023052', ('250', '259'))	('NRF2', 'Gene', '4780', (387, 391))	('HIF-2alpha', 'Gene', '2034', (339, 349))	('ARNT', 'Gene', '405', (318, 322))	('D28F3', 'Var', (324, 329))	('ACSL4', 'Gene', (218, 223))	('8H10D10', 'Var', (421, 428))	('beta-Actin', 'Gene', (409, 419))	('beta-Actin', 'Gene', '728378', (409, 419))	('NRF2', 'Gene', (387, 391))	('ARNT', 'Gene', (318, 322))
162640	30272265	In addition, multilevel whole-genome analysis has revealed that STC2 is one of the genes hypomethylated in copy number gains in ccRCC.	('copy number gains', 'Var', (107, 124))	('STC2', 'Gene', '8614', (64, 68))	('RCC', 'Disease', (130, 133))	('STC2', 'Gene', (64, 68))	('RCC', 'Disease', 'MESH:C538614', (130, 133))
162670	33461589	Differentially methylated CpGs (DMCpGs) were enriched in regulatory regions and genes modulating cell growth and invasion.	('cell growth', 'biological_process', 'GO:0016049', ('97', '108'))	('Differentially methylated', 'Var', (0, 25))	('DMCpGs', 'Chemical', '-', (32, 38))	('cell growth', 'CPA', (97, 108))
162671	33461589	A subset of DMCpGs stratified low SSIGN groups into high and low risk of recurrence in independent data sets, indicating that DNA methylation enhances the prognostic power of the SSIGN score.	('DNA methylation', 'biological_process', 'GO:0006306', ('126', '141'))	('prognostic power', 'MPA', (155, 171))	('DMCpGs', 'Chemical', '-', (12, 18))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('DNA methylation', 'Var', (126, 141))	('enhances', 'PosReg', (142, 150))
162679	33461589	Dysregulation of the von Hippel-Lindau tumor suppressor (VHL) gene is nearly universal in ccRCC and typically the initiating event.	('von Hippel-Lindau tumor suppressor', 'Gene', (21, 55))	('Dysregulation', 'Var', (0, 13))	('VHL', 'Gene', (57, 60))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor suppressor', 'biological_process', 'GO:0051726', ('39', '55'))	('VHL', 'Gene', '7428', (57, 60))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('39', '55'))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('von Hippel-Lindau tumor suppressor', 'Gene', '7428', (21, 55))
162681	33461589	CcRCCs manifest among the lowest frequency of structural and copy number variants.	('copy number variants', 'Var', (61, 81))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('RCC', 'Disease', (2, 5))	('RCC', 'Disease', 'MESH:C538614', (2, 5))
162682	33461589	Additionally, they are on the low end of the frequency spectrum for all types of genetic variation, including many of the classical cancer-associated driver pathways (e.g.	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('genetic variation', 'Var', (81, 98))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
162685	33461589	This is especially true when coupled with the loss of the VHL gene, and our previous study showing that SETD2 mutations drive a DNA hypermethylator phenotype linked to more aggressive clinical features.	('SETD2', 'Gene', (104, 109))	('mutations', 'Var', (110, 119))	('hyper', 'Disease', 'MESH:D053306', (132, 137))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('VHL', 'Gene', (58, 61))	('hyper', 'Disease', (132, 137))	('VHL', 'Gene', '7428', (58, 61))	('SETD2', 'Gene', '29072', (104, 109))
162686	33461589	In addition to the importance of elucidating roles for epigenetic deregulation in understanding the molecular underpinnings of ccRCC, other studies highlight the significant potential of epigenetic modifications as ccRCC prognostic and diagnostic signatures.	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('ccRCC', 'Phenotype', 'HP:0006770', (215, 220))	('RCC', 'Disease', (217, 220))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('RCC', 'Disease', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('epigenetic modifications', 'Var', (187, 211))	('RCC', 'Phenotype', 'HP:0005584', (217, 220))
162689	33461589	Alterations in 5mC and 5hmC are common events across all cancers, and typically manifest as genome-wide reduction and regional increases in 5mC and 5hmC levels.	('5hmC', 'Chemical', 'MESH:C011865', (148, 152))	('increases', 'PosReg', (127, 136))	('reduction', 'NegReg', (104, 113))	('Alterations', 'Var', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('5mC', 'Chemical', 'MESH:D044503', (15, 18))	('5hmC', 'Chemical', 'MESH:C011865', (23, 27))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('5mC', 'Chemical', 'MESH:D044503', (140, 143))
162694	33461589	Collectively, these findings emphasize the importance of epigenetic deregulation in the development of ccRCC.	('epigenetic deregulation', 'Var', (57, 80))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))
162717	33461589	The latter emphasizes the robust hypermethylation that typifies the STS group of low SSIGN score ccRCC patients (Fig.	('low SSIGN score', 'Var', (81, 96))	('hyper', 'Disease', 'MESH:D053306', (33, 38))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('hyper', 'Disease', (33, 38))	('patients', 'Species', '9606', (103, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))
162718	33461589	Closer examination of genomic features associated with the 5929 DMCpGs revealed they were significantly over-represented in gene bodies, normal kidney enhancers, and intergenic regions, and under-represented in promoters (Fig.	('over-represented', 'PosReg', (104, 120))	('under-represented', 'NegReg', (190, 207))	('DMCpGs', 'Chemical', '-', (64, 70))	('DMCpGs', 'Var', (64, 70))	('5929 DMCpGs', 'Var', (59, 70))
162719	33461589	Furthermore, the majority (n = 5231) of DMCpGs overlap with one or more of three histone marks characteristic of gene regulatory regions based on ENCODE data from normal adult kidney, including H3K4me3 +- H3K27ac (active promoter), H3K4me1 only (poised enhancer), and H3K4me1 + H3K27ac (no H3K4me3, active enhancers, Fig.	('H3K4me3 +- H3K27ac', 'Var', (194, 212))	('DMCpGs', 'Chemical', '-', (40, 46))	('DMCpGs', 'Gene', (40, 46))	('H3K4me1 only', 'Var', (232, 244))	('H3K4me1 + H3K27ac', 'Var', (268, 285))
162729	33461589	Applying the same criteria to cohort 2 ( Deltabeta(STS-LTS) >= 0.1, p value < 0.01), yielded 2888 DMCpGs between STS and LTS patients (hypermethylated in STS, n = 2186; hypomethylated in STS, n = 702).	('hypomethylated', 'Var', (169, 183))	('hyper', 'Disease', 'MESH:D053306', (135, 140))	('hyper', 'Disease', (135, 140))	('DMCpGs', 'Chemical', '-', (98, 104))	('patients', 'Species', '9606', (125, 133))
162738	33461589	The analyses reported above were focused on identifying epigenetic differences that further stratify STS and LTS amongst patients predicted to be low risk from the Mayo SSIGN score.	('Mayo', 'Species', '162683', (164, 168))	('patients', 'Species', '9606', (121, 129))	('epigenetic differences', 'Var', (56, 78))	('STS', 'Disease', (101, 104))
162749	33461589	In a parallel approach, we hypothesized that methylation changes at the extremes of the range, that is hypermethylation at CpGs in STS tumors that have no/low methylation in the LTS group (termed LTS fully unmethylated sites) and hypomethylation of CpGs in STS tumors that are highly methylated in LTS ccRCCs (termed LTS fully methylated sites, Fig.	('hyper', 'Disease', 'MESH:D053306', (103, 108))	('methylation', 'MPA', (45, 56))	('STS tumors', 'Disease', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('hypomethylation', 'Var', (230, 245))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('hyper', 'Disease', (103, 108))	('STS tumors', 'Disease', 'MESH:D016114', (257, 267))	('RCC', 'Phenotype', 'HP:0005584', (304, 307))	('methylation', 'biological_process', 'GO:0032259', ('159', '170'))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('RCC', 'Disease', 'MESH:C538614', (304, 307))	('RCC', 'Disease', (304, 307))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('STS tumors', 'Disease', 'MESH:D016114', (131, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (302, 307))	('STS tumors', 'Disease', (257, 267))
162754	33461589	On the other hand, the LTS hypomethylated CpGs (red dots/circles) are more highly methylated in normal kidney, and hypomethylated in both LTS and STS ccRCC, however this hypomethylation was more extensive in STS patients.	('hypomethylated', 'Var', (115, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (150, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('highly', 'PosReg', (75, 81))	('methylated', 'MPA', (82, 92))	('patients', 'Species', '9606', (212, 220))	('STS ccRCC', 'Gene', (146, 155))	('STS ccRCC', 'Gene', '412', (146, 155))
162760	33461589	CpGs with HR > 1 are associated with worse survival when hypermethylated.	('hyper', 'Disease', (57, 62))	('hyper', 'Disease', 'MESH:D053306', (57, 62))	('HR > 1', 'Var', (10, 16))
162764	33461589	Using this independent cohort, we conducted stepwise recursive partitioning and found that as few as 5/43 CpGs in common between TCGA-KIRC and cohort 1 RRBS (cg24304972, cg16108059, cg14010015, cg02966332, and cg02139853) segregated LTS from STS with an AUC = 1.000 (Fig.	('cg14010015', 'Var', (182, 192))	('LTS', 'Disease', (233, 236))	('cg24304972', 'Var', (158, 168))	('segregated', 'Reg', (222, 232))	('cg02966332', 'Var', (194, 204))	('RRBS', 'Chemical', '-', (152, 156))	('cg16108059', 'Var', (170, 180))	('cg02139853', 'Var', (210, 220))
162765	33461589	When the 43 CpGs were examined in all tumors in KIRC where SSIGN score could be calculated (n = 252), we observed the formation of three clusters of tumor samples (hypermethylated, hypomethylated, and intermediate) that had significantly different median SSIGN scores (medianhyper = 7, medianhypo = 2, medianintermediate = 5; p < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('hyper', 'Disease', (164, 169))	('tumors', 'Disease', (38, 44))	('hyper', 'Disease', (275, 280))	('hyper', 'Disease', 'MESH:D053306', (275, 280))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('formation', 'biological_process', 'GO:0009058', ('118', '127'))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('hypomethylated', 'Var', (181, 195))	('tumor', 'Disease', (149, 154))	('SSIGN scores', 'MPA', (255, 267))	('hyper', 'Disease', 'MESH:D053306', (164, 169))
162776	33461589	SSIGN score, tumor stage) in a broader patient group than our Mayo Clinic cohorts (TCGA, Swedish cohort), consistent with the fact that they were originally identified in epigenetically more aggressive short-term survivor SSIGN 0-3 tumors.	('tumor', 'Disease', (13, 18))	('epigenetically', 'Var', (171, 185))	('patient', 'Species', '9606', (39, 46))	('Mayo', 'Species', '162683', (62, 66))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumor', 'Disease', (232, 237))	('tumors', 'Disease', (232, 238))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
162784	33461589	While promising as high-risk biomarkers, genes associated with the differentially methylated regions are enriched in processes such as EMT, VEGF and TGF-beta signaling, stemness, and cancer/metastasis signaling pathways, suggesting that these epigenetic changes functionally drive disease aggressiveness.	('cancer', 'Disease', (183, 189))	('differentially', 'Var', (67, 81))	('VEGF', 'Gene', '7422', (140, 144))	('signaling', 'biological_process', 'GO:0023052', ('158', '167'))	('EMT', 'biological_process', 'GO:0001837', ('135', '138'))	('aggressiveness', 'Disease', 'MESH:D001523', (289, 303))	('TGF-beta', 'Gene', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('drive', 'PosReg', (275, 280))	('VEGF', 'Gene', (140, 144))	('aggressiveness', 'Disease', (289, 303))	('signaling', 'biological_process', 'GO:0023052', ('201', '210'))	('TGF-beta', 'Gene', '7039', (149, 157))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('aggressiveness', 'Phenotype', 'HP:0000718', (289, 303))
162786	33461589	Taken together, our study reveals novel epigenetic differences characteristic of high risk ccRCCs that are paradoxically classified as lower risk by the SSIGN score.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('RCC', 'Disease', (93, 96))	('epigenetic differences', 'Var', (40, 62))
162792	33461589	Several other laboratories have more broadly reported epigenetic features related to poor outcome in ccRCC regardless of tumor risk and SSIGN score, some of which are applicable to biomarker development.	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('related', 'Reg', (74, 81))	('epigenetic features', 'Var', (54, 73))	('ccRCC regardless of tumor', 'Disease', (101, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('ccRCC regardless of tumor', 'Disease', 'MESH:D009369', (101, 126))
162796	33461589	's work on the interplay between DNA methylation and its oxidation product, hydroxymethylation, showed that 5hmC loss was linked to DNA hypermethylation and that low global 5hmC was associated with poor outcome in ccRCC.	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('132', '152'))	('low', 'Var', (162, 165))	('5hmC', 'Gene', (108, 112))	('5hmC', 'Chemical', 'MESH:C011865', (173, 177))	('DNA methylation', 'biological_process', 'GO:0006306', ('33', '48'))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('hyper', 'Disease', 'MESH:D053306', (136, 141))	('loss', 'NegReg', (113, 117))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('RCC', 'Disease', (216, 219))	('hyper', 'Disease', (136, 141))	('RCC', 'Phenotype', 'HP:0005584', (216, 219))	('5hmC', 'Chemical', 'MESH:C011865', (108, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (214, 219))
162811	33461589	We previously showed that SETD2 mutation in ccRCC was associated with a DNA hypermethylator phenotype, worse patient survival, and greater metastatic potential, which was confirmed by TCGA.	('patient', 'Species', '9606', (109, 116))	('RCC', 'Disease', (46, 49))	('SETD2', 'Gene', '29072', (26, 31))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('hyper', 'Disease', (76, 81))	('metastatic potential', 'CPA', (139, 159))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('SETD2', 'Gene', (26, 31))	('hyper', 'Disease', 'MESH:D053306', (76, 81))	('greater', 'PosReg', (131, 138))	('mutation', 'Var', (32, 40))	('associated', 'Reg', (54, 64))
162813	33461589	Presumably this is achieved through a combination of tumor suppressor gene hypermethylation and/or silencing of key regulators of EMT and metastasis.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('53', '69'))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('EMT', 'biological_process', 'GO:0001837', ('130', '133'))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('hyper', 'Disease', (75, 80))	('hyper', 'Disease', 'MESH:D053306', (75, 80))	('tumor', 'Disease', (53, 58))	('silencing', 'Var', (99, 108))	('tumor suppressor', 'biological_process', 'GO:0051726', ('53', '69'))
162815	33461589	Indeed, globally hypermethylated glioma cells (due to IDH1/2 mutation, another driver of the hypermethylator phenotype) are hypersensitive to DNA hypomethylating drugs.	('DNA', 'cellular_component', 'GO:0005574', ('142', '145'))	('hyper', 'Disease', (17, 22))	('hyper', 'Disease', 'MESH:D053306', (17, 22))	('hyper', 'Disease', (93, 98))	('hyper', 'Disease', 'MESH:D053306', (93, 98))	('hypermethylated glioma', 'Disease', 'MESH:D005910', (17, 39))	('IDH1/2', 'Gene', (54, 60))	('mutation', 'Var', (61, 69))	('hyper', 'Disease', (124, 129))	('hyper', 'Disease', 'MESH:D053306', (124, 129))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('IDH1/2', 'Gene', '3417;3418', (54, 60))	('hypermethylated glioma', 'Disease', (17, 39))
162820	33461589	In mouse models of metastatic lung, breast, and esophageal cancers, adjuvant epigenetic therapy following resection of the primary tumor disrupted the premetastatic microenvironment and inhibited lung metastases, at least in part, by inducing differentiation of myeloid derived suppressor cells.	('inducing', 'Reg', (234, 242))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mouse', 'Species', '10090', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('esophageal cancers', 'Disease', (48, 66))	('premetastatic microenvironment', 'CPA', (151, 181))	('disrupted', 'NegReg', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('epigenetic therapy', 'Var', (77, 95))	('tumor', 'Disease', (131, 136))	('esophageal cancers', 'Disease', 'MESH:D004938', (48, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('differentiation', 'CPA', (243, 258))	('lung metastases', 'Disease', (196, 211))	('lung metastases', 'Disease', 'MESH:D009362', (196, 211))	('inhibited', 'NegReg', (186, 195))	('adjuvant', 'Var', (68, 76))
162895	31788359	Although somatic gene mutations, including VHL, BAP-1, PBRM-1, KDM5C, SETD2, and MTOR genes are involved in the pathogenesis of ccRCC, the molecular mechanism of ccRCC is still not fully elucidated.	('ccRCC', 'Disease', 'MESH:D002292', (128, 133))	('involved', 'Reg', (96, 104))	('PBRM-1', 'Gene', '55193', (55, 61))	('ccRCC', 'Disease', (128, 133))	('VHL', 'Disease', (43, 46))	('PBRM-1', 'Gene', (55, 61))	('MTOR', 'Gene', (81, 85))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('MTOR', 'Gene', '2475', (81, 85))	('KDM5C', 'Gene', '8242', (63, 68))	('ccRCC', 'Disease', 'MESH:D002292', (162, 167))	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('BAP-1', 'Gene', '8314', (48, 53))	('mutations', 'Var', (22, 31))	('SETD2', 'Gene', (70, 75))	('ccRCC', 'Disease', (162, 167))	('VHL', 'Disease', 'MESH:D006623', (43, 46))	('BAP-1', 'Gene', (48, 53))	('pathogenesis', 'biological_process', 'GO:0009405', ('112', '124'))	('SETD2', 'Gene', '29072', (70, 75))	('ccRCC', 'Phenotype', 'HP:0006770', (162, 167))	('KDM5C', 'Gene', (63, 68))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))
162942	31788359	The most common genetic changes associated with the development of ccRCC are the deletion of the short arm of chromosome 3.	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('ccRCC', 'Disease', (67, 72))	('ccRCC', 'Disease', 'MESH:D002292', (67, 72))	('deletion', 'Var', (81, 89))	('chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('short arm', 'Phenotype', 'HP:0009824', (97, 106))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
162952	31788359	Aberrations of the mitotic cell cycle play important roles in the carcinogenesis or progression of tumors.	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('roles', 'Reg', (53, 58))	('carcinogenesis', 'Disease', 'MESH:D063646', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mitotic cell cycle', 'CPA', (19, 37))	('carcinogenesis', 'Disease', (66, 80))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('Aberrations', 'Var', (0, 11))	('mitotic cell cycle', 'biological_process', 'GO:0000278', ('19', '37'))	('tumors', 'Disease', (99, 105))
162953	31788359	Dysregulation of the cell cycle is recognized as a hallmark of malignancy.	('Dysregulation', 'Var', (0, 13))	('cell cycle', 'CPA', (21, 31))	('hallmark of malignancy', 'Disease', 'MESH:D009369', (51, 73))	('hallmark of malignancy', 'Disease', (51, 73))	('cell cycle', 'biological_process', 'GO:0007049', ('21', '31'))
162957	31788359	Overexpression of DTL is related to the poor outcome in gastric carcinoma, breast and lung cancers.	('DTL', 'Gene', '51514', (18, 21))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (56, 73))	('DTL', 'Gene', (18, 21))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('gastric carcinoma', 'Disease', 'MESH:D013274', (56, 73))	('gastric carcinoma', 'Disease', (56, 73))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast and lung cancers', 'Disease', 'MESH:D001943', (75, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('lung cancers', 'Phenotype', 'HP:0100526', (86, 98))
162976	31788359	Overexpression of KIF20A is correlated with poor overall survival of hepatocellular carcinoma, lung adenocarcinoma and ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('KIF20A', 'Gene', (18, 24))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (69, 93))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (95, 114))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (69, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('poor', 'NegReg', (44, 48))	('hepatocellular carcinoma', 'Disease', (69, 93))	('ccRCC', 'Disease', (119, 124))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (95, 114))	('KIF20A', 'Gene', '10112', (18, 24))	('lung adenocarcinoma', 'Disease', (95, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('Overexpression', 'Var', (0, 14))	('ccRCC', 'Disease', 'MESH:D002292', (119, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))
162996	31788359	Dysregulation of NCAPG may contribute to the progression of gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('NCAPG', 'Gene', '64151', (17, 22))	('Dysregulation', 'Var', (0, 13))	('gastric cancer', 'Disease', (60, 74))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('NCAPG', 'Gene', (17, 22))	('contribute', 'Reg', (27, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))
162999	31788359	In the present study, low-expression of ACADM is involved in the ccRCC tumorigenesis.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('involved', 'Reg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('ACADM', 'Gene', '34', (40, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('ccRCC', 'Disease', (65, 70))	('ccRCC', 'Disease', 'MESH:D002292', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('low-expression', 'Var', (22, 36))	('ACADM', 'Gene', (40, 45))	('tumor', 'Disease', (71, 76))
163003	31788359	Another study also showed that in a breast cancer transgenic mouse model, attenuating medium-chain acyl-CoA dehydrogenase activity accelerated cancer progression.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('breast cancer', 'Disease', (36, 49))	('accelerated', 'PosReg', (131, 142))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))	('cancer', 'Disease', (43, 49))	('attenuating', 'Var', (74, 85))	('acyl-CoA', 'Chemical', 'MESH:D000214', (99, 107))	('medium-chain acyl-CoA dehydrogenase', 'Enzyme', (86, 121))	('medium-chain acyl-CoA dehydrogenase activity', 'molecular_function', 'GO:0070991', ('86', '130'))	('medium-chain acyl-CoA dehydrogenase activity', 'molecular_function', 'GO:0003995', ('86', '130'))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('mouse', 'Species', '10090', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('activity', 'MPA', (122, 130))
163022	28203091	Expression of microRNA-30c via lentivirus vector inhibits the proliferation and enhances the sensitivity of highly aggressive ccRCC Caki-1 cells to anticancer agents The clear cell renal cell carcinoma (ccRCC) is one of the most fatal urologic tumors, and the prognosis remains very poor for advanced or metastatic ccRCC.	('clear cell renal cell carcinoma', 'Disease', (170, 201))	('urologic tumors', 'Disease', 'MESH:D014571', (235, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('urologic tumors', 'Disease', (235, 250))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('proliferation', 'CPA', (62, 75))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (170, 201))	('enhances', 'PosReg', (80, 88))	('Caki-1', 'CellLine', 'CVCL:0234', (132, 138))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('microRNA-30c', 'Var', (14, 26))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (170, 201))	('ccRCC', 'Phenotype', 'HP:0006770', (315, 320))	('inhibits', 'NegReg', (49, 57))	('sensitivity', 'MPA', (93, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (203, 208))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (181, 201))
163042	28203091	Aberrant expression of miRs would participate in the proliferation, survival, and metastasis of many types of human cancers.	('Aberrant expression', 'Var', (0, 19))	('survival', 'CPA', (68, 76))	('participate in', 'Reg', (34, 48))	('human', 'Species', '9606', (110, 115))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('proliferation', 'CPA', (53, 66))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('metastasis', 'CPA', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('miRs', 'Gene', (23, 27))	('cancers', 'Disease', (116, 123))
163044	28203091	Expression of miR-122, 34a, 452, 125b, 148a, 137 or let-7 would inhibit the proliferation of cancer cells and enhance the sensitivity of cancer cells to antitumor agents.	('tumor', 'Disease', (157, 162))	('miR-122', 'Gene', '406906', (14, 21))	('miR-122', 'Gene', (14, 21))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('enhance', 'PosReg', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('452', 'Var', (28, 31))	('148a', 'Var', (39, 43))	('inhibit', 'NegReg', (64, 71))	('cancer', 'Disease', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('let-7', 'Gene', (52, 57))	('34a', 'Var', (23, 26))
163058	28203091	MTA-1 vector containing mutated full length of MTA-1 were synthesized by chemical synthesis (Gene Ray Company, Shanghai, People's Republic of China) and cloned into pcDNA3.1 plasmids.	('mutated full length', 'Var', (24, 43))	('MTA-1', 'Gene', (47, 52))	('synthesis', 'biological_process', 'GO:0009058', ('82', '91'))	("People's Republic", 'Disease', (121, 138))	('MTA-1', 'Gene', '9112', (47, 52))	('MTA-1', 'Gene', '9112', (0, 5))	('MTA-1', 'Gene', (0, 5))	("People's Republic", 'Disease', 'MESH:D006212', (121, 138))
163100	28203091	As shown in Figure 6, infection of miR-30c decreased the in vivo growth of Caki-1 cells compared with control.	('Caki-1', 'CellLine', 'CVCL:0234', (75, 81))	('infection', 'Var', (22, 31))	('miR-30c', 'Gene', (35, 42))	('miR-30c', 'Gene', '407031', (35, 42))	('decreased', 'NegReg', (43, 52))	('in vivo growth of Caki-1 cells', 'CPA', (57, 87))
163104	28203091	Furthermore, co-transfection inhibitor of miR-30c or MTA-1 mutation almost blocked the effect of miR-30c in Caki-1 cells (Figure 7D and E).	('Caki-1', 'CellLine', 'CVCL:0234', (108, 114))	('blocked', 'NegReg', (75, 82))	('miR-30c', 'Gene', (42, 49))	('MTA-1', 'Gene', '9112', (53, 58))	('mutation', 'Var', (59, 67))	('MTA-1', 'Gene', (53, 58))	('miR-30c', 'Gene', '407031', (42, 49))	('miR-30c', 'Gene', (97, 104))	('miR-30c', 'Gene', '407031', (97, 104))
163108	28203091	Transfection of miR-30c inhibitor or MTA-1 mutation almost blocked the activity of miR-30c.	('miR-30c', 'Gene', '407031', (83, 90))	('mutation', 'Var', (43, 51))	('MTA-1', 'Gene', '9112', (37, 42))	('MTA-1', 'Gene', (37, 42))	('miR-30c', 'Gene', (83, 90))	('activity', 'MPA', (71, 79))	('miR-30c', 'Gene', (16, 23))	('blocked', 'NegReg', (59, 66))	('miR-30c', 'Gene', '407031', (16, 23))
163110	28203091	Infection of miR-30c inhibitor or MTA-1 mutation almost blocked the activity of miR-30c on Caki-1 colony formation.	('mutation', 'Var', (40, 48))	('MTA-1', 'Gene', (34, 39))	('miR-30c', 'Gene', (13, 20))	('miR-30c', 'Gene', '407031', (13, 20))	('miR-30c', 'Gene', '407031', (80, 87))	('Caki-1', 'CellLine', 'CVCL:0234', (91, 97))	('formation', 'biological_process', 'GO:0009058', ('105', '114'))	('Caki-1 colony formation', 'CPA', (91, 114))	('activity', 'MPA', (68, 76))	('miR-30c', 'Gene', (80, 87))	('MTA-1', 'Gene', '9112', (34, 39))	('blocked', 'NegReg', (56, 63))
163114	28203091	As highly aggressive ccRCC cell lines, infection of miR-30c disrupted the migration and invasion of Caki-1.	('infection', 'Var', (39, 48))	('invasion', 'CPA', (88, 96))	('disrupted', 'NegReg', (60, 69))	('migration', 'CPA', (74, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (21, 26))	('miR-30c', 'Gene', (52, 59))	('miR-30c', 'Gene', '407031', (52, 59))	('Caki-1', 'CellLine', 'CVCL:0234', (100, 106))
163116	28203091	Therefore, MTA-1 may be an interesting novel target for the treatment of highly aggressive ccRCC, and expression of miR-30c would be a potential strategy for ccRCC treatment.	('MTA-1', 'Gene', (11, 16))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('miR-30c', 'Gene', (116, 123))	('miR-30c', 'Gene', '407031', (116, 123))	('ccRCC', 'Phenotype', 'HP:0006770', (158, 163))	('expression', 'Var', (102, 112))	('ccRCC', 'Disease', (158, 163))	('MTA-1', 'Gene', '9112', (11, 16))
163166	33461545	In recent years, accumulating evidence suggest that snoRNAs play a crucial role in the tumorigenesis and tumor development, aberration of their expression has been observed in multiple many cancers, some of which are cancer type-specific.	('snoRNA', 'Gene', '84546', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('cancer', 'Disease', (190, 196))	('expression', 'MPA', (144, 154))	('snoRNA', 'Gene', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Disease', (105, 110))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('aberration', 'Var', (124, 134))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('observed', 'Reg', (164, 172))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Disease', (217, 223))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
163177	33461545	Importantly, SNORD63 in US and SNORD96A in plasma possessed the favorable diagnostic efficiency, suggesting that aberrant expression of SNORD63 and SNORD96A act as diagnostic promising biomarkers for ccRCC.	('SNORD96A', 'Gene', (148, 156))	('SNORD96A', 'Gene', '619571', (31, 39))	('SNORD63', 'Gene', '26785', (136, 143))	('SNORD63', 'Gene', (136, 143))	('SNORD63', 'Gene', '26785', (13, 20))	('SNORD63', 'Gene', (13, 20))	('SNORD96A', 'Gene', (31, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (200, 205))	('SNORD96A', 'Gene', '619571', (148, 156))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('RCC', 'Disease', (202, 205))	('RCC', 'Phenotype', 'HP:0005584', (202, 205))	('aberrant', 'Var', (113, 121))
163218	33461545	4a, in plasma, the areas under the curves (AUCs) of SNORD63 and SNORD96A were 0.5161 with 95% sensitivity and 27.3% specificity, 0.8909 with 90% sensitivity and 80% specificity, respectively.	('0.5161', 'Var', (78, 84))	('SNORD96A', 'Gene', (64, 72))	('SNORD63', 'Gene', '26785', (52, 59))	('SNORD63', 'Gene', (52, 59))	('SNORD96A', 'Gene', '619571', (64, 72))
163225	33461545	In plasma, the AUCs of SNORD63 and SNORD96A were 0.6144 with 95% sensitivity and 39.1% specificity, 0.9359 with 95% sensitivity and 87% specificity, respectively.	('SNORD63', 'Gene', '26785', (23, 30))	('SNORD63', 'Gene', (23, 30))	('0.6144', 'Var', (49, 55))	('SNORD96A', 'Gene', '619571', (35, 43))	('SNORD96A', 'Gene', (35, 43))
163226	33461545	6a); In US, the AUCs of SNORD63 and SNORD96A were 0.6884 with 47.9% sensitivity and 82.1% specificity, 0.6701 with 53.1% sensitivity and 79.5% specificity, respectively (Fig.	('0.6884', 'Var', (50, 56))	('SNORD63', 'Gene', '26785', (24, 31))	('SNORD63', 'Gene', (24, 31))	('0.6701', 'Var', (103, 109))	('SNORD96A', 'Gene', '619571', (36, 44))	('SNORD96A', 'Gene', (36, 44))
163227	33461545	Previous studies demonstrated that SNORA70B, SNORD93, SNORD12B, SNORA59B, SNORA2, SNORD116-2 were abnormal expression in ccRCC, indicating the important role of snoRNAs in the development of ccRCC and the potential value of snoRNAs as diagnostic biomarkers for ccRCC patients.	('SNORA59B', 'Gene', '677882', (64, 72))	('SNORD12B', 'Gene', (54, 62))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (121, 126))	('SNORD93', 'Gene', (45, 52))	('SNORD93', 'Gene', '692210', (45, 52))	('SNORD12B', 'Gene', '100113393', (54, 62))	('RCC', 'Disease', (193, 196))	('patients', 'Species', '9606', (267, 275))	('RCC', 'Phenotype', 'HP:0005584', (193, 196))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('SNORA59B', 'Gene', (64, 72))	('snoRNA', 'Gene', '84546', (161, 167))	('SNORA70B', 'Gene', '100124537', (35, 43))	('ccRCC', 'Phenotype', 'HP:0006770', (191, 196))	('snoRNA', 'Gene', '84546', (224, 230))	('SNORA70B', 'Gene', (35, 43))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('RCC', 'Disease', (263, 266))	('RCC', 'Phenotype', 'HP:0005584', (263, 266))	('SNORA2', 'Var', (74, 80))	('ccRCC', 'Phenotype', 'HP:0006770', (261, 266))	('SNORD116-2', 'Gene', '100033414', (82, 92))	('RCC', 'Disease', 'MESH:C538614', (263, 266))	('snoRNA', 'Gene', (161, 167))	('SNORD116-2', 'Gene', (82, 92))	('snoRNA', 'Gene', (224, 230))
163242	33461545	Importantly, SNORD63 in US and SNORD96A in plasma possessed the favorable diagnostic efficiency, suggesting that aberrant expression of SNORD63 and SNORD96A act as a diagnostic promising biomarker for ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (201, 206))	('SNORD96A', 'Gene', '619571', (31, 39))	('SNORD63', 'Gene', '26785', (136, 143))	('SNORD63', 'Gene', (136, 143))	('SNORD63', 'Gene', '26785', (13, 20))	('SNORD63', 'Gene', (13, 20))	('SNORD96A', 'Gene', (31, 39))	('SNORD96A', 'Gene', '619571', (148, 156))	('RCC', 'Disease', 'MESH:C538614', (203, 206))	('SNORD96A', 'Gene', (148, 156))	('RCC', 'Disease', (203, 206))	('RCC', 'Phenotype', 'HP:0005584', (203, 206))	('aberrant', 'Var', (113, 121))
163263	33029112	In renal cancer cell lines, the PPARalpha antagonist GW6471 can arrest the cell cycle in G0/G1 phase by attenuating cell cycle regulatory proteins, thereby inducing cell apoptosis.	('G1 phase', 'biological_process', 'GO:0051318', ('92', '100'))	('GW6471', 'Var', (53, 59))	('GW6471', 'Chemical', 'MESH:C449302', (53, 59))	('renal cancer', 'Phenotype', 'HP:0009726', (3, 15))	('inducing', 'Reg', (156, 164))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cell cycle regulatory proteins', 'Protein', (116, 146))	('cell apoptosis', 'CPA', (165, 179))	('cell cycle in G0/G1 phase', 'CPA', (75, 100))	('cell cycle', 'biological_process', 'GO:0007049', ('116', '126'))	('apoptosis', 'biological_process', 'GO:0097194', ('170', '179'))	('apoptosis', 'biological_process', 'GO:0006915', ('170', '179'))	('attenuating', 'NegReg', (104, 115))	('cell cycle', 'biological_process', 'GO:0007049', ('75', '85'))
163278	33029112	Recently, another study showed that PPARG/PPARgamma overexpression might help to better treat patients with CRC by inhibiting the process of EMT (epithelial-mesenchymal transition).	('EMT', 'biological_process', 'GO:0001837', ('141', '144'))	('CRC', 'Disease', 'MESH:D015179', (108, 111))	('inhibiting', 'NegReg', (115, 125))	('PPARG/PPARgamma', 'Var', (36, 51))	('CRC', 'Disease', (108, 111))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('146', '179'))
163279	33029112	PPARG/PPARgamma in KIRC can promote cell apoptosis and inhibit cell migration and proliferation by inhibiting SIX2.	('apoptosis', 'biological_process', 'GO:0097194', ('41', '50'))	('apoptosis', 'biological_process', 'GO:0006915', ('41', '50'))	('cell apoptosis', 'CPA', (36, 50))	('inhibiting', 'NegReg', (99, 109))	('promote', 'PosReg', (28, 35))	('PPARG/PPARgamma', 'Var', (0, 15))	('cell migration', 'biological_process', 'GO:0016477', ('63', '77'))	('SIX2', 'Gene', (110, 114))	('inhibit', 'NegReg', (55, 62))	('SIX2', 'Gene', '10736', (110, 114))
163282	33029112	In KIRC, the low expression of ACADM may affect the metabolism of medium-chain fatty acids, and then the metabolism of triglycerides, and play an essential role in apoptosis through the function of light chains.	('metabolism', 'biological_process', 'GO:0008152', ('52', '62'))	('low expression', 'Var', (13, 27))	('ACADM', 'Gene', (31, 36))	('apoptosis', 'CPA', (164, 173))	('metabolism', 'biological_process', 'GO:0008152', ('105', '115'))	('apoptosis', 'biological_process', 'GO:0006915', ('164', '173'))	('metabolism of medium-chain fatty acids', 'MPA', (52, 90))	('apoptosis', 'biological_process', 'GO:0097194', ('164', '173'))	('metabolism of triglycerides', 'MPA', (105, 132))	('affect', 'Reg', (41, 47))	('play', 'Reg', (138, 142))	('triglycerides', 'Chemical', 'MESH:D014280', (119, 132))
163287	33029112	Silencing CPT2 can induce chemical resistance to cisplatin.	('CPT', 'molecular_function', 'GO:0004095', ('10', '13'))	('CPT2', 'Gene', (10, 14))	('chemical resistance to cisplatin', 'MPA', (26, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('induce', 'Reg', (19, 25))	('Silencing', 'Var', (0, 9))	('CPT', 'molecular_function', 'GO:0004142', ('10', '13'))
163333	28974261	Why are mutation rates in epidermal growth factor receptor (EGFR) and erb-b2 receptor tyrosine kinase 2 (ERBB2) higher in lung cancer from never smokers than that from smokers?	('epidermal growth factor receptor', 'Gene', '1956', (26, 58))	('ERBB2', 'Gene', (105, 110))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('erb-b2 receptor tyrosine kinase 2', 'Gene', (70, 103))	('higher', 'PosReg', (112, 118))	('lung cancer', 'Disease', (122, 133))	('ERBB2', 'Gene', '2064', (105, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('rat', 'Species', '10116', (17, 20))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('26', '49'))	('EGFR', 'molecular_function', 'GO:0005006', ('60', '64'))	('erb-b2 receptor tyrosine kinase 2', 'Gene', '2064', (70, 103))	('mutation', 'Var', (8, 16))	('epidermal growth factor receptor', 'Gene', (26, 58))	('EGFR', 'Gene', (60, 64))
163341	28974261	One widely accepted theory about how gene mutations may drive cancer development is that certain gene mutations may give competitive edges of host cells over neighboring cells, leading to their proliferation.	('rat', 'Species', '10116', (201, 204))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('leading to', 'Reg', (177, 187))	('men', 'Species', '9606', (76, 79))	('proliferation', 'CPA', (194, 207))	('mutations', 'Var', (102, 111))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('drive', 'PosReg', (56, 61))
163346	28974261	Therefore, it is reasonable to hypothesize that mutations in pre-cancerous cells are selected to better cope with certain stresses rather than simply having a competitive edge in a normal tissue condition.	('rat', 'Species', '10116', (131, 134))	('cancerous', 'Disease', 'MESH:D009369', (65, 74))	('pre', 'molecular_function', 'GO:0003904', ('61', '64'))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancerous', 'Disease', (65, 74))	('mutations', 'Var', (48, 57))
163348	28974261	However, it has been yet to establish which of these or other stresses or their combinations are the cancer-defining stresses that drive the underlying cells to select specific mutations for survival.	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('mutations', 'Var', (177, 186))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
163361	28974261	In our recently published study, we found that plasma microRNA-141 (miR-141) is a novel biomarker that complements CEA in detecting colon cancer with distant metastasis and that high levels of miR-141 in plasma are associated with poor prognosis.	('high levels', 'Var', (178, 189))	('microRNA-141', 'Gene', (54, 66))	('miR-141', 'Gene', (193, 200))	('colon cancer', 'Disease', (132, 144))	('CEA', 'Gene', (115, 118))	('miR-141', 'Gene', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('CEA', 'Gene', '1084', (115, 118))	('miR-141', 'Gene', '406933', (193, 200))	('microRNA-141', 'Gene', '406933', (54, 66))	('miR-141', 'Gene', '406933', (68, 75))	('men', 'Species', '9606', (109, 112))	('colon cancer', 'Phenotype', 'HP:0003003', (132, 144))	('colon cancer', 'Disease', 'MESH:D015179', (132, 144))
163382	28974261	EGFR and Kirsten rat sarcoma viral oncogene homolog (KRAS) gene mutations and anaplastic lymphoma kinase (ALK) rearrangements are 3 major recurrent oncogenic alterations associated with lung cancer in never-smokers.	('anaplastic lymphoma kinase', 'Gene', '266802', (78, 104))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('sarcoma', 'Disease', 'MESH:D012509', (21, 28))	('KRAS', 'Gene', (53, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('sarcoma', 'Disease', (21, 28))	('lymphoma', 'Phenotype', 'HP:0002665', (89, 97))	('mutations', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('men', 'Species', '9606', (120, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('EGFR', 'Gene', (0, 4))	('KRAS', 'Gene', '24525', (53, 57))	('lung cancer', 'Disease', (186, 197))	('rat', 'Species', '10116', (162, 165))	('anaplastic lymphoma kinase', 'Gene', (78, 104))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (78, 97))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('rat', 'Species', '10116', (17, 20))
163383	28974261	Specifically, EGFR mutations have been reported in approximately 50% of never-smoker lung cancer patients compared with 10% of smoker lung cancer patients.	('lung cancer', 'Disease', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('lung cancer', 'Disease', (85, 96))	('EGFR', 'Gene', (14, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('mutations', 'Var', (19, 28))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('reported', 'Reg', (39, 47))	('patients', 'Species', '9606', (146, 154))	('patients', 'Species', '9606', (97, 105))
163384	28974261	In non-small cell lung carcinoma, adenocarcinoma subtype, female never smokers were found to have a much higher frequency of EGFR gene mutations and echinoderm microtubule associated protein like 4 (EML4)-ALK transcript fusions than smokers.	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (3, 32))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('EML4', 'Gene', (199, 203))	('mutations', 'Var', (135, 144))	('echinoderm microtubule associated protein like 4', 'Gene', '27436', (149, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('EGFR', 'molecular_function', 'GO:0005006', ('125', '129'))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('microtubule', 'cellular_component', 'GO:0005874', ('160', '171'))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (7, 32))	('EML4', 'Gene', '27436', (199, 203))	('EGFR gene', 'Gene', (125, 134))	('echinoderm microtubule associated protein like 4', 'Gene', (149, 197))	('non-small cell lung carcinoma, adenocarcinoma subtype', 'Disease', 'MESH:D002289', (3, 56))
163386	28974261	ERBB2 mutations, although occurring in a low frequency overall in lung cancer, also exhibited augmented mutation rate in non-smoker lung cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mutation rate', 'MPA', (104, 117))	('ERBB2', 'Gene', '2064', (0, 5))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('men', 'Species', '9606', (97, 100))	('lung cancer', 'Disease', (66, 77))	('ERBB2', 'Gene', (0, 5))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))	('rat', 'Species', '10116', (113, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('augmented', 'PosReg', (94, 103))	('patients', 'Species', '9606', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('lung cancer', 'Disease', (132, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('mutations', 'Var', (6, 15))
163389	28974261	These cancers have been recently shown to respond to anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy.	('PD-1', 'Gene', (78, 82))	('ligand', 'molecular_function', 'GO:0005488', ('101', '107'))	('PD-1', 'Gene', '5133', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('PD-L1', 'Gene', '29126', (111, 116))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('PD-L1', 'Gene', (111, 116))	('anti-programmed', 'Var', (53, 68))
163391	28974261	However, these tumors are shown to have increased EGFR and ERBB2 mutations, thus may benefit from targeted therapies.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('ERBB2', 'Gene', (59, 64))	('mutations', 'Var', (65, 74))	('ERBB2', 'Gene', '2064', (59, 64))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('increased', 'PosReg', (40, 49))	('EGFR', 'Gene', (50, 54))	('tumors', 'Disease', (15, 21))
163393	28974261	A reasonable hypothesis for exploration in this direction is that a smoker's lung might generate a physiological environment that favors tumors with a high mutation load while inhibiting EGFR and ERBB2 signaling that is activated in non-smoking-related cancers.	('high mutation load', 'Var', (151, 169))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('favors tumors', 'Disease', (130, 143))	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('cancers', 'Disease', (253, 260))	('cancers', 'Disease', 'MESH:D009369', (253, 260))	('favors tumors', 'Disease', 'MESH:D009369', (130, 143))	('rat', 'Species', '10116', (33, 36))	('rat', 'Species', '10116', (92, 95))	('inhibiting', 'NegReg', (176, 186))	('ERBB2', 'Gene', '2064', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('ERBB2', 'Gene', (196, 201))	('signaling', 'biological_process', 'GO:0023052', ('202', '211'))	('EGFR', 'molecular_function', 'GO:0005006', ('187', '191'))	('EGFR', 'MPA', (187, 191))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('men', 'Species', '9606', (120, 123))
163449	30334010	While in the past the search for new chemotherapies in cancer (and many other diseases) has been an exercise in the brute force trial-and-error approach of new toxic therapies, and sheer luck on the part of the patient and his/her physician, we now have the ability to predict what will likely work for each patient's disease based on genomics or specific mutational analysis (as has been the case for several years) and, more recently, on metabolomics.	('patient', 'Species', '9606', (308, 315))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('mutational', 'Var', (356, 366))	('patient', 'Species', '9606', (211, 218))	('cancer', 'Disease', (55, 61))
163450	30334010	While mutations have been targeted in other cancers with a high degree of success, this has not been the case for ccRCC and will not be further discussed in this commentary.	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))	('mutations', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
163457	30334010	While the chemically modified glucose analog 2- deoxy-D-glucose (2-DG) acts as substrate to inhibit hexokinase, 3-bromopyruvate (3-BrPa) is believed to interfere directly with HK enzymatic activity and bind to hexokinase 2.	('hexokinase 2', 'Gene', '3099', (210, 222))	('hexokinase', 'Gene', (100, 110))	('glucose', 'Chemical', 'MESH:D005947', (56, 63))	('HK', 'Gene', '3098', (176, 178))	('hexokinase', 'Gene', (210, 220))	('2-DG', 'Chemical', 'MESH:D003847', (65, 69))	('2- deoxy-D-glucose', 'Chemical', 'MESH:D003847', (45, 63))	('3-bromopyruvate', 'Chemical', 'MESH:C017092', (112, 127))	('hexokinase', 'Gene', '3098', (100, 110))	('glucose', 'Chemical', 'MESH:D005947', (30, 37))	('inhibit', 'NegReg', (92, 99))	('3-bromopyruvate', 'Var', (112, 127))	('hexokinase 2', 'Gene', (210, 222))	('hexokinase', 'Gene', '3098', (210, 220))	('interfere', 'NegReg', (152, 161))	('bind', 'Interaction', (202, 206))	('3-BrPa', 'Chemical', 'MESH:C017092', (129, 135))
163459	30334010	Recent studies targeting HIFalpha using PT2385 resulted in inhibition of tumor growth in several different RCC cell lines and now is being tested in clinical trials.	('inhibition', 'NegReg', (59, 69))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('RCC', 'Disease', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('PT2385', 'Var', (40, 46))
92515	30334010	Inhibition of FASN by cerulin or its derivative C75 induced a rapid increase in malonyl-coA with a marked reduction in lipogenesis in multiple cancer models, including RCC cells.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cerulin', 'Chemical', '-', (22, 29))	('malonyl-coA', 'MPA', (80, 91))	('lipogenesis', 'MPA', (119, 130))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('FASN', 'Gene', (14, 18))	('lipogenesis', 'biological_process', 'GO:0008610', ('119', '130'))	('reduction', 'NegReg', (106, 115))	('FASN', 'Gene', '2194', (14, 18))	('malonyl-coA', 'Chemical', 'MESH:D008316', (80, 91))	('increase', 'PosReg', (68, 76))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', (143, 149))	('C75', 'Gene', (48, 51))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('RCC', 'Disease', (168, 171))
163466	30334010	Inhibition of IDO prevents the purported immunosuppressive effect and enables T-cell activation in a murine RCC model.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('immunosuppressive effect', 'MPA', (41, 65))	('murine', 'Species', '10090', (101, 107))	('T-cell activation', 'CPA', (78, 95))	('IDO', 'molecular_function', 'GO:0033754', ('14', '17'))	('Inhibition', 'Var', (0, 10))	('T-cell activation', 'biological_process', 'GO:0042110', ('78', '95'))	('prevents', 'NegReg', (18, 26))	('IDO', 'Gene', (14, 17))	('IDO', 'molecular_function', 'GO:0047719', ('14', '17'))
163469	30334010	Furthermore glutamine in ccRCC is feeding the glutathione/oxidized glutathione pathway (GSH/GSSG), an important pathway for neutralizing ROS in cells.	('ROS', 'Chemical', 'MESH:D017382', (137, 140))	('glutamine', 'Chemical', 'MESH:D005973', (12, 21))	('glutathione', 'Chemical', 'MESH:D005978', (67, 78))	('glutamine', 'Var', (12, 21))	('ccRCC', 'Phenotype', 'HP:0006770', (25, 30))	('GSH', 'Chemical', '-', (88, 91))	('glutathione', 'Chemical', 'MESH:D005978', (46, 57))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('GSSG', 'Chemical', 'MESH:D019803', (92, 96))	('RCC', 'Disease', (27, 30))
163476	28717191	MLN4924 (Pevonedistat), a protein neddylation inhibitor, suppresses proliferation and migration of human clear cell renal cell carcinoma Neddylation is a post-translational protein modification associated with cancer development.	('MLN4924', 'Var', (0, 7))	('suppresses', 'NegReg', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('post-translational protein modification', 'biological_process', 'GO:0043687', ('154', '193'))	('protein', 'cellular_component', 'GO:0003675', ('173', '180'))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (111, 136))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (105, 136))	('cell renal cell carcinoma', 'Disease', (111, 136))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (116, 136))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('Pevonedistat', 'Chemical', 'MESH:C539933', (9, 21))	('protein neddylation', 'biological_process', 'GO:0045116', ('26', '45'))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('cancer', 'Disease', (210, 216))	('human', 'Species', '9606', (99, 104))
163477	28717191	MLN4924 is a neddylation inhibitor currently under investigation in multiple phase I studies on various malignancies, and its clincal name is Pevonedistat.	('MLN4924', 'Var', (0, 7))	('malignancies', 'Disease', 'MESH:D009369', (104, 116))	('neddylation', 'Protein', (13, 24))	('malignancies', 'Disease', (104, 116))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))
163478	28717191	It has been documented that MLN4924 blocks Cullins neddylation and inactivates CRLs and, in turn, triggers cell-cycle arrest, apoptosis, senescence and autophagy in many cancer cells.	('cancer', 'Disease', (170, 176))	('MLN4924', 'Var', (28, 35))	('apoptosis', 'CPA', (126, 135))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('arrest', 'Disease', (118, 124))	('CRL', 'Gene', '133396', (79, 82))	('blocks', 'NegReg', (36, 42))	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('inactivates', 'NegReg', (67, 78))	('triggers', 'Reg', (98, 106))	('neddylation', 'MPA', (51, 62))	('MLN4924', 'Chemical', 'MESH:C539933', (28, 35))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('107', '124'))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('Cullins', 'Gene', '8454', (43, 50))	('arrest', 'Disease', 'MESH:D006323', (118, 124))	('autophagy', 'biological_process', 'GO:0016236', ('152', '161'))	('senescence', 'biological_process', 'GO:0010149', ('137', '147'))	('autophagy', 'CPA', (152, 161))	('CRL', 'Gene', (79, 82))	('senescence', 'CPA', (137, 147))	('autophagy', 'biological_process', 'GO:0006914', ('152', '161'))	('Cullins', 'Gene', (43, 50))
163479	28717191	In this study, we investigated the anti-tumor effect of MLN4924 in human clear cell renal carcinoma (ccRCC).	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (73, 99))	('RCC', 'Disease', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('MLN4924', 'Var', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (73, 99))	('renal carcinoma', 'Phenotype', 'HP:0005584', (84, 99))	('clear cell renal carcinoma', 'Disease', (73, 99))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('human', 'Species', '9606', (67, 72))	('MLN4924', 'Chemical', 'MESH:C539933', (56, 63))
163481	28717191	Moreover, MLN4924 treatment led to rapid inhibition of Cullin1 neddylation and notably suppressed growth and survival as well as migration in a dose-and time-dependent manner.	('Cullin1', 'Gene', (55, 62))	('MLN4924', 'Var', (10, 17))	('Cullin1', 'Gene', '8454', (55, 62))	('suppressed', 'NegReg', (87, 97))	('MLN4924', 'Chemical', 'MESH:C539933', (10, 17))	('inhibition', 'NegReg', (41, 51))
163482	28717191	Mechanistic studies revealed that MLN4924 induced the accumulation of a number of CRL substrates, including p21, p27 and Wee1 to trigger DNA damage and induce growth arrest at the G2/M phase.	('arrest', 'Disease', (166, 172))	('M phase', 'biological_process', 'GO:0000279', ('183', '190'))	('MLN4924', 'Var', (34, 41))	('growth arrest', 'Phenotype', 'HP:0001510', (159, 172))	('Wee1', 'Gene', (121, 125))	('DNA', 'cellular_component', 'GO:0005574', ('137', '140'))	('induce', 'Reg', (152, 158))	('DNA damage', 'MPA', (137, 147))	('CRL', 'Gene', (82, 85))	('p21', 'Gene', (108, 111))	('trigger', 'Reg', (129, 136))	('p21', 'Gene', '644914', (108, 111))	('arrest', 'Disease', 'MESH:D006323', (166, 172))	('Wee1', 'Gene', '7465', (121, 125))	('MLN4924', 'Chemical', 'MESH:C539933', (34, 41))	('accumulation', 'PosReg', (54, 66))	('p27', 'Gene', '3429', (113, 116))	('p27', 'Gene', (113, 116))	('CRL', 'Gene', '133396', (82, 85))
163483	28717191	MLN4924 also induced anti-migration and anti-invasion by activating E-cadherin and repressing Vimentin.	('MLN4924', 'Var', (0, 7))	('repressing', 'NegReg', (83, 93))	('Vimentin', 'Gene', (94, 102))	('Vimentin', 'cellular_component', 'GO:0045098', ('94', '102'))	('activating', 'PosReg', (57, 67))	('E-cadherin', 'Gene', (68, 78))	('E-cadherin', 'Gene', '999', (68, 78))	('Vimentin', 'cellular_component', 'GO:0045099', ('94', '102'))	('anti-invasion', 'CPA', (40, 53))	('Vimentin', 'Gene', '7431', (94, 102))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('anti-migration', 'CPA', (21, 35))	('cadherin', 'molecular_function', 'GO:0008014', ('70', '78'))	('induced', 'PosReg', (13, 20))
163484	28717191	Taken together, this study provides the first evidence that neddylation pathway is overactive in ccRCC and that MLN4924 induces dose-dependent anti-proliferation, anti-migration, anti-invasion in ccRCC cells.	('anti-migration', 'CPA', (163, 177))	('overactive', 'PosReg', (83, 93))	('neddylation pathway', 'Pathway', (60, 79))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('RCC', 'Disease', (198, 201))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('MLN4924', 'Chemical', 'MESH:C539933', (112, 119))	('anti-proliferation', 'CPA', (143, 161))	('RCC', 'Disease', (99, 102))	('anti-invasion', 'CPA', (179, 192))	('MLN4924', 'Var', (112, 119))
163485	28717191	The study thus indicates that MLN4924 has potential therapeutic value for the clinical treatment of renal cancer.	('renal cancer', 'Disease', (100, 112))	('MLN4924', 'Chemical', 'MESH:C539933', (30, 37))	('renal cancer', 'Disease', 'MESH:D007680', (100, 112))	('renal cancer', 'Phenotype', 'HP:0009726', (100, 112))	('MLN4924', 'Var', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
163497	28717191	Cullin neddylation leads to activation of Cullin-RING ligases (CRLs), the largest family of E3 ubiquitin ligases, which are responsible for ubiquitylation and degradation of many key signaling or regulatory proteins.	('Cullin', 'Gene', '143384', (42, 48))	('neddylation', 'Var', (7, 18))	('Cullin', 'Gene', '143384', (0, 6))	('signaling', 'biological_process', 'GO:0023052', ('183', '192'))	('CRL', 'Gene', (63, 66))	('degradation', 'biological_process', 'GO:0009056', ('159', '170'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('95', '104'))	('activation', 'PosReg', (28, 38))	('CRL', 'Gene', '133396', (63, 66))	('Cullin', 'Gene', (42, 48))	('Cullin', 'Gene', (0, 6))
163499	28717191	It is anticipated that deregulation of CRLs is associated with uncontrolled proliferative diseases such as cancer.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('CRL', 'Gene', '133396', (39, 42))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('associated', 'Reg', (47, 57))	('cancer', 'Disease', (107, 113))	('CRL', 'Gene', (39, 42))	('deregulation', 'Var', (23, 35))
163502	28717191	MLN4924 is a specific small molecule inhibitor of NAE and has been advanced into several phase I clinical trials for certain solid tumors and hematologic malignancies because of its significant anticancer efficacy in preclinical studies.	('hematologic malignancies', 'Disease', 'MESH:D019337', (142, 166))	('MLN4924', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (198, 204))	('hematologic malignancies', 'Disease', (142, 166))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumors', 'Disease', (131, 137))	('NAE', 'Chemical', 'MESH:C090359', (50, 53))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))
163503	28717191	The underlying mechanism of MLN4924 has been thought to be its inhibitory effects on NAE activities by binding to NAE to create a covalent Nedd8-MLN4924 adduct.	('MLN4924', 'Chemical', 'MESH:C539933', (145, 152))	('MLN4924', 'Var', (28, 35))	('binding', 'Interaction', (103, 110))	('binding', 'molecular_function', 'GO:0005488', ('103', '110'))	('NAE', 'Chemical', 'MESH:C090359', (114, 117))	('Nedd8', 'Gene', '4738', (139, 144))	('NAE', 'Chemical', 'MESH:C090359', (85, 88))	('Nedd8', 'Gene', (139, 144))	('MLN4924', 'Chemical', 'MESH:C539933', (28, 35))
163504	28717191	Consequently, MLN4924 efficiently blocks neddylation of all Cullins, leading to accumulation of their substrates, which in turn triggers DNA replication stress, DNA damage response, cell-cycle arrest, apoptosis, autophagy, and senescence, collectively suppressing the growth of cancer cells.	('arrest', 'Disease', 'MESH:D006323', (193, 199))	('DNA', 'MPA', (161, 164))	('DNA replication', 'MPA', (137, 152))	('cancer', 'Disease', (278, 284))	('autophagy', 'CPA', (212, 221))	('MLN4924', 'Chemical', 'MESH:C539933', (14, 21))	('Cullins', 'Gene', '8454', (60, 67))	('substrates', 'MPA', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('autophagy', 'biological_process', 'GO:0016236', ('212', '221'))	('blocks', 'NegReg', (34, 40))	('senescence', 'biological_process', 'GO:0010149', ('227', '237'))	('neddylation', 'Protein', (41, 52))	('DNA', 'cellular_component', 'GO:0005574', ('137', '140'))	('apoptosis', 'CPA', (201, 210))	('triggers', 'Reg', (128, 136))	('senescence', 'CPA', (227, 237))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('autophagy', 'biological_process', 'GO:0006914', ('212', '221'))	('arrest', 'Disease', (193, 199))	('Cullins', 'Gene', (60, 67))	('accumulation', 'PosReg', (80, 92))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('182', '199'))	('MLN4924', 'Var', (14, 21))	('DNA replication', 'biological_process', 'GO:0006260', ('137', '152'))	('DNA damage response', 'biological_process', 'GO:0006974', ('161', '180'))	('apoptosis', 'biological_process', 'GO:0097194', ('201', '210'))	('apoptosis', 'biological_process', 'GO:0006915', ('201', '210'))	('suppressing', 'NegReg', (252, 263))
163505	28717191	Neddylation pathway components and CRL1/SCF E3 ligase are potential anti-cancer biomarkers, to which MLN4924 could serve as a promising drug for cancer therapy.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('Neddylation pathway', 'Pathway', (0, 19))	('MLN4924', 'Chemical', 'MESH:C539933', (101, 108))	('SCF', 'Gene', (40, 43))	('CRL1', 'Gene', '9466', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('MLN4924', 'Var', (101, 108))	('SCF', 'Gene', '4254', (40, 43))	('CRL1', 'Gene', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('SCF', 'molecular_function', 'GO:0005173', ('40', '43'))
163506	28717191	In renal cancer, a cancer type highly resistant to chemotherapy, the efficacy of MLN4924 is unknown but may be a significant interest.	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('renal cancer', 'Disease', (3, 15))	('cancer', 'Disease', (19, 25))	('MLN4924', 'Chemical', 'MESH:C539933', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('renal cancer', 'Phenotype', 'HP:0009726', (3, 15))	('MLN4924', 'Var', (81, 88))	('renal cancer', 'Disease', 'MESH:D007680', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
163507	28717191	In this study, our data showed that MLN4924 markedly inhibited the growth of renal cancer cells by blocking Cullin1 neddylation and subsequent accumulation their substrates.	('Cullin1', 'Gene', (108, 115))	('accumulation', 'PosReg', (143, 155))	('inhibited', 'NegReg', (53, 62))	('renal cancer', 'Disease', 'MESH:D007680', (77, 89))	('renal cancer', 'Phenotype', 'HP:0009726', (77, 89))	('MLN4924', 'Chemical', 'MESH:C539933', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('substrates', 'MPA', (162, 172))	('MLN4924', 'Var', (36, 43))	('Cullin1', 'Gene', '8454', (108, 115))	('renal cancer', 'Disease', (77, 89))	('blocking', 'NegReg', (99, 107))	('neddylation', 'MPA', (116, 127))
163509	28717191	What's more, we found that MLN4924 blocked migration of renal cancer cells through upregulating E-cadherin and repressing of Vimentin.	('migration of renal cancer', 'Disease', 'MESH:D007680', (43, 68))	('repressing', 'NegReg', (111, 121))	('MLN4924', 'Var', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Vimentin', 'Gene', (125, 133))	('Vimentin', 'cellular_component', 'GO:0045098', ('125', '133'))	('cadherin', 'molecular_function', 'GO:0008014', ('98', '106'))	('upregulating', 'PosReg', (83, 95))	('Vimentin', 'Gene', '7431', (125, 133))	('E-cadherin', 'Gene', (96, 106))	('renal cancer', 'Phenotype', 'HP:0009726', (56, 68))	('blocked', 'NegReg', (35, 42))	('MLN4924', 'Chemical', 'MESH:C539933', (27, 34))	('Vimentin', 'cellular_component', 'GO:0045099', ('125', '133'))	('migration of renal cancer', 'Disease', (43, 68))	('E-cadherin', 'Gene', '999', (96, 106))
163510	28717191	Collectively, our study demonstrated that MLN4924 effectively suppressed proliferation, survival and migration of renal cancer cells.	('survival', 'CPA', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('MLN4924', 'Var', (42, 49))	('proliferation', 'CPA', (73, 86))	('renal cancer', 'Phenotype', 'HP:0009726', (114, 126))	('suppressed', 'NegReg', (62, 72))	('migration of renal cancer', 'Disease', (101, 126))	('migration of renal cancer', 'Disease', 'MESH:D007680', (101, 126))	('MLN4924', 'Chemical', 'MESH:C539933', (42, 49))
163518	28717191	Given that there has been no previous studies on a potential correlation between Cullin1 neddylation and sensitivity to MLN4924 in renal cancer cells, we firstly tested four renal cancer lines, ACHN, OSRC2, 786-O and A498 for their response to MLN4924 in Cullin1 neddylation.	('MLN4924', 'Chemical', 'MESH:C539933', (244, 251))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tested', 'Reg', (162, 168))	('renal cancer', 'Disease', 'MESH:D007680', (174, 186))	('MLN4924', 'Var', (244, 251))	('Cullin1', 'Gene', '8454', (81, 88))	('renal cancer', 'Phenotype', 'HP:0009726', (174, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('ACHN', 'Gene', (194, 198))	('Cullin1', 'Gene', (81, 88))	('renal cancer', 'Disease', (131, 143))	('MLN4924', 'Chemical', 'MESH:C539933', (120, 127))	('renal cancer', 'Disease', (174, 186))	('Cullin1', 'Gene', '8454', (255, 262))	('renal cancer', 'Phenotype', 'HP:0009726', (131, 143))	('ACHN', 'Gene', '55323', (194, 198))	('renal cancer', 'Disease', 'MESH:D007680', (131, 143))	('Cullin1', 'Gene', (255, 262))
163519	28717191	As shown in Figs 1c,d and S1a,b, MLN4924 indeed caused a concentration dose-dependent inactivation of Cullin1 neddylation in all four renal cancer cells, as evidenced by reduced levels of neddylated Cullin1.	('renal cancer', 'Disease', 'MESH:D007680', (134, 146))	('MLN4924', 'Chemical', 'MESH:C539933', (33, 40))	('neddylation', 'MPA', (110, 121))	('renal cancer', 'Phenotype', 'HP:0009726', (134, 146))	('Cullin1', 'Gene', '8454', (102, 109))	('inactivation', 'NegReg', (86, 98))	('reduced', 'NegReg', (170, 177))	('MLN4924', 'Var', (33, 40))	('Cullin1', 'Gene', '8454', (199, 206))	('levels', 'MPA', (178, 184))	('Cullin1', 'Gene', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('renal cancer', 'Disease', (134, 146))	('Cullin1', 'Gene', (199, 206))
163520	28717191	We futher detected the total Nedd8 and found that the expression of Nedd8 was markedly enhanced in the MLN4924-treated cells compared to the controls (Fig.1c,d).	('expression', 'MPA', (54, 64))	('Nedd8', 'Gene', '4738', (68, 73))	('Nedd8', 'Gene', (68, 73))	('MLN4924-treated', 'Var', (103, 118))	('enhanced', 'PosReg', (87, 95))	('Nedd8', 'Gene', '4738', (29, 34))	('Nedd8', 'Gene', (29, 34))	('MLN4924', 'Chemical', 'MESH:C539933', (103, 110))
163521	28717191	Furthermore, MLN4924 also caused a time dose-dependent inactivation of neddylated Cullin1 signal and upregulation of Nedd8 (Fig.	('upregulation', 'PosReg', (101, 113))	('Nedd8', 'Gene', '4738', (117, 122))	('inactivation', 'NegReg', (55, 67))	('Cullin1', 'Gene', '8454', (82, 89))	('Nedd8', 'Gene', (117, 122))	('Cullin1', 'Gene', (82, 89))	('MLN4924', 'Chemical', 'MESH:C539933', (13, 20))	('MLN4924', 'Var', (13, 20))
163522	28717191	These results collectively indicates that inhibition of Cullin1 neddylation by MLN4924 is effective in human renal cancer cells.	('MLN4924', 'Chemical', 'MESH:C539933', (79, 86))	('renal cancer', 'Disease', 'MESH:D007680', (109, 121))	('Cullin1', 'Gene', (56, 63))	('human', 'Species', '9606', (103, 108))	('neddylation', 'Protein', (64, 75))	('MLN4924', 'Var', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('renal cancer', 'Disease', (109, 121))	('Cullin1', 'Gene', '8454', (56, 63))	('renal cancer', 'Phenotype', 'HP:0009726', (109, 121))
163523	28717191	We next evaluated the ability of MLN4924 to reduce cell viability in vitro by treating the human renal cancer cell lines with serial dilutions of MLN4924 (0.1-1 muM) for 3 days.	('MLN4924', 'Chemical', 'MESH:C539933', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('muM', 'Gene', (161, 164))	('MLN4924', 'Var', (146, 153))	('MLN4924', 'Chemical', 'MESH:C539933', (33, 40))	('renal cancer', 'Disease', (97, 109))	('MLN4924', 'Var', (33, 40))	('renal cancer', 'Phenotype', 'HP:0009726', (97, 109))	('renal cancer', 'Disease', 'MESH:D007680', (97, 109))	('muM', 'Gene', '56925', (161, 164))	('human', 'Species', '9606', (91, 96))
163524	28717191	Indeed, 3 days of MLN4924 treatment showed a marked and dose-dependent reduction of cell viability in all four renal cancer cells (Fig.	('MLN4924', 'Chemical', 'MESH:C539933', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('reduction', 'NegReg', (71, 80))	('MLN4924', 'Var', (18, 25))	('renal cancer', 'Disease', (111, 123))	('cell viability', 'CPA', (84, 98))	('renal cancer', 'Phenotype', 'HP:0009726', (111, 123))	('renal cancer', 'Disease', 'MESH:D007680', (111, 123))
163525	28717191	As a matter of fact, MLN4924 effect was very potent, but the drug sensitivity seems different in the four renal cancer cells.	('renal cancer', 'Disease', (106, 118))	('renal cancer', 'Disease', 'MESH:D007680', (106, 118))	('renal cancer', 'Phenotype', 'HP:0009726', (106, 118))	('drug sensitivity', 'Phenotype', 'HP:0020174', (61, 77))	('MLN4924', 'Chemical', 'MESH:C539933', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('MLN4924 effect', 'Var', (21, 35))
163526	28717191	Notably, 1 muM MLN4924 almost completely inhibited cell viability in ACHN and 786-O cells, the effect on A498 and OSRC2 were comparably weak.	('ACHN', 'Gene', (69, 73))	('muM', 'Gene', (11, 14))	('MLN4924', 'Chemical', 'MESH:C539933', (15, 22))	('ACHN', 'Gene', '55323', (69, 73))	('inhibited', 'NegReg', (41, 50))	('MLN4924', 'Var', (15, 22))	('muM', 'Gene', '56925', (11, 14))
163527	28717191	Considering that ACHN cell line was derived from metastatic renal adenocarcinoma, it indicated that MLN4924 may intend to be more efficient and sensltive to treat invasive renal cancer.We chose to perform subsequent experiments on ACHN and A498 cells, as the former are more susceptible to MLN4924 treatment, while the latter are more resistant.	('ACHN', 'Gene', '55323', (231, 235))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('ACHN', 'Gene', (17, 21))	('ACHN', 'Gene', (231, 235))	('renal adenocarcinoma', 'Disease', 'MESH:C538614', (60, 80))	('ACHN', 'Gene', '55323', (17, 21))	('MLN4924', 'Chemical', 'MESH:C539933', (290, 297))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('renal cancer', 'Phenotype', 'HP:0009726', (172, 184))	('MLN4924', 'Var', (290, 297))	('renal adenocarcinoma', 'Disease', (60, 80))	('invasive renal cancer', 'Disease', (163, 184))	('invasive renal cancer', 'Disease', 'MESH:D007680', (163, 184))	('renal adenocarcinoma', 'Phenotype', 'HP:0005584', (60, 80))	('MLN4924', 'Chemical', 'MESH:C539933', (100, 107))
163528	28717191	We further carried out clonogenic assays to determine the long-term anti-proliferative effects of MLN4924 in ACHN and A498 cells.	('ACHN', 'Gene', '55323', (109, 113))	('ACHN', 'Gene', (109, 113))	('anti-proliferative effects', 'MPA', (68, 94))	('MLN4924', 'Chemical', 'MESH:C539933', (98, 105))	('MLN4924', 'Var', (98, 105))
163529	28717191	Twelve days of MLN4924 treatment strongly inhibited clone formation in a dose-dependent manner in both cell lines (Fig.	('clone formation', 'CPA', (52, 67))	('MLN4924', 'Chemical', 'MESH:C539933', (15, 22))	('inhibited', 'NegReg', (42, 51))	('formation', 'biological_process', 'GO:0009058', ('58', '67'))	('MLN4924', 'Var', (15, 22))
163530	28717191	Specifically, 0.01 muM MLN4924 reduced clone numbers, and 0.1 muM MLN4924 completely blocked clone formation.	('muM', 'Gene', '56925', (62, 65))	('muM', 'Gene', (19, 22))	('clone numbers', 'CPA', (39, 52))	('clone formation', 'CPA', (93, 108))	('reduced', 'NegReg', (31, 38))	('muM', 'Gene', (62, 65))	('MLN4924', 'Chemical', 'MESH:C539933', (23, 30))	('blocked', 'NegReg', (85, 92))	('0.1', 'Var', (58, 61))	('MLN4924', 'Var', (23, 30))	('MLN4924', 'Chemical', 'MESH:C539933', (66, 73))	('muM', 'Gene', '56925', (19, 22))	('formation', 'biological_process', 'GO:0009058', ('99', '108'))	('MLN4924', 'Var', (66, 73))
163531	28717191	Taken together, these findings demonstrate that inhibiting the neddylation pathway with MLN4924 effectively reduces survival and growth of renal cancer cells.	('renal cancer', 'Disease', 'MESH:D007680', (139, 151))	('survival', 'CPA', (116, 124))	('inhibiting', 'NegReg', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('reduces', 'NegReg', (108, 115))	('MLN4924', 'Chemical', 'MESH:C539933', (88, 95))	('renal cancer', 'Disease', (139, 151))	('MLN4924', 'Var', (88, 95))	('neddylation pathway', 'Pathway', (63, 82))	('renal cancer', 'Phenotype', 'HP:0009726', (139, 151))	('growth', 'CPA', (129, 135))
163532	28717191	To determine the mechanisms underlying MLN4924-induced inhibition, we treated renal cancer cells with three sub-toxic concentrations of MLN4924 (0, 0.5, 1, 1.5 muM) for 12 hrs and detected the effects on levels of tumor-suppressive CRLs substrates using western blotting analysis.	('muM', 'Gene', (160, 163))	('renal cancer', 'Disease', 'MESH:D007680', (78, 90))	('CRL', 'Gene', '133396', (232, 235))	('renal cancer', 'Phenotype', 'HP:0009726', (78, 90))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('MLN4924', 'Chemical', 'MESH:C539933', (136, 143))	('MLN4924', 'Chemical', 'MESH:C539933', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('MLN4924', 'Var', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('MLN4924-induced', 'Var', (39, 54))	('tumor', 'Disease', (214, 219))	('muM', 'Gene', '56925', (160, 163))	('CRL', 'Gene', (232, 235))	('renal cancer', 'Disease', (78, 90))
163533	28717191	When the CRL E3 ligase function was inhibited by MLN4924, the degradation of CRLs substrates would also be inhibited.	('function', 'MPA', (23, 31))	('CRL', 'Gene', '133396', (9, 12))	('inhibited', 'NegReg', (36, 45))	('MLN4924', 'Var', (49, 56))	('CRL', 'Gene', '133396', (77, 80))	('degradation', 'biological_process', 'GO:0009056', ('62', '73'))	('CRL', 'Gene', (9, 12))	('MLN4924', 'Chemical', 'MESH:C539933', (49, 56))	('CRL', 'Gene', (77, 80))	('inhibited', 'NegReg', (107, 116))
163534	28717191	Indeed, MLN4924 treatment led to rapid accumulation of a panel of CRLs substrates, including p27, p21 and Wee1 (Fig.	('Wee1', 'Gene', '7465', (106, 110))	('MLN4924', 'Chemical', 'MESH:C539933', (8, 15))	('p21', 'Gene', '644914', (98, 101))	('p27', 'Gene', (93, 96))	('CRL', 'Gene', (66, 69))	('p27', 'Gene', '3429', (93, 96))	('MLN4924 treatment', 'Var', (8, 25))	('p21', 'Gene', (98, 101))	('CRL', 'Gene', '133396', (66, 69))	('Wee1', 'Gene', (106, 110))	('accumulation', 'PosReg', (39, 51))
163536	28717191	It is noteworthy that MLN4924 increased p27, p21 and Wee1 levels very sharply and rapidly, even at a low concentration.	('p21', 'Gene', (45, 48))	('p21', 'Gene', '644914', (45, 48))	('MLN4924', 'Chemical', 'MESH:C539933', (22, 29))	('MLN4924', 'Var', (22, 29))	('increased', 'PosReg', (30, 39))	('Wee1', 'Gene', '7465', (53, 57))	('Wee1', 'Gene', (53, 57))	('p27', 'Gene', '3429', (40, 43))	('p27', 'Gene', (40, 43))
163537	28717191	MLN4924 decreased the turnover of p27, p21 and Wee1, thereby leading to an accumulation of their protein levels.	('MLN4924', 'Var', (0, 7))	('p21', 'Gene', '644914', (39, 42))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('p27', 'Gene', '3429', (34, 37))	('p27', 'Gene', (34, 37))	('protein levels', 'MPA', (97, 111))	('p21', 'Gene', (39, 42))	('decreased', 'NegReg', (8, 17))	('Wee1', 'Gene', (47, 51))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('turnover', 'MPA', (22, 30))	('accumulation', 'PosReg', (75, 87))	('Wee1', 'Gene', '7465', (47, 51))
163538	28717191	The same effects of MLN4924 on CRLs substrates were observed in all the four kind of renal cancer cells.	('MLN4924', 'Var', (20, 27))	('renal cancer', 'Phenotype', 'HP:0009726', (85, 97))	('renal cancer', 'Disease', 'MESH:D007680', (85, 97))	('CRL', 'Gene', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('MLN4924', 'Chemical', 'MESH:C539933', (20, 27))	('CRL', 'Gene', '133396', (31, 34))	('renal cancer', 'Disease', (85, 97))
163539	28717191	These results indicate that inhibition of Cullin neddylation by MLN4924 causes accumulation of tumor suppressive proteins in renal cancer cells.	('Cullin', 'Gene', '143384', (42, 48))	('accumulation', 'PosReg', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('renal cancer', 'Disease', (125, 137))	('inhibition', 'NegReg', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('MLN4924', 'Chemical', 'MESH:C539933', (64, 71))	('renal cancer', 'Phenotype', 'HP:0009726', (125, 137))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('Cullin', 'Gene', (42, 48))	('renal cancer', 'Disease', 'MESH:D007680', (125, 137))	('MLN4924', 'Var', (64, 71))	('tumor', 'Disease', (95, 100))
163540	28717191	Since MLN4924 increased the levels of several critical cell cycle regulators, including p21, Wee1 and p27, we next examined whether these alterations resulted in cell cycle arrest in renal caner cells.	('levels', 'MPA', (28, 34))	('increased', 'PosReg', (14, 23))	('MLN4924', 'Var', (6, 13))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (162, 179))	('p27', 'Gene', '3429', (102, 105))	('p27', 'Gene', (102, 105))	('cell cycle', 'biological_process', 'GO:0007049', ('55', '65'))	('Wee1', 'Gene', (93, 97))	('arrest', 'Disease', 'MESH:D006323', (173, 179))	('Wee1', 'Gene', '7465', (93, 97))	('resulted', 'Reg', (150, 158))	('p21', 'Gene', (88, 91))	('arrest', 'Disease', (173, 179))	('MLN4924', 'Chemical', 'MESH:C539933', (6, 13))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('162', '179'))	('p21', 'Gene', '644914', (88, 91))
163541	28717191	MLN4924 increased the population of cells in the G2 phase while reducing the S phase population in ACHN cell line, which seems to be more sensitive to the treatment of MLN4924.	('MLN4924', 'Var', (0, 7))	('reducing', 'NegReg', (64, 72))	('G2 phase', 'biological_process', 'GO:0051319', ('49', '57'))	('ACHN', 'Gene', '55323', (99, 103))	('S phase', 'biological_process', 'GO:0051320', ('77', '84'))	('increased', 'PosReg', (8, 17))	('ACHN', 'Gene', (99, 103))	('MLN4924', 'Chemical', 'MESH:C539933', (168, 175))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('MLN4924', 'Var', (168, 175))
163542	28717191	To evaluate whether MLN4924 might cause DNA damage in renal cancer cells, we examined the levels of gamma-H2AX (phosphorylated H2AX (S139)), a typical bio-marker of DNA damage.	('MLN4924', 'Var', (20, 27))	('MLN4924', 'Chemical', 'MESH:C539933', (20, 27))	('H2AX', 'Gene', '3014', (127, 131))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('H2AX', 'Gene', '3014', (106, 110))	('H2AX', 'Gene', (106, 110))	('renal cancer', 'Disease', (54, 66))	('DNA', 'cellular_component', 'GO:0005574', ('165', '168'))	('H2AX', 'Gene', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('renal cancer', 'Disease', 'MESH:D007680', (54, 66))	('renal cancer', 'Phenotype', 'HP:0009726', (54, 66))
163543	28717191	After MLN4924 treatment, there was an marked increase in gamma-H2AX levels in renal cancer cell lines, compared with DMSO control.	('H2AX', 'Gene', (63, 67))	('MLN4924', 'Var', (6, 13))	('renal cancer', 'Disease', 'MESH:D007680', (78, 90))	('renal cancer', 'Phenotype', 'HP:0009726', (78, 90))	('H2AX', 'Gene', '3014', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('MLN4924', 'Chemical', 'MESH:C539933', (6, 13))	('renal cancer', 'Disease', (78, 90))	('DMSO', 'Chemical', 'MESH:D004121', (117, 121))	('increase', 'PosReg', (45, 53))
163544	28717191	We thus perform statistical analysis to validate the levels of gamma-H2AX and MLN4924 treatment upregulated the expression of gamma-H2AX (Fig.	('H2AX', 'Gene', (69, 73))	('H2AX', 'Gene', '3014', (132, 136))	('H2AX', 'Gene', (132, 136))	('MLN4924', 'Chemical', 'MESH:C539933', (78, 85))	('upregulated', 'PosReg', (96, 107))	('MLN4924 treatment', 'Var', (78, 95))	('H2AX', 'Gene', '3014', (69, 73))
163545	28717191	Immunofluorescence staining further confirmed that MLN4924 substantially increased gamma-H2AX fluorescence in the ACHN cell lines as compared with DMSO control (Fig.	('increased', 'PosReg', (73, 82))	('ACHN', 'Gene', '55323', (114, 118))	('MLN4924', 'Var', (51, 58))	('ACHN', 'Gene', (114, 118))	('DMSO', 'Chemical', 'MESH:D004121', (147, 151))	('H2AX', 'Gene', '3014', (89, 93))	('MLN4924', 'Chemical', 'MESH:C539933', (51, 58))	('H2AX', 'Gene', (89, 93))
163546	28717191	To confirm the cooperative DNA damaging properties of MLN4924, we conducted alkaline comet assays to quantify the impact of drug treatment on the tail moment in ACHN cells.	('MLN4924', 'Chemical', 'MESH:C539933', (54, 61))	('ACHN', 'Gene', '55323', (161, 165))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))	('ACHN', 'Gene', (161, 165))	('MLN4924', 'Var', (54, 61))	('comet', 'Species', '302767', (85, 90))
163547	28717191	Our results were consistent with those of our gamma-H2AX immunocyto-chemistry analyses in that exposure to MLN4924 induced higher levels of DNA damage than untreated control (Fig.	('MLN4924', 'Chemical', 'MESH:C539933', (107, 114))	('H2AX', 'Gene', (52, 56))	('MLN4924', 'Var', (107, 114))	('higher', 'PosReg', (123, 129))	('DNA damage', 'MPA', (140, 150))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('H2AX', 'Gene', '3014', (52, 56))
163548	28717191	These data collectively showed that MLN4924 triggered DNA damage in renal cancer cells, and we speculated that MLN4924-induced DNA damage might be a common response to the upregulation of Wee1, p21 and p27.	('MLN4924', 'Chemical', 'MESH:C539933', (111, 118))	('renal cancer', 'Disease', 'MESH:D007680', (68, 80))	('renal cancer', 'Phenotype', 'HP:0009726', (68, 80))	('p27', 'Gene', '3429', (202, 205))	('p27', 'Gene', (202, 205))	('MLN4924', 'Chemical', 'MESH:C539933', (36, 43))	('DNA damage', 'MPA', (54, 64))	('MLN4924-induced', 'Var', (111, 126))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('MLN4924', 'Var', (36, 43))	('p21', 'Gene', (194, 197))	('Wee1', 'Gene', (188, 192))	('renal cancer', 'Disease', (68, 80))	('p21', 'Gene', '644914', (194, 197))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('Wee1', 'Gene', '7465', (188, 192))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))
163549	28717191	Because MLN4924 induced notable occurrence of DNA damage, we next examined the apoptotic effect of MLN4924 in renal cancer cell lines by using Annexin V-FITC/PI labeling flow cytometry.	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('MLN4924', 'Chemical', 'MESH:C539933', (8, 15))	('Annexin V', 'Gene', '308', (143, 152))	('Annexin V', 'Gene', (143, 152))	('DNA damage', 'MPA', (46, 56))	('FITC', 'Chemical', 'MESH:D016650', (153, 157))	('renal cancer', 'Disease', (110, 122))	('MLN4924', 'Var', (8, 15))	('MLN4924', 'Chemical', 'MESH:C539933', (99, 106))	('renal cancer', 'Disease', 'MESH:D007680', (110, 122))	('renal cancer', 'Phenotype', 'HP:0009726', (110, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('MLN4924', 'Var', (99, 106))
163550	28717191	4a and b, treatment with MLN4924 at 1 muM for 12 h induced apoptosis in 26.45% of ACHN cells, and in 28.35% of A498 cells.	('apoptosis', 'biological_process', 'GO:0097194', ('59', '68'))	('MLN4924', 'Var', (25, 32))	('apoptosis', 'biological_process', 'GO:0006915', ('59', '68'))	('muM', 'Gene', '56925', (38, 41))	('ACHN', 'Gene', '55323', (82, 86))	('muM', 'Gene', (38, 41))	('apoptosis', 'CPA', (59, 68))	('ACHN', 'Gene', (82, 86))	('MLN4924', 'Chemical', 'MESH:C539933', (25, 32))
163551	28717191	Under these conditions, the levels of apoptosis-associated proteins, caspase-3, Noxa and Bax proteins, were also seen to increase by MLN4924 (Fig.	('Noxa', 'Gene', (80, 84))	('levels of apoptosis-associated proteins', 'MPA', (28, 67))	('caspase-3', 'Gene', '836', (69, 78))	('increase', 'PosReg', (121, 129))	('Bax', 'Gene', (89, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('38', '47'))	('apoptosis', 'biological_process', 'GO:0006915', ('38', '47'))	('MLN4924', 'Chemical', 'MESH:C539933', (133, 140))	('Noxa', 'Gene', '5366', (80, 84))	('MLN4924', 'Var', (133, 140))	('caspase-3', 'Gene', (69, 78))	('Bax', 'Gene', '581', (89, 92))
163552	28717191	To explore whether MLN4924 affects migration of renal cancer cells, we used the Transwell migration assays as functional readouts.	('MLN4924', 'Chemical', 'MESH:C539933', (19, 26))	('renal cancer', 'Phenotype', 'HP:0009726', (48, 60))	('MLN4924', 'Var', (19, 26))	('migration of renal cancer', 'Disease', (35, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('migration of renal cancer', 'Disease', 'MESH:D007680', (35, 60))
163553	28717191	ACHN has been observed to possess more significant cell migration and invasion, and we therefore determined the effects of MLN4924 on cell migration with this cell line by Transwell migration assay.	('cell migration', 'biological_process', 'GO:0016477', ('51', '65'))	('cell migration', 'CPA', (51, 65))	('ACHN', 'Gene', '55323', (0, 4))	('MLN4924', 'Chemical', 'MESH:C539933', (123, 130))	('ACHN', 'Gene', (0, 4))	('cell migration', 'biological_process', 'GO:0016477', ('134', '148'))	('MLN4924', 'Var', (123, 130))	('invasion', 'CPA', (70, 78))
163556	28717191	Indeed, MLN4924 significantly reduced cell migration in a dosage-dependent manner in ACHN cells (Fig.	('cell migration', 'CPA', (38, 52))	('MLN4924', 'Chemical', 'MESH:C539933', (8, 15))	('ACHN', 'Gene', '55323', (85, 89))	('MLN4924', 'Var', (8, 15))	('cell migration', 'biological_process', 'GO:0016477', ('38', '52'))	('ACHN', 'Gene', (85, 89))	('reduced', 'NegReg', (30, 37))
163557	28717191	MLN4924 increased the expression of E-cadherin, an epithelial biomarker in a dosage-dependent manner in both renal cancer cell lines.	('MLN4924', 'Var', (0, 7))	('renal cancer', 'Disease', 'MESH:D007680', (109, 121))	('E-cadherin', 'Gene', (36, 46))	('E-cadherin', 'Gene', '999', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('increased', 'PosReg', (8, 17))	('renal cancer', 'Disease', (109, 121))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('renal cancer', 'Phenotype', 'HP:0009726', (109, 121))	('expression', 'MPA', (22, 32))
163559	28717191	To determine whether altered degradation of E-cadherin could be responsible for its accumulation upon MLN4924, we measured protein half-life of E-cadherin by blocking new protein synthesis using cycloheximide (CHX) and found that MLN4924 had minimal effect on E-cadherin degradation (Fig.	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('degradation', 'biological_process', 'GO:0009056', ('29', '40'))	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('E-cadherin', 'Gene', (260, 270))	('E-cadherin', 'Gene', '999', (260, 270))	('MLN4924', 'Chemical', 'MESH:C539933', (102, 109))	('new protein synthesis', 'MPA', (167, 188))	('E-cadherin', 'Gene', (44, 54))	('E-cadherin', 'Gene', '999', (44, 54))	('cadherin', 'molecular_function', 'GO:0008014', ('262', '270'))	('MLN4924', 'Var', (230, 237))	('cadherin', 'molecular_function', 'GO:0008014', ('146', '154'))	('E-cadherin', 'Gene', (144, 154))	('E-cadherin', 'Gene', '999', (144, 154))	('cadherin', 'molecular_function', 'GO:0008014', ('46', '54'))	('CHX', 'Chemical', 'MESH:D003513', (210, 213))	('cycloheximide', 'Chemical', 'MESH:D003513', (195, 208))	('MLN4924', 'Var', (102, 109))	('degradation', 'biological_process', 'GO:0009056', ('271', '282'))	('blocking', 'NegReg', (158, 166))	('protein', 'MPA', (123, 130))	('protein synthesis', 'biological_process', 'GO:0006412', ('171', '188'))	('MLN4924', 'Chemical', 'MESH:C539933', (230, 237))	('accumulation', 'PosReg', (84, 96))
163560	28717191	We next determined potential effect in E-cadherin transcription and found that MLN4924 dramatically increased E-cadherin mRNA level in a dosage-dependent manner (Fig.	('MLN4924', 'Chemical', 'MESH:C539933', (79, 86))	('increased', 'PosReg', (100, 109))	('E-cadherin', 'Gene', (39, 49))	('E-cadherin', 'Gene', '999', (39, 49))	('MLN4924', 'Var', (79, 86))	('transcription', 'biological_process', 'GO:0006351', ('50', '63'))	('cadherin', 'molecular_function', 'GO:0008014', ('112', '120'))	('cadherin', 'molecular_function', 'GO:0008014', ('41', '49'))	('E-cadherin', 'Gene', (110, 120))	('E-cadherin', 'Gene', '999', (110, 120))
163561	28717191	5d), suggesting the transcriptional activation is accountable for its accumulation upon MLN4924 treatment.	('MLN4924', 'Var', (88, 95))	('accumulation', 'PosReg', (70, 82))	('MLN4924', 'Chemical', 'MESH:C539933', (88, 95))	('transcriptional', 'MPA', (20, 35))
163562	28717191	Taken together, our results show that MLN4924-induced suppression of cell migration is likely mediated by transcriptional upregulation of E-cadherin.	('MLN4924-induced', 'Var', (38, 53))	('cadherin', 'molecular_function', 'GO:0008014', ('140', '148'))	('cell migration', 'biological_process', 'GO:0016477', ('69', '83'))	('cell migration', 'CPA', (69, 83))	('upregulation', 'PosReg', (122, 134))	('suppression', 'NegReg', (54, 65))	('MLN4924', 'Chemical', 'MESH:C539933', (38, 45))	('E-cadherin', 'Gene', (138, 148))	('E-cadherin', 'Gene', '999', (138, 148))
163571	28717191	Recent studies have shown targeting CRL via inhibiting neddylation pathway by a small molecule inhibitor MLN4924 is an effective anticancer approach, as demonstrated in both preclinical and clinical settings.	('inhibiting', 'NegReg', (44, 54))	('neddylation pathway', 'Pathway', (55, 74))	('CRL', 'Gene', '133396', (36, 39))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('MLN4924', 'Chemical', 'MESH:C539933', (105, 112))	('cancer', 'Disease', (133, 139))	('CRL', 'Gene', (36, 39))	('MLN4924', 'Var', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
163572	28717191	In this study, we focused on whether MLN4924 could be therapeutically beneficial for human renal cancer.	('MLN4924', 'Chemical', 'MESH:C539933', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('renal cancer', 'Disease', (91, 103))	('MLN4924', 'Var', (37, 44))	('renal cancer', 'Phenotype', 'HP:0009726', (91, 103))	('human', 'Species', '9606', (85, 90))	('renal cancer', 'Disease', 'MESH:D007680', (91, 103))
163575	28717191	Together, these findings indicate that neddylation plays a key role in sustaining ccRCC survival and suggest that MLN4924 might help treat ccRCC in most patients.	('RCC', 'Disease', (141, 144))	('MLN4924', 'Chemical', 'MESH:C539933', (114, 121))	('patients', 'Species', '9606', (153, 161))	('treat', 'PosReg', (133, 138))	('MLN4924', 'Var', (114, 121))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
163576	28717191	We have further demonstrated that MLN4924 prominently reduces the neddylation modification of Cullin1 and the proliferation of several renal cancer cells.	('Cullin1', 'Gene', (94, 101))	('renal cancer', 'Phenotype', 'HP:0009726', (135, 147))	('MLN4924', 'Var', (34, 41))	('MLN4924', 'Chemical', 'MESH:C539933', (34, 41))	('neddylation modification', 'MPA', (66, 90))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('renal cancer', 'Disease', (135, 147))	('Cullin1', 'Gene', '8454', (94, 101))	('reduces', 'NegReg', (54, 61))	('renal cancer', 'Disease', 'MESH:D007680', (135, 147))
163579	28717191	There have been several lines of evidence from our study supportting the essential role of apoptosis in MLN4924-mediated anti-tumor activity.	('MLN4924', 'Chemical', 'MESH:C539933', (104, 111))	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('apoptosis', 'CPA', (91, 100))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('MLN4924-mediated', 'Var', (104, 120))	('tumor', 'Disease', (126, 131))
163580	28717191	This study has shown that MLN4924 treatment activates apoptosis signaling, including the cleavage of caspase3, Bax and pro-apoptotic BH3-only protein Noxa induced apoptotic signaling.	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('apoptosis signaling', 'biological_process', 'GO:0006915', ('54', '73'))	('Bax', 'Gene', (111, 114))	('Noxa', 'Gene', '5366', (150, 154))	('caspase3', 'Gene', (101, 109))	('Noxa', 'Gene', (150, 154))	('cleavage', 'MPA', (89, 97))	('MLN4924', 'Chemical', 'MESH:C539933', (26, 33))	('caspase3', 'Gene', '836', (101, 109))	('Bax', 'Gene', '581', (111, 114))	('signaling', 'biological_process', 'GO:0023052', ('173', '182'))	('activates', 'PosReg', (44, 53))	('apoptosis signaling', 'MPA', (54, 73))	('MLN4924', 'Var', (26, 33))	('apoptotic signaling', 'MPA', (163, 182))
163581	28717191	Previous studies have showed, in several other cancers, that the accumulation of the Noxa is the mainly mechanism that MLN4924-induced apoptosis.	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('Noxa', 'Gene', '5366', (85, 89))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('MLN4924', 'Chemical', 'MESH:C539933', (119, 126))	('Noxa', 'Gene', (85, 89))	('cancers', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))	('MLN4924-induced', 'Var', (119, 134))
163582	28717191	Hence, we speculate that Bcl-2 protein member Bax is also important for MLN4924-induced apoptosis.	('MLN4924-induced', 'Var', (72, 87))	('Bax', 'Gene', (46, 49))	('apoptosis', 'biological_process', 'GO:0006915', ('88', '97'))	('Bcl-2', 'Gene', (25, 30))	('Bcl-2', 'Gene', '596', (25, 30))	('Bax', 'Gene', '581', (46, 49))	('MLN4924', 'Chemical', 'MESH:C539933', (72, 79))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('apoptosis', 'biological_process', 'GO:0097194', ('88', '97'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('25', '30'))
163583	28717191	Therefore, our data support the conclusions of previous studies in other cancers that MLN4924 inhibits cell proliferation via multiple pathways.	('MLN4924', 'Var', (86, 93))	('cancers', 'Disease', (73, 80))	('cell proliferation', 'CPA', (103, 121))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('inhibits', 'NegReg', (94, 102))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('MLN4924', 'Chemical', 'MESH:C539933', (86, 93))	('cell proliferation', 'biological_process', 'GO:0008283', ('103', '121'))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
163584	28717191	Our experimental data have also clearly demonstrated that renal cancer cell lines vary in their sensitivity to MLN4924 treatment.	('MLN4924', 'Chemical', 'MESH:C539933', (111, 118))	('renal cancer', 'Disease', (58, 70))	('sensitivity', 'MPA', (96, 107))	('MLN4924', 'Var', (111, 118))	('renal cancer', 'Phenotype', 'HP:0009726', (58, 70))	('renal cancer', 'Disease', 'MESH:D007680', (58, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
163585	28717191	Amongst these cell lines, ACHN is the most sensitive to MLN4924.	('MLN4924', 'Var', (56, 63))	('ACHN', 'Gene', (26, 30))	('ACHN', 'Gene', '55323', (26, 30))	('MLN4924', 'Chemical', 'MESH:C539933', (56, 63))
163586	28717191	As shown in Figs 1c and 2b, a low concentration treatment of MLN4924 totally abolishes the activity of Cullin1 in ACHN cells, and dramatically inhibits the cell proliferation.	('Cullin1', 'Gene', (103, 110))	('inhibits', 'NegReg', (143, 151))	('ACHN', 'Gene', '55323', (114, 118))	('ACHN', 'Gene', (114, 118))	('abolishes', 'NegReg', (77, 86))	('activity', 'MPA', (91, 99))	('MLN4924', 'Chemical', 'MESH:C539933', (61, 68))	('cell proliferation', 'biological_process', 'GO:0008283', ('156', '174'))	('Cullin1', 'Gene', '8454', (103, 110))	('cell proliferation', 'CPA', (156, 174))	('MLN4924', 'Var', (61, 68))
163587	28717191	Since the ACHN cell line was derived from metastatic renal adenocarcinoma and is highly aggressive in nature, we speculate that MLN4924 is more efficient and in treating invasive and metastasized renal cancer.	('renal adenocarcinoma', 'Disease', 'MESH:C538614', (53, 73))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('MLN4924', 'Chemical', 'MESH:C539933', (128, 135))	('renal cancer', 'Phenotype', 'HP:0009726', (196, 208))	('MLN4924', 'Var', (128, 135))	('invasive and', 'Disease', (170, 182))	('ACHN', 'Gene', '55323', (10, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('renal adenocarcinoma', 'Disease', (53, 73))	('renal adenocarcinoma', 'Phenotype', 'HP:0005584', (53, 73))	('ACHN', 'Gene', (10, 14))	('metastasized renal cancer', 'Disease', (183, 208))	('metastasized renal cancer', 'Disease', 'MESH:D009362', (183, 208))
163588	28717191	Our study has further disclosed that MLN4924 suppressed migration of ccRCC via multiple mechanisms, by regulating key player protein E-cadherin at transcriptional levels.	('migration', 'CPA', (56, 65))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('E-cadherin', 'Gene', (133, 143))	('RCC', 'Disease', (71, 74))	('MLN4924', 'Chemical', 'MESH:C539933', (37, 44))	('suppressed', 'NegReg', (45, 55))	('cadherin', 'molecular_function', 'GO:0008014', ('135', '143'))	('regulating', 'Reg', (103, 113))	('E-cadherin', 'Gene', '999', (133, 143))	('MLN4924', 'Var', (37, 44))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))
163591	28717191	In contrast, Vimentin, a marker of mesenchymally-derived cells or cells undergoing an epithelial-to-mesenchymal transition (EMT) during both normal development and metastatic progression, can be down-regulated by MLN4924 treatment.	('Vimentin', 'Gene', '7431', (13, 21))	('Vimentin', 'cellular_component', 'GO:0045099', ('13', '21'))	('down-regulated', 'NegReg', (195, 209))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('86', '122'))	('EMT', 'biological_process', 'GO:0001837', ('124', '127'))	('MLN4924', 'Chemical', 'MESH:C539933', (213, 220))	('Vimentin', 'Gene', (13, 21))	('Vimentin', 'cellular_component', 'GO:0045098', ('13', '21'))	('MLN4924', 'Var', (213, 220))
163592	28717191	In summary, our study proposes the following working model: Through inhibiting neddylation E1, MLN4924 inactivates CRL by blocking Cullin neddylation, which is followed by accumulation of many CRL substrates in a cell type and context dependent manner.	('CRL', 'Gene', '133396', (193, 196))	('CRL', 'Gene', '133396', (115, 118))	('inhibiting', 'NegReg', (68, 78))	('neddylation E1', 'Protein', (79, 93))	('Cullin', 'Gene', (131, 137))	('inactivates', 'NegReg', (103, 114))	('MLN4924', 'Chemical', 'MESH:C539933', (95, 102))	('Cullin', 'Gene', '143384', (131, 137))	('CRL', 'Gene', (193, 196))	('MLN4924', 'Var', (95, 102))	('CRL', 'Gene', (115, 118))	('blocking', 'NegReg', (122, 130))
163594	28717191	The sustainable treatment of MLN4924 led to apoptosis of tumor cells with the upregulation of Noxa and Bax.	('Noxa', 'Gene', (94, 98))	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('apoptosis', 'CPA', (44, 53))	('Bax', 'Gene', '581', (103, 106))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('MLN4924', 'Chemical', 'MESH:C539933', (29, 36))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('upregulation', 'PosReg', (78, 90))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Noxa', 'Gene', '5366', (94, 98))	('MLN4924', 'Var', (29, 36))	('tumor', 'Disease', (57, 62))	('Bax', 'Gene', (103, 106))
163595	28717191	Finally, MLN4924 activates the expression of E-cadherin and inhibits Vimentin via a yet-to-be identified mechanism to remain cancer cells in an epithelial phenotype to prevent EMT.	('Vimentin', 'Gene', (69, 77))	('MLN4924', 'Chemical', 'MESH:C539933', (9, 16))	('Vimentin', 'cellular_component', 'GO:0045098', ('69', '77'))	('EMT', 'biological_process', 'GO:0001837', ('176', '179'))	('Vimentin', 'Gene', '7431', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('EMT', 'CPA', (176, 179))	('MLN4924', 'Var', (9, 16))	('Vimentin', 'cellular_component', 'GO:0045099', ('69', '77'))	('expression', 'MPA', (31, 41))	('cadherin', 'molecular_function', 'GO:0008014', ('47', '55'))	('inhibits', 'NegReg', (60, 68))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('activates', 'PosReg', (17, 26))	('E-cadherin', 'Gene', (45, 55))	('E-cadherin', 'Gene', '999', (45, 55))
163596	28717191	The final outcome of these comprehensive MLN4924 effect in ccRCC is effective suppression of proliferation, survival and migration.	('migration', 'CPA', (121, 130))	('MLN4924', 'Var', (41, 48))	('proliferation', 'CPA', (93, 106))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('survival', 'CPA', (108, 116))	('RCC', 'Disease', (61, 64))	('suppression', 'NegReg', (78, 89))	('MLN4924', 'Chemical', 'MESH:C539933', (41, 48))
163619	28717191	performed the main experimental work of MLN4924 anti-tumour promoting function study on the cellular.	('tumour', 'Disease', (53, 59))	('MLN4924', 'Chemical', 'MESH:C539933', (40, 47))	('MLN4924', 'Var', (40, 47))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (53, 59))
163623	31761563	First, cytosolic FBP2 antagonizes elevated glycolysis associated with the "Warburg effect", thereby inhibiting sarcoma cell proliferation.	('FBP2', 'Gene', (17, 21))	('sarcoma', 'Disease', 'MESH:D012509', (111, 118))	('glycolysis', 'MPA', (43, 53))	('sarcoma', 'Disease', (111, 118))	('inhibiting', 'NegReg', (100, 110))	('antagonizes', 'NegReg', (22, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('elevated', 'PosReg', (34, 42))	('glycolysis', 'biological_process', 'GO:0006096', ('43', '53'))	('cytosolic', 'Var', (7, 16))
163627	31761563	demonstrate that the loss of fructose-1,6-bisphosphatase 2 (FBP2) is a common metabolic feature of soft tissue sarcomas (STSs).	('loss', 'Var', (21, 25))	('fructose-1,6-bisphosphatase 2', 'Gene', '8789', (29, 58))	('sarcomas', 'Disease', 'MESH:D012509', (111, 119))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (99, 118))	('sarcomas', 'Phenotype', 'HP:0100242', (111, 119))	('STSs', 'Phenotype', 'HP:0030448', (121, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('sarcomas', 'Disease', (111, 119))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (99, 119))	('FBP2', 'Gene', (60, 64))
163628	31761563	Restoration of FBP2 in STS cells suppresses sarcoma growth through two mechanisms, including inhibiting glycolysis and restraining mitochondrial biogenesis by inhibiting c-Myc-driven transcriptional activity.	('suppresses', 'NegReg', (33, 43))	('c-Myc', 'Gene', '4609', (170, 175))	('sarcoma', 'Disease', 'MESH:D012509', (44, 51))	('Restoration', 'Var', (0, 11))	('glycolysis', 'biological_process', 'GO:0006096', ('104', '114'))	('c-Myc', 'Gene', (170, 175))	('sarcoma', 'Disease', (44, 51))	('restraining', 'NegReg', (119, 130))	('FBP2', 'Gene', (15, 19))	('sarcoma', 'Phenotype', 'HP:0100242', (44, 51))	('inhibiting', 'NegReg', (93, 103))	('inhibiting', 'NegReg', (159, 169))	('mitochondrial biogenesis', 'MPA', (131, 155))	('glycolysis', 'MPA', (104, 114))
163635	31761563	A broad array of oncogenes and tumor suppressors that regulate metabolic pathways are mutated in sarcomas, such as PIK3CA (catalytic subunit of phosphatidylinositol 3-kinase), TP53, and NF1.	('mutated', 'Var', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('metabolic pathways', 'Pathway', (63, 81))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('NF1', 'Gene', (186, 189))	('TP53', 'Gene', '7157', (176, 180))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('tumor', 'Disease', (31, 36))	('NF1', 'Gene', '4763', (186, 189))	('TP53', 'Gene', (176, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('sarcomas', 'Disease', (97, 105))	('PIK3CA', 'Gene', (115, 121))	('PIK3CA', 'Gene', '5290', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
163643	31761563	Several mechanisms are implicated in downregulating FBP1, including transcription factor repression, epigenetic silencing and proteasome degradation.	('proteasome', 'molecular_function', 'GO:0004299', ('126', '136'))	('proteasome', 'cellular_component', 'GO:0000502', ('126', '136'))	('transcription factor', 'molecular_function', 'GO:0000981', ('68', '88'))	('transcription', 'biological_process', 'GO:0006351', ('68', '81'))	('transcription', 'MPA', (68, 81))	('FBP1', 'Gene', '2203', (52, 56))	('proteasome degradation', 'biological_process', 'GO:1903009', ('126', '148'))	('repression', 'NegReg', (89, 99))	('epigenetic silencing', 'Var', (101, 121))	('proteasome degradation', 'MPA', (126, 148))	('downregulating', 'NegReg', (37, 51))	('FBP1', 'Gene', (52, 56))
163649	31761563	Isotope tracing and unbiased mass spectrometry analyses of liposarcoma, fibrosarcoma and UPS cells demonstrated that glycolysis and TCA cycle activity are inhibited by FBP2 restoration.	('fibrosarcoma', 'Phenotype', 'HP:0100244', (72, 84))	('fibrosarcoma', 'Disease', 'MESH:D005354', (72, 84))	('activity', 'MPA', (142, 150))	('TCA', 'Chemical', 'MESH:D014238', (132, 135))	('FBP2', 'Gene', (168, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('liposarcoma', 'Disease', (59, 70))	('restoration', 'Var', (173, 184))	('fibrosarcoma', 'Disease', (72, 84))	('inhibited', 'NegReg', (155, 164))	('glycolysis', 'biological_process', 'GO:0006096', ('117', '127'))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('TCA', 'Enzyme', (132, 135))	('TCA cycle', 'biological_process', 'GO:0006099', ('132', '141'))	('glycolysis', 'MPA', (117, 127))	('liposarcoma', 'Disease', 'MESH:D008080', (59, 70))	('liposarcoma', 'Phenotype', 'HP:0012034', (59, 70))
163650	31761563	Both FBP1 and FBP2 isozymes share a consensus nuclear localization sequence (NLS), and a nucleus-excluded FBP2 mutant has no effect on mitochondrial biogenesis and OXPHOS, indicating that nuclear FBP2 regulates mitochondrial function independent of its enzymatic activity.	('OXPHOS', 'MPA', (164, 170))	('FBP2', 'Gene', (106, 110))	('localization', 'biological_process', 'GO:0051179', ('54', '66'))	('mitochondrial function', 'MPA', (211, 233))	('FBP1', 'Gene', (5, 9))	('mutant', 'Var', (111, 117))	('nucleus', 'cellular_component', 'GO:0005634', ('89', '96'))	('mitochondrial biogenesis', 'MPA', (135, 159))	('FBP1', 'Gene', '2203', (5, 9))	('OXPHOS', 'biological_process', 'GO:0002082', ('164', '170'))	('regulates', 'Reg', (201, 210))
163664	31761563	In addition, FBP2 re-expression in SW872, HT1080 and KP250 cells dramatically impaired anchorage-independent growth in 3D soft agar colony assays (Figure 2B).	('SW872', 'CellLine', 'CVCL:1730', (35, 40))	('impaired', 'NegReg', (78, 86))	('HT1080', 'CellLine', 'CVCL:0317', (42, 48))	('anchorage-independent growth', 'CPA', (87, 115))	('re-expression', 'Var', (18, 31))	('FBP2', 'Gene', (13, 17))
163665	31761563	We also exploited a doxycycline (dox)-inducible system to restore FBP2 expression in LPS246 cells (LPS246 TetO-FBP2) and identified dox concentrations that produced FBP2 protein in LPS246 TetO-FBP2 cells comparable to control HSMM cells (Figure S3E).	('LPS246', 'Var', (181, 187))	('expression', 'MPA', (71, 81))	('doxycycline', 'Chemical', 'MESH:D004318', (20, 31))	('LPS246', 'Chemical', '-', (181, 187))	('dox', 'Chemical', 'MESH:D004318', (132, 135))	('FBP2', 'Gene', (66, 70))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('dox', 'Chemical', 'MESH:D004318', (33, 36))	('dox', 'Chemical', 'MESH:D004318', (20, 23))	('LPS246', 'Chemical', '-', (99, 105))	('LPS246', 'Chemical', '-', (85, 91))
163666	31761563	To further evaluate the role of FBP2 in tumor growth and maintenance in vivo, highly immunodeficient NSG mice were injected subcutaneously with LPS246 TetO-FBP2 cells and tumors allowed to grow to 100 mm3.	('immunodeficient', 'Disease', 'MESH:D007153', (85, 100))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('immunodeficient', 'Disease', (85, 100))	('LPS246', 'Chemical', '-', (144, 150))	('LPS246', 'Var', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (40, 45))	('mice', 'Species', '10090', (105, 109))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
163667	31761563	Subsequent dox-induced FBP2 expression decreased tumor growth (volume and mass) without affecting mouse body weight (Figure 2C-E, Figure S3F).	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mouse', 'Species', '10090', (98, 103))	('decreased tumor', 'Disease', 'MESH:D002303', (39, 54))	('decreased tumor', 'Disease', (39, 54))	('expression', 'Var', (28, 38))	('dox', 'Chemical', 'MESH:D004318', (11, 14))	('FBP2', 'Gene', (23, 27))
163672	31761563	Since FBP2 is a rate-limiting enzyme in gluconeogenesis, FBP2 re-expression is likely to antagonize glycolysis and therefore reduce glucose uptake.	('glucose uptake', 'MPA', (132, 146))	('glucose', 'Chemical', 'MESH:D005947', (132, 139))	('glycolysis', 'biological_process', 'GO:0006096', ('100', '110'))	('glucose uptake', 'biological_process', 'GO:0046323', ('132', '146'))	('reduce', 'NegReg', (125, 131))	('antagonize', 'NegReg', (89, 99))	('gluconeogenesis', 'biological_process', 'GO:0006094', ('40', '55'))	('glycolysis', 'MPA', (100, 110))	('re-expression', 'Var', (62, 75))	('FBP2', 'Gene', (57, 61))
163674	31761563	FBP2 significantly decreased glucose uptake and lactate secretion without affecting glutamine uptake in LPS224, LPS246, T1000, HT1080, and KP250 cells cultured in 10 mM glucose (Figure 3A-C).	('lactate secretion', 'biological_process', 'GO:0046722', ('48', '65'))	('glucose uptake', 'MPA', (29, 43))	('uptake', 'biological_process', 'GO:0098739', ('94', '100'))	('glucose uptake', 'biological_process', 'GO:0046323', ('29', '43'))	('FBP2', 'Gene', (0, 4))	('glucose', 'Chemical', 'MESH:D005947', (169, 176))	('glucose', 'Chemical', 'MESH:D005947', (29, 36))	('glutamine', 'Chemical', 'MESH:D005973', (84, 93))	('lactate secretion', 'MPA', (48, 65))	('uptake', 'biological_process', 'GO:0098657', ('94', '100'))	('LPS246', 'Var', (112, 118))	('HT1080', 'CellLine', 'CVCL:0317', (127, 133))	('decreased', 'NegReg', (19, 28))	('LPS224', 'Chemical', '-', (104, 110))	('LPS246', 'Chemical', '-', (112, 118))	('lactate', 'Chemical', 'MESH:D019344', (48, 55))
163676	31761563	Analysis of culture media confirmed reduced [1,2-13C]glucose uptake and M1- and M2-labeled 13C-lactate secretion in FBP2-expressing LPS246 cells (Figure 3E-F), indicating decreased conversion of glucose to lactate.	('13C-lactate', 'Chemical', '-', (91, 102))	('decreased', 'NegReg', (171, 180))	('lactate secretion', 'biological_process', 'GO:0046722', ('95', '112'))	('FBP2-expressing', 'Gene', (116, 131))	('LPS246', 'Var', (132, 138))	('glucose', 'Chemical', 'MESH:D005947', (53, 60))	('lactate', 'Chemical', 'MESH:D019344', (95, 102))	('glucose uptake', 'biological_process', 'GO:0046323', ('53', '67'))	('reduced', 'NegReg', (36, 43))	('lactate', 'Chemical', 'MESH:D019344', (206, 213))	('LPS246', 'Chemical', '-', (132, 138))	('conversion of glucose to lactate', 'MPA', (181, 213))	('1,2-13C', 'Chemical', '-', (45, 52))	('M2-labeled 13C-lactate secretion', 'MPA', (80, 112))	('glucose', 'Chemical', 'MESH:D005947', (195, 202))
163678	31761563	Interestingly, we found that FBP2 re-expression reduced PPP flux (Figure 3G), which is important for the synthesis of ribonucleotides and NADPH.	('synthesis', 'biological_process', 'GO:0009058', ('105', '114'))	('ribonucleotides', 'Chemical', 'MESH:D012265', (118, 133))	('reduced', 'NegReg', (48, 55))	('NADPH', 'Gene', (138, 143))	('NADPH', 'Gene', '1666', (138, 143))	('re-expression', 'Var', (34, 47))	('FBP2', 'Gene', (29, 33))	('PPP flux', 'MPA', (56, 64))
163682	31761563	In both cell lines, ectopic FBP2 expression significantly reduced steady-state abundance of metabolites in glycolysis (glucose-6-phosphate, pyruvate, lactate) (Figure S4A), serine metabolism (serine and glycine) (Figure S4B) and the TCA cycle (citrate, alpha-ketoglutarate, fumarate, malate, oxaloacetate) (Figure S4C).	('pyruvate', 'Chemical', 'MESH:D019289', (140, 148))	('lactate', 'Chemical', 'MESH:D019344', (150, 157))	('glycine', 'Chemical', 'MESH:D005998', (203, 210))	('malate', 'Chemical', 'MESH:C030298', (284, 290))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (253, 272))	('reduced', 'NegReg', (58, 65))	('citrate', 'Chemical', 'MESH:D019343', (244, 251))	('malate', 'MPA', (284, 290))	('TCA', 'Chemical', 'MESH:D014238', (233, 236))	('fumarate', 'Chemical', 'MESH:D005650', (274, 282))	('expression', 'Var', (33, 43))	('serine', 'Chemical', 'MESH:D012694', (192, 198))	('FBP2', 'Gene', (28, 32))	('glycolysis', 'biological_process', 'GO:0006096', ('107', '117'))	('oxaloacetate', 'Chemical', 'MESH:D062907', (292, 304))	('metabolism', 'biological_process', 'GO:0008152', ('180', '190'))	('ectopic', 'Var', (20, 27))	('glucose', 'Chemical', 'MESH:D005947', (119, 126))	('serine', 'Chemical', 'MESH:D012694', (173, 179))	('TCA cycle', 'biological_process', 'GO:0006099', ('233', '242'))
163684	31761563	To investigate whether the growth inhibitory effect of FBP2 is dependent on its enzymatic activity, we generated a catalytically inactive FBP2 mutant by replacing a glycine residue at position 260 with arginine (FBP2G260R) as previously described (Figure S5A).	('FBP2', 'Gene', (138, 142))	('replacing', 'Var', (153, 162))	('mutant', 'Var', (143, 149))	('glycine residue at position 260 with arginine', 'Mutation', 'p.R260G', (165, 210))
163685	31761563	Upon wild-type FBP2 and FBP2G260R expression at comparable levels in LPS246 cells (Figure S5B), FBP2G260R inhibited cell growth, although to a lesser extent than wild-type FBP2 (Figure S5C), implying that FBP2 has catalytic activity-independent cellular functions.	('catalytic activity', 'molecular_function', 'GO:0003824', ('214', '232'))	('cell growth', 'biological_process', 'GO:0016049', ('116', '127'))	('inhibited', 'NegReg', (106, 115))	('FBP2G260R', 'Var', (96, 105))	('LPS246', 'Chemical', '-', (69, 75))	('FBP2G260R', 'Gene', (24, 33))	('cell growth', 'CPA', (116, 127))
163688	31761563	By replacing four lysine residues in the NLS with alanine, we generated a nucleus-excluded form of FBP2 without disrupting its catalytic activity (Figure 4C-D), and FBP24KA expression in LPS246 cells decreased cell proliferation albeit, not as dramatically as wild-type FBP2, suggesting that nuclear FBP2 contributes functionally to its growth inhibitory properties (Figure 4E-F).	('FBP2', 'Gene', (99, 103))	('lysine', 'Chemical', 'MESH:D008239', (18, 24))	('cell proliferation', 'biological_process', 'GO:0008283', ('210', '228'))	('cell proliferation', 'CPA', (210, 228))	('decreased', 'NegReg', (200, 209))	('alanine', 'Chemical', 'MESH:D000409', (50, 57))	('catalytic activity', 'molecular_function', 'GO:0003824', ('127', '145'))	('FBP24KA', 'Var', (165, 172))	('LPS246', 'Chemical', '-', (187, 193))	('nucleus', 'cellular_component', 'GO:0005634', ('74', '81'))	('replacing', 'Var', (3, 12))
163693	31761563	We confirmed differential expression of several genes involved in OXPHOS (MT-ND1, MT-MYB, MT-CO1 and MT-ATP6) by qRT-PCR analysis and found that FBP2, but not FBP24KA, significantly decreased their expression (Figure 4J).	('MT-ND1', 'Gene', (74, 80))	('MT-CO1', 'Gene', (90, 96))	('decreased', 'NegReg', (182, 191))	('OXPHOS', 'biological_process', 'GO:0002082', ('66', '72'))	('MT-CO1', 'Gene', '4512', (90, 96))	('MT-ND1', 'Gene', '4535', (74, 80))	('FBP2', 'Var', (145, 149))	('MT-ATP6', 'Gene', (101, 108))	('expression', 'MPA', (198, 208))	('MT-ATP6', 'Gene', '4508', (101, 108))
163696	31761563	Decreased mitochondrial biogenesis in FBP2-expressing LPS246 cells was further confirmed by transmission electron microscopy, indicated by reduced number of mitochondria and swollen mitochondria with disorganized cristae (Figure 5D).	('reduced number of mitochondria', 'Phenotype', 'HP:0040013', (139, 169))	('cristae', 'cellular_component', 'GO:0030061', ('213', '220'))	('FBP2-expressing', 'Gene', (38, 53))	('mitochondria', 'cellular_component', 'GO:0005739', ('157', '169'))	('Decreased', 'NegReg', (0, 9))	('number of mitochondria', 'MPA', (147, 169))	('mitochondria', 'cellular_component', 'GO:0005739', ('182', '194'))	('mitochondrial biogenesis', 'MPA', (10, 34))	('reduced', 'NegReg', (139, 146))	('LPS246', 'Var', (54, 60))	('LPS246', 'Chemical', '-', (54, 60))
163697	31761563	Consistently, LPS246 xenograft sections exhibited reduced staining of Vdac (voltage-dependent anion channel) and Tomm20 (a constitutively expressed mitochondrial protein) in dox-treated tumors, supporting decreased mitochondrial mass caused by FBP2 expression (Figure 5E).	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('LPS246', 'Var', (14, 20))	('FBP2', 'Gene', (244, 248))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('LPS246', 'Chemical', '-', (14, 20))	('expression', 'Var', (249, 259))	('decreased mitochondrial mass', 'Phenotype', 'HP:0040013', (205, 233))	('staining', 'MPA', (58, 66))	('tumors', 'Disease', (186, 192))	('mitochondrial mass', 'MPA', (215, 233))	('decreased', 'NegReg', (205, 214))	('reduced', 'NegReg', (50, 57))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('dox', 'Chemical', 'MESH:D004318', (174, 177))	('Tomm20', 'Gene', '9804', (113, 119))	('Tomm20', 'Gene', (113, 119))
163699	31761563	Collectively, these data demonstrate that nuclear FBP2 inhibits mitochondrial biogenesis in LPS246 cells.	('mitochondrial biogenesis', 'MPA', (64, 88))	('inhibits', 'NegReg', (55, 63))	('FBP2', 'Gene', (50, 54))	('nuclear', 'Var', (42, 49))	('LPS246', 'Chemical', '-', (92, 98))
163701	31761563	We observed increased apoptosis in dox-treated LPS246 TetO-FBP2 cells cultured in galactose medium (Figure 6A, S6A) compared to vehicle-treated cells, indicating that mitochondrial OXPHOS is critically impaired upon FBP2 induction.	('LPS246', 'Chemical', '-', (47, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('22', '31'))	('OXPHOS', 'biological_process', 'GO:0002082', ('181', '187'))	('apoptosis', 'CPA', (22, 31))	('mitochondrial OXPHOS', 'MPA', (167, 187))	('LPS246', 'Var', (47, 53))	('TetO-FBP2', 'Gene', (54, 63))	('galactose medium', 'Chemical', '-', (82, 98))	('apoptosis', 'biological_process', 'GO:0097194', ('22', '31'))	('dox', 'Chemical', 'MESH:D004318', (35, 38))
163702	31761563	Furthermore, oxygen consumption rates (OCR) and ATP production were lower in FBP2-expressing LPS246 cells compared to controls (Figure 6B, 6D, S6B).	('FBP2-expressing', 'Gene', (77, 92))	('oxygen', 'Chemical', 'MESH:D010100', (13, 19))	('lower', 'NegReg', (68, 73))	('ATP production', 'MPA', (48, 62))	('LPS246', 'Var', (93, 99))	('oxygen consumption rates', 'MPA', (13, 37))	('ATP', 'Chemical', 'MESH:D000255', (48, 51))	('LPS246', 'Chemical', '-', (93, 99))
163704	31761563	Loss of ATP-generating capacity stimulated glycolytic compensation in both LPS246 TetO-FBP2 and TetO-FBP24KA cells, as indicated by extracellular acidification rate (ECAR) (Figure S6D).	('LPS246', 'Chemical', '-', (75, 81))	('acidification', 'biological_process', 'GO:0045851', ('146', '159'))	('stimulated', 'PosReg', (32, 42))	('extracellular', 'cellular_component', 'GO:0005576', ('132', '145'))	('extracellular acidification rate', 'MPA', (132, 164))	('glycolytic compensation', 'MPA', (43, 66))	('Loss', 'NegReg', (0, 4))	('LPS246', 'Var', (75, 81))	('ATP', 'Chemical', 'MESH:D000255', (8, 11))	('ATP-generating capacity', 'MPA', (8, 31))
163705	31761563	Interestingly, ECAR was lower in both FBP2- and FBP24KA-expressing LPS246 cells than control cells (Figure S6D), indicating inhibition of glycolysis by each protein.	('inhibition', 'NegReg', (124, 134))	('ECAR', 'MPA', (15, 19))	('FBP2-', 'Var', (38, 43))	('lower', 'NegReg', (24, 29))	('LPS246', 'Var', (67, 73))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('inhibition of glycolysis', 'biological_process', 'GO:0045820', ('124', '148'))	('LPS246', 'Chemical', '-', (67, 73))	('glycolysis', 'MPA', (138, 148))	('FBP24KA-expressing LPS246', 'Var', (48, 73))
163713	31761563	In contrast, ectopic FBP24KA expression had no effect on M1 and M2 enrichment of TCA intermediates and products compared with control cells (Figure S6E-H), further indicating that it is nuclear FBP2 that restrains mitochondrial function and metabolism.	('TCA', 'Chemical', 'MESH:D014238', (81, 84))	('ectopic', 'Var', (13, 20))	('restrains', 'NegReg', (204, 213))	('FBP24KA', 'Gene', (21, 28))	('metabolism', 'biological_process', 'GO:0008152', ('241', '251'))	('metabolism', 'MPA', (241, 251))	('mitochondrial function', 'MPA', (214, 236))
163715	31761563	Quantitative RT-PCR analyses revealed significant downregulation of NRF1 and TFAM expression upon FBP2 restoration (Figure 7A).	('FBP2', 'Gene', (98, 102))	('downregulation', 'NegReg', (50, 64))	('TFAM', 'Gene', '7019', (77, 81))	('expression', 'MPA', (82, 92))	('TFAM', 'Gene', (77, 81))	('restoration', 'Var', (103, 114))	('NRF1', 'Gene', (68, 72))	('NRF1', 'Gene', '4899', (68, 72))
163716	31761563	Ectopic expression of TFAM or NRF1 reversed the suppression of target genes associated with OXPHOS (MT-ND1, MT-CYB, MT-CO1 and MT-ATP) (Figure 7B-C, Figure S7A-B), and partially restored mitochondrial mass (Figure 7D, Figure S7C).	('NRF1', 'Gene', '4899', (30, 34))	('TFAM', 'Gene', (22, 26))	('MT-ND1', 'Gene', '4535', (100, 106))	('TFAM', 'Gene', '7019', (22, 26))	('restored', 'NegReg', (178, 186))	('ATP', 'Chemical', 'MESH:D000255', (130, 133))	('Ectopic expression', 'Var', (0, 18))	('NRF1', 'Gene', (30, 34))	('MT-CYB', 'Gene', '4519', (108, 114))	('MT-CYB', 'Gene', (108, 114))	('MT-CO1', 'Gene', (116, 122))	('MT-ND1', 'Gene', (100, 106))	('suppression', 'MPA', (48, 59))	('mitochondrial mass', 'MPA', (187, 205))	('OXPHOS', 'biological_process', 'GO:0002082', ('92', '98'))	('MT-CO1', 'Gene', '4512', (116, 122))
163717	31761563	Moreover, ectopic TFAM or NRF1 expression partially reversed cell apoptosis (Figure 7E, Figure S7D) and proliferation (Figure 7F, Figure S7E) in dox-treated LPS246 TetO-FBP2 cells.	('dox', 'Chemical', 'MESH:D004318', (145, 148))	('apoptosis', 'biological_process', 'GO:0006915', ('66', '75'))	('cell apoptosis', 'CPA', (61, 75))	('proliferation', 'CPA', (104, 117))	('NRF1', 'Gene', (26, 30))	('LPS246', 'Chemical', '-', (157, 163))	('TFAM', 'Gene', '7019', (18, 22))	('apoptosis', 'biological_process', 'GO:0097194', ('66', '75'))	('TFAM', 'Gene', (18, 22))	('ectopic', 'Var', (10, 17))	('reversed', 'NegReg', (52, 60))	('expression', 'Var', (31, 41))	('NRF1', 'Gene', '4899', (26, 30))
163721	31761563	To ascertain that FBP2 diminishes c-Myc transcriptional activity, we measured c-Myc luciferase-reporter intensity and found FBP2 decreased c-Myc functionality (Figure 7G).	('diminishes', 'NegReg', (23, 33))	('c-Myc', 'Gene', (34, 39))	('c-Myc', 'Gene', '4609', (139, 144))	('c-Myc', 'Gene', (139, 144))	('FBP2', 'Var', (124, 128))	('c-Myc', 'Gene', '4609', (78, 83))	('c-Myc', 'Gene', (78, 83))	('c-Myc', 'Gene', '4609', (34, 39))	('decreased', 'NegReg', (129, 138))
163722	31761563	Transcript levels of c-Myc target genes (CCND2, eIF2A, NPM1, PSAT1) were also decreased in FBP2-expressing cells (Figure 7H).	('CCND2', 'Gene', '894', (41, 46))	('eIF2', 'cellular_component', 'GO:0005850', ('48', '52'))	('c-Myc', 'Gene', (21, 26))	('PSAT1', 'Gene', '29968', (61, 66))	('PSAT1', 'Gene', (61, 66))	('NPM1', 'Gene', (55, 59))	('eIF2A', 'Gene', (48, 53))	('FBP2-expressing', 'Var', (91, 106))	('Transcript levels', 'MPA', (0, 17))	('decreased', 'NegReg', (78, 87))	('c-Myc', 'Gene', '4609', (21, 26))	('CCND2', 'Gene', (41, 46))	('eIF2A', 'Gene', '83939', (48, 53))	('NPM1', 'Gene', '4869', (55, 59))
163742	31761563	Previous studies uncovered frequently mutated genes in STS, including TP53, NF1 and PIK3CA, further confirmed by recent large-scale analyses of 206 adult soft tissue sarcomas representing 6 major subtypes using multi-platform molecular profiling.	('mutated', 'Var', (38, 45))	('PIK3CA', 'Gene', '5290', (84, 90))	('NF1', 'Gene', '4763', (76, 79))	('TP53', 'Gene', '7157', (70, 74))	('sarcomas', 'Disease', 'MESH:D012509', (166, 174))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (154, 173))	('sarcomas', 'Phenotype', 'HP:0100242', (166, 174))	('sarcoma', 'Phenotype', 'HP:0100242', (166, 173))	('TP53', 'Gene', (70, 74))	('sarcomas', 'Disease', (166, 174))	('PIK3CA', 'Gene', (84, 90))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (154, 174))	('NF1', 'Gene', (76, 79))
163744	31761563	Furthermore, PIK3CA mutations, among the most frequent somatic mutations found in STS along with gain of function mutations in c-KIT and PDGFRalpha, are implicated in activation of the AKT/mTOR pathway, stimulating a shift towards aerobic glycolysis.	('PDGFRalpha', 'Gene', '5156', (137, 147))	('AKT', 'Gene', (185, 188))	('mTOR', 'Gene', (189, 193))	('shift towards aerobic glycolysis', 'MPA', (217, 249))	('PIK3CA', 'Gene', (13, 19))	('stimulating', 'Reg', (203, 214))	('mutations', 'Var', (114, 123))	('PDGFRalpha', 'Gene', (137, 147))	('c-KIT', 'Gene', (127, 132))	('activation', 'PosReg', (167, 177))	('KIT', 'molecular_function', 'GO:0005020', ('129', '132'))	('PIK3CA', 'Gene', '5290', (13, 19))	('c-KIT', 'Gene', '3815', (127, 132))	('glycolysis', 'biological_process', 'GO:0006096', ('239', '249'))	('AKT', 'Gene', '207', (185, 188))	('gain of function', 'PosReg', (97, 113))	('mutations', 'Var', (20, 29))	('mTOR', 'Gene', '2475', (189, 193))
163747	31761563	Furthermore, FBP2 restoration reduces PPP activity needed for ribonucleotide production and reducing equivalents in the form of NADPH.	('reducing', 'NegReg', (92, 100))	('PPP activity needed for ribonucleotide production', 'MPA', (38, 87))	('restoration', 'Var', (18, 29))	('NADPH', 'Gene', (128, 133))	('reduces', 'NegReg', (30, 37))	('NADPH', 'Gene', '1666', (128, 133))	('ribonucleotide', 'Chemical', 'MESH:D012265', (62, 76))	('FBP2', 'Gene', (13, 17))
163751	31761563	Of note, nuclear FBP2 also plays a role in suppressing glycolysis, as nucleus-excluded FBP24KA exhibited less potent inhibition of glucose uptake and lactate secretion than wild-type FBP2, as indicated by [1,2-13C]glucose labeling experiments (e.g.	('glycolysis', 'MPA', (55, 65))	('suppressing', 'NegReg', (43, 54))	('glucose uptake', 'biological_process', 'GO:0046323', ('131', '145'))	('lactate secretion', 'MPA', (150, 167))	('lactate', 'Chemical', 'MESH:D019344', (150, 157))	('less', 'NegReg', (105, 109))	('glucose', 'Chemical', 'MESH:D005947', (131, 138))	('glycolysis', 'biological_process', 'GO:0006096', ('55', '65'))	('glucose', 'Chemical', 'MESH:D005947', (214, 221))	('nucleus', 'cellular_component', 'GO:0005634', ('70', '77'))	('inhibition', 'NegReg', (117, 127))	('glucose uptake', 'MPA', (131, 145))	('FBP24KA', 'Var', (87, 94))	('1,2-13C', 'Chemical', '-', (206, 213))	('lactate secretion', 'biological_process', 'GO:0046722', ('150', '167'))
163752	31761563	26% decrease in glucose consumption by FBP2 versus 14% by FBP24KA).	('glucose', 'Chemical', 'MESH:D005947', (16, 23))	('FBP2', 'Var', (39, 43))	('glucose consumption', 'MPA', (16, 35))	('decrease', 'NegReg', (4, 12))
163754	31761563	c-Myc regulates virtually all genes involved in glycolysis, including the essential glycolytic enzymes LDHA, PDK1 and ENO1, consistent with our observation that nuclear FBP2 also contributes to changes in glucose catabolism.	('PDK1', 'Gene', (109, 113))	('glucose', 'Chemical', 'MESH:D005947', (205, 212))	('changes', 'Reg', (194, 201))	('LDHA', 'Gene', (103, 107))	('PDK1', 'molecular_function', 'GO:0004740', ('109', '113'))	('glycolysis', 'biological_process', 'GO:0006096', ('48', '58'))	('ENO1', 'Gene', (118, 122))	('ENO1', 'Gene', '2023', (118, 122))	('regulates', 'Reg', (6, 15))	('LDHA', 'Gene', '3939', (103, 107))	('glucose catabolism', 'MPA', (205, 223))	('nuclear', 'Var', (161, 168))	('c-Myc', 'Gene', '4609', (0, 5))	('FBP2', 'Gene', (169, 173))	('glucose catabolism', 'biological_process', 'GO:0006007', ('205', '223'))	('PDK1', 'Gene', '5163', (109, 113))	('c-Myc', 'Gene', (0, 5))
163762	31761563	Recent isotope tracing analysis of human ccRCC confirmed enhanced glycolysis and suppressed glucose oxidation by the TCA cycle in these tumors, likely due to HIF stabilization caused by frequent von Hippel-Lindau (VHL) mutations.	('tumors', 'Disease', (136, 142))	('suppressed', 'NegReg', (81, 91))	('suppressed glucose oxidation', 'Phenotype', 'HP:0040270', (81, 109))	('VHL', 'Gene', (214, 217))	('human', 'Species', '9606', (35, 40))	('TCA cycle', 'Enzyme', (117, 126))	('TCA', 'Chemical', 'MESH:D014238', (117, 120))	('enhanced', 'PosReg', (57, 65))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('von Hippel-Lindau', 'Gene', (195, 212))	('glucose oxidation', 'MPA', (92, 109))	('glucose', 'Chemical', 'MESH:D005947', (92, 99))	('VHL', 'Gene', '7428', (214, 217))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('glycolysis', 'biological_process', 'GO:0006096', ('66', '76'))	('von Hippel-Lindau', 'Gene', '7428', (195, 212))	('glycolysis', 'MPA', (66, 76))	('mutations', 'Var', (219, 228))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('TCA cycle', 'biological_process', 'GO:0006099', ('117', '126'))
163777	31761563	We have not delineated consequences of FBP2 loss during sarcoma initiation thus far; future studies will assess Fbp2 deletion in genetically engineered mouse models of STS, such as a "KP" UPS model.	('Fbp2', 'Gene', '14120', (112, 116))	('sarcoma initiation', 'Disease', 'MESH:D012509', (56, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('mouse', 'Species', '10090', (152, 157))	('Fbp2', 'Gene', (112, 116))	('sarcoma initiation', 'Disease', (56, 74))	('deletion', 'Var', (117, 125))
163791	31761563	The FBP24KA and FBP2G260R mutants were generated using Q5 Site-Directed Mutagenesis Kit (NEB, E0554).	('Mutagenesis', 'biological_process', 'GO:0006280', ('72', '83'))	('Kit', 'Gene', (84, 87))	('FBP24KA', 'Var', (4, 11))	('Kit', 'Gene', '3815', (84, 87))	('FBP2G260R', 'Var', (16, 25))
163792	31761563	Multiple cultures of LPS246, T449, T778, T1000, HT1080, and KP250 cells were plated in 60 mm plates at a density of 8 x 104 cells supplemented with either DMEM containing 1% FBS or glucose-free DMEM supplemented with 10% FBS and 5 mM D-(+)-Glucose (Sigma-Aldrich, G8270).	('LPS246', 'Var', (21, 27))	('T778', 'Var', (35, 39))	('DMEM', 'Chemical', '-', (155, 159))	('LPS246', 'Chemical', '-', (21, 27))	('Glucose', 'Chemical', 'MESH:D005947', (240, 247))	('DMEM', 'Chemical', '-', (194, 198))	('HT1080', 'CellLine', 'CVCL:0317', (48, 54))	('T449', 'Var', (29, 33))	('glucose', 'Chemical', 'MESH:D005947', (181, 188))
163800	31761563	Pre-designed Taqman primers were obtained from Life Technologies for the following genes: 18S (HS03928985_G1), MT-ND1 (HS02596873_S1), MT-MYB (HS02596867_S1), MT-CO1 (HS02596864_G1), and MT-ATP6 (HS02596862_G1).	('HS03928985_G1', 'Var', (95, 108))	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('MT-ND1', 'Gene', '4535', (111, 117))	('HS02596864_G1', 'Var', (167, 180))	('HS02596867_S1', 'Var', (143, 156))	('MT-CO1', 'Gene', (159, 165))	('HS02596873_S1', 'Var', (119, 132))	('MT-ND1', 'Gene', (111, 117))	('HS02596862_G1', 'Var', (196, 209))	('MT-CO1', 'Gene', '4512', (159, 165))	('MT-ATP6', 'Gene', (187, 194))	('MT-ATP6', 'Gene', '4508', (187, 194))
163812	31761563	Vector control 293T cells, or 293T cells expressing FBP2, FBP24KA or FBP2G260R were harvested in lysis buffer used for western blot analysis.	('293T', 'CellLine', 'CVCL:0063', (30, 34))	('FBP2G260R', 'Var', (69, 78))	('FBP2', 'Var', (52, 56))	('FBP24KA', 'Var', (58, 65))	('293T', 'CellLine', 'CVCL:0063', (15, 19))	('lysis', 'biological_process', 'GO:0019835', ('97', '102'))
163816	31761563	LPS246 TetO-FBP2 (PBS or Dox treated) and LPS246 TetO-FBP24KA (PBS or Dox treated) cells were seeded in 6-well plates at a density of 1.5 x 105 per well.	('LPS246', 'Var', (0, 6))	('LPS246 TetO-FBP24KA', 'Var', (42, 61))	('Dox', 'Chemical', 'MESH:D004317', (70, 73))	('LPS246', 'Chemical', '-', (42, 48))	('LPS246', 'Chemical', '-', (0, 6))	('PBS', 'Chemical', 'MESH:D007854', (63, 66))	('PBS', 'Chemical', 'MESH:D007854', (18, 21))	('Dox', 'Chemical', 'MESH:D004317', (25, 28))
163830	31761563	LPS246 tumors were fixed in 4% paraformaldehyde (PFA)/PBS overnight at 4  C. Fixed tissues were dehydrated in 30% sucrose solution and embedded in OCT for frozen sectioning.	('LPS246', 'Var', (0, 6))	('PBS', 'Chemical', 'MESH:D007854', (54, 57))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('LPS246', 'Chemical', '-', (0, 6))	('sucrose', 'Chemical', 'MESH:D013395', (114, 121))	('OCT', 'Gene', (147, 150))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (31, 47))	('OCT', 'Gene', '5362', (147, 150))	('PFA', 'Chemical', 'MESH:C003043', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
163857	31761563	6 replicates were set up for each of the following groups: (1) LPS246 TetO-FBP2 + Veh; (2) LPS246 TetO-FBP2 + Dox; (3) LPS246 TetO-FBP24KA + Veh; (4) LPS246 TetO-FBP24KA + Dox.	('LPS246', 'Chemical', '-', (91, 97))	('LPS246', 'Chemical', '-', (150, 156))	('Dox', 'Chemical', 'MESH:D004317', (172, 175))	('Dox', 'Chemical', 'MESH:D004317', (110, 113))	('LPS246', 'Var', (63, 69))	('LPS246', 'Chemical', '-', (119, 125))	('LPS246', 'Chemical', '-', (63, 69))	('LPS246', 'Var', (91, 97))	('LPS246 TetO-FBP24KA', 'Var', (119, 138))	('LPS246 TetO-FBP24KA', 'Var', (150, 169))
163865	31761563	Here, Celeste Simon and her colleagues show that fructose-1,6-bisphosphatase 2 (FBP2) is lost in many STS subtypes, and FBP2 re-expression dramatically inhibits sarcoma growth.	('sarcoma', 'Disease', (161, 168))	('FBP2', 'Gene', (120, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('lost', 'NegReg', (89, 93))	('inhibits', 'NegReg', (152, 160))	('FBP2', 'Gene', (80, 84))	('fructose-1,6-bisphosphatase 2', 'Gene', '8789', (49, 78))	('sarcoma', 'Disease', 'MESH:D012509', (161, 168))	('re-expression', 'Var', (125, 138))
163867	31761563	Both these aspects of FBP2 starve the cancer of energy, providing a rationale for why loss of FBP2 is so often seen in STSs and why its re-expression is a therapeutic option.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('loss', 'Var', (86, 90))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('FBP2', 'Gene', (94, 98))	('cancer', 'Disease', (38, 44))	('STSs', 'Phenotype', 'HP:0030448', (119, 123))
163869	29805586	A total of 5 ccRCC tissue samples and 5 normal kidney tissue samples were contained in each profile of GSE96574 and GSE71302, and 46 ccRCC tissue samples and 46 normal kidney tissue samples were involved in GSE61441.	('GSE96574', 'Var', (103, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (15, 18))	('RCC', 'Disease', (135, 138))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('GSE71302', 'Var', (116, 124))
163878	29805586	The results of the present study indicated that HAPLN1, hsa-miR-204 and hsa-miR-218 may be involved in the pathogenesis of ccRCC.	('involved', 'Reg', (91, 99))	('HAPLN1', 'Gene', '1404', (48, 54))	('hsa-miR-218', 'Var', (72, 83))	('hsa-miR-204', 'Gene', (56, 67))	('hsa-miR-204', 'Gene', '406987', (56, 67))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('HAPLN1', 'Gene', (48, 54))	('pathogenesis', 'biological_process', 'GO:0009405', ('107', '119'))
163889	29805586	A larger number of miRNAs are associated with key pathogenesis mechanisms of hypoxia and epithelial-to-mesenchymal transition, including miR-200, miR-210, miR-155, miR-8a, miR-424, miR-381, miR-34a, miR-17-5p and miR-224.	('miR-381', 'Gene', '494330', (181, 188))	('miR-424', 'Gene', '494336', (172, 179))	('miR-34a', 'Gene', '407040', (190, 197))	('miR-210', 'Gene', '406992', (146, 153))	('miR-155', 'Gene', (155, 162))	('epithelial-to-mesenchymal transition', 'CPA', (89, 125))	('miR-210', 'Gene', (146, 153))	('associated', 'Reg', (30, 40))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('89', '125'))	('hypoxia', 'Disease', (77, 84))	('miR-155', 'Gene', '406947', (155, 162))	('miR-17-5p', 'Gene', '406952', (199, 208))	('pathogenesis', 'biological_process', 'GO:0009405', ('50', '62'))	('miR-17-5p', 'Gene', (199, 208))	('miR-381', 'Gene', (181, 188))	('hypoxia', 'Disease', 'MESH:D000860', (77, 84))	('miR-200', 'Var', (137, 144))	('miR-8a', 'Var', (164, 170))	('miR-34a', 'Gene', (190, 197))	('miR-224', 'Gene', '407009', (213, 220))	('miR-224', 'Gene', (213, 220))	('miR-424', 'Gene', (172, 179))
163891	29805586	Ricketts et al reported that certain tumor suppressor genes were methylated in RCC tumor tissue (e.g., SLC34A2 was specifically methylated in 63% of RCC cases, OVOL1 in 40%, DLEC1 in 20%, TMPRSS2 in 26%, SST in 31% and BMP4 in 35%).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', (83, 88))	('BMP4', 'Gene', (219, 223))	('methylated', 'Var', (128, 138))	('TMPRSS2', 'Gene', '7113', (188, 195))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('DLEC1', 'Gene', (174, 179))	('SLC34A2', 'Gene', '10568', (103, 110))	('TMPRSS2', 'Gene', (188, 195))	('SLC34A2', 'Gene', (103, 110))	('OVOL1', 'Gene', '5017', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('SST', 'Gene', (204, 207))	('RCC tumor', 'Disease', (79, 88))	('BMP4', 'Gene', '652', (219, 223))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('OVOL1', 'Gene', (160, 165))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('37', '53'))	('RCC', 'Disease', (79, 82))	('RCC', 'Disease', (149, 152))	('DLEC1', 'Gene', '9940', (174, 179))	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('RCC tumor', 'Disease', 'MESH:C538614', (79, 88))	('SST', 'Gene', '6750', (204, 207))	('tumor', 'Disease', (37, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('37', '53'))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
163895	29805586	For the profiles of GSE96574, GSE71302 and GSE61441, the raw data were obtained and normalized using the preprocess core function package V3.5 .	('V3.5', 'Gene', (138, 142))	('GSE61441', 'Var', (43, 51))	('core', 'cellular_component', 'GO:0019013', ('116', '120'))	('V3.5', 'Gene', '28474', (138, 142))	('GSE96574', 'Var', (20, 28))	('GSE71302', 'Var', (30, 38))
163919	29805586	HAPLN1 had the most significant differences in expression and was regulated by hsa-miR-204 and hsa-miR-218.	('hsa-miR-204', 'Gene', '406987', (79, 90))	('HAPLN1', 'Gene', '1404', (0, 6))	('hsa-miR-218', 'Var', (95, 106))	('HAPLN1', 'Gene', (0, 6))	('expression', 'MPA', (47, 57))	('hsa-miR-204', 'Gene', (79, 90))
163921	29805586	Genetic variations are associated with the occurrence and development of RCC.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('Genetic variations', 'Var', (0, 18))	('associated', 'Reg', (23, 33))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
163923	29805586	The methylation status of certain genes is associated with cancer development and metastatic recurrence in ccRCC.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('metastatic recurrence', 'CPA', (82, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('associated', 'Reg', (43, 53))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('methylation status', 'Var', (4, 22))
163938	29805586	Furthermore, HAPLN1 exhibited the most pronounced differences in expression, and was negatively regulated by hsa-miR-204 and hsa-miR-218.	('hsa-miR-218', 'Var', (125, 136))	('hsa-miR-204', 'Gene', (109, 120))	('HAPLN1', 'Gene', (13, 19))	('hsa-miR-204', 'Gene', '406987', (109, 120))	('expression', 'MPA', (65, 75))	('negatively', 'NegReg', (85, 95))	('HAPLN1', 'Gene', '1404', (13, 19))
163959	27941608	Mutations in the Mitochondrial ND1 Gene Are Associated with Postoperative Prognosis of Localized Renal Cell Carcinoma We analyzed mutations in the mitochondrial ND1 gene to determine their association with clinicopathological parameters and postoperative recurrence of renal cell carcinoma (RCC) in Japanese patients.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (269, 289))	('ND1', 'Gene', (31, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (269, 289))	('patients', 'Species', '9606', (308, 316))	('Associated', 'Reg', (44, 54))	('ND1', 'Gene', '4535', (31, 34))	('Mutations', 'Var', (0, 9))	('RCC', 'Disease', (291, 294))	('RCC', 'Phenotype', 'HP:0005584', (291, 294))	('ND1', 'Gene', '4535', (161, 164))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (97, 117))	('Carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('RCC', 'Disease', 'MESH:C538614', (291, 294))	('ND1', 'Gene', (161, 164))	('Postoperative Prognosis of Localized Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (60, 117))	('renal cell carcinoma', 'Disease', (269, 289))
163961	27941608	The 5-year recurrence-free survival (RFS) rate was significantly worse in patients with tumors >40 mm in diameter (p = 0.0091), pathological T (pT) stage >=3 (p = 0.0122), Fuhrman nuclear atypia grade >=III (p = 0.0070), and ND1 mutations (p = 0.0006).	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('worse', 'NegReg', (65, 70))	('ND1', 'Gene', '4535', (225, 228))	('mutations', 'Var', (229, 238))	('patients', 'Species', '9606', (74, 82))	('ND1', 'Gene', (225, 228))	('recurrence-free survival', 'CPA', (11, 35))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
163962	27941608	Multivariate analysis using these factors revealed that mutations in ND1 were significantly associated with the 5-year RFS rate (p = 0.0044).	('RFS', 'Disease', (119, 122))	('mutations', 'Var', (56, 65))	('ND1', 'Gene', (69, 72))	('associated', 'Reg', (92, 102))	('ND1', 'Gene', '4535', (69, 72))
163963	27941608	These results suggest a strong correlation between the presence of ND1 mutations in cancer tissue and postoperative recurrence of localized RCC in Japanese patients.	('patients', 'Species', '9606', (156, 164))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('ND1', 'Gene', '4535', (67, 70))	('cancer', 'Disease', (84, 90))	('ND1', 'Gene', (67, 70))	('mutations', 'Var', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))
163977	27941608	Recent studies proposed that mutations in mtDNA might be utilized as molecular markers for early detection, assessment of the degree of malignancy, and prediction of recurrence and prognosis after radical surgery in several cancer types.. mtDNA mutations that resulted in ROS accumulation were shown to be correlated with the acquisition of metastatic potential and poor prognosis.	('malignancy', 'Disease', (136, 146))	('mutations', 'Var', (245, 254))	('metastatic potential', 'CPA', (341, 361))	('ROS', 'Chemical', 'MESH:D017382', (272, 275))	('mtDNA', 'Gene', (239, 244))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('mtDNA', 'cellular_component', 'GO:0000262', ('239', '244'))	('mtDNA', 'cellular_component', 'GO:0000262', ('42', '47'))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('malignancy', 'Disease', 'MESH:D009369', (136, 146))	('accumulation', 'PosReg', (276, 288))	('cancer', 'Disease', (224, 230))	('ROS', 'MPA', (272, 275))
163979	27941608	In addition, mutations in NADH dehydrogenase subunit 1 (ND1), a subunit of oxidative phosphorylation complex, were detected in breast and nasopharyngeal carcinomas.	('NADH dehydrogenase subunit 1', 'Gene', (26, 54))	('ND1', 'Gene', '4535', (56, 59))	('breast', 'Disease', (127, 133))	('ND1', 'Gene', (56, 59))	('NADH dehydrogenase subunit 1', 'Gene', '4535', (26, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (153, 163))	('detected', 'Reg', (115, 123))	('carcinomas', 'Disease', 'MESH:D002277', (153, 163))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('75', '100'))	('carcinomas', 'Disease', (153, 163))	('mutations', 'Var', (13, 22))	('nasopharyngeal carcinomas', 'Phenotype', 'HP:0100630', (138, 163))
163980	27941608	identified 11 missense mutations in ND1 from colorectal tumor tissue specimens.	('colorectal tumor', 'Disease', 'MESH:D015179', (45, 61))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('ND1', 'Gene', '4535', (36, 39))	('ND1', 'Gene', (36, 39))	('missense mutations', 'Var', (14, 32))	('colorectal tumor', 'Disease', (45, 61))
163981	27941608	Studies also showed that mutations in ND1 may lead to changes in the secondary structure of the protein and subsequent inactivation of enzymes.	('mutations', 'Var', (25, 34))	('secondary structure of the protein', 'MPA', (69, 103))	('ND1', 'Gene', (38, 41))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('enzymes', 'MPA', (135, 142))	('ND1', 'Gene', '4535', (38, 41))	('inactivation', 'NegReg', (119, 131))	('lead to changes', 'Reg', (46, 61))
163982	27941608	The studies described above indicate that there was a correlation between various types of cancer and the ND1 mutations, which may lead to subsequent abrogation of its enzymatic activity.	('enzymatic activity', 'MPA', (168, 186))	('mutations', 'Var', (110, 119))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('abrogation', 'NegReg', (150, 160))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ND1', 'Gene', '4535', (106, 109))	('correlation', 'Interaction', (54, 65))	('ND1', 'Gene', (106, 109))
163983	27941608	These studies provide strong evidence for the utility of mtDNA mutations as potential prognostic factors for recurrence and progression in various types of cancer.	('mutations', 'Var', (63, 72))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('mtDNA', 'Gene', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('mtDNA', 'cellular_component', 'GO:0000262', ('57', '62'))
163984	27941608	In this study, we aimed to determine the correlation between mtDNA mutations and postoperative recurrence in RCC.	('mtDNA', 'cellular_component', 'GO:0000262', ('61', '66'))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('mutations', 'Var', (67, 76))	('RCC', 'Disease', (109, 112))	('mtDNA', 'Gene', (61, 66))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))
163994	27941608	We determined that the NST was 0.005, indicating that RCC was significantly associated with mutations in the mitochondrial ND1 gene.	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('mutations', 'Var', (92, 101))	('associated', 'Reg', (76, 86))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('ND1', 'Gene', '4535', (123, 126))	('ND1', 'Gene', (123, 126))
163997	27941608	In addition, C3328Y, C4197Y, and C4141Y with heteroplasmic mutations were novel mutations that were not previously reported in Japanese patients.	('C4197Y', 'Var', (21, 27))	('C4197Y', 'Mutation', 'p.C4197Y', (21, 27))	('C3328Y', 'Mutation', 'p.C3328Y', (13, 19))	('C4141Y', 'Mutation', 'p.C4141Y', (33, 39))	('patients', 'Species', '9606', (136, 144))	('C3328Y', 'Var', (13, 19))	('C4141Y', 'Var', (33, 39))
163998	27941608	Moreover, mutations leading to amino acid changes were observed at 12 sites in 10 cases (52.6%, 10/19 patients).	('mutations', 'Var', (10, 19))	('patients', 'Species', '9606', (102, 110))	('amino acid changes', 'Var', (31, 49))
163999	27941608	The ND1 region of patient hk383 harbored a mutation, insertion of a C at position 3572, which caused a frameshift.	('insertion', 'Var', (53, 62))	('caused', 'Reg', (94, 100))	('patient', 'Species', '9606', (18, 25))	('ND1', 'Gene', '4535', (4, 7))	('frameshift', 'Var', (103, 113))	('ND1', 'Gene', (4, 7))
164000	27941608	Heteroplasmic mutations were observed at 24 sites in 16 cases (84.2%, 16/19 patients), and 84% of the cases with mutations harbored heteroplasmic mutations (Table 2).	('patients', 'Species', '9606', (76, 84))	('mutations', 'Var', (113, 122))	('harbored', 'Reg', (123, 131))
164006	27941608	As a result, three factors (maximum tumor diameter, pT stage, and ND1 mutation) were found to be significantly associated with CSS: tumor diameter (5-year CSS, 100% and 90% for <=40 mm and >40 mm, respectively; p = 0.0415), pT stage (5-year CSS, 98.2% and 80.0% for <=pT2 and >=pT3, respectively; p = 0.0330), and somatic mutation in ND1 (5-year CSS, 89.5% and 100% for the presence and absence of somatic mutation/s in ND1, respectively; p = 0.0341) (Table 5).	('ND1', 'Gene', (66, 69))	('CSS', 'Chemical', '-', (155, 158))	('associated', 'Reg', (111, 121))	('tumor', 'Disease', (132, 137))	('ND1', 'Gene', '4535', (66, 69))	('CSS', 'Chemical', '-', (346, 349))	('tumor', 'Disease', (36, 41))	('CSS', 'Chemical', '-', (241, 244))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('ND1', 'Gene', (334, 337))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('ND1', 'Gene', '4535', (334, 337))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('CSS', 'Disease', (127, 130))	('ND1', 'Gene', (420, 423))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('CSS', 'Chemical', '-', (127, 130))	('ND1', 'Gene', '4535', (420, 423))	('mutation', 'Var', (70, 78))
164007	27941608	Multivariate analysis using the Cox proportional hazards model for these three factors showed that there was no factor significantly associated with CSS; however, somatic mutation in ND1 showed a tendency toward deterioration of CSS in the presence of ND1 mutation (p = 0.0827) (Table 6).	('ND1', 'Gene', '4535', (183, 186))	('CSS', 'Disease', (229, 232))	('CSS', 'Chemical', '-', (149, 152))	('ND1', 'Gene', '4535', (252, 255))	('deterioration', 'NegReg', (212, 225))	('mutation', 'Var', (256, 264))	('ND1', 'Gene', (183, 186))	('CSS', 'Chemical', '-', (229, 232))	('ND1', 'Gene', (252, 255))	('Cox', 'Gene', '1351', (32, 35))	('Cox', 'Gene', (32, 35))
164008	27941608	These findings suggest that mutations in ND1 might also be considered as a prognostic factor for recurrence and a possible predictor of CSS.	('ND1', 'Gene', (41, 44))	('CSS', 'Disease', (136, 139))	('CSS', 'Chemical', '-', (136, 139))	('ND1', 'Gene', '4535', (41, 44))	('mutations', 'Var', (28, 37))
164010	27941608	As a result of the log-rank test, three factors (maximum tumor diameter (p = 0.0161), Fuhrman grade (p = 0.0051), and ND1 mutation (p = 0.0042)) were candidates of becoming independent predictors of RFS.	('ND1', 'Gene', '4535', (118, 121))	('mutation', 'Var', (122, 130))	('ND1', 'Gene', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('RFS', 'Disease', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
164011	27941608	Finally, ND1 mutation was the only statistically significant predictive factor of RFS in the ccRCC sub group according to the Cox proportional hazards model (p = 0.0208) (Table 7).	('RFS', 'Disease', (82, 85))	('Cox', 'Gene', '1351', (126, 129))	('mutation', 'Var', (13, 21))	('Cox', 'Gene', (126, 129))	('ND1', 'Gene', '4535', (9, 12))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('ND1', 'Gene', (9, 12))	('RCC', 'Disease', (95, 98))
164013	27941608	As a result, 30 mutations were found in the ND1 sequence of 19 patients.	('ND1', 'Gene', '4535', (44, 47))	('ND1', 'Gene', (44, 47))	('mutations', 'Var', (16, 25))	('patients', 'Species', '9606', (63, 71))
164014	27941608	These mutations were not found in healthy Japanese subjects based on the GenBank database and were confirmed to be somatic by comparing with the paired non-cancerous tissue specimens.	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('mutations', 'Var', (6, 15))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))
164015	27941608	Heteroplasmy suggests the presence of a pathogenic mutation as a cause or result of cancer and was previously shown to have a strong association with mutations.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mutation', 'Var', (51, 59))	('cancer', 'Disease', (84, 90))
164016	27941608	In six cases, there were three new mutation sites (C3328Y, C4141Y, and C4197Y) that were not previously reported and were not found in the database.	('C3328Y', 'Var', (51, 57))	('C4141Y', 'Mutation', 'p.C4141Y', (59, 65))	('C4197Y', 'Var', (71, 77))	('C4141Y', 'Var', (59, 65))	('C3328Y', 'Mutation', 'p.C3328Y', (51, 57))	('C4197Y', 'Mutation', 'p.C4197Y', (71, 77))
164017	27941608	Of these new mutation sites, C3328Y and C4141Y were missense mutations, whereas L8F and R279W were amino acid changes resulting from the mutations.	('R279W', 'Var', (88, 93))	('C4141Y', 'Var', (40, 46))	('C3328Y', 'Var', (29, 35))	('C4141Y', 'Mutation', 'p.C4141Y', (40, 46))	('C3328Y', 'Mutation', 'p.C3328Y', (29, 35))	('R279W', 'Mutation', 'p.R279W', (88, 93))
164018	27941608	With respect to amino acid changes, we found mutations that led to changes in amino acids at 12 sites in 10 cases (52.6%; 10/19 patients).	('patients', 'Species', '9606', (128, 136))	('mutations', 'Var', (45, 54))	('changes', 'Reg', (67, 74))	('amino acids at 12', 'MPA', (78, 95))
164019	27941608	We identified an insertion of C at position 3572 (C3572ins) in patient hk383, which caused a frameshift and an amino acid change.	('C3572ins', 'Var', (50, 58))	('frameshift', 'MPA', (93, 103))	('caused', 'Reg', (84, 90))	('patient', 'Species', '9606', (63, 70))	('amino acid change', 'MPA', (111, 128))	('hk383', 'Gene', (71, 76))	('C3572ins', 'Mutation', 'c.3572insC', (50, 58))
164020	27941608	With this insertion, the protein structure of ND1 and complex I function may be significantly altered.	('complex', 'MPA', (54, 61))	('complex I', 'cellular_component', 'GO:0030964', ('54', '63'))	('altered', 'Reg', (94, 101))	('ND1', 'Gene', '4535', (46, 49))	('ND1', 'Gene', (46, 49))	('insertion', 'Var', (10, 19))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('protein structure', 'MPA', (25, 42))
164021	27941608	This specific mutation in mitochondrial ND1 has been reported in oncocytic thyroid carcinoma, oncocytic pituitary adenoma, renal oncocytoma, and chromophobe RCC (eosinophilic variant), suggesting that C3572ins mutation in ND1 is associated with oncocytic tumors or variants.	('C3572ins', 'Var', (201, 209))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('renal oncocytoma', 'Disease', (123, 139))	('chromophobe RCC', 'Disease', (145, 160))	('C3572ins', 'Mutation', 'c.3572insC', (201, 209))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (104, 121))	('oncocytic tumors', 'Disease', 'MESH:C535584', (245, 261))	('oncocytic tumors', 'Disease', (245, 261))	('oncocytic pituitary adenoma', 'Disease', 'MESH:D010911', (94, 121))	('ND1', 'Gene', (40, 43))	('associated', 'Reg', (229, 239))	('ND1', 'Gene', '4535', (40, 43))	('renal oncocytoma', 'Disease', 'MESH:C537750', (123, 139))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (75, 92))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (123, 139))	('ND1', 'Gene', (222, 225))	('oncocytic pituitary adenoma', 'Disease', (94, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('variants', 'Disease', (265, 273))	('oncocytic thyroid carcinoma', 'Disease', 'MESH:C535584', (65, 92))	('chromophobe RCC', 'Disease', 'MESH:C538614', (145, 160))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('ND1', 'Gene', '4535', (222, 225))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('oncocytic thyroid carcinoma', 'Disease', (65, 92))
164023	27941608	The patient with the C3572ins mutation (case hk383) also had a granular eosinophilic cytoplasm and was diagnosed with an eosinophilic variant of ccRCC.	('granular eosinophilic', 'Disease', 'MESH:D004802', (63, 84))	('C3572ins', 'Mutation', 'c.3572insC', (21, 29))	('patient', 'Species', '9606', (4, 11))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('cytoplasm', 'cellular_component', 'GO:0005737', ('85', '94'))	('granular eosinophilic', 'Disease', (63, 84))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('C3572ins', 'Var', (21, 29))
164024	27941608	While a correlation between oncocytosis and tumorigenesis has been suggested, the relationship between C3572ins and tumor progression is not clear.	('C3572ins', 'Var', (103, 111))	('oncocytosis', 'Disease', (28, 39))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('oncocytosis', 'Disease', 'None', (28, 39))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('C3572ins', 'Mutation', 'c.3572insC', (103, 111))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (44, 49))
164025	27941608	In this study, our patient with the C3572ins mutation had metastatic recurrence in the lymph nodes and the adrenal glands eight months after surgery.	('patient', 'Species', '9606', (19, 26))	('C3572ins', 'Var', (36, 44))	('metastatic recurrence in the', 'CPA', (58, 86))	('C3572ins', 'Mutation', 'c.3572insC', (36, 44))
164026	27941608	Our log-rank test revealed that tumor diameter >40 mm, pT stage>= 3, Fuhrman grade >=III, and ND1 mutation were associated with worse RFS rates in patients who underwent surgery for localized RCC.	('ND1', 'Gene', '4535', (94, 97))	('mutation', 'Var', (98, 106))	('ND1', 'Gene', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('patients', 'Species', '9606', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('worse', 'NegReg', (128, 133))	('RCC', 'Disease', (192, 195))	('RCC', 'Phenotype', 'HP:0005584', (192, 195))	('tumor', 'Disease', (32, 37))	('RFS', 'MPA', (134, 137))
164027	27941608	Multivariate analysis using these factors revealed that mutations in ND1 were significantly associated with RFS rates.	('mutations', 'Var', (56, 65))	('ND1', 'Gene', (69, 72))	('RFS rates', 'Disease', (108, 117))	('associated', 'Reg', (92, 102))	('ND1', 'Gene', '4535', (69, 72))
164028	27941608	Although larger tumor size, pT stage, and Fuhrman grade were previously reported as poor prognostic factors, this is the first study to show that mutations in ND1 were predictors of recurrence in localized RCC.	('ND1', 'Gene', (159, 162))	('mutations', 'Var', (146, 155))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('ND1', 'Gene', '4535', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('RCC', 'Phenotype', 'HP:0005584', (206, 209))	('RCC', 'Disease', 'MESH:C538614', (206, 209))	('RCC', 'Disease', (206, 209))
164030	27941608	For example, mutations of the von Hippel-Lindau (VHL) gene on the short arm of chromosome 3 and another locus on the long arm of chromosome 5 were shown to be associated with the carcinogenesis of RCC and are considered as candidate tumor suppressor genes.	('RCC', 'Disease', 'MESH:C538614', (197, 200))	('carcinogenesis', 'Disease', (179, 193))	('von Hippel-Lindau', 'Gene', (30, 47))	('chromosome', 'cellular_component', 'GO:0005694', ('129', '139'))	('chromosome', 'cellular_component', 'GO:0005694', ('79', '89'))	('tumor', 'Disease', (233, 238))	('carcinogenesis', 'Disease', 'MESH:D063646', (179, 193))	('associated with', 'Reg', (159, 174))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('233', '249'))	('short arm', 'Phenotype', 'HP:0009824', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor suppressor', 'biological_process', 'GO:0051726', ('233', '249'))	('von Hippel-Lindau', 'Gene', '7428', (30, 47))	('VHL', 'Gene', (49, 52))	('mutations', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('RCC', 'Phenotype', 'HP:0005584', (197, 200))	('RCC', 'Disease', (197, 200))	('VHL', 'Gene', '7428', (49, 52))
164032	27941608	In this study, we focused on mitochondria, in particular, since its relationship with oxidative stress and consequent mtDNA mutations might affect the prognosis of patients with RCC.	('mutations', 'Var', (124, 133))	('mitochondria', 'cellular_component', 'GO:0005739', ('29', '41'))	('oxidative stress', 'Phenotype', 'HP:0025464', (86, 102))	('mtDNA', 'Gene', (118, 123))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('affect', 'Reg', (140, 146))	('RCC', 'Disease', (178, 181))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('patients', 'Species', '9606', (164, 172))	('mtDNA', 'cellular_component', 'GO:0000262', ('118', '123'))
164039	27941608	This is the first study that demonstrates the relationship between mitochondrial ND1 mutations and postoperative recurrence of RCC in a Japanese patient cohort.	('ND1', 'Gene', '4535', (81, 84))	('patient', 'Species', '9606', (145, 152))	('mutations', 'Var', (85, 94))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('ND1', 'Gene', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))
164043	27941608	Finally, our findings showing that over 80% of the mutations found were heteroplasmic provide very strong evidence that mutations in ND1 can be used as indicators of cancer prognosis in the future.	('cancer', 'Disease', (166, 172))	('mutations', 'Var', (51, 60))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('ND1', 'Gene', '4535', (133, 136))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('ND1', 'Gene', (133, 136))
164047	27941608	F3274 (5'-ACAGTCAGAGGTTCAATTCCTCTTCT-3'), R3590 (5'-ATAGGAGGCCTAGGTTGAGGTTGACCA-3'), F3590 (5'-TGGTCAACCTCAACCTAGGCCTCCTAT-3'), R3725 (5'-GATGGCTAGGGTGACTTCATATGAGA-3'), F3731 (5'-ATGAAGTCACCCTAGCCATCATTCTACTA-3'), R4021 (5'-TCATATGTTGTTCCTAGGAAGATTGTAGT-3'), ND1-F (5'-TCCGAACTAGTCTCAGGCTTCA-3'), ND1-R (5'-CACGGAGAATTTTGGATTCTCAG-3').	('F3731', 'Var', (170, 175))	('ND1', 'Gene', '4535', (260, 263))	('R3725', 'Var', (128, 133))	('ND1', 'Gene', '4535', (298, 301))	('ND1', 'Gene', (260, 263))	('F3590', 'Var', (85, 90))	('R4021', 'Var', (215, 220))	('R3590', 'Var', (42, 47))	('ND1', 'Gene', (298, 301))
164054	27941608	Accession numbers for the nucleotide sequences of ND1 obtained from 62 patients included in the present study are LC178840-LC178901.	('patients', 'Species', '9606', (71, 79))	('ND1', 'Gene', '4535', (50, 53))	('ND1', 'Gene', (50, 53))	('LC178840-LC178901', 'Var', (114, 131))
164060	27941608	By extracting the sequence data of the non-cancerous renal tissue of the same patient, the mutations in the RCC tissue were confirmed to be unique and somatic.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('patient', 'Species', '9606', (78, 85))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('cancer', 'Disease', (43, 49))	('cancerous renal tissue', 'Phenotype', 'HP:0009726', (43, 65))	('mutations', 'Var', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
164064	27941608	The nine factors considered were as follows: age (<=60 years vs. >60 years), sex (male vs. female), nephrectomy (full vs. partial), tumor diameter (<=40 mm vs. >40 mm), histology type (ccRCC vs. nccRCC), pT stage (<=pT2 vs. >=pT3), Fuhrman grade (I/II vs. III/IV), microvessel invasion (absence or presence), and ND1 mutations (presence or absence).	('mutations', 'Var', (317, 326))	('microvessel invasion', 'CPA', (265, 285))	('Fuhrman grade', 'CPA', (232, 245))	('ND1', 'Gene', (313, 316))	('RCC', 'Disease', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('RCC', 'Phenotype', 'HP:0005584', (187, 190))	('RCC', 'Disease', 'MESH:C538614', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('RCC', 'Disease', (198, 201))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('tumor', 'Disease', (132, 137))	('ND1', 'Gene', '4535', (313, 316))
164070	27941608	This is the first study to demonstrate a relationship between mutations in ND1 and postoperative recurrence of RCC in Japanese patients.	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('ND1', 'Gene', '4535', (75, 78))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('patients', 'Species', '9606', (127, 135))	('ND1', 'Gene', (75, 78))	('mutations', 'Var', (62, 71))
164072	27941608	The NST value of 0.005 indicated that RCC was significantly associated with mutations in the mitochondrial ND1 gene.	('RCC', 'Disease', (38, 41))	('mutations', 'Var', (76, 85))	('RCC', 'Disease', 'MESH:C538614', (38, 41))	('ND1', 'Gene', (107, 110))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('associated', 'Reg', (60, 70))	('ND1', 'Gene', '4535', (107, 110))
164075	27941608	Additionally, 12 sites had mutations that led to amino acid change mutations and were frequent in 10 out of the 19 patients.	('mutations', 'Var', (27, 36))	('patients', 'Species', '9606', (115, 123))	('amino', 'MPA', (49, 54))
164076	27941608	Furthermore, the RFS was significantly worse in patients with larger tumors with a diameter of over >40 mm, those with >=pT stage 3, those with Fuhrman grade >=III, and those with ND1 mutations in RCC specimens.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('ND1', 'Gene', '4535', (180, 183))	('mutations', 'Var', (184, 193))	('RCC', 'Phenotype', 'HP:0005584', (197, 200))	('ND1', 'Gene', (180, 183))	('RCC', 'Disease', 'MESH:C538614', (197, 200))	('RCC', 'Disease', (197, 200))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('patients', 'Species', '9606', (48, 56))	('tumors', 'Disease', (69, 75))	('worse', 'NegReg', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('RFS', 'MPA', (17, 20))
164077	27941608	Moreover, multivariate analysis revealed that the presence of ND1 mutations was significantly associated with worse RFS.	('mutations', 'Var', (66, 75))	('RFS', 'Disease', (116, 119))	('presence', 'Var', (50, 58))	('ND1', 'Gene', '4535', (62, 65))	('ND1', 'Gene', (62, 65))
164079	31131312	Epigenetic dysregulation by aberrant metabolism in renal cell carcinoma can be reversed with Ascorbic acid Our recently published study uncovered mechanisms and prognostic impact of aberrant DNA methylation/hydroxymethylation in clear cell renal cell carcinoma, and comprehensively explored the potential of Ascorbic acid in reversing the epigenetic aberrancy.	('Ascorbic acid', 'Chemical', 'MESH:D001205', (308, 321))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (240, 260))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (51, 71))	('DNA', 'cellular_component', 'GO:0005574', ('191', '194'))	('aberrant', 'Var', (182, 190))	('metabolism', 'biological_process', 'GO:0008152', ('37', '47'))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (229, 260))	('clear cell renal cell carcinoma', 'Disease', (229, 260))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (240, 260))	('Ascorbic acid', 'Chemical', 'MESH:D001205', (93, 106))	('DNA methylation', 'biological_process', 'GO:0006306', ('191', '206'))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (229, 260))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (51, 71))	('renal cell carcinoma', 'Disease', (51, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
164083	31131312	In our recent study, through analysis of 576 primary ccRCC cases, we reported that loss of 5hmC is associated with aggressive clinicopathologic features and is an independent adverse prognostic factor in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('loss', 'Var', (83, 87))	('5hmC', 'Chemical', 'MESH:C011865', (91, 95))	('5hmC', 'Protein', (91, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (204, 209))	('ccRCC', 'Disease', (204, 209))	('associated', 'Reg', (99, 109))
164088	31131312	We showed that gain of 5mC and loss of 5hmC in ccRCC is not due to mutational or transcriptional inactivation of TET enzymes, but by their functional inactivation by l-2-hydroxyglutarate (L2HG), an oncometabolite that accumulates largely due to the deletion and under-expression of l-2-hydroxyglutarate dehydrogenase (L2HGDH).	('l-2-hydroxyglutarate dehydrogenase', 'Gene', (282, 316))	('L2HGDH', 'Gene', '79944', (318, 324))	('inactivation', 'NegReg', (150, 162))	('TET', 'Chemical', '-', (113, 116))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('ccRCC', 'Disease', (47, 52))	('deletion', 'Var', (249, 257))	('5hmC', 'Chemical', 'MESH:C011865', (39, 43))	('L2HG', 'Chemical', '-', (318, 322))	('L2HG', 'Chemical', '-', (188, 192))	('5mC', 'Chemical', 'MESH:D044503', (23, 26))	('L2HGDH', 'Gene', (318, 324))	('l-2-hydroxyglutarate', 'Chemical', '-', (282, 302))	('l-2-hydroxyglutarate', 'Chemical', '-', (166, 186))	('l-2-hydroxyglutarate dehydrogenase', 'Gene', '79944', (282, 316))	('under-expression', 'NegReg', (262, 278))
164092	31131312	Furthermore, loss of L2HGDH conferred worse prognosis (The Cancer Genome Atlas) (Figure 1.	('Cancer', 'Phenotype', 'HP:0002664', (59, 65))	('L2HGDH', 'Gene', '79944', (21, 27))	('worse', 'NegReg', (38, 43))	('L2HGDH', 'Gene', (21, 27))	('Cancer', 'Disease', (59, 65))	('Cancer', 'Disease', 'MESH:D009369', (59, 65))	('loss', 'Var', (13, 17))
164097	31131312	l-2-hydroxyglutarate (L2HG) is an oncometabolite which accumulates in clear cell renal cell carcinoma (ccRCC) primarily due to the deletion and under-expression of l-2-hydroxyglutarate dehydrogenase (L2HGDH).	('accumulates', 'PosReg', (55, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (81, 101))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (70, 101))	('l-2-hydroxyglutarate', 'Chemical', '-', (164, 184))	('l-2-hydroxyglutarate', 'Chemical', '-', (0, 20))	('L2HG', 'Chemical', '-', (200, 204))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('L2HGDH', 'Gene', (200, 206))	('under-expression', 'NegReg', (144, 160))	('L2HG', 'Chemical', '-', (22, 26))	('l-2-hydroxyglutarate dehydrogenase', 'Gene', (164, 198))	('L2HGDH', 'Gene', '79944', (200, 206))	('l-2-hydroxyglutarate dehydrogenase', 'Gene', '79944', (164, 198))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (70, 101))	('clear cell renal cell carcinoma', 'Disease', (70, 101))	('deletion', 'Var', (131, 139))
164098	31131312	L2HG inhibits the Ten-Eleven Translocation (TET) enzymes by competing with the natural co-substrate 2-oxoglutarate (2OG), thereby resulting in a gain of DNA 5-methylcytosine (5mC) and a loss of 5-hydroxymethylcytosine (5hmC).	('TET', 'Chemical', '-', (44, 47))	('DNA', 'cellular_component', 'GO:0005574', ('153', '156'))	('loss', 'NegReg', (186, 190))	('5-hydroxymethylcytosine', 'MPA', (194, 217))	('L2HG', 'Var', (0, 4))	('gain', 'PosReg', (145, 149))	('2-oxoglutarate', 'Chemical', 'MESH:D007656', (100, 114))	('DNA 5-methylcytosine', 'MPA', (153, 173))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (194, 217))	('inhibits', 'NegReg', (5, 13))	('5hmC', 'Chemical', 'MESH:C011865', (219, 223))	('5mC', 'Chemical', 'MESH:D044503', (175, 178))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (157, 173))	('L2HG', 'Chemical', '-', (0, 4))
164099	31131312	Loss of 5hmC is an independent adverse prognostic factor in ccRCC.	('5hmC', 'Chemical', 'MESH:C011865', (8, 12))	('5hmC', 'Protein', (8, 12))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('ccRCC', 'Disease', (60, 65))	('Loss', 'Var', (0, 4))
164101	31131312	There were some important considerations and findings while studying the effects of Ascorbic acid as an anti-cancer agent in vitro and in vivo: Ascorbate reduces catalytic metal ions such as ferric ions to ferrous ions.	('ferric', 'Chemical', '-', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('metal', 'Chemical', 'MESH:D008670', (172, 177))	('Ascorbate', 'Var', (144, 153))	('cancer', 'Disease', (109, 115))	('Ascorbate', 'Chemical', 'MESH:D001205', (144, 153))	('ferrous ions', 'Chemical', '-', (206, 218))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Ascorbic acid', 'Chemical', 'MESH:D001205', (84, 97))	('reduces', 'NegReg', (154, 161))	('catalytic metal ions', 'MPA', (162, 182))
164103	31131312	Fe2+ + O2   Fe3+ + O2*- Superoxide radicals then dismutes to H2O2 and O2.	('Fe2+', 'Chemical', '-', (0, 4))	('O2', 'Chemical', 'MESH:D010100', (70, 72))	('O2', 'Chemical', 'MESH:D010100', (63, 65))	('Superoxide', 'Chemical', 'MESH:D013481', (24, 34))	('Fe2+ + O2   Fe3+ + O2*-', 'Var', (0, 23))	('H2O2', 'MPA', (61, 65))	('O2', 'Chemical', 'MESH:D010100', (19, 21))	('H2O2', 'Chemical', 'MESH:D006861', (61, 65))	('dismutes', 'MPA', (49, 57))	('Fe3+', 'Chemical', '-', (12, 16))	('O2', 'Chemical', 'MESH:D010100', (7, 9))
164106	31131312	Although AA is an anti-oxidant, in the presence of free catalytic ions in culture media, it produces pro-oxidant hydrogen peroxide through the following reactions:  H2O2 is toxic to cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (113, 130))	('cancer', 'Disease', (182, 188))	('H2O2', 'Chemical', 'MESH:D006861', (165, 169))	('H2O2', 'Var', (165, 169))
164107	31131312	It is therefore important to neutralize H2O2 with catalase prior to studying epigenetic (or other cofactor related) effects of AA.	('catalase', 'Gene', (50, 58))	('neutralize', 'Var', (29, 39))	('H2O2', 'Chemical', 'MESH:D006861', (40, 44))	('catalase', 'Gene', '847', (50, 58))
164119	31131312	There was no signal (either in the series by Cameron/Pauling in which oral AA was used after the first 7-10 days of intravenous AA treatment or in the Mayo studies in which only oral AA was used) to suggest that hypermethylated malignancies such as kidney cancer fared any better with oral AA treatment.	('Mayo', 'Species', '162683', (151, 155))	('kidney cancer', 'Disease', (249, 262))	('malignancies', 'Disease', (228, 240))	('kidney cancer', 'Phenotype', 'HP:0009726', (249, 262))	('hypermethylated', 'Var', (212, 227))	('kidney cancer', 'Disease', 'MESH:D007680', (249, 262))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('malignancies', 'Disease', 'MESH:D009369', (228, 240))
164127	31131312	In vitro cancer cell cytotoxicity with short-term exposure to high dose AA is almost solely due to H2O2, given the complete reversal with catalase.	('catalase', 'Gene', (138, 146))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('catalase', 'Gene', '847', (138, 146))	('cancer cell cytotoxicity', 'Disease', (9, 33))	('H2O2', 'Chemical', 'MESH:D006861', (99, 103))	('H2O2', 'Var', (99, 103))	('cancer cell cytotoxicity', 'Disease', 'MESH:D064420', (9, 33))
164136	31131312	The above findings not only enhance our understanding of the epigenetic dysregulation in kidney cancer in terms of mechanisms and prognostic impact, but also provide the rationale for testing high dose intravenous Ascorbic acid in the clinical setting in this malignancy.	('kidney cancer', 'Phenotype', 'HP:0009726', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('epigenetic dysregulation', 'Var', (61, 85))	('kidney cancer', 'Disease', (89, 102))	('enhance', 'PosReg', (28, 35))	('malignancy', 'Disease', 'MESH:D009369', (260, 270))	('Ascorbic acid', 'Chemical', 'MESH:D001205', (214, 227))	('kidney cancer', 'Disease', 'MESH:D007680', (89, 102))	('malignancy', 'Disease', (260, 270))
164143	30057905	Finally, target prediction and subsequent pathway analysis reveals that miRNAs previously unannotated in kidney tissues may target genes involved in ccRCC tumourigenesis and disease biology.	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('ccRCC', 'Phenotype', 'HP:0006770', (149, 154))	('miRNAs', 'Var', (72, 78))	('tumour', 'Disease', (155, 161))
164152	30057905	For instance, a cluster of miRNAs (miR-17~92) has been shown to regulate nephrogenesis; both miR-9 and miR-374 are observed to suppress claudin-14 and affect Ca2+ readsorption in the ascending limb of Henle; and recent studies have detected aberrant expression of miRNAs in kidney tumours.	('affect', 'Reg', (151, 157))	('claudin-14', 'Gene', (136, 146))	('miR-374', 'Var', (103, 110))	('tumour', 'Phenotype', 'HP:0002664', (281, 287))	('tumours', 'Phenotype', 'HP:0002664', (281, 288))	('nephrogenesis', 'biological_process', 'GO:0001822', ('73', '86'))	('suppress', 'NegReg', (127, 135))	('kidney tumours', 'Disease', (274, 288))	('miR-9', 'Var', (93, 98))	('miR-17~92', 'Gene', (35, 44))	('nephrogenesis', 'biological_process', 'GO:0072006', ('73', '86'))	('miR-17~92', 'Gene', '407975', (35, 44))	('Ca2+ readsorption in the ascending limb of Henle', 'MPA', (158, 206))	('kidney tumours', 'Disease', 'MESH:D007680', (274, 288))	('regulate', 'Reg', (64, 72))	('Ca2+', 'Chemical', 'MESH:D000069285', (158, 162))	('nephrogenesis', 'Disease', (73, 86))	('nephrogenesis', 'Disease', 'None', (73, 86))	('claudin-14', 'Gene', '23562', (136, 146))
164170	30057905	The renal cancer cell line TK-10 and the immortalized nonmalignant embryonic kidney cell line HEK-293T were used to further explore the expression of the previously unannotated miRNAs and their deregulation in ccRCC tumours in vitro.	('HEK-293T', 'CellLine', 'CVCL:0063', (94, 102))	('ccRCC tumours', 'Disease', 'MESH:D009369', (210, 223))	('renal cancer', 'Disease', (4, 16))	('deregulation', 'MPA', (194, 206))	('tumour', 'Phenotype', 'HP:0002664', (216, 222))	('miRNAs', 'Var', (177, 183))	('renal cancer', 'Disease', 'MESH:D007680', (4, 16))	('renal cancer', 'Phenotype', 'HP:0009726', (4, 16))	('tumours', 'Phenotype', 'HP:0002664', (216, 223))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('embryonic kidney', 'Disease', (67, 83))	('ccRCC tumours', 'Disease', (210, 223))	('ccRCC', 'Phenotype', 'HP:0006770', (210, 215))	('embryonic kidney', 'Disease', 'MESH:D007674', (67, 83))
164179	30057905	Manual filtering based on read quality, likelihood of miRNA-like secondary structure, and significant folding values, followed by probing the degree of similarity with known miRNAs using the BLASTn algorithm, and removal of sequences with aberrant GC content, resulted in 40 nonmalignant and 143 tumour previously unannotated miRNAs (Figure 1, Supplemental Table 1).	('nonmalignant', 'CPA', (275, 287))	('tumour', 'Phenotype', 'HP:0002664', (296, 302))	('tumour', 'Disease', 'MESH:D009369', (296, 302))	('folding', 'MPA', (102, 109))	('aberrant', 'Var', (239, 247))	('tumour', 'Disease', (296, 302))
164191	30057905	For example, the previously unannotated miRNA Knm22_2209 has an almost complete loss of expression in ccRCC tumours (28-fold downregulated in tumours, BH-p = 5.3 x 10-23), while previously unannotated miRNAs Knm3_1968 and Knm17_1130 show a 100- and 13-fold increase in expression in ccRCC samples, respectively (BH-p = 1.4 x 10-21, 2.6 x 10-14).	('Knm22_2209', 'Var', (46, 56))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('ccRCC tumours', 'Disease', 'MESH:D009369', (102, 115))	('expression', 'MPA', (88, 98))	('BH', 'Chemical', '-', (151, 153))	('increase', 'PosReg', (257, 265))	('tumours', 'Disease', (142, 149))	('ccRCC tumours', 'Disease', (102, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('expression', 'MPA', (269, 279))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('downregulated', 'NegReg', (125, 138))	('ccRCC', 'Phenotype', 'HP:0006770', (283, 288))	('tumours', 'Disease', 'MESH:D009369', (142, 149))	('tumours', 'Disease', (108, 115))	('loss', 'NegReg', (80, 84))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('BH', 'Chemical', '-', (312, 314))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('tumours', 'Disease', 'MESH:D009369', (108, 115))
164197	30057905	Again, the unannotated miRNA Knm22_2209 (28-fold downregulated in ccRCC, BH-p = 5.3 x 10-23) is particularly noteworthy due to the clear correlation between its low expression and poor overall survival (Figure 3(a), p = 0.045).	('overall survival', 'CPA', (185, 201))	('BH', 'Chemical', '-', (73, 75))	('expression', 'MPA', (165, 175))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('downregulated', 'NegReg', (49, 62))	('Knm22_2209', 'Var', (29, 39))	('ccRCC', 'Disease', (66, 71))
164198	30057905	Alternatively, the Knm6_2419 miRNA is significantly upregulated in ccRCC tumours (FC = 5.5, BH-p = 1.6 x 10-5), and its high expression is significantly associated with a worsened overall patient survival (Figure 3(b), p = 0.038).	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('ccRCC tumours', 'Disease', (67, 80))	('Knm6_2419', 'Var', (19, 28))	('patient', 'Species', '9606', (188, 195))	('BH', 'Chemical', '-', (92, 94))	('worsened', 'NegReg', (171, 179))	('ccRCC tumours', 'Disease', 'MESH:D009369', (67, 80))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('high expression', 'MPA', (120, 135))	('upregulated', 'PosReg', (52, 63))
164203	30057905	In order to experimentally confirm the existence of these transcripts and their consequent deregulation in tumour tissues, we performed RT-qPCR using custom primers specific to Knm3_1968 and Knm17_1130, previously unannotated miRNAs strongly overexpressed in ccRCC samples.	('ccRCC', 'Phenotype', 'HP:0006770', (259, 264))	('ccRCC', 'Disease', (259, 264))	('Knm17_1130', 'Var', (191, 201))	('deregulation', 'MPA', (91, 103))	('Knm3_1968', 'Var', (177, 186))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('overexpressed', 'PosReg', (242, 255))	('tumour', 'Disease', (107, 113))
164205	30057905	RT-qPCR results were consistent with expression data from RNA-sequencing, wherein both Knm3_1968 and Knm17_1130 were found to be overexpressed in TK-10 cells relative to HEK-293T cells (average RQ = 8.56; 16.54, resp.	('Knm17_1130', 'Var', (101, 111))	('RNA', 'cellular_component', 'GO:0005562', ('58', '61'))	('HEK-293T', 'CellLine', 'CVCL:0063', (170, 178))	('Knm3_1968', 'Var', (87, 96))	('overexpressed', 'PosReg', (129, 142))
164215	30057905	These cases:particularly Knm22_2209, Knm17_1130, and Knm3_1968:suggest that the manipulation of miRNA expression may be a factor in the tumourigenesis of ccRCC tumours.	('manipulation', 'Var', (80, 92))	('tumour', 'Disease', (160, 166))	('factor', 'Reg', (122, 128))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (154, 159))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('ccRCC tumours', 'Disease', (154, 167))	('tumour', 'Disease', (136, 142))	('tumours', 'Phenotype', 'HP:0002664', (160, 167))	('ccRCC tumours', 'Disease', 'MESH:D009369', (154, 167))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('miRNA', 'Protein', (96, 101))	('tumour', 'Disease', 'MESH:D009369', (160, 166))
164218	30057905	Specifically, the miRNAs Knm22_2209 and Knm6_2419 display significant relationships with the poor outcome of ccRCC patients.	('patients', 'Species', '9606', (115, 123))	('Knm6_2419', 'Var', (40, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('Knm22_2209', 'Var', (25, 35))	('ccRCC', 'Disease', (109, 114))	('relationships', 'Reg', (70, 83))
164220	30057905	The axon guidance pathway mediates neuronal migration and positioning; in the kidney, this pathway has been shown to play key roles in organ development, in which deletion of critical pathway genes has been shown to lead to after-birth death due to kidney abnormalities.	('axon', 'cellular_component', 'GO:0030424', ('4', '8'))	('kidney abnormalities', 'Disease', 'MESH:D007674', (249, 269))	('deletion', 'Var', (163, 171))	('death', 'Disease', 'MESH:D003643', (236, 241))	('axon guidance', 'biological_process', 'GO:0007411', ('4', '17'))	('death', 'Disease', (236, 241))	('kidney abnormalities', 'Disease', (249, 269))	('kidney abnormalities', 'Phenotype', 'HP:0000077', (249, 269))	('neuronal migration', 'biological_process', 'GO:0001764', ('35', '53'))	('lead to', 'Reg', (216, 223))
164222	30057905	The newly detected miRNAs in the kidney were found to target several components of the vascular endothelial growth factor (VEGF) pathway, a major regulator of angiogenesis, as well as signaling cascades in response to extracellular stimuli, such as the insulin receptor signaling cascades and FGRF and EGFR signaling.	('VEGF', 'Gene', '7422', (123, 127))	('insulin', 'Gene', (253, 260))	('EGFR', 'Gene', '1956', (302, 306))	('VEGF', 'Gene', (123, 127))	('vascular endothelial growth factor', 'Gene', (87, 121))	('FGRF', 'Disease', 'None', (293, 297))	('miRNAs', 'Var', (19, 25))	('EGFR', 'molecular_function', 'GO:0005006', ('302', '306'))	('extracellular', 'cellular_component', 'GO:0005576', ('218', '231'))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('87', '121'))	('insulin', 'Gene', '3630', (253, 260))	('EGFR', 'Gene', (302, 306))	('FGRF', 'Disease', (293, 297))	('angiogenesis', 'biological_process', 'GO:0001525', ('159', '171'))	('insulin', 'molecular_function', 'GO:0016088', ('253', '260'))	('vascular endothelial growth factor', 'Gene', '7422', (87, 121))	('signaling', 'biological_process', 'GO:0023052', ('270', '279'))	('signaling', 'biological_process', 'GO:0023052', ('307', '316'))	('signaling', 'biological_process', 'GO:0023052', ('184', '193'))
164240	28903320	As a remarkable oncogene for ccRCC, high HIF-2alpha levels closely correlated with E2F3 upregulation.	('E2F3', 'Gene', (83, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('upregulation', 'PosReg', (88, 100))	('HIF-2alpha levels', 'MPA', (41, 58))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('high', 'Var', (36, 40))	('RCC', 'Disease', (31, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
164256	28903320	Thus, in cells with inactivating mutations of both VHL alleles, HIF-alpha subunits are stabilized at high levels irrespective of cellular hypoxia.	('VHL', 'Gene', '7428', (51, 54))	('hypoxia', 'Disease', (138, 145))	('hypoxia', 'Disease', 'MESH:D000860', (138, 145))	('VHL', 'Gene', (51, 54))	('inactivating mutations', 'Var', (20, 42))
164257	28903320	It is well known that VHL is highly mutated in sporatdic ccRCC and there are also lots of studies reporting that VHL inactivation in ccRCC leads to HIF up-regulation.	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('VHL', 'Gene', (22, 25))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('up-regulation', 'PosReg', (152, 165))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('VHL', 'Gene', (113, 116))	('VHL', 'Gene', '7428', (22, 25))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))	('HIF', 'MPA', (148, 151))	('inactivation', 'Var', (117, 129))	('VHL', 'Gene', '7428', (113, 116))	('regulation', 'biological_process', 'GO:0065007', ('155', '165'))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
164258	28903320	In addition, VHL inactivation in ccRCC is not only through mutation, but also though promoter methylation.	('RCC', 'Disease', (35, 38))	('methylation', 'biological_process', 'GO:0032259', ('94', '105'))	('VHL', 'Gene', (13, 16))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('mutation', 'Var', (59, 67))	('VHL', 'Gene', '7428', (13, 16))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('inactivation', 'NegReg', (17, 29))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
164262	28903320	In a further study, the investigation into the mechanism of aberrant HIF-2alpha expression in ccRCC was conducted without VHL inactivation.	('RCC', 'Disease', (96, 99))	('HIF-2alpha', 'Gene', (69, 79))	('expression', 'Species', '29278', (80, 90))	('VHL', 'Gene', (122, 125))	('VHL', 'Gene', '7428', (122, 125))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('aberrant', 'Var', (60, 68))
164273	28903320	Strikingly, as Figure 1C showed, patients with low E2F3 cytoplasmic expression levels had significantly higher overall survival rates than those with high E2F3 expression (p = 0.0003; HR 0.342(95%CI:0.191-0.610)).	('expression', 'Species', '29278', (68, 78))	('patients', 'Species', '9606', (33, 41))	('low', 'NegReg', (47, 50))	('overall survival rates', 'CPA', (111, 133))	('E2F3', 'Var', (51, 55))	('higher', 'PosReg', (104, 110))	('expression', 'Species', '29278', (160, 170))
164277	28903320	Consistent with the mRNA level data, depletion of E2F3 severely impaired HIF-2alpha expression in tumor cells 786-O and OS-RC-2 transfected with siE2F3 (Figures 2C and 2D).	('E2F3', 'Var', (50, 54))	('siE2F3', 'Var', (145, 151))	('impaired HIF-2alpha', 'Disease', (64, 83))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('depletion', 'MPA', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('impaired HIF-2alpha', 'Disease', 'MESH:D009422', (64, 83))	('expression', 'Species', '29278', (84, 94))	('tumor', 'Disease', (98, 103))	('OS-RC-2', 'CellLine', 'CVCL:1626', (120, 127))	('expression', 'MPA', (84, 94))
164279	28903320	The above data implied that E2F3 is essential for cancer cells to promote HIF-2alpha expression.	('HIF-2alpha', 'Protein', (74, 84))	('expression', 'MPA', (85, 95))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('promote', 'PosReg', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('expression', 'Species', '29278', (85, 95))	('E2F3', 'Var', (28, 32))
164280	28903320	The link between E2F3 and HIF-2alpha expression was further substantiated by confocal microscopy on 786-O, OS-RC-2, and ACHN.	('OS-RC-2', 'CellLine', 'CVCL:1626', (107, 114))	('ACHN', 'Chemical', '-', (120, 124))	('E2F3', 'Var', (17, 21))	('expression', 'Species', '29278', (37, 47))	('HIF-2alpha', 'Gene', (26, 36))
164282	28903320	The results demonstrated that the promoter of HIF-2alpha was evidently activated by E2F1 and E2F3, whereas E2F2 had no effect.	('activated', 'PosReg', (71, 80))	('E2F2', 'Gene', '1870', (107, 111))	('E2F1', 'Gene', '1869', (84, 88))	('E2F1', 'Gene', (84, 88))	('HIF-2alpha', 'Gene', (46, 56))	('E2F2', 'Gene', (107, 111))	('promoter', 'MPA', (34, 42))	('E2F3', 'Var', (93, 97))
164283	28903320	E2F1, E2F2, and E2F3 overexpression were verified by Western blot analysis (Figure 3A).	('E2F2', 'Gene', '1870', (6, 10))	('expression', 'Species', '29278', (25, 35))	('E2F3', 'Var', (16, 20))	('E2F2', 'Gene', (6, 10))	('E2F1', 'Gene', '1869', (0, 4))	('E2F1', 'Gene', (0, 4))
164286	28903320	293T cells transfected with HIF-2alpha promoter fragment (-1617/+1) showed clear induction of luciferase activity with increasing amounts of E2F3.	('293T', 'CellLine', 'CVCL:0063', (0, 4))	('-1617/+1', 'Var', (58, 66))	('luciferase activity', 'molecular_function', 'GO:0047077', ('94', '113'))	('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))
164290	28903320	The addition of the lentiviral particles of HIF-2alpha into the siE2F3 group regained cell proliferative ability, whereas introducing siHIF-2alpha into the E2F3-expressed ACHN cells inhibited cell growth (Figure 4B).	('siHIF-2alpha', 'Var', (134, 146))	('cell growth', 'biological_process', 'GO:0016049', ('192', '203'))	('cell proliferative ability', 'CPA', (86, 112))	('regained', 'PosReg', (77, 85))	('ACHN', 'Chemical', '-', (171, 175))	('cell growth', 'CPA', (192, 203))	('inhibited', 'NegReg', (182, 191))
164291	28903320	E2F3 overexpression in ACHN cells drove the cell cycle from G1 phase into S phase while the HIF-2alpha knockdown restored the cell into G1 phase, suggesting that E2F3 may promote the proliferation of ccRCC cell lines through the activation of HIF-2alpha (Figure 4D).	('ACHN', 'Chemical', '-', (23, 27))	('cell cycle', 'biological_process', 'GO:0007049', ('44', '54'))	('expression', 'Species', '29278', (9, 19))	('promote', 'PosReg', (171, 178))	('activation', 'PosReg', (229, 239))	('proliferation', 'CPA', (183, 196))	('ccRCC', 'Phenotype', 'HP:0006770', (200, 205))	('G1 phase', 'biological_process', 'GO:0051318', ('136', '144'))	('S phase', 'biological_process', 'GO:0051320', ('74', '81'))	('G1 phase', 'biological_process', 'GO:0051318', ('60', '68'))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('RCC', 'Disease', (202, 205))	('RCC', 'Phenotype', 'HP:0005584', (202, 205))	('E2F3', 'Var', (162, 166))	('HIF-2alpha', 'Protein', (243, 253))
164294	28903320	Supplementary Figure S1 showed that CDK6 and CyclinD1 were significantly downregulated in the knockdown of E2F3, 786-O, and OS-RC-2 cells accompanied with reduced HIF-2alpha expression.	('CDK6', 'Gene', (36, 40))	('expression', 'Species', '29278', (174, 184))	('knockdown', 'Var', (94, 103))	('OS-RC-2', 'CellLine', 'CVCL:1626', (124, 131))	('expression', 'MPA', (174, 184))	('reduced', 'NegReg', (155, 162))	('CDK', 'molecular_function', 'GO:0004693', ('36', '39'))	('CDK6', 'Gene', '496334', (36, 40))	('HIF-2alpha', 'Protein', (163, 173))	('downregulated', 'NegReg', (73, 86))	('CyclinD1', 'Gene', (45, 53))	('E2F3', 'Var', (107, 111))
164297	28903320	Since HIF-2alpha is a transcription factor, the mRNA levels of E-Cadherin, N-Cadherin, Vimentin, and ZEB1 were subsequently examined after interference of E2F3 and HIF-2a (Figure 5A).	('N-Cadherin', 'Gene', '1000', (75, 85))	('Vimentin', 'Gene', '7431', (87, 95))	('Cadherin', 'molecular_function', 'GO:0008014', ('77', '85'))	('HIF-2a', 'Gene', '2034', (164, 170))	('HIF-2a', 'Gene', '2034', (6, 12))	('E-Cadherin', 'Gene', '999', (63, 73))	('E2F3', 'Var', (155, 159))	('ZEB1', 'Gene', (101, 105))	('Vimentin', 'cellular_component', 'GO:0045098', ('87', '95'))	('Vimentin', 'Gene', (87, 95))	('Cadherin', 'molecular_function', 'GO:0008014', ('65', '73'))	('transcription factor', 'molecular_function', 'GO:0000981', ('22', '42'))	('transcription', 'biological_process', 'GO:0006351', ('22', '35'))	('HIF-2a', 'Gene', (164, 170))	('HIF-2a', 'Gene', (6, 12))	('E-Cadherin', 'Gene', (63, 73))	('ZEB1', 'Gene', '6935', (101, 105))	('Vimentin', 'cellular_component', 'GO:0045099', ('87', '95'))	('N-Cadherin', 'Gene', (75, 85))
164298	28903320	As shown in Figure 5C, HIF-2alpha overexpression rescued the inhibitory effect of E2F3 knockdown on OS-RC-2 migration and invasion (p<0.001), suggesting that HIF-2alpha was involved in E2F3-mediated cell aggressiveness.	('expression', 'Species', '29278', (38, 48))	('aggressiveness', 'Phenotype', 'HP:0000718', (204, 218))	('OS-RC-2 migration', 'CPA', (100, 117))	('invasion', 'CPA', (122, 130))	('inhibitory effect', 'MPA', (61, 78))	('cell aggressiveness', 'Disease', 'MESH:D001523', (199, 218))	('OS-RC-2', 'CellLine', 'CVCL:1626', (100, 107))	('E2F3', 'Gene', (82, 86))	('cell aggressiveness', 'Disease', (199, 218))	('knockdown', 'Var', (87, 96))
164299	28903320	Meanwhile, silencing HIF-2alpha significantly abrogated the invasive ability of E2F3 cell overexpression compared with the control group.	('silencing', 'Var', (11, 20))	('HIF-2alpha', 'Protein', (21, 31))	('abrogated', 'NegReg', (46, 55))	('expression', 'Species', '29278', (94, 104))	('invasive ability of E2F3 cell overexpression', 'CPA', (60, 104))
164301	28903320	N-Cadherin, Vimentin, and ZEB1 were greatly downregulated after E2F3 knockdown, whereas E-Cadherin expression presented the adverse effect in OS-RC-2 (Figure 5B).	('downregulated', 'NegReg', (44, 57))	('OS-RC-2', 'CellLine', 'CVCL:1626', (142, 149))	('E-Cadherin', 'Gene', '999', (88, 98))	('N-Cadherin', 'Gene', (0, 10))	('ZEB1', 'Gene', '6935', (26, 30))	('Vimentin', 'Gene', (12, 20))	('N-Cadherin', 'Gene', '1000', (0, 10))	('ZEB1', 'Gene', (26, 30))	('Vimentin', 'Gene', '7431', (12, 20))	('Vimentin', 'cellular_component', 'GO:0045099', ('12', '20'))	('Vimentin', 'cellular_component', 'GO:0045098', ('12', '20'))	('E2F3', 'Gene', (64, 68))	('Cadherin', 'molecular_function', 'GO:0008014', ('90', '98'))	('expression', 'Species', '29278', (99, 109))	('knockdown', 'Var', (69, 78))	('Cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('E-Cadherin', 'Gene', (88, 98))
164304	28903320	Then, the knockdown of HIF-2alpha counteracted the aggressiveness of cancer cells and changed the EMT-related gene expression levels as well.	('changed', 'Reg', (86, 93))	('EMT-related gene expression levels', 'MPA', (98, 132))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('expression', 'Species', '29278', (115, 125))	('EMT', 'biological_process', 'GO:0001837', ('98', '101'))	('knockdown', 'Var', (10, 19))	('aggressiveness', 'Phenotype', 'HP:0000718', (51, 65))	('HIF-2alpha counteracted the aggressiveness of cancer', 'Disease', 'MESH:D009369', (23, 75))	('gene expression', 'biological_process', 'GO:0010467', ('110', '125'))
164306	28903320	In OS-RC-2, the E2F3 knockdown group had slower space coverage compared with the control group, whereas the HIF-2alpha transfection regained the migratory ability of siE2F3 group cells.	('space coverage', 'CPA', (48, 62))	('E2F3 knockdown', 'Var', (16, 30))	('slower', 'NegReg', (41, 47))	('OS-RC-2', 'CellLine', 'CVCL:1626', (3, 10))	('migratory ability', 'CPA', (145, 162))	('knockdown', 'Var', (21, 30))
164307	28903320	In E2F3 lower-expressed cell line ACHN, the adoption of E2F3 plasmid speeded up cell migration while the HIF-2alpha knockdown impaired the migration ability (Figure 5D).	('speeded up', 'PosReg', (69, 79))	('cell migration', 'CPA', (80, 94))	('ACHN', 'Chemical', '-', (34, 38))	('cell migration', 'biological_process', 'GO:0016477', ('80', '94'))	('E2F3', 'Var', (56, 60))	('HIF-2alpha knockdown impaired the migration ability', 'Disease', 'MESH:D054081', (105, 156))
164308	28903320	To confirm the role of E2F3 in renal cancer cell invasion, the tumor growth was monitored in 32 mice in vivo.	('tumor', 'Disease', (63, 68))	('renal cancer', 'Disease', (31, 43))	('mice', 'Species', '10090', (96, 100))	('E2F3', 'Var', (23, 27))	('renal cancer', 'Disease', 'MESH:D007680', (31, 43))	('renal cancer', 'Phenotype', 'HP:0009726', (31, 43))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
164314	28903320	Vimentin protein expression levels in shE2F3 group were significantly attenuated compared with control group in OS-RC-2 cells.	('Vimentin', 'Gene', '7431', (0, 8))	('expression', 'Species', '29278', (17, 27))	('attenuated', 'NegReg', (70, 80))	('Vimentin', 'cellular_component', 'GO:0045098', ('0', '8'))	('shE2F3', 'Var', (38, 44))	('Vimentin', 'cellular_component', 'GO:0045099', ('0', '8'))	('OS-RC-2', 'CellLine', 'CVCL:1626', (112, 119))	('protein', 'cellular_component', 'GO:0003675', ('9', '16'))	('Vimentin', 'Gene', (0, 8))
164316	28903320	As expected, the expression of E2F3 in tumors with E2F3 knockdown was evidently lower than that observed in tumors from mice injected with control cells.	('mice', 'Species', '10090', (120, 124))	('expression', 'Species', '29278', (17, 27))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('E2F3', 'Gene', (31, 35))	('expression', 'MPA', (17, 27))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('lower', 'NegReg', (80, 85))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumors', 'Disease', (39, 45))	('E2F3', 'Gene', (51, 55))	('knockdown', 'Var', (56, 65))
164323	28903320	As a master player, E2F3a was found to be essential in boosting the proliferation of ovarian cancer cells in response to the EGFR-driven mitogenic cell signal.	('ovarian cancer', 'Phenotype', 'HP:0100615', (85, 99))	('proliferation', 'CPA', (68, 81))	('ovarian cancer', 'Disease', 'MESH:D010051', (85, 99))	('EGFR', 'Gene', '1956', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('EGFR', 'Gene', (125, 129))	('ovarian cancer', 'Disease', (85, 99))	('E2F3a', 'Var', (20, 25))	('EGFR', 'molecular_function', 'GO:0005006', ('125', '129'))	('boosting', 'PosReg', (55, 63))
164325	28903320	For prostate cancer, E2F3 may be an independent factor predicting overall and cause-specific survival.	('prostate cancer', 'Disease', 'MESH:D011471', (4, 19))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('prostate cancer', 'Phenotype', 'HP:0012125', (4, 19))	('E2F3', 'Var', (21, 25))	('prostate cancer', 'Disease', (4, 19))
164331	28903320	Inactivation of pVHL plays an imperative role in the development of ccRCC, expressing either HIF-2alpha alone or both HIF-1alpha and HIF-2alpha.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (118, 143))	('pVHL', 'Gene', '7428', (16, 20))	('Inactivation', 'Var', (0, 12))	('pVHL', 'Gene', (16, 20))
164339	28903320	The findings were in line with previous results of Nils Kroeger's study that tumors with high HIF-2alpha nuclear expression had smaller tumor sizes, lower T stages, and less advanced Fuhrman grades than those without.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('HIF-2alpha', 'Gene', (94, 104))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('high', 'Var', (89, 93))	('smaller', 'NegReg', (128, 135))	('T stages', 'CPA', (155, 163))	('expression', 'Species', '29278', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('Fuhrman grades', 'CPA', (183, 197))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('lower', 'NegReg', (149, 154))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', (136, 141))
164342	28903320	The propensity of E2F3 and HIF-2alpha in the same cellular location (cytoplasm) of ccRCC indicated that they may cooperate to facilitate tumor progression but the mechanism still needs to be explored.	('cooperate', 'Reg', (113, 122))	('tumor', 'Disease', (137, 142))	('cytoplasm', 'cellular_component', 'GO:0005737', ('69', '78'))	('HIF-2alpha', 'Protein', (27, 37))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('RCC', 'Disease', (85, 88))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('E2F3', 'Var', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('facilitate', 'PosReg', (126, 136))
164346	28903320	In the following study, we aim to investigate the mechanism of E2F3 in ccRCC progression and its relationship with HIF-2alpha.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('RCC', 'Disease', (73, 76))	('E2F3', 'Var', (63, 67))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
164348	28903320	Chromatin immunoprecipitation assays showed the association of E2F3 with the HIF-2alpha promoters and luciferase experiments showed that HIF-2alpha promoters were responsive to E2F1 and E2F3.	('E2F3', 'Var', (186, 190))	('Chromatin', 'cellular_component', 'GO:0000785', ('0', '9'))	('association', 'Interaction', (48, 59))	('E2F1', 'Gene', '1869', (177, 181))	('E2F1', 'Gene', (177, 181))	('HIF-2alpha', 'Gene', (137, 147))	('E2F3', 'Gene', (63, 67))
164350	28903320	As expected, transfection of siE2F3 inhibited HIF-2alpha expression.	('expression', 'MPA', (57, 67))	('inhibited', 'NegReg', (36, 45))	('transfection', 'Var', (13, 25))	('siE2F3', 'Gene', (29, 35))	('HIF-2alpha', 'Protein', (46, 56))	('expression', 'Species', '29278', (57, 67))
164355	28903320	High levels of Vimentin, ZEB1, and N-Cadherin and low levels of E-cadherin were observed thereafter, suggesting that E2F3 may be a potential driver of EMT process through the activation of HIF-2alpha.	('EMT', 'biological_process', 'GO:0001837', ('151', '154'))	('cadherin', 'molecular_function', 'GO:0008014', ('66', '74'))	('Vimentin', 'cellular_component', 'GO:0045099', ('15', '23'))	('Cadherin', 'molecular_function', 'GO:0008014', ('37', '45'))	('activation', 'PosReg', (175, 185))	('E-cadherin', 'Gene', (64, 74))	('Vimentin', 'Gene', (15, 23))	('N-Cadherin', 'Gene', (35, 45))	('HIF-2alpha', 'Protein', (189, 199))	('N-Cadherin', 'Gene', '1000', (35, 45))	('ZEB1', 'Gene', (25, 29))	('E-cadherin', 'Gene', '999', (64, 74))	('Vimentin', 'cellular_component', 'GO:0045098', ('15', '23'))	('ZEB1', 'Gene', '6935', (25, 29))	('Vimentin', 'Gene', '7431', (15, 23))	('E2F3', 'Var', (117, 121))
164356	28903320	Herein, we elucidated that cells expressing high levels of E2F3 could activate HIF-2alpha expression, thus leading to a series of EMT alterations.	('HIF-2alpha', 'Protein', (79, 89))	('EMT', 'biological_process', 'GO:0001837', ('130', '133'))	('EMT alterations', 'CPA', (130, 145))	('expression', 'Species', '29278', (90, 100))	('activate', 'PosReg', (70, 78))	('expression', 'MPA', (90, 100))	('E2F3', 'Var', (59, 63))	('leading to', 'Reg', (107, 117))
164360	28903320	An increasing amount of evidence suggested that E2F3 can trigger cancer cell growth and proliferation.	('cell growth', 'biological_process', 'GO:0016049', ('72', '83'))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('E2F3', 'Var', (48, 52))	('trigger', 'PosReg', (57, 64))
164362	28903320	MiR-195 can suppress the G1/S transition by blocking Rb-E2F signals through targeting E2F3, indicating that E2F3 affects cell cycle modulation of HCC.	('MiR-195', 'Chemical', '-', (0, 7))	('Rb-E2F signals', 'MPA', (53, 67))	('E2F3', 'Gene', (86, 90))	('affects', 'Reg', (113, 120))	('suppress', 'NegReg', (12, 20))	('MiR-195', 'Var', (0, 7))	('blocking', 'NegReg', (44, 52))	('cell cycle modulation', 'biological_process', 'GO:0051726', ('121', '142'))	('cell', 'MPA', (121, 125))	('G1/S transition', 'CPA', (25, 40))
164364	28903320	Meanwhile, knockdown of E2F3 decreased proliferation velocity and led to G1 restoration in ccRCC cell line 786-O.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('RCC', 'Disease', (93, 96))	('proliferation velocity', 'CPA', (39, 61))	('decreased', 'NegReg', (29, 38))	('knockdown', 'Var', (11, 20))	('E2F3', 'Gene', (24, 28))
164366	28903320	Interestingly, HIF-2alpha overexpression was able to rescue the inhibition of cancer cell proliferation by E2F3 knockdown.	('cell proliferation', 'biological_process', 'GO:0008283', ('85', '103'))	('E2F3', 'Gene', (107, 111))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('knockdown', 'Var', (112, 121))	('inhibition', 'NegReg', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('expression', 'Species', '29278', (30, 40))
164367	28903320	Taken together, our data indicated that E2F3 triggered tumor cell growth and proliferation concomitantly with HIF-2alpha level.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cell growth', 'biological_process', 'GO:0016049', ('61', '72'))	('E2F3', 'Var', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('HIF-2alpha', 'MPA', (110, 120))	('proliferation', 'CPA', (77, 90))	('triggered', 'PosReg', (45, 54))
164374	28903320	E-Cadherin, Vimentin, ZEB1, and N-Cadherin were introduced as the indicators in cancer progression, and their fluctuations were associated with the E2F3 and HIF-2alpha change.	('fluctuations', 'MPA', (110, 122))	('Cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('E2F3', 'Var', (148, 152))	('Vimentin', 'Gene', (12, 20))	('ZEB1', 'Gene', (22, 26))	('Cadherin', 'molecular_function', 'GO:0008014', ('34', '42'))	('ZEB1', 'Gene', '6935', (22, 26))	('Vimentin', 'Gene', '7431', (12, 20))	('Vimentin', 'cellular_component', 'GO:0045098', ('12', '20'))	('E-Cadherin', 'Gene', (0, 10))	('associated', 'Reg', (128, 138))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Vimentin', 'cellular_component', 'GO:0045099', ('12', '20'))	('N-Cadherin', 'Gene', (32, 42))	('E-Cadherin', 'Gene', '999', (0, 10))	('cancer', 'Disease', (80, 86))	('N-Cadherin', 'Gene', '1000', (32, 42))
164390	28903320	Small interfering RNAs (siRNAs) against E2F3, E2F1, E2F2, and HIF-2alpha were designed and synthesized from GenePharma (Shanghai, China) (Table S1).	('E2F3', 'Var', (40, 44))	('E2F1', 'Gene', '1869', (46, 50))	('E2F1', 'Gene', (46, 50))	('E2F2', 'Gene', '1870', (52, 56))	('E2F2', 'Gene', (52, 56))
164409	28903320	After transfection for 48 h, the 786-O and ACHN cells were collected, washed with PBS, and fixed in 70% ice-cold ethanol overnight.	('ACHN', 'Chemical', '-', (43, 47))	('transfection', 'Var', (6, 18))	('PBS', 'Disease', 'MESH:D011535', (82, 85))	('PBS', 'Disease', (82, 85))	('ethanol', 'Chemical', 'MESH:D000431', (113, 120))
164490	32481542	Five out of the eight all-relevant features were significantly associated with the von Hippel-Lindau gene mutation.	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (83, 100))	('associated', 'Reg', (63, 73))	('mutation', 'Var', (106, 114))	('von Hippel-Lindau', 'Disease', (83, 100))
164510	32481542	BRCA1-associated protein (BAP1) gene mutations are found in ~15% of ccRCC and are associated with high-grade tumors and poor prognosis as reported in genome-wide association studies.	('BAP1', 'Gene', (26, 30))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('associated with', 'Reg', (82, 97))	('RCC', 'Disease', (70, 73))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('mutations', 'Var', (37, 46))	('BAP1', 'Gene', '8314', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('BRCA1-associated protein', 'Gene', (0, 24))	('tumors', 'Disease', (109, 115))	('BRCA1-associated protein', 'Gene', '8315', (0, 24))
164511	32481542	tested radiomics to predict BAP1 mutation status on ccRCC and found an AUC of 0.71 for features retrieved from the NP phase of CECT scans.	('BAP1', 'Gene', '8314', (28, 32))	('mutation', 'Var', (33, 41))	('RCC', 'Disease', (54, 57))	('BAP1', 'Gene', (28, 32))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))
164512	32481542	aimed to predict the presence of gene PBRM1 mutations by creating an ANN algorithm and ML-based TA from CMP images; they found that the former outperformed the latter, upholding 95% accuracy and 0.987 AUC for PBRM1 mutation status.	('TA', 'Chemical', '-', (96, 98))	('PBRM1', 'Gene', (209, 214))	('PBRM1', 'Gene', '55193', (209, 214))	('PBRM1', 'Gene', (38, 43))	('PBRM1', 'Gene', '55193', (38, 43))	('mutations', 'Var', (44, 53))	('upholding', 'PosReg', (168, 177))
164513	32481542	This tumor suppressor gene's mutation was associated with advanced-stage and higher grade ccRCC, and it was also suggested to influence response rates to immune checkpoint inhibitors.	('mutation', 'Var', (29, 37))	('associated', 'Reg', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('influence', 'Reg', (126, 135))	('response', 'MPA', (136, 144))	('tumor suppressor', 'biological_process', 'GO:0051726', ('5', '21'))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('tumor', 'Disease', (5, 10))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('5', '21'))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))
164543	32286325	Computational analysis of pathological images enables a better diagnosis of TFE3 Xp11.2 translocation renal cell carcinoma TFE3 Xp11.2 translocation renal cell carcinoma (TFE3-RCC) generally progresses more aggressively compared with other RCC subtypes, but it is challenging to diagnose TFE3-RCC by traditional visual inspection of pathological images.	('renal cell carcinoma', 'Disease', (149, 169))	('TFE3', 'Gene', (76, 80))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (149, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('TFE3', 'Gene', (288, 292))	('TFE3', 'Gene', '7030', (76, 80))	('TFE3', 'Gene', '7030', (288, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (102, 122))	('RCC', 'Phenotype', 'HP:0005584', (240, 243))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (149, 169))	('RCC', 'Phenotype', 'HP:0005584', (293, 296))	('TFE3', 'Gene', (123, 127))	('translocation', 'Var', (135, 148))	('aggressively', 'PosReg', (207, 219))	('TFE3', 'Gene', (171, 175))	('renal cell carcinoma', 'Disease', (102, 122))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (102, 122))	('TFE3', 'Gene', '7030', (123, 127))	('progresses', 'PosReg', (191, 201))	('TFE3', 'Gene', '7030', (171, 175))
164548	32286325	Translocation renal cell carcinoma is an aggressive form of renal cancer that is often misdiagnosed to other subtypes.	('Translocation', 'Var', (0, 13))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (14, 34))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (14, 34))	('renal cancer', 'Disease', (60, 72))	('renal cell carcinoma', 'Disease', (14, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('renal cancer', 'Disease', 'MESH:D007680', (60, 72))	('renal cancer', 'Phenotype', 'HP:0009726', (60, 72))
164568	32286325	We want to apply machine learning to digitized H&E-stained pathological images and study whether it can help identify TFE3-RCC unique image features and distinguish TFE3-RCC from the most common RCC subtype, ccRCC.	('TFE3', 'Gene', (118, 122))	('H&E', 'Chemical', '-', (47, 50))	('identify', 'Gene', (109, 117))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('TFE3', 'Gene', (165, 169))	('TFE3', 'Gene', '7030', (118, 122))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('distinguish', 'Var', (153, 164))	('RCC', 'Phenotype', 'HP:0005584', (195, 198))	('RCC', 'Phenotype', 'HP:0005584', (210, 213))	('TFE3', 'Gene', '7030', (165, 169))
164569	32286325	Recent years have witnessed a growing interest in applying machine learning to H&E-stained pathological images for various tasks including prognosis prediction, cancer classification, and genetic status prediction, such as microsatellite instability and gene mutation.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('and gene', 'Var', (250, 258))	('as microsatellite', 'Var', (220, 237))	('H&E', 'Chemical', '-', (79, 82))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))
164587	32286325	Of those features, rMean_bin8, rMean_bin9, rMean_mean, rMean_skewness, and gMean_mean were overrepresented for TFE3-RCC cases.	('TFE3', 'Gene', (111, 115))	('rMean_bin8', 'Var', (19, 29))	('TFE3', 'Gene', '7030', (111, 115))	('rMean_skewness', 'Var', (55, 69))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('overrepresented', 'PosReg', (91, 106))
164604	32286325	For example, in comparison with ccRCC, TFE3-RCC had higher proportions of very small and very large nuclei (see area_bin1, area_bin9, and area_bin10 in Fig.	('TFE3', 'Gene', (39, 43))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('TFE3', 'Gene', '7030', (39, 43))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('area_bin10', 'Var', (138, 148))
164610	32286325	Since the TFE3 translocation causes overexpression of the TFE3 protein, immunohistochemistry (IHC) for TFE3 protein has been considered a surrogate for this genetic event.	('TFE3', 'Gene', '7030', (10, 14))	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('overexpression', 'PosReg', (36, 50))	('TFE3', 'Gene', '7030', (58, 62))	('TFE3', 'Gene', '7030', (103, 107))	('protein', 'Protein', (63, 70))	('translocation', 'Var', (15, 28))	('TFE3', 'Gene', (10, 14))	('TFE3', 'Gene', (58, 62))	('TFE3', 'Gene', (103, 107))	('causes', 'Reg', (29, 35))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
164633	32286325	No TFEB rearranged translocation RCC was included in the analysis.	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('rearranged', 'Var', (8, 18))	('TFEB', 'Gene', (3, 7))	('TFEB', 'Gene', '7942', (3, 7))
164648	32286325	The TFE3 fusion resulted in a split-signal pattern.	('fusion', 'Var', (9, 15))	('TFE3', 'Gene', '7030', (4, 8))	('split-signal pattern', 'MPA', (30, 50))	('TFE3', 'Gene', (4, 8))
164659	27926518	In kidney clear cell cancer patients with high PD-L1 mRNA level and low PD-L1 mRNA level in tumors, the median overall survival periods were 45.0 and 37.1 months respectively (p=0.002).	('kidney clear cell cancer', 'Disease', (3, 27))	('PD-L1 mRNA level', 'MPA', (72, 88))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('kidney clear cell cancer', 'Disease', 'MESH:D008649', (3, 27))	('low', 'NegReg', (68, 71))	('PD-L1 mRNA level', 'MPA', (47, 63))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('clear cell cancer', 'Phenotype', 'HP:0006770', (10, 27))	('high', 'Var', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('patients', 'Species', '9606', (28, 36))	('tumors', 'Disease', (92, 98))
164661	27926518	However, no significant difference in overall survival status was found between high and low PD-L1 groups in kidney papillary cell carcinoma and kidney chromophobe cohorts.	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('low', 'NegReg', (89, 92))	('kidney papillary cell carcinoma and kidney chromophobe', 'Disease', 'MESH:D007681', (109, 163))	('PD-L1', 'Gene', (93, 98))	('high', 'Var', (80, 84))
164662	27926518	Gene-set enrichment analysis on the data from databases of TCGA and GSE53757 dataset in Gene Expression Omnibus databases showed that several pathways relating to immunological functions were activated in kidney clear cell cancers with high PD-L1 mRNA expression, and glycolysis and epithelial-mesenchymal transition pathways relating to tumor progression and metastasis were increased in kidney clear cell cancers with low PD-L1 mRNA level.	('cancers', 'Phenotype', 'HP:0002664', (407, 414))	('kidney clear cell cancers', 'Disease', (205, 230))	('kidney clear cell cancers', 'Disease', (389, 414))	('tumor', 'Disease', (338, 343))	('pathways', 'Pathway', (142, 150))	('clear cell cancer', 'Phenotype', 'HP:0006770', (212, 229))	('cancer', 'Phenotype', 'HP:0002664', (407, 413))	('Gene Expression', 'biological_process', 'GO:0010467', ('88', '103'))	('epithelial-mesenchymal transition pathways', 'Pathway', (283, 325))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('glycolysis', 'biological_process', 'GO:0006096', ('268', '278'))	('increased', 'PosReg', (376, 385))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('283', '316'))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('kidney clear cell cancers', 'Disease', 'MESH:D008649', (389, 414))	('kidney clear cell cancers', 'Disease', 'MESH:D008649', (205, 230))	('high', 'Var', (236, 240))	('PD-L1 mRNA expression', 'MPA', (241, 262))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('activated', 'PosReg', (192, 201))	('clear cell cancer', 'Phenotype', 'HP:0006770', (396, 413))
13864	27926518	Recently, mutations in PBRM1, BAP1 and SETD2 are identified to be the molecular biomarkers for the prognosis of RCC.	('PBRM1', 'Gene', (23, 28))	('PBRM1', 'Gene', '55193', (23, 28))	('BAP1', 'Gene', (30, 34))	('SETD2', 'Gene', (39, 44))	('BAP1', 'Gene', '8314', (30, 34))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('mutations', 'Var', (10, 19))	('SETD2', 'Gene', '29072', (39, 44))
164682	27926518	In KIRC cohort, patients in high PD-L1 group had a median overall survival of 45.0 months (0-149.1 months) longer than the median overall survival of 37.1 months (0-133.6 months) in low PD-L1 group.	('high PD-L1', 'Var', (28, 38))	('overall survival', 'MPA', (58, 74))	('patients', 'Species', '9606', (16, 24))	('longer', 'PosReg', (107, 113))
164683	27926518	Then we included the variables including age, gender, laterality, tumor grade, clinical stage, tumor stage, metastasis, and PD-L1 mRNA level into a multivariate Cox regression model and found that PD-L1 mRNA level was an independent predictor for overall survival status of KIRC patients (HR=0.7, 95% CI 0.5-0.9, p=0.007; Table 2).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('PD-L1', 'Var', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('patients', 'Species', '9606', (279, 287))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (95, 100))
164684	27926518	In addition to the significant difference in overall survival status between low PD-L1 group and high PD-L1 group, no differences were detected in clinical characteristics including age, laterality, clinical stage, tumor stage, metastasis, and tumor grade, except for a higher male ratio in low PD-L1 group (p=0.026, Table 3).	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('low', 'Var', (77, 80))	('tumor', 'Disease', (244, 249))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
164685	27926518	We further analyzed the gene expression data in tumors to compare the differences in cell processes such as immune, proliferation, metabolism and DNA damage repair between high PD-L1 group and low PD-L1 group in the KIRC cohort (Table 4).	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('gene expression', 'biological_process', 'GO:0010467', ('24', '39'))	('metabolism', 'biological_process', 'GO:0008152', ('131', '141'))	('metabolism', 'MPA', (131, 141))	('DNA damage', 'MPA', (146, 156))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('DNA', 'cellular_component', 'GO:0005574', ('146', '149'))	('immune', 'CPA', (108, 114))	('proliferation', 'CPA', (116, 129))	('high PD-L1', 'Var', (172, 182))
164686	27926518	A total of 10 pathways were upregulated in high PD-L1 group, and a total of 3 pathways were upregulated in low PD-L1 group of KIRC patients in both TCGA and GEO databases.	('patients', 'Species', '9606', (131, 139))	('upregulated', 'PosReg', (92, 103))	('high PD-L1', 'Var', (43, 53))	('low PD-L1', 'Var', (107, 116))	('pathways', 'Pathway', (14, 22))	('upregulated', 'PosReg', (28, 39))
164693	27926518	reported that mutations in von Hippel-Lindau (VHL) gene positively correlated with PD-L1 expression in KIRC cells but not in KIRP and KICH cells, suggesting that PD-L1 may play different role in different RCC subtypes and that anti-PD-1/PD-L1 therapy may not be suitable for all RCC patients.	('VHL', 'Gene', (46, 49))	('expression', 'MPA', (89, 99))	('RCC', 'Disease', (205, 208))	('VHL', 'Gene', '7428', (46, 49))	('von Hippel-Lindau', 'Gene', (27, 44))	('correlated', 'Reg', (67, 77))	('patients', 'Species', '9606', (283, 291))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('RCC', 'Disease', 'MESH:C538614', (279, 282))	('RCC', 'Phenotype', 'HP:0005584', (205, 208))	('PD-L1', 'Gene', (83, 88))	('von Hippel-Lindau', 'Gene', '7428', (27, 44))	('mutations', 'Var', (14, 23))	('RCC', 'Disease', (279, 282))	('RCC', 'Phenotype', 'HP:0005584', (279, 282))
164699	27926518	Recently, a prospective study revealed that tumors with higher PD-L1 expression had a better response to high-dose IL-2 than those with negative PD-L1 expression.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('IL-2', 'Gene', '3558', (115, 119))	('IL-2', 'Gene', (115, 119))	('PD-L1', 'Gene', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('higher', 'PosReg', (56, 62))	('IL-2', 'molecular_function', 'GO:0005134', ('115', '119'))	('expression', 'Var', (69, 79))
164723	32219034	The mRNA expression levels in the NFI family were significantly downregulated in most cancers compared with normal tissues and DNA hypermethylation might downregulate the NFI family expression.	('expression', 'MPA', (182, 192))	('NFI family', 'Gene', (34, 44))	('hypermethylation', 'Var', (131, 147))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mRNA expression levels', 'MPA', (4, 26))	('downregulate', 'NegReg', (154, 166))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('127', '147'))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('NFI', 'Protein', (171, 174))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))	('downregulated', 'NegReg', (64, 77))
164726	32219034	Further survival analyses based on the KM plotter and SurvExpress databases showed dysregulations of the NFI genes were significantly correlated with survival outcomes in breast, lung, and head and neck cancers.	('NFI genes', 'Gene', (105, 114))	('head and neck cancer', 'Phenotype', 'HP:0012288', (189, 209))	('head and neck cancers', 'Phenotype', 'HP:0012288', (189, 210))	('head and neck cancers', 'Disease', 'MESH:D006258', (189, 210))	('neck', 'cellular_component', 'GO:0044326', ('198', '202'))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('dysregulations', 'Var', (83, 97))	('breast', 'Disease', (171, 177))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('lung', 'Disease', (179, 183))	('correlated with', 'Reg', (134, 149))
164774	32219034	Breast invasive carcinoma patients with a NFIX gene alteration showed significantly poor overall survival (OS) and disease-free survival (DFS) compared with breast invasive carcinoma patients without NFIX gene alteration.	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (157, 182))	('OS', 'Chemical', '-', (107, 109))	('poor', 'NegReg', (84, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('Breast invasive carcinoma', 'Disease', (0, 25))	('Breast invasive carcinoma', 'Phenotype', 'HP:0003002', (0, 25))	('alteration', 'Var', (52, 62))	('disease-free survival', 'CPA', (115, 136))	('NFIX', 'Gene', (42, 46))	('Breast invasive carcinoma', 'Disease', 'MESH:D018270', (0, 25))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (157, 182))	('overall survival', 'CPA', (89, 105))	('breast invasive carcinoma', 'Disease', (157, 182))
164779	32219034	Decreased NFIA expression showed better RFS, OS and DMFS in the HER2-enriched subtype.	('OS', 'Chemical', '-', (45, 47))	('NFIA', 'Protein', (10, 14))	('Decreased', 'NegReg', (0, 9))	('DMFS', 'Var', (52, 56))	('RFS', 'MPA', (40, 43))	('expression', 'MPA', (15, 25))	('better', 'PosReg', (33, 39))
164793	32219034	The NFI genes in lung cancer were analyzed and depicted as oncoprints representing mutation, amplification, deep deletion, mRNA high, mRNA low, and multiple alterations (Figs.	('amplification', 'Var', (93, 106))	('deep deletion', 'Var', (108, 121))	('lung cancer', 'Disease', (17, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('NFI', 'Gene', (4, 7))
164794	32219034	Lung adenocarcinoma patients with NFIB gene alteration showed better DFS compared with lung adenocarcinoma patients without NFIB gene alteration (Fig.	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('lung adenocarcinoma', 'Disease', (87, 106))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (87, 106))	('better', 'PosReg', (62, 68))	('DFS', 'MPA', (69, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('Lung adenocarcinoma', 'Disease', (0, 19))	('NFIB', 'Gene', (34, 38))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (87, 106))	('gene alteration', 'Var', (39, 54))
164795	32219034	Lung squamous cell carcinoma patients with NFIA gene alteration showed worse OS compared with lung squamous cell carcinoma patients without NFIA gene alterations (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (94, 122))	('gene alteration', 'Var', (48, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 122))	('lung squamous cell carcinoma', 'Disease', (94, 122))	('OS', 'Chemical', '-', (77, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (5, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('squamous cell carcinoma', 'Disease', (5, 28))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 122))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (5, 28))
164812	32219034	Bladder urothelial carcinoma patients with NFIB gene alteration showed significantly better OS compared with bladder urothelial patients without NFIB gene alteration.	('better', 'PosReg', (85, 91))	('urothelial carcinoma', 'Disease', (8, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('gene alteration', 'Var', (48, 63))	('NFIB', 'Gene', (43, 47))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (8, 28))	('OS', 'Chemical', '-', (92, 94))	('bladder urothelial', 'Disease', 'MESH:D001745', (109, 127))	('bladder urothelial', 'Disease', (109, 127))
164827	32219034	Head and neck cancer patients with NFIA gene alteration showed better OS compared with head and neck cancer patients without NFIA gene alteration.	('OS', 'Chemical', '-', (70, 72))	('neck', 'cellular_component', 'GO:0044326', ('9', '13'))	('neck cancer', 'Disease', 'MESH:D006258', (96, 107))	('NFIA', 'Gene', (35, 39))	('head and neck cancer', 'Phenotype', 'HP:0012288', (87, 107))	('neck cancer', 'Disease', 'MESH:D006258', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('neck cancer', 'Disease', (9, 20))	('Head and neck cancer', 'Phenotype', 'HP:0012288', (0, 20))	('better', 'PosReg', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('neck', 'cellular_component', 'GO:0044326', ('96', '100'))	('gene alteration', 'Var', (40, 55))	('neck cancer', 'Disease', (96, 107))
164856	32219034	The NFI genes in kidney cancer were analyzed and depicted as oncoprints representing mutation, amplification, deep deletion, mRNA high, mRNA low and multiple alterations (Figs.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('kidney cancer', 'Phenotype', 'HP:0009726', (17, 30))	('kidney cancer', 'Disease', 'MESH:D007680', (17, 30))	('deep deletion', 'Var', (110, 123))	('kidney cancer', 'Disease', (17, 30))	('amplification', 'Var', (95, 108))	('NFI', 'Gene', (4, 7))
164858	32219034	Kidney renal papillary cell carcinoma patients with NFIX gene alteration showed worse OS compared with kidney renal papillary cell carcinoma patients without NFIX gene alteration (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('kidney renal papillary cell carcinoma', 'Disease', (103, 140))	('OS', 'Chemical', '-', (86, 88))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (103, 140))	('Kidney renal papillary cell carcinoma', 'Disease', (0, 37))	('gene alteration', 'Var', (57, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('Kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (0, 37))	('NFIX', 'Gene', (52, 56))
164895	32219034	In the KM plotter database, high NFIA and NFIX expression predicted better OS and disease-specific survival (DSS) in liver cancer patients.	('DSS', 'Chemical', '-', (109, 112))	('NFIX', 'Protein', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('disease-specific survival', 'CPA', (82, 107))	('better', 'PosReg', (68, 74))	('liver cancer', 'Phenotype', 'HP:0002896', (117, 129))	('OS', 'Chemical', '-', (75, 77))	('liver cancer', 'Disease', 'MESH:D006528', (117, 129))	('liver cancer', 'Disease', (117, 129))	('NFIA', 'Protein', (33, 37))	('high', 'Var', (28, 32))
164913	32219034	Survival analysis indicated that almost none of the NFI genes with gene alterations were associated with OS or DFS.	('associated', 'Reg', (89, 99))	('gene alterations', 'Var', (67, 83))	('NFI genes', 'Gene', (52, 61))	('OS', 'Chemical', '-', (105, 107))	('DFS', 'Disease', (111, 114))
164914	32219034	These findings indicate that NFI gene alterations might not independently influence its transcription in various tumors.	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('transcription', 'biological_process', 'GO:0006351', ('88', '101'))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('alterations', 'Var', (38, 49))	('NFI gene', 'Gene', (29, 37))	('transcription', 'MPA', (88, 101))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
164918	32219034	Glioblastoma multiforme (GBM) patients with higher NFIB expression survived significantly longer than patients with lower NFIB expression.	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (0, 23))	('NFIB', 'Protein', (51, 55))	('Glioblastoma multiforme', 'Disease', (0, 23))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('expression', 'Var', (56, 66))
164919	32219034	In another study, NFIX DNA hypermethylation was reportedly associated with significantly decreased NFIX expression and was related to shorter OS and RFS in patients with lung adenocarcinoma.	('hypermethylation', 'Var', (27, 43))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (170, 189))	('RFS', 'MPA', (149, 152))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('23', '43'))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('OS', 'Chemical', '-', (142, 144))	('DNA', 'cellular_component', 'GO:0005574', ('23', '26'))	('lung adenocarcinoma', 'Disease', (170, 189))	('shorter OS', 'Disease', (134, 144))	('expression', 'MPA', (104, 114))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (170, 189))	('NFIX', 'Protein', (99, 103))	('NFIX', 'Gene', (18, 22))	('decreased', 'NegReg', (89, 98))
164921	32219034	In a previous study, high NFIA expression was shown an independent predictor of poor prognosis in esophageal squamous carcinoma, and high NFIB expression was a negative prognostic value in esophagogastric junction adenocarcinoma.	('high', 'Var', (133, 137))	('esophagogastric junction adenocarcinoma', 'Phenotype', 'HP:0011459', (189, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('high', 'Var', (21, 25))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (109, 127))	('esophagogastric junction adenocarcinoma', 'Disease', (189, 228))	('esophagogastric junction adenocarcinoma', 'Disease', 'MESH:C537006', (189, 228))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (98, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (98, 127))	('esophageal squamous carcinoma', 'Disease', (98, 127))
164923	32219034	In the present study, high expression of NFIA, NFIB and NFIX was significantly associated with improved prognosis in breast cancer.	('high expression', 'Var', (22, 37))	('NFIX', 'Gene', (56, 60))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('NFIB', 'Gene', (47, 51))	('improved', 'PosReg', (95, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('NFIA', 'Gene', (41, 45))
164929	32219034	In gastric cancer, high NFIX expression was significantly correlated with better overall prognosis in gastric cancer and HER2+ gastric cancer, and marginally correlated with PPS in HER2-gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('HER2-gastric cancer', 'Disease', 'MESH:D013274', (181, 200))	('gastric cancer', 'Disease', (102, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (186, 200))	('gastric cancer', 'Disease', (127, 141))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('gastric cancer', 'Disease', 'MESH:D013274', (127, 141))	('better', 'PosReg', (74, 80))	('HER2-gastric cancer', 'Disease', (181, 200))	('PPS', 'Chemical', '-', (174, 177))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('NFIX expression', 'MPA', (24, 39))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (127, 141))	('high', 'Var', (19, 23))	('gastric cancer', 'Disease', 'MESH:D013274', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
164935	32219034	The breast cancer cell line, MCF7, treated with NFIC siRNA, enhanced EMT, motility, migration and invasion.	('EMT', 'biological_process', 'GO:0001837', ('69', '72'))	('EMT', 'CPA', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('NFIC', 'Var', (48, 52))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('MCF7', 'CellLine', 'CVCL:0031;0.06756287128990074', (29, 33))	('invasion', 'CPA', (98, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('motility', 'CPA', (74, 82))	('enhanced', 'PosReg', (60, 68))
164938	32219034	Genomic analysis showed the alterations in each NFI family gene were less frequent in various tumors and had little influence on survival outcomes.	('NFI family gene', 'Gene', (48, 63))	('alterations', 'Var', (28, 39))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('less', 'NegReg', (69, 73))
164940	32219034	A certain negative correlation was observed, indicating that epigenetic alteration is an important mechanism of dysregulated NFI expression in human cancers.	('cancers', 'Disease', (149, 156))	('NFI', 'Gene', (125, 128))	('cancers', 'Disease', 'MESH:D009369', (149, 156))	('epigenetic alteration', 'Var', (61, 82))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))
164963	31672930	reported that proliferation of Treg cells induced by PD-1 blockade results in the inhibition of antitumor immunity, which reduces the effect of anti-PD-1.	('PD-1', 'Gene', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('proliferation', 'CPA', (14, 27))	('tumor', 'Disease', (100, 105))	('inhibition', 'NegReg', (82, 92))	('blockade', 'Var', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
164996	31672930	A recent study reported that mutated and overexpressed LCK promoted the proliferation of acute myeloid leukemia cell lines.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (95, 111))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (89, 111))	('proliferation', 'CPA', (72, 85))	('leukemia', 'Phenotype', 'HP:0001909', (103, 111))	('acute myeloid leukemia', 'Disease', (89, 111))	('LCK', 'Gene', (55, 58))	('promoted', 'PosReg', (59, 67))	('mutated', 'Var', (29, 36))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (89, 111))
165002	31672930	Consistently, studies also demonstrated that mice that received adoptive transfer of MAP4K1 knockout T cells became resistant to lung cancer growth via mounting effective anti-tumor immune responses, suggesting that inhibition of MAP4K1 could be a viable approach for cancer immune therapy by promoting the effector functions of T cells.	('mice', 'Species', '10090', (45, 49))	('MAP4K1', 'Gene', (230, 236))	('promoting', 'PosReg', (293, 302))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('MAP4K1', 'Gene', (85, 91))	('tumor', 'Disease', (176, 181))	('cancer', 'Disease', (134, 140))	('inhibition', 'Var', (216, 226))	('effector functions', 'CPA', (307, 325))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('MAP', 'molecular_function', 'GO:0004239', ('230', '233'))	('cancer', 'Disease', (268, 274))	('lung cancer', 'Disease', (129, 140))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('MAP', 'molecular_function', 'GO:0004239', ('85', '88'))
165003	31672930	reported that inhibition of MAP4K1 will synergize with immune checkpoint modulator blockade as well as targets related to the prostaglandin E2 and adenosine pathways.	('adenosine', 'Chemical', 'MESH:D000241', (147, 156))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (126, 142))	('MAP4K1', 'Gene', (28, 34))	('MAP', 'molecular_function', 'GO:0004239', ('28', '31'))	('inhibition', 'Var', (14, 24))
165036	32547210	Mutations and other genomic alterations can lead to aberrant activation of RTKs, causing dysregulated cell signaling that promotes angiogenesis, proliferation, and protection from apoptosis; resulting in tumor growth and metastasis.	('dysregulated cell signaling', 'MPA', (89, 116))	('angiogenesis', 'CPA', (131, 143))	('RTKs', 'Gene', (75, 79))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('signaling', 'biological_process', 'GO:0023052', ('107', '116'))	('promotes', 'PosReg', (122, 130))	('apoptosis', 'biological_process', 'GO:0097194', ('180', '189'))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('angiogenesis', 'biological_process', 'GO:0001525', ('131', '143'))	('proliferation', 'CPA', (145, 158))	('activation', 'PosReg', (61, 71))	('apoptosis', 'biological_process', 'GO:0006915', ('180', '189'))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (204, 209))	('protection', 'CPA', (164, 174))
165058	32547210	Therefore, inhibitors of CYP3A4 and MRP2, along with high-fat diet or hepatic impairment, can increase its systemic exposure.	('MRP2', 'Gene', '1244', (36, 40))	('MRP2', 'Gene', (36, 40))	('increase', 'PosReg', (94, 102))	('CYP3A4', 'Gene', (25, 31))	('hepatic impairment', 'Disease', 'MESH:D008107', (70, 88))	('inhibitors', 'Var', (11, 21))	('systemic exposure', 'MPA', (107, 124))	('CYP3A4', 'Gene', '1576', (25, 31))	('CYP3A4', 'molecular_function', 'GO:0033780', ('25', '31'))	('hepatic impairment', 'Disease', (70, 88))
165076	32547210	In PD-L1 positive patients (>=1%), cabozantinib had a non-statistically significant longer median PFS (5.6 months vs 3.7 months; HR 0.66 95% CI 0.40-1.11) and longer median OS (18.4 months vs 13.9 months, HR 0.82; 95% CI 0.47-1.41) as compared to everolimus.	('cabozantinib', 'Var', (35, 47))	('PD-L1', 'Gene', '29126', (3, 8))	('PFS', 'MPA', (98, 101))	('cabozantinib', 'Chemical', 'MESH:C558660', (35, 47))	('OS', 'Gene', '17451', (173, 175))	('patients', 'Species', '9606', (18, 26))	('PD-L1', 'Gene', (3, 8))	('everolimus', 'Chemical', 'MESH:D000068338', (247, 257))	('longer', 'PosReg', (84, 90))
165090	32547210	In patients with MET-positive tumors (defined as >=50% of tumor cells staining 2+ or 3+ by immunohistochemistry), cabozantinib showed a higher median PFS of 13.8 months, as compared to 3.0 months with sunitinib (HR 0.32; 95% CI, 0.16-0.63).	('tumors', 'Disease', (30, 36))	('tumor', 'Disease', (58, 63))	('cabozantinib', 'Var', (114, 126))	('PFS', 'MPA', (150, 153))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('cabozantinib', 'Chemical', 'MESH:C558660', (114, 126))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('higher', 'PosReg', (136, 142))	('sunitinib', 'Chemical', 'MESH:D000077210', (201, 210))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('MET-positive', 'Var', (17, 29))	('tumor', 'Disease', (30, 35))
165095	32547210	In PD-L1 negative patients, cabozantinib showed a longer median PFS (11 months vs 5 months; HR 0.47, 95% CI 0.26-0.86) and a non-statistically significant longer median OS (30.3 months vs 22.4 months, HR 0.71, 95% CI 0.39-1.29), as compared to sunitinib.	('PD-L1', 'Gene', '29126', (3, 8))	('PFS', 'MPA', (64, 67))	('cabozantinib', 'Var', (28, 40))	('sunitinib', 'Chemical', 'MESH:D000077210', (244, 253))	('OS', 'Gene', '17451', (169, 171))	('cabozantinib', 'Chemical', 'MESH:C558660', (28, 40))	('patients', 'Species', '9606', (18, 26))	('PD-L1', 'Gene', (3, 8))
165097	32547210	In vitro, MET knockdown was shown to prevent MHCC97-L cells from proliferating by arresting cells at the G0-G1 phase.	('HCC', 'Gene', '619501', (46, 49))	('proliferating', 'CPA', (65, 78))	('prevent', 'NegReg', (37, 44))	('G1 phase', 'biological_process', 'GO:0051318', ('108', '116'))	('HCC', 'Gene', (46, 49))	('knockdown', 'Var', (14, 23))
165108	32547210	In the randomized phase, where patients were randomized to receive cabozantinib versus placebo after the 12-week treatment with cabozantinib, there was a numerical increase in the median PFS with cabozantinib (2.5 months, 95% CI 1.3-6.8 months) as compared to placebo (1.4 months, 95% CI, 1.3-4.2 months), although this difference was not statistically significant.	('cabozantinib', 'Chemical', 'MESH:C558660', (128, 140))	('patients', 'Species', '9606', (31, 39))	('PFS', 'MPA', (187, 190))	('cabozantinib', 'Chemical', 'MESH:C558660', (196, 208))	('cabozantinib', 'Chemical', 'MESH:C558660', (67, 79))	('increase', 'PosReg', (164, 172))	('cabozantinib', 'Var', (196, 208))
165122	32547210	Regarding quality of life assessments, cabozantinib was associated with a slight decrease in health utility initially, but an overall increase in health utility with continued treatment.	('health utility', 'MPA', (146, 160))	('health utility', 'MPA', (93, 107))	('decrease', 'NegReg', (81, 89))	('cabozantinib', 'Chemical', 'MESH:C558660', (39, 51))	('cabozantinib', 'Var', (39, 51))	('increase', 'PosReg', (134, 142))
165127	32547210	In mutant TPR-MET transformed Ba/F3 cells, cabozantinib treatment has shown to give rise to a broad range of unique mutants, such as F1200 and G1163R, etc., that are associated with cabozantinib resistance.	('mutant', 'Var', (3, 9))	('cabozantinib', 'Chemical', 'MESH:C558660', (182, 194))	('F1200', 'Var', (133, 138))	('Ba/F3', 'CellLine', 'CVCL:0161', (30, 35))	('TPR-MET', 'Gene', (10, 17))	('G1163R', 'Mutation', 'p.G1163R', (143, 149))	('associated', 'Reg', (166, 176))	('G1163R', 'Var', (143, 149))	('cabozantinib', 'Chemical', 'MESH:C558660', (43, 55))
165128	32547210	In advanced RET-rearranged lung cancers, MDM2 amplification has been implicated in primary and acquired resistance to cabozantinib.	('lung cancers', 'Disease', (27, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('amplification', 'Var', (46, 59))	('MDM2', 'Gene', '4193', (41, 45))	('lung cancers', 'Disease', 'MESH:D008175', (27, 39))	('RET', 'Gene', '5979', (12, 15))	('MDM2', 'Gene', (41, 45))	('cabozantinib', 'Chemical', 'MESH:C558660', (118, 130))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('RET', 'Gene', (12, 15))	('lung cancers', 'Phenotype', 'HP:0100526', (27, 39))	('implicated', 'Reg', (69, 79))
165129	32547210	In NTRK1 gene rearranged KM12 colorectal cancer cells, activation of IGF1R has shown to mediate resistance to cabozantinib, as have various NTRK1 mutations like G595R, G595L, L564H, F646I, and D679G.	('G595L', 'Mutation', 'p.G595L', (168, 173))	('L564H', 'Var', (175, 180))	('F646I', 'Mutation', 'p.F646I', (182, 187))	('NTRK1', 'Gene', '4914', (3, 8))	('D679G', 'Mutation', 'p.D679G', (193, 198))	('colorectal cancer', 'Phenotype', 'HP:0003003', (30, 47))	('G595R', 'Mutation', 'rs746049437', (161, 166))	('G595R', 'Var', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('L564H', 'Mutation', 'p.L564H', (175, 180))	('NTRK1', 'Gene', (3, 8))	('F646I', 'Var', (182, 187))	('G595L', 'Var', (168, 173))	('IGF1R', 'Gene', '3480', (69, 74))	('colorectal cancer', 'Disease', 'MESH:D015179', (30, 47))	('IGF1R', 'Gene', (69, 74))	('activation', 'PosReg', (55, 65))	('resistance to cabozantinib', 'MPA', (96, 122))	('colorectal cancer', 'Disease', (30, 47))	('cabozantinib', 'Chemical', 'MESH:C558660', (110, 122))	('NTRK1', 'Gene', '4914', (140, 145))	('D679G', 'Var', (193, 198))	('NTRK1', 'Gene', (140, 145))
165161	31861377	The group of Prof. Ian Frew showed that deletion of renal expression of the tumor suppressor von Hippel-Lindau (VHL) protein altered the urine concentration capability in mice.	('urine concentration capability', 'MPA', (137, 167))	('von Hippel-Lindau', 'Disease', (93, 110))	('mice', 'Species', '10090', (171, 175))	('deletion', 'Var', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('altered', 'Reg', (125, 132))	('VHL', 'Gene', (112, 115))	('rat', 'Species', '10116', (150, 153))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('76', '92'))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (93, 110))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('76', '92'))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
165177	31861377	Interestingly, the induction of ELF5 expression was higher in VHL+ cells than in VHL-deficient cells.	('induction', 'MPA', (19, 28))	('VHL+', 'Var', (62, 66))	('ELF5', 'Gene', '2001', (32, 36))	('higher', 'PosReg', (52, 58))	('expression', 'MPA', (37, 47))	('ELF5', 'Gene', (32, 36))
165195	31861377	In a recent manuscript that we have submitted to Cancers we were able to show that the deletion of VHL also reduced the expression of several other hyper-osmolality-induced genes.	('expression', 'MPA', (120, 130))	('reduced', 'NegReg', (108, 115))	('VHL', 'Gene', (99, 102))	('Cancers', 'Phenotype', 'HP:0002664', (49, 56))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Cancers', 'Disease', (49, 56))	('Cancers', 'Disease', 'MESH:D009369', (49, 56))	('deletion', 'Var', (87, 95))
165357	30740580	Although being T2 hypointense may mimic a pRCC, the specificity and accuracy for discriminating angiomyolipoma from RCC using T2 hypointensity combined with the enhancement pattern has been described as 99% and 96%, respectively.	('pRCC', 'Gene', '5546', (42, 46))	('T2 hypointensity', 'Var', (126, 142))	('angiomyolipoma', 'Disease', (96, 110))	('angiomyolipoma', 'Disease', 'MESH:D018207', (96, 110))	('angiomyolipoma', 'Phenotype', 'HP:0006772', (96, 110))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('pRCC', 'Gene', (42, 46))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))
165416	29033582	Mutation or silencing of the von Hippel-Lindau gene (VHL) occurs in nearly 80% of sporadic ccRCC tumors.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('RCC', 'Disease', (93, 96))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (29, 46))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('VHL', 'Gene', (53, 56))	('Mutation', 'Var', (0, 8))	('silencing', 'Var', (12, 21))	('von Hippel-Lindau', 'Disease', (29, 46))	('VHL', 'Gene', '7428', (53, 56))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
165418	29033582	In the absence of pVHL, HIF subunits (HIF-1alpha and HIF-2alpha) are stabilized, translocate to the nucleus, dimerize with the stable beta-subunit (ARNT) and promote the expression of their target genes such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).	('VEGF', 'Gene', '7422', (247, 251))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('257', '287'))	('ARNT', 'Gene', '405', (148, 152))	('vascular endothelial growth factor', 'Gene', '7422', (211, 245))	('pVHL', 'Gene', '7428', (18, 22))	('PDGF', 'molecular_function', 'GO:0005161', ('289', '293'))	('pVHL', 'Gene', (18, 22))	('promote', 'PosReg', (158, 165))	('platelet-derived', 'Gene', (257, 273))	('ARNT', 'Gene', (148, 152))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (38, 63))	('VEGF', 'Gene', (247, 251))	('dimerize', 'Var', (109, 117))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('211', '245'))	('nucleus', 'cellular_component', 'GO:0005634', ('100', '107'))	('vascular endothelial growth factor', 'Gene', (211, 245))	('translocate', 'MPA', (81, 92))	('expression', 'MPA', (170, 180))
165475	29033582	Significant association with lower PFS was identified for double c-Myc/HIF-2alpha-positive staining (4.3 vs 11.5 months) in tumors with at least one negative biomarker (HR =2.64, 95% CI: 1.03-6.80, P=0.0360), as shown in Figure 3.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('c-Myc', 'Gene', (65, 70))	('HIF-2alpha', 'Gene', (71, 81))	('PFS', 'MPA', (35, 38))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('HIF-2alpha', 'Gene', '2034', (71, 81))	('lower', 'NegReg', (29, 34))	('c-Myc', 'Gene', '4609', (65, 70))	('double', 'Var', (58, 64))
165490	29033582	Many clinical studies have correlated the presence of either HIF-alpha subunit with poor patient outcomes.	('patient', 'Species', '9606', (89, 96))	('presence', 'Var', (42, 50))	('HIF-alpha', 'Protein', (61, 70))
165509	28740578	Clinical performance of E2Fs 1-3 in kidney clear cell renal cancer, evidence from bioinformatics analysis Extensive research on the E2F transcription factor family has led to numerous insights that E2Fs were involved not only in proliferation and tumorigenesis but also in apoptosis and differentiation.	('E2Fs 1-3', 'Gene', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('kidney clear cell renal cancer', 'Disease', 'MESH:D007680', (36, 66))	('proliferation', 'CPA', (229, 242))	('apoptosis', 'biological_process', 'GO:0097194', ('273', '282'))	('transcription', 'biological_process', 'GO:0006351', ('136', '149'))	('transcription factor', 'molecular_function', 'GO:0000981', ('136', '156'))	('apoptosis', 'biological_process', 'GO:0006915', ('273', '282'))	('involved', 'Reg', (208, 216))	('kidney clear cell renal cancer', 'Disease', (36, 66))	('differentiation', 'CPA', (287, 302))	('clear cell renal cancer', 'Phenotype', 'HP:0006770', (43, 66))	('apoptosis', 'CPA', (273, 282))	('tumor', 'Disease', (247, 252))	('E2Fs', 'Var', (198, 202))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('E2Fs 1-3', 'Gene', '1869;1870;1871', (24, 32))	('renal cancer', 'Phenotype', 'HP:0009726', (54, 66))
165511	28740578	The results showed that E2F1, E2F2 and E2F3 expression was increased in KIRC tissues than matched normal tissues (E2F1, P < 0.001; E2F2, P < 0.001, E2F3, P = 0.001), respectively.	('E2F2', 'Gene', '1870', (30, 34))	('E2F2', 'Gene', (131, 135))	('expression', 'MPA', (44, 54))	('E2F2', 'Gene', (30, 34))	('E2F3', 'Gene', (39, 43))	('E2F2', 'Gene', '1870', (131, 135))	('increased', 'PosReg', (59, 68))	('E2F1', 'Gene', (24, 28))	('E2F1', 'Var', (114, 118))
165512	28740578	E2F1, E2F2 and E2F3 were significantly different in metastasis status, lymph node status, stage, and T stage in KIRC patients (all P < 0.01).	('lymph node status', 'CPA', (71, 88))	('E2F2', 'Gene', '1870', (6, 10))	('E2F3', 'Var', (15, 19))	('metastasis status', 'CPA', (52, 69))	('stage', 'CPA', (90, 95))	('E2F1', 'Var', (0, 4))	('E2F2', 'Gene', (6, 10))	('different', 'Reg', (39, 48))	('patients', 'Species', '9606', (117, 125))	('T stage', 'CPA', (101, 108))
165513	28740578	E2F1 and E2F2 had the sensitivity of 96.1% and 93.1% and the specificity of 87.2% and 91.7% in discriminating KIRC from normal controls.	('E2F2', 'Gene', (9, 13))	('E2F1', 'Var', (0, 4))	('E2F2', 'Gene', '1870', (9, 13))
165514	28740578	High E2F1, E2F2 and E2F3 expression were correlated to worsen overall survival (all P < 0.01), and high E2F3 expression had worse disease free survival (P = 0.0404).	('High E2F1', 'Var', (0, 9))	('E2F1', 'Var', (5, 9))	('overall survival', 'CPA', (62, 78))	('high E2F3', 'Var', (99, 108))	('E2F2', 'Gene', '1870', (11, 15))	('E2F3', 'Var', (20, 24))	('disease free survival', 'CPA', (130, 151))	('E2F2', 'Gene', (11, 15))	('worsen', 'NegReg', (55, 61))
165515	28740578	Multivariate Cox regression analysis revealed that E2F1 and E2F3 were independent prognostic factors for overall survival.	('E2F3', 'Var', (60, 64))	('Cox', 'Gene', (13, 16))	('E2F1', 'Var', (51, 55))	('overall', 'MPA', (105, 112))	('Cox', 'Gene', '1351', (13, 16))
165516	28740578	Taken together, E2F1 and E2F2 may serve as valuable diagnostic markers for KIRC.	('E2F2', 'Gene', '1870', (25, 29))	('E2F1', 'Var', (16, 20))	('E2F2', 'Gene', (25, 29))	('KIRC', 'Disease', (75, 79))
165517	28740578	Moreover, E2F1, E2F2 and E2F3 could provide valuable prognostic information for KIRC patients.	('KIRC', 'Disease', (80, 84))	('E2F2', 'Gene', (16, 20))	('E2F1', 'Var', (10, 14))	('patients', 'Species', '9606', (85, 93))	('E2F3', 'Var', (25, 29))	('E2F2', 'Gene', '1870', (16, 20))
165524	28740578	The E2F family of transcription factors consists of eight proteins (E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, E2F7 and E2F8) that bind to the consensus E2F motif (TTTCGCGC).	('E2F3', 'Var', (80, 84))	('E2F5', 'Gene', '1875', (92, 96))	('E2F4', 'Gene', (86, 90))	('E2F7', 'Gene', '144455', (104, 108))	('E2F1', 'Var', (68, 72))	('E2F7', 'Gene', (104, 108))	('E2F2', 'Gene', (74, 78))	('E2F8', 'Gene', (113, 117))	('E2F4', 'Gene', '1874', (86, 90))	('transcription', 'biological_process', 'GO:0006351', ('18', '31'))	('E2F2', 'Gene', '1870', (74, 78))	('E2F8', 'Gene', '79733', (113, 117))	('E2F6', 'Gene', '1876', (98, 102))	('E2F6', 'Gene', (98, 102))	('E2F5', 'Gene', (92, 96))
165525	28740578	The E2Fs members are divided into two subfamilies: E2Fs 1-3 are activators of transcription, whereas E2Fs 4-8 act as repressors.	('E2Fs 4-8', 'Gene', (101, 109))	('E2Fs 4-8', 'Gene', '1874;1875;1876;144455;79733', (101, 109))	('E2Fs', 'Var', (51, 55))	('activators', 'MPA', (64, 74))	('transcription', 'biological_process', 'GO:0006351', ('78', '91'))
165526	28740578	There is growing evidence that deregulation of the E2F family itself is crucially involved in carcinogenesis.	('involved', 'Reg', (82, 90))	('deregulation', 'Var', (31, 43))	('E2F family', 'Protein', (51, 61))	('carcinogenesis', 'Disease', 'MESH:D063646', (94, 108))	('carcinogenesis', 'Disease', (94, 108))
165527	28740578	However, most of the studies done thus far focused on the deregulation of proliferation-promoting members of the E2F family, especially E2F1, E2F2, and E2F3.	('E2F1', 'Var', (136, 140))	('E2F2', 'Gene', '1870', (142, 146))	('E2F2', 'Gene', (142, 146))	('proliferation-promoting', 'CPA', (74, 97))	('E2F', 'Gene', (113, 116))	('deregulation', 'MPA', (58, 70))	('E2F3', 'Var', (152, 156))
165530	28740578	Recent study reported that E2F3 acted to transactivate HIF-2alpha transcription in ccRCC, which in turn exerted a serial effect on the pivotal epithelial-mesenchymal transition-related genes.	('HIF-2alpha', 'Gene', (55, 65))	('transactivate', 'PosReg', (41, 54))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('143', '176'))	('transcription', 'biological_process', 'GO:0006351', ('66', '79'))	('HIF-2alpha', 'Gene', '2034', (55, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('ccRCC', 'Disease', (83, 88))	('E2F3', 'Var', (27, 31))
165537	28740578	As shown in Figure 1, E2F1, E2F2 and E2F3 mRNA levels were increased in KIRC tissues than matched normal tissues (E2F1, P < 0.001; E2F2, P < 0.001, E2F3, P = 0.001), respectively.	('E2F2', 'Gene', (131, 135))	('mRNA levels', 'MPA', (42, 53))	('E2F2', 'Gene', '1870', (28, 32))	('E2F3', 'Var', (37, 41))	('E2F2', 'Gene', '1870', (131, 135))	('increased', 'PosReg', (59, 68))	('E2F2', 'Gene', (28, 32))	('E2F1', 'MPA', (22, 26))
165538	28740578	Moreover, E2F1, E2F2 and E2F3 were on average 1.38-fold, 1.74-fold, and 1.02-fold over-expressed in KIRC tissues.	('E2F2', 'Gene', (16, 20))	('E2F1', 'Var', (10, 14))	('E2F3', 'Var', (25, 29))	('E2F2', 'Gene', '1870', (16, 20))	('over-expressed', 'PosReg', (82, 96))
165542	28740578	However, no significant difference was observed in age, gender, and tumor size for E2F1 and E2F2, and no significant difference in age and gender for E2F3 expression (all P > 0.05).	('tumor', 'Disease', (68, 73))	('E2F2', 'Gene', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('E2F1', 'Var', (83, 87))	('E2F2', 'Gene', '1870', (92, 96))
165543	28740578	The diagnostic performances of E2F1, E2F2 and E2F3 were examined by performing receiver operating characteristic (ROC) curve analysis.	('E2F2', 'Gene', (37, 41))	('E2F1', 'Var', (31, 35))	('E2F3', 'Var', (46, 50))	('E2F2', 'Gene', '1870', (37, 41))
165544	28740578	As shown in Figure 2, the area under curve (AUC) values of E2F1and E2F2 were 0.944 (95%CI: 0.904-0.983) and 0.942 (95%CI: 0.903-0.982), respectively.	('E2F2', 'Gene', '1870', (67, 71))	('E2F1and', 'Var', (59, 66))	('E2F2', 'Gene', (67, 71))
165545	28740578	The sensitivity and specificity reached 96.1% and 87.2% for E2F1, and 93.1% and 91.7% for E2F2 in discriminating KIRC from normal controls.	('E2F2', 'Gene', '1870', (90, 94))	('E2F2', 'Gene', (90, 94))	('E2F1', 'Var', (60, 64))
165546	28740578	Based on the median of E2F1, E2F2 and E2F3, we performed the Kaplan-Meier analysis to estimate patient's OS and DFS.	('E2F2', 'Gene', (29, 33))	('patient', 'Species', '9606', (95, 102))	('E2F1', 'Var', (23, 27))	('E2F3', 'Var', (38, 42))	('OS', 'Chemical', '-', (105, 107))	('E2F2', 'Gene', '1870', (29, 33))
165547	28740578	As shown in Figure 3, Kaplan-Meier survival curve showed that patients with high E2F1 expression had worse OS in KIRC patients (hazard ratio [HR] = 1.537 [95%CI: 1.139-2.069], P = 0.0049).	('OS', 'Chemical', '-', (107, 109))	('expression', 'MPA', (86, 96))	('high', 'Var', (76, 80))	('E2F1', 'Gene', (81, 85))	('patients', 'Species', '9606', (62, 70))	('patients', 'Species', '9606', (118, 126))
165549	28740578	Furthermore, high E2F3 expression was also found to be correlated with worse OS in KIRC patients (HR = 1.813 [95%CI: 1.325-2.405], P = 0.0001).	('E2F3', 'Gene', (18, 22))	('high', 'Var', (13, 17))	('patients', 'Species', '9606', (88, 96))	('OS', 'Chemical', '-', (77, 79))	('worse OS', 'Disease', (71, 79))	('expression', 'MPA', (23, 33))
165554	28740578	Multivariate COX regression analysis revealed that age (HR = 1.641 [95%CI: 1.194-2.255], P = 0.002), stage (HR = 3.260 [95%CI: 2.350-4.522], P < 0.001), E2F1 (HR = 1.418 [95%CI: 1.035-1.942], P = 0.029) and E2F3 (HR = 1.490 [95%CI: 1.080-2.055], P = 0.015) were independent prognostic factors for OS.	('COX', 'Gene', (13, 16))	('COX', 'Gene', '1351', (13, 16))	('OS', 'Chemical', '-', (297, 299))	('E2F3', 'Var', (207, 211))	('E2F1', 'Var', (153, 157))
165563	28740578	Moreover, univariate and multivariate Cox regression analysis demonstrated that E2F1 and E2F3 were independent prognostic factors for overall survival.	('Cox', 'Gene', '1351', (38, 41))	('E2F3', 'Var', (89, 93))	('E2F1', 'Var', (80, 84))	('Cox', 'Gene', (38, 41))
165566	28740578	Mounting evidence indicated that E2F1was a key regulator of the G1/S transition by inducing cell cycle protein including CDC2, CDC25a, and cyclin E. Recent studies have shown that E2F1 can promote cell invasion and chemoresistance, though the targets underlying these processes are still poorly defined.	('E2F1', 'Var', (180, 184))	('CDC2', 'Gene', (127, 131))	('cyclin', 'molecular_function', 'GO:0016538', ('139', '145'))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('chemoresistance', 'CPA', (215, 230))	('CDC2', 'Gene', '983', (127, 131))	('CDC25a', 'Gene', (127, 133))	('CDC2', 'Gene', '983', (121, 125))	('CDC25a', 'Gene', '993', (127, 133))	('CDC2', 'Gene', (121, 125))	('cell cycle', 'biological_process', 'GO:0007049', ('92', '102'))	('promote', 'PosReg', (189, 196))	('cell invasion', 'CPA', (197, 210))
165567	28740578	Moreover, high levels of E2F1 were correlated closely with ccRCC development and metastasis, and could augment EMT-related induction.	('men', 'Species', '9606', (72, 75))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('ccRCC', 'Disease', (59, 64))	('EMT', 'biological_process', 'GO:0001837', ('111', '114'))	('EMT', 'Gene', (111, 114))	('E2F1', 'Var', (25, 29))	('augment', 'NegReg', (103, 110))	('metastasis', 'CPA', (81, 91))	('EMT', 'Gene', '3702', (111, 114))	('men', 'Species', '9606', (106, 109))
165580	28740578	The results suggested that E2F1, E2F2 and E2F3 were significantly associated with metastasis status, lymph node status, stage, and T stage, indicating E2F1-3 play important roles in the progression of KIRC.	('E2F2', 'Gene', (33, 37))	('associated', 'Reg', (66, 76))	('E2F1-3', 'Gene', (151, 157))	('E2F1', 'Var', (27, 31))	('metastasis status', 'CPA', (82, 99))	('E2F2', 'Gene', '1870', (33, 37))	('E2F1-3', 'Gene', '1869;1870;1871', (151, 157))	('lymph node status', 'CPA', (101, 118))	('E2F3', 'Var', (42, 46))	('stage', 'CPA', (120, 125))	('T stage', 'CPA', (131, 138))
165581	28740578	The diagnostic values of E2F1, E2F2 and E2F3 in the detection of KIRC were evaluated using ROC curves.	('E2F2', 'Gene', '1870', (31, 35))	('E2F1', 'Var', (25, 29))	('E2F3', 'Var', (40, 44))	('E2F2', 'Gene', (31, 35))
165582	28740578	E2F1 and E2F2 had the sensitivity of 96.1% and 93.1%, the specificity of 87.2% and 91.7%, and the AUC of 0.944 and 0.942, suggesting that measuring E2F1 and E2F2 levels are the promising biomarkers for KIRC diagnosis.	('E2F2', 'Gene', (9, 13))	('E2F2', 'Gene', (157, 161))	('E2F1', 'Var', (0, 4))	('E2F2', 'Gene', '1870', (9, 13))	('E2F2', 'Gene', '1870', (157, 161))
165583	28740578	The high E2F1, E2F2 and E2F3 expression was related to the reduction in OS, and high E2F3 expression was associated with decreased DFS, as shown by the Kaplan-Meier curves.	('E2F1', 'Var', (9, 13))	('OS', 'Chemical', '-', (72, 74))	('E2F2', 'Gene', (15, 19))	('high E2F1', 'Var', (4, 13))	('decreased', 'NegReg', (121, 130))	('E2F3', 'Var', (24, 28))	('reduction', 'NegReg', (59, 68))	('high E2F3', 'Var', (80, 89))	('E2F2', 'Gene', '1870', (15, 19))	('DFS', 'Disease', (131, 134))
165584	28740578	However, multivariate Cox regression analysis revealed that E2F1 and E2F3 were the independent prognostic factors for patients' overall survival.	('E2F1', 'Var', (60, 64))	('patients', 'Species', '9606', (118, 126))	('Cox', 'Gene', '1351', (22, 25))	('E2F3', 'Var', (69, 73))	('Cox', 'Gene', (22, 25))
165585	28740578	Moreover, E2F1 and E2F2 had preferable diagnostic performance in discriminating KIRC from normal controls.	('E2F1', 'Var', (10, 14))	('KIRC', 'Disease', (80, 84))	('E2F2', 'Gene', '1870', (19, 23))	('E2F2', 'Gene', (19, 23))
165586	28740578	Moreover, E2F1 and E2F3 were the independent prognostic factors for patients' overall survival.	('E2F1', 'Var', (10, 14))	('patients', 'Species', '9606', (68, 76))	('E2F3', 'Var', (19, 23))
165591	28740578	The expression levels of E2F1, E2F2 and E2F3 were compared between KIRC and normal controls.	('E2F2', 'Gene', '1870', (31, 35))	('E2F1', 'Var', (25, 29))	('E2F3', 'Var', (40, 44))	('E2F2', 'Gene', (31, 35))
165592	28740578	Then, fold-changes (KIRC/normal) were used to measure the degrees of E2F1, E2F2, and E2F3 changes between KIRC tissues and matched normal controls.	('E2F3', 'Var', (85, 89))	('E2F2', 'Gene', '1870', (75, 79))	('E2F2', 'Gene', (75, 79))
165593	28740578	We further analyzed the association of E2F1, E2F2, and E2F3 with different clinical features, which include age, gender, tumor size, metastasis, lymph node status, clinical stage, and T stage.	('E2F2', 'Gene', '1870', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('E2F1', 'Var', (39, 43))	('analyzed', 'Reg', (11, 19))	('association', 'Interaction', (24, 35))	('tumor', 'Disease', (121, 126))	('E2F2', 'Gene', (45, 49))	('E2F3', 'Var', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
165594	28740578	The diagnostic performance of E2F1, E2F2 and E2F3 were evaluated using ROC curves.	('E2F1', 'Var', (30, 34))	('E2F2', 'Gene', '1870', (36, 40))	('E2F3', 'Var', (45, 49))	('E2F2', 'Gene', (36, 40))
165597	28740578	In addition, univariate and multivariate Cox regression models were used to identify the prognostic effects of clinical features and E2Fs 1-3.	('Cox', 'Gene', '1351', (41, 44))	('Cox', 'Gene', (41, 44))	('E2Fs 1-3', 'Var', (133, 141))
165604	27748938	Pathway analysis of 210 differentially expressed proteins showed that dysregulated proteins are related to many cancer-related biological processes such as oxidative phosphorylation, glycolysis and amino acid synthetic pathways.	('proteins', 'Protein', (83, 91))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('156', '181'))	('glycolysis', 'MPA', (183, 193))	('cancer', 'Disease', (112, 118))	('amino acid', 'Pathway', (198, 208))	('dysregulated', 'Var', (70, 82))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('oxidative phosphorylation', 'MPA', (156, 181))	('glycolysis', 'biological_process', 'GO:0006096', ('183', '193'))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
165617	27748938	Then, we verified the dysregulated expression of several interesting proteins and assessed their clinical diagnostic significance of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))	('expression', 'MPA', (35, 45))	('dysregulated', 'Var', (22, 34))
165655	27748938	The results showed that high expression of RPN1 (p=0.029) and DARS (p=0.036) correlated with worsened OS, whereas high CYP4F2 (p=0.049) and GSTM3 (p=0.048) levels were associated with increased OS (Fig.	('RPN1', 'Gene', (43, 47))	('GSTM3', 'Gene', (140, 145))	('DARS', 'Gene', '1615', (62, 66))	('GSTM3', 'Gene', '2947', (140, 145))	('high', 'Var', (24, 28))	('CYP4F2', 'Gene', (119, 125))	('CYP4F2', 'Gene', '8529', (119, 125))	('worsened OS', 'Disease', (93, 104))	('expression', 'MPA', (29, 39))	('RPN1', 'Gene', '6184', (43, 47))	('DARS', 'Gene', (62, 66))
165724	33015999	We discovered that for survival analysis, TYROBP has a higher statistical significance than HRG, with P values of 0.00081 and 0.047, respectively (Fig.	('TYROBP', 'Var', (42, 48))	('HRG', 'Gene', '3273', (92, 95))	('HRG', 'Gene', (92, 95))
165733	33015999	Compared with normal tissues, the expression of TYROBP in ccRCC tissues was significantly higher, which is consistent with our research (Fig.	('was', 'Gene', (72, 75))	('expression', 'MPA', (34, 44))	('was', 'Gene', '445527', (72, 75))	('ccRCC', 'Disease', (58, 63))	('TYROBP', 'Var', (48, 54))	('higher', 'PosReg', (90, 96))
165734	33015999	We analyzed the connection between TYROBP and immune cells infiltration, and the results showed the high expression of TYROBP is linked to higher infiltration rate in immune cells, containing B cells, CD8+ T cells, CD4+T cells, macrophage, neutrophil and dendritic cells (Fig.	('TYROBP', 'Var', (119, 125))	('CD4', 'Gene', (215, 218))	('CD8', 'Gene', (201, 204))	('CD4', 'Gene', '920', (215, 218))	('CD8', 'Gene', '925', (201, 204))	('infiltration rate', 'CPA', (146, 163))	('higher', 'PosReg', (139, 145))
165746	33015999	In ccRCC, high expression of PAI-1 is closely related to aggressive characteristics, including high nuclear grade and distant metastasis [30].	('high nuclear grade', 'CPA', (95, 113))	('distant metastasis [', 'CPA', (118, 138))	('related', 'Reg', (46, 53))	('PAI-1', 'Gene', '5054', (29, 34))	('high', 'Var', (10, 14))	('ccRCC', 'Disease', (3, 8))	('PAI-1', 'Gene', (29, 34))
165757	33015999	In addition, a previous study has identified TYROBP as a hub gene in ccRCC progression through weighted gene coexpression network analysis, indicating that TYROBP is strongly linked to clinical trait and vital BPs [35].	('TYROBP', 'Var', (156, 162))	('hub', 'Gene', '1993', (57, 60))	('hub', 'Gene', (57, 60))	('ccRCC', 'Disease', (69, 74))	('linked', 'Reg', (175, 181))
165762	33015999	To further confirm the relationship between candidate genes and patient survival, we performed a survival analysis, and we found that TYROBP was more statistically significant than HRG.	('was', 'Gene', (141, 144))	('patient', 'Species', '9606', (64, 71))	('was', 'Gene', '445527', (141, 144))	('TYROBP', 'Var', (134, 140))	('HRG', 'Gene', '3273', (181, 184))	('HRG', 'Gene', (181, 184))
165772	33015999	To further identify the mechanism of TYROBP expression in the development of ccRCC, we analyzed the connection of TYROBP expression levels with immune cells infiltration, and we discovered that TYROBP is related to high infiltration rate in immune cells, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells.	('CD8', 'Gene', (274, 277))	('CD8', 'Gene', '925', (274, 277))	('CD4', 'Gene', (288, 291))	('TYROBP', 'Var', (194, 200))	('CD4', 'Gene', '920', (288, 291))
165776	33015999	TYROBP probably promotes tumor progression by interacting with immune cells.	('promotes', 'PosReg', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('interacting', 'Interaction', (46, 57))	('tumor', 'Disease', (25, 30))	('TYROBP', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
165782	33015999	CTLA-4, PD-1 and PDL-1 inhibitors are among the most effective immunotherapy methods for cancer treatment [47].	('inhibitors', 'Var', (23, 33))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('PDL-1', 'Gene', (17, 22))	('cancer', 'Disease', (89, 95))	('PD-1', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
165785	33015999	CTLA-4 is expressed only in T cells; PD-1 is expressed in activated T cells, B cells and NK cells; and high expressed PD-1 or CTLA-4 are linked to invasiveness and poor prognosis of ccRCC [48].	('invasiveness', 'Disease', (147, 159))	('linked to', 'Reg', (137, 146))	('high expressed', 'Var', (103, 117))	('invasiveness', 'Disease', 'MESH:D009361', (147, 159))	('CTLA-4', 'Gene', (126, 132))	('ccRCC [48]', 'Disease', (182, 192))	('PD-1', 'Gene', (118, 122))
165787	33015999	We processed a series of bioinformatics analyses to seek ccRCC-related hub genes; after repeated multiple validations, TYROBP was identified as the potential prognostic biomarker.	('hub', 'Gene', (71, 74))	('TYROBP', 'Var', (119, 125))	('was', 'Gene', (126, 129))	('hub', 'Gene', '1993', (71, 74))	('was', 'Gene', '445527', (126, 129))
165790	32236611	A number of reports have demonstrated that HOXA11-AS functions as a protein scaffold for polycomb repressive complex 2 (PRC2), lysine-specific histone demethylase 1 (LSD1) and DNA methyltransferase 1 (DNMT1) to perform epigenetic modifications on chromosomes in the nucleus.	('DNA', 'cellular_component', 'GO:0005574', ('176', '179'))	('DNA methyltransferase 1', 'Gene', (176, 199))	('DNMT1', 'Gene', (201, 206))	('LSD1', 'Gene', (166, 170))	('lysine-specific histone demethylase 1', 'Gene', (127, 164))	('DNA methyltransferase 1', 'Gene', '1786', (176, 199))	('RC', 'Phenotype', 'HP:0009726', (121, 123))	('LSD1', 'Gene', '23028', (166, 170))	('DNMT1', 'Gene', '1786', (201, 206))	('methyltransferase 1', 'molecular_function', 'GO:0047152', ('180', '199'))	('epigenetic', 'Var', (219, 229))	('PR', 'Gene', '5241', (120, 122))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('nucleus', 'cellular_component', 'GO:0005634', ('266', '273'))	('lysine-specific histone demethylase 1', 'Gene', '23028', (127, 164))	('AS', 'Phenotype', 'HP:0002621', (50, 52))
165791	32236611	In addition, HOXA11-AS may be useful as a biomarker for the diagnosis and prognosis of cancer.	('cancer', 'Disease', (87, 93))	('HOXA11-AS', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('AS', 'Phenotype', 'HP:0002621', (20, 22))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
165815	32236611	The dosage compensation effect of the X chromosome in mammals provides a striking instance of lncRNA-mediated chromatin regulation.	('chromatin', 'cellular_component', 'GO:0000785', ('110', '119'))	('dosage compensation', 'biological_process', 'GO:0007549', ('4', '23'))	('dosage compensation', 'Var', (4, 23))	('ncRNA', 'Gene', (95, 100))	('X chromosome', 'cellular_component', 'GO:0000805', ('38', '50'))	('ncRNA', 'Gene', '220202', (95, 100))	('regulation', 'biological_process', 'GO:0065007', ('120', '130'))
165821	32236611	The interaction between DNA and lncRNA is achieved either via sequence complementation or via combination in helical structures.	('helical', 'MPA', (109, 116))	('interaction', 'Interaction', (4, 15))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('ncRNA', 'Gene', '220202', (33, 38))	('men', 'Species', '9606', (77, 80))	('sequence complementation', 'Var', (62, 86))	('combination', 'Interaction', (94, 105))	('ncRNA', 'Gene', (33, 38))
165828	32236611	Findings demonstrated that improvements in cell invasion and proliferation mediated by HOXA11-AS were reversed by miR-124.	('HOXA11-AS', 'Var', (87, 96))	('improvements', 'PosReg', (27, 39))	('AS', 'Phenotype', 'HP:0002621', (94, 96))	('cell invasion', 'CPA', (43, 56))	('men', 'Species', '9606', (34, 37))
165830	32236611	For instance, lncRNA LOC554202 was shown to be the putative precursor of miR-31, exerting an important role in preventing metastasis of BC.	('miR-31', 'Gene', '407035', (73, 79))	('ncRNA', 'Gene', (15, 20))	('LOC554202', 'Var', (21, 30))	('preventing', 'NegReg', (111, 121))	('BC', 'Phenotype', 'HP:0003002', (136, 138))	('miR-31', 'Gene', (73, 79))	('ncRNA', 'Gene', '220202', (15, 20))	('BC', 'Phenotype', 'HP:0009725', (136, 138))	('metastasis', 'CPA', (122, 132))
165838	32236611	When exosomes containing lncARSR reached the sensitive RCC cells, lncARSR was released into the cytoplasm.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('CC', 'Phenotype', 'HP:0002664', (56, 58))	('lncARSR', 'Var', (25, 32))	('RC', 'Phenotype', 'HP:0009726', (55, 57))	('cytoplasm', 'cellular_component', 'GO:0005737', ('96', '105'))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
165839	32236611	The expression of the receptor tyrosine kinases AXL and c-MET in RCC cells was promoted by lncARSR competitively binding miR-34/miR-449, thus promoting sunitinib resistance.	('miR-34', 'Gene', (121, 127))	('AXL', 'Gene', (48, 51))	('expression', 'MPA', (4, 14))	('c-MET', 'Gene', '4233', (56, 61))	('promoted', 'PosReg', (79, 87))	('c-MET', 'Gene', (56, 61))	('binding', 'molecular_function', 'GO:0005488', ('113', '120'))	('CC', 'Phenotype', 'HP:0002664', (66, 68))	('binding', 'Interaction', (113, 120))	('RCC', 'Disease', (65, 68))	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('miR-34', 'Gene', '407040', (121, 127))	('lncARSR', 'Var', (91, 98))	('AXL', 'Gene', '558', (48, 51))	('sunitinib resistance', 'MPA', (152, 172))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('promoting', 'PosReg', (142, 151))	('sunitinib', 'Chemical', 'MESH:D000077210', (152, 161))	('RC', 'Phenotype', 'HP:0009726', (65, 67))
165840	32236611	AXL and c-MET are responsible for lncARSR-mediated sunitinib resistance in RCC.	('RC', 'Phenotype', 'HP:0009726', (75, 77))	('sunitinib', 'Chemical', 'MESH:D000077210', (51, 60))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('c-MET', 'Gene', (8, 13))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('AXL', 'Gene', '558', (0, 3))	('RCC', 'Disease', (75, 78))	('lncARSR-mediated', 'Var', (34, 50))	('CC', 'Phenotype', 'HP:0002664', (76, 78))	('AXL', 'Gene', (0, 3))	('c-MET', 'Gene', '4233', (8, 13))
165856	32236611	HOXA11-AS is a novel lncRNA that functions as an oncogene or tumor-suppressor gene in diverse types of tumor.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('61', '77'))	('ncRNA', 'Gene', (22, 27))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('AS', 'Phenotype', 'HP:0002621', (7, 9))	('ncRNA', 'Gene', '220202', (22, 27))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('61', '77'))	('HOXA11-AS', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (61, 66))
165857	32236611	For example, HOXA11-AS can serve as an oncogene in non-small cell lung cancer (NSCLC), HCC, glioma, BC, GC, renal cancer (RC), uveal melanoma (UM), laryngeal squamous cell carcinoma (LSCC), cervical cancer (CC), ESCC and osteosarcoma.	('renal cancer', 'Disease', (108, 120))	('GC', 'Phenotype', 'HP:0012126', (104, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('renal cancer', 'Phenotype', 'HP:0009726', (108, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (158, 181))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (199, 205))	('SCC', 'Phenotype', 'HP:0002860', (184, 187))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('HCC', 'Disease', (87, 90))	('HCC', 'Phenotype', 'HP:0001402', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('SCC', 'Phenotype', 'HP:0002860', (213, 216))	('cancer', 'Disease', (71, 77))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('renal cancer', 'Disease', 'MESH:D007680', (108, 120))	('osteosarcoma', 'Phenotype', 'HP:0002669', (221, 233))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (158, 181))	('HOXA11-AS', 'Var', (13, 22))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('RC', 'Phenotype', 'HP:0009726', (122, 124))	('lung cancer', 'Disease', (66, 77))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (51, 77))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('CC', 'Phenotype', 'HP:0002664', (185, 187))	('CC', 'Phenotype', 'HP:0002664', (214, 216))	('UM', 'Phenotype', 'HP:0007716', (143, 145))	('osteosarcoma', 'Disease', 'MESH:D012516', (221, 233))	('squamous cell carcinoma', 'Disease', (158, 181))	('CC', 'Phenotype', 'HP:0002664', (207, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (55, 77))	('BC', 'Phenotype', 'HP:0009725', (100, 102))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('CC', 'Phenotype', 'HP:0002664', (88, 90))	('ESCC', 'Disease', (212, 216))	('SCLC', 'Phenotype', 'HP:0030357', (80, 84))	('AS', 'Phenotype', 'HP:0002621', (20, 22))	('glioma', 'Disease', (92, 98))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('BC', 'Phenotype', 'HP:0003002', (100, 102))	('osteosarcoma', 'Disease', (221, 233))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('uveal melanoma', 'Phenotype', 'HP:0007716', (127, 141))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))	('NSCLC', 'Disease', (79, 84))	('cancer', 'Disease', (114, 120))
165858	32236611	By contrast, HOXA11-AS functions as a tumor suppressor in epithelial ovarian cancer (EOC).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('HOXA11-AS', 'Var', (13, 22))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('38', '54'))	('AS', 'Phenotype', 'HP:0002621', (20, 22))	('tumor suppressor', 'biological_process', 'GO:0051726', ('38', '54'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (69, 83))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (58, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('epithelial ovarian cancer', 'Disease', (58, 83))
165865	32236611	Zhang et al reported that the expression of HOXA11-AS is higher in both squamous cell carcinoma (SCC) and lung adenocarcinoma (LUAD) compared with that in normal lung tissues, and HOXA11-AS knockdown suppresses tumorigenesis, angiogenesis, proliferation, migration and invasion of NSCLC cells, inducing apoptosis by impeding the cell cycle at the G0/G1 or the G2/M phase.	('invasion', 'CPA', (269, 277))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('AS', 'Phenotype', 'HP:0002621', (187, 189))	('migration', 'CPA', (255, 264))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('AS', 'Phenotype', 'HP:0002621', (51, 53))	('tumor', 'Disease', (211, 216))	('suppresses', 'NegReg', (200, 210))	('LUAD', 'Phenotype', 'HP:0030078', (127, 131))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 95))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('SCLC', 'Phenotype', 'HP:0030357', (282, 286))	('M phase', 'biological_process', 'GO:0000279', ('363', '370'))	('apoptosis', 'biological_process', 'GO:0097194', ('303', '312'))	('lung adenocarcinoma', 'Disease', (106, 125))	('cell cycle at the G0/G1', 'CPA', (329, 352))	('apoptosis', 'biological_process', 'GO:0006915', ('303', '312'))	('HOXA11-AS', 'Gene', (44, 53))	('NSCLC', 'Disease', 'MESH:D002289', (281, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('CC', 'Phenotype', 'HP:0002664', (98, 100))	('squamous cell carcinoma', 'Disease', (72, 95))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('NSCLC', 'Disease', (281, 286))	('apoptosis', 'CPA', (303, 312))	('inducing', 'NegReg', (294, 302))	('HOXA11-AS knockdown', 'Var', (180, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('angiogenesis', 'biological_process', 'GO:0001525', ('226', '238'))	('proliferation', 'CPA', (240, 253))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (106, 125))	('expression', 'MPA', (30, 40))	('knockdown', 'Var', (190, 199))	('impeding', 'NegReg', (316, 324))	('higher', 'PosReg', (57, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (281, 286))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (106, 125))	('angiogenesis', 'CPA', (226, 238))	('cell cycle', 'biological_process', 'GO:0007049', ('329', '339'))
165866	32236611	Moreover, Chen et al identified that high levels of HOXA11-AS predict poor prognosis in patients with NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('high', 'Var', (37, 41))	('SCLC', 'Phenotype', 'HP:0030357', (103, 107))	('patients', 'Species', '9606', (88, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('AS', 'Phenotype', 'HP:0002621', (59, 61))	('HOXA11-AS', 'Protein', (52, 61))	('NSCLC', 'Disease', (102, 107))
165869	32236611	Those authors conjectured that HOXA11-AS could have an oncogenic role in the development and progression of NSCLC by modulating various pathways, such as the transforming growth factor (TGF)-beta pathway, the phosphoinositide 3-kinase (PI3K)-Akt pathway and the Hippo signaling pathway, and genes, such as DOCK8 gene.	('Hippo signaling pathway', 'Pathway', (262, 285))	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('HOXA11-AS', 'Var', (31, 40))	('phosphoinositide 3-kinase', 'Gene', '5295', (209, 234))	('AS', 'Phenotype', 'HP:0002621', (38, 40))	('modulating', 'Reg', (117, 127))	('Akt', 'Gene', (242, 245))	('phosphoinositide 3-kinase', 'Gene', (209, 234))	('NSCLC', 'Disease', (108, 113))	('DOCK8', 'Gene', '81704', (306, 311))	('men', 'Species', '9606', (84, 87))	('transforming growth factor (TGF)-beta', 'Gene', '7039', (158, 195))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('SCLC', 'Phenotype', 'HP:0030357', (109, 113))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('262', '285'))	('Akt', 'Gene', '207', (242, 245))	('PI3K', 'molecular_function', 'GO:0016303', ('236', '240'))	('DOCK8', 'Gene', (306, 311))
165870	32236611	In other studies, the same authors demonstrated that the expression of HOXA11-AS co-expressed genes in NSCLC may be partly regulated by the NSCLC pathway and that HOXA11-AS could affect various biological processes of NSCLC via regulation of the expression of miR-642b-3p by targeting the expression of phosphodiesterase 4D (PDE4D) or other target genes.	('HOXA11-AS', 'Gene', (71, 80))	('NSCLC', 'Disease', (103, 108))	('SCLC', 'Phenotype', 'HP:0030357', (141, 145))	('targeting', 'Reg', (275, 284))	('expression', 'MPA', (289, 299))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('phosphodiesterase 4D', 'Gene', '5144', (303, 323))	('phosphodiesterase', 'molecular_function', 'GO:0008081', ('303', '320'))	('AS', 'Phenotype', 'HP:0002621', (170, 172))	('expression', 'MPA', (57, 67))	('PDE4D', 'Gene', '5144', (325, 330))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('PDE', 'molecular_function', 'GO:0004114', ('325', '328'))	('SCLC', 'Phenotype', 'HP:0030357', (219, 223))	('NSCLC', 'Disease', 'MESH:D002289', (218, 223))	('NSCLC', 'Disease', (140, 145))	('affect', 'Reg', (179, 185))	('SCLC', 'Phenotype', 'HP:0030357', (104, 108))	('PDE4D', 'Gene', (325, 330))	('HOXA11-AS', 'Var', (163, 172))	('NSCLC', 'Disease', (218, 223))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('miR-642b-3p', 'Gene', (260, 271))	('regulation', 'biological_process', 'GO:0065007', ('228', '238'))	('phosphodiesterase 4D', 'Gene', (303, 323))	('NSCLC', 'Phenotype', 'HP:0030358', (218, 223))	('AS', 'Phenotype', 'HP:0002621', (78, 80))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))
165871	32236611	Additionally, Chen et al found that HOXA11-AS interacts with DNA (cytosine-5)-methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2), recruiting these proteins to the promoter regions of miR-200b and mediating methylation silencing of miR-200b in NSCLC cells, a process that promotes both NSCLC cell epithelial-mesenchymal transition (EMT) via regulation of the protein levels of E-cadherin, N-cadherin, Snail1/2 and ZEB1/2 and tumor progression.	('AS', 'Phenotype', 'HP:0002621', (43, 45))	('N-cadherin', 'Gene', '1000', (404, 414))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('312', '345'))	('cadherin', 'molecular_function', 'GO:0008014', ('394', '402'))	('miR-200b', 'Gene', (199, 207))	('NSCLC', 'Disease', (301, 306))	('silencing', 'NegReg', (234, 243))	('NSCLC', 'Disease', 'MESH:D002289', (259, 264))	('E-cadherin', 'Gene', (392, 402))	('DNMT1', 'Gene', '1786', (99, 104))	('protein', 'cellular_component', 'GO:0003675', ('374', '381'))	('SCLC', 'Phenotype', 'HP:0030357', (260, 264))	('E-cadherin', 'Gene', '999', (392, 402))	('EMT', 'biological_process', 'GO:0001837', ('347', '350'))	('miR-200b', 'Gene', '406984', (247, 255))	('Snail1/2', 'Gene', (416, 424))	('NSCLC', 'Phenotype', 'HP:0030358', (301, 306))	('methylation', 'Var', (222, 233))	('tumor', 'Disease', (440, 445))	('cadherin', 'molecular_function', 'GO:0008014', ('406', '414'))	('NSCLC', 'Disease', (259, 264))	('ZEB1/2', 'Gene', (429, 435))	('tumor', 'Disease', 'MESH:D009369', (440, 445))	('NSCLC', 'Phenotype', 'HP:0030358', (259, 264))	('regulation', 'biological_process', 'GO:0065007', ('356', '366'))	('DNA (cytosine-5)-methyltransferase 1', 'Gene', '1786', (61, 97))	('enhancer of zeste homolog 2', 'Gene', '2146', (110, 137))	('miR-200b', 'Gene', '406984', (199, 207))	('Snail1/2', 'Gene', '6615;6591', (416, 424))	('methylation', 'biological_process', 'GO:0032259', ('222', '233'))	('DNMT1', 'Gene', (99, 104))	('methyltransferase 1', 'molecular_function', 'GO:0047152', ('78', '97'))	('promotes', 'PosReg', (287, 295))	('ZEB1/2', 'Gene', '6935;9839', (429, 435))	('tumor', 'Phenotype', 'HP:0002664', (440, 445))	('SCLC', 'Phenotype', 'HP:0030357', (302, 306))	('miR-200b', 'Gene', (247, 255))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('enhancer of zeste homolog 2', 'Gene', (110, 137))	('EZH2', 'Gene', '2146', (139, 143))	('NSCLC', 'Disease', 'MESH:D002289', (301, 306))	('EZH2', 'Gene', (139, 143))	('N-cadherin', 'Gene', (404, 414))
165872	32236611	Futhermore, those authors found that HOXA11-AS can serve as an oncogene by promoting EMT via regulation of the protein levels of E-cadherin, beta-catenin, vimentin and the EMT-mediating transcription factors Slug and Snail in NSCLC.	('AS', 'Phenotype', 'HP:0002621', (44, 46))	('regulation', 'MPA', (93, 103))	('cadherin', 'molecular_function', 'GO:0008014', ('131', '139'))	('transcription', 'biological_process', 'GO:0006351', ('186', '199'))	('vimentin', 'cellular_component', 'GO:0045098', ('155', '163'))	('EMT', 'CPA', (85, 88))	('NSCLC', 'Disease', 'MESH:D002289', (226, 231))	('Snail', 'Gene', (217, 222))	('SCLC', 'Phenotype', 'HP:0030357', (227, 231))	('HOXA11-AS', 'Var', (37, 46))	('Slug', 'Gene', '6591', (208, 212))	('promoting', 'PosReg', (75, 84))	('NSCLC', 'Disease', (226, 231))	('regulation', 'biological_process', 'GO:0065007', ('93', '103'))	('vimentin', 'cellular_component', 'GO:0045099', ('155', '163'))	('beta-catenin', 'Gene', (141, 153))	('E-cadherin', 'Gene', (129, 139))	('E-cadherin', 'Gene', '999', (129, 139))	('beta-catenin', 'Gene', '1499', (141, 153))	('NSCLC', 'Phenotype', 'HP:0030358', (226, 231))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('vimentin', 'Gene', '7431', (155, 163))	('vimentin', 'Gene', (155, 163))	('EMT', 'biological_process', 'GO:0001837', ('85', '88'))	('Snail', 'Gene', '6615', (217, 222))	('EMT', 'biological_process', 'GO:0001837', ('172', '175'))	('Slug', 'Gene', (208, 212))	('protein levels', 'MPA', (111, 125))
165873	32236611	Zhao et al discovered that, in human LUAD cells, HOXA11-AS can function as a ceRNA to facilitate cisplatin tolerance through the miR-454-3p/Stat3 pathway (the abovementioned mechanisms are shown in Fig.	('HOXA11-AS', 'Var', (49, 58))	('facilitate', 'PosReg', (86, 96))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('human', 'Species', '9606', (31, 36))	('Stat3', 'Gene', '6774', (140, 145))	('AS', 'Phenotype', 'HP:0002621', (56, 58))	('cisplatin tolerance', 'MPA', (97, 116))	('LUAD', 'Phenotype', 'HP:0030078', (37, 41))	('Stat3', 'Gene', (140, 145))	('men', 'Species', '9606', (164, 167))
165875	32236611	These findings indicate that HOXA11-AS has several functions associated with oncogenesis, regulating various physiological activities in NSCLC.	('NSCLC', 'Disease', (137, 142))	('AS', 'Phenotype', 'HP:0002621', (36, 38))	('oncogenesis', 'biological_process', 'GO:0007048', ('77', '88'))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('HOXA11-AS', 'Var', (29, 38))	('SCLC', 'Phenotype', 'HP:0030357', (138, 142))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))
165880	32236611	Liu et al found that high expression levels of HOXA11-AS are significantly correlated with vascular invasion, cirrhosis, tumor size and Edmondson grade.	('AS', 'Phenotype', 'HP:0002621', (54, 56))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cirrhosis', 'Disease', (110, 119))	('tumor', 'Disease', (121, 126))	('correlated', 'Reg', (75, 85))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('Edmondson', 'Disease', (136, 145))	('HOXA11-AS', 'Var', (47, 56))	('vascular invasion', 'CPA', (91, 108))	('expression levels', 'MPA', (26, 43))	('cirrhosis', 'Phenotype', 'HP:0001394', (110, 119))	('cirrhosis', 'Disease', 'MESH:D005355', (110, 119))
165881	32236611	The overall survival (OS) rate of patients with high levels of HOXA11-AS expression is markedly shorter compared with those with lower levels of HOXA11-AS expression.	('HOXA11-AS expression', 'Var', (63, 83))	('shorter', 'NegReg', (96, 103))	('high levels', 'Var', (48, 59))	('AS', 'Phenotype', 'HP:0002621', (70, 72))	('patients', 'Species', '9606', (34, 42))	('overall survival', 'MPA', (4, 20))	('AS', 'Phenotype', 'HP:0002621', (152, 154))
165882	32236611	Yu et al reported that HOXA11-AS recruits PRC2 to the promoter region of large tumor suppressor 1 (LATS1) to obstruct its transcription, thereby promoting HCC growth and inhibiting apoptosis and cell cycle progression at the G0/G1 phase.	('HCC growth', 'CPA', (155, 165))	('LATS1', 'Gene', (99, 104))	('apoptosis', 'CPA', (181, 190))	('HOXA11-AS', 'Var', (23, 32))	('LATS1', 'Gene', '9113', (99, 104))	('CC', 'Phenotype', 'HP:0002664', (156, 158))	('large tumor suppressor 1', 'Gene', '9113', (73, 97))	('G1 phase', 'biological_process', 'GO:0051318', ('228', '236'))	('cell cycle progression at the G0/G1 phase', 'CPA', (195, 236))	('RC', 'Phenotype', 'HP:0009726', (43, 45))	('HCC', 'Phenotype', 'HP:0001402', (155, 158))	('inhibiting', 'NegReg', (170, 180))	('obstruct', 'NegReg', (109, 117))	('promoting', 'PosReg', (145, 154))	('large tumor suppressor 1', 'Gene', (73, 97))	('PR', 'Gene', '5241', (42, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('181', '190'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('79', '95'))	('transcription', 'biological_process', 'GO:0006351', ('122', '135'))	('transcription', 'MPA', (122, 135))	('AS', 'Phenotype', 'HP:0002621', (30, 32))	('apoptosis', 'biological_process', 'GO:0006915', ('181', '190'))	('cell cycle', 'biological_process', 'GO:0007049', ('195', '205'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('79', '95'))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
165884	32236611	Zhan et al showed that the overexpression of HOXA11-AS is able to facilitate HCC proliferation and invasion, and induce EMT by repressing the expression of miR-214-3p.	('HOXA11-AS', 'Var', (45, 54))	('induce', 'PosReg', (113, 119))	('facilitate', 'PosReg', (66, 76))	('CC', 'Phenotype', 'HP:0002664', (78, 80))	('HCC', 'Phenotype', 'HP:0001402', (77, 80))	('HCC proliferation', 'CPA', (77, 94))	('miR-214-3p', 'Chemical', '-', (156, 166))	('AS', 'Phenotype', 'HP:0002621', (52, 54))	('invasion', 'CPA', (99, 107))	('miR-214-3p', 'Var', (156, 166))	('EMT', 'biological_process', 'GO:0001837', ('120', '123'))	('overexpression', 'PosReg', (27, 41))	('EMT', 'CPA', (120, 123))
165885	32236611	In addition, these authors demonstrated that the expression of miR-214-3p in early clinical stages (I-II) was higher than that in advanced clinical stages (III-IV).	('miR-214-3p', 'Chemical', '-', (63, 73))	('higher', 'PosReg', (110, 116))	('miR-214-3p', 'Var', (63, 73))	('expression', 'MPA', (49, 59))
165887	32236611	HOXA11-AS performs an oncogenic role in HCC by interacting with PRC2 (the abovementioned mechanisms are shown in Fig.	('men', 'Species', '9606', (79, 82))	('HCC', 'Disease', (40, 43))	('RC', 'Phenotype', 'HP:0009726', (65, 67))	('HCC', 'Phenotype', 'HP:0001402', (40, 43))	('AS', 'Phenotype', 'HP:0002621', (7, 9))	('interacting', 'Interaction', (47, 58))	('CC', 'Phenotype', 'HP:0002664', (41, 43))	('PR', 'Gene', '5241', (64, 66))	('HOXA11-AS', 'Var', (0, 9))
165888	32236611	HOXA11-AS may function as an oncogene in HCC development.	('men', 'Species', '9606', (52, 55))	('AS', 'Phenotype', 'HP:0002621', (7, 9))	('CC', 'Phenotype', 'HP:0002664', (42, 44))	('HCC', 'Disease', (41, 44))	('HCC', 'Phenotype', 'HP:0001402', (41, 44))	('HOXA11-AS', 'Var', (0, 9))
165894	32236611	Wang et al discovered that high levels of HOXA11-AS expression are closely correlated with OS in high-grade glioma, and HOXA11-AS may be an independent prognostic factor for GBM.	('glioma', 'Disease', (108, 114))	('AS', 'Phenotype', 'HP:0002621', (127, 129))	('expression', 'MPA', (52, 62))	('correlated', 'Reg', (75, 85))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('AS', 'Phenotype', 'HP:0002621', (49, 51))	('HOXA11-AS', 'Var', (120, 129))
165896	32236611	Those authors reported that the expression levels of HOTTIP, HOXA9, HOXA10, and HOXA13 are prominently correlated with HOXA11-AS expression, and HOXA11-AS can alter the expression of cell cycle-associated proteins, thus regulating cell cycle progression.	('HOXA13', 'Gene', (80, 86))	('HOXA10', 'Gene', (68, 74))	('expression', 'MPA', (169, 179))	('cell cycle-associated proteins', 'Protein', (183, 213))	('regulating', 'Reg', (220, 230))	('HOTTIP', 'Gene', (53, 59))	('expression', 'MPA', (32, 42))	('AS', 'Phenotype', 'HP:0002621', (152, 154))	('alter', 'Reg', (159, 164))	('cell cycle', 'biological_process', 'GO:0007049', ('183', '193'))	('HOXA10', 'Gene', '3206', (68, 74))	('HOXA9', 'Gene', (61, 66))	('AS', 'Phenotype', 'HP:0002621', (126, 128))	('HOTTIP', 'Gene', '100316868', (53, 59))	('HOXA9', 'Gene', '3205', (61, 66))	('cell cycle', 'biological_process', 'GO:0007049', ('231', '241'))	('HOXA11-AS', 'Var', (145, 154))	('HOXA13', 'Gene', '3209', (80, 86))	('cell cycle progression', 'CPA', (231, 253))
165898	32236611	In addition, Xu et al found that the overexpression of HOXA11-AS is associated with advanced stages of glioma and poor prognosis.	('overexpression', 'PosReg', (37, 51))	('associated', 'Reg', (68, 78))	('HOXA11-AS', 'Var', (55, 64))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('AS', 'Phenotype', 'HP:0002621', (62, 64))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('glioma', 'Disease', (103, 109))
165899	32236611	Authors of that study reported that knocking down the expression of HOXA11-AS leads to suppression of the proliferation, migration, and invasion rates of glioma cells in vitro, with the consequent further enhancement of cell cycle arrest at the G0/G1 stage and improved apoptotic responses.	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('migration', 'CPA', (121, 130))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('improved', 'PosReg', (261, 269))	('HOXA11-AS', 'Gene', (68, 77))	('suppression', 'NegReg', (87, 98))	('enhancement', 'PosReg', (205, 216))	('invasion rates', 'CPA', (136, 150))	('apoptotic responses', 'CPA', (270, 289))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('220', '237'))	('glioma', 'Disease', (154, 160))	('arrest', 'Disease', 'MESH:D006323', (231, 237))	('knocking down', 'Var', (36, 49))	('arrest', 'Disease', (231, 237))	('AS', 'Phenotype', 'HP:0002621', (75, 77))	('men', 'Species', '9606', (212, 215))
165900	32236611	Cui et al showed that miR-140-5p is able to directly target the 3'-UTR of HOXA11-AS, and the effects of HOXA11-AS knockdown are shown to be reversed by an miR-140-5p inhibitor, as determined by its effects on cell cycle arrest, proliferation and apoptosis.	('AS', 'Phenotype', 'HP:0002621', (111, 113))	('miR-140-5p', 'Chemical', '-', (22, 32))	('apoptosis', 'CPA', (246, 255))	('AS', 'Phenotype', 'HP:0002621', (81, 83))	('knockdown', 'Var', (114, 123))	('arrest', 'Disease', (220, 226))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('209', '226'))	('apoptosis', 'biological_process', 'GO:0097194', ('246', '255'))	('proliferation', 'CPA', (228, 241))	('HOXA11-AS', 'Gene', (104, 113))	('apoptosis', 'biological_process', 'GO:0006915', ('246', '255'))	('miR-140-5p', 'Chemical', '-', (155, 165))	('arrest', 'Disease', 'MESH:D006323', (220, 226))
165902	32236611	It was thereby confirmed that HOXA11-AS may serve in an oncogenic role by regulating the miR-214-3p/EZH2 pathway.	('AS', 'Phenotype', 'HP:0002621', (37, 39))	('regulating', 'Reg', (74, 84))	('EZH2', 'Gene', '2146', (100, 104))	('EZH2', 'Gene', (100, 104))	('miR-214-3p', 'Chemical', '-', (89, 99))	('HOXA11-AS', 'Var', (30, 39))
165903	32236611	Yang et al found that HOXA11-AS leads to a marked increase in proliferation, invasion and migration rates, while inhibiting apoptosis by absorbing miR-124-3p in glioma cells.	('miR-124-3p', 'Gene', (147, 157))	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('migration rates', 'CPA', (90, 105))	('proliferation', 'CPA', (62, 75))	('inhibiting', 'NegReg', (113, 123))	('glioma', 'Disease', 'MESH:D005910', (161, 167))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('invasion', 'CPA', (77, 85))	('increase', 'PosReg', (50, 58))	('HOXA11-AS', 'Var', (22, 31))	('miR-124-3p', 'Gene', '406909', (147, 157))	('apoptosis', 'CPA', (124, 133))	('AS', 'Phenotype', 'HP:0002621', (29, 31))	('glioma', 'Disease', (161, 167))	('absorbing', 'NegReg', (137, 146))
165904	32236611	Furthermore, Xu et al found that HOXA11-AS can exert its oncogenic role by directly binding to miR-130a-5p as a ceRNA, which inhibits the inhibitory effect of miR-130a-5p on HMGB2 expression.	('HMGB2', 'Gene', '3148', (174, 179))	('AS', 'Phenotype', 'HP:0002621', (40, 42))	('-130a', 'Chemical', '-', (162, 167))	('HMGB2', 'Gene', (174, 179))	('expression', 'MPA', (180, 190))	('HOXA11-AS', 'Var', (33, 42))	('binding', 'molecular_function', 'GO:0005488', ('84', '91'))	('inhibits', 'NegReg', (125, 133))	('-130a', 'Chemical', '-', (98, 103))	('binding', 'Interaction', (84, 91))	('inhibitory effect', 'MPA', (138, 155))
165912	32236611	Moreover, Chen et al reported that the level of HOXA11-AS was markedly upregulated in CRC patients with liver metastasis, and the migration and invasion of CRC cells was facilitated by HOXA11-AS.	('HOXA11-AS', 'Var', (185, 194))	('HOXA11-AS', 'MPA', (48, 57))	('RC', 'Phenotype', 'HP:0009726', (157, 159))	('invasion of CRC cells', 'CPA', (144, 165))	('facilitated', 'PosReg', (170, 181))	('liver metastasis', 'Disease', 'MESH:D009362', (104, 120))	('CRC', 'Phenotype', 'HP:0003003', (86, 89))	('liver metastasis', 'Disease', (104, 120))	('AS', 'Phenotype', 'HP:0002621', (192, 194))	('CRC', 'Phenotype', 'HP:0003003', (156, 159))	('RC', 'Phenotype', 'HP:0009726', (87, 89))	('AS', 'Phenotype', 'HP:0002621', (55, 57))	('patients', 'Species', '9606', (90, 98))	('CRC', 'Disease', (86, 89))	('upregulated', 'PosReg', (71, 82))
165913	32236611	In addition, Chen et al found that HOXA11-AS can act as a ceRNA sequestering miR-125a-5p to modulate the expression of protein-arginine deiminase type-2 (PADI2), which was shown to facilitate metastasis and the invasion of CRC (the abovementioned mechanisms are shown in Fig.	('invasion', 'CPA', (211, 219))	('AS', 'Phenotype', 'HP:0002621', (42, 44))	('modulate', 'Reg', (92, 100))	('miR-125a', 'Gene', (77, 85))	('expression', 'MPA', (105, 115))	('PADI2', 'Gene', (154, 159))	('sequestering', 'biological_process', 'GO:0051235', ('64', '76'))	('protein-arginine deiminase type-2', 'Gene', '11240', (119, 152))	('men', 'Species', '9606', (237, 240))	('PADI2', 'Gene', '11240', (154, 159))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('facilitate', 'PosReg', (181, 191))	('CRC', 'Disease', (223, 226))	('protein-arginine deiminase type-2', 'Gene', (119, 152))	('HOXA11-AS', 'Var', (35, 44))	('CRC', 'Phenotype', 'HP:0003003', (223, 226))	('RC', 'Phenotype', 'HP:0009726', (224, 226))	('metastasis', 'CPA', (192, 202))	('miR-125a', 'Gene', '406910', (77, 85))
165917	32236611	Su and Hu discovered that lncRNA HOXA11-AS is overexpressed in human BC, and the expression of HOXA11-AS is markedly associated with metastasis, tumor size and TNM staging.	('BC', 'Phenotype', 'HP:0009725', (69, 71))	('AS', 'Phenotype', 'HP:0002621', (40, 42))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('human', 'Species', '9606', (63, 68))	('AS', 'Phenotype', 'HP:0002621', (102, 104))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('associated with', 'Reg', (117, 132))	('expression', 'Var', (81, 91))	('metastasis', 'CPA', (133, 143))	('tumor', 'Disease', (145, 150))	('BC', 'Phenotype', 'HP:0003002', (69, 71))	('HOXA11-AS', 'Var', (95, 104))	('ncRNA', 'Gene', (27, 32))	('TNM staging', 'CPA', (160, 171))	('ncRNA', 'Gene', '220202', (27, 32))
165918	32236611	Clinical statistics revealed that the expression of HOXA11-AS was correlated with Ki-67 protein and human epidermal growth factor receptor (HER2), but not with estrogen receptor (ER) or progesterone receptor (PR).	('progesterone receptor', 'Gene', (186, 207))	('progesterone receptor', 'Gene', '5241', (186, 207))	('AS', 'Phenotype', 'HP:0002621', (59, 61))	('HER2', 'Gene', (140, 144))	('estrogen receptor', 'Gene', '2099', (160, 177))	('correlated', 'Reg', (66, 76))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('ER', 'Gene', '2099', (141, 143))	('Ki-67 protein', 'Protein', (82, 95))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('106', '129'))	('expression', 'MPA', (38, 48))	('HOXA11-AS', 'Var', (52, 61))	('PR', 'Gene', '5241', (209, 211))	('estrogen receptor', 'Gene', (160, 177))	('HER2', 'Gene', '2064', (140, 144))	('epidermal growth factor receptor', 'Gene', (106, 138))	('ER', 'Gene', '2099', (179, 181))	('epidermal growth factor receptor', 'Gene', '1956', (106, 138))	('human', 'Species', '9606', (100, 105))
165919	32236611	Their results indicated that decreased expression levels of HOXA11-AS in human BC led to suppression in the rates of cell proliferation, migration and invasion, and cell cycle arrest at the G0/G1 phase.	('arrest', 'Disease', 'MESH:D006323', (176, 182))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('165', '182'))	('arrest', 'Disease', (176, 182))	('human', 'Species', '9606', (73, 78))	('suppression', 'NegReg', (89, 100))	('cell proliferation', 'biological_process', 'GO:0008283', ('117', '135'))	('decreased', 'NegReg', (29, 38))	('G1 phase', 'biological_process', 'GO:0051318', ('193', '201'))	('expression levels', 'MPA', (39, 56))	('BC', 'Phenotype', 'HP:0003002', (79, 81))	('HOXA11-AS', 'Var', (60, 69))	('BC', 'Phenotype', 'HP:0009725', (79, 81))	('AS', 'Phenotype', 'HP:0002621', (67, 69))
165920	32236611	Li et al also reported that low levels of HOXA11-AS expression inhibited cell proliferation and induced tumor cell apoptosis by inducing cell cycle arrest at the G0/G1 stage.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('137', '154'))	('cell proliferation', 'biological_process', 'GO:0008283', ('73', '91'))	('HOXA11-AS', 'Var', (42, 51))	('induced', 'PosReg', (96, 103))	('arrest', 'Disease', 'MESH:D006323', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('inducing', 'NegReg', (128, 136))	('tumor', 'Disease', (104, 109))	('apoptosis', 'biological_process', 'GO:0097194', ('115', '124'))	('apoptosis', 'biological_process', 'GO:0006915', ('115', '124'))	('arrest', 'Disease', (148, 154))	('cell proliferation', 'CPA', (73, 91))	('inhibited', 'NegReg', (63, 72))	('AS', 'Phenotype', 'HP:0002621', (49, 51))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
165921	32236611	By contrast, high levels of HOXA11-AS expression facilitated metastasis and invasion both in vitro and in vivo by exerting an influence on EMT in BC (the abovementioned mechanisms are shown in Fig.	('BC', 'Phenotype', 'HP:0009725', (146, 148))	('men', 'Species', '9606', (159, 162))	('EMT', 'biological_process', 'GO:0001837', ('139', '142'))	('influence', 'Reg', (126, 135))	('metastasis', 'CPA', (61, 71))	('AS', 'Phenotype', 'HP:0002621', (35, 37))	('invasion', 'CPA', (76, 84))	('BC', 'Phenotype', 'HP:0003002', (146, 148))	('HOXA11-AS', 'Var', (28, 37))	('facilitated', 'PosReg', (49, 60))
165923	32236611	These studies, however, have confirmed that HOXA11-AS exerts carcinogenic effects in BC, thereby providing some novel insights for even earlier diagnosis in the future, and for the therapy of BC.	('carcinogenic', 'Disease', 'MESH:D063646', (61, 73))	('BC', 'Phenotype', 'HP:0003002', (85, 87))	('carcinogenic', 'Disease', (61, 73))	('BC', 'Phenotype', 'HP:0003002', (192, 194))	('BC', 'Phenotype', 'HP:0009725', (85, 87))	('BC', 'Phenotype', 'HP:0009725', (192, 194))	('AS', 'Phenotype', 'HP:0002621', (51, 53))	('HOXA11-AS', 'Var', (44, 53))
165930	32236611	By contrast, Liu et al reported that HOXA11-AS knockdown induces G0/G1 phase arrest in GC cells and decreases GC cell metastasis, migration and invasion, both in vitro and in vivo.	('GC cell metastasis', 'CPA', (110, 128))	('induces', 'Reg', (57, 64))	('AS', 'Phenotype', 'HP:0002621', (44, 46))	('GC', 'Phenotype', 'HP:0012126', (87, 89))	('GC', 'Phenotype', 'HP:0012126', (110, 112))	('invasion', 'CPA', (144, 152))	('decreases', 'NegReg', (100, 109))	('knockdown', 'Var', (47, 56))	('arrest', 'Disease', 'MESH:D006323', (77, 83))	('HOXA11-AS', 'Var', (37, 46))	('G1 phase', 'biological_process', 'GO:0051318', ('68', '76'))	('migration', 'CPA', (130, 139))	('arrest', 'Disease', (77, 83))
165931	32236611	In terms of the underlying mechanism, Sun et al demonstrated that HOXA11-AS acts as a protein scaffold to recruit EZH2, accompanied by DNMT1 or LSD1.	('LSD1', 'Gene', (144, 148))	('DNMT1', 'Gene', (135, 140))	('DNMT1', 'Gene', '1786', (135, 140))	('HOXA11-AS', 'Var', (66, 75))	('EZH2', 'Gene', '2146', (114, 118))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('AS', 'Phenotype', 'HP:0002621', (73, 75))	('recruit', 'PosReg', (106, 113))	('EZH2', 'Gene', (114, 118))	('LSD1', 'Gene', '23028', (144, 148))
165936	32236611	Knockdown of HOXA11-AS suppresses the binding capability of DNA with several chromatin modification factors (namely, PRC2, LSD1 and DNMT1).	('HOXA11-AS', 'Var', (13, 22))	('PR', 'Gene', '5241', (117, 119))	('DNMT1', 'Gene', (132, 137))	('binding', 'Interaction', (38, 45))	('suppresses', 'NegReg', (23, 33))	('DNMT1', 'Gene', '1786', (132, 137))	('AS', 'Phenotype', 'HP:0002621', (20, 22))	('chromatin', 'cellular_component', 'GO:0000785', ('77', '86'))	('LSD1', 'Gene', (123, 127))	('binding', 'molecular_function', 'GO:0005488', ('38', '45'))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('chromatin modification', 'biological_process', 'GO:0006325', ('77', '99'))	('RC', 'Phenotype', 'HP:0009726', (118, 120))	('LSD1', 'Gene', '23028', (123, 127))	('chromatin modification', 'biological_process', 'GO:0016569', ('77', '99'))
165939	32236611	Liu et al identified that HOXA11-AS enhances beta-catenin transcription by interacting with WD repeat-containing protein 5 (WDR5), and p21 transcription is subsequently inhibited via binding with EZH2.	('WD repeat-containing protein 5', 'Gene', '11091', (92, 122))	('transcription', 'biological_process', 'GO:0006351', ('58', '71'))	('WDR5', 'Gene', '11091', (124, 128))	('WDR5', 'Gene', (124, 128))	('AS', 'Phenotype', 'HP:0002621', (33, 35))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('p21', 'Gene', (135, 138))	('p21', 'Gene', '644914', (135, 138))	('inhibited', 'NegReg', (169, 178))	('beta-catenin', 'Gene', (45, 57))	('EZH2', 'Gene', '2146', (196, 200))	('EZH2', 'Gene', (196, 200))	('beta-catenin', 'Gene', '1499', (45, 57))	('binding', 'Interaction', (183, 190))	('transcription', 'MPA', (139, 152))	('WD repeat-containing protein 5', 'Gene', (92, 122))	('enhances', 'PosReg', (36, 44))	('binding', 'molecular_function', 'GO:0005488', ('183', '190'))	('transcription', 'MPA', (58, 71))	('interacting', 'Interaction', (75, 86))	('transcription', 'biological_process', 'GO:0006351', ('139', '152'))	('HOXA11-AS', 'Var', (26, 35))
165940	32236611	In addition, HOXA11-AS can interact with double-stranded RNA-binding protein staufen homolog 1 (STAU1) to promote KLF2 mRNA degradation.	('interact', 'Interaction', (27, 35))	('HOXA11-AS', 'Var', (13, 22))	('double-stranded RNA-binding protein staufen homolog 1', 'Gene', '6780', (41, 94))	('STAU1', 'Gene', '6780', (96, 101))	('double-stranded RNA-binding', 'molecular_function', 'GO:0003725', ('41', '68'))	('promote', 'PosReg', (106, 113))	('KLF2', 'Gene', '10365', (114, 118))	('AS', 'Phenotype', 'HP:0002621', (20, 22))	('RNA', 'cellular_component', 'GO:0005562', ('57', '60'))	('KLF2', 'Gene', (114, 118))	('mRNA degradation', 'biological_process', 'GO:0006402', ('119', '135'))	('STAU1', 'Gene', (96, 101))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))
165948	32236611	Regarding the mechanism, Yang et al discovered that HOXA11-AS functions as a ceRNA to suppress the expression of miR-146b-5p, which subsequently modulates the expression of its downstream target, matrix metalloproteinase-16 (MMP16) in RC.	('RC', 'Phenotype', 'HP:0009726', (235, 237))	('expression', 'MPA', (99, 109))	('MMP', 'molecular_function', 'GO:0004235', ('225', '228'))	('miR-146b-5p', 'Var', (113, 124))	('suppress', 'NegReg', (86, 94))	('matrix metalloproteinase-16', 'Gene', (196, 223))	('MMP16', 'Gene', (225, 230))	('matrix metalloproteinase-16', 'Gene', '4325', (196, 223))	('modulates', 'Reg', (145, 154))	('expression', 'MPA', (159, 169))	('AS', 'Phenotype', 'HP:0002621', (59, 61))	('MMP16', 'Gene', '4325', (225, 230))
165949	32236611	Therefore, HOXA11-AS promotes RC cell invasion and proliferation by regulating the miR-146b-5p/MMP16 pathway (Fig.	('HOXA11-AS', 'Var', (11, 20))	('RC', 'Phenotype', 'HP:0009726', (30, 32))	('regulating', 'Reg', (68, 78))	('promotes', 'PosReg', (21, 29))	('RC cell invasion', 'CPA', (30, 46))	('proliferation', 'CPA', (51, 64))	('MMP16', 'Gene', '4325', (95, 100))	('AS', 'Phenotype', 'HP:0002621', (18, 20))	('MMP16', 'Gene', (95, 100))	('MMP', 'molecular_function', 'GO:0004235', ('95', '98'))
165954	32236611	Authors of that study also reported that HOXA11-AS recruits EZH2 to the promoter region of p21 and mediates H3K27me3 to suppress its transcription.	('EZH2', 'Gene', (60, 64))	('transcription', 'biological_process', 'GO:0006351', ('133', '146'))	('p21', 'Gene', '644914', (91, 94))	('AS', 'Phenotype', 'HP:0002621', (48, 50))	('p21', 'Gene', (91, 94))	('H3K27me3', 'Var', (108, 116))	('suppress', 'NegReg', (120, 128))	('EZH2', 'Gene', '2146', (60, 64))	('transcription', 'MPA', (133, 146))
165955	32236611	Furthermore, HOXA11-AS acts as a ceRNA for miR-124, which directly targets EZH2, and the cell proliferation and invasion-increasing effects of HOXA11-AS were attenuated upon miR-124 overexpression (Fig.	('invasion-increasing', 'CPA', (112, 131))	('attenuated', 'NegReg', (158, 168))	('EZH2', 'Gene', (75, 79))	('miR-124', 'Gene', (43, 50))	('cell proliferation', 'CPA', (89, 107))	('AS', 'Phenotype', 'HP:0002621', (150, 152))	('AS', 'Phenotype', 'HP:0002621', (20, 22))	('cell proliferation', 'biological_process', 'GO:0008283', ('89', '107'))	('overexpression', 'PosReg', (182, 196))	('EZH2', 'Gene', '2146', (75, 79))	('HOXA11-AS', 'Var', (143, 152))
165960	32236611	A large number of studies have shown that not only HOXA11-AS, but also many other lncRNAs act as oncogenes or tumor suppressor genes in different cancers.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('HOXA11-AS', 'Var', (51, 60))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('AS', 'Phenotype', 'HP:0002621', (58, 60))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ncRNA', 'Gene', (83, 88))	('tumor suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('ncRNA', 'Gene', '220202', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
165962	32236611	HOXA11-AS exerts opposing effects in different types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('AS', 'Phenotype', 'HP:0002621', (7, 9))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('HOXA11-AS', 'Var', (0, 9))
165964	32236611	For example, in EOC, HOXA11-AS can act as a tumor suppressor gene, which is different from the tumor mentioned above.	('HOXA11-AS', 'Var', (21, 30))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('44', '60'))	('men', 'Species', '9606', (101, 104))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('AS', 'Phenotype', 'HP:0002621', (28, 30))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor suppressor', 'biological_process', 'GO:0051726', ('44', '60'))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', (95, 100))
165965	32236611	It has been reported that common germline genetic variants or single nucleotide polymorphisms (SNPs) affecting lncRNAs are conducive to the development of various types of cancer, such as EOC.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('single nucleotide polymorphisms', 'Var', (62, 93))	('ncRNA', 'Gene', (112, 117))	('cancer', 'Disease', (172, 178))	('EOC', 'Disease', (188, 191))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('ncRNA', 'Gene', '220202', (112, 117))	('variants', 'Var', (50, 58))	('conducive to', 'Reg', (123, 135))	('men', 'Species', '9606', (147, 150))
165966	32236611	Richards et al reported that overexpression of HOXA11-AS results in a clear reduction in cell proliferation and survival, which are two main cellular processes associated with EOC development in both common and minor allele constructs.	('AS', 'Phenotype', 'HP:0002621', (54, 56))	('reduction', 'NegReg', (76, 85))	('overexpression', 'PosReg', (29, 43))	('cell proliferation', 'CPA', (89, 107))	('men', 'Species', '9606', (187, 190))	('cell proliferation', 'biological_process', 'GO:0008283', ('89', '107'))	('HOXA11-AS', 'Var', (47, 56))
165968	32236611	The finding has identified a greatly decreased risk of EOC among women who have the HOXA11-AS rs17427875 T allele.	('rs17427875 T', 'Var', (94, 106))	('AS', 'Phenotype', 'HP:0002621', (91, 93))	('EOC', 'Disease', (55, 58))	('women', 'Species', '9606', (65, 70))	('rs17427875', 'Mutation', 'rs17427875', (94, 104))	('decreased', 'NegReg', (37, 46))
165974	32236611	Qu et al found that the expression levels of HOXA11-AS are closely correlated with pathological grade, T (tumor) grade, clinical stage, neck nodal metastasis and advanced tumors of grade T3 to T4 in LSCC.	('HOXA11-AS', 'Var', (45, 54))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('neck', 'cellular_component', 'GO:0044326', ('136', '140'))	('expression levels', 'MPA', (24, 41))	('neck nodal metastasis', 'CPA', (136, 157))	('correlated', 'Reg', (67, 77))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('AS', 'Phenotype', 'HP:0002621', (52, 54))	('CC', 'Phenotype', 'HP:0002664', (201, 203))	('SCC', 'Phenotype', 'HP:0002860', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Disease', (171, 177))	('tumor', 'Disease', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
165981	32236611	In terms of the underlying mechanism, HOXA11-AS promotes CC cell migration and invasion by upregulating the levels of MMP-9, MMP-2, and vascular endothelial growth factor (VEGF), and disordering of the EMT-associated genes suggested that HOXA11-AS may be involved in cell migration and invasion in CC (Fig.	('MMP-2', 'Gene', '4313', (125, 130))	('vascular endothelial growth factor', 'Gene', (136, 170))	('MMP-2', 'molecular_function', 'GO:0004228', ('125', '130'))	('involved', 'Reg', (255, 263))	('MMP-9', 'Gene', '4318', (118, 123))	('VEGF', 'Gene', '7422', (172, 176))	('cell migration', 'biological_process', 'GO:0016477', ('60', '74'))	('MMP-9', 'Gene', (118, 123))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('136', '170'))	('HOXA11-AS', 'Var', (38, 47))	('VEGF', 'Gene', (172, 176))	('CC', 'Phenotype', 'HP:0002664', (298, 300))	('MMP-2', 'Gene', (125, 130))	('CC', 'Phenotype', 'HP:0002664', (57, 59))	('invasion', 'CPA', (79, 87))	('invasion', 'CPA', (286, 294))	('AS', 'Phenotype', 'HP:0002621', (245, 247))	('disordering', 'Var', (183, 194))	('EMT', 'biological_process', 'GO:0001837', ('202', '205'))	('vascular endothelial growth factor', 'Gene', '7422', (136, 170))	('MMP-9', 'molecular_function', 'GO:0004229', ('118', '123'))	('CC cell migration', 'CPA', (57, 74))	('promotes', 'PosReg', (48, 56))	('AS', 'Phenotype', 'HP:0002621', (45, 47))	('EMT-associated', 'Gene', (202, 216))	('cell migration', 'CPA', (267, 281))	('upregulating', 'PosReg', (91, 103))	('cell migration', 'biological_process', 'GO:0016477', ('267', '281'))
165988	32236611	Taking all these findings into consideration, HOXA11-AS may have an oncogenic role in ESCC, and therefore HOXA11-AS may also represent a predictive marker in postoperative ESCC patients.	('AS', 'Phenotype', 'HP:0002621', (113, 115))	('CC', 'Phenotype', 'HP:0002664', (88, 90))	('patients', 'Species', '9606', (177, 185))	('CC', 'Phenotype', 'HP:0002664', (174, 176))	('HOXA11-AS', 'Var', (46, 55))	('HOXA11-AS', 'Var', (106, 115))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('SCC', 'Phenotype', 'HP:0002860', (173, 176))	('ESCC', 'Disease', (172, 176))	('ESCC', 'Disease', (86, 90))	('AS', 'Phenotype', 'HP:0002621', (53, 55))
165992	32236611	Their study suggested that HOXA11-AS knockdown in osteosarcoma induces cell cycle arrest at the G0/G1 phase, and HOXA11-AS overexpression led to a substantial improvement in cell invasion and growth rates in osteosarcoma cells via the competitive binding of miR-124-3p, which targets Rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) (Fig.	('miR-124-3p', 'Gene', (258, 268))	('knockdown', 'Var', (37, 46))	('AS', 'Phenotype', 'HP:0002621', (34, 36))	('ROCK1', 'Gene', '6093', (341, 346))	('arrest', 'Disease', 'MESH:D006323', (82, 88))	('osteosarcoma', 'Phenotype', 'HP:0002669', (208, 220))	('AS', 'Phenotype', 'HP:0002621', (120, 122))	('osteosarcoma', 'Disease', (50, 62))	('growth rates', 'CPA', (192, 204))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('71', '88'))	('osteosarcoma', 'Disease', 'MESH:D012516', (50, 62))	('binding', 'molecular_function', 'GO:0005488', ('247', '254'))	('binding', 'Interaction', (247, 254))	('protein', 'cellular_component', 'GO:0003675', ('323', '330'))	('osteosarcoma', 'Phenotype', 'HP:0002669', (50, 62))	('men', 'Species', '9606', (166, 169))	('G1 phase', 'biological_process', 'GO:0051318', ('99', '107'))	('osteosarcoma', 'Disease', (208, 220))	('ROCK1', 'Gene', (341, 346))	('miR-124-3p', 'Gene', '406909', (258, 268))	('cell invasion', 'CPA', (174, 187))	('osteosarcoma', 'Disease', 'MESH:D012516', (208, 220))	('improvement', 'PosReg', (159, 170))	('arrest', 'Disease', (82, 88))	('Rho-associated, coiled-coil-containing protein kinase 1', 'Gene', '6093', (284, 339))
165993	32236611	In this manner, HOXA11-AS may exert oncogenic functions by regulating the miR-124-3p/ROCK1 pathway.	('AS', 'Phenotype', 'HP:0002621', (23, 25))	('ROCK1', 'Gene', '6093', (85, 90))	('ROCK1', 'Gene', (85, 90))	('miR-124-3p', 'Gene', '406909', (74, 84))	('regulating', 'Reg', (59, 69))	('HOXA11-AS', 'Var', (16, 25))	('miR-124-3p', 'Gene', (74, 84))
165999	32236611	In addition, HOXA11-AS can act as a ceRNA by sequestering miR-124-3p to inhibit cell proliferation and enhance apoptosis (Fig.	('HOXA11-AS', 'Var', (13, 22))	('sequestering', 'MPA', (45, 57))	('miR-124-3p', 'Gene', (58, 68))	('sequestering', 'biological_process', 'GO:0051235', ('45', '57'))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('AS', 'Phenotype', 'HP:0002621', (20, 22))	('enhance', 'PosReg', (103, 110))	('cell proliferation', 'CPA', (80, 98))	('cell proliferation', 'biological_process', 'GO:0008283', ('80', '98'))	('inhibit', 'NegReg', (72, 79))	('miR-124-3p', 'Gene', '406909', (58, 68))	('apoptosis', 'CPA', (111, 120))
166003	32236611	Mechanistically, those authors revealed that HOXA11-AS recruits LSD1 and EZH2 proteins to the RND3 gene promoter region in the nucleus to repress its expression in trophoblast cells.	('expression', 'MPA', (150, 160))	('HOXA11-AS', 'Var', (45, 54))	('RND3', 'Gene', '390', (94, 98))	('repress', 'NegReg', (138, 145))	('LSD1', 'Gene', '23028', (64, 68))	('EZH2', 'Gene', '2146', (73, 77))	('AS', 'Phenotype', 'HP:0002621', (52, 54))	('EZH2', 'Gene', (73, 77))	('LSD1', 'Gene', (64, 68))	('proteins', 'Protein', (78, 86))	('RND3', 'Gene', (94, 98))	('nucleus', 'cellular_component', 'GO:0005634', ('127', '134'))
166006	32236611	These studies revealed that HOXA11-AS may have an oncogenic function via modulating the LSD1/EZH2-RND3 and HOXA11-AS/miR-15b-5p/HOXA7 pathways.	('RND3', 'Gene', (98, 102))	('miR-15b', 'Gene', (117, 124))	('HOXA7', 'Gene', (128, 133))	('EZH2', 'Gene', '2146', (93, 97))	('RND3', 'Gene', '390', (98, 102))	('HOXA7', 'Gene', '3204', (128, 133))	('LSD1', 'Gene', (88, 92))	('EZH2', 'Gene', (93, 97))	('modulating', 'Reg', (73, 83))	('miR-15b', 'Gene', '406949', (117, 124))	('AS', 'Phenotype', 'HP:0002621', (35, 37))	('LSD1', 'Gene', '23028', (88, 92))	('AS', 'Phenotype', 'HP:0002621', (114, 116))	('HOXA11-AS', 'Var', (28, 37))
166007	32236611	Consequently, these results have verified that abnormal expression of HOXA11-AS is involved in the occurrence and development of PE, and that this lncRNA may function as a putative target for diagnosis and treatment in PE.	('PE', 'Phenotype', 'HP:0100602', (219, 221))	('AS', 'Phenotype', 'HP:0002621', (77, 79))	('ncRNA', 'Gene', '220202', (148, 153))	('men', 'Species', '9606', (121, 124))	('involved', 'Reg', (83, 91))	('men', 'Species', '9606', (211, 214))	('HOXA11-AS', 'Gene', (70, 79))	('PE', 'Phenotype', 'HP:0100602', (129, 131))	('ncRNA', 'Gene', (148, 153))	('abnormal', 'Var', (47, 55))
166013	32236611	Mechanistically, HOXA11-AS knockdown reduces the expression of proliferation-associated gene (PCNA), the cell cycle-related genes p21 and p53, and platelet-derived growth factor (PDGF)-induced growth and migration of vascular smooth muscle cells (VSMCs) is repressed, significantly downregulating the expression of inflammation-associated genes in VSMCs induced by tumor necrosis factor-alpha (TNF-alpha).	('p21', 'Gene', (130, 133))	('p53', 'Gene', (138, 141))	('PCNA', 'Gene', '5111', (94, 98))	('p21', 'Gene', '644914', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (365, 370))	('tumor necrosis factor-alpha', 'Gene', '7124', (365, 392))	('inflammation', 'Disease', 'MESH:D007249', (315, 327))	('necrosis', 'biological_process', 'GO:0008220', ('371', '379'))	('TNF-alpha', 'Gene', '7124', (394, 403))	('PDGF', 'molecular_function', 'GO:0005161', ('179', '183'))	('downregulating', 'NegReg', (282, 296))	('TNF-alpha', 'Gene', (394, 403))	('PCNA', 'molecular_function', 'GO:0003892', ('94', '98'))	('expression', 'MPA', (49, 59))	('necrosis', 'biological_process', 'GO:0070265', ('371', '379'))	('cell cycle', 'biological_process', 'GO:0007049', ('105', '115'))	('necrosis', 'biological_process', 'GO:0019835', ('371', '379'))	('inflammation', 'Disease', (315, 327))	('necrosis', 'biological_process', 'GO:0001906', ('371', '379'))	('expression', 'MPA', (301, 311))	('knockdown', 'Var', (27, 36))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('147', '177'))	('tumor necrosis factor-alpha', 'Gene', (365, 392))	('AS', 'Phenotype', 'HP:0002621', (24, 26))	('PCNA', 'Gene', (94, 98))	('p53', 'Gene', '7157', (138, 141))	('inflammation', 'biological_process', 'GO:0006954', ('315', '327'))	('necrosis', 'biological_process', 'GO:0008219', ('371', '379'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('365', '386'))	('reduces', 'NegReg', (37, 44))
166015	32236611	Low expression levels of HOXA11-AS inhibited the PDGF-induced stimulation of the PI3K/AKT pathway by inhibiting the phosphorylation of PI3K and AKT in VSMCs and VECs (Fig.	('PI3K', 'molecular_function', 'GO:0016303', ('81', '85'))	('AS', 'Phenotype', 'HP:0002621', (32, 34))	('PI3K', 'Pathway', (135, 139))	('HOXA11-AS', 'Var', (25, 34))	('AKT', 'Gene', (144, 147))	('AKT', 'Gene', (86, 89))	('phosphorylation', 'MPA', (116, 131))	('phosphorylation', 'biological_process', 'GO:0016310', ('116', '131'))	('PDGF', 'molecular_function', 'GO:0005161', ('49', '53'))	('inhibited', 'NegReg', (35, 44))	('PI3K', 'molecular_function', 'GO:0016303', ('135', '139'))	('AKT', 'Gene', '207', (144, 147))	('AKT', 'Gene', '207', (86, 89))	('PDGF-induced', 'Gene', (49, 61))	('stimulation', 'MPA', (62, 73))	('inhibiting', 'NegReg', (101, 111))
166017	32236611	In conclusion, an increasing number of studies have shown that lncRNAs are dysregulated in various types of cancer, and aberrant expression of lncRNAs is involved in the occurrence, development, and metastasis of cancer.	('aberrant', 'Var', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('men', 'Species', '9606', (189, 192))	('expression', 'MPA', (129, 139))	('involved', 'Reg', (154, 162))	('ncRNA', 'Gene', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ncRNA', 'Gene', (144, 149))	('cancer', 'Disease', (213, 219))	('ncRNA', 'Gene', '220202', (64, 69))	('ncRNA', 'Gene', '220202', (144, 149))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
166035	31886185	Moreover, macrophage-associated VSIG4 was demonstrated to facilitate lung carcinoma and multiple myeloma development, which provided a promising immunotherapeutic target and prognostic indicator.	('facilitate', 'PosReg', (58, 68))	('lung carcinoma', 'Disease', (69, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('multiple myeloma', 'Phenotype', 'HP:0006775', (88, 104))	('macrophage-associated', 'Var', (10, 31))	('multiple myeloma', 'Disease', 'MESH:D009101', (88, 104))	('multiple myeloma', 'Disease', (88, 104))	('lung carcinoma', 'Disease', 'MESH:D008175', (69, 83))
166036	31886185	HSD11B1 exhibits oncogenic potential in primary imatinib-naive gastrointestinal stromal tumors driven by HSD11B1 copy-number gain or missense mutations.	('gastrointestinal stromal tumors', 'Disease', (63, 94))	('imatinib', 'Chemical', 'MESH:D000068877', (48, 56))	('HSD11B1', 'Gene', (105, 112))	('missense mutations', 'Var', (133, 151))	('gain', 'PosReg', (125, 129))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (63, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (63, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('copy-number', 'Var', (113, 124))
166053	31440091	These findings suggest that B7-H3-expressing ccRCCs may exert tumor-promoting immunity by interacting with FOXP3+ regulatory T cells in the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('exert', 'Reg', (56, 61))	('interacting', 'Interaction', (90, 101))	('B7-H3-expressing', 'Var', (28, 44))	('tumor', 'Disease', (140, 145))
166080	31440091	For the multivariable analysis, we initially included age (<65 years vs >=65 years), sex (male vs female), tumor size (<40 mm vs >=40 mm), Fuhrman grade (1-2 vs 3-4), pathological stage (I-II vs III-IV), and FOXP3+ cell density (low vs high).	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('<40', 'Var', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))
166083	31440091	Among 252 cases of ccRCC, high tumor cell expression of B7-H3 was observed in 37 cases (15%), whereas high expression levels of B7-H3 in the tumor vasculature were observed in 137 cases (54%; Figure 1).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (141, 146))	('B7-H3', 'Var', (56, 61))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('RCC', 'Disease', (21, 24))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (19, 24))
166087	31440091	High B7-H3 expression in the vasculature was also associated with large tumor size (P=0.013), advanced pathological stage (P=0.015), old age (P=0.029), and high Fuhrman grade (P=0.032).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('High', 'Var', (0, 4))	('tumor', 'Disease', (72, 77))	('B7-H3', 'Protein', (5, 10))	('high Fuhrman grade', 'CPA', (156, 174))	('expression', 'MPA', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
166089	31440091	In an independent manner, FOXP3+ cell density was positively associated with B7-H3 expression in both tumor cells [odds ratio (OR) =2.93, 95% CI=1.40-6.56; P=0.0041] and the tumor vasculature (OR=2.45, 95% CI=1.46-4.17; P=0.0007; Table 2).	('tumor', 'Disease', (174, 179))	('associated', 'Interaction', (61, 71))	('B7-H3', 'Gene', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('FOXP3+', 'Var', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('expression', 'MPA', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
166093	31440091	In the Kaplan-Meier analysis, high B7-H3 expression in the tumor vasculature was associated with increased disease-specific death (log-rank P=0.0081; Figure 2C) and overall mortality (log-rank P=0.0021; Figure 2D).	('disease-specific', 'Disease', (107, 123))	('B7-H3', 'Protein', (35, 40))	('increased', 'PosReg', (97, 106))	('tumor', 'Disease', (59, 64))	('high', 'Var', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
166094	31440091	In the Cox regression univariable analysis, high B7-H3 expression in the tumor vasculature was associated with increased disease-specific death (HR=2.48, 95% CI=1.27-5.19; P=0.0069) and overall mortality (HR =2.41, 95% CI=1.38-4.42; P=0.0017; Table 3).	('B7-H3', 'Protein', (49, 54))	('high', 'Var', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('increased', 'PosReg', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('overall mortality', 'CPA', (186, 203))	('disease-specific death', 'CPA', (121, 143))	('tumor', 'Disease', (73, 78))
166095	31440091	In the multivariable analysis, high B7-H3 expression in the tumor vasculature was independently associated with increased overall mortality (HR=1.86, 95% CI=1.05-3.45; P=0.035).	('expression', 'MPA', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('B7-H3', 'Protein', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('high', 'Var', (31, 35))	('tumor', 'Disease', (60, 65))
166097	31440091	High B7-H3 expression in tumor cells was associated with increased disease-specific mortality in the high FOXP3+ cell density group (log-rank P=0.0084; Figure 3B) but not in the low cell density group (log-rank P=0.70; Figure 3A).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('High', 'Var', (0, 4))	('disease-specific', 'Disease', (67, 83))	('B7-H3', 'Protein', (5, 10))	('tumor', 'Disease', (25, 30))	('increased', 'PosReg', (57, 66))	('high FOXP3+', 'Var', (101, 112))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
166098	31440091	High B7-H3 expression in the tumor vasculature was also associated with increased disease-specific death in the high FOXP3+ cell density group (log-rank P=0.0051; Figure 3D) but not in the low cell density group (log-rank P=0.47; Figure 3C).	('increased', 'PosReg', (72, 81))	('High', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('B7-H3', 'Protein', (5, 10))	('disease-specific death', 'CPA', (82, 104))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('high FOXP3+ cell', 'Var', (112, 128))
166099	31440091	In a Cox regression univariable analysis, high B7-H3 expression in tumor cells was associated with increased disease-specific mortality in the high FOXP3+ cell density group (HR=2.98, 95% CI=1.23-6.91; P=0.017) but not in the low cell density group (P=0.71; Table 3).	('B7-H3', 'Gene', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('disease-specific', 'Disease', (109, 125))	('high FOXP3+', 'Var', (143, 154))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('high', 'Var', (42, 46))
166100	31440091	High B7-H3 expression in the tumor vasculature was also associated with increased disease-specific mortality in the high FOXP3+ cell density group (HR=4.86, 95% CI=1.65-20.7; P=0.0025) but not in the low cell density group (P=0.48; Table 3).	('increased', 'PosReg', (72, 81))	('High', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('high FOXP3+', 'Var', (116, 127))	('B7-H3', 'Protein', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('disease-specific', 'Disease', (82, 98))	('tumor', 'Disease', (29, 34))
166101	31440091	High B7-H3 expression in the tumor vasculature was independently associated with increased overall mortality in the high FOXP3+ cell density group (HR =3.13, 95% CI=1.28-9.38; P=0.010) but not in the low cell density group (P=0.36).	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('High', 'Var', (0, 4))	('high FOXP3+', 'Var', (116, 127))	('B7-H3', 'Protein', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('increased', 'PosReg', (81, 90))
166117	31440091	B7-H3 inhibits the proliferation of both CD4+ and CD8+ T cells and reduces the production of effector cytokines (eg, IL-2 and interferon-gamma) by suppressing NFAT, NFKB, and AP-1 transcriptional activities.	('B7-H3', 'Var', (0, 5))	('CD4', 'Gene', (41, 44))	('production of effector cytokines', 'MPA', (79, 111))	('inhibits', 'NegReg', (6, 14))	('CD4', 'Gene', '12504', (41, 44))	('IL-2', 'Gene', '16183', (117, 121))	('suppressing', 'NegReg', (147, 158))	('AP-1', 'Gene', (175, 179))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('126', '142'))	('IL-2', 'Gene', (117, 121))	('NFAT', 'Protein', (159, 163))	('proliferation', 'CPA', (19, 32))	('interferon-gamma', 'Gene', '15978', (126, 142))	('IL-2', 'molecular_function', 'GO:0005134', ('117', '121'))	('reduces', 'NegReg', (67, 74))	('NFKB', 'Protein', (165, 169))	('interferon-gamma', 'Gene', (126, 142))	('AP-1', 'cellular_component', 'GO:0005907', ('175', '179'))
166119	31440091	Moreover, administration of an anti-B7-H3 antibody during the induction phase enhances the severity of Th2 (T helper 2)-mediated experimental allergic conjunctivitis.	('antibody', 'cellular_component', 'GO:0019814', ('42', '50'))	('antibody', 'molecular_function', 'GO:0003823', ('42', '50'))	('experimental allergic conjunctivitis', 'Disease', (129, 165))	('enhances', 'PosReg', (78, 86))	('anti-B7-H3', 'Var', (31, 41))	('antibody', 'cellular_component', 'GO:0042571', ('42', '50'))	('allergic conjunctivitis', 'Phenotype', 'HP:0007879', (142, 165))	('antibody', 'cellular_component', 'GO:0019815', ('42', '50'))	('experimental allergic conjunctivitis', 'Disease', 'MESH:D004342', (129, 165))	('conjunctivitis', 'Phenotype', 'HP:0000509', (151, 165))
166124	31440091	B7-H3 blockade, in combination with the targeting of FOXP3+ cells, might be an effective strategy for managing B7-H3-expressing RCC.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('B7-H3-expressing', 'Var', (111, 127))	('B7-H3', 'Protein', (0, 5))
166135	31440091	On the basis of our findings, the targeting of B7-H3 and FOXP3+ regulatory T cells may serve as a promising strategy for the treatment of B7-H3-expressing RCC.	('B7-H3-expressing', 'Var', (138, 154))	('RCC', 'Disease', (155, 158))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('RCC', 'Disease', 'MESH:C538614', (155, 158))
166144	29388770	By targeting cancer-associated biochemical variations at the molecular level, this imaging modality can detect tumors at the earliest stages of malignancy.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('malignancy', 'Disease', (144, 154))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('variations', 'Var', (43, 53))	('malignancy', 'Disease', 'MESH:D009369', (144, 154))
166150	29388770	Meanwhile, 124I-girentuximab targets the cell-surface carbonic anhydrase IX that is homogeneously overexpressed in more than 95% of clear cell renal cell carcinoma (ccRCC).	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (132, 163))	('124I-girentuximab', 'Var', (11, 28))	('clear cell renal cell carcinoma', 'Disease', (132, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('ccRCC', 'Phenotype', 'HP:0006770', (165, 170))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (132, 163))	('124I-girentuximab', 'Chemical', 'MESH:C581012', (11, 28))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (143, 163))	('cell-surface', 'cellular_component', 'GO:0009986', ('41', '53'))
166171	29388770	The specific binding of the directly labeled 131I-A5B7 to the SW1222 cells and derived xenografts is well documented in the literature.	('binding', 'molecular_function', 'GO:0005488', ('13', '20'))	('131I-A5B7', 'Var', (45, 54))	('131I-A5B7', 'Chemical', '-', (45, 54))	('binding', 'Interaction', (13, 20))
166172	29388770	Furthermore, 131I-A5B7 has been employed in several clinical trials for radioimmunotherapy of metastatic colorectal tumors and advanced gastrointestinal carcinomas.	('gastrointestinal carcinomas', 'Phenotype', 'HP:0002672', (136, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('gastrointestinal carcinomas', 'Disease', 'MESH:D004067', (136, 163))	('colorectal tumors', 'Disease', 'MESH:D015179', (105, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (153, 163))	('gastrointestinal carcinomas', 'Disease', (136, 163))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('colorectal tumors', 'Disease', (105, 122))	('131I-A5B7', 'Var', (13, 22))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
166187	29388770	HRMS (EI, m/z) [M + H]: calcd 414.0972 for C24H16NO6+, found 414.0978.	('HRMS', 'Disease', (0, 4))	('HRMS', 'Disease', 'None', (0, 4))	('C24H16NO6+', 'Var', (43, 53))	('C24H16NO6', 'Chemical', '-', (43, 52))
166277	33589528	For holistic CD8+T cells density in Discovery Cohort, >=86/ mm2 was defined as high and <86/ mm2 was defined as low.	('>=86/', 'Var', (54, 59))	('CD8', 'Gene', '925', (13, 16))	('CD8', 'Gene', (13, 16))
166354	33589528	Studies also reported that CXCL13 promoted progression through PI3K/AKT pathway in ccRCC.	('PI3K', 'molecular_function', 'GO:0016303', ('63', '67'))	('progression', 'MPA', (43, 54))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('AKT', 'Gene', '207', (68, 71))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('RCC', 'Disease', (85, 88))	('CXCL13', 'Var', (27, 33))	('AKT', 'Gene', (68, 71))
166371	31585940	Genetic and therapeutic inhibition of AXL signaling in ccRCC tumor xenografts reduced tumor vessel density and growth under the renal capsule.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('growth under the renal capsule', 'CPA', (111, 141))	('AXL', 'Protein', (38, 41))	('ccRCC tumor', 'Disease', (55, 66))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('ccRCC tumor', 'Disease', 'MESH:D009369', (55, 66))	('inhibition', 'Var', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('reduced', 'NegReg', (78, 85))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (61, 66))	('capsule', 'cellular_component', 'GO:0042603', ('134', '141'))
166396	31585940	Moreover, S100A10 in ccRCC cells is sufficient to promote AXL-mediated plasmin production, endothelial invasion and angiogenesis.	('plasmin', 'Gene', (71, 78))	('promote', 'PosReg', (50, 57))	('angiogenesis', 'CPA', (116, 128))	('endothelial invasion', 'CPA', (91, 111))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (21, 26))	('RCC', 'Disease', (23, 26))	('S100A10', 'Var', (10, 17))	('plasmin', 'Gene', '5340', (71, 78))	('angiogenesis', 'biological_process', 'GO:0001525', ('116', '128'))
166398	31585940	Finally, therapeutic blockade of GAS6/AXL signaling reduced ccRCC and patient derived xenograft tumor vessel density and growth in the kidney.	('GAS6', 'Gene', (33, 37))	('growth in the kidney', 'CPA', (121, 141))	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('GAS6', 'Gene', '2621', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('reduced', 'NegReg', (52, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('patient', 'Species', '9606', (70, 77))	('tumor', 'Disease', (96, 101))	('blockade', 'Var', (21, 29))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('GAS', 'molecular_function', 'GO:0034005', ('33', '36'))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
166413	31585940	The primary antibodies used for IHC staining are AXL (1:100, AF154, R&D), S100A10 (1:200, 4E7E10, Santa Cruz), CD31 (1:200, ab28364, ABcam), Ku70 (1:200, AB18560, ABcam), CAIX (1:500, NB-100-417, Novus), CD117 (1:200, CME296, Biocare Medical), CD10 (1:200, CM129AK, Biocare Medical) and CK7 (1:200, OV-TL 12/30, Dako Agilent).	('CD10', 'molecular_function', 'GO:0004245', ('244', '248'))	('CD31', 'Gene', '5175', (111, 115))	('CME', 'biological_process', 'GO:0072583', ('218', '221'))	('C', 'Chemical', 'MESH:D002244', (218, 219))	('C', 'Chemical', 'MESH:D002244', (34, 35))	('Ku70', 'Gene', '2547', (141, 145))	('C', 'Chemical', 'MESH:D002244', (257, 258))	('CD117', 'Gene', '3815', (204, 209))	('CK7', 'Gene', (287, 290))	('C', 'Chemical', 'MESH:D002244', (287, 288))	('CD31', 'Gene', (111, 115))	('and', 'Var', (283, 286))	('C', 'Chemical', 'MESH:D002244', (111, 112))	('C', 'Chemical', 'MESH:D002244', (104, 105))	('Ku70', 'Gene', (141, 145))	('CAIX', 'Gene', (171, 175))	('CD117', 'Gene', (204, 209))	('CK7', 'Gene', '3855', (287, 290))	('CAIX', 'Gene', '768', (171, 175))	('C', 'Chemical', 'MESH:D002244', (244, 245))	('CD10', 'Gene', '4311', (244, 248))	('CME296', 'CellLine', 'CVCL:J924', (218, 224))	('C', 'Chemical', 'MESH:D002244', (204, 205))	('C', 'Chemical', 'MESH:D002244', (171, 172))	('CD10', 'Gene', (244, 248))
166433	31585940	For GAS6 stimulation, cells were serum deprived for 48 h. Cells were then pretreated with PP2 (500 nM) or dasatinib (50 nM) for 2 hours followed by addition of GAS6 (200 ng/mL) for 4 hours.	('dasatinib', 'Chemical', 'MESH:D000069439', (106, 115))	('GAS6', 'Gene', (160, 164))	('50 nM', 'Var', (117, 122))	('GAS6', 'Gene', '2621', (160, 164))	('GAS', 'molecular_function', 'GO:0034005', ('160', '163'))	('PP2', 'Gene', (90, 93))	('GAS6', 'Gene', '2621', (4, 8))	('GAS6', 'Gene', (4, 8))	('PP2', 'Gene', '4888', (90, 93))	('GAS', 'molecular_function', 'GO:0034005', ('4', '7'))	('C', 'Chemical', 'MESH:D002244', (58, 59))
166447	31585940	Mice were administered 0.1 mL of pazopanib (30mg/kg/day for RCC054, NCI597326 and NCI961994), axitinib (36mg/kg/day for NCI961994), cabozantinib (10mg/kg/day for RCC054 and M62) or vehicle by oral garage.	('C', 'Chemical', 'MESH:D002244', (62, 63))	('C', 'Chemical', 'MESH:D002244', (121, 122))	('axitinib', 'Chemical', 'MESH:D000077784', (94, 102))	('RCC', 'Disease', (162, 165))	('C', 'Chemical', 'MESH:D002244', (69, 70))	('NCI961994', 'Chemical', '-', (120, 129))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('cabozantinib', 'Chemical', 'MESH:C558660', (132, 144))	('C', 'Chemical', 'MESH:D002244', (163, 164))	('RCC', 'Disease', (60, 63))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('NCI961994', 'Chemical', '-', (82, 91))	('C', 'Chemical', 'MESH:D002244', (61, 62))	('C', 'Chemical', 'MESH:D002244', (164, 165))	('Mice', 'Species', '10090', (0, 4))	('pazopanib', 'Chemical', 'MESH:C516667', (33, 42))	('C', 'Chemical', 'MESH:D002244', (83, 84))	('NCI597326', 'Var', (68, 77))
166452	31585940	Total RNA from 786-O-shSCM1, 786-O-shAXL1, M62-shSCM1 and M62-shAXL1 cell were used for the preparation of RNA-Seq libraries with Illumina's TruSeq RNA Library Prep Kit v2 according to manufacturer's protocol.	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('Kit', 'Gene', '3815', (165, 168))	('RNA', 'cellular_component', 'GO:0005562', ('107', '110'))	('C', 'Chemical', 'MESH:D002244', (50, 51))	('M62-shSCM1', 'Var', (43, 53))	('RNA', 'cellular_component', 'GO:0005562', ('148', '151'))	('Kit', 'Gene', (165, 168))	('C', 'Chemical', 'MESH:D002244', (24, 25))
166460	31585940	To investigate the role of AXL in regulating the angiogenic potential of ccRCC cells in vivo, we first utilized a genetic approach to knock down AXL expression in two VHL deficient ccRCC cell lines (786-O and M62,).	('AXL', 'Gene', (145, 148))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('knock', 'Var', (134, 139))	('VHL deficient ccRCC', 'Disease', (167, 186))	('RCC', 'Disease', (183, 186))	('ccRCC', 'Phenotype', 'HP:0006770', (181, 186))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('VHL deficient ccRCC', 'Disease', 'MESH:D006623', (167, 186))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))
166461	31585940	Endogenous AXL expression in both ccRCC cell lines was significantly repressed by the AXL shRNA targeting sequences relative to the control shRNA sequences (Supplementary Fig.	('repressed', 'NegReg', (69, 78))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('men', 'Species', '9606', (163, 166))	('RCC', 'Disease', (36, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (34, 39))	('AXL shRNA', 'Gene', (86, 95))	('Endogenous AXL expression', 'MPA', (0, 25))	('sequences', 'Var', (106, 115))
166464	31585940	In contrast, primary ccRCC tumor growth under the renal capsule was significantly impaired in mice injected with AXL knockdown tumor cells compared to mice injected with AXL wild type shSCM cells (Fig.	('primary', 'CPA', (13, 20))	('C', 'Chemical', 'MESH:D002244', (187, 188))	('mice', 'Species', '10090', (94, 98))	('ccRCC tumor', 'Disease', (21, 32))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (27, 32))	('impaired', 'NegReg', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('C', 'Chemical', 'MESH:D002244', (24, 25))	('C', 'Chemical', 'MESH:D002244', (25, 26))	('ccRCC tumor', 'Disease', 'MESH:D009369', (21, 32))	('AXL', 'Gene', (113, 116))	('capsule', 'cellular_component', 'GO:0042603', ('56', '63'))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mice', 'Species', '10090', (151, 155))	('tumor', 'Disease', (127, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('knockdown', 'Var', (117, 126))
166465	31585940	Both histologic analysis and quantification of CD31 positive blood vessels revealed that tumor vessel density was significantly reduced in AXL knockdown tumors compared to AXL wild type ccRCC tumors (Fig.	('tumors', 'Disease', (192, 198))	('CD31', 'Gene', '5175', (47, 51))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('ccRCC tumors', 'Disease', (186, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('reduced', 'NegReg', (128, 135))	('tumor', 'Disease', (153, 158))	('ccRCC tumors', 'Disease', 'MESH:D009369', (186, 198))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (192, 197))	('CD31', 'Gene', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('ccRCC', 'Phenotype', 'HP:0006770', (186, 191))	('knockdown', 'Var', (143, 152))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
166472	31585940	The S100A10-annexin II plasminogen receptor complex has been shown to enhance the formation of plasmin to promote ECM degradation, neovascularization, invasion, metastasis and drug resistance.	('C', 'Chemical', 'MESH:D002244', (115, 116))	('enhance', 'PosReg', (70, 77))	('promote', 'PosReg', (106, 113))	('drug resistance', 'CPA', (176, 191))	('degradation', 'biological_process', 'GO:0009056', ('118', '129'))	('metastasis', 'CPA', (161, 171))	('S100A10-annexin', 'Var', (4, 19))	('ECM degradation', 'CPA', (114, 129))	('receptor complex', 'cellular_component', 'GO:0043235', ('35', '51'))	('plasmin', 'Gene', (95, 102))	('invasion', 'CPA', (151, 159))	('drug resistance', 'Phenotype', 'HP:0020174', (176, 191))	('plasmin', 'Gene', '5340', (95, 102))	('plasmin', 'Gene', (23, 30))	('drug resistance', 'biological_process', 'GO:0009315', ('176', '191'))	('drug resistance', 'biological_process', 'GO:0042493', ('176', '191'))	('neovascularization', 'CPA', (131, 149))	('plasmin', 'Gene', '5340', (23, 30))	('formation', 'biological_process', 'GO:0009058', ('82', '91'))
166473	31585940	In addition to S100A10, Annexin A2 (ANXA2) expression was reduced >1.7 fold in both AXL knockdown cell lines compared to control lines (Fig.	('Annexin A2', 'Gene', (24, 34))	('expression', 'MPA', (43, 53))	('reduced', 'NegReg', (58, 65))	('S100A10', 'Var', (15, 22))	('Annexin A2', 'Gene', '302', (24, 34))
166474	31585940	In human ccRCC samples, AXL expression correlates with S100A10 and increased S100A10 expression independently correlates with poor patient survival in ccRCC patients (Fig.	('expression', 'MPA', (85, 95))	('S100A10', 'Gene', (77, 84))	('patient', 'Species', '9606', (157, 164))	('human', 'Species', '9606', (3, 8))	('AXL expression', 'MPA', (24, 38))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('patients', 'Species', '9606', (157, 165))	('RCC', 'Disease', (153, 156))	('increased', 'PosReg', (67, 76))	('S100A10', 'Var', (55, 62))	('poor', 'NegReg', (126, 130))	('ccRCC', 'Phenotype', 'HP:0006770', (151, 156))	('patient', 'Species', '9606', (131, 138))	('ccRCC', 'Phenotype', 'HP:0006770', (9, 14))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))
166476	31585940	Additionally, AXL expression correlates with ANXA2 and increased ANXA2 expression independently correlates with poor patient survival in ccRCC patients indicating that the S100A10/ANXA2 plasminogen pathway may contribute to ccRCC tumor progression (Fig.	('S100A10/ANXA2', 'Var', (172, 185))	('increased', 'PosReg', (55, 64))	('ccRCC tumor', 'Disease', 'MESH:D009369', (224, 235))	('RCC', 'Disease', (226, 229))	('plasmin', 'Gene', (186, 193))	('patient', 'Species', '9606', (143, 150))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('plasmin', 'Gene', '5340', (186, 193))	('RCC', 'Disease', (139, 142))	('contribute', 'Reg', (210, 220))	('ccRCC', 'Phenotype', 'HP:0006770', (224, 229))	('RCC', 'Disease', 'MESH:C538614', (226, 229))	('expression', 'MPA', (71, 81))	('ANXA2', 'Gene', (65, 70))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('patient', 'Species', '9606', (117, 124))	('ccRCC tumor', 'Disease', (224, 235))	('patients', 'Species', '9606', (143, 151))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
166478	31585940	Genetic inactivation of AXL significantly reduced S100A10 mRNA and protein as determined by real time PCR and western blot analyses respectively (Fig.	('Genetic inactivation', 'Var', (0, 20))	('reduced', 'NegReg', (42, 49))	('C', 'Chemical', 'MESH:D002244', (103, 104))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('AXL', 'Protein', (24, 27))
166481	31585940	While AXL inactivation reduced ANXA2 at the mRNA level, ANXA2 total protein levels were not consistently reduced in AXL knockdown cells relative to the shSCM cells (Supplementary Fig.	('reduced', 'NegReg', (23, 30))	('C', 'Chemical', 'MESH:D002244', (155, 156))	('inactivation', 'Var', (10, 22))	('AXL', 'Gene', (116, 119))	('knockdown', 'Var', (120, 129))	('reduced', 'NegReg', (105, 112))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('ANXA2 total protein levels', 'MPA', (56, 82))	('men', 'Species', '9606', (171, 174))	('ANXA2', 'MPA', (31, 36))
166490	31585940	Therefore, we compared the rates of plasmin generation between AXL deficient and AXL wild type ccRCC cells.	('RCC', 'Disease', (97, 100))	('plasmin', 'Gene', (36, 43))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('deficient', 'Var', (67, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('plasmin', 'Gene', '5340', (36, 43))
166491	31585940	Using an in vitro assay that measures the conversion of plasminogen to plasmin, we found that the rate of plasmin generation was significantly reduced in shAXL knockdown ccRCC (786-O and M62 cells) compared to shSCM cells (Supplementary Fig.	('plasmin', 'Gene', (71, 78))	('C', 'Chemical', 'MESH:D002244', (174, 175))	('rate', 'MPA', (98, 102))	('knockdown', 'Var', (160, 169))	('C', 'Chemical', 'MESH:D002244', (213, 214))	('ccRCC', 'Phenotype', 'HP:0006770', (170, 175))	('plasmin', 'Gene', '5340', (56, 63))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('C', 'Chemical', 'MESH:D002244', (173, 174))	('plasmin', 'Gene', (106, 113))	('men', 'Species', '9606', (229, 232))	('shAXL', 'Gene', (154, 159))	('plasmin', 'Gene', '5340', (71, 78))	('plasmin', 'Gene', (56, 63))	('RCC', 'Disease', (172, 175))	('plasmin', 'Gene', '5340', (106, 113))	('reduced', 'NegReg', (143, 150))
166495	31585940	These findings demonstrate that both AXL and S100A10 in ccRCC cells promote plasmin production from plasminogen.	('plasmin', 'Gene', (76, 83))	('plasmin', 'Gene', '5340', (100, 107))	('promote', 'PosReg', (68, 75))	('S100A10', 'Var', (45, 52))	('plasmin', 'Gene', '5340', (76, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('RCC', 'Disease', (58, 61))	('plasmin', 'Gene', (100, 107))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
166499	31585940	We examined whether the conditioned media from siAXL or siS100A10 ccRCC cultures affected endothelial (HUVEC) invasion compared to siControl conditioned media.	('C', 'Chemical', 'MESH:D002244', (107, 108))	('C', 'Chemical', 'MESH:D002244', (69, 70))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('affected', 'Reg', (81, 89))	('siS100A10', 'Var', (56, 65))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('RCC', 'Disease', (68, 71))	('siAXL', 'Disease', 'None', (47, 52))	('C', 'Chemical', 'MESH:D002244', (133, 134))	('siAXL', 'Disease', (47, 52))
166503	31585940	Rag2-/-IL2rg-/- mice were injected subcutaneously with matrigel containing supernatant from siControl, siAXL, or siS100A10 treated ccRCC cells.	('IL2rg', 'Gene', '16186', (7, 12))	('siAXL', 'Disease', 'None', (103, 108))	('Rag2', 'Gene', '19374', (0, 4))	('IL2rg', 'Gene', (7, 12))	('C', 'Chemical', 'MESH:D002244', (135, 136))	('C', 'Chemical', 'MESH:D002244', (94, 95))	('Rag2', 'Gene', (0, 4))	('siAXL', 'Disease', (103, 108))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('siS100A10', 'Var', (113, 122))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('IL2', 'molecular_function', 'GO:0005134', ('7', '10'))	('C', 'Chemical', 'MESH:D002244', (134, 135))	('mice', 'Species', '10090', (16, 20))
166504	31585940	The hemoglobin concentration of matrigel plugs containing siAXL and siS100A10 conditioned media was reduced (5-fold) compared to matrigel plugs containing siControl conditioned media (Fig.	('siAXL', 'Disease', 'None', (58, 63))	('siAXL', 'Disease', (58, 63))	('reduced', 'NegReg', (100, 107))	('hemoglobin concentration', 'MPA', (4, 28))	('C', 'Chemical', 'MESH:D002244', (157, 158))	('siS100A10', 'Var', (68, 77))
166505	31585940	These findings demonstrate that AXL and S100A10 promote the angiogenic potential of ccRCC cells in vivo.	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('angiogenic potential', 'CPA', (60, 80))	('promote', 'PosReg', (48, 55))	('RCC', 'Disease', (86, 89))	('S100A10', 'Var', (40, 47))
166506	31585940	To determine if S100A10 is a key factor promoting the angiogenic potential of ccRCC cells mediated by AXL signaling.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('RCC', 'Disease', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('promoting', 'PosReg', (40, 49))	('angiogenic potential', 'CPA', (54, 74))	('S100A10', 'Var', (16, 23))	('AXL signaling', 'MPA', (102, 115))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))
166509	31585940	The results above identify an important role for AXL signaling in mediating ccRCC tumor growth and angiogenesis, raising the intriguing possibility that AXL inhibitors may be effective in blocking ccRCC tumor progression at multiple tissue sites when utilized alone or in combination with antiangiogenic agents.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('ccRCC tumor', 'Disease', (76, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (197, 202))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('ccRCC tumor', 'Disease', (197, 208))	('inhibitors', 'Var', (157, 167))	('angiogenesis', 'biological_process', 'GO:0001525', ('99', '111'))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('ccRCC tumor', 'Disease', 'MESH:D009369', (76, 87))	('blocking', 'NegReg', (188, 196))	('ccRCC tumor', 'Disease', 'MESH:D009369', (197, 208))
166526	31585940	Moreover, histological and immunohistochemical analysis of the PDX tumor showed that the PDX tumor maintained the ccRCC phenotype and expressed AXL as well as S100A10 (Fig.	('PDX', 'Gene', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('AXL', 'Protein', (144, 147))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', (93, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('S100A10', 'Var', (159, 166))	('tumor', 'Disease', (67, 72))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
166527	31585940	Sequencing analysis of the PDX tissue revealed a deletion within VHL at position 492 (Fig.	('VHL', 'Gene', '7428', (65, 68))	('VHL', 'Gene', (65, 68))	('deletion', 'Var', (49, 57))
166539	31585940	We demonstrate that genetic and therapeutic inactivation of AXL in ccRCC cells is sufficient to reduce tumor vessel density and growth at the kidney.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('RCC', 'Disease', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('growth at the kidney', 'CPA', (128, 148))	('tumor', 'Disease', (103, 108))	('reduce', 'NegReg', (96, 102))	('inactivation', 'Var', (44, 56))	('AXL', 'Protein', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
166546	31585940	Moreover, S100A10 deficient endothelial cells have impaired neovascularization in matrigel plugs in vivo associated with reduced tumor growth and vascular density suggesting a role for S100A10 in angiogenesis.	('neovascularization in matrigel plugs', 'CPA', (60, 96))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('reduced', 'NegReg', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('angiogenesis', 'biological_process', 'GO:0001525', ('196', '208'))	('deficient', 'Var', (18, 27))	('S100A10', 'Gene', (10, 17))	('impaired', 'NegReg', (51, 59))	('vascular density', 'CPA', (146, 162))
166551	31585940	We demonstrate that elevated S100A10 correlates with poor survival in ccRCC patients, suggesting S100A10 may be an important factor in the pathogenesis of ccRCC.	('patients', 'Species', '9606', (76, 84))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('S100A10', 'Gene', (29, 36))	('poor', 'NegReg', (53, 57))	('pathogenesis', 'biological_process', 'GO:0009405', ('139', '151'))	('ccRCC', 'Phenotype', 'HP:0006770', (70, 75))	('elevated', 'PosReg', (20, 28))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', (157, 160))	('S100A10', 'Var', (97, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (155, 160))
166585	33819300	Both betaglycan and endoglin knockouts (KOs) are lethal during embryonic development due to heart and liver defects and defective vascular development, respectively, highlighting the shared physiological importance of these coreceptors.	('betaglycan', 'molecular_function', 'GO:0070123', ('5', '15'))	('endoglin', 'molecular_function', 'GO:0070123', ('20', '28'))	('endoglin', 'Gene', '2022', (20, 28))	('knockouts', 'Var', (29, 38))	('defective', 'NegReg', (120, 129))	('liver defects', 'Disease', (102, 115))	('liver defects', 'Phenotype', 'HP:0001392', (102, 115))	('betaglycan', 'Gene', (5, 15))	('endoglin', 'Gene', (20, 28))	('embryonic', 'Disease', 'MESH:D020964', (63, 72))	('betaglycan', 'Gene', '7049', (5, 15))	('liver defects', 'Disease', 'MESH:D056486', (102, 115))	('embryonic', 'Disease', (63, 72))
166591	33819300	Evidence in ovarian cancer also suggests that endoglin expression may impact metastasis.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('endoglin', 'Gene', (46, 54))	('endoglin', 'molecular_function', 'GO:0070123', ('46', '54'))	('ovarian cancer', 'Disease', (12, 26))	('metastasis', 'CPA', (77, 87))	('endoglin', 'Gene', '2022', (46, 54))	('ovarian cancer', 'Phenotype', 'HP:0100615', (12, 26))	('impact', 'Reg', (70, 76))	('ovarian cancer', 'Disease', 'MESH:D010051', (12, 26))	('expression', 'Var', (55, 65))
166599	33819300	Similarly a peptide domain of betaglycan called p144 and soluble betaglycan have been tested in multiple cancer types as an anti-TGF-beta treatment strategy that decreases tumor growth, angiogenesis, metastasis, and augments immunotherapy.	('immunotherapy', 'CPA', (225, 238))	('angiogenesis', 'CPA', (186, 198))	('angiogenesis', 'biological_process', 'GO:0001525', ('186', '198'))	('decreases tumor', 'Disease', (162, 177))	('cancer', 'Disease', (105, 111))	('augments', 'NegReg', (216, 224))	('p144', 'Var', (48, 52))	('rat', 'Species', '10116', (150, 153))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('betaglycan', 'Gene', (65, 75))	('TGF-beta', 'Gene', '7039', (129, 137))	('decreases tumor', 'Disease', 'MESH:D002303', (162, 177))	('betaglycan', 'Gene', '7049', (65, 75))	('betaglycan', 'molecular_function', 'GO:0070123', ('30', '40'))	('TGF-beta', 'Gene', (129, 137))	('soluble', 'cellular_component', 'GO:0005625', ('57', '64'))	('betaglycan', 'molecular_function', 'GO:0070123', ('65', '75'))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('betaglycan', 'Gene', (30, 40))	('betaglycan', 'Gene', '7049', (30, 40))	('metastasis', 'CPA', (200, 210))
166609	33819300	The Affymetrix Probe IDs used in gene chip analysis in KM Plotter were: INHA (210141_s_at), INHBA (204926_at), INHBB (205258_at), TGFBR3 (204731_at), and ENG (201808_s_at).	('210141_s_at', 'Var', (78, 89))	('204926_at', 'Var', (99, 108))	('INHBA', 'Gene', (92, 97))	('INHBB', 'Gene', (111, 116))	('INHBB', 'Gene', '3625', (111, 116))	('205258_at', 'Var', (118, 127))	('204731_at', 'Var', (138, 147))	('INHBA', 'Gene', '3624', (92, 97))
166631	33819300	To begin to evaluate the impact of this relationship more broadly in cancers we analyzed gene alterations including mutations, amplifications, and deletions for the genes encoding inhibin/activin subunits (Fig 1a) INHA, INHBA, INHBB, and the key coreceptors:TGFBR3, and ENG in all public datasets available in cBioPortal (Fig 1b, S1 Table).	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('INHBB', 'Gene', (227, 232))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('TGFBR3', 'Gene', (258, 264))	('activin', 'molecular_function', 'GO:0005160', ('188', '195'))	('activin', 'molecular_function', 'GO:0016915', ('188', '195'))	('inhibin', 'molecular_function', 'GO:0016916', ('180', '187'))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('inhibin', 'molecular_function', 'GO:0005160', ('180', '187'))	('activin', 'Gene', (188, 195))	('deletions', 'Var', (147, 156))	('INHBA', 'Gene', '3624', (220, 225))	('rat', 'Species', '10116', (98, 101))	('INHBB', 'Gene', '3625', (227, 232))	('activin', 'Gene', '83729', (188, 195))	('INHBA', 'Gene', (220, 225))	('cancers', 'Disease', (69, 76))
166644	33819300	For these analyses, we used the DepMap project (www.depmap.org) which is a comprehensive library of human genes that have been either knocked down or knocked out through CRISPR technology in 1,776 human cell lines representing multiple cancer types.	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('knocked', 'Var', (134, 141))	('cancer', 'Disease', (236, 242))	('human', 'Species', '9606', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('human', 'Species', '9606', (197, 202))	('knocked out', 'NegReg', (150, 161))
166650	33819300	In an attempt to identify genes most impacted by alteration to each of the individual genes, we examined how RNAi and CRISPR interventions would affect their correlation to specific genes.	('RNAi', 'biological_process', 'GO:0016246', ('109', '113'))	('affect', 'Reg', (145, 151))	('rat', 'Species', '10116', (53, 56))	('alteration', 'Var', (49, 59))	('N', 'Chemical', 'MESH:D009584', (110, 111))	('correlation', 'MPA', (158, 169))
166654	33819300	Since alterations in expression of inhibin, activin, TGFBR3 and ENG exist in human cancers and prior studies have implicated each of these in patient outcomes; we conducted a comprehensive analysis of each of these genes on overall survival (OS), progression-free survival (PFS), or relapse free survival (RFS) in a broad panel of cancers.	('alterations', 'Var', (6, 17))	('activin', 'Gene', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('ENG', 'Gene', (64, 67))	('cancers', 'Disease', 'MESH:D009369', (331, 338))	('relapse', 'Disease', (283, 290))	('TGFBR3', 'Gene', (53, 59))	('activin', 'Gene', '83729', (44, 51))	('activin', 'molecular_function', 'GO:0005160', ('44', '51'))	('patient', 'Species', '9606', (142, 149))	('overall', 'Disease', (224, 231))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('inhibin', 'molecular_function', 'GO:0016916', ('35', '42'))	('activin', 'molecular_function', 'GO:0016915', ('44', '51'))	('human', 'Species', '9606', (77, 82))	('cancers', 'Phenotype', 'HP:0002664', (331, 338))	('cancers', 'Disease', (331, 338))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('rat', 'Species', '10116', (10, 13))	('inhibin', 'molecular_function', 'GO:0005160', ('35', '42'))	('cancers', 'Disease', (83, 90))
166657	33819300	Patients in KM plotter with p53 mutation status known showed 83% were mutated, cBioportal data sets showed 82.5% frequency of p53 mutation, and it has been reported that over 90% of ovarian cancers present p53 mutations.	('p53', 'Gene', (206, 209))	('p53', 'Gene', (28, 31))	('p53', 'Gene', '7157', (206, 209))	('p53', 'Gene', '7157', (126, 129))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('mutations', 'Var', (210, 219))	('p53', 'Gene', '7157', (28, 31))	('ovarian cancer', 'Phenotype', 'HP:0100615', (182, 196))	('mutation', 'Var', (130, 138))	('ovarian cancers', 'Phenotype', 'HP:0100615', (182, 197))	('Patients', 'Species', '9606', (0, 8))	('ovarian cancers', 'Disease', (182, 197))	('ovarian cancers', 'Disease', 'MESH:D010051', (182, 197))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('p53', 'Gene', (126, 129))
166660	33819300	However, in p53 mutated cancers, INHA was a strong negative predictor of survival for both breast and ovarian cancers (HR = 1.99, p = 0.0056 and HR = 1.55, p = 0.0039, respectively), along with ENG in ovarian cancer (HR = 1.36, p = 0.0098, Figs 2 and 3).	('ovarian cancer', 'Disease', 'MESH:D010051', (201, 215))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('negative', 'NegReg', (51, 59))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (91, 117))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('cancers', 'Disease', (24, 31))	('cancers', 'Disease', (110, 117))	('ovarian cancer', 'Disease', 'MESH:D010051', (102, 116))	('ovarian cancer', 'Disease', (201, 215))	('p53', 'Gene', '7157', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ovarian cancer', 'Phenotype', 'HP:0100615', (201, 215))	('ovarian cancers', 'Phenotype', 'HP:0100615', (102, 117))	('p53', 'Gene', (12, 15))	('mutated', 'Var', (16, 23))	('ovarian cancer', 'Disease', (102, 116))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('ovarian cancer', 'Phenotype', 'HP:0100615', (102, 116))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
166674	33819300	In this analysis, we find that that when separating patients into high or low expressing TGFBR3 or ENG groups (Table 1) in p53 mutated breast cancers, where INHA is a negative predictor of survival in all patients (Fig 2), INHA was only a predictor of poor survival in patients with low TGFBR3 (HR = 2.29, p = 0.015) or low ENG (HR = 2.24, p = 0.035).	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))	('patients', 'Species', '9606', (205, 213))	('low', 'Var', (283, 286))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('breast cancers', 'Phenotype', 'HP:0003002', (135, 149))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('breast cancers', 'Disease', 'MESH:D001943', (135, 149))	('p53', 'Gene', (123, 126))	('breast cancers', 'Disease', (135, 149))	('patients', 'Species', '9606', (52, 60))	('p53', 'Gene', '7157', (123, 126))	('mutated', 'Var', (127, 134))	('patients', 'Species', '9606', (269, 277))	('rat', 'Species', '10116', (45, 48))
166676	33819300	In contrast to breast and renal clear cell cancers where TGFBR3 and ENG both impacted the effect of INHA on survival, TGFBR3 levels did not change INHA's impact on p53 mutated serous ovarian cancers (Table 1).	('mutated', 'Var', (168, 175))	('impacted', 'Reg', (77, 85))	('p53', 'Gene', '7157', (164, 167))	('ovarian cancers', 'Phenotype', 'HP:0100615', (183, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('serous ovarian cancers', 'Disease', (176, 198))	('breast and renal clear cell cancers', 'Disease', 'MESH:D001943', (15, 50))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('ovarian cancer', 'Phenotype', 'HP:0100615', (183, 197))	('p53', 'Gene', (164, 167))	('serous ovarian cancers', 'Disease', 'MESH:D018284', (176, 198))	('effect', 'MPA', (90, 96))
166677	33819300	In ENG high p53 mutated serous ovarian cancer patients, INHA had a more significant negative prediction outcome (HR = 2.12, p = 1.8E-6) compared to ENG low (HR = 0.8, p = 0.18, Table 1).	('patients', 'Species', '9606', (46, 54))	('ENG', 'Gene', (3, 6))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (24, 45))	('ovarian cancer', 'Phenotype', 'HP:0100615', (31, 45))	('p53', 'Gene', (12, 15))	('mutated', 'Var', (16, 23))	('p53', 'Gene', '7157', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('high', 'Var', (7, 11))	('negative', 'NegReg', (84, 92))	('serous ovarian cancer', 'Disease', (24, 45))
166679	33819300	However, INHA remained a robust negative predictor of survival in lung adenocarcinomas patients expressing low ENG (HR = 2.12, p = 0.00041) but was not significant in ENG high expressing patients (HR = 1.25, p = 0.14) (Table 1).	('patients', 'Species', '9606', (187, 195))	('lung adenocarcinomas', 'Disease', (66, 86))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (66, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (66, 86))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (66, 85))	('low ENG', 'Var', (107, 114))	('negative', 'NegReg', (32, 40))	('patients', 'Species', '9606', (87, 95))
166680	33819300	Together, these findings suggest that INHA expression as a predictive tool for survival is influenced by the coreceptors ENG and TGFBR3 in renal clear cell, lung, and p53 mutated breast and ovarian cancers.	('p53', 'Gene', (167, 170))	('ovarian cancers', 'Phenotype', 'HP:0100615', (190, 205))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('ENG', 'Gene', (121, 124))	('influenced', 'Reg', (91, 101))	('p53', 'Gene', '7157', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('ovarian cancer', 'Phenotype', 'HP:0100615', (190, 204))	('mutated', 'Var', (171, 178))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (179, 205))	('TGFBR3', 'Gene', (129, 135))	('renal clear cell', 'Disease', (139, 155))	('lung', 'Disease', (157, 161))
166725	33819300	In both breast and ovarian cancers, INHA was a negative predictor of survival in patients that had p53 mutations indicating a potential dependency of INHA functions on the p53 status.	('mutations', 'Var', (103, 112))	('negative', 'NegReg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('ovarian cancers', 'Phenotype', 'HP:0100615', (19, 34))	('p53', 'Gene', '7157', (172, 175))	('patients', 'Species', '9606', (81, 89))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (8, 34))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('ovarian cancer', 'Phenotype', 'HP:0100615', (19, 33))	('p53', 'Gene', '7157', (99, 102))	('p53', 'Gene', (99, 102))	('p53', 'Gene', (172, 175))
166726	33819300	INHA expression alterations have been observed in p53 mutated adrenocortical tumors and INHA was suggested to be a contributing factor to tumorigenesis in these cancers.	('expression', 'MPA', (5, 15))	('tumor', 'Disease', (138, 143))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (62, 83))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('mutated', 'Var', (54, 61))	('p53', 'Gene', (50, 53))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Disease', (161, 168))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('adrenocortical tumors', 'Disease', (62, 83))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('INHA', 'Gene', (0, 4))	('rat', 'Species', '10116', (20, 23))	('alterations', 'Reg', (16, 27))	('p53', 'Gene', '7157', (50, 53))	('tumor', 'Disease', (77, 82))
166727	33819300	One of the most characterized transcriptional activators of INHA is GATA4, which can also regulate p53 in cancer and could contribute to the different survival outcomes observed for INHA in p53 mutated cancers versus wild-type p53 cancers.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('p53', 'Gene', (227, 230))	('cancer', 'Disease', (106, 112))	('GATA4', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('cancers', 'Disease', (231, 238))	('cancer', 'Disease', (231, 237))	('p53', 'Gene', '7157', (190, 193))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('p53', 'Gene', (190, 193))	('GATA4', 'Gene', '2626', (68, 73))	('mutated', 'Var', (194, 201))	('p53', 'Gene', '7157', (99, 102))	('regulate', 'Reg', (90, 98))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('p53', 'Gene', '7157', (227, 230))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('cancer', 'Disease', (202, 208))	('p53', 'Gene', (99, 102))	('cancers', 'Disease', (202, 209))
166728	33819300	INHA's link to functional outcomes in the background on p53 mutations remains to be fully elucidated.	('mutations', 'Var', (60, 69))	('p53', 'Gene', '7157', (56, 59))	('p53', 'Gene', (56, 59))
166730	33819300	In p53 mutated cancers, ENG remained a negative predictor.	('p53', 'Gene', '7157', (3, 6))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('p53', 'Gene', (3, 6))	('cancers', 'Disease', (15, 22))	('mutated', 'Var', (7, 14))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
166732	33819300	However, a previous study showed that positive ENG expression was associated with increased survival in breast cancer patients who had undergone anthracycline treatment.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('anthracycline', 'Chemical', 'MESH:D018943', (145, 158))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('positive', 'Var', (38, 46))	('breast cancer', 'Disease', (104, 117))	('survival', 'MPA', (92, 100))	('increased', 'PosReg', (82, 91))	('ENG', 'Protein', (47, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('patients', 'Species', '9606', (118, 126))
166744	33819300	Expression of ENG and TGFBR3 was not significantly different between wild-type and p53 mutated cancers indicating p53 likely does not impact expression itself.	('mutated', 'Var', (87, 94))	('p53', 'Gene', (83, 86))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (83, 86))	('p53', 'Gene', '7157', (114, 117))	('ENG', 'Gene', (14, 17))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('TGFBR3', 'Gene', (22, 28))
166745	33819300	Whether protein secretion of these coreceptors is altered in these cancers is currently unknown, and cannot be ruled out, as previous studies have shown increased endoglin folding and maturation in p53 mutation settings.	('endoglin', 'Gene', (163, 171))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('maturation', 'MPA', (184, 194))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('increased', 'PosReg', (153, 162))	('endoglin', 'molecular_function', 'GO:0070123', ('163', '171'))	('mutation', 'Var', (202, 210))	('protein secretion', 'biological_process', 'GO:0009306', ('8', '25'))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('altered', 'Reg', (50, 57))	('p53', 'Gene', (198, 201))	('p53', 'Gene', '7157', (198, 201))	('endoglin', 'Gene', '2022', (163, 171))	('rat', 'Species', '10116', (188, 191))
166747	33819300	Alterations in protein maturation could explain the differential patient outcomes observed between wild-type and p53 mutated cancers, when assessing for ENG and TGFBR3, despite changes in expression not being observed.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('mutated', 'Var', (117, 124))	('cancers', 'Disease', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('protein maturation', 'MPA', (15, 33))	('p53', 'Gene', '7157', (113, 116))	('rat', 'Species', '10116', (27, 30))	('patient', 'Species', '9606', (65, 72))	('p53', 'Gene', (113, 116))	('protein maturation', 'biological_process', 'GO:0051604', ('15', '33'))	('rat', 'Species', '10116', (4, 7))	('Alterations', 'Reg', (0, 11))
166751	33819300	We found INHA to only be a negative predictor of survival in patients expressing low ENG indicating INHA might act independent of either coreceptor in these cancer types.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('low', 'Var', (81, 84))	('patients', 'Species', '9606', (61, 69))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('ENG', 'Gene', (85, 88))
166916	31648964	Monosomy of Chromosome 9 is Associated with Higher Grade, Advanced Stage and Adverse Outcome in Clear Cell Renal Cell Carcinoma The objective of the study was to evaluate the frequency and the outcomes of whole chromosome 9 loss in 103 patients with clear cell renal cell carcinoma (ccRCC) using Single nucleotide polymorphism-based chromosome microarray (CMA) analysis.	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (96, 127))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (107, 127))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (250, 281))	('Carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('Monosomy', 'Var', (0, 8))	('patients', 'Species', '9606', (236, 244))	('Chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))	('chromosome', 'cellular_component', 'GO:0005694', ('211', '221'))	('loss', 'NegReg', (224, 228))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (96, 127))	('chromosome', 'cellular_component', 'GO:0005694', ('333', '343'))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (250, 281))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (261, 281))	('RCC', 'Disease', (285, 288))	('Clear Cell Renal Cell Carcinoma', 'Disease', (96, 127))	('clear cell renal cell carcinoma', 'Disease', (250, 281))	('CMA', 'biological_process', 'GO:0061684', ('356', '359'))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))	('RCC', 'Disease', 'MESH:C538614', (285, 288))
166925	31648964	In 59 non-metastatic ccRCC patients, chromosome 9 loss was also associated with higher recurrence rate and shorter recurrence-free survival (RFS) [(12-month RFS=77.8% (95%CI:36.5-93.9%) for chromosome 9 loss vs 95.7%, (95%CI:84.0-98.9%) for no loss, p=0.002].	('chromosome', 'cellular_component', 'GO:0005694', ('37', '47'))	('chromosome', 'Var', (190, 200))	('loss', 'NegReg', (50, 54))	('recurrence-free survival', 'MPA', (115, 139))	('patients', 'Species', '9606', (27, 35))	('shorter', 'NegReg', (107, 114))	('RCC', 'Disease', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('chromosome', 'cellular_component', 'GO:0005694', ('190', '200'))	('recurrence rate', 'CPA', (87, 102))	('chromosome 9', 'Gene', (37, 49))	('higher', 'PosReg', (80, 86))	('loss', 'NegReg', (203, 207))
166934	31648964	Inactivating germline mutations of the VHL tumor suppressor gene, on chromosome arm 3p, are a frequent early molecular change that predispose patients to develop clear cell RCC (ccRCC), especially in the form of numerous bilateral tumors.	('Inactivating germline mutations', 'Var', (0, 31))	('VHL tumor', 'Disease', (39, 48))	('RCC', 'Disease', (173, 176))	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('43', '59'))	('RCC', 'Disease', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('predispose', 'Reg', (131, 141))	('VHL tumor', 'Disease', 'MESH:D006623', (39, 48))	('chromosome', 'cellular_component', 'GO:0005694', ('69', '79'))	('numerous bilateral tumors', 'Disease', 'MESH:D009396', (212, 237))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor suppressor', 'biological_process', 'GO:0051726', ('43', '59'))	('numerous bilateral tumors', 'Disease', (212, 237))	('patients', 'Species', '9606', (142, 150))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('develop', 'PosReg', (154, 161))
166935	31648964	Clinicopathological correlations and prognostic implications of copy number aberrations (CNAs) in ccRCC have been reported in some studies.	('copy number aberrations', 'Var', (64, 87))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))
166936	31648964	Deletion of chromosome 9 is one of the most common genomic imbalances detected in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('imbalances', 'Phenotype', 'HP:0002172', (59, 69))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))	('Deletion', 'Var', (0, 8))
166952	31648964	Three tumors with partial chromosome 9 alteration were excluded from the comparison of total loss vs no loss.	('alteration', 'Var', (39, 49))	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
166959	31648964	Of 103 tumors, 69 (67%) had no chromosome 9 loss, three tumors (3%) showed partial chromosome 9 alterations (2 tumors with 9p deletions and 1 tumor with 9q deletion), and 31 (30%) showed monosomy of chromosome 9 including one tumor with copy neutral loss of heterozygosity (cnLOH) of whole chromosome 9 (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', (56, 62))	('loss', 'NegReg', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('chromosome', 'cellular_component', 'GO:0005694', ('290', '300'))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('monosomy', 'Var', (187, 195))	('chromosome', 'cellular_component', 'GO:0005694', ('31', '41'))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (56, 61))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('alterations', 'Reg', (96, 107))	('chromosome', 'cellular_component', 'GO:0005694', ('199', '209'))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', (7, 12))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('chromosome', 'cellular_component', 'GO:0005694', ('83', '93'))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Disease', (226, 231))
166963	31648964	In contrast, chromosome 9 loss was seen in 30/68 (44%) of high grade tumors (Grade 3: 11 of 34 (32%), grade 4: 19 of 34 (56%), p<0.001).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('loss', 'NegReg', (26, 30))	('chromosome', 'Var', (13, 23))	('chromosome', 'cellular_component', 'GO:0005694', ('13', '23'))
166969	31648964	Several groups have reported frequent deletion of 9p in ccRCC pathogenesis, with the incidence of this finding ranging between 14% and 44%, but the actual frequency of whole chromosome 9 loss in each grade has not been well established.	('chromosome', 'cellular_component', 'GO:0005694', ('174', '184'))	('pathogenesis', 'biological_process', 'GO:0009405', ('62', '74'))	('RCC', 'Disease', (58, 61))	('deletion', 'Var', (38, 46))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
166970	31648964	In our study, only a small proportion of ccRCCs with alterations of chromosome 9 (i.e., 2 of 34) were deletions of 9p; the remainder involved whole chromosome copy number losses or, in one case, cnLOH of the entire chromosome 9.	('cnLOH', 'Var', (195, 200))	('chromosome', 'cellular_component', 'GO:0005694', ('215', '225'))	('deletions', 'Var', (102, 111))	('chromosome', 'cellular_component', 'GO:0005694', ('68', '78'))	('alterations', 'Var', (53, 64))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('chromosome', 'cellular_component', 'GO:0005694', ('148', '158'))
166980	31648964	Somatic inactivation of CDKN2B through allelic loss or promoter hypermethylation has been found in many human neoplasms, including leukemia, lymphoma, and myelodysplastic syndrome.	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (155, 179))	('neoplasms', 'Phenotype', 'HP:0002664', (110, 119))	('promoter', 'MPA', (55, 63))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (155, 179))	('lymphoma', 'Disease', (141, 149))	('lymphoma', 'Disease', 'MESH:D008223', (141, 149))	('CDKN2B', 'Gene', '1030', (24, 30))	('allelic loss', 'Var', (39, 51))	('found', 'Reg', (90, 95))	('inactivation', 'NegReg', (8, 20))	('neoplasms', 'Disease', 'MESH:D009369', (110, 119))	('human', 'Species', '9606', (104, 109))	('myelodysplastic syndrome', 'Disease', (155, 179))	('neoplasms', 'Disease', (110, 119))	('leukemia', 'Phenotype', 'HP:0001909', (131, 139))	('lymphoma', 'Phenotype', 'HP:0002665', (141, 149))	('CDKN2B', 'Gene', (24, 30))	('leukemia', 'Disease', 'MESH:D007938', (131, 139))	('leukemia', 'Disease', (131, 139))
166992	31648964	LOH of TSC1 in RCC identified in more than 30% of specimens reviewed in The Cancer Genome Atlas (TCGA) project.	('men', 'Species', '9606', (55, 58))	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('LOH', 'Var', (0, 3))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('RCC', 'Disease', (15, 18))	('Cancer', 'Disease', (76, 82))	('TSC1', 'Gene', '7248', (7, 11))	('Cancer', 'Disease', 'MESH:D009369', (76, 82))	('TSC1', 'Gene', (7, 11))
166993	31648964	In a study with mouse models, deletion of Tsc1/Tsc2 which are located upstream of mTORC1, leads to the progression of a variety of tumors, including lung, kidney and prostate carcinomas as well as mesotheliomas.	('leads to', 'Reg', (90, 98))	('mouse', 'Species', '10090', (16, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (175, 185))	('kidney and prostate carcinomas', 'Disease', 'MESH:D011471', (155, 185))	('Tsc2', 'Gene', (47, 51))	('mTORC1', 'cellular_component', 'GO:0031931', ('82', '88'))	('mTORC1', 'Gene', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('progression', 'PosReg', (103, 114))	('Tsc1', 'Gene', '64930', (42, 46))	('mTORC1', 'Gene', '382056', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('deletion', 'Var', (30, 38))	('Tsc1', 'Gene', (42, 46))	('lung', 'Disease', (149, 153))	('tumors', 'Disease', (131, 137))	('mesotheliomas', 'Disease', (197, 210))	('Tsc2', 'Gene', '22084', (47, 51))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('mesotheliomas', 'Disease', 'MESH:D008654', (197, 210))
166994	31648964	Additionally, monosomy 9 results in loss of one copy of multiple tumor suppressor genes, e.g., CDKN2A/B, TSC1, FBP1, PTCH1 and NOTCH1, distributed throughout the short and long arms of this chromosome.	('FBP1', 'Gene', (111, 115))	('loss', 'NegReg', (36, 40))	('tumor suppressor', 'biological_process', 'GO:0051726', ('65', '81'))	('monosomy 9', 'Var', (14, 24))	('chromosome', 'cellular_component', 'GO:0005694', ('190', '200'))	('NOTCH1', 'Gene', (127, 133))	('short and long arms', 'Phenotype', 'HP:0009824', (162, 181))	('CDKN2A/B', 'Gene', (95, 103))	('tumor', 'Disease', (65, 70))	('TSC1', 'Gene', (105, 109))	('PTCH1', 'Gene', (117, 122))	('NOTCH1', 'Gene', '4851', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('TSC1', 'Gene', '7248', (105, 109))	('FBP1', 'Gene', '2203', (111, 115))	('CDKN2A/B', 'Gene', '1029;1030', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('65', '81'))	('PTCH1', 'Gene', '5727', (117, 122))
167002	31648964	Taken together, this study emphasizes the importance of CMA analysis in the workup of ccRCC patients and suggests that whole chromosome 9 loss can be used as a major prognostic predictor in ccRCC patients.	('chromosome', 'cellular_component', 'GO:0005694', ('125', '135'))	('loss', 'NegReg', (138, 142))	('whole chromosome', 'Var', (119, 135))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('CMA', 'biological_process', 'GO:0061684', ('56', '59'))	('RCC', 'Disease', (88, 91))	('patients', 'Species', '9606', (92, 100))	('patients', 'Species', '9606', (196, 204))	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('RCC', 'Disease', (192, 195))
167013	33572811	As part of the work, it was shown that low-frequency EMF shows an inhibitory effect on the proliferation of primary cancer cells, diminishing their migratory, invasive, and metastatic abilities.	('invasive', 'CPA', (159, 167))	('EMF', 'Gene', (53, 56))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('rat', 'Species', '10116', (98, 101))	('diminishing', 'NegReg', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('rat', 'Species', '10116', (151, 154))	('migratory', 'CPA', (148, 157))	('low-frequency', 'Var', (39, 52))
167023	33572811	Inversely, at low levels, ROS may alter intracellular redox states that activate redox-sensitive pathways, including the MAPK and PI3K pathways, and consequently also the mTOR pathway.	('PI3K', 'molecular_function', 'GO:0016303', ('130', '134'))	('intracellular', 'cellular_component', 'GO:0005622', ('40', '53'))	('redox-sensitive', 'MPA', (81, 96))	('ROS', 'Chemical', 'MESH:D017382', (26, 29))	('MAPK', 'molecular_function', 'GO:0004707', ('121', '125'))	('activate', 'PosReg', (72, 80))	('alter', 'Reg', (34, 39))	('intracellular redox states', 'MPA', (40, 66))	('ROS', 'Var', (26, 29))	('mTOR', 'Gene', (171, 175))	('mTOR', 'Gene', '2475', (171, 175))	('PI3K pathways', 'Pathway', (130, 143))
167042	33572811	Results present on the graph bar (Figure 4) show that low-frequency EMF significantly inhibits the migratory and invasive abilities of tumor cells, without changing these properties in healthy cells.	('EMF', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('inhibits', 'NegReg', (86, 94))	('tumor', 'Disease', (135, 140))	('rat', 'Species', '10116', (102, 105))	('low-frequency', 'Var', (54, 67))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
167072	33572811	Examination of this in detail is quite important because the most sensitive to oxidative stress are the epithelial cells of the renal tubules and their damage may lead to kidney damage.	('kidney damage', 'Phenotype', 'HP:0000112', (171, 184))	('kidney damage', 'Disease', (171, 184))	('oxidative stress', 'Phenotype', 'HP:0025464', (79, 95))	('damage', 'Var', (152, 158))	('kidney damage', 'Disease', 'MESH:D007674', (171, 184))	('lead to', 'Reg', (163, 170))
167117	29479523	Renal Cell Carcinoma in von Hippel-Lindau Disease:From Tumor Genetics to Novel Therapeutic Strategies von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome caused by mutations in the VHL tumor-suppressor gene, leading to the dysregulation of many hypoxia-induced genes.	('hypoxia', 'Disease', 'MESH:D000860', (259, 266))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('199', '215'))	('tumor-suppressor', 'Gene', '7248', (199, 215))	('Renal Cell Carcinoma in von Hippel-Lindau Disease', 'Disease', (0, 49))	('Tumor', 'Phenotype', 'HP:0002664', (55, 60))	('caused by', 'Reg', (168, 177))	('VHL', 'Gene', (195, 198))	('tumor-suppressor', 'Gene', (199, 215))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (0, 20))	('Carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('dysregulation', 'MPA', (237, 250))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (140, 167))	('Renal Cell Carcinoma in von Hippel-Lindau Disease', 'Disease', 'MESH:D006623', (0, 49))	('hypoxia', 'Disease', (259, 266))	('von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (102, 133))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('199', '215'))	('autosomal dominant syndrome', 'Disease', (140, 167))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('mutations', 'Var', (178, 187))
167119	29479523	Following the eponymous VHL gene inactivation, ccRCCs evolve through additional genetic alterations, resulting in both intratumor and intertumor heterogeneity.	('RCC', 'Disease', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('tumor', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('VHL', 'Gene', (24, 27))	('inactivation', 'Var', (33, 45))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
167120	29479523	Genomic studies have identified frequent mutations in genes involved in epigenetic regulation and phosphoinositide 3-kinase-AKT-mechanistic target of rapamycin (mTOR) pathway activation.	('mutations', 'Var', (41, 50))	('phosphoinositide 3-kinase', 'Gene', '5290', (98, 123))	('phosphoinositide 3-kinase', 'Gene', (98, 123))	('regulation', 'biological_process', 'GO:0065007', ('83', '93'))	('AKT', 'Gene', (124, 127))	('mechanistic target of rapamycin', 'Gene', (128, 159))	('mTOR', 'Gene', '2475', (161, 165))	('mechanistic target of rapamycin', 'Gene', '2475', (128, 159))	('mTOR', 'Gene', (161, 165))	('AKT', 'Gene', '207', (124, 127))
167129	29479523	von Hippel-Lindau disease is caused by mutations in the VHL tumor-suppressor gene, located on chromosome 3p25-26.	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (0, 25))	('caused by', 'Reg', (29, 38))	('tumor-suppressor', 'Gene', '7248', (60, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('94', '104'))	('tumor-suppressor', 'Gene', (60, 76))	('mutations', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('60', '76'))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('60', '76'))	('von Hippel-Lindau disease', 'Disease', (0, 25))
167135	29479523	However, repeated surgery for multifocal bilateral disease is followed by increased risk of end-stage renal disease (ESRD) requiring renal transplantation or dialysis.	('end-stage renal disease', 'Disease', (92, 115))	('end-stage renal disease', 'Disease', 'MESH:D007676', (92, 115))	('multifocal', 'Var', (30, 40))	('ESRD', 'Disease', (117, 121))	('renal disease', 'Phenotype', 'HP:0000112', (102, 115))	('end-stage renal disease', 'Phenotype', 'HP:0003774', (92, 115))	('ESRD', 'Phenotype', 'HP:0003774', (117, 121))	('ESRD', 'Disease', 'MESH:D007676', (117, 121))
167136	29479523	Whether hereditary or sporadic, ccRCC is characterized by mutations in the VHL tumor-suppressor gene on chromosome 3 (3p25-26) and a subsequent loss of heterozygosity.	('3p25-26', 'Gene', (118, 125))	('tumor-suppressor', 'Gene', (79, 95))	('mutations', 'Var', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (32, 37))	('VHL', 'Gene', (75, 78))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('79', '95'))	('chromosome', 'cellular_component', 'GO:0005694', ('104', '114'))	('tumor-suppressor', 'Gene', '7248', (79, 95))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('79', '95'))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('loss', 'NegReg', (144, 148))	('RCC', 'Disease', (34, 37))
167139	29479523	Mutations of TCEB1 that abrogate binding of Elongin B to VHL can also increase HIFalpha expression in ccRCCs with intact VHL.	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('increase', 'PosReg', (70, 78))	('TCEB1', 'Gene', '6921', (13, 18))	('HIFalpha expression', 'MPA', (79, 98))	('Elongin B', 'Gene', '6923', (44, 53))	('TCEB1', 'Gene', (13, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('Mutations', 'Var', (0, 9))	('binding', 'Interaction', (33, 40))	('Elongin B', 'Gene', (44, 53))	('abrogate', 'NegReg', (24, 32))	('RCC', 'Disease', (104, 107))
167140	29479523	Mutations in VHL and TCEB1 were mutually exclusive, supporting a permissive role for VHL complex degradation and HIFalpha stabilization in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('TCEB1', 'Gene', '6921', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('VHL', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('TCEB1', 'Gene', (21, 26))	('degradation', 'biological_process', 'GO:0009056', ('97', '108'))	('VHL complex', 'cellular_component', 'GO:0030891', ('85', '96'))
167142	29479523	Exome sequencing of tumors identified additional inactivating mutations on chromosome 3 in tumor suppressors polybromo-1 (PBRM1), SET domain-containing 2 (SETD2), and BRCA1-associated protein-1 (BAP1), which are chromatin and histone regulators located at 3p21.	('PBRM1', 'Gene', (122, 127))	('protein', 'cellular_component', 'GO:0003675', ('184', '191'))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('SET domain-containing 2', 'Gene', '29072', (130, 153))	('SETD2', 'Gene', '29072', (155, 160))	('tumor', 'Disease', (91, 96))	('BRCA1-associated protein-1', 'Gene', '8314', (167, 193))	('chromosome', 'cellular_component', 'GO:0005694', ('75', '85'))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('BRCA1-associated protein-1', 'Gene', (167, 193))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('polybromo-1', 'Gene', '55193', (109, 120))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('chromatin', 'cellular_component', 'GO:0000785', ('212', '221'))	('SET domain-containing 2', 'Gene', (130, 153))	('BAP1', 'Gene', '8314', (195, 199))	('tumors', 'Disease', (20, 26))	('inactivating mutations', 'Var', (49, 71))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('polybromo-1', 'Gene', (109, 120))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('BAP1', 'Gene', (195, 199))	('PBRM1', 'Gene', '55193', (122, 127))	('SETD2', 'Gene', (155, 160))	('tumor', 'Disease', (20, 25))
167143	29479523	PBRM1 and BAP1 mutations are mutually exclusive, with BAP1 mutations correlating with higher grade disease.	('higher grade disease', 'Disease', (86, 106))	('BAP1', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('BAP1', 'Gene', '8314', (54, 58))	('mutations', 'Var', (59, 68))	('BAP1', 'Gene', (54, 58))	('BAP1', 'Gene', '8314', (10, 14))
167150	29479523	PBRM1 inactivation was a frequent mutation, occurring early as a truncal mutation in three tumors and as a later event in three others.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Disease', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('inactivation', 'Var', (6, 18))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('truncal mutation', 'MPA', (65, 81))
167151	29479523	Distinct subclones, spatially separated within a single tumor, contained mutations that appeared in a branched rather than linear manner.	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('mutations', 'Var', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))
167154	29479523	Recurrent mutations in PBRM1, SETD2, BAP1, and KDM5C suggest an evolutionary selection for epigenetic dysregulation in tumorigenesis.	('PBRM1', 'Gene', (23, 28))	('tumor', 'Disease', (119, 124))	('PBRM1', 'Gene', '55193', (23, 28))	('KDM5C', 'Gene', (47, 52))	('SETD2', 'Gene', '29072', (30, 35))	('BAP1', 'Gene', '8314', (37, 41))	('KDM5C', 'Gene', '8242', (47, 52))	('epigenetic dysregulation', 'MPA', (91, 115))	('SETD2', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('mutations', 'Var', (10, 19))	('BAP1', 'Gene', (37, 41))
167156	29479523	The central role of chromosome remodeling in the development and the progression of ccRCC implicates epigenetic dysregulation as a permissive factor in tumorigenesis and a novel target for therapeutic agents and candidate biomarkers.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('implicates', 'Reg', (90, 100))	('epigenetic dysregulation', 'Var', (101, 125))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('chromosome', 'cellular_component', 'GO:0005694', ('20', '30'))	('RCC', 'Disease', (86, 89))
167157	29479523	Mutations and copy number alterations were detected in mTOR (mammalian target of rapamycin), PIK3CA (PI3K catalytic subunit-alpha), TSC1, and PTEN.	('PTEN', 'Gene', (142, 146))	('mTOR', 'Gene', (55, 59))	('PTEN', 'Gene', '5728', (142, 146))	('TSC1', 'Gene', '7248', (132, 136))	('PIK3CA', 'Gene', '5290', (93, 99))	('mammalian target of rapamycin', 'Gene', (61, 90))	('mTOR', 'Gene', '2475', (55, 59))	('mammalian target of rapamycin', 'Gene', '2475', (61, 90))	('copy number alterations', 'Var', (14, 37))	('Mutations', 'Var', (0, 9))	('PI3K', 'molecular_function', 'GO:0016303', ('101', '105'))	('PIK3CA', 'Gene', (93, 99))	('TSC1', 'Gene', (132, 136))
167158	29479523	Mutually exclusive gene alterations of the PI3K/Akt/mTOR pathway were detected in approximately 28% of tumors.	('mTOR', 'Gene', (52, 56))	('Akt', 'Gene', (48, 51))	('mTOR', 'Gene', '2475', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('gene alterations', 'Var', (19, 35))	('PI3K', 'molecular_function', 'GO:0016303', ('43', '47'))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('Akt', 'Gene', '207', (48, 51))
167170	29479523	However, the lack of overlapping sets of single-nucleotide variants as well as copy number variants between tumors indicated that ccRCCs evolved independently.	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (130, 135))	('RCC', 'Disease', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('copy', 'Var', (79, 83))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
167171	29479523	For example, type 1 VHL disease (without PCC) is associated with truncation or exon deletion of germline VHL, whereas missense mutation is associated with type 2 disease (with PCC).	('truncation', 'Var', (65, 75))	('VHL', 'Gene', (105, 108))	('VHL disease', 'Disease', (20, 31))	('PCC', 'Phenotype', 'HP:0002666', (176, 179))	('exon deletion', 'Var', (79, 92))	('PCC', 'cellular_component', 'GO:0120205', ('41', '44'))	('associated', 'Reg', (49, 59))	('PCC', 'cellular_component', 'GO:0120205', ('176', '179'))	('VHL disease', 'Disease', 'MESH:D006623', (20, 31))	('associated', 'Reg', (139, 149))	('missense mutation', 'Var', (118, 135))	('germline', 'Gene', (96, 104))	('PCC', 'Phenotype', 'HP:0002666', (41, 44))	('type 2 disease', 'Disease', 'MESH:D005776', (155, 169))	('type 2 disease', 'Disease', (155, 169))
167175	29479523	Genetically engineered animal models of biallelic mutation of VHL alone in both mouse and zebrafish recapitulate features of early human disease, but not the formation of ccRCC.	('RCC', 'Disease', (173, 176))	('biallelic mutation', 'Var', (40, 58))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('ccRCC', 'Phenotype', 'HP:0006770', (171, 176))	('human', 'Species', '9606', (131, 136))	('zebrafish', 'Species', '7955', (90, 99))	('mouse', 'Species', '10090', (80, 85))	('VHL', 'Gene', (62, 65))	('formation', 'biological_process', 'GO:0009058', ('158', '167'))
167177	29479523	Homozygous deletion of Vhl is embryonic lethal at 10.5-12.5 days in mice due to defective placental vasculogenesis; heterozygous mice fail to develop kidney tumors.	('mice', 'Species', '10090', (68, 72))	('vasculogenesis', 'biological_process', 'GO:0001570', ('100', '114'))	('kidney tumors', 'Disease', (150, 163))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('Vhl', 'Gene', (23, 26))	('kidney tumors', 'Disease', 'MESH:D007674', (150, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mice', 'Species', '10090', (129, 133))	('kidney tumors', 'Phenotype', 'HP:0009726', (150, 163))	('placental vasculogenesis', 'CPA', (90, 114))	('deletion', 'Var', (11, 19))	('defective', 'NegReg', (80, 89))	('fail to develop kidney', 'Phenotype', 'HP:0000104', (134, 156))
167178	29479523	Kidney-specific inactivation of Vhl is insufficient for ccRCC development, but results in multiple cysts with constitutive HIF-alpha expression and metabolic alterations marked by lipid and glycogen accumulation similar to early human disease.	('expression', 'MPA', (133, 143))	('Vhl', 'Gene', (32, 35))	('HIF-alpha', 'Protein', (123, 132))	('lipid', 'Chemical', 'MESH:D008055', (180, 185))	('inactivation', 'Var', (16, 28))	('glycogen', 'Chemical', 'MESH:D006003', (190, 198))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('RCC', 'Disease', (58, 61))	('human', 'Species', '9606', (229, 234))	('results in', 'Reg', (79, 89))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('metabolic alterations', 'MPA', (148, 169))
167180	29479523	Likewise in zebrafish embryos, homozygous inactivation of VHL (vhl-/-) results in a kidney with enlarged proximal pronephric tubules, disorganized cilia, accumulated lipid and glycogen, cell proliferation, and apoptosis.	('disorganized cilia', 'CPA', (134, 152))	('cell proliferation', 'biological_process', 'GO:0008283', ('186', '204'))	('enlarged', 'PosReg', (96, 104))	('glycogen', 'Chemical', 'MESH:D006003', (176, 184))	('inactivation', 'Var', (42, 54))	('lipid', 'Chemical', 'MESH:D008055', (166, 171))	('cell proliferation', 'CPA', (186, 204))	('VHL', 'Gene', (58, 61))	('accumulated', 'PosReg', (154, 165))	('zebrafish', 'Species', '7955', (12, 21))	('apoptosis', 'biological_process', 'GO:0097194', ('210', '219'))	('apoptosis', 'biological_process', 'GO:0006915', ('210', '219'))	('apoptosis', 'CPA', (210, 219))
167182	29479523	The identification of additional mutations underlying ccRCC has informed the development of genetically engineered mouse models that are more analogous to human disease.	('RCC', 'Disease', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('human', 'Species', '9606', (155, 160))	('mouse', 'Species', '10090', (115, 120))	('mutations', 'Var', (33, 42))
167184	29479523	Kidney-specific dual inactivation of Vhl and Bap1 or Pbrm1 using Pax8-Cre in mice recapitulated human ccRCC with cytoplasmic accumulation of glycogen and lipids.	('mice', 'Species', '10090', (77, 81))	('Bap1', 'Gene', '104416', (45, 49))	('inactivation', 'Var', (21, 33))	('Bap1', 'Gene', (45, 49))	('Pbrm1', 'Gene', (53, 58))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('human', 'Species', '9606', (96, 101))	('Vhl', 'Gene', (37, 40))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('glycogen', 'Chemical', 'MESH:D006003', (141, 149))	('lipids', 'Chemical', 'MESH:D008055', (154, 160))	('dual inactivation', 'Var', (16, 33))	('RCC', 'Disease', (104, 107))
167186	29479523	Pbrm1-deficient tumors were converted from low to high grade by disruption of one Tsc1 allele, resulting in mTORC1 activation.	('activation', 'PosReg', (115, 125))	('Tsc1', 'Gene', '7248', (82, 86))	('Tsc1', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('disruption', 'Var', (64, 74))	('Pbrm1-deficient tumors', 'Disease', 'MESH:D009369', (0, 22))	('mTORC1', 'cellular_component', 'GO:0031931', ('108', '114'))	('mTORC1', 'Gene', '382056', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('Pbrm1-deficient tumors', 'Disease', (0, 22))	('mTORC1', 'Gene', (108, 114))
167188	29479523	Kidney-specific inactivation of Vhl and Pbrm1 using Ksp-Cre model the histopathological and molecular features, and gradual onset of human ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (139, 144))	('RCC', 'Disease', (141, 144))	('Pbrm1', 'Gene', (40, 45))	('Vhl', 'Gene', (32, 35))	('inactivation', 'Var', (16, 28))	('human', 'Species', '9606', (133, 138))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
167191	29479523	Loss of PBRM1 further amplified the activation of HIF1 (hetereodimer HIF-1alpha and HIF-1beta) and STAT3 pathways caused by loss of Vhl.	('HIF1', 'Gene', (50, 54))	('hetereodimer HIF-1alpha and HIF-1beta', 'Disease', 'None', (56, 93))	('loss', 'Var', (124, 128))	('PBRM1', 'Gene', '55193', (8, 13))	('activation', 'PosReg', (36, 46))	('STAT3', 'Gene', '6774', (99, 104))	('HIF1', 'Gene', '3091', (50, 54))	('STAT3', 'Gene', (99, 104))	('Loss', 'Var', (0, 4))	('amplified', 'PosReg', (22, 31))	('PBRM1', 'Gene', (8, 13))	('Vhl', 'Gene', (132, 135))
167193	29479523	Inactivation of Vhl, Rb1, and Trp53 in mice induced precursor cysts and gradually developing ccRCC tumors.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('Vhl', 'Gene', (16, 19))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('Trp53', 'Gene', '22059', (30, 35))	('induced', 'Reg', (44, 51))	('mice', 'Species', '10090', (39, 43))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('RCC', 'Disease', (95, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('precursor cysts', 'CPA', (52, 67))	('Rb1', 'Gene', (21, 24))	('Rb1', 'Gene', '19645', (21, 24))	('Inactivation', 'Var', (0, 12))	('Trp53', 'Gene', (30, 35))	('tumors', 'Disease', (99, 105))
167194	29479523	Mutations were observed in genes involved in the primary cilium, Kif3a and Kif3b.	('primary cilium', 'cellular_component', 'GO:0097731', ('49', '63'))	('Kif3b', 'Gene', '9371', (75, 80))	('Kif3b', 'Gene', (75, 80))	('Kif3a', 'Gene', '11127', (65, 70))	('Mutations', 'Var', (0, 9))	('primary cilium', 'cellular_component', 'GO:0005929', ('49', '63'))	('Kif3a', 'Gene', (65, 70))
167197	29479523	Zebrafish with multiple mutations of VHL disease-related genes are another potential preclinical model for exploring the progression and metastasis of ccRCC with the advantage of live imaging.	('VHL disease', 'Disease', 'MESH:D006623', (37, 48))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('RCC', 'Disease', (153, 156))	('ccRCC', 'Phenotype', 'HP:0006770', (151, 156))	('VHL disease', 'Disease', (37, 48))	('mutations', 'Var', (24, 33))	('Zebrafish', 'Species', '7955', (0, 9))
167207	29479523	Delaying the interval to kidney surgery without increasing the risk of metastases prolongs sufficient renal function and delays dialysis.	('metastases prolongs sufficient renal function', 'Disease', (71, 116))	('metastases prolongs sufficient renal function', 'Disease', 'MESH:D009362', (71, 116))	('Delaying', 'Var', (0, 8))	('dialysis', 'MPA', (128, 136))
167260	29479523	For example, mutations in MTOR, TSC1, or TSC2 were associated with response to mTOR inhibitors, 21% in responders versus 11% in non-responders.	('mTOR', 'Gene', (79, 83))	('mTOR', 'Gene', '2475', (79, 83))	('TSC1', 'Gene', (32, 36))	('TSC2', 'Gene', (41, 45))	('MTOR', 'Gene', (26, 30))	('associated', 'Reg', (51, 61))	('mutations', 'Var', (13, 22))	('MTOR', 'Gene', '2475', (26, 30))	('TSC2', 'Gene', '7249', (41, 45))	('TSC1', 'Gene', '7248', (32, 36))
167261	29479523	But many responders (56%) had no mTOR pathway mutation.	('mTOR', 'Gene', (33, 37))	('mTOR', 'Gene', '2475', (33, 37))	('mutation', 'Var', (46, 54))
167262	29479523	A positive response to first-line everolimus was associated with PBRM1 mutations, and a negative response with BAP1 mutations.	('positive', 'PosReg', (2, 10))	('BAP1', 'Gene', '8314', (111, 115))	('PBRM1', 'Gene', (65, 70))	('PBRM1', 'Gene', '55193', (65, 70))	('BAP1', 'Gene', (111, 115))	('mutations', 'Var', (71, 80))	('everolimus', 'Chemical', 'MESH:D000068338', (34, 44))
167263	29479523	In addition, KDM5 mutations were associated with better response with first-line sunitinib than with everolimus.	('response', 'MPA', (56, 64))	('everolimus', 'Chemical', 'MESH:D000068338', (101, 111))	('sunitinib', 'Chemical', 'MESH:D000077210', (81, 90))	('KDM5', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
167270	29479523	Sensitivity to PT2399 correlated with a higher level of HIF-2alpha expression, and the presence of p53.	('p53', 'Gene', (99, 102))	('presence', 'Var', (87, 95))	('higher', 'PosReg', (40, 46))	('PT2399', 'Var', (15, 21))	('PT2399', 'Chemical', 'MESH:C000614278', (15, 21))	('HIF-2alpha', 'Protein', (56, 66))	('p53', 'Gene', '7157', (99, 102))	('expression', 'MPA', (67, 77))
167287	27595394	PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumors, and was better tolerated.	('PT2399', 'Chemical', 'MESH:C000614278', (0, 6))	('sunitinib', 'Chemical', 'MESH:D000077210', (58, 67))	('active', 'MPA', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('activity', 'MPA', (19, 27))	('sunitinib', 'Chemical', 'MESH:D000077210', (33, 42))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('PT2399', 'Var', (0, 6))
167290	27595394	Illustrating drug specificity, gene expression was largely unaffected by PT2399 in resistant tumors.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('PT2399', 'Var', (73, 79))	('PT2399', 'Chemical', 'MESH:C000614278', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('gene expression', 'MPA', (31, 46))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('gene expression', 'biological_process', 'GO:0010467', ('31', '46'))
167293	27595394	We identified a binding site and second site suppressor mutation in HIF-2alpha and HIF-1beta respectively.	('binding', 'Interaction', (16, 23))	('mutation', 'Var', (56, 64))	('binding', 'molecular_function', 'GO:0005488', ('16', '23'))	('HIF-2alpha and HIF-1beta', 'Disease', 'None', (68, 92))
167299	27595394	PT2399 did not induce weight loss, whereas sunitinib, at doses matching human exposures, did (Fig.	('PT2399', 'Chemical', 'MESH:C000614278', (0, 6))	('weight loss', 'Phenotype', 'HP:0001824', (22, 33))	('human', 'Species', '9606', (72, 77))	('weight loss', 'Disease', 'MESH:D015431', (22, 33))	('sunitinib', 'Chemical', 'MESH:D000077210', (43, 52))	('PT2399', 'Var', (0, 6))	('weight loss', 'Disease', (22, 33))
167300	27595394	However, PT2399 caused modest anemia and leukopenia (Fig.	('PT2399', 'Var', (9, 15))	('leukopenia', 'Disease', 'MESH:D007970', (41, 51))	('PT2399', 'Chemical', 'MESH:C000614278', (9, 15))	('anemia', 'Disease', (30, 36))	('anemia', 'Disease', 'MESH:D000740', (30, 36))	('leukopenia', 'Phenotype', 'HP:0001882', (41, 51))	('anemia', 'Phenotype', 'HP:0001903', (30, 36))	('leukopenia', 'Disease', (41, 51))
167303	27595394	PT2399 decreased tumor growth by 60% across TGs (p<0.0001) (Fig.	('PT2399', 'Chemical', 'MESH:C000614278', (0, 6))	('tumor', 'Disease', (17, 22))	('decreased', 'NegReg', (7, 16))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('PT2399', 'Var', (0, 6))	('TG', 'Chemical', '-', (44, 46))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('TGs', 'biological_process', 'GO:0006342', ('44', '47'))
167307	27595394	PT2399 was more active than sunitinib (p=0.0126) (Fig.	('PT2399', 'Var', (0, 6))	('PT2399', 'Chemical', 'MESH:C000614278', (0, 6))	('sunitinib', 'Chemical', 'MESH:D000077210', (28, 37))	('active', 'MPA', (16, 22))
167310	27595394	PT2399 reduced tumor cell density and increased fibrosis (Extended Data Fig.	('reduced', 'NegReg', (7, 14))	('PT2399', 'Chemical', 'MESH:C000614278', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('fibrosis', 'Disease', 'MESH:D005355', (48, 56))	('fibrosis', 'Disease', (48, 56))	('tumor', 'Disease', (15, 20))	('PT2399', 'Var', (0, 6))	('increased', 'PosReg', (38, 47))
167311	27595394	By Ki67 immunohistochemistry (IHC), PT2399 inhibited tumor cell proliferation 3.5 fold (mean value change of -19.5 +-2.4; p<0.0001; Extended Data Fig.	('Ki67', 'Gene', '17345', (3, 7))	('inhibited', 'NegReg', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('PT2399', 'Var', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('PT2399', 'Chemical', 'MESH:C000614278', (36, 42))	('tumor', 'Disease', (53, 58))	('Ki67', 'Gene', (3, 7))
167314	27595394	In addition, PT2399 collapsed the tumor vasculature, decreasing vascular area 3-fold (p=0.0011) (Extended Data Fig.	('decreasing', 'NegReg', (53, 63))	('tumor', 'Disease', (34, 39))	('vascular area', 'MPA', (64, 77))	('PT2399', 'Var', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('PT2399', 'Chemical', 'MESH:C000614278', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
167316	27595394	PT2399 suppressed circulating human VEGF by 93%, but mouse VEGF was unaffected (Extended Data Fig.	('human', 'Species', '9606', (30, 35))	('PT2399', 'Chemical', 'MESH:C000614278', (0, 6))	('circulating human VEGF', 'MPA', (18, 40))	('suppressed', 'NegReg', (7, 17))	('PT2399', 'Var', (0, 6))	('mouse', 'Species', '10090', (53, 58))
167322	27595394	PT2399 specifically disassembled HIF-2 but not HIF-1 complexes (Fig.	('PT2399', 'Var', (0, 6))	('PT2399', 'Chemical', 'MESH:C000614278', (0, 6))	('disassembled', 'Reg', (20, 32))
167323	27595394	Correspondingly, PT2399 reduced the expression of HIF-2 target genes (VEGF, SERPINE1 [encoding PAI-1], IGFBP3, CCND1 [encoding Cyclin D1], TGFA, and SLC2A1 [encoding GLUT1]) (all comparisons, p<0.05; Fig.	('CCND1', 'Gene', '12443', (111, 116))	('IGFBP3', 'Gene', (103, 109))	('Cyclin D1', 'Gene', '12443', (127, 136))	('SERPINE1', 'Gene', (76, 84))	('IGFBP3', 'Gene', '16009', (103, 109))	('PT2399', 'Var', (17, 23))	('PAI-1', 'Gene', (95, 100))	('SLC2A1', 'Gene', '20525', (149, 155))	('SLC2A1', 'Gene', (149, 155))	('PT2399', 'Chemical', 'MESH:C000614278', (17, 23))	('Cyclin D1', 'Gene', (127, 136))	('CCND1', 'Gene', (111, 116))	('GLUT1', 'Gene', '20525', (166, 171))	('reduced', 'NegReg', (24, 31))	('Cyclin', 'molecular_function', 'GO:0016538', ('127', '133'))	('GLUT1', 'Gene', (166, 171))	('TGFA', 'Gene', (139, 143))	('PAI-1', 'Gene', '18787', (95, 100))	('SERPINE1', 'Gene', '18787', (76, 84))	('expression', 'MPA', (36, 46))	('TGFA', 'Gene', '21802', (139, 143))
167325	27595394	Notably, PT2399 did not affect the majority of HIF-2 target genes in resistant tumors (Fig.	('PT2399', 'Var', (9, 15))	('PT2399', 'Chemical', 'MESH:C000614278', (9, 15))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
167327	27595394	2d), Hif-2 was indeed inhibited by PT2399 in mice with resistant tumors.	('inhibited', 'NegReg', (22, 31))	('PT2399', 'Chemical', 'MESH:C000614278', (35, 41))	('mice', 'Species', '10090', (45, 49))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('PT2399', 'Var', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Hif-2', 'Gene', (5, 10))
167329	27595394	Thus, somewhat unexpectedly PT2399 disassembled HIF-2 in resistant tumors, but HIF-2 target genes were largely unaffected.	('disassembled', 'Reg', (35, 47))	('PT2399', 'Chemical', 'MESH:C000614278', (28, 34))	('HIF-2', 'Gene', (48, 53))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('PT2399', 'Var', (28, 34))	('tumors', 'Disease', (67, 73))
167335	27595394	Consistent with this notion, PT2399 had a lesser impact on overall gene expression than subtle differences across patients' tumors (Extended Data Fig.	('PT2399', 'Var', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('PT2399', 'Chemical', 'MESH:C000614278', (29, 35))	('gene expression', 'biological_process', 'GO:0010467', ('67', '82'))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Disease', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('patients', 'Species', '9606', (114, 122))	('gene expression', 'MPA', (67, 82))
167338	27595394	PT2399 increased the expression of 168 protein-coding genes, including fibrosis-related genes, such as PDGFD, HIF1A (previously shown to be induced by HIF-2alpha knockdown), and FBP1, a gluconeogenic gene recently reported to suppress RCC progression (Fig.	('PT2399', 'Chemical', 'MESH:C000614278', (0, 6))	('increased', 'PosReg', (7, 16))	('FBP1', 'Gene', '14121', (178, 182))	('fibrosis', 'Disease', 'MESH:D005355', (71, 79))	('fibrosis', 'Disease', (71, 79))	('PDGFD', 'Gene', '71785', (103, 108))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('HIF1A', 'Gene', '15251', (110, 115))	('expression', 'MPA', (21, 31))	('RCC', 'Disease', (235, 238))	('FBP1', 'Gene', (178, 182))	('PDGFD', 'Gene', (103, 108))	('HIF1A', 'Gene', (110, 115))	('HIF-2alpha', 'Gene', '13819', (151, 161))	('PT2399', 'Var', (0, 6))	('suppress', 'NegReg', (226, 234))	('HIF-2alpha', 'Gene', (151, 161))
167360	27595394	PT2399 resistance was associated with increased tumor vascularity and higher tumor VEGF production (Fig.	('PT2399', 'Chemical', 'MESH:C000614278', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('PT2399 resistance', 'Var', (0, 17))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('higher', 'PosReg', (70, 76))	('tumor', 'Disease', (77, 82))	('increased', 'PosReg', (38, 47))	('VEGF production', 'biological_process', 'GO:0010573', ('83', '98'))
167361	27595394	We sequenced the HIF-2alpha gene (EPAS1) and identified a c.968G>A heterozygous mutation resulting in a G323E substitution in one tumor (Fig.	('G323E', 'Mutation', 'rs1221715868', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('c.968G>A', 'Mutation', 'rs1221715868', (58, 66))	('c.968G>A', 'Var', (58, 66))	('EPAS1', 'Gene', (34, 39))	('HIF-2alpha', 'Gene', '13819', (17, 27))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('EPAS1', 'Gene', '13819', (34, 39))	('tumor', 'Disease', (130, 135))	('G323E', 'Var', (104, 109))	('HIF-2alpha', 'Gene', (17, 27))
167363	27595394	Structural analyses of HIF-2 quaternary structure showed that G323 is at the entrance of the cavity, where PT2399 binds (Fig.	('G323', 'Var', (62, 66))	('PT2399', 'Chemical', 'MESH:C000614278', (107, 113))	('binds', 'Interaction', (114, 119))	('G323', 'Chemical', '-', (62, 66))	('HIF-2', 'Gene', (23, 28))	('PT2399', 'Var', (107, 113))
167365	27595394	Consistent with this notion, PT2399 failed to dissociate HIF-2 complexes in mutant tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('PT2399', 'Chemical', 'MESH:C000614278', (29, 35))	('mutant', 'Var', (76, 82))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
167368	27595394	Interestingly, sequencing of passaged tumors revealed a heterozygous c.1338C>A mutation resulting in a F446L substitution in the HIF-1beta PAS-B domain (Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('c.1338C>A', 'Var', (69, 78))	('c.1338C>A', 'Mutation', 'c.1338C>A', (69, 78))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('PAS', 'cellular_component', 'GO:0000407', ('139', '142'))	('F446L', 'Mutation', 'p.F446L', (103, 108))	('F446L', 'Var', (103, 108))
167370	27595394	We postulate that F446L functions as a second-site suppressor mutation and that a more flexible side chain at the complex interface accommodates conformational changes induced by PT2399 allowing drug-bound HIF-2alpha to bind to HIF-1beta.	('PT2399', 'Chemical', 'MESH:C000614278', (179, 185))	('PT2399', 'Gene', (179, 185))	('conformational', 'MPA', (145, 159))	('F446L', 'Mutation', 'p.F446L', (18, 23))	('HIF-2alpha', 'Gene', '13819', (206, 216))	('F446L', 'Var', (18, 23))	('bind', 'Interaction', (220, 224))	('HIF-2alpha', 'Gene', (206, 216))
167371	27595394	Both HIF-1beta (F446L) and HIF-2alpha (G323E), when expressed in cells, were sufficient to preserve HIF-2 dimers despite PT2399 and the effects appeared additive (Fig.	('PT2399', 'Chemical', 'MESH:C000614278', (121, 127))	('HIF-2alpha', 'Gene', (27, 37))	('F446L', 'Var', (16, 21))	('HIF-2', 'Gene', (100, 105))	('F446L', 'Mutation', 'p.F446L', (16, 21))	('G323E', 'Mutation', 'rs1221715868', (39, 44))	('dimers', 'MPA', (106, 112))	('HIF-2alpha', 'Gene', '13819', (27, 37))	('PT2399', 'Var', (121, 127))
167407	27595394	Primary antibodies: HIF-1alpha (1:500, NB100-105, Novus), HIF-2alpha (1:200, sc-46691, Santa Cruz), Ki67 (ready-to-use, IR-626, Dako) and CD31 (1:200, LS-B1932, LifeSpan BioSciences).	('Ki67', 'Gene', '17345', (100, 104))	('HIF-1alpha', 'Gene', '15251', (20, 30))	('1:500', 'Var', (32, 37))	('HIF-2alpha', 'Gene', '13819', (58, 68))	('CD31', 'Gene', '18613', (138, 142))	('Ki67', 'Gene', (100, 104))	('1:200', 'Var', (70, 75))	('HIF-1alpha', 'Gene', (20, 30))	('CD31', 'Gene', (138, 142))	('HIF-2alpha', 'Gene', (58, 68))
167422	27595394	HIF2-I sensitive ccRCC tumorgrafts that had wild-type VHL status (XP164, XP373, XP453, and XP454) were tested for VHL methylation using the Affymetrix Promoter Methylation PCR Kit (MP1100).	('RCC tumorgrafts', 'Disease', 'MESH:C538614', (19, 34))	('XP453', 'Var', (80, 85))	('Methylation', 'biological_process', 'GO:0032259', ('160', '171'))	('RCC tumorgrafts', 'Disease', (19, 34))	('ccRCC', 'Phenotype', 'HP:0006770', (17, 22))	('methylation', 'biological_process', 'GO:0032259', ('118', '129'))	('XP454', 'Var', (91, 96))	('XP164', 'Var', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('XP373', 'Var', (73, 78))
167427	27595394	For western blot analysis, both HIF-1alpha antibody (A300-286A, Bethyl) and HIF-2alpha antibody (NB100-122, Novus) were diluted at 1:1,000 in 5% BSA and incubated overnight at 4  C. Tubulin antibody (T5168, Sigma) was diluted at 1:5,000.	('antibody', 'cellular_component', 'GO:0019815', ('43', '51'))	('antibody', 'molecular_function', 'GO:0003823', ('190', '198'))	('HIF-1alpha antibody', 'Disease', 'MESH:D007153', (32, 51))	('antibody', 'cellular_component', 'GO:0019814', ('43', '51'))	('antibody', 'cellular_component', 'GO:0019814', ('87', '95'))	('antibody', 'cellular_component', 'GO:0019815', ('87', '95'))	('antibody', 'cellular_component', 'GO:0042571', ('43', '51'))	('HIF-2alpha antibody', 'Disease', 'MESH:D007153', (76, 95))	('antibody', 'cellular_component', 'GO:0042571', ('190', '198'))	('antibody', 'molecular_function', 'GO:0003823', ('43', '51'))	('antibody', 'molecular_function', 'GO:0003823', ('87', '95'))	('antibody', 'cellular_component', 'GO:0019815', ('190', '198'))	('HIF-1alpha antibody', 'Disease', (32, 51))	('HIF-2alpha antibody', 'Disease', (76, 95))	('antibody', 'cellular_component', 'GO:0042571', ('87', '95'))	('antibody', 'cellular_component', 'GO:0019814', ('190', '198'))	('A300-286A', 'Var', (53, 62))
167429	27595394	Mutations in the PAS-B domain of HIF2A were identified with primers: Forward: GTGGTGCACACCCCTGCCCC; Reverse: CTGGGAAGCTTGGGCACCCCC; and in HIF1B with: Forward: GTCTCTGAAAGGAAGCATGAG; Reverse: CACATAGGGCATCAGAAGTG HEK293T cells (ATCC; no perceived need for authentication or mycoplasma testing) were cotransfected with the indicated expression plasmids using Lipofectamine 2000 (Invitrogen) following manufacturer's instructions.	('HIF1B', 'Gene', (139, 144))	('TG', 'Chemical', '-', (79, 81))	('TG', 'Chemical', '-', (110, 112))	('TG', 'Chemical', '-', (165, 167))	('TG', 'Chemical', '-', (210, 212))	('HIF2A', 'Gene', (33, 38))	('HIF1B', 'Gene', '11863', (139, 144))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (358, 376))	('HEK293T', 'CellLine', 'CVCL:0063', (213, 220))	('Mutations', 'Var', (0, 9))	('TG', 'Chemical', '-', (92, 94))	('TG', 'Chemical', '-', (177, 179))	('TG', 'Chemical', '-', (82, 84))	('HIF2A', 'Gene', '13819', (33, 38))	('TG', 'Chemical', '-', (119, 121))	('PAS', 'cellular_component', 'GO:0000407', ('17', '20'))
167432	27595394	Plasmids #930 (pcDNA3.1 Flag-HIF1beta), #931 (pcDNA3.1 Flag-HIF1beta [F446L]), #932 (pLVX HA-HIF-2alpha-IRES-zsGreen), and #933 (pLVX-HA-HIF-2alpha [G323E]-IRES-zsGreen).	('F446L', 'Mutation', 'p.F446L', (70, 75))	('HIF-2alpha', 'Gene', '13819', (93, 103))	('Flag-HIF1beta', 'Disease', (24, 37))	('Flag-HIF1beta', 'Disease', 'None', (24, 37))	('HIF-2alpha', 'Gene', (93, 103))	('#933', 'Var', (123, 127))	('pLVX', 'Var', (85, 89))	('Flag-HIF1beta', 'Disease', 'None', (55, 68))	('G323E', 'Mutation', 'rs1221715868', (149, 154))	('Flag-HIF1beta', 'Disease', (55, 68))	('HIF-2alpha', 'Gene', '13819', (137, 147))	('HIF-2alpha', 'Gene', (137, 147))
167433	27595394	The G323E and F446L mutations were evaluated using PyMOL and Protein Data Bank 4ZP4.	('G323E', 'Var', (4, 9))	('F446L', 'Mutation', 'p.F446L', (14, 19))	('G323E', 'Mutation', 'rs1221715868', (4, 9))	('F446L', 'Var', (14, 19))
167439	27595394	Mouse anti-HIF-1alpha (NB100-105, Novus), mouse anti-HIF-2alpha (sc-46691X, Santa Cruz) and Rabbit anti-ARNT/HIF-1beta (A302-765A, Bethyl) were used.	('ARNT', 'Gene', '11863', (104, 108))	('mouse', 'Species', '10090', (42, 47))	('HIF-2alpha', 'Gene', '13819', (53, 63))	('HIF-2alpha', 'Gene', (53, 63))	('ARNT', 'Gene', (104, 108))	('Rabbit', 'Species', '9986', (92, 98))	('Mouse', 'Species', '10090', (0, 5))	('sc-46691X', 'Var', (65, 74))	('HIF-1alpha', 'Gene', '15251', (11, 21))	('HIF-1alpha', 'Gene', (11, 21))
167444	27595394	Briefly, slides were washed with Wash Buffer A, ligation solution containing ligase at a 1:40 dilution was added, and slides were incubated in a pre-heated humidity chamber for 30 min at 37 C. After washing in 1x Wash Buffer A with gentle agitation, amplification solution containing polymerase was added at a 1:80 dilution, and slides were then incubated in a pre-heated humidity chamber for 100 min at 37 C. After washing slides in 1x Wash Buffer B and then 0.01x Wash Buffer B, slides were dried at RT in the dark, and mounted with a cover slip using a minimal volume of Duolink In Situ Mounting Medium with DAPI (DUO82040, Sigma-Aldrich).	('pre', 'molecular_function', 'GO:0003904', ('145', '148'))	('gentle agitation', 'Disease', (232, 248))	('0.01x', 'Var', (460, 465))	('gentle agitation', 'Disease', 'MESH:D011595', (232, 248))	('agitation', 'Phenotype', 'HP:0000713', (239, 248))	('pre', 'molecular_function', 'GO:0003904', ('361', '364'))
167445	27595394	23 vehicle- and 23 PT2399-treated tumor RNA samples, including 5 sensitive XPs (XP144, XP164, XP373, XP374, and XP453) and 4 resistant XPs (XP169, XP296, XP490, and XP506) underwent RNA sequencing at the New York Genome Center.	('XP490', 'Var', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('XP453', 'Var', (112, 117))	('XP296', 'Var', (147, 152))	('XP144', 'Var', (80, 85))	('XP164', 'Var', (87, 92))	('RNA', 'cellular_component', 'GO:0005562', ('182', '185'))	('XP169', 'Var', (140, 145))	('XP373', 'Var', (94, 99))	('PT2399', 'Chemical', 'MESH:C000614278', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('XP374', 'Var', (101, 106))	('XP506', 'Var', (165, 170))
167456	28152006	Taken together, the present study shows loss of ZHX1 is correlated with ccRCC progression and suggests it is an independent prognostic marker in ccRCC.	('RCC', 'Disease', (74, 77))	('ZHX1', 'Gene', '11244', (48, 52))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('loss', 'Var', (40, 44))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('ZHX1', 'Gene', (48, 52))	('correlated', 'Reg', (56, 66))
167460	28152006	Karnofksy performance status, low level of hemoglobin, elevated platelet count, and elevated corrected calcium are known as risk factors in RCC, and poor risk patients have a 2-year overall survival of only 7%.	('calcium', 'Chemical', 'MESH:D002118', (103, 110))	('corrected calcium', 'MPA', (93, 110))	('elevated platelet count', 'Phenotype', 'HP:0001894', (55, 78))	('low level of hemoglobin', 'Phenotype', 'HP:0001903', (30, 53))	('elevated', 'PosReg', (84, 92))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('platelet count', 'MPA', (64, 78))	('low', 'Var', (30, 33))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('elevated platelet', 'Phenotype', 'HP:0001894', (55, 72))	('RCC', 'Disease', (140, 143))	('elevated', 'PosReg', (55, 63))	('patients', 'Species', '9606', (159, 167))
167470	28152006	Similarly, ectopic ZHX2 expression reduced HCC cell and tumor xenograft growth in mice.	('mice', 'Species', '10090', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('reduced', 'NegReg', (35, 42))	('tumor', 'Disease', (56, 61))	('HCC', 'Phenotype', 'HP:0001402', (43, 46))	('ectopic', 'Var', (11, 18))	('ZHX2', 'Gene', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
167471	28152006	The above-mentioned observations suggest loss of ZHX family members is associated with cancer progression and might be of clinical importance.	('cancer', 'Disease', (87, 93))	('loss', 'Var', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ZHX family', 'Gene', (49, 59))	('ZHX', 'Chemical', '-', (49, 52))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('associated', 'Reg', (71, 81))
167534	28152006	The prognostic value of ZHX1 expression was significant in normal/elevated hemoglobin group (p = 0.007), in low/normal platelet group (p = 0.009) and in low/normal serum calcium group (p = 0.037) (Fig 3 and S4 and S5 Figs).	('normal/elevated', 'Var', (59, 74))	('calcium', 'Chemical', 'MESH:D002118', (170, 177))	('ZHX1', 'Gene', '11244', (24, 28))	('low/normal serum calcium', 'Phenotype', 'HP:0002901', (153, 177))	('elevated hemoglobin', 'Phenotype', 'HP:0001900', (66, 85))	('ZHX1', 'Gene', (24, 28))	('normal/elevated hemoglobin', 'Phenotype', 'HP:0001903', (59, 85))
167549	28152006	Interestingly, the prognostic value of ZHX1 is significant in advanced stage group, normal/elevated hemoglobin group, low/normal platelet group and low/normal serum calcium group.	('advanced', 'Disease', (62, 70))	('elevated hemoglobin', 'Phenotype', 'HP:0001900', (91, 110))	('normal/elevated hemoglobin', 'Phenotype', 'HP:0001903', (84, 110))	('low/normal serum calcium', 'Phenotype', 'HP:0002901', (148, 172))	('significant', 'Reg', (47, 58))	('ZHX1', 'Gene', (39, 43))	('low/normal platelet group', 'MPA', (118, 143))	('calcium', 'Chemical', 'MESH:D002118', (165, 172))	('low/normal', 'Var', (148, 158))	('ZHX1', 'Gene', '11244', (39, 43))
167599	33947142	Downregulating either member of the PVT1/Mcl-1 axis inhibits proliferation and colony formation and promotes apoptosis.	('PVT1', 'Gene', '5820', (36, 40))	('apoptosis', 'CPA', (109, 118))	('formation', 'biological_process', 'GO:0009058', ('86', '95'))	('promotes', 'PosReg', (100, 108))	('inhibits', 'NegReg', (52, 60))	('Downregulating', 'Var', (0, 14))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))	('PVT1', 'Gene', (36, 40))
167601	33947142	On a molecular level, the most frequent cause of either sporadic or hereditary RCC is the inactivation of the von Hippel-Lindau (VHL) gene.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('cause', 'Reg', (40, 45))	('VHL', 'Gene', (129, 132))	('von Hippel-Lindau', 'Gene', '7428', (110, 127))	('VHL', 'Gene', '7428', (129, 132))	('von Hippel-Lindau', 'Gene', (110, 127))	('inactivation', 'Var', (90, 102))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
167602	33947142	Mutations causing the loss of heterozygosity of the 3p chromosome or hypermethylation of the VHL promotor are common in RCC patients.	('hypermethylation', 'Var', (69, 85))	('VHL', 'Gene', '7428', (93, 96))	('loss of', 'NegReg', (22, 29))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('VHL', 'Gene', (93, 96))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))	('patients', 'Species', '9606', (124, 132))
167603	33947142	Defective protein VHL enables the stabilization of the hypoxia-induced factor (HIF) protein family, which would be otherwise degraded in a proteasome.	('VHL', 'Gene', '7428', (18, 21))	('proteasome', 'cellular_component', 'GO:0000502', ('139', '149'))	('proteasome', 'molecular_function', 'GO:0004299', ('139', '149'))	('protein', 'Protein', (10, 17))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('hypoxia', 'Disease', 'MESH:D000860', (55, 62))	('stabilization', 'MPA', (34, 47))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('Defective', 'Var', (0, 9))	('hypoxia', 'Disease', (55, 62))	('VHL', 'Gene', (18, 21))
167606	33947142	tie the involvement of PVT1 in MYC and VHL regulation together (Figure 1), as their team identified a unique polymorphism at 8q24.21 associated with renal cancer susceptibility.	('regulation', 'biological_process', 'GO:0065007', ('43', '53'))	('PVT1', 'Gene', (23, 27))	('associated with', 'Reg', (133, 148))	('MYC', 'Gene', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('VHL', 'Gene', (39, 42))	('PVT1', 'Gene', '5820', (23, 27))	('renal cancer', 'Disease', (149, 161))	('VHL', 'Gene', '7428', (39, 42))	('polymorphism at', 'Var', (109, 124))	('MYC', 'Gene', '4609', (31, 34))	('renal cancer', 'Phenotype', 'HP:0009726', (149, 161))	('renal cancer', 'Disease', 'MESH:D007680', (149, 161))
167607	33947142	The polymorphism influences the expression of MYC and PVT1, as it is localized in the HIF-binding enhancer, affecting both the cellular MYC (c-MYC) gene and PVT1 gene.	('MYC', 'Gene', (136, 139))	('influences', 'Reg', (17, 27))	('binding', 'molecular_function', 'GO:0005488', ('90', '97'))	('PVT1', 'Gene', '5820', (54, 58))	('c-MYC', 'Gene', (141, 146))	('PVT1', 'Gene', (157, 161))	('MYC', 'Gene', '4609', (136, 139))	('PVT1', 'Gene', (54, 58))	('MYC', 'Gene', (46, 49))	('MYC', 'Gene', '4609', (143, 146))	('affecting', 'Reg', (108, 117))	('c-MYC', 'Gene', '4609', (141, 146))	('PVT1', 'Gene', '5820', (157, 161))	('expression', 'MPA', (32, 42))	('MYC', 'Gene', (143, 146))	('polymorphism', 'Var', (4, 16))	('MYC', 'Gene', '4609', (46, 49))
167608	33947142	The polymorphism's effect is restricted to renal tubular cells, and the renal cancer susceptibility depends on the genotype of the respective polymorphism site in the enhancer, affecting its accessibility to HIF proteins.	('affecting', 'Reg', (177, 186))	('polymorphism', 'Var', (142, 154))	('renal cancer', 'Disease', (72, 84))	('renal cancer', 'Phenotype', 'HP:0009726', (72, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('renal cancer', 'Disease', 'MESH:D007680', (72, 84))	('accessibility to HIF proteins', 'MPA', (191, 220))
167609	33947142	pVHL defects enhanced expression of c-MYC and PVT1, hence the notorious upregulation of PVT1 in RCC.	('RCC', 'Disease', (96, 99))	('pVHL', 'Gene', '7428', (0, 4))	('PVT1', 'Gene', '5820', (46, 50))	('upregulation', 'PosReg', (72, 84))	('enhanced', 'PosReg', (13, 21))	('pVHL', 'Gene', (0, 4))	('c-MYC', 'Gene', '4609', (36, 41))	('PVT1', 'Gene', '5820', (88, 92))	('defects', 'Var', (5, 12))	('PVT1', 'Gene', (46, 50))	('c-MYC', 'Gene', (36, 41))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('expression', 'MPA', (22, 32))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('PVT1', 'Gene', (88, 92))
167610	33947142	The polymorphisms in the HIF-responding regulatory elements could affect renal tumorigenesis.	('affect', 'Reg', (66, 72))	('tumor', 'Disease', (79, 84))	('polymorphisms', 'Var', (4, 17))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
167620	33947142	The authors further identified a new splicing variant of PVT1, whose levels were even higher in the tumor tissue and tumor cell lines than the levels of the full-length original splicing variant and had an even higher effect on the cell proliferation.	('splicing variant', 'Var', (37, 53))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('levels', 'MPA', (69, 75))	('PVT1', 'Gene', (57, 61))	('splicing', 'biological_process', 'GO:0045292', ('178', '186'))	('cell proliferation', 'biological_process', 'GO:0008283', ('232', '250'))	('higher', 'PosReg', (211, 217))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('PVT1', 'Gene', '5820', (57, 61))	('splicing', 'biological_process', 'GO:0045292', ('37', '45'))	('higher', 'PosReg', (86, 92))	('cell proliferation', 'CPA', (232, 250))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
167622	33947142	An in-silico target prediction showed that miR-16-5p is a target of PVT1.	('miR-16-5p', 'Chemical', '-', (43, 52))	('PVT1', 'Gene', (68, 72))	('PVT1', 'Gene', '5820', (68, 72))	('miR-16-5p', 'Var', (43, 52))
167624	33947142	Moreover, the strong negative regulatory connection of PVT1 and miR-16-5p has been observed in colorectal cancer.	('negative', 'NegReg', (21, 29))	('colorectal cancer', 'Disease', (95, 112))	('miR-16-5p', 'Chemical', '-', (64, 73))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('PVT1', 'Gene', (55, 59))	('miR-16-5p', 'Var', (64, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('PVT1', 'Gene', '5820', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
167626	33947142	In their work, they found the interactions of miR-145 miR-211, miR-216a, mIR-133a, and miR-133b with PVT1.	('miR-216a', 'Gene', (63, 71))	('mIR-133a', 'Var', (73, 81))	('miR-216a', 'Gene', '406998', (63, 71))	('PVT1', 'Gene', '5820', (101, 105))	('interactions', 'Interaction', (30, 42))	('miR-145', 'Gene', (46, 53))	('miR-133b', 'Gene', '442890', (87, 95))	('miR-145', 'Gene', '406937', (46, 53))	('miR-133b', 'Gene', (87, 95))	('miR-211', 'Var', (54, 61))	('PVT1', 'Gene', (101, 105))
167630	33947142	In PVT1, though, SP1 has been identified as a potential target of PVT1, miR-145, miR-133a, and miR-133b.	('miR-145', 'Gene', '406937', (72, 79))	('PVT1', 'Gene', (3, 7))	('miR-133a', 'Var', (81, 89))	('PVT1', 'Gene', (66, 70))	('miR-133b', 'Gene', '442890', (95, 103))	('miR-145', 'Gene', (72, 79))	('PVT1', 'Gene', '5820', (3, 7))	('miR-133b', 'Gene', (95, 103))	('PVT1', 'Gene', '5820', (66, 70))
167664	33947142	Dysregulation of the PVT1 expression is easily detectable and correlates with a specific clinical behavior and RCC subtype.	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('Dysregulation', 'Var', (0, 13))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('PVT1', 'Gene', (21, 25))	('PVT1', 'Gene', '5820', (21, 25))
167709	29184790	The relative risks of developing AKI after laparoscopic surgery (compared to open) were 1.16 and 1.94 in patients with T1/2 and T3/4 tumours, respectively.	('T1/2', 'Var', (119, 123))	('patients', 'Species', '9606', (105, 113))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumours', 'Phenotype', 'HP:0002664', (133, 140))	('tumours', 'Disease', 'MESH:D009369', (133, 140))	('tumours', 'Disease', (133, 140))	('AKI', 'Disease', (33, 36))	('T3/4', 'Var', (128, 132))
167718	29184790	In a Korean single-centre retrospective cohort study of 543 RN patients grouped by preoperative CKD stage, patients with stage I, II and III CKD, respectively, experienced 31%, 27% and 13% reductions in eGFR, which was partially attributed to greater functional hyperfiltration in the stage III group.	('CKD', 'Var', (141, 144))	('CKD', 'Phenotype', 'HP:0012622', (96, 99))	('eGFR', 'MPA', (203, 207))	('CKD', 'Phenotype', 'HP:0012622', (141, 144))	('patients', 'Species', '9606', (63, 71))	('patients', 'Species', '9606', (107, 115))	('reductions', 'NegReg', (189, 199))	('eGFR', 'molecular_function', 'GO:0005006', ('203', '207'))
167722	29184790	Although there was minimal association between ACR and eGFR, patients with low preoperative eGFR were more likely to have a higher ACR than those with a normal eGFR (P=0.005), which may have also contributed to this association, where patients with preoperative kidney functional impairment also had albuminuria.	('kidney functional impairment also had albuminuria', 'Disease', (262, 311))	('ACR', 'Gene', (47, 50))	('eGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('ACR', 'Gene', '49', (131, 134))	('eGFR', 'molecular_function', 'GO:0005006', ('160', '164'))	('low', 'Var', (75, 78))	('patients', 'Species', '9606', (235, 243))	('patients', 'Species', '9606', (61, 69))	('ACR', 'Gene', '49', (47, 50))	('eGFR', 'Gene', (92, 96))	('ACR', 'Gene', (131, 134))	('kidney functional impairment also had albuminuria', 'Disease', 'MESH:D000419', (262, 311))	('higher', 'PosReg', (124, 130))	('eGFR', 'molecular_function', 'GO:0005006', ('55', '59'))	('albuminuria', 'Phenotype', 'HP:0012592', (300, 311))
167751	29184790	In contrast to the present findings, previous reports of short- and long-term follow-up of patients undergoing RN identified that smaller tumours were associated with increased risk of poorer postoperative kidney function in patients managed with RN.	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (225, 233))	('poorer postoperative kidney function', 'MPA', (185, 221))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('smaller', 'Var', (130, 137))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('tumours', 'Disease', 'MESH:D009369', (138, 145))	('tumours', 'Disease', (138, 145))
167763	29184790	They found that CKD (defined as eGFR <60 mL/min per 1.73 m2) at three years postoperatively was more prevalent in patients with postoperative AKI (50%) compared to those without (32%), and that AKI was an independent predictor of CKD (OR: 4.24; 95% CI: 2.28, 7.89).	('eGFR', 'molecular_function', 'GO:0005006', ('32', '36'))	('CKD', 'Phenotype', 'HP:0012622', (230, 233))	('CKD', 'Disease', (16, 19))	('AKI', 'Var', (142, 145))	('patients', 'Species', '9606', (114, 122))	('CKD', 'Phenotype', 'HP:0012622', (16, 19))
167767	31924838	Germline polymorphisms in the Von Hippel-Lindau and Hypoxia-inducible factor 1-alpha genes, gene-environment and gene-gene interactions and renal cell cancer We investigated the relationship between germline single nucleotide polymorphisms (SNPs) in Von Hippel-Lindau (VHL) and Hypoxia-inducible factor 1-alpha (HIF1A), and their gene-environment and gene-gene interactions, and clear-cell RCC (ccRCC) risk.	('Von Hippel-Lindau', 'Gene', '7428', (30, 47))	('Von Hippel-Lindau', 'Gene', (30, 47))	('interactions', 'Interaction', (361, 373))	('ccRCC', 'Disease', 'MESH:D002292', (395, 400))	('Hypoxia-inducible factor 1-alpha', 'Gene', '3091', (52, 84))	('HIF1A', 'Gene', '3091', (312, 317))	('Von Hippel-Lindau', 'Gene', '7428', (250, 267))	('VHL', 'Gene', '7428', (269, 272))	('clear-cell RCC', 'Disease', 'MESH:D002292', (379, 393))	('Von Hippel-Lindau', 'Gene', (250, 267))	('men', 'Species', '9606', (104, 107))	('ccRCC', 'Disease', (395, 400))	('single nucleotide polymorphisms', 'Var', (208, 239))	('men', 'Species', '9606', (342, 345))	('clear-cell RCC', 'Disease', (379, 393))	('Hypoxia-inducible factor 1-alpha', 'Gene', (52, 84))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('renal cell cancer', 'Disease', 'MESH:D002292', (140, 157))	('ccRCC', 'Phenotype', 'HP:0006770', (395, 400))	('renal cell cancer', 'Disease', (140, 157))	('HIF1A', 'Gene', (312, 317))	('Hypoxia-inducible factor 1-alpha', 'Gene', '3091', (278, 310))	('investigated', 'Reg', (161, 173))	('renal cell cancer', 'Phenotype', 'HP:0005584', (140, 157))	('VHL', 'Gene', (269, 272))	('Hypoxia-inducible factor 1-alpha', 'Gene', (278, 310))
167777	31924838	No associations were found between gene-environment and gene-gene interactions and (cc)RCC risk and between VHL promoter methylation and VHL SNPs.	('methylation', 'biological_process', 'GO:0032259', ('121', '132'))	('VHL', 'Gene', '7428', (108, 111))	('RCC', 'Disease', (87, 90))	('RCC', 'Disease', 'MESH:D002292', (87, 90))	('VHL', 'Gene', (137, 140))	('interactions', 'Var', (66, 78))	('men', 'Species', '9606', (47, 50))	('VHL', 'Gene', '7428', (137, 140))	('VHL', 'Gene', (108, 111))
167778	31924838	Genetic and epigenetic alterations in the Von Hippel-Lindau (VHL) gene are important drivers of carcinogenesis in clear-cell renal cell carcinoma (ccRCC).	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (114, 145))	('clear-cell renal cell carcinoma', 'Disease', (114, 145))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:D002292', (114, 145))	('VHL', 'Gene', '7428', (61, 64))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (125, 145))	('epigenetic alterations', 'Var', (12, 34))	('carcinogenesis', 'Disease', 'MESH:D063646', (96, 110))	('Von Hippel-Lindau', 'Gene', '7428', (42, 59))	('VHL', 'Gene', (61, 64))	('ccRCC', 'Disease', (147, 152))	('ccRCC', 'Phenotype', 'HP:0006770', (147, 152))	('carcinogenesis', 'Disease', (96, 110))	('Von Hippel-Lindau', 'Gene', (42, 59))	('ccRCC', 'Disease', 'MESH:D002292', (147, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))
167779	31924838	For sporadic ccRCC, biallelic inactivation of VHL because of rare, but highly penetrant, somatic mutations is relatively common.	('VHL', 'Gene', (46, 49))	('biallelic inactivation', 'Var', (20, 42))	('VHL', 'Gene', '7428', (46, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('ccRCC', 'Disease', (13, 18))	('ccRCC', 'Disease', 'MESH:D002292', (13, 18))
167780	31924838	Previous studies have estimated that 50-82% of patients with sporadic ccRCC have a mutation in the VHL gene.	('VHL', 'Gene', (99, 102))	('patients', 'Species', '9606', (47, 55))	('VHL', 'Gene', '7428', (99, 102))	('mutation', 'Var', (83, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (70, 75))	('ccRCC', 'Disease', (70, 75))	('ccRCC', 'Disease', 'MESH:D002292', (70, 75))
167782	31924838	Inactivation of pVHL leads to the unchecked accumulation of hypoxia-inducible factor 1 alpha (HIF1A), which facilitates oxygen delivery, adaptation to oxygen deprivation and angiogenesis.	('oxygen', 'Chemical', 'MESH:D010100', (120, 126))	('hypoxia-inducible factor 1 alpha', 'Gene', '3091', (60, 92))	('oxygen', 'Chemical', 'MESH:D010100', (151, 157))	('hypoxia-inducible factor 1 alpha', 'Gene', (60, 92))	('adaptation', 'MPA', (137, 147))	('angiogenesis', 'biological_process', 'GO:0001525', ('174', '186'))	('angiogenesis', 'CPA', (174, 186))	('facilitates', 'PosReg', (108, 119))	('oxygen delivery', 'MPA', (120, 135))	('HIF1A', 'Gene', (94, 99))	('HIF1A', 'Gene', '3091', (94, 99))	('pVHL', 'Gene', '7428', (16, 20))	('Inactivation', 'Var', (0, 12))	('pVHL', 'Gene', (16, 20))	('accumulation', 'PosReg', (44, 56))
167783	31924838	Therefore, genetic or epigenetic alterations in VHL and HIF1A may lead to enhanced cell survival and carcinogenesis.	('VHL', 'Gene', '7428', (48, 51))	('cell survival', 'CPA', (83, 96))	('carcinogenesis', 'Disease', (101, 115))	('epigenetic alterations', 'Var', (22, 44))	('genetic', 'Var', (11, 18))	('HIF1A', 'Gene', (56, 61))	('HIF1A', 'Gene', '3091', (56, 61))	('VHL', 'Gene', (48, 51))	('carcinogenesis', 'Disease', 'MESH:D063646', (101, 115))	('enhanced', 'PosReg', (74, 82))
167784	31924838	In contrast to the rare, but highly penetrant, sequence alterations leading to VHL loss, some germline Single Nucleotide Polymorphisms (SNPs) are highly frequent, but have a low penetrance.	('VHL', 'Gene', '7428', (79, 82))	('Single Nucleotide Polymorphisms', 'Var', (103, 134))	('VHL', 'Gene', (79, 82))
167787	31924838	In previous studies, HIF1A SNPs have been associated with RCC prognosis, but not with (cc)RCC development.	('RCC', 'Disease', 'MESH:D002292', (90, 93))	('associated', 'Reg', (42, 52))	('men', 'Species', '9606', (101, 104))	('HIF1A', 'Gene', (21, 26))	('HIF1A', 'Gene', '3091', (21, 26))	('SNPs', 'Var', (27, 31))	('RCC', 'Disease', (58, 61))	('RCC', 'Disease', 'MESH:D002292', (58, 61))	('RCC', 'Disease', (90, 93))
167800	31924838	In both age- and sex-adjusted analyses and multivariable-adjusted analyses, an association with (cc)RCC risk was observed for SNPs in VHL_rs779805, but not for SNPs in VHL_rs1642739, VHL_rs265318 and HIF1A_rs2301111 (Table 2).	('VHL', 'Gene', '7428', (183, 186))	('VHL', 'Gene', (168, 171))	('association', 'Interaction', (79, 90))	('SNPs', 'Var', (126, 130))	('VHL', 'Gene', (134, 137))	('VHL', 'Gene', '7428', (168, 171))	('HIF1A', 'Gene', (200, 205))	('HIF1A', 'Gene', '3091', (200, 205))	('VHL', 'Gene', '7428', (134, 137))	('RCC', 'Disease', 'MESH:D002292', (100, 103))	('RCC', 'Disease', (100, 103))	('VHL', 'Gene', (183, 186))
167811	31924838	Sensitivity analyses between smoking status (ever/never), hypertension (no self-reported hypertension or no self-reported antihypertensive medication, hypertension with self-reported hypertensive medication) and BMI (<20 kg/m2, 20-<25 kg/m2, 25-<30 kg/m2 and 30+ kg/m2) and SNP status showed similar associations compared to main gene-environment analyses (Supplementary Table 2).	('hypertensive medication', 'Phenotype', 'HP:0000822', (183, 206))	('antihypertensive medication', 'Phenotype', 'HP:0000822', (122, 149))	('hypertensive', 'Disease', 'MESH:D006973', (126, 138))	('hypertension', 'Disease', 'MESH:D006973', (58, 70))	('hypertensive', 'Disease', (183, 195))	('men', 'Species', '9606', (342, 345))	('<20 kg/m2', 'Var', (217, 226))	('hypertension', 'Disease', (58, 70))	('hypertension', 'Disease', 'MESH:D006973', (89, 101))	('hypertension', 'Disease', 'MESH:D006973', (151, 163))	('hypertensive medication', 'Phenotype', 'HP:0000822', (126, 149))	('hypertension', 'Disease', (89, 101))	('hypertension', 'Phenotype', 'HP:0000822', (58, 70))	('hypertension', 'Disease', (151, 163))	('men', 'Species', '9606', (363, 366))	('hypertensive', 'Disease', (126, 138))	('associations', 'Interaction', (300, 312))	('hypertensive', 'Disease', 'MESH:D006973', (183, 195))	('hypertension', 'Phenotype', 'HP:0000822', (151, 163))	('hypertension', 'Phenotype', 'HP:0000822', (89, 101))
167814	31924838	Among ccRCC cases, 19 (7.5%) participants had a methylated CpG island in the VHL promoter region of which 13 had at least one mutant allele for the selected VHL SNPs (Supplementary Table 3).	('participants', 'Species', '9606', (29, 41))	('methylated', 'Var', (48, 58))	('cases', 'Reg', (12, 17))	('VHL', 'Gene', (77, 80))	('men', 'Species', '9606', (173, 176))	('VHL', 'Gene', (157, 160))	('ccRCC', 'Disease', (6, 11))	('VHL', 'Gene', '7428', (77, 80))	('ccRCC', 'Phenotype', 'HP:0006770', (6, 11))	('ccRCC', 'Disease', 'MESH:D002292', (6, 11))	('VHL', 'Gene', '7428', (157, 160))
167828	31924838	This might indicate that VHL polymorphisms lead to an increased susceptibility for ccRCC in particular.	('VHL', 'Gene', (25, 28))	('ccRCC', 'Disease', (83, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('VHL', 'Gene', '7428', (25, 28))	('polymorphisms', 'Var', (29, 42))	('ccRCC', 'Disease', 'MESH:D002292', (83, 88))
167839	31924838	Disruptions in the VHL tumor suppressor gene are thought to play a role in the constitutive activation of hypoxia-inducible factors, as regulated in part by HIF1A, which may lead to carcinogenesis.	('HIF1A', 'Gene', (157, 162))	('HIF1A', 'Gene', '3091', (157, 162))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('23', '39'))	('Disruptions', 'Var', (0, 11))	('activation', 'PosReg', (92, 102))	('VHL', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('lead to', 'Reg', (174, 181))	('hypoxia', 'Disease', (106, 113))	('hypoxia', 'Disease', 'MESH:D000860', (106, 113))	('carcinogenesis', 'Disease', 'MESH:D063646', (182, 196))	('VHL', 'Gene', '7428', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor suppressor', 'biological_process', 'GO:0051726', ('23', '39'))	('carcinogenesis', 'Disease', (182, 196))	('tumor', 'Disease', (23, 28))
167841	31924838	Previous studies have found a relationship between VHL promoter hypermethylation and SNPs in VHL_rs779805 in sporadic ccRCC cases.	('VHL', 'Gene', '7428', (51, 54))	('ccRCC', 'Disease', (118, 123))	('ccRCC', 'Disease', 'MESH:D002292', (118, 123))	('VHL', 'Gene', (93, 96))	('VHL', 'Gene', '7428', (93, 96))	('SNPs', 'Var', (85, 89))	('VHL', 'Gene', (51, 54))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))
167845	31924838	While the number of cases with known promoter methylation status was similar in size to the study of Moore et al., our study had a smaller proportion of cases with VHL promoter methylation (7.5% vs. 9.8%).	('methylation', 'biological_process', 'GO:0032259', ('177', '188'))	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('VHL', 'Gene', (164, 167))	('VHL', 'Gene', '7428', (164, 167))	('promoter methylation', 'Var', (168, 188))
167846	31924838	reported an even higher proportion of sporadic ccRCC cases with a methylated VHL promoter (20.4%), but had a smaller study population.	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('ccRCC', 'Disease', (47, 52))	('VHL', 'Gene', (77, 80))	('methylated', 'Var', (66, 76))	('VHL', 'Gene', '7428', (77, 80))	('ccRCC', 'Disease', 'MESH:D002292', (47, 52))
167847	31924838	In general, there are large differences in the proportion of methylated VHL promoters per SNP between studies, which may explain these unstable point estimates.	('methylated', 'Var', (61, 71))	('VHL', 'Gene', '7428', (72, 75))	('VHL', 'Gene', (72, 75))
167850	31924838	Interestingly, SNPs in the VHL and HIF1A genes have not (yet) been identified as potential risk variants, while there is a biological plausibility for the involvement of these genes based on current evidence on the development of RCC.	('SNPs', 'Var', (15, 19))	('men', 'Species', '9606', (162, 165))	('HIF1A', 'Gene', (35, 40))	('men', 'Species', '9606', (222, 225))	('VHL', 'Gene', (27, 30))	('HIF1A', 'Gene', '3091', (35, 40))	('RCC', 'Disease', 'MESH:D002292', (230, 233))	('RCC', 'Disease', (230, 233))	('VHL', 'Gene', '7428', (27, 30))
167856	31924838	As a result, there is ample opportunity to discover new, rarer, RCC risk variants in future research.	('variants', 'Var', (73, 81))	('RCC', 'Disease', 'MESH:D002292', (64, 67))	('RCC', 'Disease', (64, 67))
167881	31924838	Consequently, three VHL SNPs (rs779805, rs265318 and rs1642739) and one HIF1A SNP (rs2301111) were selected.	('rs265318', 'Var', (40, 48))	('rs265318', 'DBSNP_MENTION', 'None', (40, 48))	('rs1642739', 'Var', (53, 62))	('rs779805', 'DBSNP_MENTION', 'None', (30, 38))	('HIF1A', 'Gene', (72, 77))	('HIF1A', 'Gene', '3091', (72, 77))	('VHL', 'Gene', (20, 23))	('rs2301111', 'DBSNP_MENTION', 'None', (83, 92))	('rs779805', 'Var', (30, 38))	('rs1642739', 'DBSNP_MENTION', 'None', (53, 62))	('VHL', 'Gene', '7428', (20, 23))	('rs2301111', 'Var', (83, 92))
167926	32784737	To tackle these limitations, tumor-related genetic and/or epigenetic alterations may be used as biomarkers, ultimately improving patient survival and quality of life, while reducing healthcare costs through avoidance of futile therapeutic interventions.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('quality of life', 'CPA', (150, 165))	('tumor', 'Disease', (29, 34))	('patient survival', 'CPA', (129, 145))	('improving', 'PosReg', (119, 128))	('epigenetic alterations', 'Var', (58, 80))	('reducing', 'NegReg', (173, 181))	('patient', 'Species', '9606', (129, 136))
167927	32784737	Epigenetic regulation involves four major types of modifications: DNA methylation, histone modifications/variants, chromatin remodeling complexes, and non-coding RNAs (ncRNAs).	('modifications/variants', 'Var', (91, 113))	('chromatin', 'cellular_component', 'GO:0000785', ('115', '124'))	('DNA methylation', 'biological_process', 'GO:0006306', ('66', '81'))	('regulation', 'biological_process', 'GO:0065007', ('11', '21'))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('ncRNA', 'Gene', (168, 173))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('115', '135'))	('histone', 'Protein', (83, 90))	('ncRNA', 'Gene', '220202', (168, 173))
167928	32784737	Abnormalities in the normal function of the epigenetic machinery have been linked to several human conditions, including cancer.	('Abnormalities', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('human', 'Species', '9606', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('linked', 'Reg', (75, 81))	('cancer', 'Disease', (121, 127))
167929	32784737	Epigenetic deregulation often occurs early in tumorigenesis leading to a switch in the normal epigenetic patterns and accumulates during disease progression.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Epigenetic deregulation', 'Var', (0, 23))	('tumor', 'Disease', (46, 51))	('switch', 'MPA', (73, 79))	('normal epigenetic patterns', 'MPA', (87, 113))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
167930	32784737	It is acknowledged that some of these epigenetic alterations might occur prior to the emergence of the malignant phenotype, thus constituting a valuable marker for cancer screening.	('epigenetic alterations', 'Var', (38, 60))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))
167954	32784737	Small interfering RNAs (SiRNAs) are also classified as sncRNAs, but this review solely focused on miRNAs and piRNAs, as these are the most well studied.	('miR', 'Gene', '220972', (98, 101))	('miR', 'Gene', (98, 101))	('Small', 'Var', (0, 5))	('ncRNA', 'Gene', (56, 61))	('ncRNA', 'Gene', '220202', (56, 61))
167955	32784737	Deregulated miRNA expression in cancer was first reported in the early 2000s by Calin and colleagues.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('Deregulated', 'Var', (0, 11))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('miR', 'Gene', '220972', (12, 15))	('miR', 'Gene', (12, 15))
167957	32784737	Dysregulation of miRNA expression occurs in various steps of tumorigenesis and in several tumor models, including RCT.	('Dysregulation', 'Var', (0, 13))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('RCT', 'Disease', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
167971	32784737	In 2015, Busch and colleagues reported that piR-30924, piR-57125, and piR-38756 were differentially expressed in ccRCC compared to NRT and the combination of these piRNAs identified malignant disease with 91% sensitivity, 86% specificity, and an AUC of 0.910.	('piR-30924', 'Var', (44, 53))	('piR-38756', 'Var', (70, 79))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (113, 118))	('RCC', 'Disease', (115, 118))	('malignant disease', 'Disease', 'MESH:D009369', (182, 199))	('piR-57125', 'Var', (55, 64))	('identified', 'Reg', (171, 181))	('malignant disease', 'Disease', (182, 199))
167972	32784737	Notably, the combination of the duo piR-30924 and piR-57125 distinguished metastatic-ccRCC (mccRCC) from non-metastatic ccRCC (non-mccRCC) with 73.0 sensitivity, 74.0 specificity, and an AUC of 0.760.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (120, 125))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (132, 137))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('RCC', 'Disease', (95, 98))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('piR-57125', 'Var', (50, 59))	('RCC', 'Disease', (134, 137))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))
167981	32784737	Subsequently, Lou and colleagues showed that miR-144-3p detected RCT with 87.1% sensitivity and 83.0% specificity.	('miR-144-3p', 'Var', (45, 55))	('miR-144-3p', 'Chemical', '-', (45, 55))	('RCT', 'Disease', (65, 68))	('detected', 'Reg', (56, 64))
167982	32784737	Notably, miR-144-3p was also able to distinguish ccRCC from benign mesenchymal tumors (angiomyolipomas) with 75.0% sensitivity and 71.7% specificity.	('angiomyolipomas', 'Disease', (87, 102))	('benign mesenchymal tumors', 'Disease', 'MESH:C535700', (60, 85))	('miR-144-3p', 'Chemical', '-', (9, 19))	('angiomyolipomas', 'Disease', 'MESH:D018207', (87, 102))	('miR-144-3p', 'Var', (9, 19))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('benign mesenchymal tumors', 'Disease', (60, 85))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('RCC', 'Disease', (51, 54))
167995	32784737	Furthermore, high miR-27a-3p expression levels associated with shorter progression-free survival (PFS), whereas low miR-155 expression entailed 5-fold increase risk to die from the disease.	('high', 'Var', (13, 17))	('miR-155', 'Gene', (116, 123))	('low', 'NegReg', (112, 115))	('miR', 'Gene', '220972', (116, 119))	('shorter', 'NegReg', (63, 70))	('miR', 'Gene', (116, 119))	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (18, 21))	('expression', 'MPA', (29, 39))	('progression-free survival', 'CPA', (71, 96))	('miR-155', 'Gene', '406947', (116, 123))
168018	32784737	Gao and colleagues reported that transfecting mimic miR-200c into ccRCC cell lines resistant to imatinib and sorafenib re-sensitized cells to therapy.	('miR-200c', 'Gene', '406985', (52, 60))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('RCC', 'Disease', (68, 71))	('transfecting', 'Var', (33, 45))	('sorafenib', 'Chemical', 'MESH:D000077157', (109, 118))	('imatinib', 'Chemical', 'MESH:D000068877', (96, 104))	('miR-200c', 'Gene', (52, 60))
168049	32784737	Patients with lncARSR-high expression displayed significantly shorter RFS, doubling the risk of recurrence comparatively to the lncARSR-low expression group.	('RFS', 'MPA', (70, 73))	('Patients', 'Species', '9606', (0, 8))	('lncARSR-high expression', 'Var', (14, 37))	('shorter', 'NegReg', (62, 69))
168051	32784737	Indeed, patients with high lncRNA PVT1 expression depicted 1.5 and 3.5 times higher risk of death or recurrence, respectively, compared to patients with low lncRNA PVT1 expression.	('death', 'Disease', 'MESH:D003643', (92, 97))	('death', 'Disease', (92, 97))	('patients', 'Species', '9606', (139, 147))	('ncRNA', 'Gene', '220202', (28, 33))	('PVT1', 'Gene', (34, 38))	('high', 'Var', (22, 26))	('PVT1', 'Gene', (164, 168))	('ncRNA', 'Gene', (158, 163))	('ncRNA', 'Gene', (28, 33))	('expression', 'MPA', (39, 49))	('PVT1', 'Gene', '5820', (164, 168))	('PVT1', 'Gene', '5820', (34, 38))	('ncRNA', 'Gene', '220202', (158, 163))	('patients', 'Species', '9606', (8, 16))
168062	32784737	In vitro studies revealed that lncSRLR knockdown in sorafenib-resistant RCC cell lines resulted in increased sensitivity to the treatment.	('sensitivity to the treatment', 'MPA', (109, 137))	('lncSRLR', 'Gene', (31, 38))	('sorafenib', 'Chemical', 'MESH:D000077157', (52, 61))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('knockdown', 'Var', (39, 48))	('lncSRLR', 'Gene', '109729161', (31, 38))	('increased', 'PosReg', (99, 108))
168075	32382017	We further discovered that ZHX2 overexpression could increase VEGF secretion and transcriptional activate the MEK/ERK1/2 and promote its downstream targets.	('ZHX2', 'Gene', (27, 31))	('ERK1', 'molecular_function', 'GO:0004707', ('114', '118'))	('ERK1/2', 'Gene', (114, 120))	('activate', 'PosReg', (97, 105))	('overexpression', 'Var', (32, 46))	('increase', 'PosReg', (53, 61))	('MEK', 'Gene', (110, 113))	('ERK1/2', 'Gene', '5595;5594', (114, 120))	('VEGF', 'Gene', '7422', (62, 66))	('MEK', 'Gene', '5609', (110, 113))	('secretion', 'biological_process', 'GO:0046903', ('67', '76'))	('VEGF', 'Gene', (62, 66))	('promote', 'PosReg', (125, 132))
168077	32382017	In summary, these results indicate that ZHX2 drivers cell growth, migration though increase VEGF expression, and transcriptional activate MEK/ERK1/2 signaling pathway, and could induce Sunitinib resistance by regulating self-protective autophagy, these may provide new insight in advanced ccRCC treatment.	('ccRCC', 'Disease', (289, 294))	('ERK1', 'molecular_function', 'GO:0004707', ('142', '146'))	('self-protective autophagy', 'CPA', (220, 245))	('induce', 'PosReg', (178, 184))	('ZHX2', 'Var', (40, 44))	('signaling pathway', 'biological_process', 'GO:0007165', ('149', '166'))	('VEGF', 'Gene', (92, 96))	('cell growth', 'biological_process', 'GO:0016049', ('53', '64'))	('ccRCC', 'Phenotype', 'HP:0006770', (289, 294))	('MEK', 'Gene', '5609', (138, 141))	('expression', 'MPA', (97, 107))	('activate', 'PosReg', (129, 137))	('increase', 'PosReg', (83, 91))	('cell growth', 'CPA', (53, 64))	('regulating', 'Reg', (209, 219))	('increase VEGF expression', 'Phenotype', 'HP:0030269', (83, 107))	('ERK1/2', 'Gene', (142, 148))	('ERK1/2', 'Gene', '5595;5594', (142, 148))	('autophagy', 'biological_process', 'GO:0016236', ('236', '245'))	('MEK', 'Gene', (138, 141))	('migration', 'CPA', (66, 75))	('autophagy', 'biological_process', 'GO:0006914', ('236', '245'))	('Sunitinib', 'Chemical', 'MESH:D000077210', (185, 194))	('VEGF', 'Gene', '7422', (92, 96))	('Sunitinib resistance', 'MPA', (185, 205))
168078	32382017	Since the tumor suppressor gene VHL was identified as the key point of the Von Hippel-Lindau (VHL) disease in 1993, it has been clearly proved that hypoxia or gene mutation could lead to the inactivation of VHL and induce the loss function of VHL complex (VBC, including elongin B and C), which targeting hypoxia-inducible factors (HIFs) for ubiquitylation and proteasomal degradation.	('hypoxia', 'Disease', 'MESH:D000860', (305, 312))	('VHL', 'Gene', '7428', (32, 35))	('elongin B', 'Gene', '6923', (271, 280))	('VHL', 'Gene', '7428', (207, 210))	('Von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (75, 106))	('loss', 'NegReg', (226, 230))	('VHL', 'Gene', '7428', (94, 97))	('ubiquitylation', 'MPA', (342, 356))	('tumor', 'Disease', (10, 15))	('inactivation', 'MPA', (191, 203))	('VHL', 'Gene', (243, 246))	('proteasomal', 'MPA', (361, 372))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('10', '26'))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('gene mutation', 'Var', (159, 172))	('tumor suppressor', 'biological_process', 'GO:0051726', ('10', '26'))	('degradation', 'biological_process', 'GO:0009056', ('373', '384'))	('VHL', 'Gene', '7428', (243, 246))	('HIFs', 'Disease', (332, 336))	('VHL complex', 'cellular_component', 'GO:0030891', ('243', '254'))	('hypoxia', 'Disease', (148, 155))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('VHL', 'Gene', (207, 210))	('VHL', 'Gene', (32, 35))	('hypoxia', 'Disease', (305, 312))	('elongin B', 'Gene', (271, 280))	('HIFs', 'Disease', 'None', (332, 336))	('hypoxia', 'Disease', 'MESH:D000860', (148, 155))	('VHL', 'Gene', (94, 97))
168082	32382017	have found that Zinc fingers and homeoboxes 2 (ZHX2) is a novel VHL substrate transcription factor by using a genome-wide human cDNA library strategy; and they reported that depletion of ZHX2 could inhibit the proliferation of VHL-deficient ccRCC cell lines through impairing NF-kappaB pathway.	('human', 'Species', '9606', (122, 127))	('VHL-deficient ccRCC', 'Disease', (227, 246))	('VHL', 'Gene', '7428', (227, 230))	('transcription', 'biological_process', 'GO:0006351', ('78', '91'))	('proliferation', 'CPA', (210, 223))	('inhibit', 'NegReg', (198, 205))	('VHL', 'Gene', (64, 67))	('depletion', 'Var', (174, 183))	('VHL-deficient ccRCC', 'Disease', 'MESH:D006623', (227, 246))	('ccRCC', 'Phenotype', 'HP:0006770', (241, 246))	('ZHX2', 'Gene', (187, 191))	('impairing', 'NegReg', (266, 275))	('NF-kappaB', 'Gene', '4790', (276, 285))	('VHL', 'Gene', '7428', (64, 67))	('transcription factor', 'molecular_function', 'GO:0000981', ('78', '98'))	('Zinc fingers and homeoboxes 2', 'Gene', '22882', (16, 45))	('VHL', 'Gene', (227, 230))	('NF-kappaB', 'Gene', (276, 285))
168085	32382017	demonstrated that ZHX2 promoter region was hypermethylated in hepatocellular carcinoma (HCC) samples, suggesting it might functions as a tumor suppressor.	('functions', 'Reg', (122, 131))	('hepatocellular carcinoma', 'Disease', (62, 86))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (62, 86))	('tumor', 'Disease', (137, 142))	('ZHX2', 'Gene', (18, 22))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('137', '153'))	('hypermethylated', 'Var', (43, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('HCC', 'Phenotype', 'HP:0001402', (88, 91))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (62, 86))	('tumor suppressor', 'biological_process', 'GO:0051726', ('137', '153'))
168086	32382017	On the other side, another immunohistochemical research reported that ZHX2 was highly expressed in tumor samples compared to adjacent tissues in HCC patients, and the prognostic analysis showed ZHX2 was associated with poorer outcomes, seems it act as an oncogenic biomarker.	('tumor', 'Disease', (99, 104))	('patients', 'Species', '9606', (149, 157))	('associated', 'Reg', (203, 213))	('ZHX2', 'Gene', (70, 74))	('ZHX2', 'Var', (194, 198))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('HCC', 'Phenotype', 'HP:0001402', (145, 148))
168130	32382017	The prognostic analysis showed that the patients with high ZHX2 have worse progression-free survival (PFS) while there was no significant relation with overall survival (OS) (Fig.	('ZHX2', 'Gene', (59, 63))	('high', 'Var', (54, 58))	('worse', 'NegReg', (69, 74))	('patients', 'Species', '9606', (40, 48))	('progression-free survival', 'CPA', (75, 100))
168133	32382017	As reported, ZHX2 depletion could inhibit the VHL-deficient ccRCC cell growth.	('cell growth', 'biological_process', 'GO:0016049', ('66', '77'))	('VHL-deficient ccRCC', 'Disease', 'MESH:D006623', (46, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('VHL-deficient ccRCC', 'Disease', (46, 65))	('depletion', 'Var', (18, 27))	('inhibit', 'NegReg', (34, 41))
168134	32382017	We used the siRNA to knockdown the ZHX2 expression in 786-O cells as well as EPAS1 (Encode HIF-2a), and both genes silenced could inhibit the cell proliferation (Fig.	('EPAS1', 'Gene', '2034', (77, 82))	('HIF-2a', 'Gene', (91, 97))	('EPAS1', 'Gene', (77, 82))	('inhibit', 'NegReg', (130, 137))	('ZHX2', 'Gene', (35, 39))	('HIF-2a', 'Gene', '2034', (91, 97))	('cell proliferation', 'biological_process', 'GO:0008283', ('142', '160'))	('cell proliferation', 'CPA', (142, 160))	('knockdown', 'Var', (21, 30))
168136	32382017	Apoptosis analysis showed that either EPAS1 or ZHX2 knockdown could induce cell apoptosis (Fig.	('induce', 'Reg', (68, 74))	('cell apoptosis', 'CPA', (75, 89))	('EPAS1', 'Gene', '2034', (38, 43))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('EPAS1', 'Gene', (38, 43))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('knockdown', 'Var', (52, 61))	('ZHX2', 'Gene', (47, 51))
168152	32382017	The enrichment of KEGG analysis showed several cancer-related pathways were activated in ZHX2 overexpression cells, especially MAPK signaling pathway (Fig.	('MAPK signaling pathway', 'Pathway', (127, 149))	('activated', 'PosReg', (76, 85))	('ZHX2', 'Gene', (89, 93))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('overexpression', 'Var', (94, 108))	('MAPK signaling', 'biological_process', 'GO:0000165', ('127', '141'))	('signaling pathway', 'biological_process', 'GO:0007165', ('132', '149'))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('MAPK', 'molecular_function', 'GO:0004707', ('127', '131'))
168167	32382017	The ratio of LC3-II/LC3-I was increased in ZHX2 overexpression cells, which meant autophagy was over-activated (Fig.	('LC3', 'Gene', (13, 16))	('LC3', 'Gene', '84557', (20, 23))	('ratio', 'MPA', (4, 9))	('autophagy', 'biological_process', 'GO:0016236', ('82', '91'))	('overexpression', 'Var', (48, 62))	('LC3', 'Gene', (20, 23))	('autophagy', 'biological_process', 'GO:0006914', ('82', '91'))	('autophagy', 'CPA', (82, 91))	('increased', 'PosReg', (30, 39))	('ZHX2', 'Gene', (43, 47))	('over-activated', 'PosReg', (96, 110))	('LC3', 'Gene', '84557', (13, 16))
168176	32382017	We observed that high ZHX2 expression significantly correlated with worse outcome, and ZHX2 could activate VEGFA like HIF-2a did, and it markedly promoted cell proliferation, migration by transcriptional activating MEK1/ERK1/2 signaling.	('MEK1', 'Gene', (215, 219))	('HIF-2a', 'Gene', '2034', (118, 124))	('signaling', 'biological_process', 'GO:0023052', ('227', '236'))	('ZHX2', 'Gene', (87, 91))	('expression', 'MPA', (27, 37))	('VEGFA', 'Gene', '7422', (107, 112))	('ERK1', 'molecular_function', 'GO:0004707', ('220', '224'))	('activating', 'PosReg', (204, 214))	('HIF-2a', 'Gene', (118, 124))	('ZHX2', 'Gene', (22, 26))	('cell proliferation', 'biological_process', 'GO:0008283', ('155', '173'))	('MEK1', 'Gene', '5604', (215, 219))	('activate', 'PosReg', (98, 106))	('promoted', 'PosReg', (146, 154))	('MEK1', 'molecular_function', 'GO:0004708', ('215', '219'))	('VEGFA', 'Gene', (107, 112))	('ERK1/2', 'Gene', (220, 226))	('ERK1/2', 'Gene', '5595;5594', (220, 226))	('high', 'Var', (17, 21))	('cell proliferation', 'CPA', (155, 173))	('migration', 'CPA', (175, 184))
168179	32382017	reported it worked as a transcriptional repressor, and the changes of ZHX2 could regulate several oncogenes expression in human disease.	('human', 'Species', '9606', (122, 127))	('ZHX2', 'Gene', (70, 74))	('regulate', 'Reg', (81, 89))	('oncogenes', 'Gene', (98, 107))	('changes', 'Var', (59, 66))
168188	32382017	More importantly, RNA-seq analysis showed that ZHX2 could activate some other signals, especially MAPK/ERK pathway.	('ERK', 'molecular_function', 'GO:0004707', ('103', '106'))	('ERK', 'Gene', (103, 106))	('activate', 'PosReg', (58, 66))	('RNA', 'cellular_component', 'GO:0005562', ('18', '21'))	('ZHX2', 'Var', (47, 51))	('MAPK', 'molecular_function', 'GO:0004707', ('98', '102'))	('ERK', 'Gene', '5594', (103, 106))
168195	32382017	On the one hand, activated STAT3 can promote the transcription of HIF and regulate the expression of VEGF; on the other hand, activated STAT3 can promote the transcription activity of VEGF by directly binding to its promoter.	('VEGF', 'Gene', (101, 105))	('STAT3', 'Gene', '6774', (136, 141))	('transcription', 'MPA', (49, 62))	('binding', 'Interaction', (201, 208))	('VEGF', 'Gene', '7422', (184, 188))	('transcription', 'biological_process', 'GO:0006351', ('49', '62'))	('regulate', 'Reg', (74, 82))	('VEGF', 'Gene', (184, 188))	('transcription activity', 'MPA', (158, 180))	('expression', 'MPA', (87, 97))	('activated', 'Var', (126, 135))	('STAT3', 'Gene', (27, 32))	('binding', 'molecular_function', 'GO:0005488', ('201', '208'))	('promote', 'PosReg', (37, 44))	('VEGF', 'Gene', '7422', (101, 105))	('transcription', 'biological_process', 'GO:0006351', ('158', '171'))	('STAT3', 'Gene', (136, 141))	('promote', 'PosReg', (146, 153))	('STAT3', 'Gene', '6774', (27, 32))
168196	32382017	In our in vitro study, ZHX2 silencing could part decrease VEGF expression and ZHX2 overexpression could significantly activate VEGF.	('VEGF', 'Gene', '7422', (127, 131))	('VEGF', 'Gene', (58, 62))	('expression', 'MPA', (63, 73))	('VEGF', 'Gene', '7422', (58, 62))	('decrease', 'NegReg', (49, 57))	('VEGF', 'Gene', (127, 131))	('activate', 'PosReg', (118, 126))	('ZHX2', 'Gene', (78, 82))	('ZHX2', 'Gene', (23, 27))	('silencing', 'Var', (28, 37))
168202	32382017	These results indicated that ZHX2 overexpression might induce sunitinib resistance by self-protective autophagy, and the more detail mechanism investigation is still needed.	('overexpression', 'Var', (34, 48))	('sunitinib', 'Chemical', 'MESH:D000077210', (62, 71))	('sunitinib resistance', 'MPA', (62, 82))	('self-protective autophagy', 'CPA', (86, 111))	('ZHX2', 'Gene', (29, 33))	('autophagy', 'biological_process', 'GO:0016236', ('102', '111'))	('induce', 'PosReg', (55, 61))	('autophagy', 'biological_process', 'GO:0006914', ('102', '111'))
168223	34001147	A research suggests that the dysregulation of miRNAs is associated with the biological characteristics of ccRCC, and it may serve as a novel potential biomarker for prognosis and treatment.	('miR', 'Gene', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('associated', 'Reg', (56, 66))	('dysregulation', 'Var', (29, 42))	('miR', 'Gene', '220972', (46, 49))
168240	34001147	Human renal tubular cell line HK-2 (BNCC339833), human renal carcinoma cell line A498 (BNCC100609), and human ccRCC cell lines 786-O (BNCC338472), 769-P (BNCC100976) and Caki-1 (BNCC100682) were all purchased from BeNa Culture Collection (BNCC; China).	('BNCC100682', 'Var', (178, 188))	('Human', 'Species', '9606', (0, 5))	('BNCC339833', 'Var', (36, 46))	('human', 'Species', '9606', (49, 54))	('renal carcinoma', 'Disease', 'MESH:C538614', (55, 70))	('BNCC338472', 'Var', (134, 144))	('human', 'Species', '9606', (104, 109))	('RCC', 'Disease', (112, 115))	('renal carcinoma', 'Phenotype', 'HP:0005584', (55, 70))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('HK-2', 'molecular_function', 'GO:0008256', ('30', '34'))	('HK-2', 'CellLine', 'CVCL:0302', (30, 34))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('renal carcinoma', 'Disease', (55, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))	('A498', 'CellLine', 'CVCL:1056', (81, 85))
168248	34001147	After being denatured at a high temperature, proteins were isolated by sodium dodecyl sulfate-polyacrylamide gelelectrophoresis (SDS-PAGE) and transferred onto polyvinylidene fluoride membranes (PVDF; Millipore), which were then blocked with 5 % skim milk for 2 h. Then the membranes were incubated with primary antibodies overnight at 4 C. Primary antibodies including mouse anti-SPN (ab233969, 1:100) and mouse anti-beta-Actin (ab20272, 1:5000) were both purchased from Abcam (Shanghai, China).	('SPN', 'Gene', (381, 384))	('SPN', 'Gene', '6693', (381, 384))	('ab233969', 'Var', (386, 394))	('beta-Actin', 'Gene', (418, 428))	('beta-Actin', 'Gene', '728378', (418, 428))
168258	34001147	To determine the binding relationship between miR-129-5p and SPN 3'-UTR, luciferase vectors pmirGLO (Promega, USA) fused with wild type (WT) SPN 3'-UTR or mutant (MUT) SPN 3'-UTR were established.	('SPN', 'Gene', '6693', (141, 144))	('SPN', 'Gene', (141, 144))	('miR-129-5p', 'Gene', '100302178', (46, 56))	('mutant', 'Var', (155, 161))	('binding', 'molecular_function', 'GO:0005488', ('17', '24'))	('miR-129-5p', 'Gene', (46, 56))	('SPN', 'Gene', '6693', (61, 64))	('SPN', 'Gene', '6693', (168, 171))	('SPN', 'Gene', (61, 64))	('SPN', 'Gene', (168, 171))
168303	34001147	There are few studies on the biological function of SPN in the progression of cancers, and only one study discussing the role of aberrant CD43 glycosylation as a cancer biomarker.	('glycosylation', 'biological_process', 'GO:0070085', ('143', '156'))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('SPN', 'Gene', '6693', (52, 55))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('SPN', 'Gene', (52, 55))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('CD43', 'Protein', (138, 142))	('aberrant', 'Var', (129, 137))
168318	33648519	GSEA indicated that high CDCA7 expression was related to the apoptosis pathway, cell cycle pathway, JAK-STAT pathway, NOD like receptor pathway, P53 pathway, T cell receptor pathway and toll like receptor pathway, etc.	('related', 'Reg', (46, 53))	('T cell receptor pathway', 'Pathway', (158, 181))	('apoptosis pathway', 'Pathway', (61, 78))	('STAT', 'Gene', '6774', (104, 108))	('STAT', 'Gene', (104, 108))	('JAK', 'Gene', '3717', (100, 103))	('NOD like receptor pathway', 'Pathway', (118, 143))	('CDCA7', 'Gene', (25, 30))	('JAK', 'molecular_function', 'GO:0004713', ('100', '103'))	('JAK', 'Gene', (100, 103))	('cell cycle pathway', 'Pathway', (80, 98))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))	('GSEA', 'Chemical', '-', (0, 4))	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('toll like receptor pathway', 'Pathway', (186, 212))	('expression', 'MPA', (31, 41))	('P53', 'Gene', (145, 148))	('high', 'Var', (20, 24))	('CDCA7', 'Gene', '83879', (25, 30))	('cell cycle', 'biological_process', 'GO:0007049', ('80', '90'))	('P53', 'Gene', '7157', (145, 148))
168381	33648519	3b), and high CDCA7 expression predicted a poorer OS (HR = 1.125; P < 0.001).	('expression', 'MPA', (20, 30))	('poorer OS', 'CPA', (43, 52))	('CDCA7', 'Gene', '83879', (14, 19))	('CDCA7', 'Gene', (14, 19))	('high', 'Var', (9, 13))
168399	33648519	In addition, the DNA methyltransferase DNMT1 (P < 0.001), DNMT2 (P < 0.05), DNMT3 (P < 0.001), DNMT4 (P < 0.001) were also significantly associated with the CDCA7 expression level in ccRCC (Fig.	('RCC', 'Disease', (185, 188))	('associated', 'Reg', (137, 147))	('ccRCC', 'Phenotype', 'HP:0006770', (183, 188))	('DNMT3', 'Var', (76, 81))	('expression level', 'MPA', (163, 179))	('DNMT2', 'Gene', '1787', (58, 63))	('CDCA7', 'Gene', '83879', (157, 162))	('DNMT2', 'Gene', (58, 63))	('CDCA7', 'Gene', (157, 162))	('DNMT4', 'Var', (95, 100))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('RCC', 'Disease', 'MESH:C538614', (185, 188))
168428	33648519	Previous reports revealed that mutations in CDCA7 and HELLS, respectively could cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome types 3 and 4.	('HELLS', 'Gene', '3070', (54, 59))	('immunodeficiency', 'Disease', 'MESH:D007153', (86, 102))	('mutations', 'Var', (31, 40))	('immunodeficiency', 'Phenotype', 'HP:0002721', (86, 102))	('immunodeficiency', 'Disease', (86, 102))	('centromeric instability', 'Disease', (104, 127))	('facial anomalies (ICF) syndrome', 'Disease', 'MESH:C537362', (133, 164))	('CDCA7', 'Gene', '83879', (44, 49))	('CDCA7', 'Gene', (44, 49))	('HELLS', 'Gene', (54, 59))	('cause', 'Reg', (80, 85))	('facial anomalies', 'Phenotype', 'HP:0000271', (133, 149))
168460	29158829	cG250, a chimeric monoclonal antibody, has been labeled with an assortment of radionuclides (124I, 111In, 89Zr, 131I, 90Y, and 177Lu) and is the most extensively investigated CA-IX radiopharmaceutical.	('177Lu', 'Chemical', 'MESH:C000615061', (127, 132))	('CA-IX', 'Gene', '768', (175, 180))	('131I', 'Var', (112, 116))	('antibody', 'cellular_component', 'GO:0042571', ('29', '37'))	('124I', 'Chemical', 'MESH:C000614959', (93, 97))	('antibody', 'cellular_component', 'GO:0019815', ('29', '37'))	('89Zr', 'Var', (106, 110))	('111In', 'Var', (99, 104))	('radionuclides', 'Chemical', 'MESH:D011868', (78, 91))	('cG250', 'Chemical', 'MESH:C106533', (0, 5))	('131I', 'Chemical', 'MESH:C000614965', (112, 116))	('antibody', 'cellular_component', 'GO:0019814', ('29', '37'))	('cG250', 'Gene', (0, 5))	('CA-IX', 'Gene', (175, 180))	('antibody', 'molecular_function', 'GO:0003823', ('29', '37'))	('90Y', 'Var', (118, 121))	('124I', 'Var', (93, 97))
168468	29158829	In xenograft models, pharmacological inhibition of CA-IX has been shown to reduce primary tumour growth and its propensity for distant metastasis.	('primary tumour growth', 'Disease', 'MESH:D006130', (82, 103))	('reduce', 'NegReg', (75, 81))	('CA-IX', 'Gene', '768', (51, 56))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('primary tumour growth', 'Disease', (82, 103))	('pharmacological inhibition', 'Var', (21, 47))	('CA-IX', 'Gene', (51, 56))
168498	29158829	For ccRCC, the inactivation of VHL either through mutations, loss of heterozygosity or epigenetic silencing leads to constitutive HIF-1alpha activation and CA-IX expression, even in the absence of hypoxia.	('loss of heterozygosity', 'Var', (61, 83))	('HIF-1alpha', 'Gene', '3091', (130, 140))	('CA-IX', 'Gene', (156, 161))	('mutations', 'Var', (50, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (4, 9))	('constitutive', 'MPA', (117, 129))	('inactivation', 'Var', (15, 27))	('VHL', 'Disease', (31, 34))	('hypoxia', 'Disease', 'MESH:D000860', (197, 204))	('VHL', 'Disease', 'MESH:D006623', (31, 34))	('epigenetic silencing', 'Var', (87, 107))	('expression', 'MPA', (162, 172))	('CA-IX', 'Gene', '768', (156, 161))	('HIF-1alpha', 'Gene', (130, 140))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('activation', 'PosReg', (141, 151))	('RCC', 'Disease', (6, 9))	('hypoxia', 'Disease', (197, 204))
168511	29158829	Monoclonal antibodies (mAbs) have had a significant impact in cancer management as therapeutics.	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', (62, 68))	('Monoclonal', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))
168518	29158829	In a phase I study, 16 preoperative patients suspected of having RCC received an intravenous dose of 131I-mAbG250 a week prior to nephrectomy.	('131I-mAbG250', 'Var', (101, 113))	('patients', 'Species', '9606', (36, 44))	('131I', 'Chemical', 'MESH:C000614965', (101, 105))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
168528	29158829	Overall, fractionated RIT with 131I-cG250 was unable to alleviate myelotoxicity or improve clinical responses for metastatic RCC patients.	('131I-cG250', 'Chemical', '-', (31, 41))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('patients', 'Species', '9606', (129, 137))	('RCC', 'Disease', (125, 128))	('myelotoxicity', 'Disease', 'MESH:D001855', (66, 79))	('131I-cG250', 'Var', (31, 41))	('clinical responses', 'CPA', (91, 109))	('myelotoxicity', 'Disease', (66, 79))
168532	29158829	Patients that did not show grade 4 hematological toxicity or develop HACA (n = 19) received a second cycle of low dose diagnostic infusion and high dose therapeutic infusion of 131I-cG250 (1110 MBq/m2 to 1665 MBq/m2).	('hematological toxicity', 'Disease', 'MESH:D006402', (35, 57))	('hematological toxicity', 'Disease', (35, 57))	('Patients', 'Species', '9606', (0, 8))	('131I-cG250', 'Chemical', '-', (177, 187))	('131I-cG250', 'Var', (177, 187))
168539	29158829	The cG250 conjugates radiolabeled with residualizing radionuclides, 88Y and 177Lu, had significantly higher uptake than the cG250 conjugates labeled with 125I or 186Re.	('uptake', 'MPA', (108, 114))	('higher', 'PosReg', (101, 107))	('cG250', 'Chemical', 'MESH:C106533', (4, 9))	('177Lu', 'Chemical', 'MESH:C000615061', (76, 81))	('177Lu', 'Var', (76, 81))	('125I', 'Chemical', 'MESH:C000614960', (154, 158))	('cG250', 'Gene', (4, 9))	('cG250', 'Chemical', 'MESH:C106533', (124, 129))	('uptake', 'biological_process', 'GO:0098657', ('108', '114'))	('radionuclides', 'Chemical', 'MESH:D011868', (53, 66))	('uptake', 'biological_process', 'GO:0098739', ('108', '114'))	('88Y', 'Var', (68, 71))
168540	29158829	At 7 d p.i., tumour uptake for 177Lu-SCN-Bz-DTPA-cG250 (DTPA: diethylenetriaminepentaacetic acid), 88Y-SCN-Bz-DTPA-cG250, 125I-cG250 and 186Re-MAG3-cG250 (MAG3: mercaptoacetyltriglycine) were 87.3 +- 14.0 %ID/g, 70.9 +- 8.4 %ID/g, 9.1 +- 2.0 %ID/g, and 7.9 +- 2.0 %ID/g, respectively.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('DTPA', 'Chemical', 'MESH:D004369', (44, 48))	('SCN-Bz-DTPA', 'Chemical', 'MESH:C054343', (37, 48))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('125I', 'Chemical', 'MESH:C000614960', (122, 126))	('tumour', 'Disease', (13, 19))	('cG250', 'Chemical', 'MESH:C106533', (49, 54))	('186Re-MAG3-cG250', 'Var', (137, 153))	('MAG3', 'Chemical', '-', (155, 159))	('125I-cG250', 'Var', (122, 132))	('177Lu-SCN-Bz-DTPA', 'Chemical', '-', (31, 48))	('cG250', 'Chemical', 'MESH:C106533', (127, 132))	('cG250', 'Chemical', 'MESH:C106533', (148, 153))	('uptake', 'biological_process', 'GO:0098657', ('20', '26'))	('88Y-SCN-Bz-DTPA-cG250', 'Var', (99, 120))	('DTPA', 'Chemical', 'MESH:D004369', (110, 114))	('MAG3', 'Chemical', '-', (143, 147))	('cG250', 'Chemical', 'MESH:C106533', (115, 120))	('SCN-Bz-DTPA', 'Chemical', 'MESH:C054343', (103, 114))	('DTPA', 'Chemical', 'MESH:D004369', (56, 60))	('uptake', 'biological_process', 'GO:0098739', ('20', '26'))	('mercaptoacetyltriglycine', 'Chemical', '-', (161, 185))	('diethylenetriaminepentaacetic acid', 'Chemical', 'MESH:D004369', (62, 96))
168541	29158829	In RIT experiments conducted at MTD, 177Lu-SCN-Bz-DTPA-cG250 was able to deliver a calculated absorbed tumour dose of 807 Gy, while the other radioimmunoconjugates delivered between 76-104 Gy.	('MTD', 'Gene', '4493', (32, 35))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('177Lu-SCN-Bz-DTPA', 'Chemical', '-', (37, 54))	('MTD', 'Gene', (32, 35))	('cG250', 'Chemical', 'MESH:C106533', (55, 60))	('tumour', 'Disease', (103, 109))	('177Lu-SCN-Bz-DTPA-cG250', 'Var', (37, 60))
168543	29158829	An added advantage of 177Lu as a therapeutic radionuclide is the sparing of thyroid tissue.	('177Lu', 'Var', (22, 27))	('177Lu', 'Chemical', 'MESH:C000615061', (22, 27))	('radionuclide', 'Chemical', 'MESH:D011868', (45, 57))	('sparing', 'CPA', (65, 72))
168545	29158829	Patients treated with 131I-cG250 were given potassium iodine and potassium perchlorate to reduce uptake of released radioiodine.	('potassium perchlorate', 'Chemical', 'MESH:C009006', (65, 86))	('potassium iodine', 'Chemical', '-', (44, 60))	('131I-cG250', 'Chemical', '-', (22, 32))	('uptake of released radioiodine', 'MPA', (97, 127))	('Patients', 'Species', '9606', (0, 8))	('uptake', 'biological_process', 'GO:0098657', ('97', '103'))	('reduce', 'NegReg', (90, 96))	('uptake', 'biological_process', 'GO:0098739', ('97', '103'))	('radioiodine', 'Chemical', 'MESH:C000614965', (116, 127))	('131I-cG250', 'Var', (22, 32))
168560	29158829	While 177Lu-cG250 RIT can stabilize progressive disease, how it will be integrated into clinical practice remains to be seen.	('177Lu-cG250 RIT', 'Var', (6, 21))	('progressive disease', 'Disease', (36, 55))	('177Lu', 'Chemical', 'MESH:C000615061', (6, 11))	('cG250', 'Chemical', 'MESH:C106533', (12, 17))
168563	29158829	131I-G250 and 131I-cG250, as part of the RIT study protocols, were used for whole body planar scintigraphy to monitor treatment response.	('131I-cG250', 'Chemical', '-', (14, 24))	('131I-cG250', 'Var', (14, 24))	('131I-G250', 'Var', (0, 9))	('131I-G250', 'Chemical', '-', (0, 9))
168574	29158829	A phase III study was performed comparing the efficacy of 124I-cG250 PET with contrast enhanced CT (CECT) for the detection of ccRCC in pre-treatment setting (Figure 2).	('124I-cG250', 'Chemical', '-', (58, 68))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('RCC', 'Disease', (129, 132))	('124I-cG250 PET', 'Var', (58, 72))	('pre', 'molecular_function', 'GO:0003904', ('136', '139'))	('CECT', 'Chemical', '-', (100, 104))
168578	29158829	124I-cG250 had better average sensitivity (86% vs. 76%) and selectivity (76% vs. 47%) than CECT for differentiating ccRCC from non-ccRCC.	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('RCC', 'Disease', (118, 121))	('124I-cG250', 'Chemical', '-', (0, 10))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('CECT', 'Chemical', '-', (91, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('124I-cG250', 'Var', (0, 10))
168579	29158829	Moreover, 124I-cG250 had PPV and NPV of 94% and 69%, compared to 80% and 41% for CECT.	('CECT', 'Chemical', '-', (81, 85))	('124I-cG250', 'Chemical', '-', (10, 20))	('PPV', 'MPA', (25, 28))	('124I-cG250', 'Var', (10, 20))
168597	29158829	At 7 d p.i., 111In-DOTA-cG250 had tumour uptake of 26.4 +- 5.7 %ID/g, which corresponded to tumour-to-blood (T:B) and tumour-to-muscle (T:M) ratios of 6.6 and 69.	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('tumour', 'Disease', (118, 124))	('uptake', 'biological_process', 'GO:0098739', ('41', '47'))	('tumour', 'Disease', (92, 98))	('uptake', 'biological_process', 'GO:0098657', ('41', '47'))	('tumour-to-muscle', 'Disease', (118, 134))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumour-to-blood', 'Disease', 'MESH:D009369', (92, 107))	('tumour-to-muscle', 'Disease', 'MESH:D009217', (118, 134))	('tumour', 'Disease', (34, 40))	('111In-DOTA-cG250', 'Var', (13, 29))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('111In-DOTA-cG250', 'Chemical', '-', (13, 29))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('tumour-to-blood', 'Disease', (92, 107))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
168598	29158829	111In-DOTA-F(ab')2-cG250 had lower tumour uptake at 9.3 +- 2.1 %ID/g at 24 h p.i., and T:B and T:M ratios of 4.6 and 8.9.	('cG250', 'Chemical', 'MESH:C106533', (19, 24))	('DOTA', 'Chemical', 'MESH:C071349', (6, 10))	('uptake', 'biological_process', 'GO:0098657', ('42', '48'))	('uptake', 'biological_process', 'GO:0098739', ('42', '48'))	('2-cG250', 'Var', (17, 24))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('lower', 'NegReg', (29, 34))	('tumour', 'Disease', (35, 41))
168600	29158829	It was concluded that imaging with cG250-Fab or cG250-F(ab')2 would be less sensitive and accurate than intact cG250.	('cG250', 'Chemical', 'MESH:C106533', (35, 40))	('cG250-F', 'Var', (48, 55))	('cG250', 'Chemical', 'MESH:C106533', (48, 53))	('Fab', 'Gene', '2187', (41, 44))	('Fab', 'Gene', (41, 44))	('cG250', 'Chemical', 'MESH:C106533', (111, 116))
168605	29158829	According to the authors, specific accumulation of 89Zr-cG250-F(ab')2 was achieved by 4 h p.i., compared to 24 h p.i.	('accumulation', 'PosReg', (35, 47))	('89Zr-cG250-F', 'Var', (51, 63))	('cG250', 'Chemical', 'MESH:C106533', (56, 61))
168613	29158829	125I-M75 showed selective accumulation in both HT-29 human colorectal cancer (15.3 +- 3.6 %ID/g at 48 h p.i.)	('accumulation', 'PosReg', (26, 38))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('125I-M75', 'Var', (0, 8))	('HT-29', 'CellLine', 'CVCL:0320', (47, 52))	('colorectal cancer', 'Disease', (59, 76))	('human', 'Species', '9606', (53, 58))	('125I', 'Chemical', 'MESH:C000614960', (0, 4))	('colorectal cancer', 'Disease', 'MESH:D015179', (59, 76))
168620	29158829	177Lu-SIP(A3) had low uptake in tumour (2.41 +- 0.19 %ID/g), but generated decent contrast for T:B ratio (16.7).	('177Lu-SIP', 'Var', (0, 9))	('uptake', 'MPA', (22, 28))	('tumour', 'Disease', (32, 38))	('uptake', 'biological_process', 'GO:0098739', ('22', '28'))	('uptake', 'biological_process', 'GO:0098657', ('22', '28'))	('T:B ratio', 'MPA', (95, 104))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
168628	29158829	Although 125I-CaIX-P1 showed preferential uptake in CA-IX-expressing cell lines in vitro, binding affinity was not determined.	('125I', 'Chemical', 'MESH:C000614960', (9, 13))	('binding', 'molecular_function', 'GO:0005488', ('90', '97'))	('CA-IX', 'Gene', '768', (52, 57))	('uptake', 'biological_process', 'GO:0098657', ('42', '48'))	('uptake', 'biological_process', 'GO:0098739', ('42', '48'))	('125I-CaIX-P1', 'Var', (9, 21))	('preferential', 'PosReg', (29, 41))	('uptake', 'MPA', (42, 48))	('CA-IX', 'Gene', (52, 57))	('125I-CaIX-P1', 'Gene', (9, 21))
168629	29158829	Biodistribution studies were performed in SK-RC-52 xenograft mice, with uptake of 131I-CaIX-P1 in tumour being lower than blood at all evaluated time points.	('mice', 'Species', '10090', (61, 65))	('uptake', 'biological_process', 'GO:0098739', ('72', '78'))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('uptake', 'biological_process', 'GO:0098657', ('72', '78'))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('131I-CaIX-P1', 'Var', (82, 94))	('tumour', 'Disease', (98, 104))	('lower', 'NegReg', (111, 116))	('uptake', 'MPA', (72, 78))	('131I', 'Chemical', 'MESH:C000614965', (82, 86))
168636	29158829	125I-PGLR-P1 showed reduced binding to CA-II and CA-XII in vitro, but affinity remained at micromolar range.	('-P1', 'Chemical', '-', (9, 12))	('reduced', 'NegReg', (20, 27))	('CA-XII', 'Gene', '771', (49, 55))	('binding', 'Interaction', (28, 35))	('125I-PGLR-P1', 'Var', (0, 12))	('125I', 'Chemical', 'MESH:C000614960', (0, 4))	('binding', 'molecular_function', 'GO:0005488', ('28', '35'))	('CA-II', 'Gene', '760', (39, 44))	('CA-II', 'Gene', (39, 44))	('CA-XII', 'Gene', (49, 55))
168652	29158829	At physiological pH, the free carboxylate group of 18F-VM4-037 is deprotonated, introducing a negative charge that renders the compound membrane-impermeable.	('membrane', 'cellular_component', 'GO:0016020', ('136', '144'))	('18F-VM4-037', 'Var', (51, 62))	('carboxylate', 'Chemical', '-', (30, 41))	('introducing', 'Reg', (80, 91))	('VM4-037', 'Chemical', 'MESH:C000598170', (55, 62))	('negative charge', 'MPA', (94, 109))
168663	29158829	18F-VM4-037 showed high accumulation in the gastrointestinal tract and in kidneys, but was unexpectedly unable to detect CA-IX expression in either tumour model.	('tumour', 'Disease', (148, 154))	('18F-VM4-037', 'Var', (0, 11))	('accumulation', 'PosReg', (24, 36))	('VM4-037', 'Chemical', 'MESH:C000598170', (4, 11))	('CA-IX', 'Gene', '768', (121, 126))	('gastrointestinal tract', 'Disease', (44, 66))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (44, 66))	('tumour', 'Disease', 'MESH:D009369', (148, 154))	('CA-IX', 'Gene', (121, 126))
168673	29158829	The high uptake of 18F-U-104 in blood (13.92 +- 3.07 %ID/g) suggested that it may have bound intracellular CA-I and/or CA-II expressed in erythrocytes.	('CA-I', 'Gene', '759', (119, 123))	('18F-U-104', 'Var', (19, 28))	('bound', 'Interaction', (87, 92))	('CA-II', 'Gene', (119, 124))	('CA-II', 'Gene', '760', (119, 124))	('CA-I', 'Gene', (119, 123))	('18F-U-104', 'Chemical', '-', (19, 28))	('uptake', 'biological_process', 'GO:0098739', ('9', '15'))	('intracellular', 'cellular_component', 'GO:0005622', ('93', '106'))	('CA-I', 'Gene', '759', (107, 111))	('uptake', 'biological_process', 'GO:0098657', ('9', '15'))	('CA-I', 'Gene', (107, 111))	('uptake', 'MPA', (9, 15))
168683	29158829	The Ki values for CA-IX were 35.7 nM and 8.5 nM for 19F-AmBF3-(AEBS)3 and 19F-AmBF3-(ABS)3, respectively.	('CA-IX', 'Gene', '768', (18, 23))	('-AmBF3', 'Chemical', '-', (77, 83))	('ABS', 'Chemical', '-', (85, 88))	('CA-IX', 'Gene', (18, 23))	('-AmBF3', 'Chemical', '-', (55, 61))	('19F-AmBF3-(AEBS)3', 'Chemical', '-', (52, 69))	('19F-AmBF3-', 'Var', (52, 62))
168697	29158829	99mTc-3d had 5-fold higher uptake for HeLa cells cultured under hypoxic conditions than cells cultured under normoxic conditions.	('hypoxic conditions', 'Disease', (64, 82))	('hypoxic conditions', 'Disease', 'MESH:D009135', (64, 82))	('higher', 'PosReg', (20, 26))	('uptake', 'biological_process', 'GO:0098657', ('27', '33'))	('uptake', 'biological_process', 'GO:0098739', ('27', '33'))	('99mTc-3d', 'Var', (0, 8))	('HeLa', 'CellLine', 'CVCL:0030', (38, 42))	('uptake', 'MPA', (27, 33))
168710	29158829	The monomeric 68Ga-DOTA-AEBSA had lowest tumour uptake but also the highest contrast (T:M ratio of 5.02 +- 0.22).	('AEBS', 'Chemical', 'MESH:C097944', (24, 28))	('contrast', 'MPA', (76, 84))	('uptake', 'biological_process', 'GO:0098739', ('48', '54'))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('uptake', 'biological_process', 'GO:0098657', ('48', '54'))	('lowest', 'NegReg', (34, 40))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('68Ga-DOTA-AEBSA', 'Var', (14, 29))	('DOTA', 'Chemical', 'MESH:C071349', (19, 23))	('tumour', 'Disease', (41, 47))
168726	29158829	With 64Cu-XYIMSR-06, maximal tumour uptake was observed at 4 h p.i.	('tumour', 'Disease', (29, 35))	('uptake', 'biological_process', 'GO:0098657', ('36', '42'))	('uptake', 'biological_process', 'GO:0098739', ('36', '42'))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('64Cu-XYIMSR-06', 'Var', (5, 19))
168744	29158829	For the 99mTc-labeled derivatives, tumour uptake ranged from 4.3 +- 0.7 %ID/g to 16.3 +- 0.9 %ID/g at 4 h p.i., with 99mTc-(HE)3-ZCAIX:2 having the highest absolute uptake and contrasts (T:B and T:M ratios of 44 +- 7 and 109 +- 11, respectively).	('uptake', 'biological_process', 'GO:0098657', ('165', '171'))	('HE', 'Chemical', 'MESH:D006371', (124, 126))	('uptake', 'biological_process', 'GO:0098739', ('165', '171'))	('uptake', 'biological_process', 'GO:0098657', ('42', '48'))	('uptake', 'biological_process', 'GO:0098739', ('42', '48'))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('99mTc-(HE)3-ZCAIX:2', 'Var', (117, 136))	('tumour', 'Disease', (35, 41))
168746	29158829	While 125I-ZCAIX:2 demonstrated the highest tumour uptake (19 +- 2 %ID/g) and contrast (T:B and T:M ratios of 21 +- 5 and 129 +- 42, respectively), tumour uptake was lower than kidney retention.	('tumour', 'Disease', (148, 154))	('retention', 'biological_process', 'GO:0051235', ('184', '193'))	('kidney retention', 'Disease', 'MESH:D016055', (177, 193))	('125I-ZCAIX:2', 'Var', (6, 18))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('uptake', 'biological_process', 'GO:0098739', ('51', '57'))	('tumour', 'Disease', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('uptake', 'biological_process', 'GO:0098657', ('51', '57'))	('kidney retention', 'Disease', (177, 193))	('lower', 'NegReg', (166, 171))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('uptake', 'biological_process', 'GO:0098739', ('155', '161'))	('uptake', 'biological_process', 'GO:0098657', ('155', '161'))	('125I', 'Chemical', 'MESH:C000614960', (6, 10))	('tumour', 'Disease', 'MESH:D009369', (148, 154))
168760	29158829	Indeed 177Lu-cG250 RIT has been proposed for use in adjuvant setting with vascular endothelial growth factor receptor tyrosine kinase inhibitors, assuming that myelotoxicity associated with RIT can be safely mitigated or controlled.	('177Lu-cG250', 'Var', (7, 18))	('myelotoxicity', 'Disease', (160, 173))	('tyrosine', 'Chemical', 'MESH:D014443', (118, 126))	('cG250', 'Chemical', 'MESH:C106533', (13, 18))	('myelotoxicity', 'Disease', 'MESH:D001855', (160, 173))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('74', '108'))	('177Lu', 'Chemical', 'MESH:C000615061', (7, 12))
168766	33539322	In vitro experiment indicated that ENMA is downregulated in ccRCC, and its knockdown could promote proliferation in two cancer cell lines (OSRC-2 and SW839).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('downregulated', 'NegReg', (43, 56))	('promote', 'PosReg', (91, 98))	('SW839', 'CellLine', 'CVCL:3604', (150, 155))	('ccRCC', 'Disease', (60, 65))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('knockdown', 'Var', (75, 84))	('ENMA', 'Protein', (35, 39))	('proliferation', 'CPA', (99, 112))
168829	33539322	In hepatocellular carcinoma, miR-515-5p inhibits the invasion and migration of cancer cells by suppressing the IL6/JAK/STAT3 pathway.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('suppressing', 'NegReg', (95, 106))	('miR-515-5p', 'Chemical', '-', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('IL6', 'molecular_function', 'GO:0005138', ('111', '114'))	('STAT3', 'Gene', '6774', (119, 124))	('JAK', 'molecular_function', 'GO:0004713', ('115', '118'))	('inhibits', 'NegReg', (40, 48))	('miR-515-5p', 'Var', (29, 39))	('STAT3', 'Gene', (119, 124))	('IL6', 'Gene', '3569', (111, 114))	('IL6', 'Gene', (111, 114))	('cancer', 'Disease', (79, 85))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))
168870	30631037	Herein, we report that deficiency in the E3 ligase subunit cullin 5 (CUL5) promotes chromosomal instability and is an independent negative prognostic factor in ccRCC.	('deficiency', 'Var', (23, 33))	('chromosomal instability', 'Phenotype', 'HP:0040012', (84, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (160, 165))	('promotes', 'PosReg', (75, 83))	('ccRCC', 'Disease', (160, 165))	('chromosomal instability', 'MPA', (84, 107))	('CUL5', 'Gene', (69, 73))	('CUL5', 'Gene', '8065', (69, 73))
168875	30631037	A re-analysis of the TCGA ccRCC cohort showed that a reduced CUL5 gene expression or CUL5 deletion were associated with a significantly worse overall patient survival.	('expression', 'MPA', (71, 81))	('deletion', 'Var', (90, 98))	('worse', 'NegReg', (136, 141))	('CUL5', 'Gene', (61, 65))	('patient', 'Species', '9606', (150, 157))	('CUL5', 'Gene', (85, 89))	('ccRCC', 'Phenotype', 'HP:0006770', (26, 31))	('CUL5', 'Gene', '8065', (61, 65))	('reduced', 'NegReg', (53, 60))	('CUL5', 'Gene', '8065', (85, 89))	('gene expression', 'biological_process', 'GO:0010467', ('66', '81'))
168880	30631037	Whole chromosome copy number changes (aneuploidy) are also frequent findings in ccRCC, which, together with structural changes and single-nucleotide variants contribute to the extensive intratumoral genetic heterogeneity characteristic of ccRCC.	('ccRCC', 'Disease', (80, 85))	('ccRCC', 'Phenotype', 'HP:0006770', (239, 244))	('chromosome', 'cellular_component', 'GO:0005694', ('6', '16'))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('ccRCC', 'Disease', (239, 244))	('aneuploidy', 'Disease', 'MESH:D000782', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('aneuploidy', 'Disease', (38, 48))	('Whole chromosome copy number changes', 'Var', (0, 36))
168882	30631037	In ccRCC, the inactivation of the VHL tumor suppressor gene, which occurs in the large majority of patients, has been shown to lead to defective mitoses and also to interfere with DNA double-strand break (DSB) repair.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('defective', 'NegReg', (135, 144))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('38', '54'))	('lead', 'Reg', (127, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('inactivation', 'Var', (14, 26))	('interfere', 'NegReg', (165, 174))	('VHL tumor', 'Disease', (34, 43))	('patients', 'Species', '9606', (99, 107))	('ccRCC', 'Disease', (3, 8))	('DNA', 'cellular_component', 'GO:0005574', ('180', '183'))	('DNA double-strand break', 'MPA', (180, 203))	('mitoses', 'CPA', (145, 152))	('tumor suppressor', 'biological_process', 'GO:0051726', ('38', '54'))	('VHL tumor', 'Disease', 'MESH:D006623', (34, 43))
168891	30631037	Our results show that CUL5 is critically involved in the regulation of centriole duplication and DNA damage repair, and that loss of expression is a negative prognostic factor in ccRCC patients.	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('CUL5', 'Gene', (22, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (179, 184))	('loss of expression', 'Var', (125, 143))	('CUL5', 'Gene', '8065', (22, 26))	('regulation', 'biological_process', 'GO:0065007', ('57', '67'))	('centriole duplication', 'biological_process', 'GO:0007099', ('71', '92'))	('ccRCC', 'Disease', (179, 184))	('patients', 'Species', '9606', (185, 193))	('negative', 'NegReg', (149, 157))	('centriole', 'cellular_component', 'GO:0005814', ('71', '80'))
168896	30631037	We found that knock-down of CUL5 leads to an overduplication of centrioles in a very high percentage of cells (56.9%, p <= 0.001; Fig.	('centrioles', 'MPA', (64, 74))	('CUL5', 'Gene', '8065', (28, 32))	('CUL5', 'Gene', (28, 32))	('knock-down', 'Var', (14, 24))	('overduplication', 'MPA', (45, 60))
168898	30631037	Following depletion of CUL5, we observed several centriole overduplication defects including centriole multiplication and daughter-daughter pairs (Fig.	('centriole', 'cellular_component', 'GO:0005814', ('49', '58'))	('overduplication defects', 'Disease', 'MESH:D005128', (59, 82))	('overduplication defects', 'Disease', (59, 82))	('CUL5', 'Gene', '8065', (23, 27))	('centriole', 'cellular_component', 'GO:0005814', ('93', '102'))	('centriole multiplication', 'CPA', (93, 117))	('centriole', 'CPA', (49, 58))	('depletion', 'Var', (10, 19))	('daughter-daughter pairs', 'CPA', (122, 145))	('CUL5', 'Gene', (23, 27))
168902	30631037	Knock-down of CUL5 by shRNA increased the number of cells with centriole overduplication to 21.5% as compared to 4% with the shRNA control vector (p <= 0.001; Suppl.	('increased', 'PosReg', (28, 37))	('centriole', 'cellular_component', 'GO:0005814', ('63', '72'))	('centriole overduplication', 'MPA', (63, 88))	('CUL5', 'Gene', (14, 18))	('Knock-down', 'Var', (0, 10))	('CUL5', 'Gene', '8065', (14, 18))
168908	30631037	When we performed an immunofluorescence microscopic analysis of U-2 OS/centrin-GFP cells for gamma-tubulin after depletion of CUL5 by siRNA, we found a sixfold increase in the number of gamma-tubulin dots per cell (not shown) underscoring that supernumerary centrioles induced by knock-down of CUL5 undergo maturation and can hence potentially function as microtubule-organizing centers in cells.	('supernumerary centrioles', 'CPA', (244, 268))	('CUL5', 'Gene', (294, 298))	('maturation', 'CPA', (307, 317))	('microtubule', 'cellular_component', 'GO:0005874', ('356', '367'))	('CUL5', 'Gene', '8065', (294, 298))	('U-2', 'Gene', '26853', (64, 67))	('CUL5', 'Gene', (126, 130))	('increase', 'PosReg', (160, 168))	('CUL5', 'Gene', '8065', (126, 130))	('U-2', 'Gene', (64, 67))	('undergo', 'Reg', (299, 306))	('knock-down', 'Var', (280, 290))
168911	30631037	Taken together, these results suggest that CUL5 depletion results in an increase in supernumerary centrioles through genuine disruption of the centriole duplication cycle and that a significant fraction of these overduplicated centrioles are capable of recruiting gamma-tubulin, indicating that they are functional.	('CUL5', 'Gene', (43, 47))	('centriole duplication', 'biological_process', 'GO:0007099', ('143', '164'))	('increase', 'PosReg', (72, 80))	('disruption', 'NegReg', (125, 135))	('recruiting', 'CPA', (253, 263))	('CUL5', 'Gene', '8065', (43, 47))	('centriole duplication cycle', 'MPA', (143, 170))	('supernumerary centrioles', 'CPA', (84, 108))	('gamma-tubulin', 'Protein', (264, 277))	('centriole', 'cellular_component', 'GO:0005814', ('143', '152'))	('depletion', 'Var', (48, 57))
168912	30631037	We next determined the consequences of CUL5 knock-down on mitotic fidelity.	('CUL5', 'Gene', (39, 43))	('CUL5', 'Gene', '8065', (39, 43))	('knock-down', 'Var', (44, 54))
168913	30631037	CUL5 depletion significantly increased the percentage of cells exhibiting abnormal mitosis (multipolar and pseudo-bipolar combined) from 19% in control cells to 38% in CUL5 siRNA-transfected cells (p <= 0.001).	('depletion', 'Var', (5, 14))	('CUL5', 'Gene', (0, 4))	('CUL5', 'Gene', (168, 172))	('abnormal mitosis', 'Disease', (74, 90))	('increased', 'PosReg', (29, 38))	('mitosis', 'biological_process', 'GO:0000278', ('83', '90'))	('CUL5', 'Gene', '8065', (0, 4))	('abnormal mitosis', 'Disease', 'MESH:D000014', (74, 90))	('CUL5', 'Gene', '8065', (168, 172))
168915	30631037	These results further underscore that supernumerary centrioles induced by CUL5 depletion are functional and can promote abnormal mitoses, thereby potentially promoting chromosomal instability in daughter cells.	('CUL5', 'Gene', (74, 78))	('CUL5', 'Gene', '8065', (74, 78))	('promote', 'PosReg', (112, 119))	('chromosomal instability', 'Phenotype', 'HP:0040012', (168, 191))	('depletion', 'Var', (79, 88))	('chromosomal instability', 'CPA', (168, 191))	('abnormal mitoses', 'CPA', (120, 136))	('promoting', 'PosReg', (158, 167))
168919	30631037	In particular, there was a significant increase of cells containing micronuclei from 3.3% in controls to 12.2% in cells transfected with DN-CUL5 (p <= 0.0001; Fig.	('increase', 'PosReg', (39, 47))	('DN-CUL5', 'Gene', '8065', (137, 144))	('DN-CUL5', 'Gene', (137, 144))	('micronuclei', 'Var', (68, 79))
168920	30631037	Taken together, our results show that depletion of CUL5 rapidly causes mitotic defects and chromosome segregation errors but also alterations suggestive of additional structural chromosomal damage.	('mitotic defects', 'Disease', (71, 86))	('mitotic defects', 'Disease', 'MESH:C536987', (71, 86))	('chromosome segregation', 'biological_process', 'GO:0007059', ('91', '113'))	('causes', 'Reg', (64, 70))	('chromosomal damage', 'Disease', 'MESH:D004194', (178, 196))	('chromosomal damage', 'Disease', (178, 196))	('CUL5', 'Gene', (51, 55))	('depletion', 'Var', (38, 47))	('chromosome segregation errors', 'CPA', (91, 120))	('chromosome', 'cellular_component', 'GO:0005694', ('91', '101'))	('CUL5', 'Gene', '8065', (51, 55))
168921	30631037	Having shown that CUL5 depletion leads to a significant increase of cells with micronuclei, we next explored a possible role of CUL5 in the cellular response to DNA damage.	('cells with micronuclei', 'CPA', (68, 90))	('increase', 'PosReg', (56, 64))	('depletion', 'Var', (23, 32))	('CUL5', 'Gene', (18, 22))	('CUL5', 'Gene', (128, 132))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('CUL5', 'Gene', '8065', (18, 22))	('CUL5', 'Gene', '8065', (128, 132))
168931	30631037	We found an increase of the tail moment in CUL5 siRNA-transfected cells compared to controls in the absence of IR, suggesting that CUL5 depletion by itself can induce DNA breakage.	('CUL5', 'Gene', (43, 47))	('tail moment', 'MPA', (28, 39))	('CUL5', 'Gene', '8065', (131, 135))	('depletion', 'Var', (136, 145))	('CUL5', 'Gene', '8065', (43, 47))	('increase', 'PosReg', (12, 20))	('DNA', 'cellular_component', 'GO:0005574', ('167', '170'))	('induce', 'Reg', (160, 166))	('CUL5', 'Gene', (131, 135))	('DNA breakage', 'CPA', (167, 179))
168939	30631037	ACHN cells have also been tested for mutations in CUL5 and were found to be negative except for a silent mutation in exon 3.	('mutations', 'Var', (37, 46))	('CUL5', 'Gene', (50, 54))	('CUL5', 'Gene', '8065', (50, 54))
168944	30631037	Patients harboring tumors with low expression levels of CUL5 displayed a shorter survival (a median of 5.2 years) compared to high CUL5 expressing tumors (a median of 7.5 years) (p = 0.003, Fig.	('CUL5', 'Gene', '8065', (131, 135))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('expression', 'MPA', (35, 45))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('shorter', 'NegReg', (73, 80))	('Patients', 'Species', '9606', (0, 8))	('survival', 'MPA', (81, 89))	('CUL5', 'Gene', (131, 135))	('CUL5', 'Gene', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('CUL5', 'Gene', '8065', (56, 60))	('low', 'Var', (31, 34))
168945	30631037	Patients with chromosomal deletions in the CUL5 locus showed a significantly impaired cancer-specific survival (median of 2.7 years compared to 6.5 years, p = 0.0012, Fig.	('CUL5', 'Gene', (43, 47))	('impaired cancer', 'Disease', 'MESH:D009422', (77, 92))	('CUL5', 'Gene', '8065', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('impaired cancer', 'Disease', (77, 92))	('Patients', 'Species', '9606', (0, 8))	('chromosomal deletions', 'Var', (14, 35))
168948	30631037	Advanced age (higher than median), high grade, metastasis at diagnosis (M+), high tumor stage and low CUL5 expression were independently associated with poor survival in ccRCC patients by being present in the final step of the multivariate Cox model.	('CUL5', 'Gene', (102, 106))	('ccRCC', 'Disease', (170, 175))	('patients', 'Species', '9606', (176, 184))	('poor', 'NegReg', (153, 157))	('Cox', 'Gene', '1351', (240, 243))	('CUL5', 'Gene', '8065', (102, 106))	('low', 'NegReg', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (170, 175))	('high grade', 'Var', (35, 45))	('Cox', 'Gene', (240, 243))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
168954	30631037	In the present report, we show that a reduced CUL5 gene expression or CUL5 deletion is associated with significantly impaired overall survival in ccRCC patients and with more rapid tumor progression, respectively.	('CUL5', 'Gene', '8065', (70, 74))	('CUL5', 'Gene', '8065', (46, 50))	('tumor', 'Disease', (181, 186))	('gene expression', 'biological_process', 'GO:0010467', ('51', '66'))	('reduced', 'NegReg', (38, 45))	('deletion', 'Var', (75, 83))	('CUL5', 'Gene', (70, 74))	('expression', 'MPA', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('ccRCC', 'Disease', (146, 151))	('overall survival', 'MPA', (126, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('CUL5', 'Gene', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('patients', 'Species', '9606', (152, 160))	('impaired', 'NegReg', (117, 125))
168956	30631037	Mechanistically, we show that loss of CUL5 can rapidly disrupt mitotic fidelity and induce structural chromosomal damage, very likely with an attenuation of DNA DSB repair as a strong contributing factor.	('chromosomal damage', 'Disease', 'MESH:D004194', (102, 120))	('chromosomal damage', 'Disease', (102, 120))	('CUL5', 'Gene', (38, 42))	('disrupt', 'NegReg', (55, 62))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('mitotic fidelity', 'CPA', (63, 79))	('CUL5', 'Gene', '8065', (38, 42))	('induce', 'Reg', (84, 90))	('loss', 'Var', (30, 34))
168958	30631037	Chromosome 11q loss has not been found to represent a hotspot for somatic copy number alterations in the TRACERx cohort and our findings showing a CUL5 deletion in approximately 10% of ccRCC patients are in line with this finding.	('deletion', 'Var', (152, 160))	('patients', 'Species', '9606', (191, 199))	('CUL5', 'Gene', (147, 151))	('ccRCC', 'Phenotype', 'HP:0006770', (185, 190))	('ccRCC', 'Disease', (185, 190))	('CUL5', 'Gene', '8065', (147, 151))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))
168962	30631037	It is hence possible that downregulation or loss of CUL5 in ccRCC may further fuel neo-angiogenesis, which plays a central role in ccRCC driven by VHL loss, thus promoting tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('VHL loss', 'Disease', 'MESH:D006623', (147, 155))	('VHL loss', 'Disease', (147, 155))	('promoting', 'PosReg', (162, 171))	('downregulation', 'NegReg', (26, 40))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('CUL5', 'Gene', (52, 56))	('neo-angiogenesis', 'CPA', (83, 99))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('loss', 'Var', (44, 48))	('CUL5', 'Gene', '8065', (52, 56))	('fuel', 'PosReg', (78, 82))	('ccRCC', 'Disease', (131, 136))	('angiogenesis', 'biological_process', 'GO:0001525', ('87', '99'))
168978	30631037	shRNA vectors for CUL5 (TR313638) were obtained from OriGene Technologies, Inc. (Rockville, MD, USA).	('CUL5', 'Gene', '8065', (18, 22))	('CUL5', 'Gene', (18, 22))	('TR313638', 'Var', (24, 32))
169022	30934624	Genomic profiling on paired epithelial and sarcomatoid areas of sRCC by next-generation sequencing confirmed different driver mutations between sRCC and ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('RCC', 'Disease', (155, 158))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('sarcomatoid', 'Disease', 'MESH:C538614', (43, 54))	('RCC', 'Disease', 'MESH:C538614', (155, 158))	('sarcomatoid', 'Disease', (43, 54))	('mutations', 'Var', (126, 135))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('RCC', 'Disease', (65, 68))
169025	30934624	Indeed, the authors found fewer deletions at 3p21-25, a lower rate of two-hit loss of VHL and PBRM1, but more mutations in TP53, PTEN, and RELN.	('PBRM1', 'Gene', '55193', (94, 99))	('deletions', 'Var', (32, 41))	('mutations', 'Var', (110, 119))	('VHL', 'Disease', (86, 89))	('VHL', 'Disease', 'MESH:D006623', (86, 89))	('PTEN', 'Gene', (129, 133))	('lower', 'NegReg', (56, 61))	('PTEN', 'Gene', '5728', (129, 133))	('fewer', 'NegReg', (26, 31))	('two-hit loss', 'CPA', (70, 82))	('RELN', 'Gene', (139, 143))	('PBRM1', 'Gene', (94, 99))	('TP53', 'Gene', '7157', (123, 127))	('RELN', 'Gene', '5649', (139, 143))	('TP53', 'Gene', (123, 127))
169026	30934624	Moreover, mutations in known cancer drivers, such as AT-rich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1), were significantly mutated in sarcomatoid patterns and mutually exclusive with TP53 and each other.	('sarcomatoid patterns', 'Disease', 'MESH:C538614', (161, 181))	('cancer', 'Disease', (29, 35))	('BAP1', 'Gene', '8314', (124, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('TP53', 'Gene', (210, 214))	('sarcomatoid patterns', 'Disease', (161, 181))	('AT', 'Disease', 'None', (53, 55))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('BAP1', 'Gene', (124, 128))	('BRCA1 associated protein 1', 'Gene', '8314', (96, 122))	('mutations', 'Var', (10, 19))	('mutated', 'Var', (150, 157))	('BRCA1 associated protein 1', 'Gene', (96, 122))	('ARID1A', 'Gene', '8289', (84, 90))	('ARID1A', 'Gene', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('TP53', 'Gene', '7157', (210, 214))
169047	29682443	Checkpoint Kinase 2 (CHEK2) Mutation in Renal Cell Carcinoma: A Single-Center Experience Renal cell carcinoma (RCC) occurs in sporadic and heritable forms.	('Renal cell carcinoma', 'Disease', 'MESH:C538614', (89, 109))	('CHEK2', 'Gene', '11200', (21, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('Renal Cell Carcinoma', 'Disease', (40, 60))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('CHEK2', 'Gene', (21, 26))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('Mutation', 'Var', (28, 36))	('Renal cell carcinoma', 'Phenotype', 'HP:0005584', (89, 109))	('Carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('Checkpoint Kinase 2', 'Gene', (0, 19))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (40, 60))	('Checkpoint Kinase 2', 'Gene', '11200', (0, 19))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (40, 60))	('Renal cell carcinoma', 'Disease', (89, 109))
169048	29682443	Genetic mutations have been identified as risk factors in 1-2% of RCC.	('Genetic mutations', 'Var', (0, 17))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('RCC', 'Disease', 'MESH:C538614', (66, 69))
169049	29682443	The aim of this study was to evaluate I157T and CHEK2*1100delC mutations of checkpoint kinase 2 (CHEK2) gene in RCC.	('CHEK2', 'Gene', '11200', (48, 53))	('CHEK2', 'Gene', (48, 53))	('checkpoint kinase 2', 'Gene', '11200', (76, 95))	('CHEK2', 'Gene', '11200', (97, 102))	('RCC', 'Disease', (112, 115))	('CHEK2*1100delC', 'DELETION', 'None', (48, 62))	('CHEK2*1100delC', 'Var', (48, 62))	('CHEK2', 'Gene', (97, 102))	('I157T', 'Mutation', 'rs17879961', (38, 43))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('checkpoint kinase 2', 'Gene', (76, 95))
169051	29682443	Only three female patients had CHEK2 mutation (I157T).	('I157T', 'Var', (47, 52))	('CHEK2', 'Gene', '11200', (31, 36))	('CHEK2', 'Gene', (31, 36))	('I157T', 'Mutation', 'rs17879961', (47, 52))	('patients', 'Species', '9606', (18, 26))
169055	29682443	Overall, RCC from patients with CHEK2 mutation did not display any special characteristics when compared with those without the mutation.	('RCC', 'Disease', 'MESH:C538614', (9, 12))	('RCC', 'Disease', (9, 12))	('RCC', 'Phenotype', 'HP:0005584', (9, 12))	('CHEK2', 'Gene', '11200', (32, 37))	('mutation', 'Var', (38, 46))	('patients', 'Species', '9606', (18, 26))	('CHEK2', 'Gene', (32, 37))
169056	29682443	While no association between CHEK2 mutation and RCC could be established, all three patients with CHEK2 mutation developed second neoplasms many years after first diagnosis.	('developed', 'Reg', (113, 122))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('neoplasm', 'Phenotype', 'HP:0002664', (130, 138))	('patients', 'Species', '9606', (84, 92))	('neoplasms', 'Phenotype', 'HP:0002664', (130, 139))	('CHEK2', 'Gene', '11200', (29, 34))	('mutation', 'Var', (104, 112))	('CHEK2', 'Gene', '11200', (98, 103))	('CHEK2', 'Gene', (29, 34))	('CHEK2', 'Gene', (98, 103))	('neoplasms', 'Disease', 'MESH:D009369', (130, 139))	('RCC', 'Disease', (48, 51))	('neoplasms', 'Disease', (130, 139))
169057	29682443	Further studies, especially regarding CHEK2 mutation as a predictive factor for second neoplasm in RCC patients, are warranted.	('CHEK2', 'Gene', (38, 43))	('mutation', 'Var', (44, 52))	('neoplasm', 'Disease', (87, 95))	('neoplasm', 'Disease', 'MESH:D009369', (87, 95))	('neoplasm', 'Phenotype', 'HP:0002664', (87, 95))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('patients', 'Species', '9606', (103, 111))	('CHEK2', 'Gene', '11200', (38, 43))
169060	29682443	Genetic mutations have been identified as the cause of inherited cancer in 1-2% of RCC.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('inherited cancer', 'Disease', (55, 71))	('inherited cancer', 'Disease', 'MESH:D009386', (55, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cause', 'Reg', (46, 51))	('Genetic mutations', 'Var', (0, 17))
169063	29682443	Familial clear cell RCC is the most frequently diagnosed condition as a consequence of aberrations in VHL gene.	('aberrations', 'Var', (87, 98))	('VHL', 'Gene', (102, 105))	('VHL', 'Gene', '7428', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('consequence', 'Reg', (72, 83))	('RCC', 'Disease', (20, 23))
169064	29682443	Apart from VHL, mutations of MET, FLCN, TSC1, TSC2, FH, and SDH genes also are risk factors for the development of RCC.	('SDH', 'Gene', (60, 63))	('MET', 'Gene', (29, 32))	('FLCN', 'Gene', (34, 38))	('TSC1', 'Gene', (40, 44))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('men', 'Species', '9606', (107, 110))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('mutations', 'Var', (16, 25))	('FLCN', 'Gene', '201163', (34, 38))	('TSC2', 'Gene', '7249', (46, 50))	('VHL', 'Gene', (11, 14))	('TSC2', 'Gene', (46, 50))	('risk factors', 'Reg', (79, 91))	('VHL', 'Gene', '7428', (11, 14))	('TSC1', 'Gene', '7248', (40, 44))
169070	29682443	CHEK2 mutation has been reported in breast cancer, colorectal cancer, malignant melanoma, and bladder cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (51, 68))	('colorectal cancer', 'Disease', (51, 68))	('malignant melanoma', 'Disease', (70, 88))	('CHEK2', 'Gene', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('bladder cancer', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('reported', 'Reg', (24, 32))	('malignant melanoma', 'Phenotype', 'HP:0002861', (70, 88))	('colorectal cancer', 'Phenotype', 'HP:0003003', (51, 68))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('malignant melanoma', 'Disease', 'MESH:D008545', (70, 88))	('CHEK2', 'Gene', '11200', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (36, 49))	('mutation', 'Var', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
169071	29682443	Especially, the polymorphic variant of CHEK2 gene (1100delC) is associated with increased risk of breast, prostate, colorectal, and thyroid cancers, whereas the missense variant I157T, in addition to the above cancers, is known to increase the risk of kidney cancer, ovarian adenocarcinoma, and borderline ovarian cancers.	('kidney cancer', 'Disease', (252, 265))	('colorectal', 'Disease', 'MESH:D015179', (116, 126))	('ovarian adenocarcinoma', 'Disease', 'MESH:D010051', (267, 289))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancers', 'Disease', (314, 321))	('1100delC', 'Mutation', 'rs555607708', (51, 59))	('thyroid cancers', 'Disease', 'MESH:D013964', (132, 147))	('borderline ovarian cancers', 'Disease', 'MESH:D010051', (295, 321))	('borderline ovarian cancers', 'Disease', (295, 321))	('1100delC', 'Var', (51, 59))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (267, 289))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (210, 217))	('I157T', 'Var', (178, 183))	('cancers', 'Disease', 'MESH:D009369', (314, 321))	('colorectal', 'Disease', (116, 126))	('thyroid cancers', 'Disease', (132, 147))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('kidney cancer', 'Disease', 'MESH:D007680', (252, 265))	('I157T', 'Mutation', 'rs17879961', (178, 183))	('CHEK2', 'Gene', (39, 44))	('ovarian adenocarcinoma', 'Disease', (267, 289))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast', 'Disease', (98, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('increase', 'PosReg', (231, 239))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('prostate', 'Disease', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('CHEK2', 'Gene', '11200', (39, 44))	('cancers', 'Disease', (140, 147))	('ovarian cancers', 'Phenotype', 'HP:0100615', (306, 321))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('kidney cancer', 'Phenotype', 'HP:0009726', (252, 265))	('cancers', 'Disease', (210, 217))	('cancers', 'Phenotype', 'HP:0002664', (314, 321))
169073	29682443	showed that the constitutive mutation I157T in CHEK2 gene is responsible for the development of ccRCC.	('CHEK2', 'Gene', (47, 52))	('I157T', 'Var', (38, 43))	('responsible', 'Reg', (61, 72))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('I157T', 'Mutation', 'rs17879961', (38, 43))	('men', 'Species', '9606', (88, 91))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('CHEK2', 'Gene', '11200', (47, 52))
169074	29682443	reported that a rare variant of CHEK2, rs17879961, was associated with decreased risk of renal cell cancer.	('renal cell cancer', 'Disease', 'MESH:C538614', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('renal cell cancer', 'Phenotype', 'HP:0005584', (89, 106))	('rs17879961', 'Var', (39, 49))	('CHEK2', 'Gene', '11200', (32, 37))	('CHEK2', 'Gene', (32, 37))	('rs17879961', 'Mutation', 'rs17879961', (39, 49))	('renal cell cancer', 'Disease', (89, 106))	('decreased', 'NegReg', (71, 80))
169076	29682443	The aim of this retrospective study was to further evaluate the role of I157T and CHEK2*1100delC mutations of CHEK2 gene in ccRCC.	('I157T', 'Mutation', 'rs17879961', (72, 77))	('CHEK2*1100delC', 'DELETION', 'None', (82, 96))	('CHEK2', 'Gene', '11200', (110, 115))	('I157T', 'Var', (72, 77))	('CHEK2*1100delC', 'Var', (82, 96))	('CHEK2', 'Gene', (110, 115))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('CHEK2', 'Gene', '11200', (82, 87))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('CHEK2', 'Gene', (82, 87))
169081	29682443	Status of CHEK2*1100delC and I157T mutations was assessed by ASA-PCR and RFLP-PCR techniques, respectively.	('CHEK2*1100delC', 'DELETION', 'None', (10, 24))	('CHEK2*1100delC', 'Var', (10, 24))	('I157T', 'Var', (29, 34))	('I157T', 'Mutation', 'rs17879961', (29, 34))
169083	29682443	The relatively common missense variant I157T is the result of the substitution of isoleucine 157 by threonine.	('isoleucine', 'Var', (82, 92))	('I157T', 'Var', (39, 44))	('I157T', 'Mutation', 'rs17879961', (39, 44))	('isoleucine 157 by threonine', 'Mutation', 'rs17879961', (82, 109))
169094	29682443	Only three patients had CHEK2 mutation (I157T), and all were females.	('mutation (I157T', 'Var', (30, 45))	('CHEK2', 'Gene', (24, 29))	('CHEK2', 'Gene', '11200', (24, 29))	('I157T', 'Mutation', 'rs17879961', (40, 45))	('patients', 'Species', '9606', (11, 19))
169097	29682443	Overall, RCC from patients with CHEK2 mutation showed no special characteristics when compared with RCC from patients without CHEK2 mutation.	('CHEK2', 'Gene', (126, 131))	('patients', 'Species', '9606', (109, 117))	('RCC', 'Disease', 'MESH:C538614', (9, 12))	('RCC', 'Disease', (9, 12))	('RCC', 'Phenotype', 'HP:0005584', (9, 12))	('CHEK2', 'Gene', (32, 37))	('mutation', 'Var', (38, 46))	('patients', 'Species', '9606', (18, 26))	('CHEK2', 'Gene', '11200', (32, 37))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('CHEK2', 'Gene', '11200', (126, 131))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
169100	29682443	Our results showed no association between CHEK2 mutation and cancer in the family.	('CHEK2', 'Gene', '11200', (42, 47))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('CHEK2', 'Gene', (42, 47))	('cancer', 'Disease', (61, 67))	('mutation', 'Var', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
169101	29682443	In all patients with CHEK2 mutation, second neoplasms developed many years after the first diagnosis: breast cancer 15 years post-nephrectomy; renal cancer 2 years post-nephrectomy; and meningioma 9 years post-nephrectomy.	('neoplasms', 'Disease', (44, 53))	('meningioma', 'Phenotype', 'HP:0002858', (186, 196))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('CHEK2', 'Gene', (21, 26))	('renal cancer', 'Disease', 'MESH:D007680', (143, 155))	('mutation', 'Var', (27, 35))	('neoplasm', 'Phenotype', 'HP:0002664', (44, 52))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('patients', 'Species', '9606', (7, 15))	('breast cancer', 'Disease', (102, 115))	('CHEK2', 'Gene', '11200', (21, 26))	('meningioma', 'Disease', 'MESH:D008577', (186, 196))	('neoplasms', 'Phenotype', 'HP:0002664', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('neoplasms', 'Disease', 'MESH:D009369', (44, 53))	('renal cancer', 'Disease', (143, 155))	('renal cancer', 'Phenotype', 'HP:0009726', (143, 155))	('meningioma', 'Disease', (186, 196))
169102	29682443	In this retrospective study, we analyzed the presence of CHEK2 mutation and its relationship with cancers in family history of patients with ccRCC.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('mutation', 'Var', (63, 71))	('patients', 'Species', '9606', (127, 135))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('cancers', 'Disease', (98, 105))	('CHEK2', 'Gene', '11200', (57, 62))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', (143, 146))	('CHEK2', 'Gene', (57, 62))
169105	29682443	Overall, CHEK2 mutation (variant I157T) was detected in only three patients.	('patients', 'Species', '9606', (67, 75))	('I157T', 'Mutation', 'rs17879961', (33, 38))	('CHEK2', 'Gene', '11200', (9, 14))	('variant I157T', 'Var', (25, 38))	('CHEK2', 'Gene', (9, 14))
169106	29682443	CHEK2 mutation neither appeared to have conformed any special characteristics to these tumors nor had a role in family history.	('CHEK2', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mutation', 'Var', (6, 14))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('CHEK2', 'Gene', '11200', (0, 5))
169107	29682443	The putative role of CHEK2 mutation has been reported in other cancers.	('CHEK2', 'Gene', '11200', (21, 26))	('reported', 'Reg', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('CHEK2', 'Gene', (21, 26))	('mutation', 'Var', (27, 35))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
169108	29682443	reported that while the I157T CHEK2 mutation increases the risk of colorectal cancer in Polish population, truncating mutations may be associated with a low or no risk.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('I157T', 'Var', (24, 29))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('colorectal cancer', 'Disease', (67, 84))	('I157T', 'Mutation', 'rs17879961', (24, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('CHEK2', 'Gene', '11200', (30, 35))	('CHEK2', 'Gene', (30, 35))
169109	29682443	Similar results (an increased risk of sporadic and familiar colorectal cancer in patients with CHEK2 I157T mutation) were reported by Kilpivaara et al..	('I157T', 'Mutation', 'rs17879961', (101, 106))	('CHEK2', 'Gene', (95, 100))	('colorectal cancer', 'Disease', 'MESH:D015179', (60, 77))	('patients', 'Species', '9606', (81, 89))	('colorectal cancer', 'Phenotype', 'HP:0003003', (60, 77))	('I157T mutation', 'Var', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('sporadic', 'Disease', (38, 46))	('CHEK2', 'Gene', '11200', (95, 100))	('colorectal cancer', 'Disease', (60, 77))
169110	29682443	The increased risk of breast cancer in patients with CHEK2 mutation is supported by many studies.	('breast cancer', 'Disease', (22, 35))	('patients', 'Species', '9606', (39, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('CHEK2', 'Gene', '11200', (53, 58))	('mutation', 'Var', (59, 67))	('CHEK2', 'Gene', (53, 58))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
169111	29682443	CHEK2 missense variant I157T is found to be associated with a 1.5-fold risk of breast cancer, and CHEK2*1100delC heterozygosity is associated with a three-fold risk of breast cancer in women in the general population.	('CHEK2', 'Gene', (0, 5))	('missense', 'Var', (6, 14))	('CHEK2*1100delC', 'DELETION', 'None', (98, 112))	('CHEK2*1100delC', 'Var', (98, 112))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('I157T', 'Mutation', 'rs17879961', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Disease', (168, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('women', 'Species', '9606', (185, 190))	('CHEK2', 'Gene', '11200', (98, 103))	('CHEK2', 'Gene', '11200', (0, 5))	('CHEK2', 'Gene', (98, 103))	('I157T', 'Var', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
169112	29682443	A meta-analysis conducted in 26,000 patients and 27,000 controls showed that CHEK2*1100delC increases the risk of breast cancer three-to five-fold.	('CHEK2*1100delC', 'DELETION', 'None', (77, 91))	('patients', 'Species', '9606', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('CHEK2*1100delC', 'Var', (77, 91))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('increases', 'PosReg', (92, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', (114, 127))
169113	29682443	The risk of breast cancer at age 70 years in CHEK2*1100delC heterozygotes is almost as high as that for BRCA1 and BRCA2 mutation heterozygotes.	('breast cancer', 'Disease', (12, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('BRCA2', 'Gene', (114, 119))	('BRCA1', 'Gene', '672', (104, 109))	('BRCA2', 'Gene', '675', (114, 119))	('CHEK2*1100delC', 'DELETION', 'None', (45, 59))	('BRCA1', 'Gene', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('CHEK2*1100delC', 'Var', (45, 59))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))
169114	29682443	In some meta-analyses, CHEK2*1100delC heterozygotes have a two-fold risk of malignant melanoma.In addition, Zlowocka et al.	('CHEK2*1100delC', 'Var', (23, 37))	('malignant melanoma', 'Phenotype', 'HP:0002861', (76, 94))	('malignant melanoma', 'Disease', 'MESH:D008545', (76, 94))	('malignant melanoma', 'Disease', (76, 94))	('CHEK2*1100delC', 'DELETION', 'None', (23, 37))
169115	29682443	have found that CHEK2 mutations increase the risk of bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (53, 67))	('bladder cancer', 'Disease', (53, 67))	('CHEK2', 'Gene', '11200', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (22, 31))	('CHEK2', 'Gene', (16, 21))	('bladder cancer', 'Phenotype', 'HP:0009725', (53, 67))
169116	29682443	In our previous study, breast cancer patients with CHEK2 mutation were characterized by older age, history of gastric cancer in family, and lower stage of disease.	('breast cancer', 'Disease', (23, 36))	('mutation', 'Var', (57, 65))	('gastric cancer', 'Disease', (110, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('patients', 'Species', '9606', (37, 45))	('CHEK2', 'Gene', '11200', (51, 56))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('CHEK2', 'Gene', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
169117	29682443	Pertinent to RCC, a relationship with CHEK2 mutations has been reported previously.	('CHEK2', 'Gene', (38, 43))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('mutations', 'Var', (44, 53))	('RCC', 'Disease', (13, 16))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('CHEK2', 'Gene', '11200', (38, 43))
169118	29682443	Specifically, the missense variant I157T was associated with an increased risk of kidney cancer.	('kidney cancer', 'Disease', (82, 95))	('I157T', 'Mutation', 'rs17879961', (35, 40))	('I157T', 'Var', (35, 40))	('kidney cancer', 'Phenotype', 'HP:0009726', (82, 95))	('kidney cancer', 'Disease', 'MESH:D007680', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
169120	29682443	However, the most important finding is that all three patients with CHEK2 mutation developed second neoplasms.	('mutation', 'Var', (74, 82))	('CHEK2', 'Gene', (68, 73))	('neoplasm', 'Phenotype', 'HP:0002664', (100, 108))	('patients', 'Species', '9606', (54, 62))	('neoplasms', 'Disease', 'MESH:D009369', (100, 109))	('neoplasms', 'Disease', (100, 109))	('developed', 'Reg', (83, 92))	('CHEK2', 'Gene', '11200', (68, 73))	('neoplasms', 'Phenotype', 'HP:0002664', (100, 109))
169121	29682443	Thus, the study provides a rationale for further exploration of the role of CHEK2 mutation in RCC, especially its utility as a predictive factor for secondary neoplasms.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('mutation', 'Var', (82, 90))	('neoplasm', 'Phenotype', 'HP:0002664', (159, 167))	('neoplasms', 'Disease', 'MESH:D009369', (159, 168))	('neoplasms', 'Disease', (159, 168))	('CHEK2', 'Gene', (76, 81))	('CHEK2', 'Gene', '11200', (76, 81))	('neoplasms', 'Phenotype', 'HP:0002664', (159, 168))
169186	30037718	Comparison among these miRNAs showed that nine miRNAs (miR-21, miR-214, miR-222, miR-34a, miR-129, miR-143, miR-200a, miR-26a and miR-27b) have high consistency on revealing the prognostic effect in urologic cancers.	('miR-143', 'Gene', '406935', (99, 106))	('urologic cancers', 'Disease', (199, 215))	('miR-143', 'Gene', (99, 106))	('miR-21', 'Gene', (63, 69))	('miR-21', 'Gene', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('miR-200a', 'Gene', (108, 116))	('miR-26a', 'Gene', (118, 125))	('miR-222', 'Gene', (72, 79))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('miR-26a', 'Gene', '407015', (118, 125))	('miR-27b', 'Gene', (130, 137))	('miR-34a', 'Gene', (81, 88))	('miR-27b', 'Gene', '407019', (130, 137))	('miR-222', 'Gene', '407007', (72, 79))	('miR-34a', 'Gene', '407040', (81, 88))	('miR-214', 'Gene', '406996', (63, 70))	('miR-200a', 'Gene', '406983', (108, 116))	('urologic cancers', 'Disease', 'MESH:D014571', (199, 215))	('miR-21', 'Gene', '406991', (63, 69))	('miR-21', 'Gene', '406991', (55, 61))	('miR-129', 'Var', (90, 97))	('miR-214', 'Gene', (63, 70))
169191	30037718	miR-21, which was the most frequently studied miRNA and had high consistency among these studies, was significantly associated with an unfavourable prognostic effect among the 3 clinical events and the 4 survival events in our meta-analyses, which demonstrated that the high expression of miR-21 was associated with a poor prognosis in three urologic cancers, whether in OS (HR:2.699, 1.76-4.14, P < 0.001), DFS (HR:1.865, 1.119-3.109, P = 0.017), PFS (HR:2, 1.318-3.034, P = 0.001) or CSS (HR:4.295, 1.43-12.901, P = 0.009) (Fig.	('high expression', 'Var', (270, 285))	('urologic cancers', 'Disease', (342, 358))	('cancers', 'Phenotype', 'HP:0002664', (351, 358))	('CSS', 'Disease', (486, 489))	('cancer', 'Phenotype', 'HP:0002664', (351, 357))	('DFS', 'Disease', (408, 411))	('miR-21', 'Gene', (0, 6))	('urologic cancers', 'Disease', 'MESH:D014571', (342, 358))	('miR-21', 'Gene', (289, 295))	('CSS', 'Chemical', '-', (486, 489))	('PFS', 'Disease', (448, 451))	('miR-21', 'Gene', '406991', (0, 6))	('OS', 'Chemical', '-', (371, 373))	('miR-21', 'Gene', '406991', (289, 295))
169237	30037718	For instance, miR-143, -155 in BCa, miR-125b, -126 in KCa, miR-21 in three urologic cancers and so on.	('urologic cancers', 'Disease', (75, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('BCa', 'Disease', (31, 34))	('miR-21', 'Gene', (59, 65))	('KCa', 'Gene', (54, 57))	('urologic cancers', 'Disease', 'MESH:D014571', (75, 91))	('KCa', 'Gene', '1448', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('miR-143', 'Gene', '406935', (14, 21))	('miR-143', 'Gene', (14, 21))	('miR-21', 'Gene', '406991', (59, 65))	('miR-125b', 'Var', (36, 44))
169249	30037718	Thousands of aberrant miRNAs are involved in each type of cancer.	('involved', 'Reg', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('aberrant miRNAs', 'Var', (13, 28))
169268	28968973	Cell proliferation was evaluated by MTT assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay kit, which indicated that inhibition of miR-367 could suppress the ccRCC proliferation.	('MTT', 'Chemical', 'MESH:C070243', (36, 39))	("5-Ethynyl-2'-deoxyuridine", 'Chemical', 'MESH:C031086', (50, 75))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('EdU', 'Chemical', 'MESH:C031086', (77, 80))	('miR-367', 'Gene', '442912', (128, 135))	('miR-367', 'Gene', (128, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (155, 160))	('ccRCC', 'Disease', (155, 160))	('inhibition', 'Var', (114, 124))	('suppress', 'NegReg', (142, 150))
169298	28968973	The results demonstrated that more proliferative cells double labeled with EdU and Hoechst 33342 were observed in the group treated with miR-367 mimics versus miR-control, whereas a markedly reduction was seen after transfection of miR-367 inhibitor (Figure 2G and 2H).	('proliferative cells', 'CPA', (35, 54))	('EdU', 'Chemical', 'MESH:C031086', (75, 78))	('miR-367', 'Gene', '442912', (232, 239))	('miR', 'Gene', '220972', (137, 140))	('more', 'PosReg', (30, 34))	('miR', 'Gene', (137, 140))	('Hoechst 33342', 'Chemical', 'MESH:C017807', (83, 96))	('2H', 'Chemical', 'MESH:D003903', (265, 267))	('miR-367', 'Gene', (232, 239))	('miR-367', 'Gene', '442912', (137, 144))	('miR', 'Gene', '220972', (159, 162))	('mimics', 'Var', (145, 151))	('miR', 'Gene', (159, 162))	('miR', 'Gene', '220972', (232, 235))	('miR-367', 'Gene', (137, 144))	('miR', 'Gene', (232, 235))
169312	28968973	Inhibition of miR-367 increased MTA3 protein level both in 786-O and Caki-1 cells, while adverse results were observed when treated with miR-367 mimics (Figure 6B and 6C).	('miR-367', 'Gene', '442912', (14, 21))	('Caki-1', 'CellLine', 'CVCL:0234', (69, 75))	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('miR-367', 'Gene', (14, 21))	('MTA3', 'Gene', (32, 36))	('increased', 'PosReg', (22, 31))	('miR-367', 'Gene', '442912', (137, 144))	('Inhibition', 'Var', (0, 10))	('miR-367', 'Gene', (137, 144))	('MTA3', 'Gene', '57504', (32, 36))
169315	28968973	Emerging evidence suggested that MTA3 aberrantly expressed in multiple cancers, including carcinoma of the esophagus, breast, lung, uterus and nasopharynx.	('MTA3', 'Gene', '57504', (33, 37))	('multiple cancers', 'Disease', (62, 78))	('carcinoma of the esophagus', 'Disease', 'MESH:D004938', (90, 116))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('lung', 'Disease', (126, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (90, 116))	('multiple cancers', 'Disease', 'MESH:D009369', (62, 78))	('MTA3', 'Gene', (33, 37))	('breast', 'Disease', (118, 124))	('uterus', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('aberrantly expressed', 'Var', (38, 58))	('carcinoma of the esophagus', 'Disease', (90, 116))	('nasopharynx', 'Disease', (143, 154))
169327	28968973	Inhibition of miR-367 could suppress the proliferation, migration and invasion both in 786-O and Caki-1 cells (Figure 2, 3 and 4).	('migration', 'CPA', (56, 65))	('suppress', 'NegReg', (28, 36))	('Caki-1', 'CellLine', 'CVCL:0234', (97, 103))	('miR-367', 'Gene', '442912', (14, 21))	('miR-367', 'Gene', (14, 21))	('Inhibition', 'Var', (0, 10))	('invasion', 'CPA', (70, 78))	('proliferation', 'CPA', (41, 54))
169333	28968973	Recent studies suggested that dysregulation of miRNAs was involved in various aspects of cancer progressions.	('dysregulation', 'Var', (30, 43))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('involved', 'Reg', (58, 66))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
169334	28968973	Aberrant expression of miR-367 has been described in multiple types of cancers, such as lung cancer, hepatocellular and esophagus cancers.	('lung cancer', 'Disease', (88, 99))	('hepatocellular', 'Disease', (101, 115))	('esophagus cancers', 'Disease', 'MESH:D004938', (120, 137))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))	('Aberrant expression', 'Var', (0, 19))	('miR-367', 'Gene', '442912', (23, 30))	('esophagus cancers', 'Disease', (120, 137))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('miR-367', 'Gene', (23, 30))	('described', 'Reg', (40, 49))
169385	31855296	Renal tumors were divided into 25 immune cell subsets (4 CD4+ T cells, 7 CD8+ T cells, 1 B cells, 8 macrophages, 1 dendritic cells, 2 natural killer (NK) cells, 1 granulocyte, and 1 other subset) and 7 stem-like cells subsets (based on positivity of vimentin, CD326, CD34, CD90, CD13, CD44, and CD47).	('CD13', 'Gene', '290', (279, 283))	('vimentin', 'Gene', '7431', (250, 258))	('vimentin', 'Gene', (250, 258))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('CD34', 'Gene', '947', (267, 271))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('vimentin', 'cellular_component', 'GO:0045099', ('250', '258'))	('CD13', 'molecular_function', 'GO:0004179', ('279', '283'))	('CD90', 'Gene', (273, 277))	('CD44', 'Gene', '960', (285, 289))	('CD8', 'Gene', (73, 76))	('CD47', 'Gene', '961', (295, 299))	('CD44', 'Gene', (285, 289))	('Renal tumors', 'Disease', 'MESH:D007674', (0, 12))	('Renal tumors', 'Disease', (0, 12))	('CD90', 'Gene', '7070', (273, 277))	('Renal tumors', 'Phenotype', 'HP:0009726', (0, 12))	('CD326', 'Var', (260, 265))	('CD13', 'Gene', (279, 283))	('CD34', 'Gene', (267, 271))	('vimentin', 'cellular_component', 'GO:0045098', ('250', '258'))	('CD8', 'Gene', '925', (73, 76))	('CD47', 'Gene', (295, 299))
169428	31855296	A 20-well barcoding group was composed of unique combinations of six barcoding metals (102 Pd, 104 Pd, 105 Pd, 106 Pd, 108 Pd, and 110 Pd.	('A 20', 'Gene', (0, 4))	('102 Pd', 'Var', (87, 93))	('A 20', 'Gene', '28935', (0, 4))	('metal', 'Chemical', 'MESH:D008670', (79, 84))
169463	31855296	Renal tumors were divided into 7 stem-like cells subsets (based on positivity of vimentin, CD326, CD34, CD90, CD13, CD44, and CD47), and some stem-like cells subsets have the characteristics of co-expression (Figure 3B).	('CD34', 'Gene', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('vimentin', 'cellular_component', 'GO:0045098', ('81', '89'))	('CD47', 'Gene', (126, 130))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('CD13', 'Gene', '290', (110, 114))	('vimentin', 'Gene', '7431', (81, 89))	('vimentin', 'Gene', (81, 89))	('Renal tumors', 'Disease', 'MESH:D007674', (0, 12))	('CD90', 'Gene', (104, 108))	('Renal tumors', 'Disease', (0, 12))	('CD34', 'Gene', '947', (98, 102))	('CD13', 'molecular_function', 'GO:0004179', ('110', '114'))	('Renal tumors', 'Phenotype', 'HP:0009726', (0, 12))	('CD90', 'Gene', '7070', (104, 108))	('vimentin', 'cellular_component', 'GO:0045099', ('81', '89'))	('CD47', 'Gene', '961', (126, 130))	('CD44', 'Gene', '960', (116, 120))	('CD44', 'Gene', (116, 120))	('CD326', 'Var', (91, 96))	('CD13', 'Gene', (110, 114))
169488	31855296	We found 7 stem-like cells subsets in the renal tumors (based on the expression of vimentin, CD326, CD34, CD90, CD13, CD44, and CD47).	('vimentin', 'Gene', (83, 91))	('vimentin', 'cellular_component', 'GO:0045099', ('83', '91'))	('renal tumor', 'Phenotype', 'HP:0009726', (42, 53))	('CD34', 'Gene', '947', (100, 104))	('CD13', 'Gene', '290', (112, 116))	('CD47', 'Gene', '961', (128, 132))	('renal tumors', 'Disease', (42, 54))	('CD90', 'Gene', (106, 110))	('CD326', 'Var', (93, 98))	('vimentin', 'cellular_component', 'GO:0045098', ('83', '91'))	('CD34', 'Gene', (100, 104))	('renal tumors', 'Disease', 'MESH:D007674', (42, 54))	('CD90', 'Gene', '7070', (106, 110))	('CD13', 'molecular_function', 'GO:0004179', ('112', '116'))	('CD44', 'Gene', '960', (118, 122))	('CD44', 'Gene', (118, 122))	('renal tumors', 'Phenotype', 'HP:0009726', (42, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('CD47', 'Gene', (128, 132))	('CD13', 'Gene', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('vimentin', 'Gene', '7431', (83, 91))
169504	32409702	Our study is the first to explore (i) how estrogen receptor beta (ERbeta) can up-regulate ANGPT-2 in RCC cells, and (ii) how ERbeta-increased ANGPT-2 can promote the HUVEC tube formation and reduce sunitinib sensitivity.	('up-regulate', 'PosReg', (78, 89))	('ERbeta-increased', 'Var', (125, 141))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('promote', 'PosReg', (154, 161))	('ANGPT-2', 'Gene', (90, 97))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('estrogen receptor beta', 'Gene', '2099', (42, 64))	('RCC', 'Disease', (101, 104))	('sunitinib sensitivity', 'MPA', (198, 219))	('sunitinib', 'Chemical', 'MESH:D000077210', (198, 207))	('tube formation', 'biological_process', 'GO:0035148', ('172', '186'))	('HUVEC tube formation', 'CPA', (166, 186))	('reduce', 'NegReg', (191, 197))	('estrogen receptor beta', 'Gene', (42, 64))
169521	32409702	Also, it was reported that ERbeta could increase the vasculogenic mimicry (VM) formation in lung cancer and promote bladder cancer metastasis via alterations of miR-92a/DAB2IP signals.	('ERbeta', 'Var', (27, 33))	('DAB2IP', 'Gene', (169, 175))	('lung cancer', 'Disease', (92, 103))	('alterations', 'Reg', (146, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('bladder cancer', 'Phenotype', 'HP:0009725', (116, 130))	('increase', 'PosReg', (40, 48))	('bladder cancer', 'Disease', 'MESH:D001749', (116, 130))	('bladder cancer', 'Disease', (116, 130))	('DAB2IP', 'Gene', '153090', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('formation', 'biological_process', 'GO:0009058', ('79', '88'))	('promote', 'PosReg', (108, 115))
169592	32409702	1g, h, revealed that increasing ERbeta in A498 cells resulted in higher numbers and lengths of micro-vessels (g) that sprouted from the aortic ring and micro-vessel sensitivity (h) to Sunitinib treatment, while suppressing ERbeta in 786-O cells reduced the numbers of the micro-vessel sprouting from the aortic ring (g) and micro-vessel sensitivity (h) to Sunitinib treatment.	('Sunitinib', 'Chemical', 'MESH:D000077210', (184, 193))	('A498', 'CellLine', 'CVCL:1056', (42, 46))	('increasing', 'PosReg', (21, 31))	('ERbeta', 'Gene', (32, 38))	('micro-vessel sprouting from the', 'CPA', (272, 303))	('Sunitinib', 'Chemical', 'MESH:D000077210', (356, 365))	('micro-vessels', 'CPA', (95, 108))	('higher', 'PosReg', (65, 71))	('A498', 'Var', (42, 46))
169603	32409702	Results revealed that altering the ERbeta expression led to significantly changing the expression of ANGPT-2 and HGF, overexpression of ERbeta in A498 cells can increased their expressions, and knockdown of ERbeta in 786-O cells could down-regulate the expressions of ANGPT-2, bFGF, HB-EGF, HGF, Leptin, and VEGF-A (Fig.	('bFGF', 'Gene', (277, 281))	('HGF', 'Gene', (291, 294))	('HGF', 'Gene', '3082', (113, 116))	('HB-EGF', 'Gene', '1839', (283, 289))	('VEGF-A', 'Gene', '7422', (308, 314))	('down-regulate', 'NegReg', (235, 248))	('HGF', 'Gene', (113, 116))	('expressions', 'MPA', (253, 264))	('changing', 'Reg', (74, 82))	('knockdown', 'Var', (194, 203))	('ANGPT-2', 'Gene', (268, 275))	('ANGPT-2', 'Gene', (101, 108))	('increased', 'PosReg', (161, 170))	('EGF', 'molecular_function', 'GO:0005154', ('286', '289'))	('HB-EGF', 'Gene', (283, 289))	('Leptin', 'Gene', (296, 302))	('expression', 'MPA', (87, 97))	('expressions', 'MPA', (177, 188))	('bFGF', 'Gene', '2247', (277, 281))	('VEGF-A', 'Gene', (308, 314))	('ERbeta', 'Gene', (35, 41))	('HGF', 'Gene', '3082', (291, 294))	('A498', 'CellLine', 'CVCL:1056', (146, 150))	('Leptin', 'Gene', '3952', (296, 302))
169604	32409702	The results from the 3rd RCC cell line, Caki-1 also revealed that knockdown of ERbeta led to suppressing the expressions of ANGPT-2 and HGF (Fig.	('ERbeta', 'Gene', (79, 85))	('HGF', 'Gene', (136, 139))	('ANGPT-2', 'Gene', (124, 131))	('Caki-1', 'CellLine', 'CVCL:0234', (40, 46))	('HGF', 'Gene', '3082', (136, 139))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('suppressing', 'NegReg', (93, 104))	('knockdown', 'Var', (66, 75))	('RCC', 'Disease', (25, 28))	('expressions', 'MPA', (109, 120))
169606	32409702	We then tested the impacts of knocking down HGF (plko-shHGF) and ANGPT-2 (plko-shANGPT-2) in 786-0 cell to further validate their roles on the HUVEC tube formation.	('tested', 'Reg', (8, 14))	('HGF', 'Gene', (44, 47))	('tube formation', 'biological_process', 'GO:0035148', ('149', '163'))	('HUVEC tube formation', 'CPA', (143, 163))	('HGF', 'Gene', '3082', (44, 47))	('ANGPT-2', 'Gene', (65, 72))	('HGF', 'Gene', (56, 59))	('knocking down', 'Var', (30, 43))	('HGF', 'Gene', '3082', (56, 59))
169607	32409702	Results revealed that only plko-shANGPT-2, but not the plko-shHGF, could decrease the HUVEC tube formation (Fig.	('HGF', 'Gene', (62, 65))	('tube formation', 'biological_process', 'GO:0035148', ('92', '106'))	('HUVEC tube formation', 'CPA', (86, 106))	('plko-shANGPT-2', 'Var', (27, 41))	('HGF', 'Gene', '3082', (62, 65))	('decrease', 'NegReg', (73, 81))
169609	32409702	Western blot data also showed that adding ERbeta in A498 cells led to increasing the ANGPT-2 protein expression in the A498 cells and knocking down ERbeta in 786-O cells decreased the ANGPT-2 protein expression in the 786-O cells (Fig.	('knocking', 'Var', (134, 142))	('ANGPT-2 protein', 'Protein', (85, 100))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('A498', 'CellLine', 'CVCL:1056', (52, 56))	('increasing', 'PosReg', (70, 80))	('decreased', 'NegReg', (170, 179))	('protein', 'cellular_component', 'GO:0003675', ('192', '199'))	('A498', 'CellLine', 'CVCL:1056', (119, 123))
169615	32409702	4a-e suggest that ERbeta can promote the HUVEC cell tube formation and increase the HUVEC cell resistance to the sunitinib treatment via increasing the ANGPT-2/Tie-2 signaling.	('promote', 'PosReg', (29, 36))	('tube formation', 'biological_process', 'GO:0035148', ('52', '66'))	('HUVEC cell tube formation', 'CPA', (41, 66))	('ERbeta', 'Var', (18, 24))	('increasing', 'PosReg', (137, 147))	('ANGPT-2/Tie-2 signaling', 'MPA', (152, 175))	('increase', 'PosReg', (71, 79))	('signaling', 'biological_process', 'GO:0023052', ('166', '175'))	('HUVEC cell resistance', 'CPA', (84, 105))	('sunitinib', 'Chemical', 'MESH:D000077210', (113, 122))
169619	32409702	5a-g suggest that ERbeta can increase ANGPT-2 expression via transcriptional regulation with direct binding to the ERE (-490 to -476 bp) on the 5' promoter of ANGPT-2 in RCC cells.	('-490', 'Var', (120, 124))	('transcriptional regulation', 'MPA', (61, 87))	('RCC', 'Disease', (170, 173))	('ANGPT-2', 'Gene', (38, 45))	('binding', 'Interaction', (100, 107))	('increase', 'PosReg', (29, 37))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('binding', 'molecular_function', 'GO:0005488', ('100', '107'))	('expression', 'MPA', (46, 56))	('regulation', 'biological_process', 'GO:0065007', ('77', '87'))
169657	32409702	In renal cancer, ICI 182,780 can block the ERbeta/TGF-beta1/SMAD3 signals pathway, thereby better inhibiting the progression of RCC.	('ICI', 'Var', (17, 20))	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('SMAD3', 'Gene', (60, 65))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('renal cancer', 'Disease', (3, 15))	('progression', 'CPA', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('TGF-beta1', 'Gene', '7040', (50, 59))	('renal cancer', 'Phenotype', 'HP:0009726', (3, 15))	('TGF-beta1', 'Gene', (50, 59))	('block', 'NegReg', (33, 38))	('renal cancer', 'Disease', 'MESH:D007680', (3, 15))	('SMAD3', 'Gene', '4088', (60, 65))
169686	30064463	Patients with high circ-CER expression have significantly worse overall survival (OS) than those with low circ-CER expression.	('worse', 'NegReg', (58, 63))	('high circ-CER expression', 'Var', (14, 38))	('overall survival', 'MPA', (64, 80))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (82, 84))
169694	30064463	In addition, the overexpression of hsa_circ_0000064 in lung cancer is positively correlated with T and N stage.	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('lung cancer', 'Disease', (55, 66))	('hsa_circ_0000064', 'Var', (35, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('overexpression', 'PosReg', (17, 31))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('T and', 'Disease', (97, 102))
169698	30064463	A recent study has identified two circRNAs (hsa_circ_0122662 and hsa_circ_0001358) in five patients with DCIS/IDC and the MCF-7 invasive breast cancer cell line.	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('patients', 'Species', '9606', (91, 99))	('hsa_circ_0122662', 'Var', (44, 60))	('MCF-7 invasive breast cancer', 'Disease', (122, 150))	('MCF-7 invasive breast cancer', 'Disease', 'MESH:D001943', (122, 150))	('hsa_circ_0001358', 'Var', (65, 81))	('IDC', 'Gene', '4000', (110, 113))	('IDC', 'Gene', (110, 113))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
169704	30064463	The combination of hsa_circ_006054, hsa_circ_100219, and hsa_circ_406697 provides valuable insights into the diagnosis of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('hsa_circ_406697', 'Var', (57, 72))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('hsa_circ_006054', 'Var', (19, 34))
169709	30064463	A total of 25 binding sites of circ-Foxo3 for eight miRNAs (miR-22, miR-136, miR-138, miR-149, miR-433, miR-762, miR-3614-5p, and miR-3622b-5p) are detected, and transfection of these miRNAs into MDA-MB-231 cells can reduce apoptosis.	('miR-762', 'Gene', '100313837', (104, 111))	('miR', 'Gene', (77, 80))	('miR', 'Gene', '220972', (68, 71))	('miR', 'Gene', '220972', (60, 63))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (196, 206))	('binding', 'Interaction', (14, 21))	('miR', 'Gene', '220972', (52, 55))	('miR-22', 'Gene', '407004', (60, 66))	('miR-22', 'Gene', (60, 66))	('miR-762', 'Gene', (104, 111))	('miR', 'Gene', '220972', (113, 116))	('miR', 'Gene', (68, 71))	('miR', 'Gene', (60, 63))	('apoptosis', 'biological_process', 'GO:0097194', ('224', '233'))	('miR-149', 'Gene', (86, 93))	('miR', 'Gene', '220972', (130, 133))	('Foxo3', 'Gene', (36, 41))	('apoptosis', 'biological_process', 'GO:0006915', ('224', '233'))	('miR', 'Gene', '220972', (104, 107))	('miR-433', 'Gene', (95, 102))	('miR', 'Gene', (52, 55))	('miR', 'Gene', '220972', (184, 187))	('miR', 'Gene', '220972', (95, 98))	('miR', 'Gene', (113, 116))	('reduce', 'NegReg', (217, 223))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (130, 133))	('apoptosis', 'CPA', (224, 233))	('miR-149', 'Gene', '406941', (86, 93))	('transfection', 'Var', (162, 174))	('miR', 'Gene', (104, 107))	('miR-136', 'Gene', (68, 75))	('Foxo3', 'Gene', '2309', (36, 41))	('miR', 'Gene', (184, 187))	('miR-136', 'Gene', '406927', (68, 75))	('miR', 'Gene', '220972', (77, 80))	('miR', 'Gene', (95, 98))	('miR', 'Gene', (86, 89))	('miR-433', 'Gene', '574034', (95, 102))	('binding', 'molecular_function', 'GO:0005488', ('14', '21'))
169712	30064463	In addition, circ_000911 is poorly expressed in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('breast cancer', 'Disease', (48, 61))	('circ_000911', 'Var', (13, 24))
169713	30064463	In vitro experiments have confirmed that upregulation of circ_000911 increases Notch1 expression via binding to miR-449a, thereby suppressing the proliferation, invasion, and metastasis of breast cancer cells.	('suppressing', 'NegReg', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('increases', 'PosReg', (69, 78))	('proliferation', 'CPA', (146, 159))	('Notch1', 'Gene', (79, 85))	('miR-449a', 'Gene', '554213', (112, 120))	('circ_000911', 'Var', (57, 68))	('invasion', 'CPA', (161, 169))	('metastasis of breast cancer', 'Disease', 'MESH:D009362', (175, 202))	('expression', 'MPA', (86, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('Notch1', 'Gene', '4851', (79, 85))	('binding', 'Interaction', (101, 108))	('metastasis of breast cancer', 'Disease', (175, 202))	('binding', 'molecular_function', 'GO:0005488', ('101', '108'))	('upregulation', 'PosReg', (41, 53))	('miR-449a', 'Gene', (112, 120))
169714	30064463	In contrast, hsa_circ_0001982, hsa_circ_0005239, and hsa_circ_0008717 are upregulated in breast cancer, and knockdown of their expressions inhibits cell proliferation and promotes apoptosis.	('knockdown', 'Var', (108, 117))	('hsa_circ_0008717', 'Var', (53, 69))	('cell proliferation', 'biological_process', 'GO:0008283', ('148', '166'))	('promotes', 'PosReg', (171, 179))	('upregulated', 'PosReg', (74, 85))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('180', '189'))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('apoptosis', 'biological_process', 'GO:0006915', ('180', '189'))	('cell proliferation', 'CPA', (148, 166))	('inhibits', 'NegReg', (139, 147))	('apoptosis', 'CPA', (180, 189))
169715	30064463	circ_0006528 is highly expressed in chemotherapy-resistant breast cancer cell lines, and the sensitivity of these cells to chemotherapy is significantly increased after knocking down circ_0006528.	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('increased', 'PosReg', (153, 162))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('sensitivity', 'MPA', (93, 104))	('knocking down circ_0006528', 'Var', (169, 195))	('circ_0006528', 'Var', (183, 195))
169718	30064463	Several dysregulated circRNAs are found in ESCC, including hsa_circ_000167, hsa_circ_001059, hsa_circ_0067934, and circ-ITCH.	('-ITCH', 'Phenotype', 'HP:0000989', (119, 124))	('ITCH', 'Gene', (120, 124))	('ESCC', 'Disease', (43, 47))	('hsa_circ_000167', 'Var', (59, 74))	('hsa_circ_001059', 'Var', (76, 91))	('ITCH', 'Gene', '83737', (120, 124))	('hsa_circ_0067934', 'Var', (93, 109))
169721	30064463	identified more than 3700 human circRNAs, among which hsa_circ_000167 and hsa_circ_001059 in the KYSE-150R human radiation-resistant esophageal cancer cell line are significantly different from the KYSE-150 parental cell line.	('hsa_circ_001059', 'Var', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('human', 'Species', '9606', (107, 112))	('esophageal cancer', 'Disease', (133, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('human', 'Species', '9606', (26, 31))
169723	30064463	found that hsa_circ_0067934 encoded by PRKCI is upregulated in 51 cases of ESCC tissues compared to adjacent noncancerous tissues, and they reported that hsa_circ_0067934 is associated with poor tumor differentiation and advanced TNM stage.	('TNM', 'Gene', '10178', (230, 233))	('tumor', 'Disease', (195, 200))	('associated', 'Reg', (174, 184))	('PRKCI', 'Gene', '5584', (39, 44))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('PRKCI', 'Gene', (39, 44))	('ESCC', 'Disease', (75, 79))	('hsa_circ_0067934', 'Var', (154, 170))	('TNM', 'Gene', (230, 233))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('upregulated', 'PosReg', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
169724	30064463	Silencing hsa_circ_0067934 by siRNA induces cell cycle arrest and inhibits proliferation and migration of ESCC cells.	('arrest', 'Disease', 'MESH:D006323', (55, 61))	('inhibits', 'NegReg', (66, 74))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('44', '61'))	('arrest', 'Disease', (55, 61))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (44, 61))	('Silencing', 'Var', (0, 9))	('hsa_circ_0067934', 'Gene', (10, 26))	('induces', 'Reg', (36, 43))
169725	30064463	Given that TNM staging is applied to predict patient outcomes, hsa_circ_0067934 may serve as a potential prognostic marker for ESCC.	('TNM', 'Gene', '10178', (11, 14))	('ESCC', 'Disease', (127, 131))	('TNM', 'Gene', (11, 14))	('patient', 'Species', '9606', (45, 52))	('hsa_circ_0067934', 'Var', (63, 79))
169730	30064463	Hsa_circ_0047905, hsa_circ_0087198, and hsa_circ_0138960 are also highly expressed in gastric cancer tissues.	('gastric cancer', 'Disease', 'MESH:D013274', (86, 100))	('gastric cancer', 'Phenotype', 'HP:0012126', (86, 100))	('Hsa_circ_0047905', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gastric cancer', 'Disease', (86, 100))	('hsa_circ_0138960', 'Var', (40, 56))
169734	30064463	Knockdown of hsa_circ_0000096 reduces the expression of cyclin D1, CDK6, matrix metalloproteinase (MPP)-2, and MMP-9, and it significantly inhibits cell proliferation and migration and blocks cell cycle (preventing gastric cancer cells from leaving G0/G1 phase to enter S phase), as well as inhibits tumor growth in a xenograft nude mouse model.	('G1 phase', 'biological_process', 'GO:0051318', ('252', '260'))	('cell proliferation', 'biological_process', 'GO:0008283', ('148', '166'))	('matrix metalloproteinase (MPP)-2', 'Gene', '50997', (73, 105))	('CDK6', 'Gene', (67, 71))	('expression', 'MPA', (42, 52))	('gastric cancer', 'Disease', (215, 229))	('cyclin D1', 'Gene', '12443', (56, 65))	('cyclin D1', 'Gene', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('cell cycle', 'biological_process', 'GO:0007049', ('192', '202'))	('mouse', 'Species', '10090', (333, 338))	('cell cycle', 'CPA', (192, 202))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cyclin', 'molecular_function', 'GO:0016538', ('56', '62'))	('MPP', 'molecular_function', 'GO:0004240', ('99', '102'))	('gastric cancer', 'Disease', 'MESH:D013274', (215, 229))	('S phase', 'biological_process', 'GO:0051320', ('270', '277'))	('inhibits', 'NegReg', (291, 299))	('CDK', 'molecular_function', 'GO:0004693', ('67', '70'))	('blocks', 'NegReg', (185, 191))	('inhibits', 'NegReg', (139, 147))	('gastric cancer', 'Phenotype', 'HP:0012126', (215, 229))	('reduces', 'NegReg', (30, 37))	('hsa_circ_0000096', 'Var', (13, 29))	('tumor', 'Disease', (300, 305))	('MMP-9', 'Gene', '17395', (111, 116))	('MMP-9', 'Gene', (111, 116))	('cell proliferation', 'CPA', (148, 166))	('MMP-9', 'molecular_function', 'GO:0004229', ('111', '116'))	('tumor', 'Disease', 'MESH:D009369', (300, 305))
169735	30064463	The circRNA database shows that hsa_circ_0000096 can interact with 17 different types of miRNAs.	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', (89, 92))	('hsa_circ_0000096', 'Var', (32, 48))	('interact', 'Interaction', (53, 61))
169736	30064463	Downregulation of hsa_circ_0000096 results in a decrease in miR-224 (a modulator of CD40) and an increase in miR-200a (targeting E-cadherin).	('increase', 'PosReg', (97, 105))	('Downregulation', 'NegReg', (0, 14))	('miR-224', 'Gene', (60, 67))	('cadherin', 'molecular_function', 'GO:0008014', ('131', '139'))	('miR-224', 'Gene', '407009', (60, 67))	('E-cadherin', 'Gene', (129, 139))	('E-cadherin', 'Gene', '999', (129, 139))	('CD40', 'Gene', '958', (84, 88))	('decrease', 'NegReg', (48, 56))	('hsa_circ_0000096', 'Var', (18, 34))	('CD40', 'Gene', (84, 88))	('miR-200a', 'Gene', (109, 117))	('miR-200a', 'Gene', '406983', (109, 117))
169740	30064463	Hsa_circ_002059 has also been confirmed to be downregulated in gastric cancer tissues.	('gastric cancer', 'Disease', (63, 77))	('gastric cancer', 'Disease', 'MESH:D013274', (63, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (63, 77))	('downregulated', 'NegReg', (46, 59))	('Hsa_circ_002059', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
169744	30064463	Hsa_circ_0000190 is considered to have better sensitivity and specificity compared to CEA and CA19-9.	('Hsa_circ_0000190', 'Var', (0, 16))	('CEA', 'Gene', (86, 89))	('CEA', 'Gene', '5670', (86, 89))
169746	30064463	Hsa_circ_0014717 is also lowly expressed in gastric cancer, and such downregulation is associated with distant metastasis and clinical staging.	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lowly', 'NegReg', (25, 30))	('gastric cancer', 'Disease', (44, 58))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('distant metastasis', 'CPA', (103, 121))	('Hsa_circ_0014717', 'Var', (0, 16))	('downregulation', 'NegReg', (69, 83))
169747	30064463	Hsa_circ_0000181, hsa_circ_0001649, hsa_circ_0000520, hsa_circ_0003159, and hsa_circ_0074362 are also lowly expressed in tissues or plasma of gastric cancer patients, and their expression is negatively correlated with distant metastasis and TNM staging.	('Hsa_circ_0000181', 'Var', (0, 16))	('TNM', 'Gene', '10178', (241, 244))	('gastric cancer', 'Disease', (142, 156))	('gastric cancer', 'Disease', 'MESH:D013274', (142, 156))	('distant metastasis', 'CPA', (218, 236))	('hsa_circ_0003159', 'Var', (54, 70))	('hsa_circ_0074362', 'Var', (76, 92))	('patients', 'Species', '9606', (157, 165))	('gastric cancer', 'Phenotype', 'HP:0012126', (142, 156))	('TNM', 'Gene', (241, 244))	('negatively', 'NegReg', (191, 201))	('hsa_circ_0000520', 'Var', (36, 52))	('correlated', 'Reg', (202, 212))	('expression', 'MPA', (177, 187))	('lowly', 'NegReg', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('hsa_circ_0001649', 'Var', (18, 34))
169748	30064463	The plasma levels of hsa_circ_0001017 and hsa_circ_0061276 are also downregulated, making them suitable for the diagnosis and prognosis of gastric cancer.	('gastric cancer', 'Disease', (139, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('gastric cancer', 'Disease', 'MESH:D013274', (139, 153))	('downregulated', 'NegReg', (68, 81))	('hsa_circ_0001017', 'Var', (21, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (139, 153))	('hsa_circ_0061276', 'Var', (42, 58))	('plasma levels', 'MPA', (4, 17))
169749	30064463	Moreover, hsa_circ_0000745 is expressed at a higher level in gastric cancer tissues than normal tissues, and its expression in plasma of gastric cancer patients is also higher than that of healthy controls.	('expression', 'MPA', (113, 123))	('higher', 'PosReg', (169, 175))	('gastric cancer', 'Disease', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('gastric cancer', 'Disease', 'MESH:D013274', (61, 75))	('gastric cancer', 'Disease', (137, 151))	('gastric cancer', 'Disease', 'MESH:D013274', (137, 151))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))	('higher', 'PosReg', (45, 51))	('hsa_circ_0000745', 'Var', (10, 26))	('patients', 'Species', '9606', (152, 160))	('gastric cancer', 'Phenotype', 'HP:0012126', (137, 151))
169750	30064463	Hsa_circ_0000745 expression in gastric cancer tissues and plasma is associated with tumor differentiation and lymph node metastasis, respectively, and plasma hsa_circ_0000745 combined with CEA has a greater diagnostic value for gastric cancer.	('CEA', 'Gene', '5670', (189, 192))	('lymph node metastasis', 'CPA', (110, 131))	('associated', 'Reg', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('gastric cancer', 'Disease', 'MESH:D013274', (228, 242))	('gastric cancer', 'Disease', (228, 242))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('gastric cancer', 'Phenotype', 'HP:0012126', (31, 45))	('Hsa_circ_0000745', 'Gene', (0, 16))	('gastric cancer', 'Phenotype', 'HP:0012126', (228, 242))	('tumor', 'Disease', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('hsa_circ_0000745', 'Var', (158, 174))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('CEA', 'Gene', (189, 192))	('gastric cancer', 'Disease', 'MESH:D013274', (31, 45))	('gastric cancer', 'Disease', (31, 45))
169762	30064463	In addition, hsa_circ_0001649, hsa_circ_0003906, and circRNA derived from ITCH78 are also downregulated in CRC, and the first two circRNAs are related to the pathological differentiation of CRC and may be used as diagnostic indicators of CRC.	('CRC', 'Disease', (107, 110))	('CRC', 'Disease', (238, 241))	('CRC', 'Phenotype', 'HP:0030731', (238, 241))	('ITCH', 'Gene', (74, 78))	('CRC', 'Phenotype', 'HP:0030731', (107, 110))	('CRC', 'Disease', (190, 193))	('CRC', 'Phenotype', 'HP:0030731', (190, 193))	('hsa_circ_0001649', 'Var', (13, 29))	('downregulated', 'NegReg', (90, 103))	('ITCH', 'Gene', '83737', (74, 78))
169767	30064463	As a positive regulator of CRC cell proliferation and invasion, hsa_circ_001569 exhibits higher expression in CRC tissues than noncancerous tissues.	('hsa_circ_001569', 'Var', (64, 79))	('CRC', 'Disease', (110, 113))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('CRC', 'Phenotype', 'HP:0030731', (110, 113))	('cancer', 'Disease', (130, 136))	('expression', 'MPA', (96, 106))	('higher', 'PosReg', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('CRC', 'Phenotype', 'HP:0030731', (27, 30))	('cell proliferation', 'biological_process', 'GO:0008283', ('31', '49'))
169783	30064463	Comparison of three syngeneic CRC cell lines with different KRAS mutation status, including DLD-1, DKO-1, and DKs-8, has shown that extracellular circRNAs are more abundant than intracellular circRNAs, and most circRNAs are downregulated in the KRAS-mutated CRC cell lines.	('intracellular', 'cellular_component', 'GO:0005622', ('178', '191'))	('extracellular', 'cellular_component', 'GO:0005576', ('132', '145'))	('downregulated', 'NegReg', (224, 237))	('KRAS', 'Gene', (245, 249))	('KRAS', 'Gene', (60, 64))	('KRAS', 'Gene', '3845', (245, 249))	('mutation', 'Var', (65, 73))	('CRC', 'Phenotype', 'HP:0030731', (30, 33))	('KRAS', 'Gene', '3845', (60, 64))	('extracellular circRNAs', 'MPA', (132, 154))	('CRC', 'Phenotype', 'HP:0030731', (258, 261))
169784	30064463	circRNA is associated with KRAS mutations, and it is a promising biomarker of CRC, especially for KRAS-mutated CRC.	('KRAS', 'Gene', '3845', (27, 31))	('associated', 'Reg', (11, 21))	('CRC', 'Phenotype', 'HP:0030731', (111, 114))	('CRC', 'Disease', (78, 81))	('mutations', 'Var', (32, 41))	('CRC', 'Phenotype', 'HP:0030731', (78, 81))	('KRAS', 'Gene', (98, 102))	('KRAS', 'Gene', (27, 31))	('KRAS', 'Gene', '3845', (98, 102))
169796	30064463	Hsa_circ_0001649 was also lowly expressed in HCC tissues compared to normal tissues, and the expression level of hsa_circ_0001649 is related to tumor size and tumor thrombus.	('HCC', 'Phenotype', 'HP:0001402', (45, 48))	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('hsa_circ_0001649', 'Var', (113, 129))	('HCC', 'Gene', (45, 48))	('related', 'Reg', (133, 140))	('tumor', 'Disease', (159, 164))	('tumor thrombus', 'Disease', (159, 173))	('expression', 'MPA', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor thrombus', 'Disease', 'MESH:D013927', (159, 173))	('HCC', 'Gene', '619501', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
169801	30064463	The expression level of hsa_circ_0005986 in HCC cell lines, including HepG2, Huh7, SMMC7721, HCCLM3, MHCC97H, and MHCC97L, is significantly lower than that in the L02 normal liver cell line.	('lower', 'NegReg', (140, 145))	('SMMC7721', 'CellLine', 'CVCL:0534', (83, 91))	('hsa_circ_0005986', 'Var', (24, 40))	('Huh7', 'Gene', (77, 81))	('Huh7', 'Gene', '284424', (77, 81))	('HCC', 'Gene', '619501', (102, 105))	('HCC', 'Phenotype', 'HP:0001402', (102, 105))	('HepG2', 'CellLine', 'CVCL:0027', (70, 75))	('HCC', 'Gene', '619501', (93, 96))	('HCC', 'Phenotype', 'HP:0001402', (93, 96))	('HCC', 'Gene', (102, 105))	('HCC', 'Gene', '619501', (44, 47))	('HCC', 'Gene', (93, 96))	('HCC', 'Phenotype', 'HP:0001402', (44, 47))	('HCC', 'Gene', (44, 47))	('expression level', 'MPA', (4, 20))	('HCC', 'Gene', '619501', (115, 118))	('HCC', 'Phenotype', 'HP:0001402', (115, 118))	('HCC', 'Gene', (115, 118))
169802	30064463	Both hsa_circ_0005986 and Notch1 mRNA can bind to miR-129-5p, and downregulation of hsa_circ_0005986 releases miR-129-5p to decrease the level of Notch1 mRNA, accelerating the cell proliferation by promoting G0/G1 to S phase transition.	('miR-129-5p', 'Gene', '100302178', (110, 120))	('level', 'MPA', (137, 142))	('miR-129-5p', 'Gene', (110, 120))	('downregulation', 'Var', (66, 80))	('miR-129-5p', 'Gene', '100302178', (50, 60))	('G0/G1 to S phase transition', 'CPA', (208, 235))	('accelerating', 'PosReg', (159, 171))	('cell proliferation', 'biological_process', 'GO:0008283', ('176', '194'))	('Notch1', 'Gene', (146, 152))	('miR-129-5p', 'Gene', (50, 60))	('promoting', 'PosReg', (198, 207))	('cell proliferation', 'CPA', (176, 194))	('decrease', 'NegReg', (124, 132))	('Notch1', 'Gene', (26, 32))	('hsa_circ_0005986', 'Gene', (84, 100))	('Notch1', 'Gene', '4851', (146, 152))	('S phase', 'biological_process', 'GO:0051320', ('217', '224'))	('Notch1', 'Gene', '4851', (26, 32))
169805	30064463	ciRS-7 (hsa_circ_0001946) is significantly upregulated in HCC tissues and is negatively correlated with miR-7 expression.	('ciRS-7', 'Gene', '103611090', (0, 6))	('upregulated', 'PosReg', (43, 54))	('HCC', 'Gene', (58, 61))	('miR-7', 'Gene', (104, 109))	('miR-7', 'Gene', '10859', (104, 109))	('HCC', 'Gene', '619501', (58, 61))	('ciRS-7', 'Gene', (0, 6))	('negatively', 'NegReg', (77, 87))	('HCC', 'Phenotype', 'HP:0001402', (58, 61))	('hsa_circ_0001946', 'Var', (8, 24))
169807	30064463	When ciRS-7 is knocked down, miR-7 is released and proliferation and invasion of HCC cells are also significantly inhibited.	('knocked down', 'Var', (15, 27))	('ciRS-7', 'Gene', (5, 11))	('HCC', 'Gene', '619501', (81, 84))	('miR-7', 'Gene', (29, 34))	('HCC', 'Phenotype', 'HP:0001402', (81, 84))	('released', 'PosReg', (38, 46))	('ciRS-7', 'Gene', '103611090', (5, 11))	('miR-7', 'Gene', '10859', (29, 34))	('HCC', 'Gene', (81, 84))	('inhibited', 'NegReg', (114, 123))
169813	30064463	Knockdown of has_circ_0067934 significantly inhibits the proliferation, invasion, and metastasis of Hep3B and HuH7 cells and induces apoptosis.	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('HuH7', 'Gene', (110, 114))	('apoptosis', 'CPA', (133, 142))	('Hep3B', 'CellLine', 'CVCL:0326', (100, 105))	('has_circ_0067934', 'Var', (13, 29))	('HuH7', 'Gene', '284424', (110, 114))	('induces', 'Reg', (125, 132))	('inhibits', 'NegReg', (44, 52))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('invasion', 'CPA', (72, 80))	('metastasis', 'CPA', (86, 96))
169814	30064463	Hsa_circ_0005075 is considered to be closely related to cell adhesion, which is an important part of tumor cell proliferation and metastasis.	('cell proliferation', 'biological_process', 'GO:0008283', ('107', '125'))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('Hsa_circ_0005075', 'Var', (0, 16))	('cell adhesion', 'biological_process', 'GO:0007155', ('56', '69'))	('cell', 'CPA', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
169815	30064463	A recent study showed that the expression level of hsa_circ_0005075 is significantly different between HCC and normal liver tissues and is related to HCC tumor size.	('HCC', 'Gene', (150, 153))	('different', 'Reg', (85, 94))	('related', 'Reg', (139, 146))	('HCC', 'Phenotype', 'HP:0001402', (103, 106))	('HCC tumor', 'Disease', 'MESH:D006528', (150, 159))	('HCC', 'Gene', '619501', (103, 106))	('HCC', 'Gene', '619501', (150, 153))	('hsa_circ_0005075', 'Var', (51, 67))	('HCC', 'Phenotype', 'HP:0001402', (150, 153))	('HCC', 'Gene', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('expression level', 'MPA', (31, 47))	('HCC tumor', 'Disease', (150, 159))
169816	30064463	Larger tumor sizes correlated with higher expression of hsa_circ_0005075.	('tumor', 'Disease', (7, 12))	('expression', 'MPA', (42, 52))	('hsa_circ_0005075', 'Var', (56, 72))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('higher', 'PosReg', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
169817	30064463	Thus, hsa_circ_0005075 has the potential to become an ideal biomarker for HCC.	('HCC', 'Gene', '619501', (74, 77))	('hsa_circ_0005075', 'Var', (6, 22))	('HCC', 'Gene', (74, 77))	('HCC', 'Phenotype', 'HP:0001402', (74, 77))
169827	30064463	Hsa_circ_0046701 is highly expressed in glioma tissues.	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('glioma', 'Disease', (40, 46))	('Hsa_circ_0046701', 'Var', (0, 16))	('glioma', 'Disease', 'MESH:D005910', (40, 46))
169828	30064463	Silencing hsa_circ_0046701 upregulates miR-142, resulting in a decrease of ITGB8 and inhibition of cell proliferation and invasion.	('ITGB8', 'Gene', '3696', (75, 80))	('inhibition', 'NegReg', (85, 95))	('decrease', 'NegReg', (63, 71))	('miR-142', 'Gene', '406934', (39, 46))	('hsa_circ_0046701', 'Gene', (10, 26))	('upregulates', 'PosReg', (27, 38))	('ITGB8', 'Gene', (75, 80))	('miR-142', 'Gene', (39, 46))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('85', '117'))	('Silencing', 'Var', (0, 9))
169830	30064463	circ-SHKBP1 is highly expressed in high-grade gliomas, and knockdown of circ-SHKBP1 significantly inhibits cell proliferation and metastasis.	('cell proliferation', 'biological_process', 'GO:0008283', ('107', '125'))	('SHKBP1', 'Gene', (5, 11))	('SHKBP1', 'Gene', '92799', (77, 83))	('SHKBP1', 'Gene', '92799', (5, 11))	('SHKBP1', 'Gene', (77, 83))	('gliomas', 'Disease', (46, 53))	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('knockdown', 'Var', (59, 68))	('inhibits', 'NegReg', (98, 106))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
169834	30064463	Silencing cZNF292 inactivates the Wnt/beta-catenin signaling pathway in U87MG and U251 cells, thereby arresting cell cycle and inhibiting cell proliferation.	('beta-catenin', 'Gene', (38, 50))	('cZNF292', 'Gene', (10, 17))	('arrest', 'Disease', (102, 108))	('inactivates', 'NegReg', (18, 29))	('cell cycle', 'biological_process', 'GO:0007049', ('112', '122'))	('Silencing', 'Var', (0, 9))	('beta-catenin', 'Gene', '1499', (38, 50))	('signaling pathway', 'biological_process', 'GO:0007165', ('51', '68'))	('inhibiting', 'NegReg', (127, 137))	('U87MG', 'CellLine', 'CVCL:0022', (72, 77))	('cell proliferation', 'biological_process', 'GO:0008283', ('138', '156'))	('cell proliferation', 'CPA', (138, 156))	('U251', 'CellLine', 'CVCL:0021', (82, 86))	('cell cycle', 'CPA', (112, 122))	('arrest', 'Disease', 'MESH:D006323', (102, 108))
169835	30064463	Hsa_circ_022705 (circ-FBXW7) is lowly expressed in glioma tissues and cells, and it is positively correlated with the prognosis of patients with glioma.	('patients', 'Species', '9606', (131, 139))	('glioma', 'Disease', (145, 151))	('glioma', 'Disease', (51, 57))	('correlated with', 'Reg', (98, 113))	('FBXW7', 'Gene', (22, 27))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('glioma', 'Disease', 'MESH:D005910', (145, 151))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('FBXW7', 'Gene', '55294', (22, 27))	('Hsa_circ_022705', 'Var', (0, 15))
169837	30064463	Upregulation of FBXW7-185aa significantly inhibits the proliferation of tumor cells, while silencing this protein promotes the malignant phenotype.	('Upregulation', 'PosReg', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('FBXW7', 'Gene', (16, 21))	('inhibits', 'NegReg', (42, 50))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('tumor', 'Disease', (72, 77))	('malignant phenotype', 'CPA', (127, 146))	('promotes', 'PosReg', (114, 122))	('silencing', 'Var', (91, 100))	('FBXW7', 'Gene', '55294', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
169850	30064463	High-throughput microarray analysis has been used to identify six circRNAs that are differentially expressed in bladder cancer and normal tissues as follows: circPTK2 (hsa_circ_0005273), circTCF25 (hsa_circ_0041103), circBC048201 (hsa_circ_0061265), and circZFR (hsa_circ_0072088) are significantly upregulated and circTRIM24 (hsa_circ_0082582) and circFAM169A (hsa_circ_0007158) are downregulated.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('PTK2', 'Gene', '5747', (162, 166))	('bladder cancer', 'Disease', (112, 126))	('bladder cancer', 'Disease', 'MESH:D001749', (112, 126))	('hsa_circ_0061265', 'Var', (231, 247))	('upregulated', 'PosReg', (299, 310))	('bladder cancer', 'Phenotype', 'HP:0009725', (112, 126))	('PTK2', 'Gene', (162, 166))
169865	30064463	Hsa_circ_0000977 is abnormally upregulated in pancreatic cancer tissues, and silencing hsa_circ_0000977 inhibits cell proliferation and induces cell cycle arrest.	('arrest', 'Disease', 'MESH:D006323', (155, 161))	('cell proliferation', 'CPA', (113, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (46, 63))	('inhibits', 'NegReg', (104, 112))	('pancreatic cancer', 'Disease', (46, 63))	('arrest', 'Disease', (155, 161))	('silencing', 'Var', (77, 86))	('pancreatic cancer', 'Disease', 'MESH:D010190', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('144', '161'))	('hsa_circ_0000977', 'Gene', (87, 103))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (144, 161))	('induces', 'Reg', (136, 143))	('cell proliferation', 'biological_process', 'GO:0008283', ('113', '131'))
169866	30064463	The interaction of hsa_circ_0000977, hsa-miR-874-3p, and PLK1A has been verified by dual luciferase reporter assay and fluorescence in situ hybridization (FISH) assay, and inhibition of hsa_circ_0000977 can reduce the expression of PLK1.	('reduce', 'NegReg', (207, 213))	('miR', 'Gene', '220972', (41, 44))	('PLK1', 'Gene', (57, 61))	('miR', 'Gene', (41, 44))	('inhibition', 'Var', (172, 182))	('PLK1', 'Gene', (232, 236))	('PLK1', 'Gene', '5347', (232, 236))	('PLK1', 'Gene', '5347', (57, 61))	('expression', 'MPA', (218, 228))
169867	30064463	In animal experiments, silencing hsa_circ_0000977 inhibits tumor growth.	('hsa_circ_0000977', 'Gene', (33, 49))	('tumor', 'Disease', (59, 64))	('silencing', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('inhibits', 'NegReg', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
169876	30064463	The circRNA encoded by UBAP2 is the most prominently upregulated circRNA in osteosarcoma tissues, and patients with high circUBAP2 expression are often associated with a poor OS.	('UBAP2', 'Gene', (23, 28))	('osteosarcoma tissues', 'Disease', (76, 96))	('UBAP2', 'Gene', '55833', (23, 28))	('OS', 'Chemical', '-', (175, 177))	('high', 'Var', (116, 120))	('patients', 'Species', '9606', (102, 110))	('osteosarcoma', 'Phenotype', 'HP:0002669', (76, 88))	('osteosarcoma tissues', 'Disease', 'MESH:D012516', (76, 96))	('UBAP2', 'Gene', (125, 130))	('poor OS', 'Disease', (170, 177))	('upregulated', 'PosReg', (53, 64))	('UBAP2', 'Gene', '55833', (125, 130))
169878	30064463	Hsa_circ_0001564 is significantly overexpressed in osteosarcoma tissues and cells.	('osteosarcoma', 'Phenotype', 'HP:0002669', (51, 63))	('osteosarcoma tissues', 'Disease', 'MESH:D012516', (51, 71))	('Hsa_circ_0001564', 'Var', (0, 16))	('osteosarcoma tissues', 'Disease', (51, 71))	('overexpressed', 'PosReg', (34, 47))
169881	30064463	Hsa_circ_0009910 is also overexpressed in osteosarcoma cells.	('osteosarcoma', 'Disease', (42, 54))	('overexpressed', 'PosReg', (25, 38))	('osteosarcoma', 'Phenotype', 'HP:0002669', (42, 54))	('Hsa_circ_0009910', 'Var', (0, 16))	('osteosarcoma', 'Disease', 'MESH:D012516', (42, 54))
169882	30064463	Knockdown of circ_0009910 inhibits the proliferation of osteosarcoma cells, leading to cell cycle arrest and apoptosis.	('arrest', 'Disease', (98, 104))	('inhibits', 'NegReg', (26, 34))	('apoptosis', 'CPA', (109, 118))	('osteosarcoma', 'Phenotype', 'HP:0002669', (56, 68))	('osteosarcoma', 'Disease', (56, 68))	('proliferation', 'CPA', (39, 52))	('osteosarcoma', 'Disease', 'MESH:D012516', (56, 68))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('circ_0009910', 'Var', (13, 25))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))	('arrest', 'Disease', 'MESH:D006323', (98, 104))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('87', '104'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (87, 104))
169883	30064463	However, inhibition of miR-449a eliminates this effect.	('inhibition', 'Var', (9, 19))	('miR-449a', 'Gene', '554213', (23, 31))	('miR-449a', 'Gene', (23, 31))
169884	30064463	As the sponge of miR-449a, circ_0009910 upregulates the functional target gene IL6R and promotes the development of osteosarcoma.	('promotes', 'PosReg', (88, 96))	('IL6R', 'Gene', '3570', (79, 83))	('miR-449a', 'Gene', (17, 25))	('osteosarcoma', 'Phenotype', 'HP:0002669', (116, 128))	('upregulates', 'PosReg', (40, 51))	('osteosarcoma', 'Disease', 'MESH:D012516', (116, 128))	('miR-449a', 'Gene', '554213', (17, 25))	('IL6R', 'molecular_function', 'GO:0004915', ('79', '83'))	('IL6R', 'Gene', (79, 83))	('circ_0009910', 'Var', (27, 39))	('osteosarcoma', 'Disease', (116, 128))
169885	30064463	In osteosarcoma cells and tissues, hsa_circRNA_103801 is upregulated, while hsa_circRNA_104980 is downregulated.	('osteosarcoma', 'Disease', (3, 15))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('hsa_circRNA_103801', 'Var', (35, 53))	('upregulated', 'PosReg', (57, 68))
169886	30064463	The potential target miRNAs for hsa_circRNA_103801 include hsa-miR-338-3p, hsa-miR-370-3p, and hsa-miR-877-3p, which are involved in the HIF-1, Rap1, PI3K-Akt, VEGF, and angiogenesis pathways.	('miR', 'Gene', '220972', (99, 102))	('miR', 'Gene', (21, 24))	('HIF-1', 'Gene', '3091', (137, 142))	('Rap1', 'Gene', '5906', (144, 148))	('Akt', 'Gene', (155, 158))	('HIF-1', 'Gene', (137, 142))	('miR', 'Gene', (99, 102))	('Rap1', 'Gene', (144, 148))	('Akt', 'Gene', '207', (155, 158))	('PI3K', 'molecular_function', 'GO:0016303', ('150', '154'))	('VEGF', 'Gene', '7422', (160, 164))	('hsa_circRNA_103801', 'Var', (32, 50))	('VEGF', 'Gene', (160, 164))	('miR', 'Gene', '220972', (79, 82))	('miR', 'Gene', '220972', (63, 66))	('angiogenesis', 'biological_process', 'GO:0001525', ('170', '182'))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (79, 82))	('miR', 'Gene', (63, 66))
169887	30064463	The potential target miRNAs for hsa_circRNA_104980 are hsa-miR-660-3p and hsa-miR-1298-3p, which participate in the tight junction pathway.	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('tight junction', 'cellular_component', 'GO:0070160', ('116', '130'))	('miR', 'Gene', '220972', (59, 62))	('hsa_circRNA_104980', 'Var', (32, 50))	('miR', 'Gene', (59, 62))
169895	30064463	In addition, the OS rate of ccRCC patients with high expression of circ-RIAT1 is superior to that of patients with low circ-RIAT1.	('patients', 'Species', '9606', (101, 109))	('circ-RIAT1', 'Disease', 'None', (67, 77))	('circ-RIAT1', 'Disease', (119, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (28, 33))	('circ-RIAT1', 'Disease', 'None', (119, 129))	('patients', 'Species', '9606', (34, 42))	('ccRCC', 'Disease', (28, 33))	('high expression', 'Var', (48, 63))	('circ-RIAT1', 'Disease', (67, 77))	('OS', 'Chemical', '-', (17, 19))
169903	30064463	Hsa_circ_0022383 and hsa_circ_0022392 are the most significantly downregulated circRNAs and derived from FADS2 gene.	('FADS2', 'Gene', '9415', (105, 110))	('FADS2', 'Gene', (105, 110))	('circRNAs', 'MPA', (79, 87))	('downregulated', 'NegReg', (65, 78))	('Hsa_circ_0022383', 'Var', (0, 16))
169910	30064463	Functional analysis has revealed that knockdown of circRNA_100290 reduces CDK6 expression, induces G1/S arrest, and significantly inhibits the proliferation of SCC9 cell lines.	('circRNA_100290', 'Var', (51, 65))	('S arrest', 'Disease', (102, 110))	('SCC9', 'CellLine', 'CVCL:1685', (160, 164))	('CDK6', 'Gene', (74, 78))	('expression', 'MPA', (79, 89))	('reduces', 'NegReg', (66, 73))	('S arrest', 'Disease', 'MESH:D006323', (102, 110))	('CDK', 'molecular_function', 'GO:0004693', ('74', '77'))	('proliferation of SCC9 cell lines', 'CPA', (143, 175))	('induces', 'Reg', (91, 98))	('inhibits', 'NegReg', (130, 138))
169911	30064463	In a nude mouse model, interference with circRNA_100290 also reduces tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mouse', 'Species', '10090', (10, 15))	('tumor', 'Disease', (69, 74))	('reduces', 'NegReg', (61, 68))	('circRNA_100290', 'Var', (41, 55))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
169916	30064463	Overexpression of ciRS-7 is closely related to later TNM staging, lymph node infiltration, and postoperative recurrence.	('lymph node infiltration', 'CPA', (66, 89))	('related', 'Reg', (36, 43))	('TNM', 'Gene', (53, 56))	('ciRS-7', 'Gene', '103611090', (18, 24))	('ciRS-7', 'Gene', (18, 24))	('Overexpression', 'Var', (0, 14))	('TNM', 'Gene', '10178', (53, 56))
169917	30064463	The OS of cholangiocarcinoma patients with high ciRS-7 expression is inferior to that of patients with low ciRS-7 expression.	('cholangiocarcinoma', 'Disease', (10, 28))	('patients', 'Species', '9606', (29, 37))	('ciRS-7', 'Gene', '103611090', (48, 54))	('ciRS-7', 'Gene', '103611090', (107, 113))	('OS', 'Chemical', '-', (4, 6))	('high', 'Var', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('ciRS-7', 'Gene', (48, 54))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (10, 28))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (10, 28))	('patients', 'Species', '9606', (89, 97))	('ciRS-7', 'Gene', (107, 113))	('expression', 'Var', (55, 65))
169920	30064463	Overexpression of hsa_circ_0001649 inhibits cell proliferation, migration, and invasion but induces apoptosis of KMBC and Huh-28 cells.	('Huh-28', 'CellLine', 'CVCL:0336', (122, 128))	('induces', 'Reg', (92, 99))	('cell proliferation', 'CPA', (44, 62))	('inhibits', 'NegReg', (35, 43))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('cell proliferation', 'biological_process', 'GO:0008283', ('44', '62'))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('invasion', 'CPA', (79, 87))	('migration', 'CPA', (64, 73))	('apoptosis', 'CPA', (100, 109))	('hsa_circ_0001649', 'Var', (18, 34))
169922	30064463	circRNA-000284 is significantly upregulated in cervical cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cervical cancer', 'Disease', (47, 62))	('cervical cancer', 'Disease', 'MESH:D002583', (47, 62))	('circRNA-000284', 'Var', (0, 14))	('upregulated', 'PosReg', (32, 43))
169923	30064463	It promotes the proliferation and invasion of cervical cancer cells and that knockdown of circRNA-000284 causes G0/G1 cell cycle arrest, resulting in inhibition of cell proliferation and invasion.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('118', '135'))	('cervical cancer', 'Disease', 'MESH:D002583', (46, 61))	('arrest', 'Disease', (129, 135))	('cervical cancer', 'Disease', (46, 61))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('150', '182'))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (118, 135))	('cell proliferation', 'CPA', (164, 182))	('knockdown', 'Var', (77, 86))	('invasion', 'CPA', (34, 42))	('inhibition', 'NegReg', (150, 160))	('promotes', 'PosReg', (3, 11))	('arrest', 'Disease', 'MESH:D006323', (129, 135))	('circRNA-000284', 'Gene', (90, 104))	('proliferation', 'CPA', (16, 29))	('invasion', 'CPA', (187, 195))
169924	30064463	miR-506 is a miRNA related to circRNA-000284, and circRNA-000284 positively regulates the expression of Snail-2 which is a target gene of miR-506.	('Snail-2', 'Gene', '6591', (104, 111))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('Snail-2', 'Gene', (104, 111))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('miR', 'Gene', '220972', (138, 141))	('circRNA-000284', 'Var', (50, 64))	('expression', 'MPA', (90, 100))	('miR', 'Gene', (138, 141))	('regulates', 'Reg', (76, 85))	('miR-506', 'Gene', '574511', (0, 7))	('miR-506', 'Gene', (0, 7))	('miR-506', 'Gene', '574511', (138, 145))	('miR-506', 'Gene', (138, 145))
169926	30064463	Thus, circRNA-000284 is expected to be a new therapeutic target for cervical cancer.	('circRNA-000284', 'Var', (6, 20))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cervical cancer', 'Disease', (68, 83))	('cervical cancer', 'Disease', 'MESH:D002583', (68, 83))
169932	30064463	The combination of hsa_circ_006054, hsa_circ_100219, and hsa_circ_406697 is helpful for the diagnosis of breast cancer.	('hsa_circ_406697', 'Var', (57, 72))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('hsa_circ_006054', 'Var', (19, 34))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
169933	30064463	Hsa_circ_0067934, a potential prognostic marker for ESCC, is overexpressed in ESCC tissues and correlates with poor differentiation and more advanced TNM staging.	('poor', 'NegReg', (111, 115))	('TNM', 'Gene', (150, 153))	('Hsa_circ_0067934', 'Var', (0, 16))	('ESCC', 'Disease', (52, 56))	('TNM', 'Gene', '10178', (150, 153))	('overexpressed', 'PosReg', (61, 74))	('differentiation', 'CPA', (116, 131))
169935	30064463	The downregulation of circMTO1, circ-ITCH, and cSMARCA5 or upregulation of circRNA_100338 in HCC is associated with poor prognosis.	('HCC', 'Gene', '619501', (93, 96))	('-ITCH', 'Phenotype', 'HP:0000989', (36, 41))	('ITCH', 'Gene', (37, 41))	('HCC', 'Phenotype', 'HP:0001402', (93, 96))	('SMARCA5', 'Gene', '8467', (48, 55))	('upregulation', 'PosReg', (59, 71))	('HCC', 'Gene', (93, 96))	('MTO1', 'Gene', '25821', (26, 30))	('downregulation', 'NegReg', (4, 18))	('ITCH', 'Gene', '83737', (37, 41))	('MTO1', 'Gene', (26, 30))	('SMARCA5', 'Gene', (48, 55))	('circRNA_100338', 'Var', (75, 89))
169937	30064463	Overexpression of ciRS-7 in cholangiocarcinoma is significantly correlated with later TNM staging, lymph node infiltration, and postoperative recurrence, and it may be an independent negative prognostic biomarker with good sensitivity and specificity.	('cholangiocarcinoma', 'Disease', (28, 46))	('lymph', 'Disease', (99, 104))	('TNM', 'Gene', '10178', (86, 89))	('ciRS-7', 'Gene', '103611090', (18, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (28, 46))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (28, 46))	('ciRS-7', 'Gene', (18, 24))	('Overexpression', 'Var', (0, 14))	('TNM', 'Gene', (86, 89))	('correlated', 'Reg', (64, 74))
169938	30064463	Hsa_circ_0001649 has been reported to have potential diagnostic and prognostic value in gastric cancer, CRC, HCC, and cholangiocarcinoma, and it may be a sensitive indicator for distant metastasis in gastric cancer and HCC.	('gastric cancer', 'Disease', 'MESH:D013274', (200, 214))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('HCC', 'Gene', '619501', (109, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (200, 214))	('HCC', 'Phenotype', 'HP:0001402', (109, 112))	('Hsa_circ_0001649', 'Var', (0, 16))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('CRC', 'Disease', (104, 107))	('HCC', 'Gene', (109, 112))	('HCC', 'Gene', '619501', (219, 222))	('HCC', 'Phenotype', 'HP:0001402', (219, 222))	('gastric cancer', 'Disease', (200, 214))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (118, 136))	('CRC', 'Phenotype', 'HP:0030731', (104, 107))	('gastric cancer', 'Disease', (88, 102))	('HCC', 'Gene', (219, 222))	('cholangiocarcinoma', 'Disease', (118, 136))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (118, 136))
169940	30064463	Overexpression of circ-LDLRAD3 in pancreatic cancer is significantly correlated with venous and lymphatic infiltration as well as distant metastasis, and it is also a potential diagnostic marker for pancreatic cancer.	('pancreatic cancer', 'Disease', (199, 216))	('correlated', 'Reg', (69, 79))	('pancreatic cancer', 'Disease', 'MESH:D010190', (34, 51))	('pancreatic cancer', 'Disease', 'MESH:D010190', (199, 216))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('LDLRAD3', 'Gene', (23, 30))	('distant metastasis', 'CPA', (130, 148))	('LDLRAD3', 'Gene', '143458', (23, 30))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (34, 51))	('Overexpression', 'Var', (0, 14))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (199, 216))	('pancreatic cancer', 'Disease', (34, 51))
169942	30064463	For example, hsa_circ_002059, hsa_circ_0001017, and hsa_circ_0061276 can be stably detected in the plasma of gastric cancer patients.	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gastric cancer', 'Disease', (109, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('hsa_circ_0001017', 'Var', (30, 46))	('hsa_circ_0061276', 'Var', (52, 68))	('patients', 'Species', '9606', (124, 132))	('hsa_circ_002059', 'Var', (13, 28))
169945	30064463	The sensitivity and specificity of hsa_circ_0000190 as a diagnostic marker for gastric cancer are even better than that of CEA and CA19-9.	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('hsa_circ_0000190', 'Var', (35, 51))	('CEA', 'Gene', (123, 126))	('CEA', 'Gene', '5670', (123, 126))	('gastric cancer', 'Disease', (79, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))
169946	30064463	The plasma level of hsa_circ_0000745 in gastric cancer patients is related to lymph node metastasis, and it has a good diagnostic value in combination with CEA.	('related', 'Reg', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('CEA', 'Gene', (156, 159))	('gastric cancer', 'Disease', (40, 54))	('plasma level', 'MPA', (4, 16))	('lymph node metastasis', 'CPA', (78, 99))	('CEA', 'Gene', '5670', (156, 159))	('gastric cancer', 'Disease', 'MESH:D013274', (40, 54))	('hsa_circ_0000745', 'Var', (20, 36))	('patients', 'Species', '9606', (55, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (40, 54))
169949	30064463	Alternatively, it is possible to interfere with back-splicing by antisense oligonucleotides that are complementary to the back-splice signals in the precursor mRNA.	('antisense oligonucleotides', 'Var', (65, 91))	('splicing', 'biological_process', 'GO:0045292', ('53', '61'))	('oligonucleotides', 'Chemical', 'MESH:D009841', (75, 91))	('back-splicing', 'MPA', (48, 61))	('interfere', 'Reg', (33, 42))
169955	30064463	Because some circRNAs serve as a template for protein expression, cassettes containing tumor suppressor proteins can convert circRNAs into an effective treatment method for tumors.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('tumor', 'Disease', (87, 92))	('tumor suppressor', 'biological_process', 'GO:0051726', ('87', '103'))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('87', '103'))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('cassettes', 'Var', (66, 75))
169981	30334005	The most common genetic event in ccRCC carcinogenesis is loss of the von Hippel Lindau (VHL) gene, a key tumor suppressor on chromosome 3p25 with one of its main functions being to downregulate hypoxia inducible factor 1 alpha (HIF1alpha) and 2 alpha (HIF2alpha) via VHL ubiquitinating HIF leading to proteasomal degradation.	('HIF1alpha) and 2 alpha', 'Gene', '3091;2034', (228, 250))	('HIF2alpha', 'Gene', (252, 261))	('downregulate', 'NegReg', (181, 193))	('proteasomal degradation', 'MPA', (301, 324))	('chromosome', 'cellular_component', 'GO:0005694', ('125', '135'))	('RCC', 'Disease', (35, 38))	('von Hippel Lindau', 'Gene', '7428', (69, 86))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('105', '121'))	('von Hippel Lindau', 'Gene', (69, 86))	('VHL ubiquitinating HIF', 'Disease', 'MESH:D006623', (267, 289))	('tumor suppressor', 'biological_process', 'GO:0051726', ('105', '121'))	('tumor', 'Disease', (105, 110))	('VHL', 'Disease', (88, 91))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('VHL', 'Disease', 'MESH:D006623', (267, 270))	('VHL ubiquitinating HIF', 'Disease', (267, 289))	('HIF2alpha', 'Gene', '2034', (252, 261))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('VHL', 'Disease', (267, 270))	('degradation', 'biological_process', 'GO:0009056', ('313', '324'))	('hypoxia inducible factor 1 alpha', 'Gene', '3091', (194, 226))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('hypoxia inducible factor 1 alpha', 'Gene', (194, 226))	('loss', 'Var', (57, 61))	('VHL', 'Disease', 'MESH:D006623', (88, 91))
170039	30334005	Thus, early phase clinical studies are underway to evaluate the safety and efficacy of anti- PD-1 receptor antibody in the presurgical setting both as single-agent therapy and in combination with anti-VEGF therapy or with ipilimumab, an anti-CTLA4 antibody.	('antibody', 'Var', (107, 115))	('antibody', 'molecular_function', 'GO:0003823', ('107', '115'))	('VEGF', 'Gene', (201, 205))	('antibody', 'cellular_component', 'GO:0019815', ('248', '256'))	('antibody', 'cellular_component', 'GO:0042571', ('107', '115'))	('antibody', 'cellular_component', 'GO:0019814', ('248', '256'))	('antibody', 'molecular_function', 'GO:0003823', ('248', '256'))	('anti-', 'Var', (87, 92))	('ipilimumab', 'Chemical', 'MESH:D000074324', (222, 232))	('CTLA4', 'Gene', '1493', (242, 247))	('VEGF', 'Gene', '7422', (201, 205))	('antibody', 'cellular_component', 'GO:0019815', ('107', '115'))	('CTLA4', 'Gene', (242, 247))	('antibody', 'cellular_component', 'GO:0042571', ('248', '256'))	('antibody', 'cellular_component', 'GO:0019814', ('107', '115'))
170074	33113844	The lectin pathway is activated by the recognition of sugar residues through a complex that is structurally and functionally very similar to the classical pathway.	('lectin', 'molecular_function', 'GO:0005530', ('4', '10'))	('sugar residues', 'Var', (54, 68))	('lectin pathway', 'Pathway', (4, 18))	('sugar', 'Chemical', 'MESH:D000073893', (54, 59))	('recognition', 'Var', (39, 50))
170084	33113844	Covalent deposition of C3b on the target cell by any of the three pathways induces opsonization, allowing the elimination of the pathogen/stressed cell by phagocytosis.	('C3b', 'Gene', (23, 26))	('C3b', 'Gene', '718', (23, 26))	('Covalent', 'Var', (0, 8))	('opsonization', 'MPA', (83, 95))	('phagocytosis', 'biological_process', 'GO:0006909', ('155', '167'))	('induces', 'Reg', (75, 82))	('opsonization', 'biological_process', 'GO:0008228', ('83', '95'))
170086	33113844	This triggers the terminal pathway with the generation of the C5a and C5b fragments, and finally the last reaction with the formation of the membrane attack complex (MAC: composed by the molecules C5b, C6, C7, C8 and C9).	('MAC', 'cellular_component', 'GO:0097423', ('166', '169'))	('C5b', 'Gene', (197, 200))	('triggers', 'Reg', (5, 13))	('formation', 'biological_process', 'GO:0009058', ('124', '133'))	('membrane attack complex', 'cellular_component', 'GO:0005579', ('141', '164'))	('C5b', 'Gene', '727', (70, 73))	('MAC', 'cellular_component', 'GO:0005579', ('166', '169'))	('C5b', 'Gene', (70, 73))	('C5a', 'MPA', (62, 65))	('C5b', 'Gene', '727', (197, 200))	('C9', 'Var', (217, 219))
170087	33113844	Complement activation allows the formation of three different effectors: Opsonins (C3b, C4b and C1q) that can bind the target cell surface and promote its clearance.	('cell surface', 'cellular_component', 'GO:0009986', ('126', '138'))	('clearance', 'CPA', (155, 164))	('C3b', 'Gene', '718', (83, 86))	('C1q', 'cellular_component', 'GO:0062167', ('96', '99'))	('formation', 'biological_process', 'GO:0009058', ('33', '42'))	('C4b', 'Gene', (88, 91))	('promote', 'PosReg', (143, 150))	('C4b', 'Gene', '721', (88, 91))	('Complement activation', 'biological_process', 'GO:0006956', ('0', '21'))	('C3b', 'Gene', (83, 86))	('C1q', 'Var', (96, 99))	('bind', 'Interaction', (110, 114))
170089	33113844	C5aR1 and C5aR2 seem to have opposite effects, especially in the tumor context.	('C5aR2', 'Gene', '27202', (10, 15))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('C5aR1', 'Var', (0, 5))	('C5aR2', 'Gene', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
170099	33113844	This study is in line with previous observations of an abnormal expression of complement proteins in different type of cancer, especially C1 complex, C3, C4, C5, C3aR, C5aR1, FB, FH, FI, CD46, CD55, CD59.	('FH', 'Gene', '3075', (179, 181))	('expression', 'MPA', (64, 74))	('C1 complex, C3, C4, C5', 'Gene', '720', (138, 160))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('CD46', 'Gene', '4179', (187, 191))	('abnormal expression of complement proteins', 'Phenotype', 'HP:0005339', (55, 97))	('CD46', 'Gene', (187, 191))	('CD55', 'Gene', '1604', (193, 197))	('cancer', 'Disease', (119, 125))	('CD55', 'Gene', (193, 197))	('C5aR1', 'Var', (168, 173))	('C3aR', 'Var', (162, 166))	('CD59', 'Gene', (199, 203))	('CD59', 'Gene', '966', (199, 203))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
170100	33113844	Bioinformatic analysis of the prognostic impact of the complement genes allowed to classify cancers in four groups: protective complement (concomitant occurrence of favorable prognosis associated with high expression of complement genes), protective C3 (favorable prognosis found only for high C3 expression but not for the other genes), aggressive complement (concomitant occurrence of poor prognosis, associated with high expression of complement genes) and uncertain significance of complement (when no particular pattern is observed) (Figure 2).	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('protective complement', 'Disease', (116, 137))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('complement genes', 'Gene', (438, 454))	('aggressive complement', 'Disease', 'MESH:D000081207', (338, 359))	('cancers', 'Disease', (92, 99))	('high', 'Var', (419, 423))	('aggressive complement', 'Disease', (338, 359))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('complement genes', 'Gene', (220, 236))
170106	33113844	In 1996, in thyroid carcinoma the presence of IgG, together with C4d, C3d and C5-positive staining suggested tumor-specific classical pathway activation.	('thyroid carcinoma', 'Disease', 'MESH:D013964', (12, 29))	('tumor', 'Disease', (109, 114))	('activation', 'PosReg', (142, 152))	('C3d', 'Gene', '100861467', (70, 73))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (12, 29))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('thyroid carcinoma', 'Disease', (12, 29))	('IgG', 'Protein', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('C3d', 'Gene', (70, 73))	('presence', 'Var', (34, 42))
170116	33113844	The first clue was the slower tumor growth in case of C3, C4 or C5aR deficiency in a TC1 cancer mouse model.	('C5aR', 'Gene', (64, 68))	('slower', 'NegReg', (23, 29))	('mouse', 'Species', '10090', (96, 101))	('C1', 'Chemical', 'MESH:C400149', (86, 88))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('deficiency', 'Var', (69, 79))	('cancer', 'Disease', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
170122	33113844	Its cleavage product C3a supports the recruitment of C3aR+ macrophages, and perturbation of C3a/C3aR axis disrupts immune infiltration, slowing tumor growth.	('C3a', 'Gene', '718', (96, 99))	('age', 'Gene', '5973', (9, 12))	('perturbation', 'Var', (76, 88))	('age', 'Gene', (66, 69))	('C3a', 'Gene', (21, 24))	('C3a', 'Gene', '718', (21, 24))	('tumor', 'Disease', (144, 149))	('C3a', 'Gene', (53, 56))	('immune infiltration', 'CPA', (115, 134))	('C3a', 'Gene', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('slowing', 'NegReg', (136, 143))	('C3a', 'Gene', '718', (92, 95))	('age', 'Gene', '5973', (66, 69))	('C3a', 'Gene', '718', (53, 56))	('age', 'Gene', (9, 12))	('disrupts', 'NegReg', (106, 114))	('C3a', 'Gene', (96, 99))	('recruitment', 'MPA', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
170135	33113844	The PTX3 deficiency leads to a chronic complement-mediated inflammation, favoring spontaneous skin carcinoma development in a mice model.	('inflammation', 'biological_process', 'GO:0006954', ('59', '71'))	('favoring', 'PosReg', (73, 81))	('mice', 'Species', '10090', (126, 130))	('leads to', 'Reg', (20, 28))	('skin carcinoma', 'Disease', (94, 108))	('PTX3', 'Gene', (4, 8))	('skin carcinoma', 'Disease', 'MESH:D012878', (94, 108))	('deficiency', 'Var', (9, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('inflammation', 'Disease', 'MESH:D007249', (59, 71))	('inflammation', 'Disease', (59, 71))
170141	33113844	This context-dependent role of the complement system is also true for the pro-inflammatory C3a and C5a molecules that can have anti-tumor functions and appear to be crucial for a good tumor response to radiotherapy.	('C5a', 'Var', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('C3a', 'Gene', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (184, 189))	('C3a', 'Gene', '718', (91, 94))	('tumor', 'Disease', (132, 137))
170142	33113844	In a carcinogen-induced cSCC model, C5a has an anti-tumoral impact, while in a virus-induced mouse model of cSCC, C5a has pro-tumoral impact, with the specificity to be generated independently of complement.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mouse', 'Species', '10090', (93, 98))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('cSCC', 'Phenotype', 'HP:0006739', (24, 28))	('C5a', 'Var', (36, 39))	('cSCC', 'Phenotype', 'HP:0006739', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (126, 131))
170143	33113844	Indeed, in a syngeneic lymphoma mouse model, the tumor cells producing low levels of C5a are more susceptible to apoptosis and less proliferative, leading to a smaller tumor size.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('C5a', 'Var', (85, 88))	('apoptosis', 'biological_process', 'GO:0006915', ('113', '122'))	('lymphoma', 'Disease', 'MESH:D008223', (23, 31))	('tumor', 'Disease', (168, 173))	('apoptosis', 'CPA', (113, 122))	('proliferative', 'CPA', (132, 145))	('lymphoma', 'Phenotype', 'HP:0002665', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('less', 'NegReg', (127, 131))	('mouse', 'Species', '10090', (32, 37))	('apoptosis', 'biological_process', 'GO:0097194', ('113', '122'))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('lymphoma', 'Disease', (23, 31))	('smaller', 'NegReg', (160, 167))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
170145	33113844	However, tumors with high levels of C5a present an accelerated tumor growth with less CD4+ and CD8+ T cells, in the tumor, the spleen and the tumor-draingin lymph nodes.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('CD4', 'Gene', (86, 89))	('CD8', 'Gene', '925', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('C5a', 'Var', (36, 39))	('high', 'Var', (21, 25))	('tumor', 'Disease', (9, 14))	('less', 'NegReg', (81, 85))	('tumor-draingin lymph', 'Disease', (142, 162))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('CD8', 'Gene', (95, 98))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', (142, 147))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('accelerated', 'PosReg', (51, 62))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor-draingin lymph', 'Disease', 'MESH:D000072717', (142, 162))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('CD4', 'Gene', '920', (86, 89))	('tumors', 'Disease', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (116, 121))
170153	33113844	Tissue staining and transcriptomic analysis reveal that in many cancers types the presence of complement proteins is associated with a worse outcome for the patient.	('patient', 'Species', '9606', (157, 164))	('associated', 'Reg', (117, 127))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('complement proteins', 'Protein', (94, 113))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('presence', 'Var', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
170155	33113844	In human prostate, breast, cancer or neuroblastoma, anti-tumor role of C1q is described, as an apoptosis inducer.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('neuroblastoma', 'Disease', 'MESH:D009447', (37, 50))	('human', 'Species', '9606', (3, 8))	('apoptosis', 'CPA', (95, 104))	('neuroblastoma', 'Disease', (37, 50))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('95', '104'))	('apoptosis', 'biological_process', 'GO:0006915', ('95', '104'))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('C1q', 'Var', (71, 74))	('neuroblastoma', 'Phenotype', 'HP:0003006', (37, 50))	('C1q', 'cellular_component', 'GO:0062167', ('71', '74'))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('tumor', 'Disease', (57, 62))
170156	33113844	C1q activates WWOX, a tumor suppressor gene, then the phosphorylated form of WOX1 accumulates in nuclei and sends anti-proliferative and pro-apoptotic signals.	('WWOX', 'Gene', (14, 18))	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('22', '38'))	('C1q', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('WWOX', 'Gene', '51741', (14, 18))	('accumulates', 'PosReg', (82, 93))	('tumor', 'Disease', (22, 27))	('activates', 'PosReg', (4, 13))	('WOX1', 'Gene', '51741', (77, 81))	('WOX1', 'Gene', (77, 81))	('tumor suppressor', 'biological_process', 'GO:0051726', ('22', '38'))
170158	33113844	By using its globular domains, C1q induces apoptosis via TNF-alpha (Tumor Necrosis Factor) and Fas.	('Necrosis', 'biological_process', 'GO:0008220', ('74', '82'))	('induces', 'PosReg', (35, 42))	('C1q', 'Var', (31, 34))	('Tumor', 'Phenotype', 'HP:0002664', (68, 73))	('apoptosis', 'CPA', (43, 52))	('Necrosis', 'biological_process', 'GO:0008219', ('74', '82'))	('Tumor Necrosis Factor', 'molecular_function', 'GO:0005164', ('68', '89'))	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('Tumor Necrosis Factor', 'Gene', (68, 89))	('TNF-alpha', 'Gene', '7124', (57, 66))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('C1q', 'cellular_component', 'GO:0062167', ('31', '34'))	('Necrosis', 'biological_process', 'GO:0019835', ('74', '82'))	('Necrosis', 'biological_process', 'GO:0001906', ('74', '82'))	('TNF-alpha', 'Gene', (57, 66))	('Necrosis', 'biological_process', 'GO:0070265', ('74', '82'))	('Tumor Necrosis Factor', 'Gene', '7124', (68, 89))
170159	33113844	In contrast, in melanoma, C1q favors proliferation and migration of tumor cells, increases metastasis, and decreases survival.	('tumor', 'Disease', (68, 73))	('decreases', 'NegReg', (107, 116))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('metastasis', 'CPA', (91, 101))	('melanoma', 'Disease', (16, 24))	('C1q', 'Var', (26, 29))	('favors', 'PosReg', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('proliferation', 'CPA', (37, 50))	('survival', 'CPA', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('C1q', 'cellular_component', 'GO:0062167', ('26', '29'))	('increases', 'PosReg', (81, 90))
170164	33113844	In cSCC, knock-down of C1s, C1r, FB, FH and FI exerts similar effects on the tumor growth.	('FH', 'Gene', '3075', (37, 39))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('C1r', 'Gene', '715', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cSCC', 'Phenotype', 'HP:0006739', (3, 7))	('knock-down', 'Var', (9, 19))	('C1s', 'Gene', '716', (23, 26))	('tumor', 'Disease', (77, 82))	('C1r', 'Gene', (28, 31))	('C1s', 'Gene', (23, 26))
170171	33113844	The recognition of the anaphylatoxins by their receptors (C3aR, C5aR1 and C5aR2) present at the surface of some tumor cells leads to the activation of the signaling pathways PI3K, Erk 1/2 and AKT.	('AKT', 'Gene', (192, 195))	('C5aR2', 'Gene', (74, 79))	('Erk 1/2', 'Gene', '5595;5594', (180, 187))	('Erk 1/2', 'Gene', (180, 187))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('AKT', 'Gene', '207', (192, 195))	('C3aR', 'Var', (58, 62))	('signaling pathways PI3K', 'Pathway', (155, 178))	('C5aR2', 'Gene', '27202', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('activation', 'PosReg', (137, 147))	('tumor', 'Disease', (112, 117))	('PI3K', 'molecular_function', 'GO:0016303', ('174', '178'))	('Erk 1', 'molecular_function', 'GO:0004707', ('180', '185'))
170175	33113844	Indeed, in mouse models, C5 deficiency drastically decreases the hepatic metastasis in colorectal cancer and C5aR facilitates the lung metastasis in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mouse', 'Species', '10090', (11, 16))	('colorectal cancer', 'Phenotype', 'HP:0003003', (87, 104))	('lung metastasis', 'CPA', (130, 145))	('facilitates', 'PosReg', (114, 125))	('C5aR', 'Var', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('colorectal cancer', 'Disease', (87, 104))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('C5 deficiency drastically decreases the hepatic metastasis', 'Disease', 'MESH:C537005', (25, 83))	('breast cancer', 'Disease', (149, 162))	('colorectal cancer', 'Disease', 'MESH:D015179', (87, 104))
170185	33113844	This function is, though, also context-dependent, because in a spontaneous model of breast cancer, C1q-/- mice have enhanced neoangiogenesis and hence, bigger tumors.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('enhanced', 'PosReg', (116, 124))	('mice', 'Species', '10090', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('C1q', 'cellular_component', 'GO:0062167', ('99', '102'))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('neoangiogenesis', 'CPA', (125, 140))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('C1q-/-', 'Var', (99, 105))	('breast cancer', 'Disease', (84, 97))
170197	33113844	The modifications of expression are not only found locally inside the tumor but also in the systemic compartment.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('expression', 'MPA', (21, 31))	('modifications', 'Var', (4, 17))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
170211	33113844	C5aR1 seems to have pro-tumoral role, whereas C5aR2 has more limited impact but tends to modulate the tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('C5aR2', 'Gene', '27202', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('C5aR1', 'Var', (0, 5))	('modulate', 'Reg', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', (102, 107))	('C5aR2', 'Gene', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
170219	33113844	Indeed, the study of the literature highlights cancer types with pro-tumor effects of C3aR/C5aR and others, with anti-tumor effects.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('cancer', 'Disease', (47, 53))	('tumor', 'Disease', (118, 123))	('C3aR/C5aR', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
170231	33113844	In vitro, binding of submaximal C1q promotes complement-dependent cytotoxicity (CDC) of B cells opsonized with anti-CD20 mAbs Ofatumumab or Rituximab.	('submaximal', 'Var', (21, 31))	('CD20', 'Gene', '54474', (116, 120))	('CD20', 'Gene', (116, 120))	('cytotoxicity', 'Disease', 'MESH:D064420', (66, 78))	('binding', 'molecular_function', 'GO:0005488', ('10', '17'))	('binding', 'Interaction', (10, 17))	('Rituximab', 'Chemical', 'MESH:D000069283', (140, 149))	('C1q', 'Protein', (32, 35))	('complement-dependent cytotoxicity', 'biological_process', 'GO:0097278', ('45', '78'))	('Ofatumumab', 'Chemical', 'MESH:C527517', (126, 136))	('cytotoxicity', 'Disease', (66, 78))	('C1q', 'cellular_component', 'GO:0062167', ('32', '35'))	('promotes', 'PosReg', (36, 44))
170268	33113844	This work was also supported also by grants from CARPEM (ExhauCRF program), INCa (HTE program), Canceropole Ile de France (R17054DD), Association pour la recherche en therapeutiques innovantes en cancerologie (ARTIC) to CSF.	('R17054DD', 'Var', (123, 131))	('HTE', 'Gene', '10005', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('HTE', 'Gene', (82, 85))	('INCa', 'Gene', '440068', (76, 80))	('INCa', 'Gene', (76, 80))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('Cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Cancer', 'Disease', (96, 102))	('cancer', 'Disease', (196, 202))	('Cancer', 'Disease', 'MESH:D009369', (96, 102))
170277	31159774	In the Oncomine database, FBXO11 mRNA levels were lower in normal tissues than in cancer tissues, including clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), hereditary ccRCC, non-hereditary ccRCC, VHL mutant ccRCC and VHL wild-type ccRCC.	('Oncomine', 'Chemical', '-', (7, 15))	('RCC', 'Disease', 'MESH:C538614', (223, 226))	('VHL', 'Gene', (228, 231))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (108, 139))	('cancer', 'Disease', (82, 88))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (149, 179))	('mutant', 'Var', (232, 238))	('RCC', 'Disease', (241, 244))	('RCC', 'Phenotype', 'HP:0005584', (241, 244))	('ccRCC', 'Phenotype', 'HP:0006770', (263, 268))	('RCC', 'Disease', (265, 268))	('ccRCC', 'Phenotype', 'HP:0006770', (239, 244))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('RCC', 'Disease', (201, 204))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('FBXO11', 'Gene', (26, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (199, 204))	('VHL', 'Gene', '7428', (228, 231))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (114, 139))	('RCC', 'Disease', 'MESH:C538614', (241, 244))	('cell renal cell carcinoma', 'Disease', (114, 139))	('papillary renal cell carcinoma', 'Disease', (149, 179))	('pRCC', 'Gene', '5546', (181, 185))	('RCC', 'Disease', 'MESH:C538614', (265, 268))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (159, 179))	('ccRCC', 'Phenotype', 'HP:0006770', (221, 226))	('lower', 'NegReg', (50, 55))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('VHL', 'Gene', (249, 252))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (119, 139))	('ccRCC', 'Phenotype', 'HP:0006770', (141, 146))	('RCC', 'Disease', (182, 185))	('RCC', 'Disease', (143, 146))	('pRCC', 'Phenotype', 'HP:0006766', (181, 185))	('RCC', 'Phenotype', 'HP:0005584', (223, 226))	('RCC', 'Disease', (223, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('VHL', 'Gene', '7428', (249, 252))	('pRCC', 'Gene', (181, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (149, 179))	('RCC', 'Disease', 'MESH:C538614', (143, 146))
170285	31159774	Although RCC-related mortality has decreased due to the advent of minimally invasive surgery, targeted therapy, etc., it is still a major health concern in Asia.	('RCC', 'Disease', 'MESH:C538614', (9, 12))	('RCC', 'Disease', (9, 12))	('targeted therapy', 'Var', (94, 110))	('RCC', 'Phenotype', 'HP:0005584', (9, 12))
170317	31159774	1c), as well as than that in VHL mutant and wild-type ccRCC (P < 0.001, F = 13.30, Fig.	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('VHL', 'Gene', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('VHL', 'Gene', '7428', (29, 32))	('mutant', 'Var', (33, 39))
170331	31159774	Incorporation of FBXO11 increased the predictive value of these three models, namely, when assessing OS: 0.703 versus 0.674 for the UISS score cohort, and 0.676 versus 0.598 for the SSIGN score cohort (Table 3).	('predictive', 'MPA', (38, 48))	('Incorporation', 'Var', (0, 13))	('OS', 'Chemical', '-', (101, 103))	('FBXO11', 'Gene', (17, 23))	('increased', 'PosReg', (24, 33))
170337	31159774	Taken together, these data suggest that high FBXO11 expression is associated with the degree of malignancy and poor patient prognosis for ccRCC.	('high', 'Var', (40, 44))	('malignancy', 'Disease', 'MESH:D009369', (96, 106))	('patient', 'Species', '9606', (116, 123))	('malignancy', 'Disease', (96, 106))	('expression', 'MPA', (52, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('FBXO11', 'Gene', (45, 51))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))
170347	31159774	FBXO11 gene silencing led to the development of diffuse large B-cell lymphoma (DLBCL) by targeting the degradation of Bcl-6, while FBXO11 inactivation resulted in abnormal germinal-centre formation.	('targeting', 'NegReg', (89, 98))	('gene silencing', 'biological_process', 'GO:0016458', ('7', '21'))	('B-cell lymphoma', 'Disease', (62, 77))	('gene', 'Var', (7, 11))	('lymphoma', 'Phenotype', 'HP:0002665', (69, 77))	('Bcl-6', 'Gene', '604', (118, 123))	('inactivation', 'Var', (138, 150))	('formation', 'biological_process', 'GO:0009058', ('188', '197'))	('germinal-centre formation', 'CPA', (172, 197))	('Bcl-6', 'Gene', (118, 123))	('FBXO11', 'Gene', (0, 6))	('degradation', 'biological_process', 'GO:0009056', ('103', '114'))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (62, 77))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (62, 77))
170351	31159774	For example, the Jeff mouse model of chronic otitis media harbours a FBXO11 mutation, which interferes with TGF-betasignalling.	('otitis media', 'Phenotype', 'HP:0000388', (45, 57))	('otitis', 'Disease', 'MESH:D010031', (45, 51))	('chronic otitis', 'Phenotype', 'HP:0000389', (37, 51))	('FBXO11', 'Gene', (69, 75))	('mouse', 'Species', '10090', (22, 27))	('mutation', 'Var', (76, 84))	('otitis', 'Disease', (45, 51))
170363	30815591	Clear cell RCC (ccRCC) accounts for the majority of RCC, which have mutations or epigenetic silencing of the von Hippel-Lindau (VHL) gene.	('RCC', 'Disease', (18, 21))	('von Hippel-Lindau', 'Gene', '7428', (109, 126))	('epigenetic silencing', 'Var', (81, 101))	('VHL', 'Gene', '7428', (128, 131))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('mutations', 'Var', (68, 77))	('von Hippel-Lindau', 'Gene', (109, 126))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (18, 21))	('VHL', 'Gene', (128, 131))
170368	30815591	However, 15d-PGJ2 did not increase cytotoxicities of topoisomerase inhibitors on VHL-negative 786-O cells.	('15d-PGJ2', 'Chemical', 'MESH:C097240', (9, 17))	('cytotoxicities', 'Disease', 'MESH:D064420', (35, 49))	('VHL', 'Gene', (81, 84))	('VHL', 'Gene', '7428', (81, 84))	('15d-PGJ2', 'Var', (9, 17))	('topoisomerase', 'molecular_function', 'GO:0003917', ('53', '66'))	('topoisomerase', 'molecular_function', 'GO:0003918', ('53', '66'))	('cytotoxicities', 'Disease', (35, 49))
170369	30815591	In addition, the 15d-PGJ2-enhanced antitumor activity of topoisomerase inhibitors was detected in neither VHL-positive nor VHL-negative RCC4 cells.	('topoisomerase', 'molecular_function', 'GO:0003917', ('57', '70'))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (17, 25))	('topoisomerase', 'molecular_function', 'GO:0003918', ('57', '70'))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('VHL', 'Gene', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('VHL', 'Gene', (106, 109))	('15d-PGJ2-enhanced', 'PosReg', (17, 34))	('VHL', 'Gene', '7428', (123, 126))	('15d-PGJ2-enhanced', 'Var', (17, 34))	('tumor', 'Disease', (39, 44))	('VHL', 'Gene', '7428', (106, 109))	('RCC4', 'Gene', (136, 140))	('RCC4', 'Gene', '84925', (136, 140))
170370	30815591	Our finding indicated that 15d-PGJ2 enhanced the antitumor activity of topoisomerase inhibitors independently of VHL.	('15d-PGJ2', 'Var', (27, 35))	('VHL', 'Gene', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('topoisomerase', 'Protein', (71, 84))	('VHL', 'Gene', '7428', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('topoisomerase', 'molecular_function', 'GO:0003917', ('71', '84'))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (27, 35))	('topoisomerase', 'molecular_function', 'GO:0003918', ('71', '84'))	('tumor', 'Disease', (53, 58))	('enhanced', 'PosReg', (36, 44))
170379	30815591	Although synergistic effect of 15d-PGJ2 and VP-16 on Caki-2 cells could not be detected in the absence of serum, 15d-PGJ2 elevated the anti-tumor activity of VP-16 in the presence of serum.	('VP-16', 'Gene', '3054', (44, 49))	('VP-16', 'Gene', '3054', (158, 163))	('VP-16', 'Gene', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (113, 121))	('VP-16', 'Gene', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('Caki-2', 'CellLine', 'CVCL:0235', (53, 59))	('elevated', 'PosReg', (122, 130))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (31, 39))	('15d-PGJ2', 'Var', (113, 121))	('tumor', 'Disease', (140, 145))
170385	30815591	15d-PGJ2 inhibits proliferation of primary neurons and neuroblastoma x DRG neuron hybrid cell line N18D3 via down-regulating PI3K/Akt pathway.	('neuroblastoma', 'Disease', (55, 68))	('15d-PGJ2', 'Var', (0, 8))	('PI3K', 'molecular_function', 'GO:0016303', ('125', '129'))	('proliferation', 'CPA', (18, 31))	('down-regulating', 'NegReg', (109, 124))	('neuroblastoma', 'Phenotype', 'HP:0003006', (55, 68))	('Akt', 'Gene', '207', (130, 133))	('inhibits', 'NegReg', (9, 17))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (0, 8))	('Akt', 'Gene', (130, 133))	('neuroblastoma', 'Disease', 'MESH:D009447', (55, 68))
170411	30815591	As shown in supplemental data 1, we confirmed that 15d-PGJ2 significantly enhanced the cytotoxicity of topoisomerase inhibitors.	('cytotoxicity', 'Disease', 'MESH:D064420', (87, 99))	('topoisomerase', 'molecular_function', 'GO:0003918', ('103', '116'))	('15d-PGJ2', 'Var', (51, 59))	('topoisomerase', 'molecular_function', 'GO:0003917', ('103', '116'))	('cytotoxicity', 'Disease', (87, 99))	('enhanced', 'PosReg', (74, 82))	('topoisomerase', 'Protein', (103, 116))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (51, 59))
170417	30815591	1D, 15d-PGJ2 also induced cell death in a concentration-dependent manner.	('15d-PGJ2', 'Var', (4, 12))	('cell death', 'biological_process', 'GO:0008219', ('26', '36'))	('death', 'Disease', 'MESH:D003643', (31, 36))	('death', 'Disease', (31, 36))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (4, 12))
170419	30815591	Although 15d-PGJ2 decreased the MTT-reducing activity and the cell number (Fig.	('15d-PGJ2', 'Chemical', 'MESH:C097240', (9, 17))	('decreased', 'NegReg', (18, 27))	('MTT-reducing activity', 'MPA', (32, 53))	('cell number', 'CPA', (62, 73))	('15d-PGJ2', 'Var', (9, 17))	('MTT', 'Chemical', 'MESH:C070243', (32, 35))
170443	30815591	3D, 15d-PGJ2 induced cell death in a concentration-dependent manner.	('15d-PGJ2', 'Var', (4, 12))	('death', 'Disease', 'MESH:D003643', (26, 31))	('cell death', 'biological_process', 'GO:0008219', ('21', '31'))	('death', 'Disease', (26, 31))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (4, 12))
170445	30815591	15d-PGJ2 increased the anticancer activity of CPT additively, whereas it did not those of the two topoisomerase II inhibitors.	('topoisomerase II', 'molecular_function', 'GO:0003918', ('98', '114'))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('15d-PGJ2', 'Var', (0, 8))	('CPT', 'Gene', (46, 49))	('CPT', 'Chemical', 'MESH:D002166', (46, 49))	('increased', 'PosReg', (9, 18))	('CPT', 'molecular_function', 'GO:0004142', ('46', '49'))	('CPT', 'molecular_function', 'GO:0004095', ('46', '49'))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (0, 8))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
170447	30815591	Contrary to the result obtained from the VHL-positive Caki-2 cells, 15d-PGJ2 did not enhanced the anti-cancer activity of topoisomerase inhibitors synergistically in the VHL-positive RCC4(+) cells.	('topoisomerase', 'molecular_function', 'GO:0003918', ('122', '135'))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('VHL', 'Gene', (170, 173))	('enhanced', 'PosReg', (85, 93))	('RCC4', 'Gene', '84925', (183, 187))	('VHL', 'Gene', '7428', (170, 173))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('RCC4', 'Gene', (183, 187))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (68, 76))	('Caki-2', 'CellLine', 'CVCL:0235', (54, 60))	('VHL', 'Gene', (41, 44))	('cancer', 'Disease', (103, 109))	('15d-PGJ2', 'Var', (68, 76))	('topoisomerase', 'molecular_function', 'GO:0003917', ('122', '135'))	('VHL', 'Gene', '7428', (41, 44))
170453	30815591	4D, 15d-PGJ2 induced cell death in a concentration-dependent manner.	('15d-PGJ2', 'Var', (4, 12))	('death', 'Disease', 'MESH:D003643', (26, 31))	('cell death', 'biological_process', 'GO:0008219', ('21', '31'))	('death', 'Disease', (26, 31))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (4, 12))
170457	30815591	Contrary to the result obtained from the VHL-positive Caki-2 cells, 15d-PGJ2 did not enhanced the anti-cancer activity of topoisomerase inhibitors synergistically in the VHL-positive ACHN cells.	('topoisomerase', 'molecular_function', 'GO:0003918', ('122', '135'))	('ACHN', 'Gene', (183, 187))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('VHL', 'Gene', (170, 173))	('enhanced', 'PosReg', (85, 93))	('VHL', 'Gene', '7428', (170, 173))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('ACHN', 'Gene', '55323', (183, 187))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (68, 76))	('Caki-2', 'CellLine', 'CVCL:0235', (54, 60))	('VHL', 'Gene', (41, 44))	('cancer', 'Disease', (103, 109))	('15d-PGJ2', 'Var', (68, 76))	('topoisomerase', 'molecular_function', 'GO:0003917', ('122', '135'))	('VHL', 'Gene', '7428', (41, 44))
170458	30815591	Previously, we have reported 15d-PGJ2 as the endogenous anticancer agent in Caki-2 cells.	('15d-PGJ2', 'Chemical', 'MESH:C097240', (29, 37))	('Caki-2', 'CellLine', 'CVCL:0235', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('15d-PGJ2', 'Var', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
170460	30815591	15d-PGJ2 also exhibited anti-cancerous effects in other RCCs such as 786-O, RCC4(-), RCC4(+) and ACHN.	('ACHN', 'Gene', (97, 101))	('RCC4', 'Gene', (85, 89))	('15d-PGJ2', 'Var', (0, 8))	('RCC', 'Disease', (56, 59))	('cancerous', 'Disease', (29, 38))	('RCC', 'Disease', (76, 79))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('RCCs', 'Phenotype', 'HP:0005584', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('RCC4', 'Gene', '84925', (76, 80))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', (85, 88))	('RCC4', 'Gene', (76, 80))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (0, 8))	('cancerous', 'Disease', 'MESH:D009369', (29, 38))	('ACHN', 'Gene', '55323', (97, 101))	('RCC4', 'Gene', '84925', (85, 89))
170463	30815591	Since this integrin-adapter protein (actin) -cytoskeleton complex forms the basis of a focal adhesion, it was likely that 15d-PGJ2 increased protrusions and made focal adhesion clear.	('increased', 'PosReg', (131, 140))	('actin) -cytoskeleton', 'cellular_component', 'GO:0015629', ('37', '57'))	('protrusions', 'CPA', (141, 152))	('focal adhesion', 'cellular_component', 'GO:0005925', ('87', '101'))	('focal adhesion', 'cellular_component', 'GO:0005925', ('162', '176'))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (122, 130))	('15d-PGJ2', 'Var', (122, 130))	('focal', 'MPA', (162, 167))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
170476	30815591	786-O has many characteristics of ccRCC and is defective in VHL expression, as it harbors mutated VHL.	('mutated', 'Var', (90, 97))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('VHL', 'Gene', (60, 63))	('VHL', 'Gene', (98, 101))	('harbors', 'Reg', (82, 89))	('VHL', 'Gene', '7428', (60, 63))	('VHL', 'Gene', '7428', (98, 101))
170478	30815591	Although 15d-PGJ2 induced cell death in 786-O cells, it did not potentate the anti-tumor activity of topoisomerase inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (9, 17))	('tumor', 'Disease', (83, 88))	('topoisomerase', 'molecular_function', 'GO:0003917', ('101', '114'))	('15d-PGJ2', 'Var', (9, 17))	('death', 'Disease', 'MESH:D003643', (31, 36))	('topoisomerase', 'molecular_function', 'GO:0003918', ('101', '114'))	('death', 'Disease', (31, 36))	('cell death', 'biological_process', 'GO:0008219', ('26', '36'))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
170479	30815591	Another cell line is RCC4, a VHL mutant derived from a primary tumor widely used as a model for VHL-dependent mechanisms, with a commercially available counterpart cell line with restored wild-type gene.	('tumor', 'Disease', (63, 68))	('RCC4', 'Gene', (21, 25))	('RCC4', 'Gene', '84925', (21, 25))	('VHL', 'Gene', (29, 32))	('VHL', 'Gene', '7428', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('VHL', 'Gene', (96, 99))	('mutant', 'Var', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('VHL', 'Gene', '7428', (96, 99))
170481	30815591	However, 15d-PGJ2 enhanced the anti-tumor activity of these topoisomerase inhibitors in neither RCC4(-) nor RCC4(+) cells.	('RCC4', 'Gene', '84925', (96, 100))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (9, 17))	('RCC4', 'Gene', (96, 100))	('RCC4', 'Gene', (108, 112))	('RCC4', 'Gene', '84925', (108, 112))	('topoisomerase', 'molecular_function', 'GO:0003918', ('60', '73'))	('enhanced', 'PosReg', (18, 26))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('15d-PGJ2', 'Var', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('topoisomerase', 'molecular_function', 'GO:0003917', ('60', '73'))
170485	30815591	The Akt inhibitor showed cytotoxicity with a low IC50 value, suggesting that 15d-PGJ2 exerted cytotoxicity via the inactivation of Akt.	('cytotoxicity', 'Disease', 'MESH:D064420', (25, 37))	('Akt', 'Gene', (4, 7))	('Akt', 'Gene', (131, 134))	('cytotoxicity', 'Disease', 'MESH:D064420', (94, 106))	('Akt', 'Gene', '207', (4, 7))	('Akt', 'Gene', '207', (131, 134))	('inactivation', 'NegReg', (115, 127))	('cytotoxicity', 'Disease', (25, 37))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (77, 85))	('15d-PGJ2', 'Var', (77, 85))	('cytotoxicity', 'Disease', (94, 106))
170488	30815591	In addition, the PI3K inhibitor did not enhanced cytotoxicities of another topoisomerase II inhibitor, etoposide, and a topoisomerase inhibitor I, camptothecin.	('etoposide', 'Chemical', 'MESH:D005047', (103, 112))	('topoisomerase', 'molecular_function', 'GO:0003918', ('120', '133'))	('cytotoxicities', 'Disease', 'MESH:D064420', (49, 63))	('camptothecin', 'Chemical', 'MESH:D002166', (147, 159))	('PI3K', 'molecular_function', 'GO:0016303', ('17', '21'))	('cytotoxicities', 'Disease', (49, 63))	('topoisomerase', 'molecular_function', 'GO:0003917', ('120', '133'))	('PI3K', 'Var', (17, 21))	('topoisomerase II', 'molecular_function', 'GO:0003918', ('75', '91'))
170493	29132830	Characterizing Recurrent and Lethal Small Renal Masses in Clear Cell Renal Cell Carcinoma Using Recurrent Somatic Mutations Small renal masses (SRMs) with evidence of clear cell renal cell carcinoma (ccRCC) are understudied.	('ccRCC', 'Disease', (200, 205))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (167, 198))	('ccRCC', 'Disease', 'MESH:D002292', (200, 205))	('Mutations', 'Var', (114, 123))	('Clear Cell Renal Cell Carcinoma', 'Disease', (58, 89))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (69, 89))	('Small Renal', 'Phenotype', 'HP:0000089', (36, 47))	('clear cell renal cell carcinoma', 'Disease', (167, 198))	('Carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('renal masses', 'Phenotype', 'HP:0009726', (130, 142))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (167, 198))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (178, 198))	('Renal Masses', 'Phenotype', 'HP:0009726', (42, 54))	('ccRCC', 'Phenotype', 'HP:0006770', (200, 205))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:D002292', (58, 89))	('Small renal', 'Phenotype', 'HP:0000089', (124, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (58, 89))
170499	29132830	Mutations in VHL, PBRM1, SETD2, BAP1, KDM5C, and MTOR were present in more than 5% of tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('MTOR', 'Gene', '2475', (49, 53))	('BAP1', 'Gene', '8314', (32, 36))	('tumors', 'Disease', (86, 92))	('PBRM1', 'Gene', (18, 23))	('VHL', 'Gene', (13, 16))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('Mutations', 'Var', (0, 9))	('SETD2', 'Gene', '29072', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('KDM5C', 'Gene', (38, 43))	('BAP1', 'Gene', (32, 36))	('VHL', 'Gene', '7428', (13, 16))	('PBRM1', 'Gene', '55193', (18, 23))	('KDM5C', 'Gene', '8242', (38, 43))	('MTOR', 'Gene', (49, 53))	('SETD2', 'Gene', (25, 30))
170501	29132830	Mutations in KDM5C were associated with inferior survival from either recurrence or death from disease, adjusted P-value 0.033.	('inferior', 'NegReg', (40, 48))	('KDM5C', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('death', 'Disease', 'MESH:D003643', (84, 89))	('KDM5C', 'Gene', '8242', (13, 18))	('death', 'Disease', (84, 89))
170502	29132830	We identified mutations in SRMs in ccRCC that are associated with recurrence and lethality.	('ccRCC', 'Disease', 'MESH:D002292', (35, 40))	('SRMs', 'Gene', (27, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (35, 40))	('ccRCC', 'Disease', (35, 40))	('associated', 'Reg', (50, 60))	('mutations', 'Var', (14, 23))
170503	29132830	The strongest association was seen in those with KDM5C mutations.	('KDM5C', 'Gene', '8242', (49, 54))	('KDM5C', 'Gene', (49, 54))	('mutations', 'Var', (55, 64))
170534	29132830	Statistical significance of differences in survival time between mutated and non-mutated (wild-type) tumors were assessed using the log-rank test.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('mutated', 'Var', (65, 72))
170540	29132830	Mutations in the following genes were found to be present in at least 5% of patients in our cohort: VHL (127/203, 62.6%), PBRM1 (67/203, 33.0%), SETD2 (20/203, 9.9%), BAP1 (15/203, 7.4%), MTOR (14/203, 6.9%), KDM5C (12/203, 5.9%).	('patients', 'Species', '9606', (76, 84))	('PBRM1', 'Gene', (122, 127))	('SETD2', 'Gene', '29072', (145, 150))	('PBRM1', 'Gene', '55193', (122, 127))	('MTOR', 'Gene', (188, 192))	('VHL', 'Gene', '7428', (100, 103))	('KDM5C', 'Gene', (209, 214))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (167, 171))	('MTOR', 'Gene', '2475', (188, 192))	('KDM5C', 'Gene', '8242', (209, 214))	('VHL', 'Gene', (100, 103))	('BAP1', 'Gene', (167, 171))	('SETD2', 'Gene', (145, 150))
170542	29132830	On unadjusted analysis mutations in SETD2 (p = 0.014) and KDM5C (p = 0.033) were enriched in patients with recurrence or death of disease.	('SETD2', 'Gene', '29072', (36, 41))	('patients', 'Species', '9606', (93, 101))	('death of disease', 'Disease', (121, 137))	('SETD2', 'Gene', (36, 41))	('mutations', 'Var', (23, 32))	('KDM5C', 'Gene', (58, 63))	('death of disease', 'Disease', 'MESH:D003643', (121, 137))	('KDM5C', 'Gene', '8242', (58, 63))
170545	29132830	2), KDMC5 mutations were strongly associated with either recurrence or death of disease (p = 0.005; adjusted P = 0.033).	('associated with', 'Reg', (34, 49))	('death of disease', 'Disease', 'MESH:D003643', (71, 87))	('KDMC5', 'Gene', (4, 9))	('recurrence', 'Disease', (57, 67))	('death of disease', 'Disease', (71, 87))	('mutations', 'Var', (10, 19))
170546	29132830	Patients with SETD2 (p = 0.023) and BAP1 (p = 0.050) mutations showed significance in our unadjusted survival analysis but became insignificant after adjustment for multiple testing; SETD2 adjusted P =0.071 and BAP1 adjusted P = 0.100.	('SETD2', 'Gene', (183, 188))	('BAP1', 'Gene', '8314', (211, 215))	('BAP1', 'Gene', '8314', (36, 40))	('mutations', 'Var', (53, 62))	('Patients', 'Species', '9606', (0, 8))	('SETD2', 'Gene', '29072', (14, 19))	('BAP1', 'Gene', (211, 215))	('BAP1', 'Gene', (36, 40))	('SETD2', 'Gene', (14, 19))	('SETD2', 'Gene', '29072', (183, 188))
170548	29132830	The strongest relation (adjusted P = 0.033) was seen between KDM5C mutations and the risk of recurrence or death from disease.	('KDM5C', 'Gene', (61, 66))	('death', 'Disease', 'MESH:D003643', (107, 112))	('KDM5C', 'Gene', '8242', (61, 66))	('mutations', 'Var', (67, 76))	('death', 'Disease', (107, 112))
170549	29132830	Mutations in other genes like SETD2 and BAP1 which have been associated with inferior clinical outcomes in other studies were not found to be statistically significant in our analysis after adjustment.	('SETD2', 'Gene', '29072', (30, 35))	('BAP1', 'Gene', '8314', (40, 44))	('SETD2', 'Gene', (30, 35))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', (40, 44))
170552	29132830	Despite having only 12 patients in our cohort with this mutation, it was persistently associated with an increased risk of recurrence or death from disease in our analysis.	('patients', 'Species', '9606', (23, 31))	('associated', 'Reg', (86, 96))	('death', 'Disease', 'MESH:D003643', (137, 142))	('death', 'Disease', (137, 142))	('mutation', 'Var', (56, 64))
170560	29132830	Mutations in BAP1, SETD2, and TP53 have been associated with inferior clinical results in those patients who undergo primary treatment with surgical resection.	('BAP1', 'Gene', (13, 17))	('TP53', 'Gene', (30, 34))	('SETD2', 'Gene', (19, 24))	('inferior', 'NegReg', (61, 69))	('associated', 'Reg', (45, 55))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (96, 104))	('BAP1', 'Gene', '8314', (13, 17))	('TP53', 'Gene', '7157', (30, 34))	('SETD2', 'Gene', '29072', (19, 24))
170561	29132830	In our study patients with BAP1 and SETD2 mutations appeared to have a trend for an increased risk of recurrence or death with survival analysis, however, this did not meet statistical significance (SETD2 p = 0.023, adjusted P =0.071; BAP1 p = 0.050, adjusted P = 0.100), possibly due to our small number of patients with this mutation (SETD2 = 20, 9.9%; BAP1 = 15, 7.3%).	('death', 'Disease', 'MESH:D003643', (116, 121))	('patients', 'Species', '9606', (13, 21))	('SETD2', 'Gene', (36, 41))	('patients', 'Species', '9606', (308, 316))	('BAP1 p', 'Gene', '8314', (235, 241))	('SETD2', 'Gene', '29072', (337, 342))	('BAP1', 'Gene', '8314', (355, 359))	('SETD2', 'Gene', '29072', (36, 41))	('BAP1 p', 'Gene', (235, 241))	('BAP1', 'Gene', '8314', (235, 239))	('SETD2', 'Gene', (199, 204))	('BAP1', 'Gene', '8314', (27, 31))	('death', 'Disease', (116, 121))	('BAP1', 'Gene', (355, 359))	('SETD2', 'Gene', '29072', (199, 204))	('BAP1', 'Gene', (235, 239))	('BAP1', 'Gene', (27, 31))	('SETD2', 'Gene', (337, 342))	('mutations', 'Var', (42, 51))
170570	29132830	We believe the recognition of KDM5C mutations and their association with inferior clinical outcomes in patients with ccRCC SRMs has the potential to impact possible future clinical studies of clinically aggressive SRMs.	('mutations', 'Var', (36, 45))	('KDM5C', 'Gene', (30, 35))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('ccRCC', 'Disease', (117, 122))	('KDM5C', 'Gene', '8242', (30, 35))	('patients', 'Species', '9606', (103, 111))	('impact', 'Reg', (149, 155))	('ccRCC', 'Disease', 'MESH:D002292', (117, 122))
170574	29132830	In our analysis, patients presenting with SRMs and mutations in KDM5C are associated with inferior recurrence free or cancer specific survival.	('cancer', 'Disease', (118, 124))	('mutations', 'Var', (51, 60))	('recurrence free', 'CPA', (99, 114))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('KDM5C', 'Gene', (64, 69))	('patients', 'Species', '9606', (17, 25))	('KDM5C', 'Gene', '8242', (64, 69))	('SRMs', 'Disease', (42, 46))	('inferior', 'NegReg', (90, 98))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
170576	29132830	In small renal masses, KDM5C mutations were linked to poor outcomes.	('renal masses', 'Phenotype', 'HP:0009726', (9, 21))	('KDM5C', 'Gene', (23, 28))	('mutations', 'Var', (29, 38))	('KDM5C', 'Gene', '8242', (23, 28))	('small renal', 'Phenotype', 'HP:0000089', (3, 14))
170578	29474434	MicroRNA-19a and microRNA-19b promote the malignancy of clear cell renal cell carcinoma through targeting the tumor suppressor RhoB Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma, which shows high aggressiveness and lacks biomarkers.	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (132, 163))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (67, 87))	('aggressiveness', 'Disease', (241, 255))	('renal cell carcinoma', 'Disease', (202, 222))	('aggressiveness', 'Phenotype', 'HP:0000718', (241, 255))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (202, 222))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (143, 163))	('aggressiveness', 'Disease', 'MESH:D001523', (241, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('malignancy of clear cell renal cell carcinoma', 'Disease', (42, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('microRNA-19b', 'Var', (17, 29))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('promote', 'PosReg', (30, 37))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (56, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (165, 170))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (67, 87))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (132, 163))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (143, 163))	('tumor suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (202, 222))	('Clear cell renal cell carcinoma', 'Disease', (132, 163))	('tumor', 'Disease', (110, 115))	('malignancy of clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (42, 87))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('MicroRNA-19a', 'Gene', (0, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('MicroRNA-19a', 'Gene', '406979', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
170584	29474434	In addition, the knockdown of RhoB or overexpression of miR-19a and miR-19b in ccRCC cells could promote cell proliferation, migration and invasion.	('invasion', 'CPA', (139, 147))	('cell proliferation', 'biological_process', 'GO:0008283', ('105', '123'))	('migration', 'CPA', (125, 134))	('miR-19b', 'Gene', '406980', (68, 75))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RhoB', 'Protein', (30, 34))	('miR-19a', 'Gene', (56, 63))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('overexpression', 'PosReg', (38, 52))	('miR-19b', 'Gene', (68, 75))	('knockdown', 'Var', (17, 26))	('miR-19a', 'Gene', '406979', (56, 63))	('cell proliferation', 'CPA', (105, 123))	('promote', 'PosReg', (97, 104))
170597	29474434	In addition, recent studies have shown that targeting RhoB could inhibit the tumor growth of colorectal cancer and hepatocellular carcinoma in mouse xenograft models.	('RhoB', 'Protein', (54, 58))	('mouse', 'Species', '10090', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (115, 139))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('targeting', 'Var', (44, 53))	('hepatocellular carcinoma', 'Disease', (115, 139))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (115, 139))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('colorectal cancer', 'Disease', (93, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('inhibit', 'NegReg', (65, 72))	('tumor', 'Disease', (77, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))
170632	29474434	For the mutagenesis of miRNA target sites in the 3'-UTR region of the reporter, mutations were introduced into the seed sequence by using the QuikChange Site-Directed Mutagenesis Kit II (Stratagene, USA) according to the manufacturer's protocol.	('miR', 'Gene', '220972', (23, 26))	('Mutagenesis', 'biological_process', 'GO:0006280', ('167', '178'))	('miR', 'Gene', (23, 26))	('mutations', 'Var', (80, 89))	('mutagenesis', 'biological_process', 'GO:0006280', ('8', '19'))	('mutagenesis', 'Var', (8, 19))
170658	29474434	However, the co-transfection of miR-19a and miR-19b mimics did not show obvious effects on the luciferase activity of the reporter when the RhoB 3'-UTR region was mutated (RhoB-3'UTR-mut) (Fig 2D).	('miR-19a', 'Gene', '406979', (32, 39))	('luciferase activity', 'molecular_function', 'GO:0050397', ('95', '114'))	('mutated', 'Var', (163, 170))	('luciferase activity', 'molecular_function', 'GO:0045289', ('95', '114'))	('luciferase', 'Enzyme', (95, 105))	('luciferase activity', 'molecular_function', 'GO:0047077', ('95', '114'))	('miR-19b', 'Gene', (44, 51))	('miR-19a', 'Gene', (32, 39))	('activity', 'MPA', (106, 114))	('miR-19b', 'Gene', '406980', (44, 51))	('luciferase activity', 'molecular_function', 'GO:0047712', ('95', '114'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('95', '114'))
170670	29474434	To determine the effects of miR-19a and miR-19b inhibitors on cell proliferation features, we performed MTS assay of 786-O cells transfected with miR-19a and miR-19b inhibitors or inhibitor control oligo.	('miR-19a', 'Gene', '406979', (146, 153))	('miR-19b', 'Gene', '406980', (158, 165))	('cell proliferation', 'biological_process', 'GO:0008283', ('62', '80'))	('miR-19a', 'Gene', (28, 35))	('miR-19a', 'Gene', (146, 153))	('miR-19b', 'Gene', (40, 47))	('miR-19b', 'Gene', (158, 165))	('miR-19a', 'Gene', '406979', (28, 35))	('inhibitors', 'Var', (166, 176))	('miR-19b', 'Gene', '406980', (40, 47))
170675	29474434	In the present study, we treated 786-O cells with miR-19a and miR-19b inhibitors and showed that transfection with miR-19a and miR-19b inhibitors resulted in significant increases of apoptosis as determined by Annexin V-PE staining (Fig 5A).	('miR-19b', 'Gene', (62, 69))	('apoptosis', 'biological_process', 'GO:0006915', ('183', '192'))	('miR-19a', 'Gene', '406979', (50, 57))	('miR-19b', 'Gene', '406980', (127, 134))	('increases', 'PosReg', (170, 179))	('miR-19b', 'Gene', '406980', (62, 69))	('Annexin V', 'Gene', '308', (210, 219))	('apoptosis', 'biological_process', 'GO:0097194', ('183', '192'))	('Annexin V', 'Gene', (210, 219))	('miR-19a', 'Gene', (115, 122))	('miR-19a', 'Gene', (50, 57))	('apoptosis', 'CPA', (183, 192))	('miR-19b', 'Gene', (127, 134))	('inhibitors', 'Var', (135, 145))	('miR-19a', 'Gene', '406979', (115, 122))
170691	29474434	Other studies have shown that RhoB expression changes the apoptotic response of transformed cells to FTI (Farnesyltransferase inhibitor), DNA damaging agents and paclitaxel.	('changes', 'Reg', (46, 53))	('RhoB', 'Gene', (30, 34))	('paclitaxel', 'Chemical', 'MESH:D017239', (162, 172))	('apoptotic response', 'CPA', (58, 76))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('FTI', 'Chemical', '-', (101, 104))	('expression', 'Var', (35, 45))
170812	31443717	It was found that the risk score based on 6 novel lncRNAs (CTA-384D8.35, CTD-2263F21.1, LINC01510, RP11-352G9.1, RP11-395B7.2, RP11-426C22.4) exhibited superior prognostic value for ccRCC.	('CTD-2263F21.1', 'Var', (73, 86))	('LINC01510', 'Gene', '100996266', (88, 97))	('CTA-384D8.35', 'Var', (59, 71))	('LINC01510', 'Gene', (88, 97))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('RCC', 'Disease', (184, 187))	('CTA', 'Chemical', 'MESH:C569473', (59, 62))	('RP11', 'Gene', (113, 117))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('ccRCC', 'Phenotype', 'HP:0006770', (182, 187))	('RP11', 'Gene', (127, 131))	('CTD-2263F21.1', 'CellLine', 'CVCL:L519', (73, 86))	('RP11', 'Gene', '26121', (113, 117))	('RP11', 'Gene', (99, 103))	('RP11', 'Gene', '26121', (99, 103))	('RP11', 'Gene', '26121', (127, 131))
170843	31443717	This conclusion was validated by multivariate Cox regression, and CTA-384D8.35, CTD-2263F21.1, LINC01510, RP11-352G9.1, RP11-395B7.2, and RP11-426C22.4 were confirmed to be independent prognostic biomarkers for ccRCC (Table 1 and Additional file 1: Table S1).	('RP11', 'Gene', '26121', (106, 110))	('CTD-2263F21.1', 'CellLine', 'CVCL:L519', (80, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (211, 216))	('CTD-2263F21.1', 'Var', (80, 93))	('CTA', 'Chemical', 'MESH:C569473', (66, 69))	('RP11', 'Gene', '26121', (138, 142))	('LINC01510', 'Gene', '100996266', (95, 104))	('CTA-384D8.35', 'Var', (66, 78))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('LINC01510', 'Gene', (95, 104))	('RCC', 'Disease', (213, 216))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	('RP11', 'Gene', (120, 124))	('RP11', 'Gene', (106, 110))	('Cox', 'Gene', '1351', (46, 49))	('Cox', 'Gene', (46, 49))	('RP11', 'Gene', '26121', (120, 124))	('RP11', 'Gene', (138, 142))
170845	31443717	Remarkably higher expression levels were noted for CTA-384D8.35, CTD-2263F21.1, RP11-352G9.1, RP11-395B7.2, and RP11-426C22.4, while predominantly lower expression was observed for LINC01510 in ccRCC samples (Fig.	('higher', 'PosReg', (11, 17))	('RP11', 'Gene', (80, 84))	('expression levels', 'MPA', (18, 35))	('CTA-384D8.35', 'Var', (51, 63))	('RP11', 'Gene', (94, 98))	('CTA', 'Chemical', 'MESH:C569473', (51, 54))	('RP11', 'Gene', '26121', (94, 98))	('LINC01510', 'Gene', '100996266', (181, 190))	('CTD-2263F21.1', 'CellLine', 'CVCL:L519', (65, 78))	('RP11', 'Gene', '26121', (80, 84))	('RCC', 'Disease', 'MESH:C538614', (196, 199))	('RP11', 'Gene', (112, 116))	('LINC01510', 'Gene', (181, 190))	('RCC', 'Disease', (196, 199))	('RCC', 'Phenotype', 'HP:0005584', (196, 199))	('RP11', 'Gene', '26121', (112, 116))	('CTD-2263F21.1', 'Var', (65, 78))	('ccRCC', 'Phenotype', 'HP:0006770', (194, 199))
170865	31443717	Some annotation for these 6 lncRNAs was found in the following platforms of GEO DataSets: GPL19615, GPL8841, GPL19197, GPL1707, GPL570, GPL5175, GPL15096, GPL97, and GPL96.	('GPL570', 'Chemical', '-', (128, 134))	('GPL97', 'Var', (155, 160))	('GPL5175', 'Var', (136, 143))	('GPL', 'Chemical', '-', (90, 93))	('GPL15096', 'Var', (145, 153))	('GPL19615', 'Var', (90, 98))	('GPL', 'Chemical', '-', (145, 148))	('GPL1707', 'Var', (119, 126))	('GPL', 'Chemical', '-', (128, 131))	('GPL', 'Chemical', '-', (119, 122))	('GPL', 'Chemical', '-', (136, 139))	('GPL8841', 'Var', (100, 107))	('GPL', 'Chemical', '-', (166, 169))	('GPL96', 'Var', (166, 171))	('GPL96', 'Chemical', '-', (166, 171))	('GPL', 'Chemical', '-', (109, 112))	('GPL', 'Chemical', '-', (100, 103))	('GPL', 'Chemical', '-', (155, 158))	('GPL19197', 'Var', (109, 117))	('GPL570', 'Var', (128, 134))
170866	31443717	Ultimately, only GPL19615 (GSE96574 contained LINC01510), GPL570 (GSE53757, GSE66272, GSE36895, GSE46699, and GSE22541 contained CTA-384D8.35) and GPL96 (GSE781 contained RP11-395B7.2) were included in subsequent analyses.	('GSE', 'Chemical', '-', (66, 69))	('GPL', 'Chemical', '-', (147, 150))	('GPL', 'Chemical', '-', (58, 61))	('GSE', 'Chemical', '-', (76, 79))	('RP11', 'Gene', (171, 175))	('GSE', 'Chemical', '-', (96, 99))	('GSE781', 'Chemical', '-', (154, 160))	('GPL', 'Chemical', '-', (17, 20))	('GPL96', 'Chemical', '-', (147, 152))	('GSE', 'Chemical', '-', (86, 89))	('GSE', 'Chemical', '-', (110, 113))	('GSE46699', 'Var', (96, 104))	('GSE66272', 'Var', (76, 84))	('GPL570', 'Chemical', '-', (58, 64))	('RP11', 'Gene', '26121', (171, 175))	('LINC01510', 'Gene', '100996266', (46, 55))	('LINC01510', 'Gene', (46, 55))	('GSE', 'Chemical', '-', (154, 157))	('GSE53757', 'Var', (66, 74))	('GSE', 'Chemical', '-', (27, 30))	('CTA', 'Chemical', 'MESH:C569473', (129, 132))
170867	31443717	The expression levels of CTA-384D8.35 and LINC01510 from these 6 microarrays were remarkably higher in ccRCC than those in normal controls (CTA-384D8.35: GSE53757 [P < 0.0001], GSE66272 [P = 0.0483], GSE36895 [P = 0.0007], GSE46699 [P = 0.0021]; LINC01510: GSE96574 [P < 0.005]), and the expression of RP11-395B7.2 also showed the same trend (P = 0.183).	('CTA', 'Chemical', 'MESH:C569473', (25, 28))	('GSE46699 [', 'Var', (223, 233))	('expression', 'MPA', (4, 14))	('GSE', 'Chemical', '-', (177, 180))	('GSE96574 [', 'Var', (257, 267))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', (105, 108))	('GSE', 'Chemical', '-', (200, 203))	('RP11', 'Gene', '26121', (302, 306))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('LINC01510', 'Gene', '100996266', (42, 51))	('GSE66272 [', 'Var', (177, 187))	('LINC01510', 'Gene', (42, 51))	('higher', 'PosReg', (93, 99))	('GSE', 'Chemical', '-', (223, 226))	('GSE53757 [', 'Var', (154, 164))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('GSE36895', 'Var', (200, 208))	('CTA', 'Chemical', 'MESH:C569473', (140, 143))	('RP11', 'Gene', (302, 306))	('LINC01510', 'Gene', '100996266', (246, 255))	('LINC01510', 'Gene', (246, 255))	('GSE', 'Chemical', '-', (154, 157))	('GSE', 'Chemical', '-', (257, 260))
170868	31443717	The AUC value of CTA-384D8.35 was 0.655 for anticipating advanced tumor stage, and CTA-384D8.35 had prognostic value for patients with ccRCC (P = 0.033).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('CTA', 'Chemical', 'MESH:C569473', (17, 20))	('tumor', 'Disease', (66, 71))	('CTA-384D8.35', 'Var', (83, 95))	('CTA', 'Chemical', 'MESH:C569473', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('RCC', 'Disease', (137, 140))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('patients', 'Species', '9606', (121, 129))
170870	31443717	Three of the six lncRNAs were matched, including CTD-2263F21.1, LINC01510 and RP11-426C22.4.	('CTD-2263F21.1', 'Var', (49, 62))	('LINC01510', 'Gene', '100996266', (64, 73))	('RP11', 'Gene', (78, 82))	('CTD-2263F21.1', 'CellLine', 'CVCL:L519', (49, 62))	('LINC01510', 'Gene', (64, 73))	('RP11', 'Gene', '26121', (78, 82))
170871	31443717	Kaplan-Meier survival curves of CTD-2263F21.1 and RP11-426C22.4 also showed the value of their predicted survival (P < 0.05) (Fig.	('RP11', 'Gene', (50, 54))	('CTD-2263F21.1', 'Var', (32, 45))	('CTD-2263F21.1', 'CellLine', 'CVCL:L519', (32, 45))	('RP11', 'Gene', '26121', (50, 54))
170874	31443717	Notably, the best prognostic value was achieved using a pool that consisted of 6 lncRNAs (CTA-384D8.35, CTD-2263F21.1, LINC01510, RP11-352G9.1, RP11-395B7.2, and RP11-426C22.4), which were obtained via multivariate Cox regression.	('RP11', 'Gene', (162, 166))	('CTD-2263F21.1', 'Var', (104, 117))	('RP11', 'Gene', '26121', (144, 148))	('CTA', 'Chemical', 'MESH:C569473', (90, 93))	('RP11', 'Gene', '26121', (162, 166))	('LINC01510', 'Gene', '100996266', (119, 128))	('CTA-384D8.35', 'Var', (90, 102))	('RP11', 'Gene', (130, 134))	('CTD-2263F21.1', 'CellLine', 'CVCL:L519', (104, 117))	('LINC01510', 'Gene', (119, 128))	('Cox', 'Gene', '1351', (215, 218))	('RP11', 'Gene', (144, 148))	('Cox', 'Gene', (215, 218))	('RP11', 'Gene', '26121', (130, 134))
170884	31443717	For example, an undesirable prognosis for RCC patients was connected with decreased expression of the lncRNAs NONHSAT123350, CADM1-AS1, TCL6, and lnc-ZNF180-2.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('lnc-ZNF180-2', 'Gene', (146, 158))	('patients', 'Species', '9606', (46, 54))	('CADM1-AS1', 'Disease', 'OMIM:607277', (125, 134))	('CADM1-AS1', 'Disease', (125, 134))	('TCL6', 'Gene', (136, 140))	('decreased', 'NegReg', (74, 83))	('TCL6', 'Gene', '27004', (136, 140))	('expression', 'MPA', (84, 94))	('NONHSAT123350', 'Var', (110, 123))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))
170886	31443717	Therefore, using multiple statistical methods for prognostic analysis, we found that CTA-384D8.35, CTD-2263F21.1, LINC01510, RP11-352G9.1, RP11-395B7.2, and RP11-426C22.4 were of great prognostic value.	('CTA', 'Chemical', 'MESH:C569473', (85, 88))	('CTA-384D8.35', 'Var', (85, 97))	('LINC01510', 'Gene', '100996266', (114, 123))	('CTD-2263F21.1', 'Var', (99, 112))	('RP11', 'Gene', (139, 143))	('RP11', 'Gene', (125, 129))	('CTD-2263F21.1', 'CellLine', 'CVCL:L519', (99, 112))	('LINC01510', 'Gene', (114, 123))	('RP11', 'Gene', '26121', (125, 129))	('RP11', 'Gene', '26121', (139, 143))	('RP11', 'Gene', (157, 161))	('RP11', 'Gene', '26121', (157, 161))
170888	31443717	They discovered that expression of a five-lncRNA signature (consisting of AC069513.4, AC003092.1, CTC-205M6.2, RP11-507K2.3, and U91328.21) was closely associated with kidney cancer patient OS.	('kidney cancer', 'Phenotype', 'HP:0009726', (168, 181))	('kidney cancer', 'Disease', 'MESH:D007680', (168, 181))	('RP11', 'Gene', (111, 115))	('U91328.21', 'Var', (129, 138))	('OS', 'Chemical', '-', (190, 192))	('patient', 'Species', '9606', (182, 189))	('expression', 'MPA', (21, 31))	('kidney cancer', 'Disease', (168, 181))	('RP11', 'Gene', '26121', (111, 115))	('AC069513.4', 'Var', (74, 84))	('CTC-205M6.2', 'Var', (98, 109))	('AC003092.1', 'Var', (86, 96))	('associated', 'Reg', (152, 162))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
170897	31443717	CTA-384D8.35, CTD-2263F21.1 and RP11-426C22.4 had prognostic value for patients with ccRCC, and the clinical value of three lncRNAs (CTA-384D8.35, RP11-395B7.2, and LINC01510) was also partly verified by six microarrays.	('RP11', 'Gene', '26121', (147, 151))	('CTA', 'Chemical', 'MESH:C569473', (133, 136))	('CTD-2263F21.1', 'Var', (14, 27))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('CTA-384D8.35', 'Var', (0, 12))	('RCC', 'Disease', (87, 90))	('CTA', 'Chemical', 'MESH:C569473', (0, 3))	('patients', 'Species', '9606', (71, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('RP11', 'Gene', (32, 36))	('CTD-2263F21.1', 'CellLine', 'CVCL:L519', (14, 27))	('LINC01510', 'Gene', '100996266', (165, 174))	('RP11', 'Gene', '26121', (32, 36))	('LINC01510', 'Gene', (165, 174))	('RP11', 'Gene', (147, 151))	('CTA-384D8.35', 'Var', (133, 145))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
170903	31443717	Interestingly, PIK3CA has been identified as a direct target of miR-490-5p and miR-19a in renal carcinoma.	('renal carcinoma', 'Phenotype', 'HP:0005584', (90, 105))	('miR-19a', 'Gene', '406979', (79, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('PIK3CA', 'Gene', '5290', (15, 21))	('renal carcinoma', 'Disease', 'MESH:C538614', (90, 105))	('miR-490-5p', 'Var', (64, 74))	('miR-19a', 'Gene', (79, 86))	('renal carcinoma', 'Disease', (90, 105))	('PIK3CA', 'Gene', (15, 21))
170929	30863498	The ccRCC type is often characterized by aberrations in the VHL gene on chromosome 3p, usually causing the loss of the VHL-mediated degradation of the hypoxia-inducible factor alpha (HIF-alpha) under normoxic conditions.	('chromosome', 'cellular_component', 'GO:0005694', ('72', '82'))	('loss', 'NegReg', (107, 111))	('VHL', 'Gene', (60, 63))	('VHL', 'Gene', (119, 122))	('hypoxia', 'Disease', 'MESH:D000860', (151, 158))	('VHL', 'Gene', '7428', (60, 63))	('VHL', 'Gene', '7428', (119, 122))	('degradation', 'biological_process', 'GO:0009056', ('132', '143'))	('hypoxia', 'Disease', (151, 158))	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))	('aberrations', 'Var', (41, 52))
170952	30863498	To test whether exogenous TGF-beta1 treatment has an effect on survival and growth, five ccRCC cell lines (786-O, Caki-1, Caki-2, MZ1851RC, MZ2733RC) and one pRCC cell line (MZ2858RC) were left untreated or treated with 10 ng/mL TGF-beta for 48 to 96 hours, before their cell viability, proliferation and apoptosis was analyzed.	('apoptosis', 'biological_process', 'GO:0097194', ('305', '314'))	('MZ2733RC', 'Var', (140, 148))	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('apoptosis', 'biological_process', 'GO:0006915', ('305', '314'))	('MZ1851RC', 'Var', (130, 138))	('TGF-beta', 'Gene', '7040', (229, 237))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('pRCC', 'Gene', (158, 162))	('RCC', 'Disease', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('TGF-beta', 'Gene', '7040', (26, 34))	('TGF-beta', 'Gene', (229, 237))	('MZ2733RC', 'Chemical', '-', (140, 148))	('pRCC', 'Gene', '5546', (158, 162))	('TGF-beta', 'Gene', (26, 34))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))
170958	30863498	As shown in Figure 1, heterogeneous results were obtained for the 7 different cell lines, which could be classified into 3 groups according to their extent of morphological change: MCF-10, Caki-1, and Caki-2 showed drastic changes in morphology upon TGF-beta1 stimulation (+++); MZ1851RC, MZ2733RC, and MZ2858RC showed minor differences after TGF-beta1 stimulation (+) while for 786-O no obvious differences in shape were detected after TGF-beta1 treatment (-) (Figure 1).	('MZ2733RC', 'Chemical', '-', (289, 297))	('morphology', 'MPA', (234, 244))	('MZ1851RC', 'Var', (279, 287))	('MZ2733RC', 'Var', (289, 297))	('MCF-10', 'CellLine', 'CVCL:5555', (181, 187))	('changes', 'Reg', (223, 230))	('MZ2858RC', 'Var', (303, 311))
170961	30863498	After treatment with TGF-beta1, the mRNA level of TGFBR2 was down-regulated in all RCC cells, while TGFBR1 levels were rather increased or not regulated in these cells with the exception of MZ2733RC, in which a down-regulation of TGFBR1 mRNA levels was detected (Figure 2A).	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('TGF-beta1', 'Gene', (21, 30))	('TGFBR1', 'Gene', (100, 106))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('MZ2733RC', 'Chemical', '-', (190, 198))	('down-regulated', 'NegReg', (61, 75))	('regulation', 'biological_process', 'GO:0065007', ('216', '226'))	('TGFBR2', 'Gene', (50, 56))	('MZ2733RC', 'Var', (190, 198))	('TGFBR1', 'Gene', (230, 236))	('increased', 'PosReg', (126, 135))	('mRNA level', 'MPA', (36, 46))	('TGFBR1', 'Gene', '7046', (230, 236))	('TGFBR1', 'Gene', '7046', (100, 106))
170977	30863498	In contrast, HLA-ABC, B7-H2, and B7-H3 were upregulated in the ccRCC MZ2733RC.	('B7-H3', 'Gene', '102657', (33, 38))	('B7-H3', 'Gene', (33, 38))	('B7-H2', 'Gene', '23308', (22, 27))	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('upregulated', 'PosReg', (44, 55))	('ABC', 'Gene', '10058', (17, 20))	('MZ2733RC', 'Var', (69, 77))	('B7-H2', 'Gene', (22, 27))	('MZ2733RC', 'Chemical', '-', (69, 77))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('ABC', 'Gene', (17, 20))	('RCC', 'Disease', (65, 68))
170978	30863498	Comparable to MZ2858RC, the expression of the cell adhesion molecule ICAM-1 was reduced after TGF-beta1 treatment of MZ2733RC.	('MZ2733RC', 'Chemical', '-', (117, 125))	('ICAM-1', 'Gene', '3383', (69, 75))	('expression', 'MPA', (28, 38))	('MZ2733RC', 'Var', (117, 125))	('reduced', 'NegReg', (80, 87))	('ICAM-1', 'Gene', (69, 75))	('cell adhesion', 'biological_process', 'GO:0007155', ('46', '59'))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('46', '68'))
170979	30863498	No surface expression of B7-H1 was observed for MZ2733RC.	('B7-H1', 'Gene', '29126', (25, 30))	('B7-H1', 'Gene', (25, 30))	('MZ2733RC', 'Chemical', '-', (48, 56))	('MZ2733RC', 'Var', (48, 56))
170980	30863498	Analysis of APM components on mRNA level demonstrated mostly a down-regulation of the four genes tested after TGF-beta1 treatment in both cell lines (Supplementary Figure 1) which is in accordance with MHC I surface expression in MZ2858RC, but not in MZ2733RC.	('APM', 'Gene', '290', (12, 15))	('MHC', 'Gene', '3107', (202, 205))	('regulation', 'biological_process', 'GO:0065007', ('68', '78'))	('APM', 'Gene', (12, 15))	('MZ2858RC', 'Var', (230, 238))	('MZ2733RC', 'Chemical', '-', (251, 259))	('MHC', 'Gene', (202, 205))	('down-regulation', 'NegReg', (63, 78))
170989	30863498	For the one representative ccRCC cell line MZ2733RC and the pRCC cell line MZ2858RC, the MMP2 mRNA levels directly correlate with endogenous TGFB1 mRNA levels.	('MMP2', 'Gene', (89, 93))	('mRNA levels', 'MPA', (94, 105))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('pRCC', 'Gene', (60, 64))	('TGFB1', 'Gene', '7040', (141, 146))	('MZ2733RC', 'Chemical', '-', (43, 51))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('pRCC', 'Gene', '5546', (60, 64))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('MMP2', 'Gene', '4313', (89, 93))	('TGFB1', 'Gene', (141, 146))	('RCC', 'Disease', (61, 64))	('MMP2', 'molecular_function', 'GO:0004228', ('89', '93'))	('MZ2733RC', 'Var', (43, 51))
170991	30863498	When the TGFB1 levels increased even in the absence of the exogenous stimulus, the MMP2 simultaneously increased as demonstrated for MZ2733RC.	('increased', 'PosReg', (103, 112))	('MMP2', 'Gene', (83, 87))	('TGFB1', 'Gene', '7040', (9, 14))	('MZ2733RC', 'Chemical', '-', (133, 141))	('levels', 'MPA', (15, 21))	('increased', 'PosReg', (22, 31))	('TGFB1', 'Gene', (9, 14))	('MMP2', 'molecular_function', 'GO:0004228', ('83', '87'))	('MMP2', 'Gene', '4313', (83, 87))	('MZ2733RC', 'Var', (133, 141))
171004	30863498	For MZ2858RC, the TGF-beta1 protein level reverted to the level of untreated cells after 96 h re-culturing in the presence of the inhibitor indicating that no TGF-beta1 protein was secreted anymore into the supernatant by the pRCC cells (Figure 9B).	('RCC', 'Phenotype', 'HP:0005584', (227, 230))	('TGF-beta1', 'MPA', (18, 27))	('pRCC', 'Gene', (226, 230))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('pRCC', 'Gene', '5546', (226, 230))	('MZ2858RC', 'Var', (4, 12))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
171006	30863498	In RCC, EMT can be induced by a variety of factors, such as TNF-alpha, oxidative stress, loss of VHL or FOXO3A, and deregulation of miRNAs.	('FOXO3A', 'Gene', '2309', (104, 110))	('induced by', 'Reg', (19, 29))	('VHL', 'Gene', '7428', (97, 100))	('oxidative stress', 'Phenotype', 'HP:0025464', (71, 87))	('EMT', 'Gene', (8, 11))	('miRNAs', 'Enzyme', (132, 138))	('loss', 'NegReg', (89, 93))	('oxidative stress', 'MPA', (71, 87))	('EMT', 'Gene', '3702', (8, 11))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('RCC', 'Disease', 'MESH:C538614', (3, 6))	('RCC', 'Disease', (3, 6))	('TNF-alpha', 'Gene', '7124', (60, 69))	('FOXO3A', 'Gene', (104, 110))	('EMT', 'biological_process', 'GO:0001837', ('8', '11'))	('deregulation', 'Var', (116, 128))	('VHL', 'Gene', (97, 100))	('TNF-alpha', 'Gene', (60, 69))
171013	30863498	It was found that loss of one TGFBR2 allele is associated with tumor progression and metastasis.	('tumor', 'Disease', (63, 68))	('loss', 'Var', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('metastasis', 'CPA', (85, 95))	('associated', 'Reg', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('TGFBR2', 'Gene', (30, 36))
171014	30863498	Furthermore, a tumor-suppressive role for an intact TGFBR2 and signaling pathway was shown in mice.	('signaling pathway', 'biological_process', 'GO:0007165', ('63', '80'))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('TGFBR2', 'Gene', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('mice', 'Species', '10090', (94, 98))	('intact', 'Var', (45, 51))	('signaling pathway', 'Pathway', (63, 80))
171015	30863498	These data were further underlined by the survival of RCC patients according to Kaplan-Meier curves, which showed a significantly lower overall survival in ccRCC patients with low levels of TGFBR2 in comparison to the ones with high expression of TGFBR2 (Supplementary Figure 4).	('lower', 'NegReg', (130, 135))	('patients', 'Species', '9606', (162, 170))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('TGFBR2', 'Gene', (190, 196))	('low levels', 'Var', (176, 186))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))	('overall survival', 'MPA', (136, 152))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('patients', 'Species', '9606', (58, 66))
171016	30863498	The levels of TGFBR2 were shown to regulate the downstream signaling pathway: high expression induces the Smad-dependent signaling pathway while a low expression triggers signaling via the non-Smad-dependent MAP/ERK pathway in colon cancer.	('ERK', 'molecular_function', 'GO:0004707', ('212', '215'))	('triggers', 'Reg', (162, 170))	('colon cancer', 'Disease', (227, 239))	('ERK', 'Gene', '2048', (212, 215))	('colon cancer', 'Disease', 'MESH:D015179', (227, 239))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('signaling pathway', 'biological_process', 'GO:0007165', ('59', '76'))	('high expression', 'Var', (78, 93))	('signaling', 'biological_process', 'GO:0023052', ('171', '180'))	('MAP', 'molecular_function', 'GO:0004239', ('208', '211'))	('TGFBR2', 'Gene', (14, 20))	('induces', 'Reg', (94, 101))	('colon cancer', 'Phenotype', 'HP:0003003', (227, 239))	('Smad-dependent signaling pathway', 'Pathway', (106, 138))	('signaling pathway', 'biological_process', 'GO:0007165', ('121', '138'))	('ERK', 'Gene', (212, 215))
171029	30863498	However, a correlation of high TGFB1 levels and worse overall survival was only determined for the clear cell but not for the papillary type of RCC (Supplementary Figure 5).	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('high', 'Var', (26, 30))	('papillary type', 'Phenotype', 'HP:0007482', (126, 140))	('TGFB1', 'Gene', '7040', (31, 36))	('high TGFB1 levels', 'Phenotype', 'HP:0030269', (26, 43))	('TGFB1', 'Gene', (31, 36))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))
171033	30863498	Besides similarities in EMT induction, we detected differences in surface expression of immune modulatory molecules for the representative ccRCC cell line MZ2733RC and the pRCC cell line MZ2858RC.	('RCC', 'Disease', (141, 144))	('pRCC', 'Gene', '5546', (172, 176))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('RCC', 'Disease', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('EMT', 'biological_process', 'GO:0001837', ('24', '27'))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('EMT', 'Gene', (24, 27))	('MZ2733RC', 'Var', (155, 163))	('RCC', 'Disease', 'MESH:C538614', (141, 144))	('EMT', 'Gene', '3702', (24, 27))	('differences', 'Reg', (51, 62))	('pRCC', 'Gene', (172, 176))	('MZ2733RC', 'Chemical', '-', (155, 163))	('surface expression', 'MPA', (66, 84))
171050	30863498	For MZ2733RC slightly higher TGF-beta1 protein levels relative to the untreated control were detected after 96 h inhibitor treatment.	('MZ2733RC', 'Var', (4, 12))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('higher', 'PosReg', (22, 28))	('MZ2733RC', 'Chemical', '-', (4, 12))	('TGF-beta1 protein levels', 'MPA', (29, 53))
171058	30863498	MZ1851RC, MZ2733RC, and MZ2858RC were generated from primary tumors of the clear cell or papillary subtype as previously described.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('MZ2733RC', 'Var', (10, 18))	('MZ2733RC', 'Chemical', '-', (10, 18))	('MZ1851RC', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MZ2858RC', 'Var', (24, 32))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
171066	30863498	In brief, the ccRCC cell type (MZ1851RC) and the pRCC cell type (MZ2858RC) were grown in 6-well plates +/- 10 ng/mL TGF-beta1 for 96 h to 100% confluence.	('pRCC', 'Gene', '5546', (49, 53))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('RCC', 'Disease', (16, 19))	('MZ1851RC', 'Var', (31, 39))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('pRCC', 'Gene', (49, 53))
171079	30863498	Datasets were obtained from "The Cancer Genome Atlas" (https://portal.gdc.cancer.gov) with 604 patients for TCGA-KIRC (ccRCC) and 320 patients for TCGA-KIRP (pRCC).	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('Cancer', 'Phenotype', 'HP:0002664', (33, 39))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('Cancer Genome Atlas', 'Disease', (33, 52))	('RCC', 'Disease', (121, 124))	('patients', 'Species', '9606', (95, 103))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (33, 52))	('pRCC', 'Gene', (158, 162))	('patients', 'Species', '9606', (134, 142))	('cancer', 'Disease', (74, 80))	('TCGA-KIRC', 'Var', (108, 117))	('pRCC', 'Gene', '5546', (158, 162))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))
171085	29030639	In contrast, AR-enhanced miR-185-5p also promotes HIF2alpha/VEGF-A expression via binding to the promoter region of HIF2alpha.	('VEGF-A', 'Gene', (60, 66))	('binding', 'molecular_function', 'GO:0005488', ('82', '89'))	('promotes', 'PosReg', (41, 49))	('miR-185-5p', 'Var', (25, 35))	('-5p', 'Chemical', '-', (32, 35))	('AR', 'Gene', '367', (13, 15))	('VEGF-A', 'Gene', '7422', (60, 66))	('expression', 'MPA', (67, 77))	('binding', 'Interaction', (82, 89))
171100	29030639	Here we investigated the underlying mechanisms behind these clinical findings and found AR might differentially modulate VEGF-A vs. VEGF-C expression via regulation of the microRNA (miRNA), miR-185-5p, to either promote or suppress RCC metastasis to different sites.	('suppress', 'NegReg', (223, 231))	('miR-185-5p', 'Var', (190, 200))	('VEGF-A', 'Gene', '7422', (121, 127))	('RCC', 'Phenotype', 'HP:0005584', (232, 235))	('VEGF-C', 'Gene', (132, 138))	('RCC', 'Disease', 'MESH:C538614', (232, 235))	('promote', 'PosReg', (212, 219))	('RCC', 'Disease', (232, 235))	('VEGF-A', 'Gene', (121, 127))	('modulate', 'Reg', (112, 120))	('AR', 'Gene', '367', (88, 90))	('clinical', 'Species', '191496', (60, 68))	('expression', 'MPA', (139, 149))	('VEGF-C', 'Gene', '7424', (132, 138))	('regulation', 'biological_process', 'GO:0065007', ('154', '164'))
171128	29030639	As most ccRCCs (~80-85%) harbor the VHL gene mutation, we examined AR expression in various RCC cell lines including VHL-wild type (VHL-WT) cell lines SN12-PM6, Caki-1, and ACHN and VHL-mutant (VHL-mut) cell lines A498, SW839, OSRC-2, 769-P, and 786-O cells.	('ACHN', 'Gene', '55323', (173, 177))	('VHL', 'Gene', (36, 39))	('SN12-PM6', 'CellLine', 'CVCL:9549', (151, 159))	('AR', 'Gene', '367', (67, 69))	('SW839', 'CellLine', 'CVCL:3604', (220, 225))	('ACHN', 'Gene', (173, 177))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('mutation', 'Var', (45, 53))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('A498', 'CellLine', 'CVCL:1056', (214, 218))	('VHL-WT', 'Disease', 'MESH:D006623', (132, 138))	('RCC', 'Disease', (10, 13))	('RCC', 'Phenotype', 'HP:0005584', (10, 13))	('VHL-WT', 'Disease', (132, 138))	('RCC', 'Disease', 'MESH:C538614', (10, 13))
171136	29030639	The western blot results showed that HIF2alpha and VEGF-A were increased by DHT, but not by vehicle or Enz in SW839 cells (Fig.	('increased', 'PosReg', (63, 72))	('DHT', 'Chemical', 'MESH:D013196', (76, 79))	('VEGF-A', 'Gene', '7422', (51, 57))	('HIF2alpha', 'Gene', (37, 46))	('SW839', 'CellLine', 'CVCL:3604', (110, 115))	('VEGF-A', 'Gene', (51, 57))	('DHT', 'Var', (76, 79))
171137	29030639	However, VEGF-C decreased with DHT treatment, and VEGF-D was almost unchanged (Fig.	('DHT', 'Chemical', 'MESH:D013196', (31, 34))	('VEGF-C', 'Gene', (9, 15))	('VEGF-D', 'Gene', '2277', (50, 56))	('VEGF-D', 'Gene', (50, 56))	('DHT', 'Var', (31, 34))	('VEGF-C', 'Gene', '7424', (9, 15))	('decreased', 'NegReg', (16, 25))
171138	29030639	The quantitative PCR assay confirmed that the mRNA levels of HIF2alpha and VEGF-A also increased by DHT treatment.	('increased', 'PosReg', (87, 96))	('HIF2alpha', 'Protein', (61, 70))	('DHT treatment', 'Var', (100, 113))	('mRNA levels', 'MPA', (46, 57))	('VEGF-A', 'Gene', '7422', (75, 81))	('VEGF-A', 'Gene', (75, 81))	('DHT', 'Chemical', 'MESH:D013196', (100, 103))
171141	29030639	In contrast, in SW839 cells, knocking down AR with two different AR-shRNAs reduced the expression of HIF2alpha and VEGF-A, but increased the VEGF-C expression in an AR-level-dependent manner (Fig.	('VEGF-C', 'Gene', (141, 147))	('AR', 'Gene', '367', (43, 45))	('VEGF-A', 'Gene', '7422', (115, 121))	('AR', 'Gene', '367', (165, 167))	('reduced', 'NegReg', (75, 82))	('expression', 'MPA', (87, 97))	('VEGF-A', 'Gene', (115, 121))	('knocking', 'Var', (29, 37))	('VEGF-C', 'Gene', '7424', (141, 147))	('AR', 'Gene', '367', (65, 67))	('expression', 'MPA', (148, 158))	('SW839', 'CellLine', 'CVCL:3604', (16, 21))	('HIF2alpha', 'Protein', (101, 110))	('increased', 'PosReg', (127, 136))
171143	29030639	Furthermore, knocking down AR with the two sh-ARs in SW839 cells decreased the mRNA levels of HIF2alpha and VEGF-A dramatically without significantly decreasing the VEGF-C mRNA expression (Fig.	('VEGF-C', 'Gene', (165, 171))	('decreased', 'NegReg', (65, 74))	('AR', 'Gene', '367', (46, 48))	('VEGF-A', 'Gene', '7422', (108, 114))	('VEGF-C', 'Gene', '7424', (165, 171))	('SW839', 'CellLine', 'CVCL:3604', (53, 58))	('VEGF-A', 'Gene', (108, 114))	('AR', 'Gene', '367', (27, 29))	('knocking', 'Var', (13, 21))	('mRNA levels of HIF2alpha', 'MPA', (79, 103))
171150	29030639	Yet in contrast, CM from SW839 cells with knocked down AR could suppress wound healing cell migration in HUVEC cells, yet promote this in HDLMVEC cells (Fig.	('AR', 'Gene', '367', (55, 57))	('wound healing', 'biological_process', 'GO:0042060', ('73', '86'))	('cell migration', 'biological_process', 'GO:0016477', ('87', '101'))	('suppress', 'NegReg', (64, 72))	('SW839', 'CellLine', 'CVCL:3604', (25, 30))	('promote', 'PosReg', (122, 129))	('knocked down', 'Var', (42, 54))	('wound healing cell migration', 'CPA', (73, 101))	('HUVEC', 'CellLine', 'CVCL:2959', (105, 110))	('HDLMVEC', 'CellLine', 'None', (138, 145))	('suppress wound healing', 'Phenotype', 'HP:0001058', (64, 86))
171152	29030639	3f, g), while knocking down AR in SW839 cells suppressed invasion of HUVEC cells yet promoted the invasion of HDLMVEC cells (Fig.	('invasion of HUVEC cells', 'CPA', (57, 80))	('SW839', 'Gene', (34, 39))	('SW839', 'CellLine', 'CVCL:3604', (34, 39))	('knocking down', 'Var', (14, 27))	('HUVEC', 'CellLine', 'CVCL:2959', (69, 74))	('invasion of HDLMVEC cells', 'CPA', (98, 123))	('promoted', 'PosReg', (85, 93))	('AR', 'Gene', '367', (28, 30))	('HDLMVEC', 'CellLine', 'None', (110, 117))	('suppressed', 'NegReg', (46, 56))
171156	29030639	As expected, knocking down AR in SW839 cells induced more lymphatic endothelial cell tube formation while less HUVEC tube formation (Fig.	('tube formation', 'biological_process', 'GO:0035148', ('85', '99'))	('knocking down', 'Var', (13, 26))	('more', 'PosReg', (53, 57))	('HUVEC', 'CellLine', 'CVCL:2959', (111, 116))	('SW839', 'Gene', (33, 38))	('less', 'NegReg', (106, 110))	('tube formation', 'biological_process', 'GO:0035148', ('117', '131'))	('SW839', 'CellLine', 'CVCL:3604', (33, 38))	('HUVEC tube formation', 'CPA', (111, 131))	('AR', 'Gene', '367', (27, 29))	('lymphatic endothelial cell tube formation', 'CPA', (58, 99))
171157	29030639	Importantly, interruption approaches using VEGF-A neutralizing antibody or knocking down VEGF-C in ccRCC cells then partially reversed the AR impacts on the differential effects of in vitro assays of angiogenesis (Fig.	('neutralizing', 'Var', (50, 62))	('angiogenesis', 'CPA', (200, 212))	('AR', 'Gene', '367', (139, 141))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('antibody', 'cellular_component', 'GO:0042571', ('63', '71'))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('VEGF-C', 'Gene', '7424', (89, 95))	('RCC', 'Disease', (101, 104))	('antibody', 'cellular_component', 'GO:0019815', ('63', '71'))	('angiogenesis', 'biological_process', 'GO:0001525', ('200', '212'))	('antibody', 'cellular_component', 'GO:0019814', ('63', '71'))	('antibody', 'molecular_function', 'GO:0003823', ('63', '71'))	('VEGF-A', 'Gene', '7422', (43, 49))	('VEGF-C', 'Gene', (89, 95))	('VEGF-A', 'Gene', (43, 49))	('knocking', 'Var', (75, 83))
171158	29030639	3 suggest that AR may function through modulation of the VEGF-A or VEGF-C in ccRCC cells to differentially influence the hematogenous and the lymphatic endothelial cells, thus ultimately affect different metastatic destinations.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('affect', 'Reg', (187, 193))	('VEGF-C', 'Gene', (67, 73))	('hematogenous and', 'CPA', (121, 137))	('modulation', 'Var', (39, 49))	('AR', 'Gene', '367', (15, 17))	('VEGF-A', 'Gene', '7422', (57, 63))	('metastatic destinations', 'CPA', (204, 227))	('influence', 'Reg', (107, 116))	('VEGF-A', 'Gene', (57, 63))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('VEGF-C', 'Gene', '7424', (67, 73))	('RCC', 'Disease', (79, 82))
171163	29030639	To further validate these potential miRNA candidates in AR-meditated regulation of VEGF-A and VEGF-C, we then knocked down AR in SW839 cells and found that miR-185-5p decreased more dramatically than others in response to knocking down AR (Fig.	('regulation', 'biological_process', 'GO:0065007', ('69', '79'))	('VEGF-C', 'Gene', (94, 100))	('miR-185-5p', 'MPA', (156, 166))	('AR', 'Gene', '367', (236, 238))	('VEGF-A', 'Gene', '7422', (83, 89))	('VEGF-A', 'Gene', (83, 89))	('knocked down', 'Var', (110, 122))	('knocking down', 'Var', (222, 235))	('AR', 'Gene', '367', (123, 125))	('SW839', 'CellLine', 'CVCL:3604', (129, 134))	('AR', 'Gene', '367', (56, 58))	('VEGF-C', 'Gene', '7424', (94, 100))	('decreased', 'NegReg', (167, 176))
171164	29030639	4c), suggesting miR-185-5p could be our best candidate as it was also predicted to bind to both the 3' UTR of VEGF-C and 5' promoter of HIF2alpha (Fig.	('miR-185-5p', 'Var', (16, 26))	('bind', 'Interaction', (83, 87))	('VEGF-C and 5', 'Gene', '7424', (110, 122))
171165	29030639	Importantly, a clinical survey of 22 VHL-mut ccRCC tumors also found that the miR-185-5p was positively correlated with the AR expression (Fig.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('VHL-mut ccRCC tumors', 'Disease', (37, 57))	('correlated', 'Reg', (104, 114))	('clinical', 'Species', '191496', (15, 23))	('miR-185-5p', 'Var', (78, 88))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('VHL-mut ccRCC tumors', 'Disease', 'MESH:D006623', (37, 57))	('AR', 'Gene', '367', (124, 126))
171169	29030639	The mRNA expression of HIF2alpha and VEGF-A increased in response to miR-185-5p expression in SW839 cells, while VEGF-C mRNA levels did not show a significant change (Fig.	('VEGF-C', 'Gene', '7424', (113, 119))	('HIF2alpha', 'Gene', (23, 32))	('miR-185-5p expression', 'Var', (69, 90))	('-5p', 'Chemical', '-', (76, 79))	('mRNA expression', 'MPA', (4, 19))	('SW839', 'CellLine', 'CVCL:3604', (94, 99))	('VEGF-C', 'Gene', (113, 119))	('increased', 'PosReg', (44, 53))	('VEGF-A', 'Gene', '7422', (37, 43))	('VEGF-A', 'Gene', (37, 43))
171172	29030639	We generated pGL3-basic vectors that carry the wild-type and mutant promoter region (-1117 to +257) of HIF2alpha as well as CMV-driven luciferase followed by the wild-type and mutant 3' UTR of VEGF-C (Fig.	('HIF2alpha', 'Gene', (103, 112))	('-1117 to +257', 'Var', (85, 98))	('VEGF-C', 'Gene', '7424', (193, 199))	('pGL', 'molecular_function', 'GO:0004598', ('13', '16'))	('VEGF-C', 'Gene', (193, 199))	('mutant', 'Var', (61, 67))	('pGL3', 'Gene', (13, 17))	('pGL3', 'Gene', '6391', (13, 17))
171174	29030639	The results revealed that miR-185-5p could promote the HIF2alpha promoter activity in SW839 cells (Fig.	('promote', 'PosReg', (43, 50))	('SW839', 'CellLine', 'CVCL:3604', (86, 91))	('miR-185-5p', 'Var', (26, 36))	('HIF2alpha', 'Protein', (55, 64))
171176	29030639	6a-c suggest that AR-enhanced miR-185-5p could bind to the promoter region of HIF2alpha to promote the HIF2alpha and VEGF-A expression and bind to the 3' UTR of VEGF-C to suppress its expression.	('HIF2alpha', 'Gene', (103, 112))	('promote', 'PosReg', (91, 98))	('AR', 'Gene', '367', (18, 20))	('bind', 'Interaction', (139, 143))	('VEGF-A', 'Gene', '7422', (117, 123))	('HIF2alpha', 'Gene', (78, 87))	('miR-185-5p', 'Var', (30, 40))	('VEGF-C', 'Gene', '7424', (161, 167))	('VEGF-A', 'Gene', (117, 123))	('expression', 'MPA', (124, 134))	('suppress', 'NegReg', (171, 179))	('expression', 'MPA', (184, 194))	('-5p', 'Chemical', '-', (37, 40))	('VEGF-C', 'Gene', (161, 167))
171177	29030639	We next asked how AR could modulate the expression of miR-185-5p.	('AR', 'Gene', '367', (18, 20))	('modulate', 'Reg', (27, 35))	('miR-185-5p', 'Var', (54, 64))
171178	29030639	We applied the miRStart to determine the transcriptional start site of pre-miR-185 and then examined the potential AR binding element (AREs) up to 5000 bases upstream from the transcriptional start site, and results revealed that this promoter region contains 10 potential AR binding elements that may allow AR to bind (Fig.	('AR', 'Gene', '367', (135, 137))	('AR', 'Gene', '367', (273, 275))	('AR', 'Gene', '367', (115, 117))	('bind', 'Interaction', (314, 318))	('pre-miR-185', 'Var', (71, 82))	('AR', 'Gene', '367', (308, 310))	('AR binding', 'molecular_function', 'GO:0050681', ('273', '283'))	('AR binding', 'molecular_function', 'GO:0050681', ('115', '125'))	('pre', 'molecular_function', 'GO:0003904', ('71', '74'))
171183	29030639	We first transduced the SN12-PM6 cells with luciferase and knocked down VHL simultaneously with lentiviral vectors pLV-luci-U6-VHL to generate the stable luciferase expressing VHL-mut cell line (see quantitative PCR/western blot in Supplementary Fig.	('luciferase', 'Enzyme', (44, 54))	('knocked down', 'Var', (59, 71))	('VHL', 'Gene', (72, 75))	('SN12-PM6', 'CellLine', 'CVCL:9549', (24, 32))
171184	29030639	Importantly, similar to above studies from the other ccRCC VHL-mut SW839 cells, AR could also differentially regulate VEGF-A and VEGF-C expression likely through upregulation of miR-185-5p (Supplementary Fig.	('AR', 'Gene', '367', (80, 82))	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('expression', 'MPA', (136, 146))	('upregulation', 'PosReg', (162, 174))	('VEGF-C', 'Gene', '7424', (129, 135))	('VEGF-A', 'Gene', '7422', (118, 124))	('VEGF-A', 'Gene', (118, 124))	('miR-185-5p', 'Var', (178, 188))	('VEGF-C', 'Gene', (129, 135))	('SW839', 'CellLine', 'CVCL:3604', (67, 72))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
171186	29030639	Sixty male nude mice were randomly divided into four groups for injections with SN16-PM6 control, overexpressed AR (OE-AR), knocked down miR-185-5p (Sh-miR-185), or overexpressed AR together with knocked down miR-185-5p (OE-AR + Sh-miR-185) cell xenografts.	('-5p', 'Chemical', '-', (216, 219))	('-5p', 'Chemical', '-', (144, 147))	('SN16-PM6', 'Chemical', '-', (80, 88))	('AR', 'Gene', '367', (112, 114))	('miR-185-5p', 'Gene', (137, 147))	('knocked', 'Var', (196, 203))	('AR', 'Gene', '367', (119, 121))	('knocked down', 'Var', (124, 136))	('nude mice', 'Species', '10090', (11, 20))	('AR', 'Gene', '367', (179, 181))	('AR', 'Gene', '367', (224, 226))
171195	29030639	Importantly, knocking down miR-185-5p could partially reverse the AR effect on ccRCC cells (Fig.	('knocking down', 'Var', (13, 26))	('-5p', 'Chemical', '-', (34, 37))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('AR', 'Gene', '367', (66, 68))	('miR-185-5p', 'Gene', (27, 37))
171196	29030639	IHC staining of MVD by CD34 and MLD by D2-40 further supported the conclusion showing that overexpression of AR resulted in increased MVD and a decreased MLD while knocking down miR-185-5p decreased MVD, but increased MLD (Fig.	('MLD', 'Disease', 'MESH:D007966', (32, 35))	('decreased', 'NegReg', (144, 153))	('MVD', 'MPA', (199, 202))	('knocking down', 'Var', (164, 177))	('decreased', 'NegReg', (189, 198))	('MLD', 'Disease', 'MESH:D007966', (154, 157))	('increased', 'PosReg', (124, 133))	('MLD', 'Disease', (32, 35))	('CD34', 'Gene', (23, 27))	('CD34', 'Gene', '947', (23, 27))	('MLD', 'Disease', 'MESH:D007966', (218, 221))	('MLD', 'Disease', (218, 221))	('MLD', 'Disease', (154, 157))	('AR', 'Gene', '367', (109, 111))	('increased', 'PosReg', (208, 217))	('miR-185-5p', 'Gene', (178, 188))	('MVD', 'MPA', (134, 137))
171197	29030639	Furthermore, knocking down miR-185-5p could also partially reverse the effect of AR (Fig.	('miR-185-5p', 'Var', (27, 37))	('knocking down miR-185-5p', 'Var', (13, 37))	('AR', 'Gene', '367', (81, 83))
171200	29030639	However, knocking down miR-185-5p could reverse the impact of AR (Fig.	('miR-185-5p', 'Gene', (23, 33))	('knocking down', 'Var', (9, 22))	('AR', 'Gene', '367', (62, 64))
171203	29030639	9a cartoon, AR increases hematogenous metastasis yet decreases lymphatic metastasis of RCC through differential regulation of the VEGF-A vs. VEGF-C via miR-185-5p.	('hematogenous metastasis', 'CPA', (25, 48))	('VEGF-C', 'Gene', (141, 147))	('RCC', 'Disease', (87, 90))	('lymphatic metastasis', 'CPA', (63, 83))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('miR-185-5p', 'Var', (152, 162))	('AR', 'Gene', '367', (12, 14))	('increases', 'PosReg', (15, 24))	('VEGF-C', 'Gene', '7424', (141, 147))	('decreases', 'NegReg', (53, 62))	('VEGF-A', 'Gene', '7422', (130, 136))	('VEGF-A', 'Gene', (130, 136))	('regulation', 'biological_process', 'GO:0065007', ('112', '122'))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
171215	29030639	Mechanism dissection of the differential regulation of VEGF-A and VEGF-C also led us to identify miR-185-5p that likely mediates this effect through its ability to target the 3' UTR of VEGF-C and to bind to the HIF2alpha promoter to enhance HIF2alpha transcription, thus its target gene VEGF-A (Fig.	('VEGF-C', 'Gene', (185, 191))	('VEGF-C', 'Gene', (66, 72))	('enhance', 'PosReg', (233, 240))	('miR-185-5p', 'Var', (97, 107))	('transcription', 'biological_process', 'GO:0006351', ('251', '264'))	('VEGF-A', 'Gene', '7422', (55, 61))	('VEGF-A', 'Gene', (55, 61))	('regulation', 'biological_process', 'GO:0065007', ('41', '51'))	('VEGF-A', 'Gene', (287, 293))	('VEGF-C', 'Gene', '7424', (185, 191))	('VEGF-C', 'Gene', '7424', (66, 72))	('VEGF-A', 'Gene', '7422', (287, 293))	('HIF2alpha', 'Gene', (241, 250))	('bind', 'Interaction', (199, 203))
171259	29030639	About 60 male nude mice were randomly divided into four groups without blinding for injection of cells with control, overexpression of AR (OE-AR), knockdown of miR-185-5p (Sh-miR-185), and overexpression of AR with simultaneous knockdown of miR-185-5p (OE-AR + Sh-miR-185).	('AR', 'Gene', '367', (142, 144))	('AR', 'Gene', '367', (135, 137))	('AR', 'Gene', '367', (207, 209))	('miR-185-5p', 'Var', (160, 170))	('AR', 'Gene', '367', (256, 258))	('nude mice', 'Species', '10090', (14, 23))	('knockdown', 'Var', (147, 156))
171317	31795520	The results showed that patients with deep white matter tracts and ependymal invasion on imaging (defined Class A) had a significant decrease in overall survival, whereas, in patients with the absence of such invasive imaging features (defined Class B), happened otherwise.	('decrease', 'NegReg', (133, 141))	('deep', 'Var', (38, 42))	('overall survival', 'MPA', (145, 161))	('ependymal invasion', 'CPA', (67, 85))	('patients', 'Species', '9606', (175, 183))	('patients', 'Species', '9606', (24, 32))
171322	31795520	In more detail, these imaging features were associated with the IDH-1p/19q subtype, RNASeq cluster, copy number cluster, and the cluster of clusters subtype (for details on these clusters, see Brat et al.).	('associated', 'Reg', (44, 54))	('IDH-1p', 'Gene', '3417', (64, 70))	('rat', 'Species', '10116', (194, 197))	('RNASeq cluster', 'Disease', (84, 98))	('copy number cluster', 'Var', (100, 119))	('IDH-1p', 'Gene', (64, 70))
171331	31795520	Involved miRNA (miR-29b-3p, miR495-3p, miR30c/30d, miR-26a-5p, miR296-5p, miR128-3p, miR144-3p, and miR214-3p) and genes (PTEN, COL15A1, SPARC, ANPEP, CBFB, STRN, and TMED10) unveiled several networks of tumorogenesis interest, such as tight junction signaling and p53 signaling.	('p53', 'Gene', (265, 268))	('miR296', 'Gene', (63, 69))	('miR30c', 'Gene', '407031', (39, 45))	('signaling', 'biological_process', 'GO:0023052', ('251', '260'))	('miR30c', 'Gene', (39, 45))	('CBFB', 'Gene', '865', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('SPARC', 'Gene', (137, 142))	('STRN', 'Gene', '6801', (157, 161))	('miR214-3p', 'Var', (100, 109))	('miR-29b-3p', 'Var', (16, 26))	('ANPEP', 'Gene', (144, 149))	('PTEN', 'Gene', (122, 126))	('miR128-3p', 'Var', (74, 83))	('COL15A1', 'Gene', (128, 135))	('tumorogenesis', 'Disease', (204, 217))	('SPARC', 'Gene', '6678', (137, 142))	('signaling', 'biological_process', 'GO:0023052', ('269', '278'))	('tight junction', 'cellular_component', 'GO:0070160', ('236', '250'))	('tumorogenesis', 'Disease', 'MESH:D002471', (204, 217))	('miR495-3p', 'Var', (28, 37))	('ANPEP', 'Gene', '290', (144, 149))	('miR296', 'Gene', '407022', (63, 69))	('p53', 'Gene', '7157', (265, 268))	('CBFB', 'Gene', (151, 155))	('tight junction signaling', 'MPA', (236, 260))	('miR144-3p', 'Var', (85, 94))	('COL15A1', 'Gene', '1306', (128, 135))	('miR-26a-5p', 'Var', (51, 61))	('STRN', 'Gene', (157, 161))
171344	31795520	Integrating molecular data suggested the roles of several genes/miRNA regulating proliferation (PGC1alpha/miR-199a, miR-125, and miR-129) and invasion (PAR1, HOXC6 / miR-499, miR-146b).	('miR-129', 'Var', (129, 136))	('miR-146b', 'Gene', '574447', (175, 183))	('miR-125', 'Var', (116, 123))	('miR-146b', 'Gene', (175, 183))	('miR-499', 'Gene', '574501', (166, 173))	('rat', 'Species', '10116', (88, 91))	('PGC1alpha', 'Gene', '10891', (96, 105))	('rat', 'Species', '10116', (5, 8))	('miR-499', 'Gene', (166, 173))	('proliferation', 'CPA', (81, 94))	('invasion', 'CPA', (142, 150))	('PAR1', 'Var', (152, 156))	('PGC1alpha', 'Gene', (96, 105))
171362	31795520	also showed that there were weak correlations between imaging features and copy number variation, in particular, a weak association between CDKN2A deletion and necrosis, amplification of EGFR, and an increased percentage of contrast enhancement.	('necrosis', 'Disease', 'MESH:D009336', (160, 168))	('necrosis', 'biological_process', 'GO:0070265', ('160', '168'))	('amplification', 'Var', (170, 183))	('necrosis', 'biological_process', 'GO:0008219', ('160', '168'))	('necrosis', 'biological_process', 'GO:0019835', ('160', '168'))	('increased', 'PosReg', (200, 209))	('CDKN2A', 'Gene', (140, 146))	('EGFR', 'Protein', (187, 191))	('necrosis', 'biological_process', 'GO:0008220', ('160', '168'))	('necrosis', 'Disease', (160, 168))	('deletion', 'Var', (147, 155))	('necrosis', 'biological_process', 'GO:0001906', ('160', '168'))	('CDKN2A', 'Gene', '1029', (140, 146))	('contrast enhancement', 'MPA', (224, 244))	('EGFR', 'molecular_function', 'GO:0005006', ('187', '191'))
171364	31795520	Some significative mutations were related to volumetric features: EGFR mutations displayed a significantly higher necrosis/contrast enhancing ratio and a significantly lower contrast-enhancing/tumor bulk ratio.	('necrosis', 'biological_process', 'GO:0008220', ('114', '122'))	('necrosis', 'Disease', (114, 122))	('necrosis', 'biological_process', 'GO:0001906', ('114', '122'))	('EGFR', 'Gene', (66, 70))	('lower', 'NegReg', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('rat', 'Species', '10116', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('mutations', 'Var', (71, 80))	('necrosis', 'biological_process', 'GO:0070265', ('114', '122'))	('necrosis', 'Disease', 'MESH:D009336', (114, 122))	('tumor', 'Disease', (193, 198))	('higher', 'PosReg', (107, 113))	('necrosis', 'biological_process', 'GO:0008219', ('114', '122'))	('rat', 'Species', '10116', (142, 145))	('necrosis', 'biological_process', 'GO:0019835', ('114', '122'))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
171365	31795520	Furthermore, RB1 mutations tumors showed significantly smaller T2-FLAIR hyperintensity, and TP53 significantly predicted necrosis and tumor volumes by contrast-enhancing.	('necrosis', 'Disease', (121, 129))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('necrosis', 'biological_process', 'GO:0008219', ('121', '129'))	('smaller', 'NegReg', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('TP53', 'Gene', (92, 96))	('RB1', 'Gene', (13, 16))	('mutations', 'Var', (17, 26))	('tumor', 'Disease', (27, 32))	('necrosis', 'biological_process', 'GO:0008220', ('121', '129'))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('RB1', 'Gene', '5925', (13, 16))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('predicted', 'Reg', (111, 120))	('necrosis', 'biological_process', 'GO:0070265', ('121', '129'))	('necrosis', 'biological_process', 'GO:0019835', ('121', '129'))	('necrosis', 'biological_process', 'GO:0001906', ('121', '129'))	('tumor', 'Disease', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Disease', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('necrosis', 'Disease', 'MESH:D009336', (121, 129))	('T2-FLAIR hyperintensity', 'MPA', (63, 86))
171366	31795520	Additionally, NF1 mutation status was significantly predicted by contrast-enhancing volume and tumor bulk volume, whereas PDGFR-alpha was significantly predicted by T2-FLAIR hyperintensity/total tumor volume and tumor bulk/total tumor volume ratios.	('tumor', 'Disease', (195, 200))	('predicted', 'Reg', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('PDGFR-alpha', 'Gene', (122, 133))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('NF1', 'Gene', '4763', (14, 17))	('predicted', 'Reg', (152, 161))	('mutation', 'Var', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('NF1', 'Gene', (14, 17))	('rat', 'Species', '10116', (242, 245))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', (95, 100))	('tumor', 'Disease', (212, 217))	('PDGFR-alpha', 'Gene', '5156', (122, 133))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (212, 217))
171367	31795520	The features that were significantly associated with survival were the proportion of tumor contrast enhancement on MRI and HRAS copy number variation.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('associated', 'Reg', (37, 47))	('copy number variation', 'Var', (128, 149))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('HRAS', 'Gene', (123, 127))
171368	31795520	In the same study, which included 45 patients, combining epidermal growth factor receptor (EGFR) alteration (mutation or amplification) with a relative cerebral blood volume of the non-enhancing region (rCBVNER), a significant association with OS (overall survival) was found, with worst survival in the high-rCBVNER wild-type EGFR group.	('alteration', 'Var', (97, 107))	('EGFR', 'Gene', (91, 95))	('rat', 'Species', '10116', (101, 104))	('patients', 'Species', '9606', (37, 45))	('epidermal growth factor receptor', 'Gene', '1956', (57, 89))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('57', '80'))	('EGFR', 'molecular_function', 'GO:0005006', ('327', '331'))	('EGFR', 'molecular_function', 'GO:0005006', ('91', '95'))	('high-rCBVNER', 'Var', (304, 316))	('epidermal growth factor receptor', 'Gene', (57, 89))
171405	31795520	found several quantitative MRI features (such as tumor size, shape, margin, and blood flow kinetics) associated with different molecular profiles, such as DNA mutation, miRNA expression, protein expression, pathway gene expression, and copy number variation.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('miRNA expression', 'MPA', (169, 185))	('copy number variation', 'Var', (236, 257))	('DNA', 'cellular_component', 'GO:0005574', ('155', '158'))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('gene expression', 'biological_process', 'GO:0010467', ('215', '230'))	('protein expression', 'MPA', (187, 205))	('associated', 'Reg', (101, 111))	('DNA mutation', 'Disease', (155, 167))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))	('pathway', 'MPA', (207, 214))
171409	31795520	ccRCC is the most common subtype of renal cell carcinoma (RCC), and it is distinctly caused by a somatic mutation in the Von Hippel-Lindau (VHL) tumor suppressor gene, even if several other genes have been associated with the advanced form of the disease using whole-genome sequencing.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('145', '161'))	('renal cell carcinoma', 'Disease', (36, 56))	('Von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (121, 150))	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('mutation in', 'Var', (105, 116))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (36, 56))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (36, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('tumor suppressor', 'biological_process', 'GO:0051726', ('145', '161'))	('caused by', 'Reg', (85, 94))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
171412	31795520	In detail, mutations in two distinct genes were associated with radiomic features: in the BAP1 gene, associated with ill-defined tumor margins and with the presence of calcification, and in the MUC4 gene, associated with exophytic growth.	('mutations', 'Var', (11, 20))	('calcification', 'Disease', (168, 181))	('ill-defined tumor', 'Disease', (117, 134))	('associated', 'Reg', (48, 58))	('BAP1', 'Gene', '8314', (90, 94))	('MUC4', 'Gene', '4585', (194, 198))	('exophytic growth', 'Disease', (221, 237))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('BAP1', 'Gene', (90, 94))	('associated', 'Reg', (101, 111))	('associated', 'Reg', (205, 215))	('MUC4', 'Gene', (194, 198))	('ill-defined tumor', 'Disease', 'MESH:D002908', (117, 134))	('calcification', 'Disease', 'MESH:D002114', (168, 181))
171421	31795520	m1 tumors (defined by genes related to chromatin remodeling processes and a higher frequency of PBRM1 gene mutations) were found positively correlated with a well-defined margin.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('mutations', 'Var', (107, 116))	('chromatin', 'cellular_component', 'GO:0000785', ('39', '48'))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('PBRM1', 'Gene', (96, 101))	('PBRM1', 'Gene', '55193', (96, 101))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('39', '59'))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
171422	31795520	On the other hand, m3 tumors (defined by frequently deletion of CDKN2A and mutations in PTEN) were found negatively correlated with CT features that are considered indicators of the infiltrative/invasive phenotype (well-defined margin, renal vein invasion, and urinary collecting system invasion).	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('collecting system', 'Phenotype', 'HP:0000081', (269, 286))	('renal vein invasion', 'CPA', (236, 255))	('CDKN2A', 'Gene', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('PTEN', 'Gene', (88, 92))	('CDKN2A', 'Gene', '1029', (64, 70))	('rat', 'Species', '10116', (188, 191))	('mutations', 'Var', (75, 84))	('negatively', 'NegReg', (105, 115))	('tumors', 'Disease', (22, 28))	('deletion', 'Var', (52, 60))
171451	31795520	The images represented the association between imaging features (radiomic and/or radiological) and molecular 'omic signature, which could be gene expressions, mutations, clusters, or cancer subtypes.	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('mutations', 'Var', (159, 168))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
171476	30968158	High FABP5 expression was also significantly correlated with tumor and metastasis classifications and predicted poor survival in patients with ccRCC.	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (129, 137))	('expression', 'MPA', (11, 21))	('poor', 'NegReg', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('ccRCC', 'Phenotype', 'HP:0006770', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('FABP5', 'Gene', (5, 10))	('tumor', 'Disease', (61, 66))	('correlated', 'Reg', (45, 55))
171477	30968158	In ccRCC cells, silencing of FABP5 significantly inhibited cell proliferation, while overexpression of FABP5 promoted cell proliferation when compared to the respective controls.	('promoted', 'PosReg', (109, 117))	('rat', 'Species', '10116', (71, 74))	('cell proliferation', 'CPA', (59, 77))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('silencing', 'Var', (16, 25))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('rat', 'Species', '10116', (130, 133))	('cell proliferation', 'CPA', (118, 136))	('FABP5', 'Gene', (29, 34))	('cell proliferation', 'biological_process', 'GO:0008283', ('118', '136'))	('inhibited', 'NegReg', (49, 58))
171478	30968158	In addition, treatment with the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT inhibitor, LY294002, attenuated the pro-proliferative effects of exogenous FABP5 expression in Caki-1 and 786O cells.	('AKT', 'Gene', (86, 89))	('attenuated', 'NegReg', (111, 121))	('exogenous', 'MPA', (155, 164))	('LY294002', 'Var', (101, 109))	('rat', 'Species', '10116', (137, 140))	('pro-proliferative effects', 'CPA', (126, 151))	('phosphatidylinositol-4,5-bisphosphate 3-kinase', 'Gene', '5291', (32, 78))	('AKT', 'Gene', '207', (86, 89))	('LY294002', 'Chemical', 'MESH:C085911', (101, 109))	('PI3K', 'molecular_function', 'GO:0016303', ('80', '84'))
171497	30968158	FABP5 gene silencing inhibited the proliferation and invasion of human SGC-7901 gastric cancer cells in vitro, and FABP5 stimulated hepatocellular carcinoma progression and metastasis via EMT.	('gastric cancer', 'Disease', (80, 94))	('human', 'Species', '9606', (65, 70))	('EMT', 'biological_process', 'GO:0001837', ('188', '191'))	('invasion', 'CPA', (53, 61))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (132, 156))	('gene silencing', 'Var', (6, 20))	('inhibited', 'NegReg', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('gene silencing', 'biological_process', 'GO:0016458', ('6', '20'))	('gastric cancer', 'Disease', 'MESH:D013274', (80, 94))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (132, 156))	('metastasis', 'CPA', (173, 183))	('stimulated', 'PosReg', (121, 131))	('FABP5', 'Gene', (115, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('hepatocellular carcinoma', 'Disease', (132, 156))	('SGC-7901', 'CellLine', 'CVCL:0520', (71, 79))	('proliferation', 'CPA', (35, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('rat', 'Species', '10116', (42, 45))	('FABP5', 'Gene', (0, 5))
171512	30968158	The PI3K/AKT signaling pathway inhibitor, LY294002, was purchased from MedChem Express (Monmouth Junction, NJ, USA) and added to the culture medium at a concentration of 20 microM for 24 h to inactivate the PI3K/AKT signaling pathway in vitro.	('AKT', 'Gene', (212, 215))	('AKT', 'Gene', '207', (9, 12))	('signaling pathway', 'biological_process', 'GO:0007165', ('13', '30'))	('rat', 'Species', '10116', (160, 163))	('LY294002', 'Var', (42, 50))	('AKT signaling', 'biological_process', 'GO:0043491', ('9', '22'))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('AKT signaling', 'biological_process', 'GO:0043491', ('212', '225'))	('inactivate', 'NegReg', (192, 202))	('signaling pathway', 'biological_process', 'GO:0007165', ('216', '233'))	('AKT', 'Gene', (9, 12))	('LY294002', 'Chemical', 'MESH:C085911', (42, 50))	('AKT', 'Gene', '207', (212, 215))	('PI3K', 'molecular_function', 'GO:0016303', ('207', '211'))
171556	30968158	Furthermore, univariate Cox regression analysis demonstrated that high FABP5 expression was an unfavorable prognostic parameter in patients with ccRCC (P<0.01; Table II).	('patients', 'Species', '9606', (131, 139))	('expression', 'MPA', (77, 87))	('Cox', 'Gene', '1351', (24, 27))	('ccRCC', 'Phenotype', 'HP:0006770', (145, 150))	('Cox', 'Gene', (24, 27))	('RCC', 'Disease', (147, 150))	('high', 'Var', (66, 70))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('rat', 'Species', '10116', (55, 58))	('FABP5', 'Gene', (71, 76))
171568	30968158	To investigate the role of FABP5 in regulating the PI3K/AKT signaling pathway in ccRCC cells further, 20 microM LY294002 was used to inhibit the PI3K/AKT signaling pathway in Caki-1 and 786O cells in vitro.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('RCC', 'Disease', (83, 86))	('AKT', 'Gene', '207', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('LY294002', 'Chemical', 'MESH:C085911', (112, 120))	('AKT', 'Gene', '207', (150, 153))	('AKT', 'Gene', (56, 59))	('inhibit', 'NegReg', (133, 140))	('AKT signaling', 'biological_process', 'GO:0043491', ('56', '69'))	('signaling pathway', 'biological_process', 'GO:0007165', ('60', '77'))	('PI3K', 'molecular_function', 'GO:0016303', ('145', '149'))	('AKT', 'Gene', (150, 153))	('LY294002', 'Var', (112, 120))	('signaling pathway', 'biological_process', 'GO:0007165', ('154', '171'))	('AKT signaling', 'biological_process', 'GO:0043491', ('150', '163'))
171569	30968158	5A and B, LY294002 treatment significantly reduced the viability of FABP5-overexpressing cells, as demonstrated by the CCK-8 assay results in Caki-1 (all P<0.001 vs. LV-FABP5 group; LV-NC group vs. LV-NC+LY294002 group, P<0.01; LV-FABP5+LY294002 group vs. LV-NC+LY294002 group, P<0.05; Fig.	('LY294002', 'Chemical', 'MESH:C085911', (204, 212))	('LY294002', 'Var', (10, 18))	('LY294002', 'Chemical', 'MESH:C085911', (10, 18))	('LY294002', 'Chemical', 'MESH:C085911', (262, 270))	('LY294002', 'Chemical', 'MESH:C085911', (237, 245))	('rat', 'Species', '10116', (106, 109))	('reduced', 'NegReg', (43, 50))
171573	30968158	5E) cells were significantly decreased following treatment with LY294002.	('LY294002', 'Chemical', 'MESH:C085911', (64, 72))	('LY294002', 'Var', (64, 72))	('decreased', 'NegReg', (29, 38))
171575	30968158	5F-I, the level of p-AKT in Caki-1 and 786O cells from the LV-FABP5 group was significantly increased when normalized to beta-actin and compared with controls.	('AKT', 'Gene', '207', (21, 24))	('increased', 'PosReg', (92, 101))	('beta-actin', 'Gene', '728378', (121, 131))	('beta-actin', 'Gene', (121, 131))	('LV-FABP5', 'Var', (59, 67))	('AKT', 'Gene', (21, 24))
171576	30968158	Accordingly, treatment with LY294002 significantly decreased p-AKT levels in FABP5-overexpressing Caki-1 (P<0.001; Fig.	('AKT', 'Gene', (63, 66))	('LY294002', 'Var', (28, 36))	('decreased', 'NegReg', (51, 60))	('LY294002', 'Chemical', 'MESH:C085911', (28, 36))	('AKT', 'Gene', '207', (63, 66))
171577	30968158	5G) and 786O cells (all P<0.001 apart from p-AKT (Thr308) in LV-FABP5+LY294002 group vs. LV-NC+LY294002 group, P<0.05; Fig.	('LY294002', 'Chemical', 'MESH:C085911', (95, 103))	('LY294002', 'Chemical', 'MESH:C085911', (70, 78))	('AKT', 'Gene', (45, 48))	('LV-FABP5+LY294002', 'Var', (61, 78))	('Thr308', 'Chemical', '-', (50, 56))	('AKT', 'Gene', '207', (45, 48))
171578	30968158	However, LY294002 treatment did not affect the expression of endogenous FABP5 (indicated as FABP5 only; Fig.	('FABP5', 'Gene', (72, 77))	('LY294002', 'Var', (9, 17))	('LY294002', 'Chemical', 'MESH:C085911', (9, 17))
171579	30968158	Taken together, these results suggest that the PI3K/AKT signaling pathway may participate in FABP5-induced proliferation of ccRCC cells, and that inhibiting PI3K/AKT signaling may suppress the pro-proliferative effects of FABP5 in ccRCC cells.	('AKT', 'Gene', '207', (162, 165))	('AKT signaling', 'biological_process', 'GO:0043491', ('162', '175'))	('pro-proliferative effects', 'CPA', (193, 218))	('RCC', 'Phenotype', 'HP:0005584', (233, 236))	('ccRCC', 'Phenotype', 'HP:0006770', (231, 236))	('RCC', 'Disease', (233, 236))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('signaling pathway', 'biological_process', 'GO:0007165', ('56', '73'))	('PI3K', 'molecular_function', 'GO:0016303', ('157', '161'))	('RCC', 'Disease', 'MESH:C538614', (233, 236))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))	('AKT signaling', 'biological_process', 'GO:0043491', ('52', '65'))	('AKT', 'Gene', (52, 55))	('rat', 'Species', '10116', (204, 207))	('AKT', 'Gene', (162, 165))	('participate', 'Reg', (78, 89))	('RCC', 'Disease', (126, 129))	('suppress', 'NegReg', (180, 188))	('rat', 'Species', '10116', (114, 117))	('inhibiting', 'Var', (146, 156))	('FABP5-induced', 'Gene', (93, 106))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (124, 129))	('AKT', 'Gene', '207', (52, 55))
171581	30968158	6, silencing of FABP5 did not affect the migration and invasion abilities of ccRCC cells at all time points.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('silencing', 'Var', (3, 12))	('migration', 'CPA', (41, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('invasion abilities', 'CPA', (55, 73))	('rat', 'Species', '10116', (44, 47))	('FABP5', 'Gene', (16, 21))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
171584	30968158	The tumor volumes in the FABP5-RNAi group of mice were significantly smaller than those in the NC-RNAi groups (P<0.01; Fig.	('tumor', 'Disease', (4, 9))	('RNAi', 'biological_process', 'GO:0016246', ('98', '102'))	('mice', 'Species', '10090', (45, 49))	('FABP5-RNAi', 'Var', (25, 35))	('smaller', 'NegReg', (69, 76))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('RNAi', 'biological_process', 'GO:0016246', ('31', '35'))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
171586	30968158	Furthermore, the protein expression were normalized to beta-actin, the FABP5 and p-AKT were decreased in the FABP5-RNAi group (all P<0.001 vs. NC-RNAi group apart from p-AKT (Thr308), P<0.01; Fig.	('AKT', 'Gene', '207', (83, 86))	('FABP5-RNAi', 'Var', (109, 119))	('protein expression', 'MPA', (17, 35))	('AKT', 'Gene', '207', (170, 173))	('AKT', 'Gene', (83, 86))	('RNAi', 'biological_process', 'GO:0016246', ('115', '119'))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('AKT', 'Gene', (170, 173))	('RNAi', 'biological_process', 'GO:0016246', ('146', '150'))	('beta-actin', 'Gene', '728378', (55, 65))	('decreased', 'NegReg', (92, 101))	('beta-actin', 'Gene', (55, 65))	('Thr308', 'Chemical', '-', (175, 181))
171589	30968158	8C and D), and the expression of p-AKT in the LV-FABP5 group were significantly higher than that in the LV-NC group when normalized to beta-actin (P<0.01; Fig.	('beta-actin', 'Gene', (135, 145))	('expression', 'MPA', (19, 29))	('AKT', 'Gene', (35, 38))	('LV-FABP5', 'Var', (46, 54))	('AKT', 'Gene', '207', (35, 38))	('higher', 'PosReg', (80, 86))	('beta-actin', 'Gene', '728378', (135, 145))
171601	30968158	Consequently, silencing of FABP5 led to a significant decrease in cell proliferation.	('silencing', 'Var', (14, 23))	('decrease', 'NegReg', (54, 62))	('cell proliferation', 'CPA', (66, 84))	('FABP5', 'Gene', (27, 32))	('rat', 'Species', '10116', (78, 81))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))
171603	30968158	FABP5 is also expressed at higher levels in breast cancer tissues; the FABP5/PPARdelta axis induces breast cancer cell proliferation, migration and invasion by activating EGFR, and suppression of FABP5 may present a strategy to overcome retinoic acid (RA)-resistant breast cancer.	('EGFR', 'Gene', (171, 175))	('cell proliferation', 'biological_process', 'GO:0008283', ('114', '132'))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('migration', 'CPA', (134, 143))	('RA', 'Chemical', 'MESH:D014212', (252, 254))	('activating', 'PosReg', (160, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('PPARdelta', 'Gene', (77, 86))	('EGFR', 'Gene', '1956', (171, 175))	('rat', 'Species', '10116', (126, 129))	('PPARdelta', 'Gene', '5467', (77, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (266, 279))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('FABP5', 'Gene', (196, 201))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('retinoic acid', 'Chemical', 'MESH:D014212', (237, 250))	('breast cancer', 'Disease', (100, 113))	('induces', 'PosReg', (92, 99))	('breast cancer', 'Disease', 'MESH:D001943', (266, 279))	('breast cancer', 'Disease', (266, 279))	('EGFR', 'molecular_function', 'GO:0005006', ('171', '175'))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast cancer', 'Disease', (44, 57))	('rat', 'Species', '10116', (137, 140))	('rat', 'Species', '10116', (218, 221))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('suppression', 'Var', (181, 192))	('invasion', 'CPA', (148, 156))
171608	30968158	Univariate Cox regression analysis further revealed that high FABP5 expression was an unfavorable prognostic parameter.	('expression', 'MPA', (68, 78))	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('high', 'Var', (57, 61))	('FABP5', 'Gene', (62, 67))
171612	30968158	Progress in uncovering PI3K/AKT alterations and their roles in tumorigenesis has enabled the development of novel targeted molecules for anticancer treatment.	('tumor', 'Disease', (63, 68))	('AKT', 'Gene', (28, 31))	('rat', 'Species', '10116', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('PI3K', 'molecular_function', 'GO:0016303', ('23', '27'))	('alterations', 'Var', (32, 43))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('AKT', 'Gene', '207', (28, 31))	('cancer', 'Disease', (141, 147))
171617	30968158	Silencing of FABP5 significantly inhibited ccRCC cell proliferation, while overexpressing FABP5 promoted cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('105', '123'))	('FABP5', 'Gene', (13, 18))	('rat', 'Species', '10116', (117, 120))	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('cell proliferation', 'biological_process', 'GO:0008283', ('49', '67'))	('rat', 'Species', '10116', (61, 64))	('promoted', 'PosReg', (96, 104))	('cell proliferation', 'CPA', (105, 123))	('Silencing', 'Var', (0, 9))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('inhibited', 'NegReg', (33, 42))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
171618	30968158	The results also revealed that silencing of FABP5 significantly decreased the p-AKT expression levels, while overexpression of FABP5 upregulated p-AKT levels.	('silencing', 'Var', (31, 40))	('AKT', 'Gene', '207', (80, 83))	('upregulated', 'PosReg', (133, 144))	('decreased', 'NegReg', (64, 73))	('FABP5', 'Gene', (127, 132))	('AKT', 'Gene', (80, 83))	('AKT', 'Gene', '207', (147, 150))	('FABP5', 'Gene', (44, 49))	('AKT', 'Gene', (147, 150))
171620	30968158	To test this hypothesis, the AKT inhibitor, LY294002, was used to inactivate the PI3K/AKT signaling pathway.	('PI3K', 'molecular_function', 'GO:0016303', ('81', '85'))	('AKT signaling', 'biological_process', 'GO:0043491', ('86', '99'))	('AKT', 'Gene', (86, 89))	('LY294002', 'Chemical', 'MESH:C085911', (44, 52))	('AKT', 'Gene', '207', (29, 32))	('signaling pathway', 'biological_process', 'GO:0007165', ('90', '107'))	('LY294002', 'Var', (44, 52))	('AKT', 'Gene', (29, 32))	('inactivate', 'NegReg', (66, 76))	('AKT', 'Gene', '207', (86, 89))
171621	30968158	The results demonstrated that LY294002 treatment attenuated the pro-proliferative effects of FABP5 in Caki-1 and 786O cells, suggesting that the PI3K/AKT signaling pathway, at least in part, may be involved in FABP5-induced cell proliferation.	('attenuated', 'NegReg', (49, 59))	('rat', 'Species', '10116', (236, 239))	('rat', 'Species', '10116', (75, 78))	('LY294002', 'Chemical', 'MESH:C085911', (30, 38))	('AKT', 'Gene', '207', (150, 153))	('pro-proliferative effects', 'MPA', (64, 89))	('rat', 'Species', '10116', (19, 22))	('PI3K', 'molecular_function', 'GO:0016303', ('145', '149'))	('AKT', 'Gene', (150, 153))	('AKT signaling', 'biological_process', 'GO:0043491', ('150', '163'))	('signaling pathway', 'biological_process', 'GO:0007165', ('154', '171'))	('cell proliferation', 'biological_process', 'GO:0008283', ('224', '242'))	('LY294002', 'Var', (30, 38))
171622	30968158	It was previously reported that FABP5 silencing inhibited the invasion and migration of gastric cancer cells and breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('gastric cancer', 'Disease', (88, 102))	('breast cancer', 'Disease', (113, 126))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('rat', 'Species', '10116', (78, 81))	('inhibited', 'NegReg', (48, 57))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('FABP5', 'Gene', (32, 37))	('silencing', 'Var', (38, 47))
171623	30968158	By contrast, the present study observed that FABP5 silencing did not affect the migration or invasion of ccRCC cells, indicating that the intrinsic properties of ccRCC cells may differ from gastric and breast cancer cells, and FABP5 might exert different functions in different cancer cells, which required further investigation.	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('cancer', 'Disease', (278, 284))	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('ccRCC', 'Phenotype', 'HP:0006770', (105, 110))	('RCC', 'Disease', (107, 110))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('FABP5', 'Gene', (45, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('silencing', 'Var', (51, 60))	('rat', 'Species', '10116', (83, 86))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('breast cancer', 'Disease', (202, 215))	('cancer', 'Disease', (209, 215))	('ccRCC', 'Phenotype', 'HP:0006770', (162, 167))	('RCC', 'Disease', (164, 167))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
171627	30968158	High FABP5 expression was significantly correlated with tumor stage and predicted poor patient survival.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('tumor', 'Disease', (56, 61))	('poor', 'NegReg', (82, 86))	('patient', 'Species', '9606', (87, 94))	('correlated', 'Reg', (40, 50))	('FABP5', 'Gene', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
171673	28249616	Thyroglobulin and TSH levels were 4081.0 pmol/L and 232.2 mIU/L respectively.	('4081.0', 'Var', (34, 40))	('Thyroglobulin', 'Gene', (0, 13))	('TSH levels', 'MPA', (18, 28))	('Thyroglobulin', 'Gene', '7038', (0, 13))
171720	31348313	Previous researches have demonstrated that the dysregulated expression and mutation of SLC16A12 in gene level are associated with a syndrome combining juvenile cataract with microcornea and renal glucosuria.	('expression', 'MPA', (60, 70))	('microcornea', 'Phenotype', 'HP:0000482', (174, 185))	('SLC16A12', 'Gene', (87, 95))	('juvenile cataract', 'Disease', 'OMIM:212500', (151, 168))	('microcornea and renal glucosuria', 'Disease', 'MESH:D006030', (174, 206))	('cataract', 'Phenotype', 'HP:0000518', (160, 168))	('syndrome', 'Disease', (132, 140))	('mutation', 'Var', (75, 83))	('glucosuria', 'Phenotype', 'HP:0003076', (196, 206))	('juvenile cataract', 'Phenotype', 'HP:0001118', (151, 168))	('associated', 'Reg', (114, 124))	('juvenile cataract', 'Disease', (151, 168))	('dysregulated', 'Var', (47, 59))	('SLC16A12', 'Gene', '387700', (87, 95))
171758	31348313	5A), whereas in patients with stage III and IV, the OS of patients with low SLC16A12 mRNA expression was notably worse than high expression group (P < .001, Fig.	('low', 'Var', (72, 75))	('mRNA expression', 'MPA', (85, 100))	('patients', 'Species', '9606', (16, 24))	('SLC16A12', 'Gene', (76, 84))	('N', 'Chemical', 'MESH:D009584', (87, 88))	('patients', 'Species', '9606', (58, 66))	('SLC16A12', 'Gene', '387700', (76, 84))	('worse', 'NegReg', (113, 118))
171771	31348313	So, the phenomenon that hypermethylation of SLC16A12 suggests that SLC16A12 might be a critical tumor suppressor.	('hypermethylation', 'Var', (24, 40))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('96', '112'))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('SLC16A12', 'Gene', '387700', (44, 52))	('SLC16A12', 'Gene', '387700', (67, 75))	('tumor', 'Disease', (96, 101))	('SLC16A12', 'Gene', (44, 52))	('SLC16A12', 'Gene', (67, 75))	('tumor suppressor', 'biological_process', 'GO:0051726', ('96', '112'))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
171841	31162237	Patients with VHL mutation demonstrated less NT than their counterparts (6% versus 9%; p-value= 0.0115).	('less', 'NegReg', (40, 44))	('Patients', 'Species', '9606', (0, 8))	('NT', 'Chemical', '-', (45, 47))	('mutation', 'Var', (18, 26))	('VHL', 'Gene', (14, 17))	('VHL', 'Gene', '7428', (14, 17))
171876	31162237	At the same time, our study has several strengths including the multi-institutional cohort with reliably and consistently assessed pathological specimens, exploration of non-enhancing component association with genetic mutation, and robust clinical outcomes including follow up to assess cancer recurrence and cancer specific survival.	('cancer', 'Disease', (310, 316))	('genetic mutation', 'Var', (211, 227))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('cancer', 'Disease', (288, 294))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('cancer', 'Disease', 'MESH:D009369', (310, 316))
171879	30459215	In the past decades, different studies have shown the role of epigenetic modifications and modifiers in renal disease, especially during its progression towards chronic and end-stage renal disease.	('end-stage renal disease', 'Disease', 'MESH:D007676', (173, 196))	('renal disease', 'Disease', 'MESH:D007674', (183, 196))	('end-stage renal disease', 'Phenotype', 'HP:0003774', (173, 196))	('renal disease', 'Phenotype', 'HP:0000112', (183, 196))	('epigenetic modifications', 'Var', (62, 86))	('chronic and end-stage renal disease', 'Phenotype', 'HP:0003774', (161, 196))	('renal disease', 'Disease', (104, 117))	('renal disease', 'Disease', 'MESH:D007674', (104, 117))	('end-stage renal disease', 'Disease', (173, 196))	('renal disease', 'Phenotype', 'HP:0000112', (104, 117))
171880	30459215	Thus, the identification of genetic variation associated with chronic kidney disease has resulted in better clinical management of patients.	('patients', 'Species', '9606', (131, 139))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (62, 84))	('genetic variation', 'Var', (28, 45))	('chronic kidney disease', 'Disease', 'MESH:D051436', (62, 84))	('kidney disease', 'Phenotype', 'HP:0000112', (70, 84))	('associated', 'Reg', (46, 56))	('chronic kidney disease', 'Disease', (62, 84))
171884	30459215	Nowadays, CRISPR/Cas9-based approaches also allow epigenetic modifications, and thus represent an unprecedented tool for the screening of genetic variants, epigenetic modifications or even changes in chromatin structure that are altered in renal disease.	('allow', 'Reg', (44, 49))	('chromatin', 'cellular_component', 'GO:0000785', ('200', '209'))	('epigenetic modifications', 'MPA', (50, 74))	('renal disease', 'Disease', (240, 253))	('Cas', 'cellular_component', 'GO:0005650', ('17', '20'))	('renal disease', 'Disease', 'MESH:D007674', (240, 253))	('renal disease', 'Phenotype', 'HP:0000112', (240, 253))	('variants', 'Var', (146, 154))	('epigenetic modifications', 'Var', (156, 180))
171885	30459215	Advanced glycation end products (AGEs): proteins or lipids that become glycated (sometimes also referred to as non-enzymatically glycosylated) by the covalent bonding of glucose or fructose as a result of exposure to sugars.	('lipids', 'Chemical', 'MESH:D008055', (52, 58))	('covalent', 'Var', (150, 158))	('glucose or fructose', 'Disease', (170, 189))	('sugars', 'Chemical', 'MESH:D000073893', (217, 223))	('proteins', 'Protein', (40, 48))	('glucose or fructose', 'Disease', 'MESH:D018149', (170, 189))
171892	30459215	It is characterized by frequent inactivation of VHL, which can be found in 80-90% of the cases.	('VHL', 'Gene', '7428', (48, 51))	('VHL', 'Gene', (48, 51))	('inactivation', 'Var', (32, 44))
171896	30459215	CpG silencing in promoter regions is achieved through dense CpG methylation or Polycomb recruitment.	('silencing', 'NegReg', (4, 13))	('CpG methylation', 'Var', (60, 75))	('Polycomb', 'Gene', '40358', (79, 87))	('methylation', 'biological_process', 'GO:0032259', ('64', '75'))	('Polycomb', 'Gene', (79, 87))
171898	30459215	The DSB can then be repaired through different pathways, leading to the creation small insertion and deletion mutations, or to the introduction of precise nucleotide alterations when exogenous homologous DNA templates are provided.	('introduction', 'Reg', (131, 143))	('DNA', 'cellular_component', 'GO:0005574', ('204', '207'))	('rat', 'Species', '10116', (170, 173))	('deletion mutations', 'Var', (101, 119))	('insertion', 'Var', (87, 96))
171909	30459215	GWAS typically focus on associations between single-nucleotide polymorphisms (SNPs) and traits like major human diseases, but can equally be applied to any other organism or phenotype.	('single-nucleotide polymorphisms', 'Var', (45, 76))	('human', 'Species', '9606', (106, 111))	('associations', 'Interaction', (24, 36))
171916	30459215	Histone crotonylation: post-translational modification of lysine residues in a histone by the introduction of crotonyl groups.	('post-translational modification', 'biological_process', 'GO:0043687', ('23', '54'))	('introduction', 'Reg', (94, 106))	('post-translational modification', 'MPA', (23, 54))	('crotonylation', 'Disease', (8, 21))	('crotonyl', 'Chemical', '-', (110, 118))	('crotonyl', 'Chemical', '-', (8, 16))	('crotonyl', 'Var', (110, 118))	('crotonylation', 'Disease', 'None', (8, 21))	('lysine', 'Chemical', 'MESH:D008239', (58, 64))
171943	30459215	Gene expression activation is often associated with demethylation/hypomethylation of promoter and enhancer sequences, which can be achieved through inhibition of DNMT1 or through oxidation of 5-mC into 5-hydroxymethylcytosine (5-hmC) by the ten-eleven-translocation (TET) proteins (TET1-3).	('TET1', 'Gene', (282, 286))	('TET', 'Chemical', '-', (267, 270))	('5-mC', 'Chemical', 'MESH:D044503', (192, 196))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (202, 225))	('activation', 'PosReg', (16, 26))	('demethylation/hypomethylation', 'Var', (52, 81))	('inhibition', 'NegReg', (148, 158))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('TET1', 'Gene', '80312', (282, 286))	('demethylation', 'biological_process', 'GO:0070988', ('52', '65'))	('TET', 'Chemical', '-', (282, 285))	('Gene expression', 'MPA', (0, 15))	('5-hmC', 'Chemical', 'MESH:C011865', (227, 232))	('DNMT1', 'Gene', (162, 167))
171945	30459215	So far, a growing number of studies have correlated aberrant DNA methylation with human disease.	('DNA methylation', 'biological_process', 'GO:0006306', ('61', '76'))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('aberrant', 'Var', (52, 60))	('DNA', 'Protein', (61, 64))	('human disease', 'Disease', (82, 95))	('human', 'Species', '9606', (82, 87))
171950	30459215	Histone lysine acetylation (HKac) marks - such as H3K9ac, H3K14ac, and H4Kac - are associated with active promoters.	('Histone lysine', 'Chemical', '-', (0, 14))	('lysine acetylation', 'Chemical', '-', (8, 26))	('H4Kac', 'Var', (71, 76))	('HKac', 'Chemical', '-', (28, 32))	('H3K14ac', 'Var', (58, 65))	('H3K9ac', 'Var', (50, 56))
171954	30459215	However, the dual role of SUMO in gene regulation is demonstrated by the observations that sumoylation of certain transcription factors, including Ikaros (also known as Ikzf1), enhances transcriptional activity.	('transcription', 'biological_process', 'GO:0006351', ('114', '127'))	('enhances', 'PosReg', (177, 185))	('Ikzf1', 'Gene', '10320', (169, 174))	('rat', 'Species', '10116', (60, 63))	('sumoylation', 'Var', (91, 102))	('Ikaros', 'Gene', (147, 153))	('transcriptional activity', 'MPA', (186, 210))	('Ikzf1', 'Gene', (169, 174))	('sumoylation', 'biological_process', 'GO:0016925', ('91', '102'))	('regulation', 'biological_process', 'GO:0065007', ('39', '49'))
171955	30459215	On the other hand, inducing hypersumoylation by targeting SUMO and/or Ubc9 to specific gene promoters primarily induces gene repression.	('gene repression', 'MPA', (120, 135))	('SUMO', 'Gene', (58, 62))	('induces', 'Reg', (112, 119))	('Ubc9', 'Gene', (70, 74))	('hypersumoylation', 'MPA', (28, 44))	('targeting', 'Reg', (48, 57))	('Ubc9', 'Gene', '7329', (70, 74))	('inducing', 'Var', (19, 27))
171964	30459215	It has been shown that ubiquitination of H2A by BRCA1/BARD1 promote homologous recombination, and ubiquitination by RNF168 seems to promote non-homologous end joining.	('homologous recombination', 'MPA', (68, 92))	('RNF168', 'Gene', (116, 122))	('promote', 'PosReg', (132, 139))	('promote', 'PosReg', (60, 67))	('ubiquitination', 'Var', (98, 112))	('H2A', 'Gene', '8337', (41, 44))	('BARD1', 'Gene', '580', (54, 59))	('BRCA1', 'Gene', '672', (48, 53))	('RNF168', 'Gene', '165918', (116, 122))	('H2A', 'Gene', (41, 44))	('BRCA1', 'Gene', (48, 53))	('BARD1', 'Gene', (54, 59))	('ubiquitination', 'MPA', (23, 37))	('homologous recombination', 'biological_process', 'GO:0035825', ('68', '92'))	('non-homologous end joining', 'MPA', (140, 166))
171967	30459215	These three mechanisms are responsible for tissue-specific gene expression during growth and are the key regulators of important development events, including X chromosome inactivation (Box 1), genomic imprinting (Box 1) and patterning by Hox genes (Box 1).	('X chromosome inactivation', 'Var', (159, 184))	('Hox', 'Gene', '42536', (239, 242))	('X chromosome inactivation', 'biological_process', 'GO:0009048', ('159', '184'))	('gene expression', 'biological_process', 'GO:0010467', ('59', '74'))	('Hox', 'Gene', (239, 242))	('X chromosome', 'cellular_component', 'GO:0000805', ('159', '171'))
171970	30459215	Aberrant changes in the renal epigenetic signature could lead to congenital abnormalities of the kidney and urinary tract (CAKUT; Box 1), renal disease, and progression towards chronic kidney disease (CKD; Box 1) and end-stage renal disease (ESRD; Box 1).	('chronic kidney disease', 'Disease', (177, 199))	('congenital abnormalities of the kidney', 'Disease', (65, 103))	('renal disease', 'Disease', (138, 151))	('end-stage renal disease', 'Phenotype', 'HP:0003774', (217, 240))	('CKD', 'Phenotype', 'HP:0012622', (201, 204))	('abnormalities of the kidney', 'Phenotype', 'HP:0000077', (76, 103))	('end-stage renal disease', 'Disease', 'MESH:D007676', (217, 240))	('chronic kidney disease', 'Disease', 'MESH:D051436', (177, 199))	('renal disease', 'Disease', 'MESH:D007674', (227, 240))	('Aberrant changes', 'Var', (0, 16))	('ESRD', 'Disease', (242, 246))	('renal disease', 'Disease', 'MESH:D007674', (138, 151))	('renal epigenetic signature', 'MPA', (24, 50))	('ESRD', 'Phenotype', 'HP:0003774', (242, 246))	('ESRD', 'Disease', 'MESH:D007676', (242, 246))	('kidney disease', 'Phenotype', 'HP:0000112', (185, 199))	('end-stage renal disease', 'Disease', (217, 240))	('congenital abnormalities of the kidney', 'Disease', 'MESH:D007674', (65, 103))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (177, 199))	('lead to', 'Reg', (57, 64))	('renal disease', 'Phenotype', 'HP:0000112', (227, 240))	('renal disease', 'Phenotype', 'HP:0000112', (138, 151))
171973	30459215	Here, we summarize the most recent literature describing how epigenetic processes affect kidney development and disease, and discuss the interplay of these epigenetic events during renal dysfunction.	('renal dysfunction', 'Disease', (181, 198))	('renal dysfunction', 'Disease', 'MESH:D007674', (181, 198))	('kidney development', 'CPA', (89, 107))	('rat', 'Species', '10116', (39, 42))	('disease', 'CPA', (112, 119))	('epigenetic processes', 'Var', (61, 81))	('renal dysfunction', 'Phenotype', 'HP:0000083', (181, 198))	('kidney development', 'biological_process', 'GO:0001822', ('89', '107'))	('affect', 'Reg', (82, 88))
171979	30459215	Globally, methylation of histones on lysine (K) or arginine (R) residues (Box 2) is a key epigenetic mechanism regulating gene expression during development and disease.	('lysine', 'Chemical', 'MESH:D008239', (37, 43))	('gene expression', 'biological_process', 'GO:0010467', ('122', '137'))	('arginine', 'Chemical', 'MESH:D001120', (51, 59))	('methylation', 'Var', (10, 21))	('histones', 'Protein', (25, 33))	('regulating', 'Reg', (111, 121))	('methylation', 'biological_process', 'GO:0032259', ('10', '21'))
171981	30459215	In pluripotent stem cells (PSCs), the promoters of these genes are marked by H3 lysine 4 (H3K4me3; activating) and H3 lysine 27 (H3K27me3; repressive) marks (Table 1).	('H3K27me3', 'Var', (129, 137))	('lysine', 'Chemical', 'MESH:D008239', (80, 86))	('lysine', 'Chemical', 'MESH:D008239', (118, 124))	('H3K4me3', 'Var', (90, 97))
171982	30459215	In the first study, the authors performed chromatin immunoprecipitation (ChIP)-DNA sequencing (ChIP-Seq; Box 1) with antibodies against H3K4me3 and H3K27me3 in immortalized MM mouse clonal cell lines representing the uninduced (self-renewing Six2high/Wntlow - the mK3 line) and induced (Six2low/Wnthigh - the mK4 line) MM cell populations.	('H3K27me3', 'Var', (148, 156))	('H3K4me3', 'Var', (136, 143))	('mouse', 'Species', '10090', (176, 181))	('mK3', 'Gene', (264, 267))	('mK4', 'Gene', '16682', (309, 312))	('chromatin', 'cellular_component', 'GO:0000785', ('42', '51'))	('mK4', 'Gene', (309, 312))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))	('mK3', 'Gene', '102626', (264, 267))
171985	30459215	The mK4 MM cell line showed a loss of the H3K9me2 and H3K27me3 repressive histone marks and retained the H3K4me3 activating mark on the promoters of nephrogenic lineage genes, such as Pax2, Pax8, Lef1, Jag1 or Lhx1 (Table 1; Fig.	('H3K4me3', 'Var', (105, 112))	('H3K9me2', 'Protein', (42, 49))	('Lef1', 'Gene', '16842', (196, 200))	('Pax2', 'Gene', (184, 188))	('H3K27me3', 'Var', (54, 62))	('Lhx1', 'Gene', (210, 214))	('Lef1', 'Gene', (196, 200))	('mK4', 'Gene', '16682', (4, 7))	('Pax8', 'Gene', '18510', (190, 194))	('nephrogenic', 'Disease', (149, 160))	('loss', 'NegReg', (30, 34))	('mK4', 'Gene', (4, 7))	('Pax8', 'Gene', (190, 194))	('nephrogenic', 'Disease', 'MESH:D018500', (149, 160))
171993	30459215	To investigate whether these epigenetic changes also occur in early postnatal life in mice, Lui and colleagues performed ChIP promoter tiling array (Box 1), comparing 1- to 4-week-old mice, to study temporal changes in the H3K4me3 and H3K27me3 histone marks at promoter regions throughout the kidney and lung genome.	('mice', 'Species', '10090', (184, 188))	('H3K27me3', 'Var', (235, 243))	('H3K4me3', 'Protein', (223, 230))	('mice', 'Species', '10090', (86, 90))
171994	30459215	Remarkably, alterations in H3K27me3 levels in podocytes alter the Notch pathway (Box 1).	('Notch', 'Gene', '4851', (66, 71))	('alterations', 'Var', (12, 23))	('rat', 'Species', '10116', (16, 19))	('H3K27me3', 'Protein', (27, 35))	('Notch', 'Gene', (66, 71))	('alter', 'Reg', (56, 61))
171995	30459215	This is due to the enrichment of H3K27me3 at the promoter region of the Notch ligand jagged 1 in these cells.	('Notch', 'Gene', '4851', (72, 77))	('H3K27me3', 'Var', (33, 41))	('jagged 1', 'Gene', (85, 93))	('Notch ligand', 'molecular_function', 'GO:0005112', ('72', '84'))	('Notch', 'Gene', (72, 77))	('jagged 1', 'Gene', '182', (85, 93))
171996	30459215	Conversely, the de-repression of Jag1, which encodes jagged 1, facilitated podocyte dedifferentiation, increasing the susceptibility to focal segmental glomerulosclerosis (FSGS; Box 1).	('podocyte dedifferentiation', 'CPA', (75, 101))	('focal segmental glomerulosclerosis', 'Phenotype', 'HP:0000097', (136, 170))	('de-repression', 'Var', (16, 29))	('dedifferentiation', 'biological_process', 'GO:0043696', ('84', '101'))	('focal segmental glomerulosclerosis', 'Gene', '81', (136, 170))	('FSGS', 'Gene', '81', (172, 176))	('Jag1', 'Gene', (33, 37))	('jagged 1', 'Gene', '182', (53, 61))	('increasing', 'PosReg', (103, 113))	('FSGS', 'Phenotype', 'HP:0000097', (172, 176))	('FSGS', 'Gene', (172, 176))	('glomerulosclerosis', 'Phenotype', 'HP:0000096', (152, 170))	('focal segmental glomerulosclerosis', 'Gene', (136, 170))	('facilitated', 'PosReg', (63, 74))	('jagged 1', 'Gene', (53, 61))
172000	30459215	Indeed, the same group previously demonstrated that inhibition of the H3K27 trimethylating enzyme EZH2 causes podocyte injury in diabetic rats, suggesting that the H3K27me3 mark acts as a gatekeeper of podocyte function during development and disease.	('rat', 'Species', '10116', (138, 141))	('injury', 'Disease', (119, 125))	('EZH2', 'Gene', (98, 102))	('diabetic', 'Disease', (129, 137))	('injury', 'Disease', 'MESH:D058186', (119, 125))	('EZH2', 'Gene', '312299', (98, 102))	('rats', 'Species', '10116', (138, 142))	('inhibition', 'Var', (52, 62))	('podocyte', 'Disease', (110, 118))	('rat', 'Species', '10116', (41, 44))	('gatekeeper', 'Species', '111938', (188, 198))	('diabetic', 'Disease', 'MESH:D003920', (129, 137))
172005	30459215	Importantly, mutations in WT1 lead to Wilms' tumor disease, the most common pediatric kidney cancer, which is characterized by diffuse Wilms' tumor precursor lesions exhibiting large active chromatin domains resembling those found in human ESCs (hESCs), together with a disturbed MET process.	('lead to', 'Reg', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	("Wilms' tumor", 'Disease', 'MESH:D009396', (38, 50))	('chromatin', 'cellular_component', 'GO:0000785', ('190', '199'))	('WT1', 'Gene', (26, 29))	("Wilms' tumor disease", 'Disease', (38, 58))	('WT1', 'Gene', '7490', (26, 29))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (135, 147))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (38, 50))	('mutations', 'Var', (13, 22))	('pediatric kidney cancer', 'Disease', (76, 99))	("Wilms' tumor disease", 'Disease', 'MESH:D009396', (38, 58))	('human', 'Species', '9606', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('kidney cancer', 'Phenotype', 'HP:0009726', (86, 99))	('pediatric kidney cancer', 'Disease', 'MESH:D007680', (76, 99))	("Wilms' tumor", 'Disease', (135, 147))	("Wilms' tumor", 'Disease', 'MESH:D009396', (135, 147))
172006	30459215	Around 10% of sporadic Wilms' tumor specimens have inactivating mutations in WT1, and these same tumors often also contain mutations in beta-catenin (CTNNB1).	('beta-catenin', 'Gene', '1499', (136, 148))	('WT1', 'Gene', (77, 80))	("Wilms' tumor", 'Disease', 'MESH:D009396', (23, 35))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('CTNNB1', 'Gene', (150, 156))	("Wilms' tumor", 'Disease', (23, 35))	('WT1', 'Gene', '7490', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('inactivating mutations', 'Var', (51, 73))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (23, 35))	('CTNNB1', 'Gene', '1499', (150, 156))	('tumors', 'Disease', (97, 103))	('contain', 'Reg', (115, 122))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('beta-catenin', 'Gene', (136, 148))	('mutations', 'Var', (123, 132))
172007	30459215	Indeed, mutant WT1 clones lack WNT/beta-catenin signaling activity and fail to undergo renal differentiation.	('beta-catenin', 'Gene', (35, 47))	('beta-catenin', 'Gene', '1499', (35, 47))	('renal differentiation', 'CPA', (87, 108))	('mutant', 'Var', (8, 14))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('WT1', 'Gene', '7490', (15, 18))	('lack', 'NegReg', (26, 30))	('WT1', 'Gene', (15, 18))
172022	30459215	Similarly, conditional deletion of Dicer1 in mature podocytes resulted in glomerular abnormalities, such as glomerulosclerosis and fibrosis, and podocyte-specific deletion of Drosha (Box 1) resulted in collapsing glomerulopathy comparable to the phenotype of Dicer1 knockouts.	('deletion', 'Var', (163, 171))	('deletion', 'Var', (23, 31))	('glomerulopathy', 'Phenotype', 'HP:0100820', (213, 227))	('glomerulosclerosis', 'Disease', 'MESH:D005921', (108, 126))	('Drosha', 'Gene', (175, 181))	('Dicer1', 'Gene', (35, 41))	('glomerulopathy', 'Disease', (213, 227))	('glomerular abnormalities', 'Disease', 'MESH:D007674', (74, 98))	('glomerulopathy', 'Disease', 'MESH:D007674', (213, 227))	('glomerulosclerosis', 'Disease', (108, 126))	('collapsing', 'Disease', (202, 212))	('fibrosis', 'Disease', (131, 139))	('resulted in', 'Reg', (62, 73))	('fibrosis', 'Disease', 'MESH:D005355', (131, 139))	('glomerulosclerosis', 'Phenotype', 'HP:0000096', (108, 126))	('Drosha', 'Gene', '29102', (175, 181))	('glomerular abnormalities', 'Disease', (74, 98))
172024	30459215	The authors demonstrated that Six2-Cre-mediated removal of Dicer1 resulted in elevated apoptosis and premature termination of nephrogenesis, and thus confirmed that Dicer1 is important for maintaining the viability of the Six2 self-renewing progenitor pool and, consequently, for the development of a normal nephron complement.	('nephrogenesis', 'Disease', (126, 139))	('removal', 'Var', (48, 55))	('Dicer1', 'Gene', (59, 65))	('elevated', 'PosReg', (78, 86))	('rat', 'Species', '10116', (19, 22))	('nephrogenesis', 'biological_process', 'GO:0001822', ('126', '139'))	('nephron complement', 'Disease', 'MESH:D007683', (308, 326))	('apoptosis', 'CPA', (87, 96))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))	('nephrogenesis', 'biological_process', 'GO:0072006', ('126', '139'))	('nephron complement', 'Disease', (308, 326))	('nephrogenesis', 'Disease', 'None', (126, 139))
172025	30459215	Conversely, HoxB7-Cre-mediated removal of Dicer1 caused the development of renal cysts in this model Independent studies have also shown the effects of Dicer1 deletion in Foxd1+ progenitor cells (Box 1), which give rise to renal stroma.	('HoxB7', 'Gene', '3217', (12, 17))	('rise to renal stroma', 'Disease', 'MESH:D007674', (215, 235))	('rise to renal stroma', 'Disease', (215, 235))	('renal cysts', 'Phenotype', 'HP:0000107', (75, 86))	('Dicer1', 'Gene', (152, 158))	('renal cysts', 'Disease', 'MESH:D007674', (75, 86))	('deletion', 'Var', (159, 167))	('HoxB7', 'Gene', (12, 17))	('renal cysts', 'Disease', (75, 86))	('Foxd1', 'Gene', '2297', (171, 176))	('Foxd1', 'Gene', (171, 176))
172026	30459215	Dicer1 inactivation in the Foxd1+ cortical stroma results in multiple defects of nephrogenesis, including expansion of nephron progenitors, a decrease in renin-expressing cells, fewer smooth muscle afferent arterioles, and progressive mesangial cell loss in mature glomeruli.	('Foxd1', 'Gene', (27, 32))	('Dicer1', 'Gene', (0, 6))	('inactivation', 'Var', (7, 19))	('mesangial cell', 'CPA', (235, 249))	('Foxd1', 'Gene', '2297', (27, 32))	('nephron progenitors', 'CPA', (119, 138))	('decrease in renin', 'Phenotype', 'HP:0003351', (142, 159))	('loss', 'NegReg', (250, 254))	('renin-expressing cells', 'MPA', (154, 176))	('decrease', 'NegReg', (142, 150))	('mesangial cell loss', 'Phenotype', 'HP:0012574', (235, 254))	('expansion', 'PosReg', (106, 115))	('multiple defects of nephrogenesis', 'Disease', (61, 94))	('nephrogenesis', 'biological_process', 'GO:0072006', ('81', '94'))	('multiple defects of nephrogenesis', 'Disease', 'MESH:D000015', (61, 94))	('nephrogenesis', 'biological_process', 'GO:0001822', ('81', '94'))	('smooth muscle afferent arterioles', 'CPA', (184, 217))	('fewer', 'NegReg', (178, 183))
172030	30459215	Although the nephron progenitor population was preserved in these mice, miR-17/92 deletion impaired proliferation and reduced the number of developing nephrons.	('impaired', 'NegReg', (91, 99))	('proliferation', 'CPA', (100, 113))	('reduced', 'NegReg', (118, 125))	('mice', 'Species', '10090', (66, 70))	('deletion', 'Var', (82, 90))	('nephrons', 'Disease', 'MESH:D007683', (151, 159))	('miR-17/92', 'Gene', (72, 81))	('nephrons', 'Disease', (151, 159))	('rat', 'Species', '10116', (107, 110))
172031	30459215	Interestingly, mutant mice developed signs of renal disease.	('renal disease', 'Phenotype', 'HP:0000112', (46, 59))	('mice', 'Species', '10090', (22, 26))	('developed', 'Reg', (27, 36))	('mutant', 'Var', (15, 21))	('renal disease', 'Disease', (46, 59))	('renal disease', 'Disease', 'MESH:D007674', (46, 59))
172038	30459215	After this first study, Chambers and colleagues demonstrated the association between the loci reported by Kottgen together with markers of kidney function.	('rat', 'Species', '10116', (55, 58))	('loci', 'Var', (89, 93))	('association', 'Interaction', (65, 76))
172042	30459215	However, many aspects are still unclear, and understanding the epigenetic modifications associated with CKD may pave the way towards innovative approaches targeting renal dysfunction.	('renal dysfunction', 'Disease', 'MESH:D007674', (165, 182))	('CKD', 'Disease', (104, 107))	('epigenetic modifications', 'Var', (63, 87))	('CKD', 'Phenotype', 'HP:0012622', (104, 107))	('renal dysfunction', 'Phenotype', 'HP:0000083', (165, 182))	('renal dysfunction', 'Disease', (165, 182))
172053	30459215	These studies provide a molecular basis for the epigenetic intervention targeted to the KL promoter for the treatment of kidney diseases.	('kidney diseases', 'Phenotype', 'HP:0000112', (121, 136))	('kidney disease', 'Phenotype', 'HP:0000112', (121, 135))	('kidney diseases', 'Disease', (121, 136))	('epigenetic intervention', 'Var', (48, 71))	('kidney diseases', 'Disease', 'MESH:D007674', (121, 136))
172064	30459215	Animal model studies indicate that calorie, protein or oxygen restriction are associated with lower nephron number, hypertension and microalbuminuria.	('microalbuminuria', 'Phenotype', 'HP:0012594', (133, 149))	('hypertension', 'Disease', 'MESH:D006973', (116, 128))	('albuminuria', 'Phenotype', 'HP:0012592', (138, 149))	('lower nephron number', 'Phenotype', 'HP:0005563', (94, 114))	('oxygen restriction', 'Var', (55, 73))	('albuminuria', 'Disease', 'MESH:D000419', (138, 149))	('calorie', 'Var', (35, 42))	('hypertension', 'Disease', (116, 128))	('hypertension', 'Phenotype', 'HP:0000822', (116, 128))	('lower nephron number', 'Disease', 'MESH:D007683', (94, 114))	('oxygen', 'Chemical', 'MESH:D010100', (55, 61))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('protein', 'Protein', (44, 51))	('albuminuria', 'Disease', (138, 149))	('lower nephron number', 'Disease', (94, 114))
172065	30459215	These findings have led some authors to speculate that the epigenetic differences established during development might mimic the changes observed in diabetic patients with kidney damage.	('kidney damage', 'Disease', 'MESH:D007674', (172, 185))	('diabetic', 'Disease', (149, 157))	('epigenetic differences', 'Var', (59, 81))	('diabetic', 'Disease', 'MESH:D003920', (149, 157))	('kidney damage', 'Phenotype', 'HP:0000112', (172, 185))	('kidney damage', 'Disease', (172, 185))	('patients', 'Species', '9606', (158, 166))
172067	30459215	Deb and colleagues showed that exposure of murine glomerular mesangial cells to high glucose-induced cAMP response element binding protein (CREB)-binding protein (CBP)-mediated H3K9/14 hyperacetylation in ~5000 gene promoters, including those of the major pro-fibrotic factors (Table 1).	('cAMP response element binding', 'molecular_function', 'GO:0035497', ('101', '130'))	('CBP', 'Gene', '12914', (163, 166))	('murine', 'Species', '10090', (43, 49))	('CREB', 'Gene', (140, 144))	('CBP', 'Gene', (163, 166))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('H3K9/14', 'Var', (177, 184))	('high glucose', 'Phenotype', 'HP:0003074', (80, 92))	('CREB', 'Gene', '1385', (140, 144))	('glucose', 'Chemical', 'MESH:D005947', (85, 92))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('CBP', 'molecular_function', 'GO:0008140', ('163', '166'))	('CREB)-binding', 'molecular_function', 'GO:0008140', ('140', '153'))	('hyperacetylation', 'Var', (185, 201))	('cAMP', 'Chemical', '-', (101, 105))
172074	30459215	In this regard, Eissa and colleagues screened miRNA expression in urinary exosomes from a homogenous cohort of type 2 diabetes patients classified according to the presence of normo-, micro- and macroalbuminuria.	('albuminuria', 'Phenotype', 'HP:0012592', (200, 211))	('miRNA expression', 'MPA', (46, 62))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (111, 126))	('diabetes', 'Disease', (118, 126))	('macroalbuminuria', 'Disease', (195, 211))	('macroalbuminuria', 'Disease', 'None', (195, 211))	('diabetes', 'Disease', 'MESH:D003920', (118, 126))	('patients', 'Species', '9606', (127, 135))	('micro-', 'Var', (184, 190))
172084	30459215	Bechtel and colleagues found that DNA methylation in kidney fibroblasts determines fibrogenesis, specifically via hypermethylation of the RASAL1 promoter.	('RASAL1', 'Gene', '8437', (138, 144))	('hypermethylation', 'Var', (114, 130))	('methylation', 'Var', (38, 49))	('RASAL1', 'Gene', (138, 144))	('fibrogenesis', 'CPA', (83, 95))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('DNA methylation', 'biological_process', 'GO:0006306', ('34', '49'))	('determines', 'Reg', (72, 82))
172090	30459215	The authors demonstrated that HIF-1 and lysine-specific demethylase 3A (KDM3A; Box 2) are recruited to the glucose transporter 3 (GLUT3; also known as SLC2A3) gene locus to cooperatively demethylate H3K9me2 and construct long-range looping interactions between the promoter and the distal enhancer, maximizing the hypoxic induction of GLUT3 and, consequently, increasing glucose uptake.	('lysine-specific demethylase 3A', 'Gene', '55818', (40, 70))	('GLUT3', 'Gene', '6515', (335, 340))	('KDM3A', 'Gene', (72, 77))	('glucose uptake', 'MPA', (371, 385))	('glucose', 'Chemical', 'MESH:D005947', (371, 378))	('hypoxic induction', 'MPA', (314, 331))	('GLUT3', 'Gene', (130, 135))	('SLC2A3', 'Gene', (151, 157))	('KDM3A', 'Gene', '55818', (72, 77))	('glucose', 'Chemical', 'MESH:D005947', (107, 114))	('H3K9me2', 'Protein', (199, 206))	('GLUT3', 'Gene', (335, 340))	('increasing', 'PosReg', (360, 370))	('maximizing', 'PosReg', (299, 309))	('lysine-specific demethylase 3A', 'Gene', (40, 70))	('glucose transporter 3', 'Gene', '6515', (107, 128))	('HIF-1', 'Gene', '3091', (30, 35))	('SLC2A3', 'Gene', '6515', (151, 157))	('rat', 'Species', '10116', (178, 181))	('demethylate', 'Var', (187, 198))	('HIF-1', 'Gene', (30, 35))	('glucose uptake', 'biological_process', 'GO:0046323', ('371', '385'))	('GLUT3', 'Gene', '6515', (130, 135))	('rat', 'Species', '10116', (19, 22))	('glucose transporter 3', 'Gene', (107, 128))
172092	30459215	Another mechanism of hypoxia-induced epigenetic changes is through impairing the expression and activity of Dicer1.	('activity', 'MPA', (96, 104))	('epigenetic changes', 'Var', (37, 55))	('Dicer1', 'Protein', (108, 114))	('hypoxia', 'Disease', 'MESH:D000860', (21, 28))	('impairing', 'NegReg', (67, 76))	('hypoxia', 'Disease', (21, 28))	('expression', 'MPA', (81, 91))
172099	30459215	Alterations in VHL are the most prevalent molecular features of clear cell renal cell carcinoma (ccRCC; Box 1), a major subtype of kidney cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('VHL', 'Gene', (15, 18))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (75, 95))	('Alterations', 'Var', (0, 11))	('VHL', 'Gene', '7428', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('prevalent', 'Reg', (32, 41))	('subtype of kidney cancer', 'Disease', 'MESH:D007680', (120, 144))	('kidney cancer', 'Phenotype', 'HP:0009726', (131, 144))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (64, 95))	('subtype of kidney cancer', 'Disease', (120, 144))	('clear cell renal cell carcinoma', 'Disease', (64, 95))	('rat', 'Species', '10116', (4, 7))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (64, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))
172101	30459215	Specifically, PBRM1 recognizes H3K14Ac, BAP1 deubiquitinates K119ub on H2A, SETD2 methylates H3K36Me3, JARID1C demethylates H3K4Me3 and UTX demethylates H3K27Me3.	('UTX', 'Gene', '7403', (136, 139))	('SETD2', 'Gene', (76, 81))	('K119ub', 'Var', (61, 67))	('JARID1C', 'Gene', '8242', (103, 110))	('JARID1C', 'Gene', (103, 110))	('PBRM1', 'Gene', (14, 19))	('H3K4Me3', 'Protein', (124, 131))	('H3K27Me3', 'Var', (153, 161))	('BAP1', 'Gene', '8314', (40, 44))	('H3K36Me3', 'Protein', (93, 101))	('H2A', 'Gene', '8337', (71, 74))	('PBRM1', 'Gene', '55193', (14, 19))	('demethylates', 'Reg', (111, 123))	('H3K14Ac', 'Var', (31, 38))	('UTX', 'Gene', (136, 139))	('BAP1', 'Gene', (40, 44))	('H2A', 'Gene', (71, 74))	('SETD2', 'Gene', '29072', (76, 81))
172102	30459215	Epigenetic alterations and transcriptional deregulation are thus central to ccRCC.	('Epigenetic alterations', 'Var', (0, 22))	('rat', 'Species', '10116', (15, 18))	('transcriptional', 'CPA', (27, 42))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('ccRCC', 'Disease', (76, 81))
172108	30459215	Although the molecular mechanisms underlying AKI remain unclear, epigenetic modifications driven by aging, diabetes and hypoxia have been suggested to contribute to the progression of AKI towards CKD.	('CKD', 'Disease', (196, 199))	('diabetes', 'Disease', (107, 115))	('epigenetic modifications', 'Var', (65, 89))	('hypoxia', 'Disease', (120, 127))	('hypoxia', 'Disease', 'MESH:D000860', (120, 127))	('diabetes', 'Disease', 'MESH:D003920', (107, 115))	('CKD', 'Phenotype', 'HP:0012622', (196, 199))	('contribute', 'Reg', (151, 161))	('AKI', 'Disease', (184, 187))	('aging', 'biological_process', 'GO:0007568', ('100', '105'))
172111	30459215	The authors demonstrated that progressive fibrosis and kidney failure were significantly inhibited in mice that received 5'-azacytidine from day 3 to day 28 after folic acid challenge.	('mice', 'Species', '10090', (102, 106))	('kidney failure', 'Phenotype', 'HP:0000083', (55, 69))	('inhibited', 'NegReg', (89, 98))	('rat', 'Species', '10116', (19, 22))	('fibrosis', 'Disease', (42, 50))	('fibrosis', 'Disease', 'MESH:D005355', (42, 50))	("5'-azacytidine", 'Var', (121, 135))	('kidney failure', 'Disease', (55, 69))	('kidney failure', 'Disease', 'MESH:D051437', (55, 69))	('folic acid', 'Chemical', 'MESH:D005492', (163, 173))	("5'-azacytidine", 'Chemical', 'MESH:D001374', (121, 135))
172113	30459215	On the contrary, Guo and colleagues examined the effects of the DNA methylation inhibitor 5-aza-2'-deoxycytidine and showed that it increased cisplatin-induced apoptosis in a rat kidney proximal tubular cell line.	("5-aza-2'-deoxycytidine", 'Var', (90, 112))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (90, 112))	('cisplatin-induced', 'MPA', (142, 159))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('increased', 'PosReg', (132, 141))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('rat', 'Species', '10116', (175, 178))	('DNA methylation', 'biological_process', 'GO:0006306', ('64', '79'))
172114	30459215	Furthermore, using a kidney proximal tubule (PT)-specific DNMT1 (PT-DNMT1) knockout mouse model, these authors showed a more severe AKI response to cisplatin treatment in the knockout compared with wild-type mice, suggesting that DNA methylation is protective in cisplatin-induced AKI.	('AKI', 'MPA', (132, 135))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('DNA methylation', 'biological_process', 'GO:0006306', ('230', '245'))	('PT-DNMT1', 'Gene', (65, 73))	('knockout', 'Var', (175, 183))	('PT-DNMT1', 'Gene', '13433', (65, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (263, 272))	('mouse', 'Species', '10090', (84, 89))	('mice', 'Species', '10090', (208, 212))	('DNA', 'cellular_component', 'GO:0005574', ('230', '233'))	('response to cisplatin', 'biological_process', 'GO:0072718', ('136', '157'))
172118	30459215	The levels of histone crotonylation were increased in kidney tissue from animals treated with folic-acid, which induced AKI.	('levels', 'MPA', (4, 10))	('crotonylation', 'Disease', 'None', (22, 35))	('increased', 'PosReg', (41, 50))	('crotonylation', 'Disease', (22, 35))	('folic-acid', 'Chemical', 'MESH:D005492', (94, 104))	('folic-acid', 'Var', (94, 104))
172121	30459215	Taken together, these studies show that epigenetic (de)regulation has important, although not yet completely understood, implications in kidney disease.	('kidney disease', 'Disease', 'MESH:D007674', (137, 151))	('kidney disease', 'Phenotype', 'HP:0000112', (137, 151))	('epigenetic', 'Var', (40, 50))	('regulation', 'biological_process', 'GO:0065007', ('55', '65'))	('kidney disease', 'Disease', (137, 151))
172134	30459215	Later, the same group used kidney organoids from genetically engineered hESCs for the introduction of kidney-related mutations to ascertain kidney disease-related phenotypes in an isogenic background.	('kidney disease', 'Disease', 'MESH:D007674', (140, 154))	('mutations', 'Var', (117, 126))	('kidney disease', 'Phenotype', 'HP:0000112', (140, 154))	('kidney disease', 'Disease', (140, 154))
172138	30459215	Using reprogramming and CRISPR/Cas9 editing, the authors generated patient-derived and gene-corrected isogenic control iPSCs from skin fibroblasts of the individual affected by compound-heterozygous IFT140 variants, and differentiated both iPSC lines into kidney organoids.	('IFT140', 'Gene', '9742', (199, 205))	('variants', 'Var', (206, 214))	('IFT', 'biological_process', 'GO:0042073', ('199', '202'))	('IFT140', 'Gene', (199, 205))	('rat', 'Species', '10116', (61, 64))	('Cas', 'cellular_component', 'GO:0005650', ('31', '34'))	('patient', 'Species', '9606', (67, 74))
172139	30459215	Within the tubular epithelium of unedited IFT140 mutant organoids, a classical ciliary morphology indicative of retrograde IFT dysfunction was identified.	('IFT140', 'Gene', '9742', (42, 48))	('mutant', 'Var', (49, 55))	('IFT140', 'Gene', (42, 48))	('IFT', 'biological_process', 'GO:0042073', ('123', '126'))	('retrograde IFT dysfunction', 'Disease', (112, 138))	('retrograde IFT dysfunction', 'Disease', 'MESH:D000648', (112, 138))	('IFT', 'biological_process', 'GO:0042073', ('42', '45'))
172141	30459215	Additionally, transcriptional profiling and differential gene expression analysis, comparing mutant and gene-corrected organoids, revealed dysfunctional pathogenetic pathways not previously described in IFT140-deficient disease models but characteristic of other NPHP genes, suggesting that this model could clarify the common pathogenetic mechanisms for this heterogenetic rare disease.	('IFT140-deficient disease', 'Disease', 'MESH:D030342', (203, 227))	('IFT140-deficient disease', 'Disease', (203, 227))	('mutant', 'Var', (93, 99))	('dysfunctional', 'Disease', (139, 152))	('dysfunctional', 'Disease', 'MESH:D006331', (139, 152))	('IFT', 'biological_process', 'GO:0042073', ('203', '206'))	('gene expression', 'biological_process', 'GO:0010467', ('57', '72'))
172149	30459215	In this manner, upon transient transfection of single-guide RNAs (sgRNAs) to iCas9 hPSCs and doxycycline treatment to induce expression, Cas9 is directed for site-specific DNA cleavage, efficiently generating mutant hPSCs lines.	('doxycycline', 'Chemical', 'MESH:D004318', (93, 104))	('Cas', 'cellular_component', 'GO:0005650', ('137', '140'))	('DNA', 'cellular_component', 'GO:0005574', ('172', '175'))	('hPSCs', 'Gene', (216, 221))	('rat', 'Species', '10116', (202, 205))	('mutant', 'Var', (209, 215))
172154	30459215	Additionally, Liu and colleagues have repurposed the CRISPR/Cas9 system to edit DNA methylation by fusing dCas9 with TET1 and DNMT3A (Box 2; Fig.	('dCas9', 'Gene', (106, 111))	('TET1', 'Gene', (117, 121))	('DNMT3A', 'Gene', (126, 132))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('DNMT3A', 'Gene', '1788', (126, 132))	('Cas', 'cellular_component', 'GO:0005650', ('60', '63'))	('DNA methylation', 'biological_process', 'GO:0006306', ('80', '95'))	('TET1', 'Gene', '80312', (117, 121))	('fusing', 'Var', (99, 105))
172160	30459215	In the past decades, several studies have demonstrated the impact of epigenetic modifications on renal disease and its progression towards CKD and ESRD, improving our understanding of these conditions.	('improving', 'PosReg', (153, 162))	('ESRD', 'Disease', (147, 151))	('ESRD', 'Phenotype', 'HP:0003774', (147, 151))	('CKD', 'Disease', (139, 142))	('ESRD', 'Disease', 'MESH:D007676', (147, 151))	('epigenetic modifications', 'Var', (69, 93))	('renal disease', 'Disease', (97, 110))	('renal disease', 'Disease', 'MESH:D007674', (97, 110))	('rat', 'Species', '10116', (49, 52))	('renal disease', 'Phenotype', 'HP:0000112', (97, 110))	('CKD', 'Phenotype', 'HP:0012622', (139, 142))
172164	30459215	The organoid technology represents a powerful tool that can pave the way towards the development of high-throughput systems for the screening of genetic variants, epigenetic modifications or changes in chromatin structure that drive renal disease.	('changes', 'Reg', (191, 198))	('chromatin', 'cellular_component', 'GO:0000785', ('202', '211'))	('renal disease', 'Disease', (233, 246))	('renal disease', 'Disease', 'MESH:D007674', (233, 246))	('epigenetic modifications', 'Var', (163, 187))	('renal disease', 'Phenotype', 'HP:0000112', (233, 246))	('variants', 'Var', (153, 161))
172178	32550862	According to the International Society of Urologic Pathologists/World Health Organization (ISUP/WHO) 2016 classification, the term "clear cell" is reserved for the tumor diagnostic entity characterized by morphological, immunophenotypical, and molecularly distinct characteristics such as clear cell aspects, most CAIX, CD10, cathepsin-k, and PAX-8 positive for immunoexpression and affected by VHL gene mutation.	('PAX-8', 'Gene', (343, 348))	('affected', 'Reg', (383, 391))	('tumor', 'Disease', (164, 169))	('CD10', 'Gene', (320, 324))	('CAIX', 'Gene', (314, 318))	('cathepsin-k', 'Gene', '1513', (326, 337))	('CD10', 'Gene', '4311', (320, 324))	('cathepsin-k', 'Gene', (326, 337))	('PAX-8', 'Gene', '7849', (343, 348))	('CAIX', 'Gene', '768', (314, 318))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('VHL', 'Gene', (395, 398))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('VHL', 'Gene', '7428', (395, 398))	('mutation', 'Var', (404, 412))
172180	32550862	Instead, for nccRCC, the initial oncogenic event for nccRCC is not VHL-driven, and VHL mutations are less common among the classical non-clear histologies of chromophobe, collecting duct, medullary and unclassified RCC, with these classical non-clear histologies accounting for approximately 20% of all RCC cases.	('RCC', 'Disease', 'MESH:C538614', (303, 306))	('RCC', 'Disease', (303, 306))	('RCC', 'Disease', (56, 59))	('VHL', 'Gene', '7428', (83, 86))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('VHL', 'Gene', '7428', (67, 70))	('RCC', 'Disease', (16, 19))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (215, 218))	('RCC', 'Disease', (215, 218))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (14, 19))	('mutations', 'Var', (87, 96))	('VHL', 'Gene', (83, 86))	('VHL', 'Gene', (67, 70))
172181	32550862	Along with these classical non-clear histologies, the discovery of "apparent ccRCC" with no VHL mutation and activation of other molecular pathway led to their recognition as non-clear cell entities, which, irrespective of the presence of cells with clear cytoplasm, maintain VHL function and are driven by Xp11 and TFEB rearrangements (translocation MiTF family RCC) or mutations in other molecules such as in succinate dehydrogenase-deficient RCC, acquired cystic kidney disease-associated RCC, clear cell-papillary RCC, and tubulocystic RCC.	('VHL', 'Gene', (276, 279))	('RCC', 'Disease', 'MESH:C538614', (540, 543))	('RCC', 'Disease', 'MESH:C538614', (492, 495))	('cystic kidney', 'Phenotype', 'HP:0000107', (459, 472))	('RCC', 'Disease', 'MESH:C538614', (363, 366))	('TFEB', 'Gene', (316, 320))	('cystic kidney disease', 'Disease', 'MESH:D052177', (459, 480))	('kidney disease', 'Phenotype', 'HP:0000112', (466, 480))	('VHL', 'Gene', (92, 95))	('dehydrogenase-deficient RCC', 'Disease', 'MESH:C538614', (421, 448))	('mutation', 'Var', (96, 104))	('VHL', 'Gene', '7428', (276, 279))	('RCC', 'Disease', (518, 521))	('tubulocystic RCC', 'Disease', (527, 543))	('mutations', 'Var', (371, 380))	('TFEB', 'Gene', '7942', (316, 320))	('cystic kidney disease', 'Disease', (459, 480))	('RCC', 'Disease', (445, 448))	('papillary RCC', 'Disease', 'MESH:C538614', (508, 521))	('papillary RCC', 'Disease', (508, 521))	('RCC', 'Disease', 'MESH:C538614', (518, 521))	('VHL', 'Gene', '7428', (92, 95))	('tubulocystic RCC', 'Disease', 'MESH:C538614', (527, 543))	('rearrangements', 'Var', (321, 335))	('dehydrogenase-deficient RCC', 'Disease', (421, 448))	('RCC', 'Disease', (79, 82))	('RCC', 'Disease', (492, 495))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('RCC', 'Disease', (540, 543))	('RCC', 'Disease', 'MESH:C538614', (445, 448))	('RCC', 'Disease', (363, 366))	('RCC', 'Disease', 'MESH:C538614', (79, 82))
172225	32550862	In comparative studies, patients receiving sunitinib were more likely to develop fatigue, hand-foot syndrome, or thrombocytopenia compared with pazopanib, while patients receiving pazopanib were more likely to develop elevated liver enzyme levels.	('hand-foot syndrome', 'Disease', 'MESH:D060831', (90, 108))	('elevated liver enzyme', 'Phenotype', 'HP:0002910', (218, 239))	('develop', 'PosReg', (73, 80))	('pazopanib', 'Chemical', 'MESH:C516667', (144, 153))	('liver enzyme levels', 'MPA', (227, 246))	('fatigue', 'Disease', 'MESH:D005221', (81, 88))	('patients', 'Species', '9606', (24, 32))	('thrombocytopenia', 'Disease', 'MESH:D013921', (113, 129))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (113, 129))	('patients', 'Species', '9606', (161, 169))	('fatigue', 'Phenotype', 'HP:0012378', (81, 88))	('sunitinib', 'Chemical', 'MESH:D000077210', (43, 52))	('pazopanib', 'Chemical', 'MESH:C516667', (180, 189))	('fatigue', 'Disease', (81, 88))	('sunitinib', 'Var', (43, 52))	('hand-foot syndrome', 'Disease', (90, 108))	('thrombocytopenia', 'Disease', (113, 129))
172226	32550862	Health-related quality of life was higher in the pazopanib than the sunitinib group.	('Health-related quality of life', 'CPA', (0, 30))	('pazopanib', 'Chemical', 'MESH:C516667', (49, 58))	('sunitinib', 'Chemical', 'MESH:D000077210', (68, 77))	('pazopanib', 'Var', (49, 58))	('higher', 'PosReg', (35, 41))
172301	30410595	Western blotting was performed using the following antibodies: anti-TOP2A, 1:1000 (Proteintech); anti-CDK1, 1:1000 (Abcam); anti-CDK2, 1:1000 (Abcam ); anti-CCNA1/2, 1:2000 (Abcam); anti-p-TP53, 1:1000 (Abcam); anti-TP53, 1:1000 (Abcam).	('CCNA1', 'Gene', '8900', (157, 162))	('TOP2A', 'Gene', (68, 73))	('CDK2', 'Gene', '1017', (129, 133))	('CDK', 'molecular_function', 'GO:0004693', ('102', '105'))	('CDK1', 'Gene', '983', (102, 106))	('anti-p-TP53', 'Var', (182, 193))	('CDK1', 'Gene', (102, 106))	('anti-TP53', 'Var', (211, 220))	('CDK', 'molecular_function', 'GO:0004693', ('129', '132'))	('CCNA1', 'Gene', (157, 162))	('CDK2', 'Gene', (129, 133))	('TOP2A', 'Gene', '7153', (68, 73))
172313	30410595	To explore the biological role of TOP2A in ccRCC, we established a model of TOP2A deficiency in 786-O cell line.	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('TOP2A', 'Gene', (34, 39))	('TOP2A', 'Gene', '7153', (76, 81))	('deficiency', 'Var', (82, 92))	('ccRCC', 'Disease', (43, 48))	('TOP2A', 'Gene', (76, 81))	('TOP2A', 'Gene', '7153', (34, 39))
172315	30410595	This uncovered that silencing TOP2A inhibited the proliferative capacity of ccRCC cell.	('inhibited', 'NegReg', (36, 45))	('proliferative capacity of', 'CPA', (50, 75))	('TOP2A', 'Gene', (30, 35))	('TOP2A', 'Gene', '7153', (30, 35))	('silencing', 'Var', (20, 29))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('ccRCC', 'Disease', (76, 81))
172316	30410595	Flow cytometry analysis also showed that knockdown of TOP2A triggered cell cycle arrest at G2 phase (Figure 6D).	('G2 phase', 'biological_process', 'GO:0051319', ('91', '99'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (70, 87))	('cell cycle arrest at G2 phase', 'CPA', (70, 99))	('cell cycle arrest at G2 phase', 'Phenotype', 'HP:0003214', (70, 99))	('TOP2A', 'Gene', '7153', (54, 59))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('70', '87'))	('knockdown', 'Var', (41, 50))	('TOP2A', 'Gene', (54, 59))
172317	30410595	Indeed, cell cycle related proteins such as Cyclin A1/2 and CDK1/2 were significantly decreased in the ccRCC cell in TOP2A knockdown group (Figure 6E).	('cell', 'MPA', (8, 12))	('TOP2A', 'Gene', '7153', (117, 122))	('TOP2A', 'Gene', (117, 122))	('Cyclin A1/2', 'Gene', '8900;890', (44, 55))	('cell cycle', 'biological_process', 'GO:0007049', ('8', '18'))	('Cyclin', 'molecular_function', 'GO:0016538', ('44', '50'))	('decreased', 'NegReg', (86, 95))	('CDK1/2', 'Gene', (60, 66))	('ccRCC', 'Disease', (103, 108))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('knockdown', 'Var', (123, 132))	('CDK', 'molecular_function', 'GO:0004693', ('60', '63'))	('CDK1/2', 'Gene', '51755;983;1017', (60, 66))	('Cyclin A1/2', 'Gene', (44, 55))
172318	30410595	Moreover, TOP2A deficiency strongly induced phosphorylated p53 in ccRCC cells (Figure 6F).	('p53', 'Gene', (59, 62))	('induced', 'Reg', (36, 43))	('TOP2A', 'Gene', '7153', (10, 15))	('p53', 'Gene', '7157', (59, 62))	('TOP2A', 'Gene', (10, 15))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('phosphorylated', 'MPA', (44, 58))	('deficiency', 'Var', (16, 26))
172347	29180874	B7-H3, a new member of the B7 family of costimulatory molecules, has a critical function in the T-cell-mediated antitumor immune response, and abnormal tumor B7-H3 expression is frequently associated with a poor prognosis.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('immune response', 'biological_process', 'GO:0006955', ('122', '137'))	('expression', 'MPA', (164, 174))	('B7-H3', 'Gene', (158, 163))	('associated', 'Reg', (189, 199))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('abnormal tumor', 'Phenotype', 'HP:0002664', (143, 157))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('abnormal', 'Var', (143, 151))
172355	29180874	Furthermore, B7-H3 possibly promotes ccRCC angiogenesis through the Tie-2 pathway.	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('B7-H3', 'Var', (13, 18))	('angiogenesis', 'biological_process', 'GO:0001525', ('43', '55'))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('promotes', 'PosReg', (28, 36))
172365	29180874	Studies have shown that Tie-2 acts independently of VEGF in the regulation of tumor microvascularization, and inhibition of the Tie-2 pathway alone is reported to inhibit tumor growth.	('VEGF', 'Gene', (52, 56))	('inhibit', 'NegReg', (163, 170))	('regulation', 'biological_process', 'GO:0065007', ('64', '74'))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('inhibition', 'Var', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('VEGF', 'Gene', '7422', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))
172366	29180874	TEMs purified from human tumor specimens promote tumor angiogenesis in transplanted tumors, whereas a lack of TEMs reduces angiogenesis and delays tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('promote', 'PosReg', (41, 48))	('reduces', 'NegReg', (115, 122))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', (147, 152))	('lack', 'Var', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('delays tumor', 'Disease', (140, 152))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumors', 'Disease', (84, 90))	('tumor', 'Disease', (25, 30))	('angiogenesis', 'biological_process', 'GO:0001525', ('55', '67'))	('tumor', 'Disease', (49, 54))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('angiogenesis', 'biological_process', 'GO:0001525', ('123', '135'))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('delays tumor', 'Disease', 'MESH:D009369', (140, 152))	('angiogenesis', 'CPA', (123, 135))	('tumor', 'Disease', (84, 89))	('human', 'Species', '9606', (19, 24))
172368	29180874	B7-H3 has the dual function of stimulating and inhibiting T-cell activation, with an important function in the T-cell-mediated antitumor immune response.	('B7-H3', 'Var', (0, 5))	('inhibiting', 'NegReg', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('stimulating', 'PosReg', (31, 42))	('immune response', 'biological_process', 'GO:0006955', ('137', '152'))	('tumor', 'Disease', (131, 136))	('T-cell activation', 'biological_process', 'GO:0042110', ('58', '75'))	('T-cell activation', 'CPA', (58, 75))
172419	29180874	In a breast cancer mouse model, Tie-2 gene knockout in TEMs inhibits tumor angiogenesis, indicating that the Ang/Tie-2 axis regulates the angiogenic activity of these cells.	('breast cancer', 'Phenotype', 'HP:0003002', (5, 18))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('knockout', 'Var', (43, 51))	('breast cancer', 'Disease', 'MESH:D001943', (5, 18))	('Tie-2', 'Gene', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('inhibits', 'NegReg', (60, 68))	('mouse', 'Species', '10090', (19, 24))	('angiogenesis', 'biological_process', 'GO:0001525', ('75', '87'))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('breast cancer', 'Disease', (5, 18))
172426	29180874	In this study, we evaluated B7-H3 expression in ccRCC and normal paracancerous tissues, and the results showed that B7-H3 is mainly expressed in the vascular endothelial tissue of ccRCC.	('B7-H3', 'Var', (116, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('RCC', 'Disease', (50, 53))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('RCC', 'Disease', (182, 185))	('cancer', 'Disease', (69, 75))
172432	29180874	Overall, B7-H3 is superior to Tie-2 as an effective molecular marker for estimating the degree of malignancy and predicting invasion and metastasis capacities.	('B7-H3', 'Var', (9, 14))	('malignancy', 'Disease', 'MESH:D009369', (98, 108))	('malignancy', 'Disease', (98, 108))
172434	29180874	High MVD was also reported to predict worse prognosis in various types of cancer.	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('High MVD', 'Var', (0, 8))
172440	29180874	In addition, M2 macrophages promote tumor progression through angiogenesis and inhibition of antitumor immunity, and B7-H3 signaling significantly increases IL-10 secretion and matrix metalloproteinase expression, promoting the transformation of macrophages from the M1 to the M2 phenotype.	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('expression', 'MPA', (202, 212))	('IL-10', 'molecular_function', 'GO:0005141', ('157', '162'))	('tumor', 'Disease', (36, 41))	('increases', 'PosReg', (147, 156))	('IL-10', 'Gene', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', (97, 102))	('IL-10 secretion', 'biological_process', 'GO:0072608', ('157', '172'))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('secretion', 'MPA', (163, 172))	('angiogenesis', 'CPA', (62, 74))	('B7-H3', 'Var', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('promoting', 'PosReg', (214, 223))	('promote', 'PosReg', (28, 35))	('matrix', 'Protein', (177, 183))	('angiogenesis', 'biological_process', 'GO:0001525', ('62', '74'))
172441	29180874	In hepatocellular carcinoma, B7-H3 can act as a chemokine to prompt macrophages to migrate from the peripheral blood to the tumor tissue and induce M1 to M2 cell phenotype transformation, resulting in tumor formation and development.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('formation', 'biological_process', 'GO:0009058', ('207', '216'))	('B7-H3', 'Var', (29, 34))	('induce', 'Reg', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (201, 206))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('development', 'CPA', (221, 232))
172445	29180874	Thus, we hypothesized that B7-H3 and Tie-2 have synergistic effects in ccRCC angiogenesis and that B7-H3 mainly regulates tumor angiogenesis by promoting the M1 to M2 transformation in macrophages and the TEM-mediated pathway.	('M1 to M2 transformation in macrophages', 'CPA', (158, 196))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('RCC', 'Disease', (73, 76))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))	('regulates', 'Reg', (112, 121))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('TEM-mediated pathway', 'Pathway', (205, 225))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('TEM', 'cellular_component', 'GO:0097197', ('205', '208'))	('angiogenesis', 'biological_process', 'GO:0001525', ('128', '140'))	('angiogenesis', 'biological_process', 'GO:0001525', ('77', '89'))	('tumor', 'Disease', (122, 127))	('promoting', 'PosReg', (144, 153))	('B7-H3', 'Var', (99, 104))
172454	29180874	Because of its dual roles in immune regulation and anti-angiogenesis, targeting B7-H3 may be an effective treatment for renal cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('B7-H3', 'Protein', (80, 85))	('angiogenesis', 'biological_process', 'GO:0001525', ('56', '68'))	('renal cancer', 'Disease', 'MESH:D007680', (120, 132))	('renal cancer', 'Phenotype', 'HP:0009726', (120, 132))	('targeting', 'Var', (70, 79))	('regulation', 'biological_process', 'GO:0065007', ('36', '46'))	('renal cancer', 'Disease', (120, 132))
172457	29180874	In summary, this study for the first time reveals the role of B7-H3 in ccRCC angiogenesis and its correlation with the angiogenic factor Tie-2 and MVD, and the findings suggest that B7-H3 may promote tumor angiogenesis through the Tie-2 pathway.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('RCC', 'Disease', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('Tie-2 pathway', 'Pathway', (231, 244))	('B7-H3', 'Var', (182, 187))	('promote', 'PosReg', (192, 199))	('angiogenesis', 'biological_process', 'GO:0001525', ('206', '218'))	('tumor', 'Disease', (200, 205))	('angiogenesis', 'biological_process', 'GO:0001525', ('77', '89'))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
172459	27682873	Haploinsufficiency in tumor predisposition syndromes: altered genomic transcription in morphologically normal cells heterozygous for VHL or TSC mutation Tumor suppressor genes and their effector pathways have been identified for many dominantly heritable cancers, enabling efforts to intervene early in the course of disease.	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('Tumor suppressor', 'biological_process', 'GO:0051726', ('153', '169'))	('Haploinsufficiency in tumor', 'Disease', 'MESH:D058495', (0, 27))	('genomic', 'MPA', (62, 69))	('VHL', 'Gene', (133, 136))	('Tumor suppressor', 'molecular_function', 'GO:0008181', ('153', '169'))	('TSC', 'Gene', (140, 143))	('Haploinsufficiency in tumor', 'Disease', (0, 27))	('TSC', 'Gene', '7248', (140, 143))	('mutation', 'Var', (144, 152))	('VHL', 'Gene', '7428', (133, 136))	('cancers', 'Phenotype', 'HP:0002664', (255, 262))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('Tumor', 'Phenotype', 'HP:0002664', (153, 158))	('altered', 'Reg', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (255, 262))	('transcription', 'biological_process', 'GO:0006351', ('70', '83'))	('cancers', 'Disease', (255, 262))
172460	27682873	Our approach on the subject of early intervention was to investigate gene expression patterns of morphologically normal one-hit cells before they become hemizygous or homozygous for the inherited mutant gene which is usually required for tumor formation.	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('gene expression', 'biological_process', 'GO:0010467', ('69', '84'))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Disease', (238, 243))	('formation', 'biological_process', 'GO:0009058', ('244', '253'))	('mutant', 'Var', (196, 202))
172471	27682873	We chose to study two forms of hereditary kidney cancer, i.e., von Hippel-Lindau disease (VHL) and Tuberous Sclerosis Complex (TSC), due to germline mutations of VHL or TSC1/2, respectively.	('von Hippel-Lindau disease', 'Disease', (63, 88))	('VHL', 'Gene', (162, 165))	('TSC1/2', 'Gene', '7248;7249', (169, 175))	('kidney cancer', 'Phenotype', 'HP:0009726', (42, 55))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (63, 88))	('TSC1/2', 'Gene', (169, 175))	('TSC', 'Gene', (127, 130))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('TSC', 'Gene', '7248', (127, 130))	('germline mutations', 'Var', (140, 158))	('hereditary kidney cancer', 'Disease', 'MESH:D007680', (31, 55))	('Tuberous Sclerosis Complex', 'Disease', (99, 125))	('Tuberous Sclerosis Complex', 'Disease', 'MESH:D014402', (99, 125))	('hereditary kidney cancer', 'Disease', (31, 55))	('TSC', 'Gene', '7248', (169, 172))	('Tuberous Sclerosis Complex', 'cellular_component', 'GO:0033596', ('99', '125'))	('TSC', 'Gene', (169, 172))
172475	27682873	Therefore, our specific strategy has been to study histologically normal "one-hit" renal epithelial cells, i.e., heterozygous VHLmut/wt or TSC1/2mut/wt cells (referred to herein as VHL-single hit and TSC1/2-single hit cells) from affected kidneys of mutation carriers.	('TSC1/2', 'Gene', (200, 206))	('mutation', 'Var', (250, 258))	('TSC1/2', 'Gene', (139, 145))	('TSC1/2', 'Gene', '7248;7249', (200, 206))	('TSC1/2', 'Gene', '7248;7249', (139, 145))
172476	27682873	Here, we report aberrant patterns of gene expression in non-transformed VHL- or TSC1/2-"one-hit" renal epithelial cells from patients with germline VHL or TSC1/2 mutations.	('VHL', 'Gene', (148, 151))	('TSC1/2', 'Gene', (155, 161))	('TSC1/2', 'Gene', (80, 86))	('mutations', 'Var', (162, 171))	('VHL-', 'Gene', (72, 76))	('gene expression', 'biological_process', 'GO:0010467', ('37', '52'))	('TSC1/2', 'Gene', '7248;7249', (155, 161))	('TSC1/2', 'Gene', '7248;7249', (80, 86))	('patients', 'Species', '9606', (125, 133))
172480	27682873	The high rate of somatic VHL mutations in sporadic kidney cancers, particularly clear cell renal cell carcinomas (ccRCC) suggests that inactivation of the VHL protein plays a critical role in the initiation of RCC in the general population.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (91, 111))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('RCC', 'Disease', (210, 213))	('RCC', 'Phenotype', 'HP:0005584', (210, 213))	('RCC', 'Disease', (116, 119))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (80, 112))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('kidney cancer', 'Phenotype', 'HP:0009726', (51, 64))	('sporadic kidney cancers', 'Disease', (42, 65))	('kidney cancers', 'Phenotype', 'HP:0009726', (51, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', 'MESH:C538614', (210, 213))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (91, 112))	('mutations', 'Var', (29, 38))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (80, 111))	('VHL', 'Gene', (25, 28))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (80, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('clear cell renal cell carcinomas', 'Disease', (80, 112))	('sporadic kidney cancers', 'Disease', 'MESH:D007680', (42, 65))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))
172482	27682873	TSC is caused by inactivation of either TSC1 or TSC2, leading to activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1).	('target of rapamycin complex', 'cellular_component', 'GO:0038201', ('105', '132'))	('inactivation', 'Var', (17, 29))	('TSC', 'Gene', (40, 43))	('mTORC1', 'Gene', '382056', (136, 142))	('TSC', 'Gene', '7248', (40, 43))	('TSC1', 'Gene', (40, 44))	('TSC2', 'Gene', '7249', (48, 52))	('TSC2', 'Gene', (48, 52))	('TSC', 'Gene', (0, 3))	('mTORC1', 'Gene', (136, 142))	('TSC', 'Gene', (48, 51))	('TSC', 'Gene', '7248', (0, 3))	('TSC', 'Gene', '7248', (48, 51))	('mTORC1', 'cellular_component', 'GO:0031931', ('136', '142'))	('activation', 'PosReg', (65, 75))	('mammalian', 'Species', '9606', (83, 92))	('TSC1', 'Gene', '7248', (40, 44))
172484	27682873	Consistent with earlier findings, transcriptomic profiles of morphologically normal, non-transformed (MNNT) kidney epithelial cells carrying germline mutations of VHL or TSC1/2 are different from each other and from those of individuals not harboring a germline mutation (wild-type, WT) of these genes.	('transcriptomic', 'MPA', (34, 48))	('different', 'Reg', (181, 190))	('TSC1/2', 'Gene', '7248;7249', (170, 176))	('TSC1/2', 'Gene', (170, 176))	('mutations', 'Var', (150, 159))	('VHL', 'Gene', (163, 166))
172486	27682873	Our primary goal was to compare transcriptomes of MNNT renal epithelial cells harboring a mutation in one allele of VHL or TSC1/2, to monitor the earliest gene expression changes associated with one-hit inactivation of a given TSG.	('TSG', 'Gene', (227, 230))	('gene expression', 'biological_process', 'GO:0010467', ('155', '170'))	('TSG', 'Gene', '57045', (227, 230))	('VHL', 'Gene', (116, 119))	('TSC1/2', 'Gene', '7248;7249', (123, 129))	('TSC1/2', 'Gene', (123, 129))	('mutation', 'Var', (90, 98))
172488	27682873	Four different monoallelic sequence variants were identified in four cultures: an in-frame deletion c.227_229delTCT was identified in cultures VHL-4 and VHL-5, whereas missense substitutions c.499C>T and c.473T>C were found in VHL-1 and VHL-6 cells, respectively (Supplemental Table 2; Supplemental Figure 1).	('c.499C>T', 'Mutation', 'rs5030820', (191, 199))	('c.499C>T', 'Var', (191, 199))	('c.473T>C', 'Var', (204, 212))	('VHL-6', 'CellLine', 'CVCL:A248', (237, 242))	('VHL-1', 'Gene', '7428', (227, 232))	('VHL-1', 'Gene', (227, 232))	('c.473T>C', 'Mutation', 'rs121913346', (204, 212))	('c.227_229delTCT', 'Var', (100, 115))	('c.227_229delTCT', 'Mutation', 'rs5030648', (100, 115))
172490	27682873	Additionally, a likely non-pathogenic missense substitution, c.21C>A, was identified in VHL-5.	('c.21C>A', 'Mutation', 'rs1060503561', (61, 68))	('c.21C>A', 'Var', (61, 68))	('VHL-5', 'Gene', (88, 93))
172497	27682873	Figure 1 depicts a heatmap of genes differentially expressed between one-hit VHL or TSC and WT cells.	('one-hit', 'Var', (69, 76))	('TSC', 'Gene', '7248', (84, 87))	('TSC', 'Gene', (84, 87))
172498	27682873	Box plots depicting examples of differentially-expressed genes in VHL and TSC mutant cells are shown in Supplemental Figures 2 and 3, respectively.	('TSC', 'Gene', (74, 77))	('mutant', 'Var', (78, 84))	('TSC', 'Gene', '7248', (74, 77))	('VHL', 'Gene', (66, 69))
172499	27682873	Thus, comparative analyses of VHL one-hit (VHLmut/wt) vs. WT cells, and TSC one-hit (TSC1/2mut/wt) vs. WT cells revealed notable changes in the global gene expression, indicating that heterozygous germline mutations in VHL or TSC1/2 do indeed affect the expression profiles of MNNT renal epithelial cells.	('gene expression', 'biological_process', 'GO:0010467', ('151', '166'))	('expression profiles', 'MPA', (254, 273))	('changes', 'Reg', (129, 136))	('germline mutations', 'Var', (197, 215))	('TSC', 'Gene', (85, 88))	('TSC', 'Gene', '7248', (85, 88))	('TSC', 'Gene', (226, 229))	('TSC', 'Gene', '7248', (226, 229))	('global', 'MPA', (144, 150))	('TSC1/2', 'Gene', '7248;7249', (85, 91))	('TSC1/2', 'Gene', '7248;7249', (226, 232))	('TSC1/2', 'Gene', (85, 91))	('affect', 'Reg', (243, 249))	('VHL', 'Gene', (219, 222))	('TSC', 'Gene', (72, 75))	('TSC1/2', 'Gene', (226, 232))	('TSC', 'Gene', '7248', (72, 75))
172502	27682873	Using pathway analyses and data mining to evaluate the transcriptome of VHL-single hit cells, we found gene alterations involved in signal transduction, glycolysis and TCA cycle (Figure 2; Supplemental Figure 4).	('glycolysis', 'MPA', (153, 163))	('TCA', 'Chemical', 'MESH:D014233', (168, 171))	('alterations', 'Var', (108, 119))	('involved', 'Reg', (120, 128))	('signal transduction', 'biological_process', 'GO:0007165', ('132', '151'))	('TCA cycle', 'biological_process', 'GO:0006099', ('168', '177'))	('glycolysis', 'biological_process', 'GO:0006096', ('153', '163'))
172507	27682873	When stabilized either under hypoxia or pseudo-hypoxic conditions, together with HIF1beta, HIF1alpha induces downstream target genes, e.g., VEGF, TGFA, TGFB, PDGFB and GLUT1.	('hypoxia', 'Disease', (29, 36))	('hypoxia', 'Disease', 'MESH:D000860', (29, 36))	('TGFA', 'Gene', '7039', (146, 150))	('VEGF', 'Gene', '7422', (140, 144))	('HIF1alpha', 'Var', (91, 100))	('TGFB', 'Gene', '7040', (152, 156))	('GLUT1', 'Gene', (168, 173))	('TGFA', 'Gene', (146, 150))	('HIF1beta', 'Gene', '405', (81, 89))	('induces', 'PosReg', (101, 108))	('GLUT1', 'Gene', '6513', (168, 173))	('HIF1beta', 'Gene', (81, 89))	('PDGFB', 'Gene', '5155', (158, 163))	('VEGF', 'Gene', (140, 144))	('TGFB', 'Gene', (152, 156))	('PDGFB', 'Gene', (158, 163))
172513	27682873	Notably, PDK inhibits pyruvate dehydrogenase and thereby blocks import of pyruvate into the TCA cycle (Figure 2).	('pyruvate dehydrogenase', 'MPA', (22, 44))	('PDK', 'molecular_function', 'GO:0004740', ('9', '12'))	('TCA', 'Chemical', 'MESH:D014233', (92, 95))	('TCA cycle', 'biological_process', 'GO:0006099', ('92', '101'))	('import of pyruvate into the TCA cycle', 'MPA', (64, 101))	('blocks', 'NegReg', (57, 63))	('pyruvate', 'Chemical', 'MESH:D019289', (74, 82))	('inhibits', 'NegReg', (13, 21))	('pyruvate', 'Chemical', 'MESH:D019289', (22, 30))	('PDK', 'Var', (9, 12))
172517	27682873	Overexpression of PDK1 (Figure 2) would inhibit decarboxylation of pyruvate mediated by pyruvate dehydrogenase, leading to increased lactate in the cytosol.	('increased', 'PosReg', (123, 132))	('lactate in the cytosol', 'MPA', (133, 155))	('inhibit', 'NegReg', (40, 47))	('PDK1', 'molecular_function', 'GO:0004740', ('18', '22'))	('lactate', 'Chemical', 'MESH:D019344', (133, 140))	('Overexpression', 'Var', (0, 14))	('PDK1', 'Gene', '5163', (18, 22))	('PDK1', 'Gene', (18, 22))	('pyruvate', 'Chemical', 'MESH:D019289', (88, 96))	('cytosol', 'cellular_component', 'GO:0005829', ('148', '155'))	('pyruvate', 'Chemical', 'MESH:D019289', (67, 75))
172544	27682873	These lesions are examples of haploinsufficiency for TSG mutations that may cause malignancy upon transition to the homozygous state.	('haploinsufficiency', 'Disease', 'MESH:D058495', (30, 48))	('malignancy', 'Disease', (82, 92))	('haploinsufficiency', 'Disease', (30, 48))	('mutations', 'Var', (57, 66))	('TSG', 'Gene', (53, 56))	('cause', 'Reg', (76, 81))	('malignancy', 'Disease', 'MESH:D009369', (82, 92))	('TSG', 'Gene', '57045', (53, 56))
172549	27682873	In further support of our contention of incomplete hypoxic response, while changes in expression levels of both HIF1alpha, HIF2alpha are not observed in our in vitro model, an in vivo mouse model of Vhl one-hit type 2B mutation (R167Q) shows low basal level expression in both these genes similar to cells with intact VHL, suggesting the pVHL in VHL one-hit cells does not stabilize HIF proteins.	('R167Q', 'Mutation', 'rs5030821', (229, 234))	('HIF2alpha', 'Gene', '13819', (123, 132))	('Vhl', 'Gene', '22346', (199, 202))	('R167Q', 'Var', (229, 234))	('basal level expression', 'MPA', (246, 268))	('mouse', 'Species', '10090', (184, 189))	('Vhl', 'Gene', (199, 202))	('HIF2alpha', 'Gene', (123, 132))
172550	27682873	Interestingly, mice with Vhl one-hit type 2B mutation develop renal cysts and fail to progress to renal adenocarcinoma, suggesting VHL mutation alone is not sufficient for transformation.	('renal adenocarcinoma', 'Disease', 'MESH:C538614', (98, 118))	('renal cysts', 'Disease', 'MESH:D007674', (62, 73))	('renal cysts', 'Disease', (62, 73))	('Vhl', 'Gene', '22346', (25, 28))	('renal cysts', 'Phenotype', 'HP:0000107', (62, 73))	('mice', 'Species', '10090', (15, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('mutation', 'Var', (45, 53))	('Vhl', 'Gene', (25, 28))	('develop', 'PosReg', (54, 61))	('renal adenocarcinoma', 'Disease', (98, 118))	('renal adenocarcinoma', 'Phenotype', 'HP:0005584', (98, 118))
172551	27682873	In ccRCC, stabilization of HIF1alpha upon loss of VHL leads to activation of the Warburg effect through increased glucose uptake and lactate production, including restricted entry of pyruvate into mitochondria through activation of PDK1, a HIF1alpha target.	('Warburg', 'Disease', (81, 88))	('activation', 'PosReg', (218, 228))	('mitochondria', 'cellular_component', 'GO:0005739', ('197', '209'))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('PDK1', 'Gene', '5163', (232, 236))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('lactate', 'Chemical', 'MESH:D019344', (133, 140))	('pyruvate', 'Chemical', 'MESH:D019289', (183, 191))	('glucose uptake', 'MPA', (114, 128))	('increased glucose', 'Phenotype', 'HP:0003074', (104, 121))	('VHL', 'Gene', (50, 53))	('glucose', 'Chemical', 'MESH:D005947', (114, 121))	('PDK1', 'molecular_function', 'GO:0004740', ('232', '236'))	('entry of pyruvate into mitochondria', 'MPA', (174, 209))	('activation', 'PosReg', (63, 73))	('loss', 'Var', (42, 46))	('increased', 'PosReg', (104, 113))	('PDK1', 'Gene', (232, 236))	('glucose uptake', 'biological_process', 'GO:0046323', ('114', '128'))	('lactate production', 'MPA', (133, 151))
172552	27682873	Shunting of pyruvate away from the TCA cycle reduces levels of acetyl-coA, a glucose-derived carbon source for lipid biogenesis.	('acetyl-coA', 'Chemical', 'MESH:D000105', (63, 73))	('Shunting', 'Var', (0, 8))	('reduces', 'NegReg', (45, 52))	('TCA', 'Chemical', 'MESH:D014233', (35, 38))	('TCA cycle', 'biological_process', 'GO:0006099', ('35', '44'))	('glucose', 'Chemical', 'MESH:D005947', (77, 84))	('carbon', 'Chemical', 'MESH:D002244', (93, 99))	('lipid', 'Chemical', 'MESH:D008055', (111, 116))	('pyruvate', 'Chemical', 'MESH:D019289', (12, 20))	('levels of acetyl-coA', 'MPA', (53, 73))
172553	27682873	Interestingly, in vitro studies indicate that cancer cells supplement deficiency of acetyl-coA for lipid biogenesis through reductive glutamine metabolism mediated by cytoplasmic and/or mitochondrial IDH1 and IDH2, respectively.	('IDH1', 'Gene', (200, 204))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('lipid', 'Chemical', 'MESH:D008055', (99, 104))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('134', '154'))	('cancer', 'Disease', (46, 52))	('acetyl-coA', 'Chemical', 'MESH:D000105', (84, 94))	('IDH1', 'Gene', '3417', (200, 204))	('IDH2', 'Gene', (209, 213))	('reductive glutamine metabolism', 'MPA', (124, 154))	('deficiency', 'Var', (70, 80))	('glutamine', 'Chemical', 'MESH:D005973', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('IDH2', 'Gene', '3418', (209, 213))	('lipid biogenesis', 'MPA', (99, 115))
172554	27682873	In VHL-single hit cells, we observed overexpression of PDK1, suggesting that the resulting inactivation of PDH would shunt pyruvate from mitochondria to cytosol with subsequent conversion of pyruvate to lactate.	('pyruvate', 'Chemical', 'MESH:D019289', (123, 131))	('PDH', 'molecular_function', 'GO:0004739', ('107', '110'))	('PDH', 'molecular_function', 'GO:0033718', ('107', '110'))	('PDH', 'Gene', '54704', (107, 110))	('cytosol', 'cellular_component', 'GO:0005829', ('153', '160'))	('PDK1', 'molecular_function', 'GO:0004740', ('55', '59'))	('PDH', 'molecular_function', 'GO:0004246', ('107', '110'))	('conversion', 'MPA', (177, 187))	('PDK1', 'Gene', '5163', (55, 59))	('PDK1', 'Gene', (55, 59))	('mitochondria', 'cellular_component', 'GO:0005739', ('137', '149'))	('PDH', 'Gene', (107, 110))	('pyruvate', 'Chemical', 'MESH:D019289', (191, 199))	('inactivation', 'Var', (91, 103))	('lactate', 'Chemical', 'MESH:D019344', (203, 210))	('shunt', 'Reg', (117, 122))
172557	27682873	In keeping with reduced expression of GLUT1, glucose uptake is lower in VHLmut/wt vs. WT cells (Figure 3A).	('lower', 'NegReg', (63, 68))	('VHLmut/wt', 'Var', (72, 81))	('glucose uptake', 'biological_process', 'GO:0046323', ('45', '59'))	('GLUT1', 'Gene', (38, 43))	('GLUT1', 'Gene', '6513', (38, 43))	('glucose uptake', 'MPA', (45, 59))	('glucose', 'Chemical', 'MESH:D005947', (45, 52))
172565	27682873	This is also consistent with studies showing that loss of VHL leads to activation of NFkappaB through CARD9, an agonist for NFkappaB.	('activation', 'PosReg', (71, 81))	('CARD9', 'Gene', (102, 107))	('NFkappaB', 'Gene', '4790', (85, 93))	('loss', 'Var', (50, 54))	('NFkappaB', 'Gene', (85, 93))	('VHL', 'Gene', (58, 61))	('CARD9', 'Gene', '64170', (102, 107))	('NFkappaB', 'Gene', (124, 132))	('NFkappaB', 'Gene', '4790', (124, 132))
172567	27682873	TSC1 and TSC2 are negative regulators of AKT/mTOR signaling, and inhibitors of mTOR are efficacious in TSC patients.	('AKT', 'Gene', '207', (41, 44))	('inhibitors', 'Var', (65, 75))	('patients', 'Species', '9606', (107, 115))	('mTOR', 'Gene', (79, 83))	('TSC', 'Gene', '7248', (9, 12))	('TSC2', 'Gene', '7249', (9, 13))	('TSC', 'Gene', '7248', (0, 3))	('TSC1', 'Gene', (0, 4))	('TSC', 'Gene', '7248', (103, 106))	('AKT', 'Gene', (41, 44))	('mTOR', 'Gene', (45, 49))	('TSC', 'Gene', (9, 12))	('mTOR', 'Gene', '2475', (79, 83))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('TSC', 'Gene', (0, 3))	('TSC1', 'Gene', '7248', (0, 4))	('TSC2', 'Gene', (9, 13))	('TSC', 'Gene', (103, 106))	('mTOR', 'Gene', '2475', (45, 49))
172570	27682873	In conclusion, analyses of primary cell cultures from kidneys of individuals with or without VHL or TSC1/2 mutations indicate that heterozygosity for TSG mutations is associated with detectable changes in gene expression that can be characterized as the initiated state in otherwise histologically normal cells.	('gene expression', 'MPA', (205, 220))	('TSC1/2', 'Gene', (100, 106))	('TSC1/2', 'Gene', '7248;7249', (100, 106))	('changes', 'Reg', (194, 201))	('TSG', 'Gene', (150, 153))	('mutations', 'Var', (154, 163))	('gene expression', 'biological_process', 'GO:0010467', ('205', '220'))	('VHL', 'Gene', (93, 96))	('TSG', 'Gene', '57045', (150, 153))
172572	27682873	We also note that since most non-hereditary ccRCCs are mutant for VHL, these results may be relevant to the management of this much larger group of renal cancers.	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('RCC', 'Disease', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('renal cancers', 'Disease', (148, 161))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('mutant', 'Var', (55, 61))	('renal cancer', 'Phenotype', 'HP:0009726', (148, 160))	('VHL', 'Gene', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('renal cancers', 'Disease', 'MESH:D007680', (148, 161))
172576	27682873	As control tissues, we used normal renal epithelium adjacent to sporadic renal tumors from patients who underwent nephrectomy; these were designated WT, due to the absence of VHL or TSC1/2 mutations.	('renal tumors', 'Disease', (73, 85))	('patients', 'Species', '9606', (91, 99))	('absence', 'NegReg', (164, 171))	('renal tumors', 'Phenotype', 'HP:0009726', (73, 85))	('VHL', 'Gene', (175, 178))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('TSC1/2', 'Gene', '7248;7249', (182, 188))	('renal tumors', 'Disease', 'MESH:D007674', (73, 85))	('TSC1/2', 'Gene', (182, 188))	('mutations', 'Var', (189, 198))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
172577	27682873	In total, kidney epithelium was accrued from 6 VHL patients, 6 TSC1/2 mutation carriers, and 6 WT controls.	('mutation', 'Var', (70, 78))	('TSC1/2', 'Gene', '7248;7249', (63, 69))	('patients', 'Species', '9606', (51, 59))	('TSC1/2', 'Gene', (63, 69))
172594	27682873	Relative quantitation was computed using the Comparative Ct method (Applied Biosystems Reference Manual, Bulletin #2) between VHL or TSC1/2 mutants and WT primary cell RNAs.	('TSC1/2', 'Gene', '7248;7249', (133, 139))	('VHL', 'Gene', (126, 129))	('TSC1/2', 'Gene', (133, 139))	('mutants', 'Var', (140, 147))
172595	27682873	Relative quantitation is the ratio of normalized amounts of mRNA target for VHL, TSC1/2 and WT cells, and was computed as 2^(-Ct) where  Ct is the difference between mean Ct values for VHL or TSC1/2 mutant and mean  Ct values for WT RNAs.	('TSC1/2', 'Gene', '7248;7249', (81, 87))	('TSC1/2', 'Gene', (81, 87))	('TSC1/2', 'Gene', '7248;7249', (192, 198))	('VHL', 'Gene', (185, 188))	('TSC1/2', 'Gene', (192, 198))	('mutant', 'Var', (199, 205))
172597	27682873	Gene Set Enrichment Analysis (GSEA) was performed against lists of differentially expressed genes for VHL-single hit vs. WT, TSC-single hit vs. WT, and VHL-single hitVHL knock-down vs. VHL-single hitpLKO control comparisons.	('knock-down', 'Var', (170, 180))	('TSC', 'Gene', '7248', (125, 128))	('GSEA', 'Chemical', '-', (30, 34))	('TSC', 'Gene', (125, 128))
172622	30055950	It is well-known now that specific genetic and epigenetic alterations are associated with distinct phenotypes of RCC.	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('epigenetic alterations', 'Var', (47, 69))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('associated', 'Reg', (74, 84))
172623	30055950	Heterozygous germline or somatic alterations of the VHL gene on chromosome 3p are associated with the conventional clear cell phenotype; alterations of TP53 and PTEN and monosomy of characteristic chromosomes have been found in chromophobe RCC, while trisomy and tetrasomy of chromosome 7, trisomy of chromosome 17 and loss of the Y chromosome are often seen in papillary RCC.	('TP53', 'Gene', '7157', (152, 156))	('papillary RCC', 'Disease', 'MESH:C538614', (362, 375))	('VHL', 'Disease', (52, 55))	('papillary RCC', 'Disease', (362, 375))	('chromophobe RCC', 'Disease', 'MESH:C538614', (228, 243))	('PTEN', 'Gene', (161, 165))	('alterations', 'Var', (137, 148))	('RCC', 'Phenotype', 'HP:0005584', (240, 243))	('Y chromosome', 'cellular_component', 'GO:0000806', ('331', '343'))	('trisomy', 'Var', (251, 258))	('chromosome', 'cellular_component', 'GO:0005694', ('276', '286'))	('chromosome', 'cellular_component', 'GO:0005694', ('64', '74'))	('chromosome', 'cellular_component', 'GO:0005694', ('301', '311'))	('VHL', 'Disease', 'MESH:D006623', (52, 55))	('TP53', 'Gene', (152, 156))	('trisomy', 'Var', (290, 297))	('chromophobe RCC', 'Disease', (228, 243))	('PTEN', 'Gene', '5728', (161, 165))	('RCC', 'Phenotype', 'HP:0005584', (372, 375))
172630	30055950	In hypoxia and cancer cells, PHD does not hydroxylate HIF, and the mutant or absent VHL complex cannot target and degrade HIF.	('VHL', 'Disease', (84, 87))	('VHL complex', 'cellular_component', 'GO:0030891', ('84', '95'))	('PHD', 'molecular_function', 'GO:0050175', ('29', '32'))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('hypoxia', 'Disease', (3, 10))	('hypoxia', 'Disease', 'MESH:D000860', (3, 10))	('VHL', 'Disease', 'MESH:D006623', (84, 87))	('hydroxyl', 'Chemical', 'MESH:D017665', (42, 50))	('mutant', 'Var', (67, 73))	('absent', 'NegReg', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('PHD', 'Disease', 'MESH:D011547', (29, 32))	('HIF', 'MPA', (122, 125))	('degrade', 'NegReg', (114, 121))	('PHD', 'Disease', (29, 32))
172635	30055950	mutation or loss) of one of their VHL genes that results in the development of renal cysts and ccRCC.	('results in', 'Reg', (49, 59))	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('VHL', 'Disease', 'MESH:D006623', (34, 37))	('renal cysts', 'Disease', (79, 90))	('mutation', 'Var', (0, 8))	('loss', 'NegReg', (12, 16))	('VHL', 'Disease', (34, 37))	('men', 'Species', '9606', (71, 74))	('renal cysts', 'Disease', 'MESH:D007674', (79, 90))	('renal cysts', 'Phenotype', 'HP:0000107', (79, 90))
172638	30055950	Furthermore, the fact that PBRM1, SETD2, and BAP1 encode chromatin- and histone-regulating tumor suppressor proteins suggests epigenetic dysregulation as a convergent pathogenic event in the development and progression of ccRCC.	('RCC', 'Disease', (224, 227))	('RCC', 'Phenotype', 'HP:0005584', (224, 227))	('ccRCC', 'Phenotype', 'HP:0006770', (222, 227))	('BAP1', 'Gene', (45, 49))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('91', '107'))	('epigenetic dysregulation', 'Var', (126, 150))	('SETD2', 'Gene', '29072', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('BAP1', 'Gene', '8314', (45, 49))	('PBRM1', 'Gene', (27, 32))	('SETD2', 'Gene', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('PBRM1', 'Gene', '55193', (27, 32))	('tumor', 'Disease', (91, 96))	('men', 'Species', '9606', (198, 201))	('chromatin', 'cellular_component', 'GO:0000785', ('57', '66'))	('RCC', 'Disease', 'MESH:C538614', (224, 227))	('tumor suppressor', 'biological_process', 'GO:0051726', ('91', '107'))
172640	30055950	Whereas, PBRM1 is a key component of the PBAF SWI/SNF chromatin remodeling complex, and functions as a tumor suppressor by preventing amplification of HIF oncogenic signals, which may explain why its mutation in small renal masses is associated with tumor invasiveness.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('PBRM1', 'Gene', (9, 14))	('tumor', 'Disease', (250, 255))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('preventing', 'NegReg', (123, 133))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('54', '74'))	('tumor invasiveness', 'Disease', 'MESH:D009369', (250, 268))	('mutation', 'Var', (200, 208))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('103', '119'))	('amplification', 'MPA', (134, 147))	('tumor', 'Disease', (103, 108))	('renal masses', 'Phenotype', 'HP:0009726', (218, 230))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumor suppressor', 'biological_process', 'GO:0051726', ('103', '119'))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('54', '82'))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('associated', 'Reg', (234, 244))	('HIF oncogenic signals', 'MPA', (151, 172))	('tumor invasiveness', 'Disease', (250, 268))	('PBRM1', 'Gene', '55193', (9, 14))	('small renal', 'Phenotype', 'HP:0000089', (212, 223))
172642	30055950	All these molecular alterations are involved in the activation of AMP kinase and acetyl-CoA carboxylase, both of which contribute to a metabolic shift towards increased fatty acid synthesis.	('alterations', 'Var', (20, 31))	('fatty acid', 'Chemical', 'MESH:D005227', (169, 179))	('fatty acid synthesis', 'biological_process', 'GO:0006633', ('169', '189'))	('acetyl-CoA carboxylase', 'Enzyme', (81, 103))	('metabolic shift', 'MPA', (135, 150))	('increased', 'PosReg', (159, 168))	('fatty acid synthesis', 'MPA', (169, 189))	('AMP kinase', 'Enzyme', (66, 76))	('activation', 'PosReg', (52, 62))
172644	30055950	Thus, PBRM1, SETD2, BAP1 and other genetic mutations are considered as second, third or further downstream oncogenic drivers associated with tumor progression and aggressive clinical features.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('BAP1', 'Gene', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('associated', 'Reg', (125, 135))	('tumor', 'Disease', (141, 146))	('PBRM1', 'Gene', (6, 11))	('PBRM1', 'Gene', '55193', (6, 11))	('SETD2', 'Gene', '29072', (13, 18))	('mutations', 'Var', (43, 52))	('SETD2', 'Gene', (13, 18))	('clinical', 'Species', '191496', (174, 182))	('BAP1', 'Gene', '8314', (20, 24))
172681	30055950	Although VHL mutation and 3p loss of heterozygosity were found to be universally present in all primary tumors and metastases, SETD2, PBRM1, MTOR, PIK3CA, PTEN and KDM5C mutations were present heterogeneously between the primary tumors and metastatic sites, representing inter-and intra-tumor heterogeneity.	('metastases', 'Disease', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('loss', 'NegReg', (29, 33))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('intra-tumor', 'Disease', (281, 292))	('PTEN', 'Gene', (155, 159))	('primary tumors', 'Disease', (96, 110))	('PBRM1', 'Gene', '55193', (134, 139))	('PIK3CA', 'Gene', (147, 153))	('KDM5C', 'Gene', (164, 169))	('VHL', 'Disease', (9, 12))	('PBRM1', 'Gene', (134, 139))	('PTEN', 'Gene', '5728', (155, 159))	('primary tumors', 'Disease', 'MESH:D009369', (96, 110))	('intra-tumor', 'Disease', 'MESH:D009369', (281, 292))	('primary tumors', 'Disease', (221, 235))	('SETD2', 'Gene', (127, 132))	('MTOR', 'Gene', (141, 145))	('mutations', 'Var', (170, 179))	('mutation', 'Var', (13, 21))	('MTOR', 'Gene', '2475', (141, 145))	('metastases', 'Disease', 'MESH:D009362', (115, 125))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('SETD2', 'Gene', '29072', (127, 132))	('PIK3CA', 'Gene', '5290', (147, 153))	('VHL', 'Disease', 'MESH:D006623', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('primary tumors', 'Disease', 'MESH:D009369', (221, 235))	('KDM5C', 'Gene', '8242', (164, 169))
172697	30055950	Finally, in the study of multiregional exome sequencing of the primary tumor and metastasis, it was also demonstrated that a single tumor-biopsy core specimen only revealed a minority of genetic aberrations (including mutations, allelic imbalance, and ploidy) that were present in an entire tumor, indicating that a single core was not representative of the mutational landscape of the entire tumor bulk; and it may underestimate the mutational burden in the tumor.	('core', 'cellular_component', 'GO:0019013', ('145', '149'))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('tumor', 'Phenotype', 'HP:0002664', (459, 464))	('tumor', 'Disease', (393, 398))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (393, 398))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('core', 'cellular_component', 'GO:0019013', ('323', '327'))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('imbalance', 'Phenotype', 'HP:0002172', (237, 246))	('genetic aberrations', 'Disease', (187, 206))	('tumor', 'Phenotype', 'HP:0002664', (393, 398))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('genetic aberrations', 'Disease', 'MESH:D030342', (187, 206))	('tumor', 'Disease', (459, 464))	('tumor', 'Disease', (71, 76))	('men', 'Species', '9606', (155, 158))	('tumor', 'Disease', 'MESH:D009369', (459, 464))	('mutations', 'Var', (218, 227))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('ploidy', 'Var', (252, 258))	('tumor', 'Disease', (291, 296))
172706	30055950	In the 'trunk' of the cancer cell evolutionary tree, common mutations found in all tumor cells are depicted, whereas, 'branched' mutations are found in some sub-clones of tumor cells but not others; these mutations may be regionally distributed across the tumor.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Disease', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('cancer', 'Disease', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Disease', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('trunk', 'cellular_component', 'GO:0043198', ('8', '13'))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', (256, 261))
172709	30055950	Thus, identification of tumor clonal architectures and common mutations located in the "trunk" as well as in "branches" of the phylogenetic tree may contribute to more robust biomarker discovery and validation.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('trunk', 'cellular_component', 'GO:0043198', ('87', '92'))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('mutations', 'Var', (62, 71))
172710	30055950	In ccRCC, the phylogenetic model has demonstrated that the main oncogenic driving event is the VHL alteration.	('VHL', 'Disease', (95, 98))	('alteration', 'Var', (99, 109))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('VHL', 'Disease', 'MESH:D006623', (95, 98))
172722	30055950	In their study, they found that both components are derived from the same progenitor cell, however, different allelic losses were identified between clear cell and sarcomatoid components in the same tumor, indicating genetic divergence during the clonal evolution of the tumor such as mutations of TP53 and CDKN2A.	('tumor', 'Disease', (199, 204))	('mutations', 'Var', (285, 294))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('sarcomatoid component', 'Disease', (164, 185))	('CDKN2A', 'Gene', '1029', (307, 313))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('sarcomatoid component', 'Disease', 'MESH:C538614', (164, 185))	('tumor', 'Disease', (271, 276))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('TP53', 'Gene', '7157', (298, 302))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('TP53', 'Gene', (298, 302))	('CDKN2A', 'Gene', (307, 313))
172724	30055950	These sub-clones harbor distinct driver mutations and Warburg effect-related dynamic changes, such as down-regulation of gene expression in the tricarboxylic acid (TCA) cycle, and up-regulation of gene expression in the pentose phosphate pathway.	('pentose phosphate', 'Chemical', 'MESH:D010428', (220, 237))	('gene expression', 'MPA', (197, 212))	('TCA) cycle', 'biological_process', 'GO:0006099', ('164', '174'))	('up-regulation', 'PosReg', (180, 193))	('TCA', 'Chemical', 'MESH:D014233', (164, 167))	('Warburg effect-related', 'Disease', (54, 76))	('pentose phosphate pathway', 'Pathway', (220, 245))	('regulation of gene expression', 'biological_process', 'GO:0010468', ('107', '136'))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (144, 162))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('220', '245'))	('down-regulation', 'NegReg', (102, 117))	('mutations', 'Var', (40, 49))	('gene expression', 'MPA', (121, 136))	('regulation of gene expression', 'biological_process', 'GO:0010468', ('183', '212'))
172735	30055950	Therefore, the study of the PTM profile is particularly important to understand kidney cancer biology and the identification of multiple candidate protein variants.	('variants', 'Var', (155, 163))	('PTM', 'biological_process', 'GO:0043687', ('28', '31'))	('kidney cancer', 'Disease', 'MESH:D007680', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('kidney cancer', 'Phenotype', 'HP:0009726', (80, 93))	('kidney cancer', 'Disease', (80, 93))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))
172763	30055950	Sporadic ccRCC has an acquired mutation of VHL in a majority of cases, and corresponding loss of heterozygosity at the VHL locus in more than 90% of cases, thus VHL loss appears to be the main event in ccRCC development.	('VHL', 'Disease', 'MESH:D006623', (119, 122))	('RCC', 'Disease', (204, 207))	('RCC', 'Phenotype', 'HP:0005584', (204, 207))	('ccRCC', 'Phenotype', 'HP:0006770', (202, 207))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('ccRCC', 'Phenotype', 'HP:0006770', (9, 14))	('RCC', 'Disease', (11, 14))	('VHL', 'Disease', (43, 46))	('VHL', 'Disease', (161, 164))	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('men', 'Species', '9606', (215, 218))	('heterozygosity', 'MPA', (97, 111))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('VHL loss', 'Disease', (161, 169))	('VHL', 'Disease', (119, 122))	('mutation', 'Var', (31, 39))	('VHL', 'Disease', 'MESH:D006623', (43, 46))	('loss', 'NegReg', (89, 93))	('VHL loss', 'Disease', 'MESH:D006623', (161, 169))	('VHL', 'Disease', 'MESH:D006623', (161, 164))
172765	30055950	Commonly, a universal alteration on the short arm of chromosome 3 in ccRCC is followed by simultaneous one-copy loss of these tumor suppressor genes.	('alteration', 'Var', (22, 32))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('126', '142'))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('short arm', 'Phenotype', 'HP:0009824', (40, 49))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (69, 74))	('loss', 'NegReg', (112, 116))	('tumor suppressor', 'biological_process', 'GO:0051726', ('126', '142'))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('chromosome', 'cellular_component', 'GO:0005694', ('53', '63'))	('tumor', 'Disease', (126, 131))
172781	30055950	The regulation of NRF2 expression is complex: in some cases, it is related to the mutation of KEAP1 gene and involved in oxidative stress responses.	('regulation', 'biological_process', 'GO:0065007', ('4', '14'))	('NRF2', 'Gene', '4780', (18, 22))	('related', 'Reg', (67, 74))	('NRF2', 'Gene', (18, 22))	('mutation', 'Var', (82, 90))	('KEAP1', 'Gene', '9817', (94, 99))	('oxidative stress', 'Phenotype', 'HP:0025464', (121, 137))	('KEAP1', 'Gene', (94, 99))	('involved', 'Reg', (109, 117))
172782	30055950	Aberrant KEAP1 protein leads to the accumulation of NRF2 in the nucleus; where it can affect another gene, ARE (anti-oxidant response element) expression.	('Aberrant', 'Var', (0, 8))	('NRF2', 'Gene', (52, 56))	('oxidant response', 'Phenotype', 'HP:0025464', (117, 133))	('KEAP1', 'Gene', '9817', (9, 14))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('nucleus', 'cellular_component', 'GO:0005634', ('64', '71'))	('KEAP1', 'Gene', (9, 14))	('accumulation', 'PosReg', (36, 48))	('men', 'Species', '9606', (137, 140))	('NRF2', 'Gene', '4780', (52, 56))
172789	30055950	Its development and progression are multistep processes characterized by aberrant genetic, epigenetic, and proteomic changes, which subsequently lead to phenotypic cellular transformation.	('aberrant genetic', 'Var', (73, 89))	('lead to', 'Reg', (145, 152))	('men', 'Species', '9606', (11, 14))	('epigenetic', 'Var', (91, 101))
172799	29254209	PVT1 knockdown promoted apoptosis, inhibited renal cancer cell proliferation, decreased Mcl-1, and increased cleaved caspase-3 and cleaved PARP.	('renal cancer', 'Disease', (45, 57))	('Mcl-1', 'Gene', (88, 93))	('knockdown', 'Var', (5, 14))	('renal cancer', 'Phenotype', 'HP:0009726', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('PVT1', 'Gene', (0, 4))	('PARP', 'Gene', '1302', (139, 143))	('PVT1', 'Gene', '5820', (0, 4))	('promoted', 'PosReg', (15, 23))	('caspase-3', 'Gene', '836', (117, 126))	('renal cancer', 'Disease', 'MESH:D007680', (45, 57))	('decreased Mcl', 'Phenotype', 'HP:0025066', (78, 91))	('inhibited', 'NegReg', (35, 44))	('increased', 'PosReg', (99, 108))	('decreased', 'NegReg', (78, 87))	('PARP', 'Gene', (139, 143))	('caspase-3', 'Gene', (117, 126))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('Mcl-1', 'Gene', '4170', (88, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('24', '33'))	('apoptosis', 'biological_process', 'GO:0006915', ('24', '33'))	('cell proliferation', 'biological_process', 'GO:0008283', ('58', '76'))	('cleaved', 'MPA', (131, 138))	('apoptosis', 'CPA', (24, 33))
172802	29254209	In addition, in vivo experiments showed that PVT1 knockdown repressed xenograft tumor growth, while Mcl-1 overexpression partially rescued xenograft tumor growth.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('Mcl-1', 'Gene', '4170', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('PVT1', 'Gene', (45, 49))	('knockdown', 'Var', (50, 59))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (80, 85))	('Mcl-1', 'Gene', (100, 105))	('tumor', 'Disease', (149, 154))	('PVT1', 'Gene', '5820', (45, 49))
172822	29254209	CCK-8 and colony formation assays also showed that 786-O and ACHN cell proliferation and colony-forming efficiencies decreased with PVT1 knockdown (Figure 2B and 2C).	('PVT1', 'Gene', '5820', (132, 136))	('ACHN', 'Gene', '55323', (61, 65))	('decreased', 'NegReg', (117, 126))	('formation', 'biological_process', 'GO:0009058', ('17', '26'))	('knockdown', 'Var', (137, 146))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('ACHN', 'Gene', (61, 65))	('PVT1', 'Gene', (132, 136))	('colony-forming efficiencies', 'CPA', (89, 116))
172827	29254209	Western blot analysis showed that Mcl-1 was down-regulated with PVT1 knockdown, and that the expression of cleaved caspase-3 and cleaved PARP were increased in 786-O and ACHN cells (Figure 3C).	('down-regulated', 'NegReg', (44, 58))	('PARP', 'Gene', (137, 141))	('PVT1', 'Gene', (64, 68))	('increased', 'PosReg', (147, 156))	('Mcl-1', 'Gene', '4170', (34, 39))	('si', 'Chemical', 'MESH:D012825', (18, 20))	('ACHN', 'Gene', (170, 174))	('cleaved', 'MPA', (129, 136))	('PVT1', 'Gene', '5820', (64, 68))	('Mcl-1', 'Gene', (34, 39))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('caspase-3', 'Gene', '836', (115, 124))	('expression', 'MPA', (93, 103))	('PARP', 'Gene', '1302', (137, 141))	('ACHN', 'Gene', '55323', (170, 174))	('knockdown', 'Var', (69, 78))	('cleaved', 'MPA', (107, 114))	('caspase-3', 'Gene', (115, 124))
172828	29254209	The results suggest that silencing PVT1 down-regulated Mcl-1 and promoted apoptosis.	('silencing', 'Var', (25, 34))	('apoptosis', 'CPA', (74, 83))	('PVT1', 'Gene', '5820', (35, 39))	('si', 'Chemical', 'MESH:D012825', (25, 27))	('Mcl-1', 'Gene', '4170', (55, 60))	('PVT1', 'Gene', (35, 39))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('promoted', 'PosReg', (65, 73))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('Mcl-1', 'Gene', (55, 60))	('si', 'Chemical', 'MESH:D012825', (80, 82))	('down-regulated', 'NegReg', (40, 54))
172829	29254209	We next examined the contribution of Mcl-1 to the increase in cellular apoptosis after knocking down PVT1.	('PVT1', 'Gene', '5820', (101, 105))	('Mcl-1', 'Gene', (37, 42))	('knocking down', 'Var', (87, 100))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('Mcl-1', 'Gene', '4170', (37, 42))	('cellular apoptosis', 'CPA', (62, 80))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('PVT1', 'Gene', (101, 105))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))
172831	29254209	Flow cytometry confirmed that the knockdown of PVT1 enhanced apoptosis and increased cleaved caspase-3 and cleaved PARP expression.	('caspase-3', 'Gene', (93, 102))	('PVT1', 'Gene', (47, 51))	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('apoptosis', 'CPA', (61, 70))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))	('PVT1', 'Gene', '5820', (47, 51))	('si', 'Chemical', 'MESH:D012825', (126, 128))	('enhanced', 'PosReg', (52, 60))	('caspase-3', 'Gene', '836', (93, 102))	('PARP', 'Gene', '1302', (115, 119))	('PARP', 'Gene', (115, 119))	('knockdown', 'Var', (34, 43))	('increased', 'PosReg', (75, 84))	('cleaved', 'MPA', (107, 114))
172833	29254209	The suppressed colony formation from knocking-down PVT1 was rescued by overexpressing Mcl-1(Figure 4C).	('Mcl-1(Figure 4C', 'Gene', '4170', (86, 101))	('colony formation', 'CPA', (15, 31))	('formation', 'biological_process', 'GO:0009058', ('22', '31'))	('knocking-down', 'Var', (37, 50))	('PVT1', 'Gene', (51, 55))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('suppressed', 'NegReg', (4, 14))	('PVT1', 'Gene', '5820', (51, 55))
172839	29254209	When treated with transcription inhibitor actinomycin D (Act D), Mcl-1mRNA levels in ACHN cells transfected with siPVT1 were lower than those transfected with siNC (Figure 5B and 5C).	('si', 'Chemical', 'MESH:D012825', (159, 161))	('Mcl-1', 'Gene', '4170', (65, 70))	('ACHN', 'Gene', '55323', (85, 89))	('Mcl-1', 'Gene', (65, 70))	('si', 'Chemical', 'MESH:D012825', (113, 115))	('ACHN', 'Gene', (85, 89))	('lower', 'NegReg', (125, 130))	('transcription', 'biological_process', 'GO:0006351', ('18', '31'))	('actinomycin D', 'Chemical', 'MESH:D003609', (42, 55))	('siPVT1', 'Var', (113, 119))
172842	29254209	We found that silencing PVT1 reduced xenograft tumor growth, which was partially rescued by Mcl-1 overexpression (Figure 6A-6C).	('si', 'Chemical', 'MESH:D012825', (14, 16))	('Mcl-1', 'Gene', (92, 97))	('silencing', 'Var', (14, 23))	('PVT1', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('reduced', 'NegReg', (29, 36))	('Mcl-1', 'Gene', '4170', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('PVT1', 'Gene', '5820', (24, 28))	('tumor', 'Disease', (47, 52))	('si', 'Chemical', 'MESH:D012825', (108, 110))
172851	29254209	Moreover, our study revealed that PVT1 knockdown could inhibit proliferation and induce apoptosis of renal cancer cells in vivo and in vitro.	('apoptosis', 'CPA', (88, 97))	('apoptosis', 'biological_process', 'GO:0006915', ('88', '97'))	('induce', 'PosReg', (81, 87))	('proliferation', 'CPA', (63, 76))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('PVT1', 'Gene', (34, 38))	('knockdown', 'Var', (39, 48))	('renal cancer', 'Disease', (101, 113))	('renal cancer', 'Phenotype', 'HP:0009726', (101, 113))	('apoptosis', 'biological_process', 'GO:0097194', ('88', '97'))	('PVT1', 'Gene', '5820', (34, 38))	('inhibit', 'NegReg', (55, 62))	('renal cancer', 'Disease', 'MESH:D007680', (101, 113))	('si', 'Chemical', 'MESH:D012825', (94, 96))
172855	29254209	Knockdown of Mcl-1 restores sensitivity to chemotherapy in chemoresistant cells.	('Knockdown', 'Var', (0, 9))	('restores', 'PosReg', (19, 27))	('Mcl-1', 'Gene', (13, 18))	('sensitivity to chemotherapy', 'MPA', (28, 55))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('Mcl-1', 'Gene', '4170', (13, 18))
172862	29254209	The luciferase activity of pmiR-RB-PVT1 which contained PVT1 at the 3'UTR of Rluc showed no response to miR-29b-3p/ miR-30C-5p/ miR-106a-5p mimics and inhibitors (Supplementary Figure 3B and 3C).	('PVT1', 'Gene', '5820', (56, 60))	('PVT1', 'Gene', '5820', (35, 39))	('luciferase activity', 'molecular_function', 'GO:0047077', ('4', '23'))	('activity', 'MPA', (15, 23))	('luciferase activity', 'molecular_function', 'GO:0045289', ('4', '23'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('4', '23'))	('miR-29b-3p/', 'Var', (104, 115))	('miR-106a', 'Gene', '406899', (128, 136))	('PVT1', 'Gene', (56, 60))	('luciferase activity', 'molecular_function', 'GO:0050397', ('4', '23'))	('PVT1', 'Gene', (35, 39))	('luciferase', 'Enzyme', (4, 14))	('luciferase activity', 'molecular_function', 'GO:0050248', ('4', '23'))	('miR-106a', 'Gene', (128, 136))
172882	29254209	Cells were harvested 48 h after si-PVT1 or si-NC transient transfection and incubated with annexin V-FITC and PI according to the manufacturer's instructions (BD, San Diego, CA, USA).	('PVT1', 'Gene', '5820', (35, 39))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('annexin V', 'Gene', '308', (91, 100))	('PVT1', 'Gene', (35, 39))	('annexin V', 'Gene', (91, 100))	('si-NC', 'Var', (43, 48))
172890	29254209	The fragment containing human Mcl-1 promoter regions (-1693~+208) was chemically synthesized and cloned into the pGL3-Basic vector, and the resulting plasmid was named pGL3-Mcl-1.	('si', 'Chemical', 'MESH:D012825', (87, 89))	('pGL3', 'Gene', (168, 172))	('human', 'Species', '9606', (24, 29))	('Mcl-1', 'Gene', (30, 35))	('pGL3', 'Gene', '6391', (168, 172))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('Mcl-1', 'Gene', '4170', (173, 178))	('pGL3', 'Gene', (113, 117))	('-1693~+208', 'Var', (54, 64))	('pGL', 'molecular_function', 'GO:0004598', ('113', '116'))	('pGL3', 'Gene', '6391', (113, 117))	('Mcl-1', 'Gene', '4170', (30, 35))	('Mcl-1', 'Gene', (173, 178))	('pGL', 'molecular_function', 'GO:0004598', ('168', '171'))
172903	29254209	ACHN cells stably transfected with LV3-shNC, LV3-shPVT1, shPVT1+vector, and shPVT1+Mcl-1 (5 x 106 cells per mouse) were injected subcutaneously into the right flanks of the mice.	('PVT1', 'Gene', (78, 82))	('Mcl-1', 'Gene', '4170', (83, 88))	('PVT1', 'Gene', (59, 63))	('PVT1', 'Gene', (51, 55))	('LV3-shNC', 'Var', (35, 43))	('PVT1', 'Gene', '5820', (78, 82))	('ACHN', 'Gene', '55323', (0, 4))	('mouse', 'Species', '10090', (108, 113))	('Mcl-1', 'Gene', (83, 88))	('PVT1', 'Gene', '5820', (59, 63))	('ACHN', 'Gene', (0, 4))	('PVT1', 'Gene', '5820', (51, 55))	('mice', 'Species', '10090', (173, 177))
172914	33680937	Downregulation of the lncRNA ASB16-AS1 Decreases LARP1 Expression and Promotes Clear Cell Renal Cell Carcinoma Progression via miR-185-5p/miR-214-3p Clear cell renal cell carcinoma (ccRCC) comprises approximately 75% of renal cell carcinomas, which is one of the most common and lethal urologic cancers, with poor quality of life for patients and is a huge economic burden to health care systems.	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (90, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('miR-214', 'Gene', '406996', (138, 145))	('urologic cancers', 'Disease', (286, 302))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (220, 241))	('Carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (220, 240))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('miR-185', 'Gene', '406961', (127, 134))	('Downregulation', 'Var', (0, 14))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (149, 180))	('carcinomas', 'Phenotype', 'HP:0030731', (231, 241))	('cancers', 'Phenotype', 'HP:0002664', (295, 302))	('Decreases', 'NegReg', (39, 48))	('ASB16', 'Gene', (29, 34))	('miR-214', 'Gene', (138, 145))	('Clear cell renal cell carcinoma', 'Disease', (149, 180))	('AS1', 'Gene', (35, 38))	('RCC', 'Disease', (184, 187))	('LARP1', 'Gene', (49, 54))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (160, 180))	('Expression', 'MPA', (55, 65))	('Promotes Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (70, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (182, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('patients', 'Species', '9606', (334, 342))	('urologic cancers', 'Disease', 'MESH:D014571', (286, 302))	('miR-185', 'Gene', (127, 134))	('LARP1', 'Gene', '23367', (49, 54))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (79, 110))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (149, 180))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (220, 241))	('ASB16', 'Gene', '92591', (29, 34))	('Promotes Clear Cell Renal Cell Carcinoma', 'Disease', (70, 110))	('AS1', 'Gene', '5729', (35, 38))	('renal cell carcinomas', 'Disease', (220, 241))
172917	33680937	By constructing cell and mouse models, it was found that downregulated lncRNA ASB16-AS1 enhanced cell proliferation, migration, invasion, and promoted tumor growth and metastasis.	('ASB16-AS1', 'Gene', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cell proliferation', 'biological_process', 'GO:0008283', ('97', '115'))	('migration', 'CPA', (117, 126))	('downregulated', 'Var', (57, 70))	('mouse', 'Species', '10090', (25, 30))	('tumor', 'Disease', (151, 156))	('enhanced', 'PosReg', (88, 96))	('lncRNA ASB16-AS1', 'Gene', (71, 87))	('promoted', 'PosReg', (142, 150))	('cell proliferation', 'CPA', (97, 115))	('invasion', 'CPA', (128, 136))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
172918	33680937	Furthermore, by performing bioinformatics analysis, biotinylated RNA pull-downs, AGO2-RIP, and luciferase reporter assays, our findings showed that downregulated ASB16-AS1 decreased La-related protein 1 (LARP1) expression by inhibiting miR-185-5p and miR-214-3p.	('RNA', 'cellular_component', 'GO:0005562', ('65', '68'))	('-185-5p', 'Chemical', '-', (239, 246))	('miR-214-3p', 'Chemical', '-', (251, 261))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('decreased', 'NegReg', (172, 181))	('LARP1', 'Gene', (204, 209))	('miR-185', 'Gene', '406961', (236, 243))	('ASB16-AS1', 'Gene', (162, 171))	('downregulated', 'Var', (148, 161))	('miR-214-3p', 'MPA', (251, 261))	('inhibiting', 'NegReg', (225, 235))	('expression', 'MPA', (211, 221))	('miR-185', 'Gene', (236, 243))
172920	33680937	Our results revealed that downregulated ASB16-AS1 promotes ccRCC progression via a miR-185-5p-miR-214-3p-LARP1 pathway.	('ASB16-AS1', 'Gene', (40, 49))	('downregulated', 'Var', (26, 39))	('miR-214-3p', 'Chemical', '-', (94, 104))	('miR-185', 'Gene', '406961', (83, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('miR-185', 'Gene', (83, 90))	('-185-5p', 'Chemical', '-', (86, 93))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('promotes', 'PosReg', (50, 58))
172954	33680937	The primary antibodies used were; anti-LARP1 (1:1000, 13187S, CST), anti-E-cadherin (1:1,000, 14472S, CST), anti-Vimentin (1:1,000, 5741S, CST), and anti-GAPDH (1:5,000, ab8245, Abcam).	('GAPDH', 'Gene', (154, 159))	('E-cadherin', 'Gene', (73, 83))	('E-cadherin', 'Gene', '999', (73, 83))	('CST', 'Gene', (102, 105))	('CST', 'Gene', (62, 65))	('CST', 'Gene', '106478911', (139, 142))	('CST', 'Gene', '106478911', (62, 65))	('Vimentin', 'cellular_component', 'GO:0045099', ('113', '121'))	('cadherin', 'molecular_function', 'GO:0008014', ('75', '83'))	('Vimentin', 'cellular_component', 'GO:0045098', ('113', '121'))	('1:1000', 'Var', (46, 52))	('Vimentin', 'Gene', (113, 121))	('CST', 'Gene', '106478911', (102, 105))	('Vimentin', 'Gene', '7431', (113, 121))	('CST', 'Gene', (139, 142))	('GAPDH', 'Gene', '2597', (154, 159))
172963	33680937	PmirGLO vectors (Promega, USA) harboring miR-185-5p and miR-214-3p sequences with wild-type or mutant binding sites for ASB16-AS1/LARP1 were used.	('miR-185', 'Gene', '406961', (41, 48))	('miR-214-3p', 'Chemical', '-', (56, 66))	('binding', 'Interaction', (102, 109))	('-185-5p', 'Chemical', '-', (44, 51))	('miR-214-3p', 'Var', (56, 66))	('miR-185', 'Gene', (41, 48))	('binding', 'molecular_function', 'GO:0005488', ('102', '109'))	('mutant', 'Var', (95, 101))
172964	33680937	The miR-185-5p mimic, miR-214-3p mimic, and the luciferase vectors were co-transfected into 786-O and 293T cells.	('miR-214-3p mimic', 'Var', (22, 38))	('miR-185', 'Gene', '406961', (4, 11))	('miR-214-3p', 'Chemical', '-', (22, 32))	('miR-185', 'Gene', (4, 11))	('-185-5p', 'Chemical', '-', (7, 14))	('293T', 'CellLine', 'CVCL:0063', (102, 106))
172965	33680937	Biotinylated ASB16-AS1, miR-185-5p, miR-214-3p, and control probes were synthesized and purchased from GenePharma (Shanghai, China).	('miR-185', 'Gene', '406961', (24, 31))	('miR-185', 'Gene', (24, 31))	('miR-214-3p', 'Chemical', '-', (36, 46))	('-185-5p', 'Chemical', '-', (27, 34))	('miR-214-3p', 'Var', (36, 46))
172966	33680937	Cell lysates were incubated with ASB16-AS1, miR-185-5p, and miR-214-3p probe-streptavidin beads (Life, USA) overnight.	('-185-5p', 'Chemical', '-', (47, 54))	('miR-185', 'Gene', '406961', (44, 51))	('miR-214-3p', 'Chemical', '-', (60, 70))	('miR-214-3p', 'Var', (60, 70))	('miR-185', 'Gene', (44, 51))
172970	33680937	The ccRCC 786-O cells pre-transfected with Sh-NC or Sh-ASB16-AS1 were then subcutaneously inoculated into the NOD/SCID mice (1x107 cells per tumor).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('SCID', 'Disease', 'MESH:D053632', (114, 118))	('mice', 'Species', '10090', (119, 123))	('SCID', 'Disease', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('ccRCC', 'Phenotype', 'HP:0006770', (4, 9))	('tumor', 'Disease', (141, 146))	('Sh-ASB16-AS1', 'Var', (52, 64))	('pre', 'molecular_function', 'GO:0003904', ('22', '25'))	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))
172981	33680937	Moreover, ASB16-AS1 was abundantly expressed in later stage and larger tumors ( Figures 1B, C ), suggesting that ASB16-AS1 might be involved in ccRCC initiation and progression.	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('tumors', 'Disease', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('involved', 'Reg', (132, 140))	('ASB16-AS1', 'Var', (113, 122))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
172992	33680937	Lung tissues from xenografted mice using hematoxylin and eosin staining showed that downregulation of ASB16-AS1 enhanced tumor metastasis ( Figure 3D ).	('enhanced', 'PosReg', (112, 120))	('mice', 'Species', '10090', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('ASB16-AS1', 'Gene', (102, 111))	('hematoxylin', 'Chemical', 'MESH:D006416', (41, 52))	('eosin', 'Chemical', 'MESH:D004801', (57, 62))	('downregulation', 'Var', (84, 98))	('tumor metastasis', 'Disease', 'MESH:D009362', (121, 137))	('tumor metastasis', 'Disease', (121, 137))
172995	33680937	We found that miR-185-5p and miR-214-3p were abundantly expressed ( Figure 4C ).	('miR-185', 'Gene', '406961', (14, 21))	('miR-214-3p', 'Chemical', '-', (29, 39))	('miR-185', 'Gene', (14, 21))	('-185-5p', 'Chemical', '-', (17, 24))	('miR-214-3p', 'Var', (29, 39))
172996	33680937	Next, RNA pull-down assays using bio-miR-185-5p and bio-214-3p probes were performed.	('miR-185', 'Gene', (37, 44))	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('-185-5p', 'Chemical', '-', (40, 47))	('bio-214-3p', 'Var', (52, 62))	('miR-185', 'Gene', '406961', (37, 44))
172997	33680937	ASB16-AS1 was highly enriched in bio-miR-185-5p and bio-214-3p RNA complexes compared with bio-NC ( Figure 4D ).	('miR-185', 'Gene', (37, 44))	('RNA', 'cellular_component', 'GO:0005562', ('63', '66'))	('-185-5p', 'Chemical', '-', (40, 47))	('bio-214-3p', 'Var', (52, 62))	('miR-185', 'Gene', '406961', (37, 44))
172998	33680937	Subsequently, we constructed wild type (WT) and mutant (Mut) ASB16-AS1 binding sites for miR-185-5p and miR-214-3p, respectively ( Figure 4E ).	('ASB16-AS1', 'Gene', (61, 70))	('mutant', 'Var', (48, 54))	('miR-214-3p', 'Chemical', '-', (104, 114))	('miR-214-3p', 'Var', (104, 114))	('-185-5p', 'Chemical', '-', (92, 99))	('miR-185', 'Gene', '406961', (89, 96))	('binding', 'Interaction', (71, 78))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))	('miR-185', 'Gene', (89, 96))
173000	33680937	The expression of miR-185-5p and miR-214-3p in Sh-ASB16-AS1 transfected 786-O cells was significantly greater than in the control group ( Figure 4H ).	('greater', 'PosReg', (102, 109))	('Sh-ASB16-AS1', 'Gene', (47, 59))	('miR-214-3p', 'Chemical', '-', (33, 43))	('expression', 'MPA', (4, 14))	('miR-185', 'Gene', '406961', (18, 25))	('-185-5p', 'Chemical', '-', (21, 28))	('miR-214-3p', 'Var', (33, 43))	('miR-185', 'Gene', (18, 25))
173001	33680937	These data suggest that ASB16-AS1 interacted with miR-185-5p and miR-214-3p.	('-185-5p', 'Chemical', '-', (53, 60))	('miR-214-3p', 'Chemical', '-', (65, 75))	('miR-214-3p', 'Var', (65, 75))	('ASB16-AS1', 'Gene', (24, 33))	('miR-185', 'Gene', '406961', (50, 57))	('interacted', 'Interaction', (34, 44))	('miR-185', 'Gene', (50, 57))
173005	33680937	Furthermore, miR-185-5p and miR-214-3p inhibition effectively alleviated the enhancement of downregulated ASB16-AS1 on the EMT phenotype ( Figure 5E ).	('miR-214-3p', 'Var', (28, 38))	('ASB16-AS1', 'Gene', (106, 115))	('miR-185', 'Gene', (13, 20))	('-185-5p', 'Chemical', '-', (16, 23))	('EMT', 'biological_process', 'GO:0001837', ('123', '126'))	('enhancement', 'PosReg', (77, 88))	('men', 'Species', '9606', (84, 87))	('miR-185', 'Gene', '406961', (13, 20))	('miR-214-3p', 'Chemical', '-', (28, 38))	('EMT phenotype', 'CPA', (123, 136))	('alleviated', 'NegReg', (62, 72))	('downregulated', 'NegReg', (92, 105))
173006	33680937	These data indicate that ASB16-AS1 regulates ccRCC progression via miR-185-5p and miR-214-3p.	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('miR-185', 'Gene', '406961', (67, 74))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('ASB16-AS1', 'Gene', (25, 34))	('RCC', 'Disease', (47, 50))	('miR-214-3p', 'Chemical', '-', (82, 92))	('regulates', 'Reg', (35, 44))	('miR-185', 'Gene', (67, 74))	('-185-5p', 'Chemical', '-', (70, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('miR-214-3p', 'Var', (82, 92))
173007	33680937	The downstream targets of miR-185-5p and miR-214-3p were predicted using the ENCORI database .	('miR-214-3p', 'Var', (41, 51))	('-185-5p', 'Chemical', '-', (29, 36))	('miR-185', 'Gene', '406961', (26, 33))	('miR-185', 'Gene', (26, 33))	('miR-214-3p', 'Chemical', '-', (41, 51))
173009	33680937	It was found that miR-185-5p and miR-214-3p significantly suppressed La-related protein 1 (LARP1) expression ( Figures 6B, C ), results of the expression of HDGF and PIM1 NC-mimic/miR-214-3p-mimic transfected 786-O cells were in accordance with previous studies.	('PIM1', 'Gene', (166, 170))	('PIM1', 'Gene', '5292', (166, 170))	('miR-214-3p', 'Chemical', '-', (180, 190))	('HDGF', 'Gene', '3068', (157, 161))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('miR-185', 'Gene', '406961', (18, 25))	('miR-214-3p', 'Chemical', '-', (33, 43))	('suppressed', 'NegReg', (58, 68))	('-185-5p', 'Chemical', '-', (21, 28))	('HDGF', 'Gene', (157, 161))	('miR-214-3p', 'Var', (33, 43))	('La-related protein 1 (LARP1', 'Gene', (69, 96))	('miR-185', 'Gene', (18, 25))	('LARP1', 'Gene', (91, 96))	('expression', 'MPA', (98, 108))
173010	33680937	Therefore, we speculated that LARP1 might interact with miR-185-5p and miR-214-3p.	('interact', 'Interaction', (42, 50))	('miR-185', 'Gene', '406961', (56, 63))	('miR-214-3p', 'Chemical', '-', (71, 81))	('miR-185', 'Gene', (56, 63))	('-185-5p', 'Chemical', '-', (59, 66))	('miR-214-3p', 'Var', (71, 81))	('LARP1', 'Gene', (30, 35))
173011	33680937	Biotinylated RNA pull-downs using bio-miR-185-5p or bio-miR-214-3p were performed.	('miR-214-3p', 'Chemical', '-', (56, 66))	('miR-185', 'Gene', '406961', (38, 45))	('bio-miR-214-3p', 'Var', (52, 66))	('miR-185', 'Gene', (38, 45))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('-185-5p', 'Chemical', '-', (41, 48))
173012	33680937	As shown in  Figure 6E , LARP1 was significantly enriched in bio-miR-185-5p and bio-214-3p RNA complexes compared with bio-NC.	('miR-185', 'Gene', '406961', (65, 72))	('-185-5p', 'Chemical', '-', (68, 75))	('LARP1', 'Gene', (25, 30))	('miR-185', 'Gene', (65, 72))	('enriched', 'PosReg', (49, 57))	('bio-214-3p', 'Var', (80, 90))	('RNA', 'cellular_component', 'GO:0005562', ('91', '94'))
173026	33680937	Downregulation of ASB16-AS1 promoted cell proliferation, migration, and invasion, regulated EMT associated genes in ccRCC cells and promoted tumor growth and metastasis in a xenograft mouse model.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('cell proliferation', 'biological_process', 'GO:0008283', ('37', '55'))	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('regulated', 'Reg', (82, 91))	('ASB16-AS1', 'Gene', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('Downregulation', 'Var', (0, 14))	('promoted', 'PosReg', (132, 140))	('EMT associated genes', 'Gene', (92, 112))	('EMT', 'biological_process', 'GO:0001837', ('92', '95'))	('promoted', 'PosReg', (28, 36))	('invasion', 'CPA', (72, 80))	('cell proliferation', 'CPA', (37, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('RCC', 'Disease', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('tumor', 'Disease', (141, 146))	('migration', 'CPA', (57, 66))	('mouse', 'Species', '10090', (184, 189))
173027	33680937	Furthermore, it was found that ASB16-AS interacts with miR-185-5p and miR-214-3p.	('miR-214-3p', 'Chemical', '-', (70, 80))	('miR-185', 'Gene', '406961', (55, 62))	('miR-214-3p', 'Var', (70, 80))	('interacts', 'Interaction', (40, 49))	('miR-185', 'Gene', (55, 62))	('-185-5p', 'Chemical', '-', (58, 65))	('ASB16-AS', 'Gene', (31, 39))
173029	33680937	Additionally, miR-214-3p is involved in osteosarcoma, breast cancer, endometrial cancer, and lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (54, 67))	('endometrial cancer', 'Disease', (69, 87))	('miR-214-3p', 'Chemical', '-', (14, 24))	('miR-214-3p', 'Var', (14, 24))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('involved', 'Reg', (28, 36))	('endometrial cancer', 'Phenotype', 'HP:0012114', (69, 87))	('endometrial cancer', 'Disease', 'MESH:D016889', (69, 87))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', (93, 104))	('osteosarcoma', 'Disease', (40, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('osteosarcoma', 'Phenotype', 'HP:0002669', (40, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('osteosarcoma', 'Disease', 'MESH:D012516', (40, 52))
173030	33680937	These studies suggest that miR-185-5p and miR-214-3p play important roles in tumorigeneses and tumor development.	('miR-185', 'Gene', '406961', (27, 34))	('miR-214-3p', 'Var', (42, 52))	('-185-5p', 'Chemical', '-', (30, 37))	('miR-185', 'Gene', (27, 34))	('men', 'Species', '9606', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('miR-214-3p', 'Chemical', '-', (42, 52))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', (95, 100))
173032	33680937	Here, our findings suggested that ASB16-AS1 acted as a molecular sponge for miR-185-5p and miR-214-3p.	('miR-185', 'Gene', '406961', (76, 83))	('miR-214-3p', 'Chemical', '-', (91, 101))	('miR-214-3p', 'Var', (91, 101))	('miR-185', 'Gene', (76, 83))	('-185-5p', 'Chemical', '-', (79, 86))
173033	33680937	Furthermore, the promotive effects of ASB16-AS1 on cell proliferation, migration, invasion, and EMT associated gene expression were rescued by miR-185-5p and miR-214-3p inhibition.	('EMT associated', 'CPA', (96, 110))	('gene expression', 'biological_process', 'GO:0010467', ('111', '126'))	('promotive', 'CPA', (17, 26))	('cell proliferation', 'biological_process', 'GO:0008283', ('51', '69'))	('miR-185', 'Gene', (143, 150))	('ASB16-AS1', 'Gene', (38, 47))	('invasion', 'CPA', (82, 90))	('migration', 'CPA', (71, 80))	('cell proliferation', 'CPA', (51, 69))	('EMT', 'biological_process', 'GO:0001837', ('96', '99'))	('miR-214-3p', 'Chemical', '-', (158, 168))	('rescued', 'PosReg', (132, 139))	('miR-214-3p inhibition', 'Var', (158, 179))	('-185-5p', 'Chemical', '-', (146, 153))	('miR-185', 'Gene', '406961', (143, 150))
173034	33680937	While, the relationship between miR-185-5p and miR-214-3p, and their contribution in ccRCC cellular progression upon ASB16-AS1 downregulation still need further exploration.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('miR-185', 'Gene', '406961', (32, 39))	('downregulation', 'NegReg', (127, 141))	('miR-214-3p', 'Chemical', '-', (47, 57))	('ASB16-AS1', 'Gene', (117, 126))	('miR-185', 'Gene', (32, 39))	('-185-5p', 'Chemical', '-', (35, 42))	('miR-214-3p', 'Var', (47, 57))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
173036	33680937	Our findings found that LARP1 was targeted by miR-185-5p and miR-214-3p in 786-O and 293T cells.	('targeted', 'Reg', (34, 42))	('293T', 'CellLine', 'CVCL:0063', (85, 89))	('LARP1', 'Gene', (24, 29))	('miR-185', 'Gene', '406961', (46, 53))	('miR-214-3p', 'Chemical', '-', (61, 71))	('-185-5p', 'Chemical', '-', (49, 56))	('miR-214-3p', 'Var', (61, 71))	('miR-185', 'Gene', (46, 53))
173046	33680937	In the current study, we demonstrate the interaction of miR-185-5p and miR-214-3p with LARP1 and show the role of the ASB16-AS1-miR-185-5p/miR-214-3p-LARP1 pathway in ccRCC progression.	('-185-5p', 'Chemical', '-', (131, 138))	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('interaction', 'Interaction', (41, 52))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('RCC', 'Disease', (169, 172))	('miR-185', 'Gene', '406961', (128, 135))	('miR-185', 'Gene', '406961', (56, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (167, 172))	('miR-214-3p', 'Chemical', '-', (139, 149))	('miR-214-3p', 'Chemical', '-', (71, 81))	('LARP1', 'Protein', (87, 92))	('miR-185', 'Gene', (128, 135))	('miR-185', 'Gene', (56, 63))	('-185-5p', 'Chemical', '-', (59, 66))	('miR-214-3p', 'Var', (71, 81))
173047	33680937	Collectively, our data determined the role of ASB16-AS1, miR-185-5p, and miR-214-3p in ccRCC progression.	('miR-185', 'Gene', (57, 64))	('miR-214-3p', 'Chemical', '-', (73, 83))	('-185-5p', 'Chemical', '-', (60, 67))	('miR-214-3p', 'Var', (73, 83))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('ASB16-AS1', 'Gene', (46, 55))	('miR-185', 'Gene', '406961', (57, 64))
173136	29152114	qPCR was performed using TaqMan Fast Advanced Master Mix (Applied Biosystems) and TaqMan-Assays for KRT8 (Hs01595539_g1), RPL37A (Hs01102345_m1) and HPRT1 (Hs99999909_m1) (all Thermo Fisher Scientific, Waltham, MA, USA).	('Mix', 'Gene', '83881', (53, 56))	('RPL37A', 'Gene', (122, 128))	('Hs99999909_m1', 'Var', (156, 169))	('Hs01595539_g1', 'Var', (106, 119))	('KRT8', 'Gene', (100, 104))	('Mix', 'Gene', (53, 56))	('RPL37A', 'Gene', '6168', (122, 128))	('HPRT1', 'Gene', '3251', (149, 154))	('HPRT1', 'Gene', (149, 154))	('HPRT', 'molecular_function', 'GO:0004422', ('149', '153'))	('KRT8', 'Gene', '3856', (100, 104))	('Hs01102345_m1', 'Var', (130, 143))
173138	32807776	HIF-1alpha and HIF-2alpha differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice Mutational inactivation of VHL is the earliest genetic event in the majority of clear cell renal cell carcinomas (ccRCC), leading to accumulation of the HIF-1alpha and HIF-2alpha transcription factors.	('RCC', 'Disease', (242, 245))	('inflammation of clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (70, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (240, 245))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (206, 238))	('RCC', 'Disease', 'MESH:C538614', (242, 245))	('HIF-2alpha', 'Gene', '13819', (15, 25))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (217, 237))	('inflammation', 'biological_process', 'GO:0006954', ('70', '82'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (97, 117))	('HIF-1alpha', 'Gene', '15251', (279, 289))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (206, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('transcription', 'biological_process', 'GO:0006351', ('305', '318'))	('HIF-2alpha', 'Gene', '13819', (294, 304))	('carcinomas', 'Phenotype', 'HP:0030731', (228, 238))	('clear cell renal cell carcinomas', 'Disease', (206, 238))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (217, 238))	('Mutational inactivation', 'Var', (126, 149))	('inflammation of clear cell renal cell carcinoma', 'Disease', (70, 117))	('HIF-1alpha', 'Gene', '15251', (0, 10))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (206, 237))	('VHL', 'Gene', (153, 156))	('HIF-2alpha', 'Gene', (15, 25))	('HIF-1alpha', 'Gene', (279, 289))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (86, 117))	('tumour', 'Disease', (47, 53))	('HIF-2alpha', 'Gene', (294, 304))	('accumulation', 'PosReg', (259, 271))	('HIF-1alpha', 'Gene', (0, 10))
173139	32807776	While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1alpha as an inhibitor and HIF-2alpha as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed.	('aggressive tumour', 'Disease', (168, 185))	('RCC', 'Disease', (37, 40))	('aggressive tumour', 'Disease', 'MESH:D009369', (168, 185))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (35, 40))	('HIF-1alpha', 'Gene', (109, 119))	('HIF-2alpha', 'Var', (140, 150))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('tumour', 'Disease', 'MESH:D009369', (179, 185))	('tumour', 'Disease', (179, 185))	('human', 'Species', '9606', (70, 75))	('human', 'Species', '9606', (29, 34))	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('tumour', 'Disease', 'MESH:D009369', (213, 219))	('RCC', 'Disease', (78, 81))	('tumour', 'Disease', (213, 219))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('promoter', 'PosReg', (156, 164))
173140	32807776	Herein we show using an autochthonous ccRCC model that Hif1a is essential for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth.	('tumour initiation', 'Disease', 'MESH:D009369', (144, 161))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('deletion', 'Var', (109, 117))	('tumour initiation', 'Disease', (144, 161))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('RCC', 'Disease', (40, 43))	('tumour', 'Disease', (78, 84))	('growth', 'CPA', (166, 172))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('tumour', 'Disease', (144, 150))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('Hif2a', 'Gene', (103, 108))	('formation', 'biological_process', 'GO:0009058', ('85', '94'))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
173143	32807776	Single copy loss of HIF1A or high levels of HIF2A mRNA expression correlate with altered immune microenvironments in human ccRCC.	('mRNA expression', 'MPA', (50, 65))	('HIF1A', 'Gene', (20, 25))	('human', 'Species', '9606', (117, 122))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('HIF2A', 'Gene', (44, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('Single copy loss', 'Var', (0, 16))	('N', 'Chemical', 'MESH:D009584', (52, 53))
173144	32807776	These studies reveal an oncogenic role of HIF-1alpha in ccRCC initiation and suggest that alterations in the balance of HIF-1alpha and HIF-2alpha activities can affect different aspects of ccRCC biology and disease aggressiveness.	('aggressiveness', 'Disease', (215, 229))	('alterations', 'Var', (90, 101))	('rev', 'Gene', '19714', (14, 17))	('rev', 'Gene', (14, 17))	('RCC', 'Disease', (191, 194))	('aggressiveness', 'Phenotype', 'HP:0000718', (215, 229))	('RCC', 'Disease', 'MESH:C538614', (191, 194))	('ccRCC', 'Phenotype', 'HP:0006770', (189, 194))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('RCC', 'Disease', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('aggressiveness', 'Disease', 'MESH:D001523', (215, 229))	('affect', 'Reg', (161, 167))
173145	32807776	Genetic inactivation of VHL leads to stabilization of HIF-1alpha/HIF-2alpha and is associated with clear cell renal cell carcinoma (ccRCC) initiation and progression.	('Genetic inactivation', 'Var', (0, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (110, 130))	('stabilization', 'MPA', (37, 50))	('associated with', 'Reg', (83, 98))	('HIF-1alpha/HIF-2alpha', 'MPA', (54, 75))	('VHL', 'Gene', (24, 27))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (99, 130))	('ccRCC', 'Phenotype', 'HP:0006770', (132, 137))	('clear cell renal cell carcinoma (ccRCC) initiation', 'Disease', 'MESH:C538614', (99, 149))
173146	32807776	Using an autochthonous mouse model of ccRCC with Vhl deletion, here the authors show that HIF-1alpha is necessary for tumor formation, while HIF-2alpha deletion has only a moderate effect.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('formation', 'biological_process', 'GO:0009058', ('124', '133'))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('deletion', 'Var', (53, 61))	('RCC', 'Disease', (40, 43))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('tumor', 'Disease', (118, 123))	('mouse', 'Species', '10090', (23, 28))	('Vhl', 'Gene', (49, 52))
173149	32807776	Biallelic inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene is a truncal genetic event that arises in the majority of cases of ccRCC, demonstrating that loss of one or more of the various tumour suppressor functions of the pVHL protein isoforms is central to the earliest steps in the initiation of tumour formation.	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('protein', 'cellular_component', 'GO:0003675', ('245', '252'))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('tumour', 'Disease', (205, 211))	('RCC', 'Disease', (146, 149))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('arises', 'Reg', (109, 115))	('tumour', 'Disease', (54, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('formation', 'biological_process', 'GO:0009058', ('323', '332'))	('von Hippel-Lindau (VHL) tumour', 'Disease', 'MESH:D006623', (30, 60))	('tumour', 'Phenotype', 'HP:0002664', (316, 322))	('loss', 'Var', (170, 174))	('tumour', 'Disease', 'MESH:D009369', (316, 322))	('Biallelic', 'Var', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('tumour', 'Disease', (316, 322))
173150	32807776	Subsequent mutations or chromosomal copy number alterations in epigenetic regulatory genes (including PBRM1, BAP1, SETD2, and KDM5C), cell-cycle regulatory genes (including TP53, CDKN2A, and MYC) or PI3K pathway genes (including PIK3CA, PTEN, MTOR, and TSC1) arise recurrently in ccRCC and are believed to cooperate with VHL inactivation to promote the development and evolution of ccRCC tumours.	('SETD2', 'Gene', (115, 120))	('PTEN', 'Gene', (237, 241))	('mutations', 'Var', (11, 20))	('TSC1', 'Gene', '64930', (253, 257))	('KDM5C', 'Gene', (126, 131))	('RCC', 'Disease', (384, 387))	('ccRCC', 'Phenotype', 'HP:0006770', (382, 387))	('CDKN2A', 'Gene', '12578', (179, 185))	('TP53', 'Gene', (173, 177))	('ccRCC tumours', 'Disease', (382, 395))	('CDKN2A', 'Gene', (179, 185))	('MTOR', 'Gene', '56717', (243, 247))	('ccRCC', 'Phenotype', 'HP:0006770', (280, 285))	('RCC', 'Disease', (282, 285))	('TP53', 'Gene', '22059', (173, 177))	('PI3K', 'molecular_function', 'GO:0016303', ('199', '203'))	('MYC', 'Gene', (191, 194))	('PIK3CA', 'Gene', '18706', (229, 235))	('RCC', 'Disease', 'MESH:C538614', (384, 387))	('BAP1', 'Gene', (109, 113))	('promote', 'PosReg', (341, 348))	('PTEN', 'Gene', '19211', (237, 241))	('RCC', 'Disease', 'MESH:C538614', (282, 285))	('tumours', 'Phenotype', 'HP:0002664', (388, 395))	('SETD2', 'Gene', '235626', (115, 120))	('PBRM1', 'Gene', (102, 107))	('KDM5C', 'Gene', '20591', (126, 131))	('PBRM1', 'Gene', '66923', (102, 107))	('cell-cycle', 'biological_process', 'GO:0007049', ('134', '144'))	('inactivation', 'Var', (325, 337))	('tumour', 'Phenotype', 'HP:0002664', (388, 394))	('ccRCC tumours', 'Disease', 'MESH:D009369', (382, 395))	('epigenetic regulatory genes', 'Gene', (63, 90))	('MTOR', 'Gene', (243, 247))	('TSC1', 'Gene', (253, 257))	('BAP1', 'Gene', '104416', (109, 113))	('MYC', 'Gene', '17869', (191, 194))	('PIK3CA', 'Gene', (229, 235))
173151	32807776	Numerous mouse models have supported this notion of genetic cooperation by showing that renal epithelial cell-specific inactivation of different combinations of Vhl together with Pten, Tsc1, Pbrm1, Bap1, Trp53, Trp53/Rb1, Cdkn2a, or with Myc overexpression causes the formation of cystic and solid precursor lesions or ccRCC tumours.	('Cdkn2a', 'Gene', (222, 228))	('Pten', 'Gene', (179, 183))	('Pten', 'Gene', '19211', (179, 183))	('Myc', 'Gene', '17869', (238, 241))	('Pbrm1', 'Gene', (191, 196))	('ccRCC', 'Phenotype', 'HP:0006770', (319, 324))	('ccRCC tumours', 'Disease', (319, 332))	('Bap1', 'Gene', '104416', (198, 202))	('Tsc1', 'Gene', '64930', (185, 189))	('tumours', 'Phenotype', 'HP:0002664', (325, 332))	('Pbrm1', 'Gene', '66923', (191, 196))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('Vhl', 'Gene', (161, 164))	('Tsc1', 'Gene', (185, 189))	('Bap1', 'Gene', (198, 202))	('tumour', 'Phenotype', 'HP:0002664', (325, 331))	('inactivation', 'Var', (119, 131))	('formation', 'biological_process', 'GO:0009058', ('268', '277'))	('Cdkn2a', 'Gene', '12578', (222, 228))	('mouse', 'Species', '10090', (9, 14))	('causes', 'Reg', (257, 263))	('ccRCC tumours', 'Disease', 'MESH:D009369', (319, 332))	('Myc', 'Gene', (238, 241))
173153	32807776	Genetic inactivation of VHL causes the constitutive stabilisation of HIF-1alpha and HIF-2alpha, which induce gene expression programmes that play a central role in the pathogenesis of ccRCC by altering cellular metabolism, inducing angiogenesis, promoting epithelial-to-mesenchymal transition, invasion, and metastatic spread.	('Genetic inactivation', 'Var', (0, 20))	('gene expression', 'biological_process', 'GO:0010467', ('109', '124'))	('cellular metabolism', 'MPA', (202, 221))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('256', '292'))	('pathogenesis', 'biological_process', 'GO:0009405', ('168', '180'))	('inducing', 'PosReg', (223, 231))	('invasion', 'CPA', (294, 302))	('angiogenesis', 'biological_process', 'GO:0001525', ('232', '244'))	('metastatic spread', 'CPA', (308, 325))	('angiogenesis', 'CPA', (232, 244))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('RCC', 'Disease', (186, 189))	('epithelial-to-mesenchymal transition', 'CPA', (256, 292))	('altering', 'Reg', (193, 201))	('promoting', 'PosReg', (246, 255))	('VHL', 'Gene', (24, 27))	('ccRCC', 'Phenotype', 'HP:0006770', (184, 189))	('cellular metabolism', 'biological_process', 'GO:0044237', ('202', '221'))
173154	32807776	Numerous lines of evidence argue that HIF-2alpha plays a major pro-tumourigenic role in established human ccRCCs, whereas HIF-1alpha appears to function rather to inhibit aggressive tumour behaviour.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('inhibit', 'NegReg', (163, 170))	('RCC', 'Disease', (108, 111))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('tumour', 'Disease', (67, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('behaviour', 'biological_process', 'GO:0007610', ('189', '198'))	('human', 'Species', '9606', (100, 105))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('aggressive tumour', 'Disease', 'MESH:D009369', (171, 188))	('tumour', 'Disease', 'MESH:D009369', (67, 73))	('tumour', 'Disease', (182, 188))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('HIF-1alpha', 'Var', (122, 132))	('aggressive tumour', 'Disease', (171, 188))
173156	32807776	ccRCC tumours that express only HIF-2alpha have higher proliferation rates than those expressing HIF-1alpha and HIF-2alpha.	('HIF-2alpha', 'Var', (32, 42))	('ccRCC tumours', 'Disease', (0, 13))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('proliferation rates', 'CPA', (55, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('higher', 'PosReg', (48, 54))	('ccRCC tumours', 'Disease', 'MESH:D009369', (0, 13))
173157	32807776	ccRCC tumour cell lines frequently display intragenic deletions of HIF1A but express wild-type (WT) HIF-2alpha.	('ccRCC tumour', 'Disease', (0, 12))	('ccRCC tumour', 'Disease', 'MESH:D009369', (0, 12))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('deletions', 'Var', (54, 63))	('HIF1A', 'Gene', (67, 72))
173158	32807776	HIF-2alpha is necessary for the formation of ccRCC xenografts while knockdown of HIF-1alpha enhances xenograft tumour formation in cell lines that express both HIF-1alpha and HIF-2alpha.	('enhances', 'PosReg', (92, 100))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('formation', 'biological_process', 'GO:0009058', ('32', '41'))	('formation', 'biological_process', 'GO:0009058', ('118', '127'))	('HIF-1alpha', 'Gene', (81, 91))	('knockdown', 'Var', (68, 77))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('tumour', 'Disease', (111, 117))
173163	32807776	These studies have necessarily been unable to adequately assess the involvement of HIF-1alpha and HIF-2alpha throughout the entire process of tumour evolution beginning with VHL mutant cells in the context of a normal renal tubular epithelium.	('tumour', 'Disease', (142, 148))	('mutant', 'Var', (178, 184))	('VHL', 'Gene', (174, 177))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('tumour', 'Disease', 'MESH:D009369', (142, 148))
173164	32807776	To address the roles of HIF-1alpha and HIF-2alpha in the development of ccRCC we take advantage of an accurate mouse model of ccRCC based on tamoxifen-inducible renal epithelial cell-specific deletion (Ksp-CreERT2) of Vhl, Trp53, and Rb1.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('Trp53', 'Gene', (223, 228))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('mouse', 'Species', '10090', (111, 116))	('Vhl', 'Gene', (218, 221))	('RCC', 'Disease', (74, 77))	('deletion', 'Var', (192, 200))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('Rb1', 'Gene', (234, 237))	('tamoxifen', 'Chemical', 'MESH:D013629', (141, 150))
173167	32807776	We introduce floxed alleles of Hif1a and Hif2a (also known as Epas1) into this genetic background and show that HIF-1alpha is essential for tumour formation whereas deletion of HIF-2alpha has only moderate effects on tumour onset and growth rate but leads to increased intra-tumoural immune activation.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('tumour', 'Disease', 'MESH:D009369', (217, 223))	('tumour', 'Disease', 'MESH:D009369', (140, 146))	('increased', 'PosReg', (259, 268))	('HIF-2alpha', 'Gene', (177, 187))	('tumour', 'Disease', (140, 146))	('intra-tumoural', 'Disease', (269, 283))	('Epas1', 'Gene', '13819', (62, 67))	('tumour', 'Phenotype', 'HP:0002664', (275, 281))	('deletion', 'Var', (165, 173))	('tumour', 'Disease', (217, 223))	('tumour', 'Disease', 'MESH:D009369', (275, 281))	('formation', 'biological_process', 'GO:0009058', ('147', '156'))	('intra-tumoural', 'Disease', 'MESH:D009369', (269, 283))	('tumour', 'Disease', (275, 281))	('Epas1', 'Gene', (62, 67))
173175	32807776	These analyses showed that Vhl deletion accelerates tumour onset (Fig.	('accelerates', 'PosReg', (40, 51))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('deletion', 'Var', (31, 39))	('Vhl', 'Gene', (27, 30))	('tumour', 'Disease', (52, 58))
173178	32807776	Hif1a co-deletion completely abolished these tumour-promoting effects of Vhl deletion (Fig.	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('deletion', 'Var', (77, 85))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('abolished', 'NegReg', (29, 38))	('Hif1a', 'Gene', (0, 5))	('tumour', 'Disease', (45, 51))	('Vhl', 'Gene', (73, 76))
173180	32807776	In contrast, Hif2a deletion caused more moderate, yet statistically significant effects, partly delaying tumour onset (Fig.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('deletion', 'Var', (19, 27))	('tumour', 'Disease', (105, 111))	('delaying', 'NegReg', (96, 104))	('Hif2a', 'Gene', (13, 18))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
173184	32807776	These data indicate that HIF-1alpha is very important for the efficient evolution and growth of Vhl mutant ccRCCs, while HIF-2alpha is only partly required and many tumours still develop in the Vhl/Trp53/Rb1/Hif2a quadruple mutant background.	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('mutant', 'Var', (100, 106))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('tumours', 'Phenotype', 'HP:0002664', (165, 172))	('tumours', 'Disease', 'MESH:D009369', (165, 172))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('Vhl', 'Gene', (96, 99))	('tumours', 'Disease', (165, 172))
173185	32807776	Since Hif1a deletion provided such a strong phenotypic rescue we next investigated whether the Hif1a and Hif2a genes are indeed deleted in the relevant tumours to exclude that the tumours might be escapers in which Cre activity failed to correctly recombine the floxed Hif1a or Hif2a alleles.	('deletion', 'Var', (12, 20))	('tumours', 'Disease', 'MESH:D009369', (180, 187))	('tumours', 'Disease', 'MESH:D009369', (152, 159))	('tumours', 'Disease', (180, 187))	('tumours', 'Disease', (152, 159))	('Hif2a', 'Gene', (105, 110))	('tumours', 'Phenotype', 'HP:0002664', (180, 187))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('Hif1a', 'Gene', (95, 100))	('tumours', 'Phenotype', 'HP:0002664', (152, 159))	('Hif1a', 'Gene', (6, 11))
173187	32807776	To compare the extent of Cre-mediated deletion of Vhl, Trp53, Rb1, Hif1a, and Hif2a we conducted quantitative real-time PCR using primers to specifically amplify floxed exons of each gene as well as non-floxed exons of the Vhl, Trp53, and Hif2a genes (which served as normalisation controls) from genomic DNA from cortex samples from non-Cre mice (WT cortex), as well as tumours from Vhl / Trp53 / Rb1 / , Vhl / Trp53 / Rb1 / Hif1a / , and Vhl / Trp53 / Rb1 / Hif2a /  mice.	('mice', 'Species', '10090', (469, 473))	('mice', 'Species', '10090', (342, 346))	('DNA', 'cellular_component', 'GO:0005574', ('305', '308'))	('tumour', 'Phenotype', 'HP:0002664', (371, 377))	('tumours', 'Phenotype', 'HP:0002664', (371, 378))	('tumours', 'Disease', 'MESH:D009369', (371, 378))	('deletion', 'Var', (38, 46))	('tumours', 'Disease', (371, 378))	('N', 'Chemical', 'MESH:D009584', (306, 307))
173192	32807776	This data also revealed the specific reduction in the relative numbers of sequencing reads in the floxed exons compared to adjacent non-floxed exons.	('floxed', 'Var', (98, 104))	('sequencing reads', 'MPA', (74, 90))	('reduction', 'NegReg', (37, 46))	('rev', 'Gene', '19714', (15, 18))	('rev', 'Gene', (15, 18))
173193	32807776	This was true for all floxed genes in the mouse genotypes that contain the floxed alleles but not in those that do not (Supplementary Fig.	('floxed', 'Gene', (22, 28))	('floxed', 'Var', (75, 81))	('mouse', 'Species', '10090', (42, 47))
173194	32807776	In the case of Vhl, the deletion of the first exon including the first intronic mRNA splice site leads to sequencing read-through into the intron.	('sequencing read-through into the intron', 'MPA', (106, 145))	('N', 'Chemical', 'MESH:D009584', (82, 83))	('Vhl', 'Gene', (15, 18))	('deletion', 'Var', (24, 32))
173195	32807776	Since the intronic sequencing reads do not start at the same position in different tumour samples, it is difficult to assess the effect of this read-through on potential translation of the resulting mRNA transcript, however western blotting of primary cells derived from Vhlfl/fl mice demonstrated that Cre-mediated recombination results in complete loss of the pVHL protein isoforms and Supplementary Fig.	('tumour', 'Disease', (83, 89))	('N', 'Chemical', 'MESH:D009584', (201, 202))	('Cre-mediated recombination', 'Var', (303, 329))	('translation', 'biological_process', 'GO:0006412', ('170', '181'))	('pVHL protein', 'Protein', (362, 374))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('mice', 'Species', '10090', (280, 284))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('loss', 'NegReg', (350, 354))	('protein', 'cellular_component', 'GO:0003675', ('367', '374'))
173199	32807776	3c) and the protein product of this gene, CA9, showed membrane staining in tumours from Vhl / Trp53 / Rb1 /  and Vhl / Trp53 / Rb1 / Hif2a /  mice but not in tumours from Vhl / Trp53 / Rb1 / Hif1a /  mice (Fig.	('protein', 'cellular_component', 'GO:0003675', ('12', '19'))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('Vhl / Trp53 / Rb1 /', 'Var', (88, 107))	('tumours', 'Disease', 'MESH:D009369', (75, 82))	('tumours', 'Phenotype', 'HP:0002664', (158, 165))	('CA9', 'Gene', (42, 45))	('tumours', 'Disease', (75, 82))	('tumours', 'Disease', 'MESH:D009369', (158, 165))	('mice', 'Species', '10090', (142, 146))	('tumours', 'Disease', (158, 165))	('mice', 'Species', '10090', (200, 204))	('CA9', 'Gene', '230099', (42, 45))	('membrane', 'cellular_component', 'GO:0016020', ('54', '62'))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('Vhl / Trp53 / Rb1 / Hif2a /', 'Var', (113, 140))
173200	32807776	Nuclear HIF-2alpha staining was present in tumours from Vhl / Trp53 / Rb1 /  and Vhl / Trp53 / Rb1 / Hif1a /  mice but absent in all tumours from Vhl / Trp53 / Rb1 / Hif2a /  mice.	('mice', 'Species', '10090', (175, 179))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumours', 'Phenotype', 'HP:0002664', (43, 50))	('tumours', 'Phenotype', 'HP:0002664', (133, 140))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('mice', 'Species', '10090', (110, 114))	('tumours', 'Disease', 'MESH:D009369', (43, 50))	('tumours', 'Disease', (43, 50))	('Vhl / Trp53 / Rb1 / Hif1a /', 'Var', (81, 108))	('tumours', 'Disease', (133, 140))	('HIF-2alpha', 'Protein', (8, 18))	('tumours', 'Disease', 'MESH:D009369', (133, 140))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))
173202	32807776	Histomorphological analyses and comparisons were performed for the different genetic backgrounds on a total of 26 (Vhl / Trp53 / Rb1 / ), 16 (Vhl / Trp53 / Rb1 / Hif1a / ), and 21 (Vhl / Trp53 / Rb1 / Hif2a / ) H&E stained tumours.	('H&E', 'Chemical', 'MESH:D006371', (211, 214))	('tumours', 'Disease', (223, 230))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('Vhl', 'Var', (142, 145))	('tumours', 'Phenotype', 'HP:0002664', (223, 230))	('tumours', 'Disease', 'MESH:D009369', (223, 230))
173204	32807776	Since tumour grade up to grade 3 is classified mostly based on nucleolus size, these data hint that loss of HIF-1alpha or HIF-2alpha may modify processes such as transcription of ribosomal DNA genes that affect the nucleolus.	('loss', 'Var', (100, 104))	('N', 'Chemical', 'MESH:D009584', (190, 191))	('HIF-1alpha', 'Gene', (108, 118))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('transcription', 'biological_process', 'GO:0006351', ('162', '175'))	('DNA', 'cellular_component', 'GO:0005574', ('189', '192'))	('tumour', 'Disease', 'MESH:D009369', (6, 12))	('nucleolus', 'cellular_component', 'GO:0005730', ('63', '72'))	('transcription', 'MPA', (162, 175))	('modify', 'Reg', (137, 143))	('ribosomal DNA genes', 'Gene', (179, 198))	('HIF-2alpha', 'Gene', (122, 132))	('nucleolus', 'cellular_component', 'GO:0005730', ('215', '224'))	('tumour', 'Disease', (6, 12))
173209	32807776	This observation is consistent with our previous findings that HIF-1alpha is necessary for the clear cell phenotype of normal renal epithelial cells following Vhl deletion but also implicates HIF-2alpha in the clear cell phenotype in this tumour model.	('deletion', 'Var', (163, 171))	('rev', 'Gene', (41, 44))	('implicates', 'Reg', (181, 191))	('tumour', 'Disease', 'MESH:D009369', (239, 245))	('tumour', 'Disease', (239, 245))	('tumour', 'Phenotype', 'HP:0002664', (239, 245))	('rev', 'Gene', '19714', (41, 44))	('Vhl', 'Gene', (159, 162))
173210	32807776	Intra-tumoural histomorphological heterogeneity was observed mainly in Vhl / Trp53 / Rb1 /  (23%) and Vhl / Trp53 / Rb1 / Hif2a /  tumours (28%) (Supplementary Fig.	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('tumour', 'Disease', (131, 137))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))	('tumours', 'Disease', (131, 138))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('tumour', 'Disease', 'MESH:D009369', (6, 12))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('tumour', 'Disease', (6, 12))	('Vhl / Trp53 / Rb1 /', 'Var', (71, 90))	('Vhl / Trp53 / Rb1 / Hif2a /', 'Var', (102, 129))
173217	32807776	A subset of Vhl / Trp53 / Rb1 /  (15%), Vhl / Trp53 / Rb1 / Hif1a /  (25%), and Vhl / Trp53 / Rb1 / Hif2a /  tumours (19%) exhibited cystic features (Supplementary Fig.	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('tumours', 'Disease', 'MESH:D009369', (109, 116))	('Vhl / Trp53 / Rb1 / Hif2a /', 'Var', (80, 107))	('tumours', 'Disease', (109, 116))	('cystic features', 'CPA', (133, 148))	('Vhl / Trp53 / Rb1 /', 'Var', (12, 31))	('exhibited', 'Reg', (123, 132))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
173220	32807776	Since our genetic experiments demonstrated that HIF-1alpha is necessary for the efficient initiation of ccRCC formation we wondered firstly if HIF-1alpha is generally required for cellular proliferation following loss of Vhl and secondly whether established Vhl / Trp53 / Rb1 /  tumours remain dependent on HIF-1alpha or whether they might lose this dependency during tumour evolution.	('tumour', 'Disease', (368, 374))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('Vhl', 'Gene', (221, 224))	('tumour', 'Disease', 'MESH:D009369', (279, 285))	('formation', 'biological_process', 'GO:0009058', ('110', '119'))	('tumour', 'Phenotype', 'HP:0002664', (279, 285))	('tumours', 'Phenotype', 'HP:0002664', (279, 286))	('tumour', 'Phenotype', 'HP:0002664', (368, 374))	('tumour', 'Disease', 'MESH:D009369', (368, 374))	('RCC', 'Disease', (106, 109))	('tumours', 'Disease', 'MESH:D009369', (279, 286))	('tumour', 'Disease', (279, 285))	('tumours', 'Disease', (279, 286))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))	('loss', 'Var', (213, 217))
173221	32807776	To mimic the earliest events in ccRCC formation in a genetically tractable cellular system that allows long-term proliferation assays, we derived mouse embryo fibroblasts (MEFs) from wild type, Vhlfl/fl, Vhlfl/flHif1afl/fl, Vhlfl/flHif2afl/fl, and Vhlfl/flHif1afl/flHif2afl/fl embryos, infected them with Adeno-GFP as control or Adeno-Cre-GFP and confirmed the deletion of the floxed genes by real-time PCR and western blotting (Supplementary Fig.	('deletion', 'Var', (361, 369))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (32, 37))	('mouse', 'Species', '10090', (146, 151))	('infected', 'Disease', 'MESH:D007239', (286, 294))	('formation', 'biological_process', 'GO:0009058', ('38', '47'))	('MEFs', 'CellLine', 'CVCL:9115', (172, 176))	('Vhlfl/flHif1afl/flHif2afl/fl', 'Var', (248, 276))	('infected', 'Disease', (286, 294))	('floxed genes', 'Gene', (377, 389))	('RCC', 'Disease', (34, 37))
173222	32807776	Long-term proliferation assays confirmed previous findings that loss of Vhl in MEFs induces an early loss of proliferative capacity, however, in contrast to the initial claim that this senescence phenotype is independent of HIF-alpha activity, our results clearly demonstrate the dependency on Hif1a but not on Hif2a (Fig.	('rev', 'Gene', '19714', (42, 45))	('Vhl', 'Gene', (72, 75))	('rev', 'Gene', (42, 45))	('loss', 'NegReg', (101, 105))	('proliferative capacity', 'CPA', (109, 131))	('senescence', 'biological_process', 'GO:0010149', ('185', '195'))	('MEFs', 'CellLine', 'CVCL:9115', (79, 83))	('loss', 'Var', (64, 68))
173223	32807776	This proliferative rescue due to Hif1a deletion contrasts with the suppression of ccRCC initiation by Hif1a deletion in vivo.	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('deletion', 'Var', (39, 47))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('Hif1a', 'Gene', (33, 38))	('RCC', 'Disease', (84, 87))
173229	32807776	5e) as well as knocked down Hif1a with two independent shRNAs (Supplementary Fig.	('knocked down', 'Var', (15, 27))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('Hif1a', 'Gene', (28, 33))
173230	32807776	We confirmed the efficient functional re-introduction of pVHL30 and knockdown of Hif1a mRNA in reducing HIF-1alpha protein (Supplementary Fig.	('pVHL30', 'Gene', (57, 63))	('N', 'Chemical', 'MESH:D009584', (89, 90))	('knockdown', 'Var', (68, 77))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('Hif1a', 'Gene', (81, 86))	('reducing', 'NegReg', (95, 103))	('HIF-1alpha protein', 'MPA', (104, 122))
173231	32807776	5g) and showed that the knockdowns reduced the abundance of the PDK1 and LDH-A proteins, that are encoded by the HIF-1alpha transcriptional target genes Pdk1 and Ldha, equivalently to pVHL30 re-introduction (Supplementary Fig.	('proteins', 'Protein', (79, 87))	('Pdk1', 'molecular_function', 'GO:0004740', ('153', '157'))	('PDK1', 'Gene', (64, 68))	('reduced', 'NegReg', (35, 42))	('LDH-A', 'Gene', '16828', (73, 78))	('Pdk1', 'Gene', (153, 157))	('Ldha', 'Gene', '16828', (162, 166))	('LDH-A', 'Gene', (73, 78))	('knockdowns', 'Var', (24, 34))	('abundance', 'MPA', (47, 56))	('Ldha', 'Gene', (162, 166))	('Pdk1', 'Gene', '228026', (153, 157))	('PDK1', 'molecular_function', 'GO:0004740', ('64', '68'))	('PDK1', 'Gene', '228026', (64, 68))
173234	32807776	pVHL re-introduction into 2020 cells significantly delayed tumour growth (Fig.	('pVHL', 'Gene', (0, 4))	('tumour growth', 'Disease', (59, 72))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumour growth', 'Disease', 'MESH:D006130', (59, 72))	('delayed', 'NegReg', (51, 58))	('re-introduction', 'Var', (5, 20))
173235	32807776	Collectively, these studies show that HIF-1alpha in fact antagonises cellular proliferation of normal mouse cells lacking Vhl and is dispensable for proliferation and allograft tumour formation of a mouse ccRCC cell line, highlighting the specificity of the requirement for HIF-1alpha for tumour onset in the autochthonous setting.	('cellular proliferation', 'CPA', (69, 91))	('tumour', 'Disease', (289, 295))	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('mouse', 'Species', '10090', (199, 204))	('ccRCC', 'Phenotype', 'HP:0006770', (205, 210))	('tumour', 'Disease', (177, 183))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('RCC', 'Disease', (207, 210))	('tumour', 'Phenotype', 'HP:0002664', (289, 295))	('lacking', 'NegReg', (114, 121))	('tumour', 'Disease', 'MESH:D009369', (289, 295))	('Vhl', 'Gene', (122, 125))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('antagonises', 'NegReg', (57, 68))	('formation', 'biological_process', 'GO:0009058', ('184', '193'))	('mouse', 'Species', '10090', (102, 107))	('HIF-1alpha', 'Var', (38, 48))
173237	32807776	To gain further insight into in vivo relevant functions of HIF-1alpha and HIF-2alpha we compared the molecular features of tumours that developed in the presence of both HIF-1alpha and HIF-2alpha to those that were genetically restricted to develop in the absence of either HIF-1alpha or HIF-2alpha.	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('tumours', 'Disease', 'MESH:D009369', (123, 130))	('presence', 'Var', (153, 161))	('tumours', 'Disease', (123, 130))	('HIF-2alpha', 'Gene', (185, 195))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
173242	32807776	These analyses are consistent with the deletion of Vhl, Trp53, and Rb1 in all three tumour genotypes inducing large transcriptional changes, with more limited and specific contributions of HIF-1alpha and HIF-2alpha to the regulation of specific sets of genes.	('tumour', 'Disease', (84, 90))	('Rb1', 'Gene', (67, 70))	('transcriptional changes', 'MPA', (116, 139))	('Trp53', 'Gene', (56, 61))	('deletion', 'Var', (39, 47))	('inducing', 'Reg', (101, 109))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('Vhl', 'Gene', (51, 54))	('tumour', 'Disease', 'MESH:D009369', (84, 90))	('regulation', 'biological_process', 'GO:0065007', ('222', '232'))
173247	32807776	Genes that were expressed at low levels in Vhl / Trp53 / Rb1 / Hif2a /  tumours compared to the other two tumour genotypes included those involved in different DNA repair processes (e.g.	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('DNA repair', 'biological_process', 'GO:0006281', ('160', '170'))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('N', 'Chemical', 'MESH:D009584', (161, 162))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('DNA', 'cellular_component', 'GO:0005574', ('160', '163'))	('tumour', 'Disease', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('tumour', 'Disease', (72, 78))	('tumours', 'Disease', (72, 79))	('Vhl', 'Var', (43, 46))
173256	32807776	7e, were expressed at significantly lower levels (fold change < -1.7, P < 0.05) in Vhl / Trp53 / Rb1 / Hif2a /  tumours than in Vhl / Trp53 / Rb1 /  tumours.	('lower', 'NegReg', (36, 41))	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('tumours', 'Disease', (149, 156))	('tumours', 'Disease', 'MESH:D009369', (112, 119))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('tumours', 'Disease', (112, 119))	('Vhl / Trp53 / Rb1 /', 'Var', (83, 102))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('tumours', 'Phenotype', 'HP:0002664', (149, 156))	('tumours', 'Disease', 'MESH:D009369', (149, 156))
173259	32807776	We speculate that it is likely that these genes are not dependent on HIF-2alpha in the mouse model due to the fact that the deletion of Rb1 and Trp53 already strongly affects these classes of genes.	('Trp53', 'Gene', (144, 149))	('mouse', 'Species', '10090', (87, 92))	('affects', 'Reg', (167, 174))	('Rb1', 'Gene', (136, 139))	('deletion', 'Var', (124, 132))
173262	32807776	that HIF-1alpha deficiency does not strongly alter the inflammatory tumour environment in Vhl / Trp53 / Rb1 /  tumours) and that all of these signatures are further highly statistically significantly upregulated in Vhl / Trp53 / Rb1 / Hif2a /  tumours in comparison to Vhl / Trp53 / Rb1 /  tumours.	('tumours', 'Phenotype', 'HP:0002664', (290, 297))	('tumours', 'Disease', 'MESH:D009369', (290, 297))	('tumour', 'Phenotype', 'HP:0002664', (244, 250))	('Vhl / Trp53 / Rb1 / Hif2a /', 'Var', (215, 242))	('tumour', 'Disease', 'MESH:D009369', (244, 250))	('tumour', 'Disease', (244, 250))	('tumour', 'Phenotype', 'HP:0002664', (290, 296))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('HIF-1alpha deficiency', 'Disease', (5, 26))	('tumour', 'Disease', 'MESH:D009369', (290, 296))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('tumour', 'Disease', (290, 296))	('tumour', 'Disease', (68, 74))	('upregulated', 'PosReg', (200, 211))	('tumours', 'Disease', (111, 118))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('tumour', 'Disease', (111, 117))	('tumours', 'Phenotype', 'HP:0002664', (111, 118))	('tumours', 'Disease', 'MESH:D009369', (111, 118))	('tumours', 'Disease', (244, 251))	('HIF-1alpha deficiency', 'Disease', 'MESH:D007153', (5, 26))	('tumours', 'Disease', (290, 297))	('tumours', 'Phenotype', 'HP:0002664', (244, 251))	('tumours', 'Disease', 'MESH:D009369', (244, 251))
173276	32807776	ROAST analyses as well as gene set enrichment analyses of the lists of proteins that are differentially expressed between Vhl / Trp53 / Rb1 / Hif1a /  and Vhl / Trp53 / Rb1 /  tumours (Fig.	('tumours', 'Disease', 'MESH:D009369', (176, 183))	('tumours', 'Disease', (176, 183))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('Vhl / Trp53 / Rb1 /', 'Var', (122, 141))	('tumours', 'Phenotype', 'HP:0002664', (176, 183))
173283	32807776	5c) in Vhl / Trp53 / Rb1 / Hif2a /  tumours than in the tumours of the other genotypes.	('tumours', 'Disease', 'MESH:D009369', (56, 63))	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('tumours', 'Disease', (56, 63))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('Vhl', 'Var', (7, 10))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumours', 'Disease', (36, 43))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))
173285	32807776	However, tumour cells in Vhl / Trp53 / Rb1 / Hif2a /  tumours were more frequently positive than the other genotypes (Fig.	('tumour', 'Disease', (9, 15))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('Vhl / Trp53 / Rb1 / Hif2a /', 'Var', (25, 52))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('tumour', 'Disease', (54, 60))	('tumours', 'Disease', (54, 61))	('positive', 'Reg', (83, 91))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('tumour', 'Disease', 'MESH:D009369', (9, 15))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))
173286	32807776	Since MHC class II expression is upregulated by interferon-gamma signalling, these results are consistent with the fact that interferon signalling terms were upregulated in Vhl / Trp53 / Rb1 / Hif2a /  tumours in our transcriptomic and proteomic analyses.	('upregulated', 'PosReg', (33, 44))	('interferon signalling', 'MPA', (125, 146))	('expression', 'MPA', (19, 29))	('signalling', 'biological_process', 'GO:0023052', ('136', '146'))	('signalling', 'biological_process', 'GO:0023052', ('65', '75'))	('upregulated', 'PosReg', (158, 169))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('48', '64'))	('tumours', 'Phenotype', 'HP:0002664', (202, 209))	('Vhl / Trp53 / Rb1 /', 'Var', (173, 192))	('interferon-gamma', 'Gene', '15978', (48, 64))	('tumours', 'Disease', 'MESH:D009369', (202, 209))	('tumours', 'Disease', (202, 209))	('MHC class II', 'Gene', (6, 18))	('interferon-gamma', 'Gene', (48, 64))
173309	32807776	Consistent with HIF-2alpha deficient tumours showing the highest GAGE mRNA signatures of T-cell inflammation, Vhl / Trp53 / Rb1 / Hif2a /  tumours displayed increased densities of CD3 (Fig.	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('HIF-2alpha deficient tumours', 'Disease', (16, 44))	('Vhl /', 'Var', (110, 115))	('tumours', 'Disease', (139, 146))	('tumours', 'Disease', 'MESH:D009369', (37, 44))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('inflammation', 'biological_process', 'GO:0006954', ('96', '108'))	('CD3', 'Gene', '12501', (180, 183))	('tumours', 'Phenotype', 'HP:0002664', (139, 146))	('tumours', 'Disease', 'MESH:D009369', (139, 146))	('HIF-2alpha deficient tumours', 'Disease', 'MESH:D009369', (16, 44))	('inflammation', 'Disease', 'MESH:D007249', (96, 108))	('densities', 'CPA', (167, 176))	('N', 'Chemical', 'MESH:D009584', (72, 73))	('inflammation', 'Disease', (96, 108))	('tumours', 'Disease', (37, 44))	('CD3', 'Gene', (180, 183))	('increased', 'PosReg', (157, 166))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))
173312	32807776	6d) positive T cells compared to normal tissue, whereas only CD8 positive T-cell densities were significantly increased in Vhl / Trp53 / Rb1 /  and Vhl / Trp53 / Rb1 / Hif1a /  tumours compared to the respective normal tissues.	('tumours', 'Disease', 'MESH:D009369', (177, 184))	('tumours', 'Disease', (177, 184))	('CD8', 'Gene', (61, 64))	('increased', 'PosReg', (110, 119))	('Vhl / Trp53 / Rb1 /', 'Var', (123, 142))	('CD8', 'Gene', '925', (61, 64))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('tumours', 'Phenotype', 'HP:0002664', (177, 184))
173313	32807776	Notably, both Vhl / Trp53 / Rb1 / Hif1a /  and Vhl / Trp53 / Rb1 / Hif2a /  tumours exhibited higher densities of CD8 positive T cells than Vhl / Trp53 / Rb1 /  tumours, in line with the Bindea et al.	('tumours', 'Disease', 'MESH:D009369', (76, 83))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('tumours', 'Disease', (76, 83))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('tumours', 'Phenotype', 'HP:0002664', (161, 168))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('tumours', 'Disease', 'MESH:D009369', (161, 168))	('Vhl / Trp53 / Rb1 / Hif2a /', 'Var', (47, 74))	('CD8', 'Gene', (114, 117))	('CD8', 'Gene', '925', (114, 117))	('tumours', 'Disease', (161, 168))	('higher', 'PosReg', (94, 100))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))
173317	32807776	6f) revealed that all tumours showed increased T-cell activation compared to normal tissue, and that Vhl / Trp53 / Rb1 / Hif2a /  tumours showed higher levels of T-cell activation than Vhl / Trp53 / Rb1 /  or Vhl / Trp53 / Rb1 / Hif1a /  tumours, consistent with our conclusions from the GAGE analyses.	('T-cell', 'CPA', (162, 168))	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('tumours', 'Disease', 'MESH:D009369', (130, 137))	('increased', 'PosReg', (37, 46))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('tumours', 'Disease', (238, 245))	('T-cell', 'CPA', (47, 53))	('tumours', 'Phenotype', 'HP:0002664', (238, 245))	('rev', 'Gene', '19714', (4, 7))	('tumours', 'Disease', 'MESH:D009369', (238, 245))	('tumours', 'Disease', (22, 29))	('tumour', 'Phenotype', 'HP:0002664', (238, 244))	('Vhl / Trp53 / Rb1 / Hif2a /', 'Var', (101, 128))	('higher', 'PosReg', (145, 151))	('T-cell activation', 'biological_process', 'GO:0042110', ('47', '64'))	('rev', 'Gene', (4, 7))	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('T-cell activation', 'biological_process', 'GO:0042110', ('162', '179'))	('tumours', 'Disease', 'MESH:D009369', (22, 29))	('tumours', 'Disease', (130, 137))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))
173319	32807776	B220 staining revealed increased B cell density in all tumour genotypes compared to normal tissue, and higher densities in Vhl / Trp53 / Rb1 / Hif1a /  tumours than in Vhl / Trp53 / Rb1 /  or Vhl / Trp53 / Rb1 / Hif2a /  tumours (Fig.	('tumour', 'Disease', (55, 61))	('tumour', 'Disease', (221, 227))	('Vhl / Trp53 / Rb1 / Hif1a /', 'Var', (123, 150))	('rev', 'Gene', '19714', (14, 17))	('tumours', 'Disease', (152, 159))	('B220', 'Gene', '19264', (0, 4))	('tumours', 'Phenotype', 'HP:0002664', (152, 159))	('tumours', 'Disease', 'MESH:D009369', (152, 159))	('rev', 'Gene', (14, 17))	('tumours', 'Disease', (221, 228))	('B cell density', 'CPA', (33, 47))	('B220', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('tumours', 'Phenotype', 'HP:0002664', (221, 228))	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('tumours', 'Disease', 'MESH:D009369', (221, 228))	('tumour', 'Disease', (152, 158))	('densities', 'CPA', (110, 119))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Phenotype', 'HP:0002664', (221, 227))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('increased', 'PosReg', (23, 32))	('higher', 'PosReg', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (221, 227))
173326	32807776	We previously demonstrated that Vhl / Trp53 / Rb1 /  tumours show upregulation of numerous cytokines in comparison to WT cortex, however analyses of the new dataset did not reveal any cytokines that were specifically altered by the absence of HIF-1alpha or HIF-2alpha (Supplementary Fig.	('altered', 'Reg', (217, 224))	('rev', 'Gene', (4, 7))	('upregulation', 'PosReg', (66, 78))	('Vhl / Trp53 / Rb1', 'Gene', (32, 49))	('absence', 'Var', (232, 239))	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('rev', 'Gene', '19714', (173, 176))	('tumours', 'Disease', (53, 60))	('rev', 'Gene', (173, 176))	('cytokines', 'MPA', (91, 100))	('HIF-2alpha', 'Var', (257, 267))	('HIF-1alpha', 'Protein', (243, 253))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))	('rev', 'Gene', '19714', (4, 7))
173329	32807776	12c, d), arguing against a direct, soluble factor-mediated, VHL- or HIF-alpha-dependent cross-talk between ccRCC and T cells as being the mechanism that underlies the altered immune microenvironment in the Vhl / Trp53 / Rb1 / Hif1a /  and Vhl / Trp53 / Rb1 / Hif2a /  tumours.	('tumours', 'Disease', (268, 275))	('Vhl', 'Gene', (239, 242))	('Vhl / Trp53 / Rb1 /', 'Var', (206, 225))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('soluble', 'cellular_component', 'GO:0005625', ('35', '42'))	('RCC', 'Disease', (109, 112))	('tumour', 'Phenotype', 'HP:0002664', (268, 274))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('tumours', 'Phenotype', 'HP:0002664', (268, 275))	('tumours', 'Disease', 'MESH:D009369', (268, 275))
173330	32807776	To investigate whether genetic alterations in HIF1A or HIF2A might influence immune cell infiltration in human ccRCC, we analysed data from the TCGA KIRC study (Firehose-legacy dataset) using cBioPortal.	('immune cell infiltration', 'CPA', (77, 101))	('influence', 'Reg', (67, 76))	('genetic alterations', 'Var', (23, 42))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('HIF1A', 'Gene', (46, 51))	('human', 'Species', '9606', (105, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('HIF2A', 'Gene', (55, 60))
173333	32807776	ccRCC tumours that exhibit mono- or bi-allelic loss of HIF1A (collectively HIF1A loss) show worse overall survival (Fig.	('worse', 'NegReg', (92, 97))	('ccRCC tumours', 'Disease', (0, 13))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('bi-allelic', 'Var', (36, 46))	('loss', 'NegReg', (47, 51))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('HIF1A', 'Gene', (55, 60))	('ccRCC tumours', 'Disease', 'MESH:D009369', (0, 13))	('overall', 'MPA', (98, 105))
173334	32807776	13c) than unaffected tumours, whereas there are no overall or progression-free survival differences between tumours with a copy number gain of HIF2A and unaffected tumours (Fig.	('tumours', 'Disease', (108, 115))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('tumours', 'Phenotype', 'HP:0002664', (164, 171))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumours', 'Phenotype', 'HP:0002664', (21, 28))	('tumours', 'Disease', 'MESH:D009369', (21, 28))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('tumours', 'Disease', 'MESH:D009369', (164, 171))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('tumours', 'Disease', (164, 171))	('copy number gain', 'Var', (123, 139))	('HIF2A', 'Gene', (143, 148))	('tumours', 'Disease', 'MESH:D009369', (108, 115))	('tumours', 'Disease', (21, 28))
173338	32807776	However, BAP1 mutation status alone did not significantly affect survival (Supplementary Fig.	('BAP1', 'Gene', '104416', (9, 13))	('mutation', 'Var', (14, 22))	('BAP1', 'Gene', (9, 13))
173339	32807776	13g) in this cohort and removal of all BAP1 mutant tumours from the cohort did not alter the correlation of HIF1A loss with poor prognosis (Supplementary Fig.	('loss', 'NegReg', (114, 118))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('BAP1', 'Gene', '104416', (39, 43))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('tumours', 'Disease', 'MESH:D009369', (51, 58))	('HIF1A', 'Gene', (108, 113))	('mutant', 'Var', (44, 50))	('tumours', 'Disease', (51, 58))	('BAP1', 'Gene', (39, 43))
173340	32807776	The conclusion that BAP1 mutation status is not a relevant co-variant that affects survival outcome in the HIF1A loss cohort was also demonstrated by COX univariate (HR 1.839, 95% CI 1.332-2.539, P = 0.00021) and multivariate proportional hazards analyses (HR 1.776, 95% CI 1.274-2.474, P = 0.00069).	('affects', 'Reg', (75, 82))	('BAP1', 'Gene', (20, 24))	('mutation', 'Var', (25, 33))	('HIF1A', 'Gene', (107, 112))	('loss', 'NegReg', (113, 117))	('BAP1', 'Gene', '104416', (20, 24))
173352	32807776	In contrast, high HIF2A mRNA expressing tumours displayed downregulation of scores for interferon-gamma and for APM2 (measuring MHC class II antigen presentation), consistent with the upregulation of these features in mouse ccRCC tumours lacking HIF-2alpha.	('APM2', 'MPA', (112, 116))	('upregulation', 'PosReg', (184, 196))	('ccRCC tumours', 'Disease', (224, 237))	('scores', 'MPA', (76, 82))	('high', 'Var', (13, 17))	('tumours', 'Disease', (40, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (224, 229))	('HIF2A', 'Gene', (18, 23))	('tumours', 'Disease', (230, 237))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))	('tumours', 'Disease', 'MESH:D009369', (40, 47))	('N', 'Chemical', 'MESH:D009584', (26, 27))	('tumours', 'Phenotype', 'HP:0002664', (230, 237))	('downregulation', 'NegReg', (58, 72))	('tumours', 'Disease', 'MESH:D009369', (230, 237))	('ccRCC tumours', 'Disease', 'MESH:D009369', (224, 237))	('antigen presentation', 'biological_process', 'GO:0019882', ('141', '161'))	('mouse', 'Species', '10090', (218, 223))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('interferon-gamma', 'Gene', '15978', (87, 103))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('87', '103'))	('interferon-gamma', 'Gene', (87, 103))
173358	32807776	Finally, it is also noteworthy that HIF1A copy loss and HIF2A mRNA high tumours showed opposite effects on signatures for pericytes, endothelial cells and angiogenesis, implying that both HIF-1alpha and HIF-2alpha may act as positive factors that promote blood vessel formation in ccRCC tumours.	('ccRCC', 'Phenotype', 'HP:0006770', (281, 286))	('angiogenesis', 'biological_process', 'GO:0001525', ('155', '167'))	('ccRCC tumours', 'Disease', (281, 294))	('promote', 'PosReg', (247, 254))	('tumours', 'Disease', (72, 79))	('copy loss', 'Var', (42, 51))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('tumours', 'Disease', (287, 294))	('tumour', 'Phenotype', 'HP:0002664', (287, 293))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('tumours', 'Phenotype', 'HP:0002664', (287, 294))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumours', 'Disease', 'MESH:D009369', (287, 294))	('ccRCC tumours', 'Disease', 'MESH:D009369', (281, 294))	('HIF2A', 'Gene', (56, 61))	('formation', 'biological_process', 'GO:0009058', ('268', '277'))	('HIF1A', 'Gene', (36, 41))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('blood vessel formation', 'CPA', (255, 277))
173361	32807776	While it cannot be excluded that there might be differences between mice and humans, and the findings may be contextual to the Vhl/Trp53/Rb1 mutant background, this result seemingly contrasts with several independent lines of evidence from the study of human ccRCC tumours and ccRCC cell lines, which have demonstrated that HIF-2alpha possesses strong oncogenic activity and HIF-1alpha acts in the manner of a tumour suppressor to suppress aggressive tumour behaviour.	('RCC', 'Disease', 'MESH:C538614', (261, 264))	('tumour', 'Disease', 'MESH:D009369', (451, 457))	('tumour', 'Disease', (451, 457))	('suppress', 'NegReg', (431, 439))	('tumours', 'Phenotype', 'HP:0002664', (265, 272))	('oncogenic activity', 'CPA', (352, 370))	('tumour', 'Phenotype', 'HP:0002664', (410, 416))	('mice', 'Species', '10090', (68, 72))	('tumour', 'Disease', 'MESH:D009369', (410, 416))	('ccRCC tumours', 'Disease', 'MESH:D009369', (259, 272))	('tumour', 'Disease', (410, 416))	('humans', 'Species', '9606', (77, 83))	('tumour', 'Phenotype', 'HP:0002664', (265, 271))	('tumour', 'Disease', 'MESH:D009369', (265, 271))	('human', 'Species', '9606', (253, 258))	('tumour', 'Disease', (265, 271))	('RCC', 'Disease', (279, 282))	('ccRCC', 'Phenotype', 'HP:0006770', (277, 282))	('mutant', 'Var', (141, 147))	('behaviour', 'biological_process', 'GO:0007610', ('458', '467'))	('RCC', 'Disease', (261, 264))	('RCC', 'Disease', 'MESH:C538614', (279, 282))	('ccRCC tumours', 'Disease', (259, 272))	('human', 'Species', '9606', (77, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (259, 264))	('aggressive tumour', 'Disease', (440, 457))	('tumour', 'Phenotype', 'HP:0002664', (451, 457))	('aggressive tumour', 'Disease', 'MESH:D009369', (440, 457))
173365	32807776	In addition to genetic mechanisms that can irreversibly affect the balance of HIF-1alpha and HIF-2alpha activities, such as loss of one copy of chromosome 14q, encoding HIF1A, or intragenic deletions of HIF1A, several mechanisms exist that potentially provide tumour cells with a more dynamic mode of fine-tuning the relative strengths of HIF-1alpha and HIF-2alpha expression and activities.	('tumour', 'Phenotype', 'HP:0002664', (260, 266))	('tumour', 'Disease', 'MESH:D009369', (260, 266))	('rev', 'Gene', (45, 48))	('loss', 'Var', (124, 128))	('chromosome', 'cellular_component', 'GO:0005694', ('144', '154'))	('HIF1A', 'Gene', (203, 208))	('tumour', 'Disease', (260, 266))	('deletions', 'Var', (190, 199))	('rev', 'Gene', '19714', (45, 48))	('activities', 'MPA', (380, 390))
173370	32807776	Consistent with our current findings of an obligate oncogenic role of HIF-1alpha, transgenic overexpression of constitutively stabilised HIF-1alpha, but not HIF-2alpha in mouse renal tubules causes the formation of small lesions that have some features of precursor lesions of ccRCC.	('HIF-1alpha', 'Var', (137, 147))	('ccRCC', 'Phenotype', 'HP:0006770', (277, 282))	('formation', 'biological_process', 'GO:0009058', ('202', '211'))	('mouse', 'Species', '10090', (171, 176))	('causes', 'Reg', (191, 197))	('RCC', 'Disease', 'MESH:C538614', (279, 282))	('overexpression', 'PosReg', (93, 107))	('RCC', 'Disease', (279, 282))
173372	32807776	In agreement with this conclusion, numerous previous studies showed that deletion of Vhl in mouse renal epithelial cells in vivo, resulting in abrogation of the many different tumour suppressor functions of pVHL, was insufficient to cause tumour initiation either when both HIF-1alpha and HIF-2alpha were stabilised, or when the balance of HIF-1alpha and HIF-2alpha activities were genetically altered by co-deletion of Hif1a or Hif2a.	('rev', 'Gene', (45, 48))	('tumour', 'Disease', 'MESH:D009369', (239, 245))	('Hif2a', 'Gene', (429, 434))	('tumour', 'Disease', (239, 245))	('Vhl', 'Gene', (85, 88))	('rev', 'Gene', '19714', (45, 48))	('Hif1a', 'Gene', (420, 425))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('cause', 'Reg', (233, 238))	('tumour initiation', 'Disease', 'MESH:D009369', (239, 256))	('tumour', 'Disease', 'MESH:D009369', (176, 182))	('mouse', 'Species', '10090', (92, 97))	('deletion', 'Var', (73, 81))	('tumour initiation', 'Disease', (239, 256))	('tumour', 'Disease', (176, 182))	('tumour', 'Phenotype', 'HP:0002664', (239, 245))	('abrogation', 'NegReg', (143, 153))
173373	32807776	Nonetheless, deletion of either Hif1a or Hif2a was sufficient to inhibit the formation of cysts and tumours induced by Vhl/Trp53 double mutation, demonstrating that both HIF-1alpha and HIF-2alpha have pro-tumourigenic activities.	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('tumour', 'Disease', (205, 211))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('cysts and tumours', 'Disease', 'MESH:D009369', (90, 107))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('deletion', 'Var', (13, 21))	('Hif1a', 'Gene', (32, 37))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('Hif2a', 'Gene', (41, 46))	('formation', 'biological_process', 'GO:0009058', ('77', '86'))	('inhibit', 'NegReg', (65, 72))	('tumour', 'Disease', (100, 106))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('double mutation', 'Var', (129, 144))	('Vhl/Trp53', 'Gene', (119, 128))
173374	32807776	In this context, it is noteworthy that we now show that Hif2a deletion fails to strongly inhibit tumour formation in the Vhl/Trp53/Rb1 deletion model.	('tumour', 'Disease', (97, 103))	('deletion', 'Var', (135, 143))	('Hif2a', 'Gene', (56, 61))	('inhibit', 'NegReg', (89, 96))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('deletion', 'Var', (62, 70))	('tumour', 'Disease', 'MESH:D009369', (97, 103))	('formation', 'biological_process', 'GO:0009058', ('104', '113'))
173376	32807776	This predicted cell cycle promoting activity of HIF-2alpha is likely to be necessary for tumour formation in the Vhl/Trp53 background, but may become at least partly redundant due to the additional mutation of Rb1, which promotes the cell cycle by removing the negative regulation of E2F transcription factors.	('formation', 'biological_process', 'GO:0009058', ('96', '105'))	('cell cycle', 'CPA', (234, 244))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('transcription', 'biological_process', 'GO:0006351', ('288', '301'))	('negative regulation', 'MPA', (261, 280))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('cell cycle', 'biological_process', 'GO:0007049', ('15', '25'))	('cell cycle', 'biological_process', 'GO:0007049', ('234', '244'))	('tumour', 'Disease', (89, 95))	('regulation', 'biological_process', 'GO:0065007', ('270', '280'))	('mutation', 'Var', (198, 206))	('promotes', 'PosReg', (221, 229))	('Rb1', 'Gene', (210, 213))	('E2F', 'Protein', (284, 287))
173377	32807776	The patterns of copy number alterations that arise in the TGCA ccRCC dataset are consistent with the idea that the balance of HIF-1alpha and HIF-2alpha activities may be differently selected for, or tolerated, depending on the status of the network of G1-S cell cycle controlling genes.	('cell cycle', 'biological_process', 'GO:0007049', ('257', '267'))	('alterations', 'Var', (28, 39))	('copy', 'Var', (16, 20))	('TGCA', 'Gene', (58, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
173379	32807776	While HIF1A copy number losses or mutations (45%) occur in ccRCC more frequently than gains (2.5%), HIF2A losses are very rare (4%), and gains more common (15%) (Supplementary Fig.	('copy number losses', 'Var', (12, 30))	('HIF1A', 'Gene', (6, 11))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('HIF2A', 'Gene', (100, 105))	('occur', 'Reg', (50, 55))	('mutations', 'Var', (34, 43))
173380	32807776	Importantly, of the rare tumours with HIF2A losses or mutations, only 2 of 16 did not exhibit a copy number alteration in one or more genes that control the G1-S checkpoint (Supplementary Fig.	('mutations', 'Var', (54, 63))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('tumours', 'Disease', 'MESH:D009369', (25, 32))	('losses', 'NegReg', (44, 50))	('G1-S checkpoint', 'biological_process', 'GO:0000075', ('157', '172'))	('HIF2A', 'Gene', (38, 43))	('tumours', 'Disease', (25, 32))
173382	32807776	In contrast, the distribution of copy number losses of HIF1A does not correlate with the presence or absence of alterations in the G1-S network: 52 tumours harbouring HIF1A copy loss showed no alteration in G1-S genes, while 146 tumours with HIF1A copy loss did display alterations (Supplementary Fig.	('tumours', 'Disease', 'MESH:D009369', (148, 155))	('tumours', 'Disease', (148, 155))	('HIF1A', 'Gene', (167, 172))	('copy', 'Var', (173, 177))	('tumours', 'Disease', 'MESH:D009369', (229, 236))	('tumours', 'Disease', (229, 236))	('G1-S genes', 'Gene', (207, 217))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('alterations', 'Reg', (270, 281))	('tumours', 'Phenotype', 'HP:0002664', (148, 155))	('tumour', 'Phenotype', 'HP:0002664', (229, 235))	('tumours', 'Phenotype', 'HP:0002664', (229, 236))
173383	32807776	Since our current and previous mouse genetic studies collectively show that the requirement for HIF-1alpha and HIF-2alpha is dependent on the underlying genotype of the tumour (Vhl/Trp53 mutations versus Vhl/Trp53/Rb1 mutations), it will be important to test the generality of our findings in other genetic mouse models of ccRCC, particularly as epigenetic modifications resulting from mutations in Pbrm1 have been shown to alter HIF-alpha transcriptional outputs.	('Pbrm1', 'Gene', '66923', (399, 404))	('epigenetic modifications', 'Var', (346, 370))	('mutations', 'Var', (386, 395))	('tumour', 'Disease', (169, 175))	('HIF-alpha transcriptional outputs', 'MPA', (430, 463))	('RCC', 'Disease', 'MESH:C538614', (325, 328))	('mouse', 'Species', '10090', (31, 36))	('RCC', 'Disease', (325, 328))	('rev', 'Gene', '19714', (23, 26))	('mouse', 'Species', '10090', (307, 312))	('ccRCC', 'Phenotype', 'HP:0006770', (323, 328))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('rev', 'Gene', (23, 26))	('alter', 'Reg', (424, 429))	('Pbrm1', 'Gene', (399, 404))
173385	32807776	Thus, the combinations of mutations present in ccRCC cells might represent another mechanism for altering the balance of the relative activities of HIF-1alpha and HIF-2alpha, potentially affecting the genetic dependency on the two HIF-alpha proteins.	('RCC', 'Disease', (49, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('HIF-1alpha', 'Protein', (148, 158))	('HIF-2alpha', 'Gene', (163, 173))	('altering', 'Reg', (97, 105))	('mutations', 'Var', (26, 35))	('balance', 'MPA', (110, 117))	('affecting', 'Reg', (187, 196))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
173387	32807776	In contrast to the clear requirement for Hif1a in tumour formation in the autochthonous setting, we find that HIF-1alpha rather exhibits putative tumour suppressor activities in cell culture-based assays, including inducing the early loss of proliferative capacity of MEFs following Vhl deletion, inhibiting the proliferation of immortalised Vhl/Trp53 null MEFs and inhibiting anchorage independent growth of a Vhl/Trp53/Rb1 mutant mouse ccRCC cell line.	('MEFs', 'CellLine', 'CVCL:9115', (357, 361))	('HIF-1alpha', 'Var', (110, 120))	('deletion', 'Var', (287, 295))	('inhibiting', 'NegReg', (297, 307))	('RCC', 'Disease', (440, 443))	('loss', 'NegReg', (234, 238))	('ccRCC', 'Phenotype', 'HP:0006770', (438, 443))	('formation', 'biological_process', 'GO:0009058', ('57', '66'))	('Vhl', 'Gene', (283, 286))	('MEFs', 'CellLine', 'CVCL:9115', (268, 272))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('tumour', 'Disease', 'MESH:D009369', (146, 152))	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('RCC', 'Disease', 'MESH:C538614', (440, 443))	('tumour', 'Disease', (146, 152))	('inhibiting', 'NegReg', (366, 376))	('tumour', 'Disease', (50, 56))	('proliferation', 'CPA', (312, 325))	('mutant', 'Var', (425, 431))	('proliferative capacity', 'CPA', (242, 264))	('mouse', 'Species', '10090', (432, 437))	('anchorage independent growth', 'CPA', (377, 405))	('Vhl/Trp53/Rb1', 'Gene', (411, 424))
173396	32807776	Previously published mouse genetic data suggest that the latter is likely to be the case as induction of Warburg metabolism in mice through Vhl deletion alone did not cause tumour formation.	('mice', 'Species', '10090', (127, 131))	('tumour', 'Disease', (173, 179))	('metabolism', 'biological_process', 'GO:0008152', ('113', '123'))	('mouse', 'Species', '10090', (21, 26))	('rev', 'Gene', '19714', (1, 4))	('formation', 'biological_process', 'GO:0009058', ('180', '189'))	('deletion', 'Var', (144, 152))	('Vhl', 'Gene', (140, 143))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('rev', 'Gene', (1, 4))	('tumour', 'Disease', 'MESH:D009369', (173, 179))
173407	32807776	An unexpected finding was that tumours with Hif2a deletion showed stronger mRNA signatures associated with tumour immune cell infiltration, antigen presentation, and interferon activity, as well as higher densities of CD8 T cells and cells expressing the T-cell activation markers CD69 and perforin, compared to the other two tumour genotypes.	('mRNA signatures', 'MPA', (75, 90))	('Hif2a', 'Gene', (44, 49))	('N', 'Chemical', 'MESH:D009584', (77, 78))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('stronger', 'PosReg', (66, 74))	('tumour', 'Disease', (107, 113))	('CD8', 'Gene', (218, 221))	('antigen presentation', 'biological_process', 'GO:0019882', ('140', '160'))	('CD69', 'Gene', (281, 285))	('CD69', 'Gene', '12515', (281, 285))	('interferon', 'MPA', (166, 176))	('tumours', 'Disease', (31, 38))	('tumours', 'Phenotype', 'HP:0002664', (31, 38))	('tumours', 'Disease', 'MESH:D009369', (31, 38))	('T-cell activation', 'biological_process', 'GO:0042110', ('255', '272'))	('deletion', 'Var', (50, 58))	('antigen presentation', 'MPA', (140, 160))	('CD8', 'Gene', '925', (218, 221))	('tumour', 'Phenotype', 'HP:0002664', (326, 332))	('tumour', 'Disease', 'MESH:D009369', (326, 332))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumour', 'Disease', (326, 332))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('tumour', 'Disease', (31, 37))	('higher', 'PosReg', (198, 204))
173408	32807776	Furthermore, MHC class I and II genes, as well as other genes involved in antigen processing and presentation, were upregulated and tumour cells in Vhl / Trp53 / Rb1 / Hif2a /  tumours were more frequently immunohistochemically positive for MHC class II expression, suggestive of increased presentation of intracellular and extracellular epitopes in this tumour genotype.	('antigen processing and presentation', 'biological_process', 'GO:0019882', ('74', '109'))	('tumours', 'Disease', (177, 184))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('tumours', 'Phenotype', 'HP:0002664', (177, 184))	('tumour', 'Disease', (132, 138))	('tumours', 'Disease', 'MESH:D009369', (177, 184))	('increased', 'PosReg', (280, 289))	('upregulated', 'PosReg', (116, 127))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('extracellular', 'cellular_component', 'GO:0005576', ('324', '337'))	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('tumour', 'Disease', (177, 183))	('Vhl / Trp53 / Rb1 / Hif2a /', 'Var', (148, 175))	('MHC class II', 'Gene', (241, 253))	('intracellular', 'cellular_component', 'GO:0005622', ('306', '319'))	('tumour', 'Phenotype', 'HP:0002664', (355, 361))	('tumour', 'Disease', 'MESH:D009369', (355, 361))	('tumour', 'Disease', (355, 361))	('positive', 'Reg', (228, 236))
173414	32807776	Moreover, we show that loss of one copy of HIF1A correlates with a worse survival outcome, higher mRNA signatures of T-cell abundance and a broadly altered immune microenvironment in human ccRCCs.	('HIF1A', 'Gene', (43, 48))	('RCC', 'Disease', (191, 194))	('higher', 'PosReg', (91, 97))	('mRNA signatures', 'MPA', (98, 113))	('RCC', 'Disease', 'MESH:C538614', (191, 194))	('ccRCC', 'Phenotype', 'HP:0006770', (189, 194))	('human', 'Species', '9606', (183, 188))	('loss', 'Var', (23, 27))	('N', 'Chemical', 'MESH:D009584', (100, 101))
173423	32807776	A further corollary of our findings is that inhibition of HIF-1alpha and HIF-2alpha transcription factor activities in ccRCC cells could be investigated therapeutically to inhibit tumour cell proliferation and simultaneously to attempt to increase T-cell infiltration and activation.	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('HIF-2alpha', 'Gene', (73, 83))	('inhibition', 'Var', (44, 54))	('RCC', 'Disease', (121, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('cell proliferation', 'biological_process', 'GO:0008283', ('187', '205'))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('increase', 'PosReg', (239, 247))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('transcription factor', 'molecular_function', 'GO:0000981', ('84', '104'))	('inhibit', 'NegReg', (172, 179))	('T-cell infiltration', 'CPA', (248, 267))	('transcription', 'biological_process', 'GO:0006351', ('84', '97'))	('activation', 'CPA', (272, 282))	('tumour', 'Disease', (180, 186))
173436	32807776	Cells were infected with the retroviruses pBabe-PURO (Vector) or pBabe-PURO-VHL30 (VHL30) or the lentiviruses LKO.1 expressing non-silencing control shRNA (shRNA-ns), or shRNAs against Hif1a (TRCN0000232220, TRCN0000232222, or TRCN0000232223), respectively termed shRNA-Hif1a #220, shRNA-Hif1a #222, and shRNA-Hif1a #223.	('TRCN0000232220', 'Var', (192, 206))	('N', 'Chemical', 'MESH:D009584', (173, 174))	('N', 'Chemical', 'MESH:D009584', (307, 308))	('N', 'Chemical', 'MESH:D009584', (152, 153))	('N', 'Chemical', 'MESH:D009584', (211, 212))	('N', 'Chemical', 'MESH:D009584', (267, 268))	('TRCN0000232222', 'Var', (208, 222))	('N', 'Chemical', 'MESH:D009584', (230, 231))	('infected', 'Disease', 'MESH:D007239', (11, 19))	('N', 'Chemical', 'MESH:D009584', (195, 196))	('TRCN0000232223', 'Var', (227, 241))	('infected', 'Disease', (11, 19))	('N', 'Chemical', 'MESH:D009584', (159, 160))	('N', 'Chemical', 'MESH:D009584', (285, 286))
173552	28454361	MicroRNA-30e-3p inhibits cell invasion and migration in clear cell renal cell carcinoma by targeting Snail1 Clear cell renal cell carcinoma (ccRCC) is the most common type of neoplasm affecting the adult kidney.	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (108, 139))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (67, 87))	('inhibits', 'NegReg', (16, 24))	('clear cell renal cell carcinoma', 'Disease', (56, 87))	('neoplasm', 'Disease', 'MESH:D009369', (175, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('neoplasm', 'Disease', (175, 183))	('Snail1', 'Gene', (101, 107))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (56, 87))	('cell invasion', 'CPA', (25, 38))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (108, 139))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (119, 139))	('ccRCC', 'Phenotype', 'HP:0006770', (141, 146))	('Clear cell renal cell carcinoma', 'Disease', (108, 139))	('RCC', 'Disease', (143, 146))	('neoplasm', 'Phenotype', 'HP:0002664', (175, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (56, 87))	('MicroRNA-30e-3p', 'Var', (0, 15))
173555	28454361	The results revealed that overexpression of miR-30e-3p in the A498 and 786O ccRCC cell lines was able to inhibit cell invasion and migration.	('inhibit', 'NegReg', (105, 112))	('overexpression', 'PosReg', (26, 40))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('miR-30e-3p', 'Var', (44, 54))
173556	28454361	The expression level of Snail1, a potential target gene of miR-30e-3p, was inversely correlated with miR-30e-3p expression in ccRCC tissues and cell lines.	('expression level', 'MPA', (4, 20))	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('Snail1', 'Gene', (24, 30))	('Snail1', 'Gene', '6615', (24, 30))	('miR-30e-3p', 'Var', (101, 111))
173557	28454361	Furthermore, Snail1 was revealed to be directly regulated by miR-30e-3p and had an important role in mediating the biological effects of miR-30e-3p in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('RCC', 'Disease', (153, 156))	('Snail1', 'Gene', (13, 19))	('Snail1', 'Gene', '6615', (13, 19))	('ccRCC', 'Phenotype', 'HP:0006770', (151, 156))	('miR-30e-3p', 'Var', (61, 71))	('regulated', 'Reg', (48, 57))	('miR-30e-3p', 'Var', (137, 147))
173558	28454361	Restoration of Snail1 expression was able to reverse the inhibitory properties of miR-30e-3p.	('Snail1', 'Gene', (15, 21))	('Snail1', 'Gene', '6615', (15, 21))	('Restoration', 'Var', (0, 11))	('inhibitory properties', 'MPA', (57, 78))
173559	28454361	Therefore, the results of the current study suggest that miR-30e-3p exerts its anticancer functions through direct targeting of Snail1 in ccRCC cells, and may be a novel therapeutic agent for this form of cancer.	('Snail1', 'Gene', '6615', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('RCC', 'Disease', (140, 143))	('targeting', 'Reg', (115, 124))	('miR-30e-3p', 'Var', (57, 67))	('cancer', 'Disease', (83, 89))	('Snail1', 'Gene', (128, 134))
173566	28454361	Dysregulation of miRNAs has been associated with the biological characteristics of ccRCC.	('Dysregulation', 'Var', (0, 13))	('miRNAs', 'Protein', (17, 23))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('associated', 'Reg', (33, 43))	('RCC', 'Disease', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))
173568	28454361	The aim of the current study was to examine the role of miRNA (miR)-30e-3p on the invasion and migration of two ccRCC cell lines and investigate the potential underlying mechanisms.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('miRNA', 'Var', (56, 61))	('migration', 'CPA', (95, 104))
173569	28454361	The results demonstrated that miR-30e-3p potentiated the invasive and migratory behavior of ccRCC cells through the inhibition of Snail1.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Disease', (94, 97))	('Snail1', 'Gene', (130, 136))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('Snail1', 'Gene', '6615', (130, 136))	('inhibition', 'NegReg', (116, 126))	('potentiated', 'PosReg', (41, 52))	('miR-30e-3p', 'Var', (30, 40))
173587	28454361	The membranes were probed with human anti-Snail1 (#ab110490; dilution, 1:1,000; Abcam) and anti-GAPDH (#G8140; dilution, 1:1,000; United States Biological, Salem, MA, USA) primary antibodies overnight at 4 C, followed by incubation with the secondary antibody, HRP-labeled goat anti-rabbit IgG (#A0208; dilution, 1:1,000; Beyotime Institute of Biotechnology).	('GAPDH', 'Gene', '2597', (96, 101))	('goat', 'Species', '9925', (273, 277))	('#ab110490;', 'Var', (50, 60))	('GAPDH', 'Gene', (96, 101))	('rabbit', 'Species', '9986', (283, 289))	('antibody', 'cellular_component', 'GO:0042571', ('251', '259'))	('human', 'Species', '9606', (31, 36))	('Snail1', 'Gene', (42, 48))	('Snail1', 'Gene', '6615', (42, 48))	('antibody', 'cellular_component', 'GO:0019815', ('251', '259'))	('antibody', 'cellular_component', 'GO:0019814', ('251', '259'))	('antibody', 'molecular_function', 'GO:0003823', ('251', '259'))
173592	28454361	A firefly luciferase reporter vector containing the Snail1 3'-UTR or its mutant 3'-UTR were co-transfected with miRNA mimics (50 nM) into the ccRCC cells using Lipofectamine  2000 reagent, according to the manufacturer's protocol.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('Lipofectamine', 'Chemical', 'MESH:C086724', (160, 173))	('mutant', 'Var', (73, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('Snail1', 'Gene', (52, 58))	('Snail1', 'Gene', '6615', (52, 58))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))
173597	28454361	Concordant with this result, the scratch migration assays also demonstrated that miR-30e-3p mimics were able to significantly inhibit ccRCC cell migration (P<0.01; Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('miR-30e-3p mimics', 'Var', (81, 98))	('inhibit', 'NegReg', (126, 133))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('cell migration', 'biological_process', 'GO:0016477', ('140', '154'))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))
173598	28454361	Snail1 was identified by TargetScan and miRanda as a potential target of miR-30e-3p.	('Snail1', 'Gene', (0, 6))	('miR-30e-3p', 'Var', (73, 83))	('Snail1', 'Gene', '6615', (0, 6))
173600	28454361	The Snail1 levels in tumors with high levels of miR-30e-3p expression were markedly lower, compared with those in tumors with low levels of miR-30e-3p expression (Fig.	('miR-30e-3p expression', 'Var', (48, 69))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('Snail1', 'Gene', (4, 10))	('lower', 'NegReg', (84, 89))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('Snail1', 'Gene', '6615', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
173601	28454361	Western blot analysis demonstrated that Snail1 expression was markedly downregulated in ccRCC cell lines following transfection with miR-30e-3p (Fig.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('downregulated', 'NegReg', (71, 84))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('Snail1', 'Gene', (40, 46))	('Snail1', 'Gene', '6615', (40, 46))	('miR-30e-3p', 'Var', (133, 143))	('expression', 'MPA', (47, 57))	('RCC', 'Disease', (90, 93))
173602	28454361	To identify whether Snail1 is a direct target of miR-30e-3p in ccRCC cells, the potential seed sequence for miR-30e-3p in the 3'-UTR region of Snail1 was analyzed and the wild type and mutant Snail1 3'-UTR fragments were cloned into a luciferase reporter gene system (Fig.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('mutant', 'Var', (185, 191))	('Snail1', 'Gene', (20, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('Snail1', 'Gene', (192, 198))	('Snail1', 'Gene', '6615', (192, 198))	('Snail1', 'Gene', (143, 149))	('Snail1', 'Gene', '6615', (143, 149))	('Snail1', 'Gene', '6615', (20, 26))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
173603	28454361	Wild-type or mutant Snail1 3'-UTR constructs were co-transfected with miR-30e-3p or control mimics into A498 and 786O cells.	('mutant', 'Var', (13, 19))	('Snail1', 'Gene', (20, 26))	('Snail1', 'Gene', '6615', (20, 26))
173604	28454361	Overexpression of miR-30e-3p in the two ccRCC cell lines resulted in significantly reduced luciferase activity for the wild-type constructs, whereas no alteration in luciferase activity was detected with the mutant Snail1 3'-UTR luciferase reporter plasmid (P<0.05; Fig.	('Snail1', 'Gene', (215, 221))	('reduced', 'NegReg', (83, 90))	('activity', 'MPA', (102, 110))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('luciferase activity', 'molecular_function', 'GO:0047077', ('91', '110'))	('luciferase activity', 'molecular_function', 'GO:0047077', ('166', '185'))	('luciferase', 'Enzyme', (91, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('luciferase activity', 'molecular_function', 'GO:0045289', ('166', '185'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('91', '110'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('166', '185'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('91', '110'))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('Snail1', 'Gene', '6615', (215, 221))	('miR-30e-3p', 'Var', (18, 28))	('luciferase activity', 'molecular_function', 'GO:0050248', ('91', '110'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('166', '185'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('91', '110'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('166', '185'))
173605	28454361	To determine whether the suppression of ccRCC cell invasion and migration triggered by miR-30e-3p was mediated by Snail1, A498 and 786O cells were transfected with a Snail1 construct lacking a 3'-UTR, or an empty vector.	('suppression', 'NegReg', (25, 36))	('Snail1', 'Gene', '6615', (114, 120))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('Snail1', 'Gene', (166, 172))	('Snail1', 'Gene', '6615', (166, 172))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('miR-30e-3p', 'Var', (87, 97))	('lacking', 'NegReg', (183, 190))	('migration', 'CPA', (64, 73))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('Snail1', 'Gene', (114, 120))
173611	28454361	A number of previous studies have identified that miRNAs may serve as biomarkers for cancer risk stratification, outcome prediction and the classification of histological subtypes.	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('miRNAs', 'Var', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
173613	28454361	Snail1 was revealed to be a potential target gene for miR-30e-3p in the current study, which demonstrated that miR-30e-3p may negatively regulate Snail1 expression by directly targeting the 3'-UTR of Snail1 mRNA in ccRCC cells.	('negatively regulate', 'NegReg', (126, 145))	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('Snail1', 'Gene', (146, 152))	('RCC', 'Disease', (217, 220))	('Snail1', 'Gene', '6615', (146, 152))	('ccRCC', 'Phenotype', 'HP:0006770', (215, 220))	('miR-30e-3p', 'Var', (111, 121))	('Snail1', 'Gene', (200, 206))	("3'-UTR", 'MPA', (190, 196))	('Snail1', 'Gene', (0, 6))	('expression', 'MPA', (153, 163))	('targeting', 'Reg', (176, 185))	('Snail1', 'Gene', '6615', (0, 6))	('RCC', 'Phenotype', 'HP:0005584', (217, 220))	('Snail1', 'Gene', '6615', (200, 206))
173621	28454361	Subsequently, Snail1 was demonstrated to be a potential direct target gene for miR-30e-3p, and miR-30e-3p negatively regulated Snail1 expression by directly targeting the 3'-UTR of Snail mRNA in ccRCC cells.	('miR-30e-3p', 'Var', (95, 105))	('RCC', 'Disease', 'MESH:C538614', (197, 200))	('Snail1', 'Gene', (127, 133))	('Snail1', 'Gene', '6615', (14, 20))	('Snail', 'Gene', '6615', (181, 186))	('Snail', 'Gene', '6615', (127, 132))	('Snail', 'Gene', '6615', (14, 19))	('Snail1', 'Gene', (14, 20))	("3'-UTR", 'MPA', (171, 177))	('negatively', 'NegReg', (106, 116))	('expression', 'MPA', (134, 144))	('regulated', 'Reg', (117, 126))	('targeting', 'Reg', (157, 166))	('RCC', 'Phenotype', 'HP:0005584', (197, 200))	('Snail', 'Gene', (127, 132))	('Snail', 'Gene', (181, 186))	('Snail', 'Gene', (14, 19))	('RCC', 'Disease', (197, 200))	('ccRCC', 'Phenotype', 'HP:0006770', (195, 200))	('Snail1', 'Gene', '6615', (127, 133))
173622	28454361	In addition, the present study demonstrated that the inhibitory effect of miR-30e-3p on the invasion and migration of ccRCC cells was reversed by overexpression of Snail1 protein, suggesting that miR-30e-3p may inhibit ccRCC metastasis by suppressing Snail expression.	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('RCC', 'Phenotype', 'HP:0005584', (221, 224))	('miR-30e-3p', 'Var', (196, 206))	('suppressing', 'NegReg', (239, 250))	('inhibit', 'NegReg', (211, 218))	('RCC', 'Disease', 'MESH:C538614', (221, 224))	('Snail', 'Gene', '6615', (164, 169))	('Snail', 'Gene', (164, 169))	('Snail', 'Gene', (251, 256))	('RCC', 'Disease', (221, 224))	('ccRCC', 'Phenotype', 'HP:0006770', (219, 224))	('Snail1', 'Gene', (164, 170))	('Snail', 'Gene', '6615', (251, 256))	('Snail1', 'Gene', '6615', (164, 170))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))
173623	28454361	The results of the present study revealed a potential underlying molecular mechanism by which miR-30e-3p may reduce the invasion and migration of human ccRCC cells through suppression of Snail1.	('Snail1', 'Gene', (187, 193))	('reduce', 'NegReg', (109, 115))	('Snail1', 'Gene', '6615', (187, 193))	('miR-30e-3p', 'Var', (94, 104))	('human', 'Species', '9606', (146, 151))	('RCC', 'Disease', (154, 157))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('RCC', 'Phenotype', 'HP:0005584', (154, 157))	('ccRCC', 'Phenotype', 'HP:0006770', (152, 157))	('suppression', 'NegReg', (172, 183))
173675	32047554	The 20-muL PCR mix contained QX200  ddPCR  EvaGreen Supermix (Bio-Rad), 300 nM each primer and approximately 50 ng of cDNA template.	('Rad', 'Gene', (66, 69))	('mix', 'Gene', (15, 18))	('Rad', 'biological_process', 'GO:1990116', ('66', '69'))	('mix', 'Gene', '83881', (57, 60))	('mix', 'Gene', (57, 60))	('QX200  ddPCR', 'Var', (29, 41))	('Rad', 'Gene', '6236', (66, 69))	('mix', 'Gene', '83881', (15, 18))
173684	32047554	High CYP4A11 expression in the 139 RCCs was positively associated with PPARalpha expression, males, the non-ccRCC type, and high histologic grades (grade 1/2 versus grade 3/4) (p=0.001, p=0.018, p<0.001 and p<0.001).	('ccRCC', 'Disease', (108, 113))	('RCC', 'Disease', (35, 38))	('RCC', 'Disease', (110, 113))	('ccRCC', 'Disease', 'MESH:D002292', (108, 113))	('RCC', 'Disease', 'MESH:D002292', (35, 38))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('High', 'Var', (0, 4))	('RCC', 'Disease', 'MESH:D002292', (110, 113))	('expression', 'MPA', (13, 23))	('PPARalpha', 'Gene', (71, 80))	('CYP4A11', 'Gene', (5, 12))	('CYP4A11', 'Gene', '1579', (5, 12))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))
173686	32047554	Kaplan-Meier survival curves and log-rank tests showed a significant association between high CYP4A11 expression and short OS (log-rank=7.994, p=0.005), while no association with DFS was observed (log-rank=0.005, p=0.945) (Fig.	('CYP4A11', 'Gene', (94, 101))	('expression', 'MPA', (102, 112))	('CYP4A11', 'Gene', '1579', (94, 101))	('short OS', 'Disease', (117, 125))	('high', 'Var', (89, 93))
173706	32047554	In ccRCC, inactivation or loss of VHL leads to aberrant accumulation of HIF proteins, which in turn results in angiogenesis, glycolysis, apoptosis, and lipid deposition in ccRCC.	('angiogenesis', 'MPA', (111, 123))	('HIF proteins', 'Disease', 'MESH:D058495', (72, 84))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('glycolysis', 'MPA', (125, 135))	('apoptosis', 'biological_process', 'GO:0097194', ('137', '146'))	('apoptosis', 'biological_process', 'GO:0006915', ('137', '146'))	('HIF proteins', 'Disease', (72, 84))	('glycolysis', 'biological_process', 'GO:0006096', ('125', '135'))	('ccRCC', 'Disease', 'MESH:D002292', (172, 177))	('apoptosis', 'CPA', (137, 146))	('lipid deposition', 'MPA', (152, 168))	('inactivation', 'Var', (10, 22))	('angiogenesis', 'biological_process', 'GO:0001525', ('111', '123'))	('accumulation', 'PosReg', (56, 68))	('VHL', 'Gene', (34, 37))	('ccRCC', 'Disease', (172, 177))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('ccRCC', 'Disease', 'MESH:D002292', (3, 8))	('ccRCC', 'Disease', (3, 8))	('loss', 'Var', (26, 30))	('VHL', 'Gene', '7428', (34, 37))	('results in', 'Reg', (100, 110))
173742	30231375	This includes the anti-HER2 antibody in HER2-amplified breast cancer, anti-EGFR therapies in KRAS wild-type colorectal cancer, and BRAF inhibitors in BRAF mutant melanomas.	('antibody', 'molecular_function', 'GO:0003823', ('28', '36'))	('KRAS', 'Gene', (93, 97))	('melanomas', 'Disease', 'MESH:D008545', (162, 171))	('HER2', 'Gene', '2064', (40, 44))	('antibody', 'cellular_component', 'GO:0042571', ('28', '36'))	('melanomas', 'Disease', (162, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('EGFR', 'Gene', (75, 79))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('HER2', 'Gene', '2064', (23, 27))	('BRAF', 'Gene', (150, 154))	('BRAF', 'Gene', '673', (150, 154))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('antibody', 'cellular_component', 'GO:0019815', ('28', '36'))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('melanomas', 'Phenotype', 'HP:0002861', (162, 171))	('HER2', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('EGFR', 'molecular_function', 'GO:0005006', ('75', '79'))	('EGFR', 'Gene', '1956', (75, 79))	('antibody', 'cellular_component', 'GO:0019814', ('28', '36'))	('BRAF', 'Gene', '673', (131, 135))	('BRAF', 'Gene', (131, 135))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('HER2', 'Gene', (23, 27))	('mutant', 'Var', (155, 161))	('KRAS', 'Gene', '3845', (93, 97))	('colorectal cancer', 'Disease', (108, 125))
173825	30231375	This suggests that PD-L1 expression may increase the likelihood or response but cannot accurately predict which patients will not respond.	('PD-L1', 'Gene', (19, 24))	('response', 'MPA', (67, 75))	('increase', 'PosReg', (40, 48))	('patients', 'Species', '9606', (112, 120))	('PD-L1', 'Gene', '29126', (19, 24))	('expression', 'Var', (25, 35))
173866	30231375	Cabozantinib was associated with an improved PFS compared with everolimus (7.4 vs. 3.8 months), with a corresponding HR of 0.58 (95% CI, 0.45-0.75; p < .001).	('Cabozantinib', 'Var', (0, 12))	('PFS', 'MPA', (45, 48))	('Cabozantinib', 'Chemical', 'MESH:C558660', (0, 12))	('improved', 'PosReg', (36, 44))	('everolimus', 'Chemical', 'MESH:C107135', (63, 73))
173874	30231375	The ORR was also greater with nivolumab compared with everolimus (25% vs. 5%).	('ORR', 'MPA', (4, 7))	('everolimus', 'Chemical', 'MESH:C107135', (54, 64))	('nivolumab', 'Var', (30, 39))
173876	30231375	Among patients with 1% or greater PD-L1 expression, the median OS was 21.8 months (95% CI, 16.5-28.1) in the nivolumab group and 18.8 months (95% CI, 11.9-19.9) in the everolimus group (HR 0.79; 95% CI, 0.53-1.17).	('expression', 'Var', (40, 50))	('PD-L1', 'Gene', (34, 39))	('everolimus', 'Chemical', 'MESH:C107135', (168, 178))	('patients', 'Species', '9606', (6, 14))	('PD-L1', 'Gene', '29126', (34, 39))
173885	30231375	Advancements in modern genomic techniques, including next-generation sequencing, have revealed the diverse spectrum of both genetic and epigenetic changes in kidney cancer.	('kidney cancer', 'Phenotype', 'HP:0009726', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('kidney cancer', 'Disease', (158, 171))	('epigenetic', 'Var', (136, 146))	('kidney cancer', 'Disease', 'MESH:D007680', (158, 171))
173890	30231375	Interestingly, whereas mutations in PBRM1 and BAP1 tend to be mutually exclusive, mutations in PBRM1 and SETD2 appear to synergize.	('SETD2', 'Gene', '29072', (105, 110))	('PBRM1', 'Gene', (36, 41))	('PBRM1', 'Gene', (95, 100))	('PBRM1', 'Gene', '55193', (36, 41))	('SETD2', 'Gene', (105, 110))	('BAP1', 'Gene', '8314', (46, 50))	('PBRM1', 'Gene', '55193', (95, 100))	('mutations', 'Var', (23, 32))	('mutations', 'Var', (82, 91))	('BAP1', 'Gene', (46, 50))
173892	30231375	Their results demonstrated that patients with tumors harboring BAP1 mutations had significantly reduced median OS compared with those who had tumors containing PBRM1 mutations (4.6 vs. 10.6 years, respectively; HR 2.7; p = .04).	('PBRM1', 'Gene', (160, 165))	('patients', 'Species', '9606', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('BAP1', 'Gene', (63, 67))	('tumors', 'Disease', (46, 52))	('PBRM1', 'Gene', '55193', (160, 165))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('mutations', 'Var', (68, 77))	('median OS', 'MPA', (104, 113))	('BAP1', 'Gene', '8314', (63, 67))	('reduced', 'NegReg', (96, 103))
173895	30231375	BAP1 mutations were associated with worse cancer-specific survival, with an HR of 7.71 (p = .002).	('BAP1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('mutations', 'Var', (5, 14))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('BAP1', 'Gene', '8314', (0, 4))	('worse', 'NegReg', (36, 41))
173896	30231375	PBRM1 mutations appeared to have no impact on cancer-specific survival, whereas SETD2 mutations were associated with worse cancer-specific survival only in the TCGA cohort (HR 1.68; p = .036).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mutations', 'Var', (86, 95))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('SETD2', 'Gene', (80, 85))	('worse', 'NegReg', (117, 122))	('cancer', 'Disease', (46, 52))	('PBRM1', 'Gene', (0, 5))	('SETD2', 'Gene', '29072', (80, 85))	('PBRM1', 'Gene', '55193', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('mutations', 'Var', (6, 15))
173904	30231375	With regard to VEGF-targeted therapy, a number of tumor-specific factors have been studied as potential biomarkers, including VHL mutations and hypoxia-inducible factor levels.	('VHL', 'Disease', (126, 129))	('VHL', 'Disease', 'MESH:D006623', (126, 129))	('VEGF', 'Gene', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('hypoxia', 'Disease', (144, 151))	('mutations', 'Var', (130, 139))	('hypoxia', 'Disease', 'MESH:D000860', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('VEGF', 'Gene', '7422', (15, 19))	('tumor', 'Disease', (50, 55))
173918	30231375	Kucejova et al identified mutations in the mTOR-negative regulator TSC1 in ccRCC and proposed that such mutations may identify tumors most likely to respond to mTOR inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('TSC1', 'Gene', '7248', (67, 71))	('mutations', 'Var', (104, 113))	('tumors', 'Disease', (127, 133))	('ccRCC', 'Disease', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('TSC1', 'Gene', (67, 71))	('mTOR', 'Gene', '2475', (160, 164))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('mTOR', 'Gene', (160, 164))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('mutations', 'Var', (26, 35))	('ccRCC', 'Disease', 'MESH:D002292', (75, 80))	('mTOR', 'Gene', (43, 47))	('mTOR', 'Gene', '2475', (43, 47))	('respond to', 'MPA', (149, 159))
173920	30231375	Mutations in MTOR, TSC1, or TSC2 were more common for patients who experienced clinical benefit than for those who progressed.	('TSC1', 'Gene', '7248', (19, 23))	('TSC2', 'Gene', '7249', (28, 32))	('TSC1', 'Gene', (19, 23))	('TSC2', 'Gene', (28, 32))	('patients', 'Species', '9606', (54, 62))	('MTOR', 'Gene', (13, 17))	('common', 'Reg', (43, 49))	('Mutations', 'Var', (0, 9))	('MTOR', 'Gene', '2475', (13, 17))
173921	30231375	However, a substantial fraction of responders (31 of 43; 72%) had no mTOR pathway mutation identified.	('mutation', 'Var', (82, 90))	('mTOR', 'Gene', (69, 73))	('mTOR', 'Gene', '2475', (69, 73))
173940	30231375	In this analysis, they found that loss-of-function mutations in the PBRM1 gene appeared to be associated with increased clinical benefit to immune checkpoint therapy.	('PBRM1', 'Gene', (68, 73))	('PBRM1', 'Gene', '55193', (68, 73))	('mutations', 'Var', (51, 60))	('loss-of-function', 'NegReg', (34, 50))
173941	30231375	Those with PBRM1 loss had significantly prolonged OS and PFS compared with patients without PBRM1 loss (log-rank p = .0074 and p = .029, respectively).	('prolonged', 'PosReg', (40, 49))	('PFS', 'CPA', (57, 60))	('PBRM1', 'Gene', '55193', (92, 97))	('patients', 'Species', '9606', (75, 83))	('PBRM1', 'Gene', (11, 16))	('PBRM1', 'Gene', '55193', (11, 16))	('loss', 'Var', (17, 21))	('PBRM1', 'Gene', (92, 97))
173950	30231375	Type I disease was noted to bear a higher frequency of alterations in the MET proto-oncogene, whereas type II tumors had CDKN2A silencing and SETD2 mutations.	('CDKN2A', 'Gene', '1029', (121, 127))	('mutations', 'Var', (148, 157))	('alterations', 'Var', (55, 66))	('Type I disease', 'Disease', (0, 14))	('silencing', 'NegReg', (128, 137))	('Type I disease', 'Disease', 'MESH:D005776', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('SETD2', 'Gene', '29072', (142, 147))	('CDKN2A', 'Gene', (121, 127))	('II tumors', 'Disease', (107, 116))	('II tumors', 'Disease', 'MESH:D009369', (107, 116))	('MET proto-oncogene', 'Gene', (74, 92))	('SETD2', 'Gene', (142, 147))
173986	31183974	The patients with high CCND1 level appear to have a more favorable prognosis together with more frequent low-grade tumors and low rate of recurrence.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('CCND1', 'Gene', (23, 28))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('CCND1', 'Gene', '595', (23, 28))	('high', 'Var', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('patients', 'Species', '9606', (4, 12))
174012	31183974	In order to explore the expression of CCND1 in ccRCC patients, a total of 7 related GEO datasets (GSE46699, GSE40435, GSE66272, GSE15641, GSE36895, GSE14994, GSE53757) (Table S1) were employed.	('GSE46699', 'Var', (98, 106))	('RCC', 'Disease', (49, 52))	('GSE14994', 'Var', (148, 156))	('CCND1', 'Gene', '595', (38, 43))	('patients', 'Species', '9606', (53, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('GSE53757', 'Var', (158, 166))	('CCND1', 'Gene', (38, 43))	('GSE36895', 'Var', (138, 146))	('GSE15641', 'Var', (128, 136))	('GSE66272', 'Var', (118, 126))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('GSE40435', 'Var', (108, 116))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
174029	31183974	These results suggested that the level of CCND1 was associated with tumor recurrence in ccRCC.	('tumor', 'Disease', (68, 73))	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('CCND1', 'Gene', '595', (42, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('level', 'Var', (33, 38))	('associated with', 'Reg', (52, 67))	('CCND1', 'Gene', (42, 47))	('RCC', 'Disease', (90, 93))
174050	31183974	However, we found that patients with high CCND1 expression had a lower risk of tumor recurrence in ccRCC compared to those with low CCND1 expression.	('CCND1', 'Gene', '595', (42, 47))	('high', 'Var', (37, 41))	('tumor', 'Disease', (79, 84))	('patients', 'Species', '9606', (23, 31))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('CCND1', 'Gene', (132, 137))	('lower', 'NegReg', (65, 70))	('RCC', 'Disease', (101, 104))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('CCND1', 'Gene', '595', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('CCND1', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
174051	31183974	The poor prognosis of patients with low level of CCND1 may be due to the higher recurrence rate.	('CCND1', 'Gene', '595', (49, 54))	('low level', 'Var', (36, 45))	('patients', 'Species', '9606', (22, 30))	('CCND1', 'Gene', (49, 54))
174054	31183974	The patients with high CCND1 level appear to have a more favorable prognosis because they present more frequently with low-grade tumors and low rate of recurrence.	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('CCND1', 'Gene', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('CCND1', 'Gene', '595', (23, 28))	('high', 'Var', (18, 22))	('patients', 'Species', '9606', (4, 12))
174060	31183974	The molecular mechanisms underlying why the high mRNA level of CCND1 contributing to favorable prognosis of ccRCC are still unclear.	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('CCND1', 'Gene', '595', (63, 68))	('high', 'Var', (44, 48))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('mRNA level', 'MPA', (49, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('CCND1', 'Gene', (63, 68))
174092	30619768	The primary antibodies used for the detection of these 18 proteins were as follows: anti-PAX-8 (Clone MRQ-50, Ventana), anti-P504S (Clone SP116, Ventana), anti-Ki-67 (Clone 30-9, Ventana), anti-CD10 (Clone SP67, Ventana), anti-HER2 (Clone 4B5, Ventana), anti-PTEN (Clone SP218, Ventana), anti-COX2 (Clone SP21, Ventana), anti-Vimentin (Clone Vim 3B4, Ventana), anti-TFE3 (Clone MRQ-37, Ventana), anti-CA9 (Cat No.	('anti-P504S', 'Var', (120, 130))	('CA9', 'Gene', '768', (401, 404))	('anti-Ki-67', 'Var', (155, 165))	('PTEN', 'Gene', (259, 263))	('CD10', 'Gene', '4311', (194, 198))	('Vimentin', 'Gene', (326, 334))	('P504S', 'Mutation', 'rs1167794652', (125, 130))	('COX2', 'Gene', '4513', (293, 297))	('HER2', 'Gene', (227, 231))	('CD10', 'Gene', (194, 198))	('Vimentin', 'cellular_component', 'GO:0045099', ('326', '334'))	('CD10', 'molecular_function', 'GO:0004245', ('194', '198'))	('TFE3', 'Gene', (366, 370))	('PTEN', 'Gene', '5728', (259, 263))	('TFE3', 'Gene', '7030', (366, 370))	('Cat', 'molecular_function', 'GO:0004096', ('406', '409'))	('CA9', 'Gene', (401, 404))	('HER2', 'Gene', '2064', (227, 231))	('Vimentin', 'cellular_component', 'GO:0045098', ('326', '334'))	('PAX-8', 'Gene', (89, 94))	('PAX-8', 'Gene', '7849', (89, 94))	('COX2', 'Gene', (293, 297))	('Vimentin', 'Gene', '7431', (326, 334))
174107	30619768	Univariate and multivariate regression models were developed to find independent predictors, including clinical factors and IHC-related factors, for high ISUP grade ccRCC.	('RCC', 'Disease', (167, 170))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('high ISUP grade', 'Var', (149, 164))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))
174112	30619768	Patients with a high ISUP grade were more likely to be older (P = 0.001), have a larger maximal tumor diameter (P < 0.001), be symptomatic (P = 0.009), and to have undergone radical nephrectomy (P < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('high ISUP grade', 'Var', (16, 31))	('larger', 'PosReg', (81, 87))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
174113	30619768	In multivariate logistic regression models, maximal tumor diameter was associated with high ISUP grade in patients with ccRCC, with an odds ratio [OR; 95% confidence interval (CI)] of 1.264 (1.083-1.476, p = 0.003).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('ISUP grade', 'MPA', (92, 102))	('tumor', 'Disease', (52, 57))	('maximal', 'Var', (44, 51))	('high', 'Var', (87, 91))	('patients', 'Species', '9606', (106, 114))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('RCC', 'Disease', (122, 125))
174160	29746834	We characterized BKV variants from two KTRs who developed BKVN followed by renal carcinoma.	('variants', 'Var', (21, 29))	('renal carcinoma', 'Disease', (75, 90))	('renal carcinoma', 'Phenotype', 'HP:0005584', (75, 90))	('BKV', 'Gene', (17, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('renal carcinoma', 'Disease', 'MESH:C538614', (75, 90))	('B', 'Chemical', 'MESH:D001895', (58, 59))	('B', 'Chemical', 'MESH:D001895', (17, 18))
174161	29746834	Both patients showed a swarm of BKV sequence variants encoding non-silent mutations in surface loops of the viral major capsid protein.	('patients', 'Species', '9606', (5, 13))	('BKV sequence', 'Gene', (32, 44))	('variants', 'Var', (45, 53))	('B', 'Chemical', 'MESH:D001895', (32, 33))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('B', 'Chemical', 'MESH:D001895', (0, 1))
174163	29746834	The mutations also modified the spectrum of receptor glycans engaged by BKV during host cell entry.	('B', 'Chemical', 'MESH:D001895', (72, 73))	('spectrum of receptor glycans engaged', 'MPA', (32, 68))	('glycans', 'Chemical', 'MESH:D011134', (53, 60))	('modified', 'Reg', (19, 27))	('host cell', 'cellular_component', 'GO:0043657', ('83', '92'))	('mutations', 'Var', (4, 13))
174164	29746834	Intriguingly, all observed mutations were consistent with DNA damage caused by antiviral APOBEC3 cytosine deaminases.	('mutations', 'Var', (27, 36))	('APOBEC', 'cellular_component', 'GO:0030895', ('89', '95'))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('APOBEC3', 'Gene', (89, 96))	('B', 'Chemical', 'MESH:D001895', (92, 93))	('cytosine', 'Chemical', 'MESH:D003596', (97, 105))
174166	29746834	These results provide a snapshot of in-host BKV evolution and suggest that APOBEC3 may drive BKV mutagenesis in vivo.	('B', 'Chemical', 'MESH:D001895', (93, 94))	('APOBEC', 'cellular_component', 'GO:0030895', ('75', '81'))	('mutagenesis', 'biological_process', 'GO:0006280', ('97', '108'))	('APOBEC3', 'Gene', (75, 82))	('mutagenesis', 'Var', (97, 108))	('B', 'Chemical', 'MESH:D001895', (78, 79))	('drive', 'PosReg', (87, 92))	('BKV', 'Gene', (93, 96))	('B', 'Chemical', 'MESH:D001895', (44, 45))
174168	29746834	show that, during the development of nephropathy, BKV acquires mutations that confer a selective advantage to the virus.	('mutations', 'Var', (63, 72))	('nephropathy', 'Disease', (37, 48))	('nephropathy', 'Phenotype', 'HP:0000112', (37, 48))	('nephropathy', 'Disease', 'MESH:D007674', (37, 48))	('B', 'Chemical', 'MESH:D001895', (50, 51))	('advantage', 'PosReg', (97, 106))	('BKV', 'Gene', (50, 53))
174169	29746834	The sequence changes are suggestive of a role for cellular APOBEC3 DNA cytosine deaminases in driving BKV mutagenesis in vivo.	('BKV', 'Gene', (102, 105))	('changes', 'Var', (13, 20))	('cytosine', 'Chemical', 'MESH:D003596', (71, 79))	('mutagenesis', 'biological_process', 'GO:0006280', ('106', '117'))	('B', 'Chemical', 'MESH:D001895', (102, 103))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('mutagenesis', 'Var', (106, 117))	('APOBEC', 'cellular_component', 'GO:0030895', ('59', '65'))	('B', 'Chemical', 'MESH:D001895', (62, 63))
174171	29746834	BKV causes post-transplant nephropathy (BKVN) in up to 10% of kidney transplant recipients (KTRs).	('BKV', 'Var', (0, 3))	('nephropathy', 'Phenotype', 'HP:0000112', (27, 38))	('nephropathy', 'Disease', (27, 38))	('causes', 'Reg', (4, 10))	('B', 'Chemical', 'MESH:D001895', (40, 41))	('nephropathy', 'Disease', 'MESH:D007674', (27, 38))	('B', 'Chemical', 'MESH:D001895', (0, 1))
174178	29746834	In addition to dictating the cell-surface glycans used for infectious entry, mutations in VP1 apical surface loops can also allow polyomaviruses to escape from antibody-mediated neutralization.	('apical surface loops', 'Phenotype', 'HP:0032176', (94, 114))	('glycans', 'Chemical', 'MESH:D011134', (42, 49))	('VP1', 'Gene', (90, 93))	('allow', 'Reg', (124, 129))	('polyomaviruses', 'Species', '36362', (130, 144))	('dictating', 'Reg', (15, 24))	('antibody', 'cellular_component', 'GO:0042571', ('160', '168'))	('VP1', 'Gene', '29031008', (90, 93))	('antibody', 'cellular_component', 'GO:0019814', ('160', '168'))	('mutations', 'Var', (77, 86))	('antibody', 'cellular_component', 'GO:0019815', ('160', '168'))	('cell-surface', 'cellular_component', 'GO:0009986', ('29', '41'))	('polyomaviruses', 'Protein', (130, 144))	('escape', 'MPA', (148, 154))	('antibody', 'molecular_function', 'GO:0003823', ('160', '168'))	('antibody-mediated neutralization', 'biological_process', 'GO:0097282', ('160', '192'))
174179	29746834	APOBEC3 (A3) proteins are a family of ssDNA cytosine deaminases that provide innate antiviral defenses by catastrophically mutating the genomes of DNA-based viruses, including retroviruses, parvoviruses and herpesviruses.	('retroviruses', 'Disease', (176, 188))	('herpesviruses', 'Disease', (207, 220))	('cytosine', 'Chemical', 'MESH:D003596', (44, 52))	('DNA', 'cellular_component', 'GO:0005574', ('147', '150'))	('genomes', 'MPA', (136, 143))	('B', 'Chemical', 'MESH:D001895', (3, 4))	('mutating', 'Var', (123, 131))	('APOBEC', 'cellular_component', 'GO:0030895', ('0', '6'))	('parvoviruses', 'Disease', (190, 202))
174181	29746834	Evidence from in vitro models  and tumor sequencing data  suggests that nuclear DNA cytosine deamination and erroneous repair can result in substitution of the original cytosine with any base.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cytosine', 'Chemical', 'MESH:D003596', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cytosine', 'Chemical', 'MESH:D003596', (169, 177))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('nuclear DNA', 'Var', (72, 83))	('tumor', 'Disease', (35, 40))	('erroneous', 'Var', (109, 118))	('result in', 'Reg', (130, 139))	('DNA cytosine deamination', 'biological_process', 'GO:0070383', ('80', '104'))	('substitution', 'Var', (140, 152))
174185	29746834	In this study, we examine the biology of BKV variants found in two case studies of KTRs who developed BKVN followed by clear cell renal cell carcinoma (ccRCC).	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('B', 'Chemical', 'MESH:D001895', (41, 42))	('BKV', 'Gene', (41, 44))	('variants', 'Var', (45, 53))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (119, 150))	('clear cell renal cell carcinoma', 'Disease', (119, 150))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (130, 150))	('B', 'Chemical', 'MESH:D001895', (102, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (152, 157))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (119, 150))
174188	29746834	Deep sequencing of rolling circle amplification (RCA) products showed that both subjects had BKV genotype IVc2 in their serum and urine.	('B', 'Chemical', 'MESH:D001895', (93, 94))	('BKV', 'Gene', (93, 96))	('RCA', 'Chemical', '-', (49, 52))	('genotype IVc2', 'Var', (97, 110))
174189	29746834	The dominant sequence identified in Patient 1 (Pt1) was identical to isolate FIN-2 (GenBank: AB260033) except for two point differences (G2677A and T3823C), while isolate LAB-33 (GenBank: AB301097) was dominant in Patient 2 (Pt2).	('B', 'Chemical', 'MESH:D001895', (94, 95))	('G2677A', 'Var', (137, 143))	('B', 'Chemical', 'MESH:D001895', (173, 174))	('Patient', 'Species', '9606', (214, 221))	('T3823C', 'Mutation', 'g.3823T>C', (148, 154))	('Patient', 'Species', '9606', (36, 43))	('G2677A', 'Mutation', 'c.2677G>A', (137, 143))	('B', 'Chemical', 'MESH:D001895', (182, 183))	('T3823C', 'Var', (148, 154))	('B', 'Chemical', 'MESH:D001895', (189, 190))	('B', 'Chemical', 'MESH:D001895', (87, 88))
174191	29746834	In addition to the inferred wild-type (wt) VP1 protein sequence, which was identical in the two patients, we detected a total of 12 non-silent mutations in the VP1 coding region at varying abundances (as reflected in relative read counts).	('VP1', 'Gene', (160, 163))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('patients', 'Species', '9606', (96, 104))	('VP1', 'Gene', (43, 46))	('VP1', 'Gene', '29031008', (160, 163))	('mutations', 'Var', (143, 152))	('VP1', 'Gene', '29031008', (43, 46))
174194	29746834	VP1 mutations were evident in both serum and urine from Pt1, but only in urine from Pt2.	('mutations', 'Var', (4, 13))	('VP1', 'Gene', '29031008', (0, 3))	('VP1', 'Gene', (0, 3))
174196	29746834	Intriguingly, all of the 12 observed VP1 mutations are consistent with the A3B signature, with deamination affecting the antisense DNA strand.	('A3B', 'Gene', (75, 78))	('mutations', 'Var', (41, 50))	('A3B', 'Gene', '9582', (75, 78))	('VP1', 'Gene', (37, 40))	('deamination', 'MPA', (95, 106))	('DNA', 'cellular_component', 'GO:0005574', ('131', '134'))	('VP1', 'Gene', '29031008', (37, 40))	('antisense DNA', 'MPA', (121, 134))
174197	29746834	The TCW-to-TKW mutational signature is strikingly reminiscent of the dominant pattern of mutations in bladder cancers.	('bladder cancer', 'Phenotype', 'HP:0009725', (102, 116))	('TCW-to-TKW', 'Var', (4, 14))	('bladder cancers', 'Disease', 'MESH:D001749', (102, 117))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('TC', 'Chemical', 'MESH:D013667', (4, 6))	('bladder cancers', 'Disease', (102, 117))	('bladder cancers', 'Phenotype', 'HP:0009725', (102, 117))
174199	29746834	Figure 1 summarizes how VP1 mutations appear to have evolved over time.	('VP1', 'Gene', '29031008', (24, 27))	('VP1', 'Gene', (24, 27))	('mutations', 'Var', (28, 37))
174200	29746834	Discernible split peaks confirmed on both DNA strands were only observed for the major mutations within the BC loop (D62N and E73K for Pt1, D62N and D77N for Pt2).	('D62N', 'Mutation', 'p.D62N', (140, 144))	('B', 'Chemical', 'MESH:D001895', (108, 109))	('E73K', 'Mutation', 'p.E73K', (126, 130))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('D77N', 'Var', (149, 153))	('E73K', 'Var', (126, 130))	('D62N', 'Mutation', 'p.D62N', (117, 121))	('D77N', 'Mutation', 'p.D77N', (149, 153))	('D62N', 'Var', (140, 144))	('D62N', 'Var', (117, 121))
174201	29746834	In both subjects, only wt VP1 was observed at early time points, with mutations appearing around the time of BKVN diagnosis.	('B', 'Chemical', 'MESH:D001895', (109, 110))	('VP1', 'Gene', '29031008', (26, 29))	('mutations', 'Var', (70, 79))	('VP1', 'Gene', (26, 29))
174205	29746834	Beyond VP1 mutations, the deep sequencing revealed other variations across the genome of the patients' BKV isolates at the time of BKVN (Table S1).	('mutations', 'Var', (11, 20))	('B', 'Chemical', 'MESH:D001895', (103, 104))	('VP1', 'Gene', '29031008', (7, 10))	('B', 'Chemical', 'MESH:D001895', (131, 132))	('B', 'Chemical', 'MESH:D001895', (0, 1))	('patients', 'Species', '9606', (93, 101))	('VP1', 'Gene', (7, 10))	('variations', 'Var', (57, 67))
174206	29746834	A majority of the additional point mutations were consistent with the A3B signature.	('A3B', 'Gene', '9582', (70, 73))	('A3B', 'Gene', (70, 73))	('point mutations', 'Var', (29, 44))
174208	29746834	Second, we hypothesized that some of the observed non-silent mutations in VP1 might impart greater fitness to the virus by allowing escape from the recipients' neutralizing antibody responses.	('antibody', 'cellular_component', 'GO:0019814', ('173', '181'))	('non-silent mutations', 'Var', (50, 70))	('antibody', 'molecular_function', 'GO:0003823', ('173', '181'))	('antibody', 'cellular_component', 'GO:0019815', ('173', '181'))	('mutations', 'Var', (61, 70))	('antibody', 'cellular_component', 'GO:0042571', ('173', '181'))	('fitness', 'MPA', (99, 106))	('escape', 'MPA', (132, 138))	('VP1', 'Gene', (74, 77))	('greater', 'PosReg', (91, 98))	('VP1', 'Gene', '29031008', (74, 77))
174209	29746834	This scenario, in which individual point mutations allow the virus to evade antibody-mediated neutralization, would be reminiscent of recent studies of JCV.	('antibody', 'cellular_component', 'GO:0019814', ('76', '84'))	('antibody', 'molecular_function', 'GO:0003823', ('76', '84'))	('evade', 'NegReg', (70, 75))	('antibody-mediated neutralization', 'biological_process', 'GO:0097282', ('76', '108'))	('antibody', 'cellular_component', 'GO:0042571', ('76', '84'))	('point mutations', 'Var', (35, 50))	('JCV', 'Species', '10632', (152, 155))	('antibody', 'cellular_component', 'GO:0019815', ('76', '84'))
174216	29746834	Reporter pseudoviruses representing the inferred wt or patient-specific mutant VP1 (BC loop) sequences observed in NGS were tested on three different cell lines known to support infectious entry by BKV and JCV pseudoviruses (293TT, ART and SFT) and on primary renal proximal tubular epithelial (RPTE) cells.	('VP1', 'Gene', (79, 82))	('support', 'PosReg', (170, 177))	('mutant', 'Var', (72, 78))	('VP1', 'Gene', '29031008', (79, 82))	('293TT', 'CellLine', 'CVCL:1D85', (225, 230))	('B', 'Chemical', 'MESH:D001895', (198, 199))	('B', 'Chemical', 'MESH:D001895', (84, 85))	('JCV', 'Species', '10632', (206, 209))	('patient', 'Species', '9606', (55, 62))	('infectious entry', 'MPA', (178, 194))	('tested', 'Reg', (124, 130))
174218	29746834	In particular, E73K and D77H pseudoviruses were neutralized, respectively, ~90-fold and ~70-fold less efficiently than the wt pseudovirus.	('E73K', 'Var', (15, 19))	('D77H', 'Mutation', 'rs747092505', (24, 28))	('D77H', 'Var', (24, 28))	('E73K', 'Mutation', 'p.E73K', (15, 19))	('pseudoviruses', 'Protein', (29, 42))	('less', 'NegReg', (97, 101))
174219	29746834	The results confirm the hypothesis that, as we have previously reported for JCV, individual point mutations in VP1 surface loops can confer relative resistance to serum antibody-mediated neutralization.	('antibody', 'cellular_component', 'GO:0042571', ('169', '177'))	('antibody', 'cellular_component', 'GO:0019815', ('169', '177'))	('point mutations', 'Var', (92, 107))	('antibody', 'cellular_component', 'GO:0019814', ('169', '177'))	('VP1', 'Gene', (111, 114))	('antibody', 'molecular_function', 'GO:0003823', ('169', '177'))	('VP1', 'Gene', '29031008', (111, 114))	('JCV', 'Species', '10632', (76, 79))	('antibody-mediated neutralization', 'biological_process', 'GO:0097282', ('169', '201'))
174222	29746834	The fact that BKV-IV VP1 mutations mapping to the receptor-binding BC loop were associated with poorer infectivity compared to the wt strain on some cell lines led us to wonder whether the tested mutants might engage different infectious entry pathways.	('mutations', 'Var', (25, 34))	('VP1', 'Gene', '29031008', (21, 24))	('infectious', 'CPA', (227, 237))	('B', 'Chemical', 'MESH:D001895', (67, 68))	('poorer', 'NegReg', (96, 102))	('receptor-binding', 'molecular_function', 'GO:0005102', ('50', '66'))	('infectivity', 'MPA', (103, 114))	('VP1', 'Gene', (21, 24))	('B', 'Chemical', 'MESH:D001895', (14, 15))	('engage', 'Reg', (210, 216))
174224	29746834	3Fax-treated SFT cells showed dramatic resistance to all tested BKV variants (Figure S3A).	('variants', 'Var', (68, 76))	('3Fax', 'Chemical', '-', (0, 4))	('BKV', 'Gene', (64, 67))	('resistance', 'MPA', (39, 49))	('B', 'Chemical', 'MESH:D001895', (64, 65))
174225	29746834	The results indicate that the patients' BC loop mutants, like wt BKV-IV, remain dependent on sialylated glycans for infectious entry.	('glycans', 'Chemical', 'MESH:D011134', (104, 111))	('B', 'Chemical', 'MESH:D001895', (65, 66))	('mutants', 'Var', (48, 55))	('patients', 'Species', '9606', (30, 38))	('B', 'Chemical', 'MESH:D001895', (40, 41))	('sialylated glycans', 'Protein', (93, 111))
174226	29746834	To explore the possibility that mutant BKV-IV strains selectively associate with a different range of sialylated glycans than the wt strain, we performed hemagglutination assays using red blood cells (RBCs) from a variety of animal species.	('B', 'Chemical', 'MESH:D001895', (202, 203))	('BKV-IV', 'Gene', (39, 45))	('B', 'Chemical', 'MESH:D001895', (39, 40))	('mutant', 'Var', (32, 38))	('glycans', 'Chemical', 'MESH:D011134', (113, 120))	('associate', 'Interaction', (66, 75))
174230	29746834	In contrast, each of the tested mutant pseudovirions agglutinated both goose and sheep RBCs.	('agglutinated', 'PosReg', (53, 65))	('goose', 'Species', '8847', (71, 76))	('sheep', 'Species', '9940', (81, 86))	('B', 'Chemical', 'MESH:D001895', (88, 89))	('mutant', 'Var', (32, 38))
174231	29746834	This indicates that the BC loop mutants are able to engage a different spectrum of cell surface glycans than the wt pseudovirus (Figure S3B).	('B', 'Chemical', 'MESH:D001895', (138, 139))	('engage', 'MPA', (52, 58))	('mutants', 'Var', (32, 39))	('cell surface', 'cellular_component', 'GO:0009986', ('83', '95'))	('BC loop', 'Gene', (24, 31))	('B', 'Chemical', 'MESH:D001895', (24, 25))	('glycans', 'Chemical', 'MESH:D011134', (96, 103))
174232	29746834	To obtain a more general picture of BKV genotypes and VP1 mutations in additional patients, we performed a PCR/NGS analysis using multiple pairs of BKV/JCV consensus primers on DNA extracted from blood or urine collected from a cohort of 24 KTRs with ongoing BKV replication.	('mutations', 'Var', (58, 67))	('patients', 'Species', '9606', (82, 90))	('B', 'Chemical', 'MESH:D001895', (259, 260))	('B', 'Chemical', 'MESH:D001895', (148, 149))	('DNA', 'cellular_component', 'GO:0005574', ('177', '180'))	('B', 'Chemical', 'MESH:D001895', (36, 37))	('VP1', 'Gene', (54, 57))	('JCV', 'Species', '10632', (152, 155))	('VP1', 'Gene', '29031008', (54, 57))
174234	29746834	BKV genotypes and VP1 mutations observed in NGS analysis of PCR products, along with their estimated relative abundance, are listed in Table S4.	('VP1', 'Gene', (18, 21))	('VP1', 'Gene', '29031008', (18, 21))	('mutations', 'Var', (22, 31))	('B', 'Chemical', 'MESH:D001895', (0, 1))
174235	29746834	The deep sequencing revealed a high prevalence of genotype Ib2 (14 plasma/serum samples and 9 urine samples) and genotype IV (8 plasma samples and 4 urine samples).	('Ib2', 'Gene', (59, 62))	('Ib2', 'Gene', '23542', (59, 62))	('genotype', 'Var', (50, 58))
174236	29746834	Interestingly, the only observed non-silent surface (BC) loop mutation (E73Q, genotype Ib2) with an A3B signature was detected in the single patient with full-blown BKVN.	('E73Q', 'Var', (72, 76))	('E73Q', 'Mutation', 'p.E73Q', (72, 76))	('A3B', 'Gene', '9582', (100, 103))	('Ib2', 'Gene', (87, 90))	('Ib2', 'Gene', '23542', (87, 90))	('patient', 'Species', '9606', (141, 148))	('B', 'Chemical', 'MESH:D001895', (53, 54))	('A3B', 'Gene', (100, 103))	('B', 'Chemical', 'MESH:D001895', (102, 103))	('B', 'Chemical', 'MESH:D001895', (165, 166))
174237	29746834	In summary, non-silent surface loop mutations consistent with A3B damage were found in a total of 3/3 BKVN patients but not in any of 23 patients diagnosed only with BKV viremia.	('BKV viremia', 'Disease', (166, 177))	('B', 'Chemical', 'MESH:D001895', (166, 167))	('mutations', 'Var', (36, 45))	('A3B', 'Gene', (62, 65))	('patients', 'Species', '9606', (137, 145))	('BKVN', 'Disease', (102, 106))	('B', 'Chemical', 'MESH:D001895', (64, 65))	('B', 'Chemical', 'MESH:D001895', (102, 103))	('A3B', 'Gene', '9582', (62, 65))	('BKV viremia', 'Disease', 'MESH:D014766', (166, 177))	('viremia', 'Phenotype', 'HP:0020071', (170, 177))	('patients', 'Species', '9606', (107, 115))
174238	29746834	The fact that BKV infection specifically up-regulates A3B in primary cultured cells  suggests A3B-mediated editing as the most parsimonious explanation for the observed VP1 mutations.	('A3B', 'Gene', '9582', (94, 97))	('A3B', 'Gene', (54, 57))	('BKV infection', 'Disease', 'MESH:D007239', (14, 27))	('up-regulates', 'PosReg', (41, 53))	('VP1', 'Gene', (169, 172))	('mutations', 'Var', (173, 182))	('A3B', 'Gene', '9582', (54, 57))	('BKV infection', 'Disease', (14, 27))	('VP1', 'Gene', '29031008', (169, 172))	('A3B', 'Gene', (94, 97))
174246	29746834	We hypothesized that BKV-induced A3 damage to the cellular genome might serve as a durable record of the past presence of the virus in a tumor.	('BKV-induced', 'Gene', (21, 32))	('B', 'Chemical', 'MESH:D001895', (21, 22))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('A3 damage', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
174248	29746834	The sequences revealed only a low level of A3-type mutations in the tumor exome, with frequencies similar to prior analyses of kidney cancer specimens from the general population (Figure S4).	('tumor', 'Disease', (68, 73))	('kidney cancer', 'Disease', 'MESH:D007680', (127, 140))	('kidney cancer', 'Phenotype', 'HP:0009726', (127, 140))	('kidney cancer', 'Disease', (127, 140))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('A3-type', 'Var', (43, 50))
174251	29746834	The observed neutralization-escape mutations in the major capsid protein VP1 also alter the spectrum of sialylated glycans the virus engages during the infectious entry process, potentially triggering altered tissue tropism and pathogenicity.	('tropism', 'biological_process', 'GO:0009606', ('216', '223'))	('alter', 'Reg', (82, 87))	('VP1', 'Gene', (73, 76))	('glycans', 'Chemical', 'MESH:D011134', (115, 122))	('VP1', 'Gene', '29031008', (73, 76))	('neutralization-escape', 'Disease', (13, 34))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('spectrum of sialylated glycans', 'MPA', (92, 122))	('tissue', 'MPA', (209, 215))	('triggering altered', 'Reg', (190, 208))	('mutations', 'Var', (35, 44))
174252	29746834	Dominant VP1 mutations detected in BKVN patients are consistent with A3 damage, most likely A3B, which the virus is known to up-regulate.	('B', 'Chemical', 'MESH:D001895', (35, 36))	('A3B', 'Gene', (92, 95))	('patients', 'Species', '9606', (40, 48))	('B', 'Chemical', 'MESH:D001895', (94, 95))	('VP1', 'Gene', (9, 12))	('A3 damage', 'Disease', (69, 78))	('up-regulate', 'PosReg', (125, 136))	('A3B', 'Gene', '9582', (92, 95))	('VP1', 'Gene', '29031008', (9, 12))	('mutations', 'Var', (13, 22))
174253	29746834	Together, these findings suggest a model in which BKV has evolved to hijack A3B (thought to normally provide innate antiviral defense) to attract site-specific mutations that confer a selective advantage to the virus.	('mutations', 'Var', (160, 169))	('A3B', 'Gene', '9582', (76, 79))	('B', 'Chemical', 'MESH:D001895', (50, 51))	('B', 'Chemical', 'MESH:D001895', (78, 79))	('A3B', 'Gene', (76, 79))
174255	29746834	This raises the possibility that the virus could acquire, for example, the common E73Q mutation through A3 damage to the VP1 antisense/lagging DNA strand then later acquire a Q73E reversion mutation through A3 damage to the hypothetically more accessible VP1 sense/lagging-template DNA strand.	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('VP1', 'Gene', '29031008', (255, 258))	('VP1', 'Gene', (121, 124))	('Q73E', 'Mutation', 'p.Q73E', (175, 179))	('E73Q', 'Mutation', 'p.E73Q', (82, 86))	('VP1', 'Gene', '29031008', (121, 124))	('E73Q', 'Var', (82, 86))	('Q73E', 'Var', (175, 179))	('VP1', 'Gene', (255, 258))	('DNA', 'cellular_component', 'GO:0005574', ('282', '285'))
174259	29746834	Similar to the BKV VP1 mutations investigated in the current study, the most common PML-associated JCV VP1 mutations are known to alter the spectrum of glycans the virus can use for infectious entry  and also fit the typical A3B signature.	('B', 'Chemical', 'MESH:D001895', (227, 228))	('PML-associated', 'Disease', (84, 98))	('mutations', 'Var', (107, 116))	('VP1', 'Gene', (103, 106))	('alter', 'Reg', (130, 135))	('B', 'Chemical', 'MESH:D001895', (15, 16))	('glycans', 'Chemical', 'MESH:D011134', (152, 159))	('spectrum of glycans', 'MPA', (140, 159))	('JCV', 'Species', '10632', (99, 102))	('A3B', 'Gene', '9582', (225, 228))	('VP1', 'Gene', '29031008', (103, 106))	('infectious entry', 'MPA', (182, 198))	('VP1', 'Gene', (19, 22))	('VP1', 'Gene', '29031008', (19, 22))	('A3B', 'Gene', (225, 228))
174260	29746834	In contrast to BKV, the dominant PML-associated mutations in JCV affect the VP1 sense (lagging-template) DNA strand.	('affect', 'Reg', (65, 71))	('JCV', 'Gene', (61, 64))	('B', 'Chemical', 'MESH:D001895', (15, 16))	('JCV', 'Species', '10632', (61, 64))	('VP1', 'Gene', (76, 79))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('VP1', 'Gene', '29031008', (76, 79))	('mutations', 'Var', (48, 57))
174261	29746834	In a recently reported chimeric humanized mouse model of JCV/PML, various VP1 point mutations observed at an 8-week infection time point were consistent with the A3B signature affecting both the sense and antisense DNA strands underlying VP1 surface loops.	('mouse', 'Species', '10090', (42, 47))	('antisense', 'Var', (205, 214))	('JCV', 'Species', '10632', (57, 60))	('VP1', 'Gene', (238, 241))	('A3B', 'Gene', '9582', (162, 165))	('DNA', 'cellular_component', 'GO:0005574', ('215', '218'))	('mutations', 'Var', (84, 93))	('affecting', 'Reg', (176, 185))	('VP1', 'Gene', '29031008', (238, 241))	('human', 'Species', '9606', (32, 37))	('VP1', 'Gene', (74, 77))	('A3B', 'Gene', (162, 165))	('VP1', 'Gene', '29031008', (74, 77))
174264	29746834	The BC loop mutants detected in Pt1 exhibited relative resistance to neutralization during BKVN development.	('mutants', 'Var', (12, 19))	('B', 'Chemical', 'MESH:D001895', (91, 92))	('Pt1', 'Gene', (32, 35))	('BC loop', 'Gene', (4, 11))	('B', 'Chemical', 'MESH:D001895', (4, 5))
174315	29746834	In order to catalog VP1 variants, individual reads were mapped against single BKV reference genomes (found in healthy individuals) representative of each genotype found.	('VP1', 'Gene', (20, 23))	('VP1', 'Gene', '29031008', (20, 23))	('B', 'Chemical', 'MESH:D001895', (78, 79))	('variants', 'Var', (24, 32))
174362	29746834	Description: https://home.ccr.cancer.gov/Lco/protocols.asp BKV variants sequenced from kidney transplant patients during development of nephropathy BKV major capsid protein acquires surface loop mutations over time Mutations confer resistance to neutralizing antibodies and modify glycan receptor usage Mutational signatures match APOBEC3 activity and renal biopsies are positive for APOBEC3	('nephropathy', 'Disease', 'MESH:D007674', (136, 147))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('glycan receptor', 'MPA', (281, 296))	('B', 'Chemical', 'MESH:D001895', (59, 60))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('APOBEC', 'cellular_component', 'GO:0030895', ('384', '390'))	('APOBEC3', 'Gene', (331, 338))	('B', 'Chemical', 'MESH:D001895', (148, 149))	('nephropathy', 'Phenotype', 'HP:0000112', (136, 147))	('ccr', 'molecular_function', 'GO:0043880', ('26', '29'))	('patients', 'Species', '9606', (105, 113))	('variants', 'Var', (63, 71))	('resistance', 'MPA', (232, 242))	('cancer', 'Disease', (30, 36))	('activity', 'MPA', (339, 347))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('B', 'Chemical', 'MESH:D001895', (334, 335))	('APOBEC', 'cellular_component', 'GO:0030895', ('331', '337'))	('B', 'Chemical', 'MESH:D001895', (387, 388))	('nephropathy', 'Disease', (136, 147))
174369	32184452	The expression of VEGFR2 and phosphorylation of AKT and ERK in A2780, RMG1, and HeyA8 were decreased with axitinib treatment in dose-dependent manner, but not in HeyA8-MDR.	('ERK', 'Gene', '2048', (56, 59))	('A2780', 'Var', (63, 68))	('ERK', 'Gene', (56, 59))	('AKT', 'Gene', (48, 51))	('VEGFR2', 'Gene', '3791', (18, 24))	('expression', 'MPA', (4, 14))	('MDR', 'molecular_function', 'GO:0004745', ('168', '171'))	('axitinib', 'Chemical', 'MESH:D000077784', (106, 114))	('phosphorylation', 'biological_process', 'GO:0016310', ('29', '44'))	('VEGFR2', 'Gene', (18, 24))	('ERK', 'molecular_function', 'GO:0004707', ('56', '59'))	('AKT', 'Gene', '207', (48, 51))	('decreased', 'NegReg', (91, 100))	('phosphorylation', 'MPA', (29, 44))
174389	32184452	Apoptosis induction measured by active caspase-3 ELISA (24 h of treatment with 0, 1, 2, and 4 uM axitinib) and annexin V- FITC incorporation after treatment with axitinib (2 nM for A2780 and 4 nM for HeyA8, HeyA8-MDR, and RMG1) resulted in significantly increased apoptosis in axitinib-treated cells compared with control (Fig.	('increased', 'PosReg', (254, 263))	('annexin V', 'Gene', '308', (111, 120))	('A2780', 'Var', (181, 186))	('apoptosis', 'biological_process', 'GO:0097194', ('264', '273'))	('annexin V', 'Gene', (111, 120))	('caspase-3', 'Gene', (39, 48))	('axitinib', 'Chemical', 'MESH:D000077784', (97, 105))	('axitinib', 'Chemical', 'MESH:D000077784', (277, 285))	('apoptosis', 'biological_process', 'GO:0006915', ('264', '273'))	('FITC', 'Chemical', 'MESH:D016650', (122, 126))	('Apoptosis', 'CPA', (0, 9))	('HeyA8-MDR', 'Var', (207, 216))	('apoptosis', 'CPA', (264, 273))	('MDR', 'molecular_function', 'GO:0004745', ('213', '216'))	('caspase-3', 'Gene', '836', (39, 48))	('axitinib', 'Chemical', 'MESH:D000077784', (162, 170))
174392	32184452	Treatment with various doses of axitinib markedly decreased the expression of phospho-VEGFR2 in A2780, RMG1 and HeyA8 in a dose-dependent manner (Fig.	('expression', 'MPA', (64, 74))	('VEGFR2', 'Gene', '3791', (86, 92))	('A2780', 'Var', (96, 101))	('VEGFR2', 'Gene', (86, 92))	('decreased', 'NegReg', (50, 59))	('axitinib', 'Chemical', 'MESH:D000077784', (32, 40))
174400	32184452	In A2780 and RMG1 models, the tumor weight of the axitinib-treated group had significantly decreased by 50% compared with controls (Fig.	('axitinib', 'Chemical', 'MESH:D000077784', (50, 58))	('A2780', 'Var', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('decreased', 'NegReg', (91, 100))
174403	32184452	The numbers of Ki-67 positive cancer cells were significantly lower in tumors from mice treated with axitinib than in tumors from controls in A2780 and RMG1 (Fig.	('Ki-67', 'Gene', '17345', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('axitinib', 'Var', (101, 109))	('mice', 'Species', '10090', (83, 87))	('lower', 'NegReg', (62, 67))	('tumors', 'Disease', (71, 77))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Ki-67', 'Gene', (15, 20))	('tumors', 'Disease', (118, 124))	('axitinib', 'Chemical', 'MESH:D000077784', (101, 109))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
174409	32184452	Our group previously developed PDX models of EOC We selected case numbers OV-89-M6, platinum-sensitive high grade serous carcinoma, OV-64-M9, clear cell carcinoma, and OV-40-M7, platinum-resistant recurrent high grade serous carcinoma.	('OV-64-M9', 'Var', (132, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('serous carcinoma', 'Disease', (114, 130))	('serous carcinoma', 'Disease', 'MESH:D018284', (114, 130))	('EOC', 'Phenotype', 'HP:0025318', (45, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('serous carcinoma', 'Disease', (218, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('platinum', 'Chemical', 'MESH:D010984', (84, 92))	('clear cell carcinoma', 'Disease', (142, 162))	('EOC', 'Disease', 'MESH:D000077216', (45, 48))	('serous carcinoma', 'Disease', 'MESH:D018284', (218, 234))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (142, 162))	('platinum', 'Chemical', 'MESH:D010984', (178, 186))	('OV-89-M6', 'Var', (74, 82))	('EOC', 'Disease', (45, 48))
174448	32184452	Previously in clinical studies, high serum VEGF levels were correlated with higher risks of recurrence and death of EOC in a review of nine studies including 529 EOC patients.	('EOC', 'Disease', (162, 165))	('high', 'Var', (32, 36))	('EOC', 'Phenotype', 'HP:0025318', (162, 165))	('death', 'Disease', 'MESH:D003643', (107, 112))	('EOC', 'Disease', (116, 119))	('EOC', 'Disease', 'MESH:D000077216', (116, 119))	('VEGF', 'Gene', (43, 47))	('VEGF', 'Gene', '7422', (43, 47))	('death', 'Disease', (107, 112))	('EOC', 'Phenotype', 'HP:0025318', (116, 119))	('patients', 'Species', '9606', (166, 174))	('EOC', 'Disease', 'MESH:D000077216', (162, 165))
174482	32184452	Tumors were derived from one patient each with platinum-sensitive high grade serous EOC (OV-89-M5), clear cell carcinoma (OV-64-M9), and shigh grade serous EOC, platinum-resistant recurrent (OV-40-M7).	('patient', 'Species', '9606', (29, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('EOC', 'Disease', 'MESH:D000077216', (84, 87))	('EOC', 'Disease', (84, 87))	('clear cell carcinoma', 'Disease', (100, 120))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (100, 120))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('shigh grade', 'Var', (137, 148))	('EOC', 'Phenotype', 'HP:0025318', (84, 87))	('EOC', 'Phenotype', 'HP:0025318', (156, 159))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('platinum', 'Chemical', 'MESH:D010984', (161, 169))	('platinum', 'Chemical', 'MESH:D010984', (47, 55))	('EOC', 'Disease', 'MESH:D000077216', (156, 159))	('EOC', 'Disease', (156, 159))
174492	32185138	Identifying BAP1 Mutations in Clear-Cell Renal Cell Carcinoma by CT Radiomics: Preliminary Findings To evaluate the potential application of computed tomography (CT) radiomics in the prediction of BRCA1-associated protein 1 (BAP1) mutation status in patients with clear-cell renal cell carcinoma (ccRCC).	('ccRCC', 'Phenotype', 'HP:0006770', (297, 302))	('Clear-Cell Renal Cell Carcinoma', 'Disease', 'MESH:D002292', (30, 61))	('BRCA1-associated protein 1', 'Gene', (197, 223))	('Clear-Cell Renal Cell Carcinoma', 'Disease', (30, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (41, 61))	('Carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('Mutations', 'Var', (17, 26))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (264, 295))	('patients', 'Species', '9606', (250, 258))	('BAP1', 'Gene', '8314', (225, 229))	('ccRCC', 'Disease', 'MESH:D002292', (297, 302))	('BAP1', 'Gene', '8314', (12, 16))	('clear-cell renal cell carcinoma', 'Disease', (264, 295))	('Clear-Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (30, 61))	('ccRCC', 'Disease', (297, 302))	('BRCA1-associated protein 1', 'Gene', '8314', (197, 223))	('protein', 'cellular_component', 'GO:0003675', ('214', '221'))	('BAP1', 'Gene', (225, 229))	('BAP1', 'Gene', (12, 16))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (275, 295))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:D002292', (264, 295))
174494	32185138	Among these, 45 patients had wild-type BAP1 and nine patients had BAP1 mutation.	('BAP1', 'Gene', '8314', (66, 70))	('patients', 'Species', '9606', (53, 61))	('mutation', 'Var', (71, 79))	('patients', 'Species', '9606', (16, 24))	('BAP1', 'Gene', (66, 70))	('BAP1', 'Gene', '8314', (39, 43))	('BAP1', 'Gene', (39, 43))
174497	32185138	A model to predict BAP1 mutation status was constructed using Random Forest Classification algorithms, and was evaluated using leave-one-out-cross-validation.	('BAP1', 'Gene', '8314', (19, 23))	('mutation', 'Var', (24, 32))	('BAP1', 'Gene', (19, 23))
174498	32185138	Random Forest model of predict BAP1 mutation status had an accuracy of 0.83, sensitivity of 0.72, specificity of 0.87, precision of 0.65, AUC of 0.77, F-score of 0.68.	('mutation status', 'Var', (36, 51))	('BAP1', 'Gene', (31, 35))	('BAP1', 'Gene', '8314', (31, 35))
174502	32185138	Even though VHL mutation occurs in as high as 52% of ccRCC cases, meta-analysis indicates that it has no prognostic or predictive value in patients with ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (153, 158))	('ccRCC', 'Disease', (53, 58))	('ccRCC', 'Disease', (153, 158))	('mutation', 'Var', (16, 24))	('VHL', 'Gene', (12, 15))	('ccRCC', 'Disease', 'MESH:D002292', (153, 158))	('patients', 'Species', '9606', (139, 147))	('VHL', 'Gene', '7428', (12, 15))	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('ccRCC', 'Disease', 'MESH:D002292', (53, 58))
174503	32185138	BAP1 mutated in 10-15% of ccRCC, but it has recently garnered attention for several reasons.	('BAP1', 'Gene', (0, 4))	('ccRCC', 'Phenotype', 'HP:0006770', (26, 31))	('ccRCC', 'Disease', (26, 31))	('ccRCC', 'Disease', 'MESH:D002292', (26, 31))	('mutated', 'Var', (5, 12))	('BAP1', 'Gene', '8314', (0, 4))
174504	32185138	reported an association between BAP1 mutation and pathology grading of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('ccRCC', 'Disease', (71, 76))	('mutation', 'Var', (37, 45))	('BAP1', 'Gene', '8314', (32, 36))	('ccRCC', 'Disease', 'MESH:D002292', (71, 76))	('association', 'Interaction', (12, 23))	('BAP1', 'Gene', (32, 36))
174505	32185138	Moreover, greater than 50% of patients with ccRCC with BAP1 mutations exhibit coagulative tumor necrosis and have poor clinical outcomes.	('necrosis', 'biological_process', 'GO:0019835', ('96', '104'))	('exhibit', 'Reg', (70, 77))	('necrosis', 'biological_process', 'GO:0008220', ('96', '104'))	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('necrosis', 'biological_process', 'GO:0001906', ('96', '104'))	('BAP1', 'Gene', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('ccRCC', 'Disease', (44, 49))	('ccRCC', 'Disease', 'MESH:D002292', (44, 49))	('patients', 'Species', '9606', (30, 38))	('necrosis', 'biological_process', 'GO:0070265', ('96', '104'))	('mutations', 'Var', (60, 69))	('coagulative tumor necrosis', 'Disease', 'MESH:D025861', (78, 104))	('coagulative tumor necrosis', 'Disease', (78, 104))	('necrosis', 'biological_process', 'GO:0008219', ('96', '104'))	('BAP1', 'Gene', '8314', (55, 59))
174506	32185138	Other studies have demonstrated an association between BAP1 mutation and mammalian target of rapamycin (mTOR) pathway activation.	('mTOR', 'Gene', (104, 108))	('mutation', 'Var', (60, 68))	('activation', 'PosReg', (118, 128))	('mTOR', 'Gene', '2475', (104, 108))	('BAP1', 'Gene', (55, 59))	('mammalian target of rapamycin', 'Gene', '2475', (73, 102))	('mammalian target of rapamycin', 'Gene', (73, 102))	('BAP1', 'Gene', '8314', (55, 59))
174507	32185138	Patients with BAP1 mutation do not respond well to targeted therapy, and those with wild-type tumors appear to have longer progression-free survival than those with BAP1 mutation tumors.	('BAP1', 'Gene', '8314', (14, 18))	('longer', 'PosReg', (116, 122))	('mutation', 'Var', (19, 27))	('BAP1', 'Gene', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('BAP1', 'Gene', (14, 18))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('progression-free survival', 'CPA', (123, 148))	('BAP1', 'Gene', '8314', (165, 169))
174508	32185138	utilized computed tomography (CT) imaging features to predict epidermal growth factor receptor (EGFR) mutations in patients with non-small cell lung cancer.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (129, 155))	('patients', 'Species', '9606', (115, 123))	('epidermal growth factor receptor', 'Gene', (62, 94))	('EGFR', 'Gene', (96, 100))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (129, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('epidermal growth factor receptor', 'Gene', '1956', (62, 94))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('mutations', 'Var', (102, 111))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (133, 155))	('non-small cell lung cancer', 'Disease', (129, 155))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('62', '85'))	('EGFR', 'Gene', '1956', (96, 100))
174509	32185138	Their results suggest that wild-type EGFR is associated with conditions such as emphysema and airway malformation, while EGFR mutations are associated with ground-glass opacity changes.	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('associated', 'Reg', (140, 150))	('ground-glass opacity changes', 'Disease', (156, 184))	('EGFR', 'Gene', '1956', (121, 125))	('emphysema', 'Phenotype', 'HP:0002097', (80, 89))	('EGFR', 'Gene', (121, 125))	('airway malformation', 'Disease', (94, 113))	('associated', 'Reg', (45, 55))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'molecular_function', 'GO:0005006', ('121', '125'))	('ground-glass opacity', 'Phenotype', 'HP:0025179', (156, 176))	('mutations', 'Var', (126, 135))	('EGFR', 'Gene', (37, 41))	('emphysema', 'Disease', (80, 89))	('emphysema', 'Disease', 'MESH:D004646', (80, 89))
174510	32185138	In addition, the isocitrate dehydrogenase 1 (IDH1) gene mutation is considered a specific marker for glioma, and the radiomics method has been developed to reveal IDH1 status for patients with glioma.	('IDH1', 'Gene', '3417', (45, 49))	('IDH1', 'Gene', (163, 167))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Disease', (193, 199))	('glioma', 'Disease', (101, 107))	('IDH1', 'Gene', '3417', (163, 167))	('isocitrate dehydrogenase 1', 'Gene', (17, 43))	('isocitrate dehydrogenase 1', 'Gene', '3417', (17, 43))	('mutation', 'Var', (56, 64))	('patients', 'Species', '9606', (179, 187))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('IDH1', 'Gene', (45, 49))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
174511	32185138	Due to the fact that ccRCC with different genotypes may respond differently to targeted therapy, the extraction of imaging biomarkers that are capable of predicting BAP1 mutation would be of great significance for ccRCC precision therapy.	('ccRCC', 'Disease', (214, 219))	('BAP1', 'Gene', (165, 169))	('ccRCC', 'Disease', 'MESH:D002292', (214, 219))	('ccRCC', 'Phenotype', 'HP:0006770', (21, 26))	('ccRCC', 'Disease', (21, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (214, 219))	('ccRCC', 'Disease', 'MESH:D002292', (21, 26))	('BAP1', 'Gene', '8314', (165, 169))	('mutation', 'Var', (170, 178))
174512	32185138	In this study, we evaluated the potential application of the radiomics method in predicting BAP1 mutation status in patients with ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (130, 135))	('patients', 'Species', '9606', (116, 124))	('ccRCC', 'Disease', (130, 135))	('ccRCC', 'Disease', 'MESH:D002292', (130, 135))	('BAP1', 'Gene', '8314', (92, 96))	('mutation', 'Var', (97, 105))	('BAP1', 'Gene', (92, 96))
174515	32185138	The inclusion criteria were, respectively, enrolled in our study for assessment: (1) BAP1 mutation status from TCGA were available (BAP1 mutated or unmutated), (2) available CT images in TCIA (contrast enhancement).	('BAP1', 'Gene', (85, 89))	('BAP1', 'Gene', '8314', (132, 136))	('BAP1', 'Gene', (132, 136))	('BAP1', 'Gene', '8314', (85, 89))	('mutated', 'Var', (137, 144))
174516	32185138	A total of nine patients with BAP1 mutation and 45 patients with BAP1 unmutation met these criteria and thus were included in this study.	('BAP1', 'Gene', '8314', (65, 69))	('BAP1', 'Gene', (30, 34))	('patients', 'Species', '9606', (16, 24))	('BAP1', 'Gene', (65, 69))	('patients', 'Species', '9606', (51, 59))	('mutation', 'Var', (35, 43))	('BAP1', 'Gene', '8314', (30, 34))
174525	32185138	In this study, the number of patients with BAP1 mutation that met the inclusion criteria was very limited, which resulted in an imbalance between the mutation group and wild-type group.	('patients', 'Species', '9606', (29, 37))	('BAP1', 'Gene', (43, 47))	('imbalance', 'Phenotype', 'HP:0002172', (128, 137))	('BAP1', 'Gene', '8314', (43, 47))	('mutation', 'Var', (48, 56))	('imbalance', 'MPA', (128, 137))
174526	32185138	To address this problem, we performed data augmentation for the small-sized BAP1 mutation group and performed downsampling for the large-sized BAP1 wild-type group.	('BAP1', 'Gene', (143, 147))	('BAP1', 'Gene', '8314', (76, 80))	('mutation', 'Var', (81, 89))	('BAP1', 'Gene', (76, 80))	('BAP1', 'Gene', '8314', (143, 147))
174527	32185138	According to previous imbalanced data of radiomics study, each BAP1 mutation case was segmented with more samples.	('mutation', 'Var', (68, 76))	('BAP1', 'Gene', (63, 67))	('imbalance', 'Phenotype', 'HP:0002172', (22, 31))	('BAP1', 'Gene', '8314', (63, 67))
174529	32185138	We initially had 54 ccRCC cases, which included 45 cases (90 segmentations) without BAP1 mutations and nine cases (31 segmentations) with BAP1 mutations.	('BAP1', 'Gene', '8314', (138, 142))	('BAP1', 'Gene', '8314', (84, 88))	('ccRCC', 'Disease', (20, 25))	('BAP1', 'Gene', (138, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (20, 25))	('ccRCC', 'Disease', 'MESH:D002292', (20, 25))	('mutations', 'Var', (89, 98))	('BAP1', 'Gene', (84, 88))
174530	32185138	Therefore, for each LOOCV iteration, there were 180 labeled segmentations in training, which included 90 segmentations with wild-type BAP1 and 90 segmentations with BAP1 mutations.	('BAP1', 'Gene', (134, 138))	('BAP1', 'Gene', (165, 169))	('mutations', 'Var', (170, 179))	('BAP1', 'Gene', '8314', (134, 138))	('BAP1', 'Gene', '8314', (165, 169))
174536	32185138	The results suggest that RF algorithm-based high-dimensional quantitative CT radiomics analysis might be a feasible and potential method for predicting BAP1 mutation status in patients with ccRCC.	('patients', 'Species', '9606', (176, 184))	('ccRCC', 'Disease', (190, 195))	('RF', 'Chemical', '-', (25, 27))	('ccRCC', 'Disease', 'MESH:D002292', (190, 195))	('BAP1', 'Gene', '8314', (152, 156))	('mutation', 'Var', (157, 165))	('BAP1', 'Gene', (152, 156))	('ccRCC', 'Phenotype', 'HP:0006770', (190, 195))
174539	32185138	investigated the association between CT features of ccRCC and mutations in VHL, PBRM1, SETD2, KDM5C, and BAP1 genes.	('PBRM1', 'Gene', '55193', (80, 85))	('VHL', 'Gene', (75, 78))	('association', 'Interaction', (17, 28))	('KDM5C', 'Gene', '8242', (94, 99))	('BAP1', 'Gene', '8314', (105, 109))	('VHL', 'Gene', '7428', (75, 78))	('ccRCC', 'Disease', 'MESH:D002292', (52, 57))	('BAP1', 'Gene', (105, 109))	('SETD2', 'Gene', '29072', (87, 92))	('PBRM1', 'Gene', (80, 85))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('ccRCC', 'Disease', (52, 57))	('SETD2', 'Gene', (87, 92))	('KDM5C', 'Gene', (94, 99))	('mutations', 'Var', (62, 71))
174540	32185138	Their results showed that mutation of BAP1 was significantly associated with evidence of renal vein invasion.	('mutation', 'Var', (26, 34))	('BAP1', 'Gene', (38, 42))	('renal vein invasion', 'Disease', (89, 108))	('renal vein invasion', 'Disease', 'MESH:D007674', (89, 108))	('associated', 'Reg', (61, 71))	('BAP1', 'Gene', '8314', (38, 42))
174541	32185138	reported that BAP1 mutation was associated with ill-defined margins and presence of calcification.	('BAP1', 'Gene', '8314', (14, 18))	('mutation', 'Var', (19, 27))	('calcification', 'Disease', 'MESH:D002114', (84, 97))	('BAP1', 'Gene', (14, 18))	('associated', 'Reg', (32, 42))	('calcification', 'Disease', (84, 97))
174542	32185138	conducted high-dimensional quantitative CT texture analysis in 45 patients with clear cell RCC (29 without PBRM1 mutation and 16 with PBRM1 mutation).	('mutation', 'Var', (113, 121))	('PBRM1', 'Gene', (134, 139))	('clear cell RCC', 'Disease', (80, 94))	('PBRM1', 'Gene', '55193', (134, 139))	('clear cell RCC', 'Disease', 'MESH:C538445', (80, 94))	('PBRM1', 'Gene', (107, 112))	('PBRM1', 'Gene', '55193', (107, 112))	('patients', 'Species', '9606', (66, 74))
174550	32185138	Moreover, BAP1 mutation sensitizes cells to poly (ADP-ribose) polymerase inhibitors and a clinical trial of an HDAC for the treatment of patients with refractory metastatic RCC is ongoing.	('mutation', 'Var', (15, 23))	('RCC', 'Disease', (173, 176))	('HDAC', 'Gene', (111, 115))	('BAP1', 'Gene', (10, 14))	('HDAC', 'Gene', '9734', (111, 115))	('RCC', 'Disease', 'MESH:D002292', (173, 176))	('patients', 'Species', '9606', (137, 145))	('sensitizes', 'Reg', (24, 34))	('BAP1', 'Gene', '8314', (10, 14))
174552	32185138	Regarding the previous works on imaging research of BAP1 mutation based on TCGA and TCIA data, Ghost et al.	('BAP1', 'Gene', (52, 56))	('mutation', 'Var', (57, 65))	('BAP1', 'Gene', '8314', (52, 56))
174554	32185138	also adopted the strategy of oversampling to the BAP1 mutation data.	('BAP1', 'Gene', (49, 53))	('mutation', 'Var', (54, 62))	('BAP1', 'Gene', '8314', (49, 53))
174556	32185138	In the oversampling section, the oversampling of BAP1 mutation data is innovatively integrated into CV, which reduces the relevance between the data in the training set and the validation set to the fullest extent.	('mutation', 'Var', (54, 62))	('BAP1', 'Gene', (49, 53))	('relevance', 'MPA', (122, 131))	('reduces', 'NegReg', (110, 117))	('BAP1', 'Gene', '8314', (49, 53))
174558	32185138	In summary, our study demonstrated that CT radiomics has great potential in predicting BAP1 mutation status in patients with ccRCC.	('BAP1', 'Gene', '8314', (87, 91))	('predicting', 'Reg', (76, 86))	('ccRCC', 'Disease', 'MESH:D002292', (125, 130))	('BAP1', 'Gene', (87, 91))	('mutation status', 'Var', (92, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (125, 130))	('ccRCC', 'Disease', (125, 130))	('patients', 'Species', '9606', (111, 119))
174563	31076951	Solid tumor initially grows as an avascular bulk of cells carrying oncogenic mutations until diffusion distances from the nearest functional blood vessels limit delivery of nutrients and oxygen on the one hand and removal of metabolic waste on the other one.	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('limit delivery', 'Phenotype', 'HP:0001622', (155, 169))	('mutations', 'Var', (77, 86))	('limit', 'NegReg', (155, 160))	('oxygen', 'Chemical', 'MESH:D010100', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
174566	31076951	While the role of oncogenic mutations initializing and driving these processes is well established, a key contribution of non-genomic, landscaping molecular players is still less appreciated despite they can equally serve as viable targets of anticancer therapies.	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('mutations', 'Var', (28, 37))
174596	31076951	Indeed, acidosis is a potent inhibitor of T cell effector functions and neutralization of tumor acidity can improve response to immunotherapy.	('acidosis', 'Phenotype', 'HP:0001941', (8, 16))	('acidosis', 'Disease', (8, 16))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('acidosis', 'Disease', 'MESH:D000138', (8, 16))	('improve', 'PosReg', (108, 115))	('response to immunotherapy', 'CPA', (116, 141))	('neutralization', 'Var', (72, 86))
174617	31076951	Expectedly, inactivation of the pVHL tumor suppressor protein, which negatively controls HIF stability, results in the constitutive elevation of CA9 gene expression in renal cell cancers, RCC.	('VHL tumor', 'Disease', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('VHL tumor', 'Disease', 'MESH:D006623', (33, 42))	('CA9', 'Gene', '768', (145, 148))	('inactivation', 'Var', (12, 24))	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('renal cell cancers', 'Disease', (168, 186))	('elevation', 'PosReg', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('37', '53'))	('gene expression', 'biological_process', 'GO:0010467', ('149', '164'))	('renal cell cancers', 'Disease', 'MESH:C538614', (168, 186))	('CA9', 'Gene', (145, 148))	('pVHL', 'Gene', '7428', (32, 36))	('RCC', 'Disease', (188, 191))	('pVHL', 'Gene', (32, 36))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('tumor suppressor', 'biological_process', 'GO:0051726', ('37', '53'))	('expression', 'MPA', (154, 164))
174620	31076951	Impact of these modifications on the functioning of CA IX in pH regulation and cell adhesion has not been fully clarified, although glycosaminoglycan modification was shown to attenuate antibody-induced internalization of CA IX via increased association with caveolin-1 clusters in acidosis-sensitive membrane raft domains.	('acidosis', 'Disease', (282, 290))	('acidosis', 'Phenotype', 'HP:0001941', (282, 290))	('cell adhesion', 'biological_process', 'GO:0007155', ('79', '92'))	('regulation', 'biological_process', 'GO:0065007', ('64', '74'))	('antibody', 'cellular_component', 'GO:0019815', ('186', '194'))	('caveolin-1', 'Gene', (259, 269))	('modification', 'Var', (150, 162))	('antibody', 'cellular_component', 'GO:0019814', ('186', '194'))	('attenuate', 'NegReg', (176, 185))	('association', 'Interaction', (242, 253))	('caveolin-1', 'Gene', '857', (259, 269))	('membrane raft', 'cellular_component', 'GO:0045121', ('301', '314'))	('antibody', 'molecular_function', 'GO:0003823', ('186', '194'))	('increased', 'PosReg', (232, 241))	('acidosis', 'Disease', 'MESH:D000138', (282, 290))	('pH', 'Gene', '2821', (61, 63))	('antibody-induced internalization', 'MPA', (186, 218))	('antibody', 'cellular_component', 'GO:0042571', ('186', '194'))
174639	31076951	CA IX directly participates in these hallmarks, as supported by the fact that its suppression, mutation/deletion, pharmacologic inhibition, or treatment with monoclonal antibodies result in significantly reduced growth of tumor xenografts in vivo.	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('mutation/deletion', 'Var', (95, 112))	('reduced', 'NegReg', (204, 211))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('suppression', 'NegReg', (82, 93))
174661	31076951	Deletion or blocking of PG with a monoclonal antibody reduces cell adhesion to solid support, lowers lactate/proton extrusion, and decreases cell proliferation.	('antibody', 'cellular_component', 'GO:0019815', ('45', '53'))	('lactate', 'Chemical', 'MESH:D019344', (101, 108))	('antibody', 'cellular_component', 'GO:0019814', ('45', '53'))	('antibody', 'cellular_component', 'GO:0042571', ('45', '53'))	('antibody', 'molecular_function', 'GO:0003823', ('45', '53'))	('blocking', 'NegReg', (12, 20))	('lowers', 'NegReg', (94, 100))	('lactate/proton extrusion', 'MPA', (101, 125))	('cell proliferation', 'CPA', (141, 159))	('decreases', 'NegReg', (131, 140))	('cell proliferation', 'biological_process', 'GO:0008283', ('141', '159'))	('cell adhesion to solid support', 'CPA', (62, 92))	('PG', 'Chemical', '-', (24, 26))	('cell adhesion', 'biological_process', 'GO:0007155', ('62', '75'))	('reduces', 'NegReg', (54, 61))	('Deletion', 'Var', (0, 8))
174665	31076951	In this respect, it is important to discriminate between tumors that express CA IX as a consequence of the inactivating mutation of pVHL tumor suppressor protein and tumors in which CA IX is present in connection with microenvironmental hypoxia and/or acidosis.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('CA IX', 'Disease', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('VHL tumor', 'Disease', (133, 142))	('pVHL', 'Gene', '7428', (132, 136))	('pVHL', 'Gene', (132, 136))	('acidosis', 'Disease', (252, 260))	('hypoxia', 'Disease', (237, 244))	('VHL tumor', 'Disease', 'MESH:D006623', (133, 142))	('tumors', 'Disease', (166, 172))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('137', '153'))	('hypoxia', 'Disease', 'MESH:D000860', (237, 244))	('acidosis', 'Phenotype', 'HP:0001941', (252, 260))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('inactivating mutation', 'Var', (107, 128))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor suppressor', 'biological_process', 'GO:0051726', ('137', '153'))	('acidosis', 'Disease', 'MESH:D000138', (252, 260))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Disease', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
174666	31076951	The former category is represented primarily by the clear cell renal cell carcinoma (ccRCC) that often carry an inactivating mutation/deletion of the VHL tumor suppressor gene and display "constitutive" HIF stabilization and activation of HIF-regulated genes including CA IX.	('CA IX', 'Gene', (269, 274))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (63, 83))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('VHL tumor', 'Disease', (150, 159))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (63, 83))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (52, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('activation', 'PosReg', (225, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('tumor suppressor', 'biological_process', 'GO:0051726', ('154', '170'))	('inactivating mutation/deletion', 'Var', (112, 142))	('VHL tumor', 'Disease', 'MESH:D006623', (150, 159))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('154', '170'))	('renal cell carcinoma', 'Disease', (63, 83))
174682	31076951	In conclusion, these results show that patients having tumors with high CA IX expression have higher risk of disease progression, and development of metastases, independent of tumor type or site.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('CA IX', 'Protein', (72, 77))	('metastases', 'Disease', (149, 159))	('high', 'Var', (67, 71))	('patients', 'Species', '9606', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('metastases', 'Disease', 'MESH:D009362', (149, 159))	('tumor', 'Disease', (176, 181))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', (55, 60))	('disease progression', 'CPA', (109, 128))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
174694	31076951	Inhibitors of the carbonic anhydrase enzyme activity represent emerging anticancer drugs as thoroughly reviewed elsewhere.	('enzyme activity', 'molecular_function', 'GO:0003824', ('37', '52'))	('carbonic anhydrase enzyme', 'Enzyme', (18, 43))	('Inhibitors', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('activity', 'MPA', (44, 52))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
174726	31311512	Among 150 ccRCC patients, low CDK5 was detected in 83 cases (55.3%), low p21 in 97 cases (64.7%).	('CDK', 'molecular_function', 'GO:0004693', ('30', '33'))	('p21', 'Gene', '1026', (73, 76))	('RCC', 'Phenotype', 'HP:0005584', (12, 15))	('low', 'Var', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('RCC', 'Disease', (12, 15))	('p21', 'Gene', (73, 76))	('patients', 'Species', '9606', (16, 24))	('CDK5', 'Gene', (30, 34))	('ccRCC', 'Phenotype', 'HP:0006770', (10, 15))	('low', 'NegReg', (69, 72))	('CDK5', 'Gene', '1020', (30, 34))
174730	31311512	In the Cox multivariate analysis, the co-expression of CDK5 low/p21 low was identified as an independent prognostic factor in ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('CDK5', 'Gene', '1020', (55, 59))	('Cox', 'Gene', '1351', (7, 10))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('co-expression', 'Var', (38, 51))	('Cox', 'Gene', (7, 10))	('p21', 'Gene', '1026', (64, 67))	('CDK', 'molecular_function', 'GO:0004693', ('55', '58'))	('CDK5', 'Gene', (55, 59))	('patients', 'Species', '9606', (132, 140))	('p21', 'Gene', (64, 67))
174731	31311512	Together, our findings provided the first evidence that CDK5 was acting as a promising biomarker in ccRCC patients, and co-expression of CDK5 and p21 is an independent prognostic for overall survival.	('CDK', 'molecular_function', 'GO:0004693', ('56', '59'))	('co-expression', 'Var', (120, 133))	('p21', 'Gene', '1026', (146, 149))	('CDK5', 'Gene', (137, 141))	('p21', 'Gene', (146, 149))	('CDK5', 'Gene', '1020', (56, 60))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('RCC', 'Disease', (102, 105))	('patients', 'Species', '9606', (106, 114))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('CDK', 'molecular_function', 'GO:0004693', ('137', '140'))	('CDK5', 'Gene', '1020', (137, 141))	('CDK5', 'Gene', (56, 60))
174744	31311512	Furthermore, the association between high CDK5 expression and poor prognosis has showed in other human malignancies, such as pancreatic cancer, lung cancer, thyroid carcinoma.	('pancreatic cancer', 'Disease', 'MESH:D010190', (125, 142))	('human', 'Species', '9606', (97, 102))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (157, 174))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('CDK5', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('CDK5', 'Gene', '1020', (42, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('malignancies', 'Disease', 'MESH:D009369', (103, 115))	('pancreatic cancer', 'Disease', (125, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('malignancies', 'Disease', (103, 115))	('expression', 'MPA', (47, 57))	('high', 'Var', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (125, 142))	('CDK', 'molecular_function', 'GO:0004693', ('42', '45'))	('lung cancer', 'Disease', (144, 155))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (157, 174))	('thyroid carcinoma', 'Disease', (157, 174))
174753	31311512	Our previous study has found that inhibition of the LSD1 decreased the H3K4 demethylation at CDKN1A gene promoter, which was associated with the p21 upregulation and cell cycle arrest at G1/S in ccRCC cells.	('CDKN1A', 'Gene', '1026', (93, 99))	('p21', 'Gene', '1026', (145, 148))	('H3K4', 'Protein', (71, 75))	('LSD1', 'Gene', (52, 56))	('upregulation', 'PosReg', (149, 161))	('inhibition', 'Var', (34, 44))	('RCC', 'Phenotype', 'HP:0005584', (197, 200))	('p21', 'Gene', (145, 148))	('LSD1', 'Gene', '23028', (52, 56))	('RCC', 'Disease', 'MESH:C538614', (197, 200))	('cell cycle arrest', 'CPA', (166, 183))	('RCC', 'Disease', (197, 200))	('ccRCC', 'Phenotype', 'HP:0006770', (195, 200))	('demethylation', 'biological_process', 'GO:0070988', ('76', '89'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('166', '183'))	('CDKN1A', 'Gene', (93, 99))	('decreased', 'NegReg', (57, 66))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (166, 183))
174815	31311512	And the co-expression of CDK5 and p21 were also proven to be an independent prognostic factor in ccRCC patients.	('p21', 'Gene', (34, 37))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('CDK5', 'Gene', (25, 29))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('CDK', 'molecular_function', 'GO:0004693', ('25', '28'))	('patients', 'Species', '9606', (103, 111))	('co-expression', 'Var', (8, 21))	('p21', 'Gene', '1026', (34, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('CDK5', 'Gene', '1020', (25, 29))
174819	31311512	Increasing researches have revealed that the abnormal expression of CDK5 participated in the tumor progression and metastasis across various solid malignancies, including breast cancer, lung cancer, prostate cancer, and liver cancer.	('liver cancer', 'Phenotype', 'HP:0002896', (220, 232))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('liver cancer', 'Disease', (220, 232))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('abnormal expression', 'Var', (45, 64))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('breast cancer', 'Disease', (171, 184))	('metastasis', 'CPA', (115, 125))	('prostate cancer', 'Disease', 'MESH:D011471', (199, 214))	('prostate cancer', 'Phenotype', 'HP:0012125', (199, 214))	('participated in', 'Reg', (73, 88))	('prostate cancer', 'Disease', (199, 214))	('lung cancer', 'Disease', (186, 197))	('malignancies', 'Disease', 'MESH:D009369', (147, 159))	('liver cancer', 'Disease', 'MESH:D006528', (220, 232))	('CDK5', 'Gene', (68, 72))	('CDK', 'molecular_function', 'GO:0004693', ('68', '71'))	('malignancies', 'Disease', (147, 159))	('tumor', 'Disease', (93, 98))	('CDK5', 'Gene', '1020', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
174823	31311512	In our previous work, we also found that inhibition of LSD1 would suppress the ccRCC growth through upregulating p21 signaling.	('LSD1', 'Gene', (55, 59))	('suppress', 'NegReg', (66, 74))	('LSD1', 'Gene', '23028', (55, 59))	('upregulating', 'PosReg', (100, 112))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('inhibition', 'Var', (41, 51))	('p21', 'Gene', '1026', (113, 116))	('p21', 'Gene', (113, 116))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))
174827	31311512	What's more important, the patients with combination of low CDK5 and low p21 (CLPL) showed poorer survival than other groups in Fig.	('low', 'Var', (56, 59))	('p21', 'Gene', '1026', (73, 76))	('CDK5', 'Gene', (60, 64))	('p21', 'Gene', (73, 76))	('CLPL', 'Chemical', '-', (78, 82))	('patients', 'Species', '9606', (27, 35))	('CDK5', 'Gene', '1020', (60, 64))	('CDK', 'molecular_function', 'GO:0004693', ('60', '63'))	('low', 'Var', (69, 72))	('poorer', 'NegReg', (91, 97))
174934	27907930	In the univariable model, low levels of miR-204-5p was associated with a significantly increased three-fold risk of ccRCC recurrence (HR=3.01, 95% CI=1.34-6.80, P=0.008).	('miR-204', 'Gene', (40, 47))	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('RCC', 'Disease', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('low', 'Var', (26, 29))	('miR-204', 'Gene', '406987', (40, 47))
174981	27907930	Several GWAS have also linked a common variant located in IGF2BP2 (rs4402960) to risk of type 2 diabetes.	('type 2 diabetes', 'Disease', (89, 104))	('rs4402960', 'Var', (67, 76))	('IGF2BP2', 'Gene', '10644', (58, 65))	('rs4402960', 'Mutation', 'rs4402960', (67, 76))	('IGF2BP2', 'Gene', (58, 65))	('type 2 diabetes', 'Disease', 'MESH:D003924', (89, 104))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (89, 104))
174994	31063758	YAP/TAZ inhibition induces metabolic and signaling rewiring resulting in targetable vulnerabilities in NF2-deficient tumor cells Merlin/NF2 is a bona fide tumor suppressor whose mutations underlie inherited tumor syndrome Neurofibromatosis Type 2 (NF2) as well as various sporadic cancers including kidney cancer.	('YAP', 'Gene', (0, 3))	('NF2', 'Gene', (248, 251))	('NF2', 'Gene', '4771', (136, 139))	('tumor', 'Disease', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('deficient tumor', 'Disease', 'MESH:D009369', (107, 122))	('inherited tumor syndrome Neurofibromatosis Type', 'Disease', 'MESH:C537392', (197, 244))	('NF2', 'Gene', '4771', (103, 106))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('cancers', 'Disease', (281, 288))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('inherited tumor syndrome Neurofibromatosis Type', 'Disease', (197, 244))	('NF2', 'Gene', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('NF2', 'Gene', (103, 106))	('Merlin', 'Gene', '4771', (129, 135))	('Neurofibromatosis Type 2', 'Disease', 'MESH:C537392', (222, 246))	('YAP', 'Gene', '10413', (0, 3))	('underlie', 'Reg', (188, 196))	('deficient tumor', 'Disease', (107, 122))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('155', '171'))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (222, 239))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('kidney cancer', 'Disease', 'MESH:D007680', (299, 312))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('155', '171'))	('cancers', 'Disease', 'MESH:D009369', (281, 288))	('tumor', 'Disease', (207, 212))	('kidney cancer', 'Phenotype', 'HP:0009726', (299, 312))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('Merlin', 'Gene', (129, 135))	('Neurofibromatosis Type 2', 'Disease', (222, 246))	('kidney cancer', 'Disease', (299, 312))	('NF2', 'Gene', '4771', (248, 251))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('mutations', 'Var', (178, 187))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
174996	31063758	However, the molecular mechanisms underpinning the growth and survival of NF2 mutant tumors remain poorly understood.	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('NF2', 'Gene', (74, 77))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mutant', 'Var', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
174997	31063758	Using an inducible orthotopic kidney tumor model, we demonstrate that YAP/TAZ silencing is sufficient to induce regression of pre-established NF2-deficient tumors.	('pre', 'molecular_function', 'GO:0003904', ('126', '129'))	('kidney tumor', 'Phenotype', 'HP:0009726', (30, 42))	('kidney tumor', 'Disease', 'MESH:D007680', (30, 42))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('silencing', 'Var', (78, 87))	('deficient tumors', 'Disease', (146, 162))	('deficient tumors', 'Disease', 'MESH:D009369', (146, 162))	('regression', 'CPA', (112, 122))	('YAP/TAZ', 'Gene', (70, 77))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('kidney tumor', 'Disease', (30, 42))
174998	31063758	Mechanistically, YAP/TAZ depletion diminishes glycolysis-dependent growth and increases mitochondrial respiration and ROS buildup, resulting in oxidative stress-induced cell death when challenged by nutrient stress.	('cell death', 'biological_process', 'GO:0008219', ('169', '179'))	('respiration', 'biological_process', 'GO:0045333', ('102', '113'))	('ROS buildup', 'MPA', (118, 129))	('oxidative stress', 'Phenotype', 'HP:0025464', (144, 160))	('respiration', 'biological_process', 'GO:0007585', ('102', '113'))	('diminishes', 'NegReg', (35, 45))	('glycolysis-dependent growth', 'MPA', (46, 73))	('oxidative stress-induced', 'MPA', (144, 168))	('depletion', 'Var', (25, 34))	('increases', 'PosReg', (78, 87))	('mitochondrial respiration', 'MPA', (88, 113))	('ROS', 'Chemical', 'MESH:D017382', (118, 121))	('glycolysis', 'biological_process', 'GO:0006096', ('46', '56'))	('cell death', 'CPA', (169, 179))
175002	31063758	demonstrate YAP/TAZ are required for the maintenance of NF2 mutant tumors.	('NF2', 'Gene', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('mutant', 'Var', (60, 66))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
175006	31063758	Deletions or loss-of-function mutations of NF2 underlie Neurofibromatosis Type 2 (NF2), an inherited syndrome characterized by the development of bilateral vestibular schwannomas, schwannomas from cranial or peripheral nerves, meningiomas, and/or ependymomas.	('schwannomas', 'Disease', 'MESH:D009442', (167, 178))	('schwannomas', 'Phenotype', 'HP:0100008', (180, 191))	('bilateral vestibular schwannomas', 'Disease', (146, 178))	('meningiomas', 'Phenotype', 'HP:0002858', (227, 238))	('schwannomas', 'Disease', (167, 178))	('bilateral vestibular schwannomas', 'Disease', 'MESH:D009464', (146, 178))	('meningiomas', 'Disease', (227, 238))	('Neurofibromatosis Type 2', 'Disease', 'MESH:C537392', (56, 80))	('vestibular schwannomas', 'Phenotype', 'HP:0009588', (156, 178))	('inherited syndrome', 'Disease', (91, 109))	('schwannoma', 'Phenotype', 'HP:0100008', (167, 177))	('ependymomas', 'Disease', (247, 258))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (56, 73))	('schwannomas', 'Disease', 'MESH:D009442', (180, 191))	('schwannomas', 'Disease', (180, 191))	('schwannomas', 'Phenotype', 'HP:0100008', (167, 178))	('mutations', 'Var', (30, 39))	('inherited syndrome', 'Disease', 'MESH:D061325', (91, 109))	('schwannoma', 'Phenotype', 'HP:0100008', (180, 190))	('loss-of-function', 'NegReg', (13, 29))	('Neurofibromatosis Type 2', 'Disease', (56, 80))	('bilateral vestibular schwannomas', 'Phenotype', 'HP:0009589', (146, 178))	('meningioma', 'Phenotype', 'HP:0002858', (227, 237))	('NF2', 'Gene', (43, 46))	('meningiomas', 'Disease', 'MESH:D008577', (227, 238))	('ependymomas', 'Disease', 'MESH:D004806', (247, 258))	('Deletions', 'Var', (0, 9))
175007	31063758	Beyond NF2, somatic NF2 mutations are frequently detected in sporadic schwannomas, meningiomas, ependymomas and mesotheliomas, and to a lesser extent in thyroid cancer, colorectal cancer, melanoma, renal cell carcinomas (RCC) and a host of other solid tumors.	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (198, 219))	('ependymomas', 'Disease', 'MESH:D004806', (96, 107))	('RCC', 'Disease', 'MESH:C538614', (221, 224))	('colorectal cancer', 'Disease', 'MESH:D015179', (169, 186))	('schwannomas', 'Disease', 'MESH:D009442', (70, 81))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('mutations', 'Var', (24, 33))	('schwannomas', 'Disease', (70, 81))	('colorectal cancer', 'Disease', (169, 186))	('mesotheliomas', 'Disease', (112, 125))	('meningiomas', 'Disease', 'MESH:D008577', (83, 94))	('meningioma', 'Phenotype', 'HP:0002858', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('thyroid cancer', 'Disease', (153, 167))	('ependymomas', 'Disease', (96, 107))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('meningiomas', 'Phenotype', 'HP:0002858', (83, 94))	('mesotheliomas', 'Disease', 'MESH:D008654', (112, 125))	('tumors', 'Disease', (252, 258))	('meningiomas', 'Disease', (83, 94))	('detected', 'Reg', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('colorectal cancer', 'Phenotype', 'HP:0003003', (169, 186))	('thyroid cancer', 'Disease', 'MESH:D013964', (153, 167))	('schwannomas', 'Phenotype', 'HP:0100008', (70, 81))	('schwannoma', 'Phenotype', 'HP:0100008', (70, 80))	('tumors', 'Disease', 'MESH:D009369', (252, 258))	('NF2', 'Gene', (20, 23))	('RCC', 'Phenotype', 'HP:0005584', (221, 224))	('thyroid cancer', 'Phenotype', 'HP:0002890', (153, 167))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (198, 218))	('RCC', 'Disease', (221, 224))	('melanoma, renal cell carcinomas', 'Disease', 'MESH:C538614', (188, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('carcinomas', 'Phenotype', 'HP:0030731', (209, 219))
175009	31063758	Loss of Merlin/NF2 triggers deregulation of numerous signaling pathways including MST1/2-LATS1/2 (Hippo), RAC-PAK, RAS-RAF-MEK-ERK, PI3K-AKT-mTOR, FAK-SRC, STAT3, and a number of receptor tyrosine kinases (RTKs).	('mTOR', 'Gene', '2475', (141, 145))	('Merlin', 'Gene', (8, 14))	('Hippo', 'Gene', '37247', (98, 103))	('FAK', 'Gene', (147, 150))	('AKT', 'Gene', '207', (137, 140))	('SRC', 'Gene', '6714', (151, 154))	('RAF', 'Gene', '22882', (119, 122))	('deregulation', 'MPA', (28, 40))	('FAK', 'molecular_function', 'GO:0004717', ('147', '150'))	('PI3K', 'molecular_function', 'GO:0016303', ('132', '136'))	('MEK', 'Gene', '5609', (123, 126))	('ERK', 'Gene', '5594', (127, 130))	('FAK', 'Gene', '5747', (147, 150))	('SRC', 'Gene', (151, 154))	('RAF', 'Gene', (119, 122))	('LATS1/2', 'Gene', '9113;26524', (89, 96))	('Merlin', 'Gene', '4771', (8, 14))	('signaling pathways', 'Pathway', (53, 71))	('MEK', 'Gene', (123, 126))	('MST1/2', 'Gene', '4485;6788', (82, 88))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('LATS1/2', 'Gene', (89, 96))	('STAT3', 'Gene', (156, 161))	('MST1/2', 'Gene', (82, 88))	('ERK', 'Gene', (127, 130))	('Loss', 'Var', (0, 4))	('AKT', 'Gene', (137, 140))	('mTOR', 'Gene', (141, 145))	('STAT3', 'Gene', '6774', (156, 161))	('ERK', 'molecular_function', 'GO:0004707', ('127', '130'))	('Hippo', 'Gene', (98, 103))
175010	31063758	Despite their prevalent activation in NF2-mutant tumors, clinical trials with drugs targeting mTOR, MEK, and several RTKs have yielded largely disappointing results in treating NF2, underscoring the need to fully explore the molecular mechanisms that govern the growth and survival of NF2-deficient tumors.	('NF2-mutant', 'Var', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('MEK', 'Gene', (100, 103))	('mTOR', 'Gene', (94, 98))	('mTOR', 'Gene', '2475', (94, 98))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('deficient tumors', 'Disease', (289, 305))	('tumors', 'Disease', (299, 305))	('deficient tumors', 'Disease', 'MESH:D009369', (289, 305))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (299, 305))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('MEK', 'Gene', '5609', (100, 103))	('tumors', 'Phenotype', 'HP:0002664', (299, 305))	('activation', 'PosReg', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('NF2-mutant', 'Gene', (38, 48))
175015	31063758	In NF2 mutant tumors, due to the inactivation of LATS1/2, unphosphorylated YAP and TAZ become stabilized and free to enter the nucleus where they bind to and partner with the TEAD family of transcription factors to regulate gene expression.	('transcription', 'biological_process', 'GO:0006351', ('190', '203'))	('nucleus', 'cellular_component', 'GO:0005634', ('127', '134'))	('bind', 'Interaction', (146, 150))	('mutant', 'Var', (7, 13))	('LATS1/2', 'Gene', '9113;26524', (49, 56))	('partner', 'Interaction', (158, 165))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('gene expression', 'biological_process', 'GO:0010467', ('224', '239'))	('LATS1/2', 'Gene', (49, 56))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('inactivation', 'Var', (33, 45))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('NF2', 'Gene', (3, 6))	('regulate', 'Reg', (215, 223))
175016	31063758	A number of studies have assessed the effects of YAP inhibition in NF2 mutant tumor cells in vitro and in vivo.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('NF2', 'Gene', (67, 70))	('mutant', 'Var', (71, 77))	('tumor', 'Disease', (78, 83))
175017	31063758	Liver-specific YAP deletion was shown to inhibit hyperproliferation of liver progenitor cells and prevent tumorigenesis induced by NF2 deficiency.	('prevent', 'NegReg', (98, 105))	('deficiency', 'Disease', (135, 145))	('deletion', 'Var', (19, 27))	('deficiency', 'Disease', 'MESH:D007153', (135, 145))	('NF2', 'Gene', (131, 134))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('YAP', 'Gene', (15, 18))	('hyperproliferation of liver progenitor cells', 'CPA', (49, 93))	('inhibit', 'NegReg', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
175018	31063758	Similarly, YAP knockdown inhibited the initiation of NF2-deficient schwannomas in vivo, and reduced the proliferation of NF2-deficient meningioma and mesothelioma cell lines in vitro.	('meningioma', 'Phenotype', 'HP:0002858', (135, 145))	('schwannomas', 'Phenotype', 'HP:0100008', (67, 78))	('schwannoma', 'Phenotype', 'HP:0100008', (67, 77))	('knockdown', 'Var', (15, 24))	('proliferation', 'CPA', (104, 117))	('deficient schwannomas', 'Disease', (57, 78))	('initiation', 'MPA', (39, 49))	('deficient schwannomas', 'Disease', 'MESH:D009442', (57, 78))	('deficient meningioma and mesothelioma', 'Disease', 'MESH:D008654', (125, 162))	('reduced', 'NegReg', (92, 99))	('inhibited', 'NegReg', (25, 34))
175019	31063758	However, the roles of YAP and TAZ in the maintenance of NF2 mutant tumors have not been established.	('NF2', 'Gene', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('mutant', 'Var', (60, 66))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
175020	31063758	Moreover, the molecular mechanisms by which YAP and/or TAZ govern the growth and survival of NF2 mutant tumors remain poorly defined.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('NF2', 'Gene', (93, 96))	('mutant', 'Var', (97, 103))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))
175022	31063758	In particular, biallelic inactivation of NF2 has been identified in significant fractions of the more aggressive RCC subtypes including clear cell RCC (ccRCC) with sarcomatoid dedifferentiation (19%), Type II papillary RCC (pRCC, 13%) and unclassified RCC (uRCC, 18%), for which there are no standard therapies.	('NF2', 'Gene', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (252, 255))	('RCC', 'Disease', (154, 157))	('RCC', 'Phenotype', 'HP:0005584', (154, 157))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('sarcomatoid', 'Disease', (164, 175))	('RCC', 'Disease', (219, 222))	('RCC', 'Phenotype', 'HP:0005584', (219, 222))	('RCC', 'Disease', (258, 261))	('RCC', 'Disease', (225, 228))	('RCC', 'Phenotype', 'HP:0005584', (225, 228))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('dedifferentiation', 'biological_process', 'GO:0043696', ('176', '193'))	('biallelic inactivation', 'Var', (15, 37))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('pRCC', 'Gene', (224, 228))	('RCC', 'Disease', (113, 116))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('Type II papillary RCC', 'Disease', (201, 222))	('RCC', 'Disease', 'MESH:C538614', (219, 222))	('RCC', 'Disease', 'MESH:C538614', (258, 261))	('sarcomatoid', 'Disease', 'MESH:C538614', (164, 175))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('identified', 'Reg', (54, 64))	('RCC', 'Disease', (252, 255))	('Type II papillary RCC', 'Disease', 'MESH:C538614', (201, 222))	('pRCC', 'Gene', '5546', (224, 228))
175024	31063758	Here, by employing NF2 deficient RCC and schwannoma cells engineered to inducibly express shRNAs targeting YAP and TAZ, we have systematically examined the effects and mechanisms of YAP/TAZ depletion on the growth and survival of NF2 mutant tumor cells in vitro and in vivo.	('NF2', 'Gene', (230, 233))	('mutant', 'Var', (234, 240))	('survival', 'CPA', (218, 226))	('tumor', 'Disease', (241, 246))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('deficient RCC and schwannoma', 'Disease', 'MESH:C538614', (23, 51))	('schwannoma', 'Phenotype', 'HP:0100008', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
175025	31063758	Our work unravels a complex and intercalated metabolic and signaling circuitry centered around YAP/TAZ that governs the growth and survival of NF2 mutant tumor cells, laying the ground work for developing more comprehensive and better informed treatment strategies to eradicate NF2 tumors.	('mutant', 'Var', (147, 153))	('tumor', 'Disease', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('tumors', 'Disease', (282, 288))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('tumor', 'Disease', (282, 287))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('NF2', 'Gene', (143, 146))
175026	31063758	To investigate the roles of YAP and TAZ in the maintenance of NF2 deficient tumors, we stably expressed doxycycline (Dox) inducible shRNAs against YAP and TAZ (shY/T) or a vector control (Ctrl) in SN12C renal cell carcinoma cells which contain homozygous truncating NF2 mutations (Figure S1A).	('doxycycline', 'Chemical', 'MESH:D004318', (104, 115))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (203, 223))	('Dox', 'Chemical', 'MESH:D004318', (117, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('mutations', 'Var', (270, 279))	('deficient tumors', 'Disease', (66, 82))	('deficient tumors', 'Disease', 'MESH:D009369', (66, 82))	('SN12C', 'CellLine', 'CVCL:1705', (197, 202))	('NF2', 'Gene', (266, 269))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('renal cell carcinoma', 'Disease', (203, 223))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (203, 223))
175029	31063758	Dox-induced YAP/TAZ depletion led to rapid reduction in BLI signals, which remained stagnant for additional 3 weeks before starting to increase again (Figures 1B-1C).	('reduction', 'NegReg', (43, 52))	('depletion', 'Var', (20, 29))	('Dox', 'Chemical', 'MESH:D004318', (0, 3))	('BLI signals', 'MPA', (56, 67))
175038	31063758	This apparent difference between in vitro and in vivo led us to hypothesize that in conjunction with YAP/TAZ loss, additional environmental or nutrient stress experienced by tumor cells in vivo but not under standard in vitro culture conditions might be necessary to trigger cell death in NF2 null tumor cells.	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', (298, 303))	('NF2', 'Gene', (289, 292))	('null', 'Var', (293, 297))	('cell death', 'biological_process', 'GO:0008219', ('275', '285'))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))
175041	31063758	Unexpectedly, we found that lowering oxygen levels did not significantly affect the proliferation rates or survival of either shY/T or Ctrl SN12C cells, even though it did cause the anticipated increase in HIF1a protein levels in vitro (Figures S1H-S1I), thus excluding hypoxia as a major contributing factor to YAP/TAZ-depletion-induced regression of NF2 mutant tumors.	('hypoxia', 'Disease', 'MESH:D000860', (270, 277))	('tumors', 'Disease', (363, 369))	('tumors', 'Disease', 'MESH:D009369', (363, 369))	('tumors', 'Phenotype', 'HP:0002664', (363, 369))	('hypoxia', 'Disease', (270, 277))	('HIF1a', 'Gene', '3091', (206, 211))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('NF2', 'Gene', (352, 355))	('increase', 'PosReg', (194, 202))	('HIF1a', 'Gene', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('lowering oxygen levels', 'Phenotype', 'HP:0012418', (28, 50))	('SN12C', 'CellLine', 'CVCL:1705', (140, 145))	('protein levels', 'MPA', (212, 226))	('mutant', 'Var', (356, 362))	('oxygen', 'Chemical', 'MESH:D010100', (37, 43))
175046	31063758	Even though knockdown of TAZ had little effects on its own across all conditions, it enhanced the growth inhibition in nutrient replete conditions and cell death in glutamine-deprived conditions caused by YAP knockdown (Fig S2E), suggesting YAP and TAZ function redundantly in promoting the growth and survival of NF2 mutant cells.	('enhanced', 'PosReg', (85, 93))	('growth inhibition', 'CPA', (98, 115))	('cell death', 'biological_process', 'GO:0008219', ('151', '161'))	('mutant', 'Var', (318, 324))	('cell death', 'CPA', (151, 161))	('NF2', 'Gene', (314, 317))	('promoting', 'PosReg', (277, 286))	('glutamine', 'Chemical', 'MESH:D005973', (165, 174))
175052	31063758	Overexpression of a constitutively active mutant YAP was recently shown to promote aerobic glycolysis by increasing glucose uptake.	('mutant', 'Var', (42, 48))	('increasing', 'PosReg', (105, 115))	('promote', 'PosReg', (75, 82))	('glycolysis', 'biological_process', 'GO:0006096', ('91', '101'))	('YAP', 'Gene', (49, 52))	('glucose uptake', 'MPA', (116, 130))	('glucose uptake', 'biological_process', 'GO:0046323', ('116', '130'))	('glucose', 'Chemical', 'MESH:D005947', (116, 123))	('aerobic glycolysis', 'MPA', (83, 101))
175053	31063758	Consistent with these reports, we found that YAP/TAZ depletion dramatically reduced glucose uptake in SN12C cells (Figure S2G).	('glucose uptake', 'MPA', (84, 98))	('depletion', 'Var', (53, 62))	('glucose', 'Chemical', 'MESH:D005947', (84, 91))	('glucose uptake', 'biological_process', 'GO:0046323', ('84', '98'))	('reduced', 'NegReg', (76, 83))	('SN12C', 'CellLine', 'CVCL:1705', (102, 107))
175054	31063758	Moreover, YAP/TAZ depletion caused a marked reduction in glycolysis rate as well as total glycolytic capacity in SN12C cells, as demonstrated by the changes in extracellular acidification rate (ECAR) following the addition of glucose and subsequently mitochondrial ATP synthase inhibitor oligomycin (oligo) (Figure 2C).	('acidification', 'biological_process', 'GO:0045851', ('174', '187'))	('glycolysis', 'biological_process', 'GO:0006096', ('57', '67'))	('glycolysis rate', 'MPA', (57, 72))	('extracellular', 'cellular_component', 'GO:0005576', ('160', '173'))	('ATP synthase', 'molecular_function', 'GO:0016468', ('265', '277'))	('oligo', 'Chemical', 'MESH:D009840', (300, 305))	('oligo', 'Chemical', 'MESH:D009840', (288, 293))	('oligomycin', 'Chemical', 'MESH:D009840', (288, 298))	('ATP synthase', 'molecular_function', 'GO:0016467', ('265', '277'))	('extracellular acidification rate', 'MPA', (160, 192))	('glycolytic capacity', 'MPA', (90, 109))	('reduction', 'NegReg', (44, 53))	('depletion', 'Var', (18, 27))	('ATP', 'Chemical', 'MESH:D000255', (265, 268))	('SN12C', 'CellLine', 'CVCL:1705', (113, 118))	('glucose', 'Chemical', 'MESH:D005947', (226, 233))	('changes', 'Reg', (149, 156))
175056	31063758	In further support of the roles of YAP/TAZ in promoting aerobic glycolysis, liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolic profiling of Ctrl and shY/T SC4 cells showed that YAP/TAZ depletion downregulated a number of glycolytic metabolites including G6P, G3P, PEP and lactate (Figure S2J).	('G6P', 'MPA', (271, 274))	('downregulated', 'NegReg', (212, 225))	('lactate', 'MPA', (289, 296))	('G3P', 'Chemical', '-', (276, 279))	('G3P', 'MPA', (276, 279))	('glycolysis', 'biological_process', 'GO:0006096', ('64', '74'))	('YAP/TAZ', 'Gene', (194, 201))	('PEP', 'Gene', (281, 284))	('PEP', 'Gene', '5047', (281, 284))	('depletion', 'Var', (202, 211))	('glycolytic metabolites', 'MPA', (238, 260))	('G6P', 'Chemical', '-', (271, 274))	('lactate', 'Chemical', 'MESH:D019344', (289, 296))	('SC4', 'CellLine', 'CVCL:6F23', (172, 175))
175057	31063758	To directly assess how aerobic glycolysis contributes to the proliferation of NF2 mutant cells, we replaced glucose in the culture medium of SN12C cells with galactose (Gal), a glucose isomer that is processed through glycolysis but does not yield any net glycolytic-ATP.	('glycolysis', 'biological_process', 'GO:0006096', ('218', '228'))	('glucose', 'Chemical', 'MESH:D005947', (108, 115))	('SN12C', 'CellLine', 'CVCL:1705', (141, 146))	('ATP', 'Chemical', 'MESH:D000255', (267, 270))	('glucose', 'Chemical', 'MESH:D005947', (177, 184))	('galactose', 'Chemical', 'MESH:D005690', (158, 167))	('glycolysis', 'biological_process', 'GO:0006096', ('31', '41'))	('Gal', 'Chemical', 'MESH:D005690', (169, 172))	('NF2', 'Gene', (78, 81))	('mutant', 'Var', (82, 88))
175058	31063758	While galactose substitution had very little effect on shY/T cells with already compromised glycolysis, it completely blocked the proliferation of Ctrl cells (Figure S2K), underscoring the importance of high aerobic glycolysis in sustaining the proliferation of NF2 mutant tumor cells.	('blocked', 'NegReg', (118, 125))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('NF2', 'Gene', (262, 265))	('glycolysis', 'biological_process', 'GO:0006096', ('216', '226'))	('proliferation', 'CPA', (130, 143))	('galactose', 'Chemical', 'MESH:D005690', (6, 15))	('mutant', 'Var', (266, 272))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (273, 278))	('glycolysis', 'biological_process', 'GO:0006096', ('92', '102'))
175059	31063758	YAP was recently shown to increase glucose uptake in part by transcribing GLUT3, HK2 and PFKFB3.	('glucose', 'Chemical', 'MESH:D005947', (35, 42))	('PFKFB3', 'Gene', (89, 95))	('HK2', 'Gene', (81, 84))	('transcribing', 'Var', (61, 73))	('HK2', 'Gene', '3099', (81, 84))	('PFKFB3', 'Gene', '5209', (89, 95))	('increase glucose', 'Phenotype', 'HP:0003074', (26, 42))	('glucose uptake', 'biological_process', 'GO:0046323', ('35', '49'))	('GLUT3', 'Gene', '6515', (74, 79))	('HK2', 'molecular_function', 'GO:0008256', ('81', '84'))	('GLUT3', 'Gene', (74, 79))	('increase', 'PosReg', (26, 34))	('glucose uptake', 'MPA', (35, 49))
175060	31063758	Consistent with these reports, we found that YAP/TAZ depletion specifically reduced the mRNA levels of GLUT3 and HK2 as well as other glycolytic enzymes including HK1, PFKFB4, PFKP, GAPDH, PGK1, PGAM1, LDHA, PDHA1 and PDHB (Figures 2D-2E).	('depletion', 'Var', (53, 62))	('HK1', 'molecular_function', 'GO:0004673', ('163', '166'))	('PFKP', 'Gene', '5214', (176, 180))	('GLUT3', 'Gene', '6515', (103, 108))	('HK2', 'Gene', (113, 116))	('HK2', 'Gene', '3099', (113, 116))	('reduced', 'NegReg', (76, 83))	('PFKFB4', 'Gene', (168, 174))	('PGAM1', 'Gene', (195, 200))	('LDHA', 'Gene', '3939', (202, 206))	('HK1', 'Gene', '3098', (163, 166))	('PGK1', 'Gene', '5230', (189, 193))	('PGAM1', 'Gene', '5223', (195, 200))	('GAPDH', 'Gene', '2597', (182, 187))	('PFKFB4', 'Gene', '5210', (168, 174))	('GLUT3', 'Gene', (103, 108))	('HK2', 'molecular_function', 'GO:0008256', ('113', '116'))	('PDHB', 'Gene', (218, 222))	('glycolytic', 'MPA', (134, 144))	('PGK1', 'Gene', (189, 193))	('LDHA', 'Gene', (202, 206))	('GAPDH', 'Gene', (182, 187))	('PDHA1', 'Gene', '5160', (208, 213))	('PFKP', 'Gene', (176, 180))	('PDHA1', 'Gene', (208, 213))	('HK1', 'Gene', (163, 166))	('PDHB', 'Gene', '5162', (218, 222))	('PGK', 'molecular_function', 'GO:0004618', ('189', '192'))
175062	31063758	Unexpectedly, ectopic expression of GLUT3 only minimally increased proliferation in nutrient replete conditions and did not rescue cell death under nutrient deprived conditions (Figures 2F and S2L), suggesting additional mechanisms may mediate the regulation of glycolysis by YAP/TAZ.	('GLUT3', 'Gene', (36, 41))	('regulation', 'biological_process', 'GO:0065007', ('248', '258'))	('glycolysis', 'biological_process', 'GO:0006096', ('262', '272'))	('proliferation', 'CPA', (67, 80))	('glycolysis', 'MPA', (262, 272))	('cell death', 'biological_process', 'GO:0008219', ('131', '141'))	('GLUT3', 'Gene', '6515', (36, 41))	('ectopic expression', 'Var', (14, 32))
175067	31063758	As shown in Figure 2H, YAP/TAZ silencing caused substantial decrease in AKT phosphorylation, which correlated with reduced pEGFR and increased PTEN levels, implying downregulation of RTK signaling as the likely cause of AKT inactivation.	('AKT', 'Gene', (220, 223))	('silencing', 'Var', (31, 40))	('AKT', 'Gene', '207', (72, 75))	('decrease', 'NegReg', (60, 68))	('EGF', 'Gene', '1950', (124, 127))	('phosphorylation', 'biological_process', 'GO:0016310', ('76', '91'))	('signaling', 'biological_process', 'GO:0023052', ('187', '196'))	('reduced', 'NegReg', (115, 122))	('AKT', 'Gene', (72, 75))	('AKT', 'Gene', '207', (220, 223))	('EGF', 'Gene', (124, 127))	('PTEN', 'Gene', (143, 147))	('increased', 'PosReg', (133, 142))	('PTEN', 'Gene', '5728', (143, 147))
175074	31063758	Together, these findings reconciled previous reported functions of YAP/TAZ in glycolysis and regulation of RTK-AKT signaling, establishing YAP/TAZ as master regulators that coordinate the expression of glycolytic enzymes and GFs and RTK-AKT signaling to promote glycolysis, thereby sustaining the proliferation of NF2 mutant tumor cells (Figure 2M).	('AKT', 'Gene', '207', (111, 114))	('AKT', 'Gene', (237, 240))	('regulation', 'biological_process', 'GO:0065007', ('93', '103'))	('AKT signaling', 'biological_process', 'GO:0043491', ('237', '250'))	('sustaining', 'PosReg', (282, 292))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('glycolysis', 'biological_process', 'GO:0006096', ('262', '272'))	('AKT signaling', 'biological_process', 'GO:0043491', ('111', '124'))	('mutant', 'Var', (318, 324))	('promote', 'PosReg', (254, 261))	('AKT', 'Gene', (111, 114))	('NF2', 'Gene', (314, 317))	('glycolysis', 'MPA', (262, 272))	('proliferation', 'CPA', (297, 310))	('AKT', 'Gene', '207', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('tumor', 'Disease', (325, 330))	('glycolysis', 'biological_process', 'GO:0006096', ('78', '88'))
175083	31063758	We hypothesized that the increase in mitochondrial respiration induced by YAP/TAZ depletion might lead to elevated ROS production, which when compounded by reduced anti-oxidant capacity caused by glucose or glutamine starvation, might cause oxidative-stress-induced cell death.	('elevated ROS production', 'Phenotype', 'HP:0025464', (106, 129))	('respiration', 'biological_process', 'GO:0007585', ('51', '62'))	('depletion', 'Var', (82, 91))	('cell death', 'biological_process', 'GO:0008219', ('266', '276'))	('YAP/TAZ', 'Gene', (74, 81))	('respiration', 'biological_process', 'GO:0045333', ('51', '62'))	('glutamine', 'Chemical', 'MESH:D005973', (207, 216))	('ROS production', 'MPA', (115, 129))	('oxidative-stress', 'Phenotype', 'HP:0025464', (241, 257))	('elevated', 'PosReg', (106, 114))	('ROS', 'Chemical', 'MESH:D017382', (115, 118))	('increase', 'PosReg', (25, 33))	('glucose', 'Chemical', 'MESH:D005947', (196, 203))	('mitochondrial respiration', 'MPA', (37, 62))	('cause', 'Reg', (235, 240))
175086	31063758	Similarly, YAP/TAZ depletion also increased ROS levels and mitochondrial mass in SC4 cells (Figure S3G).	('depletion', 'Var', (19, 28))	('mitochondrial mass', 'MPA', (59, 77))	('SC4', 'CellLine', 'CVCL:6F23', (81, 84))	('ROS levels', 'MPA', (44, 54))	('ROS', 'Chemical', 'MESH:D017382', (44, 47))	('increased', 'PosReg', (34, 43))	('increased ROS levels', 'Phenotype', 'HP:0025464', (34, 54))
175097	31063758	Although expression of Myr-AKT largely rescued glycolysis and proliferation in shY/T cells, it did not reduce mitochondrial mass, only partially reversed the increase in intracellular ROS levels, and failed to prevent cell death caused by Gln withdrawal in shY/T cells (Figures 2J-2L and S3I-S3J).	('cell death', 'biological_process', 'GO:0008219', ('218', '228'))	('expression', 'Var', (9, 19))	('rescued', 'PosReg', (39, 46))	('AKT', 'Gene', (27, 30))	('proliferation', 'CPA', (62, 75))	('intracellular ROS levels', 'MPA', (170, 194))	('glycolysis', 'biological_process', 'GO:0006096', ('47', '57'))	('glycolysis', 'MPA', (47, 57))	('reduce mitochondrial mass', 'Phenotype', 'HP:0040013', (103, 128))	('intracellular', 'cellular_component', 'GO:0005622', ('170', '183'))	('mitochondrial mass', 'MPA', (110, 128))	('AKT', 'Gene', '207', (27, 30))	('Gln', 'Chemical', 'MESH:D005973', (239, 242))	('ROS', 'Chemical', 'MESH:D017382', (184, 187))	('increase', 'PosReg', (158, 166))	('increase in intracellular ROS levels', 'Phenotype', 'HP:0025464', (158, 194))
175098	31063758	Next, we used Pyr or Gln to directly stimulate TCA cycle and OXPHOS in Ctrl and shY/T cells, bypassing glycolysis.	('stimulate', 'PosReg', (37, 46))	('OXPHOS', 'biological_process', 'GO:0002082', ('61', '67'))	('TCA', 'Chemical', '-', (47, 50))	('Pyr', 'Var', (14, 17))	('Pyr', 'Chemical', 'MESH:D019289', (14, 17))	('TCA cycle', 'biological_process', 'GO:0006099', ('47', '56'))	('bypassing', 'NegReg', (93, 102))	('Gln', 'Var', (21, 24))	('glycolysis', 'biological_process', 'GO:0006096', ('103', '113'))	('OXPHOS', 'MPA', (61, 67))	('glycolysis', 'MPA', (103, 113))	('Gln', 'Chemical', 'MESH:D005973', (21, 24))	('TCA cycle', 'MPA', (47, 56))
175099	31063758	As shown in Figure S3K, both Pyr and Gln increased mitochondrial respiration to a significantly higher extent in YAP/TAZ-depleted cells, suggesting that YAP/TAZ suppress mitochondrial respiratory capacity and ROS production independent of their regulation of glycolysis.	('ROS', 'Chemical', 'MESH:D017382', (209, 212))	('glycolysis', 'biological_process', 'GO:0006096', ('259', '269'))	('ROS production', 'MPA', (209, 223))	('increased', 'PosReg', (41, 50))	('regulation', 'biological_process', 'GO:0065007', ('245', '255'))	('respiration', 'biological_process', 'GO:0007585', ('65', '76'))	('mitochondrial respiration', 'MPA', (51, 76))	('Gln', 'Var', (37, 40))	('Gln', 'Chemical', 'MESH:D005973', (37, 40))	('mitochondrial respiratory capacity', 'MPA', (170, 204))	('respiration', 'biological_process', 'GO:0045333', ('65', '76'))	('suppress', 'NegReg', (161, 169))	('Pyr', 'Var', (29, 32))	('Pyr', 'Chemical', 'MESH:D019289', (29, 32))
175100	31063758	Indicative of increased oxidative stress, H2AX was activated both in vitro and in vivo following YAP/TAZ knockdown (Figures 1E, 1G and S4A), which correlated with significant increase in the NAD+/NADH, NADP+/NADPH and GSSG/GSH ratios (Figure 3I).	('increased', 'PosReg', (14, 23))	('NADH', 'Chemical', 'MESH:D009243', (196, 200))	('GSH', 'Chemical', '-', (223, 226))	('oxidative stress', 'Phenotype', 'HP:0025464', (24, 40))	('NADP+', 'Chemical', 'MESH:D009249', (202, 207))	('NAD+', 'Chemical', 'MESH:D009243', (191, 195))	('H2AX', 'Gene', (42, 46))	('NAD+/NADH', 'MPA', (191, 200))	('NADPH', 'Gene', (208, 213))	('activated', 'PosReg', (51, 60))	('GSSG', 'Chemical', 'MESH:D019803', (218, 222))	('H2AX', 'Gene', '3014', (42, 46))	('NADPH', 'Gene', '1666', (208, 213))	('knockdown', 'Var', (105, 114))	('oxidative stress', 'MPA', (24, 40))	('YAP/TAZ', 'Gene', (97, 104))	('GSSG/GSH ratios', 'MPA', (218, 233))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (14, 40))	('increase', 'PosReg', (175, 183))
175102	31063758	As expected, withdrawal of glucose or glutamine raised ROS levels in both Ctrl and shY/T cells (Figure 3J).	('glutamine raised', 'Phenotype', 'HP:0003217', (38, 54))	('withdrawal', 'Var', (13, 23))	('ROS levels', 'MPA', (55, 65))	('ROS', 'Chemical', 'MESH:D017382', (55, 58))	('glutamine', 'Protein', (38, 47))	('glutamine', 'Chemical', 'MESH:D005973', (38, 47))	('raised ROS levels', 'Phenotype', 'HP:0025464', (48, 65))	('raised', 'PosReg', (48, 54))	('glucose', 'Chemical', 'MESH:D005947', (27, 34))
175106	31063758	Together, our findings expose a function for YAP/TAZ in limiting mitochondrial respiratory capacity and ROS production, which is necessary for maintaining redox balance and survival of NF2 mutant tumor cells under nutrient-deprived conditions.	('tumor', 'Disease', (196, 201))	('NF2', 'Gene', (185, 188))	('limiting', 'NegReg', (56, 64))	('mutant', 'Var', (189, 195))	('mitochondrial respiratory capacity', 'MPA', (65, 99))	('ROS', 'Chemical', 'MESH:D017382', (104, 107))	('ROS production', 'MPA', (104, 118))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
175107	31063758	Our in vitro and in vivo data so far indicate that although NF2 mutant tumor cells require YAP/TAZ for proliferation, they are capable of surviving YAP/TAZ loss and the resulting rise in ROS levels and oxidative stress when both glucose and glutamine are readily available.	('rise', 'PosReg', (179, 183))	('loss', 'NegReg', (156, 160))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('oxidative stress', 'Phenotype', 'HP:0025464', (202, 218))	('rise in ROS levels', 'Phenotype', 'HP:0025464', (179, 197))	('ROS levels', 'MPA', (187, 197))	('glucose', 'Chemical', 'MESH:D005947', (229, 236))	('NF2', 'Gene', (60, 63))	('ROS', 'Chemical', 'MESH:D017382', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('oxidative stress', 'MPA', (202, 218))	('YAP/TAZ', 'MPA', (148, 155))	('tumor', 'Disease', (71, 76))	('mutant', 'Var', (64, 70))	('glutamine', 'Chemical', 'MESH:D005973', (241, 250))
175108	31063758	This led us to investigate whether NF2 mutant tumor cells could activate certain stress response pathways to counter the redox imbalance caused by YAP/TAZ loss.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('stress response pathways', 'Pathway', (81, 105))	('counter', 'MPA', (109, 116))	('NF2', 'Gene', (35, 38))	('redox imbalance', 'MPA', (121, 136))	('tumor', 'Disease', (46, 51))	('mutant', 'Var', (39, 45))	('imbalance', 'Phenotype', 'HP:0002172', (127, 136))	('redox imbalance', 'Phenotype', 'HP:0025463', (121, 136))	('activate', 'PosReg', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
175109	31063758	Indeed, western blot analysis showed that multiple stress response pathways including ERK, AMPK and p38 were activated in response to YAP/TAZ knockdown (Figures S4A-S4B).	('p38', 'Gene', (100, 103))	('AMPK', 'Gene', '5563', (91, 95))	('AMPK', 'molecular_function', 'GO:0050405', ('91', '95'))	('ERK', 'molecular_function', 'GO:0004707', ('86', '89'))	('AMPK', 'molecular_function', 'GO:0004691', ('91', '95'))	('activated', 'PosReg', (109, 118))	('AMPK', 'Gene', (91, 95))	('p38', 'Gene', '5594', (100, 103))	('AMPK', 'molecular_function', 'GO:0047322', ('91', '95'))	('stress response pathways', 'Pathway', (51, 75))	('ERK', 'Gene', '5594', (86, 89))	('knockdown', 'Var', (142, 151))	('ERK', 'Gene', (86, 89))
175114	31063758	These results demonstrate that activation of the RAF-MEK-ERK pathway is necessary for the survival of YAP/TAZ-depleted NF2 mutant cells.	('MEK', 'Gene', (53, 56))	('RAF', 'Gene', '22882', (49, 52))	('ERK', 'molecular_function', 'GO:0004707', ('57', '60'))	('RAF', 'Gene', (49, 52))	('ERK', 'Gene', '5594', (57, 60))	('ERK', 'Gene', (57, 60))	('MEK', 'Gene', '5609', (53, 56))	('NF2', 'Gene', (119, 122))	('mutant', 'Var', (123, 129))
175117	31063758	In contrast, the MEK inhibitor Trametinib and pan-RAF inhibitors LY3009120 and Sorafenib inhibited pERK levels in shY/T cells, but did not reduce pAKT levels in Ctrl cells (Figures 4D and S4E).	('MEK', 'Gene', (17, 20))	('Trametinib', 'Chemical', 'MESH:C560077', (31, 41))	('pERK', 'Gene', '9451', (99, 103))	('pERK', 'Gene', (99, 103))	('LY3009120', 'Chemical', 'MESH:C000600963', (65, 74))	('inhibited', 'NegReg', (89, 98))	('MEK', 'Gene', '5609', (17, 20))	('LY3009120', 'Var', (65, 74))	('AKT', 'Gene', '207', (147, 150))	('RAF', 'Gene', '22882', (50, 53))	('RAF', 'Gene', (50, 53))	('Sorafenib', 'Chemical', 'MESH:D000077157', (79, 88))	('AKT', 'Gene', (147, 150))
175127	31063758	To determine which of these two mechanisms were responsible for activation of cAMP-PKA/EPAC signaling upon YAP/TAZ depletion, we treated shY/T cells with GPCR inhibitors (SCH 202676, GRA-1, or Sotalol) or a sAC inhibitor (KH7).	('cAMP', 'Gene', (78, 82))	('cAMP', 'Gene', '820', (78, 82))	('GPCR', 'Gene', '10663', (154, 158))	('SCH 202676', 'Var', (171, 181))	('EPAC', 'Gene', (87, 91))	('PKA', 'molecular_function', 'GO:0004691', ('83', '86'))	('signaling', 'biological_process', 'GO:0023052', ('92', '101'))	('sAC', 'biological_process', 'GO:0071173', ('207', '210'))	('Sotalol', 'Chemical', 'MESH:D013015', (193, 200))	('EPAC', 'Gene', '10411', (87, 91))	('KH7', 'Chemical', '-', (222, 225))	('PKA', 'cellular_component', 'GO:0005952', ('83', '86'))	('GPCR', 'Gene', (154, 158))	('activation', 'PosReg', (64, 74))	('sAC', 'cellular_component', 'GO:0035003', ('207', '210'))	('SCH 202676', 'Chemical', 'MESH:C418425', (171, 181))
175128	31063758	While none of the GPCR inhibitors reduced ERK phosphorylation, the sAC inhibitor KH7 drastically inhibited pERK levels in shY/T cells but not pAKT in Ctrl cells (Figures 4E and S4J).	('ERK', 'Gene', (42, 45))	('phosphorylation', 'biological_process', 'GO:0016310', ('46', '61'))	('AKT', 'Gene', (143, 146))	('ERK', 'Gene', (108, 111))	('ERK', 'molecular_function', 'GO:0004707', ('42', '45'))	('GPCR', 'Gene', '10663', (18, 22))	('reduced ERK', 'Phenotype', 'HP:0000654', (34, 45))	('KH7', 'Chemical', '-', (81, 84))	('pERK', 'Gene', '9451', (107, 111))	('AKT', 'Gene', '207', (143, 146))	('pERK', 'Gene', (107, 111))	('sAC', 'biological_process', 'GO:0071173', ('67', '70'))	('inhibited', 'NegReg', (97, 106))	('ERK', 'Gene', '5594', (42, 45))	('ERK', 'Gene', '5594', (108, 111))	('GPCR', 'Gene', (18, 22))	('KH7', 'Var', (81, 84))	('sAC', 'cellular_component', 'GO:0035003', ('67', '70'))
175130	31063758	In addition, intracellular calcium concentration was markedly increased in shY/T cells compared to Ctrl cells (Figure 4H).	('shY/T', 'Var', (75, 80))	('increased', 'PosReg', (62, 71))	('intracellular calcium concentration', 'MPA', (13, 48))	('calcium', 'Chemical', 'MESH:D002118', (27, 34))	('intracellular', 'cellular_component', 'GO:0005622', ('13', '26'))
175138	31063758	We therefore first investigated whether the dramatic increase in mitochondrial capacity and respiratory activity induced by YAP/TAZ silencing could be the cause of noncanonical ERK activation.	('ERK', 'Gene', '5594', (177, 180))	('ERK', 'molecular_function', 'GO:0004707', ('177', '180'))	('silencing', 'Var', (132, 141))	('ERK', 'Gene', (177, 180))	('increase', 'PosReg', (53, 61))	('respiratory activity', 'MPA', (92, 112))	('YAP/TAZ', 'Gene', (124, 131))	('mitochondrial', 'MPA', (65, 78))
175140	31063758	In line with this finding, staining of Ctrl and shY/T cells with a LAMP1 antibody or acridine orange (AO, marker of acidic vesicles) showed that YAP/TAZ knockdown caused markedly increase in the numbers of lysosomes, which was rescued by re-expression of YAP (Figures 5B and S5D-S5F).	('antibody', 'cellular_component', 'GO:0019814', ('73', '81'))	('antibody', 'molecular_function', 'GO:0003823', ('73', '81'))	('knockdown', 'Var', (153, 162))	('LAMP1', 'Gene', '3916', (67, 72))	('acridine orange', 'Chemical', 'MESH:D000165', (85, 100))	('LAMP1', 'Gene', (67, 72))	('antibody', 'cellular_component', 'GO:0042571', ('73', '81'))	('increase', 'PosReg', (179, 187))	('antibody', 'cellular_component', 'GO:0019815', ('73', '81'))	('YAP/TAZ', 'Gene', (145, 152))
175142	31063758	Treatment of Ctrl and shY/T cells with two different lysosome inhibitors (Bafilomycin and Chloroquine) under different nutrient conditions showed that YAP/TAZ depletion increased the sensitivity of NF2 mutant cells to lysosomal inhibition, especially under nutrient-deprived conditions (Figures S5G-S5H).	('Chloroquine', 'Chemical', 'MESH:D002738', (90, 101))	('Bafilomycin', 'Chemical', '-', (74, 85))	('increased', 'PosReg', (169, 178))	('sensitivity', 'MPA', (183, 194))	('NF2', 'Gene', (198, 201))	('lysosome', 'cellular_component', 'GO:0005764', ('53', '61'))	('mutant', 'Var', (202, 208))
175150	31063758	While either Yap/Taz-depletion or Trametinib treatment alone significantly delayed tumor growth compared to Ctrl tumors, simultaneous Yap/Taz knockdown and Mek inhibition halted tumor growth for several weeks (Figure 5H).	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (178, 183))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Disease', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('inhibition halted', 'NegReg', (160, 177))	('Mek', 'Gene', '5609', (156, 159))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('Trametinib', 'Chemical', 'MESH:C560077', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('delayed', 'NegReg', (75, 82))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('knockdown', 'Var', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('Mek', 'Gene', (156, 159))
175151	31063758	Taken together, our data demonstrate that NF2 mutant tumor cells compensate for YAP/TAZ loss by expanding their lysosomal capacity, which raises the cytosolic pH and calcium concentration, leading to the activation of RAF-MEK-ERK signaling, which represents a vulnerability that could be combined with YAP/TAZ inhibition to achieve more durable control of NF2 mutant tumors (Figure 5I).	('MEK', 'Gene', '5609', (222, 225))	('NF2', 'Gene', (42, 45))	('tumors', 'Disease', (367, 373))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('ERK', 'Gene', (226, 229))	('RAF', 'Gene', (218, 221))	('raises', 'PosReg', (138, 144))	('MEK', 'Gene', (222, 225))	('tumors', 'Disease', 'MESH:D009369', (367, 373))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('signaling', 'biological_process', 'GO:0023052', ('230', '239'))	('tumor', 'Disease', (367, 372))	('expanding', 'PosReg', (96, 105))	('mutant', 'Var', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (367, 372))	('lysosomal capacity', 'MPA', (112, 130))	('tumors', 'Phenotype', 'HP:0002664', (367, 373))	('ERK', 'molecular_function', 'GO:0004707', ('226', '229'))	('activation', 'PosReg', (204, 214))	('calcium', 'Chemical', 'MESH:D002118', (166, 173))	('ERK', 'Gene', '5594', (226, 229))	('RAF', 'Gene', '22882', (218, 221))	('tumor', 'Disease', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (367, 372))
175153	31063758	To assess the clinical relevance of our findings, we first generated a high-confidence YAP/TAZ signature by filtering genes downregulated by YAP/TAZ knockdown from our microarray analysis of SN12C cells against a recently published gene list ranked based on gene expression pattern similarities across 1,037 cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE) (Figure 6A).	('knockdown', 'Var', (149, 158))	('cancer', 'Disease', 'MESH:D009369', (308, 314))	('Cancer', 'Disease', 'MESH:D009369', (335, 341))	('Cancer', 'Disease', (335, 341))	('Cancer', 'Phenotype', 'HP:0002664', (335, 341))	('gene expression', 'biological_process', 'GO:0010467', ('258', '273'))	('downregulated', 'NegReg', (124, 137))	('cancer', 'Disease', (308, 314))	('SN12C', 'CellLine', 'CVCL:1705', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))
175155	31063758	Importantly, pRCC and ccRCC tumors with either NF2 mutations or copy number loss where enriched in Y/T-High groups compared to Y/T-Low groups, further validating our YAP/TAZ signature (Figure S6).	('mutations', 'Var', (51, 60))	('pRCC', 'Gene', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))	('ccRCC tumors', 'Disease', (22, 34))	('copy number loss', 'Var', (64, 80))	('pRCC', 'Gene', '5546', (13, 17))	('RCC', 'Phenotype', 'HP:0005584', (24, 27))	('NF2', 'Gene', (47, 50))	('ccRCC tumors', 'Disease', 'MESH:D009369', (22, 34))
175156	31063758	In agreement with our findings in NF2 mutant cells, primary RCC tumors from the Y/T-High groups displayed elevated expression of glycolysis genes and correspondingly decreased expression of OXPHOS and lysosomal genes compared to the tumors from the Y/T-Low groups in both pRCC and VHL-WT ccRCC datasets (Figures 6B-6C, and Table S2).	('pRCC', 'Gene', '5546', (272, 276))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('RCC', 'Phenotype', 'HP:0005584', (290, 293))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('expression', 'MPA', (176, 186))	('OXPHOS', 'biological_process', 'GO:0002082', ('190', '196'))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('glycolysis', 'biological_process', 'GO:0006096', ('129', '139'))	('decreased', 'NegReg', (166, 175))	('RCC', 'Phenotype', 'HP:0005584', (273, 276))	('pRCC', 'Gene', (272, 276))	('elevated', 'PosReg', (106, 114))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('VHL-WT ccRCC', 'Disease', (281, 293))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Disease', (233, 239))	('Y/T-High', 'Var', (80, 88))	('glycolysis', 'MPA', (129, 139))	('RCC tumors', 'Disease', (60, 70))	('expression', 'MPA', (115, 125))	('VHL-WT ccRCC', 'Disease', 'MESH:D006623', (281, 293))	('RCC tumors', 'Disease', 'MESH:C538614', (60, 70))
175158	31063758	Taken together, these results suggest YAP/TAZ activities may play important roles in determining the metabolic states of RCC tumors beyond NF2 mutations.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('RCC tumors', 'Disease', 'MESH:C538614', (121, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('RCC tumors', 'Disease', (121, 131))	('NF2', 'Gene', (139, 142))	('mutations', 'Var', (143, 152))
175159	31063758	Inactivation of NF2/Merlin has been shown to elicit deregulation of a wide array of signaling pathways, but it is unknown how NF2 mutant tumor cells rewire their metabolic and signaling network to overcome nutrient stress.	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('deregulation', 'MPA', (52, 64))	('tumor', 'Disease', (137, 142))	('Merlin', 'Gene', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('signaling', 'biological_process', 'GO:0023052', ('176', '185'))	('Merlin', 'Gene', '4771', (20, 26))	('elicit', 'Reg', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('mutant', 'Var', (130, 136))	('signaling pathways', 'Pathway', (84, 102))	('Inactivation', 'Var', (0, 12))	('NF2', 'Gene', (126, 129))
175160	31063758	Here, we identify YAP/TAZ as master regulators of transcriptional, signaling, metabolic, and organelle responses to nutrient deprivation in NF2 mutant tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('NF2', 'Gene', (140, 143))	('organelle', 'cellular_component', 'GO:0043226', ('93', '102'))	('mutant', 'Var', (144, 150))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
175163	31063758	Despite these important functions, YAP/TAZ are not absolutely required for the survival of NF2 mutant tumor cells, especially under nutrient replete conditions.	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('NF2', 'Gene', (91, 94))	('mutant', 'Var', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
175164	31063758	We find that NF2 mutant tumor cells adapt to YAP/TAZ depletion by ramping up RAF-MEK-ERK signaling through a mechanism mediated by upregulation of lysosomes and GPCR-independent activation of cAMP signaling.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cAMP', 'Gene', '820', (192, 196))	('mutant', 'Var', (17, 23))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('RAF', 'Gene', '22882', (77, 80))	('ERK', 'molecular_function', 'GO:0004707', ('85', '88'))	('NF2', 'Gene', (13, 16))	('MEK', 'Gene', '5609', (81, 84))	('cAMP', 'Gene', (192, 196))	('tumor', 'Disease', (24, 29))	('ERK', 'Gene', '5594', (85, 88))	('GPCR', 'Gene', (161, 165))	('RAF', 'Gene', (77, 80))	('cAMP signaling', 'biological_process', 'GO:0019933', ('192', '206'))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('MEK', 'Gene', (81, 84))	('upregulation', 'PosReg', (131, 143))	('ERK', 'Gene', (85, 88))	('lysosomes', 'MPA', (147, 156))	('ramping up', 'PosReg', (66, 76))	('GPCR', 'Gene', '10663', (161, 165))
175165	31063758	Previous work has implicated YAP as an oncogenic driver of NF2 mutant tumors, but the underlying molecular mechanisms have not been fully elucidated.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('NF2', 'Gene', (59, 62))	('mutant', 'Var', (63, 69))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('YAP', 'Disease', (29, 32))
175170	31063758	These findings not only serve to reconcile the long-standing controversy in the NF2 field regarding the relationship between RTK signaling and YAP/TAZ in NF2 tumorigenesis, but also shed light on the metabolic consequences of YAP/TAZ-RTK crosstalk, firmly establishing YAP/TAZ as the master regulators of a transcriptional, metabolic and signaling network necessary for sustaining the growth of NF2 mutant tumors.	('tumors', 'Disease', (406, 412))	('tumor', 'Disease', (158, 163))	('NF2', 'Gene', (395, 398))	('tumors', 'Disease', 'MESH:D009369', (406, 412))	('tumor', 'Disease', 'MESH:D009369', (406, 411))	('long-standing', 'Phenotype', 'HP:0003698', (47, 60))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (406, 411))	('tumor', 'Disease', (406, 411))	('signaling', 'biological_process', 'GO:0023052', ('129', '138'))	('mutant', 'Var', (399, 405))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (406, 412))	('signaling', 'biological_process', 'GO:0023052', ('338', '347'))
175176	31063758	We recently reported that in a liver-specific Nf2 knockout model, Nf2-loss-induced activation of Rac1 elevates cellular ROS levels, which activates p53-mediated DNA damage response, limiting the proliferation of Nf2 mutant liver epithelial cells.	('Nf2', 'Gene', (66, 69))	('p53-mediated DNA damage response', 'biological_process', 'GO:0030330', ('148', '180'))	('Nf2', 'Gene', '4771', (66, 69))	('Rac1', 'Gene', '5879', (97, 101))	('activation', 'PosReg', (83, 93))	('elevates cellular ROS levels', 'Phenotype', 'HP:0025464', (102, 130))	('mutant', 'Var', (216, 222))	('ROS', 'Chemical', 'MESH:D017382', (120, 123))	('activates', 'PosReg', (138, 147))	('proliferation', 'CPA', (195, 208))	('limiting', 'NegReg', (182, 190))	('p53', 'Gene', '7157', (148, 151))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('cellular ROS levels', 'MPA', (111, 130))	('elevates', 'PosReg', (102, 110))	('Nf2', 'Gene', '4771', (46, 49))	('Rac1', 'Gene', (97, 101))	('Nf2', 'Gene', (46, 49))	('p53', 'Gene', (148, 151))	('Nf2', 'Gene', '4771', (212, 215))	('Nf2', 'Gene', (212, 215))
175177	31063758	Our current study showed YAP/TAZ depletion increases mitochondrial respiration and further exacerbates oxidative stress, rendering NF2 mutant tumor cells even more susceptible to nutrient-stress-induced cell death.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('respiration', 'biological_process', 'GO:0007585', ('67', '78'))	('tumor', 'Disease', (142, 147))	('mutant', 'Var', (135, 141))	('exacerbates', 'PosReg', (91, 102))	('oxidative stress', 'MPA', (103, 119))	('NF2', 'Gene', (131, 134))	('respiration', 'biological_process', 'GO:0045333', ('67', '78'))	('cell death', 'biological_process', 'GO:0008219', ('203', '213'))	('increases', 'PosReg', (43, 52))	('oxidative stress', 'Phenotype', 'HP:0025464', (103, 119))	('mitochondrial respiration', 'MPA', (53, 78))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('more', 'PosReg', (159, 163))
175178	31063758	In contrast to the differential sensitivities to nutrient stress, we find that NF2 mutant cells respond similarly to hypoxia in the presence or absence of YAP/TAZ.	('hypoxia', 'Disease', (117, 124))	('NF2', 'Gene', (79, 82))	('hypoxia', 'Disease', 'MESH:D000860', (117, 124))	('mutant', 'Var', (83, 89))
175180	31063758	Given that NF2 loss leads to constitutive activation of YAP/TAZ, it would be interesting in future studies to determine whether matrix stiffness would influence how NF2 mutant tumor cells respond to YAP/TAZ inhibition.	('NF2', 'Gene', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('NF2', 'Gene', (165, 168))	('tumor', 'Disease', (176, 181))	('loss', 'NegReg', (15, 19))	('respond to YAP/TAZ inhibition', 'MPA', (188, 217))	('mutant', 'Var', (169, 175))	('activation', 'PosReg', (42, 52))	('constitutive', 'MPA', (29, 41))	('YAP/TAZ', 'MPA', (56, 63))	('influence', 'Reg', (151, 160))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
175181	31063758	Here we show that lysosomes also act as important signaling hubs, which by modulating the cytosolic calcium and pH levels, control the activity of a cAMP-PKA/EPACRAF-MEK-ERK signaling cascade that allows NF2 mutant cells to survive the loss of YAP/TAZ.	('calcium', 'Chemical', 'MESH:D002118', (100, 107))	('ERK', 'Gene', '5594', (170, 173))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('signaling cascade', 'biological_process', 'GO:0007165', ('174', '191'))	('cytosolic', 'MPA', (90, 99))	('ERK', 'molecular_function', 'GO:0004707', ('170', '173'))	('ERK', 'Gene', (170, 173))	('mutant', 'Var', (208, 214))	('activity', 'MPA', (135, 143))	('NF2', 'Gene', (204, 207))	('MEK', 'Gene', (166, 169))	('MEK', 'Gene', '5609', (166, 169))	('cAMP', 'Gene', '820', (149, 153))	('PKA', 'molecular_function', 'GO:0004691', ('154', '157'))	('PKA', 'cellular_component', 'GO:0005952', ('154', '157'))	('cAMP', 'Gene', (149, 153))
175189	31063758	YAP upregulation was previously reported to mediate resistance to RAF and MEK inhibitors in BRAF and KRAS mutant tumors.	('MEK', 'Gene', '5609', (74, 77))	('RAF', 'Gene', (66, 69))	('mutant', 'Var', (106, 112))	('YAP', 'Gene', (0, 3))	('tumors', 'Disease', (113, 119))	('BRAF', 'Gene', '673', (92, 96))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('KRAS', 'Gene', (101, 105))	('BRAF', 'Gene', (92, 96))	('RAF', 'Gene', '22882', (93, 96))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('RAF', 'Gene', (93, 96))	('KRAS', 'Gene', '3845', (101, 105))	('RAF', 'Gene', '22882', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('upregulation', 'PosReg', (4, 16))	('MEK', 'Gene', (74, 77))
175190	31063758	Here we show that a reciprocal lysosome-mediated noncanonical activation of RAF-MEK-ERK activation allows NF2 mutant tumor cells to survive YAP/TAZ inhibition, revealing that inhibition of YAP/TAZ and the RAF-MEK-ERK pathway also synergize in suppressing the growth of NF2 mutant tumor cells in vitro and in vivo.	('lysosome', 'cellular_component', 'GO:0005764', ('31', '39'))	('ERK', 'Gene', (84, 87))	('RAF', 'Gene', (76, 79))	('MEK', 'Gene', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('suppressing', 'NegReg', (243, 254))	('MEK', 'Gene', '5609', (209, 212))	('NF2', 'Gene', (269, 272))	('ERK', 'Gene', '5594', (213, 216))	('RAF', 'Gene', '22882', (205, 208))	('tumor', 'Disease', (280, 285))	('ERK', 'molecular_function', 'GO:0004707', ('84', '87'))	('MEK', 'Gene', '5609', (80, 83))	('MEK', 'Gene', (209, 212))	('ERK', 'molecular_function', 'GO:0004707', ('213', '216'))	('mutant', 'Var', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('RAF', 'Gene', (205, 208))	('ERK', 'Gene', (213, 216))	('ERK', 'Gene', '5594', (84, 87))	('RAF', 'Gene', '22882', (76, 79))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('mutant', 'Var', (273, 279))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('NF2', 'Gene', (106, 109))	('growth', 'MPA', (259, 265))
175191	31063758	This finding is highly significant, because it predicts that co-targeting of these two pathways could significantly improve the treatment outcomes of NF2 mutant tumors.	('treatment outcomes', 'CPA', (128, 146))	('improve', 'PosReg', (116, 123))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('NF2', 'Gene', (150, 153))	('mutant', 'Var', (154, 160))
175193	31063758	Moreover, recent breakthroughs in exosome-mediated delivery of siRNA could potentially be utilized to silence YAP/TAZ in NF2 mutant tumors.	('exosome-mediated', 'biological_process', 'GO:0099156', ('34', '50'))	('exosome', 'cellular_component', 'GO:0070062', ('34', '41'))	('mutant', 'Var', (125, 131))	('silence', 'NegReg', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('NF2', 'Gene', (121, 124))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('YAP/TAZ', 'MPA', (110, 117))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
175213	31063758	Successful YAP and TAZ knockdown in shY/T lines was confirmed via western blot and qRT-PCR analyses following 3-4 days of Dox treatment.	('Dox', 'Chemical', 'MESH:D004318', (122, 125))	('YAP', 'Gene', (11, 14))	('knockdown', 'Var', (23, 32))	('TAZ', 'Gene', (19, 22))
175214	31063758	To allow BLI imaging, Ctrl and shY/T SN12C cells were further infected with pHAGE-GFP-luciferase virus (Addgene plasmid #46793) produced in HEK293T as described above and sorted by flow cytometry to enrich for GFP+ cells.	('infected', 'Disease', 'MESH:D007239', (62, 70))	('SN12C', 'CellLine', 'CVCL:1705', (37, 42))	('HEK293T', 'CellLine', 'CVCL:0063', (140, 147))	('infected', 'Disease', (62, 70))	('HEK293T', 'Var', (140, 147))
175226	31063758	Unstained slides were deparaffinized, rehydrated, and heated in antigen retrieval buffer (IHC-Tek  Epitope Retrieval Solution, IHC World LLC, Woodstock, MD or TRIS solution (10mM Tris Base, 1mM EDTA Solution, 0.05% Tween 20, pH 9.0)) for 30 min at 95 C. Ki67 (1:200, #RM-9106, ThermoFisher Scientific), GLUT1 (1:5000, #07-1401, Millipore Sigma), PIMO (Hypoxyprobe, 1:500, #HP1, Hypoxyprobe, Inc.) and LAMP1 (1:200, #9091s, CST) stained tissues received IHC-Tek  antigen retrieval buffer and YAP (1: 25, #4912s, Cell signaling Technology, CST, Danvers, MA), TAZ (1:200, #4883s, CST), and pH2AX (1:100, #9718s, CST) received TRIS antigen retrieval solution.	('1:200', 'Var', (562, 567))	('Tek', 'Gene', (94, 97))	('HP1', 'Gene', (373, 376))	('GLUT1', 'Gene', '6513', (303, 308))	('CST', 'Gene', '106478911', (609, 612))	('H2AX', 'Gene', (588, 592))	('Tek', 'Gene', '7010', (94, 97))	('CST', 'Gene', (423, 426))	('LAMP1', 'Gene', (401, 406))	('CST', 'Gene', '106478911', (538, 541))	('CST', 'Gene', '106478911', (577, 580))	('signaling', 'biological_process', 'GO:0023052', ('516', '525'))	('H2AX', 'Gene', '3014', (588, 592))	('HP1', 'Gene', '23468', (373, 376))	('Tek', 'Gene', (457, 460))	('CST', 'Gene', (609, 612))	('GLUT1', 'Gene', (303, 308))	('LLC', 'cellular_component', 'GO:0038045', ('137', '140'))	('Tween 20', 'Chemical', 'MESH:D011136', (215, 223))	('CST', 'Gene', (538, 541))	('paraffin', 'Chemical', 'MESH:D010232', (24, 32))	('CST', 'Gene', (577, 580))	('Tek', 'Gene', '7010', (457, 460))	('LAMP1', 'Gene', '3916', (401, 406))	('CST', 'Gene', '106478911', (423, 426))
175287	31063758	YAP/TAZ promote glycolysis and NF2 tumor growth via transcription and PI3K AKT signaling YAP/TAZ suppress mitochondrial respiratory capacity and ROS buildup in NF2 mutant cells Lysosome biogenesis promotes compensatory MAPK activation in YAP/TAZ-depleted cells YAP/TAZ depletion with MEK inhibition results in a durable suppression of NF2 tumors	('mitochondrial respiratory capacity', 'MPA', (106, 140))	('tumor', 'Disease', (339, 344))	('MAPK', 'molecular_function', 'GO:0004707', ('219', '223'))	('glycolysis', 'biological_process', 'GO:0006096', ('16', '26'))	('MAPK', 'Gene', (219, 223))	('NF2', 'Gene', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (339, 344))	('Lysosome', 'cellular_component', 'GO:0005764', ('177', '185'))	('AKT signaling', 'biological_process', 'GO:0043491', ('75', '88'))	('MEK', 'Gene', (284, 287))	('tumors', 'Phenotype', 'HP:0002664', (339, 345))	('suppress', 'NegReg', (97, 105))	('tumor', 'Disease', (35, 40))	('AKT', 'Gene', (75, 78))	('Lysosome biogenesis', 'MPA', (177, 196))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumors', 'Disease', (339, 345))	('MAPK activation', 'biological_process', 'GO:0000187', ('219', '234'))	('ROS', 'MPA', (145, 148))	('mutant', 'Var', (164, 170))	('suppression', 'NegReg', (320, 331))	('AKT', 'Gene', '207', (75, 78))	('tumors', 'Disease', 'MESH:D009369', (339, 345))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('ROS', 'Chemical', 'MESH:D017382', (145, 148))	('transcription', 'biological_process', 'GO:0006351', ('52', '65'))	('PI3K', 'molecular_function', 'GO:0016303', ('70', '74'))	('NF2', 'Gene', (335, 338))	('MEK', 'Gene', '5609', (284, 287))
175308	33362855	Clear cell renal cell carcinoma essentially acts as a metabolic disorder with VHL mutations occurring in approximately 90% of patients and is characterized by reprogramming of several metabolic pathways.	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('metabolic disorder', 'Phenotype', 'HP:0001939', (54, 72))	('occurring', 'Reg', (92, 101))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('VHL', 'Gene', (78, 81))	('metabolic disorder', 'Disease', (54, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('mutations', 'Var', (82, 91))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('VHL', 'Gene', '7428', (78, 81))	('patients', 'Species', '9606', (126, 134))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('metabolic disorder', 'Disease', 'MESH:D008659', (54, 72))
175330	33362855	In this study, the transcriptional expression data were downloaded from the datasets of GSE53757 and GSE40435 in the GEO database, containing 72 and 101 paired ccRCC and normal kidney specimens, respectively.	('GSE40435', 'Var', (101, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (160, 165))	('men', 'Species', '9606', (189, 192))	('RCC', 'Disease', (162, 165))	('RCC', 'Phenotype', 'HP:0005584', (162, 165))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('GSE53757', 'Var', (88, 96))
175340	33362855	Online consensus survival analysis for KIRC (OSkirc)4 is a free web tool that collects a total of 629 ccRCC cases with gene expression data and clinical follow-up information from TCGA and the GEO databases (GSE22541, GSE29609, and GSE3) and can be used for survival analysis of interesting genes.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('gene expression', 'biological_process', 'GO:0010467', ('119', '134'))	('GSE22541', 'Var', (208, 216))	('RCC', 'Disease', (104, 107))
175356	33362855	Moreover, two datasets downloaded from the GEO database (GSE40435 and GSE53757) that contained 101 and 72 paired ccRCC and normal kidney samples, respectively, further confirmed that ACOT1/2/8/11/13 were significantly downregulated in ccRCC (Supplementary Figures 2, 3).	('downregulated', 'NegReg', (218, 231))	('ccRCC', 'Phenotype', 'HP:0006770', (235, 240))	('men', 'Species', '9606', (248, 251))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('ACOT1/2/8/11/13', 'Gene', '134526;641371;10965', (183, 198))	('GSE40435', 'Var', (57, 65))	('ACOT1/2/8/11/13', 'Gene', (183, 198))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (113, 118))	('RCC', 'Disease', (115, 118))	('GSE53757', 'Var', (70, 78))	('RCC', 'Disease', (237, 240))	('RCC', 'Phenotype', 'HP:0005584', (237, 240))	('RCC', 'Disease', 'MESH:C538614', (237, 240))
175414	33362855	On the contrary, ACOT12 is significantly decreased in hepatocellular carcinoma tissues, and was found to epigenetically inhibit epithelial-mesenchymal transition through regulating acetyl-CoA expression, thus suppressing tumor metastasis.	('regulating', 'Reg', (170, 180))	('ACOT12', 'Gene', '134526', (17, 23))	('epigenetically', 'Var', (105, 119))	('suppressing', 'NegReg', (209, 220))	('decreased', 'NegReg', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (181, 191))	('acetyl-CoA expression', 'MPA', (181, 202))	('inhibit', 'NegReg', (120, 127))	('epithelial-mesenchymal transition', 'CPA', (128, 161))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (54, 78))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (54, 78))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('128', '161'))	('ACOT12', 'Gene', (17, 23))	('hepatocellular carcinoma', 'Disease', (54, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
175432	33362855	However, recently it has been shown that the difference of mitochondrial DNA content and mutation in different types of cancer cells, as well as the heterogeneity in tumors make it possible for cancer cells to still be highly dependent on OXPHOS under some conditions.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('59', '76'))	('cancer', 'Disease', (194, 200))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('mutation', 'Var', (89, 97))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('OXPHOS', 'biological_process', 'GO:0002082', ('239', '245'))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('mitochondrial DNA', 'MPA', (59, 76))
175468	30176824	Hence, to further clarify the prognostic value of TN in RCC, we performed a systematic review and meta-analysis of the available published literature to evaluate whether the presence of TN has a prognostic impact on cancer-specific survival (CSS), overall survival (OS), recurrence-free survival (RFS) and progression-free-survival (PFS) in RCC patients.	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (341, 344))	('CSS', 'Chemical', '-', (242, 245))	('presence', 'Var', (174, 182))	('cancer', 'Disease', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('TN', 'Chemical', '-', (186, 188))	('progression-free-survival', 'CPA', (306, 331))	('patients', 'Species', '9606', (345, 353))	('recurrence-free survival', 'CPA', (271, 295))	('impact', 'Reg', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('TN', 'Chemical', '-', (50, 52))	('RCC', 'Disease', (56, 59))	('overall survival', 'CPA', (248, 264))	('RCC', 'Disease', (341, 344))	('RCC', 'Phenotype', 'HP:0005584', (341, 344))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('OS', 'Chemical', '-', (266, 268))
175476	30176824	When I2 < 50% or Pheterogeneity > 0.1, no obvious heterogeneity existed among the studies, and the fixed-effects (FE) model would be applied; otherwise, the random-effects (RE) model was applied.	('I2 < 50%', 'Var', (5, 13))	('FE', 'Chemical', '-', (114, 116))	('Pheterogeneity', 'Var', (17, 31))	('> 0.1', 'Var', (32, 37))
175509	30176824	Nonetheless, some studies have shown that the presence of any TN is a negative predictor of survival in RCC.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('TN', 'Chemical', '-', (62, 64))	('presence', 'Var', (46, 54))	('negative', 'NegReg', (70, 78))	('RCC', 'Disease', (104, 107))
175512	30176824	Robust evidence obtained from sensitivity analysis demonstrated that the presence of TN was associated with poor outcomes in terms of CSS (HR = 1.37, p < 0.001), OS (HR = 1.29, p < 0.0 01), RFS (HR = 1.55, p < 0.001) and PFS (HR = 1.31, p < 0.001) in patients with RCC.	('presence', 'Var', (73, 81))	('OS', 'Chemical', '-', (162, 164))	('CSS', 'Disease', (134, 137))	('RFS', 'MPA', (190, 193))	('TN', 'Chemical', '-', (85, 87))	('patients', 'Species', '9606', (251, 259))	('PFS', 'MPA', (221, 224))	('CSS', 'Chemical', '-', (134, 137))	('RCC', 'Disease', 'MESH:C538614', (265, 268))	('RCC', 'Disease', (265, 268))	('RCC', 'Phenotype', 'HP:0005584', (265, 268))
175528	28165386	Markedly, oxidative modifications of MNSOD were identified at histidine (H54 and H55), tyrosine (Y58), tryptophan (W147, W149, W205 and W210) and asparagine (N206 and N209) residues additional to methionine.	('Y58', 'Var', (97, 100))	('histidine', 'Chemical', 'MESH:D006639', (62, 71))	('tryptophan', 'Chemical', 'MESH:D014364', (103, 113))	('tyrosine', 'Chemical', 'MESH:D014443', (87, 95))	('W147', 'Var', (115, 119))	('asparagine', 'Chemical', 'MESH:D001216', (146, 156))	('H54', 'Var', (73, 76))	('MNSOD', 'Gene', (37, 42))	('methionine', 'Chemical', 'MESH:D008715', (196, 206))	('W210', 'Var', (136, 140))	('N206', 'Var', (158, 162))	('W149', 'Var', (121, 125))	('N209', 'Var', (167, 171))	('W205', 'Var', (127, 131))	('oxidative modifications', 'MPA', (10, 33))
175529	28165386	These oxidative insults were located at three hotspots near the hydrophobic pocket of the manganese binding site, of which the oxidation of Y58, W147 and W149 was up-regulated around three folds and the oxidation of H54 and H55 was detected in the cancer tissues only (p < 0.05).	('cancer', 'Disease', (248, 254))	('oxidation', 'MPA', (127, 136))	('manganese binding', 'molecular_function', 'GO:0030145', ('90', '107'))	('up-regulated', 'PosReg', (163, 175))	('W147', 'Var', (145, 149))	('W149', 'Var', (154, 158))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('manganese', 'Chemical', 'MESH:D008345', (90, 99))	('Y58', 'Var', (140, 143))	('cancer', 'Disease', 'MESH:D009369', (248, 254))
175530	28165386	When normalized to MNSOD expression levels, relative MNSOD enzymatic activity was decreased in cancer tissues, suggesting impairment of MNSOD enzymatic activity in kidney cancer due to modifications.	('kidney cancer', 'Phenotype', 'HP:0009726', (164, 177))	('kidney cancer', 'Disease', 'MESH:D007680', (164, 177))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', (171, 177))	('kidney cancer', 'Disease', (164, 177))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('modifications', 'Var', (185, 198))
175540	28165386	For example, tyrosine (Tyr) yields greater 3,4-dihydroxyphenylalanine (DOPA) and less 2,4-isomer.	('greater', 'PosReg', (35, 42))	('3,4-dihydroxyphenylalanine (DOPA) and less 2,4-isomer', 'Chemical', '-', (43, 96))	('less', 'NegReg', (81, 85))	('Tyr', 'Chemical', 'MESH:D014443', (23, 26))	('tyrosine', 'Chemical', 'MESH:D014443', (13, 21))	('tyrosine', 'Var', (13, 21))
175542	28165386	Nitration on tyrosine 58 (Y58 or Y34 when the 24 amino acids transit peptide is cleaved) of MNSOD has been detected by crystal structures and mutation analysis.	('MNSOD', 'Gene', (92, 97))	('Y34', 'Var', (33, 36))	('tyrosine', 'Chemical', 'MESH:D014443', (13, 21))
175559	28165386	High confident oxidation modifications were confirmed at tryptophan (W), tyrosine (Y), histidine (H), and asparagine (N) residues of MNSOD (Table 2).	('modifications', 'Var', (25, 38))	('tyrosine', 'Chemical', 'MESH:D014443', (73, 81))	('tryptophan', 'Chemical', 'MESH:D014364', (57, 67))	('histidine', 'MPA', (87, 96))	('asparagine', 'Chemical', 'MESH:D001216', (106, 116))	('histidine', 'Chemical', 'MESH:D006639', (87, 96))
175565	28165386	Markedly, these identified tryptophan oxidations at W147, W149, W205 and W210 were located in the hotspots that were reported to be important for the enzymatic activity of MNSOD.	('tryptophan', 'Chemical', 'MESH:D014364', (27, 37))	('tryptophan oxidations', 'MPA', (27, 48))	('W149', 'Var', (58, 62))	('W205', 'Var', (64, 68))	('W210', 'Var', (73, 77))
175568	28165386	We identified two asparagine oxidation sites at N206 and N209 in MNSOD, and the two oxidized asparagine residues were found in the peptide AIWN206VIN209WENVTER, which was located in the C-terminal.	('asparagine', 'Chemical', 'MESH:D001216', (93, 103))	('asparagine', 'Chemical', 'MESH:D001216', (18, 28))	('N206', 'Var', (48, 52))	('N209', 'Var', (57, 61))
175572	28165386	In this study, we identified two oxidized histidine residues at H54 and H55 in MNSOD.	('H55', 'Var', (72, 75))	('H54', 'Var', (64, 67))	('histidine', 'Chemical', 'MESH:D006639', (42, 51))
175579	28165386	Markedly, oxidation at H54 and H55 only found in kidney cancer tissues (p < 0.05, n = 4), and oxidation at Y58, W147 and W149 increased 2.63, 3.26 and 3.13-fold (p < 0.05, n = 4) in kidney cancer tissues, respectively, in comparison with those in adjacent non-cancer tissues of the same patient (Figure 3b).	('kidney cancer', 'Disease', 'MESH:D007680', (182, 195))	('patient', 'Species', '9606', (287, 294))	('kidney cancer', 'Phenotype', 'HP:0009726', (182, 195))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('non-cancer', 'Disease', 'MESH:D009369', (256, 266))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('kidney cancer', 'Disease', (182, 195))	('kidney cancer', 'Disease', 'MESH:D007680', (49, 62))	('non-cancer', 'Disease', (256, 266))	('kidney cancer', 'Phenotype', 'HP:0009726', (49, 62))	('W147', 'Var', (112, 116))	('kidney cancer', 'Disease', (49, 62))	('W149', 'Var', (121, 125))	('increased', 'PosReg', (126, 135))
175580	28165386	While, oxidation at N206 and N209 decreased 1.54-fold (p < 0.05, n = 4) and oxidation at W205 and W210 decreased 1.40-fold (p < 0.05, n = 4) in kidney cancer tissues.	('kidney cancer', 'Phenotype', 'HP:0009726', (144, 157))	('decreased', 'NegReg', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('kidney cancer', 'Disease', (144, 157))	('decreased', 'NegReg', (103, 112))	('kidney cancer', 'Disease', 'MESH:D007680', (144, 157))	('W210', 'Var', (98, 102))	('N209', 'Var', (29, 33))
175589	28165386	Modified sites involved two histidine (H54 and H55), one tyrosine (Y58), four tryptophan (W147, W149, W205 and W210) and two asparagine (N206 and N209), and most of the oxidized residues clustered at the C-terminus.	('tryptophan', 'Chemical', 'MESH:D014364', (78, 88))	('W210', 'Var', (111, 115))	('W147', 'Var', (90, 94))	('asparagine', 'Chemical', 'MESH:D001216', (125, 135))	('N206', 'Var', (137, 141))	('N209', 'Var', (146, 150))	('W149', 'Var', (96, 100))	('tyrosine', 'Chemical', 'MESH:D014443', (57, 65))	('histidine', 'Chemical', 'MESH:D006639', (28, 37))	('W205', 'Var', (102, 106))
175590	28165386	Consistent with our findings, it was recently reported that MNSOD could be oxidized at H54, H55 and W210 in medulloblastoma cells.	('H55', 'Var', (92, 95))	('medulloblastoma', 'Disease', (108, 123))	('H54', 'Var', (87, 90))	('medulloblastoma', 'Disease', 'MESH:D008527', (108, 123))	('MNSOD', 'Gene', (60, 65))	('medulloblastoma', 'Phenotype', 'HP:0002885', (108, 123))	('W210', 'Var', (100, 104))
175591	28165386	Notably, three hotspots at amino acid residues 54-58, 147-149, and 205-210 were observed and multiple oxidation incidents occurred simultaneously in the nearby positions, such as W147W149 and N209W210.	('W147W149', 'Var', (179, 187))	('W147W149', 'CellLine', 'CVCL:0C64', (179, 187))	('N209W210', 'Var', (192, 200))
175594	28165386	Based on three-dimensional structure (1LUV.pdb), the catalytic core (active site) of MNSOD is located between the N-terminal helices and the C-terminal alpha/beta domain, coordinating in a strained trigonal bipyramidal geometry by the side chains of His50, His98, Asp183 and His187 and the Mn ion in the active metal ion (Figure 2b and Figure 4c).	('Asp183', 'Chemical', '-', (264, 270))	('His50', 'Chemical', '-', (250, 255))	('His98', 'Var', (257, 262))	('His98', 'Chemical', '-', (257, 262))	('His187', 'Chemical', '-', (275, 281))	('MNSOD', 'Gene', (85, 90))	('Asp183', 'Var', (264, 270))	('His187', 'Var', (275, 281))	('core', 'cellular_component', 'GO:0019013', ('63', '67'))	('His50', 'Var', (250, 255))	('metal', 'Chemical', 'MESH:D008670', (311, 316))
175595	28165386	The residues near the active site were known to affect the enzymatic activity or the stability of sites involving His54, Tyr58 and Trp147.	('affect', 'Reg', (48, 54))	('stability', 'MPA', (85, 94))	('Tyr58', 'Chemical', '-', (121, 126))	('enzymatic activity', 'MPA', (59, 77))	('His54', 'Chemical', '-', (114, 119))	('His54', 'Protein', (114, 119))	('Trp147', 'Chemical', '-', (131, 137))	('Tyr58', 'Var', (121, 126))	('residues', 'Var', (4, 12))	('Trp147', 'Var', (131, 137))
175596	28165386	The hydrophobic side chains that surrounded the metal-ligand cluster including His51, His54, His55, Tyr58, Phe101, Trp102, Trp149, Tyr190, and Tyr200 could also be altered.	('metal', 'Chemical', 'MESH:D008670', (48, 53))	('Phe101', 'Chemical', '-', (107, 113))	('His54', 'Chemical', '-', (86, 91))	('Trp149', 'Var', (123, 129))	('Tyr200', 'Var', (143, 149))	('Trp102', 'Var', (115, 121))	('His51', 'Var', (79, 84))	('His55', 'Chemical', '-', (93, 98))	('hydrophobic side chains', 'MPA', (4, 27))	('altered', 'Reg', (164, 171))	('Phe101', 'Var', (107, 113))	('Tyr58', 'Chemical', '-', (100, 105))	('Trp102', 'Chemical', '-', (115, 121))	('Trp149', 'Chemical', '-', (123, 129))	('Tyr200', 'Chemical', '-', (143, 149))	('Tyr190', 'Chemical', '-', (131, 137))	('His54', 'Var', (86, 91))	('His55', 'Var', (93, 98))	('Tyr190', 'Var', (131, 137))	('ligand', 'molecular_function', 'GO:0005488', ('54', '60'))	('Tyr58', 'Var', (100, 105))	('His51', 'Chemical', '-', (79, 84))
175598	28165386	These included the residues His54 (H54), His55 (H55), Tyr58 (Y58), Trp147 (W147) and Trp149 (W149) (Figure 4).	('His54', 'Var', (28, 33))	('His55', 'Chemical', '-', (41, 46))	('Tyr58', 'Var', (54, 59))	('His54', 'Chemical', '-', (28, 33))	('Trp147', 'Var', (67, 73))	('Trp149', 'Chemical', '-', (85, 91))	('His55', 'Var', (41, 46))	('Tyr58', 'Chemical', '-', (54, 59))	('Trp147', 'Chemical', '-', (67, 73))
175600	28165386	We, therefore, speculated that the newly identified oxidative modification may initially affect the structure then compromise the catalytic activity of MNSOD, and thereby contribute to ccRCC formation and development.	('oxidative', 'Var', (52, 61))	('RCC', 'Disease', (187, 190))	('RCC', 'Phenotype', 'HP:0005584', (187, 190))	('formation', 'biological_process', 'GO:0009058', ('191', '200'))	('RCC', 'Disease', 'MESH:C538614', (187, 190))	('catalytic activity', 'MPA', (130, 148))	('contribute to', 'Reg', (171, 184))	('ccRCC', 'Phenotype', 'HP:0006770', (185, 190))	('structure', 'MPA', (100, 109))	('catalytic activity', 'molecular_function', 'GO:0003824', ('130', '148'))	('affect', 'Reg', (89, 95))	('development', 'CPA', (205, 216))	('compromise', 'NegReg', (115, 125))
175603	28165386	Although MNSOD oxidation at H54, H55 and W210 was reported in medulloblastoma cells, the extent of oxidation and its modification patterns have not been fully elucidated.	('H55', 'Var', (33, 36))	('medulloblastoma', 'Disease', 'MESH:D008527', (62, 77))	('H54', 'Var', (28, 31))	('medulloblastoma', 'Phenotype', 'HP:0002885', (62, 77))	('medulloblastoma', 'Disease', (62, 77))	('W210', 'Var', (41, 45))
175605	28165386	Label-free quantification demonstrated a significant increase of oxidation at H54, H55, Y58, W147 and W149 in ccRCC, comparing with adjacent tissues (Figure 3b).	('W147', 'Var', (93, 97))	('oxidation', 'MPA', (65, 74))	('W149', 'Var', (102, 106))	('Y58', 'Var', (88, 91))	('RCC', 'Disease', (112, 115))	('increase', 'PosReg', (53, 61))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('H55', 'Var', (83, 86))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('H54', 'Var', (78, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))
175606	28165386	As protein oxidation usually altered the enzymatic activity, we speculated that the oxidation of H54, H55, Y58, W147 and W149 mediated MNSOD activity, and thereby, contributed to ccRCC initiation.	('MNSOD', 'MPA', (135, 140))	('enzymatic activity', 'MPA', (41, 59))	('H55', 'Var', (102, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (179, 184))	('protein', 'cellular_component', 'GO:0003675', ('3', '10'))	('protein oxidation', 'biological_process', 'GO:0018158', ('3', '20'))	('H54', 'Var', (97, 100))	('W147', 'Var', (112, 116))	('altered', 'Reg', (29, 36))	('contributed', 'Reg', (164, 175))	('W149', 'Var', (121, 125))	('RCC', 'Disease', 'MESH:C538614', (181, 184))	('RCC', 'Disease', (181, 184))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))	('Y58', 'Var', (107, 110))
175610	28165386	Our observations suggest that, in addition to overexpression of MNSOD in cancer cells, MNSOD oxidation might also contribute to ROS regulation by mediation of MNSOD activity.	('MNSOD', 'Var', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (73, 79))	('ROS', 'Chemical', 'MESH:D017382', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('regulation', 'biological_process', 'GO:0065007', ('132', '142'))	('ROS regulation', 'MPA', (128, 142))	('contribute', 'Reg', (114, 124))
175647	28153029	However, both forms are associated with gene mutations to the short arm of chromosome 3 and specifically to the VHL tumor suppressor gene.	('VHL tumor', 'Disease', 'MESH:D006623', (112, 121))	('associated', 'Reg', (24, 34))	('VHL tumor', 'Disease', (112, 121))	('tumor suppressor', 'biological_process', 'GO:0051726', ('116', '132'))	('gene mutations', 'Var', (40, 54))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('116', '132'))	('short arm', 'Phenotype', 'HP:0009824', (62, 71))	('chromosome', 'cellular_component', 'GO:0005694', ('75', '85'))
175649	28153029	However, VHL is mutated or methylated in up to 90% of patients with ccRCC.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('VHL', 'Gene', (9, 12))	('patients', 'Species', '9606', (54, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('methylated', 'Var', (27, 37))	('VHL', 'Gene', '7428', (9, 12))	('mutated', 'Var', (16, 23))
175650	28153029	When the VHL gene is mutated, its tumor suppressor function is lost and HIF accumulates to high levels, leading to the activation of multiple genes including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).	('tumor', 'Disease', (34, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('VHL', 'Gene', (9, 12))	('vascular endothelial growth factor', 'Gene', (158, 192))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('158', '192'))	('VEGF', 'Gene', '7422', (194, 198))	('VEGF', 'Gene', (194, 198))	('lost', 'NegReg', (63, 67))	('VHL', 'Gene', '7428', (9, 12))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('204', '234'))	('vascular endothelial growth factor', 'Gene', '7422', (158, 192))	('activation', 'PosReg', (119, 129))	('PDGF', 'molecular_function', 'GO:0005161', ('236', '240'))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('mutated', 'Var', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))
175670	28153029	Pazopanib was shown to prolong mPFS compared to placebo (11.1 vs. 2.8 months) and to cytokine-pretreatment (7.4 vs. 4.2 months).	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('mPFS', 'CPA', (31, 35))	('Pazopanib', 'Var', (0, 9))	('prolong', 'PosReg', (23, 30))
175709	28153029	Participants were considered poor prognosis if three of the following six criteria were met: LDH >= 1.5 x ULN, Ca++ of >=10 mg/dL, diagnosis to treatment initiation of <1 year, KPS 60-70%, >=2 metastatic sites.	('Participants', 'Species', '9606', (0, 12))	('>= 1.5', 'Var', (97, 103))	('LDH', 'Disease', (93, 96))
175773	28153029	Moreover, OS was increased in the group receiving the dual-therapy compared to everolimus alone, although not statistically significant.	('increased', 'PosReg', (17, 26))	('everolimus', 'Chemical', 'MESH:D000068338', (79, 89))	('dual-therapy', 'Var', (54, 66))	('OS', 'Gene', '17451', (10, 12))
175776	28153029	The design of this three-armed study not only provides objective clinical data but also presents an emerging concept in mRCC therapy that combination drugs targeting multiple pathways (in this case VEGF and mTOR) could simultaneously inhibit two critical independent pathways synergistically and can potentially prevent resistance to single-agent therapy.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('mTOR', 'Gene', (207, 211))	('mTOR', 'Gene', '2475', (207, 211))	('VEGF', 'Gene', (198, 202))	('combination', 'Var', (138, 149))	('inhibit', 'NegReg', (234, 241))	('VEGF', 'Gene', '7422', (198, 202))
175809	28153029	mOS was 25.0 versus 19.6 months for nivolumab and everolimus, respectively, and met the predetermined criteria for significance.	('mOS', 'Gene', (0, 3))	('nivolumab', 'Chemical', 'MESH:D000077594', (36, 45))	('mOS', 'Gene', '17451', (0, 3))	('everolimus', 'Chemical', 'MESH:D000068338', (50, 60))	('nivolumab', 'Var', (36, 45))
175820	28153029	Nivolumab was associated with an improved HRQoL compared to everolimus in this study population.	('Nivolumab', 'Chemical', 'MESH:D000077594', (0, 9))	('everolimus', 'Chemical', 'MESH:D000068338', (60, 70))	('HRQoL', 'MPA', (42, 47))	('Nivolumab', 'Var', (0, 9))	('improved', 'PosReg', (33, 41))
175883	29092949	This has been previously explored in various cancers including breast, ovarian, and glioblastoma, and led to new insights into the relationship between cancer tissue morphology and genetic changes such as PTEN mutations.	('cancer', 'Disease', (152, 158))	('PTEN', 'Gene', (205, 209))	('mutations', 'Var', (210, 219))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('PTEN', 'Gene', '5728', (205, 209))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('glioblastoma', 'Phenotype', 'HP:0012174', (84, 96))	('breast', 'Disease', (63, 69))	('cancers', 'Disease', (45, 52))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('ovarian', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancer', 'Disease', (45, 51))	('glioblastoma', 'Disease', (84, 96))	('glioblastoma', 'Disease', 'MESH:D005909', (84, 96))
175915	29092949	In addition, we have shown that lmQCM can find smaller co-expressed gene modules that are often associated with structural mutations such as copy number variation in cancers.	('cancers', 'Disease', (166, 173))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('smaller', 'NegReg', (47, 54))	('copy number variation', 'Var', (141, 162))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
175922	29092949	2A and B, image features such as major_bin8, major_bin9, ratio_bin8, ratio_bin9, ratio_std, and major_std, were negatively related to prognosis, that is, patients with large values of these variables had worse prognosis than other patients.	('patients', 'Species', '9606', (231, 239))	('major_std', 'Var', (96, 105))	('patients', 'Species', '9606', (154, 162))	('major_bin8', 'Var', (33, 43))	('major_bin9', 'Var', (45, 55))	('negatively', 'NegReg', (112, 122))	('related', 'Reg', (123, 130))	('ratio_bin9', 'Var', (69, 79))	('ratio_bin8', 'Var', (57, 67))
175938	29092949	Patients with high expression of gene module 11 had significantly worse outcome than other patients (log-rank p value = 1.33e-3).	('Patients', 'Species', '9606', (0, 8))	('gene module 11', 'Gene', (33, 47))	('patients', 'Species', '9606', (91, 99))	('high expression', 'Var', (14, 29))
175939	29092949	Using univariate and multivariate Cox proportional hazards analysis, we performed a comprehensive comparison between the lasso-Cox risk index and other known prognostic biomarkers, including two clinical variables, grade (G1+G2 vs. G3+G4), stage (I+ II vs. III+ IV), six gene expression signatures, CSNK2A1, SPP1, DEFB1, CD31, EDNRB, TSPAN7, and five somatic mutation genes, VHL, PBRM1, BAP1, SETD2, TP53.	('SETD2', 'Gene', (393, 398))	('SPP1', 'Gene', (308, 312))	('gene expression', 'biological_process', 'GO:0010467', ('271', '286'))	('CD31', 'Gene', (321, 325))	('BAP1', 'Gene', '8314', (387, 391))	('SPP1', 'Gene', '6696', (308, 312))	('DEFB1', 'Gene', '1672', (314, 319))	('SETD2', 'Gene', '29072', (393, 398))	('DEFB1', 'Gene', (314, 319))	('TSPAN7', 'Gene', '7102', (334, 340))	('PBRM1', 'Gene', '55193', (380, 385))	('TP53', 'Gene', (400, 404))	('G1+G2', 'Var', (222, 227))	('VHL', 'Gene', (375, 378))	('CSNK2A1', 'Gene', (299, 306))	('CSNK2A1', 'Gene', '1457', (299, 306))	('BAP1', 'Gene', (387, 391))	('PBRM1', 'Gene', (380, 385))	('CD31', 'Gene', '5175', (321, 325))	('SPP', 'molecular_function', 'GO:0042499', ('308', '311'))	('VHL', 'Gene', '7428', (375, 378))	('EDNRB', 'Gene', '1910', (327, 332))	('TP53', 'Gene', '7157', (400, 404))	('TSPAN7', 'Gene', (334, 340))	('EDNRB', 'Gene', (327, 332))
175958	29092949	Interestingly, all the 10 genes locate on the same chromosome, straddling chromosome 14q11 to 14q32, implying potential copy number variation on 14q may be related to the prognosis of kidney patients.	('patients', 'Species', '9606', (191, 199))	('copy number variation', 'Var', (120, 141))	('chromosome', 'cellular_component', 'GO:0005694', ('74', '84'))	('chromosome', 'cellular_component', 'GO:0005694', ('51', '61'))	('related to', 'Reg', (156, 166))	('kidney patients', 'Disease', (184, 199))
175985	28643803	To date, surgery is the main treatment for this kind of cancer, while RCC is notoriously resistant to conventional chemotherapy, possibly through high expression of some multidrug resistance genes or inactivation of apoptotic pathways.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('drug resistance', 'Phenotype', 'HP:0020174', (175, 190))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('apoptotic pathways', 'Pathway', (216, 234))	('inactivation', 'Var', (200, 212))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
176040	28643803	786-O was derived from a primary clear-cell adenocarcinoma and high tumorigenic, but RCC4 was low tumorigenic.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('RCC4', 'Gene', (85, 89))	('adenocarcinoma', 'Disease', (44, 58))	('786-O', 'Var', (0, 5))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('adenocarcinoma', 'Disease', 'MESH:D000230', (44, 58))	('tumorigenic', 'CPA', (68, 79))	('RCC4', 'Gene', '84925', (85, 89))
176049	28643803	Indeed, the cytotoxicity of doxorubicin was significantly higher in the primary mouse embryo fibroblast (MEF) cells from ALDH2 knockout mice than those from wild-type mice (Fig.	('mice', 'Species', '10090', (136, 140))	('mice', 'Species', '10090', (167, 171))	('ALDH', 'molecular_function', 'GO:0004030', ('121', '125'))	('cytotoxicity', 'Disease', 'MESH:D064420', (12, 24))	('mouse', 'Species', '10090', (80, 85))	('knockout', 'Var', (127, 135))	('higher', 'PosReg', (58, 64))	('doxorubicin', 'Chemical', 'MESH:D004317', (28, 39))	('MEF', 'CellLine', 'CVCL:9115', (105, 108))	('cytotoxicity', 'Disease', (12, 24))	('ALDH2', 'Gene', (121, 126))
176050	28643803	To address the potential role of ALDH2 in cytotoxicity of anthracyclines in ccRCC cells, we silenced ALDH2 expression in RCC4/VHL cells, and found that the reduction of ALDH2 suppressed the proliferation of these cells (Supplementary Fig.	('ALDH', 'molecular_function', 'GO:0004030', ('169', '173'))	('suppressed', 'NegReg', (175, 185))	('cytotoxicity', 'Disease', (42, 54))	('proliferation', 'CPA', (190, 203))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('cytotoxicity', 'Disease', 'MESH:D064420', (42, 54))	('ALDH', 'molecular_function', 'GO:0004030', ('33', '37'))	('ALDH2', 'Gene', (169, 174))	('RCC4', 'Gene', (121, 125))	('silenced', 'NegReg', (92, 100))	('ALDH', 'molecular_function', 'GO:0004030', ('101', '105'))	('reduction', 'Var', (156, 165))	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', (121, 124))	('RCC4', 'Gene', '84925', (121, 125))	('anthracyclines', 'Chemical', 'MESH:D018943', (58, 72))	('ALDH2', 'Gene', (101, 106))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))
176051	28643803	5a), although the ALDH2 knockout did not affect the proliferation of the primary MEF cells (Supplementary Fig.	('knockout', 'Var', (24, 32))	('ALDH', 'molecular_function', 'GO:0004030', ('18', '22'))	('ALDH2', 'Gene', (18, 23))	('MEF', 'CellLine', 'CVCL:9115', (81, 84))
176053	28643803	Reciprocally, stable ectopic expression of ALDH2 decreased cytotoxicity of doxorubicin and daunorubicin in RCC4 cells (Fig.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('cytotoxicity', 'Disease', 'MESH:D064420', (59, 71))	('doxorubicin', 'Chemical', 'MESH:D004317', (75, 86))	('daunorubicin', 'Chemical', 'MESH:D003630', (91, 103))	('ALDH2', 'Gene', (43, 48))	('RCC4', 'Gene', (107, 111))	('decreased', 'NegReg', (49, 58))	('RCC4', 'Gene', '84925', (107, 111))	('ALDH', 'molecular_function', 'GO:0004030', ('43', '47'))	('cytotoxicity', 'Disease', (59, 71))	('ectopic expression', 'Var', (21, 39))
176064	28643803	In agreement, ectopic VHL expression significantly reduced 4-HNE in RCC4 cells, while ALDH2 silence increased 4-HNE in the RCC4/VHL cells, under the treatment of doxorubicin but not vincristine (Fig.	('RCC4', 'Gene', (123, 127))	('VHL', 'Gene', (22, 25))	('reduced', 'NegReg', (51, 58))	('vincristine', 'Chemical', 'MESH:D014750', (182, 193))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('4-HNE', 'MPA', (110, 115))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('silence', 'Var', (92, 99))	('RCC4', 'Gene', '84925', (123, 127))	('RCC4', 'Gene', '84925', (68, 72))	('ALDH', 'molecular_function', 'GO:0004030', ('86', '90'))	('4-HNE', 'MPA', (59, 64))	('increased', 'PosReg', (100, 109))	('4-HNE', 'Chemical', 'MESH:C027576', (110, 115))	('expression', 'Var', (26, 36))	('4-HNE', 'Chemical', 'MESH:C027576', (59, 64))	('ectopic', 'Var', (14, 21))	('ALDH2', 'Gene', (86, 91))	('RCC4', 'Gene', (68, 72))	('doxorubicin', 'Chemical', 'MESH:D004317', (162, 173))
176073	28643803	We constructed an alpha-domain mutant C162F and a beta-domain mutant Y98H of VHL, which lost its E3 ligase activity, to examine the expression of ALDH2.	('lost', 'NegReg', (88, 92))	('ALDH', 'molecular_function', 'GO:0004030', ('146', '150'))	('Y98H', 'Var', (69, 73))	('activity', 'MPA', (107, 115))	('VHL', 'Gene', (77, 80))	('ligase activity', 'molecular_function', 'GO:0016874', ('100', '115'))	('C162F', 'Mutation', 'rs397516444', (38, 43))	('C162F', 'Var', (38, 43))	('E3 ligase', 'Protein', (97, 106))	('Y98H', 'Mutation', 'rs5030809', (69, 73))
176074	28643803	The results showed that, like wild-type VHL, these two VHL mutants still upregulated ALDH2 expression, but these mutants failed to induce HIF-1alpha degradation (Supplementary Fig.	('expression', 'MPA', (91, 101))	('degradation', 'biological_process', 'GO:0009056', ('149', '160'))	('mutants', 'Var', (59, 66))	('HIF-1alpha degradation', 'Disease', 'MESH:D055959', (138, 160))	('ALDH2', 'Gene', (85, 90))	('VHL', 'Gene', (55, 58))	('upregulated', 'PosReg', (73, 84))	('HIF-1alpha degradation', 'Disease', (138, 160))	('ALDH', 'molecular_function', 'GO:0004030', ('85', '89'))
176075	28643803	Of great interest, we sequenced VHL genes from 44 cases of ccRCC cancer tissues, and found that 13 cases of them carried VHL mutations, among which 8 cases were missense mutations with no E3 ligase activities (Supplementary Fig.	('mutations', 'Var', (125, 134))	('VHL', 'Gene', (32, 35))	('cancer', 'Disease', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('missense mutations', 'Var', (161, 179))	('carried', 'Reg', (113, 120))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('VHL', 'Gene', (121, 124))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
176081	28643803	To confirm this, we showed that HNF-4alpha mRNA and protein levels were significantly upregulated in RCC4 and 786-O cells with ectopic VHL expression (Fig.	('VHL', 'Gene', (135, 138))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('HNF-4alpha', 'Gene', '3172', (32, 42))	('ectopic', 'Var', (127, 134))	('HNF-4alpha', 'Gene', (32, 42))	('RCC4', 'Gene', '84925', (101, 105))	('RCC4', 'Gene', (101, 105))	('upregulated', 'PosReg', (86, 97))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
176082	28643803	Accordingly, silencing of VHL in RCC4/VHL cells suppressed HNF-4alpha expression on mRNA and protein levels (Fig.	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('VHL', 'Gene', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('suppressed', 'NegReg', (48, 58))	('expression', 'MPA', (70, 80))	('RCC4', 'Gene', '84925', (33, 37))	('RCC4', 'Gene', (33, 37))	('HNF-4alpha', 'Gene', '3172', (59, 69))	('silencing', 'Var', (13, 22))	('HNF-4alpha', 'Gene', (59, 69))
176083	28643803	On the other hand, silencing of HNF-4alpha decreased ALDH2 expression in RCC4/VHL (Fig.	('ALDH2', 'Gene', (53, 58))	('RCC4', 'Gene', '84925', (73, 77))	('HNF-4alpha', 'Gene', '3172', (32, 42))	('silencing', 'Var', (19, 28))	('HNF-4alpha', 'Gene', (32, 42))	('RCC4', 'Gene', (73, 77))	('expression', 'MPA', (59, 69))	('decreased', 'NegReg', (43, 52))	('ALDH', 'molecular_function', 'GO:0004030', ('53', '57'))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
176086	28643803	Hence, VHL-expressing plasmids and the 1,500 bp of the HNF-4alpha promoter-driven luciferase reporter were co-transfected into 293T cells, and the results demonstrated that VHL transfection significantly increased the luciferase activity (Fig.	('VHL', 'Gene', (173, 176))	('luciferase activity', 'molecular_function', 'GO:0050248', ('218', '237'))	('HNF-4alpha', 'Gene', (55, 65))	('transfection', 'Var', (177, 189))	('luciferase', 'Enzyme', (218, 228))	('activity', 'MPA', (229, 237))	('increased', 'PosReg', (204, 213))	('luciferase activity', 'molecular_function', 'GO:0047077', ('218', '237'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('218', '237'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('218', '237'))	('293T', 'CellLine', 'CVCL:0063', (127, 131))	('HNF-4alpha', 'Gene', '3172', (55, 65))	('luciferase activity', 'molecular_function', 'GO:0047712', ('218', '237'))
176105	28643803	The double-mutant strain of C.elegans acs-20;acs-22 increases penetration of several drugs but has no effect on worm survivability.	('C.elegans', 'Species', '6239', (28, 37))	('acs-20', 'Gene', '178190', (38, 44))	('increases', 'PosReg', (52, 61))	('acs', 'molecular_function', 'GO:0043884', ('45', '48'))	('double-mutant', 'Var', (4, 17))	('acs', 'molecular_function', 'GO:0043884', ('38', '41'))	('acs-22', 'Gene', (45, 51))	('acs-20', 'Gene', (38, 44))	('penetration of several drugs', 'MPA', (62, 90))	('acs', 'molecular_function', 'GO:0003987', ('45', '48'))	('acs-22', 'Gene', '181138', (45, 51))	('acs', 'molecular_function', 'GO:0003987', ('38', '41'))
176107	28643803	Of note, this mutant strain of C.elegans had a higher toxicity of doxorubicin than its wild-type strain (Supplementary Fig.	('toxicity', 'Disease', (54, 62))	('mutant', 'Var', (14, 20))	('higher', 'PosReg', (47, 53))	('C.elegans', 'Species', '6239', (31, 40))	('doxorubicin', 'Chemical', 'MESH:D004317', (66, 77))	('toxicity', 'Disease', 'MESH:D064420', (54, 62))
176108	28643803	In addition, the RNAi of vhl-1 (corresponding to human VHL) and alh-1 (corresponding to human ALDH2) had no effect on the survival to this mutant worms (Supplementary Fig.	('alh-1', 'Gene', '175691', (64, 69))	('RNAi', 'biological_process', 'GO:0016246', ('17', '21'))	('human', 'Species', '9606', (49, 54))	('mutant', 'Var', (139, 145))	('vhl-1', 'Gene', (25, 30))	('alh-1', 'Gene', (64, 69))	('ALDH', 'molecular_function', 'GO:0004030', ('94', '98'))	('human', 'Species', '9606', (88, 93))
176109	28643803	Consistent to our findings in ccRCC cell lines, the silence of either vhl-1 or alh-1 significantly increased the toxicity of doxorubicin in C.elegans compared with treatment of DMSO with the same osmolality (Fig.	('toxicity', 'Disease', 'MESH:D064420', (113, 121))	('toxicity', 'Disease', (113, 121))	('alh-1', 'Gene', '175691', (79, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('DMSO', 'Chemical', 'MESH:D004121', (177, 181))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('silence', 'Var', (52, 59))	('vhl-1', 'Gene', (70, 75))	('RCC', 'Disease', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('increased', 'PosReg', (99, 108))	('alh-1', 'Gene', (79, 84))	('doxorubicin', 'Chemical', 'MESH:D004317', (125, 136))	('C.elegans', 'Species', '6239', (140, 149))
176110	28643803	Furthermore, vhl-1 silencing also inhibited alh-1 mRNA expression (Fig.	('vhl-1', 'Gene', (13, 18))	('silencing', 'Var', (19, 28))	('inhibited', 'NegReg', (34, 43))	('alh-1', 'Gene', (44, 49))	('alh-1', 'Gene', '175691', (44, 49))
176111	28643803	Intriguingly, loss of function vhl-1 mutant could downregulate the mRNA of nhr-69 (HNF-4alpha in mammal) and alh-1 in C.elegans (Fig.	('downregulate', 'NegReg', (50, 62))	('HNF-4alpha', 'Gene', (83, 93))	('mRNA', 'MPA', (67, 71))	('loss of function', 'NegReg', (14, 30))	('mutant', 'Var', (37, 43))	('vhl-1', 'Gene', (31, 36))	('C.elegans', 'Species', '6239', (118, 127))	('nhr-69', 'Gene', '172840', (75, 81))	('HNF-4alpha', 'Gene', '3172', (83, 93))	('alh-1', 'Gene', (109, 114))	('nhr-69', 'Gene', (75, 81))	('mammal', 'Species', '9606', (97, 103))	('alh-1', 'Gene', '175691', (109, 114))
176116	28643803	It has been reported that suppression of HIF-2alpha restores P53 activity and promotes the apoptosis induced by anthracyclines, and it has also been reported that anthracyclines inhibited the binding of HIF heterodimer to the consensus HRE and thus impaires the transcriptional response of HIF.	('activity', 'MPA', (65, 73))	('promotes', 'PosReg', (78, 86))	('restores', 'PosReg', (52, 60))	('HIF heterodimer to the consensus HRE', 'Disease', (203, 239))	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('transcriptional', 'MPA', (262, 277))	('HIF-2alpha', 'Gene', '2034', (41, 51))	('suppression', 'Var', (26, 37))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('inhibited', 'NegReg', (178, 187))	('anthracyclines', 'Chemical', 'MESH:D018943', (163, 177))	('binding', 'Interaction', (192, 199))	('impaires', 'NegReg', (249, 257))	('apoptosis', 'CPA', (91, 100))	('P53', 'Gene', (61, 64))	('binding', 'molecular_function', 'GO:0005488', ('192', '199'))	('HIF heterodimer to the consensus HRE', 'Disease', 'None', (203, 239))	('HIF-2alpha', 'Gene', (41, 51))	('anthracyclines', 'Chemical', 'MESH:D018943', (112, 126))	('P53', 'Gene', '7157', (61, 64))
176120	28643803	DOX-induced myocardial cellular toxicity has been found to be further aggravated in ALDH2 knockout mice and ameliorated in ALDH2 transgenic mice.	('ALDH2', 'Gene', (84, 89))	('mice', 'Species', '10090', (99, 103))	('ALDH', 'molecular_function', 'GO:0004030', ('84', '88'))	('aggravated', 'PosReg', (70, 80))	('DOX', 'Chemical', 'MESH:D004317', (0, 3))	('mice', 'Species', '10090', (140, 144))	('toxicity', 'Disease', 'MESH:D064420', (32, 40))	('transgenic mice', 'Species', '10090', (129, 144))	('ameliorated', 'PosReg', (108, 119))	('toxicity', 'Disease', (32, 40))	('knockout', 'Var', (90, 98))	('ALDH', 'molecular_function', 'GO:0004030', ('123', '127'))
176137	28643803	acs-20;acs-22 mutant C.elegans has defective skin barriers, and thus drugs can easily penetrate into the bodies of C.elegans, which greatly reduces the lethal dose of drugs.	('acs-22', 'Gene', '181138', (7, 13))	('reduces', 'NegReg', (140, 147))	('skin barriers', 'CPA', (45, 58))	('C.elegans', 'Species', '6239', (21, 30))	('acs-20', 'Gene', '178190', (0, 6))	('mutant', 'Var', (14, 20))	('C.elegans', 'Species', '6239', (115, 124))	('acs', 'molecular_function', 'GO:0043884', ('7', '10'))	('acs', 'molecular_function', 'GO:0003987', ('0', '3'))	('acs-20', 'Gene', (0, 6))	('acs-22', 'Gene', (7, 13))	('lethal dose of drugs', 'MPA', (152, 172))	('acs', 'molecular_function', 'GO:0043884', ('0', '3'))	('defective', 'NegReg', (35, 44))	('acs', 'molecular_function', 'GO:0003987', ('7', '10'))
176138	28643803	In our work, we have verified the drug action and candidate genes affecting cytotoxicity of anthracyclines by acs-20;acs-22 mutant and demonstrated the value of this mutant worm.	('acs', 'molecular_function', 'GO:0003987', ('110', '113'))	('anthracyclines', 'Chemical', 'MESH:D018943', (92, 106))	('cytotoxicity', 'Disease', 'MESH:D064420', (76, 88))	('acs', 'molecular_function', 'GO:0003987', ('117', '120'))	('mutant', 'Var', (124, 130))	('acs', 'molecular_function', 'GO:0043884', ('110', '113'))	('acs-20', 'Gene', '178190', (110, 116))	('acs-22', 'Gene', (117, 123))	('acs', 'molecular_function', 'GO:0043884', ('117', '120'))	('acs-20', 'Gene', (110, 116))	('cytotoxicity', 'Disease', (76, 88))	('acs-22', 'Gene', '181138', (117, 123))
176149	28643803	After the antigen retrieval and being blocked with 5% bovine serum albumin, tissue slides were immunohistochemically stained by antibodies against VHL (1:50, Abcam, ab140989), HNF-4alpha (1:50, Abcam, ab181604) and ALDH2 (1:200, Abgent, AM1831a), respectively, then visualized by standard avidin-biotinylated peroxidase complex method.	('ALDH', 'molecular_function', 'GO:0004030', ('215', '219'))	('ab181604', 'Var', (201, 209))	('ALDH2', 'Gene', (215, 220))	('bovine', 'Species', '9913', (54, 60))	('VHL', 'Gene', (147, 150))	('HNF-4alpha', 'Gene', '3172', (176, 186))	('HNF-4alpha', 'Gene', (176, 186))
176216	29158875	ccRCC is characterized by the presence of VHL gene mutation in most cases.	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('mutation', 'Var', (51, 59))	('VHL', 'Gene', (42, 45))	('VHL', 'Gene', '7428', (42, 45))
176217	29158875	However, the loss of VHL alone is not sufficient for tumor initiation and survival, and a fraction of ccRCCs contain wild-type VHL genes, suggesting additional genetic alterations are required in the course of tumor development.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('men', 'Species', '9606', (223, 226))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('tumor', 'Disease', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('VHL', 'Gene', (127, 130))	('tumor initiation', 'Disease', 'MESH:D009369', (53, 69))	('VHL', 'Gene', (21, 24))	('tumor', 'Disease', (53, 58))	('VHL', 'Gene', '7428', (127, 130))	('loss', 'Var', (13, 17))	('VHL', 'Gene', '7428', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('tumor initiation', 'Disease', (53, 69))	('RCC', 'Disease', (104, 107))
176218	29158875	Recent large-scale sequencing studies of ccRCC, including TCGA (The Cancer Genome Atlas) project have discovered several new and prevalent genomic mutations such as PBRM1 and BAP1 .	('mutations', 'Var', (147, 156))	('BAP1', 'Gene', (175, 179))	('Cancer Genome Atlas', 'Disease', (68, 87))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('PBRM1', 'Gene', (165, 170))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (68, 87))	('PBRM1', 'Gene', '55193', (165, 170))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('BAP1', 'Gene', '8314', (175, 179))
176226	29158875	Collectively, the DGMs and their associated genetic mutations lead to the identification of novel disease genes and pathways.	('mutations', 'Var', (52, 61))	('DGMs', 'Gene', (18, 22))	('DGMs', 'Chemical', '-', (18, 22))
176237	29158875	We conducted hierarchical clustering analysis, using DGMs and DEGs, respectively, on the four ccRCC datasets including the TCGA dataset, GSE36895, GSE40435 and GSE46699.	('RCC', 'Disease', (96, 99))	('GSE36895', 'Var', (137, 145))	('DEGs', 'Gene', (62, 66))	('DGMs', 'Chemical', '-', (53, 57))	('GSE40435', 'Var', (147, 155))	('DEGs', 'Gene', '8560', (62, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('GSE46699', 'Var', (160, 168))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
176238	29158875	For GSE36895 and GSE40435, both using DGMs and DEGs yielded distinctive tumor and normal tissue clusters with perfect homogeneity (Table 1).	('DGMs', 'Chemical', '-', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('yielded', 'Reg', (52, 59))	('tumor', 'Disease', (72, 77))	('DEGs', 'Gene', '8560', (47, 51))	('GSE36895', 'Var', (4, 12))	('GSE40435', 'Var', (17, 25))	('DEGs', 'Gene', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
176239	29158875	However, for the TCGA data and GSE46699, the clusters yielded by DGMs tended to be more homogeneous as compared to the clusters generated by the DEGs.	('DGMs', 'Var', (65, 69))	('GSE46699', 'Var', (31, 39))	('DEGs', 'Gene', (145, 149))	('DGMs', 'Chemical', '-', (65, 69))	('DEGs', 'Gene', '8560', (145, 149))
176258	29158875	Dysregulation of cellular proliferation is associated with the occurrence of cancer.	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cellular proliferation', 'CPA', (17, 39))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('associated', 'Reg', (43, 53))
176259	29158875	The mutation of VHL, a known ccRCC causative gene, was found to be significantly associated with multiple DGMs (FDR < 0.03, Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('VHL', 'Gene', (16, 19))	('VHL', 'Gene', '7428', (16, 19))	('mutation', 'Var', (4, 12))	('DGMs', 'Chemical', '-', (106, 110))	('multiple DGMs', 'Disease', (97, 110))	('associated', 'Reg', (81, 91))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
176262	29158875	Some mutated genes influenced many DGMs.	('DGMs', 'CPA', (35, 39))	('DGMs', 'Chemical', '-', (35, 39))	('mutated', 'Var', (5, 12))	('influenced', 'Reg', (19, 29))
176263	29158875	BAP1 and PBPM1 mutations significantly impacted 42.5% (80 of 188) and 18.1% (34/188) of the DGMs (Table 2).	('PBPM1', 'Gene', (9, 14))	('BAP1', 'Gene', (0, 4))	('DGMs', 'Chemical', '-', (92, 96))	('mutations', 'Var', (15, 24))	('BAP1', 'Gene', '8314', (0, 4))	('impacted', 'Reg', (39, 47))
176265	29158875	In addition, ccRCC patients with BAP1 somatic mutations had poor 5-year survival rates (P < 0.014, Fig.	('patients', 'Species', '9606', (19, 27))	('poor', 'NegReg', (60, 64))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('RCC', 'Disease', (15, 18))	('somatic mutations', 'Var', (38, 55))	('BAP1', 'Gene', '8314', (33, 37))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('BAP1', 'Gene', (33, 37))
176268	29158875	Interestingly, the mutations of somatic mutations of BAP1 and PBRM1 tend to be mutually exclusive (P < 0.03, Fisher Exact Test, Fig.	('mutations', 'Var', (40, 49))	('BAP1', 'Gene', '8314', (53, 57))	('PBRM1', 'Gene', (62, 67))	('PBRM1', 'Gene', '55193', (62, 67))	('BAP1', 'Gene', (53, 57))
176272	29158875	The genetic alterations of these eight genes were significantly associated with poor survival rates of ccRCC patients (P < 0.054, Supp.	('genetic alterations', 'Var', (4, 23))	('associated', 'Reg', (64, 74))	('poor', 'NegReg', (80, 84))	('patients', 'Species', '9606', (109, 117))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('survival rates', 'CPA', (85, 99))
176306	29158875	The differential gene modules-based classifier achieved over 0.92 AUC for prediction three independent ccRCC patient cohorts (GSE36895, GSE46699, and GSE40435).	('GSE46699', 'Var', (136, 144))	('patient', 'Species', '9606', (109, 116))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('GSE36895', 'Var', (126, 134))	('RCC', 'Disease', (105, 108))	('GSE40435', 'Var', (150, 158))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))
176310	29158875	The mutations of BAP1 and PRMB1 were the most frequently associated with DGMs (Table 2).	('PRMB1', 'Gene', (26, 31))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (4, 13))	('DGMs', 'Disease', (73, 77))	('DGMs', 'Chemical', '-', (73, 77))	('associated', 'Reg', (57, 67))	('BAP1', 'Gene', (17, 21))
176313	29158875	BAP1 is inactive in 15% of ccRCCs and the loss of BAP1 has defined a new class of ccRCC.	('loss', 'Var', (42, 46))	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('BAP1', 'Gene', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('RCC', 'Disease', (29, 32))	('BAP1', 'Gene', '8314', (50, 54))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (27, 32))	('BAP1', 'Gene', (50, 54))	('BAP1', 'Gene', '8314', (0, 4))
176314	29158875	The germline mutation of BAP1 has been associated with high risk of neoplasms.	('neoplasms', 'Disease', 'MESH:D009369', (68, 77))	('BAP1', 'Gene', (25, 29))	('neoplasms', 'Phenotype', 'HP:0002664', (68, 77))	('associated', 'Reg', (39, 49))	('germline mutation', 'Var', (4, 21))	('BAP1', 'Gene', '8314', (25, 29))	('neoplasms', 'Disease', (68, 77))
176315	29158875	PRBM1 (Polybromo 1), a SWI/SNF chromatin remodeling complex gene, is frequently mutated in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('RCC', 'Disease', (93, 96))	('Polybromo 1', 'Gene', '55193', (7, 18))	('Polybromo 1', 'Gene', (7, 18))	('PRBM1', 'Gene', (0, 5))	('mutated', 'Var', (80, 87))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('31', '59'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('31', '51'))
176317	29158875	The mutation of NOD2 can lead to impaired activation of NFKB in vitro and has associated with colorectal, ovarian and breast cancer.	('associated', 'Reg', (78, 88))	('NFKB', 'Protein', (56, 60))	('activation', 'MPA', (42, 52))	('impaired', 'NegReg', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colorectal, ovarian and breast cancer', 'Disease', 'MESH:D001943', (94, 131))	('mutation', 'Var', (4, 12))	('NOD2', 'Gene', '64127', (16, 20))	('NOD2', 'Gene', (16, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
176329	29158875	The significant expression difference between normal and tumor could also attribute to the other somatic alterations such as copy number variations and methylation events.	('copy number variations', 'Var', (125, 147))	('methylation events', 'Var', (152, 170))	('methylation', 'biological_process', 'GO:0032259', ('152', '163'))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('expression', 'MPA', (16, 26))
176363	33672271	The criteria of the algorithm for obtaining significant dPPIs were set as q-value < 0.10 (significantly repressed in tumor phenotype), q-value > 0.90 (significantly activated in tumor phenotype), and a normalized observation frequency either in normal or tumor phenotype > 20%.	('q-value > 0.90', 'Var', (135, 149))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('tumor', 'Disease', (117, 122))	('activated', 'PosReg', (165, 174))	('dPPIs', 'Chemical', '-', (56, 61))	('q-value < 0.10', 'Var', (74, 88))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
176400	33672271	Dysregulations in various biochemical pathways play an important role in cancer formation and development.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('biochemical pathways', 'Pathway', (26, 46))	('Dysregulations', 'Var', (0, 14))	('development', 'CPA', (94, 105))	('formation', 'biological_process', 'GO:0009058', ('80', '89'))
176428	33672271	Furthermore, ZINC73196087, ZINC72318117, ZINC72318118, ZINC73163075, ZINC73165724, ZINC73196196, and ZINC72318119 have been shown to demonstrate effective anti-proliferative activity against a panel of c-Met-amplified gastric cancer cell lines.	('c-Met', 'Gene', '4233', (202, 207))	('ZINC72318119', 'Chemical', '-', (101, 113))	('gastric cancer', 'Phenotype', 'HP:0012126', (218, 232))	('ZINC73196196', 'Var', (83, 95))	('ZINC72318118', 'Var', (41, 53))	('ZINC73196087', 'Var', (13, 25))	('ZINC73196196', 'Chemical', '-', (83, 95))	('ZINC73163075', 'Chemical', '-', (55, 67))	('ZINC72318117', 'Var', (27, 39))	('ZINC73165724', 'Chemical', '-', (69, 81))	('ZINC72318117', 'Chemical', '-', (27, 39))	('c-Met', 'Gene', (202, 207))	('ZINC73165724', 'Var', (69, 81))	('gastric cancer', 'Disease', (218, 232))	('ZINC72318119', 'Var', (101, 113))	('ZINC72318118', 'Chemical', '-', (41, 53))	('ZINC73196087', 'Chemical', '-', (13, 25))	('anti-proliferative activity', 'CPA', (155, 182))	('gastric cancer', 'Disease', 'MESH:D013274', (218, 232))	('ZINC73163075', 'Var', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
176437	30550791	Crucially, human and murine PDOs successfully modeled immune checkpoint blockade (ICB) with anti-PD-1- and/or anti-PD-L1 expanding and activating tumor antigen-specific TILs and eliciting tumor cytotoxicity.	('tumor', 'Disease', (188, 193))	('tumor cytotoxicity', 'Disease', (188, 206))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('human', 'Species', '9606', (11, 16))	('anti-PD-L1', 'Var', (110, 120))	('PDO', 'Chemical', 'MESH:C541246', (28, 31))	('anti-PD-1-', 'Var', (92, 102))	('immune checkpoint blockade', 'Disease', (54, 80))	('tumor', 'Disease', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('expanding', 'PosReg', (121, 130))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor antigen', 'molecular_function', 'GO:0008222', ('146', '159'))	('activating', 'PosReg', (135, 145))	('tumor cytotoxicity', 'Disease', 'MESH:D064420', (188, 206))	('murine', 'Species', '10090', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('eliciting', 'Reg', (178, 187))
176466	30550791	Targeted exome sequencing and copy-number variation analysis revealed expected PDO alterations such as APC loss in colorectal adenocarcinoma, KRAS codon 12 mutations in pancreatic ductal adenocarcinoma, TP53 loss in non-small cell lung cancers (NSCLC), VHL alterations in clear cell renal carcinoma (ccRCC) and BRAFV600E in thyroid carcinoma (ref.	('RCC', 'Disease', 'MESH:D002292', (302, 305))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (169, 201))	('renal carcinoma', 'Phenotype', 'HP:0005584', (283, 298))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (115, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('thyroid carcinoma', 'Disease', (324, 341))	('NSCLC', 'Disease', (245, 250))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (220, 243))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (272, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('pancreatic ductal adenocarcinoma', 'Disease', (169, 201))	('PDO', 'Chemical', 'MESH:C541246', (79, 82))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (216, 243))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (324, 341))	('TP53', 'Gene', (203, 207))	('APC', 'cellular_component', 'GO:0005680', ('103', '106'))	('carcinoma', 'Phenotype', 'HP:0030731', (332, 341))	('APC loss', 'Disease', (103, 111))	('BRAFV600E', 'Var', (311, 320))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (169, 201))	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('lung cancers', 'Phenotype', 'HP:0100526', (231, 243))	('mutations', 'Var', (156, 165))	('KRAS', 'Gene', '3845', (142, 146))	('clear cell renal carcinoma', 'Disease', (272, 298))	('loss', 'NegReg', (208, 212))	('clear cell renal carcinoma', 'Disease', 'MESH:D002292', (272, 298))	('colorectal adenocarcinoma', 'Disease', (115, 140))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('non-small cell lung cancers', 'Disease', (216, 243))	('VHL alterations', 'Disease', 'MESH:D006623', (253, 268))	('KRAS', 'Gene', (142, 146))	('TP53', 'Gene', '7157', (203, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('RCC', 'Disease', (302, 305))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (216, 243))	('VHL alterations', 'Disease', (253, 268))	('APC loss', 'Disease', 'MESH:D011125', (103, 111))	('NSCLC', 'Disease', 'MESH:D002289', (245, 250))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (324, 341))	('BRAFV600E', 'Mutation', 'rs113488022', (311, 320))
176481	30550791	ALI organoids from B16, MC38 and A20 s.c. tumors in syngeneic mouse hosts also preserved integrated immune populations without reconstitution.	('mouse', 'Species', '10090', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('integrated immune populations', 'MPA', (89, 118))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('A20', 'Gene', (33, 36))	('MC38', 'Var', (24, 28))	('A20', 'Gene', '21929', (33, 36))
176482	30550791	Organoids from all three mouse tumors contained CD3+ TILs and CD11b+ tumor-associated macrophages (TAMs) at day 7 (Figure 4A).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumor', 'Disease', (69, 74))	('CD11b', 'Gene', (62, 67))	('tumor', 'Disease', (31, 36))	('CD11b', 'Gene', '16409', (62, 67))	('mouse', 'Species', '10090', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('CD3+ TILs', 'Var', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
176509	30550791	We next examined TIL functionality within murine organoids from MC38, B16-SIY and A20-OVA s.c. tumors in syngeneic immunocompetent hosts (Figures 2E, 4).	('A20', 'Gene', '21929', (82, 85))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('MC38', 'Var', (64, 68))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('murine', 'Species', '10090', (42, 48))	('A20', 'Gene', (82, 85))	('amine', 'Chemical', 'MESH:D000588', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
176511	30550791	Both anti-PD-1 and anti-PD-L1 strongly increased CD8+ TILs per total organoid CD3+ TILs (Figure 6A) or total organoid cells (including tumor epithelium) (Figure 6B), paralleling CD8+ TIL expansion by anti-PD-1 within MC38 and B16 tumors in vivo and in patient peripheral blood.	('tumor', 'Disease', (230, 235))	('patient', 'Species', '9606', (252, 259))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('CD8', 'Gene', (178, 181))	('CD8', 'Gene', '925', (178, 181))	('tumors', 'Disease', (230, 236))	('tumor', 'Disease', (135, 140))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('CD8', 'Gene', (49, 52))	('increased', 'PosReg', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('CD8', 'Gene', '925', (49, 52))	('anti-PD-L1', 'Var', (19, 29))	('anti-PD-1', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
176513	30550791	Accordingly, anti-PD-1 and anti-PD-L1 each activated CD8+ TILs in MC38, B16-SIY and A20-OVA organoids, with prominent stimulation of Ifng, Prf1 and Gzmb mRNA (Figure 6C) even after cryopreservation and recovery (Mendeley Figure 10).	('Gzmb', 'Gene', (148, 152))	('CD8', 'Gene', (53, 56))	('anti-PD-L1', 'Var', (27, 37))	('anti-PD-1', 'Var', (13, 22))	('MC38', 'MPA', (66, 70))	('CD8', 'Gene', '925', (53, 56))	('activated', 'PosReg', (43, 52))	('A20', 'Gene', (84, 87))	('Ifng', 'Gene', (133, 137))	('Gzmb', 'Gene', '3002', (148, 152))	('Ifng', 'Gene', '3458', (133, 137))	('stimulation', 'PosReg', (118, 129))	('Prf1', 'Gene', '5551', (139, 143))	('A20', 'Gene', '21929', (84, 87))	('Prf1', 'Gene', (139, 143))
176514	30550791	Both anti-PD-L1 strongly promoted tumor epithelial cell killing in B16-SIY organoids, with 2-3-fold increased Annexin-V(+)/7-AAD(-) early apoptotic cells and 7-14 fold induction of Annexin-V(+)/7-AAD(+) late apoptotic/necrotic cells versus control IgG (Figures 6D-E, S6A).	('necrotic', 'Disease', 'MESH:D009336', (218, 226))	('Annexin-V', 'Gene', '308', (110, 119))	('increased', 'PosReg', (100, 109))	('S6A', 'Chemical', 'MESH:C012008', (267, 270))	('tumor epithelia', 'Disease', 'MESH:D009369', (34, 49))	('Annexin-V', 'Gene', (110, 119))	('promoted', 'PosReg', (25, 33))	('Annexin-V', 'Gene', '308', (181, 190))	('necrotic', 'Disease', (218, 226))	('Annexin-V', 'Gene', (181, 190))	('anti-PD-L1', 'Var', (5, 15))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor epithelia', 'Disease', (34, 49))	('cell killing', 'biological_process', 'GO:0001906', ('51', '63'))
176517	30550791	Notably, anti-PD-1 or PD-L1 expanded SIY tetramer-reactive CD8+ TILs in B16-SIY organoids (Figures 6F, 6G) with lack of staining with negative control SIINFEKL (SIIN) peptide tetramers.	('CD8', 'Gene', (59, 62))	('PD-L1', 'Gene', (22, 27))	('CD8', 'Gene', '925', (59, 62))	('anti-PD-1', 'Var', (9, 18))
176548	30550791	It has been uncertain whether anti-PD-1 antibodies expand intratumoral exhausted-like CD8+ T cells via primary action on peripheral versus tumor-infiltrating populations since PD-1 blockade increases exhausted-like TILs but also proliferation of peripheral blood PD-1+ CD8+ T cells.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('exhausted-like TILs', 'CPA', (200, 219))	('increases', 'PosReg', (190, 199))	('proliferation', 'CPA', (229, 242))	('CD8', 'Gene', (86, 89))	('tumor', 'Disease', (139, 144))	('blockade', 'Var', (181, 189))	('CD8', 'Gene', '925', (86, 89))	('CD8', 'Gene', (269, 272))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('PD-1', 'Gene', (176, 180))	('CD8', 'Gene', '925', (269, 272))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
176549	30550791	Accordingly, anti-PD-1 and anti-PD-L1 activation of TILs within human and mouse PDOs identify PD-1 axis blockade within the TME as sufficient to elicit both TIL expansion and activation.	('human', 'Species', '9606', (64, 69))	('blockade', 'Var', (104, 112))	('PDO', 'Chemical', 'MESH:C541246', (80, 83))	('mouse', 'Species', '10090', (74, 79))	('elicit', 'Reg', (145, 151))	('activation', 'MPA', (175, 185))
176556	30550791	Simultaneous determination of single cell transcriptome and TCR or Ig rearrangements links immune repertoire to various states of T and B cells, while strongly enhancing their discrimination from other immune cell types.	('TCR', 'cellular_component', 'GO:0042101', ('60', '63'))	('immune', 'MPA', (91, 97))	('TCR', 'biological_process', 'GO:0006283', ('60', '63'))	('rearrangements', 'Var', (70, 84))	('TCR', 'Gene', (60, 63))	('discrimination', 'MPA', (176, 190))	('enhancing', 'PosReg', (160, 169))	('TCR', 'Gene', '6962', (60, 63))
176592	30550791	This assay detects potentially clinically actionable mutations, as well as additional genes that are frequently mutated in cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('mutations', 'Var', (53, 62))	('cancers', 'Disease', (123, 130))	('clinical', 'Species', '191496', (31, 39))
176601	30550791	In order to remove common sequencing artifacts or residual germline variation, each mutation in the combined MAF file was subjected to a "Panel of Normals" filtering using a panel of over 4000 BAM files from normal samples.	('MAF', 'Gene', '4094', (109, 112))	('MAF', 'Gene', (109, 112))	('mutation', 'Var', (84, 92))
176603	30550791	Finally, we rescued known cancer mutations found in COSMIC and TCGA databases.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('mutations', 'Var', (33, 42))
176604	30550791	Therefore, we characterized that the sample is verified tumor if it passes all three quality control steps and either has clear SNVs/Indels or has clear CNA.	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('SNVs/Indels', 'Var', (128, 139))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))
176607	30550791	Mouse immunofluorescence analysis utilized anti-Mouse CD8a (4SM16, BD, 1:100), anti-mouse CD3e (145-2C11, BD, 1:100), anti-mouse CD4 (4SM95, BD, 1:100), anti-CD11b (ab1333357, Abcam, 1:2000), anti-Vimentin (Ab5733, EMD, 1:2000), anti-CD20(Abcam, 1:100).	('CD11b', 'Gene', (158, 163))	('CD11b', 'Gene', '16409', (158, 163))	('CD3e', 'Gene', (90, 94))	('mouse', 'Species', '10090', (123, 128))	('Vimentin', 'cellular_component', 'GO:0045098', ('197', '205'))	('ab1333357', 'Var', (165, 174))	('Ab5733', 'Var', (207, 213))	('CD20', 'Gene', (234, 238))	('EMD', 'Disease', (215, 218))	('CD3e', 'Gene', '12501', (90, 94))	('EMD', 'Disease', 'None', (215, 218))	('mouse', 'Species', '10090', (84, 89))	('CD8a', 'Gene', '12525', (54, 58))	('CD20', 'Gene', '12482', (234, 238))	('Mouse', 'Species', '10090', (0, 5))	('Vimentin', 'cellular_component', 'GO:0045099', ('197', '205'))	('Mouse', 'Species', '10090', (48, 53))	('CD8a', 'Gene', (54, 58))
176611	30550791	FACS staining cocktails for murine cells contained 10 ml anti-CD45 (30-F11, BD), 3 mul anti-CD3e (500A2, BD), anti-CD4 (RM4-5, BD) and anti-CD8a (53-6.7, BD), Anti-mouse-CD274 (B7-H1, Biolegend, 10 mg/ml) and anti-mouse-CD279 (29F.1.A12, Biolegend, 10 mg/ml).	('CD279', 'Gene', (220, 225))	('CD3e', 'Gene', '12501', (92, 96))	('CD274', 'Gene', '60533', (170, 175))	('mouse', 'Species', '10090', (164, 169))	('CD274', 'Gene', (170, 175))	('FACS', 'Gene', '14081', (0, 4))	('CD3e', 'Gene', (92, 96))	('CD8a', 'Gene', (140, 144))	('CD279', 'Gene', '5133', (220, 225))	('anti-CD45', 'Var', (57, 66))	('murine', 'Species', '10090', (28, 34))	('mouse', 'Species', '10090', (214, 219))	('anti-CD4', 'Var', (110, 118))	('FACS', 'Gene', (0, 4))	('CD8a', 'Gene', '12525', (140, 144))
176624	30550791	For human tumor cell cytotoxicity assay, PDOs were cultured for 1 week in the presence of anti-CD3 (clone HIT3a, 2 mg/ml) (cat no: 300332, BioLegend) and anti-CD28 (clone CD28.2, 2 mug/ml) (cat no: 302923, BioLegend) with either 10 mug/ml anti-PD-1 (nivolumab) or IgG4 control.	('CD28', 'Gene', (159, 163))	('PDO', 'Chemical', 'MESH:C541246', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('human', 'Species', '9606', (4, 9))	('tumor cell cytotoxicity', 'Disease', (10, 33))	('mug', 'molecular_function', 'GO:0043739', ('232', '235'))	('CD28', 'Gene', '940', (159, 163))	('CD28', 'Gene', (171, 175))	('anti-CD3', 'Var', (90, 98))	('mug', 'molecular_function', 'GO:0043739', ('181', '184'))	('tumor cell cytotoxicity', 'Disease', 'MESH:D064420', (10, 33))	('CD28', 'Gene', '940', (171, 175))	('IgG4', 'cellular_component', 'GO:0071735', ('264', '268'))	('cat', 'molecular_function', 'GO:0004096', ('190', '193'))	('cat', 'molecular_function', 'GO:0004096', ('123', '126'))
176635	30550791	GEM-RT was performed in a C1000 Touch Thermal cycler with 96-Deep Well Reaction Module (Bio-Rad; P/N 1851197): 53  C for 45 min, 85   C for 5  min; held at 4  C and stored at -20   C. The GEMs were shipped to 10x Genomics on dry ice, then broken and the single-strand cDNA was cleaned up with DynaBeads MyOne Silane Beads (Thermo Fisher Scientific; P/N 37002D).	('Rad', 'biological_process', 'GO:1990116', ('92', '95'))	('GEMs', 'cellular_component', 'GO:0015030', ('188', '192'))	('N 37002D', 'Mutation', 'p.N37002D', (351, 359))	('Rad', 'Gene', '6236', (92, 95))	('P/N 1851197', 'SUBSTITUTION', 'None', (97, 108))	('P/N 1851197', 'Var', (97, 108))	('GEMs', 'cellular_component', 'GO:0097504', ('188', '192'))	('Rad', 'Gene', (92, 95))	('Silane', 'Chemical', 'MESH:D012821', (309, 315))
176643	30550791	The presence of a CDR3 motif (Cys-to-FGXG/WGXG) is searched in in a frame defined by the start codon in the L+V region or all 6 frames in the absence of L+V region.	('Cys', 'Chemical', 'MESH:C046557', (30, 33))	('Cys-to-FGXG/WGXG', 'Var', (30, 46))	('CDR3', 'Gene', '8163', (18, 22))	('CDR3', 'Gene', (18, 22))
176799	31263677	Thus, the presence of CRP, a non-specific indicator of inflammation, may represent a microenvironment suitable for NET formation and coagulation system activation, which is conducive to the intravascular survival of CTCs, metastatic seeds.	('formation', 'biological_process', 'GO:0009058', ('119', '128'))	('coagulation', 'biological_process', 'GO:0050817', ('133', '144'))	('NE', 'Gene', '1991', (115, 117))	('CRP', 'Gene', (22, 25))	('CRP', 'Gene', '1401', (22, 25))	('inflammation', 'Disease', 'MESH:D007249', (55, 67))	('presence', 'Var', (10, 18))	('inflammation', 'biological_process', 'GO:0006954', ('55', '67'))	('inflammation', 'Disease', (55, 67))
176810	28217462	The therapeutic potential of HIF-2 antagonism in renal cell carcinoma Hypoxia, the insufficient delivery of oxygen for the demand of a tissue, contributes to the development of an aggressive phenotype, resistance to radiation therapy and chemotherapy, and is predictive of a poor outcome in numerous tumor types.	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (49, 69))	('Hypoxia', 'Disease', 'MESH:D000860', (70, 77))	('insufficient delivery', 'Phenotype', 'HP:0001622', (83, 104))	('Hypoxia', 'Disease', (70, 77))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (49, 69))	('resistance', 'CPA', (202, 212))	('numerous tumor', 'Disease', 'MESH:D009369', (291, 305))	('insufficient delivery of oxygen', 'Phenotype', 'HP:0012418', (83, 114))	('oxygen', 'Chemical', 'MESH:D010100', (108, 114))	('HIF-2', 'Gene', (29, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('antagonism', 'Var', (35, 45))	('numerous tumor', 'Disease', (291, 305))	('renal cell carcinoma', 'Disease', (49, 69))
176819	28217462	More recently, targeted therapy against the PD-1/PD-L1 immune checkpoint pathway has produced encouraging objective response rates in patients with metastatic ccRCC.	('PD-1', 'Gene', (44, 48))	('PD-1', 'Gene', '5133', (44, 48))	('PD-L1', 'Gene', '29126', (49, 54))	('ccRCC', 'Phenotype', 'HP:0006770', (159, 164))	('patients', 'Species', '9606', (134, 142))	('targeted', 'Var', (15, 23))	('PD-L1', 'Gene', (49, 54))	('metastatic ccRCC', 'Disease', (148, 164))
176825	28217462	The distinct roles of HIF-1alpha and HIF-2alpha in promoting tumor growth have been mainly defined in ccRCC because a majority of ccRCC patients (50-80%) exhibit a genetic inactivation of von Hippel-Lindau (VHL) gene resulting in the loss of pVHL, which normally mediates ubiquitination of HIF-alpha and its subsequent degradation, resulting in a constitutive expression of either HIF-1alpha and HIF-2alpha or HIF-2alpha alone.	('VHL', 'Disease', (243, 246))	('HIF-2alpha', 'Gene', '2034', (410, 420))	('ccRCC', 'Phenotype', 'HP:0006770', (130, 135))	('HIF-2alpha', 'Gene', (396, 406))	('HIF-2alpha', 'Gene', (37, 47))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('degradation', 'biological_process', 'GO:0009056', ('319', '330'))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (22, 47))	('loss', 'NegReg', (234, 238))	('von Hippel-Lindau', 'Gene', '7428', (188, 205))	('ccRCC', 'Disease', (102, 107))	('inactivation', 'Var', (172, 184))	('HIF-2alpha', 'Gene', (410, 420))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('VHL', 'Disease', (207, 210))	('VHL', 'Disease', 'MESH:D006623', (243, 246))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('pVHL', 'Gene', '7428', (242, 246))	('HIF-2alpha', 'Gene', '2034', (396, 406))	('HIF-2alpha', 'Gene', '2034', (37, 47))	('degradation', 'MPA', (319, 330))	('pVHL', 'Gene', (242, 246))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (381, 406))	('ccRCC', 'Disease', (130, 135))	('patients', 'Species', '9606', (136, 144))	('VHL', 'Disease', 'MESH:D006623', (207, 210))	('von Hippel-Lindau', 'Gene', (188, 205))	('tumor', 'Disease', (61, 66))
176828	28217462	Although transcription factors are typically considered "undruggable", the PAS-B domain of the HIF-2alpha subunit contains a large cavity within its hydrophobic core that provides a singular foothold for small-molecule to disrupt HIF-2alpha dimerization to ARNT.	('small-molecule', 'Var', (204, 218))	('dimerization', 'MPA', (241, 253))	('HIF-2alpha', 'Gene', '2034', (230, 240))	('ARNT', 'Gene', (257, 261))	('core', 'cellular_component', 'GO:0019013', ('159', '163'))	('transcription', 'biological_process', 'GO:0006351', ('9', '22'))	('HIF-2alpha', 'Gene', '2034', (95, 105))	('HIF-2alpha', 'Gene', (95, 105))	('PAS', 'cellular_component', 'GO:0000407', ('73', '76'))	('ARNT', 'Gene', '405', (257, 261))	('HIF-2alpha', 'Gene', (230, 240))	('disrupt', 'NegReg', (222, 229))
176830	28217462	A structure-based design approach developed by Peloton Therapeutics led to the discovery of closely related compounds including PT2399 and PT2385, which were evaluated for their biological activities.	('PT2385', 'Chemical', 'MESH:C000614279', (139, 145))	('PT2399', 'Var', (128, 134))	('PT2385', 'Var', (139, 145))	('PT2399', 'Chemical', 'MESH:C000614278', (128, 134))
176831	28217462	Two studies published in Nature clearly established that PT2399 specifically and functionally inhibited the dimerization of HIF-2alpha (but not HIF-1alpha) with its partner ARNT.	('HIF-2alpha', 'Gene', (124, 134))	('PT2399', 'Var', (57, 63))	('ARNT', 'Gene', '405', (173, 177))	('ARNT', 'Gene', (173, 177))	('HIF-1alpha', 'Gene', '3091', (144, 154))	('HIF-2alpha', 'Gene', '2034', (124, 134))	('PT2399', 'Chemical', 'MESH:C000614278', (57, 63))	('dimerization', 'MPA', (108, 120))	('inhibited', 'NegReg', (94, 103))	('HIF-1alpha', 'Gene', (144, 154))
176833	28217462	Using a large repertoire of ccRCC cell models, PT2399 was found to cause tumor regression in orthotopic xenografts, which correlated with reduced circulating tumor-derived VEGF.	('VEGF', 'Gene', (172, 176))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('reduced', 'NegReg', (138, 145))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('PT2399', 'Var', (47, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (28, 33))	('VEGF', 'Gene', '7422', (172, 176))	('circulating', 'MPA', (146, 157))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('PT2399', 'Chemical', 'MESH:C000614278', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
176835	28217462	Cell lines or patient-derived xenografts highly sensitive to PT2399 had stronger HIF-2alpha levels than poorly sensitive ones, suggesting that assessing HIF-2alpha activity/expression would be required as a predictive biomarker of efficacy.	('HIF-2alpha', 'Gene', (153, 163))	('PT2399', 'Var', (61, 67))	('HIF-2alpha', 'Gene', (81, 91))	('patient', 'Species', '9606', (14, 21))	('HIF-2alpha', 'Gene', '2034', (153, 163))	('PT2399', 'Chemical', 'MESH:C000614278', (61, 67))	('HIF-2alpha', 'Gene', '2034', (81, 91))	('stronger', 'PosReg', (72, 80))
176836	28217462	Importantly, prolonged treatment with PT2399 led to resistance, generated by mutations in both HIF-2alpha and its binding partner ARNT.	('ARNT', 'Gene', (130, 134))	('resistance', 'MPA', (52, 62))	('binding', 'molecular_function', 'GO:0005488', ('114', '121'))	('HIF-2alpha', 'Gene', (95, 105))	('mutations', 'Var', (77, 86))	('ARNT', 'Gene', '405', (130, 134))	('HIF-2alpha', 'Gene', '2034', (95, 105))	('PT2399', 'Chemical', 'MESH:C000614278', (38, 44))
176838	28217462	In addition, acquisition of a p53 mutation might represent another mechanism of resistance to PT2399 as reported in the 786-O ccRCC cells despite their considerable amount of HIF-2alpha.	('PT2399', 'Chemical', 'MESH:C000614278', (94, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('acquisition', 'Var', (13, 24))	('mutation', 'Var', (34, 42))	('HIF-2alpha', 'Gene', (175, 185))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('HIF-2alpha', 'Gene', '2034', (175, 185))
176839	28217462	These data suggest that mutations in some genes like p53 may impact response to HIF-2alpha antagonists similar to what has been observed in patients resistant to VEGF-targeted therapies.	('HIF-2alpha', 'Gene', (80, 90))	('VEGF', 'Gene', (162, 166))	('impact', 'Reg', (61, 67))	('response to', 'MPA', (68, 79))	('VEGF', 'Gene', '7422', (162, 166))	('HIF-2alpha', 'Gene', '2034', (80, 90))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('patients', 'Species', '9606', (140, 148))	('mutations', 'Var', (24, 33))
176841	28217462	In line with the other studies, PT2385 showed a strong inhibitory on HIF-2alpha-controlled genes without any effect on HIF-1alpha-controlled genes, associated with a potent anti-tumor activity in xenograft models and decreased circulating VEGF-A level.	('HIF-2alpha', 'Gene', (69, 79))	('tumor', 'Disease', (178, 183))	('VEGF-A', 'Gene', (239, 245))	('decreased', 'NegReg', (217, 226))	('HIF-1alpha', 'Gene', '3091', (119, 129))	('HIF-2alpha', 'Gene', '2034', (69, 79))	('inhibitory', 'NegReg', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('HIF-1alpha', 'Gene', (119, 129))	('PT2385', 'Var', (32, 38))	('PT2385', 'Chemical', 'MESH:C000614279', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('VEGF-A', 'Gene', '7422', (239, 245))
176842	28217462	Noteworthy, in animal studies, PT2385 did not exhibit the cardiovascular safety concerns observed with anti-VEGF therapies such as hypertension.	('VEGF', 'Gene', (108, 112))	('hypertension', 'Disease', (131, 143))	('hypertension', 'Phenotype', 'HP:0000822', (131, 143))	('PT2385', 'Var', (31, 37))	('PT2385', 'Chemical', 'MESH:C000614279', (31, 37))	('VEGF', 'Gene', '7422', (108, 112))	('hypertension', 'Disease', 'MESH:D006973', (131, 143))
176847	28754676	NSD1 Inactivation and SETD2 Mutation Drive a Convergence toward Loss of Function of H3K36 Writers in Clear Cell Renal Cell Carcinomas Extensive dysregulation of chromatin-modifying genes in dear cell renal cell carcinoma (ccRCC) has been uncovered through next-generation sequencing.	('SETD2', 'Gene', '29072', (22, 27))	('dear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (190, 220))	('NSD1', 'Gene', '64324', (0, 4))	('dear cell renal cell carcinoma', 'Disease', (190, 220))	('Renal Cell Carcinomas', 'Phenotype', 'HP:0005584', (112, 133))	('Clear Cell Renal Cell Carcinomas', 'Disease', 'MESH:C538614', (101, 133))	('Mutation', 'Var', (28, 36))	('H3K36 Writers', 'Protein', (84, 97))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (200, 220))	('Carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('dear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (190, 220))	('Clear Cell Renal Cell Carcinomas', 'Phenotype', 'HP:0006770', (101, 133))	('NSD1', 'Gene', (0, 4))	('chromatin', 'cellular_component', 'GO:0000785', ('161', '170'))	('Clear Cell Renal Cell Carcinomas', 'Disease', (101, 133))	('SETD2', 'Gene', (22, 27))	('Loss of Function', 'NegReg', (64, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('Inactivation', 'Var', (5, 17))
176850	28754676	Through an integrative analysis, we discovered frequent silencing of the his-tone H3 K36 methyltransferase NSD1 as the sole chromatin-modifying gene silenced by DNA methylation in ccRCC.	('DNA methylation', 'Var', (161, 176))	('silenced', 'NegReg', (149, 157))	('NSD1', 'Gene', (107, 111))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('DNA methylation', 'biological_process', 'GO:0006306', ('161', '176'))	('chromatin', 'cellular_component', 'GO:0000785', ('124', '133'))	('ccRCC', 'Disease', (180, 185))	('his', 'Chemical', 'MESH:D006639', (73, 76))	('silencing', 'NegReg', (56, 65))	('NSD1', 'Gene', '64324', (107, 111))
176851	28754676	Notably, tumors harboring NSD1 methylation were of higher grade and stage in different ccRCC datasets.	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('NSD1', 'Gene', '64324', (26, 30))	('methylation', 'Var', (31, 42))	('ccRCC', 'Disease', (87, 92))	('tumors', 'Disease', (9, 15))	('higher', 'PosReg', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('NSD1', 'Gene', (26, 30))
176852	28754676	NSD1 promoter methylation correlated with SETD2 somatic mutations across and within spatially distinct regions of primary ccRCC tumors.	('primary ccRCC tumors', 'Disease', 'MESH:D009369', (114, 134))	('NSD1', 'Gene', (0, 4))	('primary ccRCC tumors', 'Disease', (114, 134))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('methylation', 'Var', (14, 25))	('correlated', 'Reg', (26, 36))	('SETD2', 'Gene', '29072', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('NSD1', 'Gene', '64324', (0, 4))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))	('SETD2', 'Gene', (42, 47))
176853	28754676	ccRCC harboring epigenetic silencing of NSD1 displayed a specific genome-wide methylome signature consistent with the NSD1 mutation methylome signature observed in Sotos syndrome.	('NSD1', 'Gene', (118, 122))	('NSD1', 'Gene', '64324', (40, 44))	('NSD1', 'Gene', '64324', (118, 122))	('ccRCC', 'Disease', (0, 5))	('Sotos syndrome', 'Disease', 'MESH:D058495', (164, 178))	('epigenetic silencing', 'Var', (16, 36))	('Sotos syndrome', 'Disease', (164, 178))	('methylome signature', 'MPA', (78, 97))	('NSD1', 'Gene', (40, 44))
176854	28754676	Thus, we concluded that epigenetic silencing of genes involved in angio-genesis is a hallmark of the methylator phenotype in ccRCC, implying a convergence toward loss of function of epigenetic writers of the H3K36 histone mark as a root feature of aggressive ccRCC.	('epigenetic silencing', 'Var', (24, 44))	('loss', 'NegReg', (162, 166))	('aggressive ccRCC', 'Disease', (248, 264))	('his', 'Chemical', 'MESH:D006639', (214, 217))	('epigenetic', 'Var', (182, 192))	('ccRCC', 'Disease', (125, 130))
176856	28754676	ccRCC is often characterized by 3p loss and frequent mutation or methylation of the tumor suppressor gene VHL.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('mutation', 'Var', (53, 61))	('VHL', 'Disease', (106, 109))	('loss', 'NegReg', (35, 39))	('VHL', 'Disease', 'MESH:D006623', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor suppressor', 'biological_process', 'GO:0051726', ('84', '100'))	('ccRCC', 'Disease', (0, 5))	('tumor', 'Disease', (84, 89))	('methylation', 'Var', (65, 76))	('methylation', 'biological_process', 'GO:0032259', ('65', '76'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('84', '100'))
176857	28754676	The key roles of epigenetic inactivation of chromatin-remodeling genes have been uncovered through exome sequencing, revealing frequent mutations of PBRM1 (33%), BAP1 (15%), SETD2 (16%), and KDM5C (8%) genes.	('chromatin', 'cellular_component', 'GO:0000785', ('44', '53'))	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('44', '64'))	('KDM5C', 'Gene', (191, 196))	('BAP1', 'Gene', '8314', (162, 166))	('SETD2', 'Gene', '29072', (174, 179))	('KDM5C', 'Gene', '8242', (191, 196))	('BAP1', 'Gene', (162, 166))	('mutations', 'Var', (136, 145))	('SETD2', 'Gene', (174, 179))	('PBRM1', 'Gene', (149, 154))	('PBRM1', 'Gene', '55193', (149, 154))
176859	28754676	The two main mechanisms defining epigenetic alterations in cancer are related to DNA methylation and histone modification.	('his', 'Chemical', 'MESH:D006639', (101, 104))	('epigenetic alterations', 'Var', (33, 55))	('DNA methylation', 'biological_process', 'GO:0006306', ('81', '96'))	('DNA methylation', 'Var', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('histone modification', 'Var', (101, 121))	('histone modification', 'biological_process', 'GO:0016570', ('101', '121'))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
176860	28754676	A few studies have assessed the global scale of DNA methylation aberrations in ccRCC as well as the role of the polycomb repressive complex (PRC) in this setting.	('C', 'Chemical', 'MESH:D002244', (143, 144))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('his', 'Chemical', 'MESH:D006639', (150, 153))	('ccRCC', 'Disease', (79, 84))	('aberrations', 'Var', (64, 75))	('C', 'Chemical', 'MESH:D002244', (82, 83))	('DNA methylation', 'biological_process', 'GO:0006306', ('48', '63'))	('C', 'Chemical', 'MESH:D002244', (83, 84))
176870	28754676	We obtained chromatin immunoprecipitation-sequencing (ChlP-Seq) peak data for histone marks H3K4me3, H3K36me3, and H3K27me3 in the normal kidney cell line from UCSC ENCODE Histone Modification Tracks (https://genome.ucsc.edu/ENCODE/dataMatrix/encodeDataMatrixHuman.html).	('Histone Modification', 'biological_process', 'GO:0016570', ('172', '192'))	('H3K27me3', 'Var', (115, 123))	('C', 'Chemical', 'MESH:D002244', (227, 228))	('chromatin', 'cellular_component', 'GO:0000785', ('12', '21'))	('H3K4me3', 'Var', (92, 99))	('C', 'Chemical', 'MESH:D002244', (163, 164))	('his', 'Chemical', 'MESH:D006639', (78, 81))	('C', 'Chemical', 'MESH:D002244', (54, 55))	('H3K36me3', 'Var', (101, 109))	('C', 'Chemical', 'MESH:D002244', (161, 162))	('C', 'Chemical', 'MESH:D002244', (167, 168))
176871	28754676	We extracted the histone data o f fetal kidney samples for H3K4me3, H3K36me3, and H3K27me3 from the Roadmap Epigenomics Project (http://www.roadmapepigenomics.org/).	('H3K27me3', 'Var', (82, 90))	('H3K36me3', 'Var', (68, 76))	('his', 'Chemical', 'MESH:D006639', (17, 20))	('H3K4me3', 'Var', (59, 66))
176875	28754676	To explore whether ccRCC cases with NSD1 methylation harbored a methylome alteration similar to that of Sotos syndrome, we performed supervised clustering of DNA methylation on ccRCC from TCGA training dataset (n = 271 cases) using the methylation signature associated with NSD1 mutations reported in Sotos syndrome by Berdasco and colleagues.	('Sotos syndrome', 'Disease', (104, 118))	('mutations', 'Var', (279, 288))	('Sotos syndrome', 'Disease', 'MESH:D058495', (301, 315))	('NSD1', 'Gene', '64324', (36, 40))	('C', 'Chemical', 'MESH:D002244', (180, 181))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('Sotos syndrome', 'Disease', (301, 315))	('NSD1', 'Gene', '64324', (274, 278))	('C', 'Chemical', 'MESH:D002244', (23, 24))	('DNA', 'cellular_component', 'GO:0005574', ('158', '161'))	('DNA methylation', 'biological_process', 'GO:0006306', ('158', '173'))	('C', 'Chemical', 'MESH:D002244', (22, 23))	('NSD1', 'Gene', (36, 40))	('methylation', 'biological_process', 'GO:0032259', ('236', '247'))	('NSD1', 'Gene', (274, 278))	('C', 'Chemical', 'MESH:D002244', (181, 182))	('Sotos syndrome', 'Disease', 'MESH:D058495', (104, 118))	('C', 'Chemical', 'MESH:D002244', (189, 190))
176876	28754676	We used Fisher exact test to evaluate the association between the epi-clusters and frequent somatic mutations in kidney tumors.	('kidney tumors', 'Disease', (113, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('kidney tumors', 'Disease', 'MESH:D007674', (113, 126))	('kidney tumor', 'Phenotype', 'HP:0009726', (113, 125))	('epi-clusters', 'Var', (66, 78))	('association', 'Interaction', (42, 53))	('kidney tumors', 'Phenotype', 'HP:0009726', (113, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
176879	28754676	We defined samples with NSD1 methylation as those with average methylation levels that were greater than those of normal kidney samples plus three SDs.	('methylation', 'Var', (29, 40))	('methylation', 'biological_process', 'GO:0032259', ('29', '40'))	('NSD1', 'Gene', (24, 28))	('methylation', 'biological_process', 'GO:0032259', ('63', '74'))	('methylation levels', 'MPA', (63, 81))	('NSD1', 'Gene', '64324', (24, 28))	('SDs', 'Chemical', 'MESH:D012967', (147, 150))	('greater', 'PosReg', (92, 99))
176895	28754676	To examine the histone modification profiles of mRNA genes for H3K4me3 and H3K27me3 in fetal kidney and normal kidney tissues, we analyzed the promoter regions of mRNA genes for overlap with histone mark enrichment peaks.	('his', 'Chemical', 'MESH:D006639', (15, 18))	('his', 'Chemical', 'MESH:D006639', (191, 194))	('histone modification', 'biological_process', 'GO:0016570', ('15', '35'))	('H3K27me3', 'Var', (75, 83))	('H3K4me3', 'Var', (63, 70))
176899	28754676	We used targeted hybrid capture-based next-generation sequencing in collaboration with Cancer Genetics, Inc., to detect VHL and SETD2 somatic mutations in cancer and adjacent normal tissue samples.	('mutations', 'Var', (142, 151))	('SETD2', 'Gene', (128, 133))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))	('VHL', 'Disease', (120, 123))	('VHL', 'Disease', 'MESH:D006623', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('Cancer', 'Disease', 'MESH:D009369', (87, 93))	('SETD2', 'Gene', '29072', (128, 133))	('Cancer', 'Disease', (87, 93))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
176906	28754676	We assessed whether tumors belonging to the C-CIMP subgroup were associated with distinct clinicopathologic tumor features, and found that C-CIMP tumors harbored higher pathologic Fuhrman grades (P < 10-5) and higher TNM stages (P < 10-5; Table 1).	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('C-CIMP', 'Var', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('Fuhrman grades', 'CPA', (180, 194))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumors', 'Disease', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('TNM', 'Gene', '10178', (217, 220))	('C-CIMP', 'Chemical', '-', (139, 145))	('TNM', 'Gene', (217, 220))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('C-CIMP', 'Chemical', '-', (44, 50))	('higher', 'PosReg', (210, 216))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('higher', 'PosReg', (162, 168))	('tumors', 'Disease', (146, 152))	('tumor', 'Disease', (20, 25))
176907	28754676	We found that patients with C-CIMP had the worst overall survival when compared with the two other subgroups (P = 1.4 x 10-7; Fig.	('overall survival', 'MPA', (49, 65))	('C-CIMP', 'Chemical', '-', (28, 34))	('C-CIMP', 'Var', (28, 34))	('worst', 'NegReg', (43, 48))	('patients', 'Species', '9606', (14, 22))
176911	28754676	Supervised clustering for DNA methylation revealed three DNA methylation epi-clusters that were consistent with C-CIMP, low-CIMP, and no-CIMP subgroups (Supplementary Fig.	('CIMP', 'Chemical', '-', (124, 128))	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('low-CIMP', 'Var', (120, 128))	('DNA methylation', 'biological_process', 'GO:0006306', ('26', '41'))	('CIMP', 'Chemical', '-', (114, 118))	('DNA methylation', 'biological_process', 'GO:0006306', ('57', '72'))	('CIMP', 'Chemical', '-', (137, 141))	('C-CIMP', 'Disease', (112, 118))	('C-CIMP', 'Chemical', '-', (112, 118))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))
176914	28754676	Overall, 13,439 of the 67,994 (19.8%) probes were differentially methylated between the C-CIMP and no-CIMP epi-clusters [false discovery rate (FDR) <0.05; Supplementary Fig.	('C-CIMP', 'Var', (88, 94))	('false', 'biological_process', 'GO:0071877', ('121', '126'))	('differentially', 'Reg', (50, 64))	('CIMP', 'Chemical', '-', (90, 94))	('methylated', 'Var', (65, 75))	('epi-clusters [', 'Var', (107, 121))	('C-CIMP', 'Chemical', '-', (88, 94))	('CIMP', 'Chemical', '-', (102, 106))	('false', 'biological_process', 'GO:0071878', ('121', '126'))
176920	28754676	To determine the set of genes regulated epigenetically in CCIMP, we explored genes that show gains in DNA methylation in the C-CIMP subgroup (average beta-value >= 0.25) compared with the no-CIMP subgroup (average beta-value <0.2; FDR< 0.05), as well as downregulation of their expression (FDR<0.05).	('gains', 'PosReg', (93, 98))	('CIMP', 'Chemical', '-', (191, 195))	('C-CIMP', 'Chemical', '-', (125, 131))	('DNA methylation', 'MPA', (102, 117))	('expression', 'MPA', (278, 288))	('downregulation', 'NegReg', (254, 268))	('CIMP', 'Chemical', '-', (59, 63))	('DNA methylation', 'biological_process', 'GO:0006306', ('102', '117'))	('CIMP', 'Chemical', '-', (127, 131))	('C-CIMP', 'Var', (125, 131))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))
176922	28754676	VEGF receptor genes FLT4, FLT1, and KDR were methylated in 22.5%, 6.2%, and 4.4% of ccRCC samples, respectively (Fig.	('ccRCC', 'Disease', (84, 89))	('FLT1', 'Gene', '2321', (26, 30))	('VEGF', 'Gene', '7422', (0, 4))	('FLT4', 'Gene', (20, 24))	('methylated', 'Var', (45, 55))	('FLT4', 'Gene', '2324', (20, 24))	('KDR', 'Gene', (36, 39))	('FLT1', 'Gene', (26, 30))	('VEGF', 'Gene', (0, 4))	('KDR', 'Gene', '3791', (36, 39))
176934	28754676	In addition, C-CIMP was associated with increased mutational rates of BAP1 (P = 8.6 x 10-6) and SEGammaD2 (P = 0.002) genes (Supplementary Fig.	('BAP1', 'Gene', '8314', (70, 74))	('mutational rates', 'MPA', (50, 66))	('C-CIMP', 'Var', (13, 19))	('BAP1', 'Gene', (70, 74))	('increased', 'PosReg', (40, 49))	('SEGammaD2', 'Gene', (96, 105))	('C-CIMP', 'Chemical', '-', (13, 19))
176937	28754676	Likewise, 204 of the 242 (84.3%) genes were marked by H3K27me3 in the normal renal samples as compared with2,363 genes (23.4%) marked by PRCin the normal kidney samples (P < 0.0001).	('marked', 'Reg', (44, 50))	('H3K27me3', 'Var', (54, 62))	('C', 'Chemical', 'MESH:D002244', (139, 140))
176942	28754676	VHL was among those genes and was methylated in 6.2% of our total samples, which is consistent with TCGA analysis and validates the accuracy of our approach.	('C', 'Chemical', 'MESH:D002244', (101, 102))	('methylated', 'Var', (34, 44))	('VHL', 'Disease', 'MESH:D006623', (0, 3))	('VHL', 'Disease', (0, 3))
176943	28754676	To identify the genes that might act as tumor suppressor genes, we looked for genes harboring only the H3k4me3 histone mark in the fetal kidney tissue and that were without any H3K27me3 mark.	('his', 'Chemical', 'MESH:D006639', (111, 114))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('H3k4me3', 'Var', (103, 110))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor suppressor', 'biological_process', 'GO:0051726', ('40', '56'))
176949	28754676	NSD1 was methylated in 29.1% of ccRCCs.	('NSD1', 'Gene', (0, 4))	('NSD1', 'Gene', '64324', (0, 4))	('ccRCCs', 'Disease', (32, 38))	('methylated', 'Var', (9, 19))
176950	28754676	Correlation with clinicopathologic features identified a higher rate of NSD1 methylation in metastatic versus localized ccRCC cases (52% vs. 16%, P < 0.0001) as well as in tumors with Fuhrman grades III:GammaV (28% vs. 16%, P = 0.02).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('NSD1', 'Gene', '64324', (72, 76))	('methylation', 'Var', (77, 88))	('metastatic', 'Disease', (92, 102))	('methylation', 'biological_process', 'GO:0032259', ('77', '88'))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('C', 'Chemical', 'MESH:D002244', (124, 125))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('NSD1', 'Gene', (72, 76))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C', 'Chemical', 'MESH:D002244', (123, 124))
176951	28754676	We then considered whether there was a correlation between NSD1 methylation and SEGammaD2 mutations using the TCGA training set.	('NSD1', 'Gene', (59, 63))	('mutations', 'Var', (90, 99))	('C', 'Chemical', 'MESH:D002244', (111, 112))	('SEGammaD2', 'Gene', (80, 89))	('NSD1', 'Gene', '64324', (59, 63))	('methylation', 'biological_process', 'GO:0032259', ('64', '75'))
176952	28754676	Strikingly, 16 of31 (51.6%) ccRCC cases from TCGA with SETD2 mutations harbored concomitant NSD1 methylation as compared with 39 of 219 (17.8%) ccRCC cases with no SETD2 mutations (P < 0.0001; Fig.	('C', 'Chemical', 'MESH:D002244', (31, 32))	('C', 'Chemical', 'MESH:D002244', (148, 149))	('methylation', 'MPA', (97, 108))	('mutations', 'Var', (61, 70))	('C', 'Chemical', 'MESH:D002244', (46, 47))	('SETD2', 'Gene', '29072', (164, 169))	('C', 'Chemical', 'MESH:D002244', (32, 33))	('NSD1', 'Gene', '64324', (92, 96))	('methylation', 'biological_process', 'GO:0032259', ('97', '108'))	('ccRCC', 'Disease', (28, 33))	('SETD2', 'Gene', '29072', (55, 60))	('SETD2', 'Gene', (164, 169))	('NSD1', 'Gene', (92, 96))	('SETD2', 'Gene', (55, 60))	('C', 'Chemical', 'MESH:D002244', (147, 148))
176954	28754676	To assess the impact of alterations in NSD1 methylation in TCGA dataset (450 K), we analyzed the OS of 2 71 patients with ccRCC and found that NSD1 methylation was assodated with poor OS (P = 3.3 x 10-5; Fig.	('C', 'Chemical', 'MESH:D002244', (125, 126))	('ccRCC', 'Disease', (122, 127))	('NSD1', 'Gene', '64324', (39, 43))	('methylation', 'biological_process', 'GO:0032259', ('148', '159'))	('NSD1', 'Gene', '64324', (143, 147))	('C', 'Chemical', 'MESH:D002244', (60, 61))	('patients', 'Species', '9606', (108, 116))	('methylation', 'Var', (148, 159))	('methylation', 'biological_process', 'GO:0032259', ('44', '55'))	('C', 'Chemical', 'MESH:D002244', (126, 127))	('NSD1', 'Gene', (39, 43))	('NSD1', 'Gene', (143, 147))
176956	28754676	Using a stringent cutoff to define NSD1 methylation (above the methylation rate of normal tissue plus 3 SDs), 26 of 222 (11.7%) ccRCC samples harbored NSD1 methylation.	('ccRCC', 'Disease', (128, 133))	('NSD1', 'Gene', (151, 155))	('SDs', 'Chemical', 'MESH:D012967', (104, 107))	('NSD1', 'Gene', '64324', (35, 39))	('harbored', 'Reg', (142, 150))	('methylation', 'biological_process', 'GO:0032259', ('63', '74'))	('NSD1', 'Gene', (35, 39))	('methylation', 'biological_process', 'GO:0032259', ('40', '51'))	('NSD1', 'Gene', '64324', (151, 155))	('methylation', 'biological_process', 'GO:0032259', ('156', '167'))	('methylation', 'Var', (156, 167))
176957	28754676	Consistent with TCGA cohort, tumors with NSD1 methylation were more often metastatic (n = 6/22; 27.2%) as compared with those without NSD1 methylation (n = 16/200; 8%; P = 0.03); although there was no difference between NSD1 methylated cases in terms of tumor size (P = 0.57).	('NSD1', 'Gene', (220, 224))	('NSD1', 'Gene', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('methylation', 'Var', (46, 57))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('NSD1', 'Gene', '64324', (220, 224))	('NSD1', 'Gene', '64324', (134, 138))	('metastatic', 'CPA', (74, 84))	('tumors', 'Disease', (29, 35))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C', 'Chemical', 'MESH:D002244', (17, 18))	('tumor', 'Disease', (254, 259))	('NSD1', 'Gene', (41, 45))	('methylation', 'biological_process', 'GO:0032259', ('139', '150'))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('tumor', 'Disease', (29, 34))	('NSD1', 'Gene', '64324', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
176959	28754676	With a median follow-up of 21 months, median recurrence-free survival was not different between the patients with and those without NSD1 methylation (P = 0.57; Fig.	('methylation', 'biological_process', 'GO:0032259', ('137', '148'))	('methylation', 'Var', (137, 148))	('NSD1', 'Gene', (132, 136))	('patients', 'Species', '9606', (100, 108))	('NSD1', 'Gene', '64324', (132, 136))
176962	28754676	We found that NSD1 was methylated in 67.6% of metastatic ccRCCs (n = 69/102), which is consistent with the 52% rate that we discovered in metastatic ccRCCs from TCGA.	('methylated', 'Var', (23, 33))	('C', 'Chemical', 'MESH:D002244', (162, 163))	('NSD1', 'Gene', (14, 18))	('C', 'Chemical', 'MESH:D002244', (153, 154))	('C', 'Chemical', 'MESH:D002244', (152, 153))	('C', 'Chemical', 'MESH:D002244', (61, 62))	('metastatic ccRCCs', 'Disease', (46, 63))	('C', 'Chemical', 'MESH:D002244', (60, 61))	('NSD1', 'Gene', '64324', (14, 18))
176963	28754676	Methylation of FLT4, KDR, and FLT1 (13/107) had also been found, respectively, in 40.8%, 11.8%, and 12.1% of patients with metastatic ccRCC who were treated with sunitinib.	('FLT4', 'Gene', '2324', (15, 19))	('sunitinib', 'Chemical', 'MESH:D000077210', (162, 171))	('patients', 'Species', '9606', (109, 117))	('FLT1', 'Gene', '2321', (30, 34))	('Methylation', 'Var', (0, 11))	('FLT1', 'Gene', (30, 34))	('metastatic ccRCC', 'Disease', (123, 139))	('KDR', 'Gene', '3791', (21, 24))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('found', 'Reg', (58, 63))	('FLT4', 'Gene', (15, 19))	('KDR', 'Gene', (21, 24))
176965	28754676	S4A-S4C), but NSD1 methylation was assodated with the lowest progression-free survival (P = 0.03; Fig.	('methylation', 'Var', (19, 30))	('lowest', 'NegReg', (54, 60))	('NSD1', 'Gene', (14, 18))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('C', 'Chemical', 'MESH:D002244', (6, 7))	('NSD1', 'Gene', '64324', (14, 18))	('progression-free survival', 'CPA', (61, 86))
176972	28754676	We then considered whether NSD1 epigenetic silencing through DNA methylation was associated with a specific genome-wide methylome signature of ccRCC, as it is the case for NSD1 mutations in Sotos syndrome.	('Sotos syndrome', 'Disease', 'MESH:D058495', (190, 204))	('NSD1', 'Gene', '64324', (172, 176))	('NSD1', 'Gene', (172, 176))	('NSD1', 'Gene', (27, 31))	('Sotos syndrome', 'Disease', (190, 204))	('NSD1', 'Gene', '64324', (27, 31))	('DNA methylation', 'biological_process', 'GO:0006306', ('61', '76'))	('ccRCC', 'Disease', (143, 148))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('epigenetic silencing', 'Var', (32, 52))	('associated', 'Reg', (81, 91))
176973	28754676	We used the DNA methylation signature associated with NSD1 mutations as reported for the Sotos syndrome and applied it to theTCGA cohort of 271 ccRCCs assessed by Infinium 450 K arrays.	('Sotos syndrome', 'Disease', 'MESH:D058495', (89, 103))	('NSD1', 'Gene', '64324', (54, 58))	('C', 'Chemical', 'MESH:D002244', (148, 149))	('C', 'Chemical', 'MESH:D002244', (147, 148))	('DNA methylation', 'biological_process', 'GO:0006306', ('12', '27'))	('Sotos syndrome', 'Disease', (89, 103))	('mutations', 'Var', (59, 68))	('NSD1', 'Gene', (54, 58))	('C', 'Chemical', 'MESH:D002244', (126, 127))	('DNA', 'cellular_component', 'GO:0005574', ('12', '15'))	('ccRCCs', 'Disease', (144, 150))
176974	28754676	Strikingly, cluster 1 was highly enriched for tumors harboring NSD1 methylation (55.7%; n = 44/79) as compared with 9.4% (n = 18/192) in cluster 2 (P = 2.7 x 10-15; HR = 12; 95% Cl, 6.0-24.9).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('NSD1', 'Gene', (63, 67))	('methylation', 'Var', (68, 79))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('tumors', 'Disease', (46, 52))	('NSD1', 'Gene', '64324', (63, 67))	('C', 'Chemical', 'MESH:D002244', (178, 179))
176975	28754676	Cluster 1 was also enriched for tumors harboring SETD2 mutations (27.4%; n = 20/73) relative to 6.2% (n = 11/177) in cluster 2 (P = 2.3 x 10-5; HR = 5.6; 95% Cl, 2.4-14).	('mutations', 'Var', (55, 64))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('SETD2', 'Gene', '29072', (49, 54))	('tumors', 'Disease', (32, 38))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('SETD2', 'Gene', (49, 54))	('C', 'Chemical', 'MESH:D002244', (158, 159))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
176976	28754676	We found that ccRCCs with the NSD1 mutation genome-wide methylome signature were associated with poor overall survival as compared with those without the signature (P = 0.0021) ; Supplementary Fig.	('NSD1', 'Gene', (30, 34))	('poor', 'NegReg', (97, 101))	('ccRCCs', 'Disease', (14, 20))	('NSD1', 'Gene', '64324', (30, 34))	('mutation', 'Var', (35, 43))	('overall', 'MPA', (102, 109))
176978	28754676	The median number of core sections analyzed for NSD1 methylation was 3 per primary tumor (range: 2-13), with a total of 114 successfully analyzed.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('NSD1', 'Gene', (48, 52))	('core', 'cellular_component', 'GO:0019013', ('21', '25'))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('methylation', 'biological_process', 'GO:0032259', ('53', '64'))	('NSD1', 'Gene', '64324', (48, 52))	('methylation', 'Var', (53, 64))
176979	28754676	We found heterogeneity of NSD1 methylation in at least one section of the primary tumor in 7 of 20 samples (35%; Fig.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('NSD1', 'Gene', '64324', (26, 30))	('methylation', 'Var', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('NSD1', 'Gene', (26, 30))
176981	28754676	Strikingly, 100% (n = 6/6) of the ccRCC cases that harbored NSD1 methylation were grade IV tumors as compared with none of the cases that were grade I:III tumors (P <0.0001).	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('NSD1', 'Gene', '64324', (60, 64))	('ccRCC', 'Disease', (34, 39))	('tumors', 'Disease', (155, 161))	('methylation', 'Var', (65, 76))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('methylation', 'biological_process', 'GO:0032259', ('65', '76'))	('NSD1', 'Gene', (60, 64))
176982	28754676	In addition, 80% (n = 4/5) of metastatic ccRCCs harbored NSD1 methylation as compared with 13.3% (n = 3/15) of the cases with no metastasis at diagnosis (P = 0.03), which is consistent with the data on 222 primary ccRCC cases.	('methylation', 'biological_process', 'GO:0032259', ('62', '73'))	('metastatic ccRCCs', 'Disease', (30, 47))	('NSD1', 'Gene', '64324', (57, 61))	('methylation', 'Var', (62, 73))	('harbored', 'Reg', (48, 56))	('NSD1', 'Gene', (57, 61))
176983	28754676	We then decided to explore the association between SETD2 mutations and NSD1 methylation in 13 ccRCC cases for which material was available.	('ccRCC', 'Disease', (94, 99))	('SETD2', 'Gene', (51, 56))	('methylation', 'MPA', (76, 87))	('NSD1', 'Gene', '64324', (71, 75))	('mutations', 'Var', (57, 66))	('methylation', 'biological_process', 'GO:0032259', ('76', '87'))	('NSD1', 'Gene', (71, 75))	('SETD2', 'Gene', '29072', (51, 56))
176984	28754676	Of 114 samples assessed for DNA methylation, 47 sections related to 13 cases were also assessed for SETD2 mutations (Fig.	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('mutations', 'Var', (106, 115))	('DNA methylation', 'biological_process', 'GO:0006306', ('28', '43'))	('SETD2', 'Gene', '29072', (100, 105))	('SETD2', 'Gene', (100, 105))
176985	28754676	Strikingly, we observed a high rate of mutation of SETD2 (46.1%, n = 6/13), with mutational convergence of SETD2 in different loci observed in one case (HET-1).	('SETD2', 'Gene', (51, 56))	('mutation', 'Var', (39, 47))	('SETD2', 'Gene', '29072', (107, 112))	('SETD2', 'Gene', '29072', (51, 56))	('SETD2', 'Gene', (107, 112))
176986	28754676	Consistent with our analytic results on the data obtained from TCGA, we found an association between SETD2 mutations and NSD1 methylation (P = 0.0049).	('SETD2', 'Gene', (101, 106))	('methylation', 'biological_process', 'GO:0032259', ('126', '137'))	('methylation', 'MPA', (126, 137))	('mutations', 'Var', (107, 116))	('C', 'Chemical', 'MESH:D002244', (64, 65))	('NSD1', 'Gene', (121, 125))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('SETD2', 'Gene', '29072', (101, 106))	('NSD1', 'Gene', '64324', (121, 125))
176987	28754676	To our knowledge, this work represents the first integrative analysis showing frequent epigenetic silencing of NSD1 as the sole methylated and repressed H3K36 methyltransferase in ccRCC.	('H3K36', 'Protein', (153, 158))	('NSD1', 'Gene', '64324', (111, 115))	('his', 'Chemical', 'MESH:D006639', (19, 22))	('NSD1', 'Gene', (111, 115))	('epigenetic silencing', 'Var', (87, 107))	('ccRCC', 'Disease', (180, 185))
176988	28754676	Strikingly, compared with localized ccRCC, metastatic ccRCC harbored high rates of NSD1 methylation that ranged from 27.2% in Pitie-Salpetriere cohort to 67.6% in Beuselinck cohort; differences regarding NSD1 methylation rates might be related to distinct distribution of clinicopathologic tumor features.	('methylation', 'biological_process', 'GO:0032259', ('209', '220'))	('methylation', 'Var', (88, 99))	('NSD1', 'Gene', (83, 87))	('metastatic ccRCC', 'Disease', (43, 59))	('NSD1', 'Gene', '64324', (204, 208))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('NSD1', 'Gene', (204, 208))	('NSD1', 'Gene', '64324', (83, 87))	('tumor', 'Disease', (290, 295))
176989	28754676	Consistent with data showing heterogeneity of SETD2 mutations in ccRCC with convergence toward mutations in the SWI-SNF complex, our analysis uncovered an association between SETD2 somatic mutations and NSD1 methylation in two different cohorts, suggesting that loss of H3K36me3 in ccRCC might occur through crosstalk between the inactivation of NSD1 and SETD2.	('C', 'Chemical', 'MESH:D002244', (69, 70))	('inactivation', 'Var', (330, 342))	('C', 'Chemical', 'MESH:D002244', (68, 69))	('NSD1', 'Gene', (346, 350))	('H3K36me3', 'Var', (270, 278))	('methylation', 'biological_process', 'GO:0032259', ('208', '219'))	('NSD1', 'Gene', (203, 207))	('SETD2', 'Gene', (175, 180))	('SWI-SNF complex', 'cellular_component', 'GO:0016514', ('112', '127'))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('mutations', 'Var', (189, 198))	('SETD2', 'Gene', (46, 51))	('C', 'Chemical', 'MESH:D002244', (286, 287))	('SETD2', 'Gene', '29072', (175, 180))	('NSD1', 'Gene', '64324', (346, 350))	('ccRCC', 'Disease', (282, 287))	('SETD2', 'Gene', '29072', (46, 51))	('NSD1', 'Gene', '64324', (203, 207))	('loss', 'NegReg', (262, 266))	('mutations', 'Var', (52, 61))	('SETD2', 'Gene', (355, 360))	('C', 'Chemical', 'MESH:D002244', (285, 286))	('SETD2', 'Gene', '29072', (355, 360))
176990	28754676	Further explorations using animal models should be undertaken to examine whether the initiating event of metastasis in the context of ccRCC is SETD2 mutation or NSD1 methylation.	('NSD1', 'Gene', (161, 165))	('ccRCC', 'Disease', (134, 139))	('SETD2', 'Gene', '29072', (143, 148))	('SETD2', 'Gene', (143, 148))	('NSD1', 'Gene', '64324', (161, 165))	('mutation', 'Var', (149, 157))	('methylation', 'Var', (166, 177))	('methylation', 'biological_process', 'GO:0032259', ('166', '177'))
176993	28754676	Although not causative, ccRCCs with NSD1 methylation harbor the genome-wide methylome signature of Sotos syndrome, suggesting that the silencing of this histone methyltransferase affects genes involved in cellular morphogenesis.	('his', 'Chemical', 'MESH:D006639', (153, 156))	('NSD1', 'Gene', '64324', (36, 40))	('silencing', 'Var', (135, 144))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('Sotos syndrome', 'Disease', 'MESH:D058495', (99, 113))	('methylation', 'Var', (41, 52))	('cellular morphogenesis', 'biological_process', 'GO:0000902', ('205', '227'))	('affects', 'Reg', (179, 186))	('NSD1', 'Gene', (36, 40))	('Sotos syndrome', 'Disease', (99, 113))	('his', 'Chemical', 'MESH:D006639', (149, 152))
176994	28754676	Several studies have reported a possible oncogenic role for NSD1 in acute myeloid leukemia through the cryptic NLGammaP98-NSD1 fusion t(5;ll)(q 35;p l5.5).	('NSD1', 'Gene', (122, 126))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (74, 90))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (68, 90))	('NSD1', 'Gene', '64324', (60, 64))	('t(5;ll)(q', 'Var', (134, 143))	('acute myeloid leukemia', 'Disease', (68, 90))	('NSD1', 'Gene', '64324', (122, 126))	('leukemia', 'Phenotype', 'HP:0001909', (82, 90))	('NSD1', 'Gene', (60, 64))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (68, 90))	('cryptic', 'Gene', (103, 110))	('cryptic', 'Gene', '55997', (103, 110))
176998	28754676	This is also consistent with the genomic analysis of squamous cell carcinomas of the head and neck, and endometrial and gastric adenocarcinomas that revealed recurrent loss-of-function mutations in NSD1 in approximately 10% of cases.	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (120, 143))	('squamous cell carcinomas', 'Disease', (53, 77))	('his', 'Chemical', 'MESH:D006639', (1, 4))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (53, 77))	('gastric adenocarcinomas', 'Disease', (120, 143))	('NSD1', 'Gene', '64324', (198, 202))	('neck', 'cellular_component', 'GO:0044326', ('94', '98'))	('loss-of-function', 'NegReg', (168, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('NSD1', 'Gene', (198, 202))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('mutations', 'Var', (185, 194))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (53, 77))
176999	28754676	Most importantly, NSD1 hypermethylation was a predictor of poor outcome in ccRCC.	('hypermethylation', 'Var', (23, 39))	('NSD1', 'Gene', '64324', (18, 22))	('NSD1', 'Gene', (18, 22))	('ccRCC', 'Disease', (75, 80))
177000	28754676	These findings highlight the importance of NSD1 epigenetic inactivation in ccRCCs, which, concomitantly with SETD2 mutations, leads to a disrupted histone methylation landscape.	('histone methylation', 'biological_process', 'GO:0016571', ('147', '166'))	('leads to', 'Reg', (126, 134))	('disrupted', 'Reg', (137, 146))	('SETD2', 'Gene', '29072', (109, 114))	('NSD1', 'Gene', '64324', (43, 47))	('epigenetic inactivation', 'Var', (48, 71))	('SETD2', 'Gene', (109, 114))	('his', 'Chemical', 'MESH:D006639', (147, 150))	('NSD1', 'Gene', (43, 47))	('ccRCCs', 'Disease', (75, 81))	('histone methylation landscape', 'MPA', (147, 176))
177001	28754676	Patients with localized ccRCC of the C-CIMP subtype displayed poor outcomes, but this association was not independent from other clinicopathologic parameters, suggesting that aggressive tumors might acquire epigenetic aberrations during their evolution.	('epigenetic aberrations', 'Var', (207, 229))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('C-CIMP', 'Chemical', '-', (37, 43))	('aggressive tumors', 'Disease', 'MESH:D001523', (175, 192))	('ccRCC', 'Disease', (24, 29))	('his', 'Chemical', 'MESH:D006639', (82, 85))	('Patients', 'Species', '9606', (0, 8))	('aggressive tumors', 'Disease', (175, 192))
177002	28754676	Of note, genes that gain DNA methylation in CIMP were in majority repressed and marked by H3K27me3 in normal kidneys consistent with previous findings.	('methylation', 'Var', (29, 40))	('gain', 'PosReg', (20, 24))	('CIMP', 'Chemical', '-', (44, 48))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))	('H3K27me3', 'Var', (90, 98))	('DNA methylation', 'biological_process', 'GO:0006306', ('25', '40'))
177004	28754676	Strikingly, the key feature of C-CIMP was methylation of VEGF receptor genes, in particular FLT4, as a key feature of C-CIMP.	('C-CIMP', 'Chemical', '-', (31, 37))	('FLT4', 'Gene', (92, 96))	('FLT4', 'Gene', '2324', (92, 96))	('C-CIMP', 'Chemical', '-', (118, 124))	('VEGF', 'Gene', (57, 61))	('methylation', 'biological_process', 'GO:0032259', ('42', '53'))	('methylation', 'Var', (42, 53))	('VEGF', 'Gene', '7422', (57, 61))
177005	28754676	Inverse correlation between FLT4 methylation and expression was observed to be consistent with repression of these receptors.	('methylation', 'biological_process', 'GO:0032259', ('33', '44'))	('Inverse', 'NegReg', (0, 7))	('methylation', 'Var', (33, 44))	('expression', 'MPA', (49, 59))	('FLT4', 'Gene', '2324', (28, 32))	('FLT4', 'Gene', (28, 32))
177007	28754676	Despite the methylation of those receptors, response to sunitinib treatment was similar in ccRCC cases without methylation of FLT4, KDR, or FLT1 genes, which may result from heterogeneous methylation of these receptors.	('methylation', 'biological_process', 'GO:0032259', ('12', '23'))	('ccRCC', 'Disease', (91, 96))	('sunitinib', 'Chemical', 'MESH:D000077210', (56, 65))	('methylation', 'biological_process', 'GO:0032259', ('188', '199'))	('FLT1', 'Gene', '2321', (140, 144))	('KDR', 'Gene', (132, 135))	('FLT4', 'Gene', '2324', (126, 130))	('FLT4', 'Gene', (126, 130))	('methylation', 'biological_process', 'GO:0032259', ('111', '122'))	('methylation', 'Var', (12, 23))	('KDR', 'Gene', '3791', (132, 135))	('FLT1', 'Gene', (140, 144))
177012	28754676	The heterogeneous nature of the methylation of VEGF receptors, as we showed for FLT4, might limit the capacity of such measurement categories to predict treatment sensitivity.	('methylation', 'Var', (32, 43))	('VEGF', 'Gene', '7422', (47, 51))	('FLT4', 'Gene', '2324', (80, 84))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('VEGF', 'Gene', (47, 51))	('FLT4', 'Gene', (80, 84))	('limit', 'NegReg', (92, 97))
177013	28754676	Epigenetic therapy might work in a large population of patients with ccRCCs that harbor these aberrations.	('patients', 'Species', '9606', (55, 63))	('ccRCCs', 'Disease', (69, 75))	('aberrations', 'Var', (94, 105))
177014	28754676	Finally, tumors with C-CIMP showed enrichment with BAP1 and SETD2 mutations consistent with Sato dataset.	('mutations', 'Var', (66, 75))	('C-CIMP', 'Chemical', '-', (21, 27))	('BAP1', 'Gene', (51, 55))	('SETD2', 'Gene', '29072', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('SETD2', 'Gene', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('BAP1', 'Gene', '8314', (51, 55))
177018	28754676	In summary, our study provides evidence about the involvement of alterations of NSD1 concomitantly with SETD2 in metastatic ccRCC.	('SETD2', 'Gene', (104, 109))	('alterations', 'Var', (65, 76))	('metastatic ccRCC', 'Disease', (113, 129))	('involvement', 'Reg', (50, 61))	('NSD1', 'Gene', '64324', (80, 84))	('NSD1', 'Gene', (80, 84))	('SETD2', 'Gene', '29072', (104, 109))
177019	28754676	Epigenetic heterogeneity of NSD1 methylation seems to mirror SETD2 mutational heterogeneity, leading to a convergence toward alterations in the kidney epigenetic machinery.	('methylation', 'biological_process', 'GO:0032259', ('33', '44'))	('methylation', 'Var', (33, 44))	('SETD2', 'Gene', '29072', (61, 66))	('NSD1', 'Gene', (28, 32))	('SETD2', 'Gene', (61, 66))	('kidney epigenetic machinery', 'MPA', (144, 171))	('alterations', 'MPA', (125, 136))	('NSD1', 'Gene', '64324', (28, 32))
177027	29391598	Loss of TGFBR3 also enhanced cell migration in cell culture and induced expression of several mesenchymal markers in a TGF-beta-independent manner.	('enhanced', 'PosReg', (20, 28))	('cell migration', 'biological_process', 'GO:0016477', ('29', '43'))	('induced', 'Reg', (64, 71))	('TGF-beta', 'Gene', '7040', (119, 127))	('cell migration in cell culture', 'CPA', (29, 59))	('expression', 'MPA', (72, 82))	('TGFBR3', 'Gene', (8, 14))	('TGF-beta', 'Gene', (119, 127))	('Loss', 'Var', (0, 4))
177029	29391598	Taken together, our findings reveal that loss of TGFBR3 endows ccRCC cells with multiple metastatic abilities through TGF-beta-dependent and independent pathways.	('loss', 'Var', (41, 45))	('TGF-beta', 'Gene', (118, 126))	('TGFBR3', 'Gene', (49, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('TGF-beta', 'Gene', '7040', (118, 126))	('endows', 'NegReg', (56, 62))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
177042	29391598	Numerous studies have indicated that genes encoding TGF-beta signaling components, such as TGFBR2 and SMAD4, are frequently mutated or epigenetically silenced in many types of cancer cells.	('epigenetically silenced', 'Var', (135, 158))	('SMAD4', 'Gene', '4089', (102, 107))	('signaling', 'biological_process', 'GO:0023052', ('61', '70'))	('TGFBR2', 'Gene', '7048', (91, 97))	('TGF-beta', 'Gene', (52, 60))	('SMAD4', 'Gene', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('TGFBR2', 'Gene', (91, 97))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('TGF-beta', 'Gene', '7040', (52, 60))
177046	29391598	These facts are contradictory to the metastatic properties of cancer cells after TGF-beta signaling components are mutated or deleted.	('deleted', 'Var', (126, 133))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mutated', 'Var', (115, 122))	('cancer', 'Disease', (62, 68))	('TGF-beta', 'Gene', '7040', (81, 89))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('signaling', 'biological_process', 'GO:0023052', ('90', '99'))	('TGF-beta', 'Gene', (81, 89))
177050	29391598	The main cause of vascularization is a disruption in von Hippel-Lindau (VHL) tumor suppressor-hypoxia inducible factor (HIF) signaling through genetic or epigenetic mechanisms.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('77', '93'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('77', '93'))	('disruption', 'Reg', (39, 49))	('vascularization', 'CPA', (18, 33))	('hypoxia', 'Disease', 'MESH:D000860', (94, 101))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (53, 82))	('epigenetic', 'Var', (154, 164))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('hypoxia', 'Disease', (94, 101))	('cause', 'Reg', (9, 14))
177052	29391598	It was reported that the absence of VHL results in overexpression of TGF-beta1, which facilitates angiogenesis in a paracrine manner.	('TGF-beta1', 'Gene', '7040', (69, 78))	('TGF-beta1', 'Gene', (69, 78))	('facilitates', 'PosReg', (86, 97))	('angiogenesis', 'CPA', (98, 110))	('angiogenesis', 'biological_process', 'GO:0001525', ('98', '110'))	('absence', 'Var', (25, 32))	('VHL', 'Disease', (36, 39))	('VHL', 'Disease', 'MESH:D006623', (36, 39))	('overexpression', 'PosReg', (51, 65))
177057	29391598	On the basis of results using an in vivo renal orthotopic tumor model, we hypothesized that the loss of TGFBR3 enhances multiple metastatic abilities of ccRCC cells.	('ccRCC', 'Phenotype', 'HP:0006770', (153, 158))	('RCC', 'Disease', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('renal orthotopic tumor', 'Disease', (41, 63))	('loss', 'Var', (96, 100))	('TGFBR3', 'Gene', (104, 110))	('renal orthotopic tumor', 'Disease', 'MESH:D007674', (41, 63))	('enhances', 'PosReg', (111, 119))	('RCC', 'Disease', 'MESH:C538614', (155, 158))
177058	29391598	Loss of TGFBR3 increased the CIC-enriched, aldehyde dehydrogenase (ALDH)-positive cell population by attenuating TGF-beta2 signaling.	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('attenuating', 'NegReg', (101, 112))	('CIC', 'Chemical', '-', (29, 32))	('ALDH', 'molecular_function', 'GO:0004030', ('67', '71'))	('increased', 'PosReg', (15, 24))	('TGFBR3', 'Gene', (8, 14))	('TGF-beta2', 'Gene', (113, 122))	('CIC-enriched', 'CPA', (29, 41))	('TGF-beta2', 'Gene', '7042', (113, 122))	('Loss', 'Var', (0, 4))
177059	29391598	Moreover, loss of TGFBR3 enhanced cell-migratory ability through an alternative pathway independent of TGF-beta-TbetaRI signaling.	('loss', 'Var', (10, 14))	('TGF-beta', 'Gene', '7040', (103, 111))	('cell-migratory ability', 'CPA', (34, 56))	('enhanced', 'PosReg', (25, 33))	('TbetaRI', 'Gene', '7046', (112, 119))	('TGF-beta', 'Gene', (103, 111))	('TGFBR3', 'Gene', (18, 24))	('TbetaRI', 'Gene', (112, 119))	('alternative pathway', 'Pathway', (68, 87))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))
177090	29391598	3b), whereas knockdown of TGFBR3 significantly attenuated TGF-beta2 signaling in Caki-1 cells (Fig.	('knockdown', 'Var', (13, 22))	('TGFBR3', 'Gene', (26, 32))	('attenuated', 'NegReg', (47, 57))	('TGF-beta2', 'Gene', '7042', (58, 67))	('TGF-beta2', 'Gene', (58, 67))	('signaling', 'biological_process', 'GO:0023052', ('68', '77'))
177099	29391598	These results suggested that loss of TGFBR3 expression mainly impairs the tumor-suppressive role of TGF-beta2, resulting in enhanced tumor-forming ability in ccRCC cells.	('TGF-beta2', 'Gene', '7042', (100, 109))	('TGF-beta2', 'Gene', (100, 109))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('RCC', 'Disease', (160, 163))	('impairs', 'NegReg', (62, 69))	('enhanced', 'PosReg', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('ccRCC', 'Phenotype', 'HP:0006770', (158, 163))	('loss', 'Var', (29, 33))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', (133, 138))	('TGFBR3', 'Gene', (37, 43))
177104	29391598	Although introduction of TGFBR3 decreased the basal expression of ALDH1A1 mRNA, treatment with the TbetaRI inhibitor, SB431542, rescued this downregulation, suggesting that the regulation of ALDH1A1 is dependent on the TGF-beta-TbetaRI signaling pathway (Fig.	('TbetaRI', 'Gene', '7046', (99, 106))	('TGFBR3', 'Gene', (25, 31))	('TbetaRI', 'Gene', (228, 235))	('ALDH1A1', 'Gene', (191, 198))	('mRNA', 'MPA', (74, 78))	('ALDH1A1', 'Gene', '216', (66, 73))	('ALDH', 'molecular_function', 'GO:0004030', ('66', '70'))	('basal expression', 'MPA', (46, 62))	('TGF-beta', 'Gene', (219, 227))	('introduction', 'Var', (9, 21))	('TbetaRI', 'Gene', (99, 106))	('ALDH1A1', 'Gene', '216', (191, 198))	('decreased', 'NegReg', (32, 41))	('SB431542', 'Chemical', 'MESH:C459179', (118, 126))	('TbetaRI', 'Gene', '7046', (228, 235))	('signaling pathway', 'biological_process', 'GO:0007165', ('236', '253'))	('ALDH1A1', 'Gene', (66, 73))	('TGF-beta', 'Gene', '7040', (219, 227))	('ALDH', 'molecular_function', 'GO:0004030', ('191', '195'))	('regulation', 'biological_process', 'GO:0065007', ('177', '187'))
177122	29391598	Attenuation of TGF-beta2 signaling was expected to decrease the migratory ability of Caki-1 cells.	('migratory ability of Caki-1 cells', 'CPA', (64, 97))	('TGF-beta2', 'Gene', (15, 24))	('TGF-beta2', 'Gene', '7042', (15, 24))	('Attenuation', 'Var', (0, 11))	('decrease', 'NegReg', (51, 59))	('signaling', 'biological_process', 'GO:0023052', ('25', '34'))
177123	29391598	These results suggested that loss of TGFBR3 increases the migratory ability of ccRCC cells.	('migratory ability of', 'CPA', (58, 78))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('loss', 'Var', (29, 33))	('TGFBR3', 'Gene', (37, 43))	('increases', 'PosReg', (44, 53))
177125	29391598	Chamber migration and wound closure assays revealed that cellular invasion and migration were sustained even when cells were treated with SB431542 (Fig.	('SB431542', 'Chemical', 'MESH:C459179', (138, 146))	('cellular invasion', 'CPA', (57, 74))	('SB431542', 'Var', (138, 146))
177126	29391598	Although loss of TGFBR3 expression impaired TGF-beta2-mediated phosphorylation of Smad2/3 (Supplementary Figure S4B), expression of certain mesenchymal markers including fibronectin and Slug was upregulated in Caki-1-shTGFBR3 cells, even in the absence of exogenous TGF-beta2 (Fig.	('TGFBR3', 'Gene', (17, 23))	('phosphorylation', 'biological_process', 'GO:0016310', ('63', '78'))	('TGF-beta2', 'Gene', (266, 275))	('upregulated', 'PosReg', (195, 206))	('loss', 'Var', (9, 13))	('fibronectin', 'Gene', (170, 181))	('TGF-beta2', 'Gene', '7042', (266, 275))	('Slug', 'Gene', '6591', (186, 190))	('TGF-beta2', 'Gene', (44, 53))	('TGF-beta2', 'Gene', '7042', (44, 53))	('Slug', 'Gene', (186, 190))	('expression', 'MPA', (118, 128))	('impaired', 'NegReg', (35, 43))	('fibronectin', 'Gene', '2335', (170, 181))
177129	29391598	These results showed that loss of TGFBR3 enhanced migratory ability of ccRCC cells in a TGF-beta-independent manner.	('TGFBR3', 'Gene', (34, 40))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('RCC', 'Disease', (73, 76))	('enhanced', 'PosReg', (41, 49))	('TGF-beta', 'Gene', '7040', (88, 96))	('migratory ability of', 'CPA', (50, 70))	('TGF-beta', 'Gene', (88, 96))	('loss', 'Var', (26, 30))
177134	29391598	These results suggested that loss of TGFBR3 induces lamellipodium formation, which in turn endows RCC cells with multi-directional cell-migratory ability.	('induces', 'Reg', (44, 51))	('lamellipodium formation', 'biological_process', 'GO:0030032', ('52', '75'))	('multi-directional cell-migratory ability', 'CPA', (113, 153))	('RCC', 'Disease', (98, 101))	('loss', 'Var', (29, 33))	('TGFBR3', 'Gene', (37, 43))	('lamellipodium formation', 'CPA', (52, 75))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('lamellipodium', 'cellular_component', 'GO:0030027', ('52', '65'))	('endows', 'Reg', (91, 97))
177136	29391598	FAK phosphorylation was upregulated in Caki-1-shTGFBR3 cells, compared to that in Caki-1-shNTC cells (Fig.	('FAK', 'molecular_function', 'GO:0004717', ('0', '3'))	('phosphorylation', 'MPA', (4, 19))	('FAK', 'Gene', (0, 3))	('FAK', 'Gene', '5747', (0, 3))	('upregulated', 'PosReg', (24, 35))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('Caki-1-shTGFBR3', 'Var', (39, 54))
177140	29391598	In addition, treating Caki-1-shTGFBR3 cells with the FAK inhibitor PF562271 attenuated Akt phosphorylation (Fig.	('Akt', 'Gene', (87, 90))	('FAK', 'Gene', '5747', (53, 56))	('FAK', 'Gene', (53, 56))	('attenuated', 'NegReg', (76, 86))	('PF562271', 'Chemical', '-', (67, 75))	('FAK', 'molecular_function', 'GO:0004717', ('53', '56'))	('phosphorylation', 'biological_process', 'GO:0016310', ('91', '106'))	('Akt', 'Gene', '207', (87, 90))	('PF562271', 'Var', (67, 75))
177141	29391598	Treatment of Caki-1-shTGFBR3 cells with the PI3K inhibitor LY294002 led to lamellipodium regression (Fig.	('lamellipodium', 'cellular_component', 'GO:0030027', ('75', '88'))	('LY294002', 'Var', (59, 67))	('LY294002', 'Chemical', 'MESH:C085911', (59, 67))	('lamellipodium regression', 'CPA', (75, 99))	('PI3K', 'molecular_function', 'GO:0016303', ('44', '48'))
177147	29391598	Moreover, we demonstrated for the first time that silencing of TGFBR3 enhances primary tumor formation and metastasis of ccRCC cells using in vivo mouse model.	('metastasis', 'CPA', (107, 117))	('mouse', 'Species', '10090', (147, 152))	('primary tumor', 'Disease', (79, 92))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('formation', 'biological_process', 'GO:0009058', ('93', '102'))	('TGFBR3', 'Gene', (63, 69))	('primary tumor', 'Disease', 'MESH:D009369', (79, 92))	('silencing', 'Var', (50, 59))	('RCC', 'Disease', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (121, 126))	('enhances', 'PosReg', (70, 78))
177149	29391598	Further experiments in cell culture indicated that loss of TGFBR3 contributes to a metastatic phenotype in ccRCC cells by modulating tumor-forming and cell-migratory abilities through distinct pathways (Fig.	('loss', 'Var', (51, 55))	('metastatic', 'CPA', (83, 93))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('TGFBR3', 'Gene', (59, 65))	('contributes', 'Reg', (66, 77))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cell-migratory abilities', 'CPA', (151, 175))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('tumor', 'Disease', (133, 138))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('modulating', 'Reg', (122, 132))
177168	29391598	In ovarian cancer, loss of TGFBR3 regulates cell division cycle 42 (CDC42) activity through the regulation of beta-arrestin2 and enhances cell migration in a TGF-beta signaling-independent manner.	('TGF-beta', 'Gene', (158, 166))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('CDC42', 'Gene', (68, 73))	('enhances', 'PosReg', (129, 137))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('regulation', 'biological_process', 'GO:0065007', ('96', '106'))	('CDC42', 'Gene', '998', (68, 73))	('cell division cycle', 'biological_process', 'GO:0007049', ('44', '63'))	('cell migration', 'CPA', (138, 152))	('regulates', 'Reg', (34, 43))	('beta-arrestin2', 'Gene', (110, 124))	('ovarian cancer', 'Disease', (3, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('loss', 'Var', (19, 23))	('TGF-beta', 'Gene', '7040', (158, 166))	('signaling', 'biological_process', 'GO:0023052', ('167', '176'))	('beta-arrestin2', 'Gene', '409', (110, 124))	('TGFBR3', 'Gene', (27, 33))	('cell migration', 'biological_process', 'GO:0016477', ('138', '152'))	('activity', 'MPA', (75, 83))
177170	29391598	SB431542 inhibits the kinase activity of TbetaRI as well as that of type I receptors of activin (ALK-4 and ALK-7).	('activin', 'molecular_function', 'GO:0005160', ('88', '95'))	('activin', 'molecular_function', 'GO:0016915', ('88', '95'))	('ALK-7', 'Gene', '130399', (107, 112))	('kinase activity', 'MPA', (22, 37))	('TbetaRI', 'Gene', '7046', (41, 48))	('SB431542', 'Var', (0, 8))	('ALK-7', 'Gene', (107, 112))	('inhibits', 'NegReg', (9, 17))	('SB431542', 'Chemical', 'MESH:C459179', (0, 8))	('ALK-4', 'Gene', (97, 102))	('ALK-4', 'Gene', '91', (97, 102))	('kinase activity', 'molecular_function', 'GO:0016301', ('22', '37'))	('TbetaRI', 'Gene', (41, 48))
177174	29391598	However, LDN193189, which blocks BMP signaling by inhibiting type I receptors, ALK-2 and ALK-3, affects neither lamellipodium formation nor FAK activation of ccRCC cells (data not shown).	('lamellipodium formation', 'CPA', (112, 135))	('FAK', 'molecular_function', 'GO:0004717', ('140', '143'))	('ALK-3', 'Gene', '657', (89, 94))	('FAK', 'Gene', (140, 143))	('LDN193189', 'Var', (9, 18))	('ALK-3', 'Gene', (89, 94))	('lamellipodium', 'cellular_component', 'GO:0030027', ('112', '125'))	('ALK-2', 'Gene', (79, 84))	('FAK', 'Gene', '5747', (140, 143))	('inhibiting', 'NegReg', (50, 60))	('BMP', 'Gene', '649', (33, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (158, 163))	('RCC', 'Disease', (160, 163))	('affects', 'Reg', (96, 103))	('type I receptors', 'Protein', (61, 77))	('signaling', 'biological_process', 'GO:0023052', ('37', '46'))	('ALK-2', 'Gene', '90', (79, 84))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('lamellipodium formation', 'biological_process', 'GO:0030032', ('112', '135'))	('BMP', 'Gene', (33, 36))
177178	29391598	Other genomic analyses showed that some genes involved in PI3K-Akt-mTOR signaling and the upstream focal adhesion pathway are also mutated in nearly 60% of the ccRCC patients.	('PI3K', 'molecular_function', 'GO:0016303', ('58', '62'))	('ccRCC', 'Phenotype', 'HP:0006770', (160, 165))	('RCC', 'Disease', (162, 165))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('mutated', 'Var', (131, 138))	('mTOR', 'Gene', (67, 71))	('mTOR', 'Gene', '2475', (67, 71))	('Akt', 'Gene', '207', (63, 66))	('focal adhesion', 'cellular_component', 'GO:0005925', ('99', '113'))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))	('patients', 'Species', '9606', (166, 174))	('Akt', 'Gene', (63, 66))
177181	29391598	Our present study revealed that loss of TGFBR3, a component of the TGF-beta signaling pathway, affects FAK-PI3K-mediated cell migration.	('signaling pathway', 'biological_process', 'GO:0007165', ('76', '93'))	('PI3K', 'molecular_function', 'GO:0016303', ('107', '111'))	('affects', 'Reg', (95, 102))	('TGF-beta', 'Gene', '7040', (67, 75))	('FAK', 'molecular_function', 'GO:0004717', ('103', '106'))	('TGF-beta', 'Gene', (67, 75))	('loss', 'Var', (32, 36))	('cell migration', 'biological_process', 'GO:0016477', ('121', '135'))	('FAK', 'Gene', '5747', (103, 106))	('TGFBR3', 'Gene', (40, 46))	('FAK', 'Gene', (103, 106))
177188	29391598	LY294002 (Sigma-Aldrich) and PF562271 (Selleck Chemicals, Houston, TX) were reconstituted in dimethyl sulfoxide and used at a concentration of 20 muM.	('LY294002', 'Var', (0, 8))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (93, 111))	('PF562271', 'Chemical', '-', (29, 37))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('PF562271', 'Var', (29, 37))
177208	31289360	We found that expression of MTHFD2 was significantly elevated in human RCC tissues, and MTHFD2 knockdown strongly reduced xenograft tumor growth.	('human', 'Species', '9606', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('MTHFD2', 'Gene', (88, 94))	('elevated', 'PosReg', (53, 61))	('reduced', 'NegReg', (114, 121))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('knockdown', 'Var', (95, 104))	('expression', 'MPA', (14, 24))	('tumor', 'Disease', (132, 137))	('MTHFD2', 'Gene', (28, 34))
177225	31289360	Notably, MTHFD2 is crucial for mouse development, and its deletion causes embryos to be glycine auxotrophs and die after embryonic day 12.5.	('causes', 'Reg', (67, 73))	('MTHFD2', 'Gene', (9, 15))	('mouse', 'Species', '10090', (31, 36))	('deletion', 'Var', (58, 66))	('glycine auxotrophs', 'MPA', (88, 106))	('glycine', 'Chemical', 'MESH:D005998', (88, 95))
177228	31289360	N6-methyladenosine (m6A), the most common methylation modification in mammalian mRNA molecules, has been shown to be important for mRNA regulation.	('mRNA regulation', 'MPA', (131, 146))	('m6A', 'Gene', '56339', (20, 23))	('mammalian', 'Species', '9606', (70, 79))	('regulation', 'biological_process', 'GO:0065007', ('136', '146'))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('N6-methyladenosine', 'Var', (0, 18))	('methylation', 'biological_process', 'GO:0032259', ('42', '53'))	('m6A', 'Gene', (20, 23))
177232	31289360	Whereas, alterations in one-carbon metabolism are known to be associated with cancer development, whether one-carbon metabolism could affect m6A RNA modification in ccRCC and, if affected, which gene transcripts would be impacted remained unknown.	('m6A', 'Gene', (141, 144))	('m6A', 'Gene', '56339', (141, 144))	('carbon', 'Chemical', 'MESH:D002244', (28, 34))	('one-carbon metabolism', 'biological_process', 'GO:0006730', ('24', '45'))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('alterations', 'Var', (9, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (165, 170))	('one-carbon metabolism', 'biological_process', 'GO:0006730', ('106', '127'))	('carbon', 'Chemical', 'MESH:D002244', (110, 116))	('affect', 'Reg', (134, 140))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('RNA modification', 'biological_process', 'GO:0009451', ('145', '161'))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('RNA', 'cellular_component', 'GO:0005562', ('145', '148'))
177240	31289360	We mined the ccRCC dataset from the Cancer Genome Atlas (TCGA-KIRC), and found high MTHFD2 levels correlating with the stage of ccRCC, and that patients who had high levels of MTHFD2 exhibited a worse survival rate compared with patients with low MTHFD2 expression (Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('patients', 'Species', '9606', (229, 237))	('Cancer', 'Disease', 'MESH:D009369', (36, 42))	('Cancer', 'Disease', (36, 42))	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('MTHFD2', 'Var', (176, 182))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('RCC', 'Disease', (15, 18))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('patients', 'Species', '9606', (144, 152))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (130, 133))
177245	31289360	To determine whether elevated MTHFD2 levels are functionally implicated in RCC progression, we next generated two well-established RCC cell lines (786-O and CAKI-1) with stable shRNA-mediated knockdown of MTHFD2 (Fig.	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('MTHFD2', 'Gene', (205, 211))	('RCC', 'Disease', (75, 78))	('knockdown', 'Var', (192, 201))
177246	31289360	These cells were xenografted subcutaneously into immune-deficient (Nu/J) mice with one flank receiving the MTHFD2 knockdown cells (shMTHFD2) and the other flank receiving the scramble control line (shControl).	('MTHFD2', 'Gene', (107, 113))	('knockdown', 'Var', (114, 123))	('mice', 'Species', '10090', (73, 77))
177251	31289360	However, the mechanistic rationale for how MTHFD2 depletion leads to decreased tumor burden remained unclear.	('decreased tumor', 'Disease', (69, 84))	('MTHFD2', 'Gene', (43, 49))	('decreased tumor', 'Disease', 'MESH:D002303', (69, 84))	('depletion', 'Var', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
177253	31289360	In addition, treatment with MTH-1459 and MTH-1479, two novel MTHFD2 specific inhibitors (Raze Therapeutics), reduced cell proliferation in a dose-dependent manner in 786-O cells (Fig.	('MTH', 'Chemical', 'MESH:D008926', (61, 64))	('MTH-1479', 'Var', (41, 49))	('cell proliferation', 'CPA', (117, 135))	('MTH', 'Chemical', 'MESH:D008926', (41, 44))	('MTHFD2', 'Gene', (61, 67))	('MTH-1479', 'Chemical', '-', (41, 49))	('MTH-1459', 'Var', (28, 36))	('cell proliferation', 'biological_process', 'GO:0008283', ('117', '135'))	('MTH', 'Chemical', 'MESH:D008926', (28, 31))	('reduced', 'NegReg', (109, 116))
177260	31289360	Thus, to probe the metabolic reprogramming potentially caused by MTHFD2 depletion, we assessed the effect of MTHFD2 on the glycolytic status in MTHFD2 knockdown cells and found that both the basal and maximal ECAR (extracellular acidification rate) a measurement of the production of lactate from glycolysis were decreased in MTHFD2 knockdown cells (Fig.	('acidification', 'biological_process', 'GO:0045851', ('229', '242'))	('glycolysis', 'biological_process', 'GO:0006096', ('297', '307'))	('decreased', 'NegReg', (313, 322))	('lactate', 'Chemical', 'MESH:D019344', (284, 291))	('knockdown', 'Var', (333, 342))	('MTHFD2', 'Gene', (326, 332))	('extracellular', 'cellular_component', 'GO:0005576', ('215', '228'))
177263	31289360	Since one-carbon metabolism can support a range of anabolic processes, including regeneration of the methyl-donor pool for methylation of lipids, DNA, RNA and proteins, we assessed the effect of MTHFD2 knockdown on methylation marks, which are critical for fine-tuning of gene expression.	('methylation', 'biological_process', 'GO:0032259', ('123', '134'))	('anabolic', 'MPA', (51, 59))	('lipids', 'Chemical', 'MESH:D008055', (138, 144))	('carbon', 'Chemical', 'MESH:D002244', (10, 16))	('one-carbon metabolism', 'biological_process', 'GO:0006730', ('6', '27'))	('DNA', 'cellular_component', 'GO:0005574', ('146', '149'))	('MTHFD2', 'Gene', (195, 201))	('RNA', 'cellular_component', 'GO:0005562', ('151', '154'))	('regeneration', 'biological_process', 'GO:0031099', ('81', '93'))	('gene expression', 'biological_process', 'GO:0010467', ('272', '287'))	('knockdown', 'Var', (202, 211))	('methylation', 'biological_process', 'GO:0032259', ('215', '226'))
177266	31289360	Thus, MTHFD2 suppression likely lowers global m6A levels by depleting SAM.	('SAM', 'MPA', (70, 73))	('m6A', 'Gene', (46, 49))	('SAM', 'Chemical', 'MESH:D012436', (70, 73))	('suppression', 'Var', (13, 24))	('m6A', 'Gene', '56339', (46, 49))	('depleting', 'NegReg', (60, 69))	('lowers', 'NegReg', (32, 38))	('MTHFD2', 'Gene', (6, 12))
177268	31289360	Previous studies have shown methylation on N6 of adenosines (m6A) of mRNA, particularly near stop codons, can enhance translation.	('translation', 'MPA', (118, 129))	('adenosines', 'Chemical', 'MESH:D000241', (49, 59))	('enhance', 'PosReg', (110, 117))	('methylation on N6', 'Var', (28, 45))	('translation', 'biological_process', 'GO:0006412', ('118', '129'))	('m6A', 'Gene', (61, 64))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))	('m6A', 'Gene', '56339', (61, 64))
177273	31289360	Interestingly, we found HIF-2alpha mRNA, a key factor in tumor growth and survival of ccRCC tumors, to be hypomethylated in MTHFD2 depleted 786-O cells (Fig.	('HIF-2alpha', 'Gene', '2034', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('ccRCC tumors', 'Disease', 'MESH:D009369', (86, 98))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('ccRCC tumors', 'Disease', (86, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('hypomethylated', 'Var', (106, 120))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (57, 62))	('HIF-2alpha', 'Gene', (24, 34))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
177276	31289360	To further explore the effect of MTHFD2 regulation on HIF-2alpha, we measured mRNA and protein levels of HIF-2alpha in MTHFD2 knockdown and control cells.	('mRNA and', 'MPA', (78, 86))	('regulation', 'biological_process', 'GO:0065007', ('40', '50'))	('HIF-2alpha', 'Gene', (105, 115))	('HIF-2alpha', 'Gene', (54, 64))	('MTHFD2', 'Gene', (119, 125))	('HIF-2alpha', 'Gene', '2034', (105, 115))	('knockdown', 'Var', (126, 135))	('HIF-2alpha', 'Gene', '2034', (54, 64))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
177279	31289360	This supports the hypothesis that MTHFD2-dependent m6A methylation on HIF-2alpha mRNA promotes its translation.	('translation', 'biological_process', 'GO:0006412', ('99', '110'))	('m6A', 'Gene', '56339', (51, 54))	('HIF-2alpha', 'Gene', '2034', (70, 80))	('translation', 'MPA', (99, 110))	('promotes', 'PosReg', (86, 94))	('methylation', 'Var', (55, 66))	('m6A', 'Gene', (51, 54))	('HIF-2alpha', 'Gene', (70, 80))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))
177283	31289360	Mutating the m6A site (found from the meRIP-seq data) in the 3' UTR of HIF-2alpha from GGAC to 232 GCGC(HIF-2alpha Mut) effectively blunted the translation of HIF-2alpha in shControl cells, while not significantly effecting translation in the shMTHFD2 cells (Fig.	('blunted', 'NegReg', (132, 139))	('Mutating', 'Var', (0, 8))	('HIF-2alpha', 'Gene', (159, 169))	('HIF-2alpha', 'Gene', (104, 114))	('translation', 'biological_process', 'GO:0006412', ('144', '155'))	('HIF-2alpha', 'Gene', (71, 81))	('HIF-2alpha', 'Gene', '2034', (159, 169))	('HIF-2alpha', 'Gene', '2034', (104, 114))	('translation', 'biological_process', 'GO:0006412', ('224', '235'))	('translation', 'MPA', (144, 155))	('m6A', 'Gene', (13, 16))	('HIF-2alpha', 'Gene', '2034', (71, 81))	('m6A', 'Gene', '56339', (13, 16))
177286	31289360	To this end, we knocked down METTL3 in 786-O cells and measured HIF-2alpha protein levels.	('HIF-2alpha', 'Gene', '2034', (64, 74))	('knocked', 'Var', (16, 23))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('METTL3', 'Gene', '56339', (29, 35))	('HIF-2alpha', 'Gene', (64, 74))	('METTL3', 'Gene', (29, 35))	('measured', 'Reg', (55, 63))
177293	31289360	Ablating HIF-2alpha protein levels in 786-O cells by re-expressing VHL also reduced MTHD2 protein levels (Fig.	('MTH', 'Chemical', 'MESH:D008926', (84, 87))	('HIF-2alpha', 'Gene', (9, 19))	('VHL', 'Gene', '7428', (67, 70))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('HIF-2alpha', 'Gene', '2034', (9, 19))	('reduced', 'NegReg', (76, 83))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('Ablating', 'Var', (0, 8))	('MTHD2 protein levels', 'MPA', (84, 104))	('VHL', 'Gene', (67, 70))
177295	31289360	We found that MTHFD2 knockdown increased the level of HIF-1alpha in these cells while HIF-2alpha was unchanged (Fig.	('HIF-2alpha', 'Gene', (86, 96))	('MTHFD2', 'Gene', (14, 20))	('HIF-1alpha', 'Gene', '3091', (54, 64))	('increased', 'PosReg', (31, 40))	('HIF-2alpha', 'Gene', '2034', (86, 96))	('HIF-1alpha', 'Gene', (54, 64))	('knockdown', 'Var', (21, 30))
177300	31289360	These observations suggest that MTHFD2 and HIF-2alpha form a positive feedforward loop in RCC, and targeting one of these proteins can potentially affect the other's downstream effectors, limiting key RCC phenotypes.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('MTHFD2', 'Gene', (32, 38))	('HIF-2alpha', 'Gene', (43, 53))	('targeting', 'Var', (99, 108))	('limiting', 'NegReg', (188, 196))	('HIF-2alpha', 'Gene', '2034', (43, 53))	('affect', 'Reg', (147, 153))	('RCC', 'Disease', (90, 93))
177307	31289360	786-O shControl cell growth was significantly inhibited by 2-DG, whereas the effect on 786-O shMTHFD2 cells was not as pronounced.	('shControl cell growth', 'CPA', (6, 27))	('2-DG', 'Var', (59, 63))	('2-DG', 'Chemical', 'MESH:D003847', (59, 63))	('inhibited', 'NegReg', (46, 55))	('cell growth', 'biological_process', 'GO:0016049', ('16', '27'))
177313	31289360	We observed that shMTHFD2 cells with exogenous HIF-2alpha were able to uptake significantly higher levels of glucose than shMTHFD2 cells lacking exogenous HIF-2alpha (Fig.	('HIF-2alpha', 'Gene', (155, 165))	('higher', 'PosReg', (92, 98))	('uptake', 'MPA', (71, 77))	('HIF-2alpha', 'Gene', '2034', (155, 165))	('uptake', 'biological_process', 'GO:0098657', ('71', '77'))	('exogenous', 'Var', (37, 46))	('uptake', 'biological_process', 'GO:0098739', ('71', '77'))	('HIF-2alpha', 'Gene', (47, 57))	('glucose', 'Chemical', 'MESH:D005947', (109, 116))	('HIF-2alpha', 'Gene', '2034', (47, 57))
177322	31289360	We demonstrated that both genetic and pharmacological inhibition of MTHFD2 in ccRCC cells attenuates growth in culture and xenograft models, as well as attenuates metastatic potential in vitro.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('inhibition', 'Var', (54, 64))	('metastatic potential in vitro', 'CPA', (163, 192))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('attenuates', 'NegReg', (90, 100))	('attenuates', 'NegReg', (152, 162))	('MTHFD2', 'Gene', (68, 74))
177325	31289360	Consistent with our findings, a recent study has shown modulation of the one-carbon metabolism pathway can alter mitochondrial and glycolytic metabolism by directly affecting methyl modifications of tRNAs in the mitochondria.	('methyl modifications', 'MPA', (175, 195))	('one-carbon metabolism', 'biological_process', 'GO:0006730', ('73', '94'))	('modulation', 'Var', (55, 65))	('affecting', 'Reg', (165, 174))	('metabolism', 'biological_process', 'GO:0008152', ('142', '152'))	('mitochondria', 'cellular_component', 'GO:0005739', ('212', '224'))	('alter', 'Reg', (107, 112))	('one-carbon metabolism pathway', 'Pathway', (73, 102))	('carbon', 'Chemical', 'MESH:D002244', (77, 83))
177334	31289360	We speculate that because of this positive feedforward, inhibition of MTHFD2 could have additional benefits on tumor growth beyond what has been known, and opens new avenues for pursuing this enzyme as a target for therapeutic modalities.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('inhibition', 'Var', (56, 66))	('benefits', 'PosReg', (99, 107))	('MTHFD2', 'Gene', (70, 76))
177349	31289360	Stable MTHFD2 knockdown was achieved using a lentivirus generated from pLKO plasmid containing shRNA sequence (Sigma-Aldrich) transduced into the specified cell lines and selected for using puromycin.	('MTHFD2', 'Gene', (7, 13))	('puromycin', 'Chemical', 'MESH:D011691', (190, 199))	('knockdown', 'Var', (14, 23))
177362	31289360	Primary antibodies against the following proteins were used: MTHFD2 (Abcam, ab151447 for western blotting, Abcam, ab56772 for immunofluorescence), Tubulin (Santa Cruz Biotechnology, 2144S), HIF-2alpha (Cell Signaling Technology, 7096S), METTL3 (Proteintech, 15073-1-AP), H3K4Me3, H3K9Me3 (Abcam, ab8580, ab8898) H3K27Me3 (Millipore, ABE44).	('H3K9Me3', 'Var', (280, 287))	('H3K4Me3', 'Var', (271, 278))	('HIF-2alpha', 'Gene', (190, 200))	('METTL3', 'Gene', '56339', (237, 243))	('METTL3', 'Gene', (237, 243))	('HIF-2alpha', 'Gene', '2034', (190, 200))	('Signaling', 'biological_process', 'GO:0023052', ('207', '216'))	('H3K27Me3', 'Var', (312, 320))
177363	31289360	For western blots, secondary incubation with either DyLight 800 goat anti-rabbit or DyLight 680 goat anti-mouse (Invitrogen), membranes were imaged using an Odyssey scanner (LI-COR).	('COR', 'Gene', (177, 180))	('DyLight 800 goat anti-rabbit', 'Var', (52, 80))	('COR', 'Gene', '108031', (177, 180))	('DyLight 680 goat anti-mouse', 'Var', (84, 111))	('mouse', 'Species', '10090', (106, 111))
177364	31289360	For immunofluorescence, secondaries were AlexaFluor488 anti-mouse and AlexaFluor594 anti-rabbit (Invitrogen).	('AlexaFluor488', 'Chemical', '-', (41, 54))	('AlexaFluor488 anti-mouse', 'Var', (41, 65))	('AlexaFluor594', 'Chemical', '-', (70, 83))	('mouse', 'Species', '10090', (60, 65))	('AlexaFluor594', 'Var', (70, 83))
177379	31289360	Mutagenic PCR's were performed to mutate the m6A motif from GGAC to GCGC.	('mutate', 'Var', (34, 40))	('m6A', 'Gene', '56339', (45, 48))	('m6A', 'Gene', (45, 48))
177417	32081834	Co-expression of PD-1 and Tim-3 was reported to correlate with poor overall survival.	('PD-1', 'Gene', (17, 21))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('PD-1', 'Gene', '100037293', (17, 21))	('Co-expression', 'Var', (0, 13))	('Tim-3', 'Gene', (26, 31))
177465	32081834	The enrichment results showed that immune-related pathways were enriched in the high expression group, with a total of 23 pathways statistically significantly enriched (p-value < 0.05, q-value < 0.05).	('immune-related pathways', 'Pathway', (35, 58))	('si', 'Chemical', 'MESH:D012825', (145, 147))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('high', 'Var', (80, 84))
177564	28155664	The grid-search method is also applied to set the regularization parameter C and gamma in the range of C {10-5, 10-4, ..., 109, 1010} and gamma {10-9, 10-8, ..., 102, 103}, respectively.	('C', 'Chemical', 'MESH:D002244', (75, 76))	('C {', 'Var', (103, 106))	('C', 'Chemical', 'MESH:D002244', (103, 104))	('gamma {10-9', 'Var', (138, 149))
177566	28155664	Figure 1 demonstrates the alteration of the mean AUC score by the backward feature elimination.	('C', 'Chemical', 'MESH:D002244', (51, 52))	('alteration', 'Reg', (26, 36))	('AUC score', 'Disease', (49, 58))	('backward feature elimination', 'Var', (66, 94))
177609	27679479	Purified mouse monoclonal antibody M75 selectively recognizing the PG domain of CAIX (Kd ~1.5 nM), was a kind gift from Pavlina Rezacova.	('CAIX', 'Gene', (80, 84))	('antibody', 'cellular_component', 'GO:0019815', ('26', '34'))	('PG domain', 'MPA', (67, 76))	('antibody', 'cellular_component', 'GO:0019814', ('26', '34'))	('antibody', 'molecular_function', 'GO:0003823', ('26', '34'))	('CAIX', 'Gene', '768', (80, 84))	('mouse', 'Species', '10090', (9, 14))	('antibody', 'cellular_component', 'GO:0042571', ('26', '34'))	('M75', 'Var', (35, 38))
177678	27679479	Interestingly, attaching the oligonucleotide to the inhibitors improved their binding affinity several-fold (see Supplementary Data for more details on probe synthesis and testing).	('binding', 'Interaction', (78, 85))	('improved', 'PosReg', (63, 71))	('attaching', 'Var', (15, 24))	('synthesis', 'biological_process', 'GO:0009058', ('158', '167'))	('binding', 'molecular_function', 'GO:0005488', ('78', '85'))	('men', 'Species', '9606', (119, 122))	('oligonucleotide', 'Chemical', 'MESH:D009841', (29, 44))
177729	27679479	The binding of the probe to both enzymes together with capturing of their tagged variants onto neutravidin thus enabled us to rapidly develop screening assay for both targets, but such promiscuity also may have compromised the selectivity of the PSMA detection in biological matrices.	('selectivity', 'MPA', (227, 238))	('PSMA', 'Gene', (246, 250))	('binding', 'Interaction', (4, 11))	('enabled', 'Reg', (112, 119))	('binding', 'molecular_function', 'GO:0005488', ('4', '11'))	('PSMA', 'Gene', '2346', (246, 250))	('PSMA', 'molecular_function', 'GO:0043275', ('246', '250'))	('develop', 'PosReg', (134, 141))	('compromised', 'NegReg', (211, 222))	('variants', 'Var', (81, 89))	('screening assay', 'MPA', (142, 157))
177739	27679479	This result reflects relatively low endogenous expression of CAIX by HT-29 cells, higher non-selective binding of probe after CAIX capture from lysate versus capture from buffer or serum and bivalence of the CAIX probe, which leads to a larger change in Cq with increasing inhibitor concentration than would be observed with a monovalent probe.	('low', 'NegReg', (32, 35))	('non-selective', 'MPA', (89, 102))	('his', 'Chemical', 'MESH:D006639', (1, 4))	('CAIX', 'Gene', (208, 212))	('bivalence', 'Var', (191, 200))	('HT-29 cell', 'CellLine', 'CVCL:0320', (69, 79))	('higher', 'PosReg', (82, 88))	('binding', 'molecular_function', 'GO:0005488', ('103', '110'))	('CAIX', 'Gene', (61, 65))	('inhibitor concentration', 'MPA', (273, 296))	('CAIX', 'Gene', (126, 130))	('change', 'Reg', (244, 250))	('CAIX', 'Gene', '768', (208, 212))	('CAIX', 'Gene', '768', (61, 65))	('CAIX', 'Gene', '768', (126, 130))	('endogenous', 'MPA', (36, 46))
177777	30660076	Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma1 Bi-allelic inactivation of the VHL gene on chromosome 3p is the characteristic feature in most clear cell renal cell carcinomas (ccRCC).	('BAP1', 'Gene', (43, 47))	('PBRM1', 'Gene', (36, 41))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (238, 259))	('Renal Cell Carcinoma1', 'Phenotype', 'HP:0005584', (110, 131))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (227, 259))	('carcinomas', 'Phenotype', 'HP:0030731', (249, 259))	('SETD2', 'Gene', '29072', (52, 57))	('clear cell renal cell carcinomas', 'Disease', (227, 259))	('VHL', 'Gene', (163, 166))	('Clear Cell Renal Cell Carcinoma1', 'Phenotype', 'HP:0006770', (99, 131))	('Clear Cell Renal Cell Carcinoma1', 'Disease', (99, 131))	('RCC', 'Disease', (263, 266))	('BAP1', 'Gene', '8314', (43, 47))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (227, 259))	('Clear Cell Renal Cell Carcinoma1', 'Disease', 'MESH:C538614', (99, 131))	('PBRM1', 'Gene', '55193', (36, 41))	('chromosome', 'cellular_component', 'GO:0005694', ('175', '185'))	('Bi-allelic inactivation', 'Var', (132, 155))	('RCC', 'Disease', 'MESH:C538614', (263, 266))	('SETD2', 'Gene', (52, 57))
177778	30660076	Frequent gene alterations were also identified in SETD2, BAP1 and PBRM1, all of which are situated on chromosome 3p and encode histone/chromatin regulators.	('alterations', 'Var', (14, 25))	('SETD2', 'Gene', '29072', (50, 55))	('SETD2', 'Gene', (50, 55))	('PBRM1', 'Gene', (66, 71))	('chromosome', 'cellular_component', 'GO:0005694', ('102', '112'))	('chromatin', 'cellular_component', 'GO:0000785', ('135', '144'))	('BAP1', 'Gene', (57, 61))
177781	30660076	In ccRCC loss of nuclear PBRM1 (68%), BAP1 (40%) and H3K36me3 (47%) expression was significantly correlated with each other, advanced tumor stage, poor tumor differentiation (P < .0001 each), and necrosis (P < .005) Targeted next generation sequencing of 83 ccRCC samples demonstrated a significant association of genetic mutations in PBRM1, BAP1, and SETD2 with absence of PBRM1, BAP1, and HEK36me3 protein expression (P < .05, each).	('necrosis', 'biological_process', 'GO:0070265', ('196', '204'))	('RCC', 'Disease', (5, 8))	('RCC', 'Disease', 'MESH:C538614', (260, 263))	('necrosis', 'biological_process', 'GO:0019835', ('196', '204'))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('necrosis', 'biological_process', 'GO:0001906', ('196', '204'))	('genetic mutations', 'Var', (314, 331))	('BAP1', 'Gene', (381, 385))	('BAP1', 'Gene', (342, 346))	('necrosis', 'Disease', 'MESH:D009336', (196, 204))	('PBRM1', 'Gene', (335, 340))	('SETD2', 'Gene', (352, 357))	('absence', 'NegReg', (363, 370))	('PBRM1', 'Gene', (374, 379))	('tumor', 'Disease', (152, 157))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('HEK36', 'CellLine', 'CVCL:2658', (391, 396))	('protein', 'cellular_component', 'GO:0003675', ('400', '407'))	('necrosis', 'Disease', (196, 204))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('SETD2', 'Gene', '29072', (352, 357))	('loss', 'NegReg', (9, 13))	('necrosis', 'biological_process', 'GO:0008219', ('196', '204'))	('tumor', 'Disease', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('HEK36me3', 'MPA', (391, 399))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('RCC', 'Disease', (260, 263))	('necrosis', 'biological_process', 'GO:0008220', ('196', '204'))
177783	30660076	Bi-allelic inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) due to chromosome 3p deletion and gene mutation is a hallmark of clear cell RCC (ccRCC), the most common subtype of RCC.	('von Hippel-Lindau', 'Gene', '7428', (53, 70))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor suppressor', 'biological_process', 'GO:0051726', ('31', '47'))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('RCC', 'Disease', (193, 196))	('Bi-allelic inactivation', 'Var', (0, 23))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('tumor', 'Disease', (31, 36))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('RCC', 'Disease', (160, 163))	('deletion', 'Var', (98, 106))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('RCC', 'Disease', (153, 156))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('31', '47'))	('von Hippel-Lindau', 'Gene', (53, 70))	('gene mutation', 'Var', (111, 124))
177784	30660076	Despite its prominent role as multi-adaptor protein that interacts with more than 30 different binding partners involved in many oncogenic processes, functional inactivation of pVHL is not sufficient for tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('inactivation', 'Var', (161, 173))	('interacts', 'Interaction', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (204, 209))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))	('pVHL', 'Gene', (177, 181))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))
177785	30660076	Recent data suggest that additional genetic and epigenetic events in driver genes act cooperatively with a loss of pVHL function to promote ccRCC progression.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('pVHL', 'Gene', (115, 119))	('epigenetic', 'Var', (48, 58))	('promote', 'PosReg', (132, 139))
177789	30660076	Mutations in PBRM1 have been detected in 40% of ccRCC, whereas 12 and 19% have sequence alterations in BAP1 and SETD2, respectively.	('SETD2', 'Gene', '29072', (112, 117))	('PBRM1', 'Gene', (13, 18))	('BAP1', 'Gene', (103, 107))	('SETD2', 'Gene', (112, 117))	('detected', 'Reg', (29, 37))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('Mutations', 'Var', (0, 9))
177790	30660076	All three proteins are involved in cellular pathways related to tumorigenesis and the high frequency of mutations in their genes support their role as tumor suppressors in ccRCC.	('mutations', 'Var', (104, 113))	('tumor', 'Disease', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('RCC', 'Disease', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('involved', 'Reg', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
177791	30660076	Inactivation of PBRM1 has been shown to promote ccRCC cancer cell proliferation and migration as well as to enhance the HIF-response.	('promote', 'PosReg', (40, 47))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('migration', 'CPA', (84, 93))	('enhance', 'PosReg', (108, 115))	('cancer', 'Disease', (54, 60))	('RCC', 'Disease', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cell proliferation', 'biological_process', 'GO:0008283', ('61', '79'))	('Inactivation', 'Var', (0, 12))	('PBRM1', 'Gene', (16, 21))	('HIF-response', 'CPA', (120, 132))
177793	30660076	Mice deficient for either VHL or VHL together with one allele of BAP1 developed multiple lesions spanning from benign cysts to cystic and solid ccRCC suggesting a tumor suppressive cooperation between BAP1 and pVHL.	('benign cysts', 'Disease', (111, 123))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('cystic', 'Disease', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('BAP1', 'Gene', (65, 69))	('developed', 'Reg', (70, 79))	('tumor', 'Disease', (163, 168))	('Mice', 'Species', '10090', (0, 4))	('deficient', 'Var', (5, 14))
177794	30660076	Notably, a cooperative function was also reported for BAP1 and PBRM1 by demonstrating that combined loss of BAP1 and PBRM1 drive ccRCC in mice.	('loss', 'Var', (100, 104))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (131, 134))	('mice', 'Species', '10090', (138, 142))	('BAP1', 'Gene', (108, 112))	('PBRM1', 'Gene', (117, 122))
177796	30660076	Finally, SETD2 knockdown in renal primary tubular epithelial cells led to bypass the senescence barrier, facilitating a malignant transformation toward ccRCC.	('SETD2', 'Gene', (9, 14))	('facilitating', 'PosReg', (105, 117))	('knockdown', 'Var', (15, 24))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('senescence', 'biological_process', 'GO:0010149', ('85', '95'))	('RCC', 'Disease', (154, 157))	('SETD2', 'Gene', '29072', (9, 14))	('malignant transformation', 'CPA', (120, 144))
177800	30660076	To analyze the expression of PBRM1, BAP1 and H3K36me3 in RCC, two tissue microarrays (TMA) containing 721 RCC and 44 normal kidney tissue (one punch per sample) were constructed as described.	('H3K36me3', 'Var', (45, 53))	('TMA', 'Chemical', '-', (86, 89))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('RCC', 'Disease', (106, 109))	('BAP1', 'Gene', (36, 40))	('PBRM1', 'Gene', (29, 34))	('RCC', 'Disease', 'MESH:C538614', (106, 109))
177819	30660076	Nuclear and cytoplasmic BAP1 positivity was seen in most of the RCC cell lines including 769-P known to be BAP1 mutated but still expresses the protein.	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('BAP1', 'Gene', (107, 111))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))	('mutated', 'Var', (112, 119))
177820	30660076	Although SETD2 mutations have been reported for A-498, A-704, and Caki-1, all RCC cell lines were SETD2 positive.	('SETD2', 'Gene', (9, 14))	('SETD2', 'Gene', '29072', (98, 103))	('mutations', 'Var', (15, 24))	('SETD2', 'Gene', (98, 103))	('RCC', 'Disease', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('SETD2', 'Gene', '29072', (9, 14))
177822	30660076	H3K36me3 was absent in SETD2 mutated A-498 and A-704 but not in Caki-1 suggesting different effects of SETD2 mutations on SETD2 function in these cell lines.	('SETD2', 'Gene', '29072', (23, 28))	('SETD2', 'Gene', (23, 28))	('SETD2', 'Gene', '29072', (122, 127))	('H3K36me3', 'Protein', (0, 8))	('A-498', 'Var', (37, 42))	('SETD2', 'Gene', (122, 127))	('SETD2', 'Gene', '29072', (103, 108))	('mutated A-498', 'Var', (29, 42))	('SETD2', 'Gene', (103, 108))	('absent', 'NegReg', (13, 19))	('A-704', 'Var', (47, 52))
177824	30660076	Based on these results we decided to use H3K36me3-specific antibody as surrogate marker for SETD2 activity for TMA analysis.	('SETD2', 'Gene', '29072', (92, 97))	('antibody', 'cellular_component', 'GO:0019815', ('59', '67'))	('antibody', 'cellular_component', 'GO:0019814', ('59', '67'))	('SETD2', 'Gene', (92, 97))	('antibody', 'molecular_function', 'GO:0003823', ('59', '67'))	('H3K36me3-specific', 'Var', (41, 58))	('antibody', 'cellular_component', 'GO:0042571', ('59', '67'))	('TMA', 'Chemical', '-', (111, 114))
177827	30660076	Weak staining intensity may be caused by mutations and chromosomal loss of 3p, which may influence protein expression of PBRM1, BAP1, and H3K36me3, but also by the age of paraffin blocks, tissue fixation, and IHC detection protocols, making it difficult to distinguish between genomic driven and artificial reduction of protein expression.	('mutations', 'Var', (41, 50))	('protein', 'cellular_component', 'GO:0003675', ('320', '327'))	('caused', 'Reg', (31, 37))	('influence', 'Reg', (89, 98))	('BAP1', 'Gene', (128, 132))	('loss', 'NegReg', (67, 71))	('PBRM1', 'Gene', (121, 126))	('H3K36me3', 'Protein', (138, 146))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('protein expression', 'MPA', (99, 117))	('paraffin', 'Chemical', 'MESH:D010232', (171, 179))
177830	30660076	Expression frequencies of PBRM1, BAP1 and H3K36me3 in different RCC subtypes are listed in Table 1.	('PBRM1', 'Gene', (26, 31))	('H3K36me3', 'Var', (42, 50))	('BAP1', 'Gene', (33, 37))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))
177836	30660076	By linking our TMA IHC data to pathological parameters we found that loss of BAP1, H3K36me3 and PBRM1 was highly associated with late tumor stage as well as high nuclear differentiation grade (P < .0001, each; Table 2).	('TMA', 'Chemical', '-', (15, 18))	('late tumor', 'Disease', 'MESH:D009369', (129, 139))	('loss', 'Var', (69, 73))	('high nuclear differentiation grade', 'CPA', (157, 191))	('H3K36me3', 'Protein', (83, 91))	('PBRM1', 'Gene', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('late tumor', 'Disease', (129, 139))	('BAP1', 'Gene', (77, 81))	('associated', 'Reg', (113, 123))
177839	30660076	Also, loss of PBRM1, H3K36me3, and BAP1 expression was significantly associated with presence of necrosis and, excepting H3K36me3, a high density of tumor infiltrating lymphocytes (Table 3).	('expression', 'MPA', (40, 50))	('loss', 'NegReg', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('PBRM1', 'Gene', (14, 19))	('necrosis', 'Disease', (97, 105))	('H3K36me3', 'Var', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('necrosis', 'biological_process', 'GO:0008219', ('97', '105'))	('necrosis', 'biological_process', 'GO:0070265', ('97', '105'))	('necrosis', 'biological_process', 'GO:0019835', ('97', '105'))	('tumor', 'Disease', (149, 154))	('necrosis', 'Disease', 'MESH:D009336', (97, 105))	('BAP1', 'Gene', (35, 39))	('necrosis', 'biological_process', 'GO:0001906', ('97', '105'))	('necrosis', 'biological_process', 'GO:0008220', ('97', '105'))
177845	30660076	Seventeen of 83 (20%) ccRCC had PBRM1 mutations and 11 tumors had BAP1 and SETD2 mutations (13%, each).	('RCC', 'Disease', (24, 27))	('PBRM1', 'Gene', (32, 37))	('SETD2', 'Gene', '29072', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('SETD2', 'Gene', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('mutations', 'Var', (38, 47))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
177846	30660076	In 4 ccRCC (5%) both PBRM1 and BAP1 were affected, 2 tumors had mutations in PBRM1 and SETD2 (2%), and 1 tumor in BAP1 and SETD2 (1%).	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('SETD2', 'Gene', (123, 128))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('SETD2', 'Gene', '29072', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutations', 'Var', (64, 73))	('SETD2', 'Gene', (87, 92))	('tumor', 'Disease', (105, 110))	('tumors', 'Disease', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('SETD2', 'Gene', '29072', (87, 92))	('RCC', 'Disease', (7, 10))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('PBRM1', 'Gene', (77, 82))	('PBRM1', 'Gene', (21, 26))	('affected', 'Reg', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (53, 58))	('RCC', 'Disease', 'MESH:C538614', (7, 10))
177848	30660076	Sequence alterations that highly likely lead to truncation of the proteins (frameshift, nonsense, splice site) were seen in 15 of 17 (88%; PBRM1), 6 of 11 (56%; BAP1), and 9 of 11 (82%; SETD2) mutated ccRCC.	('SETD2', 'Gene', (186, 191))	('lead to', 'Reg', (40, 47))	('proteins', 'Protein', (66, 74))	('mutated', 'Var', (193, 200))	('alterations', 'Var', (9, 20))	('truncation', 'MPA', (48, 58))	('RCC', 'Disease', 'MESH:C538614', (203, 206))	('RCC', 'Disease', (203, 206))	('SETD2', 'Gene', '29072', (186, 191))
177850	30660076	4, PBRM1, BAP1, and SETD2 mutations correlated with loss of PBRM1, BAP1 expression and H3K36me3 methylation.	('loss', 'NegReg', (52, 56))	('PBRM1', 'Gene', (60, 65))	('BAP1', 'Gene', (10, 14))	('PBRM1', 'Gene', (3, 8))	('SETD2', 'Gene', '29072', (20, 25))	('expression', 'MPA', (72, 82))	('mutations', 'Var', (26, 35))	('SETD2', 'Gene', (20, 25))	('methylation', 'biological_process', 'GO:0032259', ('96', '107'))	('H3K36me3', 'Protein', (87, 95))	('BAP1', 'Gene', (67, 71))
177861	30660076	Loss of expression of the three proteins was highest in ccRCC with about 70% for PBRM1, 40% for BAP1, and 50% for H3K36me3.	('PBRM1', 'Gene', (81, 86))	('BAP1', 'Gene', (96, 100))	('Loss', 'NegReg', (0, 4))	('RCC', 'Disease', (58, 61))	('H3K36me3', 'Var', (114, 122))	('expression', 'MPA', (8, 18))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
177863	30660076	In pRCC, in which 5-10% of the tumors have also PBRM1, SETD2, and BAP1 mutations, approximately 40% were PBRM1 negative in both main subtypes type 1 and type 2.	('pRCC', 'Gene', '5546', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('PBRM1', 'Gene', (48, 53))	('pRCC', 'Gene', (3, 7))	('BAP1', 'Gene', (66, 70))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('mutations', 'Var', (71, 80))	('SETD2', 'Gene', '29072', (55, 60))	('SETD2', 'Gene', (55, 60))
177867	30660076	Mutations in PBRM1, BAP1 and SETD2 contribute to loss of protein expression.	('SETD2', 'Gene', '29072', (29, 34))	('loss', 'NegReg', (49, 53))	('BAP1', 'Gene', (20, 24))	('SETD2', 'Gene', (29, 34))	('PBRM1', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('protein expression', 'MPA', (57, 75))
177869	30660076	By doubling the number of RCCs from 300 to 600 we could confirm the results from a previous study showing that loss of PBRM1 expression is strongly linked to a more aggressive tumor behavior.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('linked to', 'Reg', (148, 157))	('aggressive tumor', 'Disease', 'MESH:D001523', (165, 181))	('loss', 'Var', (111, 115))	('aggressive tumor', 'Disease', (165, 181))	('PBRM1', 'Gene', (119, 124))	('RCC', 'Disease', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (26, 29))
177872	30660076	Following the classical two-hit hypothesis of tumor suppressor genes, gene inactivation by mechanisms such as truncating mutations occurs mainly in late stage and high grade tumors.	('tumor', 'Disease', (174, 179))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('tumor suppressor', 'biological_process', 'GO:0051726', ('46', '62'))	('gene', 'Var', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('truncating mutations', 'Var', (110, 130))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('46', '62'))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
177873	30660076	The fractions of non-expressing tumors in our tumor cohort was generally higher (40% BAP1, 50% H3K36me3, 70% PBRM1) compared to those described in several previous studies, which ranged between 10-50% for BAP1, 14-34% for SETD2, and 31-70% for PBRM1.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('BAP1', 'Var', (85, 89))	('SETD2', 'Gene', '29072', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('SETD2', 'Gene', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('tumor', 'Disease', (32, 37))	('H3K36me3', 'Var', (95, 103))	('higher', 'PosReg', (73, 79))
177875	30660076	However, regardless of the diverse patient cohorts and strategies used to examine ccRCC, the consistent finding of these studies is that loss of expression of PBRM1, SETD2 and BAP1 is closely linked to tumor progression.	('tumor', 'Disease', (202, 207))	('patient', 'Species', '9606', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('BAP1', 'Gene', (176, 180))	('loss of', 'Var', (137, 144))	('SETD2', 'Gene', '29072', (166, 171))	('PBRM1', 'Gene', (159, 164))	('SETD2', 'Gene', (166, 171))	('linked', 'Reg', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
177876	30660076	Mutations of PBRM1, BAP1 and SETD2 determined in 83 ccRCC revealed their important negative influence on protein expression, but in a considerable fraction of tumors loss or reduction of expression seem to follow mechanisms other than mutations and chromosome 3p loss.	('SETD2', 'Gene', '29072', (29, 34))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('BAP1', 'Gene', (20, 24))	('SETD2', 'Gene', (29, 34))	('PBRM1', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('RCC', 'Disease', (54, 57))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors loss', 'Disease', 'MESH:D009369', (159, 170))	('Mutations', 'Var', (0, 9))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('tumors loss', 'Disease', (159, 170))	('chromosome', 'cellular_component', 'GO:0005694', ('249', '259'))	('reduction', 'NegReg', (174, 183))	('expression', 'MPA', (187, 197))	('protein expression', 'MPA', (105, 123))
177878	30660076	Also, SETD2, BAP1 as well as PBRM1 mutations have been reported in pRCC, which has no chromosome 3p deletions.	('pRCC', 'Gene', (67, 71))	('BAP1', 'Gene', (13, 17))	('reported', 'Reg', (55, 63))	('SETD2', 'Gene', '29072', (6, 11))	('chromosome', 'cellular_component', 'GO:0005694', ('86', '96'))	('SETD2', 'Gene', (6, 11))	('pRCC', 'Gene', '5546', (67, 71))	('PBRM1', 'Gene', (29, 34))	('mutations', 'Var', (35, 44))
177881	30660076	Although gene mutations were significantly associated with loss of protein expression in our ccRCC cohort, BAP1 and H3K36me3 were expressed in a small subset of ccRCC despite BAP1 and SETD2 mutations.	('BAP1', 'Gene', (175, 179))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('H3K36me3', 'Protein', (116, 124))	('RCC', 'Disease', (163, 166))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('mutations', 'Var', (190, 199))	('BAP1', 'Gene', (107, 111))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('RCC', 'Disease', (95, 98))	('SETD2', 'Gene', '29072', (184, 189))	('loss', 'NegReg', (59, 63))	('protein expression', 'MPA', (67, 85))	('mutations', 'Var', (14, 23))	('SETD2', 'Gene', (184, 189))
177882	30660076	It is therefore conceivable that PBRM1, BAP1, and SETD2 mutations identified in ccRCC, as well as in other cancer types, may also exert diverse effects on protein expression and function.	('mutations', 'Var', (56, 65))	('function', 'MPA', (178, 186))	('SETD2', 'Gene', '29072', (50, 55))	('effects', 'Reg', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('SETD2', 'Gene', (50, 55))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('protein expression', 'MPA', (155, 173))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('BAP1', 'Gene', (40, 44))	('cancer', 'Disease', (107, 113))	('PBRM1', 'Gene', (33, 38))
177883	30660076	Inactivation of tumor suppressor genes by genetic or epigenetic events is crucial for tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('epigenetic events', 'Var', (53, 70))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', (86, 91))	('tumor suppressor', 'biological_process', 'GO:0051726', ('16', '32'))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('genetic', 'Var', (42, 49))	('tumor', 'Disease', (16, 21))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('16', '32'))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('Inactivation', 'Var', (0, 12))
177884	30660076	In this context, PBRM1, BAP1, and SETD2 mutation and loss of expression was described to be associated with advanced tumor stage, high grade and patient outcome.	('mutation', 'Var', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('BAP1', 'Gene', (24, 28))	('tumor', 'Disease', (117, 122))	('PBRM1', 'Gene', (17, 22))	('high grade', 'CPA', (130, 140))	('loss of expression', 'NegReg', (53, 71))	('SETD2', 'Gene', '29072', (34, 39))	('patient', 'Species', '9606', (145, 152))	('SETD2', 'Gene', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
177886	30660076	Our study demonstrates a significant association between PBRM1 alterations and a high amount of TIL in ccRCC.	('PBRM1', 'Gene', (57, 62))	('alterations', 'Var', (63, 74))	('TIL', 'Gene', '7096', (96, 99))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('TIL', 'Gene', (96, 99))
177887	30660076	showing an increased clinical benefit of immune checkpoint therapy in ccRCC patients with inactivated PBRM1.	('patients', 'Species', '9606', (76, 84))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('PBRM1', 'Gene', (102, 107))	('inactivated', 'Var', (90, 101))	('benefit', 'PosReg', (30, 37))
177888	30660076	PBRM1 loss-of-function mutations may thus serve as unfavorable prognostic marker but also as favorable predictive marker regarding PD-(L)1 blockade therapy.	('PD-(L)1', 'Gene', '29126', (131, 138))	('PBRM1', 'Gene', (0, 5))	('loss-of-function', 'NegReg', (6, 22))	('mutations', 'Var', (23, 32))	('PD-(L)1', 'Gene', (131, 138))
177892	30660076	In this context, it was recently shown that deletion of VHL together with either BAP1 or PBRM1 drives tumor grade.	('VHL', 'Gene', (56, 59))	('deletion', 'Var', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('drives', 'Reg', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
177893	30660076	Notably, functional inactivation of the four tumor suppressors pVHL, PBRM1, BAP1 and SETD2 affects spindle orientation, spindle assembly, histone modification, nucleosome stabilization and chromatin remodeling, all of which strongly impair chromosomal stability.	('SETD2', 'Gene', '29072', (85, 90))	('pVHL', 'Gene', (63, 67))	('tumor', 'Disease', (45, 50))	('nucleosome', 'MPA', (160, 170))	('spindle', 'cellular_component', 'GO:0005819', ('120', '127'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('189', '209'))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('histone modification', 'biological_process', 'GO:0016570', ('138', '158'))	('affects', 'Reg', (91, 98))	('chromosomal stability', 'CPA', (240, 261))	('spindle orientation', 'CPA', (99, 118))	('inactivation', 'Var', (20, 32))	('histone modification', 'MPA', (138, 158))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('impair', 'NegReg', (233, 239))	('PBRM1', 'Gene', (69, 74))	('spindle assembly', 'CPA', (120, 136))	('nucleosome', 'cellular_component', 'GO:0000786', ('160', '170'))	('spindle orientation', 'biological_process', 'GO:0051294', ('99', '118'))	('chromatin remodeling', 'CPA', (189, 209))	('chromatin', 'cellular_component', 'GO:0000785', ('189', '198'))	('spindle', 'cellular_component', 'GO:0005819', ('99', '106'))	('SETD2', 'Gene', (85, 90))	('BAP1', 'Gene', (76, 80))	('spindle assembly', 'biological_process', 'GO:0051225', ('120', '136'))
177898	30660076	Notably, in five of these subtypes PBRM1, SETD2, and BAP1 mutations play a dominant role as driver genes.	('mutations', 'Var', (58, 67))	('SETD2', 'Gene', '29072', (42, 47))	('PBRM1', 'Gene', (35, 40))	('SETD2', 'Gene', (42, 47))	('BAP1', 'Gene', (53, 57))
177899	30660076	These subtypes were defined i) by mutations in PBRM1 followed by SETD2; ii) by PBRM1 mutations followed by alterations in the PI3K/AKT pathway; iii) by mutations in PBRM1 followed by a driver somatic copy number alteration event; iv) by BAP1 mutations as the single driver event with VHL, and v) by tumors in which at least two of the genes BAP1, SETD2, PBRM1 or PTEN where clonally mutated.	('AKT', 'Gene', '207', (131, 134))	('mutations', 'Var', (152, 161))	('SETD2', 'Gene', (65, 70))	('PI3K', 'molecular_function', 'GO:0016303', ('126', '130'))	('PTEN', 'Gene', '5728', (363, 367))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('SETD2', 'Gene', '29072', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (299, 305))	('BAP1', 'Gene', (341, 345))	('BAP1', 'Gene', (237, 241))	('AKT', 'Gene', (131, 134))	('PBRM1', 'Gene', (165, 170))	('tumors', 'Disease', (299, 305))	('mutations', 'Var', (85, 94))	('SETD2', 'Gene', (347, 352))	('mutations', 'Var', (242, 251))	('tumors', 'Disease', 'MESH:D009369', (299, 305))	('SETD2', 'Gene', '29072', (347, 352))	('PTEN', 'Gene', (363, 367))	('PBRM1', 'Gene', (354, 359))	('mutations', 'Var', (34, 43))
177901	30660076	Given the subclonal diversity and its different impact on patient outcome in ccRCC, it becomes evident why the frequencies and clinical relevance of gene mutations and protein expression of BAP1, SETD2, and PBRM1, let alone their subtyping, differ from each other.	('PBRM1', 'Gene', (207, 212))	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('patient', 'Species', '9606', (58, 65))	('BAP1', 'Gene', (190, 194))	('SETD2', 'Gene', '29072', (196, 201))	('mutations', 'Var', (154, 163))	('SETD2', 'Gene', (196, 201))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
177902	30660076	The different combinations of BAP1, PBRM1 or SETD2 expression changes obtained from our TMA immunostainings support the proposed genetic and clonal evolution features and suggest that the diverse clinical phenotypes of ccRCC may also be identified by protein expression data.	('SETD2', 'Gene', (45, 50))	('TMA', 'Chemical', '-', (88, 91))	('BAP1', 'Gene', (30, 34))	('PBRM1', 'Gene', (36, 41))	('RCC', 'Disease', 'MESH:C538614', (221, 224))	('RCC', 'Disease', (221, 224))	('changes', 'Var', (62, 69))	('SETD2', 'Gene', '29072', (45, 50))	('protein', 'cellular_component', 'GO:0003675', ('251', '258'))
177907	30660076	This is in line with the hypothesis that a strong niche-specific selection of SETD2 mutant subclones induce a limited clonal growth.	('mutant', 'Var', (84, 90))	('clonal growth', 'CPA', (118, 131))	('SETD2', 'Gene', (78, 83))	('SETD2', 'Gene', '29072', (78, 83))
177910	30660076	PBRM1 driven subtypes followed by SETD2, as well as copy number alterations and alterations in the PI3K/AKT pathway were assigned to 69 (16.1%) and 72 (16.8%) tumors, respectively.	('PI3K', 'molecular_function', 'GO:0016303', ('99', '103'))	('AKT', 'Gene', (104, 107))	('copy number alterations', 'Var', (52, 75))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('PBRM1', 'Gene', (0, 5))	('SETD2', 'Gene', '29072', (34, 39))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('SETD2', 'Gene', (34, 39))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('AKT', 'Gene', '207', (104, 107))	('alterations', 'Reg', (80, 91))
177917	28753773	Integration of Recurrent Somatic Mutations with Clinical Outcomes: A Pooled Analysis of 1049 Patients with Clear Cell Renal Cell Carcinoma Analyses of associations between clinicopathologic outcomes and recurrent somatic mutations in clear cell renal cell carcinoma (ccRCC) have been limited to individual cohorts.	('RCC', 'Disease', (269, 272))	('Patients', 'Species', '9606', (93, 101))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (107, 138))	('mutations', 'Var', (221, 230))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (240, 265))	('Carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('cell renal cell carcinoma', 'Disease', (240, 265))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (245, 265))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (234, 265))	('Clear Cell Renal Cell Carcinoma', 'Disease', (107, 138))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (107, 138))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (118, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('ccRCC', 'Phenotype', 'HP:0006770', (267, 272))	('RCC', 'Phenotype', 'HP:0005584', (269, 272))	('RCC', 'Disease', 'MESH:C538614', (269, 272))
177918	28753773	To define clinicopathologic associations between specific mutations and ccRCC disease characteristics.	('mutations', 'Var', (58, 67))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))
177920	28753773	Analysis of gene mutations for associations with maximal tumor size (linear regression) and pathologic stage (logistic regression).	('associations', 'Interaction', (31, 43))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('maximal', 'Disease', (49, 56))	('tumor', 'Disease', (57, 62))	('mutations', 'Var', (17, 26))
177923	28753773	Association with tumor size was found for mutations in BAP1 (q = 0.013).	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (17, 22))	('BAP1', 'Gene', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('Association', 'Interaction', (0, 11))	('mutations', 'Var', (42, 51))	('BAP1', 'Gene', '8314', (55, 59))
177924	28753773	Mutations in BAP1 (q = 0.004) and TP53 (q = 0.001) were associated with decreased CSS in a multivariable model; only TP53 (q = 0.005) remained significant when SSIGN score was included.	('BAP1', 'Gene', (13, 17))	('TP53', 'Gene', (34, 38))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('CSS', 'Disease', (82, 85))	('decreased', 'NegReg', (72, 81))	('Mutations', 'Var', (0, 9))	('CSS', 'Chemical', '-', (82, 85))	('BAP1', 'Gene', '8314', (13, 17))	('TP53', 'Gene', '7157', (34, 38))
177925	28753773	SETD2 mutations (q = 0.047) were associated with decreased RFS in multivariable models, including models with SSIGN score.	('SETD2', 'Gene', '29072', (0, 5))	('RFS', 'Disease', (59, 62))	('decreased', 'NegReg', (49, 58))	('SETD2', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
177927	28753773	This included the more commonly mutated BAP1 and SETD2 and the less frequently mutated TP53.	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('mutated', 'Var', (32, 39))	('BAP1', 'Gene', '8314', (40, 44))	('SETD2', 'Gene', '29072', (49, 54))	('BAP1', 'Gene', (40, 44))	('SETD2', 'Gene', (49, 54))
177928	28753773	After adjustment for clinical confounders, mutations of TP53 and SETD2 were associated with decreased CSS and RFS, respectively.	('CSS', 'CPA', (102, 105))	('RFS', 'CPA', (110, 113))	('TP53', 'Gene', '7157', (56, 60))	('SETD2', 'Gene', '29072', (65, 70))	('mutations', 'Var', (43, 52))	('TP53', 'Gene', (56, 60))	('SETD2', 'Gene', (65, 70))	('CSS', 'Chemical', '-', (102, 105))	('decreased', 'NegReg', (92, 101))
177929	28753773	Using rigorous statistical methods, this study affirmed that certain mutations in clear cell renal cell carcinomamay portend inferior survival and an increased risk of recurrence.	('mutations', 'Var', (69, 78))	('clear cell renal cell carcinomamay', 'Disease', 'MESH:C538614', (82, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (93, 113))	('clear cell renal cell carcinomamay', 'Disease', (82, 116))	('survival', 'CPA', (134, 142))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (82, 113))	('renal cell carcinomamay', 'Phenotype', 'HP:0005584', (93, 116))	('clear cell renal cell carcinomamay', 'Phenotype', 'HP:0006770', (82, 116))	('inferior', 'NegReg', (125, 133))
177936	28753773	In this study, we performed comprehensive analyses of pooled publicly available cohorts, along with our institutional cohort, to identify associations between relevant mutations in ccRCC and clinicopathologic outcomes while controlling for known prognostic variables.	('RCC', 'Phenotype', 'HP:0005584', (183, 186))	('associations', 'Interaction', (138, 150))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('RCC', 'Disease', (183, 186))	('ccRCC', 'Phenotype', 'HP:0006770', (181, 186))	('mutations', 'Var', (168, 177))
177949	28753773	Linear regression analysis was used to assess the association between maximum pathologic tumor diameter and genetic mutations.	('genetic mutations', 'Var', (108, 125))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))
177960	28753773	In analyses adjusted only for cohort, mutations in BAP1 (median: 8 vs 5.2 cm; p = 0.001) and PTEN (median: 8 vs 5.9 cm; p = 0.026) were significantly associated with larger median tumor diameter.	('associated', 'Reg', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('PTEN', 'Gene', (93, 97))	('PTEN', 'Gene', '5728', (93, 97))	('BAP1', 'Gene', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('mutations', 'Var', (38, 47))	('BAP1', 'Gene', '8314', (51, 55))
177961	28753773	After adjustment for multiple comparisons, mutations in BAP1 remained significantly associated with larger tumor size (q = 0.013) (Supplementary Table 1).	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('BAP1', 'Gene', '8314', (56, 60))	('mutations', 'Var', (43, 52))	('BAP1', 'Gene', (56, 60))	('associated', 'Reg', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
177964	28753773	Of note, mutations in SETD2, PTEN, and BAP1 did show a trend toward significance for association with higher AJCC stages when comparing stage I/II versus stage III versus stage IV, with q values of 0.071, 0.084, and 0.088, respectively.	('SETD2', 'Gene', '29072', (22, 27))	('PTEN', 'Gene', (29, 33))	('mutations', 'Var', (9, 18))	('SETD2', 'Gene', (22, 27))	('PTEN', 'Gene', '5728', (29, 33))	('higher AJCC stages', 'Disease', (102, 120))	('BAP1', 'Gene', '8314', (39, 43))	('association', 'Interaction', (85, 96))	('BAP1', 'Gene', (39, 43))
177966	28753773	On analyses adjusted only for cohort, we found that mutations in BAP1 (n = 1049 for analysis; hazard ratio [HR]: 2.10; 95% confidence interval [CI]: 1.44-3.04; q < 0.001) and TP53 (n = 784 for analysis; HR: 2.63; 95% CI: 1.36-5.08; q = 0.028) were significantly associated with increased risk of death from cancer after adjustment for multiple comparisons using competing risks regression (Fig.	('mutations', 'Var', (52, 61))	('cancer', 'Disease', (307, 313))	('cancer', 'Disease', 'MESH:D009369', (307, 313))	('TP53', 'Gene', (175, 179))	('BAP1', 'Gene', '8314', (65, 69))	('associated', 'Reg', (262, 272))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('BAP1', 'Gene', (65, 69))	('death', 'Disease', 'MESH:D003643', (296, 301))	('death', 'Disease', (296, 301))	('TP53', 'Gene', '7157', (175, 179))
177968	28753773	In the first model, which was adjusted for the base set of variables as well as cohort (n = 733 for analysis), we found both BAP1 (q = 0.004) and TP53 (q = 0.001) mutations to be significantly associated with decreased CSS (Supplementary Table 5).	('TP53', 'Gene', '7157', (146, 150))	('mutations', 'Var', (163, 172))	('BAP1', 'Gene', '8314', (125, 129))	('TP53', 'Gene', (146, 150))	('BAP1', 'Gene', (125, 129))	('CSS', 'Disease', (219, 222))	('CSS', 'Chemical', '-', (219, 222))	('decreased', 'NegReg', (209, 218))
177969	28753773	In the second model, which was adjusted for the SSIGN set of variables as well as cohort (n = 554 for analysis), we found that only TP53 mutations were significantly associated with decreased CSS (Table 2).	('decreased', 'NegReg', (182, 191))	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('CSS', 'Disease', (192, 195))	('mutations', 'Var', (137, 146))	('CSS', 'Chemical', '-', (192, 195))
177971	28753773	We still found TP53 and BAP1 mutations to be associated with inferior CSS (Table 3).	('CSS', 'Chemical', '-', (70, 73))	('BAP1', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('associated', 'Reg', (45, 55))	('inferior CSS', 'Disease', (61, 73))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('BAP1', 'Gene', '8314', (24, 28))
177973	28753773	On analyses adjusted only for cohort, we found that mutations in SETD2 (HR: 1.89; 95% CI: 1.26-2.83; q = 0.007), KDM5C (HR: 2.02; 95% CI: 1.29-3.18; q = 0.007), TP53 (HR: 3.12; 95% CI: 1.39-7.00; q = 0.017), PTEN (HR: 3.78; 95% CI: 1.94-7.37; q < 0.001), and TSC1 (HR: 4.15; 95% CI: 2.04-8.41; q < 0.001) were significantly associated with increased risk of recurrence (Supplementary Table 6).	('mutations', 'Var', (52, 61))	('TSC1', 'Gene', '7248', (259, 263))	('TP53', 'Gene', (161, 165))	('TSC1', 'Gene', (259, 263))	('PTEN', 'Gene', (208, 212))	('SETD2', 'Gene', '29072', (65, 70))	('KDM5C', 'Gene', (113, 118))	('recurrence', 'Disease', (358, 368))	('associated', 'Reg', (324, 334))	('PTEN', 'Gene', '5728', (208, 212))	('SETD2', 'Gene', (65, 70))	('KDM5C', 'Gene', '8242', (113, 118))	('TP53', 'Gene', '7157', (161, 165))
177979	28753773	We identified several somatic mutations that act as an inflection point in the pathogenesis of ccRCC.	('pathogenesis', 'biological_process', 'GO:0009405', ('79', '91'))	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('mutations', 'Var', (30, 39))
177982	28753773	Previously published studies have reported a more aggressive clinical course and worse prognosis in patients who have ccRCC with BAP1 mutations.	('BAP1', 'Gene', '8314', (129, 133))	('patients', 'Species', '9606', (100, 108))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('mutations', 'Var', (134, 143))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('BAP1', 'Gene', (129, 133))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))
177983	28753773	In this investigation, BAP1 mutations were associated with increased risk of cancer-specific death, but the association did not retain significance on inclusion of the SSIGN score in a multivariable model.	('BAP1', 'Gene', (23, 27))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('BAP1', 'Gene', '8314', (23, 27))	('death', 'Disease', 'MESH:D003643', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('death', 'Disease', (93, 98))	('mutations', 'Var', (28, 37))
177984	28753773	One reason for these outcomes may be the association of BAP1 mutations with larger tumors and with histologic grade 4 disease compared with grades 1-3 (p < 0.001; data not shown).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('BAP1', 'Gene', '8314', (56, 60))	('association', 'Interaction', (41, 52))	('tumors', 'Disease', (83, 89))	('mutations', 'Var', (61, 70))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('BAP1', 'Gene', (56, 60))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
177985	28753773	Both of these pathologic variables are captured in the SSIGN score calculation, and BAP1 mutations may be surrogates for these variables.	('BAP1', 'Gene', (84, 88))	('mutations', 'Var', (89, 98))	('BAP1', 'Gene', '8314', (84, 88))
177986	28753773	Notably, we found no association between BAP1 mutations and decreased RFS, even on univariable analysis with adjustment for cohort site.	('decreased', 'NegReg', (60, 69))	('mutations', 'Var', (46, 55))	('BAP1', 'Gene', (41, 45))	('RFS', 'Disease', (70, 73))	('BAP1', 'Gene', '8314', (41, 45))
177987	28753773	A BAP1 mutation may encourage tumor cell growth, but unlike other mutations (eg, SETD2 and TP53 mutations), it may not facilitate dissemination of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('dissemination', 'CPA', (130, 143))	('TP53', 'Gene', (91, 95))	('SETD2', 'Gene', '29072', (81, 86))	('cell growth', 'biological_process', 'GO:0016049', ('36', '47'))	('SETD2', 'Gene', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('BAP1', 'Gene', '8314', (2, 6))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('mutation', 'Var', (7, 15))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('TP53', 'Gene', '7157', (91, 95))	('tumor', 'Disease', (30, 35))	('BAP1', 'Gene', (2, 6))	('encourage', 'PosReg', (20, 29))
177988	28753773	While generally rare, mutations in TP53 were predictive of several adverse clinical outcomes, including decreased CSS and RFS, in this study.	('CSS', 'Chemical', '-', (114, 117))	('TP53', 'Gene', '7157', (35, 39))	('decreased', 'NegReg', (104, 113))	('CSS', 'CPA', (114, 117))	('TP53', 'Gene', (35, 39))	('mutations', 'Var', (22, 31))	('RFS', 'CPA', (122, 125))
177989	28753773	Strikingly, TP53 mutations maintained their association with increased risk of cancer-specific death even when controlling for the validated SSIGN score.	('death', 'Disease', 'MESH:D003643', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('death', 'Disease', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('TP53', 'Gene', '7157', (12, 16))	('TP53', 'Gene', (12, 16))	('cancer', 'Disease', (79, 85))	('mutations', 'Var', (17, 26))
177990	28753773	Other investigators have reported the enrichment of TP53 mutations in patients with metastatic disease and in the aggressive sarcomatoid variant of ccRCC.	('patients', 'Species', '9606', (70, 78))	('aggressive sarcomatoid', 'Disease', 'MESH:C538614', (114, 136))	('TP53', 'Gene', '7157', (52, 56))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('TP53', 'Gene', (52, 56))	('RCC', 'Disease', (150, 153))	('aggressive sarcomatoid', 'Disease', (114, 136))	('mutations', 'Var', (57, 66))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('ccRCC', 'Phenotype', 'HP:0006770', (148, 153))	('metastatic disease', 'Disease', (84, 102))
178003	28753773	After adjustment for important clinical confounders, mutations of TP53 and SETD2 were associated with decreased CSS and RFS, respectively.	('SETD2', 'Gene', '29072', (75, 80))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('SETD2', 'Gene', (75, 80))	('mutations', 'Var', (53, 62))	('CSS', 'CPA', (112, 115))	('CSS', 'Chemical', '-', (112, 115))	('RFS', 'CPA', (120, 123))	('decreased', 'NegReg', (102, 111))
178027	27886176	Further mechanism study reveals that lncARSR interacts with Yes-associated protein (YAP) to block its phosphorylation by LATS1, facilitating YAP nuclear translocation.	('phosphorylation', 'MPA', (102, 117))	('lncARSR', 'Var', (37, 44))	('YAP', 'Gene', (141, 144))	('YAP', 'Gene', '10413', (84, 87))	('facilitating', 'Reg', (128, 140))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('phosphorylation', 'biological_process', 'GO:0016310', ('102', '117'))	('block', 'NegReg', (92, 97))	('YAP', 'Gene', (84, 87))	('LATS1', 'Gene', (121, 126))	('LATS1', 'Gene', '9113', (121, 126))	('YAP', 'Gene', '10413', (141, 144))
178029	27886176	Clinical investigation also confirms the correlation between lncARSR and YAP, and demonstrates the value of combining lncARSR and YAP to improve the prognostic accuracy for RCC patients.	('YAP', 'Gene', (130, 133))	('YAP', 'Gene', '10413', (73, 76))	('RCC', 'Disease', (173, 176))	('Clinical', 'Species', '191496', (0, 8))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('improve', 'PosReg', (137, 144))	('YAP', 'Gene', (73, 76))	('patients', 'Species', '9606', (177, 185))	('YAP', 'Gene', '10413', (130, 133))	('lncARSR', 'Var', (118, 125))
178034	27886176	1b, lncARSR levels were upregulated in sorted CD105+ or CD133+ primary ccRCC cells.	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('CD133', 'Gene', (56, 61))	('CD133', 'Gene', '8842', (56, 61))	('upregulated', 'PosReg', (24, 35))	('CD105+', 'Var', (46, 52))	('lncARSR levels', 'MPA', (4, 18))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
178041	27886176	Correlation regression analysis revealed that high lncARSR expression in ccRCC tissues was associated with aggressive clinical features (Supplementary Tables 2 and 3).	('high', 'Var', (46, 50))	('clinical', 'Species', '191496', (118, 126))	('lncARSR expression', 'MPA', (51, 69))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('aggressive', 'Disease', (107, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))	('ccRCC', 'Disease', (73, 78))	('associated', 'Reg', (91, 101))
178043	27886176	Multivariate analysis manifested that high lncARSR level was an independent predictor for poor prognosis of ccRCC patients (Supplementary Tables 4-7).	('lncARSR level', 'MPA', (43, 56))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('ccRCC', 'Disease', (108, 113))	('high', 'Var', (38, 42))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('patients', 'Species', '9606', (114, 122))
178045	27886176	Flow cytometry analysis showed that knockdown of lncARSR decreased the proportion of CD105+ or CD133+ cells (Fig.	('knockdown', 'Var', (36, 45))	('lncARSR', 'Gene', (49, 56))	('CD105+', 'MPA', (85, 91))	('CD133', 'Gene', (95, 100))	('CD133', 'Gene', '8842', (95, 100))	('decreased', 'NegReg', (57, 66))
178046	27886176	2b,c), indicating that knockdown of lncARSR attenuated the self-renewal capacity of renal T-ICs.	('renal T-', 'Phenotype', 'HP:0030409', (84, 92))	('renal T-ICs', 'Disease', 'MESH:D007674', (84, 95))	('lncARSR', 'Gene', (36, 43))	('knockdown', 'Var', (23, 32))	('renal T-ICs', 'Phenotype', 'HP:0030409', (84, 95))	('attenuated', 'NegReg', (44, 54))	('renal T-ICs', 'Disease', (84, 95))
178049	27886176	Moreover, RCC cells derived from the shlncARSR-xenografts showed impaired ability to form secondary tumours by serial passage compared to control xenografts (tumour incidence: shGFP, 4/4; shlncARSR-1, 0/4; shlncARSR-2, 0/4) (Supplementary Fig.	('tumours', 'Disease', (100, 107))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('tumour', 'Disease', (158, 164))	('shlncARSR-xenografts', 'Var', (37, 57))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('tumours', 'Disease', 'MESH:D009369', (100, 107))	('impaired', 'NegReg', (65, 73))	('RCC', 'Phenotype', 'HP:0005584', (10, 13))	('tumour', 'Disease', (100, 106))
178050	27886176	2d), indicating that interference of lncARSR impaired the tumour formation ability of renal T-ICs.	('renal T-ICs', 'Phenotype', 'HP:0030409', (86, 97))	('lncARSR', 'Var', (37, 44))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('renal T-ICs', 'Disease', (86, 97))	('tumour', 'Disease', (58, 64))	('renal T-ICs', 'Disease', 'MESH:D007674', (86, 97))	('renal T-', 'Phenotype', 'HP:0030409', (86, 94))	('impaired', 'NegReg', (45, 53))	('formation', 'biological_process', 'GO:0009058', ('65', '74'))
178053	27886176	lncARSR-overexpressing cells harboured expanded proportion of CD105+ or CD133+ cells (Fig.	('CD105+', 'Var', (62, 68))	('CD133', 'Gene', (72, 77))	('CD133', 'Gene', '8842', (72, 77))
178058	27886176	Consistently, lncARSR co-localized with YAP in the cytoplasm by RNA fluorescence in situ hybridization (RNA FISH) and immunofluorescence (Fig.	('YAP', 'Gene', '10413', (40, 43))	('cytoplasm', 'cellular_component', 'GO:0005737', ('51', '60'))	('RNA', 'cellular_component', 'GO:0005562', ('104', '107'))	('YAP', 'Gene', (40, 43))	('lncARSR', 'Var', (14, 21))	('RNA', 'cellular_component', 'GO:0005562', ('64', '67'))
178070	27886176	While knockdown of YAP eliminated the discrepant T-IC properties triggered by lncARSR overexpression (Fig.	('T-IC properties', 'MPA', (49, 64))	('eliminated', 'NegReg', (23, 33))	('YAP', 'Gene', '10413', (19, 22))	('YAP', 'Gene', (19, 22))	('knockdown', 'Var', (6, 15))
178074	27886176	To determine how lncARSR regulated YAP activity, we constructed truncated YAP mutants to unravel its binding sites with lncARSR.	('YAP', 'Gene', (35, 38))	('YAP', 'Gene', '10413', (74, 77))	('mutants', 'Var', (78, 85))	('binding', 'molecular_function', 'GO:0005488', ('101', '108'))	('YAP', 'Gene', '10413', (35, 38))	('YAP', 'Gene', (74, 77))
178078	27886176	Immunoprecipitation assay showed that lncARSR knockdown facilitated the interaction between LATS1 and YAP in RCC spheres (Fig.	('facilitated', 'PosReg', (56, 67))	('LATS1', 'Gene', (92, 97))	('knockdown', 'Var', (46, 55))	('interaction', 'Interaction', (72, 83))	('LATS1', 'Gene', '9113', (92, 97))	('YAP', 'Gene', '10413', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('lncARSR', 'Gene', (38, 45))	('YAP', 'Gene', (102, 105))
178080	27886176	As a result, YAP phosphorylation was increased by lncARSR knockdown and suppressed on overexpression of lncARSR or its 5'-segment (Supplementary Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('17', '32'))	('lncARSR', 'Gene', (50, 57))	('YAP', 'Gene', '10413', (13, 16))	('increased', 'PosReg', (37, 46))	('suppressed', 'NegReg', (72, 82))	('YAP', 'Gene', (13, 16))	('knockdown', 'Var', (58, 67))
178081	27886176	Furthermore, in vitro kinase assay showed that lncARSR or its 5'-segment could protect YAP from phosphorylation by purified active LATS1 (Fig.	('LATS1', 'Gene', '9113', (131, 136))	('YAP', 'Gene', (87, 90))	('lncARSR', 'Var', (47, 54))	('phosphorylation', 'MPA', (96, 111))	('phosphorylation', 'biological_process', 'GO:0016310', ('96', '111'))	('YAP', 'Gene', '10413', (87, 90))	('LATS1', 'Gene', (131, 136))
178089	27886176	While lncARSR levels were enhanced by introducing YAP-5SA but not YAP-5SADeltaC, a YAP mutant lacking transactivation domain (Fig.	('YAP', 'Gene', '10413', (83, 86))	('enhanced', 'PosReg', (26, 34))	('YAP-5SA', 'Gene', (66, 73))	('YAP', 'Gene', '10413', (50, 53))	('YAP', 'Gene', (83, 86))	('YAP', 'Gene', (66, 69))	('YAP-5SA', 'Gene', '10413', (50, 57))	('lacking', 'NegReg', (94, 101))	('mutant', 'Var', (87, 93))	('YAP-5SA', 'Gene', '10413', (66, 73))	('YAP-5SA', 'Gene', (50, 57))	('transactivation', 'biological_process', 'GO:2000144', ('102', '117'))	('YAP', 'Gene', (50, 53))	('transactivation domain', 'MPA', (102, 124))	('YAP', 'Gene', '10413', (66, 69))	('lncARSR levels', 'MPA', (6, 20))
178102	27886176	The ratio of patients with nuclear YAP enrichment was increased in high lncARSR group compared with that in low lncARSR group (Fig.	('YAP', 'Gene', (35, 38))	('patients', 'Species', '9606', (13, 21))	('high lncARSR', 'Var', (67, 79))	('increased', 'PosReg', (54, 63))	('YAP', 'Gene', '10413', (35, 38))
178108	27886176	In this study, we elaborated the critical role of lncARSR in renal T-ICs and the underlying mechanism.	('renal T-ICs', 'Disease', 'MESH:D007674', (61, 72))	('lncARSR', 'Var', (50, 57))	('renal T-', 'Phenotype', 'HP:0030409', (61, 69))	('renal T-ICs', 'Phenotype', 'HP:0030409', (61, 72))	('renal T-ICs', 'Disease', (61, 72))
178109	27886176	We also demonstrated the value of combining lncARSR and YAP to improve the prognostic accuracy for RCC patients.	('YAP', 'Gene', '10413', (56, 59))	('lncARSR', 'Var', (44, 51))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('YAP', 'Gene', (56, 59))	('improve', 'PosReg', (63, 70))	('RCC', 'Disease', (99, 102))	('patients', 'Species', '9606', (103, 111))
178112	27886176	In this study, we found that lncARSR, unlike scaffold lncRNAs, bound specifically to the WW1/2 domain of YAP, thus protecting YAP from interaction and phosphorylation by LATS1.	('LATS1', 'Gene', '9113', (170, 175))	('bound', 'Interaction', (63, 68))	('YAP', 'Gene', (126, 129))	('YAP', 'Gene', '10413', (105, 108))	('lncARSR', 'Var', (29, 36))	('phosphorylation', 'MPA', (151, 166))	('phosphorylation', 'biological_process', 'GO:0016310', ('151', '166'))	('protecting', 'PosReg', (115, 125))	('YAP', 'Gene', (105, 108))	('YAP', 'Gene', '10413', (126, 129))	('interaction', 'Interaction', (135, 146))	('LATS1', 'Gene', (170, 175))
178116	27886176	Herein, our study demonstrates that inhibition of lncARSR impairs YAP activity and attenuates renal T-ICs propagation.	('renal T-ICs', 'Phenotype', 'HP:0030409', (94, 105))	('attenuates renal T-ICs', 'Disease', (83, 105))	('lncARSR', 'Protein', (50, 57))	('inhibition', 'Var', (36, 46))	('YAP', 'Gene', (66, 69))	('impairs', 'NegReg', (58, 65))	('attenuates renal T-ICs', 'Disease', 'MESH:D007674', (83, 105))	('YAP', 'Gene', '10413', (66, 69))	('renal T-', 'Phenotype', 'HP:0030409', (94, 102))
178117	27886176	Thus, lncARSR might serve as a potential therapeutic target for RCCs with aberrant YAP activity in wild-type Hippo signalling.	('YAP', 'Gene', '10413', (83, 86))	('YAP', 'Gene', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('signalling', 'biological_process', 'GO:0023052', ('115', '125'))	('aberrant', 'Var', (74, 82))
178119	27886176	Consistently, our results showed that either high lncARSR expression or nuclear YAP enrichment correlated with poor prognosis of RCC patients.	('YAP', 'Gene', '10413', (80, 83))	('patients', 'Species', '9606', (133, 141))	('RCC', 'Disease', (129, 132))	('high', 'Var', (45, 49))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('YAP', 'Gene', (80, 83))
178120	27886176	Herein, we reported that the combination of high lncARSR expression and nuclear YAP accumulation predicted worse prognosis than either marker alone, suggesting a more accurate combinational marker to evaluate the prognosis of RCC patients.	('high', 'Var', (44, 48))	('YAP', 'Gene', '10413', (80, 83))	('patients', 'Species', '9606', (230, 238))	('YAP', 'Gene', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (226, 229))
178146	27886176	The plasmids YAP luciferase reporter (8xGTIIC-luciferase, #34615), pCMV-flag-YAP-5SA (#27371), pCMV-flag-YAP-5SA/S94A (#33103), pLKO.	('#27371', 'Var', (86, 92))	('YAP', 'Gene', '10413', (105, 108))	('YAP-5SA', 'Gene', '10413', (77, 84))	('YAP', 'Gene', '10413', (77, 80))	('YAP-5SA', 'Gene', '10413', (105, 112))	('S94A', 'Mutation', 'p.S94A', (113, 117))	('YAP', 'Gene', '10413', (13, 16))	('#33103', 'Var', (119, 125))	('YAP', 'Gene', (105, 108))	('YAP', 'Gene', (77, 80))	('YAP-5SA', 'Gene', (105, 112))	('YAP-5SA', 'Gene', (77, 84))	('YAP', 'Gene', (13, 16))
178147	27886176	1-shYAP (#42540), pcDNA-HA-MST2 (#33098) and pcDNA-Lats1 (#41156) were purchased from Addgene.	('MST2', 'Gene', (27, 31))	('YAP', 'Gene', (4, 7))	('Lats1', 'Gene', (51, 56))	('#41156', 'Var', (58, 64))	('MST2', 'Gene', '6788', (27, 31))	('#42540', 'Var', (9, 15))	('Lats1', 'Gene', '9113', (51, 56))	('YAP', 'Gene', '10413', (4, 7))	('#33098', 'Var', (33, 39))
178181	29214011	Furthermore, transwell assays indicated that lncRNA-H19 knockdown inhibited cells migration and invasion, but this effect was attenuated by co-transfection of lncRNA-H19 siRNA and miR-29a-3p inhibitor.	('H19', 'Gene', '283120', (52, 55))	('H19', 'Gene', (52, 55))	('H19', 'Gene', '283120', (166, 169))	('H19', 'Gene', (166, 169))	('inhibited', 'NegReg', (66, 75))	('miR', 'Gene', '220972', (180, 183))	('miR', 'Gene', (180, 183))	('knockdown', 'Var', (56, 65))
178208	29214011	The primary antibodies anti-E2F1, anti-GAPDH and the second antibodies anti-rabbit or anti-mouse IgG were purchased from Santa Cruz Biotechnology (Dallas, TX, USA).	('rabbit', 'Species', '9986', (76, 82))	('GAPDH', 'Gene', '2597', (39, 44))	('GAPDH', 'Gene', (39, 44))	('anti-E2F1', 'Var', (23, 32))	('mouse', 'Species', '10090', (91, 96))
178261	29214011	5, 786-O cells were plated in a 24-well plate and transfected with si-H19, and cell proliferation was significantly reduced at the different indicated time points using a CCK-8 assay (P < 0.05).	('cell proliferation', 'CPA', (79, 97))	('H19', 'Gene', '283120', (70, 73))	('cell proliferation', 'biological_process', 'GO:0008283', ('79', '97'))	('H19', 'Gene', (70, 73))	('transfected', 'Var', (50, 61))	('reduced', 'NegReg', (116, 123))
178265	29214011	Initially, compared to control group, knockdown of lncRNA-H19 could decrease the cell number of migration and invasion in 786-O, but was increased by co-transfected with miR-29a-3p inhibitor and siRNA-H19 (Fig.	('H19', 'Gene', (58, 61))	('H19', 'Gene', '283120', (58, 61))	('miR', 'Gene', '220972', (170, 173))	('decrease', 'NegReg', (68, 76))	('H19', 'Gene', '283120', (201, 204))	('H19', 'Gene', (201, 204))	('increased', 'PosReg', (137, 146))	('invasion in 786-O', 'CPA', (110, 127))	('knockdown', 'Var', (38, 47))	('miR', 'Gene', (170, 173))
178267	29214011	8, compared to control group, knockdown of lncRNA-H19 could decrease the cell number of migration and invasion in 786-O, but was increased by co-transfected with over expression of E2F1 and siRNA-H19 (Fig.	('decrease', 'NegReg', (60, 68))	('H19', 'Gene', (196, 199))	('over expression', 'PosReg', (162, 177))	('increased', 'PosReg', (129, 138))	('H19', 'Gene', '283120', (50, 53))	('H19', 'Gene', (50, 53))	('knockdown', 'Var', (30, 39))	('E2F1', 'Gene', (181, 185))	('invasion in 786-O', 'CPA', (102, 119))	('H19', 'Gene', '283120', (196, 199))
178283	29214011	E2F1 is the abbreviation of E2F transcription factor 1, and it encodes the protein which plays a crucial regulation role in controlling cell cycle progression and activating tumor suppressor proteins.	('tumor', 'Disease', (174, 179))	('transcription', 'biological_process', 'GO:0006351', ('32', '45'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('174', '190'))	('transcription factor', 'molecular_function', 'GO:0000981', ('32', '52'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('174', '190'))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('E2F1', 'Var', (0, 4))	('cell cycle', 'biological_process', 'GO:0007049', ('136', '146'))	('E2F transcription factor 1', 'Gene', (28, 54))	('E2F transcription factor 1', 'Gene', '1869', (28, 54))	('regulation', 'biological_process', 'GO:0065007', ('105', '115'))
178285	29214011	E2F1 can be used as an effective inducer of cancerous tumor through directly activating transcription of MDM2 and subsequent stimulation of p53-dependent manner.	('transcription', 'MPA', (88, 101))	('MDM2', 'Gene', '4193', (105, 109))	('activating', 'PosReg', (77, 87))	('MDM2', 'Gene', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('p53', 'Gene', (140, 143))	('transcription', 'biological_process', 'GO:0006351', ('88', '101'))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('E2F1', 'Var', (0, 4))	('stimulation', 'PosReg', (125, 136))	('cancerous tumor', 'Disease', 'MESH:D009369', (44, 59))	('cancerous tumor', 'Disease', (44, 59))	('p53', 'Gene', '7157', (140, 143))
178293	29214011	We found that silenced the expression of lncRNA-H19 could decrease the relative luciferase of miR-29a-3p (Fig.	('H19', 'Gene', '283120', (48, 51))	('H19', 'Gene', (48, 51))	('silenced', 'Var', (14, 22))	('decrease', 'NegReg', (58, 66))	('miR', 'Gene', '220972', (94, 97))	('miR', 'Gene', (94, 97))	('luciferase', 'Enzyme', (80, 90))
178299	29214011	Our results clearly showed that when silencing lncRNA-H19 expression, ccRCC migration and invasion was inhibited.	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('expression', 'MPA', (58, 68))	('RCC', 'Disease', (72, 75))	('silencing', 'Var', (37, 46))	('inhibited', 'NegReg', (103, 112))	('H19', 'Gene', '283120', (54, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (70, 75))	('H19', 'Gene', (54, 57))	('invasion', 'CPA', (90, 98))
178308	27634896	Prevalence of actionable mutations and copy number alterations and the price of a genomic testing panel Interest in genomic testing for the selection of cancer therapy is growing.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('mutations', 'Var', (25, 34))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('copy number alterations', 'Var', (39, 62))
178309	27634896	We sought to determine the price of identifying mutations and copy number alterations (CNAs) in theoretically actionable genes across multiple tumor types.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('copy number alterations', 'Var', (62, 85))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
178311	27634896	We used price information from a commonly used commercial genomic testing platform (FoundationOne) to determine the price of detecting mutations and CNAs in different types of tumors.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('mutations', 'Var', (135, 144))	('tumors', 'Disease', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))
178312	27634896	Although there are large variations in the prevalence by tumor type, when the detection of both mutations and CNAs was considered overall, most patients had at least one alteration in a potentially actionable gene (84% overall, range 51%- 98% among tumor types assessed).	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('patients', 'Species', '9606', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (249, 254))	('tumor', 'Disease', (57, 62))	('mutations', 'Var', (96, 105))
178314	27634896	Although the frequency of mutations and CNAs in actionable genes differs by tumor type, most patients have an actionable genomic alteration detectable by a commercially available panel.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('mutations', 'Var', (26, 35))	('patients', 'Species', '9606', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
178319	27634896	Herein, we evaluate the prevalence of genomic alterations, the likelihood of detecting mutations and copy number alterations (CNAs) in actionable genes, and the relevant prices for detecting these alterations in several cancer types.	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('copy number alterations', 'Var', (101, 124))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', (220, 226))	('mutations', 'Var', (87, 96))
178321	27634896	Table 1 shows the prevalence of testable mutations that were theoretically or pharmaceutically actionable and the average price for identifying one patient with mutations in actionable genes by cancer type.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('mutations', 'Var', (161, 170))	('patient', 'Species', '9606', (148, 155))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
178322	27634896	Among 986 breast cancer patients in TCGA data, 586 (59%) had mutations in genes that were theoretically actionable and tested in the FoundationOne test.	('breast cancer', 'Disease', 'MESH:D001943', (10, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (10, 23))	('mutations', 'Var', (61, 70))	('breast cancer', 'Disease', (10, 23))	('patients', 'Species', '9606', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
178323	27634896	The frequency of mutations in theoretically actionable genes ranged from 25% in ovarian cancer to 93% in endometrial cancer.	('ovarian cancer', 'Disease', (80, 94))	('endometrial cancer', 'Disease', 'MESH:D016889', (105, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('ovarian cancer', 'Phenotype', 'HP:0100615', (80, 94))	('endometrial cancer', 'Disease', (105, 123))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ovarian cancer', 'Disease', 'MESH:D010051', (80, 94))	('mutations', 'Var', (17, 26))	('endometrial cancer', 'Phenotype', 'HP:0012114', (105, 123))
178325	27634896	The frequency of mutations in pharmaceutically actionable genes ranged from 10% in ovarian cancer to 72% in endometrial cancer, with corresponding price ranging from $55,556 in ovarian cancer to $8,035 in endometrial cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('endometrial cancer', 'Disease', 'MESH:D016889', (205, 223))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('endometrial cancer', 'Disease', (108, 126))	('ovarian cancer', 'Disease', (177, 191))	('endometrial cancer', 'Disease', (205, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('ovarian cancer', 'Disease', 'MESH:D010051', (83, 97))	('endometrial cancer', 'Phenotype', 'HP:0012114', (108, 126))	('ovarian cancer', 'Phenotype', 'HP:0100615', (177, 191))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('endometrial cancer', 'Disease', 'MESH:D016889', (108, 126))	('endometrial cancer', 'Phenotype', 'HP:0012114', (205, 223))	('ovarian cancer', 'Disease', (83, 97))	('mutations', 'Var', (17, 26))	('ovarian cancer', 'Disease', 'MESH:D010051', (177, 191))
178327	27634896	Similarly, the prevalence of mutations in pharmaceutically actionable genes also varied substantially from 55% in glioblastoma multiforme patients to 1% in kidney clear cell carcinoma.	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (114, 137))	('mutations', 'Var', (29, 38))	('kidney clear cell carcinoma', 'Disease', (156, 183))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (156, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('patients', 'Species', '9606', (138, 146))	('glioblastoma multiforme', 'Disease', (114, 137))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))
178329	27634896	The prevalence of theoretically actionable mutations or CNAs was above 80% for all cancer types we studied except clear cell renal cell carcinoma where the prevalence was 50%.	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (114, 145))	('clear cell renal cell carcinoma', 'Disease', (114, 145))	('CNAs', 'Var', (56, 60))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (125, 145))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (114, 145))	('mutations', 'Var', (43, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
178332	27634896	In this study we found significant variations in the prevalence of actionable gene mutations and CNAs among different types of tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mutations', 'Var', (83, 92))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('actionable gene', 'Gene', (67, 82))	('CNAs', 'Gene', (97, 101))
178345	27634896	More specifically, if the copy number was above 6, the patient was considered to have copy number amplification, and if the copy number was below 1, the patient was considered to have copy number deletion; otherwise, the patient was considered to have non-significant CNAs.	('copy number', 'Var', (26, 37))	('copy number amplification', 'Var', (86, 111))	('patient', 'Species', '9606', (55, 62))	('patient', 'Species', '9606', (153, 160))	('patient', 'Species', '9606', (221, 228))	('copy number deletion', 'Var', (184, 204))
178347	27634896	As the impact of genomic analysis on therapeutic decisions may differ depending on specific genes, we have also included a table (Table 5) that shows the five most frequently observed mutations for each tumor type to allow researchers to best assess the prevalence of actionable genes.	('mutations', 'Var', (184, 193))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (203, 208))
178348	27634896	BRAF inhibitors), and gene variants known to affect drug effectiveness or toxicity, and that affect dosing guidelines and/or drug label information.	('affect', 'Reg', (45, 51))	('variants', 'Var', (27, 35))	('toxicity', 'Disease', (74, 82))	('affect', 'Reg', (93, 99))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('toxicity', 'Disease', 'MESH:D064420', (74, 82))
178364	32319572	In addition, high expression of TMSB10 predicted poor clinical outcome.	('high', 'Var', (13, 17))	('TMSB10', 'Gene', '9168', (32, 38))	('clinical', 'Species', '191496', (54, 62))	('si', 'Chemical', 'MESH:D012825', (24, 26))	('TMSB10', 'Gene', (32, 38))
178366	32319572	Furthermore, knockdown of TMSB10 impaired the proliferation of ccRCC cells, and attenuated cell and invasion in vitro.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('impaired', 'NegReg', (33, 41))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('proliferation', 'CPA', (46, 59))	('attenuated', 'NegReg', (80, 90))	('TMSB10', 'Gene', '9168', (26, 32))	('knockdown', 'Var', (13, 22))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('TMSB10', 'Gene', (26, 32))	('RCC', 'Disease', (65, 68))
178367	32319572	In addition, TMSB10 knockdown downregulated reduced the phosphorylation of PI3K and the expression of vascular endothelial growth factor.	('vascular endothelial growth factor', 'Gene', (102, 136))	('phosphorylation', 'biological_process', 'GO:0016310', ('56', '71'))	('PI3K', 'Protein', (75, 79))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('102', '136'))	('TMSB10', 'Gene', (13, 19))	('vascular endothelial growth factor', 'Gene', '7422', (102, 136))	('downregulated reduced', 'NegReg', (30, 51))	('PI3K', 'molecular_function', 'GO:0016303', ('75', '79'))	('phosphorylation', 'MPA', (56, 71))	('knockdown', 'Var', (20, 29))	('expression', 'MPA', (88, 98))	('TMSB10', 'Gene', '9168', (13, 19))	('si', 'Chemical', 'MESH:D012825', (94, 96))
178383	32319572	In this study, the Gene Expression Omnibus (GEO) microarray datasets GSE40435, GSE53000, GSE53757, GSE105261 and GSE15641 were included for further analysis.	('si', 'Chemical', 'MESH:D012825', (153, 155))	('GSE15641', 'Var', (113, 121))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('GSE53000', 'Var', (79, 87))	('GSE53757', 'Var', (89, 97))	('GSE105261', 'Var', (99, 108))	('GSE40435', 'Var', (69, 77))	('Gene Expression', 'biological_process', 'GO:0010467', ('19', '34'))
178411	32319572	ACHN cells were transfected with si-NC or si-TMSB10 at 48 h before the experiment as described by Cao et al.	('TMSB10', 'Gene', '9168', (45, 51))	('si', 'Chemical', 'MESH:D012825', (33, 35))	('ACHN', 'Gene', '55323', (0, 4))	('TMSB10', 'Gene', (45, 51))	('ACHN', 'Gene', (0, 4))	('si', 'Chemical', 'MESH:D012825', (42, 44))	('si-NC', 'Var', (33, 38))
178417	32319572	As described above, ACHN cells was transfected with si-NC or si-TMSB10 48 h prior to the experiment.	('TMSB10', 'Gene', (64, 70))	('si', 'Chemical', 'MESH:D012825', (61, 63))	('si-NC', 'Var', (52, 57))	('ACHN', 'Gene', (20, 24))	('ACHN', 'Gene', '55323', (20, 24))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('TMSB10', 'Gene', '9168', (64, 70))
178446	32319572	Moreover, DFS analysis in subgroups of patients with ccRCC revealed that high expression of TMSB10 was a useful prognostic indicator for ccRCC patients with the following features: Age <60 or >=60 years (Fig.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('TMSB10', 'Gene', (92, 98))	('patients', 'Species', '9606', (39, 47))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('patients', 'Species', '9606', (143, 151))	('RCC', 'Disease', (139, 142))	('TMSB10', 'Gene', '9168', (92, 98))	('high', 'Var', (73, 77))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
178459	32319572	Moreover, the GSEA results demonstrated that the activated gene sets 'DNA replication' and 'P53 signaling pathway' were associated with patients having a higher TMSB10 expression level (Fig.	('DNA replication', 'biological_process', 'GO:0006260', ('70', '85'))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('higher', 'PosReg', (154, 160))	('TMSB10', 'Gene', (161, 167))	('si', 'Chemical', 'MESH:D012825', (174, 176))	('P53 signaling pathway', 'biological_process', 'GO:0030330', ('92', '113'))	('patients', 'Species', '9606', (136, 144))	("'P53 signaling pathway", 'Pathway', (91, 113))	('si', 'Chemical', 'MESH:D012825', (96, 98))	("'DNA", 'Var', (69, 73))	('GSEA', 'Chemical', '-', (14, 18))	('TMSB10', 'Gene', '9168', (161, 167))	('expression level', 'MPA', (168, 184))
178464	32319572	Furthermore, knockdown of TMSB10 down-regulated the P-PI3K/total PI3K ratio and VEGF expression level (Fig.	('P-PI3K/total PI3K', 'CPA', (52, 69))	('VEGF', 'Gene', (80, 84))	('PI3K', 'molecular_function', 'GO:0016303', ('65', '69'))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('PI3K', 'molecular_function', 'GO:0016303', ('54', '58'))	('VEGF', 'Gene', '7422', (80, 84))	('TMSB10', 'Gene', '9168', (26, 32))	('expression level', 'MPA', (85, 101))	('knockdown', 'Var', (13, 22))	('down-regulated', 'NegReg', (33, 47))	('TMSB10', 'Gene', (26, 32))
178491	32319572	Overexpression of TMSB4 in SW480 colon cells also caused a marked decrease in E-cadherin, and promoted invasiveness.	('invasiveness', 'CPA', (103, 115))	('TMSB4', 'Gene', (18, 23))	('E-cadherin', 'Gene', (78, 88))	('SW480', 'CellLine', 'CVCL:0546', (27, 32))	('TMSB4', 'Gene', '7114', (18, 23))	('si', 'Chemical', 'MESH:D012825', (107, 109))	('Overexpression', 'Var', (0, 14))	('E-cadherin', 'Gene', '999', (78, 88))	('decrease', 'NegReg', (66, 74))	('cadherin', 'molecular_function', 'GO:0008014', ('80', '88'))	('promoted', 'PosReg', (94, 102))	('si', 'Chemical', 'MESH:D012825', (10, 12))
178494	32319572	Although the present study demonstrated that silencing TMSB10 reduced PI3K phosphorylation and VEGF expression, further studies of the underlying molecular mechanism of TMSB10 in ccRCC are required in the future.	('silencing', 'Var', (45, 54))	('VEGF', 'Gene', '7422', (95, 99))	('TMSB10', 'Gene', '9168', (55, 61))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))	('TMSB10', 'Gene', '9168', (169, 175))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('TMSB10', 'Gene', (55, 61))	('PI3K', 'molecular_function', 'GO:0016303', ('70', '74'))	('VEGF', 'Gene', (95, 99))	('PI3K', 'Protein', (70, 74))	('phosphorylation', 'biological_process', 'GO:0016310', ('75', '90'))	('TMSB10', 'Gene', (169, 175))	('RCC', 'Disease', 'MESH:C538614', (181, 184))	('RCC', 'Disease', (181, 184))	('reduced', 'NegReg', (62, 69))
178507	30026212	Transcriptional control of kidney cancer Clear cell renal cell carcinoma (ccRCC) is a subtype of kidney cancer characterized by von Hippel-Lindau (VHL) gene inactivation in ~90% of patients.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('inactivation', 'Var', (157, 169))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (41, 72))	('kidney cancer', 'Disease', 'MESH:D007680', (27, 40))	('kidney cancer', 'Disease', 'MESH:D007680', (97, 110))	('patients', 'Species', '9606', (181, 189))	('Clear cell renal cell carcinoma', 'Disease', (41, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (52, 72))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('kidney cancer', 'Phenotype', 'HP:0009726', (27, 40))	('kidney cancer', 'Phenotype', 'HP:0009726', (97, 110))	('kidney cancer', 'Disease', (27, 40))	('VHL', 'Gene', (147, 150))	('subtype of kidney cancer', 'Disease', (86, 110))	('von Hippel-Lindau', 'Gene', (128, 145))	('subtype of kidney cancer', 'Disease', 'MESH:D007680', (86, 110))	('VHL', 'Gene', '7428', (147, 150))	('Transcriptional control', 'biological_process', 'GO:0006355', ('0', '23'))	('cancer Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (34, 72))	('von Hippel-Lindau', 'Gene', '7428', (128, 145))
178522	30026212	ZHX2, in complex with the canonical NF-kappaB subunit p65/RelA, binds to NF-kappaB consensus motifs at a number of sites marked by H3K4me3 and H3K27ac, associated with active gene transcription (Figure 1).	('active', 'MPA', (168, 174))	('ZHX2', 'Gene', (0, 4))	('H3K27ac', 'Var', (143, 150))	('p65', 'Gene', (54, 57))	('transcription', 'biological_process', 'GO:0006351', ('180', '193'))	('NF-kappaB', 'Gene', (36, 45))	('NF-kappaB', 'Gene', '4790', (73, 82))	('p65', 'Gene', '5970', (54, 57))	('H3K4me3', 'Protein', (131, 138))	('RelA', 'Gene', (58, 62))	('ZHX2', 'Gene', '22882', (0, 4))	('NF-kappaB', 'Gene', (73, 82))	('binds', 'Interaction', (64, 69))	('RelA', 'Gene', '5970', (58, 62))	('NF-kappaB', 'Gene', '4790', (36, 45))
178523	30026212	demonstrated that genetic or pharmacologic inhibition of NF-kappaB signaling attenuates ccRCC cell growth, and that elevated expression of a number of the NF-kappaB target genes identified is associated with worse patient survival in ccRCC.	('patient', 'Species', '9606', (214, 221))	('inhibition', 'Var', (43, 53))	('ccRCC', 'Disease', (88, 93))	('NF-kappaB', 'Gene', (57, 66))	('elevated', 'PosReg', (116, 124))	('expression', 'MPA', (125, 135))	('NF-kappaB', 'Gene', '4790', (155, 164))	('NF-kappaB', 'Gene', '4790', (57, 66))	('ccRCC', 'Disease', (234, 239))	('cell growth', 'biological_process', 'GO:0016049', ('94', '105'))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))	('NF-kappaB', 'Gene', (155, 164))	('attenuates', 'NegReg', (77, 87))
178527	30026212	The hits identified in the in vitro screen performed by Zhang and colleagues likely captures proteins that would be stabilized early in disease development, as biallelic inactivation of VHL is amongst the earliest tumorigenic events preceded only by chromosome 3p loss.	('VHL', 'Gene', (186, 189))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('VHL', 'Gene', '7428', (186, 189))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('chromosome', 'cellular_component', 'GO:0005694', ('250', '260'))	('tumor', 'Disease', (214, 219))	('biallelic inactivation', 'Var', (160, 182))
178532	30026212	For example, genomic and pre-clinical data suggests small molecule inhibition of HIF-2alpha would be efficacious in treating a large majority of ccRCC patients.	('small molecule inhibition', 'Var', (52, 77))	('patients', 'Species', '9606', (151, 159))	('HIF-2alpha', 'Gene', (81, 91))	('pre', 'molecular_function', 'GO:0003904', ('25', '28'))	('HIF-2alpha', 'Gene', '2034', (81, 91))	('ccRCC', 'Disease', (145, 150))
178538	30026212	Furthermore, as ZHX2 is expressed to some degree in the renal epithelium of patients with VHL mutations, is there a function for this transcription factor in healthy kidney tissue prior to oncogenic transformation?	('ZHX2', 'Gene', '22882', (16, 20))	('patients', 'Species', '9606', (76, 84))	('VHL', 'Gene', '7428', (90, 93))	('ZHX2', 'Gene', (16, 20))	('mutations', 'Var', (94, 103))	('transcription factor', 'molecular_function', 'GO:0000981', ('134', '154'))	('transcription', 'biological_process', 'GO:0006351', ('134', '147'))	('VHL', 'Gene', (90, 93))
178544	30026212	Targets such as ZHX2 that are present in a large majority of tumors as a consequence of VHL inactivation may represent a promising therapeutic strategy, particularly for patients with metastatic disease in which limited treatments are currently effective.	('patients', 'Species', '9606', (170, 178))	('inactivation', 'Var', (92, 104))	('tumors', 'Disease', (61, 67))	('ZHX2', 'Gene', '22882', (16, 20))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('VHL', 'Gene', (88, 91))	('VHL', 'Gene', '7428', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('ZHX2', 'Gene', (16, 20))	('metastatic disease', 'Disease', (184, 202))
178559	29707125	HNF-1beta induces Chk1 phosphorylated at Ser296, but not at ATR sites (Ser317 and Ser345).	('Ser', 'cellular_component', 'GO:0005790', ('82', '85'))	('ATR', 'Gene', '545', (60, 63))	('ATR', 'Gene', (60, 63))	('Ser', 'cellular_component', 'GO:0005790', ('41', '44'))	('Ser296', 'Chemical', '-', (41, 47))	('induces', 'Reg', (10, 17))	('Ser296', 'Var', (41, 47))	('Chk1', 'Gene', (18, 22))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('Ser317', 'Chemical', '-', (71, 77))	('Ser', 'cellular_component', 'GO:0005790', ('71', '74'))	('HNF-1beta', 'Gene', (0, 9))	('Ser345', 'Chemical', '-', (82, 88))	('Chk1', 'Gene', '1111', (18, 22))
178568	29707125	Our results support for the first time a model in which HNF-1beta promotes cell cycle arrest and survival in response to genotoxic stress, by up-regulating the USP28:Claspin:p-Chk1 cascade.	('response to genotoxic stress', 'biological_process', 'GO:0006974', ('109', '137'))	('USP', 'molecular_function', 'GO:0051748', ('160', '163'))	('HNF-1beta', 'Var', (56, 65))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('75', '92'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (75, 92))	('p-Chk1', 'Gene', (174, 180))	('response to genotoxic stress', 'MPA', (109, 137))	('p-Chk1', 'Gene', '1111', (174, 180))	('promotes', 'PosReg', (66, 74))	('survival', 'CPA', (97, 105))	('up-regulating', 'PosReg', (142, 155))	('cell cycle arrest', 'CPA', (75, 92))
178574	29707125	In TOV21G si-HNF-1beta cells, p-Chk1 protein expression reached its peak 4 hours after bleomycin treatment compared with other time points (Figure 2A, p-Chk1).	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('bleomycin', 'Chemical', 'MESH:D001761', (87, 96))	('TOV21G', 'Var', (3, 9))	('p-Chk1', 'Gene', (30, 36))	('p-Chk1', 'Gene', '1111', (151, 157))	('p-Chk1', 'Gene', '1111', (30, 36))	('p-Chk1', 'Gene', (151, 157))	('si', 'Chemical', 'MESH:D012825', (51, 53))	('protein', 'Protein', (37, 44))
178584	29707125	In the absence of bleomycin treatment (Figures 2A and 2B, at 0 h), bands recognized by Claspin antibodies seem to present stronger intensity in the si-HNF-1beta sample compared to si-Ctl sample, but the difference did not reach to significant level in three independent experiments.	('si', 'Chemical', 'MESH:D012825', (148, 150))	('bleomycin', 'Chemical', 'MESH:D001761', (18, 27))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('si', 'Chemical', 'MESH:D012825', (231, 233))	('stronger', 'PosReg', (122, 130))	('intensity', 'MPA', (131, 140))	('Claspin', 'Gene', (87, 94))	('bands', 'MPA', (67, 72))	('si', 'Chemical', 'MESH:D012825', (180, 182))	('si-HNF-1beta', 'Var', (148, 160))
178589	29707125	In contrast to Claspin expression, knockdown of HNF-1beta did not affect p-PLK1 protein levels (Figure 3).	('knockdown', 'Var', (35, 44))	('si', 'Chemical', 'MESH:D012825', (29, 31))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('PLK1', 'Gene', (75, 79))	('PLK1', 'Gene', '5347', (75, 79))
178593	29707125	Next, we investigated whether knockdown of Claspin inhibits the expression of p-Chk1.	('si', 'Chemical', 'MESH:D012825', (70, 72))	('expression', 'MPA', (64, 74))	('inhibits', 'NegReg', (51, 59))	('p-Chk1', 'Gene', (78, 84))	('p-Chk1', 'Gene', '1111', (78, 84))	('knockdown', 'Var', (30, 39))
178596	29707125	Western blot showed similar results as to the protein levels of p-Chk1 in TOV21G si-HNF-1beta cells (Figure 2A) and TOV21G si-Claspin cells (Figure 2C) compared with the si-Ctl group.	('TOV21G si-HNF-1beta', 'Var', (74, 93))	('si', 'Chemical', 'MESH:D012825', (170, 172))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('p-Chk1', 'Gene', (64, 70))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('protein levels', 'MPA', (46, 60))	('TOV21G si-Claspin', 'Var', (116, 133))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('si', 'Chemical', 'MESH:D012825', (123, 125))	('p-Chk1', 'Gene', '1111', (64, 70))
178597	29707125	The p-Chk1 levels were much lower at 24 hours in the si-HNF-1beta and si-Claspin groups than in the Control si-Ctl group.	('si', 'Chemical', 'MESH:D012825', (70, 72))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('lower', 'NegReg', (28, 33))	('si-HNF-1beta', 'Var', (53, 65))	('p-Chk1', 'Gene', '1111', (4, 10))	('p-Chk1', 'Gene', (4, 10))	('si', 'Chemical', 'MESH:D012825', (108, 110))
178601	29707125	We conducted a time course for USP28 and USP29 protein expression in TOV21G si-HNF-1beta or si-Ctl cells in response to bleomycin.	('bleomycin', 'Chemical', 'MESH:D001761', (120, 129))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('USP', 'molecular_function', 'GO:0051748', ('41', '44'))	('si', 'Chemical', 'MESH:D012825', (61, 63))	('USP', 'molecular_function', 'GO:0051748', ('31', '34'))	('USP28', 'Gene', (31, 36))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('USP29', 'Gene', (41, 46))	('TOV21G', 'Var', (69, 75))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('response to bleomycin', 'MPA', (108, 129))	('response to bleomycin', 'biological_process', 'GO:1904975', ('108', '129'))	('USP29', 'Gene', '57663', (41, 46))
178605	29707125	Knockdown efficiencies were approximately 80% and 75% for USP28 and USP29, respectively (Figures 1 and 6).	('Knockdown efficiencies', 'Disease', 'MESH:C536214', (0, 22))	('USP', 'molecular_function', 'GO:0051748', ('58', '61'))	('USP29', 'Gene', (68, 73))	('Knockdown efficiencies', 'Disease', (0, 22))	('USP29', 'Gene', '57663', (68, 73))	('USP28', 'Var', (58, 63))	('USP', 'molecular_function', 'GO:0051748', ('68', '71'))
178607	29707125	We examined whether USP28 knock-down (TOV21G cells transfected with si-USP28) reduces the levels of Claspin protein.	('si-USP28', 'Var', (68, 76))	('USP', 'molecular_function', 'GO:0051748', ('20', '23'))	('levels of Claspin protein', 'MPA', (90, 115))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('USP', 'molecular_function', 'GO:0051748', ('71', '74'))	('reduces', 'NegReg', (78, 85))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
178608	29707125	Knockdown of endogenous USP28 resulted in a drastic decrease of endogenous Claspin protein accumulation (Figure 6A Claspin, si-USP28 and Figure 6B).	('USP28', 'Gene', (24, 29))	('endogenous', 'Var', (13, 23))	('USP', 'molecular_function', 'GO:0051748', ('127', '130'))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('decrease', 'NegReg', (52, 60))	('si-USP28', 'Var', (124, 132))	('USP', 'molecular_function', 'GO:0051748', ('24', '27'))	('si', 'Chemical', 'MESH:D012825', (124, 126))	('endogenous', 'MPA', (64, 74))
178610	29707125	We next examined whether USP28 knock-down (TOV21G cells transfected with si-USP28) reduces the levels of Chk1 protein.	('si', 'Chemical', 'MESH:D012825', (73, 75))	('Chk1', 'Gene', '1111', (105, 109))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('USP', 'molecular_function', 'GO:0051748', ('76', '79'))	('reduces', 'NegReg', (83, 90))	('USP', 'molecular_function', 'GO:0051748', ('25', '28'))	('levels', 'MPA', (95, 101))	('si-USP28', 'Var', (73, 81))	('Chk1', 'Gene', (105, 109))
178612	29707125	These results suggest that USP28 specifically enhances p-Chk1 protein stabilization through a de-ubiquitination event of Claspin protein.	('enhances', 'PosReg', (46, 54))	('Claspin protein', 'Protein', (121, 136))	('p-Chk1', 'Gene', '1111', (55, 61))	('protein stabilization', 'biological_process', 'GO:0050821', ('62', '83'))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('USP', 'molecular_function', 'GO:0051748', ('27', '30'))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))	('USP28', 'Var', (27, 32))	('stabilization', 'MPA', (70, 83))	('de-ubiquitination', 'MPA', (94, 111))	('p-Chk1', 'Gene', (55, 61))
178616	29707125	Knocking-down HNF-1beta increased polyubiquitination of Claspin compared to the control (Figure 7, lane 2 vs lane 1).	('HNF-1beta increased polyubiquitination', 'Disease', (14, 52))	('HNF-1beta increased polyubiquitination', 'Disease', 'MESH:D019586', (14, 52))	('Claspin', 'Protein', (56, 63))	('Knocking-down', 'Var', (0, 13))
178619	29707125	Compared to TOV21G si-Ctl cells, TOV21G si-HNF-1beta cells and si-Claspin cells significantly induced cell injury (Figure 8A).	('TOV21G', 'Var', (33, 39))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('cell injury', 'Disease', (102, 113))	('si', 'Chemical', 'MESH:D012825', (40, 42))	('cell injury', 'Disease', 'MESH:D001930', (102, 113))	('induced', 'Reg', (94, 101))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('si', 'Chemical', 'MESH:D012825', (80, 82))
178622	29707125	Results showed that bleomycin significantly damaged cell viability in cultured TOV21G si-HNF-1beta cells, si-Claspin cells and si-USP28 cells.	('bleomycin', 'Chemical', 'MESH:D001761', (20, 29))	('cell viability', 'CPA', (52, 66))	('si-HNF-1beta', 'Gene', (86, 98))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('si-USP28', 'Var', (127, 135))	('damaged', 'NegReg', (44, 51))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('si-Claspin', 'Var', (106, 116))	('si', 'Chemical', 'MESH:D012825', (127, 129))	('TOV21G', 'Var', (79, 85))	('USP', 'molecular_function', 'GO:0051748', ('130', '133'))	('si', 'Chemical', 'MESH:D012825', (86, 88))
178627	29707125	Since the mRNA expression of Claspin was not altered by HNF-1beta knockdown, HNF-1beta most likely regulates Claspin at the translational level.	('Claspin', 'Gene', (109, 116))	('knockdown', 'Var', (66, 75))	('regulates', 'Reg', (99, 108))	('si', 'Chemical', 'MESH:D012825', (21, 23))
178634	29707125	We showed that knockdown of HNF-1beta reduced Claspin protein levels, but did not affect PLK1 protein levels, suggesting that HNF-beta1 stabilizes Claspin levels in a PLK1-independent manner.	('knockdown', 'Var', (15, 24))	('reduced', 'NegReg', (38, 45))	('PLK1', 'Gene', '5347', (89, 93))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('PLK1', 'Gene', (167, 171))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))	('PLK1', 'Gene', (89, 93))	('PLK1', 'Gene', '5347', (167, 171))	('HNF-1beta', 'Gene', (28, 37))	('Claspin protein levels', 'MPA', (46, 68))
178636	29707125	However, in the HNF-1beta-overexpressing CCC cells, Claspin is predominantly stabilized by USP28.	('USP', 'molecular_function', 'GO:0051748', ('91', '94'))	('USP28', 'Var', (91, 96))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('Claspin', 'Protein', (52, 59))	('CCC', 'cellular_component', 'GO:0030896', ('41', '44'))
178641	29707125	Inhibition of HNF-1beta or its downstream targets may have significant therapeutic potential to overcome drug resistance in patients with CCC.	('drug resistance', 'biological_process', 'GO:0009315', ('105', '120'))	('drug resistance', 'biological_process', 'GO:0042493', ('105', '120'))	('CCC', 'Disease', (138, 141))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('CCC', 'cellular_component', 'GO:0030896', ('138', '141'))	('Inhibition', 'Var', (0, 10))	('drug resistance', 'Phenotype', 'HP:0020174', (105, 120))	('HNF-1beta', 'Protein', (14, 23))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('patients', 'Species', '9606', (124, 132))
178643	29707125	These data suggest that inhibition of USP28 may be lethal only in the CCC cells overexpressing HNF-1beta with limited effects on normal tissue.	('si', 'Chemical', 'MESH:D012825', (90, 92))	('USP28', 'Gene', (38, 43))	('USP', 'molecular_function', 'GO:0051748', ('38', '41'))	('CCC', 'cellular_component', 'GO:0030896', ('70', '73'))	('inhibition', 'Var', (24, 34))	('HNF-1beta', 'Gene', (95, 104))
178650	29707125	Among these synthetic lethal pairs, genetic ablation of the DNA repair response genes, including ARID1A, Chk1, Chk2, ATM and ATR, may be the important patterns causing synthetic lethality in CCC.	('Chk2', 'Gene', (111, 115))	('ATR', 'Gene', (125, 128))	('si', 'Chemical', 'MESH:D012825', (163, 165))	('ATM', 'Gene', '472', (117, 120))	('Chk1', 'Gene', '1111', (105, 109))	('CCC', 'cellular_component', 'GO:0030896', ('191', '194'))	('CCC', 'Disease', (191, 194))	('ARID1A', 'Gene', '8289', (97, 103))	('DNA repair', 'biological_process', 'GO:0006281', ('60', '70'))	('ATR', 'Gene', '545', (125, 128))	('ARID1A', 'Gene', (97, 103))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('Chk2', 'Gene', '11200', (111, 115))	('genetic ablation', 'Var', (36, 52))	('ATM', 'Gene', (117, 120))	('Chk1', 'Gene', (105, 109))
178687	29707125	The PCR amplifications were performed on StepOnePlus Real Time PCR System (Applied Biosystems, CA, USA) with 4 mul of cDNA, 10 mul of TaqMan Gene Expression Master Mix (4369016, Applied Biosystems), 1 mul of Claspin or GAPDH TaqMan Gene Expression Assay (Hs00898637_m1 or Hs03929097_g1, Applied Biosystems) and 5 mul of Nuclease-free water (129114, Qiagen).	('GAPDH', 'Gene', '2597', (219, 224))	('si', 'Chemical', 'MESH:D012825', (152, 154))	('GAPDH', 'Gene', (219, 224))	('Gene Expression', 'biological_process', 'GO:0010467', ('232', '247'))	('si', 'Chemical', 'MESH:D012825', (243, 245))	('Gene Expression', 'biological_process', 'GO:0010467', ('141', '156'))	('Hs03929097_g1', 'Var', (272, 285))	('Hs00898637_m1', 'Var', (255, 268))
178695	27467134	The genomic characterization of renal cell carcinoma (RCC) has significantly evolved since clear cell renal cell carcinoma (ccRCC) was defined simply by alterations in the von Hippel-Lindau (VHL) tumor suppressor gene.	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (91, 122))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (32, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('alterations', 'Var', (153, 164))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('196', '212'))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (102, 122))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('renal cell carcinoma', 'Disease', (32, 52))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (32, 52))	('tumor suppressor', 'biological_process', 'GO:0051726', ('196', '212'))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (172, 201))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('renal cell carcinoma', 'Disease', (102, 122))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (102, 122))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (124, 129))
178708	27467134	Chromosomal 3p loss is another ubiquitous finding in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('RCC', 'Disease', (55, 58))	('Chromosomal 3p loss', 'Var', (0, 19))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
178710	27467134	The stratification of patients with ccRCC on the basis of mutations in BAP1 and PBRM1 has been shown to correlate with clinical outcomes in localized disease.	('PBRM1', 'Gene', '55193', (80, 85))	('mutations', 'Var', (58, 67))	('RCC', 'Disease', (38, 41))	('localized disease', 'Disease', (140, 157))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('patients', 'Species', '9606', (22, 30))	('BAP1', 'Gene', '8314', (71, 75))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('PBRM1', 'Gene', (80, 85))	('correlate', 'Reg', (104, 113))	('BAP1', 'Gene', (71, 75))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
178713	27467134	For example, patients with metastatic disease and a mutation in mammalian target of rapamycin (MTOR) can show exceptional response to targeted agents such as everolimus.	('mammalian target of rapamycin', 'Gene', '2475', (64, 93))	('mammalian target of rapamycin', 'Gene', (64, 93))	('patients', 'Species', '9606', (13, 21))	('response', 'MPA', (122, 130))	('MTOR', 'Gene', (95, 99))	('metastatic disease', 'Disease', (27, 45))	('mutation', 'Var', (52, 60))	('everolimus', 'Chemical', 'MESH:D000068338', (158, 168))	('MTOR', 'Gene', '2475', (95, 99))
178715	27467134	Unfortunately, mutations in the mTOR signaling pathway are seen in only a minority of patients with RCC.	('signaling pathway', 'biological_process', 'GO:0007165', ('37', '54'))	('mTOR', 'Gene', '2475', (32, 36))	('mutations', 'Var', (15, 24))	('mTOR', 'Gene', (32, 36))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('patients', 'Species', '9606', (86, 94))
178716	27467134	A recently published report on the RECORD-3 study, and another on correlations between molecular subclassifications of ccRCC and targeted therapy response highlight several other possible mutations associated with treatment response in the metastatic setting, including BAP1, PBRM1, lysine (k)-specific demethylase 5C (KDM5C), tuberous sclerosis 1 (TSC1) and tuberous sclerosis 2 (TSC2) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA).	('TSC2', 'Gene', (381, 385))	('tuberous sclerosis 1', 'Gene', (327, 347))	('tuberous sclerosis 1', 'Gene', '7248', (327, 347))	('associated', 'Reg', (198, 208))	('BAP1', 'Gene', (270, 274))	('PBRM1', 'Gene', '55193', (276, 281))	('PIK3CA', 'Gene', (463, 469))	('KDM5C', 'Gene', '8242', (319, 324))	('tuberous sclerosis 2', 'Gene', (359, 379))	('PBRM1', 'Gene', (276, 281))	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', (121, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('TSC1', 'Gene', (349, 353))	('mutations', 'Var', (188, 197))	('tuberous sclerosis 2', 'Gene', '7249', (359, 379))	('TSC2', 'Gene', '7249', (381, 385))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('TSC1', 'Gene', '7248', (349, 353))	('BAP1', 'Gene', '8314', (270, 274))	('KDM5C', 'Gene', (319, 324))	('PIK3CA', 'Gene', '5290', (463, 469))	('lysine (k)-specific demethylase 5C', 'Gene', '8242', (283, 317))
178722	27467134	Alterations in several cancer-associated pathways were found across the spectrum of pRCC tumors, including alterations in the Hippo signaling pathway (mutations in the NF2 [neurofibromin 2] gene), in the SWI/SNF complex (PBRM1 and SMARCB1 [SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1]) and in several chromatin modifier pathways (SETD2, BAP1, and KDM6A [lysine (k)-specific demethylase 6A]).	('pRCC', 'Gene', (84, 88))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('204', '219'))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('BAP1', 'Gene', '8314', (387, 391))	('chromatin', 'cellular_component', 'GO:0000785', ('303', '312'))	('PBRM1', 'Gene', '55193', (221, 226))	('KDM6A', 'Gene', '7403', (397, 402))	('chromatin modifier pathways', 'Pathway', (351, 378))	('KDM6A', 'Gene', (397, 402))	('Hippo signaling pathway', 'Pathway', (126, 149))	('PBRM1', 'Gene', (221, 226))	('mutations', 'Var', (151, 160))	('Alterations', 'Reg', (0, 11))	('BAP1', 'Gene', (387, 391))	('SMARCB1', 'Gene', '6598', (231, 238))	('alterations', 'Reg', (107, 118))	('cancer', 'Disease', (23, 29))	('SETD2', 'Gene', (380, 385))	('SMARCB1', 'Gene', (231, 238))	('pRCC', 'Gene', '5546', (84, 88))	('RCC tumors', 'Disease', (85, 95))	('chromatin', 'cellular_component', 'GO:0000785', ('351', '360'))	('SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1', 'Gene', '6598', (240, 333))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('neurofibromin 2', 'Gene', '4771', (173, 188))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('neurofibromin 2', 'Gene', (173, 188))	('RCC tumors', 'Disease', 'MESH:C538614', (85, 95))	('SETD2', 'Gene', '29072', (380, 385))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('126', '149'))	('NF2', 'Gene', '4771', (168, 171))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('pRCC', 'Phenotype', 'HP:0006766', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('NF2', 'Gene', (168, 171))
178724	27467134	Tumors with the CpG island methylator phenotype (CIMP) had increased DNA methylation compared to loci that were unmethylated in matched normal tissue from the same patient.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('patient', 'Species', '9606', (164, 171))	('Tumors', 'Disease', (0, 6))	('CIMP', 'Chemical', '-', (49, 53))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('CpG island', 'Var', (16, 26))	('DNA methylation', 'MPA', (69, 84))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('DNA methylation', 'biological_process', 'GO:0006306', ('69', '84'))	('increased', 'PosReg', (59, 68))
178725	27467134	At the molecular and metabolic level many of these tumors have germline or somatic mutations in fumarate hydratase (FH).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('germline', 'Var', (63, 71))	('tumors', 'Disease', (51, 57))	('fumarate hydratase', 'Gene', '2271', (96, 114))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('FH', 'Gene', '2271', (116, 118))	('fumarate hydratase', 'Gene', (96, 114))
178726	27467134	Patients with germline FH mutations can develop hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome.	('renal cell cancer', 'Phenotype', 'HP:0005584', (78, 95))	('FH', 'Gene', '2271', (23, 25))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('mutations', 'Var', (26, 35))	('Patients', 'Species', '9606', (0, 8))	('germline', 'Var', (14, 22))	('develop', 'Reg', (40, 47))	('hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome', 'Disease', 'MESH:C535516', (48, 112))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
178728	27467134	The TCGA study also noted poor outcomes for patients with alterations in cyclin-dependent kinase inhibitor 2A (CDKN2A).	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('73', '106'))	('patients', 'Species', '9606', (44, 52))	('CDKN2A', 'Gene', '1029', (111, 117))	('CDKN2A', 'Gene', (111, 117))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('90', '106'))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (73, 109))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (73, 109))	('alterations', 'Var', (58, 69))
178729	27467134	A more surprising result from the TCGA study was the finding that a large number of their adult cohort of patients with pRCC type 2 were identified as having mutations or fusions in their transcription factor binding to IGHM enhancer 3 (TFE3) or transcription factor EB (TFEB) genes.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('transcription', 'biological_process', 'GO:0006351', ('246', '259'))	('transcription factor', 'molecular_function', 'GO:0000981', ('246', '266'))	('transcription factor', 'MPA', (188, 208))	('pRCC', 'Gene', (120, 124))	('TFE3', 'Gene', '7030', (237, 241))	('TFEB', 'Gene', '7942', (271, 275))	('TFEB', 'Gene', (271, 275))	('transcription', 'biological_process', 'GO:0006351', ('188', '201'))	('transcription factor EB', 'Gene', '7942', (246, 269))	('patients', 'Species', '9606', (106, 114))	('fusions', 'Var', (171, 178))	('pRCC', 'Gene', '5546', (120, 124))	('pRCC', 'Phenotype', 'HP:0006766', (120, 124))	('mutations', 'Var', (158, 167))	('TFE3', 'Gene', (237, 241))	('transcription factor EB', 'Gene', (246, 269))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('188', '216'))
178731	27467134	While germline mutations in MET occur in patients with hereditary papillary renal cell carcinoma, the high number of somatic alterations in MET for patients with spontaneous pRCC tumors presents a possible therapeutic target in select cases.	('patients', 'Species', '9606', (148, 156))	('RCC tumors', 'Disease', 'MESH:C538614', (175, 185))	('hereditary papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (55, 96))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (76, 96))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('pRCC', 'Gene', (174, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('RCC tumors', 'Disease', (175, 185))	('germline mutations', 'Var', (6, 24))	('patients', 'Species', '9606', (41, 49))	('MET', 'Gene', (28, 31))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (66, 96))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('occur', 'Reg', (32, 37))	('hereditary papillary renal cell carcinoma', 'Disease', (55, 96))	('pRCC', 'Phenotype', 'HP:0006766', (174, 178))	('pRCC', 'Gene', '5546', (174, 178))
178733	27467134	Mutations or amplifications of this gene typically result in it's over activation in pRCC tumors.	('over activation', 'PosReg', (66, 81))	('RCC tumors', 'Disease', (86, 96))	('amplifications', 'Var', (13, 27))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('pRCC', 'Gene', (85, 89))	('RCC tumors', 'Disease', 'MESH:C538614', (86, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('Mutations', 'Var', (0, 9))	('pRCC', 'Phenotype', 'HP:0006766', (85, 89))	('pRCC', 'Gene', '5546', (85, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('result in', 'Reg', (51, 60))
178741	27467134	In a cohort of 37 patients with metastatic chRCC, enrichment for these mutations was seen with TP53 mutations rising to 61% and PTEN to 27%.	('mutations', 'Var', (100, 109))	('rising', 'PosReg', (110, 116))	('PTEN', 'Gene', (128, 132))	('PTEN', 'Gene', '5728', (128, 132))	('RCC', 'Disease', (45, 48))	('patients', 'Species', '9606', (18, 26))	('TP53', 'Gene', '7157', (95, 99))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('TP53', 'Gene', (95, 99))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
178743	27467134	These TERT promoter alterations, which many times lead to increased TERT expression, are being investigated in several other malignancies and may represent a unique or enhanced pathway for tumorigenesis.	('alterations', 'Var', (20, 31))	('tumor', 'Disease', (189, 194))	('TERT', 'Gene', (68, 72))	('increased', 'PosReg', (58, 67))	('TERT', 'Gene', '7015', (68, 72))	('TERT', 'Gene', (6, 10))	('TERT', 'Gene', '7015', (6, 10))	('malignancies', 'Disease', 'MESH:D009369', (125, 137))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('malignancies', 'Disease', (125, 137))
178747	27467134	Several investigators have identified alterations in the tumor suppressor gene SMARCB1 to be frequently associated with RMC tumors, with sensitivity ranging from 30% to 100%.	('RMC tumors', 'Disease', (120, 130))	('SMARCB1', 'Gene', (79, 86))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('57', '73'))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (124, 129))	('RMC tumors', 'Disease', 'MESH:D009369', (120, 130))	('associated', 'Reg', (104, 114))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('alterations', 'Var', (38, 49))	('tumor suppressor', 'biological_process', 'GO:0051726', ('57', '73'))	('tumor', 'Disease', (57, 62))	('SMARCB1', 'Gene', '6598', (79, 86))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
178748	27467134	Loss of SMARCB1 in RMC tumors has also been associated with increased levels of EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit), which may represent a possible actionable target.	('SMARCB1', 'Gene', '6598', (8, 15))	('SMARCB1', 'Gene', (8, 15))	('RMC tumors', 'Disease', 'MESH:D009369', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('EZH2', 'Gene', (80, 84))	('EZH2', 'Gene', '2146', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('Loss', 'Var', (0, 4))	('increased', 'PosReg', (60, 69))	('RMC tumors', 'Disease', (19, 29))
178751	27467134	Both studies reported an enrichment of TP53 mutations (42.3% in Malouf et al, 31.5% in Bi et al) within tumor regions with sarcomatoid differentiation.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('sarcomatoid', 'Disease', 'MESH:C538614', (123, 134))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (39, 43))	('sarcomatoid', 'Disease', (123, 134))	('TP53', 'Gene', (39, 43))
178752	27467134	A third study reported no TP53 mutations in seven cases of ccRCC with sarcomatoid differentiation that underwent whole genome sequencing.	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('sarcomatoid', 'Disease', (70, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('sarcomatoid', 'Disease', 'MESH:C538614', (70, 81))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('TP53', 'Gene', '7157', (26, 30))
178753	27467134	Enrichment of other somatic mutations in these tumors was also identified but will need to be reproduced in larger cohort studies before their significance can be fully evaluated.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (28, 37))
178762	30406665	Loss of SETD2 induces a metabolic switch in renal cell carcinoma cell lines toward enhanced oxidative phosphorylation SETD2, a histone H3 lysine trimethyltransferase, is frequently inactivated and associated with recurrence of clear cell renal cell carcinoma (ccRCC).	('SETD2', 'Gene', '29072', (118, 123))	('RCC', 'Disease', 'MESH:C538614', (262, 265))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (227, 258))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('92', '117'))	('renal cell carcinoma', 'Disease', (44, 64))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (238, 258))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (44, 64))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (227, 258))	('SETD2', 'Gene', (8, 13))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (238, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (44, 64))	('associated with', 'Reg', (197, 212))	('clear cell renal cell carcinoma', 'Disease', (227, 258))	('Loss', 'Var', (0, 4))	('SETD2', 'Gene', '29072', (8, 13))	('RCC', 'Disease', (262, 265))	('RCC', 'Phenotype', 'HP:0005584', (262, 265))	('SETD2', 'Gene', (118, 123))	('ccRCC', 'Phenotype', 'HP:0006770', (260, 265))	('enhanced', 'PosReg', (83, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('oxidative phosphorylation', 'MPA', (92, 117))
178768	30406665	Our results indicate that SETD2 deficiency induces a metabolic switch toward enhanced oxidative phosphorylation in ccRCC, which can be related to PGC1alpha-mediated metabolic networks.	('induces', 'Reg', (43, 50))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('enhanced', 'PosReg', (77, 85))	('oxidative phosphorylation', 'MPA', (86, 111))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('SETD2', 'Gene', '29072', (26, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('86', '111'))	('PGC1alpha', 'Gene', '10891', (146, 155))	('SETD2', 'Gene', (26, 31))	('deficiency', 'Var', (32, 42))	('PGC1alpha', 'Gene', (146, 155))
178774	30406665	A common molecular feature of ccRCC is the inactivation of the von Hippel-Lindau (VHL) tumor suppressor protein through a variety of mechanisms.	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (63, 92))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('tumor suppressor', 'biological_process', 'GO:0051726', ('87', '103'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('87', '103'))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('inactivation', 'Var', (43, 55))
178777	30406665	The inactivation of VHL in ccRCC cell leads to elevated activity of HIF-1 and a number of downstream genes essential for tumor metabolism and angiogenesis, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and GLUT1.	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (27, 32))	('GLUT1', 'Gene', (249, 254))	('inactivation', 'Var', (4, 16))	('activity', 'MPA', (56, 64))	('tumor', 'Disease', (121, 126))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('vascular endothelial growth factor', 'Gene', '7422', (164, 198))	('VHL', 'Gene', (20, 23))	('VEGF', 'Gene', '7422', (200, 204))	('PDGF', 'molecular_function', 'GO:0005161', ('239', '243'))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('metabolism', 'biological_process', 'GO:0008152', ('127', '137'))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('164', '198'))	('VEGF', 'Gene', (200, 204))	('vascular endothelial growth factor', 'Gene', (164, 198))	('angiogenesis', 'biological_process', 'GO:0001525', ('142', '154'))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('207', '237'))	('GLUT1', 'Gene', '6513', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('elevated', 'PosReg', (47, 55))	('HIF-1', 'Gene', '3091', (68, 73))	('HIF-1', 'Gene', (68, 73))
178778	30406665	However, the loss of VHL has been shown to be insufficient for tumorigenesis in mice,  suggesting that other factors are also involved in ccRCC onset and progression.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mice', 'Species', '10090', (80, 84))	('VHL', 'Gene', (21, 24))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('loss', 'Var', (13, 17))
178779	30406665	In addition to functional alterations of VHL, several genes regulating chromatin remodeling in close genomic proximity to VHL are frequently mutated in RCC, including those of the SWI/SNF chromatin remodeling complex (PBRM1 and BAP-1) and histone lysine 36 trimethylase SETD2.	('mutated', 'Var', (141, 148))	('PBRM1', 'Gene', (218, 223))	('PBRM1', 'Gene', '55193', (218, 223))	('BAP-1', 'Gene', '8314', (228, 233))	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('SETD2', 'Gene', '29072', (270, 275))	('RCC', 'Disease', (152, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('188', '208'))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('188', '216'))	('SETD2', 'Gene', (270, 275))	('BAP-1', 'Gene', (228, 233))	('VHL', 'Gene', (122, 125))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('71', '91'))	('chromatin', 'cellular_component', 'GO:0000785', ('71', '80'))
178784	30406665	These reports strongly suggest that SETD2 mutations drive the ccRCC progression, but the specific mechanism remains unclear.	('SETD2', 'Gene', '29072', (36, 41))	('SETD2', 'Gene', (36, 41))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('drive', 'Reg', (52, 57))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('RCC', 'Disease', (64, 67))	('mutations', 'Var', (42, 51))
178785	30406665	Increasingly, kidney cancer is being recognized as a metabolic disease, and many mutated genes in RCC, such as VHL, fumarate hydratase (FH) and succinate dehydrogenase (SDH), are involved in cellular respiration and energy metabolism.	('VHL', 'Gene', (111, 114))	('metabolic disease', 'Disease', 'MESH:D008659', (53, 70))	('fumarate hydratase', 'Gene', (116, 134))	('mutated genes', 'Var', (81, 94))	('SDH', 'Gene', (169, 172))	('metabolism', 'biological_process', 'GO:0008152', ('223', '233'))	('succinate dehydrogenase', 'Gene', (144, 167))	('cellular respiration', 'biological_process', 'GO:0045333', ('191', '211'))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('fumarate hydratase', 'Gene', '2271', (116, 134))	('kidney cancer', 'Disease', 'MESH:D007680', (14, 27))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('FH', 'Gene', '2271', (136, 138))	('metabolic disease', 'Disease', (53, 70))	('succinate dehydrogenase', 'Gene', '6390', (144, 167))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('SDH', 'Gene', '6390', (169, 172))	('kidney cancer', 'Phenotype', 'HP:0009726', (14, 27))	('kidney cancer', 'Disease', (14, 27))
178786	30406665	For instance, loss of VHL in RCC leads to a HIF-1-dependent reprogramming of energy metabolism that includes elevated glucose uptake, glycolysis, and lactate production accompanied by a reciprocal decrease in respiration under aerobic conditions.	('glucose uptake', 'MPA', (118, 132))	('VHL', 'Gene', (22, 25))	('glucose', 'Chemical', 'MESH:D005947', (118, 125))	('glycolysis', 'biological_process', 'GO:0006096', ('134', '144'))	('lactate', 'Chemical', 'MESH:D019344', (150, 157))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('glycolysis', 'MPA', (134, 144))	('glucose uptake', 'biological_process', 'GO:0046323', ('118', '132'))	('respiration', 'biological_process', 'GO:0007585', ('209', '220'))	('loss', 'Var', (14, 18))	('respiration', 'biological_process', 'GO:0045333', ('209', '220'))	('respiration under aerobic conditions', 'MPA', (209, 245))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('reprogramming of energy metabolism', 'MPA', (60, 94))	('metabolism', 'biological_process', 'GO:0008152', ('84', '94'))	('lactate production', 'MPA', (150, 168))	('elevated glucose', 'Phenotype', 'HP:0003074', (109, 125))	('elevated', 'PosReg', (109, 117))	('HIF-1', 'Gene', '3091', (44, 49))	('HIF-1', 'Gene', (44, 49))	('decrease', 'NegReg', (197, 205))
178787	30406665	Inactivation of FH, a tricarboxylic acid (TCA) cycle enzyme, in RCC results in glucose-mediated generation of cellular reactive oxygen species (ROS) and ROS-dependent HIF-1 stabilization, which consequently enhances aerobic glycolysis and reduces reliance on mitochondrial respiration in RCC.	('TCA) cycle', 'biological_process', 'GO:0006099', ('42', '52'))	('HIF-1', 'Gene', '3091', (167, 172))	('ROS', 'Chemical', 'MESH:D017382', (153, 156))	('HIF-1', 'Gene', (167, 172))	('enhances', 'PosReg', (207, 215))	('reliance on mitochondrial respiration', 'MPA', (247, 284))	('cellular reactive oxygen species', 'MPA', (110, 142))	('ROS', 'Chemical', 'MESH:D017382', (144, 147))	('RCC', 'Disease', (288, 291))	('RCC', 'Phenotype', 'HP:0005584', (288, 291))	('respiration', 'biological_process', 'GO:0007585', ('273', '284'))	('TCA', 'Chemical', 'MESH:D014233', (42, 45))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (119, 142))	('respiration', 'biological_process', 'GO:0045333', ('273', '284'))	('reduces', 'NegReg', (239, 246))	('Inactivation', 'Var', (0, 12))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (22, 40))	('RCC', 'Disease', 'MESH:C538614', (288, 291))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', (64, 67))	('glycolysis', 'biological_process', 'GO:0006096', ('224', '234'))	('FH', 'Gene', '2271', (16, 18))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('aerobic glycolysis', 'MPA', (216, 234))	('glucose', 'Chemical', 'MESH:D005947', (79, 86))
178788	30406665	However, the impact of SETD2 inactivation on the metabolic phenotype of RCC is rarely reported and remains unknown.	('SETD2', 'Gene', '29072', (23, 28))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('SETD2', 'Gene', (23, 28))	('RCC', 'Disease', (72, 75))	('inactivation', 'Var', (29, 41))
178789	30406665	In this study, we explored metabolic alterations in SETD2 deficient cell lines.	('deficient', 'Var', (58, 67))	('SETD2', 'Gene', (52, 57))	('SETD2', 'Gene', '29072', (52, 57))
178815	30406665	Membranes were then incubated with primary antibodies: anti-H3K36me3 (1:1000, Active Motif, Carlsbad, CA), anti-CS (1:1000, Cell Signaling, Danvers, MS), and anti-PGC1alpha (1:1000, Cell Signaling) at 4  C overnight.	('Signaling', 'biological_process', 'GO:0023052', ('129', '138'))	('PGC1alpha', 'Gene', (163, 172))	('anti-H3K36me3', 'Var', (55, 68))	('CS', 'Gene', '1431', (112, 114))	('PGC1alpha', 'Gene', '10891', (163, 172))	('Signaling', 'biological_process', 'GO:0023052', ('187', '196'))
178819	30406665	We first performed proliferation assays to measure the growth rates of SETD2 deficient cells.	('SETD2', 'Gene', (71, 76))	('SETD2', 'Gene', '29072', (71, 76))	('deficient', 'Var', (77, 86))
178822	30406665	In addition, loss of SETD2 led to a global decline of H3K36me3 (Figure 1D-E), and increased cell size and intercellular complexity as indicated by forward scatter (FSC) and side scatter (SSC) histograms from 38E and 38F cells (Figure S2).	('H3K36me3', 'Protein', (54, 62))	('SETD2', 'Gene', '29072', (21, 26))	('SETD2', 'Gene', (21, 26))	('increased', 'PosReg', (82, 91))	('decline', 'NegReg', (43, 50))	('loss', 'Var', (13, 17))	('intercellular complexity', 'CPA', (106, 130))	('cell size', 'CPA', (92, 101))
178825	30406665	The OCR associated with maximal respiration, spare respiratory capacity, and non-mitochondrial oxygen consumption in 38E and 38F cells were 601.5% and 1322.4%, 1516.6% and 3438.9%, and 320.2% and 167.9% higher than those of 786-O cells, respectively.	('oxygen', 'Chemical', 'MESH:D010100', (95, 101))	('3438.9', 'Var', (172, 178))	('spare respiratory capacity', 'MPA', (45, 71))	('respiration', 'biological_process', 'GO:0007585', ('32', '43'))	('1516.6', 'Var', (160, 166))	('OCR', 'Chemical', '-', (4, 7))	('higher', 'PosReg', (203, 209))	('respiration', 'biological_process', 'GO:0045333', ('32', '43'))	('maximal respiration', 'MPA', (24, 43))	('non-mitochondrial oxygen consumption', 'MPA', (77, 113))
178837	30406665	RNAseq data showed SETD2 deficiency to cause dysregulation of many genes in ccRCC cells, and gene enrichment analysis showed the main biological processes affected by SETD2 to be mitochondrial, lipid (fatty acids), glucose, coenzyme, and purine metabolism (Figure 5A-B).	('SETD2', 'Gene', (19, 24))	('fatty acids', 'Chemical', 'MESH:D005227', (201, 212))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('lipid', 'Chemical', 'MESH:D008055', (194, 199))	('SETD2', 'Gene', '29072', (19, 24))	('SETD2', 'Gene', (167, 172))	('purine metabolism', 'biological_process', 'GO:0006144', ('238', '255'))	('purine metabolism', 'biological_process', 'GO:0006163', ('238', '255'))	('SETD2', 'Gene', '29072', (167, 172))	('lipid', 'MPA', (194, 199))	('mitochondrial', 'MPA', (179, 192))	('purine metabolism', 'biological_process', 'GO:0042278', ('238', '255'))	('purine', 'Chemical', 'MESH:C030985', (238, 244))	('deficiency', 'Var', (25, 35))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('glucose', 'Chemical', 'MESH:D005947', (215, 222))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('dysregulation', 'MPA', (45, 58))
178838	30406665	In addition, PGC1alpha and its related gene networks were altered by SETD2 mutations (Figure 5C).	('PGC1alpha', 'Gene', '10891', (13, 22))	('SETD2', 'Gene', '29072', (69, 74))	('mutations', 'Var', (75, 84))	('SETD2', 'Gene', (69, 74))	('PGC1alpha', 'Gene', (13, 22))	('altered', 'Reg', (58, 65))
178844	30406665	Although PGC1alpha protein expression is not available in public genomic datasets such as The Cancer Genome Atlas, we examined the mRNA expression of PPARGC1A, the gene that encodes PGC1alpha, in SETD2 wild-type and mutant tumors.	('PPARGC1A', 'Gene', '10891', (150, 158))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('PGC1alpha', 'Gene', (9, 18))	('Cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutant', 'Var', (216, 222))	('tumors', 'Disease', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('Cancer', 'Disease', 'MESH:D009369', (94, 100))	('PGC1alpha', 'Gene', '10891', (182, 191))	('SETD2', 'Gene', '29072', (196, 201))	('Cancer', 'Disease', (94, 100))	('PPARGC1A', 'Gene', (150, 158))	('protein', 'cellular_component', 'GO:0003675', ('19', '26'))	('PGC1alpha', 'Gene', (182, 191))	('PGC1alpha', 'Gene', '10891', (9, 18))	('SETD2', 'Gene', (196, 201))
178845	30406665	In our analysis, we found that the SETD2 mutant group produced a slightly higher expression although the difference was not significant (Figure S7, p 0.05).	('mutant', 'Var', (41, 47))	('higher', 'PosReg', (74, 80))	('SETD2', 'Gene', '29072', (35, 40))	('SETD2', 'Gene', (35, 40))	('expression', 'MPA', (81, 91))
178846	30406665	Although the connection between RCC and dysregulated metabolism has been previously reported, the effects of SETD2 inactivation on ccRCC metabolic phenotype and its contribution to tumor metastasis are still unknown.	('dysregulated metabolism', 'MPA', (40, 63))	('SETD2', 'Gene', '29072', (109, 114))	('tumor metastasis', 'Disease', 'MESH:D009362', (181, 197))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('tumor metastasis', 'Disease', (181, 197))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('metabolism', 'biological_process', 'GO:0008152', ('53', '63'))	('SETD2', 'Gene', (109, 114))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('inactivation', 'Var', (115, 127))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
178847	30406665	In this study, we observed higher luminescence of MTT and Alamar Blue in SETD2 deficient 38E/38F cells than 786-O cells.	('SETD2', 'Gene', (73, 78))	('MTT', 'Chemical', 'MESH:C070243', (50, 53))	('luminescence', 'MPA', (34, 46))	('deficient', 'Var', (79, 88))	('higher', 'PosReg', (27, 33))	('SETD2', 'Gene', '29072', (73, 78))	('Alamar Blue', 'Chemical', 'MESH:C005843', (58, 69))
178850	30406665	Thus, these results suggest that loss of SETD2 leads to increased overall metabolic activity in ccRCC cells.	('increased', 'PosReg', (56, 65))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('loss', 'Var', (33, 37))	('SETD2', 'Gene', '29072', (41, 46))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('metabolic activity', 'MPA', (74, 92))	('SETD2', 'Gene', (41, 46))
178852	30406665	Further, Seahorse results showed that SETD2 inactivation induced a significant increase in the glycolytic and mitochondrial respiration rates in RCC cells.	('increase', 'PosReg', (79, 87))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('respiration', 'biological_process', 'GO:0045333', ('124', '135'))	('SETD2', 'Gene', '29072', (38, 43))	('SETD2', 'Gene', (38, 43))	('respiration', 'biological_process', 'GO:0007585', ('124', '135'))	('inactivation', 'Var', (44, 56))	('mitochondrial respiration rates', 'MPA', (110, 141))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))
178859	30406665	Thus, our results indicate that SETD2 inactivation can enhance both glycolytic and mitochondrial respiration with greater capacity for mitochondrial oxidative metabolism in ccRCC cells.	('glycolytic', 'MPA', (68, 78))	('SETD2', 'Gene', '29072', (32, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (173, 178))	('SETD2', 'Gene', (32, 37))	('inactivation', 'Var', (38, 50))	('enhance', 'PosReg', (55, 62))	('mitochondrial respiration', 'MPA', (83, 108))	('greater', 'PosReg', (114, 121))	('respiration', 'biological_process', 'GO:0007585', ('97', '108'))	('oxidative metabolism', 'biological_process', 'GO:0045333', ('149', '169'))	('RCC', 'Disease', (175, 178))	('mitochondrial oxidative metabolism', 'MPA', (135, 169))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('respiration', 'biological_process', 'GO:0045333', ('97', '108'))	('RCC', 'Disease', 'MESH:C538614', (175, 178))
178869	30406665	We found that loss of SETD2 disturbed networks related to glucose, mitochondrial, and fatty acid metabolism.	('fatty acid', 'Chemical', 'MESH:D005227', (86, 96))	('loss', 'Var', (14, 18))	('disturbed', 'Reg', (28, 37))	('SETD2', 'Gene', '29072', (22, 27))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('86', '107'))	('SETD2', 'Gene', (22, 27))	('mitochondrial', 'MPA', (67, 80))	('glucose', 'MPA', (58, 65))	('glucose', 'Chemical', 'MESH:D005947', (58, 65))	('fatty acid metabolism', 'MPA', (86, 107))	('networks related', 'MPA', (38, 54))
178871	30406665	PGC1alpha, a master regulator for cellular energy homeostasis, was also elevated by SETD2 inactivation.	('elevated', 'PosReg', (72, 80))	('PGC1alpha', 'Gene', '10891', (0, 9))	('SETD2', 'Gene', (84, 89))	('energy homeostasis', 'biological_process', 'GO:0097009', ('43', '61'))	('inactivation', 'Var', (90, 102))	('PGC1alpha', 'Gene', (0, 9))	('SETD2', 'Gene', '29072', (84, 89))
178873	30406665	Indeed, the up-regulation of mitochondrial biogenesis has been reported in cancers, and some cancers have mutations in mitochondrial TCA cycle enzymes.	('TCA', 'Chemical', 'MESH:D014233', (133, 136))	('regulation', 'biological_process', 'GO:0065007', ('15', '25'))	('cancers', 'Disease', (93, 100))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('TCA cycle', 'biological_process', 'GO:0006099', ('133', '142'))	('cancers', 'Disease', (75, 82))	('mitochondrial TCA cycle enzymes', 'Enzyme', (119, 150))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('up-regulation', 'PosReg', (12, 25))	('mutations', 'Var', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mitochondrial biogenesis', 'MPA', (29, 53))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
178886	30406665	Taken together, our study observed that loss of SETD2 is associated with a metabolic switch in ccRCC cell lines toward enhanced oxidative phosphorylation and lipogenesis, and its mechanism can be potentially related to PGC1alpha-mediated metabolic networks (Figure 8).	('RCC', 'Disease', (97, 100))	('lipogenesis', 'MPA', (158, 169))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('oxidative phosphorylation', 'MPA', (128, 153))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('PGC1alpha', 'Gene', '10891', (219, 228))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('128', '153'))	('lipogenesis', 'biological_process', 'GO:0008610', ('158', '169'))	('loss', 'Var', (40, 44))	('SETD2', 'Gene', '29072', (48, 53))	('SETD2', 'Gene', (48, 53))	('PGC1alpha', 'Gene', (219, 228))	('enhanced', 'PosReg', (119, 127))
178887	30406665	Moreover, our results suggest a need for a comprehensive metabolomics analysis of cancer cells with SETD2 inactivation in vivo to specifically identify pathways involved in this metabolic switch, which provides a number of opportunities to identify novel therapeutic targets in kidney cancer.	('inactivation', 'Var', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('kidney cancer', 'Disease', 'MESH:D007680', (278, 291))	('kidney cancer', 'Phenotype', 'HP:0009726', (278, 291))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('kidney cancer', 'Disease', (278, 291))	('SETD2', 'Gene', '29072', (100, 105))	('cancer', 'Disease', (285, 291))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('SETD2', 'Gene', (100, 105))
178897	33618745	Furthermore, the tumor-promoting functions of circAGAP1 could be alleviated by miR-15-5p mimics in vitro and in vivo.	('tumor', 'Disease', (17, 22))	('alleviated', 'NegReg', (65, 75))	('miR-15-5p', 'Chemical', '-', (79, 88))	('miR-15-5p', 'Var', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('AGAP1', 'Gene', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('AGAP1', 'Gene', '116987', (50, 55))
178904	33618745	Recently, the aberrant expression of circRNAs has been shown to contribute to the development and progression of malignant tumors, such as glioblastoma and hepatocellular carcinoma.	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('glioblastoma', 'Phenotype', 'HP:0012174', (139, 151))	('malignant tumors', 'Disease', (113, 129))	('malignant tumors', 'Disease', 'MESH:D009369', (113, 129))	('glioblastoma and hepatocellular carcinoma', 'Disease', 'MESH:D006528', (139, 180))	('contribute', 'Reg', (64, 74))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (156, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('aberrant expression', 'Var', (14, 33))	('circRNAs', 'Gene', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
178906	33618745	In chronic lymphocytic leukemia cells, miR-15 has been reported to suppress proliferation by targeting Bcl2, whereas in neuroblastoma and pancreatic ductal adenocarcinoma, miR-15 regulates growth by modulating the expression of multiple targets.	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (11, 31))	('regulates', 'Reg', (179, 188))	('suppress', 'NegReg', (67, 75))	('miR-15', 'Chemical', '-', (39, 45))	('growth', 'MPA', (189, 195))	('neuroblastoma', 'Phenotype', 'HP:0003006', (120, 133))	('leukemia', 'Phenotype', 'HP:0001909', (23, 31))	('modulating', 'Reg', (199, 209))	('neuroblastoma and pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (120, 170))	('expression', 'MPA', (214, 224))	('lymphocytic leukemia', 'Disease', (11, 31))	('miR-15', 'Chemical', '-', (172, 178))	('miR-15', 'Var', (39, 45))	('proliferation', 'CPA', (76, 89))	('Bcl2', 'molecular_function', 'GO:0015283', ('103', '107'))	('Bcl2', 'Gene', (103, 107))	('miR-15', 'Var', (172, 178))	('Bcl2', 'Gene', '596', (103, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (138, 170))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (3, 31))
178910	33618745	Several tumor-related miRNAs have been found to target E2F3, including miR-128, miR-377, and miR-34a.	('E2F3', 'Gene', (55, 59))	('miR-34a', 'Gene', '407040', (93, 100))	('miR-128', 'Var', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('miR-377', 'Gene', (80, 87))	('miR-34a', 'Gene', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('miR-128', 'Chemical', '-', (71, 78))	('miR-377', 'Gene', '494326', (80, 87))
178936	33618745	Wild-type circAGAP1 (circAGAP1-WT) and mutant circAGAP1 (circAGAP1-MUT), which had mutations at the potential miR-15a-5p binding sites, were amplified by PCR and cloned into the pmirGlo dual-luciferase vector with restriction sites of SacI and XhoI to construct a luciferase reporter vector (pmirGLO-circ_0015756-WT and pmirGLO-circ_0015756-mut, respectively; GeneChem Co., Shanghai, China).	('mutations', 'Var', (83, 92))	('miR-15a-5p', 'Chemical', '-', (110, 120))	('AGAP1', 'Gene', (25, 30))	('AGAP1', 'Gene', (14, 19))	('AGAP1', 'Gene', (50, 55))	('AGAP1', 'Gene', '116987', (14, 19))	('AGAP1', 'Gene', '116987', (25, 30))	('AGAP1', 'Gene', '116987', (50, 55))	('mutant', 'Var', (39, 45))	('binding', 'molecular_function', 'GO:0005488', ('121', '128'))	('AGAP1', 'Gene', (61, 66))	('AGAP1', 'Gene', '116987', (61, 66))
178937	33618745	Similarly, WT E2F3 (pmirGLO-E2F3-WT) or E2F3 with mutations at the potential miR-15a-5p binding sites (pmirGLO-E2F3-MUT) were also designed by Shanghai GeneChem Co.	('mutations', 'Var', (50, 59))	('pmirGLO-E2F3-WT', 'Gene', (20, 35))	('binding', 'molecular_function', 'GO:0005488', ('88', '95'))	('pmirGLO-E2F3-WT', 'Gene', '1871', (20, 35))	('miR-15a-5p', 'Chemical', '-', (77, 87))	('miR-15a-5p', 'Gene', (77, 87))
178962	33618745	We found that many circRNAs were abnormally expressed in ccRCC, among which circ0058792 was one of the most upregulated circRNAs (fold change =21.42, p value< 0.001, Fig.	('circ0058792', 'Var', (76, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))
178963	33618745	A search of circBase (http://www.circbase.org/) showed that circ0058792 is located at chr2:236617822-236,659,132 with a sequence length of 510 bp and is generated from exons 2-6 of AGAP1 (Fig.	('chr2:236617822-236', 'STRUCTURAL_ABNORMALITY', 'None', (86, 104))	('AGAP1', 'Gene', (181, 186))	('AGAP1', 'Gene', '116987', (181, 186))	('circ0058792', 'Var', (60, 71))
178964	33618745	Moreover, RNase R exonuclease treatment revealed that circ0058792 was much more stable than the linear transcripts of AGAP1 mRNA, which were degraded by RNase R exonuclease (Fig.	('AGAP1', 'Gene', '116987', (118, 123))	('circ0058792', 'Var', (54, 65))	('AGAP1', 'Gene', (118, 123))
178976	33618745	The CCK-8 assay revealed that the viability of ACHN and A498 cells was reduced after circAGAP1 knockdown compared to that of the control cells (P < 0.001, Fig.	('AGAP1', 'Gene', (89, 94))	('AGAP1', 'Gene', '116987', (89, 94))	('viability', 'CPA', (34, 43))	('knockdown', 'Var', (95, 104))	('reduced', 'NegReg', (71, 78))
178980	33618745	Moreover, the migration and invasion abilities were reduced in cells with circAGAP1 knockdown (P < 0.001, Fig.	('AGAP1', 'Gene', '116987', (78, 83))	('AGAP1', 'Gene', (78, 83))	('knockdown', 'Var', (84, 93))	('reduced', 'NegReg', (52, 59))
178985	33618745	Thus, we searched miRNAs that could potentially bind circAGAP1 via Arraystar homemade miRNA target prediction software and found that circAGAP1 shares more than one binding site for miR-15a-5p.	('AGAP1', 'Gene', (138, 143))	('AGAP1', 'Gene', '116987', (138, 143))	('miR-15a-5p', 'Var', (182, 192))	('AGAP1', 'Gene', (57, 62))	('miR-15a-5p', 'Chemical', '-', (182, 192))	('AGAP1', 'Gene', '116987', (57, 62))	('binding', 'molecular_function', 'GO:0005488', ('165', '172'))
178986	33618745	Thus, to confirm this prediction, a biotin-coupled probe pull-down experiment was applied, and the results revealed that miR-15a-5p and circAGAP1 were present in the pull-down group but not in the control groups (Fig.	('AGAP1', 'Gene', '116987', (140, 145))	('miR-15a-5p', 'Gene', (121, 131))	('pull-down', 'Var', (166, 175))	('miR-15a-5p', 'Chemical', '-', (121, 131))	('AGAP1', 'Gene', (140, 145))	('biotin', 'Chemical', 'MESH:D001710', (36, 42))
178988	33618745	Furthermore, luciferase reporter experiment results showed that miR-15-5p mimics significantly inhibited the luciferase activities of the WT reporter but not the MUT reporter (Fig.	('miR-15-5p mimics', 'Var', (64, 80))	('miR-15-5p', 'Chemical', '-', (64, 73))	('inhibited', 'NegReg', (95, 104))	('luciferase', 'Enzyme', (109, 119))	('activities', 'MPA', (120, 130))
178991	33618745	Cotransfection of miR-15a-5p mimic and circ0058792 partially reversed the increased proliferation, migration and antiapoptotic effects in ACHN and A498 cells (Fig.	('miR-15a-5p', 'Chemical', '-', (18, 28))	('increased', 'PosReg', (74, 83))	('circ0058792', 'Var', (39, 50))	('migration', 'CPA', (99, 108))	('antiapoptotic effects', 'MPA', (113, 134))
178993	33618745	According to the results of overlapping the prediction of three different databases (miRDIP: http://ophid.utoronto.ca/mirDIP/; TargetScan: http://www.targetscan.org/vert_72/; TarBase: https://www.tarbase.com/), 21 potential miR-15a-5p target genes were found, among which E2F3 was the most likely gene targeted miR-15a-5p in ccRCC (Supplementary Fig.	('miR-15a-5p', 'Chemical', '-', (224, 234))	('E2F3', 'Gene', (272, 276))	('RCC', 'Disease', (327, 330))	('miR-15a-5p', 'Var', (311, 321))	('RCC', 'Disease', 'MESH:C538614', (327, 330))	('ccRCC', 'Phenotype', 'HP:0006770', (325, 330))	('miR-15a-5p', 'Chemical', '-', (311, 321))
179001	33618745	By contrast, we found that ectopic circAGAP1 expression partly rescued the suppressive effect of miR-15a-5p on E2F3 expression in ACHN and A498 cells (Figs.	('expression', 'MPA', (116, 126))	('E2F3', 'Gene', (111, 115))	('miR-15a-5p', 'Chemical', '-', (97, 107))	('suppressive effect', 'MPA', (75, 93))	('ectopic', 'Var', (27, 34))	('AGAP1', 'Gene', (39, 44))	('AGAP1', 'Gene', '116987', (39, 44))
179003	33618745	The results of the CCK-8 and EdU experiments revealed that the viability of ACHN and A498 cells was elevated in the E2F3-overexpressing group compared with the mock group (Fig.	('viability', 'CPA', (63, 72))	('EdU', 'Chemical', '-', (29, 32))	('elevated', 'PosReg', (100, 108))	('E2F3-overexpressing', 'Var', (116, 135))
179005	33618745	Taken together, these data suggest that circAGAP1 could regulate E2F3 by functioning as a ceRNA by sponging miR-15a-5p and that E2F3 promotes ccRCC progression.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('promotes', 'PosReg', (133, 141))	('sponging miR-15a-5p', 'MPA', (99, 118))	('E2F3', 'Gene', (65, 69))	('E2F3', 'Var', (128, 132))	('miR-15a-5p', 'Chemical', '-', (108, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('AGAP1', 'Gene', (44, 49))	('RCC', 'Disease', (144, 147))	('AGAP1', 'Gene', '116987', (44, 49))
179016	33618745	circ0091570 expression is downregulated in HCC and functions as a ceRNA by sponging miR-1307 to regulate ISM1 expression.	('downregulated', 'NegReg', (26, 39))	('circ0091570', 'Var', (0, 11))	('HCC', 'Disease', (43, 46))	('ISM1', 'Gene', (105, 109))	('miR-1307', 'Gene', (84, 92))	('regulate', 'Reg', (96, 104))	('expression', 'MPA', (110, 120))	('ISM1', 'Gene', '140862', (105, 109))	('miR-1307', 'Gene', '100302174', (84, 92))
179020	33618745	Moreover, silencing circAGAP1 inhibited ccRCC proliferation, migration and invasion, whereas circAGAP1 overexpression further verified the critical functions of circAGAP1 in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('AGAP1', 'Gene', (165, 170))	('RCC', 'Disease', (176, 179))	('AGAP1', 'Gene', (24, 29))	('AGAP1', 'Gene', '116987', (165, 170))	('invasion', 'CPA', (75, 83))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('inhibited', 'NegReg', (30, 39))	('AGAP1', 'Gene', '116987', (24, 29))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('AGAP1', 'Gene', (97, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (174, 179))	('AGAP1', 'Gene', '116987', (97, 102))	('migration', 'CPA', (61, 70))	('RCC', 'Disease', (42, 45))	('silencing', 'Var', (10, 19))
179023	33618745	Previous studies have shown that miR-15a-5p participates in the progression of many kinds of tumors in different ways.	('miR-15a-5p', 'Var', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('participates', 'Reg', (44, 56))	('miR-15a-5p', 'Chemical', '-', (33, 43))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))
179024	33618745	For example, miR-15a-5p regulates the proliferation and progression of chronic lymphocytic leukemia by suppressing the expression of DLEU2, a host gene of microRNA.	('expression', 'MPA', (119, 129))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (79, 99))	('lymphocytic leukemia', 'Disease', (79, 99))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (71, 99))	('miR-15a-5p', 'Var', (13, 23))	('suppressing', 'NegReg', (103, 114))	('regulates', 'Reg', (24, 33))	('DLEU2', 'Gene', '8847', (133, 138))	('miR-15a-5p', 'Chemical', '-', (13, 23))	('leukemia', 'Phenotype', 'HP:0001909', (91, 99))	('progression', 'CPA', (56, 67))	('DLEU2', 'Gene', (133, 138))
179027	33618745	In this study, miR-15a-5p was shown to bind to the 3'-UTR of E2F3, and ectopic expression of miR-15a-5p could partially reverse the malignant behavior of ccRCC by interacting with circAGAP1.	('interacting', 'Interaction', (163, 174))	('reverse', 'NegReg', (120, 127))	('malignant behavior', 'CPA', (132, 150))	('miR-15a-5p', 'Var', (93, 103))	('UTR', 'Gene', '2837', (54, 57))	('miR-15a-5p', 'Chemical', '-', (93, 103))	('miR-15a-5p', 'Chemical', '-', (15, 25))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('RCC', 'Disease', (156, 159))	('ccRCC', 'Phenotype', 'HP:0006770', (154, 159))	('UTR', 'Gene', (54, 57))	('AGAP1', 'Gene', (184, 189))	('AGAP1', 'Gene', '116987', (184, 189))	('E2F3', 'Gene', (61, 65))
179044	33495453	Recently, consideration of transcript-level changes within protein coding genes has enabled comprehensive characterization of isoform switching across multiple cancers, and extensive evidence now suggests noncoding transcripts and driver mutations within noncoding regions have important and functional roles in cancer by diverse mechanisms.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('cancer', 'Disease', (160, 166))	('cancers', 'Disease', (160, 167))	('mutations', 'Var', (238, 247))	('multiple cancer', 'Disease', (151, 166))	('cancer', 'Disease', 'MESH:D009369', (312, 318))	('cancer', 'Disease', (312, 318))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('multiple cancer', 'Disease', 'MESH:D009369', (151, 166))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))
179051	33495453	Likewise, PINT87aa is a circRNA-encoded small peptide, which partially controls cell proliferation and tumorigenesis in cancer cells, is expressed at a reduced level in glioblastoma tissue, and is correlated with tumor grade.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancer', 'Disease', (120, 126))	('PINT87aa', 'Var', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('N', 'Chemical', 'MESH:D009584', (12, 13))	('reduced', 'NegReg', (152, 159))	('cell proliferation', 'CPA', (80, 98))	('glioblastoma', 'Disease', 'MESH:D005909', (169, 181))	('tumor', 'Disease', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cell proliferation', 'biological_process', 'GO:0008283', ('80', '98'))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (213, 218))	('glioblastoma', 'Disease', (169, 181))	('glioblastoma', 'Phenotype', 'HP:0012174', (169, 181))	('correlated', 'Reg', (197, 207))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('controls', 'Reg', (71, 79))
179052	33495453	Cells over-expressing PINT87aa exhibit decreased tumorigenic potential in animal models.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('PINT87aa', 'Var', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('over-expressing', 'PosReg', (6, 21))	('decreased', 'NegReg', (39, 48))
179064	33495453	In addition, analysis of all the GWAS-associated variants and mutations in the Catalog of Somatic Mutations in Cancer (COSMIC) and Human Gene Mutation Database (HGMD) databases revealed that a significant proportion of variants and mutations map to apparent noncoding regions of the human genome (Fig.	('HGMD', 'Disease', 'None', (161, 165))	('variants', 'Var', (49, 57))	('variants', 'Var', (219, 227))	('map', 'Reg', (242, 245))	('HGMD', 'Disease', (161, 165))	('mutations', 'Var', (232, 241))	('Human', 'Species', '9606', (131, 136))	('Cancer', 'Disease', (111, 117))	('Cancer', 'Disease', 'MESH:D009369', (111, 117))	('human', 'Species', '9606', (283, 288))	('Cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (62, 71))
179066	33495453	2a-d shows the top ~20 examples of COSMIC or HGMD mutations mapped to sORFs, Denovogenes, and Pseudogenes, demonstrating that these regions do indeed harbor mutations.	('mutations', 'Var', (50, 59))	('HGMD', 'Disease', 'None', (45, 49))	('HGMD', 'Disease', (45, 49))	('COSMIC', 'Gene', (35, 41))
179098	33495453	This suggested many nORF transcripts may have prognostic value, particularly in kidney clear cell carcinoma.	('nORF', 'Gene', (20, 24))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (80, 107))	('kidney clear cell carcinoma', 'Disease', (80, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('transcripts', 'Var', (25, 36))
179100	33495453	For a subset of 33 nORF transcripts: (i) the transcript is reproducibly differentially expressed in cancer compared with NAT and GTEx normal tissue, (ii) transcript expression is associated with prognosis (adjusted p-value < 0.05) and (iii) transcripts up-regulated in cancer are associated with poor prognosis, and vice versa.	('poor prognosis', 'CPA', (296, 310))	('associated with', 'Reg', (179, 194))	('transcript', 'MPA', (154, 164))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('transcripts', 'Var', (241, 252))	('up-regulated', 'PosReg', (253, 265))	('prognosis', 'Disease', (195, 204))	('N', 'Chemical', 'MESH:D009584', (121, 122))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
179112	33495453	Methylation, glycosylation, and phosphorylation were found to be significantly enriched in some novel protein datasets and NeXtProt proteins, compared to their individual random controls (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('32', '47'))	('Methylation', 'Var', (0, 11))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('glycosylation', 'biological_process', 'GO:0070085', ('13', '26'))	('glycosylation', 'MPA', (13, 26))	('enriched', 'Reg', (79, 87))	('phosphorylation', 'MPA', (32, 47))
179121	33495453	Figure 5b and c (left panel and right panel) show the number of unique COSMIC and HGMD mutations along with the disease origin of these mutations for sORFs (left panel) and undefined ORFs (right panel) that are conserved in the human genome.	('HGMD', 'Disease', 'None', (82, 86))	('HGMD', 'Disease', (82, 86))	('sORFs', 'Disease', (150, 155))	('mutations', 'Var', (136, 145))	('human', 'Species', '9606', (228, 233))	('mutations', 'Var', (87, 96))
179124	33495453	Figure 5d shows (a) predicted structure of a translated product from the undefined novel ORF in an intergenic region in chr 14, (b) predicted structure of an undefined novel ORF insertion in Rps3a1 ribosomal protein (cyan) with the inserted fragment (red), and (c) predicted structure of an undefined novel ORF product antisense to Raet1.	('Rps3a1', 'Gene', (191, 197))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('198', '215'))	('insertion', 'Var', (178, 187))	('Rps3a1', 'Gene', '20091', (191, 197))	('Raet1', 'Gene', (332, 337))	('protein', 'cellular_component', 'GO:0003675', ('208', '215'))	('Raet1', 'Gene', '19368', (332, 337))
179192	33495453	2 shows examples of COSMIC or HGMD mutations mapped to all human sORFs, Denovogenes, and Pseudogenes demonstrating that these regions do indeed harbor mutations.	('human', 'Species', '9606', (59, 64))	('HGMD', 'Disease', 'None', (30, 34))	('HGMD', 'Disease', (30, 34))	('mutations', 'Var', (35, 44))
179272	32358509	Here we show that PBRM1/Pbrm1 deficiency reduces the binding of brahma-related gene 1 (BRG1) to the IFNgamma receptor 2 (Ifngr2) promoter, decreasing STAT1 phosphorylation and the subsequent expression of IFNgamma target genes.	('decreasing', 'NegReg', (139, 149))	('STAT1 phosphorylation', 'MPA', (150, 171))	('IFNgamma receptor 2', 'Gene', (100, 119))	('deficiency', 'Var', (30, 40))	('reduces', 'NegReg', (41, 48))	('PBRM1/Pbrm1', 'Gene', (18, 29))	('IFNgamma receptor 2', 'Gene', '3460', (100, 119))	('brahma-related gene 1', 'Gene', '6597', (64, 85))	('binding', 'molecular_function', 'GO:0005488', ('53', '60'))	('phosphorylation', 'biological_process', 'GO:0016310', ('156', '171'))	('BRG1', 'Gene', (87, 91))	('binding', 'Interaction', (53, 60))	('expression', 'MPA', (191, 201))	('brahma-related gene 1', 'Gene', (64, 85))
179274	32358509	Pbrm1 deficient Renca subcutaneous tumors in mice are more resistance to ICB, and a retrospective analysis of the IMmotion150 RCC study also suggests that PBRM1 mutation reduces benefit from ICB.	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (22, 41))	('benefit', 'MPA', (178, 185))	('mice', 'Species', '10090', (45, 49))	('ICB', 'Chemical', '-', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('ICB', 'Chemical', '-', (191, 194))	('Pbrm1', 'Gene', (0, 5))	('mutation', 'Var', (161, 169))	('deficient Renca subcutaneous tumors', 'Disease', (6, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (22, 40))	('deficient Renca subcutaneous tumors', 'Disease', 'MESH:D013352', (6, 41))	('PBRM1', 'Gene', (155, 160))	('reduces', 'NegReg', (170, 177))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('resistance', 'MPA', (59, 69))	('RCC', 'Disease', 'MESH:C538614', (126, 129))
179275	32358509	Our study sheds light on the influence of PBRM1 mutations on IFNgamma-STAT1 signaling and TME, and can inform additional preclinical and clinical studies in RCC.	('TME', 'MPA', (90, 93))	('signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('PBRM1', 'Gene', (42, 47))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', (157, 160))	('IFNgamma-STAT1 signaling', 'MPA', (61, 85))	('mutations', 'Var', (48, 57))	('influence', 'Reg', (29, 38))
179286	32358509	Defects in the IFNgamma signaling pathway, specifically mutations in IFNGR1, JAK1, JAK2, and STAT1, induced resistance to ICB in patients with metastatic melanoma.	('mutations', 'Var', (56, 65))	('Defects', 'NegReg', (0, 7))	('STAT1', 'Gene', (93, 98))	('patients', 'Species', '9606', (129, 137))	('JAK1', 'Gene', (77, 81))	('JAK', 'molecular_function', 'GO:0004713', ('77', '80'))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('induced', 'Reg', (100, 107))	('ICB', 'Chemical', '-', (122, 125))	('JAK', 'molecular_function', 'GO:0004713', ('83', '86'))	('JAK2', 'Gene', (83, 87))	('signaling pathway', 'biological_process', 'GO:0007165', ('24', '41'))	('IFNgamma signaling pathway', 'Pathway', (15, 41))	('IFNGR1', 'Gene', (69, 75))	('resistance to ICB', 'MPA', (108, 125))
179288	32358509	Therefore, it is conceivable that, in patients with ccRCC, the interaction between fundamental gene mutations in tumor cells and the TME also determines resistance to immunotherapy.	('tumor', 'Disease', (113, 118))	('mutations', 'Var', (100, 109))	('resistance to immunotherapy', 'CPA', (153, 180))	('interaction', 'Interaction', (63, 74))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('patients', 'Species', '9606', (38, 46))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('determines', 'Reg', (142, 152))
179290	32358509	Most ccRCC cases are associated with genetic deletions and mutations, or epigenetic silencing of the von Hippel-Lindau (VHL) gene, which results in an accumulation of hypoxia-inducible factors that drive dysregulated angiogenesis.	('accumulation', 'PosReg', (151, 163))	('associated', 'Reg', (21, 31))	('hypoxia', 'Disease', (167, 174))	('hypoxia', 'Disease', 'MESH:D000860', (167, 174))	('epigenetic silencing', 'Var', (73, 93))	('VHL', 'Gene', (120, 123))	('genetic deletions', 'Var', (37, 54))	('von Hippel-Lindau', 'Gene', (101, 118))	('mutations', 'Var', (59, 68))	('angiogenesis', 'biological_process', 'GO:0001525', ('217', '229'))	('RCC', 'Disease', 'MESH:C538614', (7, 10))	('VHL', 'Gene', '7428', (120, 123))	('RCC', 'Disease', (7, 10))	('RCC', 'Phenotype', 'HP:0005584', (7, 10))	('von Hippel-Lindau', 'Gene', '7428', (101, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (5, 10))
179292	32358509	PBRM1 or BAF180 is part of the switch/sucrose non-fermenting (SWI/SNF) chromatin remodeling complex, and ~40% of ccRCC have PBRM1 mutations.	('BAF180', 'Gene', '55193', (9, 15))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('BAF180', 'Gene', (9, 15))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('71', '99'))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (113, 118))	('RCC', 'Disease', (115, 118))	('sucrose', 'Chemical', 'MESH:D013395', (38, 45))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('71', '91'))	('mutations', 'Var', (130, 139))	('PBRM1', 'Gene', (124, 129))
179293	32358509	Recently, PBRM1 mutations were reported to be associated with clinical benefit from anti-PD-1 therapy in ccRCC patients who received prior antiangiogenic therapy.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (105, 110))	('RCC', 'Disease', (107, 110))	('mutations', 'Var', (16, 25))	('PBRM1', 'Gene', (10, 15))	('benefit', 'PosReg', (71, 78))	('patients', 'Species', '9606', (111, 119))
179294	32358509	However, other contemporary studies failed to indicate PBRM1 mutations were a positive predictive biomarker for response to ICB.	('ICB', 'Chemical', '-', (124, 127))	('mutations', 'Var', (61, 70))	('PBRM1', 'Gene', (55, 60))
179296	32358509	However, the significance of this melanoma model is unclear, since human melanoma tumors rarely harbor PBRM1 mutations and RCC demonstrated distinct immune cell-inflamed signatures that were different than melanoma and most other type of tumors.	('melanoma', 'Disease', (73, 81))	('tumors', 'Disease', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('melanoma tumors', 'Disease', 'MESH:D008545', (73, 88))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('tumors', 'Disease', (238, 244))	('melanoma', 'Disease', (206, 214))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('melanoma tumors', 'Disease', (73, 88))	('PBRM1', 'Gene', (103, 108))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mutations', 'Var', (109, 118))	('melanoma', 'Disease', 'MESH:D008545', (206, 214))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))	('human', 'Species', '9606', (67, 72))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
179299	32358509	PBRM1 inactivation was associated with a less immunogenic TME and with resistance to immunotherapy in an immunocompetent murine RCC model.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('inactivation', 'Var', (6, 18))	('PBRM1', 'Gene', (0, 5))	('murine', 'Species', '10090', (121, 127))	('less', 'NegReg', (41, 45))	('resistance', 'CPA', (71, 81))
179300	32358509	Consistent with these findings, we observed that PBRM1 mutations were associated with decreased immune infiltrates in an analysis of nearly 700 patients with ccRCC, and with poor response to ICB-containing therapy.	('immune', 'CPA', (96, 102))	('mutations', 'Var', (55, 64))	('ICB', 'Chemical', '-', (191, 194))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('decreased immune infiltrates', 'Phenotype', 'HP:0012648', (86, 114))	('RCC', 'Disease', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('ccRCC', 'Phenotype', 'HP:0006770', (158, 163))	('patients', 'Species', '9606', (144, 152))	('decreased', 'NegReg', (86, 95))	('PBRM1', 'Gene', (49, 54))
179301	32358509	Taken together, these findings demonstrate that PBRM1 is a key regulator of tumor cell-autonomous immune response in RCC, and loss of PBRM1 function likely contributes to the blunted ICB response experienced by many patients.	('immune response', 'biological_process', 'GO:0006955', ('98', '113'))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('ICB', 'Chemical', '-', (183, 186))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('PBRM1', 'Gene', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('patients', 'Species', '9606', (216, 224))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('loss', 'Var', (126, 130))
179304	32358509	Since constitutive Cas9 expression in Renca cells has previously been shown to induce immune rejection in BALB/c mice, we employed a plasmid-based Cas9 knockout system (Santa Cruz ) that resulted in transient Cas9 expression.	('Cas', 'cellular_component', 'GO:0005650', ('147', '150'))	('Cas9', 'Gene', (19, 23))	('Cas9', 'Gene', (209, 213))	('induce', 'PosReg', (79, 85))	('Cas', 'cellular_component', 'GO:0005650', ('209', '212'))	('Cas', 'cellular_component', 'GO:0005650', ('19', '22'))	('expression', 'Var', (24, 34))	('immune rejection', 'CPA', (86, 102))	('mice', 'Species', '10090', (113, 117))
179306	32358509	IFNgamma binding induces assembly of an active receptor tetramer, leading to activation of JAKs which phosphorylate signal transducer and activator of transcription 1 (STAT1) on Y701, with subsequent STAT1 homodimerization and nuclear translocation.	('Y701', 'Var', (178, 182))	('induces', 'Reg', (17, 24))	('assembly', 'MPA', (25, 33))	('signal transducer and activator of transcription 1', 'Gene', '6772', (116, 166))	('nuclear translocation', 'MPA', (227, 248))	('JAKs', 'Gene', (91, 95))	('IFNgamma', 'Protein', (0, 8))	('activation', 'PosReg', (77, 87))	('JAKs', 'Gene', '3716;16451;3717;16452', (91, 95))	('STAT1 homodimerization', 'MPA', (200, 222))	('transcription', 'biological_process', 'GO:0006351', ('151', '164'))	('binding', 'Interaction', (9, 16))	('binding', 'molecular_function', 'GO:0005488', ('9', '16'))
179316	32358509	ChIP assay with antibody against BRG1 revealed that Pbrm1 knockout reduced the binding of BRG1 to this 5hmC-enriched region in the Ifngr2 promoter, implying that PBRM1 might help BRG1 binding to Ifngr2 promoter, assist assembly of chromatin remodeling complex and initiate Ifngr2 transcription (Fig.	('binding', 'molecular_function', 'GO:0005488', ('184', '191'))	('BRG1', 'Gene', (179, 183))	('5hmC', 'Chemical', 'MESH:C011865', (103, 107))	('transcription', 'biological_process', 'GO:0006351', ('280', '293'))	('antibody', 'molecular_function', 'GO:0003823', ('16', '24'))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('231', '259'))	('antibody', 'cellular_component', 'GO:0042571', ('16', '24'))	('knockout', 'Var', (58, 66))	('BRG1', 'Gene', (90, 94))	('binding', 'molecular_function', 'GO:0005488', ('79', '86'))	('transcription', 'MPA', (280, 293))	('Pbrm1', 'Gene', (52, 57))	('binding', 'Interaction', (184, 191))	('antibody', 'cellular_component', 'GO:0019815', ('16', '24'))	('Ifngr2', 'Gene', (273, 279))	('assist', 'PosReg', (212, 218))	('binding', 'Interaction', (79, 86))	('reduced', 'NegReg', (67, 74))	('PBRM1', 'Gene', (162, 167))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('231', '251'))	('help', 'PosReg', (174, 178))	('antibody', 'cellular_component', 'GO:0019814', ('16', '24'))	('initiate', 'PosReg', (264, 272))
179318	32358509	BRG1 inhibition has been reported to reduce BRG1 binding to CCNB1 and LTBP2 promoters and decrease repressor element 1-silencing transcription factor (REST)-chromatin interaction.	('LTBP2', 'Gene', '4053', (70, 75))	('transcription factor', 'molecular_function', 'GO:0000981', ('129', '149'))	('reduce', 'NegReg', (37, 43))	('inhibition', 'Var', (5, 15))	('LTBP2', 'Gene', (70, 75))	('BRG1', 'Gene', (44, 48))	('binding', 'Interaction', (49, 56))	('repressor element 1-silencing transcription factor', 'Gene', '5978', (99, 149))	('chromatin', 'cellular_component', 'GO:0000785', ('157', '166'))	('CCNB1', 'Gene', (60, 65))	('CCNB1', 'Gene', '891', (60, 65))	('transcription', 'biological_process', 'GO:0006351', ('129', '142'))	('BRG1', 'Gene', (0, 4))	('repressor element 1-silencing transcription factor', 'Gene', (99, 149))	('decrease', 'NegReg', (90, 98))	('binding', 'molecular_function', 'GO:0005488', ('49', '56'))
179324	32358509	We found that the expression of a cytotoxic T cell marker (Cd8a), immune checkpoint markers (Ctla4 and Pdcd1), and T-cell chemoattractive factors (Cxcl10 and Icam1) were significantly lower in Pbrm1 knockout tumors than that in control knockout tumors (Fig.	('Pbrm1', 'Gene', (193, 198))	('Pdcd1', 'Gene', '5133', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('Ctla4', 'Gene', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('expression', 'MPA', (18, 28))	('lower', 'NegReg', (184, 189))	('tumors', 'Disease', (245, 251))	('Cd8a', 'Gene', '925', (59, 63))	('Ctla4', 'Gene', '1493', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('Cd8a', 'Gene', (59, 63))	('knockout', 'Var', (199, 207))	('Icam1', 'Gene', (158, 163))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('Icam1', 'Gene', '3383', (158, 163))	('tumors', 'Disease', (208, 214))	('Pdcd1', 'Gene', (103, 108))
179326	32358509	As we observed in Renca cell lines, the overall Pbrm1 mRNA level in Pbrm1 knockout tumors was much lower than that in control tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (126, 132))	('knockout', 'Var', (74, 82))	('lower', 'NegReg', (99, 104))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('Pbrm1', 'Gene', (68, 73))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('Pbrm1', 'Gene', (48, 53))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
179330	32358509	We found that CD3, CD4, CD8 T, and p-STAT1 positive cell levels were significantly higher in control knockout tumors than that in Pbrm1 knockout tumors (Fig.	('CD4', 'MPA', (19, 22))	('knockout', 'Var', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('CD3', 'Gene', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', (110, 116))	('CD8', 'Gene', (24, 27))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('CD3', 'Gene', '28134', (14, 17))	('p-STAT1 positive cell levels', 'MPA', (35, 63))	('CD8', 'Gene', '925', (24, 27))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('higher', 'PosReg', (83, 89))
179333	32358509	In support of our findings in Renca tumors, we found that Pbrm1 deficiency in pre-malignant renal cortices of mice reduced the expression of the immunomodulatory profile and the abundance of total T cells and CD8 T cells (Fig.	('CD8', 'Gene', (209, 212))	('deficiency', 'Var', (64, 74))	('T cells', 'CPA', (197, 204))	('expression', 'MPA', (127, 137))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('reduced', 'NegReg', (115, 122))	('CD8', 'Gene', '925', (209, 212))	('mice', 'Species', '10090', (110, 114))	('Pbrm1', 'Gene', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('pre', 'molecular_function', 'GO:0003904', ('78', '81'))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
179334	32358509	These results collectively indicate that Pbrm1 deficiency was associated with a less immunogenic microenvironment in different murine models.	('murine', 'Species', '10090', (127, 133))	('less immunogenic microenvironment', 'MPA', (80, 113))	('Pbrm1', 'Gene', (41, 46))	('deficiency', 'Var', (47, 57))
179336	32358509	We generated a plot of the confidence intervals for the differences of genes in the same previously mentioned list between PBRM1 wild-type tumors and PBRM1 mutated tumors.	('PBRM1', 'Gene', (150, 155))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('PBRM1', 'Gene', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('mutated', 'Var', (156, 163))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
179337	32358509	Enrichment analysis showed that PBRM1 mutated tumors exhibited coordinated downregulation of the immunomodulatory gene set relative to the PBRM1 intact group (Fig.	('mutated', 'Var', (38, 45))	('PBRM1', 'Gene', (32, 37))	('downregulation', 'NegReg', (75, 89))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
179340	32358509	Furthermore, the expression of multiple predefined immune-related profiles, including IFNgamma response, IFNalpha response, Fcgamma receptor signaling pathway, lymphocyte mediated immunity, leukocyte mediated immunity, and adaptive immune response was also reduced in tumors with PBRM1 mutations across all three RCC patient cohorts (Fig.	('reduced', 'NegReg', (257, 264))	('IFNalpha', 'Chemical', '-', (105, 113))	('signaling pathway', 'biological_process', 'GO:0007165', ('141', '158'))	('RCC', 'Disease', (313, 316))	('RCC', 'Phenotype', 'HP:0005584', (313, 316))	('adaptive immune response', 'biological_process', 'GO:0002250', ('223', '247'))	('adaptive immune response', 'CPA', (223, 247))	('PBRM1', 'Gene', (280, 285))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('IFNalpha response', 'MPA', (105, 122))	('mutations', 'Var', (286, 295))	('expression', 'MPA', (17, 27))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('lymphocyte mediated immunity', 'biological_process', 'GO:0002449', ('160', '188'))	('patient', 'Species', '9606', (317, 324))	('RCC', 'Disease', 'MESH:C538614', (313, 316))	('lymphocyte mediated immunity', 'MPA', (160, 188))	('leukocyte mediated immunity', 'MPA', (190, 217))	('tumors', 'Disease', (268, 274))	('leukocyte mediated immunity', 'biological_process', 'GO:0002443', ('190', '217'))	('Fcgamma receptor signaling pathway', 'MPA', (124, 158))	('IFNgamma response', 'MPA', (86, 103))	('tumors', 'Disease', 'MESH:D009369', (268, 274))
179341	32358509	According to the IHC intensity in the IMmotion150 dataset, CD8 T cell population was lower in tumors with PBRM1 mutations than that in PBRM1 intact tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('lower', 'NegReg', (85, 90))	('PBRM1', 'Gene', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('CD8', 'Gene', (59, 62))	('mutations', 'Var', (112, 121))	('CD8', 'Gene', '925', (59, 62))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))
179343	32358509	This gene expression-based cell type enrichment analysis revealed that CD8 T cell populations were significantly reduced in PBRM1 mutated tumors in TCGA, IMmotion150 and ICGC RCC cohorts (Fig.	('CD8', 'Gene', '925', (71, 74))	('ICGC RCC', 'Disease', 'MESH:C538614', (170, 178))	('gene expression', 'biological_process', 'GO:0010467', ('5', '20'))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('ICGC RCC', 'Disease', (170, 178))	('PBRM1', 'Gene', (124, 129))	('mutated', 'Var', (130, 137))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('reduced', 'NegReg', (113, 120))	('CD8', 'Gene', (71, 74))
179344	32358509	PBRM1 mutated tumors also demonstrated reduced PD-L1 expression on immune cells (Fig.	('reduced PD', 'Phenotype', 'HP:0032198', (39, 49))	('PBRM1', 'Gene', (0, 5))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('PD-L1', 'Protein', (47, 52))	('reduced', 'NegReg', (39, 46))	('expression', 'MPA', (53, 63))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutated', 'Var', (6, 13))
179345	32358509	To further investigate the immune landscape of PBRM1-deficient tumors, we stained a TMA from 20 RCC patients without prior treatment, including 15 samples with wild-type PBRM1 and 5 with PBRM1 mutations, and each sample was triplicated.	('RCC', 'Disease', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('PBRM1', 'Gene', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('PBRM1-deficient tumors', 'Disease', (47, 69))	('mutations', 'Var', (193, 202))	('patients', 'Species', '9606', (100, 108))	('PBRM1-deficient tumors', 'Disease', 'MESH:D009369', (47, 69))	('PBRM1', 'Gene', (187, 192))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
179346	32358509	PBRM1 mutated tumors were associated with reduced infiltration of CD3 T cells, CD45RO T cells, CD8 T cells, and CD4 T cells (Fig.	('CD45', 'Gene', (79, 83))	('reduced', 'NegReg', (42, 49))	('infiltration', 'CPA', (50, 62))	('CD8', 'Gene', '925', (95, 98))	('CD3', 'Gene', (66, 69))	('PBRM1', 'Gene', (0, 5))	('CD45', 'Gene', '5788', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('CD3', 'Gene', '28134', (66, 69))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('CD8', 'Gene', (95, 98))	('mutated', 'Var', (6, 13))
179349	32358509	We further validated our finding using a TMA from sunitinib-treated primary RCCs, including 12 samples with wild-type PBRM1 and 10 with PBRM1 mutations.	('mutations', 'Var', (142, 151))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('PBRM1', 'Gene', (136, 141))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('sunitinib', 'Chemical', 'MESH:D000077210', (50, 59))	('PBRM1', 'Gene', (118, 123))
179352	32358509	PD-L1 positivity was numerically lower in tumors harboring PBRM1 mutations, although this did not reach statistical significance (Supplementary Fig.	('positivity', 'MPA', (6, 16))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('PBRM1', 'Gene', (59, 64))	('lower', 'NegReg', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('mutations', 'Var', (65, 74))
179354	32358509	Though we found a consistently decreased immunogenic TME in ccRCC patients with PBRM1 loss across 5 patient cohorts, a previous Cas9-based screen in murine melanoma cells indicated that loss of PBRM1 may increase tumor immunogenicity.	('immunogenic TME', 'MPA', (41, 56))	('loss', 'NegReg', (86, 90))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('murine', 'Species', '10090', (149, 155))	('increase', 'PosReg', (204, 212))	('PBRM1', 'Gene', (80, 85))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('decreased', 'NegReg', (31, 40))	('loss', 'Var', (186, 190))	('patient', 'Species', '9606', (100, 107))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('patients', 'Species', '9606', (66, 74))	('tumor', 'Disease', (213, 218))	('patient', 'Species', '9606', (66, 73))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('Cas', 'cellular_component', 'GO:0005650', ('128', '131'))	('PBRM1', 'Gene', (194, 199))
179356	32358509	In contrast to ccRCC, these four tumor populations all demonstrated increased immune infiltration in tumors with loss of PBRM1 (Supplementary Fig.	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('loss', 'Var', (113, 117))	('PBRM1', 'Gene', (121, 126))	('tumor', 'Disease', (33, 38))	('RCC', 'Disease', (17, 20))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('increased', 'PosReg', (68, 77))	('immune', 'CPA', (78, 84))	('tumors', 'Disease', (101, 107))
179358	32358509	In addition to chemoattractive chemokines, aberrant vasculature in tumors also influences T-cell infiltration.	('influences', 'Reg', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('T-cell infiltration', 'CPA', (90, 109))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('aberrant', 'Var', (43, 51))
179360	32358509	CD31 IHC staining in the IMmotion150 cohort revealed that the endothelial cell population was higher in PBRM1 mutated tumors than that in PBRM1 intact tumors, which could be accurately recapitulated using the angiogenesis gene expression signature in order to analyze additional patient cohorts (Fig.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('mutated', 'Var', (110, 117))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('patient', 'Species', '9606', (279, 286))	('PBRM1', 'Gene', (104, 109))	('angiogenesis', 'biological_process', 'GO:0001525', ('209', '221'))	('endothelial cell population', 'CPA', (62, 89))	('tumors', 'Disease', (118, 124))	('gene expression', 'biological_process', 'GO:0010467', ('222', '237'))	('higher', 'PosReg', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
179361	32358509	In all three RCC patient cohorts (TCGA, IMmotion150 and ICGC), PBRM1 mutations were associated with a higher angiogenesis score (Fig.	('mutations', 'Var', (69, 78))	('angiogenesis', 'biological_process', 'GO:0001525', ('109', '121'))	('patient', 'Species', '9606', (17, 24))	('higher', 'PosReg', (102, 108))	('PBRM1', 'Gene', (63, 68))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', (13, 16))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('angiogenesis score', 'CPA', (109, 127))
179364	32358509	These findings indicate that PBRM1 inactivation led to upregulated angiogenesis in RCC, which is consistent with previous reports, and downregulated immunomodulation.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('immunomodulation', 'CPA', (149, 165))	('angiogenesis', 'CPA', (67, 79))	('inactivation', 'Var', (35, 47))	('upregulated', 'PosReg', (55, 66))	('PBRM1', 'Gene', (29, 34))	('downregulated', 'NegReg', (135, 148))	('angiogenesis', 'biological_process', 'GO:0001525', ('67', '79'))
179368	32358509	Since Pbrm1 knockout reduced IFNgamma-STAT1 activity, T-cell infiltration and PD-1 expression in our murine system, we evaluated the influence of PBRM1 loss on response to ICB.	('T-cell infiltration', 'CPA', (54, 73))	('PD-1', 'Gene', (78, 82))	('reduced', 'NegReg', (21, 28))	('knockout', 'Var', (12, 20))	('murine', 'Species', '10090', (101, 107))	('Pbrm1', 'Gene', (6, 11))	('IFNgamma-STAT1 activity', 'MPA', (29, 52))	('ICB', 'Chemical', '-', (172, 175))
179370	32358509	In untreated cohorts, Renca control knockout tumors grew quickly and all mice were sacrificed within 20 days after tumor inoculation due to tumor growth; however, Pbrm1 knockout tumors grew significantly slower and survived longer (Fig.	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('survived', 'CPA', (215, 223))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Disease', (178, 183))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('knockout', 'Var', (169, 177))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumors', 'Disease', (45, 51))	('mice', 'Species', '10090', (73, 77))	('longer', 'PosReg', (224, 230))	('Pbrm1', 'Gene', (163, 168))	('grew', 'CPA', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('slower', 'NegReg', (204, 210))	('tumor', 'Disease', (140, 145))
179371	32358509	When comparing the changes with or without treatment, anti-PD-1 treatment provided more significant survival benefit and tumor growth control in mice bearing control knockout tumors than in those with Pbrm1 knockout tumors (Fig.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', (216, 222))	('survival benefit', 'CPA', (100, 116))	('tumor', 'Disease', (216, 221))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Disease', (175, 180))	('anti-PD-1', 'Gene', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('mice', 'Species', '10090', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('knockout', 'Var', (166, 174))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
179372	32358509	Our Renca subcutaneous tumor model confirmed that PBRM1 inactivation slowed tumor progression, while Pbrm1 knockout tumors were more resistant to early treatment with PD-1 antibody.	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('antibody', 'cellular_component', 'GO:0019814', ('172', '180'))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('PBRM1', 'Gene', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('antibody', 'molecular_function', 'GO:0003823', ('172', '180'))	('antibody', 'cellular_component', 'GO:0042571', ('172', '180'))	('tumors', 'Disease', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (23, 28))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('antibody', 'cellular_component', 'GO:0019815', ('172', '180'))	('inactivation', 'Var', (56, 68))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (10, 28))	('slowed', 'NegReg', (69, 75))	('tumor', 'Disease', (116, 121))
179376	32358509	To confirm the influence of PBRM1 loss on response to ICB treatment in the clinical setting, we analyzed the IMmotion150 dataset and observed that patients with PBRM1 mutations demonstrated a significantly lower response rate to atezolizumab (anti-PD-L1) monotherapy or combination therapy with bevacizumab (anti-VEGF) (Fig.	('PBRM1', 'Gene', (161, 166))	('VEGF', 'Gene', '7422', (313, 317))	('ICB', 'Chemical', '-', (54, 57))	('mutations', 'Var', (167, 176))	('lower', 'NegReg', (206, 211))	('patients', 'Species', '9606', (147, 155))	('response', 'MPA', (212, 220))	('bevacizumab', 'Chemical', 'MESH:D000068258', (295, 306))	('atezolizumab', 'Chemical', 'MESH:C000594389', (229, 241))	('VEGF', 'Gene', (313, 317))
179378	32358509	We found that patients with PBRM1 mutations demonstrated a shorter overall survival than those with intact PBRM1 (Fig.	('overall survival', 'MPA', (67, 83))	('shorter', 'NegReg', (59, 66))	('PBRM1', 'Gene', (28, 33))	('patients', 'Species', '9606', (14, 22))	('mutations', 'Var', (34, 43))
179379	32358509	In patients from TCGA, predominately collected from non-ICB-treated patients with ccRCC, PBRM1 mutations conferred a non-significant trend towards improved survival (Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('ICB', 'Chemical', '-', (56, 59))	('survival', 'MPA', (156, 164))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('PBRM1', 'Gene', (89, 94))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('patients', 'Species', '9606', (68, 76))	('RCC', 'Disease', (84, 87))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (95, 104))	('improved', 'PosReg', (147, 155))
179380	32358509	On further analysis, PBRM1 mutations were associated with significantly prolonged overall survival in TCGA if the few patients also harboring BAP1 mutations were excluded from the cohort.	('mutations', 'Var', (27, 36))	('BAP1', 'Gene', '8314', (142, 146))	('PBRM1', 'Gene', (21, 26))	('prolonged', 'PosReg', (72, 81))	('BAP1', 'Gene', (142, 146))	('overall survival', 'MPA', (82, 98))	('patients', 'Species', '9606', (118, 126))
179384	32358509	Second, PBRM1 inactivation was associated with a less immunogenic TME in murine tumors, which was confirmed across multiple human ccRCC datasets.	('murine', 'Species', '10090', (73, 79))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (130, 135))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('inactivation', 'Var', (14, 26))	('human', 'Species', '9606', (124, 129))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('less', 'NegReg', (49, 53))	('PBRM1', 'Gene', (8, 13))
179385	32358509	Third, PBRM1 inactivation induced resistance to ICB in a Renca-BALB/c immune competent RCC model which could be recapitulated in a ccRCC patient cohort.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('inactivation', 'Var', (13, 25))	('patient', 'Species', '9606', (137, 144))	('resistance to ICB', 'MPA', (34, 51))	('PBRM1', 'Gene', (7, 12))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))	('ICB', 'Chemical', '-', (48, 51))
179391	32358509	Here we found that Pbrm1 knockout Renca tumors were associated with a less immunogenic TME, as characterized by the reduced T-cell infiltrations and decreased immunomodulatory gene expression (Fig.	('reduced', 'NegReg', (116, 123))	('T-cell infiltrations', 'CPA', (124, 144))	('Pbrm1', 'Gene', (19, 24))	('gene expression', 'biological_process', 'GO:0010467', ('176', '191'))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('knockout', 'Var', (25, 33))	('decreased', 'NegReg', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('Renca', 'Disease', (34, 39))	('less immunogenic', 'MPA', (70, 86))	('immunomodulatory gene expression', 'MPA', (159, 191))	('tumors', 'Disease', (40, 46))
179394	32358509	Using an orthogonal expression-based approach, PBRM1 mutated ccRCC tumors were enriched in a non-inflamed cluster, while BAP1 mutated tumors were enriched in an immune cell-inflamed cluster.	('tumors', 'Disease', (134, 140))	('BAP1', 'Gene', '8314', (121, 125))	('PBRM1', 'Gene', (47, 52))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('ccRCC tumors', 'Disease', (61, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('BAP1', 'Gene', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('mutated', 'Var', (53, 60))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('tumors', 'Disease', (67, 73))	('ccRCC tumors', 'Disease', 'MESH:D009369', (61, 73))
179395	32358509	reported the PBRM1 mutations correlated with increased IL6-JAK-STAT3 signaling, which would predict a less T cell-inflamed TME since STAT3 activation inhibits STAT1-dependent gene expression.	('IL6', 'molecular_function', 'GO:0005138', ('55', '58'))	('increased', 'PosReg', (45, 54))	('PBRM1', 'Gene', (13, 18))	('IL6', 'Gene', '3569', (55, 58))	('JAK', 'Gene', '3716;16451;3717;16452', (59, 62))	('STAT3', 'Gene', '6774', (133, 138))	('JAK', 'molecular_function', 'GO:0004713', ('59', '62'))	('STAT1-dependent gene expression', 'MPA', (159, 190))	('mutations', 'Var', (19, 28))	('signaling', 'biological_process', 'GO:0023052', ('69', '78'))	('STAT3', 'Gene', (133, 138))	('gene expression', 'biological_process', 'GO:0010467', ('175', '190'))	('IL6', 'Gene', (55, 58))	('STAT3', 'Gene', '6774', (63, 68))	('JAK', 'Gene', (59, 62))	('STAT3', 'Gene', (63, 68))	('inhibits', 'NegReg', (150, 158))
179404	32358509	In our study, further analysis of patients from the IMmotion150 trial treated with anti-PD-L1 or plus bevacizumab revealed a decreased response rate in tumors with PBRM1 mutations (Fig.	('response', 'MPA', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('mutations', 'Var', (170, 179))	('decreased', 'NegReg', (125, 134))	('PBRM1', 'Gene', (164, 169))	('patients', 'Species', '9606', (34, 42))	('bevacizumab', 'Chemical', 'MESH:D000068258', (102, 113))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
179405	32358509	All patients in this study had received an ICB at some point in their treatment course, and the presence of a PBRM1 mutation was associated with worse survival.	('presence', 'Var', (96, 104))	('associated', 'Reg', (129, 139))	('mutation', 'Var', (116, 124))	('worse', 'NegReg', (145, 150))	('ICB', 'Chemical', '-', (43, 46))	('patients', 'Species', '9606', (4, 12))	('PBRM1', 'Gene', (110, 115))
179407	32358509	First, in a nonrandomized study, we cannot assess the interaction between the treatment and biomarker, and the favorable prognosis of patients with PBRM1 mutations could be inappropriately interpreted as a predictive effect following ICB treatment.	('ICB', 'Chemical', '-', (234, 237))	('PBRM1', 'Gene', (148, 153))	('patients', 'Species', '9606', (134, 142))	('mutations', 'Var', (154, 163))
179408	32358509	As noted above, PBRM1 mutations were reported to be associated with a better prognosis in ccRCC patients and conditional knockout of Pbrm1 in renal tubule epithelial cells was associated with lower grade tumors with clear cell pathological characteristics in a murine model.	('Pbrm1', 'Gene', (133, 138))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('conditional knockout', 'Var', (109, 129))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('associated', 'Reg', (52, 62))	('associated', 'Reg', (176, 186))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('mutations', 'Var', (22, 31))	('patients', 'Species', '9606', (96, 104))	('tumors', 'Disease', (204, 210))	('murine', 'Species', '10090', (261, 267))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('PBRM1', 'Gene', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))
179409	32358509	Similarly, we observed that Pbrm1 knockout delayed tumor growth and prolonged survival in our model system.	('survival', 'CPA', (78, 86))	('delayed', 'NegReg', (43, 50))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('prolonged', 'PosReg', (68, 77))	('tumor', 'Disease', (51, 56))	('Pbrm1', 'Gene', (28, 33))	('knockout', 'Var', (34, 42))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
179412	32358509	PBRM1 mutated tumors have been reported to be more responsive to antiangiogenic therapy.	('PBRM1', 'Gene', (0, 5))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('more', 'PosReg', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutated', 'Var', (6, 13))
179413	32358509	Although tumor revascularization in model systems occurs fairly rapidly after antiangiogenic therapy withdrawal in model systems, clinicopathological data from tumors treated with antiangiogenic therapy show an increase in T-cell infiltration, which is predicted to potentiate response to subsequent ICB treatment.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('ICB', 'Chemical', '-', (300, 303))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('increase', 'PosReg', (211, 219))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('T-cell infiltration', 'CPA', (223, 242))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('antiangiogenic', 'Var', (180, 194))	('tumor', 'Disease', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('tumor', 'Disease', (160, 165))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
179414	32358509	reported PBRM1 mutated tumors were more responsive to ICB in patients who previously received antiangiogenic therapy.	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('patients', 'Species', '9606', (61, 69))	('ICB', 'Chemical', '-', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutated', 'Var', (15, 22))	('responsive to', 'MPA', (40, 53))	('PBRM1', 'Gene', (9, 14))	('more', 'PosReg', (35, 39))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
179415	32358509	We cannot exclude the potential direct and indirect favorable influence of prior antiangiogenic therapy on ICB response in PBRM1 mutated tumors.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('ICB', 'Chemical', '-', (107, 110))	('PBRM1', 'Gene', (123, 128))	('mutated', 'Var', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
179416	32358509	Third, PBRM1 mutations were associated with resistance to atezolizumab, an anti-PD-L1 antibody in the IMmotion 150 study, but with response to nivolumab, an anti-PD-1 antibody in the study by Brown et al.. PD-1 blockade interrupts interactions with PD-L1 as well as PD-L2.	('antibody', 'cellular_component', 'GO:0042571', ('86', '94'))	('antibody', 'cellular_component', 'GO:0019815', ('167', '175'))	('antibody', 'cellular_component', 'GO:0042571', ('167', '175'))	('antibody', 'cellular_component', 'GO:0019815', ('86', '94'))	('antibody', 'cellular_component', 'GO:0019814', ('167', '175'))	('PD-L2', 'Gene', (266, 271))	('PD-1', 'Gene', (206, 210))	('PD-L1', 'Protein', (249, 254))	('interrupts', 'NegReg', (220, 230))	('PD-L2', 'Gene', '80380', (266, 271))	('nivolumab', 'Chemical', 'MESH:D000077594', (143, 152))	('atezolizumab', 'Chemical', 'MESH:C000594389', (58, 70))	('antibody', 'molecular_function', 'GO:0003823', ('167', '175'))	('antibody', 'cellular_component', 'GO:0019814', ('86', '94'))	('interactions', 'Interaction', (231, 243))	('antibody', 'molecular_function', 'GO:0003823', ('86', '94'))	('blockade', 'Var', (211, 219))
179417	32358509	PD-L1 can also promote cancer cell survival via PD-1 independent pathways.	('promote', 'PosReg', (15, 22))	('PD-1 independent pathways', 'Pathway', (48, 73))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('PD-L1', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
179418	32358509	We cannot rule out the possibility that tumors harboring a PBRM1 mutation may respond to anti-PD-1 and anti-PD-L1 antibodies differently.	('respond', 'Reg', (78, 85))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('PBRM1', 'Gene', (59, 64))	('mutation', 'Var', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
179420	32358509	Although these studies focused on the impact of PBRM1 mutations, ccRCC patients also harbor other secondary mutations, such as BAP1 and SETD2, which might affect ICB response in different ways.	('affect', 'Reg', (155, 161))	('BAP1', 'Gene', (127, 131))	('ICB', 'Chemical', '-', (162, 165))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('patients', 'Species', '9606', (71, 79))	('RCC', 'Disease', (67, 70))	('mutations', 'Var', (54, 63))	('SETD2', 'Gene', '29072', (136, 141))	('PBRM1', 'Gene', (48, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('SETD2', 'Gene', (136, 141))	('ICB response', 'MPA', (162, 174))	('BAP1', 'Gene', '8314', (127, 131))
179424	32358509	Importantly, we found that PBRM1 deficiency was associated with a less immunogenic TME in both Renca tumors and human RCC tumors, which is consistent with the widely accepted concept that non-immunogenic tumors are more resistant to ICB therapy.	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('PBRM1', 'Gene', (27, 32))	('ICB', 'Chemical', '-', (233, 236))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('human', 'Species', '9606', (112, 117))	('less', 'NegReg', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (204, 210))	('immunogenic tumor', 'Disease', 'MESH:D009369', (192, 209))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('RCC tumors', 'Disease', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('RCC tumors', 'Disease', 'MESH:C538614', (118, 128))	('deficiency', 'Var', (33, 43))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', (122, 128))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('immunogenic tumor', 'Disease', (192, 209))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
179426	32358509	In summary, this study employed an isogenic murine system with subsequent validation in multiple patient cohorts to demonstrate that PBRM1 loss decreases IFNgamma dependent signaling and tumor immunogenicity, and suggest that PBRM1 mutation associates with ICB resistance.	('associates', 'Reg', (241, 251))	('PBRM1', 'Gene', (133, 138))	('loss decreases IFNgamma dependent', 'Disease', (139, 172))	('PBRM1', 'Gene', (226, 231))	('mutation', 'Var', (232, 240))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('murine', 'Species', '10090', (44, 50))	('tumor', 'Disease', (187, 192))	('patient', 'Species', '9606', (97, 104))	('loss decreases IFNgamma dependent', 'Disease', 'MESH:C536586', (139, 172))	('ICB', 'Chemical', '-', (257, 260))	('ICB resistance', 'Disease', (257, 271))	('signaling', 'biological_process', 'GO:0023052', ('173', '182'))
179427	32358509	The immune competent murine model presented here may assist in the development of therapeutic strategies that can improve T-cell infiltration and immunotherapy response in Pbrm1 knockout tumors, and guide the management of patients with PBRM1 mutated tumors.	('tumors', 'Disease', (251, 257))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('PBRM1', 'Gene', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('knockout', 'Var', (178, 186))	('T-cell infiltration', 'CPA', (122, 141))	('immunotherapy response', 'CPA', (146, 168))	('improve', 'PosReg', (114, 121))	('Pbrm1', 'Gene', (172, 177))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('mutated', 'Var', (243, 250))	('patients', 'Species', '9606', (223, 231))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('murine', 'Species', '10090', (21, 27))
179429	32358509	Mouse CD3 antibody (D4V8L; 99940), mouse CD8 antibody(D4W22; 98941), mouse CD4 antibody (D7D2Z; 25229), human PD-L1 antibody (E1L3N; 13684), mouse PD-L1 antibody (D5V3B; 64988), mouse PD-1 antibody (D7D5W; 84651), PBRM1 antibody (D3F7O, 91894), JAK1 antibody (6G4, 3344), JAK2 antibody (D2E12, 3230), Phospho-JAK1 antibody (D7N4Z, Tyr1034/1035, 74129), Phospho-JAK2 antibody (C80C3, Tyr1007/1008, 3776), STAT1 antibody (D1K9Y, 14994), Phospho-STAT1 antibody (58D6, Tyr701, 9167), Phospho-STAT1 antibody (D3B7, Ser727, 8826), IRF1 antibody (D5E4, 8478), and BRG1 antibody (E9O6E; 52251) were from Cell Signaling Technology.	('antibody', 'cellular_component', 'GO:0042571', ('562', '570'))	('antibody', 'molecular_function', 'GO:0003823', ('79', '87'))	('D7N4Z', 'Var', (324, 329))	('antibody', 'molecular_function', 'GO:0003823', ('250', '258'))	('antibody', 'cellular_component', 'GO:0019814', ('116', '124'))	('antibody', 'cellular_component', 'GO:0019815', ('562', '570'))	('antibody', 'cellular_component', 'GO:0042571', ('366', '374'))	('antibody', 'cellular_component', 'GO:0042571', ('153', '161'))	('antibody', 'cellular_component', 'GO:0019814', ('10', '18'))	('antibody', 'cellular_component', 'GO:0019815', ('79', '87'))	('antibody', 'cellular_component', 'GO:0042571', ('277', '285'))	('D3B7', 'Var', (504, 508))	('JAK', 'molecular_function', 'GO:0004713', ('309', '312'))	('antibody', 'cellular_component', 'GO:0042571', ('220', '228'))	('CD3', 'Gene', '28134', (6, 9))	('Signaling', 'biological_process', 'GO:0023052', ('601', '610'))	('antibody', 'cellular_component', 'GO:0019814', ('189', '197'))	('Tyr701', 'Chemical', '-', (465, 471))	('antibody', 'cellular_component', 'GO:0019814', ('250', '258'))	('antibody', 'molecular_function', 'GO:0003823', ('562', '570'))	('antibody', 'cellular_component', 'GO:0019814', ('494', '502'))	('JAK', 'molecular_function', 'GO:0004713', ('245', '248'))	('antibody', 'cellular_component', 'GO:0042571', ('45', '53'))	('antibody', 'cellular_component', 'GO:0019814', ('530', '538'))	('antibody', 'cellular_component', 'GO:0042571', ('449', '457'))	('JAK', 'molecular_function', 'GO:0004713', ('361', '364'))	('antibody', 'molecular_function', 'GO:0003823', ('366', '374'))	('JAK', 'molecular_function', 'GO:0004713', ('272', '275'))	('human', 'Species', '9606', (104, 109))	('antibody', 'molecular_function', 'GO:0003823', ('153', '161'))	('antibody', 'molecular_function', 'GO:0003823', ('277', '285'))	('antibody', 'cellular_component', 'GO:0019814', ('562', '570'))	('antibody', 'cellular_component', 'GO:0042571', ('116', '124'))	('antibody', 'molecular_function', 'GO:0003823', ('220', '228'))	('antibody', 'cellular_component', 'GO:0019815', ('366', '374'))	('antibody', 'cellular_component', 'GO:0019815', ('153', '161'))	('antibody', 'cellular_component', 'GO:0019814', ('79', '87'))	('antibody', 'cellular_component', 'GO:0042571', ('10', '18'))	('antibody', 'cellular_component', 'GO:0019815', ('277', '285'))	('antibody', 'cellular_component', 'GO:0042571', ('410', '418'))	('antibody', 'molecular_function', 'GO:0003823', ('45', '53'))	('antibody', 'molecular_function', 'GO:0003823', ('449', '457'))	('antibody', 'cellular_component', 'GO:0019815', ('220', '228'))	('mouse', 'Species', '10090', (69, 74))	('antibody', 'cellular_component', 'GO:0042571', ('314', '322'))	('CD8', 'Gene', (41, 44))	('mouse', 'Species', '10090', (141, 146))	('antibody', 'cellular_component', 'GO:0042571', ('494', '502'))	('antibody', 'cellular_component', 'GO:0019815', ('45', '53'))	('antibody', 'cellular_component', 'GO:0019815', ('449', '457'))	('antibody', 'cellular_component', 'GO:0042571', ('530', '538'))	('antibody', 'cellular_component', 'GO:0019815', ('314', '322'))	('antibody', 'molecular_function', 'GO:0003823', ('116', '124'))	('CD3', 'Gene', (6, 9))	('CD8', 'Gene', '925', (41, 44))	('Mouse', 'Species', '10090', (0, 5))	('antibody', 'molecular_function', 'GO:0003823', ('10', '18'))	('antibody', 'molecular_function', 'GO:0003823', ('410', '418'))	('antibody', 'cellular_component', 'GO:0019815', ('116', '124'))	('antibody', 'cellular_component', 'GO:0019814', ('366', '374'))	('antibody', 'molecular_function', 'GO:0003823', ('189', '197'))	('antibody', 'cellular_component', 'GO:0019814', ('153', '161'))	('antibody', 'molecular_function', 'GO:0003823', ('314', '322'))	('antibody', 'molecular_function', 'GO:0003823', ('494', '502'))	('antibody', 'cellular_component', 'GO:0042571', ('79', '87'))	('antibody', 'cellular_component', 'GO:0019814', ('277', '285'))	('antibody', 'cellular_component', 'GO:0042571', ('189', '197'))	('antibody', 'cellular_component', 'GO:0019815', ('10', '18'))	('antibody', 'cellular_component', 'GO:0042571', ('250', '258'))	('antibody', 'cellular_component', 'GO:0019815', ('410', '418'))	('antibody', 'molecular_function', 'GO:0003823', ('530', '538'))	('antibody', 'cellular_component', 'GO:0019814', ('220', '228'))	('C80C3', 'Var', (376, 381))	('Ser', 'cellular_component', 'GO:0005790', ('510', '513'))	('antibody', 'cellular_component', 'GO:0019815', ('189', '197'))	('antibody', 'cellular_component', 'GO:0019815', ('250', '258'))	('antibody', 'cellular_component', 'GO:0019814', ('410', '418'))	('antibody', 'cellular_component', 'GO:0019815', ('494', '502'))	('mouse', 'Species', '10090', (178, 183))	('antibody', 'cellular_component', 'GO:0019814', ('45', '53'))	('antibody', 'cellular_component', 'GO:0019814', ('449', '457'))	('D1K9Y', 'Var', (420, 425))	('mouse', 'Species', '10090', (35, 40))	('antibody', 'cellular_component', 'GO:0019815', ('530', '538'))	('antibody', 'cellular_component', 'GO:0019814', ('314', '322'))
179432	32358509	Renca cells were transfected with control knockout CRISPR/Cas9 plasmid (Santa Cruz Biotechnology, sc418922) or murine Pbrm1 CRISPR/Cas9 knockout plasmids (sc-426270) plus homology-directed repair (HDR) plasmid (sc-426270-HDR).	('sc-426270', 'Var', (155, 164))	('Cas', 'cellular_component', 'GO:0005650', ('58', '61'))	('Cas', 'cellular_component', 'GO:0005650', ('131', '134'))	('sc-426270-HDR', 'Var', (211, 224))	('homology-directed repair', 'biological_process', 'GO:0000724', ('171', '195'))	('HDR', 'biological_process', 'GO:0000724', ('197', '200'))	('murine', 'Species', '10090', (111, 117))	('HDR', 'biological_process', 'GO:0000724', ('221', '224'))
179441	32358509	Briefly, cells were incubated with 1% formaldehyde for 10 min at room temperature to cross-link proteins to DNA, nuclei were digested with micrococcal nuclease and sonication.	('proteins', 'Protein', (96, 104))	('formaldehyde', 'Chemical', 'MESH:D005557', (38, 50))	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('cross-link', 'Var', (85, 95))
179459	32358509	The slides were stained with primary antibodies against CD8 and PD-1, corresponding HRP conjugated secondary antibodies, and subsequently TSA dyes to generate Opal signal (CD8, Opal 520; PD-1, Opal 570, or Opal 620).	('TSA', 'molecular_function', 'GO:0033984', ('138', '141'))	('Opal 620', 'Var', (206, 214))	('CD8', 'Gene', (172, 175))	('Opal 520; PD-1', 'Var', (177, 191))	('CD8', 'Gene', '925', (172, 175))	('Opal 570', 'Var', (193, 201))	('PD-1', 'Var', (187, 191))	('CD8', 'Gene', (56, 59))	('CD8', 'Gene', '925', (56, 59))	('TSA', 'Chemical', '-', (138, 141))
179465	32358509	The confidence interval plots represent the differences in these genes between the two groups (wild-type vs. PBRM1 mutant in TCGA or control knockout vs. Pbrm1 knockout in murine tumors).	('PBRM1', 'Gene', (109, 114))	('tumors', 'Disease', (179, 185))	('mutant', 'Var', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('murine', 'Species', '10090', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))
179476	28775315	Here, we show that 1954 urologic cancers can be classified into nine major genomic subtypes, on the basis of multidimensional and comprehensive molecular characterization (including DNA methylation and copy number, and RNA and protein expression).	('protein', 'cellular_component', 'GO:0003675', ('227', '234'))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('urologic cancers', 'Disease', (24, 40))	('RNA', 'cellular_component', 'GO:0005562', ('219', '222'))	('copy number', 'Var', (202, 213))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('DNA methylation', 'biological_process', 'GO:0006306', ('182', '197'))	('urologic cancers', 'Disease', 'MESH:D014571', (24, 40))	('DNA', 'cellular_component', 'GO:0005574', ('182', '185'))	('men', 'Species', '9606', (116, 119))
179494	28775315	However, in terms of treatment, it is well understood that the different cancer types as defined by tissue of origin would represent quite distinct diseases from each other on the basis of several factors, including histologic appearance, the presence of distinct driver mutations, varying clinical course, and different responses to systemic therapy.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('men', 'Species', '9606', (26, 29))	('mutations', 'Var', (271, 280))
179515	28775315	Using established analytical approaches, the 1954 TCGA urologic cancer cases were subtyped according to each of the data platforms for DNA methylation, DNA copy alteration, mRNA expression, miRNA expression, and protein expression, with the various subtype calls for each sample then being consolidated to define multiplatform-based molecular subtypes (Table 1).	('miRNA expression', 'MPA', (190, 206))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('DNA', 'cellular_component', 'GO:0005574', ('152', '155'))	('DNA methylation', 'biological_process', 'GO:0006306', ('135', '150'))	('urologic cancer', 'Disease', (55, 70))	('copy alteration', 'Var', (156, 171))	('urologic cancer', 'Disease', 'MESH:D014571', (55, 70))	('mRNA expression', 'MPA', (173, 188))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
179528	28775315	Patterns of alteration involving p16, including epigenetic silencing and copy loss:often associated with DNA hypermethylation:differed by subtype (Fig.	('p16', 'Gene', (33, 36))	('copy loss', 'Var', (73, 82))	('epigenetic silencing', 'Var', (48, 68))	('p16', 'Gene', '1029', (33, 36))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('105', '125'))
179529	28775315	Significant anti-correlations between methylation and expression for a subset of genes could be identified (Supplementary Data 4).	('expression', 'MPA', (54, 64))	('anti-correlations', 'NegReg', (12, 29))	('methylation', 'Var', (38, 49))	('men', 'Species', '9606', (114, 117))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))
179543	28775315	Within cancer types, somatic mutation or copy alteration of specific genes could be strongly associated with pan-urologic cancer genomic subtype.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('urologic cancer', 'Disease', (113, 128))	('cancer', 'Disease', (122, 128))	('copy alteration', 'Var', (41, 56))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('urologic cancer', 'Disease', 'MESH:D014571', (113, 128))	('associated', 'Reg', (93, 103))	('cancer', 'Disease', (7, 13))	('genes', 'Gene', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
179547	28775315	MET mutations were primarily associated with KIRP.c6 cases (Supplementary Fig.	('KIRP.c6 cases', 'Disease', (45, 58))	('men', 'Species', '9606', (66, 69))	('MET mutations', 'Var', (0, 13))	('associated', 'Reg', (29, 39))	('mutations', 'Var', (4, 13))
179559	28775315	Clear cell kidney cancer is closely associated with VHL gene mutations that lead to stabilization of hypoxia-inducible factors such as HIF-1alpha.	('hypoxia', 'Disease', (101, 108))	('VHL', 'Gene', '7428', (52, 55))	('HIF-1alpha', 'Gene', (135, 145))	('kidney cancer', 'Phenotype', 'HP:0009726', (11, 24))	('Clear cell kidney cancer', 'Disease', 'MESH:D008649', (0, 24))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('HIF-1alpha', 'Gene', '3091', (135, 145))	('associated', 'Reg', (36, 46))	('Clear cell kidney cancer', 'Disease', (0, 24))	('hypoxia', 'Disease', 'MESH:D000860', (101, 108))	('VHL', 'Gene', (52, 55))
179593	28775315	Somatic DNA alterations may serve to help drive microenvironmental-associated phenomenon, e.g., VHL mutations in clear cell kidney promoting expression of hypoxia-inducible genes.	('mutations', 'Var', (100, 109))	('men', 'Species', '9606', (83, 86))	('promoting', 'PosReg', (131, 140))	('hypoxia', 'Disease', 'MESH:D000860', (155, 162))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('VHL', 'Gene', (96, 99))	('expression', 'MPA', (141, 151))	('men', 'Species', '9606', (60, 63))	('hypoxia', 'Disease', (155, 162))	('VHL', 'Gene', '7428', (96, 99))
179618	28775315	Except for FGFR, KIT, and MET genes, mutations in oncogenes (e.g., KRAS) were represented in figures, if the mutations occurred in "hotspot" residues as reported by Chang et al.	('KRAS', 'Gene', (67, 71))	('KIT', 'molecular_function', 'GO:0005020', ('17', '20'))	('mutations', 'Var', (109, 118))	('KRAS', 'Gene', '3845', (67, 71))	('FGFR', 'molecular_function', 'GO:0005007', ('11', '15'))
179625	28775315	The DNA methylation level as interrogated by cg13601799 was used for CDKN2A; as done previously , a beta value of 0.2 or above was considered evidence for epigenetic silencing.	('CDKN2A', 'Gene', '1029', (69, 75))	('cg13601799', 'Chemical', '-', (45, 55))	('epigenetic silencing', 'Var', (155, 175))	('DNA methylation', 'biological_process', 'GO:0006306', ('4', '19'))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))	('CDKN2A', 'Gene', (69, 75))
179637	28775315	RPPA profiles were also scored for a previously defined MAPK signature (average of phospho-SHC or pSHC, pRAF, pMEK, pERK, pSRK, pYB1, pP38, pJNK, and pJUN).	('pERK', 'Gene', (116, 120))	('pERK', 'Gene', '9451', (116, 120))	('MAPK', 'molecular_function', 'GO:0004707', ('56', '60'))	('pP38', 'Var', (134, 138))	('pYB1', 'Var', (128, 132))
179639	28775315	As described above, urologic cancer cases were subtyped according to each of the individual data platforms for DNA methylation, DNA copy alteration, mRNA expression, miRNA expression, and protein expression.	('miRNA expression', 'MPA', (166, 182))	('protein expression', 'MPA', (188, 206))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('urologic cancer', 'Disease', (20, 35))	('copy alteration', 'Var', (132, 147))	('DNA methylation', 'biological_process', 'GO:0006306', ('111', '126'))	('urologic cancer', 'Disease', 'MESH:D014571', (20, 35))	('mRNA expression', 'MPA', (149, 164))
179671	32884956	Downregulation of Transmembrane protein 40 by miR-138-5p Suppresses Cell Proliferation and Mobility in Clear Cell Renal Cell Carcinoma Clear cell renal cell carcinoma (ccRCC) represents approximately 70% of RCC,as the most frequent histological subtype of RCC.	('Cell Proliferation', 'biological_process', 'GO:0008283', ('68', '86'))	('Downregulation', 'NegReg', (0, 14))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (135, 166))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (114, 134))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (103, 134))	('Carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('Mobility', 'CPA', (91, 99))	('Clear cell renal cell carcinoma', 'Disease', (135, 166))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (146, 166))	('miR-138-5p', 'Chemical', '-', (46, 56))	('rat', 'Species', '10116', (80, 83))	('RCC', 'Disease', (170, 173))	('miR-138-5p', 'Var', (46, 56))	('RCC', 'Disease', (256, 259))	('ccRCC', 'Phenotype', 'HP:0006770', (168, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (135, 166))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (103, 134))	('Cell Proliferation', 'CPA', (68, 86))	('Suppresses', 'NegReg', (57, 67))	('RCC', 'Disease', (207, 210))	('RCC', 'Disease', 'MESH:C538614', (256, 259))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('Transmembrane protein 40', 'Gene', '55287', (18, 42))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('Transmembrane protein 40', 'Gene', (18, 42))	('Clear Cell Renal Cell Carcinoma', 'Disease', (103, 134))
179674	32884956	Taken together, our findings provide the first clues regarding the role of miR-138-5p as a tumor suppressor in ccRCC by directly targeting of TMEM40 Each year, approximately 65,000 new cases of kidney cancers will be diagnosed, and kidney cancer causing 13680 deaths are found in the United States .	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('cancers', 'Disease', (201, 208))	('cancer', 'Disease', (201, 207))	('TMEM40', 'Gene', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('deaths', 'Disease', (260, 266))	('kidney cancer', 'Phenotype', 'HP:0009726', (194, 207))	('kidney cancers', 'Phenotype', 'HP:0009726', (194, 208))	('ccRCC', 'Disease', (111, 116))	('kidney cancer', 'Disease', 'MESH:D007680', (232, 245))	('cancer', 'Disease', (239, 245))	('deaths', 'Disease', 'MESH:D003643', (260, 266))	('targeting', 'NegReg', (129, 138))	('kidney cancer', 'Phenotype', 'HP:0009726', (232, 245))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('kidney cancer', 'Disease', (232, 245))	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('miR-138-5p', 'Var', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('91', '107'))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('kidney cancer', 'Disease', 'MESH:D007680', (194, 207))	('kidney cancers', 'Disease', 'MESH:D007680', (194, 208))	('kidney cancers', 'Disease', (194, 208))	('tumor suppressor', 'biological_process', 'GO:0051726', ('91', '107'))
179677	32884956	In comparison with frontotemporal lobar degeneration and asymptomatic carriers, patients carrying Granulin (GRN) mutations exhibited higher levels of TMEM40 .	('Granulin', 'Gene', (98, 106))	('Granulin', 'Gene', '2896', (98, 106))	('GRN', 'Gene', (108, 111))	('TMEM40', 'MPA', (150, 156))	('higher', 'PosReg', (133, 139))	('degeneration', 'Disease', 'MESH:D012162', (40, 52))	('frontotemporal lobar degeneration', 'Phenotype', 'HP:0006892', (19, 52))	('mutations', 'Var', (113, 122))	('degeneration', 'Disease', (40, 52))	('GRN', 'Gene', '2896', (108, 111))
179682	32884956	MiR-138-5p, belonging to the miRNAs family, is a recently emerged tumor suppressor in bladder cancer , pancreatic cancer , colorectal cancer , and non-small cell lung cancer .	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('pancreatic cancer', 'Disease', (103, 120))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('66', '82'))	('colorectal cancer', 'Disease', (123, 140))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('non-small cell lung cancer', 'Disease', (147, 173))	('tumor suppressor', 'biological_process', 'GO:0051726', ('66', '82'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('colorectal cancer', 'Phenotype', 'HP:0003003', (123, 140))	('bladder cancer', 'Disease', (86, 100))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (147, 173))	('MiR-138-5p', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (151, 173))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('pancreatic cancer', 'Disease', 'MESH:D010190', (103, 120))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (147, 173))	('colorectal cancer', 'Disease', 'MESH:D015179', (123, 140))
179683	32884956	Previous studies have suggested that the involvement of miR-138-3p in the tumorigenesis and development of these types of cancers through binding  to the 3'UTR miRNA recognition elements of their target mRNAs.	('development', 'CPA', (92, 103))	('tumorigenesis', 'CPA', (74, 87))	('binding', 'molecular_function', 'GO:0005488', ('138', '145'))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('miR-138-3p', 'Var', (56, 66))	('binding', 'Interaction', (138, 145))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('involvement', 'Reg', (41, 52))	('miR-138-3p', 'Chemical', '-', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
179704	32884956	Consistently, TMEM40 knockdown inhibited invasive cell number in 786-O cells by 67.23% (siNCvs.	('TMEM40', 'Gene', (14, 20))	('invasive cell number in 786-O cells', 'CPA', (41, 76))	('siNCvs', 'Disease', (88, 94))	('inhibited', 'NegReg', (31, 40))	('knockdown', 'Var', (21, 30))	('siNCvs', 'Disease', 'None', (88, 94))
179707	32884956	MiR-138-5p is a tumor suppressor that inhibits colorectal cancer cells and S-phase entry though  targeting PD-L1 .	('PD-L1', 'Gene', '29126', (107, 112))	('colorectal cancer', 'Disease', (47, 64))	('S-phase entry', 'CPA', (75, 88))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('inhibits', 'NegReg', (38, 46))	('tumor suppressor', 'biological_process', 'GO:0051726', ('16', '32'))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('MiR-138-5p', 'Var', (0, 10))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('16', '32'))	('PD-L1', 'Gene', (107, 112))	('S-phase', 'biological_process', 'GO:0051320', ('75', '82'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (47, 64))
179708	32884956	In non-small lung cancer cells, miR-138-5p is reported to reverse the gefitinib resistance via downregulation of G-protein-coupled receptor 124 .	('lung cancer', 'Phenotype', 'HP:0100526', (13, 24))	('downregulation', 'NegReg', (95, 109))	('G-protein-coupled receptor 124', 'Gene', (113, 143))	('miR-138-5p', 'Var', (32, 42))	('gefitinib resistance', 'MPA', (70, 90))	('gefitinib', 'Chemical', 'MESH:D000077156', (70, 79))	('G-protein-coupled receptor 124', 'Gene', '25960', (113, 143))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('small lung', 'Phenotype', 'HP:0002089', (7, 17))	('reverse', 'NegReg', (58, 65))
179709	32884956	Besides, a strong correlation between miR-138-5p and SIRT1 and FOXC1 are respectively noted in the intervertebral disc degeneration (IDD) and pancreatic cancer .	('correlation', 'Reg', (18, 29))	('intervertebral disc degeneration', 'Phenotype', 'HP:0008419', (99, 131))	('IDD', 'Disease', 'MESH:C535531', (133, 136))	('SIRT1', 'Gene', (53, 58))	('disc degeneration', 'Disease', (114, 131))	('pancreatic cancer', 'Disease', (142, 159))	('disc degeneration', 'Disease', 'MESH:D055959', (114, 131))	('IDD', 'Phenotype', 'HP:0008419', (133, 136))	('FOXC1', 'Gene', '2296', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('SIRT1', 'Gene', '23411', (53, 58))	('IDD', 'Disease', (133, 136))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (142, 159))	('miR-138-5p', 'Var', (38, 48))	('FOXC1', 'Gene', (63, 68))
179710	32884956	However, few studies have supplied evidence for a relationship between miR-138-5p expression patterns and ccRCC malignant behavior.	('ccRCC malignant behavior', 'Disease', (106, 130))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('ccRCC malignant behavior', 'Disease', 'MESH:D009369', (106, 130))	('miR-138-5p', 'Var', (71, 81))
179713	32884956	More importantly, loss of TMEM40 could relieve the enhanced bladder cancer cell proliferation via the changed expression levels of p53,  p21, c-MYC, and cyclin D1.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('p21', 'Gene', '644914', (137, 140))	('bladder cancer', 'Phenotype', 'HP:0009725', (60, 74))	('cyclin D1', 'Gene', (153, 162))	('p53', 'Gene', (131, 134))	('cyclin D1', 'Gene', '595', (153, 162))	('expression levels', 'MPA', (110, 127))	('cyclin', 'molecular_function', 'GO:0016538', ('153', '159'))	('c-MYC', 'Gene', '4609', (142, 147))	('cell proliferation', 'biological_process', 'GO:0008283', ('75', '93'))	('relieve', 'PosReg', (39, 46))	('c-MYC', 'Gene', (142, 147))	('TMEM40', 'Gene', (26, 32))	('loss', 'Var', (18, 22))	('p53', 'Gene', '7157', (131, 134))	('enhanced', 'PosReg', (51, 59))	('bladder cancer', 'Disease', (60, 74))	('changed', 'Reg', (102, 109))	('p21', 'Gene', (137, 140))
179716	32884956	Recently, miR-22, miR-29s, and miR-124 are correlated with ccRCC invasion and migration, and miR-138-5p is deemed as one of the tumor suppressors in multiple types of cancer .	('miR-22', 'Gene', '407004', (10, 16))	('miR-138-5p', 'Var', (93, 103))	('miR-22', 'Gene', (10, 16))	('correlated', 'Reg', (43, 53))	('ccRCC', 'Disease', (59, 64))	('miR-124', 'Var', (31, 38))	('miR-29s', 'Chemical', '-', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('migration', 'CPA', (78, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('miR-29s', 'Var', (18, 25))
179829	28688232	Aberrant Promoter Methylation of PCDH17 (Protocadherin 17) in Serum and its Clinical Significance in Renal Cell Carcinoma Current studies indicated that PCDH17 functions as a tumor suppressor, which is frequently inactivated by aberrant promoter methylation in urologic tumors.	('PCDH17', 'Gene', '27253', (33, 39))	('PCDH17', 'Gene', '27253', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('methylation', 'biological_process', 'GO:0032259', ('246', '257'))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))	('Protocadherin 17', 'Gene', (41, 57))	('Aberrant', 'Var', (0, 8))	('Protocadherin 17', 'Gene', '27253', (41, 57))	('Methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('Renal Cell Carcinoma', 'Disease', (101, 121))	('tumor', 'Disease', (175, 180))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (101, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('175', '191'))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', (270, 275))	('urologic tumors', 'Disease', 'MESH:D014571', (261, 276))	('Carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('Promoter Methylation', 'MPA', (9, 29))	('urologic tumors', 'Disease', (261, 276))	('tumor suppressor', 'biological_process', 'GO:0051726', ('175', '191'))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (101, 121))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('PCDH17', 'Gene', (33, 39))	('PCDH17', 'Gene', (153, 159))
179833	28688232	We found that PCDH17 was more frequently methylated in RCC patients than in controls.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('PCDH17', 'Gene', '27253', (14, 20))	('methylated', 'Var', (41, 51))	('patients', 'Species', '9606', (59, 67))	('PCDH17', 'Gene', (14, 20))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
179834	28688232	Moreover, PCDH17 methylation in serum was significantly correlated with advanced stage (p=0.044), higher grade (p=0.019), lymph node metastasis (p=0.008) and tumor progression (p<0.001).	('tumor', 'Disease', (158, 163))	('advanced stage', 'CPA', (72, 86))	('PCDH17', 'Gene', '27253', (10, 16))	('methylation', 'Var', (17, 28))	('lymph node metastasis', 'CPA', (122, 143))	('higher grade', 'CPA', (98, 110))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('PCDH17', 'Gene', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('correlated', 'Reg', (56, 66))
179835	28688232	In addition, patients with methylated PCDH17 had shorter progression-free survival (p<0.001) and overall survival (p=0.017) than patients without, and PCDH17 methylation in serum was an independent prognostic factor for worse progression-free survival (HR: 4.215, 95% CI: 1.376-9.032, p<0.001) and overall survival (HR: 5.092, 95% CI: 1.149-12.357, p=0.046) of patients with RCC.	('PCDH17', 'Gene', '27253', (38, 44))	('RCC', 'Disease', (375, 378))	('RCC', 'Phenotype', 'HP:0005584', (375, 378))	('methylation', 'biological_process', 'GO:0032259', ('158', '169'))	('patients', 'Species', '9606', (361, 369))	('PCDH17', 'Gene', '27253', (151, 157))	('patients', 'Species', '9606', (129, 137))	('overall survival', 'CPA', (97, 113))	('patients', 'Species', '9606', (13, 21))	('methylated', 'Var', (27, 37))	('shorter', 'NegReg', (49, 56))	('PCDH17', 'Gene', (38, 44))	('PCDH17', 'Gene', (151, 157))	('progression-free survival', 'CPA', (57, 82))	('RCC', 'Disease', 'MESH:C538614', (375, 378))
179836	28688232	The present study indicates that PCDH17 methylation in serum is a frequent event in RCC and associated with risk factors of poor outcomes.	('methylation', 'Var', (40, 51))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('PCDH17', 'Gene', '27253', (33, 39))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('methylation', 'biological_process', 'GO:0032259', ('40', '51'))	('associated', 'Reg', (92, 102))	('PCDH17', 'Gene', (33, 39))
179837	28688232	Moreover, PCDH17 methylation in serum is a potential prognostic biomarker for patients with RCC after surgery.	('PCDH17', 'Gene', '27253', (10, 16))	('methylation', 'Var', (17, 28))	('patients', 'Species', '9606', (78, 86))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('PCDH17', 'Gene', (10, 16))
179844	28688232	Recent studies have shown that aberrant methylation of some tumor suppressor genes is involved in the initiation and progression of RCC.	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('60', '76'))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('involved', 'Reg', (86, 94))	('aberrant methylation', 'Var', (31, 51))	('methylation', 'biological_process', 'GO:0032259', ('40', '51'))	('tumor', 'Disease', (60, 65))	('tumor suppressor', 'biological_process', 'GO:0051726', ('60', '76'))
179845	28688232	Epigenetic silencing of tumor suppressor genes caused by DNA methylation, leading to increased tumor cell proliferation, invasion, and metastasis, and DNA methylation can be used as potential diagnostic or prognostic biomarkers.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor suppressor', 'biological_process', 'GO:0051726', ('24', '40'))	('methylation', 'Var', (61, 72))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('tumor', 'Disease', (24, 29))	('DNA methylation', 'biological_process', 'GO:0006306', ('57', '72'))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('cell proliferation', 'biological_process', 'GO:0008283', ('101', '119'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('24', '40'))	('DNA methylation', 'biological_process', 'GO:0006306', ('151', '166'))	('Epigenetic silencing', 'Var', (0, 20))	('increased', 'PosReg', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('invasion', 'CPA', (121, 129))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))	('tumor', 'Disease', (95, 100))
179846	28688232	Aberrant DNA methylation can be detected in tumor tissue and also in serum, and DNA methylation status in serum corresponds to those found in the tumor.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('Aberrant', 'Var', (0, 8))	('methylation', 'Var', (13, 24))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('DNA methylation', 'biological_process', 'GO:0006306', ('80', '95'))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
179847	28688232	Methylated DNA in serum can be used as potential biomarker for tumor diagnosis and prognosis, and for monitoring therapy response.	('tumor', 'Disease', (63, 68))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Methylated', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
179849	28688232	Our previous study indicated that PCDH17 methylation occurred frequently in RCC tissues, and correlated with malignant clinicopathologic characteristics as well as poor outcomes of patients.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('correlated', 'Reg', (93, 103))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('PCDH17', 'Gene', (34, 40))	('methylation', 'Var', (41, 52))	('patients', 'Species', '9606', (181, 189))	('PCDH17', 'Gene', '27253', (34, 40))
179863	28688232	Univariate and multivariate Cox proportional hazards model analysis was used to evaluate the prognostic value of PCDH17 methylation in ccRCC.	('PCDH17', 'Gene', (113, 119))	('methylation', 'Var', (120, 131))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))	('PCDH17', 'Gene', '27253', (113, 119))	('methylation', 'biological_process', 'GO:0032259', ('120', '131'))
179865	28688232	We found that PCDH17 methylation was detected in 82 (57.7%) patients (Figure 1), but no methylation was detected in the controls.	('methylation', 'biological_process', 'GO:0032259', ('21', '32'))	('PCDH17', 'Gene', '27253', (14, 20))	('patients', 'Species', '9606', (60, 68))	('methylation', 'Var', (21, 32))	('detected', 'Reg', (37, 45))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('PCDH17', 'Gene', (14, 20))
179866	28688232	The difference of PCDH17 methylation status between ccRCC patients and controls was statistically significant (p<0.001).	('RCC', 'Disease', (54, 57))	('PCDH17', 'Gene', '27253', (18, 24))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('methylation', 'Var', (25, 36))	('methylation', 'biological_process', 'GO:0032259', ('25', '36'))	('patients', 'Species', '9606', (58, 66))	('PCDH17', 'Gene', (18, 24))
179869	28688232	The results suggested that PCDH17 methylation in serum was significantly correlated with advanced stage (p=0.044), higher grade (p=0.019), lymph node metastasis (p=0.008) and tumor progression (p<0.001).	('PCDH17', 'Gene', '27253', (27, 33))	('tumor', 'Disease', (175, 180))	('correlated', 'Reg', (73, 83))	('lymph node metastasis', 'CPA', (139, 160))	('methylation', 'Var', (34, 45))	('higher grade', 'CPA', (115, 127))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('PCDH17', 'Gene', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('advanced stage', 'CPA', (89, 103))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
179874	28688232	The Kaplan-Meier survival analysis and log-rank test suggested that patients with PCDH17 methylation in serum had shorter progression-free survival (p<0.001, Figure 2) and overall survival (p=0.017, Figure 3) than patients with PCDH17 unmethylated.	('overall survival', 'CPA', (172, 188))	('patients', 'Species', '9606', (214, 222))	('methylation', 'biological_process', 'GO:0032259', ('89', '100'))	('methylation', 'Var', (89, 100))	('PCDH17', 'Gene', '27253', (228, 234))	('shorter', 'NegReg', (114, 121))	('PCDH17', 'Gene', (82, 88))	('patients', 'Species', '9606', (68, 76))	('progression-free survival', 'CPA', (122, 147))	('PCDH17', 'Gene', (228, 234))	('PCDH17', 'Gene', '27253', (82, 88))
179875	28688232	Moreover, Cox proportional hazards model analysis suggested that PCDH17 methylation in serum was an independent prognostic factor for worse progression-free survival (p<0.001, Table 2) and overall survival (p=0.046, Table 3) of patients with ccRCC.	('progression-free survival', 'CPA', (140, 165))	('RCC', 'Disease', (244, 247))	('RCC', 'Phenotype', 'HP:0005584', (244, 247))	('overall survival', 'CPA', (189, 205))	('methylation', 'biological_process', 'GO:0032259', ('72', '83'))	('PCDH17', 'Gene', '27253', (65, 71))	('patients', 'Species', '9606', (228, 236))	('methylation', 'Var', (72, 83))	('PCDH17', 'Gene', (65, 71))	('worse', 'NegReg', (134, 139))	('RCC', 'Disease', 'MESH:C538614', (244, 247))
179876	28688232	Genetic and epigenetic changes are involved in the initiation and progression of RCC.	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('involved', 'Reg', (35, 43))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('epigenetic changes', 'Var', (12, 30))
179877	28688232	However, aberrant DNA methylation is the most common epigenetic change, which can result in the inactivation of important tumor suppressor genes, and associates with tumorigenesis and progression.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('progression', 'CPA', (184, 195))	('associates with', 'Reg', (150, 165))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('aberrant DNA methylation', 'Var', (9, 33))	('tumor suppressor', 'biological_process', 'GO:0051726', ('122', '138'))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('122', '138'))	('DNA methylation', 'biological_process', 'GO:0006306', ('18', '33'))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))	('inactivation', 'MPA', (96, 108))	('tumor', 'Disease', (122, 127))
179878	28688232	DNA methylation can be detected not only in tumor tissues, but also in body fluids, especially in the serum, and aberrant DNA methylation in serum appears to be a very consistent feature of cancer.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('DNA methylation', 'biological_process', 'GO:0006306', ('122', '137'))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('DNA', 'cellular_component', 'GO:0005574', ('122', '125'))	('tumor', 'Disease', (44, 49))	('aberrant', 'Var', (113, 121))
179882	28688232	Previous studies indicated that PCDH17 was frequently inactivated by aberrant promoter methylation in RCC, and this is the first study to research PCDH17 methylation in serum of patients with RCC.	('PCDH17', 'Gene', '27253', (147, 153))	('PCDH17', 'Gene', (32, 38))	('RCC', 'Phenotype', 'HP:0005584', (192, 195))	('patients', 'Species', '9606', (178, 186))	('aberrant', 'Var', (69, 77))	('methylation', 'biological_process', 'GO:0032259', ('87', '98'))	('methylation', 'biological_process', 'GO:0032259', ('154', '165'))	('PCDH17', 'Gene', (147, 153))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('PCDH17', 'Gene', '27253', (32, 38))	('RCC', 'Disease', (102, 105))	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('RCC', 'Disease', (192, 195))	('promoter', 'MPA', (78, 86))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('inactivated', 'NegReg', (54, 65))
179883	28688232	We have found a significantly high frequency of PCDH17 methylation in serum of cases with RCC.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))	('PCDH17', 'Gene', '27253', (48, 54))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('PCDH17', 'Gene', (48, 54))	('methylation', 'Var', (55, 66))	('RCC', 'Disease', (90, 93))
179886	28688232	The results confirmed that PCDH17 methylation significantly correlated with advanced stage, higher grade, and lymph node metastasis.	('PCDH17', 'Gene', '27253', (27, 33))	('lymph node metastasis', 'CPA', (110, 131))	('methylation', 'Var', (34, 45))	('advanced stage', 'CPA', (76, 90))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('PCDH17', 'Gene', (27, 33))	('higher grade', 'CPA', (92, 104))	('correlated', 'Reg', (60, 70))
179889	28688232	Subsequently, Kaplan-Meier survival analysis and log-rank test were performed; the result suggested that patients with PCDH17 methylation in serum had shorter progression-free survival and overall survival than patients with PCDH17 unmethylated.	('methylation', 'biological_process', 'GO:0032259', ('126', '137'))	('PCDH17', 'Gene', (225, 231))	('overall survival', 'CPA', (189, 205))	('patients', 'Species', '9606', (211, 219))	('patients', 'Species', '9606', (105, 113))	('PCDH17', 'Gene', (119, 125))	('shorter', 'NegReg', (151, 158))	('methylation', 'Var', (126, 137))	('progression-free survival', 'CPA', (159, 184))	('PCDH17', 'Gene', '27253', (225, 231))	('PCDH17', 'Gene', '27253', (119, 125))
179890	28688232	Moreover, multivariate Cox proportional hazards model analysis suggested that PCDH17 methylation in serum was an independent prognostic factor for worse progression-free survival and overall survival for patients with RCC.	('patients', 'Species', '9606', (204, 212))	('methylation', 'Var', (85, 96))	('PCDH17', 'Gene', (78, 84))	('methylation', 'biological_process', 'GO:0032259', ('85', '96'))	('worse', 'NegReg', (147, 152))	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('RCC', 'Disease', (218, 221))	('RCC', 'Phenotype', 'HP:0005584', (218, 221))	('progression-free survival', 'CPA', (153, 178))	('PCDH17', 'Gene', '27253', (78, 84))
179891	28688232	These data indicated that the detection of PCDH17 methylation in serum can be a potential biomarker for predicting RCC patient prognosis and formonitoring tumor progression after surgery.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('patient', 'Species', '9606', (119, 126))	('PCDH17', 'Gene', (43, 49))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('methylation', 'biological_process', 'GO:0032259', ('50', '61'))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('tumor', 'Disease', (155, 160))	('PCDH17', 'Gene', '27253', (43, 49))	('methylation', 'Var', (50, 61))
179893	28688232	In any event, the most remarkable characteristics of PCDH17 methylation detection in serum are that it is efficient, rapid, low cost, and non invasive, and as such demonstrate potential application in the future.	('methylation', 'Var', (60, 71))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('PCDH17', 'Gene', '27253', (53, 59))	('PCDH17', 'Gene', (53, 59))
179894	28688232	In conclusion, the results of the present study indicate that PCDH17 methylation in serum is a frequent event in RCC and associated with risk factors of poor outcomes.	('PCDH17', 'Gene', '27253', (62, 68))	('associated', 'Reg', (121, 131))	('methylation', 'biological_process', 'GO:0032259', ('69', '80'))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('PCDH17', 'Gene', (62, 68))	('methylation', 'Var', (69, 80))
179901	31824835	Patients with high PD-L1 expression were more likely to exhibit adverse pathologic features including an advanced T stage (P = 0.002) and lymph node metastasis (P = 0.044).	('PD-L1', 'Gene', (19, 24))	('expression', 'MPA', (25, 35))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('lymph node metastasis', 'CPA', (138, 159))
179931	31824835	Patients with high PD-L1mRNA expression were more likely to exhibit advanced pathologic features including poorer tumor grade (P = 0.010), advanced T stage (P = 0.034), and lymph node metastasis (P = 0.005).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('PD-L1mRNA', 'Protein', (19, 28))	('lymph node metastasis', 'CPA', (173, 194))	('tumor', 'Disease', (114, 119))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))
179935	31824835	The median PFS and OS for patients with low PD-L1 mRNA expression was longer than the subgroups with high PD-L1 mRNA expression (Figures 2C,D), while the subgroup with negative PD-L1 IHC staining had better PFS and OS compared to the subgroup with positive staining (Figures 2E,F).	('low', 'NegReg', (40, 43))	('patients', 'Species', '9606', (26, 34))	('PFS', 'CPA', (11, 14))	('longer', 'PosReg', (70, 76))	('PD-L1 mRNA', 'Var', (44, 54))
179937	31824835	The univariate analyses revealed that older age at surgery, advanced T stage, lymph node metastasis, poor tumor grade, positive PD-L1 IHC staining, and high PD-L1 mRNA expression may be associated with lower PFS.	('lower', 'NegReg', (202, 207))	('PD-L1', 'Gene', (157, 162))	('PFS', 'Disease', (208, 211))	('lymph node metastasis', 'CPA', (78, 99))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('mRNA expression', 'MPA', (163, 178))	('high', 'Var', (152, 156))	('tumor', 'Disease', (106, 111))
179939	31824835	The univariate analysis revealed that prognostic factors of OS were the same as those of PFS, including older age at surgery, advanced T stage, lymph node metastasis, poor tumor grade, positive PD-L1 IHC staining, and high PD-L1 mRNA expression.	('PD-L1', 'Protein', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('positive', 'Var', (185, 193))	('PD-L1 IHC', 'Protein', (194, 203))	('lymph node metastasis', 'CPA', (144, 165))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
179950	31824835	In addition, patients with high PD-L1 expression had a significantly increased risk of disease-specific mortality and overall mortality.	('disease-specific mortality', 'CPA', (87, 113))	('patients', 'Species', '9606', (13, 21))	('PD-L1', 'Gene', (32, 37))	('high', 'Var', (27, 31))
179968	31577709	Survival analysis revealed that high S100A9 expression is an independent factor for unfavorable disease-free survival (hazard ratio, 2.423; 95% confidence interval, 1.044-5.621; P = .039) and disease-specific survival (hazard ratio, 2.428; 95% confidence interval, 1.130-5.214; P = .023) in patients with ccRCC.	('high', 'Var', (32, 36))	('expression', 'MPA', (44, 54))	('ccRCC', 'Phenotype', 'HP:0006770', (305, 310))	('disease-specific survival', 'CPA', (192, 217))	('disease-free survival', 'CPA', (96, 117))	('RCC', 'Phenotype', 'HP:0005584', (307, 310))	('ccRCC', 'Disease', (305, 310))	('ccRCC', 'Disease', 'MESH:D002292', (305, 310))	('patients', 'Species', '9606', (291, 299))	('S100A9', 'Gene', '6280', (37, 43))	('S100A9', 'Gene', (37, 43))
179998	31577709	Moreover, multivariate analysis revealed that high S100A9 expression was an independent factor for unfavorable DFS (hazard ratio, 2.423; 95% confidence interval, 1.044-5.621; P = .039) and DSS (hazard ratio, 2.428; 95% confidence interval, 1.130-5.214; P = .023) in patients with ccRCC (Table 3).	('high', 'Var', (46, 50))	('patients', 'Species', '9606', (266, 274))	('ccRCC', 'Phenotype', 'HP:0006770', (280, 285))	('RCC', 'Phenotype', 'HP:0005584', (282, 285))	('expression', 'MPA', (58, 68))	('S100A9', 'Gene', '6280', (51, 57))	('DSS', 'MPA', (189, 192))	('ccRCC', 'Disease', (280, 285))	('ccRCC', 'Disease', 'MESH:D002292', (280, 285))	('S100A9', 'Gene', (51, 57))	('DFS', 'MPA', (111, 114))
179999	31577709	Furthermore, in the Kaplan-Meier analysis with the log-rank test, the high S100A9 expression group showed significantly lower survival than the low expression group for DFS (P < .001) and DSS (P < .001) (Fig.	('lower', 'NegReg', (120, 125))	('high', 'Var', (70, 74))	('S100A9', 'Gene', '6280', (75, 81))	('survival', 'MPA', (126, 134))	('S100A9', 'Gene', (75, 81))
180003	31577709	Recent studies have shown that high S100A9 expression in tumor cells was associated with tumor progression and poor prognosis.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('expression', 'MPA', (43, 53))	('associated', 'Reg', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('high', 'Var', (31, 35))	('tumor', 'Disease', (57, 62))	('S100A9', 'Gene', '6280', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('S100A9', 'Gene', (36, 42))
180006	31577709	In the present study, we showed that high S100A9 expression significantly correlated with T stage and Fuhrman nuclear grade in ccRCC.	('S100A9', 'Gene', '6280', (42, 48))	('high', 'Var', (37, 41))	('S100A9', 'Gene', (42, 48))	('expression', 'MPA', (49, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('ccRCC', 'Disease', (127, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('T stage', 'CPA', (90, 97))	('correlated', 'Reg', (74, 84))	('ccRCC', 'Disease', 'MESH:D002292', (127, 132))
180007	31577709	Moreover, we demonstrated that high S100A9 expression is related to unfavorable DFS and DSS in patients with ccRCC.	('DFS', 'Disease', (80, 83))	('patients', 'Species', '9606', (95, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('ccRCC', 'Disease', (109, 114))	('ccRCC', 'Disease', 'MESH:D002292', (109, 114))	('high', 'Var', (31, 35))	('expression', 'MPA', (43, 53))	('S100A9', 'Gene', '6280', (36, 42))	('DSS', 'Disease', (88, 91))	('S100A9', 'Gene', (36, 42))
180008	31577709	To our knowledge, these findings are the first to reveal an association between high S100A9 expression and prognosis in patients with ccRCC.	('prognosis', 'CPA', (107, 116))	('S100A9', 'Gene', (85, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('ccRCC', 'Disease', (134, 139))	('ccRCC', 'Disease', 'MESH:D002292', (134, 139))	('patients', 'Species', '9606', (120, 128))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('high', 'Var', (80, 84))	('expression', 'MPA', (92, 102))	('S100A9', 'Gene', '6280', (85, 91))
180013	31577709	High S100A9 expression was also associated with unfavorable DFS and DSS in patients with ccRCC.	('DSS', 'Disease', (68, 71))	('DFS', 'Disease', (60, 63))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (75, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (89, 94))	('ccRCC', 'Disease', (89, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('ccRCC', 'Disease', 'MESH:D002292', (89, 94))	('expression', 'MPA', (12, 22))	('S100A9', 'Gene', '6280', (5, 11))	('S100A9', 'Gene', (5, 11))
180030	29159069	Therefore, many biomarkers for clear cell renal cell carcinoma have been discovered including VHL, VEGF, CAIX and HIF1alpha/2alpha mutations.	('HIF1alpha/2alpha', 'Gene', '3091;2034', (114, 130))	('mutations', 'Var', (131, 140))	('clear cell renal cell carcinoma', 'Disease', (31, 62))	('VHL', 'Gene', '7428', (94, 97))	('VEGF', 'Gene', '7422', (99, 103))	('CAIX', 'Gene', (105, 109))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (31, 62))	('CAIX', 'Gene', '768', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (42, 62))	('VEGF', 'Gene', (99, 103))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (31, 62))	('HIF1alpha/2alpha', 'Gene', (114, 130))	('VHL', 'Gene', (94, 97))
47049	29159069	To obtain further insight into the function of DEGs in hub module, they were uploaded to the DAVID database.	('hub', 'Gene', '1993', (55, 58))	('DEGs', 'Var', (47, 51))	('hub', 'Gene', (55, 58))
180173	30464516	Three FA proteins, phosphorylated focal adhesion kinase (pFAK) (Tyr397), vinculin, and paxillin, were strongly expressed along the cell border with some staining seen under the cell body in vehicle-treated ccRCC cells (Figure 5A).	('focal adhesion', 'cellular_component', 'GO:0005925', ('34', '48'))	('RCC', 'Phenotype', 'HP:0005584', (208, 211))	('paxillin', 'Gene', (87, 95))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('focal adhesion kinase', 'Gene', (34, 55))	('RCC', 'Disease', (208, 211))	('vinculin', 'Gene', '7414', (73, 81))	('FAK', 'Gene', (58, 61))	('vinculin', 'Gene', (73, 81))	('FAK', 'Gene', '5747', (58, 61))	('focal adhesion kinase', 'Gene', '5747', (34, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (206, 211))	('cell body', 'cellular_component', 'GO:0044297', ('177', '186'))	('Tyr397', 'Var', (64, 70))	('Tyr397', 'Chemical', '-', (64, 70))	('paxillin', 'Gene', '5829', (87, 95))
180176	30464516	Western blot analyses confirmed that the expression of pFAK (Tyr397), FAK, paxillin, and vinculin was decreased by 24 hours of CD treatment (Figure 6).	('vinculin', 'Gene', '7414', (89, 97))	('FAK', 'molecular_function', 'GO:0004717', ('70', '73'))	('expression', 'MPA', (41, 51))	('vinculin', 'Gene', (89, 97))	('FAK', 'Gene', '5747', (70, 73))	('FAK', 'Gene', '5747', (56, 59))	('CD', 'Chemical', '-', (127, 129))	('FAK', 'Gene', (70, 73))	('paxillin', 'Gene', '5829', (75, 83))	('Tyr397', 'Var', (61, 67))	('Tyr397', 'Chemical', '-', (61, 67))	('paxillin', 'Gene', (75, 83))	('decreased', 'NegReg', (102, 111))	('FAK', 'Gene', (56, 59))
180188	30464516	Although the expression of p21 has been considered as an indicator of wild-type p53 activity, prevailing notions suggest that blockade of p21 levels in RCC cell lines sensitizes the cells to undergo apoptosis in response to DNA-damaging chemotherapy.	('p21', 'Gene', (27, 30))	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('p21', 'Gene', '644914', (27, 30))	('RCC', 'Disease', (152, 155))	('p21', 'Gene', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('p53', 'Gene', (80, 83))	('sensitizes', 'Reg', (167, 177))	('blockade', 'Var', (126, 134))	('apoptosis', 'biological_process', 'GO:0097194', ('199', '208'))	('response to DNA-damaging chemotherapy', 'MPA', (212, 249))	('p53', 'Gene', '7157', (80, 83))	('p21', 'Gene', '644914', (138, 141))	('DNA', 'cellular_component', 'GO:0005574', ('224', '227'))	('apoptosis', 'biological_process', 'GO:0006915', ('199', '208'))
180199	30464516	The pharmacologic inhibition of MEK leads to the compensatory upregulation of PI3K/Akt signaling and promotes cancer cell survival.	('promotes', 'PosReg', (101, 109))	('cancer', 'Disease', (110, 116))	('Akt', 'Gene', (83, 86))	('PI3K', 'molecular_function', 'GO:0016303', ('78', '82'))	('Akt signaling', 'biological_process', 'GO:0043491', ('83', '96'))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Akt', 'Gene', '207', (83, 86))	('inhibition', 'Var', (18, 28))	('MEK', 'Gene', (32, 35))	('MEK', 'Gene', '5609', (32, 35))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('upregulation', 'PosReg', (62, 74))
180207	30464516	Furthermore, HIF-2alpha inhibition influences p53 activation through reactive oxygen species (ROS) accumulation and DNA damage in RCC cells.	('HIF-2alpha', 'Gene', '2034', (13, 23))	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('p53', 'Gene', (46, 49))	('ROS', 'Chemical', 'MESH:D017382', (94, 97))	('activation', 'PosReg', (50, 60))	('DNA damage', 'MPA', (116, 126))	('p53', 'Gene', '7157', (46, 49))	('inhibition', 'Var', (24, 34))	('HIF-2alpha', 'Gene', (13, 23))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('accumulation', 'PosReg', (99, 111))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (69, 92))
180212	28454375	A comprehensive analysis of cancer-driving mutations and genes in kidney cancer An accumulation of driver mutations is important for cancer formation and progression, and leads to the disruption of genes and signaling pathways.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('disruption', 'NegReg', (184, 194))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('kidney cancer', 'Disease', 'MESH:D007680', (66, 79))	('signaling', 'biological_process', 'GO:0023052', ('208', '217'))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('kidney cancer', 'Phenotype', 'HP:0009726', (66, 79))	('accumulation', 'PosReg', (83, 95))	('cancer', 'Disease', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('mutations', 'Var', (106, 115))	('kidney cancer', 'Disease', (66, 79))	('cancer', 'Disease', (28, 34))	('formation', 'biological_process', 'GO:0009058', ('140', '149'))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
180213	28454375	The present study was performed to identify cancer-driving mutations and genes in renal cell carcinoma (RCC), prioritizing noncoding variants with a high functional impact, in order to analyze the most informative features.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('renal cell carcinoma', 'Disease', (82, 102))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (82, 102))	('mutations', 'Var', (59, 68))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (82, 102))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('RCC', 'Disease', (104, 107))
180215	28454375	A total of 1,327 coding mutations in clear cell RCC, 258 in chromophobe RCC and 1,186 in papillary RCC were predicted to be deleterious by all three of MutationAssessor, Polyphen2 and SIFT.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('chromophobe RCC', 'Disease', (60, 75))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('SIFT', 'Disease', (184, 188))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('chromophobe RCC', 'Disease', 'MESH:C538614', (60, 75))	('SIFT', 'Disease', 'None', (184, 188))	('mutations', 'Var', (24, 33))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
180217	28454375	In conclusion, the present study identified a list of cancer-driving genes and signaling pathways, features like regulatory elements, conserved regions, replication time, expression, GC content and recombination rate are major factors that affect the distribution of high-scoring non-coding mutations in kidney cancer.	('kidney cancer', 'Disease', (304, 317))	('non-coding mutations', 'Var', (280, 300))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('cancer', 'Disease', (54, 60))	('kidney cancer', 'Disease', 'MESH:D007680', (304, 317))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('rat', 'Species', '10116', (212, 215))	('kidney cancer', 'Phenotype', 'HP:0009726', (304, 317))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
180218	28454375	Rapid advancements in sequencing technology and its wide applications have identified hundreds of thousands of mutations in cancer genomes; a small fraction of these mutations, termed drivers, are critical for carcinogenesis and are able to confer a growth advantage to tumor cells by affecting driver genes.	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', (270, 275))	('mutations', 'Var', (166, 175))	('growth advantage', 'CPA', (250, 266))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('carcinogenesis', 'Disease', 'MESH:D063646', (210, 224))	('affecting', 'Reg', (285, 294))	('driver genes', 'Gene', (295, 307))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('carcinogenesis', 'Disease', (210, 224))
180220	28454375	Various computational approaches have been developed to prioritize deleterious cancer mutations, including the Sorting Intolerant From Tolerant (SIFT) algorithm, Polymorphism Phenotyping version 2 (PolyPhen2) tool and MutationAssessor.	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('SIFT', 'Disease', (145, 149))	('SIFT', 'Disease', 'None', (145, 149))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
180223	28454375	OncodriveFM detects genes with a bias towards the accumulation of variants with high functional impacts, as evaluated by SIFT, PolyPhen2 and MutationAssessor.	('accumulation', 'PosReg', (50, 62))	('SIFT', 'Disease', 'None', (121, 125))	('SIFT', 'Disease', (121, 125))	('variants', 'Var', (66, 74))
180224	28454375	Another program, OncodriveCLUST, identifies genes with a significant bias towards gain-of-function mutations that are clustered within the protein-coding sequence, based on the knowledge that the clustering of gain-of-function mutations in specific protein regions provides an adaptive advantage to cancer cells, and is consequently positively selected for during tumoral evolution.	('protein', 'cellular_component', 'GO:0003675', ('249', '256'))	('gain-of-function', 'PosReg', (82, 98))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('gain-of-function', 'PosReg', (210, 226))	('mutations', 'Var', (99, 108))	('adaptive advantage', 'CPA', (277, 295))	('tumoral', 'Disease', (364, 371))	('tumoral', 'Disease', 'MESH:D009369', (364, 371))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('mutations', 'Var', (227, 236))
180232	28454375	The current study was conducted to analyze the somatic mutations detected by whole-genome sequencing of 14 clear-cell renal cell carcinoma (ccRCC) tissue samples and exome sequencing of 106 ccRCC tissue specimens, 65 paired chromophobe renal cell carcinoma (chRCC) tissue samples and 100 paired papillary renal cell carcinoma (PRCC) tissue samples.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('PRCC', 'Gene', '5546', (327, 331))	('papillary renal cell carcinoma', 'Disease', (295, 325))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (305, 325))	('RCC', 'Disease', 'MESH:C538614', (260, 263))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (236, 256))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (107, 138))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (224, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (118, 138))	('RCC', 'Phenotype', 'HP:0005584', (328, 331))	('RCC', 'Disease', (328, 331))	('RCC', 'Disease', (192, 195))	('RCC', 'Phenotype', 'HP:0005584', (192, 195))	('ccRCC', 'Phenotype', 'HP:0006770', (190, 195))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (295, 325))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('mutations', 'Var', (55, 64))	('chromophobe renal cell carcinoma', 'Disease', (224, 256))	('PRCC', 'Gene', (327, 331))	('RCC', 'Disease', 'MESH:C538614', (328, 331))	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (305, 325))	('PRCC', 'Phenotype', 'HP:0006766', (327, 331))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (236, 256))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (295, 325))	('renal cell carcinoma', 'Disease', (118, 138))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (118, 138))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('RCC', 'Phenotype', 'HP:0005584', (260, 263))	('RCC', 'Disease', (260, 263))
180234	28454375	The enrichment of high-scoring variants for a wide range of noncoding features was also examined to identify the features that most contribute to the functionalities of noncoding cancer mutations.	('variants', 'Var', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('mutations', 'Var', (186, 195))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (179, 185))
180236	28454375	Data for chRCC and PRCC mutations that had been identified using exome-sequencing of 65 and 100 paired chRCC and PRCC tissue samples by Lawrence et al were also obtained.	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('mutations', 'Var', (24, 33))	('RCC', 'Disease', (11, 14))	('RCC', 'Disease', (20, 23))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('PRCC', 'Gene', (19, 23))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('PRCC', 'Gene', (113, 117))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('PRCC', 'Phenotype', 'HP:0006766', (19, 23))	('PRCC', 'Phenotype', 'HP:0006766', (113, 117))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('PRCC', 'Gene', '5546', (19, 23))	('PRCC', 'Gene', '5546', (113, 117))
180237	28454375	The functional impacts of somatic mutations in the coding genome were predicted using SIFT, Polyphen2 and MutationAssessor version 3.	('SIFT', 'Disease', (86, 90))	('mutations', 'Var', (34, 43))	('SIFT', 'Disease', 'None', (86, 90))
180238	28454375	Variants were considered deleterious based on the following criteria: SIFT score <0.05; the presence of non-benign variants in the HumDiv and HumVar predictions of Polyphen2; and a MutationAssessor score >1.9.	('Variants', 'Var', (0, 8))	('SIFT', 'Disease', (70, 74))	('SIFT', 'Disease', 'None', (70, 74))	('variants', 'Var', (115, 123))	('HumDiv', 'Gene', (131, 137))
180255	28454375	In total, 70,659 noncoding variants detected by whole-genome sequencing of 14 paired ccRCC tissue samples were scored for deleteriousness using CADD v1.0 , FunSeq2.1.2  and GWAVA v1.0 , and all parameters were set to default.	('variants', 'Var', (27, 35))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
180259	28454375	In total, 76,595 somatic mutations were obtained from Sato et al, comprising 71,424 mutations generated by whole-genome sequencing of 14 ccRCC tissue samples and 5,171 mutations detected by whole-exome sequencing of 106 ccRCC specimens.	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Phenotype', 'HP:0005584', (222, 225))	('mutations', 'Var', (84, 93))	('RCC', 'Disease', (139, 142))	('rat', 'Species', '10116', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (222, 225))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('RCC', 'Disease', (222, 225))	('ccRCC', 'Phenotype', 'HP:0006770', (220, 225))
180260	28454375	A total of 1,381 mutations detected by exome sequencing of 65 paired chRCC tissue samples included 1,287 SNVs and 94 indels; whereas 6,349 mutations were detected by exome sequencing of the 100 paired PRCC specimens, consisting of 5,489 SNVs, 677 indels and 180 dinitropyrenes.	('PRCC', 'Phenotype', 'HP:0006766', (201, 205))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('PRCC', 'Gene', '5546', (201, 205))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('PRCC', 'Gene', (201, 205))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('RCC', 'Disease', (202, 205))	('RCC', 'Phenotype', 'HP:0005584', (202, 205))	('mutations', 'Var', (17, 26))	('dinitropyrenes', 'Chemical', '-', (262, 276))
180261	28454375	The fraction of mutations that were predicted to be deleterious varied greatly across cancer subtypes and prediction tools.	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutations', 'Var', (16, 25))	('cancer', 'Disease', (86, 92))
180262	28454375	The percentages of predicted deleterious mutations were as follows: 44.52% (2673/6004; SIFT), 50.45% (2393/4743; Polyphen2) and 39.18% (1941/4954; MutationAssessor) in ccRCC; 41.04% (2464/6330; SIFT), 55.91% (2110/3774; Polyphen2) and 44.47% (390/877; MutationAssessor) in chRCC; and 37.58% (519/1381; SIFT), 57.26% (469/819; Polyphen2) and 44.33% (1752/3952; MutationAssessor) in PRCC.	('SIFT', 'Disease', 'None', (87, 91))	('SIFT', 'Disease', 'None', (302, 306))	('PRCC', 'Gene', '5546', (381, 385))	('mutations', 'Var', (41, 50))	('RCC', 'Disease', 'MESH:C538614', (275, 278))	('RCC', 'Disease', (170, 173))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('SIFT', 'Disease', (194, 198))	('ccRCC', 'Phenotype', 'HP:0006770', (168, 173))	('RCC', 'Phenotype', 'HP:0005584', (382, 385))	('RCC', 'Disease', (382, 385))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('SIFT', 'Disease', 'None', (194, 198))	('SIFT', 'Disease', (87, 91))	('SIFT', 'Disease', (302, 306))	('PRCC', 'Gene', (381, 385))	('RCC', 'Disease', 'MESH:C538614', (382, 385))	('PRCC', 'Phenotype', 'HP:0006766', (381, 385))	('RCC', 'Disease', (275, 278))	('RCC', 'Phenotype', 'HP:0005584', (275, 278))
180265	28454375	T>C/A>G, C>T/G>A and C>A/G>T accounted for 24.96, 23.16 and 17.86% of the variants in ccRCC, 9.34, 57.13 and 12.53% of the variants in chRCC and 17.31, 28.29 and 12.24% of the variants in PRCC, respectively.	('C>A/G>T', 'Var', (21, 28))	('PRCC', 'Phenotype', 'HP:0006766', (188, 192))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('C>T/G>A', 'Var', (9, 16))	('T>C/A>G', 'Var', (0, 7))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('PRCC', 'Gene', '5546', (188, 192))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))	('variants', 'Var', (74, 82))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('RCC', 'Disease', (189, 192))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))	('variants', 'Var', (123, 131))	('PRCC', 'Gene', (188, 192))
180266	28454375	T>C/A>G, C>T/G>A and C>A/G>T were therefore the three most common transitions identified in kidney cancer tissues (Fig.	('C>A/G>T', 'Var', (21, 28))	('kidney cancer', 'Disease', (92, 105))	('C>T/G>A', 'Var', (9, 16))	('T>C/A>G', 'Var', (0, 7))	('kidney cancer', 'Phenotype', 'HP:0009726', (92, 105))	('kidney cancer', 'Disease', 'MESH:D007680', (92, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
180267	28454375	Predicted deleterious mutations were mapped onto established cancer genes that had been annotated in the COSMIC database, revealing that the coding regions of cancer genes had a significantly higher enrichment of deleterious mutations, in comparison with those of non-cancer genes in ccRCC (259.68 vs. 95.06 variants/Mb; P<2.2x10-16), chRCC (46.23 vs. 18.93 variants/Mb; P=4.15x10-6) and PRCC (195.78 vs. 87.69 variants/Mb; P<2.2x10-16; Fisher's exact test; Fig.	('RCC', 'Disease', 'MESH:C538614', (286, 289))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('PRCC', 'Gene', (388, 392))	('PRCC', 'Phenotype', 'HP:0006766', (388, 392))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('cancer', 'Disease', (159, 165))	('RCC', 'Disease', (337, 340))	('RCC', 'Phenotype', 'HP:0005584', (337, 340))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('non-cancer', 'Disease', 'MESH:D009369', (264, 274))	('RCC', 'Disease', (389, 392))	('PRCC', 'Gene', '5546', (388, 392))	('RCC', 'Disease', 'MESH:C538614', (337, 340))	('RCC', 'Phenotype', 'HP:0005584', (389, 392))	('cancer', 'Disease', (61, 67))	('non-cancer', 'Disease', (264, 274))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('RCC', 'Disease', 'MESH:C538614', (389, 392))	('cancer', 'Disease', (268, 274))	('RCC', 'Phenotype', 'HP:0005584', (286, 289))	('ccRCC', 'Phenotype', 'HP:0006770', (284, 289))	('mutations', 'Var', (225, 234))	('RCC', 'Disease', (286, 289))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))
180282	28454375	2C shows that conserved regions and regulatory elements contained higher densities of high-scoring variants, as predicted by all scoring methods individually and in combination, including conserved regions, conserved TFBS, promoters, H3K27ac, H2BK5ac, H4K91ac, PolII, H3K18ac, H2BK120ac, H3K4me2 and H3K4me3.	('H4K91ac', 'Var', (252, 259))	('H3K27ac', 'Var', (234, 241))	('H2BK120ac', 'Var', (277, 286))	('H3K4me2', 'Var', (288, 295))	('H3K4me3', 'Var', (300, 307))	('H2BK5ac', 'Var', (243, 250))	('H3K18ac', 'Var', (268, 275))	('TFBS', 'Chemical', '-', (217, 221))
180285	28454375	Regions with a high average recombination rate possessed a higher density of high-scoring variants compared with regions with a low average recombination rate for common variants (P=1.357x10-5), CADD (P=2.583x10-3), FunSeq2 (P=2.063x10-3) and GWAVA (P=3.834x10-6; Fisher's exact test).	('variants', 'Var', (90, 98))	('high-scoring', 'PosReg', (77, 89))	('rat', 'Species', '10116', (154, 157))	('rat', 'Species', '10116', (42, 45))
180286	28454375	In addition, the expression levels, replication time, GC content and recombination rate exhibited positive correlations with the densities of high-scoring variants (Fig.	('rat', 'Species', '10116', (83, 86))	('expression', 'MPA', (17, 27))	('variants', 'Var', (155, 163))
180287	28454375	All these findings suggest that conserved regions, regulatory elements, high expression levels, early replication time, high GC content and high recombination rate are important features that affect the functionalities of noncoding variants in kidney cancer.	('noncoding variants', 'Var', (222, 240))	('functionalities', 'MPA', (203, 218))	('kidney cancer', 'Disease', 'MESH:D007680', (244, 257))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('kidney cancer', 'Phenotype', 'HP:0009726', (244, 257))	('kidney cancer', 'Disease', (244, 257))	('affect', 'Reg', (192, 198))	('rat', 'Species', '10116', (159, 162))
180288	28454375	The current study performed a full analysis of the somatic mutations generated by whole-genome and -exome sequencing of kidney cancer samples, revealing 1,327, 258 and 1,186 deleterious coding variants in ccRCC, chRCC and PRCC, respectively, predicted by SIFT, Polyphen2 and MutationAssessor.	('PRCC', 'Gene', (222, 226))	('RCC', 'Disease', 'MESH:C538614', (223, 226))	('PRCC', 'Phenotype', 'HP:0006766', (222, 226))	('variants', 'Var', (193, 201))	('RCC', 'Disease', 'MESH:C538614', (214, 217))	('kidney cancer', 'Disease', 'MESH:D007680', (120, 133))	('PRCC', 'Gene', '5546', (222, 226))	('SIFT', 'Disease', (255, 259))	('kidney cancer', 'Phenotype', 'HP:0009726', (120, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('kidney cancer', 'Disease', (120, 133))	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('RCC', 'Disease', (207, 210))	('mutations', 'Var', (59, 68))	('RCC', 'Phenotype', 'HP:0005584', (223, 226))	('RCC', 'Disease', (223, 226))	('ccRCC', 'Phenotype', 'HP:0006770', (205, 210))	('SIFT', 'Disease', 'None', (255, 259))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('RCC', 'Disease', (214, 217))	('RCC', 'Phenotype', 'HP:0005584', (214, 217))	('rat', 'Species', '10116', (73, 76))
180295	28454375	The oncogenic role of TCEBI has been reported in ccRCC tumors containing TCEB1 mutations, which exhibited increased expression levels of hypoxia-inducible factor (HIF)-1alpha, a gene that is implicated to be dysregulated in various cancer-associated processes, including vascularization, angiogenesis, energy metabolism, cell survival and tumor invasion.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', (339, 344))	('cancer', 'Disease', (232, 238))	('angiogenesis', 'CPA', (288, 300))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (339, 344))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cell survival', 'CPA', (321, 334))	('mutations', 'Var', (79, 88))	('RCC', 'Disease', (51, 54))	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('vascularization', 'CPA', (271, 286))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('metabolism', 'biological_process', 'GO:0008152', ('309', '319'))	('tumors', 'Disease', (55, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('increased', 'PosReg', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('TCEB1', 'Gene', (73, 78))	('angiogenesis', 'biological_process', 'GO:0001525', ('288', '300'))	('tumor', 'Disease', (55, 60))	('hypoxia-inducible factor (HIF)-1alpha', 'Gene', '3091', (137, 174))	('TCEB1', 'Gene', '6921', (73, 78))
180300	28454375	Alterations in UMPP are associated with the overexpression of HIF-1alpha and HIF-2alpha, which are two crucial hypoxia regulatory factors in the HIF-1 signaling pathway; therefore, alterations in UMPP may contribute to the pathogenesis of ccRCC via the activation of the HIF-1 signaling pathway, which is important role in ccRCC tumorigenesis.	('alterations', 'Var', (181, 192))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (62, 87))	('contribute', 'Reg', (205, 215))	('HIF-1', 'Gene', '3091', (145, 150))	('UMPP', 'Chemical', '-', (15, 19))	('UMPP', 'Chemical', '-', (196, 200))	('HIF-1', 'Gene', (145, 150))	('RCC', 'Disease', (241, 244))	('RCC', 'Phenotype', 'HP:0005584', (241, 244))	('tumor', 'Disease', (329, 334))	('HIF-1', 'Gene', '3091', (271, 276))	('ccRCC', 'Phenotype', 'HP:0006770', (239, 244))	('signaling pathway', 'biological_process', 'GO:0007165', ('151', '168'))	('HIF-1', 'Gene', (271, 276))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('RCC', 'Disease', 'MESH:C538614', (241, 244))	('HIF-1', 'Gene', '3091', (62, 67))	('hypoxia', 'Disease', (111, 118))	('HIF-1', 'Gene', (62, 67))	('RCC', 'Disease', (325, 328))	('RCC', 'Phenotype', 'HP:0005584', (325, 328))	('ccRCC', 'Phenotype', 'HP:0006770', (323, 328))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('hypoxia', 'Disease', 'MESH:D000860', (111, 118))	('rat', 'Species', '10116', (4, 7))	('activation', 'PosReg', (253, 263))	('RCC', 'Disease', 'MESH:C538614', (325, 328))	('signaling pathway', 'biological_process', 'GO:0007165', ('277', '294'))	('UMPP', 'Gene', (196, 200))	('pathogenesis', 'biological_process', 'GO:0009405', ('223', '235'))	('rat', 'Species', '10116', (185, 188))
180303	28454375	An advantage of OncodriveFM and OncodriveCluster is that these two tools identify those genes and signaling pathways that accumulate variants with a high functional impact independently of cancer mutation frequency, enabling the identification of potential cancer genes and signaling pathways that are not highly mutated in cancer.	('signaling', 'biological_process', 'GO:0023052', ('274', '283'))	('cancer', 'Disease', (324, 330))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('variants', 'Var', (133, 141))	('cancer', 'Disease', 'MESH:D009369', (324, 330))	('cancer', 'Disease', (189, 195))
180308	28454375	Recombination between homologous DNA sequences may lead to rearrangements, including a loss of heterozygosity, deletions, duplications, inversions and gene fusion; therefore, a higher recombination rate may be an important cause of the development of harmful mutations in the noncoding genome and predisposition to cancer.	('loss', 'NegReg', (87, 91))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('duplications', 'Var', (122, 134))	('cancer', 'Disease', (315, 321))	('rearrangements', 'MPA', (59, 73))	('lead', 'Reg', (51, 55))	('rat', 'Species', '10116', (198, 201))	('deletions', 'Var', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('heterozygosity', 'MPA', (95, 109))
180309	28454375	This supports the hypothesis that high expression levels, early replication time, high GC content and high recombination rate characterize cancer-implicated regions within the noncoding genome, in which variants are more likely to be pathogenic.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('variants', 'Var', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('rat', 'Species', '10116', (121, 124))	('expression levels', 'MPA', (39, 56))	('pathogenic', 'Reg', (234, 244))	('cancer', 'Disease', (139, 145))
180311	28454375	Features including conservation, regulatory elements, replication time, expression levels, GC content and recombination rate may be important for the functional impact of noncoding mutations in renal cell carcinoma.	('renal cell carcinoma', 'Disease', (194, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (194, 214))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (194, 214))	('rat', 'Species', '10116', (120, 123))	('noncoding mutations', 'Var', (171, 190))
180320	30622105	Clear cell RCC (ccRCC), the most common and lethal form of RCC, is driven by distinct driver gene mutations.	('RCC', 'Disease', (18, 21))	('RCC', 'Phenotype', 'HP:0005584', (18, 21))	('RCC', 'Disease', 'MESH:C538614', (18, 21))	('mutations', 'Var', (98, 107))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (11, 14))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
180321	30622105	Inactivating mutations or methylation of von Hippel Lindau (VHL) occur in all ccRCC tumors and leads to accumulation of hypoxia inducible factor (HIF).	('methylation', 'Var', (26, 37))	('occur', 'Reg', (65, 70))	('von Hippel Lindau', 'Gene', (41, 58))	('ccRCC tumors', 'Disease', (78, 90))	('VHL', 'Gene', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('hypoxia', 'Disease', (120, 127))	('Inactivating mutations', 'Var', (0, 22))	('accumulation', 'PosReg', (104, 116))	('hypoxia', 'Disease', 'MESH:D000860', (120, 127))	('VHL', 'Gene', '7428', (60, 63))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('von Hippel Lindau', 'Gene', '7428', (41, 58))	('ccRCC tumors', 'Disease', 'MESH:D009369', (78, 90))
180325	30622105	These mutations commonly involve chromatin-remodeling genes (PBRM1, KDM5C, SETD2, and BAP1).	('chromatin', 'cellular_component', 'GO:0000785', ('33', '42'))	('SETD2', 'Gene', '29072', (75, 80))	('PBRM1', 'Gene', (61, 66))	('BAP1', 'Gene', '8314', (86, 90))	('SETD2', 'Gene', (75, 80))	('BAP1', 'Gene', (86, 90))	('KDM5C', 'Gene', (68, 73))	('involve', 'Reg', (25, 32))	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('33', '53'))	('KDM5C', 'Gene', '8242', (68, 73))	('mutations', 'Var', (6, 15))
180341	30622105	Somatic PBRM1 mutations, which previously demonstrated favorable prognostic effects among TKI-treated patients, were less frequent in cluster 4 (Fisher's Exact test, p=0.003), while cluster 4 was enriched for presence of TP53 (Fisher's Exact test, p=0.03) and BAP1 (Fisher's Exact test, p=0.05) mutations (Supplementary Fig.	('BAP1', 'Gene', (260, 264))	('TP53', 'Gene', '7157', (221, 225))	('patients', 'Species', '9606', (102, 110))	('TP53', 'Gene', (221, 225))	('BAP1', 'Gene', '8314', (260, 264))	('mutations', 'Var', (14, 23))	('PBRM1', 'Gene', (8, 13))
180344	30622105	Tumors harboring PBRM1 mutations demonstrated higher angiogenesis gene expression (Wilcoxon test, p=4.00E-4; Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('higher', 'PosReg', (46, 52))	('angiogenesis', 'biological_process', 'GO:0001525', ('53', '65'))	('angiogenesis', 'MPA', (53, 65))	('PBRM1', 'Gene', (17, 22))	('mutations', 'Var', (23, 32))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('gene expression', 'biological_process', 'GO:0010467', ('66', '81'))
180345	30622105	These findings are consistent with recent in vitro and murine studies, which suggest that PBRM1 inactivation leads to further upregulation of HIF-1 via STAT3 as well as a recent report by McDermott et al.	('HIF-1', 'Gene', (142, 147))	('inactivation', 'Var', (96, 108))	('STAT3', 'Gene', (152, 157))	('upregulation', 'PosReg', (126, 138))	('PBRM1', 'Gene', (90, 95))	('STAT3', 'Gene', '20848', (152, 157))	('murine', 'Species', '10090', (55, 61))
180346	30622105	In line with our earlier findings, we found that patients in cluster 3 had the highest frequency of PBRM1 mutations (54.2%) compared to other clusters (Chi-Square test, p=0.009).	('PBRM1', 'Gene', (100, 105))	('mutations', 'Var', (106, 115))	('patients', 'Species', '9606', (49, 57))
180347	30622105	Patients with BAP1 mutations had lower angiogenesis gene expression (Wilcoxon test, p=0.01; Fig.	('BAP1', 'Gene', '8314', (14, 18))	('angiogenesis', 'biological_process', 'GO:0001525', ('39', '51'))	('BAP1', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('Patients', 'Species', '9606', (0, 8))	('angiogenesis gene', 'Gene', (39, 56))	('lower', 'NegReg', (33, 38))	('gene expression', 'biological_process', 'GO:0010467', ('52', '67'))
180350	30622105	Utilizing the TCGA KIRC cohort, we validated the association of BAP1 mutation status (Wilcoxon test, p=4.0E-6) with lower angiogenesis gene expression, and found that PBRM1 mutant tumors demonstrated a trend towards higher angiogenesis scores; however, this did not reach statistical significance (Wilcoxon test, p=0.12) (Supplementary Fig.	('lower', 'NegReg', (116, 121))	('PBRM1', 'Gene', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('gene expression', 'biological_process', 'GO:0010467', ('135', '150'))	('angiogenesis scores', 'CPA', (223, 242))	('mutation', 'Var', (69, 77))	('mutant', 'Var', (173, 179))	('angiogenesis', 'biological_process', 'GO:0001525', ('122', '134'))	('tumors', 'Disease', (180, 186))	('higher', 'PosReg', (216, 222))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('angiogenesis gene expression', 'MPA', (122, 150))	('BAP1', 'Gene', '8314', (64, 68))	('angiogenesis', 'biological_process', 'GO:0001525', ('223', '235'))	('BAP1', 'Gene', (64, 68))
180351	30622105	In summary, PBRM1 and BAP1 mutational status correlate with angiogenesis gene expression and, overall, patients in the Angiohigh group demonstrate improved TKI response, OS, and PFS.	('PBRM1', 'Gene', (12, 17))	('PFS', 'CPA', (178, 181))	('angiogenesis', 'biological_process', 'GO:0001525', ('60', '72'))	('TKI response', 'CPA', (156, 168))	('BAP1', 'Gene', '8314', (22, 26))	('BAP1', 'Gene', (22, 26))	('angiogenesis gene', 'Gene', (60, 77))	('gene expression', 'biological_process', 'GO:0010467', ('73', '88'))	('patients', 'Species', '9606', (103, 111))	('mutational', 'Var', (27, 37))	('improved', 'PosReg', (147, 155))
180364	30622105	Furthermore, Macrophagehigh infiltration alone is associated with worse OS and decreased objective response in TKI treated patients.	('Macrophagehigh infiltration', 'Var', (13, 40))	('objective', 'MPA', (89, 98))	('decreased', 'NegReg', (79, 88))	('patients', 'Species', '9606', (123, 131))
180367	30622105	We confirmed a trend towards higher proportion of activated tumor-associated macrophage (CD45+HLADR+CD3-CD19-CD14+CD16+) infiltration in TKI non-responders compared to responders (Wilcoxon one-tailed test, p=0.052) (Fig.	('higher', 'PosReg', (29, 35))	('CD19', 'Gene', '930', (104, 108))	('non-responders', 'Var', (141, 155))	('CD14', 'Gene', '929', (109, 113))	('CD16', 'Gene', '2214', (114, 118))	('CD16', 'Gene', (114, 118))	('CD45', 'Gene', '5788', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('CD19', 'Gene', (104, 108))	('tumor', 'Disease', (60, 65))	('CD14', 'Gene', (109, 113))	('CD45', 'Gene', (89, 93))
180375	30622105	Using a stepwise Cox proportional hazard model we determined the molecular variables that demonstrate prognostic value (p<0.1) in the presence of IMDC risk grouping and included TP53 and PBRM1 mutational status, angiogenesis score, and macrophage infiltration (Supplementary Table 2).	('TP53', 'Gene', '7157', (178, 182))	('TP53', 'Gene', (178, 182))	('mutational status', 'Var', (193, 210))	('angiogenesis', 'biological_process', 'GO:0001525', ('212', '224'))	('PBRM1', 'Gene', (187, 192))
180376	30622105	Utilizing molecular variables alone, incorporating angiogenesis, macrophage infiltration, and PBRM1 and TP53 mutational status achieved a c-index of 0.63 for OS.	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('angiogenesis', 'biological_process', 'GO:0001525', ('51', '63'))	('mutational', 'Var', (109, 119))	('PBRM1', 'Gene', (94, 99))
180383	30622105	The combination of angiogenesis and macrophage infiltration significantly discriminates survival differences among pazopanib treated patients with AngiolowMacrophagehigh demonstrating the worst OS (HR 1.86; 95%CI: 1.00-3.46; p=0.05) and PFS (HR 6.01; 95%CI: 2.73-13.20; p=8.00E-6) compared to the AngiohighMacrophagelow group.	('AngiolowMacrophagehigh', 'Var', (147, 169))	('angiogenesis', 'biological_process', 'GO:0001525', ('19', '31'))	('patients', 'Species', '9606', (133, 141))	('survival', 'MPA', (88, 96))	('pazopanib', 'Chemical', 'MESH:C516667', (115, 124))	('discriminates', 'Reg', (74, 87))
180385	30622105	We tested angiogenesis alone by drug type and found that the Angiohigh group was associated with improved OS (HR 1.54; 95%CI: 1.07-2.25; p=0.022) and PFS (HR 1.56; 95%CI: 1.10-2.22; p=0.012) in the sunitinib cohort only (Supplementary Fig.	('PFS', 'CPA', (150, 153))	('angiogenesis', 'biological_process', 'GO:0001525', ('10', '22'))	('improved', 'PosReg', (97, 105))	('Angiohigh', 'Var', (61, 70))	('sunitinib', 'Chemical', 'MESH:D000077210', (198, 207))
180386	30622105	On the contrary, the Macrophagehigh group had significantly worse OS (HR 2.62; 95%CI: 1.71-4.00; p=8.56E-6) and PFS (HR 1.85; 95%CI: 1.30-2.63; p=6.74E-4) compared to Macrophagelow group in the pazopanib cohort only, and survival did not differ between the sunitinib Macrophage groups (Supplementary Fig.	('PFS', 'CPA', (112, 115))	('sunitinib', 'Chemical', 'MESH:D000077210', (257, 266))	('Macrophagehigh', 'Var', (21, 35))	('pazopanib', 'Chemical', 'MESH:C516667', (194, 203))	('worse', 'NegReg', (60, 65))
180391	30622105	Varying effects on the TME, particularly the upregulation of angiogenesis, may also underlie the different clinical impact of mutation status for PBRM1 and BAP1, two of the most commonly altered genes in this disease after VHL and cumulatively altered in >50% of patients with metastatic clear cell RCC.	('RCC', 'Phenotype', 'HP:0005584', (299, 302))	('altered', 'Reg', (244, 251))	('VHL', 'Gene', (223, 226))	('VHL', 'Gene', '7428', (223, 226))	('BAP1', 'Gene', '8314', (156, 160))	('clinical', 'Species', '191496', (107, 115))	('patients', 'Species', '9606', (263, 271))	('mutation', 'Var', (126, 134))	('angiogenesis', 'CPA', (61, 73))	('PBRM1', 'Gene', (146, 151))	('upregulation of angiogenesis', 'biological_process', 'GO:0045766', ('45', '73'))	('upregulation', 'PosReg', (45, 57))	('BAP1', 'Gene', (156, 160))	('RCC', 'Disease', 'MESH:C538614', (299, 302))	('RCC', 'Disease', (299, 302))
180392	30622105	Loss-of-function mutations in the two genes correlated inversely with outcomes in patients treated on COMPARZ, confirming findings in other TKI treated datasets.	('patients', 'Species', '9606', (82, 90))	('Loss-of-function', 'NegReg', (0, 16))	('inversely', 'NegReg', (55, 64))	('mutations', 'Var', (17, 26))
180393	30622105	We noted upregulation and suppression of angiogenesis observed with loss-of-function mutations in PBRM1 and BAP1, respectively, providing a plausible explanation for the different effects observed in clinical behaviors.	('PBRM1', 'Gene', (98, 103))	('loss-of-function', 'NegReg', (68, 84))	('upregulation', 'PosReg', (9, 21))	('BAP1', 'Gene', '8314', (108, 112))	('suppression', 'NegReg', (26, 37))	('clinical', 'Species', '191496', (200, 208))	('BAP1', 'Gene', (108, 112))	('mutations', 'Var', (85, 94))	('angiogenesis', 'biological_process', 'GO:0001525', ('41', '53'))	('angiogenesis', 'CPA', (41, 53))
180395	30622105	Patients with high angiogenesis gene score demonstrated a PFS advantage in the angio high arm (HR 0.31; 95%CI: 0.19-0.55; p<0.001).	('angio high', 'Disease', (79, 89))	('angiogenesis', 'biological_process', 'GO:0001525', ('19', '31'))	('angiogenesis gene score', 'Gene', (19, 42))	('high', 'Var', (14, 18))	('advantage', 'PosReg', (62, 71))	('Patients', 'Species', '9606', (0, 8))
180396	30622105	Similar to our analyses on COMPARZ, the authors also noted that PBRM1 mutated tumors also had higher angiogenic gene expression.	('gene expression', 'biological_process', 'GO:0010467', ('112', '127'))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('PBRM1', 'Gene', (64, 69))	('angiogenic gene expression', 'MPA', (101, 127))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('higher', 'PosReg', (94, 100))	('mutated', 'Var', (70, 77))
180401	30622105	This cluster was characterized by a high frequency of BAP1 and TP53 mutations, moderate angiogenesis, high immune infiltration, and notably higher proportion of cases with PD-L1 expression on tumor cells by IHC when compared to clusters 1-3.	('tumor', 'Disease', (192, 197))	('immune infiltration', 'CPA', (107, 126))	('TP53', 'Gene', '7157', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('TP53', 'Gene', (63, 67))	('higher', 'PosReg', (140, 146))	('angiogenesis', 'CPA', (88, 100))	('BAP1', 'Gene', '8314', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('mutations', 'Var', (68, 77))	('BAP1', 'Gene', (54, 58))	('PD-L1', 'Gene', (172, 177))	('angiogenesis', 'biological_process', 'GO:0001525', ('88', '100'))
180402	30622105	BAP1 mutations have been associated with poor outcomes among patients with ccRCC.	('BAP1', 'Gene', (0, 4))	('associated', 'Reg', (25, 35))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('patients', 'Species', '9606', (61, 69))	('mutations', 'Var', (5, 14))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('BAP1', 'Gene', '8314', (0, 4))
180404	30622105	who used an elegant approach across various xenograft models and via transcriptomic analyses defined a hyper-infiltrated molecular variant of RCC, enriched for aggressive phenotypes, including BAP1 deficient tumors.	('deficient tumors', 'Disease', 'MESH:D009369', (198, 214))	('variant', 'Var', (131, 138))	('RCC', 'Disease', (142, 145))	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('BAP1', 'Gene', '8314', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('BAP1', 'Gene', (193, 197))	('deficient tumors', 'Disease', (198, 214))
180412	30622105	Our multivariate Cox regression analysis demonstrated that loss of function TP53 and PBRM1 mutations, angiogenesis and macrophage infiltration were independently prognostic for OS and PFS after adjusting for IMDC classifications.	('PBRM1', 'Gene', (85, 90))	('TP53', 'Gene', '7157', (76, 80))	('loss of function', 'NegReg', (59, 75))	('angiogenesis', 'biological_process', 'GO:0001525', ('102', '114'))	('PFS', 'Disease', (184, 187))	('TP53', 'Gene', (76, 80))	('angiogenesis', 'CPA', (102, 114))	('mutations', 'Var', (91, 100))
180436	30622105	Formalin-fixed paraffin-embedded (FFPE) tumor blocks were collected at baseline from 486 patients, of whom 453 patients had sufficient tissue available and provided consent for analysis: 221 in the pazopanib arm and 232 in the sunitinib arm.	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('pazopanib', 'Var', (198, 207))	('sunitinib', 'Chemical', 'MESH:D000077210', (227, 236))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('pazopanib', 'Chemical', 'MESH:C516667', (198, 207))	('paraffin', 'Chemical', 'MESH:D010232', (15, 23))	('patients', 'Species', '9606', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('patients', 'Species', '9606', (111, 119))
180438	30622105	Of these, 424 (84.8%) had clinical data including cancer-specific survival (CSS), 465 (93%) RNAseq , and 499 (99.8%) mutational data for VHL, PBRM1, BAP1, KDM5C, and SETD2.	('mutational', 'Var', (117, 127))	('KDM5C', 'Gene', '8242', (155, 160))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('CSS', 'Chemical', '-', (76, 79))	('BAP1', 'Gene', '8314', (149, 153))	('VHL', 'Gene', (137, 140))	('PBRM1', 'Gene', (142, 147))	('BAP1', 'Gene', (149, 153))	('SETD2', 'Gene', '29072', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('clinical', 'Species', '191496', (26, 34))	('VHL', 'Gene', '7428', (137, 140))	('KDM5C', 'Gene', (155, 160))	('SETD2', 'Gene', (166, 171))
180480	30986931	The Complex Interplay between Metabolic Reprogramming and Epigenetic Alterations in Renal Cell Carcinoma Renal cell carcinoma (RCC) is the most common malignancy affecting the kidney.	('Renal Cell Carcinoma', 'Disease', (84, 104))	('malignancy', 'Disease', 'MESH:D009369', (151, 161))	('Carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('RC', 'Phenotype', 'HP:0009726', (127, 129))	('Renal cell carcinoma', 'Phenotype', 'HP:0005584', (105, 125))	('malignancy', 'Disease', (151, 161))	('Epigenetic Alterations', 'Var', (58, 80))	('malignancy affecting the kidney', 'Phenotype', 'HP:0009726', (151, 182))	('Renal cell carcinoma', 'Disease', (105, 125))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (84, 104))	('Renal cell carcinoma', 'Disease', 'MESH:C538614', (105, 125))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (84, 104))
180482	30986931	Presently, metabolic reprograming and epigenetic alterations are recognized cancer hallmarks and their interactions are still in its infancy concerning RCC.	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('RCC', 'Disease', (152, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer hallmarks', 'Disease', (76, 92))	('cancer hallmarks', 'Disease', 'MESH:D009369', (76, 92))	('epigenetic alterations', 'Var', (38, 60))	('RC', 'Phenotype', 'HP:0009726', (152, 154))
180483	30986931	In this review, we explore RCC biology, highlighting genetic and epigenetic alterations that contribute to metabolic deregulation of tumor cells, including high glycolytic phenotype (Warburg effect).	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('high glycolytic phenotype', 'MPA', (156, 181))	('RC', 'Phenotype', 'HP:0009726', (27, 29))	('tumor', 'Disease', (133, 138))	('metabolic deregulation', 'MPA', (107, 129))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('epigenetic alterations', 'Var', (65, 87))
180484	30986931	Moreover, we critically discuss available data concerning epigenetic enzymes' regulation by aberrant metabolite accumulation and their consequences in RCC emergence and progression.	('regulation', 'biological_process', 'GO:0065007', ('78', '88'))	('aberrant', 'Var', (92, 100))	('RC', 'Phenotype', 'HP:0009726', (151, 153))	('regulation', 'MPA', (78, 88))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (151, 154))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))
180493	30986931	Most familial ccRCC are associated with von Hippel Lindau disease, caused by von Hippel Lindau tumor suppressor gene (VHL) genetic alterations, at chromosome 3p (3p25-26).	('von Hippel Lindau disease', 'Disease', (40, 65))	('VHL', 'Gene', (118, 121))	('associated', 'Reg', (24, 34))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('chromosome', 'cellular_component', 'GO:0005694', ('147', '157'))	('RCC', 'Disease', (16, 19))	('VHL', 'Gene', '7428', (118, 121))	('caused by', 'Reg', (67, 76))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('95', '111'))	('von Hippel Lindau disease', 'Disease', 'MESH:D006623', (40, 65))	('von Hippel Lindau tumor', 'Disease', (77, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor suppressor', 'biological_process', 'GO:0051726', ('95', '111'))	('genetic alterations', 'Var', (123, 142))	('RC', 'Phenotype', 'HP:0009726', (16, 18))	('von Hippel Lindau tumor', 'Disease', 'MESH:D006623', (77, 100))
180494	30986931	Furthermore, BRCA1 associated protein 1 (BAP1) and succinate dehydrogenase (SDHB, SDHC and SDHD) gene mutations have also been associated with ccRCC hereditary forms.	('succinate', 'Chemical', 'MESH:D019802', (51, 60))	('SDHC', 'Gene', '6391', (82, 86))	('BAP1', 'Gene', (41, 45))	('SDHD', 'Gene', (91, 95))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('RCC', 'Disease', (145, 148))	('associated', 'Reg', (127, 137))	('BRCA1 associated protein 1', 'Gene', '8314', (13, 39))	('RC', 'Phenotype', 'HP:0009726', (14, 16))	('mutations', 'Var', (102, 111))	('SDHC', 'Gene', (82, 86))	('hereditary forms', 'Disease', (149, 165))	('SDHB', 'Gene', '6390', (76, 80))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RC', 'Phenotype', 'HP:0009726', (145, 147))	('BAP1', 'Gene', '8314', (41, 45))	('SDHB', 'Gene', (76, 80))	('SDHD', 'Gene', '6392', (91, 95))	('BRCA1 associated protein 1', 'Gene', (13, 39))
180496	30986931	Indeed, biallelic VHL inactivation caused by genetic mutations and/or by VHL promoter hypermethylation is considered a driving event in ccRCC carcinogenesis.	('carcinogenesis', 'Disease', (142, 156))	('VHL', 'Gene', (73, 76))	('RCC', 'Disease', (138, 141))	('hypermethylation', 'Var', (86, 102))	('VHL', 'Gene', '7428', (18, 21))	('biallelic', 'Var', (8, 17))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('VHL', 'Gene', '7428', (73, 76))	('carcinogenesis', 'Disease', 'MESH:D063646', (142, 156))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('VHL', 'Gene', (18, 21))	('RC', 'Phenotype', 'HP:0009726', (138, 140))	('genetic mutations', 'Var', (45, 62))	('inactivation', 'NegReg', (22, 34))
180501	30986931	Along with VHL loss, mutations in other genes located at chromosome 3p have also been reported in ccRCC.	('VHL loss', 'Disease', 'MESH:D006623', (11, 19))	('chromosome', 'cellular_component', 'GO:0005694', ('57', '67'))	('reported', 'Reg', (86, 94))	('RC', 'Phenotype', 'HP:0009726', (100, 102))	('VHL loss', 'Disease', (11, 19))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('mutations', 'Var', (21, 30))
180502	30986931	These include mutations in chromatin remodeling genes, e.g., polybromo 1 (PBRM1), SET domain containing 2 (SETD2) and BAP1, as well as activating mutations in mammalian target of rapamycin (mTOR) pathway, which are prevalent in ccRCC and associated with worse clinical outcome.	('RC', 'Phenotype', 'HP:0009726', (230, 232))	('chromatin', 'cellular_component', 'GO:0000785', ('27', '36'))	('activating', 'PosReg', (135, 145))	('SETD2', 'Gene', '29072', (107, 112))	('mammalian target of rapamycin', 'Gene', (159, 188))	('BAP1', 'Gene', '8314', (118, 122))	('prevalent', 'Reg', (215, 224))	('mutations', 'Var', (14, 23))	('polybromo 1', 'Gene', '55193', (61, 72))	('mTOR', 'Gene', (190, 194))	('RCC', 'Disease', (230, 233))	('BAP1', 'Gene', (118, 122))	('RCC', 'Phenotype', 'HP:0005584', (230, 233))	('PBRM1', 'Gene', '55193', (74, 79))	('mTOR', 'Gene', '2475', (190, 194))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('27', '47'))	('polybromo 1', 'Gene', (61, 72))	('RCC', 'Disease', 'MESH:C538614', (230, 233))	('mammalian target of rapamycin', 'Gene', '2475', (159, 188))	('SETD2', 'Gene', (107, 112))	('PBRM1', 'Gene', (74, 79))
180507	30986931	Besides, it is typically associated with MET proto-oncogene, receptor tyrosine kinase (MET) amplification and overexpression.	('associated', 'Reg', (25, 35))	('amplification', 'Var', (92, 105))	('MET proto-oncogene, receptor tyrosine kinase', 'Gene', '4233', (41, 85))	('MET', 'Gene', (87, 90))	('overexpression', 'PosReg', (110, 124))
180508	30986931	On the other hand, hereditary papillary renal cancer (HPRC), the familiar form of pRCC Type I, is characterized by activating mutations in the tyrosine kinase domain of MET, which is located at chromosome 7p.	('chromosome', 'cellular_component', 'GO:0005694', ('194', '204'))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('pRCC', 'Gene', (82, 86))	('renal cancer', 'Phenotype', 'HP:0009726', (40, 52))	('RC', 'Phenotype', 'HP:0009726', (56, 58))	('hereditary papillary renal cancer', 'Disease', (19, 52))	('RC', 'Phenotype', 'HP:0009726', (83, 85))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('mutations in', 'Var', (126, 138))	('MET', 'Gene', (169, 172))	('pRCC', 'Gene', '5546', (82, 86))	('papillary renal cancer', 'Phenotype', 'HP:0006766', (30, 52))	('hereditary papillary renal cancer', 'Disease', 'MESH:D007681', (19, 52))
180512	30986931	Sporadic Type II tumors are frequently associated with cyclin dependent kinase inhibitor (CDKN) 2A inactivation, either by mutation or promoter hypermethylation.	('cyclin dependent kinase inhibitor (CDKN) 2A', 'Gene', '1029', (55, 98))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mutation', 'Var', (123, 131))	('promoter hypermethylation', 'Var', (135, 160))	('Sporadic Type II tumors', 'Disease', (0, 23))	('cyclin dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('55', '88'))	('Sporadic Type II tumors', 'Disease', 'MESH:D009369', (0, 23))	('associated', 'Reg', (39, 49))	('inactivation', 'NegReg', (99, 111))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('72', '88'))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
180513	30986931	Additionally, mutations of chromatin remodeling genes (SETD2, BAP1 and PBRM1 genes) described for ccRCC have also been found.	('PBRM1', 'Gene', (71, 76))	('mutations', 'Var', (14, 23))	('BAP1', 'Gene', '8314', (62, 66))	('PBRM1', 'Gene', '55193', (71, 76))	('BAP1', 'Gene', (62, 66))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('RC', 'Phenotype', 'HP:0009726', (100, 102))	('chromatin', 'cellular_component', 'GO:0000785', ('27', '36'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('27', '47'))	('SETD2', 'Gene', '29072', (55, 60))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('SETD2', 'Gene', (55, 60))
180514	30986931	The familiar form arises from hereditary leiomyoma renal cell carcinoma (HLRCC) syndrome and it due to fumarate hydratase (FH) gene germline mutations.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (51, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('fumarate hydratase', 'Gene', '2271', (103, 121))	('hereditary leiomyoma renal cell carcinoma (HLRCC) syndrome', 'Disease', 'MESH:C535516', (30, 88))	('fumarate hydratase', 'Gene', (103, 121))	('FH', 'Gene', '2271', (123, 125))	('RC', 'Phenotype', 'HP:0009726', (75, 77))	('germline mutations', 'Var', (132, 150))
180539	30986931	As described in the previous section, RCC is characterized by mutations in genes related with cell metabolism, namely FH and SDH genes.	('RCC', 'Disease', (38, 41))	('metabolism', 'biological_process', 'GO:0008152', ('99', '109'))	('RC', 'Phenotype', 'HP:0009726', (38, 40))	('SDH', 'Gene', '6390', (125, 128))	('FH', 'Gene', '2271', (118, 120))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('SDH', 'Gene', (125, 128))	('mutations', 'Var', (62, 71))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
180550	30986931	Specifically, glucose-6-phosphate dehydrogenase (G6PD) overexpression increases PPP activity, which generates high nicotinamide adenine dinucleotide phosphate (NADPH) levels.	('glucose-6-phosphate dehydrogenase', 'Gene', (14, 47))	('high nicotinamide adenine dinucleotide phosphate', 'Phenotype', 'HP:0410206', (110, 158))	('PPP', 'Enzyme', (80, 83))	('G6PD', 'Gene', '2539', (49, 53))	('increases', 'PosReg', (70, 79))	('overexpression', 'Var', (55, 69))	('G6PD', 'Gene', (49, 53))	('activity', 'MPA', (84, 92))	('glucose-6-phosphate dehydrogenase', 'Gene', '2539', (14, 47))	('nicotinamide adenine dinucleotide phosphate', 'Chemical', 'MESH:D009249', (115, 158))	('high', 'PosReg', (110, 114))	('NADPH', 'Chemical', 'MESH:D009249', (160, 165))
180553	30986931	Remarkably, glutamine metabolism upregulation has been associated with MYC proto-oncogene (MYC) overexpression in RCC, inducing glutamine transporter and glutaminase (GLS) upregulation, followed by elevated glutamate and alpha-ketoglutarate levels, and lipid accumulation in RCC tumors.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (221, 240))	('glutamine', 'Chemical', 'MESH:D005973', (12, 21))	('upregulation', 'PosReg', (33, 45))	('inducing', 'Reg', (119, 127))	('glutamate', 'Chemical', 'MESH:D018698', (207, 216))	('RCC', 'Disease', 'MESH:C538614', (275, 278))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('MYC', 'Gene', '4609', (91, 94))	('RC', 'Phenotype', 'HP:0009726', (275, 277))	('MYC', 'Gene', (71, 74))	('glutaminase', 'Gene', '2744', (154, 165))	('elevated glutamate', 'Phenotype', 'HP:0500149', (198, 216))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('overexpression', 'Var', (96, 110))	('glutamine', 'Chemical', 'MESH:D005973', (128, 137))	('RC', 'Phenotype', 'HP:0009726', (114, 116))	('lipid', 'Chemical', 'MESH:D008055', (253, 258))	('glutamine metabolism upregulation', 'Phenotype', 'HP:0003217', (12, 45))	('RCC tumors', 'Disease', (275, 285))	('upregulation', 'PosReg', (172, 184))	('MYC', 'Gene', '4609', (71, 74))	('elevated', 'PosReg', (198, 206))	('glutaminase', 'Gene', (154, 165))	('RCC tumors', 'Disease', 'MESH:C538614', (275, 285))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('12', '32'))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('MYC', 'Gene', (91, 94))	('lipid accumulation', 'MPA', (253, 271))	('RCC', 'Disease', (275, 278))	('RCC', 'Phenotype', 'HP:0005584', (275, 278))
180556	30986931	Accordingly, high lactate levels have been associated with poor prognosis, high risk for development of metastasis and high tumor recurrence in several solid tumors.	('lactate', 'Chemical', 'MESH:D019344', (18, 25))	('men', 'Species', '9606', (96, 99))	('tumor', 'Disease', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('solid tumors', 'Disease', 'MESH:D009369', (152, 164))	('high', 'Var', (13, 17))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('solid tumors', 'Disease', (152, 164))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
180564	30986931	Epigenetic marks are crucial to maintain genomic stability, chromosome imprinting and cell differentiation in normal development.	('cell differentiation', 'biological_process', 'GO:0030154', ('86', '106'))	('cell differentiation', 'CPA', (86, 106))	('men', 'Species', '9606', (124, 127))	('Epigenetic marks', 'Var', (0, 16))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))
180571	30986931	Contrarily, cancer cells display global DNA hypomethylation resulting in genome instability with proto-oncogenes activation, loss of imprinting and high mutation rates.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('loss', 'NegReg', (125, 129))	('mutation', 'CPA', (153, 161))	('cancer', 'Disease', (12, 18))	('genome instability', 'MPA', (73, 91))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('40', '59'))	('activation', 'PosReg', (113, 123))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('DNA hypomethylation', 'Var', (40, 59))	('resulting in', 'Reg', (60, 72))
180572	30986931	Furthermore, aberrant gene promoter hypermethylation in cancer is associated with tumor suppressor genes' transcription silencing.	('associated', 'Reg', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor suppressor', 'biological_process', 'GO:0051726', ('82', '98'))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('82', '98'))	('aberrant gene', 'Var', (13, 26))	('transcription', 'biological_process', 'GO:0006351', ('106', '119'))	('tumor', 'Disease', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('transcription', 'MPA', (106, 119))	('cancer', 'Disease', (56, 62))
180577	30986931	Additionally, H4K20me3, a repressive histone mark, is also frequently found in human cancers.	('human', 'Species', '9606', (79, 84))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('H4K20me3', 'Var', (14, 22))	('found', 'Reg', (70, 75))
180579	30986931	Contrarily, deacetylation leads to DNA condensation by restoring the positive charges of lysine, with consequent transcription abrogation.	('transcription', 'MPA', (113, 126))	('restoring', 'PosReg', (55, 64))	('DNA condensation', 'biological_process', 'GO:0006323', ('35', '51'))	('DNA condensation', 'biological_process', 'GO:0030261', ('35', '51'))	('lysine', 'Chemical', 'MESH:D008239', (89, 95))	('DNA condensation', 'Disease', (35, 51))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('positive charges of lysine', 'MPA', (69, 95))	('transcription', 'biological_process', 'GO:0006351', ('113', '126'))	('deacetylation', 'Var', (12, 25))
180582	30986931	HATs and HDACs enzymes' deregulation have been implicated in tumorigenesis and metastasis.	('deregulation', 'Var', (24, 36))	('implicated', 'Reg', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('metastasis', 'CPA', (79, 89))	('tumor', 'Disease', (61, 66))
180584	30986931	Moreover, H3K9 hypoacetylation was associated with a high proliferative profile and higher recurrence rates in ependymal tumors.	('hypoacetylation', 'Var', (15, 30))	('recurrence rates', 'CPA', (91, 107))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('ependymal tumors', 'Disease', (111, 127))	('H3K9', 'Protein', (10, 14))	('high proliferative profile', 'CPA', (53, 79))	('ependymal tumors', 'Disease', 'MESH:D009369', (111, 127))	('higher', 'PosReg', (84, 90))
180585	30986931	Epigenetic mechanisms allow cell adaptation to environmental changes, but also fueling cancer cells phenotype by supporting cell proliferation and metabolic reprogramming.	('cancer', 'Disease', (87, 93))	('supporting', 'PosReg', (113, 123))	('cell proliferation', 'biological_process', 'GO:0008283', ('124', '142'))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('metabolic reprogramming', 'CPA', (147, 170))	('men', 'Species', '9606', (54, 57))	('cell proliferation', 'CPA', (124, 142))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('Epigenetic mechanisms', 'Var', (0, 21))
180588	30986931	In RCC, epigenetic silencing through gene promoter hypermethylation often downregulates genes related with Wnt/beta-catenin and transforming growth factor (TGF) beta pathway, pro-apoptotic genes, cell cycle regulator' genes and genes responsible for cell adhesion, implicated in cancer proliferation and metastization.	('cell', 'Gene', (196, 200))	('genes', 'Gene', (88, 93))	('downregulates', 'NegReg', (74, 87))	('Wnt/beta-catenin', 'Pathway', (107, 123))	('RC', 'Phenotype', 'HP:0009726', (3, 5))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('epigenetic silencing', 'Var', (8, 28))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('196', '216'))	('cell adhesion', 'biological_process', 'GO:0007155', ('250', '263'))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('196', '216'))	('RCC', 'Disease', (3, 6))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('RCC', 'Disease', 'MESH:C538614', (3, 6))
180590	30986931	BAP1-deficient ccRCC tumors are associated with poor prognosis, whereas loss of PBRM1 expression increases tumor aggressiveness.	('PBRM1', 'Gene', '55193', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('increases tumor aggressiveness', 'Disease', 'MESH:D009369', (97, 127))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('RC', 'Phenotype', 'HP:0009726', (17, 19))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('aggressiveness', 'Phenotype', 'HP:0000718', (113, 127))	('loss', 'Var', (72, 76))	('increases tumor aggressiveness', 'Disease', (97, 127))	('PBRM1', 'Gene', (80, 85))	('BAP1-deficient ccRCC tumors', 'Disease', 'MESH:D009369', (0, 27))	('BAP1-deficient ccRCC tumors', 'Disease', (0, 27))
180591	30986931	Moreover, inactivating mutations in SETD2, KDM5C and KMD6A were also found in RCC (mutated in approximately 5-15% of ccRCC cases).	('inactivating mutations', 'Var', (10, 32))	('KMD6A', 'Gene', (53, 58))	('SETD2', 'Gene', '29072', (36, 41))	('RC', 'Phenotype', 'HP:0009726', (78, 80))	('KDM5C', 'Gene', (43, 48))	('RC', 'Phenotype', 'HP:0009726', (119, 121))	('SETD2', 'Gene', (36, 41))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('KDM5C', 'Gene', '8242', (43, 48))	('RCC', 'Disease', (119, 122))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('found', 'Reg', (69, 74))
180592	30986931	As a result of HTMs and KDMs deregulation, RCC display a specific histone methylation profile.	('HTMs', 'Var', (15, 19))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('histone methylation profile', 'MPA', (66, 93))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('deregulation', 'Var', (29, 41))	('histone methylation', 'biological_process', 'GO:0016571', ('66', '85'))	('RC', 'Phenotype', 'HP:0009726', (43, 45))	('KDMs deregulation', 'Var', (24, 41))	('KDMs', 'Chemical', '-', (24, 28))
180600	30986931	Paradoxically, although ccRCC samples depict lower HDAC9 levels than normal adjacent tissues, high HDAC9 expression was associated with poor prognosis.	('RC', 'Phenotype', 'HP:0009726', (26, 28))	('HDAC9', 'Gene', (51, 56))	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('lower', 'NegReg', (45, 50))	('HDAC9', 'Gene', (99, 104))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('HDAC9', 'Gene', '9734', (99, 104))	('HDAC9', 'Gene', '9734', (51, 56))	('high', 'Var', (94, 98))
180624	30986931	In absence of glycolytic metabolism, beta-OHB is used as oxidative energy source instead of epigenetic regulator, inducing tumor growth.	('beta-OHB', 'Chemical', '-', (37, 45))	('inducing', 'PosReg', (114, 122))	('tumor', 'Disease', (123, 128))	('beta-OHB', 'Var', (37, 45))	('metabolism', 'biological_process', 'GO:0008152', ('25', '35'))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
180628	30986931	Thus, SIRTs inhibition seems to contribute to hyperacetylation and aberrant gene transcription, leading to cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('SIRTs', 'Protein', (6, 11))	('hyperacetylation', 'MPA', (46, 62))	('transcription', 'biological_process', 'GO:0006351', ('81', '94'))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('aberrant', 'Var', (67, 75))	('cancer', 'Disease', (107, 113))	('leading to', 'Reg', (96, 106))
180636	30986931	Additionally, acetyl-CoA generated from glutamine was shown to be involved in histone acetylation, inducing the expression of genes involved in lipid metabolism.	('lipid', 'Chemical', 'MESH:D008055', (144, 149))	('histone acetylation', 'biological_process', 'GO:0016573', ('78', '97'))	('glutamine', 'Chemical', 'MESH:D005973', (40, 49))	('lipid metabolism', 'biological_process', 'GO:0006629', ('144', '160'))	('glutamine', 'Var', (40, 49))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (14, 24))	('inducing', 'PosReg', (99, 107))	('expression', 'MPA', (112, 122))
180640	30986931	In tumors with SDH mutations, succinate accumulation associates with DNA hypermethylation phenotype.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('succinate accumulation', 'MPA', (30, 52))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('69', '89'))	('SDH', 'Gene', '6390', (15, 18))	('mutations', 'Var', (19, 28))	('DNA hypermethylation', 'MPA', (69, 89))	('succinate', 'Chemical', 'MESH:D019802', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('SDH', 'Gene', (15, 18))
180641	30986931	Inhibition of histone and DNA demethylases was associated with increased tumor aggressiveness and invasion potential, mediated by epigenetic silencing of genes involved in cell differentiation and epithelial mesenchymal transition (EMT).	('epigenetic silencing', 'Var', (130, 150))	('increased', 'PosReg', (63, 72))	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('epithelial mesenchymal transition', 'CPA', (197, 230))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('DNA demethylases', 'Protein', (26, 42))	('epithelial mesenchymal transition', 'biological_process', 'GO:0001837', ('197', '230'))	('tumor aggressiveness', 'Disease', (73, 93))	('EMT', 'biological_process', 'GO:0001837', ('232', '235'))	('cell differentiation', 'biological_process', 'GO:0030154', ('172', '192'))	('Inhibition', 'Var', (0, 10))	('aggressiveness', 'Phenotype', 'HP:0000718', (79, 93))	('histone', 'Protein', (14, 21))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (73, 93))	('invasion potential', 'CPA', (98, 116))
180642	30986931	Moreover, fumarate was also associated with tumor aggressiveness.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (44, 64))	('aggressiveness', 'Phenotype', 'HP:0000718', (50, 64))	('associated', 'Reg', (28, 38))	('fumarate', 'Chemical', 'MESH:D005650', (10, 18))	('fumarate', 'Var', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor aggressiveness', 'Disease', (44, 64))
180646	30986931	In RCC, increased L-2HG levels are mediated by L-2HG dehydrogenase (L2HGDH) reduced expression due to copy number loss.	('L-2HG levels', 'MPA', (18, 30))	('L2HGDH', 'Gene', (68, 74))	('L-2HG dehydrogenase', 'Gene', '79944', (47, 66))	('RC', 'Phenotype', 'HP:0009726', (3, 5))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('L-2HG dehydrogenase', 'Gene', (47, 66))	('L2HGDH', 'Gene', '79944', (68, 74))	('reduced', 'NegReg', (76, 83))	('increased', 'PosReg', (8, 17))	('copy number loss', 'Var', (102, 118))	('RCC', 'Disease', (3, 6))	('expression', 'MPA', (84, 94))	('RCC', 'Disease', 'MESH:C538614', (3, 6))
180650	30986931	Hence, owing to mutations in FH, SDH and L2HGDH genes, which lead to TET and KMDs inhibition, aberrant accumulation of oncometabolites occurs in RCC, stimulating tumor growth and aggressiveness (Figure 5B).	('stimulating', 'PosReg', (150, 161))	('tumor', 'Disease', (162, 167))	('SDH', 'Gene', '6390', (33, 36))	('FH', 'Gene', '2271', (29, 31))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('RCC', 'Disease', (145, 148))	('mutations', 'Var', (16, 25))	('L2HGDH', 'Gene', (41, 47))	('L2HGDH', 'Gene', '79944', (41, 47))	('oncometabolites', 'MPA', (119, 134))	('SDH', 'Gene', (33, 36))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('RC', 'Phenotype', 'HP:0009726', (145, 147))	('accumulation', 'PosReg', (103, 115))	('TET', 'Chemical', '-', (69, 72))	('aggressiveness', 'Disease', (179, 193))	('aggressiveness', 'Phenotype', 'HP:0000718', (179, 193))	('aggressiveness', 'Disease', 'MESH:D001523', (179, 193))
180657	30986931	Cell metabolism deregulation, particularly Warburg effect, plays a major role in RCC development, contributing to accumulation of metabolites that regulate epigenetic factors.	('Warburg effect', 'Disease', (43, 57))	('RC', 'Phenotype', 'HP:0009726', (81, 83))	('metabolism', 'biological_process', 'GO:0008152', ('5', '15'))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('deregulation', 'Var', (16, 28))	('RCC', 'Disease', (81, 84))	('accumulation', 'PosReg', (114, 126))	('Cell metabolism', 'MPA', (0, 15))	('men', 'Species', '9606', (92, 95))	('metabolites', 'MPA', (130, 141))
180776	30962867	Moreover, we reported that forkhead box protein C2 (FOXC2) and cytoskeleton-associated protein-glycine rich (CAP-Gly) domain-containing linker protein family member 4 (CLIP4) mutations were associated with clinical T1 stage ccRCC with synchronous metastasis.	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('mutations', 'Var', (175, 184))	('RCC', 'Disease', (226, 229))	('CLIP4', 'Gene', (168, 173))	('CLIP4', 'Gene', '79745', (168, 173))	('CAP', 'Chemical', '-', (109, 112))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('ccRCC', 'Phenotype', 'HP:0006770', (224, 229))	('glycine', 'Chemical', 'MESH:D005998', (95, 102))	('RCC', 'Disease', 'MESH:C538614', (226, 229))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('FOXC2', 'Gene', '2303', (52, 57))	('FOXC2', 'Gene', (52, 57))	('forkhead box protein C2', 'Gene', (27, 50))	('forkhead box protein C2', 'Gene', '2303', (27, 50))	('synchronous metastasis', 'Disease', 'MESH:D009362', (235, 257))	('associated with', 'Reg', (190, 205))	('synchronous metastasis', 'Disease', (235, 257))	('Gly', 'Chemical', 'MESH:D005998', (113, 116))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('63', '75'))
180798	30962867	Finally, the slides were evaluated by light microscopy at 100x to 400x to document the staining intensity and categorized tumors as positive-expression for presence of PBRM1 and BAP1 nuclear tissue staining and FOXC2 cytoplasm tissue staining and negative-expression for absence of PBRM1 and BAP1 nuclear tissue staining and FOXC2 cytoplasm tissue staining, respectively.	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('BAP1', 'Gene', (178, 182))	('PBRM1', 'Gene', '55193', (168, 173))	('cytoplasm', 'cellular_component', 'GO:0005737', ('217', '226'))	('BAP1', 'Gene', '8314', (292, 296))	('FOXC2', 'Gene', (325, 330))	('FOXC2', 'Gene', '2303', (325, 330))	('PBRM1', 'Gene', (168, 173))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('BAP1', 'Gene', (292, 296))	('presence', 'Var', (156, 164))	('positive-expression', 'PosReg', (132, 151))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('PBRM1', 'Gene', '55193', (282, 287))	('cytoplasm', 'cellular_component', 'GO:0005737', ('331', '340'))	('FOXC2', 'Gene', (211, 216))	('BAP1', 'Gene', '8314', (178, 182))	('tumors', 'Disease', (122, 128))	('FOXC2', 'Gene', '2303', (211, 216))	('PBRM1', 'Gene', (282, 287))
180835	30962867	In ccRCC, mutations of PBRM1 were detected in 32.5% (198/609) of the MSKCC cohort and in 33.0% (67/203) of the sample analyzed by Brandon et al., which included the MSKCC cohort along with data from three publicly available cohorts: The Caner Genome Atlas, University of Tokyo, and The International Cancer Genome Consortium.	('detected', 'Reg', (34, 42))	('PBRM1', 'Gene', (23, 28))	('PBRM1', 'Gene', '55193', (23, 28))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('RCC', 'Disease', (5, 8))	('Cancer', 'Phenotype', 'HP:0002664', (300, 306))	('mutations', 'Var', (10, 19))
180836	30962867	Analysis of the MSKCC cohort further showed a significant association of PBRM mutations with higher T stages and earlier invasion in smaller tumors, but there was no association detected with inferior clinical outcomes.	('PBRM', 'Gene', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('mutations', 'Var', (78, 87))
180837	30962867	Thus, the authors suggested that inactivation of PBRM1 is likely associated with an early, essential event in kidney tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('associated', 'Reg', (65, 75))	('PBRM1', 'Gene', (49, 54))	('PBRM1', 'Gene', '55193', (49, 54))	('inactivation', 'Var', (33, 45))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
180839	30962867	BAP1 mutation in uveal melanoma is associated with an aggressive subtype; however, in mesothelioma, BAP1 mutation is not associated with inferior clinical outcomes.	('BAP1', 'Gene', '8314', (100, 104))	('BAP1', 'Gene', (0, 4))	('associated', 'Reg', (35, 45))	('BAP1', 'Gene', (100, 104))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('uveal melanoma', 'Phenotype', 'HP:0007716', (17, 31))	('mesothelioma', 'Disease', (86, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (17, 31))	('BAP1', 'Gene', '8314', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (86, 98))	('mutation', 'Var', (5, 13))	('uveal melanoma', 'Disease', (17, 31))
180841	30962867	reported the mutually exclusive characteristics of PBRM1 and BAP1 mutations, in which BAP1-mutant tumors were associated with worse survival and a higher Fuhrman grade than PBRM1-mutant tumors.	('mutations', 'Var', (66, 75))	('tumors', 'Disease', (98, 104))	('worse', 'NegReg', (126, 131))	('Fuhrman grade', 'CPA', (154, 167))	('PBRM1', 'Gene', (51, 56))	('BAP1', 'Gene', '8314', (86, 90))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('BAP1', 'Gene', '8314', (61, 65))	('PBRM1', 'Gene', '55193', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('BAP1', 'Gene', (86, 90))	('tumors', 'Disease', (186, 192))	('higher', 'PosReg', (147, 153))	('PBRM1', 'Gene', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('BAP1', 'Gene', (61, 65))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('PBRM1', 'Gene', '55193', (51, 56))
180842	30962867	This finding was supported by the  cohort study, which indicated an association of BAP1 mutations with poor prognostic factors such as a higher T stage, higher nuclear grade, large size, more necrosis, and the presence of metastatic disease at presentation.	('necrosis', 'biological_process', 'GO:0008219', ('192', '200'))	('association', 'Interaction', (68, 79))	('metastatic disease', 'CPA', (222, 240))	('necrosis', 'biological_process', 'GO:0019835', ('192', '200'))	('necrosis', 'biological_process', 'GO:0008220', ('192', '200'))	('necrosis', 'Disease', 'MESH:D009336', (192, 200))	('BAP1', 'Gene', (83, 87))	('necrosis', 'biological_process', 'GO:0070265', ('192', '200'))	('mutations', 'Var', (88, 97))	('necrosis', 'biological_process', 'GO:0001906', ('192', '200'))	('T stage', 'CPA', (144, 151))	('necrosis', 'Disease', (192, 200))	('BAP1', 'Gene', '8314', (83, 87))
180843	30962867	Based on this background, PBRM1 mutations, which do not impact clinical outcome, appear to play a principal role in tumor initiation, while BAP1 mutations are more strongly associated with worse oncological outcomes that likely occur during disease progression.	('tumor initiation', 'Disease', (116, 132))	('BAP1', 'Gene', (140, 144))	('PBRM1', 'Gene', (26, 31))	('mutations', 'Var', (145, 154))	('PBRM1', 'Gene', '55193', (26, 31))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('associated with', 'Reg', (173, 188))	('tumor initiation', 'Disease', 'MESH:D009369', (116, 132))	('BAP1', 'Gene', '8314', (140, 144))
180868	28332632	LOY in constitutional DNA, but not in tumor DNA was associated with older age.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('constitutional DNA', 'Disease', (7, 25))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('LOY', 'Var', (0, 3))
180869	28332632	Amongst Y-linked genes that were downregulated due to LOY, KDM5D and KDM6C epigenetic modifiers have functionally-similar X-linked homologs whose deficiency is involved in ccRCC progression.	('KDM6C', 'Var', (69, 74))	('KDM5D', 'Gene', '8284', (59, 64))	('deficiency', 'Disease', (146, 156))	('KDM5D', 'Gene', (59, 64))	('ccRCC', 'Phenotype', 'HP:0006770', (172, 177))	('LOY', 'Var', (54, 57))	('ccRCC', 'Disease', (172, 177))	('deficiency', 'Disease', 'MESH:D007153', (146, 156))	('downregulated', 'NegReg', (33, 46))	('involved', 'Reg', (160, 168))
180872	28332632	For example, several oncogenes including MYC, EGFR, ERBB2 and CCND1 are recurrently amplified through chromosomal or focal gains, while multiple tumor suppressors such as ATM, PTEN and CDKN2A are commonly deleted in different cancers.	('EGFR', 'Gene', '1956', (46, 50))	('MYC', 'Gene', (41, 44))	('tumor', 'Disease', (145, 150))	('chromosomal', 'Var', (102, 113))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('ATM', 'Gene', '472', (171, 174))	('CDKN2A', 'Gene', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('CCND1', 'Gene', '595', (62, 67))	('PTEN', 'Gene', (176, 180))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('MYC', 'Gene', '4609', (41, 44))	('EGFR', 'Gene', (46, 50))	('ERBB2', 'Gene', (52, 57))	('CCND1', 'Gene', (62, 67))	('CDKN2A', 'Gene', '1029', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('PTEN', 'Gene', '5728', (176, 180))	('ATM', 'Gene', (171, 174))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('ERBB2', 'Gene', '2064', (52, 57))	('cancers', 'Disease', (226, 233))	('oncogenes', 'Gene', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
180874	28332632	Remarkably, 3p harbors the four most commonly mutated genes in ccRCC whose cancer-driving activities have been established in the disease; VHL, PBRM1, SETD2, and BAP1, which are mutated in 80%, 40%, 19% and 12% of cases, respectively.	('VHL', 'Gene', (139, 142))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('BAP1', 'Gene', '8314', (162, 166))	('PBRM1', 'Gene', (144, 149))	('VHL', 'Gene', '7428', (139, 142))	('cancer', 'Disease', (75, 81))	('mutated', 'Var', (46, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('ccRCC', 'Disease', (63, 68))	('BAP1', 'Gene', (162, 166))	('PBRM1', 'Gene', '55193', (144, 149))	('SETD2', 'Gene', '29072', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('SETD2', 'Gene', (151, 156))
180875	28332632	Inactivation of VHL leads to constitutive stabilization of the hypoxia inducible transcription factors (HIF), and abnormal activation of their downstream genes, which contribute to cancer development.	('VHL', 'Gene', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('VHL', 'Gene', '7428', (16, 19))	('contribute', 'Reg', (167, 177))	('hypoxia', 'Disease', 'MESH:D000860', (63, 70))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('transcription', 'biological_process', 'GO:0006351', ('81', '94'))	('activation', 'PosReg', (123, 133))	('hypoxia', 'Disease', (63, 70))	('cancer', 'Disease', (181, 187))	('Inactivation', 'Var', (0, 12))	('men', 'Species', '9606', (195, 198))
180878	28332632	Overall, tumors from male patients exhibited higher prevalence for the recurrent chromosomal aberrations, in particular for gain of 7q (28% in males vs. 17% in females) and deletion of 9p (25% in males vs. 10% in females) (Fig.	('recurrent chromosomal aberrations', 'Phenotype', 'HP:0040012', (71, 104))	('gain', 'PosReg', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('patients', 'Species', '9606', (26, 34))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('deletion of 9p', 'Var', (173, 187))
180881	28332632	Curiously, whereas no tumors from male patients displayed LOX, loss of chromosome Y (LOY) was the second most frequent somatic chromosome aneuploidy in these tumors (36.5% of male subjects, N = 19; Fig.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('patients', 'Species', '9606', (39, 47))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('aneuploidy', 'Disease', (138, 148))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('loss of chromosome Y', 'Var', (63, 83))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('aneuploidy', 'Disease', 'MESH:D000782', (138, 148))	('LOX', 'Chemical', '-', (58, 61))	('chromosome', 'cellular_component', 'GO:0005694', ('71', '81'))	('chromosome', 'cellular_component', 'GO:0005694', ('127', '137'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Disease', (22, 28))
180884	28332632	Of significance, LOY was the only recurrent aneuploidy in constitutional DNA of our samples that was detected in 5 male patients (9.6%; Supplementary Figure 1), of which 4 showed the deletion in more than 20% of cells (Fig.	('aneuploidy', 'Disease', 'MESH:D000782', (44, 54))	('men', 'Species', '9606', (142, 145))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('patients', 'Species', '9606', (120, 128))	('aneuploidy', 'Disease', (44, 54))	('deletion', 'Var', (183, 191))
180896	28332632	These 11 genes were located on chromosome Y, and while expressed in normal kidney tissue, exhibited lower expression in tumors of patients harboring somatic LOY, indicating that this aberration may have functional consequences through deregulation of the affected genes.	('chromosome', 'cellular_component', 'GO:0005694', ('31', '41'))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('expression', 'MPA', (106, 116))	('lower', 'NegReg', (100, 105))	('patients', 'Species', '9606', (130, 138))	('deregulation', 'Var', (235, 247))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
180899	28332632	Likewise, deletion of KDM5D has been detected in 52% of prostate cancers.	('KDM5D', 'Gene', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('prostate cancers', 'Disease', 'MESH:D011471', (56, 72))	('detected', 'Reg', (37, 45))	('deletion', 'Var', (10, 18))	('KDM5D', 'Gene', '8284', (22, 27))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('prostate cancers', 'Phenotype', 'HP:0012125', (56, 72))	('prostate cancers', 'Disease', (56, 72))
180908	28332632	As KDM5C escapes the X-inactivation, the concomitant mutations of KDM5C and LOX in the same tumors may suggest that this gene is a classical tumor suppressor affected with bi-allelic inactivation in ccRCC.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor suppressor', 'biological_process', 'GO:0051726', ('141', '157'))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('ccRCC', 'Disease', (199, 204))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('KDM5C', 'Gene', '8242', (3, 8))	('KDM5C', 'Gene', '8242', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('ccRCC', 'Phenotype', 'HP:0006770', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (92, 98))	('LOX', 'Chemical', '-', (76, 79))	('KDM5C', 'Gene', (3, 8))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('KDM5C', 'Gene', (66, 71))	('bi-allelic inactivation', 'Var', (172, 195))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('141', '157'))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', (92, 97))
180909	28332632	In male cases, we identified KDM5C mutations in tumors of 3 patients (5.8%), of which one was also affected by somatic LOY (Supplementary Figure 4).	('KDM5C', 'Gene', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('patients', 'Species', '9606', (60, 68))	('KDM5C', 'Gene', '8242', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('men', 'Species', '9606', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mutations', 'Var', (35, 44))
180911	28332632	Our list of LOY-associated down-regulated genes (Supplementary Table 2) includes another epigenome modifier with an X-linked homologue that is also recurrently mutated in ccRCC; UTY/KDM6C.	('men', 'Species', '9606', (55, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (171, 176))	('ccRCC', 'Disease', (171, 176))	('mutated', 'Var', (160, 167))	('down-regulated', 'NegReg', (27, 41))
180912	28332632	KDM6C demethylates H3K27, a function similar to that of KDM6A.	('H3K27', 'Protein', (19, 24))	('KDM6A', 'Gene', (56, 61))	('demethylates', 'Var', (6, 18))	('KDM6A', 'Gene', '7403', (56, 61))	('KDM6C', 'Var', (0, 5))
180913	28332632	Mutations of KDM6A leading to its inactivation have been recurrently observed in ccRCC, highlighting this gene as a potential key tumor suppressor in renal cancer.	('renal cancer', 'Disease', (150, 162))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('130', '146'))	('KDM6A', 'Gene', (13, 18))	('observed', 'Reg', (69, 77))	('renal cancer', 'Disease', 'MESH:D007680', (150, 162))	('renal cancer', 'Phenotype', 'HP:0009726', (150, 162))	('ccRCC', 'Disease', (81, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('KDM6A', 'Gene', '7403', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor suppressor', 'biological_process', 'GO:0051726', ('130', '146'))	('tumor', 'Disease', (130, 135))	('inactivation', 'MPA', (34, 46))
180914	28332632	In addition to being affected by somatic LOX in 7 female patients, KDM6A was also affected by focal deletion in a female patient in our cohort.	('focal deletion', 'Var', (94, 108))	('patient', 'Species', '9606', (57, 64))	('affected', 'Reg', (82, 90))	('patients', 'Species', '9606', (57, 65))	('KDM6A', 'Gene', '7403', (67, 72))	('LOX', 'Chemical', '-', (41, 44))	('KDM6A', 'Gene', (67, 72))	('patient', 'Species', '9606', (121, 128))
180921	28332632	Emerging data emphasizes an association between LOY in peripheral blood and higher risk of cancer.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('LOY', 'Var', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
180923	28332632	Recent genomic studies of ccRCC have highlighted the importance of molecular aberrations that impair the function of chromatin remodeling and epigenetic modifiers in ccRCC development.	('men', 'Species', '9606', (179, 182))	('epigenetic', 'Var', (142, 152))	('ccRCC', 'Phenotype', 'HP:0006770', (166, 171))	('ccRCC', 'Phenotype', 'HP:0006770', (26, 31))	('chromatin', 'cellular_component', 'GO:0000785', ('117', '126'))	('impair', 'NegReg', (94, 100))	('ccRCC', 'Disease', (166, 171))	('function', 'MPA', (105, 113))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('117', '137'))
180924	28332632	Our study expands these findings by highlighting the prevalence of somatic LOY among men affected by ccRCC, and suggesting a functional relevance for this aberration through down-regulation of previously unrecognized epigenetic modifiers KDM5D and KDM6C.	('KDM6C', 'Var', (248, 253))	('KDM5D', 'Gene', (238, 243))	('regulation', 'biological_process', 'GO:0065007', ('179', '189'))	('LOY', 'Var', (75, 78))	('KDM5D', 'Gene', '8284', (238, 243))	('men', 'Species', '9606', (85, 88))	('down-regulation', 'NegReg', (174, 189))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('ccRCC', 'Disease', (101, 106))
180927	28332632	These findings indicate that down-regulation of KDM5D through LOY may contribute to the pathogenesis of renal cancer.	('KDM5D', 'Gene', '8284', (48, 53))	('down-regulation', 'NegReg', (29, 44))	('renal cancer', 'Disease', (104, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('renal cancer', 'Disease', 'MESH:D007680', (104, 116))	('renal cancer', 'Phenotype', 'HP:0009726', (104, 116))	('pathogenesis', 'biological_process', 'GO:0009405', ('88', '100'))	('KDM5D', 'Gene', (48, 53))	('LOY', 'Var', (62, 65))	('regulation', 'biological_process', 'GO:0065007', ('34', '44'))
180962	33644060	Besides, knockdown of POLE2 significantly upregulated the expression levels of Bad and p21 while the expression levels of HSP70, IGF-I, IGF-II, survivin, and sTNF-R1 were significantly downregulated.	('IGF-II', 'Gene', (136, 142))	('expression levels', 'MPA', (58, 75))	('IGF-II', 'Gene', '3481', (136, 142))	('IGF-I', 'Gene', '3479', (136, 141))	('knockdown', 'Var', (9, 18))	('p21', 'Gene', '1026', (87, 90))	('IGF-I', 'Gene', (129, 134))	('p21', 'Gene', (87, 90))	('expression levels', 'MPA', (101, 118))	('IGF-I', 'Gene', (136, 141))	('POLE2', 'Gene', (22, 27))	('downregulated', 'NegReg', (185, 198))	('IGF-I', 'Gene', '3479', (129, 134))	('HSP70', 'Gene', '3308', (122, 127))	('upregulated', 'PosReg', (42, 53))	('Bad', 'MPA', (79, 82))	('HSP70', 'Gene', (122, 127))
180963	33644060	Western blot analysis also showed that knockdown of POLE2 inhibited the expression levels of Cancer-related pathway proteins including p-Akt, CCND1, MAPK9, and PIK3CA.	('CCND1', 'Gene', (142, 147))	('POLE2', 'Gene', (52, 57))	('MAPK9', 'Gene', '5601', (149, 154))	('PIK3CA', 'Gene', '5290', (160, 166))	('expression levels', 'MPA', (72, 89))	('knockdown', 'Var', (39, 48))	('CCND1', 'Gene', '595', (142, 147))	('Cancer', 'Disease', 'MESH:D009369', (93, 99))	('Akt', 'Gene', '207', (137, 140))	('MAPK', 'molecular_function', 'GO:0004707', ('149', '153'))	('Cancer', 'Phenotype', 'HP:0002664', (93, 99))	('MAPK9', 'Gene', (149, 154))	('Akt', 'Gene', (137, 140))	('inhibited', 'NegReg', (58, 67))	('Cancer', 'Disease', (93, 99))	('PIK3CA', 'Gene', (160, 166))
180972	33644060	Besides, have found that high expression of POLE2 is a biomarker for poor prognosis in squamous cell lung cancer.	('squamous cell lung cancer', 'Disease', (87, 112))	('high', 'Var', (25, 29))	('POLE2', 'Gene', (44, 49))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (87, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (87, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
180974	33644060	Therefore, in this study, we comprehensively investigated the POLE2 expression and its role and mechanism in RCC from the biological, cellular and animal levels, then clarified that POLE2 was a tumor-promoting gene of RCC, and high POLE2 expression indicated poor prognosis.	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('RCC', 'Disease', (109, 112))	('RCC', 'Disease', (218, 221))	('RCC', 'Phenotype', 'HP:0005584', (218, 221))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('tumor', 'Disease', (194, 199))	('high', 'Var', (227, 231))	('POLE2', 'Gene', (182, 187))
180983	33644060	The short hairpin RNA (shRNA) to knock down expression of POLE2 or stanniocalcin 1 (STC1) in A498 and ACHN cells were designed using the following sequences: 5'-TTCT CCGAACGTGTCACGT-3' (shCtrl), 5'-CGATTGTTCTTGG AATGATA-3' (POLE2-shRNA), 5'-CGTGAAGACTTAGTAA ATAA-3' (POLE2#2-shRNA), 5'-TAAATTTGACACTCAGGG AAA-3' (STC1-shRNA).	('knock', 'Var', (33, 38))	('stanniocalcin 1', 'Gene', '6781', (67, 82))	('AAA-3', 'Gene', '100188857', (305, 310))	('RNA', 'cellular_component', 'GO:0005562', ('18', '21'))	('STC1', 'Gene', '6781', (84, 88))	('STC1', 'Gene', (313, 317))	('AAA-3', 'Gene', (305, 310))	('stanniocalcin 1', 'Gene', (67, 82))	('STC1', 'Gene', (84, 88))	('STC1', 'Gene', '6781', (313, 317))
181000	33644060	RPN2232; Amersham), and then scanned and analyzed by ImageJ.	('age', 'Gene', '5973', (55, 58))	('RPN2232', 'Var', (0, 7))	('age', 'Gene', (55, 58))
181030	33644060	After washing with Tris-buffered saline (TBS), the sections were incubated with primary antibody against POLE2 (bs-14356R; BIOSS; diluted 1:200), STC1 (cat.	('antibody', 'cellular_component', 'GO:0019815', ('88', '96'))	('cat', 'molecular_function', 'GO:0004096', ('152', '155'))	('bs-14356R;', 'Var', (112, 122))	('antibody', 'cellular_component', 'GO:0019814', ('88', '96'))	('STC1', 'Gene', (146, 150))	('antibody', 'molecular_function', 'GO:0003823', ('88', '96'))	('antibody', 'cellular_component', 'GO:0042571', ('88', '96'))	('STC1', 'Gene', '6781', (146, 150))
181047	33644060	In addition, the RCC patients with higher level of POLE2 had higher pathological TNM stage and grade, as well as poor prognosis (Figures 1D-F).	('grade', 'CPA', (95, 100))	('TNM', 'Gene', (81, 84))	('higher', 'PosReg', (61, 67))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('TNM', 'Gene', '10178', (81, 84))	('age', 'Gene', (87, 90))	('patients', 'Species', '9606', (21, 29))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))	('POLE2', 'Var', (51, 56))	('age', 'Gene', '5973', (87, 90))
181053	33644060	Besides, the Kaplan-Meier survival curve revealed that the OS and progression-free survival of patients with POLE2 high expression was significantly lower than that of patients with POLE2 low expression (Figure 1H and Supplementary Figure 1B), which suggested that the expression of POLE2 in RCC tissues was negatively associated with prognosis.	('patients', 'Species', '9606', (95, 103))	('RCC', 'Phenotype', 'HP:0005584', (292, 295))	('progression-free survival', 'CPA', (66, 91))	('patients', 'Species', '9606', (168, 176))	('POLE2', 'Gene', (109, 114))	('lower', 'NegReg', (149, 154))	('RCC', 'Disease', 'MESH:C538614', (292, 295))	('RCC', 'Disease', (292, 295))	('high expression', 'Var', (115, 130))
181056	33644060	Furthermore, the results of Western Blot found that knockdown of POLE2 downregulated the protein levels of N-cadherin, Vimentin and Snail both in A498 and ACHN cells, indicating the cell epithelial-mesenchymal transition was suppressed (Figure 2F).	('suppressed', 'NegReg', (225, 235))	('downregulated', 'NegReg', (71, 84))	('cell epithelial-mesenchymal transition', 'CPA', (182, 220))	('Vimentin', 'cellular_component', 'GO:0045099', ('119', '127'))	('Vimentin', 'Gene', '7431', (119, 127))	('Vimentin', 'cellular_component', 'GO:0045098', ('119', '127'))	('N-cadherin', 'Gene', (107, 117))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))	('cadherin', 'molecular_function', 'GO:0008014', ('109', '117'))	('N-cadherin', 'Gene', '1000', (107, 117))	('Vimentin', 'Gene', (119, 127))	('POLE2', 'Gene', (65, 70))	('knockdown', 'Var', (52, 61))	('Snail', 'Gene', (132, 137))	('Snail', 'Gene', '6615', (132, 137))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('187', '220'))
181058	33644060	The results revealed that knockdown of POLE2 significantly inhibited cell proliferation in the RCC organoids generated from three different RCC patients (Figures 2G,H).	('POLE2', 'Gene', (39, 44))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('inhibited', 'NegReg', (59, 68))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('RCC', 'Disease', (95, 98))	('patients', 'Species', '9606', (144, 152))	('knockdown', 'Var', (26, 35))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('cell proliferation', 'biological_process', 'GO:0008283', ('69', '87'))
181059	33644060	Thus, these data suggested that knockdown of POLE2 could inhibit RCC cell proliferation and migration.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('POLE2', 'Gene', (45, 50))	('knockdown', 'Var', (32, 41))	('inhibit', 'NegReg', (57, 64))	('cell proliferation', 'biological_process', 'GO:0008283', ('69', '87'))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
181062	33644060	Besides, as shown in Figure 3C, the Ki67 protein expression in shPOLE2 group was reduced compared with the shCtrl group, and the results of HE staining pointed out that there were obvious differences in the pathological morphology of the tumor in the two groups (Figure 3D).	('Ki67 protein', 'Protein', (36, 48))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('shPOLE2', 'Var', (63, 70))	('tumor', 'Disease', (238, 243))	('reduced', 'NegReg', (81, 88))	('HE', 'Chemical', 'MESH:D006371', (140, 142))
181063	33644060	The above experiments proved that knockdown of POLE2 can inhibit the tumorigenesis of ACHN cells in mice, suggesting the promotion of POLE2 in RCC.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('promotion', 'PosReg', (121, 130))	('tumor', 'Disease', (69, 74))	('mice', 'Species', '10090', (100, 104))	('inhibit', 'NegReg', (57, 64))	('POLE2', 'Gene', (47, 52))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('knockdown', 'Var', (34, 43))	('RCC', 'Disease', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
181064	33644060	In order to clarify the molecular mechanism of POLE2 in tumorigenesis and development of RCC, the DEGs in normal ACHN cells and POLE2 knockdown ACHN cells were screened by expression profile sequencing analysis, and their expression was verified by qRT-PCR and western blot.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('RCC', 'Disease', (89, 92))	('knockdown', 'Var', (134, 143))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
181070	33644060	Then, we knockdown the expression of these proteins and found that the RCC cell proliferation was significantly inhibited after STC1 knockdown (Figure 4F), Thus, STC1 was selected as a candidate downstream gene, and the interaction of POLE2 and STC1 was detected using Co-IP method.	('STC1', 'Gene', '6781', (128, 132))	('STC1', 'Gene', '6781', (162, 166))	('inhibited', 'NegReg', (112, 121))	('STC1', 'Gene', '6781', (245, 249))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('STC1', 'Gene', (128, 132))	('knockdown', 'Var', (133, 142))	('STC1', 'Gene', (162, 166))	('cell proliferation', 'biological_process', 'GO:0008283', ('75', '93'))	('STC1', 'Gene', (245, 249))
181075	33644060	We constructed overexpressing POLE2 ACHN cells and knockdown STC1 with overexpressing POLE2 ACHN cells, then detected changes in their biological functions.	('STC1', 'Gene', (61, 65))	('STC1', 'Gene', '6781', (61, 65))	('knockdown', 'Var', (51, 60))
181076	33644060	The results showed that overexpression of POLE2 promoted the proliferation of ACHN cells and inhibited the apoptosis (Figures 5A,E), while knockdown of STC1 in overexpressing POLE2 ACHN cells inhibited the proliferation and migration of ACHN cells, and promoted their apoptosis (Figures 5A-E).	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('promoted', 'PosReg', (253, 261))	('proliferation', 'CPA', (61, 74))	('promoted', 'PosReg', (48, 56))	('proliferation', 'CPA', (206, 219))	('ACHN cells', 'CPA', (78, 88))	('STC1', 'Gene', '6781', (152, 156))	('knockdown', 'Var', (139, 148))	('apoptosis', 'biological_process', 'GO:0097194', ('268', '277'))	('inhibited', 'NegReg', (192, 201))	('STC1', 'Gene', (152, 156))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))	('apoptosis', 'CPA', (268, 277))	('apoptosis', 'CPA', (107, 116))	('inhibited', 'NegReg', (93, 102))	('apoptosis', 'biological_process', 'GO:0006915', ('268', '277'))
181078	33644060	The results pointed out that knockdown of POLE2 significantly upregulated the expression levels of Bad and p21 while the expression levels of HSP70, IGF-I, IGF-II, survivin, and sTNF-R1 were significantly down (Figures 6A-C).	('p21', 'Gene', '1026', (107, 110))	('expression levels', 'MPA', (121, 138))	('knockdown', 'Var', (29, 38))	('IGF-I', 'Gene', (149, 154))	('IGF-I', 'Gene', (156, 161))	('HSP70', 'Gene', (142, 147))	('IGF-II', 'Gene', '3481', (156, 162))	('p21', 'Gene', (107, 110))	('Bad', 'MPA', (99, 102))	('upregulated', 'PosReg', (62, 73))	('IGF-II', 'Gene', (156, 162))	('down', 'NegReg', (205, 209))	('IGF-I', 'Gene', '3479', (149, 154))	('expression levels', 'MPA', (78, 95))	('HSP70', 'Gene', '3308', (142, 147))	('POLE2', 'Gene', (42, 47))	('IGF-I', 'Gene', '3479', (156, 161))
181079	33644060	Western blot analysis also showed that knockdown of POLE2 inhibited the expression levels of cancer-related pathway proteins including p-Akt, CCND1, and PIK3CA, while the expression of MAPK9 was promoted (Figure 6D).	('MAPK9', 'Gene', (185, 190))	('CCND1', 'Gene', (142, 147))	('POLE2', 'Gene', (52, 57))	('cancer', 'Disease', (93, 99))	('expression', 'MPA', (171, 181))	('PIK3CA', 'Gene', '5290', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('expression levels', 'MPA', (72, 89))	('knockdown', 'Var', (39, 48))	('CCND1', 'Gene', '595', (142, 147))	('Akt', 'Gene', '207', (137, 140))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('promoted', 'PosReg', (195, 203))	('MAPK9', 'Gene', '5601', (185, 190))	('MAPK', 'molecular_function', 'GO:0004707', ('185', '189'))	('Akt', 'Gene', (137, 140))	('inhibited', 'NegReg', (58, 67))	('PIK3CA', 'Gene', (153, 159))
181082	33644060	Besides, we found that knockdown of POLE2 inhibited RCC cell proliferation, migration and promoted apoptosis in vitro, as well as had a negative effect on tumor occurrence and development in vivo, which was consistent with other research results.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('migration', 'CPA', (76, 85))	('negative', 'NegReg', (136, 144))	('RCC', 'Disease', (52, 55))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('knockdown', 'Var', (23, 32))	('apoptosis', 'CPA', (99, 108))	('tumor', 'Disease', (155, 160))	('POLE2', 'Gene', (36, 41))	('inhibited', 'NegReg', (42, 51))	('promoted', 'PosReg', (90, 98))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('cell proliferation', 'biological_process', 'GO:0008283', ('56', '74'))
181089	33644060	Some studied found that exogenous STC-1 could promote the RCC proliferation by reducing the levels of HIF-1alpha and Ca2+.	('STC-1', 'Gene', '6781', (34, 39))	('promote', 'PosReg', (46, 53))	('reducing', 'NegReg', (79, 87))	('HIF-1alpha', 'Gene', '3091', (102, 112))	('Ca2+', 'Chemical', 'MESH:D000069285', (117, 121))	('STC-1', 'Gene', (34, 39))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('exogenous', 'Var', (24, 33))	('HIF-1alpha', 'Gene', (102, 112))
181090	33644060	Additionally, pointed out that the expression of STC1 in clear cell renal cell carcinoma (ccRCC) was significantly upregulated, especially in metastatic ccRCC, meanwhile knockdown of STC1 expression inhibited cell proliferation, migration and invasion, as well as damage EMT of ccRCC, which was consistent with our results.	('RCC', 'Disease', (155, 158))	('cell proliferation', 'CPA', (209, 227))	('clear cell renal cell carcinoma', 'Disease', (57, 88))	('invasion', 'CPA', (243, 251))	('expression', 'MPA', (35, 45))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (68, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('EMT', 'biological_process', 'GO:0001837', ('271', '274'))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('RCC', 'Disease', 'MESH:C538614', (155, 158))	('ccRCC', 'Phenotype', 'HP:0006770', (153, 158))	('age', 'Gene', (267, 270))	('STC1', 'Gene', '6781', (49, 53))	('STC1', 'Gene', '6781', (183, 187))	('knockdown', 'Var', (170, 179))	('RCC', 'Disease', (280, 283))	('RCC', 'Phenotype', 'HP:0005584', (280, 283))	('ccRCC', 'Phenotype', 'HP:0006770', (278, 283))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (57, 88))	('upregulated', 'PosReg', (115, 126))	('RCC', 'Disease', 'MESH:C538614', (280, 283))	('inhibited', 'NegReg', (199, 208))	('age', 'Gene', '5973', (267, 270))	('cell proliferation', 'biological_process', 'GO:0008283', ('209', '227'))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (57, 88))	('STC1', 'Gene', (49, 53))	('STC1', 'Gene', (183, 187))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))
181102	33644060	Besides, they found that the expression of Akt, p-Akt, Cyclin D1, and PIK3CA were decreased, while the expression of MAPK9 was increased after POLE2 knockdown in ESCC, which was similar to our results.	('MAPK', 'molecular_function', 'GO:0004707', ('117', '121'))	('Cyclin D1', 'Gene', (55, 64))	('Akt', 'Gene', '207', (50, 53))	('knockdown', 'Var', (149, 158))	('Akt', 'Gene', '207', (43, 46))	('MAPK9', 'Gene', (117, 122))	('expression', 'MPA', (103, 113))	('Akt', 'Gene', (50, 53))	('Cyclin D1', 'Gene', '595', (55, 64))	('PIK3CA', 'Gene', (70, 76))	('Akt', 'Gene', (43, 46))	('MAPK9', 'Gene', '5601', (117, 122))	('Cyclin', 'molecular_function', 'GO:0016538', ('55', '61'))	('expression', 'MPA', (29, 39))	('PIK3CA', 'Gene', '5290', (70, 76))	('decreased', 'NegReg', (82, 91))	('increased', 'PosReg', (127, 136))
181111	33644060	The study found that RCC patients with positive MAPK9 expression have a better local prognosis and longer overall survival time after sorafenib treatment.	('MAPK', 'molecular_function', 'GO:0004707', ('48', '52'))	('longer', 'PosReg', (99, 105))	('MAPK9', 'Gene', (48, 53))	('positive', 'Var', (39, 47))	('sorafenib', 'Chemical', 'MESH:D000077157', (134, 143))	('better', 'PosReg', (72, 78))	('patients', 'Species', '9606', (25, 33))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('MAPK9', 'Gene', '5601', (48, 53))	('RCC', 'Disease', (21, 24))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('local prognosis', 'CPA', (79, 94))
181112	33644060	Taken these together, it was suggested that knockdown of POLE2 might attenuate proliferation and migration via inducing apoptosis by regulating various apoptosis-associated factors and PI3K/AKT, CCND1 signal pathway (Figure 7).	('proliferation', 'CPA', (79, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('152', '161'))	('PI3K', 'molecular_function', 'GO:0016303', ('185', '189'))	('apoptosis', 'biological_process', 'GO:0006915', ('152', '161'))	('attenuate', 'NegReg', (69, 78))	('AKT', 'Gene', '207', (190, 193))	('apoptosis', 'CPA', (120, 129))	('regulating', 'Reg', (133, 143))	('inducing', 'Reg', (111, 119))	('apoptosis', 'biological_process', 'GO:0097194', ('120', '129'))	('POLE2', 'Gene', (57, 62))	('apoptosis-associated', 'MPA', (152, 172))	('CCND1', 'Gene', (195, 200))	('knockdown', 'Var', (44, 53))	('AKT', 'Gene', (190, 193))	('apoptosis', 'biological_process', 'GO:0006915', ('120', '129'))	('CCND1', 'Gene', '595', (195, 200))
181179	29532874	In group Fuhrman, TN (P<0.0001) and MVI (P=0.0057) were independent risk factors for postoperative recurrence, while age (P=0.0059), Fuhrman grade (P=0.0497) and TN (P=0.0007) were independent risk factors for CSS (Table IV).	('MVI', 'Disease', (36, 39))	('TN', 'Chemical', '-', (18, 20))	('TN', 'Chemical', '-', (162, 164))	('CSS', 'Disease', (210, 213))	('Fuhrman', 'Var', (9, 16))	('CSS', 'Chemical', '-', (210, 213))
181180	29532874	In group ISUP, TN (P<0.0001) and MVI (P=0.0057) were independent risk factors for postoperative recurrence, while age (P=0.0327), ISUP grade (P=0.0355) and TN (P=0.0003) were independent risk factors for CSS (Table V).	('CSS', 'Disease', (204, 207))	('MVI', 'Disease', (33, 36))	('ISUP', 'Var', (9, 13))	('CSS', 'Chemical', '-', (204, 207))	('TN', 'Chemical', '-', (156, 158))	('TN', 'Chemical', '-', (15, 17))
181193	29532874	In the present study, the presence of TN affected both RFS and CSS as an independent risk factor.	('TN', 'Chemical', '-', (38, 40))	('RFS', 'Disease', (55, 58))	('presence', 'Var', (26, 34))	('RFS', 'Chemical', '-', (55, 58))	('CSS', 'Disease', (63, 66))	('CSS', 'Chemical', '-', (63, 66))
181211	29270287	The unique phenomenon of pseudo-hypoxia connected with vhl mutation was observed in clear-cell, but not in papillary RCC, and the treatment of this subtype of cancer is still challenging.	('cancer', 'Disease', (159, 165))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('an', 'Gene', '84509', (160, 162))	('RCC', 'Disease', (117, 120))	('an', 'Gene', '84509', (122, 124))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('vhl', 'Gene', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('hypoxia', 'Disease', (32, 39))	('hypoxia', 'Disease', 'MESH:D000860', (32, 39))	('mutation', 'Var', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('clear-cell', 'Disease', (84, 94))
181229	29270287	RCC subtypes are defined by specific genetic abnormalities including von Hippel Lindau (vhl), hepatocyte growth factor receptor (c-met), Birt-Hogg-Dube (bhd) and fumarate hydratase (fh) gene mutations, which was confirmed in both classical genetics and in genomic studies.	('c-met', 'Gene', '4233', (129, 134))	('genetic abnormalities', 'Disease', 'MESH:D030342', (37, 58))	('an', 'Gene', '84509', (249, 251))	('von Hippel Lindau', 'Gene', '7428', (69, 86))	('fh', 'Gene', (182, 184))	('an', 'Gene', '84509', (158, 160))	('genetic abnormalities', 'Disease', (37, 58))	('mutations', 'Var', (191, 200))	('hepatocyte growth factor receptor', 'Gene', '4233', (94, 127))	('von Hippel Lindau', 'Gene', (69, 86))	('c-met', 'Gene', (129, 134))	('fumarate hydratase', 'Gene', '2271', (162, 180))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('94', '118'))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('fumarate hydratase', 'Gene', (162, 180))	('hepatocyte growth factor receptor', 'Gene', (94, 127))	('RCC', 'Disease', (0, 3))
181256	29270287	Understanding these processes is especially significant because the hypoxia signaling pathway is frequently de-regulated in clear-cell renal cell carcinoma due to vhl mutations and limited information is available on intratumoral hypoxia-mediated signaling abnormalities in pRCC or ccRCC.	('pRCC', 'Gene', (274, 278))	('hypoxia', 'Disease', 'MESH:D000860', (68, 75))	('mutations', 'Var', (167, 176))	('vhl', 'Gene', (163, 166))	('RCC', 'Disease', 'MESH:C538614', (284, 287))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('an', 'Gene', '84509', (177, 179))	('RCC', 'Disease', 'MESH:C538614', (275, 278))	('hypoxia', 'Disease', (230, 237))	('signaling', 'biological_process', 'GO:0023052', ('247', '256'))	('signaling pathway', 'biological_process', 'GO:0007165', ('76', '93'))	('clear-cell renal cell carcinoma', 'Disease', (124, 155))	('an', 'Gene', '84509', (7, 9))	('hypoxia', 'Disease', 'MESH:D000860', (230, 237))	('pRCC', 'Gene', '5546', (274, 278))	('tumor', 'Disease', (222, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (135, 155))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('de-regulated', 'NegReg', (108, 120))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (124, 155))	('hypoxia', 'Disease', (68, 75))	('RCC', 'Phenotype', 'HP:0005584', (284, 287))	('RCC', 'Disease', (284, 287))	('an', 'Gene', '84509', (52, 54))	('RCC', 'Disease', (275, 278))	('RCC', 'Phenotype', 'HP:0005584', (275, 278))
181286	29270287	Caki-1, human metastasis of clear-cell renal cell carcinoma to the skin, expresses wild-type vhl (vhl-proficient) and forms tumors in immunocompromised mice (ATCC  HTB-46 ), and 769-P, human primary clear-cell renal cell carcinoma with vhl mutation (vhl-deficient), which forms tumors in NOD/SCID mice (ATCC  CRL-1933 ), were cultured primarily in monolayer in RPMI 1640 supplemented with GlutaMAX -I (Gibco, Cat.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('human', 'Species', '9606', (185, 190))	('an', 'Gene', '84509', (11, 13))	('SCID', 'Disease', (292, 296))	('an', 'Gene', '84509', (114, 116))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (210, 230))	('forms tumors', 'Disease', (272, 284))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (199, 230))	('Caki-1', 'CellLine', 'CVCL:0234', (0, 6))	('forms tumors', 'Disease', 'MESH:D009369', (118, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('Cat', 'molecular_function', 'GO:0004096', ('409', '412'))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('mutation', 'Var', (240, 248))	('clear-cell renal cell carcinoma', 'Disease', (28, 59))	('mice', 'Species', '10090', (297, 301))	('human', 'Species', '9606', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('forms tumors', 'Disease', (118, 130))	('an', 'Gene', '84509', (174, 176))	('mice', 'Species', '10090', (152, 156))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (28, 59))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('an', 'Gene', '84509', (188, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (39, 59))	('clear-cell renal cell carcinoma', 'Disease', (199, 230))	('SCID', 'Disease', 'MESH:D053632', (292, 296))	('vhl', 'Gene', (236, 239))	('forms tumors', 'Disease', 'MESH:D009369', (272, 284))
181298	29270287	For HKCSCs, 769-P and Caki-1 monolayer cell cultures, following drug concentrations were used in normoxia and in hypoxia for a primary screening of their response to drug treatment: sunitinib and sorafenib:C1 = 0.15 microM (maximum clinically relevant dose administered to patients), C2 = 1.5 microM, C3 = 15 microM, C4 = 150 microM; axitinib:C1 = 0.07 microM (maximum clinically relevant dose administered to patients), C2 = 0.15 microM, C3 = 1.5 microM, C4 = 15 microM.	('sorafenib', 'Chemical', 'MESH:D000077157', (196, 205))	('sunitinib', 'Chemical', 'MESH:D000077210', (182, 191))	('hypoxia', 'Disease', 'MESH:D000860', (113, 120))	('patients', 'Species', '9606', (273, 281))	('patients', 'Species', '9606', (410, 418))	('Caki-1', 'CellLine', 'CVCL:0234', (22, 28))	('C4 =', 'Var', (456, 460))	('hypoxia', 'Disease', (113, 120))	('an', 'Gene', '84509', (192, 194))	('an', 'Gene', '84509', (106, 108))	('an', 'Gene', '84509', (385, 387))	('C3 = 1.5', 'Var', (439, 447))	('response to drug', 'biological_process', 'GO:0042493', ('154', '170'))	('C1 = 0.07', 'Var', (343, 352))	('axitinib', 'Chemical', 'MESH:D000077784', (334, 342))	('an', 'Gene', '84509', (18, 20))	('an', 'Gene', '84509', (248, 250))	('C2 = 0.15 microM', 'Var', (421, 437))
181337	29270287	To increase the proteome coverage, each of the three MS/MS measurements covered different m/z ranges: 300-600, 600-900 or 900-2000 Th.	('300-600', 'Var', (102, 109))	('an', 'Gene', '84509', (95, 97))	('900-2000 Th', 'Var', (122, 133))	('600-900', 'Var', (111, 118))	('proteome coverage', 'MPA', (16, 33))	('increase', 'PosReg', (3, 11))
181411	29270287	HKCSCs cultured in normoxia were Ki67 positive (Ki67+) in 87% in comparison with HKCSCs cultured in hypoxia:74%, irrespective of TKI treatment (Fig.	('Ki67 positive', 'Var', (33, 46))	('hypoxia', 'Disease', (100, 107))	('hypoxia', 'Disease', 'MESH:D000860', (100, 107))
181452	29270287	Previously described alterations in map2k1 protein expression together with eif4b support the hypothesis that key proteins expression in hypoxic tumor niche is regulated mostly by oxygen tension.	('map2k1', 'Gene', (36, 42))	('eif4b', 'Gene', '1975', (76, 81))	('eif4b', 'Gene', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('map2k', 'molecular_function', 'GO:0004708', ('36', '41'))	('hypoxic tumor', 'Disease', (137, 150))	('oxygen', 'Chemical', 'MESH:D010100', (180, 186))	('eif4', 'cellular_component', 'GO:0008304', ('76', '80'))	('map2k1', 'Gene', '5604', (36, 42))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('hypoxic tumor', 'Disease', 'MESH:D009369', (137, 150))	('alterations', 'Var', (21, 32))	('protein', 'Protein', (43, 50))
181454	29270287	It was previously reported that inhibition of mek1 in the renal cell carcinoma xenograft model with acquired resistance to sunitinib successfully improved anti-tumor drug efficacy.	('sunitinib', 'Chemical', 'MESH:D000077210', (123, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (58, 78))	('inhibition', 'Var', (32, 42))	('an', 'Gene', '84509', (115, 117))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('an', 'Gene', '84509', (155, 157))	('improved', 'PosReg', (146, 154))	('mek1', 'molecular_function', 'GO:0004708', ('46', '50'))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('renal cell carcinoma xenograft', 'Disease', 'MESH:C538614', (58, 88))	('mek1', 'Gene', (46, 50))	('renal cell carcinoma xenograft', 'Disease', (58, 88))	('tumor', 'Disease', (160, 165))	('mek1', 'Gene', '5604', (46, 50))
181456	29270287	Our results confirm previously published clinical data, which showed eifs expression in advanced cancers inter alia in renal cell carcinomas.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('an', 'Gene', '84509', (98, 100))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (119, 140))	('cancers inter alia in renal cell carcinomas', 'Disease', (97, 140))	('cancers inter alia in renal cell carcinomas', 'Disease', 'MESH:C538614', (97, 140))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (119, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('eifs', 'Var', (69, 73))	('an', 'Gene', '84509', (91, 93))
181470	29270287	Not only is papillary renal cancer cells' protein expression profile affected by hypoxic conditions, but 1% pO2 also impacts papillary RCC cells' proliferation rate, cell cycling and response to tyrosine kinase inhibitors, which we confirmed in both the 2D and 3D cell cultures.	('pO2', 'Var', (108, 111))	('hypoxic conditions', 'Disease', 'MESH:D009135', (81, 99))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('an', 'Gene', '84509', (179, 181))	('an', 'Gene', '84509', (257, 259))	('protein expression profile', 'MPA', (42, 68))	('response', 'MPA', (183, 191))	('renal cancer', 'Phenotype', 'HP:0009726', (22, 34))	('pO2', 'Chemical', 'MESH:C093415', (108, 111))	('cell cycling', 'CPA', (166, 178))	('affected', 'Reg', (69, 77))	('papillary renal cancer', 'Phenotype', 'HP:0006766', (12, 34))	('tyrosine kinase', 'Gene', (195, 210))	('hypoxic conditions', 'Disease', (81, 99))	('tyrosine kinase', 'Gene', '7294', (195, 210))	('papillary renal cancer', 'Disease', 'MESH:D007681', (12, 34))	('papillary renal cancer', 'Disease', (12, 34))	('an', 'Gene', '84509', (29, 31))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('RCC', 'Disease', (135, 138))	('impacts', 'Reg', (117, 124))
181541	31547602	Dysregulation of the protein kinases may introduce dramatic changes in cellular processes that, in the worst case, may lead to the development of cancer or other diseases.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('changes', 'Reg', (60, 67))	('lead to', 'Reg', (119, 126))	('Dysregulation', 'Var', (0, 13))	('men', 'Species', '9606', (138, 141))	('protein kinases', 'Enzyme', (21, 36))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cellular processes', 'MPA', (71, 89))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))
181567	31547602	Inhibiting VEGFRs will also increase the circulating endothelin-1 (ET-1) concentration:a change that promotes vasoconstriction.	('endothelin-1', 'Gene', (53, 65))	('Inhibiting', 'Var', (0, 10))	('ET-1', 'Gene', '1906', (67, 71))	('rat', 'Species', '10116', (80, 83))	('endothelin-1', 'Gene', '1906', (53, 65))	('vasoconstriction', 'MPA', (110, 126))	('VEGFRs', 'Gene', (11, 17))	('ET-1', 'Gene', (67, 71))	('VEGFRs', 'Gene', '2321;2324;3791', (11, 17))	('promotes', 'PosReg', (101, 109))	('increase', 'PosReg', (28, 36))	('vasoconstriction', 'biological_process', 'GO:0042310', ('110', '126'))
181572	31547602	Blockage of the RTKs at the cell surface leads to inhibition of the intracellular phosphorylation cascade and the Raf/MEK/ERK and PI3K/AKT/mTOR pathways, thereby inhibiting the transcription of proteins involved in different functions.	('PI3K', 'molecular_function', 'GO:0016303', ('130', '134'))	('mTOR', 'Gene', (139, 143))	('AKT', 'Gene', (135, 138))	('MEK', 'Gene', (118, 121))	('inhibiting', 'NegReg', (162, 172))	('ERK', 'Gene', '5594', (122, 125))	('intracellular phosphorylation cascade', 'Pathway', (68, 105))	('Blockage', 'Var', (0, 8))	('ERK', 'molecular_function', 'GO:0004707', ('122', '125'))	('mTOR', 'Gene', '2475', (139, 143))	('proteins', 'Protein', (194, 202))	('ERK', 'Gene', (122, 125))	('MEK', 'Gene', '5609', (118, 121))	('AKT', 'Gene', '207', (135, 138))	('phosphorylation', 'biological_process', 'GO:0016310', ('82', '97'))	('inhibition', 'NegReg', (50, 60))	('cell surface', 'cellular_component', 'GO:0009986', ('28', '40'))	('intracellular', 'cellular_component', 'GO:0005622', ('68', '81'))	('transcription', 'biological_process', 'GO:0006351', ('177', '190'))	('transcription', 'MPA', (177, 190))
181591	31547602	SU12662 is further metabolised by CYP3A4 to an inactive metabolite.	('CYP3A4', 'Gene', (34, 40))	('SU12662', 'Chemical', 'MESH:C544393', (0, 7))	('CYP3A4', 'Gene', '1576', (34, 40))	('SU12662', 'Var', (0, 7))	('CYP3A4', 'molecular_function', 'GO:0033780', ('34', '40'))
181615	31547602	The median disease-free survival (DFS) was 6.8 years in patients treated with sunitinib (compared to 5.6 years in the placebo group).	('sunitinib', 'Var', (78, 87))	('patients', 'Species', '9606', (56, 64))	('sunitinib', 'Chemical', 'MESH:C473478', (78, 87))	('disease-free', 'Disease', (11, 23))
181631	31547602	The most common AEs in the axitinib arm were diarrhoea (55%), hypertension (40%) and fatigue (39%).	('fatigue', 'Phenotype', 'HP:0012378', (85, 92))	('diarrhoea', 'Disease', (45, 54))	('hypertension', 'Disease', 'MESH:D006973', (62, 74))	('axitinib', 'Chemical', 'MESH:C503983', (27, 35))	('fatigue', 'Disease', 'MESH:D005221', (85, 92))	('diarrhoea', 'Disease', 'MESH:D003967', (45, 54))	('diarrhoea', 'Phenotype', 'HP:0002014', (45, 54))	('fatigue', 'Disease', (85, 92))	('hypertension', 'Disease', (62, 74))	('axitinib', 'Var', (27, 35))	('hypertension', 'Phenotype', 'HP:0000822', (62, 74))
181634	31547602	Less than 1% of axitinib-treated patients suffered from hypertension-induced sequelae, and while axitinib caused hypertension more frequently than sorafenib, it rarely led to therapy discontinuation or cardiovascular complications.	('suffered', 'Reg', (42, 50))	('cardiovascular complications', 'Disease', 'MESH:D002318', (202, 230))	('caused', 'Reg', (106, 112))	('axitinib', 'Chemical', 'MESH:C503983', (16, 24))	('cardiovascular complications', 'Disease', (202, 230))	('hypertension', 'Disease', (113, 125))	('patients', 'Species', '9606', (33, 41))	('hypertension', 'Disease', 'MESH:D006973', (113, 125))	('sorafenib', 'Chemical', 'MESH:C471405', (147, 156))	('hypertension', 'Phenotype', 'HP:0000822', (113, 125))	('axitinib', 'Var', (97, 105))	('hypertension', 'Disease', 'MESH:D006973', (56, 68))	('axitinib', 'Chemical', 'MESH:C503983', (97, 105))	('hypertension', 'Disease', (56, 68))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (202, 230))	('hypertension', 'Phenotype', 'HP:0000822', (56, 68))
181680	31547602	VEGFR-2 inhibition abrogates NO synthesis, VEGFR-1+2 inhibition reduces PGI2 synthesis and VEGFR-(1+2+3) inhibition promotes vessel rarefaction, all of which are mechanisms involved in hypertension development.	('VEGFR-2', 'Gene', (0, 7))	('NO synthesis', 'MPA', (29, 41))	('vessel rarefaction', 'CPA', (125, 143))	('VEGFR-1', 'Gene', (43, 50))	('promotes', 'PosReg', (116, 124))	('abrogates', 'NegReg', (19, 28))	('hypertension', 'Disease', 'MESH:D006973', (185, 197))	('hypertension', 'Disease', (185, 197))	('inhibition', 'Var', (8, 18))	('reduces', 'NegReg', (64, 71))	('VEGFR', 'Gene', '3791', (43, 48))	('VEGFR', 'Gene', '3791', (91, 96))	('VEGFR', 'Gene', (91, 96))	('VEGFR', 'Gene', (43, 48))	('men', 'Species', '9606', (205, 208))	('VEGFR-1', 'Gene', '2321', (43, 50))	('hypertension', 'Phenotype', 'HP:0000822', (185, 197))	('PGI2 synthesis', 'MPA', (72, 86))	('synthesis', 'biological_process', 'GO:0009058', ('32', '41'))	('VEGFR-2', 'Gene', '3791', (0, 7))	('inhibition', 'Var', (53, 63))	('VEGFR', 'Gene', '3791', (0, 5))	('synthesis', 'biological_process', 'GO:0009058', ('77', '86'))	('VEGFR', 'Gene', (0, 5))
181716	31293899	Nonspecific serum tumor markers were elevated: AFP 150 (normal < 10), CA125 75 (normal <35), CA19-9 322 (normal < 35), HE4 169 (normal < 70); CEA, beta-HCG, and CA15-3 were normal.	('tumor', 'Disease', (18, 23))	('AFP', 'Gene', (47, 50))	('elevated', 'PosReg', (37, 45))	('HE4', 'Gene', '10406', (119, 122))	('AFP', 'Gene', '174', (47, 50))	('HE4', 'Gene', (119, 122))	('CA19-9 322', 'Var', (93, 103))	('CA125 75', 'Var', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
181719	31293899	Final pathology returned T2bN0 high-grade clear cell carcinoma with negative margin.	('clear cell carcinoma', 'Disease', 'MESH:C538614', (42, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('clear cell carcinoma', 'Disease', (42, 62))	('T2bN0', 'Var', (25, 30))
181747	33463050	Tumor cell "slimming" is a new concept in which tumor cells with abnormal lipids efficiently consume lipids to inhibit tumor progression without producing additional ATP.	('tumor', 'Disease', (119, 124))	('inhibit', 'NegReg', (111, 118))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('lipids', 'MPA', (74, 80))	('tumor', 'Disease', (48, 53))	('abnormal', 'Var', (65, 73))	('abnormal lipids', 'Phenotype', 'HP:0003119', (65, 80))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('lipids', 'Chemical', 'MESH:D008055', (74, 80))	('ATP', 'Gene', (166, 169))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('lipids', 'Chemical', 'MESH:D008055', (101, 107))	('ATP', 'Gene', '51761', (166, 169))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
181749	33463050	Screening based on sequencing data after HIF2a knockdown and three independent mitochondrial metabolism-related gene sets showed that nicotinamide nucleotide transhydrogenase (NNT) was a mediator between HIF2a and tumor cells "slimming."	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('HIF2a', 'Var', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('metabolism', 'biological_process', 'GO:0008152', ('93', '103'))	('tumor', 'Disease', (214, 219))
181758	33463050	3 ,  4  The pathogenesis of most ccRCC tumors is characterized by the activation of HIF caused by the loss of von Hippel-Lindau.	('HIF', 'CPA', (84, 87))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('ccRCC tumors', 'Disease', (33, 45))	('von Hippel-Lindau', 'Disease', (110, 127))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('pathogenesis', 'biological_process', 'GO:0009405', ('12', '24'))	('ccRCC tumors', 'Disease', 'MESH:D009369', (33, 45))	('loss', 'Var', (102, 106))	('activation', 'PosReg', (70, 80))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (110, 127))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))
181760	33463050	Nowadays, HIF1a is considered as a tumor suppressor that inhibits tumor growth, while HIF2a generally acts as an oncogene that directly promotes cell proliferation and metabolic alterations.	('HIF1a', 'Gene', '3091', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('metabolic alterations', 'CPA', (168, 189))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cell proliferation', 'biological_process', 'GO:0008283', ('145', '163'))	('tumor', 'Disease', (66, 71))	('promotes', 'PosReg', (136, 144))	('HIF2a', 'Var', (86, 91))	('tumor suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('tumor', 'Disease', (35, 40))	('HIF1a', 'Gene', (10, 15))	('cell proliferation', 'CPA', (145, 163))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('inhibits', 'NegReg', (57, 65))
181766	33463050	12  Nevertheless, the mechanisms responsible for the dispersal of HIF2a-dependent lipid storage while simultaneously reversing the pro-carcinogenesis effect of HIF2a on ccRCC remain unclear.	('lipid storage', 'MPA', (82, 95))	('pro-carcinogenesis effect', 'MPA', (131, 156))	('lipid storage', 'biological_process', 'GO:0019915', ('82', '95'))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('reversing', 'NegReg', (117, 126))	('HIF2a-dependent', 'Var', (66, 81))	('lipid', 'Chemical', 'MESH:D008055', (82, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))	('ccRCC', 'Disease', (169, 174))
181779	33463050	Our study unveiled a new mechanism by which HIF2a regulated lipid metabolism and promoted tumor progression in ccRCC; in this mechanism, HIF2a inhibits NNT expression via miR-455-5p to promote lipid accumulation, resulting in the progression of tumor.	('HIF2a', 'Var', (137, 142))	('inhibits', 'NegReg', (143, 151))	('lipid', 'Chemical', 'MESH:D008055', (60, 65))	('miR-455-5p', 'Chemical', '-', (171, 181))	('NNT', 'Gene', (152, 155))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('lipid metabolism', 'biological_process', 'GO:0006629', ('60', '76'))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('lipid accumulation', 'MPA', (193, 211))	('promote', 'PosReg', (185, 192))	('tumor', 'Disease', (245, 250))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('ccRCC', 'Disease', (111, 116))	('lipid', 'Chemical', 'MESH:D008055', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
181780	33463050	Moreover, the restoration of NNT significantly promotes lipid browning resulting in tumor cell "slimming" to reduce the abnormal lipid accumulation, leading to the repression of pro-carcinogenesis effects of HIF2a.	('abnormal lipid accumulation', 'Phenotype', 'HP:0003119', (120, 147))	('restoration', 'Var', (14, 25))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('reduce', 'NegReg', (109, 115))	('lipid browning', 'MPA', (56, 70))	('promotes', 'PosReg', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('lipid', 'Chemical', 'MESH:D008055', (56, 61))	('NNT', 'Gene', (29, 32))	('tumor', 'Disease', (84, 89))	('lipid', 'Chemical', 'MESH:D008055', (129, 134))	('abnormal lipid accumulation', 'MPA', (120, 147))
181787	33463050	Mycoplasma PCR Detection Kit (C0301S) and Mycoplasma Stain Assay Kit (C0296) are bought from Beyotime Biotechnology.	('C0301S', 'Mutation', 'p.C0301S', (30, 36))	('C0296', 'Var', (70, 75))	('C0301S', 'Var', (30, 36))
181794	33463050	HIF2a decreases the NNT level through miR-455-5p that suppresses tumor "slimming," resulting in ccRCC progression.	('NNT level', 'MPA', (20, 29))	('decreases', 'NegReg', (6, 15))	('tumor', 'Disease', (65, 70))	('miR-455-5p', 'Chemical', '-', (38, 48))	('suppresses', 'NegReg', (54, 64))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('ccRCC', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('miR-455-5p', 'Var', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
181796	33463050	The whole transcriptome sequencing after HIF2alpha stable knockdown is supported by Oebiotech, China, and the contract number is OE2017H0149S.	('HIF2alpha', 'Gene', '2034', (41, 50))	('knockdown', 'Var', (58, 67))	('HIF2alpha', 'Gene', (41, 50))
181858	33463050	By using the triglyceride assay kit, we measured the triglyceride contents in the ccRCC cell lines in which NNT was overexpressed and knocked down.	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('NNT', 'Gene', (108, 111))	('knocked down', 'Var', (134, 146))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('triglyceride', 'Chemical', 'MESH:D014280', (53, 65))	('triglyceride', 'Chemical', 'MESH:D014280', (13, 25))	('triglyceride contents', 'MPA', (53, 74))	('overexpressed', 'PosReg', (116, 129))
181874	33463050	It is obvious that NNT silencing largely reversed the effect of lipid metabolism caused by HIF2a silencing in ccRCC cells (Figure 5D).	('lipid metabolism', 'biological_process', 'GO:0006629', ('64', '80'))	('HIF2a', 'Gene', (91, 96))	('lipid', 'Chemical', 'MESH:D008055', (64, 69))	('lipid metabolism', 'MPA', (64, 80))	('silencing', 'Var', (97, 106))	('silencing', 'Var', (23, 32))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))
181878	33463050	Based on the verification of the TCGA-KIRC database and our own tissue samples, miR-455-5p was expressed at high levels in ccRCC, consistent with the logic of our hypothesis (Figure 6D).	('miR-455-5p', 'Var', (80, 90))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('ccRCC', 'Disease', (123, 128))	('miR-455-5p', 'Chemical', '-', (80, 90))
181880	33463050	Subsequently, the positive regulation between HIF2a and miR-455-5p was confirmed by qPCR in ccRCC cell lines (Figure 6F).	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('ccRCC', 'Disease', (92, 97))	('miR-455-5p', 'Chemical', '-', (56, 66))	('regulation', 'biological_process', 'GO:0065007', ('27', '37'))	('miR-455-5p', 'Var', (56, 66))
181881	33463050	To verify the regulation between NNT and miR-455-5p, specific mimic and inhibitor were used to change the miR-455-5p expression (Figures S5C and S5D).	('change', 'Reg', (95, 101))	('regulation', 'biological_process', 'GO:0065007', ('14', '24'))	('miR-455-5p', 'Chemical', '-', (41, 51))	('miR-455-5p', 'Chemical', '-', (106, 116))	('miR-455-5p', 'Var', (106, 116))
181884	33463050	As expected, overexpression of miR-455-5p partially reversed the increase in NNT expression caused by HIF2a knockdown at both the protein and mRNA levels (Figure 6H).	('increase', 'PosReg', (65, 73))	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('knockdown', 'Var', (108, 117))	('HIF2a', 'Gene', (102, 107))	('NNT', 'Gene', (77, 80))	('miR-455-5p', 'Chemical', '-', (31, 41))
181886	33463050	Luciferase reporter assays were performed to confirm the specific mechanism by which miR-455-5p regulated NNT expression.	('miR-455-5p', 'Chemical', '-', (85, 95))	('expression', 'MPA', (110, 120))	('miR-455-5p', 'Var', (85, 95))	('NNT', 'Gene', (106, 109))	('regulated', 'Reg', (96, 105))
181888	33463050	The results showed that overexpression of miR-455-5p obviously inhibited the luciferase activity of wild-type NNT 3'-UTR and NNT 3'-UTR with mutations at sites 2, 3, and 4 while statistically significant suppression of luciferase reporter activity was not observed for the NNT 3'-UTR mutated at site 1, suggesting that miR-455-5p might target NNT through the 3'-UTR site 1 (Figure 6I, Figures S5E and S5F).	('luciferase activity', 'molecular_function', 'GO:0050397', ('77', '96'))	('miR-455-5p', 'Chemical', '-', (319, 329))	('mutations', 'Var', (141, 150))	('luciferase', 'Enzyme', (77, 87))	('luciferase activity', 'molecular_function', 'GO:0047077', ('77', '96'))	('miR-455-5p', 'Chemical', '-', (42, 52))	('activity', 'MPA', (88, 96))	('inhibited', 'NegReg', (63, 72))	('luciferase activity', 'molecular_function', 'GO:0045289', ('77', '96'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('77', '96'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('77', '96'))
181891	33463050	As shown in Figure 6J, the results of CHIP assay indicated that all predicted sites of miR-455-5p could bind to HIF2a in the ccRCC cell line.	('HIF2a', 'Gene', (112, 117))	('miR-455-5p', 'Var', (87, 97))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('miR-455-5p', 'Chemical', '-', (87, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (125, 130))	('bind', 'Interaction', (104, 108))
181895	33463050	As shown in Figure 7C, the levels of markers for lipid browning were significantly increased in the group overexpressing NNT, and KI67, the marker of tumor malignancy, was significantly decreased in NNT overexpression group.	('NNT', 'Gene', (121, 124))	('increased', 'PosReg', (83, 92))	('tumor malignancy', 'Disease', (150, 166))	('KI67', 'Var', (130, 134))	('lipid', 'Chemical', 'MESH:D008055', (49, 54))	('decreased', 'NegReg', (186, 195))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor malignancy', 'Disease', 'MESH:D009369', (150, 166))	('levels of markers for lipid browning', 'MPA', (27, 63))
181896	33463050	Thus, consistent with research results at the cellular level, NNT overexpression significantly reduced the malignancy of tumors and promoted lipid browning in vivo.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('overexpression', 'Var', (66, 80))	('reduced', 'NegReg', (95, 102))	('lipid browning', 'MPA', (141, 155))	('malignancy of tumors', 'Disease', 'MESH:D009369', (107, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('lipid', 'Chemical', 'MESH:D008055', (141, 146))	('malignancy of tumors', 'Disease', (107, 127))	('NNT', 'Gene', (62, 65))	('promoted', 'PosReg', (132, 140))
181906	33463050	Mechanistic investigations showed that HIF2a suppressed NNT expression by activating miR-455-5p, which reduced the level of lipid browning-mediated tumor cell "slimming" and resulted in ccRCC progression.	('ccRCC', 'Disease', (186, 191))	('HIF2a', 'Gene', (39, 44))	('activating', 'PosReg', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('miR-455-5p', 'Chemical', '-', (85, 95))	('level of lipid browning-mediated', 'MPA', (115, 147))	('resulted in', 'Reg', (174, 185))	('tumor', 'Disease', (148, 153))	('reduced', 'NegReg', (103, 110))	('suppressed', 'NegReg', (45, 55))	('miR-455-5p', 'Var', (85, 95))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('lipid', 'Chemical', 'MESH:D008055', (124, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('NNT expression', 'MPA', (56, 70))
181917	33463050	40 ,  41  Current researchers attempted to use lipid browning as a potential target for cancer treatment, and we found that lipid browning caused tumor cell "slimming" in tumors resulting in the inhibition of tumor progression.	('cancer', 'Disease', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', (146, 151))	('lipid', 'Chemical', 'MESH:D008055', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor', 'Disease', (209, 214))	('inhibition', 'NegReg', (195, 205))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('lipid browning', 'Var', (124, 138))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('lipid', 'Chemical', 'MESH:D008055', (47, 52))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumor', 'Disease', (171, 176))
181921	33463050	In the normal process of ccRCC, HIF2a suppressed the expression of NNT, thereby inhibiting lipid browning induced by NNT.	('NNT', 'Gene', (67, 70))	('suppressed', 'NegReg', (38, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (25, 30))	('inhibiting', 'NegReg', (80, 90))	('HIF2a', 'Var', (32, 37))	('expression', 'MPA', (53, 63))	('lipid browning', 'MPA', (91, 105))	('ccRCC', 'Disease', (25, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('lipid', 'Chemical', 'MESH:D008055', (91, 96))
181931	33463050	Combined with the comprehensive phenotype of the interaction between HIF2a and NNT, NNT plays a dominant role in the tumor slimming process mediated by HIF2a.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('HIF2a', 'Var', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
181939	33463050	At the same time, it is the first time to clarify the regulatory relationship between the most important carcinogen HIF2a in ccRCC and the new concept tumor "slimming," in which HIF2a decreases the NNT level through miR-455-5 p that suppresses tumor cell "slimming," resulting in the progression of ccRCC.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('miR-455-5 p', 'Chemical', '-', (216, 227))	('tumor', 'Disease', (244, 249))	('miR-455-5 p', 'MPA', (216, 227))	('RCC', 'Phenotype', 'HP:0005584', (301, 304))	('tumor', 'Disease', (151, 156))	('decreases', 'NegReg', (184, 193))	('NNT level', 'MPA', (198, 207))	('suppresses', 'NegReg', (233, 243))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('ccRCC', 'Disease', (299, 304))	('ccRCC', 'Phenotype', 'HP:0006770', (299, 304))	('ccRCC', 'Phenotype', 'HP:0006770', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('HIF2a', 'Var', (178, 183))
182006	30881919	Variant calling of the t/RNA-NGS datasets revealed mutations in the VHL gene in tumor samples of four of the patients, which were not present in matched healthy kidney tissue, identifying these as somatic mutations.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('VHL', 'Disease', (68, 71))	('mutations', 'Var', (51, 60))	('VHL', 'Disease', 'MESH:D006623', (68, 71))	('patients', 'Species', '9606', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('RNA', 'cellular_component', 'GO:0005562', ('25', '28'))
182007	30881919	Three patients had VHL STOP mutations whereas in patient C the known pathogenic VHL p.L118P mutation was detected in one tissue biopsy, in 29% of the reads (Table 2).	('VHL', 'Disease', 'MESH:D006623', (19, 22))	('p.L118P', 'Mutation', 'rs5030830', (84, 91))	('patient', 'Species', '9606', (6, 13))	('patient', 'Species', '9606', (49, 56))	('p.L118P', 'Var', (84, 91))	('patients', 'Species', '9606', (6, 14))	('VHL', 'Disease', (80, 83))	('VHL', 'Disease', 'MESH:D006623', (80, 83))	('VHL', 'Disease', (19, 22))
182034	30881919	Interestingly, we found significantly elevated tyrosine kinase receptor MET levels in ccRCC tissues compared to healthy kidney tissue, in agreement with in vitro studies and ccRCC tissue analyses demonstrating upregulation of MET induced by inactivation of VHL.	('tyrosine kinase receptor MET levels', 'MPA', (47, 82))	('RCC', 'Disease', (176, 179))	('VHL', 'Disease', (257, 260))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('VHL', 'Disease', 'MESH:D006623', (257, 260))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('MET', 'MPA', (226, 229))	('inactivation', 'Var', (241, 253))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (174, 179))	('elevated', 'PosReg', (38, 46))	('upregulation', 'PosReg', (210, 222))	('elevated tyrosine', 'Phenotype', 'HP:0003231', (38, 55))
182041	30881919	Dysfunctional VHL due to mutations or promoter hypermethylation are known drivers of ccRCC, causing accumulation of HIF1 and its target genes.	('mutations', 'Var', (25, 34))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('accumulation', 'PosReg', (100, 112))	('HIF1', 'Gene', (116, 120))	('VHL', 'Disease', 'MESH:D006623', (14, 17))	('VHL', 'Disease', (14, 17))	('promoter hypermethylation', 'Var', (38, 63))	('Dysfunctional', 'Var', (0, 13))	('HIF1', 'Gene', '3091', (116, 120))
182045	30881919	Nonetheless, VHL mutations were detected in only four of the five ccRCC patients, and not in each of three biopsies.	('VHL', 'Disease', (13, 16))	('VHL', 'Disease', 'MESH:D006623', (13, 16))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('RCC', 'Disease', (68, 71))	('mutations', 'Var', (17, 26))	('patients', 'Species', '9606', (72, 80))
182047	30881919	Another possible explanation for failure to detect aberrant VHL is promoter hypermethylation, which was outside the scope of this study.	('aberrant', 'Var', (51, 59))	('failure', 'Disease', 'MESH:D017093', (33, 40))	('promoter', 'MPA', (67, 75))	('failure', 'Disease', (33, 40))	('VHL', 'Disease', (60, 63))	('VHL', 'Disease', 'MESH:D006623', (60, 63))
182079	31133033	have integrated multiple molecular analysis and uncovered novel associations among DNA methylation, gene mutation and/or gene expression and copy-number profiles, enabling the stratification of clinical risks for KIRC patients.	('DNA methylation', 'biological_process', 'GO:0006306', ('83', '98'))	('patients', 'Species', '9606', (218, 226))	('DNA', 'Gene', (83, 86))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('associations', 'Interaction', (64, 76))	('methylation', 'Var', (87, 98))	('gene expression', 'biological_process', 'GO:0010467', ('121', '136'))
182106	31133033	The mutation types on ERBB4 were complex, including missense mutation, intron mutation, silent mutation, frame shift insert and nonsense mutation (Fig.	('frame shift insert', 'Var', (105, 123))	('ERBB4', 'Gene', (22, 27))	('missense mutation', 'Var', (52, 69))	('silent', 'Disease', (88, 94))	('nonsense', 'Disease', (128, 136))	('ERBB4', 'Gene', '2066', (22, 27))	('intron', 'Disease', (71, 77))
182108	31133033	PIK3R1 was a famous KIRC-related gene, and more than 120 samples exhibited CNV alterations in this gene.	('PIK3R1', 'Gene', '5295', (0, 6))	('alterations', 'Var', (79, 90))	('PIK3R1', 'Gene', (0, 6))
182118	31133033	Studies have reported the important role played by aberrant phosphorylation in oncogenesis and immune disorders.	('aberrant phosphorylation', 'Var', (51, 75))	('oncogenesis', 'Disease', (79, 90))	('disorder', 'Disease', 'MESH:D030342', (102, 110))	('disorder', 'Disease', (102, 110))	('phosphorylation', 'biological_process', 'GO:0016310', ('60', '75'))	('phosphorylation', 'Var', (60, 75))	('oncogenesis', 'biological_process', 'GO:0007048', ('79', '90'))
182135	33810357	For instance, the heterogeneous nature within each cancer type which results from diverse genetic and epigenetic mutations, impairs diagnostic and monitoring efficacy.	('diagnostic', 'MPA', (132, 142))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('epigenetic mutations', 'Var', (102, 122))	('impairs', 'NegReg', (124, 131))	('results from', 'Reg', (69, 81))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
182203	33810357	For instance, TM256 in combination with LAMTOR1, highly-specific in PCa patient samples, increased sensitivity to 100%.	('PCa', 'Disease', (68, 71))	('TM256', 'Chemical', '-', (14, 19))	('TM256', 'Var', (14, 19))	('LAMTOR1', 'Gene', '55004', (40, 47))	('PCa', 'Phenotype', 'HP:0012125', (68, 71))	('patient', 'Species', '9606', (72, 79))	('LAMTOR1', 'Gene', (40, 47))	('increased', 'PosReg', (89, 98))	('sensitivity', 'MPA', (99, 110))
182210	33810357	FABP5 might also potentially be used as a biomarker to predict or confirm the presence of high-Gleason score (GS) PCa before prostatectomy.	('GS', 'Disease', 'MESH:D011125', (110, 112))	('FABP5', 'Gene', (0, 5))	('high-Gleason score', 'Var', (90, 108))	('PCa', 'Disease', (114, 117))	('PCa', 'Phenotype', 'HP:0012125', (114, 117))	('FABP5', 'Gene', '2171', (0, 5))
182244	33810357	uEV miRNA profiles, isolated with Norgen Urine Exosome RNA Isolation Kit, were compared with matched BlCa tissues and showed that miR-205, miR-200c-3p and miR-29b-3p were common to both tumor tissues and uEVs.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('Exosome', 'cellular_component', 'GO:0070062', ('47', '54'))	('miR-29b-3p', 'Var', (155, 165))	('miR-205', 'Gene', (130, 137))	('miR-200c', 'Gene', (139, 147))	('miR-200c', 'Gene', '406985', (139, 147))	('BlCa', 'Phenotype', 'HP:0009725', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('miR-205', 'Gene', '406988', (130, 137))	('tumor', 'Disease', (186, 191))	('RNA', 'cellular_component', 'GO:0005562', ('55', '58'))
182247	33810357	also extracted miRNA from uEVs by UC and used a microarray that identified five miRNAs (miR-155-5p, miR-15a-5p, miR-21-5p, miR-132-3p and miR-31-5p) overexpressed in uEVs from BlCa patients compared to healthy volunteers.	('miR-155', 'Gene', (88, 95))	('miR-132-3p', 'Gene', (123, 133))	('miR-155', 'Gene', '406947', (88, 95))	('miR-21', 'Gene', '406991', (112, 118))	('BlCa', 'Phenotype', 'HP:0009725', (176, 180))	('overexpressed', 'PosReg', (149, 162))	('miR-31', 'Gene', (138, 144))	('patients', 'Species', '9606', (181, 189))	('miR-132-3p', 'Gene', '100302255', (123, 133))	('BlCa', 'Disease', (176, 180))	('miR-15a-5p', 'Var', (100, 110))	('miR-21', 'Gene', (112, 118))	('miR-31', 'Gene', '407035', (138, 144))
182251	33810357	isolated uEV using a commercially available kit, and also by comparing with FFPE tumor tissues, showed that miR-146b-5p and miR-155-5p in uEVs might serve as biomarkers to distinguish MIBC from NMIBC.	('NMIBC', 'Disease', (194, 199))	('miR-155', 'Gene', '406947', (124, 131))	('MIBC', 'Disease', (184, 188))	('MIBC', 'Chemical', '-', (195, 199))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('miR-146b-5p', 'Var', (108, 119))	('miR-155', 'Gene', (124, 131))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('MIBC', 'Chemical', '-', (184, 188))	('tumor', 'Disease', (81, 86))
182268	33810357	Although uEVs were not characterized in this study, different miRNA combinations, including miR-126-3p, miR-449a, miR-486-5p and miR-34b-5p, were able to discriminate ccRCC patients from healthy controls, and also distinguish SRMs and benign tumors from healthy controls.	('discriminate', 'Reg', (154, 166))	('miR-126-3p', 'Gene', (92, 102))	('miR-486-5p', 'Var', (114, 124))	('SRMs', 'Disease', 'None', (226, 230))	('benign tumors', 'Disease', 'MESH:D009369', (235, 248))	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('patients', 'Species', '9606', (173, 181))	('RCC', 'Disease', (169, 172))	('miR-34b-5p', 'Var', (129, 139))	('distinguish', 'Reg', (214, 225))	('miR-449a', 'Gene', (104, 112))	('SRMs', 'Disease', (226, 230))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('benign tumors', 'Disease', (235, 248))	('miR-126-3p', 'Gene', '100302148', (92, 102))	('miR-449a', 'Gene', '554213', (104, 112))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))
182283	33810357	In addition, DTT may alter the native structure of proteins and their complexes on EV surface by reducing disulfide bonds, which may also influence the results of EV proteomic analysis.	('native structure', 'MPA', (31, 47))	('proteins', 'Protein', (51, 59))	('DTT', 'Chemical', 'MESH:D004229', (13, 16))	('alter', 'Reg', (21, 26))	('DTT', 'Var', (13, 16))	('reducing', 'NegReg', (97, 105))	('complexes', 'Interaction', (70, 79))	('disulfide', 'Chemical', 'MESH:D004220', (106, 115))	('disulfide bonds', 'MPA', (106, 121))	('influence', 'Reg', (138, 147))
182303	30419952	SETD2 mutations in primary central nervous system tumors Mutations in SETD2 are found in many tumors, including central nervous system (CNS) tumors.	('central nervous system (CNS) tumors', 'Disease', 'MESH:D016543', (112, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Mutations', 'Var', (57, 66))	('tumors', 'Disease', (141, 147))	('SETD2', 'Gene', (0, 5))	('tumors', 'Disease', (94, 100))	('found', 'Reg', (80, 85))	('central nervous system tumors', 'Phenotype', 'HP:0100006', (27, 56))	('SETD2', 'Gene', '29072', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('mutations', 'Reg', (6, 15))	('SETD2', 'Gene', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('nervous system tumors', 'Phenotype', 'HP:0004375', (35, 56))	('primary central nervous system tumors', 'Disease', 'MESH:D016543', (19, 56))	('SETD2', 'Gene', '29072', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))	('primary central nervous system tumors', 'Disease', (19, 56))
182304	30419952	Previous work has shown these mutations occur specifically in high grade gliomas of the cerebral hemispheres in pediatric and young adult patients.	('gliomas of the cerebral hemispheres', 'Disease', (73, 108))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('gliomas of the cerebral hemispheres', 'Disease', 'MESH:C564230', (73, 108))	('mutations', 'Var', (30, 39))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('patients', 'Species', '9606', (138, 146))	('occur', 'Reg', (40, 45))
182305	30419952	We investigated SETD2 mutations in a cohort of approximately 640 CNS tumors via next generation sequencing; 23 mutations were detected across 19 primary CNS tumors.	('CNS tumors', 'Disease', 'MESH:D009369', (153, 163))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CNS tumors', 'Disease', (65, 75))	('SETD2', 'Gene', '29072', (16, 21))	('primary CNS tumors', 'Disease', 'MESH:D016543', (145, 163))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('SETD2', 'Gene', (16, 21))	('primary CNS tumors', 'Disease', (145, 163))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('CNS tumor', 'Phenotype', 'HP:0100006', (65, 74))	('mutations', 'Var', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('CNS tumor', 'Phenotype', 'HP:0100006', (153, 162))	('CNS tumors', 'Disease', 'MESH:D009369', (65, 75))
182306	30419952	Mutations were found in a wide variety of tumors and locations at a broad range of allele frequencies.	('tumors', 'Disease', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('found', 'Reg', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
182307	30419952	SETD2 mutations were seen in both low and high grade gliomas as well as non-glial tumors, and occurred in patients greater than 55 years of age, in addition to pediatric and young adult patients.	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('gliomas', 'Disease', 'MESH:D005910', (53, 60))	('patients', 'Species', '9606', (186, 194))	('gliomas', 'Phenotype', 'HP:0009733', (53, 60))	('gliomas', 'Disease', (53, 60))	('occurred', 'Reg', (94, 102))	('SETD2', 'Gene', '29072', (0, 5))	('SETD2', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('patients', 'Species', '9606', (106, 114))	('non-glial tumors', 'Disease', 'MESH:D005910', (72, 88))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))	('seen', 'Reg', (21, 25))	('mutations', 'Var', (6, 15))	('non-glial tumors', 'Disease', (72, 88))
182308	30419952	High grade gliomas at first occurrence demonstrated either frameshift/truncating mutations or point mutations at high allele frequencies, whereas recurrent high grade gliomas frequently harbored subclones with point mutations in SETD2 at lower allele frequencies in the setting of higher mutational burdens.	('SETD2', 'Gene', '29072', (229, 234))	('SETD2', 'Gene', (229, 234))	('frameshift/truncating mutations', 'Var', (59, 90))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('point mutations', 'Var', (210, 225))	('point mutations', 'Var', (94, 109))	('gliomas', 'Disease', 'MESH:D005910', (167, 174))	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('gliomas', 'Disease', (167, 174))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('gliomas', 'Disease', 'MESH:D005910', (11, 18))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))	('gliomas', 'Disease', (11, 18))
182309	30419952	Finally, immunohistochemistry showed decreased staining for H3K36me3 in our cohort of SETD2 mutant tumors compared to wildtype controls.	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('H3K36me3', 'Protein', (60, 68))	('staining', 'MPA', (47, 55))	('mutant', 'Var', (92, 98))	('SETD2', 'Gene', '29072', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('decreased', 'NegReg', (37, 46))	('SETD2', 'Gene', (86, 91))	('tumors', 'Disease', (99, 105))
182310	30419952	Our data further describe the spectrum of tumors in which SETD2 mutations are found and provide a context for interpretation of these mutations in the clinical setting.	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('SETD2', 'Gene', '29072', (58, 63))	('mutations', 'Var', (64, 73))	('SETD2', 'Gene', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
182311	30419952	The disruption of normal epigenetic mechanisms secondary to mutations in histone modifying enzymes has been implicated in tumorigenesis and in chemotherapeutic resistance in cancer patients.	('epigenetic mechanisms', 'MPA', (25, 46))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('patients', 'Species', '9606', (181, 189))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mutations', 'Var', (60, 69))	('histone', 'Protein', (73, 80))	('tumor', 'Disease', (122, 127))	('implicated', 'Reg', (108, 118))
182314	30419952	Prior studies have indicated that loss of one allele of SETD2 does not significantly decrease levels of H3K36me3; however, it is important to note that biallelic inactivation of SETD2 may not be the sole mechanism leading to the loss of H3K36me3.	('SETD2', 'Gene', (56, 61))	('loss', 'Var', (34, 38))	('SETD2', 'Gene', '29072', (178, 183))	('loss', 'NegReg', (229, 233))	('biallelic inactivation', 'Var', (152, 174))	('SETD2', 'Gene', '29072', (56, 61))	('H3K36me3', 'Protein', (237, 245))	('SETD2', 'Gene', (178, 183))
182315	30419952	For example, overexpression of other proteins such as HOX Transcript Antisense RNA (HOTAIR) can decrease levels of H3K63me3 as well.	('Antisense', 'Var', (69, 78))	('HOTAIR', 'Gene', (84, 90))	('H3K63me3', 'MPA', (115, 123))	('decrease', 'NegReg', (96, 104))	('levels', 'MPA', (105, 111))	('HOTAIR', 'Gene', '100124700', (84, 90))	('overexpression', 'PosReg', (13, 27))	('Antisense RNA', 'molecular_function', 'GO:0009388', ('69', '82'))	('RNA', 'cellular_component', 'GO:0005562', ('79', '82'))
182317	30419952	Most frequently, SETD2 mutations are seen in clear cell renal cell carcinoma (CCRCC) and are thought to confer a poor prognosis.	('CCRCC', 'Phenotype', 'HP:0006770', (78, 83))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (56, 76))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (45, 76))	('mutations', 'Var', (23, 32))	('SETD2', 'Gene', '29072', (17, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('seen', 'Reg', (37, 41))	('SETD2', 'Gene', (17, 22))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (45, 76))	('clear cell renal cell carcinoma', 'Disease', (45, 76))
182318	30419952	SETD2 mutations have also been reported in neoplasms of the central nervous system (CNS).	('reported', 'Reg', (31, 39))	('neoplasms', 'Phenotype', 'HP:0002664', (43, 52))	('SETD2', 'Gene', '29072', (0, 5))	('neoplasms of the central nervous system', 'Disease', 'MESH:D016543', (43, 82))	('neoplasms of the central nervous system', 'Disease', (43, 82))	('SETD2', 'Gene', (0, 5))	('neoplasms of the central nervous', 'Phenotype', 'HP:0100006', (43, 75))	('mutations', 'Var', (6, 15))
182319	30419952	These mutations have been found to be specific to pediatric and young adult high grade gliomas located in the cerebral hemispheres, affecting 15% and 8% of pediatric and adult high grade gliomas, respectively, and not found in other gliomas.	('gliomas', 'Disease', 'MESH:D005910', (87, 94))	('glioma', 'Phenotype', 'HP:0009733', (233, 239))	('gliomas', 'Disease', (187, 194))	('gliomas', 'Phenotype', 'HP:0009733', (87, 94))	('gliomas', 'Disease', 'MESH:D005910', (187, 194))	('gliomas', 'Phenotype', 'HP:0009733', (187, 194))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('gliomas', 'Disease', (233, 240))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('gliomas', 'Disease', 'MESH:D005910', (233, 240))	('gliomas', 'Phenotype', 'HP:0009733', (233, 240))	('mutations', 'Var', (6, 15))	('gliomas', 'Disease', (87, 94))
182320	30419952	In the 2016 WHO Classification of Tumors of the Central Nervous System, SETD2 mutations are listed under frequent genetic alterations in pediatric (but not adult) high-grade diffuse astrocytic tumors within the cerebral hemispheres.	('Tumor', 'Phenotype', 'HP:0002664', (34, 39))	('Tumors of the Central Nervous', 'Disease', 'MESH:D016543', (34, 63))	('Tumors', 'Phenotype', 'HP:0002664', (34, 40))	('astrocytic tumors within the cerebral', 'Disease', (182, 219))	('Tumors of the Central Nervous System', 'Phenotype', 'HP:0100006', (34, 70))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('mutations', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('Tumors of the Central Nervous', 'Disease', (34, 63))	('SETD2', 'Gene', '29072', (72, 77))	('astrocytic tumors within the cerebral', 'Disease', 'MESH:D001929', (182, 219))	('SETD2', 'Gene', (72, 77))
182322	30419952	Similarly, immunohistochemical studies of CCRCC, chondroblastomas, and chordomas have been used to demonstrate decreased staining for H3K36me3 in tumors with SETD2 mutations.	('tumors', 'Disease', (146, 152))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('CCRCC', 'Disease', (42, 47))	('chordomas', 'Disease', 'MESH:D002817', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('decreased', 'NegReg', (111, 120))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('CCRCC', 'Phenotype', 'HP:0006770', (42, 47))	('chondroblastomas', 'Disease', 'MESH:D002804', (49, 65))	('SETD2', 'Gene', '29072', (158, 163))	('H3K36me3', 'Protein', (134, 142))	('SETD2', 'Gene', (158, 163))	('staining', 'MPA', (121, 129))	('chondroblastomas', 'Disease', (49, 65))	('mutations', 'Var', (164, 173))	('chordomas', 'Disease', (71, 80))
182324	30419952	Here we describe 19 cases of CNS tumors with mutations in SETD2.	('mutations', 'Var', (45, 54))	('CNS tumors', 'Disease', 'MESH:D009369', (29, 39))	('CNS tumors', 'Disease', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('SETD2', 'Gene', '29072', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('SETD2', 'Gene', (58, 63))	('CNS tumor', 'Phenotype', 'HP:0100006', (29, 38))
182325	30419952	SETD2 mutation allele frequency and co-occurring mutations in other genes are investigated, and results are correlated with the effects of SETD2 mutations on epigenetic change, specifically histone methylation and acetylation as shown by immunohistochemistry for H3K36me3, H3K36ac and H3K27me3.	('histone methylation', 'biological_process', 'GO:0016571', ('190', '209'))	('epigenetic change', 'MPA', (158, 175))	('acetylation', 'MPA', (214, 225))	('SETD2', 'Gene', (139, 144))	('mutations', 'Var', (145, 154))	('SETD2', 'Gene', '29072', (0, 5))	('H3K36ac', 'Chemical', '-', (273, 280))	('SETD2', 'Gene', (0, 5))	('H3K36ac', 'Var', (273, 280))	('H3K27me3', 'Var', (285, 293))	('SETD2', 'Gene', '29072', (139, 144))	('H3K36me3', 'Var', (263, 271))	('histone methylation', 'MPA', (190, 209))
182326	30419952	Our findings indicate that SETD2 mutations occur at a wide range of allele frequencies in a variety of tumors of the central nervous system and that those mutations most likely to have functional impact on the gene product are seen most often but not exclusively in pediatric and young adult high grade gliomas of the cerebral hemispheres.	('gliomas', 'Phenotype', 'HP:0009733', (303, 310))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('high', 'Disease', (292, 296))	('gliomas of the cerebral hemispheres', 'Disease', (303, 338))	('tumors of the central nervous system', 'Phenotype', 'HP:0100006', (103, 139))	('mutations', 'Var', (33, 42))	('gliomas of the cerebral hemispheres', 'Disease', 'MESH:C564230', (303, 338))	('SETD2', 'Gene', '29072', (27, 32))	('tumors of the central nervous system', 'Disease', 'MESH:D016543', (103, 139))	('glioma', 'Phenotype', 'HP:0009733', (303, 309))	('SETD2', 'Gene', (27, 32))	('tumors of the central nervous system', 'Disease', (103, 139))
182327	30419952	All CNS tumors with SETD2 mutations identified on routine next generation sequencing (NGS) studies performed September 17, 2016 through June 30, 2017 at HUP and from February 1, 2016 to June 30, 2018 at CHOP are included in the current study.	('CNS tumor', 'Phenotype', 'HP:0100006', (4, 13))	('SETD2', 'Gene', '29072', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('mutations', 'Var', (26, 35))	('SETD2', 'Gene', (20, 25))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('CNS tumors', 'Disease', 'MESH:D009369', (4, 14))	('CNS tumors', 'Disease', (4, 14))
182329	30419952	Patients whose tumor showed single nucleotide polymorphisms or otherwise benign variants in SETD2 were excluded.	('single nucleotide polymorphisms', 'Var', (28, 59))	('SETD2', 'Gene', '29072', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('SETD2', 'Gene', (92, 97))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', (15, 20))
182336	30419952	The Comprehensive Solid Tumor Panel v1 at CHOP includes sequence and copy number analyses of 237 cancer genes, and 586 known fusions and many more novel fusions associated with 106 fusion gene partners.	('cancer', 'Disease', (97, 103))	('Tumor', 'Phenotype', 'HP:0002664', (24, 29))	('fusions', 'Var', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
182339	30419952	All tumors with nonsense or frameshift mutations in SETD2 and those with missense mutations with AF greater than 40% were used for immunohistochemical (IHC) studies.	('frameshift mutations', 'Var', (28, 48))	('nonsense', 'Var', (16, 24))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('SETD2', 'Gene', '29072', (52, 57))	('AF', 'Disease', 'MESH:D001281', (97, 99))	('SETD2', 'Gene', (52, 57))
182341	30419952	H3K36me3 (Abcam ab9050), H3K36ac (Abcam ab177179), and H3K27me3 (Cell Signaling 9733) antibodies were used to stain formalin fixed paraffin embedded slides.	('H3K36ac', 'Var', (25, 32))	('Signaling', 'biological_process', 'GO:0023052', ('70', '79'))	('formalin', 'Chemical', 'MESH:D005557', (116, 124))	('H3K36me3', 'Protein', (0, 8))	('paraffin', 'Chemical', 'MESH:D010232', (131, 139))	('H3K27me3', 'Var', (55, 63))	('H3K36ac', 'Chemical', '-', (25, 32))
182344	30419952	The Cancer Genome Atlas (TCGA) dataset was retrieved from cbioportal (http://www.cbioportal.org) by searching for SETD2 mutations in "CNS/Brain" tumors (headings: diffuse glioma, glioblastoma, oligodendroglioma, pilocytic astrocytoma and medulloblastoma).	('medulloblastoma', 'Disease', (238, 253))	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('glioblastoma', 'Disease', 'MESH:D005909', (179, 191))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (212, 233))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('mutations', 'Var', (120, 129))	('oligodendroglioma', 'Disease', 'MESH:D009837', (193, 210))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('SETD2', 'Gene', (114, 119))	('pilocytic astrocytoma', 'Disease', (212, 233))	('glioblastoma', 'Disease', (179, 191))	('oligodendroglioma', 'Disease', (193, 210))	('glioblastoma', 'Phenotype', 'HP:0012174', (179, 191))	('SETD2', 'Gene', '29072', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('Brain" tumors', 'Disease', 'MESH:D001932', (138, 151))	('astrocytoma', 'Phenotype', 'HP:0009592', (222, 233))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('glioma', 'Disease', (204, 210))	('glioma', 'Disease', (171, 177))	('glioma', 'Disease', 'MESH:D005910', (204, 210))	('medulloblastoma', 'Disease', 'MESH:D008527', (238, 253))	('Cancer Genome Atlas', 'Disease', (4, 23))	('medulloblastoma', 'Phenotype', 'HP:0002885', (238, 253))	('Brain" tumors', 'Disease', (138, 151))
182348	30419952	Nineteen primary brain tumors (fifteen at the University of Pennsylvania and four at CHOP) with SETD2 mutations were identified on routine NGS studies (Tables 1 and 2).	('brain tumors', 'Phenotype', 'HP:0030692', (17, 29))	('brain tumors', 'Disease', 'MESH:D001932', (17, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutations', 'Var', (102, 111))	('brain tumors', 'Disease', (17, 29))	('SETD2', 'Gene', '29072', (96, 101))	('brain tumor', 'Phenotype', 'HP:0030692', (17, 28))	('SETD2', 'Gene', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
182349	30419952	Eleven tumors had nonsense or frameshift mutations (truncating mutations) in SETD2 and eight had missense mutations.	('SETD2', 'Gene', '29072', (77, 82))	('SETD2', 'Gene', (77, 82))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('frameshift mutations', 'Var', (30, 50))	('nonsense', 'Var', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
182350	30419952	The age of the patients ranged from 9 to 80 years old (mean 43 years, median 42 years), and there was no statistically significant difference (p = 0.49) in age between patients with nonsense or frameshift mutations and those with missense mutations (Fig.	('missense mutations', 'Var', (230, 248))	('patients', 'Species', '9606', (15, 23))	('nonsense', 'Var', (182, 190))	('patients', 'Species', '9606', (168, 176))
182351	30419952	1a); however, of high grade gliomas, recurrences often showed missense mutations, whereas frameshift and nonsense mutations were preferentially seen in de novo tumors (Tables 1 and 2).	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('frameshift', 'Var', (90, 100))	('glioma', 'Phenotype', 'HP:0009733', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('missense mutations', 'Var', (62, 80))	('tumors', 'Disease', (160, 166))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('gliomas', 'Disease', (28, 35))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
182356	30419952	In total, 23 SETD2 changes amongst the 19 tumors were detected at a wide range of VAF (range 2-51%); 4 tumors had more than one SETD2 missense mutation, 3 of which were recurrent high grade gliomas, and the fourth a medulloblastoma.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('gliomas', 'Disease', 'MESH:D005910', (190, 197))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Disease', (103, 109))	('SETD2', 'Gene', '29072', (13, 18))	('gliomas', 'Phenotype', 'HP:0009733', (190, 197))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('SETD2', 'Gene', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('SETD2', 'Gene', '29072', (128, 133))	('missense mutation', 'Var', (134, 151))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', (42, 48))	('VAF', 'Chemical', '-', (82, 85))	('medulloblastoma', 'Disease', 'MESH:D008527', (216, 231))	('gliomas', 'Disease', (190, 197))	('medulloblastoma', 'Phenotype', 'HP:0002885', (216, 231))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('SETD2', 'Gene', (13, 18))	('medulloblastoma', 'Disease', (216, 231))
182357	30419952	No statistically significant difference (p = 0.49) in VAF was seen between truncating mutations and missense mutations.	('truncating mutations', 'Var', (75, 95))	('VAF', 'Chemical', '-', (54, 57))	('missense mutations', 'Var', (100, 118))
182358	30419952	The detected mutations were distributed throughout SETD2 with the majority of the high grade glioma nonsense or frameshift mutations occurring 5' to the SET domain (VAF 4-44%) (Fig.	('SETD2', 'Gene', (51, 56))	('glioma', 'Disease', (93, 99))	('glioma', 'Disease', 'MESH:D005910', (93, 99))	('VAF', 'Chemical', '-', (165, 168))	('glioma', 'Phenotype', 'HP:0009733', (93, 99))	('nonsense', 'Var', (100, 108))	('SETD2', 'Gene', '29072', (51, 56))	('frameshift mutations', 'Var', (112, 132))
182359	30419952	The nonsense or frameshift mutations for the low grade gliomas occurred throughout the SETD2 gene (VAF 6-34%).	('gliomas', 'Disease', 'MESH:D005910', (55, 62))	('gliomas', 'Phenotype', 'HP:0009733', (55, 62))	('gliomas', 'Disease', (55, 62))	('VAF', 'Chemical', '-', (99, 102))	('frameshift mutations', 'Var', (16, 36))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('SETD2', 'Gene', '29072', (87, 92))	('nonsense', 'Var', (4, 12))	('SETD2', 'Gene', (87, 92))	('occurred', 'Reg', (63, 71))
182360	30419952	Missense mutations occurred throughout the SETD2 gene, and in gliomas, were found predominantly in recurrent high grade gliomas, including recurrent glioblastomas (Table 2).	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))	('glioblastomas', 'Phenotype', 'HP:0012174', (149, 162))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('glioblastomas', 'Disease', (149, 162))	('gliomas', 'Disease', (62, 69))	('SETD2', 'Gene', '29072', (43, 48))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('glioblastomas', 'Disease', 'MESH:D005909', (149, 162))	('SETD2', 'Gene', (43, 48))	('gliomas', 'Disease', 'MESH:D005910', (120, 127))	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('gliomas', 'Disease', (120, 127))	('recurrent', 'Disease', (139, 148))	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('Missense mutations', 'Var', (0, 18))
182362	30419952	For patient 10 in Table 2, diagnosed with an IDH-wildtype anaplastic astrocytoma, a p.I1398T change in SETD2 was found; however, this may represent a benign single nucleotide polymorphism as it is seen at > 0.1% frequency in the Ashkenazi Jewish population (http://gnomad.broadinstitute.org/).	('IDH-wildtype anaplastic astrocytoma', 'Disease', (45, 80))	('p.I1398T', 'Var', (84, 92))	('patient', 'Species', '9606', (4, 11))	('SETD2', 'Gene', '29072', (103, 108))	('astrocytoma', 'Phenotype', 'HP:0009592', (69, 80))	('p.I1398T', 'Mutation', 'rs145732065', (84, 92))	('SETD2', 'Gene', (103, 108))	('IDH-wildtype anaplastic astrocytoma', 'Disease', 'MESH:D001254', (45, 80))
182363	30419952	Patient 12, with otherwise similar characteristics, showed SETD2 p.A2242V, which we classify as a variant of uncertain significance, given that is not been identified previously.	('p.A2242V', 'Var', (65, 73))	('SETD2', 'Gene', '29072', (59, 64))	('SETD2', 'Gene', (59, 64))	('p.A2242V', 'Mutation', 'rs770913885', (65, 73))	('Patient', 'Species', '9606', (0, 7))
182364	30419952	The remaining missense mutations found in SETD2 may represent changes found with the increased mutational load seen with tumor recurrence in this cohort (4.57 +- 3.40 mutations in recurrent tumors vs. 1.41 +- 1.24 mutations in primary tumors, p < 0.01), and known in the literature, particularly after treatment with temozolomide.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumors', 'Disease', (190, 196))	('SETD2', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', (121, 126))	('SETD2', 'Gene', '29072', (42, 47))	('temozolomide', 'Chemical', 'MESH:D000077204', (317, 329))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('missense mutations', 'Var', (14, 32))	('tumor', 'Disease', (190, 195))	('tumors', 'Disease', (235, 241))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (235, 240))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('tumors', 'Disease', 'MESH:D009369', (235, 241))
182367	30419952	Within the adult cohort, tumors with missense mutations in SETD2 had more concurrent mutations than did those with truncations of SETD2 (5.17 +- 3.31 vs. 1.50 +- 1.35, p < 0.05).	('missense mutations', 'Var', (37, 55))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('SETD2', 'Gene', '29072', (130, 135))	('mutations', 'MPA', (85, 94))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('SETD2', 'Gene', '29072', (59, 64))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('SETD2', 'Gene', (130, 135))	('SETD2', 'Gene', (59, 64))
182368	30419952	Mutations in EGFR were found to be the most commonly co-occurring change with SETD2 changes and were seen in 40% of the high grade gliomas in this cohort, similar to the frequency of EGFR mutations found in high grade gliomas overall (Fig.	('seen', 'Reg', (101, 105))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('EGFR', 'Gene', '1956', (13, 17))	('gliomas', 'Disease', (131, 138))	('EGFR', 'Gene', (183, 187))	('Mutations', 'Var', (0, 9))	('gliomas', 'Disease', (218, 225))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('EGFR', 'molecular_function', 'GO:0005006', ('183', '187'))	('glioma', 'Phenotype', 'HP:0009733', (218, 224))	('gliomas', 'Disease', 'MESH:D005910', (131, 138))	('SETD2', 'Gene', (78, 83))	('gliomas', 'Disease', 'MESH:D005910', (218, 225))	('EGFR', 'Gene', (13, 17))	('SETD2', 'Gene', '29072', (78, 83))	('EGFR', 'Gene', '1956', (183, 187))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('gliomas', 'Phenotype', 'HP:0009733', (218, 225))	('co-occurring', 'Reg', (53, 65))
182369	30419952	Pathogenic mutations in TP53 were seen in 30% of high grade gliomas with SETD2 changes, and IDH mutations were seen in 20%.	('seen', 'Reg', (34, 38))	('SETD2', 'Gene', (73, 78))	('mutations', 'Var', (11, 20))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('TP53', 'Gene', (24, 28))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('gliomas', 'Disease', (60, 67))	('IDH', 'Gene', (92, 95))	('changes', 'Var', (79, 86))	('SETD2', 'Gene', '29072', (73, 78))	('IDH', 'Gene', '3417', (92, 95))	('TP53', 'Gene', '7157', (24, 28))
182370	30419952	However, TP53 and IDH mutations were only seen in tumors with missense mutations in SETD2 and not those with nonsense or frameshift mutations in SETD2.	('SETD2', 'Gene', '29072', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('SETD2', 'Gene', (84, 89))	('IDH', 'Gene', (18, 21))	('IDH', 'Gene', '3417', (18, 21))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('missense mutations', 'Var', (62, 80))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('SETD2', 'Gene', '29072', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('SETD2', 'Gene', (145, 150))
182371	30419952	No mutations in H3F3A were seen to co-occur with SETD2 changes.	('H3F3A', 'Gene', (16, 21))	('SETD2', 'Gene', (49, 54))	('SETD2', 'Gene', '29072', (49, 54))	('H3F3A', 'Gene', '3020', (16, 21))	('mutations', 'Var', (3, 12))
182373	30419952	Gliomas with SETD2 mutations showed significantly lower H-scores for H3K36me3 compared to wildtype controls (140.8 +- 65.4 vs. 228.8 +- 29.1, p < 0.01) (Fig.	('lower', 'NegReg', (50, 55))	('H-scores', 'MPA', (56, 64))	('mutations', 'Var', (19, 28))	('SETD2', 'Gene', '29072', (13, 18))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('H3K36me3', 'Protein', (69, 77))	('SETD2', 'Gene', (13, 18))	('Gliomas', 'Disease', (0, 7))
182374	30419952	In contrast, statistically significant differences in staining for H3K36ac and H3K27me3 between SETD2 mutants and controls were not observed (H3K36ac: 140.1 +- 35.7 vs. 160.0 +- 41.8, p = 0.13; H3K27me3: 206.1 +- 24.2vs.	('mutants', 'Var', (102, 109))	('H3K36ac', 'Chemical', '-', (142, 149))	('H3K36ac', 'Chemical', '-', (67, 74))	('SETD2', 'Gene', '29072', (96, 101))	('SETD2', 'Gene', (96, 101))
182376	30419952	3c); H3K36ac: F1,8 = 0.54, p = .48 with an R2 of 0.06; H3K27me3: F1,8 = 0.46, p = .53 with an R2 of 0.08].	('H3K27me3', 'Var', (55, 63))	('H3K36ac', 'Var', (5, 12))	('H3K36ac', 'Chemical', '-', (5, 12))
182377	30419952	The concordance correlation coefficients for the three antibodies were as follows: H3K36me3 concordance correlation coefficient of 0.88 [95% CI 0.69-0.96]; H3K36ac concordance correlation coefficient of 0.58 (95% CI 0.12-0.83); H3K27me3: concordance correlation coefficient of 0.51 (95% CI 0.16-0.75).	('H3K36ac', 'Chemical', '-', (156, 163))	('H3K27me3', 'Var', (228, 236))	('H3K36me3', 'Var', (83, 91))	('H3K36ac', 'Var', (156, 163))
182379	30419952	A total of 22 CNS tumors with SETD2 mutations were identified across the cohorts included in the TCGA datasets, with 0-14% of CNS tumors harboring a SETD2 mutation depending on the cohort (Fig.	('CNS tumors', 'Disease', (14, 24))	('SETD2', 'Gene', (149, 154))	('SETD2', 'Gene', '29072', (30, 35))	('CNS tumor', 'Phenotype', 'HP:0100006', (126, 135))	('mutations', 'Var', (36, 45))	('CNS tumors', 'Disease', 'MESH:D009369', (14, 24))	('CNS tumors', 'Disease', 'MESH:D009369', (126, 136))	('SETD2', 'Gene', (30, 35))	('CNS tumor', 'Phenotype', 'HP:0100006', (14, 23))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('mutation', 'Var', (155, 163))	('CNS tumors', 'Disease', (126, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('SETD2', 'Gene', '29072', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
182380	30419952	Eleven tumors had truncating mutations, ten had missense mutations and one had a splice-site mutation.	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Disease', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('missense mutations', 'Var', (48, 66))	('truncating', 'MPA', (18, 28))
182382	30419952	There was no statistically significant difference (p = 0.22) in age between patients with truncating mutations and those with missense mutations.	('patients', 'Species', '9606', (76, 84))	('missense', 'Var', (126, 134))	('truncating mutations', 'Var', (90, 110))
182383	30419952	SETD2 mutations were found in high grade gliomas (n = 14, 63%), low grade gliomas (n = 3, 14%), and medulloblastomas (n = 5, 23%).	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('medulloblastomas', 'Disease', 'MESH:D008527', (100, 116))	('SETD2', 'Gene', '29072', (0, 5))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('gliomas', 'Disease', (74, 81))	('medulloblastoma', 'Phenotype', 'HP:0002885', (100, 115))	('SETD2', 'Gene', (0, 5))	('gliomas', 'Disease', 'MESH:D005910', (74, 81))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('medulloblastomas', 'Disease', (100, 116))	('found', 'Reg', (21, 26))	('gliomas', 'Disease', 'MESH:D005910', (41, 48))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('gliomas', 'Disease', (41, 48))	('mutations', 'Var', (6, 15))
182385	30419952	Data on the location of the tumors is limited; a study of glioblastomas found that all tumors with SETD2 mutations were located in the cerebral hemispheres.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('SETD2', 'Gene', '29072', (99, 104))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('glioblastomas', 'Phenotype', 'HP:0012174', (58, 71))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('SETD2', 'Gene', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('glioblastoma', 'Phenotype', 'HP:0012174', (58, 70))	('mutations', 'Var', (105, 114))	('glioblastomas', 'Disease', 'MESH:D005909', (58, 71))	('tumors', 'Disease', (87, 93))	('glioblastomas', 'Disease', (58, 71))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
182386	30419952	However, it is likely SETD2 mutant tumors were also present in the posterior fossa as mutations were seen in 5 medulloblastomas and 2 pilocytic astrocytomas, tumors which both have a strong association with the posterior fossa.	('tumors', 'Disease', (158, 164))	('mutations', 'Var', (86, 95))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (134, 156))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('SETD2', 'Gene', '29072', (22, 27))	('astrocytoma', 'Phenotype', 'HP:0009592', (144, 155))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('medulloblastoma', 'Phenotype', 'HP:0002885', (111, 126))	('SETD2', 'Gene', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('medulloblastomas', 'Disease', 'MESH:D008527', (111, 127))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('pilocytic astrocytomas', 'Disease', (134, 156))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('medulloblastomas', 'Disease', (111, 127))
182387	30419952	In total, 26 SETD2 mutations were seen among the 22 tumors with one medulloblastoma having 3 SETD2 missense mutations.	('seen', 'Reg', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('medulloblastoma', 'Disease', 'MESH:D008527', (68, 83))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('medulloblastoma', 'Phenotype', 'HP:0002885', (68, 83))	('tumors', 'Disease', (52, 58))	('mutations', 'Var', (19, 28))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('SETD2', 'Gene', '29072', (13, 18))	('medulloblastoma', 'Disease', (68, 83))	('SETD2', 'Gene', '29072', (93, 98))	('SETD2', 'Gene', (13, 18))	('SETD2', 'Gene', (93, 98))
182389	30419952	No statistically significant difference in AF was seen between truncating mutations and missense mutations (p = 0.82).	('truncating mutations', 'Var', (63, 83))	('missense mutations', 'Var', (88, 106))	('AF', 'Disease', 'MESH:D001281', (43, 45))
182390	30419952	The mutations were distributed throughout SETD2 (Fig.	('mutations', 'Var', (4, 13))	('SETD2', 'Gene', (42, 47))	('SETD2', 'Gene', '29072', (42, 47))
182397	30419952	Epigenetic changes have been detected in a wide range of tumors, and a variety of drugs have been developed to target these changes; for a review, see.	('detected', 'Reg', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('Epigenetic changes', 'Var', (0, 18))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
182398	30419952	Epigenetic mutations in gliomas include H3 K27 M mutations in diffuse midline gliomas and H3.3 G34R/V mutations in gliomas of the cerebral hemispheres.	('H3 K27 M mutations', 'Var', (40, 58))	('gliomas', 'Disease', 'MESH:D005910', (78, 85))	('midline', 'cellular_component', 'GO:0031430', ('70', '77'))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('gliomas', 'Phenotype', 'HP:0009733', (24, 31))	('H3.3 G34R/V mutations', 'Var', (90, 111))	('gliomas', 'Disease', (115, 122))	('gliomas of the cerebral hemispheres', 'Disease', (115, 150))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('gliomas', 'Phenotype', 'HP:0009733', (78, 85))	('K27 M', 'Mutation', 'p.K27M', (43, 48))	('midline gliomas', 'Disease', 'MESH:D005910', (70, 85))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('gliomas of the cerebral hemispheres', 'Disease', 'MESH:C564230', (115, 150))	('G34R', 'Mutation', 'rs1057519902', (95, 99))	('gliomas', 'Disease', (24, 31))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('gliomas', 'Disease', (78, 85))	('midline gliomas', 'Disease', (70, 85))	('gliomas', 'Disease', 'MESH:D005910', (24, 31))
182399	30419952	In diffuse midline gliomas, the H3 K27 M mutation has been shown to globally reduce levels of H3K27me3 levels, altering transcription and driving tumorigenesis.	('midline gliomas', 'Disease', 'MESH:D005910', (11, 26))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))	('reduce', 'NegReg', (77, 83))	('driving', 'Reg', (138, 145))	('H3 K27 M mutation', 'Var', (32, 49))	('transcription', 'MPA', (120, 133))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('midline', 'cellular_component', 'GO:0031430', ('11', '18'))	('tumor', 'Disease', (146, 151))	('altering', 'Reg', (111, 119))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('levels of H3K27me3', 'MPA', (84, 102))	('K27 M', 'Mutation', 'p.K27M', (35, 40))	('midline gliomas', 'Disease', (11, 26))	('transcription', 'biological_process', 'GO:0006351', ('120', '133'))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
182401	30419952	In gliomas, mutations have also been reported in SETD2, whose protein product is an enzyme responsible for trimethylation of the lysine 36 residue on Histone 3 (H3K36me3) in humans.	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('mutations', 'Var', (12, 21))	('humans', 'Species', '9606', (174, 180))	('lysine', 'Chemical', 'MESH:D008239', (129, 135))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('SETD2', 'Gene', '29072', (49, 54))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('gliomas', 'Disease', (3, 10))	('reported', 'Reg', (37, 45))	('SETD2', 'Gene', (49, 54))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
182402	30419952	Our investigation of SETD2 mutations in brain tumors yields findings consistent with the previous report of SETD2 mutations in gliomas, which shows that loss-of-function SETD2 mutations occur in older children and young adults in high grade gliomas of the cerebral cortex.	('mutations', 'Var', (176, 185))	('SETD2', 'Gene', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('SETD2', 'Gene', (170, 175))	('children', 'Species', '9606', (201, 209))	('gliomas of the cerebral cortex', 'Disease', (241, 271))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('SETD2', 'Gene', '29072', (21, 26))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('SETD2', 'Gene', '29072', (108, 113))	('SETD2', 'Gene', '29072', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('gliomas of the cerebral cortex', 'Disease', 'MESH:C564230', (241, 271))	('gliomas', 'Disease', (241, 248))	('brain tumors', 'Disease', 'MESH:D001932', (40, 52))	('brain tumors', 'Phenotype', 'HP:0030692', (40, 52))	('brain tumor', 'Phenotype', 'HP:0030692', (40, 51))	('loss-of-function', 'NegReg', (153, 169))	('gliomas', 'Disease', 'MESH:D005910', (241, 248))	('brain tumors', 'Disease', (40, 52))	('glioma', 'Phenotype', 'HP:0009733', (241, 247))	('gliomas', 'Disease', (127, 134))	('gliomas', 'Phenotype', 'HP:0009733', (241, 248))	('high', 'Disease', (230, 234))	('SETD2', 'Gene', (21, 26))	('gliomas', 'Disease', 'MESH:D005910', (127, 134))
182403	30419952	In addition, we expand on those results to demonstrate that subclonal mutations in SETD2 are seen in a broad range of tumors and locations.	('subclonal mutations', 'Var', (60, 79))	('seen', 'Reg', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('SETD2', 'Gene', '29072', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('SETD2', 'Gene', (83, 88))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
182404	30419952	Prior studies focusing on gliomas illustrate that SETD2 mutations are found nearly exclusively within the cerebral hemispheres.	('mutations', 'Var', (56, 65))	('SETD2', 'Gene', '29072', (50, 55))	('SETD2', 'Gene', (50, 55))	('gliomas', 'Phenotype', 'HP:0009733', (26, 33))	('gliomas', 'Disease', (26, 33))	('gliomas', 'Disease', 'MESH:D005910', (26, 33))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
182405	30419952	Similarly, in our cohort, mutations were most commonly seen in high grade gliomas within the cerebral hemispheres (12 of 19 tumors).	('seen', 'Reg', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('mutations', 'Var', (26, 35))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('gliomas within the cerebral', 'Disease', 'MESH:D001929', (74, 101))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('gliomas within the cerebral', 'Disease', (74, 101))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
182406	30419952	However, our results include a broader range of CNS tumor types, and demonstrate SETD2 truncating mutations in atypical meningiomas and pilocytic astrocytomas, as well as missense mutations in a choroid plexus papilloma and a medulloblastoma.	('tumor', 'Disease', (52, 57))	('choroid plexus papilloma', 'Disease', (195, 219))	('astrocytoma', 'Phenotype', 'HP:0009592', (146, 157))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('SETD2', 'Gene', (81, 86))	('choroid plexus papilloma', 'Disease', 'MESH:D020288', (195, 219))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('SETD2', 'Gene', '29072', (81, 86))	('missense mutations', 'Var', (171, 189))	('medulloblastoma', 'Phenotype', 'HP:0002885', (226, 241))	('medulloblastoma', 'Disease', 'MESH:D008527', (226, 241))	('medulloblastoma', 'Disease', (226, 241))	('meningiomas', 'Disease', 'MESH:D008577', (120, 131))	('pilocytic astrocytomas', 'Disease', (136, 158))	('papilloma', 'Phenotype', 'HP:0012740', (210, 219))	('choroid plexus papilloma', 'Phenotype', 'HP:0200022', (195, 219))	('meningiomas', 'Phenotype', 'HP:0002858', (120, 131))	('CNS tumor', 'Phenotype', 'HP:0100006', (48, 57))	('meningiomas', 'Disease', (120, 131))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (136, 158))
182407	30419952	Data from the TCGA database also showed SETD2 mutations in pilocytic astrocytomas, an oligodendroglioma, and medulloblastomas.	('mutations', 'Var', (46, 55))	('medulloblastomas', 'Disease', (109, 125))	('pilocytic astrocytomas', 'Disease', (59, 81))	('SETD2', 'Gene', '29072', (40, 45))	('medulloblastoma', 'Phenotype', 'HP:0002885', (109, 124))	('oligodendroglioma', 'Disease', (86, 103))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (59, 81))	('SETD2', 'Gene', (40, 45))	('oligodendroglioma', 'Disease', 'MESH:D009837', (86, 103))	('astrocytoma', 'Phenotype', 'HP:0009592', (69, 80))	('medulloblastomas', 'Disease', 'MESH:D008527', (109, 125))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
182410	30419952	In contrast to previous work showing that SETD2 mutations are seen in high grade gliomas but not low grade gliomas, we found frameshift mutations in SETD2 in two diffuse astrocytomas, WHO grade II.	('astrocytomas', 'Disease', (170, 182))	('diffuse', 'Disease', (162, 169))	('SETD2', 'Gene', (149, 154))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('astrocytoma', 'Phenotype', 'HP:0009592', (170, 181))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('gliomas', 'Disease', (107, 114))	('frameshift mutations', 'Var', (125, 145))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('gliomas', 'Disease', (81, 88))	('SETD2', 'Gene', '29072', (42, 47))	('astrocytomas', 'Disease', 'MESH:D001254', (170, 182))	('SETD2', 'Gene', (42, 47))	('SETD2', 'Gene', '29072', (149, 154))
182411	30419952	However, one SETD2-mutant astrocytoma in an older patient (#6) also harbors an EGFR mutation and lacks IDH changes, and so is in essence a "molecular glioblastoma," in addition to radiologically showing a gliomatosis cerebri pattern of growth.	('EGFR', 'Gene', '1956', (79, 83))	('glioblastoma', 'Disease', (150, 162))	('SETD2', 'Gene', '29072', (13, 18))	('glioblastoma', 'Phenotype', 'HP:0012174', (150, 162))	('harbors', 'Reg', (68, 75))	('astrocytoma', 'Phenotype', 'HP:0009592', (26, 37))	('glioma', 'Phenotype', 'HP:0009733', (205, 211))	('IDH', 'Gene', (103, 106))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('gliomatosis cerebri', 'Disease', 'MESH:D018302', (205, 224))	('EGFR', 'Gene', (79, 83))	('IDH', 'Gene', '3417', (103, 106))	('astrocytoma', 'Disease', 'MESH:D001254', (26, 37))	('astrocytoma', 'Disease', (26, 37))	('glioblastoma', 'Disease', 'MESH:D005909', (150, 162))	('gliomatosis cerebri', 'Disease', (205, 224))	('SETD2', 'Gene', (13, 18))	('patient', 'Species', '9606', (50, 57))	('mutation', 'Var', (84, 92))
182412	30419952	Given the previous findings that SETD2 mutations are specific to high grade gliomas, the SETD2 change in this tumor may be hypothesized to indicate or correlate with aggressive behavior.	('change', 'Var', (95, 101))	('SETD2', 'Gene', (33, 38))	('aggressive behavior', 'Phenotype', 'HP:0000718', (166, 185))	('gliomas', 'Disease', (76, 83))	('indicate', 'Reg', (139, 147))	('aggressive behavior', 'biological_process', 'GO:0002118', ('166', '185'))	('gliomas', 'Disease', 'MESH:D005910', (76, 83))	('SETD2', 'Gene', '29072', (89, 94))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('mutations', 'Var', (39, 48))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('SETD2', 'Gene', (89, 94))	('aggressive behavior', 'CPA', (166, 185))	('SETD2', 'Gene', '29072', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
182414	30419952	Along the same lines, we found truncating mutations in three pilocytic astrocytomas.	('pilocytic astrocytomas', 'Disease', (61, 83))	('astrocytoma', 'Phenotype', 'HP:0009592', (71, 82))	('truncating mutations', 'Var', (31, 51))	('pilocytic astrocytomas', 'Disease', 'MESH:D001254', (61, 83))
182419	30419952	Also, a 60-year-old patient presented with a thalamic glioblastoma, which demonstrated a frameshift mutation in SETD2 at a 30% VAF.	('thalamic glioblastoma', 'Disease', (45, 66))	('SETD2', 'Gene', '29072', (112, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('thalamic glioblastoma', 'Disease', 'MESH:D005909', (45, 66))	('SETD2', 'Gene', (112, 117))	('VAF', 'Chemical', '-', (127, 130))	('patient', 'Species', '9606', (20, 27))	('frameshift mutation', 'Var', (89, 108))
182421	30419952	In our cohort, mutations were seen in a variety of regions within the SETD2 gene and at a broad range of VAF in tumors.	('mutations', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('VAF in tumors', 'Disease', (105, 118))	('SETD2', 'Gene', '29072', (70, 75))	('SETD2', 'Gene', (70, 75))	('VAF in tumors', 'Disease', 'MESH:D009369', (105, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
182422	30419952	In high grade gliomas, nonsense and frameshift mutations were mostly located 5' to the SET domain.	('gliomas', 'Disease', 'MESH:D005910', (14, 21))	('frameshift mutations', 'Var', (36, 56))	('nonsense', 'Var', (23, 31))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('gliomas', 'Phenotype', 'HP:0009733', (14, 21))	('gliomas', 'Disease', (14, 21))
182423	30419952	In contrast, in the low grade astrocytic tumors, nonsense or frameshift mutations often occurred 3' to the SET domain, including in tumor #6.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('astrocytic tumors', 'Disease', 'MESH:D001254', (30, 47))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', (41, 46))	('occurred', 'Reg', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (132, 137))	('astrocytic tumors', 'Disease', (30, 47))	('frameshift mutations', 'Var', (61, 81))	('nonsense', 'Var', (49, 57))
182424	30419952	Missense mutations were found throughout SETD2.	('SETD2', 'Gene', (41, 46))	('SETD2', 'Gene', '29072', (41, 46))	('Missense mutations', 'Var', (0, 18))
182425	30419952	SETD2 mutations with low VAF (defined as VAF < 10%), were seen to co-occur with an average of 3.8 +- 1.7 other mutations (range 1-6 mutations).	('SETD2', 'Gene', '29072', (0, 5))	('VAF', 'MPA', (25, 28))	('VAF', 'Chemical', '-', (41, 44))	('SETD2', 'Gene', (0, 5))	('VAF', 'Chemical', '-', (25, 28))	('mutations', 'Var', (6, 15))
182426	30419952	Those tumors with higher SETD2 mutation VAF (>=10%) had an average of 1.8 +- 2.9 additional co-occurring mutations (range 0-11 mutations).	('VAF', 'Chemical', '-', (40, 43))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('mutation', 'Var', (31, 39))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('SETD2', 'Gene', '29072', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('SETD2', 'Gene', (25, 30))
182428	30419952	Sequencing for SETD2 mutations was not performed on the prior resection specimens.	('SETD2', 'Gene', (15, 20))	('SETD2', 'Gene', '29072', (15, 20))	('mutations', 'Var', (21, 30))
182429	30419952	However, one patient (#13) had tumor recurrence and a subsequent resection which showed the same SETD2 mutation (p.I1398T) at a similar VAF.	('p.I1398T', 'Var', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('patient', 'Species', '9606', (13, 20))	('tumor', 'Disease', (31, 36))	('VAF', 'Chemical', '-', (136, 139))	('SETD2', 'Gene', '29072', (97, 102))	('p.I1398T', 'Mutation', 'rs145732065', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('SETD2', 'Gene', (97, 102))
182431	30419952	It is possible that these mutations are germline though this cannot be confirmed as paired normal sequencing for SETD2 was not performed.	('SETD2', 'Gene', '29072', (113, 118))	('mutations', 'Var', (26, 35))	('SETD2', 'Gene', (113, 118))
182432	30419952	We attempted to determine whether the SETD2 mutation resulted in a functional effect through immunohistochemical studies of epigenetic markers.	('mutation', 'Var', (44, 52))	('SETD2', 'Gene', (38, 43))	('SETD2', 'Gene', '29072', (38, 43))
182433	30419952	If SETD2 mutations are indeed driving tumorigenesis in some CNS tumors, the exact mechanism by which this occurs also requires further elucidation.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Disease', (64, 69))	('CNS tumor', 'Phenotype', 'HP:0100006', (60, 69))	('mutations', 'Var', (9, 18))	('CNS tumors', 'Disease', 'MESH:D009369', (60, 70))	('CNS tumors', 'Disease', (60, 70))	('SETD2', 'Gene', '29072', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('driving', 'Reg', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('SETD2', 'Gene', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
182434	30419952	One of the leading hypotheses suggests that loss of SETD2 function in tumor cells decreases levels of H3K36me3, which subsequently leads to alterations in gene regulation, increased spontaneous mutation frequency and chromosomal instability (Fig.	('levels of H3K36me3', 'MPA', (92, 110))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('increased', 'PosReg', (172, 181))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('chromosomal instability', 'Phenotype', 'HP:0040012', (217, 240))	('regulation', 'biological_process', 'GO:0065007', ('160', '170'))	('tumor', 'Disease', (70, 75))	('gene regulation', 'MPA', (155, 170))	('chromosomal instability', 'CPA', (217, 240))	('loss', 'Var', (44, 48))	('SETD2', 'Gene', '29072', (52, 57))	('leads to alterations', 'Reg', (131, 151))	('decreases', 'NegReg', (82, 91))	('SETD2', 'Gene', (52, 57))	('spontaneous mutation frequency', 'CPA', (182, 212))
182435	30419952	Evidence also indicates that increased levels of H3K36ac are seen when the levels of H3K36me3 decrease.	('levels', 'MPA', (39, 45))	('increased', 'PosReg', (29, 38))	('levels', 'MPA', (75, 81))	('H3K36ac', 'Chemical', '-', (49, 56))	('decrease', 'NegReg', (94, 102))	('H3K36ac', 'Var', (49, 56))
182436	30419952	We employed IHC for H3K36me3, H3K36ac and H3K27me3 to investigate the impact of SETD2 mutations on histone methylation and acetylation.	('mutations', 'Var', (86, 95))	('SETD2', 'Gene', (80, 85))	('histone methylation', 'biological_process', 'GO:0016571', ('99', '118'))	('H3K36ac', 'Chemical', '-', (30, 37))	('acetylation', 'MPA', (123, 134))	('histone', 'MPA', (99, 106))	('SETD2', 'Gene', '29072', (80, 85))
182437	30419952	We hypothesized that decreased H3K36me3 staining and increased staining for H3K36ac would be present in SETD2 mutant tumors with mutation seen at high VAF.	('SETD2', 'Gene', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('H3K36ac', 'Protein', (76, 83))	('staining', 'MPA', (40, 48))	('H3K36ac', 'Chemical', '-', (76, 83))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('decreased', 'NegReg', (21, 30))	('mutant', 'Var', (110, 116))	('VAF', 'Chemical', '-', (151, 154))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('H3K36me3', 'Protein', (31, 39))	('staining', 'MPA', (63, 71))	('increased', 'PosReg', (53, 62))	('SETD2', 'Gene', '29072', (104, 109))
182438	30419952	Based on these findings, we investigated whether staining for H3K27me3 is increased in SETD2 mutant tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', (100, 106))	('H3K27me3', 'Protein', (62, 70))	('increased', 'PosReg', (74, 83))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('mutant', 'Var', (93, 99))	('SETD2', 'Gene', '29072', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('SETD2', 'Gene', (87, 92))
182439	30419952	Immunohistochemical staining for H3K36me3 showed a statistically significant decrease in staining for SETD2 mutant gliomas compared to SETD2 wildtype histologic controls.	('H3K36me3', 'Protein', (33, 41))	('SETD2', 'Gene', (135, 140))	('gliomas', 'Disease', (115, 122))	('SETD2', 'Gene', '29072', (102, 107))	('decrease', 'NegReg', (77, 85))	('gliomas', 'Disease', 'MESH:D005910', (115, 122))	('gliomas', 'Phenotype', 'HP:0009733', (115, 122))	('mutant', 'Var', (108, 114))	('staining', 'MPA', (89, 97))	('SETD2', 'Gene', (102, 107))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('SETD2', 'Gene', '29072', (135, 140))
182440	30419952	However, given the variability in staining and the lack of correlation with allele frequency, IHC for the detection of SETD2 mutations is impractical in a clinical setting.	('SETD2', 'Gene', (119, 124))	('mutations', 'Var', (125, 134))	('SETD2', 'Gene', '29072', (119, 124))
182443	30419952	For example, the most significant decreases in staining for H3K36me3 in non-CNS tumors with SETD2 mutations were seen when both SETD2 allelic copies were lost.	('CNS tumors', 'Disease', (76, 86))	('decreases', 'NegReg', (34, 43))	('SETD2', 'Gene', (128, 133))	('SETD2', 'Gene', '29072', (92, 97))	('H3K36me3', 'Protein', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('SETD2', 'Gene', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('staining', 'MPA', (47, 55))	('mutations', 'Var', (98, 107))	('CNS tumor', 'Phenotype', 'HP:0100006', (76, 85))	('CNS tumors', 'Disease', 'MESH:D009369', (76, 86))	('SETD2', 'Gene', '29072', (128, 133))
182444	30419952	Specifically, studies of clear cell renal cell carcinoma indicate that mutations occurring at higher AFs may not result in significant decreases in H3K36me3 unless both SETD2 alleles are affected.	('SETD2', 'Gene', (169, 174))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (36, 56))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (25, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('mutations', 'Var', (71, 80))	('decreases', 'NegReg', (135, 144))	('AF', 'Disease', 'MESH:D001281', (101, 103))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (25, 56))	('clear cell renal cell carcinoma', 'Disease', (25, 56))	('SETD2', 'Gene', '29072', (169, 174))	('H3K36me3', 'Protein', (148, 156))
182445	30419952	Further studies are needed to assess whether this statistically significant decrease in levels of H3K36me3 in gliomas with heterozygous mutations in SETD2 has a function impact on tumorigenesis, as well as to determine if there is loss of the alternate allele.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('gliomas', 'Disease', (110, 117))	('SETD2', 'Gene', (149, 154))	('gliomas', 'Phenotype', 'HP:0009733', (110, 117))	('gliomas', 'Disease', 'MESH:D005910', (110, 117))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('levels', 'MPA', (88, 94))	('H3K36me3', 'Protein', (98, 106))	('SETD2', 'Gene', '29072', (149, 154))	('tumor', 'Disease', (180, 185))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('mutations', 'Var', (136, 145))	('decrease', 'NegReg', (76, 84))
182446	30419952	Immunohistochemical stains for H3K36ac and H3K27me3 did not show statistically significant differences in staining between mutants and controls, although an increase in staining for H3K27me3 were seen in SETD2 mutants compared to controls.	('SETD2', 'Gene', (204, 209))	('mutants', 'Var', (210, 217))	('H3K27me3', 'Var', (182, 190))	('SETD2', 'Gene', '29072', (204, 209))	('increase', 'PosReg', (157, 165))	('H3K36ac', 'Chemical', '-', (31, 38))
182448	30419952	An alternative mechanistic hypothesis is that SETD2 mutations are interacting with other mutations to drive tumorigenesis.	('mutations', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('SETD2', 'Gene', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('drive', 'PosReg', (102, 107))	('tumor', 'Disease', (108, 113))	('SETD2', 'Gene', '29072', (46, 51))
182450	30419952	Studies of lung adenocarcinomas found loss of H3K36me3 lead to accelerated progression of early- and late-stage tumors; however SETD2 loss alone was not sufficient to overcome the p53-regulated barrier that suppresses the formation of higher grade adenocarcinomas.	('H3K36me3', 'Protein', (46, 54))	('accelerated', 'PosReg', (63, 74))	('loss', 'Var', (38, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (11, 31))	('SETD2', 'Gene', (128, 133))	('p53', 'Gene', '7157', (180, 183))	('late-stage tumors', 'Disease', 'MESH:D062706', (101, 118))	('adenocarcinomas', 'Disease', 'MESH:D000230', (248, 263))	('adenocarcinomas', 'Disease', (248, 263))	('adenocarcinomas', 'Disease', 'MESH:D000230', (16, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('SETD2', 'Gene', '29072', (128, 133))	('adenocarcinomas', 'Disease', (16, 31))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (11, 31))	('formation', 'biological_process', 'GO:0009058', ('222', '231'))	('progression', 'CPA', (75, 86))	('p53', 'Gene', (180, 183))	('late-stage tumors', 'Disease', (101, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('loss', 'NegReg', (134, 138))	('lung adenocarcinomas', 'Disease', (11, 31))
182451	30419952	It is possible that SETD2 mutations work in conjunction with other mutations such as TP53 or mutations in growth factor pathways to promote tumorigenesis.	('TP53', 'Gene', (85, 89))	('SETD2', 'Gene', '29072', (20, 25))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('SETD2', 'Gene', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('TP53', 'Gene', '7157', (85, 89))	('growth factor pathways', 'Pathway', (106, 128))	('promote', 'PosReg', (132, 139))	('tumor', 'Disease', (140, 145))
182452	30419952	Although one of the most frequently observed concurrently mutated genes in our cohort of high grade gliomas is TP53, TP53 mutations were only seen in tumors with SETD2 missense mutations and not in those tumors with SETD2 nonsense or frameshift mutations.	('SETD2', 'Gene', (162, 167))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('TP53', 'Gene', (117, 121))	('missense mutations', 'Var', (168, 186))	('SETD2', 'Gene', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('SETD2', 'Gene', '29072', (162, 167))	('tumors', 'Disease', (150, 156))	('gliomas', 'Disease', 'MESH:D005910', (100, 107))	('TP53', 'Gene', '7157', (111, 115))	('SETD2', 'Gene', '29072', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('tumors', 'Disease', (204, 210))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('gliomas', 'Phenotype', 'HP:0009733', (100, 107))	('TP53', 'Gene', '7157', (117, 121))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('seen', 'Reg', (142, 146))	('TP53', 'Gene', (111, 115))	('gliomas', 'Disease', (100, 107))
182453	30419952	Most often, the co-occurrence of SETD2 and TP53 mutations was seen in recurrent gliomas, and the VAFs varied.	('SETD2', 'Gene', (33, 38))	('seen', 'Reg', (62, 66))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('co-occurrence', 'Reg', (16, 29))	('gliomas', 'Disease', (80, 87))	('SETD2', 'Gene', '29072', (33, 38))	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))	('VAF', 'Chemical', '-', (97, 100))
182454	30419952	These findings do not lend support to the hypothesis that SETD2 mutations synergize with TP53 mutations, and further studies are necessary.	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('SETD2', 'Gene', '29072', (58, 63))	('mutations', 'Var', (64, 73))	('SETD2', 'Gene', (58, 63))
182455	30419952	In addition to TP53, the other most frequently observed genes showing mutations concurrent with SETD2 mutation within the high grade glioma subset were EGFR and PTEN, likely due to the frequency of mutation in these genes in glioblastoma.	('mutations', 'Var', (70, 79))	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioblastoma', 'Disease', (225, 237))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('glioblastoma', 'Phenotype', 'HP:0012174', (225, 237))	('mutation', 'Var', (102, 110))	('EGFR', 'Gene', '1956', (152, 156))	('TP53', 'Gene', '7157', (15, 19))	('glioma', 'Disease', (133, 139))	('TP53', 'Gene', (15, 19))	('SETD2', 'Gene', '29072', (96, 101))	('EGFR', 'Gene', (152, 156))	('PTEN', 'Gene', (161, 165))	('SETD2', 'Gene', (96, 101))	('PTEN', 'Gene', '5728', (161, 165))	('glioblastoma', 'Disease', 'MESH:D005909', (225, 237))	('EGFR', 'molecular_function', 'GO:0005006', ('152', '156'))
182456	30419952	Recurrent tumors with SETD2 mutations had significantly more concurrent mutations than did first occurrence SETD2-mutant tumors.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('SETD2', 'Gene', (108, 113))	('SETD2', 'Gene', '29072', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('SETD2', 'Gene', (22, 27))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('SETD2', 'Gene', '29072', (108, 113))	('mutations', 'MPA', (72, 81))	('mutations', 'Var', (28, 37))
182457	30419952	IDH mutations were present in a subset (18%) of diffuse gliomas with SETD2 changes, which in this study were all SETD2 missense mutations rather than nonsense or frameshift mutations.	('changes', 'Var', (75, 82))	('IDH', 'Gene', (0, 3))	('gliomas', 'Disease', 'MESH:D005910', (56, 63))	('gliomas', 'Disease', (56, 63))	('gliomas', 'Phenotype', 'HP:0009733', (56, 63))	('SETD2', 'Gene', '29072', (113, 118))	('missense mutations', 'Var', (119, 137))	('IDH', 'Gene', '3417', (0, 3))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('SETD2', 'Gene', (113, 118))	('SETD2', 'Gene', '29072', (69, 74))	('SETD2', 'Gene', (69, 74))
182460	30419952	Twelve of sixteen patients from the TCGA cohort were still living, and the data on follow-up does not allow any conclusions to be drawn regarding the impact of the SETD2 mutations.	('SETD2', 'Gene', (164, 169))	('mutations', 'Var', (170, 179))	('SETD2', 'Gene', '29072', (164, 169))	('patients', 'Species', '9606', (18, 26))
182462	30419952	Focusing on patients with high grade gliomas, the average follow-up period from initial presentation was 18.0 +- 24.3 months (range 2 to 61 months) for truncating mutations and 36.0 +- 28.3 months (range 2 to 72 months) for missense mutations.	('patients', 'Species', '9606', (12, 20))	('truncating', 'MPA', (152, 162))	('gliomas', 'Disease', 'MESH:D005910', (37, 44))	('gliomas', 'Phenotype', 'HP:0009733', (37, 44))	('gliomas', 'Disease', (37, 44))	('missense mutations', 'Var', (224, 242))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))
182463	30419952	Two tumors with SETD2 missense mutations were positive for IDH1 mutations; when comparing tumors with SETD2 missense mutations, IDH-mutant tumors had follow-up periods of 79 and 42 months versus follow-up periods ranging from 2 to 44 months with an average follow-up of 19.7 +- 21.8 months for IDH-wildtype gliomas.	('IDH1', 'Gene', '3417', (59, 63))	('IDH', 'Gene', (128, 131))	('IDH', 'Gene', '3417', (59, 62))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('IDH', 'Gene', (294, 297))	('IDH', 'Gene', '3417', (128, 131))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (307, 313))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('IDH-wildtype gliomas', 'Disease', 'MESH:D005910', (294, 314))	('IDH', 'Gene', '3417', (294, 297))	('IDH-wildtype gliomas', 'Disease', (294, 314))	('gliomas', 'Phenotype', 'HP:0009733', (307, 314))	('SETD2', 'Gene', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('SETD2', 'Gene', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumors', 'Disease', (139, 145))	('missense mutations', 'Var', (108, 126))	('IDH1', 'Gene', (59, 63))	('SETD2', 'Gene', '29072', (16, 21))	('IDH', 'Gene', (59, 62))	('SETD2', 'Gene', '29072', (102, 107))	('tumors', 'Disease', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (139, 145))
182464	30419952	On average, longer follow-up data was available for patients with tumors with missense mutations as several of these were identified in recurrences (4 of 5 high grade gliomas with missense mutations had recurrences available for analysis).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('missense mutations', 'Var', (78, 96))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('gliomas', 'Disease', 'MESH:D005910', (167, 174))	('gliomas', 'Phenotype', 'HP:0009733', (167, 174))	('gliomas', 'Disease', (167, 174))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('patients', 'Species', '9606', (52, 60))
182466	30419952	However, one patient (#13) had an IDH-wildtype anaplastic astrocytoma recur with progression to glioblastoma; the initial frontal lobe resection and the frontal lobe recurrence demonstrated the same mutational profile, including the same SETD2 missense mutation, whereas an intervening temporoparietal tumor resection demonstrated different mutations.	('temporoparietal tumor', 'Disease', (286, 307))	('SETD2', 'Gene', '29072', (238, 243))	('missense mutation', 'Var', (244, 261))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('temporoparietal tumor', 'Disease', 'MESH:D009369', (286, 307))	('astrocytoma', 'Phenotype', 'HP:0009592', (58, 69))	('SETD2', 'Gene', (238, 243))	('patient', 'Species', '9606', (13, 20))	('glioblastoma', 'Disease', (96, 108))	('glioblastoma', 'Disease', 'MESH:D005909', (96, 108))	('IDH-wildtype anaplastic astrocytoma', 'Disease', (34, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))	('IDH-wildtype anaplastic astrocytoma', 'Disease', 'MESH:D001254', (34, 69))
182467	30419952	EGFR p.G589 V and a copy number gain of EGFR were detected in both frontal lobe resections, and EGFR p.T263P and PTEN p.T366Hfs*50 were detected in the temporoparietal resection.	('copy', 'MPA', (20, 24))	('EGFR', 'Gene', '1956', (96, 100))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', (96, 100))	('p.T263P', 'Mutation', 'rs1057519829', (101, 108))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('PTEN', 'Gene', (113, 117))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', (40, 44))	('gain', 'PosReg', (32, 36))	('PTEN', 'Gene', '5728', (113, 117))	('p.G589 V', 'Mutation', 'p.G589V', (5, 13))	('p.G589 V', 'Var', (5, 13))	('EGFR', 'Gene', '1956', (0, 4))	('p.T263P', 'Var', (101, 108))	('p.T366Hfs*50', 'Mutation', 'p.T366HfsX50', (118, 130))
182468	30419952	In these recurrent/residual high grade gliomas with changes in SETD2, longer durations of follow-up were seen after initial presentation (mean of 79 and 42 months for IDH-mutant tumors and 52.5 +- 12.0 months for IDH-wildtype tumors) than is common for high grade gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (264, 271))	('IDH-wildtype tumors', 'Disease', 'MESH:D009369', (213, 232))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('gliomas', 'Disease', 'MESH:D005910', (39, 46))	('IDH', 'Gene', (213, 216))	('IDH', 'Gene', (167, 170))	('gliomas', 'Phenotype', 'HP:0009733', (39, 46))	('IDH-wildtype tumors', 'Disease', (213, 232))	('SETD2', 'Gene', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('changes', 'Var', (52, 59))	('IDH', 'Gene', '3417', (213, 216))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('gliomas', 'Disease', (264, 271))	('IDH', 'Gene', '3417', (167, 170))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('SETD2', 'Gene', '29072', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('gliomas', 'Disease', 'MESH:D005910', (264, 271))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', (226, 232))	('gliomas', 'Disease', (39, 46))	('glioma', 'Phenotype', 'HP:0009733', (264, 270))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
182469	30419952	Further studies are required to better elucidate how nonsense or frameshift mutations and missense mutations in SETD2 relate to prognosis.	('frameshift mutations', 'Var', (65, 85))	('SETD2', 'Gene', '29072', (112, 117))	('nonsense', 'Var', (53, 61))	('SETD2', 'Gene', (112, 117))	('missense mutations', 'Var', (90, 108))	('relate', 'Reg', (118, 124))
182470	30419952	Another question that requires further investigation is the difference between truncating mutations and missense SETD2 mutations.	('SETD2', 'Gene', '29072', (113, 118))	('mutations', 'Var', (119, 128))	('missense', 'Var', (104, 112))	('SETD2', 'Gene', (113, 118))
182471	30419952	As a number of different missense mutations occurring throughout the SETD2 gene have been seen in CNS tumors, as well as in other tumor types, the role of individual missense mutations in tumorigenesis is unclear.	('tumor', 'Disease', (188, 193))	('CNS tumor', 'Phenotype', 'HP:0100006', (98, 107))	('tumor', 'Disease', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('CNS tumors', 'Disease', 'MESH:D009369', (98, 108))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('seen', 'Reg', (90, 94))	('CNS tumors', 'Disease', (98, 108))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('missense mutations', 'Var', (25, 43))	('SETD2', 'Gene', '29072', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('SETD2', 'Gene', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (130, 135))
182472	30419952	One possibility is that a subset of missense mutations are passenger mutations that occur following glioma therapy.	('glioma', 'Phenotype', 'HP:0009733', (100, 106))	('glioma', 'Disease', (100, 106))	('glioma', 'Disease', 'MESH:D005910', (100, 106))	('missense mutations', 'Var', (36, 54))
182473	30419952	Three recurrent high grade gliomas (#12, 14 and 16) in our subset had multiple missense mutations in SETD2.	('gliomas', 'Disease', 'MESH:D005910', (27, 34))	('SETD2', 'Gene', (101, 106))	('glioma', 'Phenotype', 'HP:0009733', (27, 33))	('missense mutations', 'Var', (79, 97))	('SETD2', 'Gene', '29072', (101, 106))	('gliomas', 'Phenotype', 'HP:0009733', (27, 34))	('gliomas', 'Disease', (27, 34))
182474	30419952	It is likely that the missense SETD2 mutations seen at low VAF are not drivers of tumorigenesis in these tumors.	('tumors', 'Disease', (105, 111))	('SETD2', 'Gene', (31, 36))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('VAF', 'Chemical', '-', (59, 62))	('SETD2', 'Gene', '29072', (31, 36))	('tumor', 'Disease', (82, 87))	('missense', 'Var', (22, 30))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
182475	30419952	In contrast, for the tumors with nonsense or frameshift mutations in SETD2, fewer concurrent PM were detected, and in one tumor (#3), the PM in SETD2 was the only mutation detected on the NGS panel, at a VAF of 23%.	('SETD2', 'Gene', (144, 149))	('frameshift mutations', 'Var', (45, 65))	('VAF', 'Chemical', '-', (204, 207))	('tumor', 'Disease', (21, 26))	('nonsense', 'Var', (33, 41))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('SETD2', 'Gene', '29072', (144, 149))	('SETD2', 'Gene', '29072', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('SETD2', 'Gene', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
182476	30419952	In summary, these findings suggest that SETD2 mutations, although most common in high grade gliomas of the cerebral hemispheres, may be found in a variety of primary CNS tumors and locations.	('mutations', 'Var', (46, 55))	('SETD2', 'Gene', '29072', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('SETD2', 'Gene', (40, 45))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('gliomas of the cerebral hemispheres', 'Disease', (92, 127))	('common', 'Reg', (71, 77))	('found', 'Reg', (136, 141))	('gliomas of the cerebral hemispheres', 'Disease', 'MESH:C564230', (92, 127))	('primary CNS tumors', 'Disease', 'MESH:D016543', (158, 176))	('primary CNS tumors', 'Disease', (158, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('CNS tumor', 'Phenotype', 'HP:0100006', (166, 175))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
182477	30419952	Immunohistochemistry shows a decrease in H3K36me3 in tumor with SETD2 mutations, implicating epigenetic pathways in tumor biology.	('mutations', 'Var', (70, 79))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('SETD2', 'Gene', '29072', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('H3K36me3', 'Protein', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('SETD2', 'Gene', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (53, 58))	('decrease', 'NegReg', (29, 37))
182478	30419952	Additional studies are needed to investigate the role of SETD2 mutations in tumorigenesis.	('mutations', 'Var', (63, 72))	('SETD2', 'Gene', '29072', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('SETD2', 'Gene', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
182479	30419952	CCRCC Clear cell renal cell carcinoma CHOP Children's Hospital of Philadelphia CNS Central nervous system CPD Center for Personalized Diagnostics DGD Division of Genomic Diagnostics H3K27me3 Trimethylation of the lysine 27 residue on Histone 3 H3K36ac Acetylation of the lysine 36 residue on Histone 3 H3K36me3 Trimethylation of the lysine 36 residue on Histone 3 HOTAIR HOX Transcript Antisense RNA HUP Hospital of the University of Pennsylvania IHC Immunohistochemistry MM Missense mutation NGS Next generation sequencing SETD2 SET domain-containing 2 TCGA The Cancer Genome Atlas TM Truncating mutation VAF Variant allele frequency ANV and MPN Conceived and designed the analysis; Collected the data; Contributed data; Performed the analysis; Wrote the paper.	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (6, 37))	('SET domain-containing 2', 'Gene', (530, 553))	('Variant', 'Var', (610, 617))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (563, 582))	('CPD', 'Disease', 'MESH:C565865', (106, 109))	('Children', 'Species', '9606', (43, 51))	('CPD', 'Disease', (106, 109))	('Antisense RNA', 'molecular_function', 'GO:0009388', ('386', '399'))	('Cancer Genome Atlas', 'Disease', (563, 582))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (17, 37))	('HOTAIR', 'Gene', '100124700', (364, 370))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (6, 37))	('Cancer', 'Phenotype', 'HP:0002664', (563, 569))	('RNA', 'cellular_component', 'GO:0005562', ('396', '399'))	('SETD2', 'Gene', (524, 529))	('Clear cell renal cell carcinoma', 'Disease', (6, 37))	('HOTAIR', 'Gene', (364, 370))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('VAF', 'Chemical', '-', (606, 609))	('lysine', 'Chemical', 'MESH:D008239', (271, 277))	('H3K36ac', 'Chemical', '-', (244, 251))	('SET domain-containing 2', 'Gene', '29072', (530, 553))	('CCRCC', 'Phenotype', 'HP:0006770', (0, 5))	('SETD2', 'Gene', '29072', (524, 529))	('lysine', 'Chemical', 'MESH:D008239', (333, 339))	('lysine', 'Chemical', 'MESH:D008239', (213, 219))
182481	28235946	show that VHL expression leads to increased VCAM-1 levels in renal cell carcinoma through an NF-kappaB-dependent mechanism that seems to contribute to the antitumoral immune response.	('expression', 'Var', (14, 24))	('VCAM-1', 'Gene', '7412', (44, 50))	('1 ', 'Gene', '4790', (49, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('immune response', 'biological_process', 'GO:0006955', ('167', '182'))	('tumor', 'Disease', (159, 164))	('VCAM-1', 'Gene', (44, 50))	('renal cell carcinoma', 'Disease', (61, 81))	('contribute', 'Reg', (137, 147))	(' VHL', 'Gene', '7428', (9, 13))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (61, 81))	('increased', 'PosReg', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	(' VHL', 'Gene', (9, 13))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (61, 81))
182485	28235946	Our experiments in clear cell renal cell carcinoma (ccRCC) cell lines demonstrated that von Hippel Lindau (VHL) loss, hypoxia, or PHD (for prolyl hydroxylase domain-containing proteins) inactivation decreased VCAM-1 levels through a transcriptional mechanism that was independent of the hypoxia-inducible factor and dependent on the nuclear factor kappaB signaling pathway.	('von Hippel Lindau (VHL) loss', 'Disease', 'MESH:D006623', (88, 116))	('PHD', 'molecular_function', 'GO:0050175', ('130', '133'))	('signaling pathway', 'biological_process', 'GO:0007165', ('355', '372'))	('ted ', 'Gene', '27112', (79, 83))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('clear cell renal cell carcinoma', 'Disease', (19, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('ted ', 'Gene', (79, 83))	('hypoxia', 'Disease', (287, 294))	('inactivation', 'Var', (186, 198))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (19, 50))	('1 ', 'Gene', '4790', (214, 216))	('hypoxia', 'Disease', (118, 125))	('hypoxia', 'Disease', 'MESH:D000860', (287, 294))	('VCAM-1', 'Gene', '7412', (209, 215))	('hypoxia', 'Disease', 'MESH:D000860', (118, 125))	('RCC', 'Disease', (54, 57))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (19, 50))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (30, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('VCAM-1', 'Gene', (209, 215))
182486	28235946	Conversely, VHL expression leads to high VCAM-1 levels in ccRCC, which in turn leads to better outcomes, possibly by favoring antitumor immunity through VCAM-1 interaction with the alpha4beta1 integrin expressed in immune cells.	('RCC', 'Disease', (60, 63))	('VCAM-1', 'Gene', (153, 159))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('tumor', 'Disease', (130, 135))	('VCAM-1', 'Gene', (41, 47))	(' VHL', 'Gene', '7428', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	(' VHL', 'Gene', (11, 15))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('1 ', 'Gene', '4790', (191, 193))	('beta1', 'Gene', (187, 192))	('favoring', 'PosReg', (117, 125))	('1 ', 'Gene', '4790', (158, 160))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('VCAM-1', 'Gene', '7412', (153, 159))	('1 ', 'Gene', '4790', (46, 48))	('expression', 'Var', (16, 26))	('beta1', 'Gene', '10678', (187, 192))	('VCAM-1', 'Gene', '7412', (41, 47))
182500	28235946	However, although the role of VHL and hypoxia in the regulation of HIF has proven to be important for tumor growth, other VHL functions independent of HIF help to explain why loss of VHL leads to renal cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Disease', (102, 107))	(' VHL', 'Gene', '7428', (182, 186))	(' VHL', 'Gene', '7428', (121, 125))	('renal cancer', 'Disease', 'MESH:D007680', (196, 208))	('renal cancer', 'Phenotype', 'HP:0009726', (196, 208))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	(' VHL', 'Gene', (182, 186))	('leads to', 'Reg', (187, 195))	('hypoxia', 'Disease', 'MESH:D000860', (38, 45))	('regulation', 'biological_process', 'GO:0065007', ('53', '63'))	(' VHL', 'Gene', (29, 33))	(' VHL', 'Gene', '7428', (29, 33))	(' VHL', 'Gene', (121, 125))	('hypoxia', 'Disease', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('loss', 'Var', (175, 179))	('renal cancer', 'Disease', (196, 208))
182543	28235946	Additionally, HIF-independent regulation of VCAM-1 in ccRCC cells was also confirmed in cells expressing a mutant form of VHL that has been previously reported to regulate HIF normally but is defective in promoting extracellular fibronectin matrix assembly, the naturally occurring type 2C VHL mutant L188V.	(' VHL', 'Gene', '7428', (289, 293))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	(' VHL', 'Gene', (289, 293))	('promoting', 'PosReg', (205, 214))	('extracellular fibronectin matrix assembly', 'MPA', (215, 256))	('regulation', 'biological_process', 'GO:0065007', ('30', '40'))	(' VHL', 'Gene', '7428', (121, 125))	(' VHL', 'Gene', (121, 125))	('mutant', 'Var', (294, 300))	('ted ', 'Gene', '27112', (156, 160))	('1 ', 'Gene', '4790', (49, 51))	('extracellular', 'cellular_component', 'GO:0005576', ('215', '228'))	('VCAM-1', 'Gene', '7412', (44, 50))	('L188V', 'Mutation', 'rs5030824', (301, 306))	('ted ', 'Gene', (156, 160))	('RCC', 'Disease', (56, 59))	('mutant', 'Var', (107, 113))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('VCAM-1', 'Gene', (44, 50))
182544	28235946	Our results demonstrated that VCAM-1 mRNA and protein levels in VHL mutant L188V under normoxic or hypoxic conditions were significantly decreased to levels resembling those in VHL-negative cells (Fig.	('VCAM-1', 'Gene', '7412', (30, 36))	(' VHL', 'Gene', '7428', (63, 67))	('hypoxic conditions', 'Disease', 'MESH:D009135', (99, 117))	('ted ', 'Gene', (21, 25))	('hypoxic conditions', 'Disease', (99, 117))	('L188V', 'Mutation', 'rs5030824', (75, 80))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	(' VHL', 'Gene', '7428', (176, 180))	('ted ', 'Gene', '27112', (21, 25))	(' VHL', 'Gene', (63, 67))	(' VHL', 'Gene', (176, 180))	('VCAM-1', 'Gene', (30, 36))	('1 ', 'Gene', '4790', (35, 37))	('mutant L188V', 'Var', (68, 80))	('decreased', 'NegReg', (137, 146))	('VHL-', 'Gene', (177, 181))	('VHL-', 'Gene', '7428', (177, 181))
182545	28235946	Conversely, mRNA levels of a well known HIF target gene, glut-1, were similarly regulated in VHL and VHL mutant L188V (Fig.	(' VHL', 'Gene', '7428', (100, 104))	('mRNA levels', 'MPA', (12, 23))	('L188V', 'Mutation', 'rs5030824', (112, 117))	(' VHL', 'Gene', (100, 104))	('mutant L188V', 'Var', (105, 117))	('ted ', 'Gene', (86, 90))	('glut-1', 'Gene', (57, 63))	('ted ', 'Gene', '27112', (86, 90))	(' VHL', 'Gene', '7428', (92, 96))	(' VHL', 'Gene', (92, 96))
182552	28235946	Our results demonstrated that SM7368 treatment significantly decreased VCAM-1 mRNA and protein levels (Fig.	('ted ', 'Gene', (21, 25))	('VCAM-1', 'Gene', '7412', (71, 77))	('SM7368', 'Var', (30, 36))	('ted ', 'Gene', '27112', (21, 25))	('VCAM-1', 'Gene', (71, 77))	('SM7368', 'Chemical', 'MESH:C505226', (30, 36))	('decreased', 'NegReg', (61, 70))	('1 ', 'Gene', '4790', (76, 78))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
182564	28235946	Our results proved that interference of IKKalpha, NIK, or p52 in VHL-positive cells resulted in a significant decrease of VCAM-1 levels.	('IKKalpha', 'Var', (40, 48))	('VCAM-1', 'Gene', '7412', (122, 128))	('p52', 'Gene', (58, 61))	('p52', 'Gene', '4791', (58, 61))	('ted ', 'Gene', (89, 93))	('VHL-', 'Gene', (65, 69))	('VHL-', 'Gene', '7428', (65, 69))	('ted ', 'Gene', '27112', (89, 93))	('1 ', 'Gene', '4790', (127, 129))	('NIK', 'molecular_function', 'GO:0004704', ('50', '53'))	('decrease', 'NegReg', (110, 118))	(' VHL', 'Gene', '7428', (64, 68))	('VCAM-1', 'Gene', (122, 128))	('NIK', 'Var', (50, 53))	(' VHL', 'Gene', (64, 68))
182577	28235946	More importantly, monocytic cell adhesion to VHL-positive cells was also inhibited in the presence of anti-VCAM-1 receptor-blocking antibodies, like those blocking the alpha4 or beta1 subunits of the integrin alpha4beta1, whereas no effects were observed with an alphaL-blocking antibody as a control (Fig.	('antibodies', 'Var', (132, 142))	(' beta1 ', 'Gene', '10678', (177, 184))	('ted ', 'Gene', '27112', (79, 83))	('antibody', 'cellular_component', 'GO:0019814', ('279', '287'))	('1 ', 'Gene', '4790', (112, 114))	('cell adhesion', 'biological_process', 'GO:0007155', ('28', '41'))	('ted ', 'Gene', (79, 83))	('VCAM-1', 'Gene', '7412', (107, 113))	('antibody', 'molecular_function', 'GO:0003823', ('279', '287'))	('antibody', 'cellular_component', 'GO:0042571', ('279', '287'))	('beta1, whereas no', 'Gene', '10678', (215, 232))	(' beta1 ', 'Gene', (177, 184))	('1 ', 'Gene', '4790', (182, 184))	('monocytic cell adhesion', 'CPA', (18, 41))	('VCAM-1', 'Gene', (107, 113))	('VHL-', 'Gene', (45, 49))	('VHL-', 'Gene', '7428', (45, 49))	('antibody', 'cellular_component', 'GO:0019815', ('279', '287'))	(' VHL', 'Gene', '7428', (44, 48))	(' VHL', 'Gene', (44, 48))
182583	28235946	We observed that loss of VHL conferred a cell advantage against the cytotoxic effects of activated monocytic cells because it reduced ccRCC death (Fig.	(' VHL', 'Gene', '7428', (24, 28))	('ted ', 'Gene', (95, 99))	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	(' VHL', 'Gene', (24, 28))	('ted ', 'Gene', '27112', (95, 99))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))	('loss', 'Var', (17, 21))	('reduced', 'NegReg', (126, 133))
182586	28235946	We analyzed a cohort with a total of 127 tumor samples that were divided into two groups according to the type of VHL mutation.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('ide', 'Gene', '3416', (68, 71))	('mutation', 'Var', (118, 126))	(' VHL', 'Gene', '7428', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	(' VHL', 'Gene', (113, 117))	('ide', 'Gene', (68, 71))
182588	28235946	Our results indicated that VCAM-1 levels were higher in samples included in the group of VHL missense mutations compared with nonmissense mutations, although this difference did not reach statistical significance.	(' sta', 'Gene', (187, 191))	('1 ', 'Gene', '4790', (32, 34))	('VCAM-1', 'Gene', (27, 33))	('higher', 'PosReg', (46, 52))	('ted ', 'Gene', (18, 22))	(' sta', 'Gene', '2656', (187, 191))	('VCAM-1', 'Gene', '7412', (27, 33))	('ted ', 'Gene', '27112', (18, 22))	('missense mutations', 'Var', (93, 111))	(' VHL', 'Gene', '7428', (88, 92))	(' VHL', 'Gene', (88, 92))
182591	28235946	In addition, they also point to effects on the regulation of VCAM-1 that appear to be dependent on the type of VHL mutation.	('VCAM-1', 'Gene', '7412', (61, 67))	('regulation', 'biological_process', 'GO:0065007', ('47', '57'))	(' VHL', 'Gene', '7428', (110, 114))	('regulation', 'MPA', (47, 57))	(' VHL', 'Gene', (110, 114))	('effects', 'Reg', (32, 39))	('VCAM-1', 'Gene', (61, 67))	('1 ', 'Gene', '4790', (66, 68))	('mutation', 'Var', (115, 123))
182593	28235946	Remarkably, 50-80% of sporadic RCCs and the most frequent form with clear cell histological features (ccRCC) present inactivating mutations or epigenetic silencing of VHL.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('inactivating mutations', 'Var', (117, 139))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('epigenetic silencing', 'Var', (143, 163))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('VHL.', 'Gene', (167, 171))	(' VHL', 'Gene', '7428', (166, 170))	('VHL.', 'Gene', '7428', (167, 171))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))	(' VHL', 'Gene', (166, 170))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))	('RCC', 'Disease', (104, 107))
182594	28235946	Although the role of VHL in the regulation of HIF proves to be important for tumor growth, other VHL functions independent of HIF have been reported and help to explain why loss of VHL leads to renal cancer.	(' VHL', 'Gene', '7428', (96, 100))	(' VHL', 'Gene', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('leads to', 'Reg', (185, 193))	(' VHL', 'Gene', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	(' VHL', 'Gene', '7428', (180, 184))	('regulation', 'biological_process', 'GO:0065007', ('32', '42'))	('renal cancer', 'Disease', (194, 206))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ted ', 'Gene', (145, 149))	(' VHL', 'Gene', (180, 184))	('loss', 'Var', (173, 177))	('renal cancer', 'Phenotype', 'HP:0009726', (194, 206))	('tumor', 'Disease', (77, 82))	('ted ', 'Gene', '27112', (145, 149))	(' VHL', 'Gene', '7428', (20, 24))	('renal cancer', 'Disease', 'MESH:D007680', (194, 206))
182604	28235946	However, VHL expression abolishes the canonical NF-kappaB pathway and the induction of antiapoptotic genes in those cells.	('induction', 'MPA', (74, 83))	('antiapoptotic genes', 'Gene', (87, 106))	(' VHL', 'Gene', '7428', (8, 12))	('canonical NF-kappaB pathway', 'Pathway', (38, 65))	('expression', 'Var', (13, 23))	('abolishes', 'NegReg', (24, 33))	(' VHL', 'Gene', (8, 12))
182626	28235946	In agreement with these results, we have shown that VCAM-1 expression levels were decreased in a cohort of human ccRCC carrying VHL nonmissense mutations compared with those with missense mutations.	('1 ', 'Gene', '4790', (57, 59))	(' VHL', 'Gene', (127, 131))	('VCAM-1', 'Gene', (52, 58))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('human', 'Species', '9606', (107, 112))	('RCC', 'Disease', (115, 118))	('VCAM-1', 'Gene', '7412', (52, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (113, 118))	('mutations', 'Var', (144, 153))	(' VHL', 'Gene', '7428', (127, 131))	('decreased', 'NegReg', (82, 91))
182628	28235946	These results suggest the existence of differential effects on VCAM-1 regulation and functions that might depend on the type of mutation affecting VHL.	('VCAM-1', 'Gene', (63, 69))	(' VHL', 'Gene', '7428', (146, 150))	('regulation', 'biological_process', 'GO:0065007', ('70', '80'))	('effects', 'Reg', (52, 59))	('1 ', 'Gene', '4790', (68, 70))	('VHL.', 'Gene', '7428', (147, 151))	('VHL.', 'Gene', (147, 151))	('VCAM-1', 'Gene', '7412', (63, 69))	(' VHL', 'Gene', (146, 150))	('mutation', 'Var', (128, 136))	('functions', 'MPA', (85, 94))
182629	28235946	This is also supported by our in vitro results in which we observed that TNF-mediated regulation of VCAM-1 levels was differentially affected in various VHL mutants (Fig.	('ted ', 'Gene', '27112', (19, 23))	('ted ', 'Gene', '27112', (82, 86))	('VCAM-1', 'Gene', (100, 106))	('1 ', 'Gene', '4790', (105, 107))	('ted ', 'Gene', (138, 142))	('VCAM-1', 'Gene', '7412', (100, 106))	(' VHL', 'Gene', '7428', (152, 156))	('regulation', 'biological_process', 'GO:0065007', ('86', '96'))	('ted ', 'Gene', '27112', (138, 142))	(' VHL', 'Gene', (152, 156))	('ted ', 'Gene', (19, 23))	('ted ', 'Gene', (82, 86))	('mutants', 'Var', (157, 164))
182638	28235946	Additionally, we used 786-O expressing the naturally occurring type 2C VHL mutant L188V or a nonneddylateable version of VHL termed RRR (in which lysines 159 [K159], K171, and K196, have been substituted by an arginine [R], with K159 being an essential residue for neddylation).	('L188V', 'Mutation', 'rs5030824', (82, 87))	(' VHL', 'Gene', (120, 124))	('lysines', 'Chemical', 'MESH:D008239', (146, 153))	(' VHL', 'Gene', '7428', (120, 124))	('L188V', 'Var', (82, 87))	(' VHL', 'Gene', '7428', (70, 74))	('K196', 'Var', (176, 180))	('arginine', 'Chemical', 'MESH:D001120', (210, 218))	('K171', 'Var', (166, 170))	('ted ', 'Gene', (200, 204))	(' VHL', 'Gene', (70, 74))	('lysines', 'Var', (146, 153))	('K159', 'Chemical', '-', (159, 163))	('K159', 'Chemical', '-', (229, 233))	('ted ', 'Gene', '27112', (200, 204))	('mutant L188V', 'Var', (75, 87))
182639	28235946	As a control for this mutant, we used 786-O cells transfected with another version of VHL (KRR) that carries mutations only at Lys171 and Lys196 (which do not interfere with the normal VHL function).	('Lys171', 'Chemical', '-', (127, 133))	(' VHL', 'Gene', (85, 89))	('1 ', 'Gene', '4790', (132, 134))	(' VHL', 'Gene', '7428', (184, 188))	('ted ', 'Gene', '27112', (58, 62))	('ted ', 'Gene', (58, 62))	(' VHL', 'Gene', (184, 188))	(' VHL', 'Gene', '7428', (85, 89))	('Lys196', 'Chemical', '-', (138, 144))	('Lys196', 'Var', (138, 144))
182651	28235946	Monoclonal anti-HIF-1alpha antibody (241809; mab1536) was from R&D Systems.	('HIF-1alpha', 'Disease', 'None', (16, 26))	('antibody', 'cellular_component', 'GO:0042571', ('27', '35'))	('HIF-1alpha', 'Disease', (16, 26))	('241809;', 'Var', (37, 44))	('antibody', 'cellular_component', 'GO:0019815', ('27', '35'))	('antibody', 'cellular_component', 'GO:0019814', ('27', '35'))	('antibody', 'molecular_function', 'GO:0003823', ('27', '35'))
182653	28235946	HRP-conjugated secondary polyclonal (NA9340V; GE Healthcare) or monoclonal (P0260; Dako) antibodies were used.	('NA9340V', 'Var', (37, 44))	('ted ', 'Gene', '27112', (11, 15))	('ted ', 'Gene', (11, 15))	('NA9340V', 'Chemical', '-', (37, 44))
182676	28235946	Cells were transfected with Lipofectamine 2000 (11668019; Invitrogen), according to the manufacturer's instructions.	('11668019;', 'Var', (48, 57))	('ted ', 'Gene', '27112', (19, 23))	('ted ', 'Gene', (19, 23))
182689	28235946	S3 shows the effect of VHL loss, hypoxia, and NF-kappaB inhibitors on VCAM-1 levels in HUVECs.	('NF-kappaB', 'Gene', (46, 55))	('1 ', 'Gene', '4790', (75, 77))	('hypoxia', 'Disease', (33, 40))	('hypoxia', 'Disease', 'MESH:D000860', (33, 40))	('VCAM-1', 'Gene', (70, 76))	('VCAM-1', 'Gene', '7412', (70, 76))	('inhibitors', 'Var', (56, 66))	(' VHL', 'Gene', '7428', (22, 26))	('VHL loss', 'Disease', 'MESH:D006623', (23, 31))	('VHL loss', 'Disease', (23, 31))	(' VHL', 'Gene', (22, 26))
182690	28235946	S4 shows analysis of VCAM-1 levels in VHL mutants.	(' VHL', 'Gene', (37, 41))	('mutants', 'Var', (42, 49))	('VCAM-1', 'Gene', (21, 27))	('1 ', 'Gene', '4790', (26, 28))	('s an', 'Gene', (7, 11))	('s an', 'Gene', '80218', (7, 11))	('VCAM-1', 'Gene', '7412', (21, 27))	(' VHL', 'Gene', '7428', (37, 41))
182691	30532596	Identification and validation of a four-miRNA (miRNA-21-5p, miRNA-9-5p, miR-149-5p, and miRNA-30b-5p) prognosis signature in clear cell renal cell carcinoma Clear cell renal cell carcinoma (ccRCC) is one of the most common cancers with high mortality worldwide.	('miR-149', 'Gene', (72, 79))	('miRNA-30b-5p', 'Var', (88, 100))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (125, 156))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('miRNA-21', 'Gene', '406991', (47, 55))	('miR-149', 'Gene', '406941', (72, 79))	('RCC', 'Disease', (192, 195))	('RCC', 'Phenotype', 'HP:0005584', (192, 195))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('miRNA-21', 'Gene', (47, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (190, 195))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (157, 188))	('cancers', 'Disease', (223, 230))	('clear cell renal cell carcinoma', 'Disease', (125, 156))	('Clear cell renal cell carcinoma', 'Disease', (157, 188))	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (136, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (168, 188))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (125, 156))	('cancers', 'Disease', 'MESH:D009369', (223, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
182713	30532596	Currently, abnormally expressed miRNAs have been detected in many human tumors, such as bladder cancer, lung cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, and other malignancies.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('malignancies', 'Disease', (193, 205))	('pancreatic cancer', 'Disease', 'MESH:D010190', (134, 151))	('bladder cancer', 'Disease', 'MESH:D001749', (88, 102))	('bladder cancer', 'Disease', (88, 102))	('gastric cancer', 'Disease', 'MESH:D013274', (153, 167))	('human', 'Species', '9606', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', (72, 78))	('bladder cancer', 'Phenotype', 'HP:0009725', (88, 102))	('abnormally', 'Var', (11, 21))	('pancreatic cancer', 'Disease', (134, 151))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('gastric cancer', 'Phenotype', 'HP:0012126', (153, 167))	('liver cancer', 'Disease', 'MESH:D006528', (169, 181))	('miR', 'Gene', '220972', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('detected', 'Reg', (49, 57))	('prostate cancer', 'Disease', 'MESH:D011471', (117, 132))	('prostate cancer', 'Phenotype', 'HP:0012125', (117, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (134, 151))	('liver cancer', 'Phenotype', 'HP:0002896', (169, 181))	('prostate cancer', 'Disease', (117, 132))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('liver cancer', 'Disease', (169, 181))	('miR', 'Gene', (32, 35))	('gastric cancer', 'Disease', (153, 167))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', (104, 115))	('malignancies', 'Disease', 'MESH:D009369', (193, 205))
182764	30532596	Previous studies have shown that some specific miRNAs were aberrantly expressed in RCC and participate in its development.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('aberrantly', 'Var', (59, 69))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('development', 'MPA', (110, 121))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('participate', 'Reg', (91, 102))
182787	30532596	Thus, abnormal regulation of signaling pathways may play a crucial role in the pathogenesis and progression of ccRCC.	('pathogenesis', 'biological_process', 'GO:0009405', ('79', '91'))	('abnormal', 'Var', (6, 14))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('signaling pathways', 'Pathway', (29, 47))	('regulation of signaling', 'biological_process', 'GO:0023051', ('15', '38'))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('play', 'Reg', (52, 56))
182826	29963177	Commonly accepted BMI ranges in Chinese people are normal weight (18.5-23.9 kg/m2), overweight (24-27.9 kg/m2) and obesity (over 28 kg/m2).	('over 28', 'Var', (124, 131))	('obesity', 'Disease', (115, 122))	('overweight', 'Disease', (84, 94))	('obesity', 'Phenotype', 'HP:0001513', (115, 122))	('people', 'Species', '9606', (40, 46))	('24-27.9', 'Var', (96, 103))	('obesity', 'Disease', 'MESH:D009765', (115, 122))	('overweight', 'Phenotype', 'HP:0025502', (84, 94))
182832	29963177	The immunohistochemistry results (CK7, C10, AMACR, CA IX and RCC maker) were interpreted as negative, weak (<30% staining), moderate (30-70% staining) and strong (>70% staining).	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('CK7', 'Gene', '3855', (34, 37))	('30-70', 'Var', (134, 139))	('AMACR', 'Gene', '23600', (44, 49))	('AMACR', 'Gene', (44, 49))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('CK7', 'Gene', (34, 37))	('C10', 'Gene', (39, 42))	('CA IX', 'Gene', '768', (51, 56))	('C10', 'Gene', '3226', (39, 42))	('CA IX', 'Gene', (51, 56))
182878	29963177	2I, 3B and D. According to the results of Ki67 LI, the expression of Ki67 in CCPRCC was much lower than that in CCRCC (2.19 vs. 7.07%, P<0.001; Fig.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('PRCC', 'Gene', '5546', (79, 83))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('CCRCC', 'Phenotype', 'HP:0006770', (112, 117))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('expression', 'MPA', (55, 65))	('Ki67', 'Var', (69, 73))	('lower', 'NegReg', (93, 98))	('PRCC', 'Gene', (79, 83))	('CCPRCC', 'Phenotype', 'HP:0006770', (77, 83))	('PRCC', 'Phenotype', 'HP:0006766', (79, 83))
182880	29963177	However, although the expression of Ki67 in CCRCC was still higher than that in PRCC (7.07 vs. 6.65%, P=0.848; Fig.	('CCRCC', 'Phenotype', 'HP:0006770', (44, 49))	('RCC', 'Disease', (46, 49))	('higher', 'PosReg', (60, 66))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('PRCC', 'Gene', '5546', (80, 84))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('PRCC', 'Gene', (80, 84))	('Ki67', 'Var', (36, 40))	('PRCC', 'Phenotype', 'HP:0006766', (80, 84))	('expression', 'MPA', (22, 32))
182922	29963177	Coincidentally, previous studies have documented that most of CCRCC have VHL gene mutations, which can also lead to overexpression of HIF pathway associated proteins, whereas CCPRCC lack these characteristic chromosomal abnormalities.	('VHL', 'Gene', '7428', (73, 76))	('overexpression', 'PosReg', (116, 130))	('CCRCC', 'Phenotype', 'HP:0006770', (62, 67))	('lead to', 'Reg', (108, 115))	('RCC', 'Disease', (178, 181))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('PRCC', 'Gene', '5546', (177, 181))	('HIF pathway', 'Pathway', (134, 145))	('chromosomal abnormalities', 'Disease', (208, 233))	('men', 'Species', '9606', (42, 45))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', (64, 67))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (208, 233))	('PRCC', 'Gene', (177, 181))	('VHL', 'Gene', (73, 76))	('PRCC', 'Phenotype', 'HP:0006766', (177, 181))	('mutations', 'Var', (82, 91))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('proteins', 'Protein', (157, 165))	('CCPRCC', 'Phenotype', 'HP:0006770', (175, 181))
182939	29963177	Many studies have indicated that Ki67 is a prognostic marker in several neoplasms, including kidney cancer.	('kidney cancer', 'Disease', 'MESH:D007680', (93, 106))	('neoplasms', 'Disease', 'MESH:D009369', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('neoplasms', 'Disease', (72, 81))	('kidney cancer', 'Phenotype', 'HP:0009726', (93, 106))	('neoplasm', 'Phenotype', 'HP:0002664', (72, 80))	('kidney cancer', 'Disease', (93, 106))	('neoplasms', 'Phenotype', 'HP:0002664', (72, 81))	('Ki67', 'Var', (33, 37))
182940	29963177	In this study, the Ki67 LI is significantly lower than that in CCRCC (P<0.001) or that in PRCC (P<0.001).	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('lower', 'NegReg', (44, 49))	('PRCC', 'Phenotype', 'HP:0006766', (90, 94))	('CCRCC', 'Phenotype', 'HP:0006770', (63, 68))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))	('PRCC', 'Gene', '5546', (90, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('Ki67 LI', 'Var', (19, 26))	('PRCC', 'Gene', (90, 94))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
182995	31747386	We further revealed the differential landscape of somatic tumor mutation burden (TMB) between two nomogram-score groups and observed that TMB was also a prognostic biomarker; patients with high MAGs-nomogram scores suffered from a higher TMB, potentially leading to worse prognosis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('TMB', 'MPA', (238, 241))	('higher', 'PosReg', (231, 237))	('MAGs', 'Chemical', '-', (194, 198))	('TMB', 'Chemical', '-', (138, 141))	('high', 'Var', (189, 193))	('TMB', 'Chemical', '-', (238, 241))	('patients', 'Species', '9606', (175, 183))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('TMB', 'Chemical', '-', (81, 84))
183011	31747386	successfully utilized single-cell exome sequencing and found that KCP, LOC440040, and LOC440563 mutations are novel renal cancer stem cell drivers.	('KCP', 'Gene', '375616', (66, 69))	('renal cancer', 'Phenotype', 'HP:0009726', (116, 128))	('cancer', 'Disease', (122, 128))	('LOC440040', 'Gene', (71, 80))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('LOC440563 mutations', 'Var', (86, 105))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('LOC440040', 'Gene', '440040', (71, 80))	('KCP', 'Gene', (66, 69))
183024	31747386	In addition, Kaplan-Meier analysis indicated that patients with high MAG scores suffered significantly worse OS outcomes (P = 2.904e-08), which was validated consistently in the testing cohort with P = 1.031e-10.	('MAG scores', 'Gene', (69, 79))	('high', 'Var', (64, 68))	('MAG', 'Chemical', '-', (69, 72))	('patients', 'Species', '9606', (50, 58))	('worse', 'NegReg', (103, 108))
183025	31747386	Overall, we further integrated the MAG signature with survival analysis in the total TCGA-KIRC cohort, and distribution plots suggested that high MAG risk scores correlated with more cases of death or recurrence/ progression (Figure 3G, 3H and 3I).	('MAG', 'Chemical', '-', (35, 38))	('death', 'Disease', 'MESH:D003643', (192, 197))	('death', 'Disease', (192, 197))	('MAG', 'Chemical', '-', (146, 149))	('recurrence/', 'CPA', (201, 212))	('high', 'Var', (141, 145))	('MAG', 'Gene', (146, 149))
183028	31747386	Moreover, the MAG signature possessed superior significance in predicting 5-year PFS with an AUC of 0.752 in the total TCGA-KIRC cohort (Figure 4F), and patients with high MAG scores were proven to have greater hazards regarding tumor recurrence or progression with a log-rank test P = 0 (Figure 4G).	('progression', 'CPA', (249, 260))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('MAG', 'Chemical', '-', (172, 175))	('patients', 'Species', '9606', (153, 161))	('MAG', 'Chemical', '-', (14, 17))	('high', 'Var', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('PFS', 'Disease', (81, 84))	('tumor', 'Disease', (229, 234))
183037	31747386	In addition, we calculated the differential mutation rate of mutants distributed in more than 5% of the samples, and the chi-square test revealed that SETD2, BAP1 and MTOR especially harbored more mutants in the high-risk group than in the low-risk group (Figure 6A).	('BAP1', 'Gene', '8314', (158, 162))	('BAP1', 'Gene', (158, 162))	('mutants', 'Var', (197, 204))	('MTOR', 'Gene', (167, 171))	('SETD2', 'Gene', '29072', (151, 156))	('harbored', 'Reg', (183, 191))	('MTOR', 'Gene', '2475', (167, 171))	('SETD2', 'Gene', (151, 156))
183038	31747386	Additionally, the Wilcoxon rank-sum test suggested that the MAG nomogram risk scores were significantly higher in the high TMB group than in the low TMB group (P = 2.875e-05).	('high', 'Var', (118, 122))	('TMB', 'Chemical', '-', (149, 152))	('MAG', 'Chemical', '-', (60, 63))	('MAG nomogram', 'Gene', (60, 72))	('higher', 'PosReg', (104, 110))	('TMB', 'Chemical', '-', (123, 126))
183040	31747386	We accordingly speculated that ccRCC patients with high MAG nomogram scores suffered from higher TMB levels which was also proven to be a risk factor in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (153, 158))	('RCC', 'Disease', (155, 158))	('patients', 'Species', '9606', (37, 45))	('MAG', 'Chemical', '-', (56, 59))	('TMB', 'Chemical', '-', (97, 100))	('RCC', 'Disease', (33, 36))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('high', 'Var', (51, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (31, 36))	('TMB levels', 'MPA', (97, 107))	('higher', 'PosReg', (90, 96))	('RCC', 'Disease', 'MESH:C538614', (155, 158))
183042	31747386	We observed that oxidative phosphorylation, the Wnt signaling pathway, the MAPK signaling pathway and renal cell carcinoma crosstalk were upregulated in the high-risk group.	('signaling pathway', 'biological_process', 'GO:0007165', ('80', '97'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('75', '89'))	('MAPK', 'molecular_function', 'GO:0004707', ('75', '79'))	('upregulated', 'PosReg', (138, 149))	('oxidative phosphorylation', 'MPA', (17, 42))	('Wnt signaling pathway', 'Pathway', (48, 69))	('MAPK signaling pathway', 'Pathway', (75, 97))	('high-risk', 'Var', (157, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (102, 122))	('renal cell carcinoma crosstalk', 'Disease', (102, 132))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('48', '69'))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('17', '42'))	('renal cell carcinoma crosstalk', 'Disease', 'MESH:C538614', (102, 132))
183058	31747386	performed genome-wide association studies and identified the RCC risk allele at 12p12.1, a hazard variant in an enhancer that upregulates the expression of BHLHE41, in turn inducing IL-11 to promote tumor growth.	('tumor', 'Disease', (199, 204))	('BHLHE41', 'Gene', '79365', (156, 163))	('IL-11', 'Gene', (182, 187))	('variant', 'Var', (98, 105))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('inducing', 'PosReg', (173, 181))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('IL-11', 'Gene', '3589', (182, 187))	('RCC', 'Disease', (61, 64))	('expression', 'MPA', (142, 152))	('BHLHE41', 'Gene', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('upregulates', 'PosReg', (126, 137))	('promote', 'PosReg', (191, 198))	('IL-11', 'molecular_function', 'GO:0005142', ('182', '187'))
183064	31747386	For population validation, we utilized another ICGC cohort as the external data set to further test our MAG signature and found the clinical value of MAGs in predicting OS or PFS.	('MAG', 'Chemical', '-', (104, 107))	('MAGs', 'Chemical', '-', (150, 154))	('MAGs', 'Var', (150, 154))	('MAG', 'Chemical', '-', (150, 153))	('PFS', 'Disease', (175, 178))
183068	31747386	We accordingly speculated that the four tumor-driver mutants might promote the progression of ccRCC and that a high TMB was also proven to be a potential risk factor associated with MAGs.	('RCC', 'Disease', (96, 99))	('TMB', 'Chemical', '-', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mutants', 'Var', (53, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('MAGs', 'Chemical', '-', (182, 186))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('promote', 'PosReg', (67, 74))
183069	31747386	TMB or mutational signatures revealed the process of mutation accumulation in tumors and were demonstrated to be effective predictors of the response to immunotherapy.	('revealed', 'Reg', (29, 37))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('mutation', 'Var', (53, 61))	('TMB', 'Chemical', '-', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))
183095	31747386	We wrote a Perl script to extract all mutation data from 337 patients in the TCGA-KIRC cohort consisting of deletions, insertions, and substitutions across bases and divided the data into two groups according to the MAG nomogram risk scores.	('insertions', 'Var', (119, 129))	('MAG', 'Chemical', '-', (216, 219))	('substitutions', 'Var', (135, 148))	('patients', 'Species', '9606', (61, 69))	('deletions', 'Var', (108, 117))
183103	29617669	Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes.	('DNA', 'cellular_component', 'GO:0005574', ('163', '166'))	('altered', 'Reg', (48, 55))	('metabolic pathways', 'Pathway', (56, 74))	('survival', 'MPA', (118, 126))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('163', '183'))	('gene expression', 'biological_process', 'GO:0010467', ('225', '240'))	('CDKN2A', 'Gene', (134, 140))	('increased', 'PosReg', (153, 162))	('PBRM1', 'Gene', '55193', (28, 33))	('survival', 'MPA', (277, 285))	('decreased', 'NegReg', (267, 276))	('DNA', 'MPA', (163, 166))	('BAP1', 'Gene', (22, 26))	('alteration', 'Var', (8, 18))	('increases', 'PosReg', (189, 198))	('PBRM1', 'Gene', (28, 33))	('decreased', 'NegReg', (108, 117))	('PTEN', 'Gene', (39, 43))	('alteration', 'Var', (141, 151))
183105	29617669	Somatic alteration of BAP1, PBRM1, and metabolic pathways correlates with subtype-specific decreased survival, while CDKN2A alteration, DNA hypermethylation, and Th2 immune signature correlate with decreased survival within all subtypes.	('alteration', 'Var', (8, 18))	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('CDKN2A', 'Gene', (117, 123))	('survival', 'MPA', (101, 109))	('PBRM1', 'Gene', (28, 33))	('hypermethylation', 'Var', (140, 156))	('metabolic pathways', 'Pathway', (39, 57))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('136', '156'))	('PBRM1', 'Gene', '55193', (28, 33))	('alteration', 'Var', (124, 134))	('decreased', 'NegReg', (198, 207))	('decreased', 'NegReg', (91, 100))	('BAP1', 'Gene', (22, 26))
183120	29617669	Similarly, PBRM1 mutation, which has been shown to not correlate with survival in ccRCC, was found to correlate with decreased survival in PRCC (p = 0.0008) that was specific to type 1 PRCC (p < 0.0001) (Figures 2A and S2B).	('PRCC', 'Disease', (139, 143))	('decreased', 'NegReg', (117, 126))	('mutation', 'Var', (17, 25))	('PBRM1', 'Gene', (11, 16))	('PBRM1', 'Gene', '55193', (11, 16))	('survival', 'MPA', (127, 135))
183121	29617669	CDKN2A mutation, hypermethylation, or deletion was found in 15.8% of tumors, with alterations in each RCC subtype accounting for 16.2% of ccRCC, 5.0% of type 1 PRCC, 18.6% of type 2 PRCC, 100% of CIMP-PRCC, and 19.8% of ChRCC (Figure 2B).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('type 2 PRCC', 'Disease', (175, 186))	('CIMP-PRCC', 'Disease', (196, 205))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('ccRCC', 'Disease', (138, 143))	('CIMP', 'Chemical', '-', (196, 200))	('tumors', 'Disease', (69, 75))	('mutation', 'Var', (7, 15))	('deletion', 'Var', (38, 46))	('CDKN2A', 'Gene', (0, 6))	('alterations', 'Var', (82, 93))	('hypermethylation', 'Var', (17, 33))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('ChRCC', 'Disease', (220, 225))	('found', 'Reg', (51, 56))
183123	29617669	Pathogenic SMG mutations were not detected in several tumors, particularly PRCC and ChRCC.	('ChRCC', 'Disease', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('mutations', 'Var', (15, 24))	('PRCC', 'Disease', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('SMG', 'Gene', (11, 14))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
183124	29617669	In the VHL/HIF pathway, TCEB1 and CUL2 mutations in ccRCC were mutually exclusive with VHL mutation (Figure S2D).	('CUL2', 'Gene', '8453', (34, 38))	('ccRCC', 'Gene', (52, 57))	('VHL', 'Disease', 'MESH:D006623', (7, 10))	('TCEB1', 'Gene', (24, 29))	('VHL', 'Disease', (7, 10))	('mutations', 'Var', (39, 48))	('VHL', 'Disease', 'MESH:D006623', (87, 90))	('VHL', 'Disease', (87, 90))	('CUL2', 'Gene', (34, 38))
183125	29617669	Mutations of SWI/SNF complex genes, including PBRM1, ARID1A, and SMARCA4, were the most common chromatin remodeling complex alterations within ccRCC (47.1%), followed by mutation of the histone methyltransferases including SETD2 and MLL3 (23.8%), the histone demethylases including KDM5C (13.0%), the BAP1/ASXL1 histone de-ubiquitinase complex (12.1%), and the histone acetyltransferases (4.8%), compared with frequencies of 24.1%, 23.7%, 17.3%, 6.8%, and 7.5%, respectively, in PRCCs (Figure 2D).	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('13', '28'))	('MLL3', 'Gene', '58508', (233, 237))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('95', '123'))	('ASXL1', 'Gene', (306, 311))	('alterations', 'Var', (124, 135))	('SMARCA4', 'Gene', (65, 72))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('95', '115'))	('Mutations', 'Var', (0, 9))	('MLL3', 'Gene', (233, 237))	('SWI/SNF complex genes', 'Gene', (13, 34))	('PBRM1', 'Gene', (46, 51))	('SETD2', 'Gene', '29072', (223, 228))	('SETD2', 'Gene', (223, 228))	('ASXL1', 'Gene', '171023', (306, 311))	('PBRM1', 'Gene', '55193', (46, 51))	('mutation', 'Var', (170, 178))
183131	29617669	Increased hypermethylation was associated with higher-stage disease in ccRCC, PRCC (with or without CIMP), and ChRCC (all p < 0.0001) and was associated with SETD2 mutation in ccRCC (p < 0.0001), either PBRM1 mutation or SETD2 mutation in type 2 PRCC (p = 0.0053, p = 0.0270, respectively), and TP53 mutation in ChRCC (p = 0.0119) (Figure S3B).	('higher-stage disease', 'Disease', (47, 67))	('mutation', 'Var', (164, 172))	('mutation', 'Var', (227, 235))	('CIMP', 'Chemical', '-', (100, 104))	('ccRCC', 'Disease', (71, 76))	('associated', 'Reg', (31, 41))	('mutation', 'Var', (209, 217))	('associated', 'Reg', (142, 152))	('SETD2', 'Gene', (221, 226))	('Increased', 'PosReg', (0, 9))	('PBRM1', 'Gene', '55193', (203, 208))	('hypermethylation', 'MPA', (10, 26))	('SETD2', 'Gene', (158, 163))	('SETD2', 'Gene', '29072', (221, 226))	('TP53', 'Gene', (295, 299))	('PRCC', 'Disease', (78, 82))	('SETD2', 'Gene', '29072', (158, 163))	('PBRM1', 'Gene', (203, 208))	('mutation', 'Var', (300, 308))
183132	29617669	Previous studies have identified hypermethylation of the WNT pathway regulatory genes, SFRP1 and DKK1, in ccRCC.	('SFRP1', 'Gene', (87, 92))	('ccRCC', 'Disease', (106, 111))	('hypermethylation', 'Var', (33, 49))	('DKK1', 'Gene', '22943', (97, 101))	('DKK1', 'Gene', (97, 101))
183133	29617669	Increased methylation of probes for these two genes (DKK1, cg07684796; SFRP1, cg15839448) was observed in the methylated cluster 1 samples (Figure S3C), and hypermethylation of either of these genes correlated with poorer survival in ccRCC, PRCC, and ChRCC (p = 0.0015, p < 0.0001, and p = 0.0021, respectively) and in PRCC excluding the CIMP-RCC tumors (p = 0.0035) (Figures 3C and S3D).	('PRCC', 'Disease', (241, 245))	('DKK1', 'Gene', (53, 57))	('DKK1', 'Gene', '22943', (53, 57))	('methylation', 'MPA', (10, 21))	('cg07684796', 'Chemical', '-', (59, 69))	('CIMP-RCC tumors', 'Disease', 'MESH:C538614', (338, 353))	('tumors', 'Phenotype', 'HP:0002664', (347, 353))	('cg15839448', 'Chemical', '-', (78, 88))	('CIMP-RCC tumors', 'Disease', (338, 353))	('survival', 'MPA', (222, 230))	('Increased', 'PosReg', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('ccRCC', 'Disease', (234, 239))	('ChRCC', 'Disease', (251, 256))	('hypermethylation', 'Var', (157, 173))	('methylation', 'biological_process', 'GO:0032259', ('10', '21'))	('poorer', 'NegReg', (215, 221))
183149	29617669	In the present study, comprehensive genetic and genomic analysis demonstrated that different histologically defined RCC subtypes are characterized by distinctive mutations, chromosomal copy number alterations, and expression patterns of mRNA, miRNA, and lncRNA, and that the combination of histology plus genomics provides unique insight into patient-centered management.	('mutations', 'Var', (162, 171))	('patient', 'Species', '9606', (343, 350))	('miRNA', 'MPA', (243, 248))	('lncRNA', 'Protein', (254, 260))	('alterations', 'Var', (197, 208))	('RCC', 'Disease', (116, 119))	('expression', 'MPA', (214, 224))	('mRNA', 'MPA', (237, 241))
183151	29617669	Loss of CDKN2A is known to correlate with poor outcome in ccRCC, PRCC, and other cancer types, but this demonstrates that it is a universal feature of RCC and is potentially targetable with CDK4/6 inhibitors that target the downstream effects of p16 loss.	('CDKN2A', 'Gene', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('ccRCC', 'Disease', (58, 63))	('CDK', 'molecular_function', 'GO:0004693', ('190', '193'))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('Loss', 'Var', (0, 4))
183152	29617669	This study highlighted hypermethylation of WNT pathway regulatory genes and demonstrated that analysis of hypermethylation in two specific WNT regulatory genes, SFRP1 and DKK1, recapitulated the correlation with decreased survival in ccRCC, PRCC, and ChRCC.	('PRCC', 'Disease', (241, 245))	('decreased', 'NegReg', (212, 221))	('SFRP1', 'Gene', (161, 166))	('DKK1', 'Gene', '22943', (171, 175))	('DKK1', 'Gene', (171, 175))	('ccRCC', 'Disease', (234, 239))	('ChRCC', 'Disease', (251, 256))	('hypermethylation', 'Var', (23, 39))	('hypermethylation', 'Var', (106, 122))
183153	29617669	Increased DNA methylation was associated with SETD2 mutation, which is known to alter DNA methylation patterns, in ccRCC and PRCC, and increased DNA methylation was similarly associated with PBRM1 mutation in PRCC.	('SETD2', 'Gene', (46, 51))	('PBRM1', 'Gene', (191, 196))	('PBRM1', 'Gene', '55193', (191, 196))	('DNA', 'cellular_component', 'GO:0005574', ('145', '148'))	('DNA methylation', 'biological_process', 'GO:0006306', ('10', '25'))	('SETD2', 'Gene', '29072', (46, 51))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('Increased', 'PosReg', (0, 9))	('DNA methylation', 'MPA', (10, 25))	('mutation', 'Var', (52, 60))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('DNA methylation', 'biological_process', 'GO:0006306', ('86', '101'))	('alter', 'Reg', (80, 85))	('DNA methylation', 'biological_process', 'GO:0006306', ('145', '160'))	('ccRCC', 'Disease', (115, 120))
183154	29617669	Hypermethylation of SFRP1 and DKK1 could provide a prognostic biomarker for RCC and has been previously proposed in ccRCC.	('RCC', 'Disease', (76, 79))	('SFRP1', 'Gene', (20, 25))	('Hypermethylation', 'Var', (0, 16))	('ccRCC', 'Disease', (116, 121))	('DKK1', 'Gene', (30, 34))	('DKK1', 'Gene', '22943', (30, 34))
183156	29617669	Previous studies using TCGA data and other cohorts have shown that BAP1 mutation, but not PBRM1 mutation, correlates with poor survival in ccRCC and these correlations were confirmed in a mixed cohort of ccRCC and PRCC TCGA tumors.	('ccRCC', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('poor', 'NegReg', (122, 126))	('mutation', 'Var', (72, 80))	('PBRM1', 'Gene', (90, 95))	('ccRCC', 'Disease', (204, 209))	('PBRM1', 'Gene', '55193', (90, 95))	('BAP1', 'Gene', (67, 71))
183157	29617669	By analysis of the histologic subtype of RCC, we confirmed these correlations in ccRCC and showed that while BAP1 mutations did not correlate with survival in PRCC, PBRM1 mutations did associate with poor survival in type 1 PRCC.	('poor', 'NegReg', (200, 204))	('mutations', 'Var', (114, 123))	('ccRCC', 'Disease', (81, 86))	('PBRM1', 'Gene', (165, 170))	('type 1 PRCC', 'Disease', (217, 228))	('PBRM1', 'Gene', '55193', (165, 170))	('mutations', 'Var', (171, 180))	('BAP1', 'Gene', (109, 113))
183163	29617669	While we observed the same general pattern as previously seen with PRCC overall demonstrating little expression of the immune signature associated with ccRCC, we found CIMP-RCC to have an increased immune signature expression for select immune gene signatures, including the Th2 gene signature, like that seen in ccRCC.	('CIMP', 'Chemical', '-', (168, 172))	('increased', 'PosReg', (188, 197))	('Th2 gene', 'Gene', (275, 283))	('ccRCC', 'Disease', (152, 157))	('immune signature expression', 'MPA', (198, 225))	('CIMP-RCC', 'Var', (168, 176))	('immune gene signatures', 'MPA', (237, 259))
183167	29617669	The MD-ChRCC had decreased Krebs cycle, ETC, and AMPK gene expression and increased ribose metabolism gene expression similar to higher-stage ccRCCs.	('gene expression', 'biological_process', 'GO:0010467', ('102', '117'))	('MD-ChRCC', 'Var', (4, 12))	('AMPK', 'MPA', (49, 53))	('decreased', 'NegReg', (17, 26))	('AMPK', 'molecular_function', 'GO:0047322', ('49', '53'))	('ribose metabolism gene expression', 'MPA', (84, 117))	('Krebs cycle', 'MPA', (27, 38))	('increased', 'PosReg', (74, 83))	('Krebs', 'Chemical', '-', (27, 32))	('Krebs cycle', 'biological_process', 'GO:0006099', ('27', '38'))	('AMPK', 'molecular_function', 'GO:0004691', ('49', '53'))	('metabolism', 'biological_process', 'GO:0008152', ('91', '101'))	('gene expression', 'biological_process', 'GO:0010467', ('54', '69'))	('ETC', 'MPA', (40, 43))	('ribose', 'Chemical', 'MESH:D012266', (84, 90))	('AMPK', 'molecular_function', 'GO:0050405', ('49', '53'))
183201	29617669	Unsupervised clustering was performed based on cancer-specific autosomal loci, which were defined as unmethylated probes in all normal tissue types as well as sorted blood populations (mean beta value < 0.2), but methylated (beta value > 0.3) in more than 5% samples within any of the kidney tumor type (for tumor type with less than 100 samples, we require the portion of methylated samples to be greater than 10% instead).	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('methylated', 'Var', (213, 223))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('kidney tumor', 'Disease', (285, 297))	('tumor', 'Disease', (292, 297))	('cancer', 'Disease', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('kidney tumor', 'Disease', 'MESH:D007674', (285, 297))	('tumor', 'Disease', (308, 313))	('kidney tumor', 'Phenotype', 'HP:0009726', (285, 297))	('tumor', 'Disease', 'MESH:D009369', (292, 297))
183203	29617669	The DNA methylation level as interrogated by cg07684796, cg15839448 was used for DKK1, and SFRP1, respectively, with a beta value of 0.3 or more considered evidence for epigenetic silencing.	('DNA methylation level', 'MPA', (4, 25))	('cg07684796', 'Var', (45, 55))	('cg15839448', 'Chemical', '-', (57, 67))	('cg07684796', 'Chemical', '-', (45, 55))	('DKK1', 'Gene', (81, 85))	('DKK1', 'Gene', '22943', (81, 85))	('DNA methylation', 'biological_process', 'GO:0006306', ('4', '19'))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))	('cg15839448', 'Var', (57, 67))
183205	29617669	BAM files were used as input of the MToolBox pipeline, that includes GSNAP, MUSCLE, and SAMtools, to align reads to the Revised Cambridge Reference Sequence (rCRS) for human mitochondrial DNA, extract variant alleles, quantify their heteroplasmy levels and related confidence intervals, and obtain functional annotation of the identified variants.	('human', 'Species', '9606', (168, 173))	('variant', 'Var', (201, 208))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('174', '191'))	('heteroplasmy levels', 'MPA', (233, 252))
183215	29796168	Analysis of The Cancer Genome Atlas (TCGA) ccRCC cohort showed that patients with high BRD4 expression had shorter overall survival than those with low expression.	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (16, 35))	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('overall survival', 'MPA', (115, 131))	('high', 'Var', (82, 86))	('BRD4', 'Gene', '23476', (87, 91))	('patients', 'Species', '9606', (68, 76))	('shorter', 'NegReg', (107, 114))	('RCC', 'Disease', (45, 48))	('BRD4', 'Gene', (87, 91))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('expression', 'MPA', (92, 102))	('Cancer Genome Atlas', 'Disease', (16, 35))
183217	29796168	Based on RNA sequencing analyses of ccRCC cells treated with JQ1 to elucidate the mechanisms other than MYC regulation, we identified several oncogenes that may be potential therapeutic targets or prognostic markers; patients with high expression of SCG5, SPOCD1, RGS19, and ARHGAP22 had poorer overall survival than those with low expression in TCGA ccRCC cohort.	('RCC', 'Disease', (38, 41))	('RNA', 'cellular_component', 'GO:0005562', ('9', '12'))	('SCG5', 'Gene', (250, 254))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('ARHGAP22', 'Gene', (275, 283))	('SPOCD1', 'Gene', (256, 262))	('RCC', 'Disease', (353, 356))	('RGS19', 'Gene', '10287', (264, 269))	('RGS', 'molecular_function', 'GO:0016299', ('264', '267'))	('ccRCC', 'Phenotype', 'HP:0006770', (351, 356))	('RCC', 'Disease', 'MESH:C538614', (38, 41))	('regulation', 'biological_process', 'GO:0065007', ('108', '118'))	('RCC', 'Disease', 'MESH:C538614', (353, 356))	('poorer', 'NegReg', (288, 294))	('overall', 'MPA', (295, 302))	('high expression', 'Var', (231, 246))	('RGS19', 'Gene', (264, 269))	('patients', 'Species', '9606', (217, 225))	('SCG5', 'Gene', '6447', (250, 254))	('ARHGAP22', 'Gene', '58504', (275, 283))	('SPOCD1', 'Gene', '90853', (256, 262))
183219	29796168	These results identified SCG5, SPOCD1, RGS19, and ARHGAP22 as potential prognostic markers and showed that BRD4 inhibition may have applications as a potential therapeutic approach in sunitinib-sensitive and -resistant ccRCC.	('ARHGAP22', 'Gene', '58504', (50, 58))	('inhibition', 'Var', (112, 122))	('SCG5', 'Gene', '6447', (25, 29))	('RGS19', 'Gene', '10287', (39, 44))	('SPOCD1', 'Gene', '90853', (31, 37))	('RCC', 'Disease', 'MESH:C538614', (221, 224))	('RCC', 'Disease', (221, 224))	('sunitinib', 'Chemical', 'MESH:D000077210', (184, 193))	('SCG5', 'Gene', (25, 29))	('BRD4', 'Gene', '23476', (107, 111))	('RGS', 'molecular_function', 'GO:0016299', ('39', '42'))	('ccRCC', 'Phenotype', 'HP:0006770', (219, 224))	('BRD4', 'Gene', (107, 111))	('SPOCD1', 'Gene', (31, 37))	('RGS19', 'Gene', (39, 44))	('ARHGAP22', 'Gene', (50, 58))
183221	29796168	Among these drugs, sunitinib is a common molecular-targeted drug that is recommended as a first-line therapy against advanced ccRCC; indeed, sunitinib treatment has been shown to result in relatively longer progression-free survival and higher response rate.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('sunitinib', 'Chemical', 'MESH:D000077210', (141, 150))	('progression-free survival', 'CPA', (207, 232))	('sunitinib', 'Var', (141, 150))	('higher', 'PosReg', (237, 243))	('sunitinib', 'Chemical', 'MESH:D000077210', (19, 28))	('longer', 'PosReg', (200, 206))	('response', 'CPA', (244, 252))
183226	29796168	Although HIF2alpha antagonists have promising therapeutic potency, long-term treatment results in acquired resistance through HIF mutations.	('results in', 'Reg', (87, 97))	('HIF2alpha', 'Gene', (9, 18))	('HIF', 'Gene', (126, 129))	('acquired resistance', 'MPA', (98, 117))	('mutations', 'Var', (130, 139))	('HIF2alpha', 'Gene', '2034', (9, 18))
183241	29796168	As a result, we found that the high BRD4 expression group (n = 178; top third) had significantly lower overall survival rates than patients with low and medium BRD4 (n = 354) expression (P = 0.0003, Figure 1A).	('BRD4', 'Gene', (36, 40))	('patients', 'Species', '9606', (131, 139))	('expression', 'MPA', (41, 51))	('BRD4', 'Gene', '23476', (160, 164))	('BRD4', 'Gene', '23476', (36, 40))	('lower', 'NegReg', (97, 102))	('high', 'Var', (31, 35))	('BRD4', 'Gene', (160, 164))	('overall', 'CPA', (103, 110))
183242	29796168	In addition, when the patients were divided into two groups according to the median BRD4 expression, the log-rank test showed that overall survival was still significantly shortened in patients with high BRD4 expression group (n = 266) in comparison with low BRD4 expression group (n = 266) (P = 0.0044; Supplementary Figure 1A).	('BRD4', 'Gene', (259, 263))	('BRD4', 'Gene', (204, 208))	('BRD4', 'Gene', (84, 88))	('shortened', 'NegReg', (172, 181))	('overall survival', 'CPA', (131, 147))	('patients', 'Species', '9606', (22, 30))	('high', 'Var', (199, 203))	('BRD4', 'Gene', '23476', (84, 88))	('BRD4', 'Gene', '23476', (204, 208))	('patients', 'Species', '9606', (185, 193))	('BRD4', 'Gene', '23476', (259, 263))
183247	29796168	On the other hand, when the cohort was divided into two groups, the high BRD4 expression was not significant but tended to be an independent prognostic predictor for OS (P = 0.0624, Supplementary Figure 1D).	('BRD4', 'Gene', '23476', (73, 77))	('expression', 'MPA', (78, 88))	('BRD4', 'Gene', (73, 77))	('high', 'Var', (68, 72))
183256	29796168	We hypothesized that JQ1 may have anti-cancer effects in ccRCC cells.	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('JQ1', 'Var', (21, 24))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))
183259	29796168	Cell apoptosis assays revealed that JQ1 had significant apoptotic effects in several ccRCC cells including SU-R-786-o cells (P < 0.0001, Figure 2B, Supplementary Figure 3A).	('apoptosis', 'biological_process', 'GO:0097194', ('5', '14'))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('apoptosis', 'biological_process', 'GO:0006915', ('5', '14'))	('RCC', 'Disease', (87, 90))	('JQ1', 'Var', (36, 39))	('SU-R', 'Gene', (107, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('apoptotic effects', 'CPA', (56, 73))	('SU-R', 'Gene', '6833', (107, 111))
183261	29796168	Western blot analysis showed increased cleaved PARP levels in JQ1- treated- ccRCC cells including SU-R-786-o cells compared with that in mock cells (Figure 2C, Supplementary Figure 3B).	('JQ1- treated-', 'Var', (62, 75))	('PARP', 'Gene', (47, 51))	('SU-R', 'Gene', '6833', (98, 102))	('PARP', 'Gene', '142', (47, 51))	('increased', 'PosReg', (29, 38))	('RCC', 'Disease', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('SU-R', 'Gene', (98, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))
183264	29796168	These data suggested that JQ1 may have anti-cancer effects on cancer cell growth in ccRCC, including sunitinib-resistant ccRCC.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('JQ1', 'Var', (26, 29))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('sunitinib', 'Chemical', 'MESH:D000077210', (101, 110))	('RCC', 'Disease', (123, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (121, 126))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cell growth', 'biological_process', 'GO:0016049', ('69', '80'))
183266	29796168	Wound healing assays demonstrated that cell migration activity was significantly inhibited in a concentration-dependent manner in ccRCC cell lines, including SU-R-786-o cells treated with JQ1 (2.5, 5, and 10 muM) in comparison with that in mock cells (Figure 2E).	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (130, 135))	('RCC', 'Disease', (132, 135))	('SU-R', 'Gene', '6833', (158, 162))	('inhibited', 'NegReg', (81, 90))	('cell migration', 'biological_process', 'GO:0016477', ('39', '53'))	('Wound healing', 'biological_process', 'GO:0042060', ('0', '13'))	('JQ1', 'Var', (188, 191))	('muM', 'Gene', '56925', (208, 211))	('cell migration activity', 'CPA', (39, 62))	('muM', 'Gene', (208, 211))	('SU-R', 'Gene', (158, 162))
183267	29796168	Additionally, Matrigel invasion assays demonstrated that the number of invading cells was significantly decreased in a concentration-dependent manner in 786-o and SU-R-786-o cells treated with JQ1 compared with that in mock cells (Figure 2F), although we could not find significant inhibition of invasion activities in A498 and Caki1 cells treated with JQ1 (Supplementary Figure 3C).	('JQ1', 'Var', (193, 196))	('Caki1', 'CellLine', 'CVCL:0234', (328, 333))	('Matrigel invasion assays', 'CPA', (14, 38))	('decreased', 'NegReg', (104, 113))	('SU-R', 'Gene', (163, 167))	('SU-R', 'Gene', '6833', (163, 167))
183271	29796168	We found that tumor growth was significantly suppressed in mice treated with JQ1 compared with that in vehicle-treated mice (P < 0.005, Figure 3A).	('mice', 'Species', '10090', (119, 123))	('mice', 'Species', '10090', (59, 63))	('tumor', 'Disease', (14, 19))	('JQ1', 'Var', (77, 80))	('suppressed', 'NegReg', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
183273	29796168	Several previous studies demonstrated that BRD4 could regulate MYC gene transcription and that JQ1 effectively suppresses cancer cell proliferation by inhibiting BET-mediated regulation of MYC in various types of cancer.	('regulate', 'Reg', (54, 62))	('JQ1', 'Var', (95, 98))	('BRD4', 'Gene', (43, 47))	('transcription', 'MPA', (72, 85))	('regulation', 'biological_process', 'GO:0065007', ('175', '185'))	('BET', 'Gene', (162, 165))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', (213, 219))	('BRD4', 'Gene', '23476', (43, 47))	('suppresses', 'NegReg', (111, 121))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cell proliferation', 'biological_process', 'GO:0008283', ('129', '147'))	('BET', 'Gene', '92737', (162, 165))	('MYC gene', 'Gene', (63, 71))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('inhibiting', 'NegReg', (151, 161))	('transcription', 'biological_process', 'GO:0006351', ('72', '85'))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
183283	29796168	Cell proliferation, migration, and invasion were inhibited by si-MYC transfection in SU-R-786-o cells compared with that in mock or control cells (Figure 4H).	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('inhibited', 'NegReg', (49, 58))	('SU-R', 'Gene', '6833', (85, 89))	('si-MYC', 'Protein', (62, 68))	('invasion', 'CPA', (35, 43))	('transfection', 'Var', (69, 81))	('migration', 'CPA', (20, 29))	('SU-R', 'Gene', (85, 89))	('Cell proliferation', 'CPA', (0, 18))
183286	29796168	Furthermore, downregulation of MYC by JQ1 treatment was found to play a partial role in the anti-cancer effects of sunitinib-resistant ccRCC.	('JQ1', 'Var', (38, 41))	('cancer', 'Disease', (97, 103))	('MYC', 'Protein', (31, 34))	('sunitinib', 'Chemical', 'MESH:D000077210', (115, 124))	('downregulation', 'NegReg', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('RCC', 'Disease', (137, 140))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
183311	29796168	In addition, western blot analysis showed that the protein expression levels of these four genes were reduced in JQ1-treated 786-o and SU-R-786-o cells (Figure 8A-8D).	('JQ1-treated', 'Var', (113, 124))	('SU-R', 'Gene', (135, 139))	('protein expression levels', 'MPA', (51, 76))	('reduced', 'NegReg', (102, 109))	('SU-R', 'Gene', '6833', (135, 139))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
183317	29796168	Taken together, these results strongly supported the excellent anti-cancer effects of BRD4 inhibition by JQ1 in sunitinib-resistant ccRCC and suggested that SCG5, SPOCD1, RGS19, and ARHGAP22 may be novel direct targets of the epigenetic reader BRD4 in sunitinib-resistant ccRCC.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('BRD4', 'Gene', '23476', (244, 248))	('RCC', 'Disease', (274, 277))	('ARHGAP22', 'Gene', (182, 190))	('BRD4', 'Gene', '23476', (86, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (272, 277))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('epigenetic', 'Var', (226, 236))	('RGS', 'molecular_function', 'GO:0016299', ('171', '174'))	('RGS19', 'Gene', (171, 176))	('SCG5', 'Gene', '6447', (157, 161))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('RCC', 'Disease', 'MESH:C538614', (274, 277))	('sunitinib', 'Chemical', 'MESH:D000077210', (252, 261))	('SCG5', 'Gene', (157, 161))	('inhibition', 'NegReg', (91, 101))	('BRD4', 'Gene', (244, 248))	('JQ1', 'Gene', (105, 108))	('SPOCD1', 'Gene', '90853', (163, 169))	('BRD4', 'Gene', (86, 90))	('SPOCD1', 'Gene', (163, 169))	('RGS19', 'Gene', '10287', (171, 176))	('ARHGAP22', 'Gene', '58504', (182, 190))	('cancer', 'Disease', (68, 74))	('RCC', 'Disease', (134, 137))	('sunitinib', 'Chemical', 'MESH:D000077210', (112, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (132, 137))
183325	29796168	reported that JQ1 inhibits thyroid tumor growth in a mouse model by decreasing MYC abundance and attenuating cyclin D1-CDK4-Rb-E2F3 signaling.	('CDK', 'molecular_function', 'GO:0004693', ('119', '122'))	('thyroid tumor', 'Disease', (27, 40))	('cyclin', 'molecular_function', 'GO:0016538', ('109', '115'))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cyclin D1', 'Gene', '12443', (109, 118))	('attenuating', 'NegReg', (97, 108))	('inhibits', 'NegReg', (18, 26))	('CDK4', 'Gene', (119, 123))	('thyroid tumor', 'Disease', 'MESH:D013959', (27, 40))	('decreasing', 'NegReg', (68, 78))	('cyclin D1', 'Gene', (109, 118))	('CDK4', 'Gene', '12567', (119, 123))	('thyroid tumor', 'Phenotype', 'HP:0100031', (27, 40))	('signaling', 'biological_process', 'GO:0023052', ('132', '141'))	('MYC abundance', 'MPA', (79, 92))	('mouse', 'Species', '10090', (53, 58))	('JQ1', 'Var', (14, 17))
183329	29796168	Additionally, several recent studies have reported that BRD4 inhibition suppresses the transcription of programmed death-ligand 1 (PD-L1) independently from MYC regulation.	('programmed death-ligand 1', 'Gene', (104, 129))	('programmed death-ligand 1', 'Gene', '29126', (104, 129))	('ligand', 'molecular_function', 'GO:0005488', ('121', '127'))	('suppresses', 'NegReg', (72, 82))	('inhibition', 'Var', (61, 71))	('PD-L1', 'Gene', '29126', (131, 136))	('transcription', 'biological_process', 'GO:0006351', ('87', '100'))	('transcription', 'MPA', (87, 100))	('regulation', 'biological_process', 'GO:0065007', ('161', '171'))	('BRD4', 'Gene', '23476', (56, 60))	('BRD4', 'Gene', (56, 60))	('PD-L1', 'Gene', (131, 136))
183330	29796168	In our present study, we found that JQ1 had anti-cancer effects through MYC regulation in ccRCC cells; however, these effects were observed regardless of innate MYC expression.	('JQ1', 'Var', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('regulation', 'biological_process', 'GO:0065007', ('76', '86'))	('RCC', 'Disease', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('cancer', 'Disease', (49, 55))	('MYC regulation', 'MPA', (72, 86))
183340	29796168	RGS19 overexpression has been shown to promote cell proliferation through deregulating cell cycle control and enhancing Akt signaling in several types of cancer.	('promote', 'PosReg', (39, 46))	('Akt signaling', 'biological_process', 'GO:0043491', ('120', '133'))	('RGS19', 'Gene', (0, 5))	('overexpression', 'Var', (6, 20))	('RGS19', 'Gene', '10287', (0, 5))	('Akt', 'Gene', '207', (120, 123))	('cancer', 'Disease', (154, 160))	('cell cycle control', 'CPA', (87, 105))	('deregulating', 'NegReg', (74, 86))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cell proliferation', 'biological_process', 'GO:0008283', ('47', '65'))	('enhancing', 'PosReg', (110, 119))	('cell cycle control', 'biological_process', 'GO:1901987', ('87', '105'))	('RGS', 'molecular_function', 'GO:0016299', ('0', '3'))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('Akt', 'Gene', (120, 123))	('cell proliferation', 'CPA', (47, 65))
183342	29796168	Notably, GSEA analysis in our present study suggested that JQ1 treatment may affect GPCR signaling in SU-R-786-o cells.	('SU-R', 'Gene', '6833', (102, 106))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('GSEA', 'Chemical', '-', (9, 13))	('affect', 'Reg', (77, 83))	('SU-R', 'Gene', (102, 106))	('JQ1', 'Var', (59, 62))	('GPCR signaling', 'MPA', (84, 98))
183349	29796168	reported that inhibition of PGF may be effective for the treatment of VEGFR1-expressing tumors by inducing the activity of tumor-associated macrophages for angiogenesis escape in sunitinib-resistant ccRCC.	('PGF', 'Gene', '5228', (28, 31))	('inducing', 'PosReg', (98, 106))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('PGF', 'Gene', (28, 31))	('RCC', 'Disease', (201, 204))	('tumor', 'Disease', (123, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (199, 204))	('VEGFR1', 'Gene', '2321', (70, 76))	('activity', 'MPA', (111, 119))	('angiogenesis', 'biological_process', 'GO:0001525', ('156', '168'))	('VEGFR1', 'Gene', (70, 76))	('angiogenesis escape', 'CPA', (156, 175))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', (88, 93))	('sunitinib', 'Chemical', 'MESH:D000077210', (179, 188))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('inhibition', 'Var', (14, 24))
183350	29796168	Moreover, we previously reported that silencing of transglutaminase 2 (TGM2) inhibited cancer cell proliferation and invasion and that TGM2 may function as an oncogene in ccRCC.	('TGM2', 'Gene', '7052', (135, 139))	('cancer', 'Disease', (87, 93))	('TGM2', 'Gene', (71, 75))	('transglutaminase 2', 'Gene', (51, 69))	('RCC', 'Disease', (173, 176))	('TGM2', 'Gene', (135, 139))	('TGM2', 'Gene', '7052', (71, 75))	('transglutaminase 2', 'Gene', '7052', (51, 69))	('inhibited', 'NegReg', (77, 86))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('ccRCC', 'Phenotype', 'HP:0006770', (171, 176))	('cell proliferation', 'biological_process', 'GO:0008283', ('94', '112'))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('invasion', 'CPA', (117, 125))	('silencing', 'Var', (38, 47))
183357	29796168	Therefore, these differences may be caused by genetic or epigenetic changes through acquisition of sunitinib resistance, as we had previously observed by metabolic reprograming in sunitinib-resistant cells.	('sunitinib', 'Chemical', 'MESH:D000077210', (180, 189))	('caused', 'Reg', (36, 42))	('epigenetic', 'Var', (57, 67))	('sunitinib', 'Chemical', 'MESH:D000077210', (99, 108))
183358	29796168	Moreover, resistance to JQ1 itself has also been demonstrated through SPOP mutation, which contributes to resistance to BET inhibitors through BRD4 stabilization in prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (165, 180))	('SPOP', 'Gene', '8405', (70, 74))	('BRD4', 'Gene', (143, 147))	('prostate cancer', 'Phenotype', 'HP:0012125', (165, 180))	('mutation', 'Var', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('SPOP', 'Gene', (70, 74))	('BET', 'Gene', '92737', (120, 123))	('prostate cancer', 'Disease', (165, 180))	('resistance', 'MPA', (106, 116))	('BET', 'Gene', (120, 123))	('BRD4', 'Gene', '23476', (143, 147))
183380	29796168	Immunoblotting was carried out with diluted anti-BRD4 antibodies (1:1000, ab128874; abcam, Cambridge, UK), anti-MYC antibodies (1:150, #5605; Cell Signaling Technology, Danvers, MA, USA), anti-poly-A ribose polymerase (PARP) antibodies (1:500, #9542; Cell Signaling Technology), anti-cleaved PARP antibodies (1:500, #5625; Cell Signaling Technology), anti-SCG5 antibodies (1:200, 10761-1-AP; proteintech, Chicago, IL, USA), anti-SPOCD1 antibodies (1:1000, 22243-1-AP; proteintech), anti-RGS19 antibodies (1:100, bs-3867R; Bioss, Woburn, MA, USA), anti-ARHGAP22 antibodies (1:500, 3018002; Novus Biologicals, Littleton, CO, USA) and anti-beta-actin antibodies (1:5000, bs-0061R; Bioss).	('PARP', 'Gene', '142', (292, 296))	('SPOCD1', 'Gene', '90853', (429, 435))	('beta-actin', 'Gene', '728378', (637, 647))	('ARHGAP22', 'Gene', '58504', (552, 560))	('RGS19', 'Gene', '10287', (487, 492))	('anti-poly-A ribose polymerase', 'Gene', (188, 217))	('SPOCD1', 'Gene', (429, 435))	('PARP', 'Gene', (292, 296))	('BRD4', 'Gene', (49, 53))	('PARP', 'Gene', '142', (219, 223))	('SCG5', 'Gene', '6447', (356, 360))	('Signaling', 'biological_process', 'GO:0023052', ('256', '265'))	('ARHGAP22', 'Gene', (552, 560))	('RGS', 'molecular_function', 'GO:0016299', ('487', '490'))	('PARP', 'Gene', (219, 223))	('anti-poly-A ribose polymerase', 'Gene', '142', (188, 217))	('Signaling', 'biological_process', 'GO:0023052', ('328', '337'))	('RGS19', 'Gene', (487, 492))	('BRD4', 'Gene', '23476', (49, 53))	('beta-actin', 'Gene', (637, 647))	('1:500', 'Var', (573, 578))	('SCG5', 'Gene', (356, 360))	('Signaling', 'biological_process', 'GO:0023052', ('147', '156'))
183382	29796168	Immunoprecipitation was conducted overnight using an antibody specific to BRD4 (#13440; Cell Signaling Technology) or normal rabbit IgG (#2729; Cell Signaling Technology) conjugated to Dynabeads M-280 Sheep anti-mouse IgG (#DB11201; Veritas, Tokyo, Japan), respectively.	('BRD4', 'Gene', (74, 78))	('rabbit', 'Species', '9986', (125, 131))	('Sheep', 'Species', '9940', (201, 206))	('antibody', 'molecular_function', 'GO:0003823', ('53', '61'))	('BRD4', 'Gene', '23476', (74, 78))	('Signaling', 'biological_process', 'GO:0023052', ('93', '102'))	('antibody', 'cellular_component', 'GO:0019814', ('53', '61'))	('Signaling', 'biological_process', 'GO:0023052', ('149', '158'))	('antibody', 'cellular_component', 'GO:0042571', ('53', '61'))	('#DB11201;', 'Var', (223, 232))	('antibody', 'cellular_component', 'GO:0019815', ('53', '61'))	('mouse', 'Species', '10090', (212, 217))
183447	33035959	This result provided dysregulated proteins and perturbed pathways in the ccRCC thrombus and tumor, which helped to gain an overview of the distinct characteristics of these two subtypes at the molecular mechanism level.	('ccRCC thrombus', 'Disease', 'MESH:D013927', (73, 87))	('perturbed', 'Reg', (47, 56))	('thrombus and tumor', 'Disease', 'MESH:D013927', (79, 97))	('ccRCC thrombus', 'Disease', (73, 87))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))	('dysregulated', 'Var', (21, 33))	('proteins', 'Protein', (34, 42))
183516	33035959	However, as the regulation of GGT5 and its role in cancer remains unknown, further studies are required to investigate whether the altered GGT5 expression facilitates the invasion of the tumor into the vein.	('GGT5', 'Gene', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('facilitates', 'PosReg', (155, 166))	('GGT5', 'Gene', '2687', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('GGT5', 'Gene', '2687', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Disease', (187, 192))	('altered', 'Var', (131, 138))	('regulation', 'biological_process', 'GO:0065007', ('16', '26'))	('GGT5', 'Gene', (139, 143))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
183549	30852945	Cancer is a disease caused by acquisition of somatic driver mutations that confer growth advantage to cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', (102, 108))	('Cancer', 'Disease', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('growth advantage', 'CPA', (82, 98))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (60, 69))
183550	30852945	Driver genes that carry driver mutations play a pivotal role in the formation and progression of cancers and have become a focus of cancer genomics studies.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancer', 'Disease', (132, 138))	('mutations', 'Var', (31, 40))	('cancers', 'Disease', (97, 104))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('formation', 'biological_process', 'GO:0009058', ('68', '77'))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
183553	30852945	Creighton et al  surveyed more than 400 tumors using different genomic platforms and identified chromatin modifier genes such as the VHL/Hypoxia-inducible factor (HIF) and PI(3)K/AKT pathways frequently mutated in ccRCC.	('Hypoxia', 'Disease', (137, 144))	('AKT', 'Gene', (179, 182))	('mutated', 'Var', (203, 210))	('PI(3)K', 'molecular_function', 'GO:0016303', ('172', '178'))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('VHL', 'Gene', (133, 136))	('VHL', 'Gene', '7428', (133, 136))	('chromatin', 'cellular_component', 'GO:0000785', ('96', '105'))	('AKT', 'Gene', '207', (179, 182))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('RCC', 'Disease', (216, 219))	('RCC', 'Phenotype', 'HP:0005584', (216, 219))	('Hypoxia', 'Disease', 'MESH:D000860', (137, 144))	('tumors', 'Disease', (40, 46))
183554	30852945	Li et al applied Oncodrive-FM and Dendrix to detect driver genes with middle or low mutation frequencies and performed an integrated study on the 342 driver genes; many driver genes are aberrantly expressed, demethylated, and associated with cancer prognosis, providing potential prognostic biomarkers and targeted therapies for patients with ccRCC.	('demethylated', 'Var', (208, 220))	('cancer', 'Disease', (242, 248))	('aberrantly', 'Var', (186, 196))	('associated with', 'Reg', (226, 241))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('RCC', 'Disease', (345, 348))	('RCC', 'Disease', 'MESH:C538614', (345, 348))	('RCC', 'Phenotype', 'HP:0005584', (345, 348))	('patients', 'Species', '9606', (329, 337))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
183556	30852945	Integrated CAncer GEnome Score (iCAGES) is a novel statistical framework that infers driver variants by integrating contributions from coding, noncoding, and structural variants; identifies driver genes by combining genomic information and prior biological knowledge; and then generates prioritized drug treatment.	('CAncer', 'Phenotype', 'HP:0002664', (11, 17))	('CAncer', 'Disease', 'MESH:D009369', (11, 17))	('CAncer', 'Disease', (11, 17))	('variants', 'Var', (92, 100))
183558	30852945	The second layer associates these mutations to genes using a statistical model with prior biological knowledge on cancer driver genes for specific subtypes of cancer.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('mutations', 'Var', (34, 43))	('cancer', 'Disease', (114, 120))
183586	30852945	The results showed that these driver genes contribute to tumorigenesis and progression of ccRCC mostly through involvement in metabolic processes, epigenetic modifications, and regulation of cancer-associated signaling pathways in ccRCC.	('metabolic processes', 'CPA', (126, 145))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (233, 236))	('RCC', 'Disease', (233, 236))	('contribute', 'Reg', (43, 53))	('cancer', 'Disease', (191, 197))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('RCC', 'Disease', 'MESH:C538614', (233, 236))	('tumor', 'Disease', (57, 62))	('epigenetic modifications', 'Var', (147, 171))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('signaling', 'biological_process', 'GO:0023052', ('209', '218'))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('involvement', 'Reg', (111, 122))	('progression', 'CPA', (75, 86))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('regulation', 'Reg', (177, 187))	('regulation', 'biological_process', 'GO:0065007', ('177', '187'))
183618	30852945	In line with our study, high expression of XPO1 indicates poor survival rates in gastric carcinoma, acute myeloid leukemia, pancreatic cancer, and lung adenocarcinoma.	('gastric carcinoma', 'Disease', (81, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (124, 141))	('high', 'Var', (24, 28))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (81, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('lung adenocarcinoma', 'Disease', (147, 166))	('XPO1', 'Gene', '7514', (43, 47))	('pancreatic cancer', 'Disease', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('poor', 'NegReg', (58, 62))	('acute myeloid leukemia', 'Disease', (100, 122))	('survival', 'MPA', (63, 71))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (147, 166))	('leukemia', 'Phenotype', 'HP:0001909', (114, 122))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (147, 166))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (124, 141))	('expression', 'MPA', (29, 39))	('XPO1', 'Gene', (43, 47))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (100, 122))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (106, 122))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (100, 122))	('gastric carcinoma', 'Disease', 'MESH:D013274', (81, 98))
183713	33037114	We detected pathogenic VHL mutations, the most commonly mutated gene in ccRCC, in all three of the adherent primary cultures.	('mutations', 'Var', (27, 36))	('VHL', 'Gene', (23, 26))	('pathogenic', 'Reg', (12, 22))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('VHL', 'Gene', '7428', (23, 26))
183714	33037114	Mutant PBRM1 (2 of 3), SETD2 (1 of 3), and TP53 (1 of 3) were also detected in the adherent cell cultures, all with greater than 98% mutant allele frequency, confirming a near pure population of clonal tumor cells grows out after five or more passages (online supplemental table 2).	('SETD2', 'Gene', '29072', (23, 28))	('pure', 'molecular_function', 'GO:0034023', ('176', '180'))	('tumor', 'Disease', (202, 207))	('SETD2', 'Gene', (23, 28))	('TP53', 'Gene', '7157', (43, 47))	('PBRM1', 'Gene', '55193', (7, 12))	('PBRM1', 'Gene', (7, 12))	('Mutant', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('TP53', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
183756	33037114	TILs are known to respond to a variety of tumor-associated antigens or tumor-specific neoantigens created by somatic mutations within protein coding genes which are transcribed, translated, degraded and ultimately presented as mutated peptide fragments on MHCs.	('mutations', 'Var', (117, 126))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('L', 'Gene', '21832', (2, 3))	('respond', 'Reg', (18, 25))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
183791	33037114	The significance of Gal-9/TIM-3 interaction alone has been somewhat controversial; however, this interaction has been shown to lead to the phosphorylation of tyrosine 265 on the cytoplasmic tail of TIM-3 and most evidence points to this interaction playing a role in suppressing type 1 T-cell responses.	('TIM-3', 'Gene', '84868', (26, 31))	('phosphorylation', 'MPA', (139, 154))	('tyrosine', 'Var', (158, 166))	('suppressing', 'NegReg', (267, 278))	('lead to', 'Reg', (127, 134))	('type 1 T-cell responses', 'CPA', (279, 302))	('Gal-9', 'Gene', (20, 25))	('TIM-3', 'Gene', (198, 203))	('interaction', 'Interaction', (97, 108))	('Gal-9', 'Gene', '3965', (20, 25))	('TIM-3', 'Gene', '84868', (198, 203))	('phosphorylation', 'biological_process', 'GO:0016310', ('139', '154'))	('TIM-3', 'Gene', (26, 31))	('tyrosine', 'Chemical', 'MESH:D014443', (158, 166))
183792	33037114	Other ligands of TIM-3 which have been shown to modulate function that can be restored with TIM-3 blockade are phosphatidylserine (PS), carcinoembryonic antigen cell adhesion molecule 1, and high-mobility group box 1, and these ligands have binding clefts separate from Gal-9s on the TIM-3 receptor.	('TIM-3', 'Gene', (17, 22))	('carcinoembryonic', 'Disease', 'None', (136, 152))	('TIM-3', 'Gene', '84868', (92, 97))	('TIM-3', 'Gene', '84868', (284, 289))	('function', 'MPA', (57, 65))	('high-mobility group box 1', 'Gene', (191, 216))	('blockade', 'Var', (98, 106))	('binding', 'Interaction', (241, 248))	('Gal-9', 'Gene', '3965', (270, 275))	('Gal-9', 'Gene', (270, 275))	('TIM-3', 'Gene', (284, 289))	('TIM-3', 'Gene', (92, 97))	('cell adhesion', 'biological_process', 'GO:0007155', ('161', '174'))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('161', '183'))	('carcinoembryonic', 'Disease', (136, 152))	('high-mobility group box 1', 'Gene', '3146', (191, 216))	('PS', 'Chemical', 'MESH:D010718', (131, 133))	('TIM-3', 'Gene', '84868', (17, 22))	('binding', 'molecular_function', 'GO:0005488', ('241', '248'))
183801	33037114	Indeed, the NGS data (ie, >98% allele frequency for a given mutation) suggests that short-term in vitro propagation of the adherent tumor cells leads to clonal populations.	('clonal populations', 'CPA', (153, 171))	('mutation', 'Var', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('leads to', 'Reg', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))
183854	30653515	Non-specific binding was blocked by Background Sniper (BS966, Biocare Medical) for 15 min, followed by an incubation with the primary antibody (GRP78, 1:50, SANTSC-376768, Santa Cruz Biotechnology) at room temperature for one hour.	('GRP78', 'Gene', (144, 149))	('antibody', 'cellular_component', 'GO:0019814', ('134', '142'))	('antibody', 'cellular_component', 'GO:0019815', ('134', '142'))	('antibody', 'molecular_function', 'GO:0003823', ('134', '142'))	('Non-specific binding', 'Interaction', (0, 20))	('BS966', 'Var', (55, 60))	('antibody', 'cellular_component', 'GO:0042571', ('134', '142'))	('binding', 'molecular_function', 'GO:0005488', ('13', '20'))	('GRP78', 'Gene', '3309', (144, 149))
183857	30653515	The specificity of the GRP78 antibody was tested by mixing the primary antibody with a blocking peptide (GL Biochem/Shanghai-687830, amino acid sequence: ee edkkedvgtv vgidlgttys cvgvfkngrv) at a concentration ten times of the primary antibody.	('antibody', 'cellular_component', 'GO:0019815', ('71', '79'))	('antibody', 'cellular_component', 'GO:0042571', ('29', '37'))	('edkkedvgtv', 'Var', (157, 167))	('antibody', 'cellular_component', 'GO:0019814', ('71', '79'))	('antibody', 'cellular_component', 'GO:0019815', ('29', '37'))	('antibody', 'cellular_component', 'GO:0042571', ('235', '243'))	('antibody', 'cellular_component', 'GO:0019814', ('29', '37'))	('GRP78', 'Gene', (23, 28))	('antibody', 'molecular_function', 'GO:0003823', ('71', '79'))	('GL', 'Chemical', 'MESH:C015905', (105, 107))	('GRP78', 'Gene', '3309', (23, 28))	('antibody', 'cellular_component', 'GO:0019815', ('235', '243'))	('antibody', 'molecular_function', 'GO:0003823', ('29', '37'))	('antibody', 'cellular_component', 'GO:0019814', ('235', '243'))	('antibody', 'cellular_component', 'GO:0042571', ('71', '79'))	('antibody', 'molecular_function', 'GO:0003823', ('235', '243'))
183861	30653515	Outcome variables regarding ccRCC aggressiveness were dichotomized as follows: tumor grade: low and high; tumor stage: low and high; tumor size: [<=70mm] and [>70mm]; metastases: [presence] and [absence].	('aggressiveness', 'Disease', 'MESH:D001523', (34, 48))	('[<=70mm]', 'Var', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('metastases', 'Disease', (167, 177))	('RCC', 'Disease', (30, 33))	('aggressiveness', 'Disease', (34, 48))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('aggressiveness', 'Phenotype', 'HP:0000718', (34, 48))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('[>70mm]', 'Var', (158, 165))	('metastases', 'Disease', 'MESH:D009362', (167, 177))	('tumor', 'Disease', (106, 111))
183890	30653515	Although descriptive analysis found benign tumor-associated adipose tissue exhibited higher average grey value of GRP78 staining intensity than ccRCC-associated adipose tissue (Fig 6), it is not reasonable to deduce weak GRP78 staining intensity (as demonstrated by higher average grey value) is related to a better prognosis, due to an even weaker GRP78 staining intensity that was found in grade 4 ccRCC tumor-associated adipose tissue (Fig 7).	('staining intensity', 'MPA', (227, 245))	('tumor', 'Disease', (43, 48))	('RCC', 'Disease', 'MESH:C538614', (402, 405))	('RCC', 'Disease', (146, 149))	('benign tumor', 'Disease', 'MESH:D009369', (36, 48))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', (406, 411))	('weak', 'Var', (216, 220))	('tumor', 'Disease', 'MESH:D009369', (406, 411))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('benign tumor', 'Disease', (36, 48))	('GRP78', 'Gene', '3309', (114, 119))	('GRP78', 'Gene', (114, 119))	('grey value', 'MPA', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('GRP78', 'Gene', (221, 226))	('GRP78', 'Gene', '3309', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (406, 411))	('RCC', 'Disease', (402, 405))	('GRP78', 'Gene', '3309', (349, 354))	('GRP78', 'Gene', (349, 354))
183936	30446580	2C), and P504S and negative for cytokeratin (CK) 7, thyroid transcription factor (TTF)-1, thyroglobulin, high-molecular weight CK (34betaE12), and CD10.	('P504S', 'Var', (9, 14))	('transcription', 'biological_process', 'GO:0006351', ('60', '73'))	('transcription factor', 'molecular_function', 'GO:0000981', ('60', '80'))	('cytokeratin (CK) 7', 'Gene', (32, 50))	('CD10', 'molecular_function', 'GO:0004245', ('147', '151'))	('thyroglobulin', 'Gene', '7038', (90, 103))	('thyroid transcription factor (TTF)-1', 'Gene', '7270', (52, 88))	('thyroglobulin', 'Gene', (90, 103))	('CD10', 'Gene', (147, 151))	('P504S', 'Mutation', 'p.P504S', (9, 14))	('cytokeratin (CK) 7', 'Gene', '3855', (32, 50))	('CD10', 'Gene', '4311', (147, 151))
183942	30446580	Comparison of the genomic sequencing results from the tumor against the peripheral blood (normal) sample detected a total of 25 somatic nonsynonymous single nucleotide variants (SNVs) and two truncating insertion/deletion events (indels) within coding regions.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('gain', 'Disease', (61, 65))	('gain', 'Disease', 'MESH:D015430', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('single nucleotide variants', 'Var', (150, 176))	('tumor', 'Disease', (54, 59))
183944	30446580	Six somatic variants of uncertain significance (VUSs) were detected in known cancer-related genes including KRAS, I187T; CAT, F185I; CEP290, Q284H; and CSDE1, D767N.	('KRAS', 'Gene', (108, 112))	('CSDE1', 'Gene', (152, 157))	('D767N', 'Var', (159, 164))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('AT', 'Disease', 'None', (122, 124))	('Q284H', 'Mutation', 'p.Q284H', (141, 146))	('CSDE1', 'Gene', '7812', (152, 157))	('Q284H', 'Var', (141, 146))	('D767N', 'Mutation', 'p.D767N', (159, 164))	('I187T', 'Mutation', 'rs1452019494', (114, 119))	('CEP290', 'Gene', '80184', (133, 139))	('cancer', 'Disease', (77, 83))	('I187T', 'Var', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('F185I', 'Mutation', 'p.F185I', (126, 131))	('CAT', 'molecular_function', 'GO:0004096', ('121', '124'))	('CEP290', 'Gene', (133, 139))	('F185I', 'Var', (126, 131))	('KRAS', 'Gene', '3845', (108, 112))	('CEP', 'molecular_function', 'GO:0047849', ('133', '136'))
183960	30446580	Blood genome sequences were analyzed to detect germline mutations, copy-number changes, and SVs in 98 genes previously linked to hereditary cancer.	('SVs', 'Var', (92, 95))	('hereditary cancer', 'Disease', 'MESH:D009369', (129, 146))	('copy-number changes', 'Var', (67, 86))	('hereditary cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
183971	30446580	Although both cases lacked VHL mutations, concurrent mutations in PBRM1, SETD2, and TSC1 supported the diagnosis of RCC.	('SETD2', 'Gene', (73, 78))	('TSC1', 'Gene', '7248', (84, 88))	('VHL', 'Disease', 'MESH:D006623', (27, 30))	('TSC1', 'Gene', (84, 88))	('VHL', 'Disease', (27, 30))	('mutations', 'Var', (53, 62))	('PBRM1', 'Gene', (66, 71))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('SETD2', 'Gene', '29072', (73, 78))	('PBRM1', 'Gene', '55193', (66, 71))	('RCC', 'Disease', (116, 119))
183986	30446580	Another case of TLFRCC showed monosomies in Chromosomes 7 and 17.	('monosomies', 'Var', (30, 40))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('RCC', 'Disease', (19, 22))
183993	30446580	Messenger RNA selection was performed using NEBNext Oligod(T)25 beads (NEB) with incubation at 65 C for 5 min followed by snap-chilling at 4 C to denature RNA and facilitate binding of poly(A) mRNA to the beads.	('RNA', 'cellular_component', 'GO:0005562', ('10', '13'))	('binding', 'Interaction', (174, 181))	('binding', 'molecular_function', 'GO:0005488', ('174', '181'))	('-chilling', 'Phenotype', 'HP:0025143', (126, 135))	('facilitate', 'PosReg', (163, 173))	('RNA', 'Protein', (155, 158))	('snap', 'molecular_function', 'GO:0005483', ('122', '126'))	('poly(A)', 'Chemical', 'MESH:D011061', (185, 192))	('poly(A) mRNA', 'Protein', (185, 197))	('RNA', 'cellular_component', 'GO:0005562', ('155', '158'))	('denature', 'Var', (146, 154))
183999	30446580	Having sequenced both blood and tumor samples, variants identified from aligning the first sample were labeled as germline.	('tumor', 'Disease', (32, 37))	('variants', 'Var', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))
184001	30446580	Heterozygosity and regions of copy loss and gain were assessed using hidden Markov model- based approaches, CNAseq (v0.0.6) and APOLLOH (v0.1.1).	('copy', 'Var', (30, 34))	('gain', 'Disease', (44, 48))	('gain', 'Disease', 'MESH:D015430', (44, 48))
184017	29660846	Because PLD2 knockdown effectively suppressed the cell proliferation and invasion of ccRCC as compared with PLD1 in vitro, we examined the effect of PLD2 in vivo.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('suppressed', 'NegReg', (35, 45))	('invasion', 'CPA', (73, 81))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))	('knockdown', 'Var', (13, 22))	('PLD2', 'Gene', (8, 12))	('cell proliferation', 'CPA', (50, 68))
184018	29660846	Notably, shRNA-mediated knockdown of PLD2 suppressed the growth and invasion of tumors in nude mouse xenograft models.	('PLD2', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('suppressed', 'NegReg', (42, 52))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('knockdown', 'Var', (24, 33))	('mouse', 'Species', '10090', (95, 100))
184022	29660846	Overall, we revealed for the first time that PLD2-produced PA promoted cell invasion through the expression of ANG in ccRCC cells.	('ANG', 'Gene', '283', (111, 114))	('PA', 'Chemical', 'MESH:D010712', (59, 61))	('ANG', 'Gene', (111, 114))	('PLD2-produced', 'Var', (45, 58))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('promoted', 'PosReg', (62, 70))	('cell invasion', 'CPA', (71, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))	('expression', 'MPA', (97, 107))
184050	29660846	SKRC52 and SKRC59 cells were transfected with 25 nmol/L of ON-TARGETplus human PLD1 SMART pool siRNA (L-009413-00-0005, Dharmacon, Thermo Fisher Scientific, Rockford, IL, USA), 25 nmol/L of ON-TARGETplus human PLD2 SMART pool siRNA (L-005064-00-0005) or 25 nmol/L of ON-TARGETplus non-targeting pool siRNA (D-001810-10-05) using Lipofectamine RNAiMax Reagent (Invitrogen).	('L-005064-00-0005', 'Var', (233, 249))	('SKRC59', 'CellLine', 'CVCL:6206', (11, 17))	('human', 'Species', '9606', (73, 78))	('human', 'Species', '9606', (204, 209))	('SKRC52', 'CellLine', 'CVCL:6198', (0, 6))	('L-009413-00-0005', 'Var', (102, 118))
184075	29660846	Similarly, high PLD2 expression was significantly correlated with worse clinical stage and higher tumor grade (Table 2).	('PLD2', 'Gene', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('expression', 'MPA', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('high', 'Var', (11, 15))	('tumor', 'Disease', (98, 103))
184077	29660846	To clarify the roles of PLD in the disease progression of ccRCC, we performed siRNA knockdown of PLD1 or PLD2 in 2 different VHL -/- ccRCC cell lines, SKRC52 and SKRC59, respectively.	('knockdown', 'Var', (84, 93))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (60, 63))	('PLD', 'Gene', '2822', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('PLD', 'Gene', (97, 100))	('VHL', 'Gene', (125, 128))	('PLD', 'Gene', '2822', (24, 27))	('PLD', 'Gene', (24, 27))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('SKRC52', 'CellLine', 'CVCL:6198', (151, 157))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('VHL', 'Gene', '7428', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('RCC', 'Disease', (135, 138))	('PLD', 'Gene', '2822', (105, 108))	('SKRC59', 'CellLine', 'CVCL:6206', (162, 168))	('PLD', 'Gene', (105, 108))
184079	29660846	Notably, PLD2 knockdown more effectively suppressed tumor invasion in both cells compared with PLD1 knockdown.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('suppressed', 'NegReg', (41, 51))	('knockdown', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('PLD2', 'Gene', (9, 13))
184085	29660846	For this purpose, SKRC52 cells with stably knocked-down PLD2 were established using 2 different shRNA (#1 and #2) and both successfully reduced the level of PLD2 without affecting that of PLD1 (Figure 3A).	('SKRC52', 'CellLine', 'CVCL:6198', (18, 24))	('knocked-down', 'Var', (43, 55))	('level', 'MPA', (148, 153))	('reduced', 'NegReg', (136, 143))	('PLD2', 'MPA', (157, 161))	('PLD2', 'Gene', (56, 60))
184086	29660846	Importantly, the shRNA-mediated knocking down of PLD2 suppressed the tumor growth when the cells were implanted subcutaneously (Figure 3B).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('suppressed', 'NegReg', (54, 64))	('tumor', 'Disease', (69, 74))	('PLD2', 'Gene', (49, 53))	('knocking down', 'Var', (32, 45))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
184087	29660846	We also examined the Ki-67 index in xenograft tumors infected with scramble or PLD2 shRNA, and it was revealed that SKRC52/PLD2 shRNA cells exhibited a significantly lower Ki-67 index than did SKRC52/scramble cells (Figure 3C).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('SKRC52', 'CellLine', 'CVCL:6198', (193, 199))	('SKRC52/PLD2 shRNA', 'Var', (116, 133))	('SKRC52', 'CellLine', 'CVCL:6198', (116, 122))	('Ki-67 index', 'MPA', (172, 183))	('lower', 'NegReg', (166, 171))	('xenograft tumors infected', 'Disease', (36, 61))	('xenograft tumors infected', 'Disease', 'MESH:D009369', (36, 61))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))
184092	29660846	A Kaplan-Meier analysis revealed that the high expression of PLD2 was significantly associated with a poor patient prognosis (P = .002, Figure 4A).	('PLD2', 'Gene', (61, 65))	('patient', 'Species', '9606', (107, 114))	('associated', 'Reg', (84, 94))	('high expression', 'Var', (42, 57))
184106	29660846	Conversely, treatment with recombinant human ANG significantly promoted the cell invasion ability of both cells with shRNA mediated knockdown of PLD2 (Figure 5D).	('ANG', 'Gene', (45, 48))	('knockdown', 'Var', (132, 141))	('promoted', 'PosReg', (63, 71))	('human', 'Species', '9606', (39, 44))	('ANG', 'Gene', '283', (45, 48))	('cell invasion ability', 'CPA', (76, 97))	('PLD2', 'Gene', (145, 149))
184108	29660846	Although ANG mRNA was downregulated by the knockdown of PLD2, the reduced expression was augmented by the treatment with PA in the same cells (Figure 5E).	('expression', 'MPA', (74, 84))	('ANG', 'Gene', '283', (9, 12))	('knockdown', 'Var', (43, 52))	('PA', 'Chemical', 'MESH:D010712', (121, 123))	('ANG', 'Gene', (9, 12))	('PLD2', 'Gene', (56, 60))	('downregulated', 'NegReg', (22, 35))
184110	29660846	Phospholipase D expression and activity have been previously reported to be elevated in various human cancers such as colorectal, gastric, breast and kidney cancers when compared with adjacent non-cancer tissues.12, 19, 29 The elevated expression of PLD2 was correlated with poor prognosis in colorectal cancer.29 Moreover, previous studies demonstrated that PA produced by PLD promoted cancer proliferation, invasion and metastasis by various activated cell signaling pathways such as AKT and ERK signaling.6, 14, 18  In the present study, we showed that the elevated expression of PLD2 was associated with poor prognosis, and that PLD2 ablation and PLD2 small-molecule inhibitors suppressed the cell proliferation and invasion of renal cancer cells in vitro.	('invasion of', 'CPA', (720, 731))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('breast and kidney cancers', 'Disease', 'MESH:D001943', (139, 164))	('AKT', 'Gene', '207', (486, 489))	('cancer', 'Disease', (304, 310))	('ERK', 'Gene', '5594', (494, 497))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('ablation', 'Var', (638, 646))	('PLD', 'Gene', '2822', (651, 654))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('PLD', 'Gene', (651, 654))	('cancer', 'Disease', 'MESH:D009369', (387, 393))	('ERK', 'molecular_function', 'GO:0004707', ('494', '497'))	('cell proliferation', 'biological_process', 'GO:0008283', ('697', '715'))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('suppressed', 'NegReg', (682, 692))	('PLD', 'Gene', '2822', (374, 377))	('human', 'Species', '9606', (96, 101))	('PLD', 'Gene', (374, 377))	('PLD', 'Gene', '2822', (633, 636))	('signaling', 'biological_process', 'GO:0023052', ('459', '468'))	('PLD', 'Gene', (633, 636))	('cancer', 'Disease', (738, 744))	('ERK', 'Gene', (494, 497))	('colorectal', 'Disease', (293, 303))	('colorectal', 'Disease', (118, 128))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('colorectal cancer', 'Disease', 'MESH:D015179', (293, 310))	('cancer', 'Disease', (197, 203))	('cell proliferation', 'CPA', (697, 715))	('renal cancer', 'Disease', (732, 744))	('cancer', 'Disease', (102, 108))	('PA', 'Chemical', 'MESH:D010712', (359, 361))	('cancer', 'Disease', (387, 393))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('renal cancer', 'Phenotype', 'HP:0009726', (732, 744))	('cancer', 'Disease', (157, 163))	('cancers', 'Disease', (157, 164))	('cancers', 'Disease', (102, 109))	('AKT', 'Gene', (486, 489))	('Phospholipase D', 'Gene', '2822', (0, 15))	('colorectal cancer', 'Disease', (293, 310))	('PLD', 'Gene', '2822', (250, 253))	('PLD', 'Gene', (250, 253))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('Phospholipase D', 'Gene', (0, 15))	('kidney cancers', 'Phenotype', 'HP:0009726', (150, 164))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('signaling', 'biological_process', 'GO:0023052', ('498', '507'))	('PLD', 'Gene', '2822', (583, 586))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (387, 393))	('PLD', 'Gene', (583, 586))	('expression', 'MPA', (569, 579))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancer', 'Disease', 'MESH:D009369', (738, 744))	('elevated', 'PosReg', (560, 568))	('colorectal', 'Disease', 'MESH:D015179', (293, 303))	('renal cancer', 'Disease', 'MESH:D007680', (732, 744))	('colorectal', 'Disease', 'MESH:D015179', (118, 128))
184111	29660846	We also revealed that PLD2 knockdown inhibited tumor growth and invasion using human renal cancer subcutaneous and orthotopic xenograft models.	('knockdown', 'Var', (27, 36))	('PLD2', 'Gene', (22, 26))	('human', 'Species', '9606', (79, 84))	('renal cancer', 'Phenotype', 'HP:0009726', (85, 97))	('inhibited', 'NegReg', (37, 46))	('renal cancer', 'Disease', 'MESH:D007680', (85, 97))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', (47, 52))	('renal cancer', 'Disease', (85, 97))
184123	29660846	Previous reports demonstrated that not only PLD2 but also PLD1 promoted tumor invasion in several cancers.6, 18, 39 Because high PLD1 expression was associated with higher tumor stage and worse clinical stage in patients with ccRCC (Table 1), we examined the roles of PLD1 in the regulation of ANG.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('RCC', 'Disease', 'MESH:C538614', (228, 231))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('tumor', 'Disease', (172, 177))	('patients', 'Species', '9606', (212, 220))	('cancers', 'Disease', (98, 105))	('ANG', 'Gene', (294, 297))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('higher', 'PosReg', (165, 171))	('high', 'Var', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('expression', 'MPA', (134, 144))	('tumor', 'Disease', (72, 77))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('ANG', 'Gene', '283', (294, 297))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (226, 231))	('regulation', 'biological_process', 'GO:0065007', ('280', '290'))	('RCC', 'Disease', (228, 231))	('RCC', 'Phenotype', 'HP:0005584', (228, 231))	('PLD1', 'Gene', (129, 133))
184124	29660846	In fact, it was revealed that the expression of ANG was suppressed by the knockdown of PLD1 (Figure S7).	('ANG', 'Gene', (48, 51))	('expression', 'MPA', (34, 44))	('PLD1', 'Gene', (87, 91))	('knockdown', 'Var', (74, 83))	('suppressed', 'NegReg', (56, 66))	('ANG', 'Gene', '283', (48, 51))
184128	29660846	Although the tumor volume is decreased by TKI, there are few curable patients.	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('TKI', 'Var', (42, 45))	('decreased', 'NegReg', (29, 38))	('patients', 'Species', '9606', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
184135	29660846	Our results provide the first evidence that targeting PLD2 is a good candidate for future therapeutic and clinical applications against metastatic RCC.	('PLD2', 'Gene', (54, 58))	('targeting', 'Var', (44, 53))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('RCC', 'Disease', 'MESH:C538614', (147, 150))
184147	29875134	Genetically, ccRCCs are characterized by inactivation of the von Hippel-Lindau tumor suppressor (VHL), which is lost in up to 90% of ccRCCs.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('79', '95'))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('VHL', 'Gene', '7428', (97, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('inactivation', 'Var', (41, 53))	('von Hippel-Lindau tumor', 'Disease', (61, 84))	('RCC', 'Disease', (135, 138))	('RCC', 'Disease', (15, 18))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('von Hippel-Lindau tumor', 'Disease', 'MESH:D006623', (61, 84))	('tumor suppressor', 'biological_process', 'GO:0051726', ('79', '95'))	('VHL', 'Gene', (97, 100))
184156	29875134	Specifically, altered enhancer activity can modulate cancer risk and activate oncogenes, suggesting that aberrant enhancer usage may also be critical for cancer progression and metastasis.	('altered', 'Var', (14, 21))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('activate', 'PosReg', (69, 77))	('oncogenes', 'Gene', (78, 87))	('modulate', 'Reg', (44, 52))	('enhancer activity', 'MPA', (22, 39))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('aberrant', 'Var', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
184164	29875134	To identify metastasis-associated enhancers (MAEs), we performed ChIP-seq using an antibody for acetylated histone H3 lysine 27 (H3K27ac), a chromatin modification associated with active gene regulatory elements, in four different VHL mutant models of ccRCC: the non-metastatic human cell lines 786-O and OS-RC-2, and the corresponding metastatic subpopulations 786-M1A (M1A) and OS-LM1 (LM1), respectively (Fig.	('antibody', 'molecular_function', 'GO:0003823', ('83', '91'))	('lysine', 'Chemical', 'MESH:D008239', (118, 124))	('OS-RC-2', 'CellLine', 'CVCL:1626', (305, 312))	('VHL', 'Gene', '7428', (231, 234))	('antibody', 'cellular_component', 'GO:0042571', ('83', '91'))	('chromatin modification', 'biological_process', 'GO:0016569', ('141', '163'))	('MAE', 'Gene', '6529', (45, 48))	('human', 'Species', '9606', (278, 283))	('MAE', 'Gene', (45, 48))	('antibody', 'cellular_component', 'GO:0019815', ('83', '91'))	('LM1', 'Gene', (383, 386))	('chromatin modification', 'biological_process', 'GO:0006325', ('141', '163'))	('LM1', 'Gene', (388, 391))	('antibody', 'cellular_component', 'GO:0019814', ('83', '91'))	('RCC', 'Disease', (254, 257))	('RCC', 'Phenotype', 'HP:0005584', (254, 257))	('ccRCC', 'Phenotype', 'HP:0006770', (252, 257))	('VHL', 'Gene', (231, 234))	('mutant', 'Var', (235, 241))	('LM1', 'Gene', '104187', (383, 386))	('LM1', 'Gene', '104187', (388, 391))	('OS-LM1', 'CellLine', 'CVCL:9563', (380, 386))	('RCC', 'Disease', 'MESH:C538614', (254, 257))	('chromatin', 'cellular_component', 'GO:0000785', ('141', '150'))
184166	29875134	At the molecular level, these systems harbor clinically relevant mutations in well-characterized ccRCC genes and their gene expression profiles resemble those seen in ccRCC patients with poor clinical outcome.	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('patients', 'Species', '9606', (173, 181))	('RCC', 'Disease', (169, 172))	('ccRCC', 'Phenotype', 'HP:0006770', (167, 172))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('gene expression', 'biological_process', 'GO:0010467', ('119', '134'))	('RCC', 'Disease', (99, 102))	('clinical', 'Species', '191496', (45, 53))	('clinical', 'Species', '191496', (192, 200))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('mutations', 'Var', (65, 74))
184179	29875134	To further test the clinical relevance of the MAEs identified in our experimental systems, we analyzed H3K27ac patterns and corresponding RNA-seq transcriptomic profiles in a patient cohort of ten matched cases of normal kidney and ccRCC, nine of which harbored confirmed VHL mutations.	('ccRCC', 'Phenotype', 'HP:0006770', (232, 237))	('mutations', 'Var', (276, 285))	('patient', 'Species', '9606', (175, 182))	('MAE', 'Gene', '6529', (46, 49))	('RNA', 'cellular_component', 'GO:0005562', ('138', '141'))	('VHL', 'Gene', (272, 275))	('RCC', 'Phenotype', 'HP:0005584', (234, 237))	('VHL', 'Gene', '7428', (272, 275))	('RCC', 'Disease', 'MESH:C538614', (234, 237))	('H3K27ac', 'Protein', (103, 110))	('RCC', 'Disease', (234, 237))	('clinical', 'Species', '191496', (20, 28))	('MAE', 'Gene', (46, 49))
184180	29875134	In general, H3K27ac-enriched MAEs showed stronger H3K27ac signal in ccRCCs when compared to normal kidney (Supplementary Fig.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('MAE', 'Gene', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('H3K27ac', 'Protein', (50, 57))	('H3K27ac-enriched', 'Var', (12, 28))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('stronger', 'PosReg', (41, 49))	('MAE', 'Gene', '6529', (29, 32))
184192	29875134	Histological analysis revealed that MAE inhibition had a significant negative effect on the number of lung metastatic colonies, indicating a role for MAE-1 and MAE-126 in the early steps of metastatic colonization at the distant site (Fig.	('MAE', 'Gene', (150, 153))	('inhibition', 'Var', (40, 50))	('negative', 'NegReg', (69, 77))	('number of lung metastatic colonies', 'CPA', (92, 126))	('MAE', 'Gene', '6529', (160, 163))	('MAE', 'Gene', '6529', (36, 39))	('MAE', 'Gene', (36, 39))	('MAE', 'Gene', '6529', (150, 153))	('MAE', 'Gene', (160, 163))
184197	29875134	Orthotopic implantation of cancer cells gave concordant results: MAE-1 inhibition did not affect growth in the kidney but metastatic colonization in the lungs was reduced (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('inhibition', 'Var', (71, 81))	('MAE', 'Gene', '6529', (65, 68))	('reduced', 'NegReg', (163, 170))	('MAE', 'Gene', (65, 68))	('cancer', 'Disease', (27, 33))	('metastatic colonization in the lungs', 'CPA', (122, 158))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
184227	29875134	Moreover, mutating the HIF2A binding site decreased MAE-126 reporter activity (Fig.	('mutating', 'Var', (10, 18))	('binding', 'molecular_function', 'GO:0005488', ('29', '36'))	('decreased', 'NegReg', (42, 51))	('HIF2A', 'Gene', (23, 28))	('MAE', 'Gene', '6529', (52, 55))	('HIF2A', 'Gene', '2034', (23, 28))	('MAE', 'Gene', (52, 55))	('binding', 'Interaction', (29, 36))
184228	29875134	6A), and CRISPR/Cas9-based mutational targeting of this site in the endogenous MAE-126 locus abolished CXCR4 mRNA and protein expression in M1A cells (Supplementary Fig.	('mutational targeting', 'Var', (27, 47))	('MAE', 'Gene', '6529', (79, 82))	('abolished', 'NegReg', (93, 102))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))	('CXCR4', 'Gene', '7852', (103, 108))	('MAE', 'Gene', (79, 82))	('CXCR4', 'molecular_function', 'GO:0038147', ('103', '108'))	('CXCR4', 'Gene', (103, 108))	('Cas', 'cellular_component', 'GO:0005650', ('16', '19'))
184233	29875134	S12A-B), suggesting that the MAE-1 DNA sequence determined its activity at least partially independently of the chromatin context.	('chromatin', 'cellular_component', 'GO:0000785', ('112', '121'))	('activity', 'MPA', (63, 71))	('MAE', 'Gene', (29, 32))	('S12A', 'SUBSTITUTION', 'None', (0, 4))	('S12A', 'Var', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('MAE', 'Gene', '6529', (29, 32))
184236	29875134	In line with this possibility, CRISPR/Cas9-based mutational targeting of this site abolished CXCR4 mRNA and protein expression (Fig.	('CXCR4', 'Gene', (93, 98))	('mutational targeting', 'Var', (49, 69))	('abolished', 'NegReg', (83, 92))	('Cas', 'cellular_component', 'GO:0005650', ('38', '41'))	('CXCR4', 'molecular_function', 'GO:0038147', ('93', '98'))	('CXCR4', 'Gene', '7852', (93, 98))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
184237	29875134	Mutating the putative p65/REL binding site decreased MAE-1 reporter activity (Fig.	('p65', 'Gene', (22, 25))	('MAE', 'Gene', (53, 56))	('Mutating', 'Var', (0, 8))	('p65', 'Gene', '5970', (22, 25))	('binding', 'molecular_function', 'GO:0005488', ('30', '37'))	('binding', 'Interaction', (30, 37))	('decreased', 'NegReg', (43, 52))	('MAE', 'Gene', '6529', (53, 56))
184243	29875134	Importantly, mutating the MAE-1 locus decreased the metastatic colonization potential of M1A cells (Fig.	('decreased', 'NegReg', (38, 47))	('MAE', 'Gene', (26, 29))	('metastatic colonization potential of', 'CPA', (52, 88))	('mutating', 'Var', (13, 21))	('MAE', 'Gene', '6529', (26, 29))
184246	29875134	S13A-D) and inhibition of NF-kappaB pathway activity through expression of a super repressor mutant (Supplementary Fig.	('NF-kappaB', 'Gene', '4790', (26, 35))	('S13A', 'SUBSTITUTION', 'None', (0, 4))	('inhibition', 'NegReg', (12, 22))	('NF-kappaB', 'Gene', (26, 35))	('activity', 'MPA', (44, 52))	('mutant', 'Var', (93, 99))	('S13A', 'Var', (0, 4))
184247	29875134	S13E-G) resulted in downregulation of CXCR4 in the M1A cells (Supplementary Fig.	('downregulation', 'NegReg', (20, 34))	('CXCR4', 'molecular_function', 'GO:0038147', ('38', '43'))	('CXCR4', 'Gene', '7852', (38, 43))	('S13E', 'Mutation', 'p.S13E', (0, 4))	('S13E-G', 'Var', (0, 6))	('CXCR4', 'Gene', (38, 43))
184249	29875134	Conversely, expression of a constitutively active IKK-2 mutant, a kinase that can activate the NF-kappaB pathway but also other pathways, resulted in increased NF-kappaB activity, MAE-1 activation and an increase in CXCR4 expression in 786-O cells (Supplementary Fig.	('NF-kappaB', 'Gene', '4790', (95, 104))	('NF-kappaB', 'Gene', (160, 169))	('activation', 'PosReg', (186, 196))	('CXCR4', 'Gene', '7852', (216, 221))	('CXCR4', 'molecular_function', 'GO:0038147', ('216', '221'))	('IKK-2', 'Gene', (50, 55))	('mutant', 'Var', (56, 62))	('NF-kappaB', 'Gene', (95, 104))	('increase', 'PosReg', (204, 212))	('MAE', 'Gene', '6529', (180, 183))	('CXCR4', 'Gene', (216, 221))	('IKK-2', 'molecular_function', 'GO:0008384', ('50', '55'))	('NF-kappaB', 'Gene', '4790', (160, 169))	('increased', 'PosReg', (150, 159))	('MAE', 'Gene', (180, 183))	('IKK-2', 'Gene', '3551', (50, 55))
184274	29875134	However, the level of NF-kappaB activity that directly follows VHL inactivation is insufficient for the activation of the pro-metastatic program.	('inactivation', 'Var', (67, 79))	('pro-metastatic program', 'CPA', (122, 144))	('NF-kappaB', 'Gene', (22, 31))	('VHL', 'Gene', (63, 66))	('VHL', 'Gene', '7428', (63, 66))	('NF-kappaB', 'Gene', '4790', (22, 31))
184287	29875134	The recent findings that modulation of enhancer activity can alter cancer risk, that cancer-specific enhancer elements activate oncogenes, and that cancer-associated enhancer clusters are susceptible to pharmacological inhibition have raised interest in understanding the mechanisms by which gene regulatory elements contribute to cancer progression and metastasis.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('modulation', 'Var', (25, 35))	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('alter', 'Reg', (61, 66))	('enhancer', 'Protein', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('oncogenes', 'CPA', (128, 137))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('activate', 'PosReg', (119, 127))	('contribute', 'Reg', (317, 327))
184291	29875134	The renal cancer cell lines 786-O TGL (786-O), OS-RC-2 TGL (OS-RC-2) and their metastatic derivatives 786-M1A (M1A), 786-M2B (M2B) and OS-LM1 (LM1), respectively, have been previously described and they were obtained from J. Massague (MSKCC, New York) in 2014.	('786-M1A', 'Var', (102, 109))	('renal cancer', 'Disease', (4, 16))	('LM1', 'Gene', (138, 141))	('OS-LM1', 'CellLine', 'CVCL:9563', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('renal cancer', 'Disease', 'MESH:D007680', (4, 16))	('renal cancer', 'Phenotype', 'HP:0009726', (4, 16))	('OS-RC-2', 'CellLine', 'CVCL:1626', (60, 67))	('OS-RC-2', 'CellLine', 'CVCL:1626', (47, 54))	('LM1', 'Gene', '104187', (143, 146))	('LM1', 'Gene', (143, 146))	('LM1', 'Gene', '104187', (138, 141))	('786-M2B', 'Var', (117, 124))
184293	29875134	The identity of the renal cancer cell lines has been confirmed by Sanger sequencing-based detection of known unique homozygous VHL mutations in April 2017.	('mutations', 'Var', (131, 140))	('renal cancer', 'Disease', (20, 32))	('renal cancer', 'Phenotype', 'HP:0009726', (20, 32))	('renal cancer', 'Disease', 'MESH:D007680', (20, 32))	('VHL', 'Gene', (127, 130))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('VHL', 'Gene', '7428', (127, 130))
184302	29875134	The following antibodies were used: H3K27ac (Abcam, ab4729), H3K4me1 (Abcam, ab8895), p300 (Santa Cruz, sc-585), SUZ12 (Abcam ab12073), H3K27me3 (Millipore 17-622), HIF1B (Novus, NB100-110), HIF2A (Abcam ab199) and p65 (Abcam ab16502).	('SUZ12', 'Gene', (113, 118))	('p65', 'Gene', (215, 218))	('HIF1B', 'Gene', '405', (165, 170))	('HIF2A', 'Gene', (191, 196))	('p65', 'Gene', '5970', (215, 218))	('HIF1B', 'Gene', (165, 170))	('H3K27me3', 'Var', (136, 144))	('p300', 'Gene', (86, 90))	('H3K27ac', 'Var', (36, 43))	('HIF2A', 'Gene', '2034', (191, 196))	('H3K4me1', 'Var', (61, 68))	('p300', 'Gene', '2033', (86, 90))	('SUZ12', 'Gene', '23512', (113, 118))
184322	29875134	sgRNA pairs with separate U6 promoters targeting the p300 enhancer peak were cloned in tandem into the pKLV-U6gRNA plasmid (Addgene 50946,) and lentivirally transduced into cells expressing either KRAB-dCas9-mCherry or dCas9-VPR-mCherry, for CRISPRi or CRISPRa, respectively.	('dCas9-VPR-mCherry', 'Var', (219, 236))	('p300', 'Gene', '2033', (53, 57))	('p300', 'Gene', (53, 57))
184332	29875134	H3K27ac signal in H3K27ac-enriched MAEs was normalized to the corresponding input control for all samples, after which each tumor was compared to the corresponding normal sample.	('H3K27ac-enriched', 'Var', (18, 34))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('MAE', 'Gene', '6529', (35, 38))	('tumor', 'Disease', (124, 129))	('MAE', 'Gene', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
184353	29875134	For qPCR, we used the StepOnePlus instrument (Thermo) with pre-designed TaqMan gene expression assays (Thermo): CXCR4 (Hs00607978_s1), DARS (Hs00154683_m1), IL6 (Hs00174131_m1), IL8 (Hs00174103_m1) and TBP (Hs00427620_m1).	('Hs00427620_m1', 'Var', (207, 220))	('Hs00174103_m1', 'Var', (183, 196))	('IL6', 'molecular_function', 'GO:0005138', ('157', '160'))	('pre', 'molecular_function', 'GO:0003904', ('59', '62'))	('CXCR4', 'molecular_function', 'GO:0038147', ('112', '117'))	('IL6', 'Gene', '3569', (157, 160))	('TBP', 'Gene', (202, 205))	('DARS', 'Gene', (135, 139))	('Hs00174131_m1', 'Var', (162, 175))	('Hs00154683_m1', 'Var', (141, 154))	('CXCR4', 'Gene', '7852', (112, 117))	('Hs00607978_s1', 'Var', (119, 132))	('TBP', 'Gene', '6908', (202, 205))	('gene expression', 'biological_process', 'GO:0010467', ('79', '94'))	('IL6', 'Gene', (157, 160))	('CXCR4', 'Gene', (112, 117))	('IL8', 'molecular_function', 'GO:0005153', ('178', '181'))	('IL8', 'Gene', (178, 181))	('DARS', 'Gene', '1615', (135, 139))	('IL8', 'Gene', '3576', (178, 181))
184362	29875134	Similarly, for NF-kB activation in parental ccRCC cells, the IKK-2 S177E S181E mutant (Addgene 11105,) was cloned into the pLVX-Puro vector.	('IKK-2', 'molecular_function', 'GO:0008384', ('61', '66'))	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('RCC', 'Disease', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('IKK-2', 'Gene', (61, 66))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('S177E', 'Mutation', 'p.S177E', (67, 72))	('S177E S181E', 'Var', (67, 78))	('S181E', 'Mutation', 'p.S181E', (73, 78))	('activation', 'PosReg', (21, 31))	('IKK-2', 'Gene', '3551', (61, 66))
184389	28349958	It has facilitated simple and effective recognition of commonly mutated, amplified, inserted and deleted genes across diverse cancer types.	('deleted', 'Var', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))
184502	33919186	HERV reactivation in cancer cells may result in (a) the activation of a viral defense response against cancer, (b) the production of viral proteins that can be recognized as targets by our immune system and (c) the expression of viral transcripts that can be used as therapeutic targets or markers for prognosis.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('defense response', 'biological_process', 'GO:0006952', ('78', '94'))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('production', 'MPA', (119, 129))	('reactivation', 'Var', (5, 17))	('HERV', 'Protein', (0, 4))	('viral', 'CPA', (72, 77))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('activation', 'PosReg', (56, 66))	('expression', 'MPA', (215, 225))
184526	33919186	In particular, evolutionarily old HERVs are characterized by extensive accumulation of genetic mutations or gene loss.	('HERVs', 'Gene', 'None', (34, 39))	('genetic mutations', 'Var', (87, 104))	('HERVs', 'Gene', (34, 39))	('gene', 'Var', (108, 112))
184547	33919186	Several studies indicate that young LTRs are still repressed by G9a after 5-aza-CdR treatment due to epigenetic switch.	('LTR', 'Gene', 'None', (36, 39))	('LTR', 'Gene', (36, 39))	('G9a', 'Gene', (64, 67))	('G9a', 'Gene', '10919', (64, 67))	('epigenetic switch', 'Var', (101, 118))
184550	33919186	Indeed, cancer immunotherapy may benefit from HERV reactivation induced by epigenetic drugs, and the stimulation of a viral mimicry state (Table 2).	('reactivation', 'MPA', (51, 63))	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('epigenetic drugs', 'Var', (75, 91))	('benefit', 'PosReg', (33, 40))	('mimicry state', 'Phenotype', 'HP:0011468', (124, 137))	('HERV', 'Protein', (46, 50))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
184553	33919186	As a result, HERV reactivation may lead to viral protein synthesis with the generation of newly unexplored tumor-specific antigens (TSAs).	('viral protein synthesis', 'MPA', (43, 66))	('HERV', 'Protein', (13, 17))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('viral protein synthesis', 'biological_process', 'GO:0019081', ('43', '66'))	('lead to', 'Reg', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('TSA', 'Chemical', 'MESH:C012589', (132, 135))	('reactivation', 'Var', (18, 30))
184556	33919186	Overall, HERV reactivation in cancer cells may result in (a) a viral mimicry state, (b) generation of highly tumor-specific antigens and (c) expression of LTR-activated transcripts, including lncRNAs (Figure 1).	('LTR', 'Gene', (155, 158))	('ncRNA', 'Gene', (193, 198))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('viral mimicry', 'MPA', (63, 76))	('cancer', 'Disease', (30, 36))	('ncRNA', 'Gene', '220202', (193, 198))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('result in', 'Reg', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('mimicry state', 'Phenotype', 'HP:0011468', (69, 82))	('expression', 'MPA', (141, 151))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('HERV', 'Protein', (9, 13))	('LTR', 'Gene', 'None', (155, 158))	('tumor', 'Disease', (109, 114))	('reactivation', 'Var', (14, 26))
184558	33919186	Indeed, the inherent DNA hypomethylation in some tumors may result in the activation and overexpression of HERVs.	('HERVs', 'Gene', 'None', (107, 112))	('HERVs', 'Gene', (107, 112))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('21', '40'))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('overexpression', 'PosReg', (89, 103))	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('activation', 'PosReg', (74, 84))	('result in', 'Reg', (60, 69))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('DNA hypomethylation', 'Var', (21, 40))
184567	33919186	The authors suggest that TLR7 and IRF5 (interferon regulatory factor 5), a transcription factor activated by TLR7, may play a major role in repressing ERV expression in vivo, given that mice defective for TLR7 spontaneously express ERVs.	('interferon regulatory factor 5', 'Gene', '27056', (40, 70))	('IRF5', 'Gene', (34, 38))	('ERVs', 'MPA', (232, 236))	('interferon regulatory factor 5', 'Gene', (40, 70))	('transcription factor', 'molecular_function', 'GO:0000981', ('75', '95'))	('express', 'Reg', (224, 231))	('ERV', 'Gene', (151, 154))	('mice', 'Species', '10090', (186, 190))	('transcription', 'biological_process', 'GO:0006351', ('75', '88'))	('IRF5', 'Gene', '27056', (34, 38))	('defective', 'Var', (191, 200))	('TLR7', 'Gene', (205, 209))
184575	33919186	Double-stranded RNA from HERVs may also trigger the viral defense pathway through the activation of specific members of the RLR family, including RIG-I and melanoma differentiation-associated protein 5 (MDA5).	('HERVs', 'Gene', (25, 30))	('RIG-I', 'Gene', (146, 151))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('Double-stranded RNA', 'Var', (0, 19))	('MDA5', 'Gene', (203, 207))	('viral defense pathway', 'Pathway', (52, 73))	('MDA5', 'Gene', '64135', (203, 207))	('melanoma differentiation-associated protein 5', 'Gene', '64135', (156, 201))	('protein', 'cellular_component', 'GO:0003675', ('192', '199'))	('melanoma differentiation-associated protein 5', 'Gene', (156, 201))	('trigger', 'PosReg', (40, 47))	('activation', 'PosReg', (86, 96))	('RIG-I', 'Gene', '23586', (146, 151))	('RNA', 'cellular_component', 'GO:0005562', ('16', '19'))	('HERVs', 'Gene', 'None', (25, 30))
184584	33919186	In particular, G9a and DNA methylation were shown to repress a distinct set of HERVs and their combinatorial inhibition with G9ai plus 5-aza-CdR was able to activate more HERVs than the single-agent treatment.	('activate', 'PosReg', (157, 165))	('G9a', 'Gene', (125, 128))	('G9a', 'Gene', '10919', (125, 128))	('G9a', 'Gene', (15, 18))	('G9a', 'Gene', '10919', (15, 18))	('HERVs', 'Gene', (171, 176))	('methylation', 'Var', (27, 38))	('repress', 'NegReg', (53, 60))	('HERVs', 'Gene', 'None', (171, 176))	('G9ai', 'Chemical', '-', (125, 129))	('HERVs', 'Gene', 'None', (79, 84))	('DNA methylation', 'biological_process', 'GO:0006306', ('23', '38'))	('HERVs', 'Gene', (79, 84))	('DNA', 'cellular_component', 'GO:0005574', ('23', '26'))
184586	33919186	In particular, seminomas show variable DNA hypomethylation (i.e., 0.08% methylated CpG) or virtually complete demethylation.	('demethylation', 'biological_process', 'GO:0070988', ('110', '123'))	('demethylation', 'MPA', (110, 123))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('39', '58'))	('methylated', 'Var', (72, 82))	('seminomas', 'Disease', 'MESH:D018239', (15, 24))	('seminomas', 'Disease', (15, 24))
184589	33919186	Overall, the above mentioned studies support the notion that a marked DNA hypomethylation, that can be drug-induced or tumor-constitutive, may upregulate the expression of nucleic acid sequences (e.g., dsRNA) from HERV genomic regions, triggering a viral-like immune activation status that may potentiate the antitumor immune response.	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('70', '89'))	('tumor', 'Disease', (119, 124))	('immune response', 'biological_process', 'GO:0006955', ('319', '334'))	('tumor', 'Disease', (313, 318))	('expression', 'MPA', (158, 168))	('potentiate', 'PosReg', (294, 304))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('upregulate', 'PosReg', (143, 153))	('nucleic acid', 'cellular_component', 'GO:0005561', ('172', '184'))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('hypomethylation', 'Var', (74, 89))	('triggering', 'Reg', (236, 246))
184590	33919186	The inherent dysregulation of the epigenetic state of the cancer genome may result in the expression of tumor-specific HERV proteins.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('HERV proteins', 'Protein', (119, 132))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('epigenetic', 'Var', (34, 44))	('expression', 'MPA', (90, 100))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('result in', 'Reg', (76, 85))
184607	33919186	Overall, these studies strongly support the notion that the expression of HERV antigens in cancer cells may induce high affinity B cell and T cell responses endowed with an antitumor effect, which is currently being evaluated in a phase I clinical trial (ClinicalTrials.gov Identifier: NCT03354390).	('high affinity B cell', 'CPA', (115, 135))	('expression', 'Var', (60, 70))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('induce', 'PosReg', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', (177, 182))	('HERV', 'Protein', (74, 78))
184608	33919186	Additional effects of HERV reactivation in tumor tissues are represented by T-cell infiltration, as well as upregulation of immune checkpoints, including programmed cell death-1 (PD-1) and cytotoxic T-cell-associated protein 4 (CTLA-4).	('cell-associated', 'cellular_component', 'GO:0009986', ('201', '216'))	('HERV', 'Protein', (22, 26))	('programmed cell death', 'biological_process', 'GO:0012501', ('154', '175'))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cytotoxic T-cell-associated protein 4', 'Gene', (189, 226))	('protein', 'cellular_component', 'GO:0003675', ('217', '224'))	('T-cell infiltration', 'CPA', (76, 95))	('cytotoxic T-cell-associated protein 4', 'Gene', '397286', (189, 226))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('reactivation', 'Var', (27, 39))	('immune checkpoints', 'MPA', (124, 142))	('tumor', 'Disease', (43, 48))	('upregulation', 'PosReg', (108, 120))
184621	33919186	Finally, several epigenetic genes were identified whose expression levels were significantly correlated with overall HERV expression in ccRCC, breast cancer and colon cancer, strongly supporting the notion that epigenetic dysregulation may induce HERV reactivation in multiple cancers.	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('expression', 'MPA', (122, 132))	('correlated', 'Reg', (93, 103))	('breast cancer', 'Disease', (143, 156))	('expression levels', 'MPA', (56, 73))	('colon cancer', 'Phenotype', 'HP:0003003', (161, 173))	('ccRCC', 'Disease', (136, 141))	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('HERV', 'Protein', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('colon cancer', 'Disease', 'MESH:D015179', (161, 173))	('induce', 'PosReg', (240, 246))	('epigenetic dysregulation', 'Var', (211, 235))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('HERV', 'Protein', (247, 251))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('cancers', 'Disease', (277, 284))	('colon cancer', 'Disease', (161, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('reactivation', 'MPA', (252, 264))
184622	33919186	In such a complex scenario, several factors may contribute to an effective antitumor immune response, including HERV reactivation by epigenetic drugs.	('HERV', 'Protein', (112, 116))	('tumor', 'Disease', (79, 84))	('epigenetic drugs', 'Var', (133, 149))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('immune response', 'biological_process', 'GO:0006955', ('85', '100'))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
184624	33919186	By activating HERVs, epigenetic drugs may turn "cold" tumors into "hot" tumors, promoting a robust immune cell infiltration.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('activating', 'Reg', (3, 13))	('immune cell infiltration', 'CPA', (99, 123))	('promoting', 'PosReg', (80, 89))	('tumors', 'Disease', (72, 78))	('HERVs', 'Gene', (14, 19))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('epigenetic drugs', 'Var', (21, 37))	('HERVs', 'Gene', 'None', (14, 19))	('tumors', 'Disease', (54, 60))
184626	33919186	Taken together, these results indicate that HERV reactivation significantly correlates with improved overall response in cancer patients treated with immune checkpoint inhibitors.	('HERV', 'Protein', (44, 48))	('overall response', 'CPA', (101, 117))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('patients', 'Species', '9606', (128, 136))	('improved', 'PosReg', (92, 100))	('cancer', 'Disease', (121, 127))	('reactivation', 'Var', (49, 61))
184640	33919186	LncMER52A was able to promote the invasion and metastasis of HCC cells in vitro and in vivo, regulating the EMT signaling pathway via post-translational control of p120-catenin protein stability.	('LncMER52A', 'Var', (0, 9))	('promote', 'PosReg', (22, 29))	('EMT', 'biological_process', 'GO:0001837', ('108', '111'))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('invasion', 'CPA', (34, 42))	('HCC', 'Phenotype', 'HP:0001402', (61, 64))	('metastasis', 'CPA', (47, 57))	('signaling pathway', 'biological_process', 'GO:0007165', ('112', '129'))	('p120-catenin', 'Gene', (164, 176))	('EMT signaling pathway', 'Pathway', (108, 129))	('p120-catenin', 'Gene', '1500', (164, 176))	('regulating', 'Reg', (93, 103))
184646	33919186	Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that cellular processes involved in leukocyte activation and immune responses were significantly enriched in HB samples with high HERV-K expression patterns.	('high', 'Var', (214, 218))	('HERV-K', 'Protein', (219, 225))	('expression', 'MPA', (226, 236))	('HB', 'Phenotype', 'HP:0002884', (198, 200))	('leukocyte activation', 'biological_process', 'GO:0045321', ('125', '145'))	('Gene Ontology', 'biological_process', 'GO:0003673', ('0', '13'))	('HERV-K', 'Species', '45617', (219, 225))
184653	33919186	Interestingly, the group of patients with high-level expression of HERV-K showed poor prognosis with reduced overall survival (p-value < 0.01).	('high-level expression', 'Var', (42, 63))	('overall survival', 'MPA', (109, 125))	('reduced', 'NegReg', (101, 108))	('HERV-K', 'Species', '45617', (67, 73))	('HERV-K', 'Gene', (67, 73))	('patients', 'Species', '9606', (28, 36))
184658	33919186	Current research on HERVs is gaining significant interest due to two major synergistically effects that HERV reactivation may have on the tumor-specific immune response in the setting of cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('tumor', 'Disease', (138, 143))	('cancer', 'Disease', (187, 193))	('reactivation', 'Var', (109, 121))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('immune response', 'biological_process', 'GO:0006955', ('153', '168'))	('HERVs', 'Gene', (20, 25))	('HERV', 'Gene', (104, 108))	('HERVs', 'Gene', 'None', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
184660	33919186	A second effect of HERV reactivation is associated with the expression of HERV antigens, which may ultimately evoke a vigorous tumor-specific B and T cell response.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('expression', 'Var', (60, 70))	('evoke', 'PosReg', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('HERV antigens', 'Protein', (74, 87))
184695	29700419	Taken together, these results suggested that the alteration of the 14-gene signature significantly affected the outcome of patients, while changes in the 9-gene signature did not influence the prognosis.	('alteration', 'Var', (49, 59))	('patients', 'Species', '9606', (123, 131))	('affected', 'Reg', (99, 107))
184720	29700419	Stages III + IV), T stage (T1 + T2 vs. T3 + T4), M stage (M0 vs. M1), N stage (N0 vs. N1) and neoplasm histologic grade (G1 + G2 vs. G3 + G4) in ccRCC (Fig.	('G1 + G2 vs. G3 + G4', 'Var', (121, 140))	('T1 + T2', 'Var', (27, 34))	('neoplasm', 'Disease', (94, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (145, 150))	('RCC', 'Disease', (147, 150))	('neoplasm', 'Disease', 'MESH:D009369', (94, 102))	('neoplasm', 'Phenotype', 'HP:0002664', (94, 102))	('RCC', 'Disease', 'MESH:C538614', (147, 150))
184724	29700419	We found that in ccRCC patients, 28.01% of EMT genes were dysregulated and 47.34% of EMT genes were significantly correlated with prognosis.	('correlated', 'Reg', (114, 124))	('dysregulated', 'Var', (58, 70))	('EMT genes', 'Gene', (43, 52))	('EMT', 'biological_process', 'GO:0001837', ('85', '88'))	('patients', 'Species', '9606', (23, 31))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('ccRCC', 'Phenotype', 'HP:0006770', (17, 22))	('RCC', 'Disease', (19, 22))	('EMT', 'biological_process', 'GO:0001837', ('43', '46'))
184725	29700419	In addition, the alteration of CEG was validated to be associated with worse outcomes, and the expression of 14 genes was verified to be positively associated with high histopathologic grade, high tumour stage and metastasis.	('high histopathologic grade', 'CPA', (164, 190))	('metastasis', 'CPA', (214, 224))	('associated', 'Reg', (55, 65))	('alteration', 'Var', (17, 27))	('associated', 'Reg', (148, 158))	('CEG', 'Gene', (31, 34))	('high tumour', 'Disease', (192, 203))	('high tumour', 'Disease', 'MESH:D009369', (192, 203))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))
184729	29700419	reported that a CD276-targeting ADC could simultaneously target both cancer cells and the tumour vasculature, and the m276-PBD has shown broad tumouricidal and anti-metastatic activity in vivo.	('tumour vasculature', 'Disease', (90, 108))	('CD276', 'Gene', (16, 21))	('CD276', 'Gene', '80381', (16, 21))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('anti-metastatic activity', 'CPA', (160, 184))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('m276-PBD', 'Var', (118, 126))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumour', 'Disease', (143, 149))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('tumour vasculature', 'Disease', 'MESH:C565633', (90, 108))	('tumour', 'Disease', (90, 96))	('cancer', 'Disease', (69, 75))
184810	27933273	Distinct pre-specified multivariate Cox models that analyzed the estimated effects of the plasma or urine score and established prognostic factors in ccRCC (age and performance status) also provided evidence of statistical associations with survival in the case of urine scores (likelihood ratio test p = 0.016 and Dxy = 0.50 for OS, p = 0.021 and Dxy = 0.48 for PFS).	('ccRCC', 'Phenotype', 'HP:0006770', (150, 155))	('OS', 'Chemical', '-', (330, 332))	('pre', 'molecular_function', 'GO:0003904', ('9', '12'))	('associations', 'Interaction', (223, 235))	('ccRCC', 'Disease', (150, 155))	('Cox', 'Gene', '1351', (36, 39))	('urine scores', 'Var', (265, 277))	('Cox', 'Gene', (36, 39))
184827	27933273	Taken together, these results constitute first time evidence that both the plasma and urine biomarker scores at the time of sampling could predict prognosis of ccRCC patients, both in terms of OS and PFS, and that there exists a quantitative linear increase of the risk with increasing scores.	('ccRCC', 'Phenotype', 'HP:0006770', (160, 165))	('ccRCC', 'Disease', (160, 165))	('predict', 'Reg', (139, 146))	('scores', 'Var', (286, 292))	('OS', 'Chemical', '-', (193, 195))	('patients', 'Species', '9606', (166, 174))
184844	33067881	The panoramic picture of pepsinogen gene family with pan-cancer The panoramic picture of pepsinogen gene family with pan-cancer It is well known that pepsinogen (PGs), as an important precursor of pepsin performing digestive function, has a good correlation with the occurrence and development of gastric cancer and it is also known that ectopic PGs expression is related to the prognosis of some cancers.	('correlation', 'Reg', (246, 257))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (57, 63))	('related', 'Reg', (364, 371))	('gastric cancer', 'Phenotype', 'HP:0012126', (297, 311))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (397, 404))	('cancer', 'Disease', (397, 403))	('cancers', 'Disease', (397, 404))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('PGs', 'Chemical', 'MESH:D010715', (346, 349))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('PGs', 'Chemical', 'MESH:D010715', (162, 165))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('gastric cancer', 'Disease', (297, 311))	('ectopic', 'Var', (338, 345))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('cancers', 'Disease', 'MESH:D009369', (397, 404))	('cancer', 'Disease', (305, 311))	('gastric cancer', 'Disease', 'MESH:D013274', (297, 311))	('cancer', 'Disease', (121, 127))
184846	33067881	This study focused on elucidating the expression profile, activated pathway, immune cells infiltration, mutation, and copy number variation of PGs and their potential role in human cancer.	('human', 'Species', '9606', (175, 180))	('copy number variation', 'Var', (118, 139))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('PGs', 'Chemical', 'MESH:D010715', (143, 146))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('PGs', 'Gene', (143, 146))	('cancer', 'Disease', (181, 187))
184847	33067881	Based on the next generation sequence data from TCGA, Oncomine, and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically by R language, including the expression, mutation, and copy number variation of PGs and their correlation with cancer-related signal transduction pathway, immune cell infiltration, and prognostic potential in different cancers.	('cancer', 'Disease', 'MESH:D009369', (394, 400))	('cancers', 'Disease', 'MESH:D009369', (394, 401))	('PGs', 'Chemical', 'MESH:D010715', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Disease', (286, 292))	('copy number variation', 'Var', (230, 251))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('PGs', 'Gene', (255, 258))	('PGs', 'Chemical', 'MESH:D010715', (255, 258))	('cancers', 'Phenotype', 'HP:0002664', (394, 401))	('cancers', 'Disease', (394, 401))	('cancer', 'Disease', (394, 400))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('CCLE', 'Chemical', '-', (68, 72))	('tumor', 'Disease', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (394, 400))	('Oncomine', 'Chemical', '-', (54, 62))	('signal transduction', 'biological_process', 'GO:0007165', ('301', '320'))	('tumor', 'Disease', 'MESH:D009369', (134, 139))
184852	33067881	PGs expression was significantly related to the activation or inhibition of many signal transduction pathways, in which PGC and PGA5 are more likely to be associated with cancer-related pathways.	('signal transduction pathways', 'Pathway', (81, 109))	('PGC', 'Gene', (120, 123))	('signal transduction', 'biological_process', 'GO:0007165', ('81', '100'))	('PGA5', 'Gene', (128, 132))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('PGs', 'Chemical', 'MESH:D010715', (0, 3))	('associated', 'Reg', (155, 165))	('cancer', 'Disease', (171, 177))	('PGs', 'Var', (0, 3))	('PGA5', 'Gene', '5222', (128, 132))	('activation', 'PosReg', (48, 58))	('PGC', 'Gene', '5225', (120, 123))	('inhibition', 'NegReg', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
184858	33067881	Genetic variation analysis showed that PGC gene often mutated in uterine corpus endometrial carcinoma and stomach adenocarcinoma had extensive copy number amplification in various tumor types.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('tumor', 'Disease', (180, 185))	('PGC', 'Gene', '5225', (39, 42))	('mutated', 'Var', (54, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (80, 101))	('copy number amplification', 'MPA', (143, 168))	('endometrial carcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D016889', (80, 128))	('PGC', 'Gene', (39, 42))
184859	33067881	PGC expression was upregulated with the increase of copy number in cholangiocarcinoma, esophageal carcinoma, and kidney renal papillary cell carcinoma, while in stomach adenocarcinoma, PGC was upregulated regardless of whether the copy number was increased or decreased.	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (120, 150))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('expression', 'MPA', (4, 14))	('esophageal carcinoma', 'Disease', (87, 107))	('cholangiocarcinoma', 'Disease', (67, 85))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))	('PGC', 'Gene', (185, 188))	('kidney renal papillary cell carcinoma', 'Disease', (113, 150))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (87, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (161, 183))	('upregulated', 'PosReg', (193, 204))	('upregulated', 'PosReg', (19, 30))	('PGC', 'Gene', (0, 3))	('PGC', 'Gene', '5225', (185, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('stomach adenocarcinoma', 'Disease', (161, 183))	('PGC', 'Gene', '5225', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('increase', 'PosReg', (40, 48))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (87, 107))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (113, 150))	('copy number', 'Var', (52, 63))
184863	33067881	The variation of copy number of PGC gene could affect the PGC expression.	('PGC', 'Gene', (58, 61))	('variation', 'Var', (4, 13))	('copy number', 'Var', (17, 28))	('expression', 'MPA', (62, 72))	('PGC', 'Gene', '5225', (32, 35))	('PGC', 'Gene', (32, 35))	('affect', 'Reg', (47, 53))	('PGC', 'Gene', '5225', (58, 61))
184865	33067881	Based on the next generation sequence data from TCGA and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically including the expression profiles, mutation and copy number variation of PGs and their correlation with cancer-related signal transduction pathway, immune cell infiltration and prognostic potential in different cancers.	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('signal transduction', 'biological_process', 'GO:0007165', ('283', '302'))	('CCLE', 'Chemical', '-', (57, 61))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancers', 'Disease', 'MESH:D009369', (375, 382))	('correlation', 'Reg', (251, 262))	('cancer', 'Disease', 'MESH:D009369', (375, 381))	('PGs', 'Chemical', 'MESH:D010715', (113, 116))	('cancers', 'Disease', (375, 382))	('copy number variation', 'Var', (212, 233))	('PGs', 'Gene', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Disease', (268, 274))	('PGs', 'Chemical', 'MESH:D010715', (237, 240))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancers', 'Phenotype', 'HP:0002664', (375, 382))	('cancer', 'Disease', (375, 381))
184885	33067881	In this study, by using the multilevel data from TCGA based Pan-Cancer Atlas, Oncomine and Cancer Cell Line Encyclopedia (CCLE), we focused on the elucidating expression profile, activated pathway, immune cells infiltration, mutation, and copy number variation of PGs and their prediction/diagnosis/prognosis potential in pan-cancer.	('Cancer', 'Disease', (91, 97))	('Cancer', 'Disease', (64, 70))	('Cancer', 'Disease', 'MESH:D009369', (91, 97))	('CCLE', 'Chemical', '-', (122, 126))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('-cancer', 'Disease', 'MESH:D009369', (325, 332))	('-cancer', 'Disease', (325, 332))	('Oncomine', 'Chemical', '-', (78, 86))	('PGs', 'Chemical', 'MESH:D010715', (264, 267))	('copy number variation', 'Var', (239, 260))	('PGs', 'Gene', (264, 267))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
184886	33067881	We totally collected the information of 33 different kinds of tumors in TCGA database (http://cancergenome.nih.gov/), including the information of TPM (Transcripts Per Kilobase Million) expression, mutation, and copy number variation.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('copy number variation', 'Var', (212, 233))	('TPM', 'Gene', (147, 150))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Disease', (94, 100))	('mutation', 'Var', (198, 206))
184891	33067881	CCLE database(https://portals.broadinstitute.org/ccle)was used to identify the PGs expression, mutation, and copy number variation in different cancer cell lines, including all 431 cell lines from six cancer types.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('CCLE', 'Chemical', '-', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('PGs', 'Chemical', 'MESH:D010715', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('PGs', 'Gene', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('mutation', 'Var', (95, 103))
184904	33067881	The frequency of CNV in each cancer type and cell lines was calculated as the proportion of CNV amplification and deletion.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('deletion', 'Var', (114, 122))
184916	33067881	The results showed that in stomach adenocarcinoma and lung squamous cell carcinoma, high expression of PG is a protective factor, and high expression can reduce the risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('reduce', 'NegReg', (154, 160))	('high expression', 'Var', (134, 149))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (27, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (54, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('stomach adenocarcinoma', 'Disease', (27, 49))	('lung squamous cell carcinoma', 'Disease', (54, 82))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 82))
184927	33067881	The results show that PGs expression was significantly related to the activation or inhibition of many carcinogenic pathways (Figure 7A), in which PGC and PGA5 are more likely to be associated with carcinogenic processes.	('PGC', 'Gene', (147, 150))	('carcinogenic', 'Disease', 'MESH:D063646', (198, 210))	('associated', 'Reg', (182, 192))	('carcinogenic', 'Disease', (198, 210))	('inhibition', 'NegReg', (84, 94))	('expression', 'Var', (26, 36))	('PGA5', 'Gene', (155, 159))	('PGs', 'Gene', (22, 25))	('PGA5', 'Gene', '5222', (155, 159))	('carcinogenic', 'Disease', 'MESH:D063646', (103, 115))	('carcinogenic', 'Disease', (103, 115))	('activation', 'PosReg', (70, 80))	('related', 'Reg', (55, 62))	('PGs', 'Chemical', 'MESH:D010715', (22, 25))	('PGC', 'Gene', '5225', (147, 150))
184951	33067881	The results showed that PGC gene mutations frequently occurred in uterine corpus endometrial carcinoma and stomach adenocarcinoma (Figure 10A).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('PGC', 'Gene', '5225', (24, 27))	('PGC', 'Gene', (24, 27))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (81, 102))	('endometrial carcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D016889', (81, 129))	('mutations', 'Var', (33, 42))	('occurred', 'Reg', (54, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))
184954	33067881	PGA3, PGA4, and PGA5 showed more copy number amplification in lung adenocarcinoma, esophageal carcinoma, kidney chromophobe, and copy number reduction in bladder urothelial carcinoma, lung squamous cell carcinoma, rectum adenocarcinoma, and cholangiocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (62, 81))	('copy number', 'Var', (129, 140))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (184, 212))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('PGA4', 'Gene', '643847', (6, 10))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (241, 259))	('PGA5', 'Gene', (16, 20))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (214, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('cholangiocarcinoma', 'Disease', (241, 259))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (241, 259))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (83, 103))	('copy', 'MPA', (33, 37))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (184, 212))	('lung squamous cell carcinoma', 'Disease', (184, 212))	('kidney chromophobe', 'Disease', 'MESH:D000238', (105, 123))	('PGA5', 'Gene', '5222', (16, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (189, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('esophageal carcinoma', 'Disease', (83, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('kidney chromophobe', 'Disease', (105, 123))	('PGA3', 'Chemical', '-', (0, 4))	('rectum adenocarcinoma', 'Disease', (214, 235))	('bladder urothelial carcinoma', 'Disease', (154, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('PGA4', 'Gene', (6, 10))	('lung adenocarcinoma', 'Disease', (62, 81))	('PGA3', 'Gene', (0, 4))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (83, 103))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (154, 182))
184955	33067881	In addition, CCLE database analysis revealed the mutation status of PGs in different human cancer cell lines, which showed that there were frequent mutations of PGs in colorectal cancer and gastric cancer cell lines (Figure 11).	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))	('gastric cancer', 'Disease', 'MESH:D013274', (190, 204))	('cancer', 'Disease', (198, 204))	('PGs', 'Chemical', 'MESH:D010715', (68, 71))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('colorectal cancer', 'Disease', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('PGs', 'Gene', (161, 164))	('CCLE', 'Chemical', '-', (13, 17))	('mutations', 'Var', (148, 157))	('PGs', 'Chemical', 'MESH:D010715', (161, 164))	('gastric cancer', 'Phenotype', 'HP:0012126', (190, 204))	('rectal cancer', 'Phenotype', 'HP:0100743', (172, 185))	('human', 'Species', '9606', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('cancer', 'Disease', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (179, 185))	('gastric cancer', 'Disease', (190, 204))
184956	33067881	In order to explore whether PGC self-variation affects its expression, we analyzed the correlation between PGs mutation, CNV, and PGs expression.	('PGs', 'Gene', (107, 110))	('PGC', 'Gene', '5225', (28, 31))	('PGC', 'Gene', (28, 31))	('PGs', 'Chemical', 'MESH:D010715', (130, 133))	('expression', 'MPA', (59, 69))	('PGs', 'Chemical', 'MESH:D010715', (107, 110))	('mutation', 'Var', (111, 119))
184957	33067881	The results showed that PGs mutations did not affect the PGs expression in all cancers.	('cancers', 'Disease', (79, 86))	('PGs', 'Chemical', 'MESH:D010715', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PGs', 'Chemical', 'MESH:D010715', (24, 27))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('mutations', 'Var', (28, 37))	('PGs', 'Gene', (24, 27))
184960	33067881	In this study, we used the multilevel data of TCGA, Oncomine, and CCLE to reveal the expression and activated pathways, mutation, and copy number variation, prognostic potential of PGs in all 33 types of tumors and 431 cell lines, aiming to clarify the important role of PGs in tumorigenesis and development of cancers.	('Oncomine', 'Chemical', '-', (52, 60))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('copy number variation', 'Var', (134, 155))	('tumor', 'Disease', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('CCLE', 'Chemical', '-', (66, 70))	('PGs', 'Chemical', 'MESH:D010715', (271, 274))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('cancers', 'Disease', (311, 318))	('tumor', 'Disease', (204, 209))	('PGs', 'Chemical', 'MESH:D010715', (181, 184))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
184961	33067881	The results suggest that there was differential expression of PGs between many kinds of cancer tissues and corresponding normal tissues, which is related to the prognosis of patients; PGs expression was closely associated with the activation of cancer-related pathways and immune cell infiltration; the copy number variation of PGC could affect the gene expression.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('gene expression', 'MPA', (349, 364))	('PGC', 'Gene', (328, 331))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('affect', 'Reg', (338, 344))	('gene expression', 'biological_process', 'GO:0010467', ('349', '364'))	('cancer', 'Disease', (245, 251))	('immune cell infiltration', 'CPA', (273, 297))	('PGs', 'Chemical', 'MESH:D010715', (62, 65))	('copy number variation', 'Var', (303, 324))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('PGC', 'Gene', '5225', (328, 331))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('associated', 'Reg', (211, 221))	('PGs', 'Chemical', 'MESH:D010715', (184, 187))
184980	33067881	The loss of pepsinogen in advanced esophageal squamous cell carcinoma indicates that pepsin is involved in the process of protein synthesis in the esophagus and causes esophageal carcinogenesis.	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('pepsin', 'Var', (85, 91))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (168, 193))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (35, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('causes', 'Reg', (161, 167))	('esophageal carcinogenesis', 'Disease', (168, 193))	('protein synthesis', 'biological_process', 'GO:0006412', ('122', '139'))	('esophageal squamous cell carcinoma', 'Disease', (35, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('loss', 'NegReg', (4, 8))	('pepsinogen', 'Protein', (12, 22))
184982	33067881	Both lung tissue and gastric mucosa have the same function of producing pepsinogen molecules, 11  and the injury of normal lung tissue could increase the synthesis of pepsinogen C. 22  Some studies have also suggested that the existence of pepsin in respiratory biological samples was caused by gastroesophageal reflux associated lung inhalation.	('increase', 'PosReg', (141, 149))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (295, 318))	('pepsinogen C', 'Gene', '5225', (167, 179))	('injury', 'Var', (106, 112))	('synthesis', 'biological_process', 'GO:0009058', ('154', '163'))	('pepsinogen C', 'Gene', (167, 179))	('gastroesophageal reflux', 'Disease', (295, 318))	('pepsin', 'Gene', (240, 246))	('synthesis', 'MPA', (154, 163))	('caused by', 'Reg', (285, 294))
185003	33067881	The results showed that the overall average mutation rate of PGs was 0%-5.3%, and the mutation rate of PGC was higher in stomach adenocarcinoma and endometrial carcinoma.	('higher', 'Reg', (111, 117))	('PGC', 'Gene', '5225', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('PGs', 'Chemical', 'MESH:D010715', (61, 64))	('PGC', 'Gene', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (148, 169))	('mutation', 'Var', (86, 94))	('stomach adenocarcinoma and endometrial carcinoma', 'Disease', 'MESH:D016889', (121, 169))
185004	33067881	It is worth noticed that all PGC, PGA3, and PGA5 genes had a certain degree of mutation in endometrial carcinoma, which is a tumor with high global mutation rate.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('PGA3', 'Gene', (34, 38))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (91, 112))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('PGA3', 'Chemical', '-', (34, 38))	('PGA5', 'Gene', (44, 48))	('mutation', 'Var', (79, 87))	('PGC', 'Gene', '5225', (29, 32))	('PGC', 'Gene', (29, 32))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (91, 112))	('endometrial carcinoma', 'Disease', (91, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('PGA5', 'Gene', '5222', (44, 48))
185005	33067881	31  In addition, CCLE-based analysis of human cancer cell lines showed that most of the PGs mutations were found in colorectal adenocarcinoma and stomach adenocarcinoma cell lines, suggesting PGs mutation may be the key events in tumorigenesis and development of both gastric cancer and colorectal adenocarcinoma.	('CCLE', 'Chemical', '-', (17, 21))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('gastric cancer', 'Disease', (268, 282))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (287, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('gastric cancer', 'Disease', 'MESH:D013274', (268, 282))	('colorectal adenocarcinoma', 'Disease', (116, 141))	('human', 'Species', '9606', (40, 45))	('tumor', 'Disease', (230, 235))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', (46, 52))	('PGs', 'Chemical', 'MESH:D010715', (192, 195))	('mutations', 'Var', (92, 101))	('PGs', 'Gene', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('PGs', 'Chemical', 'MESH:D010715', (88, 91))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (116, 141))	('gastric cancer', 'Phenotype', 'HP:0012126', (268, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('colorectal adenocarcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D000230', (116, 168))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('found', 'Reg', (107, 112))	('colorectal adenocarcinoma', 'Disease', (287, 312))
185006	33067881	In this study, we also found that there was extensive copy number amplification in various tumor types, which may be related to its widespread expression in various tissues.	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('copy number amplification', 'Var', (54, 79))	('tumor', 'Disease', 'MESH:D009369', (91, 96))
185008	33067881	The results showed that there was no correlation between PGs mutation and PGs expression in cancer cells.	('PGs', 'Chemical', 'MESH:D010715', (74, 77))	('cancer', 'Disease', (92, 98))	('PGs', 'Chemical', 'MESH:D010715', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutation', 'Var', (61, 69))	('PGs', 'Gene', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
185009	33067881	However, previous studies in our lab have found that PGC gene insertion-deletion fragment polymorphism and single nucleotide polymorphism from human germline cells can affect PGC expression.	('PGC', 'Gene', (175, 178))	('human', 'Species', '9606', (143, 148))	('expression', 'MPA', (179, 189))	('insertion-deletion fragment polymorphism', 'Var', (62, 102))	('single nucleotide polymorphism', 'Var', (107, 137))	('PGC', 'Gene', '5225', (53, 56))	('PGC', 'Gene', (53, 56))	('affect', 'Reg', (168, 174))	('PGC', 'Gene', '5225', (175, 178))
185011	33067881	In cholangiocarcinoma, esophageal cancer, and kidney renal papillary cell carcinoma, PGC expression was upregulated with the increase of copy number, but in stomach adenocarcinoma, both increase and deletion of PGC copy number could lead to the up-regulation of PGC expression.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('expression', 'MPA', (266, 276))	('PGC', 'Gene', '5225', (211, 214))	('stomach adenocarcinoma', 'Disease', (157, 179))	('deletion', 'Var', (199, 207))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))	('cholangiocarcinoma', 'Disease', (3, 21))	('copy number', 'Var', (215, 226))	('up-regulation', 'PosReg', (245, 258))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (46, 83))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (53, 83))	('PGC', 'Gene', (262, 265))	('upregulated', 'PosReg', (104, 115))	('PGC', 'Gene', (85, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('PGC', 'Gene', '5225', (262, 265))	('kidney renal papillary cell carcinoma', 'Disease', (46, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('PGC', 'Gene', (211, 214))	('cancer', 'Disease', (34, 40))	('PGC', 'Gene', '5225', (85, 88))	('regulation', 'biological_process', 'GO:0065007', ('248', '258'))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (157, 179))
185063	33194655	It has also been shown that TXNIP overexpression in T238 cells inhibits tumor growth and decreases metastasis in a mouse model of in situ thyroid cancer.	('T238', 'CellLine', 'CVCL:6299', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('thyroid cancer', 'Phenotype', 'HP:0002890', (138, 152))	('tumor', 'Disease', (72, 77))	('inhibits', 'NegReg', (63, 71))	('mouse', 'Species', '10090', (115, 120))	('overexpression', 'PosReg', (34, 48))	('situ thyroid cancer', 'Disease', (133, 152))	('metastasis', 'CPA', (99, 109))	('situ thyroid cancer', 'Disease', 'MESH:D013964', (133, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('decreases', 'NegReg', (89, 98))	('TXNIP', 'Var', (28, 33))
185065	33194655	The pathogenesis of PTC is related to the dysfunction of many oncogenes, apoptosis-related genes, and tumor suppressor genes.	('apoptosis', 'biological_process', 'GO:0097194', ('73', '82'))	('apoptosis', 'biological_process', 'GO:0006915', ('73', '82'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('102', '118'))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('102', '118'))	('dysfunction', 'Var', (42, 53))	('PTC', 'Gene', (20, 23))	('PTC', 'Phenotype', 'HP:0002895', (20, 23))	('pathogenesis', 'biological_process', 'GO:0009405', ('4', '16'))	('PTC', 'Gene', '5979', (20, 23))	('apoptosis-related genes', 'Gene', (73, 96))	('oncogenes', 'Gene', (62, 71))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
185099	33194655	It has also been reported that the NRF2 expression is high in PCA and that knocking down NRF2 can promote TXNIP expression by binding to the TXNIP promoter.	('expression', 'MPA', (40, 50))	('NRF2', 'Gene', '4780', (35, 39))	('NRF2', 'Gene', (89, 93))	('promote', 'PosReg', (98, 105))	('binding', 'Interaction', (126, 133))	('PCA', 'Phenotype', 'HP:0012125', (62, 65))	('NRF2', 'Gene', (35, 39))	('knocking down', 'Var', (75, 88))	('NRF2', 'Gene', '4780', (89, 93))	('binding', 'molecular_function', 'GO:0005488', ('126', '133'))	('TXNIP expression', 'MPA', (106, 122))
185139	33194655	Studies have also confirmed that TXNIP overexpression can inhibit the proliferation of esophageal cancer cells and increase the therapeutic sensitivity of cisplatin and other chemotherapy drugs used for the treatment of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('overexpression', 'PosReg', (39, 53))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('cancer', 'Disease', (231, 237))	('increase', 'PosReg', (115, 123))	('proliferation', 'CPA', (70, 83))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('TXNIP', 'Var', (33, 38))	('cancer', 'Disease', (98, 104))	('inhibit', 'NegReg', (58, 65))	('therapeutic sensitivity of cisplatin', 'MPA', (128, 164))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('men', 'Species', '9606', (212, 215))
185149	33194655	In A549 cells, the combination of gemcitabine and cisplatin results in G0/G1 phase arrest and the upregulation of TXNIP.	('arrest', 'Disease', 'MESH:D006323', (83, 89))	('gemcitabine', 'Chemical', 'MESH:C056507', (34, 45))	('A549', 'CellLine', 'CVCL:0023', (3, 7))	('arrest', 'Disease', (83, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('G1 phase', 'biological_process', 'GO:0051318', ('74', '82'))	('upregulation', 'PosReg', (98, 110))	('TXNIP', 'MPA', (114, 119))	('gemcitabine', 'Var', (34, 45))	('cisplatin', 'Var', (50, 59))
185157	33194655	The mechanism for this is that TXNIP triggers cell death by inhibiting thioredoxin and activating apoptotic signal-regulated kinase 1 (ASK1) signaling.	('inhibiting', 'NegReg', (60, 70))	('thioredoxin', 'molecular_function', 'GO:0000008', ('71', '82'))	('TXNIP', 'Var', (31, 36))	('apoptotic signal-regulated kinase 1', 'Gene', '4217', (98, 133))	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('activating', 'PosReg', (87, 97))	('ASK1', 'Gene', '4217', (135, 139))	('ASK1', 'Gene', (135, 139))	('death', 'Disease', 'MESH:D003643', (51, 56))	('death', 'Disease', (51, 56))	('thioredoxin', 'Gene', '7295', (71, 82))	('thioredoxin', 'molecular_function', 'GO:0030508', ('71', '82'))	('apoptotic signal-regulated kinase 1', 'Gene', (98, 133))	('cell death', 'biological_process', 'GO:0008219', ('46', '56'))	('thioredoxin', 'Gene', (71, 82))
185158	33194655	This drug combination can also kill mutant NSCLC and may therefore be important in the treatment of NSCLC.	('NSCLC', 'Disease', (100, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('mutant', 'Var', (36, 42))	('men', 'Species', '9606', (92, 95))	('NSCLC', 'Disease', (43, 48))	('kill', 'Disease', (31, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
185163	33194655	Several studies have shown that D-allose, a rare sugar, can inhibit the growth of many malignancies.	('D-allose', 'Chemical', '-', (32, 40))	('inhibit', 'NegReg', (60, 67))	('D-allose', 'Var', (32, 40))	('malignancies', 'Disease', 'MESH:D009369', (87, 99))	('sugar', 'Chemical', 'MESH:D000073893', (49, 54))	('malignancies', 'Disease', (87, 99))
185184	33194655	Furthermore, TXNIP is a key factor in the DNA damage and cell aging induced by PRMT5 depletion.	('cell aging', 'biological_process', 'GO:0007569', ('57', '67'))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('depletion', 'Var', (85, 94))	('cell aging', 'CPA', (57, 67))	('PRMT5', 'Gene', (79, 84))	('PRMT5', 'Gene', '10419', (79, 84))
185191	33194655	TXNIP is expressed at low levels in a variety of malignancies and the overexpression of TXNIP inhibits the proliferation of cancer cells, and so it can be considered as a potential tumor suppressor gene.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('181', '197'))	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('malignancies', 'Disease', 'MESH:D009369', (49, 61))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('inhibits', 'NegReg', (94, 102))	('tumor suppressor', 'biological_process', 'GO:0051726', ('181', '197'))	('TXNIP', 'Var', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('malignancies', 'Disease', (49, 61))	('overexpression', 'PosReg', (70, 84))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
185291	33449444	Inhibition of IGLL5 aiming to reduce the infiltration of B cells in tumors may provide a new target for combined immunotherapy.	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('reduce', 'NegReg', (30, 36))	('IGLL5', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('IGLL5', 'Gene', '100423062', (14, 19))	('infiltration', 'CPA', (41, 53))
185300	28545465	An increase in long non-coding RNA PANDAR is associated with poor prognosis in clear cell renal cell carcinoma Nearly 30% of clear cell renal cell carcinoma (ccRCC) patients present with metastasis at the time of diagnosis, and the prognosis for these patients is poor.	('PANDAR', 'Gene', '101154753', (35, 41))	('RNA', 'cellular_component', 'GO:0005562', ('31', '34'))	('PANDAR', 'Gene', (35, 41))	('patients', 'Species', '9606', (165, 173))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (79, 110))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (90, 110))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (125, 156))	('patients', 'Species', '9606', (252, 260))	('long non-coding', 'Var', (15, 30))	('clear cell renal cell carcinoma', 'Disease', (79, 110))	('clear cell renal cell carcinoma', 'Disease', (125, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (158, 163))	('metastasis', 'CPA', (187, 197))	('RCC', 'Disease', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (136, 156))	('increase', 'PosReg', (3, 11))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (125, 156))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (79, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
185310	28545465	Further experiments demonstrated that PANDAR silencing can significantly inhibit cell proliferation and invasion, induce cell cycle arrest in the G1 phase and significantly promote apoptosis in 7860 and Caki-1 cell lines.	('cell proliferation', 'CPA', (81, 99))	('silencing', 'Var', (45, 54))	('apoptosis', 'biological_process', 'GO:0097194', ('181', '190'))	('G1 phase', 'biological_process', 'GO:0051318', ('146', '154'))	('PANDAR', 'Gene', '101154753', (38, 44))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('121', '138'))	('apoptosis', 'biological_process', 'GO:0006915', ('181', '190'))	('PANDAR', 'Gene', (38, 44))	('cell proliferation', 'biological_process', 'GO:0008283', ('81', '99'))	('apoptosis', 'CPA', (181, 190))	('cell cycle arrest in the G1 phase', 'CPA', (121, 154))	('induce', 'Reg', (114, 120))	('Caki-1', 'CellLine', 'CVCL:0234', (203, 209))	('invasion', 'CPA', (104, 112))	('promote', 'PosReg', (173, 180))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (121, 138))	('inhibit', 'NegReg', (73, 80))
185312	28545465	Silencing of PANDAR also inhibited the expression of Bcl-2 and Mcl-1 and upregulated the expression of Bax in vivo.	('Bcl-2', 'molecular_function', 'GO:0015283', ('53', '58'))	('expression', 'MPA', (89, 99))	('upregulated', 'PosReg', (73, 84))	('PANDAR', 'Gene', (13, 19))	('Bcl-2', 'Gene', (53, 58))	('Mcl-1', 'Gene', (63, 68))	('Bcl-2', 'Gene', '596', (53, 58))	('Bax', 'Gene', '581', (103, 106))	('PANDAR', 'Gene', '101154753', (13, 19))	('expression', 'MPA', (39, 49))	('inhibited', 'NegReg', (25, 34))	('Silencing', 'Var', (0, 9))	('Mcl-1', 'Gene', '4170', (63, 68))	('Bax', 'Gene', (103, 106))
185317	28545465	Despite numerous studies that have shown that many genetic and epigenetic changes are associated with the development and progression of ccRCC, the molecular mechanism of renal cancer pathogenesis is still elusive, and the prognosis remains poor.	('renal cancer', 'Phenotype', 'HP:0009726', (171, 183))	('renal cancer', 'Disease', 'MESH:D007680', (171, 183))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('associated', 'Reg', (86, 96))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('RCC', 'Disease', (139, 142))	('genetic', 'Var', (51, 58))	('pathogenesis', 'biological_process', 'GO:0009405', ('184', '196'))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('epigenetic changes', 'Var', (63, 81))	('renal cancer', 'Disease', (171, 183))
185326	28545465	Recently, it has been reported that the expression of PANDAR was downregulated in non-small cell lung cancer (NSCLC) and a low level of PANDAR was associated with a poor prognosis.	('expression', 'MPA', (40, 50))	('low level', 'Var', (123, 132))	('PANDAR', 'Gene', '101154753', (136, 142))	('PANDAR', 'Gene', (54, 60))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (82, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('PANDAR', 'Gene', (136, 142))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (86, 108))	('non-small cell lung cancer', 'Disease', (82, 108))	('NSCLC', 'Disease', (110, 115))	('downregulated', 'NegReg', (65, 78))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (82, 108))	('PANDAR', 'Gene', '101154753', (54, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
185327	28545465	In contrast, PANDAR was found to be upregulated in hepatocellular and in bladder carcinoma, and a high level of PANDAR was associated with a poor prognosis.	('upregulated', 'PosReg', (36, 47))	('PANDAR', 'Gene', (112, 118))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (73, 90))	('PANDAR', 'Gene', (13, 19))	('bladder carcinoma', 'Disease', (73, 90))	('bladder carcinoma', 'Disease', 'MESH:D001749', (73, 90))	('hepatocellular', 'Disease', (51, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('high level', 'Var', (98, 108))	('PANDAR', 'Gene', '101154753', (112, 118))	('PANDAR', 'Gene', '101154753', (13, 19))
185369	28545465	The Kaplan-Meier survival curve indicated that high levels of PANDAR expression are significant predictors of poor survival (P = 0.044) (Fig.	('PANDAR', 'Gene', '101154753', (62, 68))	('high levels', 'Var', (47, 58))	('PANDAR', 'Gene', (62, 68))
185371	28545465	In addition, multivariate analysis indicated that the expression of PANDAR was an independent prognostic factor for the overall survival of patients in line with the TNM stage, the Fuhrman grade, lymph node metastases and distant metastases.	('TNM', 'Gene', (166, 169))	('metastases', 'Disease', 'MESH:D009362', (230, 240))	('PANDAR', 'Gene', '101154753', (68, 74))	('expression', 'Var', (54, 64))	('metastases', 'Disease', (207, 217))	('PANDAR', 'Gene', (68, 74))	('TNM', 'Gene', '10178', (166, 169))	('lymph node metastases', 'Disease', 'MESH:D009362', (196, 217))	('lymph node metastases', 'Disease', (196, 217))	('patients', 'Species', '9606', (140, 148))	('metastases', 'Disease', 'MESH:D009362', (207, 217))	('metastases', 'Disease', (230, 240))
185374	28545465	As illustrated by CCK-8 assays, silencing of PANDAR markedly decreased the proliferation of 7860 and Caki-1 cells compared with the control groups (Fig.	('PANDAR', 'Gene', '101154753', (45, 51))	('Caki-1', 'CellLine', 'CVCL:0234', (101, 107))	('PANDAR', 'Gene', (45, 51))	('silencing', 'Var', (32, 41))	('decreased', 'NegReg', (61, 70))	('proliferation', 'CPA', (75, 88))
185377	28545465	3d and indicate that silencing of PANDAR attenuated the invasive ability of 7860 and Caki-1 cells (P < 0.01).	('attenuated', 'NegReg', (41, 51))	('PANDAR', 'Gene', '101154753', (34, 40))	('PANDAR', 'Gene', (34, 40))	('invasive ability of 7860', 'CPA', (56, 80))	('Caki-1', 'CellLine', 'CVCL:0234', (85, 91))	('silencing', 'Var', (21, 30))
185379	28545465	The results demonstrated that the expression level of MMP2 was significantly reduced after the knockdown of PANDAR (Fig.	('MMP2', 'molecular_function', 'GO:0004228', ('54', '58'))	('MMP2', 'Gene', '4313', (54, 58))	('PANDAR', 'Gene', '101154753', (108, 114))	('knockdown', 'Var', (95, 104))	('reduced', 'NegReg', (77, 84))	('MMP2', 'Gene', (54, 58))	('PANDAR', 'Gene', (108, 114))	('expression level', 'MPA', (34, 50))
185382	28545465	3a, transfection of siRNA against PANDAR caused cell cycle arrest at the G0/G1 phase in both cell lines.	('PANDAR', 'Gene', '101154753', (34, 40))	('PANDAR', 'Gene', (34, 40))	('transfection', 'Var', (4, 16))	('G1 phase', 'biological_process', 'GO:0051318', ('76', '84'))	('cell cycle arrest at the G0/G1 phase', 'CPA', (48, 84))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('48', '65'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (48, 65))
185385	28545465	All of these data indicated that repression of PANDAR could induce a G0/G1 arrest in RCC cells via altering the expression of key proteins in the Cyclin-CDKs signal pathway.	('PANDAR', 'Gene', (47, 53))	('expression of', 'MPA', (112, 125))	('G0/G1 arrest', 'CPA', (69, 81))	('repression', 'Var', (33, 43))	('altering', 'Reg', (99, 107))	('CDKs', 'Gene', '1019', (153, 157))	('Cyclin', 'Gene', (146, 152))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('Cyclin', 'molecular_function', 'GO:0016538', ('146', '152'))	('RCC', 'Disease', (85, 88))	('CDKs', 'Gene', (153, 157))	('Cyclin', 'Gene', '5111', (146, 152))	('PANDAR', 'Gene', '101154753', (47, 53))	('induce', 'Reg', (60, 66))
185386	28545465	First we transfected the cells with si-PANDAR or si-NC for 24 h, and then stained the cells with Annexin V/PI and evaluated the cells using flow cytometry.	('Annexin V', 'Gene', '308', (97, 106))	('Annexin V', 'Gene', (97, 106))	('si-NC', 'Var', (49, 54))	('PANDAR', 'Gene', '101154753', (39, 45))	('PANDAR', 'Gene', (39, 45))
185392	28545465	4a, the levels of Bcl-2 and Mcl-1 were downregulated, while Bax was upregulated after the silencing of PANDAR.	('Mcl-1', 'Gene', '4170', (28, 33))	('Bcl-2', 'Gene', (18, 23))	('upregulated', 'PosReg', (68, 79))	('PANDAR', 'Gene', '101154753', (103, 109))	('silencing', 'Var', (90, 99))	('Bax', 'Gene', (60, 63))	('PANDAR', 'Gene', (103, 109))	('Mcl-1', 'Gene', (28, 33))	('Bcl-2', 'molecular_function', 'GO:0015283', ('18', '23'))	('Bax', 'Gene', '581', (60, 63))	('Bcl-2', 'Gene', '596', (18, 23))	('downregulated', 'NegReg', (39, 52))
185394	28545465	Therefore, we asked whether the PI3K/Akt/mTOR pathway was affected after the silencing of PANDAR.	('PI3K', 'molecular_function', 'GO:0016303', ('32', '36'))	('Akt', 'Gene', '207', (37, 40))	('PANDAR', 'Gene', '101154753', (90, 96))	('PI3', 'Gene', (32, 35))	('PANDAR', 'Gene', (90, 96))	('affected', 'Reg', (58, 66))	('silencing', 'Var', (77, 86))	('Akt', 'Gene', (37, 40))	('PI3', 'Gene', '5266', (32, 35))	('mTOR', 'Gene', (41, 45))	('mTOR', 'Gene', '2475', (41, 45))
185395	28545465	4b, after transfection with si-PANDAR for 24 h, Akt phosphorylation at Thr450 and Ser473 were inhibited remarkably, while the total protein level of Akt remained constant in both cell lines.	('Akt', 'Gene', (48, 51))	('Ser', 'cellular_component', 'GO:0005790', ('82', '85'))	('Akt', 'Gene', (149, 152))	('PANDAR', 'Gene', '101154753', (31, 37))	('PANDAR', 'Gene', (31, 37))	('Ser473', 'Var', (82, 88))	('Thr450', 'Enzyme', (71, 77))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('Akt', 'Gene', '207', (149, 152))	('Thr450', 'Chemical', '-', (71, 77))	('Ser473', 'Chemical', '-', (82, 88))	('Akt', 'Gene', '207', (48, 51))	('phosphorylation', 'biological_process', 'GO:0016310', ('52', '67'))	('inhibited', 'NegReg', (94, 103))
185402	28545465	In addition, the PI3K/Akt signaling pathway was inhibited after the silencing of PANDAR, which is in accordance with in vitro results as well.	('PANDAR', 'Gene', (81, 87))	('Akt signaling', 'biological_process', 'GO:0043491', ('22', '35'))	('PI3', 'Gene', '5266', (17, 20))	('Akt', 'Gene', (22, 25))	('inhibited', 'NegReg', (48, 57))	('signaling pathway', 'biological_process', 'GO:0007165', ('26', '43'))	('silencing', 'Var', (68, 77))	('PI3', 'Gene', (17, 20))	('PI3K', 'molecular_function', 'GO:0016303', ('17', '21'))	('PANDAR', 'Gene', '101154753', (81, 87))	('Akt', 'Gene', '207', (22, 25))
185423	28545465	To understand the biological functions of PANDAR in ccRCC, we evaluated cell proliferation, the cell cycle, apoptosis and invasion after silencing of PANDAR in 7860 and Caki-1 cells.	('PANDAR', 'Gene', '101154753', (150, 156))	('cell cycle', 'biological_process', 'GO:0007049', ('96', '106'))	('PANDAR', 'Gene', (150, 156))	('Caki-1', 'CellLine', 'CVCL:0234', (169, 175))	('cell cycle', 'CPA', (96, 106))	('PANDAR', 'Gene', '101154753', (42, 48))	('cell proliferation', 'biological_process', 'GO:0008283', ('72', '90'))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('invasion', 'CPA', (122, 130))	('PANDAR', 'Gene', (42, 48))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('cell proliferation', 'CPA', (72, 90))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('silencing', 'Var', (137, 146))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('apoptosis', 'CPA', (108, 117))
185425	28545465	who demonstrated that the silencing of PANDAR caused a G0/G1 phase arrest in breast cancer.	('G0/G1 phase arrest', 'CPA', (55, 73))	('breast cancer', 'Disease', (77, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('PANDAR', 'Gene', '101154753', (39, 45))	('silencing', 'Var', (26, 35))	('G1 phase', 'biological_process', 'GO:0051318', ('58', '66'))	('PANDAR', 'Gene', (39, 45))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
185426	28545465	In addition, we observed that the knockdown of PANDAR led to greater apoptosis in both cell lines.	('PANDAR', 'Gene', (47, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('69', '78'))	('apoptosis', 'CPA', (69, 78))	('knockdown', 'Var', (34, 43))	('PANDAR', 'Gene', '101154753', (47, 53))	('apoptosis', 'biological_process', 'GO:0097194', ('69', '78'))
185429	28545465	Here, our finding of a decrease in cyclin D1, cyclin E1 and CDK4 in both cells after silencing of PANDAR suggests the disruption of the uncontrolled cell cycle progression of 7860 and Caki-1 cells.	('decrease', 'NegReg', (23, 31))	('cyclin D1', 'Gene', (35, 44))	('Caki-1', 'CellLine', 'CVCL:0234', (184, 190))	('PANDAR', 'Gene', '101154753', (98, 104))	('cyclin D1', 'Gene', '595', (35, 44))	('cell cycle', 'biological_process', 'GO:0007049', ('149', '159'))	('PANDAR', 'Gene', (98, 104))	('cyclin', 'molecular_function', 'GO:0016538', ('35', '41'))	('cyclin E1', 'Gene', (46, 55))	('CDK4', 'Gene', (60, 64))	('uncontrolled cell cycle progression', 'CPA', (136, 171))	('CDK4', 'Gene', '1019', (60, 64))	('silencing', 'Var', (85, 94))	('cyclin', 'molecular_function', 'GO:0016538', ('46', '52'))	('CDK', 'molecular_function', 'GO:0004693', ('60', '63'))	('cyclin E1', 'Gene', '898', (46, 55))
185430	28545465	We also observed that MMP-2 and TIMP-3 were downregulated after the knockdown of PANDAR, and MMP-2 and TIMP-3 have been implicated in the regulation of the metabolism of the extracellular matrix, tumor progression and metastasis.	('downregulated', 'NegReg', (44, 57))	('TIMP-3', 'Gene', '7078', (32, 38))	('tumor', 'Disease', (196, 201))	('MMP-2', 'Gene', '4313', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('PANDAR', 'Gene', '101154753', (81, 87))	('PANDAR', 'Gene', (81, 87))	('TIMP-3', 'Gene', (103, 109))	('metabolism', 'biological_process', 'GO:0008152', ('156', '166'))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('174', '194'))	('MMP-2', 'Gene', (93, 98))	('implicated', 'Reg', (120, 130))	('metabolism of the extracellular matrix', 'MPA', (156, 194))	('knockdown', 'Var', (68, 77))	('TIMP-3', 'Gene', (32, 38))	('MMP-2', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('regulation', 'biological_process', 'GO:0065007', ('138', '148'))	('MMP-2', 'molecular_function', 'GO:0004228', ('22', '27'))	('metastasis', 'CPA', (218, 228))	('MMP-2', 'molecular_function', 'GO:0004228', ('93', '98'))	('TIMP-3', 'Gene', '7078', (103, 109))	('MMP-2', 'Gene', '4313', (93, 98))
185434	28545465	We found that caspase-3 but not caspase-8 protein was cleaved after the silencing of PANDAR.	('PANDAR', 'Gene', (85, 91))	('silencing', 'Var', (72, 81))	('caspase-3', 'Gene', '836', (14, 23))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('caspase-3', 'Gene', (14, 23))	('caspase-8', 'Gene', (32, 41))	('PANDAR', 'Gene', '101154753', (85, 91))	('caspase-8', 'Gene', '841', (32, 41))
185436	28545465	We found that silencing of PANDAR could inhibit Bcl-2 and Mcl-1 while enhancing the expression of Bax.	('Bax', 'Gene', '581', (98, 101))	('Bcl-2', 'Gene', (48, 53))	('silencing', 'Var', (14, 23))	('Bcl-2', 'Gene', '596', (48, 53))	('inhibit', 'NegReg', (40, 47))	('PANDAR', 'Gene', '101154753', (27, 33))	('PANDAR', 'Gene', (27, 33))	('Mcl-1', 'Gene', (58, 63))	('Bax', 'Gene', (98, 101))	('Bcl-2', 'molecular_function', 'GO:0015283', ('48', '53'))	('enhancing', 'PosReg', (70, 79))	('expression', 'MPA', (84, 94))	('Mcl-1', 'Gene', '4170', (58, 63))
185438	28545465	The present study also examined the signaling pathway that is possibly involved in apoptosis, and it was found that the silencing of PANDAR inhibited the expression of mTOR and the phosphorylation of PI3K and Akt.	('mTOR', 'Gene', (168, 172))	('PANDAR', 'Gene', '101154753', (133, 139))	('mTOR', 'Gene', '2475', (168, 172))	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('PANDAR', 'Gene', (133, 139))	('phosphorylation', 'biological_process', 'GO:0016310', ('181', '196'))	('PI3', 'Gene', (200, 203))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('Akt', 'Gene', '207', (209, 212))	('inhibited', 'NegReg', (140, 149))	('phosphorylation', 'MPA', (181, 196))	('silencing', 'Var', (120, 129))	('Akt', 'Gene', (209, 212))	('signaling pathway', 'biological_process', 'GO:0007165', ('36', '53'))	('PI3K', 'molecular_function', 'GO:0016303', ('200', '204'))	('PI3', 'Gene', '5266', (200, 203))	('expression', 'MPA', (154, 164))
185443	28545465	Moreover, the expression of PANDAR was demonstrated to be an independent marker for predicting the clinical outcome of ccRCC patients.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('expression', 'Var', (14, 24))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('PANDAR', 'Gene', '101154753', (28, 34))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('PANDAR', 'Gene', (28, 34))	('patients', 'Species', '9606', (125, 133))
185452	33523554	In this review, we have summarized the available information in the literature with a brief description on how transcriptional, post-transcriptional and post-translational modifications of KLF5 modulate its function in a variety of organs including the kidney with a focus of its importance on the pathogenesis of various kidney diseases.	('pathogenesis', 'biological_process', 'GO:0009405', ('298', '310'))	('KLF5', 'Gene', (189, 193))	('rat', 'Species', '10116', (72, 75))	('kidney diseases', 'Disease', (322, 337))	('modulate', 'Reg', (194, 202))	('function', 'MPA', (207, 215))	('kidney diseases', 'Phenotype', 'HP:0000112', (322, 337))	('kidney diseases', 'Disease', 'MESH:D007674', (322, 337))	('kidney disease', 'Phenotype', 'HP:0000112', (322, 336))	('modifications', 'Var', (172, 185))
185454	33523554	These studies suggest a need for more systemic investigations, particularly for generation of animal models with renal cell-specific deletion or overexpression of KLF5 gene to examine direct contributions of KLF5 to various kidney diseases.	('kidney diseases', 'Disease', 'MESH:D007674', (224, 239))	('kidney diseases', 'Phenotype', 'HP:0000112', (224, 239))	('rat', 'Species', '10116', (84, 87))	('deletion', 'Var', (133, 141))	('KLF5', 'Gene', (163, 167))	('kidney disease', 'Phenotype', 'HP:0000112', (224, 238))	('kidney diseases', 'Disease', (224, 239))	('overexpression', 'PosReg', (145, 159))
185477	33523554	20 ,  21 ,  22  Acetylation of KLF5 by p300 and deacetylation by histone deacetylase 1 (HDAC1) and histone chaperone TAF1/SET is also reported in vascular smooth muscle cells (VSMCs) and in human HeLa cells.	('deacetylation', 'MPA', (48, 61))	('HDAC1', 'Gene', (88, 93))	('TAF1', 'Gene', (117, 121))	('Acetylation', 'MPA', (16, 27))	('histone deacetylase 1', 'Gene', '3065', (65, 86))	('HDAC1', 'Gene', '3065', (88, 93))	('histone chaperone', 'biological_process', 'GO:0006334', ('99', '116'))	('histone deacetylase 1', 'Gene', (65, 86))	('HeLa', 'CellLine', 'CVCL:0030', (196, 200))	('human', 'Species', '9606', (190, 195))	('histone chaperone', 'biological_process', 'GO:0043486', ('99', '116'))	('p300', 'Var', (39, 43))	('TAF1', 'Gene', '6872', (117, 121))
185478	33523554	23 ,  24  Acetylation of KLF5 at K369 by p300 enhanced its transactivation activity, 23  while HDAC1 mediated KLF5 deacetylation inhibited its transactivation activity.	('transactivation activity', 'MPA', (59, 83))	('transactivation', 'biological_process', 'GO:2000144', ('59', '74'))	('p300', 'Var', (41, 45))	('HDAC1', 'Gene', (95, 100))	('transactivation', 'biological_process', 'GO:2000144', ('143', '158'))	('enhanced', 'PosReg', (46, 54))	('Acetylation', 'MPA', (10, 21))	('HDAC1', 'Gene', '3065', (95, 100))	('transactivation activity', 'MPA', (143, 167))
185480	33523554	25  Moreover, KLF5 phosphorylation could modulate its activation status as KLF5-Ser153 phosphorylation by protein kinase C at the CREB binding protein (CBP) interaction site promoted its transactivation function in human epithelial cells (HEC-1B), 26  while angiotensin II (Ang II)-induced extracellular signal-regulated kinase (ERK)-mediated KLF5 phosphorylation promoted interaction of KLF5 and c-Jun, resulting in the suppression of p21 expression in VSMCs.	('interaction', 'Interaction', (373, 384))	('KLF5-Ser153', 'Var', (75, 86))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('promoted', 'PosReg', (174, 182))	('suppression', 'NegReg', (421, 432))	('angiotensin II', 'Gene', '183', (258, 272))	('extracellular signal-regulated kinase', 'Gene', (290, 327))	('c-Jun', 'Gene', '3725', (397, 402))	('extracellular', 'cellular_component', 'GO:0005576', ('290', '303'))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))	('phosphorylation', 'biological_process', 'GO:0016310', ('19', '34'))	('p21', 'Gene', (436, 439))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('c-Jun', 'Gene', (397, 402))	('p21', 'Gene', '644914', (436, 439))	('transactivation', 'biological_process', 'GO:2000144', ('187', '202'))	('extracellular signal-regulated kinase', 'Gene', '5594', (290, 327))	('CBP', 'Gene', '1387', (152, 155))	('ERK', 'molecular_function', 'GO:0004707', ('329', '332'))	('human', 'Species', '9606', (215, 220))	('Ser', 'cellular_component', 'GO:0005790', ('80', '83'))	('CREB binding protein', 'Gene', (130, 150))	('CBP', 'Gene', (152, 155))	('Ser153', 'Chemical', '-', (80, 86))	('transactivation', 'MPA', (187, 202))	('angiotensin II', 'Gene', (258, 272))	('CREB binding', 'molecular_function', 'GO:0008140', ('130', '142'))	('CREB binding protein', 'Gene', '1387', (130, 150))	('phosphorylation', 'biological_process', 'GO:0016310', ('348', '363'))	('HEC-1B', 'CellLine', 'CVCL:0294', (239, 245))	('CBP', 'molecular_function', 'GO:0008140', ('152', '155'))
185488	33523554	Furthermore, treatment of ccRCC cells with 5-Aza-CdR, a DNA methyltransferase (DNMT) inhibitor, up-regulated the expression of KLF5 and repressed ccRCC cell growth, suggesting that hypermethylation might contribute to the down-regulation of KLF5 in ccRCC.	('repressed', 'CPA', (136, 145))	('expression', 'MPA', (113, 123))	('DNMT', 'Gene', '13433', (79, 83))	('ccRCC', 'Disease', (249, 254))	('5-Aza-CdR', 'Var', (43, 52))	('DNA methyltransferase', 'Gene', '13433', (56, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (26, 31))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('DNA methyltransferase', 'Gene', (56, 77))	('5-Aza-CdR', 'Chemical', '-', (43, 52))	('cell growth', 'biological_process', 'GO:0016049', ('152', '163'))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('up-regulated', 'PosReg', (96, 108))	('KLF5', 'Gene', (127, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (249, 254))	('DNMT', 'Gene', (79, 83))	('regulation', 'biological_process', 'GO:0065007', ('227', '237'))
185489	33523554	37  This epigenetic modification of KLF5 was found in renal tumour tissues and cell lines.	('renal tumour', 'Phenotype', 'HP:0009726', (54, 66))	('renal tumour', 'Disease', (54, 66))	('renal tumour', 'Disease', 'MESH:D007680', (54, 66))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('epigenetic modification', 'Var', (9, 32))
185490	33523554	Similarly, in dermal fibroblasts of systemic sclerosis, CpG methylation of KLF5 promoter contributed to down-regulation of KLF5 protein.	('systemic sclerosis', 'Disease', 'MESH:D012595', (36, 54))	('KLF5 protein', 'Protein', (123, 135))	('down-regulation', 'NegReg', (104, 119))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('regulation', 'biological_process', 'GO:0065007', ('109', '119'))	('systemic sclerosis', 'Disease', (36, 54))	('CpG methylation', 'Var', (56, 71))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('KLF5', 'Gene', (75, 79))
185494	33523554	Several studies have suggested that microRNAs, namely, miR-145, miR-152, miR-10b-3p, miR-448-3p, miR-375 and miR-9, can suppress the expression of KLF5 by directly interacting with its 3'-untranslated regions.	('expression', 'MPA', (133, 143))	('miR-152', 'Gene', (64, 71))	('miR-152', 'Gene', '406943', (64, 71))	('miR-145', 'Gene', '406937', (55, 62))	('miR-9', 'Var', (109, 114))	('miR-375', 'Gene', (97, 104))	('miR-10b-3p', 'Var', (73, 83))	('interacting', 'Interaction', (164, 175))	('miR-448-3p', 'Gene', (85, 95))	('miR-10b', 'Chemical', '-', (73, 80))	('miR-145', 'Gene', (55, 62))	('miR-448-3p', 'Gene', '100616162', (85, 95))	('suppress', 'NegReg', (120, 128))	('KLF5', 'Protein', (147, 151))	('miR-375', 'Gene', '494324', (97, 104))
185500	33523554	43  Furthermore, miR-488-3p also targeted KLF5 and promoted an anti-inflammatory pathway in macrophages in a rat model of intracranial aneurysm.	('intracranial aneurysm', 'Phenotype', 'HP:0004944', (122, 143))	('anti-inflammatory pathway in', 'Pathway', (63, 91))	('aneurysm', 'Phenotype', 'HP:0002617', (135, 143))	('miR-488-3p', 'Var', (17, 27))	('rat', 'Species', '10116', (109, 112))	('promoted', 'PosReg', (51, 59))	('targeted', 'Reg', (33, 41))	('intracranial aneurysm', 'Disease', (122, 143))	('miR-488-3p', 'Chemical', '-', (17, 27))	('KLF5', 'Protein', (42, 46))	('intracranial aneurysm', 'Disease', 'MESH:D002532', (122, 143))
185516	33523554	58  Similarly, C/EBP-alpha was shown to have a protective effect in the podocytes of mice subjected to Adriamycin-induced kidney injury as knockout of C/EBP-alpha aggravated Adriamycin-induced kidney injury.	('mice', 'Species', '10090', (85, 89))	('kidney injury', 'Disease', 'MESH:D058186', (122, 135))	('kidney injury', 'Disease', (122, 135))	('aggravated', 'PosReg', (163, 173))	('Adriamycin', 'Chemical', 'MESH:D004317', (174, 184))	('knockout', 'Var', (139, 147))	('Adriamycin', 'Chemical', 'MESH:D004317', (103, 113))	('kidney injury', 'Disease', 'MESH:D058186', (193, 206))	('kidney injury', 'Disease', (193, 206))	('C/EBP-alpha', 'Gene', (151, 162))
185535	33523554	10 ,  70  Western blot analysis demonstrated increased expression of KLF5 protein in the renal cortex of db/db mice (9-weeks of age), compared to control mice.	('mice', 'Species', '10090', (154, 158))	('increased', 'PosReg', (45, 54))	('db/db', 'Var', (105, 110))	('KLF5 protein', 'Protein', (69, 81))	('expression', 'MPA', (55, 65))	('mice', 'Species', '10090', (111, 115))	('rat', 'Species', '10116', (39, 42))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))
185542	33523554	Fujiu et al  12  examined the role of KLF5 in regulating tubulointerstitial injury of the kidney induced by UUO in C57BL6/6J (wild-type, WT) mice or in Klf5 haploinsufficient (Klf5+/-) mice on the same genetic background as WT mice, as Klf5 knockout (Klf5-/-) mice were found to be embryological lethal.	('tubulointerstitial injury of the kidney', 'Disease', 'MESH:D058186', (57, 96))	('Klf5', 'Gene', '12224', (251, 255))	('mice', 'Species', '10090', (260, 264))	('Klf5', 'Gene', (152, 156))	('tubulointerstitial injury of the kidney', 'Disease', (57, 96))	('Klf5', 'Gene', (176, 180))	('mice', 'Species', '10090', (185, 189))	('mice', 'Species', '10090', (227, 231))	('C57BL6/6J', 'Var', (115, 124))	('Klf5', 'Gene', '12224', (176, 180))	('Klf5', 'Gene', '12224', (152, 156))	('mice', 'Species', '10090', (141, 145))	('Klf5', 'Gene', (236, 240))	('UUO', 'Chemical', '-', (108, 111))	('Klf5', 'Gene', '12224', (236, 240))	('UUO', 'Phenotype', 'HP:0006000', (108, 111))	('Klf5', 'Gene', (251, 255))
185564	33523554	Meanwhile, TUNEL staining demonstrated significantly decreased renal cell apoptosis in the renal cortex and medulla of UUO-treated haploinsufficient KLF5+/- mice as compared to UUO-treated WT mice.	('UUO', 'Phenotype', 'HP:0006000', (177, 180))	('mice', 'Species', '10090', (192, 196))	('mice', 'Species', '10090', (157, 161))	('UUO', 'Chemical', '-', (119, 122))	('renal cell apoptosis', 'CPA', (63, 83))	('rat', 'Species', '10116', (33, 36))	('UUO', 'Phenotype', 'HP:0006000', (119, 122))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('haploinsufficient', 'Var', (131, 148))	('decreased', 'NegReg', (53, 62))	('UUO', 'Chemical', '-', (177, 180))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('UUO-treated', 'Gene', (119, 130))
185566	33523554	Flow cytometry analysis revealed decreased CD11b+F4/80lo cells in KLF5+/--UUO mice compared to WT-UUO mice.	('UUO', 'Chemical', '-', (74, 77))	('mice', 'Species', '10090', (102, 106))	('UUO', 'Chemical', '-', (98, 101))	('UUO', 'Phenotype', 'HP:0006000', (74, 77))	('KLF5+/--UUO', 'Var', (66, 77))	('UUO', 'Phenotype', 'HP:0006000', (98, 101))	('decreased', 'NegReg', (33, 42))	('CD11b', 'Gene', (43, 48))	('CD11b', 'Gene', '3684', (43, 48))	('mice', 'Species', '10090', (78, 82))
185579	33523554	They demonstrated that knocking down KLF5 with siRNA in SV40 MES13 cells up-regulated the expression of p27Kip1 and decreased the number of viable cells compared to control group.	('up-regulated', 'PosReg', (73, 85))	('rat', 'Species', '10116', (12, 15))	('knocking down', 'Var', (23, 36))	('number of viable cells', 'CPA', (130, 152))	('expression', 'MPA', (90, 100))	('p27Kip1', 'Gene', '12576', (104, 111))	('p27Kip1', 'Gene', (104, 111))	('decreased', 'NegReg', (116, 125))	('SV40 MES13', 'CellLine', 'CVCL:5368', (56, 66))
185584	33523554	Knocking down KLF5 by shRNA repressed the expression of cyclin D1 and blocked cell growth.	('cyclin', 'molecular_function', 'GO:0016538', ('56', '62'))	('cell growth', 'biological_process', 'GO:0016049', ('78', '89'))	('cell growth', 'CPA', (78, 89))	('cyclin D1', 'Gene', '12443', (56, 65))	('blocked', 'NegReg', (70, 77))	('Knocking', 'Var', (0, 8))	('cyclin D1', 'Gene', (56, 65))
185611	33523554	IEC6 cells treated with LPS demonstrated an increase in expression of KLF5, NF-kappaB subunits (P50, P65), TNF-alpha, IL-6 and ICAM-1.	('NF-kappaB', 'Gene', (76, 85))	('IEC6', 'CellLine', 'CVCL:0343', (0, 4))	('IL-6', 'molecular_function', 'GO:0005138', ('118', '122'))	('ICAM-1', 'Gene', (127, 133))	('P50', 'Var', (96, 99))	('TNF-alpha', 'Gene', (107, 116))	('ICAM-1', 'Gene', '25464', (127, 133))	('NF-kappaB', 'Gene', '18033', (76, 85))	('increase', 'PosReg', (44, 52))	('P65', 'Var', (101, 104))	('expression', 'MPA', (56, 66))	('rat', 'Species', '10116', (35, 38))
185612	33523554	Pretreatment of IEC6 cells with U0126, a MEK1/2 inhibitor, prior to stimulation with LPS, inhibited the aforementioned mRNA induction.	('MEK1/2', 'Gene', '170851;58960', (41, 47))	('U0126', 'Var', (32, 37))	('MEK1/2', 'Gene', (41, 47))	('MEK1', 'molecular_function', 'GO:0004708', ('41', '45'))	('mRNA induction', 'MPA', (119, 133))	('U0126', 'Chemical', 'MESH:C113580', (32, 37))	('IEC6', 'CellLine', 'CVCL:0343', (16, 20))	('inhibited', 'NegReg', (90, 99))
185613	33523554	Moreover, silencing KLF5 expression in IEC6 cells inhibited secretion of pro-inflammatory mediators TNF-alpha and IL-6.	('KLF5', 'Gene', (20, 24))	('inhibited', 'NegReg', (50, 59))	('IL-6', 'molecular_function', 'GO:0005138', ('114', '118'))	('secretion of pro-inflammatory mediators TNF-alpha', 'MPA', (60, 109))	('IEC6', 'CellLine', 'CVCL:0343', (39, 43))	('secretion', 'biological_process', 'GO:0046903', ('60', '69'))	('silencing', 'Var', (10, 19))
185619	33523554	Pretreatment with GW9662, a PPAR-gamma selective antagonist, prevented effects of KLF5 overexpression on PPAR-gamma, PGC-1alpha and TNF-alpha expression.	('PPAR-gamma', 'Gene', (28, 38))	('PPAR-gamma', 'Gene', '25664', (105, 115))	('PGC-1alpha', 'Gene', '83516', (117, 127))	('expression', 'MPA', (142, 152))	('GW9662', 'Var', (18, 24))	('PPAR-gamma', 'Gene', '25664', (28, 38))	('GW9662', 'Chemical', 'MESH:C457499', (18, 24))	('PGC-1alpha', 'Gene', (117, 127))	('PPAR-gamma', 'Gene', (105, 115))	('TNF-alpha', 'Gene', (132, 141))
185633	33523554	34  Moreover, genetic variation such as a TT Mutant Homozygote of KLF5 could increase basal metabolic rate and resting metabolic rate in Korean children.	('genetic variation', 'Var', (14, 31))	('KLF5', 'Gene', (66, 70))	('rat', 'Species', '10116', (129, 132))	('resting metabolic rate', 'MPA', (111, 133))	('basal metabolic rate', 'MPA', (86, 106))	('increase', 'PosReg', (77, 85))	('rat', 'Species', '10116', (102, 105))	('children', 'Species', '9606', (144, 152))	('TT Mutant', 'Var', (42, 51))
185638	33523554	97  Moreover, inhibition of KLF5 could suppress TNF-alpha induced MCP-1 expression in HUVECs.	('HUVEC', 'CellLine', 'CVCL:2959', (86, 91))	('MCP', 'molecular_function', 'GO:0004298', ('66', '69'))	('expression', 'MPA', (72, 82))	('MCP-1', 'Gene', (66, 71))	('suppress', 'NegReg', (39, 47))	('inhibition', 'Var', (14, 24))
185647	33523554	Silencing KLF5 by siRNA reduced the expression of TGFbeta and fibronectin induced in high-dose MK-treated HK-2 cells and alleviated renal fibrosis.	('fibronectin', 'Gene', (62, 73))	('TGFbeta', 'Gene', (50, 57))	('reduced', 'NegReg', (24, 31))	('HK-2', 'molecular_function', 'GO:0008256', ('106', '110'))	('renal fibrosis', 'Disease', 'MESH:D005355', (132, 146))	('renal fibrosis', 'Disease', (132, 146))	('fibronectin', 'Gene', '14268', (62, 73))	('renal fibrosis', 'Phenotype', 'HP:0030760', (132, 146))	('HK-2', 'CellLine', 'CVCL:0302', (106, 110))	('Silencing', 'Var', (0, 9))	('TGFbeta', 'Gene', '21802', (50, 57))	('expression', 'MPA', (36, 46))	('alleviated', 'NegReg', (121, 131))
185648	33523554	11  Similarly, Ang II-induced cardiac fibrosis was attenuated in haploinsufficient mice (Klf5+/- mice) compared to control mice.	('Klf5', 'Gene', '12224', (89, 93))	('cardiac fibrosis', 'Disease', (30, 46))	('attenuated', 'NegReg', (51, 61))	('haploinsufficient', 'Var', (65, 82))	('mice', 'Species', '10090', (83, 87))	('mice', 'Species', '10090', (97, 101))	('Ang', 'Protein', (15, 18))	('cardiac fibrosis', 'Disease', 'MESH:D005355', (30, 46))	('Klf5', 'Gene', (89, 93))	('mice', 'Species', '10090', (123, 127))
185649	33523554	73 ,  88  Additionally, dimethylnitrosamine induced significant increase in KLF5 mRNA expression and induced liver fibrosis, suggesting a role for KLF5 in the fibrotic response.	('liver fibrosis', 'Phenotype', 'HP:0001395', (109, 123))	('KLF5', 'Protein', (76, 80))	('liver fibrosis', 'Disease', (109, 123))	('liver fibrosis', 'Disease', 'MESH:D008103', (109, 123))	('increase', 'PosReg', (64, 72))	('dimethylnitrosamine', 'Var', (24, 43))	('dimethylnitrosamine', 'Chemical', 'MESH:D004128', (24, 43))	('induced', 'Reg', (101, 108))
185685	32547875	Furthermore, TCPA prognostic analysis observed that several of the key molecules of the PI3K/AKT/mTOR signaling pathway [PTEN, p-AKT (S473) and p-mTOR (S2448)] were also positively correlated with OS in patients with ccRCC (P < 0.05).	('PTEN', 'Gene', (121, 125))	('PTEN', 'Gene', '5728', (121, 125))	('signaling pathway', 'biological_process', 'GO:0007165', ('102', '119'))	('p-AKT (S473', 'Var', (127, 138))	('TCPA', 'Chemical', '-', (13, 17))	('patients', 'Species', '9606', (203, 211))	('p-mTOR (S2448)]', 'Var', (144, 159))	('ccRCC', 'Phenotype', 'HP:0006770', (217, 222))	('PI3K', 'molecular_function', 'GO:0016303', ('88', '92'))	('correlated', 'Reg', (181, 191))	('RCC', 'Disease', (219, 222))	('S473', 'Var', (134, 138))	('PI3K/AKT/mTOR signaling pathway', 'Pathway', (88, 119))	('RCC', 'Disease', 'MESH:C538614', (219, 222))
185693	32547875	Apart from the well-known von Hippel-Lindau (VHL) gene, genetic mutations in members of the PI3K/AKT/mTOR signaling pathway are also frequently observed in RCC, which promotes the hyperactivation of the PI3K/AKT/mTOR signaling cascade.	('VHL', 'Gene', '7428', (45, 48))	('von Hippel-Lindau', 'Gene', (26, 43))	('PI3K/AKT/mTOR', 'Gene', (92, 105))	('signaling cascade', 'biological_process', 'GO:0007165', ('217', '234'))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('von Hippel-Lindau', 'Gene', '7428', (26, 43))	('RCC', 'Disease', (156, 159))	('hyperactivation', 'PosReg', (180, 195))	('PI3K', 'molecular_function', 'GO:0016303', ('92', '96'))	('PI3K/AKT/mTOR signaling cascade', 'Pathway', (203, 234))	('observed', 'Reg', (144, 152))	('PI3K', 'molecular_function', 'GO:0016303', ('203', '207'))	('signaling pathway', 'biological_process', 'GO:0007165', ('106', '123'))	('VHL', 'Gene', (45, 48))	('genetic mutations', 'Var', (56, 73))
185694	32547875	The PI3K/AKT/mTOR signaling pathway, which is inhibited by phosphatase and tensin homolog (PTEN), is transduced through three checkpoint proteins or protein complexes: PI3K, AKT and mTOR.	('mTOR', 'Gene', (182, 186))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('phosphatase and tensin homolog', 'Gene', '5728', (59, 89))	('phosphatase', 'molecular_function', 'GO:0016791', ('59', '70'))	('PI3K', 'molecular_function', 'GO:0016303', ('168', '172'))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('PI3K', 'Var', (168, 172))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('59', '89'))	('AKT', 'Pathway', (174, 177))	('PI3K/AKT/mTOR signaling pathway', 'Pathway', (4, 35))	('signaling pathway', 'biological_process', 'GO:0007165', ('18', '35'))	('PTEN', 'Gene', (91, 95))	('PTEN', 'Gene', '5728', (91, 95))
185695	32547875	PTEN, PI3K, AKT and mTOR participate in the regulation of multiple biological functions, including cell survival, metabolism and tumorigenesis under context-specific physiological and pathological conditions.	('PI3K', 'Var', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('metabolism', 'CPA', (114, 124))	('AKT', 'Gene', (12, 15))	('metabolism', 'biological_process', 'GO:0008152', ('114', '124'))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('PI3K', 'molecular_function', 'GO:0016303', ('6', '10'))	('regulation', 'biological_process', 'GO:0065007', ('44', '54'))	('tumor', 'Disease', (129, 134))	('PTEN', 'Gene', (0, 4))	('participate', 'Reg', (25, 36))	('PTEN', 'Gene', '5728', (0, 4))	('cell survival', 'CPA', (99, 112))	('mTOR', 'Gene', (20, 24))
185698	32547875	The activation of PI3K phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3), which subsequently recruits AKT to the plasma membrane, where AKT is activated by 3-phosphoinositide-dependent protein kinase (PDK) phosphorylation on Thr308.	('Thr308', 'Chemical', '-', (295, 301))	('phosphorylation', 'biological_process', 'GO:0016310', ('276', '291'))	('PDK', 'molecular_function', 'GO:0004740', ('271', '274'))	('PIP3', 'Chemical', '-', (137, 141))	('AKT', 'Enzyme', (172, 175))	('PI3K', 'Var', (18, 22))	('PI3K', 'molecular_function', 'GO:0016303', ('18', '22'))	('PIP2', 'Chemical', 'MESH:D019269', (77, 81))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:D019269', (38, 75))	('protein', 'cellular_component', 'GO:0003675', ('255', '262'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('183', '198'))	('recruits', 'PosReg', (163, 171))	('phosphatidylinositol-3,4,5-trisphosphate', 'Chemical', 'MESH:C060974', (95, 135))
185702	32547875	PI3K/AKT/mTOR signaling pathway dysregulation is frequently identified in patients with RCC, and inhibitors of mTOR, including everolimus and temsirolimus, have proven efficacious in mRCC.	('signaling pathway', 'biological_process', 'GO:0007165', ('14', '31'))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('mTOR', 'Gene', (111, 115))	('RCC', 'Disease', (184, 187))	('PI3K/AKT/mTOR signaling pathway', 'Pathway', (0, 31))	('RCC', 'Disease', (88, 91))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('patients', 'Species', '9606', (74, 82))	('temsirolimus', 'Chemical', 'MESH:C401859', (142, 154))	('everolimus', 'Chemical', 'MESH:D000068338', (127, 137))	('dysregulation', 'Reg', (32, 45))	('inhibitors', 'Var', (97, 107))
185724	32547875	Briefly, seven proteins, including PTEN, PIK3CA, AKT, mTOR and three proteins modified by phosphorylation, phosphorylated (p)-AKT (S473), p-AKT (T308) and p-mTOR (S2448), were evaluated using TCPA database (n = 445) after <=150 months follow-up.	('phosphorylation', 'biological_process', 'GO:0016310', ('90', '105'))	('T308', 'Var', (145, 149))	('PTEN', 'Gene', (35, 39))	('PIK3CA', 'Gene', (41, 47))	('PTEN', 'Gene', '5728', (35, 39))	('S473', 'Var', (131, 135))	('TCPA', 'Chemical', '-', (192, 196))	('S2448', 'Var', (163, 168))	('PIK3CA', 'Gene', '5290', (41, 47))
185764	32547875	It was discovered that the higher expression levels of PTEN (log-rank P < 0.001; Cox P < 0.001), p-AKT (S473; log-rank P = 0.047; Cox P = 0.002) and p-mTOR (S2448; log-rank P = 0.004; Cox P < 0.001) were associated with an improved OS in patients with ccRCC, which is consistent with previous findings.	('PTEN', 'Gene', '5728', (55, 59))	('p-mTOR (S2448', 'Var', (149, 162))	('patients', 'Species', '9606', (238, 246))	('ccRCC', 'Phenotype', 'HP:0006770', (252, 257))	('improved', 'PosReg', (223, 231))	('higher', 'PosReg', (27, 33))	('S2448;', 'Var', (157, 163))	('RCC', 'Disease', (254, 257))	('RCC', 'Disease', 'MESH:C538614', (254, 257))	('expression levels', 'MPA', (34, 51))	('PTEN', 'Gene', (55, 59))
185767	32547875	The expression levels of PTEN, AKT and p-AKT (S473) were positively correlated with both tumor stages (P < 0.001; P = 0.045 and P < 0.001, respectively) and tumor grades ( P < 0.001; P < 0.001 and P < 0.001, respectively) in patients with ccRCC, which is consistent with previous studies.	('expression levels', 'MPA', (4, 21))	('tumor', 'Disease', (157, 162))	('AKT', 'Protein', (31, 34))	('patients', 'Species', '9606', (225, 233))	('p-AKT (S473', 'Var', (39, 50))	('RCC', 'Disease', (241, 244))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('PTEN', 'Gene', '5728', (25, 29))	('RCC', 'Disease', 'MESH:C538614', (241, 244))	('PTEN', 'Gene', (25, 29))	('correlated', 'Reg', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (239, 244))
185768	32547875	However, no significant correlation was observed between PIK3CA, mTOR and p-mTOR (S2448) expression and tumor stages or grades of patients with ccRCC (P > 0.05).	('mTOR', 'Gene', (65, 69))	('PIK3CA', 'Gene', '5290', (57, 63))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('RCC', 'Disease', (146, 149))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('tumor', 'Disease', (104, 109))	('patients', 'Species', '9606', (130, 138))	('p-mTOR', 'Gene', (74, 80))	('S2448', 'Var', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('PIK3CA', 'Gene', (57, 63))
185775	32547875	Accordingly, TCPA analysis demonstrated that the protein expression levels of PTEN, p-AKT (S473) and p-mTOR (S2448) were correlated with an improved OS (P < 0.05).	('p-AKT (S473', 'Var', (84, 95))	('improved', 'PosReg', (140, 148))	('p-mTOR (S2448', 'Var', (101, 114))	('PTEN', 'Gene', (78, 82))	('PTEN', 'Gene', '5728', (78, 82))	('TCPA', 'Chemical', '-', (13, 17))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('protein expression levels', 'MPA', (49, 74))
185778	32547875	This suggested that the function of PI3K/AKT/mTOR in ccRCC was not only dependent on the mRNA and protein expression levels, but also reliant on protein activation through phosphorylation, such as p-AKT and p-mTOR.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('RCC', 'Disease', (55, 58))	('PI3K/AKT/mTOR', 'Var', (36, 49))	('PI3K', 'molecular_function', 'GO:0016303', ('36', '40'))	('activation', 'PosReg', (153, 163))	('p-AKT', 'Disease', (197, 202))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('protein', 'MPA', (145, 152))	('phosphorylation', 'MPA', (172, 187))	('phosphorylation', 'biological_process', 'GO:0016310', ('172', '187'))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('dependent', 'Reg', (72, 81))	('p-mTOR', 'Disease', (207, 213))
185787	32547875	In addition, investigated the expression levels of mTOR and p-mTOR (S2448) in 10 ccRCC and normal kidney tissues, and found that p-mTOR (S2448), but not mTOR expression levels, were increased in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('increased', 'PosReg', (182, 191))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('p-mTOR (S2448', 'Var', (129, 142))	('RCC', 'Disease', 'MESH:C538614', (197, 200))	('ccRCC', 'Phenotype', 'HP:0006770', (195, 200))	('RCC', 'Disease', (197, 200))
185816	31943775	SNORA42,15 SNORD33, SNORD66, SNORD76,16 SNORD78 17 and SNORD114.1 18 have been reported the potential prognostic value in colorectal cancer, non-small-cell lung cancer and peripheral artery disease.	('SNORD66', 'Gene', (20, 27))	('SNORD76', 'Gene', (29, 36))	('colorectal cancer', 'Disease', (122, 139))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (141, 167))	('peripheral artery disease', 'Disease', 'MESH:D058729', (172, 197))	('SNORD114.1', 'Var', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('SNORD76', 'Gene', '692196', (29, 36))	('SNORD78', 'Gene', '692198', (40, 47))	('SNORA42', 'Gene', '677823', (0, 7))	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('SNORD78', 'Gene', (40, 47))	('non-small-cell lung cancer', 'Disease', (141, 167))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (141, 167))	('peripheral artery disease', 'Disease', (172, 197))	('SNORD33', 'Gene', '26818', (11, 18))	('peripheral artery disease', 'Phenotype', 'HP:0004950', (172, 197))	('SNORA42', 'Gene', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('SNORD33', 'Gene', (11, 18))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (145, 167))	('colorectal cancer', 'Disease', 'MESH:D015179', (122, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('SNORD66', 'Gene', '692107', (20, 27))
185828	31943775	The snoRNAs with Coei < 0 were considered as protective factors, whereas those with Coei > 0 were considered as risky factors.	('snoRNA', 'Gene', '85390', (4, 10))	('Coei < 0', 'Var', (17, 25))	('snoRNA', 'Gene', (4, 10))
185840	31943775	The SNORic (http://bioinfo.life.hust.edu.cn/SNORic) was used to examine the correlation between snoRNAs and copy number variation (CNV), DNA methylation and protein expression.	('snoRNA', 'Gene', '85390', (96, 102))	('DNA methylation', 'biological_process', 'GO:0006306', ('137', '152'))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('DNA', 'cellular_component', 'GO:0005574', ('137', '140'))	('copy number variation', 'Var', (108, 129))	('snoRNA', 'Gene', (96, 102))	('protein', 'Protein', (157, 164))
185845	31943775	Finally, six snoRNAs (P < .05) were identified as the independent risk factors markedly related to survival, including SNORA2, SNORD12B, SNORA59B, SNORA70B, SNORD93 and SNORD116-2 (Table S4).	('SNORD12B', 'Gene', (127, 135))	('snoRNA', 'Gene', '85390', (13, 19))	('SNORA70B', 'Gene', (147, 155))	('related', 'Reg', (88, 95))	('SNORD116-2', 'Gene', '100033414', (169, 179))	('SNORD116-2', 'Gene', (169, 179))	('snoRNA', 'Gene', (13, 19))	('SNORA59B', 'Gene', '677882', (137, 145))	('SNORD12B', 'Gene', '100113393', (127, 135))	('SNORA2', 'Var', (119, 125))	('SNORD93', 'Gene', '692210', (157, 164))	('SNORD93', 'Gene', (157, 164))	('SNORA59B', 'Gene', (137, 145))	('SNORA70B', 'Gene', '100124537', (147, 155))
185848	31943775	We established the risk score formula as follows: risk score = (-0.2791*SNORA2) + (-0.2461*SNORD116-2) + (-0.1322*SNORA59B) + (0.2680*SNORD93) + (0.2330*SNORD12B) + (0.4199*SNORA70B).	('SNORA59B', 'Gene', '677882', (114, 122))	('SNORD12B', 'Gene', '100113393', (153, 161))	('SNORD93', 'Gene', '692210', (134, 141))	('SNORD93', 'Gene', (134, 141))	('SNORA59B', 'Gene', (114, 122))	('SNORD116-2', 'Gene', (91, 101))	('-0.2791*SNORA2', 'Var', (64, 78))	('SNORA70B', 'Gene', '100124537', (173, 181))	('SNORD12B', 'Gene', (153, 161))	('SNORD116-2', 'Gene', '100033414', (91, 101))	('SNORA70B', 'Gene', (173, 181))
185854	31943775	Furthermore, the risk score of highly malignant cells (Caki-1) was higher than that of lowly malignant cells (786-O), which implied that our six-snoRNA signature had a good prognostic value for ccRCC (Figure 1F).	('higher', 'PosReg', (67, 73))	('snoRNA', 'Gene', '85390', (145, 151))	('snoRNA', 'cellular_component', 'GO:0005733', ('145', '151'))	('ccRCC', 'Disease', 'MESH:D002292', (194, 199))	('Caki-1', 'Var', (55, 61))	('RCC', 'Phenotype', 'HP:0005584', (196, 199))	('snoRNA', 'Gene', (145, 151))	('786-O', 'Chemical', 'MESH:C002925', (110, 115))	('ccRCC', 'Disease', (194, 199))
185858	31943775	To explore the sensitivity and specificity of the six-snoRNA signature, we conducted time-dependent ROC analysis and result showed that the prognostic accuracy of the signature was 0.701, 0.721, 0.744 and 0.759 for 1, 3, 5 and 7 years in entire series which increased with time prolonging (Figure 1H).	('0.759', 'Var', (205, 210))	('0.701', 'Var', (181, 186))	('snoRNA', 'Gene', (54, 60))	('snoRNA', 'Gene', '85390', (54, 60))	('0.744', 'Var', (195, 200))	('snoRNA', 'cellular_component', 'GO:0005733', ('54', '60'))	('0.721', 'Var', (188, 193))
185916	31943775	The result showed that the expression levels of SNORA2, SNORD12B, SNORA70B, SNORD93 and SNORD116-2 were positively correlated with their CNVs in ccRCC, respectively (Figure 5B).	('SNORD93', 'Gene', '692210', (76, 83))	('correlated', 'Reg', (115, 125))	('ccRCC', 'Disease', 'MESH:D002292', (145, 150))	('SNORD93', 'Gene', (76, 83))	('SNORD116-2', 'Gene', (88, 98))	('SNORD12B', 'Gene', (56, 64))	('SNORA70B', 'Gene', '100124537', (66, 74))	('expression', 'MPA', (27, 37))	('SNORD116-2', 'Gene', '100033414', (88, 98))	('SNORA70B', 'Gene', (66, 74))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('SNORD12B', 'Gene', '100113393', (56, 64))	('ccRCC', 'Disease', (145, 150))	('CNVs', 'MPA', (137, 141))	('SNORA2', 'Var', (48, 54))
185920	31943775	Hence interestingly, probe cg18598146 methylation of SNORD12B was protective factor for ccRCC (Figure 5C).	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('SNORD12B', 'Gene', '100113393', (53, 61))	('ccRCC', 'Disease', (88, 93))	('ccRCC', 'Disease', 'MESH:D002292', (88, 93))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))	('SNORD12B', 'Gene', (53, 61))	('cg18598146 methylation', 'Var', (27, 49))
185929	31943775	Then, we analysed the correlation between snoRNAs and their corresponding host genes, and observed that SNORA2, SNORD12B, SNORA59B, SNORA70B and SNORD116-2 were highly correlated with their host genes, respectively (Figure 6B-F).	('correlated', 'Interaction', (168, 178))	('SNORD116-2', 'Gene', '100033414', (145, 155))	('SNORD116-2', 'Gene', (145, 155))	('SNORD12B', 'Gene', '100113393', (112, 120))	('SNORA70B', 'Gene', '100124537', (132, 140))	('SNORA70B', 'Gene', (132, 140))	('SNORA59B', 'Gene', '677882', (122, 130))	('snoRNA', 'Gene', (42, 48))	('SNORD12B', 'Gene', (112, 120))	('B-F', 'Chemical', 'MESH:D005461', (224, 227))	('SNORA2', 'Var', (104, 110))	('snoRNA', 'Gene', '85390', (42, 48))	('SNORA59B', 'Gene', (122, 130))
185948	31943775	In our study, we found the six-snoRNA signature expressed stably in serum, suggesting serum snoRNAs may serve as novel non-invasive biomarkers for ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('snoRNA', 'cellular_component', 'GO:0005733', ('31', '37'))	('serum', 'Var', (86, 91))	('snoRNA', 'Gene', (92, 98))	('snoRNA', 'Gene', '85390', (92, 98))	('ccRCC', 'Disease', (147, 152))	('snoRNA', 'Gene', (31, 37))	('ccRCC', 'Disease', 'MESH:D002292', (147, 152))	('serum snoRNAs', 'Phenotype', 'HP:0025267', (86, 99))	('snoRNA', 'Gene', '85390', (31, 37))
185956	31943775	On the other hand, snoRNAs exist methylation site and have poor prognosis in KIRC, so is snoRNA methylation correlated with better survival?19 In this study, we found high expression of risky factors SNORD12B and SNORD93 was negatively correlated with methylation sites cg18598146, cg04907244 and cg22407942, respectively, and these methylation sites were associated with better survival in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (393, 396))	('KIRC', 'Disease', (77, 81))	('methylation', 'biological_process', 'GO:0032259', ('252', '263'))	('KIRC', 'Disease', 'MESH:D002292', (77, 81))	('snoRNA', 'cellular_component', 'GO:0005733', ('89', '95'))	('negatively', 'NegReg', (225, 235))	('methylation', 'biological_process', 'GO:0032259', ('333', '344'))	('cg22407942', 'Var', (297, 307))	('cg04907244', 'Var', (282, 292))	('methylation', 'biological_process', 'GO:0032259', ('33', '44'))	('snoRNA', 'Gene', '85390', (19, 25))	('ccRCC', 'Disease', 'MESH:D002292', (391, 396))	('snoRNA', 'Gene', '85390', (89, 95))	('snoRNA', 'Gene', (19, 25))	('snoRNA', 'Gene', (89, 95))	('ccRCC', 'Disease', (391, 396))	('methylation', 'MPA', (252, 263))	('better', 'PosReg', (372, 378))	('SNORD12B', 'Gene', (200, 208))	('SNORD93', 'Gene', '692210', (213, 220))	('SNORD93', 'Gene', (213, 220))	('methylation', 'biological_process', 'GO:0032259', ('96', '107'))	('SNORD12B', 'Gene', '100113393', (200, 208))	('cg18598146', 'Var', (270, 280))
185957	31943775	In addition, Ferreira et al46 suggested that the host gene-associated 5'CpG islands of SNORA59B were hypermethylated in colorectal cancer cells.	('SNORA59B', 'Gene', '677882', (87, 95))	('hypermethylated', 'Var', (101, 116))	('colorectal cancer', 'Disease', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('SNORA59B', 'Gene', (87, 95))	('colorectal cancer', 'Disease', 'MESH:D015179', (120, 137))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))
185992	31999648	To that end, we have examined the effects of PT2385, one of the HIF-2alpha antagonists that shows clinical efficacy in ccRCC, on morphological changes and hypoxic ventilatory control that are mediated by the carotid body.	('a', 'Gene', '11820', (151, 152))	('PT2385', 'Chemical', 'MESH:C000614279', (45, 51))	('a', 'Gene', '11820', (140, 141))	('a', 'Gene', '11820', (188, 189))	('a', 'Gene', '11820', (196, 197))	('PT2385', 'Var', (45, 51))	('ccRCC', 'Disease', (119, 124))	('a', 'Gene', '11820', (69, 70))	('a', 'Gene', '11820', (5, 6))	('a', 'Gene', '11820', (75, 76))	('a', 'Gene', '11820', (185, 186))	('a', 'Gene', '11820', (209, 210))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('a', 'Gene', '11820', (145, 146))	('a', 'Gene', '11820', (169, 170))	('a', 'Gene', '11820', (112, 113))	('a', 'Gene', '11820', (89, 90))	('a', 'Gene', '11820', (17, 18))	('a', 'Gene', '11820', (73, 74))	('a', 'Gene', '11820', (104, 105))	('a', 'Gene', '11820', (78, 79))	('a', 'Gene', '11820', (23, 24))
185993	31999648	We report that PT2385 blocks the proliferative and ultrastructural changes in the cells within this organ that are observed in response to hypoxia.	('hypoxia', 'Disease', 'MESH:D000860', (139, 146))	('PT2385', 'Chemical', 'MESH:C000614279', (15, 21))	('hypoxia', 'Disease', (139, 146))	('a', 'Gene', '11820', (41, 42))	('a', 'Gene', '11820', (111, 112))	('a', 'Gene', '11820', (103, 104))	('a', 'Gene', '11820', (55, 56))	('a', 'Gene', '11820', (69, 70))	('a', 'Gene', '11820', (145, 146))	('a', 'Gene', '11820', (108, 109))	('a', 'Gene', '11820', (47, 48))	('response to hypoxia', 'biological_process', 'GO:0001666', ('127', '146'))	('PT2385', 'Var', (15, 21))	('a', 'Gene', '11820', (12, 13))	('a', 'Gene', '11820', (64, 65))	('blocks', 'NegReg', (22, 28))
185994	31999648	Enhanced ventilatory sensitivity to hypoxia was rapidly and severely ablated at the doses of PT2385 for which antitumor effects have been reported.	('hypoxia', 'Disease', 'MESH:D000860', (36, 43))	('Enhanced ventilatory sensitivity to hypoxia', 'Phenotype', 'HP:0005947', (0, 43))	('PT2385', 'Chemical', 'MESH:C000614279', (93, 99))	('a', 'Gene', '11820', (110, 111))	('a', 'Gene', '11820', (77, 78))	('a', 'Gene', '11820', (45, 46))	('a', 'Gene', '11820', (69, 70))	('tumor', 'Disease', (114, 119))	('PT2385', 'Var', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('a', 'Gene', '11820', (3, 4))	('a', 'Gene', '11820', (42, 43))	('a', 'Gene', '11820', (129, 130))	('hypoxia', 'Disease', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('a', 'Gene', '11820', (72, 73))	('a', 'Gene', '11820', (56, 57))	('a', 'Gene', '11820', (49, 50))	('a', 'Gene', '11820', (15, 16))
185998	31999648	Because in clinical or physiological settings, such as chronic lung disease or altitude exposure, hypoxia is generally sustained and because genetic studies have suggested an important role for HIF-2 in this setting, we first studied the effects of PT2385 on ventilatory sensitivity in animals exposed to sustained hypoxia.	('a', 'Gene', '11820', (158, 159))	('hypoxia', 'Disease', (98, 105))	('hypoxia', 'Disease', 'MESH:D000860', (98, 105))	('a', 'Gene', '11820', (172, 173))	('a', 'Gene', '11820', (52, 53))	('chronic lung disease', 'Phenotype', 'HP:0006528', (55, 75))	('a', 'Gene', '11820', (321, 322))	('sustained hypoxia', 'Disease', 'MESH:D000860', (305, 322))	('lung disease', 'Phenotype', 'HP:0002088', (63, 75))	('a', 'Gene', '11820', (34, 35))	('a', 'Gene', '11820', (290, 291))	('PT2385', 'Chemical', 'MESH:C000614279', (249, 255))	('a', 'Gene', '11820', (123, 124))	('a', 'Gene', '11820', (3, 4))	('hypoxia', 'Disease', (315, 322))	('a', 'Gene', '11820', (265, 266))	('a', 'Gene', '11820', (114, 115))	('a', 'Gene', '11820', (136, 137))	('PT2385', 'Var', (249, 255))	('a', 'Gene', '11820', (129, 130))	('a', 'Gene', '11820', (309, 310))	('a', 'Gene', '11820', (17, 18))	('a', 'Gene', '11820', (79, 80))	('hypoxia', 'Disease', 'MESH:D000860', (315, 322))	('chronic lung disease', 'Disease', (55, 75))	('a', 'Gene', '11820', (72, 73))	('sustained hypoxia', 'Disease', (305, 322))	('a', 'Gene', '11820', (286, 287))	('a', 'Gene', '11820', (104, 105))	('chronic lung disease', 'Disease', 'MESH:D055370', (55, 75))	('a', 'Gene', '11820', (181, 182))
186007	31999648	For example, acute ventilatory responses (AVRs) to 10% oxygen with 3% carbon dioxide after 7 days of hypoxia were reduced from 9.22 +- 1.60 mL/min/g in vehicle-treated mice to 4.24 +- 0.90 mL/min/g in mice treated with 3 mg/kg PT2385 and were similar to those at baseline, i.e., before sustained hypoxia (4.18 +- 0.43 mL/min/g).	('a', 'Gene', '11820', (6, 7))	('A', 'Gene', '11820', (42, 43))	('reduced', 'NegReg', (114, 121))	('PT2385', 'Chemical', 'MESH:C000614279', (227, 233))	('hypoxia', 'Disease', 'MESH:D000860', (296, 303))	('a', 'Gene', '11820', (94, 95))	('oxygen', 'Chemical', 'MESH:D010100', (55, 61))	('a', 'Gene', '11820', (85, 86))	('a', 'Gene', '11820', (260, 261))	('sustained hypoxia', 'Disease', (286, 303))	('a', 'Gene', '11820', (13, 14))	('a', 'Gene', '11820', (234, 235))	('PT2385', 'Var', (227, 233))	('a', 'Gene', '11820', (107, 108))	('a', 'Gene', '11820', (163, 164))	('mice', 'Species', '10090', (201, 205))	('a', 'Gene', '11820', (290, 291))	('a', 'Gene', '11820', (248, 249))	('a', 'Gene', '11820', (209, 210))	('a', 'Gene', '11820', (264, 265))	('hypoxia', 'Disease', (101, 108))	('a', 'Gene', '11820', (25, 26))	('mice', 'Species', '10090', (168, 172))	('a', 'Gene', '11820', (302, 303))	('sustained hypoxia', 'Disease', 'MESH:D000860', (286, 303))	('hypoxia', 'Disease', (296, 303))	('carbon dioxide', 'Chemical', 'MESH:D002245', (70, 84))	('a', 'Gene', '11820', (71, 72))	('hypoxia', 'Disease', 'MESH:D000860', (101, 108))
186008	31999648	In the case of the 10 mg/kg dose, AVRs of mice treated with PT2385 and in 7-day hypoxia were lower than those at baseline (2.02 +- 0.62 versus 4.31 +- 0.73 mL/min/g).	('PT2385', 'Chemical', 'MESH:C000614279', (60, 66))	('hypoxia', 'Disease', (80, 87))	('mice', 'Species', '10090', (42, 46))	('a', 'Gene', '11820', (86, 87))	('A', 'Gene', '11820', (34, 35))	('a', 'Gene', '11820', (114, 115))	('lower', 'NegReg', (93, 98))	('a', 'Gene', '11820', (101, 102))	('a', 'Gene', '11820', (110, 111))	('a', 'Gene', '11820', (8, 9))	('a', 'Gene', '11820', (50, 51))	('PT2385', 'Var', (60, 66))	('a', 'Gene', '11820', (77, 78))	('a', 'Gene', '11820', (67, 68))	('hypoxia', 'Disease', 'MESH:D000860', (80, 87))
186012	31999648	Hence, the reduced sensitivity of PT2385-treated mice to carbon dioxide in this setting is also consistent with an action of PT2385 on ventilatory acclimatization to hypoxia.	('a', 'Gene', '11820', (157, 158))	('reduced', 'NegReg', (11, 18))	('PT2385', 'Var', (125, 131))	('a', 'Gene', '11820', (141, 142))	('sensitivity', 'MPA', (19, 30))	('PT2385', 'Chemical', 'MESH:C000614279', (34, 40))	('a', 'Gene', '11820', (172, 173))	('a', 'Gene', '11820', (115, 116))	('a', 'Gene', '11820', (91, 92))	('a', 'Gene', '11820', (44, 45))	('hypoxia', 'Disease', (166, 173))	('carbon dioxide', 'Chemical', 'MESH:D002245', (57, 71))	('a', 'Gene', '11820', (147, 148))	('a', 'Gene', '11820', (58, 59))	('mice', 'Species', '10090', (49, 53))	('a', 'Gene', '11820', (153, 154))	('a', 'Gene', '11820', (112, 113))	('hypoxia', 'Disease', 'MESH:D000860', (166, 173))	('PT2385', 'Chemical', 'MESH:C000614279', (125, 131))
186013	31999648	In summary, these findings reveal that treatment with PT2385 exerts striking effects on ventilatory control, essentially ablating the enhanced ventilatory sensitivity, or ventilatory acclimatization that occurs during sustained exposure to hypoxia.	('PT2385', 'Chemical', 'MESH:C000614279', (54, 60))	('a', 'Gene', '11820', (189, 190))	('a', 'Gene', '11820', (7, 8))	('a', 'Gene', '11820', (31, 32))	('a', 'Gene', '11820', (149, 150))	('a', 'Gene', '11820', (94, 95))	('hypoxia', 'Disease', (240, 247))	('PT2385', 'Var', (54, 60))	('a', 'Gene', '11820', (116, 117))	('a', 'Gene', '11820', (124, 125))	('effects', 'Reg', (77, 84))	('hypoxia', 'Disease', 'MESH:D000860', (240, 247))	('a', 'Gene', '11820', (36, 37))	('a', 'Gene', '11820', (42, 43))	('a', 'Gene', '11820', (121, 122))	('a', 'Gene', '11820', (201, 202))	('a', 'Gene', '11820', (193, 194))	('a', 'Gene', '11820', (177, 178))	('a', 'Gene', '11820', (137, 138))	('a', 'Gene', '11820', (183, 184))	('a', 'Gene', '11820', (246, 247))	('a', 'Gene', '11820', (222, 223))
186025	31999648	These responses were also reduced by PT2385, although interestingly, this appeared to require longer exposure to the compound.	('responses', 'MPA', (6, 15))	('a', 'Gene', '11820', (21, 22))	('a', 'Gene', '11820', (45, 46))	('PT2385', 'Var', (37, 43))	('reduced', 'NegReg', (26, 33))	('a', 'Gene', '11820', (74, 75))	('a', 'Gene', '11820', (78, 79))	('PT2385', 'Chemical', 'MESH:C000614279', (37, 43))
186026	31999648	Whereas PT2385 completely reversed enhanced ventilatory sensitivity to environmental hypoxia within 24 hours in WT mice (Figure 2, A and B), the enhanced sensitivity in Phd2+/- mice was progressively reduced after between 2 and 7 days of treatment with PT2385 (Figure 2, C and D).	('PT2385', 'Chemical', 'MESH:C000614279', (253, 259))	('Phd', 'molecular_function', 'GO:0050175', ('169', '172'))	('a', 'Gene', '11820', (38, 39))	('Phd2', 'Gene', (169, 173))	('PT2385', 'Var', (253, 259))	('a', 'Gene', '11820', (133, 134))	('reduced', 'NegReg', (200, 207))	('a', 'Gene', '11820', (273, 274))	('a', 'Gene', '11820', (148, 149))	('mice', 'Species', '10090', (115, 119))	('a', 'Gene', '11820', (82, 83))	('a', 'Gene', '11820', (91, 92))	('a', 'Gene', '11820', (5, 6))	('a', 'Gene', '11820', (241, 242))	('enhanced ventilatory sensitivity to environmental hypoxia', 'Phenotype', 'HP:0005947', (35, 92))	('hypoxia', 'Disease', (85, 92))	('a', 'Gene', '11820', (231, 232))	('a', 'Gene', '11820', (208, 209))	('PT2385', 'Chemical', 'MESH:C000614279', (8, 14))	('a', 'Gene', '11820', (50, 51))	('mice', 'Species', '10090', (177, 181))	('hypoxia', 'Disease', 'MESH:D000860', (85, 92))	('PT2385', 'Var', (8, 14))	('a', 'Gene', '11820', (224, 225))	('A', 'Gene', '11820', (131, 132))	('a', 'Gene', '11820', (183, 184))	('Phd2', 'Gene', '112405', (169, 173))
186030	31999648	Interestingly, in addition to reducing the enhanced ventilatory sensitivity in Phd2+/- mice, we noted that PT2385 appeared to reduce ventilatory sensitivity even in their WT littermates (Figure 2, C and D).	('a', 'Gene', '11820', (199, 200))	('PT2385', 'Var', (107, 113))	('reducing', 'NegReg', (30, 38))	('a', 'Gene', '11820', (18, 19))	('reduce', 'NegReg', (126, 132))	('a', 'Gene', '11820', (58, 59))	('mice', 'Species', '10090', (87, 91))	('Phd2', 'Gene', (79, 83))	('PT2385', 'Chemical', 'MESH:C000614279', (107, 113))	('a', 'Gene', '11820', (114, 115))	('a', 'Gene', '11820', (139, 140))	('a', 'Gene', '11820', (104, 105))	('a', 'Gene', '11820', (118, 119))	('Phd2', 'Gene', '112405', (79, 83))	('Phd', 'molecular_function', 'GO:0050175', ('79', '82'))	('a', 'Gene', '11820', (46, 47))	('a', 'Gene', '11820', (181, 182))
186031	31999648	Such an effect on baseline (unacclimatized) ventilatory sensitivity was also suggested by a reduction in sensitivity below the baseline in mice exposed to 7 days of hypoxia and treated with PT2385 at a dose of 10 mg/kg (Figure 1 and Table 1).	('a', 'Gene', '11820', (158, 159))	('reduction', 'NegReg', (92, 101))	('a', 'Gene', '11820', (180, 181))	('a', 'Gene', '11820', (173, 174))	('a', 'Gene', '11820', (30, 31))	('a', 'Gene', '11820', (197, 198))	('sensitivity', 'MPA', (105, 116))	('a', 'Gene', '11820', (171, 172))	('a', 'Gene', '11820', (234, 235))	('a', 'Gene', '11820', (69, 70))	('mice', 'Species', '10090', (139, 143))	('a', 'Gene', '11820', (36, 37))	('a', 'Gene', '11820', (19, 20))	('a', 'Gene', '11820', (5, 6))	('a', 'Gene', '11820', (90, 91))	('a', 'Gene', '11820', (200, 201))	('PT2385', 'Chemical', 'MESH:C000614279', (190, 196))	('hypoxia', 'Disease', (165, 172))	('a', 'Gene', '11820', (50, 51))	('a', 'Gene', '11820', (72, 73))	('hypoxia', 'Disease', 'MESH:D000860', (165, 172))	('PT2385', 'Var', (190, 196))	('a', 'Gene', '11820', (128, 129))	('a', 'Gene', '11820', (229, 230))
186036	31999648	These experiments revealed a clear, though partial, loss of sensitivity to gas challenge with 10% oxygen with 3% carbon dioxide in mice treated with PT2385 at 10 mg/kg (Figure 3).	('loss', 'NegReg', (52, 56))	('a', 'Gene', '11820', (48, 49))	('carbon dioxide', 'Chemical', 'MESH:D002245', (113, 127))	('a', 'Gene', '11820', (27, 28))	('a', 'Gene', '11820', (156, 157))	('oxygen', 'Chemical', 'MESH:D010100', (98, 104))	('PT2385', 'Var', (149, 155))	('a', 'Gene', '11820', (76, 77))	('a', 'Gene', '11820', (114, 115))	('a', 'Gene', '11820', (139, 140))	('PT2385', 'Chemical', 'MESH:C000614279', (149, 155))	('a', 'Gene', '11820', (22, 23))	('mice', 'Species', '10090', (131, 135))	('a', 'Gene', '11820', (32, 33))	('a', 'Gene', '11820', (44, 45))	('a', 'Gene', '11820', (81, 82))
186037	31999648	This reduction in ventilatory sensitivity was similar at all time points, including 1 hour after the first dose of PT2385, and was most clearly manifest as a reduction in tidal volume as opposed to respiratory rate (Supplemental Figure 5A).	('reduction', 'NegReg', (5, 14))	('a', 'Gene', '11820', (174, 175))	('a', 'Gene', '11820', (204, 205))	('PT2385', 'Chemical', 'MESH:C000614279', (115, 121))	('a', 'Gene', '11820', (54, 55))	('a', 'Gene', '11820', (226, 227))	('PT2385', 'Var', (115, 121))	('a', 'Gene', '11820', (139, 140))	('a', 'Gene', '11820', (156, 157))	('a', 'Gene', '11820', (43, 44))	('a', 'Gene', '11820', (91, 92))	('a', 'Gene', '11820', (211, 212))	('a', 'Gene', '11820', (123, 124))	('A', 'Gene', '11820', (237, 238))	('a', 'Gene', '11820', (51, 52))	('a', 'Gene', '11820', (145, 146))	('a', 'Gene', '11820', (184, 185))	('a', 'Gene', '11820', (153, 154))	('a', 'Gene', '11820', (57, 58))	('a', 'Gene', '11820', (24, 25))	('a', 'Gene', '11820', (128, 129))	('reduction', 'NegReg', (158, 167))
186039	31999648	Of significance, there were no differences in ventilatory sensitivity to carbon dioxide at either dose (Figure 3B and Supplemental Figure 6), suggesting that PT2385 primarily alters hypoxic, but not hypercapnic, responses.	('PT2385', 'Var', (158, 164))	('PT2385', 'Chemical', 'MESH:C000614279', (158, 164))	('hypoxic', 'MPA', (182, 189))	('sensitivity to carbon dioxide', 'Phenotype', 'HP:0012416', (58, 87))	('a', 'Gene', '11820', (52, 53))	('a', 'Gene', '11820', (11, 12))	('a', 'Gene', '11820', (155, 156))	('a', 'Gene', '11820', (114, 115))	('a', 'Gene', '11820', (128, 129))	('a', 'Gene', '11820', (74, 75))	('a', 'Gene', '11820', (169, 170))	('a', 'Gene', '11820', (88, 89))	('a', 'Gene', '11820', (205, 206))	('a', 'Gene', '11820', (175, 176))	('carbon dioxide', 'Chemical', 'MESH:D002245', (73, 87))
186043	31999648	To analyze the effects of PT2385 on this cellular proliferative response, BrdU incorporation was measured in male mice treated with PT2385 or vehicle and subjected to the same sustained exposure to hypoxia as used in the ventilatory experiments (7 days at 10% oxygen) or maintained in normal air.	('a', 'Gene', '11820', (292, 293))	('a', 'Gene', '11820', (206, 207))	('a', 'Gene', '11820', (180, 181))	('a', 'Gene', '11820', (94, 95))	('a', 'Gene', '11820', (204, 205))	('PT2385', 'Chemical', 'MESH:C000614279', (132, 138))	('a', 'Gene', '11820', (110, 111))	('a', 'Gene', '11820', (276, 277))	('BrdU', 'Chemical', 'MESH:D001973', (74, 78))	('oxygen', 'Chemical', 'MESH:D010100', (260, 266))	('a', 'Gene', '11820', (227, 228))	('a', 'Gene', '11820', (172, 173))	('PT2385', 'Var', (132, 138))	('a', 'Gene', '11820', (249, 250))	('PT2385', 'Chemical', 'MESH:C000614279', (26, 32))	('a', 'Gene', '11820', (5, 6))	('a', 'Gene', '11820', (122, 123))	('a', 'Gene', '11820', (99, 100))	('a', 'Gene', '11820', (3, 4))	('hypoxia', 'Disease', (198, 205))	('a', 'Gene', '11820', (272, 273))	('a', 'Gene', '11820', (58, 59))	('a', 'Gene', '11820', (289, 290))	('mice', 'Species', '10090', (114, 118))	('hypoxia', 'Disease', 'MESH:D000860', (198, 205))	('a', 'Gene', '11820', (87, 88))	('a', 'Gene', '11820', (253, 254))	('a', 'Gene', '11820', (150, 151))	('a', 'Gene', '11820', (47, 48))
186054	31999648	Together, these data suggest that PT2385 blocks both proliferation and oxygen-dependent vesicular functions of type I cells of the carotid body and that both these changes might contribute to reduced ventilatory sensitivity and an inability of PT2385-treated mice to acclimatize to hypoxia.	('a', 'Gene', '11820', (206, 207))	('a', 'Gene', '11820', (31, 32))	('PT2385', 'Chemical', 'MESH:C000614279', (244, 250))	('a', 'Gene', '11820', (228, 229))	('oxygen-dependent', 'CPA', (71, 87))	('a', 'Gene', '11820', (267, 268))	('mice', 'Species', '10090', (259, 263))	('hypoxia', 'Disease', 'MESH:D000860', (282, 289))	('reduced', 'NegReg', (192, 199))	('a', 'Gene', '11820', (61, 62))	('PT2385', 'Chemical', 'MESH:C000614279', (34, 40))	('a', 'Gene', '11820', (132, 133))	('a', 'Gene', '11820', (19, 20))	('a', 'Gene', '11820', (273, 274))	('a', 'Gene', '11820', (67, 68))	('PT2385', 'Var', (34, 40))	('a', 'Gene', '11820', (233, 234))	('blocks', 'NegReg', (41, 47))	('a', 'Gene', '11820', (288, 289))	('a', 'Gene', '11820', (144, 145))	('a', 'Gene', '11820', (17, 18))	('a', 'Gene', '11820', (254, 255))	('a', 'Gene', '11820', (224, 225))	('a', 'Gene', '11820', (166, 167))	('hypoxia', 'Disease', (282, 289))	('a', 'Gene', '11820', (150, 151))	('oxygen', 'Chemical', 'MESH:D010100', (71, 77))	('a', 'Gene', '11820', (95, 96))
186060	31999648	The mutant methionine residue could in principle block the drug-binding pocket locally or alter the overall conformation and stability of the protein to weaken drug binding.	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('methionine', 'Var', (11, 21))	('drug binding', 'molecular_function', 'GO:0008144', ('160', '172'))	('a', 'Gene', '11820', (7, 8))	('a', 'Gene', '11820', (127, 128))	('drug binding', 'Interaction', (160, 172))	('block', 'NegReg', (49, 54))	('a', 'Gene', '11820', (90, 91))	('a', 'Gene', '11820', (121, 122))	('a', 'Gene', '11820', (155, 156))	('a', 'Gene', '11820', (115, 116))	('a', 'Gene', '11820', (104, 105))	('drug-binding pocket', 'MPA', (59, 78))	('methionine', 'Chemical', 'MESH:D008715', (11, 21))	('a', 'Gene', '11820', (82, 83))	('drug-binding', 'molecular_function', 'GO:0008144', ('59', '71'))
186062	31999648	By comparison, the Kd of PT2385 binding to mouse HIF-2alpha S305M mutant PAS-B domain was 0.97 muM, indicating a more than 60-fold loss in binding affinity (Figure 5A).	('a', 'Gene', '11820', (7, 8))	('a', 'Gene', '11820', (54, 55))	('S305M', 'Var', (60, 65))	('loss', 'NegReg', (131, 135))	('a', 'Gene', '11820', (69, 70))	('binding', 'Interaction', (139, 146))	('a', 'Gene', '11820', (82, 83))	('binding', 'molecular_function', 'GO:0005488', ('139', '146'))	('A', 'Gene', '11820', (165, 166))	('a', 'Gene', '11820', (147, 148))	('PT2385', 'Chemical', 'MESH:C000614279', (25, 31))	('S305M', 'Mutation', 'p.S305M', (60, 65))	('a', 'Gene', '11820', (58, 59))	('binding', 'molecular_function', 'GO:0005488', ('32', '39'))	('binding', 'Interaction', (32, 39))	('PAS', 'cellular_component', 'GO:0000407', ('73', '76'))	('a', 'Gene', '11820', (105, 106))	('mouse', 'Species', '10090', (43, 48))	('a', 'Gene', '11820', (120, 121))	('a', 'Gene', '11820', (111, 112))	('a', 'Gene', '11820', (87, 88))	('A', 'Gene', '11820', (74, 75))
186066	31999648	Tm values were similar for WT and S305M HIF-2alpha proteins, in the context of both their isolated PAS-B domains alone and their HIF-2alpha/HIF-1beta heterodimers consisting of their larger bHLH-PAS-A-PAS-B segments (Figure 5B).	('a', 'Gene', '11820', (119, 120))	('A', 'Gene', '11820', (202, 203))	('a', 'Gene', '11820', (94, 95))	('a', 'Gene', '11820', (30, 31))	('a', 'Gene', '11820', (20, 21))	('a', 'Gene', '11820', (4, 5))	('A', 'Gene', '11820', (199, 200))	('S305M', 'Var', (34, 39))	('a', 'Gene', '11820', (138, 139))	('a', 'Gene', '11820', (45, 46))	('a', 'Gene', '11820', (108, 109))	('a', 'Gene', '11820', (148, 149))	('PAS', 'cellular_component', 'GO:0000407', ('201', '204'))	('S305M', 'Mutation', 'p.S305M', (34, 39))	('a', 'Gene', '11820', (184, 185))	('PAS', 'cellular_component', 'GO:0000407', ('99', '102'))	('HIF-1beta', 'Gene', '15251', (140, 149))	('PAS', 'cellular_component', 'GO:0000407', ('195', '198'))	('a', 'Gene', '11820', (113, 114))	('A', 'Gene', '11820', (196, 197))	('HIF-1beta', 'Gene', (140, 149))	('A', 'Gene', '11820', (100, 101))	('a', 'Gene', '11820', (49, 50))	('a', 'Gene', '11820', (134, 135))
186067	31999648	Closely similar Tm values for WT and S305M proteins indicate that the point mutation does not alter the global fold or stability of HIF-2alpha protein or the stability of its heterodimeric complex with HIF-1beta.	('HIF-1beta', 'Gene', (202, 211))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('a', 'Gene', '11820', (141, 142))	('a', 'Gene', '11820', (94, 95))	('a', 'Gene', '11820', (20, 21))	('S305M', 'Mutation', 'p.S305M', (37, 42))	('a', 'Gene', '11820', (13, 14))	('a', 'Gene', '11820', (108, 109))	('a', 'Gene', '11820', (210, 211))	('a', 'Gene', '11820', (121, 122))	('a', 'Gene', '11820', (33, 34))	('a', 'Gene', '11820', (57, 58))	('a', 'Gene', '11820', (137, 138))	('a', 'Gene', '11820', (79, 80))	('a', 'Gene', '11820', (63, 64))	('heterodimeric', 'Interaction', (175, 188))	('S305M', 'Var', (37, 42))	('a', 'Gene', '11820', (160, 161))	('HIF-1beta', 'Gene', '15251', (202, 211))
186068	31999648	We infer that the loss of PT2385 binding to the S305M protein is due to the larger methionine (versus serine) side chain locally occluding the PAS-B pocket where PT2385 physically binds, causing a more than 60-fold loss of binding affinity.	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('serine', 'Chemical', 'MESH:D012694', (102, 108))	('binding', 'molecular_function', 'GO:0005488', ('223', '230'))	('a', 'Gene', '11820', (117, 118))	('a', 'Gene', '11820', (204, 205))	('a', 'Gene', '11820', (77, 78))	('a', 'Gene', '11820', (188, 189))	('occluding', 'NegReg', (129, 138))	('A', 'Gene', '11820', (144, 145))	('a', 'Gene', '11820', (195, 196))	('a', 'Gene', '11820', (124, 125))	('methionine', 'Chemical', 'MESH:D008715', (83, 93))	('PT2385', 'Chemical', 'MESH:C000614279', (162, 168))	('PT2385', 'Chemical', 'MESH:C000614279', (26, 32))	('loss', 'NegReg', (18, 22))	('S305M', 'Var', (48, 53))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('a', 'Gene', '11820', (11, 12))	('loss', 'NegReg', (215, 219))	('a', 'Gene', '11820', (231, 232))	('PT2385', 'Gene', (26, 32))	('binding', 'Interaction', (33, 40))	('a', 'Gene', '11820', (175, 176))	('methionine', 'MPA', (83, 93))	('PAS', 'cellular_component', 'GO:0000407', ('143', '146'))	('binding', 'Interaction', (223, 230))	('S305M', 'Mutation', 'p.S305M', (48, 53))
186072	31999648	Taken together, these findings indicate that the S305M mutation confers resistance to PT2385 without altering the expression or conformation of HIF-2alpha.	('a', 'Gene', '11820', (42, 43))	('PT2385', 'Gene', (86, 92))	('a', 'Gene', '11820', (58, 59))	('a', 'Gene', '11820', (135, 136))	('a', 'Gene', '11820', (149, 150))	('S305M', 'Var', (49, 54))	('PT2385', 'Chemical', 'MESH:C000614279', (86, 92))	('a', 'Gene', '11820', (101, 102))	('a', 'Gene', '11820', (1, 2))	('S305M', 'Mutation', 'p.S305M', (49, 54))	('a', 'Gene', '11820', (36, 37))	('a', 'Gene', '11820', (153, 154))	('a', 'Gene', '11820', (78, 79))
186074	31999648	To test whether ventilatory sensitivity is altered by PT2385 in Epas1S305M/S305M mice, male Epas1S305M/S305M mice and WT littermate controls were exposed to hypoxia and administered 10 mg/kg PT2385 or vehicle twice daily.	('PT2385', 'Chemical', 'MESH:C000614279', (54, 60))	('a', 'Gene', '11820', (94, 95))	('a', 'Gene', '11820', (22, 23))	('PT2385', 'Var', (54, 60))	('S305M', 'Mutation', 'p.S305M', (69, 74))	('a', 'Gene', '11820', (163, 164))	('a', 'Gene', '11820', (43, 44))	('S305M', 'Mutation', 'p.S305M', (75, 80))	('a', 'Gene', '11820', (66, 67))	('hypoxia', 'Disease', (157, 164))	('a', 'Gene', '11820', (114, 115))	('PT2385', 'Chemical', 'MESH:C000614279', (191, 197))	('a', 'Gene', '11820', (88, 89))	('a', 'Gene', '11820', (169, 170))	('S305M', 'Mutation', 'p.S305M', (97, 102))	('mice', 'Species', '10090', (81, 85))	('a', 'Gene', '11820', (216, 217))	('hypoxia', 'Disease', 'MESH:D000860', (157, 164))	('a', 'Gene', '11820', (128, 129))	('S305M', 'Mutation', 'p.S305M', (103, 108))	('mice', 'Species', '10090', (109, 113))	('a', 'Gene', '11820', (165, 166))
186076	31999648	In striking contrast to WT mice, treatment of Epas1S305M/S305M mice with PT2385 did not reduce ventilatory sensitivity at any time point during sustained hypoxia (Figure 6, A and B, and Table 2).	('a', 'Gene', '11820', (119, 120))	('a', 'Gene', '11820', (182, 183))	('a', 'Gene', '11820', (101, 102))	('sustained hypoxia', 'Disease', (144, 161))	('mice', 'Species', '10090', (27, 31))	('a', 'Gene', '11820', (187, 188))	('a', 'Gene', '11820', (36, 37))	('a', 'Gene', '11820', (148, 149))	('a', 'Gene', '11820', (122, 123))	('PT2385', 'Chemical', 'MESH:C000614279', (73, 79))	('A', 'Gene', '11820', (173, 174))	('S305M', 'Mutation', 'p.S305M', (51, 56))	('a', 'Gene', '11820', (175, 176))	('reduce', 'NegReg', (88, 94))	('sustained hypoxia', 'Disease', 'MESH:D000860', (144, 161))	('a', 'Gene', '11820', (17, 18))	('a', 'Gene', '11820', (48, 49))	('S305M', 'Mutation', 'p.S305M', (57, 62))	('mice', 'Species', '10090', (63, 67))	('PT2385', 'Var', (73, 79))	('a', 'Gene', '11820', (160, 161))
186082	31999648	In contrast, PT2385 had little or no effect on hypoxia-induced Vegfa mRNA levels in type I cells in littermate mice of the Epas1S305M/S305M genotype (Figure 7).	('a', 'Gene', '11820', (53, 54))	('Vegfa', 'Gene', '22339', (63, 68))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('a', 'Gene', '11820', (21, 22))	('PT2385', 'Chemical', 'MESH:C000614279', (13, 19))	('A', 'Gene', '11820', (72, 73))	('Vegfa', 'Gene', (63, 68))	('a', 'Gene', '11820', (107, 108))	('hypoxia', 'Disease', (47, 54))	('S305M', 'Mutation', 'p.S305M', (134, 139))	('a', 'Gene', '11820', (125, 126))	('mice', 'Species', '10090', (111, 115))	('a', 'Gene', '11820', (8, 9))	('S305M', 'Mutation', 'p.S305M', (128, 133))	('a', 'Gene', '11820', (67, 68))	('PT2385', 'Var', (13, 19))
186089	31999648	All these responses were abrogated, or greatly reduced, by PT2385.	('a', 'Gene', '11820', (42, 43))	('A', 'Gene', '11820', (0, 1))	('PT2385', 'Var', (59, 65))	('a', 'Gene', '11820', (25, 26))	('PT2385', 'Chemical', 'MESH:C000614279', (59, 65))	('a', 'Gene', '11820', (30, 31))	('reduced', 'NegReg', (47, 54))
186092	31999648	From the clinical perspective, they establish that PT2385 has a range of effects on the medical physiology of hypoxia in nonneoplastic tissues, which are manifest at the same doses as antitumor effects reported in mouse xenograft studies.	('tumor', 'Disease', (188, 193))	('a', 'Gene', '11820', (62, 63))	('effects', 'Reg', (73, 80))	('a', 'Gene', '11820', (93, 94))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('mouse', 'Species', '10090', (214, 219))	('a', 'Gene', '11820', (116, 117))	('a', 'Gene', '11820', (226, 227))	('a', 'Gene', '11820', (171, 172))	('a', 'Gene', '11820', (59, 60))	('a', 'Gene', '11820', (163, 164))	('a', 'Gene', '11820', (155, 156))	('PT2385', 'Chemical', 'MESH:C000614279', (51, 57))	('hypoxia', 'Disease', (110, 117))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('PT2385', 'Var', (51, 57))	('a', 'Gene', '11820', (184, 185))	('hypoxia', 'Disease', 'MESH:D000860', (110, 117))	('a', 'Gene', '11820', (129, 130))	('a', 'Gene', '11820', (48, 49))	('a', 'Gene', '11820', (65, 66))	('a', 'Gene', '11820', (15, 16))	('a', 'Gene', '11820', (39, 40))	('a', 'Gene', '11820', (150, 151))	('a', 'Gene', '11820', (181, 182))
186095	31999648	Our work shows marked effects of PT2385 on hypoxic ventilatory control that are as pronounced or more pronounced than the erythropoietic effects in the context of sustained hypoxia.	('sustained hypoxia', 'Disease', (163, 180))	('a', 'Gene', '11820', (76, 77))	('a', 'Gene', '11820', (115, 116))	('a', 'Gene', '11820', (80, 81))	('a', 'Gene', '11820', (73, 74))	('PT2385', 'Var', (33, 39))	('effects', 'Reg', (22, 29))	('a', 'Gene', '11820', (16, 17))	('PT2385', 'Chemical', 'MESH:C000614279', (33, 39))	('sustained hypoxia', 'Disease', 'MESH:D000860', (163, 180))	('a', 'Gene', '11820', (57, 58))	('a', 'Gene', '11820', (167, 168))	('a', 'Gene', '11820', (179, 180))
186096	31999648	Taken together, these data suggest that PT2385 is likely to have broad effects on physiological and pathophysiological responses that are mediated by HIF-2alpha.	('a', 'Gene', '11820', (68, 69))	('PT2385', 'Chemical', 'MESH:C000614279', (40, 46))	('a', 'Gene', '11820', (23, 24))	('a', 'Gene', '11820', (25, 26))	('a', 'Gene', '11820', (142, 143))	('a', 'Gene', '11820', (96, 97))	('a', 'Gene', '11820', (93, 94))	('a', 'Gene', '11820', (155, 156))	('effects', 'Reg', (71, 78))	('a', 'Gene', '11820', (159, 160))	('a', 'Gene', '11820', (131, 132))	('a', 'Gene', '11820', (101, 102))	('a', 'Gene', '11820', (1, 2))	('PT2385', 'Var', (40, 46))	('a', 'Gene', '11820', (37, 38))	('a', 'Gene', '11820', (116, 117))	('a', 'Gene', '11820', (61, 62))	('a', 'Gene', '11820', (134, 135))
186103	31999648	Consistent with the classical theory on the importance of carbon dioxide in respiratory control, our demonstration of specific effects on responses to hypoxia suggests that PT2385 should not interfere markedly with respiratory control under most circumstances.	('a', 'Gene', '11820', (157, 158))	('a', 'Gene', '11820', (254, 255))	('a', 'Gene', '11820', (59, 60))	('a', 'Gene', '11820', (202, 203))	('a', 'Gene', '11820', (27, 28))	('carbon dioxide', 'Chemical', 'MESH:D002245', (58, 72))	('PT2385', 'Var', (173, 179))	('hypoxia', 'Disease', 'MESH:D000860', (151, 158))	('a', 'Gene', '11820', (170, 171))	('PT2385', 'Chemical', 'MESH:C000614279', (173, 179))	('a', 'Gene', '11820', (221, 222))	('hypoxia', 'Disease', (151, 158))	('a', 'Gene', '11820', (22, 23))	('a', 'Gene', '11820', (50, 51))	('a', 'Gene', '11820', (82, 83))	('a', 'Gene', '11820', (109, 110))
186114	31999648	PT2385 binds to HIF-2alpha and has been shown to impair its dimerization with HIF-1beta, thus preventing the formation of the DNA-binding complex and blocking HIF-2 transcriptional activity.	('DNA-binding', 'molecular_function', 'GO:0003677', ('126', '137'))	('preventing', 'NegReg', (94, 104))	('PT2385', 'Var', (0, 6))	('a', 'Gene', '11820', (86, 87))	('HIF-2', 'Gene', (159, 164))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('formation', 'biological_process', 'GO:0009058', ('109', '118'))	('a', 'Gene', '11820', (21, 22))	('a', 'Gene', '11820', (52, 53))	('HIF-1beta', 'Gene', '15251', (78, 87))	('a', 'Gene', '11820', (146, 147))	('A', 'Gene', '11820', (128, 129))	('a', 'Gene', '11820', (67, 68))	('HIF-1beta', 'Gene', (78, 87))	('a', 'Gene', '11820', (178, 179))	('a', 'Gene', '11820', (27, 28))	('a', 'Gene', '11820', (167, 168))	('blocking', 'NegReg', (150, 158))	('a', 'Gene', '11820', (113, 114))	('binds', 'Interaction', (7, 12))	('PT2385', 'Chemical', 'MESH:C000614279', (0, 6))	('a', 'Gene', '11820', (25, 26))	('a', 'Gene', '11820', (32, 33))	('a', 'Gene', '11820', (181, 182))
186120	31999648	First, at higher doses of PT2385, we observed a marked reduction in the baseline hypoxic ventilatory sensitivity in unacclimatized mice, which was manifest within 1 hour of exposure to the compound, perhaps representing an action of HIF-2alpha (or even another PAS domain-containing protein) on a process more rapid than transcription.	('a', 'Gene', '11820', (268, 269))	('reduction', 'NegReg', (55, 64))	('a', 'Gene', '11820', (7, 8))	('a', 'Gene', '11820', (323, 324))	('a', 'Gene', '11820', (118, 119))	('a', 'Gene', '11820', (276, 277))	('a', 'Gene', '11820', (46, 47))	('a', 'Gene', '11820', (203, 204))	('A', 'Gene', '11820', (262, 263))	('a', 'Gene', '11820', (220, 221))	('a', 'Gene', '11820', (124, 125))	('a', 'Gene', '11820', (242, 243))	('mice', 'Species', '10090', (131, 135))	('a', 'Gene', '11820', (148, 149))	('PT2385', 'Chemical', 'MESH:C000614279', (26, 32))	('transcription', 'biological_process', 'GO:0006351', ('321', '334'))	('protein', 'cellular_component', 'GO:0003675', ('283', '290'))	('PT2385', 'Var', (26, 32))	('a', 'Gene', '11820', (318, 319))	('a', 'Gene', '11820', (311, 312))	('a', 'Gene', '11820', (295, 296))	('a', 'Gene', '11820', (144, 145))	('PAS', 'cellular_component', 'GO:0000407', ('261', '264'))	('a', 'Gene', '11820', (223, 224))	('a', 'Gene', '11820', (49, 50))	('a', 'Gene', '11820', (73, 74))	('a', 'Gene', '11820', (238, 239))	('a', 'Gene', '11820', (253, 254))	('a', 'Gene', '11820', (95, 96))
186175	31999648	Hif-2alpha mRNA was quantified in triplicates in a duplex quantitative real-time PCR reaction using TaqMan Fast Advanced Master Mix and Hif-2alpha (Epas1) FAM and Actb VIC TaqMan Gene Expression Assays (Mm00438712_m1 and Mm01205647_g1, Thermo Fisher Scientific).	('a', 'Gene', '11820', (141, 142))	('Hif-2alpha', 'Gene', (136, 146))	('a', 'Gene', '11820', (101, 102))	('a', 'Gene', '11820', (22, 23))	('a', 'Gene', '11820', (173, 174))	('A', 'Gene', '11820', (112, 113))	('Mm01205647_g1', 'Var', (221, 234))	('Mm00438712_m1', 'Var', (203, 216))	('a', 'Gene', '11820', (115, 116))	('a', 'Gene', '11820', (108, 109))	('Hif-2alpha', 'Gene', '13819', (136, 146))	('a', 'Gene', '11820', (132, 133))	('Actb VIC TaqMan', 'Disease', (163, 178))	('a', 'Gene', '11820', (5, 6))	('Hif-2alpha', 'Gene', (0, 10))	('a', 'Gene', '11820', (122, 123))	('a', 'Gene', '11820', (60, 61))	('a', 'Gene', '11820', (217, 218))	('A', 'Gene', '11820', (14, 15))	('Actb VIC TaqMan', 'Disease', 'None', (163, 178))	('a', 'Gene', '11820', (176, 177))	('Epas1', 'Gene', '13819', (148, 153))	('a', 'Gene', '11820', (145, 146))	('a', 'Gene', '11820', (9, 10))	('Hif-2alpha', 'Gene', '13819', (0, 10))	('Epas1', 'Gene', (148, 153))	('a', 'Gene', '11820', (17, 18))	('A', 'Gene', '11820', (195, 196))	('a', 'Gene', '11820', (41, 42))	('a', 'Gene', '11820', (87, 88))	('a', 'Gene', '11820', (65, 66))	('a', 'Gene', '11820', (49, 50))	('A', 'Gene', '11820', (163, 164))	('a', 'Gene', '11820', (159, 160))	('a', 'Gene', '11820', (198, 199))	('a', 'Gene', '11820', (104, 105))	('a', 'Gene', '11820', (73, 74))	('A', 'Gene', '11820', (156, 157))	('Gene Expression', 'biological_process', 'GO:0010467', ('179', '194'))	('a', 'Gene', '11820', (150, 151))
186182	31999648	HIF-2alpha/HIF-1beta heterodimers (WT and with the S305M mutation in the HIF-2alpha subunit) consisting of bHLH-PAS-A-PAS-B domains were expressed and purified using the coexpression constructs and procedures previously published.	('a', 'Gene', '11820', (127, 128))	('a', 'Gene', '11820', (38, 39))	('HIF-1beta', 'Gene', (11, 20))	('PAS', 'cellular_component', 'GO:0000407', ('118', '121'))	('A', 'Gene', '11820', (113, 114))	('S305M', 'Var', (51, 56))	('a', 'Gene', '11820', (194, 195))	('a', 'Gene', '11820', (19, 20))	('a', 'Gene', '11820', (82, 83))	('a', 'Gene', '11820', (5, 6))	('a', 'Gene', '11820', (60, 61))	('A', 'Gene', '11820', (119, 120))	('a', 'Gene', '11820', (147, 148))	('a', 'Gene', '11820', (9, 10))	('S305M', 'Mutation', 'p.S305M', (51, 56))	('A', 'Gene', '11820', (116, 117))	('a', 'Gene', '11820', (78, 79))	('PAS', 'cellular_component', 'GO:0000407', ('112', '115'))	('HIF-1beta', 'Gene', '15251', (11, 20))
186206	28270206	MEIS1 overexpression inhibits ccRCC cells proliferation and induces G1/S arrest concomitant with marked reduction of G1/S transition regulators, Cyclin D1 and Cyclin A.	('S arrest', 'Disease', (71, 79))	('induces', 'Reg', (60, 67))	('inhibits', 'NegReg', (21, 29))	('reduction', 'NegReg', (104, 113))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('Cyclin D1', 'Gene', (145, 154))	('MEIS1', 'Gene', (0, 5))	('overexpression', 'Var', (6, 20))	('S arrest', 'Disease', 'MESH:D006323', (71, 79))	('Cyclin A', 'Gene', '890', (159, 167))	('Cyclin', 'molecular_function', 'GO:0016538', ('159', '165'))	('ccRCC cells proliferation', 'CPA', (30, 55))	('Cyclin A', 'Gene', (159, 167))	('Cyclin', 'molecular_function', 'GO:0016538', ('145', '151'))	('Cyclin D1', 'Gene', '595', (145, 154))
186207	28270206	Moreover, MEIS1-1 overexpression also induces non-apoptotic cell death of ccRCC cells via decreasing the levels of pro-survival regulators Survivin and BCL-2.	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))	('non-apoptotic cell death', 'CPA', (46, 70))	('BCL-2', 'Gene', (152, 157))	('levels of', 'MPA', (105, 114))	('pro-survival', 'biological_process', 'GO:0043066', ('115', '127'))	('induces', 'Reg', (38, 45))	('BCL-2', 'Gene', '596', (152, 157))	('MEIS1-1', 'Gene', '4211', (10, 17))	('overexpression', 'Var', (18, 32))	('Survivin', 'MPA', (139, 147))	('MEIS1-1', 'Gene', (10, 17))	('BCL-2', 'molecular_function', 'GO:0015283', ('152', '157'))	('decreasing', 'NegReg', (90, 100))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('50', '70'))
186247	28270206	Then, membranes were blocked with 5% BSA in TBST buffer and then incubated 2 h at 37  C with primary antibody against MEIS1 (1:1000), Cyclin D1 (1:500), Cyclin A (1:500), cIAP-1 (1:1000), cIAP-2 (1:1000), Survivin (1:2000), E-cadherin (1:1000), N-cadherin (1:1000), Vimentin (1:2000), BAX (1:500) and GAPDH (1:5000) diluted in TBST containing 5% BSA and subsequently washed three times in TBST for 5 min each.	('1:1000', 'Var', (257, 263))	('cIAP-2', 'Gene', '330', (188, 194))	('Vimentin', 'cellular_component', 'GO:0045098', ('266', '274'))	('antibody', 'cellular_component', 'GO:0019815', ('101', '109'))	('1:2000', 'Var', (276, 282))	('Cyclin A', 'Gene', (153, 161))	('Cyclin', 'molecular_function', 'GO:0016538', ('134', '140'))	('Cyclin D1', 'Gene', '595', (134, 143))	('Cyclin', 'molecular_function', 'GO:0016538', ('153', '159'))	('BAX', 'Gene', (285, 288))	('Cyclin D1', 'Gene', (134, 143))	('Vimentin', 'Gene', '7431', (266, 274))	('BAX', 'Gene', '581', (285, 288))	('GAPDH', 'Gene', '2597', (301, 306))	('antibody', 'cellular_component', 'GO:0019814', ('101', '109'))	('1:1000', 'Var', (125, 131))	('cadherin', 'molecular_function', 'GO:0008014', ('247', '255'))	('Vimentin', 'Gene', (266, 274))	('1:1000', 'Var', (236, 242))	('Cyclin A', 'Gene', '890', (153, 161))	('GAPDH', 'Gene', (301, 306))	('N-cadherin', 'Gene', (245, 255))	('E-cadherin', 'Gene', (224, 234))	('N-cadherin', 'Gene', '1000', (245, 255))	('cIAP-2', 'Gene', (188, 194))	('cIAP-1', 'Gene', (171, 177))	('E-cadherin', 'Gene', '999', (224, 234))	('antibody', 'molecular_function', 'GO:0003823', ('101', '109'))	('Vimentin', 'cellular_component', 'GO:0045099', ('266', '274'))	('cadherin', 'molecular_function', 'GO:0008014', ('226', '234'))	('antibody', 'cellular_component', 'GO:0042571', ('101', '109'))	('cIAP-1', 'Gene', '329', (171, 177))
186249	28270206	Caki-1 cells, which were infected with Ad-control or AD-MEIS1, were injected with 5 x 105 cells re-suspended in PBS or normal/physiological saline.	('saline', 'Chemical', 'MESH:D012965', (140, 146))	('AD-MEIS1', 'Var', (53, 61))	('PBS', 'Gene', (112, 115))	('PBS', 'Gene', '1131', (112, 115))	('Caki-1', 'CellLine', 'CVCL:0234', (0, 6))
186258	28270206	Caki-1 and 786-O cells that were infected with Ad-MEIS1 grew slower than those infected with Ad-controls or their parental cells (Fig.	('Ad-MEIS1', 'Var', (47, 55))	('Caki-1', 'CellLine', 'CVCL:0234', (0, 6))	('slower', 'NegReg', (61, 67))	('grew', 'CPA', (56, 60))
186265	28270206	MEIS1 also increased the protein level of pro-apoptosis regulator BAX.	('increased', 'PosReg', (11, 20))	('protein level of', 'MPA', (25, 41))	('MEIS1', 'Var', (0, 5))	('BAX', 'Gene', (66, 69))	('BAX', 'Gene', '581', (66, 69))	('pro-apoptosis', 'biological_process', 'GO:0043065', ('42', '55'))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))
186274	28270206	These results, which were in consistent with TMA experiments, suggested that MEIS1 overexpression could inhibit the in vitro invasion and migration of Caki-1 cells via disrupting EMT process.	('EMT', 'biological_process', 'GO:0001837', ('179', '182'))	('overexpression', 'Var', (83, 97))	('MEIS1', 'Gene', (77, 82))	('disrupting', 'NegReg', (168, 178))	('EMT process', 'CPA', (179, 190))	('TMA', 'Disease', (45, 48))	('Caki-1', 'CellLine', 'CVCL:0234', (151, 157))	('inhibit', 'NegReg', (104, 111))	('TMA', 'Disease', 'MESH:D000783', (45, 48))
186353	28178948	The smooth HR curve displayed a significant and stable prognostic difference between the high and low CCL17 expression patient groups with the cutoff value as a reference (Fig.	('patient', 'Species', '9606', (119, 126))	('CCL17', 'Gene', '6361', (102, 107))	('low', 'NegReg', (98, 101))	('high', 'Var', (89, 93))	('CCL', 'molecular_function', 'GO:0044101', ('102', '105'))	('CCL17', 'Gene', (102, 107))
186358	28178948	Patients with high CCL17 expression had a significantly better OS (P = 0.002) and RFS (P = 0.007) than patients with low CCL17 expression (Fig.	('CCL17', 'Gene', '6361', (19, 24))	('OS', 'Chemical', '-', (63, 65))	('CCL17', 'Gene', (121, 126))	('CCL17', 'Gene', (19, 24))	('better', 'PosReg', (56, 62))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('CCL', 'molecular_function', 'GO:0044101', ('19', '22'))	('RFS', 'CPA', (82, 85))	('CCL', 'molecular_function', 'GO:0044101', ('121', '124'))	('CCL17', 'Gene', '6361', (121, 126))	('patients', 'Species', '9606', (103, 111))	('expression', 'Var', (25, 35))
186362	28178948	Furthermore, in multivariate analysis, high CCL17 expression was also a favorable independent risk factor for both OS and RFS (OS, HR, 0.504, 95% CI, 0.309-0.824, P = 0.006, P = 0.011 for bootstrap; RFS, HR, 0.448, 95% CI, 0.267-0.751, P = 0.002, P = 0.025 for bootstrap).	('high', 'Var', (39, 43))	('CCL17', 'Gene', '6361', (44, 49))	('RFS', 'Disease', (122, 125))	('OS', 'Chemical', '-', (115, 117))	('expression', 'Var', (50, 60))	('CCL', 'molecular_function', 'GO:0044101', ('44', '47'))	('CCL17', 'Gene', (44, 49))	('OS', 'Chemical', '-', (127, 129))
186365	28178948	High CCL17 expression displayed as a good prognostic factor in intermediated- and high-risk groups in both OS and RFS analyses (OS, P = 0.004; RFS, P = 0.006).	('CCL17', 'Gene', '6361', (5, 10))	('OS', 'Chemical', '-', (107, 109))	('High', 'Var', (0, 4))	('OS', 'Chemical', '-', (128, 130))	('expression', 'MPA', (11, 21))	('CCL', 'molecular_function', 'GO:0044101', ('5', '8'))	('CCL17', 'Gene', (5, 10))
186374	28178948	In this study, we found that CCL17 was predominantly expressed on cytoplasm of tumor cells through immunochemistry, and high CCL17 expression turned out to be positively correlated with a better prognosis.	('CCL17', 'Gene', '6361', (29, 34))	('CCL17', 'Gene', (125, 130))	('tumor', 'Disease', (79, 84))	('CCL', 'molecular_function', 'GO:0044101', ('29', '32'))	('CCL', 'molecular_function', 'GO:0044101', ('125', '128'))	('high', 'Var', (120, 124))	('CCL17', 'Gene', (29, 34))	('correlated', 'Reg', (170, 180))	('expression', 'MPA', (131, 141))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('cytoplasm', 'cellular_component', 'GO:0005737', ('66', '75'))	('CCL17', 'Gene', '6361', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
186375	28178948	What's more, CCL17 expression was an independent prognostic factor for OS and RFS of ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('patients', 'Species', '9606', (91, 99))	('RCC', 'Disease', (87, 90))	('RFS', 'Disease', (78, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('expression', 'Var', (19, 29))	('CCL17', 'Gene', '6361', (13, 18))	('OS', 'Chemical', '-', (71, 73))	('CCL', 'molecular_function', 'GO:0044101', ('13', '16'))	('CCL17', 'Gene', (13, 18))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
186402	31988284	SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12 Inactivating mutations in the SETD2 gene, encoding for a nonredundant histone H3 methyltransferase and regulator of transcription, is a frequent molecular feature in clear cell renal cell carcinomas (ccRCC).	('SETD2', 'Gene', '29072', (118, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('renal clear cell carcinoma', 'Disease', (18, 44))	('ccRCC', 'Disease', (288, 293))	('RCC', 'Phenotype', 'HP:0005584', (290, 293))	('autophagy', 'CPA', (54, 63))	('clear cell renal cell carcinomas', 'Disease', 'MESH:D002292', (254, 286))	('autophagy', 'biological_process', 'GO:0016236', ('54', '63'))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('Inactivating mutations', 'Var', (88, 110))	('regulation', 'biological_process', 'GO:0065007', ('68', '78'))	('ccRCC', 'Phenotype', 'HP:0006770', (288, 293))	('SETD2', 'Gene', (0, 5))	('autophagy', 'biological_process', 'GO:0006914', ('54', '63'))	('ATG12', 'Gene', (82, 87))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (254, 286))	('SETD2', 'Gene', '29072', (0, 5))	('clear cell renal cell carcinomas', 'Disease', (254, 286))	('carcinomas', 'Phenotype', 'HP:0030731', (276, 286))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (265, 286))	('suppress', 'NegReg', (45, 53))	('SETD2', 'Gene', (118, 123))	('mutation', 'Var', (6, 14))	('renal clear cell carcinoma', 'Disease', 'MESH:D002292', (18, 44))	('transcription', 'biological_process', 'GO:0006351', ('204', '217'))	('ccRCC', 'Disease', 'MESH:D002292', (288, 293))
186403	31988284	SETD2 deficiency is associated with recurrence of ccRCC and bears low prognostic values.	('associated', 'Reg', (20, 30))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (50, 55))	('ccRCC', 'Disease', (50, 55))	('SETD2', 'Gene', '29072', (0, 5))	('deficiency', 'Var', (6, 16))	('ccRCC', 'Disease', 'MESH:D002292', (50, 55))	('SETD2', 'Gene', (0, 5))
186406	31988284	Here, we report that SETD2 deficiency in RCC cells is associated with the aberrant accumulation of both free ATG12 and of an additional ATG12-containing complex, distinct from the ATG5-ATG12 complex.	('ATG5', 'Gene', '9474', (180, 184))	('SETD2', 'Gene', '29072', (21, 26))	('deficiency', 'Var', (27, 37))	('accumulation', 'PosReg', (83, 95))	('ATG5', 'Gene', (180, 184))	('SETD2', 'Gene', (21, 26))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('RCC', 'Disease', 'MESH:D002292', (41, 44))	('RCC', 'Disease', (41, 44))
186407	31988284	Rescue of SETD2 functions in the SETD2 deficiency in RCC cells, or reduction of SETD2 expression level in RCC cells wild type for this enzyme, demonstrates that SETD2 deficiency in RCC is directly involved in the acquisition of these alterations in the autophagic process.	('deficiency', 'Var', (39, 49))	('RCC', 'Disease', (53, 56))	('SETD2', 'Gene', (161, 166))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('SETD2', 'Gene', (10, 15))	('RCC', 'Disease', 'MESH:D002292', (181, 184))	('expression level', 'MPA', (86, 102))	('SETD2', 'Gene', (33, 38))	('SETD2', 'Gene', '29072', (161, 166))	('SETD2', 'Gene', '29072', (10, 15))	('RCC', 'Disease', 'MESH:D002292', (53, 56))	('autophagic process', 'CPA', (253, 271))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('SETD2', 'Gene', '29072', (33, 38))	('SETD2', 'Gene', (80, 85))	('RCC', 'Disease', 'MESH:D002292', (106, 109))	('SETD2', 'Gene', '29072', (80, 85))	('deficiency', 'Var', (167, 177))	('RCC', 'Disease', (181, 184))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))
186408	31988284	Furthermore, we revealed that deficiency in SETD2, known regulator of alternative splicing, is associated with increased expression of a short ATG12 spliced isoform at the depend of the canonical long ATG12 isoform in RCC cells.	('deficiency', 'Var', (30, 40))	('increased', 'PosReg', (111, 120))	('splicing', 'biological_process', 'GO:0045292', ('82', '90'))	('SETD2', 'Gene', '29072', (44, 49))	('expression', 'MPA', (121, 131))	('SETD2', 'Gene', (44, 49))	('RCC', 'Disease', (218, 221))	('RCC', 'Disease', 'MESH:D002292', (218, 221))	('RCC', 'Phenotype', 'HP:0005584', (218, 221))
186416	31988284	The most common feature of ccRCC is the biallelic inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) due to chromosome 3p deletion and gene mutation.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('von Hippel-Lindau', 'Gene', '7428', (92, 109))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('tumor', 'Disease', (70, 75))	('deletion', 'Var', (137, 145))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('gene mutation', 'Var', (150, 163))	('ccRCC', 'Phenotype', 'HP:0006770', (27, 32))	('ccRCC', 'Disease', (27, 32))	('VHL', 'Disease', 'MESH:D006623', (111, 114))	('von Hippel-Lindau', 'Gene', (92, 109))	('VHL', 'Disease', (111, 114))	('chromosome', 'cellular_component', 'GO:0005694', ('123', '133'))	('ccRCC', 'Disease', 'MESH:D002292', (27, 32))	('biallelic inactivation', 'Var', (40, 62))
186420	31988284	Indeed, several genes regulating chromatin remodeling, located on chromosome 3p like VHL, including those of the SWI/SNF chromatin remodeling complex (PBRM1 and BAP-1) and the histone modifying enzyme SETD2 are reported to be frequently mutated in ccRCC.	('chromatin', 'cellular_component', 'GO:0000785', ('33', '42'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('121', '141'))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('121', '149'))	('chromosome', 'cellular_component', 'GO:0005694', ('66', '76'))	('VHL', 'Disease', (85, 88))	('SETD2', 'Gene', (201, 206))	('BAP-1', 'Gene', '8314', (161, 166))	('RCC', 'Phenotype', 'HP:0005584', (250, 253))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('33', '53'))	('ccRCC', 'Phenotype', 'HP:0006770', (248, 253))	('PBRM1', 'Gene', (151, 156))	('ccRCC', 'Disease', (248, 253))	('BAP-1', 'Gene', (161, 166))	('PBRM1', 'Gene', '55193', (151, 156))	('ccRCC', 'Disease', 'MESH:D002292', (248, 253))	('VHL', 'Disease', 'MESH:D006623', (85, 88))	('mutated', 'Var', (237, 244))	('SETD2', 'Gene', '29072', (201, 206))
186422	31988284	SETD2 mutations are observed in ~10% of human ccRCC primary tumors, and the frequency dramatically increase to ~30% in metastatic ccRCC patient samples, thereby suggesting a role for this genetic alteration in driving the metastatic progression of ccRCC.	('ccRCC', 'Disease', 'MESH:D002292', (46, 51))	('patient', 'Species', '9606', (136, 143))	('ccRCC', 'Phenotype', 'HP:0006770', (130, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (250, 253))	('ccRCC', 'Phenotype', 'HP:0006770', (248, 253))	('tumor', 'Disease', (60, 65))	('ccRCC', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('SETD2', 'Gene', (0, 5))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('human', 'Species', '9606', (40, 45))	('mutations', 'Var', (6, 15))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('SETD2', 'Gene', '29072', (0, 5))	('ccRCC', 'Disease', 'MESH:D002292', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ccRCC', 'Disease', 'MESH:D002292', (248, 253))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('ccRCC', 'Disease', (130, 135))	('ccRCC', 'Disease', (248, 253))
186424	31988284	Collectively, these observations argue for a role of SETD2 inactivation not only in driving the development of tumors, but as well in promoting progression of the disease.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('SETD2', 'Gene', (53, 58))	('inactivation', 'Var', (59, 71))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', (111, 116))	('promoting', 'PosReg', (134, 143))	('SETD2', 'Gene', '29072', (53, 58))
186427	31988284	The loss of SETD2 may therefor cause genomic instability, aberrant transcriptional program, widespread RNA processing defects, and impact on multiple biological processes ranging from cell proliferation, cell differentiation, and cell death.	('SETD2', 'Gene', '29072', (12, 17))	('cell death', 'biological_process', 'GO:0008219', ('230', '240'))	('RNA', 'cellular_component', 'GO:0005562', ('103', '106'))	('widespread', 'MPA', (92, 102))	('SETD2', 'Gene', (12, 17))	('transcriptional', 'MPA', (67, 82))	('aberrant', 'Var', (58, 66))	('cell death', 'CPA', (230, 240))	('cell differentiation', 'CPA', (204, 224))	('cell proliferation', 'CPA', (184, 202))	('genomic instability', 'CPA', (37, 56))	('cause', 'Reg', (31, 36))	('RNA processing', 'biological_process', 'GO:0006396', ('103', '117'))	('impact', 'Reg', (131, 137))	('cell differentiation', 'biological_process', 'GO:0030154', ('204', '224'))	('cell proliferation', 'biological_process', 'GO:0008283', ('184', '202'))	('loss', 'Var', (4, 8))
186432	31988284	Additional studies suggest that autophagic gene polymorphisms are associated with ccRCC risk and patient outcome.	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('ccRCC', 'Disease', (82, 87))	('autophagic gene', 'Gene', (32, 47))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('associated', 'Reg', (66, 76))	('ccRCC', 'Disease', 'MESH:D002292', (82, 87))	('polymorphisms', 'Var', (48, 61))	('patient', 'Species', '9606', (97, 104))
186433	31988284	However, whether the deficiency in the SETD2 histone methyltransferase observed in ccRCC could impact the autophagic core machinery and thereby this biological process is yet to be investigated.	('core', 'cellular_component', 'GO:0019013', ('117', '121'))	('SETD2', 'Gene', (39, 44))	('impact', 'Reg', (95, 101))	('autophagic core machinery', 'CPA', (106, 131))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('deficiency', 'Var', (21, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('ccRCC', 'Disease', (83, 88))	('biological process', 'biological_process', 'GO:0008150', ('149', '167'))	('ccRCC', 'Disease', 'MESH:D002292', (83, 88))	('SETD2', 'Gene', '29072', (39, 44))
186445	31988284	Moreover, in order to examine whether SETD2 deficiency has an impact on autophagic flux per se, LC3 conversion was assessed in ACHN and CAKI-1 cells in the presence of a late autophagy inhibitor, Bafilomycin A1 (BafA1), which inhibits the fusion of the autophagosome with the lysosome and eventually LC3-II degradation.	('autophagosome', 'cellular_component', 'GO:0005776', ('253', '266'))	('LC3', 'Gene', '84557', (96, 99))	('degradation', 'biological_process', 'GO:0009056', ('307', '318'))	('autophagy', 'biological_process', 'GO:0016236', ('175', '184'))	('ACHN', 'Gene', (127, 131))	('LC3', 'Gene', (300, 303))	('inhibits', 'NegReg', (226, 234))	('deficiency', 'Var', (44, 54))	('autophagy', 'biological_process', 'GO:0006914', ('175', '184'))	('impact', 'Reg', (62, 68))	('SETD2', 'Gene', (38, 43))	('Bafilomycin A1', 'Chemical', 'MESH:C040929', (196, 210))	('ACHN', 'Gene', '55323', (127, 131))	('LC3', 'Gene', '84557', (300, 303))	('LC3', 'Gene', (96, 99))	('SETD2', 'Gene', '29072', (38, 43))	('lysosome', 'cellular_component', 'GO:0005764', ('276', '284'))	('fusion', 'CPA', (239, 245))	('BafA1', 'Chemical', 'MESH:C040929', (212, 217))
186446	31988284	LC3-II/LC3-I ratio upon BafA1 treatment shows that the CAKI-1 cells that harbor a SETD2 mutation showed a decrease of autophagic flux, when compared with the SETD2-competent AHCN cells (Fig.	('LC3', 'Gene', '84557', (0, 3))	('SETD2', 'Gene', '29072', (82, 87))	('mutation', 'Var', (88, 96))	('autophagic flux', 'CPA', (118, 133))	('LC3', 'Gene', '84557', (7, 10))	('LC3', 'Gene', (7, 10))	('SETD2', 'Gene', (82, 87))	('BafA1', 'Chemical', 'MESH:C040929', (24, 29))	('LC3', 'Gene', (0, 3))	('decrease', 'NegReg', (106, 114))	('SETD2', 'Gene', '29072', (158, 163))	('SETD2', 'Gene', (158, 163))
186452	31988284	Moreover, immunofluorescence microscopy imaging for both LC3B and p62 proteins exposed a significant decrease in autophagosome formation in CAKI-1 cells, as compared with ACHN cells, as illustrated by the reduced LC3B/p62 colocalization (Fig.	('p62', 'Gene', (218, 221))	('colocalization', 'MPA', (222, 236))	('p62', 'Gene', '8878', (218, 221))	('autophagosome', 'cellular_component', 'GO:0005776', ('113', '126'))	('p62', 'Gene', '8878', (66, 69))	('p62', 'Gene', (66, 69))	('LC3B', 'Gene', (213, 217))	('LC3B', 'Gene', '81631', (57, 61))	('ACHN', 'Gene', '55323', (171, 175))	('reduced', 'NegReg', (205, 212))	('proteins', 'Var', (70, 78))	('autophagosome formation', 'CPA', (113, 136))	('LC3B', 'Gene', '81631', (213, 217))	('ACHN', 'Gene', (171, 175))	('decrease', 'NegReg', (101, 109))	('LC3B', 'Gene', (57, 61))	('autophagosome formation', 'biological_process', 'GO:0000045', ('113', '136'))
186460	31988284	Thereafter, in order to get insights on how SETD2 deficiency could impact on the autophagic flux, we undertaken to look at key component of the autophagy core machinery that contribute to the control of autophagosome formation and expansion.	('impact', 'Reg', (67, 73))	('autophagy', 'biological_process', 'GO:0016236', ('144', '153'))	('autophagosome', 'cellular_component', 'GO:0005776', ('203', '216'))	('SETD2', 'Gene', '29072', (44, 49))	('autophagosome formation', 'biological_process', 'GO:0000045', ('203', '226'))	('autophagic flux', 'CPA', (81, 96))	('autophagy', 'biological_process', 'GO:0006914', ('144', '153'))	('SETD2', 'Gene', (44, 49))	('core', 'cellular_component', 'GO:0019013', ('154', '158'))	('deficiency', 'Var', (50, 60))
186464	31988284	In fact, deficiencies in the Atg5, Atg7, and Atg12 core autophagy genes have all been reported to impair induced and constitutive autophagy in mouse models.	('autophagy', 'biological_process', 'GO:0016236', ('56', '65'))	('Atg12', 'Gene', (45, 50))	('autophagy', 'biological_process', 'GO:0016236', ('130', '139'))	('impair', 'NegReg', (98, 104))	('Atg5', 'Gene', '11793', (29, 33))	('Atg7', 'Gene', (35, 39))	('mouse', 'Species', '10090', (143, 148))	('autophagy', 'biological_process', 'GO:0006914', ('56', '65'))	('autophagy', 'biological_process', 'GO:0006914', ('130', '139'))	('deficiencies', 'Var', (9, 21))	('core', 'cellular_component', 'GO:0019013', ('51', '55'))	('Atg5', 'Gene', (29, 33))	('Atg7', 'Gene', '74244', (35, 39))	('Atg12', 'Gene', '67526', (45, 50))
186470	31988284	Moreover, to assess whether the accumulation of free ATG12 and the additional ATG12-containing complex is SETD2 dependent, four additional RCC cell lines, CAKI-2 and 769-P both lines characterized by VHL gene mutation but a wild-type SETD2 gene, as well as A498 and RCC-FG2 both lines characterized by VHL and SETD2 (loss of function) gene mutation were analyzed (Table 1).	('SETD2', 'Gene', (310, 315))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('SETD2', 'Gene', '29072', (234, 239))	('SETD2', 'Gene', '29072', (106, 111))	('RCC', 'Disease', (266, 269))	('RCC', 'Disease', 'MESH:D002292', (266, 269))	('VHL', 'Disease', 'MESH:D006623', (200, 203))	('RCC', 'Disease', (139, 142))	('VHL', 'Disease', 'MESH:D006623', (302, 305))	('mutation', 'Var', (209, 217))	('SETD2', 'Gene', (106, 111))	('SETD2', 'Gene', (234, 239))	('RCC', 'Disease', 'MESH:D002292', (139, 142))	('VHL', 'Disease', (302, 305))	('RCC', 'Phenotype', 'HP:0005584', (266, 269))	('SETD2', 'Gene', '29072', (310, 315))	('VHL', 'Disease', (200, 203))
186472	31988284	We also explored whether VHL gene mutation, the most prevalent reported gene deficiency in RCC cells, could impact on the accumulation of free ATG12 and occurrence of ATG12 additional complex.	('accumulation', 'MPA', (122, 134))	('VHL', 'Disease', 'MESH:D006623', (25, 28))	('gene deficiency', 'Disease', (72, 87))	('free ATG12', 'MPA', (138, 148))	('mutation', 'Var', (34, 42))	('RCC', 'Disease', (91, 94))	('VHL', 'Disease', (25, 28))	('RCC', 'Disease', 'MESH:D002292', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('gene deficiency', 'Disease', 'MESH:D058495', (72, 87))	('impact', 'Reg', (108, 114))
186473	31988284	Immunoblot analysis demonstrated that the aberrant accumulation of free ATG12 protein and of the additional ATG12-containing complex can be observed in all RCC cells deficient for SETD2, i.e., A498, Caki-1, and RCC-FG2 RCC cells, and that the VHL status of the cells did not impact in the acquisition of these characteristics suggesting that the phenotype observed is clearly due to SETD2 deficiency and VHL does not play role on ATG12 regulation (Fig.	('VHL', 'Disease', (243, 246))	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('RCC', 'Disease', (211, 214))	('RCC', 'Phenotype', 'HP:0005584', (211, 214))	('RCC', 'Disease', (156, 159))	('accumulation', 'PosReg', (51, 63))	('RCC', 'Disease', (219, 222))	('RCC', 'Phenotype', 'HP:0005584', (219, 222))	('VHL', 'Disease', 'MESH:D006623', (404, 407))	('SETD2', 'Gene', (383, 388))	('ATG12 protein', 'Protein', (72, 85))	('RCC', 'Disease', 'MESH:D002292', (156, 159))	('RCC', 'Disease', 'MESH:D002292', (211, 214))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('SETD2', 'Gene', '29072', (383, 388))	('VHL', 'Disease', 'MESH:D006623', (243, 246))	('RCC', 'Disease', 'MESH:D002292', (219, 222))	('deficient', 'NegReg', (166, 175))	('VHL', 'Disease', (404, 407))	('SETD2', 'Gene', (180, 185))	('SETD2', 'Gene', '29072', (180, 185))	('regulation', 'biological_process', 'GO:0065007', ('436', '446'))	('deficiency', 'Var', (389, 399))
186478	31988284	Hence, we report that SETD2 deficiency in RCC cells is associated with the aberrant accumulation of both free ATG12 and of an additional ATG12-containing complex, distinct from the ATG5-ATG12 complex, which also appears to be associated with reduced autophagic flux in these cells.	('ATG5', 'Gene', (181, 185))	('RCC', 'Disease', 'MESH:D002292', (42, 45))	('SETD2', 'Gene', '29072', (22, 27))	('autophagic flux', 'CPA', (250, 265))	('SETD2', 'Gene', (22, 27))	('deficiency', 'Var', (28, 38))	('reduced', 'NegReg', (242, 249))	('accumulation', 'PosReg', (84, 96))	('ATG5', 'Gene', '9474', (181, 185))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))
186479	31988284	In order to gain evidence that SETD2 deficiency in RCC is directly involved in the acquisition of these defects in the autophagic process, experiments aiming at the gain and loss of function of SETD2 in RCC cells were undertaken.	('SETD2', 'Gene', (31, 36))	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('SETD2', 'Gene', (194, 199))	('RCC', 'Phenotype', 'HP:0005584', (203, 206))	('SETD2', 'Gene', '29072', (194, 199))	('SETD2', 'Gene', '29072', (31, 36))	('deficiency', 'Var', (37, 47))	('RCC', 'Disease', (203, 206))	('RCC', 'Disease', 'MESH:D002292', (203, 206))	('RCC', 'Disease', 'MESH:D002292', (51, 54))	('RCC', 'Disease', (51, 54))
186487	31988284	Thereafter, we wanted to elucidate how SETD2 deficiency in RCC cells could have an impact on the expression of ATG12, and potentially control to the expression of different ATG12 variants that could lead to occurrence of free ATG12 and additional ATG12-containing complexes.	('lead to occurrence', 'Reg', (199, 217))	('RCC', 'Disease', 'MESH:D002292', (59, 62))	('SETD2', 'Gene', (39, 44))	('variants', 'Var', (179, 187))	('SETD2', 'Gene', '29072', (39, 44))	('ATG12', 'Gene', (111, 116))	('free', 'MPA', (221, 225))	('control', 'Reg', (134, 141))	('complexes', 'Interaction', (264, 273))	('RCC', 'Disease', (59, 62))	('expression', 'MPA', (149, 159))	('deficiency', 'Var', (45, 55))	('ATG12', 'Protein', (226, 231))	('impact', 'Reg', (83, 89))	('expression', 'MPA', (97, 107))	('ATG12', 'Gene', (173, 178))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
186488	31988284	SETD2-mediated H3K36 trimethylation has been implicated in the regulation of alternative splicing.	('regulation', 'biological_process', 'GO:0065007', ('63', '73'))	('H3K36', 'Protein', (15, 20))	('SETD2', 'Gene', '29072', (0, 5))	('alternative splicing', 'MPA', (77, 97))	('SETD2', 'Gene', (0, 5))	('splicing', 'biological_process', 'GO:0045292', ('89', '97'))	('trimethylation', 'Var', (21, 35))
186489	31988284	Furthermore, altering SETD2 gene expression levels is enough to influence the inclusion of exons in genes known to be alternatively spliced.	('gene expression', 'biological_process', 'GO:0010467', ('28', '43'))	('SETD2', 'Gene', '29072', (22, 27))	('inclusion of exons', 'MPA', (78, 96))	('SETD2', 'Gene', (22, 27))	('influence', 'Reg', (64, 73))	('altering', 'Var', (13, 21))
186490	31988284	Finally and of importance for the current investigation, H3K36me3-deficient ccRCC tumors have been reported to show alterations in splicing and evidence of intron retention.	('ccRCC', 'Disease', 'MESH:D002292', (76, 81))	('splicing', 'MPA', (131, 139))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('splicing', 'biological_process', 'GO:0045292', ('131', '139'))	('retention', 'biological_process', 'GO:0051235', ('163', '172'))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('alterations', 'Reg', (116, 127))	('tumor', 'Disease', (82, 87))	('H3K36me3-deficient', 'Var', (57, 75))	('ccRCC', 'Disease', (76, 81))	('intron', 'MPA', (156, 162))
186494	31988284	Given the strong evidence for SETD2-dependent regulation of alternative splicing, and the suggested existence of ATG12 isoforms issue of alternative splicing for, we speculated that dysregulation of SETD2 might impact on the differential expression of these ATG12 isoforms in RCC cells.	('regulation', 'biological_process', 'GO:0065007', ('46', '56'))	('impact', 'Reg', (211, 217))	('splicing', 'biological_process', 'GO:0045292', ('149', '157'))	('RCC', 'Disease', 'MESH:D002292', (276, 279))	('RCC', 'Disease', (276, 279))	('SETD2', 'Gene', '29072', (30, 35))	('RCC', 'Phenotype', 'HP:0005584', (276, 279))	('SETD2', 'Gene', '29072', (199, 204))	('dysregulation', 'Var', (182, 195))	('SETD2', 'Gene', (30, 35))	('SETD2', 'Gene', (199, 204))	('differential expression', 'MPA', (225, 248))	('splicing', 'biological_process', 'GO:0045292', ('72', '80'))
186498	31988284	Collectively, these data indicate that deficiency in SETD2, known regulator of alternative splicing, is associated with increased expression of the ATG12 short isoform to the depend of the canonical ATG12 long isoform in RCC cells.	('deficiency', 'Var', (39, 49))	('expression', 'MPA', (130, 140))	('SETD2', 'Gene', (53, 58))	('RCC', 'Phenotype', 'HP:0005584', (221, 224))	('RCC', 'Disease', 'MESH:D002292', (221, 224))	('RCC', 'Disease', (221, 224))	('ATG12', 'Gene', (148, 153))	('increased', 'PosReg', (120, 129))	('SETD2', 'Gene', '29072', (53, 58))	('splicing', 'biological_process', 'GO:0045292', ('91', '99'))
186502	31988284	Finally, with the purpose of exploring whether the above described deficiency in autophagy could impact on other cellular properties of RCC cells, we undertook to analysis whether the manipulation of SETD2 could impact on the migration capabilities of these cells.	('migration capabilities', 'CPA', (226, 248))	('autophagy', 'biological_process', 'GO:0016236', ('81', '90'))	('SETD2', 'Gene', (200, 205))	('manipulation', 'Var', (184, 196))	('deficiency', 'NegReg', (67, 77))	('autophagy', 'biological_process', 'GO:0006914', ('81', '90'))	('impact', 'Reg', (212, 218))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('autophagy', 'CPA', (81, 90))	('RCC', 'Disease', 'MESH:D002292', (136, 139))	('RCC', 'Disease', (136, 139))	('SETD2', 'Gene', '29072', (200, 205))	('impact', 'Reg', (97, 103))
186505	31988284	A significant increase in wound-healing (cell motility) activity was seen in ACHN cells in which the expression of SETD2 had been targeted by an antisense approach velocity, as compared with the ACHN cells control, transfected with a scramble siRNA (Supplementary Fig.	('SETD2', 'Gene', (115, 120))	('antisense', 'Var', (145, 154))	('ACHN', 'Gene', '55323', (77, 81))	('cell motility', 'biological_process', 'GO:0048870', ('41', '54'))	('wound-healing', 'biological_process', 'GO:0042060', ('26', '39'))	('ACHN', 'Gene', '55323', (195, 199))	('ACHN', 'Gene', (77, 81))	('ACHN', 'Gene', (195, 199))	('SETD2', 'Gene', '29072', (115, 120))	('Su', 'Chemical', 'MESH:C035067', (250, 252))	('increase', 'PosReg', (14, 22))
186508	31988284	Since we observe that SETD2 deficiency is associated with the appearance of free ATG12, as well as the expression additional ATG12-containing complexes, and an overall increase in total ATG12 protein expression levels, we decided to investigate whether ATG12 gene expression levels, as well as the expression of the gene, i.e., SETD2, which product is causing the global increase in ATG12 expression levels, could be used as survival prognostic factors for ccRCC patients.	('increase', 'PosReg', (168, 176))	('SETD2', 'Gene', '29072', (328, 333))	('SETD2', 'Gene', '29072', (22, 27))	('expression', 'MPA', (103, 113))	('SETD2', 'Gene', (22, 27))	('SETD2', 'Gene', (328, 333))	('deficiency', 'Var', (28, 38))	('RCC', 'Phenotype', 'HP:0005584', (459, 462))	('ccRCC', 'Phenotype', 'HP:0006770', (457, 462))	('ccRCC', 'Disease', (457, 462))	('protein', 'cellular_component', 'GO:0003675', ('192', '199'))	('ccRCC', 'Disease', 'MESH:D002292', (457, 462))	('gene expression', 'biological_process', 'GO:0010467', ('259', '274'))	('patients', 'Species', '9606', (463, 471))
186516	31988284	In recent years, SETD2 has attracted interest as a potential tumor suppressor gene, whose inactivation would therefor participate to tumor initiation and progression for a wide range of human tumors, including epithelial, central nervous system, and hematopoietic tumors.	('tumor initiation', 'Disease', (133, 149))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('epithelial', 'Disease', (210, 220))	('hematopoietic tumors', 'Disease', 'MESH:D019337', (250, 270))	('hematopoietic tumors', 'Disease', (250, 270))	('tumor', 'Disease', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('SETD2', 'Gene', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('tumor', 'Disease', (192, 197))	('participate', 'Reg', (118, 129))	('SETD2', 'Gene', '29072', (17, 22))	('tumor', 'Disease', (133, 138))	('inactivation', 'Var', (90, 102))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('61', '77'))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('central nervous system', 'Disease', (222, 244))	('human', 'Species', '9606', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('tumor suppressor', 'biological_process', 'GO:0051726', ('61', '77'))	('tumor initiation', 'Disease', 'MESH:D009369', (133, 149))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Disease', (61, 66))
186518	31988284	Furthermore, these mutations correlate with aggressive clinicophatological features, and are associated with an unfavorable prognosis in patients with ccRCC.	('ccRCC', 'Disease', 'MESH:D002292', (151, 156))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('mutations', 'Var', (19, 28))	('patients', 'Species', '9606', (137, 145))	('associated', 'Reg', (93, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (151, 156))	('ccRCC', 'Disease', (151, 156))
186519	31988284	Thus, given its frequency of inactivation in ccRCC, its critical role as a tumor suppressor, and its possible use as progression marker in ccRCC, effort have been placed to elucidate the biological consequences of SETD2 loss of function in ccRCC cells.	('ccRCC', 'Phenotype', 'HP:0006770', (139, 144))	('RCC', 'Phenotype', 'HP:0005584', (242, 245))	('ccRCC', 'Phenotype', 'HP:0006770', (240, 245))	('tumor suppressor', 'biological_process', 'GO:0051726', ('75', '91'))	('inactivation', 'Var', (29, 41))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('ccRCC', 'Disease', 'MESH:D002292', (45, 50))	('ccRCC', 'Disease', 'MESH:D002292', (139, 144))	('SETD2', 'Gene', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('ccRCC', 'Disease', 'MESH:D002292', (240, 245))	('ccRCC', 'Disease', (45, 50))	('ccRCC', 'Disease', (139, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('SETD2', 'Gene', '29072', (214, 219))	('loss of function', 'NegReg', (220, 236))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('75', '91'))	('ccRCC', 'Disease', (240, 245))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))
186521	31988284	Mechanistically, we uncovered a SETD2 loss of function-dependent occurrence of an aberrant ATG12-containing complex, in addition to the conventional ATG5/ATG12 covalent complex, as well as increased of free ATG12, in RCC cells carrying the SETD2 gene mutation.	('SETD2', 'Gene', '29072', (32, 37))	('RCC', 'Disease', 'MESH:D002292', (217, 220))	('RCC', 'Disease', (217, 220))	('ATG12-containing complex', 'MPA', (91, 115))	('SETD2', 'Gene', (32, 37))	('ATG5', 'Gene', '9474', (149, 153))	('mutation', 'Var', (251, 259))	('SETD2', 'Gene', '29072', (240, 245))	('ATG5', 'Gene', (149, 153))	('loss of function-dependent', 'NegReg', (38, 64))	('SETD2', 'Gene', (240, 245))	('RCC', 'Phenotype', 'HP:0005584', (217, 220))	('increased', 'PosReg', (189, 198))
186522	31988284	Furthermore, we confirmed the existence of two distinct ATG12 isoforms that had been suggested in protein and gene databases, a canonical long isoform and a short isoform generated by alternative splicing, and revealed that SETD2 deficiency in RCC cells promote a significant increase in the expression levels of the short isoform.	('RCC', 'Disease', 'MESH:D002292', (244, 247))	('RCC', 'Disease', (244, 247))	('RCC', 'Phenotype', 'HP:0005584', (244, 247))	('expression levels', 'MPA', (292, 309))	('splicing', 'biological_process', 'GO:0045292', ('196', '204'))	('increase', 'PosReg', (276, 284))	('deficiency', 'Var', (230, 240))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('SETD2', 'Gene', '29072', (224, 229))	('SETD2', 'Gene', (224, 229))	('short isoform', 'MPA', (317, 330))
186525	31988284	Previous studies reported that polymorphisms in autophagic gene are associated with ccRCC risk and patient outcome, indicating deficiencies in the autophagic core machinery impact in ccRCC patients.	('patient', 'Species', '9606', (99, 106))	('ccRCC', 'Disease', (84, 89))	('associated', 'Reg', (68, 78))	('ccRCC', 'Disease', 'MESH:D002292', (84, 89))	('ccRCC', 'Disease', 'MESH:D002292', (183, 188))	('deficiencies', 'NegReg', (127, 139))	('patient', 'Species', '9606', (189, 196))	('autophagic gene', 'Gene', (48, 63))	('autophagic core machinery', 'CPA', (147, 172))	('polymorphisms', 'Var', (31, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('patients', 'Species', '9606', (189, 197))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('core', 'cellular_component', 'GO:0019013', ('158', '162'))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('ccRCC', 'Phenotype', 'HP:0006770', (183, 188))	('ccRCC', 'Disease', (183, 188))
186526	31988284	Our investigation, bring an additional level of understanding, with the discovery that the prevalent SETD2 gene mutation in ccRCC, directly impact on this autophagic core machinery and thereby reduce the autophagic flux.	('SETD2', 'Gene', (101, 106))	('reduce', 'NegReg', (193, 199))	('autophagic flux', 'CPA', (204, 219))	('ccRCC', 'Disease', 'MESH:D002292', (124, 129))	('mutation', 'Var', (112, 120))	('autophagic core machinery', 'CPA', (155, 180))	('core', 'cellular_component', 'GO:0019013', ('166', '170'))	('ccRCC', 'Phenotype', 'HP:0006770', (124, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('SETD2', 'Gene', '29072', (101, 106))	('impact on', 'Reg', (140, 149))	('ccRCC', 'Disease', (124, 129))
186601	30177639	Deletion on one allele of the short arm of chromosome three harboring the von Hippel-Lindau (VHL) gene locus (3p25) has been described to occur at exceptionally high rates in large ccRCC cohorts, characterizing up to 94% of cases.	('RCC', 'Phenotype', 'HP:0005584', (183, 186))	('von Hippel-Lindau', 'Gene', '7428', (74, 91))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('RCC', 'Disease', (183, 186))	('chromosome', 'cellular_component', 'GO:0005694', ('43', '53'))	('short arm', 'Phenotype', 'HP:0009824', (30, 39))	('von Hippel-Lindau', 'Gene', (74, 91))	('VHL', 'Gene', (93, 96))	('Deletion', 'Var', (0, 8))
186606	30177639	It is interesting to note that some missense VHL mutations may favor HIF-2 accumulation while others result in activation of both HIF-1 and HIF-2 since those transcription factors target different genes.	('HIF-2 accumulation', 'MPA', (69, 87))	('activation', 'PosReg', (111, 121))	('HIF-1 and HIF-2', 'Disease', 'MESH:D003924', (130, 145))	('mutations', 'Var', (49, 58))	('transcription', 'biological_process', 'GO:0006351', ('158', '171'))	('missense', 'Var', (36, 44))	('VHL', 'Gene', (45, 48))	('favor', 'PosReg', (63, 68))
186609	30177639	In a cohort of 227 ccRCC patients, truncating mutations of PBRM1 impacting the chromatin remodeling function of the encoded protein were found in 41% of cases.	('chromatin remodeling function of the', 'MPA', (79, 115))	('chromatin', 'cellular_component', 'GO:0000785', ('79', '88'))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('PBRM1', 'Gene', (59, 64))	('PBRM1', 'Gene', '55193', (59, 64))	('impacting', 'Reg', (65, 74))	('patients', 'Species', '9606', (25, 33))	('found', 'Reg', (137, 142))	('truncating mutations', 'Var', (35, 55))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('79', '99'))	('RCC', 'Disease', (21, 24))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))
186610	30177639	Furthermore, concomitant inactivation of VHL and PBRM1 was recently reported to display synergistic effects of metabolic deregulation in ccRCC cell lines in vitro.	('inactivation', 'Var', (25, 37))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('PBRM1', 'Gene', (49, 54))	('VHL', 'Gene', (41, 44))	('PBRM1', 'Gene', '55193', (49, 54))	('metabolic deregulation', 'MPA', (111, 133))
186611	30177639	Additionally, expression of functional PBRM1 has been shown to restrain VHL loss-driven ccRCC progression, thus illustrating the existence of distinct subtypes of VHL-null ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('expression', 'Var', (14, 24))	('PBRM1', 'Gene', '55193', (39, 44))	('restrain', 'NegReg', (63, 71))	('loss-driven', 'NegReg', (76, 87))	('RCC', 'Disease', (90, 93))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('RCC', 'Disease', (174, 177))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('VHL', 'Gene', (72, 75))	('PBRM1', 'Gene', (39, 44))
186612	30177639	Conversely, in tumors displaying functional pVHL expression, high throughput molecular studies have shown that activation of the oncogenic pathway related to HIF-alpha transcription factors can be achieved through distinct genetic alterations that display mutual exclusiveness with inactivating VHL mutations.	('activation', 'PosReg', (111, 121))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('oncogenic pathway', 'Pathway', (129, 146))	('transcription', 'biological_process', 'GO:0006351', ('168', '181'))	('VHL', 'Gene', (295, 298))	('alterations', 'Var', (231, 242))	('pVHL', 'Gene', '7428', (44, 48))	('pVHL', 'Gene', (44, 48))	('mutations', 'Var', (299, 308))	('tumors', 'Disease', (15, 21))
186613	30177639	For instance, mutations in the ELOC gene (also called TCEB1) together with LOH at its 8p locus were found to inactivate the elongin C cofactor of pVHL in 40% of ccRCC patients with wild type pVHL expression.	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('TCEB1', 'Gene', (54, 59))	('elongin C', 'Gene', (124, 133))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('RCC', 'Disease', (163, 166))	('ELOC', 'Gene', (31, 35))	('pVHL', 'Gene', '7428', (191, 195))	('pVHL', 'Gene', '7428', (146, 150))	('patients', 'Species', '9606', (167, 175))	('inactivate', 'NegReg', (109, 119))	('pVHL', 'Gene', (146, 150))	('pVHL', 'Gene', (191, 195))	('elongin C', 'Gene', '6921', (124, 133))	('ELOC', 'Gene', '6921', (31, 35))	('mutations', 'Var', (14, 23))	('TCEB1', 'Gene', '6921', (54, 59))
186615	30177639	determined that 75% of all driver aberrations found in each ccRCC patient were subclonal while VHL alterations, including LOH at 3p and epigenetic silencing, were the only ubiquitous events found across all 79 tumor sites sampled from 10 ccRCC patients.	('epigenetic silencing', 'Var', (136, 156))	('LOH at 3p', 'Var', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('VHL', 'Gene', (95, 98))	('tumor', 'Disease', (210, 215))	('patient', 'Species', '9606', (244, 251))	('patient', 'Species', '9606', (66, 73))	('RCC', 'Phenotype', 'HP:0005584', (240, 243))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('patients', 'Species', '9606', (244, 252))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('RCC', 'Disease', 'MESH:C538614', (240, 243))	('RCC', 'Disease', (240, 243))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
186616	30177639	Such observations are consistent with the role of VHL inactivation as a critical founder event in the majority of ccRCC cases.	('VHL', 'Gene', (50, 53))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))	('inactivation', 'Var', (54, 66))
186621	30177639	By comparing single-cell data obtained from one patient, the authors determined that, although this particular ccRCC tumor did not bear genetic alterations of either VHL or PBRM1, over 70% of the alterations found were cell-specific while less than 30% were common to multiple cells within the tissue.	('PBRM1', 'Gene', (173, 178))	('PBRM1', 'Gene', '55193', (173, 178))	('VHL', 'Gene', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('patient', 'Species', '9606', (48, 55))	('RCC tumor', 'Disease', (113, 122))	('alterations', 'Var', (196, 207))	('RCC tumor', 'Disease', 'MESH:C538614', (113, 122))
186628	30177639	Additionally, these authors identified novel renal cancer stem cell driver mutations, affecting pathways of DNA damage repair and RNA-binding proteins, which could serve as important prognostic factors and therapeutic targets for RCC in the future.	('renal cancer', 'Disease', (45, 57))	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('renal cancer', 'Phenotype', 'HP:0009726', (45, 57))	('RNA-binding', 'molecular_function', 'GO:0003723', ('130', '141'))	('RNA-binding', 'Protein', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('renal cancer', 'Disease', 'MESH:D007680', (45, 57))	('pathways', 'MPA', (96, 104))	('mutations', 'Var', (75, 84))	('affecting', 'Reg', (86, 95))	('RCC', 'Disease', 'MESH:C538614', (230, 233))	('RCC', 'Disease', (230, 233))	('RCC', 'Phenotype', 'HP:0005584', (230, 233))	('RNA', 'cellular_component', 'GO:0005562', ('130', '133'))
186661	30177639	However, VHL alterations favoring HIF-2 accumulation would not cause this CAIX-positive phenotype among ccRCC patients.	('CAIX', 'Gene', (74, 78))	('CAIX', 'Gene', '768', (74, 78))	('alterations', 'Var', (13, 24))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('RCC', 'Disease', (106, 109))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('patients', 'Species', '9606', (110, 118))
186663	30177639	Another approach based on molecular data consists in detecting VHL gene alterations present in the peripheral blood of ccRCC patients.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('alterations', 'Var', (72, 83))	('RCC', 'Disease', (121, 124))	('VHL gene', 'Gene', (63, 71))	('patients', 'Species', '9606', (125, 133))
186665	30177639	The authors reported a 75% concordance of the VHL gene alterations detected in peripheral blood with those obtained on matched tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('alterations', 'Var', (55, 66))	('tumor', 'Disease', (127, 132))	('VHL gene', 'Gene', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
186698	30177639	Our molecular results thereby showed a complete correlation of absence of VHL mutation in the tumor and in the corresponding CCC and CRC-UMF derived from the same 4 patients.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('CCC', 'cellular_component', 'GO:0030896', ('125', '128'))	('mutation', 'Var', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('VHL', 'Gene', (74, 77))	('CCC', 'Disease', (125, 128))	('tumor', 'Disease', (94, 99))	('absence', 'NegReg', (63, 70))	('patients', 'Species', '9606', (165, 173))
186699	30177639	Remarkably, all the remaining 57 CCC as well as 104 CRC-UMF exhibited identical VHL mutations as those detected in the corresponding tumor samples, indicating the neoplastic nature of cells classified as CRC-UMF by the cytopathologists.	('VHL', 'Gene', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('CCC', 'cellular_component', 'GO:0030896', ('33', '36'))	('mutations', 'Var', (84, 93))	('tumor', 'Disease', (133, 138))
186700	30177639	Additionally, 21 CRC-UMF derived from 11 patients were found to display a distinct VHL mutational profile than that found in the corresponding tumor tissue, raising questions regarding their possible tumor or pre-tumor nature.	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('mutational', 'Var', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (200, 205))	('patients', 'Species', '9606', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('VHL', 'Gene', (83, 86))	('pre', 'molecular_function', 'GO:0003904', ('209', '212'))
186702	30177639	Additionally, 104 CRC classified as CRC-UMF by the cytopathologists were also found to carry identical VHL mutations as those detected in the corresponding tumorous tissues.	('mutations', 'Var', (107, 116))	('tumorous', 'Disease', 'MESH:D009369', (156, 164))	('tumorous', 'Disease', (156, 164))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('CRC', 'Disease', (18, 21))	('VHL', 'Gene', (103, 106))
186703	30177639	We consider that, since we found VHL mutations identical to those found in the tumor tissue in CRC having uncertain malignant features (CRC-UMF) and having acquired the capability to circulate in blood, those CRC with VHL mutation are in fact tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('mutation', 'Var', (222, 230))	('tumor', 'Disease', (79, 84))	('VHL', 'Gene', (33, 36))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
186704	30177639	Thus, among the 161 single cells found with the same VHL mutation detected in the tumor tissue, 57 (35%) have been identified as CCC by cytopathological analysis and 104 (72%) have been identified as cancer cells by genetic analysis.	('mutation', 'Var', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('VHL', 'Gene', (53, 56))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('CCC', 'cellular_component', 'GO:0030896', ('129', '132'))	('CCC', 'Disease', (129, 132))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('tumor', 'Disease', (82, 87))	('cancer', 'Disease', (200, 206))
186707	30177639	We also found 21 CRC-UMF derived from 11 patients and exhibiting a distinct VHL mutational profile than that found in the corresponding tumor tissue, raising questions regarding their possible tumor or pre-tumor nature.	('VHL', 'Gene', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('pre', 'molecular_function', 'GO:0003904', ('202', '205'))	('mutational', 'Var', (80, 90))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('patients', 'Species', '9606', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', (136, 141))
186714	30177639	Finally, the most frequent subtype of RCC:the ccRCC, which frequently carries the VHL mutation:can be used as a model to study, in the CCC and at the single cell level, the correlation between the cytomorphological and the genetic features of malignancy.	('RCC', 'Disease', (38, 41))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('CCC', 'cellular_component', 'GO:0030896', ('135', '138'))	('VHL', 'Gene', (82, 85))	('mutation', 'Var', (86, 94))	('malignancy', 'Disease', 'MESH:D009369', (243, 253))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('malignancy', 'Disease', (243, 253))	('RCC', 'Disease', (48, 51))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
186722	28152509	High TWIST1 and low miR-210-3p expression associated with poorer overall and disease-free survival as compared to low TWIST1 and high miR-210-3p expression.	('miR-210', 'Gene', '406992', (20, 27))	('low', 'NegReg', (16, 19))	('disease-free survival', 'CPA', (77, 98))	('High TWIST1', 'Var', (0, 11))	('miR-210', 'Gene', (134, 141))	('poorer', 'NegReg', (58, 64))	('miR-210', 'Gene', '406992', (134, 141))	('overall', 'CPA', (65, 72))	('miR-210', 'Gene', (20, 27))
186733	28152509	Therefore, investigating the cause and function of aberrantly expressed miRNAs is important to elucidate the clinical relevance of miRNA-mediated oncogenic pathways in tumorigenesis.	('aberrantly', 'Var', (51, 61))	('tumor', 'Disease', (168, 173))	('clinical', 'Species', '191496', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('miR', 'Gene', '220972', (72, 75))	('miR', 'Gene', '220972', (131, 134))	('miR', 'Gene', (72, 75))	('miR', 'Gene', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
186742	28152509	Further, the low miR-210-3p and the high TWIST1 expression groups had poor overall survival and disease free survival characteristics.	('poor', 'NegReg', (70, 74))	('TWIST1', 'Gene', (41, 47))	('miR-210', 'Gene', (17, 24))	('overall survival', 'CPA', (75, 91))	('miR-210', 'Gene', '406992', (17, 24))	('disease free survival', 'CPA', (96, 117))	('high', 'Var', (36, 40))
186762	28152509	We postulated that the carrier mutations of TP53 and PTEN in the 786-o cell line may have contributed to morphological differences observed between the three cell lines.	('carrier', 'molecular_function', 'GO:0005215', ('23', '30'))	('contributed', 'Reg', (90, 101))	('mutations', 'Var', (31, 40))	('PTEN', 'Gene', (53, 57))	('TP53', 'Gene', '7157', (44, 48))	('PTEN', 'Gene', '5728', (53, 57))	('TP53', 'Gene', (44, 48))
186786	28152509	The Targetscan database predicted a single putative miR-210-3p binding site in the 3'-UTR of TWIST1 (positions 3058-3064 in XM_011515496; Figure 6A).	('miR-210', 'Gene', (52, 59))	('miR-210', 'Gene', '406992', (52, 59))	('positions 3058-3064', 'Var', (101, 120))	('TWIST1', 'Gene', (93, 99))	('binding', 'molecular_function', 'GO:0005488', ('63', '70'))
186805	28152509	However, the 786-o knockdown cells showed no changes in cell morphology and TWIST1 expression in spite of significant knockdown of miR-210-3p.	('miR-210', 'Gene', (131, 138))	('knockdown', 'Var', (118, 127))	('miR-210', 'Gene', '406992', (131, 138))	('TWIST1', 'Gene', (76, 82))	('expression', 'MPA', (83, 93))
186806	28152509	This probably reflected the effects of the inherent TP53 and PTEN mutations in the 786-o cells.	('mutations', 'Var', (66, 75))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', (52, 56))	('PTEN', 'Gene', (61, 65))	('PTEN', 'Gene', '5728', (61, 65))
186807	28152509	Several studies have demonstrated that TP53 or PTEN mutations acquire resistance to chemotherapy or display neomorphic activity that is independent of its phosphatase activity.	('mutations', 'Var', (52, 61))	('phosphatase activity', 'molecular_function', 'GO:0016791', ('155', '175'))	('resistance', 'CPA', (70, 80))	('neomorphic activity', 'CPA', (108, 127))	('PTEN', 'Gene', (47, 51))	('TP53', 'Gene', '7157', (39, 43))	('PTEN', 'Gene', '5728', (47, 51))	('TP53', 'Gene', (39, 43))
186810	28152509	Also, it showed that TWIST1 was not solely responsible for the morphological changes observed upon miR-210-3p knockdown in ccRCC cells.	('knockdown', 'Var', (110, 119))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('miR-210', 'Gene', (99, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('miR-210', 'Gene', '406992', (99, 106))
186855	28152509	A498 and Caki2 cell lines that were either depleted of miR-210-3p as confirmed by qRT-PCR or transfected by mature miR-210-3p for 48h were seeded in 24-well plates (1x105 cells/well).	('miR-210', 'Gene', (55, 62))	('depleted', 'NegReg', (43, 51))	('miR-210', 'Gene', '406992', (55, 62))	('miR-210', 'Gene', (115, 122))	('miR-210', 'Gene', '406992', (115, 122))	('transfected', 'Var', (93, 104))	('Caki2', 'CellLine', 'CVCL:0235', (9, 14))
186862	28152509	A partial wild-type sequence of the TWIST1 3' UTR or the same sequence with the deleted miR-210-3p target site (positions 3058-3064 of the TWIST1 3'-UTR, according to the TargetScan program (http://www.targetscan.org/)) was inserted between the XhoI and PmeI restriction sites in the 3'-UTR of the hRluc gene in the psi-CHECK-2 vector (C8021, Promega; Madison, WI, USA).	('miR-210', 'Gene', (88, 95))	('C8021', 'Var', (336, 341))	('miR-210', 'Gene', '406992', (88, 95))	('hRluc', 'Gene', (298, 303))
186875	32059438	Deletion of Von Hippel-Lindau Interferes with Hyper Osmolality Induced Gene Expression and Induces an Unfavorable Gene Expression Pattern Loss of von Hippel-Lindau (VHL) protein function can be found in more than 90% of patients with clear cell renal carcinoma (ccRCC).	('Induces', 'Reg', (91, 98))	('renal carcinoma', 'Phenotype', 'HP:0005584', (245, 260))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('patients', 'Species', '9606', (220, 228))	('ccRCC', 'Disease', (262, 267))	('Von Hippel-Lindau', 'Gene', '7428', (12, 29))	('Hyper Osmolality Induced Gene Expression', 'MPA', (46, 86))	('Von Hippel-Lindau', 'Gene', (12, 29))	('clear cell renal carcinoma', 'Disease', (234, 260))	('von Hippel-Lindau', 'Gene', (146, 163))	('ccRCC', 'Phenotype', 'HP:0006770', (262, 267))	('Interferes', 'NegReg', (30, 40))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (234, 260))	('Deletion', 'Var', (0, 8))	('RCC', 'Phenotype', 'HP:0005584', (264, 267))	('Gene Expression', 'biological_process', 'GO:0010467', ('114', '129'))	('von Hippel-Lindau', 'Gene', '7428', (146, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('Unfavorable Gene Expression Pattern', 'MPA', (102, 137))	('Gene Expression', 'biological_process', 'GO:0010467', ('71', '86'))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (234, 260))	('Loss', 'NegReg', (138, 142))	('ccRCC', 'Disease', 'MESH:C538614', (262, 267))
186889	32059438	Several studies have been performed to generate ccRCC in mouse kidneys by inactivating Vhl.	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('rat', 'Species', '10116', (43, 46))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('inactivating', 'Var', (74, 86))	('ccRCC', 'Disease', (48, 53))	('ccRCC', 'Disease', 'MESH:C538614', (48, 53))	('mouse', 'Species', '10090', (57, 62))	('Vhl', 'Gene', (87, 90))
186892	32059438	Using Ksp1.3-Cre, as deleter Cre, led to generation of distal tubule and collecting duct (CD) specific deletion of Vhl.	('Vhl', 'Gene', (115, 118))	('rat', 'Species', '10116', (45, 48))	('deletion', 'Var', (103, 111))
186895	32059438	A further study on mouse showed that deletion of Vhl caused increased medullary vascularization and, as a physiological consequence, developed a diabetes insipidus like phenotype by excretion of highly diluted urine.	('medullary vascularization', 'CPA', (70, 95))	('diabetes insipidus', 'Disease', (145, 163))	('mouse', 'Species', '10090', (19, 24))	('deletion', 'Var', (37, 45))	('diabetes insipidus', 'Disease', 'MESH:D003919', (145, 163))	('excretion of highly diluted urine', 'MPA', (182, 215))	('excretion', 'biological_process', 'GO:0007588', ('182', '191'))	('developed', 'PosReg', (133, 142))	('Vhl', 'Gene', (49, 52))	('diabetes insipidus', 'Phenotype', 'HP:0000873', (145, 163))	('increased', 'PosReg', (60, 69))
186906	32059438	Based on these data we hypothesized that Vhl also plays an important role in the expression of hyperosmolality induced genes and that loss of Vhl function induces a ccRCC like phenotype in a normal murine collecting duct cell line.	('murine', 'Species', '10090', (198, 204))	('induces', 'Reg', (155, 162))	('ccRCC', 'Disease', (165, 170))	('ccRCC', 'Phenotype', 'HP:0006770', (165, 170))	('ccRCC', 'Disease', 'MESH:C538614', (165, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('Vhl', 'Gene', (142, 145))	('loss', 'Var', (134, 138))
186911	32059438	Based on this analysis, we selected single clones that showed InDels leading to a frameshift (Supplemental Figure S2).	('frameshift', 'Var', (82, 92))	('InDels', 'Var', (62, 68))	('men', 'Species', '9606', (100, 103))	('leading to', 'Reg', (69, 79))
186913	32059438	Since the loss of Vhl stabilizes the expression of Hif1a, we have also tested if this is the case in our model.	('loss', 'Var', (10, 14))	('stabilizes', 'Reg', (22, 32))	('Hif1a', 'Gene', (51, 56))	('expression', 'MPA', (37, 47))	('Hif1a', 'Gene', '3091', (51, 56))	('Vhl', 'Gene', (18, 21))
186932	32059438	The results showed that Vhl-KO cells had significant longer doubling time, resulting in a lower proliferation rate, compared to Scr cells (Figure 3).	('rat', 'Species', '10116', (110, 113))	('rat', 'Species', '10116', (103, 106))	('proliferation rate', 'CPA', (96, 114))	('lower', 'NegReg', (90, 95))	('Vhl-KO', 'Var', (24, 30))	('longer', 'PosReg', (53, 59))
186935	32059438	To test if the phenotype of Vhl deficient mpkCCD correlates with that of classical RCC cell lines, we tested the proliferation rate using the RCC cell line 786-0.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (83, 86))	('deficient', 'Var', (32, 41))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('tested', 'Reg', (102, 108))	('rat', 'Species', '10116', (127, 130))	('rat', 'Species', '10116', (120, 123))
186939	32059438	The results showed that Vhl-KO cells migrate at a significantly faster speed (~25% faster) compared to Scr cells (Figure 4A and Supplemental Figure S6).	('rat', 'Species', '10116', (40, 43))	('migrate', 'CPA', (37, 44))	('faster', 'PosReg', (64, 70))	('Vhl-KO', 'Var', (24, 30))	('men', 'Species', '9606', (134, 137))
186940	32059438	Similar to the results obtained for cell proliferation, VHL expression in 786-0 cells has a different effect on cell migration compared to the mpkCCD cells.	('VHL', 'Gene', (56, 59))	('expression', 'Var', (60, 70))	('cell proliferation', 'biological_process', 'GO:0008283', ('36', '54'))	('cell migration', 'biological_process', 'GO:0016477', ('112', '126'))	('rat', 'Species', '10116', (120, 123))	('cell migration', 'CPA', (112, 126))	('rat', 'Species', '10116', (48, 51))
186941	32059438	The ectopic expression of VHL induced a significantly higher cell migration speed (Supplemental Figure S7).	('higher', 'PosReg', (54, 60))	('VHL', 'Gene', (26, 29))	('cell migration speed', 'CPA', (61, 81))	('cell migration', 'biological_process', 'GO:0016477', ('61', '75'))	('ectopic expression', 'Var', (4, 22))	('men', 'Species', '9606', (89, 92))	('rat', 'Species', '10116', (69, 72))
186942	32059438	So far the data showed that functional deletion of Vhl in mpkCCD cells is associated with massive changes in cell morphology, proliferation, and migration.	('rat', 'Species', '10116', (148, 151))	('changes', 'Reg', (98, 105))	('deletion', 'Var', (39, 47))	('migration', 'CPA', (145, 154))	('rat', 'Species', '10116', (133, 136))	('Vhl', 'Gene', (51, 54))	('cell morphology', 'CPA', (109, 124))
186950	32059438	This indicates that Vhl deletion has a direct effect on AQP2 expression and probably interferes with hyperosmotic pathways.	('AQP2', 'Gene', (56, 60))	('AQP2', 'Gene', '11827', (56, 60))	('effect', 'Reg', (46, 52))	('deletion', 'Var', (24, 32))	('Vhl', 'Gene', (20, 23))	('interferes', 'NegReg', (85, 95))	('hyperosmotic pathways', 'Pathway', (101, 122))	('expression', 'MPA', (61, 71))
186968	32059438	This again demonstrates that loss of Vhl induces an unfavorable gene expression pattern.	('rat', 'Species', '10116', (18, 21))	('gene expression', 'biological_process', 'GO:0010467', ('64', '79'))	('Vhl', 'Gene', (37, 40))	('induces', 'Reg', (41, 48))	('loss', 'Var', (29, 33))	('unfavorable gene expression pattern', 'MPA', (52, 87))
186971	32059438	In all cases, high expression of these genes was associated with a significant overall survival of the patients (Supplemental Figure S11).	('associated', 'Reg', (49, 59))	('high', 'Var', (14, 18))	('men', 'Species', '9606', (119, 122))	('patients', 'Species', '9606', (103, 111))	('overall survival', 'MPA', (79, 95))
186973	32059438	The CRISPR/Cas9 technology has been used in a study before to delete VHL in the RENCA renal cancer cell line where the authors described an EMT like phenotype due to a Vhl knock out.	('delete', 'Var', (62, 68))	('Cas', 'cellular_component', 'GO:0005650', ('11', '14'))	('renal cancer', 'Disease', (86, 98))	('Vhl', 'Gene', (168, 171))	('renal cancer', 'Phenotype', 'HP:0009726', (86, 98))	('knock out', 'Var', (172, 181))	('EMT', 'biological_process', 'GO:0001837', ('140', '143'))	('VHL', 'Gene', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('renal cancer', 'Disease', 'MESH:D007680', (86, 98))
186978	32059438	Similar to RENCA cells, loss of Vhl induces a more metastatic phenotype in mpkCCD cells as they migrate faster.	('loss', 'Var', (24, 28))	('metastatic', 'CPA', (51, 61))	('Vhl', 'Gene', (32, 35))	('rat', 'Species', '10116', (99, 102))	('more', 'PosReg', (46, 50))	('migrate faster', 'CPA', (96, 110))
186980	32059438	Ectopic expression of VHL was associated with an increased cell migration speed.	('rat', 'Species', '10116', (67, 70))	('VHL', 'Gene', (22, 25))	('increased', 'PosReg', (49, 58))	('Ectopic expression', 'Var', (0, 18))	('cell migration speed', 'CPA', (59, 79))	('cell migration', 'biological_process', 'GO:0016477', ('59', '73'))
186982	32059438	However, the knockdown of Vhl in lung cancer cell lines showed similar effects to what we observed in the mpkCCD cells, higher migration and lower proliferation capacity.	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('higher', 'PosReg', (120, 126))	('Vhl', 'Gene', (26, 29))	('rat', 'Species', '10116', (154, 157))	('proliferation capacity', 'CPA', (147, 169))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('lower', 'NegReg', (141, 146))	('rat', 'Species', '10116', (130, 133))	('knockdown', 'Var', (13, 22))	('migration', 'CPA', (127, 136))	('lung cancer', 'Disease', (33, 44))
186984	32059438	A mouse model using Hoxb7-Cre as driver to delete Vhl expression in the collecting duct developed epithelial disruption, fibrosis, and hyperplasia.	('Hoxb7', 'Gene', '15415', (20, 25))	('hyperplasia', 'Disease', (135, 146))	('Hoxb7', 'Gene', (20, 25))	('delete', 'Var', (43, 49))	('fibrosis', 'Disease', 'MESH:D005355', (121, 129))	('fibrosis', 'Disease', (121, 129))	('epithelial disruption', 'CPA', (98, 119))	('mouse', 'Species', '10090', (2, 7))	('hyperplasia', 'Disease', 'MESH:D006965', (135, 146))	('Vhl expression', 'Gene', (50, 64))
186985	32059438	However, Vhl deletion alone is not sufficient and only in combination with deletion of other genetic factors it was possible to induce ccRCC.	('ccRCC', 'Disease', 'MESH:C538614', (135, 140))	('Vhl', 'Gene', (9, 12))	('deletion', 'Var', (13, 21))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('induce', 'Reg', (128, 134))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('ccRCC', 'Disease', (135, 140))
186987	32059438	The same group showed that renal Vhl deletion is associated with disturbed urine concentration capability.	('urine concentration capability', 'MPA', (75, 105))	('renal Vhl', 'Phenotype', 'HP:0030409', (27, 36))	('disturbed urine concentration capability', 'Phenotype', 'HP:0004727', (65, 105))	('disturbed', 'Reg', (65, 74))	('deletion', 'Var', (37, 45))	('rat', 'Species', '10116', (88, 91))	('renal Vhl', 'Gene', (27, 36))
187001	32059438	Loss of Vhl function was associated with more than 8500 differentially expressed genes in the RENCA RCC cell line after CRIPSR/Cas9 deletion of Vhl.	('deletion', 'Var', (132, 140))	('Vhl', 'Gene', (8, 11))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('Loss', 'NegReg', (0, 4))	('Cas', 'cellular_component', 'GO:0005650', ('127', '130'))	('differentially expressed genes', 'MPA', (56, 86))	('function', 'MPA', (12, 20))	('Vhl', 'Gene', (144, 147))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
187003	32059438	KEGG Pathway analysis showed that loss of Vhl affects, for example, "PI3K-Akt signaling pathway" or "Regulation of actin cytoskeleton" pathway.	('Akt', 'Gene', '207', (74, 77))	('loss', 'Var', (34, 38))	('affects', 'Reg', (46, 53))	('PI3K', 'molecular_function', 'GO:0016303', ('68', '72'))	('Akt', 'Gene', (74, 77))	('Vhl', 'Gene', (42, 45))
187009	32059438	These data show that Vhl deletion in mpkCCD cells induces a gene expression associated with a cancer-related phenotype and this is also supported by the enrichment of genes that are involved in "Pathways in cancer".	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('men', 'Species', '9606', (159, 162))	('gene expression', 'MPA', (60, 75))	('cancer', 'Disease', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('deletion', 'Var', (25, 33))	('Vhl', 'Gene', (21, 24))	('cancer', 'Disease', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('gene expression', 'biological_process', 'GO:0010467', ('60', '75'))	('induces', 'Reg', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
187011	32059438	Vhl deletion induced the expression of more genes that are unfavorable and predominantly reduced expression of genes that are associated with a favorable outcome of patients with RCC.	('expression', 'MPA', (25, 35))	('induced', 'Reg', (13, 20))	('expression of genes', 'MPA', (97, 116))	('deletion', 'Var', (4, 12))	('Vhl', 'Gene', (0, 3))	('reduced', 'NegReg', (89, 96))	('patients', 'Species', '9606', (165, 173))	('RCC', 'Phenotype', 'HP:0005584', (179, 182))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('RCC', 'Disease', (179, 182))
187016	32059438	For example, the expression of the E74 like ETS transcription factor 5 is not detectable in ccRCC samples and ectopic ELF5 expression reduced tumor development in mice.	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('men', 'Species', '9606', (155, 158))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('ccRCC', 'Disease', (92, 97))	('transcription', 'biological_process', 'GO:0006351', ('48', '61'))	('tumor', 'Disease', (142, 147))	('ccRCC', 'Disease', 'MESH:C538614', (92, 97))	('transcription factor', 'molecular_function', 'GO:0000981', ('48', '68'))	('mice', 'Species', '10090', (163, 167))	('ectopic', 'Var', (110, 117))	('reduced', 'NegReg', (134, 141))	('ELF5', 'Gene', (118, 122))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
187033	32059438	Nfat5 deficiency promoted hepatocellular carcinogenesis and metastasis in one study.	('Nfat5', 'Gene', (0, 5))	('hepatocellular carcinogenesis', 'Disease', 'MESH:D063646', (26, 55))	('promoted', 'PosReg', (17, 25))	('deficiency', 'Var', (6, 16))	('metastasis', 'CPA', (60, 70))	('hepatocellular carcinogenesis', 'Disease', (26, 55))
187038	32059438	The authors postulate that the miR-106b-5p and miR-122-5p are involved in the downregulation of NFAT5 and also downstream of NFAT5 target genes.	('NFAT5', 'Gene', '10725', (96, 101))	('NFAT5', 'Gene', '10725', (125, 130))	('miR-122-5p', 'Gene', '100188847', (47, 57))	('downregulation', 'NegReg', (78, 92))	('miR-106b-5p', 'Var', (31, 42))	('miR-122-5p', 'Gene', (47, 57))	('NFAT5', 'Gene', (96, 101))	('NFAT5', 'Gene', (125, 130))
187041	32059438	Since Vhl deletion alone did not induce renal cancer in mice model, it might be interesting to test if a Vhl/Nfat5 double KO develops renal cancer.	('renal cancer', 'Disease', 'MESH:D007680', (134, 146))	('renal cancer', 'Phenotype', 'HP:0009726', (134, 146))	('mice', 'Species', '10090', (56, 60))	('develops', 'Reg', (125, 133))	('deletion', 'Var', (10, 18))	('Vhl', 'Gene', (6, 9))	('renal cancer', 'Disease', (40, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('renal cancer', 'Disease', (134, 146))	('renal cancer', 'Disease', 'MESH:D007680', (40, 52))	('renal cancer', 'Phenotype', 'HP:0009726', (40, 52))
187042	32059438	Taken together, we have shown that Vhl deletion in collecting duct cells induces an EMT like phenotype, an unfavorable gene expression pattern, and that loss of Vhl function significantly regulates the expression of hyperosmolality expressed genes that are favorable prognostic markers for patients with ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (304, 309))	('RCC', 'Phenotype', 'HP:0005584', (306, 309))	('EMT like phenotype', 'CPA', (84, 102))	('patients', 'Species', '9606', (290, 298))	('ccRCC', 'Disease', (304, 309))	('regulates', 'Reg', (188, 197))	('ccRCC', 'Disease', 'MESH:C538614', (304, 309))	('Vhl', 'Gene', (35, 38))	('deletion', 'Var', (39, 47))	('expression', 'MPA', (202, 212))	('loss', 'Var', (153, 157))	('EMT', 'biological_process', 'GO:0001837', ('84', '87'))	('induces', 'Reg', (73, 80))	('gene expression', 'biological_process', 'GO:0010467', ('119', '134'))	('Vhl', 'Gene', (161, 164))	('unfavorable gene expression pattern', 'MPA', (107, 142))
187062	32059438	Against Hif1a (36169S) and Gapdh (2118S) from Cell Signaling Technology, Inc.( Danvers, MA, USA).	('Hif1a', 'Gene', '3091', (8, 13))	('Signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('Gapdh', 'Gene', (27, 32))	('36169S', 'Var', (15, 21))	('Hif1a', 'Gene', (8, 13))	('Gapdh', 'Gene', '2597', (27, 32))	('2118S', 'Var', (34, 39))
187081	32059438	Our study demonstrates that loss of Vhl function alone induces massive morphological and functional changes in a healthy renal cell line.	('morphological', 'CPA', (71, 84))	('Vhl', 'Gene', (36, 39))	('loss', 'Var', (28, 32))	('rat', 'Species', '10116', (17, 20))
187084	32059438	The following are available online at , Table S1: Sequences selected for cloning and amplification of targeted region, Figure S1: The selected gRNAs induced mutations in the Vhl locus, Figure S2: TIDE analysis leads to identification of clones with frame shift mutations, Figure S3: Effect of Vhl deletion on selected EMT marker genes, Figure S4: Hyper osmolality increases doubling time, Figure S5: VHL expression has no effect on proliferation rate of 786-0 RCC cell line, Figure S6: VHL deletion increases migration speed, Figure S7: Ectopic VHL expression induces cell migration capacity in 786-0 cells, Figure S8: The expression of Aqp2 mRNA is down regulated in Vhl-KO cells, Figure S9: Hyper osmolality causes massive changes in gene expression, Figure S10: KEGG pathway analysis, Figure S11: Kaplan-Meier analysis of survival probability for selected genes, Figure S12: Deletion of Vhl induces the expression of hyper osmolality suppressed genes with unfavorable prognostic value, Figure S13: Total Western blot membrane from Figure 1.	('rat', 'Species', '10116', (512, 515))	('EMT', 'biological_process', 'GO:0001837', ('318', '321'))	('expression', 'MPA', (906, 916))	('rat', 'Species', '10116', (439, 442))	('gene expression', 'biological_process', 'GO:0010467', ('736', '751'))	('Vhl', 'Gene', (890, 893))	('Deletion', 'Var', (878, 886))	('rat', 'Species', '10116', (576, 579))	('RCC', 'Disease', (460, 463))	('RCC', 'Phenotype', 'HP:0005584', (460, 463))	('membrane', 'cellular_component', 'GO:0016020', ('1020', '1028'))	('cell migration', 'biological_process', 'GO:0016477', ('568', '582'))	('rat', 'Species', '10116', (446, 449))	('RCC', 'Disease', 'MESH:C538614', (460, 463))	('induces', 'Reg', (894, 901))
187155	31192543	Also, the compound potentiated the expression of immune factors, IL-2-R and GM-CSF, known to be associated with optimal host anti-cancer immune responses and their presence is correlated with good prognosis.23, 26 RANCE-1's inhibitory capacities toward 5 key growth factors also adds to its therapeutic potential.	('IL-2-R', 'molecular_function', 'GO:0004911', ('65', '71'))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('IL-2-R', 'Gene', (65, 71))	('cancer', 'Disease', (130, 136))	('IL-2-R', 'Gene', '16184', (65, 71))	('prognosis.23', 'Var', (197, 209))	('GM-CSF', 'Gene', (76, 82))	('inhibitory capacities', 'MPA', (224, 245))	('RANCE-1', 'Chemical', '-', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('GM-CSF', 'Gene', '12981', (76, 82))
187185	29468160	As currently no effective therapies exist to restore kidney function after CKD- as well as cancer-induced renal damage, it is important to elucidate new regulators of kidney development and disease as new therapeutic targets.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('renal damage', 'Disease', (106, 118))	('renal damage', 'Disease', 'MESH:D007674', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('kidney development', 'biological_process', 'GO:0001822', ('167', '185'))	('CKD-', 'Var', (75, 79))	('CKD', 'Phenotype', 'HP:0012622', (75, 78))
187191	29468160	Our data indicate that most aGPCRs are expressed in different spatio-temporal patterns during kidney development and that altered aGPCR expression is associated with a variety of kidney diseases including CKD, diabetic nephropathy, lupus nephritis as well as renal cell carcinoma.	('nephropathy', 'Phenotype', 'HP:0000112', (219, 230))	('renal cell carcinoma', 'Disease', (259, 279))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (259, 279))	('diabetic nephropathy', 'Disease', 'MESH:D003928', (210, 230))	('diabetic nephropathy', 'Disease', (210, 230))	('associated', 'Reg', (150, 160))	('expression', 'MPA', (136, 146))	('kidney disease', 'Phenotype', 'HP:0000112', (179, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('kidney diseases', 'Disease', (179, 194))	('lupus nephritis', 'Disease', (232, 247))	('kidney diseases', 'Disease', 'MESH:D007674', (179, 194))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (259, 279))	('CKD', 'Disease', (205, 208))	('CKD', 'Phenotype', 'HP:0012622', (205, 208))	('altered', 'Var', (122, 129))	('nephritis', 'Phenotype', 'HP:0000123', (238, 247))	('aGPCR', 'Gene', (130, 135))	('lupus nephritis', 'Disease', 'MESH:D008181', (232, 247))	('kidney development', 'biological_process', 'GO:0001822', ('94', '112'))	('kidney diseases', 'Phenotype', 'HP:0000112', (179, 194))
187220	29468160	These are all processes that also play important roles in kidney development and disturbance of these processes are known to contribute to kidney disease (Sariola,; Schordan et al.,; Cabral and Garvin,; Xia et al.,; Gao et al.,; Kunimoto et al.,).	('kidney disease', 'Disease', (139, 153))	('kidney development', 'biological_process', 'GO:0001822', ('58', '76'))	('kidney disease', 'Phenotype', 'HP:0000112', (139, 153))	('contribute', 'Reg', (125, 135))	('kidney disease', 'Disease', 'MESH:D007674', (139, 153))	('disturbance', 'Var', (81, 92))
187225	29468160	Mutations in the corresponding genes, Pkd1 and Pkd2, have been associated with autosomal dominant polycystic kidney disease (ADPKD) (Ferreira et al.,).	('Pkd2', 'Gene', '18764', (47, 51))	('polycystic kidney', 'Phenotype', 'HP:0000113', (98, 115))	('autosomal dominant polycystic kidney disease', 'Disease', (79, 123))	('kidney disease', 'Phenotype', 'HP:0000112', (109, 123))	('associated', 'Reg', (63, 73))	('ADPKD', 'Disease', 'MESH:D007690', (125, 130))	('Mutations', 'Var', (0, 9))	('Pkd1', 'Gene', '18763', (38, 42))	('Pkd1', 'Gene', (38, 42))	('ADPKD', 'Disease', (125, 130))	('Pkd2', 'Gene', (47, 51))	('autosomal dominant polycystic kidney disease', 'Disease', 'MESH:D007690', (79, 123))
187250	29468160	Mice carrying mutations in Adgrc1 (Celsr1Crsh/Crsh and Celsr1Crsh/+) or Vangl2 (Vangl2Lp/+) exhibited branching defects in the ureteric tree at E13.5, which were more severe in Celsr1Crsh/+:Vangl2Lp/+ mice.	('Adgrc1', 'Gene', '12614', (27, 33))	('Mice', 'Species', '10090', (0, 4))	('Crsh', 'Gene', (46, 50))	('Crsh', 'Gene', '12614', (46, 50))	('Vangl2Lp/+', 'Gene', '93840', (80, 90))	('Vangl2Lp/+', 'Gene', '93840', (190, 200))	('mice', 'Species', '10090', (201, 205))	('Adgrc1', 'Gene', (27, 33))	('Vangl2Lp/+', 'Gene', (80, 90))	('Vangl2Lp/+', 'Gene', (190, 200))	('mutations', 'Var', (14, 23))	('Vangl2', 'Gene', (72, 78))	('Crsh', 'Gene', (61, 65))	('Crsh', 'Gene', '12614', (61, 65))	('Crsh', 'Gene', (41, 45))	('Crsh', 'Gene', (183, 187))	('Crsh', 'Gene', '12614', (41, 45))	('branching defects', 'CPA', (102, 119))	('Crsh', 'Gene', '12614', (183, 187))
187251	29468160	At E17.5 kidneys exhibited overall growth retardation (Celsr1Crsh/+:Vangl2Lp/+ > Celsr1Crsh/Crsh > Celsr1Crsh/+) and histological analysis revealed mitotic spindle misorientation (along the longitudinal axis of the kidney tubules), dilation of cortical tubules in Celsr1Crsh/Crsh mutants and an up-regulation of Gdnf and Ret mRNA levels in the Celsr1Crsh/+:Vangl2Lp/+ mutants.	('Crsh', 'Gene', '12614', (270, 274))	('Vangl2Lp/+', 'Gene', (68, 78))	('growth retardation', 'Phenotype', 'HP:0001510', (35, 53))	('Crsh', 'Gene', (350, 354))	('Crsh', 'Gene', (87, 91))	('Crsh', 'Gene', '12614', (350, 354))	('up-regulation', 'PosReg', (295, 308))	('Crsh', 'Gene', '12614', (87, 91))	('Crsh', 'Gene', (275, 279))	('mutants', 'Var', (280, 287))	('dilation', 'CPA', (232, 240))	('Crsh', 'Gene', '12614', (275, 279))	('growth retardation', 'Disease', 'MESH:D006130', (35, 53))	('growth retardation', 'Disease', (35, 53))	('Vangl2Lp/+', 'Gene', '93840', (357, 367))	('Crsh', 'Gene', (92, 96))	('Crsh', 'Gene', (61, 65))	('Crsh', 'Gene', '12614', (92, 96))	('Vangl2Lp/+', 'Gene', (357, 367))	('Crsh', 'Gene', '12614', (61, 65))	('mitotic spindle misorientation', 'CPA', (148, 178))	('Ret', 'Gene', (321, 324))	('Crsh', 'Gene', (105, 109))	('Ret', 'Gene', '19713', (321, 324))	('Gdnf', 'Gene', (312, 316))	('Crsh', 'Gene', '12614', (105, 109))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('148', '163'))	('Gdnf', 'Gene', '14573', (312, 316))	('Vangl2Lp/+', 'Gene', '93840', (68, 78))	('Crsh', 'Gene', (270, 274))	('regulation', 'biological_process', 'GO:0065007', ('298', '308'))
187265	29468160	Moreover, no kidney phenotype has so far been described in Adgrg6 knockout mice, neither in the lines that are embryonic lethal at E11.5 (Patra et al.,) nor in Taconic knockouts of which some are born alive (Monk et al.,).	('Adgrg6', 'Gene', (59, 65))	('E11.5', 'Var', (131, 136))	('mice', 'Species', '10090', (75, 79))
187274	29468160	Previously, it has been demonstrated that it has a well-established role in lung surfactant homeostasis and that its deletion results in glucose intolerance and insulin resistance as well as a subtle vascular phenotype (Nie et al.,; Bridges et al.,; Fukuzawa et al.,; Yang et al.,; Niaudet et al.,).	('insulin resistance', 'CPA', (161, 179))	('lung surfactant homeostasis', 'MPA', (76, 103))	('glucose intolerance', 'Phenotype', 'HP:0001952', (137, 156))	('surfactant homeostasis', 'biological_process', 'GO:0043129', ('81', '103'))	('glucose intolerance', 'Disease', 'MESH:D018149', (137, 156))	('glucose intolerance', 'Disease', (137, 156))	('insulin', 'molecular_function', 'GO:0016088', ('161', '168'))	('results in', 'Reg', (126, 136))	('insulin resistance', 'Phenotype', 'HP:0000855', (161, 179))	('rat', 'Species', '10116', (31, 34))	('deletion', 'Var', (117, 125))
187284	29468160	Moreover, endothelial-specific deletion of Adgrf5/Adgrl4 utilizing VE-Cad-Cre mice, which are known to induce recombination in the endothelium of arteries and capillaries of the glomerulus of adult kidneys (Alva et al.,), resulted in no renal phenotype.	('induce', 'Reg', (103, 109))	('mice', 'Species', '10090', (78, 82))	('Adgrl4', 'Gene', '170757', (50, 56))	('deletion', 'Var', (31, 39))	('Adgrl4', 'Gene', (50, 56))	('renal', 'MPA', (237, 242))	('VE-Cad', 'Gene', '12562', (67, 73))	('VE-Cad', 'Gene', (67, 73))
187317	29468160	CKDs represent an important risk factor for cardiovascular or cerebrovascular diseases and progress toward end-stage renal disease (ESRD) (Eckardt et al.,; Balogun et al.,), which can only be treated by renal replacement therapies (RRT) like hemodialysis, peritoneal dialysis, or transplantation (Eckardt et al.,).	('cardiovascular or cerebrovascular diseases', 'Disease', (44, 86))	('end-stage renal disease', 'Phenotype', 'HP:0003774', (107, 130))	('cardiovascular or cerebrovascular diseases', 'Disease', 'MESH:D002318', (44, 86))	('CKD', 'Phenotype', 'HP:0012622', (0, 3))	('ESRD', 'Disease', (132, 136))	('ESRD', 'Phenotype', 'HP:0003774', (132, 136))	('end-stage renal disease', 'Disease', (107, 130))	('CKDs', 'Var', (0, 4))	('end-stage renal disease', 'Disease', 'MESH:D007676', (107, 130))	('renal disease', 'Phenotype', 'HP:0000112', (117, 130))	('ESRD', 'Disease', 'MESH:D007676', (132, 136))
187332	29468160	Possible causes of ccRCC are mutations in the VHL gene (90%) as well as genetic aberrations of mTOR pathway proteins (Low et al.,; Inamura,; Shingarev and Jaimes,).	('VHL', 'Gene', (46, 49))	('VHL', 'Gene', '22346', (46, 49))	('Inamura', 'Disease', (131, 138))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('rat', 'Species', '10116', (84, 87))	('mutations', 'Var', (29, 38))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('mTOR', 'Gene', (95, 99))	('RCC', 'Disease', (21, 24))	('causes', 'Reg', (9, 15))	('mTOR', 'Gene', '56717', (95, 99))
187333	29468160	Type 1 pRCC is characterized by MET proto-oncogene-activating mutations and type 2 with activation of the NRF2/antioxidant response element pathway due to the increased oxidative stress.	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('oxidative stress', 'MPA', (169, 185))	('activation', 'PosReg', (88, 98))	('pRCC', 'Gene', '94315', (7, 11))	('NRF2', 'Gene', (106, 110))	('increased', 'PosReg', (159, 168))	('pRCC', 'Gene', (7, 11))	('NRF2', 'Gene', '18024', (106, 110))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (159, 185))	('mutations', 'Var', (62, 71))
187350	29468160	ADGRG1 knockdown resulted in melanoma growth inhibition and regression (Ke et al.,), while knockdown of the other 2 aGPCRs reduced lung (ADGRF5) (Tang et al.,) and/or bone metastasis (ADGRE5, ADGRF5) (Ward et al.,; Tang et al.,).	('melanoma growth inhibition', 'Disease', 'MESH:D008545', (29, 55))	('lung', 'CPA', (131, 135))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma growth inhibition', 'Disease', (29, 55))	('ADGRG1', 'Gene', (0, 6))	('bone metastasis', 'CPA', (167, 182))	('knockdown', 'Var', (91, 100))	('regression', 'CPA', (60, 70))	('knockdown', 'Var', (7, 16))	('reduced', 'NegReg', (123, 130))
187370	29468160	Richter and coworkers demonstrated that inhibition of Adgrg2 expression impaired colony formation in vitro (A673, SB-KMS-KS1 and TC-71) and suppressed local tumor growth and metastasis in an immunodeficient mouse xenograft model of human cancer [SB-KMS-KS1/Rag2(-/-)gammaC(-/-)].	('immunodeficient', 'Disease', (191, 206))	('formation', 'biological_process', 'GO:0009058', ('88', '97'))	('TC-71', 'Chemical', '-', (129, 134))	('human', 'Species', '9606', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mouse', 'Species', '10090', (207, 212))	('cancer', 'Disease', (238, 244))	('Adgrg2', 'Gene', '237175', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('inhibition', 'Var', (40, 50))	('suppressed', 'NegReg', (140, 150))	('rat', 'Species', '10116', (29, 32))	('tumor', 'Disease', (157, 162))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('impaired', 'NegReg', (72, 80))	('Rag2', 'Gene', (257, 261))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('colony formation', 'CPA', (81, 97))	('Adgrg2', 'Gene', (54, 60))	('Rag2', 'Gene', '5897', (257, 261))	('immunodeficient', 'Disease', 'MESH:D007153', (191, 206))
187375	29468160	In addition, it has been demonstrated that, despite the large number of MMPs known to be expressed in the healthy kidney (Catania et al.,), changes in a single MMP can cause kidney disease (Cheng et al.,).	('MMP', 'molecular_function', 'GO:0004235', ('160', '163'))	('kidney disease', 'Disease', 'MESH:D007674', (174, 188))	('rat', 'Species', '10116', (32, 35))	('kidney disease', 'Phenotype', 'HP:0000112', (174, 188))	('cause', 'Reg', (168, 173))	('changes', 'Var', (140, 147))	('MMP', 'Gene', (72, 75))	('MMP', 'Gene', '4312;17386;4313;17390;4314;4318;17386', (72, 75))	('MMP', 'Gene', '4312;17386;4313;17390;4314;4318;17386', (160, 163))	('MMPs', 'Gene', '4312;17386;4313;17390;4314;4318;17386', (72, 76))	('kidney disease', 'Disease', (174, 188))	('MMP', 'Gene', (160, 163))	('MMPs', 'Gene', (72, 76))
187379	29468160	Around half of the double-deficient mice died perinatally, while the other half showed growth impairment and all died within 3 weeks to 3 months postnatally.	('growth impairment', 'Disease', 'MESH:D006130', (87, 104))	('growth impairment', 'Phenotype', 'HP:0001510', (87, 104))	('growth impairment', 'Disease', (87, 104))	('mice', 'Species', '10090', (36, 40))	('double-deficient', 'Var', (19, 35))
187382	29468160	Notably, even though Adgrl4 and Adgrf5 are highly expressed in endothelial cells, endothelial-specific deletion of Adgrf5/Adgrl4 utilizing VE-Cad-Cre mice resulted in no renal phenotype.	('renal phenotype', 'CPA', (170, 185))	('mice', 'Species', '10090', (150, 154))	('Adgrl4', 'Gene', '170757', (21, 27))	('Adgrl4', 'Gene', (21, 27))	('VE-Cad', 'Gene', '12562', (139, 145))	('VE-Cad', 'Gene', (139, 145))	('Adgrl4', 'Gene', '170757', (122, 128))	('Adgrl4', 'Gene', (122, 128))	('deletion', 'Var', (103, 111))
187388	29468160	It should be noted that ADGRL4 is downregulated (0.179-fold) and mutated (11%) in chRCC (Table 2), which might be explained, similarly as for ADGRB1, by the different types of vessels (fragile vs. thick-walled; Low et al.,; Inamura,; Shingarev and Jaimes,).	('downregulated', 'NegReg', (34, 47))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('ADGRL4', 'Gene', (24, 30))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('ADGRB1', 'Gene', '107831', (142, 148))	('ADGRB1', 'Gene', (142, 148))	('mutated', 'Var', (65, 72))
187399	29468160	Notably, Shi and coworkers reported recently that more (2-fold) macrophages invaded the kidney of Adgrg3 knockout mice on high-fat diet (HFD) compared to HFD wildtype mice (Shi et al.,).	('knockout', 'Var', (105, 113))	('Adgrg3', 'Gene', (98, 104))	('mice', 'Species', '10090', (114, 118))	('Adgrg3', 'Gene', '54672', (98, 104))	('mice', 'Species', '10090', (167, 171))	('more', 'PosReg', (50, 54))
187401	29468160	Yet, major metabolic phenotyping showed no difference between Adgrg3 knockout and wildtype mice on HFD.	('Adgrg3', 'Gene', '54672', (62, 68))	('mice', 'Species', '10090', (91, 95))	('knockout', 'Var', (69, 77))	('Adgrg3', 'Gene', (62, 68))
187455	27490806	Clear cell RCC is characteristically associated with the loss of function of the VHL (von Hippel-Landau) gene, in the majority of tumours, whether by somatic mutation, chromosomal loss or epigenetic silencing.	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('loss of function', 'NegReg', (57, 73))	('von Hippel-Landau', 'Gene', (86, 103))	('VHL', 'Gene', (81, 84))	('tumours', 'Disease', 'MESH:D009369', (130, 137))	('VHL', 'Gene', '7428', (81, 84))	('tumours', 'Disease', (130, 137))	('chromosomal loss', 'Var', (168, 184))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('von Hippel-Landau', 'Gene', '7428', (86, 103))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('RCC', 'Disease', (11, 14))	('epigenetic silencing', 'Var', (188, 208))
187456	27490806	The VHL gene is on chromosome 3p25 and is an established two-hit tumour suppressor gene; one allele typically inactivated by mutation or promoter methylation, and the other lost due to a large deletion.	('deletion', 'Var', (193, 201))	('tumour', 'Disease', (65, 71))	('inactivated', 'NegReg', (110, 121))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('chromosome', 'cellular_component', 'GO:0005694', ('19', '29'))	('VHL', 'Gene', (4, 7))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('promoter methylation', 'Var', (137, 157))	('VHL', 'Gene', '7428', (4, 7))	('lost', 'NegReg', (173, 177))	('mutation', 'Var', (125, 133))	('methylation', 'biological_process', 'GO:0032259', ('146', '157'))
187493	27490806	With a high frequency of VHL gene mutation in ccRCC, this gene has made an attractive candidate for a possible biomarker for patient outcome.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('mutation', 'Var', (34, 42))	('VHL', 'Gene', (25, 28))	('patient', 'Species', '9606', (125, 132))	('VHL', 'Gene', '7428', (25, 28))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
187494	27490806	Despite extensive evaluation there is currently no evidence that the absence or presence of a VHL mutation or the type of mutation has any predictive or prognostic value in sporadic ccRCC.	('VHL', 'Gene', '7428', (94, 97))	('mutation', 'Var', (98, 106))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('RCC', 'Disease', (184, 187))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('VHL', 'Gene', (94, 97))
187495	27490806	VHL inactivation alone is insufficient for the formation of RCC.	('inactivation', 'Var', (4, 16))	('formation', 'biological_process', 'GO:0009058', ('47', '56'))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('VHL', 'Gene', (0, 3))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('VHL', 'Gene', '7428', (0, 3))
187496	27490806	The genetics of RCC is distinctive in that in addition to mutations in VHL, these tumours have infrequent somatic mutations in known common cancer genes, such as p53 and RAS.	('mutations', 'Var', (58, 67))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('p53', 'Gene', (162, 165))	('RCC', 'Disease', (16, 19))	('VHL', 'Gene', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('RAS', 'Disease', (170, 173))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('VHL', 'Gene', '7428', (71, 74))	('tumours', 'Disease', 'MESH:D009369', (82, 89))	('tumours', 'Disease', (82, 89))	('p53', 'Gene', '7157', (162, 165))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
187498	27490806	The loss of 3p, which is present in >90% of ccRCC would knock out one allele of all the three of these tumour suppressor genes.	('RCC', 'Disease', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('knock out', 'NegReg', (56, 65))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('tumour', 'Disease', (103, 109))	('loss of 3p', 'Var', (4, 14))
187501	27490806	SETD2 knockout is embryonically lethal in mice due to the disruption of embryonic vascular development.	('mice', 'Species', '10090', (42, 46))	('embryonic vascular', 'Disease', (72, 90))	('SETD2', 'Gene', (0, 5))	('embryonic vascular', 'Disease', 'MESH:D000783', (72, 90))	('knockout', 'Var', (6, 14))	('disruption', 'NegReg', (58, 68))	('men', 'Species', '9606', (98, 101))
187503	27490806	Case series have unanimously found that tumours with BAP1 mutations are associated with more aggressive pathological features and a worse cancer-specific survival.	('aggressive pathological features', 'CPA', (93, 125))	('mutations', 'Var', (58, 67))	('cancer', 'Disease', (138, 144))	('tumours', 'Disease', 'MESH:D009369', (40, 47))	('tumours', 'Disease', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('BAP1', 'Gene', '8314', (53, 57))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))	('BAP1', 'Gene', (53, 57))
187504	27490806	In another retrospective case series, BAP1 mutations were associated with the presence of metastatic disease at presentation and advanced clinical stage, when compared with tumours with PBRM1 mutations.	('PBRM1', 'Gene', '55193', (186, 191))	('tumours', 'Disease', 'MESH:D009369', (173, 180))	('tumours', 'Disease', (173, 180))	('associated', 'Reg', (58, 68))	('BAP1', 'Gene', (38, 42))	('metastatic', 'CPA', (90, 100))	('mutations', 'Var', (43, 52))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('PBRM1', 'Gene', (186, 191))	('BAP1', 'Gene', '8314', (38, 42))
187505	27490806	In one cohort of 145 patients with ccRCC between 1998 and 2011, median OS was 4.6 years for patients whose tumours harboured BAP1 mutations vs 10.6 years for patients whose tumours harboured PBRM1 mutations.	('tumours', 'Disease', (107, 114))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('patients', 'Species', '9606', (21, 29))	('RCC', 'Disease', (37, 40))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('patients', 'Species', '9606', (158, 166))	('tumours', 'Disease', 'MESH:D009369', (107, 114))	('PBRM1', 'Gene', '55193', (191, 196))	('BAP1', 'Gene', '8314', (125, 129))	('patients', 'Species', '9606', (92, 100))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('PBRM1', 'Gene', (191, 196))	('tumours', 'Disease', (173, 180))	('BAP1', 'Gene', (125, 129))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('tumours', 'Disease', 'MESH:D009369', (173, 180))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('mutations', 'Var', (130, 139))
187506	27490806	Data regarding the impact of PBRM1 mutations have been inconsistent, with another case series showing that small tumours (<4 cm) with PBRM1 mutations were six times more likely to attain pathological stage pT3a than pT1a.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('small tumours', 'Disease', 'MESH:D055752', (107, 120))	('PBRM1', 'Gene', '55193', (29, 34))	('PBRM1', 'Gene', (134, 139))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('PBRM1', 'Gene', '55193', (134, 139))	('small tumours', 'Disease', (107, 120))	('mutations', 'Var', (140, 149))	('PBRM1', 'Gene', (29, 34))
187508	27490806	BAP1 and PBRM1 mutations are almost always mutually exclusive, occurring together at much lower frequencies than would be expected statistically, but in case series, results for the minority of patients with both mutations have been inconsistent.	('patients', 'Species', '9606', (194, 202))	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (15, 24))	('BAP1', 'Gene', '8314', (0, 4))	('PBRM1', 'Gene', (9, 14))	('PBRM1', 'Gene', '55193', (9, 14))
187510	27490806	In a large retrospective cohort of 1400 patients could be divided into four distinct groups clinically based on their BAP1 and PBRM1 mutational status.	('patients', 'Species', '9606', (40, 48))	('PBRM1', 'Gene', (127, 132))	('BAP1', 'Gene', '8314', (118, 122))	('PBRM1', 'Gene', '55193', (127, 132))	('mutational status', 'Var', (133, 150))	('BAP1', 'Gene', (118, 122))
187513	27490806	The mechanism by which these genes responsible for chromatin remodelling may affect the biology of tumours is not understood, but it is interesting to note that in an assessment of tumour heterogeneity in ccRCC by found three different mutations in SETD2 in different metastatic loci, suggesting a role for these mutations as secondary events in the development of an invasive and metastatic phenotype.	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('chromatin', 'cellular_component', 'GO:0000785', ('51', '60'))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('SETD2', 'Gene', (249, 254))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('tumour', 'Disease', (99, 105))	('RCC', 'Disease', (207, 210))	('tumours', 'Disease', 'MESH:D009369', (99, 106))	('men', 'Species', '9606', (173, 176))	('tumour', 'Disease', 'MESH:D009369', (181, 187))	('tumours', 'Disease', (99, 106))	('mutations', 'Var', (236, 245))	('tumour', 'Disease', (181, 187))	('men', 'Species', '9606', (357, 360))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('51', '72'))
187536	27490806	Pazopanib is associated with higher rates of grade 3 or 4 LFT derangement (17% vs 4%) and is therefore inadvisable in patients with pre-existing bulky liver disease or baseline LFT derangement.	('liver disease', 'Disease', (151, 164))	('men', 'Species', '9606', (69, 72))	('pre', 'molecular_function', 'GO:0003904', ('132', '135'))	('grade 3', 'Disease', (45, 52))	('LFT', 'Gene', '167410', (58, 61))	('liver disease', 'Disease', 'MESH:D008107', (151, 164))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('LFT', 'Gene', (177, 180))	('bulky liver', 'Phenotype', 'HP:0002240', (145, 156))	('liver disease', 'Phenotype', 'HP:0001392', (151, 164))	('men', 'Species', '9606', (188, 191))	('LFT', 'Gene', '167410', (177, 180))	('LFT', 'Gene', (58, 61))	('patients', 'Species', '9606', (118, 126))	('Pazopanib', 'Var', (0, 9))
187567	27490806	Targeting mTOR is of particular relevance in RCC, because in the majority of cases, the loss of pVHL leads to constitutive activation of the HIFs, resulting in the upregulation of many HIF targets associated with angiogenesis, metabolic adaption and metastasis, including VEGF.	('VEGF', 'Gene', (272, 276))	('mTOR', 'Gene', (10, 14))	('pVHL', 'Gene', '7428', (96, 100))	('constitutive', 'MPA', (110, 122))	('pVHL', 'Gene', (96, 100))	('angiogenesis', 'biological_process', 'GO:0001525', ('213', '225'))	('VEGF', 'Gene', '7422', (272, 276))	('loss', 'Var', (88, 92))	('mTOR', 'Gene', '2475', (10, 14))	('activation', 'PosReg', (123, 133))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('upregulation', 'PosReg', (164, 176))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
187568	27490806	Mammalian target of rapamycin has been found to increase HIF at the translational level, therefore inhibition of mTOR can be seen to be particularly useful in RCC.	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('inhibition', 'Var', (99, 109))	('Mammalian target of rapamycin', 'Gene', '2475', (0, 29))	('mTOR', 'Gene', (113, 117))	('mTOR', 'Gene', '2475', (113, 117))	('Mammalian target of rapamycin', 'Gene', (0, 29))	('HIF at the translational', 'MPA', (57, 81))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))	('increase', 'PosReg', (48, 56))
187583	27490806	The anti-FGFR and anti-VEGF TKI dovitinib showed no advantage in the third line over sorafenib in patients previously treated with both a TKI and mTOR inhibitor.	('anti-FGFR', 'Var', (4, 13))	('mTOR', 'Gene', '2475', (146, 150))	('mTOR', 'Gene', (146, 150))	('dovitinib', 'Chemical', 'MESH:C500007', (32, 41))	('patients', 'Species', '9606', (98, 106))	('FGFR', 'molecular_function', 'GO:0005007', ('9', '13'))	('VEGF', 'Gene', (23, 27))	('TKI', 'Var', (28, 31))	('sorafenib', 'Chemical', 'MESH:D000077157', (85, 94))	('VEGF', 'Gene', '7422', (23, 27))
187606	27490806	Hereditary type 1 pRCC is caused by a germline mutation in the c-MET proto-oncogene, and MET mutation or overexpression is commonly found in sporadic pRCC also.	('pRCC', 'Gene', '5546', (18, 22))	('c-MET', 'Gene', '4233', (63, 68))	('caused by', 'Reg', (26, 35))	('pRCC', 'Gene', (150, 154))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('pRCC', 'Gene', (18, 22))	('germline mutation', 'Var', (38, 55))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('pRCC', 'Gene', '5546', (150, 154))	('c-MET', 'Gene', (63, 68))
187608	27490806	Ongoing phase 2 trials are assessing the role of the MET inhibitors savolitinib, cabozantinib and crizotinib in pRCC (NCT02761057 and NCT02127710).	('NCT02761057', 'Var', (118, 129))	('pRCC', 'Gene', (112, 116))	('crizotinib', 'Chemical', 'MESH:D000077547', (98, 108))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('savolitinib', 'Chemical', 'MESH:C000593259', (68, 79))	('pRCC', 'Gene', '5546', (112, 116))	('cabozantinib', 'Chemical', 'MESH:C558660', (81, 93))	('NCT02127710', 'Var', (134, 145))
187618	27490806	Rates of grade 3 or 4 toxicity were similar in the lenvatinib-containing arms and higher than in the everolimus arms (45% for the combination, 44% for lenvatinib and 38% in the everolimus group).	('toxicity', 'Disease', 'MESH:D064420', (22, 30))	('toxicity', 'Disease', (22, 30))	('everolimus', 'Chemical', 'MESH:D000068338', (101, 111))	('everolimus', 'Chemical', 'MESH:D000068338', (177, 187))	('lenvatinib', 'Chemical', 'MESH:C531958', (51, 61))	('lenvatinib', 'Chemical', 'MESH:C531958', (151, 161))	('lenvatinib-containing', 'Var', (51, 72))
187669	27490806	Other early phase studies combining TKIs with TCCI are ongoing including pembrolizumab-pazopanib (NCT02014636), pembrolizumab-axitinib (NCT02133742) and pembrolizumab-lenvatinib (NCT02501096).	('pembrolizumab', 'Chemical', 'MESH:C582435', (73, 86))	('lenvatinib', 'Chemical', 'MESH:C531958', (167, 177))	('pazopanib', 'Chemical', 'MESH:C516667', (87, 96))	('NCT02133742', 'Var', (136, 147))	('pembrolizumab', 'Chemical', 'MESH:C582435', (153, 166))	('NCT02014636', 'Var', (98, 109))	('pembrolizumab-axitinib', 'Disease', 'None', (112, 134))	('pembrolizumab', 'Chemical', 'MESH:C582435', (112, 125))	('pembrolizumab-axitinib', 'Disease', (112, 134))	('TCCI', 'Chemical', '-', (46, 50))
187676	27490806	It has been postulated that high expression levels of programmed cell death 1 ligand (PD-L1) on tumour cell surfaces may be correlated with an enhanced response to nivolumab, as blockade of this pathway restores anti-tumour immunity.	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('response to nivolumab', 'MPA', (152, 173))	('PD-L1', 'Gene', '29126', (86, 91))	('enhanced', 'PosReg', (143, 151))	('tumour', 'Disease', 'MESH:D009369', (217, 223))	('blockade', 'Var', (178, 186))	('tumour immunity', 'Disease', (217, 232))	('ligand', 'molecular_function', 'GO:0005488', ('78', '84'))	('programmed cell death', 'biological_process', 'GO:0012501', ('54', '75'))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('nivolumab', 'Chemical', 'MESH:D000077594', (164, 173))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('tumour', 'Disease', (217, 223))	('expression', 'MPA', (33, 43))	('restores', 'PosReg', (203, 211))	('tumour immunity', 'Disease', 'MESH:D009369', (217, 232))	('PD-L1', 'Gene', (86, 91))	('tumour', 'Disease', (96, 102))
187692	28593993	MYC activation results in highly penetrant pRCC tumours (MYC), while MYC activation, when combined with Vhl and Cdkn2a (Ink4a/Arf) deletion (VIM), produce kidney tumours that approximate human ccRCC.	('kidney tumours', 'Disease', (155, 169))	('pRCC tumours', 'Disease', 'MESH:D009369', (43, 55))	('pRCC tumours', 'Disease', (43, 55))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('kidney tumours', 'Disease', 'MESH:D007680', (155, 169))	('RCC', 'Disease', (44, 47))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('human', 'Species', '9606', (187, 192))	('produce', 'Reg', (147, 154))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('tumours', 'Phenotype', 'HP:0002664', (162, 169))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('RCC', 'Disease', (195, 198))	('deletion', 'Var', (131, 139))
187697	28593993	Here, the authors generate two mouse models of the most common RCC subtypes: the human papillary RCC through MYC activation and clear cell RCC through MYC activation combined with Vhl and Cdkn2a deletion.	('RCC', 'Disease', (63, 66))	('RCC', 'Disease', (97, 100))	('MYC', 'Gene', (151, 154))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('mouse', 'Species', '10090', (31, 36))	('MYC', 'MPA', (109, 112))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('activation', 'PosReg', (113, 123))	('deletion', 'Var', (195, 203))	('Cdkn2a', 'Gene', (188, 194))	('human', 'Species', '9606', (81, 86))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
187700	28593993	Inherited RCC can be caused by germline mutations in multiple genes that are linked to specific histologic subtypes.	('RCC', 'Disease', (10, 13))	('RCC', 'Disease', 'MESH:C538614', (10, 13))	('caused by', 'Reg', (21, 30))	('germline mutations', 'Var', (31, 49))
187704	28593993	The von Hippel-Lindau tumour suppressor protein (pVHL) is broadly inactivated (~80%) in sporadic ccRCC by either mutation or promoter hypermethylation and its tumour suppressor activity is dependent on its downregulation of the alpha subunits of the hypoxia-inducible factor (HIFalpha) family of transcription factors and in particular HIF2alpha (refs).	('HIF2alpha', 'Gene', '13819', (336, 345))	('tumour', 'Disease', 'MESH:D009369', (22, 28))	('inactivated', 'NegReg', (66, 77))	('tumour', 'Disease', (22, 28))	('downregulation', 'NegReg', (206, 220))	('RCC', 'Disease', (99, 102))	('mutation', 'Var', (113, 121))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('HIF2alpha', 'Gene', (336, 345))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('von Hippel-Lindau tumour', 'Disease', (4, 28))	('promoter hypermethylation', 'Var', (125, 150))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumour', 'Disease', 'MESH:D009369', (159, 165))	('transcription', 'biological_process', 'GO:0006351', ('296', '309'))	('HIFalpha', 'Gene', (276, 284))	('tumour', 'Disease', (159, 165))	('hypoxia', 'Disease', (250, 257))	('pVHL', 'Gene', (49, 53))	('HIFalpha', 'Gene', '15251;13819', (276, 284))	('pVHL', 'Gene', '22346', (49, 53))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (4, 28))	('hypoxia', 'Disease', 'MESH:D000860', (250, 257))
187706	28593993	ccRCC has a relatively low mutation burden relative to other solid tumours but does have characteristic large deletions and gains of chromosomes 3p, 14q and 5q, respectively, as well as more focal gains and losses of 8q24 (harbouring MYC) and 9p21 (harbouring CDKN2A), respectively.	('8q24', 'Gene', (217, 221))	('gains', 'PosReg', (124, 129))	('RCC', 'Disease', (2, 5))	('losses', 'NegReg', (207, 213))	('solid tumours', 'Disease', 'MESH:D009369', (61, 74))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('gains', 'PosReg', (197, 202))	('9p21', 'Gene', (243, 247))	('solid tumours', 'Disease', (61, 74))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('deletions', 'Var', (110, 119))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))
187708	28593993	Gain of 8q, as assessed by classic cytogenetics, is associated with a high risk of lymph node and distant metastases and is an independent prognostic factor.	('metastases', 'Disease', 'MESH:D009362', (106, 116))	('metastases', 'Disease', (106, 116))	('Gain', 'Var', (0, 4))
187720	28593993	MYC mice had a significantly shortened survival relative to controls (Fig.	('MYC', 'Var', (0, 3))	('survival', 'CPA', (39, 47))	('shortened', 'NegReg', (29, 38))	('mice', 'Species', '10090', (4, 8))
187744	28593993	To model the interplay of genomic events observed in human RCC, we next examined the phenotypes of kidney specific Vhl inactivation in combination with MYC overexpression or combined MYC overexpression and Ink/Arf deletion.	('deletion', 'Var', (214, 222))	('kidney specific', 'MPA', (99, 114))	('human', 'Species', '9606', (53, 58))	('inactivation', 'NegReg', (119, 131))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))
187756	28593993	Therefore, while Vhl loss combined with MYC activation is sufficient to induce modest clear cell changes, Vhl loss combined with MYC activation and Ink/Arf deletion induces bona fide clear cell RCC (Table 1).	('loss', 'NegReg', (110, 114))	('Ink/Arf', 'Gene', (148, 155))	('RCC', 'Disease', 'MESH:C538614', (194, 197))	('induces', 'Reg', (165, 172))	('RCC', 'Disease', (194, 197))	('Vhl', 'Gene', (106, 109))	('deletion', 'Var', (156, 164))
187757	28593993	We next examined whether human ccRCC tumours with similar genomic characteristics (VHL inactivation; VHL inactivation and MYC activation; and VHL inactivation, CDKN2A loss and MYC activation) have similar outcomes as those seen in our mouse models.	('VHL', 'Gene', (101, 104))	('ccRCC tumours', 'Disease', 'MESH:D009369', (31, 44))	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('CDKN2A', 'Gene', (160, 166))	('inactivation', 'NegReg', (87, 99))	('human', 'Species', '9606', (25, 30))	('inactivation', 'Var', (146, 158))	('loss', 'NegReg', (167, 171))	('inactivation', 'NegReg', (105, 117))	('mouse', 'Species', '10090', (235, 240))	('ccRCC tumours', 'Disease', (31, 44))	('MYC', 'MPA', (122, 125))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('VHL', 'Gene', (142, 145))
187758	28593993	Of TCGA KIRC tumours (n=525), 87, 13 and 31% had VHL inactivation, MYC activation and CDKN2A deletion, respectively (Fig.	('VHL', 'MPA', (49, 52))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('MYC', 'MPA', (67, 70))	('activation', 'PosReg', (71, 81))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('tumours', 'Disease', (13, 20))	('inactivation', 'NegReg', (53, 65))	('deletion', 'Var', (93, 101))	('CDKN2A', 'Gene', (86, 92))
187759	28593993	We further classified these patients as V (n=286, 54%), VM (n=26, 5%) and VIM (n=32, 6.1%) and noted that VM and VIM patients had a significantly decreased survival relative to V patients (P=0.005 and P=5.086 x 10-9, respectively (Fig.	('survival', 'MPA', (156, 164))	('decreased', 'NegReg', (146, 155))	('VIM', 'Var', (113, 116))	('patients', 'Species', '9606', (179, 187))	('patients', 'Species', '9606', (117, 125))	('patients', 'Species', '9606', (28, 36))
187774	28593993	There were a large number of genes that were differentially regulated (increased or decreased greater than two-fold; t-test FDR<0.05) by MYC activation (Dox) in both VM-3055 (799 up and 2491 down) and VIM-3039 (1017 up and 2159 down) cells (Fig.	('1017', 'Var', (211, 215))	('MYC', 'Protein', (137, 140))	('VIM-3039', 'CellLine', 'CVCL:X276', (201, 209))	('799', 'Var', (175, 178))	('Dox', 'Chemical', '-', (153, 156))	('decreased', 'NegReg', (84, 93))	('activation', 'PosReg', (141, 151))
187796	28593993	As predicted, VIM-3039 cells had significantly increased matrigel invasion (Fig.	('VIM-3039', 'CellLine', 'CVCL:X276', (14, 22))	('increased', 'PosReg', (47, 56))	('matrigel invasion', 'CPA', (57, 74))	('VIM-3039', 'Var', (14, 22))
187797	28593993	Therefore, Ink4a/Arf inactivation appears to facilitate EMT, invasion and metastases and the metastatic phenotype seen in vivo is recapitulated in vitro.	('inactivation', 'Var', (21, 33))	('EMT', 'CPA', (56, 59))	('facilitate', 'PosReg', (45, 55))	('EMT', 'biological_process', 'GO:0001837', ('56', '59'))	('metastases', 'Disease', (74, 84))	('Ink4a/Arf', 'Gene', (11, 20))	('metastases', 'Disease', 'MESH:D009362', (74, 84))
187805	28593993	Our own studies highlight the role of MYC in renal tumorigenesis and demonstrate that MYC activation is sufficient to generate papillary RCC and that when combined with Vhl and Ink4a/Arf inactivation results in bona fide clear cell renal cell carcinoma.	('results in', 'Reg', (200, 210))	('MYC', 'Gene', (86, 89))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (221, 252))	('clear cell renal cell carcinoma', 'Disease', (221, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('inactivation', 'Var', (187, 199))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (221, 252))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (232, 252))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))
187808	28593993	Combined inactivation of Vhl with Trp53 does appear to induce renal tumours, which have clear cell changes but not bona fide clear cell RCC histology.	('renal tumours', 'Disease', (62, 75))	('Trp53', 'Gene', (34, 39))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('renal tumour', 'Phenotype', 'HP:0009726', (62, 74))	('induce', 'Reg', (55, 61))	('Trp53', 'Gene', '7157', (34, 39))	('inactivation', 'Var', (9, 21))	('Vhl', 'Gene', (25, 28))	('renal tumours', 'Disease', 'MESH:D007680', (62, 75))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))
187809	28593993	A recent report demonstrated that combined inactivation of Vhl with Bap1 results in renal tumours with clear cell histology.	('Bap1', 'Gene', (68, 72))	('renal tumours', 'Disease', 'MESH:D007680', (84, 97))	('combined', 'Interaction', (34, 42))	('results in', 'Reg', (73, 83))	('renal tumour', 'Phenotype', 'HP:0009726', (84, 96))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('clear cell histology', 'CPA', (103, 123))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('renal tumours', 'Disease', (84, 97))	('Vhl', 'Gene', (59, 62))	('Bap1', 'Gene', '104416', (68, 72))	('inactivation', 'Var', (43, 55))
187810	28593993	However, while inactivation of other tumour suppressor genes such as Flcn, Tsc1 or Fh results in renal carcinomas, they are rarely of the clear cell histologic subtype and they exhibit long latency, impacting their utility for routine investigation.	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('renal carcinomas', 'Disease', (97, 113))	('tumour', 'Disease', (37, 43))	('Flcn', 'Gene', (69, 73))	('Tsc1', 'Gene', (75, 79))	('renal carcinomas', 'Phenotype', 'HP:0005584', (97, 113))	('Flcn', 'Gene', '216805', (69, 73))	('Tsc1', 'Gene', '64930', (75, 79))	('renal carcinomas', 'Disease', 'MESH:C538614', (97, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('results in', 'Reg', (86, 96))	('inactivation', 'Var', (15, 27))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
187821	28593993	VHL inactivation results in the stabilization of the alpha subunits of the hypoxia-inducible factor alpha (HIF) family of transcription factors of which HIF2alpha is thought to be a key oncogenic driver of ccRCC tumorigenesis, while emerging evidence suggests that HIF1alpha may be a tumour suppressor gene.	('hypoxia', 'Disease', (75, 82))	('hypoxia', 'Disease', 'MESH:D000860', (75, 82))	('tumour', 'Disease', 'MESH:D009369', (284, 290))	('inactivation', 'Var', (4, 16))	('transcription', 'biological_process', 'GO:0006351', ('122', '135'))	('HIF2alpha', 'Gene', (153, 162))	('stabilization', 'MPA', (32, 45))	('HIF1alpha', 'Gene', '15251', (265, 274))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('tumour', 'Disease', (284, 290))	('RCC', 'Disease', (208, 211))	('HIF1alpha', 'Gene', (265, 274))	('VHL', 'Gene', (0, 3))	('HIF2alpha', 'Gene', '13819', (153, 162))	('tumour', 'Phenotype', 'HP:0002664', (284, 290))
187824	28593993	Our studies demonstrate that Ink4a/Arf inactivation promotes liver metastases in an autochthonous ccRCC GEM model and that Ink4a/Arf loss is associated with gene expression patterns of EMT.	('gene expression', 'biological_process', 'GO:0010467', ('157', '172'))	('EMT', 'biological_process', 'GO:0001837', ('185', '188'))	('metastases', 'Disease', (67, 77))	('Ink4a/Arf', 'Gene', (123, 132))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('loss', 'NegReg', (133, 137))	('promotes', 'PosReg', (52, 60))	('metastases', 'Disease', 'MESH:D009362', (67, 77))	('inactivation', 'Var', (39, 51))	('RCC', 'Disease', (100, 103))	('Ink4a/Arf', 'Gene', (29, 38))
187876	28659173	Depletion of MRCCAT1 inhibites ccRCC cells proliferation, migration, and invasion in vitro, and ccRCC metastasis in vivo.	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('RCC', 'Disease', (14, 17))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))	('RCC', 'Disease', (33, 36))	('Depletion', 'Var', (0, 9))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (31, 36))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('invasion', 'CPA', (73, 81))	('inhibites', 'NegReg', (21, 30))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('migration', 'CPA', (58, 67))
187924	28659173	The chromatin was immunoprecipitated using anti-EZH2 (Millipore), anti-H3K27me3 (Millipore), anti-RNA Pol II antibodies.	('RNA', 'cellular_component', 'GO:0005562', ('98', '101'))	('EZH2', 'Gene', '2146', (48, 52))	('chromatin', 'cellular_component', 'GO:0000785', ('4', '13'))	('EZH2', 'Gene', (48, 52))	('anti-H3K27me3', 'Var', (66, 79))
187936	28659173	Among the upregulated lncRNAs in metastatic ccRCC, TI18530REF_ELL2_009 (ENST00000505584) is found to be significantly higher in 34 metastatic ccRCC tissues than that in 34 non-metastatic ccRCC tissues (Fig.	('higher', 'PosReg', (118, 124))	('TI18530REF_ELL2_009', 'Var', (51, 70))	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('RCC', 'Disease', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('upregulated', 'PosReg', (10, 21))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('ccRCC', 'Phenotype', 'HP:0006770', (187, 192))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('RCC', 'Disease', (144, 147))	('RCC', 'Disease', (189, 192))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))
187937	28659173	As a result, we named TI18530REF_ELL2_009 as metastatic renal cell carcinoma-associated transcript 1 (MRCCAT1).	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('metastatic renal cell carcinoma', 'Disease', 'MESH:C538445', (45, 76))	('metastatic renal cell carcinoma', 'Disease', (45, 76))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (56, 76))	('TI18530REF_ELL2_009', 'Var', (22, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))
187940	28659173	These data suggest that high MRCCAT1 expression may have an important role in ccRCC progression and metastasis.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('RCC', 'Disease', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('high', 'Var', (24, 28))	('expression', 'MPA', (37, 47))	('metastasis', 'CPA', (100, 110))
187943	28659173	Additionally, univariate analysis showed that patients with high MRCCAT1 expression, metastases, high Fuhrman grade, and large tumor size were significantly associated with an increased risk of cancer-related death.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('high Fuhrman grade', 'CPA', (97, 115))	('associated', 'Reg', (157, 167))	('cancer', 'Disease', (194, 200))	('patients', 'Species', '9606', (46, 54))	('death', 'Disease', 'MESH:D003643', (209, 214))	('tumor', 'Disease', (127, 132))	('high', 'Var', (60, 64))	('death', 'Disease', (209, 214))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('metastases', 'Disease', (85, 95))	('expression', 'MPA', (73, 83))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('metastases', 'Disease', 'MESH:D009362', (85, 95))
187944	28659173	Multivariate analysis identified high expression level of MRCCAT1 as an independent prognostic factor for ccRCC patients (Table 2).	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('high', 'Var', (33, 37))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('patients', 'Species', '9606', (112, 120))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
187955	28659173	CCK-8 assay showed that MRCCAT1 knockdown inhibites the proliferation rate of 786-O and Caki-1 cells (Fig.	('Caki-1', 'CellLine', 'CVCL:0234', (88, 94))	('proliferation rate', 'CPA', (56, 74))	('knockdown', 'Var', (32, 41))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('inhibites', 'NegReg', (42, 51))	('RCC', 'Disease', (25, 28))
187956	28659173	Wound healing assay demonstrated that MRCCAT1 knockdown suppresses the migration ability of ccRCC cells compared with NC group (Fig.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('knockdown', 'Var', (46, 55))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('Wound healing', 'biological_process', 'GO:0042060', ('0', '13'))	('RCC', 'Disease', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('migration ability of', 'CPA', (71, 91))	('suppresses', 'NegReg', (56, 66))
187957	28659173	Moreover, Transwell invasion assays revealed that MRCCAT1 knockdown inhibites ccRCC cells invasion (Fig.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('inhibites', 'NegReg', (68, 77))	('knockdown', 'Var', (58, 67))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
187961	28659173	Furthermore, MRCCAT1 overexpression promotes the migration and invasion of ccRCC cells (Fig.	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('RCC', 'Disease', (14, 17))	('overexpression', 'Var', (21, 35))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('migration', 'CPA', (49, 58))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('invasion', 'CPA', (63, 71))	('promotes', 'PosReg', (36, 44))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
187964	28659173	Compared with control group, bioluminescent signals were lower in the MRCCAT1 knockdown group (Fig.	('knockdown', 'Var', (78, 87))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('bioluminescent signals', 'MPA', (29, 51))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('lower', 'NegReg', (57, 62))
187965	28659173	Six weeks later, less and smaller metastatic lesions were microscopically detected in the lungs of nude mice inoculated with MRCCAT1 knockdown cells compared with those inoculated with control cells (Fig.	('metastatic lesions', 'CPA', (34, 52))	('knockdown', 'Var', (133, 142))	('nude mice', 'Species', '10090', (99, 108))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('smaller', 'NegReg', (26, 33))	('RCC', 'Disease', 'MESH:C538614', (126, 129))
187971	28659173	6b, Real-time PCR data showed that NPR3 mRNA level is significantly increased in MRCCAT1 knockdown 786-O and Caki-1 cells.	('NPR3', 'Gene', '4883', (35, 39))	('Caki-1', 'CellLine', 'CVCL:0234', (109, 115))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('knockdown', 'Var', (89, 98))	('NPR3', 'Gene', (35, 39))	('increased', 'PosReg', (68, 77))
187973	28659173	Furthermore, western blot analysis revealed that the protein level of NPR3 is markedly increased in response to MRCCAT1 knockdown in 786-O and Caki-1 cells (Fig.	('increased', 'PosReg', (87, 96))	('Caki-1', 'CellLine', 'CVCL:0234', (143, 149))	('NPR3', 'Gene', '4883', (70, 74))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('knockdown', 'Var', (120, 129))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('protein level', 'MPA', (53, 66))	('NPR3', 'Gene', (70, 74))
187977	28659173	6f and g, induction of NPR3 could abolish the role of MRCCAT1 in promoting cell proliferation.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('promoting', 'PosReg', (65, 74))	('RCC', 'Disease', (55, 58))	('NPR3', 'Gene', (23, 27))	('abolish', 'NegReg', (34, 41))	('induction', 'Var', (10, 19))	('NPR3', 'Gene', '4883', (23, 27))	('cell proliferation', 'biological_process', 'GO:0008283', ('75', '93'))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('cell proliferation', 'CPA', (75, 93))
188003	28659173	Additionally, multivariate analysis showed that high expression of MRCCAT1, tumor size and metastases were each independent risk factors for overall patient survival rate following surgery.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('metastases', 'Disease', (91, 101))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('patient', 'Species', '9606', (149, 156))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('high expression', 'Var', (48, 63))	('metastases', 'Disease', 'MESH:D009362', (91, 101))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
188006	28659173	MRCCAT1 knockdown could suppress ccRCC cell invasion in vitro and metastasis in vivo.	('metastasis', 'CPA', (66, 76))	('RCC', 'Disease', (35, 38))	('knockdown', 'Var', (8, 17))	('RCC', 'Disease', 'MESH:C538614', (1, 4))	('RCC', 'Disease', (1, 4))	('RCC', 'Phenotype', 'HP:0005584', (1, 4))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('suppress', 'NegReg', (24, 32))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
188011	28659173	Further study found that MRCCAT1 overexpression could decrease the mRNA levels of NPR3.	('decrease', 'NegReg', (54, 62))	('NPR3', 'Gene', (82, 86))	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('overexpression', 'Var', (33, 47))	('NPR3', 'Gene', '4883', (82, 86))
188035	28396841	Further experiments illustrated that SMURF1 knockdown significantly inhibited growth and metastasis of 769P cells, while SMURF1 overexpression promoted proliferation, migration and invasion in OSRC-2 cells.	('SMURF1', 'Gene', '57154', (121, 127))	('SMURF1', 'Gene', (121, 127))	('OSRC-2', 'CellLine', 'CVCL:1901', (193, 199))	('proliferation', 'CPA', (152, 165))	('promoted', 'PosReg', (143, 151))	('inhibited', 'NegReg', (68, 77))	('SMURF1', 'Gene', '57154', (37, 43))	('SMURF1', 'Gene', (37, 43))	('migration', 'CPA', (167, 176))	('invasion', 'CPA', (181, 189))	('knockdown', 'Var', (44, 53))
188088	28396841	p-AKT (Ser473), AKT, p-mTOR (Ser2448), mTOR, p-ERK (Thr202/Tyr204), ERK and RSK1 were obtained from Cell Signaling Technology.	('AKT', 'Gene', '207', (2, 5))	('ERK', 'Gene', (68, 71))	('Ser', 'cellular_component', 'GO:0005790', ('29', '32'))	('Thr202/Tyr204', 'Var', (52, 65))	('AKT', 'Gene', '207', (16, 19))	('Thr202', 'Chemical', '-', (52, 58))	('Ser', 'cellular_component', 'GO:0005790', ('7', '10'))	('RSK1', 'Gene', (76, 80))	('Ser2448', 'Chemical', '-', (29, 36))	('ERK', 'Gene', '5594', (47, 50))	('mTOR', 'Gene', (39, 43))	('AKT', 'Gene', (2, 5))	('mTOR', 'Gene', (23, 27))	('Tyr204', 'Chemical', '-', (59, 65))	('ERK', 'molecular_function', 'GO:0004707', ('47', '50'))	('Ser473', 'Var', (7, 13))	('Ser2448', 'Var', (29, 36))	('Ser473', 'Chemical', '-', (7, 13))	('Signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('p-ERK', 'Gene', '9451', (45, 50))	('p-ERK', 'Gene', (45, 50))	('RSK1', 'Gene', '6195', (76, 80))	('ERK', 'Gene', '5594', (68, 71))	('AKT', 'Gene', (16, 19))	('mTOR', 'Gene', '2475', (39, 43))	('mTOR', 'Gene', '2475', (23, 27))	('ERK', 'Gene', (47, 50))	('ERK', 'molecular_function', 'GO:0004707', ('68', '71'))
188106	28396841	We found that loss of SMURF1 restrained cell growth as compared with control in 769P cells (P < 0.05, Fig.	('loss', 'Var', (14, 18))	('cell growth', 'CPA', (40, 51))	('restrained', 'NegReg', (29, 39))	('SMURF1', 'Gene', '57154', (22, 28))	('cell growth', 'biological_process', 'GO:0016049', ('40', '51'))	('SMURF1', 'Gene', (22, 28))
188109	28396841	The results suggested that SMURF1 knockdown caused a prominent reduction of migration and invasion of 769P cells as compared with control cells (P < 0.05, Fig.	('SMURF1', 'Gene', '57154', (27, 33))	('migration', 'CPA', (76, 85))	('reduction', 'NegReg', (63, 72))	('knockdown', 'Var', (34, 43))	('invasion', 'CPA', (90, 98))	('SMURF1', 'Gene', (27, 33))
188110	28396841	Taken together, the results prove that loss of SMURF1 can dramatically hold up ccRCC cell growth and metastasis in vitro.	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('SMURF1', 'Gene', (47, 53))	('loss', 'Var', (39, 43))	('SMURF1', 'Gene', '57154', (47, 53))	('hold up', 'PosReg', (71, 78))	('cell growth', 'biological_process', 'GO:0016049', ('85', '96'))
188114	28396841	Furthermore, wound healing assays indicated SMURF1 overexpression facilitated the migration of OSRC-2 cells (Fig.	('migration of OSRC-2 cells', 'CPA', (82, 107))	('overexpression', 'Var', (51, 65))	('wound healing', 'biological_process', 'GO:0042060', ('13', '26'))	('OSRC-2', 'CellLine', 'CVCL:1901', (95, 101))	('SMURF1', 'Gene', (44, 50))	('SMURF1', 'Gene', '57154', (44, 50))	('facilitated', 'PosReg', (66, 77))
188118	28396841	Furthermore, DAB2IP knockdown leads to the activation of the ERK/RSK1 and PI3K/AKT/mTOR pathways in RCC cells 18.	('mTOR', 'Gene', (83, 87))	('PI3', 'Gene', '5266', (74, 77))	('AKT', 'Gene', (79, 82))	('activation', 'PosReg', (43, 53))	('knockdown', 'Var', (20, 29))	('ERK', 'Gene', (61, 64))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('mTOR', 'Gene', '2475', (83, 87))	('PI3', 'Gene', (74, 77))	('AKT', 'Gene', '207', (79, 82))	('DAB2IP', 'Gene', '153090', (13, 19))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('PI3K', 'molecular_function', 'GO:0016303', ('74', '78'))	('RSK1', 'Gene', (65, 69))	('ERK', 'Gene', '5594', (61, 64))	('DAB2IP', 'Gene', (13, 19))	('RCC', 'Disease', (100, 103))	('RSK1', 'Gene', '6195', (65, 69))	('ERK', 'molecular_function', 'GO:0004707', ('61', '64'))
188120	28396841	Interestingly, we found that the expression of DAB2IP was increased and the levels of phosphorylated AKT, mTOR, ERK and RSK1 were remarkably decreased after SMURF1 knockdown in 769P cells.	('SMURF1', 'Gene', '57154', (157, 163))	('AKT', 'Gene', '207', (101, 104))	('increased', 'PosReg', (58, 67))	('ERK', 'molecular_function', 'GO:0004707', ('112', '115'))	('DAB2IP', 'Gene', (47, 53))	('ERK', 'Gene', '5594', (112, 115))	('AKT', 'Gene', (101, 104))	('decreased', 'NegReg', (141, 150))	('ERK', 'Gene', (112, 115))	('RSK1', 'Gene', (120, 124))	('knockdown', 'Var', (164, 173))	('expression', 'MPA', (33, 43))	('mTOR', 'Gene', (106, 110))	('DAB2IP', 'Gene', '153090', (47, 53))	('mTOR', 'Gene', '2475', (106, 110))	('RSK1', 'Gene', '6195', (120, 124))	('SMURF1', 'Gene', (157, 163))
188121	28396841	SMURF1 overexpression led to a decreased level of DAB2IP and increased activation of the ERK/RSK1 and PI3K/AKT/mTOR signaling pathways (Fig.	('SMURF1', 'Gene', '57154', (0, 6))	('ERK', 'Gene', '5594', (89, 92))	('RSK1', 'Gene', (93, 97))	('PI3K', 'molecular_function', 'GO:0016303', ('102', '106'))	('DAB2IP', 'Gene', (50, 56))	('ERK', 'molecular_function', 'GO:0004707', ('89', '92'))	('ERK', 'Gene', (89, 92))	('SMURF1', 'Gene', (0, 6))	('PI3', 'Gene', '5266', (102, 105))	('RSK1', 'Gene', '6195', (93, 97))	('AKT', 'Gene', (107, 110))	('mTOR', 'Gene', (111, 115))	('activation', 'PosReg', (71, 81))	('decreased', 'NegReg', (31, 40))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))	('overexpression', 'Var', (7, 21))	('mTOR', 'Gene', '2475', (111, 115))	('DAB2IP', 'Gene', '153090', (50, 56))	('PI3', 'Gene', (102, 105))	('AKT', 'Gene', '207', (107, 110))
188125	28396841	Dysregulation of SMURF1 is a common event found in various cancers including pancreatic cancer 9, 10, breast cancer 7, 8, ovarian cancer 14 and colorectal cancer 13.	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('ovarian cancer', 'Disease', 'MESH:D010051', (122, 136))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('colorectal cancer', 'Disease', 'MESH:D015179', (144, 161))	('SMURF1', 'Gene', (17, 23))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))	('breast cancer', 'Disease', (102, 115))	('colorectal cancer', 'Disease', (144, 161))	('ovarian cancer', 'Disease', (122, 136))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('pancreatic cancer', 'Disease', (77, 94))	('ovarian cancer', 'Phenotype', 'HP:0100615', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('SMURF1', 'Gene', '57154', (17, 23))	('colorectal cancer', 'Phenotype', 'HP:0003003', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancers', 'Disease', (59, 66))
188134	28396841	Then, we explored the biology of SMURF1 in ccRCC cells and showed that loss of SMURF1 expression could inhibit cell growth and metastasis in vitro.	('SMURF1', 'Gene', (79, 85))	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('cell growth', 'biological_process', 'GO:0016049', ('111', '122'))	('SMURF1', 'Gene', '57154', (79, 85))	('SMURF1', 'Gene', (33, 39))	('expression', 'MPA', (86, 96))	('SMURF1', 'Gene', '57154', (33, 39))	('loss', 'Var', (71, 75))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('inhibit', 'NegReg', (103, 110))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
188137	28396841	Therefore, targeting SMURF1 may represent a favorable therapeutic strategy for ccRCC treatment.	('SMURF1', 'Gene', '57154', (21, 27))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('targeting', 'Var', (11, 20))	('SMURF1', 'Gene', (21, 27))
188138	28396841	We have shown that loss of SMURF1 up-regulated DAB2IP expression and down-regulated phosphorylated AKT, mTOR, ERK and RSK1.	('mTOR', 'Gene', (104, 108))	('expression', 'MPA', (54, 64))	('mTOR', 'Gene', '2475', (104, 108))	('up-regulated', 'PosReg', (34, 46))	('ERK', 'Gene', (110, 113))	('SMURF1', 'Gene', '57154', (27, 33))	('DAB2IP', 'Gene', (47, 53))	('RSK1', 'Gene', (118, 122))	('AKT', 'Gene', '207', (99, 102))	('RSK1', 'Gene', '6195', (118, 122))	('ERK', 'molecular_function', 'GO:0004707', ('110', '113'))	('phosphorylated', 'MPA', (84, 98))	('down-regulated', 'NegReg', (69, 83))	('loss', 'Var', (19, 23))	('AKT', 'Gene', (99, 102))	('DAB2IP', 'Gene', '153090', (47, 53))	('ERK', 'Gene', '5594', (110, 113))	('SMURF1', 'Gene', (27, 33))
188140	28396841	The expression of DAB2IP mRNA is regulated by DNA methylation in RCC, and DAB2IP CpG1 confers a poor survival of patients 20.	('DAB2IP', 'Gene', (18, 24))	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('DAB2IP', 'Gene', '153090', (18, 24))	('DNA methylation', 'Var', (46, 61))	('patients', 'Species', '9606', (113, 121))	('expression', 'MPA', (4, 14))	('DAB2IP', 'Gene', (74, 80))	('DAB2IP', 'Gene', '153090', (74, 80))	('poor', 'NegReg', (96, 100))	('DNA methylation', 'biological_process', 'GO:0006306', ('46', '61'))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
188163	31689495	Molecular pathway elucidation, genomic studies, and systematic genetics screens reported over the last two decades have identified several FH-inactivation driven pathways alterations, as well as rationally conceived treatment strategies that specifically target FH-/- tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Disease', (268, 273))	('FH', 'Gene', '2271', (139, 141))	('FH', 'Gene', '2271', (262, 264))	('alterations', 'Var', (171, 182))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
188184	31689495	Enzymatic assay confirmed that the mutations ablated FH enzymatic function and that the mutation follows the Knudson's two hit hypothesis.	('mutation', 'Var', (88, 96))	('ablated', 'NegReg', (45, 52))	('FH', 'Gene', '2271', (53, 55))	('mutations', 'Var', (35, 44))
188188	31689495	Since the molecular mechanism of VHL syndrome was well characterized, it was hypothesized that FH, SDH, and VHL mutations all cause dysregulation to the same pathway.	('VHL', 'Gene', '7428', (108, 111))	('dysregulation', 'MPA', (132, 145))	('SDH', 'Gene', (99, 102))	('cause', 'Reg', (126, 131))	('VHL', 'Gene', (33, 36))	('VHL syndrome', 'Disease', (33, 45))	('mutations', 'Var', (112, 121))	('VHL', 'Gene', '7428', (33, 36))	('SDH', 'Gene', '6390', (99, 102))	('VHL syndrome', 'Disease', 'MESH:D006623', (33, 45))	('FH', 'Gene', '2271', (95, 97))	('VHL', 'Gene', (108, 111))
188197	31689495	These results point to several inconsistencies as to why FH mutation is more effective at activating HIF1A in fibroids as opposed to renal tumors, and why SDH mutant HPGL tumors show more consistent HIF1A activation.	('mutation', 'Var', (60, 68))	('SDH', 'Gene', '6390', (155, 158))	('renal tumors', 'Disease', 'MESH:D007674', (133, 145))	('mutant', 'Var', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('HPGL tumors', 'Disease', 'MESH:D009369', (166, 177))	('FH', 'Gene', '2271', (57, 59))	('renal tumors', 'Disease', (133, 145))	('SDH', 'Gene', (155, 158))	('activating', 'MPA', (90, 100))	('HPGL tumors', 'Disease', (166, 177))	('HIF1A', 'Gene', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('renal tumors', 'Phenotype', 'HP:0009726', (133, 145))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
188198	31689495	To investigate tumorigenesis events that take place following biallelic FH inactivation, Pollard and co-workers developed a mouse model of Fh1 (mouse homolog of human FH) knockout.	('inactivation', 'Var', (75, 87))	('human', 'Species', '9606', (161, 166))	('mouse', 'Species', '10090', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('FH', 'Gene', '2271', (72, 74))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mouse', 'Species', '10090', (124, 129))	('knockout', 'Var', (171, 179))	('Fh1', 'Gene', (139, 142))	('tumor', 'Disease', (15, 20))	('FH', 'Gene', '2271', (167, 169))
188200	31689495	Thus, to investigate kidney tumorigenesis following Fh1 knockout, they conditionally knocked out Fh1 in the kidney using Ksp1.3/Cre.	('tumor', 'Disease', (28, 33))	('Fh1', 'Gene', (97, 100))	('knocked', 'Var', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
188202	31689495	None of the mice developed kidney tumors and immunohistochemical analyses showed an increase in nuclear HIF1A staining, and a moderate increase in nuclear HIF2A staining in the Fh1 knockout renal cyst.	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('increase', 'PosReg', (135, 143))	('kidney tumors', 'Disease', (27, 40))	('Fh1', 'Gene', (177, 180))	('renal cyst', 'Phenotype', 'HP:0000107', (190, 200))	('kidney tumors', 'Phenotype', 'HP:0009726', (27, 40))	('knockout', 'Var', (181, 189))	('nuclear HIF2A staining', 'MPA', (147, 169))	('kidney tumors', 'Disease', 'MESH:D007680', (27, 40))	('mice', 'Species', '10090', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
188204	31689495	Apart from the direct inhibition of prolyl hydroxylase by fumarate, it was also showed that FH inactivation increases cellular reactive oxygen species (ROS), which in turn drives constitutive HIF activation (Figure 2).	('constitutive HIF activation', 'MPA', (179, 206))	('increases', 'PosReg', (108, 117))	('cellular reactive oxygen species', 'MPA', (118, 150))	('drives', 'PosReg', (172, 178))	('fumarate', 'Chemical', 'MESH:D005650', (58, 66))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (127, 150))	('ROS', 'Chemical', 'MESH:D017382', (152, 155))	('FH', 'Gene', '2271', (92, 94))	('inactivation', 'Var', (95, 107))
188205	31689495	It is important to note that conditional Fh1 and Hif1a double knockout mice have been created, and the addition of the Hif1a knockout exacerbates the renal cyst development, suggesting that Hif1a activation is likely a compensatory mechanism and not a tumor promoting event.	('mice', 'Species', '10090', (71, 75))	('renal cyst development', 'CPA', (150, 172))	('knockout', 'Var', (125, 133))	('addition', 'Var', (103, 111))	('Hif1a', 'Gene', (49, 54))	('Hif1a', 'Gene', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('Hif1a', 'Gene', '15251', (119, 124))	('exacerbates', 'PosReg', (134, 145))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('Hif1a', 'Gene', '15251', (49, 54))	('tumor', 'Disease', (252, 257))	('Hif1a', 'Gene', (119, 124))	('renal cyst', 'Phenotype', 'HP:0000107', (150, 160))	('Hif1a', 'Gene', '15251', (190, 195))
188206	31689495	Genomic studies on HLRCC tumors begin with gene expression profiling of FH mutant and FH wild type uterine fibroids.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('gene expression', 'biological_process', 'GO:0010467', ('43', '58'))	('FH', 'Gene', '2271', (86, 88))	('FH', 'Gene', '2271', (72, 74))	('HLRCC tumors', 'Disease', 'MESH:C535516', (19, 31))	('HLRCC tumors', 'Disease', (19, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('uterine fibroids', 'Phenotype', 'HP:0000131', (99, 115))	('mutant', 'Var', (75, 81))
188207	31689495	The study revealed that FH mutant fibroids over-expressed genes involved in carbohydrate metabolism, iron homeostasis, and oxidoreductases.	('iron homeostasis', 'biological_process', 'GO:0006879', ('101', '117'))	('FH', 'Gene', '2271', (24, 26))	('mutant', 'Var', (27, 33))	('iron', 'Chemical', 'MESH:D007501', (101, 105))	('genes', 'Gene', (58, 63))	('carbohydrate', 'Chemical', 'MESH:D002241', (76, 88))	('iron homeostasis', 'biological_process', 'GO:0055072', ('101', '117'))	('over-expressed', 'PosReg', (43, 57))	('carbohydrate metabolism', 'biological_process', 'GO:0005975', ('76', '99'))
188208	31689495	Through the gene expression profiling analyses, a 7 gene classifier, consisting of LDHA, NQO1, LAMA2, BNIP3, MYO15B, CDKN1C and COL6A2, was able to accurately predict FH mutation status in fibroids, signifying that FH inactivation alters gene expression profile in a specific way.	('BNIP3', 'Gene', '664', (102, 107))	('COL6A2', 'Gene', '1292', (128, 134))	('MYO15B', 'Gene', '80022', (109, 115))	('mutation', 'Var', (170, 178))	('COL6A2', 'Gene', (128, 134))	('CDKN1C', 'Gene', '1028', (117, 123))	('LDHA', 'Gene', '3939', (83, 87))	('gene expression', 'biological_process', 'GO:0010467', ('12', '27'))	('inactivation', 'Var', (218, 230))	('LAMA2', 'Gene', '3908', (95, 100))	('NQO1', 'molecular_function', 'GO:0003955', ('89', '93'))	('predict', 'Reg', (159, 166))	('LAMA2', 'Gene', (95, 100))	('FH', 'Gene', '2271', (167, 169))	('MYO15B', 'Gene', (109, 115))	('NQO1', 'Gene', '1728', (89, 93))	('CDKN1C', 'Gene', (117, 123))	('alters', 'Reg', (231, 237))	('BNIP3', 'Gene', (102, 107))	('LDHA', 'Gene', (83, 87))	('gene expression', 'biological_process', 'GO:0010467', ('238', '253'))	('NQO1', 'Gene', (89, 93))	('FH', 'Gene', '2271', (215, 217))
188210	31689495	Similarly, gene expression profile analyses were performed to evaluate gene expression changes following Fh1 knockout in the kidney tissue of mice.	('knockout', 'Var', (109, 117))	('Fh1', 'Gene', (105, 108))	('mice', 'Species', '10090', (142, 146))	('gene expression', 'biological_process', 'GO:0010467', ('71', '86'))	('gene expression', 'biological_process', 'GO:0010467', ('11', '26'))
188214	31689495	As expected, ccRCC, paraganglioma, and pheochromocytoma tumors that were known to harbor either VHL or SDH mutations were enriched for HIF1A signature, but HLRCC and the morphologically similar sporadic PRCC2 tumors did not show the enrichment of the HIF1A signature.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('paraganglioma', 'Disease', (20, 33))	('tumors', 'Disease', (56, 62))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (39, 55))	('paraganglioma', 'Disease', 'MESH:D010235', (20, 33))	('pheochromocytoma tumors', 'Disease', 'MESH:D010673', (39, 62))	('pheochromocytoma tumors', 'Disease', (39, 62))	('SDH', 'Gene', '6390', (103, 106))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('paraganglioma', 'Phenotype', 'HP:0002668', (20, 33))	('ccRCC', 'Disease', (13, 18))	('VHL', 'Gene', (96, 99))	('SDH', 'Gene', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumors', 'Disease', (209, 215))	('mutations', 'Var', (107, 116))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('VHL', 'Gene', '7428', (96, 99))
188217	31689495	These computational findings were empirically validated, revealing that fumarate accumulated following FH inactivation, which in turn activates NRF2 by covalently modifying C151 and C288 of Kelch Like ECH Associated Protein 1 (KEAP1), the bonafide negative regulator of NRF2, leading to sustained NRF2 activation.	('FH', 'Gene', '2271', (103, 105))	('Kelch Like ECH Associated Protein 1', 'Gene', (190, 225))	('NRF2', 'Gene', (144, 148))	('inactivation', 'Var', (106, 118))	('Kelch Like ECH Associated Protein 1', 'Gene', '9817', (190, 225))	('modifying', 'Reg', (163, 172))	('C151', 'Var', (173, 177))	('NRF2', 'Gene', (297, 301))	('ECH', 'molecular_function', 'GO:0004300', ('201', '204'))	('activates', 'PosReg', (134, 143))	('fumarate', 'Chemical', 'MESH:D005650', (72, 80))	('C288', 'Var', (182, 186))	('activation', 'PosReg', (302, 312))
188221	31689495	Around the same time, a mouse model study involving the development of an Fh1/Hif1a double knockout mouse model also identified that Fh1 inactivation in mice drives an Nrf2 activation phenotype, reinforcing that NRF2 activation is one of the main cellular alterations following FH inactivation.	('inactivation', 'Var', (137, 149))	('mouse', 'Species', '10090', (24, 29))	('FH', 'Gene', '2271', (278, 280))	('activation', 'PosReg', (173, 183))	('Nrf2', 'Gene', '18024', (168, 172))	('Hif1a', 'Gene', '15251', (78, 83))	('mouse', 'Species', '10090', (100, 105))	('Fh1', 'Gene', (133, 136))	('Nrf2', 'Gene', (168, 172))	('mice', 'Species', '10090', (153, 157))	('Hif1a', 'Gene', (78, 83))
188222	31689495	Unlike other subtypes of kidney cancer whereby the hereditary and sporadic forms of the tumors harbor mutations to the same tumor suppressor and oncogenes, the sporadic counterpart of HLRCC rarely harbors an FH mutation.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('kidney cancer', 'Disease', 'MESH:D007680', (25, 38))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor suppressor', 'biological_process', 'GO:0051726', ('124', '140'))	('kidney cancer', 'Phenotype', 'HP:0009726', (25, 38))	('tumor', 'Disease', (124, 129))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('124', '140'))	('kidney cancer', 'Disease', (25, 38))	('mutations', 'Var', (102, 111))	('FH', 'Gene', '2271', (208, 210))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('HLRCC', 'Disease', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
188223	31689495	The answer to this question came to light when our group utilized exome sequencing on carefully curated cases of PRCC2 and found that those tumor cases harbored gain-of-function NRF2 mutations and loss-of-function mutations to CUL3.	('mutations', 'Var', (183, 192))	('NRF2', 'Gene', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('gain-of-function', 'PosReg', (161, 177))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('CUL3', 'Gene', '8452', (227, 231))	('loss-of-function', 'NegReg', (197, 213))	('CUL3', 'Gene', (227, 231))	('tumor', 'Disease', (140, 145))
188224	31689495	Functional studies confirmed the functional changes of the identified NRF2 and CUL3 mutations.	('mutations', 'Var', (84, 93))	('NRF2', 'Gene', (70, 74))	('CUL3', 'Gene', '8452', (79, 83))	('CUL3', 'Gene', (79, 83))
188225	31689495	Subsequently, The Cancer Genome Atlas (TCGA) reported in a larger cohort that mutations that drive sustained NRF2 activation, including NRF2 gain-of-function, KEAP1 loss-of-function, and CUL3 loss-of-function, were significantly enriched in sporadic PRCC2 cases, confirming our initial exome sequencing findings.	('activation', 'PosReg', (114, 124))	('PRCC2', 'Disease', (250, 255))	('loss-of-function', 'NegReg', (192, 208))	('loss-of-function', 'NegReg', (165, 181))	('Cancer', 'Disease', 'MESH:D009369', (18, 24))	('mutations', 'Var', (78, 87))	('Cancer', 'Phenotype', 'HP:0002664', (18, 24))	('NRF2', 'Gene', (109, 113))	('CUL3', 'Gene', '8452', (187, 191))	('Cancer', 'Disease', (18, 24))	('NRF2', 'Gene', (136, 140))	('CUL3', 'Gene', (187, 191))	('gain-of-function', 'PosReg', (141, 157))
188245	31689495	The succination alters cellular iron homeostasis in HLRCC and induces a pro-proliferative signaling in HLRCC cells.	('signaling', 'biological_process', 'GO:0023052', ('90', '99'))	('pro-proliferative signaling', 'MPA', (72, 99))	('iron homeostasis', 'biological_process', 'GO:0055072', ('32', '48'))	('cellular iron homeostasis', 'MPA', (23, 48))	('induces', 'Reg', (62, 69))	('succination', 'Var', (4, 15))	('iron', 'Chemical', 'MESH:D007501', (32, 36))	('iron homeostasis', 'biological_process', 'GO:0006879', ('32', '48'))	('alters', 'Reg', (16, 22))
188248	31689495	While this study did not find pKa of the sulfhydryl group to be predictive of reactivity to fumarate, protonation of fumarate in an acidic environment was shown to encourage 2-SC formation.	('2-SC', 'Chemical', 'MESH:C511650', (174, 178))	('fumarate', 'Chemical', 'MESH:D005650', (92, 100))	('formation', 'biological_process', 'GO:0009058', ('179', '188'))	('pKa', 'molecular_function', 'GO:0004691', ('30', '33'))	('pKa', 'cellular_component', 'GO:0005952', ('30', '33'))	('iron', 'Chemical', 'MESH:D007501', (142, 146))	('2-SC formation', 'MPA', (174, 188))	('fumarate', 'Chemical', 'MESH:D005650', (117, 125))	('encourage', 'PosReg', (164, 173))	('protonation', 'Var', (102, 113))
188251	31689495	Tong and co-workers demonstrated that FH inactivation decreased the intracellular labile iron pool, which resulted in IRPs repression of HIF2A translation.	('iron', 'Chemical', 'MESH:D007501', (89, 93))	('translation', 'biological_process', 'GO:0006412', ('143', '154'))	('inactivation', 'Var', (41, 53))	('translation', 'MPA', (143, 154))	('repression', 'NegReg', (123, 133))	('HIF2A', 'Gene', (137, 142))	('decreased', 'NegReg', (54, 63))	('intracellular', 'cellular_component', 'GO:0005622', ('68', '81'))	('intracellular labile iron pool', 'MPA', (68, 98))	('FH', 'Gene', '2271', (38, 40))
188252	31689495	Specifically, they showed that the absence of FH inactivates AMP-activated protein kinase (AMPK) which in turn suppresses divalent metal transporter 1 (DMT1) expression (Figure 4).	('divalent metal transporter 1', 'Gene', '4891', (122, 150))	('AMPK', 'molecular_function', 'GO:0050405', ('91', '95'))	('DMT1', 'Gene', (152, 156))	('DMT1', 'Gene', '4891', (152, 156))	('expression', 'MPA', (158, 168))	('AMPK', 'molecular_function', 'GO:0004691', ('91', '95'))	('divalent metal transporter 1', 'Gene', (122, 150))	('AMPK', 'Gene', (91, 95))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('AMP-activated protein kinase', 'Pathway', (61, 89))	('AMPK', 'Gene', '5564', (91, 95))	('AMPK', 'molecular_function', 'GO:0047322', ('91', '95'))	('FH', 'Gene', '2271', (46, 48))	('absence', 'Var', (35, 42))	('suppresses', 'NegReg', (111, 121))	('inactivates', 'NegReg', (49, 60))
188256	31689495	Interestingly, this differential HIF1A vs HIF2A activation is in discordance with the differential HIF1A vs HIF2A activation in ccRCC, which frequently harbors VHL loss-of-function mutations that lead to sustained HIF activation.	('ccRCC', 'Disease', (128, 133))	('VHL', 'Gene', (160, 163))	('loss-of-function', 'NegReg', (164, 180))	('VHL', 'Gene', '7428', (160, 163))	('mutations', 'Var', (181, 190))
188258	31689495	Accordingly, aggressive ccRCC often harbors HIF1A loss-of-function mutations that lead to selective activation of HIF2A alone, suggesting a tumor suppressive role of HIF1A in ccRCC.	('HIF1A', 'Gene', (44, 49))	('mutations', 'Var', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('loss-of-function', 'NegReg', (50, 66))	('activation', 'PosReg', (100, 110))	('tumor', 'Disease', (140, 145))
188268	31689495	As outlined in the earlier sections, biallelic FH inactivation imparts very significant changes to the transcriptome and the proteome.	('transcriptome', 'MPA', (103, 116))	('inactivation', 'Var', (50, 62))	('FH', 'Gene', '2271', (47, 49))	('changes', 'Reg', (88, 95))
188269	31689495	Since all cancer cells and only cancer cells in HLRCC patients harbor biallelic FH inactivation, biological changes driven by FH inactivation provide unique opportunities for targeted therapy.	('biallelic', 'Var', (70, 79))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('patients', 'Species', '9606', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('FH', 'Gene', '2271', (80, 82))	('FH', 'Gene', '2271', (126, 128))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
188271	31689495	Particularly FH inactivation increases cellular dependency on glycolysis for ATP production.	('cellular dependency on glycolysis', 'MPA', (39, 72))	('inactivation', 'Var', (16, 28))	('increases', 'PosReg', (29, 38))	('glycolysis', 'biological_process', 'GO:0006096', ('62', '72'))	('ATP', 'Chemical', 'MESH:D000255', (77, 80))	('FH', 'Gene', '2271', (13, 15))
188281	31689495	As such, heme biosynthesis and degradation serve to complete carbohydrate catabolism and glutaminolysis, while continually supplying the cells with NADH and biosynthetic precursors when the TCA cycle is truncated upon FH inactivation.	('TCA', 'Chemical', 'MESH:D014238', (190, 193))	('degradation', 'MPA', (31, 42))	('carbohydrate', 'Chemical', 'MESH:D002241', (61, 73))	('carbohydrate catabolism', 'MPA', (61, 84))	('heme', 'Chemical', 'MESH:D006418', (9, 13))	('heme biosynthesis', 'biological_process', 'GO:0006783', ('9', '26'))	('NADH', 'Chemical', 'MESH:D009243', (148, 152))	('FH', 'Gene', '2271', (218, 220))	('degradation', 'biological_process', 'GO:0009056', ('31', '42'))	('carbohydrate catabolism', 'biological_process', 'GO:0016052', ('61', '84'))	('inactivation', 'Var', (221, 233))	('glutaminolysis', 'MPA', (89, 103))	('heme', 'MPA', (9, 13))	('TCA cycle', 'biological_process', 'GO:0006099', ('190', '199'))
188282	31689495	Inhibiting HMOX1 and heme biosynthesis stifled the cells' ability to complete carbohydrate and glutamine metabolism and resulted in conditional cell death (Figure 5).	('Inhibiting', 'Var', (0, 10))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('95', '115'))	('heme biosynthesis', 'Enzyme', (21, 38))	('cell death', 'biological_process', 'GO:0008219', ('144', '154'))	('death', 'Disease', 'MESH:D003643', (149, 154))	('HMOX1', 'Gene', (11, 16))	('glutamine', 'Chemical', 'MESH:D005973', (95, 104))	('heme', 'Chemical', 'MESH:D006418', (21, 25))	('heme biosynthesis', 'biological_process', 'GO:0006783', ('21', '38'))	('carbohydrate', 'Chemical', 'MESH:D002241', (78, 90))	('HMOX1', 'Gene', '3162', (11, 16))	('death', 'Disease', (149, 154))
188285	31689495	Specifically, C94 of GPX4 is succinated in FH-inactivated cells and the succinated form of GPX4 has reduced activity (Figure 5).	('FH', 'Gene', '2271', (43, 45))	('activity', 'MPA', (108, 116))	('GPX4', 'Gene', (91, 95))	('GPX4', 'Gene', '2879', (91, 95))	('succinate', 'Chemical', 'MESH:D019802', (29, 38))	('GPX4', 'Gene', (21, 25))	('GPX4', 'Gene', '2879', (21, 25))	('C94', 'Var', (14, 17))	('succinate', 'Chemical', 'MESH:D019802', (72, 81))
188297	31689495	The screen identified the synthetic lethal combination of the pentose phosphate enzyme, phosphogluconate dehydrogenase (PGD) knockdown with FH-inactivation.	('phosphogluconate dehydrogenase', 'Gene', (88, 118))	('knockdown', 'Var', (125, 134))	('pentose phosphate', 'Chemical', 'MESH:D010428', (62, 79))	('PGD', 'Gene', (120, 123))	('phosphogluconate dehydrogenase', 'Gene', '5226', (88, 118))	('PGD', 'Gene', '5226', (120, 123))	('FH', 'Gene', '2271', (140, 142))
188298	31689495	Mechanistically, PGD inhibition blocks glycolysis, suppresses reductive carboxylation of glutamine, and increases the NADP+/NADPH ratio to disrupt redox homeostasis (Figure 5).	('blocks', 'NegReg', (32, 38))	('redox homeostasis', 'MPA', (147, 164))	('glycolysis', 'MPA', (39, 49))	('glycolysis', 'biological_process', 'GO:0006096', ('39', '49'))	('disrupt', 'Reg', (139, 146))	('NADPH', 'Gene', '1666', (124, 129))	('PGD', 'Gene', (17, 20))	('increases', 'PosReg', (104, 113))	('disrupt redox homeostasis', 'Phenotype', 'HP:0025463', (139, 164))	('reductive carboxylation of glutamine', 'MPA', (62, 98))	('homeostasis', 'biological_process', 'GO:0042592', ('153', '164'))	('inhibition', 'Var', (21, 31))	('NADPH', 'Gene', (124, 129))	('NADP+', 'Chemical', 'MESH:D009249', (118, 123))	('glutamine', 'Chemical', 'MESH:D005973', (89, 98))	('PGD', 'Gene', '5226', (17, 20))	('suppresses', 'NegReg', (51, 61))
188301	31689495	It is important to note that PGD loss-of-function mutation has been previously identified in the human population and is associated with occasional mild hemolytic anemia, suggesting that PGD inhibition should be well tolerated in human.	('PGD', 'Gene', '5226', (187, 190))	('PGD', 'Gene', (29, 32))	('hemolytic anemia', 'Disease', 'MESH:D000743', (153, 169))	('PGD', 'Gene', '5226', (29, 32))	('hemolytic anemia', 'Phenotype', 'HP:0001878', (153, 169))	('human', 'Species', '9606', (97, 102))	('anemia', 'Phenotype', 'HP:0001903', (163, 169))	('mutation', 'Var', (50, 58))	('human', 'Species', '9606', (230, 235))	('hemolytic anemia', 'Disease', (153, 169))	('PGD', 'Gene', (187, 190))	('loss-of-function', 'NegReg', (33, 49))
188312	31689495	This is an important study because a significant subset of lung cancer tumors harbor either somatic loss-of-function mutations to KEAP1 or somatic gain-of-function mutation to NRF2.	('lung cancer tumors', 'Disease', (59, 77))	('mutations', 'Var', (117, 126))	('KEAP1', 'Gene', (130, 135))	('lung cancer tumors', 'Disease', 'MESH:D008175', (59, 77))	('loss-of-function', 'NegReg', (100, 116))	('gain-of-function', 'PosReg', (147, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('NRF2', 'Gene', (176, 180))	('mutation', 'Var', (164, 172))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
188313	31689495	The study utilized a small sgRNA library consisting of 65 sgRNA targeting 17 NRF2 target genes and found that tumors with sustained NRF2 activation is dependent on glutaminolysis for cellular bioenergetics, whereby inhibition of the glutaminase, GLS, could selectively kill cancer cells with sustained NRF2 activation (Figure 5).	('inhibition', 'Var', (215, 225))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('glutaminase', 'Gene', (233, 244))	('cancer', 'Disease', (274, 280))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('glutaminase', 'Gene', '2744', (233, 244))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
188314	31689495	This is relevant to HLRCC because (as it was outlined in the earlier section), FH inactivation drives sustained NRF2 activation, a phenotype that unifies HLRCC with its sporadic counterpart, PRCC2.	('HLRCC', 'Disease', (154, 159))	('FH', 'Gene', '2271', (79, 81))	('activation', 'PosReg', (117, 127))	('inactivation', 'Var', (82, 94))	('NRF2', 'Gene', (112, 116))
188320	31689495	Loss-of-heterozygosity is always detected in the tumor tissues indicating bialleic FH loss as the tumor initiating event.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('Loss-of-heterozygosity', 'NegReg', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('FH loss', 'Disease', (83, 90))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('bialleic', 'Var', (74, 82))	('FH loss', 'Disease', 'MESH:D006938', (83, 90))
188322	31689495	It is measured that fumarate accumulates to millimolar concentration in HLRCC cells, and at this high concentration, fumarate directly alters various cellular signaling pathways including: increased HIF1A activity, increased NRF2 activity, and attenuated cellular iron homeostasis.	('cellular iron homeostasis', 'MPA', (255, 280))	('attenuated', 'NegReg', (244, 254))	('iron homeostasis', 'biological_process', 'GO:0006879', ('264', '280'))	('fumarate', 'Chemical', 'MESH:D005650', (20, 28))	('iron', 'Chemical', 'MESH:D007501', (264, 268))	('activity', 'MPA', (205, 213))	('iron homeostasis', 'biological_process', 'GO:0055072', ('264', '280'))	('increased', 'PosReg', (215, 224))	('activity', 'MPA', (230, 238))	('HIF1A', 'Enzyme', (199, 204))	('alters', 'Reg', (135, 141))	('fumarate', 'Chemical', 'MESH:D005650', (117, 125))	('fumarate', 'Var', (117, 125))	('signaling', 'biological_process', 'GO:0023052', ('159', '168'))	('cellular signaling pathways', 'Pathway', (150, 177))	('NRF2', 'Enzyme', (225, 229))	('increased', 'PosReg', (189, 198))
188329	31273792	More evidence indicates the presence of methylation in ccRCC cancer cells, but there is a lack of studies on methylation-driven genes in ccRCC.	('methylation', 'Var', (40, 51))	('presence', 'Reg', (28, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('methylation', 'biological_process', 'GO:0032259', ('109', '120'))	('methylation', 'biological_process', 'GO:0032259', ('40', '51'))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ccRCC cancer', 'Disease', 'MESH:D009369', (55, 67))	('ccRCC cancer', 'Disease', (55, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))
188340	31273792	Although early studies have discovered that the prognostic markers of ccRCC may be mutated genes such as VHL (Gulati et al., 2014).	('mutated', 'Var', (83, 90))	('VHL', 'Gene', (105, 108))	('VHL', 'Gene', '7428', (105, 108))	('ccRCC', 'Phenotype', 'HP:0006770', (70, 75))	('ccRCC', 'Disease', (70, 75))
188365	31273792	The results of pathway enrichment analysis showed that the methylation-driven genes were mainly enriched in the universal transcriptional pathway, RNA polymerase II transcription and gene expression, and were significantly related to the enriched events (Figure 4).	('methylation-driven genes', 'Var', (59, 83))	('gene expression', 'biological_process', 'GO:0010467', ('183', '198'))	('universal transcriptional pathway', 'Pathway', (112, 145))	('RNA', 'cellular_component', 'GO:0005562', ('147', '150'))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('men', 'Species', '9606', (29, 32))	('transcription', 'biological_process', 'GO:0006351', ('165', '178'))	('related', 'Reg', (223, 230))	('RNA', 'MPA', (147, 150))
188371	31273792	The details are as follows: zero site in C11orf21, one site in EVI2A (cg23352695), three sites in PRR15L (cg03496533, cg18052778, cg15738800), one site in RIPK4 (cg05306310), one site in SSX1 (cg17158811), and five sites in ZNF418 (cg15060012, cg11998703, cg21444693, cg26356061, cg18673377; Table 2).	('EVI2A', 'Gene', (63, 68))	('cg11998703', 'Var', (244, 254))	('C11orf21', 'Gene', '29125', (41, 49))	('cg21444693', 'Var', (256, 266))	('SSX1', 'Gene', '6756', (187, 191))	('SS', 'Phenotype', 'HP:0100242', (187, 189))	('SSX1', 'Gene', (187, 191))	('RIPK4', 'Gene', (155, 160))	('ZNF418', 'Gene', '147686', (224, 230))	('cg15738800', 'Var', (130, 140))	('RIPK4', 'Gene', '54101', (155, 160))	('PRR15L', 'Gene', (98, 104))	('cg03496533', 'Var', (106, 116))	('cg15060012', 'Var', (232, 242))	('EVI2A', 'Gene', '2123', (63, 68))	('cg26356061', 'Var', (268, 278))	('ZNF418', 'Gene', (224, 230))	('cg18673377', 'Var', (280, 290))	('PRR', 'molecular_function', 'GO:0038187', ('98', '101'))	('C11orf21', 'Gene', (41, 49))	('cg18052778', 'Var', (118, 128))	('PRR15L', 'Gene', '79170', (98, 104))
188375	31273792	Studies have shown that the changes in gene expression caused by methylation are connected with the development and regulation of a variety of human malignant tumors.	('malignant tumors', 'Disease', 'MESH:D009369', (149, 165))	('gene expression', 'MPA', (39, 54))	('human', 'Species', '9606', (143, 148))	('men', 'Species', '9606', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('regulation', 'biological_process', 'GO:0065007', ('116', '126'))	('methylation', 'biological_process', 'GO:0032259', ('65', '76'))	('connected', 'Reg', (81, 90))	('gene expression', 'biological_process', 'GO:0010467', ('39', '54'))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('methylation', 'Var', (65, 76))	('changes', 'Reg', (28, 35))	('malignant tumors', 'Disease', (149, 165))
188378	31273792	The high/low methylation of DNA is associated with the invasiveness of the disease and can significantly affect the survival of patients (X. Su et al., 2017).	('methylation', 'MPA', (13, 24))	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('invasiveness of the disease', 'Disease', (55, 82))	('survival', 'CPA', (116, 124))	('invasiveness of the disease', 'Disease', 'MESH:D009361', (55, 82))	('associated', 'Reg', (35, 45))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('DNA', 'Gene', (28, 31))	('affect', 'Reg', (105, 111))	('high/low', 'Var', (4, 12))	('patients', 'Species', '9606', (128, 136))
188380	31273792	And so far, only one methylation-driven genes, Cytohesin 1 Interacting protein, has been reported to have an effect on ccRCC in previous studies, and the paper concludes that hypermethylation of this driver gene may be a feature of good prognosis in KIRC (Gevaert, Tibshirani, & Plevritis, 2015).	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('methylation', 'biological_process', 'GO:0032259', ('21', '32'))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('ccRCC', 'Disease', (119, 124))	('Cytohesin 1 Interacting protein', 'Gene', '9595', (47, 78))	('hypermethylation', 'Var', (175, 191))	('Cytohesin 1 Interacting protein', 'Gene', (47, 78))
188385	31273792	In conclusion, we speculated that hypermethylation of methylation-driven genes affects the metabolic level of cells by inhibiting the expression of genes, which resulted in a decline in the survival of patients with ccRCC.	('decline', 'NegReg', (175, 182))	('hypermethylation', 'Var', (34, 50))	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('inhibiting', 'NegReg', (119, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (216, 221))	('ccRCC', 'Disease', (216, 221))	('metabolic level of cells', 'MPA', (91, 115))	('methylation-driven', 'Gene', (54, 72))	('survival', 'MPA', (190, 198))	('patients', 'Species', '9606', (202, 210))	('affects', 'Reg', (79, 86))	('expression of genes', 'MPA', (134, 153))
188387	31273792	Among the six genes, the high methylated level of PRR15L, ZNF418, and RIPK4 prognosticated low survival rate, and the form of high methylated/low expression represented poor prognosis.	('low', 'NegReg', (91, 94))	('PRR', 'molecular_function', 'GO:0038187', ('50', '53'))	('PRR15L', 'Gene', (50, 56))	('ZNF418', 'Gene', '147686', (58, 64))	('PRR15L', 'Gene', '79170', (50, 56))	('ZNF418', 'Gene', (58, 64))	('high', 'Var', (25, 29))	('RIPK4', 'Gene', '54101', (70, 75))	('survival rate', 'CPA', (95, 108))	('RIPK4', 'Gene', (70, 75))
188396	31273792	We made the conclusion that patients with high methylation level of PRR15L, ZNF418, and RIPK4 had a poor prognosis compared with patients with low methylation level of methylation cleared.	('methylation', 'biological_process', 'GO:0032259', ('168', '179'))	('RIPK4', 'Gene', '54101', (88, 93))	('PRR', 'molecular_function', 'GO:0038187', ('68', '71'))	('patients', 'Species', '9606', (129, 137))	('ZNF418', 'Gene', (76, 82))	('PRR15L', 'Gene', (68, 74))	('high methylation level', 'Var', (42, 64))	('RIPK4', 'Gene', (88, 93))	('ZNF418', 'Gene', '147686', (76, 82))	('PRR15L', 'Gene', '79170', (68, 74))	('methylation', 'biological_process', 'GO:0032259', ('47', '58'))	('patients', 'Species', '9606', (28, 36))	('methylation', 'biological_process', 'GO:0032259', ('147', '158'))
188400	31273792	In our study, patients with hypomethylation/high expression of EVI2A gene had a low survival rate, which was consistent with the study of MPNST.	('low', 'NegReg', (80, 83))	('EVI2A', 'Gene', (63, 68))	('hypomethylation/high expression', 'Var', (28, 59))	('survival rate', 'CPA', (84, 97))	('patients', 'Species', '9606', (14, 22))	('EVI2A', 'Gene', '2123', (63, 68))
188403	31273792	Moreover, Panigrahi et al discovered that specific chromosome translocation t (X; 18; p11; q11) is a feature of synovial sarcomas (SS), so SS18-SSX1 fusion gene can be applied to the diagnose of SS (Panigrahi et al., 2018).	('synovial sarcomas', 'Phenotype', 'HP:0012570', (112, 129))	('SS', 'Phenotype', 'HP:0100242', (195, 197))	('synovial sarcomas', 'Disease', (112, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (121, 129))	('SS', 'Phenotype', 'HP:0100242', (144, 146))	('SSX1', 'Gene', '6756', (144, 148))	('synovial sarcomas', 'Disease', 'MESH:D013584', (112, 129))	('t (X; 18; p11; q11', 'Var', (76, 94))	('chromosome', 'cellular_component', 'GO:0005694', ('51', '61'))	('SSX1', 'Gene', (144, 148))	('SS', 'Phenotype', 'HP:0100242', (131, 133))	('SS', 'Phenotype', 'HP:0100242', (139, 141))
188404	31273792	In our study, we demonstrated that EVI2A, C11orf21, and SSX1 are effective prognostic markers of ccRCC, and their hypomethylation leads to poor prognosis.	('SSX1', 'Gene', (56, 60))	('EVI2A', 'Gene', '2123', (35, 40))	('EVI2A', 'Gene', (35, 40))	('C11orf21', 'Gene', '29125', (42, 50))	('hypomethylation', 'Var', (114, 129))	('SS', 'Phenotype', 'HP:0100242', (56, 58))	('C11orf21', 'Gene', (42, 50))	('SSX1', 'Gene', '6756', (56, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('ccRCC', 'Disease', (97, 102))
188405	31273792	Finally, it was found that the related sites of EVI2A (cg23352695), PRR15L (cg03496533, cg18052778, cg15738800), RIPK4 (cg05306310), SSX1 (cg17158811) and ZNF418 (cg15060012, cg11998703, cg21444693, cg26356061, cg18673377) driving genes were negatively correlated with their expression levels, which may result from the downregulation of ccRCC gene expression that caused by hypermethylation.	('SS', 'Phenotype', 'HP:0100242', (133, 135))	('SSX1', 'Gene', (133, 137))	('EVI2A', 'Gene', (48, 53))	('gene expression', 'biological_process', 'GO:0010467', ('344', '359'))	('negatively', 'NegReg', (242, 252))	('expression levels', 'MPA', (275, 292))	('cg15060012', 'Var', (163, 173))	('ZNF418', 'Gene', (155, 161))	('PRR15L', 'Gene', (68, 74))	('cg11998703', 'Var', (175, 185))	('cg05306310', 'Var', (120, 130))	('cg26356061', 'Var', (199, 209))	('ccRCC gene', 'Gene', (338, 348))	('expression', 'MPA', (349, 359))	('cg18673377', 'Var', (211, 221))	('PRR15L', 'Gene', '79170', (68, 74))	('RIPK4', 'Gene', (113, 118))	('cg17158811', 'Var', (139, 149))	('downregulation', 'NegReg', (320, 334))	('EVI2A', 'Gene', '2123', (48, 53))	('PRR', 'molecular_function', 'GO:0038187', ('68', '71'))	('RIPK4', 'Gene', '54101', (113, 118))	('cg21444693', 'Var', (187, 197))	('ZNF418', 'Gene', '147686', (155, 161))	('ccRCC', 'Phenotype', 'HP:0006770', (338, 343))	('SSX1', 'Gene', '6756', (133, 137))
188416	31273792	Therefore, the development and evolution of ccRCC may be due in part to the methylation of these driving genes, and the genes we obtained in this study can be used as prognostic markers for ccRCC.	('ccRCC', 'Disease', (190, 195))	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('ccRCC', 'Disease', (44, 49))	('men', 'Species', '9606', (22, 25))	('methylation', 'Var', (76, 87))	('methylation', 'biological_process', 'GO:0032259', ('76', '87'))	('ccRCC', 'Phenotype', 'HP:0006770', (190, 195))
188476	31843980	Interestingly, m/z 810.52 and m/z 391.26 followed a similar trend in abundance change to what observed qualitatively (m/z 810.52 is high in cortex and m/z 391.26 is high in medulla), however, with less contribution for the PCA separation of the two regions (Supplementary Fig.	('men', 'Species', '9606', (264, 267))	('m/z 810.52', 'Var', (118, 128))	('m/z 391.26', 'Var', (151, 161))
188477	31843980	The lipid PS(38:3) at m/z 812.53, which has one less double bond and is less abundant than PS(38:4) m/z 810.52, showed a greater difference in peak intensity between cortex and medulla regions (Supplementary Fig.	('PS', 'Disease', 'MESH:C562429', (91, 93))	('lipid', 'Chemical', 'MESH:D008055', (4, 9))	('m/z 812.53', 'Var', (22, 32))	('peak intensity', 'MPA', (143, 157))	('men', 'Species', '9606', (200, 203))	('less double bond', 'MPA', (48, 64))	('PS', 'Disease', 'MESH:C562429', (10, 12))
188485	31843980	Contrasting molecular patterns between the two tumor tissue types can be even more clearly seen in the zoomed-in mass spectra (amplified by 10 times for both mass spectra) from m/z 1000-1500.	('m/z 1000-1500', 'Var', (177, 190))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
188486	31843980	In the mass range from m/z 100-400, several metabolites such as ascorbic acid (m/z 175.025, Supplementary Fig.	('m/z 175.025', 'Var', (79, 90))	('ascorbic acid', 'Chemical', 'MESH:D001205', (64, 77))	('ascorbic acid', 'MPA', (64, 77))	('men', 'Species', '9606', (98, 101))	('m/z 100-400', 'Var', (23, 34))
188487	31843980	S9), hexose (m/z 215.033), and free FA such as FA(18:1) (m/z 281.248, mass error at -2.1 ppm), and FA (20:4) (m/z 303.232, mass error at -3.1 ppm) were found at different relative abundances in RO compared to RCC.	('m/z 215.033', 'Var', (13, 24))	('hexose', 'Chemical', 'MESH:D006601', (5, 11))	('RCC', 'Disease', 'MESH:C538614', (209, 212))	('RCC', 'Disease', (209, 212))	('m/z 303.232', 'Var', (110, 121))
188488	31843980	In the mass range of m/z 600-1000, several lipid species, such as PI (20:4_18:0) (m/z 885.547, Supplementary Fig.	('lipid', 'Chemical', 'MESH:D008055', (43, 48))	('men', 'Species', '9606', (101, 104))	('m/z 885.547', 'Var', (82, 93))	('m/z', 'Var', (21, 24))
188493	31843980	Higher relative abundances of singly charged CL species in the mass range of m/z 1000-1500, such as m/z 1447.960 and m/z 1469.940, as well as doubly charged lipid dimers (CL+DG or CL+PC) which are either CL coupled with diacylglycerol (DG) or phosphatidylcholines (PC) (as shown in the inserted Fig.	('lipid', 'Chemical', 'MESH:D008055', (157, 162))	('m/z 1447.960', 'Var', (100, 112))	('m/z 1469.940', 'Var', (117, 129))	('CL+DG or CL+PC', 'Disease', (171, 185))	('CL+DG or CL+PC', 'Disease', 'MESH:D015324', (171, 185))
188500	31843980	In contrast, the two RO samples showed lower abundances of m/z 810.527 (PS(20:4_18:0)), m/z 835.531(PI(34:1)) and m/z 863.561 (PI(36:1)), but higher abundance of m/z 737.490 when compared to RCC and normal kidney tissues.	('m/z 737.490', 'Var', (162, 173))	('m/z 835.531', 'Var', (88, 99))	('RCC', 'Disease', (191, 194))	('RCC', 'Disease', 'MESH:C538614', (191, 194))	('m/z 810.527', 'Var', (59, 70))	('PS', 'Disease', 'MESH:C562429', (72, 74))	('m/z 863.561', 'Var', (114, 125))
188501	31843980	For RCCs, m/z 656.574 (Cer(d40:1)), m/z 810.527, and m/z 835.531 showed similar abundance with normal samples, but lower abundance of m/z 391.229 and m/z 863.561 when compared to both RO and normal tissues.	('m/z 391.229', 'Var', (134, 145))	('Cer', 'Chemical', 'MESH:D002518', (23, 26))	('m/z 810.527', 'Var', (36, 47))	('lower', 'NegReg', (115, 120))	('m/z 656.574', 'Var', (10, 21))	('RCC', 'Disease', (4, 7))	('RCC', 'Disease', 'MESH:C538614', (4, 7))	('m/z 835.531', 'Var', (53, 64))
188516	31843980	For example, based on characteristic fragmentation patterns of PE, PA and PS, the ions m/z 464.314, m/z 697.482, and m/z 842.589 were assigned as [PE(P-18:0)-H]-, [PA(18:1_18:2)-H]- and [PS(18:1_22:1)-H]-, respectively (Supplementary Fig.	('m/z 842.589', 'Var', (117, 128))	('PS', 'Disease', 'MESH:C562429', (74, 76))	('PE', 'Chemical', '-', (147, 149))	('men', 'Species', '9606', (226, 229))	('m/z 464.314', 'Var', (87, 98))	('PE', 'Chemical', '-', (63, 65))	('m/z 697.482', 'Var', (100, 111))	('men', 'Species', '9606', (41, 44))	('PS', 'Disease', 'MESH:C562429', (187, 189))
188519	31843980	Mutations in mitochondrial genes have been reported in both RO and chRCC.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('Mutations', 'Var', (0, 9))	('mitochondrial genes', 'Gene', (13, 32))	('reported', 'Reg', (43, 51))
188522	31843980	The ions m/z 1169.73 (assigned as lyso-CL(54:5)) and m/z 1128.27 (assigned as CL+PC(110:14)), which have the top two values in loadings 1 (Fig.	('m/z 1169.73', 'Var', (9, 20))	('CL+PC', 'Disease', (78, 83))	('CL+PC', 'Disease', 'MESH:D015324', (78, 83))	('m/z 1128.27', 'Var', (53, 64))	('lyso-CL', 'Chemical', '-', (34, 41))
188523	31843980	6B), showed significantly higher intensities in RO tissues compared with chRCC ones, while m/z 418.19 (unidentified) and m/z 201.11(assigned as [C10H18O4]-), which have the top 2 values in loadings 2, presented higher intensities in chRCC tissues.	('intensities', 'MPA', (218, 229))	('m/z 201.11', 'Var', (121, 131))	('higher', 'PosReg', (26, 32))	('higher', 'PosReg', (211, 217))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (235, 238))	('RCC', 'Disease', (235, 238))	('intensities', 'MPA', (33, 44))	('m/z 418.19', 'Var', (91, 101))
188528	31843980	Among those, m/z 421.23, which was tentatively assigned as 2-methylacetophenone (mass error is -4.7 ppm, identified by matching Metaspace database) has the highest lasso weight for chRCC prediction.	('lasso weight', 'MPA', (164, 176))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('lasso', 'Chemical', '-', (164, 169))	('RCC', 'Disease', (183, 186))	('2-methylacetophenone', 'Chemical', '-', (59, 79))	('m/z 421.23', 'Var', (13, 23))
188531	31843980	On the other hand, all 14 CL related species (Table S4), such as ox-CL(72:9) at m/z 730.47 and CL+DG (108:9) at m/z 1034.75, and all eight PE related lipid species, such as LPE(18:0) at m/z 480.31 and PE(40:5) at m/z 792.56, were given positive weights to characterize RO tissues.	('PE', 'Chemical', '-', (174, 176))	('CL+DG', 'Disease', (95, 100))	('ox-CL', 'Chemical', '-', (65, 70))	('LPE', 'Chemical', '-', (173, 176))	('CL+DG', 'Disease', 'None', (95, 100))	('PE', 'Chemical', '-', (139, 141))	('PE', 'Chemical', '-', (201, 203))	('lipid', 'Chemical', 'MESH:D008055', (150, 155))	('m/z 730.47', 'Var', (80, 90))
188539	31843980	S17), m/z 713.49, m/z 713.99, m/z 714.51) have positive lasso weights in chRCC samples.	('m/z 713.49', 'Var', (6, 16))	('m/z 713.99', 'Var', (18, 28))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('lasso', 'Chemical', '-', (56, 61))	('RCC', 'Disease', (75, 78))	('lasso', 'MPA', (56, 61))	('m/z 714.51', 'Var', (30, 40))
188545	31843980	Interestingly, although normal kidney tissue generally present high relative abundance of CLs in the DESI mass spectra, specific CL species such as CL(20:2_18:2_18:2_18:2) at m/z 737.490 were observed in high abundances in RO tissues, likely associated to the defective mitochondria processes known to occur in oncocytic tumors, as we previously discussed.	('mitochondria', 'cellular_component', 'GO:0005739', ('270', '282'))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('oncocytic tumors', 'Disease', 'MESH:C535584', (311, 327))	('oncocytic tumors', 'Disease', (311, 327))	('m/z 737.490', 'Var', (175, 186))	('CLs', 'Chemical', 'MESH:D002713', (90, 93))	('tumors', 'Phenotype', 'HP:0002664', (321, 327))
188577	28938589	Using lncRNA expression profiling data in 440 ccRCC tumors from The Cancer Genome Atlas (TCGA) data, a five-lncRNA signature (AC069513.4, AC003092.1, CTC-205M6.2, RP11-507K2.3, U91328.21) has been identified to be significantly associated with ccRCC patients' overall survival in both training set and testing set.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('AC003092.1', 'Var', (138, 148))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('U91328.21', 'Var', (177, 186))	('RP11', 'Gene', (163, 167))	('AC069513.4', 'Var', (126, 136))	('associated', 'Reg', (228, 238))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('patients', 'Species', '9606', (250, 258))	('RCC', 'Disease', (246, 249))	('tumors', 'Disease', (52, 58))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (68, 87))	('RCC', 'Disease', (48, 51))	('Cancer Genome Atlas', 'Disease', (68, 87))	('RCC', 'Disease', 'MESH:C538614', (246, 249))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('CTC-205M6.2', 'Var', (150, 161))	('RP11', 'Gene', '26121', (163, 167))
188601	28938589	The risk score formula is as following: Risk score= (1.43 x expression level of AC069513.4) + (0.81 x expression level of AC003092.1) + (1.64 x expression level of RP11-507K2.3) + (-6.56 x expression level of CTC-205M6.2) + (-1.72 x expression level of U91328.21).	('AC069513.4', 'Var', (80, 90))	('RP11', 'Gene', '26121', (164, 168))	('RP11', 'Gene', (164, 168))
188607	28938589	For patients with high risk scores, the expression profiles of lncRNAs (AC069513.4, AC003092.1 and RP11-507K2.3) were significantly up-regulated, whereas the remaining two lncRNAs (CTC-205M6.2 and U91328.21) were down-regulated.	('expression', 'MPA', (40, 50))	('AC069513.4', 'Var', (72, 82))	('up-regulated', 'PosReg', (132, 144))	('patients', 'Species', '9606', (4, 12))	('RP11', 'Gene', (99, 103))	('AC003092.1', 'Var', (84, 94))	('RP11', 'Gene', '26121', (99, 103))
188620	28938589	Many works have focused on whether aberrant expression of specific lncRNAs in cancers can serve as independent markers for diagnosis and prognosis.	('aberrant', 'Var', (35, 43))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
188670	32489889	1), positivity for cytokeratins AE1/AE3, and nonreactivity for CK7, which suggested a renal primary consistent with metastatic recurrence.	('cytokeratins AE1/AE3', 'Gene', (19, 39))	('positivity', 'Var', (4, 14))	('cytokeratins AE1/AE3', 'Gene', '6508', (19, 39))	('renal primary', 'Disease', (86, 99))	('CK7', 'Gene', (63, 66))	('CK7', 'Gene', '3855', (63, 66))
188681	32489889	For high-risk tumors (pT2-4N0 Nx or any T N+), recommended follow-up consists of initial baseline chest and abdominal scan (CT or MRI) within three to six months following surgery.	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (14, 20))	('pT2-4N0 Nx', 'Var', (22, 32))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
188685	32489889	However, surgical excision of RCC metastasis to the bladder has been shown to improve prognosis, so it is logical to assume that excision of metastasis to the distal ureter will offer similar benefit.	('improve', 'PosReg', (78, 85))	('metastasis', 'Var', (34, 44))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('prognosis', 'MPA', (86, 95))	('RCC', 'Disease', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))
188743	31598385	Human bladder cancer cell lines T24 and HT-1376 were kind gifts from Dr. Arnold I. Chin and Dr. Hanwei Zhang at UCLA and maintained in the same condition as RENCA cells.	('Human', 'Species', '9606', (0, 5))	('Dr.', 'Var', (92, 95))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('bladder cancer', 'Phenotype', 'HP:0009725', (6, 20))	('bladder cancer', 'Disease', 'MESH:D001749', (6, 20))	('bladder cancer', 'Disease', (6, 20))
188797	31598385	The HT-1376 CAM tumors often grew more robustly with large proliferating tumor cells in comparison to T24 CAM tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', (16, 22))	('HT-1376', 'Var', (4, 11))	('CAM', 'Gene', (12, 15))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('grew', 'CPA', (29, 33))	('CAM', 'Gene', '71817', (12, 15))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumor', 'Disease', (73, 78))	('CAM', 'Gene', (106, 109))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumor', 'Disease', (16, 21))	('rat', 'Species', '10116', (66, 69))	('CAM', 'Gene', '71817', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
188827	31598385	Histological analyses of the patient's tumor tissue by anti-VHL (Fig.	('anti-VHL', 'Var', (55, 63))	('patient', 'Species', '9606', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('anti-VHL', 'Gene', (55, 63))
188853	31598385	We created a novel metastatic ccRCC model by CRISPR-mediated VHL gene deletion in the murine RENCA line, and established the parental VHL wildtype (VHL-WT) and VHL knockout (VHL-KO) RENCA cells.	('deletion', 'Var', (70, 78))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('RCC', 'Disease', 'MESH:D002292', (32, 35))	('RCC', 'Disease', (32, 35))	('VHL', 'Gene', (61, 64))	('murine', 'Species', '10090', (86, 92))
188854	31598385	We have observed that VHL deletion leads to epithelial-mesenchymal transition (EMT) of VHL-KO cells and dramatic slowing in proliferation in vitro.	('EMT', 'biological_process', 'GO:0001837', ('79', '82'))	('rat', 'Species', '10116', (131, 134))	('VHL', 'Gene', (22, 25))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('44', '77'))	('deletion', 'Var', (26, 34))	('slowing', 'NegReg', (113, 120))	('epithelial-mesenchymal transition', 'CPA', (44, 77))
188884	33937021	The study was designed to identify the role and regulatory mechanism of miR-582-5p in ccRCC.	('miR-582-5p', 'Chemical', '-', (72, 82))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('miR-582-5p', 'Var', (72, 82))
188885	33937021	In this study, the low expression level of miR-582-5p were detected by qRT-PCR in ccRCC patient tumor samples and ccRCC cell lines, respectively.	('miR-582-5p', 'Var', (43, 53))	('patient', 'Species', '9606', (88, 95))	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('tumor', 'Disease', (96, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('miR-582-5p', 'Chemical', '-', (43, 53))	('RCC', 'Disease', (84, 87))	('expression level', 'MPA', (23, 39))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))
188886	33937021	The expression level of miR-582-5p was associated with tumor stage and metastasis.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('expression', 'MPA', (4, 14))	('miR-582-5p', 'Var', (24, 34))	('tumor', 'Disease', (55, 60))	('metastasis', 'CPA', (71, 81))	('associated', 'Reg', (39, 49))	('miR-582-5p', 'Chemical', '-', (24, 34))
188887	33937021	In vivo and in vitro experiments found miR-582-5p inhibit tumor growth via suppressing COL5A1 expression.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('suppressing', 'NegReg', (75, 86))	('miR-582-5p', 'Var', (39, 49))	('inhibit', 'NegReg', (50, 57))	('miR-582-5p', 'Chemical', '-', (39, 49))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('COL5A1', 'Gene', (87, 93))	('expression', 'MPA', (94, 104))	('COL5A1', 'Gene', '1289', (87, 93))
188889	33937021	Finally, the negative relation of RUNX1 and miR-582-5p was verified through rescue experiment both in vitro and in vivo.	('miR-582-5p', 'Var', (44, 54))	('miR-582-5p', 'Chemical', '-', (44, 54))	('RUNX1', 'Gene', (34, 39))	('RUNX1', 'Gene', '861', (34, 39))
188890	33937021	In summary, miR-582-5p, which was regulated by RUNX1, inhibited tumor growth and invasion by targeting COL5A1, indicating that miR-582-5p may act as a biomarker and that the RUNX1/miR-582-5p/COL5A1 axis could be a potential therapeutic target for ccRCC.	('RUNX1', 'Gene', '861', (174, 179))	('miR-582-5p', 'Chemical', '-', (12, 22))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('COL5A1', 'Gene', (191, 197))	('RCC', 'Phenotype', 'HP:0005584', (249, 252))	('miR-582-5p', 'Var', (127, 137))	('ccRCC', 'Phenotype', 'HP:0006770', (247, 252))	('RCC', 'Disease', (249, 252))	('COL5A1', 'Gene', '1289', (103, 109))	('COL5A1', 'Gene', '1289', (191, 197))	('RCC', 'Disease', 'MESH:C538614', (249, 252))	('miR-582-5p', 'Chemical', '-', (127, 137))	('miR-582-5p', 'Var', (12, 22))	('inhibited', 'NegReg', (54, 63))	('tumor', 'Disease', (64, 69))	('miR-582-5p', 'Chemical', '-', (180, 190))	('COL5A1', 'Gene', (103, 109))	('RUNX1', 'Gene', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('RUNX1', 'Gene', '861', (47, 52))	('RUNX1', 'Gene', (174, 179))	('targeting', 'Reg', (93, 102))
188899	33937021	Unexpectedly, although a majority of studies verified that miR-582-5p is a tumor suppressor, other studies held different opinions.	('miR-582-5p', 'Chemical', '-', (59, 69))	('tumor suppressor', 'biological_process', 'GO:0051726', ('75', '91'))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('75', '91'))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('miR-582-5p', 'Var', (59, 69))	('tumor', 'Disease', (75, 80))
188900	33937021	proved that miR-582-5p contributed to an increase in the proliferation of prostate cancer cells under androgen deprived conditions.	('prostate cancer', 'Disease', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('miR-582-5p', 'Chemical', '-', (12, 22))	('prostate cancer', 'Disease', 'MESH:D011471', (74, 89))	('proliferation', 'CPA', (57, 70))	('prostate cancer', 'Phenotype', 'HP:0012125', (74, 89))	('increase', 'PosReg', (41, 49))	('miR-582-5p', 'Var', (12, 22))
188901	33937021	that miR-582-5p induced progression of colorectal cancer.	('miR-582-5p', 'Var', (5, 15))	('colorectal cancer', 'Disease', 'MESH:D015179', (39, 56))	('progression', 'PosReg', (24, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('miR-582-5p', 'Chemical', '-', (5, 15))	('colorectal cancer', 'Disease', (39, 56))
188902	33937021	Considering these controversial results, we were interested in the role of miR-582-5p in RCC, which still remained unclear.	('miR-582-5p', 'Var', (75, 85))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('miR-582-5p', 'Chemical', '-', (75, 85))	('RCC', 'Disease', 'MESH:C538614', (89, 92))
188903	33937021	In the present study, we showed that miR-582-5p was down-regulated in ccRCC cell lines and tissues, and over-expression of miR-582-5p suppressed the growth and migration in vitro and in vivo.	('suppressed', 'NegReg', (134, 144))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('over-expression', 'PosReg', (104, 119))	('miR-582-5p', 'Var', (123, 133))	('miR-582-5p', 'Gene', (37, 47))	('down-regulated', 'NegReg', (52, 66))	('miR-582-5p', 'Chemical', '-', (37, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (70, 75))	('miR-582-5p', 'Chemical', '-', (123, 133))
188904	33937021	Interestingly, our findings indicated that miR-582-5p, which was mediated by RUNX1, accelerated ccRCC progression through promoting the expression of COL5A1.	('miR-582-5p', 'Var', (43, 53))	('expression', 'MPA', (136, 146))	('COL5A1', 'Gene', (150, 156))	('COL5A1', 'Gene', '1289', (150, 156))	('RUNX1', 'Gene', (77, 82))	('accelerated', 'PosReg', (84, 95))	('miR-582-5p', 'Chemical', '-', (43, 53))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('RUNX1', 'Gene', '861', (77, 82))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('promoting', 'PosReg', (122, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))
188937	33937021	The mutant (MUT) or wild-type (WT) sequences containing the predicted target site of miR-582-5p in the 3'UTRs of COL5A1 mRNA were inserted into the mir-GLO vectors (Promega Corporation, Madison, WI, USA).	('COL5A1', 'Gene', (113, 119))	('mir', 'Gene', (148, 151))	('mutant', 'Var', (4, 10))	('COL5A1', 'Gene', '1289', (113, 119))	('mir', 'Gene', '220972', (148, 151))	('miR-582-5p', 'Chemical', '-', (85, 95))
188939	33937021	A total of 1x107-5x107 cells were collected and 1% formaldehyde (Bio-Rad, CA, USA) was used to crosslink the proteins to the DNA for 25 min.	('Rad', 'Gene', (69, 72))	('formaldehyde', 'Chemical', 'MESH:D005557', (51, 63))	('proteins', 'Protein', (109, 117))	('DNA', 'cellular_component', 'GO:0005574', ('125', '128'))	('Rad', 'biological_process', 'GO:1990116', ('69', '72'))	('Rad', 'Gene', '6236', (69, 72))	('crosslink', 'Var', (95, 104))
188944	33937021	To explore the primary role of miR-582-5p in ccRCC, we quantified the expression of miR-582-5p in 40 ccRCC tissues and their adjacent normal tissues by qRT-PCR.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('miR-582-5p', 'Chemical', '-', (31, 41))	('miR-582-5p', 'Chemical', '-', (84, 94))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('miR-582-5p', 'Var', (84, 94))
188945	33937021	As compared with normal tissues, the expression level of miR-582-5p was significantly decreased in tumor tissues (P<0.001) ( Figure 1A ).	('tumor', 'Disease', (99, 104))	('miR-582-5p', 'Var', (57, 67))	('miR-582-5p', 'Chemical', '-', (57, 67))	('expression level', 'MPA', (37, 53))	('decreased', 'NegReg', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
188947	33937021	We found that miR-582-5p was high expressed in T1 stage and non-metastatic patients compared with T2-T4 stage and those metastatic patients ( Figure 1B ).	('non-metastatic', 'Disease', (60, 74))	('patients', 'Species', '9606', (131, 139))	('miR-582-5p', 'Chemical', '-', (14, 24))	('patients', 'Species', '9606', (75, 83))	('T1 stage', 'Disease', (47, 55))	('miR-582-5p', 'Var', (14, 24))
188948	33937021	As to cell lines, qRT-PCR results showed that miR-582-5p was significantly decreased in various ccRCC cell lines (including 786-O, 769-P, Caki-1, ACHN and A498) compared with human renal tubular epithelial cells (HK2) ( Figure 1C ).	('miR-582-5p', 'Var', (46, 56))	('human', 'Species', '9606', (175, 180))	('Caki-1', 'CellLine', 'CVCL:0234', (138, 144))	('HK2', 'molecular_function', 'GO:0008256', ('213', '216'))	('miR-582-5p', 'Chemical', '-', (46, 56))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('decreased', 'NegReg', (75, 84))	('HK2', 'CellLine', 'CVCL:0302', (213, 216))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('ACHN', 'Gene', '55323', (146, 150))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('ACHN', 'Gene', (146, 150))
188949	33937021	In conclusion, miR-582-5p was aberrant shrunk in ccRCC especially in higher T stage and metastatic patients.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('miR-582-5p', 'Chemical', '-', (15, 25))	('patients', 'Species', '9606', (99, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('miR-582-5p', 'Var', (15, 25))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
188950	33937021	Considering that miR-582-5p was obviously attenuated in 786-O and Caki-1 cells, these two cell lined were chosen to be transfected with miR-582-5p mimics and corresponding negative control (NC).	('miR-582-5p', 'Chemical', '-', (17, 27))	('attenuated', 'NegReg', (42, 52))	('miR-582-5p', 'Var', (136, 146))	('miR-582-5p', 'Chemical', '-', (136, 146))	('Caki-1', 'CellLine', 'CVCL:0234', (66, 72))	('miR-582-5p', 'Gene', (17, 27))
188951	33937021	To investigate the effects of miR-582-5p on cell proliferation, we first conducted CCK8 assay and found that the viability of cells which transfected with miR-582-5p mimics significantly decreased after 72h compared with NC( Figure 2B ).	('2h', 'Chemical', 'MESH:D003903', (204, 206))	('miR-582-5p', 'Chemical', '-', (155, 165))	('miR-582-5p', 'Chemical', '-', (30, 40))	('decreased', 'NegReg', (187, 196))	('miR-582-5p mimics', 'Var', (155, 172))	('cell proliferation', 'biological_process', 'GO:0008283', ('44', '62'))
188952	33937021	Furthermore, the results from colony assay reveal that miR-582-5p mimics notably inhibited the colonies ( Figure 2C ).	('colonies', 'CPA', (95, 103))	('miR-582-5p mimics', 'Var', (55, 72))	('miR-582-5p', 'Chemical', '-', (55, 65))	('inhibited', 'NegReg', (81, 90))
188954	33937021	The results displayed that overexpression of miR-582-5p notably weaken the invasive ability of 786-O and Caki-1 cells ( Figure 2D ).	('miR-582-5p', 'Chemical', '-', (45, 55))	('weaken', 'NegReg', (64, 70))	('Caki-1', 'CellLine', 'CVCL:0234', (105, 111))	('miR-582-5p', 'Var', (45, 55))	('overexpression', 'PosReg', (27, 41))
188955	33937021	Furthermore, to determine whether miR-582-5p was involved in tumorigenesis in vivo, xenograft tumor models were established in BALB/c (nu/nu) mice.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('miR-582-5p', 'Var', (34, 44))	('involved', 'Reg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (94, 99))	('mice', 'Species', '10090', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('miR-582-5p', 'Chemical', '-', (34, 44))	('tumor', 'Disease', (61, 66))
188957	33937021	The volume of the tumors derived from miR-582-5p overexpressing cells was dramatically reduced compared to that in the tumors derived from control cells ( Figure 3A ).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('reduced', 'NegReg', (87, 94))	('tumors', 'Disease', (18, 24))	('volume', 'CPA', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('miR-582-5p overexpressing', 'Var', (38, 63))	('miR-582-5p', 'Chemical', '-', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
188958	33937021	Additionally, the IHC result of tissue derived from the mice showed that miR-582-5p obviously decrease the expression Ki-67 protein ( Figure 3B ).	('Ki-67', 'Gene', '17345', (118, 123))	('miR-582-5p', 'Chemical', '-', (73, 83))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('expression', 'MPA', (107, 117))	('mice', 'Species', '10090', (56, 60))	('Ki-67', 'Gene', (118, 123))	('decrease', 'NegReg', (94, 102))	('miR-582-5p', 'Var', (73, 83))
188959	33937021	In summary, these results demonstrated that miR-582-5p inhibited ccRCC proliferation in vivo.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('miR-582-5p', 'Var', (44, 54))	('RCC', 'Disease', (67, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('miR-582-5p', 'Chemical', '-', (44, 54))	('inhibited', 'NegReg', (55, 64))
188964	33937021	Further analysis showed that there was a negative correlation between miR-582-5p and COL5A1 in tumor tissues (r=0.6433, P<0.01) ( Figure 4C ).	('miR-582-5p', 'Chemical', '-', (70, 80))	('COL5A1', 'Gene', (85, 91))	('COL5A1', 'Gene', '1289', (85, 91))	('negative', 'NegReg', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('miR-582-5p', 'Var', (70, 80))	('tumor', 'Disease', (95, 100))
188971	33937021	Taken together, above results revealed that miR-582-5p could influence COL5A1 expression by directly binding to 3'-UTR of COL5A1.	('expression', 'MPA', (78, 88))	('COL5A1', 'Gene', '1289', (71, 77))	('COL5A1', 'Gene', '1289', (122, 128))	('miR-582-5p', 'Var', (44, 54))	('influence', 'Reg', (61, 70))	('binding', 'Interaction', (101, 108))	('binding', 'molecular_function', 'GO:0005488', ('101', '108'))	('miR-582-5p', 'Chemical', '-', (44, 54))	('COL5A1', 'Gene', (71, 77))	('COL5A1', 'Gene', (122, 128))
188972	33937021	The functional relevance of COL5A1 targeting by miR-582-5P was investigated by determining whether COL5A1 overexpression could rescue the inhibitory effects of miR-582-5p on ccRCC cell proliferation and invasion.	('inhibitory', 'MPA', (138, 148))	('COL5A1', 'Gene', (99, 105))	('RCC', 'Disease', (176, 179))	('COL5A1', 'Gene', '1289', (99, 105))	('miR-582-5p', 'Var', (160, 170))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('cell proliferation', 'biological_process', 'GO:0008283', ('180', '198'))	('COL5A1', 'Gene', (28, 34))	('COL5A1', 'Gene', '1289', (28, 34))	('miR-582-5p', 'Chemical', '-', (160, 170))	('ccRCC', 'Phenotype', 'HP:0006770', (174, 179))	('invasion', 'CPA', (203, 211))
188975	33937021	CCK-8 assay and colony formation assay suggested that the overexpression of COL5A1 rescued the inhibitory effect of miR-582-5p on cell proliferation in vitro ( Figures 5B, C ).	('cell proliferation in vitro', 'CPA', (130, 157))	('cell proliferation', 'biological_process', 'GO:0008283', ('130', '148'))	('miR-582-5p', 'Var', (116, 126))	('COL5A1', 'Gene', (76, 82))	('formation', 'biological_process', 'GO:0009058', ('23', '32'))	('inhibitory effect', 'MPA', (95, 112))	('COL5A1', 'Gene', '1289', (76, 82))	('miR-582-5p', 'Chemical', '-', (116, 126))
188976	33937021	Transwell assays showed that the invasion ability inhibited by miR-582-5p was remarkably rescued by the COL5A1 overexpression ( Figure 5D ).	('miR-582-5p', 'Chemical', '-', (63, 73))	('COL5A1', 'Gene', (104, 110))	('miR-582-5p', 'Var', (63, 73))	('COL5A1', 'Gene', '1289', (104, 110))	('invasion ability', 'CPA', (33, 49))
188977	33937021	In vivo, the decreased tumor size and weight by miR-582-5p were reversed by COL5A1 overexpression ( Figure 5E ).	('decreased tumor', 'Disease', 'MESH:D002303', (13, 28))	('miR-582-5p', 'Chemical', '-', (48, 58))	('COL5A1', 'Gene', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('miR-582-5p', 'Var', (48, 58))	('overexpression', 'PosReg', (83, 97))	('COL5A1', 'Gene', '1289', (76, 82))	('decreased tumor', 'Disease', (13, 28))
188978	33937021	These results suggested that miR-582-5p influenced the growth and mobility of ccRCC cells by targeting COL5A1.	('miR-582-5p', 'Var', (29, 39))	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('growth', 'CPA', (55, 61))	('influenced', 'Reg', (40, 50))	('COL5A1', 'Gene', (103, 109))	('mobility', 'CPA', (66, 74))	('miR-582-5p', 'Chemical', '-', (29, 39))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('COL5A1', 'Gene', '1289', (103, 109))	('targeting', 'Reg', (93, 102))
188980	33937021	Of them, the putative score of RUNX1 binding to miR-582-5p was the highest ( Figure 6B ).	('binding', 'molecular_function', 'GO:0005488', ('37', '44'))	('binding', 'Interaction', (37, 44))	('RUNX1', 'Gene', (31, 36))	('miR-582-5p', 'Chemical', '-', (48, 58))	('RUNX1', 'Gene', '861', (31, 36))	('miR-582-5p', 'Var', (48, 58))
188981	33937021	Furthermore, ChIP assay indicated that RUNX1 binds to the putative binding site upstream of miR-582-5p ( Figure 6C ).	('miR-582-5p', 'Var', (92, 102))	('binding', 'molecular_function', 'GO:0005488', ('67', '74'))	('RUNX1', 'Gene', (39, 44))	('binds', 'Interaction', (45, 50))	('RUNX1', 'Gene', '861', (39, 44))	('miR-582-5p', 'Chemical', '-', (92, 102))
188985	33937021	Additionally, deletion of RUNXL1 was able to disrupt tumor cell growth both in vitro and in vivo.	('cell growth', 'biological_process', 'GO:0016049', ('59', '70'))	('disrupt', 'NegReg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('RUNXL1', 'Gene', (26, 32))	('deletion', 'Var', (14, 22))
188986	33937021	Subsequently, we recruited a rescue assay to figure out whether miR-582-5p could rescue the overexpressed RUNX1 effect.	('RUNX1', 'Gene', '861', (106, 111))	('miR-582-5p', 'Var', (64, 74))	('miR-582-5p', 'Chemical', '-', (64, 74))	('RUNX1', 'Gene', (106, 111))
188988	33937021	Moreover, the results showed that miR-582-5p overexpression could partially rescue the effects of RUNX1 on cell proliferation and invasion in ccRCC cell lines ( Figures 6H-J ).	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('miR-582-5p', 'Chemical', '-', (34, 44))	('cell proliferation', 'biological_process', 'GO:0008283', ('107', '125'))	('miR-582-5p', 'Var', (34, 44))	('invasion', 'CPA', (130, 138))	('cell proliferation', 'CPA', (107, 125))	('RUNX1', 'Gene', (98, 103))	('RUNX1', 'Gene', '861', (98, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))
188989	33937021	In vivo, the miR-582-5p induced tumor shrinkage was reversed by RUNX1 overexpression ( Figure 6K ).	('miR-582-5p', 'Chemical', '-', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('miR-582-5p', 'Var', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('RUNX1', 'Gene', (64, 69))	('tumor', 'Disease', (32, 37))	('overexpression', 'PosReg', (70, 84))	('RUNX1', 'Gene', '861', (64, 69))
188996	33937021	As shown in the schematic diagram ( Figure 7 ), RUNX1-mediated miR-582-5p regulates the cell proliferation and invasion of ccRCC by targeting COL5A1.	('targeting', 'Reg', (132, 141))	('miR-582-5p', 'Chemical', '-', (63, 73))	('regulates', 'Reg', (74, 83))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('COL5A1', 'Gene', (142, 148))	('miR-582-5p', 'Var', (63, 73))	('cell proliferation', 'CPA', (88, 106))	('cell proliferation', 'biological_process', 'GO:0008283', ('88', '106'))	('COL5A1', 'Gene', '1289', (142, 148))	('invasion', 'CPA', (111, 119))	('RUNX1', 'Gene', (48, 53))	('RUNX1', 'Gene', '861', (48, 53))
188997	33937021	Our study first proved the expression pattern and mechanism of miR-582-5p in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('miR-582-5p', 'Chemical', '-', (63, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('miR-582-5p', 'Var', (63, 73))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
189000	33937021	Findings also revealed that miR-582-5p overexpression prominently inhibited RCC cell proliferation and invasion capacities.	('overexpression', 'PosReg', (39, 53))	('miR-582-5p', 'Chemical', '-', (28, 38))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('invasion capacities', 'CPA', (103, 122))	('miR-582-5p', 'Var', (28, 38))	('cell proliferation', 'biological_process', 'GO:0008283', ('80', '98'))	('inhibited', 'NegReg', (66, 75))
189001	33937021	Additionally, cell line-derived xenograft model was utilized which further confirmed the tumor-suppressive role of miR-582-5p in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (129, 134))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('miR-582-5p', 'Chemical', '-', (115, 125))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('miR-582-5p', 'Var', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
189009	33937021	Therefore we presumed that COL5A1 was the target of miR-582-5p.	('COL5A1', 'Gene', '1289', (27, 33))	('COL5A1', 'Gene', (27, 33))	('miR-582-5p', 'Var', (52, 62))	('miR-582-5p', 'Chemical', '-', (52, 62))
189012	33937021	In addition, we then performed rescue assay to confirm the relation between miR-582-5p and COL5A1.	('miR-582-5p', 'Var', (76, 86))	('miR-582-5p', 'Chemical', '-', (76, 86))	('COL5A1', 'Gene', '1289', (91, 97))	('COL5A1', 'Gene', (91, 97))
189013	33937021	The results showed that overexpression of COL5A1 could partially reverse the inhibition of cell proliferation and invasion by miR-582-5p.	('COL5A1', 'Gene', (42, 48))	('miR-582-5p', 'Var', (126, 136))	('COL5A1', 'Gene', '1289', (42, 48))	('overexpression', 'PosReg', (24, 38))	('miR-582-5p', 'Chemical', '-', (126, 136))	('invasion', 'CPA', (114, 122))	('cell proliferation', 'CPA', (91, 109))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('77', '109'))
189017	33937021	RUNX1 was involved in the development of normal hematopoiesis, while its mutation and translocations had been associated with several types of leukemia.	('hematopoiesis', 'biological_process', 'GO:0030097', ('48', '61'))	('leukemia', 'Phenotype', 'HP:0001909', (143, 151))	('translocations', 'Var', (86, 100))	('leukemia', 'Disease', 'MESH:D007938', (143, 151))	('leukemia', 'Disease', (143, 151))	('associated', 'Reg', (110, 120))	('RUNX1', 'Gene', (0, 5))	('mutation', 'Var', (73, 81))	('RUNX1', 'Gene', '861', (0, 5))
189023	33937021	In our study, ChIP assay indicated the RUNX1 bind to the binding site upstream of miR-582-5p.	('RUNX1', 'Gene', (39, 44))	('miR-582-5p', 'Var', (82, 92))	('RUNX1', 'Gene', '861', (39, 44))	('binding', 'molecular_function', 'GO:0005488', ('57', '64'))	('bind', 'Interaction', (45, 49))	('miR-582-5p', 'Chemical', '-', (82, 92))
189024	33937021	Over-expression of RUNX1 led to decreased miR-582-5p expression and increased COL5A1 expression, which demonstrates that there is an axis among RUNX1/miR-582-5p/COL5A1 signaling.	('COL5A1', 'Gene', (78, 84))	('expression', 'MPA', (85, 95))	('miR-582-5p', 'Chemical', '-', (42, 52))	('RUNX1', 'Gene', (19, 24))	('COL5A1', 'Gene', '1289', (78, 84))	('COL5A1', 'Gene', (161, 167))	('decreased', 'NegReg', (32, 41))	('RUNX1', 'Gene', '861', (19, 24))	('RUNX1', 'Gene', '861', (144, 149))	('COL5A1', 'Gene', '1289', (161, 167))	('miR-582-5p expression', 'MPA', (42, 63))	('Over-expression', 'Var', (0, 15))	('miR-582-5p', 'Chemical', '-', (150, 160))	('RUNX1', 'Gene', (144, 149))	('signaling', 'biological_process', 'GO:0023052', ('168', '177'))	('increased', 'PosReg', (68, 77))
189025	33937021	Over-expression of RUNX1 caused increasing cell proliferation and invasion, suggesting that RUNX1 contributed to the tumor growth by modulating miR-582-5p expression.	('increasing', 'PosReg', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('RUNX1', 'Gene', (19, 24))	('cell proliferation', 'biological_process', 'GO:0008283', ('43', '61'))	('tumor', 'Disease', (117, 122))	('miR-582-5p expression', 'MPA', (144, 165))	('RUNX1', 'Gene', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('RUNX1', 'Gene', '861', (19, 24))	('RUNX1', 'Gene', '861', (92, 97))	('Over-expression', 'Var', (0, 15))	('invasion', 'CPA', (66, 74))	('cell proliferation', 'CPA', (43, 61))	('modulating', 'Reg', (133, 143))	('miR-582-5p', 'Chemical', '-', (144, 154))
189026	33937021	In summary, the study availed a better understanding of the function of miR-582-5p in ccRCC.	('miR-582-5p', 'Chemical', '-', (72, 82))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('miR-582-5p', 'Var', (72, 82))
189028	33937021	These findings indicated a tumor suppressor role of miR-582-5p in ccRCC development and might serve as a potential therapeutic target in ccRCC.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('miR-582-5p', 'Chemical', '-', (52, 62))	('tumor', 'Disease', (27, 32))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('RCC', 'Disease', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('miR-582-5p', 'Var', (52, 62))	('tumor suppressor', 'biological_process', 'GO:0051726', ('27', '43'))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('27', '43'))
189098	33072556	IHC staining of ALI PDOs showed positivity for CD8 and granzyme B (Figure 4).	('granzyme B', 'Gene', '3002', (55, 65))	('CD8', 'Gene', (47, 50))	('granzyme B', 'Gene', (55, 65))	('CD8', 'Gene', '925', (47, 50))	('positivity', 'Var', (32, 42))
189135	33072556	However, ALI PDOs provide the additional benefit that therapeutic effects can also be addressed on the tumor microenvironment.	('ALI', 'Var', (9, 12))	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
189246	31915310	In our further study, we plan to use our PDX (Patient Derived Xenograft) mouse model to test whether inhibition of EMT pathway would influence ccRCC progression.	('inhibition', 'Var', (101, 111))	('RCC', 'Disease', (145, 148))	('RCC', 'Disease', 'MESH:D002292', (145, 148))	('influence', 'Reg', (133, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (143, 148))	('EMT pathway', 'Pathway', (115, 126))	('mouse', 'Species', '10090', (73, 78))	('EMT', 'biological_process', 'GO:0001837', ('115', '118'))	('progression', 'CPA', (149, 160))	('PDX', 'Chemical', 'MESH:C113421', (41, 44))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))
189283	31099194	Methylation Signature for Prediction of Progression Free Survival in Surgically Treated Clear Cell Renal Cell Carcinoma Little is known about epigenetic silencing of genes by promoter hypermethylation in renal cell carcinoma (RCC).	('promoter hypermethylation', 'Var', (175, 200))	('renal cell carcinoma', 'Disease', (204, 224))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (88, 119))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (204, 224))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (88, 119))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (204, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('Carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('RCC', 'Disease', (226, 229))	('Clear Cell Renal Cell Carcinoma', 'Disease', (88, 119))	('RCC', 'Disease', 'MESH:C538614', (226, 229))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (99, 119))
189289	31099194	The hypermethylation of three genes were associated with advanced tumor stage and high grade tumor in ccRCC.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('associated', 'Reg', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', (93, 98))	('hypermethylation', 'Var', (4, 20))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('RCC', 'Disease', (104, 107))
189301	31099194	Although previous epigenetic studies have identified a number of frequently methylated genes in RCC, few studies have determined the prognostic implications of DNA methylation profile in RCC.	('RCC', 'Disease', (96, 99))	('RCC', 'Disease', (187, 190))	('RCC', 'Disease', 'MESH:C538614', (187, 190))	('DNA methylation', 'biological_process', 'GO:0006306', ('160', '175'))	('methylated', 'Var', (76, 86))	('DNA', 'cellular_component', 'GO:0005574', ('160', '163'))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
189318	31099194	Receiver operating characteristic curves were constructed to estimate the capability of candidate markers for the prediction of metastasis, and to determine the optimal cut-off point for dividing patients into subgroups (hypomethylation or hypermethylation) with the highest combined sensitivity and specificity.	('hypomethylation', 'Var', (221, 236))	('hypermethylation', 'Var', (240, 256))	('metastasis', 'CPA', (128, 138))	('patients', 'Species', '9606', (196, 204))
189322	31099194	Using selection criteria (  beta value > 0.25 and mean beta value of matched normal kidney < 0.15), 104 unique CpG island loci that were hypermethylated in ccRCC compared with the NCs were identified.	('hypermethylated', 'Var', (137, 152))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))
189327	31099194	The hypermethylation of three genes were associated with advanced tumor stage and higher tumor grade (all P < 0.05) (Table 3).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('associated', 'Reg', (41, 51))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('hypermethylation', 'Var', (4, 20))
189328	31099194	Multivariate analysis identified the methylation status of candidate three genes in each (ZNF278, HR, 7.012, P = 0.008; FAM155A, HR, 7.080, P = 0.008; DPP6, HR, 6.444, P = 0.011) (data not shown), or in a integrate methylation score of three candidate genes (M-score, HR, 3.804; P = 0.006) (Table 4) as an independent predictor of distant metastasis.	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('ZNF278', 'Gene', (90, 96))	('methylation', 'Var', (37, 48))	('DPP6', 'Gene', '1804', (151, 155))	('distant metastasis', 'CPA', (331, 349))	('FAM155A', 'Gene', (120, 127))	('ZNF278', 'Gene', '23598', (90, 96))	('FAM155A', 'Gene', '728215', (120, 127))	('DPP6', 'Gene', (151, 155))	('methylation', 'biological_process', 'GO:0032259', ('215', '226'))
189331	31099194	Notably, the methylation status of these candidate genes, either single or combined was closely related to not only tumor histology but also development of metastasis in surgically treated ccRCC.	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('RCC', 'Disease', (191, 194))	('men', 'Species', '9606', (148, 151))	('RCC', 'Disease', 'MESH:C538614', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('related', 'Reg', (96, 103))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('methylation status', 'Var', (13, 31))
189333	31099194	Aberrant methylation of promoter CpG islands is an important inactivation mechanism of tumor suppressors and tumor-related genes.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('Aberrant methylation', 'Var', (0, 20))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('inactivation', 'NegReg', (61, 73))	('tumor', 'Disease', (109, 114))
189334	31099194	Methylation-induced silencing in early phases of tumorigenesis could potentially be used as markers for identifying individuals at increased risk of developing malignancy or for aiding in the diagnosis of early malignancy, whereas those genes undergoing methylation during the progression of malignancy could potentially be used as prognostic markers.	('malignancy', 'Disease', (160, 170))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('malignancy', 'Disease', 'MESH:D009369', (292, 302))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('malignancy', 'Disease', (292, 302))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('malignancy', 'Disease', 'MESH:D009369', (160, 170))	('Methylation-induced', 'Var', (0, 19))	('silencing', 'NegReg', (20, 29))	('malignancy', 'Disease', 'MESH:D009369', (211, 221))	('malignancy', 'Disease', (211, 221))	('methylation', 'biological_process', 'GO:0032259', ('254', '265'))
189340	31099194	They observed differing patterns of tumour-specific CpG methylation in VHL and non VHL ccRCC and papillary RCC.	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('VHL', 'Gene', '7428', (83, 86))	('RCC', 'Disease', (107, 110))	('tumour', 'Disease', (36, 42))	('VHL', 'Gene', (71, 74))	('papillary RCC', 'Disease', 'MESH:C538614', (97, 110))	('VHL', 'Gene', '7428', (71, 74))	('RCC', 'Disease', (89, 92))	('papillary RCC', 'Disease', (97, 110))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('methylation', 'Var', (56, 67))	('VHL', 'Gene', (83, 86))
189342	31099194	They identified a number of genes, including KLHL35, QPCT, SCUBE3, ZSCAN18, CCDC8, FBN2, ATP5G2, PCDH8 and CORO6 were frequently methylated in RCC and promoter hypermethylation of these genes resulted in significant reduction of their expression level.	('promoter hypermethylation', 'Var', (151, 176))	('CCDC8', 'Gene', '83987', (76, 81))	('ATP5G2', 'Gene', '517', (89, 95))	('SCUBE3', 'Gene', '222663', (59, 65))	('ZSCAN18', 'Gene', '65982', (67, 74))	('KLHL35', 'Gene', '283212', (45, 51))	('FBN2', 'Gene', (83, 87))	('reduction', 'NegReg', (216, 225))	('QPCT', 'Gene', (53, 57))	('KLHL35', 'Gene', (45, 51))	('CORO6', 'Gene', '84940', (107, 112))	('PCDH8', 'Gene', '5100', (97, 102))	('FBN2', 'Gene', '2201', (83, 87))	('expression level', 'MPA', (235, 251))	('ZSCAN18', 'Gene', (67, 74))	('SCUBE3', 'Gene', (59, 65))	('RCC', 'Disease', (143, 146))	('ATP5G2', 'Gene', (89, 95))	('PCDH8', 'Gene', (97, 102))	('QPCT', 'Gene', '25797', (53, 57))	('CCDC8', 'Gene', (76, 81))	('CORO6', 'Gene', (107, 112))	('RCC', 'Disease', 'MESH:C538614', (143, 146))
189344	31099194	Eight novel ccRCC TSG candidates were identified, including OVOL1, DLEC1, BMP4, SST, TMPRSS2, TM6SF1, SLC34A2, and COL1A2, which demonstrated methylation in kidney cancer cell lines, re-expression in kidney cancer cell lines after 5-aza-20-deoxycytidine treatment, and tumor-specific methylation.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('RCC', 'Disease', (14, 17))	('COL1A2', 'Gene', '1278', (115, 121))	('TM6SF1', 'Gene', '53346', (94, 100))	('methylation', 'biological_process', 'GO:0032259', ('284', '295'))	('TMPRSS2', 'Gene', '7113', (85, 92))	('kidney cancer', 'Disease', 'MESH:D007680', (200, 213))	('OVOL1', 'Gene', (60, 65))	('DLEC1', 'Gene', '9940', (67, 72))	('methylation', 'Var', (142, 153))	('SST', 'Gene', (80, 83))	('BMP4', 'Gene', (74, 78))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('TMPRSS2', 'Gene', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('COL1A2', 'Gene', (115, 121))	('kidney cancer', 'Phenotype', 'HP:0009726', (200, 213))	('SLC34A2', 'Gene', '10568', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('kidney cancer', 'Disease', (200, 213))	('TM6SF1', 'Gene', (94, 100))	('kidney cancer', 'Disease', 'MESH:D007680', (157, 170))	('SLC34A2', 'Gene', (102, 109))	('methylation', 'biological_process', 'GO:0032259', ('142', '153'))	('SST', 'Gene', '6750', (80, 83))	('BMP4', 'Gene', '652', (74, 78))	('DLEC1', 'Gene', (67, 72))	('kidney cancer', 'Phenotype', 'HP:0009726', (157, 170))	('deoxycytidine', 'Chemical', 'MESH:D003841', (240, 253))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('kidney cancer', 'Disease', (157, 170))	('re-expression', 'PosReg', (183, 196))	('tumor', 'Disease', (269, 274))	('men', 'Species', '9606', (259, 262))	('OVOL1', 'Gene', '5017', (60, 65))	('5-aza-20', 'Chemical', '-', (231, 239))
189345	31099194	Moreover, OVOL1 knockdown increased c-Myc mRNA levels which may lead to c-Myc pathway activation.	('c-Myc', 'Gene', '4609', (72, 77))	('c-Myc', 'Gene', (72, 77))	('knockdown', 'Var', (16, 25))	('c-Myc', 'Gene', '4609', (36, 41))	('increased', 'PosReg', (26, 35))	('OVOL1', 'Gene', '5017', (10, 15))	('activation', 'PosReg', (86, 96))	('OVOL1', 'Gene', (10, 15))	('c-Myc', 'Gene', (36, 41))
189348	31099194	From a prognostic point of view, the methylation status of these candidate genes, either single or combined was closely related to not only tumor histology but also development of metastasis in surgically treated ccRCC.	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('RCC', 'Disease', 'MESH:C538614', (215, 218))	('RCC', 'Disease', (215, 218))	('methylation status', 'Var', (37, 55))	('related', 'Reg', (120, 127))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('men', 'Species', '9606', (172, 175))	('tumor', 'Disease', (140, 145))
189358	31099194	In conclusion, the present study identified potential methylation markers which could represent the aggressive tumor phenotype and early development of distant metastasis in ccRCC.	('men', 'Species', '9606', (144, 147))	('RCC', 'Disease', (176, 179))	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('methylation', 'Var', (54, 65))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('aggressive tumor', 'Disease', 'MESH:D001523', (100, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('aggressive tumor', 'Disease', (100, 116))
189363	32276433	Special focus is given on the impact of mutations and altered expression of ciliary genes (e.g., encoding polycystins, nephrocystins, Bardet-Biedl syndrome (BBS) proteins, ALS1, Oral-facial-digital syndrome 1 (OFD1) and others) in polycystic kidney disease and nephronophthisis, as well as rare genetic disorders, including syndromes of Joubert, Meckel-Gruber, Bardet-Biedl, Senior-Loken, Alstrom, Orofaciodigital syndrome type I and cranioectodermal dysplasia.	('Oral-facial-digital syndrome 1', 'Gene', (178, 208))	('cranioectodermal dysplasia', 'Disease', (434, 460))	('Orofaciodigital syndrome type I', 'Disease', (398, 429))	('cranioectodermal dysplasia', 'Disease', 'MESH:C562966', (434, 460))	('polycystic kidney', 'Phenotype', 'HP:0000113', (231, 248))	('nephronophthisis', 'Phenotype', 'HP:0000090', (261, 277))	('OFD1', 'Gene', (210, 214))	('cystic kidney', 'Phenotype', 'HP:0000107', (235, 248))	('Alstrom', 'Disease', (389, 396))	('mutations', 'Var', (40, 49))	('polycystic kidney disease', 'Disease', 'MESH:D007690', (231, 256))	('kidney disease', 'Phenotype', 'HP:0000112', (242, 256))	('BBS', 'Gene', (157, 160))	('nephronophthisis', 'Disease', 'MESH:C537699', (261, 277))	('cranioectodermal dysplasia', 'Phenotype', 'HP:0000968', (434, 460))	('Senior-Loken', 'Disease', (375, 387))	('ALS1', 'Gene', (172, 176))	('nephrocystins, Bardet-Biedl syndrome', 'Disease', 'MESH:D020788', (119, 155))	('BBS', 'Gene', '583', (157, 160))	('genetic disorders', 'Disease', 'MESH:D030342', (295, 312))	('ALS1', 'Gene', '6647', (172, 176))	('Bardet-Biedl', 'Disease', (361, 373))	('Orofaciodigital syndrome type I', 'Disease', 'MESH:C537134', (398, 429))	('Meckel-Gruber', 'Disease', (346, 359))	('nephronophthisis', 'Disease', (261, 277))	('genetic disorders', 'Disease', (295, 312))	('OFD1', 'Gene', '8481', (210, 214))	('polycystic kidney disease', 'Disease', (231, 256))	('Oral-facial-digital syndrome 1', 'Gene', '8481', (178, 208))
189364	32276433	We also show that RCC and classic kidney ciliopathies share commonly disturbed genes affecting cilia function, including VHL (von Hippel-Lindau tumor suppressor), PKD1 (polycystin 1, transient receptor potential channel interacting) and PKD2 (polycystin 2, transient receptor potential cation channel).	('PKD2', 'Gene', '5311', (237, 241))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('144', '160'))	('von Hippel-Lindau tumor suppressor', 'Gene', (126, 160))	('polycystin', 'molecular_function', 'GO:0005227', ('169', '179'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('144', '160'))	('classic kidney ciliopathies', 'Disease', (26, 53))	('affecting', 'Reg', (85, 94))	('polycystin 2', 'Gene', (243, 255))	('polycystin 2', 'Gene', '5311', (243, 255))	('RCC', 'Disease', (18, 21))	('RCC', 'Phenotype', 'HP:0005584', (18, 21))	('classic kidney ciliopathies', 'Disease', 'MESH:D000072661', (26, 53))	('VHL', 'Gene', (121, 124))	('von Hippel-Lindau tumor suppressor', 'Gene', '7428', (126, 160))	('RCC', 'Disease', 'MESH:C538614', (18, 21))	('cilia function', 'CPA', (95, 109))	('polycystin', 'molecular_function', 'GO:0005227', ('243', '253'))	('polycystin 1', 'Gene', '5310', (169, 181))	('PKD2', 'Gene', (237, 241))	('PKD1', 'Var', (163, 167))	('polycystin 1', 'Gene', (169, 181))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
189371	32276433	Structural or functional impairments of primary cilia caused by mutations in ciliary genes lead to dysregulation of signals transduction or inability to response to stimuli.	('inability', 'Disease', 'MESH:D007319', (140, 149))	('dysregulation of signals transduction', 'MPA', (99, 136))	('Structural or functional impairments of primary cilia', 'Disease', 'MESH:D028361', (0, 53))	('inability', 'Disease', (140, 149))	('ciliary genes', 'Gene', (77, 90))	('mutations', 'Var', (64, 73))	('transduction', 'biological_process', 'GO:0009293', ('124', '136'))	('response to stimuli', 'MPA', (153, 172))
189372	32276433	For instance, Wnt signaling pathway required for the growth of renal tubules in mouse is disrupted by mutations of Invs, a ciliary gene encoding inversin.	('Invs', 'Gene', '16348', (115, 119))	('Wnt signaling pathway', 'Pathway', (14, 35))	('Invs', 'Gene', (115, 119))	('mouse', 'Species', '10090', (80, 85))	('disrupted', 'NegReg', (89, 98))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('14', '35'))	('mutations', 'Var', (102, 111))
189373	32276433	In humans, INVS mutations cause nephronophthisis.	('cause', 'Reg', (26, 31))	('nephronophthisis', 'Phenotype', 'HP:0000090', (32, 48))	('mutations', 'Var', (16, 25))	('humans', 'Species', '9606', (3, 9))	('INVS', 'Gene', (11, 15))	('nephronophthisis', 'Disease', 'MESH:C537699', (32, 48))	('nephronophthisis', 'Disease', (32, 48))
189374	32276433	Mutations in PKD1 and PKD2 genes, encoding polycystins expressed at kidney primary cilia disrupt formation of cation channel, impairing Ca2+ influx and detection of fluid flow.	('PKD1', 'Gene', (13, 17))	('disrupt', 'NegReg', (89, 96))	('formation', 'biological_process', 'GO:0009058', ('97', '106'))	('Ca2+ influx', 'MPA', (136, 147))	('Ca2+', 'Chemical', 'MESH:D000069285', (136, 140))	('Mutations', 'Var', (0, 9))	('PKD2', 'Gene', '5311', (22, 26))	('formation of cation channel', 'MPA', (97, 124))	('PKD2', 'Gene', (22, 26))	('impairing', 'NegReg', (126, 135))	('detection of fluid flow', 'MPA', (152, 175))
189375	32276433	Finally, mutations that disrupt cilia formation disable signaling mediated by Pdgfralpha (platelet-derived growth factor receptor alpha).	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('90', '120'))	('disable', 'NegReg', (48, 55))	('mutations', 'Var', (9, 18))	('formation', 'biological_process', 'GO:0009058', ('38', '47'))	('signaling', 'MPA', (56, 65))	('Pdgfralpha (platelet-derived growth factor receptor alpha', 'Gene', '5156', (78, 135))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))	('cilia formation', 'CPA', (32, 47))
189378	32276433	Dynein arms defects are caused, among others, by mutations in genes encoding heavy chain subunits of dynein, DNAH5 and DNAH11.	('DNAH5', 'Gene', '1767', (109, 114))	('mutations', 'Var', (49, 58))	('Dynein arms defects', 'Disease', 'MESH:D001134', (0, 19))	('DNAH11', 'Gene', (119, 125))	('dynein', 'molecular_function', 'GO:0003777', ('101', '107'))	('Dynein arms defects', 'Disease', (0, 19))	('Dynein', 'molecular_function', 'GO:0003777', ('0', '6'))	('DNAH5', 'Gene', (109, 114))	('DNAH11', 'Gene', '8701', (119, 125))	('caused', 'Reg', (24, 30))
189379	32276433	One of the clinical symptoms of mutated dynein is loss of ciliary function in respiratory tract resulting in chronic respiratory infections.	('loss of cilia', 'Disease', 'MESH:C536287', (50, 63))	('respiratory infections', 'Phenotype', 'HP:0011947', (117, 139))	('mutated', 'Var', (32, 39))	('respiratory infections', 'Disease', (117, 139))	('dynein', 'molecular_function', 'GO:0003777', ('40', '46'))	('loss of cilia', 'Disease', (50, 63))	('respiratory infections', 'Disease', 'MESH:D012141', (117, 139))
189381	32276433	In the mouse node, defective cilia abolish leftward fluid flow and cause asymmetric gene expression and disturbed morphogenesis.	('cause', 'Reg', (67, 72))	('cilia', 'CPA', (29, 34))	('abolish', 'NegReg', (35, 42))	('mouse', 'Species', '10090', (7, 12))	('morphogenesis', 'biological_process', 'GO:0009653', ('114', '127'))	('gene expression', 'biological_process', 'GO:0010467', ('84', '99'))	('defective', 'Var', (19, 28))	('asymmetric gene expression', 'MPA', (73, 99))	('disturbed morphogenesis', 'CPA', (104, 127))	('leftward fluid flow', 'CPA', (43, 62))
189382	32276433	The biomedical relevance of primary cilia was disclosed through the discovery of cyst formation induced by perturbed function of ciliary protein ift88 in the mouse kidney.	('perturbed function', 'Var', (107, 125))	('mouse', 'Species', '10090', (158, 163))	('ift88', 'Gene', '21821', (145, 150))	('formation', 'biological_process', 'GO:0009058', ('86', '95'))	('cyst formation', 'Disease', (81, 95))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('ift', 'biological_process', 'GO:0042073', ('145', '148'))	('ift88', 'Gene', (145, 150))
189384	32276433	The clinical features of ciliopathies are commonly shared by pleiotropic developmental disorders, including abnormalities in neural tube closure, polydactyly, liver diseases, retinal degeneration, anosmia, cognitive defects, obesity, randomization of the left-right body axis and cystic kidneys.	('neural tube closure', 'biological_process', 'GO:0001843', ('125', '144'))	('retinal degeneration', 'Disease', 'MESH:D012162', (175, 195))	('retinal degeneration', 'Disease', (175, 195))	('obesity', 'Disease', (225, 232))	('cystic kidneys', 'Disease', 'MESH:D052177', (280, 294))	('retinal degeneration', 'Phenotype', 'HP:0000546', (175, 195))	('anosmia', 'Phenotype', 'HP:0000458', (197, 204))	('abnormalities', 'Var', (108, 121))	('pleiotropic developmental disorders', 'Disease', 'MESH:D002658', (61, 96))	('anosmia', 'Disease', 'MESH:D000857', (197, 204))	('liver diseases', 'Phenotype', 'HP:0001392', (159, 173))	('obesity', 'Disease', 'MESH:D009765', (225, 232))	('cognitive defects', 'Disease', (206, 223))	('cystic kidney', 'Phenotype', 'HP:0000107', (280, 293))	('cognitive defects', 'Disease', 'MESH:D003072', (206, 223))	('abnormalities in neural tube closure', 'Phenotype', 'HP:0045005', (108, 144))	('neural tube closure', 'Disease', (125, 144))	('liver diseases', 'Disease', 'MESH:D008107', (159, 173))	('pleiotropic developmental disorders', 'Disease', (61, 96))	('polydactyly', 'Phenotype', 'HP:0010442', (146, 157))	('cystic kidneys', 'Phenotype', 'HP:0000107', (280, 294))	('cystic kidneys', 'Disease', (280, 294))	('anosmia', 'Disease', (197, 204))	('liver diseases', 'Disease', (159, 173))	('polydactyly', 'Disease', (146, 157))	('obesity', 'Phenotype', 'HP:0001513', (225, 232))	('cognitive defects', 'Phenotype', 'HP:0100543', (206, 223))
189386	32276433	Defective fluid flow sensing triggers formation of cysts, leading to ciliopathies, including polycystic kidney disease (PKD), Nephronophthisis (NPHP), Joubert syndrome, Meckel-Gruber syndrome, Bardet-Biedl syndrome, Senior-Loken syndrome (SLS), Alstrom syndrome (AS), Orofaciodigital syndrome type I (OFD) and Cranioectodermal dysplasia (CED).	('Meckel-Gruber syndrome', 'Disease', (169, 191))	('SLS', 'Disease', 'MESH:D016111', (239, 242))	('CED', 'Disease', 'MESH:D003966', (338, 341))	('Alstrom syndrome', 'Disease', (245, 261))	('Senior-Loken syndrome', 'Disease', 'MESH:C537580', (216, 237))	('Cranioectodermal dysplasia', 'Phenotype', 'HP:0000968', (310, 336))	('Bardet-Biedl syndrome', 'Disease', (193, 214))	('PKD', 'Disease', 'MESH:C537180', (120, 123))	('CED', 'Phenotype', 'HP:0000968', (338, 341))	('PKD', 'Disease', (120, 123))	('polycystic kidney disease', 'Disease', (93, 118))	('formation', 'biological_process', 'GO:0009058', ('38', '47'))	('Defective', 'Var', (0, 9))	('CED', 'Disease', (338, 341))	('Senior-Loken syndrome', 'Disease', (216, 237))	('Joubert syndrome', 'Disease', 'MESH:C536293', (151, 167))	('Orofaciodigital syndrome type I', 'Disease', 'MESH:C537134', (268, 299))	('Alstrom syndrome', 'Disease', 'MESH:D056769', (245, 261))	('SLS', 'Disease', (239, 242))	('polycystic kidney', 'Phenotype', 'HP:0000113', (93, 110))	('leading', 'Reg', (58, 65))	('Orofaciodigital syndrome type I', 'Disease', (268, 299))	('cystic kidney', 'Phenotype', 'HP:0000107', (97, 110))	('Bardet-Biedl syndrome', 'Disease', 'MESH:D020788', (193, 214))	('Cranioectodermal dysplasia', 'Disease', (310, 336))	('Cranioectodermal dysplasia', 'Disease', 'MESH:C562966', (310, 336))	('NPHP', 'Phenotype', 'HP:0000090', (144, 148))	('kidney disease', 'Phenotype', 'HP:0000112', (104, 118))	('Joubert syndrome', 'Disease', (151, 167))	('Nephronophthisis', 'Disease', (126, 142))	('Nephronophthisis', 'Phenotype', 'HP:0000090', (126, 142))	('polycystic kidney disease', 'Disease', 'MESH:D007690', (93, 118))	('Meckel-Gruber syndrome', 'Disease', 'MESH:C536133', (169, 191))
189392	32276433	Most ADPKD cases (85%) are associated with mutations of PKD1 gene (located at 16p13.3 chromosome).	('ADPKD', 'Disease', 'MESH:D007690', (5, 10))	('associated', 'Reg', (27, 37))	('chromosome', 'cellular_component', 'GO:0005694', ('86', '96'))	('mutations', 'Var', (43, 52))	('PKD1', 'Gene', (56, 60))	('ADPKD', 'Disease', (5, 10))
189393	32276433	The mutations in PKD2 (located at 4q22.1 chromosome), found in the residual 15% of PKD patients, lead to milder kidney polycystic disease symptoms compared with patients with PKD1 mutations.	('kidney polycystic disease symptoms', 'Disease', 'MESH:D004421', (112, 146))	('kidney polycystic disease symptoms', 'Disease', (112, 146))	('PKD', 'Disease', (175, 178))	('PKD', 'Disease', (17, 20))	('PKD', 'Disease', 'MESH:C537180', (17, 20))	('PKD', 'Disease', 'MESH:C537180', (175, 178))	('patients', 'Species', '9606', (161, 169))	('PKD2', 'Gene', '5311', (17, 21))	('PKD', 'Disease', 'MESH:C537180', (83, 86))	('PKD', 'Disease', (83, 86))	('kidney polycystic disease', 'Phenotype', 'HP:0000113', (112, 137))	('mutations', 'Var', (4, 13))	('chromosome', 'cellular_component', 'GO:0005694', ('41', '51'))	('patients', 'Species', '9606', (87, 95))	('PKD2', 'Gene', (17, 21))
189404	32276433	Although it is known that PKD1 or PKD2 mutations disrupt complex formation, reducing channel permeability, the exact molecular mechanisms that contribute to the development of ADPKD are poorly understood.	('PKD1', 'Gene', (26, 30))	('disrupt', 'NegReg', (49, 56))	('PKD2', 'Gene', (34, 38))	('channel permeability', 'MPA', (85, 105))	('mutations', 'Var', (39, 48))	('complex formation', 'MPA', (57, 74))	('ADPKD', 'Disease', (176, 181))	('reducing', 'NegReg', (76, 84))	('ADPKD', 'Disease', 'MESH:D007690', (176, 181))	('PKD2', 'Gene', '5311', (34, 38))	('formation', 'biological_process', 'GO:0009058', ('65', '74'))
189406	32276433	About 30% of PKD-related PC1 mutations affect the GAIN domain and the neighboring REJ region, suggestive of impaired GPS cleavage in cells of PKD patients.	('PKD', 'Disease', 'MESH:C537180', (13, 16))	('PKD', 'Disease', (13, 16))	('impaired GPS cleavage', 'Disease', 'MESH:D055652', (108, 129))	('mutations', 'Var', (29, 38))	('affect', 'Reg', (39, 45))	('PC1', 'Gene', '5310', (25, 28))	('PKD', 'Disease', (142, 145))	('GAIN domain', 'MPA', (50, 61))	('PKD', 'Disease', 'MESH:C537180', (142, 145))	('patients', 'Species', '9606', (146, 154))	('impaired GPS cleavage', 'Disease', (108, 129))	('PC1', 'Gene', (25, 28))
189410	32276433	It was shown that the mTOR pathway is inappropriately activated in epithelial kidney cells of ADPKD patients and mouse models, suggesting a possible mechanism of pathogenic PKD1 mutations.	('mouse', 'Species', '10090', (113, 118))	('patients', 'Species', '9606', (100, 108))	('mTOR', 'Gene', '2475', (22, 26))	('ADPKD', 'Disease', (94, 99))	('mTOR', 'Gene', (22, 26))	('PKD1', 'Gene', (173, 177))	('mutations', 'Var', (178, 187))	('ADPKD', 'Disease', 'MESH:D007690', (94, 99))
189414	32276433	ARPKD is caused by mutations in PKHD1 gene.	('caused by', 'Reg', (9, 18))	('ARPKD', 'Gene', (0, 5))	('mutations', 'Var', (19, 28))	('PKHD1', 'Gene', '5314', (32, 37))	('PKHD1', 'Gene', (32, 37))	('ARPKD', 'Gene', '5314', (0, 5))
189415	32276433	The transcription of PKHD1 is controlled by TCF-2 transcription factor, of which mutations impair PKHD1 transcription and result in renal cysts.	('PKHD1', 'Gene', (21, 26))	('PKHD1', 'Gene', '5314', (21, 26))	('transcription', 'biological_process', 'GO:0006351', ('50', '63'))	('TCF-2', 'Gene', (44, 49))	('renal cysts', 'Disease', 'MESH:D007674', (132, 143))	('result in', 'Reg', (122, 131))	('transcription', 'biological_process', 'GO:0006351', ('4', '17'))	('renal cysts', 'Disease', (132, 143))	('transcription', 'biological_process', 'GO:0006351', ('104', '117'))	('transcription', 'MPA', (104, 117))	('mutations', 'Var', (81, 90))	('PKHD1', 'Gene', '5314', (98, 103))	('transcription factor', 'molecular_function', 'GO:0000981', ('50', '70'))	('TCF-2', 'Gene', '6928', (44, 49))	('impair', 'NegReg', (91, 97))	('renal cysts', 'Phenotype', 'HP:0000107', (132, 143))	('PKHD1', 'Gene', (98, 103))
189422	32276433	Similarly to PC1 and PC2, the exact mechanisms by which PKHD1 mutations contribute to the development of PKD are unknown.	('PC2', 'Gene', (21, 24))	('PC1', 'Gene', '5310', (13, 16))	('PKHD1', 'Gene', '5314', (56, 61))	('PKHD1', 'Gene', (56, 61))	('PC1', 'Gene', (13, 16))	('PC2', 'Gene', '5311', (21, 24))	('contribute', 'Reg', (72, 82))	('PKD', 'Disease', (105, 108))	('mutations', 'Var', (62, 71))	('PKD', 'Disease', 'MESH:C537180', (105, 108))
189424	32276433	DZIP1L mutations were identified in seven ARPKD patients from four families who lacked mutations in PKHD1 gene.	('PKHD1', 'Gene', '5314', (100, 105))	('DZIP1L', 'Gene', (0, 6))	('PKHD1', 'Gene', (100, 105))	('ARPKD', 'Gene', (42, 47))	('patients', 'Species', '9606', (48, 56))	('ARPKD', 'Gene', '5314', (42, 47))	('mutations', 'Var', (7, 16))
189425	32276433	The pathological significance of DZIP1L aberrations was confirmed using mice with chemically induced Dzip1l mutations which caused cystic kidney disease.	('cystic kidney', 'Phenotype', 'HP:0000107', (131, 144))	('mutations', 'Var', (108, 117))	('caused', 'Reg', (124, 130))	('Dzip1l', 'Gene', (101, 107))	('cystic kidney disease', 'Disease', 'MESH:D052177', (131, 152))	('kidney disease', 'Phenotype', 'HP:0000112', (138, 152))	('mice', 'Species', '10090', (72, 76))	('Dzip1l', 'Gene', '72507', (101, 107))	('cystic kidney disease', 'Disease', (131, 152))
189430	32276433	NPHP is associated with mutations in so far 20 identified genes, of which most encode nephrocystins, proteins localizing to the cilium transition zone.	('encode nephrocystins', 'Disease', (79, 99))	('NPHP', 'Phenotype', 'HP:0000090', (0, 4))	('NPHP', 'Disease', (0, 4))	('encode nephrocystins', 'Disease', 'MESH:C564021', (79, 99))	('associated', 'Reg', (8, 18))	('cilium transition zone', 'cellular_component', 'GO:0035869', ('128', '150'))	('mutations', 'Var', (24, 33))
189432	32276433	The ciliary functions of proteins encoded by genes most frequently mutated in nephronophthisis are discussed below.	('mutated', 'Var', (67, 74))	('nephronophthisis', 'Disease', 'MESH:C537699', (78, 94))	('nephronophthisis', 'Phenotype', 'HP:0000090', (78, 94))	('nephronophthisis', 'Disease', (78, 94))
189433	32276433	Nephrocystin 1 is crucial for proper cilia morphology, as indicated by NPHP1 knockdown in the Madin-Darby canine kidney (MDCK) cells, which results in abnormal cilia formation.	('Nephrocystin 1', 'Gene', (0, 14))	('cilia formation', 'CPA', (160, 175))	('NPHP1', 'Gene', (71, 76))	('Nephrocystin 1', 'Gene', '403780', (0, 14))	('knockdown', 'Var', (77, 86))	('results in', 'Reg', (140, 150))	('formation', 'biological_process', 'GO:0009058', ('166', '175'))	('NPHP', 'Phenotype', 'HP:0000090', (71, 75))
189437	32276433	Mouse Invs knockouts develop large cystic kidneys at an early stage.	('cystic kidneys', 'Phenotype', 'HP:0000107', (35, 49))	('knockouts', 'Var', (11, 20))	('Invs', 'Gene', (6, 10))	('Mouse', 'Species', '10090', (0, 5))	('cystic kidneys', 'Disease', 'MESH:D052177', (35, 49))	('cystic kidneys', 'Disease', (35, 49))	('cystic kidney', 'Phenotype', 'HP:0000107', (35, 48))	('Invs', 'Gene', '16348', (6, 10))
189450	32276433	In Bardet-Biedl syndrome (discussed below) MKKS mutations result in weakening or even loss of CEP290 interactions.	('CEP290', 'Protein', (94, 100))	('loss', 'NegReg', (86, 90))	('Bardet-Biedl syndrome', 'Disease', (3, 24))	('Bardet-Biedl syndrome', 'Disease', 'MESH:D020788', (3, 24))	('interactions', 'Interaction', (101, 113))	('MKKS', 'Gene', (43, 47))	('MKKS', 'Gene', '8195', (43, 47))	('CEP', 'molecular_function', 'GO:0047849', ('94', '97'))	('mutations', 'Var', (48, 57))
189451	32276433	The depletion of CEP290 reduces ciliary recruitment of BBS proteins required for primary cilia formation in mouse and human cells.	('reduces', 'NegReg', (24, 31))	('ciliary recruitment of', 'MPA', (32, 54))	('CEP290', 'Gene', (17, 23))	('CEP', 'molecular_function', 'GO:0047849', ('17', '20'))	('depletion', 'Var', (4, 13))	('BBS', 'Gene', (55, 58))	('mouse', 'Species', '10090', (108, 113))	('formation', 'biological_process', 'GO:0009058', ('95', '104'))	('human', 'Species', '9606', (118, 123))	('BBS', 'Gene', '583', (55, 58))
189452	32276433	In zebrafish model depletion of nphp5 or nphp6 leads to pronephric cysts.	('leads to', 'Reg', (47, 55))	('depletion', 'Var', (19, 28))	('nphp6', 'Gene', (41, 46))	('zebrafish', 'Species', '7955', (3, 12))	('nphp6', 'Gene', '560588', (41, 46))	('nphp5', 'Gene', '494079', (32, 37))	('nphp5', 'Gene', (32, 37))	('pronephric cysts', 'CPA', (56, 72))
189454	32276433	Mouse mutant of Glis2 shows tubular atrophy and kidney fibrosis.	('Glis2', 'Gene', '83396', (16, 21))	('mutant', 'Var', (6, 12))	('kidney fibrosis', 'Phenotype', 'HP:0030760', (48, 63))	('tubular atrophy and kidney fibrosis', 'Disease', 'MESH:D005355', (28, 63))	('tubular atrophy', 'Phenotype', 'HP:0000092', (28, 43))	('Mouse', 'Species', '10090', (0, 5))	('Glis2', 'Gene', (16, 21))
189457	32276433	Mouse Rpgrip1l knockouts develop abnormal cilia devoid of axoneme in the forebrain neuroepithelial cells.	('knockouts', 'Var', (15, 24))	('axoneme', 'cellular_component', 'GO:0005930', ('58', '65'))	('Rpgrip1l', 'Gene', (6, 14))	('Mouse', 'Species', '10090', (0, 5))	('Rpgrip1l', 'Gene', '244585', (6, 14))
189460	32276433	Morpholino-induced knockdown of nek88 in zebrafish results in pronephric cysts formation, while overexpression of human NEK8 leads to pronephros abnormalities.	('pronephros abnormalities', 'Disease', 'MESH:D018376', (134, 158))	('pronephric cysts formation', 'CPA', (62, 88))	('knockdown', 'Var', (19, 28))	('zebrafish', 'Species', '7955', (41, 50))	('nek88', 'Gene', (32, 37))	('formation', 'biological_process', 'GO:0009058', ('79', '88'))	('Morpholino', 'Chemical', 'MESH:D060172', (0, 10))	('human', 'Species', '9606', (114, 119))	('pronephros abnormalities', 'Disease', (134, 158))
189461	32276433	Nephronophthisis can be also caused by mutations in genes encoding proteins other than nephrocystins, such as TTC21B, CEP164, ANKS6, CEP83 and DCD2.	('DCD2', 'Gene', (143, 147))	('CEP164', 'Gene', (118, 124))	('CEP83', 'Gene', '51134', (133, 138))	('nephrocystins', 'Disease', (87, 100))	('caused', 'Reg', (29, 35))	('mutations', 'Var', (39, 48))	('CEP83', 'Gene', (133, 138))	('CEP', 'molecular_function', 'GO:0047849', ('133', '136'))	('Nephronophthisis', 'Disease', (0, 16))	('nephrocystins', 'Disease', 'None', (87, 100))	('TTC21B', 'Gene', (110, 116))	('Nephronophthisis', 'Phenotype', 'HP:0000090', (0, 16))	('CEP', 'molecular_function', 'GO:0047849', ('118', '121'))	('ANKS6', 'Gene', (126, 131))	('TTC21B', 'Gene', '79809', (110, 116))
189465	32276433	In zebrafish, knockdown of cep164 leads to formation of pronephric tubule cysts.	('zebrafish', 'Species', '7955', (3, 12))	('cep164', 'Gene', (27, 33))	('cep164', 'Gene', '100330675', (27, 33))	('formation', 'biological_process', 'GO:0009058', ('43', '52'))	('cep', 'molecular_function', 'GO:0047849', ('27', '30'))	('knockdown', 'Var', (14, 23))	('tubule cysts', 'Phenotype', 'HP:0200040', (67, 79))	('pronephric', 'CPA', (56, 66))
189472	32276433	Defects in genes associated with Joubert syndrome are often the main causes of other ciliopathies such as Nephronophthisis or Meckel-Gruber syndrome.	('Defects', 'Var', (0, 7))	('Joubert syndrome', 'Disease', (33, 49))	('Nephronophthisis or Meckel-Gruber syndrome', 'Disease', 'MESH:C536133', (106, 148))	('Joubert syndrome', 'Disease', 'MESH:C536293', (33, 49))	('Nephronophthisis', 'Phenotype', 'HP:0000090', (106, 122))	('Nephronophthisis or Meckel-Gruber syndrome', 'Disease', (106, 148))	('causes', 'Reg', (69, 75))
189473	32276433	Joubert syndrome was classified into 35 subtypes of which most are caused by mutations linked with kidney impairments.	('kidney impairments', 'Disease', 'MESH:D007674', (99, 117))	('caused by', 'Reg', (67, 76))	('kidney impairments', 'Disease', (99, 117))	('mutations', 'Var', (77, 86))	('Joubert syndrome', 'Disease', (0, 16))	('Joubert syndrome', 'Disease', 'MESH:C536293', (0, 16))	('kidney impairments', 'Phenotype', 'HP:0000112', (99, 117))
189477	32276433	Ahi1 knockdown in mouse leads to impaired ciliogenesis and diminished kidney with characteristics of nephronophthisis.	('nephronophthisis', 'Phenotype', 'HP:0000090', (101, 117))	('ciliogenesis', 'CPA', (42, 54))	('diminished kidney', 'Phenotype', 'HP:0000089', (59, 76))	('mouse', 'Species', '10090', (18, 23))	('knockdown', 'Var', (5, 14))	('impaired', 'NegReg', (33, 41))	('Ahi1', 'Gene', (0, 4))	('nephronophthisis', 'Disease', 'MESH:C537699', (101, 117))	('kidney', 'MPA', (70, 76))	('diminished', 'NegReg', (59, 69))	('ciliogenesis', 'biological_process', 'GO:0060271', ('42', '54'))	('nephronophthisis', 'Disease', (101, 117))	('Ahi1', 'Gene', '52906', (0, 4))
189481	32276433	ARL13 is expressed in cilia of distal renal collecting duct and its missense mutations found in JBTS patients disrupt interaction of ARL13B protein with INPP5E, disabling cilia targeting of the latter.	('ARL13', 'Gene', '392509', (0, 5))	('patients', 'Species', '9606', (101, 109))	('protein', 'Protein', (140, 147))	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('disrupt', 'NegReg', (110, 117))	('ARL13', 'Gene', (133, 138))	('missense mutations', 'Var', (68, 86))	('interaction', 'Interaction', (118, 129))	('ARL13', 'Gene', (0, 5))	('cilia targeting', 'MPA', (171, 186))	('ARL13', 'Gene', '392509', (133, 138))	('disabling', 'NegReg', (161, 170))
189482	32276433	Inactivation of Arl13b in zebrafish results in formation of renal cysts and curved tail, the specific features reflecting impaired cilia.	('Arl13b', 'Gene', '286784', (16, 22))	('formation', 'biological_process', 'GO:0009058', ('47', '56'))	('curved tail', 'CPA', (76, 87))	('renal cysts', 'Phenotype', 'HP:0000107', (60, 71))	('Arl13b', 'Gene', (16, 22))	('renal cysts', 'Disease', 'MESH:D007674', (60, 71))	('zebrafish', 'Species', '7955', (26, 35))	('Inactivation', 'Var', (0, 12))	('renal cysts', 'Disease', (60, 71))
189484	32276433	Cspp1 knockdown in zebrafish results in reduced arl13b ciliary localization and formation of pronephric cysts.	('zebrafish', 'Species', '7955', (19, 28))	('Cspp1', 'Gene', (0, 5))	('arl13b', 'Gene', '286784', (48, 54))	('ciliary localization', 'MPA', (55, 75))	('reduced', 'NegReg', (40, 47))	('arl13b', 'Gene', (48, 54))	('formation', 'biological_process', 'GO:0009058', ('80', '89'))	('knockdown', 'Var', (6, 15))	('localization', 'biological_process', 'GO:0051179', ('63', '75'))	('Cspp1', 'Gene', '103909748', (0, 5))
189485	32276433	JBTS is also associated with mutations in ARL3 (JBTS35; MIM 61816), encoding ADP-ribosylation factor-like 3, crucial for axoneme formation by cargo displacement of lipidated proteins in the cilium.	('associated', 'Reg', (13, 23))	('ARL3', 'Gene', (42, 46))	('mutations', 'Var', (29, 38))	('formation', 'biological_process', 'GO:0009058', ('129', '138'))	('JBTS', 'Disease', (0, 4))	('ARL3', 'Gene', '797451', (42, 46))	('axoneme', 'cellular_component', 'GO:0005930', ('121', '128'))	('cargo', 'molecular_function', 'GO:0140355', ('142', '147'))	('cilium', 'cellular_component', 'GO:0005929', ('190', '196'))	('ADP-ribosylation factor-like 3', 'Gene', (77, 107))	('ADP-ribosylation factor-like 3', 'Gene', '403', (77, 107))
189490	32276433	This inherited recessively ciliopathy is associated with mutations in multiple genes, encoding the protein components of the MKS module (including B9D1, B9D2, CC2D2A, MKS1, TCTN2, TMEM216, TMEM67, TMEM107 and TMEM231) as well as nephrocystins (e.g., NPHP3, NPHP6, NPHP8).	('associated', 'Reg', (41, 51))	('MKS', 'Gene', '8195', (167, 170))	('mutations', 'Var', (57, 66))	('recessively ciliopathy', 'Disease', 'MESH:D000072661', (15, 37))	('NPHP', 'Phenotype', 'HP:0000090', (257, 261))	('MKS', 'Gene', (125, 128))	('MKS', 'Gene', '8195', (125, 128))	('nephrocystins', 'Disease', 'None', (229, 242))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('NPHP3', 'Disease', (250, 255))	('B9D1', 'Gene', (147, 151))	('NPHP', 'Phenotype', 'HP:0000090', (250, 254))	('NPHP', 'Phenotype', 'HP:0000090', (264, 268))	('TMEM67', 'Gene', (189, 195))	('NPHP8', 'Gene', (264, 269))	('recessively ciliopathy', 'Disease', (15, 37))	('TMEM216', 'Gene', '51259', (180, 187))	('nephrocystins', 'Disease', (229, 242))	('MKS module', 'cellular_component', 'GO:0036038', ('125', '135'))	('TMEM216', 'Gene', (180, 187))	('B9D2', 'Gene', '80776', (153, 157))	('TMEM67', 'Gene', '91147', (189, 195))	('MKS', 'Gene', (167, 170))	('NPHP8', 'Gene', '23322', (264, 269))	('B9D1', 'Gene', '27077', (147, 151))	('B9D2', 'Gene', (153, 157))
189492	32276433	Mutations in Mks1 gene associated with Meckel-Gruber syndrome perturb Hedgehog signaling in a mouse model.	('Meckel-Gruber syndrome', 'Disease', (39, 61))	('perturb', 'NegReg', (62, 69))	('Hedgehog signaling', 'Pathway', (70, 88))	('Mks1', 'Gene', '380718', (13, 17))	('mouse', 'Species', '10090', (94, 99))	('Mutations', 'Var', (0, 9))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('associated', 'Reg', (23, 33))	('Meckel-Gruber syndrome', 'Disease', 'MESH:C536133', (39, 61))	('Mks1', 'Gene', (13, 17))
189498	32276433	Loss of meckelin or filamin A leads to abnormal basal bodies positioning, aberrant remodeling of actin cytoskeleton, deregulation of RhoA activity and hyperactivation of Wnt signaling.	('remodeling', 'MPA', (83, 93))	('deregulation', 'MPA', (117, 129))	('signaling', 'biological_process', 'GO:0023052', ('174', '183'))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('97', '115'))	('filamin A', 'Gene', (20, 29))	('meckelin', 'Gene', (8, 16))	('RhoA', 'Gene', '387', (133, 137))	('filamin A', 'Gene', '2316', (20, 29))	('RhoA', 'Gene', (133, 137))	('actin cytoskeleton', 'MPA', (97, 115))	('meckelin', 'Gene', '91147', (8, 16))	('basal bodies positioning', 'CPA', (48, 72))	('Wnt signaling', 'Pathway', (170, 183))	('Loss', 'Var', (0, 4))	('hyperactivation', 'PosReg', (151, 166))
189501	32276433	In mouse embryos Tctn1 or Tctn2 knockouts result in defective cilia, which fail to elongate the axoneme.	('axoneme', 'cellular_component', 'GO:0005930', ('96', '103'))	('mouse', 'Species', '10090', (3, 8))	('Tctn1', 'Gene', (17, 22))	('Tctn1', 'Gene', '654470', (17, 22))	('Tctn2', 'Gene', '67978', (26, 31))	('knockouts', 'Var', (32, 41))	('cilia', 'CPA', (62, 67))	('Tctn2', 'Gene', (26, 31))	('defective', 'NegReg', (52, 61))
189503	32276433	TMEM216 knockdown leads to hyperactivation and mislocalization of Rho GTPase, a protein crucial for basal bodies docking at the apical surface of plasma membrane.	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('mislocalization', 'MPA', (47, 62))	('knockdown', 'Var', (8, 17))	('TMEM216', 'Gene', (0, 7))	('plasma membrane', 'cellular_component', 'GO:0005886', ('146', '161'))	('Rho GTPase', 'Protein', (66, 76))	('GTP', 'Chemical', 'MESH:D006160', (70, 73))	('hyperactivation', 'MPA', (27, 42))	('TMEM216', 'Gene', '51259', (0, 7))
189504	32276433	In mouse IMCD3 cells, Tmem216 knockdown results in reduction of cilia length and other ciliogenesis defects.	('ciliogenesis', 'biological_process', 'GO:0060271', ('87', '99'))	('reduction', 'NegReg', (51, 60))	('mouse', 'Species', '10090', (3, 8))	('Tmem216', 'Gene', '68642', (22, 29))	('Tmem216', 'Gene', (22, 29))	('ciliogenesis defects', 'CPA', (87, 107))	('knockdown', 'Var', (30, 39))	('IMCD3', 'CellLine', 'CVCL:0429', (9, 14))	('cilia length', 'CPA', (64, 76))
189510	32276433	Bardet-Biedl syndrome has a prevalence of 1 in 125,000 and is caused by mutations in BBS genes, but also in genes associated with other ciliopathies, such as NPHP6, NPHP11, MKS1, SDCCAG8, LZTFL1, BBIP1 and IFT27.	('SDCCAG8', 'Gene', (179, 186))	('NPHP', 'Phenotype', 'HP:0000090', (158, 162))	('SDCCAG8', 'Gene', '10806', (179, 186))	('NPHP', 'Phenotype', 'HP:0000090', (165, 169))	('NPHP11', 'Gene', (165, 171))	('MKS1', 'Gene', (173, 177))	('LZTFL1', 'Gene', '54585', (188, 194))	('mutations', 'Var', (72, 81))	('IFT27', 'Gene', '11020', (206, 211))	('Bardet-Biedl syndrome', 'Disease', (0, 21))	('BBS', 'Gene', (85, 88))	('NPHP6', 'Gene', (158, 163))	('LZTFL1', 'Gene', (188, 194))	('BBS', 'Gene', '583', (85, 88))	('NPHP11', 'Gene', '91147', (165, 171))	('caused by', 'Reg', (62, 71))	('IFT', 'biological_process', 'GO:0042073', ('206', '209'))	('IFT27', 'Gene', (206, 211))	('Bardet-Biedl syndrome', 'Disease', 'MESH:D020788', (0, 21))	('BBIP1', 'Gene', (196, 201))
189527	32276433	Depletion of Lztfl1 in mouse alters Hedgehog signaling.	('signaling', 'biological_process', 'GO:0023052', ('45', '54'))	('Lztfl1', 'Gene', (13, 19))	('Depletion', 'Var', (0, 9))	('Hedgehog signaling', 'Pathway', (36, 54))	('mouse', 'Species', '10090', (23, 28))	('Lztfl1', 'Gene', '93730', (13, 19))	('alters', 'Reg', (29, 35))
189529	32276433	Depletion of BBIP1 in RPE cells increases the frequency of centrosome splitting in interphase cells, while bbip1 knockdown in zebrafish results in cystic dilations of the pronephrons.	('zebrafish', 'Species', '7955', (126, 135))	('interphase', 'biological_process', 'GO:0051325', ('83', '93'))	('cystic', 'CPA', (147, 153))	('bbip1', 'Gene', (107, 112))	('results in', 'Reg', (136, 146))	('BBIP1', 'Gene', (13, 18))	('bbip1', 'Gene', '795943', (107, 112))	('centrosome', 'cellular_component', 'GO:0005813', ('59', '69'))	('knockdown', 'Var', (113, 122))	('RPE', 'CellLine', 'CVCL:4388', (22, 25))	('increases', 'PosReg', (32, 41))
189532	32276433	Ift74 knockdown in zebrafish leads to renal abnormalities consistent with ciliopathy.	('renal abnormalities', 'Disease', (38, 57))	('zebrafish', 'Species', '7955', (19, 28))	('renal abnormalities', 'Disease', 'MESH:D007674', (38, 57))	('Ift', 'biological_process', 'GO:0042073', ('0', '3'))	('Ift74', 'Gene', '436658', (0, 5))	('ciliopathy', 'Disease', (74, 84))	('renal abnormalities', 'Phenotype', 'HP:0000077', (38, 57))	('Ift74', 'Gene', (0, 5))	('leads to', 'Reg', (29, 37))	('knockdown', 'Var', (6, 15))
189535	32276433	SLS is caused by mutations in NPHP1, NPHP4, NPHP5, NPHP6, SDCCAG8, WDR19/IFT144 and TRAF3IP1 genes.	('SDCCAG8', 'Gene', '10806', (58, 65))	('WDR19', 'Gene', '57728', (67, 72))	('NPHP4', 'Gene', '261734', (37, 42))	('SLS', 'Disease', 'MESH:D016111', (0, 3))	('NPHP6', 'Gene', (51, 56))	('NPHP5', 'Gene', '9657', (44, 49))	('NPHP', 'Phenotype', 'HP:0000090', (37, 41))	('mutations', 'Var', (17, 26))	('NPHP', 'Phenotype', 'HP:0000090', (44, 48))	('NPHP', 'Phenotype', 'HP:0000090', (30, 34))	('NPHP', 'Phenotype', 'HP:0000090', (51, 55))	('NPHP5', 'Gene', (44, 49))	('IFT144', 'Gene', (73, 79))	('NPHP1', 'Gene', (30, 35))	('WDR19', 'Gene', (67, 72))	('caused by', 'Reg', (7, 16))	('SLS', 'Disease', (0, 3))	('TRAF3IP1', 'Gene', (84, 92))	('IFT', 'biological_process', 'GO:0042073', ('73', '76'))	('NPHP4', 'Gene', (37, 42))	('IFT144', 'Gene', '57728', (73, 79))	('SDCCAG8', 'Gene', (58, 65))
189538	32276433	Knockdown of TRAF3IP1 homolog elipsa in zebrafish leads to pronephric cysts, while mouse mutants show ciliary assembly defects and diminished expression of Shh reporter.	('Shh', 'Gene', (156, 159))	('Shh', 'Gene', '20423', (156, 159))	('mouse', 'Species', '10090', (83, 88))	('elipsa', 'Gene', (30, 36))	('defects', 'NegReg', (119, 126))	('pronephric cysts', 'CPA', (59, 75))	('elipsa', 'Gene', '393572', (30, 36))	('diminished', 'NegReg', (131, 141))	('ciliary assembly', 'CPA', (102, 118))	('expression', 'MPA', (142, 152))	('mutants', 'Var', (89, 96))	('zebrafish', 'Species', '7955', (40, 49))
189541	32276433	Alstrom syndrome patients rarely live beyond 50 years of age and often require dialysis or kidney transplantation  Alstrom syndrome is caused by mutations in ALMS1 gene.	('Alstrom syndrome', 'Disease', (0, 16))	('ALMS1', 'Gene', (158, 163))	('caused by', 'Reg', (135, 144))	('mutations', 'Var', (145, 154))	('Alstrom syndrome', 'Disease', 'MESH:D056769', (0, 16))	('Alstrom syndrome', 'Disease', (115, 131))	('patients', 'Species', '9606', (17, 25))	('Alstrom syndrome', 'Disease', 'MESH:D056769', (115, 131))
189542	32276433	Mouse model of Alstrom syndrome with truncated ALMS1 protein shows cilia loss from kidney proximal tubules.	('cilia loss', 'Disease', (67, 77))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('Alstrom syndrome', 'Disease', (15, 31))	('cilia loss', 'Disease', 'MESH:C536287', (67, 77))	('protein', 'Protein', (53, 60))	('truncated', 'Var', (37, 46))	('Mouse', 'Species', '10090', (0, 5))	('ALMS1', 'Gene', (47, 52))	('Alstrom syndrome', 'Disease', 'MESH:D056769', (15, 31))
189544	32276433	Mutations of OFD1 gene cause Orofaciodigital syndrome type 1 (OFDI), distinguished from the other Orofaciodigital syndromes by X-linked dominant inheritance and cystic kidney disease.	('Orofaciodigital syndrome', 'Disease', (29, 53))	('Orofaciodigital syndrome', 'Disease', 'MESH:D009958', (29, 53))	('cystic kidney disease', 'Disease', 'MESH:D052177', (161, 182))	('Orofaciodigital syndrome', 'Disease', (98, 122))	('Orofaciodigital syndrome', 'Disease', 'MESH:D009958', (98, 122))	('OFD1', 'Gene', '8481', (13, 17))	('kidney disease', 'Phenotype', 'HP:0000112', (168, 182))	('cystic kidney disease', 'Disease', (161, 182))	('Mutations', 'Var', (0, 9))	('cystic kidney', 'Phenotype', 'HP:0000107', (161, 174))	('OFD1', 'Gene', (13, 17))	('cause', 'Reg', (23, 28))
189546	32276433	In 2017, novel classification, based on combined clinical and molecular data, reduced the number of OFD syndromes to the three main subtypes: OFDI (associated with mutations in OFD1), OFDIV (linked with mutations in TCTN3) and OFDVI (caused by mutations in TMEM216, TMEM231, TMEM138, C5orf42, TMEM107 and KIAA0753).	('caused', 'Reg', (234, 240))	('OFD', 'Disease', (100, 103))	('OFDVI', 'Disease', (227, 232))	('TMEM216', 'Gene', (257, 264))	('TMEM138', 'Gene', '51524', (275, 282))	('TMEM138', 'Gene', (275, 282))	('KIAA0753', 'Gene', (305, 313))	('C5orf42', 'Gene', '65250', (284, 291))	('C5orf42', 'Gene', (284, 291))	('TCTN3', 'Gene', (216, 221))	('OFD1', 'Gene', '8481', (177, 181))	('OFDIV', 'Disease', (184, 189))	('TMEM216', 'Gene', '51259', (257, 264))	('KIAA0753', 'Gene', '9851', (305, 313))	('mutations', 'Var', (244, 253))	('OFD1', 'Gene', (177, 181))	('associated', 'Reg', (148, 158))	('reduced', 'NegReg', (78, 85))	('mutations', 'Var', (203, 212))	('mutations', 'Var', (164, 173))	('TCTN3', 'Gene', '26123', (216, 221))	('OFDI', 'Disease', (142, 146))	('TMEM231', 'Gene', (266, 273))	('TMEM107', 'Gene', (293, 300))
189549	32276433	Inactivation of Ofd1 gene in mouse leads to progressive impairment of renal function.	('impairment of renal function', 'Disease', (56, 84))	('impairment of renal function', 'Disease', 'MESH:D007674', (56, 84))	('progressive impairment of renal function', 'Phenotype', 'HP:0012622', (44, 84))	('Ofd1', 'Gene', '237222', (16, 20))	('mouse', 'Species', '10090', (29, 34))	('Inactivation', 'Var', (0, 12))	('Ofd1', 'Gene', (16, 20))
189552	32276433	CED is caused by mutations in IFT122, WDR35, IFT43 and WDR19, the encoding components of intraflagellar transport machinery.	('WDR19', 'Gene', (55, 60))	('intraflagellar transport', 'biological_process', 'GO:0035735', ('89', '113'))	('CED', 'Disease', 'MESH:D003966', (0, 3))	('CED', 'Phenotype', 'HP:0000968', (0, 3))	('IFT', 'biological_process', 'GO:0042073', ('45', '48'))	('intraflagellar transport', 'biological_process', 'GO:0042073', ('89', '113'))	('CED', 'Disease', (0, 3))	('IFT122', 'Gene', '55764', (30, 36))	('IFT', 'biological_process', 'GO:0042073', ('30', '33'))	('WDR19', 'Gene', '57728', (55, 60))	('WDR35', 'Gene', (38, 43))	('caused by', 'Reg', (7, 16))	('mutations', 'Var', (17, 26))	('IFT43', 'Gene', (45, 50))	('IFT122', 'Gene', (30, 36))
189553	32276433	Functional analysis showed that ift122 knockdown in zebrafish embryos leads to reduced number of basal bodies and cilia in the pronephric duct and shorter primary cilia of Kupffer vesicles.	('shorter', 'NegReg', (147, 154))	('reduced', 'NegReg', (79, 86))	('knockdown', 'Var', (39, 48))	('zebrafish', 'Species', '7955', (52, 61))	('ift122', 'Gene', (32, 38))	('ift122', 'Gene', '405826', (32, 38))	('ift', 'biological_process', 'GO:0042073', ('32', '35'))
189554	32276433	In human HEK293T cells IFT122 knockout leads to cilia loss, while Wdr35 knockout in mouse fibroblasts reveals strongly reduced level of IFT43.	('IFT122', 'Gene', (23, 29))	('HEK293T', 'CellLine', 'CVCL:0063', (9, 16))	('Wdr35', 'Gene', (66, 71))	('level', 'MPA', (127, 132))	('cilia loss', 'Disease', 'MESH:C536287', (48, 58))	('human', 'Species', '9606', (3, 8))	('knockout', 'Var', (30, 38))	('mouse', 'Species', '10090', (84, 89))	('IFT', 'biological_process', 'GO:0042073', ('136', '139'))	('IFT122', 'Gene', '55764', (23, 29))	('Wdr35', 'Gene', '57539', (66, 71))	('cilia loss', 'Disease', (48, 58))	('IFT', 'biological_process', 'GO:0042073', ('23', '26'))	('reduced', 'NegReg', (119, 126))
189557	32276433	All the above mentioned studies support the unifying theory of renal cystogenesis, coined more than 15 years ago, and further developed in later studies According to this concept, mutations in genes expressed in primary cilia, basal bodies and centrosomes lead to dysfunction of cilia, thereby contributing to cell differentiation, stimulated proliferation and fluid secretion, as well as increased apoptosis of tubular cells, ultimately leading the development of cystic disease.	('proliferation', 'CPA', (343, 356))	('stimulated', 'PosReg', (332, 342))	('dysfunction', 'MPA', (264, 275))	('cilia', 'CPA', (279, 284))	('contributing to', 'Reg', (294, 309))	('cell differentiation', 'CPA', (310, 330))	('cystic disease', 'Disease', (465, 479))	('lead to', 'Reg', (256, 263))	('mutations', 'Var', (180, 189))	('cystic disease', 'Disease', 'MESH:C563237', (465, 479))	('fluid secretion', 'CPA', (361, 376))	('renal cystogenesis', 'Disease', (63, 81))	('apoptosis', 'biological_process', 'GO:0097194', ('399', '408'))	('apoptosis', 'CPA', (399, 408))	('renal cystogenesis', 'Disease', 'MESH:D007674', (63, 81))	('secretion', 'biological_process', 'GO:0046903', ('367', '376'))	('apoptosis', 'biological_process', 'GO:0006915', ('399', '408'))	('increased', 'PosReg', (389, 398))	('cell differentiation', 'biological_process', 'GO:0030154', ('310', '330'))
189563	32276433	Mutations affecting polycystin genes in ADPKD result in de-repression of CDCA, leading to aberrant proliferation of tubule cells, remodeling of base membrane and parenchyma and finally causing formation of cysts.	('CDCA', 'Gene', (73, 77))	('causing', 'Reg', (185, 192))	('ADPKD', 'Disease', (40, 45))	('ADPKD', 'Disease', 'MESH:D007690', (40, 45))	('membrane', 'cellular_component', 'GO:0016020', ('149', '157'))	('polycystin', 'molecular_function', 'GO:0005227', ('20', '30'))	('Mutations', 'Var', (0, 9))	('formation', 'biological_process', 'GO:0009058', ('193', '202'))	('de-repression', 'NegReg', (56, 69))	('CDCA', 'Chemical', '-', (73, 77))	('remodeling of base membrane', 'CPA', (130, 157))
189576	32276433	A recent study in mice triple mutant of tumor suppressors Vhl, Trp53 and Rb1 resulting in development of renal cancer, showed enrichment in ciliary genes mutations.	('Trp53', 'Gene', (63, 68))	('renal cancer', 'Phenotype', 'HP:0009726', (105, 117))	('Rb1', 'Gene', (73, 76))	('Rb1', 'Gene', '19645', (73, 76))	('Vhl', 'Gene', '22346', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mice', 'Species', '10090', (18, 22))	('Trp53', 'Gene', '22059', (63, 68))	('renal cancer', 'Disease', (105, 117))	('Vhl', 'Gene', (58, 61))	('mutations', 'Var', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('triple mutant', 'Var', (23, 36))	('renal cancer', 'Disease', 'MESH:D007680', (105, 117))
189577	32276433	Furthermore, the same study demonstrated that 40% of the analyzed 448 human ccRCC tumors bear mutations in primary cilium-associated genes.	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('mutations', 'Var', (94, 103))	('primary cilium', 'cellular_component', 'GO:0005929', ('107', '121'))	('primary', 'Gene', (107, 114))	('human', 'Species', '9606', (70, 75))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('ccRCC tumors', 'Disease', 'MESH:D009369', (76, 88))	('primary cilium', 'cellular_component', 'GO:0097731', ('107', '121'))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('ccRCC tumors', 'Disease', (76, 88))
189578	32276433	The Cancer Genome Atlas (TCGA) data indicates that damaging mutations in PKD1 and PKD2 are found in a subset of tumors of various types.	('PKD2', 'Gene', (82, 86))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('found', 'Reg', (91, 96))	('PKD1', 'Gene', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('PKD2', 'Gene', '5311', (82, 86))	('mutations', 'Var', (60, 69))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))
189584	32276433	Germline VHL mutations lead to von Hippel-Lindau disease, characterized by development of tumors in many organs, including the kidney.	('von Hippel-Lindau disease', 'Disease', (31, 56))	('lead to', 'Reg', (23, 30))	('VHL', 'Gene', (9, 12))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (31, 56))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('mutations', 'Var', (13, 22))
189591	32276433	Mutations that inactivate VHL, lead to persistent HIF upregulation and activation of hypoxia-induced genes, regardless of the oxygen status.	('oxygen', 'Chemical', 'MESH:D010100', (126, 132))	('hypoxia', 'Disease', 'MESH:D000860', (85, 92))	('VHL', 'Gene', (26, 29))	('activation', 'PosReg', (71, 81))	('hypoxia', 'Disease', (85, 92))	('upregulation', 'PosReg', (54, 66))	('Mutations', 'Var', (0, 9))	('HIF', 'MPA', (50, 53))
189594	32276433	The VHL-mediated control of cilia formation is evolutionary conserved as vhl-/- zebrafish mutants develop disorganized proximal pronephric tubules with disordered cilia.	('disordered cilia', 'Disease', 'MESH:C536287', (152, 168))	('disordered cilia', 'Disease', (152, 168))	('mutants', 'Var', (90, 97))	('vhl', 'Gene', '791202', (73, 76))	('disorganized', 'CPA', (106, 118))	('disorganized proximal pronephric tubules', 'Phenotype', 'HP:0000114', (106, 146))	('zebrafish', 'Species', '7955', (80, 89))	('vhl', 'Gene', (73, 76))	('formation', 'biological_process', 'GO:0009058', ('34', '43'))
189602	32276433	Accordingly, loss of VHL associates with reduced ciliation and enhanced proliferation of PCC tumors cells, while disruption of cilia results in enhanced proliferation of PCC cells in vitro.	('reduced', 'NegReg', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('enhanced', 'PosReg', (63, 71))	('enhanced', 'PosReg', (144, 152))	('PCC tumors', 'Disease', (89, 99))	('proliferation', 'CPA', (72, 85))	('ciliation', 'CPA', (49, 58))	('PCC', 'Phenotype', 'HP:0002666', (170, 173))	('PCC', 'cellular_component', 'GO:0120205', ('89', '92'))	('PCC', 'Phenotype', 'HP:0002666', (89, 92))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('proliferation', 'CPA', (153, 166))	('PCC', 'cellular_component', 'GO:0120205', ('170', '173'))	('VHL', 'Gene', (21, 24))	('PCC tumors', 'Disease', 'OMIM:115700', (89, 99))	('loss', 'Var', (13, 17))
189605	32276433	In ccRCC cells, loss of VHL leads to stabilization and nuclear accumulation of beta-catenin, which in turn activates transcription of AURKA, leading to activation of HDAC6, a tubulin deacetylase causing disassembly of microtubules that form the axoneme.	('activates', 'PosReg', (107, 116))	('activation', 'PosReg', (152, 162))	('stabilization', 'MPA', (37, 50))	('axoneme', 'cellular_component', 'GO:0005930', ('245', '252'))	('beta-catenin', 'Gene', '1499', (79, 91))	('transcription', 'biological_process', 'GO:0006351', ('117', '130'))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('transcription', 'MPA', (117, 130))	('HDAC6', 'Gene', '10013', (166, 171))	('loss', 'Var', (16, 20))	('HDAC6', 'Gene', (166, 171))	('VHL', 'Gene', (24, 27))	('AURKA', 'Gene', (134, 139))	('nuclear accumulation', 'MPA', (55, 75))	('beta-catenin', 'Gene', (79, 91))
189610	32276433	Specifically, NPHP4 was hypermethylated in chromophobe RCC when compared with ccRCC, papillary RCC and renal oncocytoma samples, suggestive of its involvement in renal cancer development.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('papillary RCC', 'Disease', (85, 98))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('NPHP', 'Phenotype', 'HP:0000090', (14, 18))	('involvement', 'Reg', (147, 158))	('renal oncocytoma', 'Disease', 'MESH:C537750', (103, 119))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (103, 119))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('chromophobe RCC', 'Disease', (43, 58))	('renal cancer', 'Disease', (162, 174))	('renal cancer', 'Phenotype', 'HP:0009726', (162, 174))	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('RCC', 'Disease', (95, 98))	('renal cancer', 'Disease', 'MESH:D007680', (162, 174))	('hypermethylated', 'Var', (24, 39))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('RCC', 'Disease', (55, 58))	('NPHP4', 'Gene', '261734', (14, 19))	('renal oncocytoma', 'Disease', (103, 119))	('NPHP4', 'Gene', (14, 19))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('chromophobe RCC', 'Disease', 'MESH:C538614', (43, 58))	('papillary RCC', 'Disease', 'MESH:C538614', (85, 98))
189618	32276433	The significance of cilia in ccRCC pathogenesis is strengthened by the observation that MLN4924, a compound suppressing cilia formation, attenuates proliferation and migration of ccRCC cells.	('attenuates', 'NegReg', (137, 147))	('RCC', 'Disease', 'MESH:C538614', (181, 184))	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))	('ccRCC', 'Phenotype', 'HP:0006770', (179, 184))	('formation', 'biological_process', 'GO:0009058', ('126', '135'))	('pathogenesis', 'biological_process', 'GO:0009405', ('35', '47'))	('MLN4924', 'Chemical', 'MESH:C539933', (88, 95))	('cilia formation', 'CPA', (120, 135))	('MLN4924', 'Var', (88, 95))	('suppressing', 'NegReg', (108, 119))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (181, 184))	('RCC', 'Disease', (31, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
189623	32276433	According to the unifying theory of renal cystogenesis, ciliopathies are caused by mutations in genes encoding proteins expressed in primary cilia, basal bodies and centrosomes which affect cilia functioning, thereby contributing to disturbed cilia-controlled signaling pathways.	('disturbed', 'Reg', (233, 242))	('mutations', 'Var', (83, 92))	('cilia', 'CPA', (190, 195))	('signaling', 'biological_process', 'GO:0023052', ('260', '269'))	('contributing', 'Reg', (217, 229))	('ciliopathies', 'Disease', (56, 68))	('affect', 'Reg', (183, 189))	('renal cystogenesis', 'Disease', (36, 54))	('renal cystogenesis', 'Disease', 'MESH:D007674', (36, 54))	('caused by', 'Reg', (73, 82))	('cilia-controlled signaling pathways', 'Pathway', (243, 278))
189624	32276433	Strikingly, renal cancer is characterized by cilia dysfunction, linked with inactivation of its key tumor suppressor, VHL.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('VHL', 'Gene', (118, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('100', '116'))	('cilia dysfunction', 'Disease', (45, 62))	('tumor', 'Disease', (100, 105))	('cilia dysfunction', 'Disease', 'MESH:C536287', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('renal cancer', 'Disease', (12, 24))	('tumor suppressor', 'biological_process', 'GO:0051726', ('100', '116'))	('inactivation', 'Var', (76, 88))	('renal cancer', 'Phenotype', 'HP:0009726', (12, 24))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('renal cancer', 'Disease', 'MESH:D007680', (12, 24))
189638	28900252	Whereas targeted cancer therapies may prolong survival, it is now widely recognized that inherent genetic instability and tumor plasticity ultimately leads to therapy resistance of most cancers.	('leads to', 'Reg', (150, 158))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('therapy resistance', 'CPA', (159, 177))	('genetic instability', 'Var', (98, 117))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cancer', 'Disease', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('survival', 'CPA', (46, 54))	('tumor', 'Disease', (122, 127))	('cancer', 'Disease', (186, 192))	('prolong', 'PosReg', (38, 45))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
189639	28900252	Whatever the underlying oncogenic mutations, for proliferation cancer cells need to generate ATP to maintain energy balance and ion homeostasis, import carbon and nitrogen sources for synthesis of amino acids, nucleotides and lipids and maintain redox potential to protect cells against oxidative stress.	('lipids', 'Chemical', 'MESH:D008055', (226, 232))	('oxidative stress', 'Phenotype', 'HP:0025464', (287, 303))	('synthesis', 'biological_process', 'GO:0009058', ('184', '193'))	('energy balance', 'MPA', (109, 123))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('ion homeostasis', 'MPA', (128, 143))	('redox potential', 'MPA', (246, 261))	('ATP', 'Chemical', 'MESH:D000255', (93, 96))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('carbon', 'Chemical', 'MESH:D002244', (152, 158))	('ion homeostasis', 'biological_process', 'GO:0050801', ('128', '143'))	('nitrogen', 'Chemical', 'MESH:D009584', (163, 171))	('mutations', 'Var', (34, 43))	('cancer', 'Disease', (63, 69))
189647	28900252	While metabolic adaptations are mostly seen as a consequence of carcinogenesis, it has been unequivocally established that metabolic alterations can also cause cancer, examples being mutations in genes encoding succinate dehydrogenase (SDH, pheochromocytoma and paraganglioma), fumarate hydratase (FH, papillary renal cancers) and isocitrate dehydrogenase 1 and 2 (IDH1/2, among others acute myeloid leukemia and gliomas).	('succinate dehydrogenase', 'Gene', (211, 234))	('IDH1/2', 'Gene', (365, 371))	('gliomas', 'Phenotype', 'HP:0009733', (413, 420))	('carcinogenesis', 'Disease', 'MESH:D063646', (64, 78))	('cancer', 'Disease', (318, 324))	('paraganglioma', 'Phenotype', 'HP:0002668', (262, 275))	('fumarate hydratase', 'Gene', '2271', (278, 296))	('glioma', 'Phenotype', 'HP:0009733', (269, 275))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('mutations', 'Var', (183, 192))	('cancers', 'Phenotype', 'HP:0002664', (318, 325))	('cancer', 'Disease', (160, 166))	('myeloid leukemia', 'Disease', (392, 408))	('SDH', 'Gene', '6390', (236, 239))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('FH', 'Gene', '2271', (298, 300))	('succinate dehydrogenase', 'Gene', '6390', (211, 234))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('pheochromocytoma', 'Disease', 'MESH:D010673', (241, 257))	('gliomas', 'Disease', (413, 420))	('paraganglioma', 'Disease', (262, 275))	('fumarate hydratase', 'Gene', (278, 296))	('myeloid leukemia', 'Disease', 'MESH:D007951', (392, 408))	('leukemia', 'Phenotype', 'HP:0001909', (400, 408))	('papillary renal cancers', 'Disease', 'MESH:D007681', (302, 325))	('SDH', 'Gene', (236, 239))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (392, 408))	('paraganglioma', 'Disease', 'MESH:D010235', (262, 275))	('pheochromocytoma', 'Disease', (241, 257))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('gliomas', 'Disease', 'MESH:D005910', (413, 420))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (241, 257))	('cause', 'Reg', (154, 159))	('carcinogenesis', 'Disease', (64, 78))	('papillary renal cancers', 'Disease', (302, 325))	('IDH1/2', 'Gene', '3417;3418', (365, 371))	('glioma', 'Phenotype', 'HP:0009733', (413, 419))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (386, 408))
189648	28900252	Clear cell renal cell carcinoma (ccRCC) is also considered a metabolic cancer with metabolic alterations resulting from inactivating mutations in or epigenetic silencing of VHL found in ~80% of cases.	('metabolic cancer', 'Disease', 'MESH:D009369', (61, 77))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('inactivating mutations in', 'Var', (120, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('epigenetic silencing', 'Var', (149, 169))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('VHL', 'Disease', (173, 176))	('metabolic cancer', 'Disease', (61, 77))	('VHL', 'Disease', 'MESH:D006623', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))
189650	28900252	Mutations in the aforementioned metabolic enzymes and in VHL have been shown to induce epigenetic alterations that affect expression of other metabolic enzymes in an unpredictable fashion.	('VHL', 'Disease', (57, 60))	('VHL', 'Disease', 'MESH:D006623', (57, 60))	('affect', 'Reg', (115, 121))	('induce', 'Reg', (80, 86))	('Mutations', 'Var', (0, 9))	('expression of other metabolic enzymes', 'MPA', (122, 159))	('epigenetic alterations', 'MPA', (87, 109))
189653	28900252	We further verified the ability of the assay to detect oncogenic mutations in cell lines and patient tumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('mutations', 'Var', (65, 74))	('patient', 'Species', '9606', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
189654	28900252	Our data show that targeted RNA sequencing of transcripts encoding metabolic enzymes using smMIPs predict the predominant metabolic pathways that are operational in cancer and simultaneously allows variant detection in the targeted transcripts.	('smMIPs', 'Gene', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('variant', 'Var', (198, 205))	('metabolic pathways', 'Pathway', (122, 140))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('RNA', 'cellular_component', 'GO:0005562', ('28', '31'))
189655	28900252	SmMIP-based next generation sequencing (NGS) of genomic DNA was recently introduced in routine diagnostics in our institute to detect tumor-associated mutations in DNA.	('DNA', 'Gene', (164, 167))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('DNA', 'cellular_component', 'GO:0005574', ('164', '167'))	('mutations', 'Var', (151, 160))	('tumor', 'Disease', (134, 139))
189656	28900252	To establish the strength of the technique we used the VHL-defective ccRCC cell line SKRC7 and its VHL-complemented variant SKRC7-VHLHA (expressing functional VHL with a haemagglutinin-tag) as a prototypical isogenic cell line pair with different metabolic characteristics: the lack of VHL in SKRC7 results in constitutive stabilization of HIF-1alpha and HIF-2alpha and a pseudohypoxic response.	('VHL', 'Disease', (99, 102))	('pseudohypoxic response', 'CPA', (372, 394))	('VHL', 'Disease', 'MESH:D006623', (55, 58))	('VHL', 'Disease', 'MESH:D006623', (286, 289))	('lack', 'Var', (278, 282))	('SKRC7', 'Gene', (293, 298))	('SKRC7', 'CellLine', 'CVCL:4024', (293, 298))	('VHL', 'Disease', (130, 133))	('SKRC7', 'CellLine', 'CVCL:4024', (85, 90))	('VHL', 'Disease', (159, 162))	('stabilization', 'MPA', (323, 336))	('VHL', 'Disease', 'MESH:D006623', (99, 102))	('SKRC7', 'CellLine', 'CVCL:4024', (124, 129))	('VHL', 'Disease', (55, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (69, 74))	('VHL', 'Disease', (286, 289))	('VHL', 'Disease', 'MESH:D006623', (130, 133))	('VHL', 'Disease', 'MESH:D006623', (159, 162))	('variant SKRC7-VHLHA', 'CellLine', 'CVCL:7204', (116, 135))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (340, 365))
189658	28900252	Whole RNAseq-derived gene expression data of SKRC7 cells (used here as gold standard) confirmed the presence of a nonsense and functionally inactivating Q132-stop mutation in 100% of VHL transcripts (Fig.	('Q132-stop', 'Var', (153, 162))	('VHL', 'Disease', 'MESH:D006623', (183, 186))	('SKRC7', 'CellLine', 'CVCL:4024', (45, 50))	('gene expression', 'biological_process', 'GO:0010467', ('21', '36'))	('VHL', 'Disease', (183, 186))	('Q132-stop', 'Mutation', 'rs1268787941', (153, 162))
189682	28900252	We further present evidence that profiling of clinical renal cell cancer tissues as expected shows high levels of hypoxia-induced genes suggesting extensive glycolysis, while also unambiguously revealing the presence of VHL mutations, all in line with known biology of these cancers.	('renal cell cancer', 'Disease', (55, 72))	('VHL', 'Disease', 'MESH:D006623', (220, 223))	('renal cell cancer', 'Disease', 'MESH:C538614', (55, 72))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('renal cell cancer', 'Phenotype', 'HP:0005584', (55, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('VHL', 'Disease', (220, 223))	('clinical', 'Species', '191496', (46, 54))	('glycolysis', 'biological_process', 'GO:0006096', ('157', '167'))	('cancers', 'Phenotype', 'HP:0002664', (275, 282))	('glycolysis', 'MPA', (157, 167))	('mutations', 'Var', (224, 233))	('cancers', 'Disease', 'MESH:D009369', (275, 282))	('hypoxia', 'Disease', (114, 121))	('hypoxia', 'Disease', 'MESH:D000860', (114, 121))	('cancers', 'Disease', (275, 282))
189684	28900252	This may present a problem when trying to detect mutations in VHL using smMIPs 1,8 or 10.	('VHL', 'Disease', (62, 65))	('VHL', 'Disease', 'MESH:D006623', (62, 65))	('mutations', 'Var', (49, 58))
189689	28900252	SmMIP-based transcript profiling may be a highly relevant alternative with added value in the field of cancer diagnostics as it can identify metabolic Achilles heels by simultaneously measuring relative gene expression levels and detecting variants.	('gene expression', 'biological_process', 'GO:0010467', ('203', '218'))	('variants', 'Var', (240, 248))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('relative gene expression levels', 'MPA', (194, 225))	('metabolic Achilles heels', 'Disease', (141, 165))	('detecting', 'Reg', (230, 239))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
189716	28900252	After blocking in Odyssey blocking buffer (1:1 in PBS) membranes were incubated overnight in Odyssey blocking buffer containing antibodies against HK-2 (2867S, Cell signaling technology), CA9 (M75, Dr. Oosterwijk) or gamma-tubulin (C20, Santa Cruz Biotechnology, Dallas, TX) as loading control.	('HK-2', 'Gene', (147, 151))	('CA9', 'Gene', '768', (188, 191))	('HK-2', 'molecular_function', 'GO:0008256', ('147', '151'))	('signaling', 'biological_process', 'GO:0023052', ('165', '174'))	('antibodies', 'Var', (128, 138))	('CA9', 'Gene', (188, 191))
189717	28900252	Antibodies were detected with secondary antibodies conjugated with Alexa680 or DyLight800, and signal was visualized with the Odyssey scanner (LI-COR).	('Alexa680', 'Chemical', '-', (67, 75))	('DyLight800', 'Var', (79, 89))	('Alexa680', 'Var', (67, 75))
189719	28498419	miR-590 regulates WT1 during proliferation of G401 cells Nephroblastoma (Wilms' tumor) is frequently associated with mortality in children.	("Wilms' tumor", 'Phenotype', 'HP:0002667', (73, 85))	("Wilms' tumor", 'Disease', 'MESH:D009396', (73, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Nephroblastoma', 'Disease', 'MESH:D009396', (57, 71))	('G401', 'CellLine', 'CVCL:0270', (46, 50))	('WT1', 'Gene', '7490', (18, 21))	('WT1', 'Gene', (18, 21))	('associated', 'Reg', (101, 111))	('G401', 'Var', (46, 50))	('children', 'Species', '9606', (130, 138))	('Nephroblastoma', 'Phenotype', 'HP:0002667', (57, 71))	("Wilms' tumor", 'Disease', (73, 85))	('Nephroblastoma', 'Disease', (57, 71))	('miR-590', 'Gene', (0, 7))
189727	28498419	To the best of our knowledge, the present study was the first to determine that WT1 was a target gene of miR-590 as miR-590 was able to negatively regulate WT1 expression level by binding to the specific target site within the 3'-untranslated region (3'-UTR) of WT1 in G401 cells.	('negatively regulate', 'NegReg', (136, 155))	('binding', 'molecular_function', 'GO:0005488', ('180', '187'))	('G401', 'CellLine', 'CVCL:0270', (269, 273))	('WT1', 'Gene', '7490', (262, 265))	('miR-590', 'Chemical', '-', (105, 112))	('WT1', 'Gene', '7490', (80, 83))	('miR-590', 'Var', (105, 112))	('WT1', 'Gene', '7490', (156, 159))	('miR-590', 'Chemical', '-', (116, 123))	('expression', 'Species', '29278', (160, 170))	('WT1', 'Gene', (262, 265))	('binding', 'Interaction', (180, 187))	('WT1', 'Gene', (80, 83))	('WT1', 'Gene', (156, 159))	('miR-590', 'Var', (116, 123))
189730	28498419	In conclusion, the observations indicated that miR-590 may function as an oncogene via targeting WT1 to induce G401 cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('116', '134'))	('G401', 'CellLine', 'CVCL:0270', (111, 115))	('WT1', 'Gene', '7490', (97, 100))	('induce', 'PosReg', (104, 110))	('miR-590', 'Chemical', '-', (47, 54))	('G401 cell proliferation', 'CPA', (111, 134))	('miR-590', 'Var', (47, 54))	('WT1', 'Gene', (97, 100))
189741	28498419	These previous findings may suggest that miR-590 functions as a tumor activator in various types of cancer, although the contrary results have been obtained in other types of cancer including lung cancer and T-cell acute lymphoblastic leukaemia.	('T-cell acute lymphoblastic leukaemia', 'Disease', 'MESH:D054218', (208, 244))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (175, 181))	('lung cancer', 'Disease', 'MESH:D008175', (192, 203))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('T-cell acute lymphoblastic leukaemia', 'Disease', (208, 244))	('cancer', 'Disease', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('acute lymphoblastic leukaemia', 'Phenotype', 'HP:0006721', (215, 244))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (100, 106))	('miR-590', 'Chemical', '-', (41, 48))	('miR-590', 'Var', (41, 48))	('tumor', 'Disease', (64, 69))	('lung cancer', 'Disease', (192, 203))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('T-cell acute lymphoblastic leukaemia', 'Phenotype', 'HP:0006727', (208, 244))
189744	28498419	The present study determined that the expression level of miR-590 was increased in nephroblastoma tissues and the levels were consistent with the clinical stage of the tissue, which indicated that miR-590 was involved in the pathogenesis of Wilms' tumor.	('expression level', 'MPA', (38, 54))	('expression', 'Species', '29278', (38, 48))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (241, 253))	('clinical', 'Species', '191496', (146, 154))	('increased', 'PosReg', (70, 79))	('involved', 'Reg', (209, 217))	('nephroblastoma', 'Disease', (83, 97))	('miR-590', 'Chemical', '-', (197, 204))	('pathogenesis', 'biological_process', 'GO:0009405', ('225', '237'))	('nephroblastoma', 'Phenotype', 'HP:0002667', (83, 97))	('miR-590', 'Var', (197, 204))	('miR-590', 'Chemical', '-', (58, 65))	('miR-590', 'Gene', (58, 65))	("Wilms' tumor", 'Disease', 'MESH:D009396', (241, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	("Wilms' tumor", 'Disease', (241, 253))	('nephroblastoma', 'Disease', 'MESH:D009396', (83, 97))
189772	28498419	Proteins (50 microg/lane) were segregated using 10% SDS-PAGE gel and immunoblotting was performed using polyclonal antibodies against WT1 (AB10840; 1:2,500; Abcam, Cambridge, UK) and beta-tubulin (AB6040; 1:5,000; Abcam).	('SDS', 'Chemical', 'MESH:D012967', (52, 55))	('beta-tubulin', 'Protein', (183, 195))	('WT1', 'Gene', '7490', (134, 137))	('WT1', 'Gene', (134, 137))	('AB6040;', 'Var', (197, 204))	('AB10840; 1:2,500', 'Var', (139, 155))
189775	28498419	The present study quantified the expression levels of miR-590 in Wilms' tumor to confirm the involvement of miR-590 in nephroblastoma using RT-qPCR.	('nephroblastoma', 'Disease', (119, 133))	('miR-590', 'Chemical', '-', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('miR-590', 'Var', (108, 115))	('nephroblastoma', 'Phenotype', 'HP:0002667', (119, 133))	('miR-590', 'Chemical', '-', (54, 61))	('expression', 'Species', '29278', (33, 43))	("Wilms' tumor", 'Disease', (65, 77))	('nephroblastoma', 'Disease', 'MESH:D009396', (119, 133))	("Wilms' tumor", 'Disease', 'MESH:D009396', (65, 77))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (65, 77))
189784	28498419	In order to verify that miR-590 binds to the predicted region and the binding leads to translational inhibition, a luciferase reporter plasmid with either wide-type or mutant sequence of WT1 mRNA 3'-UTR was cotransfected with miR-590 mimic or miR-control mimic.	('miR-590', 'Chemical', '-', (24, 31))	('mutant', 'Var', (168, 174))	('binding', 'molecular_function', 'GO:0005488', ('70', '77'))	('WT1', 'Gene', '7490', (187, 190))	('miR-590', 'Chemical', '-', (226, 233))	('WT1', 'Gene', (187, 190))	('translational', 'MPA', (87, 100))	('leads', 'Reg', (78, 83))
189785	28498419	Successful overexpression of exogenous miR-590 in G401 cells for 36 h downregulated the activity of the luciferase reporter, which was inserted with wild-type WT1 3'-UTR, whereas the activity with mutated WT1 was not affected, indicating that the mutant target was a potential functional site for miR-590 in WT1 3'-UTR (Fig.	('WT1', 'Gene', (308, 311))	('G401', 'CellLine', 'CVCL:0270', (50, 54))	('WT1', 'Gene', '7490', (159, 162))	('expression', 'Species', '29278', (15, 25))	('miR-590', 'Chemical', '-', (297, 304))	('activity', 'MPA', (88, 96))	('miR-590', 'Chemical', '-', (39, 46))	('luciferase reporter', 'Enzyme', (104, 123))	('miR-590', 'Var', (39, 46))	('downregulated', 'NegReg', (70, 83))	('WT1', 'Gene', '7490', (205, 208))	('WT1', 'Gene', (159, 162))	('WT1', 'Gene', (205, 208))	('overexpression', 'PosReg', (11, 25))	('WT1', 'Gene', '7490', (308, 311))
189791	28498419	miR-590 expression level was markedly upregulated in G401 cells treated with miR-590 mimics compared with control mimics, as determined by RT-qPCR (P<0.01; 100-fold).	('mimics', 'Var', (85, 91))	('expression level', 'MPA', (8, 24))	('upregulated', 'PosReg', (38, 49))	('miR-590', 'Chemical', '-', (77, 84))	('miR-590', 'Gene', (77, 84))	('G401', 'CellLine', 'CVCL:0270', (53, 57))	('expression', 'Species', '29278', (8, 18))	('miR-590', 'Chemical', '-', (0, 7))	('miR-590', 'Gene', (0, 7))
189795	28498419	Therefore, the importance of WT1 as a functional target of miR-590 was determined in G401 cell proliferation.	('miR-590', 'Var', (59, 66))	('G401', 'CellLine', 'CVCL:0270', (85, 89))	('WT1', 'Gene', '7490', (29, 32))	('cell proliferation', 'biological_process', 'GO:0008283', ('90', '108'))	('miR-590', 'Chemical', '-', (59, 66))	('WT1', 'Gene', (29, 32))
189797	28498419	WT1 si-RNA markedly reduced WT1 protein expression levels in G401 cells compared with the control siRNA.	('reduced', 'NegReg', (20, 27))	('WT1', 'Gene', '7490', (0, 3))	('RNA', 'cellular_component', 'GO:0005562', ('7', '10'))	('WT1', 'Gene', '7490', (28, 31))	('si-RNA', 'Var', (4, 10))	('WT1', 'Gene', (28, 31))	('WT1', 'Gene', (0, 3))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('G401', 'CellLine', 'CVCL:0270', (61, 65))	('expression', 'Species', '29278', (40, 50))
189812	28498419	Therefore, miR-590 may act as a tumor promoter in some malignant diseases; however, in order to elucidate the specific functions, further investigation is required.	('miR-590', 'Var', (11, 18))	('malignant diseases', 'Disease', (55, 73))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('malignant diseases', 'Disease', 'MESH:D009369', (55, 73))	('tumor', 'Disease', (32, 37))	('miR-590', 'Chemical', '-', (11, 18))
189818	28498419	For example, miR-590 downregulates PBRM1 expression, leading to increased cell proliferation and invasion in CCRCC and promotes cervical cancer cell growth and invasion by targeting CHL1.	('targeting', 'Reg', (172, 181))	('downregulates', 'NegReg', (21, 34))	('PBRM1', 'Gene', (35, 40))	('miR-590', 'Chemical', '-', (13, 20))	('CHL1', 'Gene', (182, 186))	('miR-590', 'Var', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cell proliferation', 'CPA', (74, 92))	('CCRCC', 'Phenotype', 'HP:0006770', (109, 114))	('expression', 'MPA', (41, 51))	('CCRCC', 'Disease', (109, 114))	('invasion', 'CPA', (97, 105))	('invasion', 'CPA', (160, 168))	('cell growth', 'biological_process', 'GO:0016049', ('144', '155'))	('CHL1', 'Gene', '10752', (182, 186))	('promotes', 'PosReg', (119, 127))	('expression', 'Species', '29278', (41, 51))	('PBRM1', 'Gene', '55193', (35, 40))	('increased', 'PosReg', (64, 73))	('cell proliferation', 'biological_process', 'GO:0008283', ('74', '92'))	('cervical cancer', 'Disease', (128, 143))	('cervical cancer', 'Disease', 'MESH:D002583', (128, 143))
189819	28498419	The present study demonstrated that miR-590 inhibited WT1 expression by targeting the 3'-UTR, indicating that WT1 is a direct target of miR-590.	('expression', 'Species', '29278', (58, 68))	('expression', 'MPA', (58, 68))	('inhibited', 'NegReg', (44, 53))	('miR-590', 'Chemical', '-', (136, 143))	('WT1', 'Gene', '7490', (110, 113))	('miR-590', 'Chemical', '-', (36, 43))	('miR-590', 'Var', (36, 43))	('WT1', 'Gene', (110, 113))	('WT1', 'Gene', '7490', (54, 57))	('WT1', 'Gene', (54, 57))
189820	28498419	As the Wilms' tumor transcription factor (WT1) was originally classified as a tumor suppressor, miR-590 may be a tumor activator, inversely associated with its specific target gene.	('transcription', 'biological_process', 'GO:0006351', ('20', '33'))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	("Wilms' tumor", 'Disease', (7, 19))	("Wilms' tumor", 'Disease', 'MESH:D009396', (7, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('WT1', 'Gene', (42, 45))	('tumor', 'Disease', (113, 118))	('WT1', 'Gene', '7490', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('78', '94'))	('tumor', 'Disease', (78, 83))	('miR-590', 'Chemical', '-', (96, 103))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (7, 19))	('miR-590', 'Var', (96, 103))	('tumor', 'Disease', (14, 19))	('transcription factor', 'molecular_function', 'GO:0000981', ('20', '40'))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor suppressor', 'biological_process', 'GO:0051726', ('78', '94'))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
189829	28498419	In the present study, the knockdown of WT1 expression by siRNA-WT1 had a proliferative effect on G401 cells, similar effect to overexpression of miR-590.	('WT1', 'Gene', (39, 42))	('miR-590', 'Chemical', '-', (145, 152))	('WT1', 'Gene', '7490', (63, 66))	('proliferative effect', 'CPA', (73, 93))	('G401', 'CellLine', 'CVCL:0270', (97, 101))	('expression', 'Species', '29278', (131, 141))	('knockdown', 'Var', (26, 35))	('expression', 'Species', '29278', (43, 53))	('WT1', 'Gene', (63, 66))	('WT1', 'Gene', '7490', (39, 42))
189831	28498419	Therefore, WT1 may be one of the key mediators of G401 suppression by miR-590.	('miR-590', 'Var', (70, 77))	('suppression', 'NegReg', (55, 66))	('WT1', 'Gene', '7490', (11, 14))	('G401', 'CellLine', 'CVCL:0270', (50, 54))	('WT1', 'Gene', (11, 14))	('miR-590', 'Chemical', '-', (70, 77))	('G401', 'Gene', (50, 54))
189835	28498419	A direct and functional target of miR-590, WT1, is downregulated and associated with cell proliferation in G401.	('miR-590', 'Gene', (34, 41))	('cell proliferation', 'CPA', (85, 103))	('WT1', 'Gene', (43, 46))	('G401', 'CellLine', 'CVCL:0270', (107, 111))	('cell proliferation', 'biological_process', 'GO:0008283', ('85', '103'))	('associated', 'Reg', (69, 79))	('G401', 'Var', (107, 111))	('downregulated', 'NegReg', (51, 64))	('WT1', 'Gene', '7490', (43, 46))	('miR-590', 'Chemical', '-', (34, 41))
189841	32023483	ccRCC patients with VHL loss-of-function mutations displayed elevated SFMBT1 protein levels.	('mutations', 'Var', (41, 50))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('RCC', 'Disease', (2, 5))	('loss-of-function', 'NegReg', (24, 40))	('elevated', 'PosReg', (61, 69))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('VHL', 'Gene', (20, 23))	('patients', 'Species', '9606', (6, 14))	('VHL', 'Gene', '7428', (20, 23))	('SFMBT1 protein levels', 'MPA', (70, 91))
189843	32023483	Depletion of SFMBT1 abolished ccRCC cell proliferation in vitro and inhibited orthotopic tumor growth in vivo.	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('abolished', 'NegReg', (20, 29))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('cell proliferation', 'biological_process', 'GO:0008283', ('36', '54'))	('RCC', 'Disease', (32, 35))	('inhibited', 'NegReg', (68, 77))	('Depletion', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('SFMBT1', 'Gene', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
189849	32023483	Inactivating VHL mutations play major roles in sporadic RCC, and loss of VHL accounts for up to 85% of renal cancers that are classically resistant to cytotoxic chemotherapy.	('VHL', 'Gene', (73, 76))	('RCC', 'Disease', (56, 59))	('loss', 'Var', (65, 69))	('renal cancers', 'Disease', (103, 116))	('VHL', 'Gene', '7428', (73, 76))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('Inactivating', 'Var', (0, 12))	('renal cancer', 'Phenotype', 'HP:0009726', (103, 115))	('VHL', 'Gene', (13, 16))	('VHL', 'Gene', '7428', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (17, 26))	('renal cancers', 'Disease', 'MESH:D007680', (103, 116))
189851	32023483	Loss of pVHL therefore promotes HIFalpha accumulation, which contributes to the transformation phenotype of renal cancer.	('HIFalpha accumulation', 'Disease', 'MESH:C579880', (32, 53))	('promotes', 'PosReg', (23, 31))	('renal cancer', 'Disease', (108, 120))	('renal cancer', 'Phenotype', 'HP:0009726', (108, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('renal cancer', 'Disease', 'MESH:D007680', (108, 120))	('pVHL', 'Gene', (8, 12))	('HIFalpha accumulation', 'Disease', (32, 53))	('Loss', 'Var', (0, 4))
189873	32023483	In addition, treatment of HA-pVHL expressing cells with the proteasome inhibitor MG132 also led to SFMBT1 upregulation (Figure 1F), suggesting that SFMBT1 hydroxylation leads to pVHL-mediated proteasomal degradation.	('proteasome', 'molecular_function', 'GO:0004299', ('60', '70'))	('proteasome', 'cellular_component', 'GO:0000502', ('60', '70'))	('SFMBT1', 'Var', (148, 154))	('SFMBT1', 'Gene', (99, 105))	('pVHL-mediated proteasomal degradation', 'MPA', (178, 215))	('upregulation', 'PosReg', (106, 118))	('leads to', 'Reg', (169, 177))	('degradation', 'biological_process', 'GO:0009056', ('204', '215'))	('MG132', 'Chemical', 'MESH:C072553', (81, 86))
189874	32023483	Strengthening the observation from pVHL-null ccRCC cell lines that SFMBT1 regulation is dependent on hydroxylation and proteasomal degradation, treatment of pVHL-expressing renal cells (Caki-1, HKC or 293T) with MG132, DMOG, or hypoxia also resulted in upregulation of SFMBT1 expression (Figure 1G).	('hypoxia', 'Disease', (228, 235))	('hypoxia', 'Disease', 'MESH:D000860', (228, 235))	('MG132', 'Var', (212, 217))	('MG132', 'Chemical', 'MESH:C072553', (212, 217))	('regulation', 'biological_process', 'GO:0065007', ('74', '84'))	('degradation', 'biological_process', 'GO:0009056', ('131', '142'))	('upregulation', 'PosReg', (253, 265))	('293T', 'CellLine', 'CVCL:0063', (201, 205))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('RCC', 'Disease', (47, 50))	('SFMBT1', 'Gene', (269, 275))	('expression', 'MPA', (276, 286))	('DMOG', 'Chemical', 'MESH:C040947', (219, 223))
189875	32023483	Our results suggest that SFMBT1 may undergo hydroxylation and regulation by pVHL, which is further strengthened by the ability of pan-hydroxyproline antibody to pull-down hydroxylated SFMBT1 in the presence of MG132, an effect abrogated by concurrent MG132 and DMOG treatment (Figure 2A).	('antibody', 'cellular_component', 'GO:0019814', ('149', '157'))	('antibody', 'molecular_function', 'GO:0003823', ('149', '157'))	('MG132', 'Chemical', 'MESH:C072553', (251, 256))	('MG132', 'Chemical', 'MESH:C072553', (210, 215))	('hydroxyproline antibody', 'Phenotype', 'HP:0003260', (134, 157))	('antibody', 'cellular_component', 'GO:0042571', ('149', '157'))	('MG132', 'Var', (210, 215))	('pan-hydroxyproline', 'Chemical', '-', (130, 148))	('antibody', 'cellular_component', 'GO:0019815', ('149', '157'))	('hydroxylation', 'MPA', (44, 57))	('SFMBT1', 'Gene', (25, 31))	('DMOG', 'Chemical', 'MESH:C040947', (261, 265))	('regulation', 'MPA', (62, 72))	('regulation', 'biological_process', 'GO:0065007', ('62', '72'))	('SFMBT1', 'Gene', (184, 190))
189877	32023483	GST pull-down of endogenous SFMBT1 from 786-O cells further confirmed the binding between GST-pVHL and SFMBT1, which was diminished when cells were treated with either DMOG or FG4592 (Figure S2C).	('DMOG', 'Chemical', 'MESH:C040947', (168, 172))	('binding', 'molecular_function', 'GO:0005488', ('74', '81'))	('binding', 'Interaction', (74, 81))	('FG4592', 'Var', (176, 182))	('SFMBT1', 'Gene', (103, 109))	('FG4592', 'Chemical', 'MESH:C584543', (176, 182))	('GST-pVHL', 'Gene', (90, 98))
189879	32023483	We overexpressed FLAG-tagged SFMBT1 in 293T cells followed by treatment with either MG132 or MG132 together with DMOG, and performed mass spectrometry (Figure S2D).	('SFMBT1', 'Gene', (29, 35))	('DMOG', 'Chemical', 'MESH:C040947', (113, 117))	('MG132', 'Var', (93, 98))	('MG132', 'Chemical', 'MESH:C072553', (93, 98))	('MG132', 'Var', (84, 89))	('293T', 'CellLine', 'CVCL:0063', (39, 43))	('MG132', 'Chemical', 'MESH:C072553', (84, 89))
189883	32023483	Next, we mutated SFMBT1 prolines 106 and 651 to alanines (P106A and P651A).	('P651A', 'Mutation', 'p.P651A', (68, 73))	('alanines', 'Chemical', 'MESH:D000409', (48, 56))	('P106A', 'Mutation', 'p.P106A', (58, 63))	('P651A', 'Var', (68, 73))	('prolines', 'Chemical', 'MESH:D011392', (24, 32))	('SFMBT1', 'Gene', (17, 23))
189884	32023483	Whereas WT or P106A mutant SFMBT1 bound pVHL efficiently, P651A mutant binding to pVHL was impaired, suggesting that P651 is the major hydroxylation site recognized by pVHL (Figure 2C).	('P106A', 'Var', (14, 19))	('P651A', 'Mutation', 'p.P651A', (58, 63))	('bound', 'Interaction', (34, 39))	('impaired', 'NegReg', (91, 99))	('P106A', 'Mutation', 'p.P106A', (14, 19))	('P651A', 'Var', (58, 63))	('SFMBT1', 'Gene', (27, 33))	('binding', 'Interaction', (71, 78))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))
189885	32023483	Subsequently, we synthesized WT (SFMBT1-WT) or Proline 650/651 hydroxylated (P650-OH and P651-OH) SFMBT1 peptides and performed the binding assay with pVHL (Figure 2D).	('P651-OH', 'Var', (89, 96))	('Proline', 'Chemical', 'MESH:D011392', (47, 54))	('P650-OH', 'Var', (77, 84))	('binding', 'molecular_function', 'GO:0005488', ('132', '139'))	('SFMBT1', 'Gene', (98, 104))	('binding', 'Interaction', (132, 139))
189886	32023483	Only P651-OH peptide was able to bind with pVHL strongly, similar to hydroxylated HIF1alpha peptide (Figure 2D).	('P651-OH', 'Var', (5, 12))	('HIF1alpha', 'Gene', '3091', (82, 91))	('bind', 'Interaction', (33, 37))	('pVHL', 'Protein', (43, 47))	('HIF1alpha', 'Gene', (82, 91))
189887	32023483	We noticed that there was an adjacent Proline (P650) on SFMBT1 but synthesized P650-OH peptide failed to bind with pVHL (Figure 2D), suggesting that proline 651 is the specific site undergoing hydroxylation leading to pVHL binding.	('binding', 'molecular_function', 'GO:0005488', ('223', '230'))	('Proline', 'Chemical', 'MESH:D011392', (38, 45))	('binding', 'Interaction', (223, 230))	('bind', 'Interaction', (105, 109))	('P650', 'Var', (47, 51))	('proline', 'Chemical', 'MESH:D011392', (149, 156))	('P650-OH', 'Var', (79, 86))
189888	32023483	Consistently, pan-hydroxylation IP of HA-tagged WT (WT), P106A, or P651A SFMBT1 followed by HA-SFMBT1 immunoblot showed that only P651A mutant abrogated the hydroxylation signal (Figure 2E).	('P106A', 'Mutation', 'p.P106A', (57, 62))	('P651A', 'Var', (67, 72))	('P651A', 'Var', (130, 135))	('P106A', 'Var', (57, 62))	('hydroxylation signal', 'MPA', (157, 177))	('P651A', 'Mutation', 'p.P651A', (67, 72))	('P651A', 'Mutation', 'p.P651A', (130, 135))	('abrogated', 'NegReg', (143, 152))	('SFMBT1', 'Gene', (73, 79))
189889	32023483	We also depleted endogenous SFMBT1 and restored with physiologically relevant levels of SFMBT1 WT or P651A SFMBT1 mutant followed by examination of SFMBT1 hydroxylation.	('P651A', 'Var', (101, 106))	('SFMBT1', 'Gene', (107, 113))	('endogenous', 'MPA', (17, 27))	('P651A', 'Mutation', 'p.P651A', (101, 106))
189890	32023483	Both SFMBT1 depletion and P651A mutation abrogated the hydroxylation signal (Figure 2F).	('abrogated', 'NegReg', (41, 50))	('SFMBT1', 'Gene', (5, 11))	('P651A mutation', 'Var', (26, 40))	('P651A', 'Mutation', 'p.P651A', (26, 31))	('hydroxylation signal', 'MPA', (55, 75))
189892	32023483	We also confirmed this in vivo ubiquitination assay in pVHL-deficient 786-O renal cancer cells or isogenic cells reconstituted with HA-pVHL, and observed an increase in endogenous SFMBT1 ubiquitination upon HA-pVHL expression (Figure 2G).	('pVHL-deficient 786-O renal cancer', 'Disease', (55, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ubiquitination', 'MPA', (31, 45))	('endogenous', 'MPA', (169, 179))	('renal cancer', 'Phenotype', 'HP:0009726', (76, 88))	('increase', 'PosReg', (157, 165))	('ubiquitination', 'MPA', (187, 201))	('pVHL-deficient 786-O renal cancer', 'Disease', 'MESH:D007680', (55, 88))	('HA-pVHL', 'Var', (207, 214))	('SFMBT1', 'Gene', (180, 186))
189893	32023483	To investigate whether P651 affects SFMBT1 ubiquitination by pVHL, we performed an in vivo ubiquitination assay in 293T cells.	('SFMBT1', 'Gene', (36, 42))	('293T', 'CellLine', 'CVCL:0063', (115, 119))	('ubiquitination', 'MPA', (43, 57))	('P651', 'Var', (23, 27))
189894	32023483	Consistent with Western blot data showing SFMBT1 regulation by pVHL, pVHL promoted ubiquitination of WT or P106A, but not P651A SFMBT1 (Figure 2H).	('regulation', 'biological_process', 'GO:0065007', ('49', '59'))	('promoted', 'PosReg', (74, 82))	('P106A', 'Var', (107, 112))	('P106A', 'Mutation', 'p.P106A', (107, 112))	('ubiquitination', 'MPA', (83, 97))	('P651A', 'Mutation', 'p.P651A', (122, 127))
189895	32023483	We also transduced FLAG-VHL UMRC2 cells with lentivirus expressing WT or P651A HA-SFMBT1 followed by treatment with MG132, MLN4924 (neddylation inhibitor that inhibits E3 ligase complex formation), or DMOG.	('formation', 'biological_process', 'GO:0009058', ('186', '195'))	('MG132', 'Chemical', 'MESH:C072553', (116, 121))	('VHL', 'Gene', '7428', (24, 27))	('HA-SFMBT1', 'Gene', (79, 88))	('P651A', 'Mutation', 'p.P651A', (73, 78))	('MLN4924', 'Chemical', 'MESH:C539933', (123, 130))	('UMRC2', 'CellLine', 'CVCL:2739', (28, 33))	('VHL', 'Gene', (24, 27))	('P651A', 'Var', (73, 78))	('MLN4924', 'Var', (123, 130))	('DMOG', 'Chemical', 'MESH:C040947', (201, 205))
189896	32023483	Conversely, the P651A HA-SFMBT1 mutant was not affected by these inhibitors, and was constantly upregulated compared to its WT counterpart (Figure 2I).	('P651A', 'Var', (16, 21))	('upregulated', 'PosReg', (96, 107))	('HA-SFMBT1', 'Gene', (22, 31))	('P651A', 'Mutation', 'p.P651A', (16, 21))
189903	32023483	We then depleted EglN1 and restored with physiologically relevant levels of EglN1 WT or catalytic dead (EglN1 CD) mutant, and examined SFMBT1 hydroxylation.	('EglN1', 'Gene', '54583', (17, 22))	('EglN1', 'Gene', (104, 109))	('EglN1', 'Gene', '54583', (104, 109))	('EglN1', 'Gene', '54583', (76, 81))	('mutant', 'Var', (114, 120))	('EglN1', 'Gene', (17, 22))	('depleted', 'NegReg', (8, 16))	('EglN1', 'Gene', (76, 81))
189906	32023483	Mutation of the HA-SFMBT1 prolyl hydroxylation site P651A totally abrogated the regulation of HA-SFMBT1 by EglN1 depletion (Figure 2N).	('abrogated', 'NegReg', (66, 75))	('regulation', 'MPA', (80, 90))	('EglN1', 'Gene', '54583', (107, 112))	('regulation', 'biological_process', 'GO:0065007', ('80', '90'))	('P651A', 'Mutation', 'p.P651A', (52, 57))	('HA-SFMBT1', 'Gene', (94, 103))	('prolyl', 'Chemical', '-', (26, 32))	('P651A', 'Var', (52, 57))	('HA-SFMBT1', 'Gene', (16, 25))	('EglN1', 'Gene', (107, 112))
189909	32023483	Next, to examine the physiological relevance of SFMBT1 in ccRCC, where most of patients carry VHL loss-of-function mutations, we analyzed 11 pairs of tumor and normal tissues from ccRCC patients.	('mutations', 'Var', (115, 124))	('VHL', 'Gene', '7428', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('loss-of-function', 'NegReg', (98, 114))	('patients', 'Species', '9606', (186, 194))	('RCC', 'Disease', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('patients', 'Species', '9606', (79, 87))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('RCC', 'Disease', (182, 185))	('tumor', 'Disease', (150, 155))	('VHL', 'Gene', (94, 97))
189910	32023483	Most tumors carrying splice variant, missense, or frame-shift mutations displayed consistent upregulation of SFMBT1 compared to paired normal tissues, which correlated well with HIF2alpha levels in these patients (Figure 3A).	('upregulation', 'PosReg', (93, 105))	('tumors', 'Disease', (5, 11))	('patients', 'Species', '9606', (204, 212))	('splice variant', 'Var', (21, 35))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('HIF2alpha', 'Gene', '2034', (178, 187))	('SFMBT1', 'Gene', (109, 115))	('frame-shift mutations', 'Var', (50, 71))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('missense', 'Var', (37, 45))	('HIF2alpha', 'Gene', (178, 187))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
189915	32023483	We next performed immunohistochemical (IHC) staining for these tumors and found that SFMBT1 expression was increased in the nuclei of tumors with VHL loss-of-function mutations compared to their respective adjacent normal tissues (Figure 3B).	('VHL', 'Gene', (146, 149))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('VHL', 'Gene', '7428', (146, 149))	('increased', 'PosReg', (107, 116))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('mutations', 'Var', (167, 176))	('SFMBT1', 'Gene', (85, 91))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('loss-of-function', 'NegReg', (150, 166))	('expression', 'MPA', (92, 102))
189916	32023483	We also examined SFMBT1 protein levels in tumors from a previously generated ccRCC mouse model with pVHL loss; SFMBT1 was upregulated in multiple ccRCC tumors compared to normal kidney tissues (Figure S3B), suggesting the importance of SFMBT1 in human and mouse ccRCC pathogenesis.	('RCC', 'Disease', (148, 151))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Disease', (152, 158))	('ccRCC tumors', 'Disease', (146, 158))	('pVHL', 'Gene', (100, 104))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('ccRCC tumors', 'Disease', 'MESH:D009369', (146, 158))	('ccRCC', 'Phenotype', 'HP:0006770', (262, 267))	('human', 'Species', '9606', (246, 251))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('SFMBT1', 'Gene', (111, 117))	('RCC', 'Disease', (264, 267))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mouse', 'Species', '10090', (83, 88))	('upregulated', 'PosReg', (122, 133))	('loss', 'Var', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('RCC', 'Disease', (79, 82))	('RCC', 'Disease', 'MESH:C538614', (264, 267))	('ccRCC', 'Phenotype', 'HP:0006770', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', (42, 48))	('pathogenesis', 'biological_process', 'GO:0009405', ('268', '280'))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('mouse', 'Species', '10090', (256, 261))
189922	32023483	SFMBT1 depletion significantly decreased cell proliferation (Figure 4A-B) and 3-D soft-agar growth (Figure 4C and S4A).	('cell proliferation', 'CPA', (41, 59))	('decreased', 'NegReg', (31, 40))	('agar', 'Chemical', 'MESH:D000362', (87, 91))	('3-D soft-agar growth', 'CPA', (78, 98))	('depletion', 'Var', (7, 16))	('SFMBT1', 'Gene', (0, 6))	('cell proliferation', 'biological_process', 'GO:0008283', ('41', '59'))
189923	32023483	We also observed a similar cell proliferation and 3-D soft agar growth defect upon SFMBT1 depletion in another ccRCC cell line, UMRC2 (Figure S4B-E).	('UMRC2', 'CellLine', 'CVCL:2739', (128, 133))	('agar', 'Chemical', 'MESH:D000362', (59, 63))	('cell proliferation', 'CPA', (27, 45))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('defect', 'NegReg', (71, 77))	('depletion', 'Var', (90, 99))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('SFMBT1', 'Gene', (83, 89))	('cell proliferation', 'biological_process', 'GO:0008283', ('27', '45'))
189926	32023483	SFMBT1 depletion also showed decreased cell proliferation and soft-agar growth upon doxycycline addition in UMRC2 cells (Figure 4H-I and S4G) and 786-O cells (Figure S4H-K).	('agar', 'Chemical', 'MESH:D000362', (67, 71))	('doxycycline', 'Chemical', 'MESH:D004318', (84, 95))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('depletion', 'Var', (7, 16))	('decreased', 'NegReg', (29, 38))	('SFMBT1', 'Gene', (0, 6))	('cell proliferation', 'CPA', (39, 57))	('S4G', 'Mutation', 'p.S4G', (137, 140))	('UMRC2', 'CellLine', 'CVCL:2739', (108, 113))	('soft-agar growth', 'CPA', (62, 78))
189937	32023483	Next, to identify the critical SFMBT1 target genes involved in ccRCC tumorigenesis, we applied the following stringent criteria for genes: (1) displayed positive regulation by SFMBT1 (downregulated by both SFMBT1 siRNAs) and exhibited SFMBT1 binding in the promoter (+-5 kb from transcription start site), resulting in 516 genes (Fig S5D); (2) contained H3K4me3 and H3K27ac ChIP-seq in the promoter (+-5 kb from transcription start site) (Figure 5A); (3) showed elevated expression in ccRCC patient tumors compared to normal in TCGA Kidney Clear Cell Carcinoma (KIRC) data set (Figure 5A); (4) their high expression predicted worse prognosis in ccRCC patients (Figure 5A).	('RCC', 'Disease', (647, 650))	('ccRCC tumor', 'Disease', (63, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (645, 650))	('expression', 'MPA', (471, 481))	('tumors', 'Phenotype', 'HP:0002664', (499, 505))	('regulation', 'biological_process', 'GO:0065007', ('162', '172'))	('patient', 'Species', '9606', (651, 658))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('transcription', 'biological_process', 'GO:0006351', ('279', '292'))	('RCC', 'Disease', 'MESH:C538614', (647, 650))	('TCGA Kidney Clear Cell Carcinoma', 'Disease', (528, 560))	('tumor', 'Phenotype', 'HP:0002664', (499, 504))	('patient', 'Species', '9606', (491, 498))	('ccRCC tumor', 'Disease', 'MESH:D009369', (63, 74))	('tumors', 'Disease', (499, 505))	('Carcinoma', 'Phenotype', 'HP:0030731', (551, 560))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (485, 490))	('RCC', 'Disease', (487, 490))	('H3K27ac', 'Var', (366, 373))	('RCC', 'Disease', (65, 68))	('binding', 'molecular_function', 'GO:0005488', ('242', '249'))	('TCGA Kidney Clear Cell Carcinoma', 'Disease', 'MESH:C538614', (528, 560))	('elevated', 'PosReg', (462, 470))	('tumors', 'Disease', 'MESH:D009369', (499, 505))	('RCC', 'Disease', 'MESH:C538614', (487, 490))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('patients', 'Species', '9606', (651, 659))	('high', 'PosReg', (600, 604))	('TCGA Kidney Clear Cell Carcinoma', 'Phenotype', 'HP:0006770', (528, 560))	('transcription', 'biological_process', 'GO:0006351', ('412', '425'))
189946	32023483	SFMBT1 depletion by two independent siRNAs in pVHL-null ccRCC cells led to decreased SPHK1; this effect was rescued by the expression of the siRNA-resistant version of SFMBT1 (Figure 6B and Figure S6E), but was unaffected by HIF2alpha or HIF1beta depletion (Figure S6F-G) in 786-O cells.	('HIF1beta', 'Gene', (238, 246))	('HIF2alpha', 'Gene', (225, 234))	('SPHK1', 'Gene', (85, 90))	('HIF1beta', 'Gene', '3091', (238, 246))	('SFMBT1', 'Gene', (168, 174))	('depletion', 'Var', (7, 16))	('RCC', 'Disease', (58, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('SFMBT1', 'Gene', (0, 6))	('HIF2alpha', 'Gene', '2034', (225, 234))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('decreased', 'NegReg', (75, 84))
189947	32023483	In addition to SFMBT1 knockdown experiments, we also overexpressed control, WT, or P651A mutant HA-SFMBT1 in UMRC2 cells with FLAG-pVHL restored.	('HA-SFMBT1', 'Gene', (96, 105))	('P651A', 'Mutation', 'p.P651A', (83, 88))	('UMRC2', 'CellLine', 'CVCL:2739', (109, 114))	('P651A', 'Var', (83, 88))
189948	32023483	As expected, P651A HA-SFMBT1 protein level was higher than that of its wild-type counterpart (Figure 6C), most likely due to the inability of P651A HA-SFMBT1 to be marked for degradation by pVHL.	('inability', 'Disease', (129, 138))	('P651A', 'Mutation', 'p.P651A', (13, 18))	('higher', 'PosReg', (47, 53))	('P651A', 'Mutation', 'p.P651A', (142, 147))	('P651A', 'Var', (13, 18))	('HA-SFMBT1', 'Gene', (148, 157))	('protein level', 'MPA', (29, 42))	('degradation', 'biological_process', 'GO:0009056', ('175', '186'))	('inability', 'Disease', 'MESH:D007319', (129, 138))	('P651A', 'Var', (142, 147))	('HA-SFMBT1', 'Gene', (19, 28))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))
189949	32023483	Consistently, ccRCC cells expressing P651A HA-SFMBT1 displayed higher SPHK1 protein levels, which corresponded to increased cell proliferation and soft-agar growth compared to either control vector or WT SFMBT1-infected cells (Figure 6C-E, and Figure S6H).	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('agar', 'Chemical', 'MESH:D000362', (152, 156))	('RCC', 'Disease', (16, 19))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('increased', 'PosReg', (114, 123))	('ccRCC', 'Phenotype', 'HP:0006770', (14, 19))	('cell proliferation', 'biological_process', 'GO:0008283', ('124', '142'))	('SPHK1', 'Gene', (70, 75))	('P651A', 'Mutation', 'p.P651A', (37, 42))	('soft-agar growth', 'CPA', (147, 163))	('cell proliferation', 'CPA', (124, 142))	('WT SFMBT1-infected', 'Disease', 'MESH:D007239', (201, 219))	('WT SFMBT1-infected', 'Disease', (201, 219))	('higher', 'PosReg', (63, 69))	('HA-SFMBT1', 'Gene', (43, 52))	('P651A', 'Var', (37, 42))
189950	32023483	Next, we overexpressed control, WT, or P651A mutant HA-SFMBT1 in the VHL WT cell line HKC, and saw similar effects here (Figure S6I-L) to that of FLAG-pVHL restored UMRC2 cells (Figure 6C).	('VHL', 'Gene', (152, 155))	('P651A', 'Var', (39, 44))	('VHL', 'Gene', '7428', (152, 155))	('HA-SFMBT1', 'Gene', (52, 61))	('P651A', 'Mutation', 'p.P651A', (39, 44))	('UMRC2', 'CellLine', 'CVCL:2739', (165, 170))	('VHL', 'Gene', (69, 72))	('UMRC2 cells', 'MPA', (165, 176))	('VHL', 'Gene', '7428', (69, 72))
189953	32023483	However, the cell proliferation rate for P651A expressing HKC cells was not affected by hypoxia compared to normoxia (Figure S6N).	('hypoxia', 'Disease', 'MESH:D000860', (88, 95))	('P651A', 'Mutation', 'p.P651A', (41, 46))	('cell proliferation', 'CPA', (13, 31))	('hypoxia', 'Disease', (88, 95))	('P651A expressing', 'Var', (41, 57))	('cell proliferation', 'biological_process', 'GO:0008283', ('13', '31'))
189957	32023483	Whereas P651A SFMBT1 expression upregulated SPHK1 protein level, this effect was abrogated by PF543 (Figure 6F).	('P651A', 'Var', (8, 13))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('P651A', 'Mutation', 'p.P651A', (8, 13))	('SPHK1 protein level', 'MPA', (44, 63))	('SFMBT1', 'Gene', (14, 20))	('upregulated', 'PosReg', (32, 43))
189958	32023483	ccRCC cells expressing P651A HA-SFMBT1 displayed increased cell proliferation and 3-D soft-agar growth (Figure 6G-H, and S6W); this effect was also disrupted by the co-treatment with PF543.	('agar', 'Chemical', 'MESH:D000362', (91, 95))	('RCC', 'Disease', (2, 5))	('increased', 'PosReg', (49, 58))	('cell proliferation', 'CPA', (59, 77))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('3-D soft-agar growth', 'CPA', (82, 102))	('S6W', 'Mutation', 'p.S6W', (121, 124))	('P651A', 'Mutation', 'p.P651A', (23, 28))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('HA-SFMBT1', 'Gene', (29, 38))	('P651A', 'Var', (23, 28))
189959	32023483	We also depleted SFMBT1 by shRNAs followed by either control or V5-SPHK1 overexpression; V5-SPHK1 overexpression could rescue the effect of SFMBT1 depletion on cell proliferation and soft-agar growth (Figure 6I-K, and Figure S6X).	('soft-agar growth', 'CPA', (183, 199))	('V5-SPHK1', 'Var', (89, 97))	('agar', 'Chemical', 'MESH:D000362', (188, 192))	('SFMBT1', 'Gene', (140, 146))	('cell proliferation', 'CPA', (160, 178))	('cell proliferation', 'biological_process', 'GO:0008283', ('160', '178'))	('depletion', 'MPA', (147, 156))
189960	32023483	More importantly, PF543 did not grossly affect cell proliferation in HKC cells as measured by either a 2-D MTS assay or 3D soft agar assay (Figure S7A-D).	('cell proliferation', 'biological_process', 'GO:0008283', ('47', '65'))	('agar', 'Chemical', 'MESH:D000362', (128, 132))	('PF543', 'Var', (18, 23))	('cell proliferation', 'CPA', (47, 65))
189961	32023483	We also found that depleting SPHK1 by two different shRNAs inhibited 786-O and UMRC2 cell proliferation and soft-agar growth (Figure S7E-L).	('soft-agar growth', 'CPA', (108, 124))	('cell proliferation', 'biological_process', 'GO:0008283', ('85', '103'))	('inhibited', 'NegReg', (59, 68))	('depleting', 'Var', (19, 28))	('UMRC2', 'CellLine', 'CVCL:2739', (79, 84))	('SPHK1', 'Gene', (29, 34))	('agar', 'Chemical', 'MESH:D000362', (113, 117))
189965	32023483	We next performed immunohistochemical (IHC) staining for these tumors and found that SPHK1 expression was increased in the cytoplasm of tumors with VHL loss-of-function mutations compared to their respective adjacent normal tissues (Figure 7B).	('VHL', 'Gene', (148, 151))	('tumors', 'Disease', (136, 142))	('expression', 'MPA', (91, 101))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('mutations', 'Var', (169, 178))	('VHL', 'Gene', '7428', (148, 151))	('SPHK1', 'Gene', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('cytoplasm', 'cellular_component', 'GO:0005737', ('123', '132'))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('loss-of-function', 'NegReg', (152, 168))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('increased', 'PosReg', (106, 115))
189970	32023483	Upon confirmation of tumor growth in vivo, we treated mice with PF543 to inhibit SPHK1.	('SPHK1', 'Gene', (81, 86))	('tumor', 'Disease', (21, 26))	('mice', 'Species', '10090', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('PF543', 'Var', (64, 69))	('inhibit', 'NegReg', (73, 80))
189971	32023483	PF543 did inhibit SPHK1 but not SPHK2 expression level (Figure S7O) in vivo.	('SPHK2', 'Gene', '56848', (32, 37))	('SPHK1', 'Gene', (18, 23))	('PF543', 'Var', (0, 5))	('SPHK2', 'Gene', (32, 37))	('inhibit', 'NegReg', (10, 17))
189972	32023483	PF543 also inhibited ccRCC tumor growth in vivo (Figure S7P-Q).	('ccRCC tumor', 'Disease', (21, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('ccRCC tumor', 'Disease', 'MESH:D009369', (21, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (21, 26))	('inhibited', 'NegReg', (11, 20))	('PF543', 'Var', (0, 5))
189975	32023483	Loss of pVHL leads to increased SFMBT1 level, which promotes cell proliferation and xenograft tumor growth in ccRCC cells (Figure 7F).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cell proliferation', 'biological_process', 'GO:0008283', ('61', '79'))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('RCC', 'Disease', (112, 115))	('SFMBT1 level', 'MPA', (32, 44))	('increased', 'PosReg', (22, 31))	('promotes', 'PosReg', (52, 60))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('pVHL', 'Gene', (8, 12))	('Loss', 'Var', (0, 4))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))	('cell proliferation', 'CPA', (61, 79))
189982	32023483	SFMBT1 proline 651, the major hydroxylation site that contributes to the protein stability regulated by pVHL, is located outside of its MBT domains.	('pVHL', 'Gene', (104, 108))	('protein stability', 'MPA', (73, 90))	('proline', 'Chemical', 'MESH:D011392', (7, 14))	('proline 651', 'Var', (7, 18))	('SFMBT1', 'Gene', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))
190015	32023483	Cell lysate from FLAG-SFMBT1 expressing cells treated with either MG132 or MG132 together with DMOG was immunoprecipitated from 293T cells.	('FLAG-SFMBT1', 'Gene', (17, 28))	('293T', 'CellLine', 'CVCL:0063', (128, 132))	('MG132', 'Var', (66, 71))	('MG132', 'Chemical', 'MESH:C072553', (66, 71))	('DMOG', 'Chemical', 'MESH:C040947', (95, 99))	('MG132', 'Var', (75, 80))	('MG132', 'Chemical', 'MESH:C072553', (75, 80))
190022	32023483	1 mug protein from whole cell lysate was incubated with indicated antibodies or anti-FLAG M2 affinity gel (Sigma-Aldrich, A2220) / 3F10 HA conjugated beads (Roche Applied Bioscience, 11815016001) overnight or 4h at 4 C. Lysate incubated with antibodies was added to 10 mul of protein G agarose beads (Roche Applied Bioscience, 11243233001) with rotation for an additional 3 hours at 4 C. For the binding between FLAG-VHL and HIF1alpha and SFMBT1 peptides, Comparable amounts of Biotin-tagged HIF1alpha (WT and P564-OH) or SFMBT1 (WT, P650-OH and P651-OH) peptides were incubated with NeutrAvidin Agarose Resin (Thermo, 29200) for 4h at 4 C. Mixtures were centrifuged, washed with EBC buffer and then mixed with in vitro translated (IVT) Flag-VHL overnight at 4 C. The bound complexes were then centrifuged, washed with EBC buffer, subjected to SDS-PAGE, and immunoblotted with FLAG antibody.	('protein', 'cellular_component', 'GO:0003675', ('276', '283'))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('HIF1alpha', 'Gene', (425, 434))	('antibody', 'cellular_component', 'GO:0042571', ('882', '890'))	('SDS', 'Chemical', 'MESH:D012967', (844, 847))	('VHL', 'Gene', (417, 420))	('mug', 'molecular_function', 'GO:0043739', ('2', '5'))	('antibody', 'cellular_component', 'GO:0019815', ('882', '890'))	('EBC', 'Chemical', '-', (819, 822))	('P651-OH', 'Var', (546, 553))	('HIF1alpha', 'Gene', '3091', (492, 501))	('agarose', 'Chemical', 'MESH:D012685', (286, 293))	('VHL', 'Gene', (742, 745))	('Biotin', 'Chemical', 'MESH:D001710', (478, 484))	('VHL', 'Gene', '7428', (417, 420))	('HIF1alpha', 'Gene', (492, 501))	('antibody', 'cellular_component', 'GO:0019814', ('882', '890'))	('binding', 'molecular_function', 'GO:0005488', ('396', '403'))	('VHL', 'Gene', '7428', (742, 745))	('EBC', 'Chemical', '-', (680, 683))	('HIF1alpha', 'Gene', '3091', (425, 434))	('antibody', 'molecular_function', 'GO:0003823', ('882', '890'))	('complexes', 'Interaction', (774, 783))
190026	32023483	Comparable amounts of Biotin-tagged HIF1alpha or SFMBT1 peptides were mixed with reaction buffer (50 mM HEPES, 1500 U/mL catalase, 100 muM FeSO4, 5 mM ascorbic acid, 1 mM alpha-KG) and IVT HA-EglN1, IVT HA-EglN1-CD protein (enzyme) or negative control buffer (150 mM NaCl, 5 M FeSO4, 50 mM Tris-HCl, pH 7.5).	('NaCl', 'Chemical', 'MESH:D012965', (267, 271))	('HIF1alpha', 'Gene', (36, 45))	('EglN1', 'Gene', '54583', (206, 211))	('HEPES', 'Chemical', 'MESH:D006531', (104, 109))	('HIF1alpha', 'Gene', '3091', (36, 45))	('Biotin', 'Chemical', 'MESH:D001710', (22, 28))	('EglN1', 'Gene', (192, 197))	('ascorbic acid', 'Chemical', 'MESH:D001205', (151, 164))	('EglN1', 'Gene', '54583', (192, 197))	('FeSO4', 'Chemical', '-', (139, 144))	('IVT', 'Var', (185, 188))	('Tris', 'Chemical', '-', (290, 294))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('EglN1', 'Gene', (206, 211))	('FeSO4', 'Chemical', '-', (277, 282))	('alpha-KG', 'Chemical', '-', (171, 179))	('SFMBT1', 'Gene', (49, 55))	('HCl', 'Chemical', 'MESH:D006851', (295, 298))
190032	32023483	We compared these gene expression between VHL WT and VHL mutant patients, by two-class unpaired t-test.	('patients', 'Species', '9606', (64, 72))	('VHL', 'Gene', (53, 56))	('mutant', 'Var', (57, 63))	('VHL', 'Gene', '7428', (53, 56))	('VHL', 'Gene', (42, 45))	('gene expression', 'biological_process', 'GO:0010467', ('18', '33'))	('VHL', 'Gene', '7428', (42, 45))
190043	31434797	Additionally, LINC00511 knockdown restricted ccRCC cell proliferation, colony formation, and metastasis in vitro; accelerated cell cycle arrest at G0-G1 and apoptosis in vitro; and decreased tumor growth in vivo.	('apoptosis', 'CPA', (157, 166))	('colony formation', 'CPA', (71, 87))	('cell cycle arrest at G0-G1', 'CPA', (126, 152))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('LINC00511', 'Gene', '400619', (14, 23))	('restricted', 'NegReg', (34, 44))	('decreased tumor', 'Disease', (181, 196))	('LINC00511', 'Gene', (14, 23))	('apoptosis', 'biological_process', 'GO:0097194', ('157', '166'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('126', '143'))	('apoptosis', 'biological_process', 'GO:0006915', ('157', '166'))	('metastasis', 'CPA', (93, 103))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (126, 143))	('knockdown', 'Var', (24, 33))	('accelerated', 'PosReg', (114, 125))	('si', 'Chemical', 'MESH:D012825', (100, 102))	('formation', 'biological_process', 'GO:0009058', ('78', '87'))	('si', 'Chemical', 'MESH:D012825', (163, 165))	('cell proliferation', 'biological_process', 'GO:0008283', ('51', '69'))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('decreased tumor', 'Disease', 'MESH:D009369', (181, 196))
190044	31434797	Investigation of the mechanism revealed that LINC00511 directly interacted with microRNA-625 (miR-625), and the inhibitory effects of the LINC00511 knockdown on malignant characteristics were neutralized by miR-625 silencing.	('miR-625', 'Gene', '693210', (207, 214))	('microRNA-625', 'Gene', (80, 92))	('LINC00511', 'Gene', (45, 54))	('microRNA-625', 'Gene', '693210', (80, 92))	('miR-625', 'Gene', (94, 101))	('LINC00511', 'Gene', (138, 147))	('si', 'Chemical', 'MESH:D012825', (215, 217))	('malignant characteristics', 'CPA', (161, 186))	('miR-625', 'Gene', (207, 214))	('miR-625', 'Gene', '693210', (94, 101))	('interacted', 'Interaction', (64, 74))	('LINC00511', 'Gene', '400619', (45, 54))	('knockdown', 'Var', (148, 157))	('LINC00511', 'Gene', '400619', (138, 147))
190058	31434797	Long noncoding RNAs (lncRNAs) are a series of non-protein-coding RNA molecules over 200 nucleotides long that are involved in various biological events, including genomic imprinting, epigenetic regulation, alternative splicing, cell differentiation, and tumorigenesis.	('splicing', 'biological_process', 'GO:0045292', ('218', '226'))	('RNA', 'cellular_component', 'GO:0005562', ('65', '68'))	('tumor', 'Disease', (254, 259))	('epigenetic regulation', 'Var', (183, 204))	('si', 'Chemical', 'MESH:D012825', (264, 266))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('cell differentiation', 'biological_process', 'GO:0030154', ('228', '248'))	('cell differentiation', 'CPA', (228, 248))	('involved', 'Reg', (114, 122))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('alternative splicing', 'Var', (206, 226))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('regulation', 'biological_process', 'GO:0065007', ('194', '204'))
190088	31434797	These cells were transfected with si-LINC00511 and si-NC.	('LINC00511', 'Gene', '400619', (37, 46))	('si-NC', 'Var', (51, 56))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('LINC00511', 'Gene', (37, 46))	('si', 'Chemical', 'MESH:D012825', (51, 53))
190090	31434797	The functional effect of the LINC00511 knockdown on ccRCC cell proliferation was examined by CCK-8 assays.	('LINC00511', 'Gene', '400619', (29, 38))	('knockdown', 'Var', (39, 48))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('LINC00511', 'Gene', (29, 38))	('cell proliferation', 'biological_process', 'GO:0008283', ('58', '76'))
190092	31434797	Next, colony formation assays were conducted to confirm the ccRCC cell proliferation suppression caused by the LINC00511 knockdown.	('knockdown', 'Var', (121, 130))	('LINC00511', 'Gene', '400619', (111, 120))	('formation', 'biological_process', 'GO:0009058', ('13', '22'))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('LINC00511', 'Gene', (111, 120))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('suppression', 'NegReg', (85, 96))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))
190098	31434797	This experiment revealed that the knockdown of LINC00511 led to an obvious increase in the apoptotic rate of A498 and 786-O cells (Figure 2E, P < 0.05).	('LINC00511', 'Gene', '400619', (47, 56))	('increase', 'PosReg', (75, 83))	('knockdown', 'Var', (34, 43))	('apoptotic rate', 'CPA', (91, 105))	('LINC00511', 'Gene', (47, 56))
190099	31434797	These results indicate that the knockdown of LINC00511 inhibits ccRCC cell proliferation by inducing G0-G1 phase arrest and facilitating apoptosis.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('apoptosis', 'CPA', (137, 146))	('apoptosis', 'biological_process', 'GO:0097194', ('137', '146'))	('apoptosis', 'biological_process', 'GO:0006915', ('137', '146'))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('LINC00511', 'Gene', (45, 54))	('inhibits', 'NegReg', (55, 63))	('cell proliferation', 'biological_process', 'GO:0008283', ('70', '88'))	('knockdown', 'Var', (32, 41))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('inducing', 'PosReg', (92, 100))	('G1 phase', 'biological_process', 'GO:0051318', ('104', '112'))	('si', 'Chemical', 'MESH:D012825', (143, 145))	('G0-G1 phase arrest', 'CPA', (101, 119))	('RCC', 'Disease', (66, 69))	('LINC00511', 'Gene', '400619', (45, 54))
190102	31434797	The knockdown of LINC00511 reduced the migratory ability of A498 and 786-O cells relative to that in cells transfected with si-NC (Figure 2F, P < 0.05).	('reduced', 'NegReg', (27, 34))	('LINC00511', 'Gene', (17, 26))	('LINC00511', 'Gene', '400619', (17, 26))	('knockdown', 'Var', (4, 13))	('si', 'Chemical', 'MESH:D012825', (124, 126))
190104	31434797	Collectively, these results implied that the LINC00511 knockdown exerts an inhibitory action on ccRCC growth and metastasis in vitro.	('knockdown', 'Var', (55, 64))	('LINC00511', 'Gene', (45, 54))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('LINC00511', 'Gene', '400619', (45, 54))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('inhibitory', 'NegReg', (75, 85))
190115	31434797	We next applied RT-qPCR analysis to determine the expression levels of miR-625 in A498 and 786-O cells in response to LINC00511 silencing.	('si', 'Chemical', 'MESH:D012825', (29, 31))	('miR-625', 'Gene', '693210', (71, 78))	('LINC00511', 'Gene', '400619', (118, 127))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('silencing', 'Var', (128, 137))	('miR-625', 'Gene', (71, 78))	('LINC00511', 'Gene', (118, 127))	('si', 'Chemical', 'MESH:D012825', (56, 58))
190128	31434797	The results revealed that luciferase activity was considerably decreased in A498 and 786-O cells cotransfected with the miR-625 mimics and a reporter plasmid harboring the wild-type miR-625-binding site (P < 0.05).	('si', 'Chemical', 'MESH:D012825', (53, 55))	('miR-625', 'Gene', (120, 127))	('miR-625', 'Gene', (182, 189))	('decreased', 'NegReg', (63, 72))	('binding', 'molecular_function', 'GO:0005488', ('190', '197'))	('si', 'Chemical', 'MESH:D012825', (198, 200))	('luciferase', 'Enzyme', (26, 36))	('miR-625', 'Gene', '693210', (120, 127))	('miR-625', 'Gene', '693210', (182, 189))	('luciferase activity', 'molecular_function', 'GO:0047077', ('26', '45'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('26', '45'))	('activity', 'MPA', (37, 45))	('mimics', 'Var', (128, 134))	('luciferase activity', 'molecular_function', 'GO:0047712', ('26', '45'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('26', '45'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('26', '45'))
190129	31434797	Cells cotransfection of the miR-625 mimics and mutant CCND1 3'-UTR failed to increase or decrease luciferase activity (Figure 5B).	('luciferase', 'Enzyme', (98, 108))	('luciferase activity', 'molecular_function', 'GO:0047077', ('98', '117'))	('decrease', 'NegReg', (89, 97))	('miR-625', 'Gene', (28, 35))	('CCND1', 'Gene', (54, 59))	('activity', 'MPA', (109, 117))	('luciferase activity', 'molecular_function', 'GO:0045289', ('98', '117'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('98', '117'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('98', '117'))	('CCND1', 'Gene', '595', (54, 59))	('miR-625', 'Gene', '693210', (28, 35))	('luciferase activity', 'molecular_function', 'GO:0050397', ('98', '117'))	('mutant', 'Var', (47, 53))
190139	31434797	Furthermore, the results of functional assays showed that restoration of CCND1 expression partially reversed the impact of miR-625 overexpression on the proliferation (Figure 6B, P < 0.05), colony formation (Figure 6C, P < 0.05), cell cycle status (Figure 6D, P < 0.05), apoptosis (Figure 6E, P < 0.05), migration (Figure 6F, P < 0.05), and invasiveness (Figure 6G, P < 0.05) of A498 and 786-O cells.	('si', 'Chemical', 'MESH:D012825', (345, 347))	('colony formation', 'CPA', (190, 206))	('cell cycle status', 'CPA', (230, 247))	('miR-625', 'Gene', '693210', (123, 130))	('overexpression', 'PosReg', (131, 145))	('restoration', 'Var', (58, 69))	('formation', 'biological_process', 'GO:0009058', ('197', '206'))	('CCND1', 'Gene', '595', (73, 78))	('si', 'Chemical', 'MESH:D012825', (141, 143))	('CCND1', 'Gene', (73, 78))	('invasiveness', 'CPA', (341, 353))	('migration', 'CPA', (304, 313))	('si', 'Chemical', 'MESH:D012825', (277, 279))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('cell cycle', 'biological_process', 'GO:0007049', ('230', '240'))	('apoptosis', 'biological_process', 'GO:0097194', ('271', '280'))	('apoptosis', 'biological_process', 'GO:0006915', ('271', '280'))	('miR-625', 'Gene', (123, 130))	('apoptosis', 'CPA', (271, 280))
190144	31434797	The recovery of miR-625 expression abrogated the effects of the LINC00511 knockdown on A498 and 786-O cell proliferation (Figure 7D, P < 0.05), colony formation (Figure 7E, P < 0.05), apoptosis (Figure 7F, P < 0.05), cell cycle (Figure 7G, P < 0.05), migration (Figure 7H, P < 0.05), and invasion (Figure 7I, P < 0.05).	('cell cycle', 'CPA', (217, 227))	('formation', 'biological_process', 'GO:0009058', ('151', '160'))	('LINC00511', 'Gene', '400619', (64, 73))	('miR-625', 'Gene', (16, 23))	('si', 'Chemical', 'MESH:D012825', (190, 192))	('cell cycle', 'biological_process', 'GO:0007049', ('217', '227'))	('LINC00511', 'Gene', (64, 73))	('invasion', 'CPA', (288, 296))	('knockdown', 'Var', (74, 83))	('si', 'Chemical', 'MESH:D012825', (292, 294))	('miR-625', 'Gene', '693210', (16, 23))	('migration', 'CPA', (251, 260))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('apoptosis', 'CPA', (184, 193))	('abrogated', 'NegReg', (35, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('184', '193'))	('cell proliferation', 'biological_process', 'GO:0008283', ('102', '120'))	('apoptosis', 'biological_process', 'GO:0006915', ('184', '193'))	('colony formation', 'CPA', (144, 160))
190146	31434797	To investigate the precise role of LINC00511 in vivo, nude mice were subcutaneously inoculated with 786-O cells transfected with either si-LINC00511 or si-NC.	('si', 'Chemical', 'MESH:D012825', (152, 154))	('nude mice', 'Species', '10090', (54, 63))	('LINC00511', 'Gene', '400619', (139, 148))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('LINC00511', 'Gene', (35, 44))	('si-NC', 'Var', (152, 157))	('LINC00511', 'Gene', (139, 148))	('LINC00511', 'Gene', '400619', (35, 44))
190153	31434797	Taken together, these results indicated that the LINC00511 knockdown inhibits ccRCC tumorigenicity in vivo by regulating the miR-625-CCND1 axis.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('inhibits', 'NegReg', (69, 77))	('CCND1', 'Gene', (133, 138))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('LINC00511', 'Gene', '400619', (49, 58))	('tumor', 'Disease', (84, 89))	('miR-625', 'Gene', (125, 132))	('LINC00511', 'Gene', (49, 58))	('CCND1', 'Gene', '595', (133, 138))	('regulating', 'Reg', (110, 120))	('knockdown', 'Var', (59, 68))	('miR-625', 'Gene', '693210', (125, 132))
190155	31434797	Additionally, these studies have shown that the deregulation is involved in ccRCC pathogenesis and progression through their participation in a variety of critical biological processes.	('involved', 'Reg', (64, 72))	('pathogenesis', 'biological_process', 'GO:0009405', ('82', '94'))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('deregulation', 'Var', (48, 60))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))
190166	31434797	Patients with hepatocellular carcinoma featuring high LINC00511 expression have worse overall survival rates.	('si', 'Chemical', 'MESH:D012825', (70, 72))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (14, 38))	('LINC00511', 'Gene', '400619', (54, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('hepatocellular carcinoma', 'Disease', (14, 38))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (14, 38))	('Patients', 'Species', '9606', (0, 8))	('high', 'Var', (49, 53))	('LINC00511', 'Gene', (54, 63))
190167	31434797	Moreover, expression of LINC00511 is reported to be an independent prognostic factor of overall survival among patients with hepatocellular carcinoma.	('LINC00511', 'Gene', (24, 33))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (125, 149))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('hepatocellular carcinoma', 'Disease', (125, 149))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (125, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('LINC00511', 'Gene', '400619', (24, 33))	('expression', 'Var', (10, 20))	('patients', 'Species', '9606', (111, 119))
190173	31434797	Aberrations of LINC00511 expression perform important functions in tumorigenesis and tumor progression.	('si', 'Chemical', 'MESH:D012825', (31, 33))	('tumor', 'Disease', (85, 90))	('LINC00511', 'Gene', '400619', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('tumor', 'Disease', (67, 72))	('LINC00511', 'Gene', (15, 24))	('Aberrations', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
190175	31434797	LINC00511 silencing attenuates the proliferation and motility of hepatocellular carcinoma cells.	('attenuates', 'NegReg', (20, 30))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (65, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('LINC00511', 'Gene', (0, 9))	('proliferation', 'CPA', (35, 48))	('motility of hepatocellular carcinoma', 'Disease', 'MESH:D006528', (53, 89))	('LINC00511', 'Gene', '400619', (0, 9))	('motility of hepatocellular carcinoma', 'Disease', (53, 89))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('silencing', 'Var', (10, 19))
190176	31434797	In pancreatic ductal adenocarcinoma, knockdown of LINC00511 suppresses cell proliferation, migration, and invasion decreases endothelial tube formation.	('LINC00511', 'Gene', '400619', (50, 59))	('cell proliferation', 'biological_process', 'GO:0008283', ('71', '89'))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('decreases', 'NegReg', (115, 124))	('knockdown', 'Var', (37, 46))	('suppresses', 'NegReg', (60, 70))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (3, 35))	('invasion', 'CPA', (106, 114))	('pancreatic ductal adenocarcinoma', 'Disease', (3, 35))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (3, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('LINC00511', 'Gene', (50, 59))	('tube formation', 'biological_process', 'GO:0035148', ('137', '151'))	('cell proliferation', 'CPA', (71, 89))	('endothelial tube formation', 'CPA', (125, 151))
190179	31434797	In the present study, functional experiments revealed that silencing of LINC00511 expression restricts ccRCC cell proliferation and the colony formation ability of these cells; induces G0-G1 cell cycle arrest; promotes apoptosis; and reduces cell migration and invasion in vitro and inhibits tumor growth in vivo.	('G0-G1 cell cycle arrest', 'CPA', (185, 208))	('reduces', 'NegReg', (234, 241))	('si', 'Chemical', 'MESH:D012825', (225, 227))	('LINC00511', 'Gene', (72, 81))	('cell proliferation', 'biological_process', 'GO:0008283', ('109', '127'))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('si', 'Chemical', 'MESH:D012825', (265, 267))	('promotes', 'PosReg', (210, 218))	('RCC', 'Disease', (105, 108))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('restricts', 'NegReg', (93, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('apoptosis', 'CPA', (219, 228))	('inhibits', 'NegReg', (283, 291))	('apoptosis', 'biological_process', 'GO:0097194', ('219', '228'))	('formation', 'biological_process', 'GO:0009058', ('143', '152'))	('apoptosis', 'biological_process', 'GO:0006915', ('219', '228'))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('silencing', 'Var', (59, 68))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (191, 208))	('colony formation ability of these cells', 'CPA', (136, 175))	('induces', 'Reg', (177, 184))	('cell migration', 'biological_process', 'GO:0016477', ('242', '256'))	('tumor', 'Disease', (292, 297))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('191', '208'))	('LINC00511', 'Gene', '400619', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (292, 297))
190194	31434797	Finally, restoration of CCND1 expression attenuated the tumor-suppressive effects of miR-625 overexpression on the malignant phenotype of ccRCC cells.	('attenuated', 'NegReg', (41, 51))	('CCND1', 'Gene', '595', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('miR-625', 'Gene', '693210', (85, 92))	('tumor', 'Disease', (56, 61))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('miR-625', 'Gene', (85, 92))	('restoration', 'Var', (9, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('si', 'Chemical', 'MESH:D012825', (69, 71))	('CCND1', 'Gene', (24, 29))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('overexpression', 'PosReg', (93, 107))	('malignant phenotype', 'CPA', (115, 134))
190201	31434797	LINC00511 knockdown inhibited the malignancy of ccRCC in vitro and in vivo, partly by decreasing the competitive sponging of miR-625, which decreased CCND1 expression.	('LINC00511', 'Gene', (0, 9))	('si', 'Chemical', 'MESH:D012825', (162, 164))	('inhibited', 'NegReg', (20, 29))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('RCC', 'Disease', (50, 53))	('malignancy', 'Disease', 'MESH:D009369', (34, 44))	('knockdown', 'Var', (10, 19))	('CCND1', 'Gene', '595', (150, 155))	('competitive sponging', 'CPA', (101, 121))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('CCND1', 'Gene', (150, 155))	('miR-625', 'Gene', (125, 132))	('decreased', 'NegReg', (140, 149))	('malignancy', 'Disease', (34, 44))	('LINC00511', 'Gene', '400619', (0, 9))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('expression', 'MPA', (156, 166))	('decreasing', 'NegReg', (86, 96))	('miR-625', 'Gene', '693210', (125, 132))
190242	31434797	Cells transfected with si-LINC00511 or si-NC were subcutaneously administered into BALB/c nude mice.	('si', 'Chemical', 'MESH:D012825', (39, 41))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('LINC00511', 'Gene', '400619', (26, 35))	('si-NC', 'Var', (39, 44))	('nude mice', 'Species', '10090', (90, 99))	('LINC00511', 'Gene', (26, 35))
190261	31434797	After blockage at room temperature for 2 h with 5% skim milk, the membranes were incubated with primary antibodies against CCND1 (ab16663; 1:1000 dilution; Abcam, Cambridge, UK, USA) or GAPDH (ab128915; 1:1000 dilution; Abcam, Cambridge, UK, USA).	('CCND1', 'Gene', '595', (123, 128))	('GAPDH', 'Gene', '2597', (186, 191))	('GAPDH', 'Gene', (186, 191))	('CCND1', 'Gene', (123, 128))	('ab128915;', 'Var', (193, 202))
190307	30814510	Cancer organoids and their normal counterparts were treated with SU11274 10 microM, FORETINIB 10 muM, LENVATINIB in combination with EVEROLIMUS (both at final concentration of 10 microM) and Cabozantinib 10 muM following manual instruction (Selleck, www.selleckchem.com).	('EVEROLIMUS', 'Chemical', 'MESH:D000068338', (133, 143))	('FORETINIB', 'Chemical', 'MESH:C544831', (84, 93))	('Cabozantinib', 'Chemical', 'MESH:C558660', (191, 203))	('LENVATINIB', 'Chemical', 'MESH:C531958', (102, 112))	('muM', 'Gene', '56925', (97, 100))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('LENVATINIB', 'Gene', (102, 112))	('Cancer', 'Disease', (0, 6))	('muM', 'Gene', '56925', (207, 210))	('muM', 'Gene', (97, 100))	('SU11274', 'Var', (65, 72))	('SU11274', 'Chemical', 'MESH:C478479', (65, 72))	('muM', 'Gene', (207, 210))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
190313	30814510	After 72 hours (hrs or h), suspensions were plated in a specific medium composed by low-density Matrigel supplemented with EGF, bFGF, Rho kinase (ROCK) inhibitor and A8301, a selective inhibitor of the Transforming Growth Factor beta type I Receptor (TGF-beta), the Anaplatistic lymphoma kinase 4 and 7 (ALK4 and ALK7), (Fig.	('TGF-beta', 'Gene', (251, 259))	('A8301', 'Var', (166, 171))	('A8301', 'Chemical', '-', (166, 171))	('ALK4', 'Gene', '91', (304, 308))	('EGF', 'molecular_function', 'GO:0005154', ('123', '126'))	('ALK7', 'Gene', (313, 317))	('Transforming Growth Factor beta', 'molecular_function', 'GO:0005160', ('202', '233'))	('lymphoma', 'Phenotype', 'HP:0002665', (279, 287))	('ALK4', 'Gene', (304, 308))	('ALK7', 'Gene', '130399', (313, 317))	('TGF-beta', 'Gene', '7040', (251, 259))	('Anaplatistic lymphoma', 'Disease', 'MESH:D008223', (266, 287))	('Anaplatistic lymphoma', 'Disease', (266, 287))
190350	30814510	Allele frequency of wild type and variant genes significantly demonstrated a multiclonal representative capacity of tumor organoid cultures when compared to parental cancer tissue.	('demonstrated', 'Reg', (62, 74))	('parental cancer', 'Disease', 'MESH:D063129', (157, 172))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('variant', 'Var', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('parental cancer', 'Disease', (157, 172))	('tumor', 'Disease', (116, 121))
190353	30814510	In addition, two paired normal and tumor tissues, chosen among the three above, together with their organoid counterparts were analyzed for most renal cancer frequent mutations.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', (35, 40))	('mutations', 'Var', (167, 176))	('renal cancer', 'Disease', (145, 157))	('renal cancer', 'Phenotype', 'HP:0009726', (145, 157))	('renal cancer', 'Disease', 'MESH:D007680', (145, 157))
190375	30814510	Organoids were treated with different doses and analyzed after 72 h. mTOR S2448, VEGFR2 Y996, pERK T202/Y204 gene expression levels were evaluated as driver targeted therapy genes.	('gene expression', 'biological_process', 'GO:0010467', ('109', '124'))	('mTOR', 'Gene', (69, 73))	('VEGFR2', 'Gene', (81, 87))	('Y996', 'Var', (88, 92))	('pERK', 'Gene', '9451', (94, 98))	('pERK', 'Gene', (94, 98))	('VEGFR2', 'Gene', '3791', (81, 87))
190376	30814510	Similarly, drugs did not impact on mTOR S2448, VEGFR2 Y996, pERK T202/Y204 and Cyclin D1 expression levels in tumor counterparts while Tensirolimus reduced cancer organoid capacity formation (Supplementary Fig.	('Cyclin', 'molecular_function', 'GO:0016538', ('79', '85'))	('VEGFR2', 'Gene', (47, 53))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('reduced', 'NegReg', (148, 155))	('formation', 'biological_process', 'GO:0009058', ('181', '190'))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('Y996', 'Var', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('Cyclin D1', 'Gene', '595', (79, 88))	('T202/Y204', 'Var', (65, 74))	('VEGFR2', 'Gene', '3791', (47, 53))	('pERK', 'Gene', (60, 64))	('Cyclin D1', 'Gene', (79, 88))	('pERK', 'Gene', '9451', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
190377	30814510	We enlarged evaluation of cancer organoids as drug testing model exploring the activity of on-going trial drugs based on multi-kinases inhibition i.e SU11274, Foretinib, Cabozantinib and Levantinib in combination with Everolimus.	('Foretinib', 'Chemical', 'MESH:C544831', (159, 168))	('SU11274', 'Var', (150, 157))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('SU11274', 'Chemical', 'MESH:C478479', (150, 157))	('Everolimus', 'Chemical', 'MESH:D000068338', (218, 228))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('Levantinib', 'Chemical', '-', (187, 197))	('Cabozantinib', 'Chemical', 'MESH:C558660', (170, 182))
190379	30814510	All sequences resulted wild type with the exception of a frameshift mutation in VHL gene [c.242 delC ins TG (p.Pro81Leu*50)] in one patient and retained in both tumor tissue and organoids.	('VHL', 'Gene', (80, 83))	('c.242 delC ins TG', 'Mutation', 'c.242delinsC,TG', (90, 107))	('VHL', 'Gene', '7428', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('[c.242 delC ins TG', 'Var', (89, 107))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('p.Pro81Leu', 'Mutation', 'rs193922608', (109, 119))	('patient', 'Species', '9606', (132, 139))	('tumor', 'Disease', (161, 166))
190380	30814510	In the specific residue was identified the variants c.242 C > A (Pro81 Glu), c.242 delC (Pro81 fs*78) and c.242_243 insG (p.Arg82 fs*50) as reported in COSMIC database (Supplementary Fig.	('c.242 delC', 'Var', (77, 87))	('p.Arg82 fs', 'Mutation', 'p.R82fsX', (122, 132))	('c.242_243 insG', 'Mutation', 'c.242_243insG', (106, 120))	('c.242 C > A', 'Mutation', 'rs193922608', (52, 63))	('c.242 delC', 'Mutation', 'c.242delC', (77, 87))	('c.242 C > A', 'Var', (52, 63))	('Pro81 Glu', 'Mutation', 'rs193922608', (65, 74))	('Pro81 fs*78', 'Mutation', 'p.P81fsX78', (89, 100))	('c.242_243 insG', 'Var', (106, 120))
190382	30814510	pAKT S437 and pERK T202/Y204 were used as driver targeted genes of therapy efficacy.	('T202/Y204', 'Var', (19, 28))	('pERK', 'Gene', (14, 18))	('pERK', 'Gene', '9451', (14, 18))
190383	30814510	ccRCC organoids were affected by Foretinib and SU11274 while pAKT S437 and pERK T202/Y204 expressions were reduced in all the treatments (Supplementary Figs.	('T202/Y204', 'Var', (80, 89))	('pERK', 'Gene', '9451', (75, 79))	('pERK', 'Gene', (75, 79))	('Foretinib', 'Chemical', 'MESH:C544831', (33, 42))	('ccRCC organoids', 'CPA', (0, 15))	('reduced', 'NegReg', (107, 114))	('SU11274', 'Var', (47, 54))	('affected', 'Reg', (21, 29))	('SU11274', 'Chemical', 'MESH:C478479', (47, 54))	('ccRCC organoids', 'Chemical', '-', (0, 15))
190457	33676411	On MRI, T2WI showed that the affected side was hypointense or isointense to the contralateral renal parenchyma (Fig.	('contralateral renal parenchyma', 'Disease', 'MESH:D010195', (80, 110))	('isointense', 'MPA', (62, 72))	('contralateral renal parenchyma', 'Disease', (80, 110))	('hypointense', 'Var', (47, 58))
190514	33676411	On T2WI, the parenchymal components of the four tumors were lower than those of the normal renal parenchyma.	('T2WI', 'Var', (3, 7))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('parenchymal components', 'CPA', (13, 35))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('lower', 'NegReg', (60, 65))
190555	33676411	The results showed that the specificity and positive predictive value of 18F-FDG PET/CT for distant metastasis were 100%.	('18F-FDG', 'Var', (73, 80))	('18F-FDG', 'Chemical', 'MESH:D019788', (73, 80))	('distant metastasis', 'CPA', (92, 110))
190578	28612496	Knockdown of Rab25 eliminated the augmentation of carcinoma cell proliferation, migration and invasion by ectopic RIN1.	('invasion', 'CPA', (94, 102))	('cell proliferation', 'biological_process', 'GO:0008283', ('60', '78'))	('carcinoma', 'Disease', 'MESH:D002277', (50, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('migration', 'CPA', (80, 89))	('RIN1', 'Gene', '9610', (114, 118))	('ectopic', 'Var', (106, 113))	('carcinoma', 'Disease', (50, 59))	('Rab25', 'Gene', '57111', (13, 18))	('RIN1', 'Gene', (114, 118))	('Rab25', 'Gene', (13, 18))
190595	28612496	Flag-tagged Rab25 (LPP-T4697-Lv121-200), Flag-tagged RIN1 (LPP-T2755-Lv121-200) and their corresponding control vectors were purchased from GeneCopoeia (Rockville, MD, USA).	('LPP-T2755-Lv121-200', 'Var', (59, 78))	('Rab25', 'Gene', '57111', (12, 17))	('LPP-T4697-Lv121-200', 'Var', (19, 38))	('RIN1', 'Gene', '9610', (53, 57))	('Rab25', 'Gene', (12, 17))	('RIN1', 'Gene', (53, 57))
190627	28612496	Western blotting results showed high-efficiency RIN1 gene knockdown or overexpression in indicated ccRCC cells (Fig.	('RIN1', 'Gene', '9610', (48, 52))	('overexpression', 'PosReg', (71, 85))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Disease', (101, 104))	('RIN1', 'Gene', (48, 52))	('knockdown', 'Var', (58, 67))
190628	28612496	MTT assay showed that knockdown of RIN1 dramatically reduced the proliferation of both 786-O and Caki-1 cells (Fig.	('Caki-1', 'CellLine', 'CVCL:0234', (97, 103))	('proliferation', 'CPA', (65, 78))	('RIN1', 'Gene', '9610', (35, 39))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('Caki-1 cells', 'CPA', (97, 109))	('reduced', 'NegReg', (53, 60))	('knockdown', 'Var', (22, 31))	('RIN1', 'Gene', (35, 39))
190629	28612496	Using foci-formation assays, we found that RIN1 depletion reduced foci-formation ability of 786-O and Caki-1 cells compared with the control cells (Fig.	('RIN1', 'Gene', (43, 47))	('foci-formation ability', 'CPA', (66, 88))	('RIN1', 'Gene', '9610', (43, 47))	('Caki-1', 'CellLine', 'CVCL:0234', (102, 108))	('formation', 'biological_process', 'GO:0009058', ('11', '20'))	('formation', 'biological_process', 'GO:0009058', ('71', '80'))	('depletion', 'Var', (48, 57))	('reduced', 'NegReg', (58, 65))
190630	28612496	Knockdown of RIN1 caused an apparent suppression of cell migration in both 786-O and Caki-1 cell lines using a wound-healing assay (Fig.	('RIN1', 'Gene', (13, 17))	('Knockdown', 'Var', (0, 9))	('cell migration in', 'CPA', (52, 69))	('Caki-1', 'CellLine', 'CVCL:0234', (85, 91))	('wound-healing', 'biological_process', 'GO:0042060', ('111', '124'))	('RIN1', 'Gene', '9610', (13, 17))	('cell migration', 'biological_process', 'GO:0016477', ('52', '66'))	('suppression', 'NegReg', (37, 48))
190631	28612496	Matrigel invasion assays also demonstrated that ablation of endogenous RIN1 reduced the invasive capacity of both 786-O and Caki-1 cell lines (Fig.	('RIN1', 'Gene', (71, 75))	('invasive capacity of', 'CPA', (88, 108))	('RIN1', 'Gene', '9610', (71, 75))	('reduced', 'NegReg', (76, 83))	('ablation', 'Var', (48, 56))	('Caki-1', 'CellLine', 'CVCL:0234', (124, 130))
190632	28612496	Taken together, our data suggest that loss of RIN1 attenuates ccRCC cell growth, migration and invasion in vitro.	('loss', 'Var', (38, 42))	('cell growth', 'biological_process', 'GO:0016049', ('68', '79'))	('RIN1', 'Gene', '9610', (46, 50))	('attenuates', 'NegReg', (51, 61))	('migration', 'CPA', (81, 90))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))	('RIN1', 'Gene', (46, 50))
190635	28612496	In the mouse metastasis model, we injected 786-O-con and 786-O-shRIN1 into the lateral tail vein of athymic nude mice (10 mice per group).	('nude mice', 'Species', '10090', (108, 117))	('mice', 'Species', '10090', (122, 126))	('RIN1', 'Gene', '9610', (65, 69))	('786-O-con', 'Chemical', '-', (43, 52))	('mouse', 'Species', '10090', (7, 12))	('RIN1', 'Gene', (65, 69))	('lateral tail', 'Phenotype', 'HP:0002825', (79, 91))	('mice', 'Species', '10090', (113, 117))	('786-O-con', 'Var', (43, 52))
190640	28612496	Phosphorylation of EGFR, AKT and ERK, well-known downstream molecules in the EGFR signaling pathway, were also inhibited by RIN1 knockdown in both 786-O and Caki-1 cells, and the opposite results were observed in the RIN1 overexpressing NC65 cells (Fig.	('EGFR signaling pathway', 'biological_process', 'GO:0007173', ('77', '99'))	('AKT', 'Gene', '207', (25, 28))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('EGFR', 'Gene', (19, 23))	('RIN1', 'Gene', '9610', (124, 128))	('RIN1', 'Gene', (217, 221))	('knockdown', 'Var', (129, 138))	('EGFR', 'Gene', '1956', (77, 81))	('Caki-1', 'CellLine', 'CVCL:0234', (157, 163))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('EGFR', 'molecular_function', 'GO:0005006', ('19', '23'))	('EGFR', 'Gene', '1956', (19, 23))	('ERK', 'Gene', (33, 36))	('inhibited', 'NegReg', (111, 120))	('RIN1', 'Gene', '9610', (217, 221))	('AKT', 'Gene', (25, 28))	('ERK', 'Gene', '2048', (33, 36))	('Phosphorylation', 'MPA', (0, 15))	('RIN1', 'Gene', (124, 128))	('ERK', 'molecular_function', 'GO:0004707', ('33', '36'))	('EGFR', 'Gene', (77, 81))
190641	28612496	In this proteomic analysis, the expression of p-AKT (PT308) and p-MAPK/ERK kinase 1 (PS217_S221) in the RIN1 mRNA altered group (upregulation) are significantly higher than in the RIN1 mRNA unaltered group (Fig.	('RIN1', 'Gene', '9610', (180, 184))	('PT308', 'Chemical', '-', (53, 58))	('RIN1', 'Gene', '9610', (104, 108))	('AKT', 'Gene', (48, 51))	('ERK', 'Gene', '2048', (71, 74))	('RIN1', 'Gene', (104, 108))	('ERK', 'Gene', (71, 74))	('ERK', 'molecular_function', 'GO:0004707', ('71', '74'))	('RIN1', 'Gene', (180, 184))	('mRNA altered', 'Var', (109, 121))	('PS217_S221', 'Var', (85, 95))	('higher', 'PosReg', (161, 167))	('expression', 'MPA', (32, 42))	('AKT', 'Gene', '207', (48, 51))	('MAPK', 'molecular_function', 'GO:0004707', ('66', '70'))
190644	28612496	After siRab25 and AG1478 treatment, RIN1-induced EGFR signaling was inhibited, as evidenced by the decreased expression of p-EGFR, p-AKT and p-ERK in NC65-RIN1 cells (Fig.	('decreased', 'NegReg', (99, 108))	('AG1478', 'Var', (18, 24))	('RIN1', 'Gene', (155, 159))	('ERK', 'molecular_function', 'GO:0004707', ('143', '146'))	('EGFR', 'molecular_function', 'GO:0005006', ('125', '129'))	('AKT', 'Gene', (133, 136))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('RIN1', 'Gene', '9610', (36, 40))	('EGFR', 'Gene', '1956', (125, 129))	('EGFR', 'Gene', (49, 53))	('inhibited', 'NegReg', (68, 77))	('RIN1', 'Gene', '9610', (155, 159))	('p-ERK', 'Gene', '9451', (141, 146))	('p-ERK', 'Gene', (141, 146))	('AKT', 'Gene', '207', (133, 136))	('Rab25', 'Gene', (8, 13))	('EGFR', 'Gene', '1956', (49, 53))	('signaling', 'biological_process', 'GO:0023052', ('54', '63'))	('expression', 'MPA', (109, 119))	('Rab25', 'Gene', '57111', (8, 13))	('EGFR', 'Gene', (125, 129))	('AG1478', 'Chemical', 'MESH:C101044', (18, 24))	('RIN1', 'Gene', (36, 40))
190645	28612496	The silencing of Rab25 and inhibition of EGFR strikingly reversed the ability of RIN1-overexpressing 786-O cells for growth, migration and invasion in vitro (Fig.	('Rab25', 'Gene', (17, 22))	('invasion', 'CPA', (139, 147))	('EGFR', 'Gene', (41, 45))	('RIN1', 'Gene', (81, 85))	('migration', 'CPA', (125, 134))	('growth', 'CPA', (117, 123))	('RIN1', 'Gene', '9610', (81, 85))	('EGFR', 'molecular_function', 'GO:0005006', ('41', '45'))	('Rab25', 'Gene', '57111', (17, 22))	('EGFR', 'Gene', '1956', (41, 45))	('inhibition', 'NegReg', (27, 37))	('silencing', 'Var', (4, 13))
190648	28612496	Endogenous RIN1 was found to be associated with exogenously expressed Flag-tagged Rab25 and conversely endogenous Rab25 was found to be immunoprecipitated with RIN1 (Fig.	('associated', 'Interaction', (32, 42))	('Rab25', 'Gene', '57111', (114, 119))	('Flag-tagged', 'Var', (70, 81))	('RIN1', 'Gene', '9610', (160, 164))	('Rab25', 'Gene', '57111', (82, 87))	('Rab25', 'Gene', (114, 119))	('RIN1', 'Gene', (11, 15))	('Rab25', 'Gene', (82, 87))	('RIN1', 'Gene', (160, 164))	('RIN1', 'Gene', '9610', (11, 15))
190656	28612496	Overexpression of EGFR in RCC has been shown in various research, ranging from 50% to 90%.29, 30, 31, 32, 33 EGFR intracellular tyrosine kinase domain is autophosphorylated and results in activation of several downstream signaling pathways, including the RAS-RAF-MEK-ERK and the PI3K-PTEN-AKT pathways.	('AKT', 'Gene', '207', (289, 292))	('signaling', 'biological_process', 'GO:0023052', ('221', '230'))	('EGFR', 'molecular_function', 'GO:0005006', ('18', '22'))	('EGFR', 'Gene', '1956', (109, 113))	('ERK', 'Gene', (267, 270))	('EGFR', 'molecular_function', 'GO:0005006', ('109', '113'))	('ERK', 'Gene', '2048', (267, 270))	('RCC', 'Disease', (26, 29))	('EGFR', 'Gene', (18, 22))	('ERK', 'molecular_function', 'GO:0004707', ('267', '270'))	('.29', 'Var', (89, 92))	('PI3K', 'molecular_function', 'GO:0016303', ('279', '283'))	('AKT', 'Gene', (289, 292))	('intracellular', 'cellular_component', 'GO:0005622', ('114', '127'))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('RAF', 'Gene', '22882', (259, 262))	('downstream signaling pathways', 'Pathway', (210, 239))	('EGFR', 'Gene', (109, 113))	('EGFR', 'Gene', '1956', (18, 22))	('activation', 'PosReg', (188, 198))	('RAF', 'Gene', (259, 262))
190659	28612496	Furthermore, antagonizing RIN1 caused multilevel inactivation of EGFR signaling and had obvious inhibitory effects on tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('RIN1', 'Gene', (26, 30))	('EGFR', 'Gene', (65, 69))	('inactivation', 'NegReg', (49, 61))	('EGFR', 'Gene', '1956', (65, 69))	('antagonizing', 'Var', (13, 25))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('RIN1', 'Gene', '9610', (26, 30))	('tumor', 'Disease', (118, 123))	('signaling', 'biological_process', 'GO:0023052', ('70', '79'))	('EGFR', 'molecular_function', 'GO:0005006', ('65', '69'))
190661	28612496	RIN1 is a RAS-effector protein that can affect Ras signaling at different levels:34 first, by competing with RAF1 protein for binding to activated Ras;35 second, by enhancing signaling from ABL1 and ABL2, which regulate cytoskeletal remodeling;36, 37 and, third, by activating Rab5A, possibly by functioning as a guanine nucleotide exchange factor for Rab5A, by exchanging bound GDP for free GTP, and facilitating Ras-activated receptor endocytosis.38 In our study, we found that silencing Rab25 inhibited EGFR signaling and strikingly reversed the ability of RIN1-overexpressing ccRCC cells to proliferation, migration and invasion in vitro.	('RAF1', 'Gene', (109, 113))	('Rab5A', 'Gene', (277, 282))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('Rab25', 'Gene', '57111', (490, 495))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('invasion', 'CPA', (624, 632))	('RIN1', 'Gene', '9610', (560, 564))	('Rab5A', 'Gene', '5868', (277, 282))	('endocytosis', 'biological_process', 'GO:0006897', ('437', '448'))	('inhibited', 'NegReg', (496, 505))	('EGFR', 'Gene', '1956', (506, 510))	('RCC', 'Disease', (582, 585))	('ABL1', 'Gene', (190, 194))	('reversed', 'NegReg', (536, 544))	('ABL2', 'Gene', '27', (199, 203))	('ABL2', 'Gene', (199, 203))	('RCC', 'Disease', 'MESH:C538614', (582, 585))	('ABL1', 'Gene', '25', (190, 194))	('RIN1', 'Gene', (0, 4))	('silencing', 'Var', (480, 489))	('signaling', 'biological_process', 'GO:0023052', ('511', '520'))	('Rab5A', 'Gene', (352, 357))	('RAF1', 'Gene', '5894', (109, 113))	('signaling', 'biological_process', 'GO:0023052', ('175', '184'))	('RIN1', 'Gene', (560, 564))	('EGFR', 'molecular_function', 'GO:0005006', ('506', '510'))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('EGFR', 'Gene', (506, 510))	('Rab5A', 'Gene', '5868', (352, 357))	('RIN1', 'Gene', '9610', (0, 4))	('binding', 'molecular_function', 'GO:0005488', ('126', '133'))	('Rab25', 'Gene', (490, 495))
190668	28612496	Meanwhile, antagonizing RIN1 caused multilevel inactivation of EGFR signaling and had obvious inhibitory effects on tumorigenesis.	('EGFR', 'Gene', '1956', (63, 67))	('EGFR', 'Gene', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('RIN1', 'Gene', (24, 28))	('RIN1', 'Gene', '9610', (24, 28))	('antagonizing', 'Var', (11, 23))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('tumor', 'Disease', (116, 121))	('inactivation', 'NegReg', (47, 59))	('signaling', 'biological_process', 'GO:0023052', ('68', '77'))
190676	31844035	Moreover, high GPX1 levels were positively correlated with short overall survival time, distant metastasis, lymphatic metastasis, and tumor stage.	('lymphatic metastasis', 'CPA', (108, 128))	('distant metastasis', 'CPA', (88, 106))	('short', 'NegReg', (59, 64))	('GPX1', 'MPA', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('high', 'Var', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
190680	31844035	Moreover, targeting GPX1 may represent as a new therapeutic strategy and direction for RCC patients.	('RCC', 'Disease', 'MESH:D002292', (87, 90))	('GPX1', 'Gene', (20, 24))	('RCC', 'Disease', (87, 90))	('patients', 'Species', '9606', (91, 99))	('targeting', 'Var', (10, 19))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
190690	31844035	When the balance of synthesis and degradation is broken, ROS can cause oxidative damage to proteins, DNA and membrane unsaturated fatty acids.	('oxidative damage to proteins', 'MPA', (71, 99))	('unsaturated fatty acids', 'Chemical', 'MESH:D005231', (118, 141))	('synthesis', 'biological_process', 'GO:0009058', ('20', '29'))	('degradation', 'biological_process', 'GO:0009056', ('34', '45'))	('cause', 'Reg', (65, 70))	('membrane unsaturated fatty acids', 'MPA', (109, 141))	('DNA', 'cellular_component', 'GO:0005574', ('101', '104'))	('membrane', 'cellular_component', 'GO:0016020', ('109', '117'))	('ROS', 'Var', (57, 60))
190698	31844035	Such as, the high expression of GPX1 was significantly associated with nodal metastasis, high grade, depth of tumor invasion, perineural invasion and advanced overall stage, and predicts poor prognosis in oral squamous cell carcinoma.	('oral squamous cell carcinoma', 'Disease', (205, 233))	('tumor invasion', 'Disease', (110, 124))	('depth', 'CPA', (101, 106))	('high expression', 'Var', (13, 28))	('associated', 'Reg', (55, 65))	('high grade', 'CPA', (89, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (210, 233))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('nodal metastasis', 'CPA', (71, 87))	('GPX1', 'Gene', (32, 36))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (205, 233))	('tumor invasion', 'Disease', 'MESH:D009361', (110, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('perineural invasion', 'CPA', (126, 145))
190699	31844035	In a mouse model of skin cancer, overexpression of GPX1 increased the number of tumors and promotes their growth.	('promotes', 'PosReg', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('GPX1', 'Gene', (51, 55))	('increased', 'PosReg', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('skin cancer', 'Disease', (20, 31))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('skin cancer', 'Phenotype', 'HP:0008069', (20, 31))	('growth', 'MPA', (106, 112))	('overexpression', 'Var', (33, 47))	('tumors', 'Disease', (80, 86))	('skin cancer', 'Disease', 'MESH:D012878', (20, 31))	('mouse', 'Species', '10090', (5, 10))	('tumors', 'Disease', 'MESH:D009369', (80, 86))
190701	31844035	In addition, GPX1 knockdown in prostate cancer cells could enhance radiation-induced micronuclei formation.	('knockdown', 'Var', (18, 27))	('GPX1', 'Gene', (13, 17))	('prostate cancer', 'Disease', 'MESH:D011471', (31, 46))	('formation', 'biological_process', 'GO:0009058', ('97', '106'))	('enhance', 'PosReg', (59, 66))	('prostate cancer', 'Phenotype', 'HP:0012125', (31, 46))	('radiation-induced micronuclei formation', 'CPA', (67, 106))	('prostate cancer', 'Disease', (31, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
190715	31844035	Subgroup ROC curve analysis implied that the high expression of GPX1 might have diagnostic value for ccRCC patients with pathological stage (I + II) / (III + IV) (Figure 3B, AUC = 0.6122, p < 0.0001), (G1 + G2) / (G3 + G4) stage (Figure 3C, AUC = 0.6511, p < 0.0001), (T1 + T2) / (T3 + T4) (Figure 3D, AUC = 0.5897, p = 0.0006), N0 / N1 stage (Figure 3E, AUC = 0.6935, p = 0.0096), M0 / M1 stage (Figure 3F, AUC = 0.6445, p < 0.0001).	('ccRCC', 'Disease', 'MESH:D002292', (101, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('(G1 + G2) / (G3 + G4', 'Gene', '5544;7916', (201, 221))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('T1 + T2) / (T3 + T4', 'Var', (269, 288))	('M0 /', 'Disease', (382, 386))	('G1 + G2) / (G3 + G4', 'Gene', (202, 221))	('N0 / N1 stage', 'Disease', (329, 342))	('patients', 'Species', '9606', (107, 115))	('ccRCC', 'Disease', (101, 106))	('GPX1', 'Gene', (64, 68))
190718	31844035	The analysis found that high GPX1 expression predicted a worse overall survival (OS) in ccRCC patients (Figure 4A), however, GPX1 expression does not affect disease-free survival (DFS) (Figure 4B).	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('overall survival', 'MPA', (63, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('expression', 'MPA', (34, 44))	('ccRCC', 'Disease', (88, 93))	('patients', 'Species', '9606', (94, 102))	('ccRCC', 'Disease', 'MESH:D002292', (88, 93))	('GPX1', 'Gene', (29, 33))	('high', 'Var', (24, 28))	('worse', 'NegReg', (57, 62))
190726	31844035	CCK8 assays show that knockdown of GPX1 can inhibit the proliferation of renal cancer cells (Figure 6B).	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('inhibit', 'NegReg', (44, 51))	('renal cancer', 'Disease', (73, 85))	('knockdown', 'Var', (22, 31))	('renal cancer', 'Phenotype', 'HP:0009726', (73, 85))	('GPX1', 'Gene', (35, 39))	('renal cancer', 'Disease', 'MESH:D007680', (73, 85))
190727	31844035	Colony formation assays reveal that knockdown of GPX1 can reduce clonogenic capacity of renal cancer cells (Figure 6C).	('renal cancer', 'Disease', 'MESH:D007680', (88, 100))	('GPX1', 'Gene', (49, 53))	('knockdown', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('reduce', 'NegReg', (58, 64))	('formation', 'biological_process', 'GO:0009058', ('7', '16'))	('renal cancer', 'Disease', (88, 100))	('renal cancer', 'Phenotype', 'HP:0009726', (88, 100))
190730	31844035	As shown in Figure 7A-B, knockdown of GPX1 significantly reduced the migration and invasion capability of 786-O and ACHN cells.	('ACHN', 'Gene', '55323', (116, 120))	('GPX1', 'Gene', (38, 42))	('786-O', 'Chemical', 'MESH:C002925', (106, 111))	('ACHN', 'Gene', (116, 120))	('reduced', 'NegReg', (57, 64))	('knockdown', 'Var', (25, 34))
190748	31844035	Overexpression of GPX1 increased the number of tumors and promotes their growth in a mouse model of skin cancer.	('growth', 'MPA', (73, 79))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('mouse', 'Species', '10090', (85, 90))	('skin cancer', 'Phenotype', 'HP:0008069', (100, 111))	('GPX1', 'Gene', (18, 22))	('promotes', 'PosReg', (58, 66))	('skin cancer', 'Disease', (100, 111))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('Overexpression', 'Var', (0, 14))	('increased', 'PosReg', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('skin cancer', 'Disease', 'MESH:D012878', (100, 111))
190755	31844035	Bioinformatics analysis found that high expression of GPX1 was positively correlated with tumor stage, distant metastasis and lymphatic metastasis.	('expression', 'MPA', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('correlated', 'Reg', (74, 84))	('distant metastasis', 'CPA', (103, 121))	('GPX1', 'Gene', (54, 58))	('high', 'Var', (35, 39))	('lymphatic metastasis', 'CPA', (126, 146))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
190756	31844035	ROC curve analysis found that high expression of GPX1 could effectively distinguish ccRCC from normal individuals.	('ccRCC', 'Disease', (84, 89))	('ccRCC', 'Disease', 'MESH:D002292', (84, 89))	('GPX1', 'Gene', (49, 53))	('high', 'Var', (30, 34))	('distinguish', 'Reg', (72, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))
190763	31844035	In summary, we confirm the high expression of GPX1 promoted the progression in renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('high expression', 'Var', (27, 42))	('GPX1', 'Gene', (46, 50))	('promoted', 'PosReg', (51, 59))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (79, 99))	('renal cell carcinoma', 'Disease', (79, 99))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (79, 99))
190793	33107222	Among them, mutations in ANKRD12 and DNMT1 were already identified in the early passage of a resistant PDX model, and we focused on a DNMT1 mutation as a potential candidate for developing the resistant phenotype.	('mutations', 'Var', (12, 21))	('DNMT1', 'Gene', (37, 42))	('mutation', 'Var', (140, 148))	('DNMT1', 'Gene', (134, 139))	('ANKRD12', 'Gene', '23253', (25, 32))	('ANKRD12', 'Gene', (25, 32))
190795	33107222	Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9-mediated heterozygous knockdown of DNMT1 in the temsirolimus-sensitive ccRCC (786-O) cell line was shown to result in a temsirolimus-resistant phenotype in vitro and in vivo.	('temsirolimus-sensitive ccRCC', 'Disease', 'MESH:D003807', (143, 171))	('temsirolimus-resistant', 'Disease', (215, 237))	('temsirolimus-resistant', 'Disease', 'MESH:D060467', (215, 237))	('DNMT1', 'Gene', (130, 135))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))	('result in', 'Reg', (203, 212))	('ccRCC', 'Phenotype', 'HP:0006770', (166, 171))	('knockdown', 'Var', (117, 126))	('temsirolimus-sensitive ccRCC', 'Disease', (143, 171))
190797	33107222	Present study showed the feasibility of PDX model to explore the mechanisms of mTOR resistance acquisition and suggested that genetic alterations, including that of DNMT1, which alter the methylation status in cancer cells, are one of the potential mechanisms of developing resistance to temsirolimus.	('mTOR', 'Gene', (79, 83))	('mTOR', 'Gene', '2475', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('methylation', 'biological_process', 'GO:0032259', ('188', '199'))	('alter', 'Reg', (178, 183))	('temsirolimus', 'Chemical', 'MESH:C401859', (288, 300))	('alterations', 'Var', (134, 145))	('resistance to temsirolimus', 'MPA', (274, 300))	('DNMT1', 'Gene', (165, 170))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))	('methylation status', 'MPA', (188, 206))
190798	33107222	This study showed the feasibility of PDX model to explore the mechanisms of mTOR resistance acquisition and suggested that genetic alterations, including that of DNMT1, which alter the methylation status in cancer cells, are one of the potential mechanisms of developing resistance to temsirolimus.	('resistance to temsirolimus', 'MPA', (271, 297))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('mTOR', 'Gene', (76, 80))	('temsirolimus', 'Chemical', 'MESH:C401859', (285, 297))	('cancer', 'Disease', (207, 213))	('mTOR', 'Gene', '2475', (76, 80))	('methylation', 'biological_process', 'GO:0032259', ('185', '196'))	('alterations', 'Var', (131, 142))	('alter', 'Reg', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('DNMT1', 'Gene', (162, 167))	('methylation status', 'MPA', (185, 203))
190807	33107222	Several mechanisms for acquired resistance to temsirolimus have been described, including mutations in mTOR, activation of an alternative signaling pathway, and intratumoral heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('mutations', 'Var', (90, 99))	('mTOR', 'Gene', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('signaling pathway', 'biological_process', 'GO:0007165', ('138', '155'))	('alternative signaling pathway', 'Pathway', (126, 155))	('tumor', 'Disease', (166, 171))	('temsirolimus', 'Chemical', 'MESH:C401859', (46, 58))	('mTOR', 'Gene', '2475', (103, 107))
190808	33107222	6 ,  7  A previous report showed that mTOR mutations block the binding of rapamycin-FKBP12 to mTOR, resulting in rapamycin resistance.	('FKBP12', 'Gene', '2285', (84, 90))	('resulting in', 'Reg', (100, 112))	('mTOR', 'Gene', (94, 98))	('binding', 'Interaction', (63, 70))	('rapamycin', 'Chemical', 'MESH:D020123', (74, 83))	('mTOR', 'Gene', '2475', (94, 98))	('FKBP', 'molecular_function', 'GO:0030051', ('84', '88'))	('rapamycin', 'Chemical', 'MESH:D020123', (113, 122))	('mutations', 'Var', (43, 52))	('rapamycin resistance', 'MPA', (113, 133))	('block', 'NegReg', (53, 58))	('FKBP12', 'Gene', (84, 90))	('mTOR', 'Gene', (38, 42))	('mTOR', 'Gene', '2475', (38, 42))	('binding', 'molecular_function', 'GO:0005488', ('63', '70'))
190847	33107222	SETD2 (c.5015+3A>C), ARID1A (p.Glu2250fs), and SLC27A6 (c.1165-5dupT) mutations and VHL (p.Phe76del), BAP1 (p.Pro555fs), and TP53 (p.Ala276Asp) mutations ware identified in KURC1 and KURC3 xenograft tumors, respectively.	('xenograft tumors', 'Disease', 'MESH:D009369', (189, 205))	('ARID1A', 'Gene', '8289', (21, 27))	('SLC27A6', 'Gene', (47, 54))	('c.1165-5dupT', 'Mutation', 'c.1165-5dupT', (56, 68))	('TP53', 'Gene', (125, 129))	('c.5015+3A', 'Var', (7, 16))	('BAP1', 'Gene', '8314', (102, 106))	('VHL', 'Gene', (84, 87))	('c.5015+3A>C', 'Mutation', 'c.5015+3A>C', (7, 18))	('p.Phe76del', 'Var', (89, 99))	('SETD2', 'Gene', (0, 5))	('SLC27A6', 'Gene', '28965', (47, 54))	('p.Ala276Asp', 'Var', (131, 142))	('BAP1', 'Gene', (102, 106))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (125, 129))	('p.Glu2250fs', 'Mutation', 'p.E2250fsX', (29, 40))	('SETD2', 'Gene', '29072', (0, 5))	('VHL', 'Gene', '7428', (84, 87))	('KURC1', 'Disease', (173, 178))	('p.Ala276Asp', 'Mutation', 'rs786202082', (131, 142))	('p.Phe76del', 'Mutation', 'p.76delF', (89, 99))	('p.Pro555fs', 'Mutation', 'p.P555fsX', (108, 118))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('ARID1A', 'Gene', (21, 27))	('p.Pro555fs', 'Var', (108, 118))	('xenograft tumors', 'Disease', (189, 205))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
190849	33107222	In the first passage after temsirolimus administration, KURC1 Tem/P1 and KURC3 Tem/P1 tumor growth was suppressed for around 50 days (Figure 1C).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('KURC3 Tem/P1', 'Var', (73, 85))	('tumor', 'Disease', (86, 91))	('suppressed', 'NegReg', (103, 113))	('Tem', 'cellular_component', 'GO:0097197', ('79', '82'))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('temsirolimus', 'Chemical', 'MESH:C401859', (27, 39))	('Tem', 'cellular_component', 'GO:0097197', ('62', '65'))
190862	33107222	This revealed that ANKRD12 and DNMT1 variants were already identified in KURC3 Tem/P1 tumors, while WDSUB1 and CPD variants were identified in KURC3 Tem/P2 tumors and subsequent passages (Table 2; Figure S3).	('identified', 'Reg', (59, 69))	('ANKRD12', 'Gene', (19, 26))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('Tem', 'cellular_component', 'GO:0097197', ('149', '152'))	('DNMT1', 'Gene', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', (86, 92))	('Tem', 'cellular_component', 'GO:0097197', ('79', '82'))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('WDSUB1', 'Gene', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', (156, 162))	('CPD', 'Gene', '1362', (111, 114))	('ANKRD12', 'Gene', '23253', (19, 26))	('CPD', 'Gene', (111, 114))	('WDSUB1', 'Gene', '151525', (100, 106))	('variants', 'Var', (37, 45))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
190863	33107222	Considering that KURC3 Tem/P2 tumors showed acquired resistance to temsirolimus (Figure S2), DNMT1 and ANKRD12 variants appear to be more involved in resistance.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('ANKRD12', 'Gene', (103, 110))	('variants', 'Var', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('ANKRD12', 'Gene', '23253', (103, 110))	('Tem', 'cellular_component', 'GO:0097197', ('23', '26'))	('temsirolimus', 'Chemical', 'MESH:C401859', (67, 79))	('DNMT1', 'Gene', (93, 98))
190864	33107222	The impact prediction of SNVs by FATHMM-XF suggested that only the DNMT1 variant was potentially pathogenic, while the other three variants, in ANKRD12, WDSUB1, and CPD, were not (Table 1).	('pathogenic', 'Reg', (97, 107))	('DNMT1', 'Gene', (67, 72))	('CPD', 'Gene', '1362', (165, 168))	('WDSUB1', 'Gene', '151525', (153, 159))	('ANKRD12', 'Gene', '23253', (144, 151))	('WDSUB1', 'Gene', (153, 159))	('ANKRD12', 'Gene', (144, 151))	('CPD', 'Gene', (165, 168))	('variant', 'Var', (73, 80))
190865	33107222	Therefore, we focused on the DNMT1 variant to determine whether it was associated with temsirolimus resistance.	('DNMT1', 'Gene', (29, 34))	('temsirolimus', 'Chemical', 'MESH:C401859', (87, 99))	('variant', 'Var', (35, 42))	('temsirolimus resistance', 'MPA', (87, 110))	('associated', 'Reg', (71, 81))
190866	33107222	The DNMT1 variant was identified in three of six KURC3 Tem/P1 tumors (Figure 2B).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('DNMT1', 'Gene', (4, 9))	('Tem', 'cellular_component', 'GO:0097197', ('55', '58'))	('variant', 'Var', (10, 17))
190870	33107222	However, the DNA methyltransferase (DNMT) activity/inhibition assay showed that DNMT enzyme activity was significantly decreased in KURC3 tem/P4 compared with KURC3 veh/P4 tumors (Figure 2G).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('DNA methyltransferase', 'Gene', (13, 34))	('KURC3 tem/P4', 'Var', (132, 144))	('decreased', 'NegReg', (119, 128))	('DNMT', 'Gene', '1786', (80, 84))	('DNMT', 'Gene', (80, 84))	('DNMT', 'Gene', (36, 40))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('DNMT', 'Gene', '1786', (36, 40))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tem', 'cellular_component', 'GO:0097197', ('138', '141'))	('DNA methyltransferase', 'Gene', '1786', (13, 34))	('enzyme activity', 'molecular_function', 'GO:0003824', ('85', '100'))	('KURC3 veh/P4', 'Gene', '201780', (159, 171))	('activity', 'MPA', (92, 100))	('KURC3 veh/P4', 'Gene', (159, 171))
190871	33107222	Taken together, these findings suggest that lower DNMT enzyme activity possibly caused by the heterogeneous DNMT1 variant in the KURC3 PDX tumor was associated with the acquired phenotype of temsirolimus resistance.	('lower', 'NegReg', (44, 49))	('variant', 'Var', (114, 121))	('DNMT', 'Gene', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('DNMT', 'Gene', '1786', (50, 54))	('temsirolimus resistance', 'MPA', (191, 214))	('DNMT', 'Gene', (50, 54))	('temsirolimus', 'Chemical', 'MESH:C401859', (191, 203))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('enzyme activity', 'molecular_function', 'GO:0003824', ('55', '70'))	('DNMT', 'Gene', '1786', (108, 112))
190873	33107222	Because the heterozygous DNMT1 variant was identified in KURC3 PDX tumors with temsirolimus resistance, we aimed to pick up 786-O subclones heterozygous for DNMT1 knock-out.	('PDX tumors', 'Disease', 'MESH:D009369', (63, 73))	('PDX tumors', 'Disease', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('DNMT1', 'Gene', (25, 30))	('variant', 'Var', (31, 38))	('temsirolimus', 'Chemical', 'MESH:C401859', (79, 91))
190874	33107222	Additionally, the DNMT activity/inhibition assay revealed that DNMT enzyme activity of DNMT1 knockdown 786-O cells was significantly decreased compared with parental cells (Figure 3B).	('knockdown', 'Var', (93, 102))	('DNMT', 'Gene', (63, 67))	('enzyme activity', 'molecular_function', 'GO:0003824', ('68', '83'))	('DNMT', 'Gene', (87, 91))	('DNMT', 'Gene', '1786', (87, 91))	('DNMT', 'Gene', '1786', (18, 22))	('DNMT', 'Gene', '1786', (63, 67))	('decreased', 'NegReg', (133, 142))	('DNMT', 'Gene', (18, 22))
190875	33107222	With temsirolimus administration, growth in DNMT1 knockdown cells was suppressed but could be rescued compared with parental cells (Figure 3C).	('knockdown', 'Var', (50, 59))	('growth', 'MPA', (34, 40))	('DNMT1', 'Gene', (44, 49))	('suppressed', 'NegReg', (70, 80))	('temsirolimus', 'Chemical', 'MESH:C401859', (5, 17))
190876	33107222	To evaluate the effect of other rapalogue, in vitro proliferation assay with rapamycin was also performed and showed similar results in cell growth with DNMT1 knockdown 786-O cells (Figure 3C).	('DNMT1', 'Gene', (153, 158))	('rapamycin', 'Chemical', 'MESH:D020123', (77, 86))	('knockdown', 'Var', (159, 168))	('cell growth', 'biological_process', 'GO:0016049', ('136', '147'))
190877	33107222	Moreover, the growth in DNMT1 knockdown cells was suppressed with sunitinib administration, but not rescued, compared with parental cells (Figure S4).	('suppressed', 'NegReg', (50, 60))	('sunitinib', 'Chemical', 'MESH:D000077210', (66, 75))	('knockdown', 'Var', (30, 39))	('growth', 'MPA', (14, 20))	('DNMT1', 'Gene', (24, 29))
190878	33107222	Notably, the tumor growth of xenografts from DNMT1 knockdown 786-O cells was not suppressed by treatment with temsirolimus, while that of 786-O xenografts was significantly inhibited by temsirolimus (Figure 3D).	('tumor', 'Disease', (13, 18))	('inhibited', 'NegReg', (173, 182))	('temsirolimus', 'Chemical', 'MESH:C401859', (110, 122))	('temsirolimus', 'Chemical', 'MESH:C401859', (186, 198))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('DNMT1', 'Gene', (45, 50))	('knockdown', 'Var', (51, 60))
190879	33107222	The DNMT activity/inhibition assay confirmed that the DNMT activity of DNMT1 knockdown 786-O xenograft tumors was significantly decreased compared with that of 786-O xenograft tumors (Figure 3E).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('DNMT', 'Gene', '1786', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('xenograft tumors', 'Disease', 'MESH:D009369', (93, 109))	('xenograft tumors', 'Disease', 'MESH:D009369', (166, 182))	('knockdown', 'Var', (77, 86))	('DNMT', 'Gene', '1786', (71, 75))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('DNMT', 'Gene', (71, 75))	('decreased', 'NegReg', (128, 137))	('DNMT', 'Gene', (54, 58))	('DNMT', 'Gene', '1786', (4, 8))	('xenograft tumors', 'Disease', (93, 109))	('xenograft tumors', 'Disease', (166, 182))	('DNMT', 'Gene', (4, 8))
190880	33107222	These results suggest that DNMT1 heterozygous knockdown was associated with the suppression of DNMT enzyme activity which may underlie temsirolimus resistance in ccRCC cell line tumors.	('suppression', 'NegReg', (80, 91))	('tumors', 'Disease', (178, 184))	('activity', 'MPA', (107, 115))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('heterozygous knockdown', 'Var', (33, 55))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('temsirolimus', 'Chemical', 'MESH:C401859', (135, 147))	('DNMT', 'Gene', '1786', (95, 99))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('ccRCC', 'Phenotype', 'HP:0006770', (162, 167))	('DNMT', 'Gene', (95, 99))	('RCC', 'Disease', (164, 167))	('DNMT', 'Gene', '1786', (27, 31))	('enzyme activity', 'molecular_function', 'GO:0003824', ('100', '115'))	('DNMT', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
190881	33107222	To explore whether the DNMT1 variant and the suppression of DNMT enzyme activity led to changes in genome-wide methylation profiling, we next performed methylation analysis.	('suppression', 'NegReg', (45, 56))	('enzyme activity', 'molecular_function', 'GO:0003824', ('65', '80'))	('changes', 'Reg', (88, 95))	('DNMT', 'Gene', '1786', (60, 64))	('methylation', 'biological_process', 'GO:0032259', ('152', '163'))	('variant', 'Var', (29, 36))	('activity', 'MPA', (72, 80))	('DNMT', 'Gene', '1786', (23, 27))	('methylation', 'biological_process', 'GO:0032259', ('111', '122'))	('DNMT', 'Gene', (23, 27))	('DNMT', 'Gene', (60, 64))
190885	33107222	Table 3 lists genes that were both hypomethylated and upregulated in expression or vice versa in temsirolimus-resistant KURC3 PDX tumors.	('upregulated', 'PosReg', (54, 65))	('temsirolimus-resistant KURC3 PDX tumors', 'Disease', (97, 136))	('expression', 'MPA', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('temsirolimus-resistant KURC3 PDX tumors', 'Disease', 'MESH:D060467', (97, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('hypomethylated', 'Var', (35, 49))
190889	33107222	Immunohistochemical analysis showed that pS6 protein expression was significantly suppressed in KURC3 Tem/P1 tumors compared with KURC3 Veh/P1 tumors, but that it was similar between KURC3 Tem/P4 and KURC3 Veh/P4 tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('pS6', 'Gene', '338413', (41, 44))	('suppressed', 'NegReg', (82, 92))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('Tem', 'cellular_component', 'GO:0097197', ('102', '105'))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', (213, 219))	('tumors', 'Disease', (143, 149))	('KURC3 Veh/P4', 'Gene', '201780', (200, 212))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('pS6', 'Gene', (41, 44))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('Tem', 'cellular_component', 'GO:0097197', ('189', '192'))	('KURC3 Veh/P4', 'Gene', (200, 212))	('KURC3 Tem/P1', 'Var', (96, 108))
190890	33107222	The proportion of tumor cells with nuclear phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p4EBP1)-positive staining was decreased in KURC3 Tem/P1 tumors compared with KURC3 Veh/P1 tumors, but similar between KURC3 Tem/P4 and KURC3 Veh/P4 tumors.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('KURC3 Veh/P4', 'Gene', (256, 268))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('Tem', 'cellular_component', 'GO:0097197', ('245', '248'))	('tumor', 'Disease', (211, 216))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('p4EBP1', 'Gene', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('eukaryotic translation initiation factor 4E-binding protein 1', 'Gene', '1978', (58, 119))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('tumors', 'Disease', (269, 275))	('KURC3 Veh/P4', 'Gene', '201780', (256, 268))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', (177, 182))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('binding', 'molecular_function', 'GO:0005488', ('102', '109'))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('decreased', 'NegReg', (151, 160))	('translation initiation', 'biological_process', 'GO:0006413', ('69', '91'))	('tumors', 'Disease', 'MESH:D009369', (269, 275))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('Tem', 'cellular_component', 'GO:0097197', ('170', '173'))	('KURC3 Tem/P1', 'Var', (164, 176))	('tumors', 'Disease', (211, 217))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor', 'Disease', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (177, 183))
190899	33107222	In particular, KURC3 PDX tumors that finally acquired temsirolimus resistance were shown to harbor BAP1 mutations.	('PDX tumors', 'Disease', (21, 31))	('BAP1', 'Gene', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mutations', 'Var', (104, 113))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('temsirolimus', 'Chemical', 'MESH:C401859', (54, 66))	('BAP1', 'Gene', '8314', (99, 103))	('PDX tumors', 'Disease', 'MESH:D009369', (21, 31))
190900	33107222	A previous report suggested that BAP1 prevents chromosome instability in breast cancer cells, 37  indicating that BAP1 mutations could lead to the occurrence of other de novo mutations in PDX tumors.	('PDX tumors', 'Disease', (188, 198))	('chromosome instability', 'Phenotype', 'HP:0040012', (47, 69))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('BAP1', 'Gene', '8314', (33, 37))	('BAP1', 'Gene', '8314', (114, 118))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('chromosome', 'cellular_component', 'GO:0005694', ('47', '57'))	('breast cancer', 'Disease', (73, 86))	('chromosome instability', 'MPA', (47, 69))	('mutations', 'Var', (175, 184))	('PDX tumors', 'Disease', 'MESH:D009369', (188, 198))	('BAP1', 'Gene', (33, 37))	('BAP1', 'Gene', (114, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('mutations', 'Var', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
190901	33107222	In another report of metastatic RCC patients, BAP1 mutations were associated with shorter progression-free survival following treatment with everolimus.	('everolimus', 'Chemical', 'MESH:D000068338', (141, 151))	('mutations', 'Var', (51, 60))	('patients', 'Species', '9606', (36, 44))	('BAP1', 'Gene', '8314', (46, 50))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('progression-free survival', 'CPA', (90, 115))	('BAP1', 'Gene', (46, 50))	('shorter', 'NegReg', (82, 89))
190902	33107222	38  We speculate that KURC3 tumors with BAP1 mutations acquired other mutations and resistance to mTORC1 inhibitors more readily than PDX tumors without BAP1 mutations.	('mTORC1', 'cellular_component', 'GO:0031931', ('98', '104'))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('BAP1', 'Gene', (153, 157))	('BAP1', 'Gene', (40, 44))	('mutations', 'MPA', (70, 79))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('mTORC1', 'Gene', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('PDX tumors', 'Disease', (134, 144))	('mTORC1', 'Gene', '382056', (98, 104))	('tumors', 'Disease', (28, 34))	('PDX tumors', 'Disease', 'MESH:D009369', (134, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('mutations', 'Var', (45, 54))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('BAP1', 'Gene', '8314', (153, 157))	('BAP1', 'Gene', '8314', (40, 44))	('tumors', 'Disease', (138, 144))
190904	33107222	WES for clinical anaplastic thyroid carcinoma revealed that mTOR mutations conferred resistance to mTOR inhibition, 39  while certain mTOR mutations prevented binding of the FKBP12-rapamycin complex to mTORC1.	('FKBP12', 'Gene', '2285', (174, 180))	('mTOR', 'Gene', '2475', (60, 64))	('resistance', 'MPA', (85, 95))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (28, 45))	('mTORC1', 'Gene', (202, 208))	('mTOR', 'Gene', '2475', (202, 206))	('mTOR', 'Gene', (99, 103))	('thyroid carcinoma', 'Disease', (28, 45))	('FKBP12', 'Gene', (174, 180))	('mTORC1', 'Gene', '382056', (202, 208))	('binding', 'molecular_function', 'GO:0005488', ('159', '166'))	('mTORC1', 'cellular_component', 'GO:0031931', ('202', '208'))	('prevented', 'NegReg', (149, 158))	('mTOR', 'Gene', '2475', (99, 103))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (28, 45))	('FKBP', 'molecular_function', 'GO:0030051', ('174', '178'))	('binding', 'Interaction', (159, 166))	('rapamycin', 'Chemical', 'MESH:D020123', (181, 190))	('mTOR', 'Gene', (134, 138))	('mutations', 'Var', (139, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('mTOR', 'Gene', (60, 64))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (17, 45))	('mTOR', 'Gene', '2475', (134, 138))	('mTOR', 'Gene', (202, 206))	('mutations', 'Var', (65, 74))
190910	33107222	In the present study, comparing acquired resistant PDX tumors with sensitive ones using WES identified several genetic variations in temsirolimus-resistant tumors, including those in DNMT1, ANKRD12, CPD, and WDSUB1.	('variations', 'Var', (119, 129))	('ANKRD12', 'Gene', '23253', (190, 197))	('DNMT1', 'Gene', (183, 188))	('ANKRD12', 'Gene', (190, 197))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('PDX tumors', 'Disease', (51, 61))	('temsirolimus-resistant tumors', 'Disease', 'MESH:D060467', (133, 162))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('CPD', 'Gene', '1362', (199, 202))	('WDSUB1', 'Gene', '151525', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('WDSUB1', 'Gene', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('CPD', 'Gene', (199, 202))	('temsirolimus-resistant tumors', 'Disease', (133, 162))	('PDX tumors', 'Disease', 'MESH:D009369', (51, 61))
190912	33107222	42  The deletion of Dnmt1 in a mouse model led to the global loss of DNA methylation and embryonic lethality, 43  while even conditional loss of Dnmt1 in the developing mouse brain resulted in DNA hypomethylation and postnatal lethality.	('embryonic lethality', 'Disease', 'MESH:D020964', (89, 108))	('DNA hypomethylation', 'MPA', (193, 212))	('Dnmt1', 'Gene', '13433', (145, 150))	('resulted in', 'Reg', (181, 192))	('loss', 'NegReg', (61, 65))	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('mouse', 'Species', '10090', (31, 36))	('Dnmt1', 'Gene', (20, 25))	('loss', 'NegReg', (137, 141))	('postnatal lethality', 'CPA', (217, 236))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('193', '212'))	('DNA', 'cellular_component', 'GO:0005574', ('193', '196'))	('DNA methylation', 'MPA', (69, 84))	('DNA methylation', 'biological_process', 'GO:0006306', ('69', '84'))	('Dnmt1', 'Gene', '13433', (20, 25))	('Dnmt1', 'Gene', (145, 150))	('embryonic lethality', 'Disease', (89, 108))	('mouse', 'Species', '10090', (169, 174))	('deletion', 'Var', (8, 16))
190914	33107222	42 ,  45  Considering that a DNMT1 deficiency was reported to cause increased genome instability in the APCMin/+ intestinal epithelia, 46  early passage DNMT1 mutations and the functional loss of DNMT1 could lead to the accumulation of other mutations in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('DNMT1', 'Gene', (29, 34))	('DNMT1', 'Gene', (153, 158))	('lead to', 'Reg', (208, 215))	('mutations', 'Var', (159, 168))	('mutations', 'Var', (242, 251))	('deficiency', 'Var', (35, 45))	('increased', 'PosReg', (68, 77))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('genome instability', 'MPA', (78, 96))
190915	33107222	Indeed, in TCGA cohort of ccRCC patients, DNA methyltransferase (DNMT1, DNMT3A, and DNMT3B) alterations were detected in ~8% of entire cohort, and the mutation burden in tumors with them are significantly larger than those in tumors without (Figure S5).	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('alterations', 'Var', (92, 103))	('DNMT3A', 'Gene', '1788', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('RCC', 'Disease', (28, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('DNA methyltransferase', 'Gene', '1786', (42, 63))	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('DNMT3B', 'Gene', (84, 90))	('DNMT3B', 'Gene', '1789', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('DNMT3A', 'Gene', (72, 78))	('patients', 'Species', '9606', (32, 40))	('tumors', 'Disease', (226, 232))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('DNA methyltransferase', 'Gene', (42, 63))	('tumors', 'Disease', (170, 176))
190921	33107222	In passage 1 cohorts of KURC3 PDX tumors, the DNMT1 mutation was identified at a mutation frequency of about 50%, which is almost the same as following passage 2, 3, and 4 cohorts.	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('DNMT1', 'Gene', (46, 51))	('PDX tumors', 'Disease', 'MESH:D009369', (30, 40))	('mutation', 'Var', (52, 60))	('PDX tumors', 'Disease', (30, 40))
190922	33107222	So, DNMT1 mutation in the resistant tumor cells seemed to be homogeneous heterozygous mutation.	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('mutation', 'Var', (10, 18))	('DNMT1', 'Gene', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
190923	33107222	In present study, DNMT1 mutations and loss of DNMT enzyme activity were observed in resistant KURC3 PDX tumors, and we showed that, in vitro, loss of DNMT enzyme activity leads to the phenotype of temsirolimus-resistance in certain RCC cells.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('temsirolimus', 'Chemical', 'MESH:C401859', (197, 209))	('mutations', 'Var', (24, 33))	('RCC', 'Disease', (232, 235))	('enzyme activity', 'molecular_function', 'GO:0003824', ('51', '66'))	('DNMT', 'Gene', '1786', (18, 22))	('DNMT', 'Gene', (18, 22))	('RCC', 'Disease', 'MESH:C538614', (232, 235))	('temsirolimus-resistance', 'MPA', (197, 220))	('loss', 'NegReg', (142, 146))	('DNMT', 'Gene', '1786', (46, 50))	('PDX tumors', 'Disease', (100, 110))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('DNMT', 'Gene', (46, 50))	('activity', 'MPA', (162, 170))	('enzyme activity', 'molecular_function', 'GO:0003824', ('155', '170'))	('DNMT', 'Gene', '1786', (150, 154))	('DNMT', 'Gene', (150, 154))	('PDX tumors', 'Disease', 'MESH:D009369', (100, 110))
190924	33107222	Collectively, it was suggested that the DNMT1 mutation followed by reduced enzyme activity could be partially contributed to temsirolimus resistance in these models, while further study is necessary to elucidate the functional evidence to link the DNMT mutation with temsirolimus resistance.	('temsirolimus resistance', 'MPA', (267, 290))	('contributed', 'Reg', (110, 121))	('DNMT', 'Gene', (248, 252))	('DNMT', 'Gene', '1786', (40, 44))	('enzyme activity', 'molecular_function', 'GO:0003824', ('75', '90'))	('temsirolimus', 'Chemical', 'MESH:C401859', (125, 137))	('DNMT', 'Gene', (40, 44))	('temsirolimus resistance', 'MPA', (125, 148))	('reduced', 'NegReg', (67, 74))	('enzyme activity', 'MPA', (75, 90))	('temsirolimus', 'Chemical', 'MESH:C401859', (267, 279))	('mutation', 'Var', (46, 54))	('DNMT', 'Gene', '1786', (248, 252))
190925	33107222	The role of ankyrin repeat domain 12 (ANKRD12) and the functional consequence of the ANKRD12 variation observed in the present study remain unclear.	('ANKRD12', 'Gene', '23253', (85, 92))	('ANKRD12', 'Gene', (85, 92))	('ANKRD12', 'Gene', '23253', (38, 45))	('variation', 'Var', (93, 102))	('ANKRD12', 'Gene', (38, 45))	('ankyrin repeat domain 12', 'Gene', (12, 36))	('ankyrin repeat domain 12', 'Gene', '23253', (12, 36))
190930	33107222	In breast cancer cells and prostate cancer cells, CPD knockdown suppressed nitric oxide levels and cell viability and increased apoptosis.	('prostate cancer', 'Disease', 'MESH:D011471', (27, 42))	('prostate cancer', 'Phenotype', 'HP:0012125', (27, 42))	('increased', 'PosReg', (118, 127))	('prostate cancer', 'Disease', (27, 42))	('CPD', 'Gene', '1362', (50, 53))	('CPD', 'Gene', (50, 53))	('suppressed', 'NegReg', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('nitric oxide', 'Chemical', 'MESH:D009569', (75, 87))	('nitric oxide levels', 'MPA', (75, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('apoptosis', 'biological_process', 'GO:0097194', ('128', '137'))	('apoptosis', 'biological_process', 'GO:0006915', ('128', '137'))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('knockdown', 'Var', (54, 63))	('breast cancer', 'Disease', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cell viability', 'CPA', (99, 113))	('apoptosis', 'CPA', (128, 137))
190937	33107222	In retinoblastoma cells, lncRNA-H19 knockdown suppressed cell viability, migration, and invasion together with inhibition of PI3K/AKT/mTOR pathways.	('migration', 'CPA', (73, 82))	('invasion', 'CPA', (88, 96))	('PI3K', 'molecular_function', 'GO:0016303', ('125', '129'))	('retinoblastoma', 'Phenotype', 'HP:0009919', (3, 17))	('knockdown', 'Var', (36, 45))	('AKT', 'Gene', '207', (130, 133))	('lncRNA-H19', 'Gene', (25, 35))	('cell viability', 'CPA', (57, 71))	('inhibition', 'NegReg', (111, 121))	('mTOR', 'Gene', '2475', (134, 138))	('mTOR', 'Gene', (134, 138))	('retinoblastoma', 'Disease', 'MESH:D012175', (3, 17))	('retinoblastoma', 'Disease', (3, 17))	('AKT', 'Gene', (130, 133))	('suppressed', 'NegReg', (46, 56))
190943	33107222	57  Intriguingly, silencing CUL4B was shown to suppress mTOR-mediated S6K1 phosphorylation.	('CUL4B', 'Gene', '8450', (28, 33))	('silencing', 'Var', (18, 27))	('mTOR', 'Gene', (56, 60))	('mTOR', 'Gene', '2475', (56, 60))	('suppress', 'NegReg', (47, 55))	('phosphorylation', 'biological_process', 'GO:0016310', ('75', '90'))	('CUL4B', 'Gene', (28, 33))
190948	33107222	62  WES previously revealed recurrent mTORC1-activating mutations in RRAGC, which encodes RagC, in follicular lymphoma; the mutants increased raptor binding while rendering mTORC1 signaling resistant to amino acid deprivation.	('mutants', 'Var', (124, 131))	('resistant to amino acid deprivation', 'MPA', (190, 225))	('raptor', 'Gene', (142, 148))	('mutations', 'Var', (56, 65))	('increased', 'PosReg', (132, 141))	('RagC', 'Gene', '64121', (90, 94))	('RRAGC', 'Gene', (69, 74))	('signaling', 'biological_process', 'GO:0023052', ('180', '189'))	('RagC', 'Gene', (90, 94))	('lymphoma', 'Phenotype', 'HP:0002665', (110, 118))	('binding', 'molecular_function', 'GO:0005488', ('149', '156'))	('mTORC1', 'Gene', (38, 44))	('mTORC1', 'cellular_component', 'GO:0031931', ('38', '44'))	('mTORC1', 'Gene', (173, 179))	('mTORC1', 'Gene', '382056', (38, 44))	('mTORC1', 'cellular_component', 'GO:0031931', ('173', '179'))	('raptor', 'Gene', '57521', (142, 148))	('binding', 'Interaction', (149, 156))	('lymphoma', 'Disease', (110, 118))	('RRAGC', 'Gene', '64121', (69, 74))	('mTORC1', 'Gene', '382056', (173, 179))	('lymphoma', 'Disease', 'MESH:D008223', (110, 118))
190950	33107222	64  Because mTORC1 and S6K mediate potent negative feedback loops through insulin receptor, their suppression leads to compensatory activation of upstream signaling, including PI3K and Akt, which potentially opposes the effects of the inhibitors and leads to drug resistance.	('leads to', 'Reg', (250, 258))	('PI3K', 'Pathway', (176, 180))	('mTORC1', 'cellular_component', 'GO:0031931', ('12', '18'))	('activation', 'PosReg', (132, 142))	('mTORC1', 'Gene', (12, 18))	('drug resistance', 'Phenotype', 'HP:0020174', (259, 274))	('upstream signaling', 'MPA', (146, 164))	('mTORC1', 'Gene', '382056', (12, 18))	('drug resistance', 'biological_process', 'GO:0009315', ('259', '274'))	('insulin', 'molecular_function', 'GO:0016088', ('74', '81'))	('drug resistance', 'biological_process', 'GO:0042493', ('259', '274'))	('PI3K', 'molecular_function', 'GO:0016303', ('176', '180'))	('insulin receptor', 'Gene', '3643', (74, 90))	('S6K', 'Var', (23, 26))	('negative', 'NegReg', (42, 50))	('mediate', 'Reg', (27, 34))	('insulin receptor', 'Gene', (74, 90))	('Akt', 'Gene', (185, 188))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('Akt', 'Gene', '207', (185, 188))	('suppression', 'NegReg', (98, 109))
190958	33107222	The genetic alterations including DNMT1 mutations, and changes in methylation status or gene expression in cancer cells could be one of the potential mechanisms of developing resistance to temsirolimus.	('temsirolimus', 'Chemical', 'MESH:C401859', (189, 201))	('gene expression', 'biological_process', 'GO:0010467', ('88', '103'))	('methylation status', 'MPA', (66, 84))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('methylation', 'biological_process', 'GO:0032259', ('66', '77'))	('mutations', 'Var', (40, 49))	('DNMT1', 'Gene', (34, 39))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('resistance to temsirolimus', 'MPA', (175, 201))	('changes', 'Reg', (55, 62))	('developing', 'PosReg', (164, 174))
191060	33181696	Kaplan-Meier survival curve analysis showed that the DFS and OS of the renal cancer patients with a low M1 macrophage fraction (< 0.05) were significantly longer than those of the patients with a high M1 macrophage fraction (>=0.05) (OS, P < .0001; DFS, P < .0001) (Fig.	('renal cancer', 'Phenotype', 'HP:0009726', (71, 83))	('DFS', 'MPA', (53, 56))	('patients', 'Species', '9606', (84, 92))	('OS of the renal cancer', 'Disease', 'MESH:D007680', (61, 83))	('longer', 'PosReg', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('low', 'Var', (100, 103))	('OS of the renal cancer', 'Disease', (61, 83))	('patients', 'Species', '9606', (180, 188))
191072	33181696	The presence of abundant TILs is associated with a favourable prognosis in various human solid tumours, including RCC.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('human', 'Species', '9606', (83, 88))	('tumours', 'Disease', (95, 102))	('presence', 'Var', (4, 12))	('TILs', 'Protein', (25, 29))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
191084	33181696	They find that silencing of NDUFA4L2 affects cell viability, increases mitochondrial mass, and induces ROS generation in hypoxia.	('ROS generation', 'biological_process', 'GO:1903409', ('103', '117'))	('NDUFA4L2', 'Gene', (28, 36))	('ROS', 'Chemical', '-', (103, 106))	('cell viability', 'CPA', (45, 59))	('ROS generation', 'MPA', (103, 117))	('silencing', 'Var', (15, 24))	('NDUFA4L2', 'Gene', '56901', (28, 36))	('increases', 'PosReg', (61, 70))	('mitochondrial mass', 'MPA', (71, 89))	('hypoxia', 'Disease', 'MESH:D000860', (121, 128))	('hypoxia', 'Disease', (121, 128))	('induces', 'Reg', (95, 102))
191117	31861590	Regarding the molecular characteristics of RCC, the inactivation of the Von Hippel-Lindau (VHL) gene is by far the most common oncogenic driver event in ccRCC.	('RCC', 'Disease', 'MESH:D002292', (155, 158))	('RCC', 'Disease', (155, 158))	('VHL', 'Gene', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('VHL', 'Gene', '7428', (91, 94))	('inactivation', 'Var', (52, 64))	('RCC', 'Disease', (43, 46))	('RCC', 'Disease', 'MESH:D002292', (43, 46))	('Von Hippel-Lindau', 'Gene', '7428', (72, 89))	('Von Hippel-Lindau', 'Gene', (72, 89))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))
191120	31861590	Recent advances in next-generation sequencing (NGS) and their implementation in large cohort of cancer patients (e.g., The Cancer Genome Atlas (TCGA) projects), have led to the identification of additional genes frequently mutated in ccRCC, such as PBRM1 ( 40-50%), SETD2 (12%), BAP1 (10%), and KDM5C (5%).	('BAP1', 'Gene', '8314', (279, 283))	('mutated', 'Var', (223, 230))	('PBRM1', 'Gene', '55193', (249, 254))	('RCC', 'Disease', (236, 239))	('SETD2', 'Gene', '29072', (266, 271))	('RCC', 'Phenotype', 'HP:0005584', (236, 239))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Cancer', 'Phenotype', 'HP:0002664', (123, 129))	('BAP1', 'Gene', (279, 283))	('RCC', 'Disease', 'MESH:D002292', (236, 239))	('SETD2', 'Gene', (266, 271))	('KDM5C', 'Gene', (295, 300))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('KDM5C', 'Gene', '8242', (295, 300))	('patients', 'Species', '9606', (103, 111))	('PBRM1', 'Gene', (249, 254))	('cancer', 'Disease', (96, 102))
191121	31861590	Although VHL is the initiating event in ccRCC, the acquisition of additional mutations, some in subclonal cancer cell populations, is a common characteristic during ccRCC tumor development and metastasis.	('RCC', 'Disease', 'MESH:D002292', (42, 45))	('VHL', 'Gene', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('VHL', 'Gene', '7428', (9, 12))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('mutations', 'Var', (77, 86))	('RCC', 'Disease', 'MESH:D002292', (167, 170))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
191122	31861590	In this context, multiregion sequencing-based studies have highlighted the potential relevance of PBRM1 alterations for tumor growth and metastatic capacity, which are determinant for clinical outcome.	('PBRM1', 'Gene', (98, 103))	('alterations', 'Var', (104, 115))	('metastatic capacity', 'CPA', (137, 156))	('PBRM1', 'Gene', '55193', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
191129	31861590	It is estimated that about 20% of all human tumors harbor alterations in genes encoding SWI/SNF complex subunits.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('human', 'Species', '9606', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('SWI/SNF', 'Gene', (88, 95))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('88', '103'))	('alterations', 'Var', (58, 69))
191131	31861590	Interestingly, mutations in particular SWI/SNF components are tumor type-dependent, which may indicate that these complexes carry out not only universal but also tissue-specific functions.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mutations', 'Var', (15, 24))	('tumor', 'Disease', (62, 67))	('SWI/SNF', 'Gene', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
191132	31861590	For instance, SMARCB1 is found mutated in almost 95% of malignant rhabdoid tumors and PBRM1 is mutated in  40% of ccRCC.	('SMARCB1', 'Gene', (14, 21))	('malignant rhabdoid tumors', 'Disease', (56, 81))	('PBRM1', 'Gene', (86, 91))	('mutated', 'Var', (95, 102))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (56, 81))	('PBRM1', 'Gene', '55193', (86, 91))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('RCC', 'Disease', 'MESH:D002292', (116, 119))	('RCC', 'Disease', (116, 119))	('SMARCB1', 'Gene', '6598', (14, 21))	('mutated', 'Var', (31, 38))
191133	31861590	Other components of the SWI/SNF complex, such as ARID1A, are highly mutated in several cancer types, but rarely altered in ccRCC (e.g., ARID1A is mutated in 49% of ovarian clear cell carcinomas, 39% of endometrial cancers, and only in 3% of ccRCC tumors).	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumors', 'Disease', (247, 253))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('endometrial cancers', 'Disease', (202, 221))	('endometrial cancers', 'Disease', 'MESH:D016889', (202, 221))	('RCC', 'Disease', (243, 246))	('RCC', 'Phenotype', 'HP:0005584', (243, 246))	('ARID1A', 'Gene', (136, 142))	('cancer', 'Disease', (214, 220))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('RCC', 'Disease', 'MESH:D002292', (125, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('carcinomas', 'Phenotype', 'HP:0030731', (183, 193))	('ovarian clear cell carcinomas', 'Disease', (164, 193))	('RCC', 'Disease', 'MESH:D002292', (243, 246))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('ARID1A', 'Gene', (49, 55))	('cancer', 'Disease', (87, 93))	('ARID1A', 'Gene', '8289', (136, 142))	('mutated', 'Var', (146, 153))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D010051', (164, 193))	('ARID1A', 'Gene', '8289', (49, 55))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('24', '39'))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
191136	31861590	How mutations in the gene PBRM1 promote carcinogenesis and tumor progression is still unknown.	('carcinogenesis', 'Disease', 'MESH:D063646', (40, 54))	('tumor', 'Disease', (59, 64))	('PBRM1', 'Gene', (26, 31))	('carcinogenesis', 'Disease', (40, 54))	('PBRM1', 'Gene', '55193', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('mutations', 'Var', (4, 13))	('promote', 'PosReg', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
191137	31861590	PBRM1 is considered a tumor suppressor gene and this role is supported by in vitro experiments in ccRCC derived cell-lines, which show that PBRM1 gene silencing results in increased proliferation, migration, and colony formation.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('PBRM1', 'Gene', '55193', (0, 5))	('colony formation', 'CPA', (212, 228))	('RCC', 'Disease', 'MESH:D002292', (100, 103))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('22', '38'))	('proliferation', 'CPA', (182, 195))	('increased', 'PosReg', (172, 181))	('PBRM1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('migration', 'CPA', (197, 206))	('formation', 'biological_process', 'GO:0009058', ('219', '228'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('22', '38'))	('gene silencing', 'Var', (146, 160))	('PBRM1', 'Gene', '55193', (140, 145))	('gene silencing', 'biological_process', 'GO:0016458', ('146', '160'))	('PBRM1', 'Gene', (140, 145))	('tumor', 'Disease', (22, 27))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
191138	31861590	found that re-expression of PBRM1 into A704 cells, that harbor a homozygous truncating mutation in this gene, results in diminished colony formation.	('truncating mutation', 'Var', (76, 95))	('colony formation', 'CPA', (132, 148))	('formation', 'biological_process', 'GO:0009058', ('139', '148'))	('PBRM1', 'Gene', (28, 33))	('diminished', 'NegReg', (121, 131))	('PBRM1', 'Gene', '55193', (28, 33))
191139	31861590	The role of PBRM1 as tumor suppressor is also supported by the fact that  80% of the somatic mutations found in the gene result in loss of function (LOF) of the protein, not only in ccRCC but also in other tumor types, including breast and pancreatic cancers.	('PBRM1', 'Gene', (12, 17))	('tumor', 'Disease', (21, 26))	('protein', 'Protein', (161, 168))	('tumor suppressor', 'biological_process', 'GO:0051726', ('21', '37'))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('loss of function', 'NegReg', (131, 147))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (240, 258))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('breast and pancreatic cancers', 'Disease', 'MESH:D001943', (229, 258))	('mutations', 'Var', (93, 102))	('RCC', 'Disease', (184, 187))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))	('PBRM1', 'Gene', '55193', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('RCC', 'Disease', 'MESH:D002292', (184, 187))	('tumor', 'Disease', (206, 211))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('21', '37'))	('the protein', 'Protein', (157, 168))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
191141	31861590	PBRM1 inactivation can therefore disturb p53-dependent chromatin regulation and enable ccRCC tumors to escape from p53-mediated surveillance.	('enable', 'Reg', (80, 86))	('p53', 'Gene', '7157', (41, 44))	('chromatin', 'cellular_component', 'GO:0000785', ('55', '64'))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('inactivation', 'Var', (6, 18))	('disturb', 'Reg', (33, 40))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('p53', 'Gene', (115, 118))	('RCC', 'Disease', (89, 92))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('p53', 'Gene', '7157', (115, 118))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('regulation', 'biological_process', 'GO:0065007', ('65', '75'))	('RCC', 'Disease', 'MESH:D002292', (89, 92))	('tumors', 'Disease', (93, 99))	('p53', 'Gene', (41, 44))
191144	31861590	They showed that the inactivation of PBRM1 in 786-O cells, a ccRCC cell line expressing BAF180, resulted in a reduction of cell survival and proliferation.	('RCC', 'Disease', 'MESH:D002292', (63, 66))	('RCC', 'Disease', (63, 66))	('cell survival', 'CPA', (123, 136))	('PBRM1', 'Gene', (37, 42))	('inactivation', 'Var', (21, 33))	('reduction', 'NegReg', (110, 119))	('PBRM1', 'Gene', '55193', (37, 42))	('BAF180', 'Gene', (88, 94))	('BAF180', 'Gene', '55193', (88, 94))	('proliferation', 'CPA', (141, 154))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))
191153	31861590	They are related to mutations in specific susceptibility genes such as VHL, MET, FLCN, FH, and SDHB, which increase the risk of developing specific RCC subtypes.	('RCC', 'Disease', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('VHL', 'Gene', (71, 74))	('FLCN', 'Gene', (81, 85))	('RCC', 'Disease', 'MESH:D002292', (148, 151))	('FLCN', 'Gene', '201163', (81, 85))	('SDHB', 'Gene', '6390', (95, 99))	('VHL', 'Gene', '7428', (71, 74))	('MET', 'Gene', (76, 79))	('SDHB', 'Gene', (95, 99))	('mutations', 'Var', (20, 29))
191154	31861590	Other minority inherited forms of RCC are associated with BAP1 tumor predisposition syndrome and constitutional chromosome 3 translocations.	('tumor', 'Disease', (63, 68))	('constitutional', 'Var', (97, 111))	('associated', 'Reg', (42, 52))	('BAP1', 'Gene', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('chromosome', 'cellular_component', 'GO:0005694', ('112', '122'))	('RCC', 'Disease', 'MESH:D002292', (34, 37))	('RCC', 'Disease', (34, 37))	('BAP1', 'Gene', '8314', (58, 62))
191156	31861590	Recently, a PBRM1 mutational screening in a cohort of 35 French unrelated patients with a familial history of RCC revealed one patient with a germline PBRM1 truncating mutation (p.Asp1333Glyfs).	('RCC', 'Disease', (110, 113))	('PBRM1', 'Gene', (12, 17))	('patient', 'Species', '9606', (74, 81))	('p.Asp1333Gly', 'SUBSTITUTION', 'None', (178, 190))	('PBRM1', 'Gene', '55193', (12, 17))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('RCC', 'Disease', 'MESH:D002292', (110, 113))	('patient', 'Species', '9606', (127, 134))	('patients', 'Species', '9606', (74, 82))	('p.Asp1333Gly', 'Var', (178, 190))	('PBRM1', 'Gene', (151, 156))	('PBRM1', 'Gene', '55193', (151, 156))
191157	31861590	In the family there were three additional cases with ccRCC and the truncating mutation co-segregated with the disease.	('RCC', 'Disease', 'MESH:D002292', (55, 58))	('RCC', 'Disease', (55, 58))	('truncating mutation', 'Var', (67, 86))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
191160	31861590	The somatic genomic landscape of ccRCC tumors is characterized by VHL inactivation, which is found altered in  90% of the cases.	('RCC', 'Disease', 'MESH:D002292', (35, 38))	('RCC', 'Disease', (35, 38))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('inactivation', 'Var', (70, 82))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('VHL', 'Gene', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('tumors', 'Disease', (39, 45))	('VHL', 'Gene', '7428', (66, 69))
191162	31861590	However, even if VHL biallelic inactivation is a critical founder event, it is not sufficient for tumor development and additional mutations and epigenetic changes are necessary.	('biallelic inactivation', 'Var', (21, 43))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('VHL', 'Gene', (17, 20))	('tumor', 'Disease', (98, 103))	('VHL', 'Gene', '7428', (17, 20))
191163	31861590	Extensive sequencing projects by TCGA have identified PBRM1 as the second most frequently altered gene in ccRCC (49% of explored cases, 163 point mutations, eight deep deletions, and one fusion in a total of 354 cases) Even though ccRCC is the tumor type with the highest mutational rate in PBRM1 in the TCGA Pan-Can Project, somatic PBRM1 mutations were first described in breast cancer and are also observed in other cancer types such as cholangiocarcinoma (22%) and uterine (10%).	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('breast cancer', 'Disease', (374, 387))	('breast cancer', 'Disease', 'MESH:D001943', (374, 387))	('RCC', 'Phenotype', 'HP:0005584', (233, 236))	('cancer', 'Disease', 'MESH:D009369', (419, 425))	('PBRM1', 'Gene', '55193', (334, 339))	('RCC', 'Disease', (233, 236))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (440, 458))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('RCC', 'Disease', 'MESH:D002292', (108, 111))	('cholangiocarcinoma', 'Disease', (440, 458))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (440, 458))	('mutations', 'Var', (340, 349))	('cancer', 'Disease', (381, 387))	('PBRM1', 'Gene', (334, 339))	('RCC', 'Disease', 'MESH:D002292', (233, 236))	('cancer', 'Phenotype', 'HP:0002664', (381, 387))	('PBRM1', 'Gene', '55193', (54, 59))	('PBRM1', 'Gene', '55193', (291, 296))	('cancer', 'Disease', (419, 425))	('PBRM1', 'Gene', (54, 59))	('PBRM1', 'Gene', (291, 296))	('tumor', 'Disease', (244, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (374, 387))	('cancer', 'Phenotype', 'HP:0002664', (419, 425))	('uterine', 'Disease', (469, 476))	('cancer', 'Disease', 'MESH:D009369', (381, 387))	('carcinoma', 'Phenotype', 'HP:0030731', (449, 458))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
191164	31861590	Notably, the high incidence of mutations in PBRM1 in renal cancer seems to be limited to clear cell histology and mutations are rare or not observed in other renal cancer subtypes, such as papillary (4%) or chromophobe (0%).	('renal cancer', 'Disease', 'MESH:D007680', (53, 65))	('mutations', 'Var', (31, 40))	('PBRM1', 'Gene', (44, 49))	('papillary', 'Disease', (189, 198))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('renal cancer', 'Disease', (158, 170))	('chromophobe', 'Disease', (207, 218))	('renal cancer', 'Disease', 'MESH:D007680', (158, 170))	('PBRM1', 'Gene', '55193', (44, 49))	('renal cancer', 'Phenotype', 'HP:0009726', (158, 170))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('renal cancer', 'Disease', (53, 65))	('renal cancer', 'Phenotype', 'HP:0009726', (53, 65))
191165	31861590	In agreement with its role as a tumor suppressor, most mutations observed in ccRCC are truncating (137 out of 163 mutations) while missense mutations are less frequent (23 out of 163).	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('truncating', 'MPA', (87, 97))	('mutations', 'Var', (55, 64))	('mutations', 'Var', (114, 123))	('tumor suppressor', 'biological_process', 'GO:0051726', ('32', '48'))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('32', '48'))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('RCC', 'Disease', 'MESH:D002292', (79, 82))	('RCC', 'Disease', (79, 82))
191166	31861590	Mutations in PBRM1 are found distributed along the entire gene, affecting Bromodomains, Bromo-Adjacent Homology (BAH) and High Mobility Group (HMG) domains, with some relevant hotspots of truncating mutations (Figure 2).	('PBRM1', 'Gene', (13, 18))	('affecting', 'Reg', (64, 73))	('Bromo-Adjacent Homology', 'MPA', (88, 111))	('Mutations', 'Var', (0, 9))	('PBRM1', 'Gene', '55193', (13, 18))	('Bromodomains', 'MPA', (74, 86))	('High Mobility Group', 'MPA', (122, 141))
191167	31861590	PBRM1 gene (at 3p21.1) is also affected by copy number alterations, as a consequence of the characteristic chromosome 3p deletion in ccRCC tumors.	('copy', 'Var', (43, 47))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('PBRM1', 'Gene', (0, 5))	('RCC', 'Disease', (135, 138))	('PBRM1', 'Gene', '55193', (0, 5))	('p21', 'Gene', (16, 19))	('RCC', 'Disease', 'MESH:D002292', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('chromosome', 'cellular_component', 'GO:0005694', ('107', '117'))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('p21', 'Gene', '644914', (16, 19))
191168	31861590	Intratumoral heterogeneity (ITH) is a common feature of primary ccRCC tumors, leading to somatic point mutations and copy number alterations that are only present in a subset of tumor cells within the same tumor.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Disease', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('RCC', 'Disease', 'MESH:D002292', (66, 69))	('copy number alterations', 'Var', (117, 140))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('point mutations', 'Var', (97, 112))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
191170	31861590	Mutations in PBRM1 are clonal in  75% of cases and subclonal in the remaining 25% of ccRCC primary tumors.	('RCC', 'Disease', 'MESH:D002292', (87, 90))	('RCC', 'Disease', (87, 90))	('PBRM1', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('PBRM1', 'Gene', '55193', (13, 18))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
191171	31861590	Truncal PBRM1 mutations define particular evolutionary trajectories in the tumor, that impact the prognosis and therapeutic response.	('PBRM1', 'Gene', '55193', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('impact', 'Reg', (87, 93))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', (75, 80))	('PBRM1', 'Gene', (8, 13))
191172	31861590	Three out of the seven evolutionary patterns described in primary ccRCC tumors presented somatic mutations in PBRM1 as a truncal event that precede subclonal mutations in SETD2, genes from the PI3K pathway or copy number alterations (Figure 3).	('mutations', 'Var', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('SETD2', 'Gene', '29072', (171, 176))	('tumors', 'Disease', (72, 78))	('SETD2', 'Gene', (171, 176))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('RCC', 'Disease', 'MESH:D002292', (68, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('PI3K', 'molecular_function', 'GO:0016303', ('193', '197'))	('PBRM1', 'Gene', (110, 115))	('PBRM1', 'Gene', '55193', (110, 115))
191176	31861590	Several studies have described mutual exclusivity between PBRM1 and BAP1 mutations in RCC primary tumors.	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('BAP1', 'Gene', '8314', (68, 72))	('PBRM1', 'Gene', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('PBRM1', 'Gene', '55193', (58, 63))	('RCC', 'Disease', 'MESH:D002292', (86, 89))	('BAP1', 'Gene', (68, 72))	('RCC', 'Disease', (86, 89))	('mutations', 'Var', (73, 82))
191177	31861590	Still, truncal PBRM1 mutations are observed in an additional ccRCC evolutionary subtype characterized by multiple driver clonal mutations in genes that include, in addition to PBRM1, BAP1, SETD2, or PTEN.	('RCC', 'Disease', 'MESH:D002292', (63, 66))	('RCC', 'Disease', (63, 66))	('PTEN', 'Gene', '5728', (199, 203))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('PBRM1', 'Gene', '55193', (15, 20))	('BAP1', 'Gene', '8314', (183, 187))	('SETD2', 'Gene', '29072', (189, 194))	('BAP1', 'Gene', (183, 187))	('PBRM1', 'Gene', (176, 181))	('SETD2', 'Gene', (189, 194))	('observed', 'Reg', (35, 43))	('PBRM1', 'Gene', (15, 20))	('PBRM1', 'Gene', '55193', (176, 181))	('PTEN', 'Gene', (199, 203))	('mutations', 'Var', (21, 30))
191179	31861590	BAP1 clonal mutations are characteristic of an additional ccRCC evolutionary pattern that harbors a high genomic instability and a low ITH.	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (12, 21))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('RCC', 'Disease', 'MESH:D002292', (60, 63))	('BAP1', 'Gene', '8314', (0, 4))
191180	31861590	proposed that tumor clones with mutations in PBRM1 are preferably selected for metastasis development.	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (32, 41))	('PBRM1', 'Gene', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('metastasis development', 'CPA', (79, 101))	('PBRM1', 'Gene', '55193', (45, 50))
191182	31861590	Metastatic dissemination of primary tumors harboring VHL and PBRM1 mutations as the two only clonal events, is mainly an attenuated process that leads to initial solitary or oligometastases.	('PBRM1', 'Gene', (61, 66))	('Metastatic dissemination', 'CPA', (0, 24))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('PBRM1', 'Gene', '55193', (61, 66))	('VHL', 'Gene', (53, 56))	('mutations', 'Var', (67, 76))	('VHL', 'Gene', '7428', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('metastases', 'Disease', (179, 189))	('tumors', 'Disease', (36, 42))	('metastases', 'Disease', 'MESH:D009362', (179, 189))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
191184	31861590	Therefore, mutations in PBRM1 are a key factor not only for primary tumor development but also for tumor metastatic dissemination, in which additional subclonal mutations, acquired after PBRM1 loss, seem to play a decisive role.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (99, 104))	('mutations', 'Var', (11, 20))	('PBRM1', 'Gene', '55193', (187, 192))	('loss', 'NegReg', (193, 197))	('PBRM1', 'Gene', (24, 29))	('PBRM1', 'Gene', '55193', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('PBRM1', 'Gene', (187, 192))
191187	31861590	Two small retrospective studies were conducted to compare the different prognostic implications of both BAP1 and PBRM1 mutations in localized ccRCC.	('RCC', 'Disease', 'MESH:D002292', (144, 147))	('BAP1', 'Gene', '8314', (104, 108))	('PBRM1', 'Gene', (113, 118))	('PBRM1', 'Gene', '55193', (113, 118))	('BAP1', 'Gene', (104, 108))	('mutations', 'Var', (119, 128))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))
191191	31861590	reported worse relapse free survival (RFS) in those tumors carrying BAP1 mutation when compared to PBRM1 mutant tumors, although no differences in OS were found (Table 1).	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('PBRM1', 'Gene', (99, 104))	('PBRM1', 'Gene', '55193', (99, 104))	('relapse free survival', 'CPA', (15, 36))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('worse', 'NegReg', (9, 14))	('BAP1', 'Gene', '8314', (68, 72))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('RFS', 'Chemical', '-', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutation', 'Var', (73, 81))	('BAP1', 'Gene', (68, 72))	('tumors', 'Disease', (112, 118))
191198	31861590	Their results confirmed that PBRM1 LOF is more frequent in ccRCC than in other histological subtypes, and suggested that most of truncating mutations in ccRCC negatively affect PBRM1 expression.	('RCC', 'Disease', 'MESH:D002292', (155, 158))	('RCC', 'Disease', (155, 158))	('PBRM1', 'Gene', (177, 182))	('PBRM1', 'Gene', '55193', (29, 34))	('PBRM1', 'Gene', '55193', (177, 182))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('truncating mutations', 'Var', (129, 149))	('affect', 'Reg', (170, 176))	('negatively', 'NegReg', (159, 169))	('expression', 'MPA', (183, 193))	('RCC', 'Disease', (61, 64))	('RCC', 'Disease', 'MESH:D002292', (61, 64))	('PBRM1', 'Gene', (29, 34))	('LOF', 'NegReg', (35, 38))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))
191202	31861590	However, the addition of PBRM1 mutation to BAP1 mutation, which did correlate with a poor prognosis, increased the risk of cancer death (HR 4.18).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('BAP1', 'Gene', (43, 47))	('increased', 'PosReg', (101, 110))	('mutation', 'Var', (31, 39))	('cancer death', 'Disease', (123, 135))	('BAP1', 'Gene', '8314', (43, 47))	('PBRM1', 'Gene', (25, 30))	('mutation', 'Var', (48, 56))	('cancer death', 'Disease', 'MESH:D003643', (123, 135))	('PBRM1', 'Gene', '55193', (25, 30))
191212	31861590	Patients with high expression of PBRM1 in the tumor had a significantly worse OS than those with low PBRM1 expression.	('PBRM1', 'Gene', '55193', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('worse', 'NegReg', (72, 77))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('PBRM1', 'Gene', (101, 106))	('PBRM1', 'Gene', '55193', (101, 106))	('PBRM1', 'Gene', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
191214	31861590	Consistently, patients harboring tumors with high expression of PBRM1 showed shorter OS when treated with both sunitinib and everolimus (low vs. high expression; OS 45.0 vs. 23.0 months, p = 0.035).	('everolimus', 'Chemical', 'MESH:D000068338', (125, 135))	('sunitinib', 'Chemical', 'MESH:D000077210', (111, 120))	('PBRM1', 'Gene', (64, 69))	('PBRM1', 'Gene', '55193', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('high expression', 'Var', (45, 60))	('shorter', 'NegReg', (77, 84))	('tumors', 'Disease', (33, 39))	('patients', 'Species', '9606', (14, 22))
191217	31861590	Remarkably, PBRM1 mutations were associated with a better prognosis, both in terms of PFS (HR 0.67, p = 0.004) and OS (HR 0.63, p = 0.002), whereas BAP1 mutations were associated with worse prognosis, and a significant worse OS (HR 1.51).	('PBRM1', 'Gene', (12, 17))	('PBRM1', 'Gene', '55193', (12, 17))	('BAP1', 'Gene', '8314', (148, 152))	('BAP1', 'Gene', (148, 152))	('mutations', 'Var', (18, 27))
191220	31861590	The inactivation of BAP1 and PBRM1 mainly contribute to different pathways of tumor evolution, being almost mutually exclusive events conferring different prognosis.	('inactivation', 'Var', (4, 16))	('PBRM1', 'Gene', '55193', (29, 34))	('BAP1', 'Gene', '8314', (20, 24))	('BAP1', 'Gene', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('contribute', 'Reg', (42, 52))	('tumor', 'Disease', (78, 83))	('PBRM1', 'Gene', (29, 34))
191221	31861590	As suggested, ccRCC could be initiated by a focal mutation in VHL followed by 3p loss, predisposing to BAP1 or PBRM1 inactivation.	('BAP1', 'Gene', '8314', (103, 107))	('RCC', 'Disease', 'MESH:D002292', (16, 19))	('RCC', 'Disease', (16, 19))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('BAP1', 'Gene', (103, 107))	('PBRM1', 'Gene', '55193', (111, 116))	('VHL', 'Gene', (62, 65))	('PBRM1', 'Gene', (111, 116))	('loss', 'NegReg', (81, 85))	('VHL', 'Gene', '7428', (62, 65))	('initiated by', 'Reg', (29, 41))	('mutation', 'Var', (50, 58))
191222	31861590	The mutation of the remaining allele of PBRM1 or BAP1 would lead to tumorigenesis, and depending on which gene is mutated, to different tumor aggressiveness.	('tumor', 'Disease', (68, 73))	('aggressiveness', 'Phenotype', 'HP:0000718', (142, 156))	('tumor aggressiveness', 'Disease', (136, 156))	('lead to', 'Reg', (60, 67))	('PBRM1', 'Gene', (40, 45))	('BAP1', 'Gene', (49, 53))	('PBRM1', 'Gene', '55193', (40, 45))	('mutation', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (136, 156))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', (136, 141))	('BAP1', 'Gene', '8314', (49, 53))
191223	31861590	In advanced RCC, BAP1 mutation leads to a more aggressive disease and PBRM1 mutation would be associated with a better prognosis.	('aggressive disease', 'Disease', 'MESH:D001523', (47, 65))	('mutation', 'Var', (22, 30))	('RCC', 'Phenotype', 'HP:0005584', (12, 15))	('leads to', 'Reg', (31, 39))	('RCC', 'Disease', 'MESH:D002292', (12, 15))	('aggressive disease', 'Disease', (47, 65))	('RCC', 'Disease', (12, 15))	('PBRM1', 'Gene', (70, 75))	('BAP1', 'Gene', '8314', (17, 21))	('mutation', 'Var', (76, 84))	('PBRM1', 'Gene', '55193', (70, 75))	('BAP1', 'Gene', (17, 21))
191229	31861590	Interestingly, the tumors with high angiogenesis were enriched for PBRM1 mutations.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('PBRM1', 'Gene', '55193', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('angiogenesis', 'biological_process', 'GO:0001525', ('36', '48'))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('mutations', 'Var', (73, 82))	('PBRM1', 'Gene', (67, 72))
191230	31861590	In addition, when comparing the treatment outcomes, there was a clear benefit in sunitinib PFS, compared to atezolizumab monotherapy and to atezolizumab plus bevacizumab, in tumors with PBRM1 mutations.	('PBRM1', 'Gene', '55193', (186, 191))	('tumors', 'Disease', (174, 180))	('atezolizumab', 'Chemical', 'MESH:C000594389', (140, 152))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('benefit', 'PosReg', (70, 77))	('atezolizumab plus bevacizumab', 'Disease', 'MESH:D007625', (140, 169))	('atezolizumab', 'Chemical', 'MESH:C000594389', (108, 120))	('atezolizumab plus bevacizumab', 'Disease', (140, 169))	('PBRM1', 'Gene', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('sunitinib', 'Chemical', 'MESH:D000077210', (81, 90))	('mutations', 'Var', (192, 201))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
191231	31861590	These results suggest an association between angiogenesis and PBRM1 mutations, indicating that PBRM1 mutated patients may benefit more from antiangiogenics than from immunotherapy.	('angiogenesis', 'biological_process', 'GO:0001525', ('45', '57'))	('PBRM1', 'Gene', (95, 100))	('patients', 'Species', '9606', (109, 117))	('association', 'Interaction', (25, 36))	('mutated', 'Var', (101, 108))	('PBRM1', 'Gene', '55193', (95, 100))	('PBRM1', 'Gene', (62, 67))	('PBRM1', 'Gene', '55193', (62, 67))	('angiogenesis', 'CPA', (45, 57))	('mutations', 'Var', (68, 77))	('benefit', 'PosReg', (122, 129))
191233	31861590	In agreement with IMMOTION150 study, PBRM1 mutations were significantly more frequent in patients benefiting from antiangiogenic treatment (54% vs. 7%, respectively).	('patients', 'Species', '9606', (89, 97))	('PBRM1', 'Gene', (37, 42))	('mutations', 'Var', (43, 52))	('PBRM1', 'Gene', '55193', (37, 42))
191236	31861590	High PBRM1 expression correlated with worse outcomes in patients treated with either sunitinib or everolimus.	('patients', 'Species', '9606', (56, 64))	('High', 'Var', (0, 4))	('PBRM1', 'Gene', '55193', (5, 10))	('expression', 'MPA', (11, 21))	('everolimus', 'Chemical', 'MESH:D000068338', (98, 108))	('sunitinib', 'Chemical', 'MESH:D000077210', (85, 94))	('PBRM1', 'Gene', (5, 10))
191237	31861590	When analyzing each drug separately, the effect of PBRM1 expression was stronger in patients treated with everolimus (median PFS in low and high PBRM1 expression groups was 3.0 months and 1.9 months, respectively; p = 0.10) although it did not reach statistical significance.	('patients', 'Species', '9606', (84, 92))	('high', 'Var', (140, 144))	('PBRM1', 'Gene', (51, 56))	('PBRM1', 'Gene', (145, 150))	('PBRM1', 'Gene', '55193', (145, 150))	('PBRM1', 'Gene', '55193', (51, 56))	('everolimus', 'Chemical', 'MESH:D000068338', (106, 116))
191241	31861590	In this study, patients harboring PBRM1 mutation had better outcomes than those with PBRM1 wild type tumors in the everolimus-sunitinib sequence group (MT vs. WT PFS 12.8 vs. 5.5 months; HR 0.53, p = 0.004), whereas no differences were seen in the sunitinib-everolimus sequence group (p = 0.4).	('mutation', 'Var', (40, 48))	('patients', 'Species', '9606', (15, 23))	('sunitinib', 'Chemical', 'MESH:D000077210', (126, 135))	('outcomes', 'MPA', (60, 68))	('everolimus', 'Chemical', 'MESH:D000068338', (115, 125))	('sunitinib', 'Chemical', 'MESH:D000077210', (248, 257))	('type tumors', 'Disease', 'MESH:D009369', (96, 107))	('PBRM1', 'Gene', (85, 90))	('type tumors', 'Disease', (96, 107))	('PBRM1', 'Gene', '55193', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('PBRM1', 'Gene', (34, 39))	('PBRM1', 'Gene', '55193', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('everolimus', 'Chemical', 'MESH:D000068338', (258, 268))	('better', 'PosReg', (53, 59))
191248	31861590	They tried to correlate the tumor genome profile with the clinical benefit from anti-PD1 therapy and discovered there was a correlation between PBRM1 mutations and clinical benefit.	('tumor', 'Disease', (28, 33))	('PBRM1', 'Gene', (144, 149))	('PBRM1', 'Gene', '55193', (144, 149))	('mutations', 'Var', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
191249	31861590	However, when they tried to compare the type of tumor-immune microenvironment in ccRCC tumors according to the mutational status of PBRM1, in three different cohorts (TCGA, an independent cohort of untreated ccRCC tumors and patient tumors of their study), tumors harboring PBRM1 mutations in all three cohorts showed a lower expression of immune inhibitory ligands than those with intact PBRM1.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('PBRM1', 'Gene', (274, 279))	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (214, 220))	('PBRM1', 'Gene', '55193', (389, 394))	('RCC', 'Disease', (210, 213))	('RCC', 'Phenotype', 'HP:0005584', (210, 213))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('tumor', 'Disease', (257, 262))	('expression of immune inhibitory ligands', 'MPA', (326, 365))	('tumor', 'Disease', (233, 238))	('lower', 'NegReg', (320, 325))	('PBRM1', 'Gene', (389, 394))	('tumors', 'Disease', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('RCC', 'Disease', 'MESH:D002292', (210, 213))	('RCC', 'Disease', 'MESH:D002292', (83, 86))	('tumor', 'Disease', (48, 53))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('PBRM1', 'Gene', '55193', (132, 137))	('tumors', 'Disease', (233, 239))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumors', 'Disease', (257, 263))	('PBRM1', 'Gene', '55193', (274, 279))	('mutations', 'Var', (280, 289))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('PBRM1', 'Gene', (132, 137))	('patient', 'Species', '9606', (225, 232))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
191251	31861590	The results showed a significant correlation between PRBM1 status and response to anti-PD1 therapy, with a significant benefit both in PFS and OS in those patients harboring PBRM1 mutations (HR 0.67, 95% CI, 0.47-0.96; p = 0.03, and HR 0.65, 95% CI, 0.44-0.96; p = 0.03 respectively) compared to those with PBRM1 wild type tumors.	('type tumors', 'Disease', 'MESH:D009369', (318, 329))	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('mutations', 'Var', (180, 189))	('PBRM1', 'Gene', (174, 179))	('PFS', 'Disease', (135, 138))	('PBRM1', 'Gene', '55193', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (323, 329))	('patients', 'Species', '9606', (155, 163))	('benefit', 'PosReg', (119, 126))	('PBRM1', 'Gene', (307, 312))	('type tumors', 'Disease', (318, 329))	('PBRM1', 'Gene', '55193', (307, 312))
191253	31861590	On the other hand, as discussed above, in the clinical trial IMMOTION150 the group of tumors with high angiogenesis showed an enrichment in PBRM1 mutations and these patients seemed to perform worse when treated with ICI alone (atezolizumab) than when treated with antiangiogenics alone (sunitinib) or in combination with immunotherapy (atezolizumab plus bevacizumab).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutations', 'Var', (146, 155))	('sunitinib', 'Chemical', 'MESH:D000077210', (288, 297))	('PBRM1', 'Gene', (140, 145))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('PBRM1', 'Gene', '55193', (140, 145))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('angiogenesis', 'biological_process', 'GO:0001525', ('103', '115'))	('worse', 'NegReg', (193, 198))	('atezolizumab', 'Chemical', 'MESH:C000594389', (337, 349))	('atezolizumab plus bevacizumab', 'Disease', (337, 366))	('atezolizumab plus bevacizumab', 'Disease', 'MESH:D007625', (337, 366))	('atezolizumab', 'Chemical', 'MESH:C000594389', (228, 240))	('patients', 'Species', '9606', (166, 174))
191254	31861590	Altogether, it seems that PBRM1 mutations are associated with specific molecular tumor expression profiles, and that they may have a predictive role.	('PBRM1', 'Gene', (26, 31))	('PBRM1', 'Gene', '55193', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('associated', 'Reg', (46, 56))	('tumor', 'Disease', (81, 86))
191256	31861590	Evolutionary information from the TRACERX study has shown that RCC tumors with PBRM1 mutations may have a less aggressive behavior, however, additional events may be synergistic and confer a worse prognosis.	('RCC', 'Disease', 'MESH:D002292', (63, 66))	('RCC', 'Disease', (63, 66))	('aggressive behavior', 'Disease', (111, 130))	('aggressive behavior', 'biological_process', 'GO:0002118', ('111', '130'))	('aggressive behavior', 'Phenotype', 'HP:0000718', (111, 130))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('PBRM1', 'Gene', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('PBRM1', 'Gene', '55193', (79, 84))	('mutations', 'Var', (85, 94))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('tumors', 'Disease', (67, 73))	('aggressive behavior', 'Disease', 'MESH:D001523', (111, 130))
191259	31861590	For a gene with both oncogenic and tumor-suppressor potentials, it is possible that one single mutation event would unleash its oncogenic power and abolish its tumor-suppressor function.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('oncogenic power', 'CPA', (128, 143))	('abolish', 'NegReg', (148, 155))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))	('tumor', 'Disease', (35, 40))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('160', '176'))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('160', '176'))	('tumor', 'Disease', (160, 165))	('mutation', 'Var', (95, 103))
191261	31861590	This could lead to expanding precision cancer medicine in tumors with a basis on mutations of tumor suppressor genes.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('94', '110'))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('cancer', 'Disease', (39, 45))	('tumors', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mutations', 'Var', (81, 90))	('tumor suppressor', 'biological_process', 'GO:0051726', ('94', '110'))
191285	31592114	Dysregulation of some lncRNAs are closely associated with the initiation and progression of human cancers, such as liver cancer, lung cancer, breast cancer and ccRCC.	('Dysregulation', 'Var', (0, 13))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('ccRCC', 'Disease', 'MESH:D002292', (160, 165))	('breast cancer', 'Disease', (142, 155))	('liver cancer', 'Disease', 'MESH:D006528', (115, 127))	('cancers', 'Disease', (98, 105))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('RCC', 'Phenotype', 'HP:0005584', (162, 165))	('ccRCC', 'Disease', (160, 165))	('liver cancer', 'Phenotype', 'HP:0002896', (115, 127))	('liver cancer', 'Disease', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (160, 165))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('human', 'Species', '9606', (92, 97))	('lung cancer', 'Disease', (129, 140))	('lncRNAs', 'Protein', (22, 29))	('associated', 'Reg', (42, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))
191323	31592114	Furthermore, we evaluated the prognostic value of lnc-DILC expression in ccRCC patients through Kaplan-Meier method, and the results demonstrated high-expression group had a better overall survival, as compared to low-expression group (Fig.	('overall', 'MPA', (181, 188))	('better', 'PosReg', (174, 180))	('ccRCC', 'Disease', 'MESH:D002292', (73, 78))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('DILC', 'Gene', '7027', (54, 58))	('patients', 'Species', '9606', (79, 87))	('DILC', 'Gene', (54, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))	('ccRCC', 'Disease', (73, 78))	('high-expression', 'Var', (146, 161))
191334	31592114	For further confirmation, fluorometric enzyme assay was utilized to detect the caspase-3 activity, and the results showed that activity of caspase-3 were significantly enhanced by ectopic expression of lnc-DILC in ACHN and 786-O cells (Fig.	('ACHN', 'Gene', '55323', (214, 218))	('caspase-3', 'Gene', (139, 148))	('DILC', 'Gene', (206, 210))	('caspase-3', 'Gene', '836', (79, 88))	('caspase-3 activity', 'molecular_function', 'GO:0004208', ('79', '97'))	('enhanced', 'PosReg', (168, 176))	('ACHN', 'Gene', (214, 218))	('caspase-3', 'Gene', '836', (139, 148))	('caspase-3 activity', 'molecular_function', 'GO:0030693', ('79', '97'))	('caspase-3', 'Gene', (79, 88))	('DILC', 'Gene', '7027', (206, 210))	('activity', 'MPA', (127, 135))	('ectopic expression', 'Var', (180, 198))
191340	31592114	Reciprocally, knockdown of lnc-DILC significantly facilitated the Caki-1 cells migration and invasion compared to the control group (Fig.	('DILC', 'Gene', '7027', (31, 35))	('Caki-1 cells migration', 'CPA', (66, 88))	('facilitated', 'PosReg', (50, 61))	('DILC', 'Gene', (31, 35))	('knockdown', 'Var', (14, 23))	('invasion', 'CPA', (93, 101))
191357	31592114	4g), whereas knockdown of lnc-DILC exerted opposite effects in Caki-1 cells (Fig.	('DILC', 'Gene', '7027', (30, 34))	('DILC', 'Gene', (30, 34))	('knockdown', 'Var', (13, 22))
191361	31592114	Conversely, knockdown of lnc-DILC increased PTEN ubiquitination in Caki-1 cells (Fig.	('increased', 'PosReg', (34, 43))	('DILC', 'Gene', '7027', (29, 33))	('knockdown', 'Var', (12, 21))	('PTEN', 'Gene', (44, 48))	('PTEN', 'Gene', '5728', (44, 48))	('DILC', 'Gene', (29, 33))
191363	31592114	Interestingly, we found that ectopic expression of WWP2 could partially abolished the PTEN ubiquitination reduced by lnc-DILC (Fig.	('WWP2', 'Gene', (51, 55))	('ectopic expression', 'Var', (29, 47))	('WWP2', 'Gene', '11060', (51, 55))	('PTEN', 'Gene', (86, 90))	('DILC', 'Gene', '7027', (121, 125))	('PTEN', 'Gene', '5728', (86, 90))	('abolished', 'NegReg', (72, 81))	('DILC', 'Gene', (121, 125))
191366	31592114	5e), whereas deletion of lnc-DILC1 enhanced the interaction between WWP2 and PTEN in Caki-1 cells (Fig.	('WWP2', 'Gene', '11060', (68, 72))	('DILC', 'Gene', '7027', (29, 33))	('deletion', 'Var', (13, 21))	('PTEN', 'Gene', (77, 81))	('enhanced', 'PosReg', (35, 43))	('interaction', 'Interaction', (48, 59))	('PTEN', 'Gene', '5728', (77, 81))	('WWP2', 'Gene', (68, 72))	('DILC', 'Gene', (29, 33))
191383	31592114	lncRNAs play important roles in tumor growth and metastasis via different mechanisms including cis- or trans-regulation, RNA scaffold, microRNA sponge, RNA decay, epigenetic modification, post-translational modification.	('post-translational modification', 'biological_process', 'GO:0043687', ('188', '219'))	('metastasis', 'CPA', (49, 59))	('RNA', 'cellular_component', 'GO:0005562', ('152', '155'))	('regulation', 'biological_process', 'GO:0065007', ('109', '119'))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cis-', 'MPA', (95, 99))	('RNA', 'cellular_component', 'GO:0005562', ('121', '124'))	('epigenetic modification', 'Var', (163, 186))	('tumor', 'Disease', (32, 37))	('post-translational modification', 'Var', (188, 219))
191384	31592114	Aberrant post-translational modifications of protein contribute to ccRCC initiation and progression.	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('contribute', 'Reg', (53, 63))	('Aberrant', 'Var', (0, 8))	('ccRCC', 'Disease', (67, 72))	('protein', 'Protein', (45, 52))	('ccRCC', 'Disease', 'MESH:D002292', (67, 72))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('post-translational modifications', 'MPA', (9, 41))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
191391	31592114	Previous studies have demonstrated that protein ubiquitination could be regulated by aberrant expression of lncRNAs in human cancers, such as NBAT1, lnc-UICC and OCC-1.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('aberrant expression', 'Var', (85, 104))	('cancers', 'Disease', (125, 132))	('OCC-1', 'Gene', '11167', (162, 167))	('protein ubiquitination', 'biological_process', 'GO:0016567', ('40', '62'))	('NBAT1', 'Gene', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('NBAT1', 'Gene', '729177', (142, 147))	('protein ubiquitination', 'MPA', (40, 62))	('lnc-UICC', 'Disease', (149, 157))	('OCC-1', 'Gene', (162, 167))	('lncRNAs', 'Gene', (108, 115))	('regulated', 'Reg', (72, 81))	('human', 'Species', '9606', (119, 124))
191401	31592114	Linc02023 suppresses colorectal cancer growth through blocking the interaction between PTEN and WWP2 and enhancing PTEN stability.	('PTEN', 'Gene', (87, 91))	('WWP2', 'Gene', (96, 100))	('suppresses', 'NegReg', (10, 20))	('enhancing', 'PosReg', (105, 114))	('WWP2', 'Gene', '11060', (96, 100))	('PTEN', 'Gene', '5728', (87, 91))	('PTEN', 'Gene', (115, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (21, 38))	('PTEN', 'Gene', '5728', (115, 119))	('colorectal cancer', 'Disease', (21, 38))	('blocking', 'NegReg', (54, 62))	('interaction', 'Interaction', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('Linc02023', 'Var', (0, 9))	('colorectal cancer', 'Disease', 'MESH:D015179', (21, 38))
191424	27738339	Most RCC are classified as clear cell subtype (ccRCC) that is characterized by frequent mutations of the von Hippel-Lindau (VHL) tumor suppressor gene.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('129', '145'))	('RCC', 'Disease', (49, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('mutations', 'Var', (88, 97))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (105, 134))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor suppressor', 'biological_process', 'GO:0051726', ('129', '145'))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
191437	27738339	Moreover miRs deregulation has been associated with the risk of metastasis after nephrectomy or response to the RCC treatment therapies.	('miR', 'Gene', '406985', (9, 12))	('deregulation', 'Var', (14, 26))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('metastasis', 'CPA', (64, 74))	('associated', 'Reg', (36, 46))	('miR', 'Gene', (9, 12))
191479	27738339	The most significant candidate was miR-99b-5p, which was upregulated approximately 4-fold in partial responders (Figure 4B).	('miR-99b', 'Gene', (35, 42))	('miR-99b', 'Gene', '407056', (35, 42))	('5p', 'Chemical', '-', (43, 45))	('partial responders', 'Var', (93, 111))	('upregulated', 'PosReg', (57, 68))
191484	27738339	MiR-155 and miR-210 showed a greater up regulation if analyzed with RTqPCR (294- and 214733-fold respectively) than with sequencing (22- and 14-fold respectively) in patient 8.	('CR', 'Chemical', '-', (72, 74))	('miR-210', 'Gene', (12, 19))	('miR-210', 'Gene', '406992', (12, 19))	('regulation', 'biological_process', 'GO:0065007', ('40', '50'))	('up regulation', 'PosReg', (37, 50))	('MiR-155', 'Gene', '406947', (0, 7))	('RTqPCR', 'Gene', (68, 74))	('214733-fold', 'Var', (85, 96))	('MiR-155', 'Gene', (0, 7))	('patient', 'Species', '9606', (166, 173))
191533	27738339	Additionally, specific miR expression patterns have not only been detected in tissue but also in serum of patients with various diseases, suggesting that small non-coding RNAs represent potential biomarkers for disease monitoring.	('patients', 'Species', '9606', (106, 114))	('miR', 'Gene', (23, 26))	('small non-coding RNAs', 'Var', (154, 175))	('miR', 'Gene', '406985', (23, 26))
191588	28076379	FUBP1 knockdown inhibited cell proliferation and induced cell cycle arrest and apoptosis.	('arrest', 'Disease', (68, 74))	('inhibited', 'NegReg', (16, 25))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('cell proliferation', 'biological_process', 'GO:0008283', ('26', '44'))	('arrest', 'Disease', 'MESH:D006323', (68, 74))	('FUBP1', 'Gene', (0, 5))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('57', '74'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (57, 74))	('induced', 'Reg', (49, 56))	('apoptosis', 'CPA', (79, 88))	('knockdown', 'Var', (6, 15))	('cell proliferation', 'CPA', (26, 44))	('FUBP1', 'Gene', '8880', (0, 5))
191608	28076379	In U2OS cells, FUBP1 knockdown could arrest cellular proliferation by extinguishing c-myc expression.	('extinguishing', 'NegReg', (70, 83))	('U2OS', 'CellLine', 'CVCL:0042', (3, 7))	('cellular proliferation', 'CPA', (44, 66))	('arrest', 'Disease', 'MESH:D006323', (37, 43))	('FUBP1', 'Gene', '8880', (15, 20))	('arrest', 'Disease', (37, 43))	('c-myc', 'Gene', '4609', (84, 89))	('c-myc', 'Gene', (84, 89))	('knockdown', 'Var', (21, 30))	('FUBP1', 'Gene', (15, 20))
191656	28076379	To determine the biological role of FUBP1 in the proliferation of human ccRCC cells, we used chemically synthesized siRNAs, which were designed to target distinct sites of FUBP1 mRNA for knocking down endogenous FUBP1 in ccRCC cell lines of 786-O and caki-1.	('RCC', 'Disease', 'MESH:C538614', (223, 226))	('FUBP1', 'Gene', '8880', (172, 177))	('RCC', 'Disease', (223, 226))	('FUBP1', 'Gene', (36, 41))	('FUBP1', 'Gene', (212, 217))	('human', 'Species', '9606', (66, 71))	('RCC', 'Disease', (74, 77))	('knocking', 'Var', (187, 195))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (223, 226))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('FUBP1', 'Gene', (172, 177))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('FUBP1', 'Gene', '8880', (36, 41))	('ccRCC', 'Phenotype', 'HP:0006770', (221, 226))	('FUBP1', 'Gene', '8880', (212, 217))
191657	28076379	To exclude the off-target effects, we designed three different siRNAs, Western blot analysis confirmed that all were considered efficient for FUBP1 knockdown (Fig 2A).	('FUBP1', 'Gene', '8880', (142, 147))	('FUBP1', 'Gene', (142, 147))	('knockdown', 'Var', (148, 157))
191664	28076379	We found that FUBP1 knockdown increased the percentage of cells in the G0/G1 peak and decreased the percentage of cells in the S peak as compared with those in the matched controls (Fig 3A and 3B).	('FUBP1', 'Gene', '8880', (14, 19))	('G0/G1 peak', 'MPA', (71, 81))	('FUBP1', 'Gene', (14, 19))	('increased', 'PosReg', (30, 39))	('decreased', 'NegReg', (86, 95))	('S peak', 'MPA', (127, 133))	('knockdown', 'Var', (20, 29))
191668	28076379	The data showed that FUBP1 knockdown of 786-O and caki-1 cells had a remarkably higher percentage of annexin V:FITC-positive cells than that of the control cells (Fig 4A and 4B).	('FUBP1', 'Gene', '8880', (21, 26))	('FITC', 'Chemical', 'MESH:D016650', (111, 115))	('knockdown', 'Var', (27, 36))	('annexin V', 'Gene', '308', (101, 110))	('annexin V', 'Gene', (101, 110))	('FUBP1', 'Gene', (21, 26))	('higher', 'PosReg', (80, 86))
191669	28076379	Consistent with the flow cytometry data, the expression levels of well-defined apoptosis protein markers, such as cleaved caspase 3, increased in the 786-O and caki-1 cells with the knockdown of FUBP1 expression (Fig 4C).	('expression levels', 'MPA', (45, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('cleaved caspase 3', 'MPA', (114, 131))	('FUBP1', 'Gene', (195, 200))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('increased', 'PosReg', (133, 142))	('knockdown', 'Var', (182, 191))	('FUBP1', 'Gene', '8880', (195, 200))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
191674	28076379	Moreover, after knockdown FUBP1 in 786-O and caki-1 cells, the mRNA levels of c-myc and p21 were significantly decreased (Fig 5E and 5F).	('FUBP1', 'Gene', (26, 31))	('decreased', 'NegReg', (111, 120))	('knockdown', 'Var', (16, 25))	('c-myc', 'Gene', (78, 83))	('FUBP1', 'Gene', '8880', (26, 31))	('c-myc', 'Gene', '4609', (78, 83))	('p21', 'MPA', (88, 91))
191682	28076379	reported that HCC patients with high levels of FUBP1-1/2 expression had significantly poorer cumulative survival.	('FUBP1', 'Gene', (47, 52))	('cumulative survival', 'CPA', (93, 112))	('poorer', 'NegReg', (86, 92))	('high levels', 'Var', (32, 43))	('patients', 'Species', '9606', (18, 26))	('FUBP1', 'Gene', '8880', (47, 52))	('HCC', 'Disease', (14, 17))
191685	28076379	Our results indicated that patients with high FUBP1 expression developed larger ccRCC, which is consistent with the proliferative role for FUBP1 in ccRCC.	('FUBP1', 'Gene', (139, 144))	('larger', 'PosReg', (73, 79))	('FUBP1', 'Gene', '8880', (46, 51))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('high', 'Var', (41, 45))	('RCC', 'Disease', (150, 153))	('FUBP1', 'Gene', '8880', (139, 144))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('patients', 'Species', '9606', (27, 35))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('FUBP1', 'Gene', (46, 51))	('expression', 'Var', (52, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (148, 153))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))
191689	28076379	In oligodendrogliomas FUBP1 expression was abolished because of mutations and it was considered a tumor suppressor.	('FUBP1', 'Gene', (22, 27))	('oligodendrogliomas', 'Disease', 'MESH:D009837', (3, 21))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('expression', 'MPA', (28, 38))	('tumor suppressor', 'biological_process', 'GO:0051726', ('98', '114'))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('mutations', 'Var', (64, 73))	('FUBP1', 'Gene', '8880', (22, 27))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('98', '114'))	('tumor', 'Disease', (98, 103))	('oligodendrogliomas', 'Disease', (3, 21))	('abolished', 'NegReg', (43, 52))	('gliomas', 'Phenotype', 'HP:0009733', (14, 21))
191706	28076379	Under various stimuli, such as viral infection and apoptosis, FUBP1 could translocate from the nuclei to the cytoplasm, which contributes to mRNA stability and translation, such as GAP-43, p27, and NPM, as well as the replication of viruses, such as the Japanese encephalitis virus and hepatitis C virus.	('translocate', 'MPA', (74, 85))	('encephalitis', 'Phenotype', 'HP:0002383', (263, 275))	('FUBP1', 'Gene', '8880', (62, 67))	('encephalitis virus and hepatitis C virus', 'Disease', 'MESH:D006526', (263, 303))	('replication', 'MPA', (218, 229))	('GAP-43', 'Gene', (181, 187))	('apoptosis', 'biological_process', 'GO:0097194', ('51', '60'))	('apoptosis', 'biological_process', 'GO:0006915', ('51', '60'))	('viral infection', 'Disease', (31, 46))	('mRNA stability', 'MPA', (141, 155))	('translation', 'biological_process', 'GO:0006412', ('160', '171'))	('viral infection', 'Disease', 'MESH:D001102', (31, 46))	('hepatitis', 'Phenotype', 'HP:0012115', (286, 295))	('p27', 'Var', (189, 192))	('cytoplasm', 'cellular_component', 'GO:0005737', ('109', '118'))	('GAP-43', 'Gene', '2596', (181, 187))	('translation', 'MPA', (160, 171))	('viral infection', 'biological_process', 'GO:0016032', ('31', '46'))	('FUBP1', 'Gene', (62, 67))	('NPM', 'Gene', (198, 201))	('NPM', 'Gene', '4869', (198, 201))	('contributes', 'Reg', (126, 137))
191711	28076379	By employing fluorescence in situ hybridization, the deletion at 3p25.1-25.3 with c-myc gain had a significant correlation with tumor size in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('c-myc', 'Gene', '4609', (82, 87))	('deletion', 'Var', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('gain', 'PosReg', (88, 92))	('tumor', 'Disease', (128, 133))	('c-myc', 'Gene', (82, 87))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))
191712	28076379	Furthermore, an in vitro study indicated that c-myc knockdown significantly inhibited ccRCC cell proliferation by arresting the cell cycle in the G0/G1 phase.	('cell cycle in the G0/G1 phase', 'CPA', (128, 157))	('cell cycle', 'biological_process', 'GO:0007049', ('128', '138'))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('arrest', 'Disease', 'MESH:D006323', (114, 120))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('c-myc', 'Gene', '4609', (46, 51))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('arrest', 'Disease', (114, 120))	('c-myc', 'Gene', (46, 51))	('cell proliferation', 'biological_process', 'GO:0008283', ('92', '110'))	('G1 phase', 'biological_process', 'GO:0051318', ('149', '157'))	('inhibited', 'NegReg', (76, 85))	('knockdown', 'Var', (52, 61))
191714	28076379	p21, which is the founding member of the Cip/Kip family of CKIs, can bind and inhibit a range of cyclin/Cdk complexes, thereby leads to cell cycle arrest.	('bind', 'Interaction', (69, 73))	('cyclin', 'Gene', '18538', (97, 103))	('cyclin', 'Gene', (97, 103))	('arrest', 'Disease', (147, 153))	('Cdk', 'Gene', (104, 107))	('leads to', 'Reg', (127, 135))	('cyclin', 'molecular_function', 'GO:0016538', ('97', '103'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('136', '153'))	('inhibit', 'NegReg', (78, 85))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (136, 153))	('p21', 'Var', (0, 3))	('Cdk', 'molecular_function', 'GO:0004693', ('104', '107'))	('Cdk', 'Gene', '1019;1021', (104, 107))	('arrest', 'Disease', 'MESH:D006323', (147, 153))
191716	28076379	However, an in vitro study revealed that inducing p21 expression decreased the viability of cancer cells via G1 arrest and apoptosis in A-498 cells.	('cancer', 'Disease', (92, 98))	('inducing', 'Var', (41, 49))	('decreased', 'NegReg', (65, 74))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('A-498', 'CellLine', 'CVCL:1056', (136, 141))	('apoptosis', 'CPA', (123, 132))	('arrest', 'Disease', 'MESH:D006323', (112, 118))	('apoptosis', 'biological_process', 'GO:0097194', ('123', '132'))	('p21', 'Gene', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('arrest', 'Disease', (112, 118))	('apoptosis', 'biological_process', 'GO:0006915', ('123', '132'))
191720	29481555	Although ccRCC is characterized by common recurrent genetic abnormalities, including inactivation of the von Hippel-Lindau (vhl) tumor suppressor gene resulting in stabilization of hypoxia-inducible factors (HIFs), the tumor aggressiveness and outcome of ccRCC is variable.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('129', '145'))	('tumor', 'Disease', (219, 224))	('vhl', 'Gene', (124, 127))	('RCC', 'Disease', (257, 260))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('ccRCC', 'Phenotype', 'HP:0006770', (9, 14))	('tumor suppressor', 'biological_process', 'GO:0051726', ('129', '145'))	('RCC', 'Disease', (11, 14))	('inactivation', 'Var', (85, 97))	('aggressiveness', 'Phenotype', 'HP:0000718', (225, 239))	('tumor aggressiveness', 'Disease', (219, 239))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('von Hippel-Lindau', 'Gene', (105, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (255, 260))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (257, 260))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('genetic abnormalities', 'Disease', 'MESH:D030342', (52, 73))	('stabilization', 'MPA', (164, 177))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('hypoxia', 'Disease', (181, 188))	('vhl', 'Gene', '7428', (124, 127))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (219, 239))	('genetic abnormalities', 'Disease', (52, 73))	('von Hippel-Lindau', 'Gene', '7428', (105, 122))	('hypoxia', 'Disease', 'MESH:D000860', (181, 188))
191729	29481555	This study demonstrates for the first time a link between the aggressiveness of high- Fuhrman grade ccRCC and metabolic reprogramming.	('high- Fuhrman', 'Var', (80, 93))	('aggressiveness', 'Disease', 'MESH:D001523', (62, 76))	('aggressiveness', 'Disease', (62, 76))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('RCC', 'Disease', (102, 105))	('aggressiveness', 'Phenotype', 'HP:0000718', (62, 76))	('metabolic reprogramming', 'CPA', (110, 133))
191739	29481555	Inactivation of the vhl gene, which translates into a deficit in the VHL protein (pVHL), is the initial event in tumorigenesis of ccRCC.	('deficit', 'NegReg', (54, 61))	('tumor', 'Disease', (113, 118))	('VHL', 'Gene', '7428', (83, 86))	('vhl', 'Gene', (20, 23))	('RCC', 'Disease', (132, 135))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (130, 135))	('vhl', 'Gene', '7428', (20, 23))	('VHL', 'Gene', '7428', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('pVHL', 'Gene', '7428', (82, 86))	('VHL', 'Gene', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('pVHL', 'Gene', (82, 86))	('Inactivation', 'Var', (0, 12))	('VHL', 'Gene', (83, 86))
191741	29481555	Thus, the absence of pVHL results in HIF stabilization, increased target expression irrespective of the oxygen concentration and gives a proliferative advantage to tumor cells.	('pVHL', 'Gene', (21, 25))	('tumor', 'Disease', (164, 169))	('increased', 'PosReg', (56, 65))	('oxygen', 'Chemical', 'MESH:D010100', (104, 110))	('proliferative advantage', 'CPA', (137, 160))	('target expression', 'MPA', (66, 83))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('absence', 'Var', (10, 17))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('pVHL', 'Gene', '7428', (21, 25))	('HIF stabilization', 'MPA', (37, 54))
191814	29481555	The same results were found with the TCGA cohort, high GLUT1 mRNA (median survival: 79.5 months vs not reached, p = 0.004) and high MCT1 mRNA (median survival: 79.5 months vs not reached, p = 0.007) correlated with shorter OS (S3 Fig).	('high', 'Var', (127, 131))	('MCT', 'biological_process', 'GO:0120197', ('132', '135'))	('MCT1', 'Gene', (132, 136))	('GLUT1', 'Gene', (55, 60))	('MCT1', 'Gene', '6566', (132, 136))	('GLUT1', 'Gene', '6513', (55, 60))
191821	29481555	Moreover, high expression of GLUT1 correlated with poor OS in our small cohort (43 patients).	('poor OS', 'Disease', (51, 58))	('high', 'Var', (10, 14))	('patients', 'Species', '9606', (83, 91))	('GLUT1', 'Gene', (29, 34))	('GLUT1', 'Gene', '6513', (29, 34))
191823	29481555	Overexpression of CAIX is also common in solid cancers and is a poor prognostic factor, except in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('common', 'Reg', (31, 37))	('CAIX', 'Gene', '768', (18, 22))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('solid cancers', 'Disease', (41, 54))	('Overexpression', 'Var', (0, 14))	('solid cancers', 'Disease', 'MESH:D009369', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('CAIX', 'Gene', (18, 22))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))
191839	29481555	Several scenarios could be proposed to explain these differences: (i) As ccRCC is defined by the inactivation of the vhl gene and thus by stabilization of HIF-alpha isoforms, different gene profils could be observed depending on which HIF-alpha isoform is stabilized.	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('vhl', 'Gene', (117, 120))	('inactivation', 'Var', (97, 109))	('vhl', 'Gene', '7428', (117, 120))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))
191894	32435157	As a brand new class of transcripts absent of potential coding proteins, long non-coding RNAs (lncRNAs) have been demonstrated to be critically involved in the tumorigenesis, tumor progression and tumor immune response.	('tumor', 'Disease', (175, 180))	('long non-coding RNAs', 'Var', (73, 93))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('involved', 'Reg', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('immune response', 'biological_process', 'GO:0006955', ('203', '218'))	('tumor', 'Disease', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', (197, 202))
191927	32435157	By COX Regression model, we then identified 7 IRlncRs which were associated with prognosis (sIRlncRs), such as AC008669.1, AL136295.7, AC002553.1, AC026356.2, ATP1A1-AS1, IL10RB-DT and MELTF-AS1.	('AS1', 'Gene', '5729', (166, 169))	('AS1', 'Gene', (166, 169))	('MELTF-AS1', 'Gene', '100507057', (185, 194))	('AC026356.2', 'Var', (147, 157))	('AC008669.1', 'Var', (111, 121))	('AS1', 'Gene', '5729', (191, 194))	('AC002553.1', 'Var', (135, 145))	('AS1', 'Gene', (191, 194))	('MELTF-AS1', 'Gene', (185, 194))	('IL10', 'molecular_function', 'GO:0005141', ('171', '175'))	('prognosis', 'Disease', (81, 90))	('ATP1A1', 'Gene', '476', (159, 165))	('IL10RB', 'Gene', '3588', (171, 177))	('ATP1A1', 'Gene', (159, 165))	('AL136295.7', 'Var', (123, 133))	('IL10RB', 'Gene', (171, 177))
191942	32435157	In the present study, 611 patients with ccRCC were included in a genome-wide analysis for lncRNAs, combining with 311 IRGs screened in Molecular Signatures Database v4.0 (Immune system process M13664, Immune response M19817), 39 IRlncRs were identified eventually.	('M13664', 'Var', (193, 199))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('patients', 'Species', '9606', (26, 34))	('Immune system process', 'biological_process', 'GO:0002376', ('171', '192'))	('Immune response', 'biological_process', 'GO:0006955', ('201', '216'))	('RCC', 'Disease', (42, 45))	('M19817', 'Var', (217, 223))
191950	32435157	highlighted the predicted value of nine IRlncRs (AL138966.2, AL133520.1, AC142472.1, AC127024.5, AC116913.1, AC083880.1, AC124016.1, AC008443.5, and AC092171.5) in pancreatic cancer.	('pancreatic cancer', 'Disease', (164, 181))	('AC116913.1', 'Var', (97, 107))	('AC142472.1', 'Var', (73, 83))	('pancreatic cancer', 'Disease', 'MESH:D010190', (164, 181))	('AL138966', 'Chemical', '-', (49, 57))	('AL138966.2', 'Var', (49, 59))	('AC127024.5', 'Var', (85, 95))	('AC092171.5', 'Var', (149, 159))	('AL133520', 'Chemical', '-', (61, 69))	('AC124016.1', 'Var', (121, 131))	('AC008443.5', 'Var', (133, 143))	('AC083880.1', 'Var', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (164, 181))	('AL133520.1', 'Var', (61, 71))
191982	28809959	Imbalance in components of RAS has been associated with several chronic pathologies, including cancer.	('Imbalance', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Imbalance', 'Phenotype', 'HP:0002172', (0, 9))	('associated', 'Reg', (40, 50))
192019	28809959	Substrate specificity was checked by inhibition assays with captopril for ACE and DX600 for ACE2.	('ACE2', 'Gene', (92, 96))	('DX600', 'Var', (82, 87))	('ACE', 'Gene', '1636', (74, 77))	('ACE', 'Gene', '1636', (92, 95))	('DX600', 'Chemical', '-', (82, 87))	('ACE', 'Gene', (74, 77))	('ACE2', 'Gene', '59272', (92, 96))	('ACE', 'Gene', (92, 95))	('captopril', 'Chemical', 'MESH:D002216', (60, 69))
192023	28809959	Mann-Whitney U test (Mann-U) was used to detect differences in serum enzyme activity from RCC patients and their controls, and from patients with CCRCCs with different tumor size (more or less than 7cm), grade [G1/2 (low) vs. G3/4 (high)] and stage [pT1/2 (organ confined) vs. pT3/4 (non-organ confined)].	('RCC', 'Disease', (148, 151))	('patients', 'Species', '9606', (94, 102))	('tumor', 'Disease', (168, 173))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('pT3/4', 'Gene', (277, 282))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('pT3/4', 'Gene', '7694', (277, 282))	('G3/4', 'Var', (226, 230))	('pT1/2', 'Gene', '58492', (250, 255))	('enzyme activity', 'molecular_function', 'GO:0003824', ('69', '84'))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('pT1/2', 'Gene', (250, 255))	('patients', 'Species', '9606', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('RCC', 'Disease', (90, 93))
192069	28809959	Thus, lower ACE activity was observed in serum from patients with high grades (G1/G2 717.38 +- 187.94 vs G3/G4 634,5 +- 192,592; Mann-U p = 0.029) and metastatic CCRCC (local disease 706,1 +- 192,81 vs metastatic disease 565.18 +- 147.05; Mann-U p = 0.009).	('lower', 'NegReg', (6, 11))	('ACE', 'Gene', (12, 15))	('ACE activity', 'molecular_function', 'GO:0004246', ('12', '24'))	('G1/G2', 'Var', (79, 84))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('RCC', 'Disease', (164, 167))	('ACE', 'Gene', '1636', (12, 15))	('patients', 'Species', '9606', (52, 60))
192074	28809959	Thus, when serum NEP/CD10 activity was lower than 7350 UP/L, the overall survival was significantly worse according to Kaplan-Meier curves (Fig 6A) (log-rank, p = 0,007).	('7350 UP/L', 'Var', (50, 59))	('CD10', 'molecular_function', 'GO:0004245', ('21', '25'))	('overall survival', 'CPA', (65, 81))	('NEP', 'Gene', '4311', (17, 20))	('NEP', 'Gene', (17, 20))	('serum', 'MPA', (11, 16))	('worse', 'NegReg', (100, 105))	('CD10', 'Gene', (21, 25))	('lower', 'NegReg', (39, 44))	('CD10', 'Gene', '4311', (21, 25))
192081	28809959	Increasing evidence demonstrates that imbalances in RAS favoring the ACE-Ang II-AT1 receptor axis play a critical role in vascular endothelial growth factor (VEGF)-dependent angiogenesis.	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('122', '156'))	('vascular endothelial growth factor', 'Gene', (122, 156))	('VEGF', 'Gene', '7422', (158, 162))	('AT1', 'Gene', '185', (80, 83))	('imbalances', 'Phenotype', 'HP:0002172', (38, 48))	('AT1', 'Gene', (80, 83))	('vascular endothelial growth factor', 'Gene', '7422', (122, 156))	('angiogenesis', 'biological_process', 'GO:0001525', ('174', '186'))	('Ang II', 'Gene', '183', (73, 79))	('ACE', 'Gene', '1636', (69, 72))	('Ang II', 'Gene', (73, 79))	('ACE', 'Gene', (69, 72))	('VEGF', 'Gene', (158, 162))	('imbalances', 'Var', (38, 48))	('imbalance', 'Phenotype', 'HP:0002172', (38, 47))
192083	28809959	Recent studies in xenograft models of human RCC have showed that the blockade of this axis with ACEi and ARB decreases tumor diameter, vascularization and metastatic capacity, and enhances the antiangiogenic effect of sunitinib.	('enhances', 'PosReg', (180, 188))	('human', 'Species', '9606', (38, 43))	('ARB decreases tumor', 'Disease', 'MESH:C567518', (105, 124))	('ARB decreases tumor', 'Disease', (105, 124))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('metastatic capacity', 'CPA', (155, 174))	('RCC', 'Disease', (44, 47))	('vascularization', 'CPA', (135, 150))	('ACE', 'Gene', '1636', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('sunitinib', 'Chemical', 'MESH:D000077210', (218, 227))	('blockade', 'Var', (69, 77))	('ACE', 'Gene', (96, 99))	('antiangiogenic effect', 'CPA', (193, 214))
192114	28809959	On the other, NEP/CD10 activity was lower in serum of CCRCC patients with high UISS and SSIGN scores.	('lower', 'NegReg', (36, 41))	('CD10', 'Gene', '4311', (18, 22))	('RCC', 'Disease', (56, 59))	('CD10', 'Gene', (18, 22))	('high', 'Var', (74, 78))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('patients', 'Species', '9606', (60, 68))	('NEP', 'Gene', '4311', (14, 17))	('NEP', 'Gene', (14, 17))	('CD10', 'molecular_function', 'GO:0004245', ('18', '22'))
192124	28809959	In conclusion, the present study shows that ACE in tumor vessels and APA, ACE2 and NEP/CD10 in tumor cells are differentially expressed in different renal tumor subtypes, and that the presence/abscense of these enzymes is significantly associated with tumor aggressiveness and poor outcome of patients with CCRCC.	('presence/abscense', 'Var', (184, 201))	('RCC', 'Disease', 'MESH:C538614', (309, 312))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('tumor', 'Disease', (155, 160))	('CD10', 'molecular_function', 'GO:0004245', ('87', '91'))	('NEP', 'Gene', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (252, 272))	('ACE2', 'Gene', '59272', (74, 78))	('tumor', 'Disease', (51, 56))	('renal tumor', 'Phenotype', 'HP:0009726', (149, 160))	('APA', 'Gene', (69, 72))	('renal tumor', 'Disease', 'MESH:D007674', (149, 160))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('renal tumor', 'Disease', (149, 160))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('ACE2', 'Gene', (74, 78))	('CD10', 'Gene', '4311', (87, 91))	('ACE', 'Gene', '1636', (44, 47))	('ACE', 'Gene', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('NEP', 'Gene', '4311', (83, 86))	('associated with', 'Reg', (236, 251))	('RCC', 'Disease', (309, 312))	('tumor', 'Disease', (95, 100))	('CD10', 'Gene', (87, 91))	('ACE', 'Gene', '1636', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ACE', 'Gene', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('APA', 'Gene', '2028', (69, 72))	('aggressiveness', 'Phenotype', 'HP:0000718', (258, 272))	('tumor aggressiveness', 'Disease', (252, 272))	('tumor', 'Disease', (252, 257))	('patients', 'Species', '9606', (293, 301))
192185	33613617	Although prior work has shown an association between the number of mutations and outcomes in ccRCC, no distinctions have been made between patients who were diagnosed with metastatic disease and patients who were diagnosed with localized disease (Hsieh et al.,).	('patients', 'Species', '9606', (139, 147))	('Hsieh', 'Disease', (247, 252))	('mutations', 'Var', (67, 76))	('patients', 'Species', '9606', (195, 203))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('ccRCC', 'Disease', (93, 98))	('localized disease', 'Disease', (228, 245))	('localized disease', 'Disease', 'MESH:D012594', (228, 245))	('Hsieh', 'Disease', 'None', (247, 252))
192186	33613617	However, those tumors that progress at relapse or metastatic sites may have accumulated additional genomic mutations over time, and this hypothesis is supported by data from other cancer subtypes (Yates et al.,).	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('genomic', 'Var', (99, 106))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
192197	33613617	Loss of E-cadherin promotes metastasis by inducing disaggregation of cancer cells, activating specific downstream signal transduction pathways, and causing epithelial-mesenchymal transition (EMT), which facilitate metastasis.	('facilitate', 'PosReg', (203, 213))	('inducing', 'Reg', (42, 50))	('metastasis', 'CPA', (214, 224))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('156', '189'))	('downstream signal transduction pathways', 'Pathway', (103, 142))	('signal transduction', 'biological_process', 'GO:0007165', ('114', '133'))	('causing', 'Reg', (148, 155))	('metastasis', 'CPA', (28, 38))	('cadherin', 'molecular_function', 'GO:0008014', ('10', '18'))	('disaggregation', 'CPA', (51, 65))	('promotes', 'PosReg', (19, 27))	('Loss', 'Var', (0, 4))	('cancer', 'Disease', (69, 75))	('E-cadherin', 'Gene', (8, 18))	('E-cadherin', 'Gene', '999', (8, 18))	('EMT', 'biological_process', 'GO:0001837', ('191', '194'))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('activating', 'PosReg', (83, 93))	('epithelial-mesenchymal transition', 'CPA', (156, 189))
192209	31428643	Moreover, knockdown of Vimentin inhibited cell migration and invasion, which could be prompted by hypoxia induction in RCC cells.	('cell migration', 'CPA', (42, 56))	('cell migration', 'biological_process', 'GO:0016477', ('42', '56'))	('hypoxia', 'Disease', (98, 105))	('inhibited', 'NegReg', (32, 41))	('hypoxia', 'Disease', 'MESH:D000860', (98, 105))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('Vimentin', 'Gene', (23, 31))	('RCC', 'Disease', (119, 122))	('Vimentin', 'cellular_component', 'GO:0045098', ('23', '31'))	('knockdown', 'Var', (10, 19))	('Vimentin', 'cellular_component', 'GO:0045099', ('23', '31'))	('Vimentin', 'Gene', '7431', (23, 31))
192211	31428643	In conclusion, Vimentin plays an important role in hypoxia induced VM formation of RCC cells and targeted Vimentin might be beneficial for RCC therapy.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('Vimentin', 'cellular_component', 'GO:0045099', ('15', '23'))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('Vimentin', 'Gene', '7431', (106, 114))	('Vimentin', 'cellular_component', 'GO:0045099', ('106', '114'))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('Vimentin', 'Gene', (15, 23))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('targeted', 'Var', (97, 105))	('Vimentin', 'cellular_component', 'GO:0045098', ('106', '114'))	('Vimentin', 'cellular_component', 'GO:0045098', ('15', '23'))	('formation', 'biological_process', 'GO:0009058', ('70', '79'))	('hypoxia', 'Disease', (51, 58))	('Vimentin', 'Gene', '7431', (15, 23))	('hypoxia', 'Disease', 'MESH:D000860', (51, 58))	('Vimentin', 'Gene', (106, 114))
192235	31428643	The observation time for 786-O and 769-P was 4h, and for OS-RC-2 it was between 24 and 72h.	('786-O', 'Var', (25, 30))	('OS-RC-2', 'Chemical', '-', (57, 64))	('769-P', 'Var', (35, 40))
192241	31428643	The details of antibodies using here were as follows: Vimentin (1:1000, CST, USA); AXL (1:1000, Abcam, USA); E-cadherin (1:1000, CST, USA); beta-actin (1:5000, Abbkine, USA).	('CST', 'Gene', (129, 132))	('CST', 'Gene', '106478911', (72, 75))	('AXL', 'Gene', (83, 86))	('1:1000', 'Var', (121, 127))	('Vimentin', 'cellular_component', 'GO:0045098', ('54', '62'))	('Vimentin', 'Gene', (54, 62))	('E-cadherin', 'Gene', (109, 119))	('1:1000', 'Var', (88, 94))	('E-cadherin', 'Gene', '999', (109, 119))	('beta-actin', 'Gene', '728378', (140, 150))	('beta-actin', 'Gene', (140, 150))	('CST', 'Gene', (72, 75))	('CST', 'Gene', '106478911', (129, 132))	('AXL', 'Gene', '558', (83, 86))	('cadherin', 'molecular_function', 'GO:0008014', ('111', '119'))	('Vimentin', 'Gene', '7431', (54, 62))	('1:5000', 'Var', (152, 158))	('Vimentin', 'cellular_component', 'GO:0045099', ('54', '62'))
192270	31428643	As shown in Figure 3, the expression levels of Vimentin were significantly higher in 786-O and 769-P in comparison with in OS-RC-2 under normoxia.	('Vimentin', 'Gene', '7431', (47, 55))	('769-P in', 'Var', (95, 103))	('OS-RC-2', 'Chemical', '-', (123, 130))	('higher', 'PosReg', (75, 81))	('Vimentin', 'cellular_component', 'GO:0045098', ('47', '55'))	('786-O', 'Var', (85, 90))	('Vimentin', 'cellular_component', 'GO:0045099', ('47', '55'))	('Vimentin', 'Gene', (47, 55))	('expression levels', 'MPA', (26, 43))
192275	31428643	In 786-O, reduction of VM and cell invasion and migration by knocking down the expressions of Vimentin could be overturned by induction of cell hypoxia (Figures 4(b), 4(d), and 4(f)).	('Vimentin', 'Gene', (94, 102))	('Vimentin', 'cellular_component', 'GO:0045098', ('94', '102'))	('hypoxia', 'Disease', (144, 151))	('expressions', 'MPA', (79, 90))	('hypoxia', 'Disease', 'MESH:D000860', (144, 151))	('Vimentin', 'Gene', '7431', (94, 102))	('Vimentin', 'cellular_component', 'GO:0045099', ('94', '102'))	('reduction', 'NegReg', (10, 19))	('knocking', 'Var', (61, 69))
192279	31428643	Moreover, by knocking down the expression of Vimentin, we observed the reduced AXL was accompanied with the upraised E-cadherin (Figure 5).	('Vimentin', 'Gene', (45, 53))	('AXL', 'Gene', (79, 82))	('Vimentin', 'cellular_component', 'GO:0045098', ('45', '53'))	('Vimentin', 'Gene', '7431', (45, 53))	('E-cadherin', 'Gene', '999', (117, 127))	('AXL', 'Gene', '558', (79, 82))	('expression', 'MPA', (31, 41))	('reduced', 'NegReg', (71, 78))	('Vimentin', 'cellular_component', 'GO:0045099', ('45', '53'))	('cadherin', 'molecular_function', 'GO:0008014', ('119', '127'))	('E-cadherin', 'Gene', (117, 127))	('upraised', 'PosReg', (108, 116))	('knocking', 'Var', (13, 21))
192290	31428643	Kaplan-Meier survival analysis revealed that VM positive patients and those with Vimentin overexpression had shorter OS than those without VM and Vimentin overexpression (Figure 6(c)).	('Vimentin', 'Gene', '7431', (81, 89))	('Vimentin', 'Gene', (146, 154))	('patients', 'Species', '9606', (57, 65))	('overexpression', 'Var', (90, 104))	('Vimentin', 'cellular_component', 'GO:0045099', ('81', '89'))	('Vimentin', 'cellular_component', 'GO:0045098', ('146', '154'))	('Vimentin', 'cellular_component', 'GO:0045099', ('146', '154'))	('Vimentin', 'Gene', '7431', (146, 154))	('Vimentin', 'cellular_component', 'GO:0045098', ('81', '89'))	('Vimentin', 'Gene', (81, 89))	('shorter', 'NegReg', (109, 116))
192298	31428643	These changes triggered a cascade of cellular responses and finally may result in the formation of VM by invasive cancer cells through remodeling of external cellular matrix (ECM).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('triggered', 'Reg', (14, 23))	('cellular responses', 'CPA', (37, 55))	('formation', 'biological_process', 'GO:0009058', ('86', '95'))	('changes', 'Var', (6, 13))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('result in', 'Reg', (72, 81))	('cancer', 'Disease', (114, 120))
192306	31428643	In the present study, we found that, by knocking down the expression of Vimentin with siRNA, cell invasion and migration and VM structures were significantly impaired in RCC cell lines in vitro.	('expression', 'MPA', (58, 68))	('RCC', 'Disease', (170, 173))	('Vimentin', 'Gene', (72, 80))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('Vimentin', 'cellular_component', 'GO:0045098', ('72', '80'))	('Vimentin', 'Gene', '7431', (72, 80))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('knocking', 'Var', (40, 48))	('impaired', 'NegReg', (158, 166))	('Vimentin', 'cellular_component', 'GO:0045099', ('72', '80'))
192334	27766604	Macroscopically, factors involved are individual cancer patient's race, gender, age, and the organ/tissue origin of contracted cancer; microscopically, factors are histology and tumor microenvironment; and molecularly, factors are genetics and epigenetics.	('tumor', 'Disease', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('epigenetics', 'Var', (244, 255))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('cancer', 'Disease', (127, 133))	('patient', 'Species', '9606', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('cancer', 'Disease', (49, 55))
192341	27766604	Cancer cell originates from the same copy of DNA as its host and acquires new capability through mutations.	('mutations', 'Var', (97, 106))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
192348	27766604	Both ITH and IMH thrive on diversifying through mutations and epigenetic changes, which can be viewed as an individual ever-branching cancer tree.	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('epigenetic changes', 'Var', (62, 80))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('mutations', 'Var', (48, 57))
192349	27766604	The trunk-branch model concerning ITH and IMH pinpoints the strategy for effective cancer control through targeting "trunk" lesions, explaining the known success of multiple kinase inhibitors in treating certain human cancers bearing truncal activating mutations at respective kinases.	('truncal activating mutations', 'Var', (234, 262))	('human', 'Species', '9606', (212, 217))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', (218, 224))	('cancers', 'Disease', 'MESH:D009369', (218, 225))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('trunk', 'cellular_component', 'GO:0043198', ('116', '121'))	('cancers', 'Disease', (218, 225))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('trunk', 'cellular_component', 'GO:0043198', ('4', '9'))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
192358	27766604	For example, two distinct and spatially separate mutations in TSC1 and MTOR, along the PI3 K/AKT/mTOR pathway, that activate mTOR kinase through different mechanisms were detected in different regions of the same tumor.	('tumor', 'Disease', (213, 218))	('activate', 'PosReg', (116, 124))	('mTOR', 'Gene', '2475', (125, 129))	('mutations', 'Var', (49, 58))	('mTOR', 'Gene', '2475', (97, 101))	('AKT', 'Gene', (93, 96))	('mTOR', 'Gene', (97, 101))	('mTOR', 'Gene', (125, 129))	('MTOR', 'Gene', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('MTOR', 'Gene', '2475', (71, 75))	('TSC1', 'Gene', '7248', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('PI3 K', 'molecular_function', 'GO:0016303', ('87', '92'))	('AKT', 'Gene', '207', (93, 96))	('TSC1', 'Gene', (62, 66))
192362	27766604	The heterogeneous mutations previously ascribed to the branches of tree become tributaries along the river, which retain the capability to become driver mutations and converge with other spatially or temporally distinct mutations that affect the same genes or components along critical oncogenic or tumor suppressor pathways inherent to a given cancer type.	('cancer type', 'Disease', 'MESH:D009369', (345, 356))	('tumor', 'Disease', (299, 304))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('tumor suppressor', 'biological_process', 'GO:0051726', ('299', '315'))	('oncogenic', 'Pathway', (286, 295))	('cancer type', 'Disease', (345, 356))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('299', '315'))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('mutations', 'Var', (220, 229))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('mutations', 'Var', (18, 27))
192369	32410406	CT-Based Radiomics Signature for Preoperative Prediction of Coagulative Necrosis in Clear Cell Renal Cell Carcinoma The presence of coagulative necrosis (CN) in clear cell renal cell carcinoma (ccRCC) indicates a poor prognosis, while the absence of CN indicates a good prognosis.	('necrosis', 'biological_process', 'GO:0008220', ('144', '152'))	('necrosis', 'Disease', 'MESH:D009336', (144, 152))	('Necrosis', 'biological_process', 'GO:0019835', ('72', '80'))	('Necrosis', 'biological_process', 'GO:0008220', ('72', '80'))	('RCC', 'Disease', 'MESH:C538614', (196, 199))	('presence', 'Var', (120, 128))	('Clear Cell Renal Cell Carcinoma', 'Disease', (84, 115))	('clear cell renal cell carcinoma', 'Disease', (161, 192))	('CN', 'Phenotype', 'HP:0010885', (250, 252))	('necrosis', 'biological_process', 'GO:0070265', ('144', '152'))	('necrosis', 'Disease', (144, 152))	('CN', 'Phenotype', 'HP:0010885', (154, 156))	('necrosis', 'biological_process', 'GO:0019835', ('144', '152'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (172, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('Necrosis', 'biological_process', 'GO:0001906', ('72', '80'))	('necrosis', 'biological_process', 'GO:0001906', ('144', '152'))	('Necrosis', 'biological_process', 'GO:0070265', ('72', '80'))	('Coagulative Necrosis', 'Disease', (60, 80))	('coagulative necrosis', 'Phenotype', 'HP:0010885', (132, 152))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (84, 115))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (95, 115))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (161, 192))	('Carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('Necrosis', 'biological_process', 'GO:0008219', ('72', '80'))	('Coagulative Necrosis', 'Disease', 'MESH:D001778', (60, 80))	('necrosis', 'biological_process', 'GO:0008219', ('144', '152'))	('RCC', 'Disease', (196, 199))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (84, 115))	('Coagulative Necrosis', 'Phenotype', 'HP:0010885', (60, 80))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (161, 192))	('RCC', 'Phenotype', 'HP:0005584', (196, 199))	('ccRCC', 'Phenotype', 'HP:0006770', (194, 199))
192460	30588036	RASSF1A promoter methylation correlated with RCC in tissue, blood, and urine samples.	('RASSF1A', 'Gene', (0, 7))	('correlated', 'Reg', (29, 39))	('methylation', 'Var', (17, 28))	('RASSF1A', 'Gene', '11186', (0, 7))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))
192461	30588036	On multivariate analysis, RASSF1A promoter methylation was associated with tumor grade (grade 3-4 vs 1-2: OR=3.59), clinical stage (stage 3-4 vs 1-2: OR=2.15), T classification (pT2-4 vs pT1: OR=2.66), histologic subtypes (papillary vs clear cell: OR=2.91), and cancer-specific survival (HR=1.78), but it was not linked to age, gender, lymph node status, distant metastasis, or overall survival.	('cancer', 'Disease', (262, 268))	('pT1', 'Gene', '58492', (187, 190))	('RASSF1A', 'Gene', '11186', (26, 33))	('methylation', 'Var', (43, 54))	('methylation', 'biological_process', 'GO:0032259', ('43', '54'))	('T classification', 'CPA', (160, 176))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('associated', 'Reg', (59, 69))	('pT1', 'Gene', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('RASSF1A', 'Gene', (26, 33))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('tumor', 'Disease', (75, 80))
192462	30588036	The Cancer Genome Atlas data also showed that RASSF1A methylation was significantly more likely to be seen in papillary vs clear-cell RCC (OR=23.19).	('RASSF1A', 'Gene', '11186', (46, 53))	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('methylation', 'Var', (54, 65))	('papillary', 'Disease', (110, 119))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('RCC', 'Disease', (134, 137))	('RASSF1A', 'Gene', (46, 53))	('seen', 'Reg', (102, 106))
192463	30588036	RASSF1A promoter methylation may be associated with the development and progression of RCC, as well as poor cancer-specific survival.	('RASSF1A', 'Gene', (0, 7))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('methylation', 'Var', (17, 28))	('RASSF1A', 'Gene', '11186', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('associated with', 'Reg', (36, 51))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
192464	30588036	Methylation was more frequent in papillary vs clear-cell RCC.	('Methylation', 'Var', (0, 11))	('papillary', 'Disease', (33, 42))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('frequent', 'Reg', (21, 29))
192471	30588036	DNA methylation within the promoter regions is an important mechanism underlying epigenetic modifications, which may cause inactivation of gene expression and play a crucial role in the carcinogenesis, progression, and prognosis of various human cancers.	('gene expression', 'MPA', (139, 154))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('cancers', 'Disease', (246, 253))	('human', 'Species', '9606', (240, 245))	('cancers', 'Disease', 'MESH:D009369', (246, 253))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('methylation', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('carcinogenesis', 'Disease', 'MESH:D063646', (186, 200))	('inactivation', 'MPA', (123, 135))	('gene expression', 'biological_process', 'GO:0010467', ('139', '154'))	('epigenetic modifications', 'Var', (81, 105))	('carcinogenesis', 'Disease', (186, 200))
192475	30588036	RASSF1A promoter methylation has been reported in tissue, blood, and urine samples from patients with RCC.	('RASSF1A', 'Gene', (0, 7))	('patients', 'Species', '9606', (88, 96))	('methylation', 'Var', (17, 28))	('RASSF1A', 'Gene', '11186', (0, 7))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))
192478	30588036	In contrast, RASSF1A promoter methylation was more frequent in RCC than in adjacent normal tissue samples in a study by Loginov et al.	('promoter', 'MPA', (21, 29))	('RCC', 'Disease', (63, 66))	('RASSF1A', 'Gene', (13, 20))	('methylation', 'Var', (30, 41))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('RASSF1A', 'Gene', '11186', (13, 20))	('frequent', 'Reg', (51, 59))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
192481	30588036	The following keywords and scientific search terms were used: (kidney OR renal) AND (cancer OR tumor OR neoplasm OR carcinoma) AND (methylation OR methylated OR hypermethylation OR epigene*) AND (RAS association domain family protein 1A OR RASSF1A OR RASSF1 OR RAS association domain family protein 1).	('neoplasm OR carcinoma', 'Disease', 'MESH:D009369', (104, 125))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('protein', 'cellular_component', 'GO:0003675', ('291', '298'))	('neoplasm OR carcinoma', 'Disease', (104, 125))	('RASSF1', 'Gene', '11186', (251, 257))	('RASSF1A', 'Gene', '11186', (240, 247))	('methylation', 'biological_process', 'GO:0032259', ('132', '143'))	('methylation', 'Var', (132, 143))	('RASSF1', 'Gene', (251, 257))	('RASSF1A', 'Gene', (240, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Disease', (95, 100))	('protein', 'cellular_component', 'GO:0003675', ('226', '233'))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('RASSF1', 'Gene', '11186', (240, 246))	('epigene*', 'Var', (181, 189))	('kidney OR renal) AND (cancer', 'Disease', 'MESH:D007680', (63, 91))	('RASSF1', 'Gene', (240, 246))
192503	30588036	In four studies that included the comparison of 237 patients with RCC with 142 nonmalignant blood samples, RASSF1A promoter methylation was significantly more likely in RCC than in nonmalignant blood samples (OR=11.70, 95% CI=4.82-28.39, P<0.001; Figure 2).	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('OR=11.70', 'Gene', '255725', (209, 217))	('methylation', 'biological_process', 'GO:0032259', ('124', '135'))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('RCC', 'Disease', (169, 172))	('likely', 'Reg', (159, 165))	('RASSF1A', 'Gene', (107, 114))	('OR=11.70', 'Gene', (209, 217))	('RASSF1A', 'Gene', '11186', (107, 114))	('RCC', 'Disease', (66, 69))	('methylation', 'Var', (124, 135))	('patients', 'Species', '9606', (52, 60))
192508	30588036	Four studies that included 257 patients with RCC showed that there was no correlation between RASSF1A promoter methylation and distant metastasis (OR=1.66, 95% CI=0.75-3.69, P=0.21; Figure 4).	('methylation', 'Var', (111, 122))	('RASSF1A', 'Gene', (94, 101))	('methylation', 'biological_process', 'GO:0032259', ('111', '122'))	('patients', 'Species', '9606', (31, 39))	('RASSF1A', 'Gene', '11186', (94, 101))	('distant metastasis', 'CPA', (127, 145))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))
192509	30588036	In 13 studies that included 686 patients with RCC, a significant relationship was observed between RASSF1A promoter methylation and tumor grade (OR=3.59, 95% CI=1.85-6.95, P<0.001; Figure 5).	('patients', 'Species', '9606', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('RCC', 'Disease', (46, 49))	('RASSF1A', 'Gene', '11186', (99, 106))	('methylation', 'Var', (116, 127))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('methylation', 'biological_process', 'GO:0032259', ('116', '127'))	('RASSF1A', 'Gene', (99, 106))
192510	30588036	RASSF1A promoter methylation was also linked to clinical stage in eight studies that included 463 patients with RCC (OR=2.15, 95% CI=1.34-3.45, P=0.001; Figure 5).	('RASSF1A', 'Gene', (0, 7))	('linked', 'Reg', (38, 44))	('methylation', 'Var', (17, 28))	('patients', 'Species', '9606', (98, 106))	('RCC', 'Disease', (112, 115))	('RASSF1A', 'Gene', '11186', (0, 7))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('RCC', 'Disease', 'MESH:C538614', (112, 115))
192511	30588036	In seven studies that included 306 patients with RCC, a significant correlation was found between RASSF1A promoter methylation and T classification (OR=2.66, 95% CI=1.11-6.39, P=0.029; Figure 6).	('RCC', 'Disease', (49, 52))	('methylation', 'Var', (115, 126))	('RASSF1A', 'Gene', '11186', (98, 105))	('T classification', 'Disease', (131, 147))	('methylation', 'biological_process', 'GO:0032259', ('115', '126'))	('patients', 'Species', '9606', (35, 43))	('RASSF1A', 'Gene', (98, 105))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
192520	30588036	After adjusting for tumor stage (stage 3-4 vs stage 1-2) and tumor histology (pRCC vs ccRCC), RASSF1A promoter methylation was not associated with overall survival using multivariate analysis (HR=0.921, P=0.687) in 567 RCCs.	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('RCC', 'Disease', (219, 222))	('methylation', 'Var', (111, 122))	('pRCC', 'Gene', '5546', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('RCC', 'Disease', 'MESH:C538614', (219, 222))	('RCC', 'Disease', (88, 91))	('associated', 'Reg', (131, 141))	('methylation', 'biological_process', 'GO:0032259', ('111', '122'))	('RASSF1A', 'Gene', '11186', (94, 101))	('RCC', 'Disease', (79, 82))	('tumor', 'Disease', (61, 66))	('pRCC', 'Gene', (78, 82))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RASSF1A', 'Gene', (94, 101))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('tumor', 'Disease', (20, 25))
192522	30588036	Tumor suppressor genes are commonly inactivated via promoter methylation within the CpG islands, which may affect several biological processes, including cell proliferation, cell death, cell migration, and cell invasion, and contribute to the initiation and progression of human cancers.	('cell proliferation', 'CPA', (154, 172))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor suppressor genes', 'Gene', (0, 22))	('cell migration', 'CPA', (186, 200))	('cancers', 'Phenotype', 'HP:0002664', (279, 286))	('cell migration', 'biological_process', 'GO:0016477', ('186', '200'))	('cancers', 'Disease', (279, 286))	('affect', 'Reg', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('promoter methylation', 'Var', (52, 72))	('contribute', 'Reg', (225, 235))	('biological processes', 'CPA', (122, 142))	('cell death', 'CPA', (174, 184))	('cancers', 'Disease', 'MESH:D009369', (279, 286))	('Tumor suppressor', 'molecular_function', 'GO:0008181', ('0', '16'))	('cell death', 'biological_process', 'GO:0008219', ('174', '184'))	('cell invasion', 'CPA', (206, 219))	('cell proliferation', 'biological_process', 'GO:0008283', ('154', '172'))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('inactivated', 'NegReg', (36, 47))	('Tumor suppressor', 'biological_process', 'GO:0051726', ('0', '16'))	('human', 'Species', '9606', (273, 278))
192523	30588036	Studies have indicated that methylation of the promoter of the tumor suppressor gene RASSF1A reduces its expression, which may play an important role in RCC carcinogenesis.	('RASSF1A', 'Gene', (85, 92))	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('63', '79'))	('RASSF1A', 'Gene', '11186', (85, 92))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))	('reduces', 'NegReg', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('RCC carcinogenesis', 'Disease', (153, 171))	('RCC carcinogenesis', 'Disease', 'MESH:C538614', (153, 171))	('methylation', 'Var', (28, 39))	('tumor suppressor', 'biological_process', 'GO:0051726', ('63', '79'))	('expression', 'MPA', (105, 115))	('promoter', 'MPA', (47, 55))
192527	30588036	Also, nine other studies showed that RASSF1A promoter methylation correlated positively with RCC.	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('RCC', 'Disease', (93, 96))	('RASSF1A', 'Gene', '11186', (37, 44))	('methylation', 'Var', (54, 65))	('RASSF1A', 'Gene', (37, 44))
192529	30588036	This suggests that RASSF1A promoter methylation is significantly associated with RCC carcinogenesis.	('RASSF1A', 'Gene', '11186', (19, 26))	('RCC carcinogenesis', 'Disease', (81, 99))	('RCC carcinogenesis', 'Disease', 'MESH:C538614', (81, 99))	('associated', 'Reg', (65, 75))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('RASSF1A', 'Gene', (19, 26))	('methylation', 'Var', (36, 47))
192539	30588036	These analyses suggest that RASSF1A promoter methylation may be closely associated with RCC progression.	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('RASSF1A', 'Gene', (28, 35))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('associated', 'Reg', (72, 82))	('methylation', 'Var', (45, 56))	('RASSF1A', 'Gene', '11186', (28, 35))
192547	30588036	In addition, Yu et al did not report whether RASSF1A promoter methylation was linked to clinical features (eg, gender, tumor grade, clinical stage, T classification, histologic subtypes, lymph node metastasis, and distant metastasis) and did not include an analysis of overall survival.	('tumor', 'Disease', (119, 124))	('methylation', 'biological_process', 'GO:0032259', ('62', '73'))	('RASSF1A', 'Gene', (45, 52))	('methylation', 'Var', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('RASSF1A', 'Gene', '11186', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('lymph node metastasis', 'Disease', 'MESH:D009362', (187, 208))	('linked', 'Reg', (78, 84))	('lymph node metastasis', 'Disease', (187, 208))
192552	30588036	The present findings show that RASSF1A promoter methylation correlates with RCC in tissue, blood, and urine samples.	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RASSF1A', 'Gene', (31, 38))	('RASSF1A', 'Gene', '11186', (31, 38))	('methylation', 'Var', (48, 59))
192558	28846693	Microarray processing and analysis was used to explore novel pathways involved in tumorigenesis related to PBRM1 knockdown.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('knockdown', 'Var', (113, 122))	('PBRM1', 'Gene', (107, 112))	('tumor', 'Disease', (82, 87))
192559	28846693	PBRM1 was expressed at high levels in RCC ACHN cells and lentivirus-mediated PBRM1 knockdown in these cells caused an increase in the proportion of cells in S phase of the cell cycle and promoted in vitro proliferation and migration.	('migration', 'CPA', (223, 232))	('RCC', 'Disease', (38, 41))	('PBRM1', 'Gene', (77, 82))	('increase', 'PosReg', (118, 126))	('cell cycle', 'biological_process', 'GO:0007049', ('172', '182'))	('S phase', 'biological_process', 'GO:0051320', ('157', '164'))	('promoted', 'PosReg', (187, 195))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('knockdown', 'Var', (83, 92))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
192561	28846693	In pathway gene chip analysis, the chemokine/chemokine receptor interaction pathway showed the greatest difference in gene expression upon PBRM1 knockdown.	('knockdown', 'Var', (145, 154))	('chemokine receptor', 'Gene', '7852', (45, 63))	('chemokine receptor', 'Gene', (45, 63))	('gene expression', 'MPA', (118, 133))	('gene expression', 'biological_process', 'GO:0010467', ('118', '133'))	('PBRM1', 'Gene', (139, 144))
192567	28846693	Alteration in the von Hippel-Lindau (VHL) gene is the hallmark of ccRCC; however, inactivation of VHL has not been found to consistently correlate with prognostic features of ccRCC.	('von Hippel-Lindau', 'Disease', (18, 35))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('RCC', 'Disease', (177, 180))	('VHL', 'Gene', (37, 40))	('Alteration', 'Var', (0, 10))	('RCC', 'Phenotype', 'HP:0005584', (177, 180))	('VHL', 'Gene', (98, 101))	('VHL', 'Gene', '7428', (37, 40))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (18, 35))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('VHL', 'Gene', '7428', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('inactivation', 'Var', (82, 94))
192568	28846693	Recently, exome sequencing has unveiled additional genes that are mutated in ccRCC, including PBRM1, BAP1, and SETD2.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('mutated', 'Var', (66, 73))	('BAP1', 'Gene', '8314', (101, 105))	('BAP1', 'Gene', (101, 105))	('SETD2', 'Gene', '29072', (111, 116))	('PBRM1', 'Gene', (94, 99))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('SETD2', 'Gene', (111, 116))	('RCC', 'Disease', (79, 82))
192571	28846693	Mutations in SWI/SNF, and the subsequent abnormal function of SWI/SNF complexes, are among the most frequent gene alterations in cancer.	('SWI/SNF', 'Gene', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('Mutations', 'Var', (0, 9))
192572	28846693	In ccRCC, the majority of PBRM1 mutations lead to loss of the protein.	('protein', 'Protein', (62, 69))	('PBRM1', 'Gene', (26, 31))	('loss', 'NegReg', (50, 54))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('mutations', 'Var', (32, 41))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
192578	28846693	We knocked down PBRM1 in ACHN RCC cells using three different PBRM1 RNAi sequences to study the biological functions of PBRM1.	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('RCC', 'Disease', (30, 33))	('knocked', 'Var', (3, 10))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('PBRM1', 'Gene', (16, 21))	('RNAi', 'biological_process', 'GO:0016246', ('68', '72'))
192580	28846693	The growth curve determined from an MTT assay showed that PBRM1 silencing increased the proliferation rate compared with transfection with empty virus (P < 0.05, Fig 2A).	('MTT', 'Chemical', '-', (36, 39))	('proliferation rate', 'CPA', (88, 106))	('PBRM1', 'Gene', (58, 63))	('increased', 'PosReg', (74, 83))	('silencing', 'Var', (64, 73))
192583	28846693	After subcutaneous injection of nude mice with ACHN-KD-PBRM1 and ACHN-EV, tumor volume was measured with a Vernier caliper twice a week.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('nude mice', 'Species', '10090', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('ACHN-KD-PBRM1', 'Var', (47, 60))	('tumor', 'Disease', (74, 79))
192587	28846693	Functional analysis based on the KEGG pathway database revealed that PBRM1 knockdown modulated key pathways, in particular cytokine/cytokine receptor interaction, focal adhesion, pathways in cancer, NOD-like receptor signaling pathway, and MAPK signaling pathway (Fig 4B).	('cytokine receptor', 'Gene', (132, 149))	('cancer', 'Disease', (191, 197))	('MAPK signaling pathway', 'Pathway', (240, 262))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('MAPK signaling', 'biological_process', 'GO:0000165', ('240', '254'))	('focal', 'MPA', (163, 168))	('signaling pathway', 'biological_process', 'GO:0007165', ('245', '262'))	('pathways', 'Pathway', (179, 187))	('cytokine receptor', 'Gene', '8809', (132, 149))	('knockdown', 'Var', (75, 84))	('PBRM1', 'Gene', (69, 74))	('modulated', 'Reg', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('focal adhesion', 'cellular_component', 'GO:0005925', ('163', '177'))	('NOD-like receptor signaling pathway', 'biological_process', 'GO:0035872', ('199', '234'))	('MAPK', 'molecular_function', 'GO:0004707', ('240', '244'))	('NOD-like receptor signaling pathway', 'Pathway', (199, 234))
192588	28846693	Pathway analysis revealed that chemokine/chemokine receptor interaction was the top modulated canonical pathway following PBRM1 knockdown (p<10-12) (Fig 4B).	('PBRM1', 'Gene', (122, 127))	('modulated', 'Reg', (84, 93))	('knockdown', 'Var', (128, 137))	('chemokine receptor', 'Gene', '7852', (41, 59))	('chemokine receptor', 'Gene', (41, 59))	('canonical pathway', 'Pathway', (94, 111))
192589	28846693	Based on a combination of statistical criteria and pathways analysis, we validated the protein expression of several significant pathway-associated genes and confirmed increased protein levels of interleukin (IL)-6ST and CCL2 and decreased protein levels of IL-8, IL-6, and CXCL2 after PBRM1 knockdown (Fig 4D).	('decreased', 'NegReg', (230, 239))	('CCL2', 'Gene', '6347', (221, 225))	('IL)-6', 'molecular_function', 'GO:0005138', ('209', '214'))	('IL-8', 'Gene', '3576', (258, 262))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))	('IL-8', 'molecular_function', 'GO:0005153', ('258', '262'))	('PBRM1', 'Gene', (286, 291))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('IL-6', 'Gene', '3569', (264, 268))	('protein expression', 'MPA', (87, 105))	('protein', 'cellular_component', 'GO:0003675', ('240', '247'))	('CXCL2', 'Gene', '2920', (274, 279))	('protein levels', 'MPA', (178, 192))	('IL-6', 'Gene', (264, 268))	('IL-6', 'molecular_function', 'GO:0005138', ('264', '268'))	('increased', 'PosReg', (168, 177))	('CCL', 'molecular_function', 'GO:0044101', ('221', '224'))	('CCL2', 'Gene', (221, 225))	('IL-8', 'Gene', (258, 262))	('knockdown', 'Var', (292, 301))	('CXCL2', 'Gene', (274, 279))
192590	28846693	PBRM1 re-expression in KD-PBRM1 cells showed favorable infection efficiency(Fig 5A).	('infection efficiency', 'Disease', (55, 75))	('re-expression', 'Var', (6, 19))	('infection efficiency', 'Disease', 'MESH:D007239', (55, 75))	('PBRM1', 'Gene', (0, 5))
192591	28846693	The growth curves determined from MTT assays showed that re-expression of IL-8 decreased the proliferation rate and migration ability of OE+KD-PBRM1 cells compared with KD-PBRM1 cells (P < 0.05, Fig 5B and 5C).	('IL-8', 'Gene', (74, 78))	('decreased', 'NegReg', (79, 88))	('proliferation rate', 'CPA', (93, 111))	('migration ability', 'CPA', (116, 133))	('re-expression', 'Var', (57, 70))	('IL-8', 'molecular_function', 'GO:0005153', ('74', '78'))	('MTT', 'Chemical', '-', (34, 37))	('IL-8', 'Gene', '3576', (74, 78))
192594	28846693	Clear cell renal cell carcinoma accounts for 70%-80% of all kidney cancers, and is known to exhibit very frequent inactivation of the von Hippel-Lindau gene (VHL) as a result of either somatic mutations or epigenetic alterations.	('kidney cancers', 'Disease', 'MESH:D007680', (60, 74))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('kidney cancers', 'Disease', (60, 74))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('kidney cancers', 'Phenotype', 'HP:0009726', (60, 74))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (134, 151))	('inactivation', 'NegReg', (114, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('VHL', 'Gene', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('von Hippel-Lindau', 'Disease', (134, 151))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('VHL', 'Gene', '7428', (158, 161))	('epigenetic alterations', 'Var', (206, 228))
192595	28846693	In addition to VHL, sequencing studies have revealed that truncating mutations in PBRM1, which encodes a subunit of the ATP-dependent chromatin remodeling complex of SWI/SNF, are present in more than 40% of ccRCCs.	('PBRM1', 'Gene', (82, 87))	('VHL', 'Gene', (15, 18))	('ATP', 'Chemical', 'MESH:D000255', (120, 123))	('VHL', 'Gene', '7428', (15, 18))	('ATP-dependent chromatin remodeling', 'biological_process', 'GO:0043044', ('120', '154'))	('RCC', 'Phenotype', 'HP:0005584', (209, 212))	('RCC', 'Disease', 'MESH:C538614', (209, 212))	('RCC', 'Disease', (209, 212))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('134', '162'))	('truncating mutations', 'Var', (58, 78))
192599	28846693	In the current study we examined expression of the PBRM1 gene in RCC cell lines and demonstrated that lentivirus-mediated PBRM1 knockdown in ACHN cells induces cell proliferation, migration, and invasion.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('PBRM1', 'Gene', (122, 127))	('migration', 'CPA', (180, 189))	('knockdown', 'Var', (128, 137))	('invasion', 'CPA', (195, 203))	('induces', 'PosReg', (152, 159))	('cell proliferation', 'biological_process', 'GO:0008283', ('160', '178'))	('cell proliferation', 'CPA', (160, 178))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
192601	28846693	Finally, pathway gene chip analysis revealed that PBRM1 knockdown predominantly alters the cytokine/cytokine receptor interaction pathway.	('PBRM1', 'Gene', (50, 55))	('cytokine receptor', 'Gene', '8809', (100, 117))	('alters', 'Reg', (80, 86))	('cytokine receptor', 'Gene', (100, 117))	('knockdown', 'Var', (56, 65))
192602	28846693	Increased protein levels of IL-6ST, and decreased levels of IL-8, IL-6, and CXCL2, were observed following PBRM1 knockdown.	('protein levels', 'MPA', (10, 24))	('IL-8', 'molecular_function', 'GO:0005153', ('60', '64'))	('IL-6', 'molecular_function', 'GO:0005138', ('66', '70'))	('IL-8', 'Gene', '3576', (60, 64))	('IL-6', 'Gene', '3569', (28, 32))	('IL-6ST', 'Gene', '3572', (28, 34))	('IL-6', 'Gene', (28, 32))	('decreased', 'NegReg', (40, 49))	('IL-6', 'Gene', '3569', (66, 70))	('CXCL2', 'Gene', '2920', (76, 81))	('IL-6ST', 'Gene', (28, 34))	('Increased', 'PosReg', (0, 9))	('knockdown', 'Var', (113, 122))	('Increased protein levels of IL-6ST', 'Phenotype', 'HP:0030783', (0, 34))	('IL-6', 'Gene', (66, 70))	('IL-6', 'molecular_function', 'GO:0005138', ('28', '32'))	('IL-8', 'Gene', (60, 64))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('PBRM1', 'Gene', (107, 112))	('CXCL2', 'Gene', (76, 81))
192606	28846693	PBRM1 deletion was shown to cause a deficiency in mice leading to embryonic lethality, and may also enhance Th2 differentiation and increase IL-10 expression.	('increase IL-10 expression', 'Phenotype', 'HP:0030783', (132, 157))	('Th2', 'Gene', (108, 111))	('increase', 'PosReg', (132, 140))	('expression', 'MPA', (147, 157))	('PBRM1', 'Gene', (0, 5))	('enhance', 'PosReg', (100, 107))	('embryonic lethality', 'Disease', 'MESH:D020964', (66, 85))	('Th2', 'Gene', '15111', (108, 111))	('embryonic lethality', 'Disease', (66, 85))	('deletion', 'Var', (6, 14))	('mice', 'Species', '10090', (50, 54))	('IL-10', 'molecular_function', 'GO:0005141', ('141', '146'))	('deficiency', 'Disease', (36, 46))	('IL-10', 'Protein', (141, 146))	('deficiency', 'Disease', 'MESH:D007153', (36, 46))
192608	28846693	A recent study indicated that PBRM1 knockdown leads to dysregulation of chromosomal instability and cellular proliferation, indicating that the loss of PBRM1 in RCC may give rise to a chromosomal instability/spindle checkpoint expression phenotype.	('loss', 'Var', (144, 148))	('chromosomal instability', 'MPA', (72, 95))	('dysregulation', 'MPA', (55, 68))	('spindle checkpoint', 'biological_process', 'GO:0031577', ('208', '226'))	('spindle', 'cellular_component', 'GO:0005819', ('208', '215'))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('chromosomal instability', 'Phenotype', 'HP:0040012', (72, 95))	('RCC', 'Disease', (161, 164))	('PBRM1', 'Gene', (152, 157))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('give rise to', 'Reg', (169, 181))	('chromosomal instability', 'Phenotype', 'HP:0040012', (184, 207))	('cellular proliferation', 'CPA', (100, 122))
192611	28846693	In the absence of PBRM1, enhanced Th2 differentiation and IL-10 expression was observed, and BAF recruitment and histone acetylation at the IL10 locus was increased13.	('Th2', 'Gene', (34, 37))	('Th2', 'Gene', '15111', (34, 37))	('expression', 'MPA', (64, 74))	('enhanced', 'PosReg', (25, 33))	('BAF', 'Gene', '8815', (93, 96))	('IL10', 'Gene', '3586', (140, 144))	('IL-10', 'molecular_function', 'GO:0005141', ('58', '63'))	('PBRM1', 'Gene', (18, 23))	('IL10', 'molecular_function', 'GO:0005141', ('140', '144'))	('increased13', 'PosReg', (155, 166))	('histone acetylation', 'MPA', (113, 132))	('absence', 'Var', (7, 14))	('IL-10', 'Gene', (58, 63))	('BAF', 'Gene', (93, 96))	('histone acetylation', 'biological_process', 'GO:0016573', ('113', '132'))	('IL10', 'Gene', (140, 144))
192620	28846693	ccRCC patients with VHL gene mutations revealed an association between strong CXCR4 expression and poor tumor-specific survival.	('CXCR4', 'Gene', '7852', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('CXCR4', 'molecular_function', 'GO:0038147', ('78', '83'))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', (104, 109))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('poor', 'NegReg', (99, 103))	('CXCR4', 'Gene', (78, 83))	('VHL', 'Gene', (20, 23))	('patients', 'Species', '9606', (6, 14))	('VHL', 'Gene', '7428', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
192627	28846693	Understanding the contribution of PBRM1 dysregulation and its associated pathways to clinical disease progression and outcome are important future areas of renal cancer research.	('dysregulation', 'Var', (40, 53))	('PBRM1', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('renal cancer', 'Disease', (156, 168))	('renal cancer', 'Disease', 'MESH:D007680', (156, 168))	('renal cancer', 'Phenotype', 'HP:0009726', (156, 168))
192656	30832752	Moreover, the similar biological response of silencing AFAP1-AS1 was observed in our ccRCC mice model.	('silencing', 'Var', (45, 54))	('mice', 'Species', '10090', (91, 95))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('AFAP1-AS1', 'Gene', (55, 64))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (55, 64))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
192658	30832752	Taken together, our results provide the evidences that silencing of AFAP1-AS1 inhibits cell proliferation, EMT, and metastasis through PTEN-dependent signaling, and our findings elucidate a novel potential therapeutic target or biomarker for the treatment of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (261, 264))	('ccRCC', 'Phenotype', 'HP:0006770', (259, 264))	('inhibits', 'NegReg', (78, 86))	('cell proliferation', 'biological_process', 'GO:0008283', ('87', '105'))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (68, 77))	('EMT', 'CPA', (107, 110))	('PTEN', 'Gene', (135, 139))	('silencing', 'Var', (55, 64))	('PTEN', 'Gene', '5728', (135, 139))	('cell proliferation', 'CPA', (87, 105))	('EMT', 'biological_process', 'GO:0001837', ('107', '110'))	('AFAP1-AS1', 'Gene', (68, 77))	('signaling', 'biological_process', 'GO:0023052', ('150', '159'))	('RCC', 'Disease', (261, 264))	('RCC', 'Phenotype', 'HP:0005584', (261, 264))	('men', 'Species', '9606', (251, 254))
192667	30832752	Silencing AFAP1-AS1 significantly reduces cell proliferation, clonal growth, cell migration, and invasion in hepatocellular carcinoma and gastric cancer.	('gastric cancer', 'Disease', (138, 152))	('gastric cancer', 'Disease', 'MESH:D013274', (138, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('reduces', 'NegReg', (34, 41))	('Silencing', 'Var', (0, 9))	('cell proliferation', 'CPA', (42, 60))	('gastric cancer', 'Phenotype', 'HP:0012126', (138, 152))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (10, 19))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (109, 133))	('cell migration', 'CPA', (77, 91))	('cell migration', 'biological_process', 'GO:0016477', ('77', '91'))	('hepatocellular carcinoma', 'Disease', (109, 133))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (109, 133))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cell proliferation', 'biological_process', 'GO:0008283', ('42', '60'))	('AFAP1-AS1', 'Gene', (10, 19))	('invasion', 'CPA', (97, 105))	('clonal growth', 'CPA', (62, 75))
192677	30832752	Caki-1 and ACHN cells with high-level endogenous AFAP1-AS1 were selected for silencing.	('silencing', 'Var', (77, 86))	('Caki-1', 'CellLine', 'CVCL:0234', (0, 6))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (49, 58))	('AFAP1-AS1', 'Gene', (49, 58))
192684	30832752	Antibodies against PTEN (#9188), AKT (#9272), p-AKT (#9271), proliferating cell nuclear antigen (PCNA) (#8580), E-cadherin (#3195), vimentin (#5741), and beta-actin (#8457) were purchased from Cell Signaling Technology (Beverly, MA, USA).	('#8580', 'Var', (104, 109))	('AKT', 'Gene', (48, 51))	('vimentin', 'cellular_component', 'GO:0045098', ('132', '140'))	('#3195', 'Var', (124, 129))	('#9272', 'Var', (38, 43))	('PCNA', 'Gene', (97, 101))	('proliferating cell nuclear antigen', 'Gene', '5111', (61, 95))	('PTEN', 'Gene', (19, 23))	('beta-actin', 'Gene', (154, 164))	('AKT', 'Gene', '207', (33, 36))	('Signaling', 'biological_process', 'GO:0023052', ('198', '207'))	('#5741', 'Var', (142, 147))	('AKT', 'Gene', '207', (48, 51))	('PCNA', 'Gene', '5111', (97, 101))	('vimentin', 'cellular_component', 'GO:0045099', ('132', '140'))	('PCNA', 'molecular_function', 'GO:0003892', ('97', '101'))	('#9271', 'Var', (53, 58))	('PTEN', 'Gene', '5728', (19, 23))	('proliferating cell nuclear antigen', 'Gene', (61, 95))	('#9188', 'Var', (25, 30))	('proliferating cell nuclear antigen', 'molecular_function', 'GO:0003892', ('61', '95'))	('beta-actin', 'Gene', '728378', (154, 164))	('cadherin', 'molecular_function', 'GO:0008014', ('114', '122'))	('AKT', 'Gene', (33, 36))
192702	30832752	After transfection with shAF for 24, 48, and 72 h, knockdown of AFAP1-AS1 significantly suppressed the growth of Caki-1 and ACHN cells (p < 0.05) (Fig.	('growth', 'CPA', (103, 109))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (64, 73))	('Caki-1', 'CellLine', 'CVCL:0234', (113, 119))	('AFAP1-AS1', 'Gene', (64, 73))	('suppressed', 'NegReg', (88, 98))	('knockdown', 'Var', (51, 60))
192705	30832752	As shown in Figure 2E and H, the expression level of PCNA was markedly decreased in the shAF group.	('PCNA', 'Gene', (53, 57))	('shAF', 'Var', (88, 92))	('PCNA', 'Gene', '5111', (53, 57))	('expression level', 'MPA', (33, 49))	('PCNA', 'molecular_function', 'GO:0003892', ('53', '57'))	('decreased', 'NegReg', (71, 80))
192708	30832752	Compared with the cells transfected with shNC, we observed that knockdown of AFAP1-AS1 could attenuate the migratory ability of both Caki-1 and ACHN cells (Fig.	('AFAP1-AS1', 'Gene', '84740;60312;5729', (77, 86))	('migratory ability of', 'CPA', (107, 127))	('attenuate', 'NegReg', (93, 102))	('AFAP1-AS1', 'Gene', (77, 86))	('Caki-1', 'CellLine', 'CVCL:0234', (133, 139))	('knockdown', 'Var', (64, 73))
192709	30832752	Thus, silencing of AFAP1-AS1 significantly suppressed the ability of invasion and migration of ccRCC cells.	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('AFAP1-AS1', 'Gene', (19, 28))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('silencing', 'Var', (6, 15))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (19, 28))	('suppressed', 'NegReg', (43, 53))
192713	30832752	As seen in Figure 3F and I, silencing of AFAP1-AS1 resulted in an increase in E-cadherin and decrease in vimentin in both Caki-1 and ACHN cells.	('AFAP1-AS1', 'Gene', (41, 50))	('increase', 'PosReg', (66, 74))	('vimentin', 'cellular_component', 'GO:0045099', ('105', '113'))	('vimentin', 'Protein', (105, 113))	('Caki-1', 'CellLine', 'CVCL:0234', (122, 128))	('vimentin', 'cellular_component', 'GO:0045098', ('105', '113'))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (41, 50))	('decrease', 'NegReg', (93, 101))	('E-cadherin', 'Protein', (78, 88))	('cadherin', 'molecular_function', 'GO:0008014', ('80', '88'))	('silencing', 'Var', (28, 37))
192722	30832752	As seen in Figure 4C, silencing of AFAP1-AS1 evidently upregulated PTEN expression and inactivated AKT in Caki-1 cells.	('AFAP1-AS1', 'Gene', (35, 44))	('AKT', 'Gene', '207', (99, 102))	('inactivated', 'NegReg', (87, 98))	('expression', 'MPA', (72, 82))	('silencing', 'Var', (22, 31))	('upregulated', 'PosReg', (55, 66))	('PTEN', 'Gene', (67, 71))	('Caki-1', 'CellLine', 'CVCL:0234', (106, 112))	('AKT', 'Gene', (99, 102))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (35, 44))	('PTEN', 'Gene', '5728', (67, 71))
192725	30832752	Similar to our previous result, knockdown of AFAP1-AS1 alone significantly inhibited proliferation of Caik-1 and ACHN cells, while silencing PTEN expression together evidently reversed the biological function of shAF on cell growth (Fig.	('PTEN', 'Gene', (141, 145))	('AFAP1-AS1', 'Gene', (45, 54))	('PTEN', 'Gene', '5728', (141, 145))	('silencing', 'Var', (131, 140))	('cell growth', 'biological_process', 'GO:0016049', ('220', '231'))	('inhibited', 'NegReg', (75, 84))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (45, 54))
192730	30832752	shAF lead to increase in E-cadherin and decrease in vimentin in Caki-1 cells, but the opposite regulation of E-cadherin and vimentin expressions was observed in combination with si-PTEN (Fig.	('decrease', 'NegReg', (40, 48))	('PTEN', 'Gene', '5728', (181, 185))	('regulation', 'biological_process', 'GO:0065007', ('95', '105'))	('PTEN', 'Gene', (181, 185))	('vimentin', 'cellular_component', 'GO:0045099', ('124', '132'))	('vimentin', 'cellular_component', 'GO:0045098', ('52', '60'))	('Caki-1', 'CellLine', 'CVCL:0234', (64, 70))	('vimentin', 'MPA', (52, 60))	('increase', 'PosReg', (13, 21))	('cadherin', 'molecular_function', 'GO:0008014', ('111', '119'))	('vimentin', 'cellular_component', 'GO:0045098', ('124', '132'))	('shAF', 'Var', (0, 4))	('cadherin', 'molecular_function', 'GO:0008014', ('27', '35'))	('E-cadherin', 'Protein', (25, 35))	('vimentin', 'cellular_component', 'GO:0045099', ('52', '60'))
192733	30832752	As shown in Figure 6A, AFAP1-AS1 expression level was significantly decreased in the shAF group compared with shNC xenograft mice (p < 0.001).	('AFAP1-AS1', 'Gene', '84740;60312;5729', (23, 32))	('decreased', 'NegReg', (68, 77))	('expression level', 'MPA', (33, 49))	('mice', 'Species', '10090', (125, 129))	('AFAP1-AS1', 'Gene', (23, 32))	('shAF', 'Var', (85, 89))
192734	30832752	The knockdown of AFAP1-AS1 leads to a decrease in tumor weight (Fig.	('tumor weight', 'Disease', (50, 62))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (17, 26))	('decrease', 'NegReg', (38, 46))	('tumor weight', 'Disease', 'MESH:D015431', (50, 62))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('knockdown', 'Var', (4, 13))	('AFAP1-AS1', 'Gene', (17, 26))
192747	30832752	Silencing AFAP1-AS1 by shAF significantly suppressed proliferation, invasion, and migration of ccRCC cells.	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('Silencing', 'Var', (0, 9))	('invasion', 'CPA', (68, 76))	('suppressed', 'NegReg', (42, 52))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (10, 19))	('proliferation', 'CPA', (53, 66))	('migration of', 'CPA', (82, 94))	('AFAP1-AS1', 'Gene', (10, 19))
192750	30832752	In both Caki-1 and ACHN cells, silencing AFAP1-AS1 resulted in an increase in E-cadherin and decrease in vimentin.	('silencing', 'Var', (31, 40))	('AFAP1-AS1', 'Gene', (41, 50))	('increase', 'PosReg', (66, 74))	('Caki-1', 'CellLine', 'CVCL:0234', (8, 14))	('vimentin', 'cellular_component', 'GO:0045099', ('105', '113'))	('vimentin', 'Protein', (105, 113))	('vimentin', 'cellular_component', 'GO:0045098', ('105', '113'))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (41, 50))	('decrease', 'NegReg', (93, 101))	('E-cadherin', 'Protein', (78, 88))	('cadherin', 'molecular_function', 'GO:0008014', ('80', '88'))
192751	30832752	Moreover, the similar effect of the knockdown of AFAP1-AS1 on vimentin and E-cadherin expression in our ccRCC xenograft mice model was also observed.	('vimentin', 'Protein', (62, 70))	('mice', 'Species', '10090', (120, 124))	('AFAP1-AS1', 'Gene', (49, 58))	('cadherin', 'molecular_function', 'GO:0008014', ('77', '85'))	('E-cadherin', 'Protein', (75, 85))	('knockdown', 'Var', (36, 45))	('vimentin', 'cellular_component', 'GO:0045099', ('62', '70'))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (49, 58))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('vimentin', 'cellular_component', 'GO:0045098', ('62', '70'))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))
192761	30832752	Biological function experiments showed that knockdown of AFAP1-AS1 by shRNA significantly suppressed proliferation, invasion, migration, and EMT in ccRCC cells.	('AFAP1-AS1', 'Gene', '84740;60312;5729', (57, 66))	('EMT', 'CPA', (141, 144))	('EMT', 'biological_process', 'GO:0001837', ('141', '144'))	('invasion', 'CPA', (116, 124))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('RCC', 'Disease', (150, 153))	('proliferation', 'CPA', (101, 114))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('AFAP1-AS1', 'Gene', (57, 66))	('men', 'Species', '9606', (26, 29))	('ccRCC', 'Phenotype', 'HP:0006770', (148, 153))	('knockdown', 'Var', (44, 53))	('suppressed', 'NegReg', (90, 100))	('migration', 'CPA', (126, 135))
192762	30832752	Moreover, a similar biological response of silencing AFAP1-AS1 was observed in our ccRCC mice model.	('AFAP1-AS1', 'Gene', '84740;60312;5729', (53, 62))	('mice', 'Species', '10090', (89, 93))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('AFAP1-AS1', 'Gene', (53, 62))	('silencing', 'Var', (43, 52))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('RCC', 'Disease', (85, 88))
192839	32093682	The primers specific to the HNF4A binding region within ABAT promoter region were as follows: forward-1 5'-GTTCATAGGGATTGGATTGCT-3' and reverse-1 5'-CCCCTTTACTACCCTTGACCT-3'; and forward-2 5'- ATCAACCTATGGAGCTGCCCC -3' and reverse-2 5'- CTCGCTTTCGCCACAGCCAAT -3'.	('binding', 'molecular_function', 'GO:0005488', ('34', '41'))	('TCA', 'Chemical', 'MESH:D014238', (194, 197))	('TCA', 'Chemical', 'MESH:D014238', (109, 112))	('ABAT', 'Gene', (56, 60))	('ABAT', 'Gene', '18', (56, 60))	("forward-2 5'-", 'Var', (179, 192))
192882	32093682	By analyzing the transcription factors binding to the ABAT and ALDH6A1 promoters, we found that transcription factor HNF4A could simultaneously regulate ABAT and ALDH6A1, and HNF4A has a positive correlation with ABAT and ALDH6A1 expression (Fig.	('HNF4A', 'Var', (175, 180))	('ABAT', 'Gene', (153, 157))	('ABAT', 'Gene', '18', (54, 58))	('ABAT', 'Gene', '18', (213, 217))	('ALDH6A1', 'Gene', '4329', (63, 70))	('transcription', 'biological_process', 'GO:0006351', ('96', '109'))	('HNF4A', 'Gene', (117, 122))	('ALDH', 'molecular_function', 'GO:0004030', ('63', '67'))	('transcription', 'biological_process', 'GO:0006351', ('17', '30'))	('ABAT', 'Gene', (54, 58))	('ALDH6A1', 'Gene', (63, 70))	('ALDH6A1', 'Gene', '4329', (222, 229))	('ABAT', 'Gene', (213, 217))	('transcription factor', 'molecular_function', 'GO:0000981', ('96', '116'))	('ALDH6A1', 'Gene', (222, 229))	('expression', 'MPA', (230, 240))	('ALDH', 'molecular_function', 'GO:0004030', ('162', '166'))	('ALDH', 'molecular_function', 'GO:0004030', ('222', '226'))	('binding', 'molecular_function', 'GO:0005488', ('39', '46'))	('ABAT', 'Gene', '18', (153, 157))	('ALDH6A1', 'Gene', '4329', (162, 169))	('regulate', 'Reg', (144, 152))	('ALDH6A1', 'Gene', (162, 169))
192884	32093682	The expression of HNF4A is significantly downregulated in ccRCC and loss of HNF4A promotes tumorigenesis in the kidney.	('promotes', 'PosReg', (82, 90))	('HNF4A', 'Gene', (18, 23))	('downregulated', 'NegReg', (41, 54))	('HNF4A', 'Gene', (76, 81))	('expression', 'MPA', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('ccRCC', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('ccRCC', 'Disease', 'MESH:D002292', (58, 63))	('loss', 'Var', (68, 72))	('tumor', 'Disease', (91, 96))
192888	32093682	ABAT and ALDH6A1 protein levels were also significantly increased in HNF4A overexpressing cells (Fig.	('ALDH6A1', 'Gene', (9, 16))	('ABAT', 'Gene', (0, 4))	('increased', 'PosReg', (56, 65))	('overexpressing', 'Var', (75, 89))	('HNF4A', 'Gene', (69, 74))	('ALDH6A1', 'Gene', '4329', (9, 16))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('ALDH', 'molecular_function', 'GO:0004030', ('9', '13'))	('protein levels', 'MPA', (17, 31))	('ABAT', 'Gene', '18', (0, 4))
192902	32093682	Patients with ABAT deficiency display poor chemotherapy treatment outcome.	('Patients', 'Species', '9606', (0, 8))	('ABAT', 'Gene', (14, 18))	('deficiency', 'Var', (19, 29))	('ABAT', 'Gene', '18', (14, 18))
192905	32093682	Our study identified that loss of ABAT and ALDH6A1 contributes to ccRCC tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('ALDH6A1', 'Gene', (43, 50))	('tumor', 'Disease', (72, 77))	('ABAT', 'Gene', '18', (34, 38))	('contributes', 'Reg', (51, 62))	('ALDH', 'molecular_function', 'GO:0004030', ('43', '47'))	('ALDH6A1', 'Gene', '4329', (43, 50))	('loss', 'Var', (26, 30))	('ccRCC', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('ccRCC', 'Disease', 'MESH:D002292', (66, 71))	('ABAT', 'Gene', (34, 38))
192910	32093682	The results of this study show that ABAT and ALDH6A1 are directly regulated by HNF4A, indicating that HNF4A suppresses ccRCC progression, at least in part, via the regulation of metabolic enzyme gene expression.	('gene expression', 'biological_process', 'GO:0010467', ('195', '210'))	('HNF4A', 'Var', (102, 107))	('regulation', 'biological_process', 'GO:0065007', ('164', '174'))	('ccRCC', 'Disease', (119, 124))	('ABAT', 'Gene', (36, 40))	('ABAT', 'Gene', '18', (36, 40))	('ALDH', 'molecular_function', 'GO:0004030', ('45', '49'))	('ALDH6A1', 'Gene', (45, 52))	('ccRCC', 'Disease', 'MESH:D002292', (119, 124))	('suppresses', 'NegReg', (108, 118))	('metabolic', 'MPA', (178, 187))	('ALDH6A1', 'Gene', '4329', (45, 52))
192929	30450335	Biomarker development for ICI drugs will likely require integration of multiple biologic components like PD-L1 expression, TILs and mutational load.	('mutational', 'Var', (132, 142))	('PD-L1', 'Gene', '29126', (105, 110))	('PD-L1', 'Gene', (105, 110))
192934	30450335	In this review, we will discuss: (1) Pathologic and molecular subtypes of RCC; (2) Current landscape of targeted therapy in renal cell carcinoma; (3) Overview of immunotherapy in renal cell carcinoma; (4) Predictive immunological biomarkers in renal cell carcinoma; (5) Gene expression as predictive biomarkers in renal cell carcinoma; (6) The current status of PD-L1 immunohistochemistry; (7) MMR-deficiency and mutational load in RCC; and (8) Biomarkers of acquired resistance.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (124, 144))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (244, 264))	('Gene expression', 'biological_process', 'GO:0010467', ('270', '285'))	('renal cell carcinoma', 'Disease', (179, 199))	('RCC', 'Phenotype', 'HP:0005584', (432, 435))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (179, 199))	('RCC', 'Disease', (432, 435))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('renal cell carcinoma', 'Disease', (314, 334))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (314, 334))	('MMR', 'biological_process', 'GO:0006298', ('394', '397'))	('MMR-deficiency', 'Disease', (394, 408))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (325, 334))	('RCC', 'Disease', 'MESH:C538614', (432, 435))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (124, 144))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (244, 264))	('mutational load', 'Var', (413, 428))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('PD-L1', 'Gene', (362, 367))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (179, 199))	('MMR-deficiency', 'Disease', 'MESH:C536143', (394, 408))	('PD-L1', 'Gene', '29126', (362, 367))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (314, 334))	('renal cell carcinoma', 'Disease', (124, 144))	('renal cell carcinoma', 'Disease', (244, 264))
192940	30450335	TCGA analysis of a ccRCC cohort found similar genomic changes and reported recurrent alterations in the PI(3)K/AKT pathway and several epigenetic changes in DNA methylation.	('AKT', 'Gene', '207', (111, 114))	('DNA', 'MPA', (157, 160))	('DNA', 'cellular_component', 'GO:0005574', ('157', '160'))	('alterations', 'Reg', (85, 96))	('changes in DNA methylation', 'biological_process', 'GO:0044728', ('146', '172'))	('AKT', 'Gene', (111, 114))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('RCC', 'Disease', (21, 24))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('epigenetic changes', 'Var', (135, 153))	('PI(3)K', 'molecular_function', 'GO:0016303', ('104', '110'))
192947	30450335	After angiogenesis, the finding that, the deregulation of the PI3K-Akt-mTOR pathway, activated at different levels of the signaling cascade, drives RCC progression has led to the development of the mTOR inhibitors everolimus and temsirolimus.	('PI3K', 'molecular_function', 'GO:0016303', ('62', '66'))	('RCC', 'Disease', (148, 151))	('deregulation', 'Var', (42, 54))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('Akt', 'Gene', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('mTOR', 'Gene', '2475', (198, 202))	('mTOR', 'Gene', '2475', (71, 75))	('everolimus', 'Chemical', 'MESH:D000068338', (214, 224))	('angiogenesis', 'biological_process', 'GO:0001525', ('6', '18'))	('mTOR', 'Gene', (198, 202))	('temsirolimus', 'Chemical', 'MESH:C401859', (229, 241))	('mTOR', 'Gene', (71, 75))	('signaling cascade', 'biological_process', 'GO:0007165', ('122', '139'))	('Akt', 'Gene', '207', (67, 70))
192970	30450335	Preliminary data seems to indicate that these patients with high mutational load present a higher percentage of tumors with positive PD-L1 expression.	('patients', 'Species', '9606', (46, 54))	('high mutational load', 'Var', (60, 80))	('PD-L1', 'Gene', (133, 138))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PD-L1', 'Gene', '29126', (133, 138))	('expression', 'MPA', (139, 149))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))
192983	30450335	As seen in other neoplastic diseases in which immunotherapy has been successfully tested, tumor mutational burden and non-synonymous mutation expression have been related to higher neo-antigens tumor expression and to favorable immunotherapy response.	('neoplastic diseases', 'Disease', 'MESH:D009386', (17, 36))	('non-synonymous mutation expression', 'Var', (118, 152))	('neoplastic diseases', 'Disease', (17, 36))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('higher', 'PosReg', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('neo-antigens', 'Protein', (181, 193))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
192985	30450335	Indeed, considering the subgroup analysis of the Checkmate 025 study and the significantly better results of nivolumab-ipilimumab combination in intermediate/poor risk patients in the Checkmate 214, it seems likely that tumors with worst clinical features are those that better respond to immune-checkpoint inhibitors and this may be due to a higher mutational load resulting in higher neo-antigen content.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('neo-antigen content', 'MPA', (386, 405))	('nivolumab', 'Chemical', 'MESH:D000077594', (109, 118))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('better', 'PosReg', (271, 277))	('Checkmate 025', 'Chemical', '-', (49, 62))	('tumors', 'Disease', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('patients', 'Species', '9606', (168, 176))	('mutational', 'Var', (350, 360))	('ipilimumab', 'Chemical', 'MESH:D000074324', (119, 129))	('higher', 'PosReg', (379, 385))
192989	30450335	They discovered that RCC had relatively few non-synonymous mutations and neo-antigens and, surprisingly, that among patients receiving nivolumab non-synonymous mutations were significantly higher in non-responder patients (n = 6) compared to responder patients (n = 3).	('non-synonymous mutations', 'Var', (145, 169))	('patients', 'Species', '9606', (252, 260))	('patients', 'Species', '9606', (116, 124))	('non-responder', 'Disease', (199, 212))	('higher', 'PosReg', (189, 195))	('patients', 'Species', '9606', (213, 221))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('RCC', 'Disease', (21, 24))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('nivolumab', 'Chemical', 'MESH:D000077594', (135, 144))
192996	30450335	Reportedly, the most frequent event involved in ccRCC is the loss of chromosome 3p, which is associated with the development of VHL, PBRM1, BAP1 and SETD2 alterations in about 90% of ccRCC cases.	('RCC', 'Disease', (185, 188))	('SETD2', 'Gene', (149, 154))	('PBRM1', 'Gene', (133, 138))	('alterations', 'Var', (155, 166))	('PBRM1', 'Gene', '55193', (133, 138))	('BAP1', 'Gene', (140, 144))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('chromosome', 'cellular_component', 'GO:0005694', ('69', '79'))	('RCC', 'Disease', (50, 53))	('BAP1', 'Gene', '8314', (140, 144))	('VHL', 'Disease', (128, 131))	('VHL', 'Disease', 'MESH:D006623', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('SETD2', 'Gene', '29072', (149, 154))	('loss', 'Var', (61, 65))	('RCC', 'Disease', 'MESH:C538614', (185, 188))
192999	30450335	When mutations occur in chromatin regulators PBRM1, BAP1, and SETD2, several related genes showed altered expression as compared to VHL mutation.	('BAP1', 'Gene', '8314', (52, 56))	('mutations occur', 'Var', (5, 20))	('expression', 'MPA', (106, 116))	('BAP1', 'Gene', (52, 56))	('chromatin', 'cellular_component', 'GO:0000785', ('24', '33'))	('PBRM1', 'Gene', (45, 50))	('SETD2', 'Gene', '29072', (62, 67))	('VHL', 'Disease', (132, 135))	('VHL', 'Disease', 'MESH:D006623', (132, 135))	('SETD2', 'Gene', (62, 67))	('altered', 'Reg', (98, 105))	('PBRM1', 'Gene', '55193', (45, 50))
193008	30450335	reported on the prognostic value of genetic alterations resulting in loss of function (defined by the presence of pathogenic gene variant or 2 copy deletion) of VHL, PBRM1, BAP1, SETD2, TP53, and KDM5C, which are frequently mutated in metastatic RCC, in patients with ccRCC stratified by IMDC risk classification and treated with 1st line VEGFR tyrosine kinase inhibitors.	('KDM5C', 'Gene', '8242', (196, 201))	('SETD2', 'Gene', '29072', (179, 184))	('alterations', 'Var', (44, 55))	('PBRM1', 'Gene', '55193', (166, 171))	('VHL', 'Disease', (161, 164))	('VEGFR', 'Gene', '3791', (339, 344))	('BAP1', 'Gene', '8314', (173, 177))	('PBRM1', 'Gene', (166, 171))	('VEGFR', 'Gene', (339, 344))	('TP53', 'Gene', (186, 190))	('KDM5C', 'Gene', (196, 201))	('RCC', 'Phenotype', 'HP:0005584', (246, 249))	('RCC', 'Phenotype', 'HP:0005584', (270, 273))	('RCC', 'Disease', (246, 249))	('RCC', 'Disease', (270, 273))	('BAP1', 'Gene', (173, 177))	('VHL', 'Disease', 'MESH:D006623', (161, 164))	('RCC', 'Disease', 'MESH:C538614', (246, 249))	('variant', 'Var', (130, 137))	('TP53', 'Gene', '7157', (186, 190))	('RCC', 'Disease', 'MESH:C538614', (270, 273))	('loss of function', 'NegReg', (69, 85))	('SETD2', 'Gene', (179, 184))	('patients', 'Species', '9606', (254, 262))
193010	30450335	The presence of gene alterations in VHL, PBRM1, SETD2, BAP1, TP53, and KDM5C was, respectively, 77, 43, 29, 19, 11, and 11%.	('alterations', 'Var', (21, 32))	('TP53', 'Gene', '7157', (61, 65))	('KDM5C', 'Gene', (71, 76))	('BAP1', 'Gene', (55, 59))	('KDM5C', 'Gene', '8242', (71, 76))	('SETD2', 'Gene', '29072', (48, 53))	('PBRM1', 'Gene', '55193', (41, 46))	('PBRM1', 'Gene', (41, 46))	('VHL', 'Disease', (36, 39))	('SETD2', 'Gene', (48, 53))	('VHL', 'Disease', 'MESH:D006623', (36, 39))	('TP53', 'Gene', (61, 65))	('BAP1', 'Gene', '8314', (55, 59))
193011	30450335	Gene alterations in BAP1 were associated with worst OS (HR 1.7; 95%CI 1.1-2.5, p = 0.01), while alterations in PBRM1 and KDM5C were correlated with longer OS.	('associated', 'Reg', (30, 40))	('OS', 'Chemical', '-', (52, 54))	('KDM5C', 'Gene', '8242', (121, 126))	('BAP1', 'Gene', (20, 24))	('OS', 'Chemical', '-', (155, 157))	('worst OS', 'Disease', (46, 54))	('PBRM1', 'Gene', '55193', (111, 116))	('alterations', 'Var', (5, 16))	('PBRM1', 'Gene', (111, 116))	('KDM5C', 'Gene', (121, 126))	('BAP1', 'Gene', '8314', (20, 24))
193012	30450335	Patients with tumors PBRM1 wild type and harboring gene alterations in BAP1 had worse OS (37 vs. 50 months, HR 1.9, 95% CI 1.2-2.8, p = 0.004).	('OS', 'Chemical', '-', (86, 88))	('PBRM1', 'Gene', (21, 26))	('tumors', 'Disease', (14, 20))	('PBRM1', 'Gene', '55193', (21, 26))	('Patients', 'Species', '9606', (0, 8))	('BAP1', 'Gene', '8314', (71, 75))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('gene alterations', 'Var', (51, 67))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('BAP1', 'Gene', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
193016	30450335	The list of histologic categories includes also emerging entities, such as RCC associated with ALK gene rearrangements and thyroid-like follicular RCC.	('associated', 'Reg', (79, 89))	('ALK', 'Gene', (95, 98))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('rearrangements', 'Var', (104, 118))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('ALK', 'Gene', '238', (95, 98))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('RCC', 'Disease', 'MESH:C538614', (147, 150))
193024	30450335	Some other genes:including PDCD1, CTLA4, and TLR9:were associated with worse patient survival within ccRCC-associated cases; PDL1 expression was correlated with better patient survival, though this association was confounded by copy loss of 9p region associated with aggressive clear cell RCC and worse prognosis.	('TLR9', 'Gene', '54106', (45, 49))	('RCC', 'Disease', (289, 292))	('RCC', 'Disease', (103, 106))	('CTLA4', 'Gene', '1493', (34, 39))	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (289, 292))	('RCC', 'Disease', 'MESH:C538614', (289, 292))	('better', 'PosReg', (161, 167))	('CTLA4', 'Gene', (34, 39))	('PDCD1', 'Gene', (27, 32))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('patient', 'Species', '9606', (168, 175))	('PDCD1', 'Gene', '5133', (27, 32))	('TLR9', 'Gene', (45, 49))	('patient', 'Species', '9606', (77, 84))	('copy loss', 'Var', (228, 237))	('PDL1', 'Gene', (125, 129))
193030	30450335	Low-to-no expression of PD-L1 on IC (immune cells) and TC (tumor cells) correlated with a trend toward lower response (PFS and OS) to the anti-PD-L1 drug atezolizumab compared with moderate to high PD-L1 expression levels.	('PD-L1', 'Gene', (198, 203))	('tumor', 'Disease', (59, 64))	('Low-to-no', 'Var', (0, 9))	('response', 'MPA', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('atezolizumab', 'Chemical', 'MESH:C000594389', (154, 166))	('expression', 'MPA', (10, 20))	('lower', 'NegReg', (103, 108))	('PD-L1', 'Gene', '29126', (198, 203))	('PD-L1', 'Gene', (143, 148))	('PD-L1', 'Gene', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('OS', 'Chemical', '-', (127, 129))	('PD-L1', 'Gene', '29126', (143, 148))	('PD-L1', 'Gene', '29126', (24, 29))
193031	30450335	Updated analysis further confirmed the association between high PD-L1 expression and improved OS with atezolizumab treatment.	('OS', 'Chemical', '-', (94, 96))	('improved OS', 'Disease', (85, 96))	('atezolizumab', 'Chemical', 'MESH:C000594389', (102, 114))	('PD-L1', 'Gene', (64, 69))	('expression', 'MPA', (70, 80))	('high', 'Var', (59, 63))	('PD-L1', 'Gene', '29126', (64, 69))
193042	30450335	Increasing mutational burden and neo-antigen formation have been associated with increased responsiveness to ICI in several other malignancies and recent data showed increased frequency of genomic alterations in RCC post-VEGFR therapy.	('VEGFR', 'Gene', (221, 226))	('responsiveness to ICI', 'MPA', (91, 112))	('malignancies', 'Disease', (130, 142))	('VEGFR', 'Gene', '3791', (221, 226))	('mutational burden', 'Var', (11, 28))	('formation', 'biological_process', 'GO:0009058', ('45', '54'))	('RCC', 'Disease', (212, 215))	('RCC', 'Phenotype', 'HP:0005584', (212, 215))	('increased', 'PosReg', (81, 90))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('malignancies', 'Disease', 'MESH:D009369', (130, 142))	('neo-antigen', 'Var', (33, 44))
193057	30450335	MMR deficiency can occur in patients with Lynch syndrome (HNPCC) and in patients with sporadic MMR-deficient tumors.	('MMR-deficient tumors', 'Disease', (95, 115))	('HNPCC', 'Disease', 'None', (58, 63))	('HNPCC', 'Disease', (58, 63))	('Lynch syndrome', 'Disease', 'MESH:D003123', (42, 56))	('MMR', 'biological_process', 'GO:0006298', ('95', '98'))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('Lynch syndrome', 'Disease', (42, 56))	('MMR', 'biological_process', 'GO:0006298', ('0', '3'))	('deficiency', 'Var', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('MMR', 'Gene', (0, 3))	('patients', 'Species', '9606', (28, 36))	('occur', 'Reg', (19, 24))	('MMR-deficient tumors', 'Disease', 'MESH:C536928', (95, 115))	('patients', 'Species', '9606', (72, 80))
193058	30450335	MMR-deficient tumors exhibit a higher rate of mutations (high mutational burden), which can result in the formation of neo-antigens to enhance the antitumor immune response.	('neo-antigens', 'MPA', (119, 131))	('tumor', 'Disease', (14, 19))	('mutations', 'Var', (46, 55))	('formation', 'MPA', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('MMR-deficient tumors', 'Disease', 'MESH:C536928', (0, 20))	('MMR-deficient tumors', 'Disease', (0, 20))	('tumor', 'Disease', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('formation', 'biological_process', 'GO:0009058', ('106', '115'))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('enhance', 'PosReg', (135, 142))	('MMR', 'biological_process', 'GO:0006298', ('0', '3'))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('immune response', 'biological_process', 'GO:0006955', ('157', '172'))
193064	30450335	The reality might however be much more complex; for instance, several clinical trials have shown that some MMR-deficient tumors do not respond to immunotherapy, while mutations in other genes have also been linked to high mutational burden and upregulation of immune checkpoints.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('high mutational burden', 'MPA', (217, 239))	('mutations', 'Var', (167, 176))	('not', 'NegReg', (131, 134))	('MMR-deficient tumors', 'Disease', 'MESH:C536928', (107, 127))	('MMR', 'biological_process', 'GO:0006298', ('107', '110'))	('MMR-deficient tumors', 'Disease', (107, 127))	('immune', 'CPA', (260, 266))	('upregulation', 'PosReg', (244, 256))
193074	30450335	Defects in the interferon-gamma signaling pathway have also been identified as a major mechanism of resistance.	('signaling pathway', 'biological_process', 'GO:0007165', ('32', '49'))	('interferon-gamma', 'Gene', '3458', (15, 31))	('Defects', 'Var', (0, 7))	('interferon-gamma', 'Gene', (15, 31))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('15', '31'))
193078	30450335	Mutations in JAK1/2 render cells insensitive to interferon-gamma signaling, which results in escape from PD-L1 pathway inhibition and impairs the antitumor immune response.	('impairs', 'NegReg', (134, 141))	('PD-L1', 'Gene', (105, 110))	('immune response', 'biological_process', 'GO:0006955', ('156', '171'))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('48', '64'))	('JAK1', 'Gene', (13, 17))	('JAK', 'molecular_function', 'GO:0004713', ('13', '16'))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))	('Mutations', 'Var', (0, 9))	('PD-L1', 'Gene', '29126', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('JAK1', 'Gene', '3716', (13, 17))	('interferon-gamma', 'Gene', '3458', (48, 64))	('escape', 'MPA', (93, 99))	('tumor', 'Disease', (150, 155))	('interferon-gamma', 'Gene', (48, 64))
193080	30450335	Defects in antigen presentation, such as mutations in the beta-2 microglobulin gene, have also been identified as a mechanism of resistance.	('mutations', 'Var', (41, 50))	('Defects', 'NegReg', (0, 7))	('antigen presentation', 'biological_process', 'GO:0019882', ('11', '31'))	('beta-2 microglobulin', 'Gene', (58, 78))	('antigen presentation', 'MPA', (11, 31))	('beta-2 microglobulin', 'Gene', '567', (58, 78))
193081	30450335	Beta-2 microglobulin is essential for MHC class I molecule surface expression and a defect can block CD8-Tcell recognition.	('CD8', 'Gene', '925', (101, 104))	('MHC class I molecule', 'Gene', (38, 58))	('defect', 'Var', (84, 90))	('Beta-2 microglobulin', 'Gene', (0, 20))	('MHC class I molecule', 'Gene', '3106', (38, 58))	('Beta-2 microglobulin', 'Gene', '567', (0, 20))	('block', 'NegReg', (95, 100))	('CD8', 'Gene', (101, 104))
193096	30450335	In particular, PD-1 blockade promotes the expansion of specific exhausted-like CD8-T cell population, while CTLA-4 blockade induces both an ICOS+ Th1-like CD4 effector subset and exhausted-like CD8-T cells.	('CD8', 'Gene', (194, 197))	('CD8', 'Gene', '925', (194, 197))	('Th1', 'Gene', '51497', (146, 149))	('CTLA-4', 'Gene', (108, 114))	('CD4', 'Gene', (155, 158))	('CD4', 'Gene', '920', (155, 158))	('induces', 'Reg', (124, 131))	('ICOS', 'Gene', (140, 144))	('Th1', 'Gene', (146, 149))	('CD8', 'Gene', (79, 82))	('blockade', 'Var', (20, 28))	('CD8', 'Gene', '925', (79, 82))	('ICOS', 'Gene', '29851', (140, 144))	('blockade', 'Var', (115, 123))	('expansion', 'CPA', (42, 51))	('PD-1', 'Gene', (15, 19))	('CTLA-4', 'Gene', '1493', (108, 114))
193098	30450335	Tumor responsiveness may vary according to the mutational load and the expression of immunotargets in the tumor environment, which is variable in the different phases of RCC development and progression.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('vary', 'Reg', (25, 29))	('RCC', 'Disease', (170, 173))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('mutational', 'Var', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
193107	30450335	On the other hand, pazopanib showed lower inhibitory potency and affinity against FLT3 and c-kit compared to sunitinib.	('lower', 'NegReg', (36, 41))	('pazopanib', 'Var', (19, 28))	('c-kit', 'Gene', (91, 96))	('FLT3', 'Gene', '2322', (82, 86))	('inhibitory potency', 'MPA', (42, 60))	('pazopanib', 'Chemical', 'MESH:C516667', (19, 28))	('FLT3', 'Gene', (82, 86))	('c-kit', 'Gene', '3815', (91, 96))	('affinity', 'Interaction', (65, 73))	('sunitinib', 'Chemical', 'MESH:D000077210', (109, 118))
193115	30450335	Biomarker development for ICI drugs will require integration of multiple biologic components like PD-L1 expression, TILs, mutational load, and probably many others now considered emergent biomarkers.	('mutational load', 'Var', (122, 137))	('PD-L1', 'Gene', (98, 103))	('PD-L1', 'Gene', '29126', (98, 103))
193119	30450335	Biomarker development for ICI drugs will require integration of multiple biologic components like PD-L1 expression, TILs and mutational load.	('PD-L1', 'Gene', '29126', (98, 103))	('PD-L1', 'Gene', (98, 103))	('mutational', 'Var', (125, 135))
193124	30334004	Genomic Alterations and Outcomes with VEGF-Targeted Therapy in Patients with Clear Cell Renal Cell Carcinoma Background: Mutations in VHL, PBRM1, SETD2, BAP1, and KDM5C are common in clear cell renal cell carcinoma (ccRCC), and presence of certain mutations has been associated with outcomes in patients with non-metastatic disease.	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (183, 214))	('KDM5C', 'Gene', '8242', (163, 168))	('ccRCC', 'Phenotype', 'HP:0006770', (216, 221))	('common', 'Reg', (173, 179))	('SETD2', 'Gene', '29072', (146, 151))	('BAP1', 'Gene', (153, 157))	('Mutations', 'Var', (121, 130))	('Clear Cell Renal Cell Carcinoma', 'Disease', (77, 108))	('clear cell renal cell carcinoma', 'Disease', (183, 214))	('VHL', 'Disease', 'MESH:D006623', (134, 137))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (194, 214))	('RCC', 'Disease', (218, 221))	('Patients', 'Species', '9606', (63, 71))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (88, 108))	('associated', 'Reg', (267, 277))	('KDM5C', 'Gene', (163, 168))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (77, 108))	('Carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (183, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('PBRM1', 'Gene', '55193', (139, 144))	('VEGF', 'Gene', '7422', (38, 42))	('VHL', 'Disease', (134, 137))	('patients', 'Species', '9606', (295, 303))	('BAP1', 'Gene', '8314', (153, 157))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (77, 108))	('VEGF', 'Gene', (38, 42))	('SETD2', 'Gene', (146, 151))	('PBRM1', 'Gene', (139, 144))
193129	30334004	Results: The most frequent mutations were detected in VHL (83%), PBRM1 (51%), SETD2 (35%), BAP1 (24%), KDM5C (16%), and TERT (14%).	('mutations', 'Var', (27, 36))	('BAP1', 'Gene', (91, 95))	('SETD2', 'Gene', '29072', (78, 83))	('TERT', 'Gene', (120, 124))	('TERT', 'Gene', '7015', (120, 124))	('SETD2', 'Gene', (78, 83))	('PBRM1', 'Gene', (65, 70))	('PBRM1', 'Gene', '55193', (65, 70))	('KDM5C', 'Gene', (103, 108))	('BAP1', 'Gene', '8314', (91, 95))	('VHL', 'Disease', (54, 57))	('KDM5C', 'Gene', '8242', (103, 108))	('VHL', 'Disease', 'MESH:D006623', (54, 57))
193130	30334004	Time to treatment failure with VEGF-targeted therapy differed significantly by PBRM1 mutation status (p = 0.01, median 12.0 months for MT versus 6.9 months for WT) and BAP1 mutation status (p = 0.01, median 6.4 months for MT versus 11.0 months for WT).	('MT', 'Chemical', '-', (135, 137))	('VEGF', 'Gene', (31, 35))	('BAP1', 'Gene', '8314', (168, 172))	('BAP1', 'Gene', (168, 172))	('mutation', 'Var', (85, 93))	('PBRM1', 'Gene', (79, 84))	('PBRM1', 'Gene', '55193', (79, 84))	('MT', 'Chemical', '-', (222, 224))	('VEGF', 'Gene', '7422', (31, 35))	('mutation', 'Var', (173, 181))
193131	30334004	Shorter overall survival was associated with TERT mutations (p = 0.03, median 29.6 months for MT versus 52.6 months for WT) or BAP1 mutations (p = 0.02, median 28.7 months for MT versus not reached for WT).	('BAP1', 'Gene', (127, 131))	('MT', 'Chemical', '-', (94, 96))	('BAP1', 'Gene', '8314', (127, 131))	('overall survival', 'MPA', (8, 24))	('TERT', 'Gene', (45, 49))	('mutations', 'Var', (132, 141))	('TERT', 'Gene', '7015', (45, 49))	('Shorter', 'NegReg', (0, 7))	('MT', 'Chemical', '-', (176, 178))
193132	30334004	Conclusions: Genomic alterations in ccRCC tumors have prognostic implications in patients with metastatic disease.	('ccRCC tumors', 'Disease', (36, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('Genomic alterations', 'Var', (13, 32))	('patients', 'Species', '9606', (81, 89))	('metastatic', 'CPA', (95, 105))	('ccRCC tumors', 'Disease', 'MESH:D009369', (36, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('implications', 'Reg', (65, 77))
193133	30334004	BAP1 and TERT promoter mutations may be present in higher frequency than previously thought, and based on this data, deserve further study for their association with poor prognosis.	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (23, 32))	('BAP1', 'Gene', '8314', (0, 4))	('TERT', 'Gene', (9, 13))	('TERT', 'Gene', '7015', (9, 13))
193134	30334004	The most frequent mutations in metastatic clear cell renal cell carcinoma (ccRCC) are similar to those in localized ccRCC.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (42, 73))	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('RCC', 'Disease', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (53, 73))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (42, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('clear cell renal cell carcinoma', 'Disease', (42, 73))	('mutations', 'Var', (18, 27))
193135	30334004	Certain genetic alterations, such as BAP1, PBRM1 and TERT promoter mutations, may have prognostic implications in metastatic ccRCC and should be further investigated.	('TERT', 'Gene', (53, 57))	('PBRM1', 'Gene', (43, 48))	('TERT', 'Gene', '7015', (53, 57))	('PBRM1', 'Gene', '55193', (43, 48))	('mutations', 'Var', (67, 76))	('BAP1', 'Gene', '8314', (37, 41))	('implications', 'Reg', (98, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (125, 130))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('BAP1', 'Gene', (37, 41))	('RCC', 'Disease', (127, 130))
193142	30334004	In addition to confirming VHL alterations as linchpin events in the pathogenesis of ccRCC, they uncovered other recurrent genomic events, including alterations in the tumor suppressors PBRM1, SETD2, BAP1 and KDM5C.	('alterations', 'Var', (148, 159))	('PBRM1', 'Gene', (185, 190))	('pathogenesis', 'biological_process', 'GO:0009405', ('68', '80'))	('VHL', 'Disease', (26, 29))	('BAP1', 'Gene', (199, 203))	('KDM5C', 'Gene', '8242', (208, 213))	('SETD2', 'Gene', (192, 197))	('tumor', 'Disease', (167, 172))	('SETD2', 'Gene', '29072', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('RCC', 'Disease', (86, 89))	('VHL', 'Disease', 'MESH:D006623', (26, 29))	('KDM5C', 'Gene', (208, 213))	('PBRM1', 'Gene', '55193', (185, 190))	('alterations', 'Var', (30, 41))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('BAP1', 'Gene', '8314', (199, 203))
193162	30334004	The most frequent mutations were VHL (83%), PBRM1 (51%), SETD2 (35%), BAP1 (24%), KDM5C (16%), and TERT (14%).	('VHL', 'Disease', 'MESH:D006623', (33, 36))	('SETD2', 'Gene', '29072', (57, 62))	('mutations', 'Var', (18, 27))	('PBRM1', 'Gene', (44, 49))	('TERT', 'Gene', (99, 103))	('KDM5C', 'Gene', (82, 87))	('BAP1', 'Gene', '8314', (70, 74))	('PBRM1', 'Gene', '55193', (44, 49))	('TERT', 'Gene', '7015', (99, 103))	('SETD2', 'Gene', (57, 62))	('KDM5C', 'Gene', '8242', (82, 87))	('BAP1', 'Gene', (70, 74))	('VHL', 'Disease', (33, 36))
193163	30334004	KDM5C and BAP1 mutations were mutually exclusive, while 15 of 17 tumors with KDM5C alterations also harbored mutations in PBRM1.	('PBRM1', 'Gene', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('KDM5C', 'Gene', (77, 82))	('BAP1', 'Gene', (10, 14))	('harbored', 'Reg', (100, 108))	('PBRM1', 'Gene', '55193', (122, 127))	('KDM5C', 'Gene', '8242', (77, 82))	('tumors', 'Disease', (65, 71))	('KDM5C', 'Gene', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (109, 118))	('KDM5C', 'Gene', '8242', (0, 5))	('BAP1', 'Gene', '8314', (10, 14))
193164	30334004	Only one tumor had mutations in both BAP1 and TERT (Fig.	('TERT', 'Gene', '7015', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutations', 'Var', (19, 28))	('BAP1', 'Gene', '8314', (37, 41))	('tumor', 'Disease', (9, 14))	('TERT', 'Gene', (46, 50))	('BAP1', 'Gene', (37, 41))
193168	30334004	Similar adverse association with outcome was apparent for mutation status in BAP1 (p = 0.02, median 28.7 months vs. not reached) (Fig.	('BAP1', 'Gene', '8314', (77, 81))	('BAP1', 'Gene', (77, 81))	('mutation status', 'Var', (58, 73))
193171	30334004	TTF on first VEGF-targeted therapy by mutation status is summarized in Table 3.	('VEGF', 'Gene', '7422', (13, 17))	('VEGF', 'Gene', (13, 17))	('mutation', 'Var', (38, 46))
193173	30334004	BAP1 mutation status correlated adversely with TTF in VEGF-targeted therapy treated patients (p = 0.01; median 6.4 months for MT vs. 11.0 months for WT).	('BAP1', 'Gene', (0, 4))	('patients', 'Species', '9606', (84, 92))	('VEGF', 'Gene', (54, 58))	('TTF', 'Disease', (47, 50))	('MT', 'Chemical', '-', (126, 128))	('BAP1', 'Gene', '8314', (0, 4))	('mutation', 'Var', (5, 13))	('VEGF', 'Gene', '7422', (54, 58))
193174	30334004	We found no significant correlation for patients harboring mutations in VHL, SETD2, TERT, and KDM5C.	('SETD2', 'Gene', '29072', (77, 82))	('TERT', 'Gene', (84, 88))	('TERT', 'Gene', '7015', (84, 88))	('SETD2', 'Gene', (77, 82))	('KDM5C', 'Gene', '8242', (94, 99))	('patients', 'Species', '9606', (40, 48))	('VHL', 'Disease', 'MESH:D006623', (72, 75))	('mutations', 'Var', (59, 68))	('VHL', 'Disease', (72, 75))	('KDM5C', 'Gene', (94, 99))
193177	30334004	In this cohort, recurrent alterations were detected across genes previously implicated in early stage disease, including VHL, PBRM1, SETD2, and BAP1, but at a higher frequency than in prior reports.	('early stage disease', 'Disease', (90, 109))	('SETD2', 'Gene', '29072', (133, 138))	('PBRM1', 'Gene', (126, 131))	('BAP1', 'Gene', (144, 148))	('SETD2', 'Gene', (133, 138))	('alterations', 'Var', (26, 37))	('PBRM1', 'Gene', '55193', (126, 131))	('VHL', 'Disease', 'MESH:D006623', (121, 124))	('VHL', 'Disease', (121, 124))	('BAP1', 'Gene', '8314', (144, 148))
193178	30334004	For example, as compared to results from The Cancer Genome Atlas (TCGA), PBRM1 mutations were identified in 51 vs. 33%, SETD2 in 37 vs. 12%, and BAP1 in 24 vs. 10%; this finding supports their suggested significance in the pathogenesis of this disease, including development of a metastatic phenotype.	('SETD2', 'Gene', '29072', (120, 125))	('SETD2', 'Gene', (120, 125))	('BAP1', 'Gene', '8314', (145, 149))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('pathogenesis', 'biological_process', 'GO:0009405', ('223', '235'))	('Cancer Genome Atlas', 'Disease', (45, 64))	('BAP1', 'Gene', (145, 149))	('PBRM1', 'Gene', (73, 78))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (45, 64))	('PBRM1', 'Gene', '55193', (73, 78))	('mutations', 'Var', (79, 88))
193180	30334004	The presence of BAP1 or TERT promoter mutations was associated with a significantly worse OS.	('TERT', 'Gene', (24, 28))	('BAP1', 'Gene', '8314', (16, 20))	('TERT', 'Gene', '7015', (24, 28))	('presence', 'Var', (4, 12))	('BAP1', 'Gene', (16, 20))
193182	30334004	BAP1 codes for a deubiquitinating enzyme involved in chromatin remodeling, and several studies in mostly localized RCC have found that loss of BAP1 is associated with poor prognosis.	('BAP1', 'Gene', (143, 147))	('BAP1', 'Gene', (0, 4))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('53', '73'))	('deubiquitinating enzyme', 'molecular_function', 'GO:0004843', ('17', '40'))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('loss', 'Var', (135, 139))	('chromatin', 'cellular_component', 'GO:0000785', ('53', '62'))	('BAP1', 'Gene', '8314', (143, 147))	('BAP1', 'Gene', '8314', (0, 4))
193185	30334004	An exploratory analysis was performed to investigate if acquired mutations in BAP1 or TERT were associated with MSKCC prognostic risk group or the presence of sarcomatoid features on histopathologic review.	('sarcomatoid', 'Disease', (159, 170))	('associated', 'Reg', (96, 106))	('MSKCC', 'Disease', (112, 117))	('TERT', 'Gene', (86, 90))	('BAP1', 'Gene', '8314', (78, 82))	('sarcomatoid', 'Disease', 'MESH:C538614', (159, 170))	('TERT', 'Gene', '7015', (86, 90))	('mutations', 'Var', (65, 74))	('BAP1', 'Gene', (78, 82))
193188	30334004	In this study, mutations in PBRM1 correlated with statistically longer TTF with VEGF-targeted therapy, with a trend towards superior OS (not reached for MT vs. 36.3 months for WT; p = 0.12).	('longer', 'PosReg', (64, 70))	('MT', 'Chemical', '-', (153, 155))	('VEGF', 'Gene', (80, 84))	('mutations', 'Var', (15, 24))	('PBRM1', 'Gene', (28, 33))	('TTF', 'MPA', (71, 74))	('VEGF', 'Gene', '7422', (80, 84))	('PBRM1', 'Gene', '55193', (28, 33))
193191	30334004	PBRM1 is a component of the SWI/SNF chromatin remodeling complex, and mutations of PBRM1 are an early event in ccRCC tumor development.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutations', 'Var', (70, 79))	('tumor', 'Disease', (117, 122))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('36', '56'))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('PBRM1', 'Gene', (83, 88))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('PBRM1', 'Gene', '55193', (83, 88))	('RCC', 'Disease', (113, 116))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('36', '64'))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
193192	30334004	Together, these findings may suggest that loss of PBRM1 is biologically relevant for invasiveness and metastatic spread; but once tumor cells metastasize, those with loss of PBRM1 may behave less aggressively than tumors which metastasize by other molecular means (e.g.	('PBRM1', 'Gene', '55193', (50, 55))	('loss', 'Var', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Disease', (214, 220))	('tumor', 'Disease', (130, 135))	('less', 'NegReg', (191, 195))	('PBRM1', 'Gene', (50, 55))	('aggressively', 'PosReg', (196, 208))	('invasiveness', 'Disease', (85, 97))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('PBRM1', 'Gene', '55193', (174, 179))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('behave', 'CPA', (184, 190))	('PBRM1', 'Gene', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (214, 219))	('invasiveness', 'Disease', 'MESH:D009362', (85, 97))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))
193193	30334004	mutations in BAP1 or TERT).	('BAP1', 'Gene', (13, 17))	('TERT', 'Gene', (21, 25))	('TERT', 'Gene', '7015', (21, 25))	('mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (13, 17))
193194	30334004	Such observations are limited by sample size, and without a control arm, it is not possible to determine whether PBRM1 mutation status is a predictive or prognostic biomarker.	('PBRM1', 'Gene', (113, 118))	('mutation', 'Var', (119, 127))	('PBRM1', 'Gene', '55193', (113, 118))
193195	30334004	In the prior analysis of the RECORD-3 trial, there was a significant correlation between presence of KDM5C mutation and PFS in 111 patients receiving sunitinib (median PFS 8.3 for KDM5C WT vs. 20.6 months for MT; p = 0.03), but not for 109 everolimus-treated patients (median PFS 8.2 for KDM5C WT vs. 9.8 months for MT; p = 0.03).	('KDM5C', 'Gene', (101, 106))	('MT', 'Chemical', '-', (316, 318))	('patients', 'Species', '9606', (131, 139))	('KDM5C', 'Gene', '8242', (180, 185))	('everolimus', 'Chemical', 'MESH:D000068338', (240, 250))	('patients', 'Species', '9606', (259, 267))	('KDM5C', 'Gene', '8242', (101, 106))	('KDM5C', 'Gene', (288, 293))	('PFS', 'Gene', (120, 123))	('MT', 'Chemical', '-', (209, 211))	('KDM5C', 'Gene', '8242', (288, 293))	('sunitinib', 'Chemical', 'MESH:D000077210', (150, 159))	('KDM5C', 'Gene', (180, 185))	('presence', 'Var', (89, 97))
193251	33490707	In another study, single fraction 30Gy RT to tumour nodules in a murine model resulted in an intense CD8+ T cell tumour infiltrate, and a loss of myeloid derived suppressor cells (MDSCs).	('loss', 'NegReg', (138, 142))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('murine', 'Species', '10090', (65, 71))	('tumour nodules', 'Disease', 'MESH:D009369', (45, 59))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('myeloid derived suppressor cells', 'CPA', (146, 178))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('tumour', 'Disease', (113, 119))	('30Gy RT', 'Var', (34, 41))	('tumour nodules', 'Disease', (45, 59))	('tumour', 'Disease', (45, 51))
193411	32012488	Liang et al reported that fusion of the IGLL5 gene might promote metastasis of the lymph nodes and play a role in breast cancer development (Liang et al., 2015).	('fusion', 'Var', (26, 32))	('IGLL5', 'Gene', (40, 45))	('promote', 'PosReg', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('IGLL5', 'Gene', '100423062', (40, 45))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('play', 'Reg', (99, 103))	('metastasis of the lymph nodes', 'CPA', (65, 94))	('role', 'Reg', (106, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', (114, 127))
193412	32012488	Moreover, White et al found that an IGLL5 mutation was associated with the incidence and progression of multiple myeloma (MM) (White et al., 2018).	('IGLL5', 'Gene', (36, 41))	('multiple myeloma', 'Phenotype', 'HP:0006775', (104, 120))	('multiple myeloma', 'Disease', 'MESH:D009101', (104, 120))	('IGLL5', 'Gene', '100423062', (36, 41))	('multiple myeloma', 'Disease', (104, 120))	('associated with', 'Reg', (55, 70))	('mutation', 'Var', (42, 50))
193415	32012488	Expression dysregulation or POU2AF1 mutation is also related to the development of chronic lymphocytic leukemia (CLL) (Auer et al., 2005).	('related', 'Reg', (53, 60))	('Expression', 'MPA', (0, 10))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (83, 111))	('leukemia', 'Phenotype', 'HP:0001909', (103, 111))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (83, 111))	('POU2AF1', 'Gene', '5450', (28, 35))	('CLL', 'Phenotype', 'HP:0005550', (113, 116))	('chronic lymphocytic leukemia', 'Disease', (83, 111))	('POU2AF1', 'Gene', (28, 35))	('mutation', 'Var', (36, 44))
193425	32012488	These findings increase the understanding of the mechanisms through which gene expression affects the prognosis and development of ccRCC through the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('development', 'CPA', (116, 127))	('prognosis', 'CPA', (102, 111))	('gene expression', 'Var', (74, 89))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('tumor', 'Disease', (149, 154))	('RCC', 'Disease', (133, 136))	('affects', 'Reg', (90, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('gene expression', 'biological_process', 'GO:0010467', ('74', '89'))
193431	33681728	A BAP1 synonymous mutation results in exon skipping, loss of function and worse patient prognosis Synonymous mutations are generally disregarded by genomic analyses because they are considered non-pathogenic.	('exon skipping', 'MPA', (38, 51))	('BAP1', 'Gene', '8314', (2, 6))	('mutation', 'Var', (18, 26))	('patient', 'Species', '9606', (80, 87))	('BAP1', 'Gene', (2, 6))	('loss of function', 'NegReg', (53, 69))
193432	33681728	We identified and characterized a somatic synonymous mutation in the epigenetic modifier and tumor suppressor BAP1, resulting in exon skipping and complete protein inactivation.	('synonymous mutation', 'Var', (42, 61))	('protein', 'MPA', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('BAP1', 'Gene', (110, 114))	('tumor suppressor', 'biological_process', 'GO:0051726', ('93', '109'))	('exon skipping', 'MPA', (129, 142))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('93', '109'))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
193433	33681728	This radically altered the prognosis of a clear-cell renal cell carcinoma patient from The Cancer Genome Atlas (TCGA) with a PBRM1 mutation (a predictor biomarker for positive responses to immune checkpoint inhibitors) from good (an estimated overall survival of 117 months) to a very bad prognosis (an estimated overall survival of 31 months), emphasizing the importance of scrutinizing synonymous mutations near acceptor splice sites of cancer genes for accurate precision medicine.	('Cancer', 'Disease', (91, 97))	('patient', 'Species', '9606', (74, 81))	('Cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (439, 445))	('cancer', 'Disease', (439, 445))	('cancer', 'Disease', 'MESH:D009369', (439, 445))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (53, 73))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (42, 73))	('altered', 'Reg', (15, 22))	('clear-cell renal cell carcinoma', 'Disease', (42, 73))	('PBRM1', 'Gene', (125, 130))	('PBRM1', 'Gene', '55193', (125, 130))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (42, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('mutation', 'Var', (131, 139))
193434	33681728	First synonymous BAP1 mutation that leads to exon skipping and loss of function Exon 11 skipping is a hotspot for BAP1 inactivation First synonymous mutation reported to reduce fourfold the expected patient survival Synonymous mutations can inactivate cancer genes and affect patient prognosis Human genetics; genetics; cancer; KIRC-TCGA; personalized medicine Cancer can be broadly defined as a collection of remarkably complex diseases caused by the accumulation of genomic and epigenetic modifications, such as mutations and chromatin alterations, which can be fatal when metastatic.	('affect', 'Reg', (269, 275))	('mutation', 'Var', (22, 30))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('caused', 'Reg', (438, 444))	('Cancer', 'Disease', (361, 367))	('Human', 'Species', '9606', (294, 299))	('chromatin', 'cellular_component', 'GO:0000785', ('528', '537'))	('patient', 'Species', '9606', (199, 206))	('cancer', 'Disease', 'MESH:D009369', (320, 326))	('Cancer', 'Disease', 'MESH:D009369', (361, 367))	('mutations', 'Disease', (514, 523))	('patient', 'Species', '9606', (276, 283))	('BAP1', 'Gene', (17, 21))	('cancer', 'Disease', (252, 258))	('loss of function', 'NegReg', (63, 79))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('Cancer', 'Phenotype', 'HP:0002664', (361, 367))	('cancer', 'Disease', (320, 326))
193435	33681728	For each tumor type, and preferably for each patient, it is essential to identify the 'driver' mutations that lead to tumor development among the 'passenger' mutations.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', (118, 123))	('patient', 'Species', '9606', (45, 52))	('mutations', 'Var', (95, 104))
193436	33681728	Overall, synonymous mutations (1) were found to be enriched in known cancer genes, (2) show a negative correlation of their frequency with the mutational load, indicating a selective pressure resulting in highly recurrent synonymous mutations, (3) are non-randomly distributed along the coding sequence and within internal exons and (4) differentially affect codons for specific amino acids.	('codons for', 'MPA', (359, 369))	('synonymous mutations', 'Var', (222, 242))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('affect', 'Reg', (352, 358))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('synonymous mutations', 'Var', (9, 29))	('cancer', 'Disease', (69, 75))
193438	33681728	An early event in ccRCC development is the inactivation of the pVHL pathway, followed by inactivating mutations of chromatin remodelers, such as SETD2 and PBRM1.	('pVHL', 'Gene', '7428', (63, 67))	('chromatin', 'cellular_component', 'GO:0000785', ('115', '124'))	('pVHL', 'Gene', (63, 67))	('SETD2', 'Gene', '29072', (145, 150))	('ccRCC', 'Phenotype', 'HP:0006770', (18, 23))	('ccRCC', 'Disease', (18, 23))	('PBRM1', 'Gene', (155, 160))	('PBRM1', 'Gene', '55193', (155, 160))	('inactivation', 'NegReg', (43, 55))	('inactivating mutations', 'Var', (89, 111))	('SETD2', 'Gene', (145, 150))
193440	33681728	Thus, tumors with BAP1 mutations exhibit dismal prognosis and are characterized by aggressive features, including high tumor grade, mTORC1 activation, rhabdoid and sarcomatoid histologies, tumor necrosis, and poor patient survival.	('mTORC1', 'Gene', (132, 138))	('activation', 'PosReg', (139, 149))	('tumor necrosis', 'Disease', (189, 203))	('BAP1', 'Gene', (18, 22))	('mTORC1', 'Gene', '382056', (132, 138))	('rhabdoid', 'Disease', (151, 159))	('sarcomatoid', 'Disease', (164, 175))	('necrosis', 'biological_process', 'GO:0008220', ('195', '203'))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('necrosis', 'biological_process', 'GO:0070265', ('195', '203'))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('rhabdoid', 'Disease', 'MESH:D018335', (151, 159))	('mutations', 'Var', (23, 32))	('necrosis', 'biological_process', 'GO:0019835', ('195', '203'))	('necrosis', 'biological_process', 'GO:0001906', ('195', '203'))	('mTORC1', 'cellular_component', 'GO:0031931', ('132', '138'))	('patient', 'Species', '9606', (214, 221))	('sarcomatoid', 'Disease', 'MESH:C538614', (164, 175))	('tumors', 'Disease', (6, 12))	('tumor', 'Disease', (6, 11))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', (189, 194))	('necrosis', 'biological_process', 'GO:0008219', ('195', '203'))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor necrosis', 'Disease', 'MESH:D009336', (189, 203))
193441	33681728	In contrast, patients with PBRM1 mutations only (without BAP1 mutations) have good prognosis and are characterized by low tumor grade, low mTORC1 activity, and good overall survival.	('activity', 'MPA', (146, 154))	('low tumor', 'Disease', 'MESH:D009800', (118, 127))	('patients', 'Species', '9606', (13, 21))	('mutations', 'Var', (33, 42))	('low tumor', 'Disease', (118, 127))	('PBRM1', 'Gene', (27, 32))	('mTORC1', 'Gene', '382056', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mTORC1', 'cellular_component', 'GO:0031931', ('139', '145'))	('PBRM1', 'Gene', '55193', (27, 32))	('mTORC1', 'Gene', (139, 145))
193443	33681728	Notably, several other research teams independently confirmed these discoveries and enabled the molecular genetic classification of this tumor type based on inactivating mutations in BAP1 and PBRM1, providing the rationale for precision medicine using subtype-specific therapies.	('tumor', 'Disease', (137, 142))	('PBRM1', 'Gene', (192, 197))	('BAP1', 'Gene', (183, 187))	('PBRM1', 'Gene', '55193', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('inactivating mutations', 'Var', (157, 179))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
193446	33681728	This was considerably rapid for a ccRCC patient with a PBRM1 mutation, since an analysis of TCGA data showed a median overall survival of 117 months (95% confidence interval [CI]: 84-150 months) (Figure 1A).	('patient', 'Species', '9606', (40, 47))	('mutation', 'Var', (61, 69))	('ccRCC', 'Phenotype', 'HP:0006770', (34, 39))	('ccRCC', 'Disease', (34, 39))	('PBRM1', 'Gene', (55, 60))	('PBRM1', 'Gene', '55193', (55, 60))
193447	33681728	This relatively short survival was more similar to those patients with a BAP1 mutation (median overall survival of 73 months [95% CI: 20-127 months]) or patients with mutations in both BAP1 and PBRM1 (median overall survival of 31 months [95% CI: 15-48 months]) (Figure 1A).	('mutation', 'Var', (78, 86))	('patients', 'Species', '9606', (153, 161))	('BAP1', 'Gene', (185, 189))	('patients', 'Species', '9606', (57, 65))	('BAP1', 'Gene', (73, 77))	('mutations', 'Var', (167, 176))	('PBRM1', 'Gene', (194, 199))	('PBRM1', 'Gene', '55193', (194, 199))
193448	33681728	Indeed, this patient revealed a somatic synonymous BAP1 mutation near the acceptor splice site of exon 11 (c.936T>G, p.G312G) (Figure 1B).	('BAP1', 'Gene', (51, 55))	('patient', 'Species', '9606', (13, 20))	('c.936T>G', 'Mutation', 'c.936T>G', (107, 115))	('p.G312G', 'Var', (117, 124))	('p.G312G', 'SUBSTITUTION', 'None', (117, 124))	('c.936T>G', 'Var', (107, 115))
193450	33681728	A one-sample t test showed that the BAP1 protein expression of the index patient was closer to those of patients with mutations in BAP1 or both BAP1 and PBRM1 (p = 10-10 and 0.004, respectively) than patients with mutations in PBRM1 (p = 2 10-103) or wild-type for these genes (p = 3 10-112) (Figure 1D).	('BAP1 protein', 'Protein', (36, 48))	('PBRM1', 'Gene', '55193', (153, 158))	('patients', 'Species', '9606', (200, 208))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('BAP1', 'Gene', (144, 148))	('mutations', 'Var', (118, 127))	('PBRM1', 'Gene', (227, 232))	('patients', 'Species', '9606', (104, 112))	('patient', 'Species', '9606', (73, 80))	('patient', 'Species', '9606', (104, 111))	('PBRM1', 'Gene', '55193', (227, 232))	('BAP1', 'Gene', (131, 135))	('patient', 'Species', '9606', (200, 207))	('closer', 'PosReg', (85, 91))	('PBRM1', 'Gene', (153, 158))
193452	33681728	These levels, together with the highest tumor grade (grade 4) and pathologic stage III, are typically seen in patients with inactivating mutations in both BAP1 and PBRM1, or only in BAP1, rather than just in PBRM1.	('PBRM1', 'Gene', '55193', (208, 213))	('patients', 'Species', '9606', (110, 118))	('PBRM1', 'Gene', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('inactivating mutations', 'Var', (124, 146))	('BAP1', 'Gene', (155, 159))	('PBRM1', 'Gene', '55193', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('PBRM1', 'Gene', (208, 213))
193453	33681728	Indeed, these levels were closer to tumors with BAP1 or BAP1/PBRM1 mutations than PBRM1 mutations (Figure S2).	('PBRM1', 'Gene', (82, 87))	('PBRM1', 'Gene', '55193', (82, 87))	('PBRM1', 'Gene', (61, 66))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('PBRM1', 'Gene', '55193', (61, 66))	('BAP1', 'Gene', (48, 52))	('mutations', 'Var', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
193454	33681728	Thereby, these data strongly suggest that the p.G312G synonymous BAP1 mutation results in loss of BAP1 function and, consequently, higher tumor aggressiveness.	('loss', 'NegReg', (90, 94))	('tumor aggressiveness', 'Disease', (138, 158))	('BAP1', 'Gene', (65, 69))	('function', 'MPA', (103, 111))	('aggressiveness', 'Phenotype', 'HP:0000718', (144, 158))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('p.G312G', 'Var', (46, 53))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (138, 158))	('BAP1', 'Protein', (98, 102))	('higher', 'PosReg', (131, 137))	('p.G312G', 'SUBSTITUTION', 'None', (46, 53))
193455	33681728	To understand the mechanism of inactivation of BAP1 expression caused by the synonymous mutation, we cloned the full-length cDNA of wild-type BAP1 (or a catalytically inactivating p.C91S BAP1 mutation) into pBABE-hygro vector to ensure a constitutive basal expression and we generated the c.936T>G, p.G312G mutation by site-directed mutagenesis (Figure 2A).	('c.936T>G', 'Mutation', 'c.936T>G', (289, 297))	('p.G312G', 'Var', (299, 306))	('mutagenesis', 'biological_process', 'GO:0006280', ('333', '344'))	('BAP1', 'Gene', (187, 191))	('p.C91S', 'Var', (180, 186))	('p.C91S', 'Mutation', 'p.C91S', (180, 186))	('p.G312G', 'SUBSTITUTION', 'None', (299, 306))	('c.936T>G', 'Var', (289, 297))	('BAP1', 'Gene', (47, 51))
193456	33681728	We then reconstituted the BAP1-null ccRCC cell line UMRC-6 (or UM-RC-6) with wild-type BAP1, the p.G312G BAP1 mutant or the p.C91S BAP1 mutant constructs (and corresponding empty vector control).	('p.C91S', 'Mutation', 'p.C91S', (124, 130))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('p.G312G', 'Var', (97, 104))	('UMRC-6', 'CellLine', 'CVCL:2741', (52, 58))	('p.C91S', 'Var', (124, 130))	('BAP1', 'Gene', (131, 135))	('p.G312G', 'SUBSTITUTION', 'None', (97, 104))	('BAP1', 'Gene', (105, 109))
193457	33681728	We observed similar total BAP1 protein levels (Figure 2B) and BAP1 protein stability upon blocking the protein synthesis with cycloheximide treatment in both wild-type BAP1 and the p.G312G mutant (Figure 2C).	('p.G312G', 'Var', (181, 188))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('BAP1', 'Gene', (62, 66))	('protein', 'Protein', (103, 110))	('p.G312G', 'SUBSTITUTION', 'None', (181, 188))	('protein synthesis', 'biological_process', 'GO:0006412', ('103', '120'))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('cycloheximide', 'Chemical', 'MESH:D003513', (126, 139))
193458	33681728	We found similar results in a cholangiocarcinoma cell line, TFK-1, which had a nonsense mutation in BAP1 (Figures 2C and 2E).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (30, 48))	('BAP1', 'Gene', (100, 104))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (30, 48))	('nonsense mutation', 'Var', (79, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('cholangiocarcinoma', 'Disease', (30, 48))
193459	33681728	BAP1 targets the deubiquitination of histone H2A, and we observed that the synonymous p.G312G BAP1 mutation deubiquitinated histone H2A to the same extent as the wild-type BAP1 (Figure 2F).	('deubiquitination', 'biological_process', 'GO:0016579', ('17', '33'))	('p.G312G', 'Var', (86, 93))	('p.G312G', 'SUBSTITUTION', 'None', (86, 93))	('deubiquitination', 'MPA', (17, 33))	('deubiquitinated', 'MPA', (108, 123))	('BAP1', 'Gene', (94, 98))	('histone H2A', 'Protein', (124, 135))
193460	33681728	However, UMRC-6 cells lacking BAP1 or reconstituted with the p.C91S BAP1 mutant showed strong ubiquitination of histone H2A, suggesting that the synonymous c.936T>G mutation in the full-length cDNA is not affecting the BAP1 deubiquitinating function.	('p.C91S', 'Var', (61, 67))	('c.936T>G', 'Mutation', 'c.936T>G', (156, 164))	('p.C91S', 'Mutation', 'p.C91S', (61, 67))	('histone H2A', 'Protein', (112, 123))	('mutant', 'Var', (73, 79))	('ubiquitination', 'MPA', (94, 108))	('UMRC-6', 'CellLine', 'CVCL:2741', (9, 15))	('BAP1', 'Gene', (68, 72))	('c.936T>G', 'Var', (156, 164))
193463	33681728	As expected, cells reconstituted with the p.G312G BAP1 mutant showed similar mTORC1 activation as the wild-type and the p.C91S BAP1 mutant in UMRC-6 (Figure 2G) and TFK-1 (Figure S3A) cells.	('BAP1', 'Gene', (127, 131))	('p.G312G', 'Var', (42, 49))	('p.C91S', 'Var', (120, 126))	('activation', 'PosReg', (84, 94))	('mTORC1', 'Gene', (77, 83))	('mTORC1', 'cellular_component', 'GO:0031931', ('77', '83'))	('p.G312G', 'SUBSTITUTION', 'None', (42, 49))	('p.C91S', 'Mutation', 'p.C91S', (120, 126))	('UMRC-6', 'CellLine', 'CVCL:2741', (142, 148))	('BAP1', 'Gene', (50, 54))	('mTORC1', 'Gene', '382056', (77, 83))
193464	33681728	Furthermore, cell proliferation of the p.G312G BAP1 mutant cells was comparable to the wild-type BAP1 and the p.C91S mutant, as well the empty vector control in UMRC-6 and TFK-1 cells (Figure S3B).	('p.G312G', 'SUBSTITUTION', 'None', (39, 46))	('p.C91S', 'Mutation', 'p.C91S', (110, 116))	('cell proliferation', 'CPA', (13, 31))	('UMRC-6', 'CellLine', 'CVCL:2741', (161, 167))	('p.G312G', 'Var', (39, 46))	('BAP1', 'Gene', (47, 51))	('cell proliferation', 'biological_process', 'GO:0008283', ('13', '31'))
193465	33681728	Taking together, these data suggest that the c.936T>G, p.G312G synonymous mutation is not affecting BAP1 at the cDNA level and the change of codon is not responsible for its inactivation.	('p.G312G', 'Var', (55, 62))	('BAP1', 'Gene', (100, 104))	('p.G312G', 'SUBSTITUTION', 'None', (55, 62))	('c.936T>G', 'Var', (45, 53))	('c.936T>G', 'Mutation', 'c.936T>G', (45, 53))
193466	33681728	Since the c.936T>G mutation is located 4 base pairs away from the acceptor splice site (Figure 1B), we next considered whether the synonymous mutation might affect the alternative splicing machinery, presumably by generating a new binding site for an exonic splicing silencer.	('alternative splicing machinery', 'MPA', (168, 198))	('silencer', 'Disease', (267, 275))	('splicing', 'biological_process', 'GO:0045292', ('180', '188'))	('binding', 'molecular_function', 'GO:0005488', ('231', '238'))	('c.936T>G', 'Mutation', 'c.936T>G', (10, 18))	('c.936T>G', 'Var', (10, 18))	('splicing', 'biological_process', 'GO:0045292', ('258', '266'))	('binding', 'Interaction', (231, 238))	('affect', 'Reg', (157, 163))	('silencer', 'Disease', 'None', (267, 275))
193467	33681728	As a control, we cloned a BAP1 synonymous mutation found in lung adenocarcinoma 6 base pairs away from the donor splice site in exon 7 (c.576C>T, p.D192D) obtained from the SynMICdb database.	('BAP1', 'Gene', (26, 30))	('p.D192D', 'Mutation', 'rs765527118', (146, 153))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (60, 79))	('c.576C>T', 'Mutation', 'rs765527118', (136, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('c.576C>T', 'Var', (136, 144))	('lung adenocarcinoma', 'Disease', (60, 79))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (60, 79))
193469	33681728	Controls showed similar levels of exon integration and skipping, as assessed by western blotting (Figure S5A), RT-PCR (Figure S5B) and fluorescence microscopy (Figure S5C).	('skipping', 'MPA', (55, 63))	('S5B', 'Gene', (126, 129))	('S5B', 'Gene', '5711', (126, 129))	('exon', 'Var', (34, 38))
193471	33681728	Replacement of the synthetic exon by BAP1 exon 7 resulted in exon integration, which was not affected by the c.576C>T mutation and only partially altered by the co-expression of CELF2 and MBNL3 (Figure S4).	('MBNL3', 'Gene', '55796', (188, 193))	('MBNL3', 'Gene', (188, 193))	('CELF2', 'Gene', '10659', (178, 183))	('CELF2', 'Gene', (178, 183))	('Replacement', 'Var', (0, 11))	('c.576C>T', 'Mutation', 'rs765527118', (109, 117))	('c.576C>T', 'Var', (109, 117))	('resulted in', 'Reg', (49, 60))	('exon integration', 'MPA', (61, 77))
193472	33681728	However, the synonymous p.G312G mutation near the acceptor splice site at exon 11 showed striking exon skipping, quantified as 92% by western blotting (Figure 3B), 96% by RT-PCR (Figure 3C), and 92% by fluorescence microscopy (Figure 3D).	('exon', 'MPA', (98, 102))	('p.G312G', 'SUBSTITUTION', 'None', (24, 31))	('p.G312G', 'Var', (24, 31))
193473	33681728	Exon skipping of the p.G312G mutant BAP1 was significantly higher than the wild-type BAP1 exon 11 (74% [p = 2 10-7], 84% [p = 5 10-7], and 60% [p = 2 10-11], respectively).	('p.G312G', 'Var', (21, 28))	('higher', 'PosReg', (59, 65))	('p.G312G', 'SUBSTITUTION', 'None', (21, 28))	('Exon skipping', 'MPA', (0, 13))	('BAP1', 'Gene', (36, 40))
193474	33681728	The degree of exon skipping difference between the wild-type and mutant sequence was then between 12 and 32%, which is similar to the 10-23% reduction of exon-skipping frequency previously reported for several oncogenes and TP53.	('mutant', 'Var', (65, 71))	('exon skipping', 'Var', (14, 27))	('TP53', 'Gene', '7157', (224, 228))	('TP53', 'Gene', (224, 228))
193475	33681728	Therefore, these data demonstrate that the synonymous c.936T>G, p.G312G BAP1 mutation leads to exon 11 skipping.	('c.936T>G', 'Var', (54, 62))	('p.G312G', 'SUBSTITUTION', 'None', (64, 71))	('c.936T>G', 'Mutation', 'c.936T>G', (54, 62))	('BAP1', 'Gene', (72, 76))	('p.G312G', 'Var', (64, 71))	('exon 11 skipping', 'MPA', (95, 111))
193478	33681728	However, these reads did not contain the c.936T>G, p.G312G synonymous mutation, indicating that there is an extensive mRNA degradation of BAP1, in consonance with its low gene expression (Figure 1C).	('gene expression', 'biological_process', 'GO:0010467', ('171', '186'))	('p.G312G', 'Var', (51, 58))	('BAP1', 'Gene', (138, 142))	('p.G312G', 'SUBSTITUTION', 'None', (51, 58))	('mRNA degradation', 'MPA', (118, 134))	('mRNA degradation', 'biological_process', 'GO:0006402', ('118', '134'))	('c.936T>G', 'Mutation', 'c.936T>G', (41, 49))
193481	33681728	Therefore, the lack of BAP1 mutant mRNA reads in the index patient (Figure S6A) agrees with the nonsense-mediated mRNA decay caused by premature translation termination codon due to exon 11 skipping.	('BAP1', 'Gene', (23, 27))	('mutant', 'Var', (28, 34))	('patient', 'Species', '9606', (59, 66))	('translation termination', 'biological_process', 'GO:0006415', ('145', '168'))	('nonsense-mediated mRNA decay', 'biological_process', 'GO:0000184', ('96', '124'))
193482	33681728	Unexpectedly, a close examination of the eight KIRC-TCGA patients with splice-site mutations in BAP1 revealed that two patients had mutations in the acceptor splice site of BAP1 exon 11.	('mutations', 'Var', (83, 92))	('mutations in', 'Var', (132, 144))	('BAP1', 'Gene', (96, 100))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (119, 127))	('BAP1', 'Gene', (173, 177))
193483	33681728	TCGA-BP-4798 showed a c.IVS932-2A>G mutation that was considered likely pathogenic according to dbSNP database (rs112194987) and resulted in exon 11 skipping, as evidenced by RNA-Seq reads between exons 10 and 12 (Figure 4A).	('rs112194987', 'Mutation', 'rs112194987', (112, 123))	('skipping', 'NegReg', (149, 157))	('c.IVS932-2A>G', 'Var', (22, 35))	('c.IVS932-2A>G', 'Mutation', 'c.IVS932-2A>G', (22, 35))	('RNA', 'cellular_component', 'GO:0005562', ('175', '178'))	('exon 11', 'MPA', (141, 148))
193484	33681728	TCGA-CZ-5985 showed a c.IVS932-1G>T mutation (rs9848343 in dbSNP) and solid evidence for exon 11 skipping with 4 reads between exons 10 and 12 (Figure 4B).	('skipping', 'NegReg', (97, 105))	('c.IVS932-1G>T', 'Mutation', 'c.IVS932-1G>T', (22, 35))	('CZ', 'Chemical', 'MESH:C004578', (5, 7))	('rs9848343', 'Mutation', 'rs9848343', (46, 55))	('rs9848343', 'Var', (46, 55))
193485	33681728	Similar to the index patient, both splice-site mutations resulted in low BAP1 gene expression (Figure 4C) and BAP1 protein expression (Figure 4D), especially for TCGA-CZ-5985, which displayed the second lowest BAP1 levels from KIRC-TCGA.	('patient', 'Species', '9606', (21, 28))	('CZ', 'Chemical', 'MESH:C004578', (167, 169))	('mutations', 'Var', (47, 56))	('BAP1', 'Gene', (110, 114))	('BAP1 gene', 'Gene', (73, 82))	('gene expression', 'biological_process', 'GO:0010467', ('78', '93'))	('low', 'NegReg', (69, 72))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))
193487	33681728	Considering that there are 32 splicing sites among the 17 exons of BAP1, the fact of finding 2 of 8 patients with splice-site mutations in the acceptor splice site of exon 11 is very unlikely by chance alone (p = 0.0015), according to a cumulative binomial distribution.	('patients', 'Species', '9606', (100, 108))	('splicing', 'biological_process', 'GO:0045292', ('30', '38'))	('mutations', 'Var', (126, 135))	('BAP1', 'Gene', (67, 71))
193488	33681728	Patient TCGA-BP-4798 harbored an additional missense mutation in TP53 and showed distant metastasis at diagnosis, dying almost 11 months thereafter, whereas patient TCGA-CZ-5985 was still alive 65 months after diagnosis.	('CZ', 'Chemical', 'MESH:C004578', (170, 172))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('patient', 'Species', '9606', (157, 164))	('Patient', 'Species', '9606', (0, 7))	('missense mutation', 'Var', (44, 61))
193489	33681728	This suggests that despite having a similar BAP1 mutation and inactivation, other alterations contribute decisively in the patient prognosis, such as an additional PBRM1 mutation in the index patient and a TP53 mutation in TCGA-BP-4798.	('TP53', 'Gene', '7157', (206, 210))	('patient', 'Species', '9606', (192, 199))	('TP53', 'Gene', (206, 210))	('patient', 'Species', '9606', (123, 130))	('PBRM1', 'Gene', (164, 169))	('mutation', 'Var', (49, 57))	('PBRM1', 'Gene', '55193', (164, 169))	('contribute', 'Reg', (94, 104))	('mutation', 'Var', (170, 178))
193490	33681728	In summary, we have strong evidence to claim that the somatic synonymous mutation in BAP1 of the index patient results in exon 11 skipping, frameshift and premature stop codon, leading to mRNA and protein degradation and ultimately, together with chromosome 3p loss, to the complete loss of function for BAP1 (Figure 4G).	('protein degradation', 'biological_process', 'GO:0030163', ('197', '216'))	('BAP1', 'Gene', (85, 89))	('loss of function', 'NegReg', (283, 299))	('exon 11', 'MPA', (122, 129))	('chromosome', 'cellular_component', 'GO:0005694', ('247', '257'))	('frameshift', 'Var', (140, 150))	('skipping', 'NegReg', (130, 138))	('patient', 'Species', '9606', (103, 110))	('BAP1', 'Gene', (304, 308))	('premature stop codon', 'MPA', (155, 175))	('protein', 'cellular_component', 'GO:0003675', ('197', '204'))
193491	33681728	The inactivation of BAP1 contributed to a shorter survival than the one that would be expected for a patient with ccRCC with a PBRM1 mutation.	('ccRCC', 'Disease', (114, 119))	('mutation', 'Var', (133, 141))	('inactivation', 'Var', (4, 16))	('BAP1', 'Gene', (20, 24))	('shorter', 'NegReg', (42, 49))	('survival', 'MPA', (50, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('PBRM1', 'Gene', (127, 132))	('PBRM1', 'Gene', '55193', (127, 132))	('patient', 'Species', '9606', (101, 108))
193492	33681728	We describe here a patient with renal cell carcinoma with presumably good prognosis due to a PBRM1 mutation, who experienced a relatively short survival by harboring an additional unacknowledged inactivating synonymous mutation in BAP1.	('renal cell carcinoma', 'Disease', (32, 52))	('patient', 'Species', '9606', (19, 26))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (32, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('mutation', 'Var', (99, 107))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (32, 52))	('PBRM1', 'Gene', (93, 98))	('PBRM1', 'Gene', '55193', (93, 98))	('BAP1', 'Gene', (231, 235))	('due to', 'Reg', (84, 90))
193493	33681728	The tumor with the synonymous p.G312G mutation in BAP1 showed low gene expression and one of the lowest protein expressions from KIRC-TCGA, suggesting loss of function, as evidenced by phosphorylation of ribosomal protein S6, which is associated with BAP1 loss.	('tumor', 'Disease', (4, 9))	('phosphorylation', 'biological_process', 'GO:0016310', ('185', '200'))	('phosphorylation', 'MPA', (185, 200))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('p.G312G', 'SUBSTITUTION', 'None', (30, 37))	('low', 'NegReg', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('protein expressions', 'MPA', (104, 123))	('ribosomal protein S6', 'Gene', '6194', (204, 224))	('gene expression', 'biological_process', 'GO:0010467', ('66', '81'))	('gene expression', 'MPA', (66, 81))	('p.G312G', 'Var', (30, 37))	('loss', 'NegReg', (151, 155))	('ribosomal protein S6', 'Gene', (204, 224))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('204', '221'))	('protein', 'cellular_component', 'GO:0003675', ('214', '221'))	('BAP1', 'Gene', (50, 54))	('lowest', 'NegReg', (97, 103))
193494	33681728	However, reconstitution of BAP1-deficient ccRCC and cholangiocarcinoma cell lines with the c.936T>G BAP1 mutation in the full-length cDNA showed similar protein levels, stability and histone H2A deubiquitination as the wild-type BAP1, proving that the synonymous mutation is not disrupting BAP1 at the cDNA level.	('protein levels', 'MPA', (153, 167))	('c.936T>G', 'Var', (91, 99))	('protein', 'cellular_component', 'GO:0003675', ('153', '160'))	('BAP1', 'Gene', (100, 104))	('BAP1-deficient ccRCC and cholangiocarcinoma', 'Disease', 'MESH:D018281', (27, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (42, 47))	('deubiquitination', 'biological_process', 'GO:0016579', ('195', '211'))	('c.936T>G', 'Mutation', 'c.936T>G', (91, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('histone H2A deubiquitination', 'MPA', (183, 211))	('stability', 'MPA', (169, 178))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (52, 70))
193495	33681728	Remarkably, two of eight patients with splice-site BAP1 mutations from KIRC-TCGA showed mutations in the acceptor splice site of exon 11, suggesting that exon 11 skipping might be a hotspot for BAP1 inactivation.	('mutations', 'Var', (56, 65))	('mutations', 'Var', (88, 97))	('patients', 'Species', '9606', (25, 33))	('BAP1', 'Gene', (51, 55))
193496	33681728	Hence, we provide here strong evidence to support that the c.936T>G, p.G312G synonymous mutation in BAP1 results in exon 11 skipping, frameshift, premature stop codon, mRNA degradation, protein loss and, eventually, loss of function, which contributed negatively to decrease almost fourfold the expected patient survival (from 117 to 31 months).	('skipping', 'NegReg', (124, 132))	('protein', 'MPA', (186, 193))	('patient', 'Species', '9606', (304, 311))	('exon 11', 'MPA', (116, 123))	('mRNA degradation', 'MPA', (168, 184))	('p.G312G', 'Var', (69, 76))	('BAP1', 'Gene', (100, 104))	('frameshift', 'Var', (134, 144))	('loss', 'NegReg', (194, 198))	('mRNA degradation', 'biological_process', 'GO:0006402', ('168', '184'))	('c.936T>G', 'Mutation', 'c.936T>G', (59, 67))	('p.G312G', 'SUBSTITUTION', 'None', (69, 76))	('loss', 'NegReg', (216, 220))	('protein', 'cellular_component', 'GO:0003675', ('186', '193'))	('c.936T>G', 'Var', (59, 67))	('patient survival', 'CPA', (304, 320))	('decrease', 'NegReg', (266, 274))	('premature stop codon', 'MPA', (146, 166))
193497	33681728	This study has clinical relevance, since PBRM1 mutations were reported to be predictive biomarkers for positive responses to immune checkpoint inhibitors in renal cell carcinoma.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (157, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('mutations', 'Var', (47, 56))	('renal cell carcinoma', 'Disease', (157, 177))	('PBRM1', 'Gene', (41, 46))	('PBRM1', 'Gene', '55193', (41, 46))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (157, 177))
193498	33681728	However, recent clinical trials in advanced renal cell carcinoma showed no association of PBRM1 mutations with progression-free survival.	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('renal cell carcinoma', 'Disease', (44, 64))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (44, 64))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (44, 64))	('PBRM1', 'Gene', (90, 95))	('PBRM1', 'Gene', '55193', (90, 95))	('mutations', 'Var', (96, 105))
193500	33681728	Therefore, the clinical benefits observed by treatment with immune checkpoint inhibitors in patients with ccRCC with PRBM1 mutations, most likely are simply because, as we previously described, they are mutually exclusive of BAP1 mutations, which displayed poor overall patient survival.	('patient', 'Species', '9606', (92, 99))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('patients', 'Species', '9606', (92, 100))	('patient', 'Species', '9606', (270, 277))	('ccRCC', 'Disease', (106, 111))	('PRBM1', 'Gene', (117, 122))	('mutations', 'Var', (123, 132))	('benefits', 'PosReg', (24, 32))
193501	33681728	Thus, PBRM1 mutation should not be taken solely as a predictive marker in ccRCC but rather in combination with potential BAP1 inactivation (by DNA sequencing and/or immunohistochemistry) to have a more complete picture for each patient, fostering an accurate identification of the individual cancer driver genes and facilitating precision oncology.	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('ccRCC', 'Disease', (74, 79))	('fostering', 'PosReg', (237, 246))	('PBRM1', 'Gene', (6, 11))	('PBRM1', 'Gene', '55193', (6, 11))	('oncology', 'Phenotype', 'HP:0002664', (339, 347))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('cancer', 'Disease', (292, 298))	('mutation', 'Var', (12, 20))	('patient', 'Species', '9606', (228, 235))
193502	33681728	A BAP1 missense mutation (p.N78S), but not a synonymous mutation, was recently found to lead to alternative splicing.	('p.N78S', 'Mutation', 'rs1319729011', (26, 32))	('lead to', 'Reg', (88, 95))	('missense mutation', 'Var', (7, 24))	('splicing', 'biological_process', 'GO:0045292', ('108', '116'))	('alternative splicing', 'MPA', (96, 116))	('BAP1', 'Gene', (2, 6))
193503	33681728	By comparing immunohistochemistry with mutation data, we previously showed that all frameshift mutations (11/11) and 85% (11/13) of point mutations in BAP1 were unable to be translocated to the nucleus in ccRCC tumors, indicating loss of function.	('ccRCC tumors', 'Disease', (205, 217))	('ccRCC', 'Phenotype', 'HP:0006770', (205, 210))	('unable', 'NegReg', (161, 167))	('BAP1', 'Gene', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('frameshift mutations', 'Var', (84, 104))	('translocated', 'MPA', (174, 186))	('ccRCC tumors', 'Disease', 'MESH:D009369', (205, 217))	('point mutations', 'Var', (132, 147))	('nucleus', 'cellular_component', 'GO:0005634', ('194', '201'))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))
193504	33681728	In addition, all tumors with BAP1 mutations are accompanied by chromosomal 3p loss.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('chromosomal 3p loss', 'Var', (63, 82))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', (17, 23))	('BAP1', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('mutations', 'Var', (34, 43))
193505	33681728	This work also delivers insight into an unappreciated mechanism of inactivation of a very important tumor suppressor, which is frequently mutated and drives tumorigenesis in many cancer entities besides ccRCC, including uveal melanoma, mesothelioma, and cholangiocarcinoma.	('mesothelioma', 'Disease', (236, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('mesothelioma', 'Disease', 'MESH:D008654', (236, 248))	('tumor', 'Disease', (100, 105))	('melanoma', 'Disease', 'MESH:D008545', (226, 234))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('100', '116'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (220, 234))	('drives', 'Reg', (150, 156))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (254, 272))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('tumor suppressor', 'biological_process', 'GO:0051726', ('100', '116'))	('inactivation', 'Var', (67, 79))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('cholangiocarcinoma', 'Disease', (254, 272))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (254, 272))	('ccRCC', 'Disease', (203, 208))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('melanoma', 'Disease', (226, 234))	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('ccRCC', 'Phenotype', 'HP:0006770', (203, 208))	('cancer', 'Disease', (179, 185))
193509	32319593	G6PD dysregulation has been reported in various types of human cancer, and the role of G6PD in cancer progression was demonstrated in numerous studies.	('dysregulation', 'Var', (5, 18))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (95, 101))	('G6PD', 'Protein', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (63, 69))	('human', 'Species', '9606', (57, 62))
193510	32319593	A previous study from our laboratory described the prognostic significance of G6PD in clear cell renal cell carcinoma (ccRCC), and demonstrated its proliferative role through positive feedback regulation of the phosphorylated form of signal transducer and activator of transcription 3.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('clear cell renal cell carcinoma', 'Disease', (86, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (97, 117))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('transcription', 'biological_process', 'GO:0006351', ('269', '282'))	('G6PD', 'Var', (78, 82))	('RCC', 'Disease', (121, 124))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (86, 117))	('regulation', 'biological_process', 'GO:0065007', ('193', '203'))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('signal transducer and activator of transcription 3', 'Gene', '6774', (234, 284))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (86, 117))
193512	32319593	In the present study, reverse transcription-quantitative (RT-q) PCR, western blotting, enzyme activity assay, transwell assay and immunohistochemistry analysis in cell model, xenograft mice model and human specimen studies were performed to evaluate the role of G6PD in ccRCC invasion.	('RCC', 'Disease', (272, 275))	('ccRCC', 'Phenotype', 'HP:0006770', (270, 275))	('reverse transcription', 'biological_process', 'GO:0001171', ('22', '43'))	('mice', 'Species', '10090', (185, 189))	('human', 'Species', '9606', (200, 205))	('G6PD', 'Var', (262, 266))	('enzyme activity', 'molecular_function', 'GO:0003824', ('87', '102'))	('RCC', 'Phenotype', 'HP:0005584', (272, 275))	('RCC', 'Disease', 'MESH:C538614', (272, 275))
193513	32319593	The results from the present study demonstrated that G6PD may promote ccRCC cell invasive ability by increasing matrix metalloproteinase 2 (MMP2) mRNA and protein expression both in vitro and in vivo.	('increasing', 'PosReg', (101, 111))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('G6PD', 'Var', (53, 57))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('MMP2', 'molecular_function', 'GO:0004228', ('140', '144'))	('promote', 'PosReg', (62, 69))	('ccRCC', 'Phenotype', 'HP:0006770', (70, 75))	('matrix metalloproteinase 2', 'Gene', '4313', (112, 138))	('matrix metalloproteinase 2', 'Gene', (112, 138))
193514	32319593	In addition, a positive correlation between G6PD and MMP2 expression was demonstrated by RT-qPCR and western blotting in twenty pairs of ccRCC tumor specimens and matched adjacent normal tissues.	('G6PD', 'Var', (44, 48))	('ccRCC tumor', 'Disease', 'MESH:D009369', (137, 148))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('MMP2', 'molecular_function', 'GO:0004228', ('53', '57'))	('ccRCC tumor', 'Disease', (137, 148))	('MMP2', 'Gene', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
193515	32319593	Furthermore, G6PD promoted reactive oxygen species (ROS) generation and activated the MAPK signaling pathway in ccRCC cells.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('MAPK signaling pathway', 'Pathway', (86, 108))	('MAPK', 'molecular_function', 'GO:0004707', ('86', '90'))	('G6PD', 'Var', (13, 17))	('MAPK signaling', 'biological_process', 'GO:0000165', ('86', '100'))	('ROS', 'Chemical', 'MESH:D017382', (52, 55))	('signaling pathway', 'biological_process', 'GO:0007165', ('91', '108'))	('promoted', 'PosReg', (18, 26))	('ROS) generation', 'biological_process', 'GO:1903409', ('52', '67'))	('activated', 'PosReg', (72, 81))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (27, 50))
193516	32319593	In addition, ROS significantly promoted the MAPK signaling pathway activation, which in turn contributed to MMP2 overexpression in ccRCC cells.	('ROS', 'Var', (13, 16))	('signaling pathway', 'biological_process', 'GO:0007165', ('49', '66'))	('MMP2', 'molecular_function', 'GO:0004228', ('108', '112'))	('activation', 'PosReg', (67, 77))	('contributed', 'Reg', (93, 104))	('overexpression', 'PosReg', (113, 127))	('MMP2', 'Gene', (108, 112))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('MAPK', 'molecular_function', 'GO:0004707', ('44', '48'))	('promoted', 'PosReg', (31, 39))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('MAPK signaling pathway', 'Pathway', (44, 66))	('ROS', 'Chemical', 'MESH:D017382', (13, 16))	('MAPK signaling', 'biological_process', 'GO:0000165', ('44', '58'))
193517	32319593	In conclusion, the present study demonstrated that G6PD may facilitate ccRCC cell invasive ability by enhancing MMP2 expression through ROS-MAPK axis pathway.	('MMP2', 'molecular_function', 'GO:0004228', ('112', '116'))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('enhancing', 'PosReg', (102, 111))	('RCC', 'Disease', (73, 76))	('MMP2', 'Protein', (112, 116))	('ROS', 'Chemical', 'MESH:D017382', (136, 139))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('expression', 'MPA', (117, 127))	('G6PD', 'Var', (51, 55))	('MAPK', 'molecular_function', 'GO:0004707', ('140', '144'))	('facilitate', 'PosReg', (60, 70))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
193529	32319593	G6PD, which is the principal rate-limiting enzyme of the PPP, is the main actor in PPP-mediated cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('G6PD', 'Var', (0, 4))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))
193530	32319593	Furthermore, G6PD can cooperate with numerous signaling pathways in order to promote cancer, and G6PD was reported to be overexpressed in various types of tumor, including breast carcinoma, ccRCC and lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('breast carcinoma', 'Phenotype', 'HP:0003002', (172, 188))	('overexpressed', 'PosReg', (121, 134))	('lung adenocarcinoma', 'Disease', (200, 219))	('G6PD', 'Var', (13, 17))	('breast carcinoma', 'Disease', (172, 188))	('RCC', 'Disease', (192, 195))	('RCC', 'Phenotype', 'HP:0005584', (192, 195))	('ccRCC', 'Phenotype', 'HP:0006770', (190, 195))	('promote', 'PosReg', (77, 84))	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (200, 219))	('cancer', 'Disease', (85, 91))	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (200, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast carcinoma', 'Disease', 'MESH:D001943', (172, 188))	('G6PD', 'Var', (97, 101))
193531	32319593	Previous work from our laboratory described the prognostic significance of G6PD in ccRCC, and demonstrated its role in promoting tumor growth through positive feedback regulation of phospho-signal transducer and activator of transcription 3 (p-STAT3).	('signal transducer and activator of transcription 3', 'Gene', '6774', (190, 240))	('positive', 'PosReg', (150, 158))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('G6PD', 'Var', (75, 79))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('RCC', 'Disease', (85, 88))	('promoting', 'PosReg', (119, 128))	('STAT3', 'Gene', '6774', (244, 249))	('regulation', 'biological_process', 'GO:0065007', ('168', '178'))	('transcription', 'biological_process', 'GO:0006351', ('225', '238'))	('tumor', 'Disease', (129, 134))	('STAT3', 'Gene', (244, 249))
193532	32319593	However, G6PD ability to promote ccRCC invasion remains unknown.	('G6PD', 'Var', (9, 13))	('RCC', 'Disease', (35, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('promote', 'PosReg', (25, 32))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
193533	32319593	It has been reported that G6PD serves key roles in reactive oxygen species (ROS) accumulation.	('G6PD', 'Var', (26, 30))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (51, 74))	('reactive oxygen species', 'MPA', (51, 74))	('ROS', 'Chemical', 'MESH:D017382', (76, 79))
193534	32319593	Previous results from our laboratory demonstrated that G6PD could promote ROS generation by increasing NADPH oxidase 4 activity in ccRCC.	('NADPH oxidase', 'molecular_function', 'GO:0016174', ('103', '116'))	('ROS generation', 'MPA', (74, 88))	('increasing', 'PosReg', (92, 102))	('NADPH oxidase', 'molecular_function', 'GO:0008753', ('103', '116'))	('NADPH oxidase 4', 'Gene', '50507', (103, 118))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('promote', 'PosReg', (66, 73))	('G6PD', 'Var', (55, 59))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('activity', 'MPA', (119, 127))	('RCC', 'Disease', (133, 136))	('NADPH oxidase 4', 'Gene', (103, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('ROS generation', 'biological_process', 'GO:1903409', ('74', '88'))	('ROS', 'Chemical', 'MESH:D017382', (74, 77))
193535	32319593	ROS can induce continuous activation of pSTAT3, NF-kappaB and mitogen-activated protein kinase (MAPK) signaling pathways and promote the growth of certain cancer, including ccRCC, melanoma and liver cancer, regulate angiogenesis, and accelerate tumor metastasis by promoting the expression of a series of proliferation- and metastasis-related genes, including cyclinD1 and matrix metalloproteinases (MMPs).	('tumor metastasis', 'Disease', (245, 261))	('STAT3', 'Gene', (41, 46))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('angiogenesis', 'CPA', (216, 228))	('MAPK) signaling', 'biological_process', 'GO:0000165', ('96', '111'))	('cancer', 'Disease', (199, 205))	('cyclinD1', 'Gene', (360, 368))	('NF-kappaB', 'Gene', (48, 57))	('STAT3', 'Gene', '6774', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('NF-kappaB', 'Gene', '4790', (48, 57))	('activation', 'PosReg', (26, 36))	('liver cancer', 'Phenotype', 'HP:0002896', (193, 205))	('expression', 'MPA', (279, 289))	('angiogenesis', 'biological_process', 'GO:0001525', ('216', '228'))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('ROS', 'Var', (0, 3))	('melanoma and liver cancer', 'Disease', 'MESH:D006528', (180, 205))	('promoting', 'PosReg', (265, 274))	('growth', 'MPA', (137, 143))	('MAPK', 'molecular_function', 'GO:0004707', ('96', '100'))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('RCC', 'Disease', (175, 178))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('tumor metastasis', 'Disease', 'MESH:D009362', (245, 261))	('MMPs', 'Gene', (400, 404))	('cancer', 'Disease', (155, 161))	('promote', 'PosReg', (125, 132))	('regulate', 'Reg', (207, 215))	('ccRCC', 'Phenotype', 'HP:0006770', (173, 178))	('cyclinD1', 'Gene', '595', (360, 368))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('matrix metalloproteinases', 'Gene', (373, 398))	('accelerate', 'PosReg', (234, 244))	('MMPs', 'Gene', '4312;4313;17390;4316;4318;4319;4322', (400, 404))	('RCC', 'Disease', 'MESH:C538614', (175, 178))
193555	32319593	sc-203336) was purchased from Santa Cruz Biotechnology, Inc. 786-O cells were treated with NAC (20 mM) for 24 h or H2O2 (1 mM) for 2 h. The MAPK signaling pathway inhibitors SP600125 (cat.	('NAC', 'cellular_component', 'GO:0005854', ('91', '94'))	('cat', 'molecular_function', 'GO:0004096', ('184', '187'))	('NAC', 'Chemical', 'MESH:D000111', (91, 94))	('MAPK signaling', 'biological_process', 'GO:0000165', ('140', '154'))	('H2O2', 'Chemical', 'MESH:D006861', (115, 119))	('SP600125', 'Chemical', 'MESH:C432165', (174, 182))	('MAPK', 'molecular_function', 'GO:0004707', ('140', '144'))	('signaling pathway', 'biological_process', 'GO:0007165', ('145', '162'))	('SP600125', 'Var', (174, 182))	('MAPK signaling pathway', 'Pathway', (140, 162))
193562	32319593	Mice were subcutaneously injected with 1x106 G6PD knocked down Caki-1 cells, G6PD overexpressing ACHN cells or relevant control cells into the mice oxter flank (5 mice per group).	('Caki-1', 'CellLine', 'CVCL:0234', (63, 69))	('ACHN', 'Gene', (97, 101))	('G6PD overexpressing', 'Var', (77, 96))	('mice', 'Species', '10090', (163, 167))	('Mice', 'Species', '10090', (0, 4))	('Caki-1', 'Gene', (63, 69))	('mice', 'Species', '10090', (143, 147))
193564	32319593	P3761; Sigma-Aldrich; Merck KGaA) after the last measurement and tumors were harvested for further analysis.	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('P3761', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
193591	32319593	Firstly, paraffin sections of xenografted mice tumor, human ccRCC or adjacent normal tissues were dewaxed in xylene at room temperature and rehydrated by using decreasing ethanol series (100% twice, and 90, 80, 70 and 60% once, 5 min each time at room temperature).	('100', 'Var', (187, 190))	('human', 'Species', '9606', (54, 59))	('xylene', 'Chemical', 'MESH:D014992', (109, 115))	('mice', 'Species', '10090', (42, 46))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('paraffin', 'Chemical', 'MESH:D010232', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('ethanol', 'Chemical', 'MESH:D000431', (171, 178))	('tumor', 'Disease', (47, 52))
193610	32319593	As G6PD is naturally more expressed in Caki-1 cells compared with ACHN cells, G6PD was knocked down and overexpressed in Caki-1 and ACHN cells, respectively.	('Caki-1', 'CellLine', 'CVCL:0234', (121, 127))	('Caki-1', 'CellLine', 'CVCL:0234', (39, 45))	('G6PD', 'Var', (3, 7))	('G6PD', 'Var', (78, 82))
193614	32319593	These results indicated that G6PD may facilitate ccRCC invasive ability.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('facilitate', 'PosReg', (38, 48))	('G6PD', 'Var', (29, 33))	('ccRCC invasive ability', 'Disease', 'MESH:D009361', (49, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('ccRCC invasive ability', 'Disease', (49, 71))
193617	32319593	Specifically, MMP2 and MMP7 mRNA expression was increased in G6PD-knocked down Caki-1 cells compared with Caki-1-non-silencer cells, but decreased in G6PD-overexpressing ACHN cells (Fig.	('increased', 'PosReg', (48, 57))	('MMP7', 'Gene', '4316', (23, 27))	('MMP2', 'Gene', (14, 18))	('MMP2', 'molecular_function', 'GO:0004228', ('14', '18'))	('non-silencer', 'Disease', 'MESH:C580335', (113, 125))	('G6PD-knocked down', 'Var', (61, 78))	('Caki-1', 'CellLine', 'CVCL:0234', (106, 112))	('decreased', 'NegReg', (137, 146))	('non-silencer', 'Disease', (113, 125))	('MMP7', 'molecular_function', 'GO:0004235', ('23', '27'))	('Caki-1', 'CellLine', 'CVCL:0234', (79, 85))	('MMP7', 'Gene', (23, 27))
193618	32319593	In addition, the expression of MMP9 was not modified following G6PD knockdown or overexpression (Fig.	('G6PD', 'Var', (63, 67))	('MMP9', 'Gene', (31, 35))	('MMP9', 'molecular_function', 'GO:0004229', ('31', '35'))	('MMP9', 'Gene', '4318', (31, 35))
193619	32319593	In addition, MMP10 mRNA expression was significantly increased in G6PD-overexpressing ACHN cells, which was not the case for MMP13 mRNA expression.	('MMP13', 'Gene', '4322', (125, 130))	('MMP13', 'Gene', (125, 130))	('MMP10', 'Gene', (13, 18))	('G6PD-overexpressing', 'Var', (66, 85))	('MMP13', 'molecular_function', 'GO:0030404', ('125', '130'))	('MMP10', 'Gene', '4319', (13, 18))	('increased', 'PosReg', (53, 62))	('MMP10', 'molecular_function', 'GO:0030303', ('13', '18'))
193620	32319593	MMP10 and MMP13 mRNA expression was increased in G6PD-knocked down Caki-1 cells (Fig.	('MMP10', 'Gene', (0, 5))	('Caki-1', 'CellLine', 'CVCL:0234', (67, 73))	('MMP13', 'molecular_function', 'GO:0030404', ('10', '15'))	('MMP10', 'Gene', '4319', (0, 5))	('MMP10', 'molecular_function', 'GO:0030303', ('0', '5'))	('increased', 'PosReg', (36, 45))	('MMP13', 'Gene', '4322', (10, 15))	('MMP13', 'Gene', (10, 15))	('G6PD-knocked down', 'Var', (49, 66))
193622	32319593	2B and C, MMP2 was highly expressed in G6PD overexpressing ACHN cell lines, whereas it was decreased in G6PD-knocked down Caki-1 cell lines (Fig.	('ACHN', 'Disease', (59, 63))	('G6PD', 'Var', (39, 43))	('Caki-1', 'CellLine', 'CVCL:0234', (122, 128))	('overexpressing', 'PosReg', (44, 58))	('MMP2', 'molecular_function', 'GO:0004228', ('10', '14'))	('decreased', 'NegReg', (91, 100))
193623	32319593	In G6PD-knocked down Caki-1 cells, MMP2 activity was decreased; however, in G6PD overexpressing cells, MMP2 activity was increased by 0.8-fold (Fig.	('activity', 'MPA', (108, 116))	('Caki-1', 'CellLine', 'CVCL:0234', (21, 27))	('MMP2', 'Enzyme', (35, 39))	('increased', 'PosReg', (121, 130))	('MMP2', 'molecular_function', 'GO:0004228', ('103', '107'))	('activity', 'MPA', (40, 48))	('MMP2', 'molecular_function', 'GO:0004228', ('35', '39'))	('decreased', 'NegReg', (53, 62))	('G6PD', 'Var', (76, 80))
193627	32319593	These findings indicated that G6PD may promote ccRCC cell invasion, which may be due to enhanced MMP2 expression in ccRCC cells.	('RCC', 'Disease', (49, 52))	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('promote', 'PosReg', (39, 46))	('RCC', 'Disease', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('expression', 'MPA', (102, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('G6PD', 'Var', (30, 34))	('MMP2', 'Protein', (97, 101))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('enhanced', 'PosReg', (88, 96))	('MMP2', 'molecular_function', 'GO:0004228', ('97', '101'))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
193628	32319593	It has been established that G6PD stimulates ROS production in ccRCC cell lines.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('G6PD', 'Var', (29, 33))	('ROS', 'Chemical', 'MESH:D017382', (45, 48))	('stimulates', 'PosReg', (34, 44))	('ROS production', 'MPA', (45, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
193630	32319593	The results demonstrated that ROS accumulation was significantly decreased in G6PD-knocked down Caki-1 cells compared with the Non-silencer cells (Fig.	('Non-silencer', 'Disease', 'MESH:C580335', (127, 139))	('decreased', 'NegReg', (65, 74))	('ROS accumulation', 'MPA', (30, 46))	('G6PD-knocked down', 'Var', (78, 95))	('Non-silencer', 'Disease', (127, 139))	('Caki-1', 'CellLine', 'CVCL:0234', (96, 102))	('ROS', 'Chemical', 'MESH:D017382', (30, 33))
193631	32319593	3A-C, left panel); however, G6PD overexpression increased ROS levels in ACHN cells compared with control cells (Fig.	('ROS levels', 'MPA', (58, 68))	('G6PD', 'Var', (28, 32))	('overexpression increased', 'PosReg', (33, 57))	('ROS', 'Chemical', 'MESH:D017382', (58, 61))
193633	32319593	Subsequently, the present study hypothesized that G6PD may activate MAPK signaling pathway following increased ROS accumulation in the cytoplasm, leading to increased MMP2 expression in ccRCC cells.	('signaling pathway', 'biological_process', 'GO:0007165', ('73', '90'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('68', '82'))	('G6PD', 'Var', (50, 54))	('increased', 'PosReg', (101, 110))	('activate', 'PosReg', (59, 67))	('expression', 'MPA', (172, 182))	('MMP2', 'molecular_function', 'GO:0004228', ('167', '171'))	('ROS', 'Chemical', 'MESH:D017382', (111, 114))	('RCC', 'Disease', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('ROS', 'Protein', (111, 114))	('increased', 'PosReg', (157, 166))	('ccRCC', 'Phenotype', 'HP:0006770', (186, 191))	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('MAPK', 'molecular_function', 'GO:0004707', ('68', '72'))	('MMP2', 'Gene', (167, 171))	('cytoplasm', 'cellular_component', 'GO:0005737', ('135', '144'))	('MAPK signaling pathway', 'Pathway', (68, 90))
193634	32319593	Western blotting was therefore used to determine the expression of various proteins, including ERK, p38, JNK and their phosphorylated forms, which are involved in the MAPK signaling pathway in G6PD overexpressing or knocked down ccRCC cells.	('p38', 'Gene', (100, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (229, 234))	('JNK', 'molecular_function', 'GO:0004705', ('105', '108'))	('ERK', 'Gene', '5594', (95, 98))	('MAPK', 'molecular_function', 'GO:0004707', ('167', '171'))	('knocked down', 'Var', (216, 228))	('RCC', 'Disease', (231, 234))	('JNK', 'Gene', (105, 108))	('RCC', 'Phenotype', 'HP:0005584', (231, 234))	('MAPK signaling', 'biological_process', 'GO:0000165', ('167', '181'))	('ERK', 'Gene', (95, 98))	('RCC', 'Disease', 'MESH:C538614', (231, 234))	('signaling pathway', 'biological_process', 'GO:0007165', ('172', '189'))	('p38', 'Gene', '1432', (100, 103))	('JNK', 'Gene', '5599', (105, 108))	('ERK', 'molecular_function', 'GO:0004707', ('95', '98'))
193637	32319593	These results demonstrated that G6PD overexpression may enhance ROS accumulation and activate MAPK signaling pathway, suggesting that there may be an association between ROS production and MAPK signaling pathway activation in ccRCC cells.	('MAPK signaling pathway', 'Pathway', (189, 211))	('overexpression', 'PosReg', (37, 51))	('RCC', 'Disease', 'MESH:C538614', (228, 231))	('MAPK signaling pathway', 'Pathway', (94, 116))	('enhance', 'PosReg', (56, 63))	('ROS', 'Chemical', 'MESH:D017382', (64, 67))	('activate', 'PosReg', (85, 93))	('signaling pathway', 'biological_process', 'GO:0007165', ('194', '211'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('94', '108'))	('ROS accumulation', 'MPA', (64, 80))	('MAPK', 'molecular_function', 'GO:0004707', ('94', '98'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('189', '203'))	('ccRCC', 'Phenotype', 'HP:0006770', (226, 231))	('RCC', 'Disease', (228, 231))	('RCC', 'Phenotype', 'HP:0005584', (228, 231))	('MAPK', 'molecular_function', 'GO:0004707', ('189', '193'))	('signaling pathway', 'biological_process', 'GO:0007165', ('99', '116'))	('ROS', 'Chemical', 'MESH:D017382', (170, 173))	('activation', 'PosReg', (212, 222))	('G6PD', 'Var', (32, 36))
193639	32319593	The results demonstrate that ROS level was decreased in NAC-treated cells and increased in H2O2-treated cells compared with the control (Fig.	('NAC-treated', 'Var', (56, 67))	('ROS', 'Chemical', 'MESH:D017382', (29, 32))	('increased', 'PosReg', (78, 87))	('NAC', 'cellular_component', 'GO:0005854', ('56', '59'))	('ROS level', 'MPA', (29, 38))	('H2O2', 'Chemical', 'MESH:D006861', (91, 95))	('decreased', 'NegReg', (43, 52))	('NAC', 'Chemical', 'MESH:D000111', (56, 59))
193643	32319593	Taken together, these results suggested that interactions between G6PD-mediated ROS production and MAPK signaling pathway activation may promote MMP2 expression and contribute to ccRCC invasion.	('expression', 'MPA', (150, 160))	('MAPK signaling', 'biological_process', 'GO:0000165', ('99', '113'))	('ROS', 'Chemical', 'MESH:D017382', (80, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (179, 184))	('interactions', 'Interaction', (45, 57))	('promote', 'PosReg', (137, 144))	('MMP2', 'molecular_function', 'GO:0004228', ('145', '149'))	('contribute', 'Reg', (165, 175))	('G6PD-mediated', 'Var', (66, 79))	('MAPK', 'molecular_function', 'GO:0004707', ('99', '103'))	('MAPK', 'Pathway', (99, 103))	('signaling pathway', 'biological_process', 'GO:0007165', ('104', '121'))	('RCC', 'Disease', 'MESH:C538614', (181, 184))	('MMP2', 'Protein', (145, 149))	('RCC', 'Disease', (181, 184))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))
193648	32319593	The aforementioned results suggested that MAPK over-activation may contribute to G6PD-mediated ccRCC invasion via MMP2 upregulation.	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('over-activation', 'PosReg', (47, 62))	('G6PD-mediated', 'Var', (81, 94))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('MAPK', 'molecular_function', 'GO:0004707', ('42', '46'))	('upregulation', 'PosReg', (119, 131))	('MAPK', 'Protein', (42, 46))	('MMP2', 'Gene', (114, 118))	('MMP2', 'molecular_function', 'GO:0004228', ('114', '118'))
193650	32319593	The results demonstrated that MMP2 mRNA level was significantly decreased in Caki-1 cells following treatment with ERK inhibitor U0126, p38 inhibitor SB203580 and JNK inhibitor SP600125 (Fig.	('MMP2 mRNA level', 'MPA', (30, 45))	('JNK', 'Gene', (163, 166))	('SB203580', 'Chemical', 'MESH:C093642', (150, 158))	('SP600125', 'Chemical', 'MESH:C432165', (177, 185))	('ERK', 'Gene', (115, 118))	('SB203580', 'Var', (150, 158))	('MMP2', 'molecular_function', 'GO:0004228', ('30', '34'))	('JNK', 'molecular_function', 'GO:0004705', ('163', '166'))	('p38', 'Gene', '1432', (136, 139))	('SP600125', 'Var', (177, 185))	('Caki-1', 'CellLine', 'CVCL:0234', (77, 83))	('ERK', 'Gene', '5594', (115, 118))	('JNK', 'Gene', '5599', (163, 166))	('U0126', 'Chemical', 'MESH:C113580', (129, 134))	('p38', 'Gene', (136, 139))	('ERK', 'molecular_function', 'GO:0004707', ('115', '118'))	('decreased', 'NegReg', (64, 73))
193654	32319593	Mouse xenograft models were designed by inoculating G6PD-knocked down Caki-1 cells, G6PD-overexpressing ACHN cells or their control into nude mice.	('G6PD-knocked down', 'Var', (52, 69))	('nude mice', 'Species', '10090', (137, 146))	('Mouse', 'Species', '10090', (0, 5))	('Caki-1', 'Gene', (70, 76))	('Caki-1', 'CellLine', 'CVCL:0234', (70, 76))
193655	32319593	The results demonstrated that G6PD knockdown in Caki-1 cells induced smaller tumors, and the volume of a single tumor in the Non-silencer and G6PD KD group was 634.54 and 552.06 mm3, respectively.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('Caki-1', 'Gene', (48, 54))	('smaller', 'NegReg', (69, 76))	('G6PD knockdown', 'Var', (30, 44))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Caki-1', 'CellLine', 'CVCL:0234', (48, 54))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (77, 82))	('Non-silencer and G6PD KD', 'Disease', 'MESH:C537017', (125, 149))
193656	32319593	However, G6PD overexpressing ACHN cells produced larger tumors and the volume of a single tumor in the Control and G6PD OE group was 367.27 and 540.81 mm3, respectively (Fig.	('larger', 'PosReg', (49, 55))	('G6PD', 'Var', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('G6PD', 'Var', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
193657	32319593	Furthermore, the mRNA and protein expressions of G6PD and MMP2 in the mice tumors were evaluated by RT-qPCR and western blotting, respectively.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('MMP2', 'Gene', (58, 62))	('G6PD', 'Var', (49, 53))	('mice', 'Species', '10090', (70, 74))	('MMP2', 'molecular_function', 'GO:0004228', ('58', '62'))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))
193658	32319593	7E and S2 demonstrated that protein expression of G6PD and MMP2 was significantly decreased in G6PD knockdown Caki-1-derived tumor tissues, whereas G6PD and MMP2 expressions were significantly increased in G6PD overexpressing ACHN-derived tumor specimens compared with the control group.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('MMP2', 'Gene', (59, 63))	('protein expression', 'MPA', (28, 46))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('Caki-1', 'CellLine', 'CVCL:0234', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('MMP2', 'molecular_function', 'GO:0004228', ('157', '161'))	('tumor', 'Disease', (125, 130))	('G6PD knockdown', 'Var', (95, 109))	('increased', 'PosReg', (193, 202))	('tumor', 'Disease', (239, 244))	('MMP2', 'molecular_function', 'GO:0004228', ('59', '63'))	('decreased', 'NegReg', (82, 91))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))	('G6PD', 'Var', (50, 54))
193660	32319593	The results demonstrated that the staining density and intensity of G6PD and MMP2 were weaker in G6PD knockdown Caki-1-derived tumor tissues, whereas they were stronger in G6PD overexpressing ACHN-derived tumor specimens compared with the control group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', (127, 132))	('Caki-1', 'CellLine', 'CVCL:0234', (112, 118))	('G6PD knockdown', 'Var', (97, 111))	('MMP2', 'molecular_function', 'GO:0004228', ('77', '81'))	('staining', 'MPA', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('intensity', 'MPA', (55, 64))	('MMP2', 'Gene', (77, 81))	('weaker', 'NegReg', (87, 93))	('stronger', 'PosReg', (160, 168))
193661	32319593	Taken together, these data indicated that G6PD may positively regulate MMP2 expression and may therefore contribute to ccRCC growth.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('positively', 'PosReg', (51, 61))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('growth', 'CPA', (125, 131))	('RCC', 'Disease', (121, 124))	('contribute', 'Reg', (105, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('G6PD', 'Var', (42, 46))	('expression', 'MPA', (76, 86))	('regulate', 'Reg', (62, 70))	('MMP2', 'molecular_function', 'GO:0004228', ('71', '75'))	('MMP2', 'Gene', (71, 75))
193662	32319593	Previous studies reported that G6PD serves a key role in the development of various types of human cancer, including RCC.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('human', 'Species', '9606', (93, 98))	('cancer', 'Disease', (99, 105))	('G6PD', 'Var', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
193663	32319593	G6PD, which is the rate-limiting enzyme of the PPP, is overexpressed in numerous cancers and contributes to tumor growth.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('numerous cancers', 'Disease', (72, 88))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('G6PD', 'Var', (0, 4))	('tumor', 'Disease', (108, 113))	('overexpressed', 'PosReg', (55, 68))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('contributes', 'PosReg', (93, 104))	('numerous cancers', 'Disease', 'MESH:D009369', (72, 88))
193664	32319593	In a previous study conducted in our laboratory, we found that G6PD overexpression promoted RCC cell proliferation and tumorigenesis through the positive feedback regulation of p-STAT3.	('tumor', 'Disease', (119, 124))	('regulation', 'biological_process', 'GO:0065007', ('163', '173'))	('RCC', 'Disease', (92, 95))	('G6PD', 'Var', (63, 67))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('STAT3', 'Gene', '6774', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('promoted', 'PosReg', (83, 91))	('cell proliferation', 'biological_process', 'GO:0008283', ('96', '114'))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('STAT3', 'Gene', (179, 184))
193665	32319593	A recent study demonstrated that the blockade of G6PD by polydatin not only leads to cell cycle arrest and cell apoptosis, but also inhibits tumor cell invasion, reduces tumor size and inhibits lymph node metastasis, indicating therefore the crucial role of G6PD in tumor progression.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('blockade', 'Var', (37, 45))	('reduces', 'NegReg', (162, 169))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', (266, 271))	('arrest', 'Disease', 'MESH:D006323', (96, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('112', '121'))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('apoptosis', 'biological_process', 'GO:0006915', ('112', '121'))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('inhibits', 'NegReg', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('85', '102'))	('polydatin', 'Gene', (57, 66))	('polydatin', 'Chemical', 'MESH:C058229', (57, 66))	('inhibits', 'NegReg', (185, 193))	('arrest', 'Disease', (96, 102))	('lymph node metastasis', 'CPA', (194, 215))	('tumor', 'Disease', (141, 146))	('G6PD', 'Gene', (49, 53))	('cell apoptosis', 'CPA', (107, 121))
193667	32319593	Lu et al reported that elevated G6PD expression is associated with the poor prognosis of patients with hepatocellular carcinoma, and that G6PD overexpression contributes to migration and invasion of hepatocellular carcinoma cells by stimulating the epithelial-mesenchymal transition.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (103, 127))	('hepatocellular carcinoma', 'Disease', (199, 223))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (199, 223))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (103, 127))	('elevated', 'PosReg', (23, 31))	('stimulating', 'PosReg', (233, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('migration', 'CPA', (173, 182))	('hepatocellular carcinoma', 'Disease', (103, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('249', '282'))	('G6PD expression', 'MPA', (32, 47))	('patients', 'Species', '9606', (89, 97))	('overexpression contributes', 'PosReg', (143, 169))	('G6PD', 'Var', (138, 142))	('epithelial-mesenchymal transition', 'CPA', (249, 282))	('invasion', 'CPA', (187, 195))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (199, 223))
193668	32319593	Despite these accumulating evidence on the role of G6PD in cancer progression, whether G6PD could mediate RCC invasion, and by which underlying mechanisms, remain unclear.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('G6PD', 'Var', (51, 55))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('RCC', 'Disease', 'MESH:C538614', (106, 109))
193675	32319593	The results from the present study and from previous studies suggested that G6PD may promote ROS production in RCC cells.	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('promote', 'PosReg', (85, 92))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('ROS', 'Chemical', 'MESH:D017382', (93, 96))	('ROS production', 'MPA', (93, 107))	('G6PD', 'Var', (76, 80))
193676	32319593	The present study hypothesized that G6PD could be involved in ccRCC invasion through the ROS-MAPK-MMPs axis.	('ROS', 'Chemical', 'MESH:D017382', (89, 92))	('MMPs', 'Gene', (98, 102))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('RCC', 'Disease', (64, 67))	('MMPs', 'Gene', '4312;4313;17390;4316;4318;4319;4322', (98, 102))	('MAPK', 'molecular_function', 'GO:0004707', ('93', '97'))	('involved', 'Reg', (50, 58))	('G6PD', 'Var', (36, 40))
193677	32319593	To do so, stable ccRCC cells lines where G6PD was over-expressed or knocked down were designed.	('knocked down', 'Var', (68, 80))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('ccRCC', 'Phenotype', 'HP:0006770', (17, 22))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('G6PD', 'Var', (41, 45))	('over-expressed', 'PosReg', (50, 64))
193679	32319593	The results demonstrated that G6PD overexpression increased ccRCC cell invasive ability, whereas its downregulation had the opposite effect.	('overexpression increased', 'PosReg', (35, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('G6PD', 'Var', (30, 34))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))
193680	32319593	These findings suggested that G6PD may facilitate ccRCC invasion.	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (50, 55))	('RCC', 'Disease', (52, 55))	('G6PD', 'Var', (30, 34))	('facilitate', 'PosReg', (39, 49))
193683	32319593	In addition, results from Pearson correlation analysis demonstrated a positive correlation between MMP2 and G6PD expression, suggesting that MMP2 overexpression may be dependent of G6PD dysregulation in ccRCC.	('RCC', 'Disease', (205, 208))	('RCC', 'Phenotype', 'HP:0005584', (205, 208))	('MMP2', 'molecular_function', 'GO:0004228', ('141', '145'))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('ccRCC', 'Phenotype', 'HP:0006770', (203, 208))	('MMP2', 'molecular_function', 'GO:0004228', ('99', '103'))	('dysregulation', 'Var', (186, 199))
193684	32319593	Moreover, upregulated MMP2 expression following G6PD overexpres-sion was observed in xenografted mice model.	('MMP2', 'molecular_function', 'GO:0004228', ('22', '26'))	('mice', 'Species', '10090', (97, 101))	('expression', 'MPA', (27, 37))	('upregulated', 'PosReg', (10, 21))	('G6PD', 'Var', (48, 52))	('MMP2', 'Gene', (22, 26))
193685	32319593	Taken together, these findings indicated that G6PD may stimulate ccRCC invasion by upregulating MMP2.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('MMP2', 'Protein', (96, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('MMP2', 'molecular_function', 'GO:0004228', ('96', '100'))	('upregulating', 'PosReg', (83, 95))	('G6PD', 'Var', (46, 50))	('stimulate', 'PosReg', (55, 64))
193689	32319593	Furthermore, the expression ratios of p-ERK/ERK, p-p38/p38 and p-JNK/JNK was increased in G6PD overexpressing cells and decreased in G6PD knocked down cells, indicating that activation of the MAPK signaling pathway may depend on G6PD regulation.	('JNK', 'Gene', '5599', (65, 68))	('JNK', 'molecular_function', 'GO:0004705', ('69', '72'))	('ERK', 'Gene', (44, 47))	('p38', 'Gene', '1432', (55, 58))	('increased', 'PosReg', (77, 86))	('decreased', 'NegReg', (120, 129))	('p38', 'Gene', (51, 54))	('ERK', 'Gene', '5594', (40, 43))	('expression', 'MPA', (17, 27))	('JNK', 'Gene', (69, 72))	('JNK', 'molecular_function', 'GO:0004705', ('65', '68'))	('regulation', 'biological_process', 'GO:0065007', ('234', '244'))	('MAPK', 'molecular_function', 'GO:0004707', ('192', '196'))	('JNK', 'Gene', '5599', (69, 72))	('ERK', 'Gene', (40, 43))	('ERK', 'molecular_function', 'GO:0004707', ('44', '47'))	('p38', 'Gene', '1432', (51, 54))	('MAPK signaling', 'biological_process', 'GO:0000165', ('192', '206'))	('p38', 'Gene', (55, 58))	('ERK', 'molecular_function', 'GO:0004707', ('40', '43'))	('MAPK signaling pathway', 'Pathway', (192, 214))	('signaling pathway', 'biological_process', 'GO:0007165', ('197', '214'))	('ERK', 'Gene', '5594', (44, 47))	('G6PD', 'Var', (90, 94))	('JNK', 'Gene', (65, 68))
193690	32319593	In addition, the present study confirmed that G6PD overexpression could enhance ROS production in ccRCC cells.	('RCC', 'Disease', (100, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('enhance', 'PosReg', (72, 79))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('ROS production', 'MPA', (80, 94))	('ROS', 'Chemical', 'MESH:D017382', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('G6PD', 'Var', (46, 50))	('overexpression', 'PosReg', (51, 65))
193697	32319593	ROS-mediated MAPK signaling pathway dysregulation may therefore contribute to MMP2 overexpression in ccRCC cells.	('dysregulation', 'Var', (36, 49))	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('MAPK', 'molecular_function', 'GO:0004707', ('13', '17'))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('contribute', 'Reg', (64, 74))	('overexpression', 'PosReg', (83, 97))	('signaling pathway', 'biological_process', 'GO:0007165', ('18', '35'))	('MMP2', 'molecular_function', 'GO:0004228', ('78', '82'))	('MMP2', 'Gene', (78, 82))	('MAPK signaling', 'biological_process', 'GO:0000165', ('13', '27'))
193698	32319593	In summary, the present study demonstrated that G6PD may facilitate ccRCC invasion, probably by enhancing MMP2 expression through the ROS-MAPK axis pathway (Fig.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('MMP2', 'Protein', (106, 110))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('ROS', 'Chemical', 'MESH:D017382', (134, 137))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('MMP2', 'molecular_function', 'GO:0004228', ('106', '110'))	('MAPK', 'molecular_function', 'GO:0004707', ('138', '142'))	('enhancing', 'PosReg', (96, 105))	('expression', 'MPA', (111, 121))	('G6PD', 'Var', (48, 52))	('facilitate', 'PosReg', (57, 67))
193699	32319593	The results from the present study confirmed the oncogenic role of G6PD in ccRCC progression, and may contribute to the better understanding of ccRCC invasion and the development of novel therapeutic options for ccRCC.	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('G6PD', 'Var', (67, 71))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('ccRCC', 'Phenotype', 'HP:0006770', (212, 217))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Disease', (214, 217))	('RCC', 'Phenotype', 'HP:0005584', (214, 217))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('RCC', 'Disease', 'MESH:C538614', (214, 217))
193700	32319593	2018FE468(-001), 2017FE468(-132), 2017FE468(-003), 2017FE468(-141), 2017FE468(-072) and 2018FB120].	('2018FE468', 'Var', (0, 9))	('2018FE468', 'Chemical', '-', (0, 9))	('2017FE468', 'Chemical', '-', (68, 77))	('2017FE468', 'Var', (34, 43))	('2018FB120', 'Chemical', '-', (88, 97))	('2017FE468', 'Chemical', '-', (17, 26))	('2017FE468', 'Chemical', '-', (34, 43))	('2017FE468', 'Var', (17, 26))	('2017FE468', 'Chemical', '-', (51, 60))	('2017FE468', 'Var', (51, 60))
193704	30510921	Unclassified renal cell carcinoma: diagnostic difficulties and treatment modalities Over the past few decades, the classification system of renal cell carcinoma (RCC) variants has witnessed tremendous and ongoing refinement driven by genomic profiling and morphological correlation that have provided valuable insights into tumor biology and characterization of this heterogeneous subset of tumors.	('tumors', 'Disease', (391, 397))	('renal cell carcinoma', 'Disease', (140, 160))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (140, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('tumor', 'Disease', (391, 396))	('RCC', 'Disease', (162, 165))	('tumors', 'Disease', 'MESH:D009369', (391, 397))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('tumor', 'Disease', 'MESH:D009369', (391, 396))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (13, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('variants', 'Var', (167, 175))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (140, 160))	('tumors', 'Phenotype', 'HP:0002664', (391, 397))	('tumor', 'Disease', (324, 329))	('renal cell carcinoma', 'Disease', (13, 33))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (13, 33))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
193747	30510921	Although there is extensive morphologic overlap among these entities, the underlying genetic alterations are different, with tumors with RAT morphology sharing a frequent mutation in TCEB1 gene.	('TCEB1', 'Gene', '64525', (183, 188))	('mutation', 'Var', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('TCEB1', 'Gene', (183, 188))	('RAT', 'Species', '10116', (137, 140))
193752	30510921	While gains of chromosomes 7 and 17 as well as MET alterations are seen in type 1 tumors, type 2 is increasingly recognized to represent a very distinct (from conventional pRCC) but quite heterogeneous group containing at least three distinct molecular clusters.	('MET alterations', 'Var', (47, 62))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('type 1 tumors', 'Disease', 'MESH:D009369', (75, 88))	('gains', 'PosReg', (6, 11))	('type 1 tumors', 'Disease', (75, 88))
193753	30510921	These include tumors with molecular alterations involving the NRF2-ARE pathway, chromatin-modifying genes, TFE3 fusions, CDKN2A silencing, and CpG island methylator phenotype.	('NRF2', 'Gene', '4780', (62, 66))	('CDKN2A', 'Gene', '1029', (121, 127))	('chromatin-modifying genes', 'Gene', (80, 105))	('silencing', 'NegReg', (128, 137))	('chromatin', 'cellular_component', 'GO:0000785', ('80', '89'))	('NRF2', 'Gene', (62, 66))	('TFE3', 'Gene', '7030', (107, 111))	('fusions', 'Var', (112, 119))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('CDKN2A', 'Gene', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('TFE3', 'Gene', (107, 111))
193757	30510921	MiTF-RCCs are a group of tumors characterized by recurrent rearrangements of TFE3 (at the Xp11 locus) or TFEB (at the 6p21 locus) genes, both of which are members of the MiT family of transcription factors.	('TFEB', 'Gene', '7942', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('TFEB', 'Gene', (105, 109))	('transcription', 'biological_process', 'GO:0006351', ('184', '197'))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('TFE3', 'Gene', (77, 81))	('rearrangements', 'Var', (59, 73))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('MiTF-RCC', 'Disease', (0, 8))	('TFE3', 'Gene', '7030', (77, 81))	('MiTF-RCC', 'Disease', 'MESH:C538614', (0, 8))
193762	30510921	On the other hand, tumors with PRCC-TFE3 rearrangement tend to have more of a nested, papillary, or compact architecture, with less abundant cytoplasm and lower grade nuclei.	('tumors', 'Disease', (19, 25))	('rearrangement', 'Var', (41, 54))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('cytoplasm', 'cellular_component', 'GO:0005737', ('141', '150'))	('TFE3', 'Gene', (36, 40))	('PRCC', 'Gene', '5546', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('TFE3', 'Gene', '7030', (36, 40))	('PRCC', 'Gene', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('papillary', 'CPA', (86, 95))	('nested', 'CPA', (78, 84))	('compact architecture', 'CPA', (100, 120))
193763	30510921	TFEB or t(6;11) translocation RCCs are more indolent tumors characterized by TFEB gene fusion with Alpha gene.	('t(6;11', 'Gene', (8, 14))	('TFEB', 'Gene', '7942', (77, 81))	('TFEB', 'Gene', (77, 81))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('RCC', 'Disease', (30, 33))	('TFEB', 'Gene', '7942', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('TFEB', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('translocation', 'Var', (16, 29))	('tumors', 'Disease', (53, 59))
193766	30510921	This overall pattern is seen irrespective of whether carcinomas show TFE3 or TFEB rearrangements, though often TFEB-rearranged carcinomas show quite strong expression of melanocytic markers.	('carcinomas', 'Disease', 'MESH:D002277', (127, 137))	('rearrangements', 'Var', (82, 96))	('carcinomas', 'Disease', (127, 137))	('TFEB', 'Gene', '7942', (77, 81))	('TFE3', 'Gene', (69, 73))	('TFE3', 'Gene', '7030', (69, 73))	('TFEB', 'Gene', (77, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('TFEB', 'Gene', '7942', (111, 115))	('carcinomas', 'Disease', (53, 63))	('carcinomas', 'Disease', 'MESH:D002277', (53, 63))	('expression', 'MPA', (156, 166))	('TFEB', 'Gene', (111, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))
193769	30510921	Dual-color break-apart fluorescence in situ hybridization assays for TFE3 and TFEB rearrangements are very sensitive and specific for confirming the diagnosis.	('TFEB', 'Gene', '7942', (78, 82))	('rearrangements', 'Var', (83, 97))	('TFEB', 'Gene', (78, 82))	('TFE3', 'Gene', '7030', (69, 73))	('TFE3', 'Gene', (69, 73))
193788	30510921	More recently described entities in this differential include SDH-deficient RCCs, such as that arise in the hereditary paraganglioma/pheochromocytoma syndromes (PGL1-4) or Carney Stratakis syndrome (with GISTs), in patients harboring germline mutation of SDH subunit genes.	('SDH', 'Gene', '6390', (62, 65))	('patients', 'Species', '9606', (215, 223))	('Carney Stratakis syndrome', 'Disease', (172, 197))	('SDH-deficient RCCs', 'Disease', 'MESH:D007153', (62, 80))	('Carney Stratakis syndrome', 'Disease', 'MESH:C564650', (172, 197))	('PGL1-4', 'Gene', (161, 167))	('paraganglioma', 'Phenotype', 'HP:0002668', (119, 132))	('SDH', 'Gene', (62, 65))	('PGL1-4', 'Gene', '54949;6391;6390', (161, 167))	('SDH', 'Gene', (255, 258))	('PGL', 'molecular_function', 'GO:0004598', ('161', '164'))	('germline mutation', 'Var', (234, 251))	('SDH-deficient RCCs', 'Disease', (62, 80))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (133, 149))	('SDH', 'Gene', '6390', (255, 258))	('hereditary paraganglioma/pheochromocytoma syndromes', 'Disease', 'MESH:D010673', (108, 159))
193793	30510921	In clinical practice, screening for SDH deficiency is done by SDHB immunohistochemical stain which also identifies deficiencies in other subunits of the enzyme (SDHA, SDHC, SDHD, SDHAF2) that result in destabilization of the SDH complex.	('SDHA', 'Gene', (161, 165))	('SDHAF2', 'Gene', '54949', (179, 185))	('SDHAF2', 'Gene', (179, 185))	('SDH', 'Gene', (179, 182))	('SDHA', 'Gene', '6389', (161, 165))	('SDH', 'Gene', '6390', (167, 170))	('SDH', 'Gene', (225, 228))	('SDHB', 'Gene', '6390', (62, 66))	('SDH', 'Gene', '6390', (62, 65))	('SDH deficiency', 'Disease', (36, 50))	('SDH', 'Gene', (161, 164))	('SDHC', 'Gene', '6391', (167, 171))	('SDH', 'Gene', '6390', (173, 176))	('SDH deficiency', 'Disease', 'MESH:D007153', (36, 50))	('SDHB', 'Gene', (62, 66))	('SDHD', 'Gene', '6392', (173, 177))	('SDH', 'Gene', (167, 170))	('SDH', 'Gene', (62, 65))	('SDH', 'Gene', '6390', (36, 39))	('deficiencies', 'Var', (115, 127))	('SDH', 'Gene', (173, 176))	('destabilization', 'MPA', (202, 217))	('SDH', 'Gene', '6390', (179, 182))	('SDHA', 'Gene', (179, 183))	('SDHC', 'Gene', (167, 171))	('SDHD', 'Gene', (173, 177))	('SDH', 'Gene', '6390', (225, 228))	('SDHA', 'Gene', '6389', (179, 183))	('SDH', 'Gene', (36, 39))	('SDH', 'Gene', '6390', (161, 164))
193811	30510921	The latter tumors generally arise in the syndrome of HLRCC, with cutaneous and uterine leiomyomatosis and germline mutations in the FH gene.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('HLRCC', 'Disease', 'MESH:C535516', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('leiomyomatosis', 'Disease', 'MESH:D018231', (87, 101))	('germline mutations', 'Var', (106, 124))	('tumors', 'Disease', (11, 17))	('arise in', 'Reg', (28, 36))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('FH', 'Gene', '2271', (132, 134))	('cutaneous and uterine leiomyomatosis', 'Phenotype', 'HP:0007620', (65, 101))	('leiomyomatosis', 'Disease', (87, 101))	('uterine leiomyomatosis', 'Phenotype', 'HP:0000131', (79, 101))	('HLRCC', 'Disease', (53, 58))
193814	30510921	Most cases with FH mutation demonstrate loss of expression of FH itself by immunohistochemistry, as well as aberrant expression of 2 succinyl-cysteine (2SC) on cytoplasmic and nuclear proteins, useful in confirming the diagnosis.	('FH', 'Gene', '2271', (62, 64))	('mutation', 'Var', (19, 27))	('expression', 'MPA', (117, 127))	('expression', 'MPA', (48, 58))	('aberrant', 'Var', (108, 116))	('loss', 'NegReg', (40, 44))	('FH', 'Gene', '2271', (16, 18))	('2SC', 'Chemical', 'MESH:C511650', (152, 155))	('2 succinyl-cysteine', 'Chemical', 'MESH:C511650', (131, 150))
193824	30510921	Further confirmation of the diagnosis may be supported by biallelic inactivation of SMARCB1 (INI-1) through deletion and/or genomic rearrangements, with overexpression of POU5F1 (Oct3/4) with widely available immunohistochemical assays.	('overexpression', 'PosReg', (153, 167))	('Oct3/4', 'Gene', '5460', (179, 185))	('Oct3/4', 'Gene', (179, 185))	('SMARCB1', 'Gene', '6598', (84, 91))	('INI-1', 'Gene', '6598', (93, 98))	('INI-1', 'Gene', (93, 98))	('SMARCB1', 'Gene', (84, 91))	('POU5F1', 'Gene', '5460', (171, 177))	('POU5F1', 'Gene', (171, 177))	('biallelic', 'Var', (58, 67))	('genomic rearrangements', 'Var', (124, 146))	('deletion', 'Var', (108, 116))
193829	30510921	p63, GATA3, and uroplakin 2 positivity, on the other hand, favors a primary UC.	('uroplakin 2', 'Gene', (16, 27))	('uroplakin 2', 'Gene', '7379', (16, 27))	('primary UC', 'Disease', (68, 78))	('p63', 'Gene', (0, 3))	('GATA3', 'Gene', (5, 10))	('positivity', 'Var', (28, 38))	('p63', 'Gene', '8626', (0, 3))	('GATA3', 'Gene', '2625', (5, 10))
193842	30510921	Molecular characterization of unclassified RCCs demonstrates many shared underlying genomic alterations compared with ccRCCs such as TP53 alterations, MTOR mutations, and NF2 mutations, while there are distinct differences such as lack of VHL alterations with unclassified RCC compared to ccRCC.	('VHL', 'Disease', (239, 242))	('VHL', 'Disease', 'MESH:D006623', (239, 242))	('MTOR', 'Gene', '2475', (151, 155))	('mutations', 'Var', (156, 165))	('NF2', 'Gene', '4771', (171, 174))	('RCC', 'Disease', 'MESH:C538614', (273, 276))	('RCC', 'Disease', (273, 276))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('mutations', 'Var', (175, 184))	('MTOR', 'Gene', (151, 155))	('RCC', 'Disease', (291, 294))	('RCC', 'Disease', (120, 123))	('RCC', 'Disease', 'MESH:C538614', (291, 294))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('TP53', 'Gene', '7157', (133, 137))	('TP53', 'Gene', (133, 137))	('NF2', 'Gene', (171, 174))
193907	30510921	These include CHECK2 alterations or PBRM1 alterations (potentially respond to checkpoint inhibitors), ALK translocations (ALK-targeted therapies), and ATM/BRCA2 alterations (PARP inhibitors), as examples.	('ATM', 'Gene', '472', (151, 154))	('PARP', 'Gene', '1302', (174, 178))	('PBRM1', 'Gene', (36, 41))	('alterations', 'Var', (42, 53))	('PBRM1', 'Gene', '55193', (36, 41))	('ALK', 'Gene', (102, 105))	('alterations', 'Var', (161, 172))	('CHECK2', 'Gene', (14, 20))	('PARP', 'Gene', (174, 178))	('BRCA2', 'Gene', '675', (155, 160))	('ALK', 'Gene', (122, 125))	('ATM', 'Gene', (151, 154))	('ALK', 'Gene', '238', (102, 105))	('alterations', 'Var', (21, 32))	('ALK', 'Gene', '238', (122, 125))	('BRCA2', 'Gene', (155, 160))
193934	29942157	PI3K can phosphorylate phosphatidylinositol 3,4 (PIP2) and activate the AKT.	('AKT', 'Gene', '207', (72, 75))	('PIP2', 'Chemical', 'MESH:D019269', (49, 53))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('PI3K', 'Var', (0, 4))	('AKT', 'Gene', (72, 75))	('activate', 'PosReg', (59, 67))	('phosphatidylinositol 3,4', 'Chemical', '-', (23, 47))
193954	29942157	Based on these datasets (GSE40435, GSE46699, GSE15641, GSE66272; Table S1), no change in eIF4E expression was observed in the tissues of ccRCC compared with adjacent normal renal tissues (Figure 1A-D).	('eIF4', 'cellular_component', 'GO:0008304', ('89', '93'))	('GSE46699', 'Var', (35, 43))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('eIF4E', 'Gene', '1977', (89, 94))	('RCC', 'Disease', (139, 142))	('GSE15641', 'Var', (45, 53))	('GSE40435', 'Var', (25, 33))	('GSE66272', 'Var', (55, 63))	('eIF4E', 'Gene', (89, 94))
193963	29942157	To our surprise, the mRNA and protein expression of 4E-BP1 were overexpressed in ccRCC tissues based on four datasets (GSE40435, GSE46699, GSE15641, GSE66272; Figure 3A-D and Table S1) and immunohistochemical staining of 4E-BP1 in 101 ccRCC tissues and their adjacent normal renal tissues.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('GSE46699', 'Var', (129, 137))	('RCC', 'Disease', (83, 86))	('GSE15641', 'Var', (139, 147))	('4E-BP1', 'Gene', (221, 227))	('GSE40435', 'Var', (119, 127))	('4E-BP1', 'Gene', '1978', (52, 58))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('overexpressed', 'PosReg', (64, 77))	('RCC', 'Disease', (237, 240))	('GSE66272', 'Var', (149, 157))	('4E-BP1', 'Gene', '1978', (221, 227))	('RCC', 'Disease', 'MESH:C538614', (237, 240))	('4E-BP1', 'Gene', (52, 58))
193997	27733136	Inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) in granulocytes contributes to development of liver hemangiomas in a mouse model Mutations in the tumor suppressor gene von Hippel-Lindau (VHL) underlie a hereditary cancer syndrome:VHL disease:and are also frequently observed in sporadic renal cell carcinoma of the clear cell type (ccRCC).	('sporadic renal cell carcinoma', 'Disease', (296, 325))	('VHL', 'Gene', (205, 208))	('tumor', 'Disease', (164, 169))	('sporadic renal cell carcinoma', 'Disease', 'MESH:C538614', (296, 325))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (305, 325))	('mouse', 'Species', '10090', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('Mutations', 'Var', (147, 156))	('renal cell carcinoma of the clear cell type', 'Phenotype', 'HP:0006770', (305, 348))	('tumor', 'Disease', (20, 25))	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (221, 247))	('liver hemangiomas', 'Phenotype', 'HP:0031207', (112, 129))	('VHL', 'Gene', '22346', (205, 208))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('164', '180'))	('VHL', 'Gene', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('von Hippel-Lindau', 'Gene', (186, 203))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('von Hippel-Lindau', 'Gene', (42, 59))	('hemangiomas', 'Phenotype', 'HP:0001028', (118, 129))	('hemangioma', 'Phenotype', 'HP:0001028', (118, 128))	('tumor suppressor', 'biological_process', 'GO:0051726', ('164', '180'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('20', '36'))	('VHL', 'Gene', '22346', (61, 64))	('hereditary cancer syndrome', 'Disease', (221, 247))	('VHL disease', 'Disease', 'MESH:D006623', (248, 259))	('VHL', 'Gene', (248, 251))	('von Hippel-Lindau', 'Gene', '22346', (186, 203))	('VHL disease', 'Disease', (248, 259))	('tumor suppressor', 'biological_process', 'GO:0051726', ('20', '36'))	('liver hemangiomas', 'Disease', (112, 129))	('liver hemangiomas', 'Disease', 'MESH:D006391', (112, 129))	('von Hippel-Lindau', 'Gene', '22346', (42, 59))	('liver hemangioma', 'Phenotype', 'HP:0031207', (112, 128))	('VHL', 'Gene', '22346', (248, 251))
194002	27733136	Previously we showed that inactivation of Vhlh in a subpopulation of kidney distal tubule cells resulted in hyperplastic clear-cell lesions and severe inflammation and fibrosis.	('inactivation', 'Var', (26, 38))	('inflammation', 'biological_process', 'GO:0006954', ('151', '163'))	('fibrosis', 'Disease', (168, 176))	('hyperplastic clear-cell lesions', 'CPA', (108, 139))	('fibrosis', 'Disease', 'MESH:D005355', (168, 176))	('Vhlh', 'Gene', '22346', (42, 46))	('inflammation', 'Disease', 'MESH:D007249', (151, 163))	('resulted in', 'Reg', (96, 107))	('Vhlh', 'Gene', (42, 46))	('inflammation', 'Disease', (151, 163))
194007	27733136	These results support the idea that the development of a full-blown VHL disease phenotype requires inactivation of the VHL gene not only in the tumor proper, but also in the stromal compartment.	('tumor', 'Disease', (144, 149))	('VHL disease', 'Disease', 'MESH:D006623', (68, 79))	('VHL', 'Gene', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('VHL disease', 'Disease', (68, 79))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('inactivation', 'Var', (99, 111))
194008	27733136	Patients with VHL disease are heterozygous for VHL mutations, and develop tumors when the function of the remaining wild-type VHL allele is lost via somatic mutation or epigenetic silencing.	('VHL disease', 'Disease', (14, 25))	('mutations', 'Var', (51, 60))	('develop', 'PosReg', (66, 73))	('lost', 'NegReg', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('epigenetic silencing', 'Var', (169, 189))	('VHL disease', 'Disease', 'MESH:D006623', (14, 25))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
194010	27733136	VHL mutations are also frequently observed in sporadic renal cell carcinoma (ccRCC).	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (55, 75))	('sporadic renal cell carcinoma', 'Disease', 'MESH:C538614', (46, 75))	('sporadic renal cell carcinoma', 'Disease', (46, 75))	('VHL', 'Gene', (0, 3))	('observed', 'Reg', (34, 42))	('mutations', 'Var', (4, 13))
194011	27733136	In addition, specific VHL missense mutations have been described that do not cause tumors, but result instead in recessive polycythemia, a disease characterized by an overproduction of erythrocytes.	('missense mutations', 'Var', (26, 44))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('VHL', 'Gene', (22, 25))	('result', 'Reg', (95, 101))	('recessive polycythemia', 'Disease', (113, 135))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('recessive polycythemia', 'Disease', 'MESH:D011086', (113, 135))	('polycythemia', 'Phenotype', 'HP:0001901', (123, 135))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
194013	27733136	HIF induces a metabolic switch from oxidative phosphorylation to glycolysis, which is essential for cell survival under hypoxic conditions.	('hypoxic conditions', 'Disease', (120, 138))	('HIF', 'Var', (0, 3))	('hypoxic conditions', 'Disease', 'MESH:D009135', (120, 138))	('oxidative phosphorylation', 'MPA', (36, 61))	('glycolysis', 'biological_process', 'GO:0006096', ('65', '75'))	('induces', 'Reg', (4, 11))	('metabolic switch', 'MPA', (14, 30))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('36', '61'))	('glycolysis', 'MPA', (65, 75))
194021	27733136	However, loss of HIF-independent functions of VHL, and mutations of additional tumor suppressor genes, likely also contribute to tumorigenesis.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('79', '95'))	('VHL', 'Gene', (46, 49))	('tumor', 'Disease', (79, 84))	('mutations', 'Var', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('functions', 'MPA', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (129, 134))	('tumor suppressor', 'biological_process', 'GO:0051726', ('79', '95'))	('contribute', 'Reg', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
194022	27733136	Recent animal model and cancer genome studies have indicated that VHL mutations are necessary but insufficient for tumorigenesis.	('mutations', 'Var', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('VHL', 'Gene', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
194023	27733136	Such second and even third hits conceivably can be additional genetic or epigenetic changes within the same cells, or can be within a separate cell population that contributes to the formation of tumor microenvironment.	('rat', 'Species', '10116', (138, 141))	('contributes', 'Reg', (164, 175))	('tumor', 'Disease', (196, 201))	('epigenetic', 'Var', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('formation', 'biological_process', 'GO:0009058', ('183', '192'))
194025	27733136	BAP1 gene mutations have been observed in ~10 % of ccRCC samples.	('BAP1', 'Gene', (0, 4))	('observed', 'Reg', (30, 38))	('mutations', 'Var', (10, 19))	('BAP1', 'Gene', '104416', (0, 4))	('ccRCC', 'Disease', (51, 56))
194026	27733136	Vhlh-Bap1 double knockout generated clear-cell lesions that resemble carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('carcinoma', 'Disease', (69, 78))	('rat', 'Species', '10116', (30, 33))	('Vhlh', 'Gene', '22346', (0, 4))	('Vhlh', 'Gene', (0, 4))	('Bap1', 'Gene', '104416', (5, 9))	('carcinoma', 'Disease', 'MESH:D002277', (69, 78))	('Bap1', 'Gene', (5, 9))	('double knockout', 'Var', (10, 25))
194027	27733136	On the other hand, mutations in the cancer stromal cells, including those of the well-known tumor suppressor genes p53 and PTEN, have been documented that contribute to cancer progression {reviewed in }.	('tumor suppressor', 'biological_process', 'GO:0051726', ('92', '108'))	('cancer', 'Disease', (169, 175))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('92', '108'))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('cancer', 'Disease', (36, 42))	('PTEN', 'Gene', '19211', (123, 127))	('mutations', 'Var', (19, 28))	('p53', 'Gene', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('p53', 'Gene', '22060', (115, 118))	('PTEN', 'Gene', (123, 127))	('tumor', 'Disease', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('contribute', 'Reg', (155, 165))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
194031	27733136	Hemangioblastomas are sometimes referred to as vascular tumors; however, biallelic inactivation of VHL was detected in the stromal compartment of the vascular tumors, which also have a clear cell appearance.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('vascular tumors', 'Disease', 'MESH:D019043', (150, 165))	('Hemangioblastomas are sometimes referred to as vascular tumors', 'Phenotype', 'HP:0012329', (0, 62))	('detected', 'Reg', (107, 115))	('VHL', 'Gene', (99, 102))	('Hemangioblastomas', 'Disease', (0, 17))	('vascular tumors', 'Phenotype', 'HP:0100742', (47, 62))	('vascular tumors', 'Disease', 'MESH:D019043', (47, 62))	('vascular tumors', 'Phenotype', 'HP:0100742', (150, 165))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('biallelic inactivation', 'Var', (73, 95))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('vascular tumors', 'Disease', (47, 62))	('vascular tumors', 'Disease', (150, 165))	('Hemangioblastomas', 'Disease', 'MESH:D018325', (0, 17))	('Hemangioblastoma', 'Phenotype', 'HP:0010797', (0, 16))
194036	27733136	These two models contain heterozygous and homozygous, respectively, Vhlh mutants in most cell types, including hepatocytes and endothelial cells.	('Vhlh', 'Gene', '22346', (68, 72))	('Vhlh', 'Gene', (68, 72))	('mutants', 'Var', (73, 80))
194037	27733136	More interestingly, liver hemangiomas were also observed in PEPCK-Cre driven Vhlh knockout, which inactivates Vhlh in renal proximal tubule cells and in ~20 to 30 % of hepatocytes.	('inactivates', 'Var', (98, 109))	('Vhlh', 'Gene', '22346', (77, 81))	('Vhlh', 'Gene', (77, 81))	('liver hemangioma', 'Phenotype', 'HP:0031207', (20, 36))	('liver hemangiomas', 'Phenotype', 'HP:0031207', (20, 37))	('hemangioma', 'Phenotype', 'HP:0001028', (26, 36))	('hemangiomas', 'Phenotype', 'HP:0001028', (26, 37))	('liver hemangiomas', 'Disease', (20, 37))	('Vhlh', 'Gene', '22346', (110, 114))	('Vhlh', 'Gene', (110, 114))	('liver hemangiomas', 'Disease', 'MESH:D006391', (20, 37))
194038	27733136	Likely due to early mortality, full-blown hemangiomas were not observed when a more hepatocyte-specific Cre driver, Albumin-Cre, was used to inactivate Vhlh; nonetheless, numerous blood-filled vascular cavities, and foci of increased vascularization within the hepatic parenchyma were observed.	('vascularization', 'CPA', (234, 249))	('blood-filled vascular cavities', 'CPA', (180, 210))	('hemangiomas', 'Disease', (42, 53))	('blown hemangiomas', 'Phenotype', 'HP:0012329', (36, 53))	('hemangiomas', 'Phenotype', 'HP:0001028', (42, 53))	('hemangiomas', 'Disease', 'MESH:D006391', (42, 53))	('Vhlh', 'Gene', '22346', (152, 156))	('inactivate', 'Var', (141, 151))	('hemangioma', 'Phenotype', 'HP:0001028', (42, 52))	('increased', 'PosReg', (224, 233))	('Vhlh', 'Gene', (152, 156))
194039	27733136	Inactivation of Vhlh in hepatocytes with PEPCK-Cre or Albumin-Cre also led to erythrocytosis:overproduction of erythrocytes:due to increased expression of Epo, although hemangioma-associated extramedullary erythropoiesis:as observed in hemangioblastoma:was not observed.	('hemangioma', 'Phenotype', 'HP:0001028', (169, 179))	('Vhlh', 'Gene', '22346', (16, 20))	('hemangioma', 'Disease', (169, 179))	('increased', 'PosReg', (131, 140))	('hemangioma', 'Disease', 'MESH:D006391', (169, 179))	('Vhlh', 'Gene', (16, 20))	('overproduction', 'PosReg', (93, 107))	('extramedullary erythropoiesis', 'Phenotype', 'HP:0001978', (191, 220))	('Epo', 'Gene', (155, 158))	('hemangioblastoma', 'Disease', (236, 252))	('expression', 'MPA', (141, 151))	('erythrocytosis', 'Phenotype', 'HP:0001901', (78, 92))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (236, 252))	('Epo', 'Gene', '13856', (155, 158))	('Inactivation', 'Var', (0, 12))	('hemangioblastoma', 'Disease', 'MESH:D018325', (236, 252))	('erythropoiesis', 'biological_process', 'GO:0030218', ('206', '220'))
194040	27733136	Hif-2alpha was found to mediate up-regulation of erythropoietin and multiple pro-angiogenic cytokines in these mouse models, and inactivation of Hif-2alpha or Hif-1beta/Arnt, but not Hif-1alpha, rescued hemangiomas in PEPCK-Cre or Albumin-Cre driven Vhlh knockout mice.	('hemangiomas', 'Disease', (203, 214))	('Vhlh', 'Gene', '22346', (250, 254))	('hemangiomas', 'Phenotype', 'HP:0001028', (203, 214))	('mouse', 'Species', '10090', (111, 116))	('Hif-1beta', 'Gene', (159, 168))	('hemangiomas', 'Disease', 'MESH:D006391', (203, 214))	('Hif-2alpha', 'Gene', '13819', (145, 155))	('erythropoietin', 'molecular_function', 'GO:0005128', ('49', '63'))	('rescued', 'PosReg', (195, 202))	('inactivation', 'Var', (129, 141))	('Hif-2alpha', 'Gene', (0, 10))	('Vhlh', 'Gene', (250, 254))	('erythropoietin', 'Gene', '13856', (49, 63))	('mice', 'Species', '10090', (264, 268))	('Hif-1alpha', 'Gene', '15251', (183, 193))	('hemangioma', 'Phenotype', 'HP:0001028', (203, 213))	('Hif-2alpha', 'Gene', '13819', (0, 10))	('Hif-2alpha', 'Gene', (145, 155))	('erythropoietin', 'Gene', (49, 63))	('Hif-1alpha', 'Gene', (183, 193))	('Arnt', 'Gene', (169, 173))	('Arnt', 'Gene', '11863', (169, 173))	('regulation', 'biological_process', 'GO:0065007', ('35', '45'))	('Hif-1beta', 'Gene', '11863', (159, 168))
194041	27733136	Previously we showed that inactivation of Vhlh in a subpopulation of kidney distal tubules, using the HOXB7-Cre driver, resulted in Hif-1alpha-dependent hyperplastic clear-cell lesions and severe inflammation and fibrosis.	('inflammation', 'biological_process', 'GO:0006954', ('196', '208'))	('inactivation', 'Var', (26, 38))	('fibrosis', 'Disease', 'MESH:D005355', (213, 221))	('fibrosis', 'Disease', (213, 221))	('Vhlh', 'Gene', '22346', (42, 46))	('hyperplastic clear-cell lesions', 'CPA', (153, 184))	('inflammation', 'Disease', 'MESH:D007249', (196, 208))	('Hif-1alpha', 'Gene', (132, 142))	('Vhlh', 'Gene', (42, 46))	('Hif-1alpha', 'Gene', '15251', (132, 142))	('inflammation', 'Disease', (196, 208))
194043	27733136	Interestingly, in contrast to the previous mouse models, we did not detect Vhlh inactivation in hepatocytes.	('inactivation', 'Var', (80, 92))	('Vhlh', 'Gene', '22346', (75, 79))	('Vhlh', 'Gene', (75, 79))	('mouse', 'Species', '10090', (43, 48))
194115	27733136	Conditional inactivation of Vhlh using this Cre driver resulted in fully penetrant hyperplasia, cysts, clear-cell lesions, inflammation and fibrosis in the kidney, with the hyperplastic lesions arising primarily from Tamm-Horsfall positive distal tubules.	('cysts', 'Disease', (96, 101))	('Conditional inactivation', 'Var', (0, 24))	('clear-cell lesions', 'CPA', (103, 121))	('fibrosis', 'Disease', 'MESH:D005355', (140, 148))	('fibrosis', 'Disease', (140, 148))	('inflammation', 'biological_process', 'GO:0006954', ('123', '135'))	('hyperplasia', 'Disease', 'MESH:D006965', (83, 94))	('Vhlh', 'Gene', '22346', (28, 32))	('inflammation', 'Disease', 'MESH:D007249', (123, 135))	('inflammation', 'Disease', (123, 135))	('resulted in', 'Reg', (55, 66))	('Vhlh', 'Gene', (28, 32))	('hyperplasia', 'Disease', (83, 94))
194127	27733136	Its expression is induced under hypoxic conditions by HIF transcription factor and in VHL mutant cells.	('transcription factor', 'molecular_function', 'GO:0000981', ('58', '78'))	('hypoxic conditions', 'Disease', 'MESH:D009135', (32, 50))	('transcription', 'biological_process', 'GO:0006351', ('58', '71'))	('mutant', 'Var', (90, 96))	('expression', 'MPA', (4, 14))	('VHL', 'Gene', (86, 89))	('hypoxic conditions', 'Disease', (32, 50))
194133	27733136	Previous conditional knockout mice with Vhlh inactivation in hepatocytes developed liver hemangiomas and erythrocytosis, but no hemangioma-associated extramedullary erythropoiesis.	('erythrocytosis', 'CPA', (105, 119))	('inactivation', 'Var', (45, 57))	('hemangioma', 'Phenotype', 'HP:0001028', (89, 99))	('hemangiomas', 'Phenotype', 'HP:0001028', (89, 100))	('extramedullary erythropoiesis', 'Phenotype', 'HP:0001978', (150, 179))	('hemangioma', 'Disease', 'MESH:D006391', (89, 99))	('hemangioma', 'Phenotype', 'HP:0001028', (128, 138))	('Vhlh', 'Gene', '22346', (40, 44))	('mice', 'Species', '10090', (30, 34))	('hemangioma', 'Disease', 'MESH:D006391', (128, 138))	('erythrocytosis', 'Phenotype', 'HP:0001901', (105, 119))	('liver hemangioma', 'Phenotype', 'HP:0031207', (83, 99))	('liver hemangiomas', 'Disease', 'MESH:D006391', (83, 100))	('liver hemangiomas', 'Disease', (83, 100))	('developed', 'Reg', (73, 82))	('hemangioma', 'Disease', (89, 99))	('hemangioma', 'Disease', (128, 138))	('Vhlh', 'Gene', (40, 44))	('erythropoiesis', 'biological_process', 'GO:0030218', ('165', '179'))	('liver hemangiomas', 'Phenotype', 'HP:0031207', (83, 100))
194134	27733136	In those mouse models, hemangiomas and erythrocytosis were rescued by Hif-2alpha inactivation.	('inactivation', 'Var', (81, 93))	('erythrocytosis', 'Phenotype', 'HP:0001901', (39, 53))	('hemangioma', 'Phenotype', 'HP:0001028', (23, 33))	('mouse', 'Species', '10090', (9, 14))	('rescued', 'PosReg', (59, 66))	('hemangiomas', 'Phenotype', 'HP:0001028', (23, 34))	('erythrocytosis', 'MPA', (39, 53))	('hemangiomas', 'Disease', 'MESH:D006391', (23, 34))	('hemangiomas', 'Disease', (23, 34))	('Hif-2alpha', 'Gene', (70, 80))	('Hif-2alpha', 'Gene', '13819', (70, 80))
194136	27733136	Hif-2alpha knockout rescued elevated serum Epo (Fig.	('Epo', 'Gene', (43, 46))	('elevated', 'PosReg', (28, 36))	('Epo', 'Gene', '13856', (43, 46))	('Hif-2alpha', 'Gene', '13819', (0, 10))	('knockout', 'Var', (11, 19))	('Hif-2alpha', 'Gene', (0, 10))
194137	27733136	Hif-2alpha inactivation also ameliorated the hemangioma phenotype.	('ameliorated', 'PosReg', (29, 40))	('hemangioma', 'Disease', 'MESH:D006391', (45, 55))	('inactivation', 'Var', (11, 23))	('hemangioma', 'Phenotype', 'HP:0001028', (45, 55))	('Hif-2alpha', 'Gene', '13819', (0, 10))	('rat', 'Species', '10116', (35, 38))	('hemangioma', 'Disease', (45, 55))	('Hif-2alpha', 'Gene', (0, 10))
194138	27733136	The onset of hemangiomas was delayed (25 % vs 90 % at 6 weeks), and the number of hemangiomas per liver was significantly reduced in 2 to 3-month old double knockouts (Fig.	('hemangiomas', 'Phenotype', 'HP:0001028', (13, 24))	('double knockouts', 'Var', (150, 166))	('hemangiomas per liver', 'Phenotype', 'HP:0031207', (82, 103))	('hemangioma', 'Phenotype', 'HP:0001028', (13, 23))	('hemangioma', 'Phenotype', 'HP:0001028', (82, 92))	('hemangiomas', 'Disease', 'MESH:D006391', (82, 93))	('hemangiomas', 'Disease', 'MESH:D006391', (13, 24))	('hemangiomas', 'Phenotype', 'HP:0001028', (82, 93))	('hemangiomas', 'Disease', (82, 93))	('hemangiomas', 'Disease', (13, 24))	('reduced', 'NegReg', (122, 129))
194150	27733136	Interestingly, a much stronger signal for the deleted allele was observed in hemangioma tissue compared to adjacent normal liver tissue [Fig.	('hemangioma', 'Phenotype', 'HP:0001028', (77, 87))	('stronger', 'PosReg', (22, 30))	('hemangioma', 'Disease', (77, 87))	('deleted', 'Var', (46, 53))	('hemangioma', 'Disease', 'MESH:D006391', (77, 87))
194161	27733136	6a) and were able to detect Vhlh deletion consistently in the granulocyte-enriched fraction (Fig.	('Vhlh', 'Gene', (28, 32))	('deletion', 'Var', (33, 41))	('Vhlh', 'Gene', '22346', (28, 32))	('detect', 'Reg', (21, 27))
194163	27733136	The appearance of Vhlh deletion in these non-granulocyte fractions is inconsistent; it is therefore difficult to assess their functional significance.	('Vhlh', 'Gene', '22346', (18, 22))	('Vhlh', 'Gene', (18, 22))	('deletion', 'Var', (23, 31))
194168	27733136	Interestingly, the percentage of Plgf-positive neutrophils was significantly increased (>10 folds) in the liver of knockout mice compared with the wild-type (Fig.	('knockout', 'Var', (115, 123))	('Plgf', 'Gene', (33, 37))	('Plgf', 'Gene', '18654', (33, 37))	('mice', 'Species', '10090', (124, 128))	('increased', 'PosReg', (77, 86))
194177	27733136	This indicates that Vhlh inactivation in the hematopoietic component is necessary but insufficient for the hemangioma formation.	('hemangioma', 'Disease', 'MESH:D006391', (107, 117))	('inactivation', 'Var', (25, 37))	('Vhlh', 'Gene', '22346', (20, 24))	('formation', 'biological_process', 'GO:0009058', ('118', '127'))	('Vhlh', 'Gene', (20, 24))	('hemangioma', 'Phenotype', 'HP:0001028', (107, 117))	('hemangioma', 'Disease', (107, 117))
194180	27733136	Furthermore, Hif-2alpha inactivation ameliorates the hemangioma phenotype, but has no effect on the kidney phenotype.	('hemangioma', 'Phenotype', 'HP:0001028', (53, 63))	('hemangioma', 'Disease', (53, 63))	('ameliorates', 'PosReg', (37, 48))	('inactivation', 'Var', (24, 36))	('rat', 'Species', '10116', (43, 46))	('hemangioma', 'Disease', 'MESH:D006391', (53, 63))	('Hif-2alpha', 'Gene', (13, 23))	('Hif-2alpha', 'Gene', '13819', (13, 23))
194183	27733136	However, this explanation is not favored because other kidney-specific Vhlh knockouts do not develop liver phenotype.	('Vhlh', 'Gene', '22346', (71, 75))	('Vhlh', 'Gene', (71, 75))	('knockouts', 'Var', (76, 85))
194184	27733136	Liver hemangiomas have been described previously in germline Vhlh +/- mice and in mice with Vhlh inactivation in hepatocytes (PEPCK-Cre or Albumin-Cre driven Vhlh knockout mice).	('mice', 'Species', '10090', (82, 86))	('Vhlh', 'Gene', '22346', (92, 96))	('Vhlh', 'Gene', (92, 96))	('Vhlh', 'Gene', '22346', (61, 65))	('Vhlh', 'Gene', (61, 65))	('Liver hemangiomas', 'Disease', (0, 17))	('mice', 'Species', '10090', (172, 176))	('Vhlh', 'Gene', '22346', (158, 162))	('Vhlh', 'Gene', (158, 162))	('mice', 'Species', '10090', (70, 74))	('inactivation', 'Var', (97, 109))	('Liver hemangiomas', 'Phenotype', 'HP:0031207', (0, 17))	('hemangioma', 'Phenotype', 'HP:0001028', (6, 16))	('Liver hemangiomas', 'Disease', 'MESH:D006391', (0, 17))	('hemangiomas', 'Phenotype', 'HP:0001028', (6, 17))
194187	27733136	The more hepatocyte-specific Cre (Albumin-Cre) driven Vhlh knockout also generated hemangiomas, albeit more at the microscopic level.	('hemangiomas', 'Disease', (83, 94))	('Vhlh', 'Gene', '22346', (54, 58))	('hemangiomas', 'Phenotype', 'HP:0001028', (83, 94))	('hemangiomas', 'Disease', 'MESH:D006391', (83, 94))	('hemangioma', 'Phenotype', 'HP:0001028', (83, 93))	('rat', 'Species', '10116', (77, 80))	('Vhlh', 'Gene', (54, 58))	('generated', 'Reg', (73, 82))	('knockout', 'Var', (59, 67))
194190	27733136	Furthermore, the hemangiomas in HOXB7-Cre driven Vhlh knockouts exhibit extramedullary hematopoiesis that is also observed in human hemangioblastoma but not in liver with hepatocyte Vhlh knockout (either Albumin-Cre or PEPCK-Cre driven).	('extramedullary hematopoiesis', 'Phenotype', 'HP:0001978', (72, 100))	('human', 'Species', '9606', (126, 131))	('hemangioblastoma', 'Disease', (132, 148))	('hematopoiesis', 'Disease', 'MESH:C536227', (87, 100))	('hemangioma', 'Phenotype', 'HP:0001028', (17, 27))	('knockouts', 'Var', (54, 63))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (132, 148))	('hematopoiesis', 'Disease', (87, 100))	('hemangioblastoma', 'Disease', 'MESH:D018325', (132, 148))	('hematopoiesis', 'biological_process', 'GO:0030097', ('87', '100'))	('Vhlh', 'Gene', '22346', (182, 186))	('Vhlh', 'Gene', (182, 186))	('Vhlh', 'Gene', '22346', (49, 53))	('Vhlh', 'Gene', (49, 53))	('hemangiomas', 'Disease', 'MESH:D006391', (17, 28))	('exhibit', 'Reg', (64, 71))	('hemangiomas', 'Phenotype', 'HP:0001028', (17, 28))	('hemangiomas', 'Disease', (17, 28))
194192	27733136	Erythropoietin is over-expressed in the knockout mice with hepatocyte-specific Vhlh inactivation, as well as in HOXB7-Cre driven Vhlh knockout mice.	('Vhlh', 'Gene', '22346', (129, 133))	('Erythropoietin', 'Gene', (0, 14))	('Erythropoietin', 'molecular_function', 'GO:0005128', ('0', '14'))	('Vhlh', 'Gene', (129, 133))	('Erythropoietin', 'Gene', '13856', (0, 14))	('mice', 'Species', '10090', (49, 53))	('over-expressed', 'PosReg', (18, 32))	('Vhlh', 'Gene', '22346', (79, 83))	('Vhlh', 'Gene', (79, 83))	('inactivation', 'Var', (84, 96))	('mice', 'Species', '10090', (143, 147))
194194	27733136	There is no increase in hematocrit in HOXB7-Cre driven Vhlh knockouts (data not shown).	('increase in hematocrit', 'Phenotype', 'HP:0001899', (12, 34))	('hematocrit', 'MPA', (24, 34))	('knockouts', 'Var', (60, 69))	('Vhlh', 'Gene', '22346', (55, 59))	('Vhlh', 'Gene', (55, 59))
194201	27733136	We further identified granulocytes/neutrophils as the Vhlh mutant cells in this model (Figs.	('Vhlh', 'Gene', (54, 58))	('mutant', 'Var', (59, 65))	('Vhlh', 'Gene', '22346', (54, 58))
194202	27733136	Furthermore, hemangiomas were partially rescued in HOXB7-Cre; Vhlh fl/fl mice reconstituted with wild-type hematopoietic stem cells (Fig.	('hemangiomas', 'Phenotype', 'HP:0001028', (13, 24))	('HOXB7-Cre', 'Var', (51, 60))	('mice', 'Species', '10090', (73, 77))	('hemangioma', 'Phenotype', 'HP:0001028', (13, 23))	('Vhlh', 'Gene', '22346', (62, 66))	('hemangiomas', 'Disease', 'MESH:D006391', (13, 24))	('hemangiomas', 'Disease', (13, 24))	('Vhlh', 'Gene', (62, 66))
194203	27733136	Thus, Vhlh inactivation in bone marrow-derived leukocytes contributes to hemangioma formation in this mouse model.	('hemangioma', 'Disease', (73, 83))	('inactivation', 'Var', (11, 23))	('hemangioma', 'Disease', 'MESH:D006391', (73, 83))	('Vhlh', 'Gene', '22346', (6, 10))	('Vhlh', 'Gene', (6, 10))	('formation', 'biological_process', 'GO:0009058', ('84', '93'))	('mouse', 'Species', '10090', (102, 107))	('hemangioma', 'Phenotype', 'HP:0001028', (73, 83))
194205	27733136	Thus, inactivation of Vhlh in at least one other cell type besides bone marrow-derived cells is required for hemangioma formation.	('Vhlh', 'Gene', '22346', (22, 26))	('inactivation', 'Var', (6, 18))	('hemangioma', 'Phenotype', 'HP:0001028', (109, 119))	('Vhlh', 'Gene', (22, 26))	('hemangioma', 'Disease', (109, 119))	('formation', 'biological_process', 'GO:0009058', ('120', '129'))	('hemangioma', 'Disease', 'MESH:D006391', (109, 119))
194206	27733136	It may be that HOXB7-Cre driven Vhlh knockout in kidney tubule cells contributes to systemic elevation of Epo, which in turn is required for hemangioma formation in the liver.	('hemangioma', 'Phenotype', 'HP:0001028', (141, 151))	('Vhlh', 'Gene', (32, 36))	('formation', 'biological_process', 'GO:0009058', ('152', '161'))	('knockout', 'Var', (37, 45))	('hemangioma', 'Disease', 'MESH:D006391', (141, 151))	('Epo', 'Gene', (106, 109))	('Epo', 'Gene', '13856', (106, 109))	('elevation', 'PosReg', (93, 102))	('Vhlh', 'Gene', '22346', (32, 36))	('hemangioma', 'Disease', (141, 151))
194207	27733136	However, kidney hyperplasia and tubule defects were rescued by inactivation of Hif-1alpha, but not Hif-2alpha , whereas other kidney-specific Vhlh knockout mouse models did not develop liver hemangioma.	('kidney hyperplasia', 'Disease', (9, 27))	('liver hemangioma', 'Disease', 'MESH:D006391', (185, 201))	('liver hemangioma', 'Disease', (185, 201))	('Hif-1alpha', 'Gene', '15251', (79, 89))	('kidney hyperplasia', 'Phenotype', 'HP:0000105', (9, 27))	('hemangioma', 'Phenotype', 'HP:0001028', (191, 201))	('inactivation', 'Var', (63, 75))	('Hif-1alpha', 'Gene', (79, 89))	('Hif-2alpha', 'Gene', '13819', (99, 109))	('liver hemangioma', 'Phenotype', 'HP:0031207', (185, 201))	('Hif-2alpha', 'Gene', (99, 109))	('tubule defects', 'CPA', (32, 46))	('mouse', 'Species', '10090', (156, 161))	('Vhlh', 'Gene', '22346', (142, 146))	('Vhlh', 'Gene', (142, 146))	('kidney hyperplasia', 'Disease', 'MESH:D006965', (9, 27))
194209	27733136	However, we did not detect Vhlh deletion in the erythrocyte progenitor cells, despite increased number of these progenitors.	('Vhlh', 'Gene', '22346', (27, 31))	('Vhlh', 'Gene', (27, 31))	('deletion', 'Var', (32, 40))	('increased', 'PosReg', (86, 95))
194210	27733136	We did, however, detect Vhlh deletion in liver granulocytes/neutrophils and moderately increased number of Granulocyte/Macrophage/Megakaryocyte/Erythroid (GMME) progenitors cells in the liver (data not shown).	('deletion', 'Var', (29, 37))	('increased', 'PosReg', (87, 96))	('rat', 'Species', '10116', (80, 83))	('Vhlh', 'Gene', '22346', (24, 28))	('Vhlh', 'Gene', (24, 28))
194218	27733136	Since VHL patients are heterozygous for VHL loss-of-function mutations, it is conceivable that inactivation of the remaining wild-type allele could occur in more than one cell type (as indeed it does, since patients are prone to develop tumors in several tissues), including those constituting the stromal compartments.	('patients', 'Species', '9606', (207, 215))	('VHL', 'Gene', (40, 43))	('tumors', 'Disease', (237, 243))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('mutations', 'Var', (61, 70))	('patients', 'Species', '9606', (10, 18))	('develop', 'PosReg', (229, 236))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('loss-of-function', 'NegReg', (44, 60))
194219	27733136	Mutations in the cancer stromal cells have been documented that contribute to cancer progression {reviewed in }.	('contribute', 'Reg', (64, 74))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
194225	27733136	Our mouse model shows that Vhlh inactivation in the "stromal" (non-tumor) cell population, at least in part consisting of granulocytes/neutrophils, can induce abnormal angiogenesis.	('mouse', 'Species', '10090', (4, 9))	('angiogenesis', 'biological_process', 'GO:0001525', ('166', '178'))	('non-tumor', 'Disease', 'MESH:D009369', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Vhlh', 'Gene', '22346', (27, 31))	('Vhlh', 'Gene', (27, 31))	('inactivation', 'Var', (32, 44))	('induce', 'Reg', (152, 158))	('angiogenesis', 'CPA', (168, 180))	('non-tumor', 'Disease', (63, 72))
194230	30066860	Affected patients are carriers of a germline mutation in the VHL tumor suppressor gene.	('patients', 'Species', '9606', (9, 17))	('VHL tumor', 'Disease', (61, 70))	('germline mutation', 'Var', (36, 53))	('tumor suppressor', 'biological_process', 'GO:0051726', ('65', '81'))	('VHL tumor', 'Disease', 'MESH:D006623', (61, 70))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('65', '81'))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
194231	30066860	Somatic mutations of this gene are also found in sporadic ccRCC and numerous pan-genomic studies have reported a dysregulation of microRNA (miRNA) expression in these sporadic tumors.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('miR', 'Gene', '220972', (140, 143))	('miR', 'Gene', (140, 143))	('RCC', 'Disease', (60, 63))	('mutations', 'Var', (8, 17))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('dysregulation', 'MPA', (113, 126))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))
194241	30066860	Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary syndrome caused by germline mutations in the VHL tumor suppressor gene, which is located on chromosome 3p25-26.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('autosomal dominant hereditary syndrome', 'Disease', 'MESH:D030342', (38, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('160', '170'))	('Von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (0, 31))	('VHL tumor', 'Disease', (113, 122))	('tumor suppressor', 'biological_process', 'GO:0051726', ('117', '133'))	('caused by', 'Reg', (77, 86))	('VHL tumor', 'Disease', 'MESH:D006623', (113, 122))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('117', '133'))	('mutations', 'Var', (96, 105))	('autosomal dominant hereditary syndrome', 'Disease', (38, 76))
194245	30066860	Somatic VHL inactivation is also a hallmark of the majority of cases of sporadic ccRCC, and insights into VHL gene function have resulted in the use of antiangiogenic targeted therapies, which are now first line in the treatment of advanced renal tumors.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('RCC', 'Disease', (83, 86))	('VHL', 'Gene', '7428', (8, 11))	('renal tumors', 'Disease', (241, 253))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('resulted in', 'Reg', (129, 140))	('renal tumors', 'Phenotype', 'HP:0009726', (241, 253))	('VHL', 'Gene', (106, 109))	('inactivation', 'Var', (12, 24))	('VHL', 'Gene', '7428', (106, 109))	('renal tumors', 'Disease', 'MESH:D007674', (241, 253))	('VHL', 'Gene', (8, 11))
194249	30066860	Fisher et al demonstrated that kidney tumors developing from a germline VHL mutation exhibit complementarity of the evolutionary principles of contingency and convergence.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('VHL', 'Gene', '7428', (72, 75))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('kidney tumors', 'Disease', (31, 44))	('kidney tumors', 'Disease', 'MESH:D007674', (31, 44))	('kidney tumors', 'Phenotype', 'HP:0009726', (31, 44))	('mutation', 'Var', (76, 84))	('VHL', 'Gene', (72, 75))
194255	30066860	In cancer, aberrations in the expression of specific miRNAs may have well-defined tumor-suppressing or oncogenic functions.	('aberrations', 'Var', (11, 22))	('miR', 'Gene', '220972', (53, 56))	('miR', 'Gene', (53, 56))	('expression', 'MPA', (30, 40))	('oncogenic functions', 'CPA', (103, 122))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cancer', 'Disease', (3, 9))	('tumor', 'Disease', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
194274	30066860	All processing methods used for miRNA analyses were performed on the Cy3 Median Signal in Agilent Feature software v10.7 (Agilent Technologies, Inc.).	('miR', 'Gene', (32, 35))	('miR', 'Gene', '220972', (32, 35))	('Cy3 Median', 'Var', (69, 79))
194347	30066860	The present study was supported by grants from the 'Ligue Nationale contre le Cancer' (Comites du Cher et de l'Indre), the French National Cancer Institute (INCa, PNES Kidney Cancer), the 'Association VHL France' and by 'Taxes d'Apprentissage Gustave Roussy' (P18_SG, P20_VPT et P24_MACH).	('Cancer', 'Disease', (78, 84))	('Cancer', 'Disease', (139, 145))	('INCa', 'Gene', (157, 161))	('Cancer', 'Phenotype', 'HP:0002664', (175, 181))	('Cancer', 'Disease', 'MESH:D009369', (78, 84))	('P18_SG', 'Var', (260, 266))	('PNES Kidney Cancer', 'Disease', 'MESH:D007680', (163, 181))	('Kidney Cancer', 'Phenotype', 'HP:0009726', (168, 181))	('Cancer', 'Disease', 'MESH:D009369', (139, 145))	('VHL', 'Gene', (201, 204))	('Cancer', 'Disease', (175, 181))	('INCa', 'Gene', '440068', (157, 161))	('PNES Kidney Cancer', 'Disease', (163, 181))	('PNES Kidney', 'Phenotype', 'HP:0000104', (163, 174))	('VHL', 'Gene', '7428', (201, 204))	('Cancer', 'Disease', 'MESH:D009369', (175, 181))	('Cancer', 'Phenotype', 'HP:0002664', (78, 84))	('P20_VPT et P24_MACH', 'Var', (268, 287))	('Cancer', 'Phenotype', 'HP:0002664', (139, 145))
194358	30814637	Since ccRCC tumors with PBRM1 mutations respond to targeted therapy differently than tumors with BAP1 mutations, we focused on ccRCC-specific edges associated with tumors that exhibit alternate mutation profiles: VHL-PBRM1 or VHL-BAP1.	('BAP1', 'Gene', (97, 101))	('PBRM1', 'Gene', (217, 222))	('PBRM1', 'Gene', '55193', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('RCC tumors', 'Disease', (8, 18))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('BAP1', 'Gene', (230, 234))	('PBRM1', 'Gene', (24, 29))	('RCC', 'Disease', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('RCC tumors', 'Disease', 'MESH:C538614', (8, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumors', 'Disease', (85, 91))	('RCC', 'Disease', (8, 11))	('VHL-PBRM1 or VHL-BAP1', 'Disease', 'MESH:D006623', (213, 234))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('tumors', 'Disease', (164, 170))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mutations', 'Var', (30, 39))	('tumors', 'Disease', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('BAP1', 'Gene', '8314', (97, 101))	('VHL-PBRM1 or VHL-BAP1', 'Disease', (213, 234))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('PBRM1', 'Gene', '55193', (217, 222))	('BAP1', 'Gene', '8314', (230, 234))
194365	30814637	The VHL gene is a common initiating mutation, leading to an accumulation of lipids and glycogens in the tissue.	('lipids', 'Chemical', 'MESH:D008055', (76, 82))	('glycogens', 'Chemical', 'MESH:D006003', (87, 96))	('VHL', 'Gene', (4, 7))	('VHL', 'Gene', '7428', (4, 7))	('accumulation', 'PosReg', (60, 72))	('mutation', 'Var', (36, 44))
194367	30814637	Epigenetic regulators such as PBRM1 and BAP1 - which act as tumor suppressors - are frequently mutated and associated with distinct clinical outcomes in ccRCC patients.	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('RCC', 'Disease', (155, 158))	('PBRM1', 'Gene', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('PBRM1', 'Gene', '55193', (30, 35))	('BAP1', 'Gene', '8314', (40, 44))	('mutated', 'Var', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('associated with', 'Reg', (107, 122))	('tumor', 'Disease', (60, 65))	('BAP1', 'Gene', (40, 44))	('patients', 'Species', '9606', (159, 167))	('RCC', 'Disease', 'MESH:C538614', (155, 158))
194369	30814637	BAP1 mutations occur at a near mutually exclusive manner from PBRM1 mutations, and tumors respond to standard of care molecularly-targeted drugs differently depending on which mutations they exhibit.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('BAP1', 'Gene', (0, 4))	('tumors', 'Disease', (83, 89))	('mutations', 'Var', (5, 14))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('PBRM1', 'Gene', (62, 67))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('PBRM1', 'Gene', '55193', (62, 67))	('BAP1', 'Gene', '8314', (0, 4))
194370	30814637	However, multiple clonal driver subtypes of ccRCC in which BAP1 and PBRM1 mutations co-occur are possible.	('BAP1', 'Gene', (59, 63))	('RCC', 'Disease', (46, 49))	('PBRM1', 'Gene', (68, 73))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('mutations', 'Var', (74, 83))	('PBRM1', 'Gene', '55193', (68, 73))	('BAP1', 'Gene', '8314', (59, 63))
194371	30814637	Other common ccRCC mutations include a histone methyltransferase - SETD2 - and the mTOR kinase which plays key roles in cell growth.	('mTOR', 'Gene', (83, 87))	('SETD2', 'Gene', '29072', (67, 72))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('SETD2', 'Gene', (67, 72))	('RCC', 'Disease', (15, 18))	('mutations', 'Var', (19, 28))	('histone methyltransferase', 'Gene', '56979', (39, 64))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('histone methyltransferase', 'Gene', (39, 64))	('cell growth', 'biological_process', 'GO:0016049', ('120', '131'))	('mTOR', 'Gene', '2475', (83, 87))
194372	30814637	These biomarkers are clearly relevant to understanding ccRCC biology, but aberrations in these genes are not always consistent between tumors and probably do not fully explain ccRCC tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (182, 187))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('tumor', 'Disease', (135, 140))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('tumors', 'Disease', (135, 141))	('RCC', 'Disease', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('RCC', 'Disease', (178, 181))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('aberrations', 'Var', (74, 85))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
194373	30814637	Biomarker inconsistency, a prime motivation for personalized medicine, can partly be attributed to tumor heterogeneity which is a genotyping challenge given that certain regions of a tumor may contain mutations that are unique from other regions of the tumor.	('tumor', 'Disease', (99, 104))	('mutations', 'Var', (201, 210))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', (183, 188))	('contain', 'Reg', (193, 200))	('tumor', 'Disease', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
194374	30814637	A Braided Cancer River Model (BCRM) has defined stages of mutation accumulation that lead to clear cell RCC (ccRCC): initiating, early, intermediate, and speedy mutations.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('lead to', 'Reg', (85, 92))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('mutation', 'Var', (58, 66))	('Cancer', 'Phenotype', 'HP:0002664', (10, 16))	('Cancer', 'Disease', (10, 16))	('Cancer', 'Disease', 'MESH:D009369', (10, 16))	('RCC', 'Disease', (104, 107))
194375	30814637	A key aspect of this model is that genetic pathways can operate in parallel to drive tumorigenesis, suggesting that mutations in different genes at various stages of the model can result in convergent evolution of cancer cells.	('result in', 'Reg', (180, 189))	('tumor', 'Disease', (85, 90))	('cancer', 'Disease', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('mutations', 'Var', (116, 125))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
194377	30814637	Given that mutations in chromatin-modifying genes will greatly alter mRNA expression levels, identifying RCC-subtype specific gene expression patterns may pave the way for more robust drug targeting.	('mutations', 'Var', (11, 20))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('alter', 'Reg', (63, 68))	('RCC', 'Disease', (105, 108))	('chromatin', 'cellular_component', 'GO:0000785', ('24', '33'))	('gene expression', 'biological_process', 'GO:0010467', ('126', '141'))	('mRNA expression levels', 'MPA', (69, 91))
194386	30814637	In addition, we searched for GCN edges specific to tumors with co-occurring mutations in known genes relevant to ccRCC.	('GCN', 'Chemical', '-', (29, 32))	('mutations', 'Var', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))
194410	30814637	To test if edges where specific to tumors with mutations in known RCC genes, we downloaded somatic mutation profiles for 16 genes that are relevant to RCC and detected edges that were specific to patients with ccRCC driver mutations.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('patients', 'Species', '9606', (196, 204))	('RCC', 'Phenotype', 'HP:0005584', (212, 215))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (212, 215))	('RCC', 'Disease', (151, 154))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('RCC', 'Disease', (66, 69))	('mutations', 'Var', (223, 232))
194411	30814637	Table 2 presents the number of edges that were specific to patients with mutations in these RCC-associated genes.	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('patients', 'Species', '9606', (59, 67))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('mutations', 'Var', (73, 82))
194412	30814637	In order to detect edges relevant to patients with common ccRCC mutation combinations, we performed a Fisher's exact test for co-occurring VHL and BAP1 mutations (Table 3).	('BAP1', 'Gene', (147, 151))	('VHL', 'Gene', (139, 142))	('mutations', 'Var', (152, 161))	('patients', 'Species', '9606', (37, 45))	('VHL', 'Gene', '7428', (139, 142))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('BAP1', 'Gene', '8314', (147, 151))
194413	30814637	In addition, we identified edges in the tumor GCN that are specific to patients with co-occurring VHL and PBRM1 mutations (Table 4).	('PBRM1', 'Gene', (106, 111))	('patients', 'Species', '9606', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('VHL', 'Gene', (98, 101))	('PBRM1', 'Gene', '55193', (106, 111))	('mutations', 'Var', (112, 121))	('VHL', 'Gene', '7428', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('GCN', 'Chemical', '-', (46, 49))
194415	30814637	Enrichment (Fisher's Pval < 0.001) of GO terms related to T cell activation and immune response are shared between these lists: adaptive immune response (GO:0002250), T cell activation (GO:0042110), positive regulation of natural killer cell mediated cytotoxicity (GO:0045954), and regulation of immune response (GO:0050776).	('adaptive immune response', 'CPA', (128, 152))	('GO:0002250', 'Var', (154, 164))	('T cell', 'CPA', (167, 173))	('regulation of immune response', 'biological_process', 'GO:0050776', ('282', '311'))	('cytotoxicity', 'Disease', (251, 263))	('adaptive immune response', 'biological_process', 'GO:0002250', ('128', '152'))	('T cell activation', 'biological_process', 'GO:0042110', ('167', '184'))	('T cell activation', 'biological_process', 'GO:0042110', ('58', '75'))	('cytotoxicity', 'Disease', 'MESH:D064420', (251, 263))	('GO:0042110', 'Var', (186, 196))	('positive regulation of natural killer cell mediated cytotoxicity', 'biological_process', 'GO:0045954', ('199', '263'))	('immune response', 'biological_process', 'GO:0006955', ('80', '95'))
194419	30814637	To link novel genes to known drivers of ccRCC, we identified 8 edges that are specific to KIRC primary tumors that contain VHL and BAP1 mutations and compared these to 27 edges that are specific to KIRC primary tumors that contain VHL and PBRM1 mutations.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('PBRM1', 'Gene', '55193', (239, 244))	('VHL', 'Gene', '7428', (231, 234))	('tumors', 'Disease', (103, 109))	('mutations', 'Var', (136, 145))	('PBRM1', 'Gene', (239, 244))	('VHL', 'Gene', (123, 126))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('BAP1', 'Gene', '8314', (131, 135))	('VHL', 'Gene', '7428', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('VHL', 'Gene', (231, 234))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('BAP1', 'Gene', (131, 135))
194420	30814637	These expanded ccRCC driver mutations represent two possible selection routes through the BCRM.	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('mutations', 'Var', (28, 37))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))
194421	30814637	Due to a small number of patients containing a combination of VHL, PBRM1, and BAP1 mutations, we were unable to detect edges specific to this multiple clonal driver.	('mutations', 'Var', (83, 92))	('PBRM1', 'Gene', '55193', (67, 72))	('patients', 'Species', '9606', (25, 33))	('VHL', 'Gene', (62, 65))	('BAP1', 'Gene', '8314', (78, 82))	('VHL', 'Gene', '7428', (62, 65))	('BAP1', 'Gene', (78, 82))	('PBRM1', 'Gene', (67, 72))
194422	30814637	We demonstrate that the tumor GCN edges associated with VHL-BAP1 and VHL-PBRM1 mutations contain different genes with similar biological function.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('VHL-BAP1 and VHL-PBRM1', 'Disease', 'MESH:D006623', (56, 78))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('GCN', 'Chemical', '-', (30, 33))	('mutations', 'Var', (79, 88))
194424	30814637	Several of the GCN edges associated with mutated gene sets are associated with T cell activation and immune response.	('immune response', 'CPA', (101, 116))	('T cell activation', 'biological_process', 'GO:0042110', ('79', '96'))	('T cell activation', 'CPA', (79, 96))	('associated', 'Reg', (63, 73))	('immune response', 'biological_process', 'GO:0006955', ('101', '116'))	('GCN', 'Chemical', '-', (15, 18))	('mutated gene sets', 'Var', (41, 58))
194425	30814637	The genes in Tables 3 and 4 are both enriched for the following GO ontology terms: adaptive immune response (GO:0002250), T cell activation (GO:0042110), positive regulation of natural killer cell mediated cytotoxicity (GO:0045954), and regulation of immune response (GO:0050776).	('T cell activation', 'biological_process', 'GO:0042110', ('122', '139'))	('GO:0002250', 'Var', (109, 119))	('adaptive immune response', 'biological_process', 'GO:0002250', ('83', '107'))	('adaptive immune response', 'CPA', (83, 107))	('positive', 'PosReg', (154, 162))	('cytotoxicity', 'Disease', (206, 218))	('cytotoxicity', 'Disease', 'MESH:D064420', (206, 218))	('regulation of immune response', 'biological_process', 'GO:0050776', ('237', '266'))	('positive regulation of natural killer cell mediated cytotoxicity', 'biological_process', 'GO:0045954', ('154', '218'))	('T cell activation', 'CPA', (122, 139))	('GO:0042110', 'Var', (141, 151))
194428	30814637	Regardless of whether the patient has co-occurring VHL and BAP1 mutations or co-occurring VHL and PBRM1 mutations, T cell activation genes form coordinated co-expression in the tumor (Fig.	('PBRM1', 'Gene', (98, 103))	('tumor', 'Disease', (177, 182))	('VHL', 'Gene', '7428', (90, 93))	('patient', 'Species', '9606', (26, 33))	('mutations', 'Var', (104, 113))	('VHL', 'Gene', '7428', (51, 54))	('BAP1', 'Gene', (59, 63))	('T cell activation', 'biological_process', 'GO:0042110', ('115', '132'))	('PBRM1', 'Gene', '55193', (98, 103))	('BAP1', 'Gene', '8314', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('mutations', 'Var', (64, 73))	('VHL', 'Gene', (90, 93))	('VHL', 'Gene', (51, 54))
194440	30814637	Overexpression of UBASH3A is associated with poor prognosis in metastatic breast cancer, and the gene is also associated with autoimmune disorders such as Lupus Erythematosus.	('breast cancer', 'Disease', (74, 87))	('UBASH3A', 'Gene', '53347', (18, 25))	('autoimmune disorders', 'Disease', (126, 146))	('Lupus Erythematosus', 'Phenotype', 'HP:0002725', (155, 174))	('autoimmune disorders', 'Disease', 'MESH:D001327', (126, 146))	('autoimmune disorders', 'Phenotype', 'HP:0002960', (126, 146))	('associated', 'Reg', (110, 120))	('UBASH3A', 'Gene', (18, 25))	('Lupus Erythematosus', 'Disease', (155, 174))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('Lupus Erythematosus', 'Disease', 'MESH:D008180', (155, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
194441	30814637	UBASH3A is present in 14 of the 27 edges in Table 4, highlighting its importance in ccRCC patients with co-occurring VHL and PBRM1 mutations.	('mutations', 'Var', (131, 140))	('VHL', 'Gene', '7428', (117, 120))	('UBASH3A', 'Gene', (0, 7))	('UBASH3A', 'Gene', '53347', (0, 7))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('PBRM1', 'Gene', (125, 130))	('PBRM1', 'Gene', '55193', (125, 130))	('patients', 'Species', '9606', (90, 98))	('RCC', 'Disease', (86, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('VHL', 'Gene', (117, 120))
194452	30814637	Interestingly, Table 4 contains 11 non-coding RNA genes: DARS-AS1, RP11-789C17.5, AC116366.6, CCDC147-AS1, RP11-981G7.6, AF064858.3, AC073115.2, AF064858.1, AC073115.7, AC011352.3, and AC011352.1.	('DARS-AS1', 'Gene', (57, 65))	('RP11', 'Gene', (107, 111))	('RP11', 'Gene', '26121', (107, 111))	('AF064858.1', 'Var', (145, 155))	('AC073115.7', 'Var', (157, 167))	('AC073115.2', 'Var', (133, 143))	('RP11', 'Gene', (67, 71))	('AS1', 'Gene', (102, 105))	('AF064858.3', 'Var', (121, 131))	('AS1', 'Gene', '5729', (102, 105))	('CCDC147', 'Gene', '159686', (94, 101))	('AS1', 'Gene', (62, 65))	('AS1', 'Gene', '5729', (62, 65))	('CCDC147', 'Gene', (94, 101))	('DARS-AS1', 'Gene', '101928243', (57, 65))	('RNA', 'cellular_component', 'GO:0005562', ('46', '49'))	('RP11', 'Gene', '26121', (67, 71))	('AC116366.6', 'Var', (82, 92))
194454	30814637	Notably, the antisense RNA DARS-AS1 was found to be correlated with TCRGC2, a T cell receptor gene, suggesting that this non-coding RNA might play a role in suppressing healthy T cell function.	('DARS-AS1', 'Gene', '101928243', (27, 35))	('DARS-AS1', 'Gene', (27, 35))	('suppressing', 'NegReg', (157, 168))	('healthy T cell function', 'CPA', (169, 192))	('TCRGC2', 'Gene', '6967', (68, 74))	('RNA', 'cellular_component', 'GO:0005562', ('132', '135'))	('RNA', 'cellular_component', 'GO:0005562', ('23', '26'))	('antisense RNA', 'molecular_function', 'GO:0009388', ('13', '26'))	('antisense', 'Var', (13, 22))	('TCRGC2', 'Gene', (68, 74))
194455	30814637	We also detected four edges: RP11-981G7.6- LINCR-0001, AF064858.3- AF064858.1, AC011352.3- AC011352.1, and AC073115.2- AC073115.7 that are each comprised of two long non-coding RNAs that are correlated with each other.	('AC011352.3- AC011352.1', 'Var', (79, 101))	('AF064858.3- AF064858.1', 'Var', (55, 77))	('RP11', 'Gene', (29, 33))	('RP11', 'Gene', '26121', (29, 33))	('AC073115.2- AC073115.7', 'Var', (107, 129))
194456	30814637	We speculate that these non-coding RNAs are targeting parallel genetic pathways during cancer development as per the BCRM.	('cancer', 'Disease', (87, 93))	('targeting', 'Reg', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('non-coding RNAs', 'Var', (24, 39))
194459	30814637	By linking edges to mutations in specific genes, we provide a framework for identifying edges that are relevant to specific clinical subtypes of RCC.	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('mutations', 'Var', (20, 29))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))
194462	30814637	It is possible that accumulation of driver mutations in the tumor lead to gene expression changes in adjacent normal tissue through epigenetic effects.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mutations', 'Var', (43, 52))	('gene expression changes', 'MPA', (74, 97))	('tumor', 'Disease', (60, 65))	('gene expression', 'biological_process', 'GO:0010467', ('74', '89'))
194463	30814637	These gene expression changes may lead to metastasis, tumor growth, or recurrence.	('recurrence', 'CPA', (71, 81))	('changes', 'Var', (22, 29))	('metastasis', 'CPA', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('gene expression', 'biological_process', 'GO:0010467', ('6', '21'))	('lead to', 'Reg', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
194465	30814637	While this report focused on edges associated with ccRCC driver mutations, the ccRCC-specific edges that were not mutation-associated are worthy of further exploration.	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (53, 56))	('RCC', 'Disease', (81, 84))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('mutations', 'Var', (64, 73))
194475	30814637	For co-occurring mutation tests, patients with VHL mutations and mutually exclusive mutations in PBRM1 and BAP1 were assigned the "Mutation" attribute.	('BAP1', 'Gene', '8314', (107, 111))	('mutations', 'Var', (51, 60))	('patients', 'Species', '9606', (33, 41))	('BAP1', 'Gene', (107, 111))	('VHL', 'Gene', (47, 50))	('PBRM1', 'Gene', '55193', (97, 102))	('PBRM1', 'Gene', (97, 102))	('VHL', 'Gene', '7428', (47, 50))
194478	30814637	Mutations were coded as present or absent in a tumor according to annotations found in.	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
194479	30814637	For co-occurring mutation enrichment, a "Mutation" tumor had to have both VHL-PBRM1 (but no BAP1) or VHL-BAP1 (but no PBRM1) mutations.	('mutations', 'Var', (125, 134))	('VHL-BAP1', 'Gene', '7428;8314', (101, 109))	('PBRM1', 'Gene', '55193', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('PBRM1', 'Gene', '55193', (78, 83))	('VHL-PBRM1', 'Disease', 'MESH:D006623', (74, 83))	('BAP1', 'Gene', '8314', (105, 109))	('tumor', 'Disease', (51, 56))	('VHL-BAP1', 'Gene', (101, 109))	('VHL-PBRM1', 'Disease', (74, 83))	('BAP1', 'Gene', '8314', (92, 96))	('BAP1', 'Gene', (92, 96))	('PBRM1', 'Gene', (118, 123))	('BAP1', 'Gene', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('PBRM1', 'Gene', (78, 83))
194483	30972280	LSD1 inhibition suppresses the growth of clear cell renal cell carcinoma via upregulating P21 signaling Histone lysine-specific demethylase 1 (LSD1) has been implicated in the disease progression of several types of solid tumors.	('LSD1', 'Gene', '23028', (0, 4))	('upregulating', 'PosReg', (77, 89))	('inhibition', 'Var', (5, 15))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('P21', 'Gene', '1026', (90, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('clear cell renal cell carcinoma', 'Disease', (41, 72))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (52, 72))	('P21', 'Gene', (90, 93))	('solid tumors', 'Disease', 'MESH:D009369', (216, 228))	('suppresses', 'NegReg', (16, 26))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (41, 72))	('solid tumors', 'Disease', (216, 228))	('lysine', 'Chemical', 'MESH:D008239', (112, 118))	('implicated', 'Reg', (158, 168))	('signaling', 'biological_process', 'GO:0023052', ('94', '103'))	('growth', 'MPA', (31, 37))	('LSD1', 'Gene', (143, 147))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('LSD1', 'Gene', (0, 4))	('LSD1', 'Gene', '23028', (143, 147))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (41, 72))
194486	30972280	High LSD1 expression proved to be an independent prognostic factor for poor overall survival (P<0.001) and recurrence-free survival (P<0.001) of ccRCC patients.	('High', 'Var', (0, 4))	('poor', 'NegReg', (71, 75))	('LSD1', 'Gene', (5, 9))	('expression', 'MPA', (10, 20))	('patients', 'Species', '9606', (151, 159))	('overall', 'MPA', (76, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (145, 150))	('LSD1', 'Gene', '23028', (5, 9))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('recurrence-free survival', 'CPA', (107, 131))	('RCC', 'Disease', 'MESH:C538614', (147, 150))
194488	30972280	Mechanistically, inhibition of LSD1 decreased the H3K4 demethylation at the CDKN1A gene promoter, which was associated with P21 upregulation and cell cycle arrest at G1/S in ccRCC cells.	('CDKN1A', 'Gene', '1026', (76, 82))	('P21', 'Gene', (124, 127))	('H3K4', 'Protein', (50, 54))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (145, 162))	('upregulation', 'PosReg', (128, 140))	('RCC', 'Disease', (176, 179))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('LSD1', 'Gene', '23028', (31, 35))	('demethylation', 'biological_process', 'GO:0070988', ('55', '68'))	('LSD1', 'Gene', (31, 35))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('inhibition', 'Var', (17, 27))	('ccRCC', 'Phenotype', 'HP:0006770', (174, 179))	('cell cycle arrest', 'CPA', (145, 162))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('145', '162'))	('P21', 'Gene', '1026', (124, 127))	('CDKN1A', 'Gene', (76, 82))	('decreased', 'NegReg', (36, 45))
194490	30972280	LSD1 mediates ccRCC cell proliferation: LSD1 is highly expressed in ccRCC samples and it suppresses H3K4 methylation, inducing ccRCC cell proliferation through p21 signaling dysfunction; inhibition of LSD1 restores H3K4 methylation, inducing G1/S cell-cycle arrest by increasing the level of check-point regulator p21.	('LSD1', 'Gene', '23028', (0, 4))	('H3K4', 'Protein', (215, 219))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('methylation', 'MPA', (220, 231))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('G1/S cell-cycle arrest', 'CPA', (242, 264))	('increasing', 'PosReg', (268, 278))	('p21', 'Gene', (160, 163))	('inducing', 'PosReg', (233, 241))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('247', '264'))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('inducing', 'Reg', (118, 126))	('p21', 'Gene', '1026', (314, 317))	('suppresses', 'NegReg', (89, 99))	('RCC', 'Disease', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('H3K4 methylation', 'MPA', (100, 116))	('signaling', 'biological_process', 'GO:0023052', ('164', '173'))	('cell proliferation', 'biological_process', 'GO:0008283', ('133', '151'))	('RCC', 'Disease', (16, 19))	('LSD1', 'Gene', (201, 205))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('ccRCC', 'Phenotype', 'HP:0006770', (14, 19))	('LSD1', 'Gene', '23028', (201, 205))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('p21', 'Gene', '1026', (160, 163))	('restores', 'PosReg', (206, 214))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('cell proliferation', 'biological_process', 'GO:0008283', ('20', '38'))	('inhibition', 'Var', (187, 197))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('LSD1', 'Gene', '23028', (40, 44))	('methylation', 'biological_process', 'GO:0032259', ('105', '116'))	('LSD1', 'Gene', (40, 44))	('methylation', 'biological_process', 'GO:0032259', ('220', '231'))	('p21', 'Gene', (314, 317))	('LSD1', 'Gene', (0, 4))
194495	30972280	Inactivation of the von Hippel-Lindau (VHL) gene by gene mutation, deletion or epigenetic dysregulation causes overexpression of hypoxia-inducible factor (HIF) pathway components, and is considered one of the most crucial carcinogenic factors for ccRCC.	('crucial carcinogenic', 'Disease', 'MESH:D063646', (214, 234))	('hypoxia', 'Disease', 'MESH:D000860', (129, 136))	('von Hippel-Lindau', 'Gene', (20, 37))	('hypoxia', 'Disease', (129, 136))	('deletion', 'Var', (67, 75))	('VHL', 'Gene', (39, 42))	('von Hippel-Lindau', 'Gene', '7428', (20, 37))	('RCC', 'Phenotype', 'HP:0005584', (249, 252))	('crucial carcinogenic', 'Disease', (214, 234))	('epigenetic dysregulation', 'Var', (79, 103))	('RCC', 'Disease', (249, 252))	('RCC', 'Disease', 'MESH:C538614', (249, 252))	('gene mutation', 'Var', (52, 65))	('VHL', 'Gene', '7428', (39, 42))	('ccRCC', 'Phenotype', 'HP:0006770', (247, 252))	('overexpression', 'PosReg', (111, 125))	('Inactivation', 'Var', (0, 12))
194499	30972280	Deregulation of epigenetic regulators has been implicated in cancer progression and the development of drug resistance in multiple cancers including RCC.	('cancer', 'Disease', (131, 137))	('RCC', 'Disease', (149, 152))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('epigenetic regulators', 'Protein', (16, 37))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('Deregulation', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('implicated', 'Reg', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('drug resistance', 'Phenotype', 'HP:0020174', (103, 118))	('drug resistance', 'biological_process', 'GO:0009315', ('103', '118'))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('drug resistance', 'biological_process', 'GO:0042493', ('103', '118'))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
194500	30972280	Histone lysine methylation is known as an important histone modification and plays a pivotal role in embryonic development and tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('histone modification', 'biological_process', 'GO:0016570', ('52', '72'))	('Histone lysine methylation', 'biological_process', 'GO:0034968', ('0', '26'))	('tumor', 'Disease', (127, 132))	('lysine', 'Chemical', 'MESH:D008239', (8, 14))	('Histone lysine methylation', 'Var', (0, 26))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
194504	30972280	Increasing evidence has suggested an association between high LSD1 expression and poor prognosis in some human malignancies, such as leukemia and some solid tumors.	('leukemia', 'Disease', 'MESH:D007938', (133, 141))	('LSD1', 'Gene', (62, 66))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('high', 'Var', (57, 61))	('solid tumors', 'Disease', (151, 163))	('LSD1', 'Gene', '23028', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('leukemia', 'Phenotype', 'HP:0001909', (133, 141))	('malignancies', 'Disease', 'MESH:D009369', (111, 123))	('solid tumors', 'Disease', 'MESH:D009369', (151, 163))	('expression', 'MPA', (67, 77))	('human', 'Species', '9606', (105, 110))	('leukemia', 'Disease', (133, 141))	('malignancies', 'Disease', (111, 123))
194519	30972280	After blocking with non-fat milk for almost 1 h at room temperature, the membranes were incubated overnight at 4  C with primary antibodies: anti-LSD1 (1:1000), anti-H3K4me2 (1:1000), anti-H3K9me2 (1:1000), anti-P53(1:500), anti-P21 (1:500), anti-CDK4 (1:1000), anti-CDK6 (1:1000), anti-GAPDH (1:2000) and anti-beta-actin (1:1000), which were all purchased from Cell Signaling Technology (Boston, Massachusetts, USA).	('beta-actin', 'Gene', '728378', (311, 321))	('GAPDH', 'Gene', '2597', (287, 292))	('CDK', 'molecular_function', 'GO:0004693', ('267', '270'))	('P53', 'Gene', (212, 215))	('CDK4', 'Gene', (247, 251))	('Signaling', 'biological_process', 'GO:0023052', ('367', '376'))	('GAPDH', 'Gene', (287, 292))	('LSD1', 'Gene', (146, 150))	('CDK6', 'Gene', '1021', (267, 271))	('LSD1', 'Gene', '23028', (146, 150))	('CDK', 'molecular_function', 'GO:0004693', ('247', '250'))	('beta-actin', 'Gene', (311, 321))	('CDK4', 'Gene', '1019', (247, 251))	('P53', 'Gene', '7157', (212, 215))	('P21', 'Gene', '1026', (229, 232))	('anti-H3K4me2', 'Var', (161, 173))	('anti-H3K9me2', 'Var', (184, 196))	('CDK6', 'Gene', (267, 271))	('P21', 'Gene', (229, 232))
194526	30972280	786-O and CAKI-1 cell lines associated with high LSD1 expression were selected for further research and seeded in six-well plates.	('expression', 'MPA', (54, 64))	('high', 'Var', (44, 48))	('LSD1', 'Gene', '23028', (49, 53))	('CAKI-1', 'CellLine', 'CVCL:0234', (10, 16))	('LSD1', 'Gene', (49, 53))
194556	30972280	Prognostic analysis indicated that patients with high LSD1 expression exhibited shorter overall survival (OS) and recurrence-free survival (RFS) (Fig.	('LSD1', 'Gene', (54, 58))	('shorter', 'NegReg', (80, 87))	('high', 'Var', (49, 53))	('recurrence-free survival', 'CPA', (114, 138))	('patients', 'Species', '9606', (35, 43))	('overall', 'MPA', (88, 95))	('LSD1', 'Gene', '23028', (54, 58))
194564	30972280	We then knocked down LSD1 expression in 786-O and CAKI-1 using two independent siRNAs.	('CAKI-1', 'CellLine', 'CVCL:0234', (50, 56))	('knocked', 'Var', (8, 15))	('LSD1', 'Gene', '23028', (21, 25))	('LSD1', 'Gene', (21, 25))
194566	30972280	Importantly, dowregulation of LSD1 significantly decreased the growth of 786-O and CAKI-1 cell lines (Fig.	('dowregulation', 'Var', (13, 26))	('growth', 'CPA', (63, 69))	('decreased', 'NegReg', (49, 58))	('CAKI-1', 'CellLine', 'CVCL:0234', (83, 89))	('LSD1', 'Gene', (30, 34))	('LSD1', 'Gene', '23028', (30, 34))
194568	30972280	To determine whether LSD1 downregulation caused cell growth retardation resulting from impaired demethylase activity, we treated 786-O and CAKI-1 cells with three reported LSD1 enzymatic inhibitiors, including SP2509, ORY1001 and tranylcypromine; the anticancer effects in 786-O and CAKI-1 cell lines are shown in Supporting Information Fig.	('growth retardation', 'Disease', 'MESH:D006130', (53, 71))	('growth retardation', 'Disease', (53, 71))	('cancer', 'Disease', (255, 261))	('cell growth', 'biological_process', 'GO:0016049', ('48', '59'))	('LSD1', 'Gene', '23028', (21, 25))	('CAKI-1', 'CellLine', 'CVCL:0234', (283, 289))	('LSD1', 'Gene', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('demethylase', 'Enzyme', (96, 107))	('ORY1001', 'Var', (218, 225))	('CAKI-1', 'CellLine', 'CVCL:0234', (139, 145))	('LSD1', 'Gene', (172, 176))	('activity', 'MPA', (108, 116))	('LSD1', 'Gene', '23028', (172, 176))	('tranylcypromine', 'Chemical', 'MESH:D014191', (230, 245))	('growth retardation', 'Phenotype', 'HP:0001510', (53, 71))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('demethylase activity', 'molecular_function', 'GO:0032451', ('96', '116'))	('impaired', 'NegReg', (87, 95))	('SP2509', 'Chemical', 'MESH:C000594309', (210, 216))	('downregulation', 'NegReg', (26, 40))
194569	30972280	SP2509, with the most potent impact on cell proliferation, was selected for the following studies.	('cell proliferation', 'CPA', (39, 57))	('SP2509', 'Var', (0, 6))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('SP2509', 'Chemical', 'MESH:C000594309', (0, 6))
194571	30972280	SP2509 treatment evidently increased H3K4me2 levels in both cell lines, without signicant change in H3K9me2 level (Fig.	('SP2509', 'Chemical', 'MESH:C000594309', (0, 6))	('H3K4me2 levels', 'MPA', (37, 51))	('SP2509', 'Var', (0, 6))	('increased', 'PosReg', (27, 36))
194572	30972280	In line with the siRNA depletion experiment, SP2509 treatment significantly inhibited cellular proliferation in a time- and dose-dependent manner (Fig.	('cellular proliferation', 'CPA', (86, 108))	('inhibited', 'NegReg', (76, 85))	('SP2509', 'Var', (45, 51))	('SP2509', 'Chemical', 'MESH:C000594309', (45, 51))
194578	30972280	The results demonstrated that LSD1 silencing significantly incresed the ratio of G1-phase cells, which implied an effect of G1/S arrest (Fig.	('silencing', 'Var', (35, 44))	('incresed', 'NegReg', (59, 67))	('G1-phase', 'biological_process', 'GO:0051318', ('81', '89'))	('ratio', 'MPA', (72, 77))	('LSD1', 'Gene', (30, 34))	('LSD1', 'Gene', '23028', (30, 34))
194583	30972280	In summary, the above results suggest that the impairment of LSD1 enzymatic activity inhibits the growth of ccRCC cells via arresting the cells at G1/S phase.	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('S phase', 'biological_process', 'GO:0051320', ('150', '157'))	('inhibits', 'NegReg', (85, 93))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('arresting', 'NegReg', (124, 133))	('cells at G1/S phase', 'CPA', (138, 157))	('growth', 'CPA', (98, 104))	('LSD1', 'Gene', '23028', (61, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('impairment', 'Var', (47, 57))	('LSD1', 'Gene', (61, 65))
194587	30972280	Among the affected pathways, we noticed that the P53 pathway was influenced by SP2509 treatment (Fig.	('SP2509', 'Chemical', 'MESH:C000594309', (79, 85))	('SP2509', 'Var', (79, 85))	('P53', 'Gene', (49, 52))	('P53', 'Gene', '7157', (49, 52))	('influenced', 'Reg', (65, 75))
194590	30972280	It was revealed that inhibition of LSD1 was able to elevate P21 protein expression, while the P53 level was barely affected (Fig.	('P21', 'Gene', '1026', (60, 63))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('LSD1', 'Gene', (35, 39))	('inhibition', 'Var', (21, 31))	('LSD1', 'Gene', '23028', (35, 39))	('elevate', 'PosReg', (52, 59))	('P21', 'Gene', (60, 63))	('P53', 'Gene', (94, 97))	('P53', 'Gene', '7157', (94, 97))
194591	30972280	We also examined the mRNA level of P21 following LSD1 knockdown in both 786-O and CAKI-1 cells and found that the P21 mRNA level was significantly increased compared to negative controls (Fig.	('P21', 'Gene', (35, 38))	('P21', 'Gene', (114, 117))	('increased', 'PosReg', (147, 156))	('mRNA level', 'MPA', (21, 31))	('knockdown', 'Var', (54, 63))	('LSD1', 'Gene', '23028', (49, 53))	('CAKI-1', 'CellLine', 'CVCL:0234', (82, 88))	('P21', 'Gene', '1026', (35, 38))	('P21', 'Gene', '1026', (114, 117))	('LSD1', 'Gene', (49, 53))
194592	30972280	These results suggest that P21 was transcriptionally upregulated upon LSD1 inhibition.	('inhibition', 'Var', (75, 85))	('LSD1', 'Gene', (70, 74))	('P21', 'Gene', '1026', (27, 30))	('LSD1', 'Gene', '23028', (70, 74))	('upregulated', 'PosReg', (53, 64))	('P21', 'Gene', (27, 30))
194595	30972280	The results showed the enrichment of H3K4me2 modification on the promoter of the CDKN1A gene, which encodes the P21 protein, upon LSD1 knockdown in both 786-O and CAKI-1 cell lines.	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('CDKN1A', 'Gene', (81, 87))	('P21', 'Gene', '1026', (112, 115))	('CDKN1A', 'Gene', '1026', (81, 87))	('H3K4me2', 'Var', (37, 44))	('LSD1', 'Gene', (130, 134))	('CAKI-1', 'CellLine', 'CVCL:0234', (163, 169))	('P21', 'Gene', (112, 115))	('LSD1', 'Gene', '23028', (130, 134))
194596	30972280	Consistent with this, the immunoprecipitate with anti-LSD1 antibody showed a decrease of LSD1 binding to the CDKN1A promoter following LSD1 knockdown (Fig.	('LSD1', 'Gene', '23028', (89, 93))	('binding', 'molecular_function', 'GO:0005488', ('94', '101'))	('CDKN1A', 'Gene', (109, 115))	('antibody', 'cellular_component', 'GO:0019815', ('59', '67'))	('decrease', 'NegReg', (77, 85))	('LSD1', 'Gene', (135, 139))	('binding', 'Interaction', (94, 101))	('CDKN1A', 'Gene', '1026', (109, 115))	('antibody', 'cellular_component', 'GO:0019814', ('59', '67'))	('antibody', 'cellular_component', 'GO:0042571', ('59', '67'))	('LSD1', 'Gene', '23028', (135, 139))	('LSD1', 'Gene', (54, 58))	('antibody', 'molecular_function', 'GO:0003823', ('59', '67'))	('LSD1', 'Gene', '23028', (54, 58))	('knockdown', 'Var', (140, 149))	('LSD1', 'Gene', (89, 93))
194597	30972280	These results suggest that LSD1 inhibition increased the H3K4 methylation on the CDKN1A promoter which in turn led to the transcriptional activation of P21 in ccRCC cells.	('LSD1', 'Gene', (27, 31))	('methylation', 'biological_process', 'GO:0032259', ('62', '73'))	('methylation', 'MPA', (62, 73))	('CDKN1A', 'Gene', (81, 87))	('inhibition', 'Var', (32, 42))	('H3K4', 'Protein', (57, 61))	('P21', 'Gene', (152, 155))	('CDKN1A', 'Gene', '1026', (81, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (159, 164))	('RCC', 'Disease', (161, 164))	('increased', 'PosReg', (43, 52))	('P21', 'Gene', '1026', (152, 155))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('transcriptional', 'MPA', (122, 137))	('activation', 'PosReg', (138, 148))	('LSD1', 'Gene', '23028', (27, 31))
194601	30972280	We examined CDK4 and CDK6 mRNA levels and detected an apparent decrease following LSD1 silencing (Fig.	('CDK', 'molecular_function', 'GO:0004693', ('12', '15'))	('silencing', 'Var', (87, 96))	('CDK4', 'Gene', (12, 16))	('CDK6', 'Gene', (21, 25))	('CDK6', 'Gene', '1021', (21, 25))	('mRNA levels', 'MPA', (26, 37))	('decrease', 'NegReg', (63, 71))	('CDK4', 'Gene', '1019', (12, 16))	('CDK', 'molecular_function', 'GO:0004693', ('21', '24'))	('LSD1', 'Gene', (82, 86))	('LSD1', 'Gene', '23028', (82, 86))
194602	30972280	The protein levels of CDK4 and CDK6 were decreased consistently following SP2509 or LSD1 siRNA treatment (Fig.	('protein levels', 'MPA', (4, 18))	('SP2509', 'Var', (74, 80))	('decreased', 'NegReg', (41, 50))	('CDK4', 'Gene', (22, 26))	('LSD1', 'Gene', (84, 88))	('CDK', 'molecular_function', 'GO:0004693', ('22', '25'))	('CDK6', 'Gene', (31, 35))	('LSD1', 'Gene', '23028', (84, 88))	('CDK4', 'Gene', '1019', (22, 26))	('CDK6', 'Gene', '1021', (31, 35))	('SP2509', 'Chemical', 'MESH:C000594309', (74, 80))	('CDK', 'molecular_function', 'GO:0004693', ('31', '34'))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
194603	30972280	Taking together, our findings indicate that LSD1 inhibition results in G1/S phase arrest via the upregulation of P21 signal pathway.	('upregulation', 'PosReg', (97, 109))	('P21', 'Gene', '1026', (113, 116))	('G1/S phase arrest', 'CPA', (71, 88))	('LSD1', 'Gene', (44, 48))	('P21', 'Gene', (113, 116))	('inhibition', 'Var', (49, 59))	('LSD1', 'Gene', '23028', (44, 48))	('S phase', 'biological_process', 'GO:0051320', ('74', '81'))
194606	30972280	Following the subcutaneous engraftment of 786-O and CAKI-1 cells in the flank region, mice were treated with SP2509 in a dose of 15 mg/kg for 4 weeks and tumor volumes were successively monitored and measured twice a week.	('SP2509', 'Var', (109, 115))	('mice', 'Species', '10090', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('CAKI-1', 'CellLine', 'CVCL:0234', (52, 58))	('SP2509', 'Chemical', 'MESH:C000594309', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
194607	30972280	The results showed that the average tumor volume in SP2509-treated group was significantly smaller when compared with the control group (P<0.05 in 786-O mice, P<0.01 in CAKI-1 mice) (Fig.	('SP2509', 'Chemical', 'MESH:C000594309', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('SP2509-treated', 'Var', (52, 66))	('mice', 'Species', '10090', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mice', 'Species', '10090', (153, 157))	('tumor', 'Disease', (36, 41))	('smaller', 'NegReg', (91, 98))	('CAKI-1', 'CellLine', 'CVCL:0234', (169, 175))
194608	30972280	However, the average body weight between the two groups was comparable, which indicated that SP2509 exerted its anti-tumor effects without severe toxicity (Fig.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('SP2509', 'Chemical', 'MESH:C000594309', (93, 99))	('toxicity', 'Disease', 'MESH:D064420', (146, 154))	('toxicity', 'Disease', (146, 154))	('SP2509', 'Var', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
194610	30972280	We also evaluated LSD1 and P21 expression level in the SP2509-treated group and control group by IHC and verified that SP2509 treatment was associated with obviously increased P21 expression (Fig.	('SP2509', 'Var', (119, 125))	('LSD1', 'Gene', (18, 22))	('P21', 'Gene', (176, 179))	('SP2509', 'Chemical', 'MESH:C000594309', (55, 61))	('increased', 'PosReg', (166, 175))	('LSD1', 'Gene', '23028', (18, 22))	('P21', 'Gene', '1026', (27, 30))	('expression', 'MPA', (180, 190))	('SP2509', 'Chemical', 'MESH:C000594309', (119, 125))	('P21', 'Gene', '1026', (176, 179))	('P21', 'Gene', (27, 30))
194614	30972280	Recent studies have shown that LSD1, the first identified histone lysine-specific demethylase, plays an important role in various human malignancies, suggesting that inhibition of LSD1 may be an attractive strategy for cancer treatment.	('lysine', 'Chemical', 'MESH:D008239', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('malignancies', 'Disease', 'MESH:D009369', (136, 148))	('LSD1', 'Gene', '23028', (31, 35))	('LSD1', 'Gene', (31, 35))	('malignancies', 'Disease', (136, 148))	('LSD1', 'Gene', (180, 184))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('LSD1', 'Gene', '23028', (180, 184))	('cancer', 'Disease', (219, 225))	('inhibition', 'Var', (166, 176))	('human', 'Species', '9606', (130, 135))
194620	30972280	It was found that inhibition of LSD1, either by siRNA silencing or SP2509 blockade significantly suppressed cell proliferation, mediated by G1/S cell cycle arrest, along with the accumulation of H3K4me2.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('145', '162'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (145, 162))	('SP2509', 'Gene', (67, 73))	('accumulation', 'PosReg', (179, 191))	('cell proliferation', 'CPA', (108, 126))	('silencing', 'Var', (54, 63))	('H3K4me2', 'Protein', (195, 202))	('LSD1', 'Gene', (32, 36))	('SP2509', 'Chemical', 'MESH:C000594309', (67, 73))	('LSD1', 'Gene', '23028', (32, 36))	('inhibition', 'Var', (18, 28))	('G1/S cell cycle arrest', 'CPA', (140, 162))	('suppressed', 'NegReg', (97, 107))	('cell proliferation', 'biological_process', 'GO:0008283', ('108', '126'))
194621	30972280	These results are consistent with a previous report in non-small cell lung carcinomas, demonstrating that downregulation of LSD1 suppressed cell proliferation and migration capacity.	('downregulation', 'Var', (106, 120))	('non-small cell lung carcinomas', 'Disease', (55, 85))	('cell proliferation', 'CPA', (140, 158))	('suppressed', 'NegReg', (129, 139))	('LSD1', 'Gene', (124, 128))	('LSD1', 'Gene', '23028', (124, 128))	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (55, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('migration capacity', 'CPA', (163, 181))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (59, 85))	('cell proliferation', 'biological_process', 'GO:0008283', ('140', '158'))	('non-small cell lung carcinomas', 'Disease', 'MESH:D002289', (55, 85))
194622	30972280	In our mouse model study, SP2509 treatment induced a significant decrease of tumor volume and tumor weight without obvious toxicity.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('decrease of tumor', 'Disease', (65, 82))	('SP2509', 'Var', (26, 32))	('toxicity', 'Disease', (123, 131))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mouse', 'Species', '10090', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('decrease of tumor', 'Disease', 'MESH:D009369', (65, 82))	('SP2509', 'Chemical', 'MESH:C000594309', (26, 32))	('tumor', 'Disease', (77, 82))	('toxicity', 'Disease', 'MESH:D064420', (123, 131))
194625	30972280	Furthermore, dysregulation of CKIs is a common feature in the course of tumor development across different cancer types.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Disease', (72, 77))	('dysregulation', 'Var', (13, 26))	('CKIs', 'Protein', (30, 34))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Disease', (107, 113))
194630	30972280	Of interest, we also observed that CDK4/6 was significantly suppressed by LSD1 inhibition.	('suppressed', 'NegReg', (60, 70))	('CDK', 'molecular_function', 'GO:0004693', ('35', '38'))	('inhibition', 'Var', (79, 89))	('LSD1', 'Gene', (74, 78))	('CDK4/6', 'Gene', '1019;1021', (35, 41))	('LSD1', 'Gene', '23028', (74, 78))	('CDK4/6', 'Gene', (35, 41))
194634	30972280	reported that LincRNAFEZF1-AS1 repressed P21 expression in the manner of LSD1-mediated H3K4me2 demethylation and promoted gastric cancer progression.	('LSD1', 'Gene', (73, 77))	('promoted', 'PosReg', (113, 121))	('LSD1', 'Gene', '23028', (73, 77))	('P21', 'Gene', '1026', (41, 44))	('demethylation', 'biological_process', 'GO:0070988', ('95', '108'))	('gastric cancer', 'Disease', (122, 136))	('expression', 'MPA', (45, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('AS1', 'Gene', '5729', (27, 30))	('AS1', 'Gene', (27, 30))	('H3K4me2', 'Var', (87, 94))	('P21', 'Gene', (41, 44))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))
194636	30972280	According to the GO classification in our study, we showed that the LSD1 inhibitor mainly decreased the cellular process and reduced antioxidant activity.	('antioxidant activity', 'MPA', (133, 153))	('antioxidant activity', 'molecular_function', 'GO:0016209', ('133', '153'))	('cellular process', 'CPA', (104, 120))	('cellular process', 'biological_process', 'GO:0009987', ('104', '120'))	('inhibitor', 'Var', (73, 82))	('decreased', 'NegReg', (90, 99))	('reduced', 'NegReg', (125, 132))	('LSD1', 'Gene', (68, 72))	('LSD1', 'Gene', '23028', (68, 72))	('cellular process', 'cellular_component', 'GO:0042995', ('104', '120'))
194640	30972280	Furthermore, inhibition of LSD1 expression or activity induces G1/S arrest and inhibition of cell proliferation in vitro, possibly via modulating the P21 signaling pathway.	('LSD1', 'Gene', (27, 31))	('inhibition', 'Var', (13, 23))	('modulating', 'Reg', (135, 145))	('induces', 'Reg', (55, 62))	('P21', 'Gene', (150, 153))	('cell proliferation', 'CPA', (93, 111))	('activity', 'MPA', (46, 54))	('inhibition', 'NegReg', (79, 89))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('79', '111'))	('G1/S arrest', 'CPA', (63, 74))	('signaling pathway', 'biological_process', 'GO:0007165', ('154', '171'))	('LSD1', 'Gene', '23028', (27, 31))	('P21', 'Gene', '1026', (150, 153))
194641	30972280	In vivo experiments further verify that antagonist targeting of LSD1 inhibits growth of engrafted renal tumors, suggesting that LSD1 may be a novel molecular target for new drug development for advanced ccRCC.	('renal tumors', 'Phenotype', 'HP:0009726', (98, 110))	('renal tumor', 'Phenotype', 'HP:0009726', (98, 109))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('RCC', 'Disease', (205, 208))	('LSD1', 'Gene', (128, 132))	('RCC', 'Phenotype', 'HP:0005584', (205, 208))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('inhibits', 'NegReg', (69, 77))	('renal tumors', 'Disease', 'MESH:D007674', (98, 110))	('LSD1', 'Gene', '23028', (128, 132))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('renal tumors', 'Disease', (98, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (203, 208))	('LSD1', 'Gene', (64, 68))	('LSD1', 'Gene', '23028', (64, 68))	('antagonist targeting', 'Var', (40, 60))
194642	30972280	Further research is still needed to explore in detail the mechanism by which demethylation and the P21 pathway participate in ccRCC development.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('P21', 'Gene', '1026', (99, 102))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('participate', 'Reg', (111, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('demethylation', 'Var', (77, 90))	('P21', 'Gene', (99, 102))	('demethylation', 'biological_process', 'GO:0070988', ('77', '90'))
194666	29053609	One copy of VHL is either mutated or silenced in 90% of sporadic CCRCCs, whereas another copy is typically lost through 3p deletions, according to the comprehensive molecular profiling of CCRCCs by The Cancer Genome Atlas (TCGA).	('VHL', 'Gene', (12, 15))	('VHL', 'Gene', '7428', (12, 15))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Disease', (67, 70))	('RCC', 'Disease', (190, 193))	('silenced', 'NegReg', (37, 45))	('Cancer', 'Phenotype', 'HP:0002664', (202, 208))	('RCCs', 'Phenotype', 'HP:0005584', (190, 194))	('Cancer Genome Atlas', 'Disease', (202, 221))	('mutated', 'Var', (26, 33))	('RCCs', 'Phenotype', 'HP:0005584', (67, 71))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (202, 221))
194668	29053609	According to the TCGA, CCRCCs are characterized by recurrent mutations in the PI3K/AKT/MTOR pathway (a potential therapeutic target), mutations in SETD2 (associated with widespread DNA hypomethylation), and mutations involving the SWI/SNF chromatin remodeling complex (PBRM1, ARID1A, and SMARCA4).	('AKT', 'Gene', '207', (83, 86))	('RCCs', 'Phenotype', 'HP:0005584', (25, 29))	('SETD2', 'Gene', (147, 152))	('PI3K', 'molecular_function', 'GO:0016303', ('78', '82'))	('DNA', 'cellular_component', 'GO:0005574', ('181', '184'))	('SETD2', 'Gene', '29072', (147, 152))	('mutations', 'Var', (207, 216))	('mutations', 'Var', (134, 143))	('MTOR', 'Gene', (87, 91))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('239', '259'))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('181', '200'))	('RCC', 'Disease', (25, 28))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('239', '267'))	('PBRM1', 'Gene', '55193', (269, 274))	('SMARCA4', 'Gene', '6597', (288, 295))	('MTOR', 'Gene', '2475', (87, 91))	('AKT', 'Gene', (83, 86))	('mutations', 'Var', (61, 70))	('PBRM1', 'Gene', (269, 274))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('ARID1A', 'Gene', (276, 282))	('ARID1A', 'Gene', '8289', (276, 282))	('SMARCA4', 'Gene', (288, 295))
194674	29053609	Hereditary PRCC syndrome with germline mutations in MET is associated with type 1 PRCCs.	('RCCs', 'Phenotype', 'HP:0005584', (83, 87))	('PRCC', 'Gene', (82, 86))	('PRCC', 'Gene', '5546', (11, 15))	('Hereditary PRCC syndrome', 'Disease', 'MESH:D009386', (0, 24))	('associated', 'Reg', (59, 69))	('germline mutations', 'Var', (30, 48))	('PRCC', 'Gene', (11, 15))	('Hereditary PRCC syndrome', 'Disease', (0, 24))	('MET', 'Gene', (52, 55))	('PRCC', 'Gene', '5546', (82, 86))
194681	29053609	Of note, CK7 positivity is more prominent in type 1 PRCCs and is often decreased in type 2 PRCCs.	('positivity', 'Var', (13, 23))	('CK7', 'Gene', (9, 12))	('PRCC', 'Gene', '5546', (52, 56))	('PRCC', 'Gene', (91, 95))	('CK7', 'Gene', '3855', (9, 12))	('RCCs', 'Phenotype', 'HP:0005584', (53, 57))	('PRCC', 'Gene', (52, 56))	('RCCs', 'Phenotype', 'HP:0005584', (92, 96))	('decreased', 'NegReg', (71, 80))	('PRCC', 'Gene', '5546', (91, 95))
194684	29053609	According to the comprehensive molecular profiling of PRCCs by TCGA, type 1 PRCCs are characterized by MET alterations, whereas type 2 PRCCs are characterized by CDKN2A silencing, SETD2 mutations, and increased expression of the NRF2-antioxidant response element pathway.	('RCCs', 'Phenotype', 'HP:0005584', (136, 140))	('CDKN2A', 'Gene', (162, 168))	('RCCs', 'Phenotype', 'HP:0005584', (55, 59))	('increased', 'PosReg', (201, 210))	('PRCC', 'Gene', '5546', (135, 139))	('PRCC', 'Gene', '5546', (54, 58))	('PRCC', 'Gene', (76, 80))	('NRF2', 'Gene', '4780', (229, 233))	('silencing', 'NegReg', (169, 178))	('CDKN2A', 'Gene', '1029', (162, 168))	('RCCs', 'Phenotype', 'HP:0005584', (77, 81))	('SETD2', 'Gene', (180, 185))	('mutations', 'Var', (186, 195))	('PRCC', 'Gene', '5546', (76, 80))	('NRF2', 'Gene', (229, 233))	('SETD2', 'Gene', '29072', (180, 185))	('PRCC', 'Gene', (135, 139))	('expression', 'MPA', (211, 221))	('PRCC', 'Gene', (54, 58))
194688	29053609	C2b PRCCs are associated with later stages of tumor development and SETD2 mutations.	('PRCC', 'Gene', '5546', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PRCC', 'Gene', (4, 8))	('tumor', 'Disease', (46, 51))	('mutations', 'Var', (74, 83))	('associated', 'Reg', (14, 24))	('SETD2', 'Gene', '29072', (68, 73))	('C2b', 'Gene', (0, 3))	('RCCs', 'Phenotype', 'HP:0005584', (5, 9))	('SETD2', 'Gene', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
194690	29053609	Birt-Hogg-Dube syndrome with FLCN mutations is associated with a higher incidence of ChRCCs.	('FLCN', 'Gene', '201163', (29, 33))	('RCCs', 'Phenotype', 'HP:0005584', (87, 91))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('FLCN', 'Gene', (29, 33))	('Birt-Hogg-Dube syndrome', 'Disease', (0, 23))	('mutations', 'Var', (34, 43))	('Birt-Hogg-Dube syndrome', 'Disease', 'MESH:D058249', (0, 23))
194697	29053609	Recurrent DNA rearrangement breakpoints within the TERT promoter region in 10% of examined cases of ChRCCs, which are associated with high TERT expression and manifestation of kataegis, represent a mechanism for increased TERT expression in these tumors, differing from the point mutations of TERT observed in various malignancies.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumors', 'Disease', (247, 253))	('TERT', 'Gene', (222, 226))	('TERT', 'Gene', '7015', (222, 226))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('malignancies', 'Disease', 'MESH:D009369', (318, 330))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('malignancies', 'Disease', (318, 330))	('TERT', 'Gene', (51, 55))	('DNA', 'Gene', (10, 13))	('TERT', 'Gene', '7015', (51, 55))	('RCCs', 'Phenotype', 'HP:0005584', (102, 106))	('TERT', 'Gene', (139, 143))	('rearrangement breakpoints', 'Var', (14, 39))	('TERT', 'Gene', '7015', (139, 143))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('RCC', 'Disease', (102, 105))	('TERT', 'Gene', (293, 297))	('TERT', 'Gene', '7015', (293, 297))	('increased', 'PosReg', (212, 221))
194698	29053609	A recent study has demonstrated that metastatic ChRCCs were characterized by TP53 mutations (58%), PTEN mutations (24%), and imbalanced chromosome duplication (ICD) (25%), suggesting these genomic changes are involved in metastatic evolution for ChRCCs.	('RCC', 'Disease', 'MESH:C538614', (248, 251))	('mutations', 'Var', (104, 113))	('RCC', 'Disease', (248, 251))	('ICD', 'Disease', 'OMIM:252500', (160, 163))	('RCCs', 'Phenotype', 'HP:0005584', (248, 252))	('RCCs', 'Phenotype', 'HP:0005584', (50, 54))	('ICD', 'Disease', (160, 163))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('imbalanced chromosome duplication', 'Var', (125, 158))	('mutations', 'Var', (82, 91))	('chromosome', 'cellular_component', 'GO:0005694', ('136', '146'))	('PTEN', 'Gene', (99, 103))	('TP53', 'Gene', '7157', (77, 81))	('PTEN', 'Gene', '5728', (99, 103))	('TP53', 'Gene', (77, 81))
194703	29053609	Similar to CCRCC, chromosome 3p deletions and VHL mutations were found in 74% and 25% of these tumors, respectively.	('VHL', 'Gene', (46, 49))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('mutations', 'Var', (50, 59))	('VHL', 'Gene', '7428', (46, 49))	('chromosome', 'cellular_component', 'GO:0005694', ('18', '28'))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('found', 'Reg', (65, 70))	('tumors', 'Disease', (95, 101))
194704	29053609	Xp11 TRCC was established as an RCC subtype in the 2004 WHO classification.	('Xp11', 'Var', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))
194706	29053609	Both Xp11 translocation and t(6;11) RCC are characterized by the rearrangement of the MiT transcription factors, TFE3 and TFEB.	('TFE3', 'Gene', (113, 117))	('TFEB', 'Gene', '7942', (122, 126))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('TFEB', 'Gene', (122, 126))	('TFE3', 'Gene', '7030', (113, 117))	('transcription', 'biological_process', 'GO:0006351', ('90', '103'))	('Xp11 translocation', 'Var', (5, 23))
194707	29053609	Xp11 TRCC comprises 20-40% of pediatric RCCs and 1-4% of adult RCCs, with an average age of onset of 50 years.	('RCC', 'Disease', (63, 66))	('RCCs', 'Phenotype', 'HP:0005584', (63, 67))	('Xp11', 'Var', (0, 4))	('RCC', 'Disease', (40, 43))	('RCCs', 'Phenotype', 'HP:0005584', (40, 44))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
194710	29053609	Morphologically, Xp11 TRCC is typically composed of cells with clear/eosinophilic cytoplasm with papillary and nested structures and psammoma bodies.	('Xp11', 'Var', (17, 21))	('psammoma bodies', 'Disease', 'MESH:D001835', (133, 148))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('psammoma bodies', 'Disease', (133, 148))	('cytoplasm', 'cellular_component', 'GO:0005737', ('82', '91'))
194714	29053609	Specifically, Xp11 TRCC and t(6;11) RCC display positive nuclear immunostaining for TFE3 and TFEB, respectively.	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('TFE3', 'Gene', (84, 88))	('RCC', 'Disease', (36, 39))	('Xp11', 'Var', (14, 18))	('TFE3', 'Gene', '7030', (84, 88))	('TFEB', 'Gene', '7942', (93, 97))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('TFEB', 'Gene', (93, 97))	('RCC', 'Disease', (20, 23))
194715	29053609	Xp11/TFEB TRCC is diagnosed by the utilization of TFE3/TFEB immunohistochemistry or break-apart TFE3/TFEB fluorescence in in situ hybridization in formalin-fixed paraffin-embedded (FFPE) specimens.	('TFE3', 'Gene', (50, 54))	('TFEB', 'Gene', '7942', (5, 9))	('TFEB', 'Gene', (5, 9))	('TFE3', 'Gene', '7030', (96, 100))	('paraffin', 'Chemical', 'MESH:D010232', (162, 170))	('formalin', 'Chemical', 'MESH:D005557', (147, 155))	('TFE3', 'Gene', '7030', (50, 54))	('TFE3', 'Gene', (96, 100))	('TFEB', 'Gene', '7942', (55, 59))	('TFEB', 'Gene', '7942', (101, 105))	('break-apart', 'Var', (84, 95))	('TFEB', 'Gene', (55, 59))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('TFEB', 'Gene', (101, 105))	('RCC', 'Disease', (11, 14))
194717	29053609	Another recent study demonstrated that TFEB-amplified RCCs with or without TFEB translocation were characterized by aggressive clinical behavior, variable morphology, aberrant melanocytic marker expression, and high frequency of immunohistochemical positivity for TFEB.	('aberrant', 'Var', (167, 175))	('TFEB', 'Gene', '7942', (39, 43))	('expression', 'MPA', (195, 205))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (116, 144))	('TFEB', 'Gene', (39, 43))	('TFEB', 'Gene', '7942', (75, 79))	('RCC', 'Disease', (54, 57))	('TFEB', 'Gene', (75, 79))	('RCCs', 'Phenotype', 'HP:0005584', (54, 58))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('translocation', 'Var', (80, 93))	('TFEB', 'Gene', '7942', (264, 268))	('TFEB', 'Gene', (264, 268))
194750	29053609	Genetically, the defining molecular abnormality in SDH-deficient RCC is the double-hit inactivation of one of the SDH genes, most commonly SDHB.	('SDH', 'Gene', '6390', (51, 54))	('SDH-deficient RCC', 'Disease', (51, 68))	('SDH', 'Gene', (139, 142))	('SDH', 'Gene', '6390', (114, 117))	('SDH-deficient RCC', 'Disease', 'MESH:C538614', (51, 68))	('SDHB', 'Gene', '6390', (139, 143))	('SDHB', 'Gene', (139, 143))	('inactivation', 'Var', (87, 99))	('SDH', 'Gene', '6390', (139, 142))	('SDH', 'Gene', (51, 54))	('SDH', 'Gene', (114, 117))
194755	29053609	A diagnosis of HLRCC-associated RCC is confirmed by the presence of germline FH mutations.	('mutations', 'Var', (80, 89))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))
194772	29053609	Genetically, a subgroup of this tumor demonstrates a TFE3/TFEB rearrangement.	('TFE3', 'Gene', (53, 57))	('rearrangement', 'Var', (63, 76))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('TFEB', 'Gene', '7942', (58, 62))	('TFE3', 'Gene', '7030', (53, 57))	('TFEB', 'Gene', (58, 62))	('tumor', 'Disease', (32, 37))
194780	29053609	ALK rearrangement-associated RCC occurs in children and adults, with or without sickle cell trait, comprising approximately 0.4% of all adult RCCs.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('RCCs', 'Phenotype', 'HP:0005584', (142, 146))	('RCC', 'Disease', (29, 32))	('children', 'Species', '9606', (43, 51))	('rearrangement-associated', 'Var', (4, 28))	('ALK', 'Gene', (0, 3))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('ALK', 'Gene', '238', (0, 3))
194791	29053609	Immunohistochemically, the epithelial component is typically positive for CAIX, CD10, CK7, 34betaE12, and PAX8, and negative for AMACR and HMB45.	('CK7', 'Gene', '3855', (86, 89))	('CD10', 'Gene', (80, 84))	('PAX8', 'Gene', (106, 110))	('CAIX', 'Gene', (74, 78))	('positive', 'Reg', (61, 69))	('CD10', 'Gene', '4311', (80, 84))	('34betaE12', 'Var', (91, 100))	('CAIX', 'Gene', '768', (74, 78))	('AMACR', 'Gene', (129, 134))	('AMACR', 'Gene', '23600', (129, 134))	('CD10', 'molecular_function', 'GO:0004245', ('80', '84'))	('PAX8', 'Gene', '7849', (106, 110))	('CK7', 'Gene', (86, 89))
194794	29053609	Recent evidence suggests an association of this tumor with TCEB1 mutations.	('TCEB1', 'Gene', '6921', (59, 64))	('tumor', 'Disease', (48, 53))	('TCEB1', 'Gene', (59, 64))	('association', 'Interaction', (28, 39))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mutations', 'Var', (65, 74))
194807	32206160	VHL syndrome is an autosomal dominant disease caused by germline mutations in the VHL gene.	('VHL syndrome', 'Disease', 'MESH:D006623', (0, 12))	('caused by', 'Reg', (46, 55))	('autosomal dominant disease', 'Disease', (19, 45))	('VHL', 'Gene', (82, 85))	('VHL syndrome', 'Disease', (0, 12))	('autosomal dominant disease', 'Disease', 'MESH:D030342', (19, 45))	('germline mutations', 'Var', (56, 74))
194809	32206160	Latif and colleagues were the first to identify the VHL gene, and the following year VHL was also shown to be mutated in sporadic ccRCC.	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('RCC', 'Disease', (132, 135))	('mutated', 'Var', (110, 117))	('VHL', 'Gene', (85, 88))	('VHL', 'Gene', (52, 55))
194810	32206160	Nearly two decades later, Nickerson and colleagues evaluated a cohort of 205 ccRCC samples, the largest cohort at that time, for aberrations in the VHL gene through targeted sequencing.	('VHL', 'Gene', (148, 151))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('aberrations', 'Var', (129, 140))	('RCC', 'Disease', (79, 82))
194811	32206160	They identified non-silent somatic mutations with a prevalence of 82% and VHL promoter hypermethylation in an additional 8.3% of tumors, for a total of 90% of tumors.	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('VHL', 'Gene', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('promoter hypermethylation', 'Var', (78, 103))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumors', 'Disease', 'MESH:D009369', (159, 165))
194812	32206160	In sporadic ccRCC, the initiating event is thought to be loss of 3p through a chromothripsis event.	('chromothripsis', 'Disease', 'MESH:D000072837', (78, 92))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('RCC', 'Disease', (14, 17))	('loss of 3p', 'Var', (57, 67))	('chromothripsis', 'Disease', (78, 92))
194813	32206160	While VHL loss is nearly universal in ccRCC, VHL inactivation has also been shown in preneoplastic cysts, and mice with VHL disruption in the kidneys do not develop ccRCC.	('VHL loss', 'Disease', 'MESH:D006623', (6, 14))	('VHL loss', 'Disease', (6, 14))	('RCC', 'Disease', (40, 43))	('mice', 'Species', '10090', (110, 114))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('VHL', 'Gene', (120, 123))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('RCC', 'Disease', (167, 170))	('disruption', 'Var', (124, 134))
194817	32206160	Interestingly, mutations in TCEB1 (encoding Elongin C) have been reported in up to 5% of ccRCC cases and are associated with loss of heterozygosity of chromosome 8, which contains TCEB1.	('associated', 'Reg', (109, 119))	('reported', 'Reg', (65, 73))	('Elongin C', 'Gene', (44, 53))	('TCEB1', 'Gene', '6921', (28, 33))	('mutations', 'Var', (15, 24))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('TCEB1', 'Gene', (28, 33))	('RCC', 'Disease', (91, 94))	('TCEB1', 'Gene', '6921', (180, 185))	('TCEB1', 'Gene', (180, 185))	('chromosome', 'cellular_component', 'GO:0005694', ('151', '161'))	('Elongin C', 'Gene', '6921', (44, 53))
194818	32206160	In addition, mutations in CUL2 were found in up to 1% of ccRCCs.	('CUL2', 'Gene', (26, 30))	('found', 'Reg', (36, 41))	('CUL2', 'Gene', '8453', (26, 30))	('mutations', 'Var', (13, 22))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))
194819	32206160	Mutations in TCEB1 and CUL2 tend to be mutually exclusive with VHL mutations and likely represent other mechanisms to disrupt VHL function.	('TCEB1', 'Gene', '6921', (13, 18))	('TCEB1', 'Gene', (13, 18))	('CUL2', 'Gene', (23, 27))	('mutations', 'Var', (67, 76))	('Mutations', 'Var', (0, 9))	('CUL2', 'Gene', '8453', (23, 27))	('VHL', 'Gene', (63, 66))
194820	32206160	The first large scale sequencing reports in ccRCC came out in 2009, and demonstrated frequent mutations in the chromatin remodeling genes SETD2, KDM6A (also known as UTX), KDM5C (also known as JARID1C), and MLL2.	('JARID1C', 'Gene', '8242', (193, 200))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('111', '131'))	('RCC', 'Disease', (46, 49))	('mutations', 'Var', (94, 103))	('MLL2', 'Gene', (207, 211))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('KDM6A', 'Gene', (145, 150))	('JARID1C', 'Gene', (193, 200))	('UTX', 'Gene', (166, 169))	('SETD2', 'Gene', '29072', (138, 143))	('UTX', 'Gene', '7403', (166, 169))	('KDM5C', 'Gene', '8242', (172, 177))	('KDM5C', 'Gene', (172, 177))	('KDM6A', 'Gene', '7403', (145, 150))	('MLL2', 'Gene', '8085', (207, 211))	('SETD2', 'Gene', (138, 143))	('chromatin', 'cellular_component', 'GO:0000785', ('111', '120'))
194821	32206160	These reports were limited to sequencing a panel of ~3,500 genes, a small subset of the entire human exome, and the genes identified were mutated in up to 15% of tumors.	('human', 'Species', '9606', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mutated', 'Var', (138, 145))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumors', 'Disease', (162, 168))
194823	32206160	Varela and colleagues performed WES of seven ccRCC and matching normal samples and identified truncating mutations in PBRM1 in four tumors.	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('tumors', 'Disease', (132, 138))	('truncating mutations', 'Var', (94, 114))	('PBRM1', 'Gene', (118, 123))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
194826	32206160	By incorporating tumorgrafts, our studies allowed for accurate calls of mutant allele frequencies (MAF) thereby confidently nominating putative two-hit tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mutant', 'Var', (72, 78))	('tumor suppressor', 'biological_process', 'GO:0051726', ('152', '168'))	('tumor', 'Disease', (152, 157))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('152', '168'))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
194828	32206160	Subsequent BAP1 targeted sequencing studies identified mutations in 24 out of 176 (14%) largely primary ccRCC samples.	('RCC', 'Disease', (106, 109))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('mutations', 'Var', (55, 64))
194830	32206160	The BAP1 protein is a nuclear-localized deubiquitinase which acts to deubiquitylate H2AK119ub1 to reverse polycomb-mediated gene repression.	('polycomb-mediated gene', 'Gene', (106, 128))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('40', '54'))	('BAP1', 'Gene', (4, 8))	('protein', 'cellular_component', 'GO:0003675', ('9', '16'))	('H2AK119ub1', 'Chemical', '-', (84, 94))	('H2AK119ub1', 'Var', (84, 94))	('reverse', 'PosReg', (98, 105))
194833	32206160	Notably, BAP1 and PBRM1 mutations were found to anticorrelate in ccRCC and the prevalence of combined BAP1/PBRM1 deficient ccRCC is ~1-2%, less than the ~5% rate expected given the rates of PBRM1 (~45%) and BAP1 (~12%) mutations in ccRCC.	('PBRM1', 'Gene', (190, 195))	('deficient', 'NegReg', (113, 122))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (125, 128))	('RCC', 'Disease', (67, 70))	('BAP1/PBRM1', 'Gene', (102, 112))	('PBRM1', 'Gene', (18, 23))	('BAP1', 'Gene', (207, 211))	('mutations', 'Var', (24, 33))	('BAP1', 'Gene', (9, 13))	('RCC', 'Disease', 'MESH:C538614', (234, 237))	('RCC', 'Disease', (234, 237))
194834	32206160	Furthermore, BAP1 mutant tumors exhibited higher nucleolar grade, more aggressive histology, and demonstrated worsened RCCspecific survival.	('nucleolar grade', 'MPA', (49, 64))	('BAP1', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('mutant', 'Var', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('higher', 'PosReg', (42, 48))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))	('more', 'PosReg', (66, 70))	('aggressive', 'CPA', (71, 81))	('worsened', 'NegReg', (110, 118))
194835	32206160	This finding was subsequently confirmed in metastatic RCC, as BAP1 mutations were independently associated with worsened overall survival.	('overall survival', 'MPA', (121, 137))	('RCC', 'Disease', (54, 57))	('BAP1', 'Gene', (62, 66))	('worsened', 'NegReg', (112, 120))	('mutations', 'Var', (67, 76))	('RCC', 'Disease', 'MESH:C538614', (54, 57))
194836	32206160	Together these findings led us to propose a model where following inactivation of VHL and 3p loss, inactivation of the remaining copy of BAP1 caused aggressive ccRCC and inactivation of PBRM1, less aggressive ccRCC.	('BAP1', 'Gene', (137, 141))	('aggressive ccRCC', 'Disease', 'MESH:D001523', (149, 165))	('aggressive ccRCC', 'Disease', 'MESH:D001523', (198, 214))	('caused', 'Reg', (142, 148))	('aggressive ccRCC', 'Disease', (149, 165))	('VHL', 'Gene', (82, 85))	('inactivation', 'Var', (66, 78))	('aggressive ccRCC', 'Disease', (198, 214))	('inactivation', 'Var', (170, 182))	('PBRM1', 'Gene', (186, 191))	('inactivation', 'Var', (99, 111))
194837	32206160	Using methods we developed, this model was subsequently revised by the TRACERx consortium to show that the first event in sporadic tumors is likely the loss of 3p.	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('sporadic tumors', 'Disease', 'MESH:D009369', (122, 137))	('loss of 3p', 'Var', (152, 162))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('sporadic tumors', 'Disease', (122, 137))
194840	32206160	We showed that ccRCC development required not only Vhl inactivation, but also the inactivation of Bap1 (or Pbrm1).	('inactivation', 'Var', (55, 67))	('Vhl', 'MPA', (51, 54))	('Pbrm1', 'Gene', (107, 112))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))	('inactivation', 'Var', (82, 94))
194842	32206160	However, the simultaneous inactivation of Vhl and Pbrm1 caused ccRCC.	('Pbrm1', 'Gene', (50, 55))	('inactivation', 'Var', (26, 38))	('caused', 'Reg', (56, 62))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('Vhl', 'Gene', (42, 45))	('RCC', 'Disease', (65, 68))
194846	32206160	These discoveries explain why germline VHL mutations cause kidney cancer in humans, but not in mice.	('cause', 'Reg', (53, 58))	('germline', 'Var', (30, 38))	('mice', 'Species', '10090', (95, 99))	('kidney cancer', 'Disease', 'MESH:D007680', (59, 72))	('kidney cancer', 'Phenotype', 'HP:0009726', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('VHL', 'Gene', (39, 42))	('kidney cancer', 'Disease', (59, 72))	('mutations', 'Var', (43, 52))	('humans', 'Species', '9606', (76, 82))
194847	32206160	As it turns out, we found that in mice the Bap1 and Pbrm1 genes are on a different chromosome than Vhl and as such, loss of the chromosome arm containing the Vhl gene in the mouse would have no effect on Bap1 or Pbrm1 genes.	('Bap1', 'Gene', (43, 47))	('mouse', 'Species', '10090', (174, 179))	('mice', 'Species', '10090', (34, 38))	('chromosome', 'cellular_component', 'GO:0005694', ('128', '138'))	('Pbrm1', 'Gene', (212, 217))	('Vhl', 'Gene', (158, 161))	('chromosome', 'cellular_component', 'GO:0005694', ('83', '93'))	('Pbrm1', 'Gene', (52, 57))	('Bap1', 'Gene', (204, 208))	('loss', 'Var', (116, 120))
194853	32206160	Or how do mutations in TCEB1 and CUL2, which are located on chromosome 8 and 10 respectively, lead to ccRCC formation, and what are the specific cooperating events?	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('CUL2', 'Gene', (33, 37))	('formation', 'biological_process', 'GO:0009058', ('108', '117'))	('CUL2', 'Gene', '8453', (33, 37))	('lead to', 'Reg', (94, 101))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))	('TCEB1', 'Gene', '6921', (23, 28))	('mutations', 'Var', (10, 19))	('TCEB1', 'Gene', (23, 28))	('RCC', 'Disease', (104, 107))
194858	32206160	Other findings of significance included loss of one CDKN2A allele in 16.2% of ccRCCs (mostly through deletion of 9p21.3), and mutation of TP53 in 2.6% of cases.	('deletion', 'Var', (101, 109))	('TP53', 'Gene', '7157', (138, 142))	('RCC', 'Disease', (80, 83))	('mutation', 'Var', (126, 134))	('loss', 'NegReg', (40, 44))	('TP53', 'Gene', (138, 142))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('CDKN2A', 'Gene', (52, 58))	('CDKN2A', 'Gene', '1029', (52, 58))
194859	32206160	In a similar analysis of non-ccRCC, we found distinct mutated genes and SCNA alterations highlighting the diverse molecular landscape of RCC.	('mutated genes', 'Var', (54, 67))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))
194861	32206160	Activating MET mutations were identified in 15% (10/65) of pRCC analyzed, including 4 previously unreported mutations.	('MET', 'Gene', '79811', (11, 14))	('Activating', 'PosReg', (0, 10))	('mutations', 'Var', (15, 24))	('MET', 'Gene', (11, 14))	('pRCC', 'Gene', (59, 63))	('pRCC', 'Gene', '5546', (59, 63))
194863	32206160	These findings were confirmed in a subsequent analysis of the pRCC TCGA cohort, where activating MET mutations were identified in 17% (14/75) of type I pRCC samples, which exhibited near universal gain of chromosomes 7 and 17.	('mutations', 'Var', (101, 110))	('pRCC', 'Gene', '5546', (62, 66))	('pRCC', 'Gene', '5546', (152, 156))	('MET', 'Gene', '79811', (97, 100))	('activating', 'PosReg', (86, 96))	('gain', 'PosReg', (197, 201))	('pRCC', 'Gene', (62, 66))	('MET', 'Gene', (97, 100))	('pRCC', 'Gene', (152, 156))
194866	32206160	CIMP tumors were characterized by universal hypermethylation of CDKN2A, frequent fumarate hydratase (FH) mutations (including somatic mutations; 57%), and worse survival relative to non-CIMP pRCC.	('fumarate hydratase', 'Gene', '2271', (81, 99))	('pRCC', 'Gene', '5546', (191, 195))	('survival', 'CPA', (161, 169))	('CDKN2A', 'Gene', (64, 70))	('fumarate hydratase', 'Gene', (81, 99))	('worse', 'NegReg', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('FH', 'Gene', '2271', (101, 103))	('CIMP tumors', 'Disease', 'MESH:D009369', (0, 11))	('CDKN2A', 'Gene', '1029', (64, 70))	('mutations', 'Var', (105, 114))	('hypermethylation', 'Var', (44, 60))	('pRCC', 'Gene', (191, 195))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('CIMP tumors', 'Disease', (0, 11))
194877	32206160	Studies from TCGA and our own group found that TP53 mutations were significantly enriched (P = 2.3E-5) in the classic chRCC subtype.	('mutations', 'Var', (52, 61))	('TP53', 'Gene', '7157', (47, 51))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('TP53', 'Gene', (47, 51))
194878	32206160	The two most frequently mutated genes across chRCC variants are TP53 (31.1%) and PTEN (9%).	('variants', 'Var', (51, 59))	('PTEN', 'Gene', (81, 85))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('PTEN', 'Gene', '5728', (81, 85))	('TP53', 'Gene', (64, 68))	('TP53', 'Gene', '7157', (64, 68))
194879	32206160	Mutually exclusive mutations in genes of the PI3K/AKT/mTOR pathway were observed in 23% of cases.	('observed', 'Reg', (72, 80))	('AKT', 'Gene', '207', (50, 53))	('PI3K', 'molecular_function', 'GO:0016303', ('45', '49'))	('mutations', 'Var', (19, 28))	('mTOR', 'Gene', '2475', (54, 58))	('AKT', 'Gene', (50, 53))	('mTOR', 'Gene', (54, 58))
194880	32206160	Interestingly, analysis of mitochondrial DNA in chRCC revealed recurring mutations in genes encoding components of complex 1 of the electron transport chain (ETC), although these mutations were not associated with changes in the expression of genes implicated in oxidative phosphorylation.	('electron transport chain', 'biological_process', 'GO:0022900', ('132', '156'))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('263', '288'))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('27', '44'))	('mutations', 'Var', (73, 82))
194881	32206160	chRCC are particularly enriched in mutations involving metabolic genes, including deleterious mutations in PDHB (which encodes a critical component of the pyruvate dehydrogenase complex) and PRKAG2 (encoding one of three subunits of AMP-Kinase (AMPK)).	('AMPK', 'Gene', '5562', (245, 249))	('AMPK', 'Gene', (245, 249))	('mutations', 'Var', (94, 103))	('RCC', 'Disease', (2, 5))	('AMP-Kinase', 'Gene', '5562', (233, 243))	('PDHB', 'Gene', (107, 111))	('AMPK', 'molecular_function', 'GO:0050405', ('245', '249'))	('PRKAG2', 'Gene', '51422', (191, 197))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('pyruvate dehydrogenase complex', 'cellular_component', 'GO:0045254', ('155', '185'))	('AMPK', 'molecular_function', 'GO:0004691', ('245', '249'))	('PRKAG2', 'Gene', (191, 197))	('PDHB', 'Gene', '5162', (107, 111))	('AMPK', 'molecular_function', 'GO:0047322', ('245', '249'))	('AMP-Kinase', 'Gene', (233, 243))	('mutations', 'Var', (35, 44))
194896	32206160	We previously demonstrated that BAP1 and PBRM1 expression by immunohistochemistry (IHC) are highly correlated with mutation status (P = 3E-58 and 4E-23 respectively and that BAP1/PBRM1 expression by IHC are independent predictors of both disease-free survival and overall survival in the localized disease setting.	('localized disease', 'Disease', 'MESH:D012594', (288, 305))	('mutation status', 'Var', (115, 130))	('disease-free', 'Disease', (238, 250))	('correlated', 'Reg', (99, 109))	('BAP1', 'Gene', (32, 36))	('PBRM1', 'Gene', (41, 46))	('localized disease', 'Disease', (288, 305))
194902	32206160	Many of the key driver mutations in RCC have been shown to have negative (BAP1, SETD2, PTEN, and TP53) and positive (PBRM1) prognostic significance, although it is important to interpret the prognostic implications of these mutations in the context of histology.	('PTEN', 'Gene', (87, 91))	('SETD2', 'Gene', (80, 85))	('PTEN', 'Gene', '5728', (87, 91))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('TP53', 'Gene', '7157', (97, 101))	('RCC', 'Disease', (36, 39))	('TP53', 'Gene', (97, 101))	('mutations', 'Var', (23, 32))	('negative', 'NegReg', (64, 72))	('SETD2', 'Gene', '29072', (80, 85))
194903	32206160	For example, PBRM1 mutations which tend to associate with favorable prognosis in ccRCC were strongly associated with reduced survival in type I pRCC (p<0.0001).	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('survival', 'MPA', (125, 133))	('reduced', 'NegReg', (117, 124))	('PBRM1', 'Gene', (13, 18))	('pRCC', 'Gene', (144, 148))	('mutations', 'Var', (19, 28))	('pRCC', 'Gene', '5546', (144, 148))
194911	32206160	Tumors in the e.3 cluster tended to have frequent loss of the CDKN2A gene, frequent BAP1 mutations, and overexpression of cell cycle and hypoxia-related genes.	('hypoxia', 'Disease', 'MESH:D000860', (137, 144))	('loss', 'NegReg', (50, 54))	('CDKN2A', 'Gene', '1029', (62, 68))	('cell cycle', 'biological_process', 'GO:0007049', ('122', '132'))	('hypoxia', 'Disease', (137, 144))	('Tumors', 'Disease', (0, 6))	('CDKN2A', 'Gene', (62, 68))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (89, 98))	('BAP1', 'Gene', (84, 88))	('overexpression', 'PosReg', (104, 118))
194912	32206160	Additionally, e.3 was enriched in inflammatory gene expression relative to e.2, and expression of PDCD1 (encoding for PD1) and CTLA4 were independent predictors of poor prognosis across the ccRCC subtype.	('expression', 'Var', (84, 94))	('PDCD1', 'Gene', (98, 103))	('CTLA4', 'Gene', '1493', (127, 132))	('PD1', 'Gene', '5133', (118, 121))	('CTLA4', 'Gene', (127, 132))	('gene expression', 'biological_process', 'GO:0010467', ('47', '62'))	('PD1', 'Gene', (118, 121))	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('RCC', 'Disease', (192, 195))	('PDCD1', 'Gene', '5133', (98, 103))
194918	32206160	They found that patients with the AngioHigh gene signature had an improved progression-free survival (PFS) compared to those with AngioLow with the angiogenesis inhibitor, sunitinib.	('angiogenesis', 'biological_process', 'GO:0001525', ('148', '160'))	('sunitinib', 'Chemical', 'MESH:D000077210', (172, 181))	('improved', 'PosReg', (66, 74))	('patients', 'Species', '9606', (16, 24))	('AngioHigh gene signature', 'Var', (34, 58))	('progression-free survival', 'CPA', (75, 100))
194919	32206160	In line with these findings, a similar analysis of the COMPARZ trial evaluating two anti-angiogenic agents, sunitinib and pazopanib, found that high expression of angiogenesis genes was associated with improved response rates.	('pazopanib', 'Chemical', 'MESH:C516667', (122, 131))	('improved', 'PosReg', (202, 210))	('response', 'MPA', (211, 219))	('sunitinib', 'Chemical', 'MESH:D000077210', (108, 117))	('high', 'Var', (144, 148))	('angiogenesis genes', 'Gene', (163, 181))	('angiogenesis', 'biological_process', 'GO:0001525', ('163', '175'))
194920	32206160	Furthermore, tumors with PBRM1 mutations demonstrated significantly higher angiogenesis gene expression scores than those with BAP1 mutations.	('mutations', 'Var', (31, 40))	('gene expression', 'biological_process', 'GO:0010467', ('88', '103'))	('angiogenesis gene expression scores', 'MPA', (75, 110))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('angiogenesis', 'biological_process', 'GO:0001525', ('75', '87'))	('higher', 'PosReg', (68, 74))	('PBRM1', 'Gene', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
194921	32206160	In the IMmotion150 trial, patients with the TeffHigh gene signature had improved PFS with atezo+bev compared to the sunitinib and the atezo arms.	('bev', 'Chemical', '-', (96, 99))	('atezo', 'Chemical', 'MESH:C000594389', (134, 139))	('improved', 'PosReg', (72, 80))	('patients', 'Species', '9606', (26, 34))	('atezo+bev', 'Var', (90, 99))	('PFS', 'Disease', (81, 84))	('atezo', 'Chemical', 'MESH:C000594389', (90, 95))	('TeffHigh gene', 'Var', (44, 57))	('sunitinib', 'Chemical', 'MESH:D000077210', (116, 125))
194933	32206160	Notably, the presence of such variables is associated with intermediate/poor risk disease, which suggests that inflammatory tumors are particularly aggressive in patients.	('patients', 'Species', '9606', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('intermediate/poor', 'Disease', (59, 76))	('inflammatory', 'Disease', (111, 123))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Disease', (124, 130))	('presence', 'Var', (13, 21))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))
194936	32206160	In one of the earliest attempts to measure ITH in ccRCC, Gerlinger and colleagues performed multiregional WES of two primary tumors and demonstrated that only 31% of the somatic mutations were ubiquitous amongst all sampled regions.	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (178, 187))
194941	32206160	Interestingly, while BAP1 and PBRM1 mutations could be identified in the same tumor, they were typically located in spatially distinct regions, consistent with previous reports that these mutations anticorrelate with one another and are found in different areas of the same tumors.	('PBRM1', 'Gene', (30, 35))	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('BAP1', 'Gene', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('mutations', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('tumors', 'Disease', (274, 280))
194957	32206160	NGS has allowed the identification of activating mutations in oncogenes, and these have been very effective targets in cancers such as melanoma and non-small cell lung carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('lung carcinoma', 'Disease', (163, 177))	('oncogenes', 'Protein', (62, 71))	('lung carcinoma', 'Disease', 'MESH:D008175', (163, 177))	('mutations', 'Var', (49, 58))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('activating', 'PosReg', (38, 48))	('melanoma', 'Disease', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (148, 177))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (152, 177))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
194962	32206160	In a phase III trial comparing second line cabozantinib to everolimus in ccRCC, cabozantinib was found to result in an improved OS rate (HR 0.66 [95% CI: 0.53 - 0.83]; p= 2.6E-4), as well as improved PFS (HR 0.51 [95% CI: 0.41 - 0.62]; p< 1E-4).	('cabozantinib', 'Var', (80, 92))	('OS rate', 'MPA', (128, 135))	('RCC', 'Disease', (75, 78))	('improved', 'PosReg', (191, 199))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('cabozantinib', 'Chemical', 'MESH:C558660', (80, 92))	('improved', 'PosReg', (119, 127))	('PFS', 'MPA', (200, 203))	('cabozantinib', 'Chemical', 'MESH:C558660', (43, 55))	('everolimus', 'Chemical', 'MESH:D000068338', (59, 69))
194965	32206160	For the small subset of patients with genomic data, 40% (4/10) of pRCC patients with MET mutations demonstrated partial responses.	('MET', 'Gene', (85, 88))	('pRCC', 'Gene', '5546', (66, 70))	('patients', 'Species', '9606', (71, 79))	('pRCC', 'Gene', (66, 70))	('mutations', 'Var', (89, 98))	('patients', 'Species', '9606', (24, 32))	('MET', 'Gene', '79811', (85, 88))
194967	32206160	While targeting driver mutations may provide benefit to a subset of RCC patients, techniques leveraging tumor suppressor genes therapeutically are needed to benefit the larger population.	('tumor suppressor', 'biological_process', 'GO:0051726', ('104', '120'))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('104', '120'))	('tumor', 'Disease', (104, 109))	('mutations', 'Var', (23, 32))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('patients', 'Species', '9606', (72, 80))
194968	32206160	One strategy to tackle loss-of-function mutations in tumor suppressor proteins has been to inhibit downstream effector pathways.	('loss-of-function', 'NegReg', (23, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('53', '69'))	('inhibit', 'NegReg', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutations', 'Var', (40, 49))	('downstream effector pathways', 'Pathway', (99, 127))	('tumor', 'Disease', (53, 58))	('tumor suppressor', 'biological_process', 'GO:0051726', ('53', '69'))
194971	32206160	This led to the development of PT2385 and PT2399, which were shown to be potent and highly selective inhibitors leading to the dissociation of HIF-2 complexes Preclinical testing of PT2399 in our laboratory demonstrated decreased tumor growth across ~50% of ccRCC tumorgrafts analyzed (P<0.0001), including in sunitinib resistant tumors.	('tumor', 'Disease', (330, 335))	('sunitinib', 'Chemical', 'MESH:D000077210', (310, 319))	('ccRCC tumorgrafts', 'Disease', (258, 275))	('PT2399', 'Chemical', 'MESH:C000614278', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (330, 335))	('tumor', 'Disease', (264, 269))	('tumors', 'Phenotype', 'HP:0002664', (330, 336))	('PT2399', 'Var', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('tumor', 'Disease', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('decreased', 'NegReg', (220, 229))	('tumors', 'Disease', (330, 336))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('ccRCC tumorgrafts', 'Disease', 'None', (258, 275))	('PT2399', 'Chemical', 'MESH:C000614278', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('PT2385', 'Chemical', 'MESH:C000614279', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (330, 336))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
194972	32206160	However, prolonged therapy with PT2399 led to the development of acquired resistance in tumorgraft models.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('PT2399', 'Var', (32, 38))	('PT2399', 'Chemical', 'MESH:C000614278', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('acquired resistance', 'MPA', (65, 84))
194973	32206160	Sequencing of tumorgrafts with acquired resistance to PT2399 led to the identification of point mutations which restored dimerization in the presence of inhibitors, one of which was subsequently identified in patient tumors that developed resistance to HIF-2 inhibition.	('dimerization', 'MPA', (121, 133))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', (14, 19))	('patient', 'Species', '9606', (209, 216))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('PT2399', 'Chemical', 'MESH:C000614278', (54, 60))	('PT2399', 'Gene', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('restored', 'PosReg', (112, 120))	('mutations', 'Var', (96, 105))
194980	32206160	An alternative approach to targeting tumor suppressor genes leverages "synthetic lethality," where loss of two genes results in cell death whereas loss of either gene does not.	('death', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('37', '53'))	('loss', 'Var', (99, 103))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('37', '53'))	('death', 'Disease', 'MESH:D003643', (133, 138))
194982	32206160	In one of the first such studies, Turcotte and colleagues screened a panel of ~64,000 small molecules in parallel on VHL deficient RCC4 cells and RCC4 cells with re-introduced VHL.	('RCC4', 'CellLine', 'CVCL:0498', (131, 135))	('RCC4', 'CellLine', 'CVCL:0498', (146, 150))	('deficient', 'Var', (121, 130))	('VHL', 'Gene', (117, 120))
194983	32206160	They found that STF-62247 was able to selectively induce apoptosis in VHL deficient cells, likely through inhibition of protein trafficking.	('protein', 'Protein', (120, 127))	('STF-62247', 'Var', (16, 25))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('apoptosis', 'CPA', (57, 66))	('apoptosis', 'biological_process', 'GO:0006915', ('57', '66'))	('STF-62247', 'Chemical', 'MESH:C530878', (16, 25))	('inhibition', 'NegReg', (106, 116))	('induce', 'PosReg', (50, 56))	('apoptosis', 'biological_process', 'GO:0097194', ('57', '66'))
194984	32206160	Utilizing the same screen, STF-31 which acts through inhibition of GLUT1, was also found to have preferential toxicity among VHL deficient cells.	('GLUT1', 'Gene', '6513', (67, 72))	('inhibition', 'NegReg', (53, 63))	('toxicity', 'Disease', 'MESH:D064420', (110, 118))	('STF-31', 'Var', (27, 33))	('preferential', 'PosReg', (97, 109))	('toxicity', 'Disease', (110, 118))	('GLUT1', 'Gene', (67, 72))
194988	32206160	More recently, an expanded shRNA library targeting ~1000 genes identified EZH1 depletion to be synthetically lethal with VHL loss.	('EZH1', 'Gene', '2145', (74, 78))	('VHL loss', 'Disease', 'MESH:D006623', (121, 129))	('VHL loss', 'Disease', (121, 129))	('depletion', 'Var', (79, 88))	('EZH1', 'Gene', (74, 78))
194992	32206160	Whereas EZH2 was not identified as exhibiting synthetic lethality in the aforementioned screen, there is preclinical evidence that EZH2 inhibitors may be effective in the setting of BAP1 deficiency.	('inhibitors', 'Var', (136, 146))	('BAP1', 'Gene', (182, 186))	('EZH2', 'Gene', '2146', (8, 12))	('EZH2', 'Gene', (131, 135))	('EZH2', 'Gene', '2146', (131, 135))	('deficiency', 'Var', (187, 197))	('EZH2', 'Gene', (8, 12))
194993	32206160	Mice with isolated BAP1 deficiency in hematopoietic precursors develop myelodysplastic syndrome.	('deficiency', 'Var', (24, 34))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (71, 95))	('develop', 'Reg', (63, 70))	('Mice', 'Species', '10090', (0, 4))	('BAP1', 'Gene', (19, 23))	('myelodysplastic syndrome', 'Disease', (71, 95))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (71, 95))
194994	32206160	In these models, BAP1 deficiency results in increased EZH2 expression and methylation of H3K27.	('EZH2', 'Gene', (54, 58))	('deficiency', 'Var', (22, 32))	('expression', 'MPA', (59, 69))	('H3K27', 'Protein', (89, 94))	('increased', 'PosReg', (44, 53))	('methylation', 'MPA', (74, 85))	('EZH2', 'Gene', '2146', (54, 58))	('methylation', 'biological_process', 'GO:0032259', ('74', '85'))	('BAP1', 'Gene', (17, 21))
194997	32206160	In addition, RCC-derived cell lines deficient in BAP1 overexpress EZH2, and are sensitive to EZH2 inhibitors in vitro.	('overexpress', 'PosReg', (54, 65))	('deficient', 'Var', (36, 45))	('BAP1', 'Gene', (49, 53))	('EZH2', 'Gene', '2146', (93, 97))	('EZH2', 'Gene', (66, 70))	('EZH2', 'Gene', '2146', (66, 70))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('EZH2', 'Gene', (93, 97))	('RCC', 'Disease', (13, 16))	('sensitive', 'Reg', (80, 89))
194998	32206160	Furthermore, in a sunitinib-resistant xenograft model of RCC, the EZH2 inhibitor EPZ011929 demonstrated rescue of sunitinib sensitivity through epigenetic reprograming (BAP1 status was not reported in this study).	('EPZ011929', 'Chemical', '-', (81, 90))	('rescue', 'PosReg', (104, 110))	('sunitinib', 'Chemical', 'MESH:D000077210', (18, 27))	('EZH2', 'Gene', (66, 70))	('EZH2', 'Gene', '2146', (66, 70))	('sunitinib sensitivity', 'MPA', (114, 135))	('sunitinib', 'Chemical', 'MESH:D000077210', (114, 123))	('RCC', 'Disease', (57, 60))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('epigenetic', 'Var', (144, 154))	('EPZ011929', 'Var', (81, 90))
195013	32206160	Activating mutations in ccRCC are less frequent than type II pRCC, however, emerging evidence suggests epigenetic silencing of KEAP1 may contribute to NRF2/ARE deregulation in ccRCC.	('KEAP1', 'Gene', '9817', (127, 132))	('deregulation', 'MPA', (160, 172))	('pRCC', 'Gene', (61, 65))	('KEAP1', 'Gene', (127, 132))	('RCC', 'Disease', (26, 29))	('epigenetic silencing', 'Var', (103, 123))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('contribute', 'Reg', (137, 147))	('pRCC', 'Gene', '5546', (61, 65))	('RCC', 'Disease', (178, 181))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('RCC', 'Disease', (62, 65))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('NRF2', 'Gene', '4780', (151, 155))	('NRF2', 'Gene', (151, 155))
195014	32206160	Consistent with a potential role of NRF2/ARE in ccRCC, NRF2 depletion via shRNA was recently shown to decrease proliferation and increase sensitivity to sunitinib in the 786-O ccRCC cell line.	('NRF2', 'Gene', (55, 59))	('decrease', 'NegReg', (102, 110))	('NRF2', 'Gene', '4780', (36, 40))	('proliferation', 'CPA', (111, 124))	('depletion', 'Var', (60, 69))	('NRF2', 'Gene', (36, 40))	('RCC', 'Disease', (50, 53))	('sensitivity to sunitinib', 'MPA', (138, 162))	('sunitinib', 'Chemical', 'MESH:D000077210', (153, 162))	('increase', 'PosReg', (129, 137))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('RCC', 'Disease', (178, 181))	('NRF2', 'Gene', '4780', (55, 59))
195027	30386175	The pooled results indicated that high Kindlin-2 expression was significantly associated with poor overall survival (OS) (pooled HR 1.66, 95% CI 1.44-1.92, P < 0.0001), disease-free survival (DFS)/recurrence-free survival (RFS)/progression-free survival (PFS) (pooled HR 1.73, 95% CI 1.16-2.57, P = 0.0067).	('OS', 'Chemical', '-', (117, 119))	('Kindlin-2', 'Gene', (39, 48))	('expression', 'MPA', (49, 59))	('Kindlin-2', 'Gene', '10979', (39, 48))	('RFS', 'Disease', (223, 226))	('high', 'Var', (34, 38))	('OS', 'Phenotype', 'HP:0002669', (117, 119))	('overall survival', 'CPA', (99, 115))	('RFS', 'Disease', 'MESH:D005198', (223, 226))	('disease-free survival', 'CPA', (169, 190))	('poor', 'NegReg', (94, 98))
195029	30386175	Our meta-analysis demonstrated that high Kindlin-2 expression might indicate poor outcome in patients with solid tumors and could serve as a prognostic biomarker for solid cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('solid cancer', 'Disease', (166, 178))	('solid tumors', 'Disease', (107, 119))	('solid cancer', 'Disease', 'MESH:D009369', (166, 178))	('expression', 'MPA', (51, 61))	('patients', 'Species', '9606', (179, 187))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('solid tumors', 'Disease', 'MESH:D009369', (107, 119))	('patients', 'Species', '9606', (93, 101))	('high', 'Var', (36, 40))	('Kindlin-2', 'Gene', (41, 50))	('Kindlin-2', 'Gene', '10979', (41, 50))
195035	30386175	Kindlin-1 (also known as FERMT1) is highly expressed in the skin and other tissues, whose deficiency and mutation can cause Kindler Syndrome.	('mutation', 'Var', (105, 113))	('Kindler Syndrome', 'Disease', (124, 140))	('deficiency', 'Disease', (90, 100))	('FERMT1', 'Gene', (25, 31))	('FERMT1', 'Gene', '55612', (25, 31))	('Kindlin-1', 'Gene', '55612', (0, 9))	('deficiency', 'Disease', 'MESH:D007153', (90, 100))	('Kindlin-1', 'Gene', (0, 9))	('cause', 'Reg', (118, 123))
195036	30386175	Kindlin-3 (also known as FERMT3) is generally expressed in the notochord, central nervous system, cement gland, and etc., mutations in which can contribute to leukocyte adhesion deficiency type III.	('Kindlin-3', 'Gene', '83706', (0, 9))	('FERMT3', 'Gene', '83706', (25, 31))	('leukocyte adhesion deficiency type III', 'Disease', 'MESH:C567555', (159, 197))	('deficiency type III', 'Phenotype', 'HP:0001976', (178, 197))	('adhesion deficiency', 'Phenotype', 'HP:0008352', (169, 188))	('Kindlin-3', 'Gene', (0, 9))	('leukocyte adhesion', 'biological_process', 'GO:0007159', ('159', '177'))	('mutations', 'Var', (122, 131))	('FERMT3', 'Gene', (25, 31))	('leukocyte adhesion deficiency type III', 'Disease', (159, 197))	('contribute to', 'Reg', (145, 158))
195046	30386175	The following data of each study was extracted: first author, publication year, original country, number of enrolled patients, tumor type, detected methods, cut-off value, high expression presentations, follow-up time, and HR and 95% CI of the high Kindlin-2 expression group versus the low one for various outcomes.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('Kindlin-2', 'Gene', (249, 258))	('Kindlin-2', 'Gene', '10979', (249, 258))	('high', 'Var', (244, 248))	('expression', 'MPA', (259, 269))	('patients', 'Species', '9606', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
195073	30386175	The pooled data also showed statistically association between high Kindlin-2 expression with poor RFS/DFS/PFS in ESCC (HR 1.59, 95% CI 1.10-2.28, P = 0.0129), HCC (HR 4.30, 95% CI 1.81-10.19), ccRCC (HR 1.47, 95% CI 1.05-2.06) (Fig.	('expression', 'MPA', (77, 87))	('ccRCC', 'Disease', (193, 198))	('ESCC', 'Disease', (113, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (193, 198))	('RFS', 'Disease', (98, 101))	('RFS', 'Disease', 'MESH:D005198', (98, 101))	('Kindlin-2', 'Gene', (67, 76))	('HCC', 'Gene', (159, 162))	('Kindlin-2', 'Gene', '10979', (67, 76))	('HCC', 'Gene', '619501', (159, 162))	('high', 'Var', (62, 66))	('HCC', 'Phenotype', 'HP:0001402', (159, 162))
195088	30386175	We found that there remains an obvious relation between high Kindlin-2 expression and poor prognosis of tumor patients when concerning the above features except for the subgroups as follow: patient quantity more than 100; tumor type not from digestive system; HR not extracted from COX model; NOS score no less than 8.	('expression', 'MPA', (71, 81))	('COX', 'Gene', '1351', (282, 285))	('patient', 'Species', '9606', (190, 197))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('Kindlin-2', 'Gene', (61, 70))	('tumor', 'Disease', (104, 109))	('COX', 'Gene', (282, 285))	('OS', 'Phenotype', 'HP:0002669', (294, 296))	('patient', 'Species', '9606', (110, 117))	('tumor', 'Disease', (222, 227))	('Kindlin-2', 'Gene', '10979', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('OS', 'Chemical', '-', (294, 296))	('patients', 'Species', '9606', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('high', 'Var', (56, 60))
195103	30386175	In summary, high Kindlin-2 expression might indicate poor outcome in cancer patients and might be a promising therapeutic target for solid tumor.	('patients', 'Species', '9606', (76, 84))	('high', 'Var', (12, 16))	('solid tumor', 'Disease', (133, 144))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('expression', 'MPA', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('solid tumor', 'Disease', 'MESH:D009369', (133, 144))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('Kindlin-2', 'Gene', (17, 26))	('Kindlin-2', 'Gene', '10979', (17, 26))	('cancer', 'Disease', (69, 75))
195118	29212269	Low level of NBR1 mRNA showed a significance poor prognostic of overall survival (OS), disease-free survival (DFS) with univariate and multivariate analyses in ccRCC patients and sunitinib resistance.	('Low level', 'Var', (0, 9))	('mRNA', 'MPA', (18, 22))	('sunitinib', 'Chemical', 'MESH:D000077210', (179, 188))	('ccRCC', 'Phenotype', 'HP:0006770', (160, 165))	('RCC', 'Disease', (162, 165))	('RCC', 'Phenotype', 'HP:0005584', (162, 165))	('NBR1', 'Gene', '4077', (13, 17))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('patients', 'Species', '9606', (166, 174))	('disease-free', 'Disease', (87, 99))	('poor', 'NegReg', (45, 49))	('overall', 'MPA', (64, 71))	('NBR1', 'Gene', (13, 17))
195119	29212269	Taken together, our results suggest that low level of NBR1 can predict poor clinical outcome and resistance of sunitinib in patients with ccRCC.	('NBR1', 'Gene', '4077', (54, 58))	('resistance', 'MPA', (97, 107))	('low level', 'Var', (41, 50))	('sunitinib', 'Chemical', 'MESH:D000077210', (111, 120))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('NBR1', 'Gene', (54, 58))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('patients', 'Species', '9606', (124, 132))
195155	29212269	Those results indicated that low NBR1 expression could be a potential diagnostic indicators for ccRCC patients with (T1 + T2) / (T3+T4) stage (Figure 3B, AUC= 0.6357, p < 0.0001), TNM (I+II) / (III+IV) stage (Figure 3C, AUC= 0.6390, p < 0.0001), non-metastasis / metastasis (Figure 3D, AUC= 0.6120, p = 0.001581), (G1+G2) / (G3+G4) stage (Figure 3E, AUC= 0.5962, p =0.0001466), OS living / deceased status (Figure 3F, AUC= 0.6472, p < 0.0001), OS-good / poor prognosis (Figure 3G, AUC= 0.6893, p < 0.0001), DFS status (Figure 3H, AUC=0.6203, p < 0.0001), DFS-good / poor prognosis (Figure 3I, AUC=0.6688, p = 0.0001306).	('NBR1', 'Gene', '4077', (33, 37))	('low', 'Var', (29, 32))	('patients', 'Species', '9606', (102, 110))	('DFS-good', 'Disease', (555, 563))	('NBR1', 'Gene', (33, 37))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('DFS-good', 'Disease', 'None', (555, 563))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('OS-good', 'Disease', (444, 451))	('OS-good', 'Disease', 'MESH:C567932', (444, 451))
195159	29212269	Patients with low NBR1 mRNA level had shorter OS time (Figure 4A, log-rank test, p < 0.0001).	('NBR1', 'Gene', (18, 22))	('shorter', 'NegReg', (38, 45))	('OS time', 'MPA', (46, 53))	('Patients', 'Species', '9606', (0, 8))	('NBR1', 'Gene', '4077', (18, 22))	('low', 'Var', (14, 17))	('mRNA level', 'MPA', (23, 33))
195161	29212269	Our results showed that low NBR1 expression could be a potential prognostic factor for ccRCC patients with N0 stage (Figure 4B, p < 0.0001), non-metastasis (Figure 4C, p < 0.0001), metastasis (Figure 4D, p = 0.0108), T1 + T2 stage (Figure 4E, p = 0.0092), T3 + T4 stage (Figure 4F, p = 0.0003), TNM (I+II) (Figure 4G, p = 0.0368), TNM (III+IV) stage (Figure 2H, p = 0.0004), Male (Figure 4I, p = 0.0001), female (Figure 4J, p < 0.0001), Age > 60 years (Figure 4K, p < 0.0001), Age <= 60 years (Figure 4L, p = 0.0007), G3+G4 stage (Figure 4M, p < 0.0001).	('NBR1', 'Gene', (28, 32))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('expression', 'MPA', (33, 43))	('NBR1', 'Gene', '4077', (28, 32))	('low', 'Var', (24, 27))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('patients', 'Species', '9606', (93, 101))
195170	29212269	Univariate analysis indicated that the patients with low NBR1 level exhibited a shorter OS and DFS [NBR1 mRNA OS: hazard ratio (HR) 0.396, p = 0.000 and DFS HR 0.477, p = 0.000].	('NBR1', 'Gene', (100, 104))	('patients', 'Species', '9606', (39, 47))	('NBR1', 'Gene', '4077', (57, 61))	('low', 'Var', (53, 56))	('NBR1', 'Gene', '4077', (100, 104))	('shorter', 'NegReg', (80, 87))	('NBR1', 'Gene', (57, 61))
195172	29212269	Taken together, these data suggested that low NBR1 expression level is an independent predictor of poor prognosis for ccRCC patients To further confirm the results of the TCGA-KIRC database, we next extended this observation to two additional data sets in oncomine datebase (https://www.oncomine.org).	('NBR1', 'Gene', '4077', (46, 50))	('NBR1', 'Gene', (46, 50))	('oncomine', 'Chemical', '-', (256, 264))	('oncomine', 'Chemical', '-', (287, 295))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('low', 'Var', (42, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))	('patients', 'Species', '9606', (124, 132))	('expression level', 'MPA', (51, 67))
195182	29212269	These results showed that sunitinib-resistant cell lines were successfully constructed, sunitinib-resistant cells had higher sunitinib tolerance and had a lower NBR1 expression compared with corresponding parental cell lines.	('higher', 'PosReg', (118, 124))	('sunitinib-resistant', 'Var', (88, 107))	('sunitinib', 'Chemical', 'MESH:D000077210', (26, 35))	('sunitinib', 'Chemical', 'MESH:D000077210', (125, 134))	('NBR1', 'Gene', '4077', (161, 165))	('lower', 'NegReg', (155, 160))	('sunitinib', 'Chemical', 'MESH:D000077210', (88, 97))	('sunitinib tolerance', 'MPA', (125, 144))	('expression', 'MPA', (166, 176))	('NBR1', 'Gene', (161, 165))
195223	30909397	In tumor cells' overexpression or incorrect activation of c-Met, this leads to stimulation of proliferation, survival and increase of motile activity.	('tumor', 'Disease', (3, 8))	('incorrect activation', 'Var', (34, 54))	('c-Met', 'Protein', (58, 63))	('overexpression', 'PosReg', (16, 30))	('motile activity', 'CPA', (134, 149))	('stimulation', 'PosReg', (79, 90))	('proliferation', 'CPA', (94, 107))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('increase', 'PosReg', (122, 130))	('survival', 'CPA', (109, 117))
195231	30909397	Recently, it has been shown that the acquirement of mesenchymal phenotype or lack of cell differentiation might be related to the presence of the c-Met receptor and is consequently responsible for therapy resistance.	('cell differentiation', 'CPA', (85, 105))	('cell differentiation', 'biological_process', 'GO:0030154', ('85', '105'))	('men', 'Species', '9606', (44, 47))	('acquirement', 'PosReg', (37, 48))	('lack', 'CPA', (77, 81))	('responsible', 'Reg', (181, 192))	('presence', 'Var', (130, 138))	('c-Met receptor', 'Protein', (146, 160))
195238	30909397	In tumor cells' overexpression or incorrect activation, this leads to the stimulation of proliferation, survival and an increase of motile activity.	('proliferation', 'CPA', (89, 102))	('stimulation', 'PosReg', (74, 85))	('tumor', 'Disease', (3, 8))	('motile activity', 'CPA', (132, 147))	('overexpression', 'PosReg', (16, 30))	('incorrect', 'Var', (34, 43))	('survival', 'CPA', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('increase', 'PosReg', (120, 128))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
195247	30909397	Today, MET is considered as a proto-oncogene and its mutations or overexpression leads to aberrant, often constitutive activation of the HGF/c-Met axis.	('HGF', 'Gene', (137, 140))	('mutations', 'Var', (53, 62))	('HGF', 'Gene', '3082', (137, 140))	('activation', 'PosReg', (119, 129))	('overexpression', 'PosReg', (66, 80))
195253	30909397	ccRCC creates extremely vascularized tumors due to frequent loss of function mutation in the von Hippel-Lindau tumor suppressor gene (VHL) located on chromosome 3p which is responsible for regulating the stability of hypoxia-inducible factor 1 (HIF-1).	('loss of function', 'NegReg', (60, 76))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mutation', 'Var', (77, 85))	('hypoxia-inducible factor 1', 'Gene', (217, 243))	('VHL', 'Gene', (134, 137))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('111', '127'))	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('von Hippel-Lindau tumor', 'Disease', (93, 116))	('HIF-1', 'Gene', '3091', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('HIF-1', 'Gene', (245, 250))	('tumor suppressor', 'biological_process', 'GO:0051726', ('111', '127'))	('tumors', 'Disease', (37, 43))	('VHL', 'Gene', '7428', (134, 137))	('chromosome', 'cellular_component', 'GO:0005694', ('150', '160'))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('von Hippel-Lindau tumor', 'Disease', 'MESH:D006623', (93, 116))	('hypoxia-inducible factor 1', 'Gene', '3091', (217, 243))
195256	30909397	Furthermore, it was shown that VHL mutation together with hypoxia lead to increased HGF and c-Met expression in ccRCC.	('VHL', 'Gene', '7428', (31, 34))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('HGF', 'Gene', '3082', (84, 87))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('hypoxia', 'Disease', (58, 65))	('hypoxia', 'Disease', 'MESH:D000860', (58, 65))	('increased', 'PosReg', (74, 83))	('c-Met expression', 'MPA', (92, 108))	('mutation', 'Var', (35, 43))	('VHL', 'Gene', (31, 34))	('HGF', 'Gene', (84, 87))
195287	30909397	In the latter analysis, total c-Met expression was not associated with a clinical and pathological characteristic, however, c-Met was associated with an advanced stage and the presence of metastases.	('metastases', 'Disease', (188, 198))	('c-Met', 'Var', (124, 129))	('associated with', 'Reg', (134, 149))	('metastases', 'Disease', 'MESH:D009362', (188, 198))
195291	30909397	Patients with tumors are identified by proto-oncogene mutations.	('mutations', 'Var', (54, 63))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
195292	30909397	Mutations that cause constitutive phosphorylation of the c-Met receptor are identified in papillary kidney cancer at 13% (17/129).	('papillary kidney cancer', 'Disease', 'MESH:D007681', (90, 113))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('kidney cancer', 'Phenotype', 'HP:0009726', (100, 113))	('papillary kidney cancer', 'Disease', (90, 113))	('Mutations', 'Var', (0, 9))	('papillary kidney cancer', 'Phenotype', 'HP:0006766', (90, 113))
195294	30909397	In the case of malignant tumors, chromosomal trisomy 7, 16 and 17 occurs and, among men, the loss of the Y chromosome.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('Y chromosome', 'CPA', (105, 117))	('chromosomal', 'Var', (33, 44))	('loss', 'NegReg', (93, 97))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('malignant tumors', 'Disease', 'MESH:D018198', (15, 31))	('men', 'Species', '9606', (84, 87))	('Y chromosome', 'cellular_component', 'GO:0000806', ('105', '117'))	('malignant tumors', 'Disease', (15, 31))
195295	30909397	Missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid and, when located in the tyrosine kinase domain of the MET gene, it leads to constitutive activation of the c-Met protein and papillary renal carcinomas.	('single nucleotide change', 'Var', (49, 73))	('papillary renal carcinomas', 'Disease', 'MESH:D007681', (257, 283))	('protein', 'cellular_component', 'GO:0003675', ('245', '252'))	('activation', 'PosReg', (221, 231))	('results in', 'Reg', (74, 84))	('papillary renal carcinomas', 'Disease', (257, 283))	('renal carcinoma', 'Phenotype', 'HP:0005584', (267, 282))	('c-Met protein', 'Protein', (239, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('carcinomas', 'Phenotype', 'HP:0030731', (273, 283))	('constitutive', 'MPA', (208, 220))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (257, 282))	('papillary renal carcinomas', 'Phenotype', 'HP:0006766', (257, 283))	('renal carcinomas', 'Phenotype', 'HP:0005584', (267, 283))	('Missense', 'Var', (0, 8))
195296	30909397	Missense mutations involve replacing histidine 1112 with leucine (H1112L), histidine 1124 with aspartic acid (H1124D) or tyrosine 1248 with aspartic acid (Y1248D).	('leucine', 'MPA', (57, 64))	('aspartic acid', 'MPA', (95, 108))	('H1124D', 'Mutation', 'p.H1124D', (110, 116))	('H1112L', 'Mutation', 'p.H1112L', (66, 72))	('histidine', 'MPA', (37, 46))	('Y1248D', 'Var', (155, 161))	('H1112L', 'Var', (66, 72))	('histidine 1112 with leucine', 'Mutation', 'p.H1112L', (37, 64))	('tyrosine', 'Var', (121, 129))	('tyrosine 1248 with aspartic acid', 'Mutation', 'p.Y1248D', (121, 153))	('H1124D', 'Var', (110, 116))	('histidine 1124 with aspartic acid', 'Mutation', 'p.H1124D', (75, 108))	('Y1248D', 'Mutation', 'p.Y1248D', (155, 161))
195297	30909397	The mutations in the tyrosine kinase domain (amino acids 1110 to 1268) lead to the inheritance of papillary renal carcinoma.	('amino acids 1110', 'Var', (45, 61))	('lead to', 'Reg', (71, 78))	('renal carcinoma', 'Phenotype', 'HP:0005584', (108, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (98, 123))	('papillary renal carcinoma', 'Disease', 'MESH:D007681', (98, 123))	('mutations', 'Var', (4, 13))	('papillary renal carcinoma', 'Disease', (98, 123))
195300	30909397	The promotion of c-Met kinase activity in papillary renal carcinoma also occurs during the V1110I mutation where the change of valine to leucine in the conserved ATP binding pocket of the c-Met receptor enhances its kinase activity.	('promotion', 'PosReg', (4, 13))	('V1110I', 'Var', (91, 97))	('valine', 'Chemical', 'MESH:D014633', (127, 133))	('leucine', 'Chemical', 'MESH:D007930', (137, 144))	('renal carcinoma', 'Phenotype', 'HP:0005584', (52, 67))	('papillary renal carcinoma', 'Disease', (42, 67))	('ATP', 'Chemical', 'MESH:D000255', (162, 165))	('kinase activity', 'molecular_function', 'GO:0016301', ('216', '231'))	('kinase activity', 'molecular_function', 'GO:0016301', ('23', '38'))	('V1110I', 'Mutation', 'rs786202724', (91, 97))	('enhances', 'PosReg', (203, 211))	('valine', 'MPA', (127, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('c-Met', 'MPA', (17, 22))	('papillary renal carcinoma', 'Disease', 'MESH:D007681', (42, 67))	('ATP binding', 'molecular_function', 'GO:0005524', ('162', '173'))	('kinase activity', 'MPA', (216, 231))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (42, 67))
195302	30909397	MET copy number correlates with dedifferentiation (p < 0.001), higher tumor extent (p < 0.001), positive lymph node status (p = 0.006) and distant metastasis (p = 0.02).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('distant metastasis', 'CPA', (139, 157))	('dedifferentiation', 'CPA', (32, 49))	('dedifferentiation', 'biological_process', 'GO:0043696', ('32', '49'))	('tumor', 'Disease', (70, 75))	('positive lymph node status', 'CPA', (96, 122))	('MET copy number', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
195307	30909397	showed for the first time the expression of active c-Met receptor - phosphorylated at Tyr 1349 residue.	('Tyr', 'Chemical', 'MESH:D014443', (86, 89))	('Tyr 1349 residue', 'Var', (86, 102))	('c-Met', 'Protein', (51, 56))
195308	30909397	This active pY1349 c-Met receptor was mainly detected in cancer cell membranes and was positively associated with grade (p = 0.004), lymph node metastases (p = 0.014), distant metastases (p = 0.021) and pT-stage (p < 0.001).	('metastases', 'Disease', (176, 186))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('metastases', 'Disease', 'MESH:D009362', (176, 186))	('cancer', 'Disease', (57, 63))	('lymph node metastases', 'Disease', 'MESH:D009362', (133, 154))	('pT-stage', 'Disease', (203, 211))	('associated', 'Reg', (98, 108))	('lymph node metastases', 'Disease', (133, 154))	('grade', 'CPA', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('c-Met', 'Protein', (19, 24))	('metastases', 'Disease', (144, 154))	('pY1349', 'Var', (12, 18))	('metastases', 'Disease', 'MESH:D009362', (144, 154))
195311	30909397	They reported that c-Met in ccRCC cell line was constitutively activated without HGF stimulation due to the inactivation of the VHL proto-oncogene.	('HGF', 'Gene', '3082', (81, 84))	('VHL', 'Gene', '7428', (128, 131))	('inactivation', 'Var', (108, 120))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('RCC', 'Disease', (30, 33))	('c-Met', 'Gene', (19, 24))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('HGF', 'Gene', (81, 84))	('VHL', 'Gene', (128, 131))
195313	30909397	Additionally, c-Met protein activated by the inactivation of the VHL gene modified cell adherence, including N-cadherin and beta-catenin.	('c-Met protein', 'Protein', (14, 27))	('VHL', 'Gene', '7428', (65, 68))	('beta-catenin', 'Gene', (124, 136))	('N-cadherin', 'CPA', (109, 119))	('inactivation', 'Var', (45, 57))	('beta-catenin', 'Gene', '1499', (124, 136))	('modified', 'Reg', (74, 82))	('activated', 'PosReg', (28, 37))	('cell adherence', 'CPA', (83, 97))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('cadherin', 'molecular_function', 'GO:0008014', ('111', '119'))	('VHL', 'Gene', (65, 68))
195314	30909397	Scientists concluded that inactivation of the VHL gene induced constitutive phosphorylation of the c-Met protein and modified intercellular adherence structure, triggering cell growth released from contact inhibition, finally resulting in tumorigenesis.	('intercellular adherence structure', 'MPA', (126, 159))	('VHL', 'Gene', (46, 49))	('inactivation', 'Var', (26, 38))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('modified', 'Reg', (117, 125))	('phosphorylation', 'biological_process', 'GO:0016310', ('76', '91'))	('resulting in', 'Reg', (226, 238))	('cell growth released', 'MPA', (172, 192))	('constitutive', 'MPA', (63, 75))	('triggering', 'Reg', (161, 171))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('VHL', 'Gene', '7428', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('contact inhibition', 'biological_process', 'GO:0060242', ('198', '216'))	('cell growth', 'biological_process', 'GO:0016049', ('172', '183'))	('phosphorylation', 'MPA', (76, 91))	('c-Met protein', 'Protein', (99, 112))	('tumor', 'Disease', (239, 244))
195318	30909397	Inhibiting abnormal c-Met activity can significantly increase patient survival, reduce the rate and extent of metastasis and prolong the lives of patients who are often diagnosed only at advanced stages of cancer.	('c-Met', 'Protein', (20, 25))	('Inhibiting', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('patient survival', 'CPA', (62, 78))	('patient', 'Species', '9606', (62, 69))	('prolong', 'PosReg', (125, 132))	('lives', 'CPA', (137, 142))	('increase', 'PosReg', (53, 61))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('reduce', 'NegReg', (80, 86))	('cancer', 'Disease', (206, 212))	('patient', 'Species', '9606', (146, 153))	('activity', 'MPA', (26, 34))	('patients', 'Species', '9606', (146, 154))
195334	30909397	Also, lack of influx of endothelial cells caused by lack or blockade of VEGF may cause vasculogenic mimicry within tumors that takes the role of endothelium and forms structures similar to blood vessels (Figure 1).	('cause', 'Reg', (81, 86))	('lack', 'NegReg', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('VEGF', 'Gene', (72, 76))	('tumors', 'Disease', (115, 121))	('vasculogenic mimicry', 'Disease', (87, 107))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('lack', 'Var', (52, 56))	('VEGF', 'Gene', '7422', (72, 76))	('blockade', 'NegReg', (60, 68))
195342	30909397	However, after the introduction of c-Met inhibitor PF-04217903 to crizotinib or sunitinib treatment, invasion and liver metastasis as well as c-Met and EMT markers expression were reduced.	('expression', 'MPA', (164, 174))	('sunitinib', 'Chemical', 'MESH:D000077210', (80, 89))	('c-Met', 'CPA', (142, 147))	('reduced', 'NegReg', (180, 187))	('PF-04217903', 'Chemical', 'MESH:C558663', (51, 62))	('liver metastasis', 'Disease', 'MESH:D009362', (114, 130))	('men', 'Species', '9606', (95, 98))	('liver metastasis', 'Disease', (114, 130))	('EMT', 'biological_process', 'GO:0001837', ('152', '155'))	('crizotinib', 'Chemical', 'MESH:D000077547', (66, 76))	('PF-04217903', 'Var', (51, 62))	('EMT markers', 'CPA', (152, 163))
195365	30909397	pRCC is often characterized by mutations or amplification in the MET gene.	('mutations', 'Var', (31, 40))	('RCC', 'Phenotype', 'HP:0005584', (1, 4))	('MET', 'Gene', (65, 68))	('pRCC', 'Gene', (0, 4))	('amplification', 'Var', (44, 57))	('pRCC', 'Gene', '5546', (0, 4))
195366	30909397	In the phase II randomized clinical trial on foretinib, patients were classified based on c-Met pathway activation: germline or somatic mutation, MET [7q31] amplification or gain of chromosome 7.	('gain', 'PosReg', (174, 178))	('patients', 'Species', '9606', (56, 64))	('activation', 'PosReg', (104, 114))	('MET [7q31] amplification', 'Var', (146, 170))	('foretinib', 'Chemical', 'MESH:C544831', (45, 54))	('c-Met pathway', 'Pathway', (90, 103))	('chromosome', 'cellular_component', 'GO:0005694', ('182', '192'))
195392	30909397	Similar research has shown that the silencing of the c-Met receptor in cervical cancer cells with epithelial origin induced the increase in the level of E-cadherin.	('increase', 'PosReg', (128, 136))	('cadherin', 'molecular_function', 'GO:0008014', ('155', '163'))	('level of E-cadherin', 'MPA', (144, 163))	('c-Met receptor', 'Protein', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('silencing', 'Var', (36, 45))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
195400	30909397	Our observation showed that low level of MCPIP1 in ccRCC led to an increased tumor growth, vascularization and lung metastasis in both NOD-SCID and Nude mice together with the loss of epithelial phenotype of cancer cells.	('cancer', 'Disease', (208, 214))	('lung metastasis', 'CPA', (111, 126))	('NOD-SCID', 'Disease', (135, 143))	('MCPIP1', 'Var', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('vascularization', 'CPA', (91, 106))	('increased', 'PosReg', (67, 76))	('Nude mice', 'Species', '10090', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('NOD-SCID', 'Disease', 'MESH:D020191', (135, 143))	('tumor', 'Disease', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
195407	30909397	Frequent VHL mutation and hypoxia lead to increased c-Met expression in clear cell RCC.	('increased', 'PosReg', (42, 51))	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('hypoxia', 'Disease', (26, 33))	('hypoxia', 'Disease', 'MESH:D000860', (26, 33))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('VHL', 'Gene', (9, 12))	('c-Met expression', 'MPA', (52, 68))	('mutation', 'Var', (13, 21))	('VHL', 'Gene', '7428', (9, 12))
195408	30909397	In papillary RCC, missense mutation of the MET gene causes constitutive activation of the c-Met protein, which correlates with poor survival rates.	('activation', 'PosReg', (72, 82))	('MET', 'Gene', (43, 46))	('constitutive', 'MPA', (59, 71))	('papillary RCC', 'Gene', '5546', (3, 16))	('c-Met protein', 'Protein', (90, 103))	('missense mutation', 'Var', (18, 35))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('papillary RCC', 'Gene', (3, 16))
195415	27698924	Deregulation of long non-coding RNAs (lncRNAs) has been implicated in urologic malignancies and represents potential markers or therapeutic targets.	('Deregulation', 'Var', (0, 12))	('ncRNA', 'Gene', (39, 44))	('malignancies', 'Disease', 'MESH:D009369', (79, 91))	('ncRNA', 'Gene', '220202', (39, 44))	('malignancies', 'Disease', (79, 91))	('implicated', 'Reg', (56, 66))	('long non-coding RNAs', 'Protein', (16, 36))
195435	27698924	A growing list of the validated sense-antisense pairs has been implicated in urologic cancer.	('urologic cancer', 'Disease', 'MESH:D014571', (77, 92))	('urologic cancer', 'Disease', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('sense-antisense pairs', 'Var', (32, 53))	('implicated', 'Reg', (63, 73))
195448	27698924	TRPM2 silencing leads to decreased susceptibility to cell apoptosis and necrosis.	('TRPM2', 'Gene', '7226', (0, 5))	('TRPM2', 'Gene', (0, 5))	('necrosis', 'biological_process', 'GO:0019835', ('72', '80'))	('susceptibility', 'MPA', (35, 49))	('necrosis', 'biological_process', 'GO:0001906', ('72', '80'))	('necrosis', 'biological_process', 'GO:0008220', ('72', '80'))	('necrosis', 'Disease', (72, 80))	('decreased', 'NegReg', (25, 34))	('apoptosis', 'biological_process', 'GO:0097194', ('58', '67'))	('apoptosis', 'biological_process', 'GO:0006915', ('58', '67'))	('necrosis', 'biological_process', 'GO:0008219', ('72', '80'))	('necrosis', 'Disease', 'MESH:D009336', (72, 80))	('necrosis', 'biological_process', 'GO:0070265', ('72', '80'))	('silencing', 'Var', (6, 15))
195450	27698924	Silencing of CBR3-AS1 downregulates AR, inhibits cell growth, and increases apoptosis in both androgen-dependent and independent LNCaP cells.	('CBR3-AS1', 'Gene', (13, 21))	('apoptosis', 'biological_process', 'GO:0097194', ('76', '85'))	('LNCaP', 'CellLine', 'CVCL:0395', (129, 134))	('CBR3-AS1', 'Gene', '100506428', (13, 21))	('downregulates', 'NegReg', (22, 35))	('increases', 'PosReg', (66, 75))	('cell growth', 'biological_process', 'GO:0016049', ('49', '60'))	('AR', 'Gene', '367', (36, 38))	('inhibits', 'NegReg', (40, 48))	('apoptosis', 'CPA', (76, 85))	('Silencing', 'Var', (0, 9))	('apoptosis', 'biological_process', 'GO:0006915', ('76', '85'))	('cell growth', 'CPA', (49, 60))
195457	27698924	reported a novel antisense lncRNA ZEB2NAT of ZEB2 that enhances the invasion of UBC cells through the TGFbeta1-ZEB2NAT-ZEB2 axis.	('TGFbeta1', 'Gene', (102, 110))	('ZEB2', 'Gene', '9839', (111, 115))	('ncRNA', 'Gene', (28, 33))	('ZEB2', 'Gene', (45, 49))	('ZEB2NAT', 'Gene', (34, 41))	('ncRNA', 'Gene', '220202', (28, 33))	('invasion of UBC cells', 'CPA', (68, 89))	('ZEB2', 'Gene', '9839', (45, 49))	('enhances', 'PosReg', (55, 63))	('ZEB2NAT', 'Gene', '100303491', (34, 41))	('ZEB2NAT', 'Gene', (111, 118))	('antisense', 'Var', (17, 26))	('ZEB2', 'Gene', (34, 38))	('ZEB2', 'Gene', '9839', (34, 38))	('TGFbeta1', 'Gene', '7040', (102, 110))	('ZEB2', 'Gene', (119, 123))	('ZEB2NAT', 'Gene', '100303491', (111, 118))	('ZEB2', 'Gene', (111, 115))	('ZEB2', 'Gene', '9839', (119, 123))
195458	27698924	identified antisense lncRNA MDC1-AS that upregulates the expression of tumor-suppressing MDC1 in bladder cancer.	('MDC1', 'Gene', (28, 32))	('expression', 'MPA', (57, 67))	('ncRNA', 'Gene', (22, 27))	('bladder cancer', 'Disease', 'MESH:D001749', (97, 111))	('bladder cancer', 'Disease', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('bladder cancer', 'Phenotype', 'HP:0009725', (97, 111))	('ncRNA', 'Gene', '220202', (22, 27))	('MDC1', 'Gene', '9656', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('upregulates', 'PosReg', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('MDC1', 'Gene', (89, 93))	('tumor', 'Disease', (71, 76))	('MDC1', 'Gene', '9656', (28, 32))	('antisense', 'Var', (11, 20))
195460	27698924	Disturbed imprinting in XIST, CDKN1C/KCNQ, H19/IGF2 and DLK1/MEG3 loci is commonly observed in urologic cancers.	('urologic cancers', 'Disease', (95, 111))	('XIST', 'Gene', '7503', (24, 28))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('H19', 'Gene', '283120', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('IGF2', 'Gene', '3481', (47, 51))	('Disturbed', 'Var', (0, 9))	('CDKN1C', 'Gene', '1028', (30, 36))	('imprinting', 'MPA', (10, 20))	('urologic cancers', 'Disease', 'MESH:D014571', (95, 111))	('MEG3', 'Gene', (61, 65))	('DLK1', 'Gene', '8788', (56, 60))	('DLK1', 'Gene', (56, 60))	('observed', 'Reg', (83, 91))	('CDKN1C', 'Gene', (30, 36))	('XIST', 'Gene', (24, 28))	('IGF2', 'Gene', (47, 51))	('H19', 'Gene', (43, 46))	('MEG3', 'Gene', '55384', (61, 65))
195467	27698924	KCNQ1OT1 binds both PRC2 and G9a to promote two different repressive histone marks H3K27me3 and H3K9me3, thereby mediating the silencing of the flanking genes.	('promote', 'PosReg', (36, 43))	('silencing', 'MPA', (127, 136))	('KCNQ1OT1', 'Gene', '10984', (0, 8))	('KCNQ1OT1', 'Gene', (0, 8))	('H3K9me3', 'Var', (96, 103))	('H3K27me3', 'Var', (83, 91))
195470	27698924	Defective imprinting in H19/IGF2 locus is also a common event in bladder cancer and Wilms tumors.	('bladder cancer', 'Disease', (65, 79))	('IGF2', 'Gene', (28, 32))	('Wilms tumor', 'Phenotype', 'HP:0002667', (84, 95))	('H19', 'Gene', (24, 27))	('common', 'Reg', (49, 55))	('H19', 'Gene', '283120', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('bladder cancer', 'Phenotype', 'HP:0009725', (65, 79))	('Wilms tumors', 'Phenotype', 'HP:0002667', (84, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('Wilms tumors', 'Disease', (84, 96))	('Defective imprinting', 'Var', (0, 20))	('IGF2', 'Gene', '3481', (28, 32))	('Wilms tumors', 'Disease', 'MESH:D009396', (84, 96))	('bladder cancer', 'Disease', 'MESH:D001749', (65, 79))
195475	27698924	Biallelic methylation of the H19 promoter silences H19 and causes biallelic expression of IGF2, thereby stimulating cell growth.	('biallelic expression', 'MPA', (66, 86))	('H19', 'Gene', '283120', (51, 54))	('IGF2', 'Gene', (90, 94))	('H19', 'Gene', (51, 54))	('silences', 'NegReg', (42, 50))	('cell growth', 'biological_process', 'GO:0016049', ('116', '127'))	('H19', 'Gene', '283120', (29, 32))	('causes', 'Reg', (59, 65))	('stimulating', 'PosReg', (104, 115))	('H19', 'Gene', (29, 32))	('Biallelic', 'Var', (0, 9))	('IGF2', 'Gene', '3481', (90, 94))	('cell growth', 'CPA', (116, 127))	('methylation', 'biological_process', 'GO:0032259', ('10', '21'))
195479	27698924	DLK1 and MEG3 are prevalently downregulated in prostate cancer, bladder cancer and primary renal cell carcinoma (RCC) tissues caused by the epigenetic silencing across the 14q32 imprinted gene cluster.	('MEG3', 'Gene', (9, 13))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (91, 111))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('bladder cancer', 'Disease', 'MESH:D001749', (64, 78))	('bladder cancer', 'Disease', (64, 78))	('MEG3', 'Gene', '55384', (9, 13))	('RCC', 'Disease', (113, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('primary renal cell carcinoma', 'Disease', (83, 111))	('primary renal cell carcinoma', 'Disease', 'MESH:C538614', (83, 111))	('DLK1', 'Gene', '8788', (0, 4))	('epigenetic silencing', 'Var', (140, 160))	('bladder cancer', 'Phenotype', 'HP:0009725', (64, 78))	('DLK1', 'Gene', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('prostate cancer', 'Disease', 'MESH:D011471', (47, 62))	('prostate cancer', 'Phenotype', 'HP:0012125', (47, 62))	('downregulated', 'NegReg', (30, 43))	('prostate cancer', 'Disease', (47, 62))
195503	27698924	This kind of lncRNAs always antagonize transcription regulators, so knockdown of these lncRNAs may lead to gain-of-function of its targets.	('ncRNA', 'Gene', (88, 93))	('transcription', 'biological_process', 'GO:0006351', ('39', '52'))	('ncRNA', 'Gene', '220202', (88, 93))	('knockdown', 'Var', (68, 77))	('ncRNA', 'Gene', (14, 19))	('gain-of-function', 'PosReg', (107, 123))	('ncRNA', 'Gene', '220202', (14, 19))
195520	27698924	The restoration of PTEN inhibits tumor cell proliferation.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('inhibits', 'NegReg', (24, 32))	('PTEN', 'Gene', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('PTEN', 'Gene', '5728', (19, 23))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('tumor', 'Disease', (33, 38))	('restoration', 'Var', (4, 15))
195548	27698924	rs378854 in 8q24 region is associated with expression of oncogenic lncRNA PVT1 in PCa.	('rs378854', 'Mutation', 'rs378854', (0, 8))	('PCa', 'Disease', (82, 85))	('PVT1', 'Gene', '5820', (74, 78))	('associated', 'Reg', (27, 37))	('ncRNA', 'Gene', (68, 73))	('rs378854', 'Var', (0, 8))	('expression', 'MPA', (43, 53))	('ncRNA', 'Gene', '220202', (68, 73))	('PVT1', 'Gene', (74, 78))
195549	27698924	A further lncRNA at the 8q24 region is PRNCR1  transcribed between rs1456315 and rs7463708.	('rs1456315', 'Var', (67, 76))	('rs7463708', 'Var', (81, 90))	('rs1456315', 'Mutation', 'rs1456315', (67, 76))	('PRNCR1', 'Gene', '101867536', (39, 45))	('PRNCR1', 'Gene', (39, 45))	('ncRNA', 'Gene', (11, 16))	('rs7463708', 'Mutation', 'rs7463708', (81, 90))	('ncRNA', 'Gene', '220202', (11, 16))
195550	27698924	SNPs in the H19 gene are also associated with the risk of bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('H19', 'Gene', '283120', (12, 15))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('H19', 'Gene', (12, 15))	('SNPs', 'Var', (0, 4))	('bladder cancer', 'Disease', 'MESH:D001749', (58, 72))	('bladder cancer', 'Disease', (58, 72))	('associated with', 'Reg', (30, 45))
195551	27698924	rs2839698TC and rs2107425CT in H19 significantly reduce risk of non-muscle-invasive bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (84, 98))	('rs2107425CT', 'Var', (16, 27))	('bladder cancer', 'Disease', (84, 98))	('bladder cancer', 'Disease', 'MESH:D001749', (84, 98))	('H19', 'Gene', '283120', (31, 34))	('invasive bladder', 'Phenotype', 'HP:0100645', (75, 91))	('H19', 'Gene', (31, 34))	('reduce', 'NegReg', (49, 55))	('rs2839698TC', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
195552	27698924	rs16834898 and rs6434568 in PCGEM1  indicate a lower PCa risk with Chinese population.	('lower', 'NegReg', (47, 52))	('PCGEM1', 'Gene', '64002', (28, 34))	('rs16834898', 'Mutation', 'rs16834898', (0, 10))	('rs6434568', 'Mutation', 'rs6434568', (15, 24))	('rs6434568', 'Var', (15, 24))	('rs16834898', 'Var', (0, 10))	('PCGEM1', 'Gene', (28, 34))	('PCa', 'Disease', (53, 56))
195553	27698924	However, how these variants affect cancer susceptibility remains to be elucidated.	('affect', 'Reg', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('variants', 'Var', (19, 27))	('cancer', 'Disease', (35, 41))
195566	27698924	However, the inclusion of PCA3 can improve the diagnostic accuracy of other clinical variables.	('improve', 'PosReg', (35, 42))	('inclusion', 'Var', (13, 22))	('PCA3', 'Gene', (26, 30))	('PCA3', 'Gene', '50652', (26, 30))
195577	27698924	FR0348383 transcript in post-DRE urine has diagnostic value for patient cohorts especially in the PSA grey zone.	('PSA', 'Gene', '354', (98, 101))	('FR0348383 transcript', 'Var', (0, 20))	('PSA', 'Gene', (98, 101))	('patient', 'Species', '9606', (64, 71))
195593	27698924	The variant transcript of UCA1, UCA1a (CUDR) also plays a role in bladder cancer progression.	('UCA1', 'Gene', '652995', (32, 36))	('UCA1', 'Gene', (32, 36))	('bladder cancer', 'Phenotype', 'HP:0009725', (66, 80))	('CUDR', 'Gene', '652995', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('CUDR', 'Gene', (39, 43))	('UCA1', 'Gene', '652995', (26, 30))	('UCA1', 'Gene', (26, 30))	('variant', 'Var', (4, 11))	('plays', 'Reg', (50, 55))	('bladder cancer', 'Disease', 'MESH:D001749', (66, 80))	('bladder cancer', 'Disease', (66, 80))
195607	27698924	MALAT1 silencing inhibits RCC cell proliferation and promotes apoptosis.	('inhibits', 'NegReg', (17, 25))	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('promotes', 'PosReg', (53, 61))	('MALAT1', 'Gene', '378938', (0, 6))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('MALAT1', 'Gene', (0, 6))	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('apoptosis', 'CPA', (62, 71))	('silencing', 'Var', (7, 16))	('cell proliferation', 'biological_process', 'GO:0008283', ('30', '48'))
195620	27698924	In PCa, high SChLAP1 expression is correlated with biochemical recurrence, clinical progression and mortality.	('SChLAP1', 'Gene', (13, 20))	('correlated', 'Reg', (35, 45))	('high', 'Var', (8, 12))	('PCa', 'Disease', (3, 6))	('expression', 'MPA', (21, 31))	('SChLAP1', 'Gene', '101669767', (13, 20))
195640	27698924	In vitro MALAT1 silencing inhibits metastasis of CRPC cancer cells and leads to cell cycle arrest.	('metastasis of CRPC cancer', 'Disease', (35, 60))	('inhibits', 'NegReg', (26, 34))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (80, 97))	('MALAT1', 'Gene', '378938', (9, 15))	('cell cycle arrest', 'CPA', (80, 97))	('silencing', 'Var', (16, 25))	('metastasis of CRPC cancer', 'Disease', 'MESH:D009362', (35, 60))	('MALAT1', 'Gene', (9, 15))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('80', '97'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('leads to', 'Reg', (71, 79))
195641	27698924	In vivo knock-out of MALAT1 inhibits growth of tumor xenografts.	('MALAT1', 'Gene', '378938', (21, 27))	('knock-out', 'Var', (8, 17))	('inhibits', 'NegReg', (28, 36))	('MALAT1', 'Gene', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
195657	27698924	Other possible lncRNA targeting agents are catalytic nucleic acids (CNAs) such as ribozymes and DNAzymes, which can also bind and cleave lncRNA targets and repress their expression.	('cleave', 'Var', (130, 136))	('ncRNA', 'Gene', (16, 21))	('bind', 'Interaction', (121, 125))	('ncRNA', 'Gene', '220202', (16, 21))	('repress', 'NegReg', (156, 163))	('ncRNA', 'Gene', (138, 143))	('ncRNA', 'Gene', '220202', (138, 143))	('expression', 'MPA', (170, 180))
195659	27698924	Disruption of these molecular interactions compromises the repression of the tumor suppressors and reactivates their function.	('repression', 'MPA', (59, 69))	('interactions', 'Interaction', (30, 42))	('reactivates', 'NegReg', (99, 110))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('compromises', 'NegReg', (43, 54))	('function', 'MPA', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('Disruption', 'Var', (0, 10))
195677	27698924	examined mTOR inhibition as a strategy to enhance GAS5 levels in several prostate cancer cell lines.	('prostate cancer', 'Disease', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('enhance', 'PosReg', (42, 49))	('mTOR', 'Gene', (9, 13))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('mTOR', 'Gene', '2475', (9, 13))	('GAS5', 'Gene', '60674', (50, 54))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('inhibition', 'Var', (14, 24))	('GAS5', 'Gene', (50, 54))	('GAS', 'molecular_function', 'GO:0034005', ('50', '53'))
195682	27698924	Aberrant expression of individual lncRNAs in RCC by small-scaled studies, i.e.	('ncRNA', 'Gene', '220202', (35, 40))	('Aberrant', 'Var', (0, 8))	('expression', 'MPA', (9, 19))	('ncRNA', 'Gene', (35, 40))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
195724	31953718	In the multivariate analysis, after adjustment for pathological and clinical covariates, high MPVLR (>= 3.61) was independently associated with higher long-term overall mortality in nonmetastatic ccRCC patients.	('mortality', 'Disease', (169, 178))	('higher', 'PosReg', (144, 150))	('patients', 'Species', '9606', (202, 210))	('RCC', 'Disease', (198, 201))	('high', 'Var', (89, 93))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('nonmetastatic', 'Disease', (182, 195))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('ccRCC', 'Phenotype', 'HP:0006770', (196, 201))	('mortality', 'Disease', 'MESH:D003643', (169, 178))	('MPVLR', 'Gene', (94, 99))
195755	31953718	In multivariate analysis, after adjustment for clinicopathological covariates, high MPVLR (>= 3.61) was independently associated with greater long-term mortality in nonmetastatic ccRCC patients (Table 2).	('MPVLR', 'Gene', (84, 89))	('mortality', 'Disease', (152, 161))	('ccRCC', 'Phenotype', 'HP:0006770', (179, 184))	('greater', 'PosReg', (134, 141))	('high', 'Var', (79, 83))	('mortality', 'Disease', 'MESH:D003643', (152, 161))	('patients', 'Species', '9606', (185, 193))	('RCC', 'Disease', 'MESH:C538614', (181, 184))	('RCC', 'Disease', (181, 184))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))
195769	31953718	retrospectively evaluated 652 patients with RCC and concluded that MPV is a significant predictor of recurrences and cancer-specific deaths.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('patients', 'Species', '9606', (30, 38))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('MPV', 'Var', (67, 70))	('deaths', 'Disease', (133, 139))	('cancer', 'Disease', (117, 123))	('deaths', 'Disease', 'MESH:D003643', (133, 139))	('recurrences', 'CPA', (101, 112))
195770	31953718	determined the association between lower mean platelet volume and prognosis in RCC, and reported that low MPV is a predictor of adverse clinical outcome.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('MPV', 'MPA', (106, 109))	('mean platelet volume', 'MPA', (41, 61))	('low', 'Var', (102, 105))	('lower', 'NegReg', (35, 40))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
195774	31953718	As described, the relationship between RCC and MPVLR remains complex, as MPVLR may reflect the aggressiveness of the tumor, altered platelet-mediated immunity and decreased lymphocyte-mediated immune response.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('MPVLR', 'Var', (73, 78))	('decreased lymphocyte', 'Phenotype', 'HP:0001888', (163, 183))	('altered', 'Reg', (124, 131))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('aggressiveness', 'Phenotype', 'HP:0000718', (95, 109))	('RCC', 'Disease', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('platelet-mediated immunity', 'CPA', (132, 158))	('lymphocyte-mediated immune response', 'CPA', (173, 208))	('decreased', 'NegReg', (163, 172))	('immune response', 'biological_process', 'GO:0006955', ('193', '208'))	('aggressiveness of the tumor', 'Disease', 'MESH:D001523', (95, 122))	('aggressiveness of the tumor', 'Disease', (95, 122))
195795	29239102	Dysregulated expression of these molecules might predict the prognosis of patients.	('expression', 'MPA', (13, 23))	('patients', 'Species', '9606', (74, 82))	('Dysregulated', 'Var', (0, 12))	('predict', 'Reg', (49, 56))
195800	29239102	The VHL gene mutation is the predominant cause of VHL inactivation 6.	('VHL', 'Gene', (50, 53))	('mutation', 'Var', (13, 21))	('VHL', 'Gene', '7428', (50, 53))	('cause', 'Reg', (41, 46))	('VHL', 'Gene', (4, 7))	('VHL', 'Gene', '7428', (4, 7))
195801	29239102	However, whether VHL mutation would affect the precise prognostic judgement and therapy of ccRCC patients in specific condition remains unknown.	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Disease', (93, 96))	('mutation', 'Var', (21, 29))	('affect', 'Reg', (36, 42))	('VHL', 'Gene', (17, 20))	('VHL', 'Gene', '7428', (17, 20))	('patients', 'Species', '9606', (97, 105))
195802	29239102	Serpin peptidase inhibitor clade H member 1 (SERPINH1, also called HSP47) belongs to the serpin superfamily and has a signal sequence at the N-terminus, two N-glycosylation sites and an ER retention signal (Arg-Asp-Glu-Leu, RDEL) at the C-terminus 7.	('Leu', 'Chemical', 'MESH:D007930', (219, 222))	('Serpin peptidase inhibitor clade H member 1', 'Gene', (0, 43))	('SERPINH1', 'Gene', '871', (45, 53))	('HSP47', 'Gene', (67, 72))	('SERPINH1', 'Gene', (45, 53))	('Serpin peptidase inhibitor clade H member 1', 'Gene', '871', (0, 43))	('Arg', 'Chemical', 'MESH:D001120', (207, 210))	('Glu', 'Chemical', 'MESH:D018698', (215, 218))	('glycosylation', 'biological_process', 'GO:0070085', ('159', '172'))	('serpin', 'molecular_function', 'GO:0004868', ('89', '95'))	('HSP47', 'Gene', '871', (67, 72))	('Serpin', 'molecular_function', 'GO:0004868', ('0', '6'))	('retention', 'biological_process', 'GO:0051235', ('189', '198'))	('Asp', 'Chemical', 'MESH:D001224', (211, 214))	('Arg-Asp-Glu-Leu', 'Var', (207, 222))
195804	29239102	In this study, for the first time, we demonstrate that the high level of SERPINH1 has the strongest association with poor prognosis of ccRCC patients among our EMT-related differentially expressed genes (DEGs).	('high level', 'Var', (59, 69))	('SERPINH1', 'Gene', '871', (73, 81))	('SERPINH1', 'Gene', (73, 81))	('EMT', 'biological_process', 'GO:0001837', ('160', '163'))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))	('patients', 'Species', '9606', (141, 149))
195848	29239102	These results suggest that SERPINH1 knock-down reverses the expression of EMT markers, and SERPINH1 possibly affects the prognosis of ccRCC patients by regulating the EMT process.	('knock-down', 'Var', (36, 46))	('expression', 'MPA', (60, 70))	('affects', 'Reg', (109, 116))	('SERPINH1', 'Gene', '871', (27, 35))	('EMT process', 'CPA', (167, 178))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('EMT', 'biological_process', 'GO:0001837', ('74', '77'))	('SERPINH1', 'Gene', (91, 99))	('SERPINH1', 'Gene', '871', (91, 99))	('EMT', 'biological_process', 'GO:0001837', ('167', '170'))	('patients', 'Species', '9606', (140, 148))	('SERPINH1', 'Gene', (27, 35))	('reverses', 'NegReg', (47, 55))	('RCC', 'Disease', (136, 139))	('regulating', 'Reg', (152, 162))
195863	29239102	The results showed that both high mRNA and protein levels of SERPINH1 were significantly associated with shorter OS and DFS time of ccRCC patients (P < 0.01, Fig.	('high', 'Var', (29, 33))	('SERPINH1', 'Gene', (61, 69))	('SERPINH1', 'Gene', '871', (61, 69))	('RCC', 'Disease', (134, 137))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('shorter', 'NegReg', (105, 112))	('patients', 'Species', '9606', (138, 146))
195864	29239102	In addition, a high level of SERPINH1 could predict the poor prognosis in early-stage ccRCC patients (Fig.	('high', 'Var', (15, 19))	('SERPINH1', 'Gene', '871', (29, 37))	('SERPINH1', 'Gene', (29, 37))	('RCC', 'Disease', (88, 91))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('patients', 'Species', '9606', (92, 100))
195898	29239102	Functionally, dysregulation of SERPINH1/HSP47 stimulates expression of extracellular matrix (ECM) proteins, including collagen type I that could induce EMT.	('extracellular matrix', 'cellular_component', 'GO:0031012', ('71', '91'))	('EMT', 'CPA', (152, 155))	('HSP47', 'Gene', (40, 45))	('dysregulation', 'Var', (14, 27))	('induce', 'PosReg', (145, 151))	('SERPINH1', 'Gene', '871', (31, 39))	('collagen', 'molecular_function', 'GO:0005202', ('118', '126'))	('SERPINH1', 'Gene', (31, 39))	('HSP47', 'Gene', '871', (40, 45))	('EMT', 'biological_process', 'GO:0001837', ('152', '155'))	('stimulates', 'PosReg', (46, 56))	('expression of', 'MPA', (57, 70))
195905	29239102	Our data support the notion that dysregulation of SERPINH1/HSP47 induces EMT, which is closely associated with ccRCC development and progression, and further affects the prognosis of ccRCC.	('dysregulation', 'Var', (33, 46))	('RCC', 'Disease', (185, 188))	('SERPINH1', 'Gene', (50, 58))	('induces', 'PosReg', (65, 72))	('EMT', 'CPA', (73, 76))	('HSP47', 'Gene', '871', (59, 64))	('affects', 'Reg', (158, 165))	('SERPINH1', 'Gene', '871', (50, 58))	('HSP47', 'Gene', (59, 64))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('associated', 'Reg', (95, 105))	('EMT', 'biological_process', 'GO:0001837', ('73', '76'))	('RCC', 'Disease', 'MESH:C538614', (185, 188))
195916	29239102	Antagonizing TGFbeta1 in vivo can suppress RCC tumorigenesis and regress established 786-O tumours in athymic mice 33.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('tumours', 'Disease', 'MESH:D009369', (91, 98))	('TGFbeta1', 'Gene', (13, 21))	('tumours', 'Disease', (91, 98))	('mice', 'Species', '10090', (110, 114))	('TGFbeta1', 'Gene', '21803', (13, 21))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('suppress', 'NegReg', (34, 42))	('Antagonizing', 'Var', (0, 12))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
195919	29239102	Recent studies have shown that silencing SERPINH1 by small molecules can suppress cancer cell phenotypes 36, 37 that lead to poor prognosis.	('silencing', 'Var', (31, 40))	('suppress', 'NegReg', (73, 81))	('SERPINH1', 'Gene', '871', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('SERPINH1', 'Gene', (41, 49))
195929	32184670	The telomeres may play a dual role during RCC carcinogenesis in the early stages, short telomeres may increase RCC risk and in late carcinogenesis, long telomeres seem to be associated with tumor prognosis.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('associated', 'Reg', (174, 184))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('short telomeres', 'Var', (82, 97))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('late carcinogenesis', 'Disease', (127, 146))	('tumor', 'Disease', (190, 195))	('increase', 'PosReg', (102, 110))	('short telomeres', 'Phenotype', 'HP:0031413', (82, 97))	('RCC', 'Disease', (42, 45))	('late carcinogenesis', 'Disease', 'MESH:D063646', (127, 146))
195946	32184670	TRF1 ensures telomere replication and its disruption significantly increases the levels of fragile telomeres and sister-telomere association.	('TRF1', 'Gene', (0, 4))	('TRF1', 'Gene', '7013', (0, 4))	('sister-telomere association', 'CPA', (113, 140))	('telomere', 'cellular_component', 'GO:0000781', ('120', '128'))	('increases', 'PosReg', (67, 76))	('disruption', 'Var', (42, 52))	('telomere', 'cellular_component', 'GO:0000781', ('13', '21'))	('telomere replication', 'CPA', (13, 33))	('telomere', 'cellular_component', 'GO:0005696', ('13', '21'))	('levels of fragile telomeres', 'MPA', (81, 108))	('telomere', 'cellular_component', 'GO:0005696', ('120', '128'))
195961	32184670	The upregulation of telomerase, whether it happens through the amplification of the hTERT, duplication or translocation of the locus or even through an overexpression of its promoter (since it is known that it is targeted by numerous oncogenes, tumor suppressors and other transcription factors), is one of these mechanisms.	('transcription', 'biological_process', 'GO:0006351', ('273', '286'))	('overexpression', 'PosReg', (152, 166))	('duplication', 'Var', (91, 102))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('hTERT', 'Gene', '7015', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('telomerase', 'Enzyme', (20, 30))	('tumor', 'Disease', (245, 250))	('hTERT', 'Gene', (84, 89))	('upregulation', 'PosReg', (4, 16))
195962	32184670	Other mechanisms are the inactivation of TP53 or Rb or both, initiation of ALT or other key pathways.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('ALT', 'molecular_function', 'GO:0004021', ('75', '78'))	('inactivation', 'Var', (25, 37))	('ALT', 'CPA', (75, 78))
195963	32184670	Moreover, abnormal telomeres can cause sticky chromosome ends and like that contribute to chromosomal aneuploidy.	('cause', 'Reg', (33, 38))	('abnormal telomeres', 'Phenotype', 'HP:0031412', (10, 28))	('sticky chromosome ends', 'CPA', (39, 61))	('abnormal', 'Var', (10, 18))	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('chromosomal aneuploidy', 'Disease', (90, 112))	('contribute', 'Reg', (76, 86))	('chromosomal aneuploidy', 'Disease', 'MESH:D000782', (90, 112))
195966	32184670	The knowledge of the telomeres biology allowed the definition of potential biomarkers in cancer regarding these structures, namely telomerase activity, polymorphisms associated with telomerase or TL.	('telomerase', 'Enzyme', (131, 141))	('activity', 'MPA', (142, 150))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('telomerase activity', 'molecular_function', 'GO:0003720', ('131', '150'))	('polymorphisms', 'Var', (152, 165))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
195970	32184670	The different variants of genetic polymorphisms in this gene have been associated with differences in TL and with the prognosis of patients in several tumor models, including lung, gastric, breast and kidney cancer.	('patients', 'Species', '9606', (131, 139))	('lung', 'Disease', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('gastric', 'Disease', (181, 188))	('breast and kidney cancer', 'Disease', 'MESH:D001943', (190, 214))	('variants', 'Var', (14, 22))	('kidney cancer', 'Phenotype', 'HP:0009726', (201, 214))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('differences', 'Reg', (87, 98))	('associated', 'Reg', (71, 81))
195976	32184670	Regarding cancer, several studies suggest shorter telomeres as a cancer risk factor but there is still no concordance between authors.	('shorter', 'Var', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', (10, 16))
195988	32184670	However, they did not find any differences in the size of telomeres when comparing the tumors with telomeric associations and the ones without.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('telomeric associations', 'Var', (99, 121))
196005	32184670	Pal et al, using a cohort of a hundred patients of RCC found that RCC tissues were significantly shorter than the adjacent normal parenchyma and there was a correlation between TL in different grades of ccRCC: low-grade tumors had significantly longer telomeres.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('longer', 'PosReg', (245, 251))	('patients', 'Species', '9606', (39, 47))	('RCC', 'Disease', (205, 208))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('telomeres', 'MPA', (252, 261))	('low-grade', 'Var', (210, 219))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('tumors', 'Disease', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('shorter', 'NegReg', (97, 104))	('Pal', 'molecular_function', 'GO:0004598', ('0', '3'))	('RCC', 'Disease', (66, 69))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
196007	32184670	It was a case-control study, using blood cells, where we found a significative association between shorter telomeres and risk of RCC.	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('RCC', 'Disease', (129, 132))	('shorter telomeres', 'Var', (99, 116))
196008	32184670	Moreover, we found that LTL was longer in T3/T4 patients and in patients with tumors larger than 7 cm, suggesting LTL as a potential prognostic biomarker (Morais et al; unpublished data; 2019).	('tumors', 'Disease', (78, 84))	('LTL', 'MPA', (24, 27))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('patients', 'Species', '9606', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('patients', 'Species', '9606', (48, 56))	('T3/T4', 'Var', (42, 47))
196009	32184670	In fact, shorter telomeres have been suggested as risk factors for insulin resistance, overt diabetes mellitus, cardiovascular disease or neurological disorders such as Alzheimer's disease.	('insulin', 'Gene', (67, 74))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (112, 134))	('neurological disorders', 'Disease', (138, 160))	('diabetes mellitus', 'Disease', (93, 110))	('cardiovascular disease', 'Disease', 'MESH:D002318', (112, 134))	('insulin', 'Gene', '3630', (67, 74))	('overt diabetes mellitus', 'Phenotype', 'HP:0100651', (87, 110))	('diabetes mellitus', 'Disease', 'MESH:D003920', (93, 110))	('insulin resistance', 'Phenotype', 'HP:0000855', (67, 85))	('shorter', 'Var', (9, 16))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (169, 188))	('neurological disorders', 'Disease', 'MESH:D009422', (138, 160))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (169, 188))	('cardiovascular disease', 'Disease', (112, 134))	("Alzheimer's disease", 'Disease', (169, 188))	('insulin', 'molecular_function', 'GO:0016088', ('67', '74'))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (93, 110))
196012	32184670	In general, short telomeres have been associated with an increased renal injury and decreased recovery.	('recovery', 'MPA', (94, 102))	('short telomeres', 'Phenotype', 'HP:0031413', (12, 27))	('renal injury', 'Disease', (67, 79))	('renal injury', 'Disease', 'MESH:D007674', (67, 79))	('increased', 'PosReg', (57, 66))	('short telomeres', 'Var', (12, 27))	('decreased', 'NegReg', (84, 93))
196014	32184670	A systematic review conducted by Ameh O. et al postulated a double role of TL in CKD: shortening TL is associated with CKD prevalence and declining kidney function, but an offset of this association due to the cellular telomere reparative process in those surviving longer with CKD.	('telomere', 'cellular_component', 'GO:0005696', ('219', '227'))	('shortening', 'Var', (86, 96))	('CKD', 'Disease', (278, 281))	('CKD', 'Disease', 'MESH:D051436', (81, 84))	('declining', 'NegReg', (138, 147))	('CKD', 'Disease', 'MESH:D051436', (119, 122))	('kidney function', 'MPA', (148, 163))	('CKD', 'Disease', (81, 84))	('CKD', 'Disease', (119, 122))	('CKD', 'Disease', 'MESH:D051436', (278, 281))	('telomere', 'cellular_component', 'GO:0000781', ('219', '227'))
196022	32184670	Interestingly, most tumors with BFB instability present critical telomere shortening.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('critical telomere shortening', 'MPA', (56, 84))	('instability', 'Var', (36, 47))	('telomere', 'cellular_component', 'GO:0000781', ('65', '73'))	('BFB', 'Gene', (32, 35))	('telomere', 'cellular_component', 'GO:0005696', ('65', '73'))	('telomere shortening', 'Phenotype', 'HP:0031413', (65, 84))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
196024	32184670	However, there seems to be a reactivation of telomerase by tumor cells in order to prolong neoplastic growth and facilitate tumor progression in later stages of carcinogenesis.	('tumor', 'Disease', (59, 64))	('prolong', 'PosReg', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('telomerase', 'Protein', (45, 55))	('reactivation', 'Var', (29, 41))	('neoplastic growth', 'Disease', (91, 108))	('neoplastic growth', 'Disease', 'MESH:D006130', (91, 108))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('facilitate', 'PosReg', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
196030	32184670	Also, some polymorphisms in hTERT and other specific enzymes related to TL maintenance influence the length of telomeres.	('length', 'MPA', (101, 107))	('hTERT', 'Gene', (28, 33))	('polymorphisms', 'Var', (11, 24))	('influence', 'Reg', (87, 96))	('hTERT', 'Gene', '7015', (28, 33))
196037	32184670	TL seems to have a double role in RCC carcinogenesis: in the early stages, short telomeres seem to increase RCC risk due to a rise in genomic instability and in late carcinogenesis, long telomeres seem to be associated with tumor prognosis.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('long telomeres', 'Var', (182, 196))	('tumor', 'Disease', (224, 229))	('short telomeres', 'Phenotype', 'HP:0031413', (75, 90))	('late carcinogenesis', 'Disease', (161, 180))	('associated with', 'Reg', (208, 223))	('genomic', 'MPA', (134, 141))	('increase', 'PosReg', (99, 107))	('rise', 'PosReg', (126, 130))	('short telomeres', 'Var', (75, 90))	('RCC', 'Disease', (34, 37))	('late carcinogenesis', 'Disease', 'MESH:D063646', (161, 180))
196039	33946379	Spatial Distribution of Private Gene Mutations in Clear Cell Renal Cell Carcinoma Tumours consist of multiple groups of similar cells resulting from differing evolutionary trajectories, i.e., subclones.	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (61, 81))	('Clear Cell Renal Cell Carcinoma', 'Disease', (50, 81))	('Mutations', 'Var', (37, 46))	('Carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('Tumours', 'Phenotype', 'HP:0002664', (82, 89))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (50, 81))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (50, 81))
196043	33946379	With an average of 62% of mutations having been identified in only one of the two biopsies, some of which in turn are found to impact gene expression, the complex makeup of ccRCC tumours is evident, and this can drastically influence treatment outcome.	('ccRCC', 'Phenotype', 'HP:0006770', (173, 178))	('gene expression', 'MPA', (134, 149))	('tumours', 'Phenotype', 'HP:0002664', (179, 186))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('ccRCC tumours', 'Disease', 'MESH:D009369', (173, 186))	('mutations', 'Var', (26, 35))	('impact', 'Reg', (127, 133))	('influence', 'Reg', (224, 233))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('gene expression', 'biological_process', 'GO:0010467', ('134', '149'))	('ccRCC tumours', 'Disease', (173, 186))
196050	33946379	Pairwise comparison of the two biopsies from the same tumour revealed that on average, 62% of the mutations in a patient were detected in one of the two samples.	('patient', 'Species', '9606', (113, 120))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Disease', (54, 60))	('mutations', 'Var', (98, 107))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
196052	33946379	Of the 89 ccRCC tumours, 87 (~98%) harboured private mutations, occurring in only one of the paired tumour samples.	('paired tumour', 'Disease', (93, 106))	('RCC', 'Phenotype', 'HP:0005584', (12, 15))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('ccRCC tumours', 'Disease', (10, 23))	('mutations', 'Var', (53, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (10, 15))	('harboured', 'Reg', (35, 44))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('ccRCC tumours', 'Disease', 'MESH:D009369', (10, 23))	('paired tumour', 'Disease', 'MESH:D009369', (93, 106))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))
196054	33946379	Our findings imply that shared and private mutations significantly contribute to the complexity of differential gene expression and pathway interaction and might explain the clonal evolution of different molecular renal cancer subgroups.	('renal cancer', 'Disease', 'MESH:D007680', (214, 226))	('renal cancer', 'Phenotype', 'HP:0009726', (214, 226))	('gene expression', 'biological_process', 'GO:0010467', ('112', '127'))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('mutations', 'Var', (43, 52))	('renal cancer', 'Disease', (214, 226))	('interaction', 'Interaction', (140, 151))	('contribute', 'Reg', (67, 77))
196059	33946379	A large degree of intra-tumour heterogeneity with respect to both somatic mutations and somatic copy number variations was observed in all 10 tumours, with 75% of driver events found to be subclonal.	('tumours', 'Disease', 'MESH:D009369', (142, 149))	('tumours', 'Disease', (142, 149))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('intra-tumour', 'Disease', (18, 30))	('mutations', 'Var', (74, 83))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('intra-tumour', 'Disease', 'MESH:D009369', (18, 30))	('copy number variations', 'Var', (96, 118))
196074	33946379	The assessment of whole-exome and transcriptomic sequencing data from paired tumour biopsies along with a matched normal biopsy from 16 ccRCC patients revealed an average of 40% of mutations were private and 31% of genes were differentially expressed in only a single biopsy.	('paired tumour', 'Disease', (70, 83))	('RCC', 'Disease', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('mutations', 'Var', (181, 190))	('patients', 'Species', '9606', (142, 150))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('paired tumour', 'Disease', 'MESH:D009369', (70, 83))
196077	33946379	The coverage of the whole-exome sequencing (WES) data was on average 85x, and mutation calling (see Methods) identified between 29 and 130 single-nucleotide variants (SNVs), insertions, and deletions (indels) per patient (Figure 2A).	('deletions', 'Var', (190, 199))	('single-nucleotide variants', 'Var', (139, 165))	('insertions', 'Var', (174, 184))	('patient', 'Species', '9606', (213, 220))
196078	33946379	The fraction of mutations that was only detected in one of the two biopsies from the same tumour was on average 40%, which indicates high levels of intra-tumour genetic diversity.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('intra-tumour', 'Disease', 'MESH:D009369', (148, 160))	('intra-tumour', 'Disease', (148, 160))	('mutations', 'Var', (16, 25))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumour', 'Disease', (154, 160))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('tumour', 'Disease', (90, 96))
196092	33946379	The number of SNVs as well as indels in the panel-seq data set was on average 22 per patient (Figure 3, top panel).	('SNVs', 'Var', (14, 18))	('patient', 'Species', '9606', (85, 92))	('indels', 'Var', (30, 36))
196093	33946379	Pairwise comparison of the two biopsies from the same tumour revealed that on average, 62% of the mutations in a patient were private to one of the two samples with 87 of the 89 tumours (98%) containing at least one private mutation.	('patient', 'Species', '9606', (113, 120))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumours', 'Phenotype', 'HP:0002664', (178, 185))	('tumour', 'Disease', (54, 60))	('tumours', 'Disease', 'MESH:D009369', (178, 185))	('tumour', 'Disease', 'MESH:D009369', (178, 184))	('mutations', 'Var', (98, 107))	('tumour', 'Disease', (178, 184))	('tumours', 'Disease', (178, 185))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
196096	33946379	Three mucin genes: MUC6 (42%), MUC16 (38%), and MUC3A (18%) were also frequently mutated in our cohort.	('mucin', 'Gene', '100508689', (6, 11))	('mucin', 'Gene', (6, 11))	('MUC6', 'Gene', (19, 23))	('mutated', 'Var', (81, 88))	('MUC16', 'Gene', '94025', (31, 36))	('MUC3A', 'Gene', '4584', (48, 53))	('MUC3A', 'Gene', (48, 53))	('MUC6', 'Gene', '4588', (19, 23))	('MUC16', 'Gene', (31, 36))
196099	33946379	Interestingly, in nine patients, the VHL mutations resided in only one of the two tumour samples.	('mutations', 'Var', (41, 50))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('VHL', 'Gene', (37, 40))	('patients', 'Species', '9606', (23, 31))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('VHL', 'Gene', '7428', (37, 40))	('tumour', 'Disease', (82, 88))
196100	33946379	The mutations in VHL are known to occur early in tumour development, which is in line with our observation that in 39 of 48 (81%) cases, the VHL mutations were shared between both tumour biopsies of a patient.	('tumour', 'Disease', (180, 186))	('VHL', 'Gene', '7428', (141, 144))	('mutations', 'Var', (145, 154))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('VHL', 'Gene', (17, 20))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('mutations', 'Var', (4, 13))	('VHL', 'Gene', '7428', (17, 20))	('patient', 'Species', '9606', (201, 208))	('VHL', 'Gene', (141, 144))	('tumour', 'Disease', (49, 55))
196103	33946379	Of the most frequently affected genes (Figure 3), three private mutations were found in VHL, PBRML1, and SETD2 within TU2 of patient 16, whereas 14 private mutations were identified in TU1.	('SETD2', 'Gene', '29072', (105, 110))	('affected', 'Reg', (23, 31))	('VHL', 'Gene', (88, 91))	('SETD2', 'Gene', (105, 110))	('PBRML1', 'Gene', (93, 99))	('VHL', 'Gene', '7428', (88, 91))	('mutations', 'Var', (64, 73))	('patient', 'Species', '9606', (125, 132))	('TU2', 'Chemical', '-', (118, 121))
196105	33946379	In patient 55, all seven private mutations in the most frequently mutated genes occurred in TU2, while in patient 57, 13 private mutations were found in TU2.	('TU2', 'Chemical', '-', (92, 95))	('patient', 'Species', '9606', (106, 113))	('occurred', 'Reg', (80, 88))	('patient', 'Species', '9606', (3, 10))	('mutations', 'Var', (33, 42))	('TU2', 'Gene', (92, 95))	('TU2', 'Chemical', '-', (153, 156))
196106	33946379	Like patient 16, two private mutations in each tumour sample of patient 57 impacted the same gene; however, in patient 57, that gene is LRP2.	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('patient', 'Species', '9606', (5, 12))	('patient', 'Species', '9606', (64, 71))	('LRP2', 'Gene', (136, 140))	('mutations', 'Var', (29, 38))	('tumour', 'Disease', (47, 53))	('LRP2', 'Gene', '4036', (136, 140))	('patient', 'Species', '9606', (111, 118))	('impacted', 'Reg', (75, 83))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
196108	33946379	In patient 88, the gene PBRM1 was hit by different mutations in the two tumour samples, demonstrating a pattern of convergent phenotypic evolution where a gene is affected by multiple distinct mutations across the clones in the tumour.	('tumour', 'Disease', (228, 234))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('patient', 'Species', '9606', (3, 10))	('PBRM1', 'Gene', (24, 29))	('mutations', 'Var', (193, 202))	('PBRM1', 'Gene', '55193', (24, 29))	('tumour', 'Disease', 'MESH:D009369', (228, 234))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))	('tumour', 'Disease', (72, 78))	('affected', 'Reg', (163, 171))
196109	33946379	One tumour sample, TU1, had a frameshift deletion and a missense mutation, while the other tumour sample, TU2, had a missense mutation at a different locus in PBRM1.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('TU2', 'Chemical', '-', (106, 109))	('tumour', 'Disease', (91, 97))	('missense mutation', 'Var', (56, 73))	('frameshift deletion', 'Var', (30, 49))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))	('PBRM1', 'Gene', (159, 164))	('PBRM1', 'Gene', '55193', (159, 164))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
196110	33946379	Both subclonal missense mutations of PBRM1 are predicted to be deleterious according to the SIFT annotation.	('PBRM1', 'Gene', (37, 42))	('missense mutations', 'Var', (15, 33))	('PBRM1', 'Gene', '55193', (37, 42))
196117	33946379	The two most striking clonally exclusive pathway pairs, i.e., pathways that are aberrated in different clones of the same tumour in a mutually exclusive fashion, are "major pathway of rRNA processing in the nucleolus and cytosol" (referred to as pathway 1), "O-glycosylation of TSR domain-containing proteins" (pathway 2)}, and pathway 1, "defective B3GALTL causes Peters-plus syndrome (PpS)" (pathway 3), which are clonally exclusive in both patients in which they are affected (Figure 4A,B, Supplementary Table S3), namely, patients 8 and 14 (p < 10-5).	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('defective', 'Var', (340, 349))	('tumour', 'Disease', (122, 128))	('patients', 'Species', '9606', (443, 451))	('B3GALTL', 'Gene', '145173', (350, 357))	('Peters-plus syndrome', 'Disease', 'MESH:C537617', (365, 385))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('B3GALTL', 'Gene', (350, 357))	('Peters-plus syndrome', 'Disease', (365, 385))	('patients', 'Species', '9606', (526, 534))
196126	33946379	In the first phase, the investigation of the WES and RNA-seq data of 16 ccRCC patients revealed that intra-tumour heterogeneity is very pronounced on the genetic level, with an average of 40% of mutations found to be private.	('intra-tumour', 'Disease', 'MESH:D009369', (101, 113))	('RNA', 'cellular_component', 'GO:0005562', ('53', '56'))	('patients', 'Species', '9606', (78, 86))	('RCC', 'Disease', (74, 77))	('intra-tumour', 'Disease', (101, 113))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('mutations', 'Var', (195, 204))
196134	33946379	Tumourigenesis typically starts with a large deletion on chromosome 3p, followed by mutational VHL inactivation.	('VHL', 'Gene', (95, 98))	('mutational', 'Var', (84, 94))	('VHL', 'Gene', '7428', (95, 98))	('chromosome', 'cellular_component', 'GO:0005694', ('57', '67'))	('inactivation', 'NegReg', (99, 111))	('Tumourigenesis', 'CPA', (0, 14))	('deletion', 'Var', (45, 53))
196136	33946379	Since VHL inactivation alone is insufficient, mutations in PBRM1 and BAP1 are necessary for ccRCC development.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('mutations', 'Var', (46, 55))	('BAP1', 'Gene', (69, 73))	('PBRM1', 'Gene', (59, 64))	('PBRM1', 'Gene', '55193', (59, 64))	('VHL', 'Gene', (6, 9))	('VHL', 'Gene', '7428', (6, 9))	('BAP1', 'Gene', '8314', (69, 73))
196137	33946379	Interestingly, we have seen VHL mutations in only one of the two tumour samples in nine out of eighty-nine patients.	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (32, 41))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('VHL', 'Gene', (28, 31))	('patients', 'Species', '9606', (107, 115))	('tumour', 'Disease', (65, 71))	('VHL', 'Gene', '7428', (28, 31))
196140	33946379	In addition, some of the genes were affected by multiple distinct mutations across the clones in the tumour.	('mutations', 'Var', (66, 75))	('affected', 'Reg', (36, 44))	('tumour', 'Disease', (101, 107))	('genes', 'Gene', (25, 30))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
196142	33946379	PBRM1 mutations occur in 19% of the patients in our cohort, which is less than the frequency reported from TCGA.	('PBRM1', 'Gene', '55193', (0, 5))	('PBRM1', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('patients', 'Species', '9606', (36, 44))
196143	33946379	We found a pattern of convergent phenotypic evolution in PBRM1: the gene was hit by two different deleterious missense mutations in each of the two biopsies of one patient.	('patient', 'Species', '9606', (164, 171))	('PBRM1', 'Gene', (57, 62))	('missense mutations', 'Var', (110, 128))	('PBRM1', 'Gene', '55193', (57, 62))
196145	33946379	In the TCGA data set, the mucins MUC4, and MUC16 were also among the seven most frequently mutated genes, but our mutation frequencies of MUC6, MUC16, and MUC3A are 42%, 38%, and 18%, higher than those reported in TCGA.	('MUC16', 'Gene', '94025', (43, 48))	('MUC3A', 'Gene', '4584', (155, 160))	('MUC6', 'Gene', (138, 142))	('mucin', 'Gene', (26, 31))	('MUC16', 'Gene', '94025', (144, 149))	('MUC16', 'Gene', (43, 48))	('MUC4', 'Gene', '4585', (33, 37))	('MUC6', 'Gene', '4588', (138, 142))	('mutation', 'Var', (114, 122))	('MUC3A', 'Gene', (155, 160))	('MUC4', 'Gene', (33, 37))	('mucin', 'Gene', '100508689', (26, 31))	('MUC16', 'Gene', (144, 149))
196151	33946379	How mutations in SEA domains affect MUC16's function and contribute to its release in the serum in ccRCC patients remains to be evaluated.	('release in the serum', 'MPA', (75, 95))	('patients', 'Species', '9606', (105, 113))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('affect', 'Reg', (29, 35))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('RCC', 'Disease', (101, 104))	('MUC16', 'Gene', (36, 41))	('MUC16', 'Gene', '94025', (36, 41))	('mutations', 'Var', (4, 13))	('SEA domains', 'Gene', (17, 28))	('function', 'MPA', (44, 52))
196152	33946379	It was shown that in lung cancer, MUC16 mutations can lead to its oncogenic upregulation and the overexpression of MUC16 is associated with increased tumour cell growth, cancer cell migration, and resistance to cytotoxic drugs.	('MUC16', 'Gene', '94025', (34, 39))	('cancer', 'Disease', (170, 176))	('cancer', 'Disease', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('increased', 'PosReg', (140, 149))	('cell growth', 'biological_process', 'GO:0016049', ('157', '168'))	('MUC16', 'Gene', (115, 120))	('lung cancer', 'Disease', (21, 32))	('mutations', 'Var', (40, 49))	('MUC16', 'Gene', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('oncogenic', 'MPA', (66, 75))	('lung cancer', 'Disease', 'MESH:D008175', (21, 32))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('overexpression', 'PosReg', (97, 111))	('upregulation', 'PosReg', (76, 88))	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('tumour', 'Disease', (150, 156))	('cell migration', 'biological_process', 'GO:0016477', ('177', '191'))	('MUC16', 'Gene', '94025', (115, 120))
196153	33946379	Recent studies also discovered frequent non-silent MUC16 mutations in breast cancer, another cancer type in which MUC16 was observed to be overexpressed.	('MUC16', 'Gene', (51, 56))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('MUC16', 'Gene', (114, 119))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mutations', 'Var', (57, 66))	('breast cancer', 'Disease', (70, 83))	('MUC16', 'Gene', '94025', (51, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('MUC16', 'Gene', '94025', (114, 119))
196154	33946379	Furthermore, MUC16 mutations have been implicated as cancer-driving in a pan-cancer analysis that assessed the functional impact of mutations on differential gene expression profiles.	('implicated', 'Reg', (39, 49))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('MUC16', 'Gene', '94025', (13, 18))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('mutations', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('MUC16', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('gene expression', 'biological_process', 'GO:0010467', ('158', '173'))
196155	33946379	The majority of mucin gene mutations found in our cohort have a low variant allele frequency (VAF).	('mutations', 'Var', (27, 36))	('variant allele frequency', 'MPA', (68, 92))	('mucin', 'Gene', (16, 21))	('mucin', 'Gene', '100508689', (16, 21))
196156	33946379	Specifically, more than 75% of the mutations in MUC6, MUC16, and MUC3A have a VAF below 10%, and almost half below 5%.	('MUC16', 'Gene', '94025', (54, 59))	('MUC6', 'Gene', (48, 52))	('VAF', 'MPA', (78, 81))	('MUC6', 'Gene', '4588', (48, 52))	('MUC16', 'Gene', (54, 59))	('MUC3A', 'Gene', (65, 70))	('below', 'NegReg', (82, 87))	('MUC3A', 'Gene', '4584', (65, 70))	('mutations', 'Var', (35, 44))
196162	33946379	TP53, a well-known tumour suppressor, was found to be mutated in less than 10% of ccRCC, which is confirmed in the cohort analysed here (9%).	('tumour', 'Disease', 'MESH:D009369', (19, 25))	('TP53', 'Gene', '7157', (0, 4))	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('TP53', 'Gene', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('tumour', 'Disease', (19, 25))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('mutated', 'Var', (54, 61))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
196163	33946379	TP53 mutations were associated with the reduced survival of renal cancer patients.	('survival', 'MPA', (48, 56))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mutations', 'Var', (5, 14))	('reduced', 'NegReg', (40, 47))	('renal cancer', 'Disease', (60, 72))	('patients', 'Species', '9606', (73, 81))	('renal cancer', 'Disease', 'MESH:D007680', (60, 72))	('renal cancer', 'Phenotype', 'HP:0009726', (60, 72))
196164	33946379	Of note, a previous study of the intra-tumour diversity in ten ccRCC cases revealed that mutation in TP53 were one of the most extreme examples of gene mutations being detected more often when sequencing multiple biopsies per tumour instead of a single one.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('tumour', 'Disease', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (226, 232))	('TP53', 'Gene', '7157', (101, 105))	('mutation', 'Var', (89, 97))	('intra-tumour', 'Disease', 'MESH:D009369', (33, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('TP53', 'Gene', (101, 105))	('tumour', 'Disease', (226, 232))	('intra-tumour', 'Disease', (33, 45))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
196166	33946379	This observation suggests that TP53 mutations may be a crucial subclonal event in ccRCC and explains the low prevalence of TP53 mutations in earlier studies.	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('mutations', 'Var', (36, 45))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (123, 127))
196167	33946379	have evaluated somatic alterations across different histological subtypes and reported a lower prevalence of PBRM1 mutations in ccRCC with sarcomatoid differentiation, whereas TP53 mutations had an increased prevalence in non-ccRCC with sarcomatoid differentiation.	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('lower', 'NegReg', (89, 94))	('mutations', 'Var', (115, 124))	('PBRM1', 'Gene', (109, 114))	('sarcomatoid differentiation', 'Disease', (237, 264))	('RCC', 'Disease', 'MESH:C538614', (228, 231))	('RCC', 'Disease', (228, 231))	('TP53', 'Gene', '7157', (176, 180))	('RCC', 'Phenotype', 'HP:0005584', (228, 231))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('ccRCC', 'Phenotype', 'HP:0006770', (226, 231))	('PBRM1', 'Gene', '55193', (109, 114))	('sarcomatoid differentiation', 'Disease', 'MESH:C538614', (237, 264))	('TP53', 'Gene', (176, 180))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('sarcomatoid differentiation', 'Disease', (139, 166))	('sarcomatoid differentiation', 'Disease', 'MESH:C538614', (139, 166))
196169	33946379	Similar to non-ccRCC with sarcomatoid differentiation, subclonal TP53 mutations could also be a first molecular step into the development of an aggressive phenotype of ccRCC leading to sarcomatoid differentiation.	('sarcomatoid differentiation', 'Disease', (26, 53))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('sarcomatoid differentiation', 'Disease', 'MESH:C538614', (26, 53))	('RCC', 'Disease', (170, 173))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('sarcomatoid differentiation', 'Disease', (185, 212))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('ccRCC', 'Phenotype', 'HP:0006770', (168, 173))	('sarcomatoid differentiation', 'Disease', 'MESH:C538614', (185, 212))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (15, 20))
196170	33946379	have recently identified seven ccRCC subtypes with specific angiogenesis, immune, metabolic, stromal, and cell-cycle profiles showing differential clinical outcomes to VEGF blockade alone or in combination with anti-PD-L1.	('blockade', 'Var', (173, 181))	('VEGF', 'Gene', '7422', (168, 172))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('PD-L1', 'Gene', (216, 221))	('RCC', 'Disease', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('angiogenesis', 'biological_process', 'GO:0001525', ('60', '72'))	('cell-cycle', 'biological_process', 'GO:0007049', ('106', '116'))	('ccRCC', 'Phenotype', 'HP:0006770', (31, 36))	('PD-L1', 'Gene', '29126', (216, 221))	('VEGF', 'Gene', (168, 172))
196171	33946379	These molecular clades have a differential prevalence of TP53, PBRM1, KDM5C, and CDKN2A/2B alterations.	('CDKN2A/2B', 'Gene', '1029', (81, 90))	('TP53', 'Gene', '7157', (57, 61))	('CDKN2A/2B', 'Gene', (81, 90))	('PBRM1', 'Gene', (63, 68))	('alterations', 'Var', (91, 102))	('PBRM1', 'Gene', '55193', (63, 68))	('KDM5C', 'Gene', (70, 75))	('TP53', 'Gene', (57, 61))	('KDM5C', 'Gene', '8242', (70, 75))
196172	33946379	Our observation of subclonal TP53 mutations suggests that primarily tissue samples with sarcomatoid differentiation may display high levels of intra-tumour heterogeneity.	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('sarcomatoid differentiation', 'Disease', 'MESH:C538614', (88, 115))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('intra-tumour', 'Disease', 'MESH:D009369', (143, 155))	('sarcomatoid differentiation', 'Disease', (88, 115))	('intra-tumour', 'Disease', (143, 155))	('mutations', 'Var', (34, 43))
196175	33946379	Underrating the mutational burden due to spatial heterogeneity of gene alterations is thus a common problem in cancer research as well as in molecular tumour diagnostics.	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('alterations', 'Var', (71, 82))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('tumour', 'Disease', (151, 157))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
196178	33946379	These differences could arise due to differences in tumour purity or perhaps aberrations affecting genes needed for DNA damage repair, resulting in an accumulation of mutations.	('mutations', 'MPA', (167, 176))	('accumulation', 'PosReg', (151, 163))	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour purity', 'Disease', (52, 65))	('arise', 'Reg', (24, 29))	('tumour purity', 'Disease', 'MESH:D009369', (52, 65))	('aberrations', 'Var', (77, 88))
196180	33946379	Missense mutations were found in both ERCC1 and POLR2A in TU1 of patient 16.	('POLR2A', 'Gene', (48, 54))	('ERCC1', 'Gene', '2067', (38, 43))	('ERCC1', 'Gene', (38, 43))	('POLR2A', 'Gene', '5430', (48, 54))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('patient', 'Species', '9606', (65, 72))	('Missense mutations', 'Var', (0, 18))
196184	33946379	Dysfunction in just one of these proteins may lead to an increase in the number of mutations, as seen in TU1 of patient 16.	('mutations', 'Var', (83, 92))	('patient', 'Species', '9606', (112, 119))	('increase', 'PosReg', (57, 65))	('Dysfunction', 'Var', (0, 11))
196185	33946379	In TU2 of patient 55, we identified downstream intron variants of XPC that produce a protein of the same name functioning to recognise DNA damage during the global genome-nucleotide excision repair pathway.	('XPC', 'Gene', '7508', (66, 69))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('TU2', 'Chemical', '-', (3, 6))	('patient', 'Species', '9606', (10, 17))	('variants', 'Var', (54, 62))	('global genome-nucleotide excision repair', 'biological_process', 'GO:0070911', ('157', '197'))	('XPC', 'Gene', (66, 69))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
196186	33946379	Although these XPC variants have not been classed as altering XPC function, given the large difference seen between TU1 and TU2 in patient 55, these variants may be a cause of the accumulation of mutations observed in the second biopsy.	('XPC', 'Gene', '7508', (62, 65))	('XPC', 'Gene', (15, 18))	('mutations', 'MPA', (196, 205))	('TU2', 'Chemical', '-', (124, 127))	('variants', 'Var', (149, 157))	('XPC', 'Gene', '7508', (15, 18))	('XPC', 'Gene', (62, 65))	('patient', 'Species', '9606', (131, 138))
196190	33946379	The two most striking pathway pairs include "major pathway of rRNA processing in the nucleolus and cytosol" (pathway 1), which is clonally exclusive with "O-glycosylation of TSR domain-containing proteins" (pathway 2) and "defective B3GALTL causes Peters-plus syndrome (PpS)" (pathway 3) (Figure 4A).	('defective', 'Var', (223, 232))	('causes', 'Reg', (241, 247))	('Peters-plus syndrome', 'Disease', 'MESH:C537617', (248, 268))	('B3GALTL', 'Gene', '145173', (233, 240))	('Peters-plus syndrome', 'Disease', (248, 268))	('B3GALTL', 'Gene', (233, 240))
196195	33946379	The deregulation may arise due to the mutations in THSD4 and ADAMTS14, which are members of these pathways.	('THSD4', 'Gene', '79875', (51, 56))	('ADAMTS14', 'Gene', (61, 69))	('deregulation', 'MPA', (4, 16))	('THSD4', 'Gene', (51, 56))	('mutations', 'Var', (38, 47))	('ADAMTS14', 'Gene', '140766', (61, 69))
196219	33946379	An imbalanced heterozygous germline SNP is a SNP that has a VAF between 40-60% in the normal sample, but in the tumour sample the VAF is out of these bounds, indicating a potential copy number change.	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('VAF', 'MPA', (60, 63))	('tumour', 'Disease', (112, 118))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('copy number change', 'Var', (181, 199))
196228	33946379	The generated read data from the clear cell renal cell carcinoma samples and the matched normal samples have been deposited in the European Nucleotide Archive under accession numbers ERP108328 and ERP108326.	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (33, 64))	('ERP108326', 'Var', (197, 206))	('clear cell renal cell carcinoma', 'Disease', (33, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('ERP108328', 'Var', (183, 192))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (33, 64))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (44, 64))
196234	29866440	Also, surprisingly, PPARgamma deletion had little effect on the robust lipid accumulation that typifies the "clear cell" phenotype of kidney cancer.	('kidney cancer', 'Disease', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('deletion', 'Var', (30, 38))	('PPARgamma', 'Gene', (20, 29))	('robust lipid accumulation', 'MPA', (64, 89))	('lipid', 'Chemical', 'MESH:D008055', (71, 76))	('kidney cancer', 'Phenotype', 'HP:0009726', (134, 147))	('kidney cancer', 'Disease', 'MESH:D007680', (134, 147))
196249	29866440	Interestingly, conditional deletion of Pparg within hepatocytes abrogated liver steatosis, suggesting a link between PPARgamma and lipid uptake, synthesis, and/or storage in this model.	('liver steatosis', 'Disease', 'MESH:D005234', (74, 89))	('synthesis', 'biological_process', 'GO:0009058', ('145', '154'))	('Pparg', 'Gene', (39, 44))	('deletion', 'Var', (27, 35))	('lipid', 'Chemical', 'MESH:D008055', (131, 136))	('storage', 'biological_process', 'GO:0051235', ('163', '170'))	('liver steatosis', 'Phenotype', 'HP:0001397', (74, 89))	('Pparg', 'Gene', '5468', (39, 44))	('liver steatosis', 'Disease', (74, 89))	('abrogated', 'NegReg', (64, 73))	('lipid uptake', 'biological_process', 'GO:0140354', ('131', '143'))
196251	29866440	In vitro studies investigating the role of PPARgamma in ccRCC and other cancers have largely employed natural and synthetic activating ligands including the insulin-sensitizing thiazolidinediones, yet many used super-physiologic concentrations, which can cause off-target effects and confound interpretation of results.	('thiazolidinediones', 'Chemical', 'MESH:D045162', (177, 195))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('super-physiologic', 'Var', (211, 228))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('ccRCC', 'Disease', (56, 61))	('insulin', 'molecular_function', 'GO:0016088', ('157', '164'))
196265	29866440	All experiments were performed with cells that survived puromycin selection and displayed knockdown/knockout of PPARG as assayed by western blot.	('PPARG', 'Gene', (112, 117))	('knockdown/knockout', 'Var', (90, 108))	('PPARG', 'Gene', '5468', (112, 117))	('puromycin', 'Chemical', 'MESH:D011691', (56, 65))
196271	29866440	Hs02800695_m1) and TBP (Hs00427620_m1).	('Hs02800695_m1', 'Var', (0, 13))	('TBP', 'Gene', (19, 22))	('TBP', 'Gene', '6908', (19, 22))	('Hs00427620_m1', 'Var', (24, 37))
196338	29866440	Surprisingly, we found that loss of PPARgamma did not affect lipid accumulation in either ccRCC cell line tested in vitro by Oil Red O (Figure 5A) or BODIPY 493/503 (Figure 5B) staining.	('loss', 'Var', (28, 32))	('Oil Red O', 'Chemical', 'MESH:C011049', (125, 134))	('PPARgamma', 'Gene', (36, 45))	('lipid accumulation', 'MPA', (61, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('lipid', 'Chemical', 'MESH:D008055', (61, 66))
196339	29866440	In agreement with this, expression of a number of proteins involved in de novo lipogenesis that are reduced following hepatocyte-specific deletion of PPARgamma, including sterol regulatory element-binding protein 1 (SREBP1), fatty acid synthase (FASN), and stearoyl-CoA desaturase 1 (SCD), did not change substantially following PPARgamma loss in our models (Figure 5C).	('FASN', 'Gene', (246, 250))	('protein', 'cellular_component', 'GO:0003675', ('205', '212'))	('lipogenesis', 'biological_process', 'GO:0008610', ('79', '90'))	('sterol regulatory element-binding protein 1', 'Gene', '6720', (171, 214))	('SREBP1', 'Gene', '6720', (216, 222))	('loss', 'NegReg', (339, 343))	('fatty acid synthase', 'Gene', '2194', (225, 244))	('expression', 'MPA', (24, 34))	('SREBP1', 'Gene', (216, 222))	('stearoyl-CoA desaturase 1', 'Gene', (257, 282))	('lipogenesis', 'MPA', (79, 90))	('hepatocyte-specific', 'MPA', (118, 137))	('FASN', 'Gene', '2194', (246, 250))	('sterol regulatory element-binding protein 1', 'Gene', (171, 214))	('stearoyl-CoA desaturase 1', 'Gene', '6319', (257, 282))	('PPARgamma', 'Gene', (150, 159))	('deletion', 'Var', (138, 146))	('SCD', 'Gene', '6319', (284, 287))	('SCD', 'Gene', (284, 287))	('reduced', 'NegReg', (100, 107))	('fatty acid synthase', 'Gene', (225, 244))	('binding', 'molecular_function', 'GO:0005488', ('197', '204'))
196343	29866440	"Druggability" of nuclear receptors via small molecule agonists or antagonists make them appealing therapeutic targets to treat diseases like diabetes and cancer.	('diabetes', 'Disease', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('antagonists', 'Var', (67, 78))	('diabetes', 'Disease', 'MESH:D003920', (142, 150))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
196346	29866440	We hypothesized that PPARgamma would promote ccRCC tumorigenesis due to the fact that its lipid-laden phenotype is tightly linked to cell viability and proliferation.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('promote', 'PosReg', (37, 44))	('PPARgamma', 'Var', (21, 30))	('tumor', 'Disease', (51, 56))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('lipid', 'Chemical', 'MESH:D008055', (90, 95))	('ccRCC', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
196350	29866440	PPARgamma deletion in two ccRCC cell lines affected neither viability, proliferation, migratory capacity in vitro, nor tumor growth in a subcutaneous xenograft model.	('tumor', 'Disease', (119, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (26, 31))	('PPARgamma', 'Gene', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('deletion', 'Var', (10, 18))	('proliferation', 'CPA', (71, 84))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('migratory capacity', 'CPA', (86, 104))
196362	29866440	Ectopic expression of such factors in ccRCC reduces tumor growth, further illustrating the importance of reprogramming lipid metabolism from an oxidative to anabolic state in this tumor type.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('lipid', 'Chemical', 'MESH:D008055', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (52, 57))	('lipid metabolism', 'biological_process', 'GO:0006629', ('119', '135'))	('Ectopic expression', 'Var', (0, 18))	('tumor', 'Disease', (180, 185))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('ccRCC', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('reduces', 'NegReg', (44, 51))
196376	31484429	The cytogenetic differences are a trisomy 7 and 17 in pRCC type I and the loss of 1p and 3p in pRCC type II tumors.	('pRCC type II tumors', 'Disease', 'MESH:D009369', (95, 114))	('trisomy 7', 'Var', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('pRCC', 'Gene', (95, 99))	('pRCC type II tumors', 'Disease', (95, 114))	('loss', 'NegReg', (74, 78))	('pRCC', 'Gene', '5546', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('pRCC', 'Gene', '5546', (95, 99))	('pRCC', 'Gene', (54, 58))
196377	31484429	Intra- and interchromosomal rearrangements are significantly increased in pRCC type II, leading frequently to a gene fusion involving the transcription factor TFE3, by which the promoter substitution appears to be the key molecular event, causing dysregulation of many signaling pathways already implicated in carcinogenesis.	('TFE3', 'Gene', (159, 163))	('signaling', 'biological_process', 'GO:0023052', ('269', '278'))	('transcription factor', 'molecular_function', 'GO:0000981', ('138', '158'))	('TFE3', 'Gene', '7030', (159, 163))	('increased', 'PosReg', (61, 70))	('pRCC', 'Gene', '5546', (74, 78))	('causing', 'Reg', (239, 246))	('carcinogenesis', 'Disease', 'MESH:D063646', (310, 324))	('signaling pathways', 'Pathway', (269, 287))	('transcription', 'biological_process', 'GO:0006351', ('138', '151'))	('dysregulation', 'MPA', (247, 260))	('carcinogenesis', 'Disease', (310, 324))	('substitution', 'Var', (187, 199))	('pRCC', 'Gene', (74, 78))
196378	31484429	Type I of this malignant tumor is characterized by frequent mutations in the MET oncogene, including alternative splice variants.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('malignant tumor', 'Disease', (15, 30))	('MET oncogene', 'Gene', (77, 89))	('malignant tumor', 'Disease', 'MESH:D009369', (15, 30))	('mutations', 'Var', (60, 69))
196380	31484429	Type II has more likely mutations such as SETD2, NF2, and the inactivation of CDKN2A by mutation, deletion, or CpG island hypermethylation.	('mutation', 'Var', (88, 96))	('NF2', 'Gene', (49, 52))	('CDKN2A', 'Gene', (78, 84))	('inactivation', 'NegReg', (62, 74))	('deletion', 'Var', (98, 106))	('CDKN2A', 'Gene', '1029', (78, 84))	('SETD2', 'Gene', '29072', (42, 47))	('NF2', 'Gene', '4771', (49, 52))	('SETD2', 'Gene', (42, 47))
196381	31484429	Structural variants were observed in sporadic events, including duplications in EGFR and HIF1A, and deletions in SDHB, DNMT3A, and STAG2.	('SDHB', 'Gene', '6390', (113, 117))	('HIF1A', 'Gene', (89, 94))	('HIF1A', 'Gene', '3091', (89, 94))	('duplications', 'Var', (64, 76))	('STAG2', 'Gene', (131, 136))	('STAG2', 'Gene', '10735', (131, 136))	('DNMT3A', 'Gene', (119, 125))	('SDHB', 'Gene', (113, 117))	('EGFR', 'Gene', '1956', (80, 84))	('DNMT3A', 'Gene', '1788', (119, 125))	('EGFR', 'Gene', (80, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('deletions', 'Var', (100, 109))
196384	31484429	pRCC type II tumors are more likely to metastasize, and FH mutations and DNA hypermethylation were found to be correlate with inferior prognosis.	('N', 'Chemical', 'MESH:D009584', (74, 75))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('pRCC type II tumors', 'Disease', 'MESH:D009369', (0, 19))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('73', '93'))	('pRCC type II tumors', 'Disease', (0, 19))	('metastasize', 'CPA', (39, 50))	('FH', 'Disease', 'OMIM:143890', (56, 58))	('mutations', 'Var', (59, 68))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('hypermethylation', 'Var', (77, 93))
196387	31484429	Nephrectomy or partial nephrectomy and in the presence of metastases, and treatment with vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors are currently considered the standard treatments.	('VEGF', 'Gene', (125, 129))	('partial', 'Var', (15, 22))	('vascular endothelial growth factor', 'Gene', (89, 123))	('mTOR', 'Gene', (166, 170))	('mTOR', 'Gene', '2475', (166, 170))	('vascular endothelial growth factor', 'Gene', '7422', (89, 123))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('89', '123'))	('VEGF', 'Gene', '7422', (125, 129))	('metastases', 'Disease', (58, 68))	('mammalian target of rapamycin', 'Gene', '2475', (135, 164))	('mammalian target of rapamycin', 'Gene', (135, 164))	('metastases', 'Disease', 'MESH:D009362', (58, 68))
196397	31484429	The assembly of mitochondrial whole-exome sequencing (WES) reads derived from 19 patients with pRCC and matched with adjacent healthy kidney tissues showed adequate coverage and quality for reliable mtDNA reconstruction and variant calling (Table S3).	('mtDNA', 'cellular_component', 'GO:0000262', ('199', '204'))	('pRCC', 'Gene', (95, 99))	('patients', 'Species', '9606', (81, 89))	('pRCC', 'Gene', '5546', (95, 99))	('N', 'Chemical', 'MESH:D009584', (202, 203))	('variant', 'Var', (224, 231))
196399	31484429	A total of 260 somatic mtDNA mutations were detected in pRCC samples.	('N', 'Chemical', 'MESH:D009584', (26, 27))	('pRCC', 'Gene', '5546', (56, 60))	('mutations', 'Var', (29, 38))	('mtDNA', 'cellular_component', 'GO:0000262', ('23', '28'))	('mtDNA', 'Gene', (23, 28))	('detected', 'Reg', (44, 52))	('pRCC', 'Gene', (56, 60))
196402	31484429	An analysis of copy number variations (CNV) revealed a fragmented pattern of chromosomal gains and losses spread over all chromosomes in all pRCC types (Figure S2), but no clear chromosomal patterns were identified.	('pRCC', 'Gene', '5546', (141, 145))	('N', 'Chemical', 'MESH:D009584', (40, 41))	('chromosomal', 'Var', (77, 88))	('losses', 'NegReg', (99, 105))	('gains', 'PosReg', (89, 94))	('pRCC', 'Gene', (141, 145))
196419	31484429	This was explained by several specific low-level heteroplasmic mtDNA mutations of the CI genes in renal oncocytomas.	('mutations', 'Var', (69, 78))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (98, 115))	('mtDNA', 'cellular_component', 'GO:0000262', ('63', '68'))	('renal oncocytomas', 'Disease', (98, 115))	('N', 'Chemical', 'MESH:D009584', (66, 67))	('renal oncocytomas', 'Disease', 'MESH:C537750', (98, 115))
196460	31484429	Tracing of 13C515N glutamic acid revealed a significant and (6.3-, 3.9-fold) increase of 13C515N proline after 12 h in the pRCC derived cell lines Caki-2 and ACHN versus HK-2 (Figure 6K).	('pRCC', 'Gene', '5546', (123, 127))	('13C515N proline', 'Chemical', 'MESH:C513342', (89, 104))	('N', 'Chemical', 'MESH:D009584', (95, 96))	('HK-2', 'Gene', '3099', (170, 174))	('pRCC', 'Gene', (123, 127))	('N', 'Chemical', 'MESH:D009584', (161, 162))	('HK-2', 'molecular_function', 'GO:0008256', ('170', '174'))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('13C515N glutamic acid', 'Chemical', 'MESH:C513342', (11, 32))	('increase', 'PosReg', (77, 85))	('HK-2', 'Gene', (170, 174))	('13C515N', 'Var', (89, 96))
196470	31484429	Blocking of mTOR activity was shown to augment shuttling of pyruvate into gluconeogenesis, which results in futile cycling of glucose that finally leads to a halt in cancer cell proliferation and ultimately to cell death.	('cancer', 'Disease', (166, 172))	('halt', 'NegReg', (158, 162))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('leads to', 'Reg', (147, 155))	('results in', 'Reg', (97, 107))	('Blocking', 'Var', (0, 8))	('cell death', 'biological_process', 'GO:0008219', ('210', '220'))	('cell proliferation', 'biological_process', 'GO:0008283', ('173', '191'))	('shuttling of pyruvate into gluconeogenesis', 'MPA', (47, 89))	('mTOR', 'Gene', '2475', (12, 16))	('mTOR', 'Gene', (12, 16))	('gluconeogenesis', 'biological_process', 'GO:0006094', ('74', '89'))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('glucose', 'Chemical', 'MESH:D005947', (126, 133))	('augment', 'PosReg', (39, 46))	('futile cycling of glucose', 'MPA', (108, 133))	('pyruvate', 'Chemical', 'MESH:D011773', (60, 68))
196484	31484429	Furthermore, silencing ALDOA expression in ccRCC cell lines decreased their proliferative, migratory, and invasive abilities, while ALDOA overexpression increased these abilities.	('proliferative', 'CPA', (76, 89))	('decreased', 'NegReg', (60, 69))	('ALDOA', 'Gene', (23, 28))	('ALDOA', 'Gene', (132, 137))	('invasive abilities', 'Disease', 'MESH:D009361', (106, 124))	('silencing', 'Var', (13, 22))	('invasive abilities', 'Disease', (106, 124))	('migratory', 'CPA', (91, 100))	('ALDOA', 'Gene', '226', (132, 137))	('ALDOA', 'Gene', '226', (23, 28))	('RCC', 'Disease', 'MESH:D002292', (45, 48))	('RCC', 'Disease', (45, 48))
196504	31484429	This is in agreement with another study, which found that glutamine dependence in ccRCC suppresses oxidative stress.	('suppresses', 'NegReg', (88, 98))	('oxidative stress', 'MPA', (99, 115))	('RCC', 'Disease', (84, 87))	('RCC', 'Disease', 'MESH:D002292', (84, 87))	('glutamine dependence', 'Var', (58, 78))	('glutamine', 'Chemical', 'MESH:C578860', (58, 67))	('oxidative stress', 'Phenotype', 'HP:0025464', (99, 115))
196522	31484429	The same pipeline allows haplogroup prediction of mtDNA sequences, detection of mismatches, insertions and deletions and the functional annotation of the identified variants.	('N', 'Chemical', 'MESH:D009584', (53, 54))	('mismatches', 'Var', (80, 90))	('mtDNA', 'Gene', (50, 55))	('deletions', 'Var', (107, 116))	('mtDNA', 'cellular_component', 'GO:0000262', ('50', '55'))	('insertions', 'Var', (92, 102))
196544	31484429	As GSSG can be made of either one or two labeled GSH molecules, both versions were measured (13C6 glucose: M+3 and M+6; 13C515N-glutamic acid: M+5 and M+10).	('GSH', 'Chemical', 'MESH:D005978', (49, 52))	('M+10', 'Var', (151, 155))	('glucose', 'Chemical', 'MESH:D005947', (98, 105))	('As GSSG', 'Chemical', 'MESH:D019803', (0, 7))	('M+6', 'Var', (115, 118))	('13C515N-glutamic acid', 'Chemical', 'MESH:C513342', (120, 141))
196597	30152187	The results showed that patients with high expression of COL4A4, ERMP1 and PRELID2 had a better OS (P < .05).	('COL4A4', 'Gene', (57, 63))	('COL4A4', 'Gene', '1286', (57, 63))	('PRELID2', 'Gene', (75, 82))	('ERMP1', 'Gene', '79956', (65, 70))	('high expression', 'Var', (38, 53))	('ERMP1', 'Gene', (65, 70))	('patients', 'Species', '9606', (24, 32))	('PRELID2', 'Gene', '153768', (75, 82))
196598	30152187	In addition, patients with low expression of NOG, SPI1, TGFbeta1, TYRP1 and VIM had better OS (P < .05; Figure 6).	('TYRP1', 'Gene', '7306', (66, 71))	('SPI1', 'Gene', (50, 54))	('TGFbeta1', 'Gene', '7040', (56, 64))	('VIM', 'Gene', (76, 79))	('patients', 'Species', '9606', (13, 21))	('NOG', 'Gene', '9241', (45, 48))	('low expression', 'Var', (27, 41))	('VIM', 'Gene', '7431', (76, 79))	('better', 'PosReg', (84, 90))	('SPI1', 'Gene', '6688', (50, 54))	('NOG', 'Gene', (45, 48))	('TGFbeta1', 'Gene', (56, 64))	('TYRP1', 'Gene', (66, 71))
196602	30152187	The risk score was imputed as follows: the expression of SLC25A5-AS1 * (-.005539) + the expression of COL18A1-AS1 * (-.011813) + the expression of WT1-AS * .005503 + the expression of AC016773.1 * .014487 + the expression of LINC00460 * .001143 + the expression of LINC00313 * .015264 + the expression of HOTTIP * .008013 + the expression of FGF14-AS1 * (-.193023) + the expression of AC105020.1 * .001524.	('LINC00313', 'Gene', (265, 274))	('LINC00313', 'Gene', '114038', (265, 274))	('COL18A1-AS1', 'Gene', (102, 113))	('WT1', 'Gene', '7490', (147, 150))	('AC105020.1 * .001524', 'Var', (385, 405))	('SLC25A5-AS1', 'Gene', '100303728;292;5729', (57, 68))	('HOTTIP', 'Gene', '100316868', (305, 311))	('SLC25A5-AS1', 'Gene', (57, 68))	('WT1', 'Gene', (147, 150))	('HOTTIP', 'Gene', (305, 311))	('FGF14-AS1', 'Gene', '100874081;2259;5729', (342, 351))	('COL18A1-AS1', 'Gene', '378832;80781;5729', (102, 113))	('FGF14-AS1', 'Gene', (342, 351))	('LINC00460', 'Gene', '728192', (225, 234))	('LINC00460', 'Gene', (225, 234))
196604	30152187	In contrast, the coefficients in the Cox regression of WT1-AS, AC016773.1, LINC00460, LINC00313, HOTTIP and AC105020.1 were positive.	('LINC00460', 'Gene', '728192', (75, 84))	('LINC00460', 'Gene', (75, 84))	('LINC00313', 'Gene', (86, 95))	('AC105020.1', 'Var', (108, 118))	('LINC00313', 'Gene', '114038', (86, 95))	('HOTTIP', 'Gene', '100316868', (97, 103))	('WT1', 'Gene', '7490', (55, 58))	('WT1', 'Gene', (55, 58))	('HOTTIP', 'Gene', (97, 103))	('Cox', 'Gene', '1351', (37, 40))	('Cox', 'Gene', (37, 40))
196632	30152187	The 9 lncRNA, SLC25A5-AS1, COL18A1-AS1, WT1-AS, AC016773.1, LINC00460, LINC00313, HOTTIP, FGF14-AS1 and AC105020.1, showed a significant prognostic value for the survival of ccRCC patients by multivariate Cox proportional hazards regression analysis.	('HOTTIP', 'Gene', (82, 88))	('LINC00460', 'Gene', '728192', (60, 69))	('FGF14-AS1', 'Gene', (90, 99))	('FGF14-AS1', 'Gene', '100874081;2259;5729', (90, 99))	('SLC25A5-AS1', 'Gene', '100303728;292;5729', (14, 25))	('HOTTIP', 'Gene', '100316868', (82, 88))	('Cox', 'Gene', (205, 208))	('patients', 'Species', '9606', (180, 188))	('ccRCC', 'Disease', (174, 179))	('LINC00313', 'Gene', '114038', (71, 80))	('COL18A1-AS1', 'Gene', '378832;80781;5729', (27, 38))	('WT1', 'Gene', (40, 43))	('SLC25A5-AS1', 'Gene', (14, 25))	('ccRCC', 'Phenotype', 'HP:0006770', (174, 179))	('WT1', 'Gene', '7490', (40, 43))	('LINC00460', 'Gene', (60, 69))	('AC105020.1', 'Var', (104, 114))	('LINC00313', 'Gene', (71, 80))	('COL18A1-AS1', 'Gene', (27, 38))	('Cox', 'Gene', '1351', (205, 208))
196683	31152822	Adenoviral overexpression of PCK2 in liver-specific PCK1 knockout mice showed that PCK2 supports hepatic gluconeogenesis, but is less efficient than PCK1.	('PCK2', 'Var', (83, 87))	('supports', 'PosReg', (88, 96))	('hepatic gluconeogenesis', 'MPA', (97, 120))	('mice', 'Species', '10090', (66, 70))	('gluconeogenesis', 'biological_process', 'GO:0006094', ('105', '120'))	('hepatic gluconeogenesis', 'Phenotype', 'HP:0005959', (97, 120))
196684	31152822	Silencing of PCK2 with antisense oligonucleotides in rats reduced blood glucose levels, particularly in the fed state, and diminished gluconeogenesis from lactate or amino acids in isolated hepatocytes.	('rats', 'Species', '10116', (53, 57))	('PCK2', 'Gene', (13, 17))	('blood glucose levels', 'MPA', (66, 86))	('lactate', 'Chemical', 'MESH:D019344', (155, 162))	('gluconeogenesis', 'biological_process', 'GO:0006094', ('134', '149'))	('diminished', 'NegReg', (123, 133))	('gluconeogenesis from lactate or amino acids', 'MPA', (134, 177))	('reduced blood glucose', 'Phenotype', 'HP:0001943', (58, 79))	('diminished gluconeogenesis', 'Phenotype', 'HP:0005959', (123, 149))	('antisense oligonucleotides', 'Var', (23, 49))	('Silencing', 'Var', (0, 9))	('reduced', 'NegReg', (58, 65))	('glucose', 'Chemical', 'MESH:D005947', (72, 79))
196693	31152822	Interestingly, PCK1 overexpression in Caenorhabditis elegans extends lifespan, however the mechanism is not entirely clear.	('overexpression', 'Var', (20, 34))	('PCK1', 'Gene', (15, 19))	('lifespan', 'CPA', (69, 77))	('Caenorhabditis elegans', 'Species', '6239', (38, 60))	('extends', 'PosReg', (61, 68))
196702	31152822	Elevated expression of the upstream gluconeogenesis enzyme PCK2 has been noted in the context of mutant KRAS in colon cancer cells and PCK2 was upregulated in colon carcinoma samples compared to normal colon tissue.	('upregulated', 'PosReg', (144, 155))	('KRAS', 'Gene', '3845', (104, 108))	('colon cancer', 'Disease', 'MESH:D015179', (112, 124))	('colon cancer', 'Phenotype', 'HP:0003003', (112, 124))	('PCK2', 'Gene', (59, 63))	('mutant', 'Var', (97, 103))	('colon carcinoma', 'Disease', 'MESH:D015179', (159, 174))	('Elevated', 'PosReg', (0, 8))	('colon carcinoma', 'Disease', (159, 174))	('expression', 'MPA', (9, 19))	('colon cancer', 'Disease', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('gluconeogenesis', 'biological_process', 'GO:0006094', ('36', '51'))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('PCK2', 'Gene', (135, 139))	('KRAS', 'Gene', (104, 108))
196709	31152822	Silencing of PCK2 significantly compromised cancer cell survival under glucose deprivation in two of the three NSCLC cell lines.	('PCK2', 'Gene', (13, 17))	('NSCLC', 'Disease', (111, 116))	('glucose deprivation', 'Disease', (71, 90))	('cancer', 'Disease', (44, 50))	('glucose deprivation', 'Disease', 'MESH:D018149', (71, 90))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('compromised', 'NegReg', (32, 43))	('Silencing', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
196710	31152822	PCK1/2 inhibition further enhanced apoptosis in NSCLC cells growing as 3-dimensional spheroids, which are known to exhibit gradients for glucose and O2.	('enhanced', 'PosReg', (26, 34))	('NSCLC', 'Disease', (48, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('35', '44'))	('O2', 'Chemical', 'MESH:D013481', (149, 151))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('inhibition', 'Var', (7, 17))	('PCK1/2', 'Gene', (0, 6))	('glucose', 'Chemical', 'MESH:D005947', (137, 144))	('apoptosis', 'CPA', (35, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('35', '44'))
196714	31152822	In breast cancer cells, silencing of PCK2 slightly reduced glucose consumption, lactate production and proliferation under normal conditions.	('lactate', 'Chemical', 'MESH:D019344', (80, 87))	('lactate production', 'MPA', (80, 98))	('proliferation', 'CPA', (103, 116))	('reduced', 'NegReg', (51, 58))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('glucose consumption', 'Disease', (59, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('glucose consumption', 'Disease', 'MESH:D018149', (59, 78))	('silencing', 'Var', (24, 33))	('PCK2', 'Gene', (37, 41))
196719	31152822	Importantly, in two different NSCLC cell lines, PCK2 silencing clearly reduced growth of subcutaneous xenografts in mice .	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('mice', 'Species', '10090', (116, 120))	('PCK2', 'Gene', (48, 52))	('reduced', 'NegReg', (71, 78))	('silencing', 'Var', (53, 62))	('growth of subcutaneous xenografts in mice', 'CPA', (79, 120))	('NSCLC', 'Disease', (30, 35))
196720	31152822	PCK2 silencing prevented lung cancer xenografts from growing beyond microscopic size in vivo, as recently published.	('PCK2', 'Gene', (0, 4))	('silencing', 'Var', (5, 14))	('lung cancer', 'Disease', (25, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('prevented', 'NegReg', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('lung cancer', 'Disease', 'MESH:D008175', (25, 36))
196721	31152822	In vitro analyses showed reduced colony forming ability of PCK2 silenced lung cancer cells under glucose- and serum starvation.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('reduced', 'NegReg', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('glucose', 'Chemical', 'MESH:D005947', (97, 104))	('PCK2', 'Gene', (59, 63))	('colony forming ability', 'CPA', (33, 55))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('silenced', 'Var', (64, 72))
196723	31152822	Silencing of PCK1 decreased proliferation and clonogenic growth of colon cancer cells in glucose-containing medium and clearly reduced colon cancer xenograft growth.	('reduced', 'NegReg', (127, 134))	('colon cancer', 'Phenotype', 'HP:0003003', (67, 79))	('proliferation', 'CPA', (28, 41))	('colon cancer', 'Disease', (135, 147))	('decreased', 'NegReg', (18, 27))	('colon cancer', 'Disease', 'MESH:D015179', (67, 79))	('Silencing', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('PCK1', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('glucose', 'Chemical', 'MESH:D005947', (89, 96))	('colon cancer', 'Disease', (67, 79))	('clonogenic growth', 'CPA', (46, 63))	('colon cancer', 'Phenotype', 'HP:0003003', (135, 147))	('colon cancer', 'Disease', 'MESH:D015179', (135, 147))
196727	31152822	Interestingly, PCK1 silencing has been shown to reduce cancer growth in a drosophila brain tumor model that was rescued by increasing NAD+ or oxidizing cytosolic NADH.	('brain tumor', 'Disease', (85, 96))	('PCK1', 'Gene', (15, 19))	('brain tumor', 'Disease', 'MESH:D001932', (85, 96))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('NAD', 'Chemical', 'MESH:D009243', (162, 165))	('brain tumor', 'Phenotype', 'HP:0030692', (85, 96))	('NAD', 'Chemical', 'MESH:D009243', (134, 137))	('NADH', 'Chemical', 'MESH:D009243', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('reduce', 'NegReg', (48, 54))	('drosophila', 'Species', '7227', (74, 84))	('silencing', 'Var', (20, 29))	('NAD+', 'MPA', (134, 138))	('cancer', 'Disease', (55, 61))
196729	31152822	As expected, only a minor proportion of PEP generated by PCK2 was converted (back) to pyruvate and to the TCA cycle in glucose-deprived lung cancer cells.	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('TCA cycle', 'MPA', (106, 115))	('pyruvate', 'MPA', (86, 94))	('glucose-deprived lung cancer', 'Disease', (119, 147))	('TCA', 'Chemical', 'MESH:C000589078', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('converted', 'MPA', (66, 75))	('PCK2', 'Var', (57, 61))	('glucose-deprived lung cancer', 'Disease', 'MESH:D008175', (119, 147))	('pyruvate', 'Chemical', 'MESH:D011773', (86, 94))	('TCA cycle', 'biological_process', 'GO:0006099', ('106', '115'))	('PEP', 'Enzyme', (40, 43))
196739	31152822	Importantly, PCK2 silencing led to a 30-50% reduction of absolute levels of the GPL phosphatidylethanolamine under glucose- and serum deprivation.	('GPL', 'Chemical', 'MESH:D020404', (80, 83))	('PCK2', 'Gene', (13, 17))	('silencing', 'Var', (18, 27))	('glucose', 'Chemical', 'MESH:D005947', (115, 122))	('phosphatidylethanolamine', 'Chemical', 'MESH:C483858', (84, 108))	('reduction', 'NegReg', (44, 53))
196751	31152822	High PCK2 expression in prostate cancer tissue was associated with worse overall survival.	('PCK2', 'Gene', (5, 9))	('High', 'Var', (0, 4))	('prostate cancer', 'Disease', 'MESH:D011471', (24, 39))	('prostate cancer', 'Phenotype', 'HP:0012125', (24, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('prostate cancer', 'Disease', (24, 39))	('worse', 'NegReg', (67, 72))	('overall survival', 'MPA', (73, 89))
196753	31152822	PCK2 silencing reduced the proportion of TIC, diminished their sphere-forming ability and inhibited growth of prostate cancer nodules in vivo.	('sphere-forming ability', 'CPA', (63, 85))	('TIC', 'Phenotype', 'HP:0100033', (41, 44))	('prostate cancer', 'Disease', 'MESH:D011471', (110, 125))	('PCK2', 'Gene', (0, 4))	('silencing', 'Var', (5, 14))	('growth of', 'CPA', (100, 109))	('reduced', 'NegReg', (15, 22))	('TIC', 'MPA', (41, 44))	('prostate cancer', 'Phenotype', 'HP:0012125', (110, 125))	('inhibited', 'NegReg', (90, 99))	('prostate cancer', 'Disease', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('diminished', 'NegReg', (46, 56))
196754	31152822	Interestingly, PCK2 silencing slightly enhanced survival of TIC in medium without glucose.	('survival', 'CPA', (48, 56))	('glucose', 'Chemical', 'MESH:D005947', (82, 89))	('TIC', 'Phenotype', 'HP:0100033', (60, 63))	('PCK2', 'Gene', (15, 19))	('silencing', 'Var', (20, 29))	('enhanced', 'PosReg', (39, 47))
196770	31152822	PCK2 silencing elevated acetyl-CoA levels due to enhanced production from citrate via ATP citrate lyase (ACLY), increasing histone and total protein lysine acetylation.	('acetyl', 'Chemical', 'MESH:C011632', (24, 30))	('protein lysine acetylation', 'biological_process', 'GO:0034983', ('141', '167'))	('elevated', 'PosReg', (15, 23))	('increasing', 'PosReg', (112, 122))	('ATP citrate', 'Chemical', 'MESH:C102006', (86, 97))	('enhanced', 'PosReg', (49, 57))	('PCK2', 'Gene', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('silencing', 'Var', (5, 14))	('acetyl', 'Chemical', 'MESH:C011632', (156, 162))	('citrate', 'Chemical', 'MESH:C102006', (90, 97))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (24, 34))	('production from citrate', 'MPA', (58, 81))	('lysine', 'Chemical', 'MESH:C114808', (149, 155))	('acetyl-CoA levels', 'MPA', (24, 41))	('histone', 'MPA', (123, 130))	('citrate', 'Chemical', 'MESH:C102006', (74, 81))
196771	31152822	Importantly, reducing protein acetylation by inhibiting ACLY reversed the reduction in TIC numbers by PCK2 silencing, showing that PCK2 elevates TIC numbers in prostate cancer by suppressing protein acetylation.	('PCK2', 'Gene', (102, 106))	('TIC', 'Phenotype', 'HP:0100033', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('protein acetylation', 'MPA', (191, 210))	('protein', 'cellular_component', 'GO:0003675', ('191', '198'))	('TIC numbers', 'MPA', (145, 156))	('suppressing', 'NegReg', (179, 190))	('prostate cancer', 'Disease', 'MESH:D011471', (160, 175))	('protein acetylation', 'biological_process', 'GO:0006473', ('22', '41'))	('prostate cancer', 'Phenotype', 'HP:0012125', (160, 175))	('acetyl', 'Chemical', 'MESH:C011632', (30, 36))	('silencing', 'Var', (107, 116))	('elevates', 'PosReg', (136, 144))	('prostate cancer', 'Disease', (160, 175))	('TIC', 'Phenotype', 'HP:0100033', (145, 148))	('PCK2', 'Var', (131, 135))	('protein acetylation', 'biological_process', 'GO:0006473', ('191', '210'))	('acetyl', 'Chemical', 'MESH:C011632', (199, 205))
196774	31152822	In one study, the ability to survive under low glucose conditions was decreased under forced PCK1 and partially under PCK2 overexpression, due to a considerable decrease in ATP levels, while effects under high glucose were quite variable.	('PCK1', 'Var', (93, 97))	('glucose', 'Chemical', 'MESH:D005947', (210, 217))	('decrease', 'NegReg', (161, 169))	('decreased', 'NegReg', (70, 79))	('high glucose', 'Phenotype', 'HP:0003074', (205, 217))	('ATP', 'Chemical', 'MESH:D000255', (173, 176))	('glucose', 'Chemical', 'MESH:D005947', (47, 54))	('PCK2', 'Gene', (118, 122))	('ATP levels', 'MPA', (173, 183))
196783	31152822	FBP2 silencing greatly compromised viability and proliferation of the metastatic cancer cells under glucose deprivation and delayed the growth of orthotopically implanted brain metastases in mice.	('glucose deprivation', 'Disease', (100, 119))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('FBP2', 'Gene', (0, 4))	('proliferation', 'CPA', (49, 62))	('silencing', 'Var', (5, 14))	('cancer', 'Disease', (81, 87))	('metastases', 'Disease', (177, 187))	('viability', 'CPA', (35, 44))	('FBP2', 'Species', '1412837', (0, 4))	('delayed', 'NegReg', (124, 131))	('mice', 'Species', '10090', (191, 195))	('metastases', 'Disease', 'MESH:D009362', (177, 187))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('glucose deprivation', 'Disease', 'MESH:D018149', (100, 119))	('compromised', 'NegReg', (23, 34))
196786	31152822	FBP1 overexpression suppressed proliferation in HCC cells and other tumor types and significantly reduced tumor growth in vivo in numerous studies (Table 2).	('tumor', 'Disease', (68, 73))	('proliferation', 'CPA', (31, 44))	('suppressed', 'NegReg', (20, 30))	('FBP1', 'Species', '1412837', (0, 4))	('HCC', 'Gene', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('FBP1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('reduced', 'NegReg', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('HCC', 'Gene', '619501', (48, 51))	('overexpression', 'Var', (5, 19))	('tumor', 'Disease', (106, 111))
196793	31152822	Restoration of FBP1 expression suppressed the EMT phenotype, migration and tumor growth in Snail overexpressing HCC cancer cells  and reduced EMT in gastric cancer cells.	('FBP1', 'Gene', (15, 19))	('reduced EMT', 'Phenotype', 'HP:0032198', (134, 145))	('EMT', 'CPA', (142, 145))	('Restoration', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('HCC', 'Gene', '619501', (112, 115))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Disease', (75, 80))	('gastric cancer', 'Disease', (149, 163))	('HCC', 'Gene', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('migration', 'CPA', (61, 70))	('reduced', 'NegReg', (134, 141))	('suppressed', 'NegReg', (31, 41))	('FBP1', 'Species', '1412837', (15, 19))	('EMT', 'biological_process', 'GO:0001837', ('142', '145'))	('gastric cancer', 'Disease', 'MESH:D013274', (149, 163))	('EMT', 'biological_process', 'GO:0001837', ('46', '49'))	('EMT phenotype', 'CPA', (46, 59))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))
196798	31152822	Interestingly, FBP1 expression inhibited tumor growth also in cancer types that displayed growth enhancement by PCK2, e.g.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('FBP1', 'Species', '1412837', (15, 19))	('FBP1', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Disease', (41, 46))	('enhancement', 'PosReg', (97, 108))	('expression', 'Var', (20, 30))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('inhibited', 'NegReg', (31, 40))	('growth', 'MPA', (90, 96))
196803	31152822	G6PC hydrolyzes glucose-6-phosphate and thus mediates the final step in gluconeogenesis but also in glycogen degradation e.g.	('mediates', 'Reg', (45, 53))	('glucose-6-phosphate', 'MPA', (16, 35))	('glycogen degradation', 'biological_process', 'GO:0005980', ('100', '120'))	('G6PC', 'Var', (0, 4))	('gluconeogenesis', 'biological_process', 'GO:0006094', ('72', '87'))	('glucose-6-phosphate', 'Chemical', 'MESH:D019298', (16, 35))	('gluconeogenesis', 'MPA', (72, 87))	('glycogen degradation', 'MPA', (100, 120))
196805	31152822	G6PC overexpression reduced HCC growth in mice in vivo.	('reduced', 'NegReg', (20, 27))	('mice', 'Species', '10090', (42, 46))	('HCC', 'Gene', (28, 31))	('G6PC', 'Var', (0, 4))	('HCC', 'Gene', '619501', (28, 31))
196809	31152822	G6PC silencing reduced proliferation and migration in glioblastoma cells and invasion in vivo, which was especially pronounced after 2DG treatment and recovery.	('glioblastoma', 'Disease', 'MESH:D005909', (54, 66))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('silencing', 'Var', (5, 14))	('invasion', 'CPA', (77, 85))	('reduced', 'NegReg', (15, 22))	('2DG', 'Chemical', 'MESH:C021591', (133, 136))	('proliferation', 'CPA', (23, 36))	('G6PC silencing', 'Var', (0, 14))	('glioblastoma', 'Disease', (54, 66))
196810	31152822	High G6PC expression was found to be associated with poor overall and disease-free survival in ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('ovarian cancer', 'Disease', 'MESH:D010051', (95, 109))	('High G6PC expression', 'Var', (0, 20))	('poor', 'NegReg', (53, 57))	('ovarian cancer', 'Disease', (95, 109))	('disease-free survival', 'CPA', (70, 91))	('High G6PC', 'Phenotype', 'HP:0410186', (0, 9))	('ovarian cancer', 'Phenotype', 'HP:0100615', (95, 109))
196811	31152822	Silencing or inhibition of G6PC in ovarian cancer cells led to reduced proliferation and invasion and an accumulation of glycogen in vitro.	('reduced', 'NegReg', (63, 70))	('glycogen', 'MPA', (121, 129))	('invasion', 'CPA', (89, 97))	('ovarian cancer', 'Phenotype', 'HP:0100615', (35, 49))	('ovarian cancer', 'Disease', 'MESH:D010051', (35, 49))	('G6PC', 'Protein', (27, 31))	('accumulation', 'PosReg', (105, 117))	('inhibition', 'NegReg', (13, 23))	('proliferation', 'CPA', (71, 84))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('Silencing', 'Var', (0, 9))	('ovarian cancer', 'Disease', (35, 49))
196816	31152822	PIP3 in turn inhibits different transcription factors via AKT, including forkhead box protein O1 (FoxO1).	('transcription', 'biological_process', 'GO:0006351', ('32', '45'))	('FoxO1', 'Gene', (98, 103))	('FoxO1', 'Gene', '56458', (98, 103))	('AKT', 'Pathway', (58, 61))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('inhibits', 'NegReg', (13, 21))	('PIP3', 'Var', (0, 4))	('transcription factors', 'Pathway', (32, 53))
196823	31152822	The tumor suppressor p53 activated the expression of PCK2 and G6PC in HepG2 liver cancer cells.	('tumor', 'Disease', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('PCK2', 'Gene', (53, 57))	('HepG2', 'CellLine', 'CVCL:0027', (70, 75))	('G6PC', 'Var', (62, 66))	('liver cancer', 'Disease', 'MESH:D006528', (76, 88))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('liver cancer', 'Phenotype', 'HP:0002896', (76, 88))	('tumor suppressor', 'biological_process', 'GO:0051726', ('4', '20'))	('expression', 'MPA', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('activated', 'PosReg', (25, 34))	('liver cancer', 'Disease', (76, 88))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('4', '20'))
196828	31152822	Silencing of the mitotic kinase polo-like kinase 1 (PLK1) dramatically reduced levels of PCK1 mRNA and protein in melanoma cells, while FBP1 expression was increased, suggesting that the two enzymes are not regulated in the same direction in certain cancer cell types.	('levels', 'MPA', (79, 85))	('PLK1', 'Gene', (52, 56))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('cancer', 'Disease', (250, 256))	('FBP1', 'Species', '1412837', (136, 140))	('increased', 'PosReg', (156, 165))	('FBP1', 'Gene', (136, 140))	('reduced', 'NegReg', (71, 78))	('expression', 'MPA', (141, 151))	('PCK1', 'Gene', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('Silencing', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))
196839	31152822	In different cancers, including gastric cancer, HCC, colon carcinoma, NSCLC and breast cancer hypermethylation of the FBP1 promoter decreased expression of FBP1.	('gastric cancer', 'Disease', (32, 46))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('breast cancer', 'Disease', (80, 93))	('HCC', 'Gene', '619501', (48, 51))	('FBP1', 'Gene', (156, 160))	('FBP1', 'Gene', (118, 122))	('NSCLC', 'Disease', (70, 75))	('gastric cancer', 'Disease', 'MESH:D013274', (32, 46))	('HCC', 'Gene', (48, 51))	('colon carcinoma', 'Disease', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('hypermethylation', 'Var', (94, 110))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('colon carcinoma', 'Disease', 'MESH:D015179', (53, 68))	('gastric cancer', 'Phenotype', 'HP:0012126', (32, 46))	('expression', 'MPA', (142, 152))	('cancers', 'Disease', (13, 20))	('FBP1', 'Species', '1412837', (156, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('FBP1', 'Species', '1412837', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('decreased', 'NegReg', (132, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))
196841	31152822	In ccRCC and HCC there is also gene copy number loss.	('HCC', 'Gene', (13, 16))	('HCC', 'Gene', '619501', (13, 16))	('gene copy number loss', 'Var', (31, 52))	('ccRCC', 'Disease', (3, 8))	('ccRCC', 'Disease', 'MESH:D002292', (3, 8))
196842	31152822	NSCLC cell lines showed reduced FBP1 expression, which was reversed by silencing of Zinc finger E-box-binding homeobox 1 (ZEB1) .	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('FBP1', 'Gene', (32, 36))	('reduced', 'NegReg', (24, 31))	('FBP1', 'Species', '1412837', (32, 36))	('silencing', 'Var', (71, 80))	('E-box-binding', 'molecular_function', 'GO:0070888', ('96', '109'))	('expression', 'MPA', (37, 47))	('NSCLC', 'Disease', (0, 5))
196851	31152822	The preference for PCK1 or PCK2 in glucose-deprived cancer cells appears to be largely determined by the tissue of origin.	('PCK2', 'Var', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('PCK1', 'Var', (19, 23))	('glucose-deprived cancer', 'Disease', 'MESH:D009369', (35, 58))	('glucose-deprived cancer', 'Disease', (35, 58))
196868	31152822	Inhibition of gluconeogenesis enzymes could potentially be exploited to prevent tumor cell adaptation to the nutrient-starved microenvironment.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('Inhibition of gluconeogenesis', 'biological_process', 'GO:0045721', ('0', '29'))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('prevent', 'NegReg', (72, 79))	('Inhibition of gluconeogenesis', 'Phenotype', 'HP:0005959', (0, 29))	('Inhibition', 'Var', (0, 10))	('gluconeogenesis', 'Enzyme', (14, 29))
196873	31152822	Robust anticancer effects upon silencing of PCK1 or PCK2 have been observed in different in vivo models of primary or metastatic non-hepatic cancers (Table 1), however data on the effect of inducible silencing or inhibition of these enzymes in already established tumors are missing.	('silencing', 'Var', (31, 40))	('hepatic cancer', 'Phenotype', 'HP:0002896', (133, 147))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('PCK1', 'Gene', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('non-hepatic cancers', 'Disease', 'MESH:D009369', (129, 148))	('PCK2', 'Gene', (52, 56))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (264, 270))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('non-hepatic cancers', 'Disease', (129, 148))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('primary', 'Disease', (107, 114))
196891	31152822	Macropinocytosis has been shown to enhance proliferation and survival of cancer cells under starvation and to be important for cancer growth in vivo.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('survival', 'CPA', (61, 69))	('enhance', 'PosReg', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('proliferation', 'CPA', (43, 56))	('cancer', 'Disease', (127, 133))	('Macropinocytosis', 'biological_process', 'GO:0044351', ('0', '16'))	('Macropinocytosis', 'Var', (0, 16))
196903	31152822	In contrast, abrogation of PCK1 dependent PPP decreased levels of glutathione, increased levels of reactive oxygen species and depleted CD8+ memory T-cells.	('levels of glutathione', 'MPA', (56, 77))	('increased', 'PosReg', (79, 88))	('PPP', 'Gene', (42, 45))	('levels of reactive oxygen species', 'MPA', (89, 122))	('depleted', 'NegReg', (127, 135))	('glutathione', 'Chemical', 'MESH:D005978', (66, 77))	('CD8+ memory T-cells', 'CPA', (136, 155))	('CD8', 'Chemical', 'MESH:D016827', (136, 139))	('oxygen', 'Chemical', 'MESH:D010100', (108, 114))	('decreased', 'NegReg', (46, 55))	('abrogation', 'Var', (13, 23))	('memory', 'biological_process', 'GO:0007613', ('141', '147'))
196953	28969099	The first model of circRNAs synthesis is intron-pairing-driven circularization, termed "direct back-splicing" (Figure 1A).	('synthesis', 'biological_process', 'GO:0009058', ('28', '37'))	('cir', 'Gene', (19, 22))	('cir', 'Gene', '9541', (19, 22))	('intron-pairing-driven', 'Var', (41, 62))	('cir', 'Gene', (63, 66))	('cir', 'Gene', '9541', (63, 66))
196956	28969099	Notably, it has been reported that in humans the bordering introns of circRNAs are highly enriched in ALU repeats, which contain RCMs.	('cir', 'Gene', (70, 73))	('ALU repeats', 'Var', (102, 113))	('cir', 'Gene', '9541', (70, 73))	('humans', 'Species', '9606', (38, 44))
196960	28969099	This leads to the generation of either exon circRNAs (ecircRNAs) or exon-intron circRNAs (EIciRNAs).	('leads to', 'Reg', (5, 13))	('cir', 'Gene', '9541', (55, 58))	('cir', 'Gene', (80, 83))	('cir', 'Gene', (44, 47))	('cir', 'Gene', '9541', (80, 83))	('cir', 'Gene', (55, 58))	('cir', 'Gene', '9541', (44, 47))	('exon-intron', 'MPA', (68, 79))	('exon', 'Var', (39, 43))
196986	28969099	In both cell lines transfected with empty vector (control of cir-ITCH plasmid), luciferase activity was significantly decreased, in a concentration dependent manner, by a miR-7 or miR-214 mimic.	('-ITCH', 'Phenotype', 'HP:0000989', (64, 69))	('miR-214', 'Gene', (180, 187))	('luciferase activity', 'molecular_function', 'GO:0047077', ('80', '99'))	('miR-7', 'Var', (171, 176))	('ITCH', 'Gene', '83737', (65, 69))	('ITCH', 'Phenotype', 'HP:0000989', (65, 69))	('cir', 'Gene', (61, 64))	('luciferase activity', 'molecular_function', 'GO:0047712', ('80', '99'))	('activity', 'MPA', (91, 99))	('ITCH', 'Gene', (65, 69))	('miR-214', 'Gene', '406996', (180, 187))	('luciferase activity', 'molecular_function', 'GO:0045289', ('80', '99'))	('decreased', 'NegReg', (118, 127))	('luciferase activity', 'molecular_function', 'GO:0050397', ('80', '99'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('80', '99'))	('cir', 'Gene', '9541', (61, 64))	('luciferase', 'Enzyme', (80, 90))
197007	28969099	Following the knockdown of hsa_circ_0001649 with siRNA, there was an increase in the expression level of the pro-metastatic matrix metalloproteinases (MPPs), MMP9, MMP10 and MMP13.	('MMP9', 'Gene', (158, 162))	('cir', 'Gene', '9541', (31, 34))	('increase', 'PosReg', (69, 77))	('MMP13', 'molecular_function', 'GO:0030404', ('174', '179'))	('MMP9', 'Gene', '4318', (158, 162))	('MMP10', 'Gene', (164, 169))	('MMP10', 'Gene', '4319', (164, 169))	('MMP13', 'Gene', (174, 179))	('MMP9', 'molecular_function', 'GO:0004229', ('158', '162'))	('cir', 'Gene', (31, 34))	('MMP10', 'molecular_function', 'GO:0030303', ('164', '169'))	('knockdown', 'Var', (14, 23))	('MMP13', 'Gene', '4322', (174, 179))	('expression level', 'MPA', (85, 101))
197015	28969099	When ciRS-7 is knocked-down, there is a significant inhibition of HCC cell proliferation and invasion, which is likely due to the release of miR-7.	('knocked-down', 'Var', (15, 27))	('ciRS-7', 'Gene', (5, 11))	('cell proliferation', 'biological_process', 'GO:0008283', ('70', '88'))	('HCC cell proliferation', 'CPA', (66, 88))	('ciRS-7', 'Gene', '103611090', (5, 11))	('HCC', 'Phenotype', 'HP:0001402', (66, 69))	('invasion', 'CPA', (93, 101))	('inhibition', 'NegReg', (52, 62))
197020	28969099	Consequently, the ectopic expression of circPVT1 may reduce the antineoplastic effects of miR-125b and E2F2.	('reduce', 'NegReg', (53, 59))	('ectopic expression', 'Var', (18, 36))	('E2F2', 'Gene', '1870', (103, 107))	('cir', 'Gene', (40, 43))	('cir', 'Gene', '9541', (40, 43))	('antineoplastic effects', 'CPA', (64, 86))	('miR', 'Gene', '220972', (90, 93))	('miR', 'Gene', (90, 93))	('E2F2', 'Gene', (103, 107))
197036	28969099	In a study of the CRC cell lines, HCT116 and SW480, sponge activity of cir-ITCH was demonstrated towards miR-7, miR-20a, and miR-214.	('ITCH', 'Gene', '83737', (75, 79))	('miR-20a', 'Gene', (112, 119))	('miR-7', 'Var', (105, 110))	('cir', 'Gene', (71, 74))	('miR-20a', 'Gene', '406982', (112, 119))	('miR-214', 'Gene', (125, 132))	('ITCH', 'Gene', (75, 79))	('HCT116', 'CellLine', 'CVCL:0291', (34, 40))	('sponge activity', 'MPA', (52, 67))	('CRC', 'Phenotype', 'HP:0003003', (18, 21))	('miR-214', 'Gene', '406996', (125, 132))	('cir', 'Gene', '9541', (71, 74))	('SW480', 'CellLine', 'CVCL:0546', (45, 50))	('ITCH', 'Phenotype', 'HP:0000989', (75, 79))	('-ITCH', 'Phenotype', 'HP:0000989', (74, 79))
197038	28969099	It has also been reported that the ectopic expression of cir-ITCH inhibits the expression of c-myc and cyclin D1, which are target genes of the Wnt/beta-catenin signaling pathway.	('ITCH', 'Gene', '83737', (61, 65))	('ectopic expression', 'Var', (35, 53))	('expression', 'MPA', (79, 89))	('ITCH', 'Gene', (61, 65))	('inhibits', 'NegReg', (66, 74))	('beta-catenin', 'Gene', (148, 160))	('cir', 'Gene', (57, 60))	('c-myc', 'Gene', (93, 98))	('c-myc', 'Gene', '4609', (93, 98))	('beta-catenin', 'Gene', '1499', (148, 160))	('cyclin', 'molecular_function', 'GO:0016538', ('103', '109'))	('cir', 'Gene', '9541', (57, 60))	('cyclin D1', 'Gene', '595', (103, 112))	('ITCH', 'Phenotype', 'HP:0000989', (61, 65))	('-ITCH', 'Phenotype', 'HP:0000989', (60, 65))	('cyclin D1', 'Gene', (103, 112))	('signaling pathway', 'biological_process', 'GO:0007165', ('161', '178'))
197047	28969099	Moreover, knockdown of hsa_circ_001569 in SW620 and LOVO cells has been shown to reverse invasive abilities.	('SW620', 'CellLine', 'CVCL:0547', (42, 47))	('invasive abilities', 'CPA', (89, 107))	('cir', 'Gene', (27, 30))	('reverse', 'NegReg', (81, 88))	('knockdown', 'Var', (10, 19))	('cir', 'Gene', '9541', (27, 30))
197052	28969099	A knockdown of circ-BANP using siRNA was also shown to reduce proliferation and colony formation of the CRC cell lines, HCT116 and HT29.	('BANP', 'Gene', (20, 24))	('colony formation', 'CPA', (80, 96))	('cir', 'Gene', (15, 18))	('HCT116', 'CellLine', 'CVCL:0291', (120, 126))	('proliferation', 'CPA', (62, 75))	('knockdown', 'Var', (2, 11))	('CRC', 'Phenotype', 'HP:0003003', (104, 107))	('cir', 'Gene', '9541', (15, 18))	('reduce', 'NegReg', (55, 61))	('BANP', 'Gene', '54971', (20, 24))	('formation', 'biological_process', 'GO:0009058', ('87', '96'))
197072	28969099	These results implicated the abnormally expressed circRNAs in the development of radiation resistance in the esophageal cancer cells.	('implicated', 'Reg', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('abnormally expressed', 'Var', (29, 49))	('men', 'Species', '9606', (73, 76))	('cir', 'Gene', (50, 53))	('cir', 'Gene', '9541', (50, 53))	('radiation resistance', 'CPA', (81, 101))	('esophageal cancer', 'Disease', (109, 126))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
197074	28969099	Moreover, siRNA mediated silencing of hsa_circ_0067934 suppressed ESCC cell proliferation, migration and cell cycle progression.	('silencing', 'Var', (25, 34))	('cell proliferation', 'biological_process', 'GO:0008283', ('71', '89'))	('migration', 'CPA', (91, 100))	('cell cycle', 'biological_process', 'GO:0007049', ('105', '115'))	('suppressed', 'NegReg', (55, 65))	('ESCC', 'Disease', (66, 70))	('cell cycle progression', 'CPA', (105, 127))	('cir', 'Gene', (42, 45))	('cir', 'Gene', '9541', (42, 45))
197078	28969099	The authors also identified that cir-ITCH acts as a sponge of miR-7, miR-17, and miR-214, thereby up-regulated the target gene ITCH, which negatively regulates the Wnt/beta-catenin pathway via targeting dishevelled (Dvl) protein.	('miR-17', 'Gene', (69, 75))	('ITCH', 'Gene', (127, 131))	('negatively', 'NegReg', (139, 149))	('cir', 'Gene', '9541', (33, 36))	('miR-7', 'Var', (62, 67))	('ITCH', 'Phenotype', 'HP:0000989', (37, 41))	('miR-214', 'Gene', '406996', (81, 88))	('beta-catenin', 'Gene', (168, 180))	('-ITCH', 'Phenotype', 'HP:0000989', (36, 41))	('Dvl', 'Gene', (216, 219))	('protein', 'cellular_component', 'GO:0003675', ('221', '228'))	('cir', 'Gene', (33, 36))	('beta-catenin', 'Gene', '1499', (168, 180))	('ITCH', 'Gene', '83737', (127, 131))	('ITCH', 'Gene', (37, 41))	('miR-214', 'Gene', (81, 88))	('dishevelled', 'Gene', (203, 214))	('miR-17', 'Gene', '406952', (69, 75))	('up-regulated', 'PosReg', (98, 110))	('dishevelled', 'Gene', '8215', (203, 214))	('ITCH', 'Phenotype', 'HP:0000989', (127, 131))	('regulates', 'Reg', (150, 159))	('Dvl', 'Gene', '8215', (216, 219))	('ITCH', 'Gene', '83737', (37, 41))
197082	28969099	While DCIS is generally considered to be highly curable, some women with DCIS will develop life-threatening invasive breast cancer, infiltrating ductal cancer (IDC), but the determinants of this progression remains largely unknown.	('DCIS', 'Phenotype', 'HP:0030075', (6, 10))	('develop', 'PosReg', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('invasive breast cancer', 'Disease', (108, 130))	('ductal cancer', 'Disease', 'MESH:D009369', (145, 158))	('DCIS', 'Phenotype', 'HP:0030075', (73, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('ductal cancer', 'Disease', (145, 158))	('DCIS', 'Var', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('women', 'Species', '9606', (62, 67))	('invasive breast cancer', 'Disease', 'MESH:D001943', (108, 130))
197126	28969099	Silencing of cZNF292 expression was reported to inhibit glioma cell proliferation and halt cell cycle progression in U87MG and U251 cells via inactivation of the Wnt/beta-catenin signaling pathway.	('glioma', 'Disease', (56, 62))	('beta-catenin', 'Gene', (166, 178))	('signaling pathway', 'biological_process', 'GO:0007165', ('179', '196'))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('inactivation', 'NegReg', (142, 154))	('halt', 'NegReg', (86, 90))	('beta-catenin', 'Gene', '1499', (166, 178))	('cell cycle', 'biological_process', 'GO:0007049', ('91', '101'))	('cell cycle progression', 'CPA', (91, 113))	('cZNF292', 'Gene', (13, 20))	('Silencing', 'Var', (0, 9))	('U87MG', 'CellLine', 'CVCL:0022', (117, 122))	('U251', 'CellLine', 'CVCL:0021', (127, 131))	('inhibit', 'NegReg', (48, 55))
197142	28969099	Functional analysis found that a knockdown of circRNA_100290 could induce G1/S arrest in SCC9 cell lines, and this significantly inhibited cell proliferation.	('inhibited', 'NegReg', (129, 138))	('S arrest', 'Disease', (77, 85))	('cir', 'Gene', (46, 49))	('cir', 'Gene', '9541', (46, 49))	('knockdown', 'Var', (33, 42))	('S arrest', 'Disease', 'MESH:D006323', (77, 85))	('cell proliferation', 'CPA', (139, 157))	('induce', 'Reg', (67, 73))	('SCC9', 'CellLine', 'CVCL:1685', (89, 93))	('cell proliferation', 'biological_process', 'GO:0008283', ('139', '157'))
197162	28969099	Previous studies have shown how miR expression can be regulated through mechanisms, such as DNA copy number variations, epigenetics, transcription factors and other mechanisms in cancer.	('miR', 'Gene', (32, 35))	('epigenetics', 'Var', (120, 131))	('regulated', 'Reg', (54, 63))	('transcription', 'biological_process', 'GO:0006351', ('133', '146'))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (179, 185))	('expression', 'MPA', (36, 46))	('miR', 'Gene', '220972', (32, 35))
197186	33976736	The loss of apoptosis will increase tumor cells survival time and accumulate the mutations, which can enhance invasiveness during tumor cell progression, stimulate the angiogenesis of tumors, and promote cell proliferation.	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('mutations', 'Var', (81, 90))	('apoptosis', 'Gene', (12, 21))	('tumor', 'Disease', (130, 135))	('loss', 'NegReg', (4, 8))	('tumor', 'Disease', (36, 41))	('enhance', 'PosReg', (102, 109))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', (184, 189))	('increase', 'PosReg', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('cell proliferation', 'biological_process', 'GO:0008283', ('204', '222'))	('promote', 'PosReg', (196, 203))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cell proliferation', 'CPA', (204, 222))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('stimulate', 'PosReg', (154, 163))	('tumors', 'Disease', (184, 190))	('angiogenesis', 'biological_process', 'GO:0001525', ('168', '180'))	('apoptosis', 'biological_process', 'GO:0097194', ('12', '21'))	('apoptosis', 'biological_process', 'GO:0006915', ('12', '21'))
197265	31961100	We also performed transfection experiments to overexpress EED, HOTAIR and knockdown SMARCB1.	('HOTAIR', 'Gene', '100124700', (63, 69))	('EED', 'Gene', '8726', (58, 61))	('SMARCB1', 'Gene', '6598', (84, 91))	('EED', 'Gene', (58, 61))	('knockdown', 'Var', (74, 83))	('SMARCB1', 'Gene', (84, 91))	('HOTAIR', 'Gene', (63, 69))	('overexpress', 'PosReg', (46, 57))
197272	31961100	Combination of HOTAIR overexpression and SMARCB1 knockdown in the presence of genistein revealed that genistein inhibits SNAIL transcription via the HOTAIR/SMARCB1 pathway.	('SMARCB1', 'Gene', (41, 48))	('SNAIL', 'Gene', '6615', (121, 126))	('SNAIL', 'Gene', (121, 126))	('HOTAIR', 'Gene', (149, 155))	('SMARCB1', 'Gene', '6598', (41, 48))	('SMARCB1', 'Gene', '6598', (156, 163))	('HOTAIR', 'Gene', '100124700', (149, 155))	('HOTAIR', 'Gene', (15, 21))	('SMARCB1', 'Gene', (156, 163))	('HOTAIR', 'Gene', '100124700', (15, 21))	('genistein', 'Var', (102, 111))	('transcription', 'biological_process', 'GO:0006351', ('127', '140'))	('genistein', 'Chemical', 'MESH:D019833', (78, 87))	('inhibits', 'NegReg', (112, 120))	('genistein', 'Chemical', 'MESH:D019833', (102, 111))
197295	31961100	Impaired and/or defective activity of this complex may affect tumor development.	('affect', 'Reg', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('defective', 'Var', (16, 25))
197299	31961100	Mutations in SMARCA4 have been reported for various cancers including clear cell renal cell carcinoma (ccRCC).	('SMARCA4', 'Gene', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('reported', 'Reg', (31, 39))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('SMARCA4', 'Gene', '6597', (13, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (70, 101))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('Mutations', 'Var', (0, 9))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (81, 101))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (70, 101))	('clear cell renal cell carcinoma', 'Disease', (70, 101))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
197309	31961100	EZH2 (39876), EED (61204) and SUZ12 (39878) antibodies were purchased from Active Motif.	('39878', 'Var', (37, 42))	('SUZ12', 'Gene', (30, 35))	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('EED', 'Gene', '8726', (14, 17))	('EED', 'Gene', (14, 17))	('SUZ12', 'Gene', '23512', (30, 35))	('61204', 'Var', (19, 24))
197311	31961100	INI1 (SMARCB1) (sc-166165), Brg-1 (SMARCA4) (sc-17796), ARID1A (sc-32761) and Actin (sc-47778) antibodies were purchased from Santa Cruz Biotechnology.	('Brg-1', 'Gene', (28, 33))	('Brg-1', 'Gene', '6597', (28, 33))	('sc-17796', 'Var', (45, 53))	('SMARCA4', 'Gene', (35, 42))	('SMARCA4', 'Gene', '6597', (35, 42))	('INI1', 'Gene', (0, 4))	('ARID1A', 'Gene', '8289', (56, 62))	('INI1', 'Gene', '6598', (0, 4))	('ARID1A', 'Gene', (56, 62))	('SMARCB1', 'Gene', '6598', (6, 13))	('SMARCB1', 'Gene', (6, 13))
197333	31961100	786-O and ACHN cells were co-transfected with a Renilla luciferase plasmid containing the promoter region of ZO-1 (Active Motif) and pCMVHA hEZH2 (Addgene) or pCMV6-Entry (Origene).	('ZO-1', 'Gene', (109, 113))	('hEZH2', 'Gene', (140, 145))	('ZO-1', 'Gene', '7082', (109, 113))	('pCMV6-Entry', 'Var', (159, 170))	('pCMVHA', 'Var', (133, 139))	('hEZH2', 'Gene', '2146', (140, 145))
197395	31961100	Exome sequencing studies have revealed that SMARCB1, a core component of the human SWI/SNF complex, is mutated in ccRCC, indicating that SMARCB1 also plays a vital role in ccRCC.	('mutated', 'Var', (103, 110))	('SMARCB1', 'Gene', '6598', (44, 51))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('83', '98'))	('SMARCB1', 'Gene', (44, 51))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('SMARCB1', 'Gene', '6598', (137, 144))	('ccRCC', 'Phenotype', 'HP:0006770', (172, 177))	('RCC', 'Disease', (174, 177))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('SMARCB1', 'Gene', (137, 144))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))	('core', 'cellular_component', 'GO:0019013', ('55', '59'))	('human', 'Species', '9606', (77, 82))
197404	31961100	Loss-of-function mutations in ARID1A, one of the subunits in the human SWI/SNF complex, has been reported in various cancers.	('Loss-of-function', 'NegReg', (0, 16))	('ARID1A', 'Gene', '8289', (30, 36))	('human', 'Species', '9606', (65, 70))	('ARID1A', 'Gene', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('71', '86'))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('mutations', 'Var', (17, 26))	('cancers', 'Disease', (117, 124))
197415	31961100	The software shows high-scoring ARID1A residues (1005 to 1118) in red, and low-scoring residues in blue (Fig.	('ARID1A', 'Gene', '8289', (32, 38))	('ARID1A', 'Gene', (32, 38))	('1005 to 1118', 'Var', (49, 61))
197422	31961100	To examine whether HOTAIR/SMARCB1 regulates SNAIL expression in the presence of genistein, we overexpressed HOTAIR, knocked down SMARCB1 in the presence of 25 muM genistein and performed RIP assays using SMARCB1 antibody.	('SMARCB1', 'Gene', '6598', (204, 211))	('HOTAIR', 'Gene', (108, 114))	('antibody', 'cellular_component', 'GO:0019814', ('212', '220'))	('SMARCB1', 'Gene', (204, 211))	('HOTAIR', 'Gene', '100124700', (19, 25))	('genistein', 'Chemical', 'MESH:D019833', (163, 172))	('muM', 'Gene', '56925', (159, 162))	('HOTAIR', 'Gene', (19, 25))	('SMARCB1', 'Gene', '6598', (26, 33))	('SMARCB1', 'Gene', '6598', (129, 136))	('antibody', 'molecular_function', 'GO:0003823', ('212', '220'))	('SMARCB1', 'Gene', (129, 136))	('SNAIL', 'Gene', (44, 49))	('SMARCB1', 'Gene', (26, 33))	('muM', 'Gene', (159, 162))	('SNAIL', 'Gene', '6615', (44, 49))	('antibody', 'cellular_component', 'GO:0042571', ('212', '220'))	('genistein', 'Chemical', 'MESH:D019833', (80, 89))	('knocked', 'Var', (116, 123))	('antibody', 'cellular_component', 'GO:0019815', ('212', '220'))	('HOTAIR', 'Gene', '100124700', (108, 114))
197426	31961100	IP shows that SMARCB1 knockdown reduced SMARCB1 levels in the immunoprecipitated complexes (Fig.	('SMARCB1', 'Gene', (14, 21))	('SMARCB1', 'Gene', '6598', (40, 47))	('reduced', 'NegReg', (32, 39))	('knockdown', 'Var', (22, 31))	('SMARCB1', 'Gene', (40, 47))	('SMARCB1', 'Gene', '6598', (14, 21))
197428	31961100	SMARCB1 knockdown suppressed HOTAIR interaction with SMARCB1 (Fig.	('HOTAIR', 'Gene', (29, 35))	('knockdown', 'Var', (8, 17))	('HOTAIR', 'Gene', '100124700', (29, 35))	('SMARCB1', 'Gene', '6598', (53, 60))	('SMARCB1', 'Gene', (53, 60))	('SMARCB1', 'Gene', '6598', (0, 7))	('suppressed', 'NegReg', (18, 28))	('SMARCB1', 'Gene', (0, 7))
197429	31961100	Consequently, SMARCB1 knockdown reduced SNAIL expression (Fig.	('SMARCB1', 'Gene', (14, 21))	('reduced', 'NegReg', (32, 39))	('SNAIL', 'Gene', '6615', (40, 45))	('SNAIL', 'Gene', (40, 45))	('knockdown', 'Var', (22, 31))	('SMARCB1', 'Gene', '6598', (14, 21))
197453	31961100	The human SWI/SNF, a nucleosome remodeling complex, promotes a variety of human cancers due to mutations of its components.	('human', 'Species', '9606', (4, 9))	('SWI/SNF', 'Gene', (10, 17))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('nucleosome remodeling complex', 'cellular_component', 'GO:0016585', ('21', '50'))	('promotes', 'PosReg', (52, 60))	('mutations', 'Var', (95, 104))	('human', 'Species', '9606', (74, 79))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
197454	31961100	Exome sequencing studies have revealed that SMARCB1, a core component of the human SWI/SNF complex, is mutated in ccRCC.	('mutated', 'Var', (103, 110))	('SMARCB1', 'Gene', '6598', (44, 51))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('83', '98'))	('SMARCB1', 'Gene', (44, 51))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))	('core', 'cellular_component', 'GO:0019013', ('55', '59'))	('human', 'Species', '9606', (77, 82))
197456	31961100	Loss-of-function mutations in ARID1A, one of the components in the human SWI/SNF complex have been also reported in various cancers, indicating that ARID1A is a tumor suppressor.	('Loss-of-function', 'NegReg', (0, 16))	('tumor', 'Disease', (161, 166))	('ARID1A', 'Gene', '8289', (30, 36))	('ARID1A', 'Gene', (30, 36))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('161', '177'))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('ARID1A', 'Gene', '8289', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('mutations', 'Var', (17, 26))	('ARID1A', 'Gene', (149, 155))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('73', '88'))	('human', 'Species', '9606', (67, 72))	('cancers', 'Disease', (124, 131))	('tumor suppressor', 'biological_process', 'GO:0051726', ('161', '177'))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
197457	31961100	Recent exome sequencing studies have revealed that ARID1A is mutated in clear ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('ARID1A', 'Gene', '8289', (51, 57))	('ARID1A', 'Gene', (51, 57))	('mutated', 'Var', (61, 68))
197469	31221981	The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism Cancer driver genes involved in epigenetics Among the 299 driver genes mentioned by Bailey et al., only the epigenetics-related pathways have been sorted out a20/20+: Classifies genes as an oncogene, tumor suppressor gene, or as a nondriver gene using Random Forests, http://2020plus.readthedocs.org bBLCA (bladder urothelial carcinoma), BRCA (breast invasive carcinoma), CESC (cervical squamous cell carcinoma and endocervical adenocarcinoma), CHOL (cholangiocarcinoma), DLBC (lymphoid neoplasm diffuse large B-cell lymphoma), ESCA (esophageal carcinoma), GBM (glioblastoma multiforme), HNSC (head and neck squamous cell carcinoma), KIRC (kidney renal clear cell carcinoma), KIRP (kidney renal papillary cell carcinoma), LAML (acute myeloid leukemia), LGG (brain lower grade glioma), LIHC (liver hepatocellular carcinoma), LUAD (lung adenocarcinoma), LUSC (lung squamous cell carcinoma), MESO (mesothelioma), PAAD (pancreatic adenocarcinoma), PANCAN (Pan-cancer), PRAD (prostate adenocarcinoma), SKCM (skin cutaneous melanoma), THCA (thyroid carcinoma), UCEC (uterine corpus endometrial carcinoma) Recent studies on mutations in cancer genomes have distinguished driver mutations from passenger mutations, which occur as byproducts of cancer development.	('melanoma', 'Phenotype', 'HP:0002861', (1169, 1177))	('cancer', 'Phenotype', 'HP:0002664', (1281, 1287))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (948, 972))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (981, 1000))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (1227, 1248))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (1014, 1037))	('lung squamous cell carcinoma', 'Disease', (1009, 1037))	('tumor', 'Disease', (351, 356))	('JARID1C', 'Gene', (32, 39))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (713, 736))	('AML', 'Phenotype', 'HP:0004808', (874, 877))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('carcinoma', 'Phenotype', 'HP:0030731', (611, 620))	('LAML', 'Disease', (873, 877))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (495, 520))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (879, 901))	('UTX', 'Gene', '7403', (52, 55))	('Cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mesothelioma', 'Disease', (1046, 1058))	('LAML', 'Disease', 'None', (873, 877))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (1067, 1092))	('mutations', 'Var', (1322, 1331))	('mesothelioma', 'Disease', 'MESH:D008654', (1046, 1058))	('cancer', 'Phenotype', 'HP:0002664', (1107, 1113))	('lymphoid neoplasm', 'Disease', (629, 646))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (602, 620))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (1009, 1037))	('cancer', 'Disease', (4, 10))	('glioblastoma', 'Phenotype', 'HP:0012174', (713, 725))	('glioma', 'Phenotype', 'HP:0009733', (927, 933))	('lymphoid neoplasm', 'Disease', 'MESH:D008223', (629, 646))	('KDM6A', 'Gene', (57, 62))	('thyroid carcinoma', 'Disease', (1186, 1203))	('hypoxic', 'Disease', 'MESH:D000860', (108, 115))	('tumor suppressor', 'biological_process', 'GO:0051726', ('351', '367'))	('glioblastoma multiforme', 'Disease', (713, 736))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (1067, 1092))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (661, 676))	('cancer', 'Disease', 'MESH:D009369', (1281, 1287))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (495, 520))	('BRCA', 'Gene', (489, 493))	('cervical squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (529, 593))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (1186, 1203))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (759, 782))	('leukemia', 'Phenotype', 'HP:0001909', (893, 901))	('LIHC', 'Disease', (936, 940))	('cancer', 'Disease', (133, 139))	('esophageal carcinoma', 'Disease', (685, 705))	('carcinoma', 'Phenotype', 'HP:0030731', (584, 593))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (745, 782))	('pancreatic adenocarcinoma', 'Disease', (1067, 1092))	('IDH1/2', 'Gene', '3417;3418', (24, 30))	('KDM6A', 'Gene', '7403', (57, 62))	('liver hepatocellular carcinoma', 'Disease', (942, 972))	('neck', 'cellular_component', 'GO:0044326', ('754', '758'))	('glioma', 'Disease', 'MESH:D005910', (927, 933))	('kidney renal papillary cell carcinoma', 'Disease', (833, 870))	('breast invasive carcinoma', 'Disease', (495, 520))	('cancer', 'Disease', (1281, 1287))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (745, 782))	('skin cutaneous melanoma', 'Disease', (1154, 1177))	('LUAD', 'Disease', 'None', (975, 979))	('KDM5C', 'Gene', (41, 46))	('JARID1C', 'Gene', '8242', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (1387, 1393))	('BRCA', 'Gene', '672', (489, 493))	('acute myeloid leukemia', 'Disease', (879, 901))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (840, 870))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (1159, 1177))	('metabolism', 'biological_process', 'GO:0008152', ('140', '150'))	('lymphoma', 'Phenotype', 'HP:0002665', (668, 676))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (885, 901))	('Pan-cancer', 'Disease', (1103, 1113))	('KDM5C', 'Gene', '8242', (41, 46))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (458, 486))	('cancer', 'Disease', (1387, 1393))	('carcinoma', 'Phenotype', 'HP:0030731', (552, 561))	('glioma', 'Disease', (927, 933))	('histone demethylation', 'biological_process', 'GO:0016577', ('82', '103'))	('LUAD', 'Disease', (975, 979))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('cholangiocarcinoma', 'Disease', (602, 620))	('kidney renal clear cell carcinoma', 'Disease', (791, 824))	('lung adenocarcinoma', 'Disease', (981, 1000))	('IDH1/2', 'Gene', (24, 30))	('LIHC', 'Disease', 'None', (936, 940))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (685, 705))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('351', '367'))	('Cancer', 'Disease', 'MESH:D009369', (151, 157))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (981, 1000))	('CHOL', 'Disease', (596, 600))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (1227, 1248))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (1186, 1203))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (833, 870))	('prostate adenocarcinoma', 'Disease', (1122, 1145))	('neoplasm', 'Phenotype', 'HP:0002664', (638, 646))	('carcinoma', 'Phenotype', 'HP:0030731', (477, 486))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (1009, 1037))	('cancer', 'Disease', 'MESH:D009369', (1107, 1113))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (942, 972))	('hypoxic', 'Disease', (108, 115))	('bladder urothelial carcinoma', 'Disease', (458, 486))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (538, 561))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (879, 901))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (685, 705))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (1122, 1145))	('UTX', 'Gene', (52, 55))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (791, 824))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (661, 676))	('cancer', 'Phenotype', 'HP:0002664', (1387, 1393))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (602, 620))	('cancer', 'Disease', (1107, 1113))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (1154, 1177))	('Pan-cancer', 'Disease', 'MESH:C537931', (1103, 1113))	('endometrial carcinoma', 'Disease', (1227, 1248))	('B-cell lymphoma', 'Disease', (661, 676))	('Cancer', 'Disease', (151, 157))	('CHOL', 'Disease', 'None', (596, 600))	('carcinoma', 'Phenotype', 'HP:0030731', (511, 520))
197472	31221981	Furthermore, gain-of-function mutations in genes encoding metabolic enzymes, such as isocitrate dehydrogenases (IDH)1/2, drive tumor progression by producing an oncometabolite, D-2-hydroxyglutarate (D-2HG), which is a competitive inhibitor of alpha-ketoglutarate, O2-dependent dioxygenases such as Jumonji domain-containing histone demethylases, and DNA demethylases.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('IDH)1/2', 'Gene', '3417;3418', (112, 119))	('hydroxyglutarate', 'Chemical', '-', (181, 197))	('O2', 'Chemical', 'MESH:D010100', (264, 266))	('tumor', 'Disease', (127, 132))	('gain-of-function', 'PosReg', (13, 29))	('oxygen', 'Chemical', 'MESH:D010100', (279, 285))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (243, 262))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('DNA', 'cellular_component', 'GO:0005574', ('350', '353'))	('isocitrate', 'Chemical', 'MESH:C034219', (85, 95))
197474	31221981	We have also discussed mutations in other isoforms such as the JARID1A, 1B, 1D of KDM5 subfamilies and the JMJD3/KDM6B of KDM6 subfamilies, which play opposing roles in tumor progression as oncogenes or tumor suppressors depending on the cancer cell type.	('JARID1A, 1B', 'Gene', '10765', (63, 74))	('cancer', 'Disease', (238, 244))	('tumor', 'Disease', (203, 208))	('KDM6B', 'Gene', (113, 118))	('JMJD3', 'Gene', '23135', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('mutations', 'Var', (23, 32))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('KDM6B', 'Gene', '23135', (113, 118))	('JMJD3', 'Gene', (107, 112))
197478	31221981	The mechanisms through which changes in histone methylation affect the expression of genes involved in tumor progression remain unknown.	('expression', 'MPA', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('changes', 'Var', (29, 36))	('tumor', 'Disease', (103, 108))	('affect', 'Reg', (60, 66))	('histone methylation', 'biological_process', 'GO:0016571', ('40', '59'))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
197488	31221981	The sensitivities of each histone demethylase to oncometabolites such as D(R)-2-hydroxyglutarate (HG) and L(S)-2HG vary, suggesting that histone methylation can be differently altered in response to IDH mutations and the presence of oncometabolites (Table 3).	('IDH', 'Gene', '3417', (199, 202))	('histone methylation', 'biological_process', 'GO:0016571', ('137', '156'))	('histone methylation', 'MPA', (137, 156))	('altered', 'Reg', (176, 183))	('D(R)-2-hydroxyglutarate', 'Chemical', '-', (73, 96))	('mutations', 'Var', (203, 212))	('IDH', 'Gene', (199, 202))
197492	31221981	Although several studies showed that hypoxia itself, hypoxia-induced metabolic reprogramming, and IDH mutations increase the total abundance of methylated histones in different cancer cells, the mechanism through which the increased level of histone methylation is related to cellular heterogeneity, cancer resistance, and progression remains unknown.	('hypoxia', 'Disease', (53, 60))	('hypoxia', 'Disease', 'MESH:D000860', (53, 60))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('hypoxia', 'Disease', (37, 44))	('hypoxia', 'Disease', 'MESH:D000860', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('IDH', 'Gene', '3417', (98, 101))	('abundance of methylated', 'MPA', (131, 154))	('increase', 'PosReg', (112, 120))	('mutations', 'Var', (102, 111))	('histone methylation', 'biological_process', 'GO:0016571', ('242', '261'))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('IDH', 'Gene', (98, 101))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('cancer', 'Disease', (300, 306))
197493	31221981	This review introduces recent observations regarding (i) metabolic reprogramming of the alpha-KG balance by IDH mutation and hypoxia in cancers, (ii) the tumor-suppressive functions of the cancer driver genes JARID1C/KDM5C and UTX/KDM6A, and (iii) mutations in genes encoding other isoforms in various cancers, namely, JARID1A, 1B, 1D, and JMJD3/KDM6B of the KDM5 and KDM6 subfamilies.	('mutations', 'Var', (248, 257))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('hypoxia in cancers', 'Disease', (125, 143))	('cancer', 'Disease', (136, 142))	('KDM6A', 'Gene', (231, 236))	('cancers', 'Phenotype', 'HP:0002664', (302, 309))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancers', 'Disease', (302, 309))	('cancer', 'Disease', (302, 308))	('KDM5C', 'Gene', '8242', (217, 222))	('tumor', 'Disease', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('IDH', 'Gene', (108, 111))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('alpha-KG', 'Chemical', 'MESH:D007656', (88, 96))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('KDM5C', 'Gene', (217, 222))	('cancers', 'Disease', 'MESH:D009369', (302, 309))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('KDM6A', 'Gene', '7403', (231, 236))	('JMJD3', 'Gene', '23135', (340, 345))	('hypoxia in cancers', 'Disease', 'MESH:D000860', (125, 143))	('cancer', 'Disease', (189, 195))	('KDM6B', 'Gene', (346, 351))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('IDH', 'Gene', '3417', (108, 111))	('JMJD3', 'Gene', (340, 345))	('JARID1A, 1B', 'Gene', '10765', (319, 330))	('KDM6B', 'Gene', '23135', (346, 351))
197495	31221981	Cancer genomic analyses have identified that an abnormal increase in the D-2HG level is associated with mutations in either IDH1 or IDH2.	('mutations', 'Var', (104, 113))	('IDH2', 'Gene', '3418', (132, 136))	('D-2HG level', 'MPA', (73, 84))	('IDH1', 'Gene', '3417', (124, 128))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('increase', 'PosReg', (57, 65))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('IDH1', 'Gene', (124, 128))	('IDH2', 'Gene', (132, 136))
197498	31221981	In several tumors, including glioma, AML, chondrosarcoma, intrahepatic cholangiocarcinoma, and thyroid carcinoma (Table 1), missense mutations of arginine residues in the active sites of both IDH1 and IDH2 (IDH1R123H, IDH2R140Q, or IDH2R172K) result in new activities that further convert alpha-KG to D-2HG.	('IDH1', 'Gene', (207, 211))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (42, 56))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('IDH1R123H', 'Gene', '3418', (207, 216))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (95, 112))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('IDH1', 'Gene', '3417', (192, 196))	('arginine', 'Chemical', 'MESH:D001120', (146, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('alpha-KG', 'Chemical', 'MESH:D007656', (289, 297))	('activities', 'MPA', (257, 267))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('intrahepatic cholangiocarcinoma', 'Disease', (58, 89))	('IDH1', 'Gene', '3417', (207, 211))	('convert alpha-KG', 'MPA', (281, 297))	('IDH2', 'Gene', (201, 205))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (71, 89))	('IDH2', 'Gene', '3418', (201, 205))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('IDH2', 'Gene', (218, 222))	('IDH2', 'Gene', '3418', (218, 222))	('missense mutations', 'Var', (124, 142))	('chondrosarcoma', 'Disease', (42, 56))	('chondrosarcoma', 'Disease', 'MESH:D002813', (42, 56))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('glioma', 'Disease', (29, 35))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (95, 112))	('result', 'Reg', (243, 249))	('IDH2', 'Gene', (232, 236))	('AML', 'Disease', 'MESH:D015470', (37, 40))	('tumors', 'Disease', (11, 17))	('AML', 'Phenotype', 'HP:0004808', (37, 40))	('IDH1', 'Gene', (192, 196))	('IDH1R123H', 'Gene', (207, 216))	('AML', 'Disease', (37, 40))	('IDH2', 'Gene', '3418', (232, 236))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('thyroid carcinoma', 'Disease', (95, 112))
197500	31221981	Nonetheless, the molecular mechanisms through which D-2HG promotes tumorigenesis remain poorly understood.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('promotes', 'PosReg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('D-2HG', 'Var', (52, 57))	('tumor', 'Disease', (67, 72))
197501	31221981	Since D-2HG is a competitive inhibitor of alpha-KG-dependent dioxygenases, such as histone-, DNA- and RNA demethylases, D-2HG may induce dysregulation of histone, DNA, and RNA methylation in various cancer cell lines.	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('RNA methylation', 'MPA', (172, 187))	('D-2HG', 'Var', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('RNA', 'cellular_component', 'GO:0005562', ('172', '175'))	('dysregulation', 'MPA', (137, 150))	('RNA methylation', 'biological_process', 'GO:0001510', ('172', '187'))	('histone', 'Protein', (154, 161))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('oxygen', 'Chemical', 'MESH:D010100', (63, 69))	('RNA', 'cellular_component', 'GO:0005562', ('102', '105'))	('cancer', 'Disease', (199, 205))	('induce', 'Reg', (130, 136))	('DNA', 'cellular_component', 'GO:0005574', ('163', '166'))	('DNA', 'MPA', (163, 166))	('alpha-KG', 'Chemical', 'MESH:D007656', (42, 50))
197504	31221981	Under normal conditions, the D-2HG level remains low because of the catalytic activity of endogenous D-2HG dehydrogenase (D2HGDH), which catalyzes the conversion of D-2HG to alpha-KG; however, mutant IDHs produce excess D-2HG, which accumulates in patients with glioma and AML.	('glioma', 'Disease', (262, 268))	('D-2HG dehydrogenase', 'Gene', '728294', (101, 120))	('AML', 'Disease', 'MESH:D015470', (273, 276))	('D2HGDH', 'Gene', '728294', (122, 128))	('IDH', 'Gene', (200, 203))	('excess', 'PosReg', (213, 219))	('AML', 'Disease', (273, 276))	('mutant', 'Var', (193, 199))	('D-2HG dehydrogenase', 'Gene', (101, 120))	('alpha-KG', 'Chemical', 'MESH:D007656', (174, 182))	('IDH', 'Gene', '3417', (200, 203))	('glioma', 'Disease', 'MESH:D005910', (262, 268))	('D-2HG', 'MPA', (220, 225))	('AML', 'Phenotype', 'HP:0004808', (273, 276))	('glioma', 'Phenotype', 'HP:0009733', (262, 268))	('patients', 'Species', '9606', (248, 256))	('catalytic activity', 'molecular_function', 'GO:0003824', ('68', '86'))	('D2HGDH', 'Gene', (122, 128))
197505	31221981	Similar to D-2HG (or R-2HG), excessive L-2HG (or S-2HG), an enantiomer of D-2HG, can also inhibit numerous alpha-KG-dependent enzymes.	('inhibit', 'NegReg', (90, 97))	('L-2HG', 'Var', (39, 44))	('alpha-KG', 'Chemical', 'MESH:D007656', (107, 115))	('alpha-KG-dependent enzymes', 'Enzyme', (107, 133))
197511	31221981	Similar to D-2HG, L-2HG inhibits the Jumonji family histone lysine demethylase KDM4C, resulting in aberrant accumulation of trimethylated histone 3 lysine 9 (H3K9me3).	('lysine', 'Chemical', 'MESH:D008239', (148, 154))	('accumulation', 'PosReg', (108, 120))	('inhibits', 'NegReg', (24, 32))	('KDM4C', 'Gene', (79, 84))	('trimethylated histone', 'Chemical', '-', (124, 145))	('trimethylated histone 3 lysine 9', 'MPA', (124, 156))	('KDM4C', 'Gene', '23081', (79, 84))	('lysine', 'Chemical', 'MESH:D008239', (60, 66))	('L-2HG', 'Var', (18, 23))
197516	31221981	Consistent with this idea, the NADH/NAD ratio increases when mitochondrial respiration is impaired; limited 2-HG oxidation in hematopoietic stem cells increases the levels of 2-HG, which is accompanied by inhibition of DNA and histone demethylation, leading to increased hypermethylation of both DNA and histones.	('increased', 'PosReg', (261, 270))	('NAD', 'Chemical', 'MESH:D009243', (31, 34))	('respiration', 'biological_process', 'GO:0045333', ('75', '86'))	('oxidation', 'Var', (113, 122))	('NADH', 'Chemical', 'MESH:D009243', (31, 35))	('DNA', 'cellular_component', 'GO:0005574', ('296', '299'))	('inhibition', 'NegReg', (205, 215))	('histones', 'Protein', (304, 312))	('NAD', 'Chemical', 'MESH:D009243', (36, 39))	('levels of 2-HG', 'MPA', (165, 179))	('-HG', 'Chemical', '-', (176, 179))	('hypermethylation', 'MPA', (271, 287))	('histone', 'Protein', (227, 234))	('DNA', 'Protein', (296, 299))	('DNA', 'Protein', (219, 222))	('increases', 'PosReg', (151, 160))	('histone demethylation', 'biological_process', 'GO:0016577', ('227', '248'))	('-HG', 'Chemical', '-', (109, 112))	('respiration', 'biological_process', 'GO:0007585', ('75', '86'))	('DNA', 'cellular_component', 'GO:0005574', ('219', '222'))
197517	31221981	Homozygous germline loss-of-function mutations in D2HGDH or L-2HG dehydrogenase (L2HGDH) increase the D-2HG or L-2HG levels, respectively, in both urine and blood.	('D2HGDH', 'Gene', '728294', (50, 56))	('L2HGDH', 'Gene', (81, 87))	('L-2HG dehydrogenase', 'Gene', (60, 79))	('L2HGDH', 'Gene', '79944', (81, 87))	('L-2HG levels', 'MPA', (111, 123))	('loss-of-function', 'NegReg', (20, 36))	('D-2HG', 'MPA', (102, 107))	('mutations', 'Var', (37, 46))	('D2HGDH', 'Gene', (50, 56))	('increase', 'PosReg', (89, 97))	('L-2HG dehydrogenase', 'Gene', '79944', (60, 79))
197518	31221981	Systemic L-2HG elevations arising from inherited L2HGDH mutations have been associated with brain tumors.	('elevations', 'PosReg', (15, 25))	('mutations', 'Var', (56, 65))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('brain tumors', 'Disease', 'MESH:D001932', (92, 104))	('brain tumors', 'Phenotype', 'HP:0030692', (92, 104))	('brain tumors', 'Disease', (92, 104))	('associated', 'Reg', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Systemic L-2HG', 'MPA', (0, 14))	('L2HGDH', 'Gene', (49, 55))	('L2HGDH', 'Gene', '79944', (49, 55))
197534	31221981	Furthermore, mutations in IDH1 and 2 in several cancers result in high D-2HG levels.	('cancers', 'Disease', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('D-2HG levels', 'MPA', (71, 83))	('mutations', 'Var', (13, 22))	('high', 'PosReg', (66, 70))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('IDH1 and 2', 'Gene', '3417;3418', (26, 36))
197537	31221981	(iii) What is the molecular mechanism through which changes in histone methylation influence tumor progression?	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('histone methylation', 'biological_process', 'GO:0016571', ('63', '82'))	('influence', 'Reg', (83, 92))	('changes', 'Var', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
197540	31221981	TCGA predicted JARID1C/KDM5C as a tumor suppressor, mutations in which drive cancer progression (Table 1).	('mutations', 'Var', (52, 61))	('tumor', 'Disease', (34, 39))	('KDM5C', 'Gene', (23, 28))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('KDM5C', 'Gene', '8242', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('drive', 'Reg', (71, 76))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))
197546	31221981	The ARID domain in JARID1B recognizes the GCACA/C consensus motif, whereas the PHD1 domain binds only unmethylated H3K4; thus, JARID1B persists after demethylation and is involved in repressing target genes.	('JARID1B', 'Gene', '10765', (19, 26))	('demethylation', 'biological_process', 'GO:0070988', ('150', '163'))	('JARID1B', 'Gene', (19, 26))	('JARID1B', 'Gene', '10765', (127, 134))	('ARID', 'Disease', (4, 8))	('JARID1B', 'Gene', (127, 134))	('ARID', 'Disease', (20, 24))	('demethylation', 'Var', (150, 163))	('ARID', 'Disease', (128, 132))	('ARID', 'Disease', 'None', (20, 24))	('ARID', 'Disease', 'None', (4, 8))	('ARID', 'Disease', 'None', (128, 132))	('PHD', 'molecular_function', 'GO:0050175', ('79', '82'))
197550	31221981	Mutations in JARID1C are associated with short stature, hyperreflexia, and autism.	('autism', 'Disease', (75, 81))	('associated', 'Reg', (25, 35))	('autism', 'Phenotype', 'HP:0000717', (75, 81))	('hyperreflexia', 'Phenotype', 'HP:0001347', (56, 69))	('Mutations', 'Var', (0, 9))	('hyperreflexia', 'Gene', '7974', (56, 69))	('autism', 'Disease', 'MESH:D001321', (75, 81))	('short stature', 'Phenotype', 'HP:0004322', (41, 54))	('short stature', 'Disease', 'MESH:D006130', (41, 54))	('JARID1C', 'Gene', (13, 20))	('hyperreflexia', 'Gene', (56, 69))	('short stature', 'Disease', (41, 54))
197551	31221981	Mutations in JARID1C have been identified in many cancers, such as clear cell renal cell carcinoma (ccRCC), pancreatic cancer, and human papillomavirus (HPV)-associated cancer (Table 1).	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', (50, 56))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('human papillomavirus', 'Disease', (131, 151))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (67, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', (119, 125))	('Mutations', 'Var', (0, 9))	('pancreatic cancer', 'Disease', 'MESH:D010190', (108, 125))	('human papillomavirus', 'Species', '10566', (131, 151))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('identified', 'Reg', (31, 41))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (67, 98))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('pancreatic cancer', 'Disease', (108, 125))	('HPV', 'Species', '10566', (153, 156))	('JARID1C', 'Gene', (13, 20))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('clear cell renal cell carcinoma', 'Disease', (67, 98))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (78, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (108, 125))
197555	31221981	In 786-O VHL-/- ccRCC cells, JARID1C knockdown significantly enhanced tumor growth in a xenograft mouse model, showing that JARID1C is a tumor suppressor and that its inactivating mutations in ccRCC promote tumors.	('knockdown', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumors', 'Disease', (207, 213))	('ccRCC', 'Phenotype', 'HP:0006770', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('promote', 'PosReg', (199, 206))	('ccRCC', 'Gene', (193, 198))	('inactivating mutations', 'Var', (167, 189))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('VHL', 'Disease', (9, 12))	('ccRCC', 'Phenotype', 'HP:0006770', (16, 21))	('tumor', 'Disease', (137, 142))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('137', '153'))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('mouse', 'Species', '10090', (98, 103))	('tumor', 'Disease', (207, 212))	('tumor suppressor', 'biological_process', 'GO:0051726', ('137', '153'))	('enhanced', 'PosReg', (61, 69))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('JARID1C', 'Gene', (29, 36))	('VHL', 'Disease', 'MESH:D006623', (9, 12))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
197556	31221981	Whole-exome sequencing of human pancreatic cancers identified truncating insertions and deletion mutations in JARID1C.	('truncating insertions', 'Var', (62, 83))	('JARID1C', 'Gene', (110, 117))	('deletion mutations', 'Var', (88, 106))	('pancreatic cancers', 'Disease', (32, 50))	('pancreatic cancers', 'Disease', 'MESH:D010190', (32, 50))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (32, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (32, 50))	('human', 'Species', '9606', (26, 31))
197559	31221981	JARID1C knockdown increased the expression levels of the E6 and E7 oncogenes, suggesting that JARID1C can function as a tumor suppressor in HPV-associated cancers.	('tumor suppressor', 'biological_process', 'GO:0051726', ('120', '136'))	('increased', 'PosReg', (18, 27))	('JARID1C', 'Gene', (94, 101))	('knockdown', 'Var', (8, 17))	('JARID1C', 'Gene', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('120', '136'))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('expression levels', 'MPA', (32, 49))	('cancers', 'Disease', (155, 162))	('tumor', 'Disease', (120, 125))	('HPV', 'Species', '10566', (140, 143))
197563	31221981	In ccRCC cells, JARID1C inactivation failed to reduce H3K4me3 at heterochromatic regions, preventing Suv38H1 H3K9 methyl transferase and HP1a from binding to heterochromatin.	('Suv38H1', 'Var', (101, 108))	('binding', 'Interaction', (147, 154))	('preventing', 'NegReg', (90, 100))	('inactivation', 'Var', (24, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('heterochromatin', 'cellular_component', 'GO:0000792', ('158', '173'))	('H3K4me3', 'Protein', (54, 61))	('H3K9 methyl transferase', 'Enzyme', (109, 132))	('HP1a', 'Gene', (137, 141))	('binding', 'molecular_function', 'GO:0005488', ('147', '154'))	('HP1a', 'Gene', '23468', (137, 141))
197577	31221981	JARID1D was considered a tumor suppressor because of its downregulation, mutation, or loss in prostate cancer and ccRCC.	('ccRCC', 'Disease', (114, 119))	('downregulation', 'NegReg', (57, 71))	('JARID1D', 'Gene', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('loss in prostate cancer', 'Disease', 'MESH:D011471', (86, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('25', '41'))	('tumor', 'Disease', (25, 30))	('JARID1D', 'Gene', '8284', (0, 7))	('prostate cancer', 'Phenotype', 'HP:0012125', (94, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('tumor suppressor', 'biological_process', 'GO:0051726', ('25', '41'))	('loss in prostate cancer', 'Disease', (86, 109))	('mutation', 'Var', (73, 81))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
197582	31221981	Unlike JARID1B, JARID1A knockdown altered H3K4 methylation, resulting in inhibition of proliferation and reduced drug resistance, which is suggestive of the oncogenic roles of JARID1A in breast cancer.	('altered', 'Reg', (34, 41))	('inhibition', 'NegReg', (73, 83))	('proliferation', 'CPA', (87, 100))	('JARID1A', 'Gene', '214899', (176, 183))	('reduced', 'NegReg', (105, 112))	('JARID1A', 'Gene', '214899', (16, 23))	('JARID1B', 'Gene', (7, 14))	('JARID1B', 'Gene', '10765', (7, 14))	('drug resistance', 'MPA', (113, 128))	('drug resistance', 'Phenotype', 'HP:0020174', (113, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('knockdown', 'Var', (24, 33))	('JARID1A', 'Gene', (176, 183))	('breast cancer', 'Disease', (187, 200))	('JARID1A', 'Gene', (16, 23))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('drug resistance', 'biological_process', 'GO:0009315', ('113', '128'))	('drug resistance', 'biological_process', 'GO:0042493', ('113', '128'))	('H3K4', 'Protein', (42, 46))	('methylation', 'biological_process', 'GO:0032259', ('47', '58'))	('methylation', 'MPA', (47, 58))
197583	31221981	(2009) reported that fusion of the C-terminal PHD domain of JARID1A/PHF23 to nucleoporin-98 generated potent oncoproteins in human leukemia.	('PHF23', 'Gene', (68, 73))	('PHD', 'molecular_function', 'GO:0050175', ('46', '49'))	('JARID1A', 'Gene', (60, 67))	('nucleoporin-98', 'Gene', (77, 91))	('oncoproteins', 'MPA', (109, 121))	('PHF23', 'Gene', '79142', (68, 73))	('fusion', 'Var', (21, 27))	('human', 'Species', '9606', (125, 130))	('leukemia', 'Phenotype', 'HP:0001909', (131, 139))	('leukemia', 'Disease', 'MESH:D007938', (131, 139))	('leukemia', 'Disease', (131, 139))	('JARID1A', 'Gene', '214899', (60, 67))	('nucleoporin-98', 'Gene', '4928', (77, 91))
197585	31221981	showed that loss of JARID1A/RBP2 promotes senescence and inhibits proliferation in a histone demethylase activity- and Rb-dependent manner in mouse embryonic fibroblasts (MEFs).	('promotes', 'PosReg', (33, 41))	('senescence', 'biological_process', 'GO:0010149', ('42', '52'))	('MEFs', 'CellLine', 'CVCL:9115', (171, 175))	('Rb', 'Chemical', 'MESH:D012413', (119, 121))	('proliferation', 'CPA', (66, 79))	('mouse', 'Species', '10090', (142, 147))	('JARID1A', 'Gene', '214899', (20, 27))	('loss', 'Var', (12, 16))	('histone demethylase activity', 'molecular_function', 'GO:0032452', ('85', '113'))	('JARID1A', 'Gene', (20, 27))	('senescence', 'CPA', (42, 52))	('inhibits', 'NegReg', (57, 65))
197588	31221981	Similarly, JARID1A depletion inhibits proliferation, migration, invasion, and metastasis of lung cancer, suggesting oncogenic roles of JARID1A in lung tumorigenesis and progression.	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('depletion', 'Var', (19, 28))	('proliferation', 'CPA', (38, 51))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('JARID1A', 'Gene', (135, 142))	('invasion', 'CPA', (64, 72))	('metastasis of lung cancer', 'Disease', 'MESH:D009362', (78, 103))	('tumor', 'Disease', (151, 156))	('JARID1A', 'Gene', '214899', (11, 18))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('migration', 'CPA', (53, 62))	('metastasis of lung cancer', 'Disease', (78, 103))	('inhibits', 'NegReg', (29, 37))	('JARID1A', 'Gene', (11, 18))	('JARID1A', 'Gene', '214899', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
197593	31221981	JARID1B knockdown leads to an initial acceleration of tumor growth, followed by exhaustion.	('acceleration', 'PosReg', (38, 50))	('JARID1B', 'Gene', '10765', (0, 7))	('knockdown', 'Var', (8, 17))	('JARID1B', 'Gene', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
197601	31221981	Two functional isoforms, ubiquitously transcribed tetratricopeptide repeats on the X chromosome (UTX)/KDM6A and JMJD3/KDM6B, have been identified as H3K27me3-, me2- and, me1-specific histone demethylases.	('KDM6A', 'Gene', (102, 107))	('me1', 'Gene', (170, 173))	('me1', 'Gene', '4199', (170, 173))	('X chromosome', 'cellular_component', 'GO:0000805', ('83', '95'))	('me2', 'Gene', (160, 163))	('JMJD3', 'Gene', (112, 117))	('KDM6A', 'Gene', '7403', (102, 107))	('KDM6B', 'Gene', '23135', (118, 123))	('JMJD3', 'Gene', '23135', (112, 117))	('H3K27me3-', 'Var', (149, 158))	('KDM6B', 'Gene', (118, 123))	('me2', 'Gene', '4200', (160, 163))
197602	31221981	This escape from X-inactivation contributes to sex bias in many tumors, as a single mutation in UTX is sufficient for its loss of function in males but not in females.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('sex bias in many tumors', 'Disease', 'MESH:D012735', (47, 70))	('sex bias in many tumors', 'Disease', (47, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('contributes', 'Reg', (32, 43))	('UTX', 'Gene', (96, 99))	('mutation', 'Var', (84, 92))
197603	31221981	The UTX paralog, Y chromosome-linked UTY, is inactive due to a mutation in the JmjC domain.	('Y chromosome', 'cellular_component', 'GO:0000806', ('17', '29'))	('UTY', 'Gene', '7404', (37, 40))	('UTY', 'Gene', (37, 40))	('JmjC', 'Gene', (79, 83))	('mutation in', 'Var', (63, 74))
197606	31221981	UTX/KDM6A has been identified as a cancer driver gene via TCGA, as its loss or inactivation promotes several malignancies.	('KDM6A', 'Gene', (4, 9))	('promotes', 'PosReg', (92, 100))	('malignancies', 'Disease', (109, 121))	('inactivation', 'Var', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('KDM6A', 'Gene', '7403', (4, 9))	('loss', 'NegReg', (71, 75))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('malignancies', 'Disease', 'MESH:D009369', (109, 121))	('TCGA', 'Gene', (58, 62))	('cancer', 'Disease', (35, 41))
197613	31221981	Due to its H3K27me3, me2, and me1 demethylase activities, loss of UTX increases the H3K27me3 level at its target genes.	('UTX', 'Gene', (66, 69))	('loss', 'Var', (58, 62))	('me1', 'Gene', (30, 33))	('me1', 'Gene', '4199', (30, 33))	('me2', 'Gene', '4200', (21, 24))	('increases', 'PosReg', (70, 79))	('H3K27me3', 'Enzyme', (11, 19))	('H3K27me3 level', 'MPA', (84, 98))	('activities', 'MPA', (46, 56))	('me2', 'Gene', (21, 24))
197614	31221981	Several studies showed that loss of UTX represses a certain subset of genes by increasing the levels of the repressive H3K27me3 mark, ultimately promoting proliferation, clonogenicity, adhesion, and tumorigenicity in myeloid, bladder, and lung transformation.	('tumor', 'Disease', (199, 204))	('myeloid', 'Disease', (217, 224))	('loss', 'Var', (28, 32))	('bladder', 'CPA', (226, 233))	('H3K27me3', 'Protein', (119, 127))	('proliferation', 'CPA', (155, 168))	('promoting', 'PosReg', (145, 154))	('increasing', 'PosReg', (79, 89))	('UTX', 'Gene', (36, 39))	('lung transformation', 'CPA', (239, 258))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('clonogenicity', 'CPA', (170, 183))	('levels of', 'MPA', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('adhesion', 'CPA', (185, 193))
197615	31221981	Upon loss of the UTX demethylases, H3K27 methyl transferases, such as PRC2/EZH2, determine the levels of H3K27me3 on the UTX-EZH2 target genes.	('EZH2', 'Gene', (75, 79))	('H3K27me3', 'Var', (105, 113))	('EZH2', 'Gene', '2146', (125, 129))	('loss', 'NegReg', (5, 9))	('levels', 'MPA', (95, 101))	('EZH2', 'Gene', (125, 129))	('EZH2', 'Gene', '2146', (75, 79))
197616	31221981	Consistently, loss of UTX increases cellular sensitivity to EZH2 inhibition.	('EZH2', 'Gene', (60, 64))	('loss', 'Var', (14, 18))	('UTX', 'Protein', (22, 25))	('increases', 'PosReg', (26, 35))	('EZH2', 'Gene', '2146', (60, 64))
197618	31221981	In UTX/KDM6A-mutated urothelial bladder carcinoma, PRC2/EZH2 target genes, such as IGFBP3, are deregulated due to H3K27me3 enrichment.	('KDM6A', 'Gene', (7, 12))	('deregulated', 'PosReg', (95, 106))	('IGFBP3', 'Gene', (83, 89))	('urothelial bladder carcinoma', 'Disease', 'MESH:D001749', (21, 49))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (32, 49))	('EZH2', 'Gene', (56, 60))	('KDM6A', 'Gene', '7403', (7, 12))	('EZH2', 'Gene', '2146', (56, 60))	('H3K27me3 enrichment', 'Var', (114, 133))	('IGFBP3', 'Gene', '3486', (83, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('urothelial bladder carcinoma', 'Disease', (21, 49))
197621	31221981	EZH2 inhibition also restored the normal gene expression patterns and impaired the proliferation of tumor cells harboring mutations in an H3K4 methyltransferase, MLL3/KMT2C, or a tumor suppressor, BAP1, by rebalancing the H3K27me3 levels at MLL3/BAP1 target genes.	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('BAP1', 'Gene', '8314', (246, 250))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('MLL3', 'Gene', '58508', (162, 166))	('KMT2C', 'Gene', '58508', (167, 172))	('KMT2C', 'Gene', (167, 172))	('BAP1', 'Gene', '8314', (197, 201))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))	('BAP1', 'Gene', (246, 250))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('normal gene expression patterns', 'MPA', (34, 65))	('proliferation', 'CPA', (83, 96))	('restored', 'PosReg', (21, 29))	('MLL3', 'Gene', '58508', (241, 245))	('H3K4 methyltransferase', 'Enzyme', (138, 160))	('MLL3', 'Gene', (162, 166))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('179', '195'))	('BAP1', 'Gene', (197, 201))	('gene expression', 'biological_process', 'GO:0010467', ('41', '56'))	('H3K27me3 levels', 'MPA', (222, 237))	('rebalancing', 'Reg', (206, 217))	('mutations', 'Var', (122, 131))	('tumor suppressor', 'biological_process', 'GO:0051726', ('179', '195'))	('MLL3', 'Gene', (241, 245))	('impaired', 'NegReg', (70, 78))
197622	31221981	In a range of human tumor types, a cancer-associated mutational hotspot was detected in the PHD domain of MLL3, which mediates association with BAP1.	('association', 'Interaction', (127, 138))	('human', 'Species', '9606', (14, 19))	('MLL3', 'Gene', (106, 110))	('BAP1', 'Gene', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('PHD', 'molecular_function', 'GO:0050175', ('92', '95'))	('mutational', 'Var', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('MLL3', 'Gene', '58508', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))	('tumor', 'Disease', (20, 25))	('BAP1', 'Gene', '8314', (144, 148))
197623	31221981	Cancer cells that harbored mutations in the PHD domain of MLL3 or lacked BAP1 showed reduced recruitment of UTX/KDM6A to gene enhancers, with no reduction in the levels of the repressive H3K27me3 mark.	('BAP1', 'Gene', '8314', (73, 77))	('KDM6A', 'Gene', '7403', (112, 117))	('MLL3', 'Gene', '58508', (58, 62))	('recruitment', 'MPA', (93, 104))	('BAP1', 'Gene', (73, 77))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('MLL3', 'Gene', (58, 62))	('lacked', 'NegReg', (66, 72))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutations in', 'Var', (27, 39))	('reduced', 'NegReg', (85, 92))	('PHD', 'molecular_function', 'GO:0050175', ('44', '47'))	('KDM6A', 'Gene', (112, 117))
197624	31221981	Thus, in cancer cells with MLL3 or BAP1 mutations, reduction of H3K27me3 via EZH2 inhibitors can restore the balance of H3K27me3 at enhancers where UTX is not properly recruited.	('H3K27me3', 'Protein', (64, 72))	('EZH2', 'Gene', (77, 81))	('cancer', 'Disease', (9, 15))	('reduction', 'NegReg', (51, 60))	('MLL3', 'Gene', '58508', (27, 31))	('EZH2', 'Gene', '2146', (77, 81))	('balance of H3K27me3 at', 'MPA', (109, 131))	('BAP1', 'Gene', '8314', (35, 39))	('MLL3', 'Gene', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('mutations', 'Var', (40, 49))	('BAP1', 'Gene', (35, 39))	('restore', 'PosReg', (97, 104))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
197627	31221981	However, other studies showed that in certain types of cancer, an inactive UTX paralog is required for tumor development in males concomitant with loss of UTY and that the UTX-UTY double-knockout cells exhibited higher proliferation than the single-knockout cells, suggesting demethylase-independent tumor suppressor functions of UTX/KDM6A and UTY.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor suppressor', 'biological_process', 'GO:0051726', ('300', '316'))	('UTY', 'Gene', '7404', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('KDM6A', 'Gene', (334, 339))	('higher', 'PosReg', (212, 218))	('UTY', 'Gene', '7404', (344, 347))	('UTY', 'Gene', (155, 158))	('loss', 'Var', (147, 151))	('cancer', 'Disease', (55, 61))	('proliferation', 'CPA', (219, 232))	('tumor', 'Disease', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('UTY', 'Gene', '7404', (176, 179))	('UTY', 'Gene', (344, 347))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (300, 305))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('300', '316'))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('KDM6A', 'Gene', '7403', (334, 339))	('UTY', 'Gene', (176, 179))
197628	31221981	Several studies showed that UTX is essential for the establishment of the active enhancer histone marks H3K4me1 and H3K27ac in a demethylase activity-independent manner via recruitment and coupling of an H3K4 methyltransferase complex (named COMPASS) and the histone acetyl transferase p300.	('p300', 'Gene', '2033', (286, 290))	('coupling', 'Interaction', (189, 197))	('demethylase activity', 'molecular_function', 'GO:0032451', ('129', '149'))	('enhancer', 'PosReg', (81, 89))	('p300', 'Gene', (286, 290))	('me1', 'Gene', '4199', (108, 111))	('me1', 'Gene', (108, 111))	('methyltransferase complex', 'cellular_component', 'GO:0034708', ('209', '234'))	('H3K27ac', 'Var', (116, 123))
197629	31221981	In embryonic stem cells, loss of UTX reduced the levels of H3K4me1/H3K27ac at enhancers and transcription.	('loss', 'Var', (25, 29))	('UTX', 'Protein', (33, 36))	('transcription', 'biological_process', 'GO:0006351', ('92', '105'))	('me1', 'Gene', '4199', (63, 66))	('reduced', 'NegReg', (37, 44))	('levels of', 'MPA', (49, 58))	('me1', 'Gene', (63, 66))
197632	31221981	Similarly, in many cancers and other diseases, enhancer-associated chromatin-modifying components, such as UTX and members of H3K4 methyltransferase complexes, are frequently mutated, leading to enhancer malfunction.	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('enhancer-associated', 'PosReg', (47, 66))	('cancers', 'Disease', (19, 26))	('chromatin', 'cellular_component', 'GO:0000785', ('67', '76'))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('enhancer malfunction', 'MPA', (195, 215))	('UTX', 'Disease', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutated', 'Var', (175, 182))
197633	31221981	In pancreatic cancer, loss of UTX causes aberrant activation of superenhancers that regulate oncogenes (such as Delta-Np63, MYC, and RUNX3) to drive an aggressive subtype of squamous-like pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('Delta-Np63', 'Gene', (112, 122))	('pancreatic cancer', 'Disease', (3, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (188, 205))	('MYC', 'Gene', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('drive', 'PosReg', (143, 148))	('activation', 'PosReg', (50, 60))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('RUNX3', 'Gene', (133, 138))	('UTX', 'Gene', (30, 33))	('RUNX3', 'Gene', '864', (133, 138))	('MYC', 'Gene', '4609', (124, 127))	('pancreatic cancer', 'Disease', (188, 205))	('loss', 'Var', (22, 26))	('pancreatic cancer', 'Disease', 'MESH:D010190', (188, 205))
197637	31221981	Global genomic and proteomic analyses using an Utx-null mouse leukemia model revealed that UTX suppresses myeloid leukemogenesis via noncatalytic functions.	('UTX', 'Var', (91, 94))	('myeloid leukemogenesis', 'Disease', 'MESH:D007951', (106, 128))	('myeloid leukemogenesis', 'Phenotype', 'HP:0012324', (106, 128))	('suppresses', 'NegReg', (95, 105))	('mouse', 'Species', '10090', (56, 61))	('myeloid leukemogenesis', 'Disease', (106, 128))	('leukemia', 'Disease', (62, 70))	('leukemia', 'Phenotype', 'HP:0001909', (62, 70))	('leukemia', 'Disease', 'MESH:D007938', (62, 70))
197639	31221981	These findings suggest that loss of UTX contributes to drive tumor progression via repositioning of histone modification enzymes.	('loss', 'Var', (28, 32))	('histone modification enzymes', 'Enzyme', (100, 128))	('UTX', 'Gene', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('histone modification', 'biological_process', 'GO:0016570', ('100', '120'))	('repositioning', 'Reg', (83, 96))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('drive', 'PosReg', (55, 60))	('tumor', 'Disease', (61, 66))
197646	31221981	Specific methylation of the K810 residue of Rb facilitates its interaction with CDK4 protein kinase.	('CDK4', 'Gene', (80, 84))	('methylation', 'Var', (9, 20))	('facilitates', 'PosReg', (47, 58))	('CDK4', 'Gene', '1019', (80, 84))	('K810', 'Var', (28, 32))	('Rb', 'Chemical', 'MESH:D012413', (44, 46))	('interaction', 'Interaction', (63, 74))	('CDK', 'molecular_function', 'GO:0004693', ('80', '83'))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('K810', 'Chemical', '-', (28, 32))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
197647	31221981	JMJD3 demethylates the K810 residue of Rb, which prevents CDK4 from phosphorylating the S807 and S811 residues of Rb in senescent cells.	('CDK4', 'Gene', '1019', (58, 62))	('K810', 'Chemical', '-', (23, 27))	('Rb', 'Chemical', 'MESH:D012413', (39, 41))	('CDK', 'molecular_function', 'GO:0004693', ('58', '61'))	('S807', 'Var', (88, 92))	('JMJD3', 'Gene', (0, 5))	('prevents', 'NegReg', (49, 57))	('S811 residues', 'Var', (97, 110))	('K810', 'Var', (23, 27))	('phosphorylating', 'MPA', (68, 83))	('CDK4', 'Gene', (58, 62))	('JMJD3', 'Gene', '23135', (0, 5))	('Rb', 'Chemical', 'MESH:D012413', (114, 116))
197651	31221981	p53 increases the nuclear localization of JMJD3 via protein-protein interaction and recruits JMJD3 to its target genes, such as that encoding p21, where it demethylates the H3K27me3 repressive mark.	('p53', 'Gene', (0, 3))	('increases', 'PosReg', (4, 13))	('H3K27me3', 'Protein', (173, 181))	('JMJD3', 'Gene', '23135', (42, 47))	('JMJD3', 'Gene', '23135', (93, 98))	('p53', 'Gene', '7157', (0, 3))	('p21', 'Gene', '1026', (142, 145))	('nuclear localization', 'MPA', (18, 38))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('recruits', 'PosReg', (84, 92))	('p21', 'Gene', (142, 145))	('protein-protein', 'Protein', (52, 67))	('localization', 'biological_process', 'GO:0051179', ('26', '38'))	('JMJD3', 'Gene', (42, 47))	('JMJD3', 'Gene', (93, 98))	('demethylates', 'Var', (156, 168))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
197657	31221981	Loss of JMJD3 heterozygosity at chromosome 17p13.1 increased the aggressiveness of pancreatic ductal adenocarcinoma.	('increased', 'PosReg', (51, 60))	('JMJD3', 'Gene', (8, 13))	('JMJD3', 'Gene', '23135', (8, 13))	('aggressiveness of pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (65, 115))	('Loss', 'NegReg', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('heterozygosity', 'Var', (14, 28))	('aggressiveness of pancreatic ductal adenocarcinoma', 'Disease', (65, 115))	('aggressiveness', 'Phenotype', 'HP:0000718', (65, 79))	('chromosome', 'cellular_component', 'GO:0005694', ('32', '42'))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (83, 115))
197664	31221981	For example, the absence of JMJD3 is permissive for cell division under senescence stimuli in tumors that express senescence effectors such as p16, p53, and Rb, indicating that JMJD3 functions as a tumor suppressor.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('JMJD3', 'Gene', '23135', (28, 33))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('198', '214'))	('absence', 'Var', (17, 24))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('JMJD3', 'Gene', (28, 33))	('cell division', 'biological_process', 'GO:0051301', ('52', '65'))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor suppressor', 'biological_process', 'GO:0051726', ('198', '214'))	('Rb', 'Chemical', 'MESH:D012413', (157, 159))	('JMJD3', 'Gene', '23135', (177, 182))	('tumors', 'Disease', (94, 100))	('JMJD3', 'Gene', (177, 182))	('p16', 'Gene', (143, 146))	('p53', 'Gene', '7157', (148, 151))	('senescence', 'biological_process', 'GO:0010149', ('114', '124'))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumor', 'Disease', (198, 203))	('p16', 'Gene', '1029', (143, 146))	('p53', 'Gene', (148, 151))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('senescence', 'biological_process', 'GO:0010149', ('72', '82'))	('tumor', 'Disease', (94, 99))
197669	31221981	Therefore, an increase in the robustness of the SASP due to JMJD3 reactivation might trigger both cellular senescence and immune responses.	('reactivation', 'Var', (66, 78))	('robustness', 'MPA', (30, 40))	('immune responses', 'CPA', (122, 138))	('SASP', 'Gene', (48, 52))	('trigger', 'Reg', (85, 92))	('SASP', 'Gene', '7295', (48, 52))	('cellular senescence', 'CPA', (98, 117))	('JMJD3', 'Gene', (60, 65))	('cellular senescence', 'biological_process', 'GO:0090398', ('98', '117'))	('JMJD3', 'Gene', '23135', (60, 65))	('increase', 'PosReg', (14, 22))
197670	31221981	Conversely, JMJD3 reactivation might facilitate the recruitment of stem cells to tumors to replace old damaged cells, leading to tumor progression.	('tumors', 'Disease', (81, 87))	('leading to', 'Reg', (118, 128))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('JMJD3', 'Gene', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('JMJD3', 'Gene', '23135', (12, 17))	('facilitate', 'PosReg', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('recruitment', 'CPA', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (129, 134))	('reactivation', 'Var', (18, 30))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (81, 86))
197677	31221981	A better understanding of the molecular mechanisms through which mutations in histone demethylases promote epigenetic plasticity to drive cancer progression will guide precision therapeutic strategies for the selection of histone demethylase and methyl-transferase inhibitors.	('drive', 'PosReg', (132, 137))	('cancer', 'Disease', (138, 144))	('promote', 'PosReg', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('epigenetic plasticity', 'MPA', (107, 128))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('mutations', 'Var', (65, 74))
197751	27666332	Although CCL2 expression did not affect cell proliferation in vitro, CCL2 overexpression enhanced and CCL2 knockdown suppressed tumor growth, angiogenesis, and macrophage infiltration in vivo.	('knockdown', 'Var', (107, 116))	('CCL2', 'Gene', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('CCL', 'molecular_function', 'GO:0044101', ('9', '12'))	('enhanced', 'PosReg', (89, 97))	('CCL2', 'Gene', (69, 73))	('angiogenesis', 'biological_process', 'GO:0001525', ('142', '154'))	('suppressed', 'NegReg', (117, 127))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CCL', 'molecular_function', 'GO:0044101', ('102', '105'))	('CCL', 'molecular_function', 'GO:0044101', ('69', '72'))	('tumor', 'Disease', (128, 133))	('cell proliferation', 'biological_process', 'GO:0008283', ('40', '58'))	('angiogenesis', 'CPA', (142, 154))
197759	27666332	Mutation of the von Hippel-Lindau tumor suppressor gene (VHL) occurs in approximately 60% of sporadic ccRCCs 3.	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('Mutation', 'Var', (0, 8))	('occurs', 'Reg', (62, 68))	('VHL', 'Gene', (57, 60))	('von Hippel-Lindau tumor', 'Disease', 'MESH:D006623', (16, 39))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))	('von Hippel-Lindau tumor', 'Disease', (16, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('RCC', 'Disease', (104, 107))
197806	27666332	Similarly, CCL2 expression was also higher in VHL -/- UMRC2-HA cells than wt-VHL-expressing UMRC2-VHL cells 14.	('VHL -/- UMRC2-HA', 'Var', (46, 62))	('higher', 'PosReg', (36, 42))	('UMRC2', 'CellLine', 'CVCL:2739', (92, 97))	('UMRC2', 'CellLine', 'CVCL:2739', (54, 59))	('CCL2', 'Gene', (11, 15))	('expression', 'MPA', (16, 26))	('CCL', 'molecular_function', 'GO:0044101', ('11', '14'))
197817	27666332	Immunohistochemistry for CD31 and F4/80 revealed that tumors from 786-O/shCCL2 cells showed significantly lower MVD and macrophage infiltration than tumors from 786-O scramble cells (Fig.	('F4/80', 'Gene', (34, 39))	('lower', 'NegReg', (106, 111))	('F4/80', 'Gene', '13733', (34, 39))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('786-O/shCCL2', 'Var', (66, 78))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
197823	27666332	Immunohistochemical analysis showed a lower number of infiltrated macrophages in the clodronate liposome-treated tumors compared with the control liposome-treated tumors (Fig.	('clodronate', 'Chemical', 'MESH:D004002', (85, 95))	('lower', 'NegReg', (38, 43))	('liposome-treated', 'Var', (96, 112))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
197831	27666332	We observed significantly less macrophage infiltration in xenografts with CCL2NA treatment compared with those treated with control IgG or bevacizumab, indicating that macrophage recruitment was also sensitive to CCL2 inhibition (Fig.	('CCL2NA', 'Chemical', '-', (74, 80))	('CCL', 'molecular_function', 'GO:0044101', ('213', '216'))	('bevacizumab', 'Chemical', 'MESH:D000068258', (139, 150))	('macrophage infiltration', 'CPA', (31, 54))	('macrophage recruitment', 'CPA', (168, 190))	('less', 'NegReg', (26, 30))	('CCL', 'molecular_function', 'GO:0044101', ('74', '77'))	('CCL2NA', 'Var', (74, 80))
197834	27666332	In this study, we used the primary RCC xenograft named KURC3 (Kyoto University Renal Cancer 3); the histopathological diagnosis of the primary tumor was ccRCC Fuhrman grade IV, pT3bN2M0.	('RCC', 'Disease', (35, 38))	('pT3bN2M0', 'Var', (177, 185))	('RCC', 'Disease', (155, 158))	('Cancer', 'Phenotype', 'HP:0002664', (85, 91))	('RCC', 'Disease', 'MESH:C538614', (155, 158))	('Renal Cancer', 'Phenotype', 'HP:0009726', (79, 91))	('primary tumor', 'Disease', (135, 148))	('Renal Cancer', 'Disease', 'MESH:D007680', (79, 91))	('Renal Cancer', 'Disease', (79, 91))	('primary tumor', 'Disease', 'MESH:D009369', (135, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
197838	27666332	The VHL mutation, p.Phe76del (c.227-229delTCT), was identified in primary and xenograft tumors.	('xenograft tumors', 'Disease', (78, 94))	('p.Phe76del', 'Mutation', 'rs5030648', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('xenograft tumors', 'Disease', 'MESH:D009369', (78, 94))	('VHL', 'Gene', (4, 7))	('c.227-229delTCT', 'Mutation', 'rs5030648', (30, 45))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('p.Phe76del (c.227-229delTCT', 'Var', (18, 45))
197841	27666332	As with the treatment of bevacizumab, CCL2NA significantly inhibited tumor growth compared with IgG treatment (Fig.	('CCL2NA', 'Var', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('CCL', 'molecular_function', 'GO:0044101', ('38', '41'))	('inhibited', 'NegReg', (59, 68))	('CCL2NA', 'Chemical', '-', (38, 44))	('bevacizumab', 'Chemical', 'MESH:D000068258', (25, 36))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
197842	27666332	Interestingly, the combination therapy of CCL2NA and bevacizumab resulted in significant inhibition of tumor growth compared with bevacizumab alone (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('CCL2NA', 'Var', (42, 48))	('bevacizumab', 'Chemical', 'MESH:D000068258', (53, 64))	('bevacizumab', 'Chemical', 'MESH:D000068258', (130, 141))	('tumor', 'Disease', (103, 108))	('CCL2NA', 'Chemical', '-', (42, 48))	('inhibition', 'NegReg', (89, 99))	('CCL', 'molecular_function', 'GO:0044101', ('42', '45'))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
197843	27666332	Immunohistochemical studies revealed significant decreases in MVD and macrophage infiltration of CCL2NA-treated tumors compared with IgG-treated tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('decreases', 'NegReg', (49, 58))	('tumors', 'Disease', (112, 118))	('tumors', 'Disease', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('CCL', 'molecular_function', 'GO:0044101', ('97', '100'))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('CCL2NA', 'Chemical', '-', (97, 103))	('CCL2NA-treated', 'Var', (97, 111))
197845	27666332	Upon combined treatment with CCL2NA and bevacizumab, however, macrophage infiltration was decreased compared with bevacizumab alone.	('bevacizumab', 'Chemical', 'MESH:D000068258', (114, 125))	('macrophage infiltration', 'CPA', (62, 85))	('CCL2NA', 'Var', (29, 35))	('bevacizumab', 'Chemical', 'MESH:D000068258', (40, 51))	('decreased', 'NegReg', (90, 99))	('CCL', 'molecular_function', 'GO:0044101', ('29', '32'))	('CCL2NA', 'Chemical', '-', (29, 35))
197859	27666332	Using a WT8 subclone in which CCL2 was overexpressed and a 786-O subclone in which CCL2 expression was knocked down, we found that CCL2 overexpression enhanced and CCL2 knockdown suppressed tumor growth, angiogenesis, and macrophage infiltration in vivo.	('angiogenesis', 'biological_process', 'GO:0001525', ('204', '216'))	('overexpression enhanced', 'PosReg', (136, 159))	('angiogenesis', 'CPA', (204, 216))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('CCL', 'molecular_function', 'GO:0044101', ('83', '86'))	('CCL', 'molecular_function', 'GO:0044101', ('164', '167'))	('knockdown', 'Var', (169, 178))	('CCL2', 'Gene', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('suppressed', 'NegReg', (179, 189))	('CCL', 'molecular_function', 'GO:0044101', ('131', '134'))	('tumor', 'Disease', (190, 195))	('CCL2', 'Gene', (131, 135))	('CCL', 'molecular_function', 'GO:0044101', ('30', '33'))
197863	27666332	A previous study also showed that treatment of immunodeficient mice bearing mammary tumors with anti-CCL2 antibodies resulted in significant inhibition of lung metastases and increase in survival, and the mechanism was attributed to the direct angiogenic effect of CCL2 29.	('inhibition', 'NegReg', (141, 151))	('immunodeficient', 'Disease', 'MESH:D007153', (47, 62))	('immunodeficient', 'Disease', (47, 62))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('anti-CCL2 antibodies', 'Var', (96, 116))	('metastases', 'Disease', (160, 170))	('CCL', 'molecular_function', 'GO:0044101', ('265', '268'))	('mice', 'Species', '10090', (63, 67))	('antibodies', 'Var', (106, 116))	('increase', 'PosReg', (175, 183))	('survival', 'CPA', (187, 195))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('metastases', 'Disease', 'MESH:D009362', (160, 170))	('CCL', 'molecular_function', 'GO:0044101', ('101', '104'))
197874	27666332	Indeed, we observed expression of macrophages predominantly with M2 marker MRC1/CD206 and Arginase1 but not with M1 marker iNOS, indicating these macrophages predominantly polarized to M2 phenotype in CCL2 overexpressed xenograft tumors (Fig.	('xenograft tumors', 'Disease', 'MESH:D009369', (220, 236))	('Arginase1', 'Gene', (90, 99))	('MRC1/CD206', 'Var', (75, 85))	('Arginase1', 'Gene', '383', (90, 99))	('overexpressed', 'PosReg', (206, 219))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('xenograft tumors', 'Disease', (220, 236))	('CCL2', 'Gene', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('CCL', 'molecular_function', 'GO:0044101', ('201', '204'))
197878	27666332	To examine the effect of inhibiting CCL2 activity in the clinical relevant RCC model, we administered CCL2 neutralizing antibodies to primary RCC xenografts, which similarly resulted in significant suppression of tumor growth, angiogenesis, and macrophage infiltration.	('tumor', 'Disease', (213, 218))	('CCL2', 'Gene', (102, 106))	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('angiogenesis', 'biological_process', 'GO:0001525', ('227', '239'))	('antibodies', 'Var', (120, 130))	('CCL', 'molecular_function', 'GO:0044101', ('36', '39'))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('clinical', 'Species', '191496', (57, 65))	('suppression', 'NegReg', (198, 209))	('CCL', 'molecular_function', 'GO:0044101', ('102', '105'))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('angiogenesis', 'CPA', (227, 239))	('macrophage infiltration', 'CPA', (245, 268))
197879	27666332	Although CCL2NA alone was effective, the combination therapy of CCL2NA and bevacizumab resulted in significant inhibition of tumor growth compared with each agent alone.	('CCL', 'molecular_function', 'GO:0044101', ('9', '12'))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('CCL', 'molecular_function', 'GO:0044101', ('64', '67'))	('CCL2NA', 'Chemical', '-', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('bevacizumab', 'Chemical', 'MESH:D000068258', (75, 86))	('tumor', 'Disease', (125, 130))	('combination', 'Interaction', (41, 52))	('CCL2NA', 'Chemical', '-', (9, 15))	('CCL2NA', 'Var', (64, 70))	('inhibition', 'NegReg', (111, 121))
197883	27666332	Several studies have indicated that modification in the tumor microenvironment by the CCL2 axis also modulates immunological responses.	('modification', 'Var', (36, 48))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('CCL', 'molecular_function', 'GO:0044101', ('86', '89'))	('immunological responses', 'CPA', (111, 134))	('modulates', 'Reg', (101, 110))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
197943	28596583	The K trans of ccRCC and non-ccRCC (0.459 +- 0.190 min-1 and 0.251 +- 0.130 min-1, respectively) was statistically significantly different (p < 0.001).	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('min-1', 'Gene', '966', (51, 56))	('ccRCC', 'Phenotype', 'HP:0006770', (15, 20))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))	('min-1', 'Gene', (76, 81))	('min-1', 'Gene', (51, 56))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('min-1', 'Gene', '966', (76, 81))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))	('0.251', 'Var', (61, 66))
197958	28596583	For ccRCC and non-ccRCC, K trans was statistically significantly different and K trans had a large area under the ROC curve for diagnosing ccRCC (0.819); however, the V e values were not significantly different.	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('ccRCC', 'Phenotype', 'HP:0006770', (139, 144))	('K trans', 'Var', (79, 86))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('different', 'Reg', (65, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (4, 9))	('ccRCC', 'Phenotype', 'HP:0006770', (18, 23))	('RCC', 'Disease', (20, 23))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
198069	30563989	In general, pRCC is a heterogeneous RCC subtype consisting of two distinct subtypes characterised by genetic variations in the MET-gene for type 1 pRCC and in fumarate hydratase for type 2 pRCC.	('RCC', 'Disease', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('RCC', 'Disease', (36, 39))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('pRCC', 'Gene', (147, 151))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('pRCC', 'Gene', (12, 16))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('pRCC', 'Gene', '5546', (189, 193))	('MET-gene', 'Gene', (127, 135))	('pRCC', 'Gene', '5546', (147, 151))	('variations', 'Var', (109, 119))	('RCC', 'Disease', (190, 193))	('RCC', 'Phenotype', 'HP:0005584', (190, 193))	('pRCC', 'Gene', (189, 193))	('pRCC', 'Gene', '5546', (12, 16))	('RCC', 'Disease', (13, 16))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))
198087	30563989	The presence of these solutes may affect cell metabolism, which could potentially result in the development of distinct renal cancer subtypes.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('renal cancer', 'Disease', 'MESH:D007680', (120, 132))	('renal cancer', 'Phenotype', 'HP:0009726', (120, 132))	('cell metabolism', 'MPA', (41, 56))	('result in', 'Reg', (82, 91))	('men', 'Species', '9606', (103, 106))	('metabolism', 'biological_process', 'GO:0008152', ('46', '56'))	('presence', 'Var', (4, 12))	('affect', 'Reg', (34, 40))	('renal cancer', 'Disease', (120, 132))
198112	32560494	Multiple tumor cytokines correlated with mortality, most strongly interleukin-6 (IL-6); high IL-6 expression was associated with significantly decreased survival.	('IL-6', 'molecular_function', 'GO:0005138', ('81', '85'))	('high', 'Var', (88, 92))	('IL-6', 'Gene', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('IL-6', 'Gene', '3569', (93, 97))	('decreased', 'NegReg', (143, 152))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('survival', 'MPA', (153, 161))	('mortality', 'Disease', 'MESH:D003643', (41, 50))	('interleukin-6', 'Gene', (66, 79))	('IL-6', 'Gene', (81, 85))	('correlated', 'Reg', (25, 35))	('tumor', 'Disease', (9, 14))	('IL-6', 'molecular_function', 'GO:0005138', ('93', '97'))	('IL-6', 'Gene', '3569', (81, 85))	('interleukin-6', 'Gene', '3569', (66, 79))	('mortality', 'Disease', (41, 50))	('expression', 'MPA', (98, 108))
198114	32560494	In conclusion, tumor cytokine expression, body composition, and survival are closely related, with low SKM/high IL-6 expression portending worse prognosis in ccRCC.	('SKM/high', 'Var', (103, 111))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (158, 163))	('IL-6', 'Gene', (112, 116))	('IL-6', 'molecular_function', 'GO:0005138', ('112', '116'))	('IL-6', 'Gene', '3569', (112, 116))	('tumor', 'Disease', (15, 20))	('ccRCC', 'Disease', (158, 163))	('low SKM/high', 'Var', (99, 111))
198121	32560494	Additionally, low muscle mass has been shown to be a significant predictor of sorafenib toxicity in patients with metastatic renal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('metastatic renal carcinoma', 'Disease', (114, 140))	('low muscle mass', 'Phenotype', 'HP:0003199', (14, 29))	('sorafenib', 'Chemical', 'MESH:D000077157', (78, 87))	('patients', 'Species', '9606', (100, 108))	('low', 'Var', (14, 17))	('toxicity', 'Disease', 'MESH:D064420', (88, 96))	('metastatic renal carcinoma', 'Disease', 'MESH:C538445', (114, 140))	('toxicity', 'Disease', (88, 96))	('renal carcinoma', 'Phenotype', 'HP:0005584', (125, 140))
198125	32560494	Consistent with a role for inflammatory cytokines in cachexia of patients with ccRCC, cytokines and markers of the inflammatory response such as C-reactive protein, low albumin and high neutrophil-to-lymphocyte ratio are also associated with poor outcomes in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (259, 264))	('ccRCC', 'Disease', (259, 264))	('cachexia', 'Phenotype', 'HP:0004326', (53, 61))	('C-reactive protein', 'Gene', (145, 163))	('inflammatory response', 'biological_process', 'GO:0006954', ('115', '136'))	('low albumin', 'Phenotype', 'HP:0003073', (165, 176))	('cytokines', 'Var', (86, 95))	('cachexia', 'Disease', (53, 61))	('cachexia', 'Disease', 'MESH:D002100', (53, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('high', 'Var', (181, 185))	('patients', 'Species', '9606', (65, 73))	('low', 'Var', (165, 168))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('albumin', 'MPA', (169, 176))	('C-reactive protein', 'Gene', '1401', (145, 163))
198139	32560494	The combination of low SKM/high IL-6 expression showed significantly worse overall survival than the combination of high SKM/low IL-6 expression (Figure 1C).	('IL-6', 'Gene', (32, 36))	('IL-6', 'molecular_function', 'GO:0005138', ('32', '36'))	('worse', 'NegReg', (69, 74))	('IL-6', 'Gene', (129, 133))	('IL-6', 'Gene', '3569', (32, 36))	('IL-6', 'molecular_function', 'GO:0005138', ('129', '133'))	('IL-6', 'Gene', '3569', (129, 133))	('low SKM/high', 'Var', (19, 31))	('overall survival', 'MPA', (75, 91))
198147	32560494	Of all possible combinations, low SKM/high IL-6 and low SKM/high CLCF1 demonstrated the lowest overall median survival at 26.1 months (Table 5).	('CLCF1', 'Gene', (65, 70))	('IL-6', 'Gene', (43, 47))	('low SKM/high', 'Var', (52, 64))	('IL-6', 'Gene', '3569', (43, 47))	('IL-6', 'molecular_function', 'GO:0005138', ('43', '47'))	('CLCF1', 'Gene', '23529', (65, 70))	('low SKM/high', 'Var', (30, 42))	('lowest', 'NegReg', (88, 94))
198148	32560494	The combination of low SKM/high IL-6 expression had the highest risk of mortality with HR = 5.95 (95%CI = 2.86-12.38) (Table 5).	('IL-6', 'Gene', (32, 36))	('IL-6', 'molecular_function', 'GO:0005138', ('32', '36'))	('IL-6', 'Gene', '3569', (32, 36))	('mortality', 'Disease', 'MESH:D003643', (72, 81))	('low SKM/high', 'Var', (19, 31))	('expression', 'MPA', (37, 47))	('mortality', 'Disease', (72, 81))
198151	32560494	The most notable relationship is the association of the combination of low SKM/high IL-6 expression and significantly decreased survival.	('survival', 'MPA', (128, 136))	('expression', 'MPA', (89, 99))	('IL-6', 'Gene', (84, 88))	('IL-6', 'Gene', '3569', (84, 88))	('decreased', 'NegReg', (118, 127))	('IL-6', 'molecular_function', 'GO:0005138', ('84', '88'))	('low SKM/high', 'Var', (71, 83))
198163	32560494	The combination of low SKM and high IL-6 expression was shown above to be associated with a significantly decreased overall survival.	('decreased', 'NegReg', (106, 115))	('IL-6', 'molecular_function', 'GO:0005138', ('36', '40'))	('IL-6', 'Gene', (36, 40))	('expression', 'MPA', (41, 51))	('IL-6', 'Gene', '3569', (36, 40))	('low', 'Var', (19, 22))	('high', 'Var', (31, 35))	('overall', 'MPA', (116, 123))
198192	32560494	from the Veterans Administration (grant I01 BX004177), the National Institutes of Health (grants R01 CA122596 and R01 CA194593), the IU Simon Cancer Center, the Lustgarten Foundation, and the IUPUI Signature Center for Pancreatic Cancer Research, and by grants to L.G.K.	('Pancreatic Cancer', 'Disease', (219, 236))	('Cancer', 'Disease', (230, 236))	('Cancer', 'Disease', 'MESH:D009369', (230, 236))	('Cancer', 'Phenotype', 'HP:0002664', (230, 236))	('R01 CA194593', 'Var', (114, 126))	('Cancer', 'Disease', (142, 148))	('Cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Cancer', 'Disease', 'MESH:D009369', (142, 148))	('Pancreatic Cancer', 'Disease', 'MESH:D010190', (219, 236))	('Pancreatic Cancer', 'Phenotype', 'HP:0002894', (219, 236))
198197	29938199	Indeed, preclinical and clinical data have shown that pharmacological inhibitors of HIF2alpha can efficiently combat ccRCC growth.	('pharmacological inhibitors', 'Var', (54, 80))	('combat', 'PosReg', (110, 116))	('HIF2alpha', 'Gene', (84, 93))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))
198201	29938199	ccRCCs are initiated by biallelic gene inactivation of the Von Hippel-Lindau (VHL) factor in the renal epithelium.	('RCC', 'Disease', (2, 5))	('Von Hippel-Lindau', 'Gene', '7428', (59, 76))	('VHL', 'Gene', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('Von Hippel-Lindau', 'Gene', (59, 76))	('VHL', 'Gene', '7428', (78, 81))	('ccRCCs', 'Phenotype', 'HP:0006770', (0, 6))	('biallelic', 'Var', (24, 33))
198209	29938199	Initial somatic inactivation of the VHL gene in precancerous renal tubule lesions leads to HIF1alpha activation, as well as a progressive gain in HIF1alpha and HIF2alpha expression in dysplastic and cystic lesions.	('VHL', 'Gene', (36, 39))	('HIF1alpha', 'Gene', (91, 100))	('gain', 'PosReg', (138, 142))	('activation', 'PosReg', (101, 111))	('cystic lesions', 'Disease', 'MESH:D052177', (199, 213))	('VHL', 'Gene', '7428', (36, 39))	('precancerous renal tubule lesions', 'Disease', (48, 81))	('HIF2alpha', 'MPA', (160, 169))	('dysplastic', 'Disease', (184, 194))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('HIF1alpha', 'Gene', (146, 155))	('inactivation', 'Var', (16, 28))	('dysplastic', 'Disease', 'MESH:D004416', (184, 194))	('precancerous renal tubule lesions', 'Disease', 'MESH:D007674', (48, 81))	('cystic lesions', 'Disease', (199, 213))	('expression', 'MPA', (170, 180))
198211	29938199	However, HIF1alpha expression is lost in 30-40% of overt ccRCCs, since HIF1alpha acts as a tumor suppressor during further progression of ccRCC by attenuating autonomous VHL-deficient tumor cell proliferation (Figure 1).	('VHL-deficient tumor', 'Disease', 'MESH:D006623', (170, 189))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('91', '107'))	('ccRCCs', 'Phenotype', 'HP:0006770', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('attenuating', 'NegReg', (147, 158))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor suppressor', 'biological_process', 'GO:0051726', ('91', '107'))	('VHL-deficient tumor', 'Disease', (170, 189))	('tumor', 'Disease', (184, 189))	('cell proliferation', 'biological_process', 'GO:0008283', ('190', '208'))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('tumor', 'Disease', (91, 96))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('HIF1alpha', 'Var', (71, 80))
198213	29938199	Therefore, overt ccRCC can be subdivided into those cases where both HIF1alpha and HIF2alpha are expressed, and those that only show HIF2alpha expression characterized by enhanced ccRCC cell proliferation and adverse prognosis (Figure 1).	('HIF2alpha', 'Var', (83, 92))	('enhanced', 'PosReg', (171, 179))	('cell proliferation', 'biological_process', 'GO:0008283', ('186', '204'))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('HIF1alpha', 'Var', (69, 78))	('RCC', 'Disease', (19, 22))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('RCC', 'Disease', (182, 185))
198216	29938199	In addition, PT2385 also appears to improve disease control in a patient who had been administered prior with other pharmacological therapies for ccRCC.	('improve', 'PosReg', (36, 43))	('RCC', 'Disease', (148, 151))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('patient', 'Species', '9606', (65, 72))	('disease', 'MPA', (44, 51))	('PT2385', 'Var', (13, 19))
198219	29938199	Genetic or pharmacological inhibition of HIF2alpha usually in 786-O cells impairs their ability to form xenografts in nude mice and to generate colonies in soft agar conditions.	('ability', 'CPA', (88, 95))	('impairs', 'NegReg', (74, 81))	('generate', 'Reg', (135, 143))	('nude mice', 'Species', '10090', (118, 127))	('inhibition', 'Var', (27, 37))	('colonies in soft agar conditions', 'CPA', (144, 176))	('HIF2alpha', 'Gene', (41, 50))
198220	29938199	In RCC4 cells, inhibition of HIF2alpha can attenuate their normoxic in vitro cell proliferation under standard culture conditions although the extent of this effect is much less pronounced when compared with HIF2alpha inhibition in vivo in 786-O cells.	('cell proliferation', 'biological_process', 'GO:0008283', ('77', '95'))	('HIF2alpha', 'Gene', (29, 38))	('RCC4', 'CellLine', 'CVCL:0498', (3, 7))	('normoxic', 'MPA', (59, 67))	('inhibition', 'Var', (15, 25))	('attenuate', 'NegReg', (43, 52))
198227	29938199	However, from here on we will focus on other key HIF2alpha dependent, cell autonomous mechanisms that are critical to not only explain the protumoral properties of HIF2alpha in ccRCC but also the more remarkable effect of HIF2alpha in in vivo settings that are relevant to investigate ccRCC progression.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('RCC', 'Disease', 'MESH:C538614', (287, 290))	('RCC', 'Disease', (287, 290))	('HIF2alpha', 'Var', (164, 173))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('RCC', 'Disease', (179, 182))
198229	29938199	At the molecular level, HIF2alpha induces TGF-alpha expression, which in turns activates epidermal growth factor receptor (EGFR)-dependent cell signaling and proliferation (Figure 2).	('EGFR', 'Gene', (123, 127))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('TGF-alpha', 'Gene', '7039', (42, 51))	('epidermal growth factor receptor', 'Gene', '1956', (89, 121))	('expression', 'MPA', (52, 62))	('TGF-alpha', 'Gene', (42, 51))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('89', '112'))	('EGFR', 'Gene', '1956', (123, 127))	('HIF2alpha', 'Var', (24, 33))	('activates', 'PosReg', (79, 88))	('proliferation', 'CPA', (158, 171))	('epidermal growth factor receptor', 'Gene', (89, 121))
198235	29938199	Furthermore, HIF2alpha can also attenuate EGFR endocytosis, therefore, facilitating EGFR-dependent signaling in ccRCC cells.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('EGFR', 'Gene', '1956', (42, 46))	('signaling', 'biological_process', 'GO:0023052', ('99', '108'))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('EGFR', 'Gene', (42, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('EGFR', 'Gene', '1956', (84, 88))	('facilitating', 'PosReg', (71, 83))	('HIF2alpha', 'Var', (13, 22))	('EGFR', 'Gene', (84, 88))	('endocytosis', 'biological_process', 'GO:0006897', ('47', '58'))	('attenuate', 'NegReg', (32, 41))
198236	29938199	Moreover, HIF2alpha overexpression increases EGFR protein levels in 786-O cells.	('overexpression', 'Var', (20, 34))	('EGFR', 'Gene', (45, 49))	('increases', 'PosReg', (35, 44))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('HIF2alpha', 'Gene', (10, 19))	('EGFR', 'molecular_function', 'GO:0005006', ('45', '49'))	('EGFR', 'Gene', '1956', (45, 49))
198237	29938199	However, an independent study have shown that silencing endogenous HIF2alpha in 786-O does not alter EGFR protein levels in these cells.	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('silencing', 'Var', (46, 55))	('EGFR', 'molecular_function', 'GO:0005006', ('101', '105'))	('EGFR', 'Gene', '1956', (101, 105))	('HIF2alpha', 'Gene', (67, 76))	('EGFR', 'Gene', (101, 105))
198238	29938199	Regarding the functional role of EGFR in ccRCC, silencing of EGFR signaling suppresses the ability of VHL-deficient 786-O cell lines to form xenografts.	('silencing', 'Var', (48, 57))	('signaling', 'biological_process', 'GO:0023052', ('66', '75'))	('VHL-deficient', 'Disease', 'MESH:D006623', (102, 115))	('VHL-deficient', 'Disease', (102, 115))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('33', '37'))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('61', '65'))	('EGFR', 'Gene', (33, 37))	('suppresses', 'NegReg', (76, 86))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
198242	29938199	In addition, it has also been found that the cell surface glycoprotein CUB domain-containing protein 1 (CDCP1) is induced through HIF2alpha:but not HIF1alpha:in response to hypoxia.	('CUB domain-containing protein 1', 'Gene', (71, 102))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('cell surface', 'cellular_component', 'GO:0009986', ('45', '57'))	('response to hypoxia', 'biological_process', 'GO:0001666', ('161', '180'))	('induced', 'PosReg', (114, 121))	('HIF2alpha', 'Var', (130, 139))	('CDCP1', 'Gene', '64866', (104, 109))	('hypoxia', 'Disease', 'MESH:D000860', (173, 180))	('CUB domain-containing protein 1', 'Gene', '64866', (71, 102))	('hypoxia', 'Disease', (173, 180))	('CDCP1', 'Gene', (104, 109))
198244	29938199	In this line, CDCP1 is elevated in ccRCC and poor overall survival is found in patients with high CDCP1 expression.	('CDCP1', 'Gene', '64866', (98, 103))	('CDCP1', 'Gene', (98, 103))	('elevated', 'PosReg', (23, 31))	('CDCP1', 'Gene', (14, 19))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('expression', 'MPA', (104, 114))	('poor', 'NegReg', (45, 49))	('patients', 'Species', '9606', (79, 87))	('CDCP1', 'Gene', '64866', (14, 19))	('high', 'Var', (93, 97))
198245	29938199	In addition to EGFR function, HIF2alpha also potentiates the activity of the met proto-oncogene (MET) receptor.	('EGFR', 'Gene', '1956', (15, 19))	('HIF2alpha', 'Var', (30, 39))	('EGFR', 'Gene', (15, 19))	('activity', 'MPA', (61, 69))	('EGFR', 'molecular_function', 'GO:0005006', ('15', '19'))	('potentiates', 'PosReg', (45, 56))
198246	29938199	In this line, another tyrosin-kinase receptor AXL that is highly expressed in aggressive ccRCC tumors and associated with poor outcome has been shown to be a direct target gene of HIF2alpha but not HIF1alpha isoform.	('HIF2alpha', 'Var', (180, 189))	('associated', 'Reg', (106, 116))	('AXL', 'Gene', (46, 49))	('aggressive ccRCC tumors', 'Disease', (78, 101))	('aggressive ccRCC tumors', 'Disease', 'MESH:D001523', (78, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('AXL', 'Gene', '558', (46, 49))
198248	29938199	Furthermore, HIF2alpha induces the expression of CXCR4 receptor, which facilitates the ability of its ligand:stromal cell-derived factor-1a (SDF-1a):to promote ccRCC chemotaxis and influence patient survival.	('CXCR4', 'Gene', (49, 54))	('RCC', 'Disease', (162, 165))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('expression', 'MPA', (35, 45))	('influence', 'Reg', (181, 190))	('patient survival', 'CPA', (191, 207))	('ligand', 'molecular_function', 'GO:0005488', ('102', '108'))	('CXCR4', 'Gene', '7852', (49, 54))	('HIF2alpha', 'Var', (13, 22))	('CXCR4', 'molecular_function', 'GO:0038147', ('49', '54'))	('patient', 'Species', '9606', (191, 198))	('promote', 'PosReg', (152, 159))	('chemotaxis', 'biological_process', 'GO:0006935', ('166', '176'))
198250	29938199	In addition, in ccRCC, HIF1alpha and HIF2alpha have opposite effects on some c-Myc target genes that are involved in the cell cycle, providing a molecular basis for the opposite properties of both these HIF isoforms during overt ccRCC progression.	('RCC', 'Disease', (18, 21))	('RCC', 'Disease', (231, 234))	('cell cycle', 'biological_process', 'GO:0007049', ('121', '131'))	('RCC', 'Disease', 'MESH:C538614', (231, 234))	('c-Myc', 'Gene', '4609', (77, 82))	('HIF2alpha', 'Var', (37, 46))	('effects', 'Reg', (61, 68))	('c-Myc', 'Gene', (77, 82))	('RCC', 'Disease', 'MESH:C538614', (18, 21))
198251	29938199	Indeed, HIF1alpha impairs the binding of c-Myc to the regulatory regions of genes involved in the cell cycle, reducing E2F and cyclin D2 expression, while augmenting the expression of the cell cycle blockers p21 and p27.	('cell cycle', 'biological_process', 'GO:0007049', ('188', '198'))	('binding', 'molecular_function', 'GO:0005488', ('30', '37'))	('p21', 'Gene', (208, 211))	('p21', 'Gene', '644914', (208, 211))	('expression', 'MPA', (170, 180))	('augmenting', 'PosReg', (155, 165))	('E2F', 'Protein', (119, 122))	('expression', 'MPA', (137, 147))	('c-Myc', 'Gene', (41, 46))	('reducing', 'NegReg', (110, 118))	('cyclin D2', 'Gene', '894', (127, 136))	('c-Myc', 'Gene', '4609', (41, 46))	('cyclin', 'molecular_function', 'GO:0016538', ('127', '133'))	('impairs', 'NegReg', (18, 25))	('cyclin D2', 'Gene', (127, 136))	('HIF1alpha', 'Var', (8, 17))	('cell cycle', 'CPA', (188, 198))	('p27', 'Gene', '3429', (216, 219))	('p27', 'Gene', (216, 219))	('cell cycle', 'biological_process', 'GO:0007049', ('98', '108'))	('binding', 'Interaction', (30, 37))
198255	29938199	Indeed, a genetic variant at chromosome 11q13.3 is associated with a predisposition to renal cancer by permitting HIF2alpha binding to a cyclin D1 enhancer.	('HIF2alpha', 'Protein', (114, 123))	('renal cancer', 'Disease', (87, 99))	('chromosome', 'cellular_component', 'GO:0005694', ('29', '39'))	('cyclin D1', 'Gene', '595', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('associated', 'Reg', (51, 61))	('binding', 'Interaction', (124, 131))	('renal cancer', 'Phenotype', 'HP:0009726', (87, 99))	('cyclin D1', 'Gene', (137, 146))	('permitting', 'PosReg', (103, 113))	('renal cancer', 'Disease', 'MESH:D007680', (87, 99))	('cyclin', 'molecular_function', 'GO:0016538', ('137', '143'))	('binding', 'molecular_function', 'GO:0005488', ('124', '131'))	('variant', 'Var', (18, 25))
198257	29938199	Silencing cyclin D1 in 786-O cells does not alter their in vitro cell growth, but it does markedly attenuate their ability to form xenografts.	('cyclin', 'molecular_function', 'GO:0016538', ('10', '16'))	('cell growth', 'biological_process', 'GO:0016049', ('65', '76'))	('ability to form xenografts', 'CPA', (115, 141))	('cyclin D1', 'Gene', '595', (10, 19))	('Silencing', 'Var', (0, 9))	('cyclin D1', 'Gene', (10, 19))	('attenuate', 'NegReg', (99, 108))
198260	29938199	Indeed, HIF2alpha induces the expression of several antioxidant enzymes in ccRCC, which restrict the oxidative stress-dependent p53 activation (Figure 2).	('expression', 'MPA', (30, 40))	('activation', 'PosReg', (132, 142))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (128, 131))	('induces', 'PosReg', (18, 25))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('HIF2alpha', 'Var', (8, 17))	('RCC', 'Disease', (77, 80))	('oxidative stress', 'Phenotype', 'HP:0025464', (101, 117))	('oxidative stress-dependent', 'MPA', (101, 127))
198261	29938199	Therefore, inhibition of HIF2alpha permits the accumulation of reactive oxygen species (ROS) and DNA damage, leading to apoptosis and reduced survival of ccRCC cells.	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('DNA damage', 'MPA', (97, 107))	('apoptosis', 'CPA', (120, 129))	('RCC', 'Disease', (156, 159))	('ROS', 'Chemical', 'MESH:D017382', (88, 91))	('reactive oxygen species', 'MPA', (63, 86))	('apoptosis', 'biological_process', 'GO:0097194', ('120', '129'))	('apoptosis', 'biological_process', 'GO:0006915', ('120', '129'))	('inhibition', 'Var', (11, 21))	('survival', 'CPA', (142, 150))	('reduced', 'NegReg', (134, 141))	('HIF2alpha', 'Protein', (25, 34))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (63, 86))	('reduced', 'Chemical', '-', (134, 141))	('accumulation', 'PosReg', (47, 59))
198267	29938199	Along similar lines, HIF2alpha provides both an in vitro growth advantage to ccRCC cells as well as a potentiation of mTORC1 activity when cells are exposed to low amino acid supply, which to some extent could mimic the limited intratumoral amino acid availability.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('mTORC1', 'Gene', (118, 124))	('mTORC1', 'cellular_component', 'GO:0031931', ('118', '124'))	('tumor', 'Disease', (233, 238))	('potentiation', 'PosReg', (102, 114))	('activity', 'MPA', (125, 133))	('mTORC1', 'Gene', '382056', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('HIF2alpha', 'Var', (21, 30))	('RCC', 'Disease', (79, 82))
198268	29938199	At the molecular level, HIF2alpha induces the expression of the amino acid carrier SLC7A5 (LAT-1), which is essential to promote amino acid-dependent mTORC1 activation, and to sustain the potential of 786-O cells to form xenografts in nude mice (Figure 2).	('carrier', 'molecular_function', 'GO:0005215', ('75', '82'))	('mTORC1', 'Gene', '382056', (150, 156))	('SLC7A5', 'Gene', '8140', (83, 89))	('LAT-1', 'Gene', (91, 96))	('nude mice', 'Species', '10090', (235, 244))	('SLC7A5', 'Gene', (83, 89))	('mTORC1', 'Gene', (150, 156))	('LAT-1', 'Gene', '8140', (91, 96))	('mTORC1', 'cellular_component', 'GO:0031931', ('150', '156'))	('HIF2alpha', 'Var', (24, 33))	('expression', 'MPA', (46, 56))
198275	29938199	Paradoxically, HIF2alpha also increases the expression of REDD1, a well-recognized mTORC1 inhibitor.	('expression', 'MPA', (44, 54))	('REDD1', 'Gene', (58, 63))	('HIF2alpha', 'Var', (15, 24))	('mTORC1', 'Gene', '382056', (83, 89))	('mTORC1', 'cellular_component', 'GO:0031931', ('83', '89'))	('REDD1', 'Gene', '54541', (58, 63))	('increases', 'PosReg', (30, 39))	('mTORC1', 'Gene', (83, 89))
198278	29938199	Indeed, it is likely that elevated REDD1 in ccRCC could limit full mTORC1 activation but not potent enough to prevent HIF2alpha-dependent mTORC1 activated pathways.	('mTORC1', 'Gene', (138, 144))	('RCC', 'Disease', (46, 49))	('mTORC1', 'Gene', (67, 73))	('mTORC1', 'cellular_component', 'GO:0031931', ('67', '73'))	('REDD1', 'Gene', (35, 40))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('mTORC1', 'cellular_component', 'GO:0031931', ('138', '144'))	('limit', 'NegReg', (56, 61))	('mTORC1', 'Gene', '382056', (138, 144))	('mTORC1', 'Gene', '382056', (67, 73))	('elevated', 'Var', (26, 34))	('activation', 'MPA', (74, 84))	('REDD1', 'Gene', '54541', (35, 40))
198279	29938199	However, HIF2alpha is also a potent inducer of glucose transporter-1 (GLUT-1) and of enolase 2 (ENO2) in ccRCC (Figure 2), which also anticipates an increased rate of glycolysis in cells expressing only HIF2alpha.	('GLUT-1', 'Gene', (70, 76))	('GLUT-1', 'Gene', '6513', (70, 76))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('glycolysis', 'biological_process', 'GO:0006096', ('167', '177'))	('RCC', 'Disease', (107, 110))	('glucose transporter-1', 'Gene', '6513', (47, 68))	('increased', 'PosReg', (149, 158))	('HIF2alpha', 'Var', (9, 18))	('ENO2', 'Gene', '2026', (96, 100))	('glucose transporter-1', 'Gene', (47, 68))	('enolase 2', 'Gene', '2026', (85, 94))	('inducer', 'PosReg', (36, 43))	('ENO2', 'Gene', (96, 100))	('enolase 2', 'Gene', (85, 94))
198281	29938199	Regarding the relative contribution of GLUT-1 to ccRCC biology, VHL-deficient RCC4 cells are particularly sensitive to glucose deprivation and GLUT-1 silencing provokes apoptosis of these cells.	('RCC4', 'CellLine', 'CVCL:0498', (78, 82))	('apoptosis', 'CPA', (169, 178))	('apoptosis', 'biological_process', 'GO:0097194', ('169', '178'))	('VHL-deficient', 'Disease', 'MESH:D006623', (64, 77))	('VHL-deficient', 'Disease', (64, 77))	('glucose deprivation', 'Disease', 'MESH:D012892', (119, 138))	('apoptosis', 'biological_process', 'GO:0006915', ('169', '178'))	('GLUT-1', 'Gene', (39, 45))	('GLUT-1', 'Gene', '6513', (39, 45))	('RCC', 'Disease', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('silencing', 'Var', (150, 159))	('glucose deprivation', 'Disease', (119, 138))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('provokes', 'Reg', (160, 168))	('GLUT-1', 'Gene', (143, 149))	('GLUT-1', 'Gene', '6513', (143, 149))	('RCC', 'Disease', (51, 54))
198283	29938199	Surprisingly, an independent study has shown that silencing of GLUT-1 or ENO-2 does not prevent these 786-O cells from generating xenografts.	('GLUT-1', 'Gene', (63, 69))	('GLUT-1', 'Gene', '6513', (63, 69))	('ENO-2', 'Gene', (73, 78))	('ENO-2', 'Gene', '2026', (73, 78))	('silencing', 'Var', (50, 59))
198286	29938199	Furthermore, HIF2alpha not only increases GLUT-1 expression, probably to increase in the glycolytic rate but also, it simultaneously attenuates glucose oxidation in parallel with an increase in glutamine usage via the reductive carboxylation pathway.	('increase', 'PosReg', (182, 190))	('reductive carboxylation pathway', 'Pathway', (218, 249))	('increase', 'PosReg', (73, 81))	('glutamine', 'Chemical', 'MESH:D005973', (194, 203))	('expression', 'MPA', (49, 59))	('glutamine usage', 'MPA', (194, 209))	('glucose', 'Chemical', 'MESH:D005947', (144, 151))	('HIF2alpha', 'Var', (13, 22))	('increases', 'PosReg', (32, 41))	('glucose oxidation', 'MPA', (144, 161))	('glycolytic rate', 'MPA', (89, 104))	('GLUT-1', 'Gene', (42, 48))	('GLUT-1', 'Gene', '6513', (42, 48))	('attenuates', 'NegReg', (133, 143))
198292	29938199	First, HIF2alpha drives lipid deposition in ccRCC by repressing fatty acid oxidation, specifically the rate-limiting component of mitochondrial fatty acid transport, carnitine palmitoyltransferase 1A (CPT1A).	('carnitine palmitoyltransferase 1A', 'Gene', '1374', (166, 199))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('64', '84'))	('RCC', 'Disease', (46, 49))	('lipid', 'Chemical', 'MESH:D008055', (24, 29))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('fatty acid transport', 'biological_process', 'GO:0015908', ('144', '164'))	('CPT', 'molecular_function', 'GO:0004142', ('201', '204'))	('carnitine palmitoyltransferase 1A', 'Gene', (166, 199))	('repressing', 'NegReg', (53, 63))	('CPT', 'molecular_function', 'GO:0004095', ('201', '204'))	('fatty acid', 'Chemical', 'MESH:D005227', (144, 154))	('CPT1A', 'Gene', (201, 206))	('fatty acid', 'Chemical', 'MESH:D005227', (64, 74))	('fatty acid oxidation', 'MPA', (64, 84))	('HIF2alpha', 'Var', (7, 16))	('CPT1A', 'Gene', '1374', (201, 206))
198293	29938199	Second, HIF2alpha can reduce mitochondrial content as well as key factors in mitochondrial biogenesis that also characterized VHL-deficient renal cell carcinoma cells which can also explain not only reduced fatty acid oxidation but also glucose oxidation in ccRCC cells.	('VHL-deficient renal cell carcinoma', 'Disease', 'MESH:C538614', (126, 160))	('reduce', 'NegReg', (22, 28))	('fatty acid', 'Chemical', 'MESH:D005227', (207, 217))	('reduced', 'Chemical', '-', (199, 206))	('HIF2alpha', 'Var', (8, 17))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('207', '227'))	('fatty acid oxidation', 'MPA', (207, 227))	('RCC', 'Disease', 'MESH:C538614', (260, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('VHL-deficient renal cell carcinoma', 'Disease', (126, 160))	('RCC', 'Disease', (260, 263))	('mitochondrial content', 'MPA', (29, 50))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (140, 160))	('glucose oxidation', 'MPA', (237, 254))	('reduce mitochondrial content', 'Phenotype', 'HP:0040013', (22, 50))	('glucose', 'Chemical', 'MESH:D005947', (237, 244))	('mitochondrial biogenesis', 'MPA', (77, 101))	('reduced', 'NegReg', (199, 206))
198299	29938199	In this line, HIF2alpha favors simultaneously the expression of GLUT-1 glucose transporter, SLC7A5 amino acid carrier, as well as VEGFa-dependent angiogenesis, which all together can favor ccRCC nutrient and oxygen supply in vivo.	('RCC', 'Disease', (191, 194))	('angiogenesis', 'biological_process', 'GO:0001525', ('146', '158'))	('SLC7A5', 'Gene', '8140', (92, 98))	('favor', 'PosReg', (183, 188))	('RCC', 'Disease', 'MESH:C538614', (191, 194))	('VEGFa', 'Gene', '7422', (130, 135))	('glucose', 'Chemical', 'MESH:D005947', (71, 78))	('favors', 'PosReg', (24, 30))	('VEGFa', 'Gene', (130, 135))	('GLUT-1', 'Gene', (64, 70))	('GLUT-1', 'Gene', '6513', (64, 70))	('carrier', 'molecular_function', 'GO:0005215', ('110', '117'))	('oxygen', 'Chemical', 'MESH:D010100', (208, 214))	('SLC7A5', 'Gene', (92, 98))	('HIF2alpha', 'Var', (14, 23))	('expression', 'MPA', (50, 60))
198300	29938199	Moreover, HIF2alpha also potentiates EGFR signaling and promotes signals that alleviate oxidative and ER stress promoting ccRCC survival.	('RCC', 'Disease', (124, 127))	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('EGFR', 'Gene', (37, 41))	('alleviate', 'PosReg', (78, 87))	('potentiates', 'PosReg', (25, 36))	('signals', 'MPA', (65, 72))	('EGFR', 'Gene', '1956', (37, 41))	('promotes', 'PosReg', (56, 64))	('HIF2alpha', 'Var', (10, 19))	('promoting', 'PosReg', (112, 121))
198324	32194829	Cohort A was from PREDIR and included 12 patients with hereditary pVHL mutations and 22 sporadic patients presenting tumors with wild-type pVHL or mutated pVHL; Cohort B included tissue samples from 43 patients with non-metastatic ccRCC who had undergone surgery; and Cohort C was composed of 375 non-metastatic ccRCC tumor samples from The Cancer Genome Atlas (TCGA) and was used for validation.	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('RCC', 'Disease', (233, 236))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (341, 360))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('RCC', 'Disease', (314, 317))	('tumors', 'Disease', (117, 123))	('patients', 'Species', '9606', (202, 210))	('mutations', 'Var', (71, 80))	('Cancer', 'Phenotype', 'HP:0002664', (341, 347))	('tumor', 'Disease', (318, 323))	('RCC', 'Disease', 'MESH:C538614', (233, 236))	('mutated', 'Var', (147, 154))	('Cancer Genome Atlas', 'Disease', (341, 360))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('pVHL', 'Gene', '7428', (155, 159))	('pVHL', 'Gene', '7428', (139, 143))	('RCC', 'Disease', 'MESH:C538614', (314, 317))	('pVHL', 'Gene', (155, 159))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('pVHL', 'Gene', (139, 143))	('patients', 'Species', '9606', (41, 49))	('CGA', 'Gene', (363, 366))	('patients', 'Species', '9606', (97, 105))	('pVHL', 'Gene', '7428', (66, 70))	('pVHL', 'Gene', (66, 70))	('tumor', 'Disease', (117, 122))	('CGA', 'Gene', '1113', (363, 366))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
198339	32194829	Mutations or deletions in the VHL gene, in addition to methylation, are characteristic features of: (i) a rare hereditary tumor disease caused by germline alterations of the VHL gene and (ii) sporadic clear cell renal cell carcinoma (ccRCC) lacking cilia.	('alterations', 'Var', (155, 166))	('VHL', 'Gene', (30, 33))	('RCC', 'Disease', 'MESH:C538614', (236, 239))	('deletions', 'Var', (13, 22))	('VHL', 'Gene', '7428', (174, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('caused by', 'Reg', (136, 145))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (201, 232))	('VHL', 'Gene', '7428', (30, 33))	('Mutations', 'Var', (0, 9))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (212, 232))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))	('hereditary tumor disease', 'Disease', 'MESH:D030342', (111, 135))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('hereditary tumor disease', 'Disease', (111, 135))	('RCC', 'Disease', (236, 239))	('VHL', 'Gene', (174, 177))	('renal cell carcinoma', 'Disease', (212, 232))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (212, 232))
198346	32194829	We characterized its cleavage by the asparagine endopeptidase (Legumain, LGMN) at asparagine 214 to produce VDAC1-DeltaC.	('VDAC1-DeltaC', 'Gene', (108, 120))	('asparagine', 'Var', (82, 92))	('asparagine', 'Chemical', 'MESH:D001216', (37, 47))	('VDAC1-DeltaC', 'Gene', '7416', (108, 120))	('asparagine', 'Chemical', 'MESH:D001216', (82, 92))	('LGMN', 'Gene', (73, 77))	('LGMN', 'Gene', '5641', (73, 77))
198347	32194829	We also showed that the knockout of Vdac1 in murine embryonic fibroblasts (MEFs) expressing oncogenic RAS potentiates tumor development in mice by promoting metabolic reprogramming, accelerating vascular destabilization and inflammation.	('MEFs', 'CellLine', 'CVCL:9115;0.18547283106508738', (75, 79))	('promoting', 'PosReg', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('Vdac1', 'Gene', '22333', (36, 41))	('inflammation', 'biological_process', 'GO:0006954', ('224', '236'))	('accelerating', 'PosReg', (182, 194))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('oncogenic RAS', 'Var', (92, 105))	('vascular destabilization', 'CPA', (195, 219))	('metabolic reprogramming', 'CPA', (157, 180))	('tumor', 'Disease', (118, 123))	('Vdac1', 'Gene', (36, 41))	('potentiates', 'PosReg', (106, 117))	('mice', 'Species', '10090', (139, 143))	('knockout', 'Var', (24, 32))	('murine', 'Species', '10090', (45, 51))	('inflammation', 'Disease', 'MESH:D007249', (224, 236))	('inflammation', 'Disease', (224, 236))
198372	32194829	The antibodies against HIF-2alpha (NB100-122) and ARL13b (NBP2-15463) were purchased from Novus Biologicals (Littleton, CA).	('NB100-122', 'Var', (35, 44))	('HIF-2alpha', 'Gene', (23, 33))	('ARL13b', 'Gene', (50, 56))	('HIF-2alpha', 'Gene', '2034', (23, 33))	('ARL13b', 'Gene', '200894', (50, 56))
198373	32194829	Mouse anti-acetylated alpha-tubulin (T7451), anti-beta-tubulin, HSP90 and beta-actin were from Sigma.	('alpha-tubulin', 'Gene', '10376', (22, 35))	('HSP90', 'Gene', (64, 69))	('beta-actin', 'Gene', (74, 84))	('HSP90', 'Gene', '111042', (64, 69))	('beta-actin', 'Gene', '11461', (74, 84))	('Mouse', 'Species', '10090', (0, 5))	('alpha-tubulin', 'Gene', (22, 35))	('anti-beta-tubulin', 'Var', (45, 62))	('T7451', 'Var', (37, 42))
198381	32194829	The cubes used were A4 (excitation filter BP 360/40, dichroic mirror 400, emission filter BP 470/40), L5 (BP 480/40, 505, BP 527/30), and TX2 (BP 560/40, 595, BP645/75).	('BP645/75', 'Gene', (159, 167))	('BP 527/30', 'Var', (122, 131))	('BP645/75', 'Gene', '23629', (159, 167))	('BP 480/40, 505', 'Var', (106, 120))	('BP 560/40', 'Var', (143, 152))	('BP 470/40), L5', 'Gene', '9768', (90, 104))
198412	32194829	Different parameters were available for 375 ccRCC tumor samples, with information for VHL status (methylation, mutation and deletion).	('RCC', 'Disease', (46, 49))	('methylation', 'biological_process', 'GO:0032259', ('98', '109'))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mutation', 'Var', (111, 119))	('VHL', 'Gene', (86, 89))	('deletion', 'Var', (124, 132))	('tumor', 'Disease', (50, 55))	('VHL', 'Gene', '7428', (86, 89))
198414	32194829	To assess the effect of the presence or absence of the primary cilium in ccRCC from Cohort C, we performed a differential analysis between the group expressing the primary cilium (n=48 patients) and the group expressing no primary cilium (n=327 patients) by computing the ratio and p-values obtained with a Wilcoxon rank sum test.	('primary cilium', 'cellular_component', 'GO:0005929', ('164', '178'))	('patients', 'Species', '9606', (245, 253))	('primary cilium', 'cellular_component', 'GO:0097731', ('55', '69'))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('primary cilium', 'Var', (164, 178))	('RCC', 'Disease', (75, 78))	('primary cilium', 'cellular_component', 'GO:0005929', ('55', '69'))	('primary cilium', 'cellular_component', 'GO:0097731', ('164', '178'))	('patients', 'Species', '9606', (185, 193))	('primary cilium', 'cellular_component', 'GO:0097731', ('223', '237'))	('primary cilium', 'cellular_component', 'GO:0005929', ('223', '237'))
198423	32194829	Fourteen out of 19 (73.7%) were classified with high VDAC1 expression and the presence of VDAC1-DeltaC in tumor tissues (defined as group A) whereas five out of 19 (26.3%) were classified with a low level of VDAC1 and the absence of VDAC1-DeltaC (defined as group B; Figure 1E-F).	('VDAC1', 'Gene', (53, 58))	('VDAC1-DeltaC', 'Gene', (90, 102))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('expression', 'MPA', (59, 69))	('VDAC1-DeltaC', 'Gene', '7416', (233, 245))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('presence', 'Var', (78, 86))	('VDAC1-DeltaC', 'Gene', (233, 245))	('VDAC1-DeltaC', 'Gene', '7416', (90, 102))	('tumor', 'Disease', (106, 111))
198430	32194829	As previously shown, analysis of VHL mutant RCC4 cell lines, in which the wild-type VHL gene has been restored (RCC4+pVHL), and thus mimicking normoxia with no stabilization of either HIF-1alpha or -2alpha, showed no VDAC1-DeltaC whereas RCC4 cells with both stabilization of HIF-1alpha or -2alpha expressed VDAC1-DeltaC.	('VHL', 'Gene', (118, 121))	('VDAC1-DeltaC', 'Gene', '7416', (308, 320))	('VDAC1-DeltaC', 'Gene', (308, 320))	('VHL', 'Gene', '7428', (33, 36))	('RCC4', 'Gene', '84925', (44, 48))	('VHL', 'Gene', (84, 87))	('pVHL', 'Gene', '7428', (117, 121))	('VHL', 'Gene', '7428', (118, 121))	('pVHL', 'Gene', (117, 121))	('RCC4', 'Gene', (112, 116))	('VHL', 'Gene', '7428', (84, 87))	('mutant', 'Var', (37, 43))	('VDAC1-DeltaC', 'Gene', '7416', (217, 229))	('RCC4', 'Gene', (238, 242))	('RCC4', 'Gene', '84925', (112, 116))	('VDAC1-DeltaC', 'Gene', (217, 229))	('VHL', 'Gene', (33, 36))	('RCC4', 'Gene', '84925', (238, 242))	('RCC4', 'Gene', (44, 48))
198440	32194829	However, the knockdown of HIF-2alpha alone had no effect on VDAC1-DeltaC and the primary cilium.	('primary cilium', 'cellular_component', 'GO:0005929', ('81', '95'))	('VDAC1-DeltaC', 'Gene', '7416', (60, 72))	('VDAC1-DeltaC', 'Gene', (60, 72))	('HIF-2alpha', 'Gene', (26, 36))	('primary cilium', 'cellular_component', 'GO:0097731', ('81', '95'))	('knockdown', 'Var', (13, 22))	('HIF-2alpha', 'Gene', '2034', (26, 36))
198442	32194829	In order to block the hypoxic cleavage of VDAC1, LGMN was silenced in RCC4 cells (Figure 2G).	('silenced', 'Var', (58, 66))	('RCC4', 'Gene', '84925', (70, 74))	('RCC4', 'Gene', (70, 74))	('VDAC1', 'Gene', (42, 47))	('LGMN', 'Gene', (49, 53))	('LGMN', 'Gene', '5641', (49, 53))
198453	32194829	We then knocked down GLI1 and IFT20 in RCC4+pVHL cells (Figure 3C), and observed no change in the expression of VDAC1 or VDAC1-DeltaC (Figure S2B) but a decrease in the presence of primary cilia (Figure 3D) associated with decreased invasion (Figure 3E).	('RCC4', 'Gene', (39, 43))	('decreased', 'NegReg', (223, 232))	('VDAC1', 'Gene', (112, 117))	('primary cilia', 'CPA', (181, 194))	('IFT', 'biological_process', 'GO:0042073', ('30', '33'))	('pVHL', 'Gene', '7428', (44, 48))	('invasion', 'CPA', (233, 241))	('VDAC1-DeltaC', 'Gene', '7416', (121, 133))	('GLI1', 'Gene', (21, 25))	('decrease', 'NegReg', (153, 161))	('pVHL', 'Gene', (44, 48))	('RCC4', 'Gene', '84925', (39, 43))	('GLI1', 'Gene', '2735', (21, 25))	('knocked down', 'Var', (8, 20))	('IFT20', 'Gene', (30, 35))	('VDAC1-DeltaC', 'Gene', (121, 133))
198454	32194829	Moreover, knocking down GLI1 and IFT20 in RCC4 cells (Figure S2C) also increased expression of VDAC1 and, subsequently, increased expression of VDAC1-DeltaC (Figure S2D).	('expression', 'MPA', (130, 140))	('knocking down', 'Var', (10, 23))	('IFT', 'biological_process', 'GO:0042073', ('33', '36'))	('GLI1', 'Gene', (24, 28))	('RCC4', 'Gene', '84925', (42, 46))	('VDAC1', 'Gene', (95, 100))	('RCC4', 'Gene', (42, 46))	('VDAC1-DeltaC', 'Gene', '7416', (144, 156))	('increased', 'PosReg', (71, 80))	('GLI1', 'Gene', '2735', (24, 28))	('IFT20', 'Gene', (33, 38))	('increased', 'PosReg', (120, 129))	('VDAC1-DeltaC', 'Gene', (144, 156))	('expression', 'MPA', (81, 91))
198470	32194829	First, a cohort of patients from PREDIR (Cohort A) was used with 12 patients with hereditary pVHL mutations and 22 sporadic patients presenting tumors with wild-type pVHL and mutated pVHL (Figure S6, Table S2).	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('pVHL', 'Gene', '7428', (183, 187))	('patients', 'Species', '9606', (19, 27))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('pVHL', 'Gene', (183, 187))	('pVHL', 'Gene', '7428', (93, 97))	('pVHL', 'Gene', '7428', (166, 170))	('pVHL', 'Gene', (93, 97))	('pVHL', 'Gene', (166, 170))	('mutations', 'Var', (98, 107))	('patients', 'Species', '9606', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('mutated', 'Var', (175, 182))	('patients', 'Species', '9606', (124, 132))
198486	32194829	An in depth analysis of the TCGA database revealed 310 patients with pVHL- ccRCC and 65 patients with pVHL+ ccRCC defined via deletions, mutations and promoter methylation in pVHL (Figure S9).	('RCC', 'Disease', (110, 113))	('pVHL', 'Gene', (175, 179))	('pVHL', 'Gene', '7428', (69, 73))	('CGA', 'Gene', '1113', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('pVHL', 'Gene', (69, 73))	('patients', 'Species', '9606', (88, 96))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('deletions', 'Var', (126, 135))	('RCC', 'Disease', (77, 80))	('methylation', 'biological_process', 'GO:0032259', ('160', '171'))	('mutations', 'Var', (137, 146))	('patients', 'Species', '9606', (55, 63))	('CGA', 'Gene', (29, 32))	('pVHL', 'Gene', '7428', (102, 106))	('promoter methylation', 'Var', (151, 171))	('pVHL', 'Gene', (102, 106))	('pVHL', 'Gene', '7428', (175, 179))
198502	32194829	We found that cells with VDAC1-DeltaC were significantly more sensitive to treatment than RCC4+pVHL cells (Figure S10A).	('more', 'PosReg', (57, 61))	('S10A', 'SUBSTITUTION', 'None', (114, 118))	('sensitive to', 'MPA', (62, 74))	('VDAC1-DeltaC', 'Gene', '7416', (25, 37))	('RCC4', 'Gene', '84925', (90, 94))	('S10A', 'Var', (114, 118))	('RCC4', 'Gene', (90, 94))	('VDAC1-DeltaC', 'Gene', (25, 37))	('pVHL', 'Gene', '7428', (95, 99))	('pVHL', 'Gene', (95, 99))
198503	32194829	RCC4-, RCC4 siVDAC1- and RCC4 siLGMN- cells were also treated with 5 microM of sunitinib (Figure S10B).	('RCC4', 'Gene', '84925', (25, 29))	('sunitinib', 'Chemical', 'MESH:D000077210', (79, 88))	('S10B', 'Var', (97, 101))	('LGMN', 'Gene', (32, 36))	('LGMN', 'Gene', '5641', (32, 36))	('RCC4', 'Gene', (25, 29))	('RCC4', 'Gene', (0, 4))	('RCC4', 'Gene', '84925', (0, 4))	('RCC4', 'Gene', (7, 11))	('S10B', 'SUBSTITUTION', 'None', (97, 101))	('RCC4', 'Gene', '84925', (7, 11))
198508	32194829	Moreover, the aggressiveness of RCC4 siVDAC1 or siLGMN treated with 3BP was decreased compared to the control (Figure S10E and F), suggesting a potential therapeutic use of glycolysis inhibitors.	('LGMN', 'Gene', '5641', (50, 54))	('aggressiveness', 'Disease', 'MESH:D001523', (14, 28))	('decreased', 'NegReg', (76, 85))	('RCC4', 'Gene', '84925', (32, 36))	('aggressiveness', 'Disease', (14, 28))	('S10E', 'Mutation', 'p.S10E', (118, 122))	('RCC4', 'Gene', (32, 36))	('glycolysis', 'biological_process', 'GO:0006096', ('173', '183'))	('3BP', 'Var', (68, 71))	('aggressiveness', 'Phenotype', 'HP:0000718', (14, 28))	('LGMN', 'Gene', (50, 54))
198513	32194829	In the analysis of groups A and B from Figure 1G, we also observed a significant increase of PD-L1 mRNA expression in the "primary cilium" patient group B (Figure S11A) associated with increased frequency of cytoplasmic PDL1 punctae within vesicle-like structures in patient tumor sections (Figure S11B).	('patient', 'Species', '9606', (267, 274))	('S11B', 'SUBSTITUTION', 'None', (298, 302))	('PD-L1', 'Gene', '29126', (93, 98))	('PDL1', 'Gene', '29126', (220, 224))	('increase of PD', 'Phenotype', 'HP:0008151', (81, 95))	('tumor', 'Disease', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('S11A', 'SUBSTITUTION', 'None', (163, 167))	('PDL1', 'Gene', (220, 224))	('S11A', 'Var', (163, 167))	('increase', 'PosReg', (81, 89))	('PD-L1', 'Gene', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('increased', 'PosReg', (185, 194))	('patient', 'Species', '9606', (139, 146))	('S11B', 'Var', (298, 302))
198532	32194829	The tumors in this group could be directly derived from healthy tissue but the expression of the EMT genes made the tumors of these patients more aggressive.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('more', 'PosReg', (141, 145))	('EMT', 'biological_process', 'GO:0001837', ('97', '100'))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('aggressive', 'CPA', (146, 156))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('expression', 'Var', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('EMT genes', 'Gene', (97, 106))	('patients', 'Species', '9606', (132, 140))
198541	32194829	In patients who express/re-express the primary cilium, it is unlikely that the primary cilium is the only force associated with aggressiveness.	('aggressiveness', 'Phenotype', 'HP:0000718', (128, 142))	('primary cilium', 'cellular_component', 'GO:0005929', ('79', '93'))	('primary cilium', 'cellular_component', 'GO:0005929', ('39', '53'))	('express/re-express', 'Var', (16, 34))	('primary cilium', 'cellular_component', 'GO:0097731', ('79', '93'))	('primary cilium', 'cellular_component', 'GO:0097731', ('39', '53'))	('aggressiveness', 'Disease', 'MESH:D001523', (128, 142))	('patients', 'Species', '9606', (3, 11))	('aggressiveness', 'Disease', (128, 142))
198543	32194829	Moreover, metabolic remodeling was impacted, and although cancer metabolism is a hallmark of cancer, it has been shown that aberrant metabolism supports EMT.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('EMT', 'biological_process', 'GO:0001837', ('153', '156'))	('metabolism', 'biological_process', 'GO:0008152', ('133', '143'))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('supports', 'PosReg', (144, 152))	('aberrant', 'Var', (124, 132))	('EMT', 'CPA', (153, 156))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('metabolism', 'biological_process', 'GO:0008152', ('65', '75'))
198551	32194829	Indeed, the presence of PD-L1 in group B strongly suggests an important role in promoting tumor progression.	('promoting', 'PosReg', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('presence', 'Var', (12, 20))	('tumor', 'Disease', (90, 95))	('PD-L1', 'Gene', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('PD-L1', 'Gene', '29126', (24, 29))
198556	32194829	MiRs, P53 and STAT3 were reported to epigenetically regulate PD-L1 expression.	('STAT3', 'Gene', (14, 19))	('epigenetically', 'Var', (37, 51))	('PD-L1', 'Gene', (61, 66))	('P53', 'Gene', '7157', (6, 9))	('P53', 'Gene', (6, 9))	('PD-L1', 'Gene', '29126', (61, 66))	('expression', 'MPA', (67, 77))	('STAT3', 'Gene', '6774', (14, 19))
198578	28118849	While most cancer-related bacteria are the dominant member of the microbiome, it is possible that rare members could cause driver mutations and/or that dominant members might be more abundant in tumors due to a favorable tumor microenvironment.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Disease', (195, 200))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('mutations', 'Var', (130, 139))	('cause', 'Reg', (117, 122))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('cancer', 'Disease', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
198607	28118849	Nine cancer types were examined (Table 1) and found to have differing abundances of putative bacterial read pairs ranging from 11% of patients with at least one sample containing bacterial read pairs in lung squamous cell carcinoma (LUSC) to 100% of patients having at least one sample with bacterial read pairs in STAD (Table 2).	('LUSC', 'Phenotype', 'HP:0030359', (233, 237))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (203, 231))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('bacterial read pairs', 'Var', (179, 199))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (203, 231))	('cancer', 'Disease', (5, 11))	('patients', 'Species', '9606', (250, 258))	('patients', 'Species', '9606', (134, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('lung squamous cell carcinoma', 'Disease', (203, 231))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
198611	28118849	All of the cancer types investigated had one or more samples containing read pairs present that were assigned to bacterial taxa (Table 2).	('read pairs', 'Var', (72, 82))	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))
198679	28118849	For example, plates A056 and A084 appear distinct from plates A00Z, A034, A109, A10J, A115, and A12D (Additional file 5: Figure S4).	('A084', 'Var', (29, 33))	('A10J', 'Var', (80, 84))	('A109', 'Var', (74, 78))	('A10J', 'SUBSTITUTION', 'None', (80, 84))	('A12D', 'Mutation', 'p.A12D', (96, 100))	('A115', 'Var', (86, 90))	('A12D', 'Var', (96, 100))	('A034', 'Var', (68, 72))
198799	30199304	Our study also analyzed differences in median OS between patients who would be eligible for clinical trials and patients who would not be eligible for clinical trials (KPS < 70, CNS metastasis, Hb < 9 g/dL, or any cardiovascular serious event, such as myocardial infarction unstable angina, or pulmonary embolism, in the last 12 months).	('CNS metastasis', 'CPA', (178, 192))	('pulmonary embolism', 'Phenotype', 'HP:0002204', (294, 312))	('cardiovascular serious event', 'Phenotype', 'HP:0001626', (214, 242))	('pulmonary embolism', 'Disease', (294, 312))	('patients', 'Species', '9606', (57, 65))	('pulmonary embolism', 'Disease', 'MESH:D011655', (294, 312))	('patients', 'Species', '9606', (112, 120))	('myocardial infarction', 'Phenotype', 'HP:0001658', (252, 273))	('KPS < 70', 'Var', (168, 176))	('myocardial infarction unstable angina', 'Disease', 'MESH:D000789', (252, 289))	('unstable angina', 'Phenotype', 'HP:0001681', (274, 289))	('myocardial infarction unstable angina', 'Disease', (252, 289))
198810	30199304	In the pivotal Pazopanib Versus Sunitinib in Metastatic Renal Cell Carcinoma (COMPARZ) study, patients with a KPS < 70 were not eligible, and in our cohort, 33.3% of patients had a KPS <= 70.	('Pazopanib', 'Chemical', 'MESH:C516667', (15, 24))	('patients', 'Species', '9606', (94, 102))	('Metastatic Renal Cell Carcinoma', 'Disease', (45, 76))	('Metastatic Renal Cell Carcinoma', 'Disease', 'MESH:C538445', (45, 76))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (56, 76))	('Sunitinib', 'Chemical', 'MESH:C473478', (32, 41))	('KPS <= 70', 'Var', (181, 190))	('patients', 'Species', '9606', (166, 174))	('Carcinoma', 'Phenotype', 'HP:0030731', (67, 76))
198816	30199304	In our cohort, 45.5% of patients would not be eligible for clinical trials because of multiple factors, such as low KPS, CNS metastasis, Hb < 9 g/dL, and previous cardiovascular conditions within the past 12 months (such as myocardial infarction, unstable angina, class III or IV congestive heart failure, and pulmonary embolism).	('congestive heart failure', 'Disease', 'MESH:D006333', (280, 304))	('myocardial infarction', 'Disease', (224, 245))	('congestive heart failure', 'Disease', (280, 304))	('myocardial infarction', 'Disease', 'MESH:D009203', (224, 245))	('CNS metastasis', 'CPA', (121, 135))	('class III', 'Disease', (264, 273))	('low', 'Var', (112, 115))	('patients', 'Species', '9606', (24, 32))	('pulmonary embolism', 'Phenotype', 'HP:0002204', (310, 328))	('KPS', 'MPA', (116, 119))	('unstable angina', 'Disease', (247, 262))	('unstable angina', 'Disease', 'MESH:D000789', (247, 262))	('< 9 g/dL', 'Var', (140, 148))	('pulmonary embolism', 'Disease', (310, 328))	('myocardial infarction', 'Phenotype', 'HP:0001658', (224, 245))	('pulmonary embolism', 'Disease', 'MESH:D011655', (310, 328))	('congestive heart failure', 'Phenotype', 'HP:0001635', (280, 304))	('unstable angina', 'Phenotype', 'HP:0001681', (247, 262))
198851	30159422	Although Smad3 is a key transcription factor in response to many pathogenic mediators, systemic Smad3 knockout mice shows that targeting Smad3 may cause autoimmune disease by impairing immunity.	('autoimmune disease', 'Disease', 'MESH:D001327', (153, 171))	('autoimmune disease', 'Phenotype', 'HP:0002960', (153, 171))	('immunity', 'CPA', (185, 193))	('transcription factor', 'molecular_function', 'GO:0000981', ('24', '44'))	('cause', 'Reg', (147, 152))	('targeting', 'Var', (127, 136))	('mice', 'Species', '10090', (111, 115))	('Smad3', 'Gene', (137, 142))	('impairing', 'NegReg', (175, 184))	('autoimmune disease', 'Disease', (153, 171))	('transcription', 'biological_process', 'GO:0006351', ('24', '37'))
198863	30159422	Compared with the wild-type mice, 21 novel Smad3-depedent lncRNAs including np_5318 and np_17856 were identified in both of the renal inflammation and fibrosis in a Smad3-dependent manner in vivo .	('inflammation', 'biological_process', 'GO:0006954', ('134', '146'))	('mice', 'Species', '10090', (28, 32))	('fibrosis', 'Disease', (151, 159))	('renal inflammation', 'Disease', (128, 146))	('fibrosis', 'Disease', 'MESH:D005355', (151, 159))	('ncRNA', 'Gene', (59, 64))	('renal inflammation', 'Disease', 'MESH:D007674', (128, 146))	('np_17856', 'Var', (88, 96))	('renal inflammation', 'Phenotype', 'HP:0000123', (128, 146))	('ncRNA', 'Gene', '54719', (59, 64))
198865	30159422	Interestingly, kidney-specific knockdown of Arid2-IR blunted NF-kappaB-driven renal inflammation without affecting TGF-beta1/Smad3-mediated renal fibrosis in the obstructed kidney in vivo, showing by ultrasound-microbubble-mediated gene transfer technique.	('renal fibrosis', 'Phenotype', 'HP:0030760', (140, 154))	('blunted', 'NegReg', (53, 60))	('renal fibrosis', 'Disease', (140, 154))	('Arid2-IR', 'Gene', (44, 52))	('inflammation', 'biological_process', 'GO:0006954', ('84', '96'))	('NF-kappaB-driven', 'Protein', (61, 77))	('renal inflammation', 'Phenotype', 'HP:0000123', (78, 96))	('renal inflammation', 'Disease', (78, 96))	('renal inflammation', 'Disease', 'MESH:D007674', (78, 96))	('renal fibrosis', 'Disease', 'MESH:D005355', (140, 154))	('knockdown', 'Var', (31, 40))
198866	30159422	The study discovered that silencing of Arid2-IR in UUO kidney significantly reduced inflammatory cells infiltration (F4/80+ macrophages and CD3+ T cells), cytokines production (IL-1beta, TNF-alpha, and MCP-1) and NF-kappaB signaling activation (NF-kappaB/p65 phosphorylation and nuclear localization) in the UUO kidney.	('IL-1', 'molecular_function', 'GO:0005149', ('177', '181'))	('signaling', 'biological_process', 'GO:0023052', ('223', '232'))	('Arid2-IR', 'Gene', (39, 47))	('reduced inflammatory cells infiltration', 'Phenotype', 'HP:0012648', (76, 115))	('UUO', 'Phenotype', 'HP:0006000', (308, 311))	('reduced', 'NegReg', (76, 83))	('activation', 'PosReg', (233, 243))	('MCP-1', 'Gene', '17224', (202, 207))	('p65', 'Gene', (255, 258))	('localization', 'biological_process', 'GO:0051179', ('287', '299'))	('TNF-alpha', 'Gene', (187, 196))	('UUO', 'Phenotype', 'HP:0006000', (51, 54))	('TNF-alpha', 'Gene', '21926', (187, 196))	('MCP-1', 'Gene', (202, 207))	('IL-1beta', 'Gene', '16176', (177, 185))	('MCP', 'molecular_function', 'GO:0004298', ('202', '205'))	('IL-1beta', 'Gene', (177, 185))	('p65', 'Gene', '19697', (255, 258))	('NF-kappaB signaling', 'Pathway', (213, 232))	('silencing', 'Var', (26, 35))	('cytokines production', 'MPA', (155, 175))	('phosphorylation', 'biological_process', 'GO:0016310', ('259', '274'))
198878	30159422	Nevertheless, Lan's group further revealed two Smad3-dependent lncRNAs np_5318 and np_17856 for renal fibrosis.	('renal fibrosis', 'Disease', 'MESH:D005355', (96, 110))	('renal fibrosis', 'Phenotype', 'HP:0030760', (96, 110))	('ncRNA', 'Gene', (64, 69))	('renal fibrosis', 'Disease', (96, 110))	('np_5318', 'Var', (71, 78))	('np_17856', 'Var', (83, 91))	('ncRNA', 'Gene', '54719', (64, 69))
198879	30159422	These lncRNAs were significantly evoked in the kidney of mice with UUO; their expression levels were further enhanced by the knockout of Smad7 but largely repressed by the knockout of Smad3 knockout and overexpression of Smad7.	('mice', 'Species', '10090', (57, 61))	('knockout', 'Var', (125, 133))	('ncRNA', 'Gene', '54719', (7, 12))	('UUO', 'Phenotype', 'HP:0006000', (67, 70))	('ncRNA', 'Gene', (7, 12))	('Smad7', 'Gene', (137, 142))	('expression levels', 'MPA', (78, 95))	('enhanced', 'PosReg', (109, 117))
198885	30159422	where several SNPs (especially rs2648875) with a strong association with ESRD were located within PVT1 gene.	('PVT1', 'Gene', (98, 102))	('rs2648875', 'Mutation', 'rs2648875', (31, 40))	('ESRD', 'Disease', (73, 77))	('association', 'Interaction', (56, 67))	('ESRD', 'Phenotype', 'HP:0003774', (73, 77))	('ESRD', 'Disease', 'MESH:D007676', (73, 77))	('rs2648875', 'Var', (31, 40))
198886	30159422	Using similar approach, the association between SNP (rs13447075) in PVT1 transcript variant 6 and ESRD was further suggested by Millis et al., the study also demonstrated that expression level of PVT1 transcript variant 6 was higher than other variants in human renal cells.	('ESRD', 'Disease', (98, 102))	('human', 'Species', '9606', (256, 261))	('PVT1', 'Gene', (196, 200))	('expression level', 'MPA', (176, 192))	('PVT1', 'Gene', (68, 72))	('rs13447075', 'Var', (53, 63))	('rs13447075', 'Mutation', 'rs13447075', (53, 63))	('variant', 'Var', (84, 91))	('ESRD', 'Phenotype', 'HP:0003774', (98, 102))	('ESRD', 'Disease', 'MESH:D007676', (98, 102))	('higher', 'PosReg', (226, 232))
198887	30159422	The function of PVT1 then further characterized in diabetic kidney disease by Alvarez and DiStefano: high glucose condition induced the expression of PVT1, FN1, and COL4A1 and the secretion of TGF-beta1, PAI-1, FN1, and COL4A1 in human mesangial cells (MC), but the secretion of FN1 and COL4A1 were repressed by PVT1 knockdown indicating the pathological role of PVT1 and its involvement in TGF-beta1 mediated diabetic nephropathy.	('COL4A1', 'Gene', (287, 293))	('secretion', 'biological_process', 'GO:0046903', ('180', '189'))	('nephropathy', 'Phenotype', 'HP:0000112', (419, 430))	('human', 'Species', '9606', (230, 235))	('COL4A1', 'Gene', '1282', (165, 171))	('COL4A1', 'Gene', '1282', (220, 226))	('PVT1', 'Gene', (150, 154))	('secretion', 'MPA', (180, 189))	('kidney disease', 'Phenotype', 'HP:0000112', (60, 74))	('COL4A1', 'Gene', (165, 171))	('high glucose', 'Phenotype', 'HP:0003074', (101, 113))	('COL4A1', 'Gene', '1282', (287, 293))	('COL4A1', 'Gene', (220, 226))	('glucose', 'Chemical', 'MESH:D005947', (106, 113))	('diabetic kidney disease', 'Disease', (51, 74))	('secretion', 'biological_process', 'GO:0046903', ('266', '275'))	('knockdown', 'Var', (317, 326))	('FN1', 'Gene', (156, 159))	('diabetic kidney disease', 'Disease', 'MESH:D003928', (51, 74))	('diabetic nephropathy', 'Disease', 'MESH:D003928', (410, 430))	('diabetic nephropathy', 'Disease', (410, 430))
198890	30159422	Under high glucose condition, expressions of miR-1207-5p and TGF-beta1 (time- and dose-dependent) were induced, while PMEPA1, PDPK1, and SMAD7 were repressed; PVT1 miR-1207-5p acts consistent with Pvt1 to trigger secretion of TGF-beta1, PAI-1, and FN1 in the primary murine MC in vitro .	('Pvt1', 'Gene', '19296', (197, 201))	('high glucose', 'Phenotype', 'HP:0003074', (6, 18))	('secretion', 'biological_process', 'GO:0046903', ('213', '222'))	('SMAD7', 'Gene', (137, 142))	('miR', 'Gene', '220972', (164, 167))	('Pvt1', 'Gene', (197, 201))	('miR', 'Gene', (164, 167))	('PMEPA1', 'Gene', (118, 124))	('murine', 'Species', '10090', (267, 273))	('SMAD7', 'Gene', '17131', (137, 142))	('secretion', 'MPA', (213, 222))	('miR', 'Gene', '220972', (45, 48))	('miR', 'Gene', (45, 48))	('PMEPA1', 'Gene', '65112', (118, 124))	('PDPK1', 'Gene', '18607', (126, 131))	('PDPK1', 'Gene', (126, 131))	('PVT1', 'Var', (159, 163))	('glucose', 'Chemical', 'MESH:D005947', (11, 18))
198895	30159422	Furthermore, lncRNA CYP4B1-PS1-001 regulates proliferation and fibrosis of mesangial cells in diabetic nephropathy.	('proliferation', 'CPA', (45, 58))	('fibrosis', 'Disease', 'MESH:D005355', (63, 71))	('fibrosis', 'Disease', (63, 71))	('diabetic nephropathy', 'Disease', (94, 114))	('CYP4B1-PS1-001', 'Var', (20, 34))	('nephropathy', 'Phenotype', 'HP:0000112', (103, 114))	('ncRNA', 'Gene', (14, 19))	('diabetic nephropathy', 'Disease', 'MESH:D003928', (94, 114))	('regulates', 'Reg', (35, 44))	('ncRNA', 'Gene', '54719', (14, 19))
198897	30159422	CYP4B1-PS1-001 specifically expressed in murine mesangial cells instead of human proximal tubular epithelial cell line HK-2 nor baby hamster Syrian kidney cell line BHK-21 in vitro, while its overexpression was able to inhibit the proliferation and fibrosis of mesangial cells under high glucose condition in vitro .	('HK-2', 'Gene', (119, 123))	('BHK-21', 'CellLine', 'CVCL:1914', (165, 171))	('HK-2', 'molecular_function', 'GO:0008256', ('119', '123'))	('CYP4B1-PS1-001', 'Var', (0, 14))	('HK-2', 'Gene', '3099', (166, 170))	('high glucose', 'Phenotype', 'HP:0003074', (283, 295))	('HK-2', 'Gene', (166, 170))	('glucose', 'Chemical', 'MESH:D005947', (288, 295))	('overexpression', 'PosReg', (192, 206))	('inhibit', 'NegReg', (219, 226))	('HK-2', 'Gene', '3099', (119, 123))	('hamster', 'Species', '10034', (133, 140))	('murine', 'Species', '10090', (41, 47))	('human', 'Species', '9606', (75, 80))	('fibrosis', 'Disease', 'MESH:D005355', (249, 257))	('fibrosis', 'Disease', (249, 257))
198903	30159422	Silencing of HOTAIR largely inhibited the proliferation and migration of renal carcinoma cell lines due to induction of cell cycle arrest at G0/G1 phase in vitro, cell cycle related genes (p53, p21, and p16) were modulated via histone methylation.	('p16', 'Gene', (203, 206))	('inhibited', 'NegReg', (28, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('Silencing', 'Var', (0, 9))	('migration of renal carcinoma cell', 'Disease', 'MESH:C538614', (60, 93))	('p16', 'Gene', '1029', (203, 206))	('cell cycle', 'biological_process', 'GO:0007049', ('163', '173'))	('cell cycle arrest at G0/G1 phase', 'CPA', (120, 152))	('histone methylation', 'biological_process', 'GO:0016571', ('227', '246'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (120, 137))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('120', '137'))	('p53', 'Gene', '7157', (189, 192))	('G1 phase', 'biological_process', 'GO:0051318', ('144', '152'))	('modulated', 'Reg', (213, 222))	('HOTAIR', 'Gene', '100124700', (13, 19))	('p53', 'Gene', (189, 192))	('renal carcinoma', 'Phenotype', 'HP:0005584', (73, 88))	('proliferation', 'CPA', (42, 55))	('migration of renal carcinoma cell', 'Disease', (60, 93))	('cell cycle', 'CPA', (163, 173))	('p21', 'Gene', (194, 197))	('HOTAIR', 'Gene', (13, 19))	('p21', 'Gene', '644914', (194, 197))
198904	30159422	The role of HOTAIR in tumor was further confirmed in xenograft model in vivo, where knockdown of HOTAIR silencing significantly inhibit the human tumor growth rate in mice.	('human', 'Species', '9606', (140, 145))	('HOTAIR', 'Gene', (97, 103))	('inhibit', 'NegReg', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('HOTAIR', 'Gene', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('silencing', 'Var', (104, 113))	('tumor', 'Disease', (146, 151))	('HOTAIR', 'Gene', '100124700', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('HOTAIR', 'Gene', '100124700', (12, 18))	('tumor', 'Disease', (22, 27))	('mice', 'Species', '10090', (167, 171))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
198909	30159422	Silencing of lncRNA-ATB inhibited the proliferation, invasion, and migration of renal carcinoma cells in vitro, probably due to the induction of apoptosis and reduction of EMT via vimentin and cadherin switching.	('invasion', 'CPA', (53, 61))	('migration of renal carcinoma cell', 'Disease', (67, 100))	('carcinoma cells', 'Disease', 'MESH:C538614', (86, 101))	('vimentin', 'cellular_component', 'GO:0045099', ('180', '188'))	('Silencing', 'Var', (0, 9))	('EMT', 'CPA', (172, 175))	('cadherin', 'molecular_function', 'GO:0008014', ('193', '201'))	('proliferation', 'CPA', (38, 51))	('migration of renal carcinoma cell', 'Disease', 'MESH:C538614', (67, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('carcinoma cells', 'Disease', (86, 101))	('inhibited', 'NegReg', (24, 33))	('vimentin', 'cellular_component', 'GO:0045098', ('180', '188'))	('apoptosis', 'CPA', (145, 154))	('reduction', 'NegReg', (159, 168))	('renal carcinoma', 'Phenotype', 'HP:0005584', (80, 95))	('vimentin', 'Gene', '7431', (180, 188))	('vimentin', 'Gene', (180, 188))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('132', '154'))	('ncRNA', 'Gene', (14, 19))	('EMT', 'biological_process', 'GO:0001837', ('172', '175'))	('ncRNA', 'Gene', '54719', (14, 19))
198913	30159422	In contrast, induction of lncRNA RCCRT1 is found in the human renal cell carcinoma tissues and associated with lower survival after surgery, and silencing of RCCRT1 in renal cell carcinoma cells in vitro revealed that RCCRT1 involves in the proliferation, migration, and invasion of the cancer cells.	('cancer', 'Disease', (287, 293))	('carcinoma cells', 'Disease', (179, 194))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (168, 188))	('human', 'Species', '9606', (56, 61))	('invasion', 'CPA', (271, 279))	('ncRNA', 'Gene', (27, 32))	('ncRNA', 'Gene', '54719', (27, 32))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (62, 82))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('carcinoma cells', 'Disease', 'MESH:C538614', (179, 194))	('lower', 'NegReg', (111, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('renal cell carcinoma', 'Disease', (168, 188))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (168, 188))	('silencing', 'Var', (145, 154))	('proliferation', 'CPA', (241, 254))	('RCCRT1', 'Gene', (158, 164))	('migration', 'CPA', (256, 265))	('renal cell carcinoma', 'Disease', (62, 82))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (62, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
198919	30159422	confirmed the pathogenic role of MALAT1 on animal model, silencing of MALAT1 reduced human tumor size in vivo.	('MALAT1', 'Gene', '378938', (70, 76))	('MALAT1', 'Gene', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('MALAT1', 'Gene', '378938', (33, 39))	('silencing', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('reduced', 'NegReg', (77, 84))	('MALAT1', 'Gene', (33, 39))	('tumor', 'Disease', (91, 96))	('human', 'Species', '9606', (85, 90))
198928	30159422	Silencing of SPRY4-IT1 significantly inhibited the proliferation, migration, and invasion of the renal carcinoma 786-O cells in vitro .	('renal carcinoma', 'Phenotype', 'HP:0005584', (97, 112))	('migration', 'CPA', (66, 75))	('inhibited', 'NegReg', (37, 46))	('invasion', 'CPA', (81, 89))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (13, 22))	('proliferation', 'CPA', (51, 64))	('SPRY4-IT1', 'Gene', (13, 22))	('renal carcinoma', 'Disease', 'MESH:C538614', (97, 112))	('Silencing', 'Var', (0, 9))	('renal carcinoma', 'Disease', (97, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
198964	29262573	In RCC, high c-Met expression was reported to be an independent predictor of survival in 330 nephrectomy cases using quantitative immunofluorescence.	('expression', 'MPA', (19, 29))	('high', 'Var', (8, 12))	('RCC', 'Disease', (3, 6))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('c-Met', 'Gene', (13, 18))	('RCC', 'Disease', 'MESH:C538614', (3, 6))	('c-Met', 'Gene', '4233', (13, 18))
198979	29262573	Pathologic T-stage at diagnosis was T1/T2 in 17 (38%) patients and T3/T4 in 25 (56%).	('patients', 'Species', '9606', (54, 62))	('T3/T4', 'Var', (67, 72))	('T1/T2', 'Disease', (36, 41))
198985	29262573	Higher c-Met expression in primary tumors was shown to be associated with higher FNG (4 vs 3; average c-Met CS: 52 vs. 20, p = 0.04, respectively) and patients with T-stage T3-T4 appear to have higher c-Met expressions compared to those with Tx-T2 (average c-Met CS: 30 vs. 24, p = 0.13, respectively) (Table 2).	('c-Met', 'Gene', (7, 12))	('c-Met', 'Gene', '4233', (257, 262))	('primary tumors', 'Disease', (27, 41))	('c-Met', 'Gene', '4233', (201, 206))	('CS', 'Chemical', '-', (108, 110))	('primary tumors', 'Disease', 'MESH:D009369', (27, 41))	('FNG', 'MPA', (81, 84))	('c-Met', 'Gene', (102, 107))	('c-Met', 'Gene', '4233', (102, 107))	('higher', 'PosReg', (194, 200))	('CS', 'Chemical', '-', (263, 265))	('c-Met', 'Gene', '4233', (7, 12))	('c-Met', 'Gene', (257, 262))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('c-Met', 'Gene', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('higher', 'PosReg', (74, 80))	('expression', 'MPA', (13, 23))	('patients', 'Species', '9606', (151, 159))	('expressions', 'MPA', (207, 218))	('T-stage T3-T4', 'Var', (165, 178))
198986	29262573	Of the 45 pairs of samples available for c-Met analysis, 13 (29%) displayed PD-L1 positivity in the primary tumor and 9 cases (20%) were PD-L1 positive in paired metastases, including 7 cases (16%) with PD-L1 positivity in both primary tumors and metastases.	('primary tumors', 'Disease', 'MESH:D009369', (228, 242))	('metastases', 'Disease', (162, 172))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Disease', (108, 113))	('PD-L1', 'Gene', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('PD-L1', 'Gene', '29126', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('metastases', 'Disease', 'MESH:D009362', (247, 257))	('c-Met', 'Gene', '4233', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('metastases', 'Disease', (247, 257))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('PD-L1', 'Gene', (203, 208))	('primary tumors', 'Disease', (228, 242))	('PD-L1', 'Gene', (76, 81))	('PD-L1', 'Gene', '29126', (203, 208))	('positivity', 'Var', (82, 92))	('metastases', 'Disease', 'MESH:D009362', (162, 172))	('c-Met', 'Gene', (41, 46))	('PD-L1', 'Gene', '29126', (76, 81))	('tumor', 'Disease', (236, 241))
198990	29262573	In a descriptive analysis of the 20 patients treated with VEGF-TT, those with high primary c-Met expression had numerically worse time-to-treatment failure (TTF) compared to those with low c-Met expression (estimated median TTF (95% confidence interval, CI): 6.1 (5.3-NA) vs. 9.3 (2.56-NA) months).	('time-to-treatment', 'MPA', (130, 147))	('VEGF', 'Gene', (58, 62))	('c-Met', 'Gene', '4233', (189, 194))	('high', 'Var', (78, 82))	('patients', 'Species', '9606', (36, 44))	('VEGF', 'Gene', '7422', (58, 62))	('worse', 'NegReg', (124, 129))	('c-Met', 'Gene', (91, 96))	('c-Met', 'Gene', '4233', (91, 96))	('c-Met', 'Gene', (189, 194))
198997	29262573	Given that the treatment landscape for mRCC has expanded to include small-molecule inhibition of VEGFR, MET, and AXL pathways, our findings are informative in that they suggest that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases.	('c-Met', 'Gene', (220, 225))	('inhibition', 'NegReg', (83, 93))	('AXL', 'Gene', '558', (113, 116))	('c-Met', 'Gene', '4233', (220, 225))	('RCC', 'Disease', (40, 43))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('MET', 'Gene', (104, 107))	('small-molecule', 'Var', (68, 82))	('MET', 'Gene', '4233', (104, 107))	('AXL', 'Gene', (113, 116))	('metastases', 'Disease', (260, 270))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('metastases', 'Disease', 'MESH:D009362', (260, 270))	('VEGFR', 'Gene', '3791', (97, 102))	('VEGFR', 'Gene', (97, 102))
199000	29262573	As a consequence of hypoxia and inactivation of the Von-Hippel-Lindau tumor suppressor gene (VHL), MET and AXL are upregulated.	('AXL', 'Gene', (107, 110))	('MET', 'Gene', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Von-Hippel-Lindau tumor', 'Disease', 'MESH:D006623', (52, 75))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('MET', 'Gene', '4233', (99, 102))	('AXL', 'Gene', '558', (107, 110))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('VHL', 'Disease', 'MESH:D006623', (93, 96))	('hypoxia', 'Disease', (20, 27))	('VHL', 'Disease', (93, 96))	('inactivation', 'Var', (32, 44))	('Von-Hippel-Lindau tumor', 'Disease', (52, 75))	('hypoxia', 'Disease', 'MESH:D000860', (20, 27))	('upregulated', 'PosReg', (115, 126))
199001	29262573	This knowledge provides therapeutic rationale for inhibition of these pathways to improve outcomes in RCC, as evidenced by the development of cabozantanib.	('improve', 'PosReg', (82, 89))	('inhibition', 'Var', (50, 60))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('cabozantanib', 'Chemical', '-', (142, 154))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))
199003	29262573	evaluated the prognostic significance of Met molecular status using tissue microarrays (TMAs) of primary tumor and corresponding normal renal tissue samples, and found higher Met expression and copy number associated with dedifferentiation and higher tumor extent.	('Met', 'Gene', (175, 178))	('Met', 'Gene', '4233', (41, 44))	('Met', 'Gene', '4233', (175, 178))	('tumor', 'Disease', (251, 256))	('expression', 'MPA', (179, 189))	('copy number', 'Var', (194, 205))	('dedifferentiation', 'CPA', (222, 239))	('TMAs', 'Chemical', '-', (88, 92))	('associated with', 'Reg', (206, 221))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('dedifferentiation', 'biological_process', 'GO:0043696', ('222', '239'))	('higher', 'PosReg', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Disease', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('Met', 'Gene', (41, 44))
199011	29262573	show that PD-L1 positivity was significantly associated with increased c-Met expression.	('increased', 'PosReg', (61, 70))	('PD-L1', 'Gene', (10, 15))	('c-Met', 'Gene', (71, 76))	('c-Met', 'Gene', '4233', (71, 76))	('positivity', 'Var', (16, 26))	('PD-L1', 'Gene', '29126', (10, 15))
199021	29262573	While our small sample size limited formal statistical testing, our findings are consistent with other data showing that high c-Met expression portends worse clinical prognosis.	('c-Met', 'Gene', (126, 131))	('high', 'Var', (121, 125))	('c-Met', 'Gene', '4233', (126, 131))	('expression', 'MPA', (132, 142))
199134	28545581	Inhibition of Akt blocks transcription of glucose transporter protein-1 (GLUT1) and its translocation to the plasma membrane, where it promotes glucose utilization independently of any proliferative effect.	('Akt', 'Gene', (14, 17))	('transcription', 'biological_process', 'GO:0006351', ('25', '38'))	('transcription', 'MPA', (25, 38))	('plasma membrane', 'cellular_component', 'GO:0005886', ('109', '124'))	('glucose', 'Chemical', 'MESH:D005947', (144, 151))	('glucose transporter protein-1', 'Gene', '6513', (42, 71))	('glucose utilization', 'MPA', (144, 163))	('blocks', 'NegReg', (18, 24))	('translocation to the plasma membrane', 'MPA', (88, 124))	('glucose transporter protein-1', 'Gene', (42, 71))	('GLUT1', 'Gene', (73, 78))	('promotes', 'PosReg', (135, 143))	('Inhibition', 'Var', (0, 10))	('Akt', 'Gene', '207', (14, 17))	('glucose', 'Chemical', 'MESH:D005947', (42, 49))	('GLUT1', 'Gene', '6513', (73, 78))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
199195	31863665	A recent study indicated that frequent methylation of Kelch like ECH associated protein 1 (KEAP1) gene promoter was vital for ccRCC development via KEAP1/ nuclear factor erythroid-2 related factor (NRF2) pathway.	('ECH', 'molecular_function', 'GO:0004300', ('65', '68'))	('methylation', 'Var', (39, 50))	('KEAP1', 'Gene', (91, 96))	('Kelch like ECH associated protein 1', 'Gene', '9817', (54, 89))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('KEAP1', 'Gene', '9817', (148, 153))	('Kelch like ECH associated protein 1', 'Gene', (54, 89))	('NRF2', 'Gene', '4780', (198, 202))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('ccRCC', 'Disease', (126, 131))	('KEAP1', 'Gene', '9817', (91, 96))	('KEAP1', 'Gene', (148, 153))	('NRF2', 'Gene', (198, 202))
199200	31863665	Specially, GSE53000 included two samples of lymph node metastasis and one sample of venous thrombus metastasis.	('GSE53000', 'Var', (11, 19))	('venous thrombus metastasis', 'Disease', (84, 110))	('venous thrombus metastasis', 'Disease', 'MESH:D009362', (84, 110))	('venous thrombus', 'Phenotype', 'HP:0004936', (84, 99))
199205	31863665	Results showed that there were four miRNAs (including miR-145, miR-199B, miR- 199A and miR-412), 94 up-regulated genes [such as interferon regulatory factor 7 (IRF7), TYRO protein tyrosine kinase binding protein (TYROBP) and CD14)], as well as 45 down-regulated genes [such as PPARG coactivator 1 alpha (PPARGC1A), dystroglycan 1 (DAG1) and klotho (KL)] in the present network (Fig .3).	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('PPARG coactivator 1 alpha', 'Gene', '10891', (277, 302))	('miR-145', 'Gene', '406937', (54, 61))	('protein', 'cellular_component', 'GO:0003675', ('204', '211'))	('PPARG coactivator 1 alpha', 'Gene', (277, 302))	('DAG1', 'Gene', '1605', (331, 335))	('dystroglycan 1', 'Gene', '1605', (315, 329))	('up-regulated', 'PosReg', (100, 112))	('DAG1', 'Gene', (331, 335))	('miR-145', 'Gene', (54, 61))	('PPARGC1A', 'Gene', (304, 312))	('miR-199B', 'Gene', (63, 71))	('miR-412', 'Var', (87, 94))	('klotho', 'Gene', (341, 347))	('miR- 199A', 'Var', (73, 82))	('protein tyrosine kinase binding', 'molecular_function', 'GO:1990782', ('172', '203'))	('miR-199B', 'Gene', '406978', (63, 71))	('klotho', 'Gene', '9365', (341, 347))	('dystroglycan 1', 'Gene', (315, 329))
199207	31863665	Aberration of immune system could lead to inflammatory diseases, autoimmune diseases and cancer.	('autoimmune diseases', 'Disease', 'MESH:D001327', (65, 84))	('autoimmune diseases', 'Disease', (65, 84))	('lead to', 'Reg', (34, 41))	('cancer', 'Disease', (89, 95))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (65, 84))	('inflammatory diseases', 'Disease', (42, 63))	('Aberration', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
199209	31863665	TYROBP is reported to be related to Alzheimer's pathology.	('Alzheimer', 'Disease', 'MESH:D000544', (36, 45))	('TYROBP', 'Var', (0, 6))	('Alzheimer', 'Disease', (36, 45))	('related', 'Reg', (25, 32))
199210	31863665	Deficiency of TYROBP is neuroprotective in a mouse model with early Alzheimer's pathology.	('TYROBP', 'Gene', (14, 20))	('mouse', 'Species', '10090', (45, 50))	('early Alzheimer', 'Disease', (62, 77))	('Deficiency', 'Var', (0, 10))
199211	31863665	In addition, it has been documented that TYROBP presents a general function in inflammatory responses in microglia via the Jun NH2-terminal kinase (JNK) signaling pathway.	('JNK', 'Gene', (148, 151))	('Jun NH2-terminal kinase', 'Gene', (123, 146))	('Jun NH2-terminal kinase', 'Gene', '5599', (123, 146))	('JNK', 'Gene', '5599', (148, 151))	('JNK', 'molecular_function', 'GO:0004705', ('148', '151'))	('TYROBP', 'Var', (41, 47))	('JNK) signaling pathway', 'biological_process', 'GO:0031098', ('148', '170'))	('inflammatory responses', 'CPA', (79, 101))
199212	31863665	IRF7 silencing promotes bone metastasis of breast cancer via immune escape way.	('breast cancer', 'Disease', (43, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('silencing', 'Var', (5, 14))	('immune escape', 'CPA', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('bone metastasis', 'CPA', (24, 39))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('IRF7', 'Gene', (0, 4))	('promotes', 'PosReg', (15, 23))
199216	31863665	miR-412 is a mature type of miR-142, contributing to important functions in inflammatory and immune response among different diseases.	('immune response', 'biological_process', 'GO:0006955', ('93', '108'))	('miR-142', 'Gene', '406934', (28, 35))	('miR-142', 'Gene', (28, 35))	('miR-412', 'Var', (0, 7))	('contributing', 'Reg', (37, 49))
199218	31863665	have documented that genetic variation of PPARGCA1 regulates diet-associated inflammation in colorectal cancer.	('diet-associated inflammation', 'MPA', (61, 89))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('inflammation', 'biological_process', 'GO:0006954', ('77', '89'))	('PPARGCA1', 'Gene', (42, 50))	('colorectal cancer', 'Disease', (93, 110))	('regulates', 'Reg', (51, 60))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('genetic variation', 'Var', (21, 38))
199219	31863665	Moreover, polymorphisms of PPARGCA1 and lower expression of PPARGCA1 are risk factors in the pathogenesis of non-alcoholic fatty liver disease, characterized by abnormal inflammatory response during etiology.	('PPARGCA1', 'Gene', (60, 68))	('abnormal inflammatory response', 'Phenotype', 'HP:0012647', (161, 191))	('pathogenesis', 'biological_process', 'GO:0009405', ('93', '105'))	('PPARGCA1', 'Gene', (27, 35))	('alcoholic fatty liver disease', 'Disease', 'MESH:D005234', (113, 142))	('polymorphisms', 'Var', (10, 23))	('fatty liver', 'Phenotype', 'HP:0001397', (123, 134))	('liver disease', 'Phenotype', 'HP:0001392', (129, 142))	('alcoholic fatty liver', 'Phenotype', 'HP:0006573', (113, 134))	('expression', 'MPA', (46, 56))	('alcoholic fatty liver disease', 'Disease', (113, 142))	('inflammatory response', 'biological_process', 'GO:0006954', ('170', '191'))	('lower', 'NegReg', (40, 45))
199220	31863665	In addition, miR-199b associated with poor survival of ovarian cancer patients, and loss of miR-199b results in hypermethylation in ovarian cancer.	('ovarian cancer', 'Disease', (55, 69))	('hypermethylation in ovarian cancer', 'Disease', (112, 146))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('miR-199b', 'Gene', (13, 21))	('ovarian cancer', 'Phenotype', 'HP:0100615', (55, 69))	('miR-199b', 'Gene', (92, 100))	('ovarian cancer', 'Phenotype', 'HP:0100615', (132, 146))	('loss', 'Var', (84, 88))	('hypermethylation in ovarian cancer', 'Disease', 'MESH:D010051', (112, 146))	('ovarian cancer', 'Disease', 'MESH:D010051', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('ovarian cancer', 'Disease', 'MESH:D010051', (132, 146))
199222	32586940	Macrophage HIF-1alpha is an independent prognostic indicator in kidney cancer Clear cell renal cell carcinoma (ccRCC) is frequently associated with inactivation of the von Hippel Lindau tumor suppressor, resulting in activation of HIF-1alpha and HIF-2alpha.	('HIF-1alpha', 'Gene', '3091', (11, 21))	('inactivation', 'Var', (148, 160))	('kidney cancer', 'Disease', 'MESH:D007680', (64, 77))	('activation', 'PosReg', (217, 227))	('cancer Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (71, 109))	('von Hippel Lindau tumor suppressor', 'Gene', (168, 202))	('RCC', 'Disease', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('kidney cancer', 'Phenotype', 'HP:0009726', (64, 77))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (78, 109))	('kidney cancer', 'Disease', (64, 77))	('HIF-1alpha', 'Gene', (11, 21))	('HIF-1alpha', 'Gene', '3091', (231, 241))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('186', '202'))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('Clear cell renal cell carcinoma', 'Disease', (78, 109))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('associated', 'Reg', (132, 142))	('HIF-2alpha', 'Protein', (246, 256))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (89, 109))	('tumor suppressor', 'biological_process', 'GO:0051726', ('186', '202'))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('HIF-1alpha', 'Gene', (231, 241))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (78, 109))	('von Hippel Lindau tumor suppressor', 'Gene', '7428', (168, 202))
199236	32586940	For example, anerobic glycolysis appears to be predominantly controlled by HIF-1alpha, whereas erythropoietin synthesis is largely HIF-2alpha-regulated.	('erythropoietin', 'molecular_function', 'GO:0005128', ('95', '109'))	('controlled', 'Reg', (61, 71))	('synthesis', 'biological_process', 'GO:0009058', ('110', '119'))	('erythropoietin', 'Gene', (95, 109))	('anerobic glycolysis', 'MPA', (13, 32))	('anerobic glycolysis', 'Phenotype', 'HP:0004366', (13, 32))	('HIF-1alpha', 'Var', (75, 85))	('glycolysis', 'biological_process', 'GO:0006096', ('22', '32'))	('erythropoietin', 'Gene', '2056', (95, 109))
199245	32586940	The HIF-2 bias observed in ccRCC has been attributed to the increased potency of HIF-2alpha compared to HIF-1alpha in promoting expression of pro-tumorigenic factors such as Cyclin D1, TGF-alpha and VEGFA.	('VEGFA', 'Gene', (199, 204))	('TGF-alpha', 'Gene', '7039', (185, 194))	('Cyclin', 'molecular_function', 'GO:0016538', ('174', '180'))	('HIF-2alpha', 'Var', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('RCC', 'Disease', (29, 32))	('tumor', 'Disease', (146, 151))	('promoting', 'PosReg', (118, 127))	('Cyclin D1', 'Gene', '595', (174, 183))	('VEGFA', 'Gene', '7422', (199, 204))	('potency', 'MPA', (70, 77))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('TGF-alpha', 'Gene', (185, 194))	('expression', 'MPA', (128, 138))	('Cyclin D1', 'Gene', (174, 183))	('increased', 'PosReg', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
199295	32586940	Similar to overall HIF-1alpha staining, HIF-1alpha (stroma), was significantly associated with higher grade and with increased heterogeneity in grade 4, larger tumors or tumors with LVI.	('associated', 'Reg', (79, 89))	('LVI', 'CPA', (182, 185))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumors or tumors', 'Disease', (160, 176))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('higher grade', 'CPA', (95, 107))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('HIF-1alpha', 'Var', (40, 50))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumors or tumors', 'Disease', 'MESH:D009369', (160, 176))
199300	32586940	Similarly, each increase of 0.10 in HAF expression was associated with a 12% reduction in risk of death (HR=0.88 [95%CI: 0.80, 0.98]; p=0.02; Fig.	('death', 'Disease', 'MESH:D003643', (98, 103))	('death', 'Disease', (98, 103))	('HAF', 'Gene', (36, 39))	('expression', 'Var', (40, 50))	('HAF', 'Gene', '2161', (36, 39))	('reduction', 'NegReg', (77, 86))	('increase', 'PosReg', (16, 24))
199302	32586940	Thus, in the univariable setting, high HIF-1alpha or high HIF-1alpha (stroma) was significantly correlated with decreased OS, whereas high HAF or high HIF-2alpha was significantly correlated with increased OS.	('high HIF-1alpha', 'Var', (53, 68))	('HAF', 'Gene', '2161', (139, 142))	('high HIF-1alpha', 'Var', (34, 49))	('HAF', 'Gene', (139, 142))	('decreased', 'NegReg', (112, 121))
199351	32586940	When we investigated the impact of hypoxia on RCC cells, we found that while cells with wild-type VHL showed robust HIF-1alpha and HIF-2alpha accumulation under hypoxic conditions, pVHL deficient cells showed constitutively low levels of HIF-1alpha in both normoxia and hypoxia, supporting the previously reported notion of HIF-1alpha loss in ccRCC (Fig.	('hypoxia', 'Disease', 'MESH:D000860', (270, 277))	('pVHL', 'Gene', '7428', (181, 185))	('hypoxic conditions', 'Disease', 'MESH:D000071069', (161, 179))	('hypoxic conditions', 'Disease', (161, 179))	('RCC', 'Disease', (46, 49))	('pVHL', 'Gene', (181, 185))	('hypoxia', 'Disease', (270, 277))	('RCC', 'Disease', (345, 348))	('RCC', 'Disease', 'MESH:C538614', (345, 348))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('VHL', 'Gene', (98, 101))	('VHL', 'Gene', (182, 185))	('hypoxia', 'Disease', 'MESH:D000860', (35, 42))	('low', 'NegReg', (224, 227))	('VHL', 'Gene', '7428', (98, 101))	('VHL', 'Gene', '7428', (182, 185))	('hypoxia', 'Disease', (35, 42))	('deficient', 'Var', (186, 195))
199352	32586940	By contrast, HIF-2alpha levels remained relatively constant in pVHL mutant cells irrespective of oxygen tension, whereas HAF levels generally decreased in hypoxia similar to our previous observations (Fig.	('HAF', 'Gene', '2161', (121, 124))	('HAF', 'Gene', (121, 124))	('pVHL', 'Gene', '7428', (63, 67))	('pVHL', 'Gene', (63, 67))	('decreased', 'NegReg', (142, 151))	('HIF-2alpha levels', 'MPA', (13, 30))	('hypoxia', 'Disease', 'MESH:D000860', (155, 162))	('hypoxia', 'Disease', (155, 162))	('oxygen', 'Chemical', 'MESH:D010100', (97, 103))	('mutant', 'Var', (68, 74))
199359	32586940	Although HIF-1alpha had been proposed as a tumor suppressor in ccRCC, our study has revealed an unexpected role of HIF-1alpha in TAMs as an independent indicator of poor outcome.	('TAMs', 'Chemical', '-', (129, 133))	('HIF-1alpha', 'Var', (115, 125))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor suppressor', 'biological_process', 'GO:0051726', ('43', '59'))	('TAMs', 'Disease', (129, 133))	('tumor', 'Disease', (43, 48))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('43', '59'))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
199365	32586940	Intriguingly, a recent meta-analysis found that although HIF-2alpha was negatively associated with overall survival in a variety of solid tumor types, HIF-2alpha was a positive prognostic biomarker for metastasis-free survival in kidney cancer.	('kidney cancer', 'Phenotype', 'HP:0009726', (230, 243))	('kidney cancer', 'Disease', 'MESH:D007680', (230, 243))	('negatively', 'NegReg', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Disease', (138, 143))	('kidney cancer', 'Disease', (230, 243))	('HIF-2alpha', 'Gene', (57, 67))	('HIF-2alpha', 'Var', (151, 161))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
199387	29587389	Lynch Syndrome-Related Clear Cell Carcinoma of the Cervix: A Case Report Lynch syndrome, a hereditary cancer syndrome, occurs because of germline mutations in at least one of four DNA mismatch repair genes (MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6), and PMS1 Homolog 2 (PMS2)).	('MutS Homolog 2', 'Gene', '4436', (230, 244))	('Clear Cell Carcinoma of the Cervix', 'Phenotype', 'HP:0031522', (23, 57))	('Lynch syndrome', 'Disease', 'MESH:D003123', (73, 87))	('PMS2', 'Gene', '5395', (296, 300))	('mismatch repair', 'biological_process', 'GO:0006298', ('184', '199'))	('MLH1', 'Gene', '4292', (223, 227))	('a hereditary cancer syndrome', 'Disease', 'MESH:D009386', (89, 117))	('DNA', 'cellular_component', 'GO:0005574', ('180', '183'))	('MSH2', 'Gene', (246, 250))	('Carcinoma of the Cervix', 'Phenotype', 'HP:0030079', (34, 57))	('MSH6', 'Gene', (269, 273))	('PMS1 Homolog 2', 'Gene', '5395', (280, 294))	('PMS1 Homolog 2', 'Gene', (280, 294))	('occurs because', 'Reg', (119, 133))	('MSH6', 'Gene', '2956', (269, 273))	('MutL Homolog 1', 'Gene', (207, 221))	('MSH2', 'Gene', '4436', (246, 250))	('MLH1', 'Gene', (223, 227))	('MutS Homolog 6', 'Gene', (253, 267))	('PMS2', 'Gene', (296, 300))	('Carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('MutS Homolog 6', 'Gene', '2956', (253, 267))	('Lynch Syndrome-Related Clear Cell Carcinoma', 'Disease', 'MESH:C538614', (0, 43))	('MutS Homolog 2', 'Gene', (230, 244))	('a hereditary cancer syndrome', 'Disease', (89, 117))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mutations', 'Var', (146, 155))	('Lynch syndrome', 'Disease', (73, 87))	('Lynch Syndrome-Related Clear Cell Carcinoma', 'Disease', (0, 43))	('MutL Homolog 1', 'Gene', '4292', (207, 221))
199393	29587389	Lynch syndrome (also called hereditary non-polyposis colorectal cancer) is an autosomal dominant disorder that arises because of a germline mutation in at least one of four DNA mismatch repair (MMR) genes (MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6), and PMS1 Homolog 2 (PMS2)).	('MLH1', 'Gene', (222, 226))	('mutation', 'Var', (140, 148))	('MutL Homolog 1', 'Gene', '4292', (206, 220))	('colorectal cancer', 'Phenotype', 'HP:0003003', (53, 70))	('MutS Homolog 2', 'Gene', (229, 243))	('MSH2', 'Gene', (245, 249))	('autosomal dominant disorder', 'Disease', (78, 105))	('mismatch repair', 'biological_process', 'GO:0006298', ('177', '192'))	('MSH6', 'Gene', (268, 272))	('MLH1', 'Gene', '4292', (222, 226))	('non-polyposis colorectal cancer', 'Disease', (39, 70))	('non-polyposis colorectal cancer', 'Disease', 'MESH:D015179', (39, 70))	('PMS2', 'Gene', '5395', (295, 299))	('MSH6', 'Gene', '2956', (268, 272))	('MMR', 'biological_process', 'GO:0006298', ('194', '197'))	('MSH2', 'Gene', '4436', (245, 249))	('PMS1 Homolog 2', 'Gene', '5395', (279, 293))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('MutS Homolog 2', 'Gene', '4436', (229, 243))	('PMS1 Homolog 2', 'Gene', (279, 293))	('hereditary non-polyposis colorectal cancer', 'Phenotype', 'HP:0006716', (28, 70))	('MutL Homolog 1', 'Gene', (206, 220))	('Lynch syndrome', 'Disease', (0, 14))	('PMS2', 'Gene', (295, 299))	('MutS Homolog 6', 'Gene', (252, 266))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (78, 105))	('MutS Homolog 6', 'Gene', '2956', (252, 266))	('DNA', 'cellular_component', 'GO:0005574', ('173', '176'))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))
199395	29587389	Individuals who carry MMR mutations are at higher risk of developing a number of epithelial malignancies, such as colorectal, endometrial, ovarian, stomach, pancreas, small intestine, renal, ureteral, and brain cancer.	('colorectal', 'Disease', (114, 124))	('pancreas', 'Disease', (157, 165))	('MMR', 'biological_process', 'GO:0006298', ('22', '25'))	('MMR', 'Gene', (22, 25))	('stomach', 'Disease', (148, 155))	('mutations', 'Var', (26, 35))	('renal', 'Disease', (184, 189))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (81, 104))	('epithelial malignancies', 'Disease', 'MESH:D002277', (81, 104))	('brain cancer', 'Disease', (205, 217))	('ovarian', 'Disease', (139, 146))	('pancreas', 'Disease', 'MESH:D010190', (157, 165))	('ovarian', 'Disease', 'MESH:D010051', (139, 146))	('colorectal', 'Disease', 'MESH:D015179', (114, 124))	('endometrial', 'Disease', (126, 137))	('brain cancer', 'Phenotype', 'HP:0030692', (205, 217))	('epithelial malignancies', 'Disease', (81, 104))	('small intestine', 'Disease', (167, 182))	('ureteral', 'Disease', (191, 199))	('brain cancer', 'Disease', 'MESH:D001932', (205, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
199396	29587389	There is some evidence that MMR gene mutation carriers might be at increased risk of cervical cancer; however, it is currently uncertain whether cervical cancer is associated with Lynch syndrome.	('MMR', 'Gene', (28, 31))	('MMR', 'biological_process', 'GO:0006298', ('28', '31'))	('Lynch syndrome', 'Disease', (180, 194))	('mutation', 'Var', (37, 45))	('cervical cancer', 'Disease', 'MESH:D002583', (85, 100))	('Lynch syndrome', 'Disease', 'MESH:D003123', (180, 194))	('cervical cancer', 'Disease', (85, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cervical cancer', 'Disease', 'MESH:D002583', (145, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cervical cancer', 'Disease', (145, 160))
199427	29587389	Few case reports have described Lynch-related endocervical adenocarcinoma, the typical cervical cancer observed in women believed or shown to have MMR gene mutations.	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (46, 73))	('mutations', 'Var', (156, 165))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('endocervical adenocarcinoma', 'Disease', (46, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('MMR', 'Gene', (147, 150))	('cervical cancer', 'Disease', 'MESH:D002583', (87, 102))	('MMR', 'biological_process', 'GO:0006298', ('147', '150'))	('women', 'Species', '9606', (115, 120))	('cervical cancer', 'Disease', (87, 102))
199428	29587389	One case reported a germline mutation in MSH2, in which the tumor was immunohistochemically deficient for MSH2 and MSH6 with high levels of MSI, and another reported the Muir-Torre variant of Lynch syndrome, where individuals have defects in either MSH2 or MLH1.	('Lynch syndrome', 'Disease', (192, 206))	('MSH2', 'Gene', (106, 110))	('Lynch syndrome', 'Disease', 'MESH:D003123', (192, 206))	('MSH2', 'Gene', '4436', (249, 253))	('MSH6', 'Gene', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('MSH2', 'Gene', (41, 45))	('MSH2', 'Gene', '4436', (106, 110))	('MLH1', 'Gene', '4292', (257, 261))	('MSH2', 'Gene', '4436', (41, 45))	('MLH1', 'Gene', (257, 261))	('germline mutation', 'Var', (20, 37))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('MSH6', 'Gene', '2956', (115, 119))	('deficient', 'NegReg', (92, 101))	('MSH2', 'Gene', (249, 253))
199431	29587389	A third report described a case of gastric-type adenocarcinoma of the cervix in a patient with Lynch syndrome secondary to a germline mutation in the MSH6 MMR gene.	('carcinoma of the cervix', 'Phenotype', 'HP:0030079', (53, 76))	('patient', 'Species', '9606', (82, 89))	('MSH6', 'Gene', '2956', (150, 154))	('gastric-type adenocarcinoma', 'Disease', 'MESH:D013274', (35, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('gastric-type adenocarcinoma', 'Disease', (35, 62))	('secondary to', 'Reg', (110, 122))	('Lynch syndrome', 'Disease', (95, 109))	('MMR', 'biological_process', 'GO:0006298', ('155', '158'))	('MSH6', 'Gene', (150, 154))	('Lynch syndrome', 'Disease', 'MESH:D003123', (95, 109))	('germline mutation', 'Var', (125, 142))
199436	29587389	Although Lynch syndrome is most often linked to colorectal and endometrial tumors, MMR gene mutation carriers commonly develop tumors at other sites at higher rates compared to those observed in the general population.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('linked', 'Reg', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('MMR', 'biological_process', 'GO:0006298', ('83', '86'))	('mutation', 'Var', (92, 100))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('Lynch syndrome', 'Disease', (9, 23))	('MMR gene', 'Gene', (83, 91))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('Lynch syndrome', 'Disease', 'MESH:D003123', (9, 23))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('develop', 'PosReg', (119, 126))	('tumors', 'Disease', (75, 81))	('colorectal and endometrial tumors', 'Disease', 'MESH:D016889', (48, 81))
199437	29587389	Therefore, further studies should examine the contribution of MMR deficiency to tumorigenesis and include prospectively examined epidemiological data, tumor tissue, and tissue obtained following risk-reducing surgery in MMR gene mutation carriers, without discrimination against the involved organ.	('mutation', 'Var', (229, 237))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', (80, 85))	('MMR', 'biological_process', 'GO:0006298', ('220', '223'))	('MMR deficiency', 'Disease', (62, 76))	('MMR deficiency', 'Disease', 'MESH:C536143', (62, 76))	('MMR', 'Gene', (220, 223))	('MMR', 'biological_process', 'GO:0006298', ('62', '65'))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
199438	29587389	It is possible that cervical cancer in MMR gene mutation carriers may arise from the activation of tumorigenic pathways following human papilloma virus exposure.	('tumor', 'Disease', (99, 104))	('human papilloma virus', 'Species', '10566', (130, 151))	('papilloma', 'Phenotype', 'HP:0012740', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('activation', 'PosReg', (85, 95))	('cervical cancer', 'Disease', 'MESH:D002583', (20, 35))	('mutation', 'Var', (48, 56))	('MMR', 'Gene', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cervical cancer', 'Disease', (20, 35))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('MMR', 'biological_process', 'GO:0006298', ('39', '42'))
199523	32537867	Intriguingly, the high NDRG1 expression was correlated with lower Furman grade, TNM stage and longer survival for ccRCC patients compared with the low NDRG1 expression.	('TNM', 'Gene', (80, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('NDRG1', 'Gene', (23, 28))	('high', 'Var', (18, 22))	('Furman grade', 'CPA', (66, 78))	('longer', 'PosReg', (94, 100))	('TNM', 'Gene', '10178', (80, 83))	('survival', 'CPA', (101, 109))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('expression', 'MPA', (29, 39))	('RCC', 'Disease', (116, 119))	('patients', 'Species', '9606', (120, 128))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('lower', 'NegReg', (60, 65))
199539	32537867	Receptor tyrosine kinases inhibitors (such as gefitinib and erlotinib) and mTOR inhibitors (such as rapamycin) are thought to reduce tumour angiogenesis by indirectly reducing the synthesis of HIF-alpha subunits.	('erlotinib', 'Var', (60, 69))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('synthesis', 'biological_process', 'GO:0009058', ('180', '189'))	('reducing', 'NegReg', (167, 175))	('reduce', 'NegReg', (126, 132))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('synthesis', 'MPA', (180, 189))	('angiogenesis', 'biological_process', 'GO:0001525', ('140', '152'))	('HIF-alpha subunits', 'Protein', (193, 211))	('gefitinib', 'Chemical', 'MESH:D000077156', (46, 55))	('tumour', 'Disease', (133, 139))	('erlotinib', 'Chemical', 'MESH:D000069347', (60, 69))	('mTOR', 'Gene', (75, 79))	('mTOR', 'Gene', '2475', (75, 79))	('rapamycin', 'Chemical', 'MESH:D020123', (100, 109))
199544	32537867	Importantly, more than 90% of ccRCC tumours harbour biallelic inactivation of VHL via point mutation, deletion or methylation, which occur at the earliest stage of tumour formation.	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('VHL', 'Gene', (78, 81))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('tumour', 'Disease', (164, 170))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumour', 'Disease', (36, 42))	('point mutation', 'Var', (86, 100))	('deletion', 'Var', (102, 110))	('ccRCC tumours', 'Disease', 'MESH:D009369', (30, 43))	('VHL', 'Gene', '7428', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('methylation', 'Var', (114, 125))	('biallelic inactivation', 'Var', (52, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('formation', 'biological_process', 'GO:0009058', ('171', '180'))	('ccRCC tumours', 'Disease', (30, 43))	('methylation', 'biological_process', 'GO:0032259', ('114', '125'))
199545	32537867	12  In ccRCC, the alterations of VHL mostly disrupt the function of pVHL so that HIF-1/2alpha cannot be degraded and are accumulated in the cancer cell even under normoxic conditions.	('alterations', 'Var', (18, 29))	('RCC', 'Disease', 'MESH:C538614', (9, 12))	('VHL', 'Gene', (33, 36))	('RCC', 'Disease', (9, 12))	('RCC', 'Phenotype', 'HP:0005584', (9, 12))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('HIF-1/2alpha', 'Gene', '3091;2034', (81, 93))	('VHL', 'Gene', '7428', (33, 36))	('function', 'MPA', (56, 64))	('ccRCC', 'Phenotype', 'HP:0006770', (7, 12))	('pVHL', 'Gene', '7428', (68, 72))	('VHL', 'Gene', (69, 72))	('disrupt', 'NegReg', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('pVHL', 'Gene', (68, 72))	('VHL', 'Gene', '7428', (69, 72))	('HIF-1/2alpha', 'Gene', (81, 93))
199546	32537867	Inactivation of VHL is thought to be an early event in the pathogenesis of ccRCC.	('VHL', 'Gene', (16, 19))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('pathogenesis', 'biological_process', 'GO:0009405', ('59', '71'))	('VHL', 'Gene', '7428', (16, 19))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('Inactivation', 'Var', (0, 12))
199565	32537867	VHL (68547S) and HIF2alpha (7096S) antibodies were from Cell Signaling Technology.	('7096S', 'Var', (28, 33))	('HIF2alpha', 'Gene', '2034', (17, 26))	('Signaling', 'biological_process', 'GO:0023052', ('61', '70'))	('VHL', 'Gene', (0, 3))	('S', 'Chemical', 'MESH:D013455', (32, 33))	('S', 'Chemical', 'MESH:D013455', (61, 62))	('68547S', 'Var', (5, 11))	('VHL', 'Gene', '7428', (0, 3))	('HIF2alpha', 'Gene', (17, 26))	('S', 'Chemical', 'MESH:D013455', (10, 11))
199626	32537867	To validate the proteomic results that HIF-1alpha/2alpha regulated NDRG1, reintroduction of VHL into VHL-deficient 786-O and RCC4 cells decreased the protein level of HIF-1/2alpha.	('VHL', 'Gene', (101, 104))	('HIF-1/2alpha', 'Gene', (167, 179))	('VHL', 'Gene', '7428', (101, 104))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('VHL', 'Gene', (92, 95))	('RCC4', 'Gene', '84925', (125, 129))	('HIF-1/2alpha', 'Gene', '3091;2034', (167, 179))	('HIF-1alpha/2alpha', 'Gene', '3091;2034', (39, 56))	('RCC4', 'Gene', (125, 129))	('VHL', 'Gene', '7428', (92, 95))	('NDRG1', 'Gene', (67, 72))	('reintroduction', 'Var', (74, 88))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))	('decreased', 'NegReg', (136, 145))	('protein level', 'MPA', (150, 163))	('HIF-1alpha/2alpha', 'Gene', (39, 56))
199627	32537867	Vice versa, both the protein of HIF-1alpha and NDRG1 were significantly up-regulated by silencing VHL expression in Caki-1 cells (Figure 3C).	('up-regulated', 'PosReg', (72, 84))	('VHL', 'Gene', (98, 101))	('Caki-1', 'CellLine', 'CVCL:0234', (116, 122))	('HIF-1alpha', 'Gene', (32, 42))	('silencing', 'Var', (88, 97))	('VHL', 'Gene', '7428', (98, 101))	('NDRG1', 'Gene', (47, 52))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('protein', 'Protein', (21, 28))	('HIF-1alpha', 'Gene', '3091', (32, 42))
199628	32537867	Next, we disturbed the HIF-1alpha expression in RCC4 cells and knocked down HIF-2alpha in 786-O cells.	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('expression', 'MPA', (34, 44))	('HIF-2alpha', 'Gene', '2034', (76, 86))	('RCC4', 'Gene', '84925', (48, 52))	('HIF-1alpha', 'Gene', '3091', (23, 33))	('RCC4', 'Gene', (48, 52))	('disturbed', 'Reg', (9, 18))	('HIF-1alpha', 'Gene', (23, 33))	('knocked', 'Var', (63, 70))	('HIF-2alpha', 'Gene', (76, 86))
199629	32537867	As shown in Figure 3D, the deletion of HIF-1alpha in RCC4 decreased the expression of NDRG1 in protein levels.	('NDRG1', 'Gene', (86, 91))	('HIF-1alpha', 'Gene', '3091', (39, 49))	('decreased', 'NegReg', (58, 67))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('deletion', 'Var', (27, 35))	('expression', 'MPA', (72, 82))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('HIF-1alpha', 'Gene', (39, 49))	('RCC4', 'Gene', (53, 57))	('RCC4', 'Gene', '84925', (53, 57))
199630	32537867	This is also true that the protein of NDRG1 was significantly down-regulated by silencing HIF-2alpha expression in 786-O cells (Figure 3E).	('silencing', 'Var', (80, 89))	('protein', 'Protein', (27, 34))	('HIF-2alpha', 'Gene', (90, 100))	('down-regulated', 'NegReg', (62, 76))	('HIF-2alpha', 'Gene', '2034', (90, 100))	('expression', 'MPA', (101, 111))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))	('NDRG1', 'Gene', (38, 43))
199632	32537867	Three consecutive tumour sections were obtained from each tumour tissue specimen and were stained by anti-NDRG1, anti-HIF-1alpha and 2alpha antibody, respectively, by IHC.	('antibody', 'cellular_component', 'GO:0019814', ('140', '148'))	('antibody', 'molecular_function', 'GO:0003823', ('140', '148'))	('anti-NDRG1', 'Var', (101, 111))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('antibody', 'cellular_component', 'GO:0042571', ('140', '148'))	('tumour', 'Disease', (58, 64))	('HIF-1alpha and 2alpha', 'Gene', '3091;2034', (118, 139))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('antibody', 'cellular_component', 'GO:0019815', ('140', '148'))	('tumour', 'Disease', (18, 24))
199652	32537867	We found that the overall survival time of the patients with high NDRG1 expression (n = 275) was longer than that of the patients with low NDRG1 expression (n = 370) (P = .001) (Figure 4J).	('NDRG1', 'Gene', (66, 71))	('high', 'Var', (61, 65))	('patients', 'Species', '9606', (47, 55))	('patients', 'Species', '9606', (121, 129))	('longer', 'PosReg', (97, 103))	('P', 'Chemical', 'MESH:D010758', (167, 168))
199654	32537867	The incidence of metastasis in initially diagnosed patients was significantly lower in high NDRG1 expression patient than that in low NDRG1 expression ones (P = .021) (n = 645; Figure 4L).	('P', 'Chemical', 'MESH:D010758', (157, 158))	('patient', 'Species', '9606', (109, 116))	('NDRG1', 'Gene', (92, 97))	('high', 'Var', (87, 91))	('patient', 'Species', '9606', (51, 58))	('patients', 'Species', '9606', (51, 59))	('metastasis', 'CPA', (17, 27))	('lower', 'NegReg', (78, 83))
199657	32537867	Similarly, impaired NDRG1 expression increased the colony formation capacities of ccRCC cells (Figure 5C and D).	('expression', 'MPA', (26, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('colony formation capacities', 'CPA', (51, 78))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('impaired', 'Var', (11, 19))	('formation', 'biological_process', 'GO:0009058', ('58', '67'))	('increased', 'PosReg', (37, 46))	('NDRG1', 'Gene', (20, 25))	('S', 'Chemical', 'MESH:D013455', (0, 1))
199661	32537867	To further examine the impact of NDRG1 in vivo, we implanted nude mice with shNDRG1 transfected 786-O cells and control cells (n = 4 for each group).	('nude mice', 'Species', '10090', (61, 70))	('transfected', 'Var', (84, 95))	('shNDRG1', 'Gene', (76, 83))
199662	32537867	The dynamic quantitative tumour volume of the shNDRG1 group was consistently bigger than that of the control group (Figure 5E).	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('bigger', 'PosReg', (77, 83))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('shNDRG1', 'Var', (46, 53))	('tumour', 'Disease', (25, 31))
199672	32537867	In addition, the higher NDRG1 was found to suppress the development of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('RCC', 'Disease', (73, 76))	('higher', 'Var', (17, 23))	('suppress', 'NegReg', (43, 51))	('development of', 'CPA', (56, 70))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))	('NDRG1', 'Gene', (24, 29))
199679	32537867	In the Figure 7B, the expression of cyclin D1 (CCND1), sirtuin 1 (SIRT1), Snail, Slug, Zeb-2, MMP-2, ADAM-12, VEGFa, Vim, Cav-1 and VCAM-1 was increased when NDRG1 was knocked down in 786-O cells.	('MMP-2', 'Gene', '4313', (94, 99))	('increased', 'PosReg', (143, 152))	('Slug', 'Gene', (81, 85))	('Cav-1', 'Gene', (122, 127))	('cyclin D1', 'Gene', '595', (36, 45))	('Cav-1', 'Gene', '857', (122, 127))	('SIRT1', 'Gene', '23411', (66, 71))	('cyclin', 'molecular_function', 'GO:0016538', ('36', '42'))	('ADAM-12', 'Gene', (101, 108))	('Snail', 'Gene', (74, 79))	('MMP-2', 'Gene', (94, 99))	('CCND1', 'Gene', '595', (47, 52))	('VCAM-1', 'Gene', '7412', (132, 138))	('SIRT1', 'Gene', (66, 71))	('Zeb-2', 'Gene', (87, 92))	('Slug', 'Gene', '6591', (81, 85))	('Vim', 'Gene', (117, 120))	('Zeb-2', 'Gene', '9839', (87, 92))	('VEGFa', 'Gene', (110, 115))	('CCND1', 'Gene', (47, 52))	('knocked down', 'Var', (168, 180))	('ADAM-12', 'Gene', '8038', (101, 108))	('Vim', 'Gene', '7431', (117, 120))	('sirtuin 1', 'Gene', '23411', (55, 64))	('sirtuin 1', 'Gene', (55, 64))	('Snail', 'Gene', '6615', (74, 79))	('expression', 'MPA', (22, 32))	('VEGFa', 'Gene', '7422', (110, 115))	('VCAM-1', 'Gene', (132, 138))	('cyclin D1', 'Gene', (36, 45))	('NDRG1', 'Gene', (158, 163))	('MMP-2', 'molecular_function', 'GO:0004228', ('94', '99'))
199709	32537867	Notably, when the expression level of NDRG1 was adjusted, the high-HIF group patients had a much worse survival than the low-HIF group ones (Figure 6).	('survival', 'MPA', (103, 111))	('high-HIF', 'Var', (62, 70))	('worse', 'NegReg', (97, 102))	('patients', 'Species', '9606', (77, 85))	('NDRG1', 'Gene', (38, 43))
199743	28178674	High IL-8 levels were also associated with significantly shorter OS (HR = 3.55; 95% CI: 1.55-8.14).	('IL-8', 'Gene', '3576', (5, 9))	('OS', 'Chemical', '-', (65, 67))	('High', 'Var', (0, 4))	('IL-8', 'Gene', (5, 9))	('IL-8', 'molecular_function', 'GO:0005153', ('5', '9'))	('shorter', 'NegReg', (57, 64))
199745	28178674	The non-clear cell types (nccRCC) account for approximately 25% of all renal cell carcinoma (RCC) cases and represent a genetically and histologically diverse group of cancers that, in descending order of prevalence, includes papillary, chromophobe, unclassified RCC, Xp11.2 translocation RCC, and other rare subtypes.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', (93, 96))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (71, 91))	('cancers', 'Disease', (168, 175))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('RCC', 'Disease', (289, 292))	('RCC', 'Phenotype', 'HP:0005584', (289, 292))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('papillary', 'Disease', (226, 235))	('RCC', 'Disease', 'MESH:C538614', (289, 292))	('renal cell carcinoma', 'Disease', (71, 91))	('RCC', 'Disease', (263, 266))	('RCC', 'Phenotype', 'HP:0005584', (263, 266))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (71, 91))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('RCC', 'Disease', 'MESH:C538614', (263, 266))	('Xp11.2', 'Var', (268, 274))
199750	28178674	Alterations of the von Hippel-Lindau (VHL) gene, a known hallmark of ccRCC, have been reported in approximately 16% of nccRCCs.	('Alterations', 'Var', (0, 11))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('VHL', 'Disease', 'MESH:D006623', (38, 41))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('reported', 'Reg', (86, 94))	('VHL', 'Disease', (38, 41))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))
199751	28178674	Furthermore, mutations in the hepatocyte growth factor (HGF) receptor MET are often found in patients with papillary RCC.	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('found', 'Reg', (84, 89))	('papillary RCC', 'Disease', 'MESH:C538614', (107, 120))	('papillary RCC', 'Disease', (107, 120))	('hepatocyte growth factor (HGF) receptor', 'Gene', '4233', (30, 69))	('mutations', 'Var', (13, 22))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('30', '54'))	('patients', 'Species', '9606', (93, 101))
199768	28178674	In addition, high IL-8 levels were independently associated with significantly shorter OS in both treatment groups (HR = 3.55; 95% CI: 1.55-8.14; p=0.003) (Figure 1B).	('high', 'Var', (13, 17))	('shorter', 'NegReg', (79, 86))	('OS', 'Chemical', '-', (87, 89))	('IL-8', 'molecular_function', 'GO:0005153', ('18', '22'))	('IL-8', 'Gene', '3576', (18, 22))	('IL-8', 'Gene', (18, 22))
199769	28178674	Cox regression models evaluating the effect of IL-8, IL-13 or sTNF-RII on PFS (Figure 2) alone or in combination showed that patients with high levels of all three CAFs had significantly shorter PFS compared with those that had zero (HR = 43.5; 95% CI: 4.4-500; p=0.001) or only one (HR = 6.5; 95% CI: 2.1-20; p=0.001) CAFs elevated.	('IL-8', 'Gene', '3576', (47, 51))	('PFS', 'MPA', (195, 198))	('CAFs', 'Chemical', '-', (319, 323))	('CAFs', 'Chemical', '-', (164, 168))	('high', 'Var', (139, 143))	('IL-8', 'Gene', (47, 51))	('TNF-RI', 'Gene', '7132', (63, 69))	('IL-13', 'Gene', (53, 58))	('IL-8', 'molecular_function', 'GO:0005153', ('47', '51'))	('shorter', 'NegReg', (187, 194))	('IL-13', 'molecular_function', 'GO:0005144', ('53', '58'))	('IL-13', 'Gene', '3596', (53, 58))	('TNF-RI', 'Gene', (63, 69))	('patients', 'Species', '9606', (125, 133))
199773	28178674	Whereas patients with low baseline sgp130 levels had similar PFS when treated with either drug (HR = 1.28; 95% CI: 0.46-3.60; p=0.637), patients with high sgp130 levels had significantly longer PFS when treated with sunitinib compared with everolimus (HR = 0.30; 95% CI: 0.11-0.85; p=0.024) (Figure 3).	('everolimus', 'Chemical', 'MESH:D000068338', (240, 250))	('patients', 'Species', '9606', (8, 16))	('high', 'Var', (150, 154))	('gp130', 'Gene', (36, 41))	('gp130', 'Gene', (156, 161))	('patients', 'Species', '9606', (136, 144))	('gp130', 'Gene', '3572', (156, 161))	('PFS', 'MPA', (194, 197))	('sunitinib', 'Chemical', 'MESH:D000077210', (216, 225))	('gp130', 'Gene', '3572', (36, 41))	('longer', 'PosReg', (187, 193))
199795	28178674	We identified high plasma sgp130 concentrations to be predictive of a better response to sunitinib compared with everolimus.	('gp130', 'Gene', '3572', (27, 32))	('response', 'MPA', (77, 85))	('high', 'Var', (14, 18))	('everolimus', 'Chemical', 'MESH:D000068338', (113, 123))	('gp130', 'Gene', (27, 32))	('sunitinib', 'Chemical', 'MESH:D000077210', (89, 98))
199918	33993889	In our cohort, tumor seeding within the perinephric adipose tissue along the biopsy needle tract was observed in 6 % (6/98) of all RCC resection cases, but exclusively among patients with PRCC (6/28, 21 %).	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('PRCC', 'Phenotype', 'HP:0006766', (188, 192))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('resection', 'Var', (135, 144))	('patients', 'Species', '9606', (174, 182))	('tumor', 'Disease', (15, 20))	('PRCC', 'Gene', '5546', (188, 192))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('RCC', 'Disease', (189, 192))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))	('PRCC', 'Gene', (188, 192))
199939	33993889	Localized pT1a or pT1b renal cell carcinomas are considered as low-risk disease, with recurrence risk of 1-8 %.	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (23, 44))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (23, 43))	('renal cell carcinomas', 'Disease', (23, 44))	('Localized', 'Disease', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('carcinomas', 'Phenotype', 'HP:0030731', (34, 44))	('pT1b', 'Var', (18, 22))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (23, 44))
199952	33993889	The follow-up data based on our series of PRCC seem to show a low risk of recurrence between patients with low grade pT1a disease with and without tumor seeding in the perinephric adipose tissue.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('PRCC', 'Gene', '5546', (42, 46))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('low grade', 'Var', (107, 116))	('PRCC', 'Gene', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('PRCC', 'Phenotype', 'HP:0006766', (42, 46))	('patients', 'Species', '9606', (93, 101))	('pT1a', 'Gene', (117, 121))
199968	31801939	TMEM45A inactivation decreased cell proliferation and modulated cell responses to cisplatin.	('modulated', 'Reg', (54, 63))	('decreased', 'NegReg', (21, 30))	('cell proliferation', 'CPA', (31, 49))	('TMEM45A', 'Gene', (0, 7))	('inactivation', 'Var', (8, 20))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('TMEM45A', 'Gene', '55076', (0, 7))	('cell proliferation', 'biological_process', 'GO:0008283', ('31', '49'))	('cell', 'CPA', (64, 68))
199969	31801939	Indeed, TMEM45A inactivation increased the sensitivity of SQD9 cells to cisplatin, whereas it rendered RCC4 + pVHL cells resistant to this anticancer agent.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('pVHL', 'Gene', '7428', (110, 114))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('cisplatin', 'Chemical', 'MESH:D002945', (72, 81))	('RCC4', 'Gene', '84925', (103, 107))	('pVHL', 'Gene', (110, 114))	('RCC4', 'Gene', (103, 107))	('TMEM45A', 'Gene', '55076', (8, 15))	('increased', 'PosReg', (29, 38))	('inactivation', 'Var', (16, 28))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('SQD9', 'CellLine', 'CVCL:D774', (58, 62))	('TMEM45A', 'Gene', (8, 15))	('sensitivity', 'MPA', (43, 54))
200007	31801939	TMEM45A knockdown was achieved using siGENOMESMART pool human TMEM45A (#M-021085-00 containing a mix of four siRNA: CAAUGUACUUCUGGAGCUA, GGGAAAUGCUGGACAUCUU, AAGCGAACCUGCUAUCUUG, UAAACAAGGUCACUGGAAU from Dharmacon).	('mix', 'Gene', (97, 100))	('N', 'Chemical', 'MESH:D009584', (112, 113))	('knockdown', 'Var', (8, 17))	('TMEM45A', 'Gene', (0, 7))	('human', 'Species', '9606', (56, 61))	('TMEM45A', 'Gene', (62, 69))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('TMEM45A', 'Gene', '55076', (0, 7))	('mix', 'Gene', '83881', (97, 100))	('TMEM45A', 'Gene', '55076', (62, 69))
200053	31801939	Since pVHL is mutated in ccRCC, HIF1alpha is no longer degraded, hence conferring a state of pseudo-hypoxia.	('pVHL', 'Gene', '7428', (6, 10))	('mutated', 'Var', (14, 21))	('pVHL', 'Gene', (6, 10))	('RCC', 'Disease', 'MESH:D002292', (27, 30))	('HIF1alpha', 'Gene', '3091', (32, 41))	('hypoxia', 'Disease', 'MESH:D000860', (100, 107))	('hypoxia', 'Disease', (100, 107))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('HIF1alpha', 'Gene', (32, 41))
200063	31801939	A strong decrease in both TMEM45A mRNA and protein levels was observed in both cell lines for both inactivation strategies (Supplementary Fig.	('TMEM45A', 'Gene', (26, 33))	('N', 'Chemical', 'MESH:D009584', (36, 37))	('TMEM45A', 'Gene', '55076', (26, 33))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('decrease', 'NegReg', (9, 17))	('inactivation', 'Var', (99, 111))
200066	31801939	In order to identify putative pathways deregulated upon TMEM45A inactivation, a transcriptome analysis by RNA sequencing was performed in SQD9 cells.	('inactivation', 'Var', (64, 76))	('TMEM45A', 'Gene', '55076', (56, 63))	('N', 'Chemical', 'MESH:D009584', (107, 108))	('RNA', 'cellular_component', 'GO:0005562', ('106', '109'))	('TMEM45A', 'Gene', (56, 63))	('SQD9', 'CellLine', 'CVCL:D774', (138, 142))
200073	31801939	In order to identify pathways affected by TMEM45A knockdown, bioinformatic analysis using Babelomics analysis and Gene Set Enrichment Analysis (GSEA) was performed.	('TMEM45A', 'Gene', '55076', (42, 49))	('knockdown', 'Var', (50, 59))	('TMEM45A', 'Gene', (42, 49))
200074	31801939	In parallel, a decrease of about 30% in the proliferation rate for both SQD9 and RCC4 + pVHL cells was observed in the knockdown cells compared to control cells (Fig.	('RCC4', 'Gene', (81, 85))	('RCC4', 'Gene', '84925', (81, 85))	('decrease', 'NegReg', (15, 23))	('SQD9', 'CellLine', 'CVCL:D774', (72, 76))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('pVHL', 'Gene', '7428', (88, 92))	('knockdown', 'Var', (119, 128))	('pVHL', 'Gene', (88, 92))	('proliferation rate', 'CPA', (44, 62))
200076	31801939	Several deregulated pathways in TMEM45A knockdown cells were related to apoptosis (Supplementary Fig.	('TMEM45A', 'Gene', '55076', (32, 39))	('knockdown', 'Var', (40, 49))	('apoptosis', 'biological_process', 'GO:0097194', ('72', '81'))	('apoptosis', 'biological_process', 'GO:0006915', ('72', '81'))	('apoptosis', 'CPA', (72, 81))	('deregulated pathways', 'Pathway', (8, 28))	('TMEM45A', 'Gene', (32, 39))
200086	31801939	TMEM45A overexpressing cells were more resistant to cisplatin than control cells (Supplementary Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('overexpressing', 'Var', (8, 22))	('TMEM45A', 'Gene', (0, 7))	('resistant', 'MPA', (39, 48))	('TMEM45A', 'Gene', '55076', (0, 7))
200090	31801939	TMEM45A was knockdown using shRNA and the cells were incubated with or without 20 muM of cisplatin for 48 h. Surprisingly, TMEM45A knockdown led to a significant decrease in the cleavage of PARP and caspase 3 compared to control cells (Fig.	('TMEM45A', 'Gene', '55076', (123, 130))	('caspase 3', 'Gene', '836', (199, 208))	('knockdown', 'Var', (131, 140))	('cleavage', 'MPA', (178, 186))	('TMEM45A', 'Gene', (123, 130))	('PARP', 'Gene', '142', (190, 194))	('TMEM45A', 'Gene', (0, 7))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('decrease', 'NegReg', (162, 170))	('TMEM45A', 'Gene', '55076', (0, 7))	('PARP', 'Gene', (190, 194))	('caspase 3', 'Gene', (199, 208))
200093	31801939	RCC4 + pVHL cells were thus more resistant to cisplatin when TMEM45A was knockdown, meaning that, in this cell type, TMEM45A exerts a pro-apoptotic role.	('pVHL', 'Gene', '7428', (7, 11))	('TMEM45A', 'Gene', '55076', (61, 68))	('RCC4', 'Gene', (0, 4))	('TMEM45A', 'Gene', (61, 68))	('pVHL', 'Gene', (7, 11))	('TMEM45A', 'Gene', '55076', (117, 124))	('RCC4', 'Gene', '84925', (0, 4))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('TMEM45A', 'Gene', (117, 124))	('knockdown', 'Var', (73, 82))
200101	31801939	These results suggest that TMEM45A inactivation had no effect on the DNA damage induction or detection.	('TMEM45A', 'Gene', '55076', (27, 34))	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('DNA damage', 'MPA', (69, 79))	('inactivation', 'Var', (35, 47))	('TMEM45A', 'Gene', (27, 34))	('N', 'Chemical', 'MESH:D009584', (70, 71))
200105	31801939	After 4 h and 20 h of recovery, gammaH2AX reappeared and was significantly increased in the knockdown cells compared to control cells.	('increased', 'PosReg', (75, 84))	('H2AX', 'Gene', (37, 41))	('H2AX', 'Gene', '3014', (37, 41))	('knockdown', 'Var', (92, 101))
200113	31801939	ATM is recruited and activated by DNA double strand breaks and phosphorylates several targets such as H2AX.	('N', 'Chemical', 'MESH:D009584', (35, 36))	('H2AX', 'Gene', '3014', (102, 106))	('ATM', 'Gene', (0, 3))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('DNA double strand breaks', 'Var', (34, 58))	('activated', 'PosReg', (21, 30))	('recruited', 'PosReg', (7, 16))	('H2AX', 'Gene', (102, 106))	('ATM', 'Gene', '472', (0, 3))
200114	31801939	Figure 4c shows no difference in ATM/ATR substrate phosphorylation profile in the knockdown cells compared to control cells.	('ATR', 'Gene', '545', (37, 40))	('ATR', 'Gene', (37, 40))	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('ATM', 'Gene', (33, 36))	('knockdown', 'Var', (82, 91))	('ATM', 'Gene', '472', (33, 36))
200115	31801939	These results confirm that TMEM45A inactivation did not impact the induction or the recognition of DNA damage.	('TMEM45A', 'Gene', '55076', (27, 34))	('inactivation', 'Var', (35, 47))	('TMEM45A', 'Gene', (27, 34))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))	('N', 'Chemical', 'MESH:D009584', (100, 101))
200127	31801939	These results suggest that TMEM45A silencing had an impact on DNA damage repair through a lack of dephosphorylation of gammaH2AX by EYA3, hence inducing a decrease in the recruitment of proteins involved in DNA damage repair and, consequently, cell death.	('EYA3', 'Gene', '2140', (132, 136))	('H2AX', 'Gene', '3014', (124, 128))	('EYA3', 'Gene', (132, 136))	('decrease', 'NegReg', (155, 163))	('dephosphorylation', 'MPA', (98, 115))	('TMEM45A', 'Gene', '55076', (27, 34))	('proteins', 'Protein', (186, 194))	('lack', 'NegReg', (90, 94))	('recruitment', 'MPA', (171, 182))	('N', 'Chemical', 'MESH:D009584', (208, 209))	('dephosphorylation', 'biological_process', 'GO:0016311', ('98', '115'))	('DNA', 'cellular_component', 'GO:0005574', ('207', '210'))	('cell death', 'biological_process', 'GO:0008219', ('244', '254'))	('N', 'Chemical', 'MESH:D009584', (63, 64))	('TMEM45A', 'Gene', (27, 34))	('DNA damage repair', 'MPA', (62, 79))	('silencing', 'Var', (35, 44))	('H2AX', 'Gene', (124, 128))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('impact', 'Reg', (52, 58))
200130	31801939	Furthermore, the absence of RAD51 recruitment was associated with the presence of gammaH2AX labeling meaning that the DNA damage was still present and detected (Fig.	('RAD51', 'Gene', (28, 33))	('H2AX', 'Gene', (87, 91))	('presence', 'Var', (70, 78))	('DNA', 'cellular_component', 'GO:0005574', ('118', '121'))	('RAD51', 'Gene', '5888', (28, 33))	('absence', 'NegReg', (17, 24))	('N', 'Chemical', 'MESH:D009584', (119, 120))	('recruitment', 'MPA', (34, 45))	('H2AX', 'Gene', '3014', (87, 91))	('RAD', 'biological_process', 'GO:1990116', ('28', '31'))
200131	31801939	These results indicate that the absence of TMEM45A increased SQD9 cell chemosensitivity by decreasing RAD51-associated DNA damage repair.	('absence', 'Var', (32, 39))	('decreasing', 'NegReg', (91, 101))	('increased', 'PosReg', (51, 60))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('TMEM45A', 'Gene', (43, 50))	('RAD', 'biological_process', 'GO:1990116', ('102', '105'))	('SQD9', 'CellLine', 'CVCL:D774', (61, 65))	('SQD9 cell chemosensitivity', 'CPA', (61, 87))	('N', 'Chemical', 'MESH:D009584', (120, 121))	('TMEM45A', 'Gene', '55076', (43, 50))	('RAD51', 'Gene', (102, 107))	('RAD51', 'Gene', '5888', (102, 107))
200135	31801939	Indeed, some studies showed that UPR activation led to resistance to cell death induced by cisplatin, while it has been shown that cisplatin can induce apoptotic signaling via UPR activation, independently of DNA damage in enucleated cells.	('cell death', 'biological_process', 'GO:0008219', ('69', '79'))	('DNA', 'cellular_component', 'GO:0005574', ('209', '212'))	('signaling', 'biological_process', 'GO:0023052', ('162', '171'))	('cisplatin', 'Chemical', 'MESH:D002945', (131, 140))	('induce', 'Reg', (145, 151))	('resistance', 'CPA', (55, 65))	('N', 'Chemical', 'MESH:D009584', (210, 211))	('cisplatin', 'Chemical', 'MESH:D002945', (91, 100))	('cisplatin', 'Var', (131, 140))	('apoptotic signaling', 'MPA', (152, 171))	('UPR activation', 'PosReg', (176, 190))
200147	31801939	These results suggest that TMEM45A inactivation has opposite effects on the cisplatin-induced UPR activation in the two cell lines.	('TMEM45A', 'Gene', '55076', (27, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('inactivation', 'Var', (35, 47))	('TMEM45A', 'Gene', (27, 34))	('cisplatin-induced UPR activation', 'MPA', (76, 108))
200148	31801939	In this study, we demonstrated that TMEM45A inactivation impacted several functions.	('TMEM45A', 'Gene', (36, 43))	('impacted', 'Reg', (57, 65))	('TMEM45A', 'Gene', '55076', (36, 43))	('functions', 'MPA', (74, 83))	('inactivation', 'Var', (44, 56))
200155	31801939	This result means that the absence of TMEM45A in SQD9 cells may induce metabolic changes.	('metabolic changes', 'CPA', (71, 88))	('induce', 'Reg', (64, 70))	('TMEM45A', 'Gene', (38, 45))	('SQD9', 'CellLine', 'CVCL:D774', (49, 53))	('absence', 'Var', (27, 34))	('TMEM45A', 'Gene', '55076', (38, 45))
200159	31801939	Furthermore, upon cisplatin exposure, the basal activation induced by TMEM45A inactivation could modify the response to cisplatin.	('inactivation', 'Var', (78, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (18, 27))	('modify', 'Reg', (97, 103))	('TMEM45A', 'Gene', '55076', (70, 77))	('response to cisplatin', 'MPA', (108, 129))	('basal', 'MPA', (42, 47))	('TMEM45A', 'Gene', (70, 77))	('response to cisplatin', 'biological_process', 'GO:0072718', ('108', '129'))	('activation', 'PosReg', (48, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))
200161	31801939	RNA-sequencing analysis also suggested that TMEM45A silencing impacts SQD9 cell responses to cisplatin through the deregulation of DNA damage responses.	('SQD9', 'CellLine', 'CVCL:D774', (70, 74))	('N', 'Chemical', 'MESH:D009584', (132, 133))	('silencing', 'Var', (52, 61))	('TMEM45A', 'Gene', (44, 51))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('impacts', 'Reg', (62, 69))	('TMEM45A', 'Gene', '55076', (44, 51))	('DNA damage responses', 'MPA', (131, 151))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('DNA', 'cellular_component', 'GO:0005574', ('131', '134'))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('SQD9 cell', 'CPA', (70, 79))
200166	31801939	The absence of TMEM45A also led to a significant decrease in cell proliferation as already shown in human ovarian cancer cells and in human glioma cells, indicating that at least in four different cancer types, cell proliferation is a pathway dependent on TMEM45A expression.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('cell proliferation', 'biological_process', 'GO:0008283', ('211', '229'))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('ovarian cancer', 'Disease', 'MESH:D010051', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('TMEM45A', 'Gene', (15, 22))	('ovarian cancer', 'Disease', (106, 120))	('TMEM45A', 'Gene', '55076', (256, 263))	('cell proliferation', 'biological_process', 'GO:0008283', ('61', '79'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (106, 120))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('human', 'Species', '9606', (134, 139))	('cancer', 'Disease', (197, 203))	('decrease', 'NegReg', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cell proliferation', 'CPA', (61, 79))	('TMEM45A', 'Gene', (256, 263))	('human', 'Species', '9606', (100, 105))	('TMEM45A', 'Gene', '55076', (15, 22))	('glioma', 'Disease', (140, 146))	('absence', 'Var', (4, 11))	('cell proliferation', 'CPA', (211, 229))	('cancer', 'Disease', (114, 120))
200172	31801939	Indeed, TMEM45A knockdown modulated cisplatin-activation of UPR pathway, leading to the resistance of RCC4 + pVHL cells, whereas it increased SQD9 cell sensitivity to cisplatin through the deregulation of cell responses to cisplatin-induced DNA damage.	('pVHL', 'Gene', '7428', (109, 113))	('cisplatin', 'Chemical', 'MESH:D002945', (167, 176))	('pVHL', 'Gene', (109, 113))	('cisplatin', 'Chemical', 'MESH:D002945', (223, 232))	('N', 'Chemical', 'MESH:D009584', (242, 243))	('increased', 'PosReg', (132, 141))	('modulated', 'Reg', (26, 35))	('SQD9', 'CellLine', 'CVCL:D774', (142, 146))	('UPR pathway', 'Pathway', (60, 71))	('resistance', 'MPA', (88, 98))	('TMEM45A', 'Gene', '55076', (8, 15))	('RCC4', 'Gene', (102, 106))	('cell responses to cisplatin-induced', 'MPA', (205, 240))	('RCC4', 'Gene', '84925', (102, 106))	('knockdown', 'Var', (16, 25))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('TMEM45A', 'Gene', (8, 15))	('DNA', 'cellular_component', 'GO:0005574', ('241', '244'))
200208	31639017	RNA immunoprecipitation assays and functional assays on an MCPIP1 mutant with a mutated PIN domain showed that these transcripts interact with MCPIP1 and that their levels depend on the active form of MCPIP1 (Fig.	('levels', 'MPA', (165, 171))	('mutant', 'Var', (66, 72))	('MCPIP1', 'Gene', (59, 65))	('PIN', 'Gene', (88, 91))	('mutated', 'Var', (80, 87))	('N', 'Chemical', 'MESH:D009584', (90, 91))	('PIN', 'Gene', '8655', (88, 91))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('interact', 'Interaction', (129, 137))	('N', 'Chemical', 'MESH:D009584', (1, 2))
200223	31639017	Further investigation indicated that in those cells, miRNA-3613-3p overexpression negatively regulated the expression of apoptotic protease activating factor 1 (APAF1).	('apoptotic protease activating factor 1', 'Gene', (121, 159))	('expression', 'MPA', (107, 117))	('APAF1', 'Gene', '317', (161, 166))	('apoptotic protease activating factor 1', 'Gene', '317', (121, 159))	('miRNA-3613-3p', 'Var', (53, 66))	('APAF1', 'Gene', (161, 166))	('N', 'Chemical', 'MESH:D009584', (56, 57))	('negatively', 'NegReg', (82, 92))
200224	31639017	Overexpression of wild-type but not mutated MCPIP1 (with deletion of the PIN domain) in BE(2)-C cells resulted in miR-3613-3p downregulation and significant increases in pro-apoptotic DFFB and APAF1 at the mRNA and protein levels.	('PIN', 'Gene', '8655', (73, 76))	('PIN', 'Gene', (73, 76))	('miR-3613-3p', 'MPA', (114, 125))	('downregulation', 'NegReg', (126, 140))	('deletion', 'Var', (57, 65))	('N', 'Chemical', 'MESH:D009584', (75, 76))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('APAF1', 'Gene', (193, 198))	('mutated', 'Var', (36, 43))	('DFFB', 'Gene', '1677', (184, 188))	('APAF1', 'Gene', '317', (193, 198))	('increases', 'PosReg', (157, 166))	('MCPIP1', 'Gene', (44, 50))	('N', 'Chemical', 'MESH:D009584', (208, 209))	('DFFB', 'Gene', (184, 188))
200225	31639017	Thus, in several cancer cells characterized by low levels of MCPIP1, upregulated miR-3613-3p may decrease the possibility of apoptosis activation, whereas BE(2)-C cells overexpressing miR-3613-3p exhibit inhibition of caspase-9 proteolysis.	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('apoptosis activation', 'CPA', (125, 145))	('apoptosis', 'biological_process', 'GO:0097194', ('125', '134'))	('caspase-9', 'Gene', (218, 227))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('apoptosis', 'biological_process', 'GO:0006915', ('125', '134'))	('cancer', 'Disease', (17, 23))	('upregulated', 'PosReg', (69, 80))	('proteolysis', 'biological_process', 'GO:0006508', ('228', '239'))	('decrease', 'NegReg', (97, 105))	('caspase-9', 'Gene', '842', (218, 227))	('miR-3613-3p', 'Var', (81, 92))	('MCPIP1', 'Var', (61, 67))
200244	31639017	MCPIP1 depletion in ccRCC cells significantly enhanced tumour cell proliferation in both examined cell lines, Caki-1 and Caki-2.	('tumour', 'Disease', (55, 61))	('cell proliferation', 'biological_process', 'GO:0008283', ('62', '80'))	('MCPIP1', 'Gene', (0, 6))	('ccRCC', 'Phenotype', 'HP:0006770', (20, 25))	('ccRCC', 'Disease', (20, 25))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('ccRCC', 'Disease', 'MESH:D002292', (20, 25))	('depletion', 'Var', (7, 16))	('enhanced', 'PosReg', (46, 54))	('tumour', 'Disease', 'MESH:D009369', (55, 61))
200246	31639017	These experiments proved that inhibition of MCPIP1 in Caki-1 cells affected both tumour growth and weight.	('tumour growth', 'Disease', (81, 94))	('affected', 'Reg', (67, 75))	('inhibition', 'Var', (30, 40))	('tumour growth', 'Disease', 'MESH:D006130', (81, 94))	('weight', 'CPA', (99, 105))	('MCPIP1', 'Gene', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
200250	31639017	Caki-1 cells expressing MCPIP1 showed significantly higher expression of p21Cip1 protein and mRNA than control and D141N cells (with a point mutation in MCPIP1 resulting in an inactive catalytic site).	('mRNA', 'MPA', (93, 97))	('N', 'Chemical', 'MESH:D009584', (95, 96))	('p21Cip1', 'Gene', (73, 80))	('D141N', 'Mutation', 'p.D141N', (115, 120))	('MCPIP1', 'Var', (24, 30))	('N', 'Chemical', 'MESH:D009584', (119, 120))	('expression', 'MPA', (59, 69))	('point mutation', 'Var', (135, 149))	('higher', 'PosReg', (52, 58))	('p21Cip1', 'Gene', '1026', (73, 80))	('MCPIP1', 'Gene', (153, 159))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))
200256	31639017	In addition, siRNA silencing of MCPIP1 in human primary keratinocytes was shown to decrease the levels of phosphorylated p53 and p21 proteins and to upregulate Cyclin D1 expression after exposure to UVB radiation stress, which may serve as a mechanism of survival promotion in MCPIP1-depleted cells.	('Cyclin D1', 'Gene', '595', (160, 169))	('N', 'Chemical', 'MESH:D009584', (16, 17))	('human', 'Species', '9606', (42, 47))	('p53', 'Gene', (121, 124))	('Cyclin D1', 'Gene', (160, 169))	('p53', 'Gene', '7157', (121, 124))	('silencing', 'Var', (19, 28))	('Cyclin', 'molecular_function', 'GO:0016538', ('160', '166'))	('decrease', 'NegReg', (83, 91))	('p21', 'Gene', '1026', (129, 132))	('p21', 'Gene', (129, 132))	('MCPIP1', 'Gene', (32, 38))	('expression', 'MPA', (170, 180))	('upregulate', 'PosReg', (149, 159))
200264	31639017	A study by Qu and coauthors showed that MCPIP1 weakens the LPS induction of miR-146a in THP-1 cells treated with type I interferon (IFN).	('IFN', 'Gene', (132, 135))	('MCPIP1', 'Var', (40, 46))	('LPS', 'Gene', (59, 62))	('miR-146a', 'Gene', '406938', (76, 84))	('interferon', 'Gene', '3439', (120, 130))	('interferon', 'Gene', (120, 130))	('miR-146a', 'Gene', (76, 84))	('weakens', 'NegReg', (47, 54))	('THP-1', 'Gene', (88, 93))	('THP-1', 'Gene', '2736', (88, 93))	('LPS', 'Gene', '3664', (59, 62))	('IFN', 'Gene', '3439', (132, 135))
200276	31639017	Overexpression of MCPIP1 has been described to suppress VCAM-1 expression and monocyte adhesion to human endothelial cells.	('VCAM-1', 'Gene', (56, 62))	('expression', 'MPA', (63, 73))	('suppress', 'NegReg', (47, 55))	('MCPIP1', 'Gene', (18, 24))	('Overexpression', 'Var', (0, 14))	('monocyte adhesion to human endothelial cells', 'CPA', (78, 122))	('human', 'Species', '9606', (99, 104))
200278	31639017	Moreover, correlations have been found between increased levels of MCPIP1 and both inhibition of TNFalpha-induced VCAM-1 expression in HUVECs and LPS-induced VCAM-1 expression in mice.	('inhibition', 'NegReg', (83, 93))	('mice', 'Species', '10090', (179, 183))	('LPS', 'Gene', '3664', (146, 149))	('expression', 'MPA', (165, 175))	('expression', 'MPA', (121, 131))	('VCAM-1', 'Gene', (114, 120))	('increased', 'PosReg', (47, 56))	('LPS', 'Gene', (146, 149))	('MCPIP1', 'Var', (67, 73))	('TNFalpha-induced', 'Gene', (97, 113))
200279	31639017	In addition, inhibition of MALT1 protease activity significantly inhibits TNFalpha-induced adhesion of THP-1 monocytic cells to HUVECs.	('MALT1', 'Gene', '10892', (27, 32))	('MALT1', 'Gene', (27, 32))	('activity', 'MPA', (42, 50))	('inhibits', 'NegReg', (65, 73))	('TNFalpha-induced', 'Gene', (74, 90))	('inhibition', 'Var', (13, 23))	('THP-1', 'Gene', '2736', (103, 108))	('THP-1', 'Gene', (103, 108))	('protease activity', 'molecular_function', 'GO:0008233', ('33', '50'))	('adhesion', 'MPA', (91, 99))
200282	31639017	Moreover, the Kollatukudy group showed that transfection of HUVECs with an MCPIP-GFP expression vector induced HIF-1alpha and VEGF production, whereas silencing of MCPIP1 by siRNA suppressed MCP-1-induced expression of HIF-1alpha and VEGF.	('VEGF production', 'biological_process', 'GO:0010573', ('126', '141'))	('silencing', 'Var', (151, 160))	('MCP-1', 'Gene', (191, 196))	('HIF-1alpha', 'Gene', (111, 121))	('N', 'Chemical', 'MESH:D009584', (177, 178))	('MCP', 'molecular_function', 'GO:0004298', ('191', '194'))	('MCP-1', 'Gene', '6347', (191, 196))	('VEGF', 'Gene', '7422', (234, 238))	('MCPIP1', 'Gene', (164, 170))	('VEGF', 'Gene', '7422', (126, 130))	('HIF-1alpha', 'Gene', '3091', (219, 229))	('induced', 'PosReg', (103, 110))	('HIF-1alpha', 'Gene', '3091', (111, 121))	('VEGF', 'Gene', (126, 130))	('expression', 'MPA', (205, 215))	('VEGF', 'Gene', (234, 238))	('HIF-1alpha', 'Gene', (219, 229))
200283	31639017	Further studies showed that low levels of MCPIP1 in ccRCC induce endothelial cell angiogenesis and that the lack of MCPIP1 RNase activity is responsible for the secretion of proangiogenic factors:VEGF, IL-8 and IL-6:by tumour cells.	('tumour', 'Phenotype', 'HP:0002664', (219, 225))	('induce', 'Reg', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (219, 225))	('angiogenesis', 'biological_process', 'GO:0001525', ('82', '94'))	('IL-6', 'Gene', '3569', (211, 215))	('tumour', 'Disease', (219, 225))	('IL-8', 'molecular_function', 'GO:0005153', ('202', '206'))	('N', 'Chemical', 'MESH:D009584', (124, 125))	('IL-6', 'Gene', (211, 215))	('IL-8', 'Gene', '3576', (202, 206))	('RNase', 'Enzyme', (123, 128))	('RNase activity', 'molecular_function', 'GO:0004522', ('123', '137'))	('lack', 'Var', (108, 112))	('ccRCC', 'Disease', 'MESH:D002292', (52, 57))	('IL-6', 'molecular_function', 'GO:0005138', ('211', '215'))	('ccRCC', 'Disease', (52, 57))	('VEGF', 'Gene', '7422', (196, 200))	('secretion', 'MPA', (161, 170))	('endothelial cell angiogenesis', 'CPA', (65, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('secretion', 'biological_process', 'GO:0046903', ('161', '170'))	('IL-8', 'Gene', (202, 206))	('activity', 'MPA', (129, 137))	('VEGF', 'Gene', (196, 200))	('MCPIP1', 'Gene', (116, 122))
200292	31639017	Conversely, silencing of MCPIP1 upregulated miR-20b and miR-34a expression upon stimulation with TNF-alpha or IL1-beta.	('miR-34a', 'Gene', '407040', (56, 63))	('expression', 'MPA', (64, 74))	('miR-20b', 'Gene', '574032', (44, 51))	('TNF-alpha', 'Gene', '7124', (97, 106))	('miR-34a', 'Gene', (56, 63))	('MCPIP1', 'Gene', (25, 31))	('TNF-alpha', 'Gene', (97, 106))	('silencing', 'Var', (12, 21))	('IL1-beta', 'Gene', (110, 118))	('IL1', 'molecular_function', 'GO:0005149', ('110', '113'))	('miR-20b', 'Gene', (44, 51))	('IL1-beta', 'Gene', '3553', (110, 118))	('upregulated', 'PosReg', (32, 43))
200298	31639017	Studies in Caki-1 cells showed that MCPIP1 silencing increases SDF-1 expression both in vitro and in vivo and that the RNase activity of MCPIP1 controls the level of SDF-1 mRNA .	('SDF-1', 'Gene', '6387', (63, 68))	('RNase activity', 'molecular_function', 'GO:0004522', ('119', '133'))	('SDF-1', 'Gene', (63, 68))	('N', 'Chemical', 'MESH:D009584', (120, 121))	('expression', 'MPA', (69, 79))	('silencing', 'Var', (43, 52))	('N', 'Chemical', 'MESH:D009584', (174, 175))	('SDF-1', 'Gene', '6387', (166, 171))	('SDF-1', 'Gene', (166, 171))	('increases', 'PosReg', (53, 62))	('MCPIP1', 'Gene', (36, 42))
200308	31639017	Moreover, silencing of MCPIP1 in ccRCC cells was associated with both an increased number of circulating tumour cells in mouse blood and augmented lung metastasis .	('ccRCC', 'Disease', (33, 38))	('increased', 'PosReg', (73, 82))	('MCPIP1', 'Gene', (23, 29))	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('ccRCC', 'Disease', 'MESH:D002292', (33, 38))	('tumour', 'Disease', (105, 111))	('augmented lung metastasis', 'Disease', (137, 162))	('mouse', 'Species', '10090', (121, 126))	('augmented lung metastasis', 'Disease', 'MESH:D009362', (137, 162))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('silencing', 'Var', (10, 19))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))
200313	31639017	The gene coding for c-Met is considered a protooncogene because abnormal activation of c-Met can promote the development and progression of multiple cancers, such as liver, lung, colon, breast, pancreatic, ovarian, prostate, and gastric carcinomas, in addition to cancers of the nervous system, such as glioblastoma.	('colon', 'Disease', (179, 184))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('multiple cancers', 'Disease', (140, 156))	('promote', 'PosReg', (97, 104))	('c-Met', 'Gene', (20, 25))	('cancers', 'Disease', (264, 271))	('c-Met', 'Gene', '4233', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('breast', 'Disease', (186, 192))	('glioblastoma', 'Disease', 'MESH:D005909', (303, 315))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('carcinomas', 'Phenotype', 'HP:0030731', (237, 247))	('activation', 'PosReg', (73, 83))	('cancers', 'Disease', (149, 156))	('gastric carcinomas', 'Disease', 'MESH:D013274', (229, 247))	('gastric carcinomas', 'Disease', (229, 247))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('glioblastoma', 'Disease', (303, 315))	('lung', 'Disease', (173, 177))	('progression', 'CPA', (125, 136))	('glioblastoma', 'Phenotype', 'HP:0012174', (303, 315))	('cancers', 'Disease', 'MESH:D009369', (264, 271))	('c-Met', 'Gene', '4233', (20, 25))	('c-Met', 'Gene', (87, 92))	('multiple cancers', 'Disease', 'MESH:D009369', (140, 156))	('pancreatic, ovarian, prostate', 'Disease', 'MESH:D010051', (194, 223))	('abnormal', 'Var', (64, 72))	('liver', 'Disease', (166, 171))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
200314	31639017	MCPIP1 overexpression has been shown to reduce the expression and endogenous phosphorylation levels of c-Met and decrease the level of Src kinase in ccRCC .	('Src', 'Gene', (135, 138))	('c-Met', 'Gene', (103, 108))	('overexpression', 'Var', (7, 21))	('decrease', 'NegReg', (113, 121))	('c-Met', 'Gene', '4233', (103, 108))	('ccRCC', 'Disease', 'MESH:D002292', (149, 154))	('reduce', 'NegReg', (40, 46))	('MCPIP1', 'Gene', (0, 6))	('Src', 'Gene', '6714', (135, 138))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('expression', 'MPA', (51, 61))	('endogenous phosphorylation levels', 'MPA', (66, 99))	('ccRCC', 'Phenotype', 'HP:0006770', (149, 154))	('ccRCC', 'Disease', (149, 154))
200315	31639017	The gene coding for C-Met is a direct target of NFkappaB, and MET participates in NFkappaB-mediated cell survival.	('MET', 'Var', (62, 65))	('participates', 'Reg', (66, 78))	('C-Met', 'Gene', '4233', (20, 25))	('NFkappaB', 'Gene', '4790', (82, 90))	('NFkappaB', 'Gene', (82, 90))	('NFkappaB', 'Gene', (48, 56))	('NFkappaB', 'Gene', '4790', (48, 56))	('C-Met', 'Gene', (20, 25))
200317	31639017	In a recent study of cell migration at the single-cell level, Zhuang and coauthors found that the expression of MCPIP1 is related to the mobility of cancer cells.	('MCPIP1', 'Gene', (112, 118))	('cancer', 'Disease', (149, 155))	('expression', 'Var', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('related to', 'Reg', (122, 132))	('cell migration', 'biological_process', 'GO:0016477', ('21', '35'))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
200320	31639017	The authors further showed that inhibiting TGF-beta in MDA-MB-231 cells with low levels of MCPIP1 expression restored their migratory phenotype to that observed in the corresponding cells with high levels of MCPIP1 expression.	('TGF-beta', 'Gene', '7040', (43, 51))	('inhibiting', 'Var', (32, 42))	('TGF-beta', 'Gene', (43, 51))	('MCPIP1', 'Gene', (91, 97))	('restored', 'PosReg', (109, 117))	('migratory phenotype', 'CPA', (124, 143))
200321	31639017	This mechanism was further validated in an in vivo xenograft model, in which high MCPIP1 expression inhibited tumour growth and inhibit breast cancer invasion, while additional treatment of xenografts with low levels of MCPIP1 expression with a TGF-beta inhibitor attenuated their growth phenotype.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('inhibit', 'NegReg', (128, 135))	('breast cancer invasion', 'Disease', (136, 158))	('breast cancer invasion', 'Disease', 'MESH:D001943', (136, 158))	('high', 'Var', (77, 81))	('MCPIP1', 'Gene', (82, 88))	('TGF-beta', 'Gene', '7040', (245, 253))	('expression', 'Var', (89, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('tumour growth', 'Disease', (110, 123))	('TGF-beta', 'Gene', (245, 253))	('inhibited', 'NegReg', (100, 109))	('tumour growth', 'Disease', 'MESH:D006130', (110, 123))
200338	31639017	MCPIP1 can regulate the level of transcripts directly by degrading them or indirectly by degrading the regulators of their expression, e.g., the mRNAs of transcription factors that regulate the expression of these transcripts, or by degrading specific miRNAs.	('N', 'Chemical', 'MESH:D009584', (255, 256))	('expression', 'MPA', (123, 133))	('specific miRNAs', 'MPA', (243, 258))	('degrading', 'NegReg', (57, 66))	('level', 'MPA', (24, 29))	('MCPIP1', 'Var', (0, 6))	('degrading', 'NegReg', (89, 98))	('N', 'Chemical', 'MESH:D009584', (147, 148))	('mRNAs', 'MPA', (145, 150))	('them', 'MPA', (67, 71))	('degrading', 'NegReg', (233, 242))	('transcription', 'biological_process', 'GO:0006351', ('154', '167'))	('regulators of', 'MPA', (103, 116))
200343	30428910	Downregulation of CLDN7 due to promoter hypermethylation is associated with human clear cell renal cell carcinoma progression and poor prognosis Metastasis is the primary cause of death in renal cell carcinoma (RCC).	('CLDN7', 'Gene', (18, 23))	('death in renal cell carcinoma', 'Disease', (180, 209))	('RCC', 'Disease', (211, 214))	('Downregulation', 'NegReg', (0, 14))	('RCC', 'Phenotype', 'HP:0005584', (211, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('RCC', 'Disease', 'MESH:C538614', (211, 214))	('CLDN7', 'Gene', '1366', (18, 23))	('death in renal cell carcinoma', 'Disease', 'MESH:C538614', (180, 209))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (82, 113))	('human', 'Species', '9606', (76, 81))	('clear cell renal cell carcinoma', 'Disease', (82, 113))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (82, 113))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (93, 113))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (189, 209))	('associated', 'Reg', (60, 70))	('promoter hypermethylation', 'Var', (31, 56))
200352	30428910	Our findings revealed that CLDN7 is frequently downregulated via hypermethylation of its promoter in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('hypermethylation', 'Var', (65, 81))	('downregulated', 'NegReg', (47, 60))	('CLDN7', 'Gene', (27, 32))
200354	30428910	Interestingly, hypermethylation of the CLDN7 promoter was related to advanced ccRCC status and poor prognosis.	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('related', 'Reg', (58, 65))	('hypermethylation', 'Var', (15, 31))	('CLDN7', 'Gene', (39, 44))
200357	30428910	We have demonstrated a previously undescribed role of CLDN7 as a ccRCC suppressor and suggest that loss of CLDN7 potentiates EMT and tumor progression.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('CLDN7', 'Gene', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('potentiates', 'PosReg', (113, 124))	('tumor', 'Disease', (133, 138))	('loss', 'Var', (99, 103))	('EMT', 'biological_process', 'GO:0001837', ('125', '128'))
200370	30428910	In this study, we confirmed that downregulation of CLDN7 due to hypermethylation may help predict aggressive tumor status and poor prognosis in ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('aggressive tumor', 'Disease', (98, 114))	('CLDN7', 'Gene', (51, 56))	('patients', 'Species', '9606', (150, 158))	('hypermethylation', 'Var', (64, 80))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('aggressive tumor', 'Disease', 'MESH:D001523', (98, 114))	('downregulation', 'NegReg', (33, 47))
200382	30428910	Additionally, gene-set enrichment analysis (GSEA) was performed to compare differences in molecular pathways in cell processes between the low CLDN7 and high CLDN7 groups on the data from the ccRCC dataset of TCGA.	('RCC', 'Disease', 'MESH:C538614', (194, 197))	('RCC', 'Disease', (194, 197))	('RCC', 'Phenotype', 'HP:0005584', (194, 197))	('low CLDN7', 'Var', (139, 148))	('high CLDN7', 'Var', (153, 163))	('GSEA', 'Chemical', '-', (44, 48))	('molecular pathways', 'Pathway', (90, 108))
200396	30428910	GAPDH (TA309157) and Ki-67 (TA500265) were purchased from ZSGB-BIO, Beijing, China.	('TA309157', 'Var', (7, 15))	('GAPDH', 'Gene', '2597', (0, 5))	('TA500265', 'Var', (28, 36))	('GAPDH', 'Gene', (0, 5))
200420	30428910	Ten minutes after D-Luciferin, sodium salt (150 mg/kg) was injected intraperitoneally, and cancer cells were detected with an in vivo imaging system, Xenogen IVIS (PerkinElmer, MA, USA).	('D-Luciferin', 'Var', (18, 29))	('D-Luciferin', 'Chemical', 'MESH:C532924', (18, 29))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('sodium salt', 'Chemical', '-', (31, 42))
200443	30428910	Epigenetic alterations, such as promoter CpG methylation, could mediate the activation of oncogene and inactivate tumor suppressor genes, thus contributing to tumorigenesis.	('Epigenetic alterations', 'Var', (0, 22))	('oncogene', 'Gene', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('114', '130'))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('promoter CpG methylation', 'Var', (32, 56))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', (159, 164))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('114', '130'))	('inactivate', 'NegReg', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('activation', 'PosReg', (76, 86))	('contributing', 'Reg', (143, 155))
200445	30428910	In the TCGA ccRCC dataset, we generated a comparable heatmap in which we found that when some regions of the CLDN7 promoter were hypermethylated, CLDN7 expression was lower (Fig.	('lower', 'NegReg', (167, 172))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('RCC', 'Disease', (14, 17))	('hypermethylated', 'Var', (129, 144))	('CLDN7', 'Gene', (146, 151))	('expression', 'MPA', (152, 162))	('CLDN7', 'Gene', (109, 114))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
200446	30428910	Moreover, we observed that CLDN7 methylation status was negatively related to its mRNA and protein expression in the TCGA ccRCC dataset (Fig.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('methylation', 'biological_process', 'GO:0032259', ('33', '44'))	('methylation', 'Var', (33, 44))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('negatively', 'NegReg', (56, 66))	('CLDN7', 'Gene', (27, 32))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))
200450	30428910	Hypermethylated CLDN7 was significantly correlated with advanced age, pathologic T and histologic G, which agrees with our bioinformatic analysis of the TCGA ccRCC Methylation 450 K dataset (n = 319, Additional file 7: Table S4).	('Hypermethylated', 'Var', (0, 15))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('RCC', 'Disease', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('Methylation', 'biological_process', 'GO:0032259', ('164', '175'))	('correlated', 'Reg', (40, 50))	('CLDN7', 'Gene', (16, 21))	('pathologic T', 'Disease', (70, 82))
200451	30428910	Therefore, hypermethylation of CLDN7 promoter was associated with downregulation of CLDN7 and a poor prognosis in ccRCC patients.	('hypermethylation', 'Var', (11, 27))	('CLDN7', 'Gene', (31, 36))	('CLDN7', 'Gene', (84, 89))	('patients', 'Species', '9606', (120, 128))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('downregulation', 'NegReg', (66, 80))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))
200452	30428910	2, promoter hypermethylation was associated with low CLDN7 expression in ccRCC patients.	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('expression', 'MPA', (59, 69))	('low', 'NegReg', (49, 52))	('patients', 'Species', '9606', (79, 87))	('CLDN7', 'Gene', (53, 58))	('promoter hypermethylation', 'Var', (3, 28))
200456	30428910	CLDN7 hypermethylation was also found in 34/108 (31.5%) ccRCC tissues (Fig.	('hypermethylation', 'Var', (6, 22))	('found', 'Reg', (32, 37))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('CLDN7', 'Gene', (0, 5))
200464	30428910	Consistent with the weak proliferative ability and high apoptotic rate observed in the CLDN7 overexpressed Caki-1 and A498 cells, a xenograft experiment in mice found that CLDN7 overexpressed tumors grew slower than those in a control group (Fig.	('CLDN7', 'Gene', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('CLDN7', 'Var', (172, 177))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('A498', 'CellLine', 'CVCL:1056', (118, 122))	('mice', 'Species', '10090', (156, 160))	('slower', 'NegReg', (204, 210))	('grew', 'CPA', (199, 203))
200466	30428910	A transwell migratory and invasive assay also found that migratory and invasive cells were clearly attenuated in Caki-1 and A498 cells that overexpressed CLDN7, compared with control cells (Fig.	('CLDN7', 'Gene', (154, 159))	('overexpressed', 'Var', (140, 153))	('attenuated', 'NegReg', (99, 109))	('A498', 'CellLine', 'CVCL:1056', (124, 128))
200467	30428910	To understand the tumor suppressive role of CLDN7 in ccRCC, gene-set enrichment analysis on the data from the database of TCGA was used to compare the differences in cell processes between the low- and high- CLDN7 groups.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('tumor', 'Disease', (18, 23))	('high- CLDN7', 'Var', (202, 213))	('low-', 'Var', (193, 197))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
200468	30428910	Interestingly, the results suggest that several pathways relating to cancer and TGF-beta, WNT, Focal adhesion and NOTCH pathways relating to epithelial-mesenchymal transition (EMT) and tumor progression were all decreased in ccRCC with high CLDN7 mRNA expression (Additional file 9: Figure S5 and Additional file 10: Table S5).	('Focal adhesion', 'cellular_component', 'GO:0005925', ('95', '109'))	('WNT', 'Pathway', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Disease', (185, 190))	('RCC', 'Disease', (227, 230))	('RCC', 'Phenotype', 'HP:0005584', (227, 230))	('mRNA expression', 'MPA', (247, 262))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('141', '174'))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('Focal adhesion', 'CPA', (95, 109))	('decreased', 'NegReg', (212, 221))	('RCC', 'Disease', 'MESH:C538614', (227, 230))	('TGF-beta', 'Gene', '7040', (80, 88))	('high', 'Var', (236, 240))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('cancer', 'Disease', (69, 75))	('NOTCH pathways', 'Pathway', (114, 128))	('EMT', 'biological_process', 'GO:0001837', ('176', '179'))	('CLDN7', 'Gene', (241, 246))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('TGF-beta', 'Gene', (80, 88))	('epithelial-mesenchymal transition', 'CPA', (141, 174))
200473	30428910	Cell pro-apoptotic markers, such as cleaved-PARP1 and cleaved-Caspase3, were upregulated by CLDN7 in Caki-1 and A498 cells, and the anti-apoptotic marker BCL2 was downregulated (Fig.	('A498', 'CellLine', 'CVCL:1056', (112, 116))	('Caspase3', 'Gene', '836', (62, 70))	('BCL2', 'Gene', (154, 158))	('Caspase3', 'Gene', (62, 70))	('CLDN7', 'Var', (92, 97))	('upregulated', 'PosReg', (77, 88))	('BCL2', 'molecular_function', 'GO:0015283', ('154', '158'))	('PARP1', 'Gene', '142', (44, 49))	('BCL2', 'Gene', '596', (154, 158))	('PARP1', 'Gene', (44, 49))
200479	30428910	Bioinformatic Data Mining found that DNA hypermethylation in the promoter of CLDN7, and MSP and BGS results confirmed the CLDN7 promoter hypermethylation in ccRCC tissues.	('BGS', 'Disease', (96, 99))	('hypermethylation', 'Var', (41, 57))	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('BGS', 'Disease', 'MESH:C536788', (96, 99))	('hypermethylation', 'Var', (137, 153))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('37', '57'))	('CLDN7', 'Gene', (77, 82))	('CLDN7', 'Gene', (122, 127))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))
200481	30428910	To explore the molecular mechanism of the tumor suppressive function of CLDN7 in ccRCC, GSEA was performed to evaluate the different gene expression profiles between low- and high-CLDN7 expression groups of ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('tumor', 'Disease', (42, 47))	('high-CLDN7', 'Gene', (175, 185))	('high-CLDN7', 'Var', (175, 185))	('RCC', 'Phenotype', 'HP:0005584', (209, 212))	('GSEA', 'Chemical', '-', (88, 92))	('RCC', 'Disease', 'MESH:C538614', (209, 212))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('RCC', 'Disease', (209, 212))	('patients', 'Species', '9606', (213, 221))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('gene expression', 'biological_process', 'GO:0010467', ('133', '148'))
200482	30428910	We found that cancer pathways and EMT-related pathways both decreased in ccRCC patients with high CLDN7 expression.	('cancer', 'Disease', (14, 20))	('decreased', 'NegReg', (60, 69))	('EMT-related', 'CPA', (34, 45))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('EMT', 'biological_process', 'GO:0001837', ('34', '37'))	('patients', 'Species', '9606', (79, 87))	('CLDN7', 'Gene', (98, 103))	('high', 'Var', (93, 97))
200485	30428910	Previous study has shown that TGFB1 exposure decreased expression of CLDN7 and diminished epithelial barrier function, however, CLDN7 overexpression resulted in protection from TGFB1-mediated barrier dysfunction.	('TGFB1', 'Gene', (177, 182))	('TGFB1', 'Gene', (30, 35))	('CLDN7', 'Gene', (69, 74))	('decreased', 'NegReg', (45, 54))	('epithelial', 'MPA', (90, 100))	('expression', 'MPA', (55, 65))	('CLDN7', 'Gene', (128, 133))	('diminished', 'NegReg', (79, 89))	('TGFB1', 'Gene', '7040', (30, 35))	('TGFB1', 'Gene', '7040', (177, 182))	('overexpression', 'Var', (134, 148))
200494	30428910	And CLDN7 was revealed to increase chemosensitivity through the activation of caspase pathway in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('chemosensitivity', 'MPA', (35, 51))	('CLDN7', 'Var', (4, 9))	('activation', 'PosReg', (64, 74))	('caspase pathway', 'Pathway', (78, 93))	('lung cancer', 'Disease', (97, 108))	('increase', 'PosReg', (26, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))
200509	33673719	A high percentage of sporadic CRC is characterized by deletions, translocations and other chromosomal rearrangements identified as chromosomal instability (CIN).	('translocations', 'Var', (65, 79))	('CIN', 'Disease', 'MESH:D007674', (156, 159))	('CIN', 'Phenotype', 'HP:0040012', (156, 159))	('CRC', 'Disease', (30, 33))	('CRC', 'Phenotype', 'HP:0003003', (30, 33))	('chromosomal instability', 'Phenotype', 'HP:0040012', (131, 154))	('deletions', 'Var', (54, 63))	('CIN', 'Disease', (156, 159))
200510	33673719	Moreover, CpG island methylation phenotype (CIMP), is an epigenetic cause of CRC, as it induces silencing of a range of tumor suppressor genes, including MutL Homolog 1 (MLH1), and one of the MMR genes.	('induces', 'Reg', (88, 95))	('tumor suppressor', 'biological_process', 'GO:0051726', ('120', '136'))	('MutL Homolog 1', 'Gene', (154, 168))	('methylation', 'biological_process', 'GO:0032259', ('21', '32'))	('CRC', 'Disease', (77, 80))	('silencing', 'MPA', (96, 105))	('MutL Homolog 1', 'Gene', '4292', (154, 168))	('methylation', 'Var', (21, 32))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('120', '136'))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('MMR', 'biological_process', 'GO:0006298', ('192', '195'))	('MLH1', 'Gene', '4292', (170, 174))	('CRC', 'Phenotype', 'HP:0003003', (77, 80))	('MLH1', 'Gene', (170, 174))	('tumor', 'Disease', (120, 125))
200514	33673719	This drug inhibits DNA replication, replacing thymidine with fluorinated nucleotides into the DNA, hereby causing cell death.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('inhibits', 'NegReg', (10, 18))	('replacing', 'Var', (36, 45))	('DNA replication', 'MPA', (19, 34))	('DNA replication', 'biological_process', 'GO:0006260', ('19', '34'))	('thymidine', 'MPA', (46, 55))	('thymidine', 'Chemical', 'MESH:D013936', (46, 55))	('fluorinated nucleotides', 'MPA', (61, 84))	('cell death', 'biological_process', 'GO:0008219', ('114', '124'))	('causing', 'Reg', (106, 113))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
200515	33673719	The active metabolite of 5-FU, fluorodeoxyuridine mono-phosphate (FdUMP), inhibits thymidylate synthase (TS), the enzyme essential for the conversion of deoxyuridine mono-phosphate to deoxythymidine monophosphate in the DNA synthesis pathway.	('DNA', 'cellular_component', 'GO:0005574', ('220', '223'))	('TS', 'Gene', '7298', (105, 107))	('deoxythymidine monophosphate', 'Chemical', 'MESH:D013938', (184, 212))	('deoxyuridine mono-phosphate', 'Chemical', '-', (153, 180))	('5-FU', 'Chemical', 'MESH:D005472', (25, 29))	('deoxyuridine mono-phosphate', 'Chemical', '-', (37, 64))	('fluorodeoxyuridine mono-phosphate', 'Chemical', '-', (31, 64))	('thymidylate synthase', 'Gene', (83, 103))	('inhibits', 'NegReg', (74, 82))	('DNA synthesis', 'biological_process', 'GO:0071897', ('220', '233'))	('FdUMP', 'Chemical', '-', (66, 71))	('fluorodeoxyuridine', 'Var', (31, 49))	('thymidylate synthase', 'Gene', '7298', (83, 103))
200522	33673719	Moreover, the literature reports that changes in the status of p53 affects the sensitivity to TS inhibitors, suggesting that analysis of the status of p53 (e.g., wild type or mutant and functionally active or not) could be useful to predict the clinical outcome of the chemotherapy with TS inhibitors.	('TS', 'Gene', '7298', (287, 289))	('p53', 'Gene', (63, 66))	('affects', 'Reg', (67, 74))	('TS', 'Gene', '7298', (94, 96))	('changes', 'Var', (38, 45))	('mutant', 'Var', (175, 181))
200524	33673719	Oxaliplatin causes DNA breaks that are difficult to repair, hereby improving its tumor cell killing potential.	('DNA breaks', 'Disease', (19, 29))	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (0, 11))	('Oxaliplatin', 'Var', (0, 11))	('improving', 'PosReg', (67, 76))	('cell killing', 'biological_process', 'GO:0001906', ('87', '99'))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
200531	33673719	If the Irinotecan resistance is due to the epigenetic changes occurring in CRC, the use of histone deacetylase (HDAC) inhibitors could solve the resistance of the CRC cells to Irinotecan.	('Irinotecan', 'Chemical', 'MESH:D000077146', (7, 17))	('resistance', 'MPA', (145, 155))	('solve', 'Reg', (135, 140))	('epigenetic changes', 'Var', (43, 61))	('Irinotecan', 'Chemical', 'MESH:D000077146', (176, 186))	('due', 'Reg', (32, 35))	('Irinotecan resistance', 'MPA', (7, 28))	('CRC', 'Phenotype', 'HP:0003003', (163, 166))	('CRC', 'Phenotype', 'HP:0003003', (75, 78))
200543	33673719	In this way p53 leads to the inhibition of cancer cell proliferation and the induction of cellular senescence.	('p53', 'Var', (12, 15))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('inhibition', 'NegReg', (29, 39))	('cancer', 'Disease', (43, 49))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cellular senescence', 'CPA', (90, 109))	('cellular senescence', 'biological_process', 'GO:0090398', ('90', '109'))
200550	33673719	The literature reports that both C3HC4-typezinc finger-containing 1 (RBCK1), also known as HOIL-1L (a protein with an N-terminal ubiquitin like (UBL) domain) and the 3-ubiquitin ligase FBXW7 (a protein that influences the epithelial-stromal micro environmental interactions) increase epithelial-mesenchymal transition (EMT) and contribute to chemoresistance and stemness in CRC.	('C3HC4-typezinc', 'Var', (33, 47))	('contribute', 'Reg', (328, 338))	('FBXW7', 'Gene', '55294', (185, 190))	('CRC', 'Phenotype', 'HP:0003003', (374, 377))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('284', '317'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('129', '138'))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('FBXW7', 'Gene', (185, 190))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('EMT', 'biological_process', 'GO:0001837', ('319', '322'))	('chemoresistance', 'CPA', (342, 357))	('stemness', 'CPA', (362, 370))	('ubiquitin', 'molecular_function', 'GO:0031386', ('168', '177'))	('RBCK1', 'Gene', (69, 74))	('CRC', 'Disease', (374, 377))	('increase', 'PosReg', (275, 283))	('RBCK1', 'Gene', '10616', (69, 74))
200557	33673719	Genes encoding for TRIM proteins are present in all metazoans and mutations in these genes are implicated in a variety of human diseases including cancer.	('mutations', 'Var', (66, 75))	('cancer', 'Disease', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('implicated', 'Reg', (95, 105))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('human diseases', 'Disease', (122, 136))	('human diseases', 'Disease', 'MESH:D015658', (122, 136))
200567	33673719	At the basis of the correlation between TRIMs, altered expression and tumor onset, there are, generally, several mechanisms, not fully understood, such as chromosomal translocations (resulting in oncogenic gain-of-function fusion genes), that likely contribute to oncogenesis through the constitutive activation of oncogenic signaling pathways, hyper- or hypo- methylation of CpG islands present in the TRIMs promoter regions.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('hypo- methylation', 'Var', (355, 372))	('signaling', 'biological_process', 'GO:0023052', ('325', '334'))	('tumor', 'Disease', (70, 75))	('activation', 'PosReg', (301, 311))	('oncogenic signaling pathways', 'Pathway', (315, 343))	('hyper-', 'Var', (345, 351))	('methylation', 'biological_process', 'GO:0032259', ('361', '372'))	('gain-of-function', 'PosReg', (206, 222))	('oncogenesis', 'CPA', (264, 275))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('oncogenesis', 'biological_process', 'GO:0007048', ('264', '275'))
200570	33673719	The pivotal role of TRIMs, in the pathological as well as in the physiological cellular life, is now clear if we consider that one or more TRIM members can influence diverse key downstream effector cellular pathways, such as p53 controlled pathways, the Wnt/beta-catenin signaling, Transforming Growth Factor-beta (TGF-beta), Phosphoinositide-3-kinase /Protein Kinase B (PI3K/Akt) pathways and the pro-inflammatory Signal transducer and activator of transcription 3- Nuclear Factor kappa-light-chain-enhancer of activated B cells (STAT3-NF-kappaB) pathways.	('Protein Kinase B', 'Gene', '2185', (353, 369))	('PI3K', 'molecular_function', 'GO:0016303', ('371', '375'))	('Transforming Growth Factor-beta', 'molecular_function', 'GO:0005160', ('282', '313'))	('Transforming Growth Factor-beta', 'Gene', '7124', (282, 313))	('p53', 'Gene', (225, 228))	('TGF-beta', 'Gene', '7039', (315, 323))	('STAT3', 'Gene', (531, 536))	('transcription', 'biological_process', 'GO:0006351', ('450', '463'))	('TGF-beta', 'Gene', (315, 323))	('STAT3', 'Gene', '6774', (531, 536))	('Signal transducer and activator of transcription 3', 'Gene', '6774', (415, 465))	('Protein Kinase B', 'Gene', (353, 369))	('influence', 'Reg', (156, 165))	('NF-kappaB', 'Gene', (537, 546))	('Akt', 'Gene', (376, 379))	('TRIMs', 'Var', (20, 25))	('NF-kappaB', 'Gene', '4790', (537, 546))	('Akt', 'Gene', '207', (376, 379))	('beta-catenin', 'Gene', (258, 270))	('signaling', 'biological_process', 'GO:0023052', ('271', '280'))	('beta-catenin', 'Gene', '1499', (258, 270))	('Transforming Growth Factor-beta', 'Gene', (282, 313))
200572	33673719	A high percentage of tumors show inactivation of p53 function due to gene mutation (with a consequent not-functional p53 protein) or to network inactivation (also in the presence of a wild-type p53 protein).	('p53', 'Gene', (49, 52))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('network', 'MPA', (136, 143))	('protein', 'cellular_component', 'GO:0003675', ('198', '205'))	('inactivation', 'NegReg', (33, 45))	('gene mutation', 'Var', (69, 82))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('function', 'MPA', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
200576	33673719	These TRIMs are downregulated in tumors (e.g., TRIM3, TRIM8, TRIM13, TRIM19 and TRIM67) (Table 1).	('TRIM8', 'Var', (54, 59))	('TRIM19', 'Gene', '5371', (69, 75))	('TRIM3', 'Gene', (47, 52))	('TRIM13', 'Gene', (61, 67))	('TRIM3', 'Gene', '10612', (47, 52))	('TRIM19', 'Gene', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('TRIM67', 'Gene', (80, 86))	('TRIM13', 'Gene', '10206', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('TRIM67', 'Gene', '440730', (80, 86))	('downregulated', 'NegReg', (16, 29))
200597	33673719	In particular, the aberrant STAT3 signaling is mainly due to persisting signaling events caused by the deregulation of specific signaling modules.	('STAT3', 'Gene', (28, 33))	('signaling', 'biological_process', 'GO:0023052', ('128', '137'))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('deregulation', 'Var', (103, 115))	('STAT3', 'Gene', '6774', (28, 33))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))
200598	33673719	The aberrant TRIMs expression seems to be clinically relevant for constitutive STAT signaling in several tumors, particularly those of the gastrointestinal (GI) tract.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('TRIMs', 'Gene', (13, 18))	('aberrant', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('STAT', 'Gene', (79, 83))	('STAT', 'Gene', '6774;20848', (79, 83))
200602	33673719	Moreover, the aberrant NF-kappaB activation is linked with several tumors' onset.	('activation', 'PosReg', (33, 43))	('NF-kappaB', 'Gene', (23, 32))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('aberrant', 'Var', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('23', '43'))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('linked', 'Reg', (47, 53))	('NF-kappaB', 'Gene', '4790', (23, 32))	('tumors', 'Disease', (67, 73))
200607	33673719	Contrary to oncogenic TRIMs, there are also some tumor suppressors, TRIMs protein that are able to antagonize NF-kB activity by promoting inhibitor of nuclear factor kappaB kinase subunit gamma (IKKgamma) neddylation with the consequent stabilization of the IkappaBalpha protein and the impairing of the NF-kappaB activation, even in the presence of NF-kappaB activating cytokines.	('protein', 'cellular_component', 'GO:0003675', ('271', '278'))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('NF-kappaB', 'Gene', (350, 359))	('inhibitor', 'MPA', (138, 147))	('impairing', 'NegReg', (287, 296))	('NF-kappaB', 'Gene', '4790', (350, 359))	('IKKgamma', 'Gene', (195, 203))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('304', '324'))	('activation', 'MPA', (314, 324))	('neddylation', 'Var', (205, 216))	('stabilization', 'MPA', (237, 250))	('IKKgamma', 'Gene', '8517', (195, 203))	('IkappaBalpha', 'Gene', (258, 270))	('tumor', 'Disease', (49, 54))	('antagonize', 'NegReg', (99, 109))	('IkappaBalpha', 'Gene', '4792', (258, 270))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('NF-kappaB', 'Gene', (304, 313))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('promoting', 'PosReg', (128, 137))	('NF-kappaB', 'Gene', '4790', (304, 313))
200609	33673719	Cancer cells, through different mechanisms such as inactivation of the tumor suppressor gene p53, may acquire resistance to chemotherapy.	('tumor suppressor', 'biological_process', 'GO:0051726', ('71', '87'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('71', '87'))	('p53', 'Gene', (93, 96))	('inactivation', 'Var', (51, 63))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('acquire', 'PosReg', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('resistance', 'CPA', (110, 120))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', (71, 76))
200610	33673719	For this reason, the reactivation of wild type p53, through the TRIM proteins, could be a promising strategy to restore sensitivity to the treatment of chemotherapy in all tumors including CRC.	('sensitivity to the treatment of chemotherapy', 'MPA', (120, 164))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('restore', 'PosReg', (112, 119))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('CRC', 'Phenotype', 'HP:0003003', (189, 192))	('reactivation', 'Var', (21, 33))	('CRC', 'Disease', (189, 192))
200618	33673719	Therefore, the reduction of TRIM59 levels reversed the expression of epithelial-mesenchymal transformation-related proteins vimentin, in p53 wild-type and p53 mutated cells, demonstrating that the TRIM59 oncogenic action is p53 independent.	('mutated', 'Var', (159, 166))	('p53', 'Gene', (155, 158))	('TRIM59', 'Gene', (28, 34))	('reduction', 'NegReg', (15, 24))	('vimentin', 'Gene', (124, 132))	('vimentin', 'cellular_component', 'GO:0045099', ('124', '132'))	('TRIM59', 'Gene', '286827', (197, 203))	('expression', 'MPA', (55, 65))	('vimentin', 'cellular_component', 'GO:0045098', ('124', '132'))	('TRIM59', 'Gene', (197, 203))	('p53', 'Gene', (137, 140))	('TRIM59', 'Gene', '286827', (28, 34))	('vimentin', 'Gene', '7431', (124, 132))
200641	33673719	In contrast to the oncogenic action of the TRIMs described so far, TRIM67, TRIM58 and TRIM8 are downregulated in CRC, playing a tumor suppressor role.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('128', '144'))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('TRIM67', 'Gene', '440730', (67, 73))	('CRC', 'Disease', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('TRIM8', 'Var', (86, 91))	('TRIM58', 'Gene', (75, 81))	('downregulated', 'NegReg', (96, 109))	('TRIM58', 'Gene', '25893', (75, 81))	('tumor', 'Disease', (128, 133))	('tumor suppressor', 'biological_process', 'GO:0051726', ('128', '144'))	('CRC', 'Phenotype', 'HP:0003003', (113, 116))	('TRIM67', 'Gene', (67, 73))
200642	33673719	The reduction of TRIM67 levels in CRC is caused by methylation of two loci (cg21178978 and cg27504802).	('cg21178978', 'Chemical', '-', (76, 86))	('cg27504802', 'Var', (91, 101))	('cg21178978', 'Var', (76, 86))	('CRC', 'Phenotype', 'HP:0003003', (34, 37))	('TRIM67', 'Gene', (17, 23))	('methylation', 'biological_process', 'GO:0032259', ('51', '62'))	('TRIM67', 'Gene', '440730', (17, 23))	('methylation', 'Var', (51, 62))	('reduction', 'NegReg', (4, 13))	('cg27504802', 'Chemical', '-', (91, 101))
200644	33673719	TRIM58 plays a critical role of tumor suppressor by limiting Wnt/beta-catenin dependent EMT; indeed, the recovery of TRIM58 reduces tumor invasion.	('TRIM58', 'Gene', (0, 6))	('TRIM58', 'Gene', (117, 123))	('TRIM58', 'Gene', '25893', (0, 6))	('TRIM58', 'Gene', '25893', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor suppressor', 'biological_process', 'GO:0051726', ('32', '48'))	('beta-catenin', 'Gene', '1499', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('reduces', 'NegReg', (124, 131))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('32', '48'))	('recovery', 'Var', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (132, 137))	('EMT', 'biological_process', 'GO:0001837', ('88', '91'))	('tumor', 'Disease', (32, 37))	('beta-catenin', 'Gene', (65, 77))
200650	33673719	The authors showed frequent deletion or loss of heterozygosity in the TRIM8 gene in glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (84, 97))	('glioblastomas', 'Disease', (84, 97))	('glioblastomas', 'Phenotype', 'HP:0012174', (84, 97))	('loss of', 'NegReg', (40, 47))	('deletion', 'Var', (28, 36))	('TRIM8', 'Gene', (70, 75))
200654	33673719	Moreover, knockdown of TRIM8 can significantly enhance breast cancer cell proliferation and migration both in vitro and in vivo.	('enhance', 'PosReg', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('TRIM8', 'Gene', (23, 28))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('migration', 'CPA', (92, 101))	('breast cancer', 'Disease', (55, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('knockdown', 'Var', (10, 19))	('cell proliferation', 'biological_process', 'GO:0008283', ('69', '87'))
200659	33673719	Generally, the most aggressive chemo-resistant tumors have mutations in the p53 gene or inactivation in its pathway through alterations of its regulators.	('aggressive', 'CPA', (20, 30))	('regulators', 'MPA', (143, 153))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('alterations', 'Reg', (124, 135))	('p53', 'Gene', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mutations', 'Var', (59, 68))	('inactivation', 'NegReg', (88, 100))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('pathway', 'Pathway', (108, 115))
200661	33673719	Strikingly, it has been demonstrated that in HCT116 colon, carcinoma and in ccRCC cell lines, TRIM8 silencing induced p53 inactivation and MDM2 stabilization impairing Cisplatin and Nutlin-3 effect.	('MDM2', 'Gene', (139, 143))	('inactivation', 'NegReg', (122, 134))	('silencing', 'Var', (100, 109))	('Cisplatin', 'Chemical', 'MESH:D002945', (168, 177))	('colon, carcinoma', 'Disease', 'MESH:D003110', (52, 68))	('p53', 'Gene', (118, 121))	('stabilization', 'MPA', (144, 157))	('HCT116', 'CellLine', 'CVCL:0291', (45, 51))	('Nutlin-3', 'Chemical', 'MESH:C482205', (182, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('impairing', 'NegReg', (158, 167))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('TRIM8', 'Gene', (94, 99))
200671	33673719	Interestingly, miR-17-5p and miR-106b-5p silencing increases TRIM8 expression levels, which in turn stabilizes and activates p53 towards a cell proliferation arrest program.	('miR-106b', 'Gene', '406900', (29, 37))	('activates', 'PosReg', (115, 124))	('silencing', 'Var', (41, 50))	('stabilizes', 'MPA', (100, 110))	('TRIM8 expression levels', 'MPA', (61, 84))	('p53', 'Gene', (125, 128))	('increases', 'PosReg', (51, 60))	('cell proliferation', 'biological_process', 'GO:0008283', ('139', '157'))	('miR-17-5p', 'Gene', '406952', (15, 24))	('arrest', 'Disease', 'MESH:D006323', (158, 164))	('miR-106b', 'Gene', (29, 37))	('miR-17-5p', 'Gene', (15, 24))	('arrest', 'Disease', (158, 164))
200672	33673719	Moreover, p53 promotes the transcription of miR-34a, which turns off the oncogenic effect of N-MYC, linking p53 to N-MYC.	('N-MYC', 'Gene', '4613', (115, 120))	('miR-34a', 'Gene', '407040', (44, 51))	('transcription', 'biological_process', 'GO:0006351', ('27', '40'))	('transcription', 'MPA', (27, 40))	('promotes', 'PosReg', (14, 22))	('N-MYC', 'Gene', (93, 98))	('miR-34a', 'Gene', (44, 51))	('p53', 'Var', (10, 13))	('N-MYC', 'Gene', (115, 120))	('N-MYC', 'Gene', '4613', (93, 98))
200675	33673719	Indeed, in TRIM8-treated tumors, cell proliferation stops completely compared to tumors treated with a control vector.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('cell proliferation', 'biological_process', 'GO:0008283', ('33', '51'))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('TRIM8-treated', 'Var', (11, 24))	('stops', 'NegReg', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cell proliferation', 'CPA', (33, 51))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
200698	33466827	Various non-metallic (11C, 13N, 15O, 18F, and 124I, etc.)	('d', 'Chemical', 'MESH:D003903', (44, 45))	('11C', 'Var', (22, 25))	('13N', 'Chemical', 'MESH:C000615247', (27, 30))	('124I', 'Chemical', 'MESH:C000614959', (46, 50))	('11C', 'Chemical', 'MESH:C000615233', (22, 25))	('15O', 'Var', (32, 35))	('metal', 'Chemical', 'MESH:D008670', (12, 17))
200717	33466827	Some of the suitable metallic (e.g., 44Sc, 52Mn, 55Co, 64Cu, 66Ga, 86Y, 89Zr, etc.)	('55Co', 'Var', (49, 53))	('52Mn', 'Var', (43, 47))	('89Zr', 'Chemical', 'MESH:C000615502', (72, 76))	('66Ga', 'Var', (61, 65))	('metal', 'Chemical', 'MESH:D008670', (21, 26))	('Cu', 'Chemical', 'MESH:D003300', (57, 59))	('64Cu', 'Var', (55, 59))	('86Y', 'Var', (67, 70))
200719	33466827	Thermodynamically stable and kinetically inert radiolabeled metal (e.g., 64Cu, 89Zr, 66Ga, and 86Y, etc.)	('89Zr', 'Chemical', 'MESH:C000615502', (79, 83))	('66Ga', 'Var', (85, 89))	('Cu', 'Chemical', 'MESH:D003300', (75, 77))	('64Cu', 'Var', (73, 77))	('89Zr', 'Var', (79, 83))	('d', 'Chemical', 'MESH:D003903', (6, 7))	('d', 'Chemical', 'MESH:D003903', (27, 28))	('d', 'Chemical', 'MESH:D003903', (58, 59))	('d', 'Chemical', 'MESH:D003903', (93, 94))	('d', 'Chemical', 'MESH:D003903', (49, 50))	('metal', 'Chemical', 'MESH:D008670', (60, 65))
200755	33466827	However, the most well-known iodine radionuclides are 123I, 124I, 125I, and 131I, which are used in preclinical and clinical environments for medical applications.	('d', 'Chemical', 'MESH:D003903', (74, 75))	('124I', 'Var', (60, 64))	('123I', 'Chemical', 'MESH:C000614958', (54, 58))	('d', 'Chemical', 'MESH:D003903', (46, 47))	('iodine radionuclides', 'Chemical', '-', (29, 49))	('123I', 'Var', (54, 58))	('d', 'Chemical', 'MESH:D003903', (95, 96))	('d', 'Chemical', 'MESH:D003903', (31, 32))	('d', 'Chemical', 'MESH:D003903', (144, 145))	('men', 'Species', '9606', (132, 135))	('d', 'Chemical', 'MESH:D003903', (38, 39))	('124I', 'Chemical', 'MESH:C000614959', (60, 64))	('125I', 'Var', (66, 70))	('131I', 'Var', (76, 80))	('d', 'Chemical', 'MESH:D003903', (114, 115))
200771	33466827	FDA approved 131I-labeled products are, iobenguane 131I, a form of 131I-MIBG, for the treatment of paragangliomas and pheochromocytomas, 131I-labeled HSA for determination of total blood and plasma volumes, cardiac output, cardiac and pulmonary blood volumes and circulation times, protein turnover studies, heart and great vessel delineation, localization of the placenta, and localization of cerebral neoplasms, and [131I]NaI for the diagnostics and the therapeutic applications.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (118, 134))	('NaI', 'Chemical', '-', (424, 427))	('neoplasms', 'Phenotype', 'HP:0002664', (403, 412))	('d', 'Chemical', 'MESH:D003903', (24, 25))	('131I-MIBG', 'Chemical', '-', (67, 76))	('d', 'Chemical', 'MESH:D003903', (302, 303))	('cerebral neoplasms', 'Phenotype', 'HP:0030692', (394, 412))	('localization', 'biological_process', 'GO:0051179', ('378', '390'))	('paragangliomas', 'Disease', (99, 113))	('protein', 'cellular_component', 'GO:0003675', ('282', '289'))	('cerebral neoplasms', 'Disease', (394, 412))	('I-', 'Chemical', 'MESH:D007455', (16, 18))	('d', 'Chemical', 'MESH:D003903', (158, 159))	('d', 'Chemical', 'MESH:D003903', (189, 190))	('d', 'Chemical', 'MESH:D003903', (436, 437))	('d', 'Chemical', 'MESH:D003903', (261, 262))	('pheochromocytomas', 'Disease', (118, 135))	('pheochromocytomas', 'Disease', 'MESH:D010673', (118, 135))	('d', 'Chemical', 'MESH:D003903', (316, 317))	('d', 'Chemical', 'MESH:D003903', (331, 332))	('d', 'Chemical', 'MESH:D003903', (29, 30))	('cerebral neoplasms', 'Disease', 'MESH:D002551', (394, 412))	('I-', 'Chemical', 'MESH:D007455', (70, 72))	('d', 'Chemical', 'MESH:D003903', (116, 117))	('d', 'Chemical', 'MESH:D003903', (226, 227))	('d', 'Chemical', 'MESH:D003903', (450, 451))	('d', 'Chemical', 'MESH:D003903', (376, 377))	('I-', 'Chemical', 'MESH:D007455', (140, 142))	('d', 'Chemical', 'MESH:D003903', (249, 250))	('paragangliomas', 'Disease', 'MESH:D010235', (99, 113))	('paragangliomas', 'Phenotype', 'HP:0002668', (99, 113))	('iobenguane', 'Chemical', 'MESH:D019797', (40, 50))	('d', 'Chemical', 'MESH:D003903', (148, 149))	('localization', 'biological_process', 'GO:0051179', ('344', '356'))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (118, 135))	('d', 'Chemical', 'MESH:D003903', (185, 186))	('d', 'Chemical', 'MESH:D003903', (233, 234))	('men', 'Species', '9606', (91, 94))	('d', 'Chemical', 'MESH:D003903', (416, 417))	('d', 'Chemical', 'MESH:D003903', (11, 12))	('d', 'Chemical', 'MESH:D003903', (210, 211))	('[131I]NaI', 'Var', (418, 427))
200777	33466827	In addition to positron emissions, 124I emits a rather large portion of gamma rays during its decay (Figure 1), with the majority (63%) of which is 603 keV energy (Table 2).	('d', 'Chemical', 'MESH:D003903', (5, 6))	('124I', 'Chemical', 'MESH:C000614959', (35, 39))	('d', 'Chemical', 'MESH:D003903', (4, 5))	('gamma rays', 'MPA', (72, 82))	('d', 'Chemical', 'MESH:D003903', (83, 84))	('603 keV energy', 'Var', (148, 162))	('d', 'Chemical', 'MESH:D003903', (94, 95))	('rat', 'Species', '10116', (48, 51))
200799	33466827	Irradiation of a natTe target with proton beam will, consequently, produce a mixture of various unwanted iodine isotopes with long half-lives, making the production and purification process inefficient and challenging and the 124I produced being unusable.	('d', 'Chemical', 'MESH:D003903', (107, 108))	('mixture of', 'MPA', (77, 87))	('d', 'Chemical', 'MESH:D003903', (70, 71))	('d', 'Chemical', 'MESH:D003903', (167, 168))	('produce', 'Reg', (67, 74))	('natTe', 'Chemical', '-', (17, 22))	('d', 'Chemical', 'MESH:D003903', (157, 158))	('d', 'Chemical', 'MESH:D003903', (4, 5))	('Irradiation', 'Var', (0, 11))	('d', 'Chemical', 'MESH:D003903', (234, 235))	('d', 'Chemical', 'MESH:D003903', (220, 221))	('d', 'Chemical', 'MESH:D003903', (103, 104))	('124I', 'Chemical', 'MESH:C000614959', (226, 230))	('iodine', 'Chemical', 'MESH:D007455', (105, 111))	('d', 'Chemical', 'MESH:D003903', (204, 205))	('d', 'Chemical', 'MESH:D003903', (238, 239))
200803	33466827	In our laboratories, we have used the enriched target material with the following specifications: 124Te (99.3%), 120Te, 122Te, 126Te (<0.01%), 123Te (<0.05), 128Te (0.03%), 130Te (0.02), and 125Te (0.6%).	('Te', 'Chemical', 'MESH:D013691', (146, 148))	('120Te', 'Var', (113, 118))	('d', 'Chemical', 'MESH:D003903', (32, 33))	('122Te', 'Var', (120, 125))	('Te', 'Chemical', 'MESH:D013691', (101, 103))	('Te', 'Chemical', 'MESH:D013691', (116, 118))	('Te', 'Chemical', 'MESH:D013691', (194, 196))	('Te', 'Chemical', 'MESH:D013691', (130, 132))	('d', 'Chemical', 'MESH:D003903', (189, 190))	('Te', 'Chemical', 'MESH:D013691', (123, 125))	('d', 'Chemical', 'MESH:D003903', (45, 46))	('126Te', 'Var', (127, 132))	('rat', 'Species', '10116', (11, 14))	('Te', 'Chemical', 'MESH:D013691', (161, 163))	('Te', 'Chemical', 'MESH:D013691', (176, 178))	('125Te', 'Chemical', '-', (191, 196))	('124Te', 'Chemical', '-', (98, 103))	('123Te', 'Var', (143, 148))
200846	33466827	Since the decay of 123I is 7.6 times faster than 124I, overnight storage of the mixture is required in the production process for removal of 123I improving the purity of 124I; although it decreases the overall yield of 124I production.	('124I', 'Chemical', 'MESH:C000614959', (49, 53))	('124I production', 'MPA', (219, 234))	('removal', 'Var', (130, 137))	('improving', 'PosReg', (146, 155))	('decreases', 'NegReg', (188, 197))	('123I', 'Chemical', 'MESH:C000614958', (19, 23))	('d', 'Chemical', 'MESH:D003903', (214, 215))	('yield', 'MPA', (210, 215))	('d', 'Chemical', 'MESH:D003903', (110, 111))	('123I', 'Var', (141, 145))	('purity', 'MPA', (160, 166))	('storage', 'biological_process', 'GO:0051235', ('65', '72'))	('d', 'Chemical', 'MESH:D003903', (188, 189))	('d', 'Chemical', 'MESH:D003903', (227, 228))	('124I', 'Chemical', 'MESH:C000614959', (219, 223))	('d', 'Chemical', 'MESH:D003903', (98, 99))	('124I', 'Chemical', 'MESH:C000614959', (170, 174))	('d', 'Chemical', 'MESH:D003903', (10, 11))	('123I', 'Chemical', 'MESH:C000614958', (141, 145))
200859	33466827	For the energy range window employed for proton irradiation of 124Te enriched target using low energy cyclotrons, the primary reactions to consider are: 124Te(p,n)124I, 124Te(p,2n)123I, 125Te(p,n)125I, and 125Te(p,2n)124I.	('125Te', 'Var', (206, 211))	('p,n)124I', 'Var', (159, 167))	('124I', 'Chemical', 'MESH:C000614959', (217, 221))	('124Te', 'Chemical', '-', (63, 68))	('d', 'Chemical', 'MESH:D003903', (24, 25))	('d', 'Chemical', 'MESH:D003903', (144, 145))	('124I', 'Chemical', 'MESH:C000614959', (163, 167))	('125Te', 'Chemical', '-', (206, 211))	('124Te', 'Chemical', '-', (169, 174))	('d', 'Chemical', 'MESH:D003903', (52, 53))	('124Te', 'Chemical', '-', (153, 158))	('125Te', 'Chemical', '-', (186, 191))	('d', 'Chemical', 'MESH:D003903', (76, 77))	('d', 'Chemical', 'MESH:D003903', (35, 36))	('d', 'Chemical', 'MESH:D003903', (204, 205))	('123I', 'Chemical', 'MESH:C000614958', (180, 184))
200861	33466827	On the other hand, a mixture of 124I and 125I will give 124I with lower purity with time, as the half-life 124I decay is 15 times faster than 125I decay.	('d', 'Chemical', 'MESH:D003903', (16, 17))	('d', 'Chemical', 'MESH:D003903', (39, 40))	('d', 'Chemical', 'MESH:D003903', (112, 113))	('124I', 'Chemical', 'MESH:C000614959', (107, 111))	('124I', 'Chemical', 'MESH:C000614959', (56, 60))	('124I', 'Chemical', 'MESH:C000614959', (32, 36))	('purity', 'MPA', (72, 78))	('d', 'Chemical', 'MESH:D003903', (147, 148))	('124I', 'Var', (107, 111))
200927	33466827	With histidine, substitution occurs at the 2-position of the five-member imidazole ring.	('substitution', 'Var', (16, 28))	('imidazole', 'Chemical', 'MESH:C029899', (73, 82))	('occurs', 'Reg', (29, 35))	('histidine', 'Chemical', 'MESH:D006639', (5, 14))
200954	33466827	It is important to note that the reducing agent, Na2S2O5, used for reaction quenching can also cause cleavage of the disulfide bridges within the protein molecules and alter the tertiary structure of the protein.	('Na2S2O5', 'Chemical', 'MESH:C005200', (49, 56))	('disulfide', 'Chemical', 'MESH:D004220', (117, 126))	('d', 'Chemical', 'MESH:D003903', (130, 131))	('Na2S2O5', 'Var', (49, 56))	('d', 'Chemical', 'MESH:D003903', (61, 62))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('d', 'Chemical', 'MESH:D003903', (35, 36))	('protein', 'cellular_component', 'GO:0003675', ('204', '211'))	('alter', 'Reg', (168, 173))	('tertiary structure of the', 'MPA', (178, 203))	('d', 'Chemical', 'MESH:D003903', (117, 118))	('d', 'Chemical', 'MESH:D003903', (124, 125))	('d', 'Chemical', 'MESH:D003903', (166, 167))	('cleavage', 'MPA', (101, 109))
201018	33466827	Some of the 124I-labeled PET imaging pharmaceuticals based on the small molecule (with the target given in the parenthesis) are 124I-MIBG (adrenergic activity), 124I-IAZA and 124I-IAZG (hypoxia agent), 124I-dRFIB, 124I-IUdR and 124I-CDK4/6 inhibitors (cell proliferation), 124I-hypericin (protein-kinase C), 124I-FIAU (herpes virus thymidine kinase), m-124I-IPPM (opioid receptors), 124I-IPQA ((EGFR kinase activity), 124I-labeled-6-anilino-quinazoline (EGFR inhibitors), 124I-purpurinimide (tumor imaging).	('tumor', 'Phenotype', 'HP:0002664', (492, 497))	('CDK4/6', 'Gene', '1019;1021', (233, 239))	('d', 'Chemical', 'MESH:D003903', (57, 58))	('124I', 'Chemical', 'MESH:C000614959', (128, 132))	('124I', 'Chemical', 'MESH:C000614959', (383, 387))	('d', 'Chemical', 'MESH:D003903', (429, 430))	('I-', 'Chemical', 'MESH:D007455', (311, 313))	('124I', 'Chemical', 'MESH:C000614959', (175, 179))	('hypoxia', 'Disease', 'MESH:D000860', (186, 193))	('d', 'Chemical', 'MESH:D003903', (221, 222))	('d', 'Chemical', 'MESH:D003903', (207, 208))	('d', 'Chemical', 'MESH:D003903', (23, 24))	('I-', 'Chemical', 'MESH:D007455', (421, 423))	('m-124I-IPPM', 'Var', (351, 362))	('I-', 'Chemical', 'MESH:D007455', (231, 233))	('124I', 'Chemical', 'MESH:C000614959', (214, 218))	('I-', 'Chemical', 'MESH:D007455', (356, 358))	('124I', 'Chemical', 'MESH:C000614959', (308, 312))	('124I', 'Chemical', 'MESH:C000614959', (418, 422))	('d', 'Chemical', 'MESH:D003903', (173, 174))	('I-', 'Chemical', 'MESH:D007455', (475, 477))	('I-', 'Chemical', 'MESH:D007455', (217, 219))	('protein', 'cellular_component', 'GO:0003675', ('289', '296'))	('CDK', 'molecular_function', 'GO:0004693', ('233', '236'))	('I-', 'Chemical', 'MESH:D007455', (178, 180))	('tumor', 'Disease', (492, 497))	('EGFR', 'molecular_function', 'GO:0005006', ('395', '399'))	('d', 'Chemical', 'MESH:D003903', (226, 227))	('d', 'Chemical', 'MESH:D003903', (140, 141))	('I-', 'Chemical', 'MESH:D007455', (205, 207))	('I-', 'Chemical', 'MESH:D007455', (276, 278))	('CDK4/6', 'Gene', (233, 239))	('124I', 'Chemical', 'MESH:C000614959', (228, 232))	('d', 'Chemical', 'MESH:D003903', (488, 489))	('I-', 'Chemical', 'MESH:D007455', (15, 17))	('EGFR', 'molecular_function', 'GO:0005006', ('454', '458'))	('d', 'Chemical', 'MESH:D003903', (337, 338))	('124I', 'Chemical', 'MESH:C000614959', (353, 357))	('tumor', 'Disease', 'MESH:D009369', (492, 497))	('I-', 'Chemical', 'MESH:D007455', (164, 166))	('124I', 'Chemical', 'MESH:C000614959', (202, 206))	('d', 'Chemical', 'MESH:D003903', (369, 370))	('I-', 'Chemical', 'MESH:D007455', (131, 133))	('cell proliferation', 'biological_process', 'GO:0008283', ('252', '270'))	('I-', 'Chemical', 'MESH:D007455', (386, 388))	('kinase activity', 'molecular_function', 'GO:0016301', ('400', '415'))	('124I', 'Chemical', 'MESH:C000614959', (12, 16))	('124I', 'Chemical', 'MESH:C000614959', (472, 476))	('124I', 'Chemical', 'MESH:C000614959', (273, 277))	('rat', 'Species', '10116', (264, 267))	('124I', 'Chemical', 'MESH:C000614959', (161, 165))	('hypoxia', 'Disease', (186, 193))
201047	33466827	However, tumor-to-organ ratios were appreciably higher for 124I-labeled affibody due to its more rapid clearance from blood and normal organs.	('124I', 'Chemical', 'MESH:C000614959', (59, 63))	('d', 'Chemical', 'MESH:D003903', (78, 79))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('d', 'Chemical', 'MESH:D003903', (122, 123))	('d', 'Chemical', 'MESH:D003903', (81, 82))	('d', 'Chemical', 'MESH:D003903', (126, 127))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('affibody', 'Gene', (72, 80))	('clearance', 'MPA', (103, 112))	('tumor', 'Disease', (9, 14))	('higher', 'PosReg', (48, 54))	('d', 'Chemical', 'MESH:D003903', (70, 71))	('d', 'Chemical', 'MESH:D003903', (101, 102))	('rat', 'Species', '10116', (24, 27))	('124I-labeled', 'Var', (59, 71))	('I-', 'Chemical', 'MESH:D007455', (62, 64))
201053	33466827	ch806, a chimeric form of mAb 806 which has been validated as an effective therapeutic antibody, showed specific accumulation of the antibody at multiple tumor sites and potential for molecular imaging.	('d', 'Chemical', 'MESH:D003903', (57, 58))	('antibody', 'cellular_component', 'GO:0019815', ('87', '95'))	('d', 'Chemical', 'MESH:D003903', (168, 169))	('accumulation', 'PosReg', (113, 125))	('tumor', 'Disease', (154, 159))	('antibody', 'cellular_component', 'GO:0019815', ('133', '141'))	('antibody', 'cellular_component', 'GO:0019814', ('87', '95'))	('d', 'Chemical', 'MESH:D003903', (102, 103))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('d', 'Chemical', 'MESH:D003903', (93, 94))	('d', 'Chemical', 'MESH:D003903', (53, 54))	('antibody', 'cellular_component', 'GO:0019814', ('133', '141'))	('antibody', 'molecular_function', 'GO:0003823', ('87', '95'))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('antibody', 'cellular_component', 'GO:0042571', ('87', '95'))	('d', 'Chemical', 'MESH:D003903', (139, 140))	('ch806', 'Var', (0, 5))	('antibody', 'molecular_function', 'GO:0003823', ('133', '141'))	('antibody', 'cellular_component', 'GO:0042571', ('133', '141'))	('ch806', 'Chemical', '-', (0, 5))
201054	33466827	Biodistribution studies, in BALB/c nude mice bearing de2-7 EGFR-expressing xenografts, revealed that 125I-labeled ch806 did not show significant tumor retention.	('nude mice', 'Species', '10090', (35, 44))	('retention', 'biological_process', 'GO:0051235', ('151', '160'))	('d', 'Chemical', 'MESH:D003903', (19, 20))	('d', 'Chemical', 'MESH:D003903', (53, 54))	('d', 'Chemical', 'MESH:D003903', (112, 113))	('d', 'Chemical', 'MESH:D003903', (37, 38))	('I-', 'Chemical', 'MESH:D007455', (104, 106))	('tumor retention', 'Disease', 'MESH:D016055', (145, 160))	('d', 'Chemical', 'MESH:D003903', (122, 123))	('ch806', 'Chemical', '-', (114, 119))	('d', 'Chemical', 'MESH:D003903', (120, 121))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('ch806', 'Var', (114, 119))	('d', 'Chemical', 'MESH:D003903', (3, 4))	('EGFR', 'molecular_function', 'GO:0005006', ('59', '63'))	('d', 'Chemical', 'MESH:D003903', (94, 95))	('tumor retention', 'Disease', (145, 160))
201055	33466827	However, specific and prolonged tumor localization of 111In-labeled ch806 was demonstrated with the uptake of 31% ID/g and a tumor to blood ratio of 5:1 observed at 7 days post- injection.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('d', 'Chemical', 'MESH:D003903', (167, 168))	('uptake', 'biological_process', 'GO:0098657', ('100', '106'))	('d', 'Chemical', 'MESH:D003903', (89, 90))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('d', 'Chemical', 'MESH:D003903', (78, 79))	('d', 'Chemical', 'MESH:D003903', (160, 161))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('rat', 'Species', '10116', (85, 88))	('uptake', 'biological_process', 'GO:0098739', ('100', '106'))	('ch806', 'Var', (68, 73))	('d', 'Chemical', 'MESH:D003903', (30, 31))	('d', 'Chemical', 'MESH:D003903', (20, 21))	('d', 'Chemical', 'MESH:D003903', (138, 139))	('rat', 'Species', '10116', (140, 143))	('tumor', 'Disease', (32, 37))	('ch806', 'Chemical', '-', (68, 73))	('localization', 'biological_process', 'GO:0051179', ('38', '50'))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (125, 130))	('d', 'Chemical', 'MESH:D003903', (66, 67))	('d', 'Chemical', 'MESH:D003903', (121, 122))	('uptake', 'MPA', (100, 106))
201057	33466827	The biodistribution data analysis showed 30.95 +- 6.01% (% ID/g) tumor uptake of 124I-IMP-R4-ch806 injected dose at 48 h post-injection, with prolonged tumor retention (6.07 +- 0.80%I D/g at 216 h post-injection).	('124I-IMP-R4-ch806', 'Chemical', '-', (81, 98))	('prolonged tumor retention', 'Disease', 'MESH:D016055', (142, 167))	('d', 'Chemical', 'MESH:D003903', (39, 40))	('tumor', 'Disease', (65, 70))	('d', 'Chemical', 'MESH:D003903', (150, 151))	('uptake', 'biological_process', 'GO:0098657', ('71', '77'))	('tumor', 'Disease', (152, 157))	('d', 'Chemical', 'MESH:D003903', (7, 8))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('d', 'Chemical', 'MESH:D003903', (20, 21))	('retention', 'biological_process', 'GO:0051235', ('158', '167'))	('uptake', 'biological_process', 'GO:0098739', ('71', '77'))	('IMP', 'cellular_component', 'GO:0042720', ('86', '89'))	('d', 'Chemical', 'MESH:D003903', (108, 109))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('IMP', 'molecular_function', 'GO:0004244', ('86', '89'))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('d', 'Chemical', 'MESH:D003903', (106, 107))	('prolonged tumor retention', 'Disease', (142, 167))	('124I-IMP-R4-ch806', 'Var', (81, 98))
201059	33466827	PET images of 124I-IMP-R4-ch806 were able to detect the U87MG.de2-7 tumors at 24 h post- injection and for at least 168 h post-injection.	('IMP', 'cellular_component', 'GO:0042720', ('19', '22'))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('IMP', 'molecular_function', 'GO:0004244', ('19', '22'))	('U87MG.de2-7', 'Var', (56, 67))	('124I-IMP-R4-ch806', 'Chemical', '-', (14, 31))	('d', 'Chemical', 'MESH:D003903', (62, 63))	('d', 'Chemical', 'MESH:D003903', (45, 46))	('d', 'Chemical', 'MESH:D003903', (101, 102))	('124I-IMP-R4-ch806', 'Var', (14, 31))
201060	33466827	Similarly, the mean uptake of 124I-PEG4-tptddYddtpt-ch806 by U87MG.de2-7 glioma xenografts reached a maximum of 36.03% +-5.08% ID/g at 72 h post injection.	('124I-PEG4-tptddYddtpt-ch806', 'Var', (30, 57))	('glioma', 'Disease', (73, 79))	('d', 'Chemical', 'MESH:D003903', (67, 68))	('ch806', 'Chemical', '-', (52, 57))	('d', 'Chemical', 'MESH:D003903', (46, 47))	('d', 'Chemical', 'MESH:D003903', (43, 44))	('d', 'Chemical', 'MESH:D003903', (44, 45))	('d', 'Chemical', 'MESH:D003903', (47, 48))	('I-', 'Chemical', 'MESH:D007455', (33, 35))	('uptake', 'MPA', (20, 26))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('d', 'Chemical', 'MESH:D003903', (97, 98))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('uptake', 'biological_process', 'GO:0098739', ('20', '26'))	('124I', 'Chemical', 'MESH:C000614959', (30, 34))	('uptake', 'biological_process', 'GO:0098657', ('20', '26'))
201068	33466827	A single intravenous injection of [124I]-SHPPVG76e into tumor-bearing mice showed a time-dependent and specific localization of the tracer to the tumor tissue.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (146, 151))	('d', 'Chemical', 'MESH:D003903', (89, 90))	('mice', 'Species', '10090', (70, 74))	('localization', 'biological_process', 'GO:0051179', ('112', '124'))	('[124I]-SHPPVG76e', 'Var', (34, 50))	('d', 'Chemical', 'MESH:D003903', (94, 95))	('d', 'Chemical', 'MESH:D003903', (101, 102))	('d', 'Chemical', 'MESH:D003903', (80, 81))	('localization', 'MPA', (112, 124))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
201069	33466827	High tumor-to-background contrast and distribution of [124I]-SHPPVG76e in the major organs were seen in the whole-body animal PET imaging studies.	('d', 'Chemical', 'MESH:D003903', (36, 37))	('[124I]-SHPPVG76e', 'Var', (54, 70))	('d', 'Chemical', 'MESH:D003903', (23, 24))	('d', 'Chemical', 'MESH:D003903', (116, 117))	('d', 'Chemical', 'MESH:D003903', (141, 142))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('d', 'Chemical', 'MESH:D003903', (38, 39))	('High tumor', 'Disease', (0, 10))	('High tumor', 'Disease', 'MESH:D009369', (0, 10))
201070	33466827	These studies support further development of [124I]-SHPP-VG76e as an immunoPET imaging pharmaceutical for measuring tumor levels of VEGF in humans.	('d', 'Chemical', 'MESH:D003903', (30, 31))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('humans', 'Species', '9606', (140, 146))	('[124I]-SHPP-VG76e', 'Var', (45, 62))	('men', 'Species', '9606', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('d', 'Chemical', 'MESH:D003903', (9, 10))
201080	33466827	The scFv-8 and Cys-Db were labeled with 124I and 131I for PET imaging and biodistribution, respectively, at 2, 4, 10, and 20 h. Mice bearing 38C13-huCD20 (positive) and wild-type 38C13 (negative) tumors were used.	('d', 'Chemical', 'MESH:D003903', (33, 34))	('Mice', 'Species', '10090', (128, 132))	('d', 'Chemical', 'MESH:D003903', (167, 168))	('d', 'Chemical', 'MESH:D003903', (120, 121))	('CD', 'Chemical', '-', (149, 151))	('124I', 'Chemical', 'MESH:C000614959', (40, 44))	('d', 'Chemical', 'MESH:D003903', (72, 73))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('d', 'Chemical', 'MESH:D003903', (47, 48))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('d', 'Chemical', 'MESH:D003903', (77, 78))	('tumors', 'Disease', (196, 202))	('Cys-Db', 'Chemical', '-', (15, 21))	('d', 'Chemical', 'MESH:D003903', (13, 14))	('d', 'Chemical', 'MESH:D003903', (172, 173))	('scFv-8', 'Chemical', '-', (4, 10))	('38C13-huCD20', 'Var', (141, 153))	('d', 'Chemical', 'MESH:D003903', (211, 212))	('tumors', 'Disease', 'MESH:D009369', (196, 202))
201091	33466827	Many PD-L1 inhibitors, durvalumab, pembrolizumab, atezolizumab, and avelumab, are in development as immuno-oncology therapies and are showing good results in clinical trials.	('pembrolizumab', 'Chemical', 'MESH:C582435', (35, 48))	('d', 'Chemical', 'MESH:D003903', (23, 24))	('d', 'Chemical', 'MESH:D003903', (85, 86))	('PD-L1', 'Gene', (5, 10))	('PD-L1', 'Gene', '29126', (5, 10))	('durvalumab', 'Chemical', 'MESH:C000613593', (23, 33))	('inhibitors', 'Var', (11, 21))	('d', 'Chemical', 'MESH:D003903', (66, 67))	('oncology', 'Phenotype', 'HP:0002664', (107, 115))	('men', 'Species', '9606', (92, 95))	('atezolizumab', 'Chemical', 'MESH:C000594389', (50, 62))	('d', 'Chemical', 'MESH:D003903', (128, 129))	('d', 'Chemical', 'MESH:D003903', (145, 146))	('avelumab', 'Chemical', 'MESH:C000609138', (68, 76))
201097	33466827	CA19-9 is the most highly expressed tumor antigen, present on cellular membrane proteins in more than 90% of pancreas cancer patients.	('pancreas cancer', 'Disease', (109, 124))	('d', 'Chemical', 'MESH:D003903', (34, 35))	('pancreas cancer', 'Disease', 'MESH:D010190', (109, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor antigen', 'molecular_function', 'GO:0008222', ('36', '49'))	('cellular membrane', 'cellular_component', 'GO:0005886', ('62', '79'))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('CA19-9', 'Var', (0, 6))	('pancreas cancer', 'Phenotype', 'HP:0002894', (109, 124))	('tumor', 'Disease', (36, 41))	('patients', 'Species', '9606', (125, 133))
201105	33466827	Pancreas xenograft imaging of BxPC3/MiaPaca-2 and Capan-2/MiaPaca-2 models with the anti-CA19-9 diabody demonstrated an average tumor: blood ratio of 5.0 and 2.0, respectively, and an average positive: negative tumor ratio of 11 and 6, respectively.	('anti-CA19-9', 'Var', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('d', 'Chemical', 'MESH:D003903', (48, 49))	('tumor', 'Disease', (211, 216))	('d', 'Chemical', 'MESH:D003903', (104, 105))	('d', 'Chemical', 'MESH:D003903', (96, 97))	('rat', 'Species', '10116', (141, 144))	('rat', 'Species', '10116', (111, 114))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('d', 'Chemical', 'MESH:D003903', (70, 71))	('d', 'Chemical', 'MESH:D003903', (101, 102))	('d', 'Chemical', 'MESH:D003903', (179, 180))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (128, 133))	('d', 'Chemical', 'MESH:D003903', (115, 116))	('d', 'Chemical', 'MESH:D003903', (231, 232))	('d', 'Chemical', 'MESH:D003903', (139, 140))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('d', 'Chemical', 'MESH:D003903', (156, 157))	('Capan-2/MiaPaca', 'CellLine', 'CVCL:0428', (50, 65))	('BxPC3/MiaPaca-2', 'CellLine', 'CVCL:4011', (30, 45))	('rat', 'Species', '10116', (217, 220))
201106	33466827	An Fc-mutated, anti-CA19-9 antibody fragment, scFv-Fc H310A, 105 kD dimer, was created for microPET imaging of pancreatic cancer xenografts.	('d', 'Chemical', 'MESH:D003903', (33, 34))	('antibody', 'cellular_component', 'GO:0042571', ('27', '35'))	('H310A', 'SUBSTITUTION', 'None', (54, 59))	('d', 'Chemical', 'MESH:D003903', (12, 13))	('d', 'Chemical', 'MESH:D003903', (85, 86))	('d', 'Chemical', 'MESH:D003903', (68, 69))	('pancreatic cancer', 'Disease', 'MESH:D010190', (111, 128))	('antibody', 'cellular_component', 'GO:0019815', ('27', '35'))	('pancreatic cancer', 'Disease', (111, 128))	('H310A', 'Var', (54, 59))	('scFv', 'Gene', '652070', (46, 50))	('men', 'Species', '9606', (40, 43))	('antibody', 'cellular_component', 'GO:0019814', ('27', '35'))	('scFv', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('antibody', 'molecular_function', 'GO:0003823', ('27', '35'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (111, 128))
201107	33466827	The 124I-scFv-Fc H310A localized to the antigen-positive tumor xenografts and confirmed by microPET imaging.	('124I', 'Chemical', 'MESH:C000614959', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('H310A', 'SUBSTITUTION', 'None', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('d', 'Chemical', 'MESH:D003903', (86, 87))	('d', 'Chemical', 'MESH:D003903', (31, 32))	('d', 'Chemical', 'MESH:D003903', (76, 77))	('tumor', 'Disease', (57, 62))	('H310A', 'Var', (17, 22))
201118	33466827	To improve the T/B ratio of the engineered antibody fragments, mutation of the residues in the Fc fragment was performed.	('antibody', 'cellular_component', 'GO:0019815', ('43', '51'))	('antibody', 'cellular_component', 'GO:0019814', ('43', '51'))	('improve', 'PosReg', (3, 10))	('men', 'Species', '9606', (56, 59))	('d', 'Chemical', 'MESH:D003903', (119, 120))	('mutation', 'Var', (63, 71))	('rat', 'Species', '10116', (19, 22))	('d', 'Chemical', 'MESH:D003903', (83, 84))	('antibody', 'molecular_function', 'GO:0003823', ('43', '51'))	('d', 'Chemical', 'MESH:D003903', (41, 42))	('d', 'Chemical', 'MESH:D003903', (49, 50))	('antibody', 'cellular_component', 'GO:0042571', ('43', '51'))	('men', 'Species', '9606', (102, 105))	('T/B ratio', 'MPA', (15, 24))
201120	33466827	The PET imaging with a 124I-labeled scFv-Fc with double mutation (H310A/H435Q) quickly localized to the tumor site, rapidly cleared from animal circulation, and produced clear images.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('d', 'Chemical', 'MESH:D003903', (120, 121))	('I-', 'Chemical', 'MESH:D007455', (26, 28))	('d', 'Chemical', 'MESH:D003903', (168, 169))	('H435Q', 'SUBSTITUTION', 'None', (72, 77))	('d', 'Chemical', 'MESH:D003903', (49, 50))	('d', 'Chemical', 'MESH:D003903', (159, 160))	('H435Q', 'Var', (72, 77))	('d', 'Chemical', 'MESH:D003903', (95, 96))	('124I', 'Chemical', 'MESH:C000614959', (23, 27))	('scFv', 'Gene', '652070', (36, 40))	('scFv', 'Gene', (36, 40))	('tumor', 'Disease', (104, 109))	('d', 'Chemical', 'MESH:D003903', (164, 165))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('H310A', 'Var', (66, 71))	('d', 'Chemical', 'MESH:D003903', (130, 131))	('d', 'Chemical', 'MESH:D003903', (34, 35))	('H310A', 'SUBSTITUTION', 'None', (66, 71))
201123	33466827	Typically, mice are implanted with CEA-expressing LS174T human colonic tumors, a bispecific monoclonal anti-CEA/anti-HSG/anti-hapten antibody is given to the mice, followed by an administration of a radiolabeled hapten peptide.	('colonic tumors', 'Disease', (63, 77))	('mice', 'Species', '10090', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('d', 'Chemical', 'MESH:D003903', (224, 225))	('human', 'Species', '9606', (57, 62))	('antibody', 'cellular_component', 'GO:0019815', ('133', '141'))	('d', 'Chemical', 'MESH:D003903', (180, 181))	('LS174T', 'Var', (50, 56))	('rat', 'Species', '10116', (187, 190))	('antibody', 'cellular_component', 'GO:0019814', ('133', '141'))	('d', 'Chemical', 'MESH:D003903', (171, 172))	('mice', 'Species', '10090', (11, 15))	('d', 'Chemical', 'MESH:D003903', (28, 29))	('d', 'Chemical', 'MESH:D003903', (139, 140))	('antibody', 'molecular_function', 'GO:0003823', ('133', '141'))	('antibody', 'cellular_component', 'GO:0042571', ('133', '141'))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('d', 'Chemical', 'MESH:D003903', (210, 211))	('d', 'Chemical', 'MESH:D003903', (201, 202))	('colonic tumors', 'Disease', 'MESH:D003110', (63, 77))
201134	33466827	Greater uptake, retention, and superior PET images for 89Zr-labeled cG250, due to trapping inside the tumor cell, compared to 124I-labeled cG250, due to internalization and release of 124I, were observed.	('89Zr', 'Chemical', 'MESH:C000615502', (55, 59))	('PET images', 'MPA', (40, 50))	('d', 'Chemical', 'MESH:D003903', (137, 138))	('124I', 'Chemical', 'MESH:C000614959', (184, 188))	('uptake', 'biological_process', 'GO:0098739', ('8', '14'))	('retention', 'MPA', (16, 25))	('I-', 'Chemical', 'MESH:D007455', (129, 131))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('89Zr-labeled', 'Var', (55, 67))	('Greater', 'PosReg', (0, 7))	('d', 'Chemical', 'MESH:D003903', (95, 96))	('d', 'Chemical', 'MESH:D003903', (29, 30))	('124I', 'Chemical', 'MESH:C000614959', (126, 130))	('uptake', 'MPA', (8, 14))	('retention', 'biological_process', 'GO:0051235', ('16', '25'))	('d', 'Chemical', 'MESH:D003903', (171, 172))	('d', 'Chemical', 'MESH:D003903', (146, 147))	('tumor', 'Disease', (102, 107))	('cG250', 'Chemical', 'MESH:C106533', (139, 144))	('d', 'Chemical', 'MESH:D003903', (75, 76))	('cG250', 'Chemical', 'MESH:C106533', (68, 73))	('uptake', 'biological_process', 'GO:0098657', ('8', '14'))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('d', 'Chemical', 'MESH:D003903', (202, 203))	('cG250', 'Gene', (68, 73))	('d', 'Chemical', 'MESH:D003903', (66, 67))	('d', 'Chemical', 'MESH:D003903', (121, 122))
201145	33466827	U36, an anti-CD44v6 chimeric (mouse/human) monoclonal antibody (cmAb), was found to target CD44v6 antigen.	('d', 'Chemical', 'MESH:D003903', (60, 61))	('antibody', 'cellular_component', 'GO:0019815', ('54', '62'))	('U36', 'Gene', (0, 3))	('CD44v6', 'Var', (91, 97))	('U36', 'Gene', '26842', (0, 3))	('antibody', 'cellular_component', 'GO:0019814', ('54', '62'))	('antibody', 'molecular_function', 'GO:0003823', ('54', '62'))	('CD', 'Chemical', '-', (91, 93))	('d', 'Chemical', 'MESH:D003903', (79, 80))	('human', 'Species', '9606', (36, 41))	('antibody', 'cellular_component', 'GO:0042571', ('54', '62'))	('mouse', 'Species', '10090', (30, 35))	('CD', 'Chemical', '-', (13, 15))
201150	33466827	Tumor uptake was higher for the 89Zr- and 88Y-labeled cMAb U36 than the 124I-, 131I-, and 186Re-labeled cMAb U36.	('U36', 'Gene', (109, 112))	('d', 'Chemical', 'MESH:D003903', (88, 89))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cMAb', 'Chemical', '-', (54, 58))	('I-', 'Chemical', 'MESH:D007455', (82, 84))	('d', 'Chemical', 'MESH:D003903', (40, 41))	('d', 'Chemical', 'MESH:D003903', (102, 103))	('124I', 'Chemical', 'MESH:C000614959', (72, 76))	('U36', 'Gene', (59, 62))	('88Y-labeled', 'Var', (42, 53))	('uptake', 'biological_process', 'GO:0098657', ('6', '12'))	('U36', 'Gene', '26842', (109, 112))	('uptake', 'biological_process', 'GO:0098739', ('6', '12'))	('d', 'Chemical', 'MESH:D003903', (52, 53))	('cMAb', 'Chemical', '-', (104, 108))	('89Zr-', 'Var', (32, 37))	('89Zr', 'Chemical', 'MESH:C000615502', (32, 36))	('U36', 'Gene', '26842', (59, 62))	('I-', 'Chemical', 'MESH:D007455', (75, 77))	('higher', 'PosReg', (17, 23))	('Tumor uptake', 'CPA', (0, 12))
201158	33466827	The 7E11-C5.3 antibody is of the IgG1, kappa subclass (IgG1kappa).	('antibody', 'molecular_function', 'GO:0003823', ('14', '22'))	('IgG1', 'cellular_component', 'GO:0071735', ('55', '59'))	('IgG1', 'Gene', '16017', (33, 37))	('IgG1', 'Gene', (55, 59))	('d', 'Chemical', 'MESH:D003903', (20, 21))	('antibody', 'cellular_component', 'GO:0042571', ('14', '22'))	('7E11-C5.3', 'Var', (4, 13))	('IgG1', 'Gene', (33, 37))	('IgG1', 'cellular_component', 'GO:0071735', ('33', '37'))	('antibody', 'cellular_component', 'GO:0019815', ('14', '22'))	('IgG1', 'Gene', '16017', (55, 59))	('antibody', 'cellular_component', 'GO:0019814', ('14', '22'))
201167	33466827	Although tumor uptake was relatively lower for the 124I-Capromab than 111In-Capromab in LNCaP xenografts (13 +- 8% vs. 29 +- 9% ID/g), it showed lower uptake in normal organs compared to its 111In counterpart.	('124I', 'Chemical', 'MESH:C000614959', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('LNCaP', 'CellLine', 'CVCL:0395', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('uptake', 'biological_process', 'GO:0098657', ('151', '157'))	('uptake', 'biological_process', 'GO:0098739', ('151', '157'))	('124I-Capromab', 'Var', (51, 64))	('tumor', 'Disease', (9, 14))	('I-', 'Chemical', 'MESH:D007455', (54, 56))	('d', 'Chemical', 'MESH:D003903', (182, 183))	('d', 'Chemical', 'MESH:D003903', (143, 144))	('lower', 'NegReg', (145, 150))	('lower', 'NegReg', (37, 42))	('uptake', 'biological_process', 'GO:0098739', ('15', '21'))	('uptake', 'MPA', (151, 157))	('uptake', 'biological_process', 'GO:0098657', ('15', '21'))
201169	33466827	The uptake of 124I-scFv was found to be very high and specific for PSMA-positive cells.	('d', 'Chemical', 'MESH:D003903', (32, 33))	('PSMA', 'Gene', (67, 71))	('uptake', 'biological_process', 'GO:0098657', ('4', '10'))	('uptake', 'biological_process', 'GO:0098739', ('4', '10'))	('PSMA', 'Gene', '2346', (67, 71))	('PSMA', 'molecular_function', 'GO:0043275', ('67', '71'))	('d', 'Chemical', 'MESH:D003903', (52, 53))	('uptake', 'MPA', (4, 10))	('124I-scFv', 'Var', (14, 23))	('124I', 'Chemical', 'MESH:C000614959', (14, 18))
201171	33466827	It was demonstrated recently that 124I- and 89Zr-labeled J591 had comparable surface binding and internalization rates in preclinical prostate models.	('124I', 'Chemical', 'MESH:C000614959', (34, 38))	('d', 'Chemical', 'MESH:D003903', (88, 89))	('124I-', 'Var', (34, 39))	('d', 'Chemical', 'MESH:D003903', (64, 65))	('d', 'Chemical', 'MESH:D003903', (95, 96))	('rat', 'Species', '10116', (113, 116))	('rat', 'Species', '10116', (14, 17))	('d', 'Chemical', 'MESH:D003903', (42, 43))	('J591', 'Gene', (57, 61))	('I-', 'Chemical', 'MESH:D007455', (37, 39))	('d', 'Chemical', 'MESH:D003903', (7, 8))	('89Zr', 'Chemical', 'MESH:C000615502', (44, 48))	('d', 'Chemical', 'MESH:D003903', (18, 19))	('internalization', 'MPA', (97, 112))	('d', 'Chemical', 'MESH:D003903', (55, 56))	('binding', 'molecular_function', 'GO:0005488', ('85', '92'))	('d', 'Chemical', 'MESH:D003903', (145, 146))	('J591', 'Chemical', 'MESH:C478680', (57, 61))
201172	33466827	These studies imply that PCa theranostics using 177Lu- and 124I- or 89Zr- labeled J591 is feasible, safe, and may have superior targeting toward bone lesions relative to conventional imaging modalities.	('bone lesions', 'CPA', (145, 157))	('124I', 'Chemical', 'MESH:C000614959', (59, 63))	('J591', 'Chemical', 'MESH:C478680', (82, 86))	('d', 'Chemical', 'MESH:D003903', (57, 58))	('89Zr', 'Chemical', 'MESH:C000615502', (68, 72))	('PCa', 'Disease', (25, 28))	('d', 'Chemical', 'MESH:D003903', (193, 194))	('J591', 'Gene', (82, 86))	('d', 'Chemical', 'MESH:D003903', (143, 144))	('targeting', 'MPA', (128, 137))	('177Lu-', 'Var', (48, 54))	('d', 'Chemical', 'MESH:D003903', (108, 109))	('d', 'Chemical', 'MESH:D003903', (80, 81))	('I-', 'Chemical', 'MESH:D007455', (62, 64))	('d', 'Chemical', 'MESH:D003903', (9, 10))
201179	33466827	Micro PET imaging of the PSCA positive tumors showed 124I-2B3 minibody to target and image PSCA-expressing xenografts with high contrast at earlier time points than the 124I-labeled intact hu1G8 anti-PSCA mAb.	('I-', 'Chemical', 'MESH:D007455', (56, 58))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('124I-2B3', 'Var', (53, 61))	('d', 'Chemical', 'MESH:D003903', (68, 69))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('d', 'Chemical', 'MESH:D003903', (83, 84))	('124I', 'Chemical', 'MESH:C000614959', (169, 173))	('d', 'Chemical', 'MESH:D003903', (180, 181))	('124I', 'Chemical', 'MESH:C000614959', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('PSCA', 'Disease', (25, 29))	('d', 'Chemical', 'MESH:D003903', (51, 52))	('I-', 'Chemical', 'MESH:D007455', (172, 174))	('tumors', 'Disease', (39, 45))
201182	33466827	124I-p2B3-Db8 and bm2B3-Db8 were evaluated in bio-distribution and for tumor imaging studies in nude mice bearing xenografts of the LAPC-9 and PC-3 (PSCA-negative) tumor cell lines.	('d', 'Chemical', 'MESH:D003903', (88, 89))	('d', 'Chemical', 'MESH:D003903', (50, 51))	('tumor', 'Disease', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('d', 'Chemical', 'MESH:D003903', (41, 42))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('d', 'Chemical', 'MESH:D003903', (65, 66))	('nude mice', 'Species', '10090', (96, 105))	('124I', 'Chemical', 'MESH:C000614959', (0, 4))	('d', 'Chemical', 'MESH:D003903', (16, 17))	('PC-3', 'CellLine', 'CVCL:0035', (143, 147))	('d', 'Chemical', 'MESH:D003903', (141, 142))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('LAPC-9', 'CellLine', 'CVCL:4746', (132, 138))	('tumor', 'Disease', (71, 76))	('bm2B3-Db8', 'Var', (18, 27))	('124I-p2B3-Db8', 'Var', (0, 13))	('d', 'Chemical', 'MESH:D003903', (98, 99))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('I-', 'Chemical', 'MESH:D007455', (3, 5))
201183	33466827	The uptake of 124I-p2B3-Db8 and 124I-bm2B3-Db8 in PSCA-positive tumors was lower than that of 124I-2B3 minibody in the same tumor model.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('124I-p2B3-Db8', 'Var', (14, 27))	('uptake', 'biological_process', 'GO:0098739', ('4', '10'))	('tumor', 'Disease', (124, 129))	('124I', 'Chemical', 'MESH:C000614959', (32, 36))	('PSCA-positive tumors', 'Disease', 'MESH:D009369', (50, 70))	('uptake', 'MPA', (4, 10))	('I-', 'Chemical', 'MESH:D007455', (17, 19))	('PSCA-positive tumors', 'Disease', (50, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('lower', 'NegReg', (75, 80))	('I-', 'Chemical', 'MESH:D007455', (97, 99))	('124I-bm2B3-Db8', 'Var', (32, 46))	('124I', 'Chemical', 'MESH:C000614959', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('d', 'Chemical', 'MESH:D003903', (30, 31))	('124I', 'Chemical', 'MESH:C000614959', (94, 98))	('d', 'Chemical', 'MESH:D003903', (109, 110))	('d', 'Chemical', 'MESH:D003903', (132, 133))	('tumor', 'Disease', (64, 69))	('uptake', 'biological_process', 'GO:0098657', ('4', '10'))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('I-', 'Chemical', 'MESH:D007455', (35, 37))
201184	33466827	PET imaging with 124I-bm2B3-Db8 visualized the LAPC-9 tumor as early as 4 h post injection with a higher contrast at 12 h post injection.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('d', 'Chemical', 'MESH:D003903', (41, 42))	('I-', 'Chemical', 'MESH:D007455', (20, 22))	('LAPC-9', 'Gene', (47, 53))	('tumor', 'Disease', (54, 59))	('LAPC-9', 'CellLine', 'CVCL:4746', (47, 53))	('124I-bm2B3-Db8', 'Var', (17, 31))	('124I', 'Chemical', 'MESH:C000614959', (17, 21))
201185	33466827	Subsequent affinity maturation of the 2B3 minibody created the A11 anti-PSCA minibody, which showed improved immunoPET performance.	('immunoPET', 'MPA', (109, 118))	('d', 'Chemical', 'MESH:D003903', (98, 99))	('d', 'Chemical', 'MESH:D003903', (57, 58))	('improved', 'PosReg', (100, 108))	('A11 anti-PSCA', 'Var', (63, 76))	('d', 'Chemical', 'MESH:D003903', (83, 84))	('d', 'Chemical', 'MESH:D003903', (48, 49))	('d', 'Chemical', 'MESH:D003903', (107, 108))	('rat', 'Species', '10116', (24, 27))
201187	33466827	The non-residualizing 124I-labeled minibody had lower tumor uptake (3.62 +- 1.18% ID/g 22Rv1-PSCA, 3.63 +- 0.59% ID/g LAPC-9) than the residualizing 89Zr-labeled minibody (7.87 +- 0.52% ID/g 22Rv1-PSCA, 9.33 +- 0.87% ID/g LAPC-9.	('d', 'Chemical', 'MESH:D003903', (33, 34))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('d', 'Chemical', 'MESH:D003903', (168, 169))	('124I-labeled', 'Var', (22, 34))	('d', 'Chemical', 'MESH:D003903', (41, 42))	('LAPC-9', 'CellLine', 'CVCL:4746', (222, 228))	('uptake', 'biological_process', 'GO:0098739', ('60', '66'))	('I-', 'Chemical', 'MESH:D007455', (25, 27))	('d', 'Chemical', 'MESH:D003903', (160, 161))	('89Zr', 'Chemical', 'MESH:C000615502', (149, 153))	('LAPC-9', 'CellLine', 'CVCL:4746', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('d', 'Chemical', 'MESH:D003903', (46, 47))	('lower', 'NegReg', (48, 53))	('Rv1', 'Gene', '14349', (193, 196))	('Rv1', 'Gene', '14349', (89, 92))	('124I', 'Chemical', 'MESH:C000614959', (22, 26))	('d', 'Chemical', 'MESH:D003903', (139, 140))	('Rv1', 'Gene', (193, 196))	('d', 'Chemical', 'MESH:D003903', (12, 13))	('Rv1', 'Gene', (89, 92))	('tumor', 'Disease', (54, 59))	('uptake', 'biological_process', 'GO:0098657', ('60', '66'))
201188	33466827	However, the 124I-labeled minibody achieved higher imaging contrast because of lower nonspecific uptake and better tumor-to-soft-tissue ratios.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('d', 'Chemical', 'MESH:D003903', (32, 33))	('higher', 'PosReg', (44, 50))	('d', 'Chemical', 'MESH:D003903', (106, 107))	('lower', 'NegReg', (79, 84))	('tumor', 'Disease', (115, 120))	('I-', 'Chemical', 'MESH:D007455', (16, 18))	('d', 'Chemical', 'MESH:D003903', (24, 25))	('d', 'Chemical', 'MESH:D003903', (42, 43))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('uptake', 'biological_process', 'GO:0098657', ('97', '103'))	('better', 'PosReg', (108, 114))	('124I', 'Chemical', 'MESH:C000614959', (13, 17))	('rat', 'Species', '10116', (136, 139))	('124I-labeled', 'Var', (13, 25))	('uptake', 'biological_process', 'GO:0098739', ('97', '103'))	('nonspecific uptake', 'MPA', (85, 103))	('imaging contrast', 'MPA', (51, 67))
201192	33466827	ImmunoPET imaging using dual-labeled 124I-A11 cMb-Cy5.5 showed specific targeting to both 22Rv1-PSCA and PC3-PSCA.	('124I-A11', 'Var', (37, 45))	('Cy5', 'Chemical', 'MESH:C085321', (50, 53))	('d', 'Chemical', 'MESH:D003903', (61, 62))	('d', 'Chemical', 'MESH:D003903', (24, 25))	('PC3-PSCA', 'Disease', (105, 113))	('124I', 'Chemical', 'MESH:C000614959', (37, 41))	('Rv1', 'Gene', (92, 95))	('Rv1', 'Gene', '14349', (92, 95))	('d', 'Chemical', 'MESH:D003903', (103, 104))	('d', 'Chemical', 'MESH:D003903', (35, 36))
201216	33466827	Higher tumor uptake of 124I-trastuzumab than 124I-IgG1 in HER2-positive PDX mouse models at 24 h was seen.	('124I', 'Chemical', 'MESH:C000614959', (45, 49))	('uptake', 'biological_process', 'GO:0098739', ('13', '19'))	('tumor', 'Disease', (7, 12))	('IgG1', 'cellular_component', 'GO:0071735', ('50', '54'))	('124I-trastuzumab', 'Var', (23, 39))	('mouse', 'Species', '10090', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('Higher', 'PosReg', (0, 6))	('124I', 'Chemical', 'MESH:C000614959', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('d', 'Chemical', 'MESH:D003903', (84, 85))	('uptake', 'biological_process', 'GO:0098657', ('13', '19'))	('124I-trastuzumab', 'Chemical', '-', (23, 39))
201217	33466827	The low tumor uptake of 124I-trastuzumab in HER2-negative PDX models further confirmed the specificity.	('low tumor', 'Disease', (4, 13))	('d', 'Chemical', 'MESH:D003903', (85, 86))	('124I-trastuzumab', 'Chemical', '-', (24, 40))	('d', 'Chemical', 'MESH:D003903', (64, 65))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('124I-trastuzumab', 'Var', (24, 40))	('uptake', 'biological_process', 'GO:0098657', ('14', '20'))	('uptake', 'biological_process', 'GO:0098739', ('14', '20'))	('low tumor', 'Disease', 'MESH:D009800', (4, 13))
201237	33466827	Twenty-six patients with renal masses who were scheduled to undergo surgical resection were given a single intravenous infusion of 124I-cG250.	('124I-cG250', 'Var', (131, 141))	('d', 'Chemical', 'MESH:D003903', (62, 63))	('124I-cG250', 'Chemical', '-', (131, 141))	('renal masses', 'Phenotype', 'HP:0009726', (25, 37))	('d', 'Chemical', 'MESH:D003903', (51, 52))	('patients', 'Species', '9606', (11, 19))	('d', 'Chemical', 'MESH:D003903', (55, 56))	('renal masses', 'Disease', (25, 37))
201240	33466827	Additional clinical studies involving 195 patients validated the safety and superior diagnostic value of 124I-cG250 in ccRCC with an average sensitivity and specificity of 86.2% and 85.9%, respectively.	('d', 'Chemical', 'MESH:D003903', (74, 75))	('d', 'Chemical', 'MESH:D003903', (2, 3))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('d', 'Chemical', 'MESH:D003903', (23, 24))	('RCC', 'Disease', (121, 124))	('124I-cG250', 'Chemical', '-', (105, 115))	('d', 'Chemical', 'MESH:D003903', (85, 86))	('d', 'Chemical', 'MESH:D003903', (155, 156))	('124I-cG250', 'Var', (105, 115))	('d', 'Chemical', 'MESH:D003903', (59, 60))	('patients', 'Species', '9606', (42, 50))	('d', 'Chemical', 'MESH:D003903', (180, 181))	('d', 'Chemical', 'MESH:D003903', (55, 56))	('d', 'Chemical', 'MESH:D003903', (1, 2))
201243	33466827	Furthermore, cG250 (Girentuximab) has been labeled with an assortment of radionuclides (124I, 111In, 89Zr, 131I, 90Y, and 177Lu) and is the most extensively investigated as CA-IX theranostics pharmaceuticals.	('radionuclides', 'Chemical', 'MESH:D011868', (73, 86))	('d', 'Chemical', 'MESH:D003903', (120, 121))	('d', 'Chemical', 'MESH:D003903', (168, 169))	('124I', 'Chemical', 'MESH:C000614959', (88, 92))	('89Zr', 'Var', (101, 105))	('d', 'Chemical', 'MESH:D003903', (49, 50))	('CA-IX', 'Gene', (173, 178))	('men', 'Species', '9606', (65, 68))	('90Y', 'Var', (113, 116))	('89Zr', 'Chemical', 'MESH:C000615502', (101, 105))	('Girentuximab', 'Chemical', 'MESH:C106533', (20, 32))	('111In', 'Var', (94, 99))	('cG250', 'Chemical', 'MESH:C106533', (13, 18))	('d', 'Chemical', 'MESH:D003903', (83, 84))	('CA-IX', 'Gene', '768', (173, 178))	('cG250', 'Gene', (13, 18))	('131I', 'Var', (107, 111))	('d', 'Chemical', 'MESH:D003903', (131, 132))	('124I', 'Var', (88, 92))	('d', 'Chemical', 'MESH:D003903', (75, 76))
201246	33466827	In a clinical study, 124I-codrituzumab (aka GC33), an antibody directed at Glypican 3, was evaluated in 14 patients with hepatocellular carcinoma (HCC).	('d', 'Chemical', 'MESH:D003903', (60, 61))	('124I-codrituzumab', 'Var', (21, 38))	('antibody', 'cellular_component', 'GO:0019815', ('54', '62'))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (121, 145))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (121, 145))	('d', 'Chemical', 'MESH:D003903', (99, 100))	('d', 'Chemical', 'MESH:D003903', (63, 64))	('antibody', 'cellular_component', 'GO:0019814', ('54', '62'))	('d', 'Chemical', 'MESH:D003903', (28, 29))	('hepatocellular carcinoma', 'Disease', (121, 145))	('d', 'Chemical', 'MESH:D003903', (17, 18))	('antibody', 'molecular_function', 'GO:0003823', ('54', '62'))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('d', 'Chemical', 'MESH:D003903', (70, 71))	('Glypican', 'molecular_function', 'GO:0015017', ('75', '83'))	('patients', 'Species', '9606', (107, 115))	('124I-codrituzumab', 'Chemical', '-', (21, 38))	('antibody', 'cellular_component', 'GO:0042571', ('54', '62'))
201415	28257806	Pseudohypoxia Induced by miR-126 Deactivation Promotes Migration and Therapeutic Resistance in Renal Cell Carcinoma Pseudohypoxia plays a central role in the progression and therapeutic resistance of clear cell renal cell carcinoma (ccRCC); however, the underlying mechanisms are poorly understood.	('Deactivation', 'Var', (33, 45))	('Renal Cell Carcinoma', 'Disease', (95, 115))	('clear cell renal cell carcinoma', 'Disease', (200, 231))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (211, 231))	('hypoxia', 'Disease', (122, 129))	('RCC', 'Phenotype', 'HP:0005584', (235, 238))	('ccRCC', 'Phenotype', 'HP:0006770', (233, 238))	('RCC', 'Disease', (235, 238))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (95, 115))	('Promotes', 'PosReg', (46, 54))	('Migration', 'CPA', (55, 64))	('hypoxia', 'Disease', 'MESH:D000860', (122, 129))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (200, 231))	('miR-126', 'Gene', (25, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('RCC', 'Disease', 'MESH:C538614', (235, 238))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (95, 115))	('Therapeutic Resistance', 'CPA', (69, 91))	('Carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('hypoxia', 'Disease', (6, 13))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (200, 231))	('miR-126', 'Gene', '406913', (25, 32))	('hypoxia', 'Disease', 'MESH:D000860', (6, 13))
201417	28257806	Through RNA-seq profiling to evaluate the impact of overexpression or CRISPR knockout of miR-126, we have identified SERPINE1 as a miR-126-5p target regulating cell motility, and SLC7A5 as a miR-126-3p target regulating the mTOR/HIF pathway.	('RNA', 'cellular_component', 'GO:0005562', ('8', '11'))	('SERPINE1', 'Gene', '5054', (117, 125))	('SERPINE1', 'Gene', (117, 125))	('miR-126', 'Gene', (89, 96))	('miR-126-5p', 'Gene', '100302116', (131, 141))	('knockout', 'Var', (77, 85))	('miR-126-5p', 'Gene', (131, 141))	('cell motility', 'biological_process', 'GO:0048870', ('160', '173'))	('miR-126-3p', 'Gene', '100302148', (191, 201))	('cell motility', 'CPA', (160, 173))	('mTOR/HIF pathway', 'Pathway', (224, 240))	('miR-126-3p', 'Gene', (191, 201))
201418	28257806	Specifically, miR-126 inhibits HIFalpha protein expression independent of von Hippel-Lindau tumor suppressor (VHL).	('VHL', 'Gene', '7428', (110, 113))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('92', '108'))	('inhibits', 'NegReg', (22, 30))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('von Hippel-Lindau tumor', 'Disease', 'MESH:D006623', (74, 97))	('miR-126', 'Var', (14, 21))	('von Hippel-Lindau tumor', 'Disease', (74, 97))	('HIFalpha protein', 'Protein', (31, 47))	('VHL', 'Gene', (110, 113))	('tumor suppressor', 'biological_process', 'GO:0051726', ('92', '108'))
201419	28257806	On the other hand, deactivation of miR-126 induces a pseudohypoxia state due to increased HIFalpha expression, which further enhances therapeutic resistance and cell motility mediated by SLC7A5 and SERPINE1, respectively.	('induces', 'Reg', (43, 50))	('expression', 'MPA', (99, 109))	('enhances', 'PosReg', (125, 133))	('cell motility', 'CPA', (161, 174))	('pseudohypoxia', 'Disease', (53, 66))	('increased', 'PosReg', (80, 89))	('deactivation', 'Var', (19, 31))	('cell motility', 'biological_process', 'GO:0048870', ('161', '174'))	('pseudohypoxia', 'Disease', 'None', (53, 66))	('SERPINE1', 'Gene', '5054', (198, 206))	('SERPINE1', 'Gene', (198, 206))	('miR-126', 'Gene', (35, 42))	('HIFalpha', 'Protein', (90, 98))	('therapeutic resistance', 'CPA', (134, 156))
201424	28257806	Besides VHL inactivation, other gene defects have also been demonstrated to be involved in the development of ccRCC, including mutations in MTOR, TSC1, PIK3CA, and PTEN, all of which are important components or regulators of the mammalian target of rapamycin (mTOR) pathway.	('MTOR', 'Gene', '2475', (140, 144))	('mammalian target of rapamycin', 'Gene', '2475', (229, 258))	('mammalian target of rapamycin', 'Gene', (229, 258))	('VHL', 'Gene', '7428', (8, 11))	('PIK3CA', 'Gene', '5290', (152, 158))	('PIK3CA', 'Gene', (152, 158))	('involved', 'Reg', (79, 87))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('MTOR', 'Gene', (140, 144))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('TSC1', 'Gene', '7248', (146, 150))	('PTEN', 'Gene', (164, 168))	('mutations', 'Var', (127, 136))	('PTEN', 'Gene', '5728', (164, 168))	('ccRCC', 'Phenotype', 'HP:0006770', (110, 115))	('VHL', 'Gene', (8, 11))	('TSC1', 'Gene', (146, 150))
201425	28257806	mTOR activation resulting from these defects in ccRCC stimulates the translation of numerous proteins including HIFalpha.	('translation', 'biological_process', 'GO:0006412', ('69', '80'))	('stimulates', 'PosReg', (54, 64))	('mTOR', 'MPA', (0, 4))	('translation of numerous proteins', 'MPA', (69, 101))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('activation', 'PosReg', (5, 15))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('RCC', 'Disease', (50, 53))	('defects', 'Var', (37, 44))
201426	28257806	HIFalpha accumulation, caused by pVHL inactivation and mTOR activation, further facilitates secretion of several growth factors including VEGF and PDGF, which function as upstream activators of mTOR and thus form a positive feedback circuit.	('mTOR', 'Gene', (55, 59))	('secretion', 'biological_process', 'GO:0046903', ('92', '101'))	('secretion of several', 'MPA', (92, 112))	('inactivation', 'Var', (38, 50))	('PDGF', 'molecular_function', 'GO:0005161', ('147', '151'))	('facilitates', 'PosReg', (80, 91))	('pVHL', 'Gene', '7428', (33, 37))	('accumulation', 'PosReg', (9, 21))	('VEGF', 'Gene', '7422', (138, 142))	('pVHL', 'Gene', (33, 37))	('VEGF', 'Gene', (138, 142))
201442	28257806	Antibodies used in this study include anti-HIF1alpha (EMD Millipore 04-1006), anti-HIF2alpha (Novus NB100-132), anti-phospho-mTOR (Cell Signaling #5536), anti-S6 ribosomal protein (Cell Signaling #2217), anti-phospho-S6 ribosomal protein (Cell Signaling #4857), and anti-beta-Actin (Sigma A5441).	('beta-Actin', 'Gene', (271, 281))	('beta-Actin', 'Gene', '728378', (271, 281))	('HIF1alpha', 'Gene', '3091', (43, 52))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('220', '237'))	('HIF2alpha', 'Gene', '2034', (83, 92))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('Signaling', 'biological_process', 'GO:0023052', ('136', '145'))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('162', '179'))	('Signaling', 'biological_process', 'GO:0023052', ('244', '253'))	('anti-phospho-S6', 'Var', (204, 219))	('anti-phospho-mTOR', 'Var', (112, 129))	('Signaling', 'biological_process', 'GO:0023052', ('186', '195'))	('anti-S6', 'Var', (154, 161))	('protein', 'cellular_component', 'GO:0003675', ('230', '237'))	('HIF1alpha', 'Gene', (43, 52))	('HIF2alpha', 'Gene', (83, 92))
201458	28257806	After siRNA transfection, the medium was discarded and the cells were washed three times with DPBS.	('transfection', 'Var', (12, 24))	('DPBS', 'Chemical', 'MESH:C012939', (94, 98))	('siRNA', 'Gene', (6, 11))
201478	28257806	CRISPR/Cas9 assays were employed to knock out the miR-126 gene, which resulted in drastic suppression of both miR-126-5p and miR-126-3p expression in various cell lines (Supplementary Fig.	('miR-126', 'Gene', (50, 57))	('knock out', 'Var', (36, 45))	('suppression', 'NegReg', (90, 101))	('Cas', 'cellular_component', 'GO:0005650', ('7', '10'))	('miR-126-5p', 'Gene', '100302116', (110, 120))	('miR-126-5p', 'Gene', (110, 120))	('miR-126-3p', 'Gene', '100302148', (125, 135))	('miR-126-3p', 'Gene', (125, 135))
201483	28257806	The expression of SERPINE1 was most significantly impacted by miR-126 as compared to FRMD6 and UAP1 under both miR-126 overexpression and knockout conditions.	('UAP1', 'Gene', (95, 99))	('SERPINE1', 'Gene', (18, 26))	('SERPINE1', 'Gene', '5054', (18, 26))	('FRMD6', 'Gene', (85, 90))	('UAP1', 'Gene', '6675', (95, 99))	('expression', 'MPA', (4, 14))	('FRMD6', 'Gene', '122786', (85, 90))	('miR-126', 'Var', (62, 69))	('impacted', 'Reg', (50, 58))
201502	28257806	Given that loss of miR-126 significantly increased HIF1alpha/2alpha protein expression, we hypothesized that these HIF1alpha-induced miRNAs are upregulated in miR-126 knockout cells.	('miR-126', 'Gene', (19, 26))	('increased', 'PosReg', (41, 50))	('loss', 'Var', (11, 15))	('HIF1alpha', 'Gene', (51, 60))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('HIF1alpha', 'Gene', (115, 124))	('HIF1alpha/2alpha', 'Gene', (51, 67))	('HIF1alpha', 'Gene', '3091', (51, 60))	('HIF1alpha/2alpha', 'Gene', '3091;2034', (51, 67))	('HIF1alpha', 'Gene', '3091', (115, 124))
201509	28257806	miR-126 knockout increased the expression of HIF2alpha protein (Supplementary Fig.	('increased', 'PosReg', (17, 26))	('HIF2alpha', 'Gene', (45, 54))	('HIF2alpha', 'Gene', '2034', (45, 54))	('miR-126', 'Gene', (0, 7))	('expression', 'MPA', (31, 41))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('knockout', 'Var', (8, 16))
201514	28257806	To further explore how miR-126 is involved in tumor metastasis in RCC, we first evaluated the motility of 786-O cells with altered miR-126 expression by transwell assay.	('altered', 'Var', (123, 130))	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('tumor metastasis', 'Disease', 'MESH:D009362', (46, 62))	('expression', 'MPA', (139, 149))	('RCC', 'Disease', (66, 69))	('miR-126', 'Gene', (131, 138))	('tumor metastasis', 'Disease', (46, 62))
201524	28257806	Since we have identified SLC7A5 as a miR-126-3p target, we next sought to examine whether the mTOR activity is impacted by miR-126 through SLC7A5.	('miR-126', 'Var', (123, 130))	('mTOR activity', 'MPA', (94, 107))	('impacted', 'Reg', (111, 119))	('miR-126-3p', 'Gene', '100302148', (37, 47))	('miR-126-3p', 'Gene', (37, 47))
201525	28257806	mTOR activity was measured by the expression of phosphorylated mTOR at Ser-2448 as well as its well-established downstream target, S6, phosphorylated at Ser-235/236.	('expression', 'MPA', (34, 44))	('mTOR activity', 'MPA', (0, 13))	('Ser-2448', 'Var', (71, 79))	('Ser', 'cellular_component', 'GO:0005790', ('153', '156'))	('Ser', 'Chemical', 'MESH:D012694', (153, 156))	('Ser', 'cellular_component', 'GO:0005790', ('71', '74'))	('Ser', 'Chemical', 'MESH:D012694', (71, 74))
201530	28257806	In the 786-O cells with miR-126 knockout, the lactate production was increased by about 1.7 fold as compared to negative control cells (Fig.	('increased', 'PosReg', (69, 78))	('knockout', 'Var', (32, 40))	('lactate', 'Chemical', 'MESH:D019344', (46, 53))	('lactate production', 'MPA', (46, 64))	('miR-126', 'Gene', (24, 31))
201542	28257806	On the other hand, miR-126 deactivation by CRISPR/Cas9 knockout resulted in resistance to cisplatin or X-ray treatment of the cancer cells.	('miR-126', 'Gene', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('resistance to cisplatin', 'MPA', (76, 99))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('knockout', 'Var', (55, 63))	('cancer', 'Disease', (126, 132))	('resulted', 'Reg', (64, 72))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('CRISPR/Cas9', 'Gene', (43, 54))	('deactivation', 'NegReg', (27, 39))	('Cas', 'cellular_component', 'GO:0005650', ('50', '53'))
201556	28257806	Specifically in ccRCC cells, multiple genes controlling these two pathways, such as TSC1, TSC2, PTEN and VHL, are frequently mutated.	('RCC', 'Disease', (18, 21))	('PTEN', 'Gene', '5728', (96, 100))	('RCC', 'Phenotype', 'HP:0005584', (18, 21))	('VHL', 'Gene', (105, 108))	('TSC1', 'Gene', '7248', (84, 88))	('TSC2', 'Gene', '7249', (90, 94))	('mutated', 'Var', (125, 132))	('TSC1', 'Gene', (84, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (16, 21))	('VHL', 'Gene', '7428', (105, 108))	('TSC2', 'Gene', (90, 94))	('PTEN', 'Gene', (96, 100))	('RCC', 'Disease', 'MESH:C538614', (18, 21))
201557	28257806	These gene defects can lead to activation of HIFalpha, which contributes greatly to two well-known phenotypes of ccRCC: highly vascularized tumors and drastic increase in fatty acid synthesis.	('fatty acid synthesis', 'biological_process', 'GO:0006633', ('171', '191'))	('defects', 'Var', (11, 18))	('fatty acid synthesis', 'MPA', (171, 191))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (113, 118))	('RCC', 'Disease', (115, 118))	('fatty acid', 'Chemical', 'MESH:D005227', (171, 181))	('HIFalpha', 'Gene', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('activation', 'PosReg', (31, 41))	('increase', 'PosReg', (159, 167))
201559	28257806	miR-126-3p deactivation results in increased expression of SLC7A5, which in turn leads to elevated mTOR activity and HIFalpha protein expression.	('HIFalpha protein', 'Protein', (117, 133))	('elevated', 'PosReg', (90, 98))	('increased', 'PosReg', (35, 44))	('miR-126-3p', 'Gene', '100302148', (0, 10))	('mTOR activity', 'MPA', (99, 112))	('SLC7A5', 'Gene', (59, 65))	('miR-126-3p', 'Gene', (0, 10))	('expression', 'MPA', (45, 55))	('deactivation', 'Var', (11, 23))	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))
201560	28257806	Meanwhile, miR-126-5p deactivation stimulates HIFalpha expression at the protein level through currently unknown mechanisms.	('miR-126-5p', 'Gene', '100302116', (11, 21))	('miR-126-5p', 'Gene', (11, 21))	('expression', 'MPA', (55, 65))	('deactivation', 'Var', (22, 34))	('stimulates', 'PosReg', (35, 45))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('HIFalpha', 'Gene', (46, 54))
201565	28257806	Moreover, our results also demonstrated that miR-126 could significantly suppress the EMT pathway by targeting SERPINE1, leading to potential improvement in treating metastatic RCC.	('suppress', 'NegReg', (73, 81))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('RCC', 'Disease', (177, 180))	('SERPINE1', 'Gene', (111, 119))	('improvement', 'PosReg', (142, 153))	('EMT pathway', 'Pathway', (86, 97))	('SERPINE1', 'Gene', '5054', (111, 119))	('RCC', 'Phenotype', 'HP:0005584', (177, 180))	('miR-126', 'Var', (45, 52))	('targeting', 'Reg', (101, 110))	('EMT', 'biological_process', 'GO:0001837', ('86', '89'))
201566	28257806	Thus, miR-126 could serve as a potent multi-targeting agent for the treatment of RCC.	('miR-126', 'Var', (6, 13))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))
201567	28257806	By targeting SLC7A5 and SERPINE1, miR-126 plays a major role in regulation of the mTOR/HIF pathway in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('SLC7A5', 'Gene', (13, 19))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('regulation', 'biological_process', 'GO:0065007', ('64', '74'))	('SERPINE1', 'Gene', '5054', (24, 32))	('SERPINE1', 'Gene', (24, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('miR-126', 'Var', (34, 41))	('targeting', 'Reg', (3, 12))	('mTOR/HIF pathway', 'Pathway', (82, 98))	('RCC', 'Disease', (104, 107))
201570	27594736	New Progress of Epigenetic Biomarkers in Urological Cancer Urological cancers consist of bladder, kidney, prostate, and testis cancers and they are generally silenced at their early stage, which leads to the loss of the best opportunity for early diagnosis and treatment.	('testis cancers', 'Disease', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('kidney', 'Disease', (98, 104))	('testis cancer', 'Phenotype', 'HP:0010788', (120, 133))	('Cancer', 'Disease', (52, 58))	('testis cancers', 'Disease', 'MESH:D013736', (120, 134))	('bladder', 'Disease', (89, 96))	('prostate', 'Disease', (106, 114))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('Cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (127, 134))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (70, 77))	('Epigenetic', 'Var', (16, 26))
201572	27594736	Epigenetic alterations are characteristic of nearly all kinds of human malignances including DNA methylation, histone modification, and miRNA regulation.	('Epigenetic alterations', 'Var', (0, 22))	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('human', 'Species', '9606', (65, 70))	('histone modification', 'Disease', (110, 130))	('regulation', 'biological_process', 'GO:0065007', ('142', '152'))	('miR', 'Gene', (136, 139))	('miR', 'Gene', '22877', (136, 139))	('histone modification', 'biological_process', 'GO:0016570', ('110', '130'))	('DNA methylation', 'Disease', (93, 108))	('DNA methylation', 'biological_process', 'GO:0006306', ('93', '108'))
201579	27594736	In this review, we focus on epigenetic-based biomarkers in urology system and summarize current state of research on epigenetic alterations, holding the promise to provide new ideas for the diagnosis, treatment, and prediction of urological cancer.	('urological cancer', 'Disease', 'MESH:D014571', (230, 247))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('epigenetic alterations', 'Var', (117, 139))	('urological cancer', 'Disease', (230, 247))
201582	27594736	DNA methylation and demethylation are known to be associated with tumorigenesis and result in silencing tumor suppressor genes and activating oncogenes, respectively.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('silencing', 'NegReg', (94, 103))	('tumor suppressor', 'biological_process', 'GO:0051726', ('104', '120'))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('104', '120'))	('tumor', 'Disease', (66, 71))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumor', 'Disease', (104, 109))	('demethylation', 'Var', (20, 33))	('activating', 'PosReg', (131, 141))	('demethylation', 'biological_process', 'GO:0070988', ('20', '33'))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('DNA methylation', 'Var', (0, 15))	('associated', 'Reg', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('oncogenes', 'Gene', (142, 151))
201586	27594736	For instance, histone acetylation enhances the transcriptional activity of gene for lowering the affinity of histone tails to the DNA, while histone deacetylases result in gene repression.	('affinity', 'Interaction', (97, 105))	('lowering', 'NegReg', (84, 92))	('transcriptional activity', 'MPA', (47, 71))	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('histone tails', 'Protein', (109, 122))	('histone acetylation', 'biological_process', 'GO:0016573', ('14', '33'))	('histone acetylation', 'Var', (14, 33))	('acetylation', 'Var', (22, 33))	('histone deacetylase', 'Gene', '9734', (141, 160))	('enhances', 'PosReg', (34, 42))	('histone deacetylase', 'Gene', (141, 160))
201595	27594736	The ways that miRNAs alter gene expression include deletion, amplification, mutation, and chromosomal abnormalities.	('gene expression', 'biological_process', 'GO:0010467', ('27', '42'))	('gene expression', 'MPA', (27, 42))	('amplification', 'Var', (61, 74))	('chromosomal abnormalities', 'Disease', (90, 115))	('alter', 'Reg', (21, 26))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (90, 115))	('miR', 'Gene', (14, 17))	('mutation', 'Var', (76, 84))	('deletion', 'Var', (51, 59))	('miR', 'Gene', '22877', (14, 17))
201596	27594736	Some studies found that miRNA can influence gene expression via targeting a specific gene region for DNA methylation and histone modifications and the expression of miRNA can be regulated by other epigenetic modifications such as DNA methylation, which indicated the interactions between miRNAs and other epigenetic mechanisms.	('gene expression', 'MPA', (44, 59))	('methylation', 'Var', (105, 116))	('histone modifications', 'MPA', (121, 142))	('gene expression', 'biological_process', 'GO:0010467', ('44', '59'))	('miR', 'Gene', (288, 291))	('DNA methylation', 'biological_process', 'GO:0006306', ('230', '245'))	('miR', 'Gene', '22877', (288, 291))	('DNA methylation', 'biological_process', 'GO:0006306', ('101', '116'))	('influence', 'Reg', (34, 43))	('miR', 'Gene', (165, 168))	('regulated', 'Reg', (178, 187))	('miR', 'Gene', (24, 27))	('DNA', 'cellular_component', 'GO:0005574', ('101', '104'))	('miR', 'Gene', '22877', (165, 168))	('miR', 'Gene', '22877', (24, 27))	('DNA', 'cellular_component', 'GO:0005574', ('230', '233'))
201599	27594736	Epigenetic biomarkers can decrease the use of invasive methods and provide the early diagnosis of bladder cancer allowing for more effective treatment.	('decrease', 'NegReg', (26, 34))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('bladder cancer', 'Disease', (98, 112))	('Epigenetic biomarkers', 'Var', (0, 21))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
201604	27594736	They concluded that RSPH9 methylation can be of value for the assessment of disease recurrence and an independent prognostic indicator in NMIBC patients.	('methylation', 'Var', (26, 37))	('MIBC', 'Chemical', '-', (139, 143))	('RSPH9', 'Gene', (20, 25))	('BC', 'Phenotype', 'HP:0009725', (141, 143))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('patients', 'Species', '9606', (144, 152))	('NMIBC', 'Disease', (138, 143))	('RSPH9', 'Gene', '221421', (20, 25))
201605	27594736	reported that the hypermethylation of PCDH10 (50%, n = 117) and PCDH17 (52%, n = 151) was related to the development of bladder cancer and it was an independent predictor of cancer-specific survival time.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('PCDH10', 'Gene', (38, 44))	('hypermethylation', 'Var', (18, 34))	('PCDH17', 'Gene', (64, 70))	('PCDH10', 'Gene', '57575', (38, 44))	('bladder cancer', 'Phenotype', 'HP:0009725', (120, 134))	('bladder cancer', 'Disease', 'MESH:D001749', (120, 134))	('related to', 'Reg', (90, 100))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('bladder cancer', 'Disease', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('PCDH17', 'Gene', '27253', (64, 70))	('cancer', 'Disease', (128, 134))
201611	27594736	Another study discovered that a methylation gene panel which consisted of 4 genes (CDH1, CDH13, RASSF1A, and APC) had significant correlations with poor prognosis (cancer with high grade, advanced stages, and aneuploidies).	('CDH1', 'Gene', (83, 87))	('advanced stages', 'CPA', (188, 203))	('RASSF1A', 'Gene', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('APC', 'Disease', (109, 112))	('APC', 'cellular_component', 'GO:0005680', ('109', '112'))	('CDH1', 'Gene', '999', (89, 93))	('aneuploidies', 'Var', (209, 221))	('CDH1', 'Gene', '999', (83, 87))	('CDH13', 'Gene', (89, 94))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('RASSF1A', 'Gene', '11186', (96, 103))	('APC', 'Disease', 'MESH:D011125', (109, 112))	('CDH13', 'Gene', '1012', (89, 94))	('CDH1', 'Gene', (89, 93))
201613	27594736	Histone modifications were also found to relate to the pathogenesis of bladder cancer and regulation of cancer cell proliferation.	('pathogenesis', 'biological_process', 'GO:0009405', ('55', '67'))	('Histone', 'Protein', (0, 7))	('bladder cancer', 'Disease', 'MESH:D001749', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (79, 85))	('cell proliferation', 'biological_process', 'GO:0008283', ('111', '129'))	('modifications', 'Var', (8, 21))	('bladder cancer', 'Disease', (71, 85))	('regulation', 'biological_process', 'GO:0065007', ('90', '100'))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('relate', 'Reg', (41, 47))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (71, 85))
201614	27594736	A study in 2011 identified global histone H4K20 trimethylation that could predict cancer-specific survival in patients with muscle-invasive bladder cancer.	('cancer', 'Disease', (148, 154))	('trimethylation', 'Var', (48, 62))	('muscle-invasive bladder cancer', 'Disease', (124, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (124, 154))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('bladder cancer', 'Phenotype', 'HP:0009725', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('predict', 'Reg', (74, 81))	('histone H4K20', 'Protein', (34, 47))	('invasive bladder', 'Phenotype', 'HP:0100645', (131, 147))	('histone H4K20 trimethylation', 'biological_process', 'GO:0034773', ('34', '62'))	('patients', 'Species', '9606', (110, 118))
201615	27594736	showed that merged odds ratio of the effect between slow acetylation and bladder cancer was 1.31 (95% confidence odds ratio interval = 1.11-1.55), illustrating that slow acetylation modestly increases the risk of bladder cancer.	('bladder cancer', 'Disease', (73, 87))	('bladder cancer', 'Phenotype', 'HP:0009725', (213, 227))	('bladder cancer', 'Disease', 'MESH:D001749', (213, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('increases', 'PosReg', (191, 200))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('bladder cancer', 'Disease', (213, 227))	('slow acetylation', 'Var', (165, 181))	('bladder cancer', 'Disease', 'MESH:D001749', (73, 87))
201617	27594736	Their results indicated that deacetylated KLF4 can act as an oncogene accelerating bladder cancer proliferation; on the contrary, acetylation of KLF4 performs as a tumor suppressor, which may be a good target for bladder cancer therapy.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('KLF4', 'Gene', (145, 149))	('bladder cancer', 'Phenotype', 'HP:0009725', (213, 227))	('bladder cancer', 'Phenotype', 'HP:0009725', (83, 97))	('tumor suppressor', 'biological_process', 'GO:0051726', ('164', '180'))	('KLF4', 'Gene', '9314', (42, 46))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('164', '180'))	('bladder cancer', 'Disease', 'MESH:D001749', (213, 227))	('acetylation', 'Var', (130, 141))	('KLF4', 'Gene', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('KLF4', 'Gene', '9314', (145, 149))	('bladder cancer', 'Disease', 'MESH:D001749', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('bladder cancer', 'Disease', (213, 227))	('bladder cancer', 'Disease', (83, 97))
201618	27594736	In addition, another study found that expression levels of H3K4me1, H4K20me1, H4K20me2, and H4K20me3 were correlated with advanced pathological stage and that H4K20me3 was an independent prognosis factor for the survival of patients with muscle-invasive bladder cancer.	('H4K20me1', 'Var', (68, 76))	('muscle-invasive bladder cancer', 'Disease', (238, 268))	('H3K4me1', 'Var', (59, 66))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (238, 268))	('bladder cancer', 'Phenotype', 'HP:0009725', (254, 268))	('expression', 'MPA', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('H4K20me3', 'Var', (92, 100))	('H4K20me2', 'Var', (78, 86))	('patients', 'Species', '9606', (224, 232))	('H4K20me3', 'Var', (159, 167))	('invasive bladder', 'Phenotype', 'HP:0100645', (245, 261))	('correlated', 'Reg', (106, 116))
201635	27594736	Recently, another similar outcome showed that two genes, SMPD3 and FBXW10, are hypermethylated in ccRCC tissue samples compared with paired normal tissues.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('SMPD3', 'Gene', '55512', (57, 62))	('FBXW10', 'Gene', (67, 73))	('SMPD3', 'Gene', (57, 62))	('FBXW10', 'Gene', '10517', (67, 73))	('hypermethylated', 'Var', (79, 94))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
201638	27594736	suggests that DAB2IP CpG1 methylation is a practical and repeatable biomarker for ccRCC, which can provide prognostic value that complements the current staging system.	('methylation', 'Var', (26, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('DAB2IP', 'Gene', '153090', (14, 20))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('RCC', 'Disease', (84, 87))	('DAB2IP', 'Gene', (14, 20))
201641	27594736	Patients with positive immunostaining of H3K4me2 and H3K18Ac but accounting for a lower proportion generally had a shorter 1-year survival probability than those with more histone modifications.	('H3K18Ac', 'Var', (53, 60))	('1-year', 'MPA', (123, 129))	('shorter', 'NegReg', (115, 122))	('Patients', 'Species', '9606', (0, 8))	('H3K4me2', 'Var', (41, 48))
201659	27594736	The high exposing of PCDH17 and TCF21 methylation in prostate cancer cell lines was significantly different from primary tumor tissues.	('prostate cancer', 'Disease', (53, 68))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('methylation', 'Var', (38, 49))	('tumor', 'Disease', (121, 126))	('TCF21', 'Gene', '6943', (32, 37))	('PCDH17', 'Gene', (21, 27))	('prostate cancer', 'Disease', 'MESH:D011471', (53, 68))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('prostate cancer', 'Phenotype', 'HP:0012125', (53, 68))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))	('TCF21', 'Gene', (32, 37))	('PCDH17', 'Gene', '27253', (21, 27))
201743	31921657	Higher levels of HIF-1alpha or HIF-2alpha at immunohistochemistry correlated with complete or a partial response to sunitinib therapy; particularly high levels of HIF-1alpha at baseline was associated with longer PFS (42.0 weeks, 95% CI 31.0-56.3) than low HIF-1alpha levels (30.4 weeks, 95% CI 22.2-43.9, HR = 1.55, p = 0.034).	('HIF-1alpha', 'Gene', (17, 27))	('HIF-1alpha', 'Gene', (257, 267))	('HIF-1alpha', 'Gene', (163, 173))	('sunitinib', 'Chemical', 'MESH:C473478', (116, 125))	('HIF-2alpha', 'Gene', '2034', (31, 41))	('HIF-1alpha', 'Gene', '3091', (17, 27))	('HIF-1alpha', 'Gene', '3091', (257, 267))	('high', 'Var', (148, 152))	('HIF-1alpha', 'Gene', '3091', (163, 173))	('PFS', 'Disease', (213, 216))	('HIF-2alpha', 'Gene', (31, 41))
201749	31921657	As a result of alternative splicing of the eight-exon VEGF-A gene, VEGF-A presents several isoforms, and its expression is associated with both histology and prognosis.	('splicing', 'biological_process', 'GO:0045292', ('27', '35'))	('VEGF-A', 'Gene', (54, 60))	('associated', 'Reg', (123, 133))	('expression', 'MPA', (109, 119))	('alternative splicing', 'Var', (15, 35))	('VEGF-A', 'Gene', '7422', (67, 73))	('VEGF-A', 'Gene', (67, 73))	('VEGF-A', 'Gene', '7422', (54, 60))
201753	31921657	Alternative splicing of KDR, the gene that encodes VEGFR2, results in a soluble 679-amino acid truncated extracellular-domain product (sVEGFR2).	('KDR', 'Gene', '3791', (24, 27))	('VEGFR2', 'Gene', (136, 142))	('KDR', 'Gene', (24, 27))	('VEGFR2', 'Gene', '3791', (51, 57))	('soluble', 'cellular_component', 'GO:0005625', ('72', '79'))	('VEGFR2', 'Gene', (51, 57))	('extracellular', 'cellular_component', 'GO:0005576', ('105', '118'))	('679-amino acid', 'Chemical', 'MESH:C059141', (80, 94))	('VEGFR2', 'Gene', '3791', (136, 142))	('Alternative splicing', 'Var', (0, 20))	('results in', 'Reg', (59, 69))	('splicing', 'biological_process', 'GO:0045292', ('12', '20'))
201760	31921657	In fact, patients with low vs. high baseline IL-6 levels showed a HR for survival favoring pazopanib compared to placebo of 0.55 vs. 0.31.	('patients', 'Species', '9606', (9, 17))	('pazopanib', 'Chemical', 'MESH:C516667', (91, 100))	('pazopanib', 'Var', (91, 100))	('IL-6', 'molecular_function', 'GO:0005138', ('45', '49'))	('IL-6', 'Gene', (45, 49))	('IL-6', 'Gene', '3569', (45, 49))
201763	31921657	Some studies suggest that SNPs in vascular endothelial growth factor receptor 3 (VEGFR3), cytochrome P450 3A5 (CYP3A5*1), IL-8, fibroblast growth factor receptor 2 (FGFR2), nuclear receptor subfamily 1 group I member 2 (NR1I2), and ATP binding cassette subfamily B member 1 (ABCB1) may predict efficacy and tolerance.	('cytochrome P450 3A5', 'Gene', '1577', (90, 109))	('nuclear receptor subfamily 1 group I member 2', 'Gene', '8856', (173, 218))	('IL-8', 'Gene', (122, 126))	('VEGFR3', 'Gene', '2324', (81, 87))	('IL-8', 'molecular_function', 'GO:0005153', ('122', '126'))	('fibroblast growth factor receptor 2', 'Gene', (128, 163))	('ATP binding', 'molecular_function', 'GO:0005524', ('232', '243'))	('tolerance', 'CPA', (307, 316))	('ATP binding cassette subfamily B member 1', 'Gene', (232, 273))	('efficacy', 'CPA', (294, 302))	('fibroblast growth factor receptor 2', 'Gene', '2263', (128, 163))	('nuclear receptor subfamily 1 group I member 2', 'Gene', (173, 218))	('NR1I2', 'Gene', '8856', (220, 225))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('128', '152'))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('34', '68'))	('FGFR', 'molecular_function', 'GO:0005007', ('165', '169'))	('IL-8', 'Gene', '3576', (122, 126))	('CYP3A5', 'Gene', '1577', (111, 117))	('ATP binding cassette subfamily B member 1', 'Gene', '5243', (232, 273))	('cytochrome P450', 'molecular_function', 'GO:0005490', ('90', '105'))	('FGFR2', 'Gene', (165, 170))	('VEGFR3', 'Gene', (81, 87))	('CYP3A5', 'Gene', (111, 117))	('predict', 'Reg', (286, 293))	('cytochrome P450', 'molecular_function', 'GO:0019825', ('90', '105'))	('SNPs', 'Var', (26, 30))	('vascular endothelial growth factor receptor 3', 'Gene', '2324', (34, 79))	('vascular endothelial growth factor receptor 3', 'Gene', (34, 79))	('ABCB1', 'Gene', (275, 280))	('ABCB1', 'Gene', '5243', (275, 280))	('NR1I2', 'Gene', (220, 225))	('cytochrome P450 3A5', 'Gene', (90, 109))	('FGFR2', 'Gene', '2263', (165, 170))
201766	31921657	VHL loss is often the result of gene mutation or promoter hyper-methylation in RCC, but its implications in response to treatment are unknown.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('VHL loss', 'Disease', 'MESH:D006623', (0, 8))	('VHL loss', 'Disease', (0, 8))	('gene mutation', 'Var', (32, 45))	('promoter', 'MPA', (49, 57))	('men', 'Species', '9606', (125, 128))	('methylation', 'biological_process', 'GO:0032259', ('64', '75'))	('RCC', 'Disease', 'MESH:D002292', (79, 82))	('RCC', 'Disease', (79, 82))
201768	31921657	The response rate (RR) was 41% in mRCC patients with VHL inactivation vs. 31% in the wild-type VHL subgroup (p = 0.34).	('RCC', 'Disease', 'MESH:D002292', (35, 38))	('RCC', 'Disease', (35, 38))	('VHL', 'Gene', (95, 98))	('subgroup', 'Species', '167158', (99, 107))	('patients', 'Species', '9606', (39, 47))	('VHL', 'Gene', (53, 56))	('VHL', 'Gene', '7428', (95, 98))	('VHL', 'Gene', '7428', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('inactivation', 'Var', (57, 69))
201769	31921657	The presence of aberrant VHL gene, particularly loss-of-function mutations (frameshift, nonsense, splice, and in-frame deletions/insertions) corresponded to a 52% of RR.	('aberrant', 'Var', (16, 24))	('frameshift', 'Var', (76, 86))	('nonsense', 'Var', (88, 96))	('splice', 'Var', (98, 104))	('VHL', 'Gene', (25, 28))	('in-frame deletions/insertions', 'Var', (110, 139))	('loss-of-function', 'NegReg', (48, 64))	('VHL', 'Gene', '7428', (25, 28))
201770	31921657	Thus, VHL loss-of-function mutations represent an independent prognostic factor linked to improved RR, but do not reflect progression-free survival (PFS) or OS.	('mutations', 'Var', (27, 36))	('improved', 'PosReg', (90, 98))	('OS', 'Gene', '17451', (157, 159))	('VHL loss-of-function', 'Disease', (6, 26))	('VHL loss-of-function', 'Disease', 'MESH:D006623', (6, 26))
201772	31921657	The PBRM1 /BAF180 tumor suppressor gene is mutated in 30-50% of ccRCC cases.	('RCC', 'Disease', 'MESH:D002292', (66, 69))	('tumor', 'Disease', (18, 23))	('PBRM1', 'Gene', (4, 9))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('PBRM1', 'Gene', '55193', (4, 9))	('tumor suppressor', 'biological_process', 'GO:0051726', ('18', '34'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('18', '34'))	('BAF180', 'Gene', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('mutated', 'Var', (43, 50))	('RCC', 'Disease', (66, 69))	('BAF180', 'Gene', '55193', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
201773	31921657	PBRM1 is implicated in cell proliferation, and is found mutated at early stages of ccRCC.	('mutated', 'Var', (56, 63))	('PBRM1', 'Gene', (0, 5))	('cell proliferation', 'biological_process', 'GO:0008283', ('23', '41'))	('PBRM1', 'Gene', '55193', (0, 5))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('RCC', 'Disease', 'MESH:D002292', (85, 88))	('RCC', 'Disease', (85, 88))
201774	31921657	Mutations of PBRM1 are reported in small (<4 cm) RCC masses with an aggressive clinical behavior.	('RCC', 'Disease', 'MESH:D002292', (49, 52))	('RCC', 'Disease', (49, 52))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (68, 96))	('PBRM1', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('PBRM1', 'Gene', '55193', (13, 18))	('reported', 'Reg', (23, 31))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))
201775	31921657	Mutations of BAP1, a ubiquitin carboxyl-terminal hydrolase, correlate with negative histologic features (e.g., high nuclear grade) and poor cancer-specific survival.	('carboxyl', 'Chemical', 'MESH:C041069', (31, 39))	('BAP1', 'Gene', (13, 17))	('poor', 'NegReg', (135, 139))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (13, 17))	('ubiquitin', 'molecular_function', 'GO:0031386', ('21', '30'))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
201776	31921657	Inactivating mutations are reported in 15% of ccRCC.	('Inactivating mutations', 'Var', (0, 22))	('RCC', 'Disease', 'MESH:D002292', (48, 51))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
201777	31921657	Mutation in the BAF180 gene excludes mutation of the BAP1 gene in most cases.	('BAF180', 'Gene', (16, 22))	('Mutation', 'Var', (0, 8))	('BAF180', 'Gene', '55193', (16, 22))	('BAP1', 'Gene', '8314', (53, 57))	('excludes', 'NegReg', (28, 36))	('BAP1', 'Gene', (53, 57))
201782	31921657	As recently shown, there are some single nucleotide polymorphisms (SNPs) (e.g., in genes involved in the VEGF pathway) that are associated with the risk of RCC as well as with RR and adverse events in patients receiving TTs.	('single nucleotide polymorphisms', 'Var', (34, 65))	('patients', 'Species', '9606', (201, 209))	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('RCC', 'Disease', 'MESH:D002292', (156, 159))	('RCC', 'Disease', (156, 159))	('VEGF', 'Gene', (105, 109))	('associated', 'Reg', (128, 138))	('VEGF', 'Gene', '7422', (105, 109))
201783	31921657	An analysis of 397 RCC patients receiving pazopanib assessed the clinical significance of 27 polymorphisms in 13 genes involved in angiogenesis, metabolism and drug transport.	('metabolism', 'biological_process', 'GO:0008152', ('145', '155'))	('drug transport', 'biological_process', 'GO:0015893', ('160', '174'))	('patients', 'Species', '9606', (23, 31))	('angiogenesis', 'biological_process', 'GO:0001525', ('131', '143'))	('pazopanib', 'Chemical', 'MESH:C516667', (42, 51))	('RCC', 'Disease', 'MESH:D002292', (19, 22))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('polymorphisms', 'Var', (93, 106))
201785	31921657	RR was lower in patients with the VEGFA 1498CC vs. 1498TT genotype (33 vs. 51%, p <= 0.05).	('patients', 'Species', '9606', (16, 24))	('lower', 'NegReg', (7, 12))	('VEGFA', 'Gene', '7422', (34, 39))	('1498TT', 'Var', (51, 57))	('VEGFA', 'Gene', (34, 39))
201786	31921657	Median PFS was significantly shorter in patients with two IL-8 polymorphisms associated with higher IL-8 gene expression than in those with wild-type IL-8 (27 vs. 48 weeks).	('higher', 'PosReg', (93, 99))	('gene expression', 'MPA', (105, 120))	('gene expression', 'biological_process', 'GO:0010467', ('105', '120'))	('PFS', 'MPA', (7, 10))	('IL-8', 'Gene', '3576', (150, 154))	('IL-8', 'molecular_function', 'GO:0005153', ('150', '154'))	('patients', 'Species', '9606', (40, 48))	('IL-8', 'molecular_function', 'GO:0005153', ('58', '62'))	('IL-8', 'Gene', '3576', (100, 104))	('polymorphisms', 'Var', (63, 76))	('IL-8', 'Gene', (150, 154))	('IL-8', 'Gene', (100, 104))	('IL-8', 'Gene', '3576', (58, 62))	('IL-8', 'molecular_function', 'GO:0005153', ('100', '104'))	('shorter', 'NegReg', (29, 36))	('IL-8', 'Gene', (58, 62))
201788	31921657	Variant alleles of IL-8 polymorphisms have been associated with worse OS in pazopanib- or sunitinib-treated mRCC patients.	('IL-8', 'Gene', '3576', (19, 23))	('OS', 'Gene', '17451', (70, 72))	('IL-8', 'Gene', (19, 23))	('associated', 'Reg', (48, 58))	('patients', 'Species', '9606', (113, 121))	('polymorphisms', 'Var', (24, 37))	('RCC', 'Disease', 'MESH:D002292', (109, 112))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('IL-8', 'molecular_function', 'GO:0005153', ('19', '23'))	('pazopanib', 'Chemical', 'MESH:C516667', (76, 85))	('sunitinib', 'Chemical', 'MESH:C473478', (90, 99))	('Variant', 'Var', (0, 7))
201790	31921657	Of the sixteen polymorphisms assessed in nine genes, Two VEGFR3 missense polymorphisms predicted a shorter PFS and a variant of CYP3A5*1 predicted higher toxicity at multivariate analysis.	('shorter', 'NegReg', (99, 106))	('CYP3A5', 'Gene', (128, 134))	('toxicity', 'Disease', 'MESH:D064420', (154, 162))	('toxicity', 'Disease', (154, 162))	('VEGFR3', 'Gene', '2324', (57, 63))	('PFS', 'MPA', (107, 110))	('CYP3A5', 'Gene', '1577', (128, 134))	('higher', 'PosReg', (147, 153))	('variant', 'Var', (117, 124))	('VEGFR3', 'Gene', (57, 63))
201791	31921657	While VEGF or VEGFR SNPs were associated with outcomes, patients presenting VEGF SNP 936 and VEGFR2 SNP 889 had longer OS after adjusting for their risk group (p = 0.03).	('patients', 'Species', '9606', (56, 64))	('VEGF', 'Gene', (76, 80))	('VEGF', 'Gene', (93, 97))	('VEGFR', 'Gene', '3791', (14, 19))	('VEGF', 'Gene', '7422', (14, 18))	('VEGF', 'Gene', '7422', (6, 10))	('OS', 'Gene', '17451', (119, 121))	('VEGFR', 'Gene', '3791', (93, 98))	('VEGFR2', 'Gene', '3791', (93, 99))	('VEGF', 'Gene', '7422', (76, 80))	('VEGFR2', 'Gene', (93, 99))	('VEGF', 'Gene', '7422', (93, 97))	('VEGFR', 'Gene', (14, 19))	('VEGFR', 'Gene', (93, 98))	('SNP 936', 'Var', (81, 88))	('VEGF', 'Gene', (14, 18))	('VEGF', 'Gene', (6, 10))	('longer', 'PosReg', (112, 118))
201792	31921657	A retrospective study including 136 patients with metastatic ccRCC receiving sunitinib showed that SNPs in CYP3A5, ligand-activated nuclear receptor NR1I3, and ABCB1VEGF and VEGFR-2 were able to predict survival.	('RCC', 'Disease', 'MESH:D002292', (63, 66))	('RCC', 'Disease', (63, 66))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('ligand', 'molecular_function', 'GO:0005488', ('115', '121'))	('sunitinib', 'Chemical', 'MESH:C473478', (77, 86))	('VEGFR-2', 'Gene', (174, 181))	('patients', 'Species', '9606', (36, 44))	('NR1I3', 'Gene', '9970', (149, 154))	('ABCB1VEGF', 'Gene', (160, 169))	('CYP3A5', 'Gene', '1577', (107, 113))	('SNPs', 'Var', (99, 103))	('NR1I3', 'Gene', (149, 154))	('VEGFR-2', 'Gene', '3791', (174, 181))	('predict', 'Reg', (195, 202))	('CYP3A5', 'Gene', (107, 113))
201794	31921657	In an analysis of 138 VEGF SNPs assessed in patients treated with bevacizumab enrolled in the AVOREN trial VEGFR1 SNP codifying for aminoacids located in its tyrosine-kinase domain associated with poor PFS (HR = 1.81, 95% CI 1.08-3.05, p = 0.033), although no association was found with OS (HR = 0.91, 95% CI 0.45-1.82, p = 0.78).	('VEGF', 'Gene', '7422', (22, 26))	('VEGF', 'Gene', (107, 111))	('patients', 'Species', '9606', (44, 52))	('VEGFR1', 'Gene', '2321', (107, 113))	('VEGFR1', 'Gene', (107, 113))	('poor', 'NegReg', (197, 201))	('PFS', 'MPA', (202, 205))	('OS', 'Gene', '17451', (287, 289))	('aminoacids', 'Var', (132, 142))	('VEGF', 'Gene', '7422', (107, 111))	('tyrosine', 'Chemical', 'None', (158, 166))	('VEGF', 'Gene', (22, 26))
201795	31921657	In patients receiving axitinib in the AXIS (Comparative effectiveness of axitinib vs. sorafenib in advanced renal cell carcinoma) trial those with VEGFA rs699947 and rs833061 polymorphisms showed longer OS (27.0 vs. 13.4 months, HR = 0.39, p = 0.015), while those positive for the VEGFR2 rs2071559 polymorphism treated with sorafenib in this trial, had longer OS (26.8 vs. 13.8 months, HR = 0.41, p = 0.030).	('VEGFA', 'Gene', (147, 152))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (108, 128))	('VEGFR2', 'Gene', (281, 287))	('rs2071559', 'DBSNP_MENTION', 'None', (288, 297))	('VEGFR2', 'Gene', '3791', (281, 287))	('axitinib', 'Chemical', 'MESH:C503983', (73, 81))	('OS', 'Gene', '17451', (203, 205))	('rs699947', 'DBSNP_MENTION', 'None', (153, 161))	('VEGFA', 'Gene', '7422', (147, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('OS', 'Gene', '17451', (360, 362))	('rs833061', 'Var', (166, 174))	('rs2071559', 'Var', (288, 297))	('sorafenib', 'Chemical', 'MESH:C471405', (86, 95))	('sorafenib', 'Chemical', 'MESH:C471405', (324, 333))	('rs833061', 'DBSNP_MENTION', 'None', (166, 174))	('patients', 'Species', '9606', (3, 11))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (108, 128))	('axitinib', 'Chemical', 'MESH:C503983', (22, 30))	('rs699947', 'Var', (153, 161))	('renal cell carcinoma', 'Disease', (108, 128))
201796	31921657	At multivariate analysis only VEGFR2 rs2071559 predicted PFS (p = 0.0053) and OS (p = 0.0027) in patients receiving sorafenib.	('rs2071559', 'Var', (37, 46))	('VEGFR2', 'Gene', (30, 36))	('rs2071559', 'DBSNP_MENTION', 'None', (37, 46))	('OS', 'Gene', '17451', (78, 80))	('VEGFR2', 'Gene', '3791', (30, 36))	('sorafenib', 'Chemical', 'MESH:C471405', (116, 125))	('PFS', 'Disease', (57, 60))	('predicted', 'Reg', (47, 56))	('patients', 'Species', '9606', (97, 105))
201797	31921657	Another study including 121 mRCC patients receiving sunitinib found the VEGFR1 SNP rs9582036 to be associated with OS.	('patients', 'Species', '9606', (33, 41))	('rs9582036', 'DBSNP_MENTION', 'None', (83, 92))	('VEGFR1', 'Gene', '2321', (72, 78))	('OS', 'Gene', '17451', (115, 117))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('VEGFR1', 'Gene', (72, 78))	('RCC', 'Disease', 'MESH:D002292', (29, 32))	('sunitinib', 'Chemical', 'MESH:C473478', (52, 61))	('rs9582036', 'Var', (83, 92))	('associated', 'Reg', (99, 109))
201798	31921657	VEGFA SNPs have been associated with axitinib efficacy, while SNPs in VEGFR3 have been associated with sunitinib efficacy.	('axitinib', 'Chemical', 'MESH:C503983', (37, 45))	('associated', 'Reg', (21, 31))	('VEGFA', 'Gene', '7422', (0, 5))	('VEGFR3', 'Gene', (70, 76))	('associated', 'Reg', (87, 97))	('axitinib', 'MPA', (37, 45))	('SNPs', 'Var', (6, 10))	('sunitinib', 'Chemical', 'MESH:C473478', (103, 112))	('SNPs', 'Var', (62, 66))	('VEGFR3', 'Gene', '2324', (70, 76))	('VEGFA', 'Gene', (0, 5))
201799	31921657	suggested that, although some VEGFR1 genetic variants, such as VEGFR1 rs9582036 and rs9554320, were involved in sunitinib therapy outcomes, their clinical use as predictive biomarkers was limited, considering the negative results of all existing studies.	('VEGFR1', 'Gene', (30, 36))	('VEGFR1', 'Gene', '2321', (63, 69))	('sunitinib', 'Chemical', 'MESH:C473478', (112, 121))	('rs9554320', 'DBSNP_MENTION', 'None', (84, 93))	('VEGFR1', 'Gene', (63, 69))	('involved', 'Reg', (100, 108))	('rs9582036', 'DBSNP_MENTION', 'None', (70, 79))	('rs9554320', 'Var', (84, 93))	('VEGFR1', 'Gene', '2321', (30, 36))	('rs9582036', 'Var', (70, 79))
201803	31921657	One study found that simultaneous assessment of miR-21-5p, 142-3p, let-7g-5p, let- 7i-5p, and 424-5p and miR-204-5p could predict stage, grade, and time to progression ccRCC.	('miR-21-5p', 'Gene', (48, 57))	('142-3p', 'Var', (59, 65))	('let- 7i-5p', 'Var', (78, 88))	('RCC', 'Disease', 'MESH:D002292', (170, 173))	('RCC', 'Disease', (170, 173))	('miR-21-5p', 'Gene', '406997', (48, 57))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('miR-204-5p', 'Var', (105, 115))	('men', 'Species', '9606', (40, 43))	('let-7g-5p', 'Var', (67, 76))	('424-5p', 'Var', (94, 100))	('predict', 'Reg', (122, 129))
201804	31921657	Upregulation of miR942, miR-133a, miR-628-5p, and miR-484 was associated with sunitinib resistance in mRCC patients.	('Upregulation', 'PosReg', (0, 12))	('sunitinib resistance', 'MPA', (78, 98))	('RCC', 'Disease', 'MESH:D002292', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('sunitinib', 'Chemical', 'MESH:C473478', (78, 87))	('associated', 'Reg', (62, 72))	('miR-484', 'Gene', (50, 57))	('miR-628-5p', 'Var', (34, 44))	('miR-484', 'Gene', '619553', (50, 57))	('miR942', 'Gene', (16, 22))	('miR942', 'Gene', '100126331', (16, 22))	('miR-133a', 'Var', (24, 32))	('patients', 'Species', '9606', (107, 115))
201825	31921657	The ccrcc1/ccrcc4 subtypes, resulted non-responders to sunitinib, and expressed common molecular characteristics like upregulation of MYC targets or a hypermethylated status associated with a less differentiated (76% of Fuhrman grade 4) phenotype.	('sunitinib', 'Chemical', 'MESH:C473478', (55, 64))	('ccrcc1/ccrcc4', 'Gene', (4, 17))	('upregulation', 'PosReg', (118, 130))	('MYC targets', 'Protein', (134, 145))	('hypermethylated', 'Var', (151, 166))	('less', 'Disease', (192, 196))
201826	31921657	PBRM1 and aberrant VHL gene were most frequently identified in ccrcc1/ccrcc2.	('identified', 'Reg', (49, 59))	('VHL', 'Gene', (19, 22))	('aberrant', 'Var', (10, 18))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('VHL', 'Gene', '7428', (19, 22))	('ccrcc1/ccrcc2', 'Disease', (63, 76))
201827	31921657	The ccrcc4 had higher inflammation score, sarcomatoid dedifferentiation, mutated BAP1, low frequency of aberrant VHL and wilde type PBRM1.	('ccrcc4', 'Gene', (4, 10))	('BAP1', 'Gene', '8314', (81, 85))	('PBRM1', 'Gene', '55193', (132, 137))	('mutated', 'Var', (73, 80))	('sarcomatoid', 'Disease', (42, 53))	('higher', 'PosReg', (15, 21))	('BAP1', 'Gene', (81, 85))	('VHL', 'Gene', (113, 116))	('dedifferentiation', 'biological_process', 'GO:0043696', ('54', '71'))	('VHL', 'Gene', '7428', (113, 116))	('inflammation', 'Disease', 'MESH:D007249', (22, 34))	('inflammation', 'biological_process', 'GO:0006954', ('22', '34'))	('inflammation', 'Disease', (22, 34))	('PBRM1', 'Gene', (132, 137))
201832	31921657	Angiogenesis expression signatures correlate with outcomes on VEGFRi treatments: high Angioscore correlates with good outcomes, generally associated with loss of PBRM1, conversely BAP1 loss associates with decreased angiogenic signaling and poor outcomes.	('Angiogenesis', 'biological_process', 'GO:0001525', ('0', '12'))	('VEGFR', 'Gene', '3791', (62, 67))	('signaling', 'biological_process', 'GO:0023052', ('227', '236'))	('BAP1', 'Gene', '8314', (180, 184))	('decreased', 'NegReg', (206, 215))	('angiogenic signaling', 'MPA', (216, 236))	('PBRM1', 'Gene', (162, 167))	('men', 'Species', '9606', (74, 77))	('BAP1', 'Gene', (180, 184))	('Angioscore', 'MPA', (86, 96))	('VEGFR', 'Gene', (62, 67))	('loss', 'NegReg', (185, 189))	('PBRM1', 'Gene', '55193', (162, 167))	('loss', 'Var', (154, 158))
201837	31921657	The expression of the immune checkpoint molecule programmed death-ligand 1 (PD-L1) on tumor cells and/or tumor-infiltrating immune cells (IC) has been reported to inhibit antitumor immunity and correlated with poor prognosis in mccRCC.	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('ligand', 'molecular_function', 'GO:0005488', ('66', '72'))	('death', 'Disease', 'MESH:D003643', (60, 65))	('expression', 'Var', (4, 14))	('tumor', 'Disease', (105, 110))	('inhibit', 'NegReg', (163, 170))	('tumor', 'Disease', (175, 180))	('RCC', 'Disease', (231, 234))	('RCC', 'Phenotype', 'HP:0005584', (231, 234))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('PD-L1', 'Gene', (76, 81))	('death', 'Disease', (60, 65))	('tumor', 'Disease', (86, 91))	('PD-L1', 'Gene', '29126', (76, 81))	('RCC', 'Disease', 'MESH:D002292', (231, 234))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('correlated with', 'Reg', (194, 209))
201845	31921657	VEGFRi (Sunitinib) efficacy was higher in angiogenic tumors (AngioHigh), while the combination of atezolizumab + bevacizumab showed a larger clinical benefit in TeffHigh and in TeffHighMyeloidLow, particularly in TeffHighMyeloidHigh in which atezolizumab monotherapy failed, supporting the role of VEGFRi to overcome innate inflammation-mediated resistance.	('VEGFR', 'Gene', '3791', (0, 5))	('VEGFR', 'Gene', '3791', (298, 303))	('inflammation', 'Disease', 'MESH:D007249', (324, 336))	('higher', 'PosReg', (32, 38))	('inflammation', 'biological_process', 'GO:0006954', ('324', '336'))	('TeffHighMyeloidLow', 'Disease', (177, 195))	('inflammation', 'Disease', (324, 336))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('TeffHigh', 'Disease', (161, 169))	('TeffHighMyeloidHigh', 'Var', (213, 232))	('Sunitinib', 'Chemical', 'MESH:C473478', (8, 17))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('VEGFR', 'Gene', (298, 303))	('VEGFR', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('TeffHighMyeloidLow', 'Disease', 'None', (177, 195))	('tumors', 'Disease', (53, 59))
201857	31921657	Patients enrolled in the AXIS trial who reported a diastolic blood pressure >=90 mmHg within the first 8 or 12 weeks of randomization had a longer survival independently on the treatment arm: 20.7 months (95% CI 18.4-24.6) vs. 12.9 months (95% CI 10.1-20.4) in the axitinib group (p = 0.01), and 20.2 months (95% CI 17.1-32.0) vs. 14.8 months (95% CI 12.0-17.7) in the sorafenib group (p = 0.002).	('longer', 'PosReg', (140, 146))	('>=90', 'Var', (76, 80))	('diastolic blood pressure', 'MPA', (51, 75))	('axitinib', 'Chemical', 'MESH:C503983', (265, 273))	('sorafenib', 'Chemical', 'MESH:C471405', (369, 378))	('Patients', 'Species', '9606', (0, 8))	('survival', 'MPA', (147, 155))	('men', 'Species', '9606', (182, 185))
201878	31921657	The angiogenesis plays a central role in the ccRCC tumorigenesis and progression, regulating the immune landscape through abnormal tumor vessel formation, dysregulation of various immune cells and promoting an immunosuppressive tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Disease', (131, 136))	('RCC', 'Disease', 'MESH:D002292', (47, 50))	('promoting', 'PosReg', (197, 206))	('dysregulation', 'Var', (155, 168))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('formation', 'biological_process', 'GO:0009058', ('144', '153'))	('tumor', 'Disease', (51, 56))	('men', 'Species', '9606', (246, 249))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('immune', 'MPA', (97, 103))	('angiogenesis', 'biological_process', 'GO:0001525', ('4', '16'))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('regulating', 'Reg', (82, 92))	('abnormal tumor', 'Phenotype', 'HP:0002664', (122, 136))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('tumor', 'Disease', (228, 233))
201880	31921657	Different phase 3 trials evaluated or are evaluating combination of immune checkpoint inhibitors, such as anti PD-1 nivolumab and anti CTLA-4 ipilimumab, or anti PD-1/PDL-1 and VEGF/VEGFRi in first-line treatment, with superb results that will consequently change the therapeutic sequence in the first and second-line.	('VEGF', 'Gene', '7422', (177, 181))	('anti', 'Var', (157, 161))	('CTLA-4', 'Gene', (135, 141))	('VEGFR', 'Gene', '3791', (182, 187))	('PDL-1', 'Gene', (167, 172))	('VEGF', 'Gene', (177, 181))	('VEGF', 'Gene', '7422', (182, 186))	('men', 'Species', '9606', (208, 211))	('change', 'Reg', (257, 263))	('PD-1', 'Gene', (111, 115))	('PD-1', 'Gene', (162, 166))	('PD-1', 'Gene', '5133', (111, 115))	('PD-1', 'Gene', '5133', (162, 166))	('VEGFR', 'Gene', (182, 187))	('CTLA-4', 'Gene', '1493', (135, 141))	('VEGF', 'Gene', (182, 186))	('PDL-1', 'Gene', '29126', (167, 172))
201895	31921657	Furthermore, in the AXIS trial, the following factors were found to be associated with shorter OS: prior treatment with sunitinib, ECOG performance status >= 1, <1 year from initial diagnosis to the first treatment, more than one metastatic site, particularly liver or bone metastases, anemia, neutrophilia, hypercalcemia or high level of LDH and alkaline phosphatase.	('neutrophilia', 'Disease', (294, 306))	('men', 'Species', '9606', (210, 213))	('hypercalcemia', 'Disease', 'MESH:D006934', (308, 321))	('sunitinib', 'Chemical', 'MESH:C473478', (120, 129))	('men', 'Species', '9606', (110, 113))	('liver', 'Disease', (260, 265))	('neutrophilia', 'Disease', 'MESH:C563010', (294, 306))	('anemia', 'Phenotype', 'HP:0001903', (286, 292))	('metastases', 'Disease', (274, 284))	('phosphatase', 'molecular_function', 'GO:0016791', ('356', '367'))	('>= 1', 'Var', (155, 159))	('metastases', 'Disease', 'MESH:D009362', (274, 284))	('OS', 'Gene', '17451', (95, 97))	('hypercalcemia', 'Phenotype', 'HP:0003072', (308, 321))	('neutrophilia', 'Phenotype', 'HP:0011897', (294, 306))	('anemia', 'Disease', 'MESH:D000740', (286, 292))	('hypercalcemia', 'Disease', (308, 321))	('anemia', 'Disease', (286, 292))
201923	31221219	Here, we investigated whether alterations in macrophage expression of the transcriptional regulator for myeloid commitment and function, interferon regulatory factor-8 (IRF8), could predict survival of clear cell renal cell carcinoma patients.	('IRF8', 'Gene', (169, 173))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (202, 233))	('interferon regulatory factor-8', 'Gene', (137, 167))	('IRF8', 'Gene', '3394', (169, 173))	('alterations', 'Var', (30, 41))	('patients', 'Species', '9606', (234, 242))	('interferon regulatory factor-8', 'Gene', '3394', (137, 167))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (202, 233))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (213, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('predict', 'Reg', (182, 189))	('clear cell renal cell carcinoma', 'Disease', (202, 233))
201927	31221219	Patients with high levels of IRF8 expression within metastatic sites had prolonged overall survival (log-rank P < 0.01, HR = 0.44, 95% C.I.	('overall survival', 'MPA', (83, 99))	('high levels', 'Var', (14, 25))	('IRF8', 'Gene', (29, 33))	('prolonged', 'PosReg', (73, 82))	('IRF8', 'Gene', '3394', (29, 33))	('Patients', 'Species', '9606', (0, 8))
201943	31221219	Expression of IRF8 in the human myeloid compartment is essential for the development of adaptive immunity, whereby patients with mutations in IRF8 harbor significant deficiencies in circulating monocytes or dendritic cells.	('IRF8', 'Gene', '3394', (14, 18))	('IRF8', 'Gene', (142, 146))	('patients', 'Species', '9606', (115, 123))	('IRF8', 'Gene', '3394', (142, 146))	('mutations', 'Var', (129, 138))	('deficiencies', 'NegReg', (166, 178))	('IRF8', 'Gene', (14, 18))	('human', 'Species', '9606', (26, 31))
201978	31221219	Based on availability of outcome data, we evaluated disease-free and overall survival and found that patients with high levels of IRF8 expression had longer disease-free survival than those with low IRF8 expression (Fig.	('patients', 'Species', '9606', (101, 109))	('longer', 'PosReg', (150, 156))	('IRF8', 'Gene', '3394', (199, 203))	('disease-free survival', 'CPA', (157, 178))	('high levels', 'Var', (115, 126))	('IRF8', 'Gene', (130, 134))	('IRF8', 'Gene', '3394', (130, 134))	('IRF8', 'Gene', (199, 203))
201981	31221219	Although no difference in overall survival was observed based on TAM infiltration (Additional file 1: Figure S1B), we found that patients with low levels of TAMs had prolonged disease-free survival (Fig.	('TAM', 'Gene', (157, 160))	('TAMs', 'Chemical', '-', (157, 161))	('TAM', 'Gene', (65, 68))	('patients', 'Species', '9606', (129, 137))	('TAM', 'Gene', '8205', (157, 160))	('low', 'Var', (143, 146))	('disease-free survival', 'CPA', (176, 197))	('prolonged', 'PosReg', (166, 175))	('TAM', 'Gene', '8205', (65, 68))
201994	31221219	Comparisons of IRF8 scores with survival data showed a trend towards improved progression-free survival with high levels of IRF8 expression that did not reach significance (P = 0.0596, Fig.	('improved', 'PosReg', (69, 77))	('expression', 'MPA', (129, 139))	('IRF8', 'Gene', '3394', (124, 128))	('IRF8', 'Gene', (15, 19))	('IRF8', 'Gene', '3394', (15, 19))	('high levels', 'Var', (109, 120))	('progression-free survival', 'CPA', (78, 103))	('IRF8', 'Gene', (124, 128))
202002	31221219	Analysis of IRF8 expression by CD68+ TAMs within metastatic ccRCC samples showed prolonged progression-free survival of patients with high expression of IRF8 (Fig.	('CD68', 'Gene', (31, 35))	('prolonged', 'PosReg', (81, 90))	('IRF8', 'Gene', (153, 157))	('high expression', 'Var', (134, 149))	('IRF8', 'Gene', (12, 16))	('CD68', 'Gene', '968', (31, 35))	('IRF8', 'Gene', '3394', (153, 157))	('patients', 'Species', '9606', (120, 128))	('IRF8', 'Gene', '3394', (12, 16))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('progression-free survival', 'CPA', (91, 116))	('TAMs', 'Chemical', '-', (37, 41))
202003	31221219	Patients with high levels of IRF8 by TAMs within metastatic lesions had an overall survival advantage of more than 80 months (P < 0.01, Fig.	('IRF8', 'Gene', (29, 33))	('IRF8', 'Gene', '3394', (29, 33))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('TAMs', 'Chemical', '-', (37, 41))
202005	31221219	However, when patients were further stratified according to the frequency of CD68+ TAMs and IRF8 expression, patients with low levels of TAMs and high IRF8 expression had a significantly improved survival outcome compared to those who had low levels of TAMs and low IRF8 expression (median overall survival of 143 month to 21 months, respectively, Fig.	('IRF8', 'Gene', '3394', (151, 155))	('IRF8', 'Gene', (266, 270))	('survival', 'CPA', (196, 204))	('patients', 'Species', '9606', (109, 117))	('TAMs', 'Chemical', '-', (83, 87))	('low', 'NegReg', (123, 126))	('improved', 'PosReg', (187, 195))	('IRF8', 'Gene', (92, 96))	('IRF8', 'Gene', '3394', (266, 270))	('CD68', 'Gene', (77, 81))	('IRF8', 'Gene', '3394', (92, 96))	('IRF8', 'Gene', (151, 155))	('high', 'Var', (146, 150))	('CD68', 'Gene', '968', (77, 81))	('TAMs', 'Chemical', '-', (253, 257))	('TAMs', 'Chemical', '-', (137, 141))	('patients', 'Species', '9606', (14, 22))
202006	31221219	Metastatic tissues containing low levels of TAMs and IRF8 expression were also correlated with lower levels of CD3+ T cells (Additional file 1: Figure S5A-B).	('lower', 'NegReg', (95, 100))	('IRF8', 'Gene', (53, 57))	('expression', 'Var', (58, 68))	('levels of CD3+ T cells', 'MPA', (101, 123))	('IRF8', 'Gene', '3394', (53, 57))	('TAMs', 'Chemical', '-', (44, 48))
202024	31221219	Research reported here was supported by R01CA172105 from the National Cancer Institute/NIH (to SIA) and the National Center for Advancing Translational Sciences of the NIH under award number UL1TR001412 to the University at Buffalo.	('SIA', 'Disease', (95, 98))	('R01CA172105', 'Var', (40, 51))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('SIA', 'Disease', 'None', (95, 98))	('Cancer', 'Disease', (70, 76))	('Cancer', 'Disease', 'MESH:D009369', (70, 76))
202032	30705246	Hypoxia enhanced HAF:neurofibromin binding independently of HAF-SUMOylation, whereas HAF knockdown increased neurofibromin levels primarily in hypoxia, supporting the role of HAF as a hypoxia-specific neurofibromin regulator.	('HAF', 'Gene', (60, 63))	('HAF', 'Gene', '2161', (85, 88))	('enhanced', 'PosReg', (8, 16))	('SUMOylation', 'biological_process', 'GO:0016925', ('64', '75'))	('neurofibromin', 'Gene', '4763', (109, 122))	('neurofibromin', 'Gene', '4763', (21, 34))	('hypoxia', 'Disease', (184, 191))	('neurofibromin', 'Gene', '4763', (201, 214))	('binding', 'Interaction', (35, 42))	('HAF', 'Gene', '2161', (60, 63))	('hypoxia', 'Disease', (143, 150))	('HAF', 'Gene', (17, 20))	('increased', 'PosReg', (99, 108))	('hypoxia', 'Disease', 'MESH:D000860', (184, 191))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('Hypoxia', 'Disease', (0, 7))	('hypoxia', 'Disease', 'MESH:D000860', (143, 150))	('HAF', 'Gene', (175, 178))	('binding', 'molecular_function', 'GO:0005488', ('35', '42'))	('knockdown', 'Var', (89, 98))	('HAF', 'Gene', '2161', (17, 20))	('neurofibromin', 'Gene', (109, 122))	('increased neurofibromin', 'Phenotype', 'HP:0001067', (99, 122))	('neurofibromin', 'Gene', (21, 34))	('neurofibromin', 'Gene', (201, 214))	('HAF', 'Gene', (85, 88))	('HAF', 'Gene', '2161', (175, 178))
202033	30705246	HAF overexpression increased p-ERK levels and promoted resistance of clear cell kidney cancer (CCRCC) cells to sorafenib and sunitinib in both normoxia and hypoxia.	('resistance', 'MPA', (55, 65))	('clear cell kidney cancer', 'Disease', (69, 93))	('promoted', 'PosReg', (46, 54))	('overexpression', 'Var', (4, 18))	('sunitinib', 'Chemical', 'MESH:D000077210', (125, 134))	('sorafenib', 'Chemical', 'MESH:D000077157', (111, 120))	('p-ERK', 'Gene', '9451', (29, 34))	('normoxia and hypoxia', 'Disease', 'MESH:D000860', (143, 163))	('p-ERK', 'Gene', (29, 34))	('clear cell kidney cancer', 'Phenotype', 'HP:0006770', (69, 93))	('increased', 'PosReg', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('kidney cancer', 'Phenotype', 'HP:0009726', (80, 93))	('ERK', 'molecular_function', 'GO:0004707', ('31', '34'))	('HAF', 'Gene', '2161', (0, 3))	('HAF', 'Gene', (0, 3))	('clear cell kidney cancer', 'Disease', 'MESH:D007680', (69, 93))
202039	30705246	Neurofibromin is the protein product of the gene NF1, whose loss-of-function mutation(s) results in one of the most common inherited tumor predisposition syndromes - Neurofibromatosis Type 1 (NF1).	('inherited tumor', 'Disease', 'None', (123, 138))	('inherited tumor', 'Disease', (123, 138))	('mutation', 'Var', (77, 85))	('Neurofibromatosis Type 1', 'Gene', '4763', (166, 190))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('NF1', 'Gene', (192, 195))	('Neurofibromin', 'Gene', '4763', (0, 13))	('Neurofibromin', 'Gene', (0, 13))	('NF1', 'Gene', '4763', (192, 195))	('NF1', 'Gene', (49, 52))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (166, 183))	('loss-of-function', 'NegReg', (60, 76))	('Neurofibromatosis Type 1', 'Gene', (166, 190))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('NF1', 'Gene', '4763', (49, 52))
202044	30705246	Indeed, the best understood function of neurofibromin is in promoting the hydrolysis of active Ras-GTP to inactive Ras-GDP as the NF1 GRD is able to complement yeast IRA (inhibitory regulators of the Ras-cAMP pathway) mutants.	('yeast', 'Species', '4932', (160, 165))	('cAMP', 'Chemical', '-', (204, 208))	('neurofibromin', 'Gene', (40, 53))	('Ras-GDP', 'Chemical', '-', (115, 122))	('Ras', 'Chemical', 'MESH:D011883', (115, 118))	('Ras-GTP', 'Chemical', '-', (95, 102))	('NF1', 'Gene', (130, 133))	('Ras', 'Chemical', 'MESH:D011883', (200, 203))	('Ras', 'Chemical', 'MESH:D011883', (95, 98))	('neurofibromin', 'Gene', '4763', (40, 53))	('mutants', 'Var', (218, 225))	('NF1', 'Gene', '4763', (130, 133))	('hydrolysis', 'MPA', (74, 84))	('promoting', 'PosReg', (60, 69))
202045	30705246	The Ras-GAP function of neurofibromin is enhanced by protein kinase C (PKC) phosphorylation within the cysteine-serine rich domain (CSRD) within exons 11-17, which also harbors clusters of missense mutations among NF1 patients.	('cysteine', 'Chemical', 'MESH:D003545', (103, 111))	('Ras', 'Chemical', 'MESH:D011883', (4, 7))	('neurofibromin', 'Gene', (24, 37))	('patients', 'Species', '9606', (218, 226))	('phosphorylation', 'biological_process', 'GO:0016310', ('76', '91'))	('enhanced', 'PosReg', (41, 49))	('missense mutations', 'Var', (189, 207))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('NF1', 'Gene', '4763', (214, 217))	('NF1', 'Gene', (214, 217))	('Ras-GAP function', 'MPA', (4, 20))	('phosphorylation', 'MPA', (76, 91))	('PKC', 'molecular_function', 'GO:0004697', ('71', '74'))	('serine', 'Chemical', 'MESH:D012694', (112, 118))	('neurofibromin', 'Gene', '4763', (24, 37))
202048	30705246	Reduction or loss of neurofibromin in NF1 disorder primarily leads to activation of the Ras pathway, resulting in the activation of a cascade of downstream signaling pathways, including the Ras-Raf-MEK-ERK (Ras-ERK), and PI3K-Akt-mTOR (PI3K-mTOR) pathways, which are commonly activated in cancer.	('Raf', 'Gene', (194, 197))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('ERK', 'Gene', (211, 214))	('Ras', 'Chemical', 'MESH:D011883', (190, 193))	('loss', 'Var', (13, 17))	('MEK', 'Gene', (198, 201))	('ERK', 'Gene', (202, 205))	('neurofibromin', 'Gene', '4763', (21, 34))	('NF1', 'Gene', '4763', (38, 41))	('mTOR', 'Gene', (241, 245))	('Ras pathway', 'Pathway', (88, 99))	('ERK', 'Gene', '2048', (211, 214))	('PI3K', 'molecular_function', 'GO:0016303', ('236', '240'))	('Raf', 'Gene', '22882', (194, 197))	('ERK', 'molecular_function', 'GO:0004707', ('202', '205'))	('ERK', 'Gene', '2048', (202, 205))	('ERK', 'molecular_function', 'GO:0004707', ('211', '214'))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('NF1', 'Gene', (38, 41))	('mTOR', 'Gene', (230, 234))	('cascade of', 'MPA', (134, 144))	('Akt', 'Gene', (226, 229))	('mTOR', 'Gene', '2475', (241, 245))	('Akt', 'Gene', '207', (226, 229))	('activation', 'PosReg', (70, 80))	('mTOR', 'Gene', '2475', (230, 234))	('PI3K', 'molecular_function', 'GO:0016303', ('221', '225'))	('activation', 'PosReg', (118, 128))	('cancer', 'Disease', (289, 295))	('neurofibromin', 'Gene', (21, 34))	('Ras', 'Chemical', 'MESH:D011883', (207, 210))	('Ras', 'Chemical', 'MESH:D011883', (88, 91))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))	('MEK', 'Gene', '5609', (198, 201))
202049	30705246	In addition to genetically inherited NF1 disorder, somatic mutations in NF1 have been identified in a variety of neoplasms, particularly in glioblastoma and melanoma, where they play critical roles in tumor initiation and progression, and in the acquisition of drug resistance.	('NF1', 'Gene', '4763', (72, 75))	('glioblastoma', 'Disease', 'MESH:D005909', (140, 152))	('neoplasms', 'Disease', (113, 122))	('NF1', 'Gene', (72, 75))	('tumor initiation', 'Disease', 'MESH:D009369', (201, 217))	('glioblastoma', 'Disease', (140, 152))	('NF1', 'Gene', '4763', (37, 40))	('tumor initiation', 'Disease', (201, 217))	('roles', 'Reg', (192, 197))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('glioblastoma', 'Phenotype', 'HP:0012174', (140, 152))	('inherited NF1 disorder', 'Disease', 'MESH:C537392', (27, 49))	('identified', 'Reg', (86, 96))	('NF1', 'Gene', (37, 40))	('neoplasms', 'Phenotype', 'HP:0002664', (113, 122))	('mutations', 'Var', (59, 68))	('drug resistance', 'biological_process', 'GO:0009315', ('261', '276'))	('drug resistance', 'biological_process', 'GO:0042493', ('261', '276'))	('drug resistance', 'Phenotype', 'HP:0020174', (261, 276))	('inherited NF1 disorder', 'Disease', (27, 49))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('play', 'Reg', (178, 182))	('neoplasms', 'Disease', 'MESH:D009369', (113, 122))
202054	30705246	In hypoxia, or in the presence of pVHL mutations, HIF-1/2alpha is stabilized and form active transcriptional complexes with HIF-1beta.	('HIF-1', 'Gene', '3091', (124, 129))	('pVHL', 'Gene', '7428', (34, 38))	('HIF-1beta', 'Gene', '3091', (124, 133))	('pVHL', 'Gene', (34, 38))	('HIF-1', 'Gene', (124, 129))	('active', 'MPA', (86, 92))	('hypoxia', 'Disease', (3, 10))	('mutations', 'Var', (39, 48))	('HIF-1', 'Gene', '3091', (50, 55))	('hypoxia', 'Disease', 'MESH:D000860', (3, 10))	('HIF-1beta', 'Gene', (124, 133))	('HIF-1', 'Gene', (50, 55))
202055	30705246	pVHL loss-of-function mutations are a frequent initiating event in clear cell renal cell carcinoma (CCRCC), which drives constitutive HIF activation associated CCRCC progression.	('pVHL', 'Gene', '7428', (0, 4))	('pVHL', 'Gene', (0, 4))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (67, 98))	('clear cell renal cell carcinoma', 'Disease', (67, 98))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (78, 98))	('mutations', 'Var', (22, 31))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (67, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('loss-of-function', 'NegReg', (5, 21))
202064	30705246	Sorafenib tosylate was purchased from Astatech Inc. (Bristol, PA), MG132 was from Sigma-Aldrich (St Louis, MO) and SCH772984 was from Selleckchem (Houston, TX).	('SCH772984', 'Var', (115, 124))	('Sorafenib tosylate', 'Chemical', 'MESH:D000077157', (0, 18))	('MG132', 'Var', (67, 72))	('SCH772984', 'Chemical', 'MESH:C587178', (115, 124))	('MG132', 'Chemical', 'MESH:C072553', (67, 72))
202066	30705246	Stable cells lines overexpressing HAF and HAF DM (HAF K94R K141R) were generated by retroviral infection using pMX-IRES-GFP.	('K94R', 'Mutation', 'rs1255808515', (54, 58))	('HAF', 'Gene', '2161', (50, 53))	('HAF DM', 'Disease', 'MESH:D009223', (42, 48))	('HAF', 'Gene', '2161', (42, 45))	('HAF', 'Gene', (50, 53))	('HAF DM', 'Disease', (42, 48))	('K141R', 'Mutation', 'p.K141R', (59, 64))	('HAF', 'Gene', '2161', (34, 37))	('HAF', 'Gene', (42, 45))	('HAF', 'Gene', (34, 37))	('K94R K141R', 'Var', (54, 64))
202067	30705246	786-0 cells containing homozygous loss of HIF-2alpha (EPAS1): 786-0 EPAS1-/- #4, EPAS1 -/- #11, and control (Nic Con) clones were generated using plasmids targeting different regions within exon 2 (sc400647-NIC, sc400647-NIC-2, or control double nickase plasmid sc-437281 respectively, from Santa Cruz Biotechnology (Dallas, TX).	('EPAS1', 'Gene', (81, 86))	('EPAS1', 'Gene', (54, 59))	('EPAS1', 'Gene', '2034', (68, 73))	('HIF-2alpha', 'Gene', '2034', (42, 52))	('sc400647-NIC-2', 'Var', (212, 226))	('sc400647-NIC', 'Var', (198, 210))	('EPAS1', 'Gene', (68, 73))	('HIF-2alpha', 'Gene', (42, 52))	('EPAS1', 'Gene', '2034', (81, 86))	('EPAS1', 'Gene', '2034', (54, 59))
202087	30705246	Hypoxic exposure resulted in marked decreases in neurofibromin and increases in ERK phosphorylation (p-ERK) in ACHN (pVHL wild-type renal cancer cells), MIAPaCa-2 (pancreatic cancer cells with mutant KRas), HEK293 (human embryonic kidney cells), U87 (glioblastoma cells expressing wild-type NF1) and RCC4 (pVHL mutant renal cancer cells).	('renal cancer', 'Disease', 'MESH:D007680', (318, 330))	('glioblastoma', 'Disease', (251, 263))	('renal cancer', 'Disease', (132, 144))	('RCC4', 'Gene', '84925', (300, 304))	('ERK', 'Gene', '2048', (80, 83))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mutant', 'Var', (193, 199))	('U87', 'CellLine', 'CVCL:0022', (246, 249))	('glioblastoma', 'Phenotype', 'HP:0012174', (251, 263))	('increases', 'PosReg', (67, 76))	('renal cancer', 'Phenotype', 'HP:0009726', (132, 144))	('HEK293', 'CellLine', 'CVCL:0045', (207, 213))	('KRas', 'Gene', '3845', (200, 204))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('pVHL', 'Gene', '7428', (117, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (164, 181))	('pVHL', 'Gene', (117, 121))	('NF1', 'Gene', '4763', (291, 294))	('neurofibromin', 'Gene', (49, 62))	('renal cancer', 'Disease', 'MESH:D007680', (132, 144))	('decreases', 'NegReg', (36, 45))	('human', 'Species', '9606', (215, 220))	('ERK', 'molecular_function', 'GO:0004707', ('80', '83'))	('ACHN', 'Gene', (111, 115))	('pancreatic cancer', 'Disease', (164, 181))	('p-ERK', 'Gene', '9451', (101, 106))	('NF1', 'Gene', (291, 294))	('pVHL', 'Gene', '7428', (306, 310))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('p-ERK', 'Gene', (101, 106))	('pVHL', 'Gene', (306, 310))	('renal cancer', 'Disease', (318, 330))	('renal cancer', 'Phenotype', 'HP:0009726', (318, 330))	('neurofibromin', 'Gene', '4763', (49, 62))	('ERK', 'Gene', (103, 106))	('MIAPaCa-2', 'CellLine', 'CVCL:0428', (153, 162))	('ERK', 'molecular_function', 'GO:0004707', ('103', '106'))	('ERK', 'Gene', (80, 83))	('glioblastoma', 'Disease', 'MESH:D005909', (251, 263))	('RCC4', 'Gene', (300, 304))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (164, 181))	('ACHN', 'Gene', '55323', (111, 115))	('KRas', 'Gene', (200, 204))	('ERK', 'Gene', '2048', (103, 106))
202088	30705246	LN229 cells that harbor a total NF1 gene deletion showed an attenuated induction of P-ERK in hypoxia, which may be due to hypoxia-dependent activation of the SDF-1-CXCR7 pathway, previously reported in this cell line (Fig.	('NF1', 'Gene', (32, 35))	('induction', 'MPA', (71, 80))	('CXCR7', 'molecular_function', 'GO:0038147', ('164', '169'))	('hypoxia', 'Disease', (122, 129))	('CXCR7', 'Gene', (164, 169))	('LN229', 'CellLine', 'CVCL:0393', (0, 5))	('CXCR7', 'Gene', '57007', (164, 169))	('hypoxia', 'Disease', 'MESH:D000860', (122, 129))	('SDF-1', 'Gene', '6387', (158, 163))	('SDF-1', 'Gene', (158, 163))	('P-ERK', 'Gene', (84, 89))	('hypoxia', 'Disease', (93, 100))	('ERK', 'molecular_function', 'GO:0004707', ('86', '89'))	('NF1', 'Gene', '4763', (32, 35))	('activation', 'PosReg', (140, 150))	('deletion', 'Var', (41, 49))	('hypoxia', 'Disease', 'MESH:D000860', (93, 100))	('attenuated', 'NegReg', (60, 70))	('P-ERK', 'Gene', '9451', (84, 89))
202091	30705246	Pre-treatment with the proteasome inhibitor, MG132 attenuated the hypoxia-induced decrease in neurofibromin in pVHL wild-type HEK293 and ACHN cells, and in pVHL mutant RCC4 cells, suggesting that the hypoxia-induced decrease in neurofibromin was proteasomal-dependent and pVHL-independent (Fig.	('pVHL', 'Gene', '7428', (111, 115))	('attenuated', 'NegReg', (51, 61))	('neurofibromin', 'Gene', '4763', (94, 107))	('neurofibromin', 'Gene', '4763', (228, 241))	('pVHL', 'Gene', (111, 115))	('ACHN', 'Gene', (137, 141))	('hypoxia', 'Disease', 'MESH:D000860', (66, 73))	('hypoxia', 'Disease', (200, 207))	('mutant', 'Var', (161, 167))	('HEK293', 'CellLine', 'CVCL:0045', (126, 132))	('MG132', 'Chemical', 'MESH:C072553', (45, 50))	('pVHL', 'Gene', '7428', (156, 160))	('pVHL', 'Gene', (156, 160))	('proteasome', 'molecular_function', 'GO:0004299', ('23', '33'))	('hypoxia', 'Disease', 'MESH:D000860', (200, 207))	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('RCC4', 'Gene', (168, 172))	('ACHN', 'Gene', '55323', (137, 141))	('decrease', 'NegReg', (216, 224))	('proteasome', 'cellular_component', 'GO:0000502', ('23', '33'))	('neurofibromin', 'Gene', (228, 241))	('neurofibromin', 'Gene', (94, 107))	('pVHL', 'Gene', '7428', (272, 276))	('pVHL', 'Gene', (272, 276))	('RCC4', 'Gene', '84925', (168, 172))	('hypoxia', 'Disease', (66, 73))
202092	30705246	The effects of MG132 on p-ERK levels were difficult to ascertain as MG132 also systemically perturbs the intracellular phosphoproteome, potentially impacting ERK signaling at multiple levels.	('signaling', 'biological_process', 'GO:0023052', ('162', '171'))	('MG132', 'Var', (68, 73))	('p-ERK', 'Gene', (24, 29))	('perturbs', 'Reg', (92, 100))	('MG132', 'Chemical', 'MESH:C072553', (68, 73))	('ERK', 'molecular_function', 'GO:0004707', ('26', '29'))	('ERK', 'Gene', (26, 29))	('ERK', 'Gene', '2048', (26, 29))	('ERK', 'Gene', '2048', (158, 161))	('intracellular', 'cellular_component', 'GO:0005622', ('105', '118'))	('impacting', 'Reg', (148, 157))	('ERK', 'Gene', (158, 161))	('MG132', 'Chemical', 'MESH:C072553', (15, 20))	('p-ERK', 'Gene', '9451', (24, 29))	('ERK', 'molecular_function', 'GO:0004707', ('158', '161'))	('intracellular phosphoproteome', 'MPA', (105, 134))
202096	30705246	We evaluated HAF and the HAF SUMOylation deficient mutant HAF K94R K141R (HAF double mutant, DM), which is deficient in HIF-2alpha binding and activation while retaining HIF-1alpha E3 ligase activity.	('activation', 'MPA', (143, 153))	('K141R', 'Mutation', 'p.K141R', (67, 72))	('HAF', 'Gene', '2161', (13, 16))	('activity', 'MPA', (191, 199))	('HIF-2alpha', 'Gene', '2034', (120, 130))	('HAF', 'Gene', (58, 61))	('HIF-1alpha', 'Gene', '3091', (170, 180))	('K94R K141R', 'Var', (62, 72))	('HAF', 'Gene', (74, 77))	('SUMOylation', 'biological_process', 'GO:0016925', ('29', '40'))	('binding', 'Interaction', (131, 138))	('HAF', 'Gene', '2161', (58, 61))	('HAF', 'Gene', (25, 28))	('HAF SUMOylation deficient', 'Disease', 'MESH:D005175', (25, 50))	('HAF SUMOylation deficient', 'Disease', (25, 50))	('HAF', 'Gene', '2161', (74, 77))	('HIF-2alpha', 'Gene', (120, 130))	('HIF-1alpha', 'Gene', (170, 180))	('HAF', 'Gene', '2161', (25, 28))	('DM', 'Disease', 'MESH:D009223', (93, 95))	('ligase activity', 'molecular_function', 'GO:0016874', ('184', '199'))	('HAF', 'Gene', (13, 16))	('binding', 'molecular_function', 'GO:0005488', ('131', '138'))	('K94R', 'Mutation', 'rs1255808515', (62, 66))
202100	30705246	Consistent with a proteasomal-dependent mechanism of degradation, neurofibromin loss was reversible by treatment with MG132 (Fig.	('neurofibromin', 'Gene', '4763', (66, 79))	('loss', 'NegReg', (80, 84))	('neurofibromin', 'Gene', (66, 79))	('MG132', 'Var', (118, 123))	('MG132', 'Chemical', 'MESH:C072553', (118, 123))	('degradation', 'biological_process', 'GO:0009056', ('53', '64'))
202101	30705246	Intriguingly, HAF knockdown using siRNA increased neurofibromin levels only in hypoxia, suggesting that endogenous HAF may function as a ubiquitin ligase for neurofibromin primarily under hypoxic conditions (Fig.	('knockdown', 'Var', (18, 27))	('HAF', 'Gene', (14, 17))	('HAF', 'Gene', '2161', (115, 118))	('neurofibromin', 'Gene', '4763', (50, 63))	('neurofibromin', 'Gene', (158, 171))	('HAF', 'Gene', (115, 118))	('increased neurofibromin', 'Phenotype', 'HP:0001067', (40, 63))	('ubiquitin', 'molecular_function', 'GO:0031386', ('137', '146'))	('increased', 'PosReg', (40, 49))	('hypoxia', 'Disease', (79, 86))	('function', 'Reg', (123, 131))	('neurofibromin', 'Gene', (50, 63))	('neurofibromin', 'Gene', '4763', (158, 171))	('hypoxia', 'Disease', 'MESH:D000860', (79, 86))	('HAF', 'Gene', '2161', (14, 17))
202102	30705246	We also observed a reduction in HAF levels in hypoxia and induction of HIF-1alpha with HAF knockdown (Fig.	('HAF', 'Gene', (87, 90))	('hypoxia', 'Disease', (46, 53))	('hypoxia', 'Disease', 'MESH:D000860', (46, 53))	('reduction', 'NegReg', (19, 28))	('induction', 'Reg', (58, 67))	('HIF-1alpha', 'Gene', '3091', (71, 81))	('HAF', 'Gene', '2161', (32, 35))	('HAF', 'Gene', (32, 35))	('knockdown', 'Var', (91, 100))	('HIF-1alpha', 'Gene', (71, 81))	('HAF', 'Gene', '2161', (87, 90))
202111	30705246	To determine the impact of HAF on neurofibromin ubiquitination, we transiently transfected HA-tagged ubiquitin into ACHN cells overexpressing HAF, then exposed cells to normoxia or hypoxia for 24 hours, with MG132 added for the last 6 hours.	('HAF', 'Gene', (142, 145))	('ACHN', 'Gene', '55323', (116, 120))	('HA-tagged', 'Var', (91, 100))	('neurofibromin', 'Gene', (34, 47))	('hypoxia', 'Disease', 'MESH:D000860', (181, 188))	('ACHN', 'Gene', (116, 120))	('hypoxia', 'Disease', (181, 188))	('HAF', 'Gene', '2161', (27, 30))	('MG132', 'Chemical', 'MESH:C072553', (208, 213))	('HAF', 'Gene', (27, 30))	('ubiquitin', 'molecular_function', 'GO:0031386', ('101', '110'))	('neurofibromin', 'Gene', '4763', (34, 47))	('HAF', 'Gene', '2161', (142, 145))
202118	30705246	By contrast, HAF knockdown increased neurofibromin half-life in normoxia from 35 hours in control cells to >48 hours with HAF siRNA transfection (Fig.	('increased', 'PosReg', (27, 36))	('HAF', 'Gene', '2161', (13, 16))	('neurofibromin', 'Gene', '4763', (37, 50))	('HAF', 'Gene', (13, 16))	('HAF', 'Gene', '2161', (122, 125))	('knockdown', 'Var', (17, 26))	('increased neurofibromin', 'Phenotype', 'HP:0001067', (27, 50))	('HAF', 'Gene', (122, 125))	('neurofibromin', 'Gene', (37, 50))
202120	30705246	Nevertheless, in the absence of cycloheximide, HAF knockdown increased neurofibromin half-life in hypoxia from 2 hours to 4 hours (Fig.	('neurofibromin', 'Gene', (71, 84))	('increased neurofibromin', 'Phenotype', 'HP:0001067', (61, 84))	('hypoxia', 'Disease', (98, 105))	('hypoxia', 'Disease', 'MESH:D000860', (98, 105))	('HAF', 'Gene', '2161', (47, 50))	('cycloheximide', 'Chemical', 'MESH:D003513', (32, 45))	('increased', 'PosReg', (61, 70))	('neurofibromin', 'Gene', '4763', (71, 84))	('HAF', 'Gene', (47, 50))	('knockdown', 'Var', (51, 60))
202121	30705246	Thus, we show that HAF overexpression increased, whereas HAF knockdown decreased, neurofibromin turnover in both normoxia and hypoxia.	('neurofibromin', 'Gene', (82, 95))	('normoxia and hypoxia', 'Disease', 'MESH:D000860', (113, 133))	('HAF', 'Gene', (19, 22))	('knockdown', 'Var', (61, 70))	('HAF', 'Gene', (57, 60))	('neurofibromin', 'Gene', '4763', (82, 95))	('HAF', 'Gene', '2161', (19, 22))	('HAF', 'Gene', '2161', (57, 60))	('decreased', 'NegReg', (71, 80))
202134	30705246	HAF overexpression was associated with increased resistance to sorafenib in both normoxia and hypoxia, independently of pVHL status (Fig.	('sorafenib', 'Chemical', 'MESH:D000077157', (63, 72))	('overexpression', 'Var', (4, 18))	('resistance to', 'MPA', (49, 62))	('normoxia and hypoxia', 'Disease', 'MESH:D000860', (81, 101))	('increased', 'PosReg', (39, 48))	('HAF', 'Gene', '2161', (0, 3))	('pVHL', 'Gene', '7428', (120, 124))	('HAF', 'Gene', (0, 3))	('pVHL', 'Gene', (120, 124))
202152	30705246	To determine whether HIF-2alpha is required for HAF-mediated p-ERK activation and/or resistance to sorafenib, we generated 786-0 cells with HIF-2alpha (EPAS1) deletion using a Crispr/Cas9 double nickase strategy.	('HAF', 'Gene', (48, 51))	('HIF-2alpha', 'Gene', '2034', (21, 31))	('p-ERK', 'Gene', (61, 66))	('ERK', 'molecular_function', 'GO:0004707', ('63', '66'))	('Cas', 'cellular_component', 'GO:0005650', ('183', '186'))	('p-ERK', 'Gene', '9451', (61, 66))	('HIF-2alpha', 'Gene', (140, 150))	('EPAS1', 'Gene', '2034', (152, 157))	('EPAS1', 'Gene', (152, 157))	('deletion', 'Var', (159, 167))	('HIF-2alpha', 'Gene', (21, 31))	('HIF-2alpha', 'Gene', '2034', (140, 150))	('sorafenib', 'Chemical', 'MESH:D000077157', (99, 108))	('HAF', 'Gene', '2161', (48, 51))
202153	30705246	Cells with deletions at two distinct sites within exon 2 of the EPAS1 gene (EPAS1#4 and EPAS1#11) were generated, verified (Fig.	('EPAS1', 'Gene', (88, 93))	('EPAS1', 'Gene', '2034', (64, 69))	('EPAS1', 'Gene', (64, 69))	('deletions', 'Var', (11, 20))	('EPAS1', 'Gene', '2034', (76, 81))	('EPAS1', 'Gene', (76, 81))	('EPAS1', 'Gene', '2034', (88, 93))
202156	30705246	We also saw increased levels of total ERK with HIF-2alpha deletion although the significance of this is unclear.	('ERK', 'molecular_function', 'GO:0004707', ('38', '41'))	('increased', 'PosReg', (12, 21))	('ERK', 'Gene', '2048', (38, 41))	('HIF-2alpha', 'Gene', (47, 57))	('levels', 'MPA', (22, 28))	('deletion', 'Var', (58, 66))	('HIF-2alpha', 'Gene', '2034', (47, 57))	('ERK', 'Gene', (38, 41))
202171	30705246	Intriguingly, patients with high SART1 transcript showed significantly decreased overall survival compared to those with low SART1 in TCGA-KIRC (p = 0.0007; Fig.	('SART1', 'Gene', '9092', (33, 38))	('SART1', 'Gene', (125, 130))	('SART1', 'Gene', (33, 38))	('overall survival', 'MPA', (81, 97))	('high', 'Var', (28, 32))	('SART1', 'Gene', '9092', (125, 130))	('patients', 'Species', '9606', (14, 22))	('decreased', 'NegReg', (71, 80))
202186	30705246	HIF-2alpha deletion abrogated HAF-mediated sorafenib resistance only in normoxia, suggesting the existence of distinct pathways of HAF-mediated sorafenib resistance (Fig.	('HAF', 'Gene', '2161', (131, 134))	('HIF-2alpha', 'Gene', '2034', (0, 10))	('HAF', 'Gene', (131, 134))	('sorafenib', 'Chemical', 'MESH:D000077157', (144, 153))	('HAF', 'Gene', (30, 33))	('HAF', 'Gene', '2161', (30, 33))	('abrogated', 'NegReg', (20, 29))	('sorafenib', 'Chemical', 'MESH:D000077157', (43, 52))	('deletion', 'Var', (11, 19))	('HIF-2alpha', 'Gene', (0, 10))
202191	30705246	Since P-S6RP is HIF-2alpha-dependent in 786-0 cells, this suggests a potential HIF-2alpha-driven pathway of sorafenib resistance via the mTOR-S6RP axis.	('HIF-2alpha', 'Gene', '2034', (79, 89))	('P-S6RP', 'Var', (6, 12))	('sorafenib', 'Chemical', 'MESH:D000077157', (108, 117))	('HIF-2alpha', 'Gene', (16, 26))	('mTOR', 'Gene', (137, 141))	('mTOR', 'Gene', '2475', (137, 141))	('HIF-2alpha', 'Gene', '2034', (16, 26))	('HIF-2alpha', 'Gene', (79, 89))
202197	29272308	Our previous work showed that loss of DIO1 enhances proliferation and migration of renal cancer cells.	('DIO1', 'Gene', '1733', (38, 42))	('proliferation', 'CPA', (52, 65))	('enhances', 'PosReg', (43, 51))	('renal cancer', 'Phenotype', 'HP:0009726', (83, 95))	('migration of renal cancer', 'Disease', (70, 95))	('migration of renal cancer', 'Disease', 'MESH:D007680', (70, 95))	('DIO1', 'Gene', (38, 42))	('loss', 'Var', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
202210	29272308	The key molecular alteration in ccRCC pathology is inactivation of VHL tumor suppressor that leads to persistent activation of hypoxia-induced transcription factors (HIFs), resulting in induction of proliferation, invasion and angiogenesis.	('tumor suppressor', 'biological_process', 'GO:0051726', ('71', '87'))	('invasion', 'CPA', (214, 222))	('VHL tumor', 'Disease', (67, 76))	('proliferation', 'CPA', (199, 212))	('angiogenesis', 'biological_process', 'GO:0001525', ('227', '239'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('71', '87'))	('inactivation', 'Var', (51, 63))	('hypoxia', 'Disease', (127, 134))	('hypoxia', 'Disease', 'MESH:D000860', (127, 134))	('VHL tumor', 'Disease', 'MESH:D006623', (67, 76))	('activation', 'PosReg', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('induction', 'Reg', (186, 195))	('transcription', 'biological_process', 'GO:0006351', ('143', '156'))	('angiogenesis', 'CPA', (227, 239))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('RCC', 'Disease', (34, 37))
202221	29272308	Considering the importance of T3 in the regulation of cellular metabolism, one can also expect, that changes in DIO1 expression could affect metabolic pathways in ccRCC tumors.	('T3', 'Chemical', '-', (30, 32))	('metabolic pathways', 'Pathway', (141, 159))	('expression', 'MPA', (117, 127))	('RCC tumors', 'Disease', 'MESH:C538614', (165, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('regulation of cellular metabolism', 'biological_process', 'GO:0031323', ('40', '73'))	('DIO1', 'Gene', (112, 116))	('affect', 'Reg', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('DIO1', 'Gene', '1733', (112, 116))	('RCC tumors', 'Disease', (165, 175))	('changes', 'Var', (101, 108))
202223	29272308	The presence of DIO1 activity in renal cancer cells introduces major changes in cellular proteome, affecting i) the key metabolic pathways that are altered in ccRCC tissues, ii) the elements of the anti-oxidative system as well as iii) expression levels of proteins that drive oncogenic transformation of renal cells.	('proteins', 'Protein', (257, 265))	('renal cancer', 'Disease', 'MESH:D007680', (33, 45))	('affecting', 'Reg', (99, 108))	('metabolic', 'Enzyme', (120, 129))	('DIO1', 'Gene', (16, 20))	('cellular proteome', 'MPA', (80, 97))	('altered', 'Reg', (148, 155))	('renal cancer', 'Phenotype', 'HP:0009726', (33, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('elements', 'MPA', (182, 190))	('renal cancer', 'Disease', (33, 45))	('RCC', 'Disease', (161, 164))	('DIO1', 'Gene', '1733', (16, 20))	('presence', 'Var', (4, 12))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('expression levels of', 'MPA', (236, 256))	('changes', 'Reg', (69, 76))	('anti-oxidative system', 'MPA', (198, 219))
202233	29272308	Both cell lysates and cell culture medium supernatants were spiked with a mixture of internal standards (for supernatants: in 5 muL DMSO, for cell lysates: in 100 muL in DMSO: methanol: water 5:45:45% v/v/v containing 0.1% formic acid) composed of isotopically-labelled 3,3-T2, T3, rT3,T4, 3-T1AM, T0Ac and T1Ac at a final concentration of 100 nM.	('rT3', 'Var', (282, 285))	('T0Ac', 'Var', (298, 302))	('methanol', 'Chemical', 'MESH:D000432', (176, 184))	('formic acid', 'Chemical', 'MESH:C030544', (223, 234))	('T3', 'Chemical', '-', (278, 280))	('3-T1AM', 'Var', (290, 296))	('T1Ac', 'Var', (307, 311))	('T3', 'Chemical', '-', (283, 285))	('water', 'Chemical', 'MESH:D014867', (186, 191))
202260	29272308	Consistently, the most prominent classes of proteins affected by DIO1 expression featured activities of hydrolases, oxidoreductases and transferases (Fig 3).	('oxidoreductases', 'Enzyme', (116, 131))	('transferases', 'Enzyme', (136, 148))	('activities', 'MPA', (90, 100))	('DIO1', 'Gene', '1733', (65, 69))	('expression', 'Var', (70, 80))	('hydrolases', 'Enzyme', (104, 114))	('DIO1', 'Gene', (65, 69))
202284	29272308	Finally, to see if the ectopic DIO1 expression influenced the levels of thyroid hormones, we measured intracellular concentrations of T4 and T3.	('DIO1', 'Gene', '1733', (31, 35))	('DIO1', 'Gene', (31, 35))	('ectopic', 'Var', (23, 30))	('influenced', 'Reg', (47, 57))	('levels of', 'MPA', (62, 71))	('T3', 'Chemical', '-', (141, 143))	('intracellular', 'cellular_component', 'GO:0005622', ('102', '115'))
202287	29272308	In our previous report we found that restoration of DIO1 expression in renal cancer cells inhibits their proliferation and migration.	('DIO1', 'Gene', '1733', (52, 56))	('expression', 'MPA', (57, 67))	('DIO1', 'Gene', (52, 56))	('renal cancer', 'Disease', 'MESH:D007680', (71, 83))	('renal cancer', 'Phenotype', 'HP:0009726', (71, 83))	('inhibits', 'NegReg', (90, 98))	('renal cancer', 'Disease', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('restoration', 'Var', (37, 48))
202290	29272308	We also demonstrate that DIO1 expression induces expression of both subunits of the thyroid hormone transporter LAT1 and increases intracellular T4 concentrations.	('induces', 'PosReg', (41, 48))	('increases', 'PosReg', (121, 130))	('expression', 'Var', (30, 40))	('expression', 'MPA', (49, 59))	('LAT1', 'Gene', '8140', (112, 116))	('intracellular T4 concentrations', 'MPA', (131, 162))	('LAT1', 'Gene', (112, 116))	('DIO1', 'Gene', (25, 29))	('intracellular', 'cellular_component', 'GO:0005622', ('131', '144'))	('DIO1', 'Gene', '1733', (25, 29))
202295	29272308	In our study, restoration of DIO1 expression resulted in moderate induction of enzymes involved in key pathways that undergo metabolic reprogramming in ccRCC tumors such as transketolase (TKT), nicotinamide phosphoribosyltransferase (NAMPT), and mitochondrial isoform of isocitrate dehydrogenase (IDH2).	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('restoration', 'Var', (14, 25))	('RCC tumors', 'Disease', 'MESH:C538614', (154, 164))	('induction', 'PosReg', (66, 75))	('nicotinamide phosphoribosyltransferase', 'Gene', (194, 232))	('TKT', 'Gene', '7086', (188, 191))	('NAMPT', 'Gene', '10135', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('TKT', 'Gene', (188, 191))	('enzymes', 'MPA', (79, 86))	('DIO1', 'Gene', (29, 33))	('transketolase', 'Gene', (173, 186))	('NAMPT', 'Gene', (234, 239))	('IDH2', 'Gene', (297, 301))	('DIO1', 'Gene', '1733', (29, 33))	('IDH2', 'Gene', '3418', (297, 301))	('transketolase', 'Gene', '7086', (173, 186))	('RCC tumors', 'Disease', (154, 164))	('nicotinamide phosphoribosyltransferase', 'Gene', '10135', (194, 232))
202297	29272308	Strikingly, and counterintuitively to the anti-tumor activity of DIO1, restoration of DIO1 expression resulted in moderate increase of TKT, NAMPT and IDH2 protein levels (Table 1).	('DIO1', 'Gene', (86, 90))	('expression', 'MPA', (91, 101))	('IDH2', 'Gene', '3418', (150, 154))	('DIO1', 'Gene', '1733', (86, 90))	('TKT', 'Gene', '7086', (135, 138))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('increase', 'PosReg', (123, 131))	('IDH2', 'Gene', (150, 154))	('restoration', 'Var', (71, 82))	('NAMPT', 'Gene', (140, 145))	('TKT', 'Gene', (135, 138))	('NAMPT', 'Gene', '10135', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('DIO1', 'Gene', '1733', (65, 69))	('DIO1', 'Gene', (65, 69))
202302	29272308	Increased levels of TKT, NAMPT, IDH2, LAT1, NDUFA3, and CYP4F11 proteins indicate that restored DIO1 expression further boosts pro-tumorous metabolic changes in ccRCC cells.	('boosts', 'PosReg', (120, 126))	('NAMPT', 'Gene', (25, 30))	('RCC', 'Disease', (163, 166))	('tumorous', 'Disease', 'MESH:D009369', (131, 139))	('NDUFA3', 'Gene', (44, 50))	('LAT1', 'Gene', '8140', (38, 42))	('LAT1', 'Gene', (38, 42))	('restored', 'Var', (87, 95))	('CYP4F11', 'Gene', (56, 63))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('tumorous', 'Disease', (131, 139))	('TKT', 'Gene', '7086', (20, 23))	('TKT', 'Gene', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('DIO1', 'Gene', (96, 100))	('NAMPT', 'Gene', '10135', (25, 30))	('CYP4F11', 'Gene', '57834', (56, 63))	('IDH2', 'Gene', (32, 36))	('NDUFA3', 'Gene', '4696', (44, 50))	('IDH2', 'Gene', '3418', (32, 36))	('expression', 'MPA', (101, 111))	('DIO1', 'Gene', '1733', (96, 100))
202314	29272308	Strikingly, induced DIO1 expression resulted also in initiation of mechanisms that can mitigate the ROS scavenging activity.	('ROS', 'Chemical', 'MESH:D017382', (100, 103))	('ROS scavenging activity', 'MPA', (100, 123))	('expression', 'Var', (25, 35))	('DIO1', 'Gene', '1733', (20, 24))	('DIO1', 'Gene', (20, 24))	('mechanisms', 'MPA', (67, 77))
202319	29272308	This data suggests that while on one hand DIO1 expression results in induction of proteins involved in antioxidative protection, on the other hand it can also potentially attenuate the activity of the key ROS-scavanger, GPx.	('activity', 'MPA', (185, 193))	('DIO1', 'Gene', '1733', (42, 46))	('induction', 'PosReg', (69, 78))	('expression', 'Var', (47, 57))	('antioxidative protection', 'MPA', (103, 127))	('ROS', 'Chemical', 'MESH:D017382', (205, 208))	('proteins', 'Protein', (82, 90))	('DIO1', 'Gene', (42, 46))	('attenuate', 'NegReg', (171, 180))
202320	29272308	The fact that restoration of DIO1 expression in ccRCC cells leads to attenuation of proliferation and migration indicates that anti-oxidative response observed in this study could be inefficient and that oxidative stress generated by DIO1-induced acceleration of pro-tumorous metabolism could exceed antioxidative capacities of ccRCC cells, initiating mechanisms leading to cell death.	('RCC', 'Disease', (330, 333))	('restoration', 'Var', (14, 25))	('DIO1', 'Gene', '1733', (29, 33))	('DIO1', 'Gene', (29, 33))	('cell death', 'biological_process', 'GO:0008219', ('374', '384'))	('oxidative stress', 'MPA', (204, 220))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('tumorous', 'Disease', 'MESH:D009369', (267, 275))	('oxidative stress', 'Phenotype', 'HP:0025464', (204, 220))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumorous', 'Disease', (267, 275))	('metabolism', 'biological_process', 'GO:0008152', ('276', '286'))	('attenuation', 'NegReg', (69, 80))	('DIO1', 'Gene', '1733', (234, 238))	('acceleration', 'PosReg', (247, 259))	('DIO1', 'Gene', (234, 238))	('RCC', 'Disease', 'MESH:C538614', (330, 333))
202328	29272308	Inhibition of TGM2 activity attenuates growth of RCC xenografts in mice.	('RCC', 'Disease', (49, 52))	('attenuates', 'NegReg', (28, 38))	('activity', 'MPA', (19, 27))	('TGM2', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('mice', 'Species', '10090', (67, 71))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
202330	29272308	These results raise an interesting hypothesis that DIO1 expression may interfere with autophagy mechanisms by local provision of T3 known to be involved in regulation of autophagy either directly or via acting as ligand for the T3 receptor.	('ligand', 'molecular_function', 'GO:0005488', ('213', '219'))	('interfere', 'NegReg', (71, 80))	('T3', 'Chemical', '-', (129, 131))	('autophagy mechanisms', 'CPA', (86, 106))	('autophagy', 'biological_process', 'GO:0016236', ('86', '95'))	('regulation of autophagy', 'biological_process', 'GO:0010506', ('156', '179'))	('DIO1', 'Gene', (51, 55))	('T3', 'Chemical', '-', (228, 230))	('expression', 'Var', (56, 66))	('autophagy', 'biological_process', 'GO:0006914', ('86', '95'))	('DIO1', 'Gene', '1733', (51, 55))
202334	29272308	Thus, it may be concluded that DIO1 re-expression in ccRCC cells results in global downregulation of proteins that directly promote cancerous proliferation, migration and invasion.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('DIO1', 'Gene', '1733', (31, 35))	('DIO1', 'Gene', (31, 35))	('cancerous proliferation', 'Disease', 'MESH:D009369', (132, 155))	('invasion', 'CPA', (171, 179))	('re-expression', 'Var', (36, 49))	('proteins', 'Protein', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('downregulation', 'NegReg', (83, 97))	('promote', 'PosReg', (124, 131))	('migration', 'CPA', (157, 166))	('cancerous proliferation', 'Disease', (132, 155))
202341	29272308	Unfortunately, we could not detect T3 in these cells but our recent study suggested that DIO1 ectopically expressed in renal cancer cells deiodinates T4 to produce T3 that induces changes in expression of target genes.	('renal cancer', 'Phenotype', 'HP:0009726', (119, 131))	('changes', 'Reg', (180, 187))	('renal cancer', 'Disease', 'MESH:D007680', (119, 131))	('T3', 'Chemical', '-', (164, 166))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('deiodinates', 'Var', (138, 149))	('T3', 'Chemical', '-', (35, 37))	('renal cancer', 'Disease', (119, 131))	('expression', 'MPA', (191, 201))	('DIO1', 'Gene', '1733', (89, 93))	('DIO1', 'Gene', (89, 93))
202342	29272308	Specifically, we showed that that supplementation of KIJ265T and KIJ308T cells (not transfected with DIO1-expressing plasmids) with T3 did not recapitulate the effects of ectopic DIO1 expression, suggesting inefficient intracellular transport of T3.	('KIJ308T', 'Var', (65, 72))	('T3', 'Chemical', '-', (132, 134))	('DIO1', 'Gene', (101, 105))	('DIO1', 'Gene', '1733', (101, 105))	('KIJ308T', 'CellLine', 'CVCL:AV54', (65, 72))	('intracellular', 'MPA', (219, 232))	('intracellular', 'cellular_component', 'GO:0005622', ('219', '232'))	('DIO1', 'Gene', '1733', (179, 183))	('DIO1', 'Gene', (179, 183))	('intracellular transport', 'biological_process', 'GO:0046907', ('219', '242'))	('KIJ265T', 'Chemical', '-', (53, 60))	('T3', 'Chemical', '-', (246, 248))
202346	29272308	These results indicated that ectopic DIO1 expression enabled conversion of T4 to T3 which could further affect the expression of target genes.	('affect', 'Reg', (104, 110))	('ectopic', 'Var', (29, 36))	('T3', 'Chemical', '-', (81, 83))	('DIO1', 'Gene', '1733', (37, 41))	('DIO1', 'Gene', (37, 41))	('expression', 'MPA', (115, 125))
202364	29272308	This may possibly suggest that DIO1 re-expression may result in initiation of transcriptional reprograming.	('transcriptional reprograming', 'CPA', (78, 106))	('result', 'Reg', (54, 60))	('DIO1', 'Gene', '1733', (31, 35))	('DIO1', 'Gene', (31, 35))	('re-expression', 'Var', (36, 49))
202365	29272308	Interestingly, DIO1 expression resulted in decreased levels of transcriptional regulators, STAT3 and WIZ.	('STAT3', 'MPA', (91, 96))	('WIZ', 'Gene', (101, 104))	('DIO1', 'Gene', '1733', (15, 19))	('DIO1', 'Gene', (15, 19))	('WIZ', 'Gene', '58525', (101, 104))	('expression', 'Var', (20, 30))	('levels of transcriptional regulators', 'MPA', (53, 89))	('decreased', 'NegReg', (43, 52))
202367	29272308	Inhibition of STAT3 pathway in ccRCC induces apoptosis, attenuates angiogenesis and metastasis in renal cancer mouse models.	('induces', 'Reg', (37, 44))	('renal cancer', 'Phenotype', 'HP:0009726', (98, 110))	('metastasis in renal cancer', 'Disease', (84, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mouse', 'Species', '10090', (111, 116))	('attenuates', 'NegReg', (56, 66))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('Inhibition', 'Var', (0, 10))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('apoptosis', 'CPA', (45, 54))	('metastasis in renal cancer', 'Disease', 'MESH:D009362', (84, 110))	('STAT3 pathway', 'Pathway', (14, 27))	('angiogenesis', 'biological_process', 'GO:0001525', ('67', '79'))
202372	29272308	The remarkable correlations between the expression of DIO1 transcript and some of DIO1-affected genes in tissue samples derived from ccRCC patients may possibly suggest that loss of DIO1 expression in ccRCC tumors may influence the pattern of gene expression in vivo.	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('DIO1', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('RCC', 'Disease', (203, 206))	('loss', 'Var', (174, 178))	('DIO1', 'Gene', (182, 186))	('gene expression', 'biological_process', 'GO:0010467', ('243', '258'))	('DIO1', 'Gene', '1733', (54, 58))	('RCC', 'Disease', 'MESH:C538614', (203, 206))	('pattern of gene expression', 'MPA', (232, 258))	('DIO1', 'Gene', '1733', (182, 186))	('patients', 'Species', '9606', (139, 147))	('correlations', 'Reg', (15, 27))	('DIO1', 'Gene', (82, 86))	('RCC tumors', 'Disease', (203, 213))	('influence', 'Reg', (218, 227))	('RCC tumors', 'Disease', 'MESH:C538614', (203, 213))	('RCC', 'Disease', (135, 138))	('DIO1', 'Gene', '1733', (82, 86))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))
202373	29272308	It would be interesting to see if changes in DIO1 expression may affect other cells and processes that contribute to tumor formation, in particular angiogenesis or infiltrating cells of immune system.	('affect', 'Reg', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('angiogenesis', 'biological_process', 'GO:0001525', ('148', '160'))	('DIO1', 'Gene', (45, 49))	('tumor', 'Disease', (117, 122))	('DIO1', 'Gene', '1733', (45, 49))	('changes', 'Var', (34, 41))	('angiogenesis', 'CPA', (148, 160))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('expression', 'MPA', (50, 60))	('formation', 'biological_process', 'GO:0009058', ('123', '132'))
202375	29272308	In summary, the results of this and our previous study suggest that restoration of DIO1 expression affects functioning of cancer cells in two modes (Fig 10).	('DIO1', 'Gene', '1733', (83, 87))	('DIO1', 'Gene', (83, 87))	('affects', 'Reg', (99, 106))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('restoration', 'Var', (68, 79))	('expression', 'MPA', (88, 98))
202381	29272308	At the same time, the results of our study may possibly suggest that loss of DIO1 expression in ccRCC tumors could be an adaptive mechanism, protecting the cells against overstimulation of cancer metabolism and induction of autophagy and or apoptosis.	('autophagy', 'CPA', (224, 233))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('loss', 'Var', (69, 73))	('RCC tumors', 'Disease', (98, 108))	('overstimulation', 'MPA', (170, 185))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('apoptosis', 'biological_process', 'GO:0097194', ('241', '250'))	('metabolism', 'biological_process', 'GO:0008152', ('196', '206'))	('apoptosis', 'biological_process', 'GO:0006915', ('241', '250'))	('DIO1', 'Gene', '1733', (77, 81))	('DIO1', 'Gene', (77, 81))	('apoptosis', 'CPA', (241, 250))	('autophagy', 'biological_process', 'GO:0016236', ('224', '233'))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('autophagy', 'biological_process', 'GO:0006914', ('224', '233'))	('RCC tumors', 'Disease', 'MESH:C538614', (98, 108))	('cancer', 'Disease', (189, 195))
202459	31200666	1), MMP11 expression differences yielded particularly high fold changes and high AUCs.	('MMP11', 'Gene', '4320', (4, 9))	('MMP11', 'molecular_function', 'GO:0004249', ('4', '9'))	('differences', 'Var', (21, 32))	('high AUCs', 'MPA', (76, 85))	('fold changes', 'MPA', (59, 71))	('MMP11', 'Gene', (4, 9))
202474	31200666	MMP-7 activation is directly associated with APC, and it is well established that APC mutations are frequently implicated as among the first mutations that occurs in the disease history of colon polyps as they progress to cancer.	('mutations', 'Var', (86, 95))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('APC', 'Disease', 'MESH:D011125', (82, 85))	('MMP-7', 'Gene', (0, 5))	('APC', 'Disease', (82, 85))	('cancer', 'Disease', (222, 228))	('colon polyps', 'Disease', (189, 201))	('APC', 'cellular_component', 'GO:0005680', ('82', '85'))	('MMP-7', 'Gene', '4316', (0, 5))	('APC', 'cellular_component', 'GO:0005680', ('45', '48'))	('APC', 'Disease', 'MESH:D011125', (45, 48))	('MMP-7', 'molecular_function', 'GO:0004235', ('0', '5'))	('APC', 'Disease', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('colon polyps', 'Disease', 'MESH:D003111', (189, 201))
202475	31200666	APC mutations often lead to increased beta-catenin and thus overexpression of MMP-7.	('beta-catenin', 'Gene', (38, 50))	('increased', 'PosReg', (28, 37))	('MMP-7', 'Gene', (78, 83))	('MMP-7', 'Gene', '4316', (78, 83))	('MMP-7', 'molecular_function', 'GO:0004235', ('78', '83'))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('overexpression', 'PosReg', (60, 74))	('beta-catenin', 'Gene', '1499', (38, 50))	('APC', 'cellular_component', 'GO:0005680', ('0', '3'))	('APC', 'Disease', (0, 3))	('mutations', 'Var', (4, 13))
202493	31200666	It is likely that the dysregulation of one MMP alters the MMP ecosystem and means that MMPs are better predictors when analyzed in combination as opposed to individually.	('dysregulation', 'Var', (22, 35))	('MMP ecosystem', 'MPA', (58, 71))	('MMP', 'molecular_function', 'GO:0004235', ('43', '46'))	('alters', 'Reg', (47, 53))	('MMPs', 'Gene', (87, 91))	('MMP', 'molecular_function', 'GO:0004235', ('58', '61'))	('MMPs', 'Gene', '4312;4313;4314;4316;4317;4318;4319;4320;4321;4322;4323;4324;4325;4326;4327;64386;9313;118856;8510;10893;79148;64386;10893;79148;64386;10893;64066;79148', (87, 91))
202508	31200666	VHL mutation, whether inherited or sporadic is frequently implicated in the tumorigenesis of renal clear cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (93, 119))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('renal clear cell carcinoma', 'Disease', (93, 119))	('mutation', 'Var', (4, 12))	('VHL', 'Gene', (0, 3))	('implicated', 'Reg', (58, 68))	('VHL', 'Gene', '7428', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
202509	31200666	With the loss of VHL, HIF is no longer properly degraded and free to induce the expression of proteins needed in hypoxic conditions.	('hypoxic conditions', 'Disease', (113, 131))	('hypoxic conditions', 'Disease', 'MESH:D009135', (113, 131))	('loss', 'Var', (9, 13))	('VHL', 'Gene', (17, 20))	('VHL', 'Gene', '7428', (17, 20))
202510	31200666	This leads to the upregulation of MMP14 in kidney clear cell carcinoma in patients with deletion of VHL.	('upregulation', 'PosReg', (18, 30))	('MMP', 'molecular_function', 'GO:0004235', ('34', '37'))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (43, 70))	('deletion', 'Var', (88, 96))	('patients', 'Species', '9606', (74, 82))	('MMP14', 'Gene', '4323', (34, 39))	('kidney clear cell carcinoma', 'Disease', (43, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('MMP14', 'Gene', (34, 39))	('VHL', 'Gene', (100, 103))	('VHL', 'Gene', '7428', (100, 103))
202526	32397610	In uni- and multivariate Cox regression analysis, ccRCC patients with higher levels of PANTR1 showed significantly poorer disease-free survival in our own respective cohort (n = 175, hazard ratio: 4.3, 95% confidence interval: 1.45-12.75, p = 0.008) in accordance with significantly poorer overall survival in a large The Cancer Genome Atlas database (TCGA) cohort (n = 530, hazard ratio: 2.19, 95% confidence interval: 1.59-3.03, p <= 0.001).	('Cancer', 'Phenotype', 'HP:0002664', (322, 328))	('Cancer', 'Disease', (322, 328))	('PANTR1', 'Gene', (87, 93))	('disease-free survival', 'CPA', (122, 143))	('patients', 'Species', '9606', (56, 64))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('Cancer', 'Disease', 'MESH:D009369', (322, 328))	('RCC', 'Disease', (52, 55))	('poorer', 'NegReg', (115, 121))	('PANTR1', 'Gene', '100506421', (87, 93))	('higher levels', 'Var', (70, 83))
202530	32397610	On the molecular level, knock-down of PANTR1 led to a decrease in Vascular Endothelial growth factor A (VEGF-A) and cell adhesion molecule laminin subunit gamma-2 (LAMC2) expression, corroborated by a positive correlation in RCC tissue (for VEGF-A R = 0.19, p < 0.0001, for LAMC2 R = 0.13, p = 0.0028).	('decrease', 'NegReg', (54, 62))	('Vascular Endothelial growth factor A', 'Gene', (66, 102))	('PANTR1', 'Gene', '100506421', (38, 44))	('VEGF-A', 'Gene', (241, 247))	('Vascular Endothelial growth factor A', 'Gene', '7422', (66, 102))	('PANTR1', 'Gene', (38, 44))	('LAMC2', 'Gene', (274, 279))	('LAMC2', 'Gene', '3918', (164, 169))	('RCC', 'Disease', (225, 228))	('laminin subunit gamma-2', 'Gene', '3918', (139, 162))	('VEGF-A', 'Gene', (104, 110))	('Vascular Endothelial growth factor', 'molecular_function', 'GO:0005172', ('66', '100'))	('LAMC2', 'Gene', '3918', (274, 279))	('cell adhesion', 'biological_process', 'GO:0007155', ('116', '129'))	('laminin subunit gamma-2', 'Gene', (139, 162))	('VEGF-A', 'Gene', '7422', (241, 247))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('116', '138'))	('expression', 'MPA', (171, 181))	('knock-down', 'Var', (24, 34))	('VEGF-A', 'Gene', '7422', (104, 110))	('LAMC2', 'Gene', (164, 169))
202535	32397610	In addition, this knowledge led to the recent development of specific HIF2a inhibitors in the metastatic setting of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('RCC', 'Disease', (118, 121))	('HIF2a', 'Gene', '2034', (70, 75))	('HIF2a', 'Gene', (70, 75))	('inhibitors', 'Var', (76, 86))
202537	32397610	Aberrant functions of lncRNAs affect several hallmarks of cancer such as cell proliferation, apoptosis, angiogenesis, promotion of metastasis, and mesenchymal-to-endothelial transition.	('cell proliferation', 'biological_process', 'GO:0008283', ('73', '91'))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('metastasis', 'CPA', (131, 141))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('Aberrant functions', 'Var', (0, 18))	('lncRNAs', 'Gene', (22, 29))	('angiogenesis', 'CPA', (104, 116))	('promotion', 'PosReg', (118, 127))	('angiogenesis', 'biological_process', 'GO:0001525', ('104', '116'))	('mesenchymal-to-endothelial transition', 'CPA', (147, 184))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cell proliferation', 'CPA', (73, 91))	('cancer', 'Disease', (58, 64))	('apoptosis', 'CPA', (93, 102))	('affect', 'Reg', (30, 36))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))
202553	32397610	As shown in Figure 1f, high levels of PANTR1 expression was associated with significantly shorter recurrence-free survival (p = 0.045).	('recurrence-free survival', 'CPA', (98, 122))	('shorter', 'NegReg', (90, 97))	('PANTR1', 'Gene', '100506421', (38, 44))	('PANTR1', 'Gene', (38, 44))	('expression', 'MPA', (45, 55))	('high levels', 'Var', (23, 34))
202556	32397610	As shown in Figure S1, high PANTR1 expression prevailed as a poor prognostic factor for overall survival in this external cohort (hazard ration: 2.19, 95% confidence interval: 1.59-3.03, p < 0.001).	('high', 'Var', (23, 27))	('PANTR1', 'Gene', '100506421', (28, 34))	('PANTR1', 'Gene', (28, 34))	('expression', 'MPA', (35, 45))
202564	32397610	To confirm the increased apoptotic activity with a second independent method, western blot analysis confirmed an increased cleavage of PARP1 in PANTR1 knocked-down cells (89 kDa band, which is a marker for increased apoptosis) (Figure 3d-f).	('cleavage', 'MPA', (123, 131))	('PARP1', 'Gene', '142', (135, 140))	('PANTR1', 'Gene', '100506421', (144, 150))	('PANTR1', 'Gene', (144, 150))	('PARP1', 'Gene', (135, 140))	('apoptosis', 'biological_process', 'GO:0097194', ('216', '225'))	('apoptosis', 'biological_process', 'GO:0006915', ('216', '225'))	('knocked-down', 'Var', (151, 163))	('increased', 'PosReg', (113, 122))
202566	32397610	We firstly confirmed the expression (Figure S2) as well as the successful siRNA-mediated knock down of PANTR1 (Figure S5) in a cell line model system for endothelial cells i.e., human umbilical vein endothelial cells (HUVECs).	('PANTR1', 'Gene', '100506421', (103, 109))	('knock down', 'Var', (89, 99))	('PANTR1', 'Gene', (103, 109))	('human', 'Species', '9606', (178, 183))
202567	32397610	After performing a tube formation assay and by consecutive analysis and comparison of several key parameters involved in tube formation, we revealed that PANTR1 knock-down led to a significantly reduced capacity of tube formation in comparison to control conditions (Figure 4a-e).	('reduced', 'NegReg', (195, 202))	('knock-down', 'Var', (161, 171))	('PANTR1', 'Gene', '100506421', (154, 160))	('PANTR1', 'Gene', (154, 160))	('tube formation', 'biological_process', 'GO:0035148', ('19', '33'))	('tube formation', 'CPA', (215, 229))	('tube formation', 'biological_process', 'GO:0035148', ('121', '135'))	('tube formation', 'biological_process', 'GO:0035148', ('215', '229'))
202569	32397610	Knock-down of PANTR1 resulted in reduced cellular migration of HUVECs when compared to control conditions (Figure 4f).	('Knock-down', 'Var', (0, 10))	('cellular migration of HUVECs', 'CPA', (41, 69))	('reduced', 'NegReg', (33, 40))	('PANTR1', 'Gene', '100506421', (14, 20))	('PANTR1', 'Gene', (14, 20))
202570	32397610	To explore whether PANTR1 influences angiogenesis-related factors in ccRCC cancer cells, we measured the gene expression levels of several angiogenetic factors upon PANTR1 knock-down.	('PANTR1', 'Gene', '100506421', (19, 25))	('gene expression', 'biological_process', 'GO:0010467', ('105', '120'))	('ccRCC cancer', 'Disease', (69, 81))	('PANTR1', 'Gene', (19, 25))	('knock-down', 'Var', (172, 182))	('PANTR1', 'Gene', '100506421', (165, 171))	('PANTR1', 'Gene', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('angiogenesis', 'biological_process', 'GO:0001525', ('37', '49'))	('ccRCC cancer', 'Disease', 'MESH:D009369', (69, 81))
202578	32397610	Humans with mutations of the POU3F3 gene display a wide range of features directly linked to the size of the mutation spanning from mild cognitive impairment and mild dysmorphosis to complex malformation of the kidney, corpus callosum, heart and anus.	('Humans', 'Species', '9606', (0, 6))	('POU3F3', 'Gene', (29, 35))	('cognitive impairment', 'Disease', (137, 157))	('dysmorphosis', 'Disease', (167, 179))	('dysmorphosis', 'Disease', 'None', (167, 179))	('linked', 'Reg', (83, 89))	('mutations', 'Var', (12, 21))	('mild cognitive impairment', 'Phenotype', 'HP:0001256', (132, 157))	('cognitive impairment', 'Disease', 'MESH:D003072', (137, 157))	('cognitive impairment', 'Phenotype', 'HP:0100543', (137, 157))
202585	32397610	In ccRCC, frequent loss of chromosome 3p occurs which includes deletion of 3p25 where the vHL gene resides.	('chromosome', 'cellular_component', 'GO:0005694', ('27', '37'))	('loss', 'NegReg', (19, 23))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('RCC', 'Disease', (5, 8))	('deletion', 'Var', (63, 71))	('vHL', 'Gene', '7428', (90, 93))	('3p25', 'Gene', (75, 79))	('vHL', 'Gene', (90, 93))
202586	32397610	Mutated vHL leads to several inappropriate functions of the cell, the most relevant being the activation of HIF subunits by polyubiquitination.	('vHL', 'Gene', (8, 11))	('vHL', 'Gene', '7428', (8, 11))	('inappropriate functions', 'MPA', (29, 52))	('Mutated', 'Var', (0, 7))	('polyubiquitination', 'MPA', (124, 142))	('activation', 'PosReg', (94, 104))
202588	32397610	In non-cancerous conditions such as the von-Hippel-Lindau-syndrome, mutated vHL protein also causes angiogenesis-dependent tumors including haemangioblastomas, a tumor arising from blood vessel in the central nervous system.	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('vHL', 'Gene', (76, 79))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('tumor', 'Disease', (162, 167))	('von-Hippel-Lindau-syndrome', 'Disease', 'MESH:D006623', (40, 66))	('haemangioblastomas', 'Disease', (140, 158))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Disease', (123, 128))	('haemangioblastomas', 'Disease', 'MESH:D018325', (140, 158))	('von-Hippel-Lindau-syndrome', 'Disease', (40, 66))	('protein', 'Protein', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('vHL', 'Gene', '7428', (76, 79))	('mutated', 'Var', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('cancerous', 'Disease', 'MESH:D009369', (7, 16))	('angiogenesis', 'biological_process', 'GO:0001525', ('100', '112'))	('causes', 'Reg', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumors', 'Disease', (123, 129))	('cancerous', 'Disease', (7, 16))
202598	32397610	In our study, we found significantly higher expression levels of PANTR1 in ccRCC tissue compared to normal kidney tissue and that high PANTR1 expression is associated with poor clinical outcome of patients in two independent cohorts.	('patients', 'Species', '9606', (197, 205))	('higher', 'PosReg', (37, 43))	('expression levels', 'MPA', (44, 61))	('high', 'Var', (130, 134))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('associated', 'Reg', (156, 166))	('expression', 'MPA', (142, 152))	('PANTR1', 'Gene', '100506421', (65, 71))	('PANTR1', 'Gene', '100506421', (135, 141))	('PANTR1', 'Gene', (65, 71))	('PANTR1', 'Gene', (135, 141))
202602	32397610	We could demonstrate that knock-down of PANTR1 leads to significantly reduced cellular growth in all three ccRCC cell lines.	('knock-down', 'Var', (26, 36))	('reduced', 'NegReg', (70, 77))	('cellular growth', 'CPA', (78, 93))	('PANTR1', 'Gene', '100506421', (40, 46))	('PANTR1', 'Gene', (40, 46))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('cellular growth', 'biological_process', 'GO:0016049', ('78', '93'))
202605	32397610	In order to clarify the mode of cellular action observed by reduced cellular growth, we investigated apoptotic activity after PANTR1 knock-down.	('knock-down', 'Var', (133, 143))	('PANTR1', 'Gene', '100506421', (126, 132))	('PANTR1', 'Gene', (126, 132))	('apoptotic', 'CPA', (101, 110))	('investigated', 'Reg', (88, 100))	('cellular growth', 'biological_process', 'GO:0016049', ('68', '83'))
202607	32397610	Pro-apoptotic activity of PANTR1 knock-down was demonstrated by significantly elevated activities of caspases 3 and 7 after PANTR1 knock-down.	('PANTR1', 'Gene', '100506421', (26, 32))	('PANTR1', 'Gene', (26, 32))	('elevated', 'PosReg', (78, 86))	('activities', 'MPA', (87, 97))	('knock-down', 'Var', (131, 141))	('knock-down', 'Var', (33, 43))	('PANTR1', 'Gene', '100506421', (124, 130))	('PANTR1', 'Gene', (124, 130))	('caspases 3 and 7', 'Gene', '836;840', (101, 117))
202614	32397610	The expression of VEGF-A, a major growth factor downstream of vHL and HIF, was significantly decreased after PANTR1 knock-down as a further proof that angiogenesis is regulated on a multilayered process by PANTR1.	('PANTR1', 'Gene', '100506421', (109, 115))	('knock-down', 'Var', (116, 126))	('PANTR1', 'Gene', (109, 115))	('expression', 'MPA', (4, 14))	('VEGF-A', 'Gene', '7422', (18, 24))	('decreased', 'NegReg', (93, 102))	('vHL', 'Gene', '7428', (62, 65))	('vHL', 'Gene', (62, 65))	('angiogenesis', 'biological_process', 'GO:0001525', ('151', '163'))	('VEGF-A', 'Gene', (18, 24))	('PANTR1', 'Gene', '100506421', (206, 212))	('angiogenesis', 'CPA', (151, 163))	('PANTR1', 'Gene', (206, 212))
202616	32397610	Moreover, after knock-down of PANTR1 we could further demonstrate a significant decrease of LAMC2 mRNA expression in ccRCC cells.	('PANTR1', 'Gene', '100506421', (30, 36))	('mRNA expression', 'MPA', (98, 113))	('PANTR1', 'Gene', (30, 36))	('LAMC2', 'Gene', (92, 97))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))	('LAMC2', 'Gene', '3918', (92, 97))	('decrease', 'NegReg', (80, 88))	('knock-down', 'Var', (16, 26))
202623	32397610	Some representative examples are the epigenetic regulation of the INK4b/ARF/INK4a locus via the lncRNA Antisense Noncoding RNA In The INK4 Locus (ANRIL), the upregulation of NKD inhibitor of WNT signaling pathway 1 (NKD1) transcription by lncRNA H19 via NKD inhibitor of WNT signaling pathway 1 (EZH2) or HOX Transcript Antisense RNA (HOTAIR)-mediated repression of polycomb repressive complex 2 (PRC2) transcription.	('EZH2', 'Gene', '2146', (296, 300))	('H19', 'Gene', (246, 249))	('INK4', 'Gene', (66, 70))	('EZH2', 'Gene', (296, 300))	('PRC2', 'Gene', (397, 401))	('HOTAIR', 'Gene', '100124700', (335, 341))	('INK4b', 'Gene', (66, 71))	('INK4', 'Gene', '1029', (134, 138))	('ARF/INK4a', 'Gene', '1029', (72, 81))	('H19', 'Gene', '283120', (246, 249))	('ANRIL', 'Gene', '100048912', (146, 151))	('HOTAIR', 'Gene', (335, 341))	('NKD1', 'Gene', (216, 220))	('RNA', 'cellular_component', 'GO:0005562', ('330', '333'))	('upregulation', 'PosReg', (158, 170))	('WNT signaling pathway', 'biological_process', 'GO:0016055', ('271', '292'))	('ARF/INK4a', 'Gene', (72, 81))	('repression', 'NegReg', (352, 362))	('INK4', 'Gene', (134, 138))	('INK4b', 'Gene', '1030', (66, 71))	('regulation', 'biological_process', 'GO:0065007', ('48', '58'))	('INK4', 'Gene', '1029', (76, 80))	('ANRIL', 'Gene', (146, 151))	('WNT signaling pathway', 'biological_process', 'GO:0016055', ('191', '212'))	('transcription', 'biological_process', 'GO:0006351', ('403', '416'))	('Antisense RNA', 'molecular_function', 'GO:0009388', ('320', '333'))	('NKD1', 'Gene', '85407', (216, 220))	('INK4', 'Gene', '1029', (66, 70))	('INK4', 'Gene', (76, 80))	('RNA', 'cellular_component', 'GO:0005562', ('123', '126'))	('transcription', 'biological_process', 'GO:0006351', ('222', '235'))	('NKD', 'Var', (254, 257))
202643	32397610	Three sections of each sample were hybridized with the following probes: Hs-LINC1158 (#514801, i.e., PANTR1), negative control DapB (#310043) and positive control Hs-PPIB (#313901).	('PANTR1', 'Gene', (101, 107))	('#313901', 'Var', (172, 179))	('PPIB', 'Gene', (166, 170))	('#310043', 'Var', (133, 140))	('#514801', 'Var', (86, 93))	('PPIB', 'Gene', '5479', (166, 170))	('PANTR1', 'Gene', '100506421', (101, 107))
202669	32397610	(a-c) Validation of siRNA-mediated PANTR1 knock-down efficiency in three RCC cell lines 48 h after transfection (RCC-FG, RCC-MF, 769-P via qRT-PCR using gene specific primers; n = 3; mean +- SD; ** p < 0.01, *** p < 0.001, Figure S4.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (73, 76))	('RCC', 'Disease', (121, 124))	('knock-down', 'Var', (42, 52))	('RCC-FG, RCC-MF', 'Disease', 'MESH:C538614', (113, 127))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('PANTR1', 'Gene', '100506421', (35, 41))	('PANTR1', 'Gene', (35, 41))
202670	32397610	Validation of siRNA-mediated PANTR1 knock-down efficiency 48 h after transfection in HUVECs via qRT-PCR using gene specific primers; n = 3; mean +- SD; ** p < 0.01, *** p < 0.001, Table S1: Sequences of primers used for qRT-PCR.	('knock-down', 'Var', (36, 46))	('PANTR1', 'Gene', '100506421', (29, 35))	('PANTR1', 'Gene', (29, 35))	('*** p', 'Var', (165, 170))
202671	31870811	Transcriptomic signatures related to the obesity paradox in patients with clear cell renal cell carcinoma: a retrospective cohort study Obesity is associated with an increased risk of developing clear cell renal cell carcinoma (ccRCC) but, paradoxically, with improved oncologic outcomes.	('obesity', 'Phenotype', 'HP:0001513', (41, 48))	('clear cell renal cell carcinoma', 'Disease', (74, 105))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (85, 105))	('Obesity', 'Var', (136, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('Obesity', 'Phenotype', 'HP:0001513', (136, 143))	('patients', 'Species', '9606', (60, 68))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (195, 226))	('obesity', 'Disease', (41, 48))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (74, 105))	('obesity', 'Disease', 'MESH:D009765', (41, 48))	('clear cell renal cell carcinoma', 'Disease', (195, 226))	('RCC', 'Disease', (230, 233))	('RCC', 'Phenotype', 'HP:0005584', (230, 233))	('improved', 'PosReg', (260, 268))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (206, 226))	('ccRCC', 'Phenotype', 'HP:0006770', (228, 233))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (74, 105))	('RCC', 'Disease', 'MESH:C538614', (230, 233))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (195, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
202736	31870811	Pre-treatment (COMPARZ, MSK IO) or pre-surgical BMI (TCGA, peritumoral adipose tissue cohort) was calculated and categorized into normal weight (BMI < 25 kg/m2), overweight (25kg/m2 <= BMI < 30kg/m2), and obese (BMI >= 30kg/m2) in accordance with World Health Organization criteria.	('obese', 'Disease', 'MESH:D009765', (205, 210))	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('men', 'Species', '9606', (9, 12))	('pre', 'molecular_function', 'GO:0003904', ('35', '38'))	('obese', 'Disease', (205, 210))	('tumoral', 'Disease', (63, 70))	('tumoral', 'Disease', 'MESH:D009369', (63, 70))	('25kg/m2', 'Var', (174, 181))	('overweight', 'Phenotype', 'HP:0025502', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
202766	31870811	We found no differences in total mutational burden (appendix p 16) or frequency of PBRM1, BAP1 or TP53 mutations in the tumors of obese vs. normal weight patients.	('mutations', 'Var', (103, 112))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('BAP1', 'Gene', '8314', (90, 94))	('p 16', 'Gene', '1029', (61, 65))	('patients', 'Species', '9606', (154, 162))	('PBRM1', 'Gene', (83, 88))	('PBRM1', 'Gene', '55193', (83, 88))	('BAP1', 'Gene', (90, 94))	('TP53', 'Gene', '7157', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('p 16', 'Gene', (61, 65))	('tumors of obese', 'Disease', (120, 135))	('tumors of obese', 'Disease', 'MESH:D009765', (120, 135))	('TP53', 'Gene', (98, 102))
202783	31870811	Survival analyses demonstrated improved survival among patients treated with TKI therapy, after adjustment for IMDC risk score, with the most significant association being noted among patients treated with sunitinib.	('improved', 'PosReg', (31, 39))	('patients', 'Species', '9606', (184, 192))	('sunitinib', 'Chemical', 'MESH:D000077210', (206, 215))	('survival', 'MPA', (40, 48))	('patients', 'Species', '9606', (55, 63))	('men', 'Species', '9606', (102, 105))	('TKI', 'Var', (77, 80))
202803	31870811	where DIO in tumor-bearing mice cause increased CD8+ T-cell infiltration and T-cell dysfunction as measured by increased immune checkpoint molecule expression (Lag3, Tim3, PD-1).	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('Lag3', 'Gene', '16768', (160, 164))	('increased', 'PosReg', (111, 120))	('PD-1', 'Gene', '18566', (172, 176))	('mice', 'Species', '10090', (27, 31))	('PD-1', 'Gene', (172, 176))	('T-cell dysfunction', 'CPA', (77, 95))	('Lag3', 'Gene', (160, 164))	('CD8', 'Gene', (48, 51))	('T-cell dysfunction', 'Phenotype', 'HP:0005435', (77, 95))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('DIO', 'Phenotype', 'HP:0012743', (6, 9))	('Tim3', 'Gene', '171285', (166, 170))	('Tim3', 'Gene', (166, 170))	('CD8', 'Gene', '925', (48, 51))	('increased', 'PosReg', (38, 47))	('DIO', 'Var', (6, 9))
202825	31870811	Future studies should focus on the utility of body size (e.g., BMI) or body composition measures as a predictive factor in combination with clinicopathologic and tumor-specific features (e.g., mutational status) and further explore mechanisms of fat-tumor cross-talk that can be exploited to improve patient outcomes.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('mutational', 'Var', (193, 203))	('patient', 'Species', '9606', (300, 307))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('fat-tumor cross-talk', 'Disease', (246, 266))	('tumor', 'Disease', (250, 255))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('fat-tumor cross-talk', 'Disease', 'MESH:D020922', (246, 266))
202837	31870811	Specifically, gene expression differences in angiogenic and inflammatory programs within the tumor microenvironment (tumor and peritumoral adipose tissue) may help explain the survival advantage experienced by obese as compared to normal weight patients.	('obese', 'Disease', (210, 215))	('patients', 'Species', '9606', (245, 253))	('tumor', 'Disease', (131, 136))	('gene expression', 'biological_process', 'GO:0010467', ('14', '29'))	('obese', 'Disease', 'MESH:D009765', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('survival advantage', 'CPA', (176, 194))	('angiogenic', 'CPA', (45, 55))	('differences', 'Reg', (30, 41))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('men', 'Species', '9606', (111, 114))	('inflammatory programs', 'CPA', (60, 81))	('tumoral', 'Disease', (131, 138))	('tumoral', 'Disease', 'MESH:D009369', (131, 138))	('gene expression', 'Var', (14, 29))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
202868	29079639	VHL is mutated in most hereditary ccRCC and in 52% of sporadic ccRCC.	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('VHL', 'Disease', 'MESH:D006623', (0, 3))	('RCC', 'Disease', (36, 39))	('VHL', 'Disease', (0, 3))	('mutated', 'Var', (7, 14))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
202870	29079639	Mutationally inactivated VHL therefore results in intracellular accumulation of HIF and, consequently, activation of downstream pathways involved in hypoxia signalling including the production of VEGF, which stimulates angiogenesis, cell growth and survival.	('stimulates', 'PosReg', (208, 218))	('signalling', 'biological_process', 'GO:0023052', ('157', '167'))	('VHL', 'Disease', (25, 28))	('cell growth', 'biological_process', 'GO:0016049', ('233', '244'))	('activation', 'PosReg', (103, 113))	('hypoxia', 'Disease', (149, 156))	('results in', 'Reg', (39, 49))	('angiogenesis', 'biological_process', 'GO:0001525', ('219', '231'))	('hypoxia', 'Disease', 'MESH:D000860', (149, 156))	('survival', 'CPA', (249, 257))	('cell growth', 'CPA', (233, 244))	('Mutationally inactivated', 'Var', (0, 24))	('VEGF', 'Gene', '7422', (196, 200))	('VHL', 'Disease', 'MESH:D006623', (25, 28))	('HIF', 'MPA', (80, 83))	('intracellular', 'cellular_component', 'GO:0005622', ('50', '63'))	('intracellular accumulation', 'MPA', (50, 76))	('VEGF', 'Gene', (196, 200))	('angiogenesis', 'CPA', (219, 231))
202874	29079639	Type 1 papillary RCCs are closely associated with mutations in the met oncogene (c-Met.)	('associated', 'Reg', (34, 44))	('mutations', 'Var', (50, 59))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))	('c-Met', 'Gene', (81, 86))	('c-Met', 'Gene', '4233', (81, 86))
202877	29079639	Chromophobe RCCs harbour a fairly indolent behaviour and will only rarely metastasize, with mutations found in TP53 (32% of cases) and phosphatase and tensin homologue (PTEN) (9% of cases).	('TP53', 'Gene', '7157', (111, 115))	('PTEN', 'Gene', (169, 173))	('Chromophobe RCCs', 'Disease', (0, 16))	('PTEN', 'Gene', '5728', (169, 173))	('mutations', 'Var', (92, 101))	('TP53', 'Gene', (111, 115))	('phosphatase and tensin homologue', 'Gene', '5728', (135, 167))	('behaviour', 'biological_process', 'GO:0007610', ('43', '52'))	('Chromophobe RCCs', 'Disease', 'MESH:D000238', (0, 16))	('phosphatase', 'molecular_function', 'GO:0016791', ('135', '146'))
202878	29079639	Mutations in the mTOR pathway have been found in chromophobe tumours (23% of cases).	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('chromophobe tumours', 'Disease', 'MESH:D000238', (49, 68))	('chromophobe tumours', 'Disease', (49, 68))	('found', 'Reg', (40, 45))	('Mutations', 'Var', (0, 9))	('mTOR', 'Gene', (17, 21))	('mTOR', 'Gene', '2475', (17, 21))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
202935	29079639	This work led to the development of anti-CTLA-4 antibodies, which have become a standard of care for metastatic melanoma.	('anti-CTLA-4', 'Gene', (36, 47))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('anti-CTLA-4', 'Var', (36, 47))
202937	29079639	CTLA-4 is predominantly expressed on CD4+ helper cells; therefore enhanced CD8+ responses in anti-CTLA-4 treated patients are likely to be an indirect effect related to activation of CD4+ cells.	('CD8', 'Gene', '925', (75, 78))	('anti-CTLA-4', 'Var', (93, 104))	('CD4', 'Gene', (183, 186))	('patients', 'Species', '9606', (113, 121))	('enhanced', 'PosReg', (66, 74))	('CD4', 'Gene', '920', (183, 186))	('CD4', 'Gene', (37, 40))	('CD8', 'Gene', (75, 78))	('CD4', 'Gene', '920', (37, 40))
202938	29079639	In cancer, CTLA-4/CD28 engagement down-modulates helper T-cell activity and enhances Tregs immunosuppressive activity.	('down-modulates', 'NegReg', (34, 48))	('helper T-cell activity', 'CPA', (49, 71))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('Tregs immunosuppressive activity', 'CPA', (85, 117))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('CD28', 'Gene', (18, 22))	('engagement', 'Var', (23, 33))	('CD28', 'Gene', '940', (18, 22))	('enhances', 'PosReg', (76, 84))
202940	29079639	In humans, CTLA-4 gene polymorphisms have been associated with the onset of several autoimmune conditions including autoimmune hypothyroidism and type 1 diabetes.	('polymorphisms', 'Var', (23, 36))	('CTLA-4', 'Gene', (11, 17))	('associated with', 'Reg', (47, 62))	('autoimmune hypothyroidism and type 1 diabetes', 'Disease', 'MESH:D003922', (116, 161))	('autoimmune conditions', 'Phenotype', 'HP:0002960', (84, 105))	('humans', 'Species', '9606', (3, 9))	('hypothyroidism', 'Phenotype', 'HP:0000821', (127, 141))	('autoimmune hypothyroidism', 'Phenotype', 'HP:0011771', (116, 141))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (146, 161))
202952	29079639	In renal cancer, PD-L1 (also known as B7-H1, CD274) expression on either tumour cells or TILs in primary tumours correlates with a worse prognosis, with reduced OS compared with PD-L1 negative tumours.	('B7-H1', 'Gene', '29126', (38, 43))	('reduced', 'NegReg', (153, 160))	('tumours', 'Disease', (193, 200))	('tumours', 'Disease', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('CD274', 'Gene', '29126', (45, 50))	('primary tumours', 'Disease', 'MESH:D009369', (97, 112))	('PD-L1', 'Gene', (17, 22))	('expression', 'Var', (52, 62))	('primary tumours', 'Disease', (97, 112))	('tumours', 'Phenotype', 'HP:0002664', (193, 200))	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('tumours', 'Disease', 'MESH:D009369', (193, 200))	('OS', 'Chemical', '-', (161, 163))	('tumours', 'Disease', 'MESH:D009369', (105, 112))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('tumour', 'Disease', 'MESH:D009369', (193, 199))	('CD274', 'Gene', (45, 50))	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('B7-H1', 'Gene', (38, 43))	('tumour', 'Disease', (193, 199))	('renal cancer', 'Disease', (3, 15))	('tumour', 'Disease', (105, 111))	('renal cancer', 'Phenotype', 'HP:0009726', (3, 15))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('tumour', 'Disease', (73, 79))	('renal cancer', 'Disease', 'MESH:D007680', (3, 15))
202956	29079639	Mouse models with knockout of PD-1 and its known ligands result in mild phenotypes, with organ-specific inflammation, which is a stark contrast with the CTLA-4 knockout models where death occurs by 4 weeks of age.	('inflammation', 'Disease', (104, 116))	('PD-1', 'Gene', (30, 34))	('Mouse', 'Species', '10090', (0, 5))	('knockout', 'Var', (18, 26))	('inflammation', 'Disease', 'MESH:D007249', (104, 116))	('inflammation', 'biological_process', 'GO:0006954', ('104', '116'))
202999	29079639	G3/4 AEs occurred in 20% of patients receiving nivolumab compared with 37% in the everolimus group.	('nivolumab', 'Chemical', 'MESH:D000077594', (47, 56))	('occurred', 'Reg', (9, 17))	('AEs', 'Chemical', '-', (5, 8))	('G3/4 AEs', 'Disease', (0, 8))	('nivolumab', 'Var', (47, 56))	('everolimus', 'Chemical', 'MESH:D000068338', (82, 92))	('patients', 'Species', '9606', (28, 36))
203012	29079639	A first in-human phase I trial administered BMS-936559 twice weekly to 207 patients with solid cancers, 17 of whom had aRCC.	('BMS-936559', 'Var', (44, 54))	('human', 'Species', '9606', (11, 16))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('patients', 'Species', '9606', (75, 83))	('solid cancers', 'Disease', (89, 102))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('solid cancers', 'Disease', 'MESH:D009369', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
203028	29079639	Interestingly, patients with poor prognostic features such as poor MSKCC prognostic status, high Fuhrman grade and/or sarcomatoid features demonstrated a higher ORR.	('sarcomatoid', 'Disease', 'MESH:C538614', (118, 129))	('patients', 'Species', '9606', (15, 23))	('high', 'Var', (92, 96))	('sarcomatoid', 'Disease', (118, 129))
203040	29079639	Subgroup analysis of the nivolumab cohort demonstrated higher response rates in patients with tumours with  >=1% PD-L1 expression.	('tumours', 'Disease', (94, 101))	('patients', 'Species', '9606', (80, 88))	('PD-L1', 'Gene', (113, 118))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('expression', 'Var', (119, 129))	('nivolumab', 'Chemical', 'MESH:D000077594', (25, 34))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('response', 'MPA', (62, 70))	('higher', 'PosReg', (55, 61))	('tumours', 'Disease', 'MESH:D009369', (94, 101))
203059	29079639	Updated results with 2-year follow-up reported ORR of 40% in both treatment arms (nivo3 and ipi1, nivo1 and ipi3) and median DOR of 20.4 weeks (nivo3 and ipi1, n=47) and 19.4 weeks (nivo1 and ipi3, n=47).	('ipi3', 'Gene', (192, 196))	('nivo3', 'Chemical', '-', (144, 149))	('ipi1', 'Gene', '54881', (154, 158))	('ipi3', 'Gene', '57418', (192, 196))	('nivo1', 'Var', (98, 103))	('nivo1', 'Chemical', '-', (182, 187))	('ipi3', 'Gene', (108, 112))	('nivo3', 'Chemical', '-', (82, 87))	('ipi1', 'Gene', (92, 96))	('ipi3', 'Gene', '57418', (108, 112))	('ipi1', 'Gene', '54881', (92, 96))	('ipi1', 'Gene', (154, 158))	('nivo1', 'Chemical', '-', (98, 103))
203062	29079639	Encouraging early results from JAVELIN Renal 100, a phase 1b, dose-finding study, demonstrated durable responses in six of six treatment-naive patients evaluable for response to avelumab (MSB0010718C), a PD-L1 inhibitory mAb, given in combination with axitinib.	('avelumab', 'Chemical', 'MESH:C000609138', (178, 186))	('axitinib', 'Chemical', 'MESH:D000077784', (252, 260))	('JAVELIN Renal 100', 'Disease', 'MESH:D007674', (31, 48))	('MSB0010718C', 'Var', (188, 199))	('MSB', 'cellular_component', 'GO:0150086', ('188', '191'))	('patients', 'Species', '9606', (143, 151))	('JAVELIN Renal 100', 'Disease', (31, 48))
203089	28473526	Modeling Renal Cell Carcinoma in mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade Clear cell renal cell carcinoma (ccRCC) is characterized by BAP1 and PBRM1 mutation, which are associated with tumors of different grade and prognosis.	('PBRM1', 'Gene', (154, 159))	('Tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Pbrm1', 'Gene', (48, 53))	('BAP1', 'Gene', (145, 149))	('Modeling Renal Cell Carcinoma', 'Disease', (0, 29))	('Modeling Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (0, 29))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('Carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('Inactivation', 'NegReg', (54, 66))	('Pbrm1', 'Gene', '66923', (48, 53))	('Bap1', 'Gene', '104416', (39, 43))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (9, 29))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (96, 116))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (85, 116))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('mutation', 'Var', (160, 168))	('Clear cell renal cell carcinoma', 'Disease', (85, 116))	('tumors', 'Disease', (196, 202))	('mice', 'Species', '10090', (33, 37))	('RCC', 'Disease', (120, 123))	('Bap1', 'Gene', (39, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (85, 116))
203093	28473526	In contrast, targeting with Pax8, a developmental lineage-specific transcription factor, led to ccRCC of different grade.	('transcription factor', 'molecular_function', 'GO:0000981', ('67', '87'))	('RCC', 'Disease', (98, 101))	('Pax8', 'Gene', (28, 32))	('transcription', 'biological_process', 'GO:0006351', ('67', '80'))	('targeting', 'Var', (13, 22))	('RCC', 'Disease', 'MESH:C538614', (98, 101))
203095	28473526	Disrupting one allele of the mTORC1 negative regulator, Tsc1, in Pbrm1-deficient kidneys triggered higher grade ccRCC.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('mTORC1', 'Gene', (29, 35))	('RCC', 'Disease', (114, 117))	('Pbrm1-deficient kidneys', 'Disease', (65, 88))	('deficient kidneys', 'Phenotype', 'HP:0000089', (71, 88))	('Disrupting', 'Var', (0, 10))	('mTORC1', 'Gene', '382056', (29, 35))	('Pbrm1-deficient kidneys', 'Disease', 'MESH:D007674', (65, 88))	('Tsc1', 'Gene', (56, 60))	('mTORC1', 'cellular_component', 'GO:0031931', ('29', '35'))	('Tsc1', 'Gene', '64930', (56, 60))	('triggered', 'Reg', (89, 98))
203099	28473526	Inactivation of the von Hippel-Lindau (VHL) gene by either mutation or methylation is observed in over 80% of ccRCC.	('methylation', 'Var', (71, 82))	('von Hippel-Lindau', 'Gene', (20, 37))	('VHL', 'Gene', (39, 42))	('von Hippel-Lindau', 'Gene', '22346', (20, 37))	('RCC', 'Disease', (112, 115))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('mutation', 'Var', (59, 67))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('Inactivation', 'NegReg', (0, 12))
203100	28473526	Germline loss-of-function mutations in VHL lead to VHL syndrome and a high incidence of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('VHL syndrome', 'Disease', 'MESH:D006623', (51, 63))	('VHL', 'Gene', (39, 42))	('mutations', 'Var', (26, 35))	('loss-of-function', 'NegReg', (9, 25))	('VHL syndrome', 'Disease', (51, 63))	('RCC', 'Disease', (90, 93))
203102	28473526	Intragenic mutation in one copy of VHL followed by 3p LOH are early events in ccRCC tumorigenesis, in fact the only known "truncal" events.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('RCC', 'Disease', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('tumor', 'Disease', (84, 89))	('VHL', 'Gene', (35, 38))	('mutation', 'Var', (11, 19))
203103	28473526	Recurrent mutations in other tumor suppressor genes have also been identified in ccRCC with varying frequencies.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor suppressor', 'biological_process', 'GO:0051726', ('29', '45'))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('29', '45'))	('identified', 'Reg', (67, 77))	('tumor', 'Disease', (29, 34))	('mutations', 'Var', (10, 19))
203104	28473526	Mutations in the Polybromo-1 (PBRM1) gene, also known as BRG1-associated factor 180 (BAF180), a component of the SWI/SNF-B (PBAF) chromatin-remodeling complex, are observed in roughly 50% of ccRCC.	('PBRM1', 'Gene', (30, 35))	('RCC', 'Disease', (193, 196))	('BRG1-associated factor 180', 'Gene', (57, 83))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('BAF180', 'Gene', '66923', (85, 91))	('BAF180', 'Gene', (85, 91))	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('130', '150'))	('Mutations', 'Var', (0, 9))	('chromatin-remodeling complex', 'cellular_component', 'GO:0016585', ('130', '158'))	('BRG1-associated factor 180', 'Gene', '66923', (57, 83))	('observed', 'Reg', (164, 172))	('Polybromo-1', 'Gene', (17, 28))	('Polybromo-1', 'Gene', '66923', (17, 28))
203105	28473526	BRCA1 associated protein-1 (BAP1), a deubiquitinating enzyme of the ubiquitin carboxyl-terminal hydrolase (UCH) family, and Set domain-containing 2 (SETD2), a histone methyltransferase that is specific for lysine 36 of histone H3, are found to be mutated in ~10 to 15% of ccRCC.	('SETD2', 'Gene', (149, 154))	('BRCA1 associated protein-1', 'Gene', '104416', (0, 26))	('BRCA1 associated protein-1', 'Gene', (0, 26))	('Set domain-containing 2', 'Gene', (124, 147))	('Set domain-containing 2', 'Gene', '235626', (124, 147))	('SETD2', 'Gene', '235626', (149, 154))	('RCC', 'Disease', (274, 277))	('BAP1', 'Gene', (28, 32))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('RCC', 'Disease', 'MESH:C538614', (274, 277))	('deubiquitinating enzyme', 'molecular_function', 'GO:0004843', ('37', '60'))	('mutated', 'Var', (247, 254))	('ubiquitin', 'molecular_function', 'GO:0031386', ('68', '77'))	('lysine', 'Chemical', 'MESH:D008239', (206, 212))
203106	28473526	Remarkably, PBRM1 mutation tends to anticorrelate with BAP1 mutation in ccRCC, and tumors with BAP1 versus PBRM1 mutation exhibit distinct biology with markedly different outcomes.	('PBRM1', 'Gene', (12, 17))	('mutation', 'Var', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('BAP1', 'Gene', (55, 59))	('RCC', 'Disease', (74, 77))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('mutation', 'Var', (18, 26))
203107	28473526	Tumors with BAP1 mutation are higher grade and more aggressive compared with PBRM1-deficient tumors, and patients have significantly shorter survival rates.	('survival rates', 'CPA', (141, 155))	('shorter', 'NegReg', (133, 140))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('more', 'PosReg', (47, 51))	('patients', 'Species', '9606', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('aggressive', 'CPA', (52, 62))	('PBRM1-deficient tumors', 'Disease', (77, 99))	('mutation', 'Var', (17, 25))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('PBRM1-deficient tumors', 'Disease', 'MESH:D009369', (77, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('BAP1', 'Gene', (12, 16))
203113	28473526	A possible explanation for this may be that in the mouse, Vhl is located on chromosome 6 while Pbrm1 and Bap1 are on chromosome 14, and thus LOH in the Vhl region in chromosome 6 would still leave two copies of Pbrm1 and Bap1 intact.	('Pbrm1', 'Gene', (211, 216))	('Pbrm1', 'Gene', '66923', (211, 216))	('chromosome', 'cellular_component', 'GO:0005694', ('117', '127'))	('Pbrm1', 'Gene', (95, 100))	('Pbrm1', 'Gene', '66923', (95, 100))	('mouse', 'Species', '10090', (51, 56))	('chromosome', 'cellular_component', 'GO:0005694', ('76', '86'))	('chromosome', 'cellular_component', 'GO:0005694', ('166', '176'))	('Bap1', 'Gene', (221, 225))	('LOH', 'Var', (141, 144))
203123	28473526	Here, we report a novel RCC GEMM based on Pax8-Cre deletion of Vhl together with either Bap1 or Pbrm1, and show that Bap1 and Pbrm1 are not only drivers of RCC, but also determinants of tumor grade.	('RCC', 'Disease', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('RCC', 'Disease', (156, 159))	('Pbrm1', 'Gene', (126, 131))	('Pbrm1', 'Gene', '66923', (126, 131))	('tumor', 'Disease', (186, 191))	('Pbrm1', 'Gene', (96, 101))	('Pbrm1', 'Gene', '66923', (96, 101))	('Vhl', 'Gene', (63, 66))	('deletion', 'Var', (51, 59))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
203143	28473526	Mouse cohorts harboring Pax8-Cre-driven deletion of Vhl and Bap1 were generated.	('deletion', 'Var', (40, 48))	('Vhl', 'Gene', (52, 55))	('Bap1', 'Gene', (60, 64))	('Mouse', 'Species', '10090', (0, 5))
203145	28473526	Deletion of Vhl leads to Hif-2 and Hif-1 activation and increased expression of target genes, including CyclinD1, Pai-1, Vegf, Glut1, Igfbp3, Pgk1, and Tgfa (Fig.	('CyclinD1', 'Gene', '12443', (104, 112))	('Igfbp3', 'Gene', '16009', (134, 140))	('Vegf', 'Gene', '22339', (121, 125))	('Hif-1', 'Gene', (35, 40))	('expression', 'MPA', (66, 76))	('Hif-2', 'Gene', (25, 30))	('Pai-1', 'Gene', '18787', (114, 119))	('Igfbp3', 'Gene', (134, 140))	('Vhl', 'Gene', (12, 15))	('3, Pgk', 'molecular_function', 'GO:0004618', ('139', '145'))	('activation', 'PosReg', (41, 51))	('CyclinD1', 'Gene', (104, 112))	('Pgk1', 'Gene', (142, 146))	('Deletion', 'Var', (0, 8))	('Tgfa', 'Gene', (152, 156))	('Pgk1', 'Gene', '18655', (142, 146))	('Tgfa', 'Gene', '21802', (152, 156))	('increased', 'PosReg', (56, 65))	('Glut1', 'Gene', '20512', (127, 132))	('Vegf', 'Gene', (121, 125))	('Pai-1', 'Gene', (114, 119))	('Glut1', 'Gene', (127, 132))
203147	28473526	BAP1 deubiquitinates H2A (lysine 119 in both human and mouse) and the level of ubiquitinated histone H2A protein (Ub-H2A) was dramatically increased (Fig.	('H2A', 'Gene', '8337', (21, 24))	('level of ubiquitinated histone', 'MPA', (70, 100))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('BAP1', 'Gene', (0, 4))	('H2A', 'Gene', (21, 24))	('H2A', 'Gene', '8337', (117, 120))	('increased', 'PosReg', (139, 148))	('H2A', 'Gene', '8337', (101, 104))	('lysine', 'Chemical', 'MESH:D008239', (26, 32))	('human', 'Species', '9606', (45, 50))	('mouse', 'Species', '10090', (55, 60))	('lysine 119', 'Var', (26, 36))	('H2A', 'Gene', (117, 120))	('H2A', 'Gene', (101, 104))	('deubiquitinates', 'MPA', (5, 20))
203148	28473526	Pax8-Cre;VhlF/F;Bap1F/F mice were born at expected Mendelian ratios, and lived longer than Six2-Cre;VhlF/F;Bap1F/F mice, which die shortly after birth.	('Six2', 'Gene', (91, 95))	('Pax8-Cre', 'Var', (0, 8))	('mice', 'Species', '10090', (24, 28))	('Six2', 'Gene', '20472', (91, 95))	('mice', 'Species', '10090', (115, 119))
203160	28473526	CAIX, a HIF target and marker of ccRCC, along with CD10, another routinely used ccRCC marker, exhibited the classic membranous (and cytoplasmic) staining pattern in cysts and neoplastic nodules in the mutants (Fig.	('RCC', 'Disease', (35, 38))	('neoplastic nodules', 'Phenotype', 'HP:0002664', (175, 193))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('mutants', 'Var', (201, 208))	('RCC', 'Disease', (82, 85))	('CD10', 'molecular_function', 'GO:0004245', ('51', '55'))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
203167	28473526	Cytologic features were similar to Pax8-Cre;VhlF/F;Bap1F/F cells, but were more pronounced including pleomorphism, nucleolar prominence, atypia, and mitosis (Fig.	('mitosis', 'Disease', (149, 156))	('mitosis', 'Disease', 'None', (149, 156))	('atypia', 'CPA', (137, 143))	('nucleolar prominence', 'CPA', (115, 135))	('pleomorphism', 'Var', (101, 113))	('mitosis', 'biological_process', 'GO:0000278', ('149', '156'))
203172	28473526	These data are consistent with the notion that loss of Vhl is insufficient for tumorigenesis.	('tumor', 'Disease', (79, 84))	('loss', 'Var', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('Vhl', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
203183	28473526	In contrast, Pax8-Cre;VhlF/F;Pbrm1F/F mice were born at expected Mendelian ratios, but were runty and smaller over the course of their lifetime compared to littermate controls (Fig.	('Pbrm1', 'Gene', (29, 34))	('Pbrm1', 'Gene', '66923', (29, 34))	('mice', 'Species', '10090', (38, 42))	('Pax8-Cre', 'Var', (13, 21))
203204	28473526	Spontaneous renal tumor development in Pax8-Cre;VhlF/F;Pbrm1F/F mice, but not other genetic configurations, indicates that Pax8-Cre-driven inactivation of both alleles of Vhl and Pbrm1 is required for ccRCC tumorigenesis.	('tumor', 'Disease', (18, 23))	('RCC', 'Disease', (203, 206))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('Pbrm1', 'Gene', (179, 184))	('Spontaneous renal tumor', 'Disease', 'MESH:D007674', (0, 23))	('Pbrm1', 'Gene', '66923', (179, 184))	('renal tumor', 'Phenotype', 'HP:0009726', (12, 23))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('Vhl', 'Gene', (171, 174))	('Spontaneous renal tumor', 'Disease', (0, 23))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('RCC', 'Disease', 'MESH:C538614', (203, 206))	('tumor', 'Disease', (207, 212))	('inactivation', 'Var', (139, 151))	('Pbrm1', 'Gene', (55, 60))	('mice', 'Species', '10090', (64, 68))	('Pbrm1', 'Gene', '66923', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
203210	28473526	To assess the role of mTORC1 in ccRCC tumor grade, we disrupted a single allele of the mTORC1 negative regulator, Tsc1.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('mTORC1', 'Gene', (87, 93))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('disrupted', 'Var', (54, 63))	('Tsc1', 'Gene', '64930', (114, 118))	('mTORC1', 'cellular_component', 'GO:0031931', ('87', '93'))	('mTORC1', 'Gene', (22, 28))	('mTORC1', 'cellular_component', 'GO:0031931', ('22', '28'))	('mTORC1', 'Gene', '382056', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('RCC', 'Disease', (34, 37))	('mTORC1', 'Gene', '382056', (22, 28))	('Tsc1', 'Gene', (114, 118))
203213	28473526	Interestingly, loss of one copy of Tsc1 in Pax8-Cre;VhlF/F;Pbrm1F/F;Tsc1F/+ mice led to the development of higher grade tumors in fifty percent of the mice analyzed (Fig.	('Tsc1', 'Gene', '64930', (35, 39))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('mice', 'Species', '10090', (151, 155))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('Tsc1', 'Gene', (68, 72))	('Tsc1', 'Gene', '64930', (68, 72))	('Pbrm1', 'Gene', (59, 64))	('loss', 'Var', (15, 19))	('mice', 'Species', '10090', (76, 80))	('Pbrm1', 'Gene', '66923', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('Tsc1', 'Gene', (35, 39))
203218	28473526	Consistent with our hypothesis, strong phospho-S6 was seen in the high grade tumors while low grade tumors in the same mice had weak (or absent) phospho-S6 expression (Fig.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('mice', 'Species', '10090', (119, 123))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('phospho-S6', 'Var', (39, 49))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))
203219	28473526	Overall, these data suggest that loss of one Tsc1 allele promotes the progression of lower grade Pbrm1-deficient tumors, into higher grade ccRCC, albeit at low frequency.	('RCC', 'Disease', (141, 144))	('Pbrm1-deficient tumors', 'Disease', (97, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('RCC', 'Disease', 'MESH:C538614', (141, 144))	('Tsc1', 'Gene', '64930', (45, 49))	('Tsc1', 'Gene', (45, 49))	('loss', 'Var', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('Pbrm1-deficient tumors', 'Disease', 'MESH:D009369', (97, 119))	('promotes', 'PosReg', (57, 65))
203221	28473526	Finally, while TSC1 mutations are infrequent in ccRCC, an analysis of COSMIC identifies several human ccRCC with mutations in VHL, PBRM1 and TSC1, establishing a proof-of-principle for this gene combination (Supplementary Fig.	('TSC1', 'Gene', (141, 145))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('TSC1', 'Gene', (15, 19))	('human', 'Species', '9606', (96, 101))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('mutations', 'Var', (113, 122))	('TSC1', 'Gene', '7248', (141, 145))	('VHL', 'Gene', (126, 129))	('PBRM1', 'Gene', (131, 136))	('TSC1', 'Gene', '7248', (15, 19))	('RCC', 'Disease', (104, 107))
203230	28473526	Interestingly, murine cohorts harboring Villin-Cre- or Sglt2-Cre-driven deletion of both alleles of Vhl together with both alleles of either Bap1 or Pbrm1 (n >= 14 for each genotype) failed to develop tumors even at an old age (24 to 30 months) (Supplementary Fig.	('Pbrm1', 'Gene', (149, 154))	('Pbrm1', 'Gene', '66923', (149, 154))	('murine', 'Species', '10090', (15, 21))	('Sglt2', 'Gene', '246787', (55, 60))	('Sglt2', 'Gene', (55, 60))	('develop', 'PosReg', (193, 200))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('Vhl', 'Gene', (100, 103))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('deletion', 'Var', (72, 80))
203233	28473526	While we cannot exclude that failure to develop tumors with Villin and Sglt2 drivers results from a reduced number of targeted cells, taken together, our data suggest that Villin- and Sglt2-lineage cells are not transformed by the combined loss of Vhl and either Bap1 or Pbrm1 and that these cells are not the likely source for ccRCC.	('RCC', 'Disease', (330, 333))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('loss', 'Var', (240, 244))	('Bap1', 'Gene', (263, 267))	('Pbrm1', 'Gene', '66923', (271, 276))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('Sglt2', 'Gene', '246787', (184, 189))	('Sglt2', 'Gene', (184, 189))	('Sglt2', 'Gene', '246787', (71, 76))	('Pbrm1', 'Gene', (271, 276))	('Sglt2', 'Gene', (71, 76))	('Vhl', 'Gene', (248, 251))	('RCC', 'Disease', 'MESH:C538614', (330, 333))
203235	28473526	Genomic analyses of ccRCC by us and others identified frequent mutation of the PBRM1 and BAP1 genes in 50% and 15% of tumors, respectively.	('BAP1', 'Gene', (89, 93))	('RCC', 'Disease', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('PBRM1', 'Gene', (79, 84))	('mutation', 'Var', (63, 71))	('RCC', 'Disease', 'MESH:C538614', (22, 25))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
203236	28473526	However, whether loss of BAP1 and PBRM1 causes ccRCC is not well understood.	('RCC', 'Disease', (49, 52))	('causes', 'Reg', (40, 46))	('BAP1', 'Gene', (25, 29))	('PBRM1', 'Gene', (34, 39))	('loss', 'Var', (17, 21))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
203237	28473526	Germline mutations in BAP1 and PBRM1 have been associated with ccRCC familial syndromes, but these mutations are rare and BAP1 germline mutations are primarily associated with other tumor types such as melanoma and mesothelioma.	('Germline mutations', 'Var', (0, 18))	('BAP1', 'Gene', (122, 126))	('mesothelioma', 'Disease', 'MESH:D008654', (215, 227))	('tumor', 'Disease', (182, 187))	('associated', 'Reg', (160, 170))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('PBRM1', 'Gene', (31, 36))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Disease', (202, 210))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('mesothelioma', 'Disease', (215, 227))	('associated', 'Reg', (47, 57))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('BAP1', 'Gene', (22, 26))	('RCC', 'Disease', (65, 68))
203242	28473526	We show that there is substantial overlap between Bap1 expression and the Pax8 lineage, and that by targeting Bap1 in this compartment, the survival of mice can be extended allowing for greater time to observe tumor development.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (210, 215))	('Bap1', 'Gene', (110, 114))	('mice', 'Species', '10090', (152, 156))	('Bap1', 'Gene', (50, 54))	('targeting', 'Var', (100, 109))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
203245	28473526	We previously reported that BAP1 and PBRM1 mutations in ccRCC tend to anticorrelate.	('PBRM1', 'Gene', (37, 42))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (43, 52))	('RCC', 'Disease', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
203247	28473526	Here, we show that targeting Pbrm1 (along with Vhl) to the Pax8 lineage also causes ccRCC.	('Pbrm1', 'Gene', (29, 34))	('targeting', 'Var', (19, 28))	('Pbrm1', 'Gene', '66923', (29, 34))	('causes', 'Reg', (77, 83))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))
203248	28473526	These data show that the Pax8 lineage contains cells capable of transformation by the loss of both Bap1 and Pbrm1.	('loss', 'Var', (86, 90))	('Bap1', 'Gene', (99, 103))	('Pbrm1', 'Gene', (108, 113))	('Pbrm1', 'Gene', '66923', (108, 113))
203251	28473526	These data suggest that gene targeting in proximal tubules is not sufficient to give rise to tumors challenging the notion that ccRCC arises from this compartment.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('gene targeting', 'Var', (24, 38))	('rise to tumors challenging', 'Disease', (85, 111))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('RCC', 'Disease', (130, 133))	('rise to tumors challenging', 'Disease', 'MESH:D009369', (85, 111))	('RCC', 'Disease', 'MESH:C538614', (130, 133))
203268	28473526	Targeting Tsc1 in kidneys along with Vhl and Pbrm1 led to the development of tumors that were similar to those observed in kidneys with intact Tsc1, but of higher grade.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('Tsc1', 'Gene', (143, 147))	('Tsc1', 'Gene', '64930', (143, 147))	('Tsc1', 'Gene', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('Tsc1', 'Gene', '64930', (10, 14))	('Pbrm1', 'Gene', (45, 50))	('Pbrm1', 'Gene', '66923', (45, 50))	('Targeting', 'Var', (0, 9))
203272	28473526	Overall, these data suggest that inactivation of one Tsc1 allele promotes the progression of lower grade Pbrm1-deficient tumors to high grade.	('Tsc1', 'Gene', (53, 57))	('Pbrm1-deficient tumors', 'Disease', 'MESH:D009369', (105, 127))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('progression', 'MPA', (78, 89))	('Tsc1', 'Gene', '64930', (53, 57))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('promotes', 'PosReg', (65, 73))	('Pbrm1-deficient tumors', 'Disease', (105, 127))	('inactivation', 'Var', (33, 45))
203274	28473526	Interestingly, while somatic mutations in TSC1 are infrequent in human ccRCC, several human ccRCC with mutations in VHL, PBRM1 and TSC1 have been reported.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('mutations', 'Var', (103, 112))	('TSC1', 'Gene', (131, 135))	('RCC', 'Disease', (94, 97))	('RCC', 'Disease', (73, 76))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('human', 'Species', '9606', (65, 70))	('human', 'Species', '9606', (86, 91))	('VHL', 'Gene', (116, 119))	('PBRM1', 'Gene', (121, 126))	('TSC1', 'Gene', '7248', (42, 46))	('TSC1', 'Gene', '7248', (131, 135))	('TSC1', 'Gene', (42, 46))
203278	28473526	While this manuscript was under review, a manuscript was published reporting the generation of mice with targeted disruption of Vhl and Pbrm1 in the mouse kidney.	('mice', 'Species', '10090', (95, 99))	('Pbrm1', 'Gene', (136, 141))	('Pbrm1', 'Gene', '66923', (136, 141))	('mouse', 'Species', '10090', (149, 154))	('disruption', 'Var', (114, 124))	('Vhl', 'Gene', (128, 131))
203337	28473526	Furthermore, we show that the conversion from low grade to high grade can be accelerated by activation of mTORC1.	('mTORC1', 'cellular_component', 'GO:0031931', ('106', '112'))	('activation', 'Var', (92, 102))	('mTORC1', 'Gene', (106, 112))	('mTORC1', 'Gene', '382056', (106, 112))
203343	32425115	MiR-148a-3p was a target miRNA of circUBAP2 in ccRCC cells, and its expression levels in ccRCC tissues and cell lines were negatively correlated with circUBAP2 levels.	('circUBAP2', 'Gene', (150, 159))	('RCC', 'Disease', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('MiR-148a-3p', 'Chemical', '-', (0, 11))	('negatively', 'NegReg', (123, 133))	('MiR-148a-3p', 'Var', (0, 11))	('circUBAP2', 'Gene', '55833', (150, 159))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (89, 94))	('miR', 'Gene', '220972', (25, 28))	('expression levels', 'MPA', (68, 85))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('RCC', 'Disease', (49, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('miR', 'Gene', (25, 28))	('correlated', 'Reg', (134, 144))	('circUBAP2', 'Gene', (34, 43))	('RCC', 'Disease', 'MESH:C538614', (49, 52))	('circUBAP2', 'Gene', '55833', (34, 43))
203344	32425115	Moreover, miR-148a-3p reversed the inhibitory effects of circUBAP2 on cell proliferation, migration, and invasion in ccRCC cells.	('invasion', 'CPA', (105, 113))	('circUBAP2', 'Gene', '55833', (57, 66))	('migration', 'CPA', (90, 99))	('circUBAP2', 'Gene', (57, 66))	('cell proliferation', 'biological_process', 'GO:0008283', ('70', '88'))	('cell proliferation', 'CPA', (70, 88))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('miR-148a-3p', 'Chemical', '-', (10, 21))	('RCC', 'Disease', (119, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('miR-148a-3p', 'Var', (10, 21))
203345	32425115	Additionally, forkhead box K2 (FOXK2) was found to be a target gene of miR-148a-3p and regulated by miR-148a-3p in ccRCC cells.	('miR-148a-3p', 'Chemical', '-', (71, 82))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('FOXK2', 'Gene', (31, 36))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('miR-148a-3p', 'Var', (71, 82))	('forkhead box K2', 'Gene', '3607', (14, 29))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('forkhead box K2', 'Gene', (14, 29))	('miR-148a-3p', 'Chemical', '-', (100, 111))	('FOXK2', 'Gene', '3607', (31, 36))	('regulated', 'Reg', (87, 96))	('miR-148a-3p', 'Var', (100, 111))
203346	32425115	Furthermore, knockdown of FOXK2 reversed the inhibitory effects of miR-148a-3p inhibitor on ccRCC cells.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('FOXK2', 'Gene', '3607', (26, 31))	('FOXK2', 'Gene', (26, 31))	('knockdown', 'Var', (13, 22))	('miR-148a-3p', 'Chemical', '-', (67, 78))	('inhibitory', 'MPA', (45, 55))
203362	32425115	These findings suggest that abnormal expression of circUBAP2 is involved in the development and progression of tumors.	('involved', 'Reg', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('abnormal', 'Var', (28, 36))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('circUBAP2', 'Gene', '55833', (51, 60))	('expression', 'MPA', (37, 47))	('circUBAP2', 'Gene', (51, 60))
203394	32425115	The wild-type (Wt) or mutant (Mut) sequences of circUBAP2 were cloned into the pMIR-REPORT luciferase vector (Ambion) and named as pMIR-circUBAP2-Wt and pMIR-circUBAP2-Mut, respectively.	('circUBAP2', 'Gene', '55833', (158, 167))	('circUBAP2', 'Gene', '55833', (136, 145))	('circUBAP2', 'Gene', (158, 167))	('circUBAP2', 'Gene', (136, 145))	('mutant', 'Var', (22, 28))	('circUBAP2', 'Gene', '55833', (48, 57))	('circUBAP2', 'Gene', (48, 57))
203403	32425115	After 48 h, circUBAP2 expression was markedly increased in pcDNA3.1-circUBAP2 transfected Caki-1 cells (Fig.	('circUBAP2', 'Gene', '55833', (12, 21))	('circUBAP2', 'Gene', (12, 21))	('increased', 'PosReg', (46, 55))	('circUBAP2', 'Gene', '55833', (68, 77))	('circUBAP2', 'Gene', (68, 77))	('expression', 'MPA', (22, 32))	('transfected', 'Var', (78, 89))	('Caki-1', 'CellLine', 'CVCL:0234', (90, 96))
203416	32425115	The results proved that miR-148a-3p expressions were markedly increased in both ccRCC tissues and cell lines, which indicated a negative correlation between miR-148a-3p and circUBAP2 levels (Fig.	('increased', 'PosReg', (62, 71))	('circUBAP2', 'Gene', '55833', (173, 182))	('circUBAP2', 'Gene', (173, 182))	('miR-148a-3p', 'Chemical', '-', (157, 168))	('negative', 'NegReg', (128, 136))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('miR-148a-3p', 'Chemical', '-', (24, 35))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('miR-148a-3p', 'Gene', (24, 35))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('miR-148a-3p', 'Var', (157, 168))	('expressions', 'MPA', (36, 47))
203420	32425115	6A, the expression of miR-148a-3p was significantly increased in circUBAP2-overexpressing Caki-1 cells.	('miR-148a-3p', 'Chemical', '-', (22, 33))	('increased', 'PosReg', (52, 61))	('miR-148a-3p', 'Var', (22, 33))	('expression', 'MPA', (8, 18))	('circUBAP2', 'Gene', '55833', (65, 74))	('circUBAP2', 'Gene', (65, 74))	('Caki-1', 'CellLine', 'CVCL:0234', (90, 96))
203421	32425115	Furthermore, compared to the circUBAP2-overexpressing Caki-1 cells, the proliferative ability of miR-148a-3p mimics-transfected Caki-1 cells was significantly increased (Fig.	('circUBAP2', 'Gene', '55833', (29, 38))	('circUBAP2', 'Gene', (29, 38))	('miR-148a-3p', 'Var', (97, 108))	('Caki-1', 'CellLine', 'CVCL:0234', (128, 134))	('proliferative ability', 'CPA', (72, 93))	('Caki-1', 'CellLine', 'CVCL:0234', (54, 60))	('increased', 'PosReg', (159, 168))	('miR-148a-3p', 'Chemical', '-', (97, 108))
203422	32425115	Besides, the migrative and invasive abilities were also promoted by transfection with miR-148a-3p mimics (Fig.	('transfection', 'Var', (68, 80))	('miR-148a-3p', 'Chemical', '-', (86, 97))	('promoted', 'PosReg', (56, 64))	('invasive abilities', 'CPA', (27, 45))	('miR-148a-3p', 'Var', (86, 97))
203424	32425115	The result indicated that there were complementarities between miR-148a-3p and FOXK2 (Fig.	('FOXK2', 'Gene', '3607', (79, 84))	('miR-148a-3p', 'Var', (63, 74))	('miR-148a-3p', 'Chemical', '-', (63, 74))	('FOXK2', 'Gene', (79, 84))
203425	32425115	Cotransfection with pMIR-FOXK2-Wt and miR-148a-3p mimics significantly suppressed the relative luciferase activity of Caki-1 cells, indicating that miR-148a-3p might directly bound to the 3'UTR of FOXK2 (Fig.	('FOXK2', 'Gene', (25, 30))	('luciferase activity', 'molecular_function', 'GO:0050248', ('95', '114'))	('miR-148a-3p', 'Var', (148, 159))	('bound', 'Interaction', (175, 180))	('Caki-1', 'CellLine', 'CVCL:0234', (118, 124))	('FOXK2', 'Gene', '3607', (197, 202))	('luciferase activity', 'molecular_function', 'GO:0045289', ('95', '114'))	('luciferase', 'Enzyme', (95, 105))	('FOXK2', 'Gene', (197, 202))	('miR-148a-3p', 'Chemical', '-', (38, 49))	('luciferase activity', 'molecular_function', 'GO:0047077', ('95', '114'))	('FOXK2', 'Gene', '3607', (25, 30))	('activity', 'MPA', (106, 114))	('luciferase activity', 'molecular_function', 'GO:0050397', ('95', '114'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('95', '114'))	('miR-148a-3p', 'Chemical', '-', (148, 159))	('suppressed', 'NegReg', (71, 81))
203426	32425115	In addition, western blot results showed that the protein expression level of FOXK2 was obviously suppressed by miR-148a-3p in Caki-1 cells (Fig.	('suppressed', 'NegReg', (98, 108))	('FOXK2', 'Gene', '3607', (78, 83))	('miR-148a-3p', 'Chemical', '-', (112, 123))	('FOXK2', 'Gene', (78, 83))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('miR-148a-3p', 'Var', (112, 123))	('protein expression level', 'MPA', (50, 74))	('Caki-1', 'CellLine', 'CVCL:0234', (127, 133))
203429	32425115	However, knockdown of FOXK2 was able to abolish the inhibitory effects of miR-148a-3p inhibitor on cell proliferation, migration, and invasion.	('cell proliferation', 'CPA', (99, 117))	('knockdown', 'Var', (9, 18))	('miR-148a-3p', 'Chemical', '-', (74, 85))	('FOXK2', 'Gene', '3607', (22, 27))	('FOXK2', 'Gene', (22, 27))	('invasion', 'CPA', (134, 142))	('cell proliferation', 'biological_process', 'GO:0008283', ('99', '117'))	('abolish', 'NegReg', (40, 47))	('migration', 'CPA', (119, 128))
203430	32425115	Increasing evidence showed that dysregulation of circRNAs is involved in a variety of diseases, including cancers, through modulating the cancer-related processes such as apoptosis, vascularization, invasion, and metastasis.	('modulating', 'Reg', (123, 133))	('cancer', 'Disease', (138, 144))	('circRNAs', 'Gene', (49, 57))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', (106, 112))	('cancers', 'Disease', (106, 113))	('metastasis', 'CPA', (213, 223))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('apoptosis', 'CPA', (171, 180))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('vascularization', 'CPA', (182, 197))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('invasion', 'CPA', (199, 207))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('apoptosis', 'biological_process', 'GO:0097194', ('171', '180'))	('dysregulation', 'Var', (32, 45))	('apoptosis', 'biological_process', 'GO:0006915', ('171', '180'))	('involved', 'Reg', (61, 69))
203445	32425115	It has been demonstrated that miR-148a-3p might be an oncogene in several cancers.	('miR-148a-3p', 'Chemical', '-', (30, 41))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('miR-148a-3p', 'Var', (30, 41))	('cancers', 'Disease', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
203447	32425115	MiR-148a-3p expression level is significantly higher in bladder cancer tissues than control tissues.	('MiR-148a-3p', 'Var', (0, 11))	('expression level', 'MPA', (12, 28))	('higher', 'PosReg', (46, 52))	('bladder cancer', 'Phenotype', 'HP:0009725', (56, 70))	('MiR-148a-3p', 'Chemical', '-', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('bladder cancer', 'Disease', 'MESH:D001749', (56, 70))	('bladder cancer', 'Disease', (56, 70))
203448	32425115	MiR-148a-3p promotes proliferation of bladder cancer cells and inhibits apoptosis of the cells, indicating a potential role in the future treatment of bladder cancer.	('bladder cancer', 'Disease', (151, 165))	('MiR-148a-3p', 'Var', (0, 11))	('proliferation', 'CPA', (21, 34))	('apoptosis of the cells', 'CPA', (72, 94))	('bladder cancer', 'Phenotype', 'HP:0009725', (38, 52))	('inhibits', 'NegReg', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('bladder cancer', 'Phenotype', 'HP:0009725', (151, 165))	('apoptosis', 'biological_process', 'GO:0097194', ('72', '81'))	('apoptosis', 'biological_process', 'GO:0006915', ('72', '81'))	('bladder cancer', 'Disease', 'MESH:D001749', (38, 52))	('bladder cancer', 'Disease', (38, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('promotes', 'PosReg', (12, 20))	('MiR-148a-3p', 'Chemical', '-', (0, 11))	('bladder cancer', 'Disease', 'MESH:D001749', (151, 165))
203449	32425115	demonstrated that miR-148a-3p is up-regulated in RCC and associates with DNA damage responses, cell cycle progression, and apoptosis.	('miR-148a-3p', 'Var', (18, 29))	('RCC', 'Disease', (49, 52))	('cell cycle', 'biological_process', 'GO:0007049', ('95', '105'))	('DNA damage responses', 'MPA', (73, 93))	('apoptosis', 'CPA', (123, 132))	('up-regulated', 'PosReg', (33, 45))	('apoptosis', 'biological_process', 'GO:0097194', ('123', '132'))	('associates', 'Reg', (57, 67))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('cell cycle progression', 'CPA', (95, 117))	('miR-148a-3p', 'Chemical', '-', (18, 29))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('apoptosis', 'biological_process', 'GO:0006915', ('123', '132'))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
203450	32425115	However, there is a gap in the study of miR-148a-3p in the development of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('miR-148a-3p', 'Chemical', '-', (40, 51))	('miR-148a-3p', 'Var', (40, 51))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))
203456	32425115	Many studies have investigated the potential role of FOXK2 deregulation in tumorigenesis.	('FOXK2', 'Gene', '3607', (53, 58))	('deregulation', 'Var', (59, 71))	('FOXK2', 'Gene', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
203460	32425115	We found that FOXK2 might be a target gene of miR-148a-3p and regulated by miR-148a-3p in Caki-1 cells.	('miR-148a-3p', 'Chemical', '-', (46, 57))	('miR-148a-3p', 'Chemical', '-', (75, 86))	('miR-148a-3p', 'Var', (46, 57))	('miR-148a-3p', 'Var', (75, 86))	('FOXK2', 'Gene', '3607', (14, 19))	('regulated', 'Reg', (62, 71))	('FOXK2', 'Gene', (14, 19))	('Caki-1', 'CellLine', 'CVCL:0234', (90, 96))
203461	32425115	Additionally, knockdown of FOXK2 in Caki-1 cells reversed the inhibitory effects of miR-148a-3p inhibitor on cell proliferation, migration, and invasion, indicating a crucial role of miR-148a-3p/FOXK2 axis underlying the mechanism of circUBAP2 in ccRCC.	('cell proliferation', 'CPA', (109, 127))	('miR-148a-3p', 'Chemical', '-', (183, 194))	('miR-148a-3p', 'Chemical', '-', (84, 95))	('Caki-1', 'CellLine', 'CVCL:0234', (36, 42))	('invasion', 'CPA', (144, 152))	('migration', 'CPA', (129, 138))	('RCC', 'Phenotype', 'HP:0005584', (249, 252))	('FOXK2', 'Gene', '3607', (195, 200))	('RCC', 'Disease', 'MESH:C538614', (249, 252))	('circUBAP2', 'Gene', '55833', (234, 243))	('RCC', 'Disease', (249, 252))	('circUBAP2', 'Gene', (234, 243))	('FOXK2', 'Gene', '3607', (27, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (247, 252))	('knockdown', 'Var', (14, 23))	('cell proliferation', 'biological_process', 'GO:0008283', ('109', '127'))	('FOXK2', 'Gene', (195, 200))	('FOXK2', 'Gene', (27, 32))
203472	29108390	The OS and RFS were shortened among the 198 (49.4%) patients with high Truncated-O-glycan score than among the 203 (50.6%) patients with low score (hazard ratio for OS, 7.060; 95% confidence interval [CI]: 2.765 to 18.027; p <0.001; for RFS, 4.612; 95% CI: 2.141 to 9.931; p <0.001).	('OS', 'Chemical', '-', (165, 167))	('OS', 'Chemical', '-', (4, 6))	('shortened', 'NegReg', (20, 29))	('to 9', 'Species', '1214577', (263, 267))	('patients', 'Species', '9606', (123, 131))	('RFS', 'Chemical', '-', (11, 14))	('Truncated-O-glycan', 'Protein', (71, 89))	('RFS', 'Chemical', '-', (237, 240))	('Truncated-O-glycan', 'Chemical', '-', (71, 89))	('high', 'Var', (66, 70))	('RFS', 'CPA', (11, 14))	('patients', 'Species', '9606', (52, 60))
203476	29108390	In summary, the high Truncated-O-glycan score could predict adverse clinical outcome in localized ccRCC patients after surgery.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('high', 'Var', (16, 20))	('patients', 'Species', '9606', (104, 112))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('Truncated-O-glycan score', 'Protein', (21, 45))	('Truncated-O-glycan', 'Chemical', '-', (21, 39))
203488	29108390	One of most common consequence is the expression of truncated O-glycans which occur infrequently in normal cells and tissues.	('O-glycans', 'Protein', (62, 71))	('truncated', 'Var', (52, 61))	('O-glycans', 'Chemical', '-', (62, 71))
203504	29108390	The specific expression of truncated O-glycans was observed in both cell membrane and intracellular space (Figure 1A, 1B, 1C, 1D).	('cell membrane', 'cellular_component', 'GO:0005886', ('68', '81'))	('O-glycans', 'Chemical', '-', (37, 46))	('truncated', 'Var', (27, 36))	('O-glycans', 'Protein', (37, 46))	('intracellular', 'cellular_component', 'GO:0005622', ('86', '99'))
203509	29108390	Patients with high Tn-antigen expression tended to have high Fuhrman grade, necrosis rate and sacromatoid risk (p = < 0.001, 0.001 and 0.036, respectively; Table 1).	('sacromatoid risk', 'Disease', (94, 110))	('necrosis', 'biological_process', 'GO:0070265', ('76', '84'))	('necrosis', 'biological_process', 'GO:0008219', ('76', '84'))	('necrosis', 'Disease', (76, 84))	('necrosis', 'biological_process', 'GO:0019835', ('76', '84'))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('necrosis', 'biological_process', 'GO:0008220', ('76', '84'))	('necrosis', 'Disease', 'MESH:D009336', (76, 84))	('Tn-antigen', 'Protein', (19, 29))	('high Tn-antigen', 'Phenotype', 'HP:0410372', (14, 29))	('high Fuhrman grade', 'CPA', (56, 74))	('necrosis', 'biological_process', 'GO:0001906', ('76', '84'))
203511	29108390	Patients with low sT-antigen expression tended to have smaller tumor size, lower necrosis rate and lower TNM stage (p = 0.032, 0.013 and 0.017, respectively; Table 1).	('necrosis', 'biological_process', 'GO:0008219', ('81', '89'))	('tumor', 'Disease', (63, 68))	('TNM', 'Gene', (105, 108))	('sT-antigen', 'Protein', (18, 28))	('lower', 'NegReg', (75, 80))	('necrosis', 'biological_process', 'GO:0019835', ('81', '89'))	('lower', 'NegReg', (99, 104))	('necrosis', 'biological_process', 'GO:0008220', ('81', '89'))	('necrosis', 'Disease', 'MESH:D009336', (81, 89))	('necrosis', 'biological_process', 'GO:0001906', ('81', '89'))	('smaller', 'NegReg', (55, 62))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('TNM', 'Gene', '10178', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('necrosis', 'Disease', (81, 89))	('low', 'Var', (14, 17))	('necrosis', 'biological_process', 'GO:0070265', ('81', '89'))
203513	29108390	As shown in Supplementary Figure S3, high Tn-, sTn- or sT-antigen expression tumors were associated with a worse prognosis than were low expression tumors (OS, p < 0.001; RFS, p < 0.001).	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('sTn', 'Gene', (47, 50))	('RFS', 'Chemical', '-', (171, 174))	('OS', 'Chemical', '-', (156, 158))	('sTn', 'Gene', '1917', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('high Tn-', 'Var', (37, 45))
203524	29108390	As a result, high Truncated-O-glycan score tumors is more common among tumor with high Fuhrman grade (p < 0.001) and high necrosis risk (p = 0.01).	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('necrosis', 'biological_process', 'GO:0019835', ('122', '130'))	('necrosis', 'biological_process', 'GO:0008220', ('122', '130'))	('high', 'Var', (13, 17))	('necrosis', 'Disease', 'MESH:D009336', (122, 130))	('necrosis', 'biological_process', 'GO:0001906', ('122', '130'))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('Truncated-O-glycan', 'Chemical', '-', (18, 36))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (43, 48))	('tumors', 'Disease', (43, 49))	('tumor', 'Disease', (71, 76))	('tumors', 'Disease', 'MESH:D009369', (43, 49))	('necrosis', 'biological_process', 'GO:0070265', ('122', '130'))	('necrosis', 'biological_process', 'GO:0008219', ('122', '130'))	('necrosis', 'Disease', (122, 130))
203525	29108390	Following Truncated-O-glycan score construction, we applied Harrell C-index to further evaluate the prognostic power of Truncated-O-glycan score compared to Tn-, sTn- and sT-antigen.	('Truncated-O-glycan score', 'Var', (120, 144))	('sTn', 'Gene', (162, 165))	('Truncated-O-glycan', 'Chemical', '-', (120, 138))	('Truncated-O-glycan', 'Chemical', '-', (10, 28))	('sTn', 'Gene', '1917', (162, 165))
203527	29108390	Patients with high Truncated-O-glycan score correlated with worse outcomes than those with low score (Figure 2A-2B), low rates of 5-year overall survival (76.3% vs 97.3%) and 5-year recurrence-free survival (76.3% vs 96.3%).	('Truncated-O-glycan', 'Protein', (19, 37))	('Truncated-O-glycan', 'Chemical', '-', (19, 37))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('low', 'NegReg', (117, 120))	('overall survival', 'CPA', (137, 153))
203529	29108390	In the analysis of overall survival, the hazard ratio for death of Truncated-O-glycan score was 7.060 (95% CI: 2.765 to 18.027; p < 0.001); and in the analysis of recurrence-free survival, the hazard ratio for relapse was 4.812 (95% CI: 2.141 to 9.931; p < 0.001).	('death', 'Disease', 'MESH:D003643', (58, 63))	('relapse', 'Disease', (210, 217))	('death', 'Disease', (58, 63))	('to 9', 'Species', '1214577', (243, 247))	('Truncated-O-glycan', 'Chemical', '-', (67, 85))	('Truncated-O-glycan score', 'Var', (67, 91))
203530	29108390	The consistent result has been observed when evaluate Truncated O-glycans score as a continuous variable in the COX regression analysis in addition to as a dichotomous variable (low/high) (Supplementary Table S5).	('O-glycans', 'Chemical', '-', (64, 73))	('Truncated', 'Var', (54, 63))	('COX', 'Gene', '1351', (112, 115))	('O-glycans', 'Protein', (64, 73))	('Truncated', 'Chemical', '-', (54, 63))	('COX', 'Gene', (112, 115))
203532	29108390	Patients with earlier TNM stages or lower SSIGN score associated high score displayed worse outcomes compared with those with low score associated advanced TNM stage or higher SSIGN score (p = 0.029).	('lower', 'NegReg', (36, 41))	('TNM', 'Gene', (22, 25))	('SSIGN score', 'MPA', (42, 53))	('high score', 'Var', (65, 75))	('TNM', 'Gene', '10178', (156, 159))	('Patients', 'Species', '9606', (0, 8))	('TNM', 'Gene', '10178', (22, 25))	('TNM', 'Gene', (156, 159))
203538	29108390	High score tumors were associated with worse prognosis than were low score tumors, with lower rates of 5-year overall survival risk and 5-year recurrence-free survival risk.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('High score', 'Var', (0, 10))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('lower', 'NegReg', (88, 93))	('tumors', 'Disease', (75, 81))
203544	29108390	For instance, localized ccRCC patients with high score may need adjuvant therapy and a more frequent follow-up after surgery, even though they are low-risk patients according to TNM stage.	('patients', 'Species', '9606', (156, 164))	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('TNM', 'Gene', (178, 181))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('patients', 'Species', '9606', (30, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (24, 29))	('high score', 'Var', (44, 54))	('TNM', 'Gene', '10178', (178, 181))
203659	30065959	Several pathological mechanisms have been proposed for AvWD, including specific or nonspecific antibodies to vWF, aberrant tumor expression of GP1b or GP IIb/IIIa receptors resulting in absorption of vWF, increased proteolytic degradation of vWF, or loss of high-volume vWF multimers under shear stress.	('GP IIb', 'Gene', '3674', (151, 157))	('increased', 'PosReg', (205, 214))	('vWF', 'Gene', (200, 203))	('vWF', 'Gene', '7450', (109, 112))	('vWF', 'Gene', (270, 273))	('degradation', 'biological_process', 'GO:0009056', ('227', '238'))	('tumor', 'Disease', (123, 128))	('vWF', 'Gene', '7450', (242, 245))	('loss', 'NegReg', (250, 254))	('vWD', 'Gene', '7450', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('vWF', 'Gene', (109, 112))	('GP1b', 'Gene', (143, 147))	('vWF', 'Gene', (242, 245))	('GP IIb', 'Gene', (151, 157))	('high-volume', 'MPA', (258, 269))	('proteolytic degradation', 'MPA', (215, 238))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('absorption', 'MPA', (186, 196))	('vWF', 'Gene', '7450', (200, 203))	('multimers under shear stress', 'MPA', (274, 302))	('aberrant', 'Var', (114, 122))	('vWD', 'Phenotype', 'HP:0012147', (56, 59))	('vWF', 'Gene', '7450', (270, 273))	('vWD', 'Gene', (56, 59))	('GP1b', 'Gene', '2811', (143, 147))
203673	33414440	MiR-153-5p was identified as a candidate miRNA to promote ccRCC occurrence and progression.	('promote', 'PosReg', (50, 57))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('progression', 'CPA', (79, 90))	('MiR-153-5p', 'Chemical', '-', (0, 10))	('MiR-153-5p', 'Var', (0, 10))
203674	33414440	Clinically, we found that miR-153-5p was significantly upregulated and related to unfavorable clinical features in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('miR-153-5p', 'Chemical', '-', (26, 36))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('miR-153-5p', 'Var', (26, 36))	('related', 'Reg', (71, 78))	('upregulated', 'PosReg', (55, 66))
203676	33414440	Functionally, miR-153-5p depletion remarkably inhibited the proliferation and metastasis of ccRCC via the phosphatidylinositol 3-kinase (PI3K)/Akt signaling.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('Akt signaling', 'biological_process', 'GO:0043491', ('143', '156'))	('PI3K', 'molecular_function', 'GO:0016303', ('137', '141'))	('Akt', 'Gene', (143, 146))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (106, 135))	('Akt', 'Gene', '207', (143, 146))	('miR-153-5p depletion', 'Var', (14, 34))	('miR-153-5p', 'Chemical', '-', (14, 24))	('proliferation', 'CPA', (60, 73))	('phosphatidylinositol 3-kinase', 'Gene', (106, 135))	('metastasis', 'CPA', (78, 88))	('inhibited', 'NegReg', (46, 55))
203677	33414440	Furthermore, AGO1 was proved to be a direct target of miR-153-5p.	('AGO1', 'Gene', '26523', (13, 17))	('miR-153-5p', 'Chemical', '-', (54, 64))	('AGO1', 'Gene', (13, 17))	('miR-153-5p', 'Var', (54, 64))
203679	33414440	Besides, we observed that AGO1 knockdown significantly promoted tumor proliferation and metastasis.	('AGO1', 'Gene', '26523', (26, 30))	('tumor', 'Disease', (64, 69))	('metastasis', 'CPA', (88, 98))	('AGO1', 'Gene', (26, 30))	('promoted', 'PosReg', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('knockdown', 'Var', (31, 40))
203680	33414440	Downregulation of AGO1 partly abolished the oncogenic effects of miR-153-5p knockdown.	('AGO1', 'Gene', (18, 22))	('Downregulation', 'NegReg', (0, 14))	('AGO1', 'Gene', '26523', (18, 22))	('oncogenic effects', 'CPA', (44, 61))	('miR-153-5p', 'Chemical', '-', (65, 75))	('miR-153-5p', 'Var', (65, 75))	('abolished', 'NegReg', (30, 39))
203681	33414440	Furthermore, miR-153-5p combined with AGO1 showed more robust prognostic significance in ccRCC.	('AGO1', 'Gene', '26523', (38, 42))	('miR-153-5p', 'Chemical', '-', (13, 23))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))	('miR-153-5p', 'Var', (13, 23))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('AGO1', 'Gene', (38, 42))
203690	33414440	miRNAs function as tumor suppressors or oncomiRNAs through downregulating the transcription of cancer-related genes by binding directly to the target sites in its 3'-untranslated regions (3'-UTR).	('binding', 'molecular_function', 'GO:0005488', ('119', '126'))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('downregulating', 'NegReg', (59, 73))	('cancer', 'Disease', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('transcription', 'MPA', (78, 91))	('tumor', 'Disease', (19, 24))	('miRNAs', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('binding', 'Interaction', (119, 126))	('transcription', 'biological_process', 'GO:0006351', ('78', '91'))
203691	33414440	Recent studies have reported that several miRNAs, such as miR-543, miR-223-3p, and miR-200b, were dysregulated and showed prognostic significance in kidney tumors.	('miR-223-3p', 'Var', (67, 77))	('miR-200b', 'Gene', '406984', (83, 91))	('kidney tumors', 'Disease', 'MESH:D007680', (149, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('kidney tumors', 'Disease', (149, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('miR-200b', 'Gene', (83, 91))	('significance', 'Reg', (133, 145))	('miR-543', 'Gene', (58, 65))	('dysregulated', 'Var', (98, 110))	('miR-543', 'Gene', '100126335', (58, 65))	('kidney tumors', 'Phenotype', 'HP:0009726', (149, 162))
203692	33414440	MiR-153-5p, generated from the 5'-arm of precursor miR-153, was found to be implicated in the pathological processes of cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('miR-153', 'Gene', '387171', (51, 58))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('implicated', 'Reg', (76, 86))	('MiR-153-5p', 'Chemical', '-', (0, 10))	('miR-153', 'Gene', (51, 58))	('MiR-153-5p', 'Var', (0, 10))
203693	33414440	A recent study has illustrated that miR-153-5p could abolish circPAN3-induced promotion of chemo-resistance in acute myeloid leukemia.	('miR-153-5p', 'Chemical', '-', (36, 46))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (117, 133))	('miR-153-5p', 'Var', (36, 46))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (111, 133))	('circPAN3', 'Gene', (61, 69))	('abolish', 'NegReg', (53, 60))	('promotion', 'PosReg', (78, 87))	('circPAN3', 'Gene', '255967', (61, 69))	('leukemia', 'Phenotype', 'HP:0001909', (125, 133))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (111, 133))	('acute myeloid leukemia', 'Disease', (111, 133))	('chemo-resistance', 'MPA', (91, 107))
203694	33414440	Interestingly, as the 3'-arm of precursor miR-153, miR-153-3p was reported to be downregulated and function as a tumor suppressor via targeting ZEB2 and Uc.416 + A in ccRCC.	('tumor', 'Disease', (113, 118))	('Uc.416 + A', 'Var', (153, 163))	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('targeting', 'Reg', (134, 143))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('113', '129'))	('downregulated', 'NegReg', (81, 94))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('RCC', 'Disease', (169, 172))	('tumor suppressor', 'biological_process', 'GO:0051726', ('113', '129'))	('ZEB2', 'Gene', '9839', (144, 148))	('miR-153', 'Gene', '387171', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('ZEB2', 'Gene', (144, 148))	('miR-153', 'Gene', '387171', (42, 49))	('miR-153-3p', 'Chemical', '-', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('miR-153', 'Gene', (42, 49))	('miR-153', 'Gene', (51, 58))
203697	33414440	MiR-153-5p was identified as overexpressed in ccRCC and closely related to poor prognosis and metastasis.	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('metastasis', 'CPA', (94, 104))	('related', 'Reg', (64, 71))	('overexpressed', 'PosReg', (29, 42))	('MiR-153-5p', 'Chemical', '-', (0, 10))	('RCC', 'Disease', (48, 51))	('MiR-153-5p', 'Var', (0, 10))
203698	33414440	We first demonstrated the oncogenic role of miR-153-5p and its underlying molecular mechanism in ccRCC.	('miR-153-5p', 'Chemical', '-', (44, 54))	('miR-153-5p', 'Var', (44, 54))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))
203699	33414440	Moreover, we initially verified argonaute (AGO) RNA-induced silencing complex (RISC) catalytic component 1 (AGO1) as the direct target of miR-153-5p and the function of AGO1 as a tumor suppressor in ccRCC.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('AGO1', 'Gene', (108, 112))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('AGO1', 'Gene', (169, 173))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('AGO1', 'Gene', '26523', (108, 112))	('RNA-induced silencing complex', 'cellular_component', 'GO:0016442', ('48', '77'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('179', '195'))	('miR-153-5p', 'Chemical', '-', (138, 148))	('miR-153-5p', 'Var', (138, 148))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('179', '195'))	('AGO1', 'Gene', '26523', (169, 173))	('tumor', 'Disease', (179, 184))
203700	33414440	According to our findings, we proposed that miR-153-5p combined with AGO1 may be a promising clinical prognostic assessment tool and therapeutic target.	('miR-153-5p', 'Var', (44, 54))	('AGO1', 'Gene', '26523', (69, 73))	('AGO1', 'Gene', (69, 73))	('miR-153-5p', 'Chemical', '-', (44, 54))
203705	33414440	Results indicated that miR-153-5p was significantly overexpressed in ccRCC tissue and downregulated in M0 groups as well as in the 5-yr group.	('miR-153-5p', 'Chemical', '-', (23, 33))	('miR-153-5p', 'Var', (23, 33))	('overexpressed', 'PosReg', (52, 65))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('downregulated', 'NegReg', (86, 99))
203706	33414440	Thus, we identified miR-153-5p as a candidate miRNA promoting ccRCC progression.	('promoting', 'PosReg', (52, 61))	('miR-153-5p', 'Chemical', '-', (20, 30))	('miR-153-5p', 'Var', (20, 30))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))
203708	33414440	2, the expression levels of miR-153-5p were significantly increased in ccRCC than those in normal tissue (Fig.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('increased', 'PosReg', (58, 67))	('RCC', 'Disease', (73, 76))	('expression levels', 'MPA', (7, 24))	('miR-153-5p', 'Chemical', '-', (28, 38))	('miR-153-5p', 'Var', (28, 38))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
203710	33414440	Higher expression of miR-153-5p was observed in the M1 group compared to that in the M0 group (Fig.	('expression', 'MPA', (7, 17))	('miR-153-5p', 'Chemical', '-', (21, 31))	('Higher', 'PosReg', (0, 6))	('miR-153-5p', 'Var', (21, 31))
203711	33414440	2C, P = 0.014) and, likewise, miR-153-5p overexpression was closely related to an increased prevalence of M1 (Table 1).	('overexpression', 'PosReg', (41, 55))	('miR-153-5p', 'Var', (30, 40))	('miR-153-5p', 'Chemical', '-', (30, 40))
203712	33414440	The upregulation of miR-153-5p was remarkably associated with the higher TNM (T: the size of tumor; N: lymph nodes involvement; M: distant metastasis) stage (Fig.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('miR-153-5p', 'Chemical', '-', (20, 30))	('TNM', 'Gene', '10178', (73, 76))	('miR-153-5p', 'Var', (20, 30))	('tumor', 'Disease', (93, 98))	('TNM', 'Gene', (73, 76))	('upregulation', 'PosReg', (4, 16))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
203713	33414440	Besides, the expression levels of miR-153-5p were elevated in patients with lymph node metastasis and higher T stage (Fig.	('expression levels', 'MPA', (13, 30))	('lymph node metastasis', 'CPA', (76, 97))	('elevated', 'PosReg', (50, 58))	('miR-153-5p', 'Chemical', '-', (34, 44))	('miR-153-5p', 'Var', (34, 44))	('patients', 'Species', '9606', (62, 70))
203714	33414440	Higher miR-153-5p was found in ccRCC with advanced histological grade (Fig.	('miR-153-5p', 'Chemical', '-', (7, 17))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('miR-153-5p', 'Var', (7, 17))
203715	33414440	2G, P = 0.008) and miR-153-5p overexpression showed a remarkable correlation with higher histologic grade (Table 1, P = 0.001).	('miR-153-5p', 'Var', (19, 29))	('overexpression', 'PosReg', (30, 44))	('miR-153-5p', 'Chemical', '-', (19, 29))
203716	33414440	Otherwise, ccRCC cell lines increased the expression of miR-153-5p compared to human renal tubular epithelial cells (Fig.	('increased', 'PosReg', (28, 37))	('human', 'Species', '9606', (79, 84))	('expression', 'MPA', (42, 52))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', (13, 16))	('miR-153-5p', 'Chemical', '-', (56, 66))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('miR-153-5p', 'Var', (56, 66))
203718	33414440	Results showed that low expression of miR-153-5p contributed to a favorable overall survival in ccRCC (Fig.	('expression', 'MPA', (24, 34))	('miR-153-5p', 'Chemical', '-', (38, 48))	('miR-153-5p', 'Var', (38, 48))	('low', 'NegReg', (20, 23))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (98, 101))
203720	33414440	These findings indicated that miR-153-5p was an independent prognostic biomarker in ccRCC.	('miR-153-5p', 'Chemical', '-', (30, 40))	('miR-153-5p', 'Var', (30, 40))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))
203722	33414440	Results showed that miR-153-5p was mainly enriched in DNA replication, proliferation, and other functions, and closely associated with PI3K/Akt signaling pathway (Fig.	('DNA replication', 'biological_process', 'GO:0006260', ('54', '69'))	('signaling pathway', 'biological_process', 'GO:0007165', ('144', '161'))	('miR-153-5p', 'Chemical', '-', (20, 30))	('miR-153-5p', 'Var', (20, 30))	('Akt', 'Gene', '207', (140, 143))	('Akt signaling', 'biological_process', 'GO:0043491', ('140', '153'))	('proliferation', 'CPA', (71, 84))	('PI3K', 'molecular_function', 'GO:0016303', ('135', '139'))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('Akt', 'Gene', (140, 143))	('DNA replication', 'CPA', (54, 69))	('associated', 'Reg', (119, 129))
203724	33414440	Results showed that the expression level of miR-153-5p was remarkably decreased after miR-153-5p depletion (Fig.	('expression level', 'MPA', (24, 40))	('miR-153-5p', 'Chemical', '-', (44, 54))	('decreased', 'NegReg', (70, 79))	('miR-153-5p depletion', 'Var', (86, 106))	('miR-153-5p', 'Chemical', '-', (86, 96))
203725	33414440	MiR-153-5p knockdown significantly downregulated cell proliferation rate (Fig.	('cell proliferation', 'biological_process', 'GO:0008283', ('49', '67'))	('cell proliferation rate', 'CPA', (49, 72))	('MiR-153-5p knockdown', 'Var', (0, 20))	('downregulated', 'NegReg', (35, 48))	('knockdown', 'Var', (11, 20))	('MiR-153-5p', 'Chemical', '-', (0, 10))
203726	33414440	Transwell assay showed that the migration and invasion ability of ccRCC cells obviously decreased after transfection with miR-153-5p inhibitor (Fig.	('miR-153-5p', 'Chemical', '-', (122, 132))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('decreased', 'NegReg', (88, 97))	('miR-153-5p inhibitor', 'Var', (122, 142))
203727	33414440	Likewise, miR-153-5p upregulation with miR-153-5p mimics significantly elevated proliferation, migration, and invasion of ccRCC (Fig.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('miR-153-5p mimics', 'Var', (39, 56))	('proliferation', 'CPA', (80, 93))	('elevated', 'PosReg', (71, 79))	('miR-153-5p', 'Chemical', '-', (10, 20))	('upregulation', 'PosReg', (21, 33))	('miR-153-5p', 'Chemical', '-', (39, 49))	('invasion', 'CPA', (110, 118))	('migration', 'CPA', (95, 104))
203729	33414440	Further investigation of the underlying mechanism of miR-153-5p, we found that miR-153-5p knockdown could significantly reduce the relative expression level of PI3K and p-Akt.	('PI3K', 'Pathway', (160, 164))	('knockdown', 'Var', (90, 99))	('reduce', 'NegReg', (120, 126))	('PI3K', 'molecular_function', 'GO:0016303', ('160', '164'))	('miR-153-5p', 'Chemical', '-', (79, 89))	('Akt', 'Gene', '207', (171, 174))	('Akt', 'Gene', (171, 174))	('relative expression level', 'MPA', (131, 156))	('miR-153-5p knockdown', 'Var', (79, 99))	('miR-153-5p', 'Chemical', '-', (53, 63))
203731	33414440	These results indicated that the PI3K/Akt pathway was involved in the stimulative effects of miR-153-5p on proliferation and metastasis (Fig.	('proliferation', 'CPA', (107, 120))	('Akt', 'Gene', '207', (38, 41))	('miR-153-5p', 'Chemical', '-', (93, 103))	('miR-153-5p', 'Var', (93, 103))	('PI3K', 'molecular_function', 'GO:0016303', ('33', '37'))	('Akt', 'Gene', (38, 41))
203735	33414440	We found AGO1 and CCDC68 were significantly downregulated in 786-O after transfection with miR-153-5p, whereas AGO1 were downregulated in TK10 (Fig.	('miR-153-5p', 'Var', (91, 101))	('downregulated', 'NegReg', (44, 57))	('CCDC68', 'Gene', (18, 24))	('AGO1', 'Gene', (111, 115))	('AGO1', 'Gene', (9, 13))	('CCDC68', 'Gene', '80323', (18, 24))	('downregulated', 'NegReg', (121, 134))	('AGO1', 'Gene', '26523', (111, 115))	('AGO1', 'Gene', '26523', (9, 13))	('miR-153-5p', 'Chemical', '-', (91, 101))
203738	33414440	Thus, we speculated that AGO1 may be the potential target of miR-153-5p.	('miR-153-5p', 'Chemical', '-', (61, 71))	('AGO1', 'Gene', '26523', (25, 29))	('miR-153-5p', 'Var', (61, 71))	('AGO1', 'Gene', (25, 29))
203739	33414440	4C, the sequence of the putative bindings are in 497-504, 1623-1630, and 4322-4329 bp of AGO1 3'-UTR.	('4322-4329 bp', 'Var', (73, 85))	('AGO1', 'Gene', '26523', (89, 93))	('AGO1', 'Gene', (89, 93))
203740	33414440	The protein expression of AGO1 was remarkably decreased after overexpression of miR-153-5p (Fig.	('protein expression', 'MPA', (4, 22))	('AGO1', 'Gene', '26523', (26, 30))	('AGO1', 'Gene', (26, 30))	('decreased', 'NegReg', (46, 55))	('miR-153-5p', 'Chemical', '-', (80, 90))	('miR-153-5p', 'Var', (80, 90))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
203742	33414440	We co-transfected HEK293T cells with miR-NC or miR-153-5p and pmiRGLO-3'-UTR vectors.	('miR-153-5p', 'Chemical', '-', (47, 57))	('miR-NC', 'Var', (37, 43))	('miR-153-5p', 'Var', (47, 57))	('HEK293T', 'CellLine', 'CVCL:0063', (18, 25))
203743	33414440	4F, the relative luciferase activities of wild-type AGO1 3'-UTR1 and 3'-UTR2 vectors were significantly reduced after transfection with miR-153-5p.	('activities', 'MPA', (28, 38))	('AGO1', 'Gene', (52, 56))	('reduced', 'NegReg', (104, 111))	('miR-153-5p', 'Chemical', '-', (136, 146))	('miR-153-5p', 'Var', (136, 146))	('UTR2', 'Gene', (72, 76))	('UTR2', 'Gene', '2837', (72, 76))	('AGO1', 'Gene', '26523', (52, 56))	('luciferase', 'Enzyme', (17, 27))
203744	33414440	On the contrary, the decrease of luciferase activity was fully abolished when mutant AGO1 3'-UTR1 and 3'-UTR2 were co-transfected with miR-153-5p.	('luciferase activity', 'molecular_function', 'GO:0050248', ('33', '52'))	('luciferase', 'Enzyme', (33, 43))	('luciferase activity', 'molecular_function', 'GO:0047077', ('33', '52'))	('abolished', 'NegReg', (63, 72))	('AGO1', 'Gene', '26523', (85, 89))	('activity', 'MPA', (44, 52))	('UTR2', 'Gene', (105, 109))	('UTR2', 'Gene', '2837', (105, 109))	('luciferase activity', 'molecular_function', 'GO:0045289', ('33', '52'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('33', '52'))	('miR-153-5p', 'Chemical', '-', (135, 145))	('AGO1', 'Gene', (85, 89))	('luciferase activity', 'molecular_function', 'GO:0050397', ('33', '52'))	('mutant', 'Var', (78, 84))
203745	33414440	However, the luciferase activity of wild-type AGO1 3'-UTR3 did not significantly downregulated when co-transfected with miR-153-5p.	('luciferase activity', 'molecular_function', 'GO:0045289', ('13', '32'))	('miR-153-5p', 'Chemical', '-', (120, 130))	('luciferase activity', 'molecular_function', 'GO:0047712', ('13', '32'))	('activity', 'MPA', (24, 32))	('downregulated', 'NegReg', (81, 94))	('luciferase activity', 'molecular_function', 'GO:0050397', ('13', '32'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('13', '32'))	('miR-153-5p', 'Var', (120, 130))	('AGO1', 'Gene', (46, 50))	('luciferase', 'Enzyme', (13, 23))	('luciferase activity', 'molecular_function', 'GO:0047077', ('13', '32'))	('AGO1', 'Gene', '26523', (46, 50))
203746	33414440	Collectively, these results demonstrated that AGO1 serves as a direct target of miR-153-5p.	('miR-153-5p', 'Var', (80, 90))	('miR-153-5p', 'Chemical', '-', (80, 90))	('AGO1', 'Gene', '26523', (46, 50))	('AGO1', 'Gene', (46, 50))
203752	33414440	AGO1 expression was decreased in patients with N1; however, no statistical significance was observed (Fig.	('patients', 'Species', '9606', (33, 41))	('decreased', 'NegReg', (20, 29))	('AGO1', 'Gene', '26523', (0, 4))	('N1', 'Var', (47, 49))	('AGO1', 'Gene', (0, 4))
203755	33414440	Our results have demonstrated that AGO1 was the direct target of miR-153-5p; we further determined whether AGO1 serves as a functional target gene.	('AGO1', 'Gene', (107, 111))	('AGO1', 'Gene', (35, 39))	('AGO1', 'Gene', '26523', (107, 111))	('miR-153-5p', 'Chemical', '-', (65, 75))	('miR-153-5p', 'Var', (65, 75))	('AGO1', 'Gene', '26523', (35, 39))
203757	33414440	6B, C, AGO1 knockdown significantly elevated the proliferation, migration, and invasion of ccRCC.	('AGO1', 'Gene', (7, 11))	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Disease', (93, 96))	('elevated', 'PosReg', (36, 44))	('proliferation', 'CPA', (49, 62))	('knockdown', 'Var', (12, 21))	('AGO1', 'Gene', '26523', (7, 11))	('invasion', 'CPA', (79, 87))	('migration', 'CPA', (64, 73))
203758	33414440	Besides, transfection with miR-153-5p inhibitor and/or si-AGO1 showed no obvious effects on the cell proliferation under serum-free culture conditions (Fig.	('miR-153-5p', 'Chemical', '-', (27, 37))	('si-AGO1', 'Gene', (55, 62))	('cell proliferation', 'CPA', (96, 114))	('si-AGO1', 'Gene', '26523', (55, 62))	('miR-153-5p', 'Var', (27, 37))	('cell proliferation', 'biological_process', 'GO:0008283', ('96', '114'))
203759	33414440	Next, we investigated whether the role of miR-153-5p on tumor progression was mediated via downregulation of AGO1.	('AGO1', 'Gene', '26523', (109, 113))	('downregulation', 'NegReg', (91, 105))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('miR-153-5p', 'Chemical', '-', (42, 52))	('AGO1', 'Gene', (109, 113))	('miR-153-5p', 'Var', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
203761	33414440	Results showed that proliferation, migration, and invasion were remarkably downregulated by the effect of miR-153-5p knockdown, which was significantly reversed by co-transfection with si-AGO1 (Fig.	('proliferation', 'CPA', (20, 33))	('invasion', 'CPA', (50, 58))	('migration', 'CPA', (35, 44))	('si-AGO1', 'Gene', (185, 192))	('downregulated', 'NegReg', (75, 88))	('si-AGO1', 'Gene', '26523', (185, 192))	('miR-153-5p', 'Chemical', '-', (106, 116))	('miR-153-5p knockdown', 'Var', (106, 126))	('knockdown', 'Var', (117, 126))
203762	33414440	To further explore the underlying mechanism of the AGO1-mediated effect of miR-153-5p, PI3K/Akt pathway was examined when cells were co-transfected with miR-153-5p inhibitor and si-AGO1.	('miR-153-5p', 'Chemical', '-', (75, 85))	('si-AGO1', 'Gene', (178, 185))	('miR-153-5p', 'Var', (75, 85))	('si-AGO1', 'Gene', '26523', (178, 185))	('Akt', 'Gene', '207', (92, 95))	('AGO1', 'Gene', '26523', (181, 185))	('AGO1', 'Gene', '26523', (51, 55))	('Akt', 'Gene', (92, 95))	('PI3K', 'molecular_function', 'GO:0016303', ('87', '91'))	('miR-153-5p', 'Chemical', '-', (153, 163))	('AGO1', 'Gene', (181, 185))	('AGO1', 'Gene', (51, 55))
203763	33414440	Results showed that the PI3K/Akt pathway was obviously suppressed by the effect of miR-153-5p knockdown, which was significantly reversed by co-transfection with si-AGO1 (Fig.	('knockdown', 'Var', (94, 103))	('Akt', 'Gene', '207', (29, 32))	('si-AGO1', 'Gene', (162, 169))	('Akt', 'Gene', (29, 32))	('PI3K', 'molecular_function', 'GO:0016303', ('24', '28'))	('si-AGO1', 'Gene', '26523', (162, 169))	('suppressed', 'NegReg', (55, 65))	('miR-153-5p', 'Chemical', '-', (83, 93))	('miR-153-5p knockdown', 'Var', (83, 103))
203764	33414440	Taken together, we concluded that AGO1 is a direct functional target of miR-153-5p.	('AGO1', 'Gene', '26523', (34, 38))	('miR-153-5p', 'Chemical', '-', (72, 82))	('AGO1', 'Gene', (34, 38))	('miR-153-5p', 'Var', (72, 82))
203765	33414440	We performed in vivo tumor growth assay to validate the effect of miR-153-5p in vivo.	('tumor', 'Disease', (21, 26))	('miR-153-5p', 'Chemical', '-', (66, 76))	('miR-153-5p', 'Var', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
203767	33414440	Results showed that the growth speed of tumors in the anti-miR-NC group was significantly faster than that in the anti-miR-153-5p group (Fig.	('miR-153-5p', 'Chemical', '-', (119, 129))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('anti-miR-NC', 'Var', (54, 65))	('faster', 'PosReg', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
203768	33414440	Besides, we conducted a prognosis analysis stratified by the expression level of miR-153-5p and AGO1 according to the TCGA dataset (Fig.	('AGO1', 'Gene', (96, 100))	('miR-153-5p', 'Chemical', '-', (81, 91))	('AGO1', 'Gene', '26523', (96, 100))	('miR-153-5p', 'Var', (81, 91))
203774	33414440	MiR-153-5p was identified as a candidate oncomiRNA and showed independent prognostic significance in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('MiR-153-5p', 'Chemical', '-', (0, 10))	('MiR-153-5p', 'Var', (0, 10))
203775	33414440	We found miR-153-5p knockdown remarkably inhibited ccRCC cell invasion, migration, and proliferation.	('miR-153-5p knockdown', 'Var', (9, 29))	('migration', 'CPA', (72, 81))	('proliferation', 'CPA', (87, 100))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('miR-153-5p', 'Chemical', '-', (9, 19))	('inhibited', 'NegReg', (41, 50))
203776	33414440	Suppression of PI3K/Akt signaling was observed after knockdown of miR-153-5p.	('PI3K', 'molecular_function', 'GO:0016303', ('15', '19'))	('miR-153-5p', 'Chemical', '-', (66, 76))	('Akt', 'Gene', '207', (20, 23))	('Akt signaling', 'biological_process', 'GO:0043491', ('20', '33'))	('miR-153-5p', 'Var', (66, 76))	('Suppression', 'NegReg', (0, 11))	('Akt', 'Gene', (20, 23))
203777	33414440	Moreover, AGO1 was verified to be a direct target of miR-153-5p and exhibited independent prognostic value.	('AGO1', 'Gene', (10, 14))	('miR-153-5p', 'Chemical', '-', (53, 63))	('AGO1', 'Gene', '26523', (10, 14))	('miR-153-5p', 'Var', (53, 63))
203779	33414440	In the rescue experiments, AGO1 knockdown could partly abolish the inhibition of proliferation and metastasis and reverse the suppression of PI3K/Akt signaling induced by knockdown of miR-153-5p.	('PI3K', 'molecular_function', 'GO:0016303', ('141', '145'))	('inhibition', 'NegReg', (67, 77))	('abolish', 'NegReg', (55, 62))	('Akt', 'Gene', (146, 149))	('AGO1', 'Gene', '26523', (27, 31))	('knockdown', 'Var', (32, 41))	('Akt signaling', 'biological_process', 'GO:0043491', ('146', '159'))	('Akt', 'Gene', '207', (146, 149))	('knockdown', 'Var', (171, 180))	('miR-153-5p', 'Chemical', '-', (184, 194))	('metastasis', 'CPA', (99, 109))	('proliferation', 'CPA', (81, 94))	('AGO1', 'Gene', (27, 31))	('miR-153-5p', 'Var', (184, 194))
203780	33414440	Furthermore, miR-153-5p combined with AGO1 may be a promising clinical prognostic assessment tool.	('AGO1', 'Gene', '26523', (38, 42))	('AGO1', 'Gene', (38, 42))	('miR-153-5p', 'Chemical', '-', (13, 23))	('miR-153-5p', 'Var', (13, 23))
203783	33414440	MiR-153-5p, as the homological fragment of miR-153-3p, its related studies are rare and the role of miR-153-5p on ccRCC remains to be explored.	('miR-153-3p', 'Chemical', '-', (43, 53))	('miR-153-5p', 'Chemical', '-', (100, 110))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))	('MiR-153-5p', 'Chemical', '-', (0, 10))	('MiR-153-5p', 'Var', (0, 10))
203784	33414440	Our results showed that miR-153-5p was significantly upregulated in the ccRCC tissues and cell lines.	('miR-153-5p', 'Chemical', '-', (24, 34))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('miR-153-5p', 'Var', (24, 34))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('upregulated', 'PosReg', (53, 64))
203785	33414440	MiR-153-5p depletion remarkably inhibited ccRCC cell proliferation and metastasis.	('MiR-153-5p depletion', 'Var', (0, 20))	('inhibited', 'NegReg', (32, 41))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('metastasis', 'CPA', (71, 81))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('MiR-153-5p', 'Chemical', '-', (0, 10))	('cell proliferation', 'biological_process', 'GO:0008283', ('48', '66'))
203786	33414440	Moreover, miR-153-5p is related to unfavorable clinical features and serves as an independent prognostic biomarker in ccRCC.	('miR-153-5p', 'Chemical', '-', (10, 20))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('miR-153-5p', 'Var', (10, 20))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))
203787	33414440	These findings suggested that miR-153-5p played a crucial role in tumorigenesis and progression.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('miR-153-5p', 'Chemical', '-', (30, 40))	('tumor', 'Disease', (66, 71))	('progression', 'CPA', (84, 95))	('miR-153-5p', 'Var', (30, 40))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
203789	33414440	MiR-153-5p was mainly enriched in PI3K/Akt signaling.	('Akt', 'Gene', '207', (39, 42))	('Akt signaling', 'biological_process', 'GO:0043491', ('39', '52'))	('PI3K', 'molecular_function', 'GO:0016303', ('34', '38'))	('Akt', 'Gene', (39, 42))	('MiR-153-5p', 'Chemical', '-', (0, 10))	('MiR-153-5p', 'Var', (0, 10))
203795	33414440	In the present study, we found that the PI3K/AKT pathway was significantly inhibited after miR-153-5p depletion, indicating that PI3K/AKT signaling may be involved in the oncogenic effect of miR-153-5p.	('AKT', 'Gene', (134, 137))	('depletion', 'Var', (102, 111))	('AKT', 'Gene', (45, 48))	('inhibited', 'NegReg', (75, 84))	('PI3K', 'molecular_function', 'GO:0016303', ('129', '133'))	('miR-153-5p', 'Chemical', '-', (191, 201))	('AKT signaling', 'biological_process', 'GO:0043491', ('134', '147'))	('AKT', 'Gene', '207', (134, 137))	('AKT', 'Gene', '207', (45, 48))	('PI3K', 'molecular_function', 'GO:0016303', ('40', '44'))	('miR-153-5p', 'Chemical', '-', (91, 101))	('miR-153-5p depletion', 'Var', (91, 111))
203802	33414440	Here we first found AGO1 was a direct target of oncomiRNA miR-153-5p and served as an independent biomarker in ccRCC with an HR value of 0.44.	('miR-153-5p', 'Chemical', '-', (58, 68))	('AGO1', 'Gene', '26523', (20, 24))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('miR-153-5p', 'Var', (58, 68))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('AGO1', 'Gene', (20, 24))
203803	33414440	AGO1 remarkably inhibited the proliferation and metastasis of ccRCC, and significantly abolished the oncogenic effects of miR-153-5p.	('oncogenic effects', 'CPA', (101, 118))	('inhibited', 'NegReg', (16, 25))	('abolished', 'NegReg', (87, 96))	('miR-153-5p', 'Chemical', '-', (122, 132))	('miR-153-5p', 'Var', (122, 132))	('AGO1', 'Gene', '26523', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))	('metastasis', 'CPA', (48, 58))	('AGO1', 'Gene', (0, 4))	('proliferation', 'CPA', (30, 43))
203804	33414440	Downregulation of AGO1 could reverse the inhibition of PI3K/Akt signaling caused by miR-153-5p knockdown.	('AGO1', 'Gene', (18, 22))	('Akt', 'Gene', '207', (60, 63))	('Downregulation', 'NegReg', (0, 14))	('miR-153-5p knockdown', 'Var', (84, 104))	('AGO1', 'Gene', '26523', (18, 22))	('knockdown', 'Var', (95, 104))	('Akt', 'Gene', (60, 63))	('PI3K', 'molecular_function', 'GO:0016303', ('55', '59'))	('Akt signaling', 'biological_process', 'GO:0043491', ('60', '73'))	('miR-153-5p', 'Chemical', '-', (84, 94))
203805	33414440	These findings demonstrated that AGO1, function as a tumor suppressor gene, was responsible for the oncogenic role of miR-153-5p.	('miR-153-5p', 'Var', (118, 128))	('tumor suppressor', 'biological_process', 'GO:0051726', ('53', '69'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('53', '69'))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('AGO1', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('miR-153-5p', 'Chemical', '-', (118, 128))	('AGO1', 'Gene', '26523', (33, 37))
203806	33414440	Notably, survival analysis showed that ccRCC patients with high miR-153-5p and low AGO1 had the worst prognosis than other patients, indicating that miR-153-5p together with AGO1 may be a promising clinical prognostic assessment tool.	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('AGO1', 'Gene', (83, 87))	('miR-153-5p', 'Chemical', '-', (64, 74))	('AGO1', 'Gene', '26523', (174, 178))	('patients', 'Species', '9606', (123, 131))	('AGO1', 'Gene', '26523', (83, 87))	('patients', 'Species', '9606', (45, 53))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('low', 'Var', (79, 82))	('miR-153-5p', 'Chemical', '-', (149, 159))	('miR-153-5p', 'Var', (149, 159))	('AGO1', 'Gene', (174, 178))	('RCC', 'Disease', (41, 44))	('high miR-153-5p', 'Var', (59, 74))
203809	33414440	Emerging evidence has indicated that several miRNAs, such as miR-221-3p and miR-126, could target VEGF signaling to mediate angiogenesis.	('VEGF', 'Gene', '7422', (98, 102))	('target', 'Reg', (91, 97))	('angiogenesis', 'biological_process', 'GO:0001525', ('124', '136'))	('miR-126', 'Gene', '406913', (76, 83))	('miR-221-3p', 'Var', (61, 71))	('VEGF', 'Gene', (98, 102))	('angiogenesis', 'CPA', (124, 136))	('VEGF signaling', 'biological_process', 'GO:0038084', ('98', '112'))	('miR-126', 'Gene', (76, 83))
203811	33414440	Recent studies have indicated that miR-153-5p could directly target Notch and regulate the angiogenesis in bladder tumors by targeting indoleamine 2,3-dioxygenase 1.	('angiogenesis', 'biological_process', 'GO:0001525', ('91', '103'))	('bladder tumors', 'Disease', (107, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('target', 'Reg', (61, 67))	('angiogenesis', 'CPA', (91, 103))	('regulate', 'Reg', (78, 86))	('Notch', 'Protein', (68, 73))	('miR-153-5p', 'Chemical', '-', (35, 45))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('miR-153-5p', 'Var', (35, 45))	('targeting', 'Reg', (125, 134))	('bladder tumors', 'Disease', 'MESH:D001749', (107, 121))	('bladder tumors', 'Phenotype', 'HP:0009725', (107, 121))	('indoleamine 2,3-dioxygenase 1', 'Gene', '3620', (135, 164))
203815	33414440	In summary, we demonstrated that miR-153-5p depletion could significantly inhibit the proliferation and metastasis of ccRCC, which was mediated via PI3K/Akt signaling.	('miR-153-5p depletion', 'Var', (33, 53))	('Akt', 'Gene', '207', (153, 156))	('metastasis', 'CPA', (104, 114))	('proliferation', 'CPA', (86, 99))	('inhibit', 'NegReg', (74, 81))	('Akt', 'Gene', (153, 156))	('PI3K', 'molecular_function', 'GO:0016303', ('148', '152'))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('miR-153-5p', 'Chemical', '-', (33, 43))	('Akt signaling', 'biological_process', 'GO:0043491', ('153', '166'))
203816	33414440	AGO1 was identified as a direct functional target of miR-153-5p.	('miR-153-5p', 'Chemical', '-', (53, 63))	('AGO1', 'Gene', (0, 4))	('miR-153-5p', 'Var', (53, 63))	('AGO1', 'Gene', '26523', (0, 4))
203818	33414440	Moreover, miR-153-5p combined with AGO1 showed more robust prognostic significance in ccRCC.	('AGO1', 'Gene', (35, 39))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('miR-153-5p', 'Chemical', '-', (10, 20))	('miR-153-5p', 'Var', (10, 20))	('AGO1', 'Gene', '26523', (35, 39))
203824	33414440	Antibodies to AGO1 (#5053), Akt (#9272 S), p-Akt (#9271 S), PI3K (#13857), and GAPDH (#5174 T) were from Cell Signaling Technology (Beverly, USA).	('Akt', 'Gene', (28, 31))	('Akt', 'Gene', (45, 48))	('GAPDH', 'Gene', (79, 84))	('PI3K', 'molecular_function', 'GO:0016303', ('60', '64'))	('AGO1', 'Gene', '26523', (14, 18))	('Akt', 'Gene', '207', (45, 48))	('#13857', 'Var', (66, 72))	('#9271 S', 'Var', (50, 57))	('#9272 S', 'Var', (33, 40))	('#5053', 'Var', (20, 25))	('Akt', 'Gene', '207', (28, 31))	('GAPDH', 'Gene', '2597', (79, 84))	('AGO1', 'Gene', (14, 18))	('#5174 T', 'Var', (86, 93))	('Signaling', 'biological_process', 'GO:0023052', ('110', '119'))
203830	33414440	After incubation overnight, the cells were transfected with miR-153-5p inhibitor/mimic, inhibitor/mimic NC, or AGO1 siRNA.	('miR-153-5p', 'Var', (60, 70))	('AGO1', 'Gene', (111, 115))	('miR-153-5p', 'Chemical', '-', (60, 70))	('AGO1', 'Gene', '26523', (111, 115))
203839	33414440	Primers of several genes were designed including miR-153-5p, AGO1, beta-actin, CCDC68, CDC73, PTEN, ATE1, and SCAI.	('beta-actin', 'Gene', '728378', (67, 77))	('CDC73', 'Gene', (87, 92))	('beta-actin', 'Gene', (67, 77))	('CCDC68', 'Gene', (79, 85))	('PTEN', 'Gene', (94, 98))	('SCAI', 'Gene', (110, 114))	('AGO1', 'Gene', '26523', (61, 65))	('SCAI', 'Gene', '286205', (110, 114))	('PTEN', 'Gene', '5728', (94, 98))	('ATE1', 'Gene', '11101', (100, 104))	('CDC73', 'Gene', '79577', (87, 92))	('CCDC68', 'Gene', '80323', (79, 85))	('miR-153-5p', 'Chemical', '-', (49, 59))	('miR-153-5p', 'Var', (49, 59))	('AGO1', 'Gene', (61, 65))	('ATE1', 'Gene', (100, 104))
203842	33414440	Cells were seeded in 24-well plates and then co-transfected with wild-type or mutated AGO1 3'-UTR constructs, and miR-153-5p mimics or NC.	('AGO1', 'Gene', (86, 90))	('miR-153-5p', 'Chemical', '-', (114, 124))	('AGO1', 'Gene', '26523', (86, 90))	('mutated', 'Var', (78, 85))
203852	33414440	GEPIA, LinkedOmics, and OncoLnc websites were employed to conduct the expression analysis and survival analysis of miR-153-5p or AGO1.	('AGO1', 'Gene', '26523', (129, 133))	('OncoLnc websites', 'Disease', (24, 40))	('AGO1', 'Gene', (129, 133))	('miR-153-5p', 'Chemical', '-', (115, 125))	('miR-153-5p', 'Var', (115, 125))	('OncoLnc websites', 'Disease', 'None', (24, 40))
203853	28765116	Bap1 and Pbrm1: Determinants of Tumor Grade and mTOR Activation in VHL-Deficient Mouse Models of Renal Cell Carcinoma Large genome sequencing efforts have identified frequent mutations in the histone-modifying and chromatin-remodeling genes BAP1 and PBRM1 in clear cell renal cell carcinoma (ccRCC).	('PBRM1', 'Gene', (250, 255))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (97, 117))	('mTOR', 'Gene', '56717', (48, 52))	('BAP1', 'Gene', (241, 245))	('mutations', 'Var', (175, 184))	('Tumor', 'Phenotype', 'HP:0002664', (32, 37))	('Pbrm1', 'Gene', '66923', (9, 14))	('Bap1', 'Gene', '104416', (0, 4))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (259, 290))	('VHL-Deficient', 'Disease', (67, 80))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (97, 117))	('Carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('mTOR', 'Gene', (48, 52))	('chromatin', 'cellular_component', 'GO:0000785', ('214', '223'))	('clear cell renal cell carcinoma', 'Disease', (259, 290))	('Bap1', 'Gene', (0, 4))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (270, 290))	('ccRCC', 'Phenotype', 'HP:0006770', (292, 297))	('RCC', 'Disease', (294, 297))	('RCC', 'Phenotype', 'HP:0005584', (294, 297))	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('214', '234'))	('VHL-Deficient', 'Disease', 'MESH:D006623', (67, 80))	('Mouse', 'Species', '10090', (81, 86))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (259, 290))	('RCC', 'Disease', 'MESH:C538614', (294, 297))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('Pbrm1', 'Gene', (9, 14))	('Renal Cell Carcinoma', 'Disease', (97, 117))
203854	28765116	In this issue of Cancer Discovery, Gu and colleagues model these genetic events in mice and report that dual inactivation of Vhl with either Bap1 or Pbrm1 results in faithful genetically engineered murine models of ccRCC.	('Pbrm1', 'Gene', (149, 154))	('Vhl', 'Gene', (125, 128))	('RCC', 'Disease', (217, 220))	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('murine', 'Species', '10090', (198, 204))	('ccRCC', 'Phenotype', 'HP:0006770', (215, 220))	('Cancer', 'Disease', (17, 23))	('mice', 'Species', '10090', (83, 87))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('Bap1', 'Gene', (141, 145))	('inactivation', 'Var', (109, 121))	('RCC', 'Phenotype', 'HP:0005584', (217, 220))
203857	28765116	Clear cell RCC (ccRCC) is the most common histology, and multiple studies have now established that inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is a key event in the vast majority of ccRCCs.	('RCC', 'Disease', (18, 21))	('RCC', 'Phenotype', 'HP:0005584', (18, 21))	('ccRCC', 'Phenotype', 'HP:0006770', (205, 210))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('144', '160'))	('inactivation', 'Var', (100, 112))	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('RCC', 'Disease', (207, 210))	('ccRCC', 'Phenotype', 'HP:0006770', (16, 21))	('von Hippel-Lindau (VHL) tumor suppressor', 'Gene', '22346', (120, 160))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (18, 21))	('tumor suppressor', 'biological_process', 'GO:0051726', ('144', '160'))
203858	28765116	Large-scale cancer genomic projects within the past half decade have identified recurrent, previously unrecognized loss-of-function mutations in multiple genes, including polybromo-1 (PBRM1), encoding BRG1-associated factor (BAF) 180, and BRCA1-associated protein-1 (BAP1), encoding a histone deubiquitinating enzyme of the ubiquitin carboxyl-terminal hydrolase (UCH) family.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('polybromo-1', 'Gene', (171, 182))	('BRG1-associated factor (BAF) 180', 'Gene', '66923', (201, 233))	('cancer', 'Disease', (12, 18))	('BRCA1-associated protein-1', 'Gene', (239, 265))	('ubiquitin', 'molecular_function', 'GO:0031386', ('324', '333'))	('mutations', 'Var', (132, 141))	('deubiquitinating enzyme', 'molecular_function', 'GO:0004843', ('293', '316'))	('loss-of-function', 'NegReg', (115, 131))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('BRCA1-associated protein-1', 'Gene', '104416', (239, 265))	('protein', 'cellular_component', 'GO:0003675', ('256', '263'))	('PBRM1', 'Gene', (184, 189))	('polybromo-1', 'Gene', '66923', (171, 182))	('BAP1', 'Gene', (267, 271))
203859	28765116	PBRM1 and BAP1 are mutated in 29% to 41% and 6% to 10% of ccRCCs, respectively, and mutations of PBRM1 and BAP1 are well documented to be mutually exclusive of each other, with BAP1-mutant ccRCC having a significant association with higher grade and worse prognosis.	('BAP1-mutant', 'Var', (177, 188))	('RCC', 'Disease', (191, 194))	('RCC', 'Phenotype', 'HP:0005584', (191, 194))	('BAP1', 'Gene', (10, 14))	('PBRM1', 'Gene', (0, 5))	('RCC', 'Disease', (60, 63))	('BAP1', 'Gene', (107, 111))	('mutated', 'Var', (19, 26))	('RCC', 'Disease', 'MESH:C538614', (191, 194))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (189, 194))	('PBRM1', 'Gene', (97, 102))
203864	28765116	Prior work by Brugarolas and colleagues has shown that deletion of Vhl and Bap1 using Six2-Cre in the kidney results in early lethality shortly after birth but that Vhl-null, Bap1 heterozygous mice develop ccRCC with a longer latency.	('Six2', 'Gene', '20472', (86, 90))	('Vhl', 'Gene', (67, 70))	('Bap1', 'Gene', (75, 79))	('RCC', 'Phenotype', 'HP:0005584', (208, 211))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('Six2', 'Gene', (86, 90))	('RCC', 'Disease', (208, 211))	('mice', 'Species', '10090', (193, 197))	('ccRCC', 'Phenotype', 'HP:0006770', (206, 211))	('deletion', 'Var', (55, 63))
203865	28765116	Codeletion of Vhl together with deletion of either Pbrm1 (Pax8-Cre; VhlF/F; Pbrm1F/F) or Bap1 (Pax8-Cre; VhlF/F; Bap1F/F) resulted in kidney tumors with features that faithfully recapitulate human ccRCC, including expression of markers CD10, vimentin, CAIX, and PAX8 and cytoplasmic accumulation of glycogen and lipid (Fig.	('deletion', 'Var', (32, 40))	('kidney tumors', 'Phenotype', 'HP:0009726', (134, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('CD10', 'Gene', (236, 240))	('CD10', 'molecular_function', 'GO:0004245', ('236', '240'))	('lipid', 'Chemical', 'MESH:D008055', (312, 317))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('vimentin', 'cellular_component', 'GO:0045098', ('242', '250'))	('cytoplasmic', 'MPA', (271, 282))	('human', 'Species', '9606', (191, 196))	('kidney tumors', 'Disease', (134, 147))	('glycogen', 'Chemical', 'MESH:D006003', (299, 307))	('Bap1', 'Gene', (89, 93))	('CAIX', 'Gene', (252, 256))	('resulted in', 'Reg', (122, 133))	('CAIX', 'Gene', '768', (252, 256))	('RCC', 'Disease', (199, 202))	('RCC', 'Phenotype', 'HP:0005584', (199, 202))	('vimentin', 'cellular_component', 'GO:0045099', ('242', '250'))	('ccRCC', 'Phenotype', 'HP:0006770', (197, 202))	('vimentin', 'Gene', '7431', (242, 250))	('kidney tumors', 'Disease', 'MESH:D007680', (134, 147))	('vimentin', 'Gene', (242, 250))	('CD10', 'Gene', '4311', (236, 240))	('Pbrm1', 'Gene', (51, 56))	('RCC', 'Disease', 'MESH:C538614', (199, 202))
203867	28765116	In general, the histologic features, penetrance, and latency of the tumors seen in the Pax8-Cre; VhlF/F; Pbrm1F/F mice were similar to recent work by Nargund and colleagues, who used the Ksp-Cre system to drive deletion of Vhl and Pbrm1.	('deletion', 'Var', (211, 219))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('Vhl', 'Gene', (223, 226))	('mice', 'Species', '10090', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Pbrm1', 'Gene', (231, 236))
203870	28765116	The authors go on to establish a causal role for aberrant mTORC1 activation as a determinant of tumor grade in Vhl-Pbrm1-deficient tumors.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('mTORC1', 'Gene', '382056', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('aberrant', 'Var', (49, 57))	('tumor', 'Disease', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Disease', (131, 136))	('deficient tumors', 'Disease', (121, 137))	('deficient tumors', 'Disease', 'MESH:D009369', (121, 137))	('mTORC1', 'Gene', (58, 64))	('mTORC1', 'cellular_component', 'GO:0031931', ('58', '64'))	('activation', 'PosReg', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
203871	28765116	Specifically, deletion of a single allele of the Tuberous Sclerosis 1 gene, Tsc1, which negatively regulates mTORC1, in Pax8-Cre; VhlF/F; Pbrm1F/F mice (Pax8-Cre; VhlF/F; Pbrm1F/F; TscF/+) resulted in an increased rate of high-grade tumors and a shortened tumor latency relative to Pax8-Cre; VhlF/F; Pbrm1F/F mice.	('shortened', 'NegReg', (246, 255))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('increased', 'PosReg', (204, 213))	('mTORC1', 'cellular_component', 'GO:0031931', ('109', '115'))	('Tuberous Sclerosis 1', 'Gene', '64930', (49, 69))	('Tsc1', 'Gene', '64930', (76, 80))	('mice', 'Species', '10090', (147, 151))	('Tuberous Sclerosis 1', 'Gene', (49, 69))	('tumor', 'Disease', (233, 238))	('deletion', 'Var', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('Tsc1', 'Gene', (76, 80))	('tumor', 'Disease', (256, 261))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Disease', (233, 239))	('mice', 'Species', '10090', (309, 313))	('mTORC1', 'Gene', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('mTORC1', 'Gene', '382056', (109, 115))
203873	28765116	Interestingly, a clinical trial that enriched for patients with poor-prognosis metastatic RCC, which although not known, likely enriches for high-grade ccRCC tumors, demonstrated that patients treated with temsirolimus have a longer overall survival and progression-free survival compared with patients treated with standard IFNalpha, thus confirming the importance of mTOR activation and potential of mTOR targeting in poor prognosis ccRCC.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('IFNalpha', 'Gene', '3439', (325, 333))	('RCC', 'Disease', (154, 157))	('RCC', 'Phenotype', 'HP:0005584', (154, 157))	('ccRCC', 'Phenotype', 'HP:0006770', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('RCC', 'Disease', (90, 93))	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('longer', 'PosReg', (226, 232))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('overall survival', 'CPA', (233, 249))	('ccRCC tumors', 'Disease', (152, 164))	('IFNalpha', 'Gene', (325, 333))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('patients', 'Species', '9606', (50, 58))	('RCC', 'Disease', (437, 440))	('RCC', 'Phenotype', 'HP:0005584', (437, 440))	('ccRCC tumors', 'Disease', 'MESH:D009369', (152, 164))	('progression-free survival', 'CPA', (254, 279))	('RCC', 'Disease', 'MESH:C538614', (437, 440))	('patients', 'Species', '9606', (184, 192))	('patients', 'Species', '9606', (294, 302))	('ccRCC', 'Phenotype', 'HP:0006770', (435, 440))	('temsirolimus', 'Var', (206, 218))	('temsirolimus', 'Chemical', 'MESH:C401859', (206, 218))
203874	28765116	Nonetheless, the mechanisms underlying how mTORC1 is activated by BAP1 loss and whether BAP1 mutation truly imparts enhanced sensitivity to mTOR inhibition remain unclear.	('enhanced', 'PosReg', (116, 124))	('activated', 'PosReg', (53, 62))	('mTORC1', 'Gene', (43, 49))	('BAP1', 'Gene', (66, 70))	('mTORC1', 'cellular_component', 'GO:0031931', ('43', '49'))	('loss', 'NegReg', (71, 75))	('sensitivity to mTOR inhibition', 'MPA', (125, 155))	('mTORC1', 'Gene', '382056', (43, 49))	('mutation', 'Var', (93, 101))	('BAP1', 'Gene', (88, 92))
203875	28765116	With respect to the latter point, analysis of a subset of patients from the RECORD-3 trial (randomized trial comparing first-line everolimus and sunitinib) demonstrates that of the everolimus-treated patients with metastatic ccRCC, those with BAP1 mutations had a shorter median progression-free survival than those with PBRM1 mutations, the opposite of what would be predicted by the current work.	('PBRM1', 'Gene', (321, 326))	('BAP1', 'Gene', (243, 247))	('RCC', 'Disease', (227, 230))	('mutations', 'Var', (248, 257))	('RCC', 'Phenotype', 'HP:0005584', (227, 230))	('patients', 'Species', '9606', (200, 208))	('RCC', 'Disease', 'MESH:C538614', (227, 230))	('progression-free survival', 'CPA', (279, 304))	('sunitinib', 'Chemical', 'MESH:D000077210', (145, 154))	('shorter', 'NegReg', (264, 271))	('everolimus', 'Chemical', 'MESH:D000068338', (130, 140))	('everolimus', 'Chemical', 'MESH:D000068338', (181, 191))	('patients', 'Species', '9606', (58, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (225, 230))
203881	28765116	Second, although inactivation of VhlF/F; Bap1F/F or VhlF/F; Pbrm1F/F using Pax8-Cre gave rise to ccRCC as above, inactivation of these same genes using Cre drivers expressed solely in proximal tubules (Villin-Cre and Sglt2-Cre) did not give rise to renal tumors (Fig.	('inactivation', 'Var', (17, 29))	('renal tumors', 'Disease', 'MESH:D007674', (249, 261))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('renal tumors', 'Disease', (249, 261))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('renal tumors', 'Phenotype', 'HP:0009726', (249, 261))	('inactivation', 'Var', (113, 125))
203888	28765116	The faithful Vhl-Bap1 and Vhl-Pbrm1 GEM models developed by Gu and colleagues add to the recent salvo of GEM models of ccRCC based upon concurrent deletion of Vhl, p53, and Rb1 by Frew and colleagues or the inactivation of Vhl and Cdkn2a with concurrent activation of MYC by our group.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('Rb1', 'Gene', (173, 176))	('Cdkn2a', 'Gene', '12578', (231, 237))	('RCC', 'Disease', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('Rb1', 'Gene', '19645', (173, 176))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('MYC', 'Gene', '17869', (268, 271))	('Cdkn2a', 'Gene', (231, 237))	('MYC', 'Gene', (268, 271))	('deletion', 'Var', (147, 155))	('Vhl', 'Gene', (223, 226))	('inactivation', 'Var', (207, 219))	('p53', 'Gene', '22059', (164, 167))	('p53', 'Gene', (164, 167))	('Vhl', 'Gene', (159, 162))
203907	32226492	Clear cell renal cell carcinoma(ccRCC), associated with mutation of von Hippel-Lindau gene(VHL), is the most common subtype of RCC.	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (68, 85))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (32, 37))	('VHL', 'Disease', (91, 94))	('VHL', 'Disease', 'MESH:D006623', (91, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('von Hippel-Lindau', 'Disease', (68, 85))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('mutation', 'Var', (56, 64))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('associated', 'Reg', (40, 50))	('RCC', 'Disease', (34, 37))
203945	32226492	Next, membranes were washed with TBST, blocked with 5% skimmed milk and incubated with antibodies against GAPDH (1:1000, sc-202525, Santa Cruz, CA, USA) and HIF1A (1:1000, ab16066, Abcam, USA).	('GAPDH', 'Gene', (106, 111))	('HIF1A', 'Gene', (157, 162))	('HIF1A', 'Gene', '3091', (157, 162))	('1:1000', 'Var', (113, 119))	('GAPDH', 'Gene', '2597', (106, 111))	('1:1000', 'Var', (164, 170))
203968	32226492	Moreover, the clinical information of 517 ccRCC patients in TCGA showed that patients with low expression of HIF1A and high expression of PVT1 have poorer survival (Fig.4E and 4F).	('low', 'NegReg', (91, 94))	('clinical', 'Species', '191496', (14, 22))	('HIF1A', 'Gene', (109, 114))	('high expression', 'Var', (119, 134))	('HIF1A', 'Gene', '3091', (109, 114))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (42, 47))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('poorer', 'NegReg', (148, 154))	('PVT1', 'Gene', (138, 142))	('patients', 'Species', '9606', (77, 85))	('patients', 'Species', '9606', (48, 56))	('PVT1', 'Gene', '5820', (138, 142))	('survival', 'MPA', (155, 163))
203991	32226492	A large number of researches had indicated that abnormally expressed miRNAs could be served as an early diagnosis or prognostic markers for various cancer patients.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('abnormally expressed', 'Var', (48, 68))	('miRNAs', 'Protein', (69, 75))	('patients', 'Species', '9606', (155, 163))
203997	32226492	In the present study, we obtained mRNA datasets (GSE66270, GSE53757) and miRNA datasets (GSE12105, GSE23085) from GEO database to screen the DEGs and DEMs between ccRCC and adjacent normal tissues by bioinformatics analyses.	('GSE66270', 'Var', (49, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (163, 168))	('GSE53757', 'Var', (59, 67))	('GSE12105', 'Var', (89, 97))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('RCC', 'Disease', (165, 168))
204011	32226492	In addition, Data of TCGA reveal that patients with high expression of miRNA-18a had significantly poorer overall survival and it is an independent risk factor.	('poorer', 'NegReg', (99, 105))	('overall', 'MPA', (106, 113))	('miRNA-18a', 'Gene', (71, 80))	('patients', 'Species', '9606', (38, 46))	('high expression', 'Var', (52, 67))	('miRNA-18a', 'Gene', '406953', (71, 80))
204014	32226492	ccRCC clear cell renal cell carcinoma DEGs different expressed genes GEO Gene Expression Omnibus TCGA The Cancer Genome Atlas HR hazard ratio CI confidence interval IHC Immunohistochemistry OS overall survival HIF1A hypoxia inducible factor 1 subunit alpha PVT1 Plasmacytoma Variant Translocation 1	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (6, 37))	('Plasmacytoma', 'Phenotype', 'HP:0011857', (262, 274))	('Cancer Genome Atlas', 'Disease', (106, 125))	('hypoxia', 'Disease', (216, 223))	('Variant', 'Var', (275, 282))	('RCC', 'Disease', (2, 5))	('OS', 'Chemical', 'MESH:D009992', (190, 192))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('Cancer', 'Phenotype', 'HP:0002664', (106, 112))	('hypoxia', 'Disease', 'MESH:D000860', (216, 223))	('Gene Expression', 'biological_process', 'GO:0010467', ('73', '88'))	('HIF1A', 'Gene', '3091', (210, 215))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (17, 37))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (6, 37))	('PVT1', 'Gene', (257, 261))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('PVT1', 'Gene', '5820', (257, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('clear cell renal cell carcinoma', 'Disease', (6, 37))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (106, 125))	('HIF1A', 'Gene', (210, 215))
204018	33302383	We identified death-associated protein kinase 3 (DAPK3); transcription activation suppressor (TASOR); family with sequence similarity 27, member C, long non-coding RNA (FAM27C); and UDP-N-acetylglucosaminyltransferase subunit (ALG13) as the gene master regulators of the four profiled regions and proposed molecular mechanisms by which expression manipulation of TASOR and ALG13 may selectively destroy the cancer cells without affecting many of the normal cells.	('death-associated protein kinase 3', 'Gene', (14, 47))	('cancer', 'Disease', (407, 413))	('cancer', 'Phenotype', 'HP:0002664', (407, 413))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('ALG13', 'Gene', '79868', (373, 378))	('DAPK3', 'Gene', '1613', (49, 54))	('ALG13', 'Gene', '79868', (227, 232))	('cancer', 'Disease', 'MESH:D009369', (407, 413))	('expression manipulation', 'Var', (336, 359))	('ALG13', 'Gene', (373, 378))	('death-associated protein kinase 3', 'Gene', '1613', (14, 47))	('RNA', 'cellular_component', 'GO:0005562', ('164', '167'))	('TASOR', 'Gene', (363, 368))	('transcription', 'biological_process', 'GO:0006351', ('57', '70'))	('DAPK3', 'Gene', (49, 54))	('ALG13', 'Gene', (227, 232))	('FAM27C', 'Gene', (169, 175))	('destroy', 'NegReg', (395, 402))	('FAM27C', 'Gene', '100132948', (169, 175))
204034	33302383	Thus, only VHL (von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase; 5.64%), PBRM1 (polybromo 1; 4.83%), TTN (titin; 4.67%), and MUC4 (mucin 4, cell surface associated; 2.67%) were mutated in more than 2% of the profiled cases.	('MUC4', 'Gene', '4585', (141, 145))	('PBRM1', 'Gene', '55193', (89, 94))	('ubiquitin', 'molecular_function', 'GO:0031386', ('55', '64'))	('MUC4', 'Gene', (141, 145))	('polybromo 1', 'Gene', '55193', (96, 107))	('mucin 4', 'Gene', '4585', (147, 154))	('PBRM1', 'Gene', (89, 94))	('von Hippel-Lindau tumor', 'Disease', 'MESH:D006623', (16, 39))	('VHL', 'Gene', (11, 14))	('titin', 'Gene', '7273', (122, 127))	('TTN', 'Gene', '7273', (117, 120))	('titin', 'Gene', (122, 127))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('polybromo 1', 'Gene', (96, 107))	('mucin 4', 'Gene', (147, 154))	('mutated', 'Var', (193, 200))	('TTN', 'Gene', (117, 120))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('VHL', 'Gene', '7428', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))	('cell surface', 'cellular_component', 'GO:0009986', ('156', '168'))	('von Hippel-Lindau tumor', 'Disease', (16, 39))
204037	33302383	concluded that in the cohort of profiled RCC patients, VHL was mutated in 41.3% of the cases and PRBM1 in 38.1%, although neither of these high frequencies was associated with the overall survival.	('mutated', 'Var', (63, 70))	('patients', 'Species', '9606', (45, 53))	('VHL', 'Gene', (55, 58))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))	('PRBM1', 'Gene', (97, 102))	('VHL', 'Gene', '7428', (55, 58))
204110	33302383	We are yet to figure out a likely action mechanism for the non-coding FAM27C in PTB.	('FAM27C', 'Gene', (70, 76))	('non-coding', 'Var', (59, 69))	('FAM27C', 'Gene', '100132948', (70, 76))
204119	33302383	Therefore, we hypothesize that knocking down ALG13 will significantly slow down the cell cycle (hence cell proliferation) in CWM by downregulating the synergistically expressed CC genes.	('ALG13', 'Gene', '79868', (45, 50))	('knocking down', 'Var', (31, 44))	('slow down', 'NegReg', (70, 79))	('cell cycle', 'biological_process', 'GO:0007049', ('84', '94'))	('downregulating', 'NegReg', (132, 146))	('cell proliferation', 'biological_process', 'GO:0008283', ('102', '120'))	('cell cycle', 'CPA', (84, 94))	('ALG13', 'Gene', (45, 50))	('cell proliferation', 'CPA', (102, 120))
204120	33302383	In NOR cells, acceleration and deceleration caused by knocking down ALG13 will be practically balanced (Figure 8b), owing to the 3:4 synergistic/antagonistic pairing with ALG13.	('ALG13', 'Gene', (68, 73))	('ALG13', 'Gene', (171, 176))	('ALG13', 'Gene', '79868', (171, 176))	('knocking down', 'Var', (54, 67))	('NOR', 'cellular_component', 'GO:0005731', ('3', '6'))	('ALG13', 'Gene', '79868', (68, 73))
204122	33302383	Therefore, it is expected that knocking down ALG13 will downregulate these genes in CWM while upregulating them in NOR.	('ALG13', 'Gene', '79868', (45, 50))	('knocking down', 'Var', (31, 44))	('NOR', 'cellular_component', 'GO:0005731', ('115', '118'))	('downregulate', 'NegReg', (56, 68))	('ALG13', 'Gene', (45, 50))	('upregulating', 'PosReg', (94, 106))
204123	33302383	The knocking down of ALG13 would restore the normal CC pathway in CWM affected by the upregulation of 25% of its genes (0% downregulation).	('CC pathway', 'Pathway', (52, 62))	('restore', 'PosReg', (33, 40))	('knocking down', 'Var', (4, 17))	('upregulation', 'PosReg', (86, 98))	('ALG13', 'Gene', '79868', (21, 26))	('ALG13', 'Gene', (21, 26))
204136	33302383	However, we validated that manipulation of the expression of a gene has transcriptomic effects positively correlated with the GCH of that gene  (iii) At the time, we also had no possibility to perform additional molecular experiments for functional validation of the investigated pathways.	('transcriptomic', 'MPA', (72, 86))	('men', 'Species', '9606', (228, 231))	('manipulation', 'Var', (27, 39))
204162	33302383	We used the coordination analysis to identify the molecular mechanisms by which manipulation of cancer GMRs may selectively affect the cancer cells.	('manipulation', 'Var', (80, 92))	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('affect', 'Reg', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
204176	33302383	Correlation analysis further indicated that silencing ALG13 via siRNA or CRISPR (clustered regularly interspaced short palindromic repeats) would downregulate numerous cell cycle genes in CWM while keeping a relative balance in NOR.	('cell cycle genes', 'Gene', (168, 184))	('cell cycle', 'biological_process', 'GO:0007049', ('168', '178'))	('NOR', 'cellular_component', 'GO:0005731', ('228', '231'))	('ALG13', 'Gene', (54, 59))	('silencing', 'Var', (44, 53))	('ALG13', 'Gene', '79868', (54, 59))	('downregulate', 'NegReg', (146, 158))
204177	33302383	High expression of ALG13 was associated with poor overall survival in non-small cell lung cancer.	('ALG13', 'Gene', (19, 24))	('lung cancer', 'Disease', (85, 96))	('High', 'Var', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (74, 96))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (70, 96))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('ALG13', 'Gene', '79868', (19, 24))	('poor', 'NegReg', (45, 49))
204178	33302383	Thus, silencing ALG13 would have both direct and indirect (mediated by CC genes) on the cancer cells.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('ALG13', 'Gene', '79868', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('silencing', 'Var', (6, 15))	('ALG13', 'Gene', (16, 21))
204183	33302383	In time, the industry will produce shelf-ready constructs for almost all genes, which will considerably reduce not only the costs of the therapy but also the interval from genomic diagnostic to the treatment application.	('genes', 'Var', (73, 78))	('men', 'Species', '9606', (203, 206))	('reduce', 'NegReg', (104, 110))
204194	27572319	Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer Renal cell carcinoma (RCC) is increasing in incidence, and a complete cure remains elusive.	('Inhibiting', 'Var', (0, 10))	('tryptophan', 'Chemical', 'MESH:D014364', (11, 21))	('cancer Renal cell carcinoma', 'Phenotype', 'HP:0005584', (71, 98))	('enhances', 'PosReg', (33, 41))	('tryptophan metabolism', 'biological_process', 'GO:0006568', ('11', '32'))	('Renal cell carcinoma', 'Disease', (78, 98))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('interferon therapy', 'MPA', (42, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('kidney cancer', 'Disease', 'MESH:D007680', (64, 77))	('kidney cancer', 'Phenotype', 'HP:0009726', (64, 77))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('Renal cell carcinoma', 'Disease', 'MESH:C538614', (78, 98))	('kidney cancer', 'Disease', (64, 77))
204212	27572319	In light of these associations and our previous data, we asked whether inhibition of the kynurenine pathway in vivo inhibits tumor growth in a mouse model of immune-stimulated kidney cancer.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('stimulated kidney', 'Phenotype', 'HP:0000105', (165, 182))	('inhibition', 'Var', (71, 81))	('kynurenine', 'Chemical', 'MESH:D007737', (89, 99))	('mouse', 'Species', '10090', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('kidney cancer', 'Phenotype', 'HP:0009726', (176, 189))	('kidney cancer', 'Disease', 'MESH:D007680', (176, 189))	('tumor', 'Disease', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('kynurenine pathway', 'Pathway', (89, 107))	('kidney cancer', 'Disease', (176, 189))	('inhibits', 'NegReg', (116, 124))
204226	27572319	In addition, the IDO1 and/or IDO2 competitive inhibitors 1-L-MT, 1-D-MT and MTH-trp had no effects on cell growth across human and mouse renal cancer cell lines (Figure 3).	('IDO', 'molecular_function', 'GO:0047719', ('29', '32'))	('1-L-MT', 'Var', (57, 63))	('human', 'Species', '9606', (121, 126))	('MT, 1', 'molecular_function', 'GO:0047152', ('61', '66'))	('MT, 1', 'molecular_function', 'GO:0043834', ('61', '66'))	('IDO', 'molecular_function', 'GO:0033754', ('17', '20'))	('MTH-trp', 'Chemical', '-', (76, 83))	('renal cancer', 'Disease', (137, 149))	('IDO1', 'Gene', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('renal cancer', 'Phenotype', 'HP:0009726', (137, 149))	('IDO2', 'Gene', (29, 33))	('mouse', 'Species', '10090', (131, 136))	('MTH-trp', 'Var', (76, 83))	('1-L-MT', 'Chemical', '-', (57, 63))	('cell growth', 'CPA', (102, 113))	('IDO', 'molecular_function', 'GO:0033754', ('29', '32'))	('IDO', 'molecular_function', 'GO:0047719', ('17', '20'))	('renal cancer', 'Disease', 'MESH:D007680', (137, 149))	('cell growth', 'biological_process', 'GO:0016049', ('102', '113'))	('MT, 1', 'molecular_function', 'GO:0043791', ('61', '66'))
204230	27572319	Levels of IDO1 were markedly increased in RENCA cells by mouse IFNgamma (100 ng/ml), and in two human RCC cell lines by human IFNgamma (50 ng/ml), with maximal induction after 48-72h (Figure 4A).	('human', 'Species', '9606', (120, 125))	('IDO1', 'Gene', (10, 14))	('IDO', 'molecular_function', 'GO:0033754', ('10', '13'))	('100 ng/ml', 'Var', (73, 82))	('human', 'Species', '9606', (96, 101))	('increased', 'PosReg', (29, 38))	('RENCA', 'Phenotype', 'HP:0005584', (42, 47))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('IDO', 'molecular_function', 'GO:0047719', ('10', '13'))	('mouse', 'Species', '10090', (57, 62))
204234	27572319	To determine whether inhibition of IDO attenuates the kynurenine pathway in RCC cells in vitro, and as a prelude to in vivo studies, we evaluated the dose-response of the kynurenine pathway to IFNgamma which, of the two IFNs, evoked the higher induction of IDO1.	('kynurenine', 'Chemical', 'MESH:D007737', (171, 181))	('kynurenine', 'Chemical', 'MESH:D007737', (54, 64))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('IDO', 'molecular_function', 'GO:0047719', ('257', '260'))	('RCC', 'Disease', (76, 79))	('IDO1', 'Gene', (257, 261))	('IDO', 'molecular_function', 'GO:0033754', ('35', '38'))	('induction', 'MPA', (244, 253))	('inhibition', 'Var', (21, 31))	('attenuates', 'NegReg', (39, 49))	('IDO', 'molecular_function', 'GO:0047719', ('35', '38'))	('IDO', 'molecular_function', 'GO:0033754', ('257', '260'))	('kynurenine pathway', 'Pathway', (54, 72))
204237	27572319	While treatment with 1-L-MT (100 muM) did not reduce the IFNgamma-induced production of kynurenine (data not shown), an MTH-trp dose curve revealed that 100 muM MTH-trp (25.9 mug/ml) realized maximal inhibition of kynurenine production (Figure 6B).	('1-L-MT', 'Chemical', '-', (21, 27))	('MTH-trp', 'Var', (161, 168))	('inhibition', 'NegReg', (200, 210))	('muM', 'Gene', (33, 36))	('muM', 'Gene', (157, 160))	('MTH-trp', 'Chemical', '-', (120, 127))	('MTH-trp', 'Chemical', '-', (161, 168))	('kynurenine production', 'MPA', (214, 235))	('mug', 'molecular_function', 'GO:0043739', ('175', '178'))	('muM', 'Gene', '56925', (33, 36))	('muM', 'Gene', '56925', (157, 160))	('kynurenine', 'Chemical', 'MESH:D007737', (88, 98))	('kynurenine', 'Chemical', 'MESH:D007737', (214, 224))
204240	27572319	Notably the combination of MTH-trp and IFNgamma significantly inhibited kynurenine production in all cell lines compared to IFNgamma treatment (Figure 6C-6F).	('MTH-trp', 'Var', (27, 34))	('kynurenine production', 'MPA', (72, 93))	('kynurenine', 'Chemical', 'MESH:D007737', (72, 82))	('inhibited', 'NegReg', (62, 71))	('MTH-trp', 'Chemical', '-', (27, 34))
204244	27572319	While neither MTH-trp nor IFNalpha alone inhibited tumor growth, the combination of IFNalpha and MTH-trp significantly reduced both the rate of tumor growth and the final tumor weight compared to treatment with IFNalpha alone (P < 0.05; Figure 7A and 7B).	('tumor', 'Disease', (144, 149))	('IFNalpha', 'Gene', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', (51, 56))	('MTH-trp', 'Var', (97, 104))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('rat', 'Species', '10116', (136, 139))	('MTH-trp', 'Chemical', '-', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('MTH-trp', 'Chemical', '-', (97, 104))	('reduced', 'NegReg', (119, 126))	('combination', 'Interaction', (69, 80))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
204247	27572319	Previous work has shown that inhibition of IDO-1 restores activity of T cells in the tumor environment, but the potential of IDO inhibition to alter the overall tumor immune landscape has not been determined.	('tumor', 'Disease', (85, 90))	('IDO-1', 'Gene', '3620', (43, 48))	('IDO', 'molecular_function', 'GO:0047719', ('125', '128'))	('activity', 'MPA', (58, 66))	('IDO-1', 'Gene', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('IDO', 'molecular_function', 'GO:0033754', ('43', '46'))	('IDO', 'molecular_function', 'GO:0033754', ('125', '128'))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('restores', 'PosReg', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('IDO', 'molecular_function', 'GO:0047719', ('43', '46'))	('tumor', 'Disease', (161, 166))	('inhibition', 'Var', (29, 39))
204263	27572319	In addition to the disappointing responses of these cancers to such treatments, patients undergoing these therapies experienced serious adverse effects that, with the advent of targeted therapies like mTOR and VEGFR inhibitors, led to the near-abandonment of IFNalpha and IL-2 as mainstream RCC therapies.	('VEGFR', 'Gene', (210, 215))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('mTOR', 'Gene', (201, 205))	('patients', 'Species', '9606', (80, 88))	('mTOR', 'Gene', '2475', (201, 205))	('IL-2', 'Gene', (272, 276))	('IL-2', 'Gene', '3558', (272, 276))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('IL-2', 'molecular_function', 'GO:0005134', ('272', '276'))	('VEGFR', 'Gene', '3791', (210, 215))	('RCC', 'Disease', (291, 294))	('inhibitors', 'Var', (216, 226))	('RCC', 'Disease', 'MESH:C538614', (291, 294))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
204272	27572319	Our data suggest that MTH-trp reduces IDO activity and production of kynurenine pathway metabolites and thus potentially prevents or reverses these effects.	('MTH-trp', 'Chemical', '-', (22, 29))	('IDO activity', 'MPA', (38, 50))	('kynurenine', 'Chemical', 'MESH:D007737', (69, 79))	('IDO', 'molecular_function', 'GO:0033754', ('38', '41'))	('MTH-trp', 'Var', (22, 29))	('production of kynurenine pathway metabolites', 'MPA', (55, 99))	('prevents', 'NegReg', (121, 129))	('reduces', 'NegReg', (30, 37))	('IDO', 'molecular_function', 'GO:0047719', ('38', '41'))
204278	27572319	Given what is known about alterations in the immune environment which occur in response to tryptophan catabolism, we expected that the major effects of MTH-trp would manifest as an alteration in the tumor's immune environment; however our data (at least after 10 days) do not support that hypothesis as treatment of the animals with MTH-trp did not alter the anatomical, topological, or phenotypic composition, nor the absolute number tumor-infiltrating immune cell subsets.	('tumor', 'Disease', (199, 204))	('rat', 'Species', '10116', (447, 450))	('MTH-trp', 'Var', (333, 340))	('tumor', 'Phenotype', 'HP:0002664', (435, 440))	('tryptophan catabolism', 'biological_process', 'GO:0006569', ('91', '112'))	('MTH-trp', 'Chemical', '-', (333, 340))	('rat', 'Species', '10116', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (435, 440))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tryptophan', 'Chemical', 'MESH:D014364', (91, 101))	('MTH-trp', 'Chemical', '-', (152, 159))	('rat', 'Species', '10116', (185, 188))	('tumor', 'Disease', (435, 440))
204282	27572319	Two combination IDO inhibitor and checkpoint antibody studies (clinicaltrials.gov NCT02178722, NCT02318277), a combination IDO inhibitor and JAK inhibitor study in advanced solid tumors (NCT02559492), and an IDO inhibitor alone study on refractory solid tumors (NCT02048709) are all recruiting.	('antibody', 'molecular_function', 'GO:0003823', ('45', '53'))	('JAK', 'molecular_function', 'GO:0004713', ('141', '144'))	('antibody', 'cellular_component', 'GO:0042571', ('45', '53'))	('solid tumors', 'Disease', (173, 185))	('IDO', 'molecular_function', 'GO:0047719', ('208', '211'))	('solid tumors', 'Disease', 'MESH:D009369', (248, 260))	('IDO', 'molecular_function', 'GO:0047719', ('123', '126'))	('IDO', 'molecular_function', 'GO:0047719', ('16', '19'))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('antibody', 'cellular_component', 'GO:0019815', ('45', '53'))	('NCT02318277', 'Var', (95, 106))	('solid tumors', 'Disease', 'MESH:D009369', (173, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('solid tumors', 'Disease', (248, 260))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('antibody', 'cellular_component', 'GO:0019814', ('45', '53'))	('IDO', 'molecular_function', 'GO:0033754', ('123', '126'))	('IDO', 'molecular_function', 'GO:0033754', ('208', '211'))	('IDO', 'molecular_function', 'GO:0033754', ('16', '19'))
204285	27572319	Despite the absence of an effect on the composition of the tumor immune microenvironment in a subacute setting, MTH-trp may alter the functionality of intratumoral leukocytes, setting the stage for improved therapeutic effects of IFNalpha.	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('MTH-trp', 'Chemical', '-', (112, 119))	('rat', 'Species', '10116', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('improved', 'PosReg', (198, 206))	('tumor', 'Disease', (156, 161))	('alter', 'Reg', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('MTH-trp', 'Var', (112, 119))
204312	27572319	Paraffin sections (4 mum) of formalin-fixed tissue were stained for IDO1 using heat-induced antigen retrieval in citrate buffer (pH 6.0) and anti-human IDO1 (Cell Signaling Technology), followed by Mach 2 Rabbit HRP-Polymer (BioCare Medical, Concord, CA) and ImmPACT diaminobenzidine peroxidase substrate (Vector Laboratories, Burlingame, CA).	('rat', 'Species', '10116', (300, 303))	('rat', 'Species', '10116', (317, 320))	('IDO', 'molecular_function', 'GO:0033754', ('68', '71'))	('Paraffin', 'Chemical', 'MESH:D010232', (0, 8))	('formalin', 'Chemical', 'MESH:D005557', (29, 37))	('Rabbit', 'Species', '9986', (205, 211))	('IDO', 'molecular_function', 'GO:0033754', ('152', '155'))	('IDO', 'molecular_function', 'GO:0047719', ('68', '71'))	('mum', 'Gene', '56925', (21, 24))	('human', 'Species', '9606', (146, 151))	('IDO', 'molecular_function', 'GO:0047719', ('152', '155'))	('anti-human', 'Var', (141, 151))	('rat', 'Species', '10116', (116, 119))	('Signaling', 'biological_process', 'GO:0023052', ('163', '172'))	('citrate', 'Chemical', 'MESH:D019343', (113, 120))	('mum', 'Gene', (21, 24))	('IDO1', 'Gene', (68, 72))
204337	32392781	Mutations of several tumor suppressor genes (polybromo 1 (PBRM1), BRCA1-associated 1 (BAP1), and SET domain-containing 2 (SETD2)) are associated with clear cell RCC (ccRCC) tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('polybromo 1', 'Gene', (45, 56))	('tumor', 'Disease', (21, 26))	('tumor suppressor', 'biological_process', 'GO:0051726', ('21', '37'))	('SETD2', 'Gene', (122, 127))	('PBRM1', 'Gene', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('associated', 'Reg', (134, 144))	('BAP1', 'Gene', '8314', (86, 90))	('SETD2', 'Gene', '29072', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('Mutations', 'Var', (0, 9))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('RCC', 'Disease', (161, 164))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('RCC', 'Disease', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('SET domain-containing 2', 'Gene', '29072', (97, 120))	('BAP1', 'Gene', (86, 90))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('polybromo 1', 'Gene', '55193', (45, 56))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('SET domain-containing 2', 'Gene', (97, 120))	('tumor', 'Disease', (173, 178))	('PBRM1', 'Gene', '55193', (58, 63))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('21', '37'))
204338	32392781	PBRM1 and BAP1 mutations are largely mutually exclusive, where mutations of BAP1 mutations are significantly associated with high-grade, high-stage tumors that result in low survival.	('mutations', 'Var', (63, 72))	('associated', 'Reg', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('low', 'NegReg', (170, 173))	('BAP1', 'Gene', (10, 14))	('BAP1', 'Gene', '8314', (76, 80))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('BAP1', 'Gene', (76, 80))	('tumors', 'Disease', (148, 154))	('mutations', 'Var', (81, 90))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('BAP1', 'Gene', '8314', (10, 14))	('high-grade', 'Disease', (125, 135))
204339	32392781	Furthermore, mutations of lysine-specific demethylase 5C (KDM5C) are associated with poor oncological outcomes.	('lysine-specific demethylase 5C', 'Gene', (26, 56))	('oncological outcomes', 'CPA', (90, 110))	('associated', 'Reg', (69, 79))	('KDM5C', 'Gene', (58, 63))	('mutations', 'Var', (13, 22))	('KDM5C', 'Gene', '8242', (58, 63))	('lysine-specific demethylase 5C', 'Gene', '8242', (26, 56))
204340	32392781	Our previous studies have demonstrated that forkhead box protein C2 (FOXC2) and cytoskeleton-associated, protein-glycine (CAP-Gly)-rich, domain-containing linker protein family member 4 (CLIP4) mutations were associated with early-stage ccRCC, and a synchronous metastasis and validation study confirmed that PBRM1, BAP1, and FOXC2 were shown to be significantly associated with aggressive early-stage ccRCC through target sequencing and immunohistochemistry.	('associated with', 'Reg', (209, 224))	('RCC', 'Disease', 'MESH:C538614', (404, 407))	('PBRM1', 'Gene', '55193', (309, 314))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('glycine', 'Chemical', 'MESH:D005998', (113, 120))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('80', '92'))	('FOXC2', 'Gene', (69, 74))	('PBRM1', 'Gene', (309, 314))	('BAP1', 'Gene', '8314', (316, 320))	('FOXC2', 'Gene', '2303', (69, 74))	('associated', 'Reg', (363, 373))	('forkhead box protein C2', 'Gene', (44, 67))	('forkhead box protein C2', 'Gene', '2303', (44, 67))	('RCC', 'Disease', (239, 242))	('RCC', 'Phenotype', 'HP:0005584', (239, 242))	('BAP1', 'Gene', (316, 320))	('synchronous metastasis', 'Disease', 'MESH:D009362', (250, 272))	('synchronous metastasis', 'Disease', (250, 272))	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('CLIP4', 'Gene', '79745', (187, 192))	('RCC', 'Disease', (404, 407))	('CLIP4', 'Gene', (187, 192))	('RCC', 'Phenotype', 'HP:0005584', (404, 407))	('mutations', 'Var', (194, 203))	('RCC', 'Disease', 'MESH:C538614', (239, 242))	('FOXC2', 'Gene', '2303', (326, 331))	('FOXC2', 'Gene', (326, 331))
204364	32392781	To the best of our knowledge, this is the first study on the comparison between mRNA profiles of representative genes in plasma and frozen tissues in localized pathological T1N0M0 stage ccRCC.	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('RCC', 'Disease', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('T1N0M0', 'Var', (173, 179))
204381	32392781	The Cancer Genome Atlas (TCGA) revealed that alterations in DNA methylation correlate with SETD2 mutations.	('mutations', 'Var', (97, 106))	('SETD2', 'Gene', '29072', (91, 96))	('DNA methylation', 'biological_process', 'GO:0006306', ('60', '75'))	('DNA methylation', 'MPA', (60, 75))	('SETD2', 'Gene', (91, 96))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('alterations', 'Reg', (45, 56))
204382	32392781	SETD2 mutations have been reported at rates of 11.6% and 7.4% in TCGA and Memorial Sloan-Kettering Cancer Center cohorts, respectively, and Liu et al.	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('SETD2', 'Gene', '29072', (0, 5))	('SETD2', 'Gene', (0, 5))	('Memorial Sloan-Kettering Cancer', 'Disease', 'MESH:D009369', (74, 105))	('Memorial Sloan-Kettering Cancer', 'Disease', (74, 105))	('mutations', 'Var', (6, 15))
204384	32392781	SETD2 mutation has been found to be associated with adverse oncological outcomes in our previous study and other multicenter studies, thereby suggesting a general role of SETD2 in disease progression.	('SETD2', 'Gene', '29072', (171, 176))	('SETD2', 'Gene', '29072', (0, 5))	('mutation', 'Var', (6, 14))	('SETD2', 'Gene', (171, 176))	('SETD2', 'Gene', (0, 5))	('associated', 'Reg', (36, 46))	('oncological outcomes', 'CPA', (60, 80))
204611	30693167	Histologically, it had a papillary architecture mimicking ovarian serous carcinoma and was immunopositive for paired box gene 8 (PAX8), vimentin, P504S, P53, and CK20 (focal) and negative for CK7, WT-1, high molecular weight cytokeratin and p63, CK5/6, CD10, and estrogen receptors, supporting the diagnosis of RCCU.	('P53', 'Gene', (153, 156))	('CK20', 'Gene', '54474', (162, 166))	('CK7', 'Gene', (192, 195))	('estrogen receptor', 'Gene', '2099', (263, 280))	('WT-1', 'Gene', (197, 201))	('PAX8', 'Gene', (129, 133))	('CK5/6', 'Gene', '3852', (246, 251))	('paired box gene 8', 'Gene', (110, 127))	('P53', 'Gene', '7157', (153, 156))	('paired box gene 8', 'Gene', '7849', (110, 127))	('PAX8', 'Gene', '7849', (129, 133))	('ovarian serous carcinoma', 'Disease', (58, 82))	('P504S', 'Mutation', 'p.P504S', (146, 151))	('vimentin', 'Gene', '7431', (136, 144))	('vimentin', 'cellular_component', 'GO:0045098', ('136', '144'))	('CK7', 'Gene', '3855', (192, 195))	('P504S', 'Var', (146, 151))	('vimentin', 'Gene', (136, 144))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (58, 82))	('CD10', 'molecular_function', 'GO:0004245', ('253', '257'))	('CD10', 'Gene', '4311', (253, 257))	('estrogen receptor', 'Gene', (263, 280))	('CK5/6', 'Gene', (246, 251))	('p63', 'Gene', (241, 244))	('CK20', 'Gene', (162, 166))	('WT-1', 'Gene', '7490', (197, 201))	('vimentin', 'cellular_component', 'GO:0045099', ('136', '144'))	('p63', 'Gene', '8626', (241, 244))	('CD10', 'Gene', (253, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
204614	29080283	 TCF21 hypermethylation regulates renal tumor cell clonogenic proliferation and migration We recently identified hypermethylation at the gene promoter of transcription factor 21 (TCF21) in clear cell sarcoma of the kidney (CCSK), a rare pediatric renal tumor.	('renal tumor', 'Disease', 'MESH:D007674', (247, 258))	('clear cell sarcoma of the kidney', 'Phenotype', 'HP:0006770', (189, 221))	('TCF21', 'Gene', '6943', (1, 6))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('sarcoma of the kidney', 'Disease', 'MESH:D007674', (200, 221))	('TCF21', 'Gene', (179, 184))	('transcription factor', 'molecular_function', 'GO:0000981', ('154', '174'))	('pediatric renal tumor', 'Disease', (237, 258))	('transcription', 'biological_process', 'GO:0006351', ('154', '167'))	('sarcoma of the kidney', 'Disease', (200, 221))	('CCSK', 'Chemical', '-', (223, 227))	('pediatric renal tumor', 'Disease', 'MESH:D007674', (237, 258))	('TCF21', 'Gene', (1, 6))	('TCF21', 'Gene', '6943', (179, 184))	('identified', 'Reg', (102, 112))	('renal tumor', 'Disease', 'MESH:D007674', (34, 45))	('renal tumor', 'Phenotype', 'HP:0009726', (34, 45))	('renal tumor', 'Disease', (34, 45))	('hypermethylation', 'Var', (113, 129))	('sarcoma of the kidney', 'Phenotype', 'HP:0008663', (200, 221))	('renal tumor', 'Phenotype', 'HP:0009726', (247, 258))
204618	29080283	Furthermore, mRNA expression of the mesenchymal markers vimentin (VIM) and SNAI1 was not significantly decreased in TCF21-expressing 786-O cells, while protein levels of VIM were markedly decreased.	('vimentin', 'Gene', '7431', (56, 64))	('decreased', 'NegReg', (188, 197))	('protein levels', 'MPA', (152, 166))	('SNAI1', 'Gene', (75, 80))	('decreased', 'NegReg', (103, 112))	('SNAI1', 'Gene', '6615', (75, 80))	('vimentin', 'Gene', (56, 64))	('mRNA expression', 'MPA', (13, 28))	('TCF21-expressing', 'Var', (116, 132))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('vimentin', 'cellular_component', 'GO:0045099', ('56', '64'))	('vimentin', 'cellular_component', 'GO:0045098', ('56', '64'))
204619	29080283	We conclude that re-expression of TCF21 in renal cancer cells that have silenced their endogenous TCF21 locus through hypermethylation results in reduced clonogenic proliferation, reduced migration, and reduced mesenchymal-like characteristics, suggesting a tumor suppressor function for transcription factor 21.	('tumor', 'Disease', (258, 263))	('reduced', 'NegReg', (203, 210))	('reduced', 'NegReg', (146, 153))	('mesenchymal-like characteristics', 'CPA', (211, 243))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('258', '274'))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('hypermethylation', 'Var', (118, 134))	('transcription factor', 'molecular_function', 'GO:0000981', ('288', '308'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('258', '274'))	('migration', 'CPA', (188, 197))	('TCF21', 'Gene', (98, 103))	('renal cancer', 'Disease', (43, 55))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('renal cancer', 'Phenotype', 'HP:0009726', (43, 55))	('TCF21', 'Gene', (34, 39))	('renal cancer', 'Disease', 'MESH:D007680', (43, 55))	('transcription', 'biological_process', 'GO:0006351', ('288', '301'))	('reduced', 'NegReg', (180, 187))	('clonogenic proliferation', 'CPA', (154, 178))
204624	29080283	Our study as part of the NCI-initiated therapeutically applicable research to generate effective treatment project (TARGET) identified hypermethylation of the 5' region of transcription factor 21 (TCF21) in all studied CCSK samples, except for samples harboring the YWHAE-NUTM2 fusion transcript (Gooskens et al., 2015).	('TCF21', 'Gene', (197, 202))	('YWHAE', 'Gene', (266, 271))	('CCSK', 'Disease', (219, 223))	('transcription', 'biological_process', 'GO:0006351', ('172', '185'))	('CCSK', 'Chemical', '-', (219, 223))	('transcription factor', 'molecular_function', 'GO:0000981', ('172', '192'))	('YWHAE', 'Gene', '7531', (266, 271))	('hypermethylation', 'Var', (135, 151))
204628	29080283	Antisense inhibition of TCF21 has been reported to disrupt epithelial differentiation and branching morphogenesis of the epithelium in murine embryonic kidney, suggesting a role for TCF21 in epithelial-mesenchymal interactions (Quaggin et al., 1999).	('epithelial differentiation', 'CPA', (59, 85))	('disrupt', 'NegReg', (51, 58))	('TCF21', 'Gene', (24, 29))	('embryonic kidney', 'Disease', (142, 158))	('branching morphogenesis of the epithelium', 'CPA', (90, 131))	('embryonic kidney', 'Disease', 'MESH:D007674', (142, 158))	('Antisense inhibition', 'Var', (0, 20))	('murine', 'Species', '10090', (135, 141))	('branching morphogenesis', 'biological_process', 'GO:0001763', ('90', '113'))
204629	29080283	Gene deletion studies in chimeric mice have shown that loss of TCF21 in the kidney results in decreased glomerulogenesis and tubulogenesis (Cui et al., 2003).	('mice', 'Species', '10090', (34, 38))	('TCF21', 'Gene', (63, 68))	('tubulogenesis', 'biological_process', 'GO:0048754', ('125', '138'))	('loss', 'Var', (55, 59))	('decreased', 'NegReg', (94, 103))
204631	29080283	Currently, no CCSK cell lines or models are available to functionally verify the role of TCF21 hypermethylation in this renal tumor type.	('TCF21', 'Gene', (89, 94))	('renal tumor', 'Phenotype', 'HP:0009726', (120, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('CCSK', 'Chemical', '-', (14, 18))	('renal tumor', 'Disease', (120, 131))	('hypermethylation', 'Var', (95, 111))	('renal tumor', 'Disease', 'MESH:D007674', (120, 131))
204632	29080283	A literature search revealed that TCF21 hypermethylation is also present in clear cell renal cell carcinomas (ccRCC): renal tumors with another biology and phenotype, which most often occur in adults (Costa et al., 2011; Ye et al., 2012).	('renal tumors', 'Disease', (118, 130))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (87, 107))	('TCF21', 'Gene', (34, 39))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (76, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (76, 107))	('renal tumors', 'Phenotype', 'HP:0009726', (118, 130))	('RCC', 'Disease', (112, 115))	('hypermethylation', 'Var', (40, 56))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (76, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('clear cell renal cell carcinomas', 'Disease', (76, 108))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (87, 108))	('renal tumors', 'Disease', 'MESH:D007674', (118, 130))	('renal tumor', 'Phenotype', 'HP:0009726', (118, 129))
204642	29080283	Eight colonies were selected for functional assays: four from pBABE-puro mock-transfected 786-O cells (N1F4, B5F1, N1G4, and B6D10) and four expressing HA-tagged exogenous TCF21 (2B12, 5D2, 9D12, and 9H9).	('H9', 'CellLine', 'CVCL:1240', (201, 203))	('TCF21', 'Gene', (172, 177))	('2B12', 'Var', (179, 183))
204657	29080283	We trypsinized cells from each clone and stained unfixed live cells with anti-E-cadherin (Cat # 563571; BD Biosciences, Vianen, the Netherlands) and anti-CD24 (Cat # 562789; BD Biosciences).	('Cat # 563571;', 'Var', (90, 103))	('Cat', 'molecular_function', 'GO:0004096', ('160', '163'))	('CD24', 'Gene', '100133941', (154, 158))	('Cat # 562789', 'Var', (160, 172))	('CD24', 'Gene', (154, 158))	('cadherin', 'molecular_function', 'GO:0008014', ('80', '88'))	('Cat', 'molecular_function', 'GO:0004096', ('90', '93'))	('anti-E-cadherin', 'Protein', (73, 88))
204664	29080283	To investigate whether TCF21 expression results in a reduction in cell proliferation in the context of the ccRCC cell line 786-O, we performed standard growth curves on the four clones that were pBABE-mock-transfected and compared them to standard growth curves from the four clones expressing TCF21 after 2, 4, and 5 days.	('expression', 'Var', (29, 39))	('cell proliferation', 'CPA', (66, 84))	('reduction', 'NegReg', (53, 62))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('TCF21', 'Gene', (23, 28))
204665	29080283	We therefore suggest that TCF21 expression moderately suppressed proliferation of this 786-O cancer cell line and that the hypothesis that proliferation is suppressed by TCF21 warranted further investigation.	('cancer', 'Disease', (93, 99))	('proliferation', 'CPA', (65, 78))	('TCF21', 'Gene', (26, 31))	('suppressed', 'NegReg', (54, 64))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('expression', 'Var', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
204667	29080283	We have previously generated a zebrafish model with biallelic constitutive vhl mutations and have reported the embryonic renal phenotype as exhibiting an alveolar hyperplastic morphology (van Rooijen et al., 2011).	('alveolar hyperplastic', 'Phenotype', 'HP:0009085', (154, 175))	('embryonic renal phenotype', 'Disease', (111, 136))	('zebrafish', 'Species', '7955', (31, 40))	('embryonic renal phenotype', 'Disease', 'MESH:D007674', (111, 136))	('alveolar hyperplastic morphology', 'CPA', (154, 186))	('vhl', 'Gene', (75, 78))	('mutations', 'Var', (79, 88))
204674	29080283	The inhibition of migration in ccRCC cells by re-expression of TCF21 (Fig.	('migration', 'CPA', (18, 27))	('re-expression', 'Var', (46, 59))	('TCF21', 'Gene', (63, 68))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('inhibition', 'NegReg', (4, 14))
204675	29080283	No changes were observed in mRNA levels of the mesenchymal markers VIM and snail (SNAI1), but we did observe significant upregulation of epithelial marker E-cadherin (CDH1) both at the mRNA and at the protein level in the clones expressing ectopic TCF21 (Fig.	('snail', 'Gene', '6615', (75, 80))	('CDH1', 'Gene', '999', (167, 171))	('protein', 'cellular_component', 'GO:0003675', ('201', '208'))	('upregulation', 'PosReg', (121, 133))	('SNAI1', 'Gene', (82, 87))	('TCF21', 'Gene', (248, 253))	('SNAI1', 'Gene', '6615', (82, 87))	('cadherin', 'molecular_function', 'GO:0008014', ('157', '165'))	('snail', 'Gene', (75, 80))	('ectopic', 'Var', (240, 247))	('CDH1', 'Gene', (167, 171))
204676	29080283	These data could suggest that cells with hypermethylated TCF21 promoters are more predisposed to EMT, thereby potentially contributing to the tumor suppressor function of TCF21 in renal tumors.	('contributing', 'Reg', (122, 134))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('renal tumors', 'Disease', 'MESH:D007674', (180, 192))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('142', '158'))	('renal tumors', 'Disease', (180, 192))	('EMT', 'biological_process', 'GO:0001837', ('97', '100'))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (142, 147))	('EMT', 'CPA', (97, 100))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Disease', (186, 191))	('renal tumor', 'Phenotype', 'HP:0009726', (180, 191))	('hypermethylated', 'Var', (41, 56))	('renal tumors', 'Phenotype', 'HP:0009726', (180, 192))	('tumor suppressor', 'biological_process', 'GO:0051726', ('142', '158'))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('TCF21', 'Gene', (57, 62))
204677	29080283	In a melanoma cell line (C8161), re-expression of TCF21 was described to activate expression of the metastatic suppressor KISS1 and consequently inhibit motility of the cells (Arab et al., 2011; Zhang et al., 2012).	('TCF21', 'Gene', (50, 55))	('re-expression', 'Var', (33, 46))	('expression', 'MPA', (82, 92))	('C8161', 'CellLine', 'CVCL:6813', (25, 30))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('melanoma', 'Disease', (5, 13))	('KISS1', 'Gene', (122, 127))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('activate', 'PosReg', (73, 81))	('KISS1', 'Gene', '3814', (122, 127))	('motility of the cells', 'CPA', (153, 174))	('inhibit', 'NegReg', (145, 152))
204678	29080283	We investigated KISS1 expression levels in 786-O clones expressing pBABE-mock and clones expressing pBABE-TCF21; expression levels were undetectably low in both untransfected and transfected 786-O cells, while being robustly expressed in control human placenta (average C q value 21.4).	('KISS1', 'Gene', '3814', (16, 21))	('pBABE-TCF21', 'Var', (100, 111))	('human', 'Species', '9606', (246, 251))	('KISS1', 'Gene', (16, 21))
204686	29080283	For example, re-expression of TCF21 reduced cell growth and colony formation in lung cancer cells in vitro and in vivo (Smith et al., 2006), reduced cell proliferation, promoted apoptosis and suppressed cell invasion and migration in colorectal cancer in vitro (Dai et al., 2016), and reduced cell proliferation and epithelial-mesenchymal transition in breast cancer cells in vitro (Wang et al., 2015).	('cancer', 'Phenotype', 'HP:0002664', (360, 366))	('promoted', 'PosReg', (169, 177))	('cell invasion', 'CPA', (203, 216))	('cell proliferation', 'biological_process', 'GO:0008283', ('149', '167'))	('suppressed', 'NegReg', (192, 202))	('apoptosis', 'biological_process', 'GO:0097194', ('178', '187'))	('apoptosis', 'biological_process', 'GO:0006915', ('178', '187'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('316', '349'))	('TCF21', 'Gene', (30, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (234, 251))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('colony formation', 'CPA', (60, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('formation', 'biological_process', 'GO:0009058', ('67', '76'))	('reduced', 'NegReg', (285, 292))	('reduced', 'NegReg', (141, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (353, 366))	('cell growth', 'biological_process', 'GO:0016049', ('44', '55'))	('apoptosis', 'CPA', (178, 187))	('cell proliferation', 'CPA', (293, 311))	('colorectal cancer', 'Disease', 'MESH:D015179', (234, 251))	('cell proliferation', 'CPA', (149, 167))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cell proliferation', 'biological_process', 'GO:0008283', ('293', '311'))	('breast cancer', 'Disease', 'MESH:D001943', (353, 366))	('breast cancer', 'Disease', (353, 366))	('colorectal cancer', 'Disease', (234, 251))	('lung cancer', 'Disease', (80, 91))	('cell growth', 'CPA', (44, 55))	('epithelial-mesenchymal transition', 'CPA', (316, 349))	('reduced', 'NegReg', (36, 43))	('re-expression', 'Var', (13, 26))
204687	29080283	In addition, downregulation of TCF21 through hypermethylation has been reported to be associated with poor outcome in patients with ccRCC and metastatic melanoma (Ye et al., 2012).	('hypermethylation', 'Var', (45, 61))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma', 'Disease', (153, 161))	('downregulation', 'NegReg', (13, 27))	('TCF21', 'Gene', (31, 36))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('RCC', 'Disease', (134, 137))	('patients', 'Species', '9606', (118, 126))
204688	29080283	TCF21 hypermethylation has also been demonstrated in other ccRCC cell lines and human ccRCC tissue samples (Costa et al., 2011; Xin et al., 2016; Ye et al., 2012).	('TCF21', 'Gene', (0, 5))	('hypermethylation', 'Var', (6, 22))	('Xin', 'Gene', (128, 131))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('demonstrated', 'Reg', (37, 49))	('Xin', 'Gene', '165904', (128, 131))	('human', 'Species', '9606', (80, 85))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))
204689	29080283	Likewise, in other human cancer types, such as gastric cancer, colorectal cancer, melanoma, head and neck cancer, and non-small-cell lung carcinoma, hypermethylation is described to be the predominant mechanism for TCF21 downregulation (Arab et al., 2011; Dai et al., 2016; Smith et al., 2006; Yang et al., 2015).	('gastric cancer', 'Disease', (47, 61))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', (106, 112))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('lung carcinoma', 'Disease', (133, 147))	('cancer', 'Disease', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('head and neck cancer', 'Phenotype', 'HP:0012288', (92, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('downregulation', 'NegReg', (221, 235))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('neck cancer', 'Disease', 'MESH:D006258', (101, 112))	('neck cancer', 'Disease', (101, 112))	('gastric cancer', 'Disease', 'MESH:D013274', (47, 61))	('colorectal cancer', 'Disease', (63, 80))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('cancer', 'Disease', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('lung carcinoma', 'Disease', 'MESH:D008175', (133, 147))	('neck', 'cellular_component', 'GO:0044326', ('101', '105'))	('hypermethylation', 'Var', (149, 165))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('gastric cancer', 'Phenotype', 'HP:0012126', (47, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('human', 'Species', '9606', (19, 24))	('TCF21', 'Gene', (215, 220))
204697	29080283	Recently, we reported that CCSKs bearing the BCOR internal tandem duplication showed hypermethylation of TCF21, while CCSKs bearing the translocation t(10;17)(q22;p13) showed significantly lower methylation levels of the TCF21, suggesting that internal tandem duplication of BCOR may be directly or indirectly responsible for TCF21 hypermethylation in CCSKs (Gooskens et al., 2016).	('BCOR', 'Gene', '54880', (275, 279))	('CCSKs', 'Chemical', '-', (118, 123))	('BCOR', 'Gene', '54880', (45, 49))	('lower', 'NegReg', (189, 194))	('methylation levels', 'MPA', (195, 213))	('CCSKs', 'Chemical', '-', (27, 32))	('internal tandem duplication', 'Var', (244, 271))	('CCSKs', 'Chemical', '-', (352, 357))	('hypermethylation', 'MPA', (85, 101))	('internal tandem duplication', 'Var', (50, 77))	('t(10;17)(q22;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (150, 167))	('BCOR', 'Gene', (45, 49))	('methylation', 'biological_process', 'GO:0032259', ('195', '206'))	('BCOR', 'Gene', (275, 279))	('TCF21', 'Gene', (105, 110))
204698	29080283	To functionally validate the tumorigenic role of TCF21 hypermethylation in CCSKs, CCSK models urgently need to be developed.	('CCSKs', 'Chemical', '-', (75, 80))	('CCSK', 'Chemical', '-', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('hypermethylation', 'Var', (55, 71))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('TCF21', 'Gene', (49, 54))	('tumor', 'Disease', (29, 34))	('CCSKs', 'Disease', (75, 80))	('CCSK', 'Chemical', '-', (75, 79))
204705	29079774	Promoter DNA methylation analysis reveals a novel diagnostic CpG-based biomarker and RAB25 hypermethylation in clear cell renel cell carcinoma Clear-cell renal cell carcinoma (ccRCC) is a common aggressive urinary malignant tumor that cannot be easily diagnosed at an early stage.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('Clear-cell renal cell carcinoma', 'Disease', (143, 174))	('Clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (143, 174))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (154, 174))	('ccRCC', 'Phenotype', 'HP:0006770', (176, 181))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('RCC', 'Disease', (178, 181))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('carcinoma', 'Disease', (133, 142))	('carcinoma', 'Disease', (165, 174))	('aggressive urinary malignant tumor', 'Disease', 'MESH:D001749', (195, 229))	('hypermethylation', 'Var', (91, 107))	('Clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (143, 174))	('RAB25', 'Gene', '57111', (85, 90))	('aggressive urinary malignant tumor', 'Disease', (195, 229))	('carcinoma', 'Disease', 'MESH:D002277', (133, 142))	('RAB25', 'Gene', (85, 90))	('carcinoma', 'Disease', 'MESH:D002277', (165, 174))
204709	29079774	We found that both CYP4B1 and RAB25 are downregulated with promoter hypermethylation and CA9 is upregulated with promoter hypomethylation, and we validated their mRNA differential expressions in 19 ccRCCs and 10 GEO datasets.	('CA9', 'Gene', '768', (89, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (198, 203))	('RAB25', 'Gene', '57111', (30, 35))	('CYP4B1', 'Gene', '1580', (19, 25))	('RCC', 'Disease', (200, 203))	('downregulated', 'NegReg', (40, 53))	('RCC', 'Phenotype', 'HP:0005584', (200, 203))	('RCC', 'Disease', 'MESH:C538614', (200, 203))	('CYP4B1', 'Gene', (19, 25))	('RAB25', 'Gene', (30, 35))	('upregulated', 'PosReg', (96, 107))	('promoter hypermethylation', 'Var', (59, 84))	('CA9', 'Gene', (89, 92))	('promoter hypomethylation', 'Var', (113, 137))
204710	29079774	We further confirmed that hypermethylated RAB25 is inversely correlated with its mRNA level.	('hypermethylated', 'Var', (26, 41))	('RAB25', 'Gene', '57111', (42, 47))	('correlated', 'Reg', (61, 71))	('mRNA level', 'MPA', (81, 91))	('RAB25', 'Gene', (42, 47))
204711	29079774	Log-rank test showed that ccRCC patients with low levels of CA9 promoter methylation had a higher survival rate.	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('patients', 'Species', '9606', (32, 40))	('methylation', 'biological_process', 'GO:0032259', ('73', '84'))	('higher', 'PosReg', (91, 97))	('ccRCC', 'Phenotype', 'HP:0006770', (26, 31))	('RCC', 'Phenotype', 'HP:0005584', (28, 31))	('RCC', 'Disease', (28, 31))	('CA9', 'Gene', (60, 63))	('low levels', 'Var', (46, 56))	('survival rate', 'CPA', (98, 111))	('CA9', 'Gene', '768', (60, 63))
204719	29079774	Evidences have suggested that DNA methylation plays a key role in ccRCC as one of the most common epigenetic changes.	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('DNA', 'Var', (30, 33))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('DNA methylation', 'biological_process', 'GO:0006306', ('30', '45'))
204720	29079774	DNA methylation patterns are prone to CpG islands, most of which are found in the proximal promoter regions of almost 60% of human genes in the mammalian genomes.	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('CpG', 'Disease', (38, 41))	('human', 'Species', '9606', (125, 130))	('methylation', 'Var', (4, 15))	('mammalian', 'Species', '9606', (144, 153))
204722	29079774	In this study, we profiled promoter-region DNA methylation in 265 ccRCC primary tumors and 133 adjacent tissues with Illumina HumanMethylation450 from The Cancer Genome Atlas data (TCGA), and found that a CpG-based biomarker (cg11201447, cg25247520, cg13309012, cg08995609) can efficiently distinguish ccRCCs from adjacent tissues and that RAB25 is hypermethylated in ccRCC tissues.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('RCC', 'Disease', (68, 71))	('tumors', 'Disease', (80, 86))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (370, 373))	('RCC', 'Disease', (370, 373))	('Human', 'Species', '9606', (126, 131))	('cg11201447', 'Var', (226, 236))	('RCC', 'Phenotype', 'HP:0005584', (304, 307))	('cg11201447', 'Chemical', '-', (226, 236))	('RCC', 'Disease', (304, 307))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('ccRCC', 'Phenotype', 'HP:0006770', (302, 307))	('DNA methylation', 'biological_process', 'GO:0006306', ('43', '58'))	('RCC', 'Disease', 'MESH:C538614', (370, 373))	('cg25247520', 'Var', (238, 248))	('RAB25', 'Gene', '57111', (340, 345))	('RAB25', 'Gene', (340, 345))	('RCC', 'Disease', 'MESH:C538614', (304, 307))	('cg13309012', 'Var', (250, 260))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (368, 373))	('cg08995609', 'Var', (262, 272))	('Cancer', 'Phenotype', 'HP:0002664', (155, 161))
204724	29079774	Our results provide new information about aberrant DNA methylation within the promoters of ccRCC and suggest a potential diagnostic biomarker for the disease.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('RCC', 'Disease', (93, 96))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('aberrant', 'Var', (42, 50))	('DNA', 'MPA', (51, 54))	('DNA methylation', 'biological_process', 'GO:0006306', ('51', '66'))
204728	29079774	By using the linear models for microarray data (limma) approach to identify the statistically different DNA methylation status between ccRCC and adjacent tissues, 13617 CpGs were found to be significantly different (FDR < 1E-10,  Delta Beta  > 0.2).	('CpGs', 'Chemical', 'MESH:C015772', (169, 173))	('CpGs', 'Var', (169, 173))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('different', 'Reg', (205, 214))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('RCC', 'Disease', (137, 140))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('DNA methylation', 'biological_process', 'GO:0006306', ('104', '119'))
204729	29079774	Compared to adjacent tissue, 4552 CpGs were hypermethylated and 9065 CpGs were hypomethylated in ccRCC (Fig.	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('CpGs', 'Chemical', 'MESH:C015772', (34, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('CpGs', 'Chemical', 'MESH:C015772', (69, 73))	('hypomethylated', 'Var', (79, 93))
204735	29079774	To identify a set of CpGs that could best distinguish ccRCCs from adjacent tissues, based on the 986 differential CpGs from promoter regions, we performed shrunken centroids classifier analysis and found 4 hypomethylated CpGs in ccRCC (cg11201447, cg25247520, cg13309012 and cg08995609) that best discriminate between tumor tissues and adjacent tissues.	('CpGs', 'Chemical', 'MESH:C015772', (221, 225))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('CpGs', 'Chemical', 'MESH:C015772', (21, 25))	('tumor', 'Disease', (318, 323))	('cg13309012', 'Var', (260, 270))	('cg25247520', 'Var', (248, 258))	('cg08995609', 'Var', (275, 285))	('ccRCC', 'Phenotype', 'HP:0006770', (229, 234))	('RCC', 'Disease', (231, 234))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('RCC', 'Phenotype', 'HP:0005584', (231, 234))	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('CpGs', 'Chemical', 'MESH:C015772', (114, 118))	('RCC', 'Disease', 'MESH:C538614', (231, 234))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('cg11201447', 'Var', (236, 246))	('cg11201447', 'Chemical', '-', (236, 246))
204737	29079774	The cg11201447 and cg25247520 remain located in the same transcript of microRNA1204 and had higher degrees of similar methylated levels than other two CpGs, suggesting that methylation levels could be related to chromosomal locations (Fig.	('cg25247520', 'Var', (19, 29))	('cg11201447', 'Var', (4, 14))	('methylation', 'biological_process', 'GO:0032259', ('173', '184'))	('CpGs', 'Chemical', 'MESH:C015772', (151, 155))	('cg11201447', 'Chemical', '-', (4, 14))	('methylated levels', 'MPA', (118, 135))	('microRNA1204', 'Gene', (71, 83))
204740	29079774	Comparison with high-grade (grade I-II) showed that the methylation of 3 of 4 CpGs were statistically hypomethylation in low-grade (grade III-IV) ccRCCs (P < 0.05), except fot cg08995609, indicating that the 4 CpGs in tumor genesis and progression are dynamic change (Fig.	('hypomethylation', 'Var', (102, 117))	('RCC', 'Disease', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('CpGs', 'Chemical', 'MESH:C015772', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('methylation', 'MPA', (56, 67))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('tumor', 'Disease', (218, 223))	('CpGs', 'Chemical', 'MESH:C015772', (210, 214))
204741	29079774	To validate the possible diagnostic ability of the 4 CpGs, we first performed pyrosequencing analysis of the cg08995609 in RIN1.	('CpGs', 'Chemical', 'MESH:C015772', (53, 57))	('RIN1', 'Gene', '9610', (123, 127))	('cg08995609', 'Var', (109, 119))	('RIN1', 'Gene', (123, 127))
204742	29079774	The methylation level of the cg08995609 in the 19 ccRCCs was significantly hypomethylated (P = 0.700E-3) (Fig.	('cg08995609', 'Var', (29, 39))	('methylation level', 'MPA', (4, 21))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('hypomethylated', 'MPA', (75, 89))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (50, 55))	('RCC', 'Disease', (52, 55))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))
204743	29079774	We then analyzed three public datasets, including GSE61441 (46 ccRCCs and matched adjacent tissues from GEO database), E-MTAB-2007 (106 ccRCCs and 6 adjacent tissues from ArrayExpress database) and GSE70303 (6 ccRCCs and matched adjacent tissues from GEO database) that were analyzed in TCGA Illumina HumanMethylation450 microarray.	('RCC', 'Disease', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('GSE61441', 'Var', (50, 58))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('GSE70303', 'Var', (198, 206))	('ccRCC', 'Phenotype', 'HP:0006770', (63, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (210, 215))	('RCC', 'Disease', (212, 215))	('RCC', 'Phenotype', 'HP:0005584', (212, 215))	('MTAB', 'molecular_function', 'GO:0047152', ('121', '125'))	('Human', 'Species', '9606', (301, 306))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
204744	29079774	Intriguingly, in all three datasets, cg11201447, cg25247520, cg13309012 and cg08995609 in the ccRCC tissues were significantly lower than in the adjacent tissues (Supplementary Figure 1A).	('RCC', 'Disease', (96, 99))	('cg13309012', 'Var', (61, 71))	('lower', 'NegReg', (127, 132))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('cg11201447', 'Var', (37, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('cg25247520', 'Var', (49, 59))	('cg08995609', 'Var', (76, 86))	('cg11201447', 'Chemical', '-', (37, 47))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
204745	29079774	In Supplementary Figure 1B,C,D, ROC curves reveal AUC of 0.996, 0.998 and 1.000 (P < 0.05), which are almost identical to that of the TCGA data.	('0.998', 'Var', (64, 69))	('Supplementary Figure 1B', 'Disease', (3, 26))	('Supplementary Figure 1B', 'Disease', 'MESH:D017034', (3, 26))
204746	29079774	The fact that outstanding biomarkers have tissue specificity prompted us to evaluate methylated levels of the cg11201447, cg25247520, cg13309012 and cg08995609 in other carcinomas.	('cg08995609', 'Var', (149, 159))	('cg25247520', 'Var', (122, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('carcinomas', 'Disease', 'MESH:D002277', (169, 179))	('cg11201447', 'Var', (110, 120))	('carcinomas', 'Disease', (169, 179))	('cg11201447', 'Chemical', '-', (110, 120))	('cg13309012', 'Var', (134, 144))
204748	29079774	The simultaneous hypomethylations of cg11201447, cg25247520, cg13309012 and cg08995609 with P < 0.05 and Delta Beta >  = -0.2 only showed in kidney renal papillary cell carcinoma, but not in the other 10 carcinomas (Supplementary Table 4).	('kidney renal papillary cell carcinoma', 'Disease', (141, 178))	('cg13309012', 'Var', (61, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('carcinomas', 'Disease', (204, 214))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (141, 178))	('carcinomas', 'Disease', 'MESH:D002277', (204, 214))	('cg11201447', 'Var', (37, 47))	('showed', 'Reg', (131, 137))	('cg25247520', 'Var', (49, 59))	('cg08995609', 'Var', (76, 86))	('cg11201447', 'Chemical', '-', (37, 47))
204749	29079774	From our TCGA data analysis, we found that in ccRCC samples, RAB25 (Delta Beta = 0.202, Methylation FDR = 1.080E-56, mRNA FDR = 1.180E-38, log2 FC = -3.505) and CYP4B1 (Delta Beta = 0.314, Methylation FDR = 1.600E-48, mRNA FDR = 4.070E-05, log2 FC = -1.836) are both downregulated with promoter hypermethylations and CA9 is upregulated with promoter hypomethylation (Delta Beta = 0.220, Methylation FDR = 6.790E-61, mRNA FDR = 2.350E-211, log2 FC = 5.836).	('Methylation', 'Var', (387, 398))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('RCC', 'Disease', (48, 51))	('RAB25', 'Gene', '57111', (61, 66))	('CYP4B1', 'Gene', (161, 167))	('upregulated', 'PosReg', (324, 335))	('promoter hypermethylations', 'Var', (286, 312))	('CA9', 'Gene', (317, 320))	('RAB25', 'Gene', (61, 66))	('CA9', 'Gene', '768', (317, 320))	('CYP4B1', 'Gene', '1580', (161, 167))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('Methylation', 'biological_process', 'GO:0032259', ('387', '398'))	('Delta Beta = 0.220', 'Var', (367, 385))	('Methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('Methylation', 'biological_process', 'GO:0032259', ('189', '200'))	('downregulated', 'NegReg', (267, 280))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
204757	29079774	However, CYP4B1 had significantly low expressions in GSE16449, GSE16441 and GSE53757 (Fig.	('GSE16441', 'Gene', (63, 71))	('expressions', 'MPA', (38, 49))	('GSE16449', 'Var', (53, 61))	('CYP4B1', 'Gene', (9, 15))	('low', 'NegReg', (34, 37))	('GSE53757', 'Var', (76, 84))	('CYP4B1', 'Gene', '1580', (9, 15))
204758	29079774	Additionally, three upregulated genes with hypomethylations (ESM1, EVI2B, TNFAIP6) and two downregulated genes with hypermethylations (SLC34A1, SOSTDC1) were also confirmed in the 10 GEO datasets (Supplementary Table 5).	('hypomethylations', 'Var', (43, 59))	('SLC34A1', 'Gene', '6569', (135, 142))	('SOSTDC1', 'Gene', (144, 151))	('EVI2B', 'Gene', '2124', (67, 72))	('ESM1', 'Gene', '11082', (61, 65))	('SLC34A1', 'Gene', (135, 142))	('upregulated', 'PosReg', (20, 31))	('SOSTDC1', 'Gene', '25928', (144, 151))	('ESM1', 'Gene', (61, 65))	('TNFAIP6', 'Gene', (74, 81))	('TNFAIP6', 'Gene', '7130', (74, 81))	('EVI2B', 'Gene', (67, 72))
204762	29079774	The above analyses prompted us to test the pattern of RAB25 promoter methylation in ccRCC, and we performed MassArray quantitative DNA methylation sequencing of the promoter regions (-918 to -430 bp upstream from the transcription start sites based on UCSC hg19).	('RAB25', 'Gene', '57111', (54, 59))	('test', 'Reg', (34, 38))	('methylation', 'biological_process', 'GO:0032259', ('69', '80'))	('transcription', 'biological_process', 'GO:0006351', ('217', '230'))	('RAB25', 'Gene', (54, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('-918', 'Var', (183, 187))	('DNA methylation', 'biological_process', 'GO:0006306', ('131', '146'))	('DNA', 'cellular_component', 'GO:0005574', ('131', '134'))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))
204765	29079774	We also validated the hypermethylation of RAB25 promoter in GSE61441, E-MTAB-2007 and GSE70303 (Fig.	('GSE70303', 'Var', (86, 94))	('hypermethylation', 'MPA', (22, 38))	('GSE61441', 'Var', (60, 68))	('MTAB', 'molecular_function', 'GO:0047152', ('72', '76'))	('RAB25', 'Gene', '57111', (42, 47))	('RAB25', 'Gene', (42, 47))
204766	29079774	All these are consistent with our TCGA analysis results and suggest that RAB25 promoter hypermethylation may result in gene silencing.	('RAB25', 'Gene', (73, 78))	('gene silencing', 'biological_process', 'GO:0016458', ('119', '133'))	('gene', 'MPA', (119, 123))	('hypermethylation', 'Var', (88, 104))	('RAB25', 'Gene', '57111', (73, 78))
204776	29079774	The genes involved in hypermethylated CpGs, however, were mainly enriched in the pathway of neuroactive ligand-receptor interaction (Bonferroni = 4.400E-06), biological processes of cell adhesion, and signaling transduction, etc (Supplementary Figure 3B).	('signaling', 'biological_process', 'GO:0023052', ('201', '210'))	('transduction', 'biological_process', 'GO:0009293', ('211', '223'))	('hypermethylated', 'Var', (22, 37))	('cell adhesion', 'biological_process', 'GO:0007155', ('182', '195'))	('ligand', 'molecular_function', 'GO:0005488', ('104', '110'))	('neuroactive ligand-receptor interaction', 'MPA', (92, 131))	('CpGs', 'Chemical', 'MESH:C015772', (38, 42))
204778	29079774	A CpG-based biomarker, including 4 hypomethylated CpG sites (cg11201447, g25247520, cg13309012 and cg0899560) were identified to discriminate ccRCC from adjacent tissues.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('cg11201447', 'Chemical', '-', (61, 71))	('g25247520', 'Var', (73, 82))	('cg13309012', 'Var', (84, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('cg0899560', 'Var', (99, 108))	('cg11201447', 'Var', (61, 71))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))
204784	29079774	In early stages of carcinogenesis, the appearing of DNA hypomethylation seems to cause genomic instability and activate the transcriptions and expressions of proto-oncogenes, which may contribute to cancer pathogenesis.	('cause', 'Reg', (81, 86))	('carcinogenesis', 'Disease', 'MESH:D063646', (19, 33))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('DNA hypomethylation', 'Var', (52, 71))	('pathogenesis', 'biological_process', 'GO:0009405', ('206', '218'))	('expressions', 'MPA', (143, 154))	('genomic instability', 'CPA', (87, 106))	('carcinogenesis', 'Disease', (19, 33))	('contribute', 'Reg', (185, 195))	('activate', 'PosReg', (111, 119))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('52', '71'))	('cancer', 'Disease', (199, 205))	('transcriptions', 'MPA', (124, 138))
204785	29079774	Thus, we can assume that promoter hypomethylation preferentially contribute to ccRCC pathologies.	('promoter hypomethylation', 'Var', (25, 49))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('contribute', 'Reg', (65, 75))
204787	29079774	Human microRNA-1204, which is residing in 60 kb downstream of MYC and within the exon 1b of PVT1, depresses tumor suppressor genes and contributes to ovarian and breast tumor proliferations and patients' survival.	('microRNA-1204', 'Var', (6, 19))	('depresses tumor', 'Disease', (98, 113))	('PVT1', 'Gene', (92, 96))	('MYC', 'Gene', (62, 65))	('patients', 'Species', '9606', (194, 202))	('Human', 'Species', '9606', (0, 5))	('tumor suppressor', 'biological_process', 'GO:0051726', ('108', '124'))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('depresses tumor', 'Disease', 'MESH:D000275', (98, 113))	('PVT1', 'Gene', '5820', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('108', '124'))	("patients' survival", 'CPA', (194, 212))	('MYC', 'Gene', '4609', (62, 65))	('ovarian and breast tumor proliferations', 'Disease', 'MESH:D001943', (150, 189))	('breast tumor', 'Phenotype', 'HP:0100013', (162, 174))	('contributes', 'Reg', (135, 146))
204790	29079774	Compared with normal kidney tissue, microRNA-155 had a significant overexpression in ccRCC, so it could serve as a predictive marker for survival in patients with stage III and IV ccRCC.	('microRNA-155', 'Var', (36, 48))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('patients', 'Species', '9606', (149, 157))	('RCC', 'Disease', (87, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('overexpression', 'PosReg', (67, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('RCC', 'Disease', (182, 185))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
204791	29079774	MicroRNA-155 could promote cell proliferations and migratory activities and it could suppress apoptosis in renal cancer cell by targeting a suppressor gene BACH1.	('migratory activities', 'CPA', (51, 71))	('cell proliferations', 'CPA', (27, 46))	('promote', 'PosReg', (19, 26))	('BACH1', 'Gene', '571', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('renal cancer', 'Disease', (107, 119))	('renal cancer', 'Phenotype', 'HP:0009726', (107, 119))	('targeting', 'Reg', (128, 137))	('BACH1', 'Gene', (156, 161))	('renal cancer', 'Disease', 'MESH:D007680', (107, 119))	('MicroRNA-155', 'Var', (0, 12))	('apoptosis', 'CPA', (94, 103))	('suppress', 'NegReg', (85, 93))	('apoptosis', 'biological_process', 'GO:0006915', ('94', '103'))	('apoptosis', 'biological_process', 'GO:0097194', ('94', '103'))
204794	29079774	However, for breast cancer, DNA methylation with RIN1 promoter was involved in silencing its expression, which may contribute to adenocarcinoma progression.	('DNA methylation', 'Var', (28, 43))	('adenocarcinoma', 'Disease', (129, 143))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('adenocarcinoma', 'Disease', 'MESH:D000230', (129, 143))	('RIN1', 'Gene', (49, 53))	('breast cancer', 'Disease', (13, 26))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('expression', 'MPA', (93, 103))	('DNA methylation', 'biological_process', 'GO:0006306', ('28', '43'))	('silencing', 'NegReg', (79, 88))	('contribute', 'Reg', (115, 125))	('RIN1', 'Gene', '9610', (49, 53))
204795	29079774	It has been reported that the cg14391855 located at RIN1 was one of prognostic and diagnostic markers for ccRCC by Wei et al.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('RIN1', 'Gene', (52, 56))	('cg14391855', 'Var', (30, 40))	('RIN1', 'Gene', '9610', (52, 56))
204796	29079774	Our TCGA study revealed that RIN1 promoter in ccRCC tissues was hypomethylated (FDR = 9.850E-76,  Delta Beta  = -0.251), suggesting that DNA methylation of RIN1 promoter could be related to the ccRCC.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('RIN1', 'Gene', '9610', (156, 160))	('RIN1', 'Gene', '9610', (29, 33))	('DNA methylation', 'biological_process', 'GO:0006306', ('137', '152'))	('RIN1', 'Gene', (29, 33))	('ccRCC', 'Phenotype', 'HP:0006770', (194, 199))	('related', 'Reg', (179, 186))	('DNA', 'cellular_component', 'GO:0005574', ('137', '140'))	('ccRCC', 'Phenotype', 'HP:0006770', (46, 51))	('RIN1', 'Gene', (156, 160))	('RCC', 'Disease', 'MESH:C538614', (196, 199))	('RCC', 'Disease', (196, 199))	('RCC', 'Phenotype', 'HP:0005584', (196, 199))	('DNA methylation', 'Var', (137, 152))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
204797	29079774	Our study suggested that tumorous epigenetic marker drifts could occur preferentially in transcribed regions, which is an interesting insight in neoplasm.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('neoplasm', 'Disease', (145, 153))	('neoplasm', 'Phenotype', 'HP:0002664', (145, 153))	('neoplasm', 'Disease', 'MESH:D009369', (145, 153))	('epigenetic marker drifts', 'Var', (34, 58))	('tumorous', 'Disease', (25, 33))	('tumorous', 'Disease', 'MESH:D009369', (25, 33))
204798	29079774	Oncogenes and tumor suppressor genes within promoter regions induce aberrant DNA methylation, resulting in the development and progression of neoplasms.	('DNA methylation', 'MPA', (77, 92))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('14', '30'))	('tumor', 'Disease', (14, 19))	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('neoplasms', 'Disease', (142, 151))	('neoplasm', 'Phenotype', 'HP:0002664', (142, 150))	('neoplasms', 'Disease', 'MESH:D009369', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('DNA methylation', 'biological_process', 'GO:0006306', ('77', '92'))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('neoplasms', 'Phenotype', 'HP:0002664', (142, 151))	('resulting in', 'Reg', (94, 106))	('development', 'CPA', (111, 122))	('tumor suppressor', 'biological_process', 'GO:0051726', ('14', '30'))	('aberrant', 'Var', (68, 76))
204799	29079774	Our goal of this study is to detect tumor-related genes that suffered from methylation variations within promoter regions.	('methylation', 'biological_process', 'GO:0032259', ('75', '86'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('methylation variations', 'Var', (75, 97))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
204800	29079774	It was reported that the tyrosine of CA9 could be phosphorylated in an epidermal growth factor dependent manner, interacts with the regulatory subunit of PI-3-Kinase, and activates Akt.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('71', '94'))	('Akt', 'Pathway', (181, 184))	('tyrosine', 'Var', (25, 33))	('interacts', 'Interaction', (113, 122))	('activates', 'PosReg', (171, 180))	('CA9', 'Gene', '768', (37, 40))	('CA9', 'Gene', (37, 40))	('tyrosine', 'Chemical', 'MESH:D014443', (25, 33))
204807	29079774	Thus, the inactivation of RAB25 caused by promoter hypermethylation could have considerable effects on the development and progression of ccRCC.	('RAB25', 'Gene', '57111', (26, 31))	('inactivation', 'NegReg', (10, 22))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('rab', 'Gene', (86, 89))	('RAB25', 'Gene', (26, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('rab', 'Gene', '57111;53868', (86, 89))	('effects', 'Reg', (92, 99))	('promoter hypermethylation', 'Var', (42, 67))
204817	29079774	The CpG hypermethylation of the promoter region of the E-cadherin gene mediated cell adhesions and inactivated its mRNA expression in renal cell carcinoma.	('E-cadherin', 'Gene', (55, 65))	('E-cadherin', 'Gene', '999', (55, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('mediated', 'Reg', (71, 79))	('hypermethylation', 'Var', (8, 24))	('cell adhesions', 'CPA', (80, 94))	('renal cell carcinoma', 'Disease', (134, 154))	('cadherin', 'molecular_function', 'GO:0008014', ('57', '65'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (134, 154))	('inactivated', 'NegReg', (99, 110))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (134, 154))	('mRNA expression', 'MPA', (115, 130))
204818	29079774	Therefore, promoter hypermethylation depresses cell adhesion-related genes' expressions, which contribute to the malignance of ccRCC cells.	('depresses', 'NegReg', (37, 46))	('promoter hypermethylation', 'Var', (11, 36))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('ccRCC', 'Phenotype', 'HP:0006770', (127, 132))	('RCC', 'Disease', (129, 132))	('expressions', 'MPA', (76, 87))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('cell adhesion', 'biological_process', 'GO:0007155', ('47', '60'))	('cell adhesion-related genes', 'Gene', (47, 74))
204819	29079774	These suggest that, indirectly, promoter DNA methylation could regulate critical genes of biological processes or pathways, and thus alter the effects of processes or pathways in ccRCC progression.	('alter', 'Reg', (133, 138))	('effects', 'MPA', (143, 150))	('DNA methylation', 'biological_process', 'GO:0006306', ('41', '56'))	('ccRCC', 'Phenotype', 'HP:0006770', (179, 184))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('promoter DNA methylation', 'Var', (32, 56))	('regulate', 'Reg', (63, 71))	('RCC', 'Disease', 'MESH:C538614', (181, 184))	('RCC', 'Disease', (181, 184))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))
204824	29079774	Meanwhile, our findings of aberrant DNA methylation in ccRCC need to be more explored in the vitro and vivo model.	('aberrant', 'Var', (27, 35))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('DNA methylation', 'biological_process', 'GO:0006306', ('36', '51'))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))
204825	29079774	In conclusion, we have showed that together the methylation levels of cg11201447, cg25247520, cg13309012 and cg08995609 CpGs could be a potential biomarker for ccRCC.	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('ccRCC', 'Phenotype', 'HP:0006770', (160, 165))	('RCC', 'Disease', (162, 165))	('RCC', 'Phenotype', 'HP:0005584', (162, 165))	('cg11201447', 'Var', (70, 80))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('methylation', 'MPA', (48, 59))	('cg25247520', 'Var', (82, 92))	('cg08995609', 'Var', (109, 119))	('cg13309012', 'Var', (94, 104))	('cg11201447', 'Chemical', '-', (70, 80))	('CpGs', 'Chemical', 'MESH:C015772', (120, 124))
204849	29079774	The datasets, including GSE68417, GSE76351, GSE53757, GSE40435, GSE36895, GSE16441, GSE16449, GSE17895, GSE14994, GSE6344, were applied to validate the mRNA expressions.	('GSE6344', 'Chemical', '-', (114, 121))	('GSE36895', 'Var', (64, 72))	('GSE40435', 'Var', (54, 62))	('GSE16441', 'Var', (74, 82))	('GSE16449', 'Var', (84, 92))	('GSE17895', 'Var', (94, 102))	('GSE14994', 'Var', (104, 112))
204904	31565700	Thus, it is important to recognize the presence of intranuclear inclusions in primary and metastatic RCCs, particularly in tumors with high nucleoli-grade.	('RCCs', 'Disease', (101, 105))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('RCCs', 'Phenotype', 'HP:0005584', (101, 105))	('RCCs', 'Disease', 'MESH:D002292', (101, 105))	('metastatic', 'CPA', (90, 100))	('intranuclear', 'Var', (51, 63))	('intranuclear inclusions', 'Phenotype', 'HP:0100304', (51, 74))	('intranuclear inclusion', 'Phenotype', 'HP:0100304', (51, 73))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
204937	31192266	Hydroxylation of two prolines (P402 and P564 of HIF-1alpha, P405 and P531 of HIF-2alpha) by proline hydroxylases (PHDs) targets the protein for proteasomal degradation via the von-Hippel-Lindau (VHL)-ubiquitin-ligase complex, and asparagine hydroxylation (N803 of HIF-1alpha, N847 of HIF-2alpha) by factor inhibiting HIF (FIH) leads to its transcriptional inactivation.	('von-Hippel-Lindau', 'Disease', 'MESH:D006623', (176, 193))	('inhibiting', 'NegReg', (306, 316))	('HIF', 'Gene', (48, 51))	('HIF', 'Gene', (317, 320))	('HIF', 'Gene', '405', (264, 267))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('PHD', 'Disease', (114, 117))	('HIF', 'Gene', (77, 80))	('HIF', 'Gene', (284, 287))	('asparagine', 'Chemical', 'MESH:D001216', (230, 240))	('N803', 'Var', (256, 260))	('von-Hippel-Lindau', 'Disease', (176, 193))	('HIF', 'Gene', '405', (48, 51))	('HIF', 'Gene', '405', (317, 320))	('PHD', 'Disease', 'MESH:D011547', (114, 117))	('VHL', 'Gene', (195, 198))	('transcriptional', 'MPA', (340, 355))	('HIF', 'Gene', '405', (77, 80))	('ubiquitin-ligase complex', 'cellular_component', 'GO:0000151', ('200', '224'))	('HIF', 'Gene', '405', (284, 287))	('degradation', 'biological_process', 'GO:0009056', ('156', '167'))	('N847', 'Var', (276, 280))	('ubiquitin', 'molecular_function', 'GO:0031386', ('200', '209'))	('P405', 'Var', (60, 64))	('P531', 'Var', (69, 73))	('VHL', 'Gene', '7428', (195, 198))	('HIF', 'Gene', (264, 267))	('P402', 'Var', (31, 35))
204938	31192266	Both PHD and FIH enzymes require ascorbate as a cofactor, and absence of ascorbate leads to increased HIF activation.	('PHD', 'Disease', (5, 8))	('HIF', 'Gene', (102, 105))	('HIF', 'Gene', '405', (102, 105))	('ascorbate', 'Chemical', 'MESH:D001205', (73, 82))	('ascorbate', 'Chemical', 'MESH:D001205', (33, 42))	('increased', 'PosReg', (92, 101))	('absence', 'Var', (62, 69))	('ascorbate', 'Protein', (73, 82))	('PHD', 'molecular_function', 'GO:0050175', ('5', '8'))	('activation', 'PosReg', (106, 116))	('PHD', 'Disease', 'MESH:D011547', (5, 8))
204942	31192266	Using recombinant proteins, Jaakkola et al demonstrated that PHDs rely on ascorbate for full activity for the hydroxylation of P564.	('PHD', 'Disease', 'MESH:D011547', (61, 64))	('P564', 'Var', (127, 131))	('PHD', 'Disease', (61, 64))	('hydroxylation', 'MPA', (110, 123))	('ascorbate', 'Chemical', 'MESH:D001205', (74, 83))
204944	31192266	Subsequently, the dependence of both PHD2 and FIH on ascorbate was investigated in reactions with different short HIF-1alpha peptides each containing one of the three hydroxylation sites (P402, P564 or N803) using matrix-assisted laser desorption ionization-time of flight mass spectrometry.	('P564', 'Var', (194, 198))	('PHD', 'molecular_function', 'GO:0050175', ('37', '40'))	('N803', 'Var', (202, 206))	('P402', 'Var', (188, 192))	('PHD2', 'Gene', '54583', (37, 41))	('HIF-1alpha', 'Gene', (114, 124))	('PHD2', 'Gene', (37, 41))	('flight', 'biological_process', 'GO:0060361', ('266', '272'))	('ascorbate', 'Chemical', 'MESH:D001205', (53, 62))
204949	31192266	Clear cell renal cell carcinoma (ccRCC) is a serious urological malignancy that harbors alterations in the VHL tumor suppressor gene leading to uncontrolled accumulation of HIF.	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('RCC', 'Disease', (35, 38))	('malignancy', 'Disease', (64, 74))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('VHL tumor', 'Disease', 'MESH:D006623', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('alterations', 'Var', (88, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('HIF', 'Gene', (173, 176))	('HIF', 'Gene', '405', (173, 176))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('VHL tumor', 'Disease', (107, 116))	('tumor suppressor', 'biological_process', 'GO:0051726', ('111', '127'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('111', '127'))	('malignancy', 'Disease', 'MESH:D009369', (64, 74))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
204950	31192266	Human ccRCC cell lines are available with different VHL mutation status, and these are valuable for investigating the involvement of VHL in the HIF response to ascorbate.	('Human', 'Species', '9606', (0, 5))	('RCC', 'Disease', (8, 11))	('VHL', 'Gene', '7428', (52, 55))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('VHL', 'Gene', (133, 136))	('HIF', 'Gene', (144, 147))	('HIF', 'Gene', '405', (144, 147))	('ccRCC', 'Phenotype', 'HP:0006770', (6, 11))	('ascorbate', 'Chemical', 'MESH:D001205', (160, 169))	('VHL', 'Gene', '7428', (133, 136))	('mutation', 'Var', (56, 64))	('VHL', 'Gene', (52, 55))
204957	31192266	Caki-1 cells express both HIF-1alpha and HIF-2alpha and have a VHL wild-type status, Caki-2 express only HIF-1alpha and have a mutant VHL status (VHL status was confirmed by Sanger sequencing due to conflicting published data, results not shown), and 786-0 cells express only HIF-2alpha and have a mutant VHL status.	('mutant', 'Var', (127, 133))	('VHL', 'Gene', (146, 149))	('VHL', 'Gene', '7428', (146, 149))	('VHL', 'Gene', (305, 308))	('Caki-1', 'CellLine', 'CVCL:0234', (0, 6))	('VHL', 'Gene', '7428', (305, 308))	('VHL', 'Gene', (134, 137))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (26, 51))	('VHL', 'Gene', (63, 66))	('Caki-2', 'CellLine', 'CVCL:0235', (85, 91))	('VHL', 'Gene', '7428', (134, 137))	('VHL', 'Gene', '7428', (63, 66))
204986	31192266	Levels of the HIF-1 target BNIP3 were increased 3-fold at 0.1% O2 (p<0.05; Figure 2E).	('HIF-1', 'Gene', (14, 19))	('Levels', 'MPA', (0, 6))	('O2', 'Chemical', 'MESH:D010100', (63, 65))	('0.1%', 'Var', (58, 62))	('BNIP3', 'Gene', (27, 32))	('HIF-1', 'Gene', '3091', (14, 19))	('BNIP3', 'Gene', '664', (27, 32))	('increased', 'PosReg', (38, 47))
205016	31192266	Western blot analysis indicated an increase of hydroxylated-HIF-1alpha at P564 compared to total HIF-1 alpha protein across ascorbate doses (Figure 7E), although differences between groups were not significant (1-way ANOVA with Bonferroni post-test).	('P564', 'Var', (74, 78))	('increase', 'PosReg', (35, 43))	('HIF-1 alpha', 'Gene', (97, 108))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('HIF-1 alpha', 'Gene', '3091', (97, 108))	('ascorbate', 'Chemical', 'MESH:D001205', (124, 133))	('hydroxylated-HIF-1alpha', 'MPA', (47, 70))
205047	31192266	Functional studies and in vitro experiments with other cell types have shown that FIH was more susceptible to ascorbate deprivation than PHD, and elevating ascorbate levels was able to increase FIH activity independent of HIF stability.	('increase', 'PosReg', (185, 193))	('ascorbate levels', 'MPA', (156, 172))	('PHD', 'Disease', 'MESH:D011547', (137, 140))	('PHD', 'Disease', (137, 140))	('ascorbate', 'Chemical', 'MESH:D001205', (156, 165))	('ascorbate', 'Chemical', 'MESH:D001205', (110, 119))	('ascorbate', 'MPA', (110, 119))	('activity', 'MPA', (198, 206))	('elevating', 'Var', (146, 155))	('PHD', 'molecular_function', 'GO:0050175', ('137', '140'))	('HIF', 'Gene', '405', (222, 225))	('HIF', 'Gene', (222, 225))
205055	31192266	We observed an increase in hydroxylation of HIF-1alpha at P564 in 786-HIF1 cells treated with ascorbate.	('hydroxylation', 'MPA', (27, 40))	('ascorbate', 'Chemical', 'MESH:D001205', (94, 103))	('increase', 'PosReg', (15, 23))	('HIF1', 'Gene', '3091', (70, 74))	('HIF-1alpha', 'Protein', (44, 54))	('P564', 'Var', (58, 62))	('HIF1', 'Gene', (70, 74))
205065	31192266	Together, these data indicate a growth disadvantage of forced HIF expression in VHL-defective ccRCC cells, which might explain the progressive loss of HIF-1alpha expression in 786-HIF1 cells over time in culture.	('RCC', 'Disease', (96, 99))	('HIF1', 'Gene', (180, 184))	('forced', 'Var', (55, 61))	('HIF', 'Gene', '405', (180, 183))	('VHL-defective', 'Disease', 'MESH:D006623', (80, 93))	('HIF', 'Gene', (151, 154))	('HIF', 'Gene', (62, 65))	('HIF', 'Gene', '405', (62, 65))	('HIF', 'Gene', '405', (151, 154))	('HIF1', 'Gene', '3091', (180, 184))	('loss', 'NegReg', (143, 147))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('HIF', 'Gene', (180, 183))	('VHL-defective', 'Disease', (80, 93))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
205068	31192266	Elevating intracellular ascorbate levels increased hydroxylation of HIF-1alpha on P564, confirming that PHDs rely on ascorbate for full activity to hydroxylate HIF-1alpha, and this finding reinforces the need for maintaining sufficient intracellular levels of ascorbate for the regulation of HIF pathway activity.	('ascorbate', 'Chemical', 'MESH:D001205', (24, 33))	('increased', 'PosReg', (41, 50))	('HIF', 'Gene', (68, 71))	('P564', 'Var', (82, 86))	('hydroxylation', 'MPA', (51, 64))	('HIF', 'Gene', '405', (68, 71))	('ascorbate', 'Chemical', 'MESH:D001205', (117, 126))	('intracellular', 'cellular_component', 'GO:0005622', ('236', '249'))	('HIF', 'Gene', (292, 295))	('HIF', 'Gene', '405', (292, 295))	('PHD', 'Disease', 'MESH:D011547', (104, 107))	('PHD', 'Disease', (104, 107))	('intracellular ascorbate levels', 'MPA', (10, 40))	('intracellular', 'cellular_component', 'GO:0005622', ('10', '23'))	('HIF', 'Gene', '405', (160, 163))	('ascorbate', 'Chemical', 'MESH:D001205', (260, 269))	('HIF', 'Gene', (160, 163))	('regulation', 'biological_process', 'GO:0065007', ('278', '288'))
205079	31965534	Previous studies have shown that altered lncRNA expression has an effect on oncogenesis whereby they are emerging as potent regulators of tumor development.	('effect', 'Reg', (66, 72))	('tumor', 'Disease', (138, 143))	('lncRNA', 'Protein', (41, 47))	('oncogenesis', 'CPA', (76, 87))	('altered', 'Var', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('oncogenesis', 'biological_process', 'GO:0007048', ('76', '87'))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
205108	31965534	Finally, high Fer1L4 expression was predictive for progression-free survival (PFS, log rank p = 0.008), cancer-specific survival (CSS, log rank p < 0.001), and overall survival (OS, log rank p < 0.001); see Fig.	('Fer1L4', 'Gene', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('progression-free survival', 'CPA', (51, 76))	('Fer1L4', 'Gene', '80307', (14, 20))	('expression', 'MPA', (21, 31))	('overall survival', 'CPA', (160, 176))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('high', 'Var', (9, 13))
205124	31965534	Additionally, siRNA-mediated knockdown of Fer1L4 decreased invasiveness of glioblastoma cells and induced apoptosis.	('Fer1L4', 'Gene', '80307', (42, 48))	('decreased invasiveness of glioblastoma', 'Disease', (49, 87))	('knockdown', 'Var', (29, 38))	('induced', 'Reg', (98, 105))	('apoptosis', 'CPA', (106, 115))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('glioblastoma', 'Phenotype', 'HP:0012174', (75, 87))	('decreased invasiveness of glioblastoma', 'Disease', 'MESH:D005909', (49, 87))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('Fer1L4', 'Gene', (42, 48))
205125	31965534	In breast cancer, upregulation of Fer1L4 is linked to promoter hypomethylation suggesting that Fer1L4 expression is epigenetically regulated.	('upregulation', 'PosReg', (18, 30))	('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))	('Fer1L4', 'Gene', (95, 101))	('Fer1L4', 'Gene', '80307', (95, 101))	('Fer1L4', 'Gene', (34, 40))	('Fer1L4', 'Gene', '80307', (34, 40))	('promoter hypomethylation', 'Var', (54, 78))
205141	31959902	In a NF2-mutant sRCC model, YAP1 knockdown and NF2 reconstitution suppressed cell proliferation, tumour growth and invasion, both in vitro and in vivo.	('cell proliferation', 'biological_process', 'GO:0008283', ('77', '95'))	('sRCC', 'Disease', (16, 20))	('tumour growth', 'Disease', 'MESH:D006130', (97, 110))	('YAP1', 'Gene', (28, 32))	('tumour growth', 'Disease', (97, 110))	('suppressed', 'NegReg', (66, 76))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('sRCC', 'Disease', 'MESH:D002292', (16, 20))	('NF2-mutant', 'Gene', (5, 15))	('NF2-mutant', 'Var', (5, 15))	('NF2', 'Gene', (47, 50))	('cell proliferation', 'CPA', (77, 95))	('invasion', 'CPA', (115, 123))
205149	31959902	An analysis of another 65 sarcomatoid kidney tumours of varying histological subtypes reported increased mutations of PTEN and chromatin remodelling genes BAP1 and SETD2 in clear cell subtypes, increased NF2 mutations in papillary subtypes and increased TP53 alterations in both.	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('mutations', 'Var', (208, 217))	('PTEN', 'Gene', (118, 122))	('SETD2', 'Gene', '29072', (164, 169))	('mutations', 'Var', (105, 114))	('chromatin', 'cellular_component', 'GO:0000785', ('127', '136'))	('sarcomatoid kidney tumours', 'Disease', (26, 52))	('TP53', 'Gene', '7157', (254, 258))	('sarcomatoid kidney tumours', 'Disease', 'MESH:D007680', (26, 52))	('PTEN', 'Gene', '5728', (118, 122))	('alterations', 'Reg', (259, 270))	('BAP1', 'Gene', '8314', (155, 159))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('127', '148'))	('NF2', 'Gene', (204, 207))	('sarcomatoid kidney', 'Phenotype', 'HP:0008663', (26, 44))	('TP53', 'Gene', (254, 258))	('BAP1', 'Gene', (155, 159))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('SETD2', 'Gene', (164, 169))	('increased', 'PosReg', (244, 253))
205150	31959902	In one study that performed systematic microdissection of epithelial and sarcomatoid components of renal cell carcinomas, 21 tumours with mixed histology had sarcomatoid components harbouring a greater mutational load than paired epithelial components, as well as greater numbers of mutations of TP53, chromatin modifiers BAP1 and ARID1 and Hippo pathway gene FAT2.	('TP53', 'Gene', '7157', (296, 300))	('sarcomatoid component', 'Disease', (158, 179))	('sarcomatoid component', 'Disease', 'MESH:D002292', (158, 179))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (99, 119))	('Hippo', 'Pathway', (341, 346))	('mutational', 'Var', (202, 212))	('FAT2', 'Gene', '2196', (360, 364))	('sarcomatoid components of renal cell carcinomas', 'Disease', 'MESH:D002292', (73, 120))	('BAP1', 'Gene', '8314', (322, 326))	('chromatin', 'cellular_component', 'GO:0000785', ('302', '311'))	('ARID1', 'Gene', (331, 336))	('sarcomatoid components of renal cell carcinomas', 'Disease', (73, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('FAT2', 'Gene', (360, 364))	('TP53', 'Gene', (296, 300))	('mutations', 'Var', (283, 292))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (99, 120))	('sarcomatoid component', 'Disease', 'MESH:D002292', (73, 94))	('BAP1', 'Gene', (322, 326))	('tumours', 'Disease', (125, 132))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))	('tumours', 'Disease', 'MESH:D009369', (125, 132))
205153	31959902	We show that alterations in the Hippo pathway are frequent in sRCCs, and that inhibition of downstream Hippo effectors inhibit cell proliferation, tumour growth and invasion.	('tumour growth', 'Disease', (147, 160))	('cell proliferation', 'biological_process', 'GO:0008283', ('127', '145'))	('Hippo pathway', 'Pathway', (32, 45))	('sRCC', 'Disease', 'MESH:D002292', (62, 66))	('cell proliferation', 'CPA', (127, 145))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumour growth', 'Disease', 'MESH:D006130', (147, 160))	('inhibition', 'Var', (78, 88))	('inhibit', 'NegReg', (119, 126))	('invasion', 'CPA', (165, 173))	('alterations', 'Var', (13, 24))	('sRCC', 'Disease', (62, 66))
205154	31959902	Ours is the first report of Hippo pathway alterations as a candidate actionable driver of sarcomatoid dedifferentiation in ccRCC.	('Hippo', 'Protein', (28, 33))	('alterations', 'Var', (42, 53))	('sarcomatoid dedifferentiation', 'Disease', (90, 119))	('dedifferentiation', 'biological_process', 'GO:0043696', ('102', '119'))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('ccRCC', 'Disease', (123, 128))	('sarcomatoid dedifferentiation', 'Disease', 'MESH:D002292', (90, 119))	('ccRCC', 'Disease', 'MESH:D002292', (123, 128))
205158	31959902	Interestingly, 9 of the 20 mutations of SETD2 involved a hotspot frameshift mutation (K2fs).	('mutations', 'Var', (27, 36))	('K2fs', 'Var', (86, 90))	('SETD2', 'Gene', '29072', (40, 45))	('SETD2', 'Gene', (40, 45))	('involved', 'Reg', (46, 54))	('K2fs', 'FRAMESHIFT', 'None', (86, 90))
205159	31959902	Recurrent mutations of TERT were identified in 9 samples (18%), including 6 C228T hotspot mutations and 2 C250T hotspot mutations, both located in the TERT promoter.	('C228T', 'Mutation', 'c.228C>T', (76, 81))	('TERT', 'Gene', (23, 27))	('TERT', 'Gene', '7015', (23, 27))	('C228T', 'Var', (76, 81))	('C250T', 'Var', (106, 111))	('TERT', 'Gene', (151, 155))	('TERT', 'Gene', '7015', (151, 155))	('C250T', 'Mutation', 'rs200901835', (106, 111))
205160	31959902	Additional mutations found in >10% of samples involved MTOR pathway members PTEN (7/50, 14%) and TSC2 (6/50, 12%), as well as Hippo pathway members NF2 (5/50, 10%) and FAT1 (5/50, 10%).	('mutations', 'Var', (11, 20))	('MTOR', 'Gene', '2475', (55, 59))	('PTEN', 'Gene', (76, 80))	('TSC2', 'Gene', '7249', (97, 101))	('PTEN', 'Gene', '5728', (76, 80))	('TSC2', 'Gene', (97, 101))	('Hippo pathway', 'Pathway', (126, 139))	('FAT1', 'Gene', '2195', (168, 172))	('MTOR', 'Gene', (55, 59))	('FAT1', 'Gene', (168, 172))
205161	31959902	As recurrent mutations of the Hippo pathway were not previously described with this high rate in ccRCC, we assessed the functional impact of these mutations and found that all mutations of NF2 and FAT1 were deleterious and affected functional domains of the proteins (Fig.	('proteins', 'Protein', (258, 266))	('mutations', 'Var', (176, 185))	('NF2', 'Gene', (189, 192))	('ccRCC', 'Disease', 'MESH:D002292', (97, 102))	('FAT1', 'Gene', '2195', (197, 201))	('functional domains of the', 'MPA', (232, 257))	('FAT1', 'Gene', (197, 201))	('affected', 'Reg', (223, 231))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('ccRCC', 'Disease', (97, 102))
205162	31959902	Along with VHL mutations, the most frequent alterations affected chromatin remodelling genes (36/50, 72%).	('VHL', 'Disease', 'MESH:D006623', (11, 14))	('mutations', 'Var', (15, 24))	('VHL', 'Disease', (11, 14))	('alterations affected', 'Reg', (44, 64))	('chromatin', 'cellular_component', 'GO:0000785', ('65', '74'))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('65', '86'))	('chromatin remodelling genes', 'Gene', (65, 92))
205163	31959902	In addition to recurrent mutations of BAP1, PBRM1 and SETD2 previously described, we found mutations of SWI/SNF members ARID1B in 3 samples and ARID1A in one, as well as mutations of epigenetic regulators KDM6A (4%), MLL (4%), ASXL1 (4%), NSD1 (4%), DNMT3A (2%), MLL2 (2%) and MLL3 (2%).	('PBRM1', 'Gene', (44, 49))	('ARID1B', 'Gene', '57492', (120, 126))	('SETD2', 'Gene', '29072', (54, 59))	('MLL', 'Gene', (217, 220))	('MLL2', 'Gene', (263, 267))	('MLL', 'Gene', '4297', (217, 220))	('NSD1', 'Gene', '64324', (239, 243))	('ASXL1', 'Gene', '171023', (227, 232))	('MLL', 'Gene', (263, 266))	('BAP1', 'Gene', '8314', (38, 42))	('MLL', 'Gene', '4297', (263, 266))	('ARID1A', 'Gene', (144, 150))	('MLL3', 'Gene', (277, 281))	('DNMT3A', 'Gene', (250, 256))	('KDM6A', 'Gene', '7403', (205, 210))	('ASXL1', 'Gene', (227, 232))	('ARID1A', 'Gene', '8289', (144, 150))	('MLL', 'Gene', (277, 280))	('MLL', 'Gene', '4297', (277, 280))	('BAP1', 'Gene', (38, 42))	('KDM6A', 'Gene', (205, 210))	('NSD1', 'Gene', (239, 243))	('MLL2', 'Gene', '9757', (263, 267))	('DNMT3A', 'Gene', '1788', (250, 256))	('mutations', 'Var', (170, 179))	('PBRM1', 'Gene', '55193', (44, 49))	('SETD2', 'Gene', (54, 59))	('mutations', 'Var', (91, 100))	('MLL3', 'Gene', '58508', (277, 281))	('ARID1B', 'Gene', (120, 126))
205164	31959902	Notably, 2 paired epithelial and mesenchymal samples from one tumour presented with convergent mutations of SETD2 and NSD1, which have been described to be associated with an aggressive phenotype in ccRCC.	('SETD2', 'Gene', (108, 113))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (199, 204))	('NSD1', 'Gene', '64324', (118, 122))	('ccRCC', 'Disease', (199, 204))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('ccRCC', 'Disease', 'MESH:D002292', (199, 204))	('tumour', 'Disease', (62, 68))	('mutations', 'Var', (95, 104))	('NSD1', 'Gene', (118, 122))	('SETD2', 'Gene', '29072', (108, 113))	('associated with', 'Reg', (156, 171))
205166	31959902	Alterations of SETD2 and TERT repeatedly differed between mesenchymal and epithelial components, with 8/20 mutations of SETD2 and 5/9 mutations of TERT not shared (Fig.	('SETD2', 'Gene', '29072', (15, 20))	('mutations', 'Var', (107, 116))	('SETD2', 'Gene', '29072', (120, 125))	('TERT', 'Gene', (147, 151))	('TERT', 'Gene', (25, 29))	('SETD2', 'Gene', (15, 20))	('SETD2', 'Gene', (120, 125))	('TERT', 'Gene', '7015', (147, 151))	('TERT', 'Gene', '7015', (25, 29))	('SETD2 and 5', 'Gene', '29072;55209', (120, 131))
205167	31959902	These observations are in line with recent studies reporting that SETD2 alterations are associated with high rates of subclonality.	('associated', 'Reg', (88, 98))	('SETD2', 'Gene', '29072', (66, 71))	('SETD2', 'Gene', (66, 71))	('alterations', 'Var', (72, 83))
205169	31959902	Apart from known ccRCC oncogenic alterations, one tumour harboured NF2 and CDKN2A mutations exclusively in its mesenchymal component, and 2 tumours had TP53 mutations that were present exclusively in the mesenchymal component of these tumours.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('tumours', 'Phenotype', 'HP:0002664', (235, 242))	('tumours', 'Disease', 'MESH:D009369', (235, 242))	('CDKN2A', 'Gene', (75, 81))	('tumour', 'Disease', 'MESH:D009369', (140, 146))	('TP53', 'Gene', '7157', (152, 156))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('tumour', 'Disease', (140, 146))	('ccRCC', 'Disease', (17, 22))	('tumours', 'Disease', 'MESH:D009369', (140, 147))	('tumour', 'Phenotype', 'HP:0002664', (235, 241))	('tumour', 'Disease', 'MESH:D009369', (235, 241))	('tumour', 'Disease', (235, 241))	('ccRCC', 'Phenotype', 'HP:0006770', (17, 22))	('CDKN2A', 'Gene', '1029', (75, 81))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Disease', (50, 56))	('NF2', 'Gene', (67, 70))	('TP53', 'Gene', (152, 156))	('mutations', 'Var', (82, 91))	('tumours', 'Disease', (235, 242))	('tumours', 'Disease', (140, 147))	('ccRCC', 'Disease', 'MESH:D002292', (17, 22))
205174	31959902	Notably, 3 tumours harboured deleterious mutations of the core Hippo pathway member LATS2, one tumour with a splicing mutation and 2 with missense mutations.	('mutations', 'Var', (41, 50))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('splicing', 'biological_process', 'GO:0045292', ('109', '117'))	('tumour', 'Disease', (95, 101))	('tumour', 'Disease', 'MESH:D009369', (11, 17))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('core', 'cellular_component', 'GO:0019013', ('58', '62'))	('tumours', 'Disease', 'MESH:D009369', (11, 18))	('tumour', 'Disease', (11, 17))	('tumours', 'Disease', (11, 18))	('LATS2', 'Gene', (84, 89))	('LATS2', 'Gene', '26524', (84, 89))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
205175	31959902	One additional tumour had a frameshift mutation of NF2 (Fig.	('frameshift mutation', 'Var', (28, 47))	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('NF2', 'Gene', (51, 54))	('tumour', 'Disease', (15, 21))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))
205179	31959902	Thus, the frequency of Hippo pathway mutations was significantly higher in sRCCs than in non-sRCCs (p = 0.001).	('sRCC', 'Disease', (93, 97))	('Hippo pathway', 'Pathway', (23, 36))	('sRCC', 'Disease', 'MESH:D002292', (93, 97))	('sRCC', 'Disease', (75, 79))	('mutations', 'Var', (37, 46))	('higher', 'PosReg', (65, 71))	('sRCC', 'Disease', 'MESH:D002292', (75, 79))
205180	31959902	To explore the relevance of mutations affecting Hippo genes in sRCC, we determined YAP/TAZ protein expression and intracellular localization by immunohistochemistry in 8 Hippo-mutated sRCC and 8 Wild-type sRCC.	('expression', 'MPA', (99, 109))	('sRCC', 'Disease', (205, 209))	('sRCC', 'Disease', 'MESH:D002292', (63, 67))	('intracellular', 'cellular_component', 'GO:0005622', ('114', '127'))	('sRCC', 'Disease', 'MESH:D002292', (184, 188))	('Hippo-mutated', 'Gene', (170, 183))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('sRCC', 'Disease', 'MESH:D002292', (205, 209))	('sRCC', 'Disease', (63, 67))	('intracellular localization', 'biological_process', 'GO:0051641', ('114', '140'))	('YAP/TAZ', 'Gene', (83, 90))	('sRCC', 'Disease', (184, 188))	('mutations', 'Var', (28, 37))
205181	31959902	Strikingly, when we focused on NF2-mutant cases (n = 3), we observed a stronger nuclear YAP/TAZ protein as compared to wild-type sRCC (p = 0.019) and other Hippo-mutants (LATS1 and FAT1) (p = 0.049) (Fig.	('stronger', 'PosReg', (71, 79))	('sRCC', 'Disease', (129, 133))	('LATS1', 'Gene', (171, 176))	('nuclear YAP/TAZ protein', 'Protein', (80, 103))	('NF2-mutant', 'Gene', (31, 41))	('NF2-mutant', 'Var', (31, 41))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('LATS1', 'Gene', '9113', (171, 176))	('FAT1', 'Gene', '2195', (181, 185))	('FAT1', 'Gene', (181, 185))	('sRCC', 'Disease', 'MESH:D002292', (129, 133))
205182	31959902	To analyse the functional role of hippo core genes mutations, we used JHRCC12, a NF2-mutant sRCC cell line, as a model.	('mutations', 'Var', (51, 60))	('sRCC', 'Disease', (92, 96))	('core', 'cellular_component', 'GO:0019013', ('40', '44'))	('JHRCC12', 'CellLine', 'CVCL:Z029', (70, 77))	('hippo core genes', 'Gene', (34, 50))	('sRCC', 'Disease', 'MESH:D002292', (92, 96))
205183	31959902	As YAP1 expression has been shown to strongly induce expression of mesenchymal genes such as SLUG (SNAI2), we then investigated the effect of NF2 reconstitution and YAP1 knockdown on SLUG expression; as expected, we found decrease of SLUG which was more profound with YAP1 knockdown than with NF2 reconstitution (Fig.	('decrease', 'NegReg', (222, 230))	('SNAI2', 'Gene', (99, 104))	('YAP1', 'Gene', (3, 7))	('SNAI2', 'Gene', '6591', (99, 104))	('SLUG', 'Gene', '6591', (234, 238))	('YAP1', 'Gene', (268, 272))	('SLUG', 'Gene', (234, 238))	('knockdown', 'Var', (273, 282))	('SLUG', 'Gene', '6591', (183, 187))	('SLUG', 'Gene', (183, 187))	('SLUG', 'Gene', '6591', (93, 97))	('expression', 'MPA', (53, 63))	('SLUG', 'Gene', (93, 97))
205185	31959902	YAP1 knockdown in JHRCC12 cells suppressed cell proliferation, invasion, and tumour growth and induced change in their morphology (Fig.	('tumour growth', 'Disease', 'MESH:D006130', (77, 90))	('YAP1', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('cell proliferation', 'biological_process', 'GO:0008283', ('43', '61'))	('tumour growth', 'Disease', (77, 90))	('change', 'Reg', (103, 109))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('invasion', 'CPA', (63, 71))	('JHRCC12', 'CellLine', 'CVCL:Z029', (18, 25))	('morphology', 'CPA', (119, 129))	('cell proliferation', 'CPA', (43, 61))	('suppressed', 'NegReg', (32, 42))
205188	31959902	Our study highlights for the first time an association between alterations of the Hippo pathway, a key regulator of organ growth, and sarcomatoid dedifferentiation in ccRCC.	('sarcomatoid dedifferentiation', 'Disease', 'MESH:D002292', (134, 163))	('dedifferentiation', 'biological_process', 'GO:0043696', ('146', '163'))	('alterations', 'Var', (63, 74))	('organ growth', 'biological_process', 'GO:0035265', ('116', '128'))	('ccRCC', 'Phenotype', 'HP:0006770', (167, 172))	('ccRCC', 'Disease', (167, 172))	('Hippo pathway', 'Pathway', (82, 95))	('ccRCC', 'Disease', 'MESH:D002292', (167, 172))	('sarcomatoid dedifferentiation', 'Disease', (134, 163))
205189	31959902	Mutations of NF2, FAT1 and LATS2 were the most frequent Hippo pathway alterations.	('FAT1', 'Gene', (18, 22))	('Hippo pathway', 'Pathway', (56, 69))	('alterations', 'Reg', (70, 81))	('Mutations', 'Var', (0, 9))	('LATS2', 'Gene', (27, 32))	('LATS2', 'Gene', '26524', (27, 32))	('NF2', 'Gene', (13, 16))	('FAT1', 'Gene', '2195', (18, 22))
205190	31959902	Most notably, sRCCs exhibited more frequent mutations in Hippo genes than non-sRCC controls.	('Hippo genes', 'Gene', (57, 68))	('sRCC', 'Disease', 'MESH:D002292', (14, 18))	('sRCC', 'Disease', (78, 82))	('mutations', 'Var', (44, 53))	('sRCC', 'Disease', (14, 18))	('sRCC', 'Disease', 'MESH:D002292', (78, 82))
205191	31959902	We showed that downstream effectors of the Hippo pathway were upregulated in patients with alteration in Hippo pathway genes.	('Hippo pathway genes', 'Gene', (105, 124))	('alteration', 'Var', (91, 101))	('Hippo pathway', 'Pathway', (43, 56))	('upregulated', 'PosReg', (62, 73))	('patients', 'Species', '9606', (77, 85))
205192	31959902	Finally, mechanistic studies in vitro and in vivo demonstrated that YAP1 inhibition or NF2 reconstitution impaired tumour growth and proliferation.	('inhibition', 'Var', (73, 83))	('impaired tumour', 'Disease', (106, 121))	('tumour growth', 'Disease', 'MESH:D006130', (115, 128))	('NF2', 'Gene', (87, 90))	('impaired tumour', 'Disease', 'MESH:D008113', (106, 121))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('reconstitution', 'Var', (91, 105))	('tumour growth', 'Disease', (115, 128))	('YAP1', 'Gene', (68, 72))
205193	31959902	Thus, Hippo pathway mutations appear as one of the most frequent potential oncogenic mechanisms in sRCC.	('sRCC', 'Disease', 'MESH:D002292', (99, 103))	('Hippo', 'Gene', (6, 11))	('mutations', 'Var', (20, 29))	('sRCC', 'Disease', (99, 103))
205194	31959902	The finding of one tumour with deleterious NF2 mutation in its sarcomatoid component only, suggest that Hippo pathway mutations might be late events in ccRCCs with sarcomatoid dedifferentiation.	('tumour', 'Disease', 'MESH:D009369', (19, 25))	('ccRCC', 'Disease', 'MESH:D002292', (152, 157))	('Hippo pathway', 'Gene', (104, 117))	('sarcomatoid component', 'Disease', (63, 84))	('mutation', 'Var', (47, 55))	('tumour', 'Disease', (19, 25))	('mutations', 'Var', (118, 127))	('sarcomatoid dedifferentiation', 'Disease', 'MESH:D002292', (164, 193))	('sarcomatoid component', 'Disease', 'MESH:D002292', (63, 84))	('sarcomatoid dedifferentiation', 'Disease', (164, 193))	('ccRCC', 'Phenotype', 'HP:0006770', (152, 157))	('ccRCC', 'Disease', (152, 157))	('NF2', 'Gene', (43, 46))	('dedifferentiation', 'biological_process', 'GO:0043696', ('176', '193'))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
205195	31959902	The prevalence of Hippo pathway gene alterations in this study is supported by previous observations from Bi et al.	('Hippo pathway gene', 'Gene', (18, 36))	('Bi', 'Chemical', 'MESH:D001729', (106, 108))	('alterations', 'Var', (37, 48))
205196	31959902	of increased FAT family member mutations in the sarcomatoid component of kidney tumours.	('mutations', 'Var', (31, 40))	('sarcomatoid component of kidney tumours', 'Disease', 'MESH:D007680', (48, 87))	('sarcomatoid component of kidney tumours', 'Disease', (48, 87))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))
205197	31959902	Notably, the role of tumour suppressor TP53 in sRCCs is still unclear, as we found a lower frequency of TP53 alterations than expected, reported in 19% of sRCCs.	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('sRCC', 'Disease', (47, 51))	('sRCC', 'Disease', 'MESH:D002292', (155, 159))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('alterations', 'Var', (109, 120))	('TP53', 'Gene', '7157', (39, 43))	('tumour', 'Disease', (21, 27))	('sRCC', 'Disease', 'MESH:D002292', (47, 51))	('sRCC', 'Disease', (155, 159))	('TP53', 'Gene', (39, 43))
205198	31959902	Conversely, TP53 mutations were found in 31% and 42%, respectively, of sarcomatoid kidney tumours with mixed histology in the studies by Bi et al.	('sarcomatoid kidney tumours', 'Disease', (71, 97))	('sarcomatoid kidney tumours', 'Disease', 'MESH:D007680', (71, 97))	('found', 'Reg', (32, 37))	('sarcomatoid kidney', 'Phenotype', 'HP:0008663', (71, 89))	('Bi', 'Chemical', 'MESH:D001729', (137, 139))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('TP53', 'Gene', '7157', (12, 16))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('TP53', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
205201	31959902	It is yet unknown whether this high rate of TERT and TP53 alterations is related to subclonal evolution in aggressive and heterogeneous tumors, or could be directly associated with epithelial mesenchymal transition mechanisms.	('tumors', 'Disease', (136, 142))	('TERT', 'Gene', (44, 48))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('TERT', 'Gene', '7015', (44, 48))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('related', 'Reg', (73, 80))	('associated', 'Reg', (165, 175))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('TP53', 'Gene', '7157', (53, 57))	('epithelial mesenchymal transition', 'biological_process', 'GO:0001837', ('181', '214'))	('TP53', 'Gene', (53, 57))	('alterations', 'Var', (58, 69))
205203	31959902	Our study also highlighted recurrent mutations of NF2 in sRCCs, which contrasts with previous reports of NF2 alterations that were specific to sarcomatoid tumours with papillary histology.	('sRCC', 'Disease', (57, 61))	('sarcomatoid tumours', 'Phenotype', 'HP:0100242', (143, 162))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('mutations', 'Var', (37, 46))	('tumours', 'Phenotype', 'HP:0002664', (155, 162))	('sarcomatoid tumours', 'Disease', 'MESH:D002292', (143, 162))	('NF2', 'Gene', (50, 53))	('sRCC', 'Disease', 'MESH:D002292', (57, 61))	('papillary histology', 'Phenotype', 'HP:0007482', (168, 187))	('sarcomatoid tumours', 'Disease', (143, 162))
205206	31959902	These data pinpoint that Hippo alterations might be a marker of tumour aggressiveness regardless of histology.	('alterations', 'Var', (31, 42))	('tumour aggressiveness regardless', 'Disease', (64, 96))	('Hippo', 'Protein', (25, 30))	('aggressiveness', 'Phenotype', 'HP:0000718', (71, 85))	('tumour aggressiveness regardless', 'Disease', 'MESH:D001523', (64, 96))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
205211	31959902	Among the hyper-altered cancer types, mesotheliomas and papillary renal cell carcinomas were the most significant, and this finding was likely related to a high frequency of NF2, LATS2, and SAV1 mutations.	('papillary renal cell carcinomas', 'Disease', (56, 87))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (66, 86))	('hyper-altered cancer', 'Disease', 'MESH:D009369', (10, 30))	('mesotheliomas', 'Disease', 'MESH:D008654', (38, 51))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('mesotheliomas', 'Disease', (38, 51))	('SAV1', 'Gene', (190, 194))	('LATS2', 'Gene', (179, 184))	('LATS2', 'Gene', '26524', (179, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (56, 87))	('hyper-altered cancer', 'Disease', (10, 30))	('papillary renal cell carcinomas', 'Disease', 'MESH:D002292', (56, 87))	('mutations', 'Var', (195, 204))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('NF2', 'Gene', (174, 177))	('SAV1', 'Gene', '60485', (190, 194))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (66, 87))
205240	33142830	Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression Oxygen homeostasis regulation is the most fundamental cellular process for adjusting physiological oxygen variations, and its irregularity leads to various human diseases, including cancer.	('cellular process', 'cellular_component', 'GO:0042995', ('133', '149'))	('Oxygen', 'Chemical', 'MESH:D010100', (79, 85))	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('irregularity', 'Var', (205, 217))	('Oxygen homeostasis', 'biological_process', 'GO:0032364', ('79', '97'))	('Cancer', 'Disease', (60, 66))	('Oxygen', 'Chemical', 'MESH:D010100', (12, 18))	('cancer', 'Disease', (261, 267))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('oxygen', 'Chemical', 'MESH:D010100', (178, 184))	('Hypoxia', 'Disease', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('Cancer', 'Disease', 'MESH:D009369', (60, 66))	('cellular process', 'biological_process', 'GO:0009987', ('133', '149'))	('human diseases', 'Disease', (235, 249))	('human', 'Species', '9606', (235, 240))	('Signaling', 'biological_process', 'GO:0023052', ('27', '36'))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('leads to', 'Reg', (218, 226))	('regulation', 'biological_process', 'GO:0065007', ('98', '108'))
205252	33142830	The interactions of these molecules form a fundamental molecular framework for how variations of oxygen levels can affect transcriptional responses and provides therapeutic targets for multiple diseases, such as anemia, cardiovascular disease, and cancer.	('cancer', 'Disease', (248, 254))	('anemia', 'Phenotype', 'HP:0001903', (212, 218))	('cardiovascular disease', 'Disease', (220, 242))	('interactions', 'Interaction', (4, 16))	('affect', 'Reg', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (220, 242))	('transcriptional responses', 'MPA', (122, 147))	('variations', 'Var', (83, 93))	('anemia', 'Disease', (212, 218))	('cardiovascular disease', 'Disease', 'MESH:D002318', (220, 242))	('anemia', 'Disease', 'MESH:D000740', (212, 218))	('oxygen', 'Chemical', 'MESH:D010100', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (248, 254))
205282	33142830	For example, an antisense HIF transcript might negatively modulate HIF-1alpha expression by destabilizing HIF-1alpha mRNA.	('expression', 'MPA', (78, 88))	('HIF', 'Gene', (106, 109))	('destabilizing', 'NegReg', (92, 105))	('HIF', 'Gene', '405', (106, 109))	('HIF', 'Gene', '405', (26, 29))	('antisense', 'Var', (16, 25))	('HIF', 'Gene', (67, 70))	('negatively', 'NegReg', (47, 57))	('modulate', 'Reg', (58, 66))	('HIF', 'Gene', '405', (67, 70))	('HIF', 'Gene', (26, 29))
205297	33142830	At the organ or organism level, coordinated responses to altered HIF activity include metabolic regulation, erythropoiesis, angiogenesis, tissue remodeling, and wound healing.	('metabolic regulation', 'CPA', (86, 106))	('erythropoiesis', 'biological_process', 'GO:0030218', ('108', '122'))	('wound healing', 'biological_process', 'GO:0042060', ('161', '174'))	('tissue remodeling', 'biological_process', 'GO:0048771', ('138', '155'))	('wound healing', 'CPA', (161, 174))	('tissue remodeling', 'CPA', (138, 155))	('HIF', 'Gene', (65, 68))	('HIF', 'Gene', '405', (65, 68))	('regulation', 'biological_process', 'GO:0065007', ('96', '106'))	('angiogenesis', 'biological_process', 'GO:0001525', ('124', '136'))	('angiogenesis', 'CPA', (124, 136))	('altered', 'Var', (57, 64))	('erythropoiesis', 'CPA', (108, 122))
205308	33142830	In the presence of oxygen, HIF-alpha is trans-4-hydroxylated at prolyl residues (Pro402 and Pro564 in HIF-1alpha; Pro405 and Pro531 in HIF-2alpha; Pro492 in HIF-3alpha), resulting in a >1000-fold increase in affinity for pVHL.	('Pro531', 'Var', (125, 131))	('Pro564', 'Var', (92, 98))	('Pro405', 'Chemical', '-', (114, 120))	('affinity', 'MPA', (208, 216))	('pVHL', 'Protein', (221, 225))	('Pro564', 'Chemical', '-', (92, 98))	('HIF-alpha', 'Chemical', '-', (27, 36))	('Pro531', 'Chemical', '-', (125, 131))	('HIF-3alpha', 'Gene', (157, 167))	('oxygen', 'Chemical', 'MESH:D010100', (19, 25))	('Pro492', 'Chemical', '-', (147, 153))	('HIF-3alpha', 'Gene', '64344', (157, 167))	('prolyl', 'Chemical', '-', (64, 70))	('Pro492', 'Var', (147, 153))	('increase', 'PosReg', (196, 204))	('Pro402', 'Var', (81, 87))	('Pro402', 'Chemical', '-', (81, 87))	('Pro405', 'Var', (114, 120))
205317	33142830	The disease is caused by germline mutations in VHL, a tumor-suppressor gene located on chromosome 3p25.1.	('chromosome', 'cellular_component', 'GO:0005694', ('87', '97'))	('caused by', 'Reg', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('54', '70'))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('VHL', 'Gene', (47, 50))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('54', '70'))	('germline mutations', 'Var', (25, 43))	('VHL', 'Gene', '7428', (47, 50))	('tumor', 'Disease', (54, 59))
205318	33142830	Patients who inherit a single faulty copy of VHL develop the disease only after spontaneous inactivation or loss of the second, wild-type VHL allele.	('VHL', 'Gene', '7428', (45, 48))	('VHL', 'Gene', '7428', (138, 141))	('develop', 'Reg', (49, 56))	('Patients', 'Species', '9606', (0, 8))	('VHL', 'Gene', (45, 48))	('faulty copy', 'Var', (30, 41))	('VHL', 'Gene', (138, 141))
205327	33142830	Through genetic ablation, pharmacologic inhibition, or new carbon-based proteolysis targeting chimera specifically, TBK1 was depleted/inhibited in vitro, suppressing VHL-deficient kidney cancer cell proliferation while having no effect on VHL wild-type cells.	('depleted/inhibited', 'NegReg', (125, 143))	('VHL', 'Gene', (166, 169))	('TBK1', 'Gene', (116, 120))	('suppressing', 'NegReg', (154, 165))	('proteolysis', 'biological_process', 'GO:0006508', ('72', '83'))	('VHL', 'Gene', '7428', (166, 169))	('VHL-deficient kidney cancer', 'Disease', 'MESH:D007680', (166, 193))	('VHL', 'Gene', (239, 242))	('cell proliferation', 'biological_process', 'GO:0008283', ('194', '212'))	('kidney cancer', 'Phenotype', 'HP:0009726', (180, 193))	('ablation', 'Var', (16, 24))	('VHL-deficient kidney cancer', 'Disease', (166, 193))	('VHL', 'Gene', '7428', (239, 242))	('carbon', 'Chemical', 'MESH:D002244', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('TBK1', 'Gene', '29110', (116, 120))	('deficient kidney', 'Phenotype', 'HP:0000089', (170, 186))	('TBK1', 'molecular_function', 'GO:0008384', ('116', '120'))
205328	33142830	Similarly, TBK1 depletion abrogates kidney tumorigenesis in an orthotopic xenograft tumor model.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('TBK1', 'Gene', '29110', (11, 15))	('depletion', 'Var', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('abrogates', 'NegReg', (26, 35))	('TBK1', 'Gene', (11, 15))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('TBK1', 'molecular_function', 'GO:0008384', ('11', '15'))	('tumor', 'Disease', (43, 48))
205329	33142830	Mechanistically, hydroxylation on Pro48 of TBK1 triggers both pVHL and phosphatase PPM1B binding, leading to TBK1 de-phosphorylation.	('binding', 'Interaction', (89, 96))	('TBK1', 'Gene', (43, 47))	('binding', 'molecular_function', 'GO:0005488', ('89', '96'))	('pVHL', 'Protein', (62, 66))	('hydroxylation', 'Var', (17, 30))	('TBK1', 'Gene', (109, 113))	('phosphatase', 'molecular_function', 'GO:0016791', ('71', '82'))	('de-phosphorylation', 'MPA', (114, 132))	('TBK1', 'Gene', '29110', (109, 113))	('TBK1', 'molecular_function', 'GO:0008384', ('109', '113'))	('TBK1', 'molecular_function', 'GO:0008384', ('43', '47'))	('PPM1B', 'Gene', '5495', (83, 88))	('phosphorylation', 'biological_process', 'GO:0016310', ('117', '132'))	('TBK1', 'Gene', '29110', (43, 47))	('triggers', 'Reg', (48, 56))	('PPM1B', 'Gene', (83, 88))
205349	33142830	Specific naturally occurring mutations within this region of human PHD2 have marked effects on selectivity for the prolyl hydroxylation at the NODD or CODD.	('PHD2', 'Gene', '54583', (67, 71))	('PHD2', 'Gene', (67, 71))	('mutations', 'Var', (29, 38))	('prolyl', 'Chemical', '-', (115, 121))	('PHD', 'molecular_function', 'GO:0050175', ('67', '70'))	('NODD', 'MPA', (143, 147))	('effects', 'Reg', (84, 91))	('selectivity', 'MPA', (95, 106))	('human', 'Species', '9606', (61, 66))	('prolyl hydroxylation', 'MPA', (115, 135))
205354	33142830	Another hydroxylase, FIH, modulates HIF-alpha by catalyzing the C-3 hydroxylation of an asparagine residue in the C-terminal transactivation domain (Asn803 in HIF-1alpha and Asn851 in HIF-2alpha).	('modulates', 'Reg', (26, 35))	('FIH', 'Gene', (21, 24))	('Asn803', 'Chemical', '-', (149, 155))	('asparagine', 'Chemical', 'MESH:D001216', (88, 98))	('transactivation', 'biological_process', 'GO:2000144', ('125', '140'))	('C-3 hydroxylation', 'MPA', (64, 81))	('Asn851', 'Chemical', '-', (174, 180))	('FIH', 'Gene', '319594', (21, 24))	('Asn803', 'Var', (149, 155))	('Asn851', 'Var', (174, 180))	('HIF-alpha', 'Chemical', '-', (36, 45))
205355	33142830	This modification substantially reduces the otherwise tight binding of HIF-alpha to the p300-CREB-binding protein transcriptional co-activators.	('modification', 'Var', (5, 17))	('HIF-alpha', 'Protein', (71, 80))	('binding', 'molecular_function', 'GO:0005488', ('60', '67'))	('p300', 'Gene', '2033', (88, 92))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('CREB-binding protein', 'Gene', (93, 113))	('CREB-binding protein', 'Gene', '1387', (93, 113))	('reduces', 'NegReg', (32, 39))	('p300', 'Gene', (88, 92))	('HIF-alpha', 'Chemical', '-', (71, 80))	('binding', 'Interaction', (60, 67))	('CREB-binding', 'molecular_function', 'GO:0008140', ('93', '105'))
205367	33142830	The most common epigenetic modification in DNA of mammals is the methylation of cytosine to 5-methylcytosine (5mC), and for a while, it was assumed that methylation, which was associated with gene repression, was an irreversible process.	('epigenetic modification', 'Var', (16, 39))	('cytosine', 'Chemical', 'MESH:D003596', (80, 88))	('5mC', 'Chemical', 'MESH:D044503', (110, 113))	('methylation', 'MPA', (65, 76))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (92, 108))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('cytosine', 'Chemical', 'MESH:D003596', (100, 108))	('methylation', 'biological_process', 'GO:0032259', ('65', '76'))	('methylation', 'biological_process', 'GO:0032259', ('153', '164'))
205377	33142830	In diseases, TET proteins have received the greatest research attention in the context of hematological malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome, along with metabolic and epigenetic dysregulation that is a hallmark of cancer.	('AML', 'Disease', (149, 152))	('myelodysplastic syndrome', 'Disease', (158, 182))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (158, 182))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (125, 147))	('TET', 'Chemical', '-', (13, 16))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('hematological malignancies', 'Phenotype', 'HP:0004377', (90, 116))	('AML', 'Disease', 'MESH:D015470', (149, 152))	('cancer', 'Disease', (256, 262))	('epigenetic dysregulation', 'Var', (209, 233))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (125, 147))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (158, 182))	('hematological malignancies', 'Disease', (90, 116))	('hematological malignancies', 'Disease', 'MESH:D019337', (90, 116))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('leukemia', 'Phenotype', 'HP:0001909', (139, 147))	('acute myeloid leukemia', 'Disease', (125, 147))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (131, 147))
205379	33142830	Mutations in all three TET proteins have been identified in colorectal cancer, and TET2 mutations and/or deletions are a characteristic of 16% of ccRCCs.	('TET', 'Chemical', '-', (23, 26))	('TET2', 'Gene', (83, 87))	('deletions', 'Var', (105, 114))	('colorectal cancer', 'Disease', 'MESH:D015179', (60, 77))	('mutations', 'Var', (88, 97))	('ccRCCs', 'Disease', (146, 152))	('Mutations', 'Var', (0, 9))	('TET', 'Chemical', '-', (83, 86))	('colorectal cancer', 'Phenotype', 'HP:0003003', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('identified', 'Reg', (46, 56))	('TET2', 'Gene', '54790', (83, 87))	('colorectal cancer', 'Disease', (60, 77))
205396	33142830	It is notable that the KDMs can act on trimethylated nitrogen sites and that N-methylation and demethylation can be either transcriptionally activating or repressive depending on the context.	('nitrogen', 'Chemical', 'MESH:D009584', (53, 61))	('trimethylated nitrogen sites', 'MPA', (39, 67))	('demethylation', 'Var', (95, 108))	('N-methylation', 'Var', (77, 90))	('act', 'Reg', (32, 35))	('methylation', 'biological_process', 'GO:0032259', ('79', '90'))	('KDMs', 'Chemical', '-', (23, 27))	('demethylation', 'biological_process', 'GO:0070988', ('95', '108'))	('KDMs', 'Var', (23, 27))
205401	33142830	Mechanistically, under normoxic conditions, KDM3A binds to and demethylates proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1alpha ) at lysine 224, increasing PGC-1alpha activity, an essential process for NRF1/NRF2-mediated mitochondrial biogenesis.	('PGC-1alpha', 'Gene', '10891', (135, 145))	('activity', 'MPA', (185, 193))	('NRF1', 'Gene', '4899', (220, 224))	('NRF2', 'Gene', '4780', (225, 229))	('PGC-1alpha', 'Gene', (174, 184))	('lysine', 'Chemical', 'MESH:D008239', (151, 157))	('KDM3A', 'Gene', '55818', (44, 49))	('PGC-1alpha', 'Gene', '10891', (174, 184))	('NRF2', 'Gene', (225, 229))	('NRF1', 'Gene', (220, 224))	('PGC-1alpha', 'Gene', (135, 145))	('lysine 224', 'Var', (151, 161))	('binds', 'Interaction', (50, 55))	('increasing', 'PosReg', (163, 173))	('KDM3A', 'Gene', (44, 49))
205407	33142830	Pharmacological modulation of HIF signaling and activity represents a promising therapeutic approach for numerous diseases.	('HIF', 'Gene', (30, 33))	('HIF', 'Gene', '405', (30, 33))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('activity', 'MPA', (48, 56))	('numerous diseases', 'Disease', (105, 122))	('modulation', 'Var', (16, 26))	('numerous diseases', 'Disease', 'MESH:D003141', (105, 122))
205417	33142830	SU5416, as a tyrosine kinase inhibitor targeting the VEGF receptor, blocks the expression of VEGF and HIF-1alpha.	('SU5416', 'Var', (0, 6))	('VEGF', 'Gene', (93, 97))	('expression', 'MPA', (79, 89))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('22', '38'))	('blocks', 'NegReg', (68, 74))	('VEGF', 'Gene', (53, 57))	('VEGF', 'Gene', '7422', (93, 97))	('SU5416', 'Chemical', 'MESH:C116890', (0, 6))	('HIF-1alpha', 'Protein', (102, 112))	('VEGF', 'Gene', '7422', (53, 57))
205418	33142830	SU5416 transcriptionally diminishes VEGF expression by inhibiting HIF-1 DNA binding activity through the decrease of p70S6K1 phosphorylation, AKT phosphorylation, and PI3K activity.	('HIF-1', 'Gene', (66, 71))	('VEGF', 'Gene', (36, 40))	('AKT', 'Gene', (142, 145))	('phosphorylation', 'biological_process', 'GO:0016310', ('146', '161'))	('SU5416', 'Var', (0, 6))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('p70S6K', 'Gene', (117, 123))	('AKT', 'Gene', '207', (142, 145))	('decrease', 'NegReg', (105, 113))	('DNA binding', 'Interaction', (72, 83))	('activity', 'MPA', (84, 92))	('phosphorylation', 'biological_process', 'GO:0016310', ('125', '140'))	('PI3K', 'molecular_function', 'GO:0016303', ('167', '171'))	('DNA binding', 'molecular_function', 'GO:0003677', ('72', '83'))	('diminishes', 'NegReg', (25, 35))	('PI3K activity', 'CPA', (167, 180))	('SU5416', 'Chemical', 'MESH:C116890', (0, 6))	('inhibiting', 'NegReg', (55, 65))	('p70S6K', 'Gene', '6198', (117, 123))	('VEGF', 'Gene', '7422', (36, 40))	('HIF-1', 'Gene', '3091', (66, 71))
205419	33142830	In addition, PX-478 down-regulates HIF-1 expression at multiple levels, including modulating HIF-1alpha deubiquitylation, inhibiting HIF-1alpha transcription and translation, and decreasing HIF- 1alpha mRNA.	('HIF-1', 'Gene', '3091', (35, 40))	('transcription', 'MPA', (144, 157))	('deubiquitylation', 'MPA', (104, 120))	('HIF-1', 'Gene', (35, 40))	('translation', 'biological_process', 'GO:0006412', ('162', '173'))	('decreasing', 'NegReg', (179, 189))	('translation', 'MPA', (162, 173))	('HIF- 1alpha', 'Gene', (190, 201))	('modulating', 'Reg', (82, 92))	('inhibiting', 'NegReg', (122, 132))	('transcription', 'biological_process', 'GO:0006351', ('144', '157'))	('expression', 'MPA', (41, 51))	('HIF-1', 'Gene', '3091', (133, 138))	('HIF- 1alpha', 'Gene', '3091', (190, 201))	('down-regulates', 'NegReg', (20, 34))	('HIF-1', 'Gene', (133, 138))	('HIF-1', 'Gene', '3091', (93, 98))	('PX-478', 'Var', (13, 19))	('HIF-1', 'Gene', (93, 98))
205426	33142830	PT-2399, a 2,3-dihydro-1H-inden-4-yl-oxy derivative (Peloton Therapeutics, Inc., now Merck, Kenilworth, NJ, USA), and PT-2385 specifically inhibit HIF-2alpha-ARNT dimerization, leading to anti-angiogenic influences in human primary and metastatic VHL-defective ccRCC cell xenografted mouse models.	('PT', 'Chemical', 'MESH:D010984', (118, 120))	('dimerization', 'MPA', (163, 175))	('PT', 'Chemical', 'MESH:D010984', (0, 2))	('ARNT', 'Gene', (158, 162))	('anti-angiogenic influences', 'CPA', (188, 214))	('inhibit', 'NegReg', (139, 146))	('PT-2399', 'Gene', (0, 7))	('VHL', 'Gene', (247, 250))	('human', 'Species', '9606', (218, 223))	('PT-2385', 'Chemical', 'MESH:C000614279', (118, 125))	('VHL', 'Gene', '7428', (247, 250))	('PT-2385', 'Var', (118, 125))	('ARNT', 'Gene', '405', (158, 162))	('2,3-dihydro-1H-inden-4-yl-oxy', 'Chemical', '-', (11, 40))	('mouse', 'Species', '10090', (284, 289))
205427	33142830	PT-2385 reduces the levels of human tumor-induced circulating VEGFA in the human lung cancer cell xenografted mouse model.	('human', 'Species', '9606', (30, 35))	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('VEGFA', 'Gene', (62, 67))	('PT-2385', 'Chemical', 'MESH:C000614279', (0, 7))	('PT-2385', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mouse', 'Species', '10090', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('reduces', 'NegReg', (8, 15))	('VEGFA', 'Gene', '7422', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('human', 'Species', '9606', (75, 80))	('tumor', 'Disease', (36, 41))
205429	33142830	PT-2385 treatment also enhances the anti-metastatic activity of sorafenib by repressing HIF-2alpha-related Stat-3/Akt/Erk signaling in human hepatocellular carcinoma cells.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (141, 165))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('Erk', 'Gene', '2048', (118, 121))	('hepatocellular carcinoma', 'Disease', (141, 165))	('PT-2385', 'Chemical', 'MESH:C000614279', (0, 7))	('anti-metastatic activity', 'CPA', (36, 60))	('Stat-3', 'Gene', (107, 113))	('Erk', 'molecular_function', 'GO:0004707', ('118', '121'))	('human', 'Species', '9606', (135, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('Akt', 'Gene', (114, 117))	('enhances', 'PosReg', (23, 31))	('Erk', 'Gene', (118, 121))	('Akt', 'Gene', '207', (114, 117))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (141, 165))	('PT-2385', 'Var', (0, 7))	('repressing', 'NegReg', (77, 87))	('sorafenib', 'Chemical', 'MESH:D000077157', (64, 73))	('Stat-3', 'Gene', '6774', (107, 113))
205431	33142830	Furthermore, TC-S 7009 specifically represses HIF-2alpha-induced EPO, but not HIF-1alpha-induced PGK1 in hypoxic hepatoma cells.	('EPO', 'Gene', (65, 68))	('PGK1', 'Gene', (97, 101))	('hypoxic hepatoma', 'Disease', (105, 121))	('PGK1', 'Gene', '5230', (97, 101))	('EPO', 'Gene', '2056', (65, 68))	('TC-S 7009', 'Chemical', '-', (13, 22))	('PGK', 'molecular_function', 'GO:0004618', ('97', '100'))	('represses', 'NegReg', (36, 45))	('hypoxic hepatoma', 'Disease', 'MESH:D006528', (105, 121))	('TC-S', 'Var', (13, 17))
205433	33142830	In addition, Compound-76 is able to repress chemo-resistance and stemness by inhibiting HIF-2alpha-EFEMP1 hypoxic signaling in a human breast cancer stem cell xenografted mouse model.	('Compound-76', 'Var', (13, 24))	('inhibiting', 'NegReg', (77, 87))	('signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('EFEMP1', 'Gene', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('chemo-resistance', 'CPA', (44, 60))	('stemness', 'CPA', (65, 73))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('human', 'Species', '9606', (129, 134))	('mouse', 'Species', '10090', (171, 176))	('repress', 'NegReg', (36, 43))	('EFEMP1', 'Gene', '2202', (99, 105))	('breast cancer', 'Disease', (135, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
205481	33578778	Thus, imbalances in components of the intrarenal RAS, such as the up-regulation of AT1Rs in RCC cells and ACE in tumour vessels, have been associated with renal cancer development and progression.	('renal cancer', 'Disease', (155, 167))	('up-regulation', 'PosReg', (66, 79))	('renal cancer', 'Phenotype', 'HP:0009726', (155, 167))	('AT1R', 'Gene', '185', (83, 87))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('imbalances', 'Var', (6, 16))	('associated with', 'Reg', (139, 154))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('AT1R', 'Gene', (83, 87))	('regulation', 'biological_process', 'GO:0065007', ('69', '79'))	('imbalances', 'Phenotype', 'HP:0002172', (6, 16))	('renal cancer', 'Disease', 'MESH:D007680', (155, 167))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('tumour', 'Disease', (113, 119))	('ACE', 'Gene', '1636', (106, 109))	('ACE', 'Gene', (106, 109))
205530	33578778	PRR expression at the centre and at the infiltration front of pT2 tumours was significantly higher than in pT1 ones.	('higher', 'PosReg', (92, 98))	('PRR', 'molecular_function', 'GO:0038187', ('0', '3'))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('expression', 'MPA', (4, 14))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('pT2', 'Var', (62, 65))	('pT1', 'Gene', (107, 110))	('PRR', 'Gene', '10159', (0, 3))	('tumours', 'Disease', 'MESH:D009369', (66, 73))	('PRR', 'Gene', (0, 3))	('tumours', 'Disease', (66, 73))	('pT1', 'Gene', '58492', (107, 110))
205658	28507622	Surgical removal of CCRCC with high VEGF-A expression in the lower stages, without metastasis, is associated with increased cancer-free survival.	('cancer', 'Disease', (124, 130))	('CCRCC', 'Phenotype', 'HP:0006770', (20, 25))	('RCC', 'Disease', (22, 25))	('increased', 'PosReg', (114, 123))	('RCC', 'Disease', 'MESH:C538614', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('VEGF-A', 'Gene', '7422', (36, 42))	('high', 'Var', (31, 35))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('VEGF-A', 'Gene', (36, 42))
205665	28507622	High VEGF-A expression patients will benefit from anti-angiogenic treatment with VEGF blockers or VEGF receptor blockers.	('VEGF', 'Gene', '7422', (81, 85))	('VEGF', 'Gene', '7422', (98, 102))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (23, 31))	('VEGF', 'Gene', (5, 9))	('men', 'Species', '9606', (71, 74))	('VEGF', 'Gene', (81, 85))	('VEGF', 'Gene', (98, 102))	('VEGF', 'Gene', '7422', (5, 9))	('VEGF-A', 'Gene', '7422', (5, 11))	('VEGF-A', 'Gene', (5, 11))
205666	28507622	On the other hand, low VEGF-A expression patients will not benefit from this therapy, and they should be treated with alternative medications.	('VEGF-A', 'Gene', '7422', (23, 29))	('patients', 'Species', '9606', (41, 49))	('low', 'Var', (19, 22))	('VEGF-A', 'Gene', (23, 29))
205746	33151035	In specific tumors, antiangiogenics produced increased invasiveness and metastatic dissemination, while in others aggressiveness remained unchanged.	('invasiveness', 'CPA', (55, 67))	('aggressiveness', 'Phenotype', 'HP:0000718', (114, 128))	('antiangiogenics', 'Var', (20, 35))	('increased', 'PosReg', (45, 54))	('metastatic dissemination', 'CPA', (72, 96))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('aggressiveness', 'Disease', 'MESH:D001523', (114, 128))	('tumors', 'Disease', (12, 18))	('aggressiveness', 'Disease', (114, 128))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
205756	33151035	These unique models revealed the patient-specific pro-malignant effects of antiangiogenics: antiangiogenic therapies resulted in increased invasiveness and metastatic dissemination in a subset of tumors, while in others, aggressiveness remained unchanged.	('patient', 'Species', '9606', (33, 40))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('aggressiveness', 'Phenotype', 'HP:0000718', (221, 235))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('invasiveness', 'CPA', (139, 151))	('increased', 'PosReg', (129, 138))	('metastatic dissemination', 'CPA', (156, 180))	('aggressiveness', 'Disease', 'MESH:D001523', (221, 235))	('antiangiogenic', 'Var', (92, 106))	('aggressiveness', 'Disease', (221, 235))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
205768	33151035	Indeed, anti-VEGF therapy produces ECM remodeling and pro-aggressive tumor behavior in other tumor types (Aguilera et al, 2014; Rahbari et al, 2016).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', (93, 98))	('aggressive tumor behavior', 'Disease', 'MESH:D001523', (58, 83))	('aggressive tumor behavior', 'Disease', (58, 83))	('anti-VEGF', 'Var', (8, 17))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
205773	33151035	Can they also be a proper tool to investigate whether inhibition of VEGF pathway could promote RCC progression?	('inhibition', 'Var', (54, 64))	('VEGF pathway', 'Pathway', (68, 80))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('RCC', 'Disease', (95, 98))	('promote', 'PosReg', (87, 94))
205784	33151035	In order to study the consequences of VEGF blockade on 786-O orthoxenograft tumors, we administered tumor-bearing mice with anti-VEGFR2 DC101 (DC) or anti-human VEGF bevacizumab (Beva) (Fig 1A).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('anti-VEGFR2 DC101', 'Var', (124, 141))	('DC', 'Chemical', 'MESH:C511761', (136, 138))	('Beva', 'Chemical', 'MESH:D000068258', (179, 183))	('DC', 'Chemical', 'MESH:C511761', (143, 145))	('tumor', 'Disease', (100, 105))	('bevacizumab', 'Chemical', 'MESH:D000068258', (166, 177))	('human', 'Species', '9606', (155, 160))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('DC101', 'Var', (136, 141))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('mice', 'Species', '10090', (114, 118))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
205806	33151035	Studies from genomic consortiums such as TCGA have demonstrated that ccRCC tumors are characterized by prototypical mutations in some common genes such as VHL, PBRM1, BAP1, SETD2, and TSC1 among others (Atlas, 2013).	('PBRM1', 'Gene', (160, 165))	('TSC1', 'Gene', (184, 188))	('VHL', 'Gene', '7428', (155, 158))	('SETD2', 'Gene', (173, 178))	('ccRCC tumors', 'Disease', 'MESH:D009369', (69, 81))	('PBRM1', 'Gene', '55193', (160, 165))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('mutations', 'Var', (116, 125))	('BAP1', 'Gene', '8314', (167, 171))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('ccRCC tumors', 'Disease', (69, 81))	('TSC1', 'Gene', '7248', (184, 188))	('VHL', 'Gene', (155, 158))	('BAP1', 'Gene', (167, 171))	('SETD2', 'Gene', '29072', (173, 178))
205810	33151035	We found potentially pathogenic truncating or frameshift mutation in VHL and PBRM1 genes that control processes frequently altered in ccRCC (Atlas, 2013).	('truncating', 'Var', (32, 42))	('PBRM1', 'Gene', (77, 82))	('frameshift mutation', 'Var', (46, 65))	('PBRM1', 'Gene', '55193', (77, 82))	('VHL', 'Gene', '7428', (69, 72))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('VHL', 'Gene', (69, 72))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))	('pathogenic', 'Reg', (21, 31))
205812	33151035	Other potentially pathogenic mutations were found in ATM, BAP1, MLL3, mTOR, SETD2, and TSC1 genes (Fig 2D and Appendix Table S4), fully concordant with previously published TCGA mutation profile for clear cell kidney cancer (Atlas, 2013).	('SETD2', 'Gene', (76, 81))	('MLL3', 'Gene', (64, 68))	('mTOR', 'Gene', '2475', (70, 74))	('BAP1', 'Gene', (58, 62))	('clear cell kidney cancer', 'Disease', 'MESH:D007680', (199, 223))	('SETD2', 'Gene', '29072', (76, 81))	('clear cell kidney cancer', 'Disease', (199, 223))	('kidney cancer', 'Phenotype', 'HP:0009726', (210, 223))	('clear cell kidney cancer', 'Phenotype', 'HP:0006770', (199, 223))	('ATM', 'Gene', '472', (53, 56))	('mutations', 'Var', (29, 38))	('MLL3', 'Gene', '58508', (64, 68))	('TSC1', 'Gene', (87, 91))	('BAP1', 'Gene', '8314', (58, 62))	('pathogenic', 'Reg', (18, 28))	('mTOR', 'Gene', (70, 74))	('ATM', 'Gene', (53, 56))	('TSC1', 'Gene', '7248', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
205813	33151035	Furthermore, in order to determine whether individual PDOX were reproducing the genomic alterations of their original patient's tumor, we performed a whole-exome sequencing (WES) analysis to compare the genomic profile of Ren50-PDOX and its original human tumor specimen.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Disease', (128, 133))	('human', 'Species', '9606', (250, 255))	('patient', 'Species', '9606', (118, 125))	('Ren50-PDOX', 'Var', (222, 232))	('tumor', 'Disease', (256, 261))
205815	33151035	Only 9/355 variants were exclusive of PDOX tumor, therefore, 97.5% of Ren-PDOX variants were already present in original human tumor (Fig 2E).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('variants', 'Var', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('Ren-PDOX', 'Gene', (70, 78))	('human', 'Species', '9606', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', (43, 48))
205843	33151035	Taken together, our observations suggest that inhibition of VEGF signaling pathway could have different inter-tumor impact therefore resulting in contrasting local and subsequently systemic effects (Fig 5D).	('signaling pathway', 'biological_process', 'GO:0007165', ('65', '82'))	('inhibition', 'Var', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('VEGF signaling pathway', 'Pathway', (60, 82))	('inhibition of VEGF signaling', 'biological_process', 'GO:1900747', ('46', '74'))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
205876	33151035	Interestingly, a representation of Ren-PDOX collection showed potentially pathogenic mutations in most common mutated genes in RCC such as VHL, PBRM1, BAP1, SETD2 (TCGA, 2013; Brugarolas, 2014; Liao et al, 2015).	('VHL', 'Gene', (139, 142))	('BAP1', 'Gene', (151, 155))	('SETD2', 'Gene', '29072', (157, 162))	('PBRM1', 'Gene', (144, 149))	('VHL', 'Gene', '7428', (139, 142))	('SETD2', 'Gene', (157, 162))	('pathogenic', 'Reg', (74, 84))	('mutations', 'Var', (85, 94))	('PBRM1', 'Gene', '55193', (144, 149))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('BAP1', 'Gene', '8314', (151, 155))
205931	33151035	Only non-synonymous/stop gain SNVs and frameshift indel novels or with reported allele frequency <= 1% (MAF <= 0.01) were included in Fig 2D and E and Appendix Table S4.	('frameshift indel novels', 'Var', (39, 62))	('MAF', 'Gene', '4094', (104, 107))	('MAF', 'Gene', (104, 107))	('non-synonymous/stop', 'Var', (5, 24))
205935	33151035	RNA-seq reads were aligned to the human (GRCh38/hg38) and mouse (GRCm38/mm10) reference genomes using STAR (version 2.5.1b) and GSNAP (version 2015-06-23), respectively, with ENCODE parameters for long RNA.	('human', 'Species', '9606', (34, 39))	('mouse', 'Species', '10090', (58, 63))	('hg38', 'Gene', (48, 52))	('hg38', 'Gene', '8549', (48, 52))	('GRCm38/mm10', 'Var', (65, 76))	('RNA', 'cellular_component', 'GO:0005562', ('202', '205'))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))
205969	32423154	RO60 is highly conserved, and its functions include the binding of aberrant or mis-folded non-coding RNAs (ncRNA) such as 5S rRNA or U2 snRNA.	('RO60', 'Gene', '6738', (0, 4))	('RO60', 'Gene', (0, 4))	('binding', 'Interaction', (56, 63))	('binding', 'molecular_function', 'GO:0005488', ('56', '63'))	('aberrant', 'Var', (67, 75))
205972	32423154	RNA-mediated depletion (RNAi) has been successfully used to knock down the intracellular amount of hY1, hY3, and hY4, demonstrating that this treatment on any of those is sufficient to halt or strongly reduce both processes, while the artificial re-expression of any of them in the same cells is sufficient to restore a pre-treatment situation.	('hY4', 'Gene', (113, 116))	('men', 'Species', '9606', (147, 150))	('hY3', 'Gene', (104, 107))	('hY4', 'Gene', '6086', (113, 116))	('intracellular', 'cellular_component', 'GO:0005622', ('75', '88'))	('RNAi', 'biological_process', 'GO:0016246', ('24', '28'))	('knock', 'Var', (60, 65))	('pre', 'molecular_function', 'GO:0003904', ('320', '323'))	('reduce', 'NegReg', (202, 208))	('hY3', 'Gene', '6085', (104, 107))	('hY1', 'Gene', (99, 102))	('hY1', 'Gene', '6084', (99, 102))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('men', 'Species', '9606', (329, 332))	('intracellular', 'MPA', (75, 88))
205973	32423154	Similar results were achieved by Y RNA inactivation mediated by antisense morpholino oligonucleotides (MOs) micro-injected in vertebrate and worm embryos, causing their death.	('death', 'Disease', (169, 174))	('Y RNA', 'MPA', (33, 38))	('causing', 'Reg', (155, 162))	('morpholino oligonucleotides', 'Chemical', 'MESH:D060172', (74, 101))	('antisense', 'Var', (64, 73))	('death', 'Disease', 'MESH:D003643', (169, 174))	('RNA', 'cellular_component', 'GO:0005562', ('35', '38'))
205974	32423154	The role of Y RNA in DNA replication is uncoupled from that of RO60 RNP; immuno-depletion in human cells of either RO60 or SSB is not sufficient to inhibit DNA replication and the same happens in case of mutations deleting either the RO60 or SSB binding site inside Y RNA.	('DNA replication', 'biological_process', 'GO:0006260', ('21', '36'))	('RNA', 'cellular_component', 'GO:0005562', ('14', '17'))	('RO60', 'Gene', (234, 238))	('RO60', 'Gene', (115, 119))	('RO60', 'Gene', '6738', (234, 238))	('SSB', 'Gene', '6741', (242, 245))	('RO60', 'Gene', '6738', (115, 119))	('inhibit', 'NegReg', (148, 155))	('SSB', 'Gene', '6741', (123, 126))	('mutations', 'Var', (204, 213))	('human', 'Species', '9606', (93, 98))	('DNA', 'cellular_component', 'GO:0005574', ('156', '159'))	('RNA', 'cellular_component', 'GO:0005562', ('268', '271'))	('RNP', 'cellular_component', 'GO:1990904', ('68', '71'))	('RO60', 'Gene', (63, 67))	('binding', 'molecular_function', 'GO:0005488', ('246', '253'))	('SSB', 'Gene', (242, 245))	('binding', 'Interaction', (246, 253))	('SSB', 'Gene', (123, 126))	('DNA replication', 'MPA', (156, 171))	('deleting', 'NegReg', (214, 222))	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('RO60', 'Gene', '6738', (63, 67))	('DNA replication', 'biological_process', 'GO:0006260', ('156', '171'))
206009	32423154	The relationships between non-coding RNA, even intended as causal factors, and bladder cancer are complex, and involve, beside Y RNA, long non-coding RNA (lncRNA), circular RNA (circRNA), small interfering RNA (siRNA), Piwi-interacting RNA (piRNA), small nucleolar RNA (snoRNA), etc..	('snoRNA', 'Gene', (270, 276))	('snoRNA', 'cellular_component', 'GO:0005733', ('270', '276'))	('RNA', 'cellular_component', 'GO:0005562', ('37', '40'))	('bladder cancer', 'Disease', 'MESH:D001749', (79, 93))	('bladder cancer', 'Disease', (79, 93))	('RNA', 'cellular_component', 'GO:0005562', ('129', '132'))	('small interfering', 'Var', (188, 205))	('bladder cancer', 'Phenotype', 'HP:0009725', (79, 93))	('RNA', 'cellular_component', 'GO:0005562', ('206', '209'))	('small nucleolar RNA', 'molecular_function', 'GO:0005569', ('249', '268'))	('small nucleolar RNA', 'Gene', '84546', (249, 268))	('Piwi', 'Gene', (219, 223))	('RNA', 'cellular_component', 'GO:0005562', ('150', '153'))	('small nucleolar RNA', 'Gene', (249, 268))	('RNA', 'cellular_component', 'GO:0005562', ('173', '176'))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('RNA', 'cellular_component', 'GO:0005562', ('236', '239'))	('snoRNA', 'Gene', '84546', (270, 276))	('small nucleolar RNA', 'cellular_component', 'GO:0005733', ('249', '268'))	('circular RNA', 'MPA', (164, 176))	('Piwi', 'Gene', '9271', (219, 223))
206039	32423154	Nicolas and coworkers also showed that, in HeLa cells (an immortal cell line derived from cervical cancer cells), there is an enrichment of hY5 fragments upon poly(I:C) treatment.	('poly(I:C)', 'Chemical', 'MESH:D011070', (159, 168))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('hY5', 'Gene', (140, 143))	('men', 'Species', '9606', (148, 151))	('men', 'Species', '9606', (132, 135))	('HeLa', 'CellLine', 'CVCL:0030', (43, 47))	('cancer', 'Disease', (99, 105))	('hY5', 'Gene', '6090', (140, 143))	('poly(I:C) treatment', 'Var', (159, 178))	('men', 'Species', '9606', (174, 177))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
206072	32423154	Moreover, either exosomes or hY4 alone is sufficient to activate cytokine release in monocytes and trigger in these cells the activation of Toll-like receptor 7 (TLR7), a protein that specifically recognizes single stranded RNA and participates in the activation of the innate immunity.	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('TLR7', 'Gene', '51284', (162, 166))	('Toll-like receptor 7', 'Gene', '51284', (140, 160))	('cytokine release', 'MPA', (65, 81))	('activation', 'PosReg', (126, 136))	('hY4', 'Gene', '6086', (29, 32))	('Toll-like receptor 7', 'Gene', (140, 160))	('activate', 'PosReg', (56, 64))	('TLR7', 'Gene', (162, 166))	('innate immunity', 'biological_process', 'GO:0045087', ('270', '285'))	('hY4', 'Gene', (29, 32))	('single stranded', 'Var', (208, 223))	('RNA', 'cellular_component', 'GO:0005562', ('224', '227'))
206085	32423154	Anaplastic large cell lymphoma (ALCL) is a fast-growing non-Hodgkin lymphoma (NHL) and accounts for 10-15% of pediatric and adolescent NHL; ALCL in pediatric patients is almost always ALK-positive and mutant cells show the t(2;5)(p23;q35) translocation, constitutively expressing the NPM-ALK fusion protein.	('LC', 'Phenotype', 'HP:0100526', (141, 143))	('non-Hodgkin lymphoma', 'Disease', (56, 76))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (56, 76))	('mutant', 'Var', (201, 207))	('patients', 'Species', '9606', (158, 166))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (56, 76))	('Anaplastic large cell lymphoma', 'Disease', 'MESH:D017728', (0, 30))	('ALK', 'Gene', '238', (288, 291))	('ALK', 'Gene', (288, 291))	('ALK', 'Gene', '238', (184, 187))	('LC', 'Phenotype', 'HP:0100526', (33, 35))	('Anaplastic large cell lymphoma', 'Disease', (0, 30))	('ALK', 'Gene', (184, 187))	('t(2;5)(p23;q35) translocation', 'Var', (223, 252))	('NPM', 'Gene', '4869', (284, 287))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (60, 76))	('NPM', 'Gene', (284, 287))	('cell lymphoma', 'Phenotype', 'HP:0012191', (17, 30))	('t(2;5)(p23;q35)', 'STRUCTURAL_ABNORMALITY', 'None', (223, 238))	('NHL', 'Phenotype', 'HP:0012539', (135, 138))	('lymphoma', 'Phenotype', 'HP:0002665', (22, 30))	('lymphoma', 'Phenotype', 'HP:0002665', (68, 76))	('NHL', 'Phenotype', 'HP:0012539', (78, 81))	('protein', 'cellular_component', 'GO:0003675', ('299', '306'))
206096	32423154	The same report also shows that RNAi against hY1 is sufficient to reduce the number of S phase WI38 lung fibroblast cells, likely by inhibiting DNA replication.	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))	('hY1', 'Gene', (45, 48))	('inhibiting', 'NegReg', (133, 143))	('S phase WI38 lung fibroblast cells', 'CPA', (87, 121))	('hY1', 'Gene', '6084', (45, 48))	('S phase', 'biological_process', 'GO:0051320', ('87', '94'))	('DNA replication', 'MPA', (144, 159))	('DNA replication', 'biological_process', 'GO:0006260', ('144', '159'))	('reduce', 'NegReg', (66, 72))	('RNAi', 'biological_process', 'GO:0016246', ('32', '36'))	('RNAi', 'Var', (32, 36))
206109	32423154	The presence of the RNY4 gene and RNY4P pseudogene sequences strongly characterizes these EV, accounting for more than 98% of their respective Y RNA.	('RNY4', 'Gene', '6086', (34, 38))	('RNY4', 'Gene', '6086', (20, 24))	('RNA', 'cellular_component', 'GO:0005562', ('145', '148'))	('RNY4', 'Gene', (34, 38))	('RNY4', 'Gene', (20, 24))	('pseudogene sequences', 'Var', (40, 60))
206137	32423154	Over the years, evidence has accumulated of a direct relation between tumorigenesis and alterations of the RO60 function, as well as between tumorigenesis and inflammation (see for example the section above, about blood cancers).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('inflammation', 'Disease', (159, 171))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (70, 75))	('blood cancers', 'Disease', 'MESH:D007022', (214, 227))	('inflammation', 'biological_process', 'GO:0006954', ('159', '171'))	('tumor', 'Disease', (141, 146))	('alterations', 'Var', (88, 99))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('RO60', 'Gene', (107, 111))	('RO60', 'Gene', '6738', (107, 111))	('blood cancers', 'Disease', (214, 227))	('inflammation', 'Disease', 'MESH:D007249', (159, 171))	('blood cancers', 'Phenotype', 'HP:0001909', (214, 227))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('function', 'MPA', (112, 120))
206143	32423154	The work of Liu and collaborators shows that RO60 expression is increased in PDAC tissues compared with normal pancreatic tissues, while the knockdown of RO60 by siRNA significantly decreases cell proliferation and invasion in vitro and inhibits the growth of subcutaneous tumors in vivo.	('knockdown', 'Var', (141, 150))	('decreases', 'NegReg', (182, 191))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (260, 279))	('PDAC', 'Disease', (77, 81))	('RO60', 'Gene', (45, 49))	('RO60', 'Gene', (154, 158))	('RO60', 'Gene', '6738', (154, 158))	('PDAC', 'Phenotype', 'HP:0006725', (77, 81))	('inhibits', 'NegReg', (237, 245))	('tumors', 'Phenotype', 'HP:0002664', (273, 279))	('RO60', 'Gene', '6738', (45, 49))	('cell proliferation', 'biological_process', 'GO:0008283', ('192', '210'))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumors', 'Disease', 'MESH:D009369', (273, 279))	('increased', 'PosReg', (64, 73))	('tumors', 'Disease', (273, 279))	('expression', 'MPA', (50, 60))
206153	32423154	and S.G.; data mining for human cancers, R.V., R.N., L.B., S.Z., A.B.	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Disease', (32, 39))	('L.B.', 'Var', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('human', 'Species', '9606', (26, 31))
206159	29997523	Pooled results showed that high level of HMGA2 was significantly correlated with poor OS (HR = 1.88, 95% confidence interval (CI) = 1.68-2.11, P < 0.001) and poor DFS (HR = 2.49, 95% CI = 1.44-4.28, P = 0.001) in cancer patients.	('poor', 'Disease', (158, 162))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('HMGA2', 'Gene', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('patients', 'Species', '9606', (220, 228))	('HMGA2', 'Gene', '8091', (41, 46))	('cancer', 'Disease', (213, 219))	('high level', 'Var', (27, 37))	('poor OS', 'Disease', (81, 88))
206160	29997523	However, subgroup analyses revealed that the high expressed HMGA2 was associated with poor OS in head and neck cancer, gastric cancer and colorectal cancer, but not esophageal cancer and ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (187, 201))	('esophageal cancer', 'Disease', (165, 182))	('HMGA2', 'Gene', '8091', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('gastric cancer', 'Disease', (119, 133))	('neck', 'cellular_component', 'GO:0044326', ('106', '110'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('ovarian cancer', 'Disease', (187, 201))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('high expressed', 'Var', (45, 59))	('ovarian cancer', 'Phenotype', 'HP:0100615', (187, 201))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('HMGA2', 'Gene', (60, 65))	('head and neck cancer', 'Phenotype', 'HP:0012288', (97, 117))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('esophageal cancer', 'Disease', 'MESH:D004938', (165, 182))	('poor OS', 'Disease', (86, 93))	('colorectal cancer', 'Disease', (138, 155))	('head and neck cancer', 'Disease', 'MESH:D006258', (97, 117))
206195	29997523	Pooled results also demonstrated that high HMGA2 expression was associated with shorter DFS in cancer patients (HR = 2.49, 95% CI = 1.44-4.28) (Figure 3).	('DFS', 'MPA', (88, 91))	('HMGA2', 'Gene', '8091', (43, 48))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('patients', 'Species', '9606', (102, 110))	('cancer', 'Disease', (95, 101))	('high', 'Var', (38, 42))	('HMGA2', 'Gene', (43, 48))	('expression', 'MPA', (49, 59))	('shorter', 'NegReg', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
206199	29997523	Results show that high expression level of HMGA2 was associated with poor OS in gastric cancer (HR = 1.94, 95% CI = 1.42-2.65, P < 0.001), head and neck cancer (HR = 1.77, 95% CI = 1.37-2.29, P < 0.001), colorectal cancer (HR = 2.13, 95% CI = 1.48-3.05, P < 0.001) and other cancers (HR = 2, 95% CI = 1.68-2.40, P < 0.001), but not esophageal cancer (HR = 1.15, 95% CI = 0.55-2.37, P = 0.712) and ovarian cancer (HR = 1.07, 95% CI = 0.55-2.37, P = 0.712).	('gastric cancer', 'Disease', (80, 94))	('HMGA2', 'Gene', '8091', (43, 48))	('poor OS', 'Disease', (69, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (204, 221))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('neck', 'cellular_component', 'GO:0044326', ('148', '152'))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancers', 'Disease', 'MESH:D009369', (275, 282))	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('high expression level', 'Var', (18, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (80, 94))	('head and neck cancer', 'Phenotype', 'HP:0012288', (139, 159))	('ovarian cancer', 'Disease', 'MESH:D010051', (397, 411))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('colorectal cancer', 'Disease', 'MESH:D015179', (204, 221))	('HMGA2', 'Gene', (43, 48))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('cancers', 'Phenotype', 'HP:0002664', (275, 282))	('colorectal cancer', 'Disease', (204, 221))	('cancers', 'Disease', (275, 282))	('head and neck cancer', 'Disease', 'MESH:D006258', (139, 159))	('ovarian cancer', 'Disease', (397, 411))	('esophageal cancer', 'Disease', 'MESH:D004938', (332, 349))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('ovarian cancer', 'Phenotype', 'HP:0100615', (397, 411))	('esophageal cancer', 'Disease', (332, 349))
206200	29997523	As a result, we found that high level of HMGA2 was related with poor OS in 13 types of cancers.	('cancers', 'Disease', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('HMGA2', 'Gene', (41, 46))	('HMGA2', 'Gene', '8091', (41, 46))	('related', 'Reg', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('high level', 'Var', (27, 37))	('poor OS', 'Disease', (64, 71))
206206	29997523	Results showed that there was no publication bias existed in studies on HMGA2 overexpression in association with OS (P = 0.597.	('overexpression', 'Var', (78, 92))	('HMGA2', 'Gene', '8091', (72, 77))	('HMGA2', 'Gene', (72, 77))
206212	29997523	Significant association between high expressed HMGA2 and poor overall survival in patients was found in 14 types of cancers.	('HMGA2', 'Gene', '8091', (47, 52))	('high expressed', 'Var', (32, 46))	('poor', 'NegReg', (57, 61))	('patients', 'Species', '9606', (82, 90))	('HMGA2', 'Gene', (47, 52))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('overall survival', 'MPA', (62, 78))
206214	29997523	Considering the TCGA datasets and our meta-analysis, we identified correlation between high HMGA2 expression and head and neck cancer, pancreatic ductal adenocarcinoma, ccRCC, hepatocellular carcinoma, esophageal adenocarcinoma and ovarian carcinoma, except breast cancer and gastric cancer.	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (135, 167))	('esophageal adenocarcinoma and ovarian carcinoma', 'Disease', 'MESH:D010051', (202, 249))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('hepatocellular carcinoma', 'Disease', (176, 200))	('high', 'Var', (87, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))	('gastric cancer', 'Disease', (276, 290))	('HMGA2', 'Gene', (92, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('neck', 'cellular_component', 'GO:0044326', ('122', '126'))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (258, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (202, 227))	('head and neck cancer', 'Phenotype', 'HP:0012288', (113, 133))	('correlation', 'Interaction', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', 'MESH:D001943', (258, 271))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (135, 167))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (176, 200))	('gastric cancer', 'Disease', 'MESH:D013274', (276, 290))	('breast cancer', 'Disease', (258, 271))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (232, 249))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('HMGA2', 'Gene', '8091', (92, 97))	('pancreatic ductal adenocarcinoma', 'Disease', (135, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('head and neck cancer', 'Disease', 'MESH:D006258', (113, 133))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (176, 200))	('gastric cancer', 'Phenotype', 'HP:0012126', (276, 290))	('ccRCC', 'Disease', (169, 174))	('expression', 'MPA', (98, 108))
206222	29997523	The meta-analysis results suggested that high expression of HMGA2 was associated with shorter OS and DFS in patients with cancers.	('patients', 'Species', '9606', (108, 116))	('HMGA2', 'Gene', '8091', (60, 65))	('shorter', 'NegReg', (86, 93))	('high expression', 'Var', (41, 56))	('HMGA2', 'Gene', (60, 65))	('DFS', 'CPA', (101, 104))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))
206226	29997523	Patients with high expressed HMGA2 in ccRCC, head and neck cancer, hepatocellular carcinoma and pancreatic ductal adenocarcinoma showed a significant shorter OS than patients with a low level of HMGA2 expression.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (67, 91))	('head and neck cancer', 'Phenotype', 'HP:0012288', (45, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (96, 128))	('HMGA2', 'Gene', (29, 34))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (67, 91))	('Patients', 'Species', '9606', (0, 8))	('HMGA2', 'Gene', (195, 200))	('ccRCC', 'Disease', (38, 43))	('pancreatic ductal adenocarcinoma', 'Disease', (96, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('head and neck cancer', 'Disease', 'MESH:D006258', (45, 65))	('high expressed', 'Var', (14, 28))	('neck', 'cellular_component', 'GO:0044326', ('54', '58'))	('hepatocellular carcinoma', 'Disease', (67, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (96, 128))	('shorter', 'NegReg', (150, 157))	('HMGA2', 'Gene', '8091', (29, 34))	('HMGA2', 'Gene', '8091', (195, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('patients', 'Species', '9606', (166, 174))
206235	29997523	A study conducted by suggested silencing HMGA2 expression in ovarian cancer cells could have a therapeutic effect on ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (61, 75))	('silencing', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (117, 131))	('ovarian cancer', 'Disease', 'MESH:D010051', (117, 131))	('ovarian cancer', 'Disease', (61, 75))	('HMGA2', 'Gene', '8091', (41, 46))	('ovarian cancer', 'Disease', (117, 131))	('HMGA2', 'Gene', (41, 46))	('ovarian cancer', 'Phenotype', 'HP:0100615', (61, 75))
206245	30513765	Hypoxia-inducible factors (HIFs), angiogenic growth factors, von Hippel-Lindau (VHL) gene mutations, and oncogenic microRNAs (miRNAs) play essential roles in the pathogenesis and drug resistance of clear cell renal cell carcinoma.	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('VHL', 'Gene', (80, 83))	('mutations', 'Var', (90, 99))	('von Hippel-Lindau', 'Gene', '7428', (61, 78))	('Hypoxia', 'Disease', (0, 7))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (198, 229))	('clear cell renal cell carcinoma', 'Disease', (198, 229))	('VHL', 'Gene', '7428', (80, 83))	('drug resistance', 'Phenotype', 'HP:0020174', (179, 194))	('drug resistance', 'biological_process', 'GO:0009315', ('179', '194'))	('pathogenesis', 'biological_process', 'GO:0009405', ('162', '174'))	('drug resistance', 'biological_process', 'GO:0042493', ('179', '194'))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (198, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (209, 229))	('von Hippel-Lindau', 'Gene', (61, 78))
206248	30513765	Various histone deacetylase (HDAC) inhibitors, selenium, and agents like PT2385 and PT2977 are being explored in various clinical trials as potential HIF inhibitors, to ameliorate the outcomes of RCC patients.	('ameliorate', 'PosReg', (169, 179))	('histone deacetylase', 'Gene', (8, 27))	('PT2977', 'Var', (84, 90))	('patients', 'Species', '9606', (200, 208))	('histone deacetylase', 'Gene', '9734', (8, 27))	('HDAC', 'Gene', (29, 33))	('PT2385', 'Var', (73, 79))	('PT2385', 'Chemical', 'MESH:C000614279', (73, 79))	('HDAC', 'Gene', '9734', (29, 33))	('selenium', 'Chemical', 'MESH:D012643', (47, 55))	('RCC', 'Disease', 'MESH:C538614', (196, 199))	('RCC', 'Disease', (196, 199))	('RCC', 'Phenotype', 'HP:0005584', (196, 199))
206273	30513765	In ccRCC, a wide range of intragenic mutations, deletions (complete or partial) and splicing defects have been identified that derange normal function of the VHL gene, which creates a situation similar to cellular hypoxia and the accumulation of HIFs.	('derange', 'NegReg', (127, 134))	('defects', 'Var', (93, 100))	('hypoxia', 'Disease', (214, 221))	('hypoxia', 'Disease', 'MESH:D000860', (214, 221))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('mutations', 'Var', (37, 46))	('VHL', 'Gene', (158, 161))	('deletions', 'Var', (48, 57))	('normal function', 'MPA', (135, 150))	('splicing', 'biological_process', 'GO:0045292', ('84', '92'))	('VHL', 'Gene', '7428', (158, 161))
206275	30513765	These include folliculin (FLCN; chromophobe RCC/oncocytoma in Birt-Hogg-Dube syndrome), papillary type 1 RCC (MET), fumarate hydratase (FH; papillary type 2 RCC in hereditary leiomyomatosis and renal cell cancer syndrome), SDHB/SDHD/SDHC/SDHA (succinate dehydrogenase subunit-related RCC), chromosome 3 translocations-associated clear cell RCC, papillary RCC (PTEN), and BAP1 (clear cell RCC).	('Birt-Hogg-Dube syndrome', 'Disease', 'MESH:D058249', (62, 85))	('RCC', 'Disease', (355, 358))	('hereditary leiomyomatosis and renal cell cancer syndrome', 'Disease', 'MESH:C535516', (164, 220))	('fumarate hydratase', 'Gene', (116, 134))	('RCC', 'Disease', 'MESH:C538614', (284, 287))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('SDHC', 'Gene', '6391', (233, 237))	('papillary RCC', 'Disease', 'MESH:C538614', (345, 358))	('papillary RCC', 'Disease', (345, 358))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', 'MESH:C538614', (340, 343))	('SDHB', 'Gene', (223, 227))	('BAP1', 'Gene', '8314', (371, 375))	('RCC', 'Phenotype', 'HP:0005584', (340, 343))	('chromophobe RCC/oncocytoma', 'Disease', (32, 58))	('chromophobe RCC/oncocytoma', 'Disease', 'MESH:C538614', (32, 58))	('RCC', 'Disease', 'MESH:C538614', (355, 358))	('chromosome', 'cellular_component', 'GO:0005694', ('290', '300'))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('chromosome', 'Var', (290, 300))	('RCC', 'Disease', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('SDHA', 'Gene', (238, 242))	('folliculin', 'Gene', (14, 24))	('PTEN', 'Gene', (360, 364))	('fumarate hydratase', 'Gene', '2271', (116, 134))	('SDHD', 'Gene', '6392', (228, 232))	('SDHC', 'Gene', (233, 237))	('BAP1', 'Gene', (371, 375))	('SDHA', 'Gene', '6389', (238, 242))	('papillary type', 'Phenotype', 'HP:0007482', (140, 154))	('folliculin', 'Gene', '201163', (14, 24))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (388, 391))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('RCC', 'Disease', 'MESH:C538614', (388, 391))	('PTEN', 'Gene', '5728', (360, 364))	('FLCN', 'Gene', '201163', (26, 30))	('RCC', 'Phenotype', 'HP:0005584', (284, 287))	('SDHD', 'Gene', (228, 232))	('RCC', 'Disease', (284, 287))	('RCC', 'Disease', (157, 160))	('SDHB', 'Gene', '6390', (223, 227))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('RCC', 'Disease', (340, 343))	('FLCN', 'Gene', (26, 30))	('Birt-Hogg-Dube syndrome', 'Disease', (62, 85))	('renal cell cancer', 'Phenotype', 'HP:0005584', (194, 211))	('papillary type', 'Phenotype', 'HP:0007482', (88, 102))
206284	30513765	In a phase III, open-label study of pazopanib in patients with no prior treatment or one prior cytokine-based treatment, PFS was prolonged significantly with pazopanib versus a placebo.	('pazopanib', 'Chemical', 'MESH:C516667', (158, 167))	('men', 'Species', '9606', (115, 118))	('men', 'Species', '9606', (77, 80))	('pazopanib', 'Var', (158, 167))	('PFS', 'MPA', (121, 124))	('patients', 'Species', '9606', (49, 57))	('prolonged', 'PosReg', (129, 138))	('pazopanib', 'Chemical', 'MESH:C516667', (36, 45))
206290	30513765	Symptoms associated with discomfort, such as fatigue, hand-foot syndrome, and mouth sores occurred more frequently with sunitinib, while pazopanib was associated with elevations in liver-function tests, weight loss, and changes in hair color.	('weight loss', 'Disease', 'MESH:D015431', (203, 214))	('liver-function tests', 'MPA', (181, 201))	('hand-foot syndrome', 'Disease', 'MESH:D060831', (54, 72))	('weight loss', 'Phenotype', 'HP:0001824', (203, 214))	('pazopanib', 'Chemical', 'MESH:C516667', (137, 146))	('mouth', 'Disease', (78, 83))	('hair color', 'MPA', (231, 241))	('fatigue', 'Disease', (45, 52))	('mouth sores', 'Phenotype', 'HP:0000155', (78, 89))	('fatigue', 'Phenotype', 'HP:0012378', (45, 52))	('mouth', 'Disease', 'MESH:D009059', (78, 83))	('weight loss', 'Disease', (203, 214))	('changes', 'Reg', (220, 227))	('sunitinib', 'Var', (120, 129))	('elevations', 'PosReg', (167, 177))	('fatigue', 'Disease', 'MESH:D005221', (45, 52))	('hand-foot syndrome', 'Disease', (54, 72))	('sunitinib', 'Chemical', 'MESH:D000077210', (120, 129))	('elevations in liver-function tests', 'Phenotype', 'HP:0002910', (167, 201))
206291	30513765	The study also showed lower monthly use of medical resources with pazopanib than with sunitinib.	('pazopanib', 'Chemical', 'MESH:C516667', (66, 75))	('sunitinib', 'Chemical', 'MESH:D000077210', (86, 95))	('lower', 'NegReg', (22, 27))	('pazopanib', 'Var', (66, 75))
206333	30513765	Inhibiting the HIF pathway and subsequently its translational activity is an attractive treatment modality, as it blocks the activation of all downstream genes.	('Inhibiting', 'Var', (0, 10))	('men', 'Species', '9606', (93, 96))	('translational', 'MPA', (48, 61))	('activation', 'MPA', (125, 135))	('blocks', 'NegReg', (114, 120))	('HIF pathway', 'Pathway', (15, 26))
206337	30513765	In a small study of mRCC, HIF expression was predictive of increased response to sunitinib treatment.	('men', 'Species', '9606', (96, 99))	('RCC', 'Disease', (21, 24))	('expression', 'Var', (30, 40))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('sunitinib', 'Chemical', 'MESH:D000077210', (81, 90))	('increased', 'PosReg', (59, 68))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('response to', 'MPA', (69, 80))
206353	30513765	Selenium can also affect the tumor microenvironment (TME), and may be able to stabilize the TME to improve drug delivery.	('drug delivery', 'MPA', (107, 120))	('Selenium', 'Chemical', 'MESH:D012643', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('improve', 'PosReg', (99, 106))	('affect', 'Reg', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('men', 'Species', '9606', (47, 50))	('Selenium', 'Var', (0, 8))
206426	32086382	This work considered the neoantigen-class I MHC binding affinity and only retained the top neoantigens resulting from missense mutations with the highest binding affinity within each tumor clone.	('binding', 'molecular_function', 'GO:0005488', ('48', '55'))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('MHC', 'Gene', (44, 47))	('binding', 'Interaction', (48, 55))	('binding', 'molecular_function', 'GO:0005488', ('154', '161'))	('MHC', 'Gene', '3107', (44, 47))	('tumor', 'Disease', (183, 188))	('missense mutations', 'Var', (118, 136))
206432	32086382	Subclonal mutations are unique to different clones, and if a subclonal mutation is in a clone with a larger clonal fraction, the neoantigens associated with this mutation are likely to have a stronger effect on the survival of the tumor cells than subclonal mutations associated with minor clones.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('stronger', 'PosReg', (192, 200))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('effect', 'Reg', (201, 207))	('tumor', 'Disease', (231, 236))	('neoantigens', 'MPA', (129, 140))	('mutation', 'Var', (162, 170))
206433	32086382	Besides, each somatic mutation could generate a different number of neoantigens of different peptide lengths (8 to 11 amino acids for class I MHC-binding peptides, 15 amino acids for class II-binding peptides), with different registers (a sliding window of protein segments around the mutated position) and presented by different HLA alleles (class I and class II).	('MHC', 'Gene', (142, 145))	('protein', 'cellular_component', 'GO:0003675', ('257', '264'))	('mutation', 'Var', (22, 30))	('MHC', 'Gene', '3107', (142, 145))	('binding', 'molecular_function', 'GO:0005488', ('146', '153'))	('generate', 'Reg', (37, 45))	('neoantigens', 'MPA', (68, 79))	('binding', 'molecular_function', 'GO:0005488', ('192', '199'))
206434	32086382	We hypothesize that a favorable distribution of neoantigens and tumor mutations occurs when immunogenic neoantigens are concentrated on truncal mutations (Fig.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('truncal', 'Var', (136, 143))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
206435	32086382	When the mutations with higher VAFs are also the mutations that generate more neoantigens (favorable distribution), the product value will be larger (a higher CSiN score).	('VAFs', 'Disease', (31, 35))	('larger', 'PosReg', (142, 148))	('mutations', 'Var', (9, 18))	('VAFs', 'Disease', 'None', (31, 35))	('neoantigens', 'MPA', (78, 89))	('product', 'MPA', (120, 127))
206470	32086382	In this cohort, CSiN scores of patients with DCB are higher than CSiN scores of patients with NCB with marginal significance (Fig.	('higher', 'PosReg', (53, 59))	('patients', 'Species', '9606', (80, 88))	('DCB', 'Var', (45, 48))	('DCB', 'Chemical', 'MESH:D015101', (45, 48))	('CSiN scores', 'MPA', (16, 27))	('patients', 'Species', '9606', (31, 39))
206482	32086382	We observed patients with higher CSiN scores had a non-significant trend of better survival than patients with low CSiN scores in the high T cell infiltration subset of patients (Fig.	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (169, 177))	('scores', 'Var', (38, 44))	('better', 'PosReg', (76, 82))	('patients', 'Species', '9606', (97, 105))
206485	32086382	Our implementations of the CSiN, neoantigen load, and neoantigen fitness indices have considered both MHC class I and class II neoantigens, and also neoantigens generated from insertions/deletions and stop-loss mutations.	('MHC', 'Gene', '3107', (102, 105))	('MHC', 'Gene', (102, 105))	('stop-loss mutations', 'Var', (201, 220))	('insertions/deletions', 'Var', (176, 196))
206487	32086382	made a qualitative observation that CTLA-4-resistant tumors could be enriched for subclonal mutations, which may enhance total neoantigen burden but not elicit an effective antitumor response due to the subclonal nature of these neoantigens.	('CTLA-4', 'Gene', '1493', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('mutations', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('CTLA-4', 'Gene', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (53, 58))	('total neoantigen burden', 'MPA', (121, 144))	('tumor', 'Disease', (177, 182))	('tumors', 'Disease', (53, 59))	('enhance', 'PosReg', (113, 120))
206496	32086382	While RCCs have low neoantigen/mutation loads, Turajlic et al discovered that RCCs have the highest number of insertion/deletion mutations on a pan-cancer basis, which tend to encode high quality neoantigens.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('insertion/deletion mutations', 'Var', (110, 138))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))
206512	32086382	The name CSiN was selected because the pairing of tumor mutations and neoantigens and its effect on the overall score bear analogy to the Cauchy-Schwarz inequality, which describes the upper bound of the product sum of two vectors of real numbers and the condition for the equality to be achieved.	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mutations', 'Var', (56, 65))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))
206515	32086382	All SNPs and Indels were combined and only kept if there were at least 7 total (wild type and variant) reads in the normal sample and at least 3 variant reads in the tumor sample.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('variant', 'Var', (94, 101))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))
206548	32218829	The differences in prognosis between patients with high- and low-MYBL2 expression were analyzed via the Kaplan-Meier method and Cox regression analysis.	('patients', 'Species', '9606', (37, 45))	('MYBL2', 'Gene', (65, 70))	('MYBL2', 'Gene', '4605', (65, 70))	('high-', 'Var', (51, 56))
206561	32218829	Overexpressed MYBL2 promotes proliferation and inhibits apoptosis of breast cancer cells targeted by miR-143-3p.	('MYBL2', 'Gene', (14, 19))	('promotes', 'PosReg', (20, 28))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('proliferation', 'CPA', (29, 42))	('breast cancer', 'Disease', (69, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('miR-143-3p', 'Var', (101, 111))	('apoptosis', 'biological_process', 'GO:0097194', ('56', '65'))	('apoptosis', 'CPA', (56, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('56', '65'))	('MYBL2', 'Gene', '4605', (14, 19))	('inhibits', 'NegReg', (47, 55))
206562	32218829	Moreover, MYBL2 knockdown suppressed the growth of esophageal squamous cell and colorectal carcinoma cells via regulation of the cell cycle.	('MYBL2', 'Gene', '4605', (10, 15))	('cell cycle', 'CPA', (129, 139))	('MYBL2', 'Gene', (10, 15))	('esophageal squamous', 'Disease', 'MESH:D000077277', (51, 70))	('growth', 'CPA', (41, 47))	('esophageal squamous', 'Disease', (51, 70))	('suppressed', 'NegReg', (26, 36))	('colorectal carcinoma', 'Disease', (80, 100))	('regulation', 'Reg', (111, 121))	('regulation', 'biological_process', 'GO:0065007', ('111', '121'))	('knockdown', 'Var', (16, 25))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (80, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('cell cycle', 'biological_process', 'GO:0007049', ('129', '139'))
206563	32218829	In other cancer types, including hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma, high MYBL2 expression also promoted the progression of tumors and resulted in a poorer prognosis.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (69, 91))	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('non-small cell lung cancer', 'Disease', (65, 91))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('hepatocellular carcinoma', 'Disease', (33, 57))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (104, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('NSCLC', 'Disease', (93, 98))	('promoted', 'PosReg', (165, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('pancreatic ductal adenocarcinoma', 'Disease', (104, 136))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('MYBL2', 'Gene', (143, 148))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (65, 91))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (33, 57))	('cancer', 'Disease', (85, 91))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('HCC', 'Gene', '619501', (59, 62))	('HCC', 'Phenotype', 'HP:0001402', (59, 62))	('high', 'Var', (138, 142))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (104, 136))	('MYBL2', 'Gene', '4605', (143, 148))	('progression', 'CPA', (178, 189))	('HCC', 'Gene', (59, 62))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (65, 91))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (33, 57))	('tumors', 'Disease', (193, 199))
206591	32218829	The median follow-up times for the high- and low-MYBL2 expression groups were 967 and 951 months, respectively.	('high-', 'Var', (35, 40))	('MYBL2', 'Gene', (49, 54))	('MYBL2', 'Gene', '4605', (49, 54))
206594	32218829	Kaplan-Meier analysis revealed that patients with ccRCC with high MYBL2 expression exhibited a poorer OS rate compared with the low-expression group (Fig.	('MYBL2', 'Gene', '4605', (66, 71))	('OS', 'Chemical', '-', (102, 104))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('patients', 'Species', '9606', (36, 44))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (50, 55))	('MYBL2', 'Gene', (66, 71))	('high', 'Var', (61, 65))	('poorer', 'NegReg', (95, 101))
206595	32218829	Moreover, the univariate Cox regression analysis indicated that high MYBL2 expression was strongly associated with a poor prognosis.	('MYBL2', 'Gene', '4605', (69, 74))	('MYBL2', 'Gene', (69, 74))	('high', 'Var', (64, 68))	('expression', 'MPA', (75, 85))
206597	32218829	Moreover, multivariate analysis revealed that high MYBL2 expression, age and distant metastasis were independently associated with a poor prognosis (Table III).	('high', 'Var', (46, 50))	('expression', 'MPA', (57, 67))	('MYBL2', 'Gene', '4605', (51, 56))	('MYBL2', 'Gene', (51, 56))	('distant metastasis', 'CPA', (77, 95))
206607	32218829	Other findings indicated that MYBL2 regulated breast cancer cell proliferation and apoptosis via the targeting of microRNA-143-3p.	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('cell proliferation', 'biological_process', 'GO:0008283', ('60', '78'))	('microRNA-143-3p', 'Var', (114, 129))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('MYBL2', 'Gene', '4605', (30, 35))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('apoptosis', 'CPA', (83, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('breast cancer', 'Disease', (46, 59))	('MYBL2', 'Gene', (30, 35))
206630	31278396	This Opinion article provides examples of alternative TSAs to the traditional single nucleotide variant neoantigens and the novel computational tools to identify them with the view to broaden the number of targetable antigens that can be used for cancer vaccine development.	('cancer', 'Disease', (247, 253))	('single nucleotide variant', 'Var', (78, 103))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))
206632	31278396	Neoantigens [G] are defined here as a subset of TSAs generated by nonsynonymous mutations and other genetic variations specific to the genome of a tumour, presented by major histocompatibility complex (MHC) molecules, and recognized by endogenous T cells.	('nonsynonymous mutations', 'Var', (66, 89))	('major histocompatibility complex', 'biological_process', 'GO:0046776', ('168', '200'))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('variations', 'Var', (108, 118))	('tumour', 'Disease', (147, 153))
206633	31278396	The most commonly studied class of neoantigens are those derived from single nucleotide variants (SNVs), which cause non-synonymous changes in a protein that subsequently may trigger antigen-specific T-cell responses against the tumour.	('changes', 'Reg', (132, 139))	('single nucleotide variants', 'Var', (70, 96))	('tumour', 'Disease', 'MESH:D009369', (229, 235))	('protein', 'Protein', (145, 152))	('tumour', 'Disease', (229, 235))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('trigger', 'Reg', (175, 182))	('tumour', 'Phenotype', 'HP:0002664', (229, 235))
206642	31278396	This is exemplified by clear cell renal cell carcinoma (ccRCC), an immune checkpoint inhibitor sensitive cancer which contains a low predicted SNV burden but high expression of predicted frameshift-neoantigens and tumour-specific endogenous retroviral antigen.	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (23, 54))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('tumour', 'Disease', (214, 220))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('clear cell renal cell carcinoma', 'Disease', (23, 54))	('frameshift-neoantigens', 'Var', (187, 209))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (23, 54))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (34, 54))	('tumour', 'Disease', 'MESH:D009369', (214, 220))	('ccRCC', 'Disease', (56, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('ccRCC', 'Disease', 'MESH:D002292', (56, 61))
206643	31278396	Additionally, leukemia and sarcoma (which contain among the lowest predicted SNV burden of any cancers) express gene fusion mutations and splice variant transcripts shared across multiple tumours, potentially allowing for universal off-the-shelf therapies.	('splice variant transcripts', 'Var', (138, 164))	('multiple tumours', 'Disease', (179, 195))	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('tumours', 'Phenotype', 'HP:0002664', (188, 195))	('leukemia and sarcoma', 'Disease', 'MESH:D012509', (14, 34))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancers', 'Disease', (95, 102))	('leukemia', 'Phenotype', 'HP:0001909', (14, 22))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('multiple tumours', 'Disease', 'MESH:D009378', (179, 195))
206649	31278396	Variant calling is the identification of genomic regions with tumour specificity.	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('tumour', 'Disease', (62, 68))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('Variant', 'Var', (0, 7))
206650	31278396	In the case of SNVs, insertion or deletion [G] (INDEL) mutations, and gene fusions, variants are derived from mutations within the tumour exome that are not expressed by germline DNA.	('tumour', 'Disease', (131, 137))	('insertion', 'Var', (21, 30))	('deletion [', 'Var', (34, 44))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('DNA', 'cellular_component', 'GO:0005574', ('179', '182'))
206653	31278396	Cancer types particularly relevant for targeting of INDEL-neoantigens include microsatellite instability-high (MSI-H) tumours as well as all renal cell carcinomas (RCCs).	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('MSI-H) tumours', 'Disease', 'MESH:D053842', (111, 125))	('renal cell carcinomas', 'Disease', 'MESH:D002292', (141, 162))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (141, 161))	('renal cell carcinomas', 'Disease', (141, 162))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))	('INDEL-neoantigens', 'Var', (52, 69))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('carcinomas', 'Phenotype', 'HP:0030731', (152, 162))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('RCCs', 'Disease', (164, 168))	('RCCs', 'Disease', 'MESH:D002292', (164, 168))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (141, 162))	('microsatellite', 'Var', (78, 92))	('RCCs', 'Phenotype', 'HP:0005584', (164, 168))
206658	31278396	The association between INDEL burden and presence of tumour infiltrating T cells has been well described in the literature, providing early support for the hypothesis that MSI-H tumours would be susceptible to immunotherapies.	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('tumour', 'Disease', (53, 59))	('tumours', 'Phenotype', 'HP:0002664', (178, 185))	('tumours', 'Disease', 'MESH:D009369', (178, 185))	('tumour', 'Disease', 'MESH:D009369', (178, 184))	('tumour', 'Disease', (178, 184))	('tumours', 'Disease', (178, 185))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('INDEL burden', 'Var', (24, 36))	('MSI', 'Gene', '5928', (172, 175))	('MSI', 'Gene', (172, 175))	('tumour', 'Disease', 'MESH:D009369', (53, 59))
206662	31278396	whereby examining the pan-cancer INDEL profile in the cancer genome atlas (TCGA) dataset revealed that all RCC subtypes (clear cell RCC (ccRCC), renal papillary cell carcinoma and chromophobe RCC) have the highest proportion and number of INDEL mutations of any cancer types.	('INDEL mutations', 'Var', (239, 254))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('ccRCC', 'Disease', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('renal papillary cell carcinoma', 'Disease', (145, 175))	('cancer', 'Disease', (262, 268))	('clear cell RCC', 'Disease', (121, 135))	('clear cell RCC', 'Disease', 'MESH:C538445', (121, 135))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('chromophobe RCC', 'Disease', 'MESH:D002292', (180, 195))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('renal papillary cell carcinoma', 'Disease', 'MESH:D002292', (145, 175))	('chromophobe RCC', 'Disease', (180, 195))	('ccRCC', 'Disease', 'MESH:D002292', (137, 142))	('cancer', 'Disease', 'MESH:D009369', (262, 268))
206664	31278396	While the number of predicted INDELs across the pan-cancer cohort were orders of magnitude lower than SNV mutations, they were estimated to produce approximately 3-to-9-times more predicted neoantigens [G] per mutation than SNVs.	('lower', 'NegReg', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (106, 115))	('cancer', 'Disease', (52, 58))	('INDELs', 'Var', (30, 36))	('to-9', 'Species', '1214577', (164, 168))	('neoantigens [G]', 'MPA', (190, 205))
206666	31278396	A rare example of a publicly shared neoantigen has been observed from a common frameshift mutation in the gene transforming growth factor beta receptor type 2 (TGFbetaR2), frequently found in Lynch syndrome and 15% of sporadic gastric and colon cancers with MSI.	('MSI', 'Gene', (258, 261))	('Lynch syndrome', 'Disease', 'MESH:D003123', (192, 206))	('frameshift mutation', 'Var', (79, 98))	('colon cancer', 'Phenotype', 'HP:0003003', (239, 251))	('TGFbetaR2', 'Gene', (160, 169))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('found in', 'Reg', (183, 191))	('TGFbetaR', 'molecular_function', 'GO:0005024', ('160', '168'))	('colon cancers', 'Disease', (239, 252))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('111', '142'))	('colon cancers', 'Phenotype', 'HP:0003003', (239, 252))	('colon cancers', 'Disease', 'MESH:D015179', (239, 252))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('Lynch syndrome', 'Disease', (192, 206))	('MSI', 'Gene', '5928', (258, 261))
206667	31278396	Three independent studies published in 2001 demonstrated HLA-specific epitopes generated from mutated TGFbetaR2 capable of generating antigen-specific T cells, one associated with MHC class I-CD8+ T cell responses and one with MHC class II-CD4+ T cell responses.	('mutated', 'Var', (94, 101))	('T cells', 'CPA', (151, 158))	('CD8', 'Gene', (192, 195))	('TGFbetaR', 'molecular_function', 'GO:0005024', ('102', '110'))	('CD8', 'Gene', '925', (192, 195))	('TGFbetaR2', 'Gene', (102, 111))	('generating', 'PosReg', (123, 133))	('antigen-specific', 'MPA', (134, 150))
206669	31278396	The transfected T cells demonstrated evidence of efficacy against colon cancer cell lines containing the TGFbetaRII mutation in vitro (cytotoxicity and cytokine release) and in vivo (an immunodeficient xenograft mouse model).	('colon cancer', 'Disease', (66, 78))	('colon cancer', 'Disease', 'MESH:D015179', (66, 78))	('mutation', 'Var', (116, 124))	('cytotoxicity', 'Disease', 'MESH:D064420', (135, 147))	('TGFbetaRII', 'Gene', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('colon cancer', 'Phenotype', 'HP:0003003', (66, 78))	('immunodeficient', 'Disease', 'MESH:D007153', (186, 201))	('immunodeficient', 'Disease', (186, 201))	('cytotoxicity', 'Disease', (135, 147))	('mouse', 'Species', '10090', (212, 217))
206674	31278396	Splice variant antigens are post-transcriptionally derived TSAs arising from alternative splicing events, including from mRNA splice junction mutations, intron retention, or dysregulation of the spliceosome [G] machinery in the tumour cell.	('mutations', 'Var', (142, 151))	('spliceosome', 'cellular_component', 'GO:0005681', ('195', '206'))	('tumour', 'Disease', (228, 234))	('dysregulation', 'Var', (174, 187))	('splicing', 'biological_process', 'GO:0045292', ('89', '97'))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))	('tumour', 'Disease', 'MESH:D009369', (228, 234))	('retention', 'biological_process', 'GO:0051235', ('160', '169'))
206678	31278396	In haematological cancers where SNV burden is relatively low, splice variant antigens could broaden the number of available TSA targets for therapeutic application.	('cancers', 'Disease', (18, 25))	('TSA', 'molecular_function', 'GO:0033984', ('124', '127'))	('haematological cancer', 'Phenotype', 'HP:0004377', (3, 24))	('cancers', 'Disease', 'MESH:D009369', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('splice variant antigens', 'Var', (62, 85))
206679	31278396	Splice variant proteins can arise through cis-acting mutations which disrupt or create splice site motifs or through trans-acting alterations in slicing factors which have historically been identified in haematologic malignancies.	('disrupt', 'Reg', (69, 76))	('splice site motifs', 'MPA', (87, 105))	('mutations', 'Var', (53, 62))	('proteins', 'Protein', (15, 23))	('haematologic malignancies', 'Disease', 'MESH:D009383', (204, 229))	('haematologic malignancies', 'Disease', (204, 229))
206680	31278396	The role of spliceosome machinery in the generation of splice variants in haematological malignancies is a current area of investigation.	('spliceosome', 'cellular_component', 'GO:0005681', ('12', '23'))	('haematological malignancies', 'Disease', 'MESH:D009383', (74, 101))	('haematological malignancies', 'Disease', (74, 101))	('splice variants', 'Var', (55, 70))
206682	31278396	Sharing of these spliceosome protein mutations across haematological cancer types has led to the hypothesis that spliceosome dysregulation may cause expression of splice variant mRNAs, which are not detectable in normal tissues, leading to translation of TSAs.	('splice variant', 'Var', (163, 177))	('haematological cancer', 'Phenotype', 'HP:0004377', (54, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('spliceosome', 'cellular_component', 'GO:0005681', ('113', '124'))	('translation', 'biological_process', 'GO:0006412', ('240', '251'))	('leading to', 'Reg', (229, 239))	('cause', 'Reg', (143, 148))	('mutations', 'Var', (37, 46))	('TSAs', 'Protein', (255, 259))	('spliceosome', 'MPA', (113, 124))	('expression', 'MPA', (149, 159))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('translation', 'MPA', (240, 251))	('spliceosome', 'cellular_component', 'GO:0005681', ('17', '28'))	('cancer', 'Disease', (69, 75))
206683	31278396	Beyond haematological malignancies, recent reanalysis of the TCGA pan-cancer dataset demonstrated strong association between somatic mutations in components of the spliceosome machinery and expression of splice variant products, providing evidence for the relevance of splice variant antigens in solid tumours.	('haematological malignancies', 'Disease', (7, 34))	('solid tumours', 'Disease', (296, 309))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumour', 'Phenotype', 'HP:0002664', (302, 308))	('spliceosome', 'cellular_component', 'GO:0005681', ('164', '175'))	('haematological malignancies', 'Disease', 'MESH:D009383', (7, 34))	('tumours', 'Phenotype', 'HP:0002664', (302, 309))	('mutations', 'Var', (133, 142))	('expression', 'MPA', (190, 200))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('solid tumours', 'Disease', 'MESH:D009369', (296, 309))
206692	31278396	WT1 derived peptides have been studied as a therapeutic target in leukemias, lung, and kidney cancers; however, these trials did not use epitopes specific for the E5+ splice variant.	('leukemias', 'Disease', (66, 75))	('WT1', 'Gene', '7490', (0, 3))	('kidney cancers', 'Disease', (87, 101))	('kidney cancers', 'Phenotype', 'HP:0009726', (87, 101))	('kidney cancers', 'Disease', 'MESH:D007680', (87, 101))	('leukemias', 'Disease', 'MESH:D007938', (66, 75))	('WT1', 'Gene', (0, 3))	('E5+', 'Var', (163, 166))	('leukemia', 'Phenotype', 'HP:0001909', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('lung', 'Disease', (77, 81))	('leukemias', 'Phenotype', 'HP:0001909', (66, 75))
206693	31278396	Additionally, an HLA-B44 restricted epitope derived from a variant of the minor histocompatibility antigen HMSD (HMSD-v) selectively expressed by primary haematological malignant cells (including those of myeloid lineage, and multiple myeloma) but also normal mature dendritic cells was observed to be targeted by CD8+ cytotoxic T cell clone 2A12-CTL.	('HLA-B', 'Gene', (17, 22))	('multiple myeloma', 'Disease', (226, 242))	('CD8', 'Gene', '925', (314, 317))	('HMSD', 'Gene', '284293', (107, 111))	('HLA-B', 'Gene', '3106', (17, 22))	('HMSD-v', 'Gene', '284293', (113, 119))	('HMSD', 'Gene', (107, 111))	('minor histocompatibility antigen', 'molecular_function', 'GO:0005558', ('74', '106'))	('HMSD', 'Gene', (113, 117))	('HMSD', 'Gene', '284293', (113, 117))	('variant', 'Var', (59, 66))	('HMSD-v', 'Gene', (113, 119))	('CD8', 'Gene', (314, 317))	('multiple myeloma', 'Phenotype', 'HP:0006775', (226, 242))	('multiple myeloma', 'Disease', 'MESH:D009101', (226, 242))
206695	31278396	described a CD20 splice variant (D393-CD20) whose expression is detectable in transformed B cells and upregulated in various B cell lymphomas.	('lymphoma', 'Phenotype', 'HP:0002665', (132, 140))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (125, 141))	('lymphomas', 'Disease', (132, 141))	('lymphomas', 'Disease', 'MESH:D008223', (132, 141))	('upregulated', 'PosReg', (102, 113))	('D393-CD20', 'Var', (33, 42))	('expression', 'MPA', (50, 60))	('lymphomas', 'Phenotype', 'HP:0002665', (132, 141))
206696	31278396	They subsequently demonstrated the capacity of D393-CD20 derived epitope vaccines to trigger both CD4+ and CD8+ T cell responses in HLA-humanized transgenic mice, supporting the use of CD20 splice variant epitopes for targeted immunotherapies in B cell malignancies.	('D393-CD20', 'Var', (47, 56))	('human', 'Species', '9606', (136, 141))	('transgenic mice', 'Species', '10090', (146, 161))	('CD4+', 'MPA', (98, 102))	('CD8', 'Gene', (107, 110))	('CD8', 'Gene', '925', (107, 110))
206697	31278396	Gene fusions were originally identified in leukemia, with subsequent observations in bladder, breast, renal, colon, and lung cancers (among others).	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('colon', 'Disease', (109, 114))	('leukemia', 'Disease', (43, 51))	('Gene fusions', 'Var', (0, 12))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('lung cancers', 'Disease', 'MESH:D008175', (120, 132))	('bladder', 'Disease', (85, 92))	('breast', 'Disease', (94, 100))	('identified', 'Reg', (29, 39))	('lung cancers', 'Phenotype', 'HP:0100526', (120, 132))	('colon', 'Disease', 'MESH:D015179', (109, 114))	('renal', 'Disease', (102, 107))	('lung cancers', 'Disease', (120, 132))	('leukemia', 'Disease', 'MESH:D007938', (43, 51))	('leukemia', 'Phenotype', 'HP:0001909', (43, 51))
206700	31278396	t(11;22)(p13;q12) in synovial sarcoma).	('synovial sarcoma', 'Disease', 'MESH:D013584', (21, 37))	('synovial sarcoma', 'Disease', (21, 37))	('t(11;22)(p13;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (0, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (21, 37))	('t(11;22)(p13;q12', 'Var', (0, 16))
206702	31278396	However, while driver mutation expression has been demonstrated to be highly clonal in early cancers, studies in non-small cell lung cancer have demonstrated highly heterogeneous driver alterations, frequent loss of HLA heterozygosity, and epigenetic silencing of neoantigen-containing genes occurring in later disease, all of which may contribute to immune escape.	('cancers', 'Disease', (93, 100))	('epigenetic silencing', 'Var', (240, 260))	('neoantigen-containing genes', 'Gene', (264, 291))	('mutation', 'Var', (22, 30))	('immune escape', 'CPA', (351, 364))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (113, 139))	('alterations', 'Var', (186, 197))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('loss', 'NegReg', (208, 212))	('non-small cell lung cancer', 'Disease', (113, 139))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('contribute', 'Reg', (337, 347))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (117, 139))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (113, 139))	('HLA heterozygosity', 'Protein', (216, 234))
206703	31278396	While overall gene fusion frequency is relatively low compared to SNV and INDEL mutations, they can be shared within and between different tumour types, making them identifiable through targeted methods (e.g.	('tumour', 'Disease', (139, 145))	('gene', 'Var', (14, 18))	('tumour', 'Disease', 'MESH:D009369', (139, 145))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))
206716	31278396	Retrotransposons can be expressed in cancer through epigenetic dysregulation, either through inherently low methylation states or following pharmacological induction of demethylation, resulting in transcription (and potential translation) of retroviral TSAs.	('demethylation', 'Var', (169, 182))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('methylation', 'biological_process', 'GO:0032259', ('108', '119'))	('demethylation', 'biological_process', 'GO:0070988', ('169', '182'))	('cancer', 'Disease', (37, 43))	('transcription', 'biological_process', 'GO:0006351', ('197', '210'))	('methylation states', 'MPA', (108, 126))	('retroviral', 'Gene', (242, 252))	('epigenetic dysregulation', 'Var', (52, 76))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('translation', 'biological_process', 'GO:0006412', ('226', '237'))	('low', 'NegReg', (104, 107))	('transcription', 'MPA', (197, 210))
206720	31278396	Transcription of tumour-specific or enriched hERVs arise through epigenetic dysregulation of the cancer genome (which can either be inherent to the epigenetic state of the cancer or pharmacologically induced through epigenetic modulating agents), resulting in expression of hERV-containing genomic regions otherwise not observed under physiological conditions.	('expression', 'MPA', (260, 270))	('hERV', 'Species', '11827', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (97, 103))	('hERVs', 'Gene', (45, 50))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('hERV-containing genomic regions', 'MPA', (274, 305))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('epigenetic dysregulation', 'Var', (65, 89))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('tumour', 'Disease', (17, 23))	('hERV', 'Species', '11827', (274, 278))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
206734	31278396	Additionally, recent evidence suggests a potential role for hERVs in the modulation of low grade glioma (where SNV burden is among the lowest of any cancer) and testicular cancer (particularly those with KIT mutations) where global DNA hypomethylation is associated with high hERV expression.	('KIT', 'molecular_function', 'GO:0005020', ('204', '207'))	('DNA', 'cellular_component', 'GO:0005574', ('232', '235'))	('KIT', 'Gene', (204, 207))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('testicular cancer', 'Disease', (161, 178))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('232', '251'))	('testicular cancer', 'Phenotype', 'HP:0010788', (161, 178))	('cancer', 'Disease', (149, 155))	('glioma', 'Disease', (97, 103))	('KIT', 'Gene', '3815', (204, 207))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('hERV', 'Species', '11827', (276, 280))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('cancer', 'Disease', (172, 178))	('expression', 'MPA', (281, 291))	('hERV', 'Protein', (276, 280))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('global DNA hypomethylation', 'Var', (225, 251))	('testicular cancer', 'Disease', 'MESH:D013736', (161, 178))	('hERV', 'Species', '11827', (60, 64))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
206751	31278396	Our analysis additionally identified a second hERV (hERV 4700) with preferential expression in ccRCC compared to normal tissues, evidence of translation, and presence of tumour infiltrating CTLs specific for hERV-4700 gag and pol derived antigens of the virus.	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('tumour', 'Disease', (170, 176))	('hERV-4700', 'Var', (208, 217))	('hERV', 'Species', '11827', (52, 56))	('ccRCC', 'Disease', (95, 100))	('hERV', 'Species', '11827', (46, 50))	('ccRCC', 'Disease', 'MESH:D002292', (95, 100))	('hERV', 'Species', '11827', (208, 212))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('preferential', 'PosReg', (68, 80))	('translation', 'biological_process', 'GO:0006412', ('141', '152'))	('tumour', 'Disease', 'MESH:D009369', (170, 176))	('gag', 'MPA', (218, 221))	('expression', 'MPA', (81, 91))
206753	31278396	where mutated HLA-A2*0201 in a ccRCC tumour promoted an antitumour T-cell response.	('promoted', 'PosReg', (44, 52))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('tumour', 'Disease', (37, 43))	('tumour', 'Disease', (60, 66))	('HLA-A2*0201', 'Protein', (14, 25))	('tumour', 'Disease', 'MESH:D009369', (37, 43))	('ccRCC', 'Phenotype', 'HP:0006770', (31, 36))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('ccRCC', 'Disease', (31, 36))	('mutated', 'Var', (6, 13))	('ccRCC', 'Disease', 'MESH:D002292', (31, 36))
206754	31278396	This study did not elucidate if the mechanism for T-cell response was a result of TCR recognition of the antigen presented by the mutated HLA or if the recognition was against the HLA molecule itself.	('TCR', 'biological_process', 'GO:0006283', ('82', '85'))	('TCR', 'Chemical', 'MESH:D017260', (82, 85))	('mutated', 'Var', (130, 137))	('TCR', 'cellular_component', 'GO:0042101', ('82', '85'))	('HLA', 'Gene', (138, 141))
206755	31278396	later demonstrated a similar finding in metastatic melanoma, with evidence that tumour-specific T cells may recognize an unknown antigen or set of antigens presented on mutated tumour HLA-A11.	('tumour', 'Disease', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('tumour', 'Disease', (177, 183))	('mutated', 'Var', (169, 176))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
206757	31278396	NetMHCpan), it is possible to predict for sets of antigens with specificity for the mutated tumour HLA and thus specificity for anti-tumour T-cell responses.	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('tumour', 'Disease', (92, 98))	('mutated', 'Var', (84, 91))	('tumour', 'Disease', (133, 139))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))
206758	31278396	Notably, a more advanced version of NetMHCpan is theoretically able to predict MHC binding to novel MHC molecules (including those containing mutations) through machine-learning prediction of MHC binding based upon the amino acid sequence of the MHC variant.	('mutations', 'Var', (142, 151))	('binding', 'molecular_function', 'GO:0005488', ('196', '203'))	('variant', 'Var', (250, 257))	('MHC', 'Gene', (246, 249))	('binding', 'Interaction', (83, 90))	('binding', 'molecular_function', 'GO:0005488', ('83', '90'))	('amino', 'Chemical', 'MESH:D000596', (219, 224))
206762	31278396	TEIPP-specific T cells can escape thymic selection in wild-type animals (but not in TAPI-deficient animals), making them promising candidates for anti-tumour therapeutic targets.	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('TEIPP-specific', 'Var', (0, 14))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('TAPI', 'Chemical', 'MESH:C099410', (84, 88))	('tumour', 'Disease', (151, 157))
206772	31278396	used mass spectrometry approaches and observed that approximately 90% of identified TSAs from two mouse cancer cell lines and seven human primary tumours were derived from non-coding regions, including introns, alternative reading frames, non-coding exons, untranslated region (UTR)-exon junctions, structural variants and endogenous retroelements.	('tumours', 'Disease', 'MESH:D009369', (146, 153))	('tumours', 'Disease', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('alternative reading frames', 'Var', (211, 237))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('human', 'Species', '9606', (132, 137))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('mouse', 'Species', '10090', (98, 103))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('non-coding exons', 'Var', (239, 255))
206780	31278396	This can be performed through a variety of molecular or immunological techniques Immunogenomic analysis: Study of the combined genomics of cancer cell and immune cell components of a tumour Insertion or deletion (INDEL): Insertion or deletion of bases into the genome of an organism, typically in the context of a mutation or genetic variation Kd: Dissociation constant that measures the concentration of a ligand necessary to reversibly bind half of its corresponding molecular pair.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('tumour', 'Disease', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('Insertion', 'Var', (190, 199))	('Insertion', 'Var', (221, 230))	('deletion', 'Var', (234, 242))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('deletion', 'Var', (203, 211))	('tumour', 'Disease', 'MESH:D009369', (183, 189))	('ligand', 'molecular_function', 'GO:0005488', ('407', '413'))	('cancer', 'Disease', (139, 145))
206788	31810986	Loss of TBK1 via genetic ablation, pharmacological inhibition, or a new Cereblon-based proteolysis targeting chimera (PROTAC) specifically inhibits VHL-deficient kidney cancer cell growth, while leaving VHL wild type cells intact.	('VHL', 'Gene', (148, 151))	('deficient kidney', 'Phenotype', 'HP:0000089', (152, 168))	('VHL', 'Gene', '7428', (148, 151))	('VHL-deficient kidney cancer', 'Disease', 'MESH:D007680', (148, 175))	('cell growth', 'biological_process', 'GO:0016049', ('176', '187'))	('kidney cancer', 'Phenotype', 'HP:0009726', (162, 175))	('TBK1', 'molecular_function', 'GO:0008384', ('8', '12'))	('proteolysis', 'biological_process', 'GO:0006508', ('87', '98'))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('VHL-deficient kidney cancer', 'Disease', (148, 175))	('VHL', 'Gene', (203, 206))	('inhibits', 'NegReg', (139, 147))	('Loss', 'Var', (0, 4))	('TBK1', 'Gene', (8, 12))	('VHL', 'Gene', '7428', (203, 206))
206789	31810986	TBK1 depletion also significantly blunts kidney tumorigenesis in an orthotopic xenograft model in vivo.	('depletion', 'Var', (5, 14))	('TBK1', 'molecular_function', 'GO:0008384', ('0', '4'))	('kidney tumor', 'Disease', (41, 53))	('blunts', 'NegReg', (34, 40))	('TBK1', 'Gene', (0, 4))	('kidney tumor', 'Phenotype', 'HP:0009726', (41, 53))	('kidney tumor', 'Disease', 'MESH:D007680', (41, 53))	('blunts kidney', 'Phenotype', 'HP:0000089', (34, 47))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
206790	31810986	Mechanistically, TBK1 hydroxylation on Proline 48 triggers VHL as well as the phosphatase PPM1B binding that leads to decreased TBK1 phosphorylation.	('hydroxylation', 'Var', (22, 35))	('Proline', 'Chemical', 'MESH:D011392', (39, 46))	('VHL', 'Gene', '7428', (59, 62))	('TBK1', 'molecular_function', 'GO:0008384', ('17', '21'))	('TBK1', 'Gene', (17, 21))	('triggers', 'Reg', (50, 58))	('phosphorylation', 'MPA', (133, 148))	('PPM1B', 'Gene', (90, 95))	('binding', 'Interaction', (96, 103))	('TBK1', 'Protein', (128, 132))	('phosphatase', 'molecular_function', 'GO:0016791', ('78', '89'))	('binding', 'molecular_function', 'GO:0005488', ('96', '103'))	('TBK1', 'molecular_function', 'GO:0008384', ('128', '132'))	('phosphorylation', 'biological_process', 'GO:0016310', ('133', '148'))	('decreased', 'NegReg', (118, 127))	('PPM1B', 'Gene', '5495', (90, 95))	('VHL', 'Gene', (59, 62))
206796	31810986	Inactivating VHL mutations also play major roles in sporadic kidney cell cancer.	('sporadic kidney cell cancer', 'Disease', (52, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('sporadic kidney cell cancer', 'Disease', 'MESH:D007680', (52, 79))	('Inactivating', 'Var', (0, 12))	('VHL', 'Gene', (13, 16))	('kidney cell cancer', 'Phenotype', 'HP:0005584', (61, 79))	('VHL', 'Gene', '7428', (13, 16))	('mutations', 'Var', (17, 26))
206805	31810986	Recent reports showed that the specific HIF2alpha inhibitor PT2399 inhibits primary tumor growth and invasion of a subset of kidney cancer.	('HIF2alpha', 'Gene', '2034', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('kidney cancer', 'Disease', 'MESH:D007680', (125, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('PT2399', 'Var', (60, 66))	('HIF2alpha', 'Gene', (40, 49))	('tumor', 'Disease', (84, 89))	('kidney cancer', 'Phenotype', 'HP:0009726', (125, 138))	('kidney cancer', 'Disease', (125, 138))	('inhibits', 'NegReg', (67, 75))	('PT2399', 'Chemical', 'MESH:C000614278', (60, 66))	('invasion', 'CPA', (101, 109))
206807	31810986	Tumor specific genetic alteration (such as VHL loss) reveals not only the biological changes that drive tumor progression but also vulnerabilities that can be exploited therapeutically.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('alteration', 'Var', (23, 33))	('tumor', 'Disease', (104, 109))	('VHL loss', 'Disease', 'MESH:D006623', (43, 51))	('VHL loss', 'Disease', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
206825	31810986	As a control, we depleted TBK1 in UMRC2 cells by specific sgRNA and found that TBK1 depletion led to decreased STING phosphorylation on Ser366 (Supplementary Fig.	('Ser366', 'Chemical', '-', (136, 142))	('depletion', 'Var', (84, 93))	('STING', 'Gene', (111, 116))	('phosphorylation', 'biological_process', 'GO:0016310', ('117', '132'))	('TBK1', 'Gene', (79, 83))	('decreased', 'NegReg', (101, 110))	('TBK1', 'molecular_function', 'GO:0008384', ('26', '30'))	('Ser', 'cellular_component', 'GO:0005790', ('136', '139'))	('UMRC2', 'CellLine', 'CVCL:2739', (34, 39))	('TBK1', 'molecular_function', 'GO:0008384', ('79', '83'))	('STING', 'Gene', '340061', (111, 116))
206828	31810986	Consistently, VHL depletion led to profound upregulation of p-TBK1 while not affecting total TBK1 levels (Fig.	('TBK1', 'molecular_function', 'GO:0008384', ('62', '66'))	('p-TBK1', 'Gene', (60, 66))	('TBK1', 'molecular_function', 'GO:0008384', ('93', '97'))	('upregulation', 'PosReg', (44, 56))	('depletion', 'Var', (18, 27))	('VHL', 'Gene', (14, 17))	('VHL', 'Gene', '7428', (14, 17))
206851	31810986	As an orthogonal approach, we also showed that TBK1 phosphorylation was upregulated in EglN1 knockout MEFs, but not in EglN2/3 knockout MEFs (Supplementary Fig.	('TBK1', 'Gene', (47, 51))	('EglN1', 'Gene', '54583', (87, 92))	('MEFs', 'CellLine', 'CVCL:9115', (102, 106))	('MEFs', 'CellLine', 'CVCL:9115', (136, 140))	('EglN2/3', 'Gene', (119, 126))	('upregulated', 'PosReg', (72, 83))	('EglN1', 'Gene', (87, 92))	('phosphorylation', 'biological_process', 'GO:0016310', ('52', '67'))	('EglN2/3', 'Gene', '112398;112399', (119, 126))	('phosphorylation', 'MPA', (52, 67))	('TBK1', 'molecular_function', 'GO:0008384', ('47', '51'))	('knockout', 'Var', (93, 101))
206854	31810986	Conversely, we also overexpressed EglN1 in Caki-1 cells and observed decreased TBK1 phosphorylation with wild type but not a catalytically dead EglN1 mutant (EglN1-CD, H374A/D376A) (Fig.1L).	('phosphorylation', 'MPA', (84, 99))	('H374A', 'SUBSTITUTION', 'None', (168, 173))	('Caki-1', 'CellLine', 'CVCL:0234', (43, 49))	('TBK1', 'molecular_function', 'GO:0008384', ('79', '83'))	('decreased', 'NegReg', (69, 78))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('TBK1', 'Gene', (79, 83))	('EglN1', 'Gene', (158, 163))	('EglN1', 'Gene', (144, 149))	('EglN1', 'Gene', (34, 39))	('H374A', 'Var', (168, 173))	('EglN1', 'Gene', '54583', (158, 163))	('D376A', 'SUBSTITUTION', 'None', (174, 179))	('EglN1', 'Gene', '54583', (144, 149))	('D376A', 'Var', (174, 179))	('EglN1', 'Gene', '54583', (34, 39))
206858	31810986	We then depleted EglN1 by two independent shRNAs and found that EglN1 depletion led to decreased binding between TBK1 and VHL, which corresponded with increased TBK1 phosphorylation (Fig.	('increased', 'PosReg', (151, 160))	('binding', 'molecular_function', 'GO:0005488', ('97', '104'))	('EglN1', 'Gene', '54583', (17, 22))	('decreased', 'NegReg', (87, 96))	('TBK1', 'molecular_function', 'GO:0008384', ('161', '165'))	('TBK1', 'Gene', (161, 165))	('EglN1', 'Gene', (64, 69))	('EglN1', 'Gene', (17, 22))	('VHL', 'Gene', (122, 125))	('binding', 'Interaction', (97, 104))	('VHL', 'Gene', '7428', (122, 125))	('depletion', 'Var', (70, 79))	('phosphorylation', 'MPA', (166, 181))	('TBK1', 'Gene', (113, 117))	('phosphorylation', 'biological_process', 'GO:0016310', ('166', '181'))	('EglN1', 'Gene', '54583', (64, 69))	('TBK1', 'molecular_function', 'GO:0008384', ('113', '117'))
206864	31810986	Next, we mutated TBK1 Proline 678 and 48 to Alanines (P678A, P48A).	('Proline 678', 'Var', (22, 33))	('Proline', 'Chemical', 'MESH:D011392', (22, 29))	('Alanines', 'Chemical', 'MESH:D000409', (44, 52))	('P678A', 'Mutation', 'p.P678A', (54, 59))	('P48A', 'Var', (61, 65))	('TBK1', 'Gene', (17, 21))	('P48A', 'Mutation', 'p.P48A', (61, 65))	('TBK1', 'molecular_function', 'GO:0008384', ('17', '21'))	('mutated', 'Reg', (9, 16))
206865	31810986	Whereas TBK1 WT or P678A mutant binds with VHL efficiently, P48A mutant displayed diminished binding with VHL confirmed by reciprocal immunoprecipitations (Fig.	('P678A', 'Mutation', 'p.P678A', (19, 24))	('P48A', 'Var', (60, 64))	('VHL', 'Gene', (43, 46))	('binding', 'molecular_function', 'GO:0005488', ('93', '100'))	('diminished', 'NegReg', (82, 92))	('TBK1', 'molecular_function', 'GO:0008384', ('8', '12'))	('VHL', 'Gene', '7428', (43, 46))	('binding', 'Interaction', (93, 100))	('binds', 'Interaction', (32, 37))	('P48A', 'Mutation', 'p.P48A', (60, 64))	('VHL', 'Gene', (106, 109))	('VHL', 'Gene', '7428', (106, 109))	('P678A', 'Var', (19, 24))
206870	31810986	Consistent with the notion that proline 48 is the major TBK1 hydroxylation site, pan-hydroxylation IP followed by FLAG immunoblot also confirmed that P48A mutant abrogated all hydroxylation signals present in WT TBK1 (Fig.	('abrogated', 'NegReg', (162, 171))	('TBK1', 'molecular_function', 'GO:0008384', ('212', '216'))	('P48A mutant', 'Var', (150, 161))	('hydroxylation signals', 'MPA', (176, 197))	('proline', 'Chemical', 'MESH:D011392', (32, 39))	('P48A', 'Mutation', 'p.P48A', (150, 154))	('TBK1', 'molecular_function', 'GO:0008384', ('56', '60'))
206871	31810986	To determine whether proline 48 site is the major site affecting TBK1 phosphorylation, we depleted endogenous TBK1 from UMRC2 cells and re-introduced either WT or P48A TBK1 into these cells (Fig.	('TBK1', 'molecular_function', 'GO:0008384', ('110', '114'))	('proline', 'Chemical', 'MESH:D011392', (21, 28))	('P48A', 'Mutation', 'p.P48A', (163, 167))	('UMRC2', 'CellLine', 'CVCL:2739', (120, 125))	('TBK1', 'molecular_function', 'GO:0008384', ('168', '172'))	('TBK1', 'Gene', (110, 114))	('TBK1', 'molecular_function', 'GO:0008384', ('65', '69'))	('phosphorylation', 'biological_process', 'GO:0016310', ('70', '85'))	('depleted', 'NegReg', (90, 98))	('P48A', 'Var', (163, 167))
206873	31810986	On the other hand, cells expressing TBK1 P48A mutant displayed constitutive TBK1 phosphorylation that is resistant towards VHL expression (Fig.	('TBK1', 'molecular_function', 'GO:0008384', ('76', '80'))	('phosphorylation', 'MPA', (81, 96))	('P48A', 'Var', (41, 45))	('VHL', 'Gene', (123, 126))	('TBK1', 'Gene', (76, 80))	('VHL', 'Gene', '7428', (123, 126))	('phosphorylation', 'biological_process', 'GO:0016310', ('81', '96'))	('TBK1', 'Gene', (36, 40))	('P48A', 'Mutation', 'p.P48A', (41, 45))	('TBK1', 'molecular_function', 'GO:0008384', ('36', '40'))
206874	31810986	It is important to note that TBK1 P48A mutant also showed higher TBK1 phosphorylation at the basal level despite a lower total TBK1 level.	('TBK1', 'molecular_function', 'GO:0008384', ('29', '33'))	('TBK1', 'molecular_function', 'GO:0008384', ('65', '69'))	('P48A', 'Var', (34, 38))	('TBK1 level', 'MPA', (127, 137))	('TBK1', 'Gene', (65, 69))	('TBK1', 'molecular_function', 'GO:0008384', ('127', '131'))	('lower', 'NegReg', (115, 120))	('phosphorylation', 'MPA', (70, 85))	('phosphorylation', 'biological_process', 'GO:0016310', ('70', '85'))	('higher', 'PosReg', (58, 64))	('TBK1', 'Gene', (29, 33))	('P48A', 'Mutation', 'p.P48A', (34, 38))
206876	31810986	On the other hand, TBK1 P48A mutant displayed constitutive upregulation of phosphorylation that was resistant to EglN1 depletion (Fig.	('P48A', 'Var', (24, 28))	('upregulation of phosphorylation', 'biological_process', 'GO:0042327', ('59', '90'))	('EglN1', 'Gene', (113, 118))	('TBK1', 'molecular_function', 'GO:0008384', ('19', '23'))	('upregulation', 'PosReg', (59, 71))	('EglN1', 'Gene', '54583', (113, 118))	('phosphorylation', 'MPA', (75, 90))	('TBK1', 'Gene', (19, 23))	('P48A', 'Mutation', 'p.P48A', (24, 28))
206878	31810986	We then examined the binding between EglN1 and TBK1-WT or P48A mutant and found that P48A could not bind with EglN1, suggesting that Proline 48 site is the major EglN1 hydroxylation site (Fig.	('EglN1', 'Gene', (110, 115))	('binding', 'Interaction', (21, 28))	('EglN1', 'Gene', (37, 42))	('Proline', 'Chemical', 'MESH:D011392', (133, 140))	('EglN1', 'Gene', '54583', (162, 167))	('P48A', 'Mutation', 'p.P48A', (85, 89))	('EglN1', 'Gene', '54583', (110, 115))	('P48A', 'Var', (58, 62))	('TBK1-WT', 'Gene', (47, 54))	('EglN1', 'Gene', '54583', (37, 42))	('EglN1', 'Gene', (162, 167))	('binding', 'molecular_function', 'GO:0005488', ('21', '28'))	('TBK1', 'molecular_function', 'GO:0008384', ('47', '51'))	('P48A', 'Mutation', 'p.P48A', (58, 62))
206879	31810986	Finally, VHL restored UMRC2 cells harboring TBK1-P48A mutant could form more colonies compared to cells harboring TBK1 WT in 3-D soft agar growth assay (Fig.	('TBK1', 'molecular_function', 'GO:0008384', ('44', '48'))	('colonies', 'CPA', (77, 85))	('agar', 'Chemical', 'MESH:D000362', (134, 138))	('VHL', 'Gene', (9, 12))	('TBK1', 'molecular_function', 'GO:0008384', ('114', '118'))	('UMRC2', 'CellLine', 'CVCL:2739', (22, 27))	('VHL', 'Gene', '7428', (9, 12))	('TBK1-P48A mutant', 'Var', (44, 60))	('P48A', 'Mutation', 'p.P48A', (49, 53))
206883	31810986	In summary, TBK1 is hydroxylated on Pro48 residue which promotes VHL binding and its decreased phosphorylation.	('VHL', 'Gene', '7428', (65, 68))	('decreased', 'NegReg', (85, 94))	('Pro48 residue', 'Var', (36, 49))	('binding', 'molecular_function', 'GO:0005488', ('69', '76'))	('phosphorylation', 'biological_process', 'GO:0016310', ('95', '110'))	('binding', 'Interaction', (69, 76))	('Pro48', 'Chemical', '-', (36, 41))	('TBK1', 'molecular_function', 'GO:0008384', ('12', '16'))	('promotes', 'PosReg', (56, 64))	('TBK1', 'Gene', (12, 16))	('VHL', 'Gene', (65, 68))	('phosphorylation', 'MPA', (95, 110))
206891	31810986	Next, we depleted VHL by two independent sgRNAs and found that VHL depletion led to decreased binding between TBK1 and PPM1B, which contributed to increased TBK1 phosphorylation (Fig.	('TBK1', 'Protein', (157, 161))	('VHL', 'Gene', '7428', (18, 21))	('TBK1', 'molecular_function', 'GO:0008384', ('110', '114'))	('depletion', 'Var', (67, 76))	('increased', 'PosReg', (147, 156))	('binding', 'molecular_function', 'GO:0005488', ('94', '101'))	('TBK1', 'molecular_function', 'GO:0008384', ('157', '161'))	('PPM1B', 'Gene', '5495', (119, 124))	('binding', 'Interaction', (94, 101))	('TBK1', 'Gene', (110, 114))	('phosphorylation', 'biological_process', 'GO:0016310', ('162', '177'))	('VHL', 'Gene', '7428', (63, 66))	('VHL', 'Gene', (63, 66))	('phosphorylation', 'MPA', (162, 177))	('PPM1B', 'Gene', (119, 124))	('decreased', 'NegReg', (84, 93))	('VHL', 'Gene', (18, 21))
206893	31810986	Since we showed that VHL loss led to TBK1 hyperactivation, we next aimed to see whether TBK1 depletion would cause synthetic lethality towards VHL null ccRCC cells.	('TBK1', 'Gene', (37, 41))	('VHL loss', 'Disease', 'MESH:D006623', (21, 29))	('VHL', 'Gene', '7428', (143, 146))	('VHL loss', 'Disease', (21, 29))	('TBK1', 'molecular_function', 'GO:0008384', ('37', '41'))	('VHL', 'Gene', (143, 146))	('VHL', 'Gene', (21, 24))	('TBK1', 'molecular_function', 'GO:0008384', ('88', '92'))	('hyperactivation', 'PosReg', (42, 57))	('depletion', 'Var', (93, 102))	('TBK1', 'Gene', (88, 92))	('VHL', 'Gene', '7428', (21, 24))
206897	31810986	Remarkably, TBK1 depletion led to profound cell proliferation defects in VHL null cells whereas VHL restored cells remained largely unaffected (Fig.	('VHL', 'Gene', (73, 76))	('TBK1', 'Gene', (12, 16))	('VHL', 'Gene', '7428', (73, 76))	('cell proliferation', 'biological_process', 'GO:0008283', ('43', '61'))	('depletion', 'Var', (17, 26))	('TBK1', 'molecular_function', 'GO:0008384', ('12', '16'))	('VHL', 'Gene', (96, 99))	('defects', 'NegReg', (62, 69))	('VHL', 'Gene', '7428', (96, 99))	('cell proliferation', 'CPA', (43, 61))
206901	31810986	To further determine whether the effect of TBK1 loss on these phenotypes was dependent on its enzymatic activity, we expressed TBK1 catalytically dead mutant K38A and found that this mutant displayed cell proliferation defects as compared to WT TBK1 (Supplementary Fig.	('TBK1', 'Gene', (43, 47))	('TBK1', 'Gene', (127, 131))	('cell proliferation', 'biological_process', 'GO:0008283', ('200', '218'))	('TBK1', 'molecular_function', 'GO:0008384', ('245', '249'))	('TBK1', 'molecular_function', 'GO:0008384', ('127', '131'))	('TBK1', 'molecular_function', 'GO:0008384', ('43', '47'))	('K38A', 'Mutation', 'p.K38A', (158, 162))	('mutant K38A', 'Var', (151, 162))	('cell proliferation defects', 'CPA', (200, 226))	('K38A', 'Var', (158, 162))
206904	31810986	We also found that these TBK1 inhibitors preferentially inhibited ccRCC cell growth when VHL is lost and they only modestly affected these cells upon VHL restoration (Supplementary Fig.	('TBK1', 'molecular_function', 'GO:0008384', ('25', '29'))	('TBK1', 'Gene', (25, 29))	('inhibitors', 'Var', (30, 40))	('VHL', 'Gene', (89, 92))	('VHL', 'Gene', (150, 153))	('cell growth', 'biological_process', 'GO:0016049', ('72', '83'))	('VHL', 'Gene', '7428', (150, 153))	('VHL', 'Gene', '7428', (89, 92))	('inhibited', 'NegReg', (56, 65))	('ccRCC', 'Disease', (66, 71))
206911	31810986	Treatment with UNC6587 efficiently eliminated TBK1 protein levels in ccRCC cells, while not affecting its close family member IKKepsilon (Supplementary Fig.	('IKKepsilon', 'Gene', '9641', (126, 136))	('protein levels', 'MPA', (51, 65))	('TBK1', 'molecular_function', 'GO:0008384', ('46', '50'))	('UNC6587', 'Chemical', '-', (15, 22))	('IKKepsilon', 'Gene', (126, 136))	('eliminated', 'NegReg', (35, 45))	('TBK1', 'Gene', (46, 50))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))	('UNC6587', 'Var', (15, 22))
206913	31810986	S6D), TBK1 degradation only caused cell growth defect on 3-D soft agar in VHL null cells (Fig.	('growth defect', 'Disease', 'MESH:D006130', (40, 53))	('degradation', 'Var', (11, 22))	('VHL', 'Gene', (74, 77))	('degradation', 'biological_process', 'GO:0009056', ('11', '22'))	('TBK1', 'Gene', (6, 10))	('VHL', 'Gene', '7428', (74, 77))	('growth defect', 'Disease', (40, 53))	('agar', 'Chemical', 'MESH:D000362', (66, 70))	('TBK1', 'molecular_function', 'GO:0008384', ('6', '10'))	('cell growth', 'biological_process', 'GO:0016049', ('35', '46'))
206914	31810986	S6E and S6F), while leaving VHL WT cells unaffected.	('VHL', 'Gene', (28, 31))	('S6F', 'Var', (8, 11))	('VHL', 'Gene', '7428', (28, 31))
206918	31810986	TBK1 depletion led to decreased cell proliferation and reduced soft-agar growth upon doxycycline addition (Fig.	('cell proliferation', 'biological_process', 'GO:0008283', ('32', '50'))	('depletion', 'Var', (5, 14))	('agar', 'Chemical', 'MESH:D000362', (68, 72))	('TBK1', 'molecular_function', 'GO:0008384', ('0', '4'))	('reduced', 'NegReg', (55, 62))	('TBK1', 'Gene', (0, 4))	('doxycycline', 'Chemical', 'MESH:D004318', (85, 96))	('soft-agar growth', 'CPA', (63, 79))	('cell proliferation', 'CPA', (32, 50))	('decreased', 'NegReg', (22, 31))
206922	31810986	Lung ex vivo imaging data showed that depletion of TBK1 also inhibited tumor cells' spontaneous lung metastasis (Fig.	('TBK1', 'molecular_function', 'GO:0008384', ('51', '55'))	('inhibited', 'NegReg', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('TBK1', 'Gene', (51, 55))	('depletion', 'Var', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
206926	31810986	8 out of 18 tumors were confirmed by sequencing that contain VHL mutations or splice variants.	('mutations', 'Var', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('VHL', 'Gene', (61, 64))	('tumors', 'Disease', (12, 18))	('VHL', 'Gene', '7428', (61, 64))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('splice variants', 'Var', (78, 93))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
206929	31810986	To validate this finding in large clinical cohorts, we also obtained two sets of ccRCC tissue microarrays (TMAs) and stained these TMAs with TBK1 and p-TBK1 with immunohistochemistry (IHC).	('p-TBK1', 'Var', (150, 156))	('TBK1', 'molecular_function', 'GO:0008384', ('141', '145'))	('TBK1', 'molecular_function', 'GO:0008384', ('152', '156'))	('TBK1', 'Gene', (141, 145))	('TMA', 'Chemical', '-', (107, 110))	('TMA', 'Chemical', '-', (131, 134))
206930	31810986	By calculating the ratio between p-TBK1 and TBK1, there was significant upregulation of p-TBK1 in ccRCC tumors compared to normal in both TMA sets, which was reflected by both representative IHC images and quantitative analyses (Fig.	('ccRCC tumors', 'Disease', 'MESH:D009369', (98, 110))	('TBK1', 'molecular_function', 'GO:0008384', ('44', '48'))	('TBK1', 'molecular_function', 'GO:0008384', ('35', '39'))	('upregulation', 'PosReg', (72, 84))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('ccRCC tumors', 'Disease', (98, 110))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('p-TBK1', 'Var', (88, 94))	('TMA', 'Chemical', '-', (138, 141))	('TBK1', 'molecular_function', 'GO:0008384', ('90', '94'))
206931	31810986	Annotation information suggested that all tumor samples, except one from TMA2, are ccRCC, which may contain up to 85% of VHL mutations.	('VHL', 'Gene', '7428', (121, 124))	('mutations', 'Var', (125, 134))	('tumor', 'Disease', (42, 47))	('ccRCC', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('TMA', 'Chemical', '-', (73, 76))	('VHL', 'Gene', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
206939	31810986	Since Akt is another TBK1 substrate which plays oncogenic function, we also examined Akt activity by detecting its phosphorylation on Ser473 and Thr308.	('activity', 'MPA', (89, 97))	('TBK1', 'molecular_function', 'GO:0008384', ('21', '25'))	('Akt', 'Gene', '207', (85, 88))	('Ser473', 'Var', (134, 140))	('phosphorylation', 'biological_process', 'GO:0016310', ('115', '130'))	('Ser', 'cellular_component', 'GO:0005790', ('134', '137'))	('Akt', 'Gene', (85, 88))	('Akt', 'Gene', '207', (6, 9))	('Thr308', 'Chemical', '-', (145, 151))	('Ser473', 'Chemical', '-', (134, 140))	('phosphorylation', 'MPA', (115, 130))	('examined', 'Reg', (76, 84))	('Akt', 'Gene', (6, 9))	('Thr308', 'Var', (145, 151))
206940	31810986	Our result suggested phosphorylation of Akt Ser473 and Thr308 was not decreased upon TBK1 depletion (Supplementary Fig.	('Akt', 'Gene', '207', (40, 43))	('TBK1', 'Gene', (85, 89))	('Ser473', 'Var', (44, 50))	('phosphorylation', 'MPA', (21, 36))	('Akt', 'Gene', (40, 43))	('Thr308', 'Chemical', '-', (55, 61))	('phosphorylation', 'biological_process', 'GO:0016310', ('21', '36'))	('Ser473', 'Chemical', '-', (44, 50))	('Ser', 'cellular_component', 'GO:0005790', ('44', '47'))	('depletion', 'Var', (90, 99))	('TBK1', 'molecular_function', 'GO:0008384', ('85', '89'))
206941	31810986	To this end, we performed an unbiased phospho-proteomic screen using UMRC2 cells treated with the specific TBK1 inhibitor CMPD1 for 0, 15min, 1hr and 3 hrs (Fig.	('CMPD', 'Disease', (122, 126))	('inhibitor', 'Var', (112, 121))	('TBK1', 'molecular_function', 'GO:0008384', ('107', '111'))	('CMPD', 'Disease', 'MESH:D055036', (122, 126))	('TBK1', 'Gene', (107, 111))	('UMRC2', 'CellLine', 'CVCL:2739', (69, 74))
206947	31810986	It is interesting to point out that another phosphorylation site on p62 (Ser403) indicated previously in innate immune signaling was not recovered in our list, suggesting the context dependent p62 phosphorylation in innate immunity versus certain cancer settings.	('p62', 'Gene', (68, 71))	('phosphorylation', 'biological_process', 'GO:0016310', ('44', '59'))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('Ser403', 'Chemical', '-', (73, 79))	('phosphorylation', 'biological_process', 'GO:0016310', ('197', '212'))	('phosphorylation', 'Var', (197, 212))	('p62', 'Gene', '8878', (193, 196))	('Ser', 'cellular_component', 'GO:0005790', ('73', '76'))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('p62', 'Gene', (193, 196))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))	('p62', 'Gene', '8878', (68, 71))	('innate immunity', 'biological_process', 'GO:0045087', ('216', '231'))
206948	31810986	Therefore, we decided to pursue the potential role of p62 as a novel TBK1 substrate and its phosphorylation (Ser366) in kidney cancer.	('Ser366', 'Var', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('TBK1', 'molecular_function', 'GO:0008384', ('69', '73'))	('kidney cancer', 'Disease', (120, 133))	('phosphorylation', 'biological_process', 'GO:0016310', ('92', '107'))	('p62', 'Gene', '8878', (54, 57))	('Ser', 'cellular_component', 'GO:0005790', ('109', '112'))	('p62', 'Gene', (54, 57))	('Ser366', 'Chemical', '-', (109, 115))	('kidney cancer', 'Phenotype', 'HP:0009726', (120, 133))	('kidney cancer', 'Disease', 'MESH:D007680', (120, 133))
206955	31810986	p62 upregulation induced by TBK1 is dependent on TBK1 enzymatic activity since the TBK1 catalytic dead mutant K38A failed to induce p62 upregulation (Supplementary Fig.	('K38A', 'Var', (110, 114))	('TBK1', 'molecular_function', 'GO:0008384', ('28', '32'))	('p62', 'Gene', '8878', (0, 3))	('TBK1', 'molecular_function', 'GO:0008384', ('83', '87'))	('p62', 'Gene', (0, 3))	('p62', 'Gene', '8878', (132, 135))	('TBK1', 'molecular_function', 'GO:0008384', ('49', '53'))	('p62', 'Gene', (132, 135))	('K38A', 'Mutation', 'p.K38A', (110, 114))	('upregulation', 'PosReg', (4, 16))
206956	31810986	Conversely, TBK1 depletion in several ccRCC cell lines (786-O, UMRC2 and UMRC6) all led to decreased p62 protein levels (Fig.	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('UMRC6', 'CellLine', 'CVCL:2741', (73, 78))	('depletion', 'Var', (17, 26))	('TBK1', 'molecular_function', 'GO:0008384', ('12', '16'))	('p62', 'Gene', '8878', (101, 104))	('UMRC2', 'CellLine', 'CVCL:2739', (63, 68))	('TBK1', 'Gene', (12, 16))	('p62', 'Gene', (101, 104))	('decreased', 'NegReg', (91, 100))
206962	31810986	Next, to examine whether p62 Ser366 phosphorylation is important for mediating TBK1 knockdown induced phenotype, we overexpressed p62 S366A or S366D in TBK1 sgRNA infected cells and found that p62 S366D could efficiently rescue TBK1 depletion induced cell proliferation defect but S366A couldn't (Fig.	('TBK1', 'molecular_function', 'GO:0008384', ('228', '232'))	('TBK1', 'molecular_function', 'GO:0008384', ('152', '156'))	('S366A', 'Mutation', 'p.S366A', (281, 286))	('cell proliferation defect', 'CPA', (251, 276))	('Ser', 'cellular_component', 'GO:0005790', ('29', '32'))	('TBK1', 'molecular_function', 'GO:0008384', ('79', '83'))	('phosphorylation', 'biological_process', 'GO:0016310', ('36', '51'))	('Ser366', 'Chemical', '-', (29, 35))	('infected', 'Disease', 'MESH:D007239', (163, 171))	('S366A', 'Var', (281, 286))	('infected', 'Disease', (163, 171))	('cell proliferation', 'biological_process', 'GO:0008283', ('251', '269'))	('S366D', 'Mutation', 'p.S366D', (143, 148))	('p62', 'Gene', '8878', (193, 196))	('S366D', 'Var', (143, 148))	('p62', 'Gene', (193, 196))	('S366A', 'Mutation', 'p.S366A', (134, 139))	('S366D', 'Mutation', 'p.S366D', (197, 202))	('TBK1', 'Gene', (228, 232))	('p62', 'Gene', '8878', (130, 133))	('p62', 'Gene', '8878', (25, 28))	('p62', 'Gene', (130, 133))	('p62', 'Gene', (25, 28))
206966	31810986	S10A and S10B; Supplementary Table S1).	('S10B', 'SUBSTITUTION', 'None', (9, 13))	('S10A', 'SUBSTITUTION', 'None', (0, 4))	('S10B', 'Var', (9, 13))	('S10A', 'Var', (0, 4))
206967	31810986	We then performed correlation analysis but failed to see significant correlation between p-TBK1/TBK1 ratio and p62 protein level.	('TBK1', 'molecular_function', 'GO:0008384', ('96', '100'))	('p62', 'Gene', '8878', (111, 114))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('p62', 'Gene', (111, 114))	('TBK1', 'molecular_function', 'GO:0008384', ('91', '95'))	('p-TBK1/TBK1', 'Var', (89, 100))
206973	31810986	However, it does not rule out the possibility that TBK1 phosphorylation may also contribute to other pathway activation beside p62 that will coordinate with 5q gain to increase kidney tumorigenesis, which will be investigated in future research.	('increase', 'PosReg', (168, 176))	('increase kidney', 'Phenotype', 'HP:0000105', (168, 183))	('TBK1', 'molecular_function', 'GO:0008384', ('51', '55'))	('phosphorylation', 'biological_process', 'GO:0016310', ('56', '71'))	('p62', 'Gene', '8878', (127, 130))	('kidney tumor', 'Disease', 'MESH:D007680', (177, 189))	('phosphorylation', 'Var', (56, 71))	('p62', 'Gene', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('kidney tumor', 'Phenotype', 'HP:0009726', (177, 189))	('TBK1', 'Gene', (51, 55))	('5q', 'Chemical', '-', (157, 159))	('kidney tumor', 'Disease', (177, 189))
206974	31810986	Taken together, our results provide novel mechanistic insight by which TBK1 hyperactivation promotes p62 phosphorylation on Ser366, which lead to upregulation of total and phosphorylation of p62 therefore contributing to ccRCC tumorigenesis.	('Ser', 'cellular_component', 'GO:0005790', ('124', '127'))	('ccRCC tumor', 'Disease', (221, 232))	('promotes', 'PosReg', (92, 100))	('phosphorylation', 'biological_process', 'GO:0016310', ('172', '187'))	('p62', 'Gene', '8878', (101, 104))	('ccRCC tumor', 'Disease', 'MESH:D009369', (221, 232))	('p62', 'Gene', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('TBK1', 'Gene', (71, 75))	('phosphorylation', 'MPA', (172, 187))	('Ser366', 'Chemical', '-', (124, 130))	('contributing', 'Reg', (205, 217))	('hyperactivation', 'Var', (76, 91))	('TBK1', 'molecular_function', 'GO:0008384', ('71', '75'))	('upregulation', 'PosReg', (146, 158))	('total', 'MPA', (162, 167))	('phosphorylation on Ser366', 'MPA', (105, 130))	('p62', 'Gene', '8878', (191, 194))	('p62', 'Gene', (191, 194))	('phosphorylation', 'biological_process', 'GO:0016310', ('105', '120'))
206991	31810986	It is interesting that the inhibitors that leads to increased autophagy caused lethality in VHL null ccRCC cells.	('lethality', 'CPA', (79, 88))	('autophagy', 'CPA', (62, 71))	('increased', 'PosReg', (52, 61))	('VHL', 'Gene', (92, 95))	('inhibitors', 'Var', (27, 37))	('VHL', 'Gene', '7428', (92, 95))	('autophagy', 'biological_process', 'GO:0016236', ('62', '71'))	('autophagy', 'biological_process', 'GO:0006914', ('62', '71'))
206995	31810986	Now at least seven distinct small molecules are known to inhibit TBK1 activity including BX795, compound II, CYT387 (momelotinib), MRT67307, GSK2292978A, amlexanox and CMPD1.	('GSK', 'molecular_function', 'GO:0050321', ('141', '144'))	('GSK2292978A', 'Var', (141, 152))	('activity', 'MPA', (70, 78))	('momelotinib', 'Chemical', 'MESH:C546012', (117, 128))	('MRT67307', 'Var', (131, 139))	('GSK2292978A', 'Chemical', '-', (141, 152))	('CYT387', 'Chemical', 'MESH:C546012', (109, 115))	('TBK1', 'molecular_function', 'GO:0008384', ('65', '69'))	('TBK1', 'Gene', (65, 69))	('inhibit', 'NegReg', (57, 64))	('CYT387', 'Var', (109, 115))	('CMPD', 'Disease', (168, 172))	('CMPD', 'Disease', 'MESH:D055036', (168, 172))	('amlexanox', 'Chemical', 'MESH:C045742', (154, 163))
206996	31810986	For example, BX-795 has been reported to inhibit other kinases including PDK1.	('PDK1', 'Gene', '5163', (73, 77))	('PDK1', 'Gene', (73, 77))	('inhibit', 'NegReg', (41, 48))	('BX-795', 'Var', (13, 19))	('PDK1', 'molecular_function', 'GO:0004740', ('73', '77'))
206997	31810986	MRT67307 may also inhibit ULK1/2 and block autophagy.	('inhibit', 'NegReg', (18, 25))	('autophagy', 'biological_process', 'GO:0006914', ('43', '52'))	('ULK1/2', 'Gene', (26, 32))	('ULK1/2', 'Gene', '8408;9706', (26, 32))	('autophagy', 'CPA', (43, 52))	('block', 'NegReg', (37, 42))	('autophagy', 'biological_process', 'GO:0016236', ('43', '52'))	('MRT67307', 'Var', (0, 8))
207002	31810986	Recent reports have shown that depletion of TBK1 can boost the efficacy of immune checkpoint inhibitors in cancers.	('TBK1', 'molecular_function', 'GO:0008384', ('44', '48'))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('boost', 'PosReg', (53, 58))	('efficacy', 'MPA', (63, 71))	('immune', 'Protein', (75, 81))	('depletion', 'Var', (31, 40))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('TBK1', 'Gene', (44, 48))
207003	31810986	Therefore, it is likely that by targeting TBK1 kinase, not only can we inhibit the tumor cell autonomous signaling, but also can boost the immunotherapy efficacy in kidney cancer.	('kidney cancer', 'Disease', 'MESH:D007680', (165, 178))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('targeting', 'Var', (32, 41))	('inhibit', 'NegReg', (71, 78))	('kidney cancer', 'Disease', (165, 178))	('tumor', 'Disease', (83, 88))	('immunotherapy efficacy', 'CPA', (139, 161))	('TBK1', 'Gene', (42, 46))	('boost', 'PosReg', (129, 134))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('kidney cancer', 'Phenotype', 'HP:0009726', (165, 178))	('TBK1', 'molecular_function', 'GO:0008384', ('42', '46'))
207007	31810986	Rabbit anti TBK1 (3504), rabbit anti TBK1 phospho-Ser172 (pTBK1, 5483), rabbit anti IKKepsilon (2905), rabbit anti IKKepsilon phospho-Ser172 (pIKKepsilon, 8766), rabbit anti STING (13647), rabbit anti STING phosphor-Ser366 (19781), rabbit anti VHL (68547), rabbit anti EglN1 (3293), rabbit anti HIF1alpha (3716), rabbit anti p62 (39749), rabbit anti GST (2625), rabbit anti HA tag (3724), rabbit anti FLAG tag (14793), rabbit anti cleaved-caspase3 (9664), mouse anti alpha-Tubulin (3873) were from Cell Signaling Technology.	('STING', 'Gene', (174, 179))	('Ser', 'cellular_component', 'GO:0005790', ('216', '219'))	('14793', 'Var', (411, 416))	('Ser366', 'Chemical', '-', (216, 222))	('STING', 'Gene', '340061', (174, 179))	('Ser', 'cellular_component', 'GO:0005790', ('134', '137'))	('Ser172', 'Chemical', '-', (134, 140))	('IKKepsilon', 'Gene', (143, 153))	('VHL', 'Gene', (244, 247))	('IKKepsilon', 'Gene', (84, 94))	('IKKepsilon', 'Gene', '9641', (143, 153))	('HIF1alpha', 'Gene', '3091', (295, 304))	('alpha-Tubulin', 'Gene', '10376', (467, 480))	('EglN1', 'Gene', '54583', (269, 274))	('TBK1', 'molecular_function', 'GO:0008384', ('37', '41'))	('IKKepsilon', 'Gene', '9641', (84, 94))	('IKKepsilon', 'Gene', (115, 125))	('HIF1alpha', 'Gene', (295, 304))	('VHL', 'Gene', '7428', (244, 247))	('STING', 'Gene', (201, 206))	('IKKepsilon', 'Gene', '9641', (115, 125))	('TBK1', 'molecular_function', 'GO:0008384', ('12', '16'))	('Ser', 'cellular_component', 'GO:0005790', ('50', '53'))	('EglN1', 'Gene', (269, 274))	('STING', 'Gene', '340061', (201, 206))	('alpha-Tubulin', 'Gene', (467, 480))	('p62', 'Gene', '8878', (325, 328))	('Ser172', 'Chemical', '-', (50, 56))	('Signaling', 'biological_process', 'GO:0023052', ('503', '512'))	('pIKKepsilon', 'Disease', 'None', (142, 153))	('p62', 'Gene', (325, 328))	('pIKKepsilon', 'Disease', (142, 153))
207010	31810986	DMOG (D1070-1g) was from Frontier Scientific, Deferoxamine (DFO) (D9533-1G), BX-795 (204001-10mg), MRT67307 (506306-5mg) and Bafilomycin-A1 (BA1, B1793) were from Millipore-Sigma, FG4592 (15294-25mg) was from Cayman Chemical.	('Deferoxamine', 'Chemical', 'MESH:D003676', (46, 58))	('MRT67307 (506306-5mg', 'Var', (99, 119))	('BX-795', 'Var', (77, 83))	('D9533-1G', 'Var', (66, 74))	('DMOG', 'Chemical', '-', (0, 4))	('BA1', 'Chemical', 'MESH:C040929', (141, 144))	('FG4592', 'Chemical', 'MESH:C584543', (180, 186))	('Bafilomycin', 'Chemical', '-', (125, 136))	('DFO', 'Chemical', 'MESH:D003676', (60, 63))
207078	32231726	Result showed that the fraction of dendritic cells resting, mast cells resting, monocytes, T cells CD4+ memory resting decreased with the increasing Fuhrman grade, whereas the fraction of T cells CD8+, T cells follicular helper, T cells regulatory (Tregs) and Macrophages M0 increased with the elevated Fuhrman grade (Figure 5; Supplementary Table 1).	('decreased', 'NegReg', (119, 128))	('CD8', 'Gene', (196, 199))	('CD8', 'Gene', '925', (196, 199))	('memory', 'biological_process', 'GO:0007613', ('104', '110'))	('CD4', 'Gene', (99, 102))	('memory resting decreased', 'Phenotype', 'HP:0002354', (104, 128))	('Fuhrman', 'Var', (149, 156))	('CD4', 'Gene', '920', (99, 102))
207119	30113474	For example, in ccRCC, overexpression of FABP7 reportedly promotes cell growth and predicts poor outcome, high RAB25 expression is associated with poor survival, and enhanced CX3CR1 expression promotes migration and proliferation.	('RAB25', 'Gene', '57111', (111, 116))	('enhanced', 'PosReg', (166, 174))	('CX3CR1', 'Gene', '1524', (175, 181))	('promotes', 'PosReg', (193, 201))	('CX3CR1', 'Gene', (175, 181))	('ccRCC', 'Phenotype', 'HP:0006770', (16, 21))	('RAB25', 'Gene', (111, 116))	('RCC', 'Disease', (18, 21))	('RCC', 'Phenotype', 'HP:0005584', (18, 21))	('expression', 'MPA', (117, 127))	('FABP7', 'Gene', (41, 46))	('promotes', 'PosReg', (58, 66))	('proliferation', 'CPA', (216, 229))	('RCC', 'Disease', 'MESH:C538614', (18, 21))	('overexpression', 'PosReg', (23, 37))	('migration', 'CPA', (202, 211))	('FABP7', 'Gene', '2173', (41, 46))	('cell growth', 'CPA', (67, 78))	('high', 'Var', (106, 110))	('cell growth', 'biological_process', 'GO:0016049', ('67', '78'))
207192	27658636	Solid tumors, in particular, develop oxygen/nutrient deprived microenvironments as cancer cells outgrow O2 supply via native blood vessels, and aberrant angiogenic signaling disrupts normal blood vessel recruitment.	('O2', 'Chemical', 'MESH:D010100', (104, 106))	('disrupts', 'NegReg', (174, 182))	('aberrant', 'Var', (144, 152))	('outgrow', 'PosReg', (96, 103))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('normal', 'MPA', (183, 189))	('iron', 'Chemical', 'MESH:D007501', (70, 74))	('angiogenic signaling', 'CPA', (153, 173))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('signaling', 'biological_process', 'GO:0023052', ('164', '173'))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('oxygen', 'Chemical', 'MESH:D010100', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('cancer', 'Disease', (83, 89))
207198	27658636	However, this is almost certainly too simple, as it fails to account for (1) differential oncogenic and tumor suppressor effects downstream of HIF expression in specific cancer types, (2) the paucity of activating HIF mutations in human cancers, (3) a lack of universal concordance between patterns of HIF protein expression and measurable hypoxia in solid tumors, and (4) basal HIF accumulation in many cancer cell lines under atmospheric conditions.	('solid tumors', 'Disease', 'MESH:D009369', (351, 363))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Disease', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (404, 410))	('tumors', 'Phenotype', 'HP:0002664', (357, 363))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('human', 'Species', '9606', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('104', '120'))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('cancers', 'Disease', (237, 244))	('cancer', 'Disease', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('tumor suppressor', 'biological_process', 'GO:0051726', ('104', '120'))	('HIF accumulation', 'Disease', 'MESH:C579880', (379, 395))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Disease', (104, 109))	('cancer', 'Disease', (404, 410))	('hypoxia', 'Disease', (340, 347))	('solid tumors', 'Disease', (351, 363))	('protein', 'cellular_component', 'GO:0003675', ('306', '313'))	('cancer', 'Phenotype', 'HP:0002664', (404, 410))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumor', 'Disease', (357, 362))	('mutations', 'Var', (218, 227))	('HIF accumulation', 'Disease', (379, 395))	('hypoxia', 'Disease', 'MESH:D000860', (340, 347))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancers', 'Disease', 'MESH:D009369', (237, 244))	('tumor', 'Disease', 'MESH:D009369', (357, 362))
207200	27658636	), as well as genetic alterations in signaling (oncogene/tumor suppressor) pathways that create a background context for HIF function.	('genetic alterations', 'Var', (14, 33))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('57', '73'))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('signaling', 'biological_process', 'GO:0023052', ('37', '46'))	('tumor', 'Disease', (57, 62))	('tumor suppressor', 'biological_process', 'GO:0051726', ('57', '73'))
207210	27658636	via activating mutations in Ras), HIF suppresses oxidative stress through a variety of mechanisms: for example, HIF-1alpha induces the expression of pyruvate dehydrogenase kinase 1 (PDK1), which phosphorylates and inhibits mitochondrial pyruvate dehydrogenase (PDH).	('pyruvate dehydrogenase', 'Gene', (237, 259))	('Ras', 'Gene', (28, 31))	('pyruvate dehydrogenase', 'Gene', '54704', (149, 171))	('pyruvate dehydrogenase kinase 1', 'Gene', '5163', (149, 180))	('PDH', 'Gene', (261, 264))	('PDK1', 'Gene', (182, 186))	('inhibits', 'NegReg', (214, 222))	('PDH', 'molecular_function', 'GO:0004246', ('261', '264'))	('HIF-1alpha', 'Gene', '3091', (112, 122))	('PDK1', 'molecular_function', 'GO:0004740', ('182', '186'))	('mutations', 'Var', (15, 24))	('PDH', 'molecular_function', 'GO:0033718', ('261', '264'))	('expression', 'MPA', (135, 145))	('oxidative stress', 'MPA', (49, 65))	('PDK1', 'Gene', '5163', (182, 186))	('PDH', 'molecular_function', 'GO:0004739', ('261', '264'))	('HIF-1alpha', 'Gene', (112, 122))	('suppresses', 'NegReg', (38, 48))	('PDH', 'Gene', '54704', (261, 264))	('induces', 'PosReg', (123, 130))	('pyruvate dehydrogenase kinase 1', 'Gene', (149, 180))	('oxidative stress', 'Phenotype', 'HP:0025464', (49, 65))	('pyruvate dehydrogenase', 'Gene', '54704', (237, 259))
207212	27658636	Inhibiting HIF-mediated PDK1 expression increases mitochondrial NADH levels, flux through the ETC, and formation of toxic ROS.	('Inhibiting', 'Var', (0, 10))	('ROS', 'Chemical', 'MESH:D017382', (122, 125))	('flux through the ETC', 'MPA', (77, 97))	('PDK1', 'Gene', '5163', (24, 28))	('PDK1', 'molecular_function', 'GO:0004740', ('24', '28'))	('PDK1', 'Gene', (24, 28))	('formation', 'biological_process', 'GO:0009058', ('103', '112'))	('mitochondrial NADH levels', 'MPA', (50, 75))	('NADH', 'Chemical', 'MESH:D009243', (64, 68))	('increases', 'PosReg', (40, 49))	('formation of toxic ROS', 'MPA', (103, 125))
207219	27658636	Similarly, HIF-1alpha induced expression of NDUFA4L2 inhibits ETC Complex I activity and reduces O2 consumption and ROS production.	('ROS production', 'MPA', (116, 130))	('Complex I', 'cellular_component', 'GO:0030964', ('66', '75'))	('ROS', 'Chemical', 'MESH:D017382', (116, 119))	('activity', 'MPA', (76, 84))	('NDUFA4L2', 'Gene', '56901', (44, 52))	('expression', 'Var', (30, 40))	('O2', 'Chemical', 'MESH:D010100', (97, 99))	('O2 consumption', 'MPA', (97, 111))	('HIF-1alpha', 'Gene', '3091', (11, 21))	('NDUFA4L2', 'Gene', (44, 52))	('inhibits', 'NegReg', (53, 61))	('reduces', 'NegReg', (89, 96))	('ETC Complex I', 'Enzyme', (62, 75))	('HIF-1alpha', 'Gene', (11, 21))
207245	27658636	Surprisingly, however, catalytically inert FBP1 mutant protein also suppresses ccRCC growth in a HIF-dependent manner.	('mutant', 'Var', (48, 54))	('FBP1', 'Gene', (43, 47))	('suppresses', 'NegReg', (68, 78))	('protein', 'Protein', (55, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('ccRCC', 'Disease', (79, 84))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('FBP1', 'Gene', '2203', (43, 47))
207247	27658636	Silencing FBP1 expression therefore results in elevated HIF activity, with consequent effects on glycolysis, PPP flux, and proliferation, and appears to be a critical step in ccRCC etiology.	('effects', 'Reg', (86, 93))	('proliferation', 'CPA', (123, 136))	('PPP flux', 'MPA', (109, 117))	('FBP1', 'Gene', '2203', (10, 14))	('HIF activity', 'MPA', (56, 68))	('glycolysis', 'MPA', (97, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (175, 180))	('elevated', 'PosReg', (47, 55))	('ccRCC', 'Disease', (175, 180))	('FBP1', 'Gene', (10, 14))	('Silencing', 'Var', (0, 9))	('glycolysis', 'biological_process', 'GO:0006096', ('97', '107'))
207249	27658636	For example, mutations in genes encoding fumarate hydratase (FH) or succinate dehydrogenase (SDH) are associated with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) or hereditary paraganglioma/pheochomocytoma syndrome, respectively.	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('associated', 'Reg', (102, 112))	('SDH', 'Gene', (93, 96))	('succinate dehydrogenase', 'Gene', (68, 91))	('SDH', 'Gene', '6390', (93, 96))	('hereditary leiomyomatosis and renal cell carcinoma', 'Disease', 'MESH:C535516', (118, 168))	('hereditary paraganglioma/pheochomocytoma syndrome', 'Disease', (180, 229))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (148, 168))	('hereditary paraganglioma/pheochomocytoma syndrome', 'Disease', 'MESH:D010235', (180, 229))	('fumarate hydratase', 'Gene', '2271', (41, 59))	('FH', 'Gene', '2271', (61, 63))	('fumarate hydratase', 'Gene', (41, 59))	('mutations', 'Var', (13, 22))	('paraganglioma', 'Phenotype', 'HP:0002668', (191, 204))	('succinate dehydrogenase', 'Gene', '6390', (68, 91))
207254	27658636	For example, mice with engineered fumurate hydratase (FH) mutations develop renal cysts; however, HIFs appear to be dispensable for cyst formation, whereas antioxidant signaling by Nrf2 plays a critical role.	('signaling', 'biological_process', 'GO:0023052', ('168', '177'))	('mutations', 'Var', (58, 67))	('mice', 'Species', '10090', (13, 17))	('Nrf2', 'Gene', '18024', (181, 185))	('formation', 'biological_process', 'GO:0009058', ('137', '146'))	('Nrf2', 'Gene', (181, 185))	('FH', 'Gene', '2271', (54, 56))	('renal cysts', 'Phenotype', 'HP:0000107', (76, 87))	('renal cysts', 'CPA', (76, 87))	('develop', 'PosReg', (68, 75))
207258	27658636	Finally, mutations in genes encoding the isocitrate dehydrogenases IDH1 and IDH2 lead to accumulation of the novel "oncometabolite" 2-hydroxyglutarate (2-HG), which inhibits TET2, and JMJD2A, and alters epigenetic gene regulation in gliomas, AML, and other tumor types.	('JMJD2A', 'Gene', (184, 190))	('mutations', 'Var', (9, 18))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (132, 150))	('alters', 'Reg', (196, 202))	('IDH1', 'Gene', '3417', (67, 71))	('gliomas', 'Disease', (233, 240))	('epigenetic gene regulation', 'MPA', (203, 229))	('tumor', 'Disease', (257, 262))	('isocitrate', 'Chemical', 'MESH:C034219', (41, 51))	('inhibits', 'NegReg', (165, 173))	('regulation', 'biological_process', 'GO:0065007', ('217', '227'))	('TET2', 'Gene', '54790', (174, 178))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('gliomas', 'Disease', 'MESH:D005910', (233, 240))	('IDH2', 'Gene', (76, 80))	('accumulation', 'PosReg', (89, 101))	('IDH2', 'Gene', '3418', (76, 80))	('gliomas', 'Phenotype', 'HP:0009733', (233, 240))	('JMJD2A', 'Gene', '9682', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('AML', 'Disease', 'MESH:D015470', (242, 245))	('AML', 'Disease', (242, 245))	('IDH1', 'Gene', (67, 71))	('TET2', 'Gene', (174, 178))
207284	27658636	Thus, changes in intracellular biochemical pathways downstream of low O2 are both HIF-dependent and HIF-independent.	('O2', 'Chemical', 'MESH:D010100', (70, 72))	('intracellular biochemical pathways', 'Pathway', (17, 51))	('changes', 'Reg', (6, 13))	('low O2', 'Var', (66, 72))	('intracellular', 'cellular_component', 'GO:0005622', ('17', '30'))
207302	27658636	As stated above, mutations in the genes encoding IDH1 and IDH2 have been documented in multiple malignancies.	('documented', 'Reg', (73, 83))	('IDH1', 'Gene', '3417', (49, 53))	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('IDH2', 'Gene', '3418', (58, 62))	('malignancies', 'Disease', (96, 108))	('mutations', 'Var', (17, 26))	('IDH2', 'Gene', (58, 62))	('IDH1', 'Gene', (49, 53))
207303	27658636	Mutant IDH1 and IDH2 enzymes exhibit "neomorphic" activity where isocitrate is instead converted to D(R)-2-hydroxyglutarate (D-2HG), an "oncometabolite" that inhibits 2-OG/O2 dependent enzymes, including TET1 and TET2.	('2-OG', 'Chemical', '-', (167, 171))	('O2', 'Chemical', 'MESH:D010100', (172, 174))	('IDH1', 'Gene', '3417', (7, 11))	('inhibits', 'NegReg', (158, 166))	('isocitrate', 'Chemical', 'MESH:C034219', (65, 75))	('IDH2', 'Gene', (16, 20))	('TET1', 'Gene', (204, 208))	('2-OG/O2 dependent enzymes', 'Enzyme', (167, 192))	('TET2', 'Gene', '54790', (213, 217))	('IDH2', 'Gene', '3418', (16, 20))	('D(R)-2-hydroxyglutarate', 'Chemical', '-', (100, 123))	('Mutant', 'Var', (0, 6))	('TET1', 'Gene', '80312', (204, 208))	('IDH1', 'Gene', (7, 11))	('TET2', 'Gene', (213, 217))
207307	27658636	histone 3 lysine 9, and lysine 27) in response to hypoxia, due to inhibition of the epigenetic modifier KDM4C, a Jumonji family histone demethylase.	('hypoxia', 'Disease', 'MESH:D000860', (50, 57))	('lysine', 'Chemical', 'MESH:D008239', (10, 16))	('lysine', 'Var', (24, 30))	('hypoxia', 'Disease', (50, 57))	('response to hypoxia', 'biological_process', 'GO:0001666', ('38', '57'))	('lysine', 'Chemical', 'MESH:D008239', (24, 30))	('response', 'MPA', (38, 46))	('KDM4C', 'Gene', (104, 109))	('inhibition', 'NegReg', (66, 76))	('KDM4C', 'Gene', '23081', (104, 109))
207314	27658636	Nevertheless, these findings have therapeutic implications for hypoxic tumors, as glutamine catabolism can be inhibited by small molecule inhibitors of glutaminase.	('hypoxic tumors', 'Disease', 'MESH:D009369', (63, 77))	('glutamine catabolism', 'biological_process', 'GO:0006543', ('82', '102'))	('glutaminase', 'Protein', (152, 163))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('glutamine', 'Chemical', 'MESH:D005973', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('small molecule inhibitors', 'Var', (123, 148))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('glutamine catabolism', 'MPA', (82, 102))	('inhibited', 'NegReg', (110, 119))	('hypoxic tumors', 'Disease', (63, 77))
207316	27658636	Restored L-2HG dehydrogenase expression increased 5-methylcytosine accumulation and suppressed renal tumor growth.	('renal tumor', 'Disease', (95, 106))	('L-2HG', 'Var', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (50, 66))	('increased', 'PosReg', (40, 49))	('renal tumor', 'Disease', 'MESH:D007674', (95, 106))	('5-methylcytosine accumulation', 'MPA', (50, 79))	('renal tumor', 'Phenotype', 'HP:0009726', (95, 106))	('suppressed', 'NegReg', (84, 94))
207355	27658636	Loss of LKB1, the upstream kinase of AMPK, increases HIF-1alpha accumulation via increased reactive oxygen species as well as mTORC1 activity.	('AMPK', 'Gene', '5563', (37, 41))	('LKB1', 'Gene', '6794', (8, 12))	('HIF-1alpha', 'Gene', '3091', (53, 63))	('AMPK', 'molecular_function', 'GO:0004691', ('37', '41'))	('mTORC1', 'Gene', '382056', (126, 132))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (91, 114))	('AMPK', 'molecular_function', 'GO:0047322', ('37', '41'))	('LKB1', 'Gene', (8, 12))	('AMPK', 'Gene', (37, 41))	('HIF-1alpha', 'Gene', (53, 63))	('mTORC1', 'Gene', (126, 132))	('mTORC1', 'cellular_component', 'GO:0031931', ('126', '132'))	('increases', 'PosReg', (43, 52))	('activity', 'MPA', (133, 141))	('increased', 'PosReg', (81, 90))	('Loss', 'Var', (0, 4))	('reactive oxygen species', 'MPA', (91, 114))	('AMPK', 'molecular_function', 'GO:0050405', ('37', '41'))
207366	27658636	Phosphorylation of CaMKII leads to activation of mTORC1, although the specific mechanism(s) are not well defined.	('CaMKII', 'cellular_component', 'GO:0005954', ('19', '25'))	('Phosphorylation', 'Var', (0, 15))	('CaMKII', 'Gene', (19, 25))	('mTORC1', 'Gene', '382056', (49, 55))	('CaMKII', 'Gene', '818', (19, 25))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('CaMKII', 'molecular_function', 'GO:0004683', ('19', '25'))	('mTORC1', 'cellular_component', 'GO:0031931', ('49', '55'))	('mTORC1', 'Gene', (49, 55))	('activation', 'PosReg', (35, 45))
207376	27658636	ATG5, ATG7, ATG12, ATG16), and LC3 conjugated to PE (LC3-II), which ultimately close the autophagosome around the targets to be degraded.	('autophagosome around the targets', 'CPA', (89, 121))	('LC3', 'Gene', '84557', (31, 34))	('ATG5', 'Gene', (0, 4))	('LC3', 'Gene', (31, 34))	('ATG7', 'Gene', '10533', (6, 10))	('ATG12', 'Gene', '9140', (12, 17))	('LC3', 'Gene', '84557', (53, 56))	('ATG7', 'Gene', (6, 10))	('ATG5', 'Gene', '9474', (0, 4))	('ATG16', 'Var', (19, 24))	('close', 'NegReg', (79, 84))	('LC3', 'Gene', (53, 56))	('autophagosome', 'cellular_component', 'GO:0005776', ('89', '102'))	('ATG12', 'Gene', (12, 17))
207402	27658636	As "drugging" genetically and epigenetically unstable cancer cells will likely result in acquired resistance over time, impacting stromal metabolism may be the best option to promote stable disease or remission.	('impacting', 'Reg', (120, 129))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('promote', 'PosReg', (175, 182))	('epigenetically unstable', 'Var', (30, 53))	('metabolism', 'biological_process', 'GO:0008152', ('136', '146'))	('result in', 'Reg', (79, 88))	('stromal metabolism', 'MPA', (130, 148))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('acquired resistance', 'CPA', (89, 108))
207403	27658636	Finally, metabolic interventions could be combined with immunotherapeutic approaches, to treat a broad spectrum of malignancies with diverse genetic or epigenetic alterations, in the future.	('malignancies', 'Disease', (115, 127))	('epigenetic alterations', 'Var', (152, 174))	('malignancies', 'Disease', 'MESH:D009369', (115, 127))
207418	33977240	He had undergone a right radical nephrectomy 3 years before and was diagnosed with PRCC type 2, pT3bN0M0 (Fig.	('PRCC', 'Gene', '5546', (83, 87))	('pT3bN0M0', 'Var', (96, 104))	('PRCC', 'Gene', (83, 87))
207473	28086852	Anti-CTLA-4 antibodies, which are used to treat advanced melanoma patients, have been reported to have an excellent therapeutic effect.	('antibodies', 'Var', (12, 22))	('CTLA-4', 'Gene', '1493', (5, 11))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('CTLA-4', 'Gene', (5, 11))	('patients', 'Species', '9606', (66, 74))
207478	28086852	Although some studies have demonstrated that a high expression of PD-L1 was associated with poor clinical outcomes, few studies have investigated PD-L1 expression in pRCC.	('PD-L1', 'Gene', '29126', (146, 151))	('PD-L1', 'Gene', '29126', (66, 71))	('high', 'Var', (47, 51))	('pRCC', 'Phenotype', 'HP:0006766', (166, 170))	('pRCC', 'Gene', '5546', (166, 170))	('expression', 'MPA', (52, 62))	('associated', 'Reg', (76, 86))	('PD-L1', 'Gene', (146, 151))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('pRCC', 'Gene', (166, 170))	('PD-L1', 'Gene', (66, 71))
207520	28086852	Although PD-L1 expression appeared to be related to worse overall survival, there was no significant correlation between PD-L1 expression and clinical prognosis.	('PD-L1', 'Gene', (121, 126))	('overall survival', 'MPA', (58, 74))	('expression', 'Var', (15, 25))	('PD-L1', 'Gene', '29126', (121, 126))	('PD-L1', 'Gene', '29126', (9, 14))	('worse', 'NegReg', (52, 57))	('PD-L1', 'Gene', (9, 14))
140872	28819401	High SLC10A2 expression was associated with good prognosis of ccRCC.	('High', 'Var', (0, 4))	('expression', 'MPA', (13, 23))	('SLC10A2', 'Gene', (5, 12))	('SLC10A2', 'Gene', '6555', (5, 12))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('RCC', 'Disease', (64, 67))
207705	28515920	The mechanisms underlying the correlation of inflammatory status with prognosis of metastatic or recurrent RCC have been considered to be as follows: First, since inflammation-associated cytokines may directly induce tumor cell growth, there may be a higher induction of RCC cell proliferation in mGPS high patients compared with that in mGPS low patients.	('induce', 'PosReg', (210, 216))	('high', 'Var', (302, 306))	('patients', 'Species', '9606', (307, 315))	('patients', 'Species', '9606', (347, 355))	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('tumor', 'Disease', (217, 222))	('RCC', 'Disease', (107, 110))	('GPS', 'Disease', (339, 342))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('RCC', 'Disease', (271, 274))	('RCC', 'Phenotype', 'HP:0005584', (271, 274))	('cell growth', 'biological_process', 'GO:0016049', ('223', '234'))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('GPS', 'Disease', (298, 301))	('cell proliferation', 'biological_process', 'GO:0008283', ('275', '293'))	('RCC', 'Disease', 'MESH:C538614', (271, 274))	('GPS', 'Disease', 'MESH:D055652', (339, 342))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('inflammation', 'biological_process', 'GO:0006954', ('163', '175'))	('GPS', 'Disease', 'MESH:D055652', (298, 301))
207716	28515920	Overall survival following termination of the initial chemotherapy in the mGPS low patients was found to be significantly longer compared with that of the mGPS high patients (median OS, 1,111 days vs. 180 days, respectively; P=0.006).	('GPS', 'Disease', (156, 159))	('longer', 'PosReg', (122, 128))	('OS', 'Chemical', '-', (182, 184))	('patients', 'Species', '9606', (83, 91))	('GPS', 'Disease', 'MESH:D055652', (156, 159))	('GPS', 'Disease', 'MESH:D055652', (75, 78))	('patients', 'Species', '9606', (165, 173))	('low', 'Var', (79, 82))	('Overall survival', 'MPA', (0, 16))	('GPS', 'Disease', (75, 78))
207722	28515920	Since inhibition of mTOR has been demonstrated to induce muscle protein wasting in cancer cachexia, it may be suggested that an mTOR inhibitor may be suitable only for mGPS low patients.	('mTOR', 'Gene', (128, 132))	('muscle protein wasting', 'MPA', (57, 79))	('mTOR', 'Gene', '2475', (128, 132))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('cancer cachexia', 'Disease', 'MESH:D002100', (83, 98))	('GPS', 'Disease', 'MESH:D055652', (169, 172))	('patients', 'Species', '9606', (177, 185))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('muscle protein wasting', 'Phenotype', 'HP:0003202', (57, 79))	('inhibition', 'Var', (6, 16))	('cachexia', 'Phenotype', 'HP:0004326', (90, 98))	('GPS', 'Disease', (169, 172))	('cancer cachexia', 'Disease', (83, 98))	('mTOR', 'Gene', '2475', (20, 24))	('mTOR', 'Gene', (20, 24))
207759	27855702	A higher number of tumor mutations is expected to result in greater numbers of MHC binding neo-antigens, which have been proposed to drive tumor immune-infiltration and response to immunotherapy.	('mutations', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('MHC binding', 'Protein', (79, 90))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('binding', 'molecular_function', 'GO:0005488', ('83', '90'))	('tumor', 'Disease', (19, 24))	('greater', 'PosReg', (60, 67))
207760	27855702	However, the modest mutation load of ccRCC compared with other immunotherapy-responsive tumor types challenges the notion that neo-antigens alone can drive immune infiltration and response to immunotherapy in these tumors.	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('mutation load', 'Var', (20, 33))	('immune infiltration', 'CPA', (156, 175))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (215, 220))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumor', 'Disease', (88, 93))	('tumors', 'Disease', (215, 221))
207790	27855702	The Spearman correlation for the NK, Treg and CD8+ T cell populations were 0.631 (p = 0.025), 0.639 (p = 0.023), and 0.4998 (p = 0.071), respectively.	('CD8', 'Gene', (46, 49))	('CD8', 'Gene', '925', (46, 49))	('0.4998', 'Var', (117, 123))	('0.639', 'Var', (94, 99))
207808	27855702	Missense mutations within tumor cells are a known source of neo-antigens that can initiate a T cell dependent immune response.	('T cell dependent immune response', 'CPA', (93, 125))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('immune response', 'biological_process', 'GO:0006955', ('110', '125'))	('initiate', 'Reg', (82, 90))	('tumor', 'Disease', (26, 31))	('Missense mutations', 'Var', (0, 18))
207809	27855702	Previous studies have reported a significant correlation between "total number of mutations" and cytolytic activity index (CYT) in a pan-cancer context.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('mutations', 'Var', (82, 91))	('cancer', 'Disease', (137, 143))	('cytolytic activity index', 'MPA', (97, 121))
207810	27855702	However, synonymous mutations do not give rise to neo-antigens, therefore the correlations between "number of missense mutations" and CYT are more relevant to study when investigating the immunogenicity of tumor types.	('tumor', 'Disease', (206, 211))	('missense mutations', 'Var', (110, 128))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))
207811	27855702	We observed that, across 18 cancer types, only glioma and stomach adenocarcinoma had significant correlations between CYT and number of missense mutations after correction for multiple hypothesis testing (Additional file 1: Figure S10c).	('correlations', 'Interaction', (97, 109))	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('missense mutations', 'Var', (136, 154))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('glioma', 'Disease', (47, 53))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (58, 80))	('CYT', 'MPA', (118, 121))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('stomach adenocarcinoma', 'Disease', (58, 80))	('cancer', 'Disease', (28, 34))	('glioma', 'Disease', 'MESH:D005910', (47, 53))
207812	27855702	When only the 5th to the 95th percentile of the missense mutation counts was used as implemented in, the number of cancer types with significant CYT versus mutation count correlations increased to a modest four (Additional file 1: Figure S10d).	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('missense', 'Var', (48, 56))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', (115, 121))
207813	27855702	Consistent with CYT findings, we also observed a lack of consistent positive pan-cancer correlations between TIS levels in tumors and the corresponding numbers of somatic missense mutations (Fig.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('missense mutations', 'Var', (171, 189))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('TIS levels', 'MPA', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
207817	27855702	For instance, tumors which acquire the ability to suppress T cell activation may continue to accumulate mutations as immune infiltration decreases.	('mutations', 'Var', (104, 113))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('T cell activation', 'biological_process', 'GO:0042110', ('59', '76'))
207818	27855702	In contrast to CD8 and memory T cells, Th2 and Treg cell levels generally showed a positive correlation with mutation load (Fig.	('correlation', 'Interaction', (92, 103))	('CD8', 'Gene', '925', (15, 18))	('mutation load', 'Var', (109, 122))	('positive', 'Reg', (83, 91))	('memory', 'biological_process', 'GO:0007613', ('23', '29'))	('Th2', 'Chemical', '-', (39, 42))	('CD8', 'Gene', (15, 18))
207874	27855702	For instance, regions in tumors RMH008 and EV007 were found to contain members in all three immune infiltration classes (T cell enriched, heterogeneously infiltrated, or non-infiltrated).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('contain', 'Reg', (63, 70))	('tumors RMH008', 'Disease', (25, 38))	('EV007', 'Var', (43, 48))	('tumors RMH008', 'Disease', 'MESH:D009369', (25, 38))
207890	27855702	The tumors from the non-infiltrated class harbored slightly more somatic missense mutations than the T cell enriched class (the median number of somatic missense mutations in the non-infiltrated group was 36.5 versus 33 in the T cell enriched group; q = 0.07, ANOVA).	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('missense mutations', 'Var', (73, 91))
207896	27855702	We then predicted the protein alterations expected to result from missense mutations in each tumor and identified those predicted to bind to MHC-I molecules (see "Methods").	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('missense mutations', 'Var', (66, 84))	('bind', 'Interaction', (133, 137))	('protein', 'Protein', (22, 29))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
207903	27855702	Compared to CIBERSORT and DeconRNA-Seq, our decomposition method has the advantages of (1) being compatible with both microarray and RNA-Seq platforms, and (2) not requiring reference expression vectors, which actually reduce the robustness of a method due to the fact that even small changes in the reference vectors may lead to substantial differences in the output when the deconvolution goal is cast into an optimization problem as in CIBERSORT and DeconRNA-Seq.	('lead to', 'Reg', (322, 329))	('differences', 'Reg', (342, 353))	('robustness', 'MPA', (230, 240))	('output', 'MPA', (361, 367))	('reduce', 'NegReg', (219, 225))	('RNA', 'cellular_component', 'GO:0005562', ('133', '136'))	('changes', 'Var', (285, 292))	('expression vectors', 'Species', '29278', (184, 202))
207905	27855702	Nevertheless, we observed that the pDC score was highly correlated with the angiogenesis score (a 40-gene signature) across many cancer types (Additional file 1: Figure S25) and this association has a known mechanism whereby pDCs induce angiogenesis.	('angiogenesis', 'biological_process', 'GO:0001525', ('76', '88'))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('correlated', 'Interaction', (56, 66))	('induce', 'PosReg', (230, 236))	('cancer', 'Disease', (129, 135))	('pDCs', 'Var', (225, 229))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('angiogenesis score', 'MPA', (76, 94))	('angiogenesis', 'biological_process', 'GO:0001525', ('237', '249'))	('angiogenesis', 'CPA', (237, 249))
207988	27855702	A MAF files containing missense mutations for each TCGA patient was obtained from cBioPortal (http://www.cbioportal.org/).	('missense mutations', 'Var', (23, 41))	('MAF', 'Gene', '4094', (2, 5))	('patient', 'Species', '9606', (56, 63))	('TCGA', 'Gene', (51, 55))	('MAF', 'Gene', (2, 5))
207989	27855702	A MAF file containing missense mutations for each SATO patient was obtained from the publication.	('MAF', 'Gene', '4094', (2, 5))	('missense mutations', 'Var', (22, 40))	('MAF', 'Gene', (2, 5))	('patient', 'Species', '9606', (55, 62))
207992	27855702	All 9 and 10-mers overlapping the missense mutations were extracted and NetMHCPan was used to predict their affinity to alleles of MHC-I.	('affinity', 'Interaction', (108, 116))	('mers', 'Species', '1335626', (13, 17))	('NetMHCPan', 'Chemical', '-', (72, 81))	('missense mutations', 'Var', (34, 52))	('MHC-I', 'Gene', (131, 136))
208011	30941304	However, obvious survival differences exist between the subgroups of stage III RCC patients (T3N0M0, 5-year survival: 20-70%; T1-3N1M0, 5-year survival: 0-20%).	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('T1-3N1M0', 'Var', (126, 134))	('patients', 'Species', '9606', (83, 91))	('T3N0M0', 'Var', (93, 99))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
208106	30941304	Deregulation of ANK3 expression has been observed in multiple human cancers, and, while it contributes to poor prognosis, its mechanism remains unknown.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ANK3', 'Gene', '288', (16, 20))	('Deregulation', 'Var', (0, 12))	('human', 'Species', '9606', (62, 67))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('ANK3', 'Gene', (16, 20))
208107	30941304	Several researchers proposed a possible connection between ANK3 dysregulation and epithelial-to-mesenchymal transition (EMT).	('dysregulation', 'Var', (64, 77))	('ANK3', 'Gene', '288', (59, 63))	('EMT', 'biological_process', 'GO:0001837', ('120', '123'))	('epithelial-to-mesenchymal transition', 'CPA', (82, 118))	('ANK3', 'Gene', (59, 63))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('82', '118'))
208127	30431025	Knocked-down AEG-1 impaired the migration and invasion of ccRCC cells in vitro.	('AEG-1', 'Gene', (13, 18))	('impaired the migration', 'Disease', 'MESH:D054081', (19, 41))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('impaired the migration', 'Disease', (19, 41))	('ccRCC', 'Disease', (58, 63))	('Knocked-down', 'Var', (0, 12))
208136	30431025	Overexpression of AEG-1 increases the anchorage-independent growth, migration, and invasion of HeLa cells and glioma cell lines.	('increases', 'PosReg', (24, 33))	('glioma', 'Disease', (110, 116))	('AEG-1', 'Gene', (18, 23))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('HeLa', 'CellLine', 'CVCL:0030', (95, 99))	('invasion', 'CPA', (83, 91))	('Overexpression', 'Var', (0, 14))	('anchorage-independent growth', 'CPA', (38, 66))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('migration', 'CPA', (68, 77))
208138	30431025	Inhibition of AEG-1 in prostate cancer cells inhibits protein kinase B (PKB) activation and increases the activity of forkhead box (FOXO) 3a.	('AEG-1', 'Gene', (14, 19))	('inhibits', 'NegReg', (45, 53))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('PKB', 'Gene', '207', (72, 75))	('prostate cancer', 'Disease', (23, 38))	('forkhead', 'Enzyme', (118, 126))	('PKB', 'Gene', (72, 75))	('prostate cancer', 'Disease', 'MESH:D011471', (23, 38))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('increases', 'PosReg', (92, 101))	('activity', 'MPA', (106, 114))	('prostate cancer', 'Phenotype', 'HP:0012125', (23, 38))	('activation', 'MPA', (77, 87))
208157	30431025	The pCLEN-Notch1 plasmid (#17704, Addgene, Cambridge, MA, USA) was deposited by Dr. Nicholas Gaiano.	('Notch1', 'Gene', '4851', (10, 16))	('#17704', 'Var', (26, 32))	('Notch1', 'Gene', (10, 16))
208184	30431025	We next explored whether the metastasis of Caki-2 or 786-O cells could be inhibited by shAEG-1 transfection.	('inhibited', 'NegReg', (74, 83))	('transfection', 'Var', (95, 107))	('metastasis', 'CPA', (29, 39))	('Caki-2', 'CellLine', 'CVCL:0235', (43, 49))	('shAEG-1', 'Gene', (87, 94))
208189	30431025	As shown in Figure 3D, the metastatic foci formed by AEG-1-OE Caki-2 or AEG-1-OE 786-O cells were remarkably increased; conversely, AEG-1 knocked-down cells resulted in less lung metastasis lesions.	('Caki-2', 'CellLine', 'CVCL:0235', (62, 68))	('lung metastasis lesions', 'Disease', (174, 197))	('less', 'NegReg', (169, 173))	('metastatic foci formed', 'CPA', (27, 49))	('lung metastasis lesions', 'Disease', 'MESH:D009362', (174, 197))	('AEG-1-OE 786-O', 'Var', (72, 86))	('AEG-1', 'Gene', (132, 137))	('AEG-1-OE', 'Var', (53, 61))	('increased', 'PosReg', (109, 118))
208192	30431025	Importantly, we confirmed that AEG-1 knock-down inhibited the protein level of Notch1 in Caki-2 cells (Figure 4B).	('protein level', 'MPA', (62, 75))	('Notch1', 'Gene', (79, 85))	('AEG-1', 'Gene', (31, 36))	('Notch1', 'Gene', '4851', (79, 85))	('inhibited', 'NegReg', (48, 57))	('Caki-2', 'CellLine', 'CVCL:0235', (89, 95))	('knock-down', 'Var', (37, 47))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
208195	30431025	As expected, pCLEN-Notch1 transfection rescued the impaired migration and invasion ability in the AEG-1-silenced Caki-2 cells (Figure 4D, 4E).	('transfection', 'Var', (26, 38))	('Notch1', 'Gene', (19, 25))	('Caki-2', 'CellLine', 'CVCL:0235', (113, 119))	('migration', 'CPA', (60, 69))	('impaired', 'NegReg', (51, 59))	('Notch1', 'Gene', '4851', (19, 25))	('invasion ability', 'CPA', (74, 90))
208197	30431025	As shown in Figure 4F, the expression of Notch1 in AEG-1-overexpressing Caki-2 cells was decreased by FLI-06.	('FLI-06', 'Var', (102, 108))	('Caki-2', 'CellLine', 'CVCL:0235', (72, 78))	('FLI-06', 'Chemical', 'MESH:C000621625', (102, 108))	('Notch1', 'Gene', (41, 47))	('Notch1', 'Gene', '4851', (41, 47))	('expression', 'MPA', (27, 37))	('decreased', 'NegReg', (89, 98))
208198	30431025	Consistently, the migration and invasion activity of Caki-2 cells promoted by AEG-1 overexpression was also suppressed by FLI-06 (Figure 4G, 4H).	('FLI-06', 'Chemical', 'MESH:C000621625', (122, 128))	('overexpression', 'PosReg', (84, 98))	('Caki-2', 'CellLine', 'CVCL:0235', (53, 59))	('suppressed', 'NegReg', (108, 118))	('AEG-1', 'Gene', (78, 83))	('FLI-06', 'Var', (122, 128))	('promoted', 'PosReg', (66, 74))	('invasion activity of Caki-2 cells', 'CPA', (32, 65))
208204	30431025	As shown in Figure 5C, 5D, the expression of AEG-1 and Notch1 in the AEG-1 shRNA group was significantly decreased compared with that in the control group.	('AEG-1', 'Gene', (45, 50))	('Notch1', 'Gene', (55, 61))	('expression', 'MPA', (31, 41))	('Notch1', 'Gene', '4851', (55, 61))	('shRNA', 'Var', (75, 80))	('decreased', 'NegReg', (105, 114))	('AEG-1 shRNA', 'Var', (69, 80))
208205	30431025	Collectively, these results suggested that AEG-1 acted as a tumor promoter in ccRCC and that depletion of AEG-1 dramatically attenuated ccRCC oncogenic properties in vivo.	('AEG-1', 'Gene', (106, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('depletion', 'Var', (93, 102))	('ccRCC', 'Disease', (78, 83))	('attenuated', 'NegReg', (125, 135))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('ccRCC', 'Disease', (136, 141))	('oncogenic properties', 'CPA', (142, 162))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
208210	30431025	Knock-down of AEG-1 reduces the abilities of migration and invasion through downregulation of MMP-2/9 in thyroid cancer cells.	('thyroid cancer', 'Disease', 'MESH:D013964', (105, 119))	('MMP-2/9', 'Gene', '4313;4318', (94, 101))	('AEG-1', 'Gene', (14, 19))	('reduces', 'NegReg', (20, 27))	('Knock-down', 'Var', (0, 10))	('MMP-2/9', 'Gene', (94, 101))	('thyroid cancer', 'Disease', (105, 119))	('thyroid cancer', 'Phenotype', 'HP:0002890', (105, 119))	('invasion', 'CPA', (59, 67))	('downregulation', 'NegReg', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('MMP-2', 'molecular_function', 'GO:0004228', ('94', '99'))
208214	30431025	We found that the migration and invasion of Caki-2 cells was remarkably suppressed when the AEG-1 gene was knocked-down by shRNA, as demonstrated by wound-healing analysis and Transwell assay.	('wound-healing', 'biological_process', 'GO:0042060', ('149', '162'))	('AEG-1 gene', 'Gene', (92, 102))	('suppressed', 'NegReg', (72, 82))	('Caki-2', 'CellLine', 'CVCL:0235', (44, 50))	('knocked-down', 'Var', (107, 119))
208215	30431025	Consistently, under-expression of AEG-1 suppressed the pulmonary metastasis of ccRCC Caki-2 cells in vivo.	('under-expression', 'Var', (14, 30))	('suppressed', 'NegReg', (40, 50))	('AEG-1', 'Gene', (34, 39))	('pulmonary metastasis', 'Disease', (55, 75))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('Caki-2', 'CellLine', 'CVCL:0235', (85, 91))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (55, 75))
208216	30431025	In vertebrates there are 4 Notch genes (Notch1, Notch2, Notch3, and Notch4), which encode receptors for at least 5 different DSL Notch ligands, including Jagged1, Jagged2, Delta1, Delta3, and Delta4.	('Delta1', 'Gene', (172, 178))	('Delta4', 'Mutation', 'c.del4', (192, 198))	('Delta3', 'Mutation', 'c.del3', (180, 186))	('Jagged2', 'Gene', (163, 170))	('Jagged1', 'Gene', '182', (154, 161))	('Delta1', 'Gene', '8788;10683;54567', (172, 178))	('Delta4', 'Var', (192, 198))	('Notch3', 'Gene', '4854', (56, 62))	('Notch4', 'Gene', (68, 74))	('Notch2', 'Gene', (48, 54))	('Notch3', 'Gene', (56, 62))	('Jagged1', 'Gene', (154, 161))	('Notch4', 'Gene', '4855', (68, 74))	('Notch1', 'Gene', '4851', (40, 46))	('Notch1', 'Gene', (40, 46))	('Notch2', 'Gene', '4853', (48, 54))	('Jagged2', 'Gene', '3714', (163, 170))	('Delta3', 'Var', (180, 186))
208219	30431025	This study demonstrates that AEG-1 knocked-down decreased the expression of Notch1 in ccRCC Caki-2 cells.	('Notch1', 'Gene', (76, 82))	('expression', 'MPA', (62, 72))	('decreased', 'NegReg', (48, 57))	('Caki-2', 'CellLine', 'CVCL:0235', (92, 98))	('Notch1', 'Gene', '4851', (76, 82))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('knocked-down', 'Var', (35, 47))	('AEG-1', 'Gene', (29, 34))
208220	30431025	Furthermore, restoration of Notch1 in AEG-1 knocked-down Caki-2 via transfection with an active form of Notch1 rescued the decreased migration and invasion of Caki-2 cells caused by AEG-1 silencing.	('Notch1', 'Gene', (28, 34))	('AEG-1', 'Protein', (182, 187))	('Caki-2', 'CellLine', 'CVCL:0235', (159, 165))	('decreased', 'NegReg', (123, 132))	('Notch1', 'Gene', (104, 110))	('Notch1', 'Gene', '4851', (28, 34))	('invasion', 'CPA', (147, 155))	('Caki-2', 'CellLine', 'CVCL:0235', (57, 63))	('migration', 'CPA', (133, 142))	('Notch1', 'Gene', '4851', (104, 110))	('silencing', 'Var', (188, 197))
208221	30431025	Additional, in the presence of the Notch inhibitor, FLI-06, the migration and invasion of Caki-2 cells promoted by AEG-1 overexpression were markedly inhibited, which suggests the vital role of Notch1 in AEG-1-induced ccRCC cell metastasis.	('invasion of Caki-2 cells', 'CPA', (78, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (218, 223))	('ccRCC', 'Disease', (218, 223))	('FLI-06', 'Var', (52, 58))	('Caki-2', 'CellLine', 'CVCL:0235', (90, 96))	('inhibited', 'NegReg', (150, 159))	('FLI-06', 'Chemical', 'MESH:C000621625', (52, 58))	('AEG-1', 'Gene', (115, 120))	('Notch1', 'Gene', (194, 200))	('Notch1', 'Gene', '4851', (194, 200))	('migration', 'CPA', (64, 73))
208222	29569387	A novel functional polymorphism of GSTM3 reduces clear cell renal cell carcinoma risk through enhancing its expression by interfering miR-556 binding Dysregulation of glutathione-S-transferase M3 (GSTM3) has been related to clear cell renal cell carcinoma (ccRCC) in our former study.	('miR-556', 'Gene', (134, 141))	('GSTM3', 'Gene', (197, 202))	('RCC', 'Phenotype', 'HP:0005584', (259, 262))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (235, 255))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (60, 80))	('ccRCC', 'Phenotype', 'HP:0006770', (257, 262))	('RCC', 'Disease', (259, 262))	('clear cell renal cell carcinoma', 'Disease', (224, 255))	('clear cell renal cell carcinoma', 'Disease', (49, 80))	('reduces', 'NegReg', (41, 48))	('binding', 'molecular_function', 'GO:0005488', ('142', '149'))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('RCC', 'Disease', 'MESH:C538614', (259, 262))	('polymorphism', 'Var', (19, 31))	('enhancing', 'PosReg', (94, 103))	('GSTM3', 'Gene', (35, 40))	('glutathione', 'Chemical', 'MESH:D005978', (167, 178))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (49, 80))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (224, 255))	('GSTM3', 'Gene', '2947', (197, 202))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (235, 255))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (60, 80))	('interfering', 'NegReg', (122, 133))	('miR-556', 'Gene', '693141', (134, 141))	('related', 'Reg', (213, 220))	('expression', 'MPA', (108, 118))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (224, 255))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (49, 80))	('GSTM3', 'Gene', '2947', (35, 40))
208224	29569387	This study aimed to examine: (1) the associations between GSTM3 single nucleotide polymorphisms (SNPs) and risk of ccRCC, and (2) the potential molecular mechanism accounting for its effects.	('single nucleotide polymorphisms', 'Var', (64, 95))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('GSTM3', 'Gene', (58, 63))	('associations', 'Interaction', (37, 49))	('GSTM3', 'Gene', '2947', (58, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))
208226	29569387	A SNP-rs1055259 was found to be significantly associated with the susceptibility of ccRCC (OR = 0.59, 95% CI = 0.41-0.92; P = .019).	('SNP-rs1055259', 'Var', (2, 15))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('rs1055259', 'Mutation', 'rs1055259', (6, 15))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))
208230	29569387	Compared to rs1055259 A-allele constructs, cells transfected with rs1055259 G-allele construct had higher transcriptional activity and were less responsive to miR-556 changes and gene expression.	('transcriptional activity', 'MPA', (106, 130))	('gene expression', 'biological_process', 'GO:0010467', ('179', '194'))	('higher', 'PosReg', (99, 105))	('rs1055259', 'Mutation', 'rs1055259', (12, 21))	('responsive to', 'MPA', (145, 158))	('rs1055259', 'Var', (66, 75))	('miR-556', 'Gene', (159, 166))	('less', 'NegReg', (140, 144))	('miR-556', 'Gene', '693141', (159, 166))	('rs1055259', 'Mutation', 'rs1055259', (66, 75))
208232	29569387	Taken together, this study indicated that a functional polymorphism of GSTM3 -rs1055259 reduced susceptibility of RCC in the Chinese population.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('susceptibility', 'MPA', (96, 110))	('polymorphism', 'Var', (55, 67))	('GSTM3', 'Gene', (71, 76))	('GSTM3', 'Gene', '2947', (71, 76))	('rs1055259', 'Mutation', 'rs1055259', (78, 87))	('reduced', 'NegReg', (88, 95))
208243	29569387	It both down-regulated in metastatic vs primary ccRCC cells and primary ccRCC cells vs adjacent normal renal tissues.7 We also studied the tumour suppressor role of GSTM3 in the progression of ccRCC and a polymorphism rs1332018 which was significantly associated with the postoperative prognosis of ccRCC.8  In the current study, we report a novel SNP in ccRCC- rs1055259 in the 3'untranslated region (UTR) of GSTM3 significantly reduced the ccRCC risk and influence the binding of miR-556 to the 3'UTR of GSTM3.	('GSTM3', 'Gene', (506, 511))	('GSTM3', 'Gene', (410, 415))	('rs1055259', 'Mutation', 'rs1055259', (362, 371))	('RCC', 'Disease', 'MESH:C538614', (444, 447))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('RCC', 'Phenotype', 'HP:0005584', (195, 198))	('miR-556', 'Gene', (482, 489))	('tumour', 'Disease', 'MESH:D009369', (139, 145))	('RCC', 'Disease', (195, 198))	('reduced', 'NegReg', (430, 437))	('tumour', 'Disease', (139, 145))	('ccRCC', 'Phenotype', 'HP:0006770', (193, 198))	('binding', 'Interaction', (471, 478))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('RCC', 'Disease', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('GSTM3', 'Gene', '2947', (165, 170))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('rs1332018', 'Mutation', 'rs1332018', (218, 227))	('GSTM3', 'Gene', '2947', (506, 511))	('RCC', 'Disease', (301, 304))	('GSTM3', 'Gene', '2947', (410, 415))	('SNP', 'Var', (348, 351))	('RCC', 'Phenotype', 'HP:0005584', (301, 304))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('ccRCC', 'Phenotype', 'HP:0006770', (355, 360))	('influence', 'Reg', (457, 466))	('RCC', 'Disease', (357, 360))	('RCC', 'Phenotype', 'HP:0005584', (357, 360))	('ccRCC', 'Phenotype', 'HP:0006770', (299, 304))	('binding', 'molecular_function', 'GO:0005488', ('471', '478'))	('RCC', 'Disease', 'MESH:C538614', (301, 304))	('GSTM3', 'Gene', (165, 170))	('RCC', 'Disease', (444, 447))	('RCC', 'Disease', 'MESH:C538614', (357, 360))	('miR-556', 'Gene', '693141', (482, 489))
208244	29569387	This might be the potential mechanism of rs1055259 impact the renal carcinoma risk.	('impact the renal carcinoma', 'Disease', (51, 77))	('impact the renal carcinoma', 'Disease', 'MESH:C538614', (51, 77))	('rs1055259', 'Var', (41, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('renal carcinoma', 'Phenotype', 'HP:0005584', (62, 77))	('rs1055259', 'Mutation', 'rs1055259', (41, 50))
208255	29569387	The candidate SNPs should meet these criteria: (1) the minor allele frequency (MAF) > 0.05; (2) r 2 < .80 (Figure 1A); (3) at the 3'UTR of GSTM3.	('GSTM3', 'Gene', '2947', (139, 144))	('GSTM3', 'Gene', (139, 144))	('r 2 < .80', 'Var', (96, 105))
208256	29569387	The significant SNP rs1055259 is located at a miR-556 binding site, with predicted proximal transcriptional regulatory potential (http://rsnp.psych.ac.cn/) (http://snpinfo.niehs.nih.gov/cgi-bin/snpinfo/ snpfunc.cgi).	('miR-556', 'Gene', '693141', (46, 53))	('binding', 'molecular_function', 'GO:0005488', ('54', '61'))	('rs1055259', 'Var', (20, 29))	('rs1055259', 'Mutation', 'rs1055259', (20, 29))	('miR-556', 'Gene', (46, 53))
208257	29569387	rs1537236, rs3814309, rs1109138 and rs5776997 were also predicted as functional SNPs, which seated in other miRNA binding sites.	('rs1537236', 'Var', (0, 9))	('rs5776997', 'Var', (36, 45))	('rs3814309', 'Var', (11, 20))	('rs3814309', 'Mutation', 'rs3814309', (11, 20))	('rs1109138', 'Var', (22, 31))	('rs1109138', 'Mutation', 'rs1109138', (22, 31))	('rs1537236', 'Mutation', 'rs1537236', (0, 9))	('rs5776997', 'Mutation', 'rs5776997', (36, 45))	('miRNA binding', 'molecular_function', 'GO:0035198', ('108', '121'))
208262	29569387	To evaluate the binding of miR-556 to 3'UTR of GSTM3, 3 reporter constructs carrying 2 copies of rs1055259-A allele, G allele or mutant sequences at the 3'UTR of luciferase gene were created.	('rs1055259', 'Mutation', 'rs1055259', (97, 106))	('binding', 'molecular_function', 'GO:0005488', ('16', '23'))	('miR-556', 'Gene', (27, 34))	('GSTM3', 'Gene', '2947', (47, 52))	('GSTM3', 'Gene', (47, 52))	('miR-556', 'Gene', '693141', (27, 34))	('rs1055259-A', 'Var', (97, 108))
208263	29569387	Firstly, three ~100-bp DNA sequences centred at rs1055259 (A or G allele) or mutant sequence were synthesized; then, 2 tandem copies of these sequences were cloned into pGL-3 Basic vector (Promega, Madison, WI, USA) using restriction enzyme sites-Sal I and BamH I.	('pGL', 'molecular_function', 'GO:0004598', ('169', '172'))	('pGL-3', 'Gene', '6391', (169, 174))	('rs1055259', 'Var', (48, 57))	('pGL-3', 'Gene', (169, 174))	('rs1055259', 'Mutation', 'rs1055259', (48, 57))	('DNA', 'cellular_component', 'GO:0005574', ('23', '26'))
208264	29569387	Day 2, cells were transfected with 0.8 mug pGL-3 Basic vectors (inserted with rs1055259- A allele, G allele or mutant sequences) and 0.16 mug pRL-TK vector (Luciferase Assay System; Promega).	('pGL', 'molecular_function', 'GO:0004598', ('43', '46'))	('mutant', 'Var', (111, 117))	('rs1055259', 'Mutation', 'rs1055259', (78, 87))	('pGL-3', 'Gene', '6391', (43, 48))	('rs1055259- A', 'Var', (78, 90))	('mug', 'molecular_function', 'GO:0043739', ('138', '141'))	('pGL-3', 'Gene', (43, 48))	('mug', 'molecular_function', 'GO:0043739', ('39', '42'))
208267	29569387	ROS activity was measured in ccRCC cells from 17 patients with different rs1055259 genotypes (AA = 8, AG = 6, GG = 3) using DCFH-DA (Beyotime).	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('DCFH-DA', 'Chemical', 'MESH:C029569', (124, 131))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('rs1055259', 'Var', (73, 82))	('patients', 'Species', '9606', (49, 57))	('ROS activity', 'MPA', (0, 12))	('rs1055259', 'Mutation', 'rs1055259', (73, 82))	('RCC', 'Disease', (31, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
208277	29569387	rs1537236, rs3814309, rs1109138, rs1055259 and rs5776997 were conformed to HWE in healthy controls, with the P value of .417, .695, .510, .728 and .315, respectively.	('rs1537236', 'Var', (0, 9))	('rs5776997', 'Var', (47, 56))	('rs3814309', 'Var', (11, 20))	('rs1055259', 'Mutation', 'rs1055259', (33, 42))	('rs3814309', 'Mutation', 'rs3814309', (11, 20))	('rs1109138', 'Var', (22, 31))	('rs1109138', 'Mutation', 'rs1109138', (22, 31))	('rs1537236', 'Mutation', 'rs1537236', (0, 9))	('rs5776997', 'Mutation', 'rs5776997', (47, 56))	('rs1055259', 'Var', (33, 42))
208278	29569387	Among the 5 candidate SNPs, rs1055259 variant was significantly associated with an decreased susceptibility of ccRCC.	('rs1055259', 'Var', (28, 37))	('decreased', 'NegReg', (83, 92))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('rs1055259', 'Mutation', 'rs1055259', (28, 37))
208279	29569387	Compared with wild-type AA, AG and AG + GG genotypes were significantly associated with reduced risk of ccRCC (AG vs AA: adjusted OR = 0.61, 95% CI = 0.43-0.90, P = .012; AG + GG vs AA: adjusted OR = 0.59, 95% CI = 0.41-0.92, P = .019).	('AG + GG', 'Var', (171, 178))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('reduced', 'NegReg', (88, 95))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))
208280	29569387	In allele comparing model, the rs1055259-G allele was significantly associated with a decreased susceptibility of ccRCC in comparison with A allele (adjusted OR = 0.72, 95% CI = 0.51-0.98, P = .040) (Table 3).	('rs1055259', 'Mutation', 'rs1055259', (31, 40))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('rs1055259-G', 'Var', (31, 42))	('decreased', 'NegReg', (86, 95))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))
208281	29569387	Bioinformatical analyses suggested that rs1055259 was located at miR-556 binding site, the 3'UTR of GSTM3.	('rs1055259', 'Var', (40, 49))	('GSTM3', 'Gene', '2947', (100, 105))	('miR-556', 'Gene', (65, 72))	('rs1055259', 'Mutation', 'rs1055259', (40, 49))	('miR-556', 'Gene', '693141', (65, 72))	('GSTM3', 'Gene', (100, 105))	('binding', 'molecular_function', 'GO:0005488', ('73', '80'))
208284	29569387	In ccRCC cells transfected with rs1055259-A allele construct, miR-556 mimic attenuated the luciferase activity by 45.43% while compared with control group; however, miR-556 mimic only reduced the luciferase activity by 25.61% in rs1055259-G allele group (Figure 2C).	('miR-556', 'Gene', (62, 69))	('activity', 'MPA', (207, 215))	('miR-556', 'Gene', '693141', (165, 172))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('rs1055259-A', 'Var', (32, 43))	('luciferase activity', 'molecular_function', 'GO:0047077', ('196', '215'))	('miR-556', 'Gene', (165, 172))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('luciferase activity', 'molecular_function', 'GO:0045289', ('196', '215'))	('reduced', 'NegReg', (184, 191))	('luciferase activity', 'molecular_function', 'GO:0047712', ('196', '215'))	('luciferase', 'Enzyme', (196, 206))	('activity', 'MPA', (102, 110))	('luciferase activity', 'molecular_function', 'GO:0047077', ('91', '110'))	('luciferase', 'Enzyme', (91, 101))	('rs1055259', 'Mutation', 'rs1055259', (32, 41))	('rs1055259', 'Mutation', 'rs1055259', (229, 238))	('luciferase activity', 'molecular_function', 'GO:0045289', ('91', '110'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('91', '110'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('196', '215'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('196', '215'))	('rs1055259-G', 'Var', (229, 240))	('miR-556', 'Gene', '693141', (62, 69))	('attenuated', 'NegReg', (76, 86))	('luciferase activity', 'molecular_function', 'GO:0050248', ('91', '110'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('91', '110'))
208287	29569387	Mutant construct losing the miR-556 binding site did not represent any obvious change.	('binding', 'molecular_function', 'GO:0005488', ('36', '43'))	('miR-556', 'Gene', (28, 35))	('miR-556', 'Gene', '693141', (28, 35))	('losing', 'NegReg', (17, 23))	('Mutant', 'Var', (0, 6))	('binding', 'Interaction', (36, 43))
208288	29569387	Based on the above evidences, miR-556 mimic could knock down GSTM3 expression in both rs1055259-A and G allele groups.	('rs1055259', 'Mutation', 'rs1055259', (86, 95))	('miR-556', 'Gene', '693141', (30, 37))	('GSTM3', 'Gene', (61, 66))	('GSTM3', 'Gene', '2947', (61, 66))	('rs1055259-A', 'Var', (86, 97))	('expression', 'MPA', (67, 77))	('knock down', 'NegReg', (50, 60))	('miR-556', 'Gene', (30, 37))
208297	29569387	To evaluate the biological effect of rs1055259 on GSTM3 activity in vivo, we measured the ROS activity in ccRCC cells from patients with AA, AG and GG genotypes.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('GSTM3', 'Gene', (50, 55))	('ROS activity', 'MPA', (90, 102))	('rs1055259', 'Mutation', 'rs1055259', (37, 46))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('patients', 'Species', '9606', (123, 131))	('ROS', 'Chemical', 'MESH:D017382', (90, 93))	('GSTM3', 'Gene', '2947', (50, 55))	('rs1055259', 'Var', (37, 46))
208298	29569387	As shown in Figure 4, the GSTM3 activity was obviously different among patients with rs1055259 AA, AG and GG genotypes.	('patients', 'Species', '9606', (71, 79))	('GSTM3', 'Gene', (26, 31))	('different', 'Reg', (55, 64))	('GSTM3', 'Gene', '2947', (26, 31))	('rs1055259', 'Mutation', 'rs1055259', (85, 94))	('rs1055259 AA', 'Var', (85, 97))
208299	29569387	The average ROS activity was highest in AA genotype, followed by AG and then lowest in GG genotype (2067.43 +- 117.76, 1310.65 +- 162.07 and 708.51 +- 79.34, respectively).	('ROS', 'Protein', (12, 15))	('ROS', 'Chemical', 'MESH:D017382', (12, 15))	('1310.65', 'Var', (119, 126))	('activity', 'MPA', (16, 24))
208300	29569387	This result suggested that rs1055259 variant, which was related with GSTM3 expression, indeed reduced ROS activity.	('ROS', 'Chemical', 'MESH:D017382', (102, 105))	('reduced', 'NegReg', (94, 101))	('GSTM3', 'Gene', '2947', (69, 74))	('rs1055259', 'Var', (27, 36))	('ROS activity', 'MPA', (102, 114))	('GSTM3', 'Gene', (69, 74))	('rs1055259', 'Mutation', 'rs1055259', (27, 36))
208304	29569387	Taken together, rs1055259 variant substantially suppressed the proliferation and invasion of ccRCC cells.	('proliferation', 'CPA', (63, 76))	('invasion', 'CPA', (81, 89))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('rs1055259', 'Mutation', 'rs1055259', (16, 25))	('rs1055259 variant', 'Var', (16, 33))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('suppressed', 'NegReg', (48, 58))	('RCC', 'Disease', (95, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))
208308	29569387	A significant association between rs1055259 and decreased ccRCC susceptibility was identified.	('rs1055259', 'Var', (34, 43))	('RCC', 'Disease', (60, 63))	('decreased', 'NegReg', (48, 57))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('rs1055259', 'Mutation', 'rs1055259', (34, 43))
208309	29569387	Variant G allele of rs1055259 enhanced GSTM3 expression via affecting the binding of miR-556 and 3'UTR, resulting in low ROS level, and further suppressing the proliferation and invasion of ccRCC cells (Figure 6).	('miR-556', 'Gene', '693141', (85, 92))	('invasion', 'CPA', (178, 186))	('ROS', 'Chemical', 'MESH:D017382', (121, 124))	('miR-556', 'Gene', (85, 92))	('GSTM3', 'Gene', '2947', (39, 44))	('RCC', 'Disease', (192, 195))	('RCC', 'Phenotype', 'HP:0005584', (192, 195))	('ccRCC', 'Phenotype', 'HP:0006770', (190, 195))	('binding', 'Interaction', (74, 81))	('rs1055259', 'Var', (20, 29))	('affecting', 'Reg', (60, 69))	('suppressing', 'NegReg', (144, 155))	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('low', 'NegReg', (117, 120))	("3'UTR", 'Protein', (97, 102))	('enhanced', 'PosReg', (30, 38))	('GSTM3', 'Gene', (39, 44))	('binding', 'molecular_function', 'GO:0005488', ('74', '81'))	('proliferation', 'CPA', (160, 173))	('ROS level', 'MPA', (121, 130))	('expression', 'MPA', (45, 55))	('rs1055259', 'Mutation', 'rs1055259', (20, 29))	('Variant', 'Var', (0, 7))
208310	29569387	rs1055259 is located at the 3'UTR of GSTM3 and predicted in a miR-556 binding site, with transcription regulatory potential.	('GSTM3', 'Gene', (37, 42))	('rs1055259', 'Var', (0, 9))	('miR-556', 'Gene', (62, 69))	('binding', 'molecular_function', 'GO:0005488', ('70', '77'))	('GSTM3', 'Gene', '2947', (37, 42))	('miR-556', 'Gene', '693141', (62, 69))	('rs1055259', 'Mutation', 'rs1055259', (0, 9))	('transcription', 'biological_process', 'GO:0006351', ('89', '102'))
208311	29569387	According to the evidences shown in Figure 2 and 3, rs1055259 A > G change increased the transcriptional activity, affected the miRNA binding and enhanced GSTM3 expression.	('transcriptional activity', 'MPA', (89, 113))	('rs1055259 A > G', 'Var', (52, 67))	('expression', 'MPA', (161, 171))	('GSTM3', 'Gene', '2947', (155, 160))	('enhanced', 'PosReg', (146, 154))	('miRNA', 'MPA', (128, 133))	('increased', 'PosReg', (75, 84))	('affected', 'Reg', (115, 123))	('rs1055259', 'Mutation', 'rs1055259', (52, 61))	('miRNA binding', 'molecular_function', 'GO:0035198', ('128', '141'))	('GSTM3', 'Gene', (155, 160))
208313	29569387	This is the first study to demonstrate the potential function of rs1055259 in GSTM3 expression and ccRCC development.	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('GSTM3', 'Gene', (78, 83))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('RCC', 'Disease', (101, 104))	('rs1055259', 'Var', (65, 74))	('GSTM3', 'Gene', '2947', (78, 83))	('expression', 'MPA', (84, 94))	('men', 'Species', '9606', (112, 115))	('rs1055259', 'Mutation', 'rs1055259', (65, 74))
208314	29569387	Another intriguing finding was that rs1055259 might be related to ROS activity, by fine tuning the GSTM3 expression.	('fine tuning', 'Reg', (83, 94))	('ROS', 'Chemical', 'MESH:D017382', (66, 69))	('rs1055259', 'Mutation', 'rs1055259', (36, 45))	('GSTM3', 'Gene', (99, 104))	('GSTM3', 'Gene', '2947', (99, 104))	('ROS', 'Disease', (66, 69))	('expression', 'MPA', (105, 115))	('rs1055259', 'Var', (36, 45))
208316	29569387	They protect cells against electrophilic damage via catalysing the conjugation of ROS and glutathione.9, 10 Dysfunction of GSTs has been implicated in the progression of RCC, because of the defect of anti-oxidant capacity.11 Our study showed that the ROS activity (reflected by DCF immunofluorescence) was highest in ccRCC cells with rs1055259 AA genotype than AG and GG genotypes.	('ROS', 'Chemical', 'MESH:D017382', (82, 85))	('glutathione', 'Chemical', 'MESH:D005978', (90, 101))	('GSTs', 'Gene', (123, 127))	('highest', 'Reg', (306, 313))	('ROS', 'Enzyme', (251, 254))	('rs1055259 AA', 'Var', (334, 346))	('RCC', 'Disease', (170, 173))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('RCC', 'Phenotype', 'HP:0005584', (319, 322))	('ccRCC', 'Phenotype', 'HP:0006770', (317, 322))	('RCC', 'Disease', (319, 322))	('rs1055259', 'Mutation', 'rs1055259', (334, 343))	('GSTs', 'Gene', '373156', (123, 127))	('ROS', 'Chemical', 'MESH:D017382', (251, 254))	('DCF', 'Chemical', 'MESH:D015649', (278, 281))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('RCC', 'Disease', 'MESH:C538614', (319, 322))	('conjugation', 'biological_process', 'GO:0000746', ('67', '78'))	('activity', 'MPA', (255, 263))
208317	29569387	However, rs1055259 variant was proven associated with GSTM3 expression.	('associated', 'Reg', (38, 48))	('rs1055259', 'Mutation', 'rs1055259', (9, 18))	('GSTM3', 'Gene', (54, 59))	('GSTM3', 'Gene', '2947', (54, 59))	('rs1055259', 'Var', (9, 18))
208318	29569387	Namely rs1055259 might modulate the ROS activity via elevating GSTM3 expression.	('rs1055259', 'Var', (7, 16))	('ROS activity', 'MPA', (36, 48))	('expression', 'MPA', (69, 79))	('modulate', 'Reg', (23, 31))	('GSTM3', 'Gene', (63, 68))	('elevating', 'PosReg', (53, 62))	('rs1055259', 'Mutation', 'rs1055259', (7, 16))	('ROS', 'Chemical', 'MESH:D017382', (36, 39))	('GSTM3', 'Gene', '2947', (63, 68))
208319	29569387	Thus, the subjects carrying A allele are more prone to ccRCC because their ROS activity tends to be higher against those with G allele.	('prone', 'Reg', (46, 51))	('allele', 'Var', (30, 36))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('ROS activity', 'MPA', (75, 87))	('RCC', 'Disease', (57, 60))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('higher', 'PosReg', (100, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))	('ROS', 'Chemical', 'MESH:D017382', (75, 78))
208320	29569387	Generous studies revealed that epigenetic inactivation of GSTM3 or low GSTM3 expression correlated with tumorigenesis and advanced AJCC stage of cancer.12, 13 These reports, together with our previously study,7 suggested that GSTM3 might function as a suppressor in tumour progression.	('cancer', 'Disease', (145, 151))	('expression', 'MPA', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumour', 'Disease', (266, 272))	('tumor', 'Disease', (104, 109))	('epigenetic inactivation', 'Var', (31, 54))	('GSTM3', 'Gene', (71, 76))	('GSTM3', 'Gene', (226, 231))	('GSTM3', 'Gene', '2947', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('GSTM3', 'Gene', (58, 63))	('GSTM3', 'Gene', '2947', (226, 231))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('GSTM3', 'Gene', '2947', (58, 63))	('tumour', 'Phenotype', 'HP:0002664', (266, 272))	('low', 'NegReg', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumour', 'Disease', 'MESH:D009369', (266, 272))
208321	29569387	Elevated ROS activity also played an important role in cancer cell survival and development.14 Thus, we detected the relationship between rs1055259, ROS activity and ccRCC development.	('men', 'Species', '9606', (179, 182))	('men', 'Species', '9606', (87, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('rs1055259', 'Mutation', 'rs1055259', (138, 147))	('rs1055259', 'Var', (138, 147))	('ROS', 'Chemical', 'MESH:D017382', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('ROS', 'Chemical', 'MESH:D017382', (9, 12))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('RCC', 'Disease', (168, 171))	('cancer', 'Disease', (55, 61))	('Elevated ROS activity', 'Phenotype', 'HP:0025464', (0, 21))
208323	29569387	With NAC+, the cell viability was notably reduced by more than 30%.	('reduced', 'NegReg', (42, 49))	('NAC+', 'Chemical', '-', (5, 9))	('NAC', 'cellular_component', 'GO:0005854', ('5', '8'))	('cell viability', 'CPA', (15, 29))	('NAC+', 'Var', (5, 9))
208325	29569387	There were several limitations in this study: (1) because all the participants were collected from eastern Han Chinese population, the association between GSTM3 variants and ccRCC risk might not be generalized to overall ethnic groups.	('variants', 'Var', (161, 169))	('RCC', 'Disease', (176, 179))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('ccRCC', 'Phenotype', 'HP:0006770', (174, 179))	('GSTM3', 'Gene', '2947', (155, 160))	('participants', 'Species', '9606', (66, 78))	('GSTM3', 'Gene', (155, 160))
208326	29569387	(2) The large cohort, multi-centre studies about association between rs1055259 and ccRCC risk should be performed to generate more potent statistical powers.	('rs1055259', 'Var', (69, 78))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('association', 'Interaction', (49, 60))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('RCC', 'Disease', (85, 88))	('rs1055259', 'Mutation', 'rs1055259', (69, 78))
208330	29569387	In summary, we demonstrated that rs1055259 in GSTM3 3'UTR affected the miR-556 binding and GSTM3 expression in ccRCC for the first time.	('miR-556', 'Gene', '693141', (71, 78))	('GSTM3', 'Gene', '2947', (46, 51))	('rs1055259', 'Mutation', 'rs1055259', (33, 42))	('GSTM3', 'Gene', (91, 96))	('GSTM3', 'Gene', '2947', (91, 96))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('binding', 'molecular_function', 'GO:0005488', ('79', '86'))	('affected', 'Reg', (58, 66))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('rs1055259', 'Var', (33, 42))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('miR-556', 'Gene', (71, 78))	('expression', 'MPA', (97, 107))	('GSTM3', 'Gene', (46, 51))
208331	29569387	The G allele of rs1055259 predisposes hosts to down-regulated GSTM3 and reduced ccRCC susceptibility.	('reduced', 'NegReg', (72, 79))	('rs1055259', 'Mutation', 'rs1055259', (16, 25))	('GSTM3', 'Gene', '2947', (62, 67))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('GSTM3', 'Gene', (62, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('down-regulated', 'NegReg', (47, 61))	('rs1055259', 'Var', (16, 25))
208339	28607325	In addition, PHF2 may act as a tumor suppressor via epigenetic regulation of p53 and is reported to be reduced in colon cancer and stomach cancer tissues.	('tumor suppressor', 'biological_process', 'GO:0051726', ('31', '47'))	('regulation', 'biological_process', 'GO:0065007', ('63', '73'))	('PHF2', 'Gene', (13, 17))	('stomach cancer', 'Disease', (131, 145))	('colon cancer', 'Disease', 'MESH:D015179', (114, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('p53', 'Gene', '7157', (77, 80))	('colon cancer', 'Disease', (114, 126))	('stomach cancer', 'Disease', 'MESH:D013274', (131, 145))	('stomach cancer', 'Phenotype', 'HP:0012126', (131, 145))	('reduced', 'NegReg', (103, 110))	('p53', 'Gene', (77, 80))	('tumor', 'Disease', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('31', '47'))	('colon cancer', 'Phenotype', 'HP:0003003', (114, 126))	('epigenetic', 'Var', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
208351	28607325	A recent study has shown that PHF2 can act as a tumor suppressor through epigenetic regulation of p53 and shows reduced expression in colon cancer and stomach cancer tissues.	('p53', 'Gene', (98, 101))	('colon cancer', 'Disease', (134, 146))	('stomach cancer', 'Disease', 'MESH:D013274', (151, 165))	('stomach cancer', 'Phenotype', 'HP:0012126', (151, 165))	('expression', 'MPA', (120, 130))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('PHF2', 'Gene', (30, 34))	('reduced', 'NegReg', (112, 119))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('48', '64'))	('regulation', 'biological_process', 'GO:0065007', ('84', '94'))	('tumor', 'Disease', (48, 53))	('epigenetic', 'Var', (73, 83))	('colon cancer', 'Phenotype', 'HP:0003003', (134, 146))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor suppressor', 'biological_process', 'GO:0051726', ('48', '64'))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('stomach cancer', 'Disease', (151, 165))	('colon cancer', 'Disease', 'MESH:D015179', (134, 146))	('p53', 'Gene', '7157', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
208365	28607325	We observed that high expression of PHF2 was significantly associated with longer cancer-specific survival (p=.002) and progression-free survival (p<.001) in CCRCC patients (Fig.	('progression-free survival', 'CPA', (120, 145))	('CCRCC', 'Disease', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('longer', 'PosReg', (75, 81))	('high', 'Var', (17, 21))	('CCRCC', 'Phenotype', 'HP:0006770', (158, 163))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('patients', 'Species', '9606', (164, 172))	('PHF2', 'Gene', (36, 40))
208367	28607325	However, multivariate analysis adjusted for age, Fuhrman nuclear grade and overall stage showed that high expression of PHF2 was not an independent prognostic factor in CCRCC patients with cancer-specific survival (p=.566) and progression-free survival (p=.099) (Table 2).	('progression-free survival', 'CPA', (227, 252))	('PHF2', 'Gene', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('patients', 'Species', '9606', (175, 183))	('CCRCC', 'Disease', (169, 174))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('high expression', 'Var', (101, 116))	('CCRCC', 'Phenotype', 'HP:0006770', (169, 174))	('cancer', 'Disease', (189, 195))
208369	28607325	We also observed that high expression of PHF2 was significantly correlated with longer cancer-specific survival and progression-free survival in patients.	('patients', 'Species', '9606', (145, 153))	('cancer', 'Disease', (87, 93))	('high', 'Var', (22, 26))	('PHF2', 'Gene', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('longer', 'PosReg', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('progression-free survival', 'CPA', (116, 141))
208370	28607325	Multivariate analysis adjusted for age, Fuhrman nuclear grade and overall stage showed that high expression of PHF2 was not an independent prognostic factor for cancer-specific survival and progression-free survival in CCRCC patients.	('high', 'Var', (92, 96))	('patients', 'Species', '9606', (225, 233))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('CCRCC', 'Disease', (219, 224))	('CCRCC', 'Phenotype', 'HP:0006770', (219, 224))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('PHF2', 'Gene', (111, 115))
208373	28607325	PHF2 demethylates the AT-rich interactive domain-containing protein 5B (ARID5B) and binds the promoter regions of target genes by forming a complex with demethylated ARID5B.	('ARID5B', 'Gene', '84159', (166, 172))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('AT-rich interactive domain-containing protein 5B', 'Gene', (22, 70))	('complex', 'Interaction', (140, 147))	('AT-rich interactive domain-containing protein 5B', 'Gene', '84159', (22, 70))	('binds', 'Interaction', (84, 89))	('PHF2', 'Gene', (0, 4))	('ARID5B', 'Gene', (72, 78))	('ARID5B', 'Gene', '84159', (72, 78))	('demethylated', 'Var', (153, 165))	('ARID5B', 'Gene', (166, 172))
208374	28607325	PHF2 interacts with CCAAT/enhancer-binding protein alpha (CEBPA), one of the major regulators of adipogenesis, and promotes adipogenesis by demethylating H3K9me2 in the promoter region of CEBPA target gene.	('adipogenesis', 'biological_process', 'GO:0060612', ('124', '136'))	('interacts', 'Interaction', (5, 14))	('demethylating', 'Var', (140, 153))	('adipogenesis', 'MPA', (124, 136))	('CCAAT/enhancer-binding protein alpha', 'Gene', '1050', (20, 56))	('adipogenesis', 'biological_process', 'GO:0045444', ('97', '109'))	('CCAAT/enhancer-binding protein alpha', 'Gene', (20, 56))	('PHF2', 'Gene', (0, 4))	('CEBPA', 'Gene', (188, 193))	('adipogenesis', 'biological_process', 'GO:0060612', ('97', '109'))	('CEBPA', 'Gene', (58, 63))	('enhancer-binding', 'molecular_function', 'GO:0035326', ('26', '42'))	('CEBPA', 'Gene', '1050', (188, 193))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('promotes', 'PosReg', (115, 123))	('adipogenesis', 'biological_process', 'GO:0045444', ('124', '136'))	('H3K9me2', 'Protein', (154, 161))	('CEBPA', 'Gene', '1050', (58, 63))
208380	28607325	In this regard, our findings suggest that adipogenic differentiation by histone modification is a new tumorigenic mechanism that reflects the clear cell morphology in CCRCC.	('CCRCC', 'Phenotype', 'HP:0006770', (167, 172))	('adipogenic differentiation', 'MPA', (42, 68))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('histone modification', 'Var', (72, 92))	('histone modification', 'biological_process', 'GO:0016570', ('72', '92'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('CCRCC', 'Disease', (167, 172))
208384	28607325	In esophageal squamous cell carcinoma, PHF2 was overexpressed in cancer cells compared to the non-neoplastic epithelium, and high cytoplasmic expression of PHF2 tended to be associated with decreased overall survival of the patients, but there was no statistical significance.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('PHF2', 'Gene', (39, 43))	('overexpressed', 'PosReg', (48, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('overall survival', 'MPA', (200, 216))	('esophageal squamous cell carcinoma', 'Disease', (3, 37))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('high cytoplasmic', 'Var', (125, 141))	('decreased', 'NegReg', (190, 199))	('patients', 'Species', '9606', (224, 232))	('neoplastic epithelium', 'Phenotype', 'HP:0031492', (98, 119))	('cancer', 'Disease', (65, 71))	('PHF2', 'Gene', (156, 160))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (3, 37))
208395	27600310	Moreover, Kaplan-Meier method was conducted and high expression of tumoral dectin-1 was associated with shorter patient recurrence free survival (RFS) and overall survival (OS) (P < 0.001 for both).	('overall survival', 'CPA', (155, 171))	('patient', 'Species', '9606', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('shorter', 'NegReg', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('patient recurrence free survival', 'CPA', (112, 144))	('high expression', 'Var', (48, 63))	('tumor', 'Disease', (67, 72))	('dectin-1', 'Gene', (75, 83))	('dectin-1', 'Gene', '64581', (75, 83))
208398	27600310	In conclusion, high tumoral dectin-1 expression was an independent predictor of adverse clinical outcome in ccRCC patients.	('high', 'Var', (15, 19))	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('dectin-1', 'Gene', (28, 36))	('dectin-1', 'Gene', '64581', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('expression', 'MPA', (37, 47))	('tumor', 'Disease', (20, 25))	('patients', 'Species', '9606', (114, 122))
208418	27600310	2A,E, the median survivals for both the low and high dectin-1 expression groups in the RFS and OS analyses were not reached during the follow-up.	('dectin-1', 'Gene', '64581', (53, 61))	('high', 'Var', (48, 52))	('expression', 'MPA', (62, 72))	('dectin-1', 'Gene', (53, 61))
208447	27600310	The DNA information from 2013 TCGA cohort data also suggested amplification of dectin-1 copies in ccRCC samples.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('dectin-1', 'Gene', (79, 87))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))	('dectin-1', 'Gene', '64581', (79, 87))	('amplification', 'Var', (62, 75))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
208448	27600310	It is not rare that tumor cells could aberrantly express some immune receptors and facilitate immune regulation function, like the PD-L1 expressed on tumor cells and its inhibition on PD-1 positive cells.	('immune regulation function', 'MPA', (94, 120))	('inhibition', 'NegReg', (170, 180))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('facilitate', 'PosReg', (83, 93))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('immune receptors', 'Protein', (62, 78))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('aberrantly', 'Var', (38, 48))	('regulation', 'biological_process', 'GO:0065007', ('101', '111'))	('PD-L1', 'Gene', '574058', (131, 136))	('tumor', 'Disease', (150, 155))	('PD-L1', 'Gene', (131, 136))	('tumor', 'Disease', (20, 25))
208451	27600310	Thus, we speculate that the aberrant dectin-1 expression on ccRCC might also interact with these identified or unidentified ligands on immune cells and interfere with their tumor surveillance function.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('aberrant', 'Var', (28, 36))	('dectin-1', 'Gene', (37, 45))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('interfere', 'NegReg', (152, 161))	('RCC', 'Disease', (62, 65))	('interact', 'Interaction', (77, 85))	('dectin-1', 'Gene', '64581', (37, 45))
208483	32420905	When TIMP1 expression was disrupted in ccRCC cell lines, this impaired their migratory and invasive capabilities.	('impaired', 'NegReg', (62, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('TIMP1', 'Gene', (5, 10))	('TIMP1', 'Gene', '7076', (5, 10))	('disrupted', 'Var', (26, 35))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))
208484	32420905	In summary, we employed an integrative bioinformatics approach to identify ccRCC-related DEGs and associated signaling pathways.	('signaling', 'biological_process', 'GO:0023052', ('109', '118'))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('DEGs', 'Var', (89, 93))
208497	32420905	In the present study, we conducted an integrative analysis of three previously published Gene Expression Omnibus (GEO) datasets (GSE66272, GSE100666, and GSE105261), and we utilized the 'limma' R package designed by the Bioconductor project as well as a Venn diagram program in order to identify cancer-related differentially expressed genes (DEGs) shared among these three datasets.	('GSE66272', 'Var', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('GSE100666', 'Var', (139, 148))	('GSE105261', 'Var', (154, 163))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('Gene Expression', 'biological_process', 'GO:0010467', ('89', '104'))	('cancer', 'Disease', (296, 302))
208512	32420905	Using data from GEPIA, it was noted that ccRCC patients exhibiting genomic alteration in TIMP1 demonstrated a reduction in overall and disease-free survival (P=6.8x10-7 for overall survival and P=3.7 x10-5 for disease-free survival) (Figure 3A, 3B).	('reduction', 'NegReg', (110, 119))	('genomic alteration', 'Var', (67, 85))	('patients', 'Species', '9606', (47, 55))	('TIMP1', 'Gene', (89, 94))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('TIMP1', 'Gene', '7076', (89, 94))
208526	32420905	Next, Pearson and Spearman correlation test were carried out to calculate the correlation and P value between mesenchymal genes and TIMP1 expression within 3 datasets (GSE66727, GSE100666, GSE105261).	('GSE66727', 'Var', (168, 176))	('TIMP1', 'Gene', (132, 137))	('TIMP1', 'Gene', '7076', (132, 137))	('GSE105261', 'Var', (189, 198))	('GSE100666', 'Var', (178, 187))
208530	32420905	qRT-PCR demonstrated a dramatic decrease in TIMP1 mRNA expression in A498 and Caki-1 cells following lentivirus transfection (Figure 7A, 7B).	('TIMP1', 'Gene', (44, 49))	('Caki-1', 'CellLine', 'CVCL:0234', (78, 84))	('TIMP1', 'Gene', '7076', (44, 49))	('decrease', 'NegReg', (32, 40))	('lentivirus transfection', 'Var', (101, 124))
208535	32420905	These results suggest that the knockdown of TIMP1 in A498 and Caki-1 cells induced transition to the epithelial phenotype.	('induced', 'Reg', (75, 82))	('transition', 'CPA', (83, 93))	('TIMP1', 'Gene', (44, 49))	('Caki-1', 'CellLine', 'CVCL:0234', (62, 68))	('TIMP1', 'Gene', '7076', (44, 49))	('knockdown', 'Var', (31, 40))
208556	32420905	We found that the increased expression of TIMP1 in ccRCC was positively correlated with malignant behavior, and high levels of TIMP1 predicted high risk of recurrence and reduced overall survival.	('overall survival', 'CPA', (179, 195))	('TIMP1', 'Gene', '7076', (42, 47))	('increased', 'PosReg', (18, 27))	('malignant behavior', 'CPA', (88, 106))	('correlated', 'Reg', (72, 82))	('expression', 'MPA', (28, 38))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('TIMP1', 'Gene', (127, 132))	('TIMP1', 'Gene', (42, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))	('TIMP1', 'Gene', '7076', (127, 132))	('high levels', 'Var', (112, 123))	('reduced', 'NegReg', (171, 178))
208557	32420905	This observation reveals a novel role for TIMP1 that influences ccRCC progression through potential DNA damage variants.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('TIMP1', 'Gene', '7076', (42, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('variants', 'Var', (111, 119))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('TIMP1', 'Gene', (42, 47))	('progression', 'CPA', (70, 81))	('influences', 'Reg', (53, 63))	('RCC', 'Disease', (66, 69))
208561	32420905	With the combined force of genetic alteration, inflammatory tumor microenvironments contribute towards tumor growth and distant metastasis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('genetic alteration', 'Var', (27, 45))	('distant metastasis', 'CPA', (120, 138))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
208615	32420905	Blots were blocked with 5% skim milk in TBST, followed by an overnight incubation with appropriate primary antibodies at 4 C. Antibodies were: anti-TIMP1 (Abcam, ab61224), and anti-Actin (Zen bioscience, 220529).	('anti-Actin', 'Var', (176, 186))	('TIMP1', 'Gene', (148, 153))	('TIMP1', 'Gene', '7076', (148, 153))
208657	30854496	Novel inhibitors of glutaminase, a key enzyme in glutamine metabolism, target glutamine addiction as a viable treatment strategy in metastatic RCC (mRCC).	('RCC', 'Disease', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('glutaminase', 'Gene', '2744', (20, 31))	('glutamine', 'Chemical', 'MESH:D005973', (49, 58))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('49', '69'))	('glutamine', 'Chemical', 'MESH:D005973', (78, 87))	('glutaminase', 'Gene', (20, 31))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('inhibitors', 'Var', (6, 16))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', (143, 146))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
208658	30854496	Here, we review glutamine metabolic pathways and how changes in cellular glutamine utilization enable the progression of RCC.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('changes', 'Var', (53, 60))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('glutamine', 'Chemical', 'MESH:D005973', (16, 25))	('cellular glutamine utilization', 'MPA', (64, 94))	('glutamine', 'Chemical', 'MESH:D005973', (73, 82))
208666	30854496	Here we review the role of glutamine in cellular metabolism, preclinical evidence of addiction of RCC cells to glutamine and glutaminase activity, and inhibitors of glutaminase as a novel strategy for the treatment of RCC.	('glutamine', 'Chemical', 'MESH:D005973', (111, 120))	('cellular metabolism', 'biological_process', 'GO:0044237', ('40', '59'))	('glutaminase', 'Gene', '2744', (125, 136))	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('glutaminase', 'Gene', (165, 176))	('RCC', 'Disease', (218, 221))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (218, 221))	('inhibitors', 'Var', (151, 161))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('glutaminase activity', 'molecular_function', 'GO:0004359', ('125', '145'))	('glutaminase', 'Gene', (125, 136))	('glutaminase', 'Gene', '2744', (165, 176))	('glutamine', 'Chemical', 'MESH:D005973', (27, 36))
208695	30854496	Interestingly, in most ccRCC tumors, expression levels of GLS1 seem not to be significantly changed, though expression of the more active GAC variant of GLS1 is slightly increased relative to the KGA variant in ccRCC cell lines.	('GAC', 'Gene', '2744', (138, 141))	('KGA', 'Gene', (196, 199))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('RCC tumors', 'Disease', (25, 35))	('RCC tumors', 'Disease', 'MESH:C538614', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('increased', 'PosReg', (170, 179))	('GLS1', 'Gene', (58, 62))	('KGA', 'Gene', '2744', (196, 199))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('GLS1', 'Gene', (153, 157))	('GAC', 'Gene', (138, 141))	('RCC', 'Disease', (25, 28))	('GLS1', 'Gene', '2744', (58, 62))	('variant', 'Var', (142, 149))	('GLS1', 'Gene', '2744', (153, 157))	('RCC', 'Disease', (213, 216))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('expression', 'MPA', (108, 118))
208707	30854496	The degree of metabolic reprogramming and glutamine dependence in ccRCC increases as tumors become more advanced and aggressive and accumulate genetic alterations in other oncogenes and tumor suppressor genes, for example in phosphoinositide 3-kinase (PI3K), c-MYC, or p53.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', (186, 191))	('RCC', 'Disease', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('phosphoinositide 3-kinase', 'Gene', '5290', (225, 250))	('glutamine', 'Chemical', 'MESH:D005973', (42, 51))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('p53', 'Gene', '7157', (269, 272))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('genetic alterations', 'Var', (143, 162))	('phosphoinositide 3-kinase', 'Gene', (225, 250))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Disease', (85, 91))	('p53', 'Gene', (269, 272))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('186', '202'))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('increases', 'PosReg', (72, 81))	('PI3K', 'molecular_function', 'GO:0016303', ('252', '256'))	('c-MYC', 'Gene', '4609', (259, 264))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumor suppressor', 'biological_process', 'GO:0051726', ('186', '202'))	('c-MYC', 'Gene', (259, 264))	('metabolic reprogramming', 'CPA', (14, 37))
208720	30854496	The c-MYC pathway is also activated in a subset of ccRCC tumors and in some rare forms of RCC caused by chromosomal translocations.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('chromosomal translocations', 'Var', (104, 130))	('RCC tumors', 'Disease', (53, 63))	('c-MYC', 'Gene', '4609', (4, 9))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('activated', 'PosReg', (26, 35))	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('RCC tumors', 'Disease', 'MESH:C538614', (53, 63))	('c-MYC', 'Gene', (4, 9))	('RCC', 'Disease', (90, 93))
208737	30854496	Inhibition of GLS1 by BPTES or CB-839 impaired the ability of VHL-deficient RCC cell to generate aspartate, required for the biosynthesis of pyrimidine nucleotides.	('CB-839', 'Gene', (31, 37))	('aspartate', 'Chemical', 'MESH:D001224', (97, 106))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('biosynthesis', 'biological_process', 'GO:0009058', ('125', '137'))	('CB-839', 'Chemical', 'MESH:C000593334', (31, 37))	('GLS1', 'Gene', (14, 18))	('pyrimidine nucleotides', 'Chemical', 'MESH:D011742', (141, 163))	('VHL-deficient RCC', 'Disease', 'MESH:C538614', (62, 79))	('BPTES', 'Chemical', 'MESH:C523193', (22, 27))	('Inhibition', 'Var', (0, 10))	('VHL-deficient RCC', 'Disease', (62, 79))	('ability', 'MPA', (51, 58))	('generate aspartate', 'MPA', (88, 106))	('GLS1', 'Gene', '2744', (14, 18))	('impaired', 'NegReg', (38, 46))
208763	30854496	For example, the BPTES analog UPGL00004 is a more potent inhibitor of the the GAC variant of GLS1 than BPTES and inhibits breast cancer growth in mice when combined with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab.	('anti-vascular endothelial growth factor', 'Gene', '22339', (174, 213))	('GLS1', 'Gene', '2744', (93, 97))	('GAC', 'Gene', (78, 81))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('179', '213'))	('variant', 'Var', (82, 89))	('antibody', 'cellular_component', 'GO:0019815', ('221', '229'))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('anti-vascular endothelial growth factor', 'Gene', (174, 213))	('mice', 'Species', '10090', (146, 150))	('antibody', 'cellular_component', 'GO:0019814', ('221', '229'))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('BPTES', 'Chemical', 'MESH:C523193', (103, 108))	('VEGF', 'Gene', (215, 219))	('BPTES', 'Chemical', 'MESH:C523193', (17, 22))	('GAC', 'Gene', '2744', (78, 81))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('inhibits', 'NegReg', (113, 121))	('VEGF', 'Gene', '22339', (215, 219))	('UPGL00004', 'Var', (30, 39))	('antibody', 'molecular_function', 'GO:0003823', ('221', '229'))	('breast cancer', 'Disease', (122, 135))	('antibody', 'cellular_component', 'GO:0042571', ('221', '229'))	('GLS1', 'Gene', (93, 97))	('bevacizumab', 'Chemical', 'MESH:D000068258', (230, 241))
208782	30854496	The findings that GLS1 inhibition in RCC cells leads to depletion of the intracellular glutamate pool, impaired synthesis of TCA cycle intermediates and thereby to increased DNA replication stress, more frequent DNA double-strand breaks, impaired glutathione synthesis, and increased ROS levels, suggests that markers in these cellular pathways may be explored as biomarkers for response to glutaminase inhibitors in RCC patients.	('RCC', 'Phenotype', 'HP:0005584', (417, 420))	('RCC', 'Disease', (417, 420))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('glutamate', 'Chemical', 'MESH:D018698', (87, 96))	('depletion of the intracellular glutamate pool', 'MPA', (56, 101))	('RCC', 'Disease', (37, 40))	('glutaminase', 'Gene', (391, 402))	('impaired glutathione synthesis', 'Phenotype', 'HP:0003343', (238, 268))	('ROS', 'Chemical', '-', (284, 287))	('DNA', 'cellular_component', 'GO:0005574', ('174', '177'))	('increased', 'PosReg', (164, 173))	('glutathione', 'Chemical', 'MESH:D005978', (247, 258))	('RCC', 'Disease', 'MESH:C538614', (417, 420))	('DNA replication stress', 'MPA', (174, 196))	('GLS1', 'Gene', (18, 22))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('increased ROS levels', 'Phenotype', 'HP:0025464', (274, 294))	('ROS levels', 'MPA', (284, 294))	('DNA replication', 'biological_process', 'GO:0006260', ('174', '189'))	('TCA cycle intermediates', 'MPA', (125, 148))	('increased', 'PosReg', (274, 283))	('GLS1', 'Gene', '2744', (18, 22))	('more', 'PosReg', (198, 202))	('DNA', 'cellular_component', 'GO:0005574', ('212', '215'))	('DNA double-strand breaks', 'MPA', (212, 236))	('TCA cycle', 'biological_process', 'GO:0006099', ('125', '134'))	('impaired', 'NegReg', (103, 111))	('glutaminase', 'Gene', '2744', (391, 402))	('patients', 'Species', '9606', (421, 429))	('inhibition', 'Var', (23, 33))	('TCA', 'Chemical', 'MESH:D014233', (125, 128))	('impaired glutathione synthesis', 'MPA', (238, 268))	('synthesis', 'biological_process', 'GO:0009058', ('112', '121'))	('glutathione synthesis', 'biological_process', 'GO:0006750', ('247', '268'))	('intracellular', 'cellular_component', 'GO:0005622', ('73', '86'))	('synthesis', 'MPA', (112, 121))
208808	30426074	A tentative diagnosis of RCC, cT3aN0M0 was made.	('cT3aN0M0', 'Var', (30, 38))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('RCC', 'Disease', (25, 28))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))
208822	30426074	A tentative diagnosis of RCC, cT3aN0M0 was made, and we planned for a hand-assisted laparoscopic radical nephrectomy.	('cT3aN0M0', 'Var', (30, 38))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('RCC', 'Disease', (25, 28))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))
208883	29967708	It is likewise theorized that retrograde flow between the right renal vein and right ovarian vein is the cause of metastatic dissemination to the vagina.	('right renal vein and right ovarian vein', 'Disease', 'MESH:D059228', (58, 97))	('retrograde flow', 'Var', (30, 45))	('cause', 'Reg', (105, 110))	('metastatic dissemination to the vagina', 'CPA', (114, 152))
208893	30647938	High Fuhrman grade CCRCC were significantly associated with advanced tumor stage (p<0.05, chi2 test).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('CCRCC', 'Disease', (19, 24))	('High Fuhrman', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('CCRCC', 'Phenotype', 'HP:0006770', (19, 24))
208950	30200918	Over the last decade, great progress has been made in genetic and epigenetic variations concerning RCC; Yet, the precise mechanism of RCC pathogenesis still remains unclear.	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('pathogenesis', 'biological_process', 'GO:0009405', ('138', '150'))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('RCC', 'Disease', (134, 137))	('RCC', 'Phenotype', 'HP:0005584', (134, 137))	('epigenetic variations', 'Var', (66, 87))
209013	30200918	As for wound healing assay, the migration viability of both A498 and 786-O cells was obviously decreased after LV-BANCR transfection compared with negative control (p < 0.05; Fig.	('decreased', 'NegReg', (95, 104))	('wound healing', 'biological_process', 'GO:0042060', ('7', '20'))	('migration viability', 'CPA', (32, 51))	('BANCR', 'Gene', '100885775', (114, 119))	('transfection', 'Var', (120, 132))	('BANCR', 'Gene', (114, 119))
209017	30200918	For example, it has been reported that a higher lncRNA UCA1 expression was found in esophageal squamous cell carcinoma tissues compared with normal tissues, while down-regulation of UCA1 decreases esophageal squamous cell ability of migration and proliferation.	('decreases esophageal squamous', 'Disease', (187, 216))	('UCA1', 'Gene', (182, 186))	('expression', 'MPA', (60, 70))	('lncRNA', 'MPA', (48, 54))	('decreases esophageal squamous', 'Disease', 'MESH:D000077277', (187, 216))	('esophageal squamous cell carcinoma tissues', 'Disease', 'MESH:D000077277', (84, 126))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('esophageal squamous cell carcinoma tissues', 'Disease', (84, 126))	('down-regulation', 'Var', (163, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('regulation', 'biological_process', 'GO:0065007', ('168', '178'))	('higher', 'PosReg', (41, 47))	('UCA1', 'Gene', '652995', (55, 59))	('UCA1', 'Gene', (55, 59))	('UCA1', 'Gene', '652995', (182, 186))
209055	30153799	Recently, many studies showed that IDH1 is mutated in various human cancers, especially in low-grade glioma.	('IDH1', 'Gene', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('IDH1', 'Gene', '3417', (35, 39))	('glioma', 'Disease', (101, 107))	('human', 'Species', '9606', (62, 67))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('mutated', 'Var', (43, 50))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
209056	30153799	The most common mutation site of IDH1 is the R132H, which acquires the ability to catalyze the reduction of a-KG to 2-hydroxyglutarate (2-HG).	('IDH1', 'Gene', (33, 37))	('R132H', 'Var', (45, 50))	('R132H', 'Mutation', 'rs121913500', (45, 50))	('IDH1', 'Gene', '3417', (33, 37))	('reduction', 'MPA', (95, 104))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (116, 134))
209057	30153799	Moreover, several studies indicated that the R132H mutation of IDH1 correlates with a favorable prognosis for patients with glioma and gastrointestinal cancer.	('IDH1', 'Gene', '3417', (63, 67))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (135, 158))	('glioma', 'Disease', (124, 130))	('R132H', 'Var', (45, 50))	('R132H', 'Mutation', 'rs121913500', (45, 50))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (135, 158))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('gastrointestinal cancer', 'Disease', (135, 158))	('IDH1', 'Gene', (63, 67))	('patients', 'Species', '9606', (110, 118))
209082	30153799	Interesting, patients with low IDH1 expression showed poorer OS (p = 0.004) and RFS (p = 0.03) than patients in high IDH1 expression group (Fig.	('poorer', 'NegReg', (54, 60))	('IDH1', 'Gene', '3417', (117, 121))	('IDH1', 'Gene', '3417', (31, 35))	('RFS', 'CPA', (80, 83))	('patients', 'Species', '9606', (13, 21))	('expression', 'Var', (36, 46))	('low', 'Var', (27, 30))	('patients', 'Species', '9606', (100, 108))	('OS', 'Chemical', '-', (61, 63))	('IDH1', 'Gene', (117, 121))	('IDH1', 'Gene', (31, 35))
209084	30153799	2c and f, IDH1 expression level showed as an adverse prognostic factor for both OS and RFS in intermediated- and high-risk groups (OS, p = 0.049; RFS, p = 0.004), while in the low-risk group it did not meet statistical significance.	('IDH1', 'Gene', '3417', (10, 14))	('OS', 'Chemical', '-', (80, 82))	('OS', 'Chemical', '-', (131, 133))	('RFS', 'Disease', (87, 90))	('IDH1', 'Gene', (10, 14))	('expression level', 'Var', (15, 31))
209095	30153799	IDH1, a NADP-dependent enzyme which involves in the control of oxidative cellular damage, was identified as a tumor suppressor since its inactivation plays a vital role in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('inactivation', 'Var', (137, 149))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Disease', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('NADP', 'Chemical', 'MESH:D009249', (8, 12))	('IDH1', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('IDH1', 'Gene', '3417', (0, 4))
209103	30153799	In recent years, mutations in IDH1 gene were reported in various tumors, which confer IDH1 the new enzymatic function of catalyzing alpha-KG to R-2-hydroxyglutarate (2-HG).	('IDH1', 'Gene', (86, 90))	('reported', 'Reg', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('alpha-KG', 'Chemical', '-', (132, 140))	('IDH1', 'Gene', '3417', (86, 90))	('IDH1', 'Gene', (30, 34))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('R-2-hydroxyglutarate', 'Chemical', '-', (144, 164))	('mutations', 'Var', (17, 26))	('IDH1', 'Gene', '3417', (30, 34))
209104	30153799	The role of IDH1 gene mutation in esophageal squamous cell carcinoma, glioma and acute myeloid leukemia (AML) have been successively reported.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (81, 103))	('glioma', 'Disease', (70, 76))	('mutation', 'Var', (22, 30))	('AML', 'Disease', 'MESH:D015470', (105, 108))	('IDH1', 'Gene', (12, 16))	('acute myeloid leukemia', 'Disease', (81, 103))	('esophageal squamous cell carcinoma', 'Disease', (34, 68))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('AML', 'Phenotype', 'HP:0004808', (105, 108))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('AML', 'Disease', (105, 108))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (81, 103))	('IDH1', 'Gene', '3417', (12, 16))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (87, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('leukemia', 'Phenotype', 'HP:0001909', (95, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (34, 68))
209107	30153799	Overexpression of IDH1 was reported in non-small cell lung (NSCL) cancer, both in plasma and tumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('IDH1', 'Gene', '3417', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('NSCL', 'Disease', 'None', (60, 64))	('NSCL', 'Disease', (60, 64))	('tumor', 'Disease', (93, 98))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('IDH1', 'Gene', (18, 22))	('cancer', 'Disease', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
209110	30153799	The mechanism of low IDH1 participates in progression of cancers has not been well elaborated.	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('IDH1', 'Gene', (21, 25))	('low', 'Var', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('IDH1', 'Gene', '3417', (21, 25))
209138	32512506	For instance, a study which examined tissues from patients who subsequently underwent VEGF directed systemic targeted therapy found that those tumors with mutations in KDM5C, PBRM1, and VHL were more likely to respond to anti-VEGF therapy.	('VEGF', 'Gene', '7422', (226, 230))	('VHL', 'Gene', (186, 189))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('mutations', 'Var', (155, 164))	('respond', 'MPA', (210, 217))	('VEGF', 'Gene', (86, 90))	('patients', 'Species', '9606', (50, 58))	('VHL', 'Gene', '7428', (186, 189))	('PBRM1', 'Gene', (175, 180))	('tumors', 'Disease', (143, 149))	('more', 'PosReg', (195, 199))	('PBRM1', 'Gene', '55193', (175, 180))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('KDM5C', 'Gene', (168, 173))	('VEGF', 'Gene', '7422', (86, 90))	('VEGF', 'Gene', (226, 230))	('KDM5C', 'Gene', '8242', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
209139	32512506	Similarly, mutations of mTOR, TSC1, and TSC2 were associated with better responses to the mTOR inhibitor everolimus.	('mutations', 'Var', (11, 20))	('mTOR', 'Gene', (90, 94))	('mTOR', 'Gene', '2475', (90, 94))	('better', 'PosReg', (66, 72))	('TSC1', 'Gene', '7248', (30, 34))	('TSC2', 'Gene', '7249', (40, 44))	('everolimus', 'Chemical', 'MESH:D000068338', (105, 115))	('TSC1', 'Gene', (30, 34))	('TSC2', 'Gene', (40, 44))	('mTOR', 'Gene', (24, 28))	('mTOR', 'Gene', '2475', (24, 28))
209143	32512506	Inhibitors that target SPOP may also enhance diagnostics using sensitive imaging modalities, such as positron emission tomography or single-photon emission computerized tomography, that can determine tumor burden.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('diagnostics', 'MPA', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('Inhibitors', 'Var', (0, 10))	('tumor', 'Disease', (200, 205))	('SPOP', 'Gene', (23, 27))	('enhance', 'PosReg', (37, 44))
209188	31649873	To assess the correlation of hub gene expression in four distinct Fuhrman grades, we conducted a linear regression analysis using two additional independent validation datasets GSE40435 and GSE73731.	('regression', 'Disease', (104, 114))	('hub', 'Gene', '1993', (29, 32))	('GSE40435', 'Var', (177, 185))	('hub', 'Gene', (29, 32))	('GSE73731', 'Var', (190, 198))	('gene expression', 'biological_process', 'GO:0010467', ('33', '48'))	('regression', 'Disease', 'MESH:C537770', (104, 114))
209258	31649873	ACAT1 gene mutation induced a deficiency in mitochondrial acetoacetyl-CoA thiolase, which was also called ketothiolase deficiency.	('deficiency', 'Disease', (30, 40))	('deficiency', 'Disease', 'None', (30, 40))	('deficiency', 'Disease', 'None', (119, 129))	('acetoacetyl-CoA', 'Chemical', 'MESH:C010667', (58, 73))	('ACAT1', 'Gene', (0, 5))	('mitochondrial', 'MPA', (44, 57))	('mutation', 'Var', (11, 19))	('ACAT1', 'Gene', '38', (0, 5))	('deficiency', 'Disease', (119, 129))
209271	31649873	Furthermore, an in vitro study indicated that overexpressed ACAT1 inhibited the proliferation and migration of renal cell ACHN and Caki1 cells, suggesting that ACAT1 might be a favorable prognostic marker in ccRCC (Figures 5E,F).	('ccRCC', 'Disease', (208, 213))	('ACHN', 'Gene', '55323', (122, 126))	('overexpressed', 'Var', (46, 59))	('ccRCC', 'Disease', 'MESH:D002292', (208, 213))	('ACAT1', 'Gene', (160, 165))	('proliferation', 'CPA', (80, 93))	('ACAT1', 'Gene', (60, 65))	('ACAT1', 'Gene', '38', (160, 165))	('ACHN', 'Gene', (122, 126))	('inhibited', 'NegReg', (66, 75))	('ACAT1', 'Gene', '38', (60, 65))	('RCC', 'Phenotype', 'HP:0005584', (210, 213))	('ccRCC', 'Phenotype', 'HP:0006770', (208, 213))
209280	33580750	Initially described as a gene causing maturity-onset diabetes of the young (MODY), HNF1beta expression deregulation and single nucleotide polymorphisms in HNF1beta have now been associated with several tumours including endometrial, prostate, ovarian, hepatocellular, renal and colorectal cancers.	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('tumours', 'Phenotype', 'HP:0002664', (202, 209))	('HNF1beta', 'Gene', '6927', (83, 91))	('tumours', 'Disease', 'MESH:D009369', (202, 209))	('ovarian', 'Disease', (243, 250))	('HNF1beta', 'Gene', (83, 91))	('diabetes', 'Disease', 'MESH:D003920', (53, 61))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('deregulation', 'PosReg', (103, 115))	('single nucleotide polymorphisms', 'Var', (120, 151))	('renal and colorectal cancers', 'Disease', 'MESH:D015179', (268, 296))	('ovarian', 'Disease', 'MESH:D010049', (243, 250))	('diabetes', 'Disease', (53, 61))	('MODY', 'Phenotype', 'HP:0004904', (76, 80))	('endometrial', 'Disease', (220, 231))	('expression', 'MPA', (92, 102))	('maturity-onset diabetes of the young', 'Phenotype', 'HP:0004904', (38, 74))	('associated', 'Reg', (178, 188))	('colorectal cancer', 'Phenotype', 'HP:0003003', (278, 295))	('cancers', 'Phenotype', 'HP:0002664', (289, 296))	('HNF1beta', 'Gene', '6927', (155, 163))	('prostate', 'Disease', (233, 241))	('tumours', 'Disease', (202, 209))	('HNF1beta', 'Gene', (155, 163))	('hepatocellular', 'Disease', (252, 266))
209288	33580750	5  Wu et al studied different domains of HNF1B in the process of nephrogenesis and identified dimerization domain, homeodomain and a conserved 26 amino acid segment between the POUS and POUH domain found in B variant of HNF1B to interfere with pronephric development.	('nephrogenesis', 'Disease', (65, 78))	('interfere', 'NegReg', (229, 238))	('nephrogenesis', 'Disease', 'None', (65, 78))	('HNF1B', 'Gene', (220, 225))	('men', 'Species', '9606', (262, 265))	('dimerization', 'MPA', (94, 106))	('variant', 'Var', (209, 216))	('nephrogenesis', 'biological_process', 'GO:0001822', ('65', '78'))	('men', 'Species', '9606', (160, 163))	('nephrogenesis', 'biological_process', 'GO:0072006', ('65', '78'))	('pronephric development', 'CPA', (244, 266))
209290	33580750	In humans, mutations in HNF1B have been recognised with multisystem phenotype.	('mutations', 'Var', (11, 20))	('humans', 'Species', '9606', (3, 9))	('HNF1B', 'Gene', (24, 29))
209291	33580750	HNF1B mutations were first defined as an intermittent genetic basis of maturity-onset diabetes of the young (MODY).	('MODY', 'Phenotype', 'HP:0004904', (109, 113))	('diabetes', 'Disease', (86, 94))	('diabetes', 'Disease', 'MESH:D003920', (86, 94))	('maturity-onset diabetes of the young', 'Phenotype', 'HP:0004904', (71, 107))	('HNF1B', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
209293	33580750	Renal cysts were found to be the main clinical aspect with HNF1B mutations and the linkage of renal cysts with diabetes steered to the description of renal cysts and diabetes syndrome.	('HNF1B', 'Gene', (59, 64))	('renal cysts', 'Disease', (150, 161))	('diabetes syndrome', 'Disease', (166, 183))	('Renal cysts', 'Phenotype', 'HP:0000107', (0, 11))	('renal cysts', 'Disease', 'MESH:D007674', (94, 105))	('diabetes', 'Disease', (111, 119))	('renal cysts', 'Disease', (94, 105))	('Renal cysts', 'Disease', (0, 11))	('renal cysts', 'Phenotype', 'HP:0000107', (150, 161))	('diabetes', 'Disease', (166, 174))	('diabetes syndrome', 'Disease', 'MESH:D003920', (166, 183))	('diabetes', 'Disease', 'MESH:D003920', (111, 119))	('Renal cysts', 'Disease', 'MESH:D007674', (0, 11))	('diabetes', 'Disease', 'MESH:D003920', (166, 174))	('renal cysts', 'Phenotype', 'HP:0000107', (94, 105))	('renal cysts', 'Disease', 'MESH:D007674', (150, 161))	('mutations', 'Var', (65, 74))
209299	33580750	14  GWAS have identified SNPs in HNF1B associated with endometrial cancer (EC) risk in European ancestry and identified rs4430796 SNP as an EC susceptible locus near HNF1B  15  and was replicated in multiethnic replication studies.	('rs4430796 SNP', 'Var', (120, 133))	('EC', 'Phenotype', 'HP:0012114', (140, 142))	('endometrial cancer', 'Disease', (55, 73))	('SNPs', 'Var', (25, 29))	('HNF1B', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('endometrial cancer', 'Phenotype', 'HP:0012114', (55, 73))	('associated', 'Reg', (39, 49))	('rs4430796', 'Mutation', 'rs4430796', (120, 129))	('endometrial cancer', 'Disease', 'MESH:D016889', (55, 73))	('EC', 'Phenotype', 'HP:0012114', (75, 77))
209301	33580750	in a large case-control cohort study on HNF1B variants identified rs7501939 SNP in addition to the rs4430796 SNP and confirmed their association with EC risk, demonstrating the association of this locus with both EC type I as well as II tumours.	('EC', 'Phenotype', 'HP:0012114', (150, 152))	('EC', 'Phenotype', 'HP:0012114', (213, 215))	('tumour', 'Phenotype', 'HP:0002664', (237, 243))	('rs7501939', 'Mutation', 'rs7501939', (66, 75))	('tumours', 'Phenotype', 'HP:0002664', (237, 244))	('rs4430796', 'Var', (99, 108))	('association', 'Reg', (133, 144))	('variants', 'Var', (46, 54))	('HNF1B', 'Gene', (40, 45))	('EC type I', 'Disease', (213, 222))	('association', 'Interaction', (177, 188))	('II tumours', 'Disease', (234, 244))	('rs7501939 SNP', 'Var', (66, 79))	('rs4430796', 'Mutation', 'rs4430796', (99, 108))	('II tumours', 'Disease', 'MESH:D009369', (234, 244))
209302	33580750	13  The minor allele of rs11263763 and rs8064454 SNPs are correlated with decreased HNF1B promotor activity suggesting the risk observed at the HNF1B locus is likely mediated due to altered HNF1B gene expression.	('rs11263763', 'Mutation', 'rs11263763', (24, 34))	('rs8064454', 'Mutation', 'rs8064454', (39, 48))	('rs11263763', 'Var', (24, 34))	('rs8064454', 'Var', (39, 48))	('HNF1B', 'Gene', (84, 89))	('HNF1B', 'Gene', (190, 195))	('gene expression', 'biological_process', 'GO:0010467', ('196', '211'))	('decreased', 'NegReg', (74, 83))	('HNF1B', 'Gene', (144, 149))
209304	33580750	SNP rs4430796, in HNF1B, was strongly linked to prostate cancer risk and was one of the first loci to be identified for prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('linked', 'Reg', (38, 44))	('HNF1B', 'Gene', (18, 23))	('prostate cancer', 'Phenotype', 'HP:0012125', (120, 135))	('prostate cancer', 'Disease', 'MESH:D011471', (48, 63))	('SNP rs4430796', 'Var', (0, 13))	('prostate cancer', 'Phenotype', 'HP:0012125', (48, 63))	('prostate cancer', 'Disease', (120, 135))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('prostate cancer', 'Disease', (48, 63))	('prostate cancer', 'Disease', 'MESH:D011471', (120, 135))	('rs4430796', 'Mutation', 'rs4430796', (4, 13))
209305	33580750	21  Another independent SNP, rs11649743, found on chromosome 17q12 was later established to correspond with prostate cancer risk.	('rs11649743', 'Var', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('prostate cancer', 'Disease', 'MESH:D011471', (108, 123))	('rs11649743', 'Mutation', 'rs11649743', (29, 39))	('prostate cancer', 'Phenotype', 'HP:0012125', (108, 123))	('chromosome', 'cellular_component', 'GO:0005694', ('50', '60'))	('correspond with', 'Reg', (92, 107))	('prostate cancer', 'Disease', (108, 123))
209307	33580750	A fine-mapping study in European ancestry indicated the role of five SNPs (rs4430796, rs4794758, rs3094509, rs7405696 and rs1016990) as the best predictors for prostate cancer risk in HNF1B gene loci.	('rs3094509', 'Var', (97, 106))	('rs4794758', 'Mutation', 'rs4794758', (86, 95))	('prostate cancer', 'Disease', (160, 175))	('rs1016990', 'Var', (122, 131))	('rs7405696', 'Mutation', 'rs7405696', (108, 117))	('rs4430796', 'Var', (75, 84))	('HNF1B', 'Gene', (184, 189))	('rs4794758', 'Var', (86, 95))	('rs7405696', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('rs1016990', 'Mutation', 'rs1016990', (122, 131))	('prostate cancer', 'Disease', 'MESH:D011471', (160, 175))	('rs4430796', 'Mutation', 'rs4430796', (75, 84))	('rs3094509', 'Mutation', 'rs3094509', (97, 106))	('prostate cancer', 'Phenotype', 'HP:0012125', (160, 175))
209308	33580750	identified two novel causal variants, rs11263763 and rs718961 in the HNF1B region, along with rs2229295 within 3'UTR to be another potential casual variant for further investigation.	('rs718961', 'Mutation', 'rs718961', (53, 61))	('HNF1B', 'Gene', (69, 74))	('rs11263763', 'Mutation', 'rs11263763', (38, 48))	('rs718961', 'Var', (53, 61))	('rs11263763', 'Var', (38, 48))	('rs2229295', 'Var', (94, 103))	('rs2229295', 'Mutation', 'rs2229295', (94, 103))
209309	33580750	23  The novel SNPs, rs11263763 in the first intron and rs718961 in the fourth intron overlapping with several bio features were regarded as promising candidates with functional impact.	('rs718961', 'Var', (55, 63))	('rs11263763', 'Mutation', 'rs11263763', (20, 30))	('rs718961', 'Mutation', 'rs718961', (55, 63))	('rs11263763', 'Var', (20, 30))
209310	33580750	discovered the loci linked with prostate cancer in North Chinese inhabitants pointing out that the risk allele of the rs4430796 SNP can be associated with high PSA levels.	('rs4430796', 'Var', (118, 127))	('prostate cancer', 'Disease', (32, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('rs4430796', 'Mutation', 'rs4430796', (118, 127))	('high PSA levels', 'Disease', (155, 170))	('associated', 'Reg', (139, 149))	('prostate cancer', 'Disease', 'MESH:D011471', (32, 47))	('prostate cancer', 'Phenotype', 'HP:0012125', (32, 47))
209311	33580750	showed SNPs rs4430796 and rs7501939 to be potential risk alleles in primary prostate tumours.	('rs7501939', 'Var', (26, 35))	('SNPs rs4430796', 'Var', (7, 21))	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('primary prostate tumours', 'Disease', 'MESH:D011471', (68, 92))	('rs4430796', 'Mutation', 'rs4430796', (12, 21))	('primary prostate tumours', 'Disease', (68, 92))	('rs7501939', 'Mutation', 'rs7501939', (26, 35))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
209312	33580750	25  Machiela et al when examining common variants between type-2 diabetes (T2D) and prostate cancer found rs757210 in HNF1B to be significantly associated with prostate cancer risk.	('diabetes', 'Disease', (65, 73))	('prostate cancer', 'Phenotype', 'HP:0012125', (160, 175))	('associated with', 'Reg', (144, 159))	('prostate cancer', 'Disease', (84, 99))	('prostate cancer', 'Disease', (160, 175))	('HNF1B', 'Gene', (118, 123))	('diabetes', 'Disease', 'MESH:D003920', (65, 73))	('rs757210', 'Mutation', 'rs757210', (106, 114))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('T2D', 'Phenotype', 'HP:0005978', (75, 78))	('prostate cancer', 'Disease', 'MESH:D011471', (160, 175))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('prostate cancer', 'Disease', 'MESH:D011471', (84, 99))	('type-2 diabetes', 'Phenotype', 'HP:0005978', (58, 73))	('rs757210', 'Var', (106, 114))
209314	33580750	26  Additionally, diabetogenic variants were also shown to be associated with multiple myeloma.	('variants', 'Var', (31, 39))	('associated', 'Reg', (62, 72))	('multiple myeloma', 'Phenotype', 'HP:0006775', (78, 94))	('multiple myeloma', 'Disease', 'MESH:D009101', (78, 94))	('multiple myeloma', 'Disease', (78, 94))
209318	33580750	Although there was no supporting evidence for this hypothesis, in-depth investigation is required into associating these risk variants with differential regulation of transcript variants/isoforms which may have tumour suppressor and/ or oncogenic roles.	('tumour', 'Disease', 'MESH:D009369', (211, 217))	('regulation', 'biological_process', 'GO:0065007', ('153', '163'))	('variants', 'Var', (126, 134))	('tumour', 'Disease', (211, 217))	('transcript', 'MPA', (167, 177))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))
209319	33580750	SNPs at HNF1B gene loci are also associated with biochemical failure and tumour aggressiveness.	('tumour aggressiveness', 'Disease', 'MESH:D009369', (73, 94))	('tumour aggressiveness', 'Disease', (73, 94))	('SNPs', 'Var', (0, 4))	('HNF1B', 'Gene', (8, 13))	('associated', 'Reg', (33, 43))	('biochemical failure', 'CPA', (49, 68))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('aggressiveness', 'Phenotype', 'HP:0000718', (80, 94))
209320	33580750	Logistic regression analysis in Korean patients (240 prostate cancer subjects and 223 controls) to evaluate the effects of 47 SNPs in HNF1B on prostate risk.	('prostate cancer', 'Disease', (53, 68))	('patients', 'Species', '9606', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('prostate cancer', 'Disease', 'MESH:D011471', (53, 68))	('SNPs', 'Var', (126, 130))	('prostate', 'Disease', (143, 151))	('prostate cancer', 'Phenotype', 'HP:0012125', (53, 68))	('HNF1B', 'Gene', (134, 139))
209321	33580750	28  The rs11868513 SNP was found to be more prevalent in patients with higher aggressive tumour stage compared to the low aggressive tumour stage.	('rs11868513', 'Mutation', 'rs11868513', (8, 18))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('aggressive tumour', 'Disease', 'MESH:D009369', (78, 95))	('patients', 'Species', '9606', (57, 65))	('aggressive tumour', 'Disease', 'MESH:D009369', (122, 139))	('low aggressive tumour', 'Disease', (118, 139))	('aggressive tumour', 'Disease', (78, 95))	('rs11868513', 'Var', (8, 18))	('low aggressive tumour', 'Disease', 'MESH:D009800', (118, 139))	('prevalent', 'Reg', (44, 53))
209322	33580750	Strong prostate cancer risk association was observed in patients with rs4430796 and rs2074429 haplotypes with a Gleason score of >=7.	('rs4430796', 'Var', (70, 79))	('patients', 'Species', '9606', (56, 64))	('rs4430796', 'Mutation', 'rs4430796', (70, 79))	('prostate cancer', 'Phenotype', 'HP:0012125', (7, 22))	('Strong prostate cancer', 'Disease', 'MESH:D011471', (0, 22))	('rs2074429', 'Var', (84, 93))	('rs2074429', 'Mutation', 'rs2074429', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('Strong prostate cancer', 'Disease', (0, 22))
209323	33580750	Although this study was the first in associating HNF1B polymorphisms with prostate cancer risk in Korean men, the statistical significance of the SNPs was limited due to the small sample size.	('prostate cancer', 'Disease', (74, 89))	('HNF1B', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('men', 'Species', '9606', (105, 108))	('prostate cancer', 'Disease', 'MESH:D011471', (74, 89))	('polymorphisms', 'Var', (55, 68))	('prostate cancer', 'Phenotype', 'HP:0012125', (74, 89))
209325	33580750	Using a multilevel molecular epidemiology approach in patients with prostatectomy and biochemical failure, 29  the rs4430796 SNP was found to be significantly associated with increased biochemical failure (p = 0.02), highlighting the biological relevance of this SNP in disease progression.	('rs4430796', 'Var', (115, 124))	('rs4430796', 'Mutation', 'rs4430796', (115, 124))	('patients', 'Species', '9606', (54, 62))	('biochemical failure', 'CPA', (185, 204))	('increased', 'PosReg', (175, 184))
209329	33580750	Although some of the known major risk loci (KITLG, SPRY4, BAK1 and DMRT1) were also implicated with this cancer risk, some of the low penetrant risk alleles such as rs7501938 SNP also need to considered for a better understanding of the genetic cause of this disease.	('rs7501938', 'Mutation', 'rs7501938', (165, 174))	('rs7501938 SNP', 'Var', (165, 178))	('DMRT1', 'Gene', '1761', (67, 72))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('SPRY4', 'Gene', (51, 56))	('BAK1', 'Gene', '578', (58, 62))	('KITLG', 'Gene', '4254', (44, 49))	('KITLG', 'Gene', (44, 49))	('DMRT1', 'Gene', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('BAK1', 'Gene', (58, 62))	('SPRY4', 'Gene', '81848', (51, 56))
209330	33580750	Despite the great knowledge of mutations in HNF1B in MODY, few studies have highlighted the role of mutations in cancer.	('mutations', 'Var', (31, 40))	('MODY', 'Phenotype', 'HP:0004904', (53, 57))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('HNF1B', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
209331	33580750	Nemejcova et al while understanding the genetic changes of HNF1B in endometrial lesions, revealed truncated variants in ovarian clear cell carcinoma (CCC).	('HNF1B', 'Gene', (59, 64))	('ovarian clear cell carcinoma', 'Disease', (120, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('variants', 'Var', (108, 116))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (120, 148))	('endometrial lesions', 'Disease', 'MESH:D014591', (68, 87))	('endometrial lesions', 'Disease', (68, 87))	('CCC', 'cellular_component', 'GO:0030896', ('150', '153'))
209332	33580750	31  The study identified 4 sequence variations and one missense mutation in ovarian CCC patients.	('patients', 'Species', '9606', (88, 96))	('ovarian CCC', 'Disease', 'MESH:C535313', (76, 87))	('CCC', 'cellular_component', 'GO:0030896', ('84', '87'))	('sequence variations', 'Var', (27, 46))	('ovarian CCC', 'Disease', (76, 87))
209333	33580750	In silico analysis suggested a nonsense mutation (p.Gln152X) to lead to premature translation termination and another missense variant in the DNA binding domain (p.Ala283Val) to have a damaging effect on the function of the protein (Refer to Table 1).	('DNA', 'cellular_component', 'GO:0005574', ('142', '145'))	('protein', 'Protein', (224, 231))	('protein', 'cellular_component', 'GO:0003675', ('224', '231'))	('translation termination', 'biological_process', 'GO:0006415', ('82', '105'))	('lead', 'Reg', (64, 68))	('premature translation termination', 'MPA', (72, 105))	('p.Ala283Val', 'Mutation', 'p.A283V', (162, 173))	('function of the', 'MPA', (208, 223))	('p.Ala283Val', 'Var', (162, 173))	('DNA binding', 'molecular_function', 'GO:0003677', ('142', '153'))	('p.Gln152X', 'Mutation', 'p.Q152X', (50, 59))	('p.Gln152X', 'Var', (50, 59))
209334	33580750	Genetic modifications and Epigenetic mechanisms influence carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (58, 72))	('carcinogenesis', 'Disease', (58, 72))	('influence', 'Reg', (48, 57))	('Epigenetic mechanisms', 'Var', (26, 47))	('Genetic modifications', 'Var', (0, 21))
209335	33580750	Identification of mutations and its associated effect on the epigenome through next-generation sequencing has broadened our understanding of cancer regulatory pathways affecting cellular characteristics.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('effect', 'Reg', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('epigenome', 'MPA', (61, 70))	('cancer', 'Disease', (141, 147))	('mutations', 'Var', (18, 27))
209336	33580750	34  In a study conducted to investigate the role of GATA4 and HNF1B methylation in Ovarian cancer (OC) patients, around 32.8% HNF1B methylation positive patterns were observed in OC tissue samples compared to controls.	('HNF1B', 'Gene', (62, 67))	('GATA4', 'Gene', '2626', (52, 57))	('GATA4', 'Gene', (52, 57))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('OC', 'Phenotype', 'HP:0100615', (99, 101))	('OC', 'Phenotype', 'HP:0100615', (179, 181))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('methylation', 'biological_process', 'GO:0032259', ('132', '143'))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('patients', 'Species', '9606', (103, 111))	('HNF1B', 'Gene', (126, 131))	('methylation', 'Var', (132, 143))
209338	33580750	36  Epigenetic silencing of the HNF1B gene was observed in the cell lines due to methylation, decreasing the expression of HNF4alpha suggesting the role of hepatocyte nuclear factor network of genes in tumours.	('decreasing', 'NegReg', (94, 104))	('HNF4alpha', 'Gene', '3172', (123, 132))	('methylation', 'biological_process', 'GO:0032259', ('81', '92'))	('expression', 'MPA', (109, 119))	('methylation', 'Var', (81, 92))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('tumours', 'Phenotype', 'HP:0002664', (202, 209))	('HNF1B', 'Gene', (32, 37))	('tumours', 'Disease', 'MESH:D009369', (202, 209))	('Epigenetic silencing', 'Var', (4, 24))	('tumours', 'Disease', (202, 209))	('HNF4alpha', 'Gene', (123, 132))
209340	33580750	Additionally, this group also highlighted HNF1B methylation patterns in colorectal, gastric and pancreatic cell lines, all of which showed silencing of HNF1B gene expression due to methylation.	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('silencing', 'NegReg', (139, 148))	('HNF1B', 'Gene', (152, 157))	('methylation', 'Var', (181, 192))	('methylation', 'biological_process', 'GO:0032259', ('181', '192'))	('expression', 'MPA', (163, 173))	('colorectal', 'Disease', 'MESH:D015179', (72, 82))	('gene expression', 'biological_process', 'GO:0010467', ('158', '173'))	('colorectal', 'Disease', (72, 82))	('HNF1B', 'Gene', (42, 47))
209342	33580750	37  Early-stage breast cancer samples exhibited 73% methylation patterns establishing the role of HNF1B methylation with epigenetic reprogramming and carcinogenesis in breast tumours, confirming the role of the epigenome in carcinogenesis.	('breast cancer', 'Disease', (16, 29))	('carcinogenesis', 'Disease', 'MESH:D063646', (150, 164))	('carcinogenesis in breast tumours', 'Disease', (150, 182))	('carcinogenesis', 'Disease', (150, 164))	('carcinogenesis in breast tumours', 'Disease', 'MESH:D001943', (150, 182))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('tumours', 'Phenotype', 'HP:0002664', (175, 182))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('HNF1B', 'Gene', (98, 103))	('methylation', 'Var', (104, 115))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('carcinogenesis', 'Disease', 'MESH:D063646', (224, 238))	('methylation', 'biological_process', 'GO:0032259', ('104', '115'))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('carcinogenesis', 'Disease', (224, 238))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
209344	33580750	Unmethylated HNF1B promoter displayed expression of the protein in clear cell tumours whereas serous tumours which displayed methylation at HNF1B lacked the protein expression.	('methylation', 'biological_process', 'GO:0032259', ('125', '136'))	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('expression', 'MPA', (38, 48))	('tumours whereas serous tumours', 'Disease', 'MESH:D009369', (78, 108))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('tumours whereas serous tumours', 'Disease', (78, 108))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))	('HNF1B', 'Gene', (140, 145))	('HNF1B', 'Gene', (13, 18))	('methylation', 'Var', (125, 136))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))
209347	33580750	A study to understand DNA methylation in colorectal cancer identified HNF1B methylation in colorectal patients.	('colorectal', 'Disease', 'MESH:D015179', (91, 101))	('colorectal cancer', 'Phenotype', 'HP:0003003', (41, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('HNF1B', 'Gene', (70, 75))	('colorectal cancer', 'Disease', (41, 58))	('patients', 'Species', '9606', (102, 110))	('DNA methylation', 'biological_process', 'GO:0006306', ('22', '37'))	('colorectal', 'Disease', 'MESH:D015179', (41, 51))	('colorectal', 'Disease', (91, 101))	('methylation', 'Var', (76, 87))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('methylation', 'biological_process', 'GO:0032259', ('76', '87'))	('colorectal cancer', 'Disease', 'MESH:D015179', (41, 58))	('colorectal', 'Disease', (41, 51))
209349	33580750	In clear cell carcinoma, a pattern of hypomethylation has a positive correlation to increased expression suggesting an oncogenic role in this disease.	('hypomethylation', 'Var', (38, 53))	('clear cell carcinoma', 'Disease', (3, 23))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (3, 23))	('increased', 'PosReg', (84, 93))	('expression', 'MPA', (94, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
209352	33580750	Alternative splicing has been vastly studied in cancer, changing the landscape and functions of many oncogenes and tumour suppressor genes.	('landscape', 'MPA', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('Alternative splicing', 'Var', (0, 20))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('changing', 'Reg', (56, 64))	('tumour', 'Disease', (115, 121))	('splicing', 'biological_process', 'GO:0045292', ('12', '20'))
209354	33580750	46  Several tumour suppressor genes also undergo alternative splicing, causing, complete or partial loss of function.	('splicing', 'biological_process', 'GO:0045292', ('61', '69'))	('tumour', 'Disease', (12, 18))	('loss of function', 'NegReg', (100, 116))	('alternative splicing', 'Var', (49, 69))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumour', 'Disease', 'MESH:D009369', (12, 18))
209361	33580750	HNF1B (A) and HNF1B (B) variants are analogous structurally and hence could exhibit functional anomaly.	('variants', 'Var', (24, 32))	('anomaly', 'Disease', 'MESH:D000014', (95, 102))	('exhibit', 'Reg', (76, 83))	('anomaly', 'Disease', (95, 102))	('HNF1B', 'Gene', (0, 5))	('HNF1B', 'Gene', (14, 19))
209399	33580750	71  Increased expression of zyxin leads to the transcriptional activity of HNF1B, on the contrary siRNA (RNA mediated) silencing of zyxin impeded the HNF1B-dependent transcription.	('RNA', 'cellular_component', 'GO:0005562', ('105', '108'))	('zyxin', 'Gene', (132, 137))	('transcriptional activity', 'MPA', (47, 71))	('transcription', 'biological_process', 'GO:0006351', ('166', '179'))	('zyxin', 'Gene', '7791', (132, 137))	('HNF1B-dependent transcription', 'MPA', (150, 179))	('HNF1B', 'Gene', (75, 80))	('zyxin', 'Gene', (28, 33))	('impeded', 'NegReg', (138, 145))	('expression', 'MPA', (14, 24))	('Increased', 'PosReg', (4, 13))	('silencing', 'Var', (119, 128))	('zyxin', 'Gene', '7791', (28, 33))
209405	33580750	74  Inactivation of HNF1B by Cre-Sox9 recombination was found to cause chronic pancreatitis with dilation of ducts, acinar-to-ductal metaplasia and lipomatosis.	('Inactivation', 'Var', (4, 16))	('metaplasia', 'biological_process', 'GO:0036074', ('133', '143'))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (71, 91))	('lipomatosis', 'Disease', 'MESH:D008068', (148, 159))	('pancreatitis', 'Disease', (79, 91))	('lipomatosis', 'Disease', (148, 159))	('Sox9', 'Gene', '20682', (33, 37))	('cause', 'Reg', (65, 70))	('dilation', 'Disease', (97, 105))	('acinar-to-ductal metaplasia', 'Disease', (116, 143))	('lipomatosis', 'Phenotype', 'HP:0001012', (148, 159))	('pancreatitis', 'Phenotype', 'HP:0001733', (79, 91))	('HNF1B', 'Gene', (20, 25))	('Sox9', 'Gene', (33, 37))	('pancreatitis', 'Disease', 'MESH:D010195', (79, 91))
209415	33580750	81  Additionally, in a recent study by Li et al on polycystic kidney disease (PKD), HNF1B was shown to have been regulated by p53S, a mutant version of the tumour suppressor p53.	('PKD', 'Disease', (78, 81))	('tumour', 'Disease', (156, 162))	('PKD', 'Disease', 'MESH:C537180', (78, 81))	('HNF1B', 'Gene', (84, 89))	('polycystic kidney disease', 'Disease', (51, 76))	('regulated', 'Reg', (113, 122))	('p53S', 'Var', (126, 130))	('polycystic kidney disease', 'Disease', 'MESH:D007690', (51, 76))	('kidney disease', 'Phenotype', 'HP:0000112', (62, 76))	('polycystic kidney', 'Phenotype', 'HP:0000113', (51, 68))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('cystic kidney', 'Phenotype', 'HP:0000107', (55, 68))
209416	33580750	82  RNA-seq analysis to understand PKD in p53 mutant mice, revealed the suppression of PKD1, PKD2, Pkhd1 (polyductin) and HNF1B expression.	('PKD2', 'Gene', '18764', (93, 97))	('polyductin', 'Gene', '241035', (106, 116))	('suppression', 'NegReg', (72, 83))	('mice', 'Species', '10090', (53, 57))	('p53', 'Gene', (42, 45))	('PKD1', 'Gene', (87, 91))	('PKD', 'Disease', (87, 90))	('PKD', 'Disease', 'MESH:C537180', (87, 90))	('expression', 'MPA', (128, 138))	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('mutant', 'Var', (46, 52))	('PKD', 'Disease', (93, 96))	('PKD', 'Disease', 'MESH:C537180', (93, 96))	('Pkhd1', 'Gene', (99, 104))	('PKD', 'Disease', (35, 38))	('PKD', 'Disease', 'MESH:C537180', (35, 38))	('PKD2', 'Gene', (93, 97))	('polyductin', 'Gene', (106, 116))	('HNF1B', 'Gene', (122, 127))	('PKD1', 'Gene', '18763', (87, 91))
209419	33580750	Higher DNA occupancy by B catenin was observed in HNF1B mutant cells.	('DNA occupancy', 'MPA', (7, 20))	('mutant', 'Var', (56, 62))	('B catenin', 'Gene', '1499', (24, 33))	('B catenin', 'Gene', (24, 33))	('Higher', 'PosReg', (0, 6))	('DNA', 'cellular_component', 'GO:0005574', ('7', '10'))	('HNF1B', 'Gene', (50, 55))
209424	33580750	There have been reports of somatic mutations of the HNF1A gene amongst various human cancers signifying its role as the tumour suppressor gene.	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('human', 'Species', '9606', (79, 84))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('HNF1A', 'Gene', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('tumour', 'Disease', (120, 126))	('cancers', 'Disease', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (35, 44))
209426	33580750	84  By mutating HNF1A by small interfering RNA in hepatocellular carcinoma cells increases overexpression of numerous genes translating cell cycle and angiogenesis regulators, growth factors receptors and components of translational machinery.	('overexpression of numerous', 'MPA', (91, 117))	('mutating', 'Var', (7, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('RNA', 'cellular_component', 'GO:0005562', ('43', '46'))	('HNF1A', 'Gene', (16, 21))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (50, 74))	('hepatocellular carcinoma', 'Disease', (50, 74))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (50, 74))	('cell cycle', 'biological_process', 'GO:0007049', ('136', '146'))	('angiogenesis', 'biological_process', 'GO:0001525', ('151', '163'))	('increases', 'PosReg', (81, 90))
209430	33580750	HNF1B deregulation has shown to be associated with epithelial to mesenchymal transition which might occur due to the destabilisation of the E-cadherin and B-catenin initiating altered cadherin/catenin nexus implicating the Wnt-targeted genes in PDAC.	('cadherin', 'molecular_function', 'GO:0008014', ('184', '192'))	('PDAC', 'Phenotype', 'HP:0006725', (245, 249))	('deregulation', 'Var', (6, 18))	('associated', 'Reg', (35, 45))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('51', '87'))	('E-cadherin', 'Gene', (140, 150))	('E-cadherin', 'Gene', '999', (140, 150))	('cadherin', 'molecular_function', 'GO:0008014', ('142', '150'))	('B-catenin', 'Gene', '1499', (155, 164))	('B-catenin', 'Gene', (155, 164))	('HNF1B', 'Gene', (0, 5))	('epithelial to mesenchymal transition', 'CPA', (51, 87))
209433	33580750	Renal diseases are homogenous phenotype which is usually associated with the mutation in transcription factor.	('mutation', 'Var', (77, 85))	('Renal diseases', 'Disease', 'MESH:D007674', (0, 14))	('transcription', 'biological_process', 'GO:0006351', ('89', '102'))	('transcription factor', 'molecular_function', 'GO:0000981', ('89', '109'))	('Renal diseases', 'Disease', (0, 14))	('associated', 'Reg', (57, 67))
209435	33580750	It has been observed that patients suffering from HNF1B mutations have varying renal functions from normal until dialysis-dependent/transplanted.	('HNF1B', 'Gene', (50, 55))	('mutations', 'Var', (56, 65))	('renal functions', 'MPA', (79, 94))	('patients', 'Species', '9606', (26, 34))
209437	33580750	suggested a germline mutation of HNF1B (46delC) was associated with cystic kidney disease and chromophobe renal cell carcinoma, whereas a somatic deletion of HNF1B was reported for renal tumour.	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (94, 126))	('46delC', 'Mutation', 'rs587776771', (40, 46))	('germline mutation', 'Var', (12, 29))	('cystic kidney disease', 'Disease', 'MESH:D052177', (68, 89))	('cystic kidney disease', 'Disease', (68, 89))	('kidney disease', 'Phenotype', 'HP:0000112', (75, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (106, 126))	('associated', 'Reg', (52, 62))	('HNF1B', 'Gene', (33, 38))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('46delC', 'Var', (40, 46))	('cystic kidney', 'Phenotype', 'HP:0000107', (68, 81))	('renal tumour', 'Disease', 'MESH:D007680', (181, 193))	('chromophobe renal cell carcinoma', 'Disease', (94, 126))	('renal tumour', 'Phenotype', 'HP:0009726', (181, 193))	('renal tumour', 'Disease', (181, 193))
209438	33580750	91  Chromophobe renal cell carcinoma was found to be associated with patients having biallelic inactivation of hepatocyte nuclear factor 1 beta.	('hepatocyte nuclear factor 1 beta', 'Gene', '6928', (111, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (16, 36))	('Chromophobe renal cell carcinoma', 'Disease', (4, 36))	('Chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (4, 36))	('associated', 'Reg', (53, 63))	('hepatocyte nuclear factor 1 beta', 'Gene', (111, 143))	('patients', 'Species', '9606', (69, 77))	('biallelic inactivation', 'Var', (85, 107))
209443	33580750	93  On the other hand another study carried out by Gad et al highlighted mutations in BHD and TP53 which is responsible for sporadic CRCC and found extremely rare events related to HNF1B mutation.	('BHD', 'Gene', (86, 89))	('Gad', 'Gene', '2571', (51, 54))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('BHD', 'Gene', '50947', (86, 89))	('Gad', 'Gene', (51, 54))	('responsible', 'Reg', (108, 119))	('mutations', 'Var', (73, 82))	('HNF1B', 'Gene', (181, 186))
209444	33580750	94  Latest report by Bartu et al reflected the consequences of somatic exonic mutations of HNF1B along with its role in the pathogenesis of kidney tumours emphasizing HNF1B could act as oncogene in papillary renal cell carcinoma (reduced HNF1B was exhibited along elevated tumour grade with T stage) whereas it may behave as a tumour suppressor in CCRCC and CHRCC (no mutations was observed whilst promotor methylation was present).	('CHRCC', 'Disease', 'None', (358, 363))	('tumours', 'Phenotype', 'HP:0002664', (147, 154))	('HNF1B', 'Protein', (238, 243))	('tumour', 'Phenotype', 'HP:0002664', (273, 279))	('tumour', 'Disease', 'MESH:D009369', (273, 279))	('papillary renal cell carcinoma', 'Disease', (198, 228))	('tumour', 'Disease', (273, 279))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('HNF1B', 'Var', (167, 172))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('methylation', 'biological_process', 'GO:0032259', ('407', '418'))	('tumour', 'Disease', (147, 153))	('kidney tumours emphasizing', 'Disease', (140, 166))	('reduced', 'NegReg', (230, 237))	('pathogenesis', 'biological_process', 'GO:0009405', ('124', '136'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (208, 228))	('tumour', 'Phenotype', 'HP:0002664', (327, 333))	('tumour', 'Disease', 'MESH:D009369', (327, 333))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (198, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('tumour', 'Disease', (327, 333))	('kidney tumours emphasizing', 'Disease', 'MESH:D007680', (140, 166))	('HNF1B', 'Gene', (91, 96))	('CCRCC', 'Disease', (348, 353))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (198, 228))	('CHRCC', 'Disease', (358, 363))
209446	33580750	Once methylated, the activity of HNF1B as a tumour suppressor is lost in course to the development of prostate cancer.	('methylated', 'Var', (5, 15))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('men', 'Species', '9606', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumour', 'Disease', (44, 50))	('prostate cancer', 'Disease', (102, 117))	('HNF1B', 'Gene', (33, 38))	('lost', 'NegReg', (65, 69))	('prostate cancer', 'Disease', 'MESH:D011471', (102, 117))	('activity', 'MPA', (21, 29))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('prostate cancer', 'Phenotype', 'HP:0012125', (102, 117))
209450	33580750	De Vas et al detected that the Notch signalling pathway is dysregulated in Hnf1b mutant pancreas, displaying a reduction in Delta-like Canonical Notch Ligand 1 (Dll1) expression and increased expression of Hairy and Enhancer of split related basic helix-loop-helix (Hey) repressors.	('reduction', 'NegReg', (111, 120))	('Hnf1b', 'Gene', (75, 80))	('Notch signalling pathway', 'Pathway', (31, 55))	('increased', 'PosReg', (182, 191))	('Delta-like Canonical Notch Ligand 1', 'Gene', (124, 159))	('expression', 'MPA', (192, 202))	('Dll1', 'Gene', (161, 165))	('Hnf1b', 'Gene', '6928', (75, 80))	('Delta-like Canonical Notch Ligand 1', 'Gene', '28514', (124, 159))	('Dll1', 'Gene', '28514', (161, 165))	('Notch Ligand', 'molecular_function', 'GO:0005112', ('145', '157'))	('mutant', 'Var', (81, 87))	('Notch signalling pathway', 'biological_process', 'GO:0007219', ('31', '55'))	('expression', 'MPA', (167, 177))
209456	33580750	highlighted the role of the HNF1B protective rs11263763 SNP allele in EC with reduced promoter activity, indicating HNF1B's oncogenic role.	('rs11263763', 'Var', (45, 55))	('rs11263763', 'Mutation', 'rs11263763', (45, 55))	('EC', 'Phenotype', 'HP:0012114', (70, 72))	('reduced', 'NegReg', (78, 85))	('promoter activity', 'MPA', (86, 103))	('HNF1B', 'Gene', (28, 33))
209457	33580750	106  This study also found intronic rs3110641 SNP to be associated with changes in HNF1B isoform expression.	('rs3110641 SNP', 'Var', (36, 49))	('HNF1B', 'Gene', (83, 88))	('isoform expression', 'MPA', (89, 107))	('rs3110641', 'Mutation', 'rs3110641', (36, 45))	('changes', 'Reg', (72, 79))
209458	33580750	Additional studies in breast cancer have also emphasized HNF1B overexpression in inducing EMT in epithelial NMuMG cells.	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('EMT', 'biological_process', 'GO:0001837', ('90', '93'))	('overexpression', 'Var', (63, 77))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('EMT in epithelial NMuMG cells', 'CPA', (90, 119))	('NMuMG', 'CellLine', 'CVCL:0075', (108, 113))	('HNF1B', 'Gene', (57, 62))	('inducing', 'PosReg', (81, 89))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
209475	33580750	117   Pancreatic abnormalities have been tested for HNF1B mutations and its prospectus as a biomarker being widely debated in renal hyperplasia and cysts.	('mutations', 'Var', (58, 67))	('HNF1B', 'Gene', (52, 57))	('renal hyperplasia', 'Phenotype', 'HP:0000105', (126, 143))	('Pancreatic abnormalities', 'Disease', (6, 30))	('renal hyperplasia', 'Disease', 'MESH:D006965', (126, 143))	('Pancreatic abnormalities', 'Disease', 'MESH:D010195', (6, 30))	('Pancreatic abnormalities', 'Phenotype', 'HP:0001732', (6, 30))	('renal hyperplasia', 'Disease', (126, 143))
209497	33580750	Moreover, the expression of HNF1B has been associated with immune cell infiltration which in turn influences the prognosis of immune cells in some cancers highlighting HNF1B as a potential immunotherapeutic target.	('expression', 'Var', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('associated', 'Reg', (43, 53))	('influences', 'Reg', (98, 108))	('immune cell infiltration', 'CPA', (59, 83))	('cancers', 'Disease', (147, 154))	('HNF1B', 'Gene', (28, 33))
209513	33795526	The characteristic of ccRCC is the loss of chromosome 3p, including mutations of genes encoding von Hippel-Lindau tumor suppressor (VHL), polybromo-1 (PBRM1), BRCA1-associated protein 1 (BAP1) and SET domain containing 2 (SETD2).	('chromosome', 'cellular_component', 'GO:0005694', ('43', '53'))	('von Hippel-Lindau tumor suppressor', 'Gene', (96, 130))	('polybromo-1', 'Gene', (138, 149))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('114', '130'))	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))	('VHL', 'Gene', (132, 135))	('tumor suppressor', 'biological_process', 'GO:0051726', ('114', '130'))	('BAP1', 'Gene', '8314', (187, 191))	('PBRM1', 'Gene', '55193', (151, 156))	('von Hippel-Lindau tumor suppressor', 'Gene', '7428', (96, 130))	('VHL', 'Gene', '7428', (132, 135))	('loss', 'NegReg', (35, 39))	('SETD2', 'Gene', (222, 227))	('BRCA1-associated protein 1', 'Gene', '8314', (159, 185))	('BAP1', 'Gene', (187, 191))	('PBRM1', 'Gene', (151, 156))	('RCC', 'Phenotype', 'HP:0005584', (24, 27))	('ccRCC', 'Phenotype', 'HP:0006770', (22, 27))	('RCC', 'Disease', (24, 27))	('SETD2', 'Gene', '29072', (222, 227))	('polybromo-1', 'Gene', '55193', (138, 149))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('BRCA1-associated protein 1', 'Gene', (159, 185))	('mutations', 'Var', (68, 77))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
209518	33795526	Conversely, PBRM1 mutation was associated with shorter survival, early tumor progression, and response to immune checkpoint therapies in ccRCC patients.	('PBRM1', 'Gene', (12, 17))	('shorter', 'NegReg', (47, 54))	('PBRM1', 'Gene', '55193', (12, 17))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('survival', 'CPA', (55, 63))	('patients', 'Species', '9606', (143, 151))	('RCC', 'Disease', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mutation', 'Var', (18, 26))	('tumor', 'Disease', (71, 76))
209519	33795526	Patients with BAP1 or SETD2 mutation were also more likely to have worse prognosis, and BAP1 mutation was related with poor response to everolimus.	('BAP1', 'Gene', '8314', (14, 18))	('SETD2', 'Gene', '29072', (22, 27))	('worse prognosis', 'MPA', (67, 82))	('SETD2', 'Gene', (22, 27))	('BAP1', 'Gene', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (28, 36))	('BAP1', 'Gene', '8314', (88, 92))	('everolimus', 'Chemical', 'MESH:D000068338', (136, 146))	('BAP1', 'Gene', (88, 92))
209526	33795526	Radiomics features extracted from CT scans have showed significant ability to predict mutation status of VHL, BAP1 and PBRM1 in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('mutation status', 'Var', (86, 101))	('VHL', 'Gene', (105, 108))	('BAP1', 'Gene', '8314', (110, 114))	('PBRM1', 'Gene', (119, 124))	('PBRM1', 'Gene', '55193', (119, 124))	('BAP1', 'Gene', (110, 114))	('VHL', 'Gene', '7428', (105, 108))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (130, 133))
209536	33795526	Previous studies have found that mutation status has an important impact on the prognosis of cancer patients.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('mutation', 'Var', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('patients', 'Species', '9606', (100, 108))	('impact', 'Reg', (66, 72))
209540	33795526	NOD-like receptors (NLRs) are closely related to autoimmune and inflammatory responses, and chronic inflammation caused by abnormal NLR signaling can promote tumorigenesis and progression, especially in gastric and colorectal cancers.	('inflammation', 'Disease', (100, 112))	('tumor', 'Disease', (158, 163))	('promote', 'PosReg', (150, 157))	('gastric and colorectal cancers', 'Disease', 'MESH:D013274', (203, 233))	('signaling', 'biological_process', 'GO:0023052', ('136', '145'))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('NLR', 'Gene', (132, 135))	('inflammation', 'Disease', 'MESH:D007249', (100, 112))	('inflammation', 'biological_process', 'GO:0006954', ('100', '112'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('progression', 'CPA', (176, 187))	('abnormal', 'Var', (123, 131))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
209551	33795526	As a hallmark of cancer, genetic instability and mutations can lead to uncontrolled cell proliferation.	('genetic instability', 'Disease', 'MESH:D030342', (25, 44))	('mutations', 'Var', (49, 58))	('cell proliferation', 'biological_process', 'GO:0008283', ('84', '102'))	('genetic instability', 'Disease', (25, 44))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('uncontrolled cell proliferation', 'CPA', (71, 102))	('cancer', 'Disease', (17, 23))	('lead to', 'Reg', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
209553	33795526	For example, random forest classifier of CT radiomics features correctly identified mutations in PBRM1 (AUC=0.987) and BAP1 (AUC=0.897) of ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (139, 144))	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('mutations', 'Var', (84, 93))	('BAP1', 'Gene', '8314', (119, 123))	('PBRM1', 'Gene', (97, 102))	('PBRM1', 'Gene', '55193', (97, 102))	('BAP1', 'Gene', (119, 123))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
209557	33795526	For instance, m1 subtype tumors had significant survival advantages and more frequent PBRM1 mutation than m2 and m3, while m3 subtype was enriched for CDKN2A deletion and PTEN mutation.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mutation', 'Var', (92, 100))	('tumors', 'Disease', (25, 31))	('advantages', 'PosReg', (57, 67))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('CDKN2A', 'Gene', '1029', (151, 157))	('PBRM1', 'Gene', (86, 91))	('CDKN2A', 'Gene', (151, 157))	('survival', 'CPA', (48, 56))	('PTEN', 'Gene', (171, 175))	('deletion', 'Var', (158, 166))	('PTEN', 'Gene', '5728', (171, 175))	('PBRM1', 'Gene', '55193', (86, 91))
209558	33795526	The m4 subtype was related with higher mutation frequency of BAP1 and mTOR.	('mTOR', 'Gene', (70, 74))	('BAP1', 'Gene', (61, 65))	('mutation', 'Var', (39, 47))	('higher', 'PosReg', (32, 38))	('mTOR', 'Gene', '2475', (70, 74))	('BAP1', 'Gene', '8314', (61, 65))
209568	33795526	However, the prognostic role of radiomics and other omics features is still controversial, for example, few studies demonstrated that VHL mutation could predict patient survival, and many genes and pathways still lack related evidence.	('predict', 'Reg', (153, 160))	('patient', 'Species', '9606', (161, 168))	('VHL', 'Gene', (134, 137))	('mutation', 'Var', (138, 146))	('VHL', 'Gene', '7428', (134, 137))
209570	33795526	In addition, small patient populations with BAP1 or SETD2 mutations might cause potential bias, which was a common problem in other radiogenomics studies.	('mutations', 'Var', (58, 67))	('patient', 'Species', '9606', (19, 26))	('BAP1', 'Gene', '8314', (44, 48))	('SETD2', 'Gene', '29072', (52, 57))	('SETD2', 'Gene', (52, 57))	('BAP1', 'Gene', (44, 48))
209604	32548715	Under stimuli, host immune cells secrete cytokines and other small inflammatory proteins to fight against tumors, but these released cytokines sometimes conversely activate malignant cells, causing specific mutations and epigenetic changes in cancer cells (Galdiero et al.,).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('activate', 'PosReg', (164, 172))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('mutations', 'Var', (207, 216))	('causing', 'Reg', (190, 197))	('malignant cells', 'CPA', (173, 188))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('epigenetic changes', 'Var', (221, 239))
209608	32548715	More specifically, cytokines such as IL-1B, interleukin 6 (IL-6), interferon gamma (IFN-gamma) and interleukin 10 (IL-10) can effectively activate immunosuppressive pathways in myeloid-derived suppressive cells (MDSCs) and induce the differentiation of MDSCs into tumor-protective dendritic and macrophage cells (Dysthe and Parihar,).	('interleukin 10', 'Gene', (99, 113))	('IL-1B', 'Gene', (37, 42))	('interleukin 6', 'Gene', '3569', (44, 57))	('IL-1B', 'Gene', '3553', (37, 42))	('IL-6', 'Gene', '3569', (59, 63))	('IL-1', 'molecular_function', 'GO:0005149', ('37', '41'))	('differentiation', 'CPA', (234, 249))	('tumor', 'Disease', (264, 269))	('induce', 'PosReg', (223, 229))	('immunosuppressive pathways', 'Pathway', (147, 173))	('activate', 'PosReg', (138, 146))	('interleukin 10', 'Gene', '3586', (99, 113))	('IL-6', 'Gene', (59, 63))	('cytokines', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('Parihar', 'Disease', (324, 331))	('interferon gamma', 'molecular_function', 'GO:0005133', ('66', '82'))	('IL-10', 'Gene', '3586', (115, 120))	('interferon gamma (IFN-gamma', 'Gene', '3458', (66, 93))	('IL-10', 'Gene', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('IL-6', 'molecular_function', 'GO:0005138', ('59', '63'))	('interleukin 6', 'Gene', (44, 57))	('IL-10', 'molecular_function', 'GO:0005141', ('115', '120'))
209615	32548715	As CCCH zinc finger proteins usually shuttle between cellular compartments, MCPIP1 was first found in the nucleus when MCPIP1-GFP was expressed in HEK293 cells (Mino et al.,), but some studies then identified MCPIP1 on ribosomes on the endoplasmic reticulum, and some studies indicated that MCPIP1 could form granule-like structures in the cytoplasm that interact with the miRISC to regulate miRNA effector pathways (Huang et al.,).	('regulate', 'Reg', (383, 391))	('MCPIP1', 'Var', (291, 297))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('236', '257'))	('nucleus', 'cellular_component', 'GO:0005634', ('106', '113'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('340', '349'))	('HEK293', 'CellLine', 'CVCL:0045', (147, 153))	('miRNA effector pathways', 'Pathway', (392, 415))
209619	32548715	HEK293 cells cotransfected with GAL4-MCPIP1 and pGal4-Luc reporter showed MCPIP1 activated luciferase reporter gene transcription to 865-fold/mg protein and mutation of the CCCH zinc finger domain or proline-rich domain was found to drastically affect its transcriptional activity.	('transcription', 'MPA', (116, 129))	('MCPIP1', 'Gene', (74, 80))	('CCCH', 'Gene', (173, 177))	('GAL4', 'Gene', '3960', (32, 36))	('luciferase', 'Enzyme', (91, 101))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('activated', 'PosReg', (81, 90))	('mutation', 'Var', (157, 165))	('affect', 'Reg', (245, 251))	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('transcription', 'biological_process', 'GO:0006351', ('116', '129'))	('proline', 'Chemical', 'MESH:D011392', (200, 207))	('transcriptional activity', 'MPA', (256, 280))	('GAL4', 'Gene', (32, 36))
209627	32548715	The block effect is specific as MCPIP1 can't inhibit PPAR gamma-induced PPREs promoter activation.	('PPAR gamma', 'Gene', '5468', (53, 63))	('MCPIP1 ca', 'Var', (32, 41))	('PPAR gamma', 'Gene', (53, 63))
209634	32548715	MCPIP1-/- mice exhibited severe autoimmune disease, with significant splenomegaly and lymphadenopathy, and usually died within 12 weeks of birth.	('splenomegaly and lymphadenopathy', 'Disease', 'MESH:D013163', (69, 101))	('mice', 'Species', '10090', (10, 14))	('died', 'Disease', (115, 119))	('died', 'Disease', 'MESH:D003643', (115, 119))	('autoimmune disease', 'Disease', 'MESH:D001327', (32, 50))	('autoimmune disease', 'Phenotype', 'HP:0002960', (32, 50))	('splenomegaly', 'Phenotype', 'HP:0001744', (69, 81))	('exhibited', 'Reg', (15, 24))	('MCPIP1-/-', 'Var', (0, 9))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (86, 101))	('autoimmune disease', 'Disease', (32, 50))
209635	32548715	MCPIP1-/- macrophages exhibited highly increased production of IL-6 and IL-12B under TLR ligand stimulation.	('IL-6', 'Gene', '3569', (63, 67))	('ligand', 'molecular_function', 'GO:0005488', ('89', '95'))	('IL-12', 'molecular_function', 'GO:0005143', ('72', '77'))	('IL-12B', 'Gene', '3593', (72, 78))	('IL-12B', 'Gene', (72, 78))	('IL-6', 'molecular_function', 'GO:0005138', ('63', '67'))	('IL-12B', 'cellular_component', 'GO:0070743', ('72', '78'))	('IL-12B', 'cellular_component', 'GO:0043514', ('72', '78'))	('increased', 'PosReg', (39, 48))	('MCPIP1-/-', 'Var', (0, 9))	('IL-6', 'Gene', (63, 67))
209636	32548715	PIN domain mutation abolished MCPIP1 RNase activity and prevented shortening of the IL6 mRNA half-life.	('IL6', 'Gene', (84, 87))	('RNase activity', 'molecular_function', 'GO:0004522', ('37', '51'))	('abolished', 'NegReg', (20, 29))	('MCPIP1 RNase', 'Enzyme', (30, 42))	('prevented', 'NegReg', (56, 65))	('IL6', 'molecular_function', 'GO:0005138', ('84', '87'))	('activity', 'MPA', (43, 51))	('IL6', 'Gene', '3569', (84, 87))	('shortening', 'MPA', (66, 76))	('PIN domain mutation', 'Var', (0, 19))
209637	32548715	In adaptive immunity, MCPIP1 was shown to negatively regulated IL-17-mediated signaling by destabilizing IL6 mRNA.	('IL6', 'Gene', (105, 108))	('signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('destabilizing', 'NegReg', (91, 104))	('IL-17', 'molecular_function', 'GO:0030367', ('63', '68'))	('IL6', 'Gene', '3569', (105, 108))	('IL-17-mediated signaling', 'MPA', (63, 87))	('IL6', 'molecular_function', 'GO:0005138', ('105', '108'))	('negatively regulated', 'NegReg', (42, 62))	('MCPIP1', 'Var', (22, 28))
209638	32548715	In addition to IL6, MCPIP1 degrades IL17RA and IL17RC mRNA and strongly inhibits the LCN2 promoter activity by accelerating NFKBIZ mRNA decay (Monin et al.,).	('IL17', 'molecular_function', 'GO:0030367', ('36', '40'))	('NFKBIZ', 'Gene', '64332', (124, 130))	('IL17', 'molecular_function', 'GO:0030367', ('47', '51'))	('MCPIP1', 'Var', (20, 26))	('LCN2', 'Gene', (85, 89))	('LCN2', 'Gene', '3934', (85, 89))	('IL6', 'Gene', '3569', (15, 18))	('NFKBIZ', 'Gene', (124, 130))	('mRNA decay', 'biological_process', 'GO:0006402', ('131', '141'))	('inhibits', 'NegReg', (72, 80))	('IL17RC', 'Gene', '84818', (47, 53))	('IL17RA', 'Gene', (36, 42))	('degrades', 'NegReg', (27, 35))	('IL6', 'molecular_function', 'GO:0005138', ('15', '18'))	('IL17RC', 'Gene', (47, 53))	('IL17RA', 'Gene', '23765', (36, 42))	('accelerating', 'PosReg', (111, 123))	('IL6', 'Gene', (15, 18))
209641	32548715	compared inflammatory cytokines levels in the serum of MCPIP1-/- and MCPIP1+/+ mice (Miao et al.,).	('mice', 'Species', '10090', (79, 83))	('MCPIP1-/-', 'Var', (55, 64))	('inflammatory cytokines levels', 'MPA', (9, 38))
209642	32548715	Their results showed that the mRNAs of the T cell cytokines IL-17, IL-12, IL-4, IL-5 and TNFalpha were elevated in MCPIP1-/- mice, but their upstream transcription factors, including T-bet, GATA3 and RORgamma, were not changed.	('mRNAs', 'MPA', (30, 35))	('RORgamma', 'Gene', (200, 208))	('GATA3', 'Gene', '14462', (190, 195))	('IL-5', 'molecular_function', 'GO:0005137', ('80', '84'))	('mice', 'Species', '10090', (125, 129))	('IL-5', 'Gene', (80, 84))	('GATA3', 'Gene', (190, 195))	('IL-4', 'Gene', (74, 78))	('TNFalpha', 'Gene', (89, 97))	('IL-17', 'molecular_function', 'GO:0030367', ('60', '65'))	('MCPIP1-/-', 'Var', (115, 124))	('T-bet', 'Gene', (183, 188))	('T-bet', 'Gene', '57765', (183, 188))	('T cell cytokines', 'MPA', (43, 59))	('RORgamma', 'Gene', '19885', (200, 208))	('elevated', 'PosReg', (103, 111))	('transcription', 'biological_process', 'GO:0006351', ('150', '163'))	('IL-4', 'molecular_function', 'GO:0005136', ('74', '78'))	('IL-5', 'Gene', '16191', (80, 84))	('IL-12', 'molecular_function', 'GO:0005143', ('67', '72'))
209644	32548715	MCPIP1 knockdown increased TET mRNA levels and then promoted the conversion of 5mC to 5hmC.	('increased', 'PosReg', (17, 26))	('TET', 'Chemical', 'MESH:C010349', (27, 30))	('TET mRNA levels', 'MPA', (27, 42))	('MCPIP1', 'Gene', (0, 6))	('conversion of 5mC to 5hmC', 'MPA', (65, 90))	('knockdown', 'Var', (7, 16))	('promoted', 'PosReg', (52, 60))
209647	32548715	As inappropriate regulation of the JNK and NF-kappaB pathways causes inflammation-induced tissue damage or malignancy, both signaling pathways should be tightly controlled to maintain transient activation, in which ubiquitination plays a key regulatory role.	('inappropriate', 'Var', (3, 16))	('inflammation', 'Disease', (69, 81))	('NF-kappaB', 'Gene', (43, 52))	('signaling', 'biological_process', 'GO:0023052', ('124', '133'))	('causes', 'Reg', (62, 68))	('JNK', 'Pathway', (35, 38))	('inflammation', 'biological_process', 'GO:0006954', ('69', '81'))	('tissue damage or malignancy', 'Disease', (90, 117))	('tissue damage or malignancy', 'Disease', 'MESH:D009369', (90, 117))	('JNK', 'molecular_function', 'GO:0004705', ('35', '38'))	('NF-kappaB', 'Gene', '4790', (43, 52))	('inflammation', 'Disease', 'MESH:D007249', (69, 81))	('regulation', 'biological_process', 'GO:0065007', ('17', '27'))
209648	32548715	The D141N, C157A, and C306R point mutations of MCPIP1 abolished its deubiquitinatase function, and the D141N mutation was also associated with its RNase activity.	('D141N', 'Mutation', 'p.D141N', (103, 108))	('D141N', 'Var', (4, 9))	('C306R', 'Mutation', 'p.C306R', (22, 27))	('associated', 'Reg', (127, 137))	('C157A', 'Mutation', 'c.157C>A', (11, 16))	('RNase activity', 'MPA', (147, 161))	('D141N', 'Var', (103, 108))	('RNase activity', 'molecular_function', 'GO:0004522', ('147', '161'))	('abolished', 'NegReg', (54, 63))	('MCPIP1', 'Gene', (47, 53))	('deubiquitinatase function', 'MPA', (68, 93))	('D141N', 'Mutation', 'p.D141N', (4, 9))	('C157A', 'Var', (11, 16))	('C306R point', 'Var', (22, 33))
209649	32548715	Furthermore, MCPIP1 expression significantly decreased TRAF2 and TRAF6 ubiquitination and affects the K48-linked ubiquitination of IkappaBalpha.	('TRAF2', 'Gene', (55, 60))	('TRAF6', 'Gene', (65, 70))	('MCPIP1', 'Gene', (13, 19))	('TRAF6', 'Gene', '7189', (65, 70))	('IkappaBalpha', 'Gene', '4792', (131, 143))	('IkappaBalpha', 'Gene', (131, 143))	('decreased', 'NegReg', (45, 54))	('expression', 'Var', (20, 30))	('K48-linked ubiquitination', 'MPA', (102, 127))	('TRAF2', 'Gene', '7186', (55, 60))	('affects', 'Reg', (90, 97))	('ubiquitination', 'MPA', (71, 85))
209650	32548715	In addition to its intrinsic deubiquitinatase activity, MCPIP1 was found to inhibit genotoxic NF-kappaB activation in a manner dependent on USP10, a member of the ubiquitin specific protease (USP) family (Niu et al.,).	('ubiquitin', 'molecular_function', 'GO:0031386', ('163', '172'))	('inhibit', 'NegReg', (76, 83))	('USP', 'molecular_function', 'GO:0051748', ('140', '143'))	('deubiquitinatase activity', 'MPA', (29, 54))	('USP10', 'Gene', (140, 145))	('NF-kappaB', 'Gene', '4790', (94, 103))	('USP', 'molecular_function', 'GO:0051748', ('192', '195'))	('MCPIP1', 'Var', (56, 62))	('USP10', 'Gene', '9100', (140, 145))	('NF-kappaB', 'Gene', (94, 103))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('94', '114'))
209655	32548715	When macrophages are stimulated by a variety of signals, such LPS or IL-1B, they are polarized to the M1 type and release proinflammatory cytokines, thus playing a protective role in the organism.	('release proinflammatory cytokines', 'MPA', (114, 147))	('LPS', 'Var', (62, 65))	('IL-1B', 'Gene', '3553', (69, 74))	('IL-1', 'molecular_function', 'GO:0005149', ('69', '73'))	('stimulated', 'PosReg', (21, 31))	('IL-1B', 'Gene', (69, 74))
209663	32548715	MCPIP1 does not alter DR5 mRNA levels but destabilizes DR5 protein through a posttranslational mechanism.	('DR5', 'Gene', (55, 58))	('DR5', 'Gene', '8795', (55, 58))	('MCPIP1', 'Var', (0, 6))	('DR5', 'Gene', (22, 25))	('DR5', 'Gene', '8795', (22, 25))	('destabilizes', 'NegReg', (42, 54))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
209664	32548715	The C157A mutation of MCPIP1 confirmed that DUB activity promotes autophagic/lysosomal degradation of DR5 and subsequently inhibits DISC formation.	('DISC', 'cellular_component', 'GO:0031264', ('132', '136'))	('autophagic/lysosomal degradation', 'CPA', (66, 98))	('DR5', 'Gene', '8795', (102, 105))	('degradation', 'biological_process', 'GO:0009056', ('87', '98'))	('MCPIP1', 'Gene', (22, 28))	('DISC formation', 'biological_process', 'GO:0071550', ('132', '146'))	('DR5', 'Gene', (102, 105))	('C157A', 'Var', (4, 9))	('inhibits', 'NegReg', (123, 131))	('C157A', 'Mutation', 'c.157C>A', (4, 9))	('DISC formation', 'CPA', (132, 146))	('promotes', 'PosReg', (57, 65))
209665	32548715	Mice overexpressing miR-17-92 and miR-155 exhibited severe autoimmune and lymphoproliferative disease (Xiao et al.,; Costinean et al.,).	('miR-17-92', 'Gene', (20, 29))	('miR-155', 'Var', (34, 41))	('lymphoproliferative disease', 'Phenotype', 'HP:0005523', (74, 101))	('miR-17-92', 'Gene', '75957', (20, 29))	('Mice', 'Species', '10090', (0, 4))	('autoimmune and lymphoproliferative disease', 'Disease', 'MESH:D056735', (59, 101))
209669	32548715	reported that expression of the LPS-induced miRNAs such as miR155 and miR146 was not altered in mouse embryonic fibroblasts from MCPIP1-/- mice and that miRNAs were not enriched by MCPIP1 CLIP-seq (Mino et al.,).	('miR146', 'Gene', (70, 76))	('mouse', 'Species', '10090', (96, 101))	('miR155', 'Var', (59, 65))	('mice', 'Species', '10090', (139, 143))	('miR146', 'Gene', '387164', (70, 76))
209683	32548715	Inactive C472A mutant MALT1 failed to cleave MCPIP1 under TCR stimulation (Jeltsch et al.,).	('TCR', 'biological_process', 'GO:0006283', ('58', '61'))	('C472A', 'Var', (9, 14))	('MCPIP1', 'Gene', (45, 51))	('TCR', 'cellular_component', 'GO:0042101', ('58', '61'))	('C472A', 'Mutation', 'c.472C>A', (9, 14))	('MALT1', 'Gene', '10892', (22, 27))	('MALT1', 'Gene', (22, 27))
209694	32548715	Accumulating evidence has demonstrated that MCPIP1 acts as a potent tumor suppressor and induces cancer cells apoptosis.	('tumor', 'Disease', (68, 73))	('cancer', 'Disease', (97, 103))	('MCPIP1', 'Var', (44, 50))	('tumor suppressor', 'biological_process', 'GO:0051726', ('68', '84'))	('apoptosis', 'biological_process', 'GO:0097194', ('110', '119'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('68', '84'))	('apoptosis', 'biological_process', 'GO:0006915', ('110', '119'))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('induces', 'PosReg', (89, 96))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
209698	32548715	In ccRCC cells, MCPIP1 depletion was found to significantly enhanced tumor cell viability and proliferation (Marona et al.,).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('depletion', 'Var', (23, 32))	('tumor', 'Disease', (69, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('proliferation', 'CPA', (94, 107))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('enhanced', 'PosReg', (60, 68))	('MCPIP1', 'Gene', (16, 22))
209699	32548715	MCPIP1 knockdown cells were observed to develop into larger tumor mass in NOD-SCID mice.	('MCPIP1', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('mice', 'Species', '10090', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('knockdown', 'Var', (7, 16))
209700	32548715	Additionally, regulation of the microRNAs, including miR-155 and miR146a, by MCPIP1 was reported not only to be involved in immune responses, but also to participate in tumor proliferation (Suzuki et al.,).	('involved', 'Reg', (112, 120))	('miR146a', 'Gene', (65, 72))	('regulation', 'biological_process', 'GO:0065007', ('14', '24'))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('immune responses', 'CPA', (124, 140))	('miR146a', 'Gene', '406938', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('participate', 'Reg', (154, 165))	('miR-155', 'Var', (53, 60))	('tumor', 'Disease', (169, 174))	('MCPIP1', 'Gene', (77, 83))
209734	32548715	Cytokines have extremely vital and complicated biological functions, and their abnormal expression is involved in many pathological processes, including autoimmune disease and cancers.	('cancers', 'Disease', (176, 183))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('autoimmune disease', 'Disease', 'MESH:D001327', (153, 171))	('abnormal', 'Var', (79, 87))	('involved', 'Reg', (102, 110))	('autoimmune disease', 'Phenotype', 'HP:0002960', (153, 171))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('autoimmune disease', 'Disease', (153, 171))
209747	30217855	Mutation or methylation of the VHL gene is the most common mutational event, followed by mutations in PBRM1, SETD2, and BAP1.	('VHL', 'Gene', '7428', (31, 34))	('methylation', 'biological_process', 'GO:0032259', ('12', '23'))	('SETD2', 'Gene', '29072', (109, 114))	('PBRM1', 'Gene', (102, 107))	('Mutation', 'Var', (0, 8))	('PBRM1', 'Gene', '55193', (102, 107))	('SETD2', 'Gene', (109, 114))	('methylation', 'Var', (12, 23))	('mutations', 'Var', (89, 98))	('BAP1', 'Gene', '8314', (120, 124))	('VHL', 'Gene', (31, 34))	('BAP1', 'Gene', (120, 124))
209750	30217855	Sequencing of primary and metastatic ccRCC revealed that tumors with low genetic diversity (intra-tumor heterogeneity [ITH]) and a low fraction of the tumor genome affected by somatic copy-number alterations (SCNAs) have an overall low metastatic potential and a better overall prognosis.	('metastatic potential', 'CPA', (236, 256))	('tumor', 'Disease', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('intra-tumor', 'Disease', 'MESH:D009369', (92, 103))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('low', 'NegReg', (69, 72))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('tumor', 'Disease', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('copy-number alterations', 'Var', (184, 207))	('tumors', 'Disease', (57, 63))	('genetic diversity', 'MPA', (73, 90))	('intra-tumor', 'Disease', (92, 103))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('low', 'NegReg', (232, 235))
209751	30217855	Primary tumors with high ITH are associated with a tempered pattern of progression often involving single sites of metastatic disease over a protracted period.	('Primary tumors', 'Disease', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('Primary tumors', 'Disease', 'MESH:D009369', (0, 14))	('high ITH', 'Var', (20, 28))
209754	30217855	Future clinical studies should test whether adjuvant or early combinatorial intervention is of benefit for primary tumors harboring 9p loss and/or low ITH with high SCNA.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('low ITH', 'Var', (147, 154))	('primary tumors', 'Disease', (107, 121))	('primary tumors', 'Disease', 'MESH:D009369', (107, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))
209761	30217855	Preclinical data support the key role for HIF2alpha in pVHL-defective ccRCC, and a human HIF2alpha genetic polymorphism is associated with an increased risk of developing ccRCC.	('associated', 'Reg', (123, 133))	('pVHL', 'Gene', '7428', (55, 59))	('HIF2alpha', 'Gene', '2034', (89, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (171, 176))	('ccRCC', 'Disease', (171, 176))	('pVHL', 'Gene', (55, 59))	('HIF2alpha', 'Gene', '2034', (42, 51))	('human', 'Species', '9606', (83, 88))	('HIF2alpha', 'Gene', (89, 98))	('genetic polymorphism', 'Var', (99, 119))	('ccRCC', 'Phenotype', 'HP:0006770', (70, 75))	('HIF2alpha', 'Gene', (42, 51))
209762	30217855	Inhibition of HIF2alpha may result in the down-regulation of activated HIF2alpha-dependent enhancer regions within ccRCC, and HIF2alpha-specific inhibitors in clinical development may provide another targeted therapeutic opportunity.	('regulation', 'biological_process', 'GO:0065007', ('47', '57'))	('HIF2alpha', 'Gene', '2034', (126, 135))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('HIF2alpha', 'Gene', '2034', (14, 23))	('HIF2alpha', 'Gene', (71, 80))	('down-regulation', 'NegReg', (42, 57))	('Inhibition', 'Var', (0, 10))	('HIF2alpha', 'Gene', (126, 135))	('HIF2alpha', 'Gene', (14, 23))	('HIF2alpha', 'Gene', '2034', (71, 80))	('ccRCC', 'Disease', (115, 120))
209766	30217855	ccRCC may be an exception among tumors, where TMB does not correlate with ORR, suggesting that those genetic alterations associated with ccRCC yield a disproportionately higher amount of neoantigens and elicit robust adaptive immune responses.	('higher', 'PosReg', (170, 176))	('neoantigens', 'MPA', (187, 198))	('elicit', 'Reg', (203, 209))	('genetic alterations', 'Var', (101, 120))	('ccRCC', 'Phenotype', 'HP:0006770', (0, 5))	('adaptive immune responses', 'CPA', (217, 242))	('ccRCC', 'Disease', (137, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('TMB', 'Chemical', '-', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
209769	30217855	PBRM1 and BAP1 are mutated in ~40% and 15% of patients, respectively, and are largely non-overlapping.	('patients', 'Species', '9606', (46, 54))	('BAP1', 'Gene', (10, 14))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('mutated', 'Var', (19, 26))	('BAP1', 'Gene', '8314', (10, 14))
209770	30217855	Truncating mutations in PBRM1 are associated with a distinct immune-related gene expression profile.	('associated', 'Reg', (34, 44))	('Truncating mutations', 'Var', (0, 20))	('gene expression', 'biological_process', 'GO:0010467', ('76', '91'))	('immune-related gene expression profile', 'MPA', (61, 99))	('PBRM1', 'Gene', (24, 29))	('PBRM1', 'Gene', '55193', (24, 29))
209772	30217855	BAP1 mutant ccRCC tumors are also correlated with an inflammatory tumor microenvironment, which is noteworthy because BAP1 deficiency is also linked to an inflammatory phenotype in primary uveal melanoma.	('ccRCC', 'Phenotype', 'HP:0006770', (12, 17))	('tumors', 'Disease', (18, 24))	('correlated', 'Reg', (34, 44))	('BAP1', 'Gene', (0, 4))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', (66, 71))	('BAP1', 'Gene', '8314', (118, 122))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('BAP1 deficiency', 'Disease', 'MESH:D007153', (118, 133))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('BAP1', 'Gene', (118, 122))	('uveal melanoma', 'Disease', 'MESH:C536494', (189, 203))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('ccRCC', 'Disease', (12, 17))	('uveal melanoma', 'Disease', (189, 203))	('linked to', 'Reg', (142, 151))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('mutant', 'Var', (5, 11))	('BAP1', 'Gene', '8314', (0, 4))	('uveal melanoma', 'Phenotype', 'HP:0007716', (189, 203))	('BAP1 deficiency', 'Disease', (118, 133))
209775	30217855	For example, blocking VEGF augments intra-tumoral T cell infiltration, partly through vascular normalization and endothelial cell activation.	('intra-tumoral T', 'Disease', 'MESH:D009369', (36, 51))	('VEGF', 'Gene', '7422', (22, 26))	('blocking', 'Var', (13, 21))	('intra-tumoral T', 'Disease', (36, 51))	('endothelial cell activation', 'biological_process', 'GO:0042118', ('113', '140'))	('augments', 'PosReg', (27, 35))	('VEGF', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
209776	30217855	Anti-VEGF antibodies may also enhance the antitumor activity of ICB by promoting T cell infiltration, up-regulating major histocompatibility complex class I expression, and reversing myeloid immunosuppression.	('reversing', 'Reg', (173, 182))	('major histocompatibility complex', 'biological_process', 'GO:0046776', ('116', '148'))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('expression', 'MPA', (157, 167))	('VEGF', 'Gene', '7422', (5, 9))	('myeloid immunosuppression', 'MPA', (183, 208))	('up-regulating', 'PosReg', (102, 115))	('tumor', 'Disease', (46, 51))	('VEGF', 'Gene', (5, 9))	('ICB', 'Chemical', '-', (64, 67))	('promoting', 'PosReg', (71, 80))	('antibodies', 'Var', (10, 20))	('enhance', 'PosReg', (30, 37))	('major histocompatibility complex class I', 'Protein', (116, 156))	('T cell infiltration', 'CPA', (81, 100))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
209781	30217855	For example, VHL and PBRM1 mutant tumors are associated with both an immune profile and an angiogenic signature, suggesting that tumors harboring both defects could benefit most from a combinatorial approach.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('mutant', 'Var', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('associated', 'Reg', (45, 55))	('VHL', 'Gene', (13, 16))	('PBRM1', 'Gene', (21, 26))	('PBRM1', 'Gene', '55193', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('VHL', 'Gene', '7428', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('immune profile', 'MPA', (69, 83))
209782	30217855	In contrast, loss of BAP1 associates with decreased angiogenic signaling and an adverse outcome to angiogenic inhibitors, and such tumors may benefit mostly from an ICB.	('angiogenic signaling', 'MPA', (52, 72))	('signaling', 'biological_process', 'GO:0023052', ('63', '72'))	('decreased', 'NegReg', (42, 51))	('BAP1', 'Gene', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('ICB', 'Chemical', '-', (165, 168))	('loss', 'Var', (13, 17))	('BAP1', 'Gene', '8314', (21, 25))
209789	31523055	Aberrations in Notch-Hedgehog signalling reveal cancer stem cells harbouring conserved oncogenic properties associated with hypoxia and immunoevasion Cancer stem cells (CSCs) have innate abilities to resist even the harshest of therapies.	('hypoxia', 'Disease', 'MESH:D000860', (124, 131))	('Notch', 'Gene', '31293', (15, 20))	('Cancer', 'Disease', 'MESH:D009369', (150, 156))	('Cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('Cancer', 'Phenotype', 'HP:0002664', (150, 156))	('Aberrations', 'Var', (0, 11))	('signalling', 'biological_process', 'GO:0023052', ('30', '40'))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('hypoxia', 'Disease', (124, 131))	('Notch', 'Gene', (15, 20))
209803	31523055	Concentrating on Notch and Hedgehog signalling pathways, we seek to attain a comprehensive understanding of how somatic copy number alterations and expression profiles of pathway genes along with their downstream targets could influence tumour progression and prognosis.	('signalling', 'biological_process', 'GO:0023052', ('36', '46'))	('tumour', 'Phenotype', 'HP:0002664', (237, 243))	('Notch', 'Gene', (17, 22))	('tumour', 'Disease', 'MESH:D009369', (237, 243))	('prognosis', 'CPA', (260, 269))	('tumour', 'Disease', (237, 243))	('Notch', 'Gene', '31293', (17, 22))	('influence', 'Reg', (227, 236))	('copy number alterations', 'Var', (120, 143))
209809	31523055	Hedgehog signalling promotes the expression of Jagged2 (a Notch ligand) and in ovarian cancer mice models, inhibition of Jagged1 would sensitise tumours to docetaxel treatment by affecting GLI2 function.	('Jagged1', 'Gene', (121, 128))	('Jagged2', 'Gene', '16450', (47, 54))	('tumours', 'Phenotype', 'HP:0002664', (145, 152))	('signalling', 'biological_process', 'GO:0023052', ('9', '19'))	('mice', 'Species', '10090', (94, 98))	('expression', 'MPA', (33, 43))	('Notch', 'Gene', (58, 63))	('affecting', 'Reg', (179, 188))	('ovarian cancer', 'Disease', 'MESH:D010051', (79, 93))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('Notch ligand', 'molecular_function', 'GO:0005112', ('58', '70'))	('sensitise tumours', 'Disease', (135, 152))	('docetaxel', 'Chemical', 'MESH:D000077143', (156, 165))	('sensitise tumours', 'Disease', 'MESH:D009369', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ovarian cancer', 'Disease', (79, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (79, 93))	('GLI2 function', 'MPA', (189, 202))	('Jagged2', 'Gene', (47, 54))	('Notch', 'Gene', '31293', (58, 63))	('inhibition', 'Var', (107, 117))	('Jagged1', 'Gene', '16449', (121, 128))
209833	31523055	Lung squamous cell carcinoma (LUSC) had the highest fraction of samples harbouring amplified Hedgehog genes, while endometrial cancer (UCEC) had the fewest somatic gains (Fig.	('amplified', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('endometrial cancer', 'Disease', (115, 133))	('Lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (0, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('Lung squamous cell carcinoma', 'Disease', (0, 28))	('endometrial cancer', 'Phenotype', 'HP:0012114', (115, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (5, 28))	('endometrial cancer', 'Disease', 'MESH:D016889', (115, 133))	('Hedgehog genes', 'Gene', (93, 107))
209882	31523055	CD105, CD29, CD44, CD73, CD90 and NESTIN were positively correlated with 13-gene scores in renal cancers (Fig.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('NESTIN', 'Gene', '10763', (34, 40))	('CD44', 'Var', (13, 17))	('correlated', 'Reg', (57, 67))	('CD29', 'Var', (7, 11))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('CD105', 'Var', (0, 5))	('CD90', 'Var', (25, 29))	('CD7', 'Gene', (19, 22))	('renal cancers', 'Disease', 'MESH:D007680', (91, 104))	('renal cancers', 'Disease', (91, 104))	('renal cancer', 'Phenotype', 'HP:0009726', (91, 103))	('CD7', 'Gene', '924', (19, 22))	('NESTIN', 'Gene', (34, 40))
209883	31523055	S4); an observation which is consistent with these genes being markers of renal CSCs.	('renal CSCs', 'Disease', (74, 84))	('genes', 'Var', (51, 56))	('renal CSCs', 'Disease', 'MESH:D007674', (74, 84))
209891	31523055	To determine whether these associations harboured prognostic information, patients were categorised by their 13-gene scores and expression profiles of individual TFs into four categories: (1) high 13-gene score and high TF expression, (2) high 13-gene score and low TF expression, (3) low 13-gene score and high TF expression and (4) low 13-gene score and low TF expression (Fig.	('expression', 'MPA', (315, 325))	('high 13-gene score', 'Var', (192, 210))	('TF', 'Gene', '2152', (266, 268))	('high', 'Var', (239, 243))	('TF', 'Gene', '2152', (360, 362))	('patients', 'Species', '9606', (74, 82))	('low', 'NegReg', (356, 359))	('TF', 'Gene', '2152', (312, 314))	('TF', 'Gene', '2152', (220, 222))	('low', 'NegReg', (262, 265))	('low', 'NegReg', (285, 288))	('TF', 'Gene', '2152', (162, 164))
209897	31523055	Glioma stem cells have increased ability to stimulate angiogenesis through VEGF upregulation and inhibition of HIFs could reduce CSC survival, self-renewal and proliferation.	('inhibition', 'Var', (97, 107))	('VEGF', 'Gene', '7422', (75, 79))	('reduce', 'NegReg', (122, 128))	('angiogenesis', 'CPA', (54, 66))	('upregulation', 'PosReg', (80, 92))	('self-renewal', 'CPA', (143, 155))	('stimulate', 'PosReg', (44, 53))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('proliferation', 'CPA', (160, 173))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('VEGF', 'Gene', (75, 79))	('Glioma', 'Disease', (0, 6))	('HIFs', 'Gene', (111, 115))	('angiogenesis', 'biological_process', 'GO:0001525', ('54', '66'))	('CSC survival', 'CPA', (129, 141))
209916	31523055	Aberrations in the Notch-Hedgehog signalling axis are frequently implicated in malignant progression.	('Notch', 'Gene', '31293', (19, 24))	('signalling', 'biological_process', 'GO:0023052', ('34', '44'))	('malignant progression', 'CPA', (79, 100))	('Aberrations', 'Var', (0, 11))	('implicated', 'Reg', (65, 75))	('Notch', 'Gene', (19, 24))
209920	31523055	In clear cell renal cell carcinoma, inhibition of Notch signalling reduced anchorage-independent growth and mice treated with Notch inhibitors had impaired growth of transplanted cancer cells.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (3, 34))	('anchorage-independent growth', 'CPA', (75, 103))	('Notch', 'Gene', (126, 131))	('inhibition', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (14, 34))	('Notch', 'Gene', '31293', (50, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('Notch', 'Gene', '31293', (126, 131))	('mice', 'Species', '10090', (108, 112))	('reduced', 'NegReg', (67, 74))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 34))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('signalling', 'biological_process', 'GO:0023052', ('56', '66'))	('impaired', 'NegReg', (147, 155))	('cancer', 'Disease', (179, 185))	('clear cell renal cell carcinoma', 'Disease', (3, 34))	('Notch', 'Gene', (50, 55))
209935	31523055	Inhibition of EZH2 in renal cancer cell lines led to increased apoptosis.	('renal cancer', 'Phenotype', 'HP:0009726', (22, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('renal cancer', 'Disease', 'MESH:D007680', (22, 34))	('EZH2', 'Gene', (14, 18))	('EZH2', 'Gene', '2146', (14, 18))	('increased', 'PosReg', (53, 62))	('apoptosis', 'CPA', (63, 72))	('Inhibition', 'Var', (0, 10))	('renal cancer', 'Disease', (22, 34))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))
209963	28978925	Statistical analyses by using Kaplan-Meier method showed that high FGL2 expression was associated with poor overall survival (OS) and recurrence-free survival (RFS) of patients with ccRCC.	('overall', 'MPA', (108, 115))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('RCC', 'Disease', (184, 187))	('recurrence-free survival', 'CPA', (134, 158))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('FGL2', 'Gene', '10875', (67, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (182, 187))	('expression', 'MPA', (72, 82))	('poor', 'NegReg', (103, 107))	('patients', 'Species', '9606', (168, 176))	('FGL2', 'Gene', (67, 71))	('OS', 'Chemical', '-', (126, 128))	('high', 'Var', (62, 66))	('RFS', 'Chemical', '-', (160, 163))
209966	28978925	FGL2 silencing led to a significant reduction in cells viability and increase in cells apoptosis, accompanied with a reduced ERK1/2 and p38 MAPK activation, in ccRCC cells.	('p38', 'Gene', '1432', (136, 139))	('activation', 'PosReg', (145, 155))	('cells viability', 'CPA', (49, 64))	('increase', 'PosReg', (69, 77))	('FGL2', 'Gene', (0, 4))	('RCC', 'Disease', (162, 165))	('RCC', 'Phenotype', 'HP:0005584', (162, 165))	('MAPK activation', 'biological_process', 'GO:0000187', ('140', '155'))	('silencing', 'Var', (5, 14))	('reduction', 'NegReg', (36, 45))	('ERK1/2', 'Enzyme', (125, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (160, 165))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('p38', 'Gene', (136, 139))	('FGL2', 'Gene', '10875', (0, 4))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))	('ERK1', 'molecular_function', 'GO:0004707', ('125', '129'))	('reduced', 'NegReg', (117, 124))	('MAPK', 'molecular_function', 'GO:0004707', ('140', '144'))	('cells apoptosis', 'CPA', (81, 96))
209967	28978925	Thus, our results suggest that high FGL2 expression is a novel, independent, and an adverse prognostic factor of clinical outcomes in patients with ccRCC.	('expression', 'MPA', (41, 51))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('FGL2', 'Gene', '10875', (36, 40))	('RCC', 'Disease', (150, 153))	('FGL2', 'Gene', (36, 40))	('patients', 'Species', '9606', (134, 142))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('ccRCC', 'Phenotype', 'HP:0006770', (148, 153))	('high', 'Var', (31, 35))
209994	28978925	Patients showing high FGL2 expression had significantly large tumours (P = 0.002), high T classification (P = 0.002), and high TNM stage (P = 0.003) (Table 1).	('TNM', 'Gene', '10178', (127, 130))	('high T classification', 'CPA', (83, 104))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('high', 'Var', (17, 21))	('TNM', 'Gene', (127, 130))	('expression', 'MPA', (27, 37))	('Patients', 'Species', '9606', (0, 8))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('FGL2', 'Gene', '10875', (22, 26))	('tumours', 'Disease', 'MESH:D009369', (62, 69))	('FGL2', 'Gene', (22, 26))	('tumours', 'Disease', (62, 69))
209998	28978925	Results of these analyses showed that patients with ccRCC who showed high FGL2 expression had significantly poorer OS (log-rank test: P < 0.001) and RFS (log-rank test: P < 0.001) than patients showing low FGL2 expression (Fig.	('FGL2', 'Gene', (206, 210))	('RFS', 'MPA', (149, 152))	('OS', 'Chemical', '-', (115, 117))	('RCC', 'Disease', (54, 57))	('patients', 'Species', '9606', (38, 46))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('poorer', 'NegReg', (108, 114))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('FGL2', 'Gene', '10875', (74, 78))	('FGL2', 'Gene', (74, 78))	('high', 'Var', (69, 73))	('patients', 'Species', '9606', (185, 193))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('RFS', 'Chemical', '-', (149, 152))	('FGL2', 'Gene', '10875', (206, 210))
210000	28978925	We found that high FGL2 expression was associated with significantly poorer OS and RFS than low FGL2 expression in patients with early-stage ccRCC (TNM stage, I + II; log-rank test, P < 0.001; Fig.	('patients', 'Species', '9606', (115, 123))	('ccRCC', 'Phenotype', 'HP:0006770', (141, 146))	('RFS', 'CPA', (83, 86))	('OS', 'Chemical', '-', (76, 78))	('FGL2', 'Gene', (96, 100))	('expression', 'MPA', (24, 34))	('FGL2', 'Gene', '10875', (19, 23))	('poorer', 'NegReg', (69, 75))	('high', 'Var', (14, 18))	('TNM', 'Gene', '10178', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('RFS', 'Chemical', '-', (83, 86))	('FGL2', 'Gene', (19, 23))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', (143, 146))	('FGL2', 'Gene', '10875', (96, 100))	('TNM', 'Gene', (148, 151))
210005	28978925	Moreover, tumour size, T classification, TNM staging, Fuhrman grade, and high FGL2 expression were significantly associated with RFS (HR, 4.214; 95% CI, 2.119-8.383; P < 0.001).	('RFS', 'Disease', (129, 132))	('TNM', 'Gene', '10178', (41, 44))	('RFS', 'Chemical', '-', (129, 132))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('FGL2', 'Gene', '10875', (78, 82))	('TNM', 'Gene', (41, 44))	('tumour', 'Disease', 'MESH:D009369', (10, 16))	('FGL2', 'Gene', (78, 82))	('expression', 'MPA', (83, 93))	('tumour', 'Disease', (10, 16))	('high', 'Var', (73, 77))	('associated', 'Reg', (113, 123))
210006	28978925	As expected, multivariate analysis based on Cox proportional hazards model showed that high FGL2 expression was an independent predictor of both OS and RFS (OS: HR, 3.396; 95% CI, 1.187-9.722; P = 0.023; RFS: HR, 2.940; 95% CI, 1.402-6.166; P = 0.004), like tumour size (P < 0.001), TNM staging (P = 0.001), Fuhrman grade (P < 0.001), and necrosis (P = 0.003).	('necrosis', 'biological_process', 'GO:0070265', ('339', '347'))	('tumour', 'Phenotype', 'HP:0002664', (258, 264))	('OS', 'Chemical', '-', (145, 147))	('necrosis', 'biological_process', 'GO:0019835', ('339', '347'))	('FGL2', 'Gene', '10875', (92, 96))	('tumour', 'Disease', 'MESH:D009369', (258, 264))	('high', 'Var', (87, 91))	('necrosis', 'biological_process', 'GO:0001906', ('339', '347'))	('RFS', 'Chemical', '-', (152, 155))	('Cox', 'Gene', '1351', (44, 47))	('tumour', 'Disease', (258, 264))	('TNM', 'Gene', '10178', (283, 286))	('TNM', 'Gene', (283, 286))	('expression', 'MPA', (97, 107))	('Cox', 'Gene', (44, 47))	('necrosis', 'biological_process', 'GO:0008219', ('339', '347'))	('necrosis', 'Disease', 'MESH:D009336', (339, 347))	('FGL2', 'Gene', (92, 96))	('RFS', 'Chemical', '-', (204, 207))	('necrosis', 'Disease', (339, 347))	('OS', 'Chemical', '-', (157, 159))	('necrosis', 'biological_process', 'GO:0008220', ('339', '347'))	('RFS', 'Disease', (152, 155))	('Fuhrman', 'Disease', (308, 315))
210014	28978925	In order to further investigate the underlying mechanism of FGL2 in promoting ccRCC, we silenced FGL2 expression in ccRCC cell line 786-O cells by small interfering RNA (siRNA) in vitro (Fig.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('small', 'Var', (147, 152))	('RCC', 'Disease', (118, 121))	('FGL2', 'Gene', '10875', (97, 101))	('RCC', 'Disease', (80, 83))	('FGL2', 'Gene', (97, 101))	('expression', 'MPA', (102, 112))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('silenced', 'NegReg', (88, 96))	('RNA', 'cellular_component', 'GO:0005562', ('165', '168'))	('FGL2', 'Gene', '10875', (60, 64))	('FGL2', 'Gene', (60, 64))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))
210015	28978925	It was found that the silencing of FGL2 expression led to a significant reduction in cells viability and an increase in cells apoptosis, accompanied with a reduced activation in ERK1/2 and p38 MAPK pathway, an important signalling pathway in ccRCC, in ccRCC cells (Fig.	('p38', 'Gene', (189, 192))	('RCC', 'Disease', (244, 247))	('RCC', 'Phenotype', 'HP:0005584', (244, 247))	('MAPK', 'molecular_function', 'GO:0004707', ('193', '197'))	('FGL2', 'Gene', (35, 39))	('RCC', 'Disease', 'MESH:C538614', (244, 247))	('increase', 'PosReg', (108, 116))	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('cells apoptosis', 'CPA', (120, 135))	('silencing', 'Var', (22, 31))	('p38', 'Gene', '1432', (189, 192))	('ERK1', 'molecular_function', 'GO:0004707', ('178', '182'))	('FGL2', 'Gene', '10875', (35, 39))	('cells viability', 'CPA', (85, 100))	('signalling pathway', 'biological_process', 'GO:0007165', ('220', '238'))	('RCC', 'Disease', (254, 257))	('RCC', 'Phenotype', 'HP:0005584', (254, 257))	('reduction', 'NegReg', (72, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (252, 257))	('reduced', 'NegReg', (156, 163))	('activation', 'PosReg', (164, 174))	('RCC', 'Disease', 'MESH:C538614', (254, 257))	('ccRCC', 'Phenotype', 'HP:0006770', (242, 247))
210018	28978925	To our knowledge, the present study is the first to show an association between high FGL2 expression and unfavourable prognosis of patients with ccRCC after surgery.	('FGL2', 'Gene', (85, 89))	('patients', 'Species', '9606', (131, 139))	('ccRCC', 'Phenotype', 'HP:0006770', (145, 150))	('expression', 'MPA', (90, 100))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('FGL2', 'Gene', '10875', (85, 89))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('high', 'Var', (80, 84))
210020	28978925	We also found that high FGL2 expression was positively correlated with the stage of ccRCC.	('FGL2', 'Gene', (24, 28))	('correlated', 'Reg', (55, 65))	('high', 'Var', (19, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('expression', 'MPA', (29, 39))	('RCC', 'Disease', (86, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('FGL2', 'Gene', '10875', (24, 28))
210029	28978925	This suggested that aberrant FGL2 expression in ccRCC interferes with tumour progression.	('aberrant', 'Var', (20, 28))	('FGL2', 'Gene', '10875', (29, 33))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('RCC', 'Disease', (50, 53))	('FGL2', 'Gene', (29, 33))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('interferes', 'NegReg', (54, 64))	('tumour', 'Disease', (70, 76))
210033	28978925	Consistent with these observations, at present study we found that FGL2 silencing significantly inhibited ccRCC cells viability and ERK1/2 and p38 activation, and promoted cells apoptosis, suggesting that FGL2 aggravates the pathogenesis of ccRCC by promoting the activation of ERK1/2 and p38 MAPK signalling pathway.	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('silencing', 'Var', (72, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('p38', 'Gene', '1432', (143, 146))	('MAPK', 'molecular_function', 'GO:0004707', ('293', '297'))	('ccRCC', 'Phenotype', 'HP:0006770', (241, 246))	('RCC', 'Disease', (243, 246))	('RCC', 'Phenotype', 'HP:0005584', (243, 246))	('apoptosis', 'biological_process', 'GO:0097194', ('178', '187'))	('apoptosis', 'biological_process', 'GO:0006915', ('178', '187'))	('activation', 'PosReg', (147, 157))	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('p38', 'Gene', (289, 292))	('ERK1', 'molecular_function', 'GO:0004707', ('278', '282'))	('FGL2', 'Gene', (205, 209))	('FGL2', 'Gene', '10875', (67, 71))	('RCC', 'Disease', 'MESH:C538614', (243, 246))	('promoting', 'PosReg', (250, 259))	('cells apoptosis', 'CPA', (172, 187))	('p38 MAPK signalling', 'biological_process', 'GO:0051403', ('289', '308'))	('inhibited', 'NegReg', (96, 105))	('ERK1/2', 'Enzyme', (132, 138))	('p38', 'Gene', '1432', (289, 292))	('p38', 'Gene', (143, 146))	('promoted', 'PosReg', (163, 171))	('FGL2', 'Gene', '10875', (205, 209))	('aggravates', 'PosReg', (210, 220))	('pathogenesis', 'biological_process', 'GO:0009405', ('225', '237'))	('FGL2', 'Gene', (67, 71))	('ERK1', 'molecular_function', 'GO:0004707', ('132', '136'))	('signalling pathway', 'biological_process', 'GO:0007165', ('298', '316'))
210039	28978925	Moreover, FGL2 knockdown delays HCC growth and tumour angiogenesis.	('FGL2', 'Gene', (10, 14))	('delays HCC growth', 'Disease', (25, 42))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('knockdown', 'Var', (15, 24))	('HCC', 'Phenotype', 'HP:0001402', (32, 35))	('tumour', 'Disease', (47, 53))	('delays HCC growth', 'Disease', 'MESH:D006528', (25, 42))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('angiogenesis', 'biological_process', 'GO:0001525', ('54', '66'))	('FGL2', 'Gene', '10875', (10, 14))
210047	28978925	High FGL2 expression was an independent prognostic factor of poor OS and RFS in patients with ccRCC, and it is better performed in especially those with early-TNM-stage ccRCC.	('OS', 'Chemical', '-', (66, 68))	('patients', 'Species', '9606', (80, 88))	('FGL2', 'Gene', '10875', (5, 9))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('RFS', 'Chemical', '-', (73, 76))	('RCC', 'Disease', (171, 174))	('poor', 'Disease', (61, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))	('High', 'Var', (0, 4))	('expression', 'MPA', (10, 20))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RCC', 'Disease', (96, 99))	('RFS', 'CPA', (73, 76))	('TNM', 'Gene', '10178', (159, 162))	('FGL2', 'Gene', (5, 9))	('TNM', 'Gene', (159, 162))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
210079	28854935	Mutations within genes that code these proteins lead to different renal disorders and diseases.	('lead to', 'Reg', (48, 55))	('Mutations', 'Var', (0, 9))	('renal disorders and diseases', 'Disease', 'MESH:D007674', (66, 94))
210092	28854935	Mutations within these genes lead to different renal disorders.	('renal disorders', 'Disease', 'MESH:D007674', (47, 62))	('Mutations', 'Var', (0, 9))	('renal disorders', 'Disease', (47, 62))	('lead to', 'Reg', (29, 36))
210109	28854935	GLUT2 has a low affinity for glucose (Km ~ 17 mM), fructose (Km ~ 76 mM), galactose (Km ~ 92 mM) and mannose (Km ~ 125 mM).	('fructose', 'Chemical', 'MESH:D005632', (51, 59))	('affinity', 'MPA', (16, 24))	('galactose', 'Chemical', 'MESH:D005690', (74, 83))	('glucose', 'Chemical', 'MESH:D005947', (29, 36))	('Km', 'Var', (61, 63))	('Km', 'Var', (85, 87))	('mannose', 'Chemical', 'MESH:D008358', (101, 108))
210114	28854935	In hepatocytes, GLUT2 releases glucose synthesized by gluconeogenesis into the blood, and in the pancreatic beta-cells it provides glucose-sensing functions for insulin secretion.	('glucose-sensing functions', 'MPA', (131, 156))	('gluconeogenesis', 'biological_process', 'GO:0006094', ('54', '69'))	('insulin secretion', 'Disease', (161, 178))	('gluconeogenesis', 'MPA', (54, 69))	('GLUT2', 'Var', (16, 21))	('glucose', 'Chemical', 'MESH:D005947', (131, 138))	('glucose synthesized', 'MPA', (31, 50))	('glucose-sensing', 'biological_process', 'GO:0051594', ('131', '146'))	('insulin', 'molecular_function', 'GO:0016088', ('161', '168'))	('insulin secretion', 'biological_process', 'GO:0030073', ('161', '178'))	('glucose', 'Chemical', 'MESH:D005947', (31, 38))	('insulin secretion', 'Disease', 'MESH:D007333', (161, 178))
210209	28854935	There are different isoforms of this cotransporter, because exon 7 may be spliced out deleting 26 aa between TMHs 5 and 6, internal splice in exon 10 means either 36 or 52 aa between TMHs 11 and 12.	('TMHs', 'Gene', (183, 187))	('internal splice in', 'Var', (123, 141))	('TMHs', 'Gene', (109, 113))	('TMHs', 'Gene', '222662', (183, 187))	('deleting', 'Var', (86, 94))	('TMHs', 'Gene', '222662', (109, 113))
210269	28854935	In humans, mutations in HNF-1alpha gene cause MODY3 (Maturity Onset Diabetes of Young).	('mutations', 'Var', (11, 20))	('cause', 'Reg', (40, 45))	('MODY3', 'Gene', '6927', (46, 51))	('Diabetes', 'Disease', 'MESH:D003920', (68, 76))	('HNF-1alpha', 'Gene', (24, 34))	('humans', 'Species', '9606', (3, 9))	('Diabetes', 'Disease', (68, 76))	('MODY3', 'Gene', (46, 51))
210283	28854935	Genetic variation of GLUT2 may be the cause of diabetic nephropathy.	('diabetic nephropathy', 'Disease', (47, 67))	('Genetic variation', 'Var', (0, 17))	('GLUT2', 'Gene', (21, 26))	('diabetic nephropathy', 'Disease', 'MESH:D003928', (47, 67))	('cause', 'Reg', (38, 43))	('nephropathy', 'Phenotype', 'HP:0000112', (56, 67))
210291	28854935	Of note is that genetic variation of GLUT1 affects nephropathy and may be associated with the risk of micro- and macroalbuminuria in the adult European Americans with type 2 diabetes.	('nephropathy', 'Disease', 'MESH:D007674', (51, 62))	('macroalbuminuria', 'Disease', (113, 129))	('macroalbuminuria', 'Disease', 'None', (113, 129))	('GLUT1', 'Gene', '6513', (37, 42))	('type 2 diabetes', 'Disease', (167, 182))	('albuminuria', 'Phenotype', 'HP:0012592', (118, 129))	('affects', 'Reg', (43, 50))	('nephropathy', 'Disease', (51, 62))	('nephropathy', 'Phenotype', 'HP:0000112', (51, 62))	('genetic variation', 'Var', (16, 33))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (167, 182))	('type 2 diabetes', 'Disease', 'MESH:D003924', (167, 182))	('associated', 'Reg', (74, 84))	('GLUT1', 'Gene', (37, 42))
210300	28854935	Therefore, inhibition of SGLT2 may protect human proximal tubular cells by lowering of glomerular hyperfiltration and by limiting hyperglycemic damage to proximal tubule cells.	('hyperglycemic damage', 'Disease', (130, 150))	('limiting', 'NegReg', (121, 129))	('SGLT2', 'Gene', (25, 30))	('lowering', 'NegReg', (75, 83))	('inhibition', 'Var', (11, 21))	('hyperglycemic damage', 'Disease', 'MESH:D006943', (130, 150))	('glomerular hyperfiltration', 'MPA', (87, 113))	('human', 'Species', '9606', (43, 48))	('rat', 'Species', '10116', (107, 110))
210302	28854935	Animal studies showed that inhibitors of SGLT2 reduce albuminuria and kidney growth.	('reduce', 'NegReg', (47, 53))	('albuminuria', 'Disease', (54, 65))	('albuminuria', 'Phenotype', 'HP:0012592', (54, 65))	('inhibitors', 'Var', (27, 37))	('SGLT2', 'Gene', (41, 46))	('albuminuria', 'Disease', 'MESH:D000419', (54, 65))	('kidney growth', 'CPA', (70, 83))
210303	28854935	Inhibitors of SGLT2 are also treated as drugs used in diabetes mellitus.	('diabetes mellitus', 'Phenotype', 'HP:0000819', (54, 71))	('SGLT2', 'Gene', (14, 19))	('Inhibitors', 'Var', (0, 10))	('diabetes mellitus', 'Disease', (54, 71))	('diabetes mellitus', 'Disease', 'MESH:D003920', (54, 71))
210304	28854935	Different inhibitors of SGLT2 are used as a novel treatment for patients with diabetes.	('patients', 'Species', '9606', (64, 72))	('SGLT2', 'Gene', (24, 29))	('inhibitors', 'Var', (10, 20))	('diabetes', 'Disease', (78, 86))	('diabetes', 'Disease', 'MESH:D003920', (78, 86))
210322	28854935	It was observed in the late 1980s that the administration of phlorizin in animal models of type 2 diabetes, induces glucosuria, and normalizes both fasting and fed plasma glucose levels.	('type 2 diabetes', 'Disease', (91, 106))	('glucosuria', 'Disease', (116, 126))	('glucosuria', 'Phenotype', 'HP:0003076', (116, 126))	('type 2 diabetes', 'Disease', 'MESH:D003924', (91, 106))	('phlorizin', 'Var', (61, 70))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (91, 106))	('induces', 'Reg', (108, 115))	('phlorizin', 'Chemical', 'MESH:D010695', (61, 70))	('glucosuria', 'Disease', 'MESH:D006030', (116, 126))	('glucose', 'Chemical', 'MESH:D005947', (171, 178))	('normalizes', 'NegReg', (132, 142))	('rat', 'Species', '10116', (51, 54))
210324	28854935	The US Food and Drug Administration has approved 3 inhibitors of SGLT2 for treatment of type 2 diabetes: canagliflozin, dapagliflozin and empagliflozin.	('SGLT2', 'Gene', (65, 70))	('empagliflozin', 'Chemical', 'MESH:C570240', (138, 151))	('rat', 'Species', '10116', (29, 32))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (88, 103))	('type 2 diabetes', 'Disease', 'MESH:D003924', (88, 103))	('dapagliflozin', 'Chemical', 'MESH:C529054', (120, 133))	('canagliflozin', 'Chemical', 'MESH:D000068896', (105, 118))	('inhibitors', 'Var', (51, 61))	('type 2 diabetes', 'Disease', (88, 103))
210325	28854935	Inhibitors of SGLT2 can be used as monotherapy or in combination with other oral agents as well as with insulin.	('insulin', 'molecular_function', 'GO:0016088', ('104', '111'))	('SGLT2', 'Gene', (14, 19))	('Inhibitors', 'Var', (0, 10))	('insulin', 'Gene', (104, 111))	('insulin', 'Gene', '3630', (104, 111))
210326	28854935	Inhibitors of SGLT2 act on the kidney without adverse gastrointestinal effect.	('adverse gastrointestinal', 'Disease', (46, 70))	('SGLT2', 'Gene', (14, 19))	('Inhibitors', 'Var', (0, 10))	('adverse gastrointestinal', 'Disease', 'MESH:D005767', (46, 70))
210329	28854935	Of note, it was shown in animal studies, that in normal animals, inhibitors of SGLT2 have no effect on plasma glucose levels.	('SGLT2', 'Gene', (79, 84))	('glucose', 'Chemical', 'MESH:D005947', (110, 117))	('plasma glucose levels', 'MPA', (103, 124))	('inhibitors', 'Var', (65, 75))
210331	28854935	It is suggested, on the basis of animal studies, that inhibitors prevent of glomerular hyperfiltration, reduces albuminuria, kidney growth, and attenuated of inflammation.	('inflammation', 'biological_process', 'GO:0006954', ('158', '170'))	('kidney growth', 'CPA', (125, 138))	('attenuated', 'NegReg', (144, 154))	('inhibitors', 'Var', (54, 64))	('reduces', 'NegReg', (104, 111))	('albuminuria', 'Disease', (112, 123))	('glomerular hyperfiltration', 'CPA', (76, 102))	('rat', 'Species', '10116', (96, 99))	('prevent', 'NegReg', (65, 72))	('albuminuria', 'Phenotype', 'HP:0012592', (112, 123))	('inflammation', 'Disease', 'MESH:D007249', (158, 170))	('albuminuria', 'Disease', 'MESH:D000419', (112, 123))	('inflammation', 'Disease', (158, 170))
210334	28854935	In patients with type 2 diabetes, inhibitors of SGLT2 stimulate glucose excretion through the kidney.	('glucose excretion', 'Disease', 'MESH:D018149', (64, 81))	('glucose excretion', 'Disease', (64, 81))	('type 2 diabetes', 'Disease', (17, 32))	('inhibitors', 'Var', (34, 44))	('SGLT2', 'Gene', (48, 53))	('patients', 'Species', '9606', (3, 11))	('excretion', 'biological_process', 'GO:0007588', ('72', '81'))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (17, 32))	('type 2 diabetes', 'Disease', 'MESH:D003924', (17, 32))	('stimulate', 'PosReg', (54, 63))
210335	28854935	The inhibitors increase glucose excretion rate of ~80 g/day.	('excretion', 'biological_process', 'GO:0007588', ('32', '41'))	('increase', 'PosReg', (15, 23))	('glucose excretion', 'Disease', (24, 41))	('glucose excretion', 'Disease', 'MESH:D018149', (24, 41))	('inhibitors', 'Var', (4, 14))	('increase glucose', 'Phenotype', 'HP:0003074', (15, 31))	('rat', 'Species', '10116', (42, 45))
210338	28854935	It was also observe that inhibitors of SGLT2 decrease of HbA1c (~ 1%), lower blood pressure (~ 5 mmHg) and cause weight loss (1,0-3,0 kg).	('weight loss', 'Disease', (113, 124))	('HbA1c', 'Protein', (57, 62))	('weight loss', 'Phenotype', 'HP:0001824', (113, 124))	('lower blood pressure', 'Phenotype', 'HP:0002615', (71, 91))	('inhibitors', 'Var', (25, 35))	('decrease', 'NegReg', (45, 53))	('weight loss', 'Disease', 'MESH:D015431', (113, 124))	('SGLT2', 'Gene', (39, 44))	('lower', 'NegReg', (71, 76))
210339	28854935	It was found, for example, an increase in the occurrence of urogenital infections in women after administration of inhibitors of SGLT2.	('rat', 'Species', '10116', (105, 108))	('women', 'Species', '9606', (85, 90))	('increase', 'PosReg', (30, 38))	('urogenital infections', 'Disease', (60, 81))	('SGLT2', 'Gene', (129, 134))	('inhibitors', 'Var', (115, 125))	('urogenital infections', 'Disease', 'MESH:D014564', (60, 81))
210340	28854935	Familial renal glycosuria (FRG) is a rare renal tubular disorder occurring due to autosomal recessive mutations in the SLC5A2 gene, characterized by the decreased reabsorption of glucose and therefore glucose is excreted through urine.	('renal tubular disorder', 'Disease', (42, 64))	('SLC5A2', 'Gene', (119, 125))	('glucose', 'Chemical', 'MESH:D005947', (201, 208))	('SLC5A2', 'Gene', '6524', (119, 125))	('renal tubular disorder', 'Disease', 'MESH:D007674', (42, 64))	('decreased', 'NegReg', (153, 162))	('mutations', 'Var', (102, 111))	('glycosuria', 'Phenotype', 'HP:0003076', (15, 25))	('reabsorption of glucose', 'MPA', (163, 186))	('glucose', 'Chemical', 'MESH:D005947', (179, 186))	('Familial renal glycosuria', 'Disease', 'MESH:D006030', (0, 25))	('glucose', 'MPA', (201, 208))	('Familial renal glycosuria', 'Disease', (0, 25))
210347	28854935	Many heterozygous individuals for SGLT2 mutations, both nonsense and missense, suffer mild glycosuria, (<10 g/1.73m2/24 h) which is relatively common.	('nonsense', 'Var', (56, 64))	('glycosuria', 'Disease', 'MESH:D006029', (91, 101))	('missense', 'Var', (69, 77))	('SGLT2', 'Gene', (34, 39))	('mutations', 'Var', (40, 49))	('glycosuria', 'Disease', (91, 101))	('glycosuria', 'Phenotype', 'HP:0003076', (91, 101))	('suffer', 'Reg', (79, 85))
210348	28854935	Patients with severe glycosuria (>=10 g/1.73m2/24 h) show the recessive inheritance with homozygosity or compound heterozygosity for SGLT2 mutations.	('compound heterozygosity', 'Var', (105, 128))	('glycosuria', 'Phenotype', 'HP:0003076', (21, 31))	('mutations', 'Var', (139, 148))	('Patients', 'Species', '9606', (0, 8))	('glycosuria', 'Disease', 'MESH:D006029', (21, 31))	('SGLT2', 'Gene', (133, 138))	('glycosuria', 'Disease', (21, 31))
210351	28854935	Decreased in SGLT2 affinity for glucose, due to missense mutations, leads to type B glycosuria.	('glucose', 'Chemical', 'MESH:D005947', (32, 39))	('Decreased', 'NegReg', (0, 9))	('SGLT2', 'Protein', (13, 18))	('glycosuria', 'Disease', (84, 94))	('missense mutations', 'Var', (48, 66))	('glycosuria', 'Phenotype', 'HP:0003076', (84, 94))	('glycosuria', 'Disease', 'MESH:D006029', (84, 94))	('leads to', 'Reg', (68, 76))
210356	28854935	GGM is a rare autosomal disease caused due to mutations within SLC5A1 gene.	('mutations', 'Var', (46, 55))	('SLC5A1', 'Gene', '6523', (63, 69))	('SLC5A1', 'Gene', (63, 69))	('autosomal disease', 'Disease', (14, 31))	('autosomal disease', 'Disease', 'MESH:D030342', (14, 31))	('GGM', 'Disease', 'MESH:C562602', (0, 3))	('caused due to', 'Reg', (32, 45))	('GGM', 'Disease', (0, 3))
210363	28854935	FBS is an autosomal recessive disorder, and a total of 34 different GLUT2 mutations homozygous and heterozygous, have been described.	('GLUT2', 'Gene', (68, 73))	('mutations', 'Var', (74, 83))	('FBS', 'Disease', 'MESH:D005198', (0, 3))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (10, 38))	('autosomal recessive disorder', 'Disease', (10, 38))	('FBS', 'Disease', (0, 3))
210368	28854935	As an effect of this disturbance, an impairment of other transport functions resulting in a tubulopathy with disproportionately severe glycosuria occurs.	('tubulopathy', 'Disease', (92, 103))	('disturbance', 'Var', (21, 32))	('tubulopathy', 'Disease', 'MESH:D007674', (92, 103))	('glycosuria', 'Disease', (135, 145))	('transport', 'biological_process', 'GO:0006810', ('57', '66'))	('glycosuria', 'Phenotype', 'HP:0003076', (135, 145))	('impairment', 'Reg', (37, 47))	('glycosuria', 'Disease', 'MESH:D006029', (135, 145))
210382	28854935	In many renal tumors, mutations of the VHL gene cause the synthesis of nonfunctional protein, leading to perpetuation of HIF-1alpha activity.	('HIF-1alpha', 'Gene', (121, 131))	('synthesis', 'biological_process', 'GO:0009058', ('58', '67'))	('renal tumors', 'Disease', (8, 20))	('activity', 'MPA', (132, 140))	('VHL', 'Gene', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('perpetuation', 'MPA', (105, 117))	('cause', 'Reg', (48, 53))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('renal tumors', 'Phenotype', 'HP:0009726', (8, 20))	('synthesis of nonfunctional protein', 'MPA', (58, 92))	('VHL', 'Gene', '7428', (39, 42))	('HIF-1alpha', 'Gene', '3091', (121, 131))	('mutations', 'Var', (22, 31))	('renal tumors', 'Disease', 'MESH:D007674', (8, 20))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
210411	28854935	The loss of nonfunctional VHL protein, due to mutations in tumor suppressor gene, occurs in about 80% of RCCs.	('tumor', 'Disease', (59, 64))	('mutations', 'Var', (46, 55))	('VHL', 'Gene', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('VHL', 'Gene', '7428', (26, 29))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor suppressor', 'biological_process', 'GO:0051726', ('59', '75'))	('loss', 'NegReg', (4, 8))	('nonfunctional', 'MPA', (12, 25))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('59', '75'))
210415	28854935	There was found an association between GLUT1 gene polymorphism with ccRCC.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('GLUT1', 'Gene', '6513', (39, 44))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('polymorphism', 'Var', (50, 62))	('GLUT1', 'Gene', (39, 44))	('association', 'Interaction', (19, 30))
210423	28854935	Mutations in the SLC2A9 gene may affect plasma uric acid levels.	('plasma uric acid levels', 'MPA', (40, 63))	('uric acid', 'Chemical', 'MESH:D014527', (47, 56))	('affect', 'Reg', (33, 39))	('SLC2A9', 'Gene', (17, 23))	('Mutations', 'Var', (0, 9))	('SLC2A9', 'Gene', '56606', (17, 23))
210426	28854935	Monogenic forms of hypouricemia have been linked with mutations in the SLC2A9 gene.	('hypouricemia', 'Phenotype', 'HP:0003537', (19, 31))	('SLC2A9', 'Gene', (71, 77))	('hypouricemia', 'Disease', (19, 31))	('mutations', 'Var', (54, 63))	('SLC2A9', 'Gene', '56606', (71, 77))	('hypouricemia', 'Disease', 'MESH:C537757', (19, 31))	('linked', 'Reg', (42, 48))
210428	28854935	This defect causes severe hypouricemia, complicated by nephrolithiasis and exercise-induced acute renal failure.	('causes', 'Reg', (12, 18))	('nephrolithiasis', 'Disease', 'MESH:D053040', (55, 70))	('acute renal failure', 'Disease', 'MESH:D058186', (92, 111))	('hypouricemia', 'Phenotype', 'HP:0003537', (26, 38))	('nephrolithiasis', 'Disease', (55, 70))	('hypouricemia', 'Disease', (26, 38))	('defect', 'Var', (5, 11))	('hypouricemia', 'Disease', 'MESH:C537757', (26, 38))	('acute renal failure', 'Phenotype', 'HP:0001919', (92, 111))	('renal failure', 'Phenotype', 'HP:0000083', (98, 111))	('acute renal failure', 'Disease', (92, 111))	('nephrolithiasis', 'Phenotype', 'HP:0000787', (55, 70))
210434	28854935	Disturbances in expression and/or function of glucose transporters cause renal diseases.	('glucose', 'Protein', (46, 53))	('cause', 'Reg', (67, 72))	('function', 'MPA', (34, 42))	('renal diseases', 'Disease', 'MESH:D007674', (73, 87))	('Disturbances', 'Var', (0, 12))	('glucose', 'Chemical', 'MESH:D005947', (46, 53))	('expression', 'MPA', (16, 26))	('renal diseases', 'Disease', (73, 87))	('renal disease', 'Phenotype', 'HP:0000112', (73, 86))
210450	32967224	Mutations in different genes, e.g., VHL, p53, PTEN, and mTor, have been associated with the development of RCC.	('p53', 'Gene', '7157', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('mTor', 'Gene', (56, 60))	('RCC', 'Disease', (107, 110))	('VHL', 'Gene', (36, 39))	('PTEN', 'Gene', (46, 50))	('VHL', 'Gene', '7428', (36, 39))	('associated with', 'Reg', (72, 87))	('PTEN', 'Gene', '5728', (46, 50))	('Mutations', 'Var', (0, 9))	('mTor', 'Gene', '2475', (56, 60))	('p53', 'Gene', (41, 44))
210469	32967224	In all ccRCC lines, the high efficacy of the ODC was primarily driven by high single drug activities, predominantly of erlotinib, dasatinib and AZD4547 (negative coefficients of single drug linear effects, Figure 1C, Figure S1.2.1-3), which constituted the final ODC of both A498 and Caki-1.	('ODC', 'Chemical', '-', (263, 266))	('dasatinib', 'Chemical', 'MESH:D000069439', (130, 139))	('RCC', 'Disease', 'MESH:C538614', (9, 12))	('erlotinib', 'Var', (119, 128))	('RCC', 'Disease', (9, 12))	('AZD4547', 'Chemical', 'MESH:C572463', (144, 151))	('single drug activities', 'MPA', (78, 100))	('erlotinib', 'Chemical', 'MESH:D000069347', (119, 128))	('ODC', 'Chemical', '-', (45, 48))	('AZD4547', 'Var', (144, 151))
210482	32967224	In general, ODC but not individual drugs majorly inhibited the phosphorylation of MAPK (ERK1/2) and RPS6, as shown by western blotting (Figure 2, Figure S2.2).	('phosphorylation', 'biological_process', 'GO:0016310', ('63', '78'))	('RPS6', 'Gene', (100, 104))	('ODC', 'Var', (12, 15))	('MAPK', 'Protein', (82, 86))	('ERK1', 'molecular_function', 'GO:0004707', ('88', '92'))	('ERK1/2', 'Gene', (88, 94))	('ERK1/2', 'Gene', '5595;5594', (88, 94))	('phosphorylation', 'MPA', (63, 78))	('RPS6', 'Gene', '6194', (100, 104))	('MAPK', 'molecular_function', 'GO:0004707', ('82', '86'))	('inhibited', 'NegReg', (49, 58))	('ODC', 'Chemical', '-', (12, 15))
210495	32967224	We therefore tested the combination of erlotinib, dasatinib and AZD4547 or axitinib, constituting the ODC in ccRCC (Figure S4.1.1-2).	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('axitinib', 'Chemical', 'MESH:D000077784', (75, 83))	('RCC', 'Disease', (111, 114))	('erlotinib', 'Chemical', 'MESH:D000069347', (39, 48))	('ODC', 'Chemical', '-', (102, 105))	('tested', 'Reg', (13, 19))	('AZD4547', 'Var', (64, 71))	('dasatinib', 'Chemical', 'MESH:D000069439', (50, 59))	('AZD4547', 'Chemical', 'MESH:C572463', (64, 71))
210497	32967224	Exchanging AZD4547 for axitinib and v.v.	('AZD4547', 'Chemical', 'MESH:C572463', (11, 18))	('axitinib', 'Chemical', 'MESH:D000077784', (23, 31))	('AZD4547', 'Gene', (11, 18))	('Exchanging', 'Var', (0, 10))
210499	32967224	HDFA are only moderately affected by the different combinations, and the AZD4547 vs. axitinib combinations had no differential effects on fibroblasts, indicating the presence of an adequate therapeutic window (Figure 4A).	('AZD4547', 'Var', (73, 80))	('HDFA', 'Disease', (0, 4))	('axitinib', 'Chemical', 'MESH:D000077784', (85, 93))	('AZD4547', 'Chemical', 'MESH:C572463', (73, 80))	('HDFA', 'Disease', 'None', (0, 4))	('combinations', 'Var', (94, 106))
210502	32967224	Interestingly, using these combinations in ACHN, essentially exchanging U-104 with dasatinib and erlotinib, considerably improved effectivity in this rather resistant cell line.	('erlotinib', 'Chemical', 'MESH:D000069347', (97, 106))	('ACHN', 'Gene', '55323', (43, 47))	('improved', 'PosReg', (121, 129))	('dasatinib', 'Chemical', 'MESH:D000069439', (83, 92))	('U-104', 'Chemical', 'MESH:C585353', (72, 77))	('ACHN', 'Gene', (43, 47))	('U-104', 'Gene', (72, 77))	('effectivity', 'MPA', (130, 141))	('exchanging', 'Var', (61, 71))
210503	32967224	Of note, erlotinib and AZD4547 showed synergistic activity in both Caki-2 and ACHN (Figure S1.2.4-5), and the drugs presented as part of the common RCC drug combination were among the most frequently selected drugs in each cell line following the two rounds of the s-FSC, resulting in the best performing set of 4 drugs (Figure 1A-D; Figure S1.2.1-6).	('ACHN', 'Gene', '55323', (78, 82))	('RCC', 'Disease', (148, 151))	('erlotinib', 'Chemical', 'MESH:D000069347', (9, 18))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('ACHN', 'Gene', (78, 82))	('synergistic activity', 'MPA', (38, 58))	('AZD4547', 'Var', (23, 30))	('erlotinib', 'Gene', (9, 18))	('AZD4547', 'Chemical', 'MESH:C572463', (23, 30))	('Caki-2', 'CPA', (67, 73))
210520	32967224	For Caki-2 and ACHN, the addition of crizotinib slightly, but non-significantly potentiates their original ODC activity (Figure 6B).	('crizotinib', 'Chemical', 'MESH:D000077547', (37, 47))	('ACHN', 'Gene', (15, 19))	('crizotinib', 'Var', (37, 47))	('ODC', 'Chemical', '-', (107, 110))	('original ODC activity', 'MPA', (98, 119))	('ACHN', 'Gene', '55323', (15, 19))	('addition', 'Var', (25, 33))	('potentiates', 'PosReg', (80, 91))
210521	32967224	Furthermore, the drug combinations clearly outperform the use of sunitinib (10 microM) as monotherapy (Figure 6B).	('sunitinib', 'Chemical', 'MESH:D000077210', (65, 74))	('combinations', 'Var', (22, 34))	('outperform', 'NegReg', (43, 53))
210522	32967224	In 3D spheroids, addition of crizotinib also tended to enhance the ODC effect (Figure S6.2), albeit non-significantly as the ODC were already much more potent in 3D as compared to 2D assays in vitro.	('ODC effect', 'MPA', (67, 77))	('crizotinib', 'Chemical', 'MESH:D000077547', (29, 39))	('enhance', 'PosReg', (55, 62))	('crizotinib', 'Var', (29, 39))	('ODC', 'Chemical', '-', (125, 128))	('ODC', 'Chemical', '-', (67, 70))
210537	32967224	ccRCC is furthermore predominantly associated with high VEGF expression, and indeed, in all ccRCC cell lines VEGF/VEGFR axis inhibitors were selected for in the ODC.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (94, 97))	('VEGF', 'Gene', (56, 60))	('VEGFR', 'Gene', (114, 119))	('RCC', 'Disease', (2, 5))	('VEGF', 'Gene', (114, 118))	('VEGF', 'Gene', '7422', (109, 113))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('ODC', 'Chemical', '-', (161, 164))	('VEGF', 'Gene', (109, 113))	('high', 'Var', (51, 55))	('VEGFR', 'Gene', '3791', (114, 119))	('VEGF', 'Gene', '7422', (56, 60))	('VEGF', 'Gene', '7422', (114, 118))	('expression', 'MPA', (61, 71))
210544	32967224	In addition, the s-FSC arrived in ccRCC cell lines unequivocally at ODC containing erlotinib, dasatinib and either axitinib or AZD4547 (Figure 1, Figure S1).	('AZD4547', 'Chemical', 'MESH:C572463', (127, 134))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('ODC', 'Chemical', '-', (68, 71))	('AZD4547', 'Var', (127, 134))	('dasatinib', 'Chemical', 'MESH:D000069439', (94, 103))	('erlotinib', 'Chemical', 'MESH:D000069347', (83, 92))	('axitinib', 'Chemical', 'MESH:D000077784', (115, 123))
210548	32967224	Fibroblasts were relatively insensitive for these combinations, while endothelial cells overall proved to be more sensitive to combinations containing axitinib as compared to those containing AZD4547 (Figure 4).	('sensitive', 'Reg', (114, 123))	('axitinib', 'Chemical', 'MESH:D000077784', (151, 159))	('AZD4547', 'Chemical', 'MESH:C572463', (192, 199))	('combinations', 'Var', (127, 139))
210582	32967224	This study was financially supported by the Dutch Cancer Society (VU2014-7234 and VU2014-5715) to A.W.G., P.N.-S. and J.R.v.B.	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('Cancer', 'Disease', (50, 56))	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('VU2014-7234', 'Var', (66, 77))	('VU2014-5715', 'Var', (82, 93))
210597	29208006	Different genetic alterations induce the development of renal tubules into RCCs of varying histological subtypes that exhibit different gene expression patterns or mutations, thus providing specific molecular candidates for targeted therapy (e.g., mTOR, VEGF, KIT, and checkpoint inhibitors).	('mTOR', 'Gene', '2475', (248, 252))	('alterations', 'Var', (18, 29))	('KIT', 'molecular_function', 'GO:0005020', ('260', '263'))	('mTOR', 'Gene', (248, 252))	('VEGF', 'Gene', '7422', (254, 258))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('development', 'CPA', (41, 52))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('gene expression', 'biological_process', 'GO:0010467', ('136', '151'))	('VEGF', 'Gene', (254, 258))	('induce', 'Reg', (30, 36))
210612	29208006	Array-based gene expression profiling of 295 tissue samples obtained from six GEO data sets (GSE12090, GSE15641, GSE19949, GSE8271, GSE7023 and GSE19982) was mainly conducted on two different Affymetrix oligonucleotide microarray platforms, GeneChip Human Genome U133A Array and U133Plus 2.0 Array.	('Human', 'Species', '9606', (250, 255))	('gene expression', 'biological_process', 'GO:0010467', ('12', '27'))	('GSE7023', 'Chemical', '-', (132, 139))	('GSE12090', 'Var', (93, 101))	('GSE19949', 'Var', (113, 121))	('GSE19982', 'Var', (144, 152))	('GSE15641', 'Var', (103, 111))	('GSE8271', 'Var', (123, 130))	('GSE7023', 'Var', (132, 139))	('GSE8271', 'Chemical', '-', (123, 130))
210757	31192947	It is considered that the abnormal expression of miRNAs is significantly associated with tumorigenesis that can act as the diagnostic and prognostic biomarker in human cancers, including ccRCC.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))	('expression', 'MPA', (35, 45))	('associated', 'Reg', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('human', 'Species', '9606', (162, 167))	('miR', 'Gene', '220972', (49, 52))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('miR', 'Gene', (49, 52))	('cancers', 'Disease', (168, 175))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('ccRCC', 'Phenotype', 'HP:0006770', (187, 192))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('RCC', 'Disease', (189, 192))	('tumor', 'Disease', (89, 94))	('abnormal', 'Var', (26, 34))
210792	31192947	Abnormal expression of miRNAs may contribute to disease, like malignancy.	('miR', 'Gene', '220972', (23, 26))	('miR', 'Gene', (23, 26))	('malignancy', 'Disease', 'MESH:D009369', (62, 72))	('malignancy', 'Disease', (62, 72))	('contribute', 'Reg', (34, 44))	('expression', 'MPA', (9, 19))	('Abnormal', 'Var', (0, 8))
210817	33207823	The comprehensive molecular characterization of Renal Cell Carcinoma shows several genes silenced and signaling pathways deregulated by epigenetic modifications, such as the abnormal expression of miRNAs.	('signaling pathways', 'Pathway', (102, 120))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (48, 68))	('miRNAs', 'Gene', (197, 203))	('epigenetic modifications', 'Var', (136, 160))	('Carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (48, 68))	('signaling', 'biological_process', 'GO:0023052', ('102', '111'))	('silenced', 'NegReg', (89, 97))	('genes', 'Gene', (83, 88))	('Renal Cell Carcinoma', 'Disease', (48, 68))	('deregulated', 'Reg', (121, 132))
210822	33207823	Previous findings showed that the epigenetic modifications, including an extensive microRNA-mediated regulation of tumor suppressor genes, are key features of RCC.	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('115', '131'))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor suppressor', 'biological_process', 'GO:0051726', ('115', '131'))	('tumor', 'Disease', (115, 120))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))	('epigenetic', 'Var', (34, 44))	('regulation', 'biological_process', 'GO:0065007', ('101', '111'))	('microRNA-mediated regulation', 'MPA', (83, 111))	('RCC', 'Disease', (159, 162))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
210833	33207823	As a consequence, the aberrant expression of miRNAs can affect a multitude of transcripts and different cancer-related signaling pathways.	('aberrant expression', 'Var', (22, 41))	('affect', 'Reg', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('multitude of transcripts', 'MPA', (65, 89))	('miRNAs', 'Gene', (45, 51))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
210850	33207823	Interestingly, in this subgroup of patients, a subset of 8 specific miRNAs, such as miR-22, miR-24, miR-99a, miR-194, miR-214, miR-335, miR-339, miR-708, strongly induced by nivolumab treatment, was identified.	('miR-24', 'Var', (92, 98))	('miR-335', 'Gene', (127, 134))	('miR-214', 'Gene', (118, 125))	('miR-335', 'Gene', '442904', (127, 134))	('miR-99a', 'Gene', (100, 107))	('miR-708', 'Var', (145, 152))	('miR-339', 'Gene', (136, 143))	('nivolumab', 'Chemical', 'MESH:D000077594', (174, 183))	('miR-99a', 'Gene', '407055', (100, 107))	('miR-22', 'Gene', '407004', (84, 90))	('miR-214', 'Gene', '406996', (118, 125))	('miR-339', 'Gene', '442907', (136, 143))	('miR-22', 'Gene', (84, 90))	('induced', 'Reg', (163, 170))	('patients', 'Species', '9606', (35, 43))	('miR-194', 'Var', (109, 116))
210864	33207823	Epigenetic modifications are emerging as central features of renal cancers.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('renal cancer', 'Phenotype', 'HP:0009726', (61, 73))	('renal cancers', 'Disease', 'MESH:D007680', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Epigenetic modifications', 'Var', (0, 24))	('renal cancers', 'Disease', (61, 74))
210866	33207823	According to the hypothesis of the importance of the epigenetic mechanisms in RCC, the comprehensive molecular characterization of RCC shows several genes silenced and signaling pathways deregulated by epigenetic modifications, such as the aberrant DNA methylation or abnormal expression of miRNA.	('signaling', 'biological_process', 'GO:0023052', ('168', '177'))	('expression', 'MPA', (277, 287))	('aberrant DNA methylation', 'Var', (240, 264))	('silenced', 'NegReg', (155, 163))	('deregulated', 'NegReg', (187, 198))	('DNA', 'cellular_component', 'GO:0005574', ('249', '252'))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('signaling pathways', 'Pathway', (168, 186))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('epigenetic modifications', 'Var', (202, 226))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('DNA methylation', 'biological_process', 'GO:0006306', ('249', '264'))	('miRNA', 'Gene', (291, 296))	('genes', 'Gene', (149, 154))
210867	33207823	Furthermore, previous studies using the combination of histology plus genomics TCGA data revealed sporadic mutations of at least one out of nine genes associated with ccRCC in 81% of tumor tissue.	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('mutations', 'Var', (107, 116))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('RCC', 'Disease', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))
210869	33207823	These chromatin modifier genes located at chromosome 3p, when mutated, may lead to an altered epigenetic control of gene expression, contributing to the development and progression of RCC.	('lead to', 'Reg', (75, 82))	('gene expression', 'biological_process', 'GO:0010467', ('116', '131'))	('altered', 'Reg', (86, 93))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('contributing to', 'Reg', (133, 148))	('RCC', 'Disease', (184, 187))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('epigenetic control of gene expression', 'MPA', (94, 131))	('chromosome', 'cellular_component', 'GO:0005694', ('42', '52'))	('chromatin', 'cellular_component', 'GO:0000785', ('6', '15'))	('mutated', 'Var', (62, 69))
210871	33207823	Through microarray analysis, our investigation showed several differentially expressed miRNAs in peripheral lymphocytes of long-responder patients, most of which are implicated in key RCC signaling pathways involving VHL-HIF, PI3K/Akt, MAPK cascade, mTOR, FOXO, and T-cell receptor.	('miRNAs', 'Var', (87, 93))	('implicated', 'Reg', (166, 176))	('Akt', 'Gene', '207', (231, 234))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('RCC', 'Disease', (184, 187))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('PI3K', 'molecular_function', 'GO:0016303', ('226', '230'))	('MAPK', 'molecular_function', 'GO:0004707', ('236', '240'))	('MAPK cascade', 'Pathway', (236, 248))	('Akt', 'Gene', (231, 234))	('mTOR', 'Gene', '2475', (250, 254))	('VHL-HIF', 'Disease', (217, 224))	('mTOR', 'Gene', (250, 254))	('signaling', 'biological_process', 'GO:0023052', ('188', '197'))	('VHL-HIF', 'Disease', 'MESH:D006623', (217, 224))	('patients', 'Species', '9606', (138, 146))	('MAPK cascade', 'biological_process', 'GO:0000165', ('236', '248'))
210872	33207823	Interestingly, we found a specific subset of miRNAs (miR-22, miR-24, miR-99a, miR-194, miR-214, miR-335, miR-339, miR-708), which we called "lymphocyte miRNA signature", specifically induced in long-responder patients recognized as the patients with CR, PR, or SD to nivolumab >18 months.	('PR', 'Gene', '140738', (254, 256))	('miR-214', 'Gene', (87, 94))	('miR-194', 'Var', (78, 85))	('nivolumab', 'Chemical', 'MESH:D000077594', (267, 276))	('miR-335', 'Gene', '442904', (96, 103))	('miR-214', 'Gene', '406996', (87, 94))	('patients', 'Species', '9606', (236, 244))	('miR-339', 'Gene', (105, 112))	('miR-99a', 'Gene', '407055', (69, 76))	('miR-339', 'Gene', '442907', (105, 112))	('miR-708', 'Var', (114, 121))	('miR-22', 'Gene', '407004', (53, 59))	('patients', 'Species', '9606', (209, 217))	('miR-22', 'Gene', (53, 59))	('miR-99a', 'Gene', (69, 76))	('induced', 'Reg', (183, 190))	('miR-335', 'Gene', (96, 103))	('miR-24', 'Var', (61, 67))
210892	33207823	Lastly, miR-708 has been shown to induce apoptosis and inhibit cell growth, invasion, migration, and tumorigenicity in renal cancer cells and murine xenograft models of human RCC.	('induce', 'PosReg', (34, 40))	('renal cancer', 'Disease', 'MESH:D007680', (119, 131))	('human', 'Species', '9606', (169, 174))	('inhibit', 'NegReg', (55, 62))	('invasion', 'CPA', (76, 84))	('murine', 'Species', '10090', (142, 148))	('migration', 'CPA', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('miR-708', 'Var', (8, 15))	('cell growth', 'CPA', (63, 74))	('apoptosis', 'biological_process', 'GO:0097194', ('41', '50'))	('apoptosis', 'biological_process', 'GO:0006915', ('41', '50'))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('RCC', 'Disease', (175, 178))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('renal cancer', 'Disease', (119, 131))	('renal cancer', 'Phenotype', 'HP:0009726', (119, 131))	('cell growth', 'biological_process', 'GO:0016049', ('63', '74'))	('tumor', 'Disease', (101, 106))	('apoptosis', 'CPA', (41, 50))	('RCC', 'Disease', 'MESH:C538614', (175, 178))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
210899	33207823	demonstrated that miR-200 suppressed the epithelial to mesenchymal transition (EMT) process by targeting PD-L1 and thus delaying cancer progression in a mouse model.	('miR-20', 'Gene', '406982', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('EMT', 'biological_process', 'GO:0001837', ('79', '82'))	('suppressed', 'NegReg', (26, 36))	('delaying', 'NegReg', (120, 128))	('PD-L1', 'Gene', (105, 110))	('targeting', 'Var', (95, 104))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('mouse', 'Species', '10090', (153, 158))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('41', '77'))	('miR-20', 'Gene', (18, 24))
210902	33207823	In our patient cohort, the inverse correlation between miR-22 and miR-24 levels and plasma PD-1 levels in long-responder patients suggests that a miRNA network could inhibit the immune checkpoint expression, mainly via the miR-20 family.	('inhibit', 'NegReg', (166, 173))	('PD-1', 'Gene', (91, 95))	('patient', 'Species', '9606', (7, 14))	('PD-1', 'Gene', '5133', (91, 95))	('miR-22', 'Gene', '407004', (55, 61))	('miRNA', 'Var', (146, 151))	('immune checkpoint expression', 'MPA', (178, 206))	('miR-22', 'Gene', (55, 61))	('miR-20', 'Gene', (223, 229))	('miR-20', 'Gene', '406982', (223, 229))	('patient', 'Species', '9606', (121, 128))	('patients', 'Species', '9606', (121, 129))
210983	31380266	Only patients with microscopically confirmed RCC (using ICD-O-3 histology/behavior codes: 8260/3, 8270/3, 8290/3, 8310/3, 8312/3, 8316/3, 8317/3, 8319/3, 8320/3, 8323/3, 8480/3, and 8510/3) were included.	('patients', 'Species', '9606', (5, 13))	('8260/3', 'Var', (90, 96))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
211092	31636844	Females treated with 5-FU showed higher levels of toxicity such as nausea, vomiting, alopecia and leukopenia than males.	('alopecia', 'Disease', (85, 93))	('vomiting', 'Phenotype', 'HP:0002013', (75, 83))	('alopecia', 'Phenotype', 'HP:0001596', (85, 93))	('leukopenia', 'Phenotype', 'HP:0001882', (98, 108))	('vomiting', 'Disease', (75, 83))	('vomiting', 'Disease', 'MESH:D014839', (75, 83))	('alopecia', 'Disease', 'MESH:D000505', (85, 93))	('leukopenia', 'Disease', 'MESH:D007970', (98, 108))	('leukopenia', 'Disease', (98, 108))	('nausea', 'Phenotype', 'HP:0002018', (67, 73))	('nausea', 'Disease', (67, 73))	('nausea', 'Disease', 'MESH:D009325', (67, 73))	('toxicity', 'Disease', 'MESH:D064420', (50, 58))	('toxicity', 'Disease', (50, 58))	('5-FU', 'Var', (21, 25))
211095	31636844	For instance, male patients with lung adenocarcinoma showed 1.636-fold higher frequency of genetic alterations than female patients, and greater genetic alterations were related to worse overall survival in males.	('patients', 'Species', '9606', (19, 27))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (33, 52))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (33, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('patients', 'Species', '9606', (123, 131))	('genetic alterations', 'Var', (91, 110))	('lung adenocarcinoma', 'Disease', (33, 52))
211104	31636844	Studies investigated the association between the risk of bladder cancer and hypomethylation of long interspersed nuclear element-1 (LINE-1).	('hypomethylation', 'Var', (76, 91))	('bladder cancer', 'Disease', 'MESH:D001749', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('bladder cancer', 'Disease', (57, 71))	('bladder cancer', 'Phenotype', 'HP:0009725', (57, 71))
211105	31636844	Hypomethylation of LINE-1 may be an effective biomarker for the risk of bladder cancer in females.	('Hypomethylation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (72, 86))	('bladder cancer', 'Disease', 'MESH:D001749', (72, 86))	('bladder cancer', 'Disease', (72, 86))
211106	31636844	The lowest degree of LINE-1 methylation in females indicates a 2.5-fold significantly higher risk of bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('bladder cancer', 'Disease', 'MESH:D001749', (101, 115))	('bladder cancer', 'Disease', (101, 115))	('methylation', 'Var', (28, 39))	('bladder cancer', 'Phenotype', 'HP:0009725', (101, 115))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))
211107	31636844	In males, however, there was no correlation between hypomethylation of LINE-1 and risk of bladder cancer.	('bladder cancer', 'Disease', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('LINE-1', 'Gene', (71, 77))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('hypomethylation', 'Var', (52, 67))	('bladder cancer', 'Disease', 'MESH:D001749', (90, 104))
211113	31636844	DNA from 251 primary tumors of Norwegian patients with colorectal carcinoma was analyzed using sequence-specific oligonucleotide probes for the presence of k-ras point mutations at codons 12 and 13.	('tumors of Norwegian', 'Disease', (21, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (55, 75))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('patients', 'Species', '9606', (41, 49))	('tumors of Norwegian', 'Disease', 'MESH:C537312', (21, 40))	('k-ras', 'Gene', (156, 161))	('colorectal carcinoma', 'Disease', (55, 75))	('k-ras', 'Gene', '3845', (156, 161))	('point mutations', 'Var', (162, 177))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
211123	31636844	In 120 sporadic colorectal cancers, methylation-specific PCR was performed to determine whether the methylation of the CpG island in the 5' region of the p16INK4a tumor suppressor gene was associated with sex or other clinicopathological characteristics.	('colorectal cancers', 'Disease', (16, 34))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('p16INK4a', 'Gene', (154, 162))	('associated', 'Reg', (189, 199))	('tumor suppressor', 'biological_process', 'GO:0051726', ('163', '179'))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('methylation', 'Var', (100, 111))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('163', '179'))	('tumor', 'Disease', (163, 168))	('p16INK4a', 'Gene', '1029', (154, 162))	('colorectal cancer', 'Phenotype', 'HP:0003003', (16, 33))	('colorectal cancers', 'Disease', 'MESH:D015179', (16, 34))	('methylation', 'biological_process', 'GO:0032259', ('100', '111'))
211124	31636844	In female patients, methylation-positive cancer was 8.8-fold higher than in male patients, and methylation of p16INK4a was associated with poorly differentiated tumors.	('associated', 'Reg', (123, 133))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))	('p16INK4a', 'Gene', '1029', (110, 118))	('methylation', 'Var', (95, 106))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('methylation', 'biological_process', 'GO:0032259', ('95', '106'))	('patients', 'Species', '9606', (81, 89))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('methylation-positive', 'MPA', (20, 40))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('p16INK4a', 'Gene', (110, 118))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('patients', 'Species', '9606', (10, 18))
211125	31636844	Female patients with p16INK4a methylation may represent an important database of molecular alterations associated with sporadic colorectal cancers.	('methylation', 'Var', (30, 41))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('colorectal cancer', 'Phenotype', 'HP:0003003', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('p16INK4a', 'Gene', (21, 29))	('colorectal cancers', 'Disease', 'MESH:D015179', (128, 146))	('p16INK4a', 'Gene', '1029', (21, 29))	('colorectal cancers', 'Disease', (128, 146))	('patients', 'Species', '9606', (7, 15))
211139	31636844	However, the 15 genes with a higher expression in female samples include cyclin dependent kinase 6 (CDK6), PROL2, FLJ20489, fibroblast growth factor receptor 2 (FGFR2), microfibrillar-associated protein 2 (MFAP), peroxiredoxin 3 (PRDX3), fibroblast growth factor receptor 3 (FGFR3), polyA site, and HSHRTPSN located on the autosome, and inactive X specific transcripts (XIST), ubiquitin specific peptidase 9 X-linked (USP9X), E1F1AX, ribosomal protein S4 X-linked (RPS4X), arylsulfatase E (ARSE), and DEAD-box helicase 3 X-linked (DDX3X) on the X chromosome.	('RPS4X', 'Gene', '6191', (465, 470))	('PROL2', 'Gene', (107, 112))	('microfibrillar-associated protein 2', 'Gene', (169, 204))	('DDX3X', 'Gene', (531, 536))	('cyclin', 'molecular_function', 'GO:0016538', ('73', '79'))	('FGFR', 'molecular_function', 'GO:0005007', ('161', '165'))	('fibroblast growth factor receptor 3', 'Gene', (238, 273))	('FGFR2', 'Gene', (161, 166))	('ARSE', 'Gene', (490, 494))	('DEAD-box helicase 3 X-linked', 'Gene', '1654', (501, 529))	('E1F1AX', 'Var', (426, 432))	('higher', 'PosReg', (29, 35))	('peroxiredoxin 3', 'Gene', '10935', (213, 228))	('FLJ20489', 'Var', (114, 122))	('ubiquitin', 'molecular_function', 'GO:0031386', ('377', '386'))	('peroxiredoxin 3', 'Gene', (213, 228))	('USP9X', 'Gene', '8239', (418, 423))	('arylsulfatase E', 'Gene', '415', (473, 488))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('238', '262'))	('XIST', 'Gene', (370, 374))	('cyclin dependent kinase 6', 'Gene', '1021', (73, 98))	('FGFR3', 'Gene', (275, 280))	('DDX3X', 'Gene', '1654', (531, 536))	('FGFR2', 'Gene', '2263', (161, 166))	('CDK6', 'Gene', '1021', (100, 104))	('USP', 'molecular_function', 'GO:0051748', ('418', '421'))	('MFAP', 'Gene', (206, 210))	('ARSE', 'Gene', '415', (490, 494))	('RPS4X', 'Gene', (465, 470))	('cyclin dependent kinase 6', 'Gene', (73, 98))	('ribosomal protein S4 X-linked', 'Gene', '6191', (434, 463))	('DEAD-box helicase 3 X-linked', 'Gene', (501, 529))	('fibroblast growth factor receptor 3', 'Gene', '2261', (238, 273))	('USP9X', 'Gene', (418, 423))	('FGFR3', 'Gene', '2261', (275, 280))	('PRDX3', 'Gene', '10935', (230, 235))	('CDK', 'molecular_function', 'GO:0004693', ('100', '103'))	('XIST', 'Gene', '7503', (370, 374))	('arylsulfatase E', 'Gene', (473, 488))	('fibroblast growth factor receptor 2', 'Gene', (124, 159))	('PRDX3', 'Gene', (230, 235))	('ribosomal protein S4 X-linked', 'Gene', (434, 463))	('CDK6', 'Gene', (100, 104))	('ubiquitin specific peptidase 9 X-linked', 'Gene', '8239', (377, 416))	('fibroblast growth factor receptor 2', 'Gene', '2263', (124, 159))	('FGFR', 'molecular_function', 'GO:0005007', ('275', '279'))	('ubiquitin specific peptidase 9 X-linked', 'Gene', (377, 416))	('polyA', 'Chemical', 'MESH:C017937', (283, 288))	('autosome', 'cellular_component', 'GO:0030849', ('323', '331'))	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))	('PROL2', 'Gene', '10957', (107, 112))	('microfibrillar-associated protein 2', 'Gene', '4237', (169, 204))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('124', '148'))	('X chromosome', 'cellular_component', 'GO:0000805', ('545', '557'))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('434', '451'))	('FLJ20489', 'Chemical', 'MESH:C035416', (114, 122))	('protein', 'cellular_component', 'GO:0003675', ('444', '451'))	('MFAP', 'Gene', '4237', (206, 210))	('expression', 'MPA', (36, 46))
211174	31636844	After treatment with carcinogens, large and diverse tumors were detected in the females with FOXA1/2 deficiency, whereas tumor growth in male mutants was reduced compared with the control.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (52, 57))	('FOXA1/2', 'Gene', (93, 100))	('tumors', 'Disease', (52, 58))	('tumor', 'Disease', (121, 126))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('FOXA1/2', 'Gene', '3169;3170', (93, 100))	('detected', 'Reg', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('deficiency', 'Var', (101, 111))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
211179	31636844	These data suggest that Gnmt deficiency not only increases the expression of tumor genes but also induces a decrease in the expression of other tumor suppressor genes in the early stages of tumorigenesis in female rats, which explains the higher risk of hepatocellular carcinoma in female Gnmt-/- mice.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (254, 278))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('144', '160'))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('decrease', 'NegReg', (108, 116))	('deficiency', 'Var', (29, 39))	('tumor suppressor', 'biological_process', 'GO:0051726', ('144', '160'))	('hepatocellular carcinoma', 'Disease', (254, 278))	('Gnmt', 'molecular_function', 'GO:0017174', ('289', '293'))	('Gnmt', 'Gene', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('Gnmt', 'molecular_function', 'GO:0017174', ('24', '28'))	('mice', 'Species', '10090', (297, 301))	('tumor', 'Disease', (144, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('expression', 'MPA', (63, 73))	('increases', 'PosReg', (49, 58))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('rats', 'Species', '10116', (214, 218))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (254, 278))	('expression', 'MPA', (124, 134))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', (77, 82))
211186	31636844	We believe that this variation may affect sex-specific cancer prognosis.	('affect', 'Reg', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('variation', 'Var', (21, 30))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
211194	31130944	In the current study, we performed a bioinformatics analysis to investigate whether C1q can serve as a potential prognostic marker for human carcinoma.	('carcinoma', 'Disease', 'MESH:D002277', (141, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('carcinoma', 'Disease', (141, 150))	('human', 'Species', '9606', (135, 140))	('C1q', 'Var', (84, 87))	('C1q', 'cellular_component', 'GO:0062167', ('84', '87'))
211196	31130944	Our results showed that high levels of C1q have a favorable prognostic index in basal-like breast cancer for disease-free survival, and in HER2-positive breast cancer for overall survival, while it showed a pro-tumorigenic role of C1q in lung adenocarcinoma, and in clear cell renal cell carcinoma.	('HER2-positive breast cancer', 'Disease', (139, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('high', 'Var', (24, 28))	('tumor', 'Disease', (211, 216))	('C1q', 'cellular_component', 'GO:0062167', ('231', '234'))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (266, 297))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('C1q', 'Var', (39, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (266, 297))	('lung adenocarcinoma', 'Disease', (238, 257))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('breast cancer', 'Disease', (91, 104))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (139, 166))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (238, 257))	('clear cell renal cell carcinoma', 'Disease', (266, 297))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (277, 297))	('C1q', 'cellular_component', 'GO:0062167', ('39', '42'))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (238, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
211200	31130944	C1q associates with the Ca2+-dependent C1r2-C1s2 tetramer, of about 360 kDa, to form the soluble pentameric C1 complex.	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('C1q', 'Var', (0, 3))	('Ca2+', 'Chemical', 'MESH:D000069285', (24, 28))	('C1r', 'Gene', '715', (39, 42))	('C1r', 'Gene', (39, 42))	('C1s', 'Gene', '716', (44, 47))	('soluble', 'cellular_component', 'GO:0005625', ('89', '96'))	('C1s', 'Gene', (44, 47))	('associates', 'Interaction', (4, 14))
211206	31130944	C1q expressed in the stroma and vascular endothelium of several human malignant tumors acted as a tumor-promoting factor by favoring adhesion, migration and proliferation of cancer cells as well as angiogenesis and metastasis.	('malignant tumors', 'Disease', 'MESH:D018198', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('metastasis', 'CPA', (215, 225))	('angiogenesis', 'biological_process', 'GO:0001525', ('198', '210'))	('tumor', 'Disease', (98, 103))	('adhesion', 'CPA', (133, 141))	('migration', 'CPA', (143, 152))	('proliferation', 'CPA', (157, 170))	('malignant tumors', 'Disease', (70, 86))	('C1q', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Disease', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('human', 'Species', '9606', (64, 69))	('favoring', 'PosReg', (124, 132))	('angiogenesis', 'CPA', (198, 210))	('tumor', 'Disease', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (174, 180))
211208	31130944	Recently, we demonstrated that C1q is abundantly present in malignant pleural mesothelioma (MPM), where it can combine with hyaluronic acid (HA), which is a principal component of the TME, and enhance the tumor growth by promoting cell adhesion and proliferation.	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (60, 90))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (70, 90))	('C1q', 'Var', (31, 34))	('cell adhesion', 'biological_process', 'GO:0007155', ('231', '244'))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('malignant pleural mesothelioma', 'Disease', (60, 90))	('hyaluronic acid', 'Chemical', 'MESH:D006820', (124, 139))	('HA', 'Chemical', 'MESH:D006820', (141, 143))	('promoting', 'PosReg', (221, 230))	('C1q', 'cellular_component', 'GO:0062167', ('31', '34'))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('cell adhesion', 'CPA', (231, 244))	('enhance', 'PosReg', (193, 200))	('combine', 'Interaction', (111, 118))
211211	31130944	In the current study, we performed a bioinformatics analysis, using Oncomine database and the survival analysis platforms Kaplan-Meier plotter, in order to investigate whether C1q can serve as a potential prognostic marker for human carcinoma, i.e., tumors of epithelial origin.	('carcinoma', 'Disease', (233, 242))	('C1q', 'Var', (176, 179))	('human', 'Species', '9606', (227, 232))	('carcinoma', 'Disease', 'MESH:D002277', (233, 242))	('tumors', 'Disease', (250, 256))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('C1q', 'cellular_component', 'GO:0062167', ('176', '179'))	('Oncomine', 'Chemical', '-', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
211212	31130944	Our results showed that high levels of C1q have a favorable prognostic index in basal-like breast cancer (BLBC) and in HER-2 positive breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('high levels', 'Var', (24, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('C1q', 'cellular_component', 'GO:0062167', ('39', '42'))	('C1q', 'MPA', (39, 42))	('HER-2', 'Gene', '2064', (119, 124))	('HER-2', 'Gene', (119, 124))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
211231	31130944	We only investigated carcinomas in which all the three C1q chains showed a significant prognostic effect by Kaplan-Meier plotter analysis.	('carcinomas', 'Phenotype', 'HP:0030731', (21, 31))	('carcinomas', 'Disease', (21, 31))	('carcinomas', 'Disease', 'MESH:D002277', (21, 31))	('C1q', 'Var', (55, 58))	('C1q', 'cellular_component', 'GO:0062167', ('55', '58'))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))
211233	31130944	These data appear to suggest that C1q can have pro- or anti-tumorigenic implications, depending on the carcinoma types (Table 1).	('C1q', 'cellular_component', 'GO:0062167', ('34', '37'))	('carcinoma', 'Disease', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('tumor', 'Disease', (60, 65))	('carcinoma', 'Disease', 'MESH:D002277', (103, 112))	('C1q', 'Var', (34, 37))
211250	31130944	C1q is present in colon, lung, breast, pancreatic carcinoma, and melanoma.	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('C1q', 'Var', (0, 3))	('lung', 'Disease', (25, 29))	('breast', 'Disease', (31, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('colon', 'Disease', (18, 23))	('pancreatic carcinoma', 'Disease', (39, 59))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (39, 59))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
211251	31130944	C1q can promote adhesion, proliferation and migration of melanoma cells.	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('C1q', 'Var', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('adhesion', 'CPA', (16, 24))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('migration', 'CPA', (44, 53))	('proliferation', 'CPA', (26, 39))	('promote', 'PosReg', (8, 15))
211253	31130944	C1q bound high and low molecular weight HA and acted as a tumor-promoting factor.	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('C1q', 'Var', (0, 3))	('bound', 'Interaction', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('high', 'Protein', (10, 14))	('HA', 'Chemical', 'MESH:D006820', (40, 42))
211254	31130944	In addition, C1q exerted a protective effect against apoptosis, suggesting an overall pro-tumorigenic activity.	('protective effect', 'CPA', (27, 44))	('apoptosis', 'CPA', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('C1q', 'cellular_component', 'GO:0062167', ('13', '16'))	('apoptosis', 'biological_process', 'GO:0097194', ('53', '62'))	('apoptosis', 'biological_process', 'GO:0006915', ('53', '62'))	('C1q', 'Var', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
211256	31130944	C1q was able to induce apoptosis and growth suppression of human prostate DU145 cells, through direct activation of the tumor suppressor WW-domain containing oxidoreductase (WOX1).	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('human', 'Species', '9606', (59, 64))	('C1q', 'Var', (0, 3))	('tumor suppressor', 'biological_process', 'GO:0051726', ('120', '136'))	('DU145', 'CellLine', 'CVCL:0105', (74, 79))	('WOX1', 'Gene', (174, 178))	('apoptosis', 'CPA', (23, 32))	('WW-domain containing oxidoreductase', 'Gene', (137, 172))	('apoptosis', 'biological_process', 'GO:0097194', ('23', '32'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('120', '136'))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('activation', 'PosReg', (102, 112))	('apoptosis', 'biological_process', 'GO:0006915', ('23', '32'))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('growth suppression', 'CPA', (37, 55))	('WW-domain containing oxidoreductase', 'Gene', '51741', (137, 172))	('tumor', 'Disease', (120, 125))	('WOX1', 'Gene', '51741', (174, 178))
211257	31130944	C1q also have a pro-apoptotic effect on an ovarian cell line, SKOV3, acting via a TNF-alpha induced apoptosis pathway that involves upregulation of Bax and Fas.	('Bax', 'Gene', (148, 151))	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('apoptosis pathway', 'Pathway', (100, 117))	('C1q', 'Var', (0, 3))	('upregulation', 'PosReg', (132, 144))	('Fas', 'Protein', (156, 159))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('TNF-alpha', 'Gene', '7124', (82, 91))	('Bax', 'Gene', '581', (148, 151))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('TNF-alpha', 'Gene', (82, 91))	('SKOV3', 'CellLine', 'CVCL:0532', (62, 67))
211262	31130944	We selected the carcinomas that showed all the three chains of human C1q statistically significant for the prognosis; in several cases, the prognosis was differentially linked to the C1q chains, or limited to one or two C1q chains.	('human', 'Species', '9606', (63, 68))	('linked', 'Reg', (169, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (16, 26))	('C1q', 'cellular_component', 'GO:0062167', ('183', '186'))	('carcinomas', 'Disease', (16, 26))	('carcinomas', 'Disease', 'MESH:D002277', (16, 26))	('C1q', 'cellular_component', 'GO:0062167', ('220', '223'))	('C1q', 'cellular_component', 'GO:0062167', ('69', '72'))	('C1q chains', 'Var', (183, 193))
211265	31130944	Our bioinformatics analysis highlighted that high levels of C1q have a favorable prognostic index in BLBCs for DFS and HER2+ breast cancer for OS, (Graphical Abstract) consistent with the in vivo studies by Bandini et al.	('BLBCs', 'Disease', (101, 106))	('HER2+', 'Var', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('C1q', 'cellular_component', 'GO:0062167', ('60', '63'))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('high', 'Var', (45, 49))	('C1q', 'Var', (60, 63))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('OS', 'Chemical', '-', (143, 145))
211268	31130944	One possible explanation for the observed positive association between C1q expression and favorable prognostic index could be due to the correlation between the presence of C1q and dendritic cells (CD11c positive cells) in TME.	('CD11c', 'Gene', (198, 203))	('C1q', 'Gene', (173, 176))	('C1q', 'cellular_component', 'GO:0062167', ('173', '176'))	('C1q', 'Gene', (71, 74))	('C1q', 'cellular_component', 'GO:0062167', ('71', '74'))	('presence', 'Var', (161, 169))	('CD11c', 'Gene', '3687', (198, 203))
211269	31130944	High CD11c expression in BLBCs is associated with a significantly higher OS (p = 0.047) as compared to low CD11c expression.	('CD11c', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('OS', 'Chemical', '-', (73, 75))	('CD11c', 'Gene', (107, 112))	('CD11c', 'Gene', '3687', (107, 112))	('higher', 'PosReg', (66, 72))	('CD11c', 'Gene', '3687', (5, 10))
211273	31130944	The analysis of publicly available data sets revealed that the genes encoding for the C1q chains were associated with a poor prognosis in BLBC using the TCGA dataset (504 patients).	('C1q', 'cellular_component', 'GO:0062167', ('86', '89'))	('C1q', 'Var', (86, 89))	('BLBC', 'Disease', (138, 142))	('patients', 'Species', '9606', (171, 179))
211278	31130944	The expression of C1q in kidney cancer is increased as compared to normal kidney tissue (Figure 3A) and C1q has a negative prognostic effect in the case of CCRCC (Figure 3B); no association was evident for PRCC.	('increased', 'PosReg', (42, 51))	('PRCC', 'Gene', '5546', (206, 210))	('CCRCC', 'Phenotype', 'HP:0006770', (156, 161))	('kidney cancer', 'Disease', 'MESH:D007680', (25, 38))	('C1q', 'Var', (104, 107))	('C1q', 'Gene', (18, 21))	('PRCC', 'Gene', (206, 210))	('kidney cancer', 'Phenotype', 'HP:0009726', (25, 38))	('C1q', 'cellular_component', 'GO:0062167', ('104', '107'))	('expression', 'MPA', (4, 14))	('C1q', 'cellular_component', 'GO:0062167', ('18', '21'))	('negative', 'NegReg', (114, 122))	('kidney cancer', 'Disease', (25, 38))	('PRCC', 'Phenotype', 'HP:0006766', (206, 210))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('CCRCC', 'Disease', (156, 161))
211281	31130944	We can hypothesize that C1q can also participate in promoting angiogenic processes in this particular tumor.	('promoting', 'PosReg', (52, 61))	('C1q', 'Var', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('C1q', 'cellular_component', 'GO:0062167', ('24', '27'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('angiogenic processes', 'CPA', (62, 82))
211282	31130944	C1q has a negative prognostic value in lung tumors limited to adenocarcinomas, the most common form of lung cancer (Figure 3D).	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('C1q', 'Var', (0, 3))	('adenocarcinomas', 'Disease', 'MESH:D000230', (62, 77))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('lung tumors', 'Disease', (39, 50))	('adenocarcinomas', 'Disease', (62, 77))	('lung tumors', 'Phenotype', 'HP:0100526', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('lung cancer', 'Disease', (103, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('lung tumors', 'Disease', 'MESH:D008175', (39, 50))
211286	31130944	C1q interaction with the ECM components can adversely interrupt its putative functions, as is the case with HA.	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('C1q', 'Var', (0, 3))	('interaction', 'Interaction', (4, 15))	('ECM', 'Gene', '22915', (25, 28))	('HA', 'Chemical', 'MESH:D006820', (108, 110))	('ECM', 'Gene', (25, 28))	('putative functions', 'MPA', (68, 86))	('interrupt', 'NegReg', (54, 63))
211322	29496470	The solid component of the entire tumor was measured and visually graded into four groups: none, <25%, 25-50% or >50%.	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('<25', 'Var', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
211366	29496470	Since one of the main criteria to categorize a mass as Bosniak 4 is the evidence of a solid component , adding this covariate to the multivariate model results in an overlap of cases and a consequent loss of the association between Bosniak score and malignancy.	('association', 'Interaction', (212, 223))	('loss', 'NegReg', (200, 204))	('malignancy', 'Disease', 'MESH:D009369', (250, 260))	('adding', 'Var', (104, 110))	('malignancy', 'Disease', (250, 260))
211403	32780490	The authors further demonstrated that both genetic knockout and antibody-based blockade of Siglec-15 significantly amplified local anti-tumor immune responses and inhibited tumor progression in a mice model.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('antibody', 'cellular_component', 'GO:0019814', ('64', '72'))	('antibody', 'molecular_function', 'GO:0003823', ('64', '72'))	('mice', 'Species', '10090', (196, 200))	('amplified', 'PosReg', (115, 124))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('antibody', 'cellular_component', 'GO:0042571', ('64', '72'))	('blockade', 'Var', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('Siglec-15', 'Gene', (91, 100))	('inhibited', 'NegReg', (163, 172))	('tumor', 'Disease', (136, 141))	('antibody', 'cellular_component', 'GO:0019815', ('64', '72'))
211434	32780490	The pLncEXP-LINC00973 plasmids (wild-type or mutant) were linearized, transcribed, and biotin-labeled in vitro with T7 RNA polymerase and biotin RNA labeling mix (MEGAscript T7 transcription Kit, ThermoFisher).	('mutant', 'Var', (45, 51))	('LINC00973', 'Gene', '100506377', (12, 21))	('biotin', 'Chemical', 'MESH:D001710', (87, 93))	('biotin', 'Chemical', 'MESH:D001710', (138, 144))	('RNA', 'cellular_component', 'GO:0005562', ('119', '122'))	('RNA', 'cellular_component', 'GO:0005562', ('145', '148'))	('transcription', 'biological_process', 'GO:0006351', ('177', '190'))	('LINC00973', 'Gene', (12, 21))
211439	32780490	Siglec-15 promoter reporter or LINC00973-fused luciferase (wild-type or putative miR-7109-recognizing site mutant) plasmids were co-transfected with scramble control, miR-7109 mimic, or miR-7109 inhibitor into HEK293T for 24 hours.	('mutant', 'Var', (107, 113))	('293T', 'CellLine', 'CVCL:0063', (213, 217))	('miR-7109', 'Gene', (186, 194))	('miR-7109', 'Gene', '102465666', (167, 175))	('miR-7109', 'Gene', '102465666', (81, 89))	('LINC00973', 'Gene', (31, 40))	('HEK293', 'CellLine', 'CVCL:0045', (210, 216))	('miR-7109', 'Gene', (167, 175))	('miR-7109', 'Gene', (81, 89))	('miR-7109', 'Gene', '102465666', (186, 194))	('LINC00973', 'Gene', '100506377', (31, 40))
211448	32780490	By data-mining the publicly available TCGA database, we uncovered an evident linkage between high LINC00973 and advanced tumor stages in KIRC (Figure 1C).	('LINC00973', 'Gene', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('LINC00973', 'Gene', '100506377', (98, 107))	('tumor', 'Disease', (121, 126))	('high', 'Var', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
211453	32780490	Next, we sought to understand the mechanistic contributions of the aberrant LINC00973 level to ccRCC at molecular level.	('LINC00973', 'Gene', '100506377', (76, 85))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('ccRCC', 'Disease', (95, 100))	('LINC00973', 'Gene', (76, 85))	('aberrant', 'Var', (67, 75))
211467	32780490	Notably, we found that the inhibited expression of Siglec-15 by LINC00973 depletion was significantly restored by co-transfection with miR-7109 inhibitor in both 769-p and Caki-1 cells (Figure 3C).	('depletion', 'Var', (74, 83))	('miR-7109', 'Gene', '102465666', (135, 143))	('LINC00973', 'Gene', (64, 73))	('Siglec-15', 'Gene', (51, 60))	('miR-7109', 'Gene', (135, 143))	('Caki-1', 'CellLine', 'CVCL:0234', (172, 178))	('inhibited', 'NegReg', (27, 36))	('LINC00973', 'Gene', '100506377', (64, 73))	('expression', 'MPA', (37, 47))
211471	32780490	Consistently, flow cytometry analysis exhibited a significant increase in the response to the combination of LINC00973 knockdown and miR-7109 inhibitor, and an evident decrease in the response to the combination of LINC00976 overexpression and miR-7109 mimics (Figure 3G, H).	('miR-7109', 'Gene', (244, 252))	('LINC00976', 'Gene', (215, 224))	('LINC00973', 'Gene', (109, 118))	('miR-7109', 'Gene', '102465666', (133, 141))	('response', 'MPA', (78, 86))	('LINC00973', 'Gene', '100506377', (109, 118))	('knockdown', 'Var', (119, 128))	('decrease', 'NegReg', (168, 176))	('miR-7109', 'Gene', (133, 141))	('miR-7109', 'Gene', '102465666', (244, 252))	('combination', 'Interaction', (94, 105))	('LINC00976', 'Gene', '106144608', (215, 224))	('increase', 'PosReg', (62, 70))
211482	32780490	Close inspection of 3'UTR of Siglec-15 revealed a potential miR-7109-binding site, based on which we constructed luciferase reporter plasmids with either intact or mutated 3'UTR of Siglec-15 (Figure 4K).	('binding', 'molecular_function', 'GO:0005488', ('69', '76'))	('miR-7109', 'Gene', '102465666', (60, 68))	('miR-7109', 'Gene', (60, 68))	('mutated', 'Var', (164, 171))
211484	32780490	However, the regulatory effects of miR-7109 on Siglec-15 were completely abolished by mutation introduced into putative binding sites on 3'UTR of Siglec-15 (Figure 4L, right).	('miR-7109', 'Gene', (35, 43))	('regulatory effects', 'MPA', (13, 31))	('binding', 'molecular_function', 'GO:0005488', ('120', '127'))	('abolished', 'NegReg', (73, 82))	('binding', 'Interaction', (120, 127))	('Siglec-15', 'Gene', (146, 155))	('miR-7109', 'Gene', '102465666', (35, 43))	('mutation', 'Var', (86, 94))	('Siglec-15', 'Gene', (47, 56))
211488	32780490	The direct association between miR-7109 and LINC00973 was exhibited by biotin-labeled RNA-pulldown assay, wherein there was significant enrichment of miR-7109 in RNA species recovered from wild-type rather than mutant LINC00973 probes in both cell lines (Figure 5C).	('LINC00973', 'Gene', (44, 53))	('LINC00973', 'Gene', '100506377', (218, 227))	('RNA', 'cellular_component', 'GO:0005562', ('86', '89'))	('miR-7109', 'Gene', '102465666', (150, 158))	('miR-7109', 'Gene', '102465666', (31, 39))	('mutant', 'Var', (211, 217))	('LINC00973', 'Gene', '100506377', (44, 53))	('biotin', 'Chemical', 'MESH:D001710', (71, 77))	('LINC00973', 'Gene', (218, 227))	('miR-7109', 'Gene', (150, 158))	('RNA', 'cellular_component', 'GO:0005562', ('162', '165'))	('miR-7109', 'Gene', (31, 39))
211503	32780490	In contrast, Siglec-15 knockdown augmented IL-2 production in co-culture medium (Figure 6E).	('knockdown', 'Var', (23, 32))	('IL-2 production', 'biological_process', 'GO:0032623', ('43', '58'))	('IL-2', 'molecular_function', 'GO:0005134', ('43', '47'))	('augmented', 'PosReg', (33, 42))	('IL-2', 'Gene', (43, 47))	('IL-2', 'Gene', '3558', (43, 47))	('Siglec-15', 'Gene', (13, 22))
211505	32780490	In contrast, IL-2 production was significantly stimulated by co-transfection with both shLINC00973 and control miR in 769-p and Caki-1 cells, and inhibited by the introduction of miR-7109 inhibitor (Figure 6G).	('miR-7109', 'Gene', (179, 187))	('IL-2', 'Gene', (13, 17))	('Caki-1', 'CellLine', 'CVCL:0234', (128, 134))	('LINC00973', 'Gene', (89, 98))	('stimulated', 'PosReg', (47, 57))	('miR', 'Gene', '220972', (179, 182))	('IL-2', 'Gene', '3558', (13, 17))	('miR', 'Gene', (179, 182))	('miR-7109', 'Gene', '102465666', (179, 187))	('inhibited', 'NegReg', (146, 155))	('IL-2 production', 'biological_process', 'GO:0032623', ('13', '28'))	('LINC00973', 'Gene', '100506377', (89, 98))	('miR', 'Gene', '220972', (111, 114))	('miR', 'Gene', (111, 114))	('co-transfection', 'Var', (61, 76))	('IL-2', 'molecular_function', 'GO:0005134', ('13', '17'))
211510	32780490	Therefore, our data not only consolidated the immune suppressive role of Siglec-15 in ccRCC but also highlighted the critical contributions of the aberrant LINC00973-miR-7109 signaling.	('LINC00973', 'Gene', '100506377', (156, 165))	('aberrant', 'Var', (147, 155))	('miR-7109', 'Gene', (166, 174))	('signaling', 'biological_process', 'GO:0023052', ('175', '184'))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('miR-7109', 'Gene', '102465666', (166, 174))	('ccRCC', 'Disease', (86, 91))	('LINC00973', 'Gene', (156, 165))	('Siglec-15', 'Protein', (73, 82))
211520	32780490	Our data implicated a tumor suppressor role of miR-7109 in ccRCC through positive activation of immune response, and demonstrated that ectopic introduction of miR-7109 mimics in ccRCC cells greatly stimulates both IL-2 and TNF-alpha production of co-cultured immune cells.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('ccRCC', 'Phenotype', 'HP:0006770', (178, 183))	('IL-2', 'Gene', '3558', (214, 218))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('22', '38'))	('miR-7109', 'Gene', (159, 167))	('miR-7109', 'Gene', '102465666', (47, 55))	('mimics', 'Var', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('activation', 'PosReg', (82, 92))	('TNF-alpha production', 'biological_process', 'GO:0032640', ('223', '243'))	('immune response', 'CPA', (96, 111))	('tumor suppressor', 'biological_process', 'GO:0051726', ('22', '38'))	('stimulates', 'PosReg', (198, 208))	('IL-2', 'molecular_function', 'GO:0005134', ('214', '218'))	('ccRCC', 'Disease', (59, 64))	('miR-7109', 'Gene', (47, 55))	('IL-2', 'Gene', (214, 218))	('TNF-alpha', 'Gene', '7124', (223, 232))	('TNF-alpha', 'Gene', (223, 232))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('tumor', 'Disease', (22, 27))	('activation of immune response', 'biological_process', 'GO:0002253', ('82', '111'))	('miR-7109', 'Gene', '102465666', (159, 167))
211523	32780490	The studies performed by both Jing et al 17  and Zinovieva et al 18  suggested intimate an association between high LINC00973 and resistance to an array of chemotherapeutic drugs in colorectal cancer cells.	('colorectal cancer', 'Phenotype', 'HP:0003003', (182, 199))	('LINC00973', 'Gene', (116, 125))	('resistance to an array of', 'MPA', (130, 155))	('LINC00973', 'Gene', '100506377', (116, 125))	('colorectal cancer', 'Disease', (182, 199))	('colorectal cancer', 'Disease', 'MESH:D015179', (182, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('high', 'Var', (111, 115))
211544	27917371	Consistent with the part of autophagy in promoting tumor progression, it has been shown that targeting autophagy reduces cell migration and invasion in vitro and attenuates metastasis in vivo in a breast cancer mouse model by promoting focal adhesion disassembly through targeted degradation of paxillin.	('paxillin', 'Protein', (295, 303))	('autophagy', 'CPA', (103, 112))	('attenuates', 'NegReg', (162, 172))	('focal adhesion disassembly', 'CPA', (236, 262))	('autophagy', 'biological_process', 'GO:0016236', ('103', '112'))	('autophagy', 'biological_process', 'GO:0016236', ('28', '37'))	('reduces', 'NegReg', (113, 120))	('promoting', 'PosReg', (226, 235))	('focal adhesion', 'cellular_component', 'GO:0005925', ('236', '250'))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('tumor', 'Disease', (51, 56))	('metastasis', 'CPA', (173, 183))	('cell migration', 'biological_process', 'GO:0016477', ('121', '135'))	('autophagy', 'biological_process', 'GO:0006914', ('103', '112'))	('autophagy', 'biological_process', 'GO:0006914', ('28', '37'))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('breast cancer', 'Disease', (197, 210))	('focal adhesion disassembly', 'biological_process', 'GO:0120181', ('236', '262'))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('degradation', 'MPA', (280, 291))	('mouse', 'Species', '10090', (211, 216))	('targeting', 'Var', (93, 102))	('degradation', 'biological_process', 'GO:0009056', ('280', '291'))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))
211554	27917371	It is now well established that hypoxia develops due to a mismatch between tumor growth and neovascularization.	('mismatch', 'Var', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('hypoxia', 'Disease', 'MESH:D000860', (32, 39))	('neovascularization', 'CPA', (92, 110))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('hypoxia', 'Disease', (32, 39))	('tumor', 'Disease', (75, 80))
211574	27917371	Antibody-based blockade of PD-1 was shown to enhance effector T cell responses and induce T cell-mediated tumor rejection in some mouse models.	('blockade', 'Var', (15, 23))	('enhance', 'PosReg', (45, 52))	('enhance effector T cell responses', 'Phenotype', 'HP:0031402', (45, 78))	('PD-1', 'Gene', (27, 31))	('induce', 'PosReg', (83, 89))	('PD-1', 'Gene', '5133', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('mouse', 'Species', '10090', (130, 135))	('tumor', 'Disease', (106, 111))	('effector T cell responses', 'CPA', (53, 78))
211581	27917371	The immune suppressive function of MDSCs, enhanced under hypoxia, was abrogated following PD-L1 blockade and hypoxia-induced upregulation of interleukin-6 and 10 (IL-6 and IL-10) in MDSCs was significantly attenuated after PD-L1 block.	('IL-6', 'Gene', (163, 167))	('upregulation', 'PosReg', (125, 137))	('abrogated', 'NegReg', (70, 79))	('interleukin-6 and 10', 'Gene', '3569;3586', (141, 161))	('upregulation of interleukin-6', 'Phenotype', 'HP:0030783', (125, 154))	('IL-6', 'molecular_function', 'GO:0005138', ('163', '167'))	('hypoxia', 'Disease', (109, 116))	('hypoxia', 'Disease', 'MESH:D000860', (109, 116))	('hypoxia', 'Disease', (57, 64))	('IL-10', 'Gene', '3586', (172, 177))	('enhanced', 'PosReg', (42, 50))	('blockade', 'Var', (96, 104))	('hypoxia', 'Disease', 'MESH:D000860', (57, 64))	('IL-6', 'Gene', '3569', (163, 167))	('IL-10', 'molecular_function', 'GO:0005141', ('172', '177'))	('IL-10', 'Gene', (172, 177))	('immune suppressive function', 'CPA', (4, 31))	('PD-L1', 'Gene', (90, 95))
211582	27917371	More recently, we showed that tumors from clear cell renal cell carcinoma (ccRCC) patients displaying VHL biallelic inactivation (i.e., loss of function) exhibit a significant increase in PD-L1 expression as compared to ccRCC tumors carrying one VHL wild-type allele.	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('VHL', 'Gene', '7428', (246, 249))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('VHL', 'Gene', (102, 105))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (53, 73))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (42, 73))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('VHL', 'Gene', '7428', (102, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumors', 'Disease', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('patients', 'Species', '9606', (82, 90))	('PD-L1', 'Gene', (188, 193))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (42, 73))	('VHL', 'Gene', (246, 249))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('increase', 'PosReg', (176, 184))	('tumors', 'Disease', (226, 232))	('ccRCC', 'Phenotype', 'HP:0006770', (220, 225))	('expression', 'MPA', (194, 204))	('biallelic inactivation', 'Var', (106, 128))	('clear cell renal cell carcinoma', 'Disease', (42, 73))
211583	27917371	Using the inducible VHL 786-O-derived cell lines with varying HIF-2alpha stabilization levels, we showed that PD-L1 expression levels positively correlate with VHL mutation and HIF-2alpha expression.	('PD-L1', 'Gene', (110, 115))	('expression', 'MPA', (116, 126))	('HIF-2alpha', 'Gene', '2034', (62, 72))	('VHL', 'Gene', (160, 163))	('HIF-2alpha', 'Gene', (177, 187))	('VHL', 'Gene', '7428', (160, 163))	('mutation', 'Var', (164, 172))	('VHL', 'Gene', (20, 23))	('HIF-2alpha', 'Gene', '2034', (177, 187))	('VHL', 'Gene', '7428', (20, 23))	('HIF-2alpha', 'Gene', (62, 72))
211586	27917371	In conclusion, VHL mutations positively correlate with PD-L1 expression in ccRCC and may influence the response to ccRCC patients to anti-PD-L1/PD-1 immunotherapy.	('correlate', 'Reg', (40, 49))	('ccRCC', 'Disease', (75, 80))	('VHL', 'Gene', (15, 18))	('influence', 'Reg', (89, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('PD-1', 'Gene', (144, 148))	('mutations', 'Var', (19, 28))	('PD-1', 'Gene', '5133', (144, 148))	('VHL', 'Gene', '7428', (15, 18))	('PD-L1', 'Gene', (55, 60))	('patients', 'Species', '9606', (121, 129))	('expression', 'MPA', (61, 71))
211595	27917371	Inactivation of Atg5-dependent autophagy increased the number of tumor foci and favored the progression from hyperplasia to adenoma in a murine model of lung cancer (with KrasG12D mutation).	('tumor foci', 'Disease', 'MESH:C565785', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('increased', 'PosReg', (41, 50))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('autophagy', 'biological_process', 'GO:0006914', ('31', '40'))	('tumor foci', 'Disease', (65, 75))	('Atg5-dependent', 'Protein', (16, 30))	('favored', 'PosReg', (80, 87))	('Kras', 'Gene', (171, 175))	('murine', 'Species', '10090', (137, 143))	('lung cancer', 'Disease', (153, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('Kras', 'Gene', '3845', (171, 175))	('hyperplasia to adenoma', 'Disease', 'MESH:D000236', (109, 131))	('autophagy', 'biological_process', 'GO:0016236', ('31', '40'))	('Inactivation', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('hyperplasia to adenoma', 'Disease', (109, 131))
211598	27917371	The authors clearly demonstrated that inactivation of autophagy in pneumocytes carrying a Kras mutation triggered a local expansion of Tregs cells, which control lung tumor initiation.	('Tregs cells', 'CPA', (135, 146))	('lung tumor initiation', 'Disease', (162, 183))	('Kras', 'Gene', '3845', (90, 94))	('autophagy', 'biological_process', 'GO:0006914', ('54', '63'))	('lung tumor', 'Phenotype', 'HP:0100526', (162, 172))	('Tregs', 'Chemical', '-', (135, 140))	('inactivation', 'Var', (38, 50))	('control', 'Reg', (154, 161))	('autophagy', 'CPA', (54, 63))	('lung tumor initiation', 'Disease', 'MESH:D008175', (162, 183))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('Kras', 'Gene', (90, 94))	('autophagy', 'biological_process', 'GO:0016236', ('54', '63'))	('mutation', 'Var', (95, 103))
211599	27917371	This study established a cause-effect relationship between defective autophagy and infiltration of immunosuppressive Tregs cells.	('autophagy', 'CPA', (69, 78))	('defective', 'Var', (59, 68))	('autophagy', 'biological_process', 'GO:0016236', ('69', '78'))	('autophagy', 'biological_process', 'GO:0006914', ('69', '78'))	('Tregs', 'Chemical', '-', (117, 122))	('infiltration', 'CPA', (83, 95))
211601	27917371	showed that conditional inactivation of the autophagy gene Atg7 in intestinal epithelial cells (IECs) suppresses the development of precancerous lesions in Apc mutant mice.	('precancerous lesions', 'Disease', 'MESH:D011230', (132, 152))	('precancerous lesions', 'Disease', (132, 152))	('autophagy', 'biological_process', 'GO:0016236', ('44', '53'))	('suppresses', 'NegReg', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutant', 'Var', (160, 166))	('Atg7', 'Gene', '74244', (59, 63))	('autophagy', 'biological_process', 'GO:0006914', ('44', '53'))	('Atg7', 'Gene', (59, 63))	('Apc', 'cellular_component', 'GO:0005680', ('156', '159'))	('mice', 'Species', '10090', (167, 171))
211603	27917371	Autophagy inactivation in IECs favored the infiltration and the expansion of interferon (IFN)-producing CD8+ T cells in the intestinal mucosa and participated in their priming.	('Autophagy', 'biological_process', 'GO:0006914', ('0', '9'))	('favored', 'PosReg', (31, 38))	('Autophagy', 'biological_process', 'GO:0016236', ('0', '9'))	('inactivation', 'Var', (10, 22))	('infiltration', 'CPA', (43, 55))	('CD8', 'Gene', (104, 107))	('expansion', 'CPA', (64, 73))	('Autophagy', 'CPA', (0, 9))	('CD8', 'Gene', '925', (104, 107))
211609	27917371	This study, once again, showed that CD8+ T cells are crucial effectors of the autophagy-induced immunomodulation, as depletion of CD8+ T cells with selective antibodies restored mammary tumor initiation and progression.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('autophagy', 'biological_process', 'GO:0016236', ('78', '87'))	('CD8', 'Gene', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('CD8', 'Gene', '925', (130, 133))	('autophagy', 'biological_process', 'GO:0006914', ('78', '87'))	('depletion', 'Var', (117, 126))	('restored', 'PosReg', (169, 177))	('CD8', 'Gene', (36, 39))	('progression', 'CPA', (207, 218))	('CD8', 'Gene', '925', (36, 39))
211624	27917371	Inhibition of ER stress-induced autophagy, by knocking down Atg5 in cancer cells, improved the maturation of IL-6 secreting DCs, and thus triggered proliferation of IFNgamma-producing CD4+ and CD8+ T cells.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('IL-6', 'Gene', (109, 113))	('IFNgamma', 'Gene', (165, 173))	('CD8', 'Gene', (193, 196))	('IFNgamma', 'Gene', '3458', (165, 173))	('Atg5', 'Gene', (60, 64))	('proliferation', 'CPA', (148, 161))	('IL-6', 'molecular_function', 'GO:0005138', ('109', '113'))	('knocking down', 'Var', (46, 59))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('maturation', 'CPA', (95, 105))	('autophagy', 'biological_process', 'GO:0016236', ('32', '41'))	('CD4', 'Gene', '920', (184, 187))	('CD8', 'Gene', '925', (193, 196))	('triggered', 'Reg', (138, 147))	('IL-6', 'Gene', '3569', (109, 113))	('CD4', 'Gene', (184, 187))	('cancer', 'Disease', (68, 74))	('autophagy', 'biological_process', 'GO:0006914', ('32', '41'))	('improved', 'PosReg', (82, 90))
211625	27917371	Moreover, inactivation of autophagy in untreated melanoma cells increased CRT surface exposure, suggesting that basal autophagy in cancer cells may support immune escape.	('cancer', 'Disease', (131, 137))	('support', 'PosReg', (148, 155))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('autophagy', 'biological_process', 'GO:0006914', ('26', '35'))	('autophagy', 'biological_process', 'GO:0006914', ('118', '127'))	('immune escape', 'CPA', (156, 169))	('inactivation', 'Var', (10, 22))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('CRT', 'Gene', '811', (74, 77))	('autophagy', 'CPA', (26, 35))	('autophagy', 'biological_process', 'GO:0016236', ('118', '127'))	('increased', 'PosReg', (64, 73))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('CRT', 'Gene', (74, 77))	('autophagy', 'biological_process', 'GO:0016236', ('26', '35'))	('melanoma', 'Disease', (49, 57))
211639	27917371	Inhibition of autophagy in melanoma cells by knocking down BECN1 significantly reduced T cell proliferation in vitro and in vivo.	('autophagy', 'CPA', (14, 23))	('BECN1', 'Gene', '8678', (59, 64))	('T cell proliferation', 'biological_process', 'GO:0042098', ('87', '107'))	('knocking down', 'Var', (45, 58))	('reduced', 'NegReg', (79, 86))	('autophagy', 'biological_process', 'GO:0006914', ('14', '23'))	('BECN1', 'Gene', (59, 64))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', (27, 35))	('autophagy', 'biological_process', 'GO:0016236', ('14', '23'))	('T cell proliferation', 'CPA', (87, 107))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('reduced T cell', 'Phenotype', 'HP:0005403', (79, 93))
211649	27917371	The aberrant STAT3 signaling in tumor cells can suppress the expression of pro-inflammatory danger signals (e.g., IFNgamma, TNF, CXCL10), while induces the expression of immunosuppressive factors (e.g., VEGF, IL-10) that inhibit DCs maturation.	('TNF', 'Gene', '7124', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('induces', 'PosReg', (144, 151))	('inhibit', 'NegReg', (221, 228))	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('CXCL10', 'Gene', '3627', (129, 135))	('STAT3', 'Gene', (13, 18))	('IFNgamma', 'Gene', (114, 122))	('suppress', 'NegReg', (48, 56))	('IFNgamma', 'Gene', '3458', (114, 122))	('IL-10', 'molecular_function', 'GO:0005141', ('209', '214'))	('CXCL10', 'Gene', (129, 135))	('STAT3', 'Gene', '6774', (13, 18))	('tumor', 'Disease', (32, 37))	('expression', 'MPA', (61, 71))	('IL-10', 'Gene', '3586', (209, 214))	('TNF', 'Gene', (124, 127))	('aberrant', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('IL-10', 'Gene', (209, 214))	('DCs maturation', 'CPA', (229, 243))	('expression', 'MPA', (156, 166))
211658	27917371	Selective inhibition of autophagy, by silencing BECN1 or ATG5 in hypoxic cancer cells, restored the susceptibility to NK-mediated lysis.	('BECN1', 'Gene', '8678', (48, 53))	('inhibition', 'NegReg', (10, 20))	('autophagy', 'biological_process', 'GO:0006914', ('24', '33'))	('NK-mediated lysis', 'CPA', (118, 135))	('susceptibility', 'MPA', (100, 114))	('lysis', 'biological_process', 'GO:0019835', ('130', '135'))	('hypoxic cancer', 'Disease', (65, 79))	('hypoxic cancer', 'Disease', 'MESH:D009369', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ATG5', 'Gene', '9474', (57, 61))	('restored', 'PosReg', (87, 95))	('BECN1', 'Gene', (48, 53))	('NK', 'Chemical', '-', (118, 120))	('autophagy', 'biological_process', 'GO:0016236', ('24', '33'))	('autophagy', 'CPA', (24, 33))	('silencing', 'Var', (38, 47))	('ATG5', 'Gene', (57, 61))
211676	27917371	The combination of both anti-CTLA-4 and anti-PD1 has been shown to be twice as effective as either treatment alone in the rejection of B16-F10 melanoma tumors.	('melanoma tumors', 'Disease', 'MESH:D008545', (143, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('anti-CTLA-4', 'Var', (24, 35))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('melanoma tumors', 'Disease', (143, 158))	('rejection', 'CPA', (122, 131))	('anti-PD1', 'Gene', (40, 48))
211679	27917371	Similarly, in mouse models of colon carcinoma (CT26 cell line) and ovarian carcinoma (ID8-VEGF cell line), dual block (both anti-PD1 and anti-CTLA-4) combined with tumor vaccine leads to effective tumor rejection through the restoration of effector T cell function.	('colon carcinoma', 'Disease', 'MESH:D015179', (30, 45))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (67, 84))	('tumor', 'Disease', (164, 169))	('colon carcinoma', 'Disease', (30, 45))	('CT26', 'CellLine', 'CVCL:7254', (47, 51))	('anti-CTLA-4', 'Var', (137, 148))	('mouse', 'Species', '10090', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (67, 84))	('ovarian carcinoma', 'Disease', (67, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (197, 202))	('effector T cell function', 'CPA', (240, 264))
211680	27917371	More interestingly, it has been reported that the combination of anti-4-1BB and anti-PD-1 is more effective than that of anti-PD-1/anti-LAG-3 in suppressing B16-F10 melanoma tumor growth without adjuvant or vaccination.	('PD-1', 'Gene', (85, 89))	('PD-1', 'Gene', '5133', (85, 89))	('PD-1', 'Gene', (126, 130))	('LAG-3', 'Gene', '3902', (136, 141))	('PD-1', 'Gene', '5133', (126, 130))	('anti-4-1BB', 'Var', (65, 75))	('LAG-3', 'Gene', (136, 141))	('melanoma tumor', 'Disease', (165, 179))	('suppressing', 'NegReg', (145, 156))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma tumor', 'Disease', 'MESH:D008545', (165, 179))
211681	27917371	In a phase 1 clinical trial with advanced melanoma patients, the combination of anti-CTLA-4 and anti-PD-1 increased the response rate up to 53% patients with severe treatment-related adverse events.	('melanoma', 'Disease', (42, 50))	('anti-CTLA-4', 'Var', (80, 91))	('patients', 'Species', '9606', (144, 152))	('PD-1', 'Gene', '5133', (101, 105))	('response', 'MPA', (120, 128))	('patients', 'Species', '9606', (51, 59))	('PD-1', 'Gene', (101, 105))	('combination', 'Interaction', (65, 76))	('increased', 'PosReg', (106, 115))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
211703	33825659	Cox regression analysis and Kaplan-Meier analysis showed that ccRCC patients with high ABCG1 expression had better overall survival (OS) than those patients with low expression (hazard ratio (HR) = 0.662, p = 0.007).	('patients', 'Species', '9606', (148, 156))	('expression', 'Var', (93, 103))	('overall survival', 'MPA', (115, 131))	('high', 'Var', (82, 86))	('ABCG1', 'Gene', (87, 92))	('ABCG1', 'Gene', '9619', (87, 92))	('patients', 'Species', '9606', (68, 76))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('better', 'PosReg', (108, 114))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))
211715	33825659	C1q/tumor necrosis factor (C1QTNF) and six-snoRNA (small nucleolar RNA) signature (SNORA2, SNORD12B, SNORA59B, SNORA70B, SNORD93, and SNORD116-2) could serve as an independent diagnostic and prognostic indicator for ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (216, 221))	('SNORA70B', 'Gene', '100124537', (111, 119))	('SNORA70B', 'Gene', (111, 119))	('SNORD116-2', 'Gene', (134, 144))	('necrosis', 'biological_process', 'GO:0008219', ('10', '18'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('4', '25'))	('RCC', 'Disease', (218, 221))	('SNORD12B', 'Gene', (91, 99))	('RCC', 'Phenotype', 'HP:0005584', (218, 221))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('SNORA2', 'Var', (83, 89))	('tumor necrosis', 'Disease', 'MESH:D009336', (4, 18))	('SNORA59B', 'Gene', '677882', (101, 109))	('SNORD12B', 'Gene', '100113393', (91, 99))	('snoRNA', 'Gene', (43, 49))	('snoRNA', 'cellular_component', 'GO:0005733', ('43', '49'))	('necrosis', 'biological_process', 'GO:0008220', ('10', '18'))	('snoRNA', 'Gene', '85389', (43, 49))	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('tumor necrosis', 'Disease', (4, 18))	('small nucleolar RNA', 'molecular_function', 'GO:0005569', ('51', '70'))	('necrosis', 'biological_process', 'GO:0070265', ('10', '18'))	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('SNORD93', 'Gene', (121, 128))	('necrosis', 'biological_process', 'GO:0019835', ('10', '18'))	('SNORD93', 'Gene', '692210', (121, 128))	('necrosis', 'biological_process', 'GO:0001906', ('10', '18'))	('SNORA59B', 'Gene', (101, 109))	('small nucleolar RNA', 'cellular_component', 'GO:0005733', ('51', '70'))	('SNORD116-2', 'Gene', '100033414', (134, 144))
211720	33825659	Abnormal changes of the ABC genes can lead to multiple diseases, such as cystic fibrosis and disorder of cholesterol metabolism.	('ABC', 'Gene', (24, 27))	('Abnormal changes', 'Var', (0, 16))	('cystic fibrosis and disorder of cholesterol metabolism', 'Disease', 'MESH:D003550', (73, 127))	('ABC', 'Gene', '10058', (24, 27))	('lead to', 'Reg', (38, 45))	('disorder of cholesterol metabolism', 'Phenotype', 'HP:0003107', (93, 127))	('cholesterol metabolism', 'biological_process', 'GO:0008203', ('105', '127'))	('multiple diseases', 'Disease', (46, 63))
211758	33825659	Kaplan-Meier analysis also showed that ccRCC patients with high ABCG1 expression was significantly associated with better OS than those patients with low ABCG1 expression (p = 0.0067, hazard ratio (HR) = 0.6621) (Figure 3).	('ABCG1', 'Gene', (64, 69))	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('ABCG1', 'Gene', '9619', (64, 69))	('ABCG1', 'Gene', '9619', (154, 159))	('expression', 'Var', (70, 80))	('high', 'Var', (59, 63))	('patients', 'Species', '9606', (136, 144))	('patients', 'Species', '9606', (45, 53))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('ABCG1', 'Gene', (154, 159))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))	('better OS', 'Disease', (115, 124))
211761	33825659	Mutations in the ABC genes could affect the phenotypes of cancer cells such as proliferation, differentiation, migration, and invasion.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('migration', 'CPA', (111, 120))	('ABC', 'Gene', '10058', (17, 20))	('affect', 'Reg', (33, 39))	('differentiation', 'CPA', (94, 109))	('invasion', 'CPA', (126, 134))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('ABC', 'Gene', (17, 20))
211770	33825659	The abnormalities in cholesterol metabolism in ccRCC cells may affect the physiological and biochemical functions of cells and produce pathological changes.	('RCC', 'Disease', (49, 52))	('cholesterol metabolism', 'Disease', (21, 43))	('affect', 'Reg', (63, 69))	('abnormalities in cholesterol metabolism', 'Phenotype', 'HP:0003107', (4, 43))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('cholesterol metabolism', 'Disease', 'MESH:D008659', (21, 43))	('physiological', 'MPA', (74, 87))	('produce', 'Reg', (127, 134))	('cholesterol metabolism', 'biological_process', 'GO:0008203', ('21', '43'))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('abnormalities', 'Var', (4, 17))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
211775	33825659	It may be hypothesized that when normal cells mutate into cancer cells, the energy demand increases, which activates a certain cholesterol transport mechanism and begins to take cholesterol from the outside.	('mutate', 'Var', (46, 52))	('activates', 'PosReg', (107, 116))	('energy demand', 'MPA', (76, 89))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cholesterol', 'Chemical', 'MESH:D002784', (127, 138))	('increases', 'PosReg', (90, 99))	('cholesterol', 'Chemical', 'MESH:D002784', (178, 189))	('cholesterol transport', 'biological_process', 'GO:0030301', ('127', '148'))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cholesterol transport mechanism', 'MPA', (127, 158))	('cancer', 'Disease', (58, 64))
211779	33825659	Moreover, we found that ccRCC patients with high expression level had longer OS time than those with low expression level.	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('OS time', 'MPA', (77, 84))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('longer', 'PosReg', (70, 76))	('patients', 'Species', '9606', (30, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (24, 29))	('high expression level', 'Var', (44, 65))
211780	33825659	It may be that the high expression of ABCG1 can inhibit the growth of cancer cells and affect the survival of cancer cells by reducing the cholesterol content in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cholesterol', 'Chemical', 'MESH:D002784', (139, 150))	('cancer', 'Disease', (110, 116))	('ABCG1', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('high expression', 'Var', (19, 34))	('affect', 'Reg', (87, 93))	('reducing', 'NegReg', (126, 134))	('cancer', 'Disease', (162, 168))	('ABCG1', 'Gene', '9619', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cholesterol content', 'MPA', (139, 158))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('inhibit', 'NegReg', (48, 55))
211782	33825659	They speculated that LXR623 could kill tumor cells by promoting cholesterol outflow.	('LXR623', 'Var', (21, 27))	('cholesterol outflow', 'MPA', (64, 83))	('cholesterol', 'Chemical', 'MESH:D002784', (64, 75))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('promoting', 'PosReg', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))
211789	33825659	Researches have shown that the deficiency of ABCG1 increases the signaling of Toll-like receptors in macrophages, leading to an enhanced inflammatory response of macrophages to LPS or other TLR ligands, and also reduces the number and proportion of M2 phenotype.	('reduces', 'NegReg', (212, 219))	('ABCG1', 'Gene', (45, 50))	('signaling', 'MPA', (65, 74))	('increases', 'PosReg', (51, 60))	('enhanced', 'PosReg', (128, 136))	('enhanced inflammatory response', 'Phenotype', 'HP:0012649', (128, 158))	('deficiency', 'Var', (31, 41))	('ABCG1', 'Gene', '9619', (45, 50))	('inflammatory response', 'biological_process', 'GO:0006954', ('137', '158'))	('inflammatory response', 'MPA', (137, 158))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))
211809	27833401	The combination of D > 0.97 x 10-3 mm2/s, D* < 28.03 x 10-3 mm2/s, and f < 13.61% maximized the diagnostic sensitivity for distinguishing non-ccRCCs from fat poor AMLs.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('AML', 'Phenotype', 'HP:0006772', (163, 166))	('mm2', 'Gene', (60, 63))	('fat', 'Gene', (154, 157))	('mm2', 'Gene', '10687', (35, 38))	('AML', 'Disease', (163, 166))	('D* < 28.03', 'Var', (42, 52))	('fat', 'Gene', '2195', (154, 157))	('f < 13.61', 'Var', (71, 80))	('mm2', 'Gene', (35, 38))	('mm2', 'Gene', '10687', (60, 63))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('AML', 'Disease', 'MESH:D015470', (163, 166))	('maximized', 'PosReg', (82, 91))
211857	27833401	An r value of 1.0 was considered as perfect agreement; 0.81-0.99, almost perfect agreement; 0.61-0.80, substantial agreement; 0.41-0.60, moderate agreement; 0.21-0.40, fair agreement; and <= 0.20, slight agreement.	('men', 'Species', '9606', (151, 154))	('men', 'Species', '9606', (49, 52))	('men', 'Species', '9606', (86, 89))	('0.21-0.40', 'Var', (157, 166))	('men', 'Species', '9606', (209, 212))	('0.41-0.60', 'Var', (126, 135))	('men', 'Species', '9606', (178, 181))	('men', 'Species', '9606', (120, 123))
211876	27833401	However, using the OR combination of D > 0.97 x 10-3 mm2/s, D* < 28.03 x 10-3 mm2/s and f < 13.61% maximized the diagnostic sensitivity.	('mm2', 'Gene', (78, 81))	('maximized', 'PosReg', (99, 108))	('D* <', 'Var', (60, 64))	('D > 0.97', 'Var', (37, 45))	('mm2', 'Gene', '10687', (53, 56))	('diagnostic sensitivity', 'MPA', (113, 135))	('mm2', 'Gene', '10687', (78, 81))	('mm2', 'Gene', (53, 56))
211885	27833401	In addition, using the OR combination of D > 0.97 x 10-3 mm2/s, D* < 28.03 x 10-3 mm2/s, and f < 13.6% maximized the diagnostic accuracy (91.4%, 32/35).	('mm2', 'Gene', (82, 85))	('mm2', 'Gene', (57, 60))	('diagnostic', 'MPA', (117, 127))	('mm2', 'Gene', '10687', (82, 85))	('D* < 28.03', 'Var', (64, 74))	('maximized', 'PosReg', (103, 112))	('mm2', 'Gene', '10687', (57, 60))	('D > 0.97 x 10-3', 'Var', (41, 56))
211925	28423633	In ccRCC cell lines, SLINKY knockdown reduced cancer cell proliferation (with cell-cycle G1 arrest) and induced transcriptome changes enriched for cell proliferation and survival processes.	('cell proliferation', 'biological_process', 'GO:0008283', ('53', '71'))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('reduced', 'NegReg', (38, 45))	('cell proliferation', 'biological_process', 'GO:0008283', ('147', '165'))	('cancer', 'Disease', (46, 52))	('transcriptome changes', 'MPA', (112, 133))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('SLINKY', 'Gene', (21, 27))	('RCC', 'Disease', (5, 8))	('cell-cycle', 'biological_process', 'GO:0007049', ('78', '88'))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('knockdown', 'Var', (28, 37))
211926	28423633	Notably, the genes affected by SLINKY knockdown in cell lines were themselves prognostic and correlated with SLINKY expression in the ccRCC patient samples.	('correlated', 'Reg', (93, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('patient', 'Species', '9606', (140, 147))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('knockdown', 'Var', (38, 47))	('RCC', 'Disease', (136, 139))
211942	28423633	Investigating its function, we found that SLINKY knockdown in ccRCC cell lines reduces cell proliferation, causes cell-cycle arrest, and alters gene expression programs related to cell growth and survival.	('knockdown', 'Var', (49, 58))	('cell-cycle arrest', 'CPA', (114, 131))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('114', '131'))	('gene expression', 'biological_process', 'GO:0010467', ('144', '159'))	('cell proliferation', 'biological_process', 'GO:0008283', ('87', '105'))	('alters', 'Reg', (137, 143))	('reduces', 'NegReg', (79, 86))	('cell proliferation', 'CPA', (87, 105))	('causes', 'Reg', (107, 113))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('RCC', 'Disease', (64, 67))	('gene expression programs', 'MPA', (144, 168))	('cell growth', 'biological_process', 'GO:0016049', ('180', '191'))
211950	28423633	SLINKY expression appeared to be cancer specific since it was not detected (RPKM < 0.001) in normal kidney samples (Figure 1F), but was measurable (RPKM > 0.001) in 59% of tumor samples (P < 0.001; Mann-Whitney U-test).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('tumor', 'Disease', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('SLINKY', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
211952	28423633	SLINKY expression did not correlate with the presence of either VHL or PBRM1 mutation (Supplementary Figure S1).	('PBRM1', 'Gene', (71, 76))	('VHL', 'Disease', 'MESH:D006623', (64, 67))	('VHL', 'Disease', (64, 67))	('men', 'Species', '9606', (93, 96))	('mutation', 'Var', (77, 85))	('PBRM1', 'Gene', '55193', (71, 76))
211961	28423633	For example, high SLINKY expression in patients with Stage III RCC was associated with an approximate 3-fold higher death rate compared to the low expression group (53% vs. 18%, P < 0.001).	('RCC', 'Disease', (63, 66))	('death', 'Disease', 'MESH:D003643', (116, 121))	('patients', 'Species', '9606', (39, 47))	('death', 'Disease', (116, 121))	('high', 'Var', (13, 17))	('SLINKY', 'Protein', (18, 24))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
211962	28423633	For the stage I and II patients, high SLINKY levels were associated with more than double the risk of death (24% vs. 11%, P < 0.01).	('high', 'Var', (33, 37))	('death', 'Disease', 'MESH:D003643', (102, 107))	('death', 'Disease', (102, 107))	('patients', 'Species', '9606', (23, 31))	('SLINKY levels', 'MPA', (38, 51))
211964	28423633	The finding that SLINKY lincRNA was highly prognostic implies a possible mechanistic role in ccRCC development and/or progression.	('SLINKY', 'Var', (17, 23))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('RCC', 'Disease', (95, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('men', 'Species', '9606', (106, 109))
211966	28423633	The two most highly expressed SLINKY transcript variants (from the TCGA ccRCC data) both include the first exon, and therefore we designed two different siRNAs targeting distinct sequences within that exon (Figure 3A).	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('variants', 'Var', (48, 56))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('RCC', 'Disease', (74, 77))
211969	28423633	Using a Matrigel cell invasion assay, we observed that SLINKY knockdown did not affect cell invasion (Supplementary Figure S3).	('SLINKY', 'Gene', (55, 61))	('men', 'Species', '9606', (108, 111))	('cell invasion', 'CPA', (87, 100))	('knockdown', 'Var', (62, 71))
211972	28423633	However, SLINKY knockdown did not alter PIK3CG expression levels (which were not detectable at baseline), measured by RNA-seq (Supplementary Figure 4B).	('PIK3CG', 'Gene', '5294', (40, 46))	('knockdown', 'Var', (16, 25))	('RNA', 'cellular_component', 'GO:0005562', ('118', '121'))	('men', 'Species', '9606', (133, 136))	('PIK3CG', 'Gene', (40, 46))	('expression', 'MPA', (47, 57))
211973	28423633	To better understand the role of SLINKY in ccRCC cells, we assayed whole-transcriptome changes (by RNA-seq) following SLINKY knockdown in 786-O and A-498 cells, using two different SLINKY siRNAs compared to non-targeting control.	('knockdown', 'Var', (125, 134))	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('RNA', 'cellular_component', 'GO:0005562', ('99', '102'))	('A-498', 'CellLine', 'CVCL:1056', (148, 153))	('SLINKY', 'Gene', (118, 124))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))
211980	28423633	In a complementary approach, we used the 93 genes showing altered expression upon SLINKY knockdown in both ccRCC cell lines to cluster the TCGA patient samples.	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('patient', 'Species', '9606', (144, 151))	('RCC', 'Disease', (109, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('knockdown', 'Var', (89, 98))	('men', 'Species', '9606', (11, 14))
211986	28423633	To evaluate the functional relevance of the SLINKY-HNRNPK interaction, we used siRNA to knockdown HNRNPK in the same ccRCC cell lines previously assessed for SLINKY knockdown.	('HNRNPK', 'Gene', (98, 104))	('HNRNPK', 'Gene', '3190', (98, 104))	('HNRNPK', 'Gene', (51, 57))	('HNRNPK', 'Gene', '3190', (51, 57))	('knockdown', 'Var', (88, 97))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('RCC', 'Disease', (119, 122))
211987	28423633	Notably, HNRNPK knockdown led to reduced cell proliferation, at least comparable with SLINKY knockdown (Figure 5C).	('cell proliferation', 'CPA', (41, 59))	('HNRNPK', 'Gene', (9, 15))	('knockdown', 'Var', (16, 25))	('HNRNPK', 'Gene', '3190', (9, 15))	('reduced', 'NegReg', (33, 40))	('cell proliferation', 'biological_process', 'GO:0008283', ('41', '59'))
211988	28423633	Moreover, the transcriptome changes induced by HNRNPK knockdown displayed a marked overlap (about one-third) with those observed with SLINKY knockdown, significantly more than expected by chance (P < 0.001; hypergeometric test; Figure 5D).	('HNRNPK', 'Gene', (47, 53))	('transcriptome changes', 'MPA', (14, 35))	('HNRNPK', 'Gene', '3190', (47, 53))	('knockdown', 'Var', (54, 63))
211989	28423633	Furthermore, in both cell lines, the altered genes common to SLINKY and HNRNPK knockdown exhibited significant enrichment for cell proliferation, cell survival and cell cycle functions by Ingenuity Pathway Analysis (Figure 5E).	('cell cycle functions', 'CPA', (164, 184))	('cell proliferation', 'CPA', (126, 144))	('HNRNPK', 'Gene', (72, 78))	('men', 'Species', '9606', (117, 120))	('HNRNPK', 'Gene', '3190', (72, 78))	('cell survival', 'CPA', (146, 159))	('cell proliferation', 'biological_process', 'GO:0008283', ('126', '144'))	('knockdown', 'Var', (79, 88))	('cell cycle', 'biological_process', 'GO:0007049', ('164', '174'))
211991	28423633	We have identified SLINKY as a potentially significant lincRNA in ccRCC biology that could serve as an important biomarker of ccRCC prognosis.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('SLINKY', 'Var', (19, 25))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('RCC', 'Disease', (68, 71))
212000	28423633	HOTAIR is over-expressed in several RCC cell lines and knockdown of HOTAIR inhibits cell proliferation.	('HOTAIR', 'Gene', '100124700', (0, 6))	('knockdown', 'Var', (55, 64))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('cell proliferation', 'biological_process', 'GO:0008283', ('84', '102'))	('HOTAIR', 'Gene', (68, 74))	('HOTAIR', 'Gene', (0, 6))	('cell proliferation', 'CPA', (84, 102))	('HOTAIR', 'Gene', '100124700', (68, 74))	('inhibits', 'NegReg', (75, 83))
212001	28423633	The lincRNAs MALAT-1and NBAT-1 have been identified in several malignancies and alteration of their expression levels has been shown to correlate with adverse outcomes in ccRCC.	('identified', 'Reg', (41, 51))	('RCC', 'Disease', (173, 176))	('expression levels', 'MPA', (100, 117))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('malignancies', 'Disease', 'MESH:D009369', (63, 75))	('MALAT-1', 'Gene', '378938', (13, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (171, 176))	('NBAT-1', 'Gene', '729177', (24, 30))	('NBAT-1', 'Gene', (24, 30))	('malignancies', 'Disease', (63, 75))	('MALAT-1', 'Gene', (13, 20))	('alteration', 'Var', (80, 90))
212008	28423633	In our study, we find that SLINKY enhances cancer cell proliferation most likely through its interaction with HNRNPK.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('HNRNPK', 'Gene', (110, 116))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('interaction', 'Interaction', (93, 104))	('SLINKY', 'Var', (27, 33))	('enhances', 'PosReg', (34, 42))	('HNRNPK', 'Gene', '3190', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
212012	28423633	In our studies, knockdown of either SLINKY or HNRNPK leads to both the upregulation and downregulation of genes, so the possible recruitment of HNRNPK to gene loci (yet to be proven) might serve to either activate or repress genes.	('downregulation', 'NegReg', (88, 102))	('HNRNPK', 'Gene', '3190', (144, 150))	('knockdown', 'Var', (16, 25))	('HNRNPK', 'Gene', '3190', (46, 52))	('upregulation', 'PosReg', (71, 83))	('HNRNPK', 'Gene', (46, 52))	('activate', 'PosReg', (205, 213))	('HNRNPK', 'Gene', (144, 150))	('men', 'Species', '9606', (136, 139))	('genes', 'Gene', (225, 230))	('repress', 'NegReg', (217, 224))
212042	28423633	48 hrs following siRNA transfection, cells were seeded in serum-free DMEM media (20,000 cells/chamber), with 10% FBS in the lower chamber serving as a chemoattractant.	('FBS', 'Disease', 'MESH:D005198', (113, 116))	('transfection', 'Var', (23, 35))	('DMEM media', 'Chemical', '-', (69, 79))	('siRNA', 'Gene', (17, 22))	('FBS', 'Disease', (113, 116))
212052	32398132	The potential role of RNA N6-methyladenosine in Cancer progression N6-methyladenosine (m6A) is considered the most common, abundant, and conserved internal transcript modification, especially in eukaryotic messenger RNA (mRNA).	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (26, 44))	('RNA', 'cellular_component', 'GO:0005562', ('22', '25'))	('N6-methyladenosine', 'Var', (67, 85))	('Cancer', 'Disease', 'MESH:D009369', (48, 54))	('Cancer', 'Disease', (48, 54))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))	('RNA', 'cellular_component', 'GO:0005562', ('216', '219'))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (67, 85))
212054	32398132	Accumulating evidence suggests that m6A RNA methylation greatly impacts RNA metabolism and is involved in the pathogenesis of many kinds of diseases, including cancers.	('RNA methylation', 'biological_process', 'GO:0001510', ('40', '55'))	('methylation', 'Var', (44, 55))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('m6A', 'Var', (36, 39))	('cancers', 'Disease', (160, 167))	('impacts', 'Reg', (64, 71))	('RNA metabolism', 'biological_process', 'GO:0016070', ('72', '86'))	('RNA', 'cellular_component', 'GO:0005562', ('72', '75'))	('RNA metabolism', 'MPA', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('involved', 'Reg', (94, 102))	('pathogenesis', 'biological_process', 'GO:0009405', ('110', '122'))
212059	32398132	Estimates suggest that more than 7000 coding and 300 noncoding RNAs contain m6A and that 0.1-0.4% of the total adenine nucleotide content is methylated in mammalian transcripts.	('mammalian', 'Species', '9606', (155, 164))	('contain', 'Reg', (68, 75))	('m6A', 'Var', (76, 79))	('adenine nucleotide', 'Chemical', 'MESH:D000227', (111, 129))
212082	32398132	It can identify specific m6A sites via its C-terminal region, and its N-terminal region binds to the SH domain of CCR4-NOT transcription complex subunit 1 (CNOT1), thus directly recruiting the CCR4-NOT deadenylase complex and eventually transporting RNA to the processing body (P-body) to accelerate the degradation of m6A-modified RNA.	('CCR4', 'Gene', '1233', (114, 118))	('CCR4-NOT transcription complex subunit 1', 'Gene', '23019', (114, 154))	('CCR4-NOT transcription complex subunit 1', 'Gene', (114, 154))	('CCR', 'molecular_function', 'GO:0043880', ('114', '117'))	('CCR', 'molecular_function', 'GO:0043880', ('193', '196'))	('recruiting', 'PosReg', (178, 188))	('CCR4', 'Gene', (193, 197))	('CNOT1', 'Gene', (156, 161))	('m6A-modified', 'Var', (319, 331))	('degradation', 'MPA', (304, 315))	('transcription', 'biological_process', 'GO:0006351', ('123', '136'))	('CCR4', 'Gene', '1233', (193, 197))	('RNA', 'cellular_component', 'GO:0005562', ('332', '335'))	('CCR4', 'Gene', (114, 118))	('P-body', 'cellular_component', 'GO:0000932', ('278', '284'))	('RNA', 'cellular_component', 'GO:0005562', ('250', '253'))	('CNOT1', 'Gene', '23019', (156, 161))	('degradation', 'biological_process', 'GO:0009056', ('304', '315'))	('accelerate', 'PosReg', (289, 299))
212089	32398132	HNRNPA2/B1 can recognize m6A on a subset of primary microRNA (pri-miRNA) transcripts and interact with drosha ribonuclease III (DROSHA) and DiGeorge syndrome critical region 8 (DGCR8), thus facilitating pri-miRNA processing.	('interact', 'Interaction', (89, 97))	('miR', 'Gene', '220972', (207, 210))	('DGCR8', 'Gene', (177, 182))	('drosha', 'Gene', (103, 109))	('facilitating', 'PosReg', (190, 202))	('HNRNPA2/B1', 'Gene', (0, 10))	('HNRNPA2/B1', 'Gene', '3181', (0, 10))	('DiGeorge syndrome critical region 8', 'Gene', (140, 175))	('miR', 'Gene', (66, 69))	('drosha', 'Gene', '29102', (103, 109))	('miR', 'Gene', '220972', (66, 69))	('DROSHA', 'Gene', '29102', (128, 134))	('DiGeorge syndrome critical region 8', 'Gene', '54487', (140, 175))	('DGCR8', 'Gene', '54487', (177, 182))	('DROSHA', 'Gene', (128, 134))	('pri-miRNA processing', 'biological_process', 'GO:0031053', ('203', '223'))	('m6A', 'Var', (25, 28))	('miR', 'Gene', (207, 210))
212090	32398132	In addition, m6A affects the secondary structure of RNA, whereas HNRNPC and HNRNPG can regulate mRNA abundance and splicing after recognizing m6A.	('RNA', 'MPA', (52, 55))	('HNRNPG', 'Gene', '3186', (76, 82))	('affects', 'Reg', (17, 24))	('secondary structure', 'MPA', (29, 48))	('HNRNPG', 'Gene', (76, 82))	('m6A', 'Var', (13, 16))	('mRNA abundance', 'MPA', (96, 110))	('HNRNPC', 'Gene', (65, 71))	('regulate', 'Reg', (87, 95))	('HNRNPC', 'Gene', '3183', (65, 71))	('splicing', 'MPA', (115, 123))	('splicing', 'biological_process', 'GO:0045292', ('115', '123'))	('RNA', 'cellular_component', 'GO:0005562', ('52', '55'))
212093	32398132	m6A in the 5' UTR region of transcripts can also directly recruit eIF3, which can recruit the 43S ribosomal preinitiation complex to promote cap-independent translation.	('eIF3', 'Gene', (66, 70))	('translation', 'biological_process', 'GO:0006412', ('157', '168'))	('promote', 'PosReg', (133, 140))	('eIF3', 'Gene', '8661', (66, 70))	('cap-independent translation', 'MPA', (141, 168))	('m6A', 'Var', (0, 3))	('eIF3', 'cellular_component', 'GO:0005852', ('66', '70'))	('preinitiation complex', 'cellular_component', 'GO:0097550', ('108', '129'))
212098	32398132	found that miR-17-5p, miR-21-5p, miR-200c-3p, and miR-let-7a-5p contain m6A methylation sites in pancreatic cancer.	('miR', 'Gene', '220972', (11, 14))	('methylation', 'biological_process', 'GO:0032259', ('76', '87'))	('miR-21', 'Gene', (22, 28))	('m6A methylation', 'Var', (72, 87))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (97, 114))	('miR', 'Gene', '220972', (50, 53))	('R-2', 'Gene', (35, 38))	('miR-17-5p', 'Gene', '406952', (11, 20))	('R-2', 'Gene', '913', (24, 27))	('miR', 'Gene', (11, 14))	('miR-17-5p', 'Gene', (11, 20))	('methylation', 'Var', (76, 87))	('miR', 'Gene', '220972', (33, 36))	('miR', 'Gene', (50, 53))	('pancreatic cancer', 'Disease', 'MESH:D010190', (97, 114))	('miR', 'Gene', '220972', (22, 25))	('miR', 'Gene', (33, 36))	('R-2', 'Gene', (24, 27))	('miR-21', 'Gene', '406991', (22, 28))	('R-2', 'Gene', '913', (35, 38))	('pancreatic cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('miR', 'Gene', (22, 25))
212101	32398132	Studies have shown that METTL3 and RBM15/15B can mediate m6A modification of lncRNA-XIST.	('XIST', 'Gene', '7503', (84, 88))	('METTL3', 'Gene', (24, 30))	('XIST', 'Gene', (84, 88))	('m6A', 'Var', (57, 60))	('RBM15', 'Gene', '64783', (35, 40))	('RBM15', 'Gene', (35, 40))
212102	32398132	In addition, YTHDC1 recognition of the m6A modification site on lncRNA-XIST is also necessary for the basic silencing functions of lncRNA-XIST.	('YTHDC1', 'Gene', '91746', (13, 19))	('XIST', 'Gene', '7503', (71, 75))	('XIST', 'Gene', (71, 75))	('silencing', 'MPA', (108, 117))	('m6A', 'Var', (39, 42))	('XIST', 'Gene', (138, 142))	('XIST', 'Gene', '7503', (138, 142))	('YTHDC1', 'Gene', (13, 19))
212103	32398132	In addition, m6A modification of circRNAs is regulated by METTL3/14 and FTO.	('METTL3/14', 'Gene', (58, 67))	('regulated', 'Reg', (45, 54))	('m6A', 'Var', (13, 16))	('METTL3/14', 'Gene', '56339;57721', (58, 67))
212104	32398132	Furthermore, m6A modification can promote circRNA translation by mediating eIF4G2 and the binding protein YTHDF3.	('eIF4', 'cellular_component', 'GO:0008304', ('75', '79'))	('translation', 'biological_process', 'GO:0006412', ('50', '61'))	('m6A modification', 'Var', (13, 29))	('YTHDF3', 'Gene', (106, 112))	('binding', 'molecular_function', 'GO:0005488', ('90', '97'))	('eIF4G2', 'Gene', (75, 81))	('promote', 'PosReg', (34, 41))	('mediating', 'Reg', (65, 74))	('YTHDF3', 'Gene', '253943', (106, 112))	('circRNA translation', 'MPA', (42, 61))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('eIF4G2', 'Gene', '1982', (75, 81))
212108	32398132	proposed a new technique that uses matrix-assisted laser desorption/ ionization time of flight mass spectrometry (MALDI-TOF-MS) to specifically detect m6A mutations in related miRNA.	('mutations', 'Var', (155, 164))	('flight', 'biological_process', 'GO:0060361', ('88', '94'))	('m6A', 'Gene', (151, 154))	('detect', 'Reg', (144, 150))	('miR', 'Gene', '220972', (176, 179))	('miR', 'Gene', (176, 179))
212110	32398132	Many studies have shown that m6A modification plays an important role in various cancers, often via the actions of writers that catalyze m6A modifications in the mRNA of oncogenes or tumor suppressor genes and then the actions of readers that recognize these marks through a series of molecular biological effects, in turn upregulating oncogene expression or downregulating tumor suppressor gene expression.	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('374', '390'))	('oncogene', 'Protein', (336, 344))	('tumor', 'Disease', (374, 379))	('tumor suppressor', 'biological_process', 'GO:0051726', ('374', '390'))	('downregulating', 'NegReg', (359, 373))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (374, 379))	('tumor', 'Disease', (183, 188))	('expression', 'MPA', (396, 406))	('m6A', 'Var', (137, 140))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('183', '199'))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('gene expression', 'biological_process', 'GO:0010467', ('391', '406'))	('expression', 'MPA', (345, 355))	('upregulating', 'PosReg', (323, 335))	('tumor suppressor', 'biological_process', 'GO:0051726', ('183', '199'))	('tumor', 'Phenotype', 'HP:0002664', (374, 379))
212118	32398132	In addition, studies have shown that METTL3 or METTL14 is beneficial to preventing GSC self-renewal and tumorigenicity and that ADAM metallopeptidase domain 19 (ADAM19) may be the target gene.	('METTL3', 'Var', (37, 43))	('ADAM metallopeptidase domain 19', 'Gene', '8728', (128, 159))	('METTL14', 'Gene', '57721', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('ADAM metallopeptidase domain 19', 'Gene', (128, 159))	('tumor', 'Disease', (104, 109))	('ADAM19', 'Gene', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('GSC', 'cellular_component', 'GO:0032593', ('83', '86'))	('GSC self-renewal', 'CPA', (83, 99))	('ADAM19', 'Gene', '8728', (161, 167))	('preventing', 'NegReg', (72, 82))	('METTL14', 'Gene', (47, 54))
212119	32398132	However, ALKBH5 was found to be highly expressed in GSCs, and silencing ALKBH5 inhibited the proliferation of GSCs.	('ALKBH5', 'Gene', (72, 78))	('silencing', 'Var', (62, 71))	('ALKBH5', 'Gene', '54890', (9, 15))	('ALKBH5', 'Gene', (9, 15))	('inhibited', 'NegReg', (79, 88))	('ALKBH5', 'Gene', '54890', (72, 78))
212121	32398132	ALKBH5 demethylated FOXM1 mRNA, thus increasing FOXM1 expression.	('expression', 'MPA', (54, 64))	('ALKBH5', 'Gene', (0, 6))	('increasing', 'PosReg', (37, 47))	('demethylated', 'Var', (7, 19))	('FOXM1', 'Gene', (20, 25))	('FOXM1', 'Gene', '2305', (20, 25))	('mRNA', 'Protein', (26, 30))	('FOXM1', 'Gene', '2305', (48, 53))	('FOXM1', 'Gene', (48, 53))	('ALKBH5', 'Gene', '54890', (0, 6))
212122	32398132	In addition, FOXM1 antisense noncoding RNA (FOXM1-AS) promoted the interaction between ALKBH5 and FOXM1 transcripts.	('promoted', 'PosReg', (54, 62))	('ALKBH5', 'Gene', '54890', (87, 93))	('antisense', 'Var', (19, 28))	('ALKBH5', 'Gene', (87, 93))	('FOXM1', 'Gene', (98, 103))	('FOXM1', 'Gene', '2305', (98, 103))	('FOXM1', 'Gene', (44, 49))	('FOXM1', 'Gene', '2305', (44, 49))	('FOXM1', 'Gene', (13, 18))	('interaction', 'Interaction', (67, 78))	('FOXM1', 'Gene', '2305', (13, 18))	('RNA', 'cellular_component', 'GO:0005562', ('39', '42'))
212123	32398132	Depleting ALKBH5 and FOXM1-AS abolished the tumorigenicity of GSCs through the FOXM1 axis.	('FOXM1', 'Gene', '2305', (21, 26))	('Depleting', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('FOXM1', 'Gene', '2305', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('ALKBH5', 'Gene', '54890', (10, 16))	('FOXM1', 'Gene', (79, 84))	('FOXM1', 'Gene', (21, 26))	('tumor', 'Disease', (44, 49))	('abolished', 'NegReg', (30, 39))	('ALKBH5', 'Gene', (10, 16))
212124	32398132	found that the imidazobenzoxazin-5-thione MV1035 significantly inhibited ALKBH5, thereby reducing GBM invasiveness.	('ALKBH5', 'Gene', '54890', (73, 79))	('GBM invasiveness', 'CPA', (98, 114))	('reducing', 'NegReg', (89, 97))	('ALKBH5', 'Gene', (73, 79))	('MV1035', 'Var', (42, 48))	('imidazobenzoxazin-5-thione', 'Chemical', '-', (15, 41))	('MV1035', 'Chemical', '-', (42, 48))	('inhibited', 'NegReg', (63, 72))
212126	32398132	m6A methylation was found to be decreased in approximately 70% of endometrial tumors, probably due to METTL14 mutation or a decrease in METTL3 expression.	('endometrial tumors', 'Disease', (66, 84))	('METTL3', 'Gene', (136, 142))	('METTL14', 'Gene', (102, 109))	('methylation', 'MPA', (4, 15))	('expression', 'MPA', (143, 153))	('METTL14', 'Gene', '57721', (102, 109))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('endometrial tumors', 'Disease', 'MESH:D016889', (66, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutation', 'Var', (110, 118))	('m6A', 'Protein', (0, 3))	('decrease', 'NegReg', (124, 132))	('decreased', 'NegReg', (32, 41))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))
212140	32398132	In pancreatic cancer cells, four miRNAs, miR-17-5p, miR-21-5p, miR-200c-3p and miR-let-7a-5p, contain m6A methylation modification sites.	('R-2', 'Gene', '913', (65, 68))	('miR', 'Gene', '220972', (52, 55))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('miR-21', 'Gene', (52, 58))	('miR', 'Gene', '220972', (41, 44))	('m6A', 'Var', (102, 105))	('miR', 'Gene', (52, 55))	('miR', 'Gene', '220972', (33, 36))	('R-2', 'Gene', '913', (54, 57))	('R-2', 'Gene', (65, 68))	('miR-17-5p', 'Gene', '406952', (41, 50))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('miR-17-5p', 'Gene', (41, 50))	('miR', 'Gene', (41, 44))	('miR', 'Gene', '220972', (79, 82))	('miR', 'Gene', '220972', (63, 66))	('methylation', 'biological_process', 'GO:0032259', ('106', '117'))	('miR', 'Gene', (33, 36))	('pancreatic cancer', 'Disease', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('miR', 'Gene', (79, 82))	('R-2', 'Gene', (54, 57))	('miR', 'Gene', (63, 66))	('miR-21', 'Gene', '406991', (52, 58))
212142	32398132	More importantly, serum levels of methylated miR-17-5p distinguish early pancreatic cancer patients from healthy controls with high sensitivity and specificity.	('methylated', 'Var', (34, 44))	('patients', 'Species', '9606', (91, 99))	('pancreatic cancer', 'Disease', (73, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('miR-17-5p', 'Gene', '406952', (45, 54))	('miR-17-5p', 'Gene', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))
212143	32398132	Research showed that the absence of METTL3 increased the sensitivity of pancreatic cancer cells to anticancer drugs, such as gemcitabine, 5-fluorouracil, and cisplatin but had little effect on cell morphology and proliferation.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('pancreatic cancer', 'Disease', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (72, 89))	('cisplatin', 'MPA', (158, 167))	('cisplatin', 'Chemical', 'MESH:D002945', (158, 167))	('5-fluorouracil', 'MPA', (138, 152))	('absence', 'Var', (25, 32))	('increased', 'PosReg', (43, 52))	('sensitivity', 'MPA', (57, 68))	('gemcitabine', 'Chemical', 'MESH:C056507', (125, 136))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (138, 152))	('METTL3', 'Gene', (36, 42))	('cancer', 'Disease', (83, 89))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (72, 89))
212149	32398132	IGF2BP2 can be a reader of m6A-modified lncRNA-DANCR and functions to stabilize DANCR, which in turn jointly promotes cancer stemness-like properties and pancreatic cancer pathogenesis.	('pancreatic cancer', 'Disease', 'MESH:D010190', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('m6A-modified', 'Var', (27, 39))	('IGF2BP2', 'Gene', '10644', (0, 7))	('turn jointly promotes cancer stemness', 'Disease', 'MESH:D009369', (96, 133))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('DANCR', 'Gene', (80, 85))	('turn jointly promotes cancer stemness', 'Disease', (96, 133))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (154, 171))	('IGF2BP2', 'Gene', (0, 7))	('DANCR', 'Gene', '57291', (80, 85))	('DANCR', 'Gene', (47, 52))	('pathogenesis', 'biological_process', 'GO:0009405', ('172', '184'))	('DANCR', 'Gene', '57291', (47, 52))	('pancreatic cancer', 'Disease', (154, 171))
212157	32398132	On the other hand, high expression of FTO in lung cancer was found to decrease the m6A levels of ubiquitin-specific peptidase 7 (USP7), improve the mRNA stability of USP7, and promote the occurrence of NSCLC.	('USP', 'molecular_function', 'GO:0051748', ('129', '132'))	('USP7', 'Gene', (129, 133))	('ubiquitin-specific peptidase 7', 'Gene', '7874', (97, 127))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('promote', 'PosReg', (176, 183))	('decrease', 'NegReg', (70, 78))	('ubiquitin-specific peptidase 7', 'Gene', (97, 127))	('lung cancer', 'Disease', (45, 56))	('USP7', 'Gene', '7874', (129, 133))	('mRNA stability', 'MPA', (148, 162))	('USP7', 'Gene', (166, 170))	('NSCLC', 'Disease', 'MESH:D002289', (202, 207))	('ubiquitin', 'molecular_function', 'GO:0031386', ('97', '106'))	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('improve', 'PosReg', (136, 143))	('high', 'Var', (19, 23))	('USP7', 'Gene', '7874', (166, 170))	('NSCLC', 'Disease', (202, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('USP', 'molecular_function', 'GO:0051748', ('166', '169'))	('FTO', 'Gene', (38, 41))
212158	32398132	Furthermore, FTO enhanced the expression of myeloid zinc finger 1 (MZF1) by reducing the m6A level in MZF1 mRNA and enhancing its stability, thus promoting the development of lung cancer.	('enhanced', 'PosReg', (17, 25))	('lung cancer', 'Disease', (175, 186))	('m6A level', 'MPA', (89, 98))	('stability', 'MPA', (130, 139))	('promoting', 'PosReg', (146, 155))	('MZF1', 'Gene', '7593', (67, 71))	('lung cancer', 'Disease', 'MESH:D008175', (175, 186))	('myeloid zinc finger 1', 'Gene', '7593', (44, 65))	('men', 'Species', '9606', (167, 170))	('MZF1', 'Gene', (102, 106))	('enhancing', 'PosReg', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('expression', 'MPA', (30, 40))	('FTO', 'Var', (13, 16))	('myeloid zinc finger 1', 'Gene', (44, 65))	('MZF1', 'Gene', '7593', (102, 106))	('reducing', 'NegReg', (76, 84))	('MZF1', 'Gene', (67, 71))
212166	32398132	Kaplan-Meier analysis showed that a low level of YTHDF1 expression was associated with better survival of HCC patients.	('YTHDF1', 'Gene', (49, 55))	('HCC', 'Gene', (106, 109))	('expression', 'MPA', (56, 66))	('HCC', 'Gene', '619501', (106, 109))	('better', 'PosReg', (87, 93))	('low level', 'Var', (36, 45))	('survival', 'CPA', (94, 102))	('patients', 'Species', '9606', (110, 118))
212170	32398132	In HCC cells, METTL3 installed m6A in the coding sequence (CDS) and 3' UTR regions of a key EMT transcription factor, Snail, thus promoting its translation.	('HCC', 'Gene', (3, 6))	('transcription factor', 'molecular_function', 'GO:0000981', ('96', '116'))	('transcription', 'biological_process', 'GO:0006351', ('96', '109'))	('EMT', 'biological_process', 'GO:0001837', ('92', '95'))	('translation', 'biological_process', 'GO:0006412', ('144', '155'))	('translation', 'MPA', (144, 155))	('HCC', 'Gene', '619501', (3, 6))	('promoting', 'PosReg', (130, 139))	('Snail', 'Gene', '6615', (118, 123))	('Snail', 'Gene', (118, 123))	('m6A', 'Var', (31, 34))
212172	32398132	METTL3-mediated m6A modification upregulated the expression of LINC00958 by stabilizing its RNA transcript, which in turn upregulated hepatocarcinoma-derived growth factor (HDGF) expression through sponging miR-3619-5p, thereby promoting HCC lipogenesis and progression.	('HCC', 'Gene', '619501', (238, 241))	('lipogenesis', 'biological_process', 'GO:0008610', ('242', '253'))	('modification', 'Var', (20, 32))	('promoting', 'PosReg', (228, 237))	('HCC', 'Gene', (238, 241))	('stabilizing', 'MPA', (76, 87))	('expression', 'MPA', (49, 59))	('RNA transcript', 'MPA', (92, 106))	('hepatocarcinoma-derived growth factor', 'Gene', (134, 171))	('upregulated', 'PosReg', (122, 133))	('LINC00958', 'Gene', '100506305', (63, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('RNA', 'cellular_component', 'GO:0005562', ('92', '95'))	('upregulated', 'PosReg', (33, 44))	('hepatocarcinoma-derived growth factor', 'Gene', '3068', (134, 171))	('LINC00958', 'Gene', (63, 72))	('expression', 'MPA', (179, 189))	('HDGF', 'Gene', (173, 177))	('HDGF', 'Gene', '3068', (173, 177))	('progression', 'CPA', (258, 269))	('miR-3619', 'Gene', '100500828', (207, 215))	('miR-3619', 'Gene', (207, 215))
212174	32398132	KIAA1429 induced methylation of the 3' UTR of GATA binding protein 3 (GATA3) pre-mRNA, resulting in isolation of the RBP HUR and degradation of GATA3 pre-mRNA.	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('GATA3', 'Gene', (144, 149))	('pre', 'molecular_function', 'GO:0003904', ('77', '80'))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))	('GATA3', 'Gene', '2625', (70, 75))	('isolation', 'MPA', (100, 109))	('GATA3', 'Gene', (70, 75))	('degradation', 'biological_process', 'GO:0009056', ('129', '140'))	('binding', 'molecular_function', 'GO:0005488', ('51', '58'))	('HUR', 'Gene', '1994', (121, 124))	('KIAA1429', 'Gene', (0, 8))	('HUR', 'Gene', (121, 124))	('degradation', 'MPA', (129, 140))	('GATA binding protein 3', 'Gene', '2625', (46, 68))	('KIAA1429', 'Gene', '25962', (0, 8))	('methylation', 'Var', (17, 28))	('GATA binding protein 3', 'Gene', (46, 68))	('pre', 'molecular_function', 'GO:0003904', ('150', '153'))	('GATA3', 'Gene', '2625', (144, 149))
212183	32398132	Database mining showed that FTO could regulate integrin signaling, inflammation signaling, epidermal growth factor receptor (EGFR) signaling, angiogenesis, and pyrimidine metabolism pathways.	('pyrimidine metabolism', 'biological_process', 'GO:0006213', ('160', '181'))	('pyrimidine metabolism', 'biological_process', 'GO:0006206', ('160', '181'))	('regulate', 'Reg', (38, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('125', '129'))	('FTO', 'Var', (28, 31))	('EGFR', 'Gene', '1956', (125, 129))	('inflammation', 'Disease', 'MESH:D007249', (67, 79))	('signaling', 'biological_process', 'GO:0023052', ('80', '89'))	('angiogenesis', 'CPA', (142, 154))	('epidermal growth factor receptor', 'Gene', (91, 123))	('epidermal growth factor receptor', 'Gene', '1956', (91, 123))	('integrin signaling', 'Pathway', (47, 65))	('angiogenesis', 'biological_process', 'GO:0001525', ('142', '154'))	('pyrimidine metabolism pathways', 'Pathway', (160, 190))	('inflammation', 'Disease', (67, 79))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('pyrimidine', 'Chemical', 'MESH:C030986', (160, 170))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('91', '114'))	('inflammation', 'biological_process', 'GO:0006954', ('67', '79'))	('EGFR', 'Gene', (125, 129))	('pyrimidine metabolism', 'biological_process', 'GO:0006220', ('160', '181'))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))
212189	32398132	Additionally, FTO was found to promote melanoma growth, while knockout of FTO increased m6A methylation of important genes in malignant melanoma cells, including PD-1, C-X-C motif chemokine receptor 4 (CXCR4), and SRY-Box transcription factor 10 (SOX10), and increased the RNA decay through YTHDF2, which further increased the sensitivity of mouse melanoma cells to interferon gamma (IFNgamma) and anti-PD-1 treatment.	('melanoma growth', 'Disease', (39, 54))	('RNA', 'cellular_component', 'GO:0005562', ('273', '276'))	('increased', 'PosReg', (259, 268))	('m6A', 'Gene', (88, 91))	('PD-1', 'Gene', (162, 166))	('RNA decay', 'MPA', (273, 282))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Disease', (136, 144))	('methylation', 'MPA', (92, 103))	('interferon gamma', 'molecular_function', 'GO:0005133', ('366', '382'))	('melanoma', 'Phenotype', 'HP:0002861', (348, 356))	('melanoma', 'Disease', (348, 356))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('FTO', 'Gene', (74, 77))	('melanoma', 'Disease', (39, 47))	('men', 'Species', '9606', (413, 416))	('methylation', 'biological_process', 'GO:0032259', ('92', '103'))	('promote', 'PosReg', (31, 38))	('malignant melanoma', 'Phenotype', 'HP:0002861', (126, 144))	('C-X-C motif chemokine receptor 4', 'Gene', (168, 200))	('SOX10', 'Gene', '20665', (247, 252))	('melanoma growth', 'Disease', 'MESH:D008545', (39, 54))	('transcription factor', 'molecular_function', 'GO:0000981', ('222', '242'))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('CXCR4', 'Gene', '12767', (202, 207))	('SOX10', 'Gene', (247, 252))	('PD-1', 'Gene', '18566', (403, 407))	('transcription', 'biological_process', 'GO:0006351', ('222', '235'))	('CXCR4', 'Gene', (202, 207))	('C-X-C motif chemokine receptor 4', 'Gene', '12767', (168, 200))	('CXCR4', 'molecular_function', 'GO:0038147', ('202', '207'))	('melanoma', 'Disease', 'MESH:D008545', (348, 356))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('PD-1', 'Gene', '18566', (162, 166))	('increased', 'PosReg', (78, 87))	('knockout', 'Var', (62, 70))	('mouse', 'Species', '10090', (342, 347))	('PD-1', 'Gene', (403, 407))
212192	32398132	In ocular melanoma, YTHDF1 was shown to promote the translation of methylated mRNA of the tumor suppressor HINT2 and inhibit tumor development.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor suppressor', 'biological_process', 'GO:0051726', ('90', '106'))	('men', 'Species', '9606', (138, 141))	('translation', 'MPA', (52, 63))	('promote', 'PosReg', (40, 47))	('ocular melanoma', 'Phenotype', 'HP:0007716', (3, 18))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (90, 95))	('HINT2', 'Gene', (107, 112))	('inhibit', 'NegReg', (117, 124))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('ocular melanoma', 'Disease', 'MESH:D008545', (3, 18))	('translation', 'biological_process', 'GO:0006412', ('52', '63'))	('HINT2', 'Gene', '84681', (107, 112))	('methylated', 'Var', (67, 77))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('90', '106'))	('tumor', 'Disease', (125, 130))	('YTHDF1', 'Gene', (20, 26))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('ocular melanoma', 'Disease', (3, 18))
212198	32398132	METTL3 downregulation was found to activate p-p38 and p-ERK in CRC; however, p38 or ERK kinase inhibitors significantly reversed the cell migration and invasion induced by METTL3 knockout.	('cell migration', 'CPA', (133, 147))	('ERK', 'Gene', (84, 87))	('downregulation', 'NegReg', (7, 21))	('METTL3', 'Gene', (0, 6))	('knockout', 'Var', (179, 187))	('p38', 'Gene', '5594', (46, 49))	('p38', 'Gene', '5594', (77, 80))	('METTL3', 'Gene', (172, 178))	('activate', 'PosReg', (35, 43))	('ERK', 'molecular_function', 'GO:0004707', ('84', '87'))	('ERK', 'Gene', '5594', (56, 59))	('cell migration', 'biological_process', 'GO:0016477', ('133', '147'))	('invasion', 'CPA', (152, 160))	('CRC', 'Disease', (63, 66))	('ERK', 'Gene', '5594', (84, 87))	('ERK', 'Gene', (56, 59))	('reversed', 'NegReg', (120, 128))	('p38', 'Gene', (46, 49))	('p38', 'Gene', (77, 80))	('ERK', 'molecular_function', 'GO:0004707', ('56', '59'))
212202	32398132	METTL3 can methylate pri-miR-1246 in CRC cells, thus further promoting the maturation of pri-miR-1246, whereas the tumor suppressor gene sprouty related EVH1 domain containing 2 (SPRED2) is a downstream target of miR-1246.	('sprouty related EVH1 domain containing 2', 'Gene', (137, 177))	('tumor', 'Disease', (115, 120))	('METTL3', 'Gene', (0, 6))	('promoting', 'PosReg', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('115', '131'))	('miR-1246', 'Gene', '100302142', (213, 221))	('miR-1246', 'Gene', (25, 33))	('sprouty related EVH1 domain containing 2', 'Gene', '200734', (137, 177))	('miR-1246', 'Gene', '100302142', (93, 101))	('methylate', 'Var', (11, 20))	('tumor suppressor', 'biological_process', 'GO:0051726', ('115', '131'))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('maturation', 'MPA', (75, 85))	('SPRED2', 'Gene', '200734', (179, 185))	('miR-1246', 'Gene', '100302142', (25, 33))	('SPRED2', 'Gene', (179, 185))	('miR-1246', 'Gene', (213, 221))	('miR-1246', 'Gene', (93, 101))
212203	32398132	Downregulation of SPRED2 further reversed the inhibitory effect on the MAPK pathway.	('Downregulation', 'Var', (0, 14))	('MAPK', 'molecular_function', 'GO:0004707', ('71', '75'))	('SPRED2', 'Gene', '200734', (18, 24))	('MAPK pathway', 'Pathway', (71, 83))	('SPRED2', 'Gene', (18, 24))
212207	32398132	In addition, silencing YTHDF1 significantly inhibited the activity of the WNT/beta-catenin pathway in CRC cells.	('activity', 'MPA', (58, 66))	('inhibited', 'NegReg', (44, 53))	('YTHDF1', 'Gene', (23, 29))	('beta-catenin', 'Gene', (78, 90))	('beta-catenin', 'Gene', '1499', (78, 90))	('silencing', 'Var', (13, 22))
212219	32398132	METTL3 was found to be upregulated in breast cancer tissues and cells, where it promoted m6A modification of the 3' UTR of B-cell/lymphoma 2 (BCL-2) mRNA.	('promoted', 'PosReg', (80, 88))	('upregulated', 'PosReg', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('BCL-2', 'Gene', '596', (142, 147))	('breast cancer', 'Disease', (38, 51))	('B-cell/lymphoma 2', 'Gene', '596', (123, 140))	('METTL3', 'Gene', (0, 6))	('B-cell/lymphoma 2', 'Gene', (123, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('lymphoma', 'Phenotype', 'HP:0002665', (130, 138))	('BCL-2', 'Gene', (142, 147))	('m6A', 'Var', (89, 92))	('BCL-2', 'molecular_function', 'GO:0015283', ('142', '147'))
212223	32398132	FTO mediates m6A demethylation in the 3' UTR of BNIP3 mRNA and induces its degradation via a YTHDF2-dependent mechanism.	('degradation', 'biological_process', 'GO:0009056', ('75', '86'))	('demethylation', 'biological_process', 'GO:0070988', ('17', '30'))	('BNIP3', 'Gene', (48, 53))	('degradation', 'MPA', (75, 86))	('m6A', 'Var', (13, 16))	('demethylation', 'MPA', (17, 30))	('BNIP3', 'Gene', '664', (48, 53))
212226	32398132	found that alterations in m6A-regulating factors in clear cell renal cell carcinoma (ccRCC) led to a significant association between the level of m6A and the worsening of clinical parameters, including survival.	('clear cell renal cell carcinoma', 'Disease', (52, 83))	('alterations', 'Var', (11, 22))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (63, 83))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (52, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('m6A', 'MPA', (146, 149))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (52, 83))
212233	32398132	A study of the TCGA database found that a low m6A signal predicted poor clinicopathological features of GC, while a decrease in m6A RNA methylation activated the carcinogenic WNT/PI3K-AKT signaling pathway and promoted the development of GC.	('AKT signaling', 'biological_process', 'GO:0043491', ('184', '197'))	('men', 'Species', '9606', (230, 233))	('m6A', 'Var', (128, 131))	('m6A signal', 'MPA', (46, 56))	('carcinogenic WNT', 'Disease', (162, 178))	('signaling pathway', 'biological_process', 'GO:0007165', ('188', '205'))	('AKT', 'Gene', '207', (184, 187))	('development', 'CPA', (223, 234))	('decrease', 'NegReg', (116, 124))	('PI3K', 'molecular_function', 'GO:0016303', ('179', '183'))	('promoted', 'PosReg', (210, 218))	('AKT', 'Gene', (184, 187))	('RNA methylation', 'biological_process', 'GO:0001510', ('132', '147'))	('low', 'NegReg', (42, 45))	('carcinogenic WNT', 'Disease', 'MESH:D063646', (162, 178))	('activated', 'PosReg', (148, 157))	('RNA', 'cellular_component', 'GO:0005562', ('132', '135'))
212234	32398132	m6A modification of zinc finger MYM-Type containing 1 (ZMYM1) mRNA by METTL3 relies on a HUR-dependent pathway to enhance its stability.	('stability', 'MPA', (126, 135))	('ZMYM1', 'Gene', (55, 60))	('HUR', 'Gene', (89, 92))	('ZMYM1', 'Gene', '79830', (55, 60))	('zinc finger MYM-Type containing 1', 'Gene', (20, 53))	('METTL3', 'Gene', (70, 76))	('modification', 'Var', (4, 16))	('zinc finger MYM-Type containing 1', 'Gene', '79830', (20, 53))	('enhance', 'PosReg', (114, 121))	('HUR', 'Gene', '1994', (89, 92))
212243	32398132	Deletion of METTL3 in a human myeloid leukemia cell line was shown to induce the differentiation and apoptosis of cells in recipient mice and delay the occurrence of leukemia.	('mice', 'Species', '10090', (133, 137))	('apoptosis', 'biological_process', 'GO:0097194', ('101', '110'))	('leukemia', 'Phenotype', 'HP:0001909', (166, 174))	('apoptosis', 'biological_process', 'GO:0006915', ('101', '110'))	('apoptosis', 'CPA', (101, 110))	('myeloid leukemia', 'Disease', (30, 46))	('human', 'Species', '9606', (24, 29))	('leukemia', 'Phenotype', 'HP:0001909', (38, 46))	('leukemia', 'Disease', 'MESH:D007938', (166, 174))	('differentiation', 'CPA', (81, 96))	('leukemia', 'Disease', (166, 174))	('Deletion', 'Var', (0, 8))	('METTL3', 'Gene', (12, 18))	('myeloid leukemia', 'Disease', 'MESH:D007951', (30, 46))	('leukemia', 'Disease', 'MESH:D007938', (38, 46))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (30, 46))	('leukemia', 'Disease', (38, 46))	('induce', 'PosReg', (70, 76))	('delay', 'NegReg', (142, 147))
212244	32398132	In addition, m6A was shown to promote the translation of c-MYC, BCL2, and PTEN mRNA in human myeloid leukemia cells.	('c-MYC', 'Gene', '4609', (57, 62))	('promote', 'PosReg', (30, 37))	('BCL2', 'molecular_function', 'GO:0015283', ('64', '68'))	('human', 'Species', '9606', (87, 92))	('myeloid leukemia', 'Disease', (93, 109))	('translation', 'biological_process', 'GO:0006412', ('42', '53'))	('PTEN', 'Gene', (74, 78))	('BCL2', 'Gene', '596', (64, 68))	('m6A', 'Var', (13, 16))	('PTEN', 'Gene', '5728', (74, 78))	('c-MYC', 'Gene', (57, 62))	('myeloid leukemia', 'Disease', 'MESH:D007951', (93, 109))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('translation', 'MPA', (42, 53))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (93, 109))	('BCL2', 'Gene', (64, 68))
212250	32398132	Additionally, METTL14 was found to be highly expressed in normal hematopoietic stem/progenitor cells (HSPCs) and AML cells carrying t (11q23), t (15;17), or t (8;21) translocations.	('t (8;21) translocations', 'Var', (157, 180))	('t (11q23', 'Var', (132, 140))	('t (15;17', 'Var', (143, 151))	('METTL14', 'Gene', '57721', (14, 21))	('AML', 'Disease', 'MESH:D015470', (113, 116))	('METTL14', 'Gene', (14, 21))	('AML', 'Disease', (113, 116))
212252	32398132	Silencing of METTL14 promoted myeloid terminal differentiation of normal HSPCs and AML cells and inhibited the survival and proliferation of AML cells.	('AML', 'Disease', (141, 144))	('AML', 'Disease', (83, 86))	('METTL14', 'Gene', (13, 20))	('METTL14', 'Gene', '57721', (13, 20))	('promoted', 'PosReg', (21, 29))	('myeloid terminal differentiation', 'CPA', (30, 62))	('terminal differentiation', 'biological_process', 'GO:0048468', ('38', '62'))	('inhibited', 'NegReg', (97, 106))	('AML', 'Disease', 'MESH:D015470', (141, 144))	('AML', 'Disease', 'MESH:D015470', (83, 86))	('Silencing', 'Var', (0, 9))
212256	32398132	FTO was found to be upregulated in AML with t (11q23)/MLL rearrangements or t (15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations.	('MLL', 'Gene', '4297', (54, 57))	('AML', 'Disease', (35, 38))	('rearrangements', 'Var', (58, 72))	('NPM1', 'Gene', (113, 117))	('mutations', 'Var', (118, 127))	('RARA', 'Gene', '5914', (90, 94))	('men', 'Species', '9606', (67, 70))	('PML', 'Gene', '5371', (86, 89))	('upregulated', 'PosReg', (20, 31))	('NPM1', 'Gene', '4869', (113, 117))	('FLT3', 'Gene', '2322', (96, 100))	('FTO', 'Gene', (0, 3))	('RARA', 'Gene', (90, 94))	('AML', 'Disease', 'MESH:D015470', (35, 38))	('PML', 'Gene', (86, 89))	('MLL', 'Gene', (54, 57))	('FLT3', 'Gene', (96, 100))
212259	32398132	Regarding the biological mechanism, R-2HG was shown to inhibit FTO activity, thus increasing the m6A mRNA modification in R-2HG-sensitive leukemia cells, reducing the stability of MYC/CEBPA transcripts, and inhibiting the related pathways.	('pathways', 'Pathway', (230, 238))	('CEBPA', 'Gene', '1050', (184, 189))	('reducing', 'NegReg', (154, 162))	('inhibit', 'NegReg', (55, 62))	('MYC', 'Gene', '4609', (180, 183))	('CEBPA', 'Gene', (184, 189))	('FTO', 'Enzyme', (63, 66))	('m6A mRNA modification', 'MPA', (97, 118))	('R-2HG', 'Chemical', '-', (122, 127))	('R-2HG', 'Chemical', '-', (36, 41))	('stability', 'MPA', (167, 176))	('leukemia', 'Phenotype', 'HP:0001909', (138, 146))	('mRNA modification', 'biological_process', 'GO:0016556', ('101', '118'))	('R-2HG', 'Var', (36, 41))	('inhibiting', 'NegReg', (207, 217))	('increasing', 'PosReg', (82, 92))	('leukemia', 'Disease', (138, 146))	('MYC', 'Gene', (180, 183))	('leukemia', 'Disease', 'MESH:D007938', (138, 146))
212260	32398132	In conclusion, R-2HG can inhibit the proliferation/survival of cancer cells with high FTO expression levels by targeting the FTO/m6A/MYC/CEBPA signaling cascade.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('proliferation/survival', 'CPA', (37, 59))	('MYC', 'Gene', '4609', (133, 136))	('signaling cascade', 'biological_process', 'GO:0007165', ('143', '160'))	('R-2HG', 'Var', (15, 20))	('R-2HG', 'Chemical', '-', (15, 20))	('CEBPA', 'Gene', (137, 142))	('targeting', 'Reg', (111, 120))	('inhibit', 'NegReg', (25, 32))	('MYC', 'Gene', (133, 136))	('FTO', 'Gene', (86, 89))	('CEBPA', 'Gene', '1050', (137, 142))	('cancer', 'Disease', (63, 69))
212261	32398132	Finally, overexpression of YTHDF2 in AML reduced the half-life of various m6A transcripts, including those of TNF receptor superfamily member 2 (TNFRSF2), which contributes to the overall function of leukemic stem cells (LSCs).	('reduced', 'NegReg', (41, 48))	('TNFRSF2', 'Gene', (145, 152))	('overexpression', 'PosReg', (9, 23))	('m6A', 'Protein', (74, 77))	('YTHDF2', 'Var', (27, 33))	('AML', 'Disease', 'MESH:D015470', (37, 40))	('contributes', 'Reg', (161, 172))	('AML', 'Disease', (37, 40))	('half-life', 'MPA', (53, 62))	('leukemic', 'Disease', (200, 208))
212264	32398132	Further mechanistic analysis showed that silencing METTL3 decreased the mRNA level of lymphoid enhancer-binding factor 1 (LEF1) and then inhibited the activity of the WNT/beta-catenin signaling pathway.	('enhancer-binding', 'molecular_function', 'GO:0035326', ('95', '111'))	('beta-catenin', 'Gene', '1499', (171, 183))	('silencing', 'Var', (41, 50))	('inhibited', 'NegReg', (137, 146))	('mRNA level of', 'MPA', (72, 85))	('LEF1', 'Gene', '51176', (122, 126))	('decreased', 'NegReg', (58, 67))	('lymphoid enhancer-binding factor 1', 'Gene', '51176', (86, 120))	('activity', 'MPA', (151, 159))	('LEF1', 'Gene', (122, 126))	('METTL3', 'Gene', (51, 57))	('beta-catenin', 'Gene', (171, 183))	('lymphoid enhancer-binding factor 1', 'Gene', (86, 120))	('signaling pathway', 'biological_process', 'GO:0007165', ('184', '201'))
212269	32398132	In addition, m6A methylation and its related regulatory factors can affect the processing of miRNAs and the biological function of lncRNAs and can even promote the translation of circRNAs.	('biological', 'MPA', (108, 118))	('methylation', 'Var', (17, 28))	('translation', 'MPA', (164, 175))	('affect', 'Reg', (68, 74))	('m6A methylation', 'Var', (13, 28))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('miR', 'Gene', '220972', (93, 96))	('miR', 'Gene', (93, 96))	('promote', 'PosReg', (152, 159))	('translation', 'biological_process', 'GO:0006412', ('164', '175'))
212271	32398132	Interestingly, m6A seems to act as a double-edgedsword in cancer.	('cancer', 'Disease', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('m6A', 'Var', (15, 18))
212272	32398132	Some genes can promote tumor development after methylation, while others, after removal of methylation, can promote tumor development.	('promote', 'PosReg', (15, 22))	('methylation', 'Var', (47, 58))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('men', 'Species', '9606', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('men', 'Species', '9606', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))	('promote', 'PosReg', (108, 115))	('methylation', 'biological_process', 'GO:0032259', ('47', '58'))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (116, 121))
212277	32398132	Collectively, these findings indicate that complex regulatory networks of m6A methylation are active in different cancers, awaiting further exploration.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('methylation', 'Var', (78, 89))	('cancers', 'Disease', (114, 121))	('m6A', 'Gene', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('methylation', 'biological_process', 'GO:0032259', ('78', '89'))	('active', 'Reg', (94, 100))
212288	29423033	High expression of ST6GalNAc-1 in tumor tissue was an independent prognostic factor for overall survival (p<0.001) and recurrence free survival (p<0.001) in multivariate analysis.	('tumor', 'Disease', (34, 39))	('High', 'Var', (0, 4))	('recurrence free survival', 'CPA', (119, 143))	('overall survival', 'CPA', (88, 104))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('ST6GalNAc-1', 'Gene', (19, 30))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
212294	29423033	ST6GalNAc-1 was an independent adverse prognostic factor for both overall survival and recurrence free survival in patients with non-metastatic ccRCC.	('patients', 'Species', '9606', (115, 123))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('ST6GalNAc-1', 'Var', (0, 11))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))
212305	29423033	Thus, we speculated that ST6GalNAc-1 might be a potential prognosticator in ccRCC.	('ST6GalNAc-1', 'Var', (25, 36))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))
212310	29423033	The survival curves showed that patients with high ST6GalNAc-1 expression tend to have significantly dismal outcome for overall survival (OS) (p<0.001, Figure 2A) and recurrence free survival (RFS) (p<0.001, Figure 2B) than those with low ST6GalNAc-1 expression patients.	('patients', 'Species', '9606', (32, 40))	('high ST6GalNAc-1', 'Var', (46, 62))	('recurrence free survival', 'CPA', (167, 191))	('overall survival', 'CPA', (120, 136))	('patients', 'Species', '9606', (262, 270))
212316	29423033	The results revealed the dismal role of ST6GalNAc-1 and its impact on patients with ccRCC by survival analyses.	('patients', 'Species', '9606', (70, 78))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('ST6GalNAc-1', 'Var', (40, 51))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))
212318	29423033	Then, we found ST6GalNAc-1 could further stratify patients' clinical outcome in Fuhrman grade (1+2) subgroup.	('stratify', 'Reg', (41, 49))	('ST6GalNAc-1', 'Var', (15, 26))	('patients', 'Species', '9606', (50, 58))
212319	29423033	The nomograms which integrated ST6GalNAc-1 with other prognostic parameters could serve as better prediction model for OS and RFS in ccRCC patients.	('ST6GalNAc-1', 'Var', (31, 42))	('patients', 'Species', '9606', (139, 147))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))
212320	29423033	The most-widely occurring cancer-associated changes in glycosylation are sialylation, fucosylation, O-glyan truncation, and N- and O-linked glycan branching.	('changes', 'Reg', (44, 51))	('N- and O-linked glycan', 'Chemical', '-', (124, 146))	('sialylation', 'MPA', (73, 84))	('fucosylation', 'biological_process', 'GO:0036065', ('86', '98'))	('sialylation', 'biological_process', 'GO:0097503', ('73', '84'))	('glycosylation', 'biological_process', 'GO:0070085', ('55', '68'))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('glycosylation', 'MPA', (55, 68))	('O-glyan', 'Var', (100, 107))	('fucosylation', 'Disease', (86, 98))
212324	29423033	It is now well established that altered sialyltransferase activation contributes to the aberrant sialylation of glycan and expression of specific tumor-associated carbohydrates.	('sialylation of glycan', 'MPA', (97, 118))	('expression', 'MPA', (123, 133))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('altered', 'Var', (32, 39))	('sialylation', 'biological_process', 'GO:0097503', ('97', '108'))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('sialyltransferase', 'Enzyme', (40, 57))	('activation', 'PosReg', (58, 68))	('glycan', 'Chemical', 'MESH:D011134', (112, 118))	('carbohydrates', 'Chemical', 'MESH:D002241', (163, 176))
212326	29423033	Hidenori Ozaki elucidated the roles of ST6GalNAc-1 by in vivo monitoring system in gastric cancer metastasis.	('gastric cancer metastasis', 'Disease', (83, 108))	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('gastric cancer metastasis', 'Disease', 'MESH:D009362', (83, 108))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ST6GalNAc-1', 'Var', (39, 50))
212327	29423033	Tamura, F showed overexpression of ST6GalNAc-1 is associated with enhanced cell growth, infiltration, and migratory of MKN74 cells, and in peritoneal dissemination model, mice had longer survival time when treated with ST6GalNAc-1 siRNA, which suggesting ST6GalNAc-1 as a potential target for treatment of malignant disease.	('malignant disease', 'Disease', (306, 323))	('mice', 'Species', '10090', (171, 175))	('ST6GalNAc-1', 'Var', (35, 46))	('infiltration', 'CPA', (88, 100))	('cell growth', 'CPA', (75, 86))	('enhanced', 'PosReg', (66, 74))	('migratory', 'CPA', (106, 115))	('overexpression', 'PosReg', (17, 31))	('longer', 'PosReg', (180, 186))	('malignant disease', 'Disease', 'MESH:D009369', (306, 323))	('cell growth', 'biological_process', 'GO:0016049', ('75', '86'))	('ST6GalNAc-1', 'Var', (219, 230))	('survival time', 'CPA', (187, 200))
212328	29423033	The researches indicated ST6GalNAc-1 might be involved in tumor development including proliferation, migration, and invasion ability.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('invasion ability', 'CPA', (116, 132))	('ST6GalNAc-1', 'Var', (25, 36))	('migration', 'CPA', (101, 110))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('involved', 'Reg', (46, 54))
212332	29423033	Meantime, aberrant sTn is commonly detected in a variety of carcinomas including colorectal, gastric, ovarian, breast carcinomas, but rarely detected in normal tissue.	('ovarian', 'Disease', 'MESH:D010051', (102, 109))	('aberrant', 'Var', (10, 18))	('colorectal', 'Disease', (81, 91))	('carcinomas', 'Disease', (118, 128))	('detected', 'Reg', (35, 43))	('breast carcinomas', 'Disease', 'MESH:D001943', (111, 128))	('breast carcinomas', 'Disease', (111, 128))	('carcinomas', 'Disease', (60, 70))	('sTn', 'Gene', '1917', (19, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('sTn', 'Gene', (19, 22))	('carcinomas', 'Disease', 'MESH:D002277', (118, 128))	('breast carcinomas', 'Phenotype', 'HP:0003002', (111, 128))	('gastric', 'Disease', (93, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('carcinomas', 'Disease', 'MESH:D002277', (60, 70))	('ovarian', 'Disease', (102, 109))
212333	29423033	S Julien found an increased tumorigenicity after transplantation of ST6GalNAc-1 transfected sTn-positive human breast cell line in to mice.	('increased', 'PosReg', (18, 27))	('mice', 'Species', '10090', (134, 138))	('tumor', 'Disease', (28, 33))	('sTn', 'Gene', '1917', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('human', 'Species', '9606', (105, 110))	('ST6GalNAc-1', 'Var', (68, 79))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('sTn', 'Gene', (92, 95))
212335	29423033	Generally speaking, it may be difficult to fully explain ST6GalNAc-1's pro-tumor effects solely by the regulation of sTn synthesis.	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('sTn', 'Gene', (117, 120))	('synthesis', 'biological_process', 'GO:0009058', ('121', '130'))	('ST6GalNAc-1', 'Var', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('sTn', 'Gene', '1917', (117, 120))	('regulation', 'biological_process', 'GO:0065007', ('103', '113'))
212337	29423033	Inhibition of ST6GaLNAc-1 could suppress STAT5b phosphorylation and then as result decreased IGF-1 expression, and then stimulate the dissemination of malignant cells.	('expression', 'MPA', (99, 109))	('ST6GaLNAc-1', 'Gene', (14, 25))	('stimulate', 'PosReg', (120, 129))	('suppress', 'NegReg', (32, 40))	('decreased', 'NegReg', (83, 92))	('decreased IGF', 'Phenotype', 'HP:0002850', (83, 96))	('STAT5b', 'Gene', (41, 47))	('dissemination of malignant cells', 'CPA', (134, 166))	('Inhibition', 'Var', (0, 10))	('ST6GaLNAc-1', 'Gene', '55808', (14, 25))	('IGF-1', 'Gene', (93, 98))	('IGF-1', 'Gene', '3479', (93, 98))	('phosphorylation', 'biological_process', 'GO:0016310', ('48', '63'))	('STAT5b', 'Gene', '6777', (41, 47))
212338	29423033	In addition, Kim et al suggests the possibility that sialylation by ST6GalNAc-1 may affect sialic acid residues on gangliosides which is essential for the activation of JAK-STAT signaling.	('gangliosides', 'Chemical', 'MESH:D005732', (115, 127))	('gangliosides', 'Protein', (115, 127))	('JAK', 'molecular_function', 'GO:0004713', ('169', '172'))	('sialic acid', 'Chemical', 'MESH:D019158', (91, 102))	('affect', 'Reg', (84, 90))	('sialylation', 'MPA', (53, 64))	('sialic acid residues on', 'MPA', (91, 114))	('sialylation', 'biological_process', 'GO:0097503', ('53', '64'))	('ST6GalNAc-1', 'Var', (68, 79))	('signaling', 'biological_process', 'GO:0023052', ('178', '187'))
212341	29423033	In conclusion, we have revealed that ST6GalNAc-1 expression is an independent prognostic factor in non-metastatic ccRCC by survival analyses.	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('ST6GalNAc-1', 'Var', (37, 48))	('RCC', 'Disease', (116, 119))
212342	29423033	Patients with higher ST6GalNAc-1 expression are more likely to suffer unfavorable clinical outcome than the counterparts.	('ST6GalNAc-1', 'Var', (21, 32))	('unfavorable clinical outcome', 'MPA', (70, 98))	('Patients', 'Species', '9606', (0, 8))	('expression', 'MPA', (33, 43))	('suffer', 'Reg', (63, 69))
212343	29423033	Therefore, we have reason to believe that ST6GalNAc-1 might play a pivotal role in ccRCC progression.	('ST6GalNAc-1', 'Var', (42, 53))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', (85, 88))
212373	28986523	In one Japanese population, the mitochondrial haplogroups A confers a significant risk for coronary atherosclerosis which is a kind of age-related disease.	('coronary atherosclerosis', 'Disease', 'MESH:D003324', (91, 115))	('atherosclerosis', 'Phenotype', 'HP:0002621', (100, 115))	('mitochondrial', 'Var', (32, 45))	('coronary atherosclerosis', 'Phenotype', 'HP:0001677', (91, 115))	('coronary atherosclerosis', 'Disease', (91, 115))
212376	28986523	We observed that the Spearman correlation coefficient can detect the most number of significant genes (11629 genes, alpha = 2.435e-06, in Table 3) in real kidney cancer RNA-seq data.	('RNA', 'cellular_component', 'GO:0005562', ('169', '172'))	('kidney cancer', 'Phenotype', 'HP:0009726', (155, 168))	('kidney cancer', 'Disease', 'MESH:D007680', (155, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('kidney cancer', 'Disease', (155, 168))	('11629', 'Var', (103, 108))
212380	28986523	And high CDCP1 expression has been correlated with poor prognosis in renal cancer.	('renal cancer', 'Disease', (69, 81))	('renal cancer', 'Disease', 'MESH:D007680', (69, 81))	('expression', 'MPA', (15, 25))	('high', 'Var', (4, 8))	('renal cancer', 'Phenotype', 'HP:0009726', (69, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('CDCP1', 'Gene', '64866', (9, 14))	('CDCP1', 'Gene', (9, 14))
212381	28986523	Emerging evidences suggest that the GSTT1 gene is involved in the detoxification of carcinogens, and the polymorphisms in this gene that result in a loss of enzyme activity may increase the risk of renal cell carcinoma (RCC).	('activity', 'MPA', (164, 172))	('GSTT1', 'Gene', (36, 41))	('renal cell carcinoma', 'Disease', (198, 218))	('loss', 'NegReg', (149, 153))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (198, 218))	('GSTT1', 'Gene', '2952', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('increase', 'PosReg', (177, 185))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('enzyme activity', 'molecular_function', 'GO:0003824', ('157', '172'))	('detoxification', 'biological_process', 'GO:0098754', ('66', '80'))	('RCC', 'Phenotype', 'HP:0005584', (220, 223))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (198, 218))	('involved', 'Reg', (50, 58))	('polymorphisms', 'Var', (105, 118))	('RCC', 'Disease', (220, 223))
212384	28986523	The rs743409 variant in MAPK1 is a variation in the microRNA (miRNA) binding site of the gene in the VHL-HIF1 alpha pathway, which was reported to be significantly associated with renal cell carcinoma.	('MAPK', 'molecular_function', 'GO:0004707', ('24', '28'))	('rs743409', 'Var', (4, 12))	('renal cell carcinoma', 'Disease', (180, 200))	('rs743409', 'Mutation', 'rs743409', (4, 12))	('associated', 'Reg', (164, 174))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (180, 200))	('MAPK1', 'Gene', (24, 29))	('miRNA) binding', 'molecular_function', 'GO:0035198', ('62', '76'))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (180, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('HIF1 alpha pathway', 'biological_process', 'GO:0097411', ('105', '123'))	('HIF1 alpha', 'Gene', '3091', (105, 115))	('MAPK1', 'Gene', '5594', (24, 29))	('HIF1 alpha', 'Gene', (105, 115))
212391	28986523	MIR17HG plays an important role in renal development, especially in the regulation of nephron development, its mutation may affect the renal function.	('nephron development', 'biological_process', 'GO:0072006', ('86', '105'))	('renal', 'MPA', (135, 140))	('affect', 'Reg', (124, 130))	('MIR17HG', 'Gene', '407975', (0, 7))	('mutation', 'Var', (111, 119))	('MIR17HG', 'Gene', (0, 7))	('regulation', 'biological_process', 'GO:0065007', ('72', '82'))
212393	28986523	Knockout of APOE causes hypercholesterolemia, which in turn leads to chronic kidney disease.	('kidney disease', 'Phenotype', 'HP:0000112', (77, 91))	('hypercholesterolemia', 'Disease', 'MESH:D006937', (24, 44))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (69, 91))	('APOE', 'Gene', (12, 16))	('causes', 'Reg', (17, 23))	('APOE', 'Gene', '348', (12, 16))	('chronic kidney disease', 'Disease', 'MESH:D051436', (69, 91))	('Knockout', 'Var', (0, 8))	('leads to', 'Reg', (60, 68))	('chronic kidney disease', 'Disease', (69, 91))	('hypercholesterolemia', 'Disease', (24, 44))	('hypercholesterolemia', 'Phenotype', 'HP:0003124', (24, 44))
212394	28986523	Mutations in BMP4 are associated with renal abnormalities.	('renal abnormalities', 'Disease', (38, 57))	('renal abnormalities', 'Disease', 'MESH:D007674', (38, 57))	('BMP4', 'Gene', (13, 17))	('renal abnormalities', 'Phenotype', 'HP:0000077', (38, 57))	('Mutations', 'Var', (0, 9))	('BMP4', 'Gene', '652', (13, 17))	('associated', 'Reg', (22, 32))
212411	28986523	In an autopsy study of 1,536 patients in Japanese elderly, haplogroups A and M7a were significantly associated with coronary atherosclerosis, with odds ratios (95% confidence intervals) of 1.80 (1.09-2.97; p = 0.023) and 1.92 (1.23-3.01; p = 0.004) respectively.	('coronary atherosclerosis', 'Disease', (116, 140))	('patients', 'Species', '9606', (29, 37))	('coronary atherosclerosis', 'Phenotype', 'HP:0001677', (116, 140))	('associated with', 'Reg', (100, 115))	('atherosclerosis', 'Phenotype', 'HP:0002621', (125, 140))	('coronary atherosclerosis', 'Disease', 'MESH:D003324', (116, 140))	('haplogroups A', 'Var', (59, 72))	('M7a', 'Var', (77, 80))
212417	28986523	The SNP rs743409 in MAPK1 is a variant of miRNA binding site single nucleotide polymorphisms (SNPs).	('SNP', 'Var', (4, 7))	('miRNA binding', 'molecular_function', 'GO:0035198', ('42', '55'))	('MAPK', 'molecular_function', 'GO:0004707', ('20', '24'))	('MAPK1', 'Gene', (20, 25))	('rs743409', 'Var', (8, 16))	('rs743409', 'Mutation', 'rs743409', (8, 16))	('MAPK1', 'Gene', '5594', (20, 25))
212418	28986523	Under the additive model, the variants were reduced with a 10% risk, indicating that there is a correlation between the miRNA binding site SNP and the RCC risk in the VHL-HIF1 alpha pathway.	('variants', 'Var', (30, 38))	('HIF1 alpha pathway', 'biological_process', 'GO:0097411', ('171', '189'))	('miRNA', 'MPA', (120, 125))	('HIF1 alpha', 'Gene', '3091', (171, 181))	('miRNA binding', 'molecular_function', 'GO:0035198', ('120', '133'))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (151, 154))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('HIF1 alpha', 'Gene', (171, 181))
212419	28986523	SALL4 is a zinc finger transcription factor that plays an important role in kidney development, and SALL4 mutation causes kidney deformity.	('transcription', 'biological_process', 'GO:0006351', ('23', '36'))	('SALL4', 'Gene', '57167', (0, 5))	('mutation', 'Var', (106, 114))	('kidney deformity', 'Disease', (122, 138))	('transcription factor', 'molecular_function', 'GO:0000981', ('23', '43'))	('SALL4', 'Gene', (0, 5))	('kidney deformity', 'Disease', 'MESH:D007674', (122, 138))	('SALL4', 'Gene', '57167', (100, 105))	('causes', 'Reg', (115, 121))	('kidney development', 'biological_process', 'GO:0001822', ('76', '94'))	('kidney deformity', 'Phenotype', 'HP:0012210', (122, 138))	('SALL4', 'Gene', (100, 105))
212454	29032465	The modified alpha-subunits then become recognized by the von Hippel Lindau (VHL) protein, part of the ubiquitin E3 ligase complex, resulting in ubiquitination and proteasomal degradation of the alpha-subunits.	('von Hippel Lindau', 'Gene', '7428', (58, 75))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('VHL', 'Gene', (77, 80))	('ubiquitination', 'MPA', (145, 159))	('von Hippel Lindau', 'Gene', (58, 75))	('VHL', 'Gene', '7428', (77, 80))	('ubiquitin', 'molecular_function', 'GO:0031386', ('103', '112'))	('modified', 'Var', (4, 12))	('degradation', 'biological_process', 'GO:0009056', ('176', '187'))	('proteasomal degradation', 'MPA', (164, 187))
212466	29032465	While high HIF-1alpha levels correlated to low tumor stage and associated with favorable patient prognosis, high HIF-2alpha expression strongly correlated to unfavorable prognosis and high tumor stage (Holmquist-Mengelbier et al.	('patient', 'Species', '9606', (89, 96))	('unfavorable prognosis', 'CPA', (158, 179))	('high tumor', 'Disease', (184, 194))	('high tumor', 'Disease', 'MESH:D009369', (184, 194))	('low tumor', 'Disease', 'MESH:D009800', (43, 52))	('HIF-1alpha', 'Gene', '3091', (11, 21))	('HIF-2alpha', 'Gene', (113, 123))	('expression', 'MPA', (124, 134))	('correlated', 'Reg', (144, 154))	('high', 'Var', (108, 112))	('low tumor', 'Disease', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('HIF-2alpha', 'Gene', '2034', (113, 123))	('HIF-1alpha', 'Gene', (11, 21))
212468	29032465	reported that HIF-1alpha levels, either estimated by immunohistochemistry or determined by ELISA, correlate positively with adverse prognostic factors like MYCN amplification, 1p deletion and 17q gain (Dungwa et al.).	('HIF-1alpha', 'Gene', (14, 24))	('1p deletion', 'Var', (176, 187))	('MYCN', 'Gene', (156, 160))	('HIF-1alpha', 'Gene', '3091', (14, 24))	('17q', 'Disease', (192, 195))	('MYCN', 'Gene', '4613', (156, 160))
212481	29032465	However, if one considers that HIF-1alpha is only stabilized in hypoxic cells and takes into account that the presence of VEGF leads to rapid neo-vascularization, oxygenation and degradation of HIF-1alpha, the apparently contradicting findings may have their explanation.	('presence', 'Var', (110, 118))	('neo-vascularization', 'CPA', (142, 161))	('VEGF', 'Gene', '7422', (122, 126))	('oxygenation', 'CPA', (163, 174))	('HIF-1alpha', 'Gene', (31, 41))	('HIF-1alpha', 'Gene', (194, 204))	('oxygen', 'Chemical', 'MESH:D010100', (163, 169))	('VEGF', 'Gene', (122, 126))	('HIF-1alpha', 'Gene', '3091', (31, 41))	('HIF-1alpha', 'Gene', '3091', (194, 204))	('degradation', 'MPA', (179, 190))	('degradation', 'biological_process', 'GO:0009056', ('179', '190'))
212499	29032465	In other cases, normoxic activation of HIFs arises from VHL mutations or inactivation of the prolylhydroxylase dioxygenases by conditions such as iron- or 2-ketoglutarate depletion, or the accumulation of succinate or succinate analogs.	('VHL', 'Gene', (56, 59))	('HIF', 'Gene', (39, 42))	('succinate', 'MPA', (205, 214))	('HIF', 'Gene', '405', (39, 42))	('oxygen', 'Chemical', 'MESH:D010100', (113, 119))	('VHL', 'Gene', '7428', (56, 59))	('prolylhydroxylase dioxygenases', 'Enzyme', (93, 123))	('iron', 'Chemical', 'MESH:D007501', (146, 150))	('inactivation', 'NegReg', (73, 85))	('accumulation', 'PosReg', (189, 201))	('succinate', 'Chemical', 'MESH:D019802', (205, 214))	('normoxic', 'MPA', (16, 24))	('2-ketoglutarate', 'Chemical', 'MESH:D007656', (155, 170))	('succinate', 'Chemical', 'MESH:D019802', (218, 227))	('mutations', 'Var', (60, 69))
212521	29032465	Inhibitors of either IGF-I or BDNF reduced HIF-1alpha-mediated VEGF and, interestingly, so did inhibitors of the PI3K/mTOR pathway, suggesting that growth factor-induced stimulation was exerted via PI3K/mTOR signaling (Beppu et al.	('VEGF', 'Gene', (63, 67))	('BDNF', 'Gene', '627', (30, 34))	('reduced', 'NegReg', (35, 42))	('signaling', 'biological_process', 'GO:0023052', ('208', '217'))	('mTOR', 'Gene', '2475', (203, 207))	('mTOR', 'Gene', (118, 122))	('Inhibitors', 'Var', (0, 10))	('HIF-1alpha', 'Gene', (43, 53))	('IGF-I', 'Gene', '3479', (21, 26))	('mTOR', 'Gene', '2475', (118, 122))	('BDNF', 'Gene', (30, 34))	('VEGF', 'Gene', '7422', (63, 67))	('PI3K', 'molecular_function', 'GO:0016303', ('198', '202'))	('IGF-I', 'Gene', (21, 26))	('mTOR', 'Gene', (203, 207))	('PI3K', 'molecular_function', 'GO:0016303', ('113', '117'))	('HIF-1alpha', 'Gene', '3091', (43, 53))
212528	29032465	Activating mutations in either of the various growth factors or their receptors, or downstream signaling pathways, which can induce HIF expression, have been detected in various cancer forms.	('mutations', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('HIF', 'Gene', '405', (132, 135))	('signaling', 'biological_process', 'GO:0023052', ('95', '104'))	('HIF', 'Gene', (132, 135))
212529	29032465	Of interest, HIF-2alpha itself has also been found to be mutated in cases of paragangliomas (Comino-Mendez et al.	('paraganglioma', 'Phenotype', 'HP:0002668', (77, 90))	('HIF-2alpha', 'Gene', '2034', (13, 23))	('mutated', 'Var', (57, 64))	('paragangliomas', 'Disease', 'MESH:D010235', (77, 91))	('HIF-2alpha', 'Gene', (13, 23))	('paragangliomas', 'Disease', (77, 91))	('paragangliomas', 'Phenotype', 'HP:0002668', (77, 91))
212531	29032465	We postulated that HIF-2 would be an interesting target in neuroblastoma, based on our observations that high HIF-2alpha associates with an aggressive tumor phenotype and that cells with intense HIF-2alpha expression are frequently located in perivascular niches and that these tumor cells are stem cell- and mesenchymal-like (Holmquist-Mengelbier et al.	('HIF', 'Gene', '405', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('aggressive tumor', 'Disease', 'MESH:D001523', (140, 156))	('HIF-2alpha', 'Gene', (110, 120))	('associates with', 'Reg', (121, 136))	('HIF', 'Gene', (110, 113))	('HIF-2alpha', 'Gene', (195, 205))	('perivascular niches', 'Phenotype', 'HP:0012520', (243, 262))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('perivascular niche', 'Phenotype', 'HP:0012520', (243, 261))	('aggressive tumor', 'Disease', (140, 156))	('HIF', 'Gene', '405', (110, 113))	('HIF', 'Gene', (195, 198))	('tumor', 'Disease', (278, 283))	('HIF-2alpha', 'Gene', '2034', (110, 120))	('neuroblastoma', 'Disease', (59, 72))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('HIF', 'Gene', (19, 22))	('HIF-2alpha', 'Gene', '2034', (195, 205))	('high', 'Var', (105, 109))	('neuroblastoma', 'Phenotype', 'HP:0003006', (59, 72))	('tumor', 'Disease', (151, 156))	('HIF', 'Gene', '405', (195, 198))	('neuroblastoma', 'Disease', 'MESH:D009447', (59, 72))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
212537	29032465	Mechanistically, the small molecule PT2385 acts as a ligand and binds to a cavity present in the PAS-B domain of HIF-2alpha, prohibiting as well as reversing HIF-2 dimerization, DNA binding and thereby transcriptional activation of downstream target genes (Scheuermann et al.).	('PAS', 'cellular_component', 'GO:0000407', ('97', '100'))	('HIF', 'Gene', (158, 161))	('HIF', 'Gene', '405', (158, 161))	('DNA', 'cellular_component', 'GO:0005574', ('178', '181'))	('binding', 'Interaction', (182, 189))	('DNA', 'MPA', (178, 181))	('dimerization', 'MPA', (164, 176))	('DNA binding', 'molecular_function', 'GO:0003677', ('178', '189'))	('ligand', 'molecular_function', 'GO:0005488', ('53', '59'))	('PT2385', 'Var', (36, 42))	('HIF-2alpha', 'Gene', (113, 123))	('reversing', 'NegReg', (148, 157))	('HIF', 'Gene', '405', (113, 116))	('prohibiting', 'NegReg', (125, 136))	('transcriptional activation', 'MPA', (202, 228))	('HIF-2alpha', 'Gene', '2034', (113, 123))	('HIF', 'Gene', (113, 116))
212538	29032465	PT2385 and its analogue PT2399, have been primarily tested in preclinical models of ccRCC, as this tumor form is in great part driven by mutations in VHL, leading to stabilization of, in particular, HIF-2alpha.	('tumor', 'Disease', (99, 104))	('ccRCC', 'Disease', (84, 89))	('HIF-2alpha', 'Gene', '2034', (199, 209))	('VHL', 'Gene', (150, 153))	('mutations', 'Var', (137, 146))	('VHL', 'Gene', '7428', (150, 153))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('HIF-2alpha', 'Gene', (199, 209))	('stabilization', 'MPA', (166, 179))
212543	29032465	Resistance could be ascribed to an acquired binding site and second site suppressor mutations, also leading to HIF-2 dimerization in the presence of PT2399 (Chen et al.).	('mutations', 'Var', (84, 93))	('HIF', 'Gene', (111, 114))	('binding', 'molecular_function', 'GO:0005488', ('44', '51'))	('leading to', 'Reg', (100, 110))	('HIF', 'Gene', '405', (111, 114))	('dimerization', 'MPA', (117, 129))
212545	29032465	Also of note, in light of the above, putative important cytoplasmic functions of HIF-2alpha, PT2385 and PT2399 only work to inhibit nuclear transcriptional activity of HIF-2 and tumors dependent on cytoplasmic, ARNT-independent, functions of HIF-2alpha would most likely be insensitive to these inhibitors.	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('HIF', 'Gene', '405', (168, 171))	('HIF-2alpha', 'Gene', '2034', (81, 91))	('PT2399', 'Var', (104, 110))	('ARNT', 'Gene', '405', (211, 215))	('HIF-2alpha', 'Gene', (242, 252))	('PT2385', 'Var', (93, 99))	('HIF', 'Gene', (242, 245))	('inhibit', 'NegReg', (124, 131))	('ARNT', 'Gene', (211, 215))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('HIF-2alpha', 'Gene', (81, 91))	('HIF', 'Gene', '405', (242, 245))	('HIF', 'Gene', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('HIF', 'Gene', (168, 171))	('tumors', 'Disease', (178, 184))	('nuclear transcriptional activity', 'MPA', (132, 164))	('HIF-2alpha', 'Gene', '2034', (242, 252))	('HIF', 'Gene', '405', (81, 84))
212547	29032465	and PT2385 has also entered a Phase I dose-escalation study in patients with advanced ccRCC (NCT02293980).	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('ccRCC', 'Disease', (86, 91))	('PT2385', 'Var', (4, 10))	('patients', 'Species', '9606', (63, 71))
212558	28976794	Clear cell renal cell carcinoma (ccRCC) is the most common RCC subtype, and alterations of chromatin remodelers (BAP1, PBRM1, and SETD2) on chromosome 3p occur in 50% of ccRCCs.	('alterations', 'Var', (76, 87))	('chromatin', 'cellular_component', 'GO:0000785', ('91', '100'))	('occur', 'Reg', (154, 159))	('SETD2', 'Gene', (130, 135))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('RCC', 'Disease', (172, 175))	('RCC', 'Disease', (59, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('RCC', 'Disease', (35, 38))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('SETD2', 'Gene', '29072', (130, 135))	('PBRM1', 'Gene', '55193', (119, 124))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('PBRM1', 'Gene', (119, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('BAP1', 'Gene', '8314', (113, 117))	('chromosome', 'cellular_component', 'GO:0005694', ('140', '150'))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (170, 175))	('BAP1', 'Gene', (113, 117))
212597	28976794	Continuous EZH2 expression was significantly associated with overall survival after adjusting for age (hazard ratio [HR], 2.26; 95% CI, 1.69 to 3.02; P < .001; Table 2).	('expression', 'Var', (16, 26))	('associated with', 'Reg', (45, 60))	('EZH2', 'Gene', (11, 15))	('EZH2', 'Gene', '2146', (11, 15))	('overall survival', 'MPA', (61, 77))
212622	28976794	After adjusting for age, SSIGN score-classified low-risk patients with high EZH2 protein expression were 6.14 times more likely to experience RCC-specific death than patients with EZH2-low tumors (HR, 6.14; 95% CI, 3.40 to 11.08; P < .001; Fig 2A, Table 3).	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('EZH2-low tumors', 'Disease', 'MESH:D009800', (180, 195))	('EZH2-low tumors', 'Disease', (180, 195))	('high', 'Var', (71, 75))	('patients', 'Species', '9606', (57, 65))	('death', 'Disease', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('EZH2', 'Gene', '2146', (76, 80))	('EZH2', 'Gene', (180, 184))	('EZH2', 'Gene', '2146', (180, 184))	('death', 'Disease', 'MESH:D003643', (155, 160))	('EZH2', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('protein', 'Protein', (81, 88))	('patients', 'Species', '9606', (166, 174))
212623	28976794	Similarly, among patients with intermediate-risk SSIGN tumors, patients with high EZH2 protein expression were 2.12 times more likely to experience RCC-specific death (95% CI, 1.54 to 2.92; P < .001).	('EZH2', 'Gene', (82, 86))	('EZH2', 'Gene', '2146', (82, 86))	('RCC', 'Disease', (148, 151))	('death', 'Disease', 'MESH:D003643', (161, 166))	('death', 'Disease', (161, 166))	('high', 'Var', (77, 81))	('protein', 'Protein', (87, 94))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('patients', 'Species', '9606', (17, 25))	('patients', 'Species', '9606', (63, 71))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('expression', 'MPA', (95, 105))
212632	28976794	In our study, we included three independent cohorts (total of 1,992 tumors) with centralized pathology review to report that EZH2 expression is associated with higher risk of poor outcome following surgery, in a univariate setting, and after adjusting for clinicopathologic prognostic factors.	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('poor outcome', 'MPA', (175, 187))	('expression', 'Var', (130, 140))	('EZH2', 'Gene', '2146', (125, 129))	('EZH2', 'Gene', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
212662	33121461	And, there are currently 14 known RCC germline variants that have been reproducibly shown to be associated with RCC risk.	('variants', 'Var', (47, 55))	('associated', 'Reg', (96, 106))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('p', 'Chemical', 'MESH:D010758', (73, 74))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('RCC', 'Disease', (34, 37))
212665	33121461	Molecular subtype was determined based on acquired mutations in BAP1, PBRM1, SETD2 and VHL.	('VHL', 'Gene', '7428', (87, 90))	('SETD2', 'Gene', '29072', (77, 82))	('mutations', 'Var', (51, 60))	('SETD2', 'Gene', (77, 82))	('PBRM1', 'Gene', (70, 75))	('BAP1', 'Gene', '8314', (64, 68))	('p', 'Chemical', 'MESH:D010758', (15, 16))	('VHL', 'Gene', (87, 90))	('PBRM1', 'Gene', '55193', (70, 75))	('BAP1', 'Gene', (64, 68))
212668	33121461	The 8q24 variant rs35252396 was significantly associated with VHL mutation status (OR = 1.6, p = 0.0037) and SSIGN score (OR = 1.9, p = 0.00094), after adjusting for multiple comparisons.	('p', 'Chemical', 'MESH:D010758', (178, 179))	('p', 'Chemical', 'MESH:D010758', (93, 94))	('VHL', 'Gene', (62, 65))	('SSIGN score', 'Disease', (109, 120))	('p', 'Chemical', 'MESH:D010758', (132, 133))	('associated', 'Reg', (46, 56))	('rs35252396', 'Var', (17, 27))	('rs35252396', 'Mutation', 'rs35252396', (17, 27))	('VHL', 'Gene', '7428', (62, 65))	('p', 'Chemical', 'MESH:D010758', (171, 172))
212669	33121461	These data further demonstrate the link between rs35252396, HIF pathway and ccRCC clinical aggressiveness, providing a more comprehensive picture of how germline genetics and tumor genetics interact with respect to tumor development and progression.	('p', 'Chemical', 'MESH:D010758', (127, 128))	('p', 'Chemical', 'MESH:D010758', (237, 238))	('aggressiveness', 'Phenotype', 'HP:0000718', (91, 105))	('ccRCC clinical aggressiveness', 'Disease', (76, 105))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('link', 'Interaction', (35, 39))	('p', 'Chemical', 'MESH:D010758', (107, 108))	('p', 'Chemical', 'MESH:D010758', (138, 139))	('p', 'Chemical', 'MESH:D010758', (227, 228))	('rs35252396', 'Var', (48, 58))	('tumor', 'Disease', (175, 180))	('ccRCC clinical aggressiveness', 'Disease', 'MESH:D059466', (76, 105))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('rs35252396', 'Mutation', 'rs35252396', (48, 58))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('p', 'Chemical', 'MESH:D010758', (207, 208))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('p', 'Chemical', 'MESH:D010758', (64, 65))
212672	33121461	Additionally, genome-wide association studies (GWAS) have to date identified 14 germline variants that are associated with risk of RCC.	('variants', 'Var', (89, 97))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('associated', 'Reg', (107, 117))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))
212673	33121461	The value of these germline genetic explorations notwithstanding, the functional impact of the germline variants associated with RCC and ccRCC specifically remains largely unknown.	('p', 'Chemical', 'MESH:D010758', (38, 39))	('p', 'Chemical', 'MESH:D010758', (83, 84))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('variants', 'Var', (104, 112))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('RCC', 'Disease', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('RCC', 'Disease', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('p', 'Chemical', 'MESH:D010758', (144, 145))
212675	33121461	In some cancers investigators have reported that germline variants are associated with specific molecularly-defined tumor subtypes, and in some cases the association is large enough to suggest clinical relevance (e.g., rs55705857 has an odds ratio > 6 in IDH-mutated glioma).	('IDH', 'Gene', (255, 258))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('p', 'Chemical', 'MESH:D010758', (127, 128))	('cancers', 'Disease', (8, 15))	('rs55705857', 'Mutation', 'rs55705857', (219, 229))	('glioma', 'Disease', (267, 273))	('IDH', 'Gene', '3417', (255, 258))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('rs55705857', 'Var', (219, 229))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('p', 'Chemical', 'MESH:D010758', (37, 38))	('p', 'Chemical', 'MESH:D010758', (88, 89))	('glioma', 'Disease', 'MESH:D005910', (267, 273))	('glioma', 'Phenotype', 'HP:0009733', (267, 273))	('tumor', 'Disease', (116, 121))	('associated', 'Reg', (71, 81))
212677	33121461	The value of identifying associations of genetic variants with specific molecular subtypes of a tumor centers on the ability to provide evidence of the involvement of specific developmental pathways that can help inform the biology of ccRCC tumor evolution, progression and novel prevention efforts.	('p', 'Chemical', 'MESH:D010758', (182, 183))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('associations', 'Interaction', (25, 37))	('p', 'Chemical', 'MESH:D010758', (258, 259))	('tumor', 'Disease', (241, 246))	('variants', 'Var', (49, 57))	('ccRCC tumor', 'Disease', (235, 246))	('p', 'Chemical', 'MESH:D010758', (211, 212))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Disease', (96, 101))	('RCC', 'Phenotype', 'HP:0005584', (237, 240))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('p', 'Chemical', 'MESH:D010758', (280, 281))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('ccRCC tumor', 'Disease', 'MESH:D009369', (235, 246))	('ccRCC', 'Phenotype', 'HP:0006770', (235, 240))	('p', 'Chemical', 'MESH:D010758', (87, 88))	('p', 'Chemical', 'MESH:D010758', (168, 169))	('p', 'Chemical', 'MESH:D010758', (128, 129))	('p', 'Chemical', 'MESH:D010758', (190, 191))	('p', 'Chemical', 'MESH:D010758', (64, 65))
212679	33121461	Motivated by the opportunity to combine data on germline genetics associated with ccRCC risk with specific acquired molecular alterations found in ccRCC tumor tissue, we advance the field by evaluating for the first time the association of known ccRCC germline variants with these acquired alterations in order to better understand ccRCC development and progression.	('ccRCC', 'Phenotype', 'HP:0006770', (82, 87))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('RCC', 'Disease', (84, 87))	('ccRCC', 'Phenotype', 'HP:0006770', (147, 152))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('p', 'Chemical', 'MESH:D010758', (354, 355))	('p', 'Chemical', 'MESH:D010758', (19, 20))	('RCC', 'Phenotype', 'HP:0005584', (334, 337))	('RCC', 'Phenotype', 'HP:0005584', (248, 251))	('ccRCC tumor', 'Disease', (147, 158))	('RCC', 'Disease', (334, 337))	('RCC', 'Disease', (248, 251))	('p', 'Chemical', 'MESH:D010758', (99, 100))	('ccRCC', 'Phenotype', 'HP:0006770', (246, 251))	('variants', 'Var', (261, 269))	('p', 'Chemical', 'MESH:D010758', (18, 19))	('ccRCC', 'Phenotype', 'HP:0006770', (332, 337))	('p', 'Chemical', 'MESH:D010758', (344, 345))	('association', 'Interaction', (225, 236))	('RCC', 'Disease', (149, 152))	('RCC', 'Disease', 'MESH:C538614', (334, 337))	('RCC', 'Disease', 'MESH:C538614', (248, 251))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('ccRCC tumor', 'Disease', 'MESH:D009369', (147, 158))	('associated', 'Reg', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
212680	33121461	Moreover, we also evaluated the association of these known germline variants with well-known and validated clinical measures of ccRCC aggressiveness.	('variants', 'Var', (68, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('ccRCC aggressiveness', 'Disease', 'MESH:D001523', (128, 148))	('aggressiveness', 'Phenotype', 'HP:0000718', (134, 148))	('ccRCC aggressiveness', 'Disease', (128, 148))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('association', 'Interaction', (32, 43))
212687	33121461	Quality control was performed on the genotying data for the 420 ccRCC TCGA patients, including 95% call rate (zero germline variants failed), 95% sample call rate (zero samples failed), Hardy-Weinberg equilibrium (821 variants failed with p < 0.000001), minor allele frequency (MAF; 216,942 variants had MAF < 0.05), sex check (100% concordance) and population stratification (all Caucasian).	('variants', 'Var', (291, 299))	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('p', 'Chemical', 'MESH:D010758', (20, 21))	('p', 'Chemical', 'MESH:D010758', (172, 173))	('patients', 'Species', '9606', (75, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (64, 69))	('p', 'Chemical', 'MESH:D010758', (149, 150))	('p', 'Chemical', 'MESH:D010758', (352, 353))	('p', 'Chemical', 'MESH:D010758', (75, 76))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('p', 'Chemical', 'MESH:D010758', (350, 351))	('p', 'Chemical', 'MESH:D010758', (239, 240))
212693	33121461	Additional genetic information, limited to what was available in HUGIn, was included such as frequently interacting regions (FIREs), topologically associating domain (TAD) boundary regions, and occupancy of histone marks H3K27ac, H3K4me1 and H3K4me3.	('TAD', 'Disease', (167, 170))	('p', 'Chemical', 'MESH:D010758', (135, 136))	('H3K27ac', 'Var', (221, 228))	('p', 'Chemical', 'MESH:D010758', (198, 199))	('TAD', 'Disease', 'None', (167, 170))	('H3K4me3', 'Var', (242, 249))	('H3K4me1', 'Var', (230, 237))
212695	33121461	We also used Hi-C data from ccRCC cell line (VHL mutant) Caki2 (GSM2827127 and GSM2827128), (VHL wild-type) embryonic kidney cell lines HEK293T (GSM1081530 and GSM1081531) and HEK293T RAD21cv that was treated with tobacco etch mosaic virus protease (GSM1081526 and GSM1081527).	('tobacco', 'Species', '4097', (214, 221))	('GSM2827127', 'Chemical', '-', (64, 74))	('GSM1081526', 'Var', (250, 260))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('embryonic kidney', 'Disease', 'MESH:D007674', (108, 124))	('Hi-C', 'Chemical', '-', (13, 17))	('VHL', 'Gene', (45, 48))	('VHL', 'Gene', (93, 96))	('GSM1081527', 'Var', (265, 275))	('GSM1081530', 'Var', (145, 155))	('GSM2827127', 'Var', (64, 74))	('RAD', 'biological_process', 'GO:1990116', ('184', '187'))	('p', 'Chemical', 'MESH:D010758', (240, 241))	('VHL', 'Gene', '7428', (45, 48))	('VHL', 'Gene', '7428', (93, 96))	('GSM2827128', 'Var', (79, 89))	('HEK293T', 'CellLine', 'CVCL:0063', (136, 143))	('ccRCC', 'Phenotype', 'HP:0006770', (28, 33))	('embryonic kidney', 'Disease', (108, 124))	('RCC', 'Disease', (30, 33))	('p', 'Chemical', 'MESH:D010758', (104, 105))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('HEK293T', 'CellLine', 'CVCL:0063', (176, 183))	('GSM1081531', 'Var', (160, 170))
212702	33121461	Of the 376 patients with available whole exome sequencing data, 150 (40%) had a VHL mutation, 34 (9%) BAP1 mutation, 119 (32%) PBRM1 mutation and 48 (13%) SETD2 mutation.	('mutation', 'Var', (133, 141))	('VHL', 'Gene', (80, 83))	('BAP1', 'Gene', (102, 106))	('VHL', 'Gene', '7428', (80, 83))	('PBRM1', 'Gene', (127, 132))	('PBRM1', 'Gene', '55193', (127, 132))	('SETD2', 'Gene', '29072', (155, 160))	('BAP1', 'Gene', '8314', (102, 106))	('patients', 'Species', '9606', (11, 19))	('mutation', 'Var', (107, 115))	('SETD2', 'Gene', (155, 160))	('mutation', 'Var', (84, 92))
212706	33121461	Using a case-case design, we evaluated the association of each of the 14 RCC germline variants with known ccRCC acquired alterations in BAP1, PBRM1, SETD2 and VHL (Table 2).	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('SETD2', 'Gene', (149, 154))	('RCC', 'Disease', (108, 111))	('BAP1', 'Gene', (136, 140))	('RCC', 'Disease', (73, 76))	('alterations', 'Var', (121, 132))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('SETD2', 'Gene', '29072', (149, 154))	('variants', 'Var', (86, 94))	('BAP1', 'Gene', '8314', (136, 140))	('PBRM1', 'Gene', (142, 147))	('VHL', 'Gene', (159, 162))	('PBRM1', 'Gene', '55193', (142, 147))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))	('VHL', 'Gene', '7428', (159, 162))
212707	33121461	We observed a statistically significant association after adjusting for multiple comparisons between the 8q24 variant rs35252396 and VHL mutation (OR = 1.60, p = 0.0037).	('p', 'Chemical', 'MESH:D010758', (158, 159))	('rs35252396', 'Mutation', 'rs35252396', (118, 128))	('rs35252396', 'Var', (118, 128))	('8q24', 'Gene', (105, 109))	('VHL', 'Gene', (133, 136))	('VHL', 'Gene', '7428', (133, 136))	('p', 'Chemical', 'MESH:D010758', (84, 85))	('significant association', 'Reg', (28, 51))	('p', 'Chemical', 'MESH:D010758', (77, 78))
212708	33121461	While not significant after adjusting for multiple testing, we also observed a candidate association between EPAS1 variant rs7579899 and SETD2 mutation (OR = 1.87, p = 0.012) (Table 2).	('EPAS1', 'Gene', '2034', (109, 114))	('p', 'Chemical', 'MESH:D010758', (164, 165))	('EPAS1', 'Gene', (109, 114))	('SETD2', 'Gene', '29072', (137, 142))	('mutation', 'Var', (143, 151))	('variant rs7579899', 'Var', (115, 132))	('rs7579899', 'Mutation', 'rs7579899', (123, 132))	('SETD2', 'Gene', (137, 142))	('rs7579899', 'Var', (123, 132))	('p', 'Chemical', 'MESH:D010758', (47, 48))
212709	33121461	We observed a statistically significant association between the 8q24 variant rs35252396 and Mayo SSIGN score (OR = 1.92, p = 0.00094) (Table 2).	('Mayo SSIGN score', 'Disease', (92, 108))	('p', 'Chemical', 'MESH:D010758', (121, 122))	('8q24', 'Gene', (64, 68))	('rs35252396', 'Mutation', 'rs35252396', (77, 87))	('rs35252396', 'Var', (77, 87))	('Mayo', 'Species', '162683', (92, 96))	('significant association', 'Reg', (28, 51))
212711	33121461	We evaluated the interaction of each of the known germline variants with putative target genes in mesendoderm cell lines and mesenchymal stem cells using publically-available Hi-C data.	('p', 'Chemical', 'MESH:D010758', (154, 155))	('interaction', 'Interaction', (17, 28))	('variants', 'Var', (59, 67))	('p', 'Chemical', 'MESH:D010758', (73, 74))	('Hi-C', 'Chemical', '-', (175, 179))
212713	33121461	Some germline variants demonstrated interactions with nearby genes: e.g., rs4381241 with FAF1 (518.5 kb away), rs57579899 with EPAS1 (16.8 kb away), rs12105918 with ZEB2/ZEB2-AS1 (~ 70 kb away), rs1800057 with ATM (50.2 kb away) and rs4903064 with DPF3 (81.4 kb away) (Fig.	('rs4381241', 'Mutation', 'rs4381241', (74, 83))	('rs57579899', 'Var', (111, 121))	('ZEB2', 'Gene', (165, 169))	('DPF3', 'Gene', '8110', (248, 252))	('rs1800057', 'Var', (195, 204))	('rs12105918', 'Mutation', 'rs12105918', (149, 159))	('EPAS1', 'Gene', '2034', (127, 132))	('ZEB2', 'Gene', '9839', (165, 169))	('rs4903064', 'Mutation', 'rs4903064', (233, 242))	('rs4903064', 'Var', (233, 242))	('FAF1', 'Gene', (89, 93))	('DPF3', 'Gene', (248, 252))	('rs1800057', 'Mutation', 'rs1800057', (195, 204))	('ATM', 'Gene', '472', (210, 213))	('ZEB2', 'Gene', (170, 174))	('ZEB2-AS1', 'Gene', '100303491;9839;5729', (170, 178))	('ZEB2-AS1', 'Gene', (170, 178))	('ZEB2', 'Gene', '9839', (170, 174))	('FAF1', 'Gene', '11124', (89, 93))	('rs4381241', 'Var', (74, 83))	('rs12105918', 'Var', (149, 159))	('EPAS1', 'Gene', (127, 132))	('rs57579899', 'Mutation', 'rs57579899', (111, 121))	('ATM', 'Gene', (210, 213))	('interactions', 'Interaction', (36, 48))
212714	33121461	However, some of these variants showed additional long-range interactions that have not been reported previously: e.g., rs4381241 with CDKN2C and TTC39A, rs7579899 with PRKCE, rs12105918 with ARHGAP15, GTDC1 and TEX41, rs1800057 with CUL5, ACAT1, NPAT and EXPH5 and rs4903064 with RGS6.	('RGS6', 'Gene', '9628', (281, 285))	('EXPH5', 'Gene', (256, 261))	('rs4381241', 'Var', (120, 129))	('GTDC1', 'Gene', (202, 207))	('rs7579899', 'Mutation', 'rs7579899', (154, 163))	('CUL5', 'Gene', '8065', (234, 238))	('PRKCE', 'Gene', '5581', (169, 174))	('CDKN2C', 'Gene', (135, 141))	('TTC39A', 'Gene', '22996', (146, 152))	('rs1800057', 'Var', (219, 228))	('rs4903064', 'Var', (266, 275))	('rs4903064', 'Mutation', 'rs4903064', (266, 275))	('rs12105918', 'Var', (176, 186))	('RGS6', 'Gene', (281, 285))	('rs4381241', 'Mutation', 'rs4381241', (120, 129))	('ACAT1', 'Gene', (240, 245))	('ACAT1', 'Gene', '38', (240, 245))	('GTDC1', 'Gene', '79712', (202, 207))	('rs1800057', 'Mutation', 'rs1800057', (219, 228))	('CDKN2C', 'Gene', '1031', (135, 141))	('PRKCE', 'Gene', (169, 174))	('TEX41', 'Gene', '401014', (212, 217))	('EXPH5', 'Gene', '23086', (256, 261))	('rs7579899', 'Var', (154, 163))	('ARHGAP15', 'Gene', (192, 200))	('ARHGAP15', 'Gene', '55843', (192, 200))	('RGS', 'molecular_function', 'GO:0016299', ('281', '284'))	('rs12105918', 'Mutation', 'rs12105918', (176, 186))	('NPAT', 'Gene', '4863', (247, 251))	('NPAT', 'Gene', (247, 251))	('TEX41', 'Gene', (212, 217))	('CUL5', 'Gene', (234, 238))	('TTC39A', 'Gene', (146, 152))	('p', 'Chemical', 'MESH:D010758', (95, 96))	('p', 'Chemical', 'MESH:D010758', (102, 103))	('interactions', 'Interaction', (61, 73))
212715	33121461	Other germline variants also demonstrated long-range interactions that have not been reported previously: e.g., rs10936602 with SEC62 and PHC3, rs67311347 with ENTPD3, CTNNB1 and ULK4, rs2241261 with PEBP4 and EGR3, rs74911261 with EXPH5, rs718314 with SSPN and ITPR2 and rs4765623 with FAM101A (Additional file 1: Figure S1).	('EXPH5', 'Gene', (232, 237))	('PEBP4', 'Gene', (200, 205))	('FAM101A', 'Gene', (287, 294))	('ENTPD3', 'Gene', '956', (160, 166))	('p', 'Chemical', 'MESH:D010758', (94, 95))	('ITPR2', 'Gene', (262, 267))	('rs718314', 'Var', (239, 247))	('ULK4', 'Gene', (179, 183))	('CTNNB1', 'Gene', '1499', (168, 174))	('rs10936602', 'Var', (112, 122))	('SSPN', 'Gene', '8082', (253, 257))	('rs718314', 'Mutation', 'rs718314', (239, 247))	('rs10936602', 'Mutation', 'rs10936602', (112, 122))	('FAM101A', 'Gene', '144347', (287, 294))	('EGR3', 'Gene', '1960', (210, 214))	('SEC62', 'Gene', (128, 133))	('EGR3', 'Gene', (210, 214))	('rs4765623', 'Mutation', 'rs4765623', (272, 281))	('rs2241261', 'Mutation', 'rs2241261', (185, 194))	('EXPH5', 'Gene', '23086', (232, 237))	('PHC3', 'Gene', (138, 142))	('CTNNB1', 'Gene', (168, 174))	('ULK4', 'Gene', '54986', (179, 183))	('SEC62', 'Gene', '7095', (128, 133))	('rs67311347', 'Mutation', 'rs67311347', (144, 154))	('rs2241261', 'Var', (185, 194))	('PHC3', 'Gene', '80012', (138, 142))	('rs74911261', 'Mutation', 'rs74911261', (216, 226))	('ITPR2', 'Gene', '3709', (262, 267))	('SSPN', 'Gene', (253, 257))	('p', 'Chemical', 'MESH:D010758', (87, 88))	('rs74911261', 'Var', (216, 226))	('rs4765623', 'Var', (272, 281))	('ENTPD3', 'Gene', (160, 166))	('rs67311347', 'Var', (144, 154))	('PEBP4', 'Gene', '157310', (200, 205))	('interactions', 'Interaction', (53, 65))
212716	33121461	Additionally, rs35252396 demonstrated interactions with PCAT1 and PCAT2 in mesenchymal stem cells but not in mesendoderm cells (Fig.	('rs35252396', 'Var', (14, 24))	('PCAT1', 'Gene', (56, 61))	('PCAT2', 'Gene', '103164619', (66, 71))	('mesenchymal stem cells', 'CPA', (75, 97))	('interactions', 'Interaction', (38, 50))	('PCAT2', 'Gene', (66, 71))	('PCAT1', 'Gene', '100750225', (56, 61))	('rs35252396', 'Mutation', 'rs35252396', (14, 24))
212717	33121461	Similarly, rs11813268 had interactions with OBFC1 in mesenchymal stem cells but not in mesendoderm cells.	('OBFC1', 'Gene', '79991', (44, 49))	('interactions', 'Interaction', (26, 38))	('mesenchymal stem cells', 'CPA', (53, 75))	('rs11813268', 'Var', (11, 21))	('OBFC1', 'Gene', (44, 49))	('rs11813268', 'Mutation', 'rs11813268', (11, 21))
212721	33121461	For example, rs10936602 interaction with SEC62, rs2241261 interactions with PEBP4 and EGR3, rs1800057 and rs74911261 interactions with EXPH5, as well as rs718314 interaction with SSPN were confirmed in all three cell lines.	('interaction', 'Interaction', (24, 35))	('SSPN', 'Gene', (179, 183))	('EGR3', 'Gene', '1960', (86, 90))	('rs1800057', 'Var', (92, 101))	('rs718314', 'Var', (153, 161))	('EGR3', 'Gene', (86, 90))	('EXPH5', 'Gene', (135, 140))	('rs718314', 'Mutation', 'rs718314', (153, 161))	('SEC62', 'Gene', (41, 46))	('interactions', 'Interaction', (58, 70))	('rs1800057', 'Mutation', 'rs1800057', (92, 101))	('SSPN', 'Gene', '8082', (179, 183))	('SEC62', 'Gene', '7095', (41, 46))	('interaction', 'Interaction', (162, 173))	('PEBP4', 'Gene', '157310', (76, 81))	('rs74911261', 'Mutation', 'rs74911261', (106, 116))	('EXPH5', 'Gene', '23086', (135, 140))	('rs2241261', 'Mutation', 'rs2241261', (48, 57))	('PEBP4', 'Gene', (76, 81))	('rs10936602', 'Var', (13, 23))	('rs74911261', 'Var', (106, 116))	('rs10936602', 'Mutation', 'rs10936602', (13, 23))	('p', 'Chemical', 'MESH:D010758', (8, 9))	('interactions', 'Interaction', (117, 129))	('rs2241261', 'Var', (48, 57))
212722	33121461	Further, rs12105918 interaction with GTDC1, rs11813268 interaction with OBFC1 and rs4765623 interaction with FAM101A were only identified in the ccRCC cell line, while rs7579899 interaction with PRKCE, rs35252396 interaction with PCAT2, and rs4903064 interaction with DPF3 were only identified in the embryonic kidney cell lines.	('PCAT2', 'Gene', (230, 235))	('embryonic kidney', 'Disease', 'MESH:D007674', (301, 317))	('GTDC1', 'Gene', '79712', (37, 42))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('PRKCE', 'Gene', (195, 200))	('rs35252396', 'Var', (202, 212))	('ccRCC', 'Phenotype', 'HP:0006770', (145, 150))	('FAM101A', 'Gene', (109, 116))	('rs4765623', 'Mutation', 'rs4765623', (82, 91))	('rs4903064', 'Var', (241, 250))	('rs12105918', 'Var', (9, 19))	('rs4903064', 'Mutation', 'rs4903064', (241, 250))	('rs11813268', 'Mutation', 'rs11813268', (44, 54))	('rs35252396', 'Mutation', 'rs35252396', (202, 212))	('rs7579899', 'Mutation', 'rs7579899', (168, 177))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('FAM101A', 'Gene', '144347', (109, 116))	('interaction', 'Interaction', (20, 31))	('GTDC1', 'Gene', (37, 42))	('rs11813268', 'Var', (44, 54))	('DPF3', 'Gene', '8110', (268, 272))	('embryonic kidney', 'Disease', (301, 317))	('rs4765623', 'Var', (82, 91))	('OBFC1', 'Gene', (72, 77))	('rs12105918', 'Mutation', 'rs12105918', (9, 19))	('PRKCE', 'Gene', '5581', (195, 200))	('OBFC1', 'Gene', '79991', (72, 77))	('DPF3', 'Gene', (268, 272))	('PCAT2', 'Gene', '103164619', (230, 235))	('rs7579899', 'Var', (168, 177))
212723	33121461	There are currently 14 known germline variants that are associated with risk of RCC; however, it remains unclear how germline genetics modify the risk of developing RCC or their association with tumor aggressiveness.	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor aggressiveness', 'Disease', (195, 215))	('variants', 'Var', (38, 46))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('aggressiveness', 'Phenotype', 'HP:0000718', (201, 215))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (195, 215))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('p', 'Chemical', 'MESH:D010758', (160, 161))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('RCC', 'Disease', (165, 168))
212727	33121461	Herein, we not only evaluated ccRCC specifically, but also the association of these 14 variants with specific molecular (BAP1, PBRM1, SETD2 and VHL) and clinically-aggressive subtypes of ccRCC.	('BAP1', 'Gene', (121, 125))	('association', 'Interaction', (63, 74))	('p', 'Chemical', 'MESH:D010758', (180, 181))	('p', 'Chemical', 'MESH:D010758', (102, 103))	('p', 'Chemical', 'MESH:D010758', (37, 38))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('VHL', 'Gene', '7428', (144, 147))	('PBRM1', 'Gene', '55193', (127, 132))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('variants', 'Var', (87, 95))	('SETD2', 'Gene', (134, 139))	('RCC', 'Disease', (32, 35))	('PBRM1', 'Gene', (127, 132))	('BAP1', 'Gene', '8314', (121, 125))	('SETD2', 'Gene', '29072', (134, 139))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('VHL', 'Gene', (144, 147))	('ccRCC', 'Phenotype', 'HP:0006770', (187, 192))	('RCC', 'Disease', (189, 192))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))
212728	33121461	Using a case-case analysis, we observed that the 8q24 germline variant rs35252396 was significantly associated with tumor VHL mutation status as well as with the Mayo SSIGN score.	('Mayo', 'Species', '162683', (162, 166))	('mutation status', 'MPA', (126, 141))	('rs35252396', 'Mutation', 'rs35252396', (71, 81))	('associated', 'Reg', (100, 110))	('rs35252396', 'Var', (71, 81))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('VHL', 'Gene', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('VHL', 'Gene', '7428', (122, 125))	('tumor', 'Disease', (116, 121))
212731	33121461	Of note, the 8q24 variant also overlaps a DNase I hypersensitive site and H3K4me1 peak from fetal kidney, indicating its location within a regulatory region.	('p', 'Chemical', 'MESH:D010758', (52, 53))	('H3K4me1 peak', 'MPA', (74, 86))	('8q24', 'Gene', (13, 17))	('hypersensitive', 'Disease', 'MESH:D004342', (50, 64))	('p', 'Chemical', 'MESH:D010758', (37, 38))	('hypersensitive', 'Disease', (50, 64))	('DNase I', 'molecular_function', 'GO:0004530', ('42', '49'))	('p', 'Chemical', 'MESH:D010758', (82, 83))	('variant', 'Var', (18, 25))
212732	33121461	Through functional laboratory studies, investigators recently demonstrated that the 8q24 germline variant affects HIF binding to a MYC enhancer.	('MYC', 'Gene', '4609', (131, 134))	('8q24', 'Var', (84, 88))	('MYC', 'Gene', (131, 134))	('affects', 'Reg', (106, 113))	('HIF', 'Protein', (114, 117))	('binding', 'molecular_function', 'GO:0005488', ('118', '125'))
212733	33121461	While the EPAS1 (rs7579899) and CCND1 (rs7105934) variants are also linked to the HIF pathway, we did not observe a statistically-significant association between these two variants and VHL mutation.	('linked', 'Reg', (68, 74))	('HIF pathway', 'Pathway', (82, 93))	('EPAS1', 'Gene', '2034', (10, 15))	('CCND1', 'Gene', (32, 37))	('p', 'Chemical', 'MESH:D010758', (86, 87))	('EPAS1', 'Gene', (10, 15))	('rs7105934', 'Var', (39, 48))	('rs7105934', 'Mutation', 'rs7105934', (39, 48))	('CCND1', 'Gene', '595', (32, 37))	('VHL', 'Gene', (185, 188))	('rs7579899', 'Mutation', 'rs7579899', (17, 26))	('rs7579899', 'Var', (17, 26))	('VHL', 'Gene', '7428', (185, 188))
212734	33121461	Additionally, while it did not pass our multiple testing significance threshold, we also observed a candidate association between the EPAS1 germline variant rs57579899 and SETD2 tumor mutation (p = 0.012).	('tumor', 'Disease', (178, 183))	('EPAS1', 'Gene', '2034', (134, 139))	('p', 'Chemical', 'MESH:D010758', (31, 32))	('rs57579899', 'Mutation', 'rs57579899', (157, 167))	('rs57579899', 'Var', (157, 167))	('EPAS1', 'Gene', (134, 139))	('p', 'Chemical', 'MESH:D010758', (45, 46))	('SETD2', 'Gene', '29072', (172, 177))	('p', 'Chemical', 'MESH:D010758', (194, 195))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('SETD2', 'Gene', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
212739	33121461	While we observed a significant association of the 8q24 germline variant and the Mayo SSIGN score, we did not observe a significant association between any of the 14 variants and the molecularly-defined ccA/ccB expression subtype that has been linked to ccRCC aggressiveness.	('p', 'Chemical', 'MESH:D010758', (213, 214))	('ccA', 'Gene', '2201', (203, 206))	('ccA', 'Gene', (203, 206))	('p', 'Chemical', 'MESH:D010758', (227, 228))	('aggressiveness', 'Phenotype', 'HP:0000718', (260, 274))	('ccRCC aggressiveness', 'Disease', (254, 274))	('ccRCC aggressiveness', 'Disease', 'MESH:D001523', (254, 274))	('ccRCC', 'Phenotype', 'HP:0006770', (254, 259))	('RCC', 'Phenotype', 'HP:0005584', (256, 259))	('8q24', 'Gene', (51, 55))	('variants', 'Var', (166, 174))	('Mayo', 'Species', '162683', (81, 85))	('association', 'Interaction', (32, 43))
212741	33121461	Herein, we used Hi-C data to identify candidate target genes underlying the association of each of the 14 germline variants with ccRCC risk.	('ccRCC', 'Phenotype', 'HP:0006770', (129, 134))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('association', 'Interaction', (76, 87))	('Hi-C', 'Chemical', '-', (16, 20))	('variants', 'Var', (115, 123))
212746	33121461	We identified a significant association between the 8q24 germline variant and the presence of VHL somatic mutation.	('VHL', 'Gene', '7428', (94, 97))	('mutation', 'Var', (106, 114))	('8q24', 'Gene', (52, 56))	('p', 'Chemical', 'MESH:D010758', (82, 83))	('VHL', 'Gene', (94, 97))
212748	33121461	Importantly, we additionally defined candidate target genes underlying the association between each of the 14 germline variants and risk of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('p', 'Chemical', 'MESH:D010758', (2, 3))	('variants', 'Var', (119, 127))	('association', 'Interaction', (75, 86))
212750	33121461	Specifically, these data further demonstrate the link between rs35252396 in the 8q24 region, HIF pathway and clinical aggressiveness, providing a more comprehensive biological understanding of the development of VHL mutated ccRCC tumors.	('rs35252396', 'Var', (62, 72))	('p', 'Chemical', 'MESH:D010758', (134, 135))	('p', 'Chemical', 'MESH:D010758', (154, 155))	('aggressiveness', 'Phenotype', 'HP:0000718', (118, 132))	('p', 'Chemical', 'MESH:D010758', (203, 204))	('ccRCC tumors', 'Disease', 'MESH:D009369', (224, 236))	('p', 'Chemical', 'MESH:D010758', (97, 98))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('aggressiveness', 'Disease', 'MESH:D001523', (118, 132))	('ccRCC tumors', 'Disease', (224, 236))	('VHL', 'Gene', (212, 215))	('p', 'Chemical', 'MESH:D010758', (1, 2))	('ccRCC', 'Phenotype', 'HP:0006770', (224, 229))	('RCC', 'Phenotype', 'HP:0005584', (226, 229))	('VHL', 'Gene', '7428', (212, 215))	('aggressiveness', 'Disease', (118, 132))	('rs35252396', 'Mutation', 'rs35252396', (62, 72))
212751	33121461	Future work should evaluate how the rs35252396 germline variant and VHL mutation interact to affect treatment outcome and prognosis.	('affect', 'Reg', (93, 99))	('rs35252396', 'Mutation', 'rs35252396', (36, 46))	('VHL', 'Gene', (68, 71))	('rs35252396', 'Var', (36, 46))	('VHL', 'Gene', '7428', (68, 71))	('p', 'Chemical', 'MESH:D010758', (122, 123))
212758	31156702	Whole-Exome Sequencing Identifies Somatic Mutations Associated With Mortality in Metastatic Clear Cell Kidney Carcinoma Clear cell renal cell carcinoma (ccRCC) is among the most aggressive histologic subtypes of kidney cancer, representing about 3% of all human cancers.	('Clear cell renal cell carcinoma', 'Disease', (120, 151))	('Carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('Metastatic Clear Cell Kidney Carcinoma', 'Disease', (81, 119))	('Mutations', 'Var', (42, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('ccRCC', 'Phenotype', 'HP:0006770', (153, 158))	('human', 'Species', '9606', (256, 261))	('Associated', 'Reg', (52, 62))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (131, 151))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (120, 151))	('Clear Cell Kidney Carcinoma', 'Phenotype', 'HP:0006770', (92, 119))	('kidney cancer', 'Disease', 'MESH:D007680', (212, 225))	('cancers', 'Phenotype', 'HP:0002664', (262, 269))	('cancers', 'Disease', (262, 269))	('Metastatic Clear Cell Kidney Carcinoma', 'Disease', 'MESH:C538445', (81, 119))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('kidney cancer', 'Phenotype', 'HP:0009726', (212, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('kidney cancer', 'Disease', (212, 225))	('cancers', 'Disease', 'MESH:D009369', (262, 269))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (120, 151))
212761	31156702	Applying WES to simultaneously interrogate virtually all exons in the human genome for somatic variation, here we analyzed the burden of coding somatic mutations in metastatic ccRCC primary tumors, and its association with patient mortality from cancer, in patients who received VEGF receptor-targeting drugs as the first-line therapy.	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('mutations', 'Var', (152, 161))	('cancer', 'Disease', (246, 252))	('primary tumors', 'Disease', (182, 196))	('VEGF', 'Gene', '7422', (279, 283))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('patient', 'Species', '9606', (257, 264))	('human', 'Species', '9606', (70, 75))	('primary tumors', 'Disease', 'MESH:D009369', (182, 196))	('patient', 'Species', '9606', (223, 230))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('patients', 'Species', '9606', (257, 265))	('ccRCC', 'Phenotype', 'HP:0006770', (176, 181))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('VEGF', 'Gene', (279, 283))
212767	31156702	Selection analysis yielded no detectable evidence of overall positive or negative selection, with the exome-wide number of nonsynonymous substitutions per synonymous site reflecting largely neutral tumor evolution.	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('nonsynonymous substitutions', 'Var', (123, 150))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))
212792	31156702	Remaining variants were considered putative somatic variation and annotated using the Ensembl Variant Effect Predictor (VEP) v91.0, particularly for gene elements, coding consequences and deleteriousness according to SIFT scoring.	('SIFT', 'Disease', (217, 221))	('SIFT', 'Disease', 'None', (217, 221))	('variants', 'Var', (10, 18))
212809	31156702	Among missense substitutions, the somatic set also displayed a larger proportion of predicted deleterious mutations, on the basis of SIFT score (54.0% vs. 40.0% of germline missense).	('SIFT', 'Disease', 'None', (133, 137))	('missense substitutions', 'Var', (6, 28))	('SIFT', 'Disease', (133, 137))	('mutations', 'Var', (106, 115))
212810	31156702	Finally, to evaluate the evidence for selection on somatic substitutions and identify any potential contamination from germline polymorphisms, the ratio of nonsynonymous substitutions per synonymous site (dN/dS) was measured for the set of somatic variants using a dN/dS model optimized for the analysis of selection in cancer.	('dS', 'Chemical', 'MESH:D003903', (208, 210))	('variants', 'Var', (248, 256))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('dN', 'Chemical', '-', (265, 267))	('dN', 'Chemical', '-', (205, 207))	('cancer', 'Disease', 'MESH:D009369', (320, 326))	('dS', 'Chemical', 'MESH:D003903', (268, 270))	('cancer', 'Disease', (320, 326))
212817	31156702	Another notable result was the presence in the list of various mucin-encoding genes (MUC5B, MUC12, and MUC16), which are commonly observed mutated in many cancers and have been previously linked to colorectal, ovarian and hepatological cancers, as well as to severe fibrotic lung disorders.	('cancers', 'Disease', 'MESH:D009369', (236, 243))	('colorectal, ovarian and hepatological cancers', 'Disease', 'MESH:D015179', (198, 243))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('fibrotic lung disorders', 'Disease', 'MESH:D008171', (266, 289))	('MUC16', 'Gene', '94025', (103, 108))	('MUC5B', 'Gene', '727897', (85, 90))	('mucin', 'Gene', (63, 68))	('fibrotic lung', 'Phenotype', 'HP:0002206', (266, 279))	('fibrotic lung disorders', 'Disease', (266, 289))	('mucin', 'Gene', '100508689', (63, 68))	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('MUC12', 'Gene', (92, 97))	('cancers', 'Disease', (236, 243))	('MUC5B', 'Gene', (85, 90))	('mutated', 'Var', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', (155, 162))	('MUC16', 'Gene', (103, 108))	('linked', 'Reg', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('MUC12', 'Gene', '10071', (92, 97))	('lung disorders', 'Phenotype', 'HP:0002088', (275, 289))
212828	31156702	Despite previous attempts to reveal molecular prognostic signatures of ccRCC based on multiomics data, this study constitutes the first exome-wide approach for revealing genes with differential accumulation of somatic mutations in relation to cancer-associated mortality in ccRCC patients.	('patients', 'Species', '9606', (280, 288))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (274, 279))	('mutations', 'Var', (218, 227))	('ccRCC', 'Disease', (274, 279))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
212829	31156702	At most, these studies revealed that recurrent mutations in PBRM1, one of the well-known ccRCC genes, might have implications in the treatment responses.	('PBRM1', 'Gene', (60, 65))	('PBRM1', 'Gene', '55193', (60, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (89, 94))	('mutations', 'Var', (47, 56))	('implications', 'Reg', (113, 125))
212831	31156702	Our study has also yielded evidence suggestive of the activity of COSMIC signature 12 in kidney cancer, in addition to two well-established endogenous mutational processes.	('kidney cancer', 'Phenotype', 'HP:0009726', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('kidney cancer', 'Disease', (89, 102))	('COSMIC signature', 'Var', (66, 82))	('activity', 'MPA', (54, 62))	('kidney cancer', 'Disease', 'MESH:D007680', (89, 102))
212850	31156702	Under such scenario, it could be speculated that coding mutations in MUC5B and PARN may play a role in oncogenesis in lung and kidney tissues.	('oncogenesis', 'biological_process', 'GO:0007048', ('103', '114'))	('PARN', 'Gene', '5073', (79, 83))	('play', 'Reg', (88, 92))	('PARN', 'Gene', (79, 83))	('coding mutations', 'Var', (49, 65))	('MUC5B', 'Gene', '727897', (69, 74))	('MUC5B', 'Gene', (69, 74))	('role', 'Reg', (95, 99))	('oncogenesis', 'CPA', (103, 114))
212859	31156702	Third, because of the capture design of WES, we were unable to assess the association of noncoding variants with patient mortality, as has been previously suggested for regulatory variants in the telomerase reverse transcriptase encoding gene TERT.	('patient', 'Species', '9606', (113, 120))	('TERT', 'Gene', (243, 247))	('TERT', 'Gene', '7015', (243, 247))	('variants', 'Var', (99, 107))	('transcriptase', 'molecular_function', 'GO:0003899', ('215', '228'))	('transcriptase', 'molecular_function', 'GO:0003968', ('215', '228'))	('transcriptase', 'molecular_function', 'GO:0034062', ('215', '228'))